PMID- 26033953 TI - Instructive Conductive 3D Silk Foam-Based Bone Tissue Scaffolds Enable Electrical Stimulation of Stem Cells for Enhanced Osteogenic Differentiation. AB - Stimuli-responsive materials enabling the behavior of the cells that reside within them to be controlled are vital for the development of instructive tissue scaffolds for tissue engineering. Herein, we describe the preparation of conductive silk foam-based bone tissue scaffolds that enable the electrical stimulation of human mesenchymal stem cells (HMSCs) to enhance their differentiation toward osteogenic outcomes. PMID- 26033954 TI - A Short Helix Formed by Cyclic beta(2,3)-Aminoxy Peptides in Protic Solvents. AB - Water-soluble cyclic beta(2,3)-aminoxy peptides have been successfully prepared and characterized in polar organic solvents and aqueous media. The monomeric and oligomeric peptides exhibit unique beta N-O turns and helical conformations, with extraordinary stability toward a wide range of pH values and temperatures. PMID- 26033955 TI - Decorin mimic promotes endothelial cell health in endothelial monolayers and endothelial-smooth muscle co-cultures. AB - Non-specific cytotoxins, including paclitaxel and sirolimus analogues, currently utilized as anti-restenotic therapeutics, affect not only smooth muscle cells (SMCs) but also neighbouring vascular endothelial cells (ECs). These drugs inhibit the formation of an intact endothelium following vessel injury, thus emphasizing the critical need for new candidate therapeutics. Utilizing our in vitro models, including EC monolayers and both hyperplastic and quiescent EC-SMC co-cultures, we investigated the ability of DS-SILY20 , a decorin mimic, to promote EC health. DS-SILY20 increased EC proliferation and migration by 1.5- and 2-fold, respectively, which corresponded to increased phosphorylation of ERK-1/2. Interestingly, IL-6 secretion and the production of both E-selectin and P selectin were reduced in the presence of 10 MUm DS-SILY20 , even in the presence of the potent pro-inflammatory cytokine platelet-derived growth factor (PDGF). In hyperplastic and quiescent EC-SMC co-cultures, DS-SILY20 treatment reduced the secretion of IFNgamma, IL-1beta, IL-6 and TNFalpha, corresponding to a 23% decrease in p38 phosphorylation. E-selectin and P-selectin expression was further reduced following DS-SILY20 treatment in both co-culture models. These results indicate that DS-SILY20 promotes EC health and that this decorin mimic could serve as a potential therapeutic to promote vessel healing following percutaneous coronary intervention (PCI). Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26033963 TI - Pretreatment of coconut mill effluent using celite-immobilized hydrolytic enzyme preparation from Staphylococcus pasteuri and its impact on anaerobic digestion. AB - Biological treatment of oil and grease (O&G)-containing industrial effluents has long been a challenging issue. Practically feasible avenues to bring down their O&G load and enhance treatability are desired. In one such endeavour, the partially purified lipase from Staphylococcus pasteuri COM-4A was immobilized on celite carrier and applied for the enzymatic hydrolysis of unsterilized coconut oil mill effluent. In batch hydrolysis experiments, optimum conditions of 1% (w/v) immobilized lipase beads, one in four effluent dilution, and a contact time of 30 h resulted in 46% and 24% increase in volatile fatty acids and long-chain fatty acids and a concomitant 52% and 32% decrease in O&G and chemical oxygen demand (COD) levels, respectively. Batch anaerobic biodegradation trials with this prehydrolyzed effluent showed 89%, 91%, and 90% decrease in COD, proteins, and reducing sugars, respectively. These results were validated in a hybrid stirred tank--upflow anaerobic sludge blanket reactor. Average COD and O&G reductions effected by the hybrid reactor were found to be 89% and 88%, whereas that by the control reactor without enzymatic hydrolysis were only 60% and 47%, respectively. A maximum of 0.86 L methane gas was generated by the hybrid reactor per gram of VS added. Hence, this celite-immobilized crude lipase, sourced from a native laboratory isolate, seems to be a workable alternative to commercial enzyme preparations for the management of lipid-rich industrial effluents. PMID- 26033964 TI - Laboratory rearing of solitary bees and wasps. AB - Ecological experiments often require standardized methods that exclude natural variation and allow manipulation of a single parameter. It has been shown that domesticated honey bee larvae are raisable in a controlled environment. Here we demonstrate that this approach is also transferable to wild solitary bees and wasps without inducing negative effects on their development. Wells may also be supplemented with the antibiotic substance oxytetracycline to control the presence of bacteria. The method thus provides a useful tool to investigate offspring recruitment and larval development in solitary bees and wasps, plus their responses to manipulation of factors as for example diets, toxins and microbiota. PMID- 26033965 TI - Fujiwara-Moritani Reaction of Weinreb Amides using a Ruthenium-Catalyzed C-H Functionalization Reaction. AB - The ruthenium-catalyzed Fujiwara-Moritani reaction (oxidative-Heck reaction) of Weinreb amides is reported herein. The reaction affords exclusively ortho-C-H olefination products, has excellent substrate scope and tolerates halogen functionalities, which increase the synthetic utility of the method. A variety of activated olefins as well as styrenes can be employed as coupling partners. PMID- 26033967 TI - Transcatheter aortic valve implantation with the new balloon-expandable Sapien 3 versus Sapien XT valve system: a propensity score-matched single-center comparison. AB - BACKGROUND: The new balloon-expandable Sapien 3 transcatheter heart valve (S3 THV) incorporates new features to reduce aortic regurgitation (AR) and vascular complications in transcatheter aortic valve implantation. Aim of this study is to compare the outcomes of the S3-THV with the preceding Sapien XT THV (SXT-THV) in patients who underwent transcatheter aortic valve implantation for symptomatic severe native aortic stenosis. METHODS AND RESULTS: Eligible patients were retrospectively identified in our institutional database and periprocedural clinical and imaging data were collected. Non-parsimonious one-to-many propensity score matching was performed to account for differences in baseline characteristics. Between November 2011 and December 2014, 167 patients underwent balloon-expandable transcatheter aortic valve implantation with either the S3-THV (n=49) or SXT-THV (n=118). Forty-four (89.8%) S3-THV patients were matched to 66 (55.9%) SXT-THV patients (mean age 80.3+/-8.4 and 80.5+/-7.8 years, median EuroSCORE 15.8 and 16.5%, respectively). In the S3-THV and SXT-THV groups, transfemoral approach (77.3% versus 78.8%) and postdilatation rates (15.9% versus 12.1%) were similar. Predischarge echocardiography demonstrated a lower incidence of >=mild AR (15.9% versus 46.2%, P=0.003) for the S3-THV, despite reduced annulus area to prosthesis oversizing (8.2+/-5.1 versus 18.2+/-10.7%, P=0.001). Transfemoral access site-related life-threatening or major bleedings and vascular complications were absent in the S3-THV group (0% versus 7.7%, P=0.15). No differences were observed in pacemaker implantation rate (9.8% versus 8.8%, P=0.94) and 30-day mortality (both 5%). CONCLUSIONS: In this retrospective, propensity score-matched analysis, the S3-THV performed superiorly to the SXT THV, as demonstrated by improved valve patency and increased transfemoral access safety. PMID- 26033966 TI - BCL-3 expression promotes colorectal tumorigenesis through activation of AKT signalling. AB - OBJECTIVE: Colorectal cancer remains the fourth most common cause of cancer related mortality worldwide. Here we investigate the role of nuclear factor kappaB (NF-kappaB) co-factor B-cell CLL/lymphoma 3 (BCL-3) in promoting colorectal tumour cell survival. DESIGN: Immunohistochemistry was carried out on 47 tumour samples and normal tissue from resection margins. The role of BCL-3/NF kappaB complexes on cell growth was studied in vivo and in vitro using an siRNA approach and exogenous BCL-3 expression in colorectal adenoma and carcinoma cells. The question whether BCL-3 activated the AKT/protein kinase B (PKB) pathway in colorectal tumour cells was addressed by western blotting and confocal microscopy, and the ability of 5-aminosalicylic acid (5-ASA) to suppress BCL-3 expression was also investigated. RESULTS: We report increased BCL-3 expression in human colorectal cancers and demonstrate that BCL-3 expression promotes tumour cell survival in vitro and tumour growth in mouse xenografts in vivo, dependent on interaction with NF-kappaB p50 or p52 homodimers. We show that BCL-3 promotes cell survival under conditions relevant to the tumour microenvironment, protecting both colorectal adenoma and carcinoma cells from apoptosis via activation of the AKT survival pathway: AKT activation is mediated via both PI3K and mammalian target of rapamycin (mTOR) pathways, leading to phosphorylation of downstream targets GSK-3beta and FoxO1/3a. Treatment with 5-ASA suppressed BCL-3 expression in colorectal cancer cells. CONCLUSIONS: Our study helps to unravel the mechanism by which BCL-3 is linked to poor prognosis in colorectal cancer; we suggest that targeting BCL-3 activity represents an exciting therapeutic opportunity potentially increasing the sensitivity of tumour cells to conventional therapy. PMID- 26033968 TI - An over-nonlocal implicit gradient-enhanced damage-plastic model for trabecular bone under large compressive strains. AB - PURPOSE: Investigation of trabecular bone strength and compaction is important for fracture risk prediction. At 1-2% compressive strain, trabecular bone undergoes strain softening, which may lead to numerical instabilities and mesh dependency in classical local damage-plastic models. The aim of this work is to improve our continuum damage-plastic model of bone by reducing the influence of finite element mesh size under large compression. METHODOLOGY: This spurious numerical phenomenon may be circumvented by incorporating the nonlocal effect of cumulated plastic strain into the constitutive law. To this end, an over-nonlocal implicit gradient model of bone is developed and implemented into the finite element software ABAQUS using a user element subroutine. The ability of the model to detect the regions of bone failure is tested against experimental stepwise loading data of 16 human trabecular bone biopsies. FINDINGS: The numerical outcomes of the nonlocal model revealed reduction of finite element mesh dependency compared with the local damage-plastic model. Furthermore, it helped reduce the computational costs of large-strain compression simulations. ORIGINALITY: To the best of our knowledge, the proposed model is the first to predict the failure and densification of trabecular bone up to large compression independently of finite element mesh size. The current development enables the analysis of trabecular bone compaction as in osteoporotic fractures and implant migration, where large deformation of bone plays a key role. PMID- 26033969 TI - Oleic acid surfactant in polycaprolactone/hydroxyapatite-composites for bone tissue engineering. AB - Bone substitutes are required to repair osseous defects caused by a number of factors, such as traumas, degenerative diseases, and cancer. Autologous bone grafting is typically used to bridge bone defects, but suffers from chronic pain at the donor-site and limited availability of graft material. Tissue engineering approaches are being investigated as viable alternatives, which ideal scaffold should be biocompatible, biodegradable, and promote cellular interactions and tissue development, need to present proper mechanical and physical properties. In this study, poly(epsilon-caprolactone) (PCL), oleic acid (OA) and hydroxyapatite (HAp) were used to obtain films whose properties were investigated by contact angle, scanning electron microscopy, atomic force microscopy, tensile mechanical tests, and in vitro tests with U2OS human osteosarcoma cells by direct contact. Our results indicate that by using OA as surfactant/dispersant, it was possible to obtain a homogenous film with HAp. The PCL/OA/Hap sample had twice the roughness of the control (PCL) and a lower contact angle, indicating increased hydrophilicity of the film. Furthermore, mechanical testing showed that the addition of HAp decreased the load at yield point and tensile strength and increased tensile modulus, indicating a more brittle composition vs. PCL matrix. Preliminary cell culture experiments carried out with the films demonstrated that U2OS cells adhered and proliferated on all surfaces. The data demonstrate the improved dispersion of HAp using OA and the important consequences of this addition on the composite, unveiling the potentially of this composition for bone growth support. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1076-1082, 2016. PMID- 26033971 TI - Ligamentization of Autogenous Hamstring Grafts After Anterior Cruciate Ligament Reconstruction: Midterm Versus Long-term Results. AB - BACKGROUND: In previous studies, unimodal, small-diameter collagen fibrils have been commonly observed as the final collagen ultrastructure of the implanted grafts used in anterior cruciate ligament (ACL) reconstruction. However, the native ACL and hamstring tendon show bimodal collagen fibril distribution, consisting of both large- and small-diameter collagen fibrils. HYPOTHESIS: Bimodal collagen fibril distribution of the graft is a common phenomenon after ACL reconstruction with hamstring tendon grafts and is time dependent. STUDY DESIGN: Controlled laboratory study. METHODS: A total of 52 patients who underwent double-bundle ACL reconstruction using autogenous hamstring tendons and who also underwent second-look arthroscopic surgery were enrolled. The patients were divided into 2 groups according to the time interval between the 2 operations: the midterm group (27 patients), with a 13- to 30-month time interval between operations, and the long-term group (25 patients) with a 31- to 62-month interval. During the second-look arthroscopic procedures, ACL graft biopsies were performed. Normal ACL tissues were harvested from 9 patients who underwent total knee replacement, and biopsy specimens of the to-be-grafted semitendinosus tendon tissues were also harvested from another 9 patients who underwent ACL reconstruction with hamstring tendons, which were designated as normal controls. Graft vascularity, cellularity, metaplasia, cellular metabolism, and collagen fibril distribution were analyzed. RESULTS: Large-diameter (>100 nm) collagen fibrils were detected in 81.5% of the specimens in the midterm group and in 68.0% of the specimens in the long-term group. A typical bimodal distribution mode was observed in 62.6% of the specimens in the midterm group and in 52.0% of the specimens in the long-term group. There was no significant difference between groups with respect to the presence of large-diameter collagen fibrils, bimodal distribution, graft vascularity, cellularity, metaplasia, or cellular metabolic status. CONCLUSION: Graft ultrastructural maturation, characterized by large diameter collagen fibrils and a bimodal collagen fibril distribution, is a common phenomenon and is not time dependent in the midterm to long term. CLINICAL RELEVANCE: After hamstring tendon ACL reconstruction, the implanted grafts can transform into ACL-like tissue with a similar ultrastructure and metabolism, implying their usefulness as grafts. PMID- 26033970 TI - Military blast exposure, ageing and white matter integrity. AB - Mild traumatic brain injury, or concussion, is associated with a range of neural changes including altered white matter structure. There is emerging evidence that blast exposure-one of the most pervasive causes of casualties in the recent overseas conflicts in Iraq and Afghanistan-is accompanied by a range of neurobiological events that may result in pathological changes to brain structure and function that occur independently of overt concussion symptoms. The potential effects of brain injury due to blast exposure are of great concern as a history of mild traumatic brain injury has been identified as a risk factor for age associated neurodegenerative disease. The present study used diffusion tensor imaging to investigate whether military-associated blast exposure influences the association between age and white matter tissue structure integrity in a large sample of veterans of the recent conflicts (n = 190 blast-exposed; 59 without exposure) between the ages of 19 and 62 years. Tract-based spatial statistics revealed a significant blast exposure * age interaction on diffusion parameters with blast-exposed individuals exhibiting a more rapid cross-sectional age trajectory towards reduced tissue integrity. Both distinct and overlapping voxel clusters demonstrating the interaction were observed among the examined diffusion contrast measures (e.g. fractional anisotropy and radial diffusivity). The regions showing the effect on fractional anisotropy included voxels both within and beyond the boundaries of the regions exhibiting a significant negative association between fractional anisotropy and age in the entire cohort. The regional effect was sensitive to the degree of blast exposure, suggesting a 'dose response' relationship between the number of blast exposures and white matter integrity. Additionally, there was an age-independent negative association between fractional anisotropy and years since most severe blast exposure in a subset of the blast-exposed group, suggesting a specific influence of time since exposure on tissue structure, and this effect was also independent of post traumatic stress symptoms. Overall, these data suggest that blast exposure may negatively affect brain-ageing trajectories at the microstructural tissue level. Additional work examining longitudinal changes in brain tissue integrity in individuals exposed to military blast forces will be an important future direction to the initial findings presented here. PMID- 26033972 TI - Local rhBMP-12 on an Absorbable Collagen Sponge as an Adjuvant Therapy for Rotator Cuff Repair - A Phase 1, Randomized, Standard of Care Control, Multicenter Study: Safety and Feasibility. AB - BACKGROUND: Recombinant human bone morphogenetic protein-12 (rhBMP-12) has been shown to induce tendon and ligament formation in rats and to improve tendon healing; however, the safety and feasibility of implanting rhBMP-12/absorbable collagen sponge (ACS) in humans are not known. PURPOSE: To investigate the safety and feasibility of rhBMP-12 on an ACS as an adjuvant therapy in open rotator cuff repair. STUDY DESIGN: Randomized controlled trial; Level of evidence, 2. METHODS: This study consisted of 20 patients with full-thickness rotator cuff tears. Patients were randomized either to standard of care (SOC) treatment (open rotator cuff repair) or to receive 0.015 mg/mL rhBMP-12/ACS and SOC treatment during their open rotator cuff repair (rhBMP-12/ACS group) at a rate of 1/4 SOC/rhBMP 12/ACS. The feasibility of implanting the product and the safety of the product were evaluated during the 1-year follow-up period. The evaluation involved up to 10 postoperative visits, which included physical examinations, radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI) scans with an emphasis on heterotopic ossification (HO), pharmacokinetics, immunogenicity, laboratory evaluations, and local and systemic adverse events at specified time points. RESULTS: Small amounts of HO were seen on follow-up CT scans in 10 of 16 patients in the rhBMP-12/ACS group and in 2 of 3 patients in the SOC group. HO did not increase at 26 weeks and was not associated with any adverse events or unsatisfactory clinical outcomes. Pharmacokinetics demonstrated that circulating levels of rhBMP-12 were not detectable after administration. Five of 16 patients showed a postoperative immunogenic response but did not show any correlating adverse events. Complete healing of the rotator cuff was observed in 14 of 16 patients; 2 of 16 imaging results could not be analyzed because of artifacts in the rhBMP-12 group on MRI scans. In the SOC group, 1 of 4 patients showed a retear at 12 weeks after surgery. CONCLUSION: The use of rhBMP-12/ACS has been shown to be feasible and safe in a concentration of 0.015 mg/mL when used in open rotator cuff repair. Higher dose concentrations of rhBMP-12 should be evaluated in the future to evaluate their safety and potential to increase rotator cuff healing after open surgical repair. PMID- 26033973 TI - Tailored Height Gradients in Vertical Nanowire Arrays via Mechanical and Electronic Modulation of Metal-Assisted Chemical Etching. AB - In current top-down nanofabrication methodologies the design freedom is generally constrained to the two lateral dimensions, and is only limited by the resolution of the employed nanolithographic technique. However, nanostructure height, which relies on certain mask-dependent material deposition or etching techniques, is usually uniform, and on-chip variation of this parameter is difficult and generally limited to very simple patterns. Herein, a novel nanofabrication methodology is presented, which enables the generation of high aspect-ratio nanostructure arrays with height gradients in arbitrary directions by a single and fast etching process. Based on metal-assisted chemical etching using a catalytic gold layer perforated with nanoholes, it is demonstrated how nanostructure arrays with directional height gradients can be accurately tailored by: (i) the control of the mass transport through the nanohole array, (ii) the mechanical properties of the perforated metal layer, and (iii) the conductive coupling to the surrounding gold film to accelerate the local electrochemical etching process. The proposed technique, enabling 20-fold on-chip variation of nanostructure height in a spatial range of a few micrometers, offers a new tool for the creation of novel types of nano-assemblies and metamaterials with interesting technological applications in fields such as nanophotonics, nanophononics, microfluidics or biomechanics. PMID- 26033974 TI - Male adaptations to minimize sexual cannibalism during reproduction in the funnel web spider Hololena curta. AB - Males of many spider species risk being attacked and cannibalized while searching for, courting, and mating with conspecific females. However, there are exceptions. We show that the funnel-web spider, Hololena curta, has 3 adaptations that minimize risk to males during courtship and mating, and enhance reproductive success. First, males detected chemical or tactile signals associated with webs of virgin females, and differentiated them from webs of mated females, enabling males to increase encounter rates with virgin females and avoid aggressive mated females. Second, males produced stereotyped vibrational signals during courting which induced female quiescence and suppressed female aggression. Third, when touched by males, sexually receptive females entered a cataleptic state, allowing males to safely approach and copulate. Because males can mate multiple times and the sex ratio in natural populations of H. curta is female biased, overall reproductive output is likely increased by males of this species avoiding sexual cannibalism. PMID- 26033975 TI - Control of Microbial Growth in Alginate/Polydopamine Core/Shell Microbeads. AB - Microbial microencapsulation not only protects microorganisms from harmful environments by physically isolating them from the outside media but also has the potential to tailor the release profile of the encapsulated cells. However, the microbial release has not yet been controlled tightly, leading to undesired detrimental exposure of microorganisms to the outside. In this work, we suggest a simple method for controlling the cell release by suppressing the microbial growth in the microbeads. Alginate microbeads, encapsulating yeast cells, were coated with ultrathin but robust polydopamine shells, and the resulting core/shell structures effectively reduced the growth rate, while maintaining the cell viability. PMID- 26033976 TI - Dynamic flow characteristics in normal and asthmatic lungs. AB - Complex flow patterns exist within the asymmetric branching airway network in the lungs. These flow patterns are known to become increasingly heterogeneous during disease as a result of various mechanisms such as bronchoconstriction or alterations in lung tissue compliance. Here, we present a coupled model of tissue deformation and network airflow enabling predictions of dynamic flow properties, including temporal flow rate, pressure distribution, and the occurrence of reverse flows. We created two patient-specific airway geometries, one for a healthy subject and one for a severe asthmatic subject, derived using a combination of high-resolution CT data and a volume-filling branching algorithm. In addition, we created virtually constricted airway geometry by reducing the airway radii of the healthy subject model. The flow model was applied to these three different geometries to solve the pressure and flow distribution over a breathing cycle. The differences in wave phase of the flows in parallel airways induced by asymmetric airway geometry and bidirectional interaction between intra acinar and airway network pressures were small in central airways but were more evident in peripheral airways. The asthmatic model showed elevated ventilation heterogeneity and significant flow disturbance. The reverse flows in the asthmatic model not only altered the local flow characteristics but also affected total lung resistance. The clinical significance of temporal flow disturbance on lung ventilation in normal airway model is obscure. However, increased flow disturbance and ventilation heterogeneity observed in the asthmatic model suggests that reverse flow may be an important factor for asthmatic lung function. PMID- 26033977 TI - Comparative study of different seeding methods based on a multilayer SIS scaffold: Which is the optimal procedure for urethral tissue engineering? AB - Seeding cells efficiently and uniformly onto three-dimensional scaffolds is key for engineering urological tissue with an ideal histological structure in vitro. Using an optimized seeding technology allows cells to cooperate positively with biomaterials, resulting in successful reconstructive surgery. In this study, we used four different types of seeding methods in a scaffold of small intestinal submucosa (SIS). The efficiency of the sandwich co-culture, layered co-culture, static-agitation seeding, and centrifugation seeding methods were compared. It was demonstrated that dynamic seeding methods, such as static-agitation and centrifugation seeding, had superior cell-matrix infiltration and mechanical properties. The seeding time could be reduced by 5-10 min using the centrifugation method. Furthermore, functional assessment of the barriers revealed that this function was better in the centrifugation seeding method than in any other method. Our study suggests that both the static-agitation and centrifugation methods are suitable for cell seeding on SIS. There is no significant change in surface area of SIS with different seeding methods. These methods reinforce the physiological and mechanical properties of biomaterials and allow for the future in vivo study of tissue-engineered urethral reconstruction. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1098-1108, 2016. PMID- 26033978 TI - Coronary high-intensity plaque on T1-weighted magnetic resonance imaging and its association with myocardial injury after percutaneous coronary intervention. AB - AIMS: Non-contrast T1-weighted imaging (T1WI) has emerged as a novel non-invasive imaging for vulnerable coronary plaque showing a high-intensity plaque (HIP). However, the association between HIP and percutaneous coronary intervention (PCI) has not been evaluated. We investigated the association between the presence of HIP and the incidence of myocardial injury after PCI. METHODS AND RESULTS: A total of 77 patients with stable angina were imaged with non-contrast T1WI by using a 1.5 T magnetic resonance system (HIP and non-HIP group, N = 31 and 46 patients, respectively). We defined HIP as a coronary plaque to myocardium signal intensity ratio (PMR) of >=1.4. High-sensitive cardiac troponin-T (hs-cTnT) was measured at baseline and 24 h after PCI. Percutaneous coronary intervention related myocardial injury (PMI) was defined as an elevation of hs-cTnT >5* 99th percentile upper reference limit. High-intensity plaque was associated with the characteristics of ultrasound attenuation and positive remodelling on intravascular ultrasound. Although baseline hs-cTnT was similar between the groups, increase in hs-cTnT was significantly greater in the HIP vs. non-HIP group (0.065 [0.023-0.304] vs. 0.017 [0.005-0.026], P < 0.001). Percutaneous coronary intervention-related myocardial injury occurred more frequently in the HIP than non-HIP group (58.1 vs. 10.9%, P < 0.001), and the cut-off value of PMR found to be 1.44 for predicting PMI (sensitivity 78.3% and specificity 81.5%). In multivariate analysis, a PMR of >=1.4 was a significant predictor of PMI (odds ratio 5.63, 95% confidence interval 1.28-24.7, P = 0.022). CONCLUSION: High intensity plaque on non-contrast T1WI was characterized as vulnerable coronary plaque on IVUS and was associated with higher incidence of PMI. PMID- 26033979 TI - Pacemaker lead endocarditis assessed by a multimodality imaging approach. PMID- 26033980 TI - Assessment of coronary artery plaque with non-contrast and T1-weighted magnetic resonance: promise for clinical use? PMID- 26033981 TI - Fundamentals in clinical coronary physiology: why coronary flow is more important than coronary pressure. AB - Wide attention for the appropriateness of coronary stenting in stable ischaemic heart disease (IHD) has increased interest in coronary physiology to guide decision making. For many, coronary physiology equals the measurement of coronary pressure to calculate the fractional flow reserve (FFR). While accumulating evidence supports the contention that FFR-guided revascularization is superior to revascularization based on coronary angiography, it is frequently overlooked that FFR is a coronary pressure-derived estimate of coronary flow impairment. It is not the same as the direct measures of coronary flow from which it was derived, and which are critical determinants of myocardial ischaemia. This review describes why coronary flow is physiologically and clinically more important than coronary pressure, details the resulting limitations and clinical consequences of FFR-guided clinical decision making, describes the scientific consequences of using FFR as a gold standard reference test, and discusses the potential of coronary flow to improve risk stratification and decision making in IHD. PMID- 26033982 TI - IMPROVEd quality of life and lower cost with an endovascular strategy for ruptured abdominal aortic aneurysms - impact on daily practice. PMID- 26033983 TI - Marfan and Sartans: time to wake up! PMID- 26033984 TI - Predicting survival after ECMO for refractory cardiogenic shock: the survival after veno-arterial-ECMO (SAVE)-score. AB - RATIONALE: Extracorporeal membrane oxygenation (ECMO) may provide mechanical pulmonary and circulatory support for patients with cardiogenic shock refractory to conventional medical therapy. Prediction of survival in these patients may assist in management of these patients and comparison of results from different centers. AIMS: To identify pre-ECMO factors which predict survival from refractory cardiogenic shock requiring ECMO and create the survival after veno arterial-ECMO (SAVE)-score. METHODS AND RESULTS: Patients with refractory cardiogenic shock treated with veno-arterial ECMO between January 2003 and December 2013 were extracted from the international Extracorporeal Life Support Organization registry. Multivariable logistic regression was performed using bootstrapping methodology with internal and external validation to identify factors independently associated with in-hospital survival. Of 3846 patients with cardiogenic shock treated with ECMO, 1601 (42%) patients were alive at hospital discharge. Chronic renal failure, longer duration of ventilation prior to ECMO initiation, pre-ECMO organ failures, pre-ECMO cardiac arrest, congenital heart disease, lower pulse pressure, and lower serum bicarbonate (HCO3) were risk factors associated with mortality. Younger age, lower weight, acute myocarditis, heart transplant, refractory ventricular tachycardia or fibrillation, higher diastolic blood pressure, and lower peak inspiratory pressure were protective. The SAVE-score (area under the receiver operating characteristics [ROC] curve [AUROC] 0.68 [95%CI 0.64-0.71]) was created. External validation of the SAVE score in an Australian population of 161 patients showed excellent discrimination with AUROC = 0.90 (95%CI 0.85-0.95). CONCLUSIONS: The SAVE-score may be a tool to predict survival for patients receiving ECMO for refractory cardiogenic shock (www.save-score.com). PMID- 26033985 TI - Low gradient severe aortic stenosis with preserved ejection fraction: reclassification of severity by fusion of Doppler and computed tomographic data. AB - AIMS: Low gradient severe aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF) may be attributed to aortic valve area index (AVAi) underestimation due to the assumption of a circular shape of the left ventricular outflow tract (LVOT) with 2-dimensional echocardiography. The current study evaluated whether fusing Doppler and multidetector computed tomography (MDCT) data to calculate AVAi results in significant reclassification of inconsistently graded severe AS. METHODS AND RESULTS: In total, 191 patients with AVAi < 0.6 cm2/m2 and LVEF >= 50% (mean age 80 +/- 7 years, 48% male) were included in the current analysis. Patients were classified according to flow (stroke volume index <35 or >=35 mL/m2) and gradient (mean transaortic pressure gradient <=40 or >40 mmHg) into four groups: normal flow-high gradient (n = 72), low flow-high gradient (n = 31), normal flow-low gradient (n = 46), and low flow-low gradient (n = 42). Left ventricular outflow tract area was measured by planimetry on MDCT and combined with Doppler haemodynamics on continuity equation to obtain the fusion AVAi. The group of patients with normal flow-low gradient had significantly larger AVAi and LVOT area index compared with the other groups. Although MDCT-derived LVOT area index was comparable among the four groups, the fusion AVAi was significantly larger in the normal flow-low gradient group. By using the fusion AVAi, 52% (n = 24) of patients with normal flow-low gradient and 12% (n = 5) of patients with low flow-low gradient would have been reclassified into moderate AS due to AVAi >= 0.6 cm2/m2. CONCLUSION: The fusion AVAi reclassifies 52% of normal flow-low gradient and 12% of low flow-low gradient severe AS into true moderate AS, by providing true cross-sectional LVOT area. PMID- 26033986 TI - Tunable Fabrication of Molybdenum Disulfide Quantum Dots for Intracellular MicroRNA Detection and Multiphoton Bioimaging. AB - Molybdenum disulfide (MoS2 ) quantum dots (QDs) (size <10 nm) possess attractive new properties due to the quantum confinement and edge effects as graphene QDs. However, the synthesis and application of MoS2 QDs has not been investigated in great detail. Here, a facile and efficient approach for synthesis of controllable size MoS2 QDs with excellent photoluminescence (PL) by using a sulfuric acid assisted ultrasonic route is developed for this investigation. Various MoS2 structures including monolayer MoS2 flake, nanoporous MoS2 , and MoS2 QDs can be yielded by simply controlling the ultrasonic durations. Comprehensive microscopic and spectroscopic tools demonstrate that the MoS2 QDs have uniform lateral size and possess excellent excitation-independent blue PL. The as-generated MoS2 QDs show high quantum yield of 9.65%, long fluorescence lifetime of 4.66 ns, and good fluorescent stability over broad pH values from 4 to 10. Given the good intrinsic optical properties and large surface area combined with excellent physiological stability and biocompatibility, a MoS2 QDs-based intracellular microRNA imaging analysis system is successfully constructed. Importantly, the MoS2 QDs show good performance as multiphoton bioimaging labeling. The proposed synthesis strategy paves a new way for facile and efficient preparing MoS2 QDs with tunable-size for biomedical imaging and optoelectronic devices application. PMID- 26033987 TI - Progress on clinical characteristics and identification of location of thoracic ossification of the ligamentum flavum. AB - Thoracic ossification of the ligamentum flavum (TOLF) is the most common cause for thoracic spinal stenosis. TOLF is usually complicated by thoracic disc herniation, ossification of the posterior longitudinal ligament and degenerative spinal diseases such as cervical spondylosis and lumbar spinal stenosis, and the ossification also usually has a discontinuous or continuous multi-segment distribution. The resultant superposition of several symptoms makes the clinical manifestations complex. Currently, the diagnosis of TOLF depends mainly on the patient's symptoms, physical examination and thoracic CT and MRI examinations. Identification of the location of TOLF depends more on the doctor's subjective judgement. Diagnostic problems are related to the specific region and level of surgical decompression: if the extent of decompression is insufficient, the treatment is inadequate, resulting in residual symptoms. Obversely, unnecessary trauma and a various complications will occur if the decompression is too extensive. Hence, the clinical features and process of diagnosis, especially the means of identifying the location, still require further improvement. It is necessary to establish a simple and accurate means of identifying the segment of TOLF that is responsible for the neurologic deficit: a number of spinal surgeons have been working hard on this. This article will provided an overview of the clinical features of TOLF and the related problems of clinical identification of the location of the segment causing the neurological deficit. The relationship between the imaging manifestations and clinical characteristics still need to be explored with the aim of establishing a simple and precise method for determining precisely whether TOLF is related to spinal cord injury or not, thus reducing surgical trauma and achieving an optimal prognosis. PMID- 26033988 TI - A systematic review of total dislocation of the talus. AB - This review summarizes the treatment and resulting outcomes for total talar dislocation. The PubMed database was searched for articles about humans with total talar dislocation published in the English language in the last twenty years. The following data were entered into a Microsoft Excel spreadsheet: type of dislocation, nature of associated fractures (if any), type of reduction/fixation utilized, immobilization, weight-bearing status, outcome, complications and average follow-up time. Thirty-nine articles reporting a total of 86 cases of total talar dislocation are included in this review. Seventy-three of these were open injuries and 13 closed. Forty-three cases had an associated foot or ankle fracture, 32 of those cases specifically having a fracture of the talus. The talus was preserved in the initial management of 74 cases, whereas the remaining 12 cases were managed by primary talectomy. The mean duration of follow up was 32 months. Twenty-two cases required a secondary arthrodesis or another additional procedure. A good outcome was achieved in 35% of cases, a fair outcome in 37% and a poor outcome in 27%. The complication of avascular necrosis (AVN) occurred in 22 cases and 14 subjects developed clinically significant osteoarthritis. Generally, the outcome of current treatments associated with total talar dislocation is not ideal, only 1/3 of cases achieving good outcomes. So far, preservation of the talus is the best treatment option. AVN is still a relatively common complication even in the absence of fracture or postoperative infection. PMID- 26033989 TI - Giant cell tumor of the pelvis: a systematic review. AB - This is a systematic review of articles concerning the morbidity, recurrence rate, treatment and treatment complications of pelvic giant cell tumors (GCTs). The key words "giant cell tumor, pelvis" were used to identify articles which included data on patients with pelvic GCTs in English and Chinese databases of published reports from 1949-2012. The articles were filtered by title, abstract and full text. Thirty-eight articles and 165 patients were identified for this review. Data on all identified patients were studies; data in different articles on the same patients was not used repeatedly. The following patient data were collected where possible and subjected to systematic analysis; age, location of GCT, treatment, follow-up, complications, recurrence and whether alive or dead. The mean age of onset was 33.2 years (range, 14-73 years), the peak ages of onset being between 21 and 40 years. A pronounced sex difference was identified, the male : female ratio being 1:1.7. The acetabulum was the commonest area for pelvic GCTs. Forty-eight tumors were primarily located in the iliac, 60 in the acetabular and 31 in the ischiopubic area. Twenty-seven patients experienced complications of treatment. Patients who had been treated by wide resection had the most complications; these included incisional infection and delayed healing of incisions. Local recurrence was common, having occurred in 39/158 patients (24.6%), comprising 24/72 (33.3%) who had undergone intralesional surgery only; 9/20 (45.0%) who had undergone radiotherapy only; 1/51 (2.0%) who had undergone wide resection; and 5/14 patients (35.7%) who had undergone radiation therapy or cryotherapy plus intralesional surgery. Mortality was low (3.2%, 5/158). Pelvic GCT is not common, the acetabular area appears to the most frequent site and the peak age is the third and fourth decades. Although the recurrence rate is high for all pelvic GCTs, the mortality is low. Treatment has a critical influence on recurrence. In spite of the associated complications, the lower local recurrence rate makes wide resection a reasonable option for patients with extensive and/or aggressive GCTs. PMID- 26033990 TI - Pedicle length and degree of slip in lumbosacral isthmic spondylolisthesis. AB - OBJECTIVE: The present retrospective study was performed to assess the anatomical features of the pedicle in isthmic spondylolisthesis and to correlate this with degree of slip. METHODS: Twenty-six patients with isthmic spondylolytic spondylolisthesis were studied. Relevant patient variables, length, width, height of the L5 pedicle, and the product of height and angle between pedicle and vertebral midline were measured. The length of the posterior compartment of the pedicle was calculated as the product of the pedicle length and angle. RESULTS: With measurements comparable to those reported in previous publications, the L5 pedicle was found to be longer, and the height and width of the body shorter, than published values for patients without spondylolysis. The difference between the length of the posterior compartment of the pedicle and height of body is significantly proportional to the degree of slip and may reflect an adaptive response for stabilizing the vertebral body with posterior elements. CONCLUSIONS: The pedicle anatomy was found to be altered in patients with L5 S1 spondylolytic spondylolisthesis. These anatomical changes have implications for surgeons performing fusion operations in terms of length of screw, landmarks used and entry approach. PMID- 26033991 TI - Total hip arthroplasty with subtrochanteric femoral shortening osteotomy for high hip dislocation. AB - OBJECTIVE: To evaluate the outcomes of total hip arthroplasty (THA) with subtrochanteric femoral shortening osteotomy for high hip dislocation. METHODS: In this retrospective study, the results of 24 primary THAs with acetabular reconstruction and subtrochanteric femoral shortening osteotomy in 21 patients with high hip dislocation were evaluated. The acetabula were reconstructed with cemented or uncemented cups and bone grafting. Transverse subtrochanteric femoral shortening osteotomies were applied and the osteotomy sites treated by bone grafting and cable fixation. Assessment was by Hip Harris scores and radiographic evaluation. RESULTS: The mean follow-up time was 42 months (18-108 months), three cases being lost to follow-up 18-27 months postoperatively. The HHS improved from 47.5 +/- 8.7 to 88.5 +/- 3.1. The mean length of femoral segments removed was 2.5 +/- 0.8 cm (range, 1.0-4.5 cm) and mean acetabular inclination 43 degrees +/- 5 degrees (range, 31 degrees -54 degrees ). Caudalization of the femoral head center was 3.2 +/- 3.0 mm (range, -3 to 12 mm) and lateralization 4.0 +/- 4.0 mm (range, -9 to 11 mm). Mean greater trochanter height relative to theoretical hip center was 5.2 +/- 1.0 cm (range, 3.5-7.1 cm) preoperatively and 0.2 +/- 0.6 cm (range, -0.9 to 1.2 cm) postoperatively. Intraoperative trochanteric fractures occurred in three cases and sciatic nerve palsy in one. CONCLUSION: THA with subtrochanteric femoral shortening osteotomy is an effective technique for treating high hip dislocation. Its advantages include improvement in limb imbalance and decreased risk of sciatic nerve injury. PMID- 26033992 TI - Minimally invasive unicompartmental knee arthroplasty for spontaneous osteonecrosis of the knee. AB - OBJECTIVE: To explore the outcome and surgical technique of minimally invasive unicompartmental knee arthroplasty (UKA) for spontaneous osteonecrosis of the knee. METHODS: Twenty-seven patients with medial compartmental spontaneous osteonecrosis treated by minimally invasive Oxford phase 3 UKA from January 2009 to June 2013 were reviewed retrospectively. Twelve subjects were men and 15 women, with an average age of 64.6 +/- 8.6 years (52-82 years). At the time of diagnosis, 11 patients had with grade III necrosis and 16 grade IV according to Mont's classification. Pain, range of motion (ROM) and Hospital for Special Surgery (HSS) knee scores were evaluated before and after UKA. Pre-and postoperative alignment of the lower limbs was measured and compared. Postoperative radiographic assessments were made according to the guidelines proposed by the Oxford group at the final follow-up. RESULTS: All patients were followed for a mean time of 27.8 +/- 15.9 months (6-59 months). There were no serious adverse events, such as infection, bearing dislocation, aseptic loosening, pulmonary embolism, deep venous thrombosis, cardio-cerebral vascular incident or psychological problems. One revision was required for unrelated causes (fracture of tibia plateau) 3 years after arthroplasty. One femoral component was tilted with a postoperative radiographic angle >10 degrees . One radiolucent line was observed in a patient with spontaneous osteonecrosis of the knee. The two patients with implant failure had no symptoms at last follow-up. Visual analogue scale scores decreased from 6.9 +/- 0.9 to 2.0 +/- 1.1 (t = 19.27, P = 0.00). Pain was relieved in 96.3% of subjects (26/27). The mean post operative ROM and femorotibial angle were 125.7 degrees +/- 9.6 degrees and 177.7 degrees +/- 3.1 degrees , respectively. HSS scores increased from 61.3 +/- 9.7 to 93.0 +/- 4.8 (t = 14.46, P = 0.00). Of the 27 patients, 26 (96.3%) were satisfied with the outcome of this surgical procedure. CONCLUSION: Minimally invasive UKA is an effective means of managing spontaneous osteonecrosis of the knee. The short-term outcome of UKA is encouraging. PMID- 26033993 TI - Tibiotalocalcaneal arthrodesis using a retrograde intramedullary nail with a valgus curve. AB - OBJECTIVE: Many different techniques have been described for performing tibiotalocalcaneal arthrodesis (TTCA) in patients with severe hindfoot disorders such as failed ankle arthroplasty and failed ankle joint arthrodesis with subsequent subtalar arthritis. The use of straight retrograde intramedullary nails is extremely limited because they may interfere with normal heel valgus position and risk damaging the lateral plantar neurovascular structures. Curved retrograde intramedullary nails have been designed to overcome these shortcomings. The purpose of this single surgeon series was to investigate the outcomes of TTCA using a curved retrograde intramedullary nail. METHODS: From June 2009 to January 2012, 22 patients underwent TTCA using intramedullary nails with a valgus curve by the same senior surgeon. All patients were available for analysis, the mean follow-up being 22.3 months (range, 6.8-38 months). The main outcome measurements included EQ-5D functional scores, the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot scale, radiologic assessment and clinical examination. RESULTS: Bony union and a plantigrade foot were achieved in 100% of subjects, the mean time to union being 3.9 months (range, 2.4 to 6.2 months). Structural bone graft was used in all patients. Postoperative radiologic results showed a good hindfoot alignment in all patients. The only complication was one case of delayed wound healing without deep infection. The mean postoperative EQ 5D functional and AOFAS ankle-hindfoot scores were 69.33 (range, 20 to 90) and 69.9 (range, 45 to 85) points, respectively. No revision surgery was necessary in our cohort. CONCLUSION: The results of the present study indicate that TTCA using a short, retrograde, curved intramedullary nail is an acceptable technique for obtaining solid fusion and good hindfoot alignment inpatients with severe hindfoot disorders. PMID- 26033994 TI - Treatment of femoral neck fracture with percutaneous compression plate: preliminary results in 74 patients. AB - OBJECTIVE: The purpose of this study was to present the surgical technique and clinical results of percutaneous compression plate (PCCP) for the treatment of femoral neck fractures. METHODS: Between December 2010 and April 2013, 74 consecutive patients with 74 femoral neck fractures were treated by closed reduction and PCCP implants in our university hospital. Their mean age was 51.3 years (range, 15-83 years); 38 (51.4%) were male and 46 (62.2%) of the fractures were on the left. The patients' clinical and radiographic data were analyzed retrospectively. RESULTS: There were 45 undisplaced (60.8%) and 29 displaced fractures (39.2%). Eight patients (10.8%) were lost to follow-up. The mean duration of follow-up was 18.8 months for the remaining 66 patients. At the last follow-up, mean Harris hip score was 92.9 (range, 75-100), and 65 patients (98.5%) had excellent and good outcomes. Sixty-five patients (98.5%) were able to walk independently and one (1.5%) with walking-sticks. The mean time to clinical fracture healing was 3.9 months. There were no cases of nonunion. Two patients (3.0%) had delayed union and two (3.0%) developed avascular necrosis, one of 29 (3.7%) with a displaced fracture and one of 45 (2.6%) with an undisplaced fracture. There were no other complications or prosthetic replacement. CONCLUSIONS: PCCP is a stable internal fixation device that resists axial and rotational stresses. Our PCCP procedure has a low incidence of nonunion and avascular necrosis. PMID- 26033995 TI - Treatment of Middle-up Part Long-segment Femoral Fracture with Long Proximal Femoral Nail Antirotation. AB - OBJECTIVE: To investigate the outcomes of treating middle-up part long-segment fractures of the femur by long proximal femoral nail antirotation (PFNA-long). METHODS: From June 2006 to December 2013, 139 cases (35 women, 104 men; mean age 48.8, range, 18-86 years) of long-segment femoral fracture in middle-up part were treated with long proximal femoral nail antirotation (PFNA, 320-380 mm) by minimally invasive percutaneous fixation and autogenous iliac bone graft. Fifty eight cases were graded as type IA long-segment femoral fractures (41.73%), 25 type IB (17.99%), four type IC (2.88%), 28 type II (20.14%), 12 type IIIA (8.63%), five type IIIB (3.60%), and seven type IV (5.04%). Clinical efficacy was evaluated with Harris hip function scores and postoperative pain with visual analogue scale. RESULTS: The operative time was 35-90 min (mean, 45 min) and mean intraoperative blood loss 78.6 mL (range 30-200 mL). Most patients were walking with assistance 4-10 days postoperatively. All patients were followed up for 3-37 months (mean, 19 months). There were no serious complications. All fractures healed after 2.8-6.8 months (mean, 3.9 months). According to Harris criteria, the clinical results were excellent in 108 patients, good in 22, fair in eight and poor in one. Ninety-three cases had no pain, 33 mild pain, 13 moderate pain and 25 occasionally needed non-steroidal analgesics. CONCLUSION: Closed reduction or limited open reduction with PFNA-long is an effective treatment for long-segment femoral fracture in middle-up part, with good strength in fixation, high rate of fracture union, early functional recovery and low rate of complications. PMID- 26033996 TI - Surgical treatment of acetabulum top compression fracture with sea gull sign. AB - OBJECTIVE: To investigate surgical procedures and their efficacy for acetabulum top compression fractures with sea gull sign. METHODS: Data of 14 patients (five women, nine men); aged from 28 to 71 years (mean, 49.9 years) who had undergone surgery for acetabulum top compression fractures with sea gull sign and been followed up were retrospectively analyzed. The time from injury to surgery was 4 14 days (mean, 9 days). All patients underwent open reduction and bone graft and internal fixation through an ilioinguinal or ilioinguinal plus Kocher-Langenbeck approach. Quality of fracture reduction was assessed according to Matta reduction criteria and hip function according to Matta acetabular fracture criteria. RESULTS: Fourteen patients were followed up for 6-60 months (mean, 36 months). All achieved bone healing within 3-4 months (mean, 3.4 months); the excellent and good rate being 78.5% (11/14). The Matta acetabular fracture scores were 10-18 scores (mean, 16.4); the excellent and good rate being 71.4% (10/14). Traumatic arthritis occurred in three patients. Pain was serious in two patients and relieved by total hip joint replacement and mild in one. One patient developed asymptomatic heterotopic ossification postoperatively. CONCLUSION: The appropriate delay between injury and surgery with acetabular roof compression fracture with sea gull sign is from 5 to 10 days. Through an ilioinguinal or ilioinguinal plus Kocher-Langenbeck approach, excellent reduction of the articular surface can be achieved and sufficient bone graft material obtained. The clinical efficacy is satisfactory. PMID- 26033997 TI - Sternal tumor resection and reconstruction with titanium mesh: a preliminary study. AB - OBJECTIVE: To explore the clinical efficacy and complications of treating sternal tumors by resection and titanium mesh thoracic reconstruction. METHODS: This retrospective analysis of eight patients with sternal tumors treated in the Department of Orthopedic Surgery at the First Affiliated Hospital of Zhengzhou University from January 2008 to June 2012 included five men and three women aged 37-66 years (mean, 50.4 years). The histological diagnoses were chondrosarcoma (two cases), osteosarcoma (one), malignant fibrous histiocytoma (two), eosinophilic granuloma (one) and sternal metastasis from breast cancer (two). The tumors were invading the manubrium sterni (three cases), manubrium sterni and body (three) and sternal body (two). All patients underwent needle or incisional biopsy prior to sternal tumor resection and titanium mesh thoracic reconstruction. RESULTS: All patients were followed for 9 months to 4 years. There were no intraoperative complications or operative or postoperative deaths. One patient developed a deep wound hematoma 1 week postoperatively; incisional drainage and debridement resulting in healing within 2 weeks. There was no loosening or exsertion of the titanium mesh and no patients developed respiratory complications or thoracic deformity. One patient with malignant fibrous histiocytoma died of lung metastases 9 months postoperatively, another with malignant fibrous histiocytoma died of liver metastases 14 months postoperatively; the remaining patients survived without tumor recurrence. CONCLUSION: Titanium mesh chest reconstruction after sternal tumor resection has the advantages of simplifying the procedure, achieving a good shape and having few complications. Titanium mesh is an ideal material for reconstruction of the sternum. PMID- 26033998 TI - Effect of advanced oxidation protein products on articular cartilage and synovium in a rabbit osteoarthritis model. AB - OBJECTIVE: Advanced oxidation protein products (AOPPs), a marker of oxidative stress, are prevalent in many kinds of disorders. Osteoarthritis (OA), mainly resulting from the regression of cartilage, chronic inflammation of the synovium and the subchondral bone remodeling. Although the inflammatory response of AOPPs on fibroblast-like synoviocytes (FLSs) were reported, the effect of AOPPs on cartilage and synovial in vivo remains unclear. Therefore, our study aims to investigate whether AOPPs have an effect on the articular cartilage and synovial in a rabbit model of OA. METHODS: OA model were created by anterior cruciate ligament transection and medial meniscus resection (ACLT + MMx). Forty-eight male New Zealand rabbits were randomly divided into 3 groups: sham-operated group, AOPPs/ACLT + MMx group, and phosphate buffered saline (PBS)/ACLT + MMx group. In sham-operated group, the anterior cruciate ligament was just exposed without transection, and then the incision was sutured. Then intra-articular injection of AOPPs or PBS was performed in the other two groups. Through four weeks and eight weeks of treatment, rabbits in each group were sacrificed. Both hind legs were removed. India ink staining and Safranin O and fast green staining were used to evaluate the macroscopic and microscopic cartilage morphology. The protein expression of matrix metalloproteinases (MMP)-3, MMP-13 in synovium was measured by Western blot. RESULT: The India ink score and Mankin score of AOPPs/ACLT + MMx group were both higher than the other two groups at the two time points. Western blot have revealed that intra-articular injection of AOPPs upregulated the protein expression of MMP-3 and MMP-13 in synovium. CONCLUSION: AOPPs participated in the occurrence and development of OA by upregulating the protein expression of MMP-3 and MMP-13 in synovium. PMID- 26033999 TI - Toxicity and bioactivity of cobalt nanoparticles on the monocytes. AB - OBJECTIVE: To explore the toxicity and biological activity of cobalt nanoparticles on the osteoclasts. Analyze the relationship between cobalt nanoparticles and osteolysis. METHODS: Monocyte-macrophages (RAW 264.7) was cultured in vitro, osteoclast-like cells were induced by lipopolysaccharides (LPS). After RAW 264.7 was induced for 24 h, Methyl Thiazolium Tetrazolium (MTT) biological toxicity test of osteoclast-like cell was preceded using Cobalt nanoparticles (set 4 concentrations: 10, 20, 50, 100 MUM) and cobalt chloride (set 4 concentrations: 10, 20, 50, 100 MUM) at 2, 4, 8, 24 and 48 h respectively. The relative expression of mRNA of CA II and Cat K after RAW 264.7 induction was determined by Q-PCR. RESULTS: mRNA relative expression of CA II, Cat K were reduced at multiple concentrations both cobalt nanoparticles and cobalt chloride, and was time and concentration dependent, cobalt nanoparticles are more significant than cobalt chloride group. But when the cobalt nanoparticles concentration is in 10-50 MUM, the mRNA relative expression of CA II, Cat K increased. CONCLUSION: Cobalt nanoparticles have biological toxicity. At multiple concentrations, the differentiation and proliferation of osteoclasts was inhibited, but when the concentration of cobalt nanoparticles is in 10-50 MUM, it has been strengthened. PMID- 26034000 TI - Anterior decompression and strut grafting for adjacent segment disease nine years after posterior lumbar interbody fusion. PMID- 26034001 TI - Intraoperative Femoral Condylar Fracture during Primary Total Knee Arthroplasty: Report of Two Cases. PMID- 26034002 TI - Anterior Reconstruction via a Relatively Noninvasive Retroperitoneal Approach for Lumbar Burst Fracture. PMID- 26034003 TI - Anterior decompression and reconstruction for lumbar burst fractures. PMID- 26034004 TI - Evaluation of the Incremental Prognostic Utility of Increasingly Complex Testing in Chronic Heart Failure. AB - BACKGROUND: Current heart failure (HF) risk prediction models do not consider how individual patient assessments occur in incremental steps; furthermore, each additional diagnostic evaluation may add cost, complexity, and potential morbidity. METHODS AND RESULTS: Using a cohort of well-treated ambulatory HF patients with reduced ejection fraction who had complete clinical, laboratory, health-related quality of life, imaging, and exercise testing data, we estimated incremental prognostic information provided by 5 assessment categories, performing an additional analysis on those with available N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels. We compared the incremental value of each additional assessment (quality of life screen, laboratory testing, echocardiography, and exercise testing) to baseline clinical assessment for predicting clinical outcomes (all-cause mortality, all-cause mortality/hospitalization, and cardiovascular death/HF hospitalizations), gauging incremental improvements in prognostic ability with more information using area under the curve and reclassification improvement (net reclassification index), with and without NT-proBNP availability. Of 2331 participants, 1631 patients had complete clinical data; of these, 1023 had baseline NT-proBNP. For prediction of all-cause mortality, models with incremental assessments sans NT-proBNP showed improvements in C-indices (0.72 [clinical model alone]-0.77 [complete model]). Compared with baseline clinical assessment alone, net reclassification index improved from 0.035 (w/laboratory data) to 0.085 (complete model). These improvements were significantly attenuated for models in the subset with measured NT-proBNP data (c-indices: 0.80 [w/laboratory data]-0.81 [full model]); net reclassification index improvements were similarly marginal (0.091->0.096); prediction of other clinical outcomes had similar findings. CONCLUSIONS: In chronic HF patients with reduced ejection fraction, the marginal benefit of complex prognostic evaluations should be weighed against potential patient discomfort and cost escalation. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437. PMID- 26034005 TI - Assessing the hierarchical structure of titanium implant surfaces. AB - The physical texture of implant surfaces are known to be one important factor in creating a stable bone-implant interface. Simple roughness parameters (for e.g., Sa or Sz) are not entirely adequate when characterizing surfaces possessing hierarchical structure (macro, micro, and nano scales). The aim of this study was to develop an analytical approach to quantify hierarchical surface structure of implant surfaces possessing nearly identical simple roughness. Titanium alloys with macro/micro texture (MM) and macro/micro/nano texture (MMN) were chosen as model surfaces to be evaluated. There was no statistical difference (p > 0.05) in either Sa (13.56 vs. 13.43 um) or Sz (91.74 vs. 92.39 um) for the MM and MMN surfaces, respectively. However, when advanced filtering algorithms were applied to these datasets, a statistical difference in roughness was found between MM (Sa = 0.54 um) and MMN (Sa = 1.06 um; p < 0.05). Additionally, a method was developed to specifically quantify the density of surface features appearing similar in geometry to natural osteoclastic pits. This analysis revealed a significantly greater numbers of these features (i.e., valleys) on the MMN surface as compared to the MM surface. Finally, atomic force microscopy showed a rougher nano-texture on the MMN surface compared with the MM surface (p < 0.05). The results support recent published studies that show a combination of appropriate micron and nano surface results in a more robust cellular response and increased osteoblast differentiation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1083-1090, 2016. PMID- 26034006 TI - Effects of cigarette smoking on rhinologic diseases: Korean National Health and Nutrition Examination Survey 2008-2011. AB - BACKGROUND: Several studies have shown a relationship between cigarette smoking and general diseases of the nose in a large Asian population. The current study was conducted to better understand the effect of cigarette smoke exposure on rhinologic diseases in Koreans. METHODS: Data were obtained from the 2008-2011 Korea National Health and Nutrition Examination Survey, a cross-sectional survey of the noninstitutionalized population in Korea. Of the 37,753 people surveyed, 11,589 adult participants had completed questionnaires on rhinologic symptoms and smoking behaviors, had undergone nasal endoscopy, and had provided urine collection were enrolled. Rhinologic diseases investigated in this study included subjective olfactory dysfunction, rhinitis symptoms, chronic rhinosinusitis (CRS), and nasal septal deviation with obstructive symptoms. The relationship between disease and cigarette smoking was evaluated using multivariate regression analyses. RESULTS: In South Korea, the weighted prevalence of subjective olfactory dysfunction, rhinitis symptoms, CRS, and nasal septal deviation with obstructive symptoms was 4.6%, 27.2%, 6.2%, and 4.0%, respectively. The only disease significantly associated with active smoking was CRS in participants 40 years of age and older after adjusting for age, sex, residency, house income, education, and occupation (adjusted odds ratio = 1.427, 95% confidence interval = 1.050 to 1.938). For each year of active smoking, CRS prevalence increased by 1.5%. None of the rhinologic diseases examined were associated with passive smoking. CONCLUSION: Our study showed that CRS seems to be associated with active smoking in older participants. Considering the relatively high prevalence of CRS in Korea, further longitudinal researches for their association and prevention are required. PMID- 26034007 TI - Tissue formation and tissue engineering through host cell recruitment or a potential injectable cell-based biocomposite with replicative potential: Molecular mechanisms controlling cellular senescence and the involvement of controlled transient telomerase activation therapies. AB - Accumulated data indicate that wound-care products should have a composition equivalent to that of the skin: a combination of particular growth factors and extracellular matrix (ECM) proteins endogenous to the skin, together with viable epithelial cells, fibroblasts, and mesenchymal stem cells (MSCs). Strategies consisting of bioengineered dressings and cell-based products have emerged for widespread clinical use; however, their performance is not optimal because chronic wounds persist as a serious unmet medical need. Telomerase, the ribonucleoprotein complex that adds telomeric repeats to the ends of chromosomes, is responsible for telomere maintenance, and its expression is associated with cell immortalization and, in certain cases, cancerogenesis. Telomerase contains a catalytic subunit, the telomerase reverse transcriptase (hTERT). Introduction of TERT into human cells extends both their lifespan and their telomeres to lengths typical of young cells. The regulation of TERT involves transcriptional and posttranscriptional molecular biology mechanisms. The manipulation, regulation of telomerase is multifactorial in mammalian cells, involving overall telomerase gene expression, post-translational protein-protein interactions, and protein phosphorylation. Reactive oxygen species (ROS) have been implicated in aging, apoptosis, and necrosis of cells in numerous diseases. Upon production of high levels of ROS from exogenous or endogenous generators, the redox balance is perturbed and cells are shifted into a state of oxidative stress, which subsequently leads to modifications of intracellular proteins and membrane lipid peroxidation and to direct DNA damage. When the oxidative stress is severe, survival of the cell is dependent on the repair or replacement of damaged molecules, which can result in induction of apoptosis in the injured with ROS cells. ROS-mediated oxidative stress induces the depletion of hTERT from the nucleus via export through the nuclear pores. Nuclear export is initiated by ROS induced phosphorylation of tyrosine 707 within hTERT by the Src kinase family. It might be presumed that protection of mitochondria against oxidative stress is an important telomere length-independent function for telomerase in cell survival. Biotechnology companies are focused on development of therapeutic telomerase vaccines, telomerase inhibitors, and telomerase promoter-driven cell killing in oncology, have a telomerase antagonist in late preclinical studies. Anti-aging medicine-oriented groups have intervened on the market with products working on telomerase activation for a broad range of degenerative diseases in which replicative senescence or telomere dysfunction may play an important role. Since oxidative damage has been shown to shorten telomeres in tissue culture models, the adequate topical, transdermal, or systemic administration of antioxidants (such as, patented ocular administration of 1% N-acetylcarnosine lubricant eye drops in the treatment of cataracts) may be beneficial at preserving telomere lengths and delaying the onset or in treatment of disease in susceptible individuals. Therapeutic strategies toward controlled transient activation of telomerase are targeted to cells and replicative potential in cell-based therapies, tissue engineering and regenerative medicine. PMID- 26034008 TI - Light or Heat? The Origin of Cargo Release from Nanoimpeller Particles Containing Upconversion Nanocrystals under IR Irradiation. AB - Nanoimpellers are mesoporous silica nanoparticles that contain azobenzene derivatives bonded inside the pores and rely on the continuous photoisomerization of multiple azobenzenes to release cargo under near UV irradiation. A recent study employs upconversion nanocrystal embedded particles to replace UV light with IR light to stimulate nanoimpellers. However, the photothermal effect of IR irradiation and its likely contribution to the observed release behavior are not examined. It is found that, in the absence of upconversion nanocrystals, the azobenzene co-condensed silica particles still respond to 980 nm illumination, which increases the nanoparticle temperature by 25 degrees C in 15 min, experimentally measured by an encapsulated nanothermometer. After suppressing the heating, the IR irradiation does not initiate the release, indicating that optical heating, not upconverted light, is responsible for the triggered cargo release. The results are explained by numerical analyses. PMID- 26034010 TI - Escherichia coli diversity in the lower intestinal tract of humans. AB - Previous studies examining the clonal diversity of Escherichia coli populations within humans have been based on faecal isolates. In this study E. coli were isolated from biopsies taken from the terminal ileum, ascending, transverse and descending colon, and rectum of 69 individuals. Multiple isolates from each biopsy were characterized using Rep-PCR. An average of 3.5 genotypes were recovered per host, and in hosts with two or more strains, the phylogroup membership of the second most abundant strain was significantly more likely to be the same as the dominant strain. There was no indication of a non-random distribution of E. coli phylogroups among the regions of the lower intestine. In hosts with multiple genotypes, as defined by Repetitive extragenic palindromic PCR, genotypes were non-randomly distributed among gut regions in over half the individuals. The phylogroup membership of an individual's numerically dominant strain explained some of the variation in the extent to which strains within an individual were heterogeneously distributed, with most heterogeneity observed when the numerically dominant strain belonged to phylogroups E or F, and the least when the dominant strain belonged to phylogroup B2. The results of this study support previous studies on pigs that demonstrated faecal sampling underestimates the genotype diversity present within a host. PMID- 26034009 TI - Role of redox homeostasis in thermo-tolerance under a climate change scenario. AB - BACKGROUND: Climate change predictions indicate a progressive increase in average temperatures and an increase in the frequency of heatwaves, which will have a negative impact on crop productivity. Over the last decade, a number of studies have addressed the question of how model plants or specific crops modify their metabolism when exposed to heat stress. SCOPE: This review provides an overview of the redox pathways that contribute to how plants cope with heat stress. The focus is on the role of reactive oxygen species (ROS), redox metabolites and enzymes in the signalling pathways leading to the activation of defence responses. Additional attention is paid to the regulating mechanisms that lead to an increase in specific ROS-scavenging systems during heat stress, which have been studied in different model systems. Finally, increasing thermo-tolerance in model and crop plants by exposing them to heat acclimation or to exogenous treatments is discussed. CONCLUSIONS: Although there is clear evidence that several strategies are specifically activated according to the intensity and the duration of heat stress, as well as the capacity of the different species or genotypes to overcome stress, an alteration in redox homeostasis seems to be a common event. Different mechanisms that act to enhance redox systems enable crops to overcome heat stress more effectively. Knowledge of thermo-tolerance within agronomic biodiversity is thus of key importance to enable researchers to identify new strategies for overcoming the impacts of climate change, and for decision-makers in planning for an uncertain future with new choices and options open to them. PMID- 26034011 TI - Luminescent Nanofibers Fabricated from Phenanthroimidazole Derivatives by Organogelation: Fluorescence Response towards Acid with High Performance. AB - Nanofibers based on phenanthroimidazole derivatives PCC, PDC, and PSC were fabricated by organogelation processes, and their fluorescence sensory properties towards acid were investigated. It was found that the emission of PCC in the nanofiber-based film could be quenched significantly upon exposure to gaseous TFA due to the formation of protonated PCC, in which ICT (intramolecular charge transfer) would occur. On the other hand, TFA vapor led to the emitting colors of PDC and PSC in the nanofiber-based films to turn to yellow and green from sky blue and blue, respectively. Additionally, we found that the decay times of PCC were 0.1 s and 1.9 s in probing the saturated vapor of TFA in nanofiber-based film and in spin-coated film, respectively. The results suggested that the high surface-to-volume ratio and large interspace in the nanofiber-based networks favored the enhanced adsorption, accumulation, and diffusion of gaseous molecules, resulting in such a high performance. PMID- 26034013 TI - Management of acute asthma exacerbations. AB - BACKGROUND: Acute asthma exacerbations are common events in the lives of asthmatics, and even the best-managed asthma patients will have acute asthma exacerbations. There are different levels of severity of exacerbations with corresponding management strategies the physician can use to treat acute events. These strategies, including some adjunctive therapies, are reviewed in this article. METHODS: A review of the English-language scientific literature was performed regarding management of acute asthma exacerbations, focusing of published guidelines, meta-analyses, and database reviews. RESULTS: Symptoms of exacerbations are reviewed with attention to determining the severity of the exacerbation and the place of management, either at home or in a more acute care setting. Medical therapies for the treatment of each severity level are reviewed as to their effectiveness. Post-exacerbation care is also discussed. CONCLUSION: Asthma exacerbations will happen and both the provider and patient need to be educated on how to manage these occurrences. Whether the patient is managed at home or in a hospital setting will be determined by the level of severity. Regardless of the medical therapies employed, continued focus should be on further prevention of additional exacerbations. PMID- 26034012 TI - Implant design and its effects on osseointegration over time within cortical and trabecular bone. AB - Healing chambers present at the interface between implant and bone have become a target for improving osseointegration. The objective of the present study was to compare osseointegration of several implant healing chamber configurations at early time points and regions of interest within bone using an in vivo animal femur model. Six implants, each with a different healing chamber configuration, were surgically implanted into each femur of six skeletally mature beagle dogs (n = 12 implants per dog, total n = 72). The implants were harvested at 3 and 5 weeks post-implantation, non-decalcified processed to slides, and underwent histomorphometry with measurement of bone-to-implant contact (BIC) and bone area fraction occupied (BAFO) within healing chambers at both cortical and trabecular bone sites. Microscopy demonstrated predominantly woven bone at 3 weeks and initial replacement of woven bone by lamellar bone by 5 weeks. BIC and BAFO were both significantly increased by 5 weeks (p < 0.001), and significantly higher in cortical than trabecular bone (p < 0.001). The trapezoidal healing chamber design demonstrated a higher BIC than other configurations. Overall, a strong temporal and region-specific dependence of implant osseointegration in femurs was noted. Moreover, the findings suggest that a trapezoidal healing chamber configuration may facilitate the best osseointegration. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1091-1097, 2016. PMID- 26034014 TI - Accelerated tissue integration into porous materials by immobilizing basic fibroblast growth factor using a biologically safe three-step reaction. AB - Soft tissue integration into a porous structure is important to prevent bacterial infection of percutaneous devices and improve tissue regeneration using porous scaffolds. Here, basic fibroblast growth factor (bFGF) was immobilized on porous polymer materials using a mild and biologically safe three-step reaction: (1) modification with a novel surface-modification peptide (penta-lysine-mussel adhesive sequence, which reacts with various matrices), (2) electrostatic binding of heparin with introduced penta-lysine, and (3) biologically specific binding of bFGF to heparin. Porous polyethylene specimens (PPSs) (D = 6.0 mm, H = 2.0 mm) with a good size for tissue integration were selected as a base material, immobilized with bFGF, and subcutaneously implanted into mice. Half of the unmodified PPSs extruded out of the body on day 112 postimplantation; however, the three-step reaction completely prevented sample rejection. Tissue integration was greatly accelerated by immobilizing bFGF. Direct physical coating of bFGF on PPS resulted in greater immobilization but lesser tissue integration than that after the three-step bFGF immobilization, indicating that heparin binds and enhances bFGF efficacy. This three-step bFGF immobilization reaction will be applicable to various polymeric, metallic, and ceramic materials and is a simple strategy to integrate tissue on porous medical devices or scaffolds for tissue regeneration. PMID- 26034015 TI - Self-Assembled Epitaxial Core-Shell Nanocrystals with Tunable Magnetic Anisotropy. AB - Epitaxial core-shell CoO-CoFe2 O4 nanocrystals are fabricated by using pulsed laser deposition with the aid of melted material (Bi2 O3 ) addition and suitable lattice mismatch provided by substrates (SrTiO3 ). Well aligned orientations among nanocrystals and reversible core-shell sequence reveal tunable magnetic anisotropy. The interfacial coupling between core and shell further engineers the nanocrystal functionality. PMID- 26034016 TI - Changes in microbial communities along redox gradients in polygonized Arctic wet tundra soils. AB - This study investigated how microbial community structure and diversity varied with depth and topography in ice wedge polygons of wet tundra of the Arctic Coastal Plain in northern Alaska and what soil variables explain these patterns. We observed strong changes in community structure and diversity with depth, and more subtle changes between areas of high and low topography, with the largest differences apparent near the soil surface. These patterns are most strongly correlated with redox gradients (measured using the ratio of reduced Fe to total Fe in acid extracts as a proxy): conditions grew more reducing with depth and were most oxidized in shallow regions of polygon rims. Organic matter and pH also changed with depth and topography but were less effective predictors of the microbial community structure and relative abundance of specific taxa. Of all other measured variables, lactic acid concentration was the best, in combination with redox, for describing the microbial community. We conclude that redox conditions are the dominant force in shaping microbial communities in this landscape. Oxygen and other electron acceptors allowed for the greatest diversity of microbes: at depth the community was reduced to a simpler core of anaerobes, dominated by fermenters (Bacteroidetes and Firmicutes). PMID- 26034017 TI - Photoinduced Formation of Peroxide Ions on La2O3 and Nd2O3 under O2: Effects of Excitation Wavelength and Crystal Structure. AB - Photoinduced formation of peroxide ions on La2O3 and Nd2O3 under O2 was studied by in-situ microprobe Raman spectroscopy with attention focused on the effect of excitation wavelength and crystal structure on the O2(2-) formation. It was found that photoexcitations at 633, 532, 514, and 325 nm can induce O2(2-) formation over La2O3 at 450 degrees C. By contrast, photoexcitation at 785 nm does not cause formation of O2(2-) up to 500 degrees C. Photoexcitation at 325 nm can induce O2(2-) formation on cubic Nd2O3 at 25 degrees C, but cannot induce O2(2-) formation on hexagonal Nd2O3 up to 200 degrees C. The significant difference in the behavior of O2(2-) formation over the Nd2O3 samples of the two structures can be related to the difference in the capacity to adsorb O2. Since the number of oxygen vacancies in cubic Nd2O3 is larger than that in the hexagonal one, the former has a higher capacity than the latter to adsorb O2. As a result, cubic Nd2O3 is more favorable to the reaction of O2 with O(2-) to generate O2(2-). The structural similarity between cubic Nd2O3 and Nd2O2(O2) may be another factor in favor of peroxide formation. PMID- 26034018 TI - Stabilization and Encapsulation of Gold Nanostars Mediated by Dithiols. AB - Surface chemistry plays a pivotal role in regulating the morphology of nanoparticles, maintaining colloidal stability, and mediating the interaction with target analytes toward practical applications such as surface-enhanced Raman scattering (SERS)-based sensing and imaging. The use of a binary ligand mixture composed of 1,4-benzenedithiol (BDT) and hexadecyltrimethylammonium chloride (CTAC) to provide gold nanostars with long-term stability is reported. This is despite BDT being a bifunctional ligand, which usually leads to bridging and loss of colloidal stability. It is found however that neither BDT nor CTAC alone are able to provide sufficient colloidal and chemical stability. BDT-coated Au nanostars are additionally used as seeds to direct the encapsulation with a gold outer shell, leading to the formation of unusual nanostructures including semishell-coated gold nanostars, which are characterized by high-resolution electron microscopy and electron tomography. Finally, BDT is exploited as a probe to reveal the enhanced local electric fields in the different nanostructures, showing that the semishell configuration provides significantly high SERS signals as compared to other core-shell configurations obtained during seeded growth, including full shells. PMID- 26034019 TI - Linking the occurrence of cutaneous opportunistic fungal invaders with elemental concentrations in false killer whale (Pseudorca crassidens) skin. AB - Cetaceans, occupying the top levels in marine food chains, are vulnerable to elevated levels of potentially toxic trace elements, such as aluminium (Al), mercury (Hg) and nickel (Ni). Negative effects associated with these toxic metals include infection by opportunistic microbial invaders. To corroborate the link between the presence of cutaneous fungal invaders and trace element levels, skin samples from 40 stranded false killer whales (FKWs) were analysed using culture techniques and inductively coupled plasma-mass spectroscopy. Twenty-two skin samples yielded 18 clinically relevant fungal species. While evidence for bioaccumulation of Hg in the skin of the FKWs was observed, a strong link was found to exist between the occurrence of opportunistic fungal invaders and higher Al : Se and Al : Zn ratios. This study provides indications that elevated levels of some toxic metals, such as Al, contribute to immunotoxicity rendering FKWs susceptible to colonization by cutaneous opportunistic fungal invaders. PMID- 26034020 TI - Culture of blame in the National Health Service; consequences and solutions. PMID- 26034021 TI - Information technology innovation: the power and perils of big data. PMID- 26034022 TI - Fentanyl-induced cough is a risk factor for postoperative nausea and vomiting. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) and fentanyl-induced cough (FIC) are two common anaesthesia-related events, which seem to have common risk factors. In this prospective cohort study, we investigate whether patients who have FIC during induction of anaesthesia have an increased incidence of PONV. METHODS: We studied adult non-smoking gynaecological surgical patients enrolled between July 1, 2011 and July 30, 2012. The presence of FIC during induction and the occurrence of PONV were recorded. Fentanyl-induced cough and other perioperative variables were subjected to multivariate analysis to determine the association between FIC and PONV. RESULTS: All 502 patients enrolled in this study had at least two risk factors for PONV, and 154 (31%) developed FIC. The incidence of PONV in the FIC group was higher than in the non-FIC group (56.5 vs 38.2%; P<0.0001). Multivariate logistic regression analysis found FIC to be a predictive risk factor for the development of PONV (adjusted odds ratio 2.08, 95% confidence interval 1.41-3.07). CONCLUSIONS: Non-smoking women undergoing gynaecological surgery who develop FIC during induction of anaesthesia have a higher incidence of PONV. PMID- 26034023 TI - Low Temperature Sintering Cu6 Sn5 Nanoparticles for Superplastic and Super uniform High Temperature Circuit Interconnections. AB - Brittle intermetallics such as Cu6 Sn5 can be transformed into low cost, nonbrittle, superplastic and high temperature-resistant interconnection materials by sintering at temperatures more than 200 degrees C lower than its bulk melting point. Confirmed via in situ TEM heating, the sintered structure is pore-free with nanograins, and the interface is super-uniform. PMID- 26034024 TI - Return on investment in dental education: is it worth it? PMID- 26034025 TI - Dental and allied dental students' attitudes towards and perceptions of intraprofessional education. AB - Interprofessional and intraprofessional learning opportunities in health professions education are vital to emphasize evidence-based practice, quality improvement, and cost-effectiveness in patients' oral health care. The aim of this study was to assess dental, dental hygiene, and dental assisting students' readiness for intraprofessional education and to evaluate their attitudes towards and perceptions of intraprofessional teamwork, communication, respect, and understanding of professional roles. In 2013, students at one dental school (N=247) were surveyed, and focus groups were conducted for this convergent parallel mixed-methods study. Survey response rates were as follows: senior dental students 54.4% (N=43), senior dental hygiene students 100% (N=32), dental assisting students 95% (N=19), junior dental students 51.8% (N=42), and junior dental hygiene students 100% (N=33). The results showed that the dental hygiene students had more positive responses about intraprofessional education than the dental and dental assisting students (p<0.05). Most (94%, N=160) of the respondents in the combined groups agreed that intraprofessional learning would help them become more effective members of the oral health care team. The three focus group sessions (N=17) revealed consistency among the groups regarding the value of an integrated clinical design and intraprofessional education. These students were eager and positive about intraprofessional learning and agreed that a shared learning model can improve communication and respect among team members, provide a better understanding of roles, and ultimately enhance patient care. PMID- 26034026 TI - Dentists' knowledge and opinions of oral-systemic disease relationships: relevance to patient care and education. AB - Population studies consistently support associations between poor oral (periodontal) health and systemic diseases such as cardiovascular disease (CVD) and diabetes. The aim of this study was to assess the knowledge of dentists and document their opinions regarding the evidence on oral-systemic disease relationships. A survey consisting of 39 items was developed and mailed to 1,350 licensed dentists in North Carolina. After three mailings, 667 dentists (49%) meeting inclusion criteria responded. The respondents were predominantly male (76.3%), in solo practice (59.5%), and in non-rural settings (74%). More than 75% of these dentists correctly identified risk factors like diet, genetics, smoking, obesity, and physical inactivity for CVD and diabetes. The majority rated the evidence linking periodontal disease with CVD and diabetes as strong (71% and 67%, respectively). These dentists were most comfortable inquiring about patients' tobacco habits (93%), treating patients with diabetes (89%) or CVD (84%) and concurrent periodontal disease, and discussing diabetes-periodontal disease risks with patients (88%). Fewer respondents were comfortable asking patients about alcohol consumption (54%) or providing alcohol counseling (49%). Most agreed that dentists should be trained to identify risk factors (96%) or actively manage systemically diseased patients (74%). Over 90% agreed that medical and dental professionals should be taught to practice more collaboratively. These data indicate that these dentists were knowledgeable about oral-systemic health associations, had mixed comfort levels translating the evidence into clinical practice, but expressed support for interprofessional education to improve their readiness to actively participate in their patients' overall health management. PMID- 26034027 TI - The ARCTIC Workshop: An Interprofessional Education Activity in an Academic Health Sciences Center. AB - The complex care required to address the needs of head and neck cancer patients requires interprofessional collaboration. Using the compelling narrative of a patient's journey through cancer treatment in the Canadian setting, the aim of this study was to engage health professions students to discover the importance of interprofessional care for complex patients, while delivering content on head and neck cancer care and providing training/experience in interprofessional education (IPE) facilitation to clinicians. In the study, 38 students from nine health disciplines participated in a three-hour workshop that included interactive presentations and facilitated small- and large-group activities. The Interdisciplinary Education Perception Scale (IEPS) was administered pre and post workshop to examine changes in students' attitudes and perceptions about IPE. Qualitative participant and facilitator feedback regarding the session was obtained using a structured questionnaire and debriefing sessions with each group. An overall improvement of scores on the IEPS was observed, while analyses of individual items showed improved scores on all items but one. Session feedback from students and facilitators was positive. The results suggest that combining case-based methods with interprofessional learning in the clinical setting allowed students to develop an appreciation for the complex needs of head and neck cancer patients and the need for collaboration to improve patient outcomes. PMID- 26034028 TI - Adequacy of patient pools to support predoctoral students' achievement of competence in pediatric dentistry in U.S. dental schools. AB - The aim of this study was to characterize the current status of predoctoral pediatric dentistry patient pools in U.S. dental schools and compare their status to that in 2001. A 2014 survey of school clinic-based and community-based dental patient pools was developed, piloted, and sent to pediatric predoctoral program directors in 57 U.S. dental schools via SurveyMonkey. Two follow-up contacts were made to increase the response rate. A total of 49 surveys were returned for a response rate of 86%. The responding program directors reported that their programs' patient pools had declined in number and had changed in character with more diversity and fewer procedures. They attributed the changes to competition, cost, and location of the dental school. The respondents reported that community based dental education clinical sites continued to provide additional service experiences for dental students, with contributions varying by the nature of the site. A large number of the respondents felt that their graduates lacked some basic pediatric dentistry clinical skills and were not ready for independent practice with children. The results of this study suggest that the predoctoral pediatric dentistry patient pool has changed and general dentists may be graduating with inadequate experiences to practice dentistry for children. PMID- 26034029 TI - Assessment skills of dental students as peer evaluators. AB - The aim of this study was to evaluate the level of assessment skills of dental students as evaluators in an introductory dental anatomy preclinical course. Three groups of evaluators independently and separately evaluated each student's wax-ups: seven third-year student evaluators, five fourth-year student evaluators, and four faculty evaluators. There were 13 criteria on which the students' wax-ups for teeth #3, 6, 8, and 12 were evaluated on a scale ranging from 1=honors/highest score to 4=fail/lowest score. Of the three groups of evaluators, scores given by the third-year students were the highest with an average of 2.47 (SD=0.69), while faculty evaluators gave the lowest scores with an average of 2.61 (SD=0.68). The percentages of marginal passes and failing scores given by the third-year students were the lowest (marginal pass=15.8% and fail=17.2%) of the three evaluator groups. The results of the study indicated that assessments were influenced by the type of evaluator. In order to utilize students more effectively as evaluators in preclinical assessments, a calibration method for student and faculty evaluators should be established along with close mentorship by faculty. Involving dental students as peer teachers could reinforce the learning experience for them and encourage them to consider a future academic career. PMID- 26034030 TI - Dental students' ability to assess their performance in a preclinical restorative course: comparison of students' and faculty members' assessments. AB - Dental education consists of both theoretical and practical learning for students to develop competence in treating patients clinically. When dental students encounter practical courses in their first year as a new educational experience, they must also learn to evaluate themselves. Self-evaluation is an essential skill to learn for dental professionals to keep increasing their competence over the course of their careers. The aim of this study was to compare the assessment scores of second- and third-year dental students and the faculty in two consecutive preclinical practical exams in restorative dentistry courses in a dental school in Turkey. Faculty- and student-assigned scores were calculated from two consecutive preclinical examinations on tooth restorations performed on both artificial casts and phantom patients. The students were formally instructed on grading procedures for tooth preparations, base and restoration placement, and polishing criteria. After each step, each item was assessed by faculty members, the student, and another student. The results indicated that the initial differences between second-year students' assessments of their own preclinical practical ability and that of the faculty decreased among the third-year students. Self-evaluation scores did not indicate whether the third-year students tended to over- or underestimate the quality of their own work. However, the second-year students not only overestimated themselves but thought they were above average. The results point to the need to develop students' self-insight with more exercises and practical training. PMID- 26034031 TI - Ability of admissions criteria to predict early academic performance among students of health science colleges at King Saud University, Saudi Arabia. AB - The aim of this study was to evaluate the ability of admissions criteria at King Saud University (KSU), Riyadh, Saudi Arabia, to predict students' early academic performance at three health science colleges (medicine, dentistry, and pharmacy). A retrospective cohort study was conducted with data from the records of students enrolled in the three colleges from the 2008-09 to 2010-11 academic years. The admissions criteria-high school grade average (HSGA), aptitude test (APT) score, and achievement test (ACT) score-were the independent variables. The dependent variable was the average of students' first- and second-year grade point average (GPA). The results showed that the ACT was a better predictor of the students' early academic performance than the HSGA (beta=0.368, beta=0.254, respectively). No significant relationship was found between the APT and students' early academic performance (beta=-0.019, p>0.01). The ACT was most predictive for pharmacy students (beta=0.405), followed by dental students (beta =0.392) and medical students (beta=0.195). Overall, the current admissions criteria explained only 25.5% of the variance in the students' early academic performance. While the ACT and HSGA were found to be predictive of students' early academic performance in health colleges at KSU, the APT was not a strong predictor. Since the combined current admissions criteria for the health science colleges at KSU were weak predictors of the variance in early academic performance, it may be necessary to consider noncognitive evaluation methods during the admission process. PMID- 26034032 TI - Topical trends in tobacco and alcohol articles published in three dental journals, 1980-2010. AB - The aim of this study was to conduct a review of articles about tobacco or alcohol published from 1980 to 2010 in the Journal of the American Dental Association (JADA), Journal of Dental Education (JDE), and Journal of Public Health Dentistry (JPHD) in an attempt to identify trends by decade in topics relevant to oral health consequences, oral cancer linkages, and cessation counseling. NVivo qualitative analysis software was used to code abstracts using the keywords "tobacco" or "alcohol." The search identified 269 articles: tobacco=211 (78%), alcohol=58 (22%). This number represented 2.4% of the total articles published in these journals for the specified years. While the percentage of tobacco-related articles increased over this period (with highs in the 1990s of 4.1% in the JDE and 9% in the JPHD), the percentage of alcohol articles reached only 1% for JADA and 3.3% for the JPHD in the 2000s. The number of tobacco-related articles addressing oral health effects, oral cancer linkages, and cessation counseling increased in the 1990s. Although there were modest increases in the number of articles about alcohol-related oral health effects and oral cancer linkages (particularly in the JPHD in the 2000s), only two articles (in JADA in the 2000s) addressed alcohol cessation counseling. This study concluded that tobacco and alcohol have received limited, though increasing, attention in these three major journals between 1980 and 2010, with alcohol receiving less attention than tobacco. These results suggest a need for more published studies on tobacco and alcohol interventions in dental and allied dental education to prepare students to contribute to this aspect of their patients' health. PMID- 26034033 TI - Dental hygiene students' perceptions of a cultural competence component in a tobacco dependence education curriculum: a pilot study. AB - First Nations and Inuit peoples have tobacco use rates three times that of the Canadian national average. Providing tobacco dependence education (TDE) requires an understanding of the factors surrounding tobacco use that are culturally specific to this population. The aim of this pilot study was to evaluate the effectiveness of a new cultural competence component for Canadian First Nations and Inuit peoples in a TDE curriculum at Dalhousie University School of Dental Hygiene, Halifax, Nova Scotia, Canada. In 2011, the TDE curriculum was revised to include a First Nations and Inuit people's cultural component. A 32-question survey was developed for the study, with questions divided into four subscales regarding students' perceived knowledge, skills, comfort level, and attitudes about working with this population. Responses from students in two succeeding years were compared: the first cohort had not participated in the revised curriculum (56% response rate), and the second cohort had (63% response rate). The results showed an overall improvement in the subscales evaluated and a significant (p=0.002) improvement in the knowledge subscale of the students who received the new TDE curriculum, specifically regarding knowledge about sociocultural characteristics, health risks, and cultural healing traditions of First Nations and Inuit people. Although the results indicated an increase in the knowledge of the culture of First Nations and Inuit peoples, it is unclear whether the students felt better prepared to provide TDE to this population. For future research, the investigators would examine what learning experiences and further changes to the curriculum could be provided to facilitate the level of preparedness to successfully deliver TDE. PMID- 26034034 TI - Does use of an electronic health record with dental diagnostic system terminology promote dental students' critical thinking? AB - The Consortium for Oral Health Research and Informatics (COHRI) is leading the way in use of the Dental Diagnostic System (DDS) terminology in the axiUm electronic health record (EHR). This collaborative pilot study had two aims: 1) to investigate whether use of the DDS terms positively impacted predoctoral dental students' critical thinking skills measured by the Health Sciences Reasoning Test (HSRT), and 2) to refine study protocols. The study design was a natural experiment with cross-sectional data collection using the HSRT for 15 classes (2013-17) of students at three dental schools. Characteristics of students who had been exposed to the DDS terms were compared with students who had not, and the differences were tested by t-tests or chi-square tests. Generalized linear models were used to evaluate the relationship between exposure and outcome on the overall critical thinking score. The results showed that exposure was significantly related to overall score (p=0.01), with not-exposed students having lower mean overall scores. This study thus demonstrated a positive impact of using the DDS terminology in an EHR on the critical thinking skills of predoctoral dental students in three COHRI schools as measured by their overall score on the HSRT. These preliminary findings support future research to further evaluate a proposed model of critical thinking in clinical dentistry. PMID- 26034035 TI - Utilizing self-assessment software to evaluate student wax-ups in dental morphology. AB - Traditionally, evaluating student work in preclinical courses has relied on the judgment of experienced clinicians utilizing visual inspection. However, research has shown significant disagreement between different evaluators (interrater reliability) and between results from the same evaluator at different times (intrarater reliability). This study evaluated a new experimental software (E4D Compare) to compare 66 student-produced tooth wax-ups at one U.S. dental school to an ideal standard after both had been digitally scanned. Using 3D surface mapping technology, a numerical evaluation was generated by calculating the surface area of the student's work that was within a set range of the ideal. The aims of the study were to compare the reliability of faculty and software grades and to determine the ideal tolerance value for the software. The investigators hypothesized that the software would provide more consistent feedback than visual grading and that a tolerance value could be determined that closely correlated with the faculty grade. The results showed that a tolerance level of 450 MUm provided 96% agreement of grades compared with only 53% agreement for faculty. The results suggest that this software could be used by faculty members as a mechanism to evaluate student work and for students to use as a self-assessment tool. PMID- 26034036 TI - Effect of Employing Different Typodonts When Using E4D Compare for Dental Student Assessment. AB - The use of computers to aid in instruction and help decrease the subjective component of assessment is steadily increasing. One of the potential barriers to the effective utilization of CAD/CAM technology for assessment purposes is the efficient scanning of the teeth being used for comparison. The purpose of this pilot study was to determine if the use of different typodonts, of the same make and model, has any significant effect on the percent comparison results when using E4D Compare. Tooth #30 was prepared by a faculty member to represent what dental students at Georgia Regents University are taught as the ideal preparation for a full gold crown. Ten typodonts of the same make and model were selected for comparison. Three different examples of students' preparations were scanned and compared to the ideal preparation. Each of the three student preparations was subjected to ten trials (occasions), one for each typodont, at five tolerance levels: 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, and 0.5 mm. The intraclass correlation coefficient (ICC) was used to measure the intrarater agreement among the typodonts at the various tolerance levels. The agreement coefficients (0.971 0.984) indicated very little variability attributable to the use of a different typodont. The high agreement coefficients achieved using different typodonts of the same make and model provide evidence for the interchangeability of typodonts when assessing a student's performance in the preclinical simulation environment. PMID- 26034037 TI - Inter- and Intrarater Reliability Using Different Software Versions of E4D Compare in Dental Education. AB - The problems associated with intra- and interexaminer reliability when assessing preclinical performance continue to hinder dental educators' ability to provide accurate and meaningful feedback to students. Many studies have been conducted to evaluate the validity of utilizing various technologies to assist educators in achieving that goal. The purpose of this study was to compare two different versions of E4D Compare software to determine if either could be expected to deliver consistent and reliable comparative results, independent of the individual utilizing the technology. Five faculty members obtained E4D digital images of students' attempts (sample model) at ideal gold crown preparations for tooth #30 performed on typodont teeth. These images were compared to an ideal (master model) preparation utilizing two versions of E4D Compare software. The percent correlations between and within these faculty members were recorded and averaged. The intraclass correlation coefficient was used to measure both inter- and intrarater agreement among the examiners. The study found that using the older version of E4D Compare did not result in acceptable intra- or interrater agreement among the examiners. However, the newer version of E4D Compare, when combined with the Nevo scanner, resulted in a remarkable degree of agreement both between and within the examiners. These results suggest that consistent and reliable results can be expected when utilizing this technology under the protocol described in this study. PMID- 26034038 TI - Tumor-Triggered Controlled Drug Release from Electrospun Fibers Using Inorganic Caps for Inhibiting Cancer Relapse. AB - A smart, tumor-trigged, controlled drug release using inorganic "caps" with CO3 (2-) functional groups in electrospun fibers is presented for inhibiting cancer relapse. When the drug-loaded intelligent electrospun fibers encounter pathological acidic environments, the inorganic gates react with the acids and produce CO2 gas, which enables water penetration into the core of the fibers to induce rapid drug release. PMID- 26034039 TI - Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management. AB - BACKGROUND: Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand-foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible. DESIGN: This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients. RESULTS: Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand-foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and tried-and-tested empirical experience with other multikinase inhibitors and cytotoxic chemotherapies. CONCLUSIONS: As recommended in this review, treatment modifications and supportive measures to prevent, reduce, and manage HFSR can allow patients to continue regorafenib at the optimal dose to derive benefit from treatment. PMID- 26034040 TI - Vascular smooth muscle LRP6 limits arteriosclerotic calcification in diabetic LDLR-/- mice by restraining noncanonical Wnt signals. AB - RATIONALE: Wnt signaling regulates key aspects of diabetic vascular disease. OBJECTIVE: We generated SM22-Cre;LRP6(fl/fl);LDLR(-/-) mice to determine contributions of Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6) in the vascular smooth muscle lineage of male low-density lipoprotein receptor-null mice, a background susceptible to diet (high-fat diet)-induced diabetic arteriosclerosis. METHODS AND RESULTS: As compared with LRP6(fl/fl);LDLR(-/-) controls, SM22-Cre;LRP6(fl/fl);LDLR(-/-) (LRP6-VKO) siblings exhibited increased aortic calcification on high-fat diet without changes in fasting glucose, lipids, or body composition. Pulse wave velocity (index of arterial stiffness) was also increased. Vascular calcification paralleled enhanced aortic osteochondrogenic programs and circulating osteopontin (OPN), a matricellular regulator of arteriosclerosis. Survey of ligands and Frizzled (Fzd) receptor profiles in LRP6-VKO revealed upregulation of canonical and noncanonical Wnts alongside Fzd10. Fzd10 stimulated noncanonical signaling and OPN promoter activity via an upstream stimulatory factor (USF)-activated cognate inhibited by LRP6. RNA interference revealed that USF1 but not USF2 supports OPN expression in LRP6-VKO vascular smooth muscle lineage, and immunoprecipitation confirmed increased USF1 association with OPN chromatin. ML141, an antagonist of cdc42/Rac1 noncanonical signaling, inhibited USF1 activation, osteochondrogenic programs, alkaline phosphatase, and vascular smooth muscle lineage calcification. Mass spectrometry identified LRP6 binding to protein arginine methyltransferase (PRMT)-1, and nuclear asymmetrical dimethylarginine modification was increased with LRP6-VKO. RNA interference demonstrated that PRMT1 inhibits OPN and TNAP, whereas PRMT4 supports expression. USF1 complexes containing the histone H3 asymmetrically dimethylated on Arg-17 signature of PRMT4 are increased with LRP6-VKO. Jmjd6, a demethylase downregulated with LRP6 deficiency, inhibits OPN and TNAP expression, USF1: histone H3 asymmetrically dimethylated on Arg-17 complex formation, and transactivation. CONCLUSIONS: LRP6 restrains vascular smooth muscle lineage noncanonical signals that promote osteochondrogenic differentiation, mediated in part via USF1- and arginine methylation-dependent relays. PMID- 26034041 TI - Differential role of an NF-kappaB transcriptional response element in endothelial versus intimal cell VCAM-1 expression. AB - RATIONALE: Human and murine Vcam1 promoters contain 2 adjacent nuclear factor kappaB (NF-kappaB)-binding elements. Both are essential for cytokine-induced transcription of transiently transfected promoter-reporter constructs. However, the relevance of these insights to regulation of the endogenous Vcam1 gene and to pathophysiological processes in vivo remained unknown. OBJECTIVE: Determine the role of the 5' NF-kappaB-binding element in expression of the endogenous Vcam1 gene. METHODS AND RESULTS: Homologous recombination in embryonic stem cells was used to inactivate the 5' NF-kappaB element in the Vcam1 promoter and alter 3 nucleotides in the 5' untranslated region to allow direct comparison of wild-type versus mutant allele RNA expression and chromatin configuration in heterozygous mice. Systemic treatment with inflammatory cytokines or endotoxin (lipopolysaccharide) induced lower expression of the mutant allele relative to wild-type by endothelial cells in the aorta, heart, and lungs. The mutant allele also showed lower endothelial expression in 2-week atherosclerotic lesions in Vcam1 heterozygous/low-density lipoprotein receptor-deficient mice fed a cholesterol-rich diet. In vivo chromatin immunoprecipitation assays of heart showed diminished lipopolysaccharide-induced association of RNA polymerase 2 and NF-kappaB p65 with the mutant promoter. In contrast, expression of mutant and wild-type alleles was comparable in intimal cells of wire-injured carotid artery and 4- to 12-week atherosclerotic lesions. CONCLUSIONS: This study highlights differences between in vivo and in vitro promoter analyses, and reveals a differential role for a NF-kappaB transcriptional response element in endothelial vascular cell adhesion molecule-1 expression induced by inflammatory cytokines or a cholesterol-rich diet versus intimal cell expression in atherosclerotic lesions and injured arteries. PMID- 26034042 TI - Mechanosensitive PPAP2B Regulates Endothelial Responses to Atherorelevant Hemodynamic Forces. AB - RATIONALE: PhosPhatidic Acid Phosphatase type 2B (PPAP2B), an integral membrane protein known as lipid phosphate phosphatase (LPP3) that inactivates lysophosphatidic acid, was implicated in coronary artery disease (CAD) by genome wide association studies. However, it is unclear whether genome-wide association studies-identified coronary artery disease genes, including PPAP2B, participate in mechanotransduction mechanisms by which vascular endothelia respond to local atherorelevant hemodynamics that contribute to the regional nature of atherosclerosis. OBJECTIVE: To establish the critical role of PPAP2B in endothelial responses to hemodynamics. METHODS AND RESULTS: Reduced PPAP2B was detected in vivo in mouse and swine aortic arch (AA) endothelia exposed to chronic disturbed flow, and in mouse carotid artery endothelia subjected to surgically induced acute disturbed flow. In humans, PPAP2B was reduced in the downstream part of carotid plaques where low shear stress prevails. In culture, reduced PPAP2B was measured in human aortic endothelial cells under atherosusceptible waveform mimicking flow in human carotid sinus. Flow-sensitive microRNA-92a and transcription factor KLF2 were identified as upstream inhibitor and activator of endothelial PPAP2B, respectively. PPAP2B suppression abrogated atheroprotection of unidirectional flow; inhibition of lysophosphatidic acid receptor 1 restored the flow-dependent, anti-inflammatory phenotype in PPAP2B deficient cells. PPAP2B inhibition resulted in myosin light-chain phosphorylation and intercellular gaps, which were abolished by lysophosphatidic acid receptor 1/2 inhibition. Expression quantitative trait locus mapping demonstrated PPAP2B coronary artery disease risk allele is not linked to PPAP2B expression in various human tissues but significantly associated with reduced PPAP2B in human aortic endothelial cells. CONCLUSIONS: Atherorelevant flows dynamically modulate endothelial PPAP2B expression through miR-92a and KLF2. Mechanosensitive PPAP2B plays a critical role in promoting anti-inflammatory phenotype and maintaining vascular integrity of endothelial monolayer under atheroprotective flow. PMID- 26034044 TI - A review of salivary gland histopathology in primary Sjogren's syndrome with a focus on its potential as a clinical trials biomarker. AB - Salivary gland changes, characterised by a focal lymphocytic sialadenitits, play an important role in the diagnosis of primary Sjogren's syndrome (PSS) and were first described over 40 years ago. Recent evidence suggests that minor salivary gland biopsy may also provide information useful for prognostication and stratification, yet difficulties may arise in the histopathological interpretation and scoring, and evidence exists that reporting is variable. With the increasing number of actual and proposed clinical trials in PSS, we review the evidence that might support the role of histopathology as a biomarker for stratification and response to therapy and highlight areas where further validation work is required. PMID- 26034045 TI - Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. AB - OBJECTIVES: Immunity to citrullinated antigens is a hallmark of rheumatoid arthritis (RA). We set out to elucidate its biology by identifying and characterising citrullinated antigen-specific B cells in peripheral blood of patients with RA. METHODS: Differentially labelled streptavidin and extravidin tetramers were conjugated to biotinylated CCP2 or control antigens and used in flow cytometry to identify citrullinated antigen-specific B cells in peripheral blood. Tetramer-positive and tetramer-negative B cells were isolated by fluorescence activated cell sorting (FACS) followed by in vitro culture and analysis of culture supernatants for the presence of antibodies against citrullinated protein antigens (ACPA) by ELISA. Cells were phenotypically characterised by flow cytometry. RESULTS: By combining differentially labelled CCP2 tetramers, we successfully separated citrullinated antigen-specific B cells from non-specific background signals. Isolated tetramer-positive B cells, but not tetramer-negative cells, produced large amounts of ACPA upon in vitro stimulation. Phenotypic analyses revealed that citrullinated antigen-specific B cells displayed markers of class-switched memory B cells and plasmablasts, whereas only few cells displayed a naive phenotype. The frequency of tetramer positive cells was high (up to 1/500 memory B cells with a median of 1/12 500 total B cells) and correlated with ACPA serum titres and spontaneous ACPA production in culture. CONCLUSIONS: We developed a technology to identify and isolate citrullinated antigen-specific B cells from peripheral blood of patients with RA. Most cells have a memory phenotype, express IgA or IgG and are present in relatively high frequencies. These data pave the path for a direct and detailed molecular characterisation of ACPA-expressing B cells and could lead to the identification of novel therapeutic targets. PMID- 26034043 TI - Genetic Analysis Reveals a Longevity-Associated Protein Modulating Endothelial Function and Angiogenesis. AB - RATIONALE: Long living individuals show delay of aging, which is characterized by the progressive loss of cardiovascular homeostasis, along with reduced endothelial nitric oxide synthase activity, endothelial dysfunction, and impairment of tissue repair after ischemic injury. OBJECTIVE: Exploit genetic analysis of long living individuals to reveal master molecular regulators of physiological aging and new targets for treatment of cardiovascular disease. METHODS AND RESULTS: We show that the polymorphic variant rs2070325 (Ile229Val) in bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) associates with exceptional longevity, under a recessive genetic model, in 3 independent populations. Moreover, the expression of BPIFB4 is instrumental to maintenance of cellular and vascular homeostasis through regulation of protein synthesis. BPIFB4 phosphorylation/activation by protein-kinase-R-like endoplasmic reticulum kinase induces its complexing with 14-3-3 and heat shock protein 90, which is facilitated by the longevity-associated variant. In isolated vessels, BPIFB4 is upregulated by mechanical stress, and its knock-down inhibits endothelium-dependent vasorelaxation. In hypertensive rats and old mice, gene transfer of longevity-associated variant-BPIFB4 restores endothelial nitric oxide synthase signaling, rescues endothelial dysfunction, and reduces blood pressure levels. Furthermore, BPIFB4 is implicated in vascular repair. BPIFB4 is abundantly expressed in circulating CD34(+) cells of long living individuals, and its knock-down in endothelial progenitor cells precludes their capacity to migrate toward the chemoattractant SDF-1. In a murine model of peripheral ischemia, systemic gene therapy with longevity-associated variant-BPIFB4 promotes the recruitment of hematopoietic stem cells, reparative vascularization, and reperfusion of the ischemic muscle. CONCLUSIONS: Longevity-associated variant BPIFB4 may represent a novel therapeutic tool to fight endothelial dysfunction and promote vascular reparative processes. PMID- 26034046 TI - Pinpointing the sources of the Asian mortality advantage in the USA. AB - BACKGROUND: Asian-Americans outlive whites by an average of nearly 8 years. By determining the sources of the Asian mortality advantage, we can pinpoint where there is the greatest potential for raising the life expectancy of whites and other groups in the USA. METHODS: Our analyses include all Asian and white deaths in the USA between 2006 and 2010, from the Center for Disease Control. Using the International Classification of Diseases (V.10), we code causes of deaths into 19 categories, based on the most common causes as well as causes particularly relevant to racial differences. We then create life tables and apply a newly developed demographic method to determine whether Asians have longer life expectancy because they are less likely than whites to die of causes of death that strike at younger ages, or because they tend to outlive whites regardless of cause of death. RESULTS: Nearly 90% of the Asian-white life expectancy gap is attributable to the fact that Asians tend to outlive whites regardless of the cause of death. The causes that contribute the most to the gap are heart disease (24%) and cancers (18%). Men contribute somewhat more to the gap than women do (55% vs 45%), primarily because Asian-white differences in mortality are greater among men than among women with respect to suicide, traffic accidents and accidental poisoning. CONCLUSIONS: For almost all causes of death, Asian victims tend to be older than white victims. The greatest potential for raising the life expectancy of whites to that of Asians, then, resides in efforts that effectively increase whites' average age at death for the most common causes of death. PMID- 26034047 TI - Factors associated with pregnancy among adolescents in low-income and lower middle-income countries: a systematic review. AB - BACKGROUND: Pregnancy-related morbidity and mortality is much more prevalent among adolescents than adults. Adolescent pregnancy is therefore a significant public health problem. Most births to adolescents (95%) occur in resource constrained countries. OBJECTIVE: The aim was to review the available evidence about the factors associated with adolescent pregnancy in low-income and lower middle-income countries. METHODS: The review used the PRISMA procedure of identification, screening and eligibility of publications. PubMed, OVID MEDLINE, SCOPUS and CINAHL plus were searched systematically for peer-reviewed English language papers published before December 2013. FINDINGS: In total, 2005 articles were identified and 12 met the inclusion criteria and were reviewed. Despite varied methods, there was substantial consistency in the findings. Limited education, low socioeconomic position, insufficient access to and non-use of contraception were consistently found to be risks for pregnancy among adolescents. There was some evidence that early marriage, living in a rural area, early sexual initiation, belonging to an ethnic and religious minority group also increased the risk of adolescent pregnancy. Higher education, access to income generating work and family support were found to protect against adolescent pregnancy. CONCLUSIONS: In resource-constrained countries, as in well-resourced countries, low socioeconomic position appears to increase the risk of pregnancy among adolescents. Additional risks specific to these contexts include cultural traditions such as early marriage and inaccurate beliefs about contraception. It is unlikely that strategies to reduce pregnancy among women aged less than 20 years will be effective unless these are addressed directly. PMID- 26034048 TI - Increasing active travel: results of a quasi-experimental study of an intervention to encourage walking and cycling. AB - BACKGROUND: There is increased interest in the effectiveness and co-benefits of measures to promote walking and cycling, including health gains from increased physical activity and reductions in fossil fuel use and vehicle emissions. This paper analyses the changes in walking and cycling in two New Zealand cities that accompanied public investment in infrastructure married with programmes to encourage active travel. METHOD: Using a quasi-experimental two-group pre-post study design, we estimated changes in travel behaviour from baseline in 2011 to mid-programme in 2012, and postprogramme in 2013. The intervention and control cities were matched in terms of sociodemographic variables and baseline levels of walking and cycling. A face-to-face survey obtained information on walking and cycling. We also drew from the New Zealand Travel Survey, a national ongoing survey of travel behaviour, which was conducted in the study areas. Estimates from the two surveys were combined using meta-analysis techniques. RESULTS: The trips and physical activity were evaluated. Relative to the control cities, the odds of trips being by active modes (walking or cycling) increased by 37% (95% CI 8% to 73%) in the intervention cities between baseline and postintervention. The net proportion of trips made by active modes increased by about 30%. In terms of physical activity levels, there was little evidence of an overall change. DISCUSSION: Comparing the intervention cities with the matched controls, we found substantial changes in walking and cycling, and conclude that the improvements in infrastructure and associated programmes appear to have successfully arrested the general decline in active mode use evident in recent years. PMID- 26034049 TI - Putative linkages between below- and aboveground mutualisms during alien plant invasions. AB - Evidence of the fundamental role of below-aboveground links in controlling ecosystem processes is mostly based on studies done with soil herbivores or mutualists and aboveground herbivores. Much less is known about the links between belowground and aboveground mutualisms, which have been studied separately for decades. It has not been until recently that these mutualisms-mycorrhizas and legume-rhizobia on one hand, and pollinators and seed dispersers on the other hand-have been found to influence each other, with potential ecological and evolutionary consequences. Here we review the mechanisms that may link these two level mutualisms, mostly reported for native plant species, and make predictions about their relevance during alien plant invasions. We propose that alien plants establishing effective mutualisms with belowground microbes might improve their reproductive success through positive interactions between those mutualists and pollinators and seed dispersers. On the other hand, changes in the abundance and diversity of soil mutualists induced by invasion can also interfere with below aboveground links for native plant species. We conclude that further research on this topic is needed in the field of invasion ecology as it can provide interesting clues on synergistic interactions and invasional meltdowns during alien plant invasions. PMID- 26034052 TI - Expanding the Reach of Anti-PD-1 Therapy. AB - Results from three studies, including KEYNOTE-012 and CheckMate 057, indicate that anti-PD-1 drugs look promising in cancers other than melanoma. Pembrolizumab was twice as effective as cetuximab for advanced head and neck squamous cell carcinoma; nivolumab induced durable antitumor activity in advanced liver cancer; and nivolumab extended the median overall survival of patients with advanced non squamous non-small cell lung cancer. PMID- 26034050 TI - Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. AB - Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8(+) T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established "exhausted" CD8(+) T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8(+) T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8(+) TEX cells. These results demonstrate that CD8(+) T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation. PMID- 26034053 TI - Combo Therapy Effective for Relapsed CLL. PMID- 26034055 TI - Pacritinib Bests Available Therapies for Myelofibrosis. PMID- 26034058 TI - Aortic valve and aneurysms. PMID- 26034057 TI - Patients' experience of portacaths in cystic fibrosis: questionnaire-based study. AB - BACKGROUNDS AND AIMS: Portacaths are regularly used in children with cystic fibrosis (CF). We aimed to assess patient satisfaction with lateral chest wall portacaths in children with CF. METHODS: All children in a geographical region with CF and portacath in situ were identified. Site of chest wall placement was identified on X-ray; only children with lateral chest wall portacaths were sent questionnaires. Data collected included preoperative information, cosmesis and interference with activities. RESULTS: Of the 46 patients identified, 42 had lateral chest wall ports. 25 of this 42(60%) submitted their questionnaires. 22(88%) were happy with preoperative information although only 8(32%) recall being offered choice of position. 23(92%) were satisfied with cosmesis. 2 patients reported problems with physiotherapy only with indwelling needles. 6(24%) patients had problems with clothing, 7(32%) with sports and 3(12%) with seatbelts. CONCLUSIONS: Lateral chest wall portacaths are cosmetically acceptable. Impact on daily activities is less common than that reported with anterior chest wall placement. PMID- 26034059 TI - The National Cardiac Societies of the European Society of Cardiology. AB - The National Cardiac Societies are one of the Constituent Bodies of the European Society of Cardiology (ESC). They are the backbone of the ESC and together form the "Cardiology of Europe" in 56 European and Mediterranean countries. PMID- 26034056 TI - A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences. AB - A genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 * 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 * 10(-23)) and SLC22A3 (P = 3.2 * 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 * 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P < 1.0 * 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004). SIGNIFICANCE: Taken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations. PMID- 26034060 TI - Combined endobronchial and esophageal endosonography for the diagnosis and staging of lung cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). AB - This is an official guideline of the European Society of Gastrointestinal Endoscopy (ESGE), produced in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). It addresses the benefit and burden associated with combined endobronchial and esophageal mediastinal nodal staging of lung cancer. The Scottish Intercollegiate Guidelines Network (SIGN) approach was adopted to define the strength of recommendations and the quality of evidence.The article has been co-published with permission in Endoscopy and the European Respiratory Journal. PMID- 26034061 TI - Ambra1 at a glance. AB - The activating molecule in Beclin-1-regulated autophagy (Ambra1), also known as autophagy/Beclin-1 regulator 1, is a highly intrinsically disordered and vertebrate-conserved adapter protein that is part of the autophagy signaling network. It acts in an early step of mammalian target of rapamycin complex 1 (mTORC1)-dependent autophagy by favouring formation of the autophagosome core complex. However, recent studies have revealed that Ambra1 can also coordinate a cell response upon starvation or other stresses that involve translocation of the autophagosome core complex to the endoplasmic reticulum (ER), regulative ubiquitylation and stabilization of the kinase ULK1, selective mitochondria removal and cell cycle downregulation. Moreover, Ambra1 itself appears to be targeted by a number of regulatory processes, such as cullin-dependent degradation, caspase cleavage and several modifications, ranging from phosphorylation to ubiquitylation. Altogether, this complex network of regulation highlights the importance of Ambra1 in crucial physiological events, including metabolism, cell death and cell division. In addition, Ambra1 is an important regulator of embryonic development, and its mutation or inactivation has been shown to correlate with several pathologies of the nervous system and to be involved in carcinogenesis. In this Cell Science at a Glance article and the accompanying poster, we discuss recent advances in the Ambra1 field, particularly the role of this pro-autophagic protein in cellular pathophysiology. PMID- 26034062 TI - Characterization and regulation of an additional actin-filament-binding site in large isoforms of the stereocilia actin-bundling protein espin. PMID- 26034063 TI - Mango: a bias-correcting ChIA-PET analysis pipeline. AB - MOTIVATION: Chromatin Interaction Analysis by Paired-End Tag sequencing (ChIA PET) is an established method for detecting genome-wide looping interactions at high resolution. Current ChIA-PET analysis software packages either fail to correct for non-specific interactions due to genomic proximity or only address a fraction of the steps required for data processing. We present Mango, a complete ChIA-PET data analysis pipeline that provides statistical confidence estimates for interactions and corrects for major sources of bias including differential peak enrichment and genomic proximity. RESULTS: Comparison to the existing software packages, ChIA-PET Tool and ChiaSig revealed that Mango interactions exhibit much better agreement with high-resolution Hi-C data. Importantly, Mango executes all steps required for processing ChIA-PET datasets, whereas ChiaSig only completes 20% of the required steps. Application of Mango to multiple available ChIA-PET datasets permitted the independent rediscovery of known trends in chromatin loops including enrichment of CTCF, RAD21, SMC3 and ZNF143 at the anchor regions of interactions and strong bias for convergent CTCF motifs. AVAILABILITY AND IMPLEMENTATION: Mango is open source and distributed through github at https://github.com/dphansti/mango. CONTACT: mpsnyder@standford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26034064 TI - FourCSeq: analysis of 4C sequencing data. AB - MOTIVATION: Circularized Chromosome Conformation Capture (4C) is a powerful technique for studying the spatial interactions of a specific genomic region called the 'viewpoint' with the rest of the genome, both in a single condition or comparing different experimental conditions or cell types. Observed ligation frequencies typically show a strong, regular dependence on genomic distance from the viewpoint, on top of which specific interaction peaks are superimposed. Here, we address the computational task to find these specific peaks and to detect changes between different biological conditions. RESULTS: We model the overall trend of decreasing interaction frequency with genomic distance by fitting a smooth monotonically decreasing function to suitably transformed count data. Based on the fit, z-scores are calculated from the residuals, and high z-scores are interpreted as peaks providing evidence for specific interactions. To compare different conditions, we normalize fragment counts between samples, and call for differential contact frequencies using the statistical method DESEQ2: adapted from RNA-Seq analysis. AVAILABILITY AND IMPLEMENTATION: A full end-to-end analysis pipeline is implemented in the R package FourCSeq available at www.bioconductor.org. CONTACT: felix.klein@embl.de or whuber@embl.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26034065 TI - Association of soft drink consumption with increased waist circumference should be adjusted for body mass index. PMID- 26034066 TI - Erratum for Vadiveloo et al. Greater healthful food variety as measured by the US Healthy Food Diversity Index is associated with lower odds of metabolic syndrome and its components in US adults. J Nutr 2015;145:564-71. PMID- 26034067 TI - Erratum for Hector et al. Whey protein supplementation preserves postprandial myofibrillar protein synthesis during short-term energy restriction in overweight and obese adults. J Nutr 2015;145:246-52. PMID- 26034069 TI - The small GTPase Rab8 interacts with VAMP-3 to regulate the delivery of recycling T-cell receptors to the immune synapse. AB - IFT20, a component of the intraflagellar transport (IFT) system that controls ciliogenesis, regulates immune synapse assembly in the non-ciliated T-cell by promoting T-cell receptor (TCR) recycling. Here, we have addressed the role of Rab8 (for which there are two isoforms Rab8a and Rab8b), a small GTPase implicated in ciliogenesis, in TCR traffic to the immune synapse. We show that Rab8, which colocalizes with IFT20 in Rab11(+) endosomes, is required for TCR recycling. Interestingly, as opposed to in IFT20-deficient T-cells, TCR(+) endosomes polarized normally beneath the immune synapse membrane in the presence of dominant-negative Rab8, but were unable to undergo the final docking or fusion step. This could be accounted for by the inability of the vesicular (v)-SNARE VAMP-3 to cluster at the immune synapse in the absence of functional Rab8, which is responsible for its recruitment. Of note, and similar to in T-cells, VAMP-3 interacts with Rab8 at the base of the cilium in NIH-3T3 cells, where it regulates ciliary growth and targeting of the protein smoothened. The results identify Rab8 as a new player in vesicular traffic to the immune synapse and provide insight into the pathways co-opted by different cell types for immune synapse assembly and ciliogenesis. PMID- 26034070 TI - Apoptotic-cell-derived membrane microparticles and IFN-alpha induce an inflammatory immune response. AB - A dysregulation in the clearance of apoptotic material is considered a major pathogenetic factor for the emergence of autoimmune diseases. Apoptotic-cell derived membrane microparticles (AdMPs), which are released from the cell surface during apoptosis, have been implicated in the pathogenesis of autoimmunity. Also of importance are cytokines, such as interferon-alpha (IFN-alpha), which is known to be a major player in patients with systemic lupus erythematosus (SLE). This study investigates the combined effect of AdMPs and IFN-alpha on professional phagocytes. In the presence of IFN-alpha, phagocytosis of AdMPs by human monocytes was significantly increased in a dose-dependent manner. The combination of AdMPs and raised IFN-alpha concentrations resulted in an increase in the secretion of pro-inflammatory cytokines and an upregulation of surface molecule expression involved in antigen uptake. In addition, macrophage polarisation was shifted towards a more inflammatory type of cell. The synergism between IFN-alpha and AdMPs seemed to be mediated by an upregulation of phosphorylated STAT1. Our results indicate that IFN-alpha, together with AdMPs, amplify the initiation and maintenance of inflammation. This mechanism might especially play a crucial role in disorders with a defective clearance of apoptotic material. PMID- 26034071 TI - Hippocampal spine changes across the sleep-wake cycle: corticosterone and kinases. AB - The corticosterone (CORT) level changes along the circadian rhythm. Hippocampus is sensitive to CORT, since glucocorticoid receptors are highly expressed. In rat hippocampus fixed in a living state every 3 h, we found that the dendritic spine density of CA1 pyramidal neurons increased upon waking (within 3 h), as compared with the spine density in the sleep state. Particularly, the large-head spines increased. The observed change in the spine density may be due to the change in the hippocampal CORT level, since the CORT level at awake state (~30 nM) in cerebrospinal fluid was higher than that at sleep state (~3 nM), as observed from our earlier study. In adrenalectomized (ADX) rats, such a wake-induced increase of the spine density disappeared. S.c. administration of CORT into ADX rats rescued the decreased spine density. By using isolated hippocampal slices, we found that the application of 30 nM CORT increased the spine density within 1 h and that the spine increase was mediated via PKA, PKC, ERK MAPK, and LIMK signaling pathways. These findings suggest that the moderately rapid increase of the spine density on waking might mainly be caused by the CORT-driven kinase networks. PMID- 26034072 TI - MECHANISMS IN ENDOCRINOLOGY: Metabolic syndrome through the female life cycle. AB - The normal function of the female reproductive system is closely linked to energy homeostasis with the ultimate scope of fertility and human race perpetuation through the centuries. During a woman's lifetime there are normal events such as puberty, pregnancy and menopause which are related to alterations in energy homeostasis and gonadal steroids levels followed by increase of body fat and insulin resistance, important components of metabolic syndrome (MetS). Pathological conditions such as premature adrenarche, polycystic ovary syndrome and gestational diabetes also present with shifts in gonadal steroid levels and reduced insulin sensitivity. The aim of this review is to discuss these conditions, both normal and pathological, analyzing the changes or abnormalities in ovarian function that coexist with metabolic abnormalities which resemble MetS in relationship with environmental, genetic and epigenetic factors. PMID- 26034073 TI - GH signaling in human adipose and muscle tissue during 'feast and famine': amplification of exercise stimulation following fasting compared to glucose administration. AB - OBJECTIVE: Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original 'feast and famine hypothesis' by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression. DESIGN AND METHODS: Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion ('feast') and ii) after a 36 h fast ('famine'). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise. RESULTS: GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days. CONCLUSIONS: This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the 'feast and famine hypothesis'; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization. PMID- 26034074 TI - STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability. AB - CONTEXT AND OBJECTIVE: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. METHODS: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. RESULTS: Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrier relatives (P = 0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P = 0.028) and IGFBP3 (P = 0.02) than their non-carrier relatives. The 17 heterozygous first degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of -1.4 +/- 0.8 when compared with population-matched controls (P < 0.001). CONCLUSIONS: STAT5B mutations in the heterozygous state have a significant negative impact on height (~ 3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability. PMID- 26034075 TI - Elevated heart rate predicts beta cell function in non-diabetic individuals: the RISC cohort. AB - CONTEXT: Elevated heart rate has been associated with insulin resistance and incident type 2 diabetes but its relationship with beta-cell function is not known. Our aim was to investigate whether baseline heart rate is associated with beta-cell function and hyperglycaemia. METHODS: We used the prospective RISC cohort with 1005 non-diabetic individuals who had an oral glucose tolerance test (OGTT) at baseline and after 3 years. Impaired glucose regulation was defined as a fasting plasma glucose >= 6.1 mmol/l or a 2-h plasma glucose >= 7.8 mmol/l. Insulin sensitivity was assessed by the OGIS index and insulin secretion and beta cell glucose sensitivity at both baseline and 3 years. RESULTS: Baseline heart rate was positively related to both fasting (P < 0.0001) and 2 h glucose levels (P = 0.02) at year 3 and predicted the presence of impaired glucose regulation at year 3 in a logistic regression model adjusting for insulin sensitivity at inclusion (OR/10 beats per min: 1.31; 95% CI (1.07-1.61); P = 0.01). Baseline heart rate was associated with lower insulin sensitivity (beta = -0.11; P < .0001), a decrease in both beta-cell glucose sensitivity (beta = -0.11; P = 0.003) and basal insulin secretion rate (beta = -0.11; P = 0.002) at 3 years in an adjusted multivariable regression model. Baseline heart rate predicted the 3 year decrease in beta-cell glucose sensitivity (beta = -0.10; P = 0.007) and basal insulin secretion (beta = -0.12; P = 0.007). CONCLUSIONS: Heart rate predicts beta-cell function and impaired glucose regulation at 3 years in non diabetic individuals, independently of the level of insulin sensitivity. These findings suggest a possible effect of the sympathetic nervous system on beta-cell dysfunction, which deserves further investigation. PMID- 26034076 TI - Elevated level of serum carbohydrate antigen 19.9 as predictor of mortality in patients with advanced medullary thyroid cancer. AB - BACKGROUND: Medullary thyroid cancer (MTC) is capable of secreting several proteins, such as calcitonin (Ct), carcinoembryonic antigen (CEA), chromogranin and others. Recently, we observed an aggressive MTC with high levels of serum carbohydrate antigen 19.9 (Ca 19.9) and a rapid evolution to death. OBJECTIVE: The aim of this study was to evaluate whether high levels of serum Ca 19.9 could be a prognostic factor of death in patients with advanced MTC. PATIENTS AND METHODS: We measured Ca 19.9, CEA and Ct in 100 advanced structural recurrent/persistent MTC patients and in 100 cured or biochemically affected MTC patients. Clinical and pathological data were also collected. RESULTS: Sixteen percent of the patients with advanced MTC had high levels of Ca 19.9. The group with abnormal Ca 19.9 levels had significantly higher levels of CEA and Ct compared with the group with normal values of Ca 19.9 (P<0.0001 for both Ct and CEA). At variance, all 100 patients in the MTC control group showed normal levels of Ca 19.9. Moreover, among the advanced cases, the Ca 19.9-positive group showed a higher mortality rate than the group with normal levels. A logistic regression analysis demonstrated that an elevated level of Ca 19.9 is a predictor of mortality (OR=3.78, P=0.04), independent from Ct doubling time. CONCLUSIONS: These results demonstrated that an elevated value of serum Ca 19.9 appears to be a predictive factor of poor prognosis in advanced MTC patients and identifies those cases with a higher risk of mortality in the short term. PMID- 26034077 TI - Use of statins is associated with lower serum total and non-sex hormone-binding globulin-bound testosterone levels in male participants of the Rotterdam Study. AB - OBJECTIVE: Statins, or HMG-CoA reductase inhibitors, decrease cholesterol production. Because cholesterol is a precursor of the testosterone biosynthesis pathway, there is some concern that statins might lower serum testosterone levels. The objective of the present study was to investigate the association between the use of statins and serum testosterone levels in men. DESIGN: Cross sectional study within the prospective population-based Rotterdam Study. SUBJECTS AND METHODS: We included 4166 men with available data on total testosterone, non sex hormone-binding globulin (SHBG)-bound testosterone, and medication use. Multivariable linear regression analysis was used to compare the differences in serum testosterone levels (nmol/l) between current, past, and never statin users. We considered dose and duration of use. Analyses were adjusted for age, BMI, cardiovascular disease, diabetes mellitus, hypertension, and estradiol levels. RESULTS: We identified 577 current (mean age 64.1 years), 148 past (mean age 64.6 years), and 3441 never (mean age 64.6 years) statin users. Adjusted for all covariables, current statin use of 1-<= 6 months or >6 months was significantly associated with lower total testosterone levels as compared to non-users (beta 1.24, 95% CI -2.17, -0.31, and beta -1.14, 95% CI -2.07, -0.20 respectively). Current use of 1-<= 6 months was also associated with significantly lower non SHBG-bound testosterone levels (beta -0.42, 95% CI -0.82, -0.02). There was a trend toward lower testosterone levels at higher statin doses both for total (P(trend) 2.9 * 10(-5)) and non-SHBG-bound (P(trend) 2.0 * 10(-4)) testosterone. No association between past statin use and testosterone levels was found. CONCLUSION: We showed that current use of statins was associated with significantly lower serum total and non-SHBG-bound testosterone levels. The clinical relevance of this association should be further investigated. PMID- 26034078 TI - Proteomic surveillance of putative new autoantigens in thyroid orbitopathy. AB - AIMS: Thyroid orbitopathy (TO) is an autoimmune inflammatory disorder characterised by several ocular manifestations. Several autoantigens have been proposed to be involved in the pathogenesis of TO, but the autoantigen system and the mechanism of TO would be rather complex. In this study, an immunoproteomic method was used to survey novel autoantigens expressed in the orbital fat tissue of patients with TO. METHODS: We used immunoproteomic, ELISA and immunohistochemical staining methods to survey novel autoantigens expressed in the orbital fat tissue of patients with TO. RESULTS: Six protein spots showing high reactivity with the serum from the patients with TO were detected as candidate orbital autoantigens, and two of them (carbonic anhydrase 1 (CA1) and alcohol dehydrogenase 1B (ADH1B)) were further verified by ELISA and immunohistochemical staining. We found that CA1 and ADH1B could attribute target autoantigens in this autoimmune disease. We discovered anti-CA1 and anti-ADH1B antibody prevalence to be higher in patients with TO (68.57%/51.43%) or Graves' disease (GD) (72%/48%) than in healthy controls respectively. Immunohistochemical staining study revealed the significantly enhanced expressions of CA1 and ADH1B in orbital fat of TO compared with that in healthy controls. CONCLUSIONS: We found that CA1 and ADH1B could attribute target autoantigens in this autoimmune disease. The high prevalence of these autoantibodies against CA1 and ADH1B in patients with TO and GD clarifies the potential clinical role for anti-CA1 and anti-ADH1B antibodies as biomarkers for GD and TO. PMID- 26034079 TI - The Boston Keratoprosthesis type 1 as primary penetrating corneal procedure. AB - BACKGROUND/AIMS: Penetrating keratoplasty (PK) has a poor prognosis in certain corneal eye diseases. The safety and efficacy of Boston type 1 Keratoprosthesis (KPro) surgery as a primary penetrating corneal surgery were evaluated for patients with corneal blindness and poor prognosis for PK. METHODS: In this retrospective interventional comparative study, all patients who underwent KPro implantation by a single surgeon between October 2008 and March 2011 at the Centre Hospitalier de l'Universite de Montreal were divided into two groups. Thirty patients with KPro as a primary procedure (group 1) were compared with 40 patients who had PK prior to KPro (group 2). A chart review examining preoperative and postoperative best-corrected visual acuity (BCVA), intraoperative and postoperative complications and KPro retention rate over the first postoperative year was performed. RESULTS: Preoperative BCVA was 20/200 or better in 10% of eyes in group 1 (range 20/150 light perception (LP)), and in 5% of eyes in group 2 (range 20/100 LP; p=0.42). BCVA was significantly better in group 1 throughout the follow-up (p<0.05). At 12 months, 87% and 63% of eyes achieved a BCVA better than 20/200 in groups 1 and 2, respectively (p<0.05). The complication rates and retention rate were similar in the two groups. CONCLUSIONS: This study demonstrates that the Boston KPro implantation may be successful as a primary procedure in patients at high risk of failure with traditional PK. Further, there appears to be a visual benefit to primary KPro surgery. PMID- 26034080 TI - Long-term outcomes and complications of Moscow Eye Microsurgery Complex in Russia (MICOF) keratoprosthesis following ocular surface burns: clinical experience in China. AB - OBJECTIVE: The aim of this study was to evaluate the clinical outcomes of the implantation of MICOF keratoprosthesis (Kpro) in patients with alkaline, acid and thermal ocular burns. METHODS: This is a retrospective, non-competitive, interventional case series. Ninety eyes of 90 patients with ocular burns underwent MICOF KPro surgery at the Chinese People's Liberation Army General Hospital between April 2000 and December 2012. Preoperative and postoperative findings were recorded. Retention of the prostheses and the treatment for postoperative complications were investigated. RESULTS: The mean age of patients was 40.26+/-12.18 years (range: 8-64 years), and the mean duration after ocular trauma was 4.8+/-6.2 years (range: 1.5-12 years). The mean follow-up period was 58.22+/-36.28 months (range: 1-145 months). Eighty patients were followed for >=1 year and 73 eyes (81.11%) achieved the best-corrected visual acuity of 20/200 or better and 39 eyes (43.33%) achieved best-corrected visual acuity of >=20/40. The common complications were glaucoma, corneal melt and conjunctiva overgrowth, and the incidences of these complications were 59.99%, 40% and 31.11%, respectively. One patient experienced KPro extrusion, and two patients exhibited leakage from the area of the implant. Seven with endophthalmitis eyes had final visual acuities of light perception. There was no significant difference in the effectiveness of the implants among the different causes of injuries, including acid, alkali and thermal burns. CONCLUSIONS: MICOF Kpro is an effective alternative for patients with ocular burn with corneal blindness. Glaucoma and endophthalmitis were identified as significant risk factors for visual loss. PMID- 26034082 TI - Are at least 12 months of dual antiplatelet therapy needed for all patients with drug-eluting stents? All patients with drug-eluting stents need at least 12 months of dual antiplatelet therapy. PMID- 26034081 TI - Characterization of CM572, a Selective Irreversible Partial Agonist of the Sigma 2 Receptor with Antitumor Activity. AB - The sigma-2 receptors are promising therapeutic targets because of their significant upregulation in tumor cells compared with normal tissue. Here, we characterize CM572 [3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)-6 isothiocyanatobenzo[d]oxazol-2(3H)-one] (sigma-1 Ki >= 10 uM, sigma-2 Ki = 14.6 +/- 6.9 nM), a novel isothiocyanate derivative of the putative sigma-2 antagonist, SN79 [6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1 yl)butyl)benzo[d]oxazol-2(3H)-one]. CM572 bound irreversibly to sigma-2 receptors by virtue of the isothiocyanate moiety but not to sigma-1. Studies in human SK-N SH neuroblastoma cells revealed that CM572 induced an immediate dose-dependent increase in cytosolic calcium concentration. A 24-hour treatment of SK-N-SH cells with CM572 induced dose-dependent cell death, with an EC50 = 7.6 +/- 1.7 uM. This effect was sustained over 24 hours even after a 60-minute pretreatment with CM572, followed by extensive washing to remove ligand, indicating an irreversible effect consistent with the irreversible binding data. Western blot analysis revealed that CM572 also induced cleavage activation of proapoptotic BH3 interacting domain death agonist. These data suggest irreversible agonist-like activity. Low concentrations of CM572 that were minimally effective were able to attenuate significantly the calcium signal and cell death induced by the sigma-2 agonist CB-64D [(+)-1R,5R-(E)-8-benzylidene-5-(3-hydroxyphenyl)-2-methylmorphan-7 one]. CM572 was also cytotoxic against PANC-1 pancreatic and MCF-7 breast cancer cell lines. The cytotoxic activity of CM572 was selective for cancer cells over normal cells, being much less potent against primary human melanocytes and human mammary epithelial cells. Taken together, these data show that CM572 is a selective, irreversible sigma-2 receptor partial agonist. This novel irreversible ligand may further our understanding of the endogenous role of this receptor, in addition to having potential use in targeted cancer diagnosis and therapy. PMID- 26034083 TI - Are at least 12 months of dual antiplatelet therapy needed for all patients with drug-eluting stents? Not all patients with drug-eluting stents need at least 12 months of dual antiplatelet therapy. PMID- 26034084 TI - ECG Response: June 2, 2015. PMID- 26034085 TI - Mesenteric massive gas caused by an infected abdominal aortic aneurysm. PMID- 26034086 TI - Pulmonary artery dissection caused by extension of a chronic type a aortic dissection through a patent ductus arteriosus. PMID- 26034087 TI - A rare case with pulmonary and cardiac inflammatory myofibroblastic tumor. PMID- 26034088 TI - Letter by Kain regarding article, "Vitamin D promotes vascular regeneration". PMID- 26034089 TI - Response to letter regarding article, "Vitamin D promotes vascular regeneration". PMID- 26034090 TI - Letter by Longtin et al regarding article, "Rates of and factors associated with infection in 200 909 Medicare implantable cardioverter-defibrillator implants: results from the National Cardiovascular Data Registry". PMID- 26034091 TI - Response to letter regarding article, "Rates of and factors associated with infection in 200 909 Medicare implantable cardioverter-defibrillator implants: results from the National Cardiovascular Data Registry". PMID- 26034092 TI - Added value of pulmonary venous flow Doppler assessment in patients with preserved ejection fraction and its contribution to the diastolic grading paradigm. AB - AIMS: To evaluate the prognostic role of pulmonary venous flow parameters and their role in patients with preserved ejection fraction (EF). METHODS AND RESULTS: Pulmonary venous flow parameters were measured in 365 patients in sinus rhythm, without significant mitral disease, and EF >50% (age 64.9 +/- 19; 52% female) by a single sonographer. Survival, time to re-admission for heart failure, and to a combined cardiac end point (cardiac death, heart failure, and atrial fibrillation) were retrospectively analysed and correlated to echo parameters. Systolic (S) and diastolic (D) pulmonary vein flow were obtainable in 73% of patients and Ar in 65%. The lower peak S/D ratio and higher DeltaAr-A time were associated with higher rate of heart failure readmission (P = 0.03 for both). The S/D integral ratio was the best pulmonary vein flow predictor of heart failure readmissions (P = 0.0009), better than the peak S/D ratio, or DeltaA-Ar time (P < 0.01 for both), and independently predicted worse outcome even when adjusted for diastolic grading (using recent guidelines), left ventricle mass index, E/e', and left atrial volume index (P < 0.05 for all). The addition S/D ratio to diastolic grading recognized patients with pseudo-normal filling pattern and S/D ratio >1 with similar clinical outcomes to grade I (P > 0.5), but worse clinical outcomes than in the pseudo-normal patients with lower S/D ratio (P < 0.01). CONCLUSIONS: PVFP are obtainable in most patients, add prognostic information on top of routine diastolic parameters, and define an early stage of diastolic dysfunction resembling the pseudo-normal pattern in which S/D ratio is >1, and outcome is excellent. PMID- 26034093 TI - Serial changes in longitudinal graft function and implications of acute cellular graft rejections during the first year after heart transplantation. AB - AIMS: The aim of this prospective study was to use left ventricular global longitudinal strain (LV-GLS) as a non-invasive tool for the monitoring of graft function in relation to acute cellular rejection (ACR) during the first year after heart transplantation (HTX). METHODS AND RESULTS: The study population consisted of 36 patients undergoing HTX from November 2010 until October 2013. Patients were followed by comprehensive echocardiography and biopsies at 2 weeks and 1, 3, 6, and 12 months after HTX. ACRs were classified based on the ISHLT classification (0R-3R). Patients were divided into two groups according to the presence of one or more episodes of biopsy proven >=grade 2R ACR during follow up. We found that LV-GLS and tricuspid annular plane systolic excursion (TAPSE) were significantly related to ACR burden in a linear regression model. The absolute difference in LV-GLS between patients in the ACR group (-14.4%) and patients in the ACR-free group (-16.8%) was -2.4% (P < 0.01) 12 months after HTX. In the ACR group, patients' LV-GLS did not improve between 1 and 12 months, whereas an improvement of -2.9% was seen in the ACR-free group in this period (P < 0.01). The two groups appeared not to differ in terms of diastolic Doppler parameters or LV ejection fraction, but TAPSE was 15.3 +/- 2.8 mm in the ACR-free group vs. 13.2 +/- 2.1 mm ACR group, P < 0.05, 12 months after HTX. CONCLUSION: Gradual improvement of longitudinal LV and RV function was seen within the first year after HTX, but the degree of recovery was strongly influenced by ACR episodes. PMID- 26034094 TI - Apical traction: a novel visual echocardiographic parameter to predict survival in patients with pulmonary hypertension. AB - AIMS: In some pulmonary hypertension (PH) patients, we noted a motion pattern where the right ventricular (RV) apex is pulled towards to left ventricle (LV) during systole, caused by traction from the LV ('apical traction', AT). Herein, we characterize patients with AT to investigate its prognostic significance. METHODS AND RESULTS: Echocardiograms of 62 pre-capillary PH patients (42 females, age 61 +/- 15 years) were retrospectively analysed. The presence of AT was assessed visually and confirmed by speckle-tracking analysis. Fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), RV free-wall longitudinal strain (LS) as well as LV function were measured. A primary end point of death or heart/lung transplantation was set. AT was observed in 31 patients. They had worse functional capacity, lower TAPSE (1.3 +/- 0.2 vs. 1.9 +/ 0.4, P <= 0.001) and FAC (20.3 +/- 6.1 vs. 33 +/- 7.1%, P <= 0.001), worse RV free-wall LS (-12.4 +/- 3.4 vs. -20.8 +/- 4.9%, P < 0.001), and higher systolic pulmonary arterial pressure (92 +/- 15 vs. 75 +/- 23, P < 0.001). LV function was similar in both groups. The primary end point occurred in 16 patients with and 8 without AT. AT was an independent predictor of the outcome (HR: 14.826, 95% CI: 1.696-129.642, P = 0.015). CONCLUSION: AT occurs in RVs with impaired systolic function in PH patients. It may serve as a new, easily to assess visual parameter to predict the outcome in these patients. Its prognostic importance needs to be validated by prospective studies. PMID- 26034095 TI - Usefulness of contrast-enhanced transoesophageal echocardiography to guide thoracic endovascular aortic repair procedure. AB - AIMS: Thoracic endovascular aortic repair (TEVAR) is commonly considered as a valid alternative to surgery. Endoleaks occurrence is one of the principal limitations of TEVAR. Transoesophageal echocardiography (TEE) is often adopted in adjunct to fluoroscopy and angiography (ANGIO) during stent-graft implantation. In the present study, we compare intraprocedural ANGIO, TEE, and contrast enhanced TEE (cTEE), and we also evaluate their accuracy in early endoleaks detection and characterization. METHODS AND RESULTS: Fifty-four patients with thoracic aortic disease suitable for TEVAR were prospectively enrolled in the study. After stent placement, the result of the procedure was assessed by ANGIO, TEE, and cTEE. The use of contrast (Sonovue, Bracco) significantly improved TEE quality (P = 0.0001). cTEE was superior in entry tears, false and true lumen and aneurysm thrombosis identification, and microtears and ulcer-like projections detection before stent deployment. After stent deployment, cTEE was more accurate than TEE and ANGIO in the detection of slow flow in the false lumen and in the aneurismal sac (P = 0.0001), and in the remaining flow identification (P = 0.0001). Notably, cTEE is more accurate in the endoleaks detection (P = 0.0001) and in the incomplete stent expansion diagnosis and need for a further balloon inflation (P 0.002), or a further stent implantation (P 0.006), compared with TEE and ANGIO. CONCLUSION: TEVAR procedures are improved by the complimentary use of contrast fluoroscopy, multiplane TEE with Doppler flow interrogation, and cTEE. This triple imaging approach provides additional information in all phases of the procedure improving safety of stent-grafting and the procedural outcomes. PMID- 26034096 TI - Circulating tumor DNA in early-stage breast cancer: personalized biomarkers for occult metastatic disease and risk of relapse? AB - The availability of blood-based markers to predict response of a solid tumor to treatment, estimate patient prognosis and diagnose relapse well before clinical symptoms arise, is a long-standing hope in clinical oncology. Ideally, assays designed to provide such information should be inexpensive (at least in the foreseeable future), simple, and, of course, predictive of the clinical evolution of the disease. While early research focused on circulating glycosylated tumor derived protein biomarkers, the focus is now rapidly shifting to new opportunities, such as circulating tumor cells, extracellular vesicles, micro RNAs and cancer-derived cell-free DNA a.k.a. circulating tumor-derived DNA (ctDNA). PMID- 26034097 TI - Variation, cost, and the quality of care. PMID- 26034099 TI - From tonsils to scopes: 80 years of variation in the practice of otolaryngology. AB - Variation in medicine and surgery is a critical contemporary health policy issue. Recent research demonstrates that variation in Medicare payments to otolaryngologists in a single metropolitan area was attributable to differences in health care resource utilization among physicians and that the hospital with the highest Medicare payments per physician had a higher proportion of office endoscopy-related relative value units than that of other providers, relying less on evaluation and management office visits for revenue. This study is the latest in a line of fascinating case records of variation in otolaryngology and other surgical specialties dating back to the work of J. Alison Glover in 1938. PMID- 26034098 TI - Practice arrangement and medicare physician payment in otolaryngology. AB - OBJECTIVE: Medicare Part B physician payment indicates a cost to Medicare beneficiaries for a physician service and connotes physician clinical productivity. The objective of this study was to determine whether there was an association between practice arrangement and Medicare physician payment. STUDY DESIGN: Cross-sectional study. SETTING: Medicare provider utilization and payment data. SUBJECTS AND METHODS: Otolaryngologists from 1 metropolitan area were included as part of a pilot study. A generalized linear model was used to determine the effect of practice-specific variables including patient volumes on physician payment. RESULTS: Of 67 otolaryngologists included, 23 (34%) provided services through an independent practice, while others were employed by 1 of 3 local academic centers. Median payment was $58,895 per physician for the year, although some physicians received substantially higher payments. Reimbursements to faculty at 1 academic department were higher than to those at other institutions or to independent practitioners. After adjustments were made for patient volumes, physician subspecialty, and gender, payments to each faculty at Hospital C were 2 times higher than to those at Hospital A (relative ratio [RR] 2.03; 95% CI, 1.27-3.27; P = .003); 2 times higher than to faculty at Hospital B (RR 2.04; 95% CI, 1.4-2.7; P = .0001); and 1.6 times higher than to independent practitioners (RR 1.6; 95% CI, 1.04-2.7; P = .03). Payments to physicians in the other groups were not significantly different. Differences in reimbursement corresponded to an emphasis on procedures over office visits but not Medicare case mix adjustments for patient discharges from associated institutions. CONCLUSIONS: Variation in the cost of academic otolaryngology care may be subject in part to institutional factors. PMID- 26034100 TI - Do geographic variations signify overuse? PMID- 26034102 TI - Limitations of the review and meta-analysis of the role of n-3 long-chain PUFA supplementation and cognitive function. PMID- 26034101 TI - Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiation. AB - The transcription factor p63 plays a pivotal role in keratinocyte proliferation and differentiation in the epidermis. However, how p63 regulates epidermal genes during differentiation is not yet clear. Using epigenome profiling of differentiating human primary epidermal keratinocytes, we characterized a catalog of dynamically regulated genes and p63-bound regulatory elements that are relevant for epithelial development and related diseases. p63-bound regulatory elements occur as single or clustered enhancers, and remarkably, only a subset is active as defined by the co-presence of the active enhancer mark histone modification H3K27ac in epidermal keratinocytes. We show that the dynamics of gene expression correlates with the activity of p63-bound enhancers rather than with p63 binding itself. The activity of p63-bound enhancers is likely determined by other transcription factors that cooperate with p63. Our data show that inactive p63-bound enhancers in epidermal keratinocytes may be active during the development of other epithelial-related structures such as limbs and suggest that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates genes through temporal- and spatial-specific active enhancers. PMID- 26034103 TI - Reply to EB Nelson and ME Van Elswyk. PMID- 26034104 TI - The widening BMI distribution in the United States. PMID- 26034105 TI - Reply to M Kivimaki et al. and AB Jenkins and LV Campbell. PMID- 26034106 TI - Variation in genetic susceptibility drives increasing dispersion of population BMI. PMID- 26034107 TI - Achieving a transparent, actionable framework for public-private partnerships for food and nutrition research. AB - Officers and other representatives of more than a dozen food-, nutrition-, and health-related scientific societies and organizations, food industry scientists, and staff of the USDA, the CDC, the Food and Drug Administration, and the NIH convened on 8 December 2014 in Washington, DC, to reach a consensus among individuals participating on guiding principles for the development of research oriented, food- and nutrition-related public-private partnerships. During the daylong working meeting, participants discussed and revised 12 previously published guidelines to ensure integrity in the conduct of food and nutrition research collaborations among public, nonprofit, and private sectors. They agreed to reconvene periodically to reassess the public-private partnership principles. This article presents the guiding principles and potential benefits, outlines key discussion points, and articulates points of agreement and reservation. PMID- 26034110 TI - The ins and outs of erythroid heme transport. PMID- 26034111 TI - Health-related quality of life in patients with multiple myeloma--does it matter? PMID- 26034112 TI - Personalized medicine in lymphoma: is it worthwhile? The mantle cell lymphoma experience. PMID- 26034114 TI - Bcl11b drives the birth of ILC2 innate lymphocytes. PMID- 26034113 TI - T-cell and natural killer cell therapies for hematologic malignancies after hematopoietic stem cell transplantation: enhancing the graft-versus-leukemia effect. AB - Hematopoietic stem cell transplantation has revolutionized the treatment of hematologic malignancies, but infection, graft-versus-host disease and relapse are still important problems. Calcineurin inhibitors, T-cell depletion strategies, and immunomodulators have helped to prevent graft-versus-host disease, but have a negative impact on the graft-versus-leukemia effect. T cells and natural killer cells are both thought to be important in the graft-versus leukemia effect, and both cell types are amenable to ex vivo manipulation and clinical manufacture, making them versatile immunotherapeutics. We provide an overview of these immunotherapeutic strategies following hematopoietic stem cell transplantation, with discussions centered on natural killer and T-cell biology. We discuss the contributions of each cell type to graft-versus-leukemia effects, as well as the current research directions in the field as related to adoptive cell therapy after hematopoietic stem cell transplantation. PMID- 26034115 TI - Pentraxin 3 innately preps damaged tissue for wound healing. PMID- 26034116 TI - Inflammation on the move. PMID- 26034117 TI - Augmenting NF-kappaB in poor-risk CLL: A general paradigm for other cancers? PMID- 26034118 TI - Risk factors, treatment and prognosis in men and women with heart failure with and without diabetes. AB - OBJECTIVE: To test the hypothesis that risk factor pattern, treatment and prognosis differ between men and women with heart failure (HF) with and without diabetes in the Swedish Heart Failure Registry. METHODS: Patients with (n=8809) and without (n=27 465) type 2 diabetes (T2DM) included in the Swedish Heart Failure Registry (2003-2011) were followed for mortality during a median follow up of 1.9 years (range 0-8.7 years). All-cause mortality, differences in background and HF characteristics were analysed in women and men with and without T2DM and with a special regard to different age groups. RESULTS: Of 36 274 patients, 24% had T2DM and 39% were women. In patients with T2DM, women were older than men (78 years vs 73 years), more frequently had hypertension, renal dysfunction and preserved ventricular function. Regardless of T2DM status, women with reduced ventricular function, compared with their male counterparts, were less frequently offered, for example, ACE inhibitors/angiotensin receptor II blockers (ARB). Absolute mortality was 48% in women with T2DM, 40% in women without; corresponding male mortality rates were 43% and 35%, respectively. Kaplan-Meier curves revealed shorter longevity in women with T2DM but female sex did not remain a significant mortality predictor following adjustment (OR 95% CI 0.90; 0.79 to 1.03). In those without T2DM, women compared with men lived longer; this pattern remained after adjustment (OR 0.72; 0.66 to 0.78). T2DM was a stronger predictor of mortality in women (OR 1.72; 1.53 to 1.94) than in men (OR 1.47; 1.34 to 1.61). CONCLUSIONS: T2DM is a strong mortality predictor in men and women with HF, somewhat stronger in women. The shorter survival time in women with T2DM and HF related to comorbidities rather than sex per se. Evidence-based management was less prevalent in women. Mechanisms behind these findings remain incompletely understood and need further attention. PMID- 26034119 TI - Short telomere length is associated with arterial aging in patients with type 2 diabetes mellitus. AB - It is known that glucose disturbances contribute to micro- and macrovascular complications and vascular aging. Telomere length is considered to be a cellular aging biomarker. It is important to determine the telomere length role in vascular structural and functional changes in patients with diabetes mellitus. We conducted a cross-sectional observational study in a high-risk population from Moscow, Russia. The study included 50 patients with diabetes and without clinical cardiovascular disease and 49 control group participants. Glucose metabolism assessment tests, measuring intima-media complex thickness and determining the presence of atherosclerotic plaques, pulse wave velocity measurement, and telomere length measurement were administered to all participants. Vascular changes were more dramatic in patients with diabetes than in the control group, and the telomeres were shorter in patients with diabetes. Significant differences were found in the vascular wall condition among diabetes patients, and there were no substantial differences in the arterial structure between patients with 'long' telomeres; however, there were statistically significant differences in the vascular wall condition between patients with 'short' telomeres. Vascular ageing signs were more prominent in patients with diabetes. However, despite diabetes, vascular changes in patients with long telomeres were very modest and were similar to the vascular walls in healthy individuals. Thus, long lymphocyte telomeres may have a protective effect on the vascular wall and may prevent vascular wall deterioration caused by glucose metabolism disorders. PMID- 26034120 TI - Rising trend in vitamin D status from 1993 to 2013: dual concerns for the future. AB - BACKGROUND: The Institute of Medicine 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D specified higher intakes for all age groups compared to the 1997 report, but also cautioned against spurious claims about an epidemic of vitamin D deficiency and against advocates of higher intake requirements. Over 40 years, we have noted marked improvement in vitamin D status but we are concerned about hypervitaminosis D. OBJECTIVE: We sought to evaluate the 25-hydroxyvitamin D (25OHD) trend over 20 years. DESIGN: We retrieved all results of serum 25OHD from 1993 to 2013 (n=69 012) that was trimmed to one sample per person (n=43 782). We conducted a time series analysis of the monthly averages for 25OHD using a simple sequence chart and a running median smoothing function. We modelled the data using univariate auto-regressive integrated moving average (ARIMA) and forecast 25OHD levels up to 2016. RESULTS: The time series sequence chart and smoother function demonstrated a steady upward trend with seasonality. The yearly average 25OHD increased from 36.1 nmol/l in 1993 to 57.3 nmol/l in 2013. The ARIMA model was a good fit for the 25OHD time series; it forecasted monthly average 25OHD up to the end of 2016 with a positive stationary R(2) of 0.377. CONCLUSIONS: Vitamin D status improved over the past 40 years, but there remains a dual problem: there are groups at risk of vitamin D deficiency who need public health preventative measures; on the other hand, random members of the population are taking unnecessarily high vitamin D intakes for unsubstantiated claims. PMID- 26034121 TI - Steroidogenic enzyme profile in an androgen-secreting adrenocortical oncocytoma associated with hirsustism. AB - Hirsutism induced by hyperandrogenism can be associated with polycystic ovary syndrome, 21-hydroxylase (OH) deficiency or androgen-secreting tumors, including ovarian and adrenal tumors. Adrenal androgen-secreting tumors are frequently malignant. Adrenal oncocytomas represent rare causes of hyperandrogenism. The aim of the study was to investigate steroidogenic enzyme expression and steroid secretion in an androgen-secreting adrenal oncocytoma in a young woman presenting with hirsutism. Hyperandrogenism was diagnosed on the basis of elevated plasma Delta4-androstenedione and testosterone levels. Pelvic ultrasound was normal, CT scanning revealed a right adrenal mass. Androgens were assessed in adrenal and ovarian vein samples and proved a right adrenal origin. Adrenalectomy normalized androgen levels and the adrenal tumor was diagnosed as an oncocytoma. Real time PCR, immunohistochemistry and cell culture studies were performed on tumor explants to investigate the steroid secretion profile. Among enzymes required for cortisol synthesis, 17alpha-OH and 3beta-hydroxysteroid dehydrogenase 2 (3beta HSD2) were highly expressed whereas 21-OH and 11beta-OH were weakly produced at the mRNA and/or protein levels. Enzymes involved in testosterone production, 17beta-HSD5 and 17beta-HSD3, were also detected. ACTH receptor was present in the tissue. Cortisol, Delta4-androstenedione and testosterone secretions by cultured cells were increased by ACTH. These results provide the first demonstration, to our knowledge, of abnormal expression profile of steroidogenic enzymes in an adrenocortical oncocytoma. Our results also indicate that Delta4-androstenedione hypersecretion resulted from high 17alpha-OH and 3beta-HSD2 expression in combination with low expression of 21-OH and 11beta-OH. Testosterone production was ascribed to occurrence of 17beta-HSD5 and 17beta-HSD3. Finally, our results indicate that androgen secretion was stimulated by ACTH. PMID- 26034122 TI - Minor contributions of the maxillary sinus to the air-conditioning performance in macaque monkeys. AB - The nasal passages mainly adjust the temperature and humidity of inhaled air to reach the alveolar condition required in the lungs. By contrast to most other non human primates, macaque monkeys are distributed widely among tropical, temperate and subarctic regions, and thus some species need to condition the inhaled air in cool and dry ambient atmospheric areas. The internal nasal anatomy is believed to have undergone adaptive modifications to improve the air-conditioning performance. Furthermore, the maxillary sinus (MS), an accessory hollow communicating with the nasal cavity, is found in macaques, whereas it is absent in most other extant Old World monkeys, including savanna monkeys. In this study, we used computational fluid dynamics simulations to simulate the airflow and heat and water exchange over the mucosal surface in the nasal passage. Using the topology models of the nasal cavity with and without the MS, we demonstrated that the MS makes little contribution to the airflow pattern and the air-conditioning performance within the nasal cavity in macaques. Instead, the inhaled air is conditioned well in the anterior portion of the nasal cavity before reaching the MS in both macaques and savanna monkeys. These findings suggest that the evolutionary modifications and coetaneous variations in the nasal anatomy are rather independent of transitions and variations in the climate and atmospheric environment found in the habitats of macaques. PMID- 26034123 TI - Evidence of ectoparasite-induced endocrine disruption in an imperiled giant salamander, the eastern hellbender (Cryptobranchus alleganiensis). AB - Parasitic leeches and trypanosomes release chemical signals into their hosts to evade immuno-detection, but it is unknown whether these compounds manipulate host behavior or endocrine physiology. We determined whether parasitic infections with leeches and/or trypanosomes affected the immune and stress response of an imperiled giant species of amphibian, the eastern hellbender (Cryptobranchus alleganiensis Daudin). We monitored corticosterone and white blood cell counts in response to restraint and injection with adrenocorticotropin hormone (ACTH) or saline for up to 50 h. The presence of leeches dampened hellbender corticosterone responses to restraint and reduced diel patterns of plasma corticosterone. Injection with ACTH restored the normal inter-renal responses of hellbenders, suggesting that leeches, possibly through neurotransmitters in leech saliva, cause down-regulation of corticosterone release at the level of the pituitary or hypothalamus. Infection with leeches also increased the relative abundance of eosinophils, white blood cells often recruited into circulation in response to parasitic infection. Lastly, neutrophil to lymphocyte (N:L) ratios increased in all animals after 24 h of capture and remained elevated for up to 50 h, but these temporal dynamics did not differ with parasite infection. Trypanosome infection did not affect any aspect of hellbender physiology that we measured. Our findings reveal a previously undocumented host-parasite dynamic. While the functional significance to the parasite is unclear, the physiological and behavioral implications for the host are great, given the important role of glucocorticoids in regulating physiology and behavior. PMID- 26034124 TI - Run don't walk: locomotor performance of geckos on wet substrates. AB - The gecko adhesive system has been under particular scrutiny for over a decade, as the field has recently attracted attention for its application to bio-inspired design. However, little is known about how the adhesive system behaves in ecologically relevant conditions. Geckos inhabit a variety of environments, many of which are characterized by high temperature, humidity and rain. The van der Waals-based gecko adhesive system should be particularly challenged by wet substrates because water can disrupt the intimate contact necessary for adhesion. While a few previous studies have focused on the clinging ability of geckos on wet substrates, we tested a dynamic performance characteristic, sprint velocity. To better understand how substrate wettability and running orientation affect locomotor performance of multiple species on wet substrates, we measured average sprint velocity of five species of gecko on substrates that were either hydrophilic or intermediately wetting and oriented either vertically or horizontally. Surprisingly, we found no indication that wet substrates impact average sprint velocity over 1 m, and rather, in some species, sprint velocity was increased on wet substrates rather than reduced. When investigating physical characteristics and behavior that may be associated with running on wet substrates, such as total number of stops, slips and wet toes at the completion of a race, we found that there may be habitat-related differences between some species. Our results show that in general, unlike clinging and walking, geckos running along wet substrates suffer no significant loss in locomotor performance over short distances. PMID- 26034125 TI - Diurnal oscillation of vocal development associated with clustered singing by juvenile songbirds. AB - Spaced practice affects learning efficiency in humans and other animals. However, it is not well understood how spaced practice contributes to learning during development. Here, we show the behavioral significance of singing frequency in song development in a songbird, the zebra finch. Songbirds learn a complex song pattern by trial-and-error vocalizations as self-motivated practice, which is executed over a thousand times per day during the sensitive period of vocal learning. Notably, juveniles generate songs with a high frequency of singing in clusters with dense singing, whereas adults sing with low frequency in short clusters. This juvenile-specific clustered singing was characterized by clear separations of daily time for intense practice and rest. During the epochs of vocal practice in juveniles, the song structure approached that of song produced at the end of the day. In contrast, during the epochs of vocal rest, the structure of juvenile songs regressed toward that of songs produced at the beginning of the day, indicating a dynamic progression and regression of song development over the course of the day. When the singing frequency was manipulated to decrease it at the juvenile stage, the oscillation rate of song development was dramatically reduced. Although the juvenile-specific clustered singing occurred in non-tutored socially isolated birds or those with auditory deprivation, the diurnal oscillation of vocal development was only observed in non-tutored isolated juveniles. These results show the impact of 'self-motivated' vocal practice on diurnal song developmental plasticity, modulated by the amount of vocal output and auditory feedback. PMID- 26034126 TI - SLFN11: Achilles' Heel or Troublemaker. AB - SLFN11 expression correlates with sensitivity of tumors to topoisomerase and DNA targeting drugs and consequently with prognosis. Regulation of SLFN11 by ETS factors opens new avenues to treatment optimization, maximizing antitumor activity and minimizing adverse side effects. Interrogating drug-induced gene expression signatures for SLFN11 modulations may affect the design of therapeutic regimens. PMID- 26034127 TI - Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle. AB - PURPOSE: Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways-horizontal blockade-is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. EXPERIMENTAL DESIGN: AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor targeting nanoscale drug formulation-layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. RESULTS: Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 +/- 20 nm, -40 +/- 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug loaded nanoparticles exhibited progressive disease. CONCLUSIONS: Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic. PMID- 26034128 TI - Combined endobronchial and oesophageal endosonography for the diagnosis and staging of lung cancer. European Society of Gastrointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). PMID- 26034130 TI - LeasyScan: a novel concept combining 3D imaging and lysimetry for high-throughput phenotyping of traits controlling plant water budget. AB - In this paper, we describe the thought process and initial data behind the development of an imaging platform (LeasyScan) combined with lysimetric capacity, to assess canopy traits affecting water use (leaf area, leaf area index, transpiration). LeasyScan is based on a novel 3D scanning technique to capture leaf area development continuously, a scanner-to-plant concept to increase imaging throughput and analytical scales to combine gravimetric transpiration measurements. The paper presents how the technology functions, how data are visualised via a web-based interface and how data extraction and analysis is interfaced through 'R' libraries. Close agreement between scanned and observed leaf area data of individual plants in different crops was found (R(2) between 0.86 and 0.94). Similar agreement was found when comparing scanned and observed area of plants cultivated at densities reflecting field conditions (R(2) between 0.80 and 0.96). An example in monitoring plant transpiration by the analytical scales is presented. The last section illustrates some of the early ongoing applications of the platform to target key phenotypes: (i) the comparison of the leaf area development pattern of fine mapping recombinants of pearl millet; (ii) the leaf area development pattern of pearl millet breeding material targeted to different agro-ecological zones; (iii) the assessment of the transpiration response to high VPD in sorghum and pearl millet. This new platform has the potential to phenotype for traits controlling plant water use at a high rate and precision, of critical importance for drought adaptation, and creates an opportunity to harness their genetics for the breeding of improved varieties. PMID- 26034129 TI - The Arabidopsis Pep-PEPR system is induced by herbivore feeding and contributes to JA-mediated plant defence against herbivory. AB - A number of plant endogenous elicitors have been identified that induce pattern triggered immunity upon perception. In Arabidopsis thaliana eight small precursor proteins, called PROPEPs, are thought to be cleaved upon danger to release eight peptides known as the plant elicitor peptides Peps. As the expression of some PROPEPs is induced upon biotic stress and perception of any of the eight Peps triggers a defence response, they are regarded as amplifiers of immunity. Besides the induction of defences directed against microbial colonization Peps have also been connected with herbivore deterrence as they share certain similarities to systemins, known mediators of defence signalling against herbivores in solanaceous plants, and they positively interact with the phytohormone jasmonic acid. A recent study using maize indicated that the application of ZmPep3, a maize AtPep-orthologue, elicits anti-herbivore responses. However, as this study only assessed the responses triggered by the exogenous application of Peps, the biological significance of these findings remained open. By using Arabidopsis GUS reporter lines, it is now shown that the promoters of both Pep-receptors, PEPR1 and PEPR2, as well as PROPEP3 are strongly activated upon herbivore attack. Moreover, pepr1 pepr2 double mutant plants, which are insensitive to Peps, display a reduced resistance to feeding Spodoptera littoralis larvae and a reduced accumulation of jasmonic acid upon exposure to herbivore oral secretions. Taken together, these lines of evidence extend the role of the AtPep-PEPR system as a danger detection mechanism from microbial pathogens to herbivores and further underline its strong interaction with jasmonic acid signalling. PMID- 26034131 TI - XRCC3 is essential for proper double-strand break repair and homologous recombination in rice meiosis. AB - RAD51 paralogues play important roles in the assembly and stabilization of RAD51 nucleoprotein filaments, which promote homologous pairing and strand exchange reactions in organisms ranging from yeast to vertebrates. XRCC3, a RAD51 paralogue, has been characterized in budding yeast, mouse, and Arabidopsis. In the present study, XRCC3 in rice was identified and characterized. The rice xrcc3 mutant exhibited normal vegetative growth but complete male and female sterility. Cytological investigations revealed that homologous pairing and synapsis were severely disrupted in the mutant. Meiotic chromosomes were frequently entangled from diplotene to metaphase I, resulting in chromosome fragmentation at anaphase I. The immunostaining signals from gammaH2AX were regular, implying that double strand break (DSB) formation was normal in xrcc3 meiocytes. However, COM1 was not detected on early prophase I chromosomes, suggesting that the DSB end-processing system was destroyed in the mutant. Moreover, abnormal chromosome localization of RAD51C, DMC1, ZEP1, ZIP4, and MER3 was observed in xrcc3. Taken together, the results suggest that XRCC3 plays critical roles in both DSB repair and homologous chromosome recombination during rice meiosis. PMID- 26034132 TI - Comparing vegetation indices for remote chlorophyll measurement of white poplar and Chinese elm leaves with different adaxial and abaxial surfaces. AB - Quick non-destructive assessment of leaf chlorophyll content (LCC) is important for studying phenotypes related to plant growth and stress resistance. This study was undertaken to investigate the quantitative relationship between LCC and different vegetation indices (VIs) on both adaxial and abaxial surfaces of white poplar (Populus alba), which has dense tubular hairs on its abaxial surface, and Chinese elm (Ulmus pumila var. pendula), which does not show obvious superficial differences except for lighter colour on the abaxial surface. Some published and newly developed VIs were tested to relate them to LCC. The results showed that most of the published VIs had strong relationships with LCC on the one-surface dataset, but did not show a clear relationship with LCC when both adaxial and abaxial surface reflectance data were included. Among the reflectance indices tested, the modified Datt index, (R719-R726)/(R719-R743), performed best and is proposed as a new index for remote estimation of chlorophyll content in plants with varying leaf surface structures. It explained 92% of LCC variation in this research, and the root mean square error of the LCC prediction was 5.23 MUg/cm(2). This new index is insensitive to the effects of adaxial and abaxial leaf surface structures and is strongly related to the variation in reflectance caused by chlorophyll content. PMID- 26034133 TI - Dystrophic muscle improvement in zebrafish via increased heme oxygenase signaling. PMID- 26034134 TI - Knockout of RP2 decreases GRK1 and rod transducin subunits and leads to photoreceptor degeneration in zebrafish. AB - Retinitis pigmentosa (RP) affects about 1.8 million individuals worldwide. X linked retinitis pigmentosa (XLRP) is one of the most severe forms of RP. Nearly 85% of XLRP cases are caused by mutations in the X-linked retinitis pigmentosa 2 (RP2) and RPGR. RP2 has been considered to be a GTPase activator protein for ARL3 and to play a role in the traffic of ciliary proteins. The mechanism of how RP2 mutations cause RP is still unclear. In this study, we generated an RP2 knockout zebrafish line using transcription activator-like effector nuclease technology. Progressive retinal degeneration could be observed in the mutant zebrafish. The degeneration of rods' outer segments (OSs) is predominant, followed by the degeneration of cones' OS. These phenotypes are similar to the characteristics of RP2 patients, and also partly consistent with the phenotypes of RP2 knockout mice and morpholino-mediated RP2 knockdown zebrafish. For the first time, we found RP2 deletion leads to decreased protein levels and abnormal retinal localizations of GRK1 and rod transducin subunits (GNAT1 and GNB1) in zebrafish. Furthermore, the distribution of the total farnesylated proteins in zebrafish retina is also affected by RP2 ablation. These molecular alterations observed in the RP2 knockout zebrafish might probably be responsible for the gradual loss of the photoreceptors' OSs. Our work identified the progression of retinal degeneration in RP2 knockout zebrafish, provided a foundation for revealing the pathogenesis of RP caused by RP2 mutations, and would help to develop potential therapeutics against RP in further studies. PMID- 26034135 TI - Mobilization of epithelial mesenchymal transition genes distinguishes active from inactive lesional tissue in patients with ulcerative colitis. AB - Ulcerative colitis (UC) is a chronic, relapsing and debilitating idiopathic inflammation, with variable and complex pathophysiologies. Our objective was to elucidate patterns of gene expression underlying the progression of UC disease. Single endoscopic pinch FFPE biopsies (n = 41) were sampled at both active and inactive stages at the same site in individual UC patients and compared with each other and with non-inflammatory bowel disease healthy controls. Gene expression results were validated by quantitative reverse transcriptase-PCR (QRT-PCR), and results at the protein level were validated by immunohistochemistry and western blot. Analysis of microarray results demonstrated that UC patients in remission display an intermediate gene expression phenotype between active UC patients and controls. It is clear that UC active site recovery does not revert fully back to a healthy control phenotype. Both UC active and inactive tissue displayed evidence, at both the gene expression and protein level, of a positive precancerous state as indicated by increases in the expression of Chitinase 3 Like-1, and the colorectal cancer metastasis marker MMP1. A key distinguishing feature between active and inactive UC, however, was the mobilization of marker genes and proteins for the Epithelial Mesenchymal Transition (EMT) pathway only in active UC. Analysis of the gene expression signatures associated with UC remission identified multiple pathways which appear to be permanently dysregulated in UC patients at formerly active sites in spite of clear histological recovery. Among these pathways, the EMT pathway was specifically up regulated only in active UC emphasizing the potential for cancer progression in these patients. PMID- 26034136 TI - Loss of MyD88 alters neuroinflammatory response and attenuates early Purkinje cell loss in a spinocerebellar ataxia type 6 mouse model. AB - Spinocerebellar ataxia type 6 (SCA6) is dominantly inherited neurodegenerative disease, caused by an expansion of CAG repeat encoding a polyglutamine (PolyQ) tract in the Cav2.1 voltage-gated calcium channel. Its key pathological features include selective degeneration of the cerebellar Purkinje cells (PCs), a common target for PolyQ-induced toxicity in various SCAs. Mutant Cav2.1 confers toxicity primarily through a toxic gain-of-function mechanism; however, its molecular basis remains elusive. Here, we studied the cerebellar gene expression patterns of young Sca6-MPI(118Q/118Q) knockin (KI) mice, which expressed mutant Cav2.1 from an endogenous locus and recapitulated many phenotypic features of human SCA6. Transcriptional signatures in the MPI(118Q/118Q) mice were distinct from those in the Sca1(154Q/2Q) mice, a faithful SCA1 KI mouse model. Temporal expression profiles of the candidate genes revealed that the up-regulation of genes associated with microglial activation was initiated before PC degeneration and was augmented as the disease progressed. Histological analysis of the MPI(118Q/118Q) cerebellum showed the predominance of M1-like pro-inflammatory microglia and it was concomitant with elevated expression levels of tumor necrosis factor, interleukin-6, Toll-like receptor (TLR) 2 and 7. Genetic ablation of MyD88, a major adaptor protein conveying TLR signaling, altered expression patterns of M1/M2 microglial phenotypic markers in the MPI(118Q/118Q) cerebellum. More importantly, it ameliorated PC loss and partially rescued motor impairments in the early disease phase. These results suggest that early neuroinflammatory response may play an important role in the pathogenesis of SCA6 and its modulation could pave the way for slowing the disease progression during the early stage of the disease. PMID- 26034138 TI - Mitochondrial Genetic Structure and Matrilineal Origin of White Sharks, Carcharodon carcharias, in the Northeastern Pacific: Implications for Their Conservation. AB - White sharks (Carcharodon carcharias, WS henceforth) are globally and regionally threatened. Understanding their patterns of abundance and connectivity, as they relate to habitat use, is central for delineating conservation units and identifying priority areas for conservation. We analyzed mitochondrial data to test the congruence between patterns of genetic connectivity and of individual movements in the Northeastern Pacific (NEP) and to trace the matrilineal origin of immature WS from coastal California and Baja California to adult aggregation areas. We analyzed 186 mitochondrial control region sequences from sharks sampled in Central California (CC; n = 61), Southern California Bight (SCB; n = 25), Baja California Pacific coast (BCPC; n = 9), Bahia Vizcaino (BV; n = 39), Guadalupe Island (GI; n = 45), and the Gulf of California (GC; n = 7). Significant mitochondrial differentiation between adult aggregation areas (CC, GI) revealed two reproductive populations in the NEP. We found general concordance between movement patterns of young and adult WS with genetic results. Young sharks from coastal California and Baja California were more likely born from females from GI. Mitochondrial differentiation of young-of-the-year from SCB and BV suggests philopatry to nursery areas in females from GI. These results provide a genetic basis of female reproductive behavior at a regional scale and point to a preponderance of sharks from GI in the use of the sampled coastal region as pupping habitat. These findings should be considered in Mexican and US management and conservation strategies of the WS NEP population. PMID- 26034137 TI - Increased burden of de novo predicted deleterious variants in complex congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is a serious birth defect that accounts for 8% of all major birth anomalies. Approximately 40% of cases occur in association with other anomalies. As sporadic complex CDH likely has a significant impact on reproductive fitness, we hypothesized that de novo variants would account for the etiology in a significant fraction of cases. We performed exome sequencing in 39 CDH trios and compared the frequency of de novo variants with 787 unaffected controls from the Simons Simplex Collection. We found no significant difference in overall frequency of de novo variants between cases and controls. However, among genes that are highly expressed during diaphragm development, there was a significant burden of likely gene disrupting (LGD) and predicted deleterious missense variants in cases (fold enrichment = 3.2, P-value = 0.003), and these genes are more likely to be haploinsufficient (P-value = 0.01) than the ones with benign missense or synonymous de novo variants in cases. After accounting for the frequency of de novo variants in the control population, we estimate that 15% of sporadic complex CDH patients are attributable to de novo LGD or deleterious missense variants. We identified several genes with predicted deleterious de novo variants that fall into common categories of genes related to transcription factors and cell migration that we believe are related to the pathogenesis of CDH. These data provide supportive evidence for novel genes in the pathogenesis of CDH associated with other anomalies and suggest that de novo variants play a significant role in complex CDH cases. PMID- 26034139 TI - Health promotion applied to infectious diseases. PMID- 26034140 TI - Preparing for Ebola outbreaks: not without the social sciences! PMID- 26034144 TI - Investigation of Complement-activating Pattern Recognition Molecules and Associated Enzymes as Possible Inflammatory Markers in Oligoarticular and Systemic Juvenile Idiopathic Arthritis. AB - OBJECTIVE: The complement system plays a crucial role in the pathogenesis of inflammatory processes. The lectin pathway of the complement system is activated through the recognition of pathogens by soluble pattern recognition molecules (PRM), i.e., mannan-binding lectin (MBL), collectin-LK, and the ficolins. PRM are reportedly correlated to disease activity in rheumatoid arthritis (RA). The aim was to evaluate the pathogenic role of PRM in juvenile idiopathic arthritis (JIA). METHODS: We measured MBL, M-ficolin, H-ficolin, MBL-associated serine proteases (MASP) 1, MASP-2, MASP-3, and 2 alternative splice products, MBL associated protein (MAp) 44 and MAp19, in plasma and synovial fluid (SF) of children with persistent oligoarticular (n = 109 in plasma, n = 38 in SF) and systemic JIA (n = 19 in plasma, n = 11 in SF). The concentrations of the proteins were measured by in-house time-resolved immunofluorometric assays. RESULTS: We observed significantly higher levels of M-ficolin, MASP-1, MASP-2, and MASP-3 in plasma and SF from patients with systemic JIA compared with persistent oligoarticular JIA (p < 0.001). In paired samples of plasma and SF from 47 patients with oligoarticular and systemic JIA, we observed higher concentrations in plasma for both subtypes for 7 of the measured proteins while the reverse relationship was observed for MASP-3. M-ficolin and MASP-2 correlated to erythrocyte sedimentation rate, C-reactive protein, white blood cell count, and platelet count (p < 0.001). M-ficolin was in addition related to the number of active joints and inversely related to hemoglobin levels. CONCLUSION: Our results point to plasma M-ficolin and MASP-2 as inflammatory markers in JIA. The levels of all proteins are higher in plasma than in SF, except for MASP-3, indicating that MASP-3 may be produced locally in joints. PMID- 26034145 TI - Magnetic Resonance Imaging Assessment of Temporomandibular Joint Involvement and Mandibular Growth Following Corticosteroid Injection in Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To assess whether intraarticular corticosteroid injection (CSI) reduces inflammation of the temporomandibular joint (TMJ), prevents growth disturbances of the mandibular condyle, and restores normal growth of the mandibular ramus. METHODS: Retrospective longitudinal magnetic resonance imaging (MRI) evaluation of inflammatory activity, TMJ deformity, and mandibular ramus height in 33 children (23 girls, median age 5.2 yrs) over a median period of 5 years following repetitive CSI to the TMJ. RESULTS: Intraarticular location of CSI led to inflammatory grade improvement in 53% at first MRI followup compared to 20% with extraarticular location (p = 0.005), with more improvement of the mean inflammatory grade after intraarticular CSI (p = 0.001). Rate of osseous deformities of the TMJ deteriorated from 51% at study inclusion to 62% at end of observation period, with progression to severe condylar destruction in 26% of joints including 24% with development of intraarticular calcifications/ossifications. Mean short-term growth rates of the mandibular ramus were negative for intraarticular CSI while positive for extraarticular CSI (p = 0.036). Mean longterm mandibular ramus growth rate (0.7 +/- 0.8 mm/yr) after CSI was significantly lower than reported normal mean age- and sex-matched growth rate (1.4 +/- 0.1 mm/yr, p < 0.0001). CONCLUSION: Despite improving the inflammatory activity as seen on MRI, repetitive CSI to the TMJ does not reach the treatment goals to prevent progressive osseous deformation and to normalize mandibular ramus growth in children with juvenile idiopathic arthritis. PMID- 26034146 TI - Use of Laser Speckle Contrast Imaging to Assess Digital Microvascular Function in Primary Raynaud Phenomenon and Systemic Sclerosis: A Comparison Using the Raynaud Condition Score Diary. AB - OBJECTIVE: Evaluate objective assessment of digital microvascular function using laser speckle contrast imaging (LSCI) in a cross-sectional study of patients with primary Raynaud phenomenon (RP) and systemic sclerosis (SSc), comparing LSCI with both infrared thermography (IRT) and subjective assessment using the Raynaud Condition Score (RCS) diary. METHODS: Patients with SSc (n = 25) and primary RP (n = 18) underwent simultaneous assessment of digital perfusion using LSCI and IRT with a cold challenge on 2 occasions, 2 weeks apart. The RCS diary was completed between assessments. The relationship between objective and subjective assessments of RP was evaluated. Reproducibility of LSCI/IRT was assessed, along with differences between primary RP and SSc, and the effect of sex. RESULTS: There was moderate-to-good correlation between LSCI and IRT (Spearman rho 0.58 0.84, p < 0.01), but poor correlation between objective assessments and the RCS diary (p > 0.05 for all analyses). Reproducibility of IRT and LSCI was moderate at baseline (ICC 0.51-0.63) and immediately following cold challenge (ICC 0.56 0.86), but lower during reperfusion (ICC 0.3-0.7). Neither subjective nor objective assessments differentiated between primary RP and SSc. Men reported lower median daily frequency of RP attacks (0.82 vs 1.93, p = 0.03). Perfusion using LSCI/IRT was higher in men for the majority of assessments. CONCLUSION: Objective and subjective methods provide differing information on microvascular function in RP. There is good convergent validity of LSCI with IRT and acceptable reproducibility of both modalities. Neither subjective nor objective assessments could differentiate between primary RP and SSc. Influence of sex on subjective and objective assessment of RP warrants further evaluation. PMID- 26034147 TI - Treatment Patterns of Multimorbid Patients with Rheumatoid Arthritis: Results from an International Cross-sectional Study. AB - OBJECTIVE: To describe the treatment profile of multimorbid patients with rheumatoid arthritis (RA) in contrast to patients with RA only. METHODS: COMORA (Comorbidities in Rheumatoid Arthritis) is a cross-sectional, international study assessing morbidities, outcomes, and treatment of patients with RA. Patients were grouped according to their multimorbidity profile assessed by a counted multimorbidity index (cMMI). Treatment for RA was categorized as use of biologic disease-modifying antirheumatic drugs (bDMARD), in particular tumor necrosis factor inhibitors (TNFi), synthetic DMARD (sDMARD) use only, nonsteroidal antiinflammatory drug (NSAID) use, and corticosteroid use. Logistic regression models were performed to determine the OR of bDMARD, TNFi, sDMARD, NSAID, or corticosteroid use based on a patient's cMMI and global region after adjusting for age, disease activity, disease duration, educational level, and previous DMARD therapy. RESULTS: Out of 3920 patients, 32.7% received bDMARD; 59.9% sDMARD only, 51.1% used concomitant NSAID, and 54.8% used corticosteroid. Regional differences were observed with the most frequent use of bDMARD in the United States (46.5%) and lowest in North Africa (9%). After adjusting for confounders in logistic regression, the OR for bDMARD use was reduced for each additional morbidity (OR 0.89, 95% CI 0.83-0.96). Similar results were found for TNFi (OR 0.91, 95% CI 0.84-0.99), whereas the OR for use of sDMARD was increased (1.13, 95% CI 1.05-1.22). No significant change of OR was found for NSAID or corticosteroid use. CONCLUSION: In this study, the odds of bDMARD use decreases 11% for each additional chronic morbid condition after adjustment for regional differences, disease activity, and other covariates. PMID- 26034148 TI - Anakinra in Systemic Juvenile Idiopathic Arthritis: A Single-center Experience. AB - OBJECTIVE: To assess anakinra as a therapy for systemic juvenile idiopathic arthritis (sJIA) in a single-center series. METHODS: We reviewed 25 patients with sJIA treated with anakinra for at least 6 months. The primary outcome was the number of patients who achieved clinically inactive disease at 6 months, according to preliminary criteria for inactive disease and clinical remission of JIA. RESULTS: Among 25 patients evaluated, 14 (56%) met the criteria for inactive disease at 6 months and were classified as responders. For each individual patient, we compared the dose administered with the ideal dose of anakinra and we found that there was no relation with response. We also compared demographic characteristics and clinical and laboratory features at baseline in responders and non-responders: no differences were observed in relation with the number of active joints before starting anakinra or concomitant glucocorticoids treatment. The only variable significantly associated with response was the time from disease onset to receiving anakinra, with earlier treatment being associated with a better outcome. CONCLUSION: Anakinra is associated with rapid attainment of inactive disease in a significant portion of patients. We found that only the earlier treatment is associated with better outcome. However, formal studies on early treatment and on the pathophysiology and response to treatments, including anakinra, of early- and late-onset sJIA are needed to optimize the management of this challenging disease. PMID- 26034149 TI - Longterm Safety of Tocilizumab: Results from 3 Years of Followup Postmarketing Surveillance of 5573 Patients with Rheumatoid Arthritis in Japan. AB - OBJECTIVE: To evaluate the longterm safety of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Japan. METHODS: In this longterm extension of a single-arm, observational postmarketing surveillance study, a total of 5573 patients who initiated intravenous TCZ between April 2008 and July 2009 were observed for 3 years, regardless of its continuation, for incidence of fatal events, serious infections, malignancy, gastrointestinal perforations, and serious cardiac dysfunction. RESULTS: Of the 5573 patients who were enrolled, 4527 patients (81.23%) completed 3 years of followup. There were no increases in the proportions of patients with fatal events, serious infection, malignancy, GI perforation, or serious cardiac dysfunction over 3 years. The all-cause mortality rate during followup was 2.58% (0.95/100 patient-yrs), and the standardized mortality ratio was 1.27 (95% CI, 1.08 to 1.50). Patients who were older with longer disease duration and respiratory comorbidities were more likely to discontinue TCZ treatment following serious infection during the first year. Among patients who completed 3 years of TCZ treatment, serious infection developed at a constant rate during the 3-year treatment period. The proportion of malignancy during followup was 2.24% (0.83/100 patient-yrs), and the standardized incidence ratio was 0.79 (95% CI, 0.66 to 0.95). CONCLUSION: The safety profile of TCZ was consistent over time regarding mortality, serious infections, malignancy, gastrointestinal perforation, and serious cardiac dysfunction. These data confirm the longterm safety of TCZ use in patients with RA in a real-world clinical setting. PMID- 26034150 TI - Efficacy and Safety of Pregabalin in Patients with Fibromyalgia and Comorbid Depression Taking Concurrent Antidepressant Medication: A Randomized, Placebo controlled Study. AB - OBJECTIVE: To assess pregabalin efficacy and safety in patients with fibromyalgia (FM) with comorbid depression taking concurrent antidepressant medication. METHODS: This randomized, placebo-controlled, double-blind, 2-period, 2-way crossover study was composed of two 6-week treatment periods separated by a 2 week taper/washout phase. Patients with FM (aged >= 18 yrs) taking a stable dose of a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) for depression were randomized 1:1 to receive pregabalin/placebo or placebo/pregabalin (optimized to 300 or 450 mg/day). Antidepressant medication was continued throughout the study. The primary efficacy outcome was the mean pain score on an 11-point numerical rating scale. Secondary efficacy outcomes included measures of anxiety, depression, patient function, and sleep. RESULTS: Of 197 patients randomized to treatment, 181 and 177 received >= 1 dose of pregabalin and placebo, respectively. At baseline, 52.3% of patients were taking an SSRI and 47.7% an SNRI, and mean pain score was 6.7. Mean pain scores at endpoint were statistically significantly reduced with pregabalin (least squares mean difference from placebo -0.61, 95% CI -0.91 - 0.31, p = 0.0001). Pregabalin significantly improved Hospital Anxiety and Depression Scale-Anxiety (difference -0.95, p < 0.0001) and -Depression (difference -0.88, p = 0.0005) scores, Fibromyalgia Impact Questionnaire total score (difference -6.60, p < 0.0001), and sleep quality (difference 0.57, p < 0.0001), but not EuroQol 5-Dimensions score (difference 0.02, p = 0.3854). Pregabalin safety was consistent with previous studies and current product labeling. CONCLUSION: Compared with placebo, pregabalin statistically significantly improved FM pain and other symptoms in patients taking antidepressant medication for comorbid depression. ClinicalTrials.gov identifier: NCT01432236. PMID- 26034151 TI - Is Etanercept 25 mg Once Weekly as Effective as 50 mg at Maintaining Response in Patients with Ankylosing Spondylitis? A Randomized Control Trial. AB - OBJECTIVE: To investigate, in a pilot randomized controlled trial, whether etanercept (ETN) 25 mg once weekly is effective at maintaining a clinical response in patients with ankylosing spondylitis (AS) who have responded to the standard 50 mg dose. METHODS: Adults with AS not responding to conventional therapies were prescribed ETN 50 mg once weekly for 6 months. Responders as defined by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) were randomly assigned to taper to 25 mg once weekly or continue on 50 mg and followed for a further 6 months. The primary outcome measure was maintenance of a 50% reduction in the BASDAI or fall in BASDAI by >= 2 units and a >= 2-unit reduction in BASDAI spinal pain as measured on a 10-point visual analog scale at 6 months postrandomization. RESULTS: Of 89 patients assessed for eligibility, 59 were enrolled; 47 (80%) had sufficient clinical response and were eligible for randomization, 24 were assigned to continue receiving ETN 50 mg, and 23 to taper to 25 mg. After 6 months, 20 (83%) of the 50 mg arm maintained clinical response compared with 12 (52%) of the 25 mg arm (a difference of -31%, 95% CI -58% - 5%). CONCLUSION: Although this pilot study demonstrates that treatment with ETN 25 mg was less effective at maintaining treatment response in the stepdown phase, 52% of participants maintained treatment response. Future research should address which patients are suitable for tapering. PMID- 26034153 TI - Of Mice and Men: Defining the Role of Interleukin 17 in Rheumatoid Arthritis. PMID- 26034152 TI - Knee Pain and a Prior Injury Are Associated with Increased Risk of a New Knee Injury: Data from the Osteoarthritis Initiative. AB - OBJECTIVE: We explored whether knee pain or a history of knee injury were associated with a knee injury in the following 12 months. METHODS: We conducted longitudinal knee-based analyses among knees in the Osteoarthritis Initiative. We included both knees of all participants who had at least 1 followup visit with complete data. Our first sets of exposures were knee pain (chronic knee symptoms and severity) at baseline, 12-month, 24-month, and 36-month visits. Another exposure was a history of injury that we defined as a self-reported injury at any time prior to baseline, 12-month, 24-month, or 36-month visit. The outcome was self-reported knee injury during the past year at 12-month, 24-month, 36-month, and 48-month visits. We evaluated the association between ipsilateral and contralateral knee pain or history of injury and a new knee injury within 12 months of the exposure using generalized linear mixed model for repeated binary outcomes. RESULTS: A knee with reported chronic knee symptoms or ipsilateral or contralateral history of an injury was more likely to experience a new knee injury in the following 12 months than a knee without chronic knee symptoms (OR 1.84, 95% CI 1.57-2.16) or prior injury (prior ipsilateral knee injury: OR 1.81, 95% CI 1.56-2.09. Prior contralateral knee injury: OR 1.43, 95% CI 1.23-1.66). CONCLUSION: Knee pain and a history of injury are associated with new knee injuries. It may be beneficial for individuals with knee pain or a history of injury to participate in injury prevention programs. PMID- 26034154 TI - Can the Cancer-related Fatigue Case-definition Criteria Be Applied to Chronic Medical Illness? A Comparison between Breast Cancer and Systemic Sclerosis. AB - OBJECTIVE: Fatigue is a crucial determinant of quality of life across rheumatic diseases, but the lack of agreed-upon standards for identifying clinically significant fatigue hinders research and clinical management. Case definition criteria for cancer-related fatigue were proposed for inclusion in the International Classification of Diseases. The objective was to evaluate whether the cancer-related fatigue case definition performed equivalently in women with breast cancer and systemic sclerosis (SSc) and could be used to identify patients with chronic illness-related fatigue. METHODS: The cancer-related fatigue interview (case definition criteria met if >= 5 of 9 fatigue-related symptoms present with functional impairment) was completed by 291 women with SSc and 278 women successfully treated for breast cancer. Differential item functioning was assessed with the multiple indicator multiple cause model. RESULTS: Items 3 (concentration) and 10 (short-term memory) were endorsed significantly less often by women with SSc compared with cancer, controlling for responses on other items. Omitting these 2 items from the case definition and requiring 4 out of the 7 remaining symptoms resulted in a similar overall prevalence of cancer-related fatigue in the cancer sample compared with the original criteria (37.4% vs 37.8%, respectively), with 97.5% of patients diagnosed identically with both definitions. Prevalence of chronic illness-related fatigue was 36.1% in SSc using 4 of 7 symptoms. CONCLUSION: The cancer-related fatigue criteria can be used equivalently to identify patients with chronic illness-related fatigue when 2 cognitive fatigue symptoms are omitted. Harmonized definitions and measurement of clinically significant fatigue will advance research and clinical management of fatigue in rheumatic diseases and other conditions. PMID- 26034155 TI - Evaluation of Minimally Invasive, Ultrasound-guided Synovial Biopsy Techniques by the OMERACT Filter--Determining Validation Requirements. AB - OBJECTIVE: Because limited data currently support the clinical utility of peripherally expressed biomarkers in guiding treatment decisions for patients with rheumatoid arthritis, the search has turned to the disease tissue. The strategic aim of the Outcome Measures in Rheumatology (OMERACT) synovitis working group over the years has been to develop novel diagnostic and prognostic synovial biomarkers. A critical step in this process is to refine and validate minimally invasive, technically simple, robust techniques to sample synovial tissue, for use both in clinical trials and routine clinical practice. The objective of the synovitis working group (SWG) at OMERACT 12 (2014) was to examine whether recently developed ultrasound (US)-guided synovial biopsy techniques could be validated according to the OMERACT filter for future clinical use recommendation. METHODS: The SWG examined whether current data reporting US-guided synovial biopsy of both large and small joints addressed the OMERACT filters of truth, discrimination, and feasibility. RESULTS: There are currently limited data examining the performance of US-guided synovial biopsy, mainly from observational studies. Thus, it remains critical to evaluate its performance, within the clinical trials context, against the current gold standard of arthroscopic biopsy, with particular reference to: (1) synovial tissue yield, (2) capacity to determine treatment response as measured by a validated synovial biomarker, and (3) tolerability of the procedure. CONCLUSION: We summarize the discrete work packages agreed to as requirements to validate US-guided synovial biopsy and therefore lead to a global consensus on the use of synovial biopsy for research and clinical practice. PMID- 26034156 TI - Minimal Clinically Important Difference as Applied in Rheumatology: An OMERACT Rasch Working Group Systematic Review and Critique. AB - OBJECTIVE: We aimed to evaluate how minimal (clinically) important differences (MCID/MID) were calculated in rheumatology in the past 2 decades and demonstrate how the calculation is compromised by the lack of interval scaling. METHODS: We conducted a systematic literature review on articles reporting MCID calculation in osteoarthritis (OA) and rheumatoid arthritis (RA) from January 1, 1989, to May 9, 2014. We evaluated the methods of MCID calculation and recorded the ranges of MCID for common patient-reported outcome measures (PROM). Taking data from the Health Assessment Questionnaire (HAQ), we showed the effects of performing mathematical calculations on ordinal data. RESULTS: A total of 330 abstracts were reviewed and 123 articles chosen for full text review. Thirty-six (19 OA, 16 RA and 1 OA-RA) articles were included in the final evaluation. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was the most frequently reported PROM with relevant calculations in OA, and the HAQ in RA. Sixteen articles used anchor-based methods alone for calculation of MCID, and 1 article used distribution-based methods alone. Nineteen articles used both anchor and distribution-based methods. Only 1 article calculated MCID using an interval scale. Wide ranges in MCID for the WOMAC in OA and HAQ in RA were noted. Ordinal based derivations of MCID are shown to understate true change at the margins, and overstate change in the mid-range of a scale. CONCLUSION: The anchor-based method is commonly used in the calculation of MCID. However, the lack of interval scaling is shown to compromise validity of MCID calculation. PMID- 26034157 TI - Evaluation of the Satisfaction with Appearance Scale and Its Short Form in Systemic Sclerosis: Analysis from the UCLA Scleroderma Quality of Life Study. AB - OBJECTIVE: Changes in appearance are common in patients with systemic sclerosis (SSc) and can significantly affect well-being. The Satisfaction with Appearance Scale (SWAP) measures body image dissatisfaction in persons with visible disfigurement; the Brief-Satisfaction with Appearance Scale (Brief-SWAP) is its short form. The present study evaluated the reliability and validity of SWAP and Brief-SWAP scores in SSc. METHODS: A sample of 207 patients with SSc participating in the University of California, Los Angeles Scleroderma Quality of Life Study completed the SWAP. Brief-SWAP scores were derived from the SWAP. The structural validity of both measures was investigated using confirmatory factor analysis. Internal consistency reliability of total and subscale scores was assessed with Cronbach's alpha coefficients. Convergent and divergent validity was evaluated using the Center for Epidemiological Studies Depression Scale, the Health Assessment Questionnaire-Disability Index, and the Medical Outcomes Study Short Form-36 questionnaire. RESULTS: SWAP and Brief-SWAP total scores were highly correlated (r = 0.97). The 4-factor structure of the SWAP fit well descriptively; the 2-factor structure of the Brief-SWAP fit well descriptively and statistically. Internal consistencies for total and subscale scores were good, and results supported convergent and divergent validity. CONCLUSION: Both versions are suitable for use in patients with SSc. The Brief-SWAP is most efficient; the full SWAP yields additional subscales that may be informative in understanding body image issues in patients with SSc. PMID- 26034158 TI - Relationship between Serum Magnesium Concentration and Radiographic Knee Osteoarthritis. AB - OBJECTIVE: To establish whether there is a relationship between serum magnesium (Mg) concentration and radiographic knee osteoarthritis (OA). METHODS: There were 2855 subjects in this cross-sectional study. Serum Mg concentration was measured using the chemiluminescence method. Radiographic OA of the knee was defined as changes consistent with Kellgren-Lawrence (K-L) grade 2 on at least 1 side. Mg concentration was classified into 1 of 4 quartiles: <= 0.87, 0.88-0.91, 0.92 0.96, or >= 0.97 mmol/l. Multivariable logistic analysis was used to test the association between serum Mg and radiographic knee OA after adjustment for potentially confounding factors. The OR with 95% CI for the association between radiographic knee OA and serum Mg concentration were calculated for each quartile. The quartile with the lowest value was regarded as the reference category. RESULTS: Significant association between serum Mg concentration and radiographic knee OA was observed in the model after adjustment for age, sex, and body mass index, as well as in the multivariable model. The multivariable adjusted OR (95% CI) for radiographic knee OA in the second, third, and fourth serum Mg concentration quartiles were 0.90 (95% CI 0.71-1.13), 0.92 (95% CI 0.73 1.16), and 0.72 (95% CI 0.57-0.92), respectively, compared with the lowest (first) quartile. A clear trend (p for trend was 0.01) was observed. The relative odds of radiographic knee OA was decreased by 0.72 times in the fourth serum Mg quartile compared with the lowest quartile. CONCLUSION: Serum Mg concentration may have an inverse relationship with radiographic OA of the knee. PMID- 26034159 TI - The OMERACT First-time Participant ("Newbie") Program: Initial Assessment and Lessons Learned. AB - OBJECTIVE: To describe the experience of a first-time participant ("newbie") training program at the Outcome Measures in Rheumatology 12 meeting in 2014. METHODS: We conducted newbie sessions at OMERACT 12, including a 2-hour introductory session on Day 1, followed by 1-h evening followup sessions on days 1-4 of OMERACT 12. Pre- and postmeeting surveys assessed participants' level of comfort with the principles of the OMERACT Filters 1.0 (truth, discrimination, feasibility), and Filter 2.0 (the essential tools for OMERACT methodology), the different types of OMERACT sessions, and whether participants felt welcome. RESULTS: In all, 25 new attendees participated in the introductory session and 10 16 attended followup sessions. Fewer participants reported being somewhat or extremely uncomfortable with the meeting, comparing Day 1 (preintroductory session) to days 1-4 (post): (1) with different OMERACT sessions: 56% (pre) versus 6%, 0%, 8%, and 6% (post days 1-4, respectively); and (2) with principles of the OMERACT filter, 64% (pre) versus 7%, 0%, 8%, and 0% (post), respectively. Most reported feeling welcome (100%) and that they were able to contribute substantively to breakout sessions (87%) on Day 1 evening; results were sustained on days 2-4. CONCLUSION: First-time participant training sessions increased the comfort level of the participants with the OMERACT meeting structure and filter, and increased the ability of the new attendees to feel they could contribute to the OMERACT process. PMID- 26034160 TI - Epidemiology of Bacteremia in Previously Healthy Febrile Infants: A Follow-up Study. AB - OBJECTIVE: Describe the etiology of bacteremia among a geographically diverse sample of previously well infants with fever admitted for general pediatric care and to characterize demographic and clinical characteristics of infants with bacteremia according to bacterial etiology. We hypothesized that the epidemiology of bacteremia in febrile infants from a geographically diverse cohort would show similar results to smaller or single-center cohorts previously reported. METHODS: This was a retrospective review of positive, pathogenic blood cultures in previously healthy, febrile infants<=90 days old admitted to a general unit. In total, there were 17 participating sites from diverse geographic regions of the United States. Cultures were included if the results were positive for bacteria, obtained from an infant 90 days old or younger with a temperature>=38.0 degrees C, analyzed using an automated detection system, and treated as pathogenic. RESULTS: Escherichia coli was the most prevalent species, followed by group B Streptococcus, Streptococcus viridans, and Staphylococcus aureus. Among the most prevalent bacteria, there was no association between gender and species (Ps>.05). Age at presentation was associated only with Streptococcus pneumoniae. There were no cases of Listeria monocytogenes. CONCLUSIONS: Our study confirms the data from smaller or single-center studies and suggests that the management of febrile well appearing infants should change to reflect the current epidemiology of bacteremia. Further research is needed into the role of lumbar puncture, as well as the role of Listeria and Enterococcus species in infantile bacteremia. PMID- 26034161 TI - Communication at pediatric rapid response events: a survey of health care providers. AB - OBJECTIVES: The objective of this study was to explore perceptions of communication quality at pediatric rapid response events and to determine whether these perceptions differed between rapid response team (RRT) members (RRTm) and floor providers (FP). METHODS: This survey study was conducted of clinical providers involved in RRT events at a tertiary care children's hospital. Perceptions of RRT communication were assessed by using a 5-point Likert scale, and qualitative comments were collected. Responses were compared between RRTm (responder nurses and intensive care fellows) and FP (floor nurses and resident physicians). RESULTS: Survey response was 64% (18 of 28) for RRTm and 70% (194 of 278) for FP. RRTm gave lower ratings than FP for communication of: (1) the purpose of the call; (2) airway and breathing; (3) circulation; (4) background information; and (5) possible diagnosis and treatment. RRTm were more likely than FP to indicate that description of background information delayed communication of critical management problems ("often": RRTm, 7 of 17 [41%]; FP, 23 of 175 [13%]; "always": RRTm, 2 of 18 [12%]; FP, 19 of 175 [11%]; P=.001 for overall comparison). A structured approach for communication was generally supported, although less strongly among floor nurses. Themes from qualitative responses included role confusion, fractured room entry, and a dismissive attitude by RRTm. CONCLUSIONS: A disconnect in perceived quality of communication was observed between RRTm and FP at pediatric rapid response events. A structured approach with well-defined roles may improve communication quality. PMID- 26034162 TI - The practice patterns of recently graduated internal medicine-pediatric hospitalists. AB - OBJECTIVES: To identify the current practice patterns and professional activities of internal medicine-pediatrics (med-peds) hospitalists who have graduated in the past 5 years (June 2009-June 2013). METHODS: The national Medicine-Pediatrics Program Directors Association (MPPDA) conducted a cross-sectional survey study of the 79 residency program directors who are members of the MPPDA regarding the practice patterns of recent graduates (from 2009-2013) currently practicing as hospitalists. The survey was distributed in the spring of 2014 on the MPPDA listserv. The survey inquired about time spent caring for hospitalized adults and children, medical school appointments, practice in freestanding children's hospitals, and completion of hospital medicine (HM) fellowships. RESULTS: Forty nine program directors (62%) completed the survey and provided data on 1042 graduates from 46 programs. Of those graduates, 26.4% (n=275) practice as hospitalists, and none had completed an HM fellowship. Approximately two-thirds (65%) of med-peds hospitalists provide care to hospitalized children and adults, with one-third providing care solely to hospitalized adults. Approximately one half (53.5%) have an appointment with a medical school and roughly one-quarter (28%) practice in a freestanding children's hospital. CONCLUSIONS: An increasing percentage of recent med-peds graduates are pursuing careers in HM, and two thirds are providing care to hospitalized children. As consideration for an accredited pediatric HM fellowship continues, certifying and accrediting bodies should consider how this will impact the med-peds workforce and allow med-peds graduates flexibility in their training requirements that will permit them to acquire the necessary skills to care for hospitalized children and adults. PMID- 26034163 TI - The New Hampshire Ten Steps to Successful Breastfeeding Collaborative: A Statewide QI Initiative. AB - BACKGROUND AND OBJECTIVE: Despite national recognition for their breastfeeding friendly practices, many New Hampshire hospitals are still not achieving the Ten Steps to Successful Breastfeeding. To increase achievement of the Ten Steps in New Hampshire's birthing hospitals, facilitate Baby-Friendly Hospital Initiative (BFHI) designation for interested hospitals, and improve rates of in-hospital any and exclusive breastfeeding. METHODS: After a 2010 needs assessment, we conducted 2 statewide workshops targeting 6 of the Ten Steps found to be most deficient among New Hampshire birthing hospitals. Eighteen of 20 hospitals attended at least 1 workshop, and 6 participated in an intensive collaborative. In 2013, we analyzed interval Ten Step achievement and in-hospital breastfeeding trends. RESULTS: Staff education showed the greatest improvement, increasing step 2 achievement from 1 to 6 hospitals (P=.05). Although the number of hospitals implementing step 6 (breast milk only) and step 9 (no artificial nipples) increased, differences were not statistically significant. Intensive collaborative hospitals achieved an average of 1.5 new steps, whereas non-Baby Friendly hospitals lost 0.7 steps (P=.05). In-hospital breastfeeding rates increased in intensive collaborative hospitals and were significantly higher than those in non-Baby Friendly hospitals by the end of the study (any breastfeeding, 89% vs 73%, P=.03; exclusive breastfeeding, 84% vs 61%, P<.001). CONCLUSIONS: A statewide improvement collaborative facilitated increases in Ten Step achievement and in-hospital breastfeeding for hospitals participating in an intensive collaborative. Active work in Ten Step implementation, including staff education, appears to be more effective in increasing in-hospital breastfeeding than does BFHI designation alone. PMID- 26034164 TI - Blood Culture in Evaluation of Pediatric Community-Acquired Pneumonia: A Systematic Review and Meta-analysis. AB - BACKGROUND AND OBJECTIVE: Current guidelines strongly recommend collection of blood cultures (BCs) in children requiring hospitalization for presumed moderate to severe bacterial community-acquired pneumonia (CAP). Our objective was to systematically review the international pediatric literature to evaluate how often BCs are positive in hospitalized children with CAP, identify the most commonly isolated pathogens, and determine the impact of positive BCs on clinical management. METHODS: We identified articles in PubMed and Scopus published from January 1970 through December 2013 that addressed BCs in children with CAP. We extracted total number of BCs collected and prevalence of positive BCs and used meta-regression to evaluate whether subgroups had any impact on prevalence. RESULTS: Meta-analysis showed that the overall prevalence of positive BCs was 5.14% (95% confidence interval 3.61-7.28). Studies focusing on severe CAP had a significant effect on prevalence (P=.008), at 9.89% (95% CI 6.79-14.19) compared with 4.17% (95% confidence interval 2.79-6.18) for studies not focusing on severe CAP. The most commonly isolated organisms were Streptococcus pneumoniae (76.7%) followed by Haemophilus influenzae (3.1%) and Staphylococcus aureus (2.1%). Contaminants accounted for 14.7%. Only 3 studies reported on BC-driven change in management, with contrasting findings. CONCLUSIONS: BCs in pediatric CAP identified organisms in only a small percentage of patients, predominantly S. pneumoniae. False-positive BC rates can be substantial. The 3 studies that examined BC-driven changes in management had conflicting results. This systematic review was limited by heterogeneous case definitions, which may overestimate the true prevalence of positive BCs in hospitalized children. PMID- 26034165 TI - Impact of antibiotic pretreatment on bone biopsy yield for children with acute hematogenous osteomyelitis. AB - OBJECTIVE: Pediatric acute hematogenous osteomyelitis (AHO) is a relatively common reason for hospitalization, but many variables require additional study, including the impact of antibiotic treatment on bone biopsy culture yield. METHODS: This was a retrospective study of children 60 days to 18 years old with AHO seen from 2011 to 2012 in whom bone biopsy cultures were obtained. RESULTS: A total of 67 children had biopsies; median age was 7 years; 40 were pretreated with antibiotics. Microbiologic confirmation was obtained for 72%: in 34%, both blood and bone cultures were positive; in 33%, bone cultures alone were positive; and 4% had only positive blood cultures. There was no difference in bone biopsy cultures for children who did and did not receive antibiotics before biopsy (28/40 [70%] vs 17/27 [63%], odds ratio 1.37, 95% confidence interval 0.49-3.86). For pretreated patients, the mean duration of therapy was longer in children with negative cultures (79 vs 40 hours, P=.04). Bacteremia was seen in 26 (39%), and was more common in antibiotic-pretreated children (55% vs 15%, odds ratio 7, 95% confidence interval 2.1-24.1). Among the 41 nonbacteremic children, bone cultures provided the only microbiologic diagnosis for 22 (54%): 20 Staphylococcus aureus, 2 Streptococcus pyogenes. CONCLUSIONS: In conclusion, although bone biopsy results were not affected by previous antibiotic administration, a longer duration of antibiotic therapy before bone biopsy was associated with lower culture yield. In one-third of children, only the bone biopsy resulted in an organism being isolated. As it may take longer to sterilize bone than blood, a bone biopsy/culture should be considered a crucial part of the AHO evaluation to increase diagnostic yield. PMID- 26034166 TI - An Observed Structured Teaching Evaluation Demonstrates the Impact of a Resident as-Teacher Curriculum on Teaching Competency. AB - BACKGROUND AND OBJECTIVE: Residents play a critical role in the education of peers and medical students, yet attainment of teaching skills is not routinely assessed. The primary aim of this study was to develop a novel, skill-based Observed Structured Teaching Evaluation (OSTE) and self-assessment survey to measure the impact of a resident-as-teacher curriculum on teaching competency. The secondary aim was to determine interrater reliability of the OSTE. METHODS: A prospective study quantitatively assessed intern teaching competency via videotaped teaching encounters (videos) before and after a month-long hospital medicine rotation and self-assessment surveys over a 5-month period. The intervention group received the resident-as-teacher curriculum. Videos were evaluated by 2 blinded faculty via an OSTE covering 9 skills within 3 core components: preparation, teaching, and reflection. Pre- to post-HM rotation month differences were evaluated within and between groups using the Wilcoxon signed rank test and Wilcoxon rank-sum test, respectively. RESULTS: Twenty-two of 25 (88%) control and 27 of 28 (96%) intervention interns participated; 100% of participants completed the study. The intervention group's pre-post difference for the total OSTE score and the average self-assessed competence statistically improved; however, no significant difference was seen between groups. The difference in preparation scores was significant for the intervention compared with the control. The OSTE's interrater reliability demonstrated good agreement with weighted kappas of 0.86 for preparation, 0.71 for teaching, and 0.93 for reflection. CONCLUSIONS: Implementation of an objective, skill-based OSTE detected observable changes in interns' teaching competency after implementation of a brief resident-as-teacher curriculum. The OSTE's good interrater reliability may allow standardized assessment of skill attainment over time. PMID- 26034167 TI - A 12-year-old boy with dyspnea, hypertension, hematuria, and proteinuria. PMID- 26034168 TI - Trickle-down professionalism: hidden curriculum and the pediatric hospitalist. PMID- 26034169 TI - More bark, less bite. PMID- 26034170 TI - Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells. AB - Establishment of self-tolerance in the thymus depends on promiscuous expression of tissue-restricted Ags (TRA) by thymic epithelial cells (TEC). This promiscuous gene expression (pGE) is regulated in part by the autoimmune regulator (AIRE). To evaluate the commonalities and discrepancies between AIRE-dependent and independent pGE, we analyzed the transcriptome of the three main TEC subsets in wild-type and Aire knockout mice. We found that the impact of AIRE-dependent pGE is not limited to generation of TRA. AIRE decreases, via non-cell autonomous mechanisms, the expression of genes coding for positive regulators of cell proliferation, and it thereby reduces the number of cortical TEC. In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that enhance cell cell interactions (e.g., claudins, integrins, and selectins) and are probably of prime relevance to tolerance induction. We also found that AIRE-dependent and independent TRA present several distinctive features. In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater splicing complexity. Furthermore, we report that AIRE-dependent versus independent TRA project nonredundant representations of peripheral tissues in the thymus. PMID- 26034171 TI - Neonatal Basophils Stifle the Function of Early-Life Dendritic Cells To Curtail Th1 Immunity in Newborn Mice. AB - Neonatal immunity exhibits weak Th1 but excessive Th2 responses, and the underlying mechanisms remain elusive. In this article, we show that neonatal basophils readily produce IL-4, a cytokine that proved to be pivotal in shaping the programs of both lymphocyte subsets. Besides promoting Th2 programs, IL-4 is captured by the IL-4 heteroreceptor (IL-4Ralpha/IL-13Ralpha1) expressed on dendritic cells and instigates IL-12 downregulation. Under these circumstances, differentiating Th1 cells upregulate IL-13Ralpha1, leading to an unusual expression of the heteroreceptor, which will serve as a death marker for these Th1 cells during rechallenge with Ag. The resulting Th1/Th2 imbalance impacts childhood immunity culminating in sensitivity to allergic reactions, susceptibility to microbial infection and perhaps poor efficacy of pediatric vaccines. PMID- 26034172 TI - Bruton's Tyrosine Kinase Synergizes with Notch2 To Govern Marginal Zone B Cells in Nonobese Diabetic Mice. AB - Expansion of autoimmune-prone marginal zone (MZ) B cells has been implicated in type 1 diabetes. To test disease contributions of MZ B cells in NOD mice, Notch2 haploinsufficiency (Notch2(+/-)) was introduced but failed to eliminate the MZ, as it does in C57BL/6 mice. Notch2(+/-)/NOD have MZ B cell numbers similar to those of wild-type C57BL/6, yet still develop diabetes. To test whether BCR signaling supports Notch2(+/-)/NOD MZ B cells, Bruton's tyrosine kinase (Btk) deficiency was introduced. Surprisingly, MZ B cells failed to develop in Btk deficient Notch2(+/-)/NOD mice. Expression of Notch2 and its transcriptional target, Hes5, was increased in NOD MZ B cells compared with C57BL/6 MZ B cells. Btk deficiency reduced Notch2(+/-) signaling exclusively in NOD B cells, suggesting that BCR signaling enhances Notch2 signaling in this autoimmune model. The role of BCR signaling was further investigated using an anti-insulin transgenic (Tg) BCR (125Tg). Anti-insulin B cells in 125Tg/Notch2(+/-)/NOD mice populate an enlarged MZ, suggesting that low-level BCR signaling overcomes reliance on Notch2. Tracking clonotypes of anti-insulin B cells in H chain-only VH125Tg/NOD mice showed that BTK-dependent selection into the MZ depends on strength of antigenic binding, whereas Notch2-mediated selection does not. Importantly, anti-insulin B cell numbers were reduced by Btk deficiency, but not Notch2 haploinsufficiency. These studies show that 1) Notch2 haploinsufficiency limits NOD MZ B cell expansion without preventing type 1 diabetes, 2) BTK supports the Notch2 pathway in NOD MZ B cells, and 3) autoreactive NOD B cell survival relies on BTK more than Notch2, regardless of MZ location, which may have important implications for disease-intervention strategies. PMID- 26034173 TI - The Importance of IL-6 in the Development of LAT-Mediated Autoimmunity. AB - Linker for activation of T cells (LAT) is a transmembrane adaptor protein that is highly tyrosine phosphorylated upon engagement of the TCR. Phosphorylated LAT binds Grb2, Gads, and phospholipase C (PLC)gamma1 to mediate T cell activation, proliferation, and cytokine production. T cells from mice harboring a mutation at the PLCgamma1 binding site of LAT (Y136F) have impaired calcium flux and Erk activation. Interestingly, these T cells are highly activated, resulting in the development of a lymphoproliferative syndrome in these mice. CD4(+) T cells in LATY136F mice are Th2 skewed, producing large amounts of IL-4. In this study, we showed that the LATY136F T cells could also overproduce IL-6 due to activated NF kappaB, AKT, and p38 pathways. By crossing LATY136F mice with IL-6-deficient mice, we demonstrated that IL-6 is required for uncontrolled T cell expansion during the early stage of disease development. Reduced CD4(+) T cell expansion was not due to a further block in thymocyte development or an increase in the number of regulatory T cells, but was caused by reduction in cell survival. In aged IL-6(-/-) LATY136F mice, CD4(+) T cells began to hyperproliferate and induced splenomegaly; however, isotype switching and autoantibody production were diminished. Our data indicated that the LAT-PLCgamma1 interaction is important for controlling IL-6 production by T cells and demonstrated a critical role of IL 6 in the development of this lymphoproliferative syndrome. PMID- 26034174 TI - Cutting Edge: Roles for Batf3-Dependent APCs in the Rejection of Minor Histocompatibility Antigen-Mismatched Grafts. AB - In transplantation, a major obstacle for graft acceptance in MHC-matched individuals is the mismatch of minor histocompatibility Ags. Minor histocompatibility Ags are peptides derived from polymorphic proteins that can be presented by APCs on MHC molecules. The APC subtype uniquely responsible for the rejection of minor Ag-mismatched grafts has not yet been identified. In this study, we examined graft rejection in three mouse models: 1) mismatch of male specific minor Ags, 2) mismatch of minor Ags distinct from male-specific minor Ags, and 3) skin transplant. This study demonstrates that in the absence of pathogen-associated molecular patterns, Batf3-dependent dendritic cells elicit the rejection of cells and grafts expressing mismatched minor Ags. The implication of our findings in clinical transplantation may be significant, as minor Ag reactivity has been implicated in the pathogenesis of multiple allograft tissues. PMID- 26034176 TI - The role of social media in reducing stigma and discrimination. AB - This editorial explores the implications of social media practices whereby people with mental health problems share their experiences in online public spaces and challenge mental health stigma. Social media enable individuals to bring personal experience into the public domain with the potential to affect public attitudes and mainstream media. We draw tentative conclusions regarding the use of social media by campaigning organisations. PMID- 26034175 TI - CD11c-Expressing B Cells Are Located at the T Cell/B Cell Border in Spleen and Are Potent APCs. AB - In addition to the secretion of Ag-specific Abs, B cells may play an important role in the generation of immune responses by efficiently presenting Ag to T cells. We and other investigators recently described a subpopulation of CD11c(+) B cells (Age/autoimmune-associated B cells [ABCs]) that appear with age, during virus infections, and at the onset of some autoimmune diseases and participate in autoimmune responses by secreting autoantibodies. In this study, we assessed the ability of these cells to present Ag and activate Ag-specific T cells. We demonstrated that ABCs present Ag to T cells, in vitro and in vivo, better than do follicular B cells (FO cells). Our data indicate that ABCs express higher levels of the chemokine receptor CCR7, have higher responsiveness to CCL21 and CCL19 than do FO cells, and are localized at the T/B cell border in spleen. Using multiphoton microscopy, we show that, in vivo, CD11c(+) B cells form significantly more stable interactions with T cells than do FO cells. Together, these data identify a previously undescribed role for ABCs as potent APCs and suggest another potential mechanism by which these cells can influence immune responses and/or the development of autoimmunity. PMID- 26034177 TI - Closing forensic psychiatric hospitals in Italy: a new revolution begins? AB - On 30 May 2014 the Italian Parliament approved a new law regarding forensic psychiatric hospitals. Forensic psychiatric hospitals are facilities that admit individuals who have committed a criminal offence but lack criminal responsibility because of a mental disorder and are deemed as dangerous to public safety. Here we report the key aspects of the new legislation together with some critical considerations. PMID- 26034178 TI - Learning and performance outcomes of mental health staff training in de escalation techniques for the management of violence and aggression. AB - BACKGROUND: De-escalation techniques are a recommended non-physical intervention for the management of violence and aggression in mental health. Although taught as part of mandatory training for all National Health Service (NHS) mental health staff, there remains a lack of clarity around training effectiveness. AIMS: To conduct a systematic review of the learning, performance and clinical safety outcomes of de-escalation techniques training. METHOD: The review process involved a systematic literature search of 20 electronic databases, eligibility screening of results, data extraction, quality appraisal and data synthesis. RESULTS: A total of 38 relevant studies were identified. The strongest impact of training appears to be on de-escalation-related knowledge, confidence to manage aggression and deescalation performance (although limited to artificial training scenarios). No strong conclusions could be drawn about the impact of training on assaults, injuries, containment and organisational outcomes owing to the low quality of evidence and conflicting results. CONCLUSIONS: It is assumed that de escalation techniques training will improve staff's ability to de-escalate violent and aggressive behaviour and improve safety in practice. There is currently limited evidence that this training has these effects. PMID- 26034179 TI - How much therapy is too much? - extra. PMID- 26034183 TI - Guidance on switching away from Piportil Depot(r) (pipotiazine palmitate) injection. PMID- 26034184 TI - Undergraduate psychiatry teaching should happen in primary care. PMID- 26034185 TI - Authors' reply. PMID- 26034186 TI - Comorbid medical illness in bipolar disorder. PMID- 26034187 TI - Authors' reply. PMID- 26034188 TI - Kaleidoscope. PMID- 26034191 TI - Decision-making in female fertility preservation is balancing the expected burden of fertility preservation treatment and the wish to conceive. AB - STUDY QUESTION: What are the decisive factors in fertility preservation (FP) decision-making in young women scheduled for gonadotoxic therapy? SUMMARY ANSWER: FP decision-making in young women scheduled for gonadotoxic therapy is mainly based on weighing two issues: the intensity of the wish to conceive a child in the future and the expected burden of undergoing FP treatment. WHAT IS KNOWN ALREADY: Future fertility is of importance for young cancer patients whose reproductive function is being threatened by oncological therapy. To prevent or reduce severe psychological effects of infertility as well as feelings of regret about their FP decision after cancer treatment, the quality of fertility preservation counselling (FPC) should be improved. To improve care, those issues forming a decisive factor in FP decision-making for patients should be clarified, as these issues deserve extensive discussion during FPC. Until now, decisive factors have not been isolated from the complex interplay of all aspects of FP that women contemplate during FP decision-making. STUDY DESIGN, SIZE, DURATION: By using a mixed methods methodology, a questionnaire developed after qualitative research involving a selected group of five women who previously received FPC was retrospectively sent to eligible patients (n = 143) who had received FPC (1999 - July 2013) and to whom at least one FP option was offered. PARTICIPANTS/MATERIALS, SETTING, METHODS: Patients had received FPC at a university hospital in the Netherlands, in a setting where financial factors do not play a role in FP. They were aged >=16 years and were scheduled for gonadotoxic treatment. The relationship between patients' baseline characteristics, their attributed importance to 28 relevant importance items and their FP choices was investigated. MAIN RESULTS AND THE ROLE OF CHANCE: After five interviews, 28 importance items for FP decision-making were identified and included in our questionnaire. Of these 28 importance items, 24 items could be clustered into seven importance themes. A total of 87 patients (61%) responded to our questionnaire. After performing a multivariable logistic regression analysis, proceeding with FP was related to higher attributed importance during FP decision making to the theme 'Wish to conceive (in the future)' (odds ratio (OR) 10.8, 95% confidence interval (CI) 3.5-34.4) and the item 'Having a stable partner relationship' (OR 2.0, 95% CI 1.0-4.1), while higher attributed importance to the theme 'Expected burden of FP' during FP decision-making (OR 0.08, 95% CI 0.02 0.3) more often resulted in refraining from treatment. LIMITATIONS, REASONS FOR CAUTION: Besides possible recall and selection bias, the fact that this study was performed in Dutch patients aged >=16 years counselled in a single centre, where finance was not an additional consideration, possibly limits the generalizability of our results to a broader European population of cancer patients. Furthermore, we are not able to draw conclusions about the causality of the associations observed in our study. WIDER IMPLICATIONS OF THE FINDINGS: The wish to conceive and the expected burden of FP treatment should be discussed carefully with patients during FP decision-making, either by the referring healthcare provider or by reproductive medicine specialist. Prospective research is needed to explore the causality of the associations found in this study. Furthermore, in order to deliver high quality patient-centred care, the development of tools to explore patients' wish to conceive (for example in different age categories) and tools to provide clear information about the burden of FP treatments (using the preferred information channels suggested by patients) is needed. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Radboud Institute for Health Sciences (research school affiliated to the Radboud university medical center). The authors have declared no conflicts of interest with respect to this work. PMID- 26034192 TI - The sedentary office: an expert statement on the growing case for change towards better health and productivity. AB - An international group of experts convened to provide guidance for employers to promote the avoidance of prolonged periods of sedentary work. The set of recommendations was developed from the totality of the current evidence, including long-term epidemiological studies and interventional studies of getting workers to stand and/or move more frequently. The evidence was ranked in quality using the four levels of the American College of Sports Medicine. The derived guidance is as follows: for those occupations which are predominantly desk based, workers should aim to initially progress towards accumulating 2 h/day of standing and light activity (light walking) during working hours, eventually progressing to a total accumulation of 4 h/day (prorated to part-time hours). To achieve this, seated-based work should be regularly broken up with standing-based work, the use of sit-stand desks, or the taking of short active standing breaks. Along with other health promotion goals (improved nutrition, reducing alcohol, smoking and stress), companies should also promote among their staff that prolonged sitting, aggregated from work and in leisure time, may significantly and independently increase the risk of cardiometabolic diseases and premature mortality. It is appreciated that these recommendations should be interpreted in relation to the evidence from which they were derived, largely observational and retrospective studies, or short-term interventional studies showing acute cardiometabolic changes. While longer term intervention studies are required, the level of consistent evidence accumulated to date, and the public health context of rising chronic diseases, suggest initial guidelines are justified. We hope these guidelines stimulate future research, and that greater precision will be possible within future iterations. PMID- 26034193 TI - Femoral cannulation: a safe vascular access option for cardiopulmonary bypass in minimally invasive cardiac surgery. AB - Femoral cannulation during cardiopulmonary bypass has become a common approach for many cardiac procedures and serves as an important access option, especially during minimally invasive cardiac surgery. Opponents, however, argue that there is significant risk, including site-specific and overall morbidity, which makes the use of this modality dangerous compared to conventional aortoatrial cannulation techniques. We analyzed our institutional experience to elucidate the safety and efficacy of femoral cannulation. All data were collected from a single hospital's cardiac surgery database. A total of 346 cardiac surgeries were evaluated from September 2012 to September 2013, of which 85/346 (24.6%) utilized a minimally invasive approach. Of the 346 operations performed, 72/346 (20.8%) utilized femoral cannulation while 274/346 (79.2%) used aortoatrial cannulation. Stroke occurred in 1/72 (1.39%) after femoral cannulation, specifically, in a conventional sternotomy patient, while it occurred in 6/274 (2.19%) [p=0.67] after aortoatrial cannulation. When comparing postoperative complications between the femoral cannulation and aortoatrial cannulation groups, the rates of atrial fibrillation [10/72 (13.9%) versus 46/274 (16.8%), p=0.55], renal failure [2/72 (2.78%) versus 11/274 (4.01%), p=0.62], prolonged ventilation time [4/72 (5.56%) versus 27/274 (9.85%), p=0.26] and re-operation for bleeding [3/72 (4.17%) versus 13/274 (4.74%), p=0.84] showed no significant difference. Selective femoral cannulation provides a safe alternative to aortoatrial cannulation for cardiopulmonary bypass and is especially important when performing minimally invasive cardiac surgery. When comparing aortoatrial and femoral cannulation, we found no significant difference in the postoperative complication rates and overall mortality. PMID- 26034194 TI - Are perioperative near-infrared spectroscopy values correlated with clinical and biochemical parameters in cyanotic and acyanotic infants following corrective cardiac surgery? AB - BACKGROUND: Near-infrared spectroscopy (NIRS) is a useful non-invasive tool for monitoring infants undergoing cardiac surgery. In this study, we aimed to determine the NIRS values in cyanotic and acyanotic patients who underwent corrective cardiac surgery for congenital heart diseases. METHODS: Thirty consecutive infants who were operated on with the diagnosis of ventricular septal defect (n=15) and tetralogy of Fallot (n=15) were evaluated retrospectively. A definitive repair of the underlying cardiac pathology was achieved in all cases. A total of six measurements of cerebral and renal NIRS were performed at different stages of the perioperative period. The laboratory data, mean urine output and serum lactate levels were evaluated along with NIRS values in each group. RESULTS: The NIRS values differ in both groups, even after the corrective surgical procedure is performed. The recovery of renal NIRS values is delayed in the cyanotic patients. CONCLUSION: Even though definitive surgical repair is performed in cyanotic infants, recovery of the renal vasculature may be delayed by up to two days, which is suggestive of a vulnerable period for renal dysfunction. PMID- 26034195 TI - Protecting the aged heart during cardiac surgery: single-dose del Nido cardioplegia is superior to multi-dose del Nido cardioplegia in isolated rat hearts. AB - BACKGROUND: Aged hearts are particularly vulnerable to reperfusion injury. We recently showed that single-dose del Nido cardioplegia was superior to 'standard' multi-dose 4:1 blood cardioplegia in aged rat hearts. This study seeks to determine if multi-dose del Nido cardioplegia offers additional benefits over single-dose del Nido cardioplegia. METHODS: Functional recovery after 60 min of cardioplegic arrest was assessed in isolated, working, senescent rat hearts. Single-dose del Nido cardioplegia (n=14) was compared to multi-dose del Nido cardioplegia (n=12) delivered every 20 min. RESULTS: Troponin release during reperfusion was similar in the single (0.263 +/- 0.056 ng/ml) and multi-dose groups (0.261 +/- 0.055 ng/ml). Although functional recovery was similar early after reperfusion (stroke work 91 +/- 6 ml*mmHg*g(-1) vs. 91 +/- 8 ml*mmHg*g(-1) for single- vs. multi-dose), it declined over time in the multi-dose group (71 +/ 9 vs. 43 +/- 9 ml*mmHg*g(-1) at 60 min, p=0.0175) CONCLUSIONS: In aged rat hearts, a single-dose del Nido cardioplegia strategy results in superior functional recovery compared to a multi-dose del Nido cardioplegia strategy. PMID- 26034196 TI - Evidence-based practice knowledge and perfusionists' clinical behavior. AB - INTRODUCTION: Evidence-based practice (EBP) has been widely studied and adopted in allied health professions education. Current practitioners may have challenges in adopting EBP into current practice. EBP skills have not been previously assessed in perfusionists, therefore, the purpose of this study is to identify a preliminary analysis of perfusionists' EBP knowledge and its possible relationship to clinical behavior and educational level METHODS: A non-randomized convenience study using the Evidence-Based Practice Questionnaire (EBPQ) was used to measure EBP of practicing U.S. perfusionists. The EBPQ is a validated survey instrument designed to measure EBP practice, attitude and knowledge subscales. The EBPQ consisted of 24 items on a 1 to 7 Likert Scale, with higher numbers indicating frequent use of skill. Practitioner experience, educational background and employment type were also collected. RESULTS: Two hundred and fifty-four responses met the inclusion criteria and were analyzed. The mean EBPQ score was 5.0 (SD = 0.9) with similar means for the subscales. There were important differences found in the EBPQ scores, depending on the educational level and work status. There was a positive correlation between the knowledge and practice subscales, demonstrating a relationship in the sample and a possible relationship in the population as a whole. CONCLUSION: The results suggest that perfusionists' use of EBP in practice does vary, based upon educational level and employment type. The findings also demonstrated areas of lower EBP aptitude. The correlation between EBP knowledge and practice may guide educational efforts at improving EBP practice. PMID- 26034197 TI - Novel use of the AngioVac(r) system to remove thrombus during simultaneous extracorporeal membrane oxygenation life support. AB - Extracorporeal membrane oxygenation (ECMO) was introduced to clinical medicine over 40 years ago. While initially used as a treatment for acute respiratory failure in infants, the use of ECMO has grown to include respiratory and circulatory failure in both children and adults, cardiogenic shock, pulmonary embolism, sepsis, trauma, malignancy, pulmonary hemorrhage and as a treatment for hypothermic drowning.(1) Recent technological improvements in ECMO circuitry make it possible to minimize anticoagulation of the ECMO patient, decreasing the incidence of bleeding. Thrombus deposition within the ECMO circuit can be a life threating complication. ECMO circuit thrombus can be contained in the circuit, adherent to cannula and deposited within the patient. The ability to remove thrombus while the patient remains on ECMO support could be a life-saving measure for some patients. The present case report outlines use of the AngioVac((r)) thrombus removal system in concert with ECMO to remove a large thrombus adherent to an ECMO cannula. PMID- 26034198 TI - Minimized extracorporeal circulation is improving outcome of coronary artery bypass surgery in the elderly. AB - Advanced age is a known risk factor for morbidity and mortality after coronary artery bypass grafting (CABG). Minimized extracorporeal circulation (MECC) has been shown to reduce the negative effects associated with conventional extracorporeal circulation (CECC). This trial assesses the impact of MECC on the outcome of elderly patients undergoing CABG. Eight hundred and seventy-five patients (mean age 78.35 years) underwent isolated CABG using CECC (n=345) or MECC (n=530). The MECC group had a significantly shorter extracorporeal circulation time (ECCT), cross-clamp time and reperfusion time and lower transfusion needs. Postoperatively, these patients required significantly less inotropic support, fewer blood transfusions, less postoperative hemodialysis and developed less delirium compared to CECC patients. In the MECC group, intensive care unit (ICU) stay was significantly shorter and 30-day mortality was significantly reduced [2.6% versus 7.8%; p<0.001]. In conclusion, MECC improves outcome in elderly patients undergoing CABG surgery. PMID- 26034199 TI - Interferon-Induced Transmembrane Protein-Mediated Inhibition of Host Cell Entry of Ebolaviruses. AB - Ebolaviruses are highly pathogenic in humans and nonhuman primates and pose a severe threat to public health. The interferon-induced transmembrane (IFITM) proteins can restrict entry of ebolaviruses, influenza A viruses, and other enveloped viruses. However, the breadth and mechanism of the antiviral activity of IFITM proteins are incompletely understood. Here, we employed ebolavirus glycoprotein-pseudotyped vectors and ebolavirus-like particles to address this question. We show that IFITM proteins inhibit the cellular entry of diverse ebolaviruses and demonstrate that type I interferon induces IFITM protein expression in macrophages, major viral targets. Moreover, we show that IFITM proteins block entry of influenza A viruses and ebolaviruses by different mechanisms and provide evidence that antibodies and IFITM proteins can synergistically inhibit cellular entry of ebolaviruses. These results provide insights into the role of IFITM proteins in infection by ebolaviruses and suggest a mechanism by which antibodies, though poorly neutralizing in vitro, might contribute to viral control in vivo. PMID- 26034200 TI - AMPK Dilates Resistance Arteries via Activation of SERCA and BKCa Channels in Smooth Muscle. AB - The protective effects of 5'-AMP-activated protein kinase (AMPK) on the metabolic syndrome may include direct effects on resistance artery vasomotor function. However, the precise actions of AMPK on microvessels and their potential interaction are largely unknown. Thus, we set to determine the effects of AMPK activation on vascular smooth muscle tone and the underlying mechanisms. Resistance arteries isolated from hamster and mouse exhibited a pronounced endothelium-independent dilation on direct pharmacological AMPK activation by 2 structurally unrelated compounds (PT1 and A769662). The dilation was associated with a decrease of intracellular-free calcium [Ca(2+)]i in vascular smooth muscle cell. AMPK stimulation induced activation of BKCa channels as assessed by patch clamp studies in freshly isolated hamster vascular smooth muscle cell and confirmed by direct proof of membrane hyperpolarization in intact arteries. The BKCa channel blocker iberiotoxin abolished the hyperpolarization but only partially reduced the dilation and did not affect the decrease of [Ca(2+)]i. By contrast, the sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) inhibitor thapsigargin largely reduced these effects, whereas combined inhibition of SERCA and BKCa channels virtually abolished them. AMPK stimulation significantly increased the phosphorylation of the SERCA modulator phospholamban at the regulatory T17 site. Stimulation of smooth muscle AMPK represents a new, potent vasodilator mechanism in resistance vessels. AMPK directly relaxes vascular smooth muscle cell by a decrease of [Ca(2+)]i. This is achieved by calcium sequestration via SERCA activation, as well as activation of BKCa channels. There is in part a mutual compensation of both calcium-lowering mechanisms. However, SERCA activation which involves an AMPK-dependent phosphorylation of phospholamban is the predominant mechanism in resistance vessels. PMID- 26034201 TI - Superoxide enhances Ca2+ entry through L-type channels in the renal afferent arteriole. AB - Reactive oxygen species regulate cardiovascular and renal function in health and disease. Superoxide participates in acute calcium signaling in afferent arterioles and renal vasoconstriction produced by angiotensin II, endothelin, thromboxane, and pressure-induced myogenic tone. Known mechanisms by which superoxide acts include quenching of nitric oxide and increased ADP ribosyl cyclase/ryanodine-mediated calcium mobilization. The effect(s) of superoxide on other calcium signaling pathways in the renal microcirculation is poorly understood. The present experiments examined the acute effect of superoxide generated by paraquat on calcium entry pathways in isolated rat afferent arterioles. The peak increase in cytosolic calcium concentration caused by KCl (40 mmol/L) was 99+/-14 nmol/L. The response to this membrane depolarization was mediated exclusively by L-type channels because it was abolished by nifedipine but was unaffected by the T-type channel blocker mibefradil. Paraquat increased superoxide production (dihydroethidium fluorescence), tripled the peak response to KCl to 314+/-68 nmol/L (P<0.001) and doubled the plateau response. These effects were abolished by tempol and nitroblue tetrazolium, but not by catalase, confirming actions of superoxide and not of hydrogen peroxide. Unaffected by paraquat and superoxide was calcium entry through store-operated calcium channels activated by thapsigargin-induced calcium depletion of sarcoplasmic reticular stores. Also unresponsive to paraquat was ryanodine receptor-mediated calcium induced calcium release from the sarcoplasmic reticulum. Our results provide new evidence that superoxide enhances calcium entry through L-type channels activated by membrane depolarization in rat cortical afferent arterioles, without affecting calcium entry through store-operated entry or ryanodine receptor-mediated calcium mobilization. PMID- 26034202 TI - Tumor necrosis factor receptor-associated factor 3 is a positive regulator of pathological cardiac hypertrophy. AB - Cardiac hypertrophy, a common early symptom of heart failure, is regulated by numerous signaling pathways. Here, we identified tumor necrosis factor receptor associated factor 3 (TRAF3), an adaptor protein in tumor necrosis factor-related signaling cascades, as a key regulator of cardiac hypertrophy in response to pressure overload. TRAF3 expression was upregulated in hypertrophied mice hearts and failing human hearts. Four weeks after aortic banding, cardiac-specific conditional TRAF3-knockout mice exhibited significantly reduced cardiac hypertrophy, fibrosis, and dysfunction. Conversely, transgenic mice overexpressing TRAF3 in the heart developed exaggerated cardiac hypertrophy in response to pressure overload. TRAF3 also promoted an angiotensin II- or phenylephrine-induced hypertrophic response in isolated cardiomyocytes. Mechanistically, TRAF3 directly bound to TANK-binding kinase 1 (TBK1), causing increased TBK1 phosphorylation in response to hypertrophic stimuli. This interaction between TRAF3 and TBK1 further activated AKT signaling, which ultimately promoted the development of cardiac hypertrophy. Our findings not only reveal a key role of TRAF3 in regulating the hypertrophic response but also uncover TRAF3-TBK1-AKT as a novel signaling pathway in the development of cardiac hypertrophy and heart failure. This pathway may represent a potential therapeutic target for this pathological process. PMID- 26034203 TI - Metabolomic identification of a novel pathway of blood pressure regulation involving hexadecanedioate. AB - High blood pressure is a major contributor to the global burden of disease and discovering novel causal pathways of blood pressure regulation has been challenging. We tested blood pressure associations with 280 fasting blood metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality was performed on significant independent metabolites (P<8.9*10(-5)). Replication was conducted in 2 independent cohorts KORA (n=1494) and Hertfordshire (n=1515). Three independent animal experiments were performed to establish causality: (1) blood pressure change after increasing circulating metabolite levels in Wistar Kyoto rats; (2) circulating metabolite change after salt-induced blood pressure elevation in spontaneously hypertensive stroke-prone rats; and (3) mesenteric artery response to noradrenaline and carbachol in metabolite treated and control rats. Of the15 metabolites that showed an independent significant association with blood pressure, only hexadecanedioate, a dicarboxylic acid, showed concordant association with blood pressure (systolic BP: beta [95% confidence interval], 1.31 [0.83-1.78], P=6.81*10(-8); diastolic BP: 0.81 [0.5-1.11], P=2.96*10(-7)) and mortality (hazard ratio [95% confidence interval], 1.49 [1.08 2.05]; P=0.02) in TwinsUK. The blood pressure association was replicated in KORA and Hertfordshire. In the animal experiments, we showed that oral hexadecanedioate increased both circulating hexadecanedioate and blood pressure in Wistar-Kyoto rats, whereas blood pressure elevation with oral sodium chloride in hypertensive rats did not affect hexadecanedioate levels. Vascular reactivity to noradrenaline was significantly increased in mesenteric resistance arteries from hexadecanedioate-treated rats compared with controls, indicated by the shift to the left of the concentration-response curve (P=0.013). Relaxation to carbachol did not show any difference. Our findings indicate that hexadecanedioate is causally associated with blood pressure regulation through a novel pathway that merits further investigation. PMID- 26034204 TI - Comparing You = Comparing Me: Social Comparisons of the Expanded Self. AB - We examine whether individuals respond to comparisons involving romantic partners as they would to comparisons involving the self. Four studies (N = 2,210) using recalled (Studies 1-3) and actual (Study 4) comparisons about attractiveness (Study 1) and relationship skills (Studies 2-4) demonstrated that individuals high in self-other overlap decrease domain relevance following upward but not downward comparisons to protect their positive partner perceptions. This strategy was absent among those low in self-other overlap. Study 2 demonstrated that this effect extends to best friends, but not casual friends, due to the degree of self other overlap. Furthermore, when reminded of their partner's inferiority in a domain, high overlap participants maintained positive global partner perceptions, whereas low overlap participants' global perceptions were negatively affected (Study 3). These results suggest that individuals do experience partner-other comparisons as if they were directly involved, but only if their partner is incorporated into their self-identity. PMID- 26034205 TI - The future of murine sepsis and trauma research models. AB - Recent comparisons of the murine and human transcriptome in health and disease have called into question the appropriateness of the use of murine models for human sepsis and trauma research. More specifically, researchers have debated the suitability of mouse models of severe inflammation that is intended for eventual translation to human patients. This mini-review outlines this recent research, as well as specifically defines the arguments for and against murine models of sepsis and trauma research based on these transcriptional studies. In addition, we review newer advancements in murine models of infection and injury and define what we envision as an evolving but viable future for murine studies of sepsis and trauma. PMID- 26034206 TI - CD4+CD28null T lymphocytes resemble CD8+CD28null T lymphocytes in their responses to IL-15 and IL-21 in HIV-infected patients. AB - HIV-infected individuals suffer from accelerated immunologic aging. One of the most prominent changes during T lymphocyte aging is the accumulation of CD28(null) T lymphocytes, mainly CD8(+) but also CD4(+) T lymphocytes. Enhancing the functional properties of these cells may be important because they provide antigen-specific defense against chronic infections. The objective of this study was to compare the responses of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes from HIV-infected patients to the immunomodulatory effects of cytokines IL-15 and IL-21. We quantified the frequencies of CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes in peripheral blood from 110 consecutive, HIV infected patients and 25 healthy controls. Patients showed increased frequencies of CD4(+)CD28(null) and CD8(+)CD28(null). Both subsets were positively correlated to each other and showed an inverse correlation with the absolute counts of CD4(+) T lymphocytes. Higher frequencies of HIV-specific and CMV-specific cells were found in CD28(null) than in CD28(+) T lymphocytes. Activation of STAT5 by IL 15 and STAT3 by IL-21 was higher in CD28(null) compared with CD28(+) T lymphocytes. Proliferation, expression of CD69, and IFN-gamma production in CD28(null) T lymphocytes were increased after treatment with IL-15, and IL-21 potentiated most of those effects. Nevertheless, IL-21 alone reduced IFN-gamma production in response to anti-CD3 stimulation but increased CD28 expression, even counteracting the inhibitory effect of IL-15. Intracytoplasmic stores of granzyme B and perforin were increased by IL-15, whereas IL-21 and simultaneous treatment with the 2 cytokines also significantly enhanced degranulation in CD4(+)CD28(null) and CD8(+)CD28(null) T lymphocytes. IL-15 and IL-21 could have a role in enhancing the effector response of CD28(null) T lymphocytes against their specific chronic antigens in HIV-infected patients. PMID- 26034207 TI - Delta9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells. AB - Immune cells have been shown to express cannabinoid receptors and to produce endogenous ligands. Moreover, activation of cannabinoid receptors on immune cells has been shown to trigger potent immunosuppression. Despite such studies, the role of cannabinoids in transplantation, specifically to prevent allograft rejection, has not, to our knowledge, been investigated previously. In the current study, we tested the effect of THC on the suppression of HvGD as well as rejection of skin allografts. To this end, we studied HvGD by injecting H-2(k) splenocytes into H-2(b) mice and analyzing the immune response in the draining ingLNs. THC treatment significantly reduced T cell proliferation and activation in draining LNs of the recipient mice and decreased early stage rejection indicator cytokines, including IL-2 and IFN-gamma. THC treatment also increased the allogeneic skin graft survival. THC treatment in HvGD mice led to induction of MDSCs. Using MDSC depletion studies as well as adoptive transfer experiments, we found that THC-induced MDSCs were necessary for attenuation of HvGD. Additionally, using pharmacological inhibitors of CB1 and CB2 receptors and CB1 and CB2 knockout mice, we found that THC was working preferentially through CB1. Together, our research shows, for the first time to our knowledge, that targeting cannabinoid receptors may provide a novel treatment modality to attenuate HvGD and prevent allograft rejection. PMID- 26034208 TI - Altered effector functions of NK cells in chronic hepatitis C are associated with IFNL3 polymorphism. AB - Interferon alpha-mediated effector functions of NK cells may contribute to the control of HCV replication and the pathogenesis of liver disease. The single nucleotide polymorphism rs12979860 near IFNL3 (previously known as IL28B) is important in response to IFN-alpha treatment and in spontaneous resolution of acute hepatitis C. The role of the IFNL3 polymorphism in NK cell function is unclear. Thus, we investigated the role of IFNL3 polymorphism in type I IFN dependent regulation of NK cell functions in patients with cHC and healthy control subjects. We demonstrated a marked polarization of NK cells toward cytotoxicity in response to IFN-alpha stimulation in patients with hepatitis C. That TRAIL up-regulation was present, particularly in patients with the IFNL3-TT allele, was supported by a shift in the pSTAT-1:pSTAT-4 ratios toward pSTAT-1. In patients bearing the IFNL3-TT allele, NK cell effector function correlated with liver disease activity. In contrast, higher cytokine production of NK cells was observed in healthy individuals with the IFNL3-CC genotype, which may support spontaneous HCV clearance in acute infection. Overall, these findings show that the role of NK cells may differ in chronic infection vs. early antiviral defense and that the IFNL3 genotype differentially influences NK cell function. PMID- 26034209 TI - Noncanonical activation of beta-catenin by Porphyromonas gingivalis. AB - Porphyromonas gingivalis is an established pathogen in periodontal disease and an emerging pathogen in serious systemic conditions, including some forms of cancer. We investigated the effect of P. gingivalis on beta-catenin signaling, a major pathway in the control of cell proliferation and tumorigenesis. Infection of gingival epithelial cells with P. gingivalis did not influence the phosphorylation status of beta-catenin but resulted in proteolytic processing. The use of mutants deficient in gingipain production, along with gingipain specific inhibitors, revealed that gingipain proteolytic activity was required for beta-catenin processing. The beta-catenin destruction complex components Axin1, adenomatous polyposis coli (APC), and GSK3beta were also proteolytically processed by P. gingivalis gingipains. Cell fractionation and Western blotting demonstrated that beta-catenin fragments were translocated to the nucleus. The accumulation of beta-catenin in the nucleus following P. gingivalis infection was confirmed by immunofluorescence microscopy. A luciferase reporter assay showed that P. gingivalis increased the activity of the beta-catenin-dependent TCF/LEF promoter. P. gingivalis did not increase Wnt3a mRNA levels, a finding consistent with P. gingivalis-induced proteolytic processing causing the increase in TCF/LEF promoter activity. Thus, our data indicate that P. gingivalis can induce the noncanonical activation of beta-catenin and disassociation of the beta-catenin destruction complex by gingipain-dependent proteolytic processing. beta-Catenin activation in epithelial cells by P. gingivalis may contribute to a proliferative phenotype. PMID- 26034210 TI - Sensing of interleukin-1 cytokines during Streptococcus pneumoniae colonization contributes to macrophage recruitment and bacterial clearance. AB - Streptococcus pneumoniae (the pneumococcus), a leading cause of bacterial disease, is most commonly carried in the human nasopharynx. Colonization induces inflammation that promotes the organism's growth and transmission. This inflammatory response is dependent on intracellular sensing of bacterial components that access the cytosolic compartment via the pneumococcal pore forming toxin pneumolysin. In vitro, cytosolic access results in cell death that includes release of the proinflammatory cytokine interleukin-1beta (IL-1beta). IL 1 family cytokines, including IL-1beta, are secreted upon activation of inflammasomes, although the role of this activation in the host immune response to pneumococcal carriage is unknown. Using a murine model of pneumococcal nasopharyngeal colonization, we show that mice deficient in the interleukin-1 receptor type 1 (Il1r1(-/-)) have reduced numbers of neutrophils early after infection, fewer macrophages later in carriage, and prolonged bacterial colonization. Moreover, intranasal administration of Il-1beta promoted clearance. Macrophages are the effectors of clearance, and characterization of macrophage chemokines in colonized mice revealed that Il1r1(-/-) mice have lower expression of the C-C motif chemokine ligand 6 (CCL6), correlating with reduced macrophage recruitment to the nasopharynx. IL-1 family cytokines are known to promote adaptive immunity; however, we observed no difference in the development of humoral or cellular immunity to pneumococcal colonization between wild-type and Il1r1(-/-) mice. Our findings show that sensing of IL-1 cytokines during colonization promotes inflammation without immunity, which may ultimately benefit the pneumococcus. PMID- 26034211 TI - Preserved dendritic cell HLA-DR expression and reduced regulatory T cell activation in asymptomatic Plasmodium falciparum and P. vivax infection. AB - Clinical illness with Plasmodium falciparum or Plasmodium vivax compromises the function of dendritic cells (DC) and expands regulatory T (Treg) cells. Individuals with asymptomatic parasitemia have clinical immunity, restricting parasite expansion and preventing clinical disease. The role of DC and Treg cells during asymptomatic Plasmodium infection is unclear. During a cross-sectional household survey in Papua, Indonesia, we examined the number and activation of blood plasmacytoid DC (pDC), CD141(+), and CD1c(+) myeloid DC (mDC) subsets and Treg cells using flow cytometry in 168 afebrile children (of whom 15 had P. falciparum and 36 had P. vivax infections) and 162 afebrile adults (of whom 20 had P. falciparum and 20 had P. vivax infections), alongside samples from 16 patients hospitalized with uncomplicated malaria. Unlike DC from malaria patients, DC from children and adults with asymptomatic, microscopy-positive P. vivax or P. falciparum infection increased or retained HLA-DR expression. Treg cells in asymptomatic adults and children exhibited reduced activation, suggesting increased immune responsiveness. The pDC and mDC subsets varied according to clinical immunity (asymptomatic or symptomatic Plasmodium infection) and, in asymptomatic infection, according to host age and parasite species. In conclusion, active control of asymptomatic infection was associated with and likely contingent upon functional DC and reduced Treg cell activation. PMID- 26034212 TI - Interleukin-1 (IL-1) signaling in intestinal stromal cells controls KC/ CXCL1 secretion, which correlates with recruitment of IL-22- secreting neutrophils at early stages of Citrobacter rodentium infection. AB - Attaching and effacing pathogens, including enterohemorrhagic Escherichia coli in humans and Citrobacter rodentium in mice, raise serious public health concerns. Here we demonstrate that interleukin-1 receptor (IL-1R) signaling is indispensable for protection against C. rodentium infection in mice. Four days after infection with C. rodentium, there were significantly fewer neutrophils (CD11b+ Ly6C+ Ly6G+) in the colons of IL-1R-/- mice than in wild-type mice. Levels of mRNA and protein of KC/CXCL1 were also significantly reduced in colon homogenates of infected IL-1R-/- mice relative to wild-type mice. Of note, infiltrated CD11b+ Ly6C+ Ly6G+ neutrophils were the main source of IL-22 secretion after C. rodentium infection. Interestingly, intestinal stromal cells isolated from IL-1R-/- mice secreted lower levels of KC/CXCL1 than stromal cells from wild-type mice during C. rodentium infection. Similar effects were found when mouse intestinal stromal cells and human nasal polyp stromal cells were treated with IL-1R antagonists (i.e., anakinra) in vitro. These results suggest that IL-1 signaling plays a pivotal role in activating mucosal stromal cells to secrete KC/CXCL1, which is essential for infiltration of IL-22-secreting neutrophils upon bacterial infection. PMID- 26034213 TI - Microinjection of Francisella tularensis and Listeria monocytogenes reveals the importance of bacterial and host factors for successful replication. AB - Certain intracellular bacteria use the host cell cytosol as the replicative niche. Although it has been hypothesized that the successful exploitation of this compartment requires a unique metabolic adaptation, supportive evidence is lacking. For Francisella tularensis, many genes of the Francisella pathogenicity island (FPI) are essential for intracellular growth, and therefore, FPI mutants are useful tools for understanding the prerequisites of intracytosolic replication. We compared the growth of bacteria taken up by phagocytic or nonphagocytic cells with that of bacteria microinjected directly into the host cytosol, using the live vaccine strain (LVS) of F. tularensis; five selected FPI mutants thereof, i.e., DeltaiglA, DeltaiglC DeltaiglG, DeltaiglI, and DeltapdpE strains; and Listeria monocytogenes. After uptake in bone marrow-derived macrophages (BMDM), ASC(-/-) BMDM, MyD88(-/-) BMDM, J774 cells, or HeLa cells, LVS, DeltapdpE and DeltaiglG mutants, and L. monocytogenes replicated efficiently in all five cell types, whereas the DeltaiglA and DeltaiglC mutants showed no replication. After microinjection, all 7 strains showed effective replication in J774 macrophages, ASC(-/-) BMDM, and HeLa cells. In contrast to the rapid replication in other cell types, L. monocytogenes showed no replication in MyD88( /-) BMDM and LVS showed no replication in either BMDM or MyD88(-/-) BMDM after microinjection. Our data suggest that the mechanisms of bacterial uptake as well as the permissiveness of the cytosolic compartment per se are important factors for the intracytosolic replication. Notably, none of the investigated FPI proteins was found to be essential for intracytosolic replication after microinjection. PMID- 26034214 TI - Murine model of chemotherapy-induced extraintestinal pathogenic Escherichia coli translocation. AB - Escherichia coli is a major cause of life-threatening infections in patients with neutropenia, particularly those receiving chemotherapy for the treatment of cancer. In most cases, these infections originate from opportunistic strains living within the patient's gastrointestinal tract which then translocate to major organ systems. There are no animal models that faithfully recapitulate these infections, and, as such, the host or bacterial factors that govern this process remain unidentified. We present here a novel model of chemotherapy induced bacterial translocation of E. coli. Oral gavage of BALB/c mice with a clinical isolate of extraintestinal pathogenic E. coli (ExPEC) leads to stable and long-term colonization of the murine intestine. Following the induction of neutropenia with the chemotherapeutic drug cyclophosphamide, ExPEC translocates from the intestine to the lungs, liver, spleen, and kidneys with concomitant morbidity in infected animals. Translocation can also occur in mice bearing mammary tumors, even in the absence of chemotherapy. Translocation of ExPEC is also associated with an increase of the diversity of bacterial DNA detected in the blood. This is the first report of a chemotherapy-based animal model of ExPEC translocation in cancerous mice, a system that can be readily used to identify important virulence factors for this process. PMID- 26034217 TI - CCR 20th Anniversary Commentary: Determining a Pharmacokinetic/Pharmacodynamic Relationship for Sunitinib-A Look Back. AB - The article by Mendel and colleagues, published in the January 1, 2003, issue of Clinical Cancer Research, described their novel preclinical approach to developing a thorough understanding of the exposure-activity relationship for sunitinib, a multitargeted receptor tyrosine kinase inhibitor being developed for oncology therapy. This work successfully set exposure guidelines to identify a biologically active dose in early clinical trials. PMID- 26034215 TI - Interleukin-7 produced by intestinal epithelial cells in response to Citrobacter rodentium infection plays a major role in innate immunity against this pathogen. AB - Interleukin-7 (IL-7) engages multiple mechanisms to overcome chronic viral infections, but the role of IL-7 in bacterial infections, especially enteric bacterial infections, remains unclear. Here we characterized the previously unexplored role of IL-7 in the innate immune response to the attaching and effacing bacterium Citrobacter rodentium. C. rodentium infection induced IL-7 production from intestinal epithelial cells (IECs). IL-7 production from IECs in response to C. rodentium was dependent on gamma interferon (IFN-gamma)-producing NK1.1(+) cells and IL-12. Treatment with anti-IL-7Ralpha antibody during C. rodentium infection resulted in a higher bacterial burden, enhanced intestinal damage, and greater weight loss and mortality than observed with the control IgG treatment. IEC-produced IL-7 was only essential for protective immunity against C. rodentium during the first 6 days after infection. An impaired bacterial clearance upon IL-7Ralpha blockade was associated with a significant decrease in macrophage accumulation and activation in the colon. Moreover, C. rodentium induced expansion and activation of intestinal CD4(+) lymphoid tissue inducer (LTi) cells was completely abrogated by IL-7Ralpha blockade. Collectively, these data demonstrate that IL-7 is produced by IECs in response to C. rodentium infection and plays a critical role in the protective immunity against this intestinal attaching and effacing bacterium. PMID- 26034218 TI - New strategies in melanoma: entering the era of combinatorial therapy. AB - The treatment of metastatic melanoma has been revolutionized over the past decade as effective molecularly targeted therapies and immunotherapies entered the clinic. It is hoped that deeper insights into the characteristics of patients and tumors that are most responsive will allow more precise patient selection for these therapies while understanding mechanisms of resistance will facilitate the develop of rational combinations or next-generation agents aimed at novel targets. PMID- 26034220 TI - Correction: Validation of a standardized method for enumerating circulating endothelial cells and progenitors: flow cytometry and molecular and ultrastructural analyses. PMID- 26034221 TI - Correction: Gene signature-guided dasatinib therapy in metastatic breast cancer. PMID- 26034219 TI - Safety and Pharmacokinetics/Pharmacodynamics of the First-in-Class Dual Action HER3/EGFR Antibody MEHD7945A in Locally Advanced or Metastatic Epithelial Tumors. AB - PURPOSE: The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of MEHD7945A. EXPERIMENTAL DESIGN: Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3. RESULTS: No dose-limiting toxicities or MEHD7945A-related grade >= 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in >=20% of patients <=24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease >=8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non-small cell lung cancer (n = 3). CONCLUSIONS: MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer. PMID- 26034222 TI - Do atmospheric conditions influence the first episode of primary spontaneous pneumothorax? AB - OBJECTIVES: Several studies suggest that changes in airway pressure may influence the onset of primary spontaneous pneumothorax (PSP). The aim of this study was to investigate the influence of atmospheric changes on the onset of the first episode of PSP. METHODS: We retrospectively analysed cases of pneumothorax admitted to our department between 1 January 2009 and 31 October 2013. Patients with recurrent pneumothorax, traumatic pneumothorax, older than 35 years or presenting history of underlying pulmonary disease were excluded. Meteorological data were collected from the Meteo-France archives. Variation (Delta) of mean atmospheric pressure, and relative humidity, were calculated for each day between the day at which symptoms began (D-day), the day before first symptoms (D-1), 2 days before the first symptoms (D-2) and 3 days before the first symptoms (D-3). RESULTS: Six hundred and thirty-eight cases of pneumothorax were observed during the period of this study; 106 of them (16.6%) were a first episode of PSP. We did not observe any significant differences between days with or without PSP admission for any of the weather parameters that we tested. We could not find any thresholds in the variation of atmospheric pressure that could be used to determine the probability of PSP occurrence. CONCLUSIONS: Variation of atmospheric pressure, relative humidity, rainfall, wind speed and temperature were not significantly related to the onset of the first episode of PSP in healthy patients. These results suggest that the scientific community should focus on other possible aetiological factors than airway pressure modifications. PMID- 26034223 TI - Mitral valve plasty for a hammock mitral valve in an adult patient. AB - A 50-year old woman presented with arterial thrombosis in the right leg. Echocardiography revealed a mobile left atrial thrombus and severe mitral stenosis. She underwent a left atrial thrombectomy, the maze procedure and mitral valve plasty. Anterior and posterior mitral leaflets arose directly from the anterior papillary muscle, and from the posterior papillary muscle intervened by short chordae. This suggested a hammock mitral valve. A posterior papillary muscle division and commissurotomy were performed. The anterior leaflet was divided off the anterior papillary muscle, then extended by a triangular-shaped autologous pericardial patch and apically reattached. The postoperative mean pressure gradient of the mitral valve was 2.2 mmHg, and there was no regurgitation. The patient was in NYHA Class 1 and in sinus rhythm, 14 months after the operation. PMID- 26034224 TI - Does the complexity of coronary artery disease affect outcomes after complete revascularization with long segmental reconstruction of the left anterior descending artery using the left internal thoracic artery? AB - OBJECTIVES: We evaluated the influence of the complexity of coronary artery disease stratified by the Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery (SYNTAX) score on early or late outcomes after complete revascularization with long segmental reconstruction of the left anterior descending artery using the left internal thoracic artery. METHODS: From March 1995 to December 2003, a total of 102 patients with triple-vessel and/or left main disease underwent complete revascularization with long segmental left anterior descending artery reconstruction (>=2 cm) with or without endarterectomy using the left internal thoracic artery. The patients were divided into two groups according to the median SYNTAX score: the low group (SYNTAX score of <32, n = 50) and the high group (SYNTAX score of >=32, n = 52). Outcomes were compared between the two groups, and predictors of follow-up death and major adverse cardiac and cerebrovascular events were determined. RESULTS: The mean number of distal anastomoses was 4.2 +/- 1.1, and complete revascularization was achieved in 96% of patients. The early mortality rate was 2.9%, and no significant differences in the perioperative results were observed between groups. There were no significant differences in overall survival or major adverse cardiac and cerebrovascular event-free survival between the two groups. The hazard ratio of SYNTAX score for early mortality was 0.94 (95% confidence interval: 0.88-1.01) and for major adverse cardiac and cerebrovascular events was 0.97 (95% confidence interval: 0.92-1.02). CONCLUSIONS: The complexity of coronary artery disease had no impact on early or late outcomes after complete revascularization with long segmental left anterior descending artery reconstruction using the left internal thoracic artery. PMID- 26034225 TI - Coronary arteriovenous fistula between left circumflex artery and superior vena cava. AB - A 52-year old man presented with exertional angina and shortness of breath and was diagnosed with double-vessel coronary artery disease with a large coronary artery fistula between the left circumflex artery and superior vena cava. He was managed with off-pump coronary artery bypass grafting with closure of the fistula. PMID- 26034227 TI - Defining remission in psoriatic arthritis: are we getting closer? PMID- 26034226 TI - Changes in pulse pressure during hemodialysis treatment and survival in maintenance dialysis patients. AB - BACKGROUND AND OBJECTIVES: Pulse pressure has been shown as a risk factor for mortality in patients on maintenance hemodialysis (MHD). However, the effect of change in pulse pressure during hemodialysis on survival in a large cohort of patients on MHD has not been sufficiently investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study examined the association between time varying Delta pulse pressure (postdialysis minus predialysis pulse pressure) and mortality in a cohort of 98,577 patients on MHD (July 2001-June 2006) using Cox proportional hazard models with restricted cubic splines. RESULTS: The average patient age was 62 years old; among the patients, 33% were black and 59% had diabetes. During 134,814 patient-years of at-risk time, 16,054 (16%) patients died, with 6827 (43%) of the deaths caused by cardiovascular causes. In the models including adjustment for either predialysis systolic BP or mean arterial BP, there was a U-shaped association between change in pulse pressure during hemodialysis and all-cause mortality. In the systolic BP plus case mix plus malnutrition-inflammation complex syndrome-adjusted model, large declines in pulse pressure (>-25 mmHg) and increases in pulse pressure >5 mmHg were associated with higher all-cause mortality (reference: >=-5 to <5 mmHg): hazard ratios (95% confidence intervals [95% CIs]) for change pulse pressures of <-25, >=-25 to <-15, >=-15 to <-5, 5 to <15, 15 to <25, and >=25 mmHg were 1.21 (95% CI, 1.14 to 1.29), 1.03 (95% CI, 0.97 to 1.10), 1.01 (95% CI, 0.96 to 1.06), 1.06 (95% CI, 1.01 to 1.11), 1.17 (95% CI, 1.11 to 1.24), and 1.15 (95% CI, 1.08 to 1.23), respectively. The U-shaped association was observed with cardiovascular death. CONCLUSIONS: Modest reductions in pulse pressure after hemodialysis are associated with the greatest survival, whereas large declines or rises in pulse pressure are related to higher mortality. Trials determining how to modify pulse pressure response to improve survival in the hemodialysis population are indicated. PMID- 26034228 TI - Participation in Leisure Activities among Canadian Children with Arthritis. A Wakeup Call for Physicians. PMID- 26034229 TI - Extraarticular Manifestations of Rheumatoid Arthritis in Patients under Anti tumor Necrosis Factor-alpha Treatment. PMID- 26034230 TI - Anti-Jo1 Antibody in Polymyositis/dermatomyositis Is Still Closely Associated with Lung rather than Joints. PMID- 26034231 TI - Drs. Negoescu and Abraham reply. PMID- 26034232 TI - Primary or secondary synostosis: the culmination of the spondyloarthritis form of erosive arthritis? PMID- 26034233 TI - Dr. Vencovsky, et al reply. PMID- 26034234 TI - Drs. Maharaj and Chandran reply. PMID- 26034235 TI - Anticyclic Citrullinated Peptide Antibodies in Patients with Rheumatic Diseases other than Rheumatoid Arthritis: Clinical or Pathogenic Significance? PMID- 26034236 TI - Infantile-onset LMNA-associated Muscular Dystrophy Mimicking Juvenile Idiopathic Inflammatory Myopathy. PMID- 26034238 TI - Laryngeal schwannoma: excision via a laryngofissure approach. AB - Schwannomas are peripheral nerve neurogenic tumours and although not common, laryngeal schwannomas can provide a unique challenge in diagnostic and treatment management. There are limited reports in the literature on approaches to management. A 73-year-old lady presented to the otolaryngology department after a MRI scan demonstrated an incidental right supraglottic mass. Further investigations included CT scanning and microlaryngoscopy, which only confirmed the presence of the mass with no histology diagnosis. Excision was undertaken by a laryngofissure approach and tracheostomy. Histology confirmed a benign ancient schwannoma. PMID- 26034239 TI - A huge benign prostatic hyperplasia presenting with renal failure. AB - Although transurethral resection of the prostate is still standard of care in many patients suffering from benign prostatic hyperplasia, traditional open prostatectomy (OP) seems as a widely applied method in larger glands. In spite of the fact that holmium laser enucleation can be performed in large glands, upper limits of prostate size in this method are not clearly identified in the current literature. In this case, we aim to report feasibility and efficacy of OP in huge prostate size measured as 680 ml by transrectal ultrasound and review the current literature. PMID- 26034240 TI - Physician Communication Training and Parental Vaccine Hesitancy: A Randomized Trial. AB - BACKGROUND AND OBJECTIVES: Physicians have a major influence on parental vaccine decisions. We tested a physician-targeted communication intervention designed to (1) reduce vaccine hesitancy in mothers of infants seen by trained physicians and (2) increase physician confidence in communicating about vaccines. METHODS: We conducted a community-based, clinic-level, 2-arm cluster randomized trial in Washington State. Intervention clinics received physician-targeted communications training. We enrolled mothers of healthy newborns from these clinics at the hospital of birth. Mothers and physicians were surveyed at baseline and 6 months. The primary outcome was maternal vaccine hesitancy measured by Parental Attitudes on Childhood Vaccines score; secondary outcome was physician self-efficacy in communicating with parents by using 3 vaccine communication domains. RESULTS: We enrolled 56 clinics and 347 mothers. We conducted intervention trainings at 30 clinics, reaching 67% of eligible physicians; 26 clinics were randomized to the control group. Maternal vaccine hesitancy at baseline and follow-up changed from 9.8% to 7.5% in the intervention group and 12.6% to 8.0% in the control group. At baseline, groups were similar on all variables except maternal race and ethnicity. The intervention had no detectable effect on maternal vaccine hesitancy (adjusted odds ratio 1.22, 95% confidence interval 0.47-2.68). At follow-up, physician self-efficacy in communicating with parents was not significantly different between intervention and control groups. CONCLUSIONS: This physician-targeted communication intervention did not reduce maternal vaccine hesitancy or improve physician self-efficacy. Research is needed to identify physician communication strategies effective at reducing parental vaccine hesitancy in the primary care setting. PMID- 26034241 TI - Recovery From Central Nervous System Acute Demyelination in Children. AB - BACKGROUND: Few prospective studies have systematically evaluated the extent of recovery from incident acquired demyelinating syndromes (ADS) of the central nervous system in children. METHODS: In a national cohort study of pediatric ADS, severity of the incident attack and extent of recovery by 12 months were evaluated. Annual evaluations were used to determine current diagnoses (monophasic ADS or multiple sclerosis [MS]) and new deficits. RESULTS: Of 283 children, 244 (86%) required hospitalization for a median (interquartile range [IQR]) of 6 (3-10) days, and 184 had moderate or severe deficits; 41 children were profoundly encephalopathic, 129 were unable to ambulate independently, and 59 with optic neuritis (ON) had moderately or severely impaired vision. Those with transverse myelitis (TM) and patients with monophasic disease were more likely to have moderate or severe deficits at onset. Twenty-seven children (10%) did not experience full neurologic recovery from their incident attack; 12 have severe residual deficits. Monophasic illness, TM, and moderate or severe deficits at onset were associated with poor recovery. After a median (IQR) follow-up of 5.06 (3.41-6.97) years, 59 children (21%) were diagnosed with MS; all recovered fully from their incident ADS attacks, although 6 subsequently acquired irreversible deficits after a median (IQR) observation period of 5.93 (4.01-7.02) years. CONCLUSIONS: ADS is a serious illness, with 86% of affected Canadian children requiring hospitalization. More than 90% of children recovered physically from their ADS event, including those children experiencing onset of MS. However, permanent visual or spinal cord impairment occurred in some children with ON or TM. PMID- 26034242 TI - Personal Belief Exemptions to Vaccination in California: A Spatial Analysis. AB - BACKGROUND: School vaccination rates in California have fallen as more parents opt for personal belief exemptions (PBEs) for their children. Our goals were to (1) spatially analyze PBE patterns over time, (2) determine correlates of PBEs, and (3) examine their spatial overlap with personal medical exemptions (PMEs). METHODS: PBE and PME data for California kindergarten classes from the 2001/2002 to 2013/2014 school years were matched to the locations of schools. Nonspatial clustering algorithms were implemented to group 5147 schools according to their trends in PBE percentages among kindergartners. Cluster assignments were mapped and hotspot analysis was performed to find areas in California where schools sharing trends in PBEs over time were colocated. Schools were further associated both with school-level data on minority enrollment and free and reduced price lunch participation and with charter/private and rural/urban status. Spatial regression was implemented to determine which school-level variables were correlated with PBE rates in the 2013/2014 school year. RESULTS: Distinct spatial patterns are observed in California when PBE cluster assignments are mapped. Results indicate that schools belonging to the "high PBE" cluster are spatially buffered from those in "low PBE" areas by "medium PBE" schools. Further, PBE rates are positively associated with the percentage of white students, charter status, and private schools. CONCLUSIONS: Hotspots of high PBE schools are in some cases colocated with schools that have elevated PME rates, prompting concern that herd immunity is diminished for school populations where students have no choice but to remain unvaccinated. PMID- 26034243 TI - Global and Regional Burden of Isoniazid-Resistant Tuberculosis. AB - BACKGROUND: Isoniazid has been the backbone of tuberculosis chemotherapy for 6 decades. Resistance to isoniazid threatens the efficacy of treatment of tuberculosis disease and infection. To inform policies around treatment of tuberculosis disease and infection in children, we sought to estimate both the proportion of child tuberculosis cases with isoniazid resistance and the number of incident isoniazid-resistant tuberculosis cases in children, by region. METHODS: We determined the relationship between rates of isoniazid resistance among child cases and among treatment-naive adult cases through a systematic literature review. We applied this relationship to regional isoniazid resistance estimates to estimate proportions of childhood tuberculosis cases with isoniazid resistance. We applied these proportions to childhood tuberculosis incidence estimates to estimate numbers of children with isoniazid-resistant tuberculosis. RESULTS: We estimated 12.1% (95% confidence interval [CI] 9.8% to 14.8%) of all children with tuberculosis had isoniazid-resistant disease, representing 120,872 (95% CI 96,628 to 149,059) incident cases of isoniazid-resistant tuberculosis in children in 2010. The majority of these occurred in the Western Pacific and Southeast Asia regions; the European region had the highest proportion of child tuberculosis cases with isoniazid resistance, 26.1% (95% CI: 20.0% to 33.6%). CONCLUSIONS: The burden of isoniazid-resistant tuberculosis in children is substantial, and risk varies considerably by setting. The large number of child cases signals extensive ongoing transmission from adults with isoniazid-resistant tuberculosis. The risk of isoniazid resistance must be considered when evaluating treatment options for children with disease or latent infection to avoid inadequate treatment and consequent poor outcomes. PMID- 26034244 TI - Progressive Aortic Dilation Associated With ACTA2 Mutations Presenting in Infancy. AB - Mutations in the gene ACTA2 are a recognized cause of aortic aneurysms with aortic dissection in adulthood. Recently, a specific mutation (Arg179His) in this gene has been associated with multisystem smooth muscle dysfunction presenting in childhood. We describe 3 patients with an R179H mutation, all of whom presented with an aneurysmal patent ductus arteriosus. Detailed information on the rate of aortic disease progression throughout childhood is provided. Death or need for ascending aortic replacement occurred in all patients. Genetic testing for ACTA2 mutations should be considered in all infants presenting with ductal aneurysms. PMID- 26034245 TI - Automated Assessment of Children's Postoperative Pain Using Computer Vision. AB - BACKGROUND: Current pain assessment methods in youth are suboptimal and vulnerable to bias and underrecognition of clinical pain. Facial expressions are a sensitive, specific biomarker of the presence and severity of pain, and computer vision (CV) and machine-learning (ML) techniques enable reliable, valid measurement of pain-related facial expressions from video. We developed and evaluated a CVML approach to measure pain-related facial expressions for automated pain assessment in youth. METHODS: A CVML-based model for assessment of pediatric postoperative pain was developed from videos of 50 neurotypical youth 5 to 18 years old in both endogenous/ongoing and exogenous/transient pain conditions after laparoscopic appendectomy. Model accuracy was assessed for self reported pain ratings in children and time since surgery, and compared with by proxy parent and nurse estimates of observed pain in youth. RESULTS: Model detection of pain versus no-pain demonstrated good-to-excellent accuracy (Area under the receiver operating characteristic curve 0.84-0.94) in both ongoing and transient pain conditions. Model detection of pain severity demonstrated moderate to-strong correlations (r = 0.65-0.86 within; r = 0.47-0.61 across subjects) for both pain conditions. The model performed equivalently to nurses but not as well as parents in detecting pain versus no-pain conditions, but performed equivalently to parents in estimating pain severity. Nurses were more likely than the model to underestimate youth self-reported pain ratings. Demographic factors did not affect model performance. CONCLUSIONS: CVML pain assessment models derived from automatic facial expression measurements demonstrated good-to excellent accuracy in binary pain classifications, strong correlations with patient self-reported pain ratings, and parent-equivalent estimation of children's pain levels over typical pain trajectories in youth after appendectomy. PMID- 26034246 TI - Youth Drinking in the United States: Relationships With Alcohol Policies and Adult Drinking. AB - BACKGROUND: The relationship between the alcohol policy environment (ie, the combined effectiveness and implementation of multiple existing alcohol policies) and youth drinking in the United States has not been assessed. We hypothesized that stronger alcohol policy environments are inversely associated with youth drinking, and this relationship is partly explained by adult drinking. METHODS: Alcohol Policy Scale (APS) scores that characterized the strength of the state level alcohol policy environments were assessed with repeated cross-sectional Youth Risk Behavior Survey data of representative samples of high school students in grades 9 to 12, from biennial years between 1999 and 2011. RESULTS: In fully adjusted models, a 10 percentage point increase in APS scores (representing stronger policy environments) was associated with an 8% reduction in the odds of youth drinking and a 7% reduction in the odds of youth binge drinking. After we accounted for youth-oriented alcohol policies, the subgroup of population oriented policies was independently associated with lower odds of youth drinking (adjusted odds ratio 0.94; 95% confidence interval 0.92-0.97) and youth binge drinking (adjusted odds ratio 0.96; 95% confidence interval 0.94-0.99). State level per capita consumption mediated the relationship between population oriented alcohol policies and binge drinking among youth. CONCLUSIONS: Stronger alcohol policies, including those that do not target youth specifically, are related to a reduced likelihood of youth alcohol consumption. These findings suggest that efforts to reduce youth drinking should incorporate population-based policies to reduce excessive drinking among adults as part of a comprehensive approach to preventing alcohol-related harms. Future research should examine influence of alcohol policy subgroups and discrete policies. PMID- 26034247 TI - Physician Communication With Vaccine-Hesitant Parents: The Start, Not the End, of the Story. PMID- 26034248 TI - Medical-Legal Strategies to Improve Infant Health Care: A Randomized Trial. AB - BACKGROUND: Changes in health care delivery create opportunities to improve systems to better meet the needs of low-income families while achieving quality benchmarks. METHODS: Families of healthy newborns receiving primary care at a single large urban safety-net hospital participated. Intervention families were randomly assigned a family specialist who provided support until the 6-month routine health care visit. The Developmental Understanding and Legal Collaboration for Everyone (DULCE) intervention is based on the Strengthening Families approach and incorporated components of the Healthy Steps and Medical Legal Partnership models. Medical record reviews determined use of preventive and emergency care. Surveys conducted at baseline, postintervention (6 months), and follow-up (12 months) were used to determine hardship and attainment of concrete supports. RESULTS: Three hundred thirty families participated in the study. At baseline, 73% of families reported economic hardships. Intervention parents had an average of 14 contacts with the family specialist, and 5 hours of total contact time. Intervention infants were more likely to have completed their 6 month immunization schedule by age 7 months (77% vs 63%, P < .005) and by 8 months (88% vs 77%, P < .01). Intervention infants were more likely to have 5 or more routine preventive care visits by age 1 year (78% vs 67%, P < .01) and were less likely to have visited the emergency department by age 6 months (37% vs 49.7%, P < .03). The DULCE intervention accelerated access to concrete resources (P = .029). CONCLUSIONS: Assignment to the Project DULCE intervention led to improvements in preventive health care delivery and utilization and accelerated access to concrete supports among low-income families. PMID- 26034249 TI - Maternal Sensitivity in Parenting Preterm Children: A Meta-analysis. AB - BACKGROUND AND OBJECTIVES: Preterm birth is a significant stressor for parents and may adversely impact maternal parenting behavior. However, findings have been inconsistent. The objective of this meta-analysis was to determine whether mothers of preterm children behave differently (eg, less responsive or sensitive) in their interactions with their children after they are discharged from the hospital than mothers of term children. METHODS: Medline, PsychInfo, ERIC, PubMed, and Web of Science were searched from January 1980 through May 2014 with the following keywords: "premature", "preterm", "low birth weight" in conjunction with "maternal behavio*r", "mother-infant interaction", "maternal sensitivity", and "parenting". Both longitudinal and cross-sectional studies that used an observational measure of maternal parenting behavior were eligible. Study results relating to parenting behaviors defined as sensitivity, facilitation, and responsivity were extracted, and mean estimates were combined with random-effects meta-analysis. RESULTS: Thirty-four studies were included in the meta-analysis. Mothers of preterm and full-term children did not differ significantly from each other in terms of their behavior toward their children (Hedges' g = -0.07; 95% confidence interval: -0.22 to 0.08; z = -0.94; P = .35). The heterogeneity between studies was significant and high (Q = 156.42; I(2) = 78.9, P = .001) and not explained by degree of prematurity, publication date, geographical area, infant age, or type of maternal behavior. CONCLUSIONS: Mothers of preterm children were not found to be less sensitive or responsive toward their children than mothers of full-term children. PMID- 26034250 TI - Blueprint for Action: Visioning Summit on the Future of the Workforce in Pediatrics. AB - The Federation of Pediatric Organizations engaged members of the pediatric community in an 18-month process to envision the future of the workforce in pediatrics, culminating in a Visioning Summit on the Future of the Workforce in Pediatrics. This article documents the planning process and methods used. Four working groups were based on the 4 domains that are likely to affect the future workforce: Child Health Research and Training, Diversity and Inclusion, Gender and Generations, and Pediatric Training Along the Continuum. These groups identified the issues and trends and prioritized their recommendations. Before the summit, 5 key megatrends cutting across all domains were identified:1. Aligning Education to the Emerging Health Needs of Children and Families 2. Promoting Future Support for Research Training and for Child Health Research 3. Striving Toward Mastery Within the Profession 4. Aligning and Optimizing Pediatric Practice in a Changing Health Care Delivery System 5. Taking Advantage of the Changing Demographics and Expertise of the Pediatric Workforce At the Visioning Summit, we assembled members of each of the working groups, the Federation of Pediatric Organizations Board of Directors, and several invited guests to discuss the 5 megatrends and develop the vision, solutions, and actions for each megatrend. Based on this discussion, we offer 10 recommendations for the field of pediatrics and its leading organizations to consider taking action. PMID- 26034252 TI - Crib of Horrors: One Hospital's Approach to Promoting a Culture of Safety. PMID- 26034251 TI - A Comparison of the Request Process and Outcomes in Adult and Pediatric Organ Donation. AB - BACKGROUND AND OBJECTIVES: Although existing studies suggest that factors affecting families' decisions regarding pediatric organ donation mirror those for adult patients, health professionals working in this area maintain that pediatric and adult decision-makers differ in significant ways. This study compared the request process, experiences, and authorization decisions between family decision makers (FDMs) of adult and pediatric donors and nondonors. METHODS: Perceptions of the donation request were collected via telephone interviews with 1601 FDMs approached by staff from 9 US organ procurement organizations (OPOs). Authorization regarding donation (ie, authorized/refused) was obtained from FDM reports and verified by using OPO records. Tests of association were used to estimate differences between FDMs of adult and pediatric patients. A logistic regression analysis was conducted to identify variables predicting FDM authorization. RESULTS: FDMs of children were significantly more likely to authorize donation than were FDMs of adults (89.7% vs 83.2%; chi(2) = 6.2, P = .01). Differences were found between pediatric and adult families' initial feelings toward donation, donation-related topics discussed, communication behaviors and techniques used, perceptions of the request, and receipt and preference of grief information. The likelihood of FDM authorization increased with the number of topics discussed and communication skills employed during requests. Authorization was not predicted by patient age (ie, adult versus pediatric). CONCLUSIONS: FDMs of children are willing to donate and experience no more psychological distress from the request for donation than do FDMs of adults. Communication emerged as a critical factor of family authorization, reinforcing its importance in requests for donation. PMID- 26034253 TI - Vaccine safety: medical contraindications, myths, and risk communication. AB - On the basis of first principles, anaphylaxis to a vaccine or vaccine component is a contraindication to future receipt of that vaccine. * On the basis of strong evidence, live viral vaccines should not be administered to severely immunocompromised children. * On the basis of some evidence with consensus, children with egg allergies may receive inactivated influenza vaccine. * On the basis of strong evidence, neither measles-mumps-rubella vaccine nor thimerosal causes autism. * On the basis of some evidence with consensus, alternative vaccination schedules have no benefit and receipt of human papillomavirus vaccines does not result in promiscuity. * On the basis of first principles and consensus, vaccine risk communication requires a tailored approach to each individual family. PMID- 26034254 TI - Hyperthyroidism in children. AB - On the basis of strong research evidence, hyperthyroidism is a rare but potentially serious disorder in childhood that, if uncontrolled, can lead to a wide range of complications, including effects on growth and development. * On the basis of strong research evidence, Graves' disease is the most common cause of hyperthyroidism in children, accounting for greater than 95% of cases. It is caused by stimulating antibodies to the thyroid-stimulating hormone receptor. * On the basis of some research evidence and consensus, history, physical examination, and thyroid function tests help diagnose hyperthyroidism. The condition is characterized by suppressed serum thyrotropin and elevated serum triiodothyronine and thyroxine. Radioactive iodine (or technetium-99) uptake and serum thyroid antibody measurements help determine the cause of hyperthyroidism. * On the basis of some research evidence and consensus, treatment options for Graves' disease in children include antithyroid medications, radioactive iodine, and surgery. Antithyroid medications are commonly used as the first-line therapy in children. However, because of the low rates of spontaneous remission, most children eventually require permanent treatment with radioactive iodine or surgery. Of the available antithyroid medications, current guidelines recommend use of methimazole and not propylthiouracil because of the unacceptable risk of hepatotoxicity associated with propylthiouracil. * On the basis of strong research evidence, thyroid storm is a rare life-threatening endocrine emergency that should be suspected in children with hyperthyroidism who demonstrate evidence of systemic decompensation. * On the basis of strong research evidence, neonatal hyperthyroidism can occur in infants born to mothers with a history of Graves' disease due to transplacental passage of TSH receptor stimulating antibodies. PMID- 26034255 TI - Immunizations: vaccinations in general. AB - The childhood immunization schedule is complex and nuanced. Although serious adverse reactions to immunizations are uncommon, clinicians must be well-versed in these reactions as well as the contraindications and precautions to each vaccine. * Conjugate vaccine technology links polysaccharide antigens to carrier proteins, triggering T-cell-dependent immunity to polysaccharides, thereby strengthening immune memory. * On the basis of some research evidence and consensus, live vaccines are generally contraindicated in immunocompromised patients and in pregnancy. Most live vaccines can be administered to household contacts of immunocompromised patients. * On the basis of some research and consensus, modified administration of meningococcal, pneumococcal, and less commonly, other vaccines may be indicated to protect immunocompromised patients. * On the basis of disease epidemiology and consensus, international travelers should be up-to-date with all routine immunizations; depending on destination, additional vaccines or immune globulin may be required. PMID- 26034256 TI - Case 1: Recurrent Apneic Episodes in a 6-week-old Infant. PMID- 26034257 TI - Case 2: Fever and Neck Swelling in a 3-year-old Boy. PMID- 26034258 TI - Case 3: Hepatosplenomegaly in a 2-year-old Boy. PMID- 26034259 TI - Child safety and injury prevention. PMID- 26034261 TI - Erratum. PMID- 26034260 TI - Chromosome 22q11.2 deletion syndrome. PMID- 26034262 TI - Visual Diagnosis: Pinpoint, Nonfollicular, Sterile Pustules on Edematous Erythema in a 15-year-old. AB - AGEP is a rare skin reaction that causes the formation of numerous aseptic pustules on an erythematous base. In most cases, it presents after exposure to drugs, more often antibiotics. Fever and leukocytosis are common. The history, clinical appearance, and histology of the pustules confirm the diagnosis of AGEP. Pustular psoriasis, SJM, and EM must be ruled out. The lesions heal spontaneously within 2 weeks after discontinuation of the offending agent, an occurrence that further supports the diagnosis. Immediate withdrawal of the causative agent and supportive therapy is the mainstay of treatment for AGEP. PMID- 26034263 TI - Extreme Aridity Pushes Trees to Their Physical Limits. PMID- 26034264 TI - Salinity Is an Agent of Divergent Selection Driving Local Adaptation of Arabidopsis to Coastal Habitats. AB - Understanding the molecular mechanism of adaptive evolution in plants provides insights into the selective forces driving adaptation and the genetic basis of adaptive traits with agricultural value. The genomic resources available for Arabidopsis (Arabidopsis thaliana) make it well suited to the rapid molecular dissection of adaptive processes. Although numerous potentially adaptive loci have been identified in Arabidopsis, the consequences of divergent selection and migration (both important aspects of the process of local adaptation) for Arabidopsis are not well understood. Here, we use a multiyear field-based reciprocal transplant experiment to detect local populations of Arabidopsis composed of multiple small stands of plants (demes) that are locally adapted to the coast and adjacent inland habitats in northeastern Spain. We identify fitness tradeoffs between plants from these different habitats when grown together in inland and coastal common gardens and also, under controlled conditions in soil excavated from coastal and inland sites. Plants from the coastal habitat also outperform those from inland when grown under high salinity, indicating local adaptation to soil salinity. Sodium can be toxic to plants, and we find its concentration to be elevated in soil and plants sampled at the coast. We conclude that the local adaptation that we observe between adjacent coastal and inland populations is caused by ongoing divergent selection driven by the differential salinity between coastal and inland soils. PMID- 26034265 TI - Multiple Interactions between Glucose and Brassinosteroid Signal Transduction Pathways in Arabidopsis Are Uncovered by Whole-Genome Transcriptional Profiling. AB - Brassinosteroid (BR) and glucose (Glc) regulate many common responses in plants. Here, we demonstrate that under etiolated growth conditions, extensive interdependence/overlap occurs between BR- and Glc-regulated gene expression as well as physiological responses. Glc could regulate the transcript level of 72% of BR-regulated genes at the whole-genome level, of which 58% of genes were affected synergistically and 42% of genes were regulated antagonistically. Presence of Glc along with BR in medium could affect BR induction/repression of 85% of BR-regulated genes. Glc could also regulate several genes involved in BR metabolism and signaling. Both BR and Glc coregulate a large number of genes involved in abiotic/biotic stress responses and growth and development. Physiologically, Glc and BR interact to regulate hypocotyl elongation growth of etiolated Arabidopsis (Arabidopsis thaliana) seedlings in a dose-dependent manner. Glc may interact with BR via a hexokinase1 (HXK1)-mediated pathway to regulate etiolated hypocotyl elongation. Brassinosteroid insensitive1 (BRI1) is epistatic to HXK1, as the Glc insensitive2bri1-6 double mutant displayed severe defects in hypocotyl elongation growth similar to its bri1-6 parent. Analysis of Glc and BR sensitivity in mutants defective in auxin response/signaling further suggested that Glc and BR signals may converge at S-phase kinase-associated protein1-Cullin-F-box-transport inhibitor response1/auxin-related f-box auxin/indole-3-acetic acid-mediated auxin-signaling machinery to regulate etiolated hypocotyl elongation growth in Arabidopsis. PMID- 26034267 TI - DNA metabarcoding illuminates dietary niche partitioning by African large herbivores. AB - Niche partitioning facilitates species coexistence in a world of limited resources, thereby enriching biodiversity. For decades, biologists have sought to understand how diverse assemblages of large mammalian herbivores (LMH) partition food resources. Several complementary mechanisms have been identified, including differential consumption of grasses versus nongrasses and spatiotemporal stratification in use of different parts of the same plant. However, the extent to which LMH partition food-plant species is largely unknown because comprehensive species-level identification is prohibitively difficult with traditional methods. We used DNA metabarcoding to quantify diet breadth, composition, and overlap for seven abundant LMH species (six wild, one domestic) in semiarid African savanna. These species ranged from almost-exclusive grazers to almost-exclusive browsers: Grass consumption inferred from mean sequence relative read abundance (RRA) ranged from >99% (plains zebra) to <1% (dik-dik). Grass RRA was highly correlated with isotopic estimates of % grass consumption, indicating that RRA conveys reliable quantitative information about consumption. Dietary overlap was greatest between species that were similar in body size and proportional grass consumption. Nonetheless, diet composition differed between all species-even pairs of grazers matched in size, digestive physiology, and location-and dietary similarity was sometimes greater across grazing and browsing guilds than within them. Such taxonomically fine-grained diet partitioning suggests that coarse trophic categorizations may generate misleading conclusions about competition and coexistence in LMH assemblages, and that LMH diversity may be more tightly linked to plant diversity than is currently recognized. PMID- 26034266 TI - Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. AB - The structure, dynamic behavior, and spatial organization of microtubules are regulated by microtubule-associated proteins. An important microtubule-associated protein is the protein Tau, because its microtubule interaction is impaired in the course of Alzheimer's disease and several other neurodegenerative diseases. Here, we show that Tau binds to microtubules by using small groups of evolutionary conserved residues. The binding sites are formed by residues that are essential for the pathological aggregation of Tau, suggesting competition between physiological interaction and pathogenic misfolding. Tau residues in between the microtubule-binding sites remain flexible when Tau is bound to microtubules in agreement with a highly dynamic nature of the Tau-microtubule interaction. By binding at the interface between tubulin heterodimers, Tau uses a conserved mechanism of microtubule polymerization and, thus, regulation of axonal stability and cell morphology. PMID- 26034268 TI - Microbial invasion of the Caribbean by an Indo-Pacific coral zooxanthella. AB - Human-induced environmental changes have ushered in the rapid decline of coral reef ecosystems, particularly by disrupting the symbioses between reef-building corals and their photosymbionts. However, escalating stressful conditions enable some symbionts to thrive as opportunists. We present evidence that a stress tolerant "zooxanthella" from the Indo-Pacific Ocean, Symbiodinium trenchii, has rapidly spread to coral communities across the Greater Caribbean. In marked contrast to populations from the Indo-Pacific, Atlantic populations of S. trenchii contained exceptionally low genetic diversity, including several widespread and genetically similar clones. Colonies with this symbiont tolerate temperatures 1-2 degrees C higher than other host-symbiont combinations; however, calcification by hosts harboring S. trenchii is reduced by nearly half, compared with those harboring natives, and suggests that these new symbioses are maladapted. Unforeseen opportunism and geographical expansion by invasive mutualistic microbes could profoundly influence the response of reef coral symbioses to major environmental perturbations but may ultimately compromise ecosystem stability and function. PMID- 26034269 TI - Body composition in Pan paniscus compared with Homo sapiens has implications for changes during human evolution. AB - The human body has been shaped by natural selection during the past 4-5 million years. Fossils preserve bones and teeth but lack muscle, skin, fat, and organs. To understand the evolution of the human form, information about both soft and hard tissues of our ancestors is needed. Our closest living relatives of the genus Pan provide the best comparative model to those ancestors. Here, we present data on the body composition of 13 bonobos (Pan paniscus) measured during anatomical dissections and compare the data with Homo sapiens. These comparative data suggest that both females and males (i) increased body fat, (ii) decreased relative muscle mass, (iii) redistributed muscle mass to lower limbs, and (iv) decreased relative mass of skin during human evolution. Comparison of soft tissues between Pan and Homo provides new insights into the function and evolution of body composition. PMID- 26034271 TI - Financial competitiveness of organic agriculture on a global scale. AB - To promote global food and ecosystem security, several innovative farming systems have been identified that better balance multiple sustainability goals. The most rapidly growing and contentious of these systems is organic agriculture. Whether organic agriculture can continue to expand will likely be determined by whether it is economically competitive with conventional agriculture. Here, we examined the financial performance of organic and conventional agriculture by conducting a meta-analysis of a global dataset spanning 55 crops grown on five continents. When organic premiums were not applied, benefit/cost ratios (-8 to -7%) and net present values (-27 to -23%) of organic agriculture were significantly lower than conventional agriculture. However, when actual premiums were applied, organic agriculture was significantly more profitable (22-35%) and had higher benefit/cost ratios (20-24%) than conventional agriculture. Although premiums were 29-32%, breakeven premiums necessary for organic profits to match conventional profits were only 5-7%, even with organic yields being 10-18% lower. Total costs were not significantly different, but labor costs were significantly higher (7-13%) with organic farming practices. Studies in our meta-analysis accounted for neither environmental costs (negative externalities) nor ecosystem services from good farming practices, which likely favor organic agriculture. With only 1% of the global agricultural land in organic production, our findings suggest that organic agriculture can continue to expand even if premiums decline. Furthermore, with their multiple sustainability benefits, organic farming systems can contribute a larger share in feeding the world. PMID- 26034270 TI - Rab3-interacting molecules 2alpha and 2beta promote the abundance of voltage gated CaV1.3 Ca2+ channels at hair cell active zones. AB - Ca(2+) influx triggers the fusion of synaptic vesicles at the presynaptic active zone (AZ). Here we demonstrate a role of Ras-related in brain 3 (Rab3) interacting molecules 2alpha and beta (RIM2alpha and RIM2beta) in clustering voltage-gated CaV1.3 Ca(2+) channels at the AZs of sensory inner hair cells (IHCs). We show that IHCs of hearing mice express mainly RIM2alpha, but also RIM2beta and RIM3gamma, which all localize to the AZs, as shown by immunofluorescence microscopy. Immunohistochemistry, patch-clamp, fluctuation analysis, and confocal Ca(2+) imaging demonstrate that AZs of RIM2alpha-deficient IHCs cluster fewer synaptic CaV1.3 Ca(2+) channels, resulting in reduced synaptic Ca(2+) influx. Using superresolution microscopy, we found that Ca(2+) channels remained clustered in stripes underneath anchored ribbons. Electron tomography of high-pressure frozen synapses revealed a reduced fraction of membrane-tethered vesicles, whereas the total number of membrane-proximal vesicles was unaltered. Membrane capacitance measurements revealed a reduction of exocytosis largely in proportion with the Ca(2+) current, whereas the apparent Ca(2+) dependence of exocytosis was unchanged. Hair cell-specific deletion of all RIM2 isoforms caused a stronger reduction of Ca(2+) influx and exocytosis and significantly impaired the encoding of sound onset in the postsynaptic spiral ganglion neurons. Auditory brainstem responses indicated a mild hearing impairment on hair cell-specific deletion of all RIM2 isoforms or global inactivation of RIM2alpha. We conclude that RIM2alpha and RIM2beta promote a large complement of synaptic Ca(2+) channels at IHC AZs and are required for normal hearing. PMID- 26034272 TI - Gain of cis-regulatory activities underlies novel domains of wingless gene expression in Drosophila. AB - Changes in gene expression during animal development are largely responsible for the evolution of morphological diversity. However, the genetic and molecular mechanisms responsible for the origins of new gene-expression domains have been difficult to elucidate. Here, we sought to identify molecular events underlying the origins of three novel features of wingless (wg) gene expression that are associated with distinct pigmentation patterns in Drosophila guttifera. We compared the activity of cis-regulatory sequences (enhancers) across the wg locus in D. guttifera and Drosophila melanogaster and found strong functional conservation among the enhancers that control similar patterns of wg expression in larval imaginal discs that are essential for appendage development. For pupal tissues, however, we found three novel wg enhancer activities in D. guttifera associated with novel domains of wg expression, including two enhancers located surprisingly far away in an intron of the distant Wnt10 gene. Detailed analysis of one enhancer (the vein-tip enhancer) revealed that it overlapped with a region controlling wg expression in wing crossveins (crossvein enhancer) in D. guttifera and other species. Our results indicate that one novel domain of wg expression in D. guttifera wings evolved by co-opting pre-existing regulatory sequences governing gene activity in the developing wing. We suggest that the modification of existing enhancers is a common path to the evolution of new gene-expression domains and enhancers. PMID- 26034273 TI - Asymptomatic spread of huanglongbing and implications for disease control. AB - Huanglongbing (HLB) is a bacterial infection of citrus trees transmitted by the Asian citrus psyllid Diaphorina citri. Mitigation of HLB has focused on spraying of insecticides to reduce the psyllid population and removal of trees when they first show symptoms of the disease. These interventions have been only marginally effective, because symptoms of HLB do not appear on leaves for months to years after initial infection. Limited knowledge about disease spread during the asymptomatic phase is exemplified by the heretofore unknown length of time from initial infection of newly developing cluster of young leaves, called flush, by adult psyllids until the flush become infectious. We present experimental evidence showing that young flush become infectious within 15 d after receiving an inoculum of Candidatus Liberibacter asiaticus (bacteria). Using this critical fact, we specify a microsimulation model of asymptomatic disease spread and intensity in a grove of citrus trees. We apply a range of psyllid introduction scenarios to show that entire groves can become infected with up to 12,000 psyllids per tree in less than 1 y, before most of the trees show any symptoms. We also show that intervention strategies that reduce the psyllid population by 75% during the flushing periods can delay infection of a full grove, and thereby reduce the amount of insecticide used throughout a year. This result implies that psyllid surveillance and control, using a variety of recently available technologies, should be used from the initial detection of invasion and throughout the asymptomatic period. PMID- 26034274 TI - New approaches narrow global species estimates for beetles, insects, and terrestrial arthropods. AB - It has been suggested that we do not know within an order of magnitude the number of all species on Earth [May RM (1988) Science 241(4872):1441-1449]. Roughly 1.5 million valid species of all organisms have been named and described [Costello MJ, Wilson S, Houlding B (2012) Syst Biol 61(5):871-883]. Given Kingdom Animalia numerically dominates this list and virtually all terrestrial vertebrates have been described, the question of how many terrestrial species exist is all but reduced to one of how many arthropod species there are. With beetles alone accounting for about 40% of all described arthropod species, the truly pertinent question is how many beetle species exist. Here we present four new and independent estimates of beetle species richness, which produce a mean estimate of 1.5 million beetle species. We argue that the surprisingly narrow range (0.9 2.1 million) of these four autonomous estimates--derived from host-specificity relationships, ratios with other taxa, plant:beetle ratios, and a completely novel body-size approach--represents a major advance in honing in on the richness of this most significant taxon, and is thus of considerable importance to the debate on how many species exist. Using analogous approaches, we also produce independent estimates for all insects, mean: 5.5 million species (range 2.6-7.8 million), and for terrestrial arthropods, mean: 6.8 million species (range 5.9 7.8 million), which suggest that estimates for the world's insects and their relatives are narrowing considerably. PMID- 26034275 TI - A tyrosine-based motif in the HIV-1 envelope glycoprotein tail mediates cell-type and Rab11-FIP1C-dependent incorporation into virions. AB - Lentiviruses such as HIV-1 encode envelope glycoproteins (Env) with long cytoplasmic tails (CTs) that include motifs mediating interactions with host-cell trafficking factors. We demonstrated recently that Rab11-family interacting protein 1C (FIP1C) is required for CT-dependent incorporation of Env into HIV-1 particles. Here, we used viruses bearing targeted substitutions within CT to map the FIP1C-dependent incorporation of Env. We identified YW795 as a critical motif mediating cell-type-dependent Env incorporation. Disruption of YW795 reproduced the cell-type-dependent particle incorporation of Env that had previously been observed with large truncations of CT. A revertant virus bearing a single amino acid change near the C terminus of CT restored wild-type levels of Env incorporation, Gag-Env colocalization on the plasma membrane, and viral replication. These findings highlight the importance of YW795 in the cell-type dependent incorporation of Env and support a model of HIV assembly in which FIP1C/RCP mediates Env trafficking to the particle assembly site. PMID- 26034276 TI - Precision-guided antimicrobial peptide as a targeted modulator of human microbial ecology. AB - One major challenge to studying human microbiome and its associated diseases is the lack of effective tools to achieve targeted modulation of individual species and study its ecological function within multispecies communities. Here, we show that C16G2, a specifically targeted antimicrobial peptide, was able to selectively kill cariogenic pathogen Streptococcus mutans with high efficacy within a human saliva-derived in vitro oral multispecies community. Importantly, a significant shift in the overall microbial structure of the C16G2-treated community was revealed after a 24-h recovery period: several bacterial species with metabolic dependency or physical interactions with S. mutans suffered drastic reduction in their abundance, whereas S. mutans' natural competitors, including health-associated Streptococci, became dominant. This study demonstrates the use of targeted antimicrobials to modulate the microbiome structure allowing insights into the key community role of specific bacterial species and also indicates the therapeutic potential of C16G2 to achieve a healthy oral microbiome. PMID- 26034277 TI - Imaging transient melting of a nanocrystal using an X-ray laser. AB - There is a fundamental interest in studying photoinduced dynamics in nanoparticles and nanostructures as it provides insight into their mechanical and thermal properties out of equilibrium and during phase transitions. Nanoparticles can display significantly different properties from the bulk, which is due to the interplay between their size, morphology, crystallinity, defect concentration, and surface properties. Particularly interesting scenarios arise when nanoparticles undergo phase transitions, such as melting induced by an optical laser. Current theoretical evidence suggests that nanoparticles can undergo reversible nonhomogenous melting with the formation of a core-shell structure consisting of a liquid outer layer. To date, studies from ensembles of nanoparticles have tentatively suggested that such mechanisms are present. Here we demonstrate imaging transient melting and softening of the acoustic phonon modes of an individual gold nanocrystal, using an X-ray free electron laser. The results demonstrate that the transient melting is reversible and nonhomogenous, consistent with a core-shell model of melting. The results have implications for understanding transient processes in nanoparticles and determining their elastic properties as they undergo phase transitions. PMID- 26034278 TI - Temperature dependence of amino acid hydrophobicities. AB - The hydrophobicities of the 20 common amino acids are reflected in their tendencies to appear in interior positions in globular proteins and in deeply buried positions of membrane proteins. To determine whether these relationships might also have been valid in the warm surroundings where life may have originated, we examined the effect of temperature on the hydrophobicities of the amino acids as measured by the equilibrium constants for transfer of their side chains from neutral solution to cyclohexane (K(w > c)). The hydrophobicities of most amino acids were found to increase with increasing temperature. Because that effect is more pronounced for the more polar amino acids, the numerical range of K(w > c) values decreases with increasing temperature. There are also modest changes in the ordering of the more polar amino acids. However, those changes are such that they would have tended to minimize the otherwise disruptive effects of a changing thermal environment on the evolution of protein structure. Earlier, the genetic code was found to be organized in such a way that--with a single exception (threonine)--the side-chain dichotomy polar/nonpolar matches the nucleic acid base dichotomy purine/pyrimidine at the second position of each coding triplet at 25 degrees C. That dichotomy is preserved at 100 degrees C. The accessible surface areas of amino acid side-chains in folded proteins are moderately correlated with hydrophobicity, but when free energies of vapor-to cyclohexane transfer (corresponding to size) are taken into consideration, a closer relationship becomes apparent. PMID- 26034280 TI - Histone chaperone Anp32e removes H2A.Z from DNA double-strand breaks and promotes nucleosome reorganization and DNA repair. AB - The repair of DNA double-strand breaks (DSBs) requires open, flexible chromatin domains. The NuA4-Tip60 complex creates these flexible chromatin structures by exchanging histone H2A.Z onto nucleosomes and promoting acetylation of histone H4. Here, we demonstrate that the accumulation of H2A.Z on nucleosomes at DSBs is transient, and that rapid eviction of H2A.Z is required for DSB repair. Anp32e, an H2A.Z chaperone that interacts with the C-terminal docking domain of H2A.Z, is rapidly recruited to DSBs. Anp32e functions to remove H2A.Z from nucleosomes, so that H2A.Z levels return to basal within 10 min of DNA damage. Further, H2A.Z removal by Anp32e disrupts inhibitory interactions between the histone H4 tail and the nucleosome surface, facilitating increased acetylation of histone H4 following DNA damage. When H2A.Z removal by Anp32e is blocked, nucleosomes at DSBs retain elevated levels of H2A.Z, and assume a more stable, hypoacetylated conformation. Further, loss of Anp32e leads to increased CtIP-dependent end resection, accumulation of single-stranded DNA, and an increase in repair by the alternative nonhomologous end joining pathway. Exchange of H2A.Z onto the chromatin and subsequent rapid removal by Anp32e are therefore critical for creating open, acetylated nucleosome structures and for controlling end resection by CtIP. Dynamic modulation of H2A.Z exchange and removal by Anp32e reveals the importance of the nucleosome surface and nucleosome dynamics in processing the damaged chromatin template during DSB repair. PMID- 26034281 TI - tRNA acceptor stem and anticodon bases form independent codes related to protein folding. AB - Aminoacyl-tRNA synthetases recognize tRNA anticodon and 3' acceptor stem bases. Synthetase Urzymes acylate cognate tRNAs even without anticodon-binding domains, in keeping with the possibility that acceptor stem recognition preceded anticodon recognition. Representing tRNA identity elements with two bits per base, we show that the anticodon encodes the hydrophobicity of each amino acid side-chain as represented by its water-to-cyclohexane distribution coefficient, and this relationship holds true over the entire temperature range of liquid water. The acceptor stem codes preferentially for the surface area or size of each side chain, as represented by its vapor-to-cyclohexane distribution coefficient. These orthogonal experimental properties are both necessary to account satisfactorily for the exposed surface area of amino acids in folded proteins. Moreover, the acceptor stem codes correctly for beta-branched and carboxylic acid side-chains, whereas the anticodon codes for a wider range of such properties, but not for size or beta-branching. These and other results suggest that genetic coding of 3D protein structures evolved in distinct stages, based initially on the size of the amino acid and later on its compatibility with globular folding in water. PMID- 26034282 TI - Epigenetic changes in the developing brain: Effects on behavior. PMID- 26034283 TI - Amphetamine modulates brain signal variability and working memory in younger and older adults. AB - Better-performing younger adults typically express greater brain signal variability relative to older, poorer performers. Mechanisms for age and performance-graded differences in brain dynamics have, however, not yet been uncovered. Given the age-related decline of the dopamine (DA) system in normal cognitive aging, DA neuromodulation is one plausible mechanism. Hence, agents that boost systemic DA [such as d-amphetamine (AMPH)] may help to restore deficient signal variability levels. Furthermore, despite the standard practice of counterbalancing drug session order (AMPH first vs. placebo first), it remains understudied how AMPH may interact with practice effects, possibly influencing whether DA up-regulation is functional. We examined the effects of AMPH on functional-MRI-based blood oxygen level-dependent (BOLD) signal variability (SD(BOLD)) in younger and older adults during a working memory task (letter n back). Older adults expressed lower brain signal variability at placebo, but met or exceeded young adult SD(BOLD) levels in the presence of AMPH. Drug session order greatly moderated change-change relations between AMPH-driven SD(BOLD) and reaction time means (RT(mean)) and SDs (RT(SD)). Older adults who received AMPH in the first session tended to improve in RT(mean) and RT(SD) when SD(BOLD) was boosted on AMPH, whereas younger and older adults who received AMPH in the second session showed either a performance improvement when SD(BOLD) decreased (for RT(mean)) or no effect at all (for RT(SD)). The present findings support the hypothesis that age differences in brain signal variability reflect aging-induced changes in dopaminergic neuromodulation. The observed interactions among AMPH, age, and session order highlight the state- and practice-dependent neurochemical basis of human brain dynamics. PMID- 26034284 TI - New chronology for Ksar 'Akil (Lebanon) supports Levantine route of modern human dispersal into Europe. AB - Modern human dispersal into Europe is thought to have occurred with the start of the Upper Paleolithic around 50,000-40,000 y ago. The Levantine corridor hypothesis suggests that modern humans from Africa spread into Europe via the Levant. Ksar 'Akil (Lebanon), with its deeply stratified Initial (IUP) and Early (EUP) Upper Paleolithic sequence containing modern human remains, has played an important part in the debate. The latest chronology for the site, based on AMS radiocarbon dates of shell ornaments, suggests that the appearance of the Levantine IUP is later than the start of the first Upper Paleolithic in Europe, thus questioning the Levantine corridor hypothesis. Here we report a series of AMS radiocarbon dates on the marine gastropod Phorcus turbinatus associated with modern human remains and IUP and EUP stone tools from Ksar 'Akil. Our results, supported by an evaluation of individual sample integrity, place the EUP layer containing the skeleton known as "Egbert" between 43,200 and 42,900 cal B.P. and the IUP-associated modern human maxilla known as "Ethelruda" before ~ 45,900 cal B.P. This chronology is in line with those of other Levantine IUP and EUP sites and demonstrates that the presence of modern humans associated with Upper Paleolithic toolkits in the Levant predates all modern human fossils from Europe. The age of the IUP-associated Ethelruda fossil is significant for the spread of modern humans carrying the IUP into Europe and suggests a rapid initial colonization of Europe by our species. PMID- 26034285 TI - Quantum tunneling observed without its characteristic large kinetic isotope effects. AB - Classical transition-state theory is fundamental to describing chemical kinetics; however, quantum tunneling is also important in explaining the unexpectedly large reaction efficiencies observed in many chemical systems. Tunneling is often indicated by anomalously large kinetic isotope effects (KIEs), because a particle's ability to tunnel decreases significantly with its increasing mass. Here we experimentally demonstrate that cold hydrogen (H) and deuterium (D) atoms can add to solid benzene by tunneling; however, the observed H/D KIE was very small (1-1.5) despite the large intrinsic H/D KIE of tunneling (? 100). This strong reduction is due to the chemical kinetics being controlled not by tunneling but by the surface diffusion of the H/D atoms, a process not greatly affected by the isotope type. Because tunneling need not be accompanied by a large KIE in surface and interfacial chemical systems, it might be overlooked in other systems such as aerosols or enzymes. Our results suggest that surface tunneling reactions on interstellar dust may contribute to the deuteration of interstellar aromatic and aliphatic hydrocarbons, which could represent a major source of the deuterium enrichment observed in carbonaceous meteorites and interplanetary dust particles. These findings could improve our understanding of interstellar physicochemical processes, including those during the formation of the solar system. PMID- 26034286 TI - Spatiotemporal expression and transcriptional perturbations by long noncoding RNAs in the mouse brain. AB - Long noncoding RNAs (lncRNAs) have been implicated in numerous cellular processes including brain development. However, the in vivo expression dynamics and molecular pathways regulated by these loci are not well understood. Here, we leveraged a cohort of 13 lncRNAnull mutant mouse models to investigate the spatiotemporal expression of lncRNAs in the developing and adult brain and the transcriptome alterations resulting from the loss of these lncRNA loci. We show that several lncRNAs are differentially expressed both in time and space, with some presenting highly restricted expression in only selected brain regions. We further demonstrate altered regulation of genes for a large variety of cellular pathways and processes upon deletion of the lncRNA loci. Finally, we found that 4 of the 13 lncRNAs significantly affect the expression of several neighboring proteincoding genes in a cis-like manner. By providing insight into the endogenous expression patterns and the transcriptional perturbations caused by deletion of the lncRNA locus in the developing and postnatal mammalian brain, these data provide a resource to facilitate future examination of the specific functional relevance of these genes in neural development, brain function, and disease. PMID- 26034279 TI - An estimate of the number of tropical tree species. AB - The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory database from closed canopy forests, consisting of 657,630 trees belonging to 11,371 species, we use a fitted value of Fisher's alpha and an approximate pantropical stem total to estimate the minimum number of tropical forest tree species to fall between ~ 40,000 and ~ 53,000, i.e., at the high end of previous estimates. Contrary to common assumption, the Indo-Pacific region was found to be as species-rich as the Neotropics, with both regions having a minimum of ~ 19,000-25,000 tree species. Continental Africa is relatively depauperate with a minimum of ~ 4,500-6,000 tree species. Very few species are shared among the African, American, and the Indo-Pacific regions. We provide a methodological framework for estimating species richness in trees that may help refine species richness estimates of tree-dependent taxa. PMID- 26034287 TI - Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders. AB - Increasing evidence in the last years indicates that the vast amount of regulatory information contained in mammalian genomes is organized in precise 3D chromatin structures. However, the impact of this spatial chromatin organization on gene expression and its degree of evolutionary conservation is still poorly understood. The Six homeobox genes are essential developmental regulators organized in gene clusters conserved during evolution. Here, we reveal that the Six clusters share a deeply evolutionarily conserved 3D chromatin organization that predates the Cambrian explosion. This chromatin architecture generates two largely independent regulatory landscapes (RLs) contained in two adjacent topological associating domains (TADs). By disrupting the conserved TAD border in one of the zebrafish Six clusters, we demonstrate that this border is critical for preventing competition between promoters and enhancers located in separated RLs, thereby generating different expression patterns in genes located in close genomic proximity. Moreover, evolutionary comparison of Six-associated TAD borders reveals the presence of CCCTC-binding factor (CTCF) sites with diverging orientations in all studied deuterostomes. Genome-wide examination of mammalian HiC data reveals that this conserved CTCF configuration is a general signature of TAD borders, underscoring that common organizational principles underlie TAD compartmentalization in deuterostome evolution. PMID- 26034288 TI - Focusing and sustaining the antitumor CTL effector killer response by agonist anti-CD137 mAb. AB - Cancer immunotherapy is undergoing significant progress due to recent clinical successes by refined adoptive T-cell transfer and immunostimulatory monoclonal Ab (mAbs). B16F10-derived OVA-expressing mouse melanomas resist curative immunotherapy with either adoptive transfer of activated anti-OVA OT1 CTLs or agonist anti-CD137 (4-1BB) mAb. However, when acting in synergistic combination, these treatments consistently achieve tumor eradication. Tumor-infiltrating lymphocytes that accomplish tumor rejection exhibit enhanced effector functions in both transferred OT-1 and endogenous cytotoxic T lymphocytes (CTLs). This is consistent with higher levels of expression of eomesodermin in transferred and endogenous CTLs and with intravital live-cell two-photon microscopy evidence for more efficacious CTL-mediated tumor cell killing. Anti-CD137 mAb treatment resulted in prolonged intratumor persistence of the OT1 CTL-effector cells and improved function with focused and confined interaction kinetics of OT-1 CTL with target cells and increased apoptosis induction lasting up to six days postadoptive transfer. The synergy of adoptive T-cell therapy and agonist anti CD137 mAb thus results from in vivo enhancement and sustainment of effector functions. PMID- 26034290 TI - Reply to Aksentijevic: It is a matter of what is countable and how neurons learn. PMID- 26034291 TI - No time for waiting: Statistical structure reflects subjective complexity. PMID- 26034292 TI - Reply to Mohlenhoff et al.: Human behavioral ecology needs a rethink that niche construction theory can provide. PMID- 26034289 TI - IL-1R signaling enables bystander cells to overcome bacterial blockade of host protein synthesis. AB - The innate immune system is critical for host defense against microbial pathogens, yet many pathogens express virulence factors that impair immune function. Here, we used the bacterial pathogen Legionella pneumophila to understand how the immune system successfully overcomes pathogen subversion mechanisms. L. pneumophila replicates within macrophages by using a type IV secretion system to translocate bacterial effectors into the host cell cytosol. As a consequence of effector delivery, host protein synthesis is blocked at several steps, including translation initiation and elongation. Despite this translation block, infected cells robustly produce proinflammatory cytokines, but the basis for this is poorly understood. By using a reporter system that specifically discriminates between infected and uninfected cells within a population, we demonstrate here that infected macrophages produced IL-1alpha and IL-1beta, but were poor producers of IL-6, TNF, and IL-12, which are critical mediators of host protection. Uninfected bystander cells robustly produced IL-6, TNF, and IL-12, and this bystander response required IL-1 receptor (IL-1R) signaling during early pulmonary infection. Our data demonstrate functional heterogeneity in production of critical protective cytokines and suggest that collaboration between infected and uninfected cells enables the immune system to bypass pathogen-mediated translation inhibition to generate an effective immune response. PMID- 26034293 TI - Optimal foraging theory and niche-construction theory do not stand in opposition. PMID- 26034294 TI - Reply to Hulme et al.: Cover of non-native species is too low to adversely affect native plant diversity at a national scale. PMID- 26034295 TI - Challenging the view that invasive non-native plants are not a significant threat to the floristic diversity of Great Britain. PMID- 26034296 TI - Reply to Chen: Under specified assumptions, adequate random samples of skewed distributions obey Taylor's law. PMID- 26034297 TI - Random sampling of skewed distributions does not necessarily imply Taylor's law. PMID- 26034298 TI - Substitutions at the cofactor phosphate-binding site of a clostridial alcohol dehydrogenase lead to unexpected changes in substrate specificity. AB - Changing the cofactor specificity of an enzyme from nicotinamide adenine dinucleotide 2'-phosphate (NADPH) to the more abundant NADH is a common strategy for increasing overall enzyme efficiency in microbial metabolic engineering. The aim of this study was to switch the cofactor specificity of the primary-secondary alcohol dehydrogenase from Clostridium autoethanogenum, a bacterium with considerable promise for the bio-manufacturing of fuels and other petrochemicals, from strictly NADPH-dependent to NADH-dependent. We used insights from a homology model to build a site-saturation library focussed on residue S199, the position deemed most likely to disrupt binding of the 2'-phosphate of NADPH. Although the CaADH(S199X) library did not yield any NADH-dependent enzymes, it did reveal that substitutions at the cofactor phosphate-binding site can cause unanticipated changes in the substrate specificity of the enzyme. Using consensus-guided site directed mutagenesis, we were able to create an enzyme that was stringently NADH dependent, albeit with a concomitant reduction in activity. This study highlights the role that distal residues play in substrate specificity and the complexity of enzyme-cofactor interactions. PMID- 26034299 TI - Mapping Anatomy to Behavior in Thy1:18 ChR2-YFP Transgenic Mice Using Optogenetics. AB - Linking the activity of defined neural populations with behavior is a key goal of neuroscience. In the context of controlling behavior, electrical stimulation affords researchers precision in the temporal domain with gross regional specificity, whereas pharmacology allows for more specific manipulation of cell types, but in the absence of temporal precision. The use of microbial opsins- light activated, genetically encoded ion channels and pumps--to control mammalian neurons now allows researchers to "sensitize" genetically and/or topologically defined populations of neurons to light to induce either depolarization or hyperpolarization in both a cell-type-specific and temporally precise manner not achievable with previous techniques. Here, we describe the use of transgenic mice expressing the blue-light gated cation channel Channelrhodopsin-2 (ChR2) under control of the Thy1 promoter for the purpose of linking neuronal activity to behavior through restricted delivery of light to an anatomic region of interest. The surgical procedure for implanting a fiber-optic light delivery guide into the mouse brain, the process of optically stimulating the brain in a behaving animal, and post hoc evaluation are given, along with necessary reagents and discussion of common technical problems and their solutions. PMID- 26034300 TI - Golgi isolation. AB - The Golgi apparatus is a membranous organelle that modifies and packages proteins and lipids into transport carriers and sends them to the proper locations in the cell. The study of Golgi structure and function can be facilitated by the isolation of this organelle from homogenates of tissues or cells. Liver cells have abundant Golgi membranes because they actively secrete proteins and lipids; therefore, liver tissue is often the preferred source. In this protocol, Golgi membranes are purified from rat liver homogenate by two sequential sucrose gradients. The relative yield of the prepared Golgi stacks is then assessed by measuring the increase in activity of a Golgi marker enzyme, beta-1,4 galactosyltransferase, over that of the total liver homogenate. A typical preparation can yield Golgi membranes that are purified 80- to 100-fold over the homogenate, and the majority (60%-70%) retain their stacked nature. PMID- 26034301 TI - Culturing primary mouse pancreatic ductal cells. AB - The most common subtype of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). PDAC resembles ductal cells morphologically. To study pancreatic ductal cell (PDC) and pancreatic intraepithelial neoplasia (PanIN)/PDAC biology, it is essential to have reliable in vitro culture conditions. Here we describe a methodology to isolate, culture, and passage PDCs and duct-like cells from the mouse pancreas. It can be used to isolate cells from genetically engineered mouse models (GEMMs), providing a valuable tool to study disease models in vitro to complement in vivo findings. The culture conditions allow epithelial cells to outgrow fibroblast and other "contaminating" cell types within a few passages. However, the resulting cultures, although mostly epithelial, are not completely devoid of fibroblasts. Regardless, this protocol provides guidelines for a robust in vitro culture system to isolate, maintain, and expand primary pancreatic ductal epithelial cells. It can be applied to virtually all GEMMs of pancreatic disease and other diseases and cancers that arise from ductal structures. Because most carcinomas resemble ductal structures, this protocol has utility in the study of other cancers in addition to PDAC, such as breast and prostate cancers. PMID- 26034302 TI - Chemical modification interference. AB - Chemical modification interference is a powerful method for surveying an entire RNA molecule to identify functionally important chemical groups. The basic idea is to generate a pool of end-labeled RNAs wherein each RNA molecule is chemically modified (e.g., by diethyl pyrocarbonate [DEPC], hydrazine, dimethyl sulfate, CMCT, or kethoxal) at a different position. The pool of RNAs is then allowed to participate in the reaction of interest. The functionally important RNA molecules (e.g., those bound by protein or that successfully participate in a processing reaction) are then separated from the nonfunctional RNA molecules (e.g., those not bound by protein or unable to participate in a processing reaction). This is often achieved by straightforward gel electrophoretic analysis. In the case of protein binding, it is necessary to be able to separate bound RNA from unbound RNA, which can be accomplished using electrophoretic mobility shift assays, filter binding, or affinity approaches (e.g., by immunoprecipitation or the use of tagged proteins). None of these techniques requires that a large fraction of RNA be bound or reacted, and, as a result, they are quite sensitive. Here we describe one example of a chemical modification interference assay in which RNA is modified with DEPC or hydrazine before binding to a protein. This technique can be readily adapted for use with other chemicals. PMID- 26034303 TI - Nucleotide analog interference mapping. AB - Methods collectively known as modification interference are exceptionally powerful approaches used to identify functionally important chemical groups in the phosphodiester backbone or nucleobases of an RNA. In a modification interference assay, end-labeled RNAs that have been modified at different positions are allowed to participate in a reaction of interest, and then functional RNA molecules (e.g., those bound by protein or that successfully participate in a processing reaction) are separated from nonfunctional RNA molecules (e.g., those not bound by protein or unable to participate in a processing reaction). Nucleotide analog interference mapping (NAIM) involves the incorporation of alpha-thionucleotides containing a modified base into the RNA molecule of interest. The sites containing the modified base are identified by cleavage with iodoethanol. NAIM is useful whenever the thiophosphate substitution on its own does not prevent or inhibit a specific reaction. To perform NAIM, it is first necessary to perform a thiophosphate interference analysis. Any positions that are not affected by thiophosphate substitution can then be analyzed by NAIM. PMID- 26034304 TI - Chromosome Conformation Capture (3C) in Budding Yeast. AB - Chromosome conformation capture (3C) is a method for studying chromosomal organization that takes advantage of formaldehyde cross-linking to measure the spatial association of two pieces of chromatin. The 3C method begins with whole cell formaldehyde fixation of chromatin. After cell lysis, solubilized chromatin is digested with a type II restriction endonuclease, and cross-linked DNA fragments are ligated together. Cross-links are reversed by degradation with proteinase K, and chimeric DNA molecules are purified by standard phenol:chloroform extraction. The resulting 3C library represents chromatin fragments that may be separated by large genomic distances or located on different chromosomes, but are close enough in three-dimensional space for cross linking. Locus-specific oligonucleotide primers are used to detect interactions of interest in the 3C library using end-point polymerase chain reaction (PCR). PMID- 26034305 TI - Randomized ligation control for chromosome conformation capture. AB - In experiments using chromosome conformation capture followed by PCR (3C-PCR) or chromosome conformation capture carbon copy (5C), it is critical to control for intrinsic biases in the restriction fragments of interest and the probes or primers used for detection. Characteristics such as GC%, annealing temperature, efficiency of 3C primers or 5C probes, and length of restriction fragment can cause variations in primer or probe performance and fragment ligation efficiency. Bias can be measured empirically by production of a random control library, as described here, to be used with the 3C library of interest. PMID- 26034306 TI - Chromosome Conformation Capture Carbon Copy (5C) in Budding Yeast. AB - Chromosome conformation capture carbon copy (5C) is a high-throughput method for detecting ligation products of interest in a chromosome conformation capture (3C) library. 5C uses ligation-mediated amplification (LMA) to generate carbon copies of 3C ligation product junctions using single-stranded oligonucleotide probes. This procedure produces a 5C library of short DNA molecules which represent the interactions between the corresponding restriction fragments. The 5C library can be amplified using universal primers containing the Illumina paired-end adaptor sequences for subsequent high-throughput sequencing. PMID- 26034307 TI - Terminal Deoxynucleotidyl Transferase (TdT)-Mediated dUTP Nick-End Labeling (TUNEL) for Detection of Apoptotic Cells in Drosophila. AB - A characteristic feature of apoptosis is DNA fragmentation. This fragmentation can be detected by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) of DNA in dying cells. Here, we present a protocol for TUNEL detection of apoptosis in Drosophila larval tissue, but these techniques can be adapted for other tissues and developmental stages. PMID- 26034308 TI - Using the vital dye acridine orange to detect dying cells in Drosophila. AB - Acridine orange is a cell-permeable fluorescent dye that binds to nucleic acids, resulting in an altered spectral emission. Acridine orange staining has been shown to be highly selective for apoptotic cells in Drosophila; however, the precise mechanism underlying this effect is not known. Advantages of acridine orange staining include the speed and ease of the staining. But there are disadvantages: It should be performed on unfixed tissue that therefore must be examined immediately, and multiple labeling cannot be performed. Slightly different protocols for the uptake of acridine orange are required for different developmental stages. Here, we present protocols for use of acridine orange to detect apoptosis in Drosophila embryos and in larval tissue. Slight modifications might be required for other Drosophila tissues. PMID- 26034309 TI - Immunostaining Using an Antibody against Active Caspase-3 to Detect Apoptotic Cells in Drosophila. AB - The activation of mammalian caspase-3 after proteolytic cleavage adjacent to residue Asp175 produces a large (17/19-kDa), active subunit. A commercially available antibody recognizes the large, active subunit of caspase-3 but not the full-length inactive caspase-3. This antibody has also been shown to detect active Drosophila effector caspases. Here, we present a protocol showing how this antibody can be used to detect apoptotic cells in various Drosophila tissues and developmental stages and discuss the specificity of the antibody. PMID- 26034310 TI - Two-Photon Imaging of Neuronal Structural Plasticity in Mice during and after Ischemia. AB - To gain insight into the dendritic structural changes that occur within minutes of ischemia, as well as circuit-level plasticity that occurs over days to weeks, it is necessary to devise stroke models for anesthetized transgenic mice that are compatible with in vivo imaging methods. In particular, we are interested in examining events during the first few minutes of ischemia that are associated with a wave of ischemic depolarization. Given the short latency to ischemic depolarization (~2 min), we have found it necessary to develop ischemia models that can be initiated while the animal is within the two-photon microscope for in vivo imaging. We describe both a global ischemia model and a targeted photothrombotic ischemia model in green fluorescent protein- and yellow fluorescent protein-expressing transgenic mice in which in vivo imaging of dendritic structure can be performed. The advantage of the global model is the speed with which ischemia can be induced and reversed, whereas the focal model lacks precise temporal control but can be targeted to a select region. PMID- 26034311 TI - Culturing mouse tumor cells. AB - Genetically engineered mouse models (GEMMs) are attractive for the study of cancer; however, they can be time-consuming and expensive to produce and maintain. Thus, in certain contexts, the use of in vitro culture systems of tumor cells may provide an efficient and effective means to test hypotheses before assessment in or to complement discoveries in GEMMs. This introduction will briefly review the issues pertaining to in vitro analyses of primary cancer cells and highlight several "best practice" protocols that can be used when working with diverse types of carcinomas. PMID- 26034312 TI - Time-domain fluorescence lifetime imaging microscopy: a quantitative method to follow transient protein-protein interactions in living cells. AB - Quantitative analysis in Forster resonance energy transfer (FRET) imaging studies of protein-protein interactions within live cells is still a challenging issue. Many cellular biology applications aim at the determination of the space and time variations of the relative amount of interacting fluorescently tagged proteins occurring in cells. This relevant quantitative parameter can be, at least partially, obtained at a pixel-level resolution by using fluorescence lifetime imaging microscopy (FLIM). Indeed, fluorescence decay analysis of a two-component system (FRET and no FRET donor species), leads to the intrinsic FRET efficiency value (E) and the fraction of the donor-tagged protein that undergoes FRET (fD). To simultaneously obtain fD and E values from a two-exponential fit, data must be acquired with a high number of photons, so that the statistics are robust enough to reduce fitting ambiguities. This is a time-consuming procedure. However, when fast-FLIM acquisitions are used to monitor dynamic changes in protein-protein interactions at high spatial and temporal resolutions in living cells, photon statistics and time resolution are limited. In this case, fitting procedures are unreliable, even for single lifetime donors. We introduce the concept of a minimal fraction of donor molecules involved in FRET (mfD), obtained from the mathematical minimization of fD. Here, we discuss different FLIM techniques and the compromises that must be made between precision and time invested in acquiring FLIM measurements. We show that mfD constitutes an interesting quantitative parameter for fast FLIM because it gives quantitative information about transient interactions in live cells. PMID- 26034314 TI - Cross-trees, Edge and Superpixel Priors-based Cost aggregation for Stereo matching. AB - In this paper, we propose a novel cross-trees structure to perform the nonlocal cost aggregation strategy, and the cross-trees structure consists of a horizontal tree and a vertical-tree. Compared to other spanning trees, the significant superiorities of the cross-trees are that the trees' constructions are efficient and the trees are exactly unique since the constructions are independent on any local or global property of the image itself. Additionally, two different priors: edge prior and superpixel prior, are proposed to tackle the false cost aggregations which cross the depth boundaries. Hence, our method contains two different algorithms in terms of cross-trees+prior. By traversing the two crossed trees successively, a fast non-local cost aggregation algorithm is performed twice to compute the aggregated cost volume. Performance evaluation on the 27 Middlebury data sets shows that both our algorithms outperform the other two tree based non-local methods, namely minimum spanning tree (MST) and segment-tree (ST). PMID- 26034313 TI - Genetic influences on social attention in free-ranging rhesus macaques. AB - An ethological approach to attention predicts that organisms orient preferentially to valuable sources of information in the environment. For many gregarious species, orienting to other individuals provides valuable social information but competes with food acquisition, water consumption and predator avoidance. Individual variation in vigilance behaviour in humans spans a continuum from inattentive to pathological levels of interest in others. To assess the comparative biology of this behavioural variation, we probed vigilance rates in free-ranging macaques during water drinking, a behaviour incompatible with the gaze and postural demands of vigilance. Males were significantly more vigilant than females. Moreover, vigilance showed a clear genetic component, with an estimated heritability of 12%. Monkeys carrying a relatively infrequent 'long' allele of TPH2, a regulatory gene that influences serotonin production in the brain, were significantly less vigilant compared to monkeys that did not carry the allele. These findings resonate with the hypothesis that the serotonin pathway regulates vigilance in primates and by extension provoke the idea that individual variation in vigilance and its underlying biology may be adaptive rather than pathological. PMID- 26034315 TI - Advances in the management of diabetic macular oedema based on evidence from the Diabetic Retinopathy Clinical Research Network. AB - The Diabetic Retinopathy Clinical Research Network (DRCR.net) performs studies on new treatments for diabetic retinopathy. This review aims to summarise recent findings from DRCR.net studies on the treatment of diabetic macular oedema. We performed a PubMed search of articles from the DRCR.net, which included all studies pertaining to the treatment of diabetic maculopathy. The main outcome measures were retinal thickening as assessed by central subfield thickness on optical coherence tomography and improvement of visual acuity on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Findings from each study were divided into modalities of treatment, namely photocoagulation, bevacizumab, triamcinolone, ranibizumab and vitrectomy. While modified ETDRS focal/grid laser remains the standard of care, intravitreal corticosteroids or anti-vascular endothelial growth factor agents have also proven to be effective, although they come with associated side effects. The choice of treatment modality for diabetic macular oedema is a clinical judgement call, and depends on the patient's clinical history and assessment. PMID- 26034316 TI - Unsuspected colorectal carcinoma on routine abdominopelvic computed tomography. AB - Colorectal carcinoma is a common lethal disease with signs and symptoms that may be nonspecific. Computed tomography (CT) of the abdomen and pelvis with or without contrast is frequently performed for various general abdominal complaints, but unlike CT colonography, the large bowel may not be optimally prepared for evaluation. As such, careful and diligent assessment of the non prepared colon in all CT images of the abdomen and pelvis is important, as it ensures that incidental colorectal malignancy is not missed, especially in older patients. This article gives an overview of multidetector CT imaging signs and subtle clues to aid in the diagnosis of colorectal carcinoma, as well as their pitfalls. PMID- 26034317 TI - Patient satisfaction after total knee arthroplasty: an Asian perspective. AB - INTRODUCTION: Total knee arthroplasty (TKA) is an effective method for alleviating pain and restoring knee function in patients with severe osteoarthritis. However, despite the improvements in surgical technique and postoperative care, it has been reported that up to 19% of patients are dissatisfied after their operations. The aim of this study was to evaluate patient satisfaction levels after TKA in an Asian cohort, as well as assess the correlation between patient satisfaction levels and the results of traditional physician-based scoring systems. METHODS: The medical data of 103 Asian patients who underwent 110 TKAs between December 2008 and June 2009 were obtained from our hospital's Joint Replacement Registry. The minimum follow-up period was one year and patient expectations were assessed before TKA. Patient satisfaction was assessed postoperatively using a 5-point Likert scale. Reasons for patient dissatisfaction were recorded. Standardised instruments (e.g. the Knee Society Score, the Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] and the generic Short Form-36 health survey) were used to assess the patient's functional status and the severity of symptoms pre- and postoperatively. RESULTS: Among the 110 TKAs performed, 92.8% resulted in patient satisfaction. Patient satisfaction correlated with postoperative WOMAC function scores (p = 0.028), postoperative WOMAC final scores (p = 0.040) and expectations being met (p = 0.033). CONCLUSION: Although there was a high level of patient satisfaction following TKA in our cohort of Asian patients, a significant minority was dissatisfied. Patient satisfaction is an important outcome measure and should be assessed in addition to traditional outcome scores. PMID- 26034318 TI - Male orthopaedic surgeons and anaesthetists: equally good at estimating fluid volumes (and changing light bulbs) but equally poor at estimating procedure duration. AB - INTRODUCTION: How many orthopods does it take to change a light bulb? One - to refer to the medics for 'Darkness ?Cause'. Additionally, anaesthetists and surgeons often disagree on the estimated blood loss during surgery and the estimated procedure duration. We designed this study to compare the ability of orthopaedic surgeons and anaesthetists in: (a) estimating fluid volumes; (b) estimating procedure durations; and (c) changing light bulbs. METHODS: Participants had to either be a specialist in anaesthesia or orthopaedic surgery, or a trainee in that specialty for at least two years. Three different fluid specimens were used for volume estimation (44 mL, 88 mL and 144 mL). Two videos of different lengths (140 seconds and 170 seconds), showing the suturing of a banana skin, were used for procedure duration estimation. To determine the ability at changing light bulbs, the participants had to match eight different light sockets to their respective bulbs. RESULTS: 30 male anaesthetists and trainees and 31 male orthopaedic surgeons and trainees participated in this study. Orthopaedic surgeons underestimated the three fluid volumes by 3.9% and anaesthetists overestimated by 5.1% (p = 0.925). Anaesthetists and orthopaedic surgeons overestimated the duration of the two procedures by 21.2% and 43.1%, respectively (p = 0.006). Anaesthetists had a faster mean time in changing light bulbs (70.1 seconds vs. 74.1 seconds, p = 0.319). CONCLUSION: In an experimental environment, male orthopaedic surgeons are as good as male anaesthetists in estimating fluid volumes (in commonly seen surgical specimens) and in changing light bulbs. Both groups are poor at estimating procedure durations. PMID- 26034319 TI - Effectiveness of medical thoracoscopy and thoracoscopic talc poudrage in patients with exudative pleural effusion. AB - INTRODUCTION: This study aimed to assess the effectiveness of medical thoracoscopy (MT) and thoracoscopic talc poudrage (TTP) in patients with exudative pleural effusion. METHODS: We evaluated the diagnostic yields, complications and outcomes of MT and TTP in 41 consecutive patients with symptomatic pleural effusions who were planned to undergo both procedures from 1 December 2011 to 30 November 2012. Data was reviewed retrospectively and prospectively up to March 2013. RESULTS: Among the 41 patients, 36 underwent MT with the intent of biopsy and talc pleurodesis, 2 underwent MT for pleurodesis only and 3 had failed MT. Aetiologies of pleural effusion included lung cancer (n = 14), tuberculosis (n = 9), breast cancer (n = 7), ovarian cancer (n = 2), malignant mesothelioma (n = 1), congestive cardiac failure (n = 1), peritoneal dialysis (n = 1) and hepatic hydrothorax (n = 1); pleural effusion was undiagnosed in five patients. The overall diagnostic yield of MT, and the yield in tubercular and malignant pleural effusions were 77.8%, 100.0% and 82.6%, respectively; it was inconclusive in 22.2%. Complications that occurred were self limiting, with no procedure-related mortality. The 30-day mortality rate was 17.1%. A total of 15 patients underwent TTP. The 30-, 60- and 90-day success rates were 77.8%, 80.0% and 80.0%, respectively, with one patient having complications (i.e. empyema). The 30-day mortality was 40.0%. CONCLUSION: MT is a safe procedure with high diagnostic yields in undiagnosed pleural effusions. TTP is an effective method to stop recurrence of pleural effusions. PMID- 26034320 TI - Health Promotion Board-Ministry of Health Clinical Practice Guidelines: Falls Prevention among Older Adults Living in the Community. AB - The Health Promotion Board (HPB) has developed the Clinical Practice Guidelines (CPG) on Falls Prevention among Older Adults Living in the Community to provide health professionals in Singapore with recommendations for evidence-based assessments and interventions for falls prevention. This article reproduces the introduction and executive summary of the key recommendations from the HPB-MOH CPG on Falls Prevention among Older Adults Living in the Community for the information of SMJ readers. The chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Health Promotion Board website: http://www.hpb.gov. sg/cpg-falls prevention. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines. PMID- 26034321 TI - Takotsubo cardiomyopathy associated with perimyocarditis: yet another important differential diagnosis to entertain. PMID- 26034322 TI - Author's reply: To PMID 25640104. PMID- 26034323 TI - Recurrent myocardial infarction secondary to Prinzmetal's variant angina. AB - Prinzmetal's variant angina describes chest pain secondary to reversible coronary artery vasospasm in the context of both diseased and non-diseased coronary arteries. Symptoms typically occur when the patient is at rest and are associated with transient ST-segment elevation. Acute episodes respond to glyceryl trinitrate, but myocardial infarction and other potentially fatal complications can occur, and long-term management can be challenging. Although it is not well understood, the underlying mechanism appears to involve a combination of endothelial damage and vasoactive mediators. In this case, a 35-year-old woman with myocardial infarction secondary to coronary artery vasospasm experienced recurrent chest pain. Coronary angiography revealed severe focal stenosis in the mid left anterior descending artery, which completely resolved after administration of intracoronary glyceryl trinitrate. The patient was discharged on nitrates and calcium channel blockers. The patient re-presented with another myocardial infarction, requiring up-titration of medical therapy. PMID- 26034325 TI - Mullerian agenesis in the presence of anorectal malformations in female newborns: a diagnostic challenge. AB - Rectovestibular fistula is the most common type of anomaly found in a female newborn with anorectal malformation. However, when the baby is found to have two orifices in the introitus, rectovaginal fistula is much less common and suspected. The rare differential diagnosis of Mullerian agenesis, a condition in which the rectum shifts anteriorly and the vagina is absent, is seldom considered. In many cases, the diagnosis of Mullerian agenesis is made only during definitive anorectoplasty. In view of its impact on management, a proper examination under anaesthesia, imaging studies and a diagnostic laparoscopy may be required to confirm the presence or absence of Mullerian structures in such patients. We herein describe a patient with the rare coexistence of VACTERL association and Mullerian agenesis, and discuss the management of anorectal malformations in female patients with Mullerian agenesis. PMID- 26034324 TI - Adult rectosigmoid junction intussusception presenting with rectal prolapse. AB - Most cases of intussusception in adults present with chronic and nonspecific symptoms, and can sometimes be challenging to diagnose. We herein report on a patient with the rare symptom of colonic intussusceptions presenting with rectal prolapse and review the existing literature of similar case reports to discuss how to reach an accurate diagnosis. A 75-year-old woman with dementia presented with per rectal bleeding, rectal prolapse and lower abdominal pain. An operation was scheduled and a large sigmoid intussusception with a polyp as a leading point was found intraoperatively. She subsequently recovered well and was discharged. As large sigmoid intussusceptions may present as rectal prolapse, intussusception should be considered as a differential diagnosis for immobile patients, especially when the leading point is a lesion. PMID- 26034326 TI - Lymphocytic colitis complicated by a mass in the terminal ileum. AB - Lymphocytic colitis is a chronic inflammatory disease affecting the bowel. The clinical course of lymphocytic colitis is believed to be benign with watery diarrhoea. We report herein what is, to the best of our knowledge, the first case of lymphocytic colitis complicated by a terminal ileal mass. A 23-year-old man presented with diarrhoea. Blind biopsies of samples taken from the terminal ileum, caecum and ascending colon showed features of lymphocytic colitis. He declined treatment with budesonide or 5-aminosalicylates. He presented 14 months later with pain over the right lumbar region and nausea. Computed tomographic enteroclysis showed a focal soft tissue enhancing mass at the terminal ileum. Excision of the soft tissue mass revealed that it was reactive nodular lymphoid hyperplasia with fibrous granulation tissue. In conclusion, an untreated lymphocytic colitis may result in the formation of an inflammatory mass lesion. PMID- 26034327 TI - Revision of loop colostomy under regional anaesthesia and sedation. AB - Patients presenting for emergency abdominal procedures often have medical issues that cause both general anaesthesia and central neuraxial blockade to pose significant risks. Regional anaesthetic techniques are often used adjunctively for abdominal procedures under general anaesthesia, but there is limited published data on procedures done under peripheral nerve or plexus blocks. We herein report the case of a patient with recent pulmonary embolism and supraventricular tachycardia who required colostomy refashioning. Ultrasonography guided regional anaesthesia was administered using a combination of ilioinguinal iliohypogastric, rectus sheath and transversus abdominis plane blocks. This was supplemented with propofol and dexmedetomidine sedation as well as intermittent fentanyl and ketamine boluses to cover for visceral stimulation. We discuss the anatomical rationale for the choice of blocks and compare the anaesthetic conduct with similar cases that were previously reported. PMID- 26034328 TI - Avoiding diagnostic pitfalls in mimics of neoplasia: the importance of a comprehensive diagnostic approach. AB - Any medical diagnosis should take a multimodal approach, especially those involving tumour-like conditions, as entities that mimic neoplasms have overlapping features and may present detrimental outcomes if they are underdiagnosed. These case reports present diagnostic pitfalls resulting from overdependence on a single diagnostic parameter for three musculoskeletal neoplasm mimics: brown tumour (BT) that was mistaken for giant cell tumour (GCT), methicillin-resistant Staphylococcus aureus osteomyelitis mistaken for osteosarcoma and a pseudoaneurysm mistaken for a soft tissue sarcoma. Literature reviews revealed five reports of BT simulating GCT, four reports of osteomyelitis mimicking osteosarcoma and five reports of a pseudoaneurysm imitating a soft tissue sarcoma. Our findings highlight the therapeutic dilemmas that arise with musculoskeletal mimics, as well as the importance of thorough investigation to distinguish mimickers from true neoplasms. PMID- 26034329 TI - Synthetic Approaches and Total Syntheses of Vinigrol, a Unique Diterpenoid. AB - This review summarizes all published total and formal syntheses as well as synthetic approaches towards vinigrol. The content is divided into sections, which are focused on each research groups contributions and how far each approach was advanced towards vinigrol. Graphical summaries of all the published vinigrol structural perspectives, starting materials used for each routes and a discussion of preferred or privileged reactions employed is also presented. PMID- 26034330 TI - Catalytic intramolecular decarbonylative coupling of 3-aminocyclobutenones and alkenes: a unique approach to [3.1.0] bicycles. AB - Here we describe a rhodium-catalyzed intramolecular decarbonylative coupling between 3-aminocyclobutenones and alkenes for synthesis of substituted [3.1.0] bicycles. This transformation represents a formal cyclopropanation reaction, in which the cyclobutenones serve as a one-carbon-unit synthon. PMID- 26034331 TI - Scalable syntheses of the BET bromodomain inhibitor JQ1. AB - We have developed methods involving the use of alternate, safer reagents for the scalable syntheses of the potent BET bromodomain inhibitor JQ1. A one-pot three step method, involving the conversion of a benzodiazepine to a thioamde using Lawesson's reagent, followed by amidrazone formation and installation of the triazole moiety furnished JQ1. This method provides good yields and a facile purification process. For the synthesis of enantiomerically enriched (+)-JQ1, the highly toxic reagent diethyl chlorophosphate, used in a previous synthesis, was replaced with the safer reagent diphenyl chlorophosphate in the three-step one pot triazole formation without effecting yields and enantiomeric purity of (+) JQ1. PMID- 26034332 TI - Triethysilyl Enol Ethers in the Synthesis of Carbapenem Precursors. AB - A diastereoselective process for the formation of intermediates suitable for the preparation of C1 substituted carbapenems was developed. The process is readily scalable and does not involve organometallics or strong bases such as LDA. PMID- 26034333 TI - Synthesis of the diaryl ether cores common to chrysophaentins A, E and F. AB - The synthesis of the diaryl ether subunits of the marine natural products chrysophaentin A, E and F is described. These natural prodcuts feature tetrasubstituted benzene rings with complex substitution patterns. The central strategy involves an SNAr reaction between a complex phenol and a polysubstituted fluoronitrobenzene. Subseqent attempts to construct the unusual E-chloroalkene linkage through several different approaches are also disclosed. PMID- 26034334 TI - Studies on the regio- and diastereo-selective epoxidation of daphnanes and tiglianes. AB - Daphnanes and tiglianes are diterpenes with a shared tricyclic 5-7-6 ring system. Many members exhibit significant biological activities often associated with protein kinase C signaling. Many of these natural products (~100) have a C6-C7 alpha-epoxide whose influence on biological activity is little studied. Using the more readily available phorbol ester PDBu as a test substrate, we report an efficient, and potentially general, alpha-epoxidation method based on a vanadium catalyzed asymmetric epoxidation with bishydroxamic acid (BHA) ligands. PMID- 26034335 TI - Self-Assembly of a Library of Polyborate Chiral Anions for Asymmetric Catalytic Quinoline Reduction. AB - The 'template' polyborate BOROX catalysts are shown to mediate the asymmetric transfer hydrogenation of 2-quinolines. The rapid and simple generation of a large family of BOROX catalysts with significantly altered asymmetric pockets is described. A transition state model that explains the enantioselectivity is proposed. PMID- 26034336 TI - Computational predictions of substituted benzyne and indolyne regioselectivities. AB - A computational study using DFT methods was performed for an array of mono and disubstituted benzynes and indolynes. The inherent distortion present in the geometry-optimized structures predicts the regioselectivity of aryne trapping by nucleophiles or cycloaddition partners. These studies will serve to enable the further use of unsymmetrical arynes in organic synthesis. PMID- 26034337 TI - Synthesis of triarylmethanols via tandem arylation/oxidation of diarylmethanes. AB - A tandem arylation/oxidation of diarylmethanes for the convenient synthesis of unsymmetrical triarylmethanols bearing different aryl and heteroaryl groups is described. A Pd(OAc)2-NiXantphos catalyst system efficiently catalyzed arylation of weakly acidic sp3-hybridized C-H bonds of diarylmethanes with aryl bromides, and the arylation products were then oxidized in situ to carbinols by simply opening the reaction flasks to air. The triarylmethanol products were obtained in 35-98% yield. PMID- 26034338 TI - Antiproliferative Compounds from Ocotea macrocarpa from the Madagascar Dry Forest1. AB - Bioassay-directed fractionation of an antiproliferative ethanol extract of the roots of Ocotea macrocarpa (Lauraceae) afforded the new butanolide macrocarpolide A (1), and the two new secobutanolides macrocarpolides B (2) and C (3), together with the known butanolides linderanolide B (4) and isolinderanolide (5). The structure elucidation of all compounds was carried out based on NMR and mass spectroscopic data analyses. The absolute configurations of all compounds isolated were determined by comparison of their optical rotation values with those found in literature. Compounds 1-5 showed good antiproliferative activities against the A2780 ovarian cell line, with IC50 values of 2.57 +/- 0.12 (1), 1.98 +/- 0.23 (2), 1.67 +/- 0.05 (3), 2.43 +/- 0.41 (4), and 1.65 +/- 0.44 uM (5), respectively. PMID- 26034339 TI - Optically Triggered Immune Response through Photocaged Oligonucleotides. AB - Bacterial and viral CpG oligonculeotides are unmethylated cytosine-phosphate guanosine dinucleotide sequences and trigger an innate immune response through activation of the toll-like receptor 9 (TLR9). We have developed synthetic photocaged CpGs via site-specific incorporation of nitropiperonyloxymethyl (NPOM) caged thymidine residues. These oligonucleotides enable the optical control of TLR9 function and thereby provide light-activation of an immune response. We provide a proof-of-concept model by applying a reporter assay in live cells and by quantification of endogenous production of interleukin 6. PMID- 26034340 TI - Copper-promoted synthesis of 1,4-benzodiazepinones via alkene diamination. AB - A new method for the synthesis of 2-aminomethyl functionalized 1,4-benzodiazepin 5-ones is presented. The benzodiazepine core is well-known to interact with biological receptors and many pharmaceutical drugs are derived from this structure. The alkene diamination strategy is employed for the first time for the synthesis of 1,4-benzodiazepinones. In this reaction, copper(2-ethylhexanoate)2 serves as promoter and a range of external amines can be coupled with 2 sulfonamido-N-allyl benzamides to generate the 1,4-benzodiazepinones in good yields. PMID- 26034341 TI - Biologic Potential of Calcium Phosphate Biopowders Produced via Decomposition Combustion Synthesis. AB - The aim of this research was to evaluate the biologic potential of calcium phosphate (CaP) biopowders produced with a novel reaction synthesis system. Decomposition combustion synthesis (DCS) is a modified combustion synthesis method capable of producing CaP powders for use in bone tissue engineering applications. During DCS, the stoichiometric ratio of reactant salt to fuel was adjusted to alter product chemistry and morphology. In vitro testing methods were utilized to determine the effects of controlling product composition on cytotoxicity, proliferation, biocompatibility and biomineralization. In vitro, human fetal osteoblasts (ATCC, CRL-11372) cultured with CaP powder displayed a flattened morphology, and uniformly encompassed the CaP particulates. Matrix vesicles containing calcium and phosphorous budded from the osteoblast cells. CaP powders produced via DCS are a source of biologically active, synthetic, bone graft substitute materials. PMID- 26034342 TI - Is Child Labor a Barrier to School Enrollment in Low- and Middle-Income Countries? AB - Achieving universal primary education is one of the Millennium Development Goals. In low- and middle-income developing countries (LMIC), child labor may be a barrier. Few multi-country, controlled studies of the relations between different kinds of child labor and schooling are available. This study employs 186,795 families with 7- to 14-year-old children in 30 LMIC to explore relations of children's work outside the home, family work, and household chores with school enrollment. Significant negative relations emerged between each form of child labor and school enrollment, but relations were more consistent for family work and household chores than work outside the home. All relations were moderated by country and sometimes by gender. These differentiated findings have nuanced policy implications. PMID- 26034343 TI - How Distinctive Processing Enhances Hits and Reduces False Alarms. AB - Distinctive processing is a concept designed to account for precision in memory, both correct responses and avoidance of errors. The principal question addressed in two experiments is how distinctive processing of studied material reduces false alarms to familiar distractors. Jacoby (Jacoby, Kelley, & McElree, 1999) has used the metaphors early selection and late correction to describe two different types of control processes. Early selection refers to limitations on access whereas late correction describes controlled monitoring of accessed information. The two types of processes are not mutually exclusive, and previous research has provided evidence for the operation of both. The data reported here extend previous work to a criterial recollection paradigm and to a recognition memory test. The results of both experiments show that variables that reduce false memory for highly familiar distracters continue to exert their effect under conditions of minimal post-access monitoring. Level of monitoring was reduced in the first experiment through test instructions and in the second experiment through speeded test responding. The results were consistent with the conclusion that both early selection and late correction operate to control accuracy in memory. PMID- 26034344 TI - Implicit and explicit contributions to statistical learning. AB - Statistical learning allows learners to detect regularities in the environment and appears to emerge automatically as a consequence of experience. Statistical learning paradigms bear many similarities to those of artificial grammar learning and other types of implicit learning. However, whether learning effects in statistical learning tasks are driven by implicit knowledge has not been thoroughly examined. The present study addressed this gap by examining the role of implicit and explicit knowledge within the context of a typical auditory statistical learning paradigm. Learners were exposed to a continuous stream of repeating nonsense words. Learning was tested (a) directly via a forced-choice recognition test combined with a remember/know procedure and (b) indirectly through a novel reaction time (RT) test. Behavior and brain potentials revealed statistical learning effects with both tests. On the recognition test, accurate responses were associated with subjective feelings of stronger recollection, and learned nonsense words relative to nonword foils elicited an enhanced late positive potential indicative of explicit knowledge. On the RT test, both RTs and P300 amplitudes differed as a function of syllable position, reflecting facilitation attributable to statistical learning. Explicit stimulus recognition did not correlate with RT or P300 effects on the RT test. These results provide evidence that explicit knowledge is accrued during statistical learning, while bringing out the possibility that dissociable implicit representations are acquired in parallel. The commonly used recognition measure primarily reflects explicit knowledge, and thus may underestimate the total amount of knowledge produced by statistical learning. Indirect measures may be more sensitive indices of learning, capturing knowledge above and beyond what is reflected by recognition accuracy. PMID- 26034345 TI - Current Trends in Retirement: Implications for Career Counseling and Vocational Psychology. AB - This paper provides an overview of emerging trends in retirement, examines demographic trends in the labor force, and provides practical recommendations for working with older workers across cultures (e.g., women and racial/ethnic minorities, among others). Increasingly, older workers in the United States remain in the workforce for reasons related to financial security, healthcare, and personal fulfillment. Although retirement trends have become more complex, there is limited empirical literature addressing this issue and the research available does not attend to the needs of a diverse workforce. Therefore, implications for training, practice, advocacy, and research with regards to working with older workers across cultures (e.g., women and racial/ethnic minorities, among others) are provided. PMID- 26034346 TI - Surgical recurrence in Crohn's disease: Are we getting better? AB - Crohn's disease (CD) still remains a challenging chronic inflammatory disorder, both for colorectal surgeons and gastroenterologists. The need for recurrent surgery following primary intestinal resection is still considerable, though recent evidence suggested a declining rate of recurrence. Several conflicting surgical parameters have been identified that might impact on the postoperative outcome positively, such as access to the abdomen, anastomotic configuration or type of disease. Additionally, promising results have been achieved with the increased use of immunosuppressive medications in CD. Consequently, the question arises if we are getting better as a result of novel medical and surgical strategies. PMID- 26034347 TI - Surgical strategies in paediatric inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) comprises two distinct but related chronic relapsing inflammatory conditions affecting different parts of the gastrointestinal tract. Crohn's disease is characterised by a patchy transmural inflammation affecting both small and large bowel segments with several distinct phenotypic presentations. Ulcerative colitis classically presents as mucosal inflammation of the rectosigmoid (distal colitis), variably extending in a contiguous manner more proximally through the colon but not beyond the caecum (pancolitis). This article highlights aspects of the presentation, diagnosis, and management of IBD that have relevance for paediatric practice with particular emphasis on surgical considerations. Since 25% of IBD cases present in childhood or teenage years, the unique considerations and challenges of paediatric management should be widely appreciated. Conversely, we argue that the organizational separation of the paediatric and adult healthcare worlds has often resulted in late adoption of new approaches particularly in paediatric surgical practice. PMID- 26034348 TI - Contemporary concepts of the medical therapy of portal hypertension under liver cirrhosis. AB - Severe complications of liver cirrhosis are mostly related to portal hypertension. At the base of the pathogenesis of portal hypertension is the increase in hepatic vascular resistance to portal blood flow with subsequent development of hyperdynamic circulation, which, despite of the formation of collateral circulation, promotes progression of portal hypertension. An important role in its pathogenesis is played by the rearrangement of vascular bed and angiogenesis. As a result, strategic directions of the therapy of portal hypertension under liver cirrhosis include selectively decreasing hepatic vascular resistance with preserving or increasing portal blood flow, and correcting hyperdynamic circulation and pathological angiogenesis, while striving to reduce the hepatic venous pressure gradient to less than 12 mmHg or 20% of the baseline. Over the last years, substantial progress in understanding the pathophysiological mechanisms of hemodynamic disorders under liver cirrhosis has resulted in the development of new drugs for their correction. Although the majority of them have so far been investigated only in animal experiments, as well as at the molecular and cellular level, it might be expected that the introduction of the new methods in clinical practice will increase the efficacy of the conservative approach to the prophylaxis and treatment of portal hypertension complications. The purpose of the review is to describe the known methods of portal hypertension pharmacotherapy and discuss the drugs that may affect the basic pathogenetic mechanisms of its development. PMID- 26034349 TI - New targeted therapies in pancreatic cancer. AB - Patients with pancreatic cancer have a poor prognosis with a median survival of 4 6 mo and a 5-year survival of less than 5%. Despite therapy with gemcitabine, patient survival does not exceed 6 mo, likely due to natural resistance to gemcitabine. Therefore, it is hoped that more favorable results can be obtained by using guided immunotherapy against molecular targets. This review summarizes the new leading targeted therapies in pancreatic cancers, focusing on passive and specific immunotherapies. Passive immunotherapy may have a role for treatment in combination with radiochemotherapy, which otherwise destroys the immune system along with tumor cells. It includes mainly therapies targeting against kinases, including epidermal growth factor receptor, Ras/Raf/mitogen-activated protein kinase cascade, human epidermal growth factor receptor 2, insulin growth factor-1 receptor, phosphoinositide 3-kinase/Akt/mTOR and hepatocyte growth factor receptor. Therapies against DNA repair genes, histone deacetylases, microRNA, and pancreatic tumor tissue stromal elements (stromal extracellular matric and stromal pathways) are also discussed. Specific immunotherapies, such as vaccines (whole cell recombinant, peptide, and dendritic cell vaccines), adoptive cell therapy and immunotherapy targeting tumor stem cells, have the role of activating antitumor immune responses. In the future, treatments will likely include personalized medicine, tailored for numerous molecular therapeutic targets of multiple pathogenetic pathways. PMID- 26034351 TI - Thrombospondin peptide ABT-898 inhibits inflammation and angiogenesis in a colitis model. AB - AIM: To evaluate the efficacy of the improved thrombospondin mimetic peptide ABT 898 in a murine model of ulcerative colitis. METHODS: The dextran sodium sulfate (DSS) was used for the induction of colitis in both TSP-1 deficient (TSP-1(-/-)) and wild type (WT) mice during 7 d. While mice were receiving the DSS dissolved in the drinking water, the ABT-898 peptide was dissolved in sterile 5% glucose solution and delivered using mini pumps subcutaneously implanted. Plasma samples were analyzed for interleukin (IL)-6 by ELISA assay and colonic tissues were harvested, fixed and processed for histological evaluation. Immunohistochemistry using antibodies for the detection of CD31 and MECA in endothelial cells was performed. Inflammation was graded in colonic sections and the number of microvessels in each lesion was assessed. Activation of signal transducer and activator of transcription 3 (STAT3) in colonic samples was quantified by immunohistochemistry and Western blotting using antibodies against total STAT3 and phosphorylated STAT3 (pSTAT3) (Ser727). RESULTS: Treatment with ABT-898 considerably diminished the inflammatory response in WT and TSP-1(-/-) mice (P < 0.0001 in both groups vs control). Identification of blood vessels highlighted by CD31/MECA immunohistochemistry, showed significantly reduced vessel counts in colitic lesions of WT and TSP-1(-/-) mice treated with ABT898 (TSP-1(-/-) controls/TSP-1(-/-) treated, P = 0.0002; WT controls/WT treated, P = 0.0005). Consistently, IL-6 was significantly diminished in plasma samples of TSP-1(-/-) and WT treated with the peptide when compared to the control mice (P = 0.0002 and P = 0.0148, respectively). pSTAT3 positive cells were quantified in WT and TSP-1( /-) treated with ABT-898. A significant decrease in positive cells for pSTAT3 was observed in treated mice (TSP-1(-/-) controls/TSP-1(-/-) treated, P = 0.0089; WT/WT treated, P = 0.0110). These results were confirmed by Western blotting analyses showing lower levels of pSTAT3 in colitic lesions from mice treated with the peptide ABT-898. CONCLUSION: These findings indicate that the new peptide ABT 898 ameliorates inflammation and angiogenesis and might be a therapeutic alternative in IBD and inflammatory diseases. PMID- 26034352 TI - Insights into glycan biosynthesis in chemically-induced hepatocellular carcinoma in rats: A glycomic analysis. AB - AIM: To evaluate the qualitative and quantitative changes in N-linked glycosylation, which occurred in association with diethyl nitrosamine-induced hepatocellular carcinoma (HCC) in rodents. METHODS: Liver tissues of (1) normal (non-tumor-bearing) rats; and (2) tumor-bearing rats; were collected and were used for histological and GlycanMap analyses. Briefly, GlycanMap analysis is a high-throughput assay that provides a structural and quantitative readout of protein-associated glycans using a unique, automated 96-well assay technology coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and custom bioinformatics. Histopathological studies were carried out to ensure the development of HCC in the tested animals. RESULTS: The N glycomic analysis revealed 5 glycans; Glc1Man9GlcNAc2, Gal2Man3GlcNac4Fuc1Neu1, Man4GlcNac2, Gal2Man3GlcNac4Neu3OAc3, and Man3GlcNac5 Fuc1, which showed significant changes in rat HCC tissues when compared with normal liver tissues. Four glycans were increased (P < 0.05) and Glc1Man9GlcNAc2 was decreased (5.89 +/ 0.45 vs 3.54 +/- 0.21, P < 0.01) in HCC tissues compared to normal liver tissues. An increase (66.5 +/- 1.05 vs 62.7 +/- 1.1, P < 0.05) in high-mannose structures in HCC rats was observed compared to normal rats. Importantly, HCC rats showed an increase (P < 0.05) in both tumor-associated carbohydrates and in branched glycans. The changes in glycans correlated well with glycan flow changes reported in the glycan biosynthetic pathway, which indicates the importance of enzyme activities involved in glycan synthesis at different subcellular localizations. CONCLUSION: The reported HCC-associated changes in glycan flow and subcellular localization explain the increase in high mannose glycans and siayl Lewis glycans common in HCC liver tissues. PMID- 26034350 TI - Androgens and esophageal cancer: What do we know? AB - Significant disparities exist between genders for the development and progression of several gastro-intestinal (GI) diseases including cancer. Differences in incidence between men vs women for colon, gastric and hepatocellular cancers suggest a role for steroid sex hormones in regulation of GI carcinogenesis. Involvement of intrinsic gender-linked mechanisms is also possible for esophageal adenocarcinoma as its incidence is disproportionally high among men. However, the cause of the observed gender differences and the potential role of androgens in esophageal carcinogenesis remains unclear, even though the cancer-promoting role of androgen receptors (AR) shown in other cancers such as prostate and bladder suggests this aspect warrants exploration. Several studies have demonstrated expression of ARs in esophageal cancer. However, only one study has suggested a potential link between AR signaling and outcome - poorer prognosis. Two groups have analyzed data from cohorts with prostate cancer and one of these found a decreased incidence of esophageal squamous and adenocarcinoma after androgen deprivation therapy. However, very limited information is available about the effects of androgen and AR-initiated signaling on esophageal cancer cell growth in vitro and in vivo. Possible mechanisms for androgens/AR involvement in the regulation of esophageal cancer growth are considered, and the potential use of AR as a prognostic factor and clinical target is highlighted, although insufficient evidence is available to support clinical trials of novel therapies. As esophageal adenocarcinoma is a gender linked cancer with a large male predominance further studies are warranted to clarify the role of androgens and ARs in shaping intracellular signaling and genomic responses in esophageal cancer. PMID- 26034353 TI - SGK1 inhibits cellular apoptosis and promotes proliferation via the MEK/ERK/p53 pathway in colitis. AB - AIM: To investigate the role of serum-and-glucocorticoid-inducible-kinase-1 (SGK1) in colitis and its potential pathological mechanisms. METHODS: SGK1 expression in mucosal biopsies from patients with active Crohn's disease (CD) and normal controls was detected by immunohistochemistry. We established an acute colitis model in mice induced by 2,4,6-trinitrobenzene sulfonicacid, and demonstrated the presence of colitis using the disease activity index, the histologic activity index and hematoxylin and eosin staining. The cellular events and potential mechanisms were implemented with small interference RNA and an inhibitor of signaling molecule (i.e., U0126) in intestinal epithelial cells (IECs). The interaction between SGK1 and the signaling molecule was assessed by co-immunoprecipitation. RESULTS: SGK1 expression was significantly increased in the inflamed epithelia of patients with active CD and TNBS-induced colitis model (0.58 +/- 0.055 vs 0.85 +/- 0.06, P < 0.01). At the cellular level, silencing of SGK1 by small interference RNA (siSGK1) significantly inhibited the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1) and the downstream molecule extracellular signal regulated protein kinase (ERK) 1/2, which induced the upregulation of p53 and Bcl-2-associated X protein, mediating the subsequent cellular apoptosis and proliferation in IECs. Cells treated with MEK1 inhibitor (i.e., U0126) before siSGK1 transfection showed a reversal of the siSGK1-induced cellular apoptosis. CONCLUSION: Our data suggested that SGK1 may protect IECs in colitis from tumor necrosis factor-alpha-induced apoptosis partly by triggering MEK/ERK activation. PMID- 26034355 TI - Expression of COX-2 and HER-2 in colorectal cancer and their correlation. AB - AIM: To detect the expression of COX-2 and HER-2 in colorectal cancer and to analyze their correlation and clinical significance. METHODS: A total of 1026 colorectal cancer surgical specimens were collected from patients treated from December 2002 to December 2007 at the First Affiliated Hospital of Anhui Medical University. All specimens were made into 4-MUm slices. The expression of COX-2 and HER-2 were detected by immunohistochemistry using the streptavidin-biotin peroxidase method. The correlations between COX-2 and HER-2 expression and colorectal cancer clinical features were analyzed. RESULTS: The positive rates of COX-2 and HER-2 expression in colorectal cancer were 77.97% (800/1026) and 46.20% (474/1026), respectively. There was a significant correlation between COX-2 and HER-2 expression in colorectal cancer (P < 0.05). In patients with tumor size >= 5 cm, the positive rates of COX-2 and HER-2 expression were 81.48% (308/378) and 57.94% (219/378), respectively. In patients with serosal invasion, the positive COX-2 and HER-2 expression rates were 80.53% (612/760) and 49.21% (374/760), respectively. In patients with lymph node metastasis, the positive expression rates were 85.04% (506/595) and 54.62% (325/595), respectively, and the positive expression rates differed significantly between patients with lymph node metastasis and those without (P < 0.05). In patients with Duke's C and D colorectal cancer, the positive COX-2 and HER-2 expression rates were 82.80% (443/535) and 57.94% (310/535), respectively. In patients with poorly differentiated colorectal cancer, the positive expression rates were 74.49% (210/282) and 52.84% (149/282), respectively (P < 0.05). In patients with distant metastasis, the positive expression rates were 82.27% (116/141) and 53.90% (76/141), respectively (P < 0.05). These findings suggest that COX-2 and HER-2 have synergistic effects in colorectal cancer. COX-2 and HER-2 expression had no significant correlation with sex, age, or tumor location. CONCLUSION: COX-2 and HER-2 are important markers for invasion and metastasis of colorectal cancer, and they act together to regulate the invasion and metastasis of colorectal cancer. PMID- 26034354 TI - Gambogic acid induces apoptosis and inhibits colorectal tumor growth via mitochondrial pathways. AB - AIM: To investigate the effect of gambogic acid (GA) on apoptosis in the HT-29 human colon cancer cell line. METHODS: H-29 cells were used for in vitro experiments in this study. Relative cell viability was assessed using MTT assays. Cell apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling and Hoechst 33342 staining, and quantified by flow cytometry. Cellular ultrastructure was observed by transmission electron microscopy. Real time PCR and Western blot analyses were used to evaluate gene and protein expression levels. For in vivo experiments, BALB/c nude mice received subcutaneous injections of HT-29 cells in the right armpit. When well-established xenografts were palpable with a tumor size of 75 mm(3), mice were randomly assigned to a vehicle (negative) control, positive control or GA treatment group (n = 6 each). The animals in the treatment group received one of three dosages of GA (in saline; 5, 10 or 20 mg/kg) via the caudal vein twice weekly, whereas animals in the negative and positive control groups were given equal volumes of 0.9% saline or 10 mg/kg docetaxel, respectively, via the caudal vein once weekly. RESULTS: The cell viability assay showed that GA inhibited proliferation of HT-29 cells in a dose- and time-dependent manner after treatment with GA (0.00, 0.31, 0.62, 1.25, 2.50, 5.00 or 10.00 MUmol/L) for 24, 48 or 72 h. After 48 h, the percentage of apoptotic cells in cells treated with 0.00, 1.25, 2.50 and 5.00 MUmol/L GA was 1.4% +/- 0.3%, 9.8% +/- 1.2%, 25.7% +/- 3.3% and 49.3% +/- 5.8%, respectively. Ultrastructural analysis of HT-29 cells treated for 48 h with 2.5 MUmol/L GA revealed apoptotic bodies and condensed and fragmented nuclei. Levels of caspase-8, -9 and -3 mRNAs were significantly increased after treatment with GA (1.25, 2.50 or 5.00 MUmol/L) for 48 h (P < 0.05 for all). Protein levels of apoptosis-related factors Fas, FasL, FADD, cytochrome c, and Apaf-1 were increased in GA-treated cells, whereas levels of pro-caspase-8, -9 and -3 were significantly decreased (P < 0.05 for all). Furthermore, GA significantly and dose-dependently inhibited the growth of HT-29 tumors in a mouse xenograft model (P < 0.05). CONCLUSION: GA inhibits HT-29 proliferation via induction of apoptosis. The anti-cancer effects are likely mediated by death receptor (extrinsic) and mitochondrial (intrinsic) pathways. PMID- 26034356 TI - CD97 promotes gastric cancer cell proliferation and invasion through exosome mediated MAPK signaling pathway. AB - AIM: To investigate the mechanism underlying the promoting role of CD97 in gastric cancer cell proliferation and invasion. METHODS: Two types of exosomes released by gastric cancer cells with high (SGC/wt) or low (SGC/kd) CD97 expression were isolated by ultracentrifugation and identified by electron microscopy and western blot analysis. The influences of the two exosomes on gastric cancer cell proliferation and invasion were investigated by proliferation and Matrigel invasion assays. Exosomal miRNAs were subsequently isolated from the two samples and their miRNA profiles were compared via microarray assay analysis. Reverse transcription-quantitative real-time polymerase chain reaction was used to validate the microarray assay. Target genes of the differently expressed microRNAs were predicted based on five independent algorithms and were then subjected to gene oncology enrichment and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. After identifying the pathway that was the most likely altered, tumor cells were treated with the two exosomes at different concentrations, and the pathway activation was identified through western blot analysis. RESULTS: Exosomes isolated from SGC/wt cells significantly promoted tumor cell proliferation in a dose-dependent manner in vitro. SGC/wt exosomes also significantly elevated the invasiveness of both SGC/wt (129.67 +/- 8.327 vs 76.00 +/- 5.292, P < 0.001) and SGC/kd (114.52 +/- 9.814 vs 45.73 +/- 4.835, P < 0.001) cells as compared to the exosomes released by SGC/kd cells. Microarray assay of the two exosomes revealed that 62 miRNAs were differently regulated with a signal intensity of > 500 and a false discovery rate < 0.05. The following KEGG analysis defined the MAPK signaling pathway as the most likely candidate pathway that regulated tumor cell proliferation and invasion. Through western blot analysis, significant up-regulations of phosphorylated MAPKs, including extracellular signal-regulated kinase, Jun NH2-terminal kinase, and p38 mitogen activated protein kinase, were detected in a dose-dependent manner in the SGC/wt exosomes treated groups, confirming activation of the MAPK signaling pathway stimulated by SGC/wt exosomes. CONCLUSION: CD97 promotes gastric cancer cell proliferation and invasion in vitro through exosome-mediated MAPK signaling pathway, and exosomal miRNAs are probably involved in activation of the CD97 associated pathway. PMID- 26034357 TI - Cholangiographic characteristics of common bile duct dilatation in children. AB - AIM: To investigate whether children with congenital common bile duct dilatation (CBDD) differ from children with obstructive CBDD in cholangiographic characteristics. METHODS: In this retrospective cohort study, the baseline data and the results of imaging analyses were reviewed among children who had endoscopic retrograde cholangiopancreatography (ERCP) due to CBDD. ERCP was performed on all pediatric patients by experienced pediatric endoscopists. The maximal transverse diameter of the common bile duct (CBD) was measured on ERCP. To assess whether age-adjusted CBDD could be used for differential diagnosis, a CBDD severity index (SI) was calculated by dividing the measured CBD diameter by the age-corrected maximal diameter of a normal CBD. RESULTS: A retrospective medical chart review revealed that 85 consecutive children under 16 years of age with hepatobiliary disease and CBDD were referred to Seoul Asan Medical Center. Fifty-five (64.7%) children had congenital CBDD and 30 (35.3%) had obstructive CBDD. The two groups did not differ significantly in terms of clinical characteristics except for sex. The congenital and obstructive CBDD groups did not differ significantly in terms of mean CBD diameter (19.3 +/- 9.6 mm vs 12.2 +/- 4.1 mm, P > 0.05). However, congenital CBDD cases had a significantly higher mean SI than obstructive CBDD cases (3.62 +/- 1.64 vs 1.98 +/- 0.71, P = 0.01). In multivariate analysis, an SI value >= 2.32 and comorbidity with anomalous union of pancreaticobiliary duct (APBDU) in ERCP independently predicted congenital CBDD. CONCLUSION: Measuring the CBD may aid the differential diagnosis of both CBDD and APBDU in children. PMID- 26034358 TI - Utility of the low-accelerating-dose regimen in 182 liver recipients with recurrent hepatitis C virus. AB - AIM: To describe our experience using a low-accelerating-dose regimen (LADR) with pegylated interferon alpha-2a and ribavirin in treatment of hepatitis C virus (HCV) recurrence. METHODS: From 2003, a protocolized LADR strategy was employed to treat liver transplant (LT) recipients with recurrent HCV at our institution. Medical records of 182 adult patients with recurrent HCV treated with LADR between 1/2003 and 1/2011 were reviewed. Histopathology from all post-LT liver biopsies were reviewed in a blinded fashion. Paired recipient and donor IL28B status were assessed. A novel technique was employed to ascertain recipient and donor IL28B (rs12979860) Gt data using DNA extracted from archival FFPE tissue from explanted native livers and donor gallbladders respectively. The primary endpoint was SVR; secondary endpoints examined include (1) patient and graft survival; (2) effect of anti-viral therapy on liver histology (fibrosis and inflammation); (3) incidence of on-treatment development of ACR, CDR, or PCH; (4) association of recipient and donor IL28B genotype with SVR; and (5) incidence of anti-viral therapy-associated adverse events (anemia, leukopenia, thrombocytopenia, depression) and hepatic decompensation. RESULTS: The overall SVR rate was 38% (29% Gt1, 67% Gt2, 86% Gt3 and 58% Gt4). HCV Gt (P < 0.0001), donor age (P = 0.003), cytomegalovirus mismatch (P = 0.001), baseline serum bilirubin (P = 0.002), and baseline viral load (P = 0.04) were independent predictors for SVR. SVR rates were significantly higher in the recipient-CC/donor non CC pairs (P = 0.007). Neither baseline fibrosis nor change in fibrosis stage after anti-viral therapy were associated with SVR. Fibrosis progressed in 72% of patients despite SVR. Median graft survival was 91 mo. Five-year patient survival was superior in patients who achieved SVR (97% vs 82%, P = 0.001). Pre-treatment ALP >= 150 U/L (P = 0.01), total bilirubin >= 1.5 mg/dL (P = 0.001) and creatinine >= 2 mg/dL (P = 0.001) were independently associated with patient survival. Only 13% of patients achieving SVR died during the follow-up period. Treatment discontinuation and treatment-related mortality occurred in 35% and 2.2% of patients, respectively. EPO, G-CSF and blood transfusion were needed in 89%, 40% and 23% of patients, respectively. Overall hospitalization rate for treatment-related serious adverse events was 21%. Forty-six (25%) of the patients were deceased; among those who died, 25 (54%) were due to liver-related complications, and 4 deaths (9%) occurred while receiving therapy (2 patients experienced hepatic decompensation and 2 sepsis). CONCLUSION: LADR strategy remains relevant in managing post-LT recurrent HCV where access to DAAs is limited. SVR is associated with improved survival, but fibrosis progression still occurs. PMID- 26034359 TI - Laboratory test variables useful for distinguishing upper from lower gastrointestinal bleeding. AB - AIM: To distinguish upper from lower gastrointestinal (GI) bleeding. METHODS: Patient records between April 2011 and March 2014 were analyzed retrospectively (3296 upper endoscopy, and 1520 colonoscopy). Seventy-six patients had upper GI bleeding (Upper group) and 65 had lower GI bleeding (Lower group). Variables were compared between the groups using one-way analysis of variance. Logistic regression was performed to identify variables significantly associated with the diagnosis of upper vs lower GI bleeding. Receiver-operator characteristic (ROC) analysis was performed to determine the threshold value that could distinguish upper from lower GI bleeding. RESULTS: Hemoglobin (P = 0.023), total protein (P = 0.0002), and lactate dehydrogenase (P = 0.009) were significantly lower in the Upper group than in the Lower group. Blood urea nitrogen (BUN) was higher in the Upper group than in the Lower group (P = 0.0065). Logistic regression analysis revealed that BUN was most strongly associated with the diagnosis of upper vs lower GI bleeding. ROC analysis revealed a threshold BUN value of 21.0 mg/dL, with a specificity of 93.0%. CONCLUSION: The threshold BUN value for distinguishing upper from lower GI bleeding was 21.0 mg/dL. PMID- 26034360 TI - Differential diagnosis of benign and malignant branch duct intraductal papillary mucinous neoplasm using contrast-enhanced endoscopic ultrasonography. AB - AIM: To elucidate the role of contrast-enhanced endoscopic ultrasonography (CE EUS) in the diagnosis of branch duct intraductal papillary mucinous neoplasm (BD IPMN). METHODS: A total of 50 patients diagnosed with BD-IPMN by computed tomography (CT) and endoscopic ultrasonography (EUS) at our institute were included in this study. CE-EUS was performed when mural lesions were detected by EUS. The diagnostic accuracy for identifying mural nodules (MNs) was evaluated by CT, EUS, and EUS combined with CE-EUS. In the patients who underwent resection, the accuracy of measuring MN height with each imaging modality was compared. The cut-off values to diagnose malignant BD-IPMNs based on MN height for each imaging modality were determined using receiver operating characteristic curve analysis. RESULTS: Fifteen patients were diagnosed with BD-IPMN with MNs and underwent resection. The remaining 35 patients were diagnosed with BD-IPMN without MNs and underwent follow-up monitoring. The pathological findings revealed 14 cases with MNs and one case without. The accuracy for diagnosing MNs was 92% using CT and 72% using EUS; the diagnostic accuracy increased to 98% when EUS and CE-EUS were combined. The accuracy for measuring MN height significantly improved when using CE-EUS compared with using CT or EUS (median measurement error value, CT: 3.3 mm vs CE-EUS: 0.6 mm, P < 0.05; EUS: 2.1 mm vs CE-EUS: 0.6 mm, P < 0.01). A cut-off value of 8.8 mm for MN height as measured by CE-EUS improved the accuracy of diagnosing malignant BD-IPMN to 93%. CONCLUSION: Using CE-EUS to measure MN height provides a highly accurate method for differentiating benign from malignant BD-IPMN. PMID- 26034361 TI - Efficacy of cap-assisted colonoscopy according to lesion location and endoscopist training level. AB - AIM: To evaluate the efficacy of cap-assisted colonoscopy (CAC) for detection of colorectal polyps and adenomas according to the lesion location and endoscopist training level. METHODS: Patients 20 years or older, who underwent their first screening colonoscopy in a single tertiary center from May 2011 to December 2012 were enrolled in this study. All patients underwent either CAC or standard colonoscopy (SC), and all of the procedures were performed by 11 endoscopists (8 trainees and 3 experts). All procedures were performed with high-definition colonoscopes and narrow band imaging. The eight trainees had experiences of performing 150 to 500 colonoscopies, and the three experts had experiences of performing more than 3000 colonoscopies. A 4-mm-long transparent cap was attached to the end of a colonoscope in the CAC group. We retrospectively evaluated the number of polyps and adenomas, polyp detection rate (PDR), and the number of adenomas and adenoma detection rate (ADR) according to the lesion location and endoscopist training level between CAC and SC. We also evaluated the number of polyps and adenomas according to their size between CAC and SC. RESULTS: Overall, PDR and ADR using CAC were significantly higher than those using SC for both whole colon (48.5% vs 40.7%, P = 0.012; 35.7% vs 28.3%, P = 0.012) and right-side colon (35.3% vs 26.6%, P = 0.002; 27.0% vs 16.9%, P < 0.001). The number of polyps and adenomas per patient using CAC was significantly higher than that using SC for both the whole colon (1.07 +/- 1.59 vs 0.82 +/- 1.31, P = 0.008; 0.72 +/- 1.32 vs 0.50 +/- 1.01, P = 0.003) and right-side colon (0.66 +/- 1.18 vs 0.41 +/- 0.83, P < 0.001; 0.46 +/- 0.97 vs 0.25 +/- 0.67, P < 0.001). In the trainee group, the PDR and ADR using CAC were significantly higher than those using SC for both the whole colon (46.7% vs 39.7%, P = 0.040; 33.9% vs 26.0%, P =0.012) and right-side colon (34.2% vs 26.5%, P = 0.015; 25.3% vs 15.9%, P = 0.001). In the expert group, the PDR and ADR using CAC were significantly higher than those using SC only for the right-side colon (42.1% vs 27.0%, P =0.035; 36.8% vs 21.0%, P = 0.020). CONCLUSION: CAC is more effective than SC for detection of colorectal polyps and adenomas, especially when performed by trainees and when the lesions are located in the right-side colon. PMID- 26034362 TI - Relationship between expression of NADPH oxidase 2 and invasion and prognosis of human gastric cancer. AB - AIM: To assess the expression and prognostic value of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) in gastric cancer, and its correlation with vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR). METHODS: Tumor and adjacent tissues were obtained from 123 patients who underwent radical surgery for gastric cancer at Renmin Hospital of Wuhan University from 2008-2009. The expression of NOX2, VEGF, EGFR and CD68 in tumor tissues was detected by immunohistochemistry. The expression of NOX2 in gastric cancer and adjacent tissues was detected by Western blot analysis. Spearman(')s correlation was performed to elucidate the relationship of NOX2 with VEGF and EGFR. The Kaplan-Meier method was used to calculate survival time, and the log-rank test was used to evaluate differences in survival. Cox's proportional hazards regression model was applied in a stepwise manner to analyze the independent prognostic factors. RESULTS: NOX2 exhibited positive expression in 47.2% (58/123) of the gastric cancer tissues. Western blot analysis revealed that NOX2 was up-regulated in tumor tissues compared to the adjacent tissue [39.0% (48/123)]. Immunohistochemistry staining revealed that CD68, which is a specific marker of macrophages, and NOX expression presented a similar localization and staining intensity. The expression of NOX2 was positively correlated with that of VEGF and EGFR. Comparison of the 5-year survival rates of the NOX2 positive and NOX2 negative groups showed that the NOX2 positive group presented a poor prognosis. CONCLUSION: NOX2 positively correlates with the levels of VEGF and EGFR. NOX2 may be used as a new biomarker and a potential therapeutic target for gastric cancer. PMID- 26034363 TI - Significance of the preoperative neutrophil-to-lymphocyte ratio in the prognosis of patients with gastric cancer. AB - AIM: To investigate the significance of the preoperative neutrophil-to-lymphocyte ratio (NLR) in the prognosis of patients with gastric cancer (GC). METHODS: The clinical data of 291 GC patients were analysed retrospectively; these patients were divided into two groups according to their preoperative NLR: a high-NLR group (NLR >= 3.5, 131 cases) and a low-NLR group (NLR < 3.5, 160 cases). The clinicopathological characteristics and five-year survival rates of the two groups were compared. The NLR and other clinicopathological factors were subjected to univariate and multivariate survival analysis to evaluate the effects of the NLR on the prognosis of GC patients. RESULTS: The lowest preoperative NLR among the 291 patients was 0.56, whereas the highest preoperative NLR was 74.5. The mean preoperative NLR was 5.99 +/- 8.98. Age, tumour size, T staging, tumour-node-metastasis (TNM) staging and platelet count were significantly different between the high- and low-NLR groups (P < 0.05). The five-year survival rate of the high-NLR group was 17.0%, which was significantly lower than that of the low-NLR group (43.6%; 17.0% vs 43.6%, P < 0.05). The univariate analysis results showed that the five-year survival rate was related to age, tumour size, T staging, N staging, TNM staging, carcinoembryonic antigen value and NLR (P < 0.05). Multivariate analysis results showed that the NLR was an independent risk factor that likely affected the five-year survival rate of GC patients (P = 0.003, HR = 0.626, 95%CI: 0.460-0.852). CONCLUSION: The preoperative NLR could be used as a prognostic factor for GC patients; in particular, a high NLR corresponded to poor prognosis of GC patients. PMID- 26034364 TI - Cholecystectomy is independently associated with nonalcoholic fatty liver disease in an Asian population. AB - AIM: To investigate the relationship between gallstone disease and nonalcoholic fatty liver disease (NAFLD) in a large Asian population. METHODS: A cross sectional study including 17612 subjects recruited from general health check-ups at the Seoul National University Hospital, Healthcare System Gangnam Center between January 2010 and December 2010 was conducted. NAFLD and gallstone disease were diagnosed based on typical ultrasonographic findings. Subjects who were positive for hepatitis B or C, or who had a history of heavy alcohol consumption (> 30 g/d for men and > 20 g/d for women) or another type of hepatitis were excluded. Gallstone disease was defined as either the presence of gallstones or previous cholecystectomy, and these two entities (gallstones and cholecystectomy) were analyzed separately. Clinical parameters including body mass index, waist circumference, hypertension, diabetes, smoking status, and regular physical activity were reviewed. Laboratory parameters, including serum levels of gamma glutamyl transpeptidase, alanine aminotransferase, aspartate aminotransferase, fasting glucose, fasting insulin, total cholesterol, triglycerides, and high density lipoprotein, were also reviewed. RESULTS: The mean age of the subjects was 48.5 +/- 11.3 years, and 49.3% were male. Approximately 30.3% and 6.1% of the subjects had NAFLD and gallstone disease, respectively. The prevalence of gallstone disease (8.3% vs 5.1%, P < 0.001), including both the presence of gallstones (5.5% vs 3.4%, P < 0.001) and a history of cholecystectomy (2.8% vs 1.7%, P < 0.001), was significantly increased in the NAFLD group. In the same manner, the prevalence of NAFLD increased with the presence of gallstone disease (41.3% vs 29.6%, P < 0.001). Multivariate regression analysis showed that cholecystectomy was associated with NAFLD (OR = 1.35, 95%CI: 1.03-1.77, P = 0.028). However, gallstones were not associated with NAFLD (OR = 1.15, 95%CI: 0.95-1.39, P = 0.153). The independent association between cholecystectomy and NAFLD was still significant after additional adjustment for insulin resistance (OR = 1.45, 95%CI: 1.01-2.08, P = 0.045). CONCLUSION: This study shows that cholecystectomy, but not gallstones, is independently associated with NAFLD after adjustment for metabolic risk factors. These data suggest that cholecystectomy may be an independent risk factor for NAFLD. PMID- 26034365 TI - Outcomes of liver transplantation for end-stage biliary disease: A comparative study with end-stage liver disease. AB - AIM: To evaluate the outcomes of patients with end-stage biliary disease (ESBD) who underwent liver transplantation, to define the concept of ESBD, the criteria for patient selection and the optimal operation for decision-making. METHODS: Between June 2002 and June 2014, 43 patients with ESBD from two Chinese organ transplantation centres were evaluated for liver transplantation. The causes of liver disease were primary biliary cirrhosis (n = 8), cholelithiasis (n = 8), congenital biliary atresia (n = 2), graft-related cholangiopathy (n = 18), Caroli's disease (n = 2), iatrogenic bile duct injury (n = 2), primary sclerosing cholangitis (n = 1), intrahepatic bile duct paucity (n = 1) and Alagille's syndrome (n = 1). The patients with ESBD were compared with an end-stage liver disease (ESLD) case control group during the same period, and the potential prognostic values of multiple demographic and clinical variables were assessed. The examined variables included recipient age, sex, pre-transplant clinical status, pre-transplant laboratory values, operation condition and postoperative complications, as well as patient and allograft survival rates. Survival analysis was performed using Kaplan-Meier curves, and the rates were compared using log rank tests. All variables identified by univariate analysis with P values < 0.100 were subjected to multivariate analysis. A Cox proportional hazard regression model was used to determine the effect of the study variables on outcomes in the study group. RESULTS: Patients in the ESBD group had lower model for end-stage liver disease (MELD)/paediatric end-stage liver disease (PELD) scores and a higher frequency of previous abdominal surgery compared to patients in the ESLD group (19.2 +/- 6.6 vs 22.0 +/- 6.5, P = 0.023 and 1.8 +/- 1.3 vs 0.1 +/- 0.2, P = 0.000). Moreover, the operation time and the time spent in intensive care were significantly higher in the ESBD group than in the ESLD group (527.4 +/- 98.8 vs 443.0 +/- 101.0, P = 0.000, and 12.74 +/- 6.6 vs 10.0 +/- 7.5, P = 0.000). The patient survival rate in the ESBD group was not significantly different from that of the ESBD group at 1, 3 and 5 years (ESBD: 90.7%, 88.4%, 79.4% vs ESLD: 84.9%, 80.92%, 79.0%, chi(2) = 0.194, P = 0.660). The graft-survival rates were also similar between the two groups at 1, 3 and 5 years (ESBD: 90.7%, 85.2%, 72.7% vs ESLD: 84.9%, 81.0%, 77.5%, chi(2) = 0.003, P = 0.958). Univariate analysis identified MELD/PELD score (HR = 1.213, 95%CI: 1.081-1.362, P = 0.001) and bleeding volume (HR = 0.103, 95%CI: 0.020-0.538, P = 0.007) as significant factors affecting the outcomes of patients in the ESBD group. However, multivariate analysis revealed that MELD/PELD score (HR = 1.132, 95%CI: 1.005 1.275, P = 0.041) was the only negative factor that was associated with short survival time. CONCLUSION: MELD/PELD criteria do not adequately measure the clinical characteristics and staging of ESBD. The allocation system based on MELD/PELD criteria should be re-evaluated for patients with ESBD. PMID- 26034366 TI - Sequential blood purification therapy for critical patients with hyperlipidemic severe acute pancreatitis. AB - AIM: To evaluate the efficacy of sequential blood purification therapy in the treatment of critical patients with hyperlipidemic severe acute pancreatitis. METHODS: Thirty-one intensive care unit (ICU) patients with hyperlipidemic severe acute pancreatitis treated at the Second Affiliated Hospital of Harbin Medical University were divided into either a study group (n = 15; July 1, 2012 to June 30, 2014) or a control group (n = 16; July 1, 2010 to June 30, 2012) based on the implementation of sequential blood purification therapy. The control group received continuous venous-venous hemofiltration (CVVH) on the basis of conventional treatments, and the therapeutic dose of CVVH was 30 mL/kg per hour. The study group received sequential plasma exchange and CVVH on the basis of conventional treatments. The anticoagulation regimen of CVVH is the regional citrate anticoagulation. Mortality rate on day 28, rates of systemic and local complications, duration of ICU, and time to target serum lipid level, as well as physiologic and laboratory indices were compared between the two groups. RESULTS: The mortality rate on day 28 was significantly lower in the study group than in the control group (13.33% vs 37.50%; P < 0.05). The duration of ICU stay was significantly shorter in the study group than in the control group (7.4 +/- 1.35 d vs 9.19 +/- 2.99 d, P < 0.05). The time to target serum lipid level was significantly shorter in the study group than in the control group (3.47 +/- 0.52 d vs 7.90 +/- 1.14 d, P < 0.01). There were no significant differences in the rates of systemic complications and local complications between the two groups (60% vs 50% and 80% vs 81%, respectively). In the comparisons of physiologic and laboratory indices, serum albumin and C-reactive protein were significantly better in the study group than in the control group after treatment (37.8 +/- 4.6 g/L vs 38.9 +/- 5.7 g/L, and 20.5 +/- 6.4 mg/L vs 28.5 +/- 7.1 mg/L, respectively, both P < 0.05). With the exception of plateletcrit, no other indices showed significant differences between the two groups. CONCLUSION: Sequential blood purification therapy is effective in the treatment of ICU patients with hyperlipidemic severe acute pancreatitis and can improve patient prognosis. PMID- 26034367 TI - Modified sequential therapy vs quadruple therapy as initial therapy in patients with Helicobacter infection. AB - AIM: To evaluate the efficacy and safety of modified sequential therapy and to compare modified sequential therapy with standard quadruple therapy for Helicobacter pylori (H. pylori) eradication. METHODS: In total, 200 consecutive patients who were diagnosed with H. pylori-infected chronic gastritis by electronic endoscopy and rapid urease testing from December 2012 to October 2013 were enrolled in this study. The patients had not previously received H. pylori eradication treatment, and were randomized into two groups. The patients in Group A (n = 101) were treated with ilaprazole + bismuth potassium citrate + amoxicillin and clavulanate potassium + levofloxacin, and the patients in Group B (n = 99) were administered a modified sequential therapy composed of ilaprazole at 5 mg bid and amoxicillin and clavulanate potassium at 914 mg for the first five days followed by ilaprazole at 5 mg bid, furazolidone at 100 mg bid and levofloxacin at 500 mg qid for the next five days. Four to six weeks after the end of treatment, a 14C-urea breath test was performed for all the subjects to confirm the eradication of H. pylori. The intention-to-treat and per-protocol eradication rates were determined. RESULTS: A total of 190 of the 200 patients completed the study. All 200 patients were included in the intention-to-treat analysis, whereas 190 patients were included in the per-protocol analysis. In the intention-to-treat analysis, the rates of H. pylori eradication in Groups A and B were 85.15% (86/101) and 81.82% (81/99), respectively. In the per-protocol analysis, the H. pylori eradication rates in Groups A and B were 88.66% (86/97) and 87.09% (81/93), respectively. No significant difference was observed (chi(2) = 0.109, P = 0.741) in the eradication rate between Groups A and B. The rates of adverse effects observed in the groups were similar at 6.19% (6/97) for Group A and 7.53% (7/93) for Group B (P > 0.05). No mortality or major morbidities were observed in any of the patients. Symptomatic improvements in the presentation of stomachache, acid regurgitation, and burning sensation were not significantly different between the two groups. CONCLUSION: Ilaprazole-based 10-d standard quadruple therapy does not offer an incremental benefit over modified sequential therapy for the treatment of H. pylori infection, as both treatment regimens appear to be effective, safe, and well-tolerated as initial treatment options. PMID- 26034368 TI - Integrative analysis of aberrant Wnt signaling in hepatitis B virus-related hepatocellular carcinoma. AB - AIM: To comprehensively understand the underlying molecular events accounting for aberrant Wnt signaling activation in hepatocellular carcinoma (HCC). METHODS: This study was retrospective. The HCC tissue specimens used in this research were obtained from patients who underwent liver surgery. The Catalogue of Somatic Mutations in Cancer (COSMIC) database was searched for the mutation statuses of CTNNB1, TP53, and protein degradation regulator genes of CTNNB1. Dual-luciferase reporter assay was performed with TOP/FOP reporters to detect whether TP53 gain of-function (GOF) mutations could enhance the transcriptional activity of Wnt signaling. Methylation sensitive restriction enzyme-quantitative PCR was used to explore the methylation status of CpG islands located in the promoters of APC, SFRP1, and SFRP5 in HCCs with different risk factors. Finally, nested-reverse transcription PCR was performed to examine the integration of HBx in front of LINE1 element and the existence of HBx-LINE1 chimeric transcript in Hepatitis B virus-related HCC. All results in this article were analyzed with the software SPSS version 19.0 for Windows, and different groups were compared by chi(2) test as appropriate. RESULTS: Based on the data from COSMIC database, compared with other solid tumors, mutation frequency of CTNNB1 was significantly higher in HCC (P < 0.01). The rate of CTNNB1 mutation was significantly less frequent in Hepatitis B virus-related HCC than in other etiologies (P < 0.01). Dual luciferase reporter system and TOP/FOP reporter assays confirmed that TP53 GOF mutants were able to enhance the transcriptional ability of Wnt signaling. An exclusive relationship between the status of TP53 and CTNNB1 mutations was observed. However, according to the COSMIC database, TP53 GOF mutation is rare in HCC, which indicates that TP53 GOF mutation is not a reason for the aberrant activation of Wnt signaling in HCC. APC and AXIN1 were mutated in HCC. By using methylation sensitive restriction enzyme-quantitative PCR, hypermethylation of APC was detected in HCC with different risk factors, whereas SFRP1 and SFRP5 were not hypermethylated in any of the HCC etiologies, which indicates that the mutation of APC and AXIN1, together with the methylation of APC could take part in the overactivation of Wnt signaling. Nested-reverse transcription PCR failed to detect the integration of HBx before the LINE1 element, or the existence of an HBx-LINE1 chimeric transcript, suggesting that integration could not play a role in the aberrant activation of Wnt signaling in HCC. CONCLUSION: In HCC, genetic/epigenetic aberration of CTNNB1 and its protein degradation regulators are the major cause of Wnt signaling overactivation. PMID- 26034370 TI - Proton pump inhibitors therapy vs H2 receptor antagonists therapy for upper gastrointestinal bleeding after endoscopy: A meta-analysis. AB - AIM: To compare the therapeutic effects of proton pump inhibitors vs H2 receptor antagonists for upper gastrointestinal bleeding in patients after successful endoscopy. METHODS: We searched the Cochrane library, MEDLINE, EMBASE and PubMed for randomized controlled trials until July 2014 for this study. The risk of bias was evaluated by the Cochrane Collaboration's tool and all of the studies had acceptable quality. The main outcomes included mortality, re-bleeding, received surgery rate, blood transfusion units and hospital stay time. These outcomes were estimated using odds ratios (OR) and mean difference with 95% confidence interval (CI). RevMan 5.3.3 software and Stata 12.0 software were used for data analyses. RESULTS: Ten randomized controlled trials involving 1283 patients were included in this review; 678 subjects were in the proton pump inhibitors (PPI) group and the remaining 605 subjects were in the H2 receptor antagonists (H2RA) group. The meta-analysis results revealed that after successful endoscopic therapy, compared with H2RA, PPI therapy had statistically significantly decreased the recurrent bleeding rate (OR = 0.36; 95%CI: 0.25-0.51) and receiving surgery rate (OR = 0.29; 95%CI: 0.09-0.96). There were no statistically significant differences in mortality (OR = 0.46; 95%CI: 0.17-1.23). However, significant heterogeneity was present in both the numbers of patients requiring blood transfusion after treatment [weighted mean difference (WMD), -0.70 unit; 95%CI: -1.64 - 0.25] and the time that patients remained hospitalized [WMD, -0.77 d; 95%CI: -1.87 - 0.34]. The Begg's test (P = 0.283) and Egger's test (P = 0.339) demonstrated that there was no publication bias in our meta-analysis. CONCLUSION: In patients with upper gastrointestinal bleeding after successful endoscopic therapy, compared with H2RA, PPI may be a more effective therapy. PMID- 26034369 TI - Risk factors for new onset diabetes mellitus after liver transplantation: A meta analysis. AB - AIM: To determine the risk factors for new-onset diabetes mellitus (NODM) after liver transplantation by conducting a systematic review and meta-analysis. METHODS: We electronically searched the databases of MEDLINE, EMBASE and the Cochrane Library from January 1980 to December 2013 to identify relevant studies reporting risk factors for NODM after liver transplantation. Two authors independently assessed the trials for inclusion and extracted the data. Discrepancies were resolved in consultation with a third reviewer. All statistical analyses were performed with the RevMan5.0 software (The Cochrane Collaboration, Oxford, United Kingdom). Pooled odds ratios (OR) or weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated using either a fixed effects or a random effects model, based on the presence (I (2) < 50%) or absence (I (2) > 50%) of significant heterogeneity. RESULTS: Twenty studies with 4580 patients were included in the meta-analysis, all of which were retrospective. The meta-analysis identified the following significant risk factors: hepatitis C virus (HCV) infection (OR = 2.68; 95%CI: 1.92-3.72); a family history of diabetes (OR = 1.69, 95%CI: 1.09-2.63, P < 0.00001); male gender (OR = 1.53; 95%CI: 1.24-1.90; P < 0.0001); impaired fasting glucose (IFG; OR = 3.27; 95%CI: 1.84-5.81; P < 0.0001); a family history of diabetes (OR = 1.69; 95%CI: 1.09-2.63; P = 0.02); use of tacrolimus (OR = 1.34; 95%CI: 1.03 1.76; P = 0.03) and body mass index (BMI)(WMD = 1.19, 95%CI: 0.69-1.68, P < 0.00001). Other factors, such as hepatitis B virus infection and alcoholism, were not found to be associated with the incidence of NODM. CONCLUSION: The study showed that HCV infection, IFG, a family history of diabetes, male gender, tacrolimus and BMI are risk factors for NODM after liver transplantation. PMID- 26034371 TI - Meta-analysis of the effectiveness and safety of vedolizumab for ulcerative colitis. AB - AIM: To conduct a meta-analysis examining the effectiveness and safety of vedolizumab for the treatment of ulcerative colitis (UC). METHODS: A search was conducted of MEDLINE, Cochrane, EMBASE, and Google Scholar on July 31, 2013. Inclusion criteria were: (1) Randomized controlled trial (RCT); (2) Patients treated for UC; and (3) Intervention was vedolizumab. The following information/data were extracted from studies that met the inclusion criteria: the name of the first author, year of publication, study design, patient demographic information, response rate, remission rate, and adverse events. The primary outcome was clinical response rate, and the secondary outcomes were clinical remission rate and serious adverse events. Odds ratio (OR) with 95%CI were calculated for each outcome. RESULTS: Of 224 studies initially identified, three RCTs examining the use of vedolizumab meeting the inclusion criteria were included in the meta-analysis. All studies examined the use of vedolizumab at dosages ranging from 0.5 to 10 mg/kg body weight (one study used a standard dose of 300 mg). The follow-up periods were approximately 6 wk. The total number of patients in the intervention groups was 901, and in the control groups was 221. The mean age of the patients was approximately 41 years, and approximately half were males. The follow-up periods ranged from 43 d to 6 wk. The clinical response and remission rates were significantly higher for patients who received vedolizumab as compared to control patients (clinical response: OR = 2.69; 95%CI: 1.94-3.74, P < 0.001 and remission rate: OR = 2.72; 95%CI: 1.76-4.19, P < 0.001). Serious adverse events were not higher in patients that received vedolizumab. CONCLUSION: This analysis supports the use of vedolizumab for the treatment of UC. PMID- 26034373 TI - Differential diagnosis of pancreatic cancer by single-shot echo-planar imaging diffusion-weighted imaging. AB - AIM: To investigate the diagnostic ability of single-shot echo-planar imaging (EPI) diffusion-weighted imaging (DWI) to differentiate between malignant and benign pancreatic lesions. METHODS: A computerized search was performed on PubMed, MEDLINE and EMBASE up to August 2014. Nine studies (10 sets of data) with a total of 304 malignant pancreatic lesions and 188 benign pancreatic lesions were included. The characteristics of each study included the study name, year of publication, magnetic resonance modalities used, patient population, strength of field, pulse time, repetition time, echo time (TE), maximum b factor, mean age, mean body weight, fat suppression, number of benign and malignant lesions, and true positive, true negative, false positive and false negative results. All analyses were performed using Meta-DiSc and Stata 11.0. RESULTS: The pooled sensitivity and specificity of single-shot EPI DWI were 0.83 (95%CI: 0.79-0.87) and 0.77 (95%CI: 0.70-0.83), respectively. The positive likelihood ratio and negative likelihood ratio were 5.09 (95%CI: 2.19-11.84) and 0.23 (95%CI: 0.15 0.36), respectively. The P value for the chi(2) heterogeneity for all pooled estimates was < 0.05. From the fitted summary receiver operating characteristic curve, the area under the curve and Q* index were 0.89 and 0.82, respectively. Publication bias was not present (t = 0.58, P = 0.58). Meta-regression analysis indicated that fat suppression, mean age, TE, and maximum b factor were not sources of heterogeneity (all P > 0.05). CONCLUSION: Single-shot EPI DWI is useful to differentiate between malignant and benign pancreatic lesions. Lesion size >= 2 cm is the limit for the diagnosis of early lesions. PMID- 26034372 TI - Meta-analysis of subtotal stomach-preserving pancreaticoduodenectomy vs pylorus preserving pancreaticoduodenectomy. AB - AIM: To investigate the differences in outcome following pylorus preserving pancreaticoduodenectomy (PPPD) and subtotal stomach-preserving pancreaticoduodenectomy (SSPPD). METHODS: Major databases including PubMed (Medline), EMBASE and Science Citation Index Expanded and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library were searched for comparative studies between patients with PPPD and SSPPD published between January 1978 and July 2014. Studies were selected based on specific inclusion and exclusion criteria. The primary outcome was delayed gastric emptying (DGE). Secondary outcomes included operation time, intraoperative blood loss, pancreatic fistula, postoperative hemorrhage, intraabdominal abscess, wound infection, time to starting liquid diet, time to starting solid diet, period of nasogastric intubation, reinsertion of nasogastric tube, mortality and hospital stay. The pooled odds ratios (OR) or weighted mean difference (WMD) with 95% confidence intervals (95%CI) were calculated using either a fixed-effects or random-effects model. RESULTS: Eight comparative studies recruiting 650 patients were analyzed, which include two RCTs, one non-randomized prospective and 5 retrospective trial designs. Patients undergoing SSPPD experienced significantly lower rates of DGE (OR = 2.75; 95%CI: 1.75-4.30, P < 0.00001) and a shorter period of nasogastric intubation (OR = 2.68; 95%CI: 0.77-4.58, P < 0.00001), with a tendency towards shorter time to liquid (WMD = 2.97, 95%CI: -0.46-7.83; P = 0.09) and solid diets (WMD = 3.69, 95%CI: -0.46-7.83; P = 0.08) as well as shorter inpatient stay (WMD = 3.92, 95%CI: -0.37-8.22; P = 0.07), although these latter three did not reach statistical significance. PPPD, however, was associated with less intraoperative blood loss than SSPPD [WMD = -217.70, 95%CI: -429.77-(-5.63); P = 0.04]. There were no differences in other parameters between the two approaches, including operative time (WMD = -5.30, 95%CI: -43.44-32.84; P = 0.79), pancreatic fistula (OR = 0.91; 95%CI: 0.56-1.49; P = 0.70), postoperative hemorrhage (OR = 0.51; 95%CI: 0.15-1.74; P = 0.29), intraabdominal abscess (OR = 1.05; 95%CI: 0.54-2.05; P = 0.89), wound infection (OR = 0.88; 95%CI: 0.39-1.97; P = 0.75), reinsertion of nasogastric tube (OR = 1.90; 95%CI: 0.91-3.97; P = 0.09) and mortality (OR = 0.31; 95%CI: 0.05-2.01; P = 0.22). CONCLUSION: SSPPD may improve intraoperative and short-term postoperative outcomes compared to PPPD, especially DGE. However, these findings need to be further ascertained by well-designed randomized controlled trials. PMID- 26034374 TI - Self-medication of achalasia with cannabis, complicated by a cannabis use disorder. AB - Achalasia is a rare esophagus motility disorder. Medical, endoscopic and surgical treatments are available, but all endorse high relapse rates. No data has been published to date reporting a therapeutic effect of cannabis use neither in achalasia nor on its influence on manometric measurements. We report the case of a patient diagnosed with achalasia. He could benefit from a large panel of therapeutic interventions, but none of them was effective over the time. He first used cannabis at age 20 and identified benefits regarding achalasia symptoms. He maintained regular moderate cannabis use for 9 years, with minimal digestive inconvenience. A manometry performed without cannabis premedication was realized at age 26 and still found a cardiospasm. Cannabis use could explain the gap between functional symptoms assessment and manometry measurement. Further investigations are warranted to explore a therapeutic effect of cannabis in achalasia and possible influence on outcome measurements. PMID- 26034375 TI - Metastasized pancreatic carcinoma with neoadjuvant FOLFIRINOX therapy and R0 resection. AB - Patients with metastasized carcinoma of the pancreas have a very poor prognosis, and long-term survival cannot be expected. This case report describes two patients with an initial diagnosis of metastatic pancreatic cancer, both with hepatic metastases and one with an additional peritoneal carcinomatosis. Initially, both patients were treated intravenously with the FOLFIRINOX chemotherapy regimen, consisting of 5-FU, folinic acid, irinotecan and oxaliplatin. Surprisingly, the FOLFIRINOX treatment resulted in complete resolution of the hepatic metastases in both patients, with no lesions detectable by computed tomography scan. Furthermore, treatment response included decreased diameter of the primary tumor in the tail of the pancreas and disappearance of the additional peritoneal carcinomatosis. Both patients were discussed by our multidisciplinary tumor board, which recommended surgical resections of the carcinoma. The R0 resection of the primary tumor was successful in both cases and, interestingly, the resected tissues showed no evidence of the hepatic metastases intraoperatively. In the first case, the patient received a postoperative 6-mo course of adjuvant chemotherapy with gemcitabine. In the second case, the patient continued to receive the FOLFIRINOX regimen for an additional 6 mo postoperatively. At 12 mo after the operation, a nonresectable retroperitoneal lymph node metastasis was detected in the first patient, whereas the second patient remained in complete remission at the time of this report (5 mo after the adjuvant therapy was discontinued). This case report is the first of its kind to describe two cases of hepatic metastatic pancreatic carcinoma that were resectable following treatment with FOLFIRINOX. Further studies are required to examine the role of FOLFIRINOX as a neoadjuvant treatment option in subgroups of patients with initially metastasized pancreatic carcinoma. PMID- 26034376 TI - Radiofrequency ablation for treatment of hypersplenism: A feasible therapeutic option. AB - We present a case of a patient with hypersplenism secondary to portal hypertension due to hepato-splenic schistosomiasis, which was accompanied by severe and refractory thrombocytopenia. We performed spleen ablation and measured the total spleen and ablated volumes with contrast-enhanced computed tomography and volumetry. No major complications occurred, thrombocytopenia was resolved, and platelet levels remained stable, which allowed for early treatment of the patient's underlying disease. Previous work has shown that splenic radiofrequency ablation is an attractive alternative treatment for hypersplenism induced by liver cirrhosis. We aimed to contribute to the currently sparse literature evaluating the role of radiofrequency ablation (RFA) in the management of hypersplenism. We conclude that splenic RFA appears to be a viable and promising option for the treatment of hypersplenism. PMID- 26034377 TI - Gastric subepithelial lesion complicated with abscess: Case report and literature review. AB - Gastric abscess is a localized pyogenic inflammation of the gastric wall, which is a rare form of suppurative gastritis. The rarity of gastric abscess may be associated with the difficulty of early diagnosis and high mortality as a result. In general, subepithelial lesions (SELs) of the stomach are incidentally detected during the course of upper endoscopy without specific clinical symptoms and signs. However, some gastric SELs present rarely as a form of hemorrhage, obstruction, perforation, and abscess. Here we report a 45-year-old man with gastric SEL presenting as a gastric abscess, which was diagnosed as an ectopic pancreas of the stomach, along with a review of the literature. Although gastric SEL presenting as an abscess is known as a serious and life-threatening lesion, the patient made a complete recovery through surgical resection as well as medical treatment. PMID- 26034378 TI - Gastrointestinal stromal tumor solitary distant recurrence in the left brachialis muscle. AB - Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract that are most commonly found in the stomach. Although GISTs can spread to the liver and peritoneum, metastasis to the skeletal muscle is very rare and only four cases have previously been reported. These cases involved concurrent skeletal metastases of primary GISTs or liver metastases. Here, we report the first case of a distant recurrence in the brachialis muscle after complete remission of an extra-luminal gastric GIST following a wedge resection of the stomach, omental excision, and adjuvant imatinib therapy for one year. Ten months after therapy completion, the patient presented with swelling and tenderness in the left arm. Magnetic resonance imaging revealed a large mass in the brachialis muscle, which showed positivity for c-kit and CD34 upon pathologic examination. This is the first reported case of a solitary distant recurrence of a GIST in the muscle after complete remission had been achieved. PMID- 26034379 TI - Liver transplantation for a giant mesenchymal hamartoma of the liver in an adult: Case report and review of the literature. AB - Mesenchymal hamartomas of the liver (MHLs) in adults are rare and potentially premalignant lesions, which present as solid/cystic neoplasms. We report a rare case of orthotopic liver transplantation in a patient with a giant MHL. In 2013, a 34-year-old female sought medical advice after a 2-year history of progressive abdominal distention and respiratory distress. Physical examination revealed an extensive mass in the abdomen. Computed tomography (CT) of her abdomen revealed multiple liver cysts, with the diameter of largest cyst being 16 cm * 14 cm. The liver hilar structures were not clearly displayed. The adjacent organs were compressed and displaced. Initial laboratory tests, including biochemical investigations and coagulation profile, were unremarkable. Tumor markers, including levels of AFP, CEA and CA19-9, were within the normal ranges. The patient underwent orthotopic liver transplantation in November 2013, the liver being procured from a 40-year-old man after cardiac death following traumatic brain injury. Warm ischemic time was 7.5 min and cold ischemic time was 3 h. The recipient underwent classical orthotopic liver transplantation. The recipient operative procedure took 8.5 h, the anhepatic phase lasting for 1 h without the use of venovenous bypass. The immunosuppressive regimen included intraoperative induction with basiliximab and high-dose methylprednisolone, and postoperative maintenance with tacrolimus, mycophenolate mofetil, and prednisone. The recipient's diseased liver weighed 21 kg (dry weight) and measured 41 cm * 32 cm * 31 cm. Histopathological examination confirmed the diagnosis of an MHL. The patient did not experience any acute rejection episode or other complication. All the laboratory tests returned to normal within one month after surgery. Three months after transplantation, the immunosuppressive therapy was reduced to tacrolimus monotherapy, and the T-tube was removed after cholangiography showed no abnormalities. Twelve months after transplantation, the patient remains well and is fulfilling all normal activities. Adult giant MHL is extremely rare. Symptoms, physical signs, laboratory results, and radiographic imaging are nonspecific and inconclusive. Surgical excision of the lesion is imperative to make a definite diagnosis and as a cure. Liver transplantation should be considered as an option in the treatment of a non-resectable MHL. PMID- 26034381 TI - Reversible sinusoidal obstruction syndrome associated with tacrolimus following liver transplantation. AB - Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno-occlusive disease, is a rare disorder in solid organ transplant patients, and is an uncommon complication after liver transplantation. Severe SOS with hepatic failure causes considerable mortality. Tacrolimus has been reported to be an offending agent, which potentially plays a role in the pathophysiological process of SOS. SOS due to tacrolimus has been reported in lung and pancreatic transplantations, but has never been described in a liver transplant recipient. Herein, we present a case of SOS after liver transplantation, which was possibly related to tacrolimus. A 27-year-old man developed typical symptoms of SOS with painful hepatomegaly, ascites and jaundice after liver transplantation, which regressed following withdrawal of tacrolimus. By excluding other possible predisposing factors, we concluded that tacrolimus was the most likely cause of SOS. PMID- 26034380 TI - Idiopathic neonatal pneumoperitoneum with favorable outcome: A case report and review. AB - Neonatal pneumoperitoneum is a surgical emergency indicative of gastrointestinal perforation that requires immediate treatment to prevent death. There have been non-surgical conditions secondary to neonatal pneumoperitoneum (e.g., mechanical ventilation, pulmonary diseases and pneumatosis cystoides intestinalis) that neonates were able to overcome without the need for abdominal exploration. Idiopathic pneumoperitoneum, although similar to perforation of the alimentary tract and the previously mentioned non-surgical conditions, is a more rare and benign condition that does not yet have a definite cause. Hence, inexperienced surgeons may have a difficult time providing the right treatment for idiopathic pneumoperitoneum. We report a case of a neonate with a massive pneumoperitoneum who obtained a favorable outcome without surgical intervention. Nonetheless, the cause of pneumoperitoneum remains unclear. We hypothesize that the right sized perforation (range: 2 mm to 4 mm in diameter) at the anterior wall of the stomach is needed for pneumoperitoneum to occur. As the baby cries (aerophagia), the air in the stomach accumulates until it can enter the intraperitoneal cavity through the leak compressed by gastric peristalsis, hence forming a large pneumoperitoneum. Small amounts of gastric juice are able to penetrate the gastric wall; therefore, no signs or symptoms of peritonitis occur. The gastric leak self-seals, preventing further passage of the air, allowing the intraperitoneal free gas to dissipate gradually. This case demonstrated that laparotomy can be avoided in neonates with idiopathic pneumoperitoneum if a timely diagnosis is established. PMID- 26034382 TI - Reconciling Reality with Fantasy: Exploration of the Sociocultural Factors influencing HIV Transmission among Black Young Men who have Sex with Men (BYMSM) within the House Ball Community: A Chicago Study. AB - Studies involving the House Ball Community (HBC) have found high rates of HIV prevalence and undiagnosed HIV infection, as well as unique social and sexual network-related HIV risk and protective behaviors (Murrill et al., 2008; Sanchez et al., 2010). Efforts to understand culturally-appropriate and effective methods of HIV prevention services within the relatively understudied HBC are scarce (Phillips et al., 2011). This qualitative study, utilizing a Diffusion of Innovation Theoretical framework, aimed to explore social norms regarding HIV and accessibility of HIV prevention services within the HBC. Thirty-seven participants (16 community leaders and 21 youth) engaged in focus group discussions. Participants discussed the perceptions of HIV and stigmatization within the HBC, general and HBC-specific risk factors for HIV transmission, as well as HIV prevention needs and strategies for culturally-appropriate HIV interventions. Findings from this qualitative study highlight both the vulnerability of the HBC to HIV transmission and the corresponding support for HIV prevention interventions. PMID- 26034383 TI - Occupational exposure to roadway emissions and inside informal settlements in sub Saharan Africa: A pilot study in Nairobi, Kenya. AB - Few studies examine urban air pollution in sub-Saharan Africa (SSA), yet urbanization rates there are among the highest in the world. In this study, we measured 8-hr average occupational exposure levels of fine particulate matter (PM2.5), black carbon (BC), ultra violet active-particulate matter (UV-PM), and trace elements for individuals who worked along roadways in Nairobi, specifically bus drivers, garage workers, street vendors, and women who worked inside informal settlements. We found BC and re-suspended dust were important contributors to PM2.5 levels for all study populations, particularly among bus drivers, while PM2.5 exposure levels for garage workers, street vendors, and informal settlement residents were not statistically different from each other. We also found a strong signal for biomass emissions and trash burning, which is common in Nairobi's low-income areas and open-air garages. These results suggest that the large portion of urban residents in SSA who walk along roadways would benefit from air quality regulations targeting roadway emissions from diesel vehicles, dust, and trash burning. This is the first study to measure occupational exposure to urban air pollution in SSA and results imply that roadway emissions are a serious public health concern. PMID- 26034384 TI - Hepatotoxicity of molecular targeted therapy. AB - A constant increase in occurrence of neoplasms is observed; hence new methods of therapy are being intensively researched. One of the methods of antineoplastic treatment is molecular targeted therapy, which aims to influence individual processes occurring in cells. Using this type of medications is associated with unwanted effects resulting from the treatment. Liver damage is a major adverse effect diagnosed during targeted therapy. Drug-induced liver damage can occur as necrosis of hepatocytes, cholestatic liver damage and cirrhosis. Hepatotoxicity is evaluated on the basis of International Consensus Criteria. Susceptibility of the liver to injury is connected not only with toxicity of the used medications but also with metastasis, coexistence of viral infections or other chronic diseases as well as the patient's age. It has been proven that in most cases the liver injury is caused by treatment with multikinase inhibitors, in particular tyrosine kinase inhibitors. The Food and Drug Administration (FDA) ordered the inclusion of additional labels - so-called "black box warnings" - indicating increased risk of liver injury when treating with pazopanib, sunitinib, lapatinib and regorafenib. A meta-analysis published in 2013 showed that treating neoplastic patients with tyrosine kinase inhibitors can increase the risk of drug induced liver damage at least twofold. Below the mechanisms of drug-induced liver injury and hepatotoxic effects of molecular targeted therapy are described. PMID- 26034385 TI - Radiotherapy and anthracyclines - cardiovascular toxicity. AB - The subject of this paper is to analyze the impact of radiotherapy and anthracyclines on the cardiovascular system, based on a survey of contemporary literature. Currently, high efficiency of anticancer therapies has increased the rate of survival in patients treated for cancer. It should be emphasized, however, that these treatments damage not only the affected but also the healthy tissue. Consequently, with the increase of survival rate in these patients, the number of patients with complaints regarding numerous organs and systems also increases as a result of earlier treatment. Thus, during the first decade of the 21(st) century, a number of concerns about the relationship between cancer treatment and dysfunction of the cardiovascular system were resolved. Anthracyclines, as well as radiotherapy, are capable of damaging the cardiovascular system, both at the central level, by the deterioration of cardiac function, and at peripheral levels, by increasing the hemodynamic and thrombotic changes. PMID- 26034386 TI - Rhabdomyosarcoma of the head and neck in children. AB - Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in children. It is localized in the head and neck region in 40% of cases. Treatment of RMS is complex, including multi-drug chemotherapy, radiotherapy and surgery. The progress that has been accomplished in oncology in recent decades significantly improved outcomes. The 5-year survival rate raised from 25% in 1970 to 73% in 2001, according to IRS-IV data. The outcome is influenced by primary tumor localization, clinical staging, histological tumor type and age at the moment of diagnosis. The relatively rare incidence of these tumors resulted in difficulties in creating more standardized therapeutic protocols. Comparison of outcomes in large patients groups led to an increase in the number of patients with complete remission. Although survival rates of RMS patients have improved, searching for new therapeutic modalities and substances is still essential to improve outcomes in cases of more advanced stages and unfavorable tumor localizations. PMID- 26034387 TI - Arsenic trioxide downregulates cancer procoagulant activity in MCF-7 and WM-115 cell lines in vitro. AB - THE AIM OF THE STUDY: To analyze human breast cancer cell line MCF-7 and human malignant melanoma cell line WM-115 in order to characterize the cellular expression of CP and to evaluate whether ATO may affect this activity, as well as the viability of the cells. MATERIAL AND METHODS: The inhibitory effect of arsenic trioxide on the proliferation of MCF-7 and WM-115 cells were measured with MTT test. The activity of cancer procoagulant after ATO exposure was determined by a specific three-stage chromogenic assay. RESULTS: ATO decreased the CP activity in a dose- and time-dependent manner in MCF-7 cells with no effect on cell proliferation at the same time. However, it affected the CP activity of WM-115 cells in a different way. Reduction in CP activity was followed by an increase after 48 h incubation. The cells viability results showed dose-and time-correlated response within high arsenic concentrations. CONCLUSIONS: Arsenic trioxide downregulates the CP expression in human breast cancer and melanoma cells. PMID- 26034388 TI - Expression of prostaglandin E2 prostanoid receptor EP2 and interleukin-1beta in laryngeal carcinoma - preliminary study. AB - AIM OF THE STUDY: Expression of EP2 protein, the prostaglandin E2 (PGE2) receptor, produced by tumour microenvironment inflammatory cells as well as tumour cells, may promote cellular proliferation and growth in an autocrine and paracrine fashion. The phenomenon involving these proteins is regulated by interleukin 1beta (IL-1beta). Many researchers indicate a connection of EP2 and IL-1beta in various types of neoplasms with higher tumour progression and poor prognosis. The aim of this study was to analyse the EP2 expression within laryngeal carcinoma tissue and IL-1beta levels in peripheral blood mononuclear cell supernatants and to find relationships between clinicomorphological features. MATERIAL AND METHODS: A group of 50 patients with verified squamous cell laryngeal carcinoma was analysed in this study. The pathological evaluation included pTNM depth of invasion according to tumour front grading criteria. Immunohistochemical analysis for membranous staining of EP2 in tumour tissues was used. The IL-1beta expression was determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Increased EP2 expression in carcinoma cells was confirmed for more advanced tumours (pT3-pT4 vs. pT1-pT2, p < 0.0001 and pN1-3 vs. pN0, p = 0.02). Tumours with the highest aggressiveness identified by deeper invasion of submucosa or cartilage were characterised by the highest expression of EP2 (p < 0.0001). In laryngeal carcinomas characterised by a lower differentiation the highest EP2 expression in tumour cells was noted (p = 0.009). A positive relationship between IL-1beta expression and the presence of lymph node metastases was also confirmed (p = 0.04). CONCLUSIONS: The study indicates the potential effect of EP2 receptor and IL-1beta on tumour progression in laryngeal carcinoma. PMID- 26034389 TI - Interleukin 35 is an independent prognostic factor and a therapeutic target for nasopharyngeal carcinoma. AB - AIM OF THE STUDY: Interleukin (IL)-35 is composed of two subunits: Epstein-Barr virus-induced gene 3 (EBI3) and IL-12p35. Recently, overexpression of IL-35 has been found in several types of cancers. However, its clinical significance in nasopharyngeal carcinoma is still obscure. We have studied the clinical significance of IL-35 expression and its correlation with outcome of nasopharyngeal carcinoma patients. MATERIAL AND METHODS: Interleukin 35 expression was investigated in 80 nasopharyngeal carcinoma cases by immunohistochemistry. Moreover, Fisher's exact test, Kaplan-Meier plots, and Cox proportional hazards regression were utilized to analyse these results. RESULTS: In the present study, IL-35 is highly expressed in the majority of nasopharyngeal carcinoma samples. EBI3 and p35 immunoreactivity in nasopharyngeal carcinoma samples was 67.5% and 51.3%, respectively. Both EBI3 and p35 expressions were significantly associated with advancement of tumour stage. In addition, EBI3 expression was also correlated with lymph node metastasis. Further analysis showed that EBI3 or p35 staining indicated unfavourable prognosis (p < 0.05). Multivariate analysis suggested EBI3 was an independent prognostic predictor (p < 0.05). CONCLUSIONS: Our results indicate for the first time that IL-35 is correlated with progression of nasopharyngeal carcinoma. Therefore, IL-35 may be a useful target for the treatment of nasopharyngeal carcinoma. PMID- 26034390 TI - Prognostic factors for gemcitabine-refractory patients with advanced pancreatic cancer: a retrospective analysis of a multicentre study (Anatolian Society of Medical Oncology). AB - AIM OF THE STUDY: Systemic chemotherapy for patients with pancreatic cancer has limited impact on overall survival (OS). Patients eligible for chemotherapy should be selected carefully. The aim of the study was to search for prognostic factors for survival in patients with gemcitabine (Gem)-refractory or with gemcitabine and cisplatin (GemCis)-refractory advanced pancreatic cancer. MATERIAL AND METHODS: We retrospectively evaluated patients with Gem- or GemCis refractory advanced pancreatic cancer. Sixteen potential prognostic variables were chosen for analysis in this study. Univariate and multivariate analyses were conducted to identify prognostic factors associated with survival. Univariate and multivariate statistical methods were used to determine prognostic factors. RESULTS: Multivariate analysis included the four prognostic significance factors in univariate analysis. Multivariate analysis showed that liver metastasis and second-line chemotherapy were considered independent prognostic factors for survival. CONCLUSIONS: Liver metastasis and second-line chemotherapy were identified as important prognostic factors in advanced pancreatic cancer patients refractory to treatment with Gem or GemCis. This prognostic factors may also facilitate pretreatment prediction of survival and can be used for selecting patients for treatment. PMID- 26034391 TI - Evaluation of outcome and prognostic factors in 739 patients with uterine cervix carcinoma: a single institution experience. AB - AIM OF THE STUDY: The aim of this retrospective chart review was to determine the long-term outcomes and identify prognostic factors that impact the survival of patients with cervical cancer. MATERIAL AND METHODS: A retrospective chart review of 739 patients with International Federation of Gynaecology and Obstetrics (FIGO) stage I-IV cervical cancer treated with surgery, radiation or chemoradiation was performed. Patient charts were evaluated in terms of demographics, clinical outcomes, and survival. Disease-free survival (DFS) and overall survival (OS) were calculated with the Kaplan-Meier method, and differences in survival were compared with the log-rank test. Multivariate analysis was performed with a Cox proportional hazards model to determine the estimated hazard ratios (HR) with 95% confidence intervals (CI) for each prognostic factor. RESULTS: The Cox proportional hazards model demonstrated that pelvic nodal metastasis (p = 0.018), parametrial invasion (p = 0.015), and presence of disease in the surgical margin (p = 0.011) were all independent prognostic factors for OS. The 5-year OS rate of patients with negative pelvic lymph nodes was 67.1%, which was higher than the rate for those with positive nodes at 49.0% (p < 0.05). The 5-year OS rate was 54.3% for patients with metastasis to the parametrium, 79.2% with a cancer-free parametrium, 60.9% with a cancer-positive surgical margin, 85.4% with a cancer-negative surgical margin, and 64.3% with a 1-3 mm close surgical margin (p < 0.05). CONCLUSIONS: Assessing pelvic lymph nodes, the parametrium, and surgical margins is important for survival and may aid in better identifying patients who would derive greater benefits from receiving adjuvant therapies and more aggressive treatments. PMID- 26034392 TI - The characteristics of oesophageal squamous cell carcinoma: an analysis of 1317 cases in southeastern China. AB - AIM OF THE STUDY: To research the demographic and histopathological features of ESCC in southeastern China. MATERIAL AND METHODS: We retrospectively reviewed the ESCC cases in the biobank of the National Engineering Centre for Biochip in Shanghai, which cooperates with lots of hospitals and research institutions in southeastern China. The patients were pathologically confirmed as having ESCC. The demographic and histopathological features of these cases were analysed subsequently. RESULTS: A total of 1317 patients were enrolled. The overall male: female ratio was 2.88: 1. 74.34% of these cases occurred in people aged between 50-70 years. Dysphagia was the most common symptom, which accounted for 93.40% of all the patients. Stage II and III were predominant (79.73%). 72.89% of patients had a tumour length greater than 3 cm. Most of the tumours (65.83%) were located in middle third of the oesophagus. There was a significant difference among the tumour stage, length, and location in different sex groups (P < 0.05), but not between different age groups (P > 0.05). In males, ESCC is usually located in the lower parts, with a longer tumour length and higher tumour stage. 24.15% of patients had lymph nodes ratio (LNR) > 0.2. CONCLUSIONS: In our analysis, dysphagia was more common in ESCC patients, to whom more attention should be paid. Additionally, males had a higher incidence, with longer and more distant disease, which gives a poor prognosis. PMID- 26034393 TI - Bone mineral density, thyroid function, and gonadal status in young adult survivors of childhood cancer. AB - INTRODUCTION: During the last years, changes in the diagnosis and treatment have caused a significant increase of the number of young adults who experienced cancer in childhood. This enlarging population is affected by many health problems, including multiple hormone deficiencies and bone mineral deficits. This is the first polish study assessing bone mineral density and endocrine status in young adult cancer survivors. MATERIAL AND METHODS: A total of 76 long-term survivors treated for pediatric cancer were identified. The mean age at the time of study was 24.1 +/-3.5 years. Bone mineral density and TSH, fT3, fT4, FSH, LH, estradiol and testosterone level were assessed for each patient. RESULTS: Nine subjects were diagnosed with subclinical hypothyroidism. We found higher level of TSH in the study group, in comparison with control group (p = 0.015). Eighteen patients had increased level of FSH. In the study group higher number of patients with high FSH level was found in comparison with the control group (p = 0.049). A low BMD was observed in 7 patients whereas mild BMD deficits were found in 19 participants. CONCLUSIONS: In conclusion, our data show that young adult cancer survivors might experienced various hormonal problems including low bone mass, thyroid impairment and gonadal dysfunction. Some of the patients required treatment, but they were not diagnosed before this study. There is the lack of proper clinical assessment among adult childhood cancer survivors in Poland. Therefore, we demonstrated the need for a comprehensive plan for longitudinal follow-up for late effects in these population. PMID- 26034394 TI - Evaluation of the quality of life of patients before treatment of squamous cell carcinoma of the head and neck by means of chemoradiotherapy. AB - AIM OF THE STUDY: To identify predictors of quality of life (QOL) in head and neck cancer patients prior to cisplatin chemotherapy and radiotherapy treatment. MATERIAL AND METHODS: A cross-sectional study at a Clinical Oncology department of a teaching hospital in the state of Sao Paulo, Brazil, from September 2011 to October 2012 was performed. QOL was assessed using the University of Washington QOL Questionnaire. Demographic and clinical characteristics were obtained through interviews with patients and collected from medical records. Multivariate linear regression was used to determine the association between QOL scores and patient related factors. RESULTS: We studied 48 head and neck cancer patients, who were mostly white (77.1%), males (83.3%), with pharyngeal cancers (66.7%), cancers with stage T4 (45.8%) and N1 (31.2%) tumours, and classified with a Karnofsky Performance Status (KPS) of 90% (37.5%). Patients had excellent scores for saliva (96.2 +/-13.5) and shoulder (93.6 +/-17.9), with pain and anxiety being the most affected domains (59.6 +/-32.4 and 57.5 +/-39.2, respectively). A significant relationship of KPS and T stage with overall QOL score was noted. The population with lowest overall QOL score was those who had low KPS scores and T4 tumours. CONCLUSIONS: Head and neck cancer patients prior to cisplatin chemotherapy and radiotherapy treatment, with a low KPS and staged as T4 tumours, have worse overall QOL, and special attention should be given to these patients. PMID- 26034395 TI - Treatment and prognosis for retrograde cervical lymph node metastases in breast cancer. AB - Metastasis in axillary and supraclavicular lymph nodes has been frequently observed in patients with breast cancer. The clinical staging and therapeutic principle determined according to the situation of lymph node metastasis are clear. One patient with infiltrating ductal carcinoma of the left breast was reported to undergo modified radical mastectomy. One and a half years later, lymphadenectasis was observed in area II, III, IV, V and VI of the left neck; therefore, cervical lymphadenectomy was performed under cervical plexus anesthesia, indicating lymph node metastatic adenocarcinoma (21/26). The patient took 10 mg tamoxifen twice per day for five years after lymphadenectomy and the review showed negative results in liver, lungs, mediastinum, neck and contralateral breast. This suggested that although breast cancer complicated with retrograde cervical lymph node metastases is rare, timely surgery is required even if the patient is in a good general condition, to avoid "delayed therapy" due to misjudgment of illness simply according to disease staging. PMID- 26034397 TI - Coexistent lung adenocarcinoma and giant cell carcinoma in different lung lobes of the same patient. PMID- 26034396 TI - Agomelatine or ramelteon as treatment adjuncts in glioblastoma and other M1- or M2-expressing cancers. AB - The impressive but sad list of over forty clinical studies using various cytotoxic chemotherapies published in the last few years has failed to increase median survival of glioblastoma beyond two years after diagnosis. In view of this apparent brick wall, adjunctive non-cytotoxic growth factor blocking drugs are being tried, as in the CUSP9* protocol. A related theme is searching for agonists at growth inhibiting receptors. One such dataset is that of melatonin agonism at M1 or M2 receptors found on glioblastoma cells, being a negative regulator of these cells' growth. Melatonin itself is an endogenous hormone, but when used as an exogenously administered drug it has many disadvantages. Agomelatine, marketed as an antidepressant, and ramelteon, marketed as a treatment for insomnia, are currently-available melatonin receptor agonists. These melatonin receptor agonists have significant advantages over the natural ligand: longer half-life, better oral absorption, and higher affinity to melatonin receptors. They have an eminently benign side effect profile. As full agonists they should function to inhibit glioblastoma growth, as demonstrated for melatonin. A potentially helpful ancillary attribute of melatonergic agonists in glioblastoma treatment is an increase in interleukin-2 synthesis, expected, at least partially, to reverse some of the immunosuppression associated with glioblastoma. PMID- 26034398 TI - Knowledge and practice of nurses towards prevention of pressure ulcer and associated factors in Gondar University Hospital, Northwest Ethiopia. AB - BACKGROUND: Pressure ulcers are the common conditions among patients hospitalized in acute and chronic care facilities and impose significant burden on patients, their relatives and caregivers. Pressure ulcers have been described as one of the most costly and physically debilitating complications since the 20(th) century. The pain and discomfort due to pressure ulcer prolongs illness, rehabilitation, time of discharge and even contribute to disability and death. This study was aimed to assess knowledge, practice and factors associated with pressure ulcer prevention among nurses in Gondar University Hospital, North-west Ethiopia. METHOD: An institution-based cross-sectional survey was conducted from March 15 - April 10, 2014 among 248 nurses in Gondar University hospital. A pretested and structured self-administered questionnaire was used for data collection. Data were entered using EPI info version 3.5.3 statistical software and analyzed using SPSS version 20 statistical package. Descriptive statistics was used to describe the study population in relation to relevant variables. Bivariate and multivariate logistic regression was also carried out to see the effect of each independent variable on the dependent variable. RESULT: Nearly half (54.4 %) of the nurses had good knowledge; similarly 48.4 % of them had good practice on prevention of pressure ulcer. Educational status [Adjusted Odds Ratio (AOR) = 2.4, 95 % CI (1.39-4.15)], work experience [AOR = 4.8, 95 % CI (1.31-10.62)] and having formal training [AOR = 4.1, 95 % CI (1.29-9.92)] were significantly associated with knowledge on prevention of pressure ulcer. While, satisfaction with nursing leadership [AOR = 1.9, 95 % CI (1.04-3.82)], staff shortage [AOR = 0.07, 95 % CI (0.03-0.13)] and inadequate facilities and equipment [AOR = 0.4, 95 % CI (0.19-0.83)] were found to be significantly associated with the practice on prevention of pressure ulcer. CONCLUSION: Knowledge and practice of the nurses regarding prevention of pressure ulcer was found to be inadequate. Having higher educational status, attending formal training and being experienced were positively associated with knowledge; while shortage of facilities and equipments, dissatisfaction with nursing leadership and inadequate staff number showed negative association with practice of nurse's pressure ulcer prevention. In-service training and upgrading courses are some of the important steps to improve nurses' knowledge and practice on prevention of ulcer pressure. PMID- 26034399 TI - Anjali S. Kumar, MD, MPH, FACS, FASCRS. PMID- 26034400 TI - Miscellaneous colitides: what the surgeon needs to know. PMID- 26034401 TI - Persistent and Recurrent Clostridium difficile Colitis. AB - Clostridium difficile infection (CDI) is the most frequent cause of nosocomial diarrhea. It has become a significant dilemma in the treatment of patients, and causes increasing morbidity that, in extreme cases, may result in death. Persistent and recurrent disease hamper attempts at eradication of this infection. Escalating levels of treatment and novel therapeutics are being utilized and developed to treat CDI. Further trials are warranted to definitively determine what protocols can be used to treat persistent and recurrent disease. PMID- 26034402 TI - Sexually transmitted proctitis. AB - There are many different sexually transmitted infections that can cause proctitis. Recognition of the common symptoms with anoscopic examination is crucial in accurate diagnosis of the pathogen. Clinicians should have a high index of suspicion of more than one inciting pathogen. Treatment should be prompt and extended to sexual partners who have been exposed to the disease. Effective treatment can alleviate the discomfort and potentially serious complications associated with sexually transmitted proctitides. This article illustrates and discusses the clinical presentations, diagnostic pearls, and treatments of sexually transmitted proctitides. PMID- 26034403 TI - Parasitic colitis. AB - Over one billion people worldwide harbor intestinal parasites. Parasitic intestinal infections have a predilection for developing countries due to overcrowding and poor sanitation but are also found in developed nations, such as the United States, particularly in immigrants or in the setting of sporadic outbreaks. Although the majority of people are asymptomatically colonized with parasites, the clinical presentation can range from mild abdominal discomfort or diarrhea to serious complications, such as perforation or bleeding. Protozoa and helminths (worms) are the two major classes of intestinal parasites. Protozoal intestinal infections include cryptosporidiosis, cystoisosporiasis, cyclosporiasis, balantidiasis, giardiasis, amebiasis, and Chagas disease, while helminth infections include ascariasis, trichuriasis, strongyloidiasis, enterobiasis, and schistosomiasis. Intestinal parasites are predominantly small intestine pathogens but the large intestine is also frequently involved. This article highlights important aspects of parasitic infections of the colon including epidemiology, transmission, symptoms, and diagnostic methods as well as appropriate medical and surgical treatment. PMID- 26034404 TI - Noninfectious colitides. AB - There are numerous etiologic and pathogenic mechanisms associated with colitis, ranging from infectious to noninfectious colitis. However, despite their different causes, their presentations are often similar making it difficult to formulate the correct diagnosis. This article describes the presentation, endoscopic and pathological findings of six different noninfectious colitides: diversion colitis, neutropenic enterocolitis, disinfectant colitis, corrosive colitis, nonsteroidal anti-inflammatory drug and salicylate-induced colitis, and toxic epidermal necrolysis. In addition, this article discusses the management and current treatment options for these six colitides. PMID- 26034405 TI - Ischemic colitis. AB - Most clinicians associate ischemic colitis with elderly patients who have underlying cardiovascular comorbidities. While the majority of cases probably occur in this population, the disease can present in younger patients as a result of different risk factors, making the diagnosis challenging. While a majority of patients respond to medical management, surgery is required in approximately 20% of the cases and is associated with high morbidity and mortality. PMID- 26034406 TI - Behcet colitis. AB - Behcet disease (BD) is a chronic, multisystem, inflammatory disease characterized by variable clinical manifestations involving systemic vasculitis of both the small and large blood vessels. The majority of BD patients present with recurrent oral ulcers in combination with other manifestations of the disease, including genital ulcers, skin lesions, arthritis, uveitis, thrombophlebitis, gastrointestinal or central nervous system involvement. Gastrointestinal BD occurs in 3 to 25% of the BD patients and shares many clinical characteristics with inflammatory bowel disease (IBD). Consequently, the differentiation between IBD and gastrointestinal manifestation of BD is very difficult. Intestinal BD should be considered in patients who present with abdominal pain, diarrhea, weight loss, and rectal bleeding who are susceptible or at a risk for intestinal BD. PMID- 26034407 TI - Radiation proctopathy. AB - Radiation therapy is a widely utilized treatment modality for pelvic malignancies, including prostate cancer, rectal cancer, and cervical cancer. Given its fixed position in the pelvis, the rectum is at a high risk for injury secondary to ionizing radiation. Despite advances made in radiation science, up to 75% of the patients will suffer from acute radiation proctitis and up to 20% may experience chronic symptoms. Symptoms can be variable and include diarrhea, bleeding, incontinence, and fistulization. A multitude of treatment options exist. This article summarizes the latest knowledge relating to radiation proctopathy focusing on the vast array of treatment options. PMID- 26034408 TI - Acute colonic pseudoobstruction. AB - Acute colonic pseudoobstruction (ACPO), often referred to as Ogilvie syndrome, is a clinical entity characterized by severe colonic distension (adult acute megacolon) in the absence of mechanical obstruction. It can result in abdominal ischemia and perforation if left untreated. This article discusses the epidemiology and current pathophysiologic theories of ACPO as well as the clinical presentation and diagnostic modalities utilized to identify the disease. In addition, this article describes the current treatment options for ACPO, which range from conservative medical therapy, therapeutic endoscopy, to subtotal colectomy. PMID- 26034409 TI - Microscopic colitis (lymphocytic and collagenous), eosinophilic colitis, and celiac disease. AB - Multiple tests are needed to diagnose a patient with noninfectious diarrhea. Some patients will be mistakenly labeled as diarrhea-predominant irritable bowel syndrome (IBS-D) because of nonspecific computed tomographic scans and grossly normal endoscopic findings. It is crucial to understand other less common pathologies to avoid these instances of misdiagnosis. This article focuses on microscopic colitis (MC), eosinophilic colitis (EC), and celiac disease. MC is an inflammatory condition of the colon that presents with two subtypes, only to be differentiated by histology. EC is a rare chronic inflammatory process. Depending on the extent of the disease, it can present with mild diarrhea, malabsorption, or at its worst, cause obstruction and perforation. Celiac disease affects the small bowel, but interestingly can present similarly to colitis. Both MC and EC respond to oral budesonide. Patients with celiac disease improve on gluten-free diets. These treatments are distinctly different from typical IBS-D care plans. PMID- 26034411 TI - Structural modulation of silicon nanowires by combining a high gas flow rate with metal catalysts. AB - We grew silicon nanowires (SiNWs) by a vapor-liquid-solid (VLS) mechanism using metal catalysts of gold (Au), titanium (Ti), manganese (Mn), and iron (Fe) under a high flow rate of hydrogen (H2). This combination of catalyst types and high gas flow rate revealed the potential for growing various SiNWs, including kinked SiNWs (with Au), ultra-thin SiNWs having diameters about 5 nm (with Ti), rough surfaced SiNWs (with Mn), and ribbon-shaped SiNWs tens of microns in width (with Fe). The high flow rate of gas affects the VLS mechanism differently for each combination; for example, it induces an unstable solid-liquid interfaces (with Au), active etching of the catalyst (with Ti), sidewall deposition by a vapor solid (VS) mechanism, and an asymmetric precipitation of Si in the catalyst (with Fe). Our combinatorial approach may provide a new path for the structural modulation of SiNWs via the VLS mechanism. PACS: 80; 81; 82. PMID- 26034410 TI - On the Nature and Evolutionary Impact of Phenotypic Robustness Mechanisms. AB - Biologists have long observed that physiological and developmental processes are insensitive, or robust, to many genetic and environmental perturbations. A complete understanding of the evolutionary causes and consequences of this robustness is lacking. Recent progress has been made in uncovering the regulatory mechanisms that underlie environmental robustness in particular. Less is known about robustness to the effects of mutations, and indeed the evolution of mutational robustness remains a controversial topic. The controversy has spread to related topics, in particular the evolutionary relevance of cryptic genetic variation. This review aims to synthesize current understanding of robustness mechanisms and to cut through the controversy by shedding light on what is and is not known about mutational robustness. Some studies have confused mutational robustness with non-additive interactions between mutations (epistasis). We conclude that a profitable way forward is to focus investigations (and rhetoric) less on mutational robustness and more on epistasis. PMID- 26034412 TI - Graphene-based optical modulators. AB - Optical modulators (OMs) are a key device in modern optical systems. Due to its unique optical properties, graphene has been recently utilized in the fabrication of optical modulators, which promise high performance such as broadband response, high modulation speed, and high modulation depth. In this paper, the latest experimental and theoretical demonstrations of graphene optical modulators (GOMs) with different structures and functions are reviewed. Particularly, the principles of electro-optical and all-optical modulators are illustrated. Additionally, the limitation of GOMs and possible methods to improve performance and practicability are discussed. At last, graphene terahertz modulators (GTMs) are introduced. PMID- 26034413 TI - Advanced light-trapping effect of thin-film solar cell with dual photonic crystals. AB - A thin-film solar cell with dual photonic crystals has been proposed, which shows an advanced light-trapping effect and superior performance in ultimate conversion efficiency (UCE). The shapes of nanocones have been optimized and discussed in detail by self-definition. The optimized shape of nanocone arrays (NCs) is a parabolic shape with a nearly linearly graded refractive index (GRI) profile from the air to Si, and the corresponding UCE is 30.3% for the NCs with a period of 300 nm and a thickness of only 2 MUm. The top NCs and bottom NCs of the thin film have been simulated respectively to investigate their optimized shapes, and their separate contributions to the light harvest have also been discussed fully. The height of the top NCs and bottom NCs will also influence the performances of the thin-film solar cell greatly, and the result indicates that the unconformal NCs have better light-trapping ability with an optimal UCE of 32.3% than the conformal NCs with an optimal UCE of 30.3%. PMID- 26034414 TI - Synthesis of Gd2O3:Eu nanoplatelets for MRI and fluorescence imaging. AB - We synthesized Gd2O3 and Gd2O3 doped by europium (Eu) (2% to 10%) nanoplatelets using the polyol chemical method. The synthesized nanoplatelets were characterized by X-ray diffraction (XRD), FESEM, TEM, and EDX techniques. The optical properties of the synthesized nanoplatelets were investigated by photoluminescence spectroscopy. We also studied the magnetic resonance imaging (MRI) contrast enhancement of T1 relaxivity using 3 T MRI. The XRD for Gd2O3 revealed a cubic crystalline structure. The XRD of Gd2O3:Eu(3+) nanoplatelets were highly consistent with Gd2O3 indicating the total incorporation of the Eu(3+) ions in the Gd2O3 matrix. The Eu doping of Gd2O3 produced red luminescence around 612 nm corresponding to the radiative transitions from the Eu-excited state (5)D0 to the (7)F2. The photoluminescence was maximal at 5% Eu doping concentration. The stimulated CIE chromaticity coordinates were also calculated. Judd-Ofelt analysis was used to obtain the radiative properties of the sample from the emission spectra. The MRI contrast enhancement due to Gd2O3 was compared to DOTAREM commercial contrast agent at similar concentration of gadolinium oxide and provided similar contrast enhancement. The incorporation of Eu, however, decreased the MRI contrast due to replacement of gadolinium by Eu. PMID- 26034415 TI - Fabrication of Fe3O4@mSiO2 Core-Shell Composite Nanoparticles for Drug Delivery Applications. AB - We report the synthesis of Fe3O4@mSiO2 nanostructures of different meso-silica (mSiO2) shell thickness, their biocompatibility and behaviors for loading and release of a model drug ibuprofen. The composite nanostructures have superparamagnetic magnetite cores of 208 nm average size and meso-silica shells of 15 to 40 nm thickness. A modified Stober method was used to grow the meso silica shells over the hydrothermally grown monodispersed magnetite particles. The composite nanoparticles show very promising drug holding and releasing behaviors, which depend on the thickness of meso-silica shell. The biocompatibility of the meso-silica-coated and uncoated magnetite nanoparticles was tested through cytotoxicity assay on breast cancer (MCF-7), ovarian cancer (SKOV3), normal human lung fibroblasts MRC-5, and IMR-90 cells. The high drug holding capacity and reasonable biocompatibility of the nanostructures make them ideal agents for targeted drug delivery applications in human body. PMID- 26034416 TI - Detection of Majorana fermions by Fano resonance in hybrid nanostructures. AB - The realization and detection of Majorana fermions in condensed matter systems are of considerable importance and interest. We propose a scheme to detect the Majorana fermions by Fano resonance in hybrid nanostructures made of semiconductor quantum dots and quantum wire in proximity to superconductor. Through detailed theoretical studies of the transport properties of our hybrid nanostructures based on the non-equilibrium Green's function technique and the equation of motion approach, it is found that the Fano resonance in the current response due to the interference among different transmission paths may give clear signature of the existence of Majorana modes. Moreover, we have found a peculiar relationship between the Fano factor q and the Majorana bound state coupling strength/the length of nanowire, which can be used for a design of an electronic nanoruler. Our method of detection of Majorana fermions based on Fano resonance is related to the global conductance profile, thus is robust to perturbations. PMID- 26034417 TI - Relation between the strength and dimensionality of defect-free carbon crystals. AB - On the basis of ab initio simulations, the value of strength of interatomic bonds in one-, two- and three-dimensional carbon crystals is obtained. It is shown that decreasing in dimensionality of crystal gives rise to nearly linear increase in strength of atomic bonds. It is ascertained that growth of strength of the crystal with a decrease in its dimensionality is due to both a reduction in coordination number of atom and increase in the angle between the directions of atomic bonds. Based on these data, it is substantiated that the one-dimensional (1D) crystals have maximum strength, and strength of carbyne is the absolute upper limit of strength of materials. PMID- 26034418 TI - Preparation, assessment, and comparison of alpha-chitin nano-fiber films with different surface charges. AB - Chitin nano-fibers with positive and negative charges have been, respectively, produced from partially deacetylated and 2,2,6,6-tetramethylpiperidine-1-oxyl radical (TEMPO)-mediated oxidized alpha-chitin. The average diameters and lengths of the TEMPO-oxidized chitin nano-fibers (TOChN) were 14 +/- 4.3 and 190 +/- 140 nm, respectively, and the average diameters and lengths of the partially deacetylated chitin nano-fibers (DEChN) were 6 +/- 1.7 and 320 +/- 105 nm, respectively. A partially deacetylated chitin nano-fiber film (DEChN-F), a TEMPO mediated and oxidized chitin nano-fiber film (TOChN-F), and a composite film (DE TO-ChN-F) consisting of a combination of the two were prepared by drying the dispersions at 40 degrees C. The DEChN-F, TOChN-F, and DE-TO-ChN-F all have similar tensile strengths of approximately 90 MPa; however, the chitosan film (Chitosan-F) had a tensile strength of approximately 30 MPa. In addition, TOChN-F and DE-TO-ChN-F have a thermal weight loss at 210 degrees C, and DEChN-F has a thermal weight loss at 280 degrees C. DEChN-F was found to have antimicrobial activity with regards to Escherichia coli. Finally, the chitin nano-fiber films could be slightly degraded by cellulase, which provided a novel biological performance of the chitin nano-material. PMID- 26034419 TI - Visible Thrombolysis Acceleration of a Nanomachine Powered by Light-Driving F0F1 ATPase Motor. AB - We report on thrombolysis acceleration of a nanomachine powered by light-driving delta-subunit-free F0F1-ATPase motor. It is composed of a mechanical device, locating device, energy storage device, and propeller. The rotory delta-subunit free F0F1-ATPase motor acts as a mechanical device, which was obtained by reconstructing an original chromatophore extracted from Rhodospirillum rubrum. We found that the bioactivity of the F0F1-ATPase motor improved greatly after reconstruction. The zeta potential of the nanomachine is about -23.4 mV. Cytotoxicity induced by the nanomachine was measured using cell counting kit (CCK)-8 assay. The A549 cells incubated with different fractional concentrations of the nanomachine within 48 h did not show obvious cytotoxicity. The locating device helps the nanomachine bind to the thrombi. Energy was easily stored by exposing the nanomachine to 600-nm-wavelength irradiation, which promoted activity of the motor. The rotation of the long propeller accelerated thrombolysis of a blood clot in vitro in the presence of urokinase (UK). This result was based on visual inspection and confirmed by a series of tests. PMID- 26034420 TI - Hematite thin films with various nanoscopic morphologies through control of self assembly structures. AB - Hematite (alpha-Fe2O3) thin films with various nanostructures were synthesized through self-assembly between iron oxide hydroxide particles, generated by hydrolysis and condensation of Fe(NO3)3 . 6H2O, and a Pluronic triblock copolymer (F127, (EO)106(PO)70(EO)106, EO = ethylene oxide, PO = propylene oxide), followed by calcination. The self-assembly structure can be tuned by introducing water in a controlled manner through the control of the humidity level in the surrounding of the as-cast films during aging stage. For the given Fe(NO3)3 . 6H2O:F127 ratio, there appear to be three different thermodynamically stable self-assembly structures depending on the water content in the film material, which correspond to mesoporous, spherical micellar, and rod-like micellar structures after removal of F127. Coupled with the thermodynamic driving forces, the kinetics of the irreversible reactions of coalescence of iron oxide hydroxide particles into larger ones induce diverse nanostructures of the resultant films. The length scale of so-obtained nanostructures ranges from 6 nm to a few hundred nanometers. In addition to water content, the effects of other experimental parameters such as aging temperature, spin rate during spin coating, type of substrate, and type of iron reagent were investigated. PMID- 26034421 TI - Photonics and nanophotonics and information and communication technologies in modern food packaging. AB - The analysis of the problem of conjunction of information and communication technologies (ICT) with packaging industry and food production was made. The perspective of combining the latest advances of nanotechnology, including nanophotonics, and ICT for creating modern smart packaging was shown. There were investigated luminescent films with zinc oxide nanoparticles, which change luminescence intensity as nano-ZnO interacts with decay compounds of food products, for active and intelligent packaging. High luminescent transparent films were obtained from colloidal suspension of ZnO and polyvinylpyrrolidone (PVP). The influence of molecular mass, concentration of nano-ZnO, and film thickness on luminescent properties of films was studied in order to optimize the content of the compositions. The possibility of covering the obtained films with polyvinyl alcohol was considered for eliminating water soluble properties of PVP. The luminescent properties of films with different covers were studied. The insoluble in water composition based on ZnO stabilized with colloidal silicon dioxide and PVP in polymethylmethacrylate was developed, and the luminescent properties of films were investigated. The compositions are non-toxic, safe, and suitable for applying to the inner surface of active and intelligent packaging by printing techniques, such as screen printing, flexography, inkjet, and pad printing. PMID- 26034422 TI - Optical characterization of In-flushed InAs/GaAs quantum dots emitting a broadband spectrum with multiple peaks at ~1 MUm. AB - We investigated optical properties of In-flushed InAs quantum dots (QDs) grown on a GaAs substrate by molecular beam epitaxy. By using the In-flush technique for setting the height of self-assembled InAs QDs, we have tuned the emission wavelength of InAs QDs to the ~1 MUm regime, which can be utilized as a non invasive and deeply penetrative probe for biological and medical imaging systems. The controlled emission exhibited a broadband spectrum comprising multiple peaks with an interval of approximately 30 meV. We examined the origin of the multiple peaks using spectral and time-resolved photoluminescence, and concluded that it is attributed to monolayer step fluctuations in the height of the In-flushed QDs. This feature can be advantageous for realizing a broadband light source centered at the ~1 MUm regime, which is especially suitable for the non-invasive cross sectional biological and medical imaging system known as optical coherence tomography. PMID- 26034423 TI - Formation of Nanocomposites by Oxidizing Annealing of SiO x and SiO x Films: Ellipsometry and FTIR Analysis. AB - The structural-phase transformations induced by air annealing of SiO x and SiO x < Er,F > films were studied by the combined use of infrared spectroscopy and ellipsometry. The films were prepared using vacuum evaporation of SiO powder and co-evaporation of SiO and ErF3 powders. The annealing took place at moderate temperatures (750 and 1000 degrees C). It was found that the micro- and macrostructure of the annealed films is similar to the structure of the Si-SiO x nanocomposites obtained by annealing SiO x in vacuum or inert atmosphere and subjected to post-annealing in oxidizing atmosphere. This proves that the phase separation in the non-stoichiometric SiO x films proceeds much faster than their oxidation. The results of the work point at a possibility to simplify the annealing technology by replacing the two-step annealing with one-step in the oxygen-containing environment while maintaining the positive effects. The differences in the structure of the nanocomposites obtained by annealing the SiO x and SiO x < Er,F > films are explained by the action of Er centers as the promoters for SiO x disproportionation, as well as the enhanced action of F on the processes of disorder-to-order transition and crystallization in amorphous silicon. PMID- 26034424 TI - Social impact of peripheral nerve injuries. AB - BACKGROUND: Disorders involving the peripheral nervous system can have devastating impacts on patients' daily functions and routines. There is a lack of consideration of the impact of injury on social/emotional well-being and function. METHODS: We performed a retrospective database and chart review of adult patients presenting between 2010 and 2012 with peripheral nerve compression, brachial plexus injury, thoracic outlet syndrome (TOS), or neuromas. At the initial assessment, patients completed a questionnaire used to obtain demographic and psychosocial variable data including the (1) average level of pain over the last month, (2) self-perceived depression, (3) how much pain impacts quality of life (QoL), (4) current level of stress, and (5) ability to cope with stress. Statistical analyses were used to assess the differences between the dependent variables and diagnostic and demographic groups. RESULTS: This study included 490 patients (mean age 50 +/- 15 years); the most common diagnosis was single nerve compression (n = 171). Impact on QoL was significantly greater in patients with TOS, cutaneous peroneal compressions, and neuroma versus single site nerve compressions. Average pain, impact on QoL, and stress at home were significantly higher in females versus males. Impact on QoL was correlated with average pain, depression, stress at home, and ability to cope with stress at home. CONCLUSIONS: Our study demonstrates that patients with single site nerve compression neuropathies experience fewer negative psychosocial effects compared to patients with more proximal upper extremity peripheral nerve disorders and neuromas. The impact on QoL was strongly correlated with pain and depression, where patients with neuromas and painful peroneal nerve entrapments reported greater detriments to QoL. PMID- 26034425 TI - A threshold disability score corresponds with an estimated diagnosis of clinical depression in patients with upper extremity disease. AB - BACKGROUND: The purpose of this study was to assess whether there is a threshold Disability of Arm, Shoulder and Hand (DASH) score among patients with common hand diagnoses that corresponds with an estimated diagnosis of clinical depression. METHODS: Two hundred sixty-nine patients with one of five common upper extremity disorders completed a measure of upper extremity-specific disability (QuickDASH or DASH) and a questionnaire assessing depressive symptoms (Patient Health Questionnaire (PHQ) or Center for Epidemiologic Studies Depression scale (CES-D). A receiver operating characteristic (ROC) analysis of the discriminatory value of a threshold DASH score for an estimated diagnosis of clinical depression was assessed. The threshold DASH score with the highest positive predictive value for an estimated diagnosis of clinical depression was selected. In bivariate analysis, the association between demographic factors, disease factors, and an estimated diagnosis of clinical depression was examined. RESULTS: The area under the ROC curve for a threshold DASH value diagnostic of an estimated diagnosis of clinical depression was 0.75, indicating clinical usefulness for a threshold DASH score as a screening test for depression. The highest positive predictive value of 72 % occurred at a threshold QuickDASH/DASH score of 55. In bivariate analysis, only diagnosis and years of education were significantly different between patients with and without an estimated diagnosis of clinical depression. CONCLUSION: A DASH score of 55 or greater in patients with common upper extremity disorders has an acceptable area under the curve and positive predictive value for an estimated diagnosis of clinical depression. LEVEL OF EVIDENCE: Level 3, diagnostic study. PMID- 26034426 TI - Prevalence of cold sensitivity in patients with hand pathology. AB - BACKGROUND: The purpose of this study was to evaluate the prevalence of cold sensitivity in patients with hand- and wrist-related diagnoses. METHODS: We included English-speaking adults who were more than 1 month following hand injury or onset of symptoms. Patients were asked if exposure to cold air or water provoked cold-related symptoms and to rank symptom severity (scale 0-10). Statistical analyses evaluated the relationships between the cold sensitivity and independent variables (age, gender, history of trauma, and time from injury/symptoms). RESULTS: There were 197 patients (mean age 49 +/- 16 years): 98 trauma and 99 non-trauma cases. Cold-induced symptoms were reported by 34 %, with 10 % reporting severe symptoms. Exposure to cold air is the most common catalyst; mean severity score was 6.7 +/- 2.2. Those with traumatic injuries compared to non-trauma diagnoses reported significantly more cold-induced symptoms (p = .04). Using backward linear regression, the significant predictors of cold symptom severity were trauma (p = .004) and time since onset (p = .003). Including only the trauma patients in the regression model, the significant predictor was time since injury (p = .005). CONCLUSIONS: Cold-induced symptoms are reported by more than 30 % of hand-related diagnoses, and exposure to cold air was the most commonly reported trigger. The significant predictors of cold-induced symptoms are traumatic injuries and longer time from injury. This study provides evidence of the common problem of cold sensitivity in patients with hand pathology. LEVEL OF EVIDENCE: Prognostic Level II. PMID- 26034427 TI - Prospective cohort study of symptom resolution outside of the ulnar nerve distribution following cubital tunnel release. AB - BACKGROUND: Resolution of symptoms including pain, numbness, and tingling outside of the median nerve distribution has been shown to occur following carpal tunnel release. We hypothesized that a similar effect would be found after release of the ulnar nerve at the elbow. METHODS: Twenty patients with isolated cubital tunnel syndrome were prospectively enrolled. The upper extremity was divided into six zones, and the location of pain, numbness, tingling, or strange sensations was recorded pre-operatively. Two-point discrimination, Semmes-Weinstein monofilament testing, and validated questionnaires were collected. The same data were collected at 6-week follow-up. Paired t tests or non-parametric Wilcoxon Signed-Rank tests were used where appropriate to examine for significant (p <= 0.05) changes between pre- and post-operative scores. RESULTS: Probability of resolution was greater outside of the ulnar nerve distribution than within at early follow-up. There was a decrease in pain, numbness, and tingling symptoms both within and outside the ulnar distribution after cubital tunnel release. There was a decrease in pain as measured by several validated questionnaires. CONCLUSION: This study documents resolution of symptoms in an extra-ulnar distribution after cubital tunnel release. Improvement in pain and function after cubital tunnel release may be associated with an improvement in symptoms both within and outside the ulnar nerve distribution. Future studies could be directed at correlating pre-operative disease severity with probability of extra territorial symptom resolution using a larger sample population. PMID- 26034428 TI - Arterialized venous flow-through flaps in the reconstruction of digital defects: case series and review of the literature. AB - BACKGROUND: Arterialized venous flow-through (AVFT) flaps are useful in reconstructing small soft tissue defects. Currently, no guidelines exist for the use of AVFT flaps for reconstructing soft tissue defects in the digits of the hand. We retrospectively reviewed our experience with AVFT flaps and developed a selection process for vascular anastomoses. METHODS: We reviewed the use of AVFT flaps in a series of ten consecutive patients requiring reconstruction of small soft tissue defects of the fingers. RESULTS: Between 2006 and 2012, ten consecutive digital reconstructions were performed using AVFT flaps. Flap sizes ranged from 5 to 13.5 cm(2). Initial congestion was seen in all flaps and resolved within 3-7 days. Leeches were utilized in two cases. All cases achieved good functional results. Three illustrative cases from our series of ten are presented, each demonstrating key decision-making factors in selecting recipient and flap vessels for anastomosis. CONCLUSIONS: AVFT flaps appear congested post operatively, resolving in days to weeks, and resulting in healthy coverage of digital soft tissue defects with good functionality. We suggest a selection process for the use of AVFT flaps in digital soft tissue reconstruction, based on dorsal vs. volar and proximal vs. distal defect location, and the flap's inherent venous architecture. PMID- 26034429 TI - Ulnar digits contribution to grip strength in patients with thumb carpometacarpal osteoarthritis is less than in normal controls. AB - BACKGROUND: Grip testing is commonly used as an objective measure of strength in the hand and upper extremity and is frequently used clinically as a proxy measure of function. Increasing knowledge of hand biomechanics, muscle strength, and prehension patterns can provide us with a better understanding of the functional capabilities of the hand. The objectives of this study were to determine the contribution of ulnar digits to overall grip strength in individuals with thumb carpometacarpal (CMC) osteoarthritis (OA). METHODS: Thirty-seven subjects participated in the study. This group consisted of 19 patients with CMC OA (aged 60-88 years) and 18 healthy subjects (60-88 years). Three hand configurations were used by the subjects during grip testing: use of the entire hand (index, middle, ring, and little fingers) (IMRL); use of the index, middle, and ring fingers (IMR); and use of only the index and middle fingers (IM). RESULTS: Grip strength findings for the two groups found that compared to their healthy counterparts, CMC OA patients had, on average, a strength deficiency of 45.6, 35.5, and 28.8 % in IMRL, IMR, and IM, respectively. The small finger contribution to grip is 14.3 % and the ring and small finger contribute 34 % in subjects with CMC OA. DISCUSSION: Grip strength decreases as the number of digits contributing decreased in both groups. The ulnar digits contribution to grip strength is greater than one third of total grip strength in subjects with CMC OA. Individuals with CMC OA demonstrate significantly decreased grip strength when compared to their healthy counterparts. PMID- 26034430 TI - Distal peripheral nerve blockade for patients undergoing hand surgery: a pilot study. AB - BACKGROUND: Data are limited regarding the use of peripheral nerve blockade at the level of the forearm, and most studies regard these procedures as rescue techniques for failed or incomplete blocks. The purpose of the study was to investigate patients undergoing hand surgery with distal peripheral nerve (forearm) blocks and compare them with patients having similar procedures under more proximal brachial plexus blockade. No investigations comparing distal nerve blockade to proximal approaches are currently reported in the literature. METHODS: Medical records were retrospectively reviewed for patients who had undergone hand surgery with a peripheral nerve block between November 2012 and October 2013. The primary outcome was the ability to provide a primary anesthetic without the need for general anesthesia or local anesthetic supplementation by the surgical team. Secondary outcome measures included narcotic administration during the block and intraoperative procedures, block performance times, and the need for rescue analgesics in the post anesthesia care unit (PACU). RESULTS: No statistical difference in conversion rates to general anesthesia was observed between the two groups. Total opiate administration for the block and surgical procedure was lower in the forearm block group. There was no difference in block performance times or need for rescue analgesics in the PACU. CONCLUSIONS: Forearm blocks are viable alternatives to proximal blockade and are effective as a primary anesthetic technique in patients undergoing hand surgery. Compared to the more proximal approaches, these blocks have the benefits of not causing respiratory compromise, the ability to be performed bilaterally, and may be safer in anticoagulated patients. PMID- 26034431 TI - Reliability of handgrip strength test in elderly subjects with unilateral thumb carpometacarpal osteoarthritis. AB - BACKGROUND: The grip strength test is widely used; however, little has been investigated about its reliability when used in elderly with subjects thumb carpometacarpal (CMC) osteoarthritis (OA). The purpose of this study was to examine the test-retest reliability of the grip strength test in elderly subjects with thumb CMC OA. METHODS: A total of 78 patients with unilateral thumb CMC OA, 84.6 % female (mean +/- SD age 83 +/- 5 years), were recruited. Each patient performed three pain free maximal isometric contractions on each hand in two occasions, 1 week apart. Intraclass correlation coefficient (ICC), standard error of measurement (SEM), and 95 % limits of agreement (LOA) were calculated. RESULTS: Test-retest reliability was excellent for side affected (ICC = 0.947; p = 0.001) and contralateral (ICC = 0.96; p = 0.001) thumb CMC OA. CONCLUSIONS: The present results indicate that maximum handgrip strength can be measured reliably, using the Jamar hand dynamometer, in patients with thumb CMC OA, which enables its use in research and in the clinic to determine the effect of interventions on improving grip. PMID- 26034432 TI - Quantitative 3-dimensional CT analyses of fractures of the middle phalanx base. AB - BACKGROUND: Quantitative 3-dimensional computed tomography (3DCT) analyses can provide a more detailed understanding of fracture morphology. For fracture dislocation of the proximal interphalangeal joint, the extent of fragmentation of the volar lip of the middle phalanx-a factor that might influence treatment-is not always apparent from radiographs. We hypothesized that there is no correlation between number of fracture fragments and the percentage of articular surface area involved in intra-articular fractures of the base of the middle phalanx using quantitative 3DCT analyses. METHODS: We used 13 computed tomography scans with a slice thickness of 1.25 mm or less to create 3-dimensional models of 15 intra-articular fractures of the base of the middle phalanx in 13 patients. We resized 3-dimensional models of a non-fractured middle phalanx of the same hand to fit the fractured middle phalanx in order to approximate the size and shape of the fractured middle phalanx in its pre-injury state. We created a heatmap to demonstrate the location of the fractured articular surface. RESULTS: With the number of scans available, we did not find a significant correlation between the percentage of articular surface area involved and the number of fracture fragments. The median percentage of articular surface area involved was 46 % (range, 21-90 %). The heatmap demonstrated that the radio-volar side of the articular surface seems to be more involved than the ulnar-volar side in intra articular fractures of the base of the middle phalanx. CONCLUSION: Quantitative 3DCT analysis of fracture fragments provides useful information that could facilitate surgery and analysis of complex fractures of the base of the middle phalanx. LEVEL OF EVIDENCE: IV, Basic Science Study, Anatomic Study, Imaging. PMID- 26034433 TI - Comparison of hand emergency triage before and after specialty templates (2007 vs. 2012). AB - BACKGROUND: Emergency hand service is a national problem both for civilian and veteran patients. The North Florida/South Georgia Veterans Health system began coordinating emergency hand coverage within the plastic surgery service in 2008. Consult templates were designed to facilitate access to the appropriate service. Trainees were taken out of transfer decisions. Clinic templates were designed to fast track urgent patients to 8 a.m. appointments. The purpose of this study was to evaluate the effectiveness of our templates and triage system. METHODS: All consults completed by the plastic surgery service were reviewed retrospectively. Emergent and urgent hand consults were identified. Time from consult submission to the patient being seen by the plastic surgery provider was recorded. Time frames were categorized as same day, next day, within 2 days, less than or equal to 7 days, and greater than 7 days. Type of emergency (trauma or infection) and treatment plan were noted. RESULTS: There were 1,090 consults in 2007 and 1,868 consults in 2012 that were completed by the plastic surgery service. We found the number of urgent and emergent hand consults increased by a factor of 6 (49 to 294). Furthermore, 16.3 % (8/49) of patients were seen greater than 1 week after consult submission in 2007, compared with 8.1 % (24/294) of patients in 2012. Only one patient from 2007 and two patients from 2012 went to the OR after regular operating room hours. CONCLUSION: A well-coordinated effort to speed access for hand emergencies can minimize expenses and improve quality of care. PMID- 26034435 TI - Outcomes of open reduction and internal fixation of acute proximal pole scaphoid fractures. AB - BACKGROUND: Proximal pole scaphoid fractures are less common than waist fractures, and successful management can be difficult. We hypothesize that time to union is increased by delays in surgical fixation, greater initial displacement, and higher energy mechanisms of injury. METHODS: A retrospective review was conducted of all patients undergoing open reduction internal fixation (ORIF) of acute proximal pole scaphoid fractures at our institution over a 19 year period. A review of clinical as well as radiographic data was undertaken. The mechanism of injury, patient demographics, timing of surgery, initial displacement, fixation method, smoking status, and lunate morphology were recorded. Functional outcome measures were recorded when available. Univariate analysis using Kaplan-Meier survival curves was performed. RESULTS: A total of 10 out of 23 patients (43 %) showed evidence of union at 14 weeks post-injury. Rates of early union were higher in non-displaced fractures (70 %) when compared to displaced fractures (23 %). Similarly, fractures sustained via low energy mechanisms had a higher rate of early union compared to high energy mechanisms (69 versus 10 %). A delay in ORIF did not appear to influence rate of union. CONCLUSIONS: Initial displacement and mechanism of injury have the most significant effects on early rates of union. Delay in ORIF of up to 28 days did not affect the rate of initial union, but the authors recommend early fixation of these fractures to prevent further displacement. Patients with widely displaced fractures or those with high energy mechanisms should be counseled regarding prolonged healing time. LEVEL OF EVIDENCE: IV-therapeutic. PMID- 26034434 TI - Factors associated with non-attendance at a hand surgery appointment. AB - BACKGROUND: Patients who miss scheduled appointments without notifying office staff--"no-shows"--disrupt practice workflow and decrease access for others, resulting in misuse of resources and lost revenue. The primary purpose of this study was to identify factors associated with no-shows in a hospital-based outpatient hand office. Secondarily, we studied factors associated with cancelations. METHODS: Of the 14,793 new adult patient appointments to our outpatient hand surgery office scheduled between January 2011 and December 2013, 880 (5.9 %) were no-shows and 2715 (18 %) were cancelations. Data on patient demographics and timing of the visit were collected to construct a multinomial logistic regression model of determinants of appointment no-shows and cancelations. RESULTS: Factors independently associated with no-shows included younger age, Hispanic or black race, unmarried status (single or divorced), appointment on a Monday or Tuesday, and residence near the office. Factors associated with cancelations were female sex, unmarried status (widowed or divorced), winter season, and appointment on a weekday other than Friday. CONCLUSIONS: Non-attendees are more likely to be younger, unmarried, non-white, to have their appointments at the start of the week, and to live near the office. Knowledge of these factors might prove useful for implementation of tailored quality improvement initiatives to reduce non-attendance and maximize productivity in the hand surgery office setting. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV. PMID- 26034436 TI - Comparisons of three radiographic views in assessing for scapholunate instability. AB - BACKGROUND: Multiple wrist x-ray images have been described to assess for scapholunate (SL) instability. Some views may be redundant. The purpose of this study was to compare three plain x-ray views in identifying a traumatic diastasis of the SL interval. METHODS: Nineteen patients (19 wrists) with a positive scaphoid shift test and surgically confirmed SL ligament damage were identified. There were 15 males and 4 females with a mean age of 39 years. Pre-operative x rays were reviewed, including posteroanterior (PA) neutral and PA ulnar deviation views of the injured wrist, and PA clenched fist views of the injured and uninjured wrists. Dynamic SL instability was defined by an SL mid-interval gap of <3 mm and static SL instability by a gap of >=3 mm in the PA neutral views. The mid-interval measurements were compared between x-ray images. RESULTS: There were 10 dynamic and 9 static SL instability cases. The PA ulnar deviation and the PA clenched fist views showed significantly greater SL gaps in comparison to the PA neutral views in dynamic but not static SL instability cases. In both categories of instability, there was no significant difference in the SL gaps between the two stress images. The PA clenched fist view of the uninjured wrist revealed SL gapping of >3 mm in 50% of patients but with generally greater gapping in the clenched fist view of the injured wrist. CONCLUSIONS: The PA ulnar deviation and clenched fist stress views were equally effective in showing a dynamic SL diastasis following wrist injury. Neither view was more effective than a neutral PA view in diagnosing static SL instability. PMID- 26034437 TI - Pyrocarbon interposition arthroplasty for proximal capitate avascular necrosis. AB - INTRODUCTION: Avascular necrosis of the capitate head is a rare condition commonly treated with partial wrist fusion. Although good functional results are usually reported, a degree of stiffness is to be expected. We report a pyrocarbon interposition arthroplasty technique in a young sportsman with 3.5 years of follow-up. METHODS: A 15-year-old rugby player presented with a 6-month history of wrist pain and stiffness with no preceding injury. The necrotic bone was replaced with interposition of a pyrocarbon interposition implant (PI(2)) (Tournier, Grenoble, France), originally designed to replace the trapezium. A concave socket was created in the distal fragment to accommodate the implant and prevent dislocation. Regular follow-up included subjective and objective measures. RESULTS: He was pain free by 6 weeks and regained good functional range of motion and grip strength by 3 months. He returned to playing rugby at the 1 year follow-up. At 2 years, he remained asymptomatic. After 3.5 years, he had no limitations in his heavy manual work as a plant mechanic and retained a good functional range of motion including the dart-thrower's motion. CONCLUSIONS: Medium-term results appear to offer the benefits of being able to return to heavy manual labour as well as retaining a functional range of motion. It is difficult to predict long-term survival, but the outcome so far is encouraging, and conversion to midcarpal fusion remains a salvage option. PMID- 26034438 TI - Incidence of symptomatic compressive peripheral neuropathy after shoulder replacement. AB - BACKGROUND: The incidence of post-operative compressive peripheral neuropathy (CPN) after shoulder arthroplasty is not known. We hypothesized that the likelihood following shoulder arthroplasty would be higher compared to a non operative cohort. METHODS: Retrospective study compared the incidence of symptomatic CPN after shoulder replacement to a 1:1 age- and gender-matched non operative control group with shoulder arthritis. Six hundred six consecutive shoulder replacements from a regional shoulder arthroplasty registry were analyzed. This included 319 primary total shoulder arthroplasties (TSR), 168 hemiarthroplasties (HA), 31 humeral resurfacings (HHR), 71 reverse arthroplasties (RTSA), and 17 revision arthroplasties. Diagnosis of post-operative CPN was obtained by documented clinical examination by a physician consistent with CPN based on patient complaints, positive nerve study results, and/or nerve decompression. Age, gender, body mass index, diabetes status, thyroid abnormalities, operative side, and anesthesiology (ASA) score were examined. RESULTS: The surgery group had 15 cases (2.5 %) of post-operative CPN (ten carpal tunnel syndrome, five cubital tunnel syndrome). This included seven TSR, six HA, one revision TSR, and one RTSA. Diagnoses included ten osteoarthritis, four rotator cuff arthropathies, and one chondrolysis. Control group had eight cases (1.3 %) of CPN (seven carpal tunnel syndrome, one cubital tunnel syndrome). In univariate analysis, age, gender, body mass index, ASA score, operative side, thyroid status, and diabetes were not predictors of post-operative CPN. CPN incidence between surgical and control groups was not statistically significant. CONCLUSION: The 1-year incidence rate of new onset clinical post-operative CPN symptoms was 2.5 %. There was no significant difference of CPN rates between surgical and non-operative groups. PMID- 26034439 TI - Comparative analysis of photograph-based clinical goniometry to standard techniques. AB - BACKGROUND: Assessment of joint range of motion (ROM) is an accepted evaluation of disability as well as an indicator of recovery from musculoskeletal injuries. Many goniometric techniques have been described to measure ROM, with variable validity due to inter-rater reliability. In this report, we assessed the validity of photograph-based goniometry in measurement of ROM and its inter-rater reliability and compared it to two other commonly used techniques. METHODS: We examined three methods for measuring ROM in the upper extremity: manual goniometry (MG), visual estimations (VE), and photograph-based goniometry (PBG). Eight motions of the upper extremity were measured in 69 participants at an academic medical center. RESULTS: We found visual estimations and photograph based goniometry to be clinically valid when tested against manual goniometry (r avg. 0.58, range 0.28 to 0.87). Photograph-based measurements afforded a satisfactory degree of inter-rater reliability (ICC avg. 0.77, range 0.28 to 0.96). CONCLUSIONS: Our study supports photograph-based goniometry as the new standard goniometric technique, as it has been clinically validated, is performed with greater consistency and better inter-rater reliability when compared with manual goniometry. It also allows for better documentation of measurements and potential incorporation into medical records in direct contrast to visual estimation. PMID- 26034440 TI - National trends in ambulatory surgery for upper extremity fractures: a 10-year analysis of the US National Survey of Ambulatory Surgery. AB - BACKGROUND: Upper extremity fractures are increasing in frequency and have profound socioeconomic implications. The purpose of this study was to assess trends in ambulatory upper extremity fracture fixation in the USA from 1996 to 2006 using data from the National Survey of Ambulatory Surgery (NSAS). METHODS: The NSAS was used to identify cases of closed forearm, carpal, metacarpal, and phalanx fractures treated with open or closed reduction with internal fixation in 1996 and 2006. Data were analyzed for trends in fracture location, age, gender, facility type, payor status, and anesthesia type. US census data were used to obtain national population estimates. RESULTS: Over the 10-year study period, there was a 54.4 % increase in the population-adjusted rate of upper extremity fractures treated with internal fixation (34.6 to 53.4 per 100,000 capita). There was a 173 % increase in the age-adjusted rate of patients over 55 years treated with internal fixation. There was a 505 % increase in the number of cases performed at freestanding surgical centers compared to hospital-based facilities. Though the majority of cases involved general anesthesia, regional anesthesia (16.6 versus 20.6 %) and monitored anesthesia care (7.1 versus 11.8 %) increased in frequency. Private insurance groups funded the majority of surgeries in both study years. CONCLUSION: The volume of ambulatory surgery for upper extremity fractures has increased dramatically from 1996 to 2006. Operative treatment of upper extremity fractures has increased markedly. Our analysis provides valuable information for providers and policy-makers for allocating the appropriate resources to help sustain this volume. PMID- 26034441 TI - Clinical outcomes following collagenase injections compared to fasciectomy in the treatment of Dupuytren's contracture. AB - INTRODUCTION: The aim of this study is to compare the efficacy of collagenase injections with that of fasciectomy in the treatment of Dupuytren's contracture. METHODS: This is a case-control retrospective study. We reviewed the electronic medical records from January 2009 through January 2013, identifying 142 consecutive patients who underwent either fasciectomy or collagenase injection. Exclusion criteria for both groups were age <18 years, pregnant women, and arthroplasty or arthrodesis of the treated joint. Follow-up data beyond 1-year duration was available for 117 of the patients: 44 patients who had undergone fasciectomy, and 73 patients who had received collagenase injection. The primary outcome measure in this study was resolution of joint contracture to 0-5 degrees deficit of full extension. Data was analyzed using two-sample t tests for continuous data and chi-square test for categorical data. A significant P value was set at <0.05. RESULTS: At the latest follow-up, significantly more joints treated with fasciectomy met the primary outcome measure. Metacarpophalangeal (MP) joints responded better than the proximal interphalangeal (PIP) joints for both treatments. At the latest follow-up (14.2 months for collagenase, 16.3 months for fasciectomy), 46 % of MP joints treated with collagenase and 68 % of MP joints treated with fasciectomy maintained resolution of joint contracture. Sub-analysis of the affected joints based on the severity of initial contracture demonstrated that MP and PIP joints with contractures <45 degrees responded better than more severely contracted joints (>45 degrees ). CONCLUSIONS: Fasciectomy yields a greater mean magnitude of correction for digital contractures at the latest follow-up when compared to collagenase. Both treatments were more effective for treatment of MP joint contracture compared to PIP joint contracture. LEVEL OF EVIDENCE: Level III, therapeutic. PMID- 26034442 TI - Epidemiologic dynamics contributing to pediatric wrist fractures in the United States. AB - BACKGROUND: The purpose of this study was to explore and evaluate national trends and factors contributing to pediatric wrist fractures. METHODS: Over a 16-year period from January 1998 to December 2013, we identified and reviewed patients aged 0-17 years old with the primary diagnosis of wrist fracture, as evaluated in US EDs and chronicled by the National Electronic Injury Surveillance System (NEISS) database of the US Consumer Product Safety Commission. We conducted descriptive epidemiologic, bivariate, and chi-square analyses. Patients were categorized into age-defined subgroups and further stratified by sex, race, location, and consumer product/activity associated with injury. RESULTS: There were 53,265 children evaluated in NEISS EDs (national estimate, 1,908,904) with wrist fractures from 1998 to 2013. Mean age was 10.9 years, with 64 % males and 36 % females. The most common locations of injury were place of recreation/sports, home, and school. The top five consumer-product-related injuries were associated with bicycles, football, playground activities, basketball, and soccer. The highest subgroup associations were with beds (0-12 months), stairs (13-36 months), playgrounds (3-5 and 6-10 years), and football (11-17 years). The greatest increase in fractures occurred between ages 0-12 and 13-36 months, with the second-largest increase between ages 3-5 and 6-10. CONCLUSIONS: It is essential to develop injury prevention and safety strategies as well as identify individual risk factors for fracture, including activity, sex, and key age transitions. Surveillance is imperative to advance our understanding of these fractures, and in the future may facilitate development of research prediction tools to anticipate or prevent injury. PMID- 26034443 TI - Rheumatoid hand surgery: is there a decline? A 22-year population-based study. AB - BACKGROUND: Rheumatoid arthritis (RA) is the most common idiopathic inflammatory arthritis affecting 0.8 % of the population. It can cause significant hand and wrist damage and dysfunction. Recent advances in anti-rheumatic treatments have the potential to decrease the prevalence of hand deformities in patients with RA. Our aim was to investigate whether there has been a decline over 22-years in the number of hand surgical procedures being undertaken for patients with RA and whether this correlates with the introduction of new anti-rheumatic therapies. METHODS: We performed a retrospective, population-based (Derbyshire) study of all patients with RA who underwent hand surgery at the Pulvertaft Hand Centre from 1990 to 2012. Index procedures included (1) teno-synovectomy and soft tissue procedures, (2) wrist arthrodesis/arthroplasty and (3) finger arthrodesis. RESULTS: A total of 297 procedures were performed in 153 Derbyshire patients with RA over the 22-year period, with mean age at surgery 59 years (range 24-88 years). The female to male ratio was 2.5:1. The overall trend showed a peak in 2004 and a subsequent decline thereafter. This coincides with an increasing tendency by local rheumatologists to introduce earlier and more intensive conventional disease-modifying drugs and biological therapies for more resistant disease. CONCLUSIONS: There has been a decline in the number of hand surgery procedures being performed on patients with RA during our 22-year population based study. It indicates that medical treatments and strategies have been successful at preventing disease progression. PMID- 26034444 TI - Language barriers in Hispanic patients: relation to upper-extremity disability. AB - BACKGROUND: Although upper-extremity disability has been shown to correlate highly with various psychosocial aspects of illness (e.g., self-efficacy, depression, kinesiophobia, and pain catastrophizing), the role of language in musculoskeletal health status is less certain. In an English-speaking outpatient hand surgery office setting, we sought to determine (1) whether a patient's primary native language (English or Spanish) is an independent predictor of upper extremity disability and (2) whether there are any differences in the contribution of measures of psychological distress to disability between native English- and Spanish-speaking patients. METHODS: A total of 122 patients (61 native English speakers and 61 Spanish speakers) presenting to an orthopaedic hand clinic completed sociodemographic information and three Patient-Reported Outcomes Measurement Information System (PROMIS)-based computerized adaptive testing questionnaires: PROMIS Pain Interference, PROMIS Depression, and PROMIS Upper-Extremity Physical Function. Bivariate and multivariable linear regression modeling were performed. RESULTS: Spanish-speaking patients reported greater upper-extremity disability, pain interference, and symptoms of depression than English-speaking patients. After adjusting for sociodemographic covariates and measures of psychological distress using multivariable regression modeling, the patient's primary language was not retained as an independent predictor of disability. PROMIS Depression showed a medium correlation (r = -0.35; p < 0.001) with disability in English-speaking patients, while the correlation was large (r = -0.52; p < 0.001) in Spanish-speaking patients. PROMIS Pain Interference had a large correlation with disability in both patient cohorts (Spanish-speaking: r = 0.66; p < 0.001; English-speaking: r = -0.77; p < 0.001). The length of time since immigration to the USA did not correlate with disability among Spanish speakers. CONCLUSION: Primary language has less influence on symptom intensity and magnitude of disability than psychological distress and ineffective coping strategies. Interventions to optimize mood and to reduce pain interference should be considered in patients of all nationalities. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II. PMID- 26034445 TI - A retrospective comparison of the management of recalcitrant lateral elbow tendinosis: platelet-rich plasma injections versus surgery. AB - BACKGROUND: The aim of this study is to compare the outcomes of platelet-rich plasma (PRP) injections to surgical release and decortication for lateral elbow tendinosis within a similar patient population. METHODS: A retrospective chart review was performed on two groups of patients, receiving either PRP injections (n = 28) or surgery (n = 50). Patient demographics, clinical presentation, pain score, worker's compensation status, and previous steroid injections were recorded. Primary outcomes included pain and symptom improvement, range of motion, return to work, and postoperative complications. RESULTS: Demographics, duration of symptoms, and exam findings were similar between the PRP and surgical patients. There was no significant difference in pain and symptom improvement. Pain improvement was reported in 89.3 % of PRP patients and 84 % of surgical patients, with a reported percent reduction in pain of 61.1 and 55 %, respectively. Symptoms other than pain improved in 85.7 and 88 % of the PRP and surgical patients, respectively. Tenderness to palpation at the lateral epicondyle (64.3 % PRP, 44 % surgical), pain with resisted wrist extension (35.7 % PRP, 30 % surgical), or residual symptoms other than pain (14.3 % PRP, 10 % surgical) were not significantly different between groups at last follow-up. Eighty-two percent of patients in both the PRP and surgical groups returned to work. No complications were reported. Mean follow-up was 315 vs. 352 days for the PRP and surgical groups, respectively. CONCLUSIONS: Similar outcomes in pain improvement and return to work may be achievable with either PRP injections or surgery in recalcitrant lateral elbow tendinosis. PRP injections may be a reasonable alternative for patients apprehensive to proceed with surgery or poor surgical candidates. PMID- 26034446 TI - Outcome following distally locked volar plating for distal radius fractures with metadiaphyseal involvement. AB - BACKGROUND: The surgical treatment of metadiaphyseal distal radius fractures may be difficult due to the associated articular or periarticular extension that limits standard fixation techniques. Longer distal radius volar locking plates allow stable fixation of the distal fragments while providing standard plate fixation in the proximal radius. We hypothesize that this plating technique allows adequate fixation to both the distal radius and metadiaphyseal fragments. The purpose of the study is to describe the outcomes, radiographic parameters, secondary surgeries, and complication rate with this device. METHODS: A retrospective chart review was conducted on adult patients with a distal radius fracture and metadiaphyseal involvement treated with a volar, distally locked plate. All patients were followed up for radiographic union, with a mean time of 219 days (range 38-575). Fracture patterns, outcomes of range of motion, grip strength, and complications, as well as injury, post open reduction and internal fixation (ORIF), and finally, healed radiographic parameters were recorded. RESULTS: Twenty patients with 21 fractures were included. At union, mean radiographic parameters were the following: volar tilt of 8 degrees , radial inclination of 27 degrees , radial height of 14 mm, and ulnar variance of -1 mm. The mean final range of motion was 52 degrees flexion, 50 degrees extension, 68 degrees pronation, and 66 degrees supination. Complications included one infection and one plate removal. Four patients developed a nonunion requiring secondary procedures. There were no incidents of hardware failure or adhesions requiring tenolysis. CONCLUSION: Distally locked long volar plating for metadiaphyseal distal radius fractures is a safe and effective treatment option for these complex fracture patterns allowing anatomic restoration of the radial shaft and distal radius. PMID- 26034447 TI - Risk factors for complications of open trigger finger release. AB - BACKGROUND: Open trigger finger release is generally considered a simple low-risk procedure. Reported complication rates vary widely from 1 to 43 %, mostly based on small studies. Our goal was to determine the incidence of complications in a large consecutive series, while also identifying potential risk factors. METHODS: All open trigger finger releases performed from 2006 to 2009 by four fellowship trained hand surgeons at a single institution were retrospectively reviewed. There were 795 digits released in 543 patients. Complications were defined as signs or symptoms requiring further treatment and/or considered unresolved by 1 month postoperatively. Complications requiring operative intervention were regarded as major. Multivariable analysis was performed to determine possible risk factors for complications. RESULTS: There were 95 documented complications among 795 digits (12 %). The most common complications involved persistent pain, stiffness, or swelling, persistent or recurrent triggering, or superficial infection. Most were treated nonoperatively with observation, therapy, steroid injection, or oral antibiotics. There were 19 reoperations (2.4 %), mostly including revision release, tenosynovectomy, and irrigation and debridement. Male gender, sedation, and general anesthesia were independently associated with complications, while age, diabetes, hypothyroidism, recent injection, and concurrent procedures were not associated. CONCLUSIONS: Open trigger finger release is generally a low-risk procedure, although there is potential for complications, some requiring reoperation. Male gender, sedation, and general anesthesia may be associated with greater risk. Surgeons should be careful to thoroughly discuss the risk of both major and minor complications when counseling patients. PMID- 26034448 TI - An unusual presentation of a digital schwannoma: case report. PMID- 26034449 TI - Radial head dislocation due to gigantic solitary osteochondroma of the proximal ulna: case report and literature review. AB - Developmental anterior dislocation of the radial head resulting from a congenital solitary osteochondroma of the proximal ulna is an extremely rare condition. We present a case of a 4-year-old girl with this condition affecting her right elbow, which was treated by a trapezoidal shortening osteotomy at the radial neck following an oblique ulnar osteotomy with angulation and elongation after a complete resection of the tumor mass. The child remained asymptomatic with symmetric carrying angles during 2.5 years of follow-up post-surgery. We discuss the nature of this condition and review the literature. PMID- 26034450 TI - Nonunion of the pisiform bone in a 9-year-old boy. AB - An isolated fracture of the pisiform bone is a rare condition, especially in children. The fracture may be missed in the emergency department because of the complex anatomy of the carpal region. Early diagnosis and treatment are, however, important for the functional outcome of the patient, since untreated dislocated carpal fractures may result in nonunion. We report one case of a 9-year-old boy with an unrecognized fracture of the pisiform bone who underwent a pisiformectomy 10 months after injury due to a nonunion of the pisiform bone. Good results were obtained and the wrist did not show any functional impairment. PMID- 26034451 TI - Retrograde headless intramedullary screw fixation for displaced fifth metacarpal neck and shaft fractures: short term results. AB - BACKGROUND: This study aimed to evaluate the early clinical outcomes of retrograde headless intramedullary screw fixation for displaced fifth metacarpal neck and shaft fractures. METHODS: We retrospectively reviewed nine patients treated with retrograde intramedullary screw fixation of fifth metacarpal neck and shaft fractures between 2011 and 2013. Patient demographics and outcomes including hand dominance, age, sex, type of injury, injury and postoperative radiographs, return to work, time to fracture union radiographically, complications, visual analog score, disabilities of the arm, shoulder, and hand scores, postoperative metacarpophalangeal joint range of motion, and grip strength were recorded. RESULTS: Nine fractures in nine patients with a mean age of 32 years (19-54) were included. There were seven metacarpal neck and two metacarpal shaft fractures. All patients sustained injury by direct impact of fist against an object. No case involved worker's compensation. Patients had a mean follow-up of 36 weeks (6-57 weeks) and at the time of latest follow-up had no pain. Mean radiographic healing was 49 days (28-85 days). Mean return to work was 6 weeks (4-10 weeks). Mean metacarpalphalangeal joint motion was 0 degrees extension and 90 degrees flexion. Mean disabilities of the arm, shoulder, and hand scores pre- and postoperatively improved from 43 to 0.7, respectively. The mean postoperative grip strength was measured of the injured hand (40 kg) and un injured hand (41 kg). CONCLUSIONS: Retrograde headless intramedullary screw fixation of fifth metacarpal neck and shaft fractures has overall favorable early outcomes and offers the benefit of stable fixation, early motion without cast immobilization, and the ability for early return to work. This technique is a viable surgical option for these fractures and may be considered in the appropriate patient population. PMID- 26034452 TI - Over 20-year follow-up of Miura reconstruction of cleft hand. AB - Several techniques have been described for cleft hand closure and web space reconstruction in patients with central deficiency; however, long-term documentation of results is rare. We present a 23-year follow-up of a patient who underwent the Miura procedure for a Manske type IIb cleft hand exhibiting long term aesthetic and functional success. In addition, early skin flap necrosis and late web space contracture, which have been seen after the Snow-Littler procedure, did not occur in this case. PMID- 26034453 TI - A simple blind tenolysis for flexor carpi radialis tendinopathy. AB - BACKGROUND: Flexor carpi radialis (FCR) tendinopathy is an entity with a chronic form (repetitiveness of work) and an acute form (acute overstretching of the wrist). Confirmation of this syndrome can be established by injection of a small amount of a local anesthetic in the sheet of the FCR at this tender point. Complete relieve of the symptoms after injection confirms the existence of a tendinopathy of the FCR. Whereas rest and/or local application of steroids do not have a persistent effect on the short term outcome, a tenolysis could be performed. Before performing a tenolysis underlying causes should be excluded or treated. METHODS: In this article a simple and save technique is described, using a small Beaver knife to open the osteofibrous tunnel of the flexor carpi radialis tendon, without opening the carpal tunnel. RESULTS: Relieve of complaints could be reached up to almost two third of all cases. CONCLUSION: In cases in which non operative treatment is not effective regarding FCR tendinopathy, a simple blind technique by opening the osteofibrous tunnel could be successful. PMID- 26034455 TI - Open metacarpophalangeal dislocations: literature review and case report. AB - BACKGROUND: Open dorsal metacarpophalangeal joint dislocations are rare. We report the case of a 62-year-old man who fell from a height of 10 m onto his left outstretched hand and presented to us with four open dorsal metacarpophalangeal joint dislocations. We review the literature and present our case to elucidate the best treatment protocol for open dorsal metacarpophalangeal joint dislocations. METHODS: A systematic review was conducted using MEDLINE, Embase, and PubMed from 1946 to present. Publications were found using key terms and cross-referencing. Detail on patient demographic, presentation, mechanism of injury, injury management, and outcome were collected. RESULTS: A total of 102 articles of metacarpophalangeal joint dislocation (excluding thumb dislocations) were identified. Of these, only four were of open dorsal metacarpophalangeal joint dislocation involving the four long fingers. Open dislocation of the metacarpophalangeal joint in these studies showed no hand predominance, nor association with hand dominance. CONCLUSION: Open dorsal metacarpophalangeal joint dislocations of the four long fingers are unusual. Based on the available case reports and our experience, we suggest addressing this injury intraoperatively with minimal delay. Most cases will be associated with volar plate injury, and we encourage its repair with figure-of-eight stitches. Postoperatively, we suggest a dorsal blocking splint for 2 weeks followed by occupational therapy consisting of passive and active range of motion (ROM) exercises and adjunctive therapies to control edema and optimize scar tissue. Inadequate management of such injuries could be highly detrimental to hand function. PMID- 26034454 TI - Treatment of an unusual trans-scaphoid perilunate avulsion fracture dislocation: a case report. AB - We describe an unusual case of trans-scaphoid perilunate injury where the proximal half of the scaphoid avulsed from all attaching ligaments and extruded into the forearm. Treatment involved anatomic reduction and internal fixation of the fracture, scapholunate (SL) ligament repair, temporary K-wire fixation, and prolonged immobilization. At 19-month follow-up, the fracture healed, SL ligament remained intact, and the patient recovered much of his hand function. PMID- 26034456 TI - Myopericytoma of the distal forearm: a case report. AB - Myopericytoma is a rare type of soft tissue tumor with perivascular myoid differentiation. Although the pathology characteristics of myopericytomas are well described in literature, the clinical characteristics of these tumors have received less attention. We report on a 44-year-old female who developed a myopericytoma in her right distal forearm. The patient presented with a painless solid mass that had been slowly increasing in size for approximately 5 years. Unlike typical myopericytoma in the extremity growing as a subcutaneous nodule, the tumor enveloped the distal ulna. This case suggests a different growth pattern for myopericytoma. Myopericytoma is a rare soft tissue tumor originating from perivascular myoid cells, which has only been recognized as a distinct condition in the past 15 years (Granter et al. Am J Surg Pathol. 22 (5):513-25, 1998). Most of these tumors present as a painless, slow-growing subcutaneous nodule. They have typically been described by pathologists who concentrate on the pathological features rather than the clinical characteristics of these tumors (Granter et al. Am J Surg Pathol. 22 (5):513-25, 1998; Dray et al. J Clin Pathol. 59 (1):67-73, 2006; Mentzel et al. Am J Surg Pathol. 30 (1):104-113 2006). We report a case of myopericytoma with an unusual growth pattern involving the distal forearm to highlight the clinicopathologic features of this tumor. PMID- 26034457 TI - Attritional extensor tendon rupture in a patient with Phialophora verrucosa tenosynovitis: case report. AB - Deep tissue fungal infections of the hand are exceedingly uncommon. We present a case of fungal tenosynovitis caused by Phialophora verrucosa that led to extensor tendon rupture in a patient who was on chronic immunosuppressive therapy. Indolent fungal cysts can elude clinical diagnosis until excision is performed with definitive pathologic examination. In immunocompromised patients, antifungal therapy may be warranted after cyst excision even in the absence of acute infection to prevent subsequent progression to tenosynovitis. PMID- 26034458 TI - Closed median nerve rupture from elbow trauma. PMID- 26034459 TI - Myopericytoma of the hypothenar eminence: case report. AB - Myopericytomas belong to a benign group of tumors consisting of perivascular myopericytes or pericytes with a characteristic myoid differentiation pattern. The tumor is histologically and radiographically heterogenous, similar to superficial myofibromas. We report on a case of a myopericytoma arising in the hypothenar eminence of a 58-year-old man with a history of over 15 years of ulnar sided and midcarpal wrist pain. Decision was made to excise the mass after it had increased in size by over 50 % over a 10-year period. Excision of the mass led to remarkable relief of his symptoms in the hypothenar as well as midcarpal regions. Consideration of this rare perivascular tumor should be included in patients with slow-growing benign appearing masses within the subcutaneous tissues of the hand. PMID- 26034460 TI - Pseudo-winging of the scapula caused by scapular osteochondroma: review of literature and case report. AB - A 20-year-old male was evaluated for winging of the scapula and an enlarging axillary mass of 4 months' duration. Imaging demonstrated a multiloculated cystic lesion that extended into the axilla and superiorly displaced the brachial plexus and axillary vessels surrounding an exostotic mass arising from the scapula. Surgery confirmed the mass to be a benign osteochondroma with a reactive bursa. The long thoracic nerve was intact and the serratus anterior muscle contracted normally with nerve stimulation. The scapular winging resolved completely following resection of the osteochondroma, and shoulder and arm function remained normal. A literature review of causes of pseudo-winging of the scapula was performed. Scapular osteochondroma is a rarely reported cause of scapula winging. PMID- 26034461 TI - Thumb volar plate reconstruction utilizing extensor pollicis brevis autograft: evaluation of a new technique. AB - BACKGROUND: Sagittal plane instability of the thumb metacarpophalangeal joint is a difficult problem with numerous surgical techniques described. The purpose of the study is to demonstrate a technique in which a distally based extensor pollicis brevis tendon autograft is utilized to reconstruct the deficient volar plate. METHODS: This is a retrospective case series of four patients who were followed a minimum of 2 years after this procedure. Patient demographics, return to work status, and objective outcomes are reported. RESULTS: This technique compared favorably to those previously described, in terms of technical ease, functional results, and patient satisfaction. Each patient returned to his previous activity level and was maintained on active duty in his current military occupational specialty. None required a permanent profile to limit the physical demands of his job. CONCLUSIONS: Preliminary data suggests this technique is anatomically sound, technically less demanding, and requires minimal surgical dissection compared to previously described procedures. PMID- 26034462 TI - The "Thumbs-up" sign and trapeziometacarpal joint injection: a useful clinical indicator. AB - BACKGROUND: Several clinical studies investigating the accuracy and efficacy of trapeziometacarpal injection exist. Some studies utilize anatomical landmarks for proper injection placement while others utilize modalities including ultrasound and fluoroscopy. The changes of limb position that occur at the time of intra articular injection can provide valuable visual and tactile feedback to the clinician. The purpose of this study is to investigate the occurrence of the "Thumbs-up" sign with injection of the thumb trapeziometacarpal joint as a useful and reliable clinical indicator of intra-articular trapeziometacarpal injection and correlate level and duration of pain relief. METHODS: Trapeziometacarpal joint injections were performed on twenty-seven thumbs utilizing anatomic landmarks. At the time of injection, the presence or absence of the "Thumbs-up" sign was noted, and needle location was verified after injection with orthogonal mini-C arm fluoroscopic images. Visual analog pain scale scores were obtained pre injection and by follow-up telephone calls at 1 week, 6 weeks, and 3 months post injection. RESULTS: Twenty-four of twenty-seven injections demonstrated a positive "Thumbs-up" sign. There were three negative "Thumbs-Up" injections. The thumbs-up sign demonstrated a 92.3 % sensitivity. Eighteen of twenty-seven thumbs had sustained relief at 3 months post injection. CONCLUSIONS: The "Thumbs-up" sign is a practical clinical tool that gives the practitioner important visual feedback at the time of injection. Patient relaxation and joint compliance are limiting factors. The "Thumbs-up" sign is an inexpensive indicator of successful intra-articular injection and may obviate the need and expense of advanced imaging modalities at the time of injection. PMID- 26034463 TI - Comment on the article "Arm Ache" by H. A. Chabok and D. Ring, HAND, volume 9, number 2, pp. 151-155 (2014). PMID- 26034464 TI - Serum biomarkers of Burkholderia mallei infection elucidated by proteomic imaging of skin and lung abscesses. AB - BACKGROUND: The bacterium Burkholderia mallei is the etiological agent of glanders, a highly contagious, often fatal zoonotic infectious disease that is also a biodefense concern. Clinical laboratory assays that analyze blood or other biological fluids are the highest priority because these specimens can be collected with minimal risk to the patient. However, progress in developing sensitive assays for monitoring B. mallei infection is hampered by a shortage of useful biomarkers. RESULTS: Reasoning that there should be a strong correlation between the proteomes of infected tissues and circulating serum, we employed imaging mass spectrometry (IMS) of thin-sectioned tissues from Chlorocebus aethiops (African green) monkeys infected with B. mallei to localize host and pathogen proteins that were associated with abscesses. Using laser-capture microdissection of specific regions identified by IMS and histology within the tissue sections, a more extensive proteomic analysis was performed by a technique that combined the physical separation capabilities of liquid chromatography (LC) with the sensitive mass analysis capabilities of mass spectrometry (LC-MS/MS). By examining standard formalin-fixed, paraffin-embedded tissue sections, this strategy resulted in the identification of several proteins that were associated with lung and skin abscesses, including the host protein calprotectin and the pathogen protein GroEL. Elevated levels of calprotectin detected by ELISA and antibody responses to GroEL, measured by a microarray of the bacterial proteome, were subsequently detected in the sera of C. aethiops, Macaca mulatta, and Macaca fascicularis primates infected with B. mallei. CONCLUSIONS: Our results demonstrate that a combination of multidimensional MS analysis of traditional histology specimens with high-content protein microarrays can be used to discover lead pairs of host-pathogen biomarkers of infection that are identifiable in biological fluids. PMID- 26034465 TI - Integrated care services: lessons learned from the deployment of the NEXES project. AB - OBJECTIVES: To identify barriers to deployment of four articulated Integrated Care Services supported by Information Technologies in three European sites. The four services covered the entire spectrum of severity of illness. The project targeted chronic patients with obstructive pulmonary disease, cardiac failure and/or type II diabetes mellitus. SETTING: One health care sector in Spain (Barcelona) (n = 11.382); six municipalities in Norway (Trondheim) (n = 450); and one hospital in Greece (Athens) (n = 388). METHOD: The four services were: (i) Home-based long-term maintenance of rehabilitation effects (n = 337); (ii) Enhanced Care for frail patients, n = 1340); (iii) Home Hospitalization and Early Discharge (n = 2404); and Support for remote diagnosis (forced spirometry testing) in primary care (Support) (n = 8139). Both randomized controlled trials and pragmatic study designs were combined. Two technological approaches were compared. The Model for Assessment of Telemedicine applications was adopted. RESULTS: The project demonstrated: (i) Sustainability of training effects over time in chronic patients with obstructive pulmonary disease (p < 0.01); (ii) Enhanced care and fewer hospitalizations in chronic respiratory patients (p < 0.05); (iii) Reduced in-hospital days for all types of patients (p < 0.001) in Home Hospitalization/Early Discharge; and (iv) Increased quality of testing (p < 0.01) for patients with respiratory symptoms in Support, with marked differences among sites. CONCLUSIONS: The four integrated care services showed high potential to enhance health outcomes with cost-containment. Change management, technological approach and legal issues were major factors modulating the success of the deployment. The project generated a business plan to foster service sustainability and health innovation. Deployment strategies require site-specific adaptations. PMID- 26034466 TI - How to build and evaluate an integrated health care system for chronic patients: study design of a clustered randomised controlled trial in rural China. AB - BACKGROUND: While integrated health care system has been proved an effective way to help improving patient health and system efficiency, the exact behaviour model and motivation approach are not so clear in poor rural areas where health human resources and continuous service provision are urgently needed. To gather solid evidence, we initiated a comprehensive intervention project in Qianjiang District, southwest part of rural China in 2012. And after one-year's pilot, we developed an intervention package of team service, comprehensive pathway and prospective- and performance-based payment system. METHODS: To testify the potential influence of payment interventions, we use clustered randomised controlled trial, 60 clusters are grouped into two treatment groups and one control group to compare the time and group differences. Difference-in differences model and structural equation modelling will be used to analyse the intervention effects and pathway. The outcomes are: quality of care, disease burden, supplier cooperative behaviour and patient utilisation behaviour and system efficiency. Repeated multivariate variance analysis will be used to statistically examine the outcome differences. DISCUSSION: This is the first trial of its kind to prove the effects and efficiency of integrated care. Though we adopted randomised controlled trial to gather the highest rank of evidence, still the fully randomisation was hard to realise in health policy reform experiment. To compensate, the designer should take efforts on control for the potential confounders as much as possible. With this trial, we assume the effects will come from: (1) improvement on the quality of life through risk factors control and lifestyles change on patient's behaviours; (2) improvement on quality of care through continuous care and coordinated supplier behaviours; (3) improvement on the system efficiency through active interaction between suppliers and patients. CONCLUSION: The integrated care system needs collaborative work from different levels of caregivers. So it is extremely important to consider the supplier cooperative behaviour. In this trial, we introduced payment system to help the delivery system integration through providing financial incentives to motivate people to play their roles. Also, the multidisciplinary team, the multi institutional pathway and system global budget and pay-for-performance payment system could afford as a solution. PMID- 26034468 TI - Developing a Patient Care Co-ordination Centre in Trafford, England: lessons from the International Foundation for Integrated Care (IFIC)/Advancing Quality Alliance integrated care fellowship experience. AB - The NHS and Social Care in England are facing one of the biggest financial challenges for a generation. Commissioners and providers need to work on collaborative schemes to manage the increasing demand on health and social care within a period of financial constraint. Different forms of care co-ordination have been developed at different levels across the world. In the north-west of England, the Trafford health and social care economy have been working through a competitive dialogue process with industry to develop an innovative and dynamic solution to deliver seamless co-ordination for all patients and service users. The strategy is to develop a new Patient Care Co-ordination Centre, which will be responsible for the delivery of co-ordinated, quality care. The Patient Care Co ordination Centre will work at clinical, service, functional and community levels across multiple providers covering risk stratification, preventative, elective and unscheduled care. I am the clinical lead for the Patient Care Co-ordination Centre and during my year as an Advancing Quality Alliance Integrated Care Fellow, I have had the opportunity to study examples of care coordination from UK and international sites. The learning from these visits has been assimilated into the design process of the Patient Care Co-ordination Centre. PMID- 26034467 TI - Developing IntegRATE: a fast and frugal patient-reported measure of integration in health care delivery. AB - BACKGROUND: Efforts have been made to measure integration in health care delivery, but few existing instruments have adopted a patient perspective, and none is sufficiently generic and brief for administration at scale. We sought to develop a brief and generic patient-reported measure of integration in health care delivery. METHODS: Drawing on both existing conceptualisations of integrated care and research on patients' perspectives, we chose to focus on four distinct domains of integration: information sharing, consistent advice, mutual respect and role clarity. We formulated candidate items and conducted cognitive interviews with end users to further develop and refine the items. We then pilot tested the measure. RESULTS: Four rounds of cognitive interviews were conducted (n = 14) and resulted in a four-item measure that was both relevant and understandable to end users. The pilot administration of the measure (n = 15) further confirmed the relevance and interpretability of items and demonstrated that the measure could be completed in less than one minute. CONCLUSIONS: This new measure, IntegRATE, represents a patient-reported measure of integration in health care delivery that is conducive to use in both routine performance monitoring and research. The psychometric properties of the measure will be assessed in the next stage of development. PMID- 26034470 TI - Payment and economic evaluation of integrated care. PMID- 26034469 TI - Provider accountability as a driving force towards physician-hospital integration: a systematic review. AB - BACKGROUND: Hospitals and physicians lie at the heart of our health care delivery system. In general, physicians provide medical care and hospitals the resources to deliver health care. In the past two decades many countries have adopted reforms in which provider financial risk bearing is increased. By making providers financially accountable for the delivered care integrated care delivery is stimulated. PURPOSE: To assess the evidence base supporting the relationship between provider financial risk bearing and physician-hospital integration and to identify the different types of methods used to measure physician-hospital integration to evaluate the functional value of these integrative models. RESULTS: Nine studies met the inclusion criteria. The evidence base is mixed and inconclusive. Our methodological analysis of previous research shows that previous studies have largely focused on the formal structures of physician hospital arrangements as an indicator of physician-hospital integration. CONCLUSION: The link between provider financial risk bearing and physician hospital integration can at this time be supported merely on the basis of theoretical insights of agency theory rather than empirical research. Physician hospital integration measurement has concentrated on the prevalence of contracting vehicles that enables joint bargaining in a managed care environment but without realizing integration and cooperation between hospital and physicians. Therefore, we argue that these studies fail to shed light on the impact of risk shifting on the hospital-physician relationship accurately. PMID- 26034471 TI - Pure laparoscopic hepatectomy combined with a pure laparoscopic pringle maneuver in patients with severe cirrhosis. AB - Laparoscopic hepatectomy is a standard surgical procedure. However, it is difficult to perform in patients with severe cirrhosis because of fibrosis and a high risk of hemorrhage. We report our recent experience in five cases of pure laparoscopic hepatectomy combined with a pure laparoscopic Pringle maneuver in patients with severe cirrhosis. From 2012 to 2014, we performed pure laparoscopic partial hepatectomy in five patients with severe liver cirrhosis (indocyanine green retention rate at 15 min [ICG R15] >30% and fibrosis stage f4). A pure laparoscopic Pringle maneuver was employed in all patients. We investigated operative time, blood loss, duration of hospitalization and the days when discharge was possible, and compared these findings with those of patients with a normal liver (ICG R15 <10%, f0) who underwent pure laparoscopic partial hepatectomy during the same period (n = 7). As a result, operative time, blood loss, duration of hospitalization and the days when discharge was possible were similar in patients with cirrhosis undergoing pure laparoscopic hepatectomy combined with a pure laparoscopic Pringle maneuver to those in patients with a normal liver undergoing pure laparoscopic partial hepatectomy. In conclusion, pure laparoscopic hepatectomy combined with a pure laparoscopic Pringle maneuver appears to be safe in patients with severe cirrhosis. PMID- 26034472 TI - New Onset, Aggravation and Recurrence of Crohn's Disease upon Treatment with Three Different Tumor Necrosis Factor Inhibitors. AB - Tumor necrosis factor (TNF) is a major cytokine in the pathogenesis of inflammatory bowel disease (IBD), and TNF inhibition is a cornerstone of contemporary IBD therapy. However, paradoxical induction of IBD has recently been reported upon treatment of rheumatologic disorders with TNF inhibitors. In previous cases, induction of IBD was associated with one single drug and IBD was successfully managed by switching TNF inhibitors. We report the case of a patient with juvenile rheumatoid arthritis under long-term treatment with etanercept. After switching TNF inhibition to adalimumab, symptoms of Crohn's disease (CD) occurred and the diagnosis of CD was established by endoscopy. Further treatment with adalimumab and subsequently infliximab aggravated the abdominal symptoms, necessitating ileocecal resection, after which symptoms resolved for several months. Etanercept treatment due to recurrent rheumatologic symptoms was followed by recurrent CD symptoms and findings, which resolved upon discontinuation of etanercept. This case suggests that induction, aggravation and recurrence of IBD can be rare class effects of TNF inhibition. PMID- 26034473 TI - Prolonged Survival in a Case of Chemotherapy-Sensitive Gastric Cancer That Produced Alpha-Fetoprotein and Protein Induced by Vitamin K Antagonist-II. AB - The number of reported cases of alpha-fetoprotein (AFP)-producing gastric cancer has gradually increased, with a reported prevalence of 1.3-1.5% of all gastric cancer cases. However, reports of gastric cancer accompanied by elevated serum levels of both AFP and protein induced by vitamin K antagonist-II (PIVKA-II) are rare. The prognosis of AFP- and PIVKA-II-producing gastric cancer has been reported to be very poor because the tumor cells were considered to have a high malignant potential and the cancer progressed rapidly. We described a case of gastric cancer producing AFP and PIVKA-II in which chemotherapy was effective and resulted in prolonged survival, and these two tumor markers were useful for monitoring the treatment response. Routine health screening using upper abdominal ultrasonography revealed hepatic tumors in an apparently healthy 65-year-old man. Whole-body computed tomography (CT) revealed multiple hepatic tumors, and an esophagogastroduodenoscopy (EGD) revealed a Bormann type 3 tumor in the lower stomach. A biopsy specimen confirmed that the tumor was immunohistochemically positive for AFP, PIVKA-II, and human epidermal growth factor receptor 2. After chemotherapy, the gastric tumor appeared as a small elevated lesion on EGD, and CT revealed a remarkable reduction in the size of the metastatic liver tumors. The patient is still alive, 35 months after the initial chemotherapy. PMID- 26034474 TI - Early squamous cell carcinoma of the anal canal resected by endoscopic submucosal dissection. AB - The standard treatment approach for squamous cell carcinoma (SCC) of the anal canal includes abdominoperineal resection and chemoradiotherapy. However, there are currently very few reports of early SCC of the anal canal resected by endoscopic submucosal dissection (ESD). We report 2 rare cases of SCC of the anal canal resected by ESD. In case 1, a 66-year-old woman underwent a colonoscopy due to blood in her stool, and an elevated lesion, 15 mm in size, was identified from the rectum to the dentate line of the anal canal on internal hemorrhoids. The lesion was diagnosed as an early SCC of the anal canal, and ESD was successfully performed. The histopathological diagnosis was SCC in situ. In case 2, a 71-year old woman underwent a colonoscopy due to constipation, and an elevated lesion, 25 mm in size, was identified from the dentate line to the anal canal. The lesion was diagnosed as early-stage SCC of the anal canal, and ESD was successfully performed. The histopathological diagnosis was SCC in situ. No complications or recurrence after ESD occurred in either case. PMID- 26034475 TI - Cutaneous Manifestations in POEMS Syndrome: Case Report and Review. AB - The authors report a case of sensorimotor polyneuropathy, diffuse cutaneous hyperpigmentation, skin sclerodermiform thickening and papular lesions in the infraclavicular and abdominal region. Besides weight loss, there were diabetes mellitus and hypothyroidism. The alterations were consistent with POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes) syndrome, which is a rare systemic disease with monoclonal proliferation of plasmacytes and slow progression. Cutaneous alterations are present in 68% of patients with diffuse cutaneous hyperpigmentation, plethora and acrocyanosis. Leukonychia, necrotizing vasculitis, hypertrichosis and cutaneous thickening of sclerodermiform type are also cited. The onset of multiple cutaneous angiomas in this syndrome has been observed in 24-44% of patients. PMID- 26034476 TI - Adult-onset acquired partial lipodystrophy accompanied by rheumatoid arthritis. AB - Lipodystrophy is a group of metabolic disorders, possibly caused by autoimmune disease. In this report, we describe a case of adult-onset acquired partial lipodystrophy accompanied by rheumatoid arthritis without a family history. Interestingly, immunohistochemical staining revealed dense infiltration of IL-27 producing cells as well as MMP-7-and MMP-28-expressing cells, both of which have been reported to facilitate the development of autoimmune disease. Our present case might suggest possible mechanisms for acquired partial lipodystrophy. PMID- 26034477 TI - Basal cell carcinoma arising from an epidermal cyst: when a cyst is not a cyst. AB - Malignant degeneration within epidermal cysts is very rare. However, these lesions may not be recognised clinically, and histological examination plays an important role in arriving at a correct diagnosis. Hence, we believe that benign looking cystic lesions with a history of progressive growth should be surgically excised and submitted for histopathological assessment. PMID- 26034478 TI - Eosinophilic fasciitis associated with myositis. AB - Eosinophilic fasciitis is clinically characterized by symmetrical scleroderma like indurations of the skin with pain. The histological features are fascial inflammation with lymphocytes and eosinophils as well as thickened and fibrotic fascia. Lymphocytic infiltration and degeneration of the underlying muscle are rarely observed. We report a 69-year-old Japanese woman who presented with multiple areas of glossy induration and painful peau d'orange-like lesions on the chest and four extremities. T2-weighted magnetic resonance imaging showed significant hyperintense thickening of the fascia of the lower extremities. Histopathological examination of a biopsy specimen from the induration showed marked fibrinoid degeneration of the fascia and the neighboring muscle with mixed cellular infiltration of lymphocytes and eosinophils. The predominant CD8+ lymphocytic infiltrates were observed by immunohistological study. A diagnosis of eosinophilic fasciitis with myositis was made. Oral administration of prednisolone and discontinuation of exercise significantly improved the lesions and pain. PMID- 26034479 TI - Idiopathic Relapsing Thrombotic Thrombocytopenic Purpura with Persistent ADAMTS13 Inhibitor Activity Treated Sequentially with Plasmapheresis, Rituximab, Cyclophosphamide and Splenectomy. AB - We here describe a patient with an idiopathic thrombotic thrombocytopenic purpura (TTP) secondary to an ADAMTS13 inhibitor that continued to be dependent on plasmapheresis until the patient was treated with rituximab. TTP manifestations subsided with rituximab treatment in spite of a persistently low ADAMTS13 activity and continued a detectable inhibitor activity until the patient developed an intolerance to rituximab due to an allergic reaction when cyclophosphamide was added; this resulted in a normalization of ADAMTS13 activity and the disappearance of the inhibitor. Later, the patient developed an intolerance to rituximab due to a severe allergic reaction. Soon after stopping rituximab, the ADAMTS13 activity level dipped below 5% in addition to the appearance of the ADAMTS13 inhibitor. The patient had a splenectomy after rituximab and cyclophosphamide treatment; the medication was stopped based on several case reports of a complete remission of TTP after splenectomy. We believe that the reason TTP went into remission in our patient was because of rituximab treatment, in spite of both persistently low ADAMTS13 activity and a detectable inhibitor activity due to reducing the release of von Willebrand factor large multimers from the endothelial cells. We found that ADAMTS13 activity normalized and the inhibitor activity became undetectable when cyclophosphamide was added to rituximab. We suggest adding cyclophosphamide to rituximab for the treatment of patients with persistent ADAMTS13 inhibitors in order to prolong the remission period and lower the rate of relapse. PMID- 26034480 TI - Various neurological symptoms by neurolymphomatosis as the initial presentation of primary testicular lymphoma. AB - Neurological symptoms induced by the infiltration of malignant lymphoma into the nervous systems are subsumed under the term neurolymphomatosis (NL). Here, we report the case of a 30-year-old Japanese man with primary testicular lymphoma complicated, as seen in various neurological findings, by secondary NL prior to testicular swelling. Painless right scrotal enlargement was noticed more than 1 month after the appearance of neurological complications such as right upper extremity numbness, dysarthria, facial palsy, and diplopia. Proactive investigation and biopsies of extranodal sites at high risk of central nervous system infiltration of malignant lymphoma, such as the testes, should be considered when secondary NL is suspected based on imaging findings. PMID- 26034481 TI - A Case of Renal Primitive Neuroectodermal Tumor Confirmed by Fluorescence in situ Hybridization. AB - Primitive neuroectodermal tumor (PNET) is a member of the Ewing's sarcoma family of tumors (ESFT). We report a case of PNET in a 66-year-old male who presented with a large solid tumor within the parenchyma of the middle pole of the left kidney with metastases to the left adrenal gland and right ischium. A fine-needle biopsy was performed and showed a small round cell tumor. Results of immunohistochemical staining suggested this tumor belonged to ESFT. Preoperative VDC-IE (combined vincristine, doxorubicin and cyclophosphamide followed by another combination of ifosfamide and etoposide) chemotherapy and left radical nephrectomy and adrenalectomy were performed. The histopathological findings of the resected tumor were similar to those in the biopsy specimen, but the results of AE1/AE3 were different. For the diagnosis, fluorescence in situ hybridization was performed. Split signals of the EWSR1 gene were detected, and transmission electron microscopy showed neuroendocrine granules and microtubules. The final diagnosis of this tumor was PNET of the kidney. PMID- 26034482 TI - Successful treatment with s-1 and oxaliplatin combination therapy in an elderly patient with metastatic colorectal cancer initially presenting with membranous nephropathy. AB - The incidence, morbidity, and mortality of colorectal cancer are increasing, largely owing to an increasingly aging population. Additionally, along with the increasing age of cancer patients, the number of patients with various comorbidities such as membranous nephropathy is also rising, and problems associated with the administration of chemotherapy to elderly patients with these conditions are becoming more common. Herein, we describe a case involving an 80 year-old woman who presented with general malaise, edematous limbs, and pleural effusion. An abdominal CT revealed multiple, relatively large, metastatic lesions in a wide area of the liver and left pleural effusion, and she was accordingly diagnosed with membranous nephropathy secondary to ascending colon cancer and multiple liver metastases. Despite her advanced age and the presence of membranous nephropathy, her general condition was favorable and chemotherapy was hence administered. Taking the toxicity profiles and the patient's preference into consideration, S-1 and oxaliplatin (SOX) therapy was selected, which showed a good tolerability. An abdominal CT after 8 cycles of SOX therapy revealed a marked reduction in the metastatic lesions in the liver and a decrease in the left pleural effusion, and the levels of tumor markers also decreased (partial response). At the latest follow-up, after the completion of 16 cycles, the condition of the patient remained stable, without any apparent signs of progressive disease. Based on this case, we conclude that, even for elderly patients with systemic complications or comorbid diseases, standard treatments should be considered after their general conditions, and therapeutic regimens have been sufficiently examined. PMID- 26034483 TI - Pilocytic astrocytoma presenting as an orbital encephalocele: a case report. AB - We describe the case of a 29-year-old male who presented with new-onset seizures. He was subsequently found to have an orbital encephalocele containing a focus of pilocytic astrocytoma. We believe that this is the first report of a pilocytic astrocytoma located within the orbit that did not originate from the optic pathway. It is also the first case of a pilocytic astrocytoma completely contained within an encephalocele. This case suggests a close pathological examination of encephaloceles for underlying diseases. PMID- 26034484 TI - A Case Report of Listeria monocytogenes Abscesses Presenting as Cortically Predominant Ring-Enhancing Lesions. AB - INTRODUCTION: Listeria monocytogenes, a common cause of bacterial meningitis, rarely involves the central nervous system (CNS) in the form of multiple cerebral ring-enhancing lesions. METHODS: An 81-year-old woman with rapidly progressive decline in her mental status in the setting of multiple cortically predominant ring-enhancing lesions was transferred to our institution. A mild upper respiratory tract infection and diarrhea symptoms preceded the mental status deterioration. Her past medical history is significant for type 2 diabetes mellitus. In light of the patient's age, the presence of hyponatremia and the history of diabetes mellitus, the empiric antimicrobial treatment was modified to include ampicillin, meropenem, vancomycin, voriconazole and pyrimethamine/sulfadiazine to prevent opportunistic infections. Intravenous dexamethasone was added due to significant perilesional vasogenic edema. RESULTS: The patient presented with stupor, but neither fever nor leukocytosis. CSF results were significant only for a mildly elevated protein level. The report of a repeat brain MRI was as follows: large areas of high FLAIR signals and tubular/lobulated/ring enhacement in bifrontal regions with a smaller focus in the left anterior midbrain, indicating for underlying multicentric glioma or multicentric primary CNS lymphoma. A brain biopsy, however, revealed an early abscess formation caused by a L. monocytogenes infection. CONCLUSION: A high index of suspicion in patients with risk factors for this infection is key to ensure the timely initiation of appropriate empirical antibiotic therapy in the setting of cerebral ring-enhancing lesions. Intravenous ampicillin is the treatment of choice, but meropenem represents a valid alternative. PMID- 26034485 TI - Brown-McLean Syndrome in a Pediatric Patient. AB - The purpose of this manuscript is to report the case of a 12-year-old patient who presented for routine ophthalmic examination after congenital cataract surgery performed at 2 months of age. The patient was diagnosed with bilateral Brown McLean syndrome by slit lamp examination. No treatment was required because the patient was asymptomatic and had a clear central cornea. This is the first described case of Brown-McLean syndrome in a pediatric patient, representing the importance of clinical examination in the pediatric age group after cataract surgery because of the risk for patients of developing peripheral edema. PMID- 26034486 TI - A Case of Acute Bilateral Irvine-Gass Syndrome following Uncomplicated Phacoemulsification, Demonstrated with Optical Coherence Tomography. AB - PURPOSE: To report a case of acute bilateral Irvine-Gass syndrome. METHODS: This is an observational case report. RESULTS: An 82-year-old man with no significant ocular history developed postsurgical pseudophakic cystoid macular edema (CME; Irvine-Gass syndrome) on consecutive phacoemulsification cataract surgeries. His initial first-eye (left) CME developed 25 days after surgery and was managed with topical preparations of dexamethasone 0.1% and ketorolac 0.4%, in addition to a routine post-cataract surgery drop regime. His left CME resolved completely on optical coherence tomography (OCT) by day 100, and he subsequently (after extensive discussion of CME risks) underwent cataract surgery on his right eye. He was commenced prophylactically on dexamethasone, ketorolac and oral indomethacin 25 mg t.d.s. immediately after surgery; however, he later developed CME (OD) on day 32 postoperatively. Within 6 months, he achieved complete resolution of his CME in both eyes. His clinical course was documented with serial OCT studies. CONCLUSION: Irvine-Gass syndrome remains an important differential diagnosis in the evaluation of blurred vision after cataract surgery, despite decreasing incidence. Those who experience CME following their first cataract operation should be counseled about the risks of developing the condition in the contralateral eye, despite prophylactic measures. PMID- 26034488 TI - Cognitive impact of lacunar infarcts and white matter hyperintensity volume. AB - BACKGROUND: Subcortical lacunar infarcts and white matter hyperintensities (WMH) are common neuroradiological findings, but few studies associate between these insults and cognition in a community-dwelling population. METHODS: The Dallas Heart Study is a population-based initiative whose assessments included demographic and clinical findings including brain MRI and the Montreal Cognitive Assessment (MoCA). The presence and number of lacunes in subjects aged over 55 years were assessed by study physicians. The WMH volume was measured by an automated method. The association between the presence and number of lacunar infarcts and of WMH volume with the total MoCA score and subdomains was assessed using linear regression with adjustment for age, gender and self-reported ethnicity. RESULTS: In 609 subjects with valid data, both the presence and the increasing number of lacunes were associated with lower MoCA scores, even after adjusting for demographic variables. The presence of lacunes was also associated with lower scores in the memory, executive and attention subdomains. The WMH volume was not significantly associated with the MoCA score. CONCLUSION: The presence and increasing number of lacunes in midlife is associated with a lower performance in multiple domains of a cognitive screening measure after adjusting for demographic factors. PMID- 26034487 TI - Early mobilization in ischemic stroke: a pilot randomized trial of safety and feasibility in a public hospital in Brazil. AB - BACKGROUND: The effect of early mobilization after acute stroke is still unclear, although some studies have suggested improvement in outcomes. We conducted a randomized, single-blind, controlled trial seeking to evaluate the feasibility, safety, and benefit of early mobilization for patients with acute ischemic stroke treated in a public teaching hospital in Southern Brazil. This report presents the feasibility and safety findings for the pilot phase of this trial. METHODS: The primary outcomes were time to first mobilization, total duration of mobilization, complications during early mobilization, falls within 3 months, mortality within 3 months, and medical complications of immobility. We included adult patients with CT- or MRI-confirmed ischemic stroke within 48 h of symptom onset who were admitted from March to November 2012 to the acute vascular unit or general emergency unit of a large urban emergency department (ED) at the Hospital de Clinicas de Porto Alegre. The severity of the neurological deficit on admission was assessed by the National Institutes of Health Stroke Scale (NIHSS). The NIHSS and modified Rankin Scale (mRS, functional outcome) scores were assessed on day 14 or at discharge as well as at 3 months. Activities of daily living (ADL) were measured with the modified Barthel Index (mBI) at 3 months. RESULTS: Thirty-seven patients (mean age 65 years, mean NIHSS score 11) were randomly allocated to an intervention group (IG) or a control group (CG). The IG received earlier (p = 0.001) and more frequent (p < 0.0001) mobilization than the CG. Of the 19 patients in the CG, only 5 (26%) underwent a physical therapy program during hospitalization. No complications (symptomatic hypotension or worsening of neurological symptoms) were observed in association with early mobilization. The rates of complications of immobility (pneumonia, pulmonary embolism, and deep vein thrombosis) and mortality were similar in the two groups. No statistically significant differences in functional independence, disability, or ADL (mBI >=85) were observed between the groups at the 3-month follow-up. CONCLUSIONS: This pilot trial conducted at a public hospital in Brazil suggests that early mobilization after acute ischemic stroke is safe and feasible. Despite some challenges and limitations, early mobilization was successfully implemented, even in the setting of a large, complex ED, and without complications. Patients from the IG were mobilized much earlier than controls receiving the standard care provided in most Brazilian hospitals. PMID- 26034489 TI - Effect Estimation of an Innovative Nursing Intervention to Improve Delirium among Home-Dwelling Older Adults: A Randomized Controlled Pilot Trial. AB - AIMS: Estimating the effect of a nursing intervention in home-dwelling older adults on the occurrence and course of delirium and concomitant cognitive and functional impairment. METHODS: A randomized clinical pilot trial using a before/after design was conducted with older patients discharged from hospital who had a medical prescription to receive home care. A total of 51 patients were randomized into the experimental group (EG) and 52 patients into the control group (CG). Besides usual home care, nursing interventions were offered by a geriatric nurse specialist to the EG at 48 h, 72 h, 7 days, 14 days, and 21 days after discharge. All patients were monitored for symptoms of delirium using the Confusion Assessment Method. Cognitive and functional statuses were measured with the Mini-Mental State Examination and the Katz and Lawton Index. RESULTS: No statistical differences with regard to symptoms of delirium (p = 0.085), cognitive impairment (p = 0.151), and functional status (p = 0.235) were found between the EG and CG at study entry and at 1 month. After adjustment, statistical differences were found in favor of the EG for symptoms of delirium (p = 0.046), cognitive impairment (p = 0.015), and functional status (p = 0.033). CONCLUSION: Nursing interventions to detect delirium at home are feasible and accepted. The nursing interventions produced a promising effect to improve delirium. PMID- 26034490 TI - Molecular detection and antimicrobial resistance of Pseudomonas aeruginosa from houseflies (Musca domestica) in Iran. AB - BACKGROUND: Pseudomonas aeruginosa is a common bacterium that can cause disease in humans and other animals. This study was conducted to screen for molecular detection and antimicrobial-resistant P. aeruginosa in Musca domestica in different locations in the Iranian provinces of Shahrekord and Isfahan. METHODS: Musca domestica were captured by both manual and sticky trap methods, during the daytime, from household kitchens, cattle farms, animal hospitals, human hospitals, slaughterhouses and chicken farms at random locations in Shahrekord and Isfahan provinces of Iran, and subsequently transported to the laboratory for detection of P. aeruginosa. In the laboratory, flies were identified and killed by refrigeration in a cold chamber at -20 degrees C, then placed in 5 mL peptone water and left at room temperature for five hours before being processed. Pseudomonas isolates were preliminarily identified to genus level based on colony morphology and gram staining, and their identity was further confirmed by polymerase chain reaction. RESULTS: Overall blaTEM gene was recovered from 8.8 % (53/600) of the P. aeruginosa isolated from houseflies collected from the two provinces. A slightly higher prevalence (10.7 %; 32/300) was recorded in Shahrekord province than Isfahan province (7.0 %; 21/300). The locations did not differ statistically (p < 0.05) in bacterial prevalence in flies. Seasonal prevalence showed a significantly lower infection frequency during autumn. CONCLUSIONS: Houseflies are important in the epidemiology of P. aeruginosa infections. PMID- 26034491 TI - A new two-step accurate CT-MRI fusion technique for post-implant prostate cancer. AB - PURPOSE: To develop an accurate method of fusing computed tomography (CT) with magnetic resonance imaging (MRI) for post-implant dosimetry after prostate seed implant brachytherapy. MATERIAL AND METHODS: Prostate cancer patients were scheduled to undergo CT and MRI after brachytherapy. We obtained the three MRI sequences on fat-suppressed T1-weighted imaging (FST1-WI), T2-weighted imaging (T2-WI), and T2*-weighted imaging (T2*-WI) in each patient. We compared the lengths and widths of 450 seed source images in the 10 study patients on CT, FST1 WI, T2-WI, and T2*-WI. After CT-MRI fusion using source positions by the least squares method, we decided the center of each seed source and measured the distance of these centers between CT and MRI to estimate the fusion accuracy. RESULTS: The measured length and width of the seeds were 6.1 +/- 0.5 mm (mean +/- standard deviation) and 3.2 +/- 0.2 mm on CT, 5.9 +/- 0.4 mm, and 2.4 +/- 0.2 mm on FST1-WI, 5.5 +/- 0.5 mm and 1.8 +/- 0.2 mm on T2-WI, and 7.8 +/- 1.0 mm and 4.1 +/- 0.7 mm on T2*-WI, respectively. The measured source location shifts on CT/FST1-WI and CT/T2-WI after image fusion in the 10 study patients were 0.9 +/- 0.4 mm and 1.4 +/- 0.2 mm, respectively. The shift on CT/FST1-WI was less than on CT/T2-WI (p = 0.005). CONCLUSIONS: For post-implant dosimetry after prostate seed implant brachytherapy, more accurate fusion of CT and T2-WI is achieved if CT and FST1-WI are fused first using the least-squares method and the center position of each source, followed by fusion of the FST1-WI and T2-WI images. This method is more accurate than direct image fusion. PMID- 26034492 TI - The impact of a vaginal brachytherapy boost to pelvic radiation in stage III endometrial cancer. AB - PURPOSE: We investigate the use and impact of a vaginal brachytherapy boost (VBB) after pelvic radiotherapy for stage III endometrial adenocarcinoma on vaginal and pelvic control. MATERIAL AND METHODS: One hundred patients treated from 1998-2011 with surgery and adjuvant therapy with or without a VBB were included. Variables examined were grade, stage, lymphovascular space invasion (LVSI), vaginal involvement (VI), cervical stromal involvement (CSI), myometrial invasion (MI), and a VBB. Failure was scored as vaginal, or pelvic. Fisher's exact test assessed association between variables with vaginal and pelvic control. RESULTS: With a median follow up of 43 months, 31% were stage IIIA, 6% stage IIIB, and 63% stage IIIC. Thirty-eight (38%) received pelvic radiotherapy alone, and 62% received adjuvant chemotherapy. Of the 100 patients, 82 were treated with a VBB, 10 were not treated with a VBB, and 8 were not treated with RT. Of the 82 patients who received a VBB, 5 failed in the vagina with vaginal and pelvic control rates of 94% and 92%. The impact of VB reached borderline significance with its impact on pelvic control, 92% vs. 70% (p = 0.056), and did not affect vaginal control, 94% and 90% (p = 0.50). Neither tumor grade, LVSI, CSI, stage, nor LVSI (p > 0.05) statistically significantly impacted vaginal control. CONCLUSIONS: There are no clinical guidelines for the use of a VBB in stage III endometrial cancer. The majority of our patients were treated with a VBB and experienced excellent pelvic and vaginal control. The presence of traditional adverse features did not negatively impact control in our patient cohort. However, the role of a VBB needs further investigation to understand the incremental benefit beyond pelvic RT. PMID- 26034493 TI - A study of high-dose-rate intracavitary brachytherapy boost for curative treatment of uterine cervical cancer. AB - PURPOSE: This study assessed the trial of boost intracavitary brachytherapy (ICBT) for the patients of uterine cervical cancer with residual malignant cells detected at the final stage of ICBT. MATERIAL AND METHODS: This is a retrospective analysis of 75 patients with cervical cancer treated radically with external beam radiotherapy and high-dose-rate intracavitary brachytherapy between August 2004 and December 2008. Eighteen patients (24%) out of 75 received one additional ICBT and five patients (7%) had two additional ICBT. All 75 patients were retrospectively analyzed. The median follow-up time was 30 months. The median age was 59 years (range 28-85 years). There were 12 patients (16%) in stage IB, 27 (36%) stage II, 22 (29%) stage III, and 14 (19%) stage IV. RESULTS: The 5-year overall survival rate was 65%. Non-hematological toxicities greater than grade 2 occurred in 12 patients (16%). Of these, only two patients received on additional ICBT. No significant difference was found in grade 3 toxicity between patients who did and did not receive additional ICBT (p = 0.8). CONCLUSIONS: The method to perform dose escalation should be examined depending on the treatment response. PMID- 26034494 TI - Is there a subset of patients with recurrent cancer in the vagina who are not candidates for interstitial brachytherapy that can be treated with multichannel vaginal brachytherapy using graphic optimization? AB - PURPOSE: To evaluate recurrent vaginal cancer treated with vaginal brachytherapy (VBT) using graphic optimization in patients not amenable to surgery and interstitial brachytherapy (ISBT). MATERIAL AND METHODS: We retrospectively reviewed the records of 5 patients with recurrent cancer in the vagina that were deemed not to be good candidates for ISBT implant because of medical reasons. All patients received computed tomography/magnetic resonance imaging (CT/MRI) based evaluation in addition to a detailed clinical examination, and were noted to have recurrent nodules in the vagina with size ranging from 10-25 mm. Four of the 5 patients had recurrent disease in the vaginal apex, whereas one patient had recurrence in the lateral vaginal wall. Subsequently, all patients were treated with external beam radiation therapy (EBRT) followed by multichannel vaginal cylinder (MVC)-based VBT using graphic optimization for shaping the isodose to improve the clinical target volume (CTV) coverage, as well as to spare the organs at risk (OAR). The dose to the bladder and rectum with regard to 0.1 cc, 1 cc, and 2 cc were recorded. RESULTS: Median age of the patients was 78 years (range 58-86 years). Thickness of the lesions before VBT ranged from 6-15 mm. All patients were followed up with MRI at 3 months. All patients but one demonstrated complete clinical/ radiological response of the tumor. No patient had any grade III/IV toxicity at 24 months. CONCLUSIONS: MVC-based VBT using graphic optimization is safe and yields favorable results if used judiciously. PMID- 26034496 TI - Dosimetric analysis and clinical outcomes in CT-based mould brachytherapy in early oral cancers in patients unfit for surgery. AB - PURPOSE: Brachytherapy in the oral cavity is an important alternative to conventional treatment, and provides a high localized dose and short overall treatment time. A rapid fall of dose beyond radioactive source makes it possible for increased tumour control and sparing surrounding tissue, while short overall treatment duration reduces risk of tumour repopulation. Moulds are fabricated to hold the catheters in position as closely as possible to tumour surface to provide adequate dose coverage of tumour volume and increase distance to other normal surrounding structures. Image based planning and dose optimisation help in better defining target volume and dose coverage. MATERIAL AND METHODS: A retrospective analysis of patients of early squamous cell carcinomas of lip and buccal mucosa from September 2011 to June 2014 to study response to mould brachytherapy. Double plane moulds were prepared for all lip cancer cases and single plane for buccal mucosa cases. Patients are being followed up till disease recurrence. In this study evaluation was done of the technique used, planning details, response to therapy, and reactions encountered. RESULTS: Nine patients treated by mould therapy were reviewed; seven cases were of lip and two of buccal mucosal cancers. Dose delivered ranged from 12.5-48 Gy in fraction sizes of 2.5 3.5 Gy. Equivalent dose in 2 Gy fractions (EQD2) ranged from 18-64 Gy. Maximum dose to organs at risk (OAR) was 91% of prescribed dose. Local mucositis was only reaction in all cases, which resolved in 3-6 weeks. Median follow-up was 19 months. Eight out of nine patients are in remission at a minimum of 7 months (1 case, rest over 14 months) post therapy and only patient had nodal recurrence at 18 months. CONCLUSIONS: Mould therapy is an effective treatment method for selected early and superficial squamous cell carcinomas of the oral cavity, although indications are limited. PMID- 26034495 TI - Evaluation of neuropathic pain occurring after high-dose-rate interstitial brachytherapy of oral tongue. AB - PURPOSE: To recognize neuropathic pain as a complication of high-dose-rate (HDR) interstitial brachytherapy of oral tongue and to evaluate the possible causes of neuropathy. MATERIAL AND METHODS: Twenty one patients who underwent interstitial brachytherapy for early cancer of oral tongue were evaluated. The patients either underwent primary brachytherapy (42-48 Gy at 3-4 Gy/fraction) or a boost (18-24 Gy at 3 Gy/fraction) after external radiation to 40 Gy. Lingual nerve was the nerve concerned and the sublingual space (SLS) was contoured as its surrogate. Dosimetric parameters were correlated with onset of pain. RESULTS: Ten patients out of 21 (47.61%) developed painful neuropathy. Five patients of six (5/6) who underwent primary brachytherapy developed neuropathy. Five out of 15 (5/15) patients who underwent brachytherapy as a boost developed neuropathy. The patients who underwent primary brachytherapy were ten times more likely to develop neuropathy. Among the patients receiving boost treatment, the equivalent dose at 2 Gy/fraction (EQD2) to 2 cc of SLS was higher (39.25 Gy) in the patients who developed pain compared to those without pain (10.29 Gy). CONCLUSIONS: This is the first report to recognize neuropathic pain as a complication of HDR brachytherapy of oral tongue. Patients undergoing primary brachytherapy were more likely to develop pain. Among other factors like dose to SLS, number of catheters, size of the primary tumor, and the dose rate, only dose to 2 cc of the SLS correlated with onset of pain. The SLS (containing the lingual nerve) may be considered an organ at risk to prevent the occurrence of this complication. PMID- 26034497 TI - Efficacy and safety of image-guided interstitial single fraction high-dose-rate brachytherapy in the management of metastatic malignant melanoma. AB - PURPOSE: Computed tomography (CT) or magnetic resonance imaging (MRI) guided brachytherapy provides high tumor control rates in hepatocellular carcinoma (HCC) and colorectal liver metastases. In contrast to thermal ablation methods such as radiofrequency ablation (RFA), much less restrictions apply with respect to tumor location or size. In this study, we determined the efficacy and safety of CT- or MRI-guided brachytherapy in metastatic melanoma. MATERIAL AND METHODS: Fifty-two metastases of malignant melanoma in 14 patients were included in this retrospective study. Local tumor control and safety were evaluated as primary and secondary endpoints. Furthermore, we evaluated overall survival and progression free survival. Tumor locations were liver (n = 31), lung (n = 15), adrenal (n = 3), lymph nodes (n = 2), and kidney (n = 1). Treatment planning was performed using three-dimensional CT or MRI data acquired after percutaneous applicator positioning under CT or open MRI guidance. Subsequently, single fraction high dose-rate (HDR) brachytherapy was applied using a (192)Iridium source. Clinical and cross-sectional follow-up were performed every 3 months post intervention. RESULTS: The median diameter of treated lesions was 1.5 cm (range: 0.7-10 cm). Doses between 15 and 20 Gy were applied (median dose: 19.9 Gy). The mean irradiation time ranged between 7-45 minutes. After treatment, there was one patient with a cholangitis. After a median follow up of five months, the median local tumor control was 90%. The median overall survival of the patients was 8 months. The median progression free survival of the patients was 6 months. CONCLUSIONS: Image-guided HDR brachytherapy is a safe and effective treatment procedure in metastatic malignant melanoma. PMID- 26034498 TI - Tandem-ring dwell time ratio in Nigeria: dose comparisons of two loading patterns in standard high-dose-rate brachytherapy planning for cervical cancer. AB - PURPOSE: In high-dose-rate (HDR) brachytherapy (BT), the source dwell times and dwell positions are essential treatment planning parameters. An optimal choice of these factors is fundamental to obtain the desired target coverage with the lowest achievable dose to the organs at risk (OARs). This study evaluates relevant dose parameters in cervix brachytherapy in order to assess existing tandem-ring dwell time ratio used at the first HDR BT center in Nigeria, and compare it with an alternative source loading pattern. MATERIAL AND METHODS: At the Radiotherapy Department, University College Hospital (UCH), Ibadan, Nigeria, a total of 370 standard treatment plans in two alternative sets were generated with HDR basic 2.6 software for one hundred and eighty five cervical cancer patients. The initial 185 individual plans were created for clinical treatment using the tandem-ring dwell time ratio of 1 : 1. Modifying the initial applicator loading ratio, the second set of plans with related dose data were also obtained for study purposes only. Total reference air kerma (TRAK), total time index (TTI), ICRU volume, treatment time, point B dose, ICRU bladder dose, and rectal points dose were evaluated for both sets of plans. RESULTS: The means of all evaluated dose parameters decreased when the existing tandem-ring dwell time ratio (1 : 1) was modified to other dwell weightings (1 : 1 - 3 : 1). These reductions were 13.43% (ICRU volume), 9.83% (rectal dose), 6.68% (point B dose), 6.08% (treatment time), 5.90% (TRAK), 5.88% (TTI), and 1.08% (bladder dose). Correspondingly, coefficients of variation changed by -7.98%, -5.02%, -5.23%, 4.20%, -3.93%, 8.65%, and 3.96% from the existing pattern to the alternative one. CONCLUSION: Tandem-ring dwell time ratio has significant influence on dosimetric parameters. This study has indicated the need to modify the existing planning approach at UCH. PMID- 26034499 TI - Evaluation of (101)Rh as a brachytherapy source. AB - PURPOSE: Recently a number of hypothetical sources have been proposed and evaluated for use in brachytherapy. In the present study, a hypothetical (101)Rh source with mean photon energy of 121.5 keV and half-life of 3.3 years, has been evaluated as an alternative to the existing high-dose-rate (HDR) sources. Dosimetric characteristics of this source model have been determined following the recommendation of the Task Group 43 (TG-43) of the American Association of the Physicist in Medicine (AAPM), and the results are compared with the published data for (57)Co source and Flexisource (192)Ir sources with similar geometries. MATERIAL AND METHODS: MCNPX Monte Carlo code was used for simulation of the (101)Rh hypothetical HDR source design. Geometric design of this hypothetical source was considered to be similar to that of Flexisource (192)Ir source. Task group No. 43 dosimetric parameters, including air kerma strength per mCi, dose rate constant, radial dose function, and two dimensional (2D) anisotropy functions were calculated for the (101)Rh source through simulations. RESULTS: Air kerma strength per activity and dose rate constant for the hypothetical (101)Rh source were 1.09 +/- 0.01 U/mCi and 1.18 +/- 0.08 cGy/(h.U), respectively. At distances beyond 1.0 cm in phantom, radial dose function for the hypothetical (101)Rh source is higher than that of (192)Ir. It has also similar 2D anisotropy functions to the Flexisource (192)Ir source. CONCLUSIONS: (101)Rh is proposed as an alternative to the existing HDR sources for use in brachytherapy. This source provides medium energy photons, relatively long half life, higher dose rate constant and radial dose function, and similar 2D anisotropy function to the Flexisource (192)Ir HDR source design. The longer half life of the source reduces the frequency of the source exchange for the clinical environment. PMID- 26034500 TI - High-dose-rate pre-operative endorectal brachytherapy for patients with rectal cancer. AB - High-dose-rate endorectal brachytherapy (HDREBT) is an image guided brachytherapy treatment for patients with rectal cancer. It is based on tumor imaging with magnetic resonance in particular, which is used to choose eligible patients and improve tumor visualization. Treatment planning is performed using 3D CT simulation and treatment planning. The treatment is given on an outpatient basis and requires minimal local anesthesia. The validation of the technique was carried out through a preoperative study and is now explored as part of a radical treatment for early rectal cancer or as a boost modality. We describe technical aspects of the HDREBT and we discuss the ongoing institutional review board approved studies exploring the clinical applications of this treatment modality for patients with rectal cancer: 1) as a neoadjuvant treatment for patients with operable rectal tumor; 2) as a option to improve local control in patients with newly diagnosed rectal cancer but with previous pelvic radiation. PMID- 26034501 TI - Commissioning and periodic tests of the Esteya((r)) electronic brachytherapy system. AB - A new electronic brachytherapy unit from Elekta, called Esteya((r)), has recently been introduced to the market. As a part of the standards in radiation oncology, an acceptance testing and commissioning must be performed prior to treatment of the first patient. In addition, a quality assurance program should be implemented. A complete commissioning and periodic testing of the Esteya((r)) device using the American Association of Physicists in Medicine (AAPM), Groupe Europeen de Curietherapie and the European Society for Radiotherapy & Oncology (GEC-ESTRO) guidelines for linacs and brachytherapy units as well as our personal experience is described in this paper. In addition to the methodology, recommendations on equipment required for each test are provided, taking into consideration their availability and traceability of the detectors. Finally, tolerance levels for all the tests are provided, and a specific frequency for each test is suggested. PMID- 26034502 TI - Islamic fasting and thyroid hormones. PMID- 26034503 TI - Dichlorvos induced autoimmune hepatitis: a case report and review of literature. AB - INTRODUCTION: Drug-induced liver injury is a frequent cause of hepatic dysfunction. Several drugs have been identified to cause autoimmune hepatitis (AIH). Environmental chemicals are capable of triggering a certain degree of liver injury. However, toxin induced AIH is rare. CASE PRESENTATION: We reported a woman with chronic (long-term) exposures to dichlorvos, which resulted in liver injury and cirrhosis. She was diagnosed after a second liver biopsy, which was correlated with laboratory findings. At the same time, she experienced hepatic cortical blindness during her first admission. CONCLUSIONS: Chronic (long-term) exposures to dichlorvos can lead to AIH. A detailed inquiry of medical history and liver biopsy are necessary for the diagnosis of toxin-induced AIH. Corticosteroid therapy is associated with favorable evolution. PMID- 26034505 TI - Protective effect of salep on liver. AB - BACKGROUND: Salep is used for various purposes in food industries and traditional medicine. Therefore, evaluation of its effect on the liver seems to be necessary. OBJECTIVES: The aim of this study was to assess salep effect on liver. MATERIALS AND METHODS: In this experimental study, various concentrations of Salep were intraperitoneally administered to five groups of Wistar rats (control, placebo and 20, 40 and 80 mg/kg salep). After one month, liver enzymes and liver tissue were evaluated and compared between different groups. RESULTS: Significant decreased level of liver enzymes, MDA (Malondialdehyde) and TOC (Total Oxidation Capacity) were found in various concentrations of salep administration. On the other hand, a significant increase was found in TAC (Total Antioxidant Capacity) level with various doses of salep. CONCLUSIONS: Elevated level of total protein and albumin and decreased level of liver enzyme by salep extract were found in this study. Therefore, this plant may be a useful medicine for patients with liver diseases. PMID- 26034504 TI - Association of PNPLA3 I148M Variant With Chronic Viral Hepatitis, Autoimmune Liver Diseases and Outcomes of Liver Transplantation. AB - CONTEXT: The PNPLA3 I148M variant has been recognized as a genetic determinant of liver fat content and a genetic risk factor of liver damage progression associated with steatohepatitis. The I148M variant is associated with many chronic liver diseases. However, its potential association with inflammatory and autoimmune liver diseases has not been established. EVIDENCE ACQUISITION: We systemically reviewed the potential associations of I148M variant with chronic viral hepatitis, autoimmune liver diseases and the outcome of liver transplantation, explored the underlying molecular mechanisms and tried to translate them into more individualized decision-making and personalized medicine. RESULTS: There were associations between I148M variant and chronic viral hepatitis and autoimmune liver diseases and differential associations of I148M variant in donors and recipients with post-liver transplant outcomes. I148M variant may activate the development of steatosis caused by host metabolic disorders in chronic viral hepatitis, but few researches were found to illustrate the mechanisms in autoimmune liver diseases. The peripherally mediated mechanism (via extrahepatic adipose tissue) may play a principal role in triglyceride accumulation regardless of adiponutrin activity in the graft liver. CONCLUSIONS: Evidences have shown the associations between I148M variant and mentioned diseases. I148M variant induced steatosis may be involved in the mechanism of chronic viral hepatitis and genetic considered personalized therapies, especially for PSC male patients. It is also crucial to pay attention to this parameter in donor selection and prognosis estimation in liver transplantation. PMID- 26034506 TI - Preoperative Glucagon-like peptide-1 receptor imaging reduces surgical trauma and pancreatic tissue loss in insulinoma patients: a report of three cases. AB - BACKGROUND: Insulinomas are rare tumors, in the majority of cases best treated by surgical resection. Preoperative localization of insulinoma is challenging. The more precise the preoperative localization the less invasive and safer is the resection. The purpose of the study is to check the impact of a new technique to localize insulinoma on the surgical strategy. FINDINGS: We present exact preoperative localization with Glucagon-like peptide-1 receptor (GLP-1R) imaging. This allows a more precise resection thereby reducing surgical access trauma, loss of healthy pancreatic tissue and increasing safety and quality of the surgical intervention. CONCLUSION: With the help of precise preoperative localization of insulinoma with GLP-1R imaging the surgeon is able to minimize the amount of resected healthy pancreatic tissue. We hypothesize that GLP-1R imaging will become a preoperative diagnostic tool to be used for many patients scheduled for open or laparoscopic insulinoma resection. PMID- 26034507 TI - Safety in surgery: the role of shared decision-making. AB - The only surgery without risk of complications is the one not performed. Shared decision-making (SDM) offers a process which can help a physician and patient move beyond passive informed consent to a more collaborative, patient-centered experience. By offering a balanced review of conservative and invasive treatment options, including the option of observation only, SDM provides patients an opportunity to express their personal values and goals in the context of health decisions. Thus, when the patient decides to accept the inherent risks of surgery, there has truly been an opportunity to understand and discuss all treatment alternatives. PMID- 26034508 TI - High incidence of post-operative infection after 'sinus tarsi' approach for treatment of intra-articular fractures of the calcaneus: a 5 year experience in an academic level one trauma center. AB - BACKGROUND: The optimal management of displaced intra-articular calcaneal fractures remains a topic of debate among trauma surgeons. The purpose of this study was to assess the safety of the sinus tarsi approach in regard to the incidence of deep infection and amputation following open reduction and internal fixation intra-articular calcaneal fractures. METHODS: We conducted a retrospective chart review of all patients with displaced intra-articular calcaneus fractures treated with internal fixation through the sinus tarsi approach in a five year period. All surgeries were performed in a single level one trauma center by a single orthopedic trauma fellowship trained surgeon. RESULTS: Seventeen patients with an average age of 36.6 +/- 13.6 years (range 12 61 years) met the inclusion criteria. The time between injury and surgery was on average 6.1 days (range 1-22 days). Average follow up was 116 +/- 78.2 days (range 3-276 days). Two patients (11.7%) had diabetes mellitus. None of the patients required amputation. Three patients (17.6%) developed deep infection and underwent subsequent formal irrigation and debridement, two of these requiring multiple repeat surgeries in addition to hardware removals. Negative pressure wound therapy and long term antibiotics via peripherally inserted central catheter (PICC) were necessary in these three patients with wound infections. CONCLUSION: The sinus tarsi approach for intra fixation intra-articular calcaneal fractures is safe as compared to the traditional extensile approach in regard to flap necrosis and amputation. However, the rate of deep infection was higher than previously described in the literature. PMID- 26034509 TI - Pentoxifylline immunomodulation in the treatment of experimental chronic pulmonary paracoccidioidomycosis. AB - BACKGROUND: Pentoxifylline (PTX) is a methylxanthine compound with immunomodulatory and antifibrotic properties. The simultaneous use of PTX and antifungal therapy (itraconazole) has previously been evaluated in an experimental model of pulmonary paracoccidioidomycosis (PCM), a systemic fungal disease caused by the fungus Paracoccidioides brasiliensis (Pb) and characterized by chronic inflammation and lung fibrosis that appears even after a successful course of antifungal therapy. The results revealed prompt and statistically significant reductions in inflammation and fibrosis when compared to itraconazole alone. However, the effect of monotherapy with PTX on the host response to PCM has not been well-documented. Our aim was to determine the effect of PTX on the course of pulmonary lesions and on the local immune response. RESULTS: At the middle and end of treatment, the Pb-infected-PTX-treated mice exhibited significant reductions in lung density compared to the Pb-infected-non-treated mice as assessed by the quantification of Hounsfield units on high-resolution computed tomography (HRCT) (p <0.05 by Kruskal-Wallis test); additionally, at the end of therapy, the lung areas involved in the inflammatory reactions were only 3 vs. 22 %, respectively, by histomorphometry (p <0.05 by Mann-Whitney test), and this reduction was associated with a lower fungal burden and limited collagen increment in the pulmonary lesions. PTX treatment restored the levels of IFN gamma, MIP-1beta, and IL-3 that had been down-regulated by Pb infection. Additionally, IL-12p70, IL-10, IL-13, and eotaxin were significantly increased, whereas Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) levels were decreased in the lungs of the Pb-infected-PTX-treated mice compared to the non-treated group. CONCLUSIONS/SIGNIFICANCE: This study showed that PTX therapy administered at an "early" stage of granulomatous inflammation controlled the progress of the PCM by diminishing the pulmonary inflammation and the fungal burden and avoiding the appearance of collagen deposits in the pulmonary lesions. PMID- 26034510 TI - Applying DEKOIS 2.0 in structure-based virtual screening to probe the impact of preparation procedures and score normalization. AB - BACKGROUND: Structure-based virtual screening techniques can help to identify new lead structures and complement other screening approaches in drug discovery. Prior to docking, the data (protein crystal structures and ligands) should be prepared with great attention to molecular and chemical details. RESULTS: Using a subset of 18 diverse targets from the recently introduced DEKOIS 2.0 benchmark set library, we found differences in the virtual screening performance of two popular docking tools (GOLD and Glide) when employing two different commercial packages (e.g. MOE and Maestro) for preparing input data. We systematically investigated the possible factors that can be responsible for the found differences in selected sets. For the Angiotensin-I-converting enzyme dataset, preparation of the bioactive molecules clearly exerted the highest influence on VS performance compared to preparation of the decoys or the target structure. The major contributing factors were different protonation states, molecular flexibility, and differences in the input conformation (particularly for cyclic moieties) of bioactives. In addition, score normalization strategies eliminated the biased docking scores shown by GOLD (ChemPLP) for the larger bioactives and produced a better performance. Generalizing these normalization strategies on the 18 DEKOIS 2.0 sets, improved the performances for the majority of GOLD (ChemPLP) docking, while it showed detrimental performances for the majority of Glide (SP) docking. CONCLUSIONS: In conclusion, we exemplify herein possible issues particularly during the preparation stage of molecular data and demonstrate to which extent these issues can cause perturbations in the virtual screening performance. We provide insights into what problems can occur and should be avoided, when generating benchmarks to characterize the virtual screening performance. Particularly, careful selection of an appropriate molecular preparation setup for the bioactive set and the use of score normalization for docking with GOLD (ChemPLP) appear to have a great importance for the screening performance. For virtual screening campaigns, we recommend to invest time and effort into including alternative preparation workflows into the generation of the master library, even at the cost of including multiple representations of each molecule. Graphical AbstractUsing DEKOIS 2.0 benchmark sets in structure based virtual screening to probe the impact of molecular preparation and score normalization. PMID- 26034511 TI - Osteoprotegerin in relation to insulin resistance and blood lipids in sub-Saharan African women with and without abdominal obesity. AB - BACKGROUND: Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily that inhibits bone resorption, has been suggested as a potential marker of cardiovascular risk. This study aimed to assess the relationship between insulin resistance, lipid profile and OPG levels in obese and non-obese sub-Saharan African women. METHODS: Sixty obese (44) and non-obese (16) volunteer women aged 18 to 40 years were recruited in this cross-sectional study. Their clinical (age, height, weight, waist circumference, systolic and diastolic blood pressures) and biochemical parameters (fasting blood glucose, total cholesterol, high density lipoprotein-cholesterol (HDL-C)) were measured using standard methods. Insulin levels were measured using an electrochemiluminescence immunoassay, while OPG levels were measured using the ELISA technique. Low density lipoprotein-cholesterol (LDL-C), body mass index (BMI) and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) were calculated using standard methods. Abdominal obesity was defined as a waist circumference >= 80 cm. RESULTS: OPG levels were higher in obese than in normal subjects, though the difference was not significant (p = 0.9). BMI, waist circumference, percent body fat and systolic blood pressure were significantly higher in obese than in non-obese subjects (p < 0.05). In these subjects, only age significantly correlated with OPG levels (r = 0.831, p = 0.003), while none of the anthropometric nor metabolic parameter did, even after adjustment for age. In obese subjects, OPG levels fairly correlated with HDL-C (r = 0.298, p = 0.058), and significantly correlated with HOMA-IR (r = -0.438, p = 0.018). After adjustment for age, OPG levels remained negatively correlated to HOMA-IR (r = 0.516, p = 0.020) and LDL-C (r = -0.535, p = 0.015) and positively correlated to HDL-C (r = 0.615, p = 0.004). In multiple linear regression analysis, age was a main determinant of OPG levels in non-obese (beta = 0.647, p = 0.006) and obese (beta = 0.356, p = 0.044) women. HDL-C was also associated to OPG levels in obese women (beta = 0.535, p = 0.009). CONCLUSION: The positive correlation of OPG with HDL-C and HOMA-IR, and its negative correlation with LDL-C suggest that it may be a marker of insulin sensitivity/resistance and atherogenic risk in obese African women. PMID- 26034512 TI - Insulin resistance by homeostasis model assessment in HIV-infected patients on highly active antiretroviral therapy: cross-sectional study. AB - BACKGROUND: The highly active antiretroviral therapy (HAART) has altered the course of HIV infection, transforming it from a fatal illness to a chronic condition, reducing morbidity and mortality. However, this therapy has led to an increased incidence of metabolic problems such as insulin resistance, dyslipidemia, lipodystrophy and impaired glucose metabolism. The objectives of this study are to determine the prevalence of insulin resistance (IR) in a cohort of human immunodeficiency virus (HIV)-infected patients on highly active antiretroviral therapy (HAART) and to investigate the potentially associated factors. METHODS: We conducted a cross-sectional study including 219 adult patients with HIV on HAART. IR was determined through the homeostasis model assessment (HOMA-IR) mathematical model, using fasting plasma glucose (FPG) and insulin. Bivariate and multivariate analyses were performed to assess the association between demographic information, clinical characteristics and laboratory results, and IR. RESULTS: 75 (34.2 %) [95 % confidence interval (CI) 28.9-40.9] HIV-patients on HAART showed IR. 61 (81 %) of these patients were on HAART for more than one year, which was mainly composed by non-protease inhibitors drugs (88 %). Metabolic syndrome (MS) was found in 59 (26.9 %) subjects. In the multivariate analysis, the factors associated with IR were age >= 46 years (Prevalence ratio = 2.767, 95 % CI 1.325 to 5.780) and greater body mass index (BMI) (Prevalence ratio = 1.148, 95 % CI 1.054 to 1.250). CONCLUSIONS: The prevalence of IR was 34.2 %. Factors associated with IR were age and BMI. We did not find any significant association between IR and protease inhibitors (PI), which may be explained by the small number of patients using PI as part of their HAART regimen included in our study. PMID- 26034513 TI - Cerebrospinal fluid amyloid-beta 42/40 ratio in clinical setting of memory centers: a multicentric study. AB - INTRODUCTION: The cerebrospinal fluid (CSF) biomarkers amyloid-beta (Abeta), tau and phosphorylated tau (p-tau181) are now used for the diagnosis of Alzheimer's disease (AD). Abeta40 is the most abundant Abeta peptide isoform in the CSF, and the Abeta 42/40 ratio has been proposed to better reflect brain amyloid production. However, its additional value in the clinical setting remains uncertain. METHODS: A total of 367 subjects with cognitive disorders who underwent a lumbar puncture were prospectively included at three French memory centers (Paris-North, Lille and Montpellier; the PLM Study). The frequency of positive, negative and indeterminate CSF profiles were assessed by various methods, and their adequacies with the diagnosis of clinicians were tested using net reclassification improvement (NRI) analyses. RESULTS: On the basis of local optimum cutoffs for Abeta42 and p-tau181, 22% of the explored patients had indeterminate CSF profiles. The systematic use of Abeta 42/40 ratio instead of Abeta42 levels alone decreased the number of indeterminate profiles (17%; P = 0.03), but it failed to improve the classification of subjects (NRI = -2.1%; P = 0.64). In contrast, the use of Abeta 42/40 ratio instead of Abeta42 levels alone in patients with a discrepancy between p-tau181 and Abeta42 led to a reduction by half of the number of indeterminate profiles (10%; P < 0.001) and was further in agreement with clinician diagnosis (NRI = 10.5%; P = 0.003). CONCLUSIONS: In patients with a discrepancy between CSF p-tau181 and CSF Abeta42, the assessment of Abeta 42/40 ratio led to a reliable biological conclusion in over 50% of cases that agreed with a clinician's diagnosis. PMID- 26034514 TI - Treatment outcome measures for randomized controlled trials of antibiotic treatment for acute bacterial skin and skin structure infections in the emergency department setting. AB - Acute bacterial skin and skin structure infections (ABSSSIs), which include cellulitis, abscesses, and wound infections, are among the most commonly encountered conditions in emergency departments (EDs) internationally. Primarily, as a result of the recent epidemic of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) in North America, ED attendances and hospital admissions secondary to ABSSSIs have increased significantly. First-line antibiotic drug therapies for ABSSSIs have therefore changed to take account of CA-MRSA and the threat of evolving antibiotic resistance. Prior to 2010, randomized controlled trials (RCTs) of antibiotic therapy for ABSSSI used broad trial inclusion criteria and utilized investigator-determined clinical resolution, 7 to 14 days after the end of therapy, as the primary outcome measure. In order to produce more objective, reproducible, and quantifiable primary outcome measures, the US Food and Drug Administration (FDA) Center for Drug Evaluation and Research and a multidisciplinary consortium convened by the Foundation for the National Institutes of Health (FNIH) issued significantly changed trial guidance criteria. The currently recommended primary outcome measure is an assessment of greater than 20% reduction in the area of erythema, edema, or induration from baseline, measured at 48 to 72 h after randomization and initiation of drug treatment. In contrast, the European Medicines Agency (EMA) still recommends measurement of clinical resolution at a later time period. We discuss the evolution of changes to trial guidance criteria issued by the FDA since 1998 and the potential difficulties of implementing the recommended primary outcome measured at an earlier time point in RCTs of outpatient antibiotic treatment performed in the ED setting. PMID- 26034515 TI - IgG4-associated orbital and ocular inflammation. AB - BACKGROUND: IgG4-associated orbital and ocular inflammation is a relatively unknown entity characterized by sclerosing inflammation with infiltration of IgG4 positive plasma cells. Some so-called idiopathic inflammation syndromes are being re-classified as IgG4-associated inflammation with histopathologic evaluation. FINDINGS: We report three cases with differing manifestations of IgG4-associated ocular and orbital inflammation: a case of recurrent, treatment-refractory sclero uveitis that was diagnosed as granulomatosis with polyangiitis with an IgG4 related component, a case of pachymeningitis with optic neuritis that resulted in permanent visual loss, and a case of orbital inflammatory pseudotumor. All three would have been incompletely diagnosed without thorough histopathologic evaluation (including immunohistochemistry). CONCLUSIONS: IgG4-associated disease is an idiopathic, multi-organ inflammatory state that can manifest as chronic, relapsing, sclerosing inflammation in virtually any organ system. There is a wide range of presentations in ocular and orbital inflammation. Ophthalmologists should keep IgG4-associated inflammation in mind when examining chronic, sclerofibrosing inflammation with multi-system involvement. The histology of biopsy specimens is crucial in making the correct diagnosis. Timely assessment may lead to fewer diagnostic tests and more targeted therapy. PMID- 26034516 TI - The age gauge: older fathers having children. PMID- 26034517 TI - Funny science: review: ha! The science of when we laugh and why and the humor code: a global search for what makes things funny. PMID- 26034518 TI - The time of your life. PMID- 26034519 TI - Truth, Justice, and the NFL Way: Review: League of Denial: The NFL, Concussions, and the Battle for Truth. PMID- 26034520 TI - Brain-to-Brain Interfaces: When Reality Meets Science Fiction. PMID- 26034521 TI - With a little help from our friends: how the brain processes empathy. PMID- 26034522 TI - The brain-games conundrum: does cognitive training really sharpen the mind? PMID- 26034523 TI - The long and winding road: review: madness and memory: the discovery of prions-a new biological principal of disease. PMID- 26034524 TI - You say you want a revolution? PMID- 26034525 TI - Appraising the risks of reefer madness. PMID- 26034526 TI - Why inspiring stories make us react: the neuroscience of narrative. PMID- 26034527 TI - Vernon remembered. AB - The world of neuroscience lost one of its pioneers when Vernon B. Mountcastle, M.D., died January 11 in Baltimore at age 96. Often referred to as "the father of neuroscience," Mountcastle defied early skeptics by showing how cylinders of neurons, dedicated to specific tasks, work together. This month's Cerebrum features remembrances from two colleagues influenced by Mountcastle-among the many who have gone on to make their own significant impacts in neuroscience. PMID- 26034529 TI - Review: power foods for the brain. PMID- 26034528 TI - The darkness within: individual differences in stress. PMID- 26034530 TI - The Prevalence of Endocervical Chlamydia trachomatis Infection Among Young Females in Kashan, Iran. AB - BACKGROUND: Chlamydia trachomatis is one of the major bacterial agents of the sexually transmitted diseases worldwide, especially among young females. There is no data regarding the prevalence of genital Chlamydia infection among young females in Kashan, Iran. OBJECTIVES: The current study aimed to determine the prevalence of endocervical C. trachomatis infection among females aged 17 - 35 years in Kashan, Iran. PATIENTS AND METHODS: In the current descriptive study, 255 endocervical swab samples were collected from the obstetrics and gynecology clinics of Kashan, Iran from December 2012 to July 2013. Cervical swabs were placed in transport media and sent to the laboratory. To identify C. trachomatis in the samples Polymerase Chain Reaction (PCR) was performed to amplify a sequence in the cryptic plasmid, generating a fragment of about 512base pair. Demographic data was collected considering the relevant risk factors by a standard questionnaire. RESULTS: A total of 255 females were tested. The prevalence of genital C. trachomatis was 2.4% (95% confidence interval [CI] 0.54% - 4.26%); 3.2% of the females in the <= 25-year-old group were positive versus 1.8% in the 26 - 35-year-old group. The most general presented symptoms of genital C. trachomatis infection were vaginal discharge (66.6%) and lumbar pain (50%). No significant relationships were found between C. trachomatis infection and the risk factors. CONCLUSIONS: To the authors' knowledge this is the first study to describe endocervical C. trachomatis infection in this area. The obtained results also emphasized the importance of routine diagnosis of C. trachomatis to control of the infection. PMID- 26034531 TI - Occurrence of SHV, TEM and CTX-M beta-Lactamase Genes Among Enteropathogenic Escherichia coli Strains Isolated From Children With Diarrhea. AB - BACKGROUND: Antibiotic resistance is widespread among diarrheagenic Escherichia coli in developing countries, where the overuse of antibiotics is common. Information regarding beta-lactamases, especially Extended-Spectrum beta Lactamases (ESBLs) in diarrheagenic pathogens should be considered in clinical management when an optimal treatment is needed. OBJECTIVES: The main objective of this study was to investigate the prevalence of bla CTX-M , bla SHV and bla TEM beta-lactamase genes among enteropathogenic E. coli (EPEC) isolates in Tehran, Iran. MATERIALS AND METHODS: Stool specimens were collected from children with diarrhea during a 17-month period from 2011 to 2013. Routine biochemical tests were performed for identification of E. coli isolates. The isolates were further examined by PCR for the presence of eae, stx1, stx2 and bfp genes. EPEC isolates have been screened for different beta-lactamase genes. Genotyping EPEC isolates harboring bla CTX-M15 gene was performed through Multi-Locus VNTR Analysis (MLVA). RESULTS: Of 42 EPEC, eight isolates carried the bla CTX-M1 . None of the isolates carried bla CTX-M2 and bla CTX-M9 . The bla CTX-M15 variant was identified in all of bla CTX-M1 -positive isolates. Furthermore, bla SHV and bla TEM genes were detected in 40.5% (n = 17) and 19% (n = 8) of all EPEC isolates, respectively. No significant association was observed between the existence of bfp gene and presence of those beta-lactamase genes (P > 0.05). MLVA analysis revealed high genetic diversity among bla CTX-M15 -positive isolates. CONCLUSIONS: Our study emphasized the increasing role of ESBL genes, especially bla CTX-M15 in EPEC isolates. PMID- 26034533 TI - Isolation of different species of Candida in patients with vulvovaginal candidiasis from sari, iran. AB - BACKGROUND: Vulvovaginal Candidiasis (VVC) is a frequent, complex and cumbersome condition that can cause physical and psychological distress for the involved individual. Candida albicans was reported as the most common agent of VVC yet it seems that we are recently encountering changes in the pattern of Candida species in VVC. OBJECTIVES: In this study we assessed different species of Candida isolated from patients with VVC, residing in Sari, Iran. PATIENTS AND METHODS: Two hundred and thirty-four patients with vulvovaginitis were enrolled in this study. Samples were collected by a wet swab. Each vaginal swab was examined microscopically and processed for fungal culture. The identification of Candida species was done by morphological and physiological methods such as culture on CHROMagar Candida media and sugar assimilation test with the HiCandida identification kit (HiMedia, Mumbai, India). RESULTS: Out of 234 patients with vulvovaginitis, 66 (28.2%) patients showed VVC. Of these patients, 16 (24.2%) had recurrent VVC (RVVC). The age group of 20 - 29 year-olds had the highest frequency of VVC (48.5%). Erythema concomitant with itching (40.9%) was the most prevalent sign in VVC patients. Fifty-seven (86.4%) of the collected samples had positive results from both microscopic examination and culture. In total, 73 colonies of Candida spp. were isolated from 66 patients with VVC. The most common identified species of Candida were C. albicans (42.5%), C. glabrata (21.9%) and C. dubliniensis (16.4%). In patients with RVVC and patients without recurrence, C. albicans and non-albicans species of Candida were frequent species, respectively. CONCLUSIONS: The results of our study showed that non-albicans species of Candida are more frequent than C. albicans in patients with VVC. This result is in line with some recent studies indicating that non-albicans species of Candida must be considered in gynecology clinics due to the reported azole resistance in these species. PMID- 26034532 TI - Isolation and Biochemical Fingerprinting of Vancomycin-Resistant Enterococcus faecium From Meat, Chicken and Cheese. AB - BACKGROUND: Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens and food chain has been considered as an assumed source for dissemination of VRE to human. OBJECTIVES: The presence of VRE isolates from food samples and typing of these isolates with Phene plate, a biochemical fingerprinting method, were investigated. MATERIALS AND METHODS: Thirty samples of meat, chicken and cheese were analyzed for VRE during 2010. Antibiotic susceptibility tests and minimum inhibitory concentration (MIC) were also examined. VRE isolates were typed with the Phene plate system (PhPlate), a biochemical fingerprinting method. RESULTS: A total of 70 VRE isolates were obtained and identified as Enterococcus faecium by species-specific PCR. All the isolates carried vanA, while none of them harbored vanB. The VRE isolates included 35, 27, and 8 isolates from meat, chicken and cheese, respectively. Typing with the PhPlate revealed a diversity index of 0.78 for E. faecium, containing 10 common and four single types. The results of antibiotic susceptibility and MIC tests showed an increased resistance to ciprofloxacin, erythromycin, ampicillin and gentamicin, to which, 100%, 100%, 100%, and 95% of VRE isolates were resistant, respectively. Only 5% of the isolates were resistant to chloramphenicol and the MIC of the isolates for vancomycin and teicoplanin was >= 256 ug/mL and for gentamicin-resistant isolates it was 1024 ug/mL. Conventional and molecular identification tests exhibited that all the isolates were E. faecium carrying vanA. None of the isolates harbored vanB. CONCLUSIONS: The results showed that enterococci are common contaminants in food. Indeed, this study indicates a high prevalence of multidrug-resistant enterococci in food of animal origin in Iran. Isolating some persisting enterococcal isolates revealed that continuous surveillance of antimicrobial resistance in enterococci from food is essential. PMID- 26034534 TI - The incidence of epstein-barr virus primary infection among suspected patients referred to namazi hospital of shiraz, iran. AB - BACKGROUND: Many children become infected with Epstein-Barr virus (EBV) during their childhood. Since the clinical profile of EBV primary infection is challenging, it is important to use the best diagnostic clinical means. Detection of IgM against viral capsid antigen (VCA) by ELISA has been shown to be a reliable method. OBJECTIVES: This study was conducted to demonstrate the incidence of EBV primary infection, among suspected patients referred to Namazi hospital, Shiraz, Iran. PATIENTS AND METHODS: The sample included 346 patients with an age range of 0 to 20 years (6.31 +/- 4.66: 10.97 years). A volume of 5 mL of blood was collected from each case. The patients were divided to four age groups. The sera were tested for the presence of VCA-IgM by commercially available Anti-EBV-VCA ELISA kit. RESULTS: The results indicated that 104 (30.0%) of the patients were EBV VCA IgM positive, with no significant difference in the incidence of EBV primary infection between males and females. However, the incidence of infection was significantly different between age group I (0 - 5 years) and III (11 - 15 years), and also between age group I (0 - 5 years) and IV (16 - 20 years) (P < 0.05). CONCLUSIONS: Considering the results, accurate and on time diagnosis of EBV primary infection in both children and adolescents will help prevent unnecessary hospitalization, medication and incorrect medical decisions. In addition, this will decrease further treatment costs and related medical procedures. PMID- 26034535 TI - Optimization of Fermentation Conditions for Recombinant Human Interferon Beta Production by Escherichia coli Using the Response Surface Methodology. AB - BACKGROUND: The periplasmic overexpression of recombinant human interferon beta (rhIFN-beta)-1b using a synthetic gene in Escherichia coli BL21 (DE3) was optimized in shake flasks using Response Surface Methodology (RSM) based on the Box-Behnken Design (BBD). OBJECTIVES: This study aimed to predict and develop the optimal fermentation conditions for periplasmic expression of rhIFN-beta-1b in shake flasks whilst keeping the acetate excretion as the lowest amount and exploit the best results condition for rhIFN-beta in a bench top bioreactor. MATERIALS AND METHODS: The process variables studied were the concentration of glucose as carbon source, cell density prior the induction (OD 600 nm) and induction temperature. Ultimately, a three-factor three-level BBD was employed during the optimization process. The rhIFN-beta production and the acetate excretion served as the evaluated responses. RESULTS: The proposed optimum fermentation condition consisted of 7.81 g L(-1) glucose, OD 600 nm prior induction 1.66 and induction temperature of 30.27 degrees C. The model prediction of 0.267 g L(-1) of rhIFN-beta and 0.961 g L(-1) of acetate at the optimum conditions was verified experimentally as 0.255 g L(-1) and 0.981 g L(-1) of acetate. This agreement between the predicted and observed values confirmed the precision of the applied method to predict the optimum conditions. CONCLUSIONS: It can be concluded that the RSM is an effective method for the optimization of recombinant protein expression using synthetic genes in E. coli. PMID- 26034536 TI - Genotyping of vancomycin resistant enterococci in arak hospitals. AB - BACKGROUND: Enterococcal species have emerged as important pathogens in Iran as well as throughout the world. With the increased use of vancomycin, Vancomycin Resistant Enterococci (VRE) has become an important nosocomial pathogen. OBJECTIVES: The aim of the present study was to determine the incidence and antimicrobial susceptibility pattern of VRE and also to determine the most important genes that cause resistance to vancomycin in clinical samples in Arak, Iran. MATERIALS AND METHODS: In total, 200 enterococci samples were collected from clinical specimens of Arak hospitals. Enterococcal species were identified using standard biochemical tests. Antibiotic susceptibility was tested by the Clinical and Laboratory Standards Institute (CLSI) disk diffusion. Minimum Inhibitory Concentration (MICs) was determined by broth micro dilution. All of the VRE isolates were examined by PCR to detect the presence of VRE genes. RESULTS: Disk diffusion agar showed that 96 strains (48%) were resistant to gentamicin, 89 (44.5%) to ciprofloxacin, 127 (63.5%) to erythromycin, 142 (71%) to tetracycline, 11 (5.5%) to teicoplanin, 32 (16%) to vancomycin, none to linezolid and 96 (48%) to co-trimoxazole. The MICs of the resistant isolates were as follows; 88 strains had MIC >= 32 MUg/mL to vancomycin and 59 strains had MIC >= 32 MUg/mL to teicoplanin. Molecular studies revealed that 59.09% of VRE contained VanA genes and 7.95% of VRE contained the VanB genes. None of the strains had vanC1 and vanC2/3 gene. CONCLUSIONS: According to the results of this study, rates of vancomycin-resistance in enterococci, in Iran like other parts of the world, is increasing. Therefore accurate methods are required for identifying strains that possess resistance genes because many cases of hospital infections are caused by these strains. PMID- 26034537 TI - Prokaryotic High-Level Expression System in Producing Adhesin Recombinant Protein E of Nontypeable Haemophilus influenzae. AB - BACKGROUND: Adhesion protein E (PE) of Haemophilus influenzae is a 16 - 18 kDa protein with 160 amino acids which causes adhesion to epithelial cells and acts as a major factor in pathogenesis. OBJECTIVES: In this study, we performed cloning, expression and purification of PE as a candidate antigen for vaccine design upon further study. MATERIALS AND METHODS: At first, the pe gene of NTHi ATCC 49766 strain (483 bp) was amplified by PCR. Then, to sequence the resulted amplicon, it was cloned into TA vector (pTZ57R/T). In the next step, the sequenced gene was sub-cloned in pBAD/gIII A vector and transformed into competent Escherichia coli TOP10. For overexpression, the recombinant bacteria were grown in broth medium containing arabinose and the recombinant protein was purified using metal affinity chromatography (Ni-nitrilotriacetic acid) (Ni-NTA agarose). Finally, the protein was detected using sodium dodecyl sulfate polyacrylamide gel electrophores (SDS-PAG) and confirmed by western blotting. RESULTS: The cloned gene was confirmed by PCR, restriction digestion and sequencing. The sequenced gene was searched for homology in GenBank and 99% similarity was found to the already deposited genes in GenBank. Then we obtained PE using Ni-NTA agarose with up to 7 mg/mL concentration. CONCLUSIONS: The pe gene was successfully cloned and confirmed by sequencing. Finally, PE was obtained with high concentration. Due to high homology and similarity among the pe gene from NTHi ATCC 49766 and other NTHi strains in GenBank, we believe that the protein is a universal antigen to be used as a vaccine design candidate and further studies to evaluate its immunogenicity is underway. PMID- 26034538 TI - Isolation and screening of lipolytic fungi from coastal waters of the southern caspian sea (north of iran). AB - BACKGROUND: Lipases (acylglycerol acylhydrolase, E. C. 3. 1. 1. 3) are widely distributed among microorganisms, animals and plants, catalyzing the hydrolysis of triglycerides to free fatty acids and glycerol. Their commercial application includes pharmaceutical, chemical, and paper industries. OBJECTIVES: This study aimed to isolate and screen lipolytic fungi from coastal waters of the southern Caspian Sea by Internal Transcribed Spacer-Polymerase Chain Reaction (ITS-PCR), and to optimize their lipolytic activity, pH and temperature. The ITS regions possess a high variation among taxonomically distinct fungal species and even within species. MATERIALS AND METHODS: All fungal were tested to determine their lipolytic activity by the Tributyrin agar plate assay. After DNA extraction, lipase-producing fungi were identified via ITS-PCR of rDNA region with ITS1 and ITS4 primers. RESULTS: Four fungal species were isolated from water samples of the Caspian Sea (north of Iran) between February and June 2011. The nucleotide sequences reported for three of these isolates have been assigned accession numbers from NCBI Gene Bank database. Among these species, Cladosporium langeronii showed maximum lipolytic activity (34 U/mL) and maximum clear zone formation (6 mm) on the Tributyrin agar plates. The optimum pH and temperature for activity were 8.0 and 35 degrees C, respectively. CONCLUSIONS: The findings of this study indicated that these isolates were plant pathogenic fungi, which entered seawater from the environment, and were likely to have a suitable lipase activity on plant oils. PMID- 26034539 TI - Evaluation of Synergistic Interactions Between Cell-Free Supernatant of Lactobacillus Strains and Amikacin and Genetamicin Against Pseudomonas aeruginosa. AB - BACKGROUND: The indiscriminate use of antibiotics in the treatment of infectious diseases can increase the development of antibiotic resistance. Therefore, there is a big demand for new sources of antimicrobial agents and alternative treatments for reduction of antibiotic dosage required to decrease the associated side effects. OBJECTIVES: In this study, the synergistic action of aminoglycoside antibiotics and cell-free supernatant (CFS) of probiotic (Lactobacillus rahmnosus and L. casei) against Pseudomonas aeruginosa PTCC 1430 was evaluated. MATERIALS AND METHODS: A growth medium for culturing of probiotic bacteria was separated by centrifugation. The antimicrobial effects of CFS of probiotic bacteria were evaluated using the agar well diffusion assay. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were evaluated using the micro dilution method. Finally, an interaction between CFS and amikacin or gentamicin against P. aeruginosa PTCC 1430 was examined through the checkerboard method and fractional inhibitory concentration (FIC). Furthermore, CFSs from Lactobacillus strains were analyzed by reversed phase HPLC (RP-HPLC) for antimicrobial compounds. RESULTS: The results showed a significant effect of CFS on the growth of P. aeruginosa. The MIC and MBC of CFS from L. casei were 62.5 uL/mL while the MIC and MBC of CFS from L. rhamnosus were 62.5 MUL/mL and 125 MUL/mL, respectively. Using the FIC indices, synergistic interactions were observed in combination of CFS and antibiotics. Fractional Inhibitory Concentration indices of CFS from L. casei and aminoglycoside antibiotics were 0.124 and 0.312 while FIC indices of CFS from L. rhamnosus and aminoglycoside antibiotics were 0.124 and 0.56, respectively showing a synergism effect. The results of RP-HPLC showed that CFS of Lactobacillus strains contained acetic acid, lactic acid and hydrogen peroxide (H2O2). CONCLUSIONS: Our findings indicate that probiotic bacterial strains of Lactobacillus have a significant inhibitory effect on the growth of P. aeruginosa PTCC 1430. The antimicrobial potency of this combination can be useful for designing and developing alternative therapeutic strategies against P. aeruginosa infections. PMID- 26034540 TI - The association between oral lichen planus and hepatitis C virus infection; a report from northeast of iran. AB - BACKGROUND: The association between hepatitis C virus (HCV) infection and oral lichen planus (OLP) has been the focus of many studies. Fifteen percent of HCV infections lead to sets of extrahepatic manifestations including lichen planus (LP). The prevalence of HCV is heavily influenced by geographical location. OBJECTIVES: This study aimed to evaluate the relationship between OLP and HCV infection in Mashhad, northeast of Iran. MATERIALS AND METHODS: Blood samples were taken from 134 OLP patients and 134 healthy controls (without OLP) to screen for anti-HCV by ELISA (third generation) and reverse transcription polymerase chain reaction (RT-PCR) for HCV-RNA. RESULTS: Of the 134 OLP patients only three (2.23 %) had HCV infection where both anti-HCV and HCV-RNA were positive. All controls were negative for both anti-HCV and HCV-RNA (P = 0.082). CONCLUSIONS: Our investigation illustrated that the prevalence of hepatitis C was higher among OLP patients compared to the control group. These findings are in line with previous results that reported a hepatitis C prevalence of 0.19% among the general population of Mashhad. PMID- 26034541 TI - Three Tests Used to Identify Non-Culturable Form of Helicobacter pylori in Water Samples. AB - BACKGROUND: Helicobacter pylori, causing the most common chronic bacterial infection, exist in two forms; bacilli and coccoid. The coccoid form is identified as viable but non-culturable bacteria. OBJECTIVES: The current study aimed to conduct culture, polymerase chain reaction (PCR), and loop-mediated isothermal amplification (LAMP) tests to identify coccoid forms of H. pylori. MATERIALS AND METHODS: The PCR and LAMP tests were optimized using specific primers for glmM gene. The sensitivity and specificity of the tests were determined. The current experimental study was conducted on 10 different strains isolated from clinical cases (H1-H10). The isolates were added to tap water and incubated at three different temperatures for one and two months intervals. After pure-culturing of the bacteria, DNAs were extracted and PCR and LAMP were performed. RESULTS: Ten copies of targeted DNA were required for PCR detection whereas only five copies gave a positive reaction by LAMP assay, with 100% specificity. Of the 10 isolates inoculated in water for one and two months at three different temperatures 4, 22, and 37 degrees C, only three cases (5%) were found positive in the first month; 13 (21.6%) and 29 cases (48.3%) were also positive by PCR and LAMP tests in the first and second months. CONCLUSIONS: Results of the current study confirmed that molecular methods such as PCR and LAMP were much more sensitive, rapid, and specific than culturing to identify non culturable coccoid forms of H. pylori in water. PMID- 26034542 TI - Efficient Conjugation of Aflatoxin M1 With Bovine Serum Albumin through Aflatoxin M1-(O-carboxymethyl) Oxime and Production of Anti-aflatoxin M1 Antibodies. AB - BACKGROUND: Aflatoxins are the most extensively studied group of mycotoxins produced by molds, especially the Aspergillus group, which are highly toxic to animals and humans. OBJECTIVES: Since immunoassay is a simple and rapid method for the analysis of many toxic substances in comparison to the chromatographic methods, it is necessary to produce specific and sensitive antibodies for detection of Aflatoxin M1 (AFM1). The current study was conducted to produce bioconjugate of Aflatoxin M1 (AFM1) with Bovine Serum Albumin (BSA) as well as to generate specific antibodies against AFM1 for immunoassay of the mycotoxin. MATERIALS AND METHODS: First, AFM1 was converted to AFM1-(O-carboxymethyl) oxime derivative. Then, AFM1-oxime was coupled with BSA and the product was assessed by UV-VIS spectrophotometry. In order to generate polyclonal antibodies against AFM1, rabbits were immunized with BSA-AFM1 conjugate. Produced antibodies were purified using ion exchange chromatography and BSA-Sepharose 4B affinity chromatography. The titers and specificity of the produced antibodies were determined by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: The results indicated that coupling of AFM1 with O-(Carboxymethyl) hydroxylamine hemihydrochloride was suitable and 12 moles of AFM1-oxime were successfully coupled to each mole of BSA. In addition, the titers and specificity of the prepared antibody were considerable compared to standard anti-AFM1 antibodies. The relative cross-reactivity of each toxin (relative to AFM1) with purified anti AFM1 antibodies, as determined by the amount of aflatoxin necessary to cause 50% inhibition of enzyme activity, was 70, 105, 240, and 2500 ng/mL for AFB1, AFB2, AFG1, and AFG2, respectively. CONCLUSIONS: The prepared antibody can be used for the development of an ELISA kit to assay AFM1 in milk and other biological fluids. PMID- 26034543 TI - human adenoviruses role in ophthalmic pterygium formation. AB - BACKGROUND: Ophthalmic pterygium is a common benign lesion of unknown origin and the pathogenesis might be vision-threatening. This problem is often associated with exposure to solar light. Recent evidence suggests that potentially oncogenic viruses such as human papillomavirus and Epstein-Barr virus may be involved in the pathogenesis of pterygia. Expression of specific adenovirus genes such as E1A and E1B, which potentially have many functions, may contribute to their oncogenic activity as well as relevance to cellular immortalization. OBJECTIVES: For the first time, we aimed to investigate involvement of adenoviruses in pterygium formation. PATIENTS AND METHODS: Fifty tissue specimens of pterygium from patients undergoing pterygium surgery (as cases), 50 conjunctival swab samples from the same patients and 10 conjunctival biopsy specimens from individuals without pterygium such as patients undergoing cataract surgery (as controls) were analyzed for evidence of adenovirus infection with polymerase chain reaction using specific primers chosen from the moderately conserved region of the hexon gene. Furthermore, beta-globin primers were used to access the quality of extracted DNA. Data was analyzed using SPSS (version 16) software. RESULTS: Of 50 patients, 20 were men and 30 women with mean age of 61.1 +/- 16.9 years ranged between 22 and 85 years. All samples of pterygia had positive results for adenoviruses DNA with polymerase chain reaction, but none of the negative control groups displayed adenoviruses. The pterygium group and the control groups were beta-globin positive. Direct sequencing of PCR products confirmed Adenovirus infection. CONCLUSIONS: Adenoviruses might act as a possible cause of pterygium formation and other factors could play a synergistic role in the development. However, further larger studies are required to confirm this hypothesis. PMID- 26034544 TI - Expression, Purification and Immunogenic Description of a Hepatitis C Virus Recombinant CoreE1E2 Protein Expressed by Yeast Pichia pastoris. AB - BACKGROUND: Gradual development of a useful vaccine can be the main point in the control and eradication of Hepatitis C virus (HCV) infection. Hepatitis C Virus envelope glycoproteins are considered as the main HCV vaccine candidate. OBJECTIVES: In this study, the Pichia pastoris expression system was used to express a recombinant HCV CoreE1E2 protein, which consists of Core (269 nt-841nt) E1 (842 nt-1417nt) and E2 (1418 nt-2506nt). MATERIALS AND METHODS: By a codon optimization technique based on the P. pastoris expression system, we could increase the rate of recombinant proteins. Moreover, the purified protein can efficiently induce anti-CoreE1E2 antibodies in rabbits, and also by developing a homemade Enzyme-Linked ELISA kit we can detect antibody of HCV Iranian patients with genotype 1a. RESULTS: In our study, the virus-like particle of rCoreE1E2 with 70 nm size, was shown by Electron microscopy and proved the self-assembly in vitro in a yeast expression system. CONCLUSIONS: These findings of the present study indicate that the recombinant CoreE1E2 glycoprotein is effective in inducing neutralizing antibodies, and is an influential HCV vaccine candidate. PMID- 26034545 TI - Molecular Detection of Genomic Islands Associated With Class 1 and 2 Integron in Haemophilus influenzae Isolated in Iran. AB - BACKGROUND: High levels of multidrug resistance are usually associated with mobile genetic elements that encode specific resistance genes. Integrons are important genetic elements involved in spreading antibiotic multi-resistance. In special cases, large exogenous segments in bacterial genomes form genomic islands, and one of the functions of these genomic islands is antibiotic resistance. Due to geographical heterogeneity in antibiotic resistance pattern, it is mandatory to determine resistance patterns that are region-specific rather than generalized. OBJECTIVES: The objective of this study was to detect class 1 and 2 integrons in clinical isolates of Haemophilus influenzae. PATIENTS AND METHODS: Antibiogram tests were carried out for twenty clinical isolates collected from different patients admitted to the Milad hospital. The PCR reactions were performed using universal primers specified for Int1 and Int2 genes attributed to class 1 and 2 integrons. Also amplification of integrase genes related to genomic islands was investigated by designing specific primers. RESULTS: Of the twenty isolates, all (100%) were resistant to clindamycin, chloramphenicol and tetracycline, 95% to amoxicillin, 50% to ceftriaxone, 45% to ciprofloxacin and 5% to azithromycin. Also, all isolates (100%) were sensitive to trimethoprim/sulfamethoxazole. Class 1 and 2 integrons were not detected in any of the isolates; however the integrase gene attributed to genomic islands was identified in twelve isolates. CONCLUSIONS: Antibiotic resistance gene cassettes may be carried on integron or other genetic elements. The purpose of this study was to detect integron or genomic islands involved in antibiotic resistance profile of the isolates of H. influenzae collected in this study. PMID- 26034546 TI - Th1 Cytokine Production Induced by Lactobacillus acidophilus in BALB/c Mice Bearing Transplanted Breast Tumor. AB - BACKGROUND: The immunomodulative effects of Lactic Acid Bacteria as probiotics have been already demonstrated. OBJECTIVES: The current study aimed to evaluate the effect of oral administration of Lactobacillus acidophilus on the immune responses and patterns of cytokine production in the BALB/c mice bearing breast cancer. MATERIALS AND METHODS: The current study used thirty inbred BALB/c mice, six- to eight-week-old; they were divided into two groups of 15 each. One group was used as control in each assay. The L. acidophilus (ATCC4356) used in the study was inoculated in MRS broth and cultivated overnight at 37 degrees C under anaerobic conditions, then collected by centrifugation, and re-suspended in Phosphate-buffered Saline (PBS) media. After preparation of the proper amount of the suspension, it was orally administered to the mice via gavage and the control mice received an equal volume of PBS in the same manner. RESULTS: The results showed that oral administration of L. acidophilus as a potent immunostimulator agent could motivate the proliferation of immune cells. Moreover, it could increase the production of IFN-gamma and decrease the production of IL-4, known as Th2 cytokines, in the spleen cell culture. The results showed that the survival time of the L. acidophilus administered mice significantly increased in comparison to that of the control mice. CONCLUSIONS: The current study findings suggested that L. acidophilus can promote immune responses with Th1 bias and may increase the antitumor response. Further, the consumption of this probiotic strain may help to manage the immune response in tumor condition, but more studies are needed to investigate the other mechanisms of this effect. PMID- 26034547 TI - Metallo-beta-Lactamase VIM-1, SPM-1, and IMP-1 Genes Among Clinical Pseudomonas aeruginosa Species Isolated in Zahedan, Iran. AB - BACKGROUND: One of the major clinical problems regarding Pseudomonas aeruginosa is attributed to metallo-beta-lactamases (MBL). This group of enzymes is a subset of beta lactamases which belong to group B of Ambler classification and cause hydrolysis of carbapenems. Based on epidemiological studies conducted worldwide, it is proved that prevalence of genes coding MBLs in P. aeruginosa species are different in various geographic zones and even in various hospitals. Therefore, according to the clinical importance of organisms generating MBLs, it is necessary to identify and control these bacteria in hospitals for therapeutic purposes. OBJECTIVES: The current study aimed to investigate the Metallo-beta Lactamase VIM-1, SPM-1, and IMP-1 genes among clinical P. aeruginosa species isolated in Zahedan, Iran. MATERIALS AND METHODS: The current study investigated the presence of MBL through phenotypic and genotypic methods and also the pattern of antibiotic resistance in P. aeruginosa species isolated in hospitals. The Minimum Inhibitory Concentration (MIC) against imipeneme was measured for 191 P. aeruginosa species isolated from Zahedan hospitals after identification through biochemical methods and determination of the antibiotic resistance pattern. Strains with MIC > 4 ug/mL were studied by phenotypic and genotypic methods. RESULTS: The rate of resistance against imipeneme was 5.7% and after carrying out the phenotypic experiments, nine species were identified as of MBL producer. Seven species were confirmed by Polymerase Chain Reaction (PCR) method. Gene VIM 1 was the predominant gene among the positive (antibiotic resistant) species. CONCLUSIONS: The study results showed that MBL genes were present in some of the species isolated from Zahedan hospitals. Regarding the importance of MBL producer bacteria in hospitals, quick identification and evaluation of these clinical species can be considered as an important and basic step for treatment and control of pseudomonad infections. PMID- 26034548 TI - Evaluation of CD4+ CD25+ FoxP3+ Regulatory T cells and FoxP3 and CTLA-4 gene Expression in Patients wwith Newly Diagnosed Tuberculosis in Northeast of Iran. AB - BACKGROUND: Tuberculosis (TB) is the world's second most common infectious disease after Human Immunodeficiency Virus Infection/Acquired Immunodeficiency Syndrome (HIV/AID) and the most frequent cause of mortality especially in developing countries. T regulatory (Treg) cells, which have suppressive activity and express forkhead winged-helix family transcriptional repressor p3 (FoxP3), suppress the immune responses against pathogens such as Mycobacterium tuberculosis. There are controversial results regarding the role of FoxP3 expressing cells in the blood of patients with TB. OBJECTIVES: The aim of this study was to evaluate the frequency CD4+ CD25+ Treg cells, and FoxP3 and Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) gene expressions in peripheral blood of patients with tuberculosis and patients with positive tuberculin skin test before and after Peripheral Blood Mononuclear Cells (PBMCs) activation with Purified Protein Derivative (PPD). PATIENTS AND METHODS: In this cross-sectional study, Peripheral Mononuclear Cells (PBMCs) were isolated from peripheral blood of 29 patients with newly diagnosed pulmonary TB and 19 patients with positive tuberculin skin test. The PBMCs were activated with PPD for 72 hours. Activated cells were harvested, RNA was extracted and cDNA was synthesized. A real-time Taqman method was designed and optimized for evaluation of Foxp3 gene expression and SYBR Green method was used and optimized for evaluation of CTLA-4 gene expression. A flow cytometry analysis was used to evaluate the frequency of CD4+ CD25+ Foxp3+ regulatory T cells in both groups. RESULTS: There was no significant difference in the frequency of CD4+ CD25+ FoxP3+ regulatory T cells between the two groups. Expression of FoxP3 and CTLA-4 in peripheral blood of patients with newly diagnosed TB was significantly lower than the control group after and before activation with PPD. CONCLUSIONS: The expression of FoxP3 and CTLA-4 in PBMCs of patients with newly diagnosed TB was low, which might suggest that Treg cells may be sequestered in the lungs. PMID- 26034549 TI - The Usefulness of Anti-HCV Signal to Cut-off Ratio in Predicting Viremia in Anti HCV in Patients With Hepatitis C Virus Infection. AB - BACKGROUND: Hepatitis C Virus (HCV) infection is diagnosed by antibody and RNA based methods. Patients with anti-HCV sample rate/cutoff rate (S/CO) ratios > 1 are reported as anti-HCV positive. RNA based methods are introduced to confirm positivity in seropositive samples. OBJECTIVES: The current study aimed to assess relationship between S/CO rates and HCV-RNA levels in the laboratory to identify HCV viremia in patients with a positive anti-HCV. PATIENTS AND METHODS: All serum samples were assayed for anti-HCV by ELISA method. A total of 265 anti-HCV positive patients were tested for HCV-RNA testing by quantitative method using Artus HCV RG Real-time Polymerase Chain Reaction (RT- PCR) kit. Statistical analysis was done by SPSS version 16. RESULTS: Of the 265 patients with HCV infection, 204 (77%) were male and the mean age was 43.53 +/- 13.17 years, ranging 1 - 81 years. No correlation was found between S/CO ratios and HCV-RNA levels. There was significant difference in S/CO ratio between viremic and non viremic subjects. The sensitivity, specificity, negative predictive value, and positive predictive value were 100%, 81.4%, 100%, and 77.2%, respectively in the S/CO ratio of 2.7. CONCLUSIONS: The present study indicated that anti-HCV S/Co ratio is useful to predict non-viremic patients. A cut-off value of 2.7 can determine the usefulness of HCV-RNA testing. Patients with S/CO < 2.7 are not viremic; therefore, HCV-RNA testing is not recommended. It is suggested that laboratories report S/CO ratio along with anti-HCV results to manage HCV infection better, especially in countries that quantitative HCV testing is expensive or not available. PMID- 26034550 TI - Expression Profiles of TGF-beta and TLR Pathways in Porphyromonas gingivalis and Prevotella intermedia Challenged Osteoblasts. AB - BACKGROUND: The presence of certain oral pathogens at implant sites can hinder the osseointegration process. However, it is unclear how and by what microorganisms it happens. OBJECTIVES: This study investigated whether the presence of oral pathogens of Porphyromonas gingivalis and Prevotella intermedia individually, play a role in the failure of bone formation by determining the expression profiles of Transforming Growth Factor Beta (TGF-beta/Bone Morphogenic Protein (BMP) and Toll-Like Receptor (TLR) pathways in challenged osteoblasts. MATERIALS AND METHODS: Cell viability of P. gingivalis and P. intermedia challenged osteoblasts were determined by WST assay. Changes in osteoblast morphology and inhibition of mineralization were observed by Scanning Electron Microscopy (SEM) and Von Kossa staining, respectively. Expression of TGF-beta and TLR pathway genes on challenged cells were identified by RT profiler array. Both P. gingivalis and P. intermedia challenges resulted in reduced viability and mineralization of osteoblasts. RESULTS: Viability was reduced to 56.8% (P. gingivalis) and 52.75% (P. intermedia) at 1000 multiplicity. Amongst 48 genes examined, expressions of BMPER, SMAD1, IL8 and NFRKB were found to be highly upregulated by both bacterial challenges (Fold Change > 4). CONCLUSIONS: P. gingivalis and P. intermedia could play a role in implant failure by changing the expression profiles of genes related to bone formation and resorption. PMID- 26034551 TI - Study of aminoglycoside resistance genes in enterococcus and salmonella strains isolated from ilam and milad hospitals, iran. AB - BACKGROUND: Aminoglycosides are a group of antibiotics that have been widely used in the treatment of life-threatening infections of Gram-negative bacteria. OBJECTIVES: This study aimed to evaluate the frequency of aminoglycoside resistance genes in Enterococcus and Salmonella strains isolated from clinical samples by PCR. MATERIALS AND METHODS: In this study, 140 and 79 isolates of Enterococcus and Salmonella were collected, respectively. After phenotypic biochemical confirmation, 117 and 77 isolates were identified as Enterococcus and Salmonella, respectively. After the biochemical identification of the isolates, antibiotic susceptibility for screening of resistance was done using the Kirby Bauer method for gentamicin, amikacin, kanamycin, tobramycin and netilmycin. DNA was extracted from resistant strains and the presence of acc (3)-Ia, aac (3')-Ib, acc (6)-IIa ,16SrRNA methylase genes (armA and rat) was detected by PCR amplification using special primers and positive controls. RESULTS: Enterococcus isolates have the highest prevalence of resistance to both kanamycin and amikacin (68.4%), and Salmonella isolates have the highest prevalence of resistance against kanamycin (6.9%). Ninety-three and 26 isolates of Enterococcus and Salmonella at least were resistant against one of the aminoglycosides, respectively. Moreover, 72.04%, 66.7%, and 36.6% of the resistant strains of Enterococcus had the aac (3')-Ia, aac (3')-IIa, and acc (6')-Ib genes, respectively. None of the Salmonella isolates have the studied aminoglycoside genes. CONCLUSIONS: Our results indicate that acetylation genes have an important role in aminoglycoside resistance of the Enterococcus isolates from clinical samples. Moreover, Salmonella strains indicate very low level of aminoglycoside resistance, and aminoglycoside resistance genes were not found in Salmonella isolates. These results indicate that other resistance mechanisms, including efflux pumps have an important role in aminoglycoside resistance of Salmonella. PMID- 26034553 TI - Identification of Development and Pathogenicity Related Gene in Botrytis cinerea via Digital Gene Expression Profile. AB - BACKGROUND: Botrytis cinerea, a haploid Euascomycete fungus that infects numerous crops, has been used as a model system for studying molecular phytopathology. Botrytis cinerea adopts various modes of infection, which are mediated by a number of pathogenicity and virulence-related genes. Many of these genes have not been reported previously. OBJECTIVES: This study aimed to investigate development and pathogenicity-related genes between a novel nonpathogenic mutant and the Wild Type (WT) in B. cinerea. MATERIALS AND METHODS: Digital Gene Expression (DGE) tag profiling can reveal novel genes that may be involved in development and pathogenicity of plant pathogen. A large volume of B. cinerea tag-seq was generated to identify differential expressed genes by the Illumina DGE tag profiling technology. RESULTS: A total of 4,182,944 and 4,182,021 clean tags were obtained from the WT and a nonpathogenic mutant stain (BCt89), respectively, and 10,410 differentially expressed genes were identified. In addition, 84 genes were expressed in the WT only while 34 genes were expressed in the mutant only. A total of 664 differentially expressed genes were involved in 91 Kyoto Encyclopedia of Genes and Genome pathways, including signaling and metabolic pathways. CONCLUSIONS: Expression levels of 1,426 genes were significantly up regulated in the mutant compared to WT. Furthermore, 301 genes were down regulated with False Discovery Rates (FDR) of < 0.001 and absolute value of log2 Ratio of >= 1. PMID- 26034554 TI - Antimicrobial Activities of the Combined Use of Cuminum Cyminum L. Essential Oil, Nisin and Storage Temperature Against Salmonella typhimurium and Staphylococcus aureus In Vitro. AB - BACKGROUND: Foodborne diseases are considered as major health problems in different countries. Concerns over the safety of some chemical preservatives and negative consumer reactions to them have prompted interest in natural alternatives for the maintenance or extension of food shelf life. In this respect, the combination of a plant essential oil and nisin has used for controlling the growth of foodborne pathogens as natural food preservative using the mathematical model. OBJECTIVES: The purpose of this study was to determine the effect of different concentrations of Cuminum cyminum L. essential oil (0, 15, 30 and 45 uL/100 mL) and nisin (0, 0.5 and 1.5 ug/mL) combination at different temperatures (10, 25 and 35 degrees C) on growth of Salmonella typhimurium and Staphylococcus aureus in the Brain-Heart Infusion (BHI) broth model. The concentrations of 0 uL/100 mL for essential oil and 0 ug/mL for nisin imply the negative control. MATERIALS AND METHODS: A multivariate variance experiment was performed. To assess the effect of essential oil, nisin and the incubation temperature on growth probability (log P%) of S. typhimurium and S. aureus, four concentrations of C. cyminum L. essential oil (0, 15, 30 and 45 uL/100 mL), three concentrations of nisin (0, 0.5 and 1.5 ug/mL) and three storage temperatures (10, 25 and 35 degrees C) were considered. RESULTS: The growth of S. typhimurium was significantly decreased by the concentration of essential oil >= 30 uL/100 mL in combination with nisin >= 0.5 ug/mL at temperature = 10 degrees C (P < 0.05). Also, in combination of the essential oil >= 15 uL/100 mL and nisin >= 0.5 ug/mL at temperature <= 25 degrees C, the growth of S. aureus was significantly reduced (P < 0.05). CONCLUSIONS: These results indicate that the combination of essential oil and nisin inhibits the growth of S. typhimurium and S. aureus bacteria and there is the possibility of using them as substitutes for chemical food preservatives. Moreover, the model (log P%) in this study can be a good tool for the reduction of microbiological hazards in food industry. PMID- 26034552 TI - Study of the Associations Between TT Virus Single and Mixed Infections With Leukemia. AB - BACKGROUND: The pathogenic association of Transfusion Transmitted Virus or Torque teno Virus (TT Virus) single and mixed infections with leukemia was under evaluation in these years but confront with controversies. This hypothesis is based on the higher prevalence of TT Virus infection in patients with leukemia compared with controls. OBJECTIVES: The aim of this study was to determine the frequency of TT Virus, Cytomegalovirus (CMV), Hepatitis B Virus (HBV), and Hepatitis C Virus (HCV) infections in patients with leukemia and healthy controls. PATIENTS AND METHODS: In this cross sectional study, 95 patients with leukemia and 100 healthy controls who were admitted to the Namazi Hospital affiliated to the Shiraz University of Medical Sciences, Shiraz, Iran, were enrolled between years 2012 and 2013. Blood samples treated with EDTA were collected from each patient with leukemia and controls. The existence of TT Virus infection was analyzed using the semi-nested PCR method. The immunological prevalence of HBV and HCV infections were evaluated using HBs-Ag and HCV-Ab ELISA based protocols, respectively. Active CMV infection was also evaluated using an immunofluorescence method. Also risk factors of leukemia and viral infections were statistically analyzed in patients with leukemia. RESULTS: The TT Virus infection was significantly found in 40 of 95 (42.1%) and 12 of 100 (12%) patients with leukemia and controls, respectively. The HBs-Ag and HCV-Ab were detected in 27 of 95 (28.4%) and 18 of 69 (26.1%) patients with leukemia but were not found in the controls. Active CMV infection was also found in 11 of 69 (16%) patients and none of the controls. Significant co-infection of TT Virus was found with HBV (15 of 40; 37.5%), HCV (14 of 40; 35%) and CMV (7 of 40; 17.5%) in patients with leukemia. CONCLUSIONS: Confirmation of the significantly higher frequency of TT Virus, HBV, HCV and CMV single infection and their co-infection in patients with leukemia compared with healthy controls, emphasizes the determinative role of TT Virus pathogenesis in clinical outcomes observed in patients with leukemia, which requires extensive evaluation by further studies. PMID- 26034555 TI - Morphological characterization of potentially pathogenic thermophilic amoebae isolated from surface water in mashhad, iran. PMID- 26034556 TI - Point-of-care ultrasound in the diagnosis of pulmonary embolism. AB - The best diagnostic strategy to confirm or exclude pulmonary embolism (PE) suspicion needs an appropriate combination of clinical assessment, plasma D-dimer measurement, and computed tomographic pulmonary angiography (CTPA). CTPA should be used with caution in some patient groups, such as patients with known allergy to contrast media, those with severe renal insufficiency, and pregnant women, and could be not immediately available in case of unstable patients. In the emergency setting, alternative diagnostic strategies should be implemented to overcome CTPA limitations. Ultrasonography is certainly a valuable alternative diagnostic tool. In addition to echocardiography and lower limb compressive venous ultrasonography, lung ultrasound (US) may play an important role in selected patients' subgroups. Recent data on the diagnostic performance of a triple point of-care US (lung, heart, and leg vein US) are discussed in the present paper, and pros and cons of triple point-of-care US are compared with those of standard diagnostic approaches. PMID- 26034557 TI - Erratum: A pilot controlled trial of insulin-like growth factor-1 in children with Phelan-McDermid syndrome. AB - [This corrects the article DOI: 10.1186/2040-2392-5-54.]. PMID- 26034558 TI - Concept selection for phenotypes and diseases using learn to rank. AB - BACKGROUND: Phenotypes form the basis for determining the existence of a disease against the given evidence. Much of this evidence though remains locked away in text - scientific articles, clinical trial reports and electronic patient records (EPR) - where authors use the full expressivity of human language to report their observations. RESULTS: In this paper we exploit a combination of off-the-shelf tools for extracting a machine understandable representation of phenotypes and other related concepts that concern the diagnosis and treatment of diseases. These are tested against a gold standard EPR collection that has been annotated with Unified Medical Language System (UMLS) concept identifiers: the ShARE/CLEF 2013 corpus for disorder detection. We evaluate four pipelines as stand-alone systems and then attempt to optimise semantic-type based performance using several learn-to-rank (LTR) approaches - three pairwise and one listwise. We observed that whilst overall Apache cTAKES tended to outperform other stand-alone systems on a strong recall (R = 0.57), precision was low (P = 0.09) leading to low-to-moderate F1 measure (F1 = 0.16). Moreover, there is substantial variation in system performance across semantic types for disorders. For example, the concept Findings (T033) seemed to be very challenging for all systems. Combining systems within LTR improved F1 substantially (F1 = 0.24) particularly for Disease or syndrome (T047) and Anatomical abnormality (T190). Whilst recall is improved markedly, precision remains a challenge (P = 0.15, R = 0.59). PMID- 26034559 TI - Region Evolution eXplorer - A tool for discovering evolution trends in ontology regions. AB - BACKGROUND: A large number of life science ontologies has been developed to support different application scenarios such as gene annotation or functional analysis. The continuous accumulation of new insights and knowledge affects specific portions in ontologies and thus leads to their adaptation. Therefore, it is valuable to study which ontology parts have been extensively modified or remained unchanged. Users can monitor the evolution of an ontology to improve its further development or apply the knowledge in their applications. RESULTS: Here we present REX (Region Evolution eXplorer) a web-based system for exploring the evolution of ontology parts (regions). REX provides an analysis platform for currently about 1,000 versions of 16 well-known life science ontologies. Interactive workflows allow an explorative analysis of changing ontology regions and can be used to study evolution trends for long-term periods. CONCLUSION: REX is a web application providing an interactive and user-friendly interface to identify (un)stable regions in large life science ontologies. It is available at http://www.izbi.de/rex. PMID- 26034560 TI - Evolution of neural computations: Mantis shrimp and human color decoding. AB - Mantis shrimp and primates both possess good color vision, but the neural implementation in the two species is very different, a reflection of the largely unrelated evolutionary lineages of these creatures. Mantis shrimp have scanning compound eyes with 12 classes of photoreceptors, and have evolved a system to decode color information at the front-end of the sensory stream. Primates have image-focusing eyes with three classes of cones, and decode color further along the visual-processing hierarchy. Despite these differences, we report a fascinating parallel between the computational strategies at the color-decoding stage in the brains of stomatopods and primates. Both species appear to use narrowly tuned cells that support interval decoding color identification. PMID- 26034561 TI - Is the perception of 3D shape from shading based on assumed reflectance and illumination? AB - The research described in the present article was designed to compare three types of image shading: one generated with a Lambertian BRDF and homogeneous illumination such that image intensity was determined entirely by local surface orientation irrespective of position; one that was textured with a linear intensity gradient, such that image intensity was determined entirely by local surface position irrespective of orientation; and another that was generated with a Lambertian BRDF and inhomogeneous illumination such that image intensity was influenced by both position and orientation. A gauge figure adjustment task was used to measure observers' perceptions of local surface orientation on the depicted surfaces, and the probe points included 60 pairs of regions that both had the same orientation. The results show clearly that observers' perceptions of these three types of stimuli were remarkably similar, and that probe regions with similar apparent orientations could have large differences in image intensity. This latter finding is incompatible with any process for computing shape from shading that assumes any plausible reflectance function combined with any possible homogeneous illumination. PMID- 26034562 TI - Instability of the perceived world while watching 3D stereoscopic imagery: A likely source of motion sickness symptoms. AB - Watching 3D content using a stereoscopic display may cause various discomforting symptoms, including eye strain, blurred vision, double vision, and motion sickness. Numerous studies have reported motion-sickness-like symptoms during stereoscopic viewing, but no causal linkage between specific aspects of the presentation and the induced discomfort has been explicitly proposed. Here, we describe several causes, in which stereoscopic capture, display, and viewing differ from natural viewing resulting in static and, importantly, dynamic distortions that conflict with the expected stability and rigidity of the real world. This analysis provides a basis for suggested changes to display systems that may alleviate the symptoms, and suggestions for future studies to determine the relative contribution of the various effects to the unpleasant symptoms. PMID- 26034563 TI - Comparing artistic and geometrical perspective depictions of space in the visual field. AB - Which is the most accurate way to depict space in our visual field? Linear perspective, a form of geometrical perspective, has traditionally been regarded as the correct method of depicting visual space. But artists have often found it is limited in the angle of view it can depict; wide-angle scenes require uncomfortably close picture viewing distances or impractical degrees of enlargement to be seen properly. Other forms of geometrical perspective, such as fisheye projections, can represent wider views but typically produce pictures in which objects appear distorted. In this study we created an artistic rendering of a hemispherical visual space that encompassed the full visual field. We compared it to a number of geometrical perspective projections of the same space by asking participants to rate which best matched their visual experience. We found the artistic rendering performed significantly better than the geometrically generated projections. PMID- 26034564 TI - A prototype-based resonance model of rhythm categorization. AB - Categorization of rhythmic patterns is prevalent in musical practice, an example of this being the transcription of (possibly not strictly metrical) music into musical notation. In this article we implement a dynamical systems' model of rhythm categorization based on the resonance theory of rhythm perception developed by Large (2010). This model is used to simulate the categorical choices of participants in two experiments of Desain and Honing (2003). The model accurately replicates the experimental data. Our results support resonance theory as a viable model of rhythm perception and show that by viewing rhythm perception as a dynamical system it is possible to model central properties of rhythm categorization. PMID- 26034566 TI - Visual attention at the tip of the tongue. AB - The brain shifts attention by selectively modulating sensory information about relevant environmental features. It has been shown that eye, head, trunk and limb position can bias spatial attention. This leads to the interesting question: Does the brain only recruit bodily information that is explicitly related to orienting behaviour to direct attention, or more generally? We tested whether tongue position, which does not explicitly functionally relate to orienting behaviour, biases attention in a visual search task. Thirty-six participants completed three visual search trial blocks of increased difficulty each consisting of three tongue positions for 50 trials. Response times and error rates were used to assess whether tongue position modulates visual attention. Results show that sensorimotor information from the tongue modulates attention in a difficult visual search task: faster responses to visual search targets presented ipsilateral with the tongue; slower responses when contralateral. In line with cognition being generally embodied, the tongue plays a surprising role in directing attention. PMID- 26034567 TI - The extent of visual space inferred from perspective angles. AB - Retinal images are perspective projections of the visual environment. Perspective projections do not explain why we perceive perspective in 3-D space. Analysis of underlying spatial transformations shows that visual space is a perspective transformation of physical space if parallel lines in physical space vanish at finite distance in visual space. Perspective angles, i.e., the angle perceived between parallel lines in physical space, were estimated for rails of a straight railway track. Perspective angles were also estimated from pictures taken from the same point of view. Perspective angles between rails ranged from 27% to 83% of their angular size in the retinal image. Perspective angles prescribe the distance of vanishing points of visual space. All computed distances were shorter than 6 m. The shallow depth of a hypothetical space inferred from perspective angles does not match the depth of visual space, as it is perceived. Incongruity between the perceived shape of a railway line on the one hand and the experienced ratio between width and length of the line on the other hand is huge, but apparently so unobtrusive that it has remained unnoticed. The incompatibility between perspective angles and perceived distances casts doubt on evidence for a curved visual space that has been presented in the literature and was obtained from combining judgments of distances and angles with physical positions. PMID- 26034565 TI - Differences in perceptual latency estimated from judgments of temporal order, simultaneity and duration are inconsistent. AB - Differences in perceptual latency (DeltaL) for two stimuli, such as an auditory and a visual stimulus, can be estimated from temporal order judgments (TOJ) and simultaneity judgments (SJ), but previous research has found evidence that DeltaL estimated from these tasks do not coincide. Here, using an auditory and a visual stimulus we confirmed this and further show that DeltaL as estimated from duration judgments also does not coincide with DeltaL estimated from TOJ or SJ. These inconsistencies suggest that each judgment is subject to different processes that bias DeltaL in different ways: TOJ might be affected by sensory interactions, a bias associated with the method of single stimuli and an order difficulty bias; SJ by sensory interactions and an asymmetrical criterion bias; duration judgments by an order duration bias. PMID- 26034568 TI - Poggendorff rides again! AB - The Poggendorff illusion is one of the most exhaustively studied illusions. Can it be revived as an interesting problem? Perhaps by moving it to a slightly different domain. Here, we consider the occlusion of a subjectively linear ramp of tonal values. In a simple experiment, we find results closely resembling those of the geometrical Poggendorff. Yet, the "explanations" offered for the latter hardly apply to the former case. Depending upon one's perspective, this may be taken to "revive" the Poggendorff illusion. PMID- 26034570 TI - And now for something completely different: Inattentional blindness during a Monty Python's Flying Circus sketch. AB - Perceptual science has frequently benefited from studying illusions created outside of academia. Here, we describe a striking, but little-known, example of inattentional blindness from the British comedy series "Monty Python's Flying Circus." Viewers fail to attend to several highly incongruous characters in the sketch, despite these characters being clearly visible onscreen. The sketch has the potential to be a valuable research and teaching resource, as well as providing a vivid illustration of how people often fail to see something completely different. PMID- 26034569 TI - Rapid gist perception of meaningful real-life scenes: Exploring individual and gender differences in multiple categorization tasks. AB - In everyday life, we are generally able to dynamically understand and adapt to socially (ir)elevant encounters, and to make appropriate decisions about these. All of this requires an impressive ability to directly filter and obtain the most informative aspects of a complex visual scene. Such rapid gist perception can be assessed in multiple ways. In the ultrafast categorization paradigm developed by Simon Thorpe et al. (1996), participants get a clear categorization task in advance and succeed at detecting the target object of interest (animal) almost perfectly (even with 20 ms exposures). Since this pioneering work, follow-up studies consistently reported population-level reaction time differences on different categorization tasks, indicating a superordinate advantage (animal versus dog) and effects of perceptual similarity (animals versus vehicles) and object category size (natural versus animal versus dog). In this study, we replicated and extended these separate findings by using a systematic collection of different categorization tasks (varying in presentation time, task demands, and stimuli) and focusing on individual differences in terms of e.g., gender and intelligence. In addition to replicating the main findings from the literature, we find subtle, yet consistent gender differences (women faster than men). PMID- 26034571 TI - Suppressive and enhancing effects in early visual cortex during illusory shape perception: A comment on. AB - In a recent functional magnetic resonance imaging study, Kok and de Lange (2014) observed that BOLD activity for a Kanizsa illusory shape stimulus, in which pacmen-like inducers elicit an illusory shape percept, was either enhanced or suppressed relative to a nonillusory control configuration depending on whether the spatial profile of BOLD activity in early visual cortex was related to the illusory shape or the inducers, respectively. The authors argued that these findings fit well with the predictive coding framework, because top-down predictions related to the illusory shape are not met with bottom-up sensory input and hence the feedforward error signal is enhanced. Conversely, for the inducing elements, there is a match between top-down predictions and input, leading to a decrease in error. Rather than invoking predictive coding as the explanatory framework, the suppressive effect related to the inducers might be caused by neural adaptation to perceptually stable input due to the trial sequence used in the experiment. PMID- 26034572 TI - Stimulus-parity synaesthesia versus stimulus-dichotomy synaesthesia: Odd, even or something else? AB - In stimulus-parity synaesthesia, a range of stimuli-for example, letters, numbers, weekdays, months, and colours (the inducers)-elicit an automatic feeling of oddness or evenness (the concurrent). This phenomenon was first described by Theodore Flournoy in 1893, and has only recently been "rediscovered." Here, we describe an individual who experiences a comparable phenomenon, but uses the labels negative and positive rather than odd and even. Stimulus-parity synaesthesia may be broader than first supposed, and it is important that assessments are sensitive to this breadth. PMID- 26034573 TI - Suppressed visual looming stimuli are not integrated with auditory looming signals: Evidence from continuous flash suppression. AB - Previous studies using binocular rivalry have shown that signals in a modality other than the visual can bias dominance durations depending on their congruency with the rivaling stimuli. More recently, studies using continuous flash suppression (CFS) have reported that multisensory integration influences how long visual stimuli remain suppressed. In this study, using CFS, we examined whether the contrast thresholds for detecting visual looming stimuli are influenced by a congruent auditory stimulus. In Experiment 1, we show that a looming visual stimulus can result in lower detection thresholds compared to a static concentric grating, but that auditory tone pips congruent with the looming stimulus did not lower suppression thresholds any further. In Experiments 2, 3, and 4, we again observed no advantage for congruent multisensory stimuli. These results add to our understanding of the conditions under which multisensory integration is possible, and suggest that certain forms of multisensory integration are not evident when the visual stimulus is suppressed from awareness using CFS. PMID- 26034574 TI - Molecular characterization and embryonic origin of the eyes in the common house spider Parasteatoda tepidariorum. AB - BACKGROUND: Two visual systems are present in most arthropod groups: median and lateral eyes. Most of our current knowledge about the developmental and molecular mechanisms involved in eye formation in arthropods comes from research in the model system Drosophila melanogaster. Here, a core set of retinal determination genes, namely, sine-oculis (so), eyes absent (eya), dachshund (dac), and the two pax6 orthologues eyeless (ey) and twin of eyeless (toy) govern early retinal development. By contrast, not much is known about the development of the up-to eight eyes present in spiders. Therefore, we analyzed the embryonic expression of core retinal determination genes in the common house spider Parasteatoda tepidariorum. RESULTS: We show that the anlagen of the median and lateral eyes in P. tepidariorum originate from different regions of the non-neurogenic ectoderm in the embryonic head. The median eyes are specified as two individual anlagen in an anterior median position in the developing head and subsequently move to their final position following extensive morphogenetic movements of the non-neurogenic ectoderm. The lateral eyes develop from a more lateral position. Intriguingly, they are specified as a unique field of cells that splits into the three individual lateral eyes during late embryonic development. Using gene expression analyses, we identified a unique combination of determination gene expression in the anlagen of the lateral and median eyes, respectively. CONCLUSIONS: This study of retinal determination genes in the common house spider P. tepidariorum represents the first comprehensive analysis of the well-known retinal determination genes in arthropods outside insects. The development of the individual lateral eyes via the subdivision of one single eye primordium might be the vestige of a larger composite eye anlage, and thus supports the notion that the composite eye is the plesiomorphic state of the lateral eyes in arthropods. The molecular distinction of the two visual systems is similar to the one described for compound eyes and ocelli in Drosophila, suggesting that a unique core determination network for median and lateral eyes, respectively, might have been in place already in the last common ancestor of spiders and insects. PMID- 26034575 TI - Differential expression of retinal determination genes in the principal and secondary eyes of Cupiennius salei Keyserling (1877). AB - BACKGROUND: Transcription factors that determine retinal development seem to be conserved in different phyla throughout the animal kingdom. In most representatives, however, only a few of the involved transcription factors have been sampled and many animal groups remain understudied. In order to fill in the gaps for the chelicerate group of arthropods, we tested the expression pattern of the candidate genes involved in the eye development in the embryo of the wandering spider Cupiennius salei. One main objective was to profile the molecular development of the eyes and to search for possible variation among eye subtype differentiation. A second aim was to form a basis for comparative studies in order to elucidate evolutionary pathways in eye development. RESULTS: We screened the spider embryonic transcriptome for retina determination gene candidates and discovered that all except one of the retinal determination genes have been duplicated. Gene expression analysis shows that the two orthologs of all the genes have different expression patterns. The genes are mainly expressed in the developing optic neuropiles of the eyes (lateral furrow, mushroom body, arcuate body) in earlier stages of development (160 to 220 h after egg laying). Later in development (180 to 280 h after egg laying), there is differential expression of the genes in disparate eye vesicles; for example, Cs-otxa is expressed only in posterior-lateral eye vesicles, Cs-otxb, Cs-six1a, and Cs-six3b in all three secondary eye vesicles, Cs-pax6a only in principal eye vesicles, Cs six1b in posterior-median, and posterior-lateral eye vesicles, and Cs-six3a in lateral and principal eye vesicles. CONCLUSIONS: Principle eye development shows pax6a (ey) expression, suggesting pax6 dependence, although secondary eyes develop independently of pax6 genes and show differential expression of several retinal determination genes. Comparing this with the other arthropods suggests that pax6-dependent median eye development is a ground pattern of eye development in this group and that the ocelli of insects, the median eyes of chelicerates, and nauplius eyes can be homologised. The expression pattern of the investigated genes makes it possible to distinguish between secondary eyes and principal eyes. Differences of gene expression among the different lateral eyes indicate disparate function combined with genetic drift. PMID- 26034576 TI - Israeli Druze women's sex preferences when choosing obstetricians and gynecologists. AB - BACKGROUND: Consideration and better understanding of patients' needs on the part of the healthcare system might help increase the number of people seeking necessary medical care. Many studies have been conducted on patients' preferences in choosing their health care provider, but the majority of them were conducted in modern western societies, establishing a need to explore other populations. The present study was performed in the Israeli Druze community which is composed of a uniquely traditional and religious population. We assessed the sex preference of Israeli Druze women regarding obstetricians/gynecologists, and identify other features that affect their choice. METHOD: We conducted a cross sectional study that included 196 Israeli Druze women who anonymously completed a 36-item questionnaire between January-July, 2011. RESULTS: Most (63.8%) of the responders preferred female obstetricians/gynecologists, while 74.5% had no sex preference for their family physicians. 68.6% of the religious women preferred female obstetricians/gynecologists as compared to 51.76% of those women who self identified as secular. Most of the women (65%) preferred female obstetricians/gynecologists for intimate procedures, such as pelvic examination and pregnancy follow-up. The main reasons given were: feeling more comfortable with a female practitioner (69.7%), the belief that females are more gentle (56.6%), and being more embarrassed with male obstetricians/gynecologists (45.4%). Three factors were associated with the responders' preferences for female obstetricians/gynecologists: their age and religious status, and the sex of their regular obstetricians/gynecologists. Women who preferred a female obstetrician/gynecologist assigned a lesser weight to the physician's knowledge when choosing them. Older and religious women as well as those who attributed less weight to the physician's professional knowledge were more likely to prefer a female obstetrician/gynecologist. CONCLUSIONS: The majority of responders to our survey (Israeli Druze women), like those in other communities where religiousness and modesty are deeply rooted, prefer female obstetricians/gynecologists, with the overwhelming reasons given being feeling more comfortable and less embarrassed with females, and the notion that female obstetricians/gynecologists are more gentle during intimate procedures. PMID- 26034577 TI - Physicians' behavior following changes in LDL cholesterol target goals. AB - BACKGROUND: In 01/2011 Clalit Health Services (CHS), changed the LDL-Cholesterol target definitions in its quality indicators program, from a universal target to values stratified by risk assessment based on ATP III criteria. The objective of this study is to evaluate the effect of this change on achievement of LDL-C targets and on physicians' prescriptions of statins. STUDY DESIGN: A descriptive study based on administrative dataset 06/2010-06/2012. METHODS: SETTING: CHS, The largest health maintenance organization in Israel that insures above 4,000,000 beneficiaries. PATIENTS: PATIENTS who had been in the same risk group throughout the study period. MEASUREMENTS: Attainment of targets for LDL-C and purchases of statins prior to, and following, implementation of the guidelines in the CHS quality indicators program. RESULTS: 433,662 patients remained in the same risk groups throughout the study period; 55.8% were women; the average age was 53.0 +/- 10.3 years; 63.9%, 13.4%, and 22.7% were at low, medium, and high risk respectively. After implementation, the proportion of patients reaching LDL C targets increased in all risk groups: from 58.6% to 61.6%, from 55.1% to 61.1%, and from 44.5% to 49.0%, in low, medium, and high risk groups respectively (p < 0.001). The proportion of patients treated with potent statins increased in all risk groups; from 3.4% to 5.6%, from 6.7% to 10.3%, and from 14.5% to 20.3% respectively (p < 0.001). CONCLUSION: The risk stratification approach as a basis for the quality indicators program was implemented and better achievement of target LDL-C levels ensued. We suggest that implementation of quality indicators that are consistent with the current literature can lead to improvements that exceeds temporal trends. PMID- 26034579 TI - Usefulness of open mixed nut challenges to exclude tree nut allergy in children. AB - BACKGROUND: To minimize the risk of accidental reactions, atopic children with multiple sensitizations to tree nuts are advised to avoid all nuts. Multiple food challenges would be needed to confirm the clinical relevance, but are too burdensome to be practical. The usefulness of open mixed nut challenges in terms of safety, reactions during challenge, tolerance of the challenge material, effect on the elimination diet and satisfaction of the parents was evaluated. FINDINGS: Open mixed nut challenges were performed in 19 children with a previous negative hazelnut challenge and long term elimination diet for tree nuts. Challenges were negative in 13 (68 %) children, in four (21 %) children (non severe) allergic symptoms were observed. The challenges were well accepted, safe and efficient. We were able to avoid multiple nut challenges in 15 (79 %) children. CONCLUSIONS: Open mixed nut challenge can efficiently exclude multiple tree nut allergies in children with a lifelong nut free diet and low suspicion of clinical allergy. PMID- 26034580 TI - Change in lumbar lordosis during prone lying knee flexion test in subjects with and without low back pain. AB - BACKGROUND: Prone lying knee flexion (PLKF) is one of the clinical tests used for assessment of the lumbo-pelvic movement pattern. Considerable increase in lumbar lordosis during this test has been considered as impairment of movement patterns in lumbar-pelvic region. However, no study has directly evaluated the change in lordosis during active PLKF test in subjects with low back pain (LBP). The purpose of this study was to investigate the change of lumbar lordosis in PLKF test in subjects with and without LBP. METHODS: A convenience sample of 80 subjects participated in the study. Subjects were categorized into two groups: those with chronic non-specific LBP (N = 40, mean age: 40.84 +/- 17.59) and with no history of LBP (N = 40, mean age: 23.57 +/- 10.61). Lumbar lordosis was measured with flexible ruler, first in prone position and then on active PKF test in both subjects with and without LBP. Data was analyzed by using statistical methods such as, independent t-test and paired t-test. RESULTS: There were statistically significant differences in lumbar lordosis between prone position and after active PLKF in both subjects with and without LBP (P < 0.0001). The amount of change in lordosis during PLKF test was not significant between the two groups (P = 0.65). However these changes were greater among patients with LBP. CONCLUSION: Increase in lumbar lordosis during this test may be due to excessive flexibility of movement of the lumbar spine in the direction of extension and abnormal movement patterns in the individuals with LBP. PMID- 26034581 TI - Non-invasive sources of cells with primary cilia from pediatric and adult patients. AB - BACKGROUND: Ciliopathies give rise to a multitude of organ-specific pathologies; obtaining relevant primary patient material is useful for both diagnostics and research. However, acquisition of primary ciliated cells from patients, particularly pediatric patients, presents multiple difficulties. Biopsies and blood samples are invasive, and patients (and their parents) may be reluctant to travel to medical centers, especially for research purposes. We sought to develop non-invasive methods of obtaining viable and ciliated primary cells from ciliopathy patients which could be obtained in the home environment. FINDINGS: We introduce two methods for the non-invasive acquisition of primary ciliated cells. In one approach, we collected spontaneously shed deciduous (milk) teeth from children. Fibroblast-like cells were observed after approximately 2 weeks of culture of fragmented teeth. Secondly, urine samples were collected from children or adults. Cellular content was isolated and after approximately 1 week, renal epithelial cells were observed. Both urine and tooth-derived cells ciliate and express ciliary proteins visible with immunofluorescence. Urine-derived renal epithelial cells (URECs) are amenable to 3D culturing, siRNA knockdown, and ex vivo drug testing. CONCLUSIONS: As evidence continues to accumulate showing that the primary cilium has a central role in development and disease, the need for readily available and ciliated patient cells will increase. Here, we introduce two methods for the non-invasive acquisition of cells with primary cilia. We believe that these cells can be used for further ex vivo study of ciliopathies and in the future, for personalized medicine. PMID- 26034582 TI - The impact of antimicrobial allergy labels on antimicrobial usage in cancer patients. AB - BACKGROUND: Antibiotic allergy labels are associated with sub-optimal prescribing patterns and poorer clinical outcomes in non-cancer populations, but the effect of labelling on antimicrobial usage in patients with cancer is unknown. FINDINGS: A retrospective review of hospitalized patients admitted to the Peter MacCallum Cancer Centre (2010-2012) identified 23 % of cancer patients (n = 198) with an antimicrobial allergy label (AA). Comparison of those with an antimicrobial allergy label to those without demonstrated increased antibiotic use per admission (3 vs. 2, p = 0.01), increased fluoroquinolone use (11 % vs. 6 %, p < 0.05), increased antibiotic course duration (15 vs. 13 days, p = 0.09), higher readmission rates (53 % vs. 28 %, p < 0.001) and poorer concordance with prescribing guidelines (47 % vs. 91 %, p < 0.001). Patients in the AA group on multivariate analysis had a higher number of antibiotics employed, longer duration of antibiotic therapy and higher rate of readmission. CONCLUSIONS: Antimicrobial usage, including the use of restricted antibiotics, is higher in patients with cancer. Antibiotic de-labelling strategies in cancer patients must be evaluated to aid antimicrobial stewardship initiatives. PMID- 26034578 TI - Sleep and REM sleep disturbance in the pathophysiology of PTSD: the role of extinction memory. AB - Post-traumatic stress disorder (PTSD) is accompanied by disturbed sleep and an impaired ability to learn and remember extinction of conditioned fear. Following a traumatic event, the full spectrum of PTSD symptoms typically requires several months to develop. During this time, sleep disturbances such as insomnia, nightmares, and fragmented rapid eye movement sleep predict later development of PTSD symptoms. Only a minority of individuals exposed to trauma go on to develop PTSD. We hypothesize that sleep disturbance resulting from an acute trauma, or predating the traumatic experience, may contribute to the etiology of PTSD. Because symptoms can worsen over time, we suggest that continued sleep disturbances can also maintain and exacerbate PTSD. Sleep disturbance may result in failure of extinction memory to persist and generalize, and we suggest that this constitutes one, non-exclusive mechanism by which poor sleep contributes to the development and perpetuation of PTSD. Also reviewed are neuroendocrine systems that show abnormalities in PTSD, and in which stress responses and sleep disturbance potentially produce synergistic effects that interfere with extinction learning and memory. Preliminary evidence that insomnia alone can disrupt sleep-dependent emotional processes including consolidation of extinction memory is also discussed. We suggest that optimizing sleep quality following trauma, and even strategically timing sleep to strengthen extinction memories therapeutically instantiated during exposure therapy, may allow sleep itself to be recruited in the treatment of PTSD and other trauma and stress-related disorders. PMID- 26034583 TI - 2012 ERA-EDTA Registry Annual Report: cautious optimism on outcomes, concern about persistent inequalities and data black-outs. AB - The 2012 ERA-EDTA Registry Annual Report contains both good news and bad news. On the bright side, the 2-year survival of patients starting renal replacement therapy (RRT) for chronic kidney disease (CKD), on dialysis or receiving a living related kidney transplantation, has progressively increased to 82.2, 79.7 and 98.3%, respectively, whereas for cadaveric kidney transplantation it remains stable (96.0-96.1%). On the dark side, inequalities persist between European citizens in access to renal transplantation and in incidence and prevalence of RRT. Living in Greece, Belgium (French- or Dutch-speaking) or Portugal (the GBP countries) is associated with higher chances of initiating RRT than living in other European countries. The adjusted RRT incidence for GBP countries was 188, 201-174 and 220* (* unadjusted) pmp in 2012, respectively (versus 122, 114 and 97 pmp in the Netherlands or two Spanish regions bordering Portugal). In lower income countries, a low RRT incidence may represent lack of access to needed healthcare (e.g. Montenegro 26 pmp). However, how can the high incidence and prevalence of RRT in the GBP countries be explained? Do GBP citizens have access to RRT that is denied, rejected or considered unnecessary in other high income countries? Does the GBP healthcare system fail to prevent progression of CKD? Do local genetic or environmental factors favour CKD progression? Unravelling the underlying reasons is an urgent research need: only an understanding of the causes will allow correction of the problem. Unavailability of data from some large countries (e.g. Germany and Italy) is not helpful. PMID- 26034585 TI - Improving patient safety in haemodialysis. AB - Thomas Inman (1820-76) wrote 'Practice two things in your dealings with disease: either help or do not harm the patient', echoing writings from the Hippocratic school. The challenge of practicing safely with the avoidance of complications or harm is perhaps only heightened in the context of modern medical settings such as the haemodialysis unit where complex interventions and treatment are routine. The current issue of CKJ reports two studies aimed at improving the care of haemodialysis patients targeting early use of arteriovenous grafts as access for haemodialysis and the implementation of a dialysis checklist to ensure the prescribed dialysis treatment is delivered. The further challenge of ensuring that such evidence-based tools are used appropriately and consistently falls to all members of the clinical team. PMID- 26034584 TI - Renal replacement therapy in Europe: a summary of the 2012 ERA-EDTA Registry Annual Report. AB - BACKGROUND: This article summarizes the 2012 European Renal Association-European Dialysis and Transplant Association Registry Annual Report (available at www.era edta-reg.org) with a specific focus on older patients (defined as >=65 years). METHODS: Data provided by 45 national or regional renal registries in 30 countries in Europe and bordering the Mediterranean Sea were used. Individual patient level data were received from 31 renal registries, whereas 14 renal registries contributed data in an aggregated form. The incidence, prevalence and survival probabilities of patients with end-stage renal disease (ESRD) receiving renal replacement therapy (RRT) and renal transplantation rates for 2012 are presented. RESULTS: In 2012, the overall unadjusted incidence rate of patients with ESRD receiving RRT was 109.6 per million population (pmp) (n = 69 035), ranging from 219.9 pmp in Portugal to 24.2 pmp in Montenegro. The proportion of incident patients >=75 years varied from 15 to 44% between countries. The overall unadjusted prevalence on 31 December 2012 was 716.7 pmp (n = 451 270), ranging from 1670.2 pmp in Portugal to 146.7 pmp in the Ukraine. The proportion of prevalent patients >=75 years varied from 11 to 32% between countries. The overall renal transplantation rate in 2012 was 28.3 pmp (n = 15 673), with the highest rate seen in the Spanish region of Catalonia. The proportion of patients >=65 years receiving a transplant ranged from 0 to 35%. Five-year adjusted survival for all RRT patients was 59.7% (95% confidence interval, CI: 59.3-60.0) which fell to 39.3% (95% CI: 38.7-39.9) in patients 65-74 years and 21.3% (95% CI: 20.8-21.9) in patients >=75 years. PMID- 26034586 TI - Implementation of a quality and safety checklist for haemodialysis sessions. AB - BACKGROUND: Patient survival and quality of life depend on each haemodialysis session being performed without fault. Monthly assessments of dialysis dose adequacy often fall short of this. This study reports the results of a feasibility study for the achievement of improved safety and quality in a haemodialysis session with the implementation of a 15-point checklist. METHODS: Fifteen quality indicators were compiled and tested in a Portuguese dialysis clinic from 1 February 2012 to 30 June 2013. The checklist was completed by the nursing staff and comprised three parts: Pre-session Safety Checks; Session Initiation Checks and Post-session Quality Checks. The maximum score that could be reached per session was 15. RESULTS: One hundred and twenty-eight patients were distributed over 2-3 shifts. Of the 16 nurses employed, 4 were full time. The final average score was between 14 and 15. No nurse-specific and no shift specific significant differences were detected. Four issues were identified that had a major effect on the results as a whole: delays in connection time; incompletely delivered treatment time; non-achievement of final body weight and failure to reach a Kt/V of at least 1.4. Improvements were most consistent in the Monday-Wednesday-Friday morning shifts compared with other shifts, and were temporarily compromised by the opening of a new shift. CONCLUSIONS: The implementation of checklists for haemodialysis is feasible in routine clinical practice, even in clinics where only part of the staff is employed full time. The application of such checklists enhances the overall quality and safety of the delivered treatment. PMID- 26034587 TI - The first year on haemodialysis: a critical transition. AB - The first year following the start of haemodialysis (HD) is associated with increased mortality, especially during the first 90-120 days after the start of dialysis. Whereas the start of dialysis has important effects on the internal environment of the patient, there are relatively few studies assessing changes in phenotype and underlying mechanisms during the transition period following pre dialysis to dialysis care, although more insight into these parameters is of importance in unravelling the causes of this increased early mortality. In this review, changes in cardiovascular, nutritional and inflammatory parameters during the first year of HD, as well as changes in physical and functional performance are discussed. Treatment-related factors that might contribute to these changes include vascular access and pre-dialysis care, dialysate prescription and the insufficient correction of the internal environment by current dialysis techniques. Patient-related factors include the ongoing loss of residual renal function and the progression of comorbid disease. Identifying phenotypic changes and targeting risk patterns might improve outcome during the transition period. Given the scarcity of data on this subject, more research is needed. PMID- 26034588 TI - Preoperative assessment and planning of haemodialysis vascular access. AB - Effective haemodialysis (HD) requires a reliable vascular access (VA). Clinical practice guidelines strongly recommend the arteriovenous fistula (AVF) as the preferred VA in HD patients. The creation of an AVF should be promoted in all eligible patients who choose HD, as it improves outcomes and reduces costs when compared with central venous catheters. Fistula eligibility is a 'work in progress'. Three steps in order to increase the pool of eligible patients can be individualized: (i) process of care, which includes three fundamental items: the VA team, early VA education and timely VA surgery referral; (ii) preoperative evaluation; (iii) surgical strategy. Nephrologists should be able to play a leading and coordinating role of the VA team. They should design a plan that identifies a sequence of options that can be used to provide adequate renal replacement therapy throughout the life span of every end-stage renal disease patient. The main points of this strategy are (i) early vascular education, in which a 'save the vein program' should always be implemented; (ii) timely VA surgery referral and preoperative evaluation: careful examination of arterial and venous beds is mandatory before VA placement; physical examination in addition to colour Doppler ultrasound mapping improves AVF outcomes; (iii) surgical strategy: a successful VA strategy must take into account vascular anatomy, clinical factors and prognosis. PMID- 26034589 TI - Current tools for prediction of arteriovenous fistula outcomes. AB - It remains challenging to accurately predict whether an individual arteriovenous fistula (AVF) will mature and be useable for haemodialysis vascular access. Current best practice involves the use of routine clinical assessment and ultrasonography complemented by selective venography and magnetic resonance imaging. The purpose of this literature review is to describe current practices in relation to pre-operative assessment prior to AVF formation and highlight potential areas for future research to improve the clinical prediction of AVF outcomes. PMID- 26034590 TI - Timing of cannulation of arteriovenous grafts: are we too cautious? AB - BACKGROUND: Timing of first cannulation of an arteriovenous graft has been the subject of great debate for clinicians worldwide. In this paper, we reviewed the current literature on the timing of first cannulation of arteriovenous grafts. METHODS: Searches of PubMed, Medline and the Cochrane Library were performed using specific search terms to identify articles, dealing primarily with the timing of dialysis graft cannulation. RESULTS: Following strict inclusion/exclusion criteria by two reviewers, eleven studies were included and divided into subgroups for ePTFE and new generation grafts. CONCLUSIONS: The current literature does not seem to support the current guidelines as there is no evidence to suggest that a delay in cannulation of grafts will improve graft survival and patency. PMID- 26034591 TI - Pregnancy in end-stage renal disease patients on dialysis: how to achieve a successful delivery. AB - Pregnancy in women with chronic kidney disease has always been considered as a challenging event both for the mother and the fetus. Over the years, several improvements have been achieved in the outcome of pregnant chronic renal patients with increasing rates of successful deliveries. To date, evidence suggests that the stage of renal failure is the main predictive factor of worsening residual kidney function and complications in pregnant women. Moreover, the possibility of success of the pregnancy depends on adequate depurative and pharmacological strategies in patients with end-stage renal disease. In this paper, we propose a review of the current literature about this topic presenting our experience as well. PMID- 26034592 TI - Disaster nephrology: a new concept for an old problem. AB - Natural and man-made mass disasters directly or indirectly affect huge populations, who need basic infrastructural help and support to survive. However, despite the potentially negative impact on survival chances, these health care issues are often neglected by the authorities. Treatment of both acute and chronic kidney diseases (CKDs) is especially problematic after disasters, because they almost always require complex technology and equipment, whereas specific drugs may be difficult to acquire for the treatment of the chronic kidney patients. Since many crush victims in spite of being rescued alive from under the rubble die afterward due to lack of dialysis possibilities, the terminology of 'renal disaster' was introduced after the Armenian earthquake. It should be remembered that apart from crush syndrome, multiple aetiologies of acute kidney injury (AKI) may be at play in disaster circumstances. The term 'seismonephrology' (or earthquake nephrology) was introduced to describe the need to treat not only a large number of AKI cases, but the management of patients with CKD not yet on renal replacement, as well as of patients on haemodialysis or peritoneal dialysis and transplanted patients. This wording was later replaced by 'disaster nephrology', because besides earthquakes, many other disasters such as hurricanes, tsunamis or wars may have a negative impact on the ultimate outcome of kidney patients. Disaster nephrology describes the handling of the many medical and logistic problems in treating kidney patients in difficult circumstances and also to avoid post-disaster chaos, which can be made possible by preparing medical and logistic scenarios. Learning and applying the basic principles of disaster nephrology is vital to minimize the risk of death both in AKI and CKD patients. PMID- 26034593 TI - A review of acute and chronic peritoneal dialysis in developing countries. AB - Various modalities of renal replacement therapy (RRT) are available for the management of acute kidney injury (AKI) and end-stage renal disease (ESRD). While developed countries mainly use hemodialysis as a form of RRT, peritoneal dialysis (PD) has been increasingly utilized in developing countries. Chronic PD offers various benefits including lower cost, home-based therapy, single access, less requirement of highly trained personnel and major infrastructure, higher number of patients under a single nephrologist with probably improved quality of life and freedom of activities. PD has been found to be lifesaving in the management of AKI in patients in developing countries where facilities for other forms of RRT are not readily available. The International Society of Peritoneal Dialysis has published guidelines regarding the use of PD in AKI, which has helped in ensuring uniformity. PD has also been successfully used in certain special situations of AKI due to snake bite, malaria, febrile illness, following cardiac surgery and in poisoning. Hemodialysis is the most common form of RRT used in ESRD worldwide, but some countries have begun to adopt a 'PD first' policy to reduce healthcare costs of RRT and ensure that it reaches the underserved population. PMID- 26034595 TI - Influenza virus vaccination and kidney graft rejection: causality or coincidence. AB - Influenza can cause significant morbidity and mortality in renal transplant recipients especially with a high rate of lower respiratory disease. Annual influenza vaccination is therefore recommended to renal transplant recipients. We report the first three cases of acute kidney injury in renal transplant recipients following influenza vaccination that all led to graft loss. They all had different native diseases and were all vaccinated in the same season of 2009 10. The time span from vaccination to decline of kidney function is shorter than the time to diagnosis since the three patients only had blood tests every 3 months or when symptoms became severe. These reports do not justify a change of current recommendations regarding influenza vaccination in renal transplant recipients, but they support the continued attention and registration of vaccinations to monitor side effects. PMID- 26034594 TI - The ABC of pneumococcal infections and vaccination in patients with chronic kidney disease. AB - BACKGROUND: In the general population, pneumococcal polysaccharide vaccines (PPV) decrease the incidence of invasive pneumococcal disease (IPD) whereas the impact on the prevention of noninvasive pneumococcal disease is less clear. As compared with PPV, pneumococcal conjugate vaccines (PCV) provoke a higher, longer-lasting immune response resulting in a 45% decreased incidence in vaccine-type pneumonia, and a 75% decrease in vaccine-type IPD. METHODS: Literature review on pneumococcal vaccination in end-stage renal disease. RESULTS: As compared with the general population, patients with chronic kidney disease (CKD) suffer increased mortality and morbidity from pneumococcal disease (PD), being up to 10 fold for those treated with dialysis. Numerous, usually small and methodological heterogeneous studies demonstrate that PPV provokes a serological response in dialysis patients, kidney transplant recipients, children with nephrotic syndrome and CKD patients receiving immunosuppressive medication. This response is of less intensity and duration than in healthy controls. Similar observations were made for the PCV. The protective value of these vaccine-elicited anti-pneumococcal antibodies in the CKD population remains to be substantiated. For patients treated with dialysis, epidemiological data demonstrate a correlation-which does not equal causality-between pneumococcal vaccination status and a slightly decreased total mortality. Clinical outcome data on the effectiveness of pneumococcal vaccination in the prevention of morbidity and mortality in the CKD population are lacking. CONCLUSIONS: Awaiting better evidence, pneumococcal vaccination should be advocated in all patients with CKD, as early in their disease course as possible. The ACIP schedule recommends a PCV-13 prime vaccination followed by a PPV-23 repeated vaccine at least 8 weeks later in pneumococcal non-vaccinated patients, and a PCV-13 vaccine at least 1 year after the latest PPV vaccine in previously vaccinated patients. In the UK, vaccination with PPV-23 only is recommended. There exist no good data supporting re vaccination after 5 years in the dialysis population. PMID- 26034596 TI - Posttransplant outcome of atypical haemolytic uraemic syndrome in a patient with thrombomodulin mutation: a case without recurrence. AB - Atypical haemolytic uraemic syndrome (aHUS) is a rare disease characterized by thrombocytopenia, microangiopathic haemolytic anaemia and renal impairment. Mutations in genes encoding inhibitors of the alternative pathway of the complement system are involved in ~50% of the cases. Thrombomodulin (THBD) gene mutations occur in ~3-5% of the cases. The risk of aHUS recurrence after kidney transplantation depends on the complement abnormality involved. In all three cases of THBD mutation reported to date, aHUS recurred after kidney transplantation (KT) with early graft loss. No data exist about therapeutic approaches before kidney transplantation to reduce the risk of recurrence in patients carrying this mutation. Favourable data on the use of eculizumab have been reported, in terms of plasmatherapy withdrawal and renal function recovery in aHUS recurrence after KT. To our knowledge, this case report presents the first case of successful kidney transplantation in a patient with aHUS due to THBD mutation who was treated with a single plasma-exchange immediately before surgery without recurrence of the disease 12 months after transplantation. PMID- 26034597 TI - Gut microbiota and inflammation in chronic kidney disease patients. AB - Inflammation is a multifactorial phenotype that in chronic kidney disease is associated with adverse patient outcomes. Recently, alterations in gut microbiota composition and intestinal barrier have been associated with inflammation and oxidative stress in CKD patients. Vanholder and Glorieux recently critically reviewed [Clin Kidney J (2015) 8 (2): 168-179] the current understanding of the role of gut microbiota in the production of uraemic toxins and the therapeutic implications. Where do we stand now? The basic mechanisms of the gut-kidney crosstalk must still be clarified. In addition, the efficacy and safety of therapeutic strategies to modulate the gut microbiota in order to decrease uraemic toxin production and inflammation in chronic kidney disease should be evaluated. Finally, an impact of such strategies on hard outcomes should be demonstrated before incorporation into routine clinical practice. PMID- 26034598 TI - Cesium-associated hypokalemia successfully treated with amiloride. AB - Self-treatment of cancer with cesium chloride, despite proven lack of efficacy, continues to produce serious adverse effects. Among these is hypokalemia predisposing to life-threatening arrhythmia. The mechanism of cesium-associated hypokalemia (CAH) has not been described. We report urinary potassium wasting responsive to amiloride therapy in a cancer patient with CAH, and discuss possible mechanisms. PMID- 26034599 TI - Heroin crystal nephropathy. AB - In this paper we present an interesting case of acute kidney injury and severe metabolic alkalosis in a patient with a history of heavy heroin abuse. Urine microscopy showed numerous broomstick-like crystals. These crystals are also identified in light and electron microscopy. We hypothesize that heroin crystalizes in an alkaline pH, resulting in tubular obstruction and acute kidney injury. Management is mainly supportive as there is no known specific therapy for this condition. This paper highlights the utility of urine microscopy in diagnosing the etiology of acute kidney injury and proposes a novel disease called heroin crystal nephropathy. PMID- 26034600 TI - The kidneys and ANCA-associated vasculitis: from pathogenesis to diagnosis. AB - Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of pauci-immune small vessel vasculitides that often affect the kidneys manifesting as rapidly progressive glomerulonephritis. Although the exact pathogenesis of AAV is not fully known, evidence from in vitro, in vivo and clinical studies all point to the involvement of ANCA in the pathogenesis of AAV. In this review, we highlight the contributory roles played by various factors (e.g. genetics, environment, B and T-regulatory cells, toll-like receptors, etc.) in the pathogenesis of AAV. Furthermore, we discuss renal involvement in AAV in terms of clinical features and the various histopathological classification patterns, which are also known to be of prognostic importance. We also present information on useful imaging techniques for localizing kidney and other organ system involvement in AAV, and also on novel laboratory methods and assays useful for rapid and more specific determination of patients' ANCA status. Finally, we demonstrate evidence on novel serum biomarkers that have been shown to correlate with disease activity in AAV. PMID- 26034601 TI - Inflammation-associated microbiota in pediatric eosinophilic esophagitis. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is an allergic disorder characterized by eosinophil-predominant esophageal inflammation, which can be ameliorated by food antigen restriction. Though recent studies suggest that changes in dietary composition may alter the distal gut microbiome, little is currently known about the impact of a restricted diet upon microbial communities of the oral and esophageal microenvironments in the context of EoE. We hypothesize that the oral and esophageal microbiomes of EoE patients are distinct from non-EoE controls, that these differences correspond to changes in esophageal inflammation, and that targeted therapeutic dietary intervention may influence community structure. Using 16S rRNA gene sequencing, we characterized the bacterial composition of the oral and esophageal microenvironments using oral swabs and esophageal biopsies from 35 non-EoE pediatric controls and compared this cohort to samples from 33 pediatric EoE subjects studied in a longitudinal fashion before and after defined dietary changes. RESULTS: Firmicutes were more abundant in esophageal samples compared to oral. Proportions of bacterial communities were significantly different comparing all EoE esophageal microbiota to non-EoE controls, with enrichment of Proteobacteria, including Neisseria and Corynebacterium in the EoE cohort, and predominance of the Firmicutes in non-EoE control subjects. We detected a statistically significant difference between actively inflamed EoE biopsies and non-EoE controls. Overall, though targeted dietary intervention did not lead to significant differences in either oral or esophageal microbiota, reintroduction of highly allergenic foods led to enrichment in Ganulicatella and Campylobacter genera in the esophagus. CONCLUSIONS: In conclusion, the esophageal microbiome in EoE is distinct from that of non-EoE controls, with maximal differences observed during active allergic inflammation. PMID- 26034602 TI - When are patients lost to follow-up in pre-antiretroviral therapy care? a retrospective assessment of patients in an Ethiopian rural hospital. AB - BACKGROUND: There is concern about the increasing rates of loss to follow-up (LTFU) among pre-antiretroviral therapy (pre-ART) patients in Ethiopia. Little information is available regarding the time when pre-ART patients are lost to follow-up in the country. This study assessed the time when LTFU occurs as well as the associated factors among adults enrolled in pre-ART care in an Ethiopian rural hospital. METHODS: Data of all adult pre-ART patients enrolled at the Sheka Zonal Hospital between 2010 and 2013 were reviewed. Patients were considered lost to follow-up if they failed to keep scheduled appointments for more than 90 days. The Cox proportional hazards regression model was used to assess factors associated with time until LTFU. The Kaplan-Meier survival table was used to compare the LTFU experiences of patients, segregated by significant predictors. RESULTS: A total of 626 pre-ART patients were followed for 319.92 person-years of observation (PYOs) from enrolment to pre-ART outcomes, with an overall LTFU rate of 55.8 per 100 PYOs. A total of 178 (28.4%) pre-ART patients were lost to follow up, 93% of which occurred within the first six months. The median follow-up time was 6.13 months. The independent predictors included: not having been started on co-trimoxazole prophylaxis (adjusted hazard ratio [AHR] = 1.77, 95% confidence interval [CI], 1.12-2.79), a baseline CD4 count of or above 350 cells/mm3 (AHR = 1.87, 95%CI, 1.02-3.45), and an undisclosed HIV status (AHR = 3.04, 95%CI, 2.07 4.45). CONCLUSION: A significant proportion of pre-ART patients is lost to follow up. Not having been started on co-trimoxazole prophylaxis, presenting to care with a baseline CD4 cell count >=350 cells/mm(3), and an undisclosed HIV status were significant predictors of LTFU among pre-ART patients. Thus, close monitoring and tracking of patients during this period is highly recommended. Those patients with identified risk factors deserve special attention. PMID- 26034604 TI - Modeling the spatial and temporal dynamics of foraging movements of humpback whales (Megaptera novaeangliae) in the Western Antarctic Peninsula. AB - BACKGROUND: A population of humpback whales (Megaptera novaeangliae) spends the austral summer feeding on Antarctic krill (Euphausia superba) along the Western Antarctic Peninsula (WAP). These whales acquire their annual energetic needs during an episodic feeding season in high latitude waters that must sustain long distance migration and fasting on low-latitude breeding grounds. Antarctic krill are broadly distributed along the continental shelf and nearshore waters during the spring and early summer, and move closer to land during late summer and fall, where they overwinter under the protective and nutritional cover of sea ice. We apply a novel space-time utilization distribution method to test the hypothesis that humpback whale distribution reflects that of krill: spread broadly during summer with increasing proximity to shore and associated embayments during fall. RESULTS: Humpback whales instrumented with satellite-linked positional telemetry tags (n = 5), show decreased home range size, amount of area used, and increased proximity to shore over the foraging season. CONCLUSIONS: This study applies a new method to model the movements of humpback whales in the WAP region throughout the feeding season, and presents a baseline for future observations of the seasonal changes in the movement patterns and foraging behavior of humpback whales (one of several krill-predators affected by climate-driven changes) in the WAP marine ecosystem. As the WAP continues to warm, it is prudent to understand the ecological relationships between sea-ice dependent krill and krill predators, as well as the interactions among recovering populations of krill predators that may be forced into competition for a shared food resource. PMID- 26034603 TI - The current status of suicide and self-injury in eating disorders: a narrative review. AB - The aim of this paper is to review recent literature on suicide and self-injury in eating disorders (ED) including anorexia nervosa (AN), bulimia nervosa (BN), and binge eating disorder (BED). Among psychiatric diagnoses, EDs are associated with increased mortality rates, even when specialized treatment is available. Of the mortalities that are reported in individuals with EDs, suicide is among the most commonly reported causes of death. Additionally, suicidal and non-suicidal self-injurious behaviors occur frequently in this clinical population. A literature search was undertaken using the databases of Medline/PubMed and PsycInfo to identify papers describing suicidality in individuals with ED diagnoses. The authors identified studies and review articles published between 2005-2013 (inclusive) that describe the relationship between EDs and suicide, and associated behaviors including self-injurious behaviors, or non-suicidal self injury (NSSI). The initial search resulted in 1095 papers that met the a priori search criteria. After careful review, 66 papers were included. The majority of papers described clinical cohorts that were studied longitudinally. The diagnosis described most frequently in selected studies was AN. There are limited current data about the prevalence of suicide and NSSI among individuals with EDs. Among the published studies that focus specifically on the relationship between EDs and suicidality, most describe AN in more detail than other EDs. Nonetheless, rates of mortality, and specifically rates of suicide, are undeniably high in ED populations, as are the rates of self-harm. Therefore, it is critical for clinicians and caretakers to carefully evaluate these patients for suicide risk and to refer promptly for appropriate treatment. PMID- 26034605 TI - Successful pregnancies and healthy live births using frozen-thawed sperm retrieved by a new modified Hotchkiss procedure in males with retrograde ejaculation: first case series. AB - BACKGROUND: In couples presenting with retrograde ejaculation refractory to medical treatment, the first choice of fertility treatment should be Assisted Reproductive Techniques using rapidly purified spermatozoa retrieved from post ejaculatory urine. The Hotchkiss technique and modified variants are simple and efficient for retrieving sperm from the bladder. We developed a new protocol, including a novel modified Hotchkiss technique involving sperm cryopreservation. The aim was to study the pregnancy rate and birth rate achieved by intra cytoplasmic sperm injection (ICSI) using frozen-thawed sperm retrieved from the bladder with this novel modified Hotchkiss technique in patients with refractory retrograde ejaculation. RESULTS: In this descriptive retrospective, single-center study, we analyzed the local database of all patients who banked sperm at the CECOS Laboratory Biology of Reproduction of La Conception University Hospital, Marseille, France, between 2004 and 2014. A total of 2171 patients banked sperm during this time, including 63 patients with retrograde ejaculation, of whom ten patients banked sperm that had been retrieved by the modified Hotchkiss technique. These ten couples underwent 26 ICSI cycles: nine clinical pregnancies were achieved in six couples, including eight after fresh embryo transfer and one after thawed embryo transfer, resulting in seven live births. The average live birth rate per transfer was 28 %. CONCLUSIONS: We report the largest series of births using frozen-thawed spermatozoa retrieved from post-ejaculatory urine by a modified Hotchkiss technique. This series of births demonstrates that this new modified Hotchkiss technique allows for successful association with sperm cryopreservation, leading to an efficient and easy management of couples with refractory retrograde ejaculation. PMID- 26034607 TI - Launch of Neuro-Oncology Practice. PMID- 26034606 TI - High body mass index and allergies in schoolchildren: the French six cities study. AB - BACKGROUND: The prevalence of allergic diseases such as asthma, allergic rhinitis and atopic dermatitis is increasing rapidly worldwide, especially among children and in western countries. This coincides with an increase in body mass index (BMI), which might be a major risk factor for atopic diseases. OBJECTIVES: To study the relationship between high BMI and allergic diseases, as well as skin prick test (SPT) positivity and exercise-induced asthma (EIA) in 6733 randomly selected schoolchildren aged 9-11 years in the French Six Cities Study. METHODS: A cross-sectional study was carried out in Bordeaux, Clermont-Ferrand, Creteil, Marseille, Reims and Strasbourg. Parental questionnaires based on the International Study on Asthma and Allergies in Childhood (ISAAC) were used to collect information on allergic diseases and potential risk factors. Skin-prick testing to common allergens was performed to identify the existence of an allergic hypersensitivity and an exercise test was also performed to assess EIA. Height and weight were collected by trained investigators. After computing the BMI (weight/height squared), the International Obesity Task Force (IOTF) cut-offs were used to define overweight and obesity. The children were also classified as wheezing or non-wheezing. RESULTS: After adjustment for confounding factors, lifetime asthma was associated with high BMI among non-wheezing children (adjusted OR, aOR=1.98, 95% CI (1.06 to 3.70)). In addition, lifetime and past year allergic rhinitis was associated with high BMI in wheezing children (aOR=1.63, (1.09 to 2.45) and aOR=2.20, (1.13 to 4.27)). However, high BMI was not significantly associated with eczema, SPT positivity or EIA. CONCLUSIONS: This study shows a positive association between high BMI and lifetime asthma in non-wheezing children. High BMI was also associated with lifetime and past-year allergic rhinitis. Further studies are needed to provide causal evidence. PMID- 26034608 TI - Integration of palliative care into the neuro-oncology practice: patterns in the United States. AB - BACKGROUND: Between 80%-85 percent of all adult brain tumors are high-grade gliomas (HGGs). Despite aggressive treatment with surgical resection, radiotherapy and chemotherapy, the survival of patients with HGG is limited. Brain tumor patients develop unique symptoms and needs throughout their disease trajectory, and the majority lose the ability to communicate during the end-of life phase. Palliative care (PC) is a proactive and systematic approach to manage issues that are important to patients and families affected by serious illness. The goal is to improve quality of life and symptom control and thereby reduce suffering. Most PC interventions take place during the end-of-life phase; however, newer data suggest that early PC interventions might improve symptom control and quality of life. METHODS: A literature review focusing on PC, hospice care, and end-of-life care was performed with the aim to describe the integration of PC into neuro-oncology practice. RESULTS: Recently there has been increased interest in the effects of PC and brain tumor patients. The origins, methodology, and conceptual models of delivering PC and how it might be applied to the field of neuro-oncology were reviewed. Patterns of referral and utilization in neuro oncology are described based on the findings of a recent survey. CONCLUSIONS: Despite a very high symptom burden, many HGG patients do not receive the same level of PC and have fewer interactions with PC services than other cancer populations. Early PC interventions and structured advance-care planning might improve symptom control and quality of life for brain tumor patients. PMID- 26034609 TI - Home care for brain tumor patients. AB - BACKGROUND: Brain tumor patients are quite different from other populations of cancer patients due to the complexity of supportive care needs, the trajectory of disease, the very short life expectancy, and resulting need for a specific palliative approach. METHODS: A pilot program of comprehensive palliative care for brain tumor patients was started in the Regina Elena National Cancer Institute of Rome in October 2000, supported by the Lazio Regional Health System. The aim of this model of assistance was to meet patient's needs for care in all stages of disease, support the families, and reduce the rehospitalization rate. The efficacy of the model of care was evaluated analyzing the place of death, caregiver satisfaction, rehospitalization rate, and the impact on costs to the health system. RESULTS: From October 2000 to December 2012, 848 patients affected by brain tumor were enrolled in a comprehensive program of neuro-oncological home care. Out of 529 patients who died, 323 (61%) were assisted at home until death, 117 (22.2%) died in hospital, and 89 (16.8%) died in hospice. A cost effectiveness analysis demonstrated a significant reduction in hospital readmission rates in the last 2 months of life compared with the control group (16.7% vs 38%; P < .001). CONCLUSIONS: Our findings concerning death at home, rehospitalization rate, quality of life, and satisfaction of patients and their relatives with the care received suggest that a neuro-oncologic palliative home care program has a positive impact on the quality of care for brain tumor patients, particularly at the end of life. PMID- 26034610 TI - Cancer around the brain. AB - BACKGROUND: Neuro-oncologists are familiar with primary brain tumors, intracerebral metastases meningeal carcinomatosis and extracerebral intracranial tumors as meningeoma. For these conditions, and also some other rare tumor entities several treatment options exist. Cancer can also involve structures around the brain as the dura, the base of the skull, the cavities of the skull and tissue around the bony skull, the skin, the tissue of the neck. and either compress, invade or spread in the central or peripheral nervous system. METHODS: A systematic literature research was conducted determining symptoms and signs, tumor sites of nerve invasion, tumor types, diagnostic techniques, mechanisms of nerve invasion, and important differential diagnosis. Additional cases from own experience were added for illustration. RESULTS: The mechanisms of tumor invasion of cranial nerves is heterogenous and not only involves several types of invasion, but also spread along the cranial nerves in antero- and retrograde fashion and even spread into different nerve territories via anastomosis. In addition the concept of angiosomas may have an influence on the spread of metastases. CONCLUSION: In addition to the well described tumor spread in meningeal carcinomatosis and base of the skull metastases, dural spread, lesions of the bony skull, the cavities of the skull and skin of the face and tissue of the neck region need to be considered, and have an impact on therapeutic decisions. PMID- 26034611 TI - The incidence of cerebrovascular accidents and second brain tumors in patients with pituitary adenoma: a population-based study. AB - BACKGROUND: To assess the risk of cerebrovascular accidents (CVAs) and second brain tumors (SBTs) in patients with pituitary adenoma after surgery or radiotherapy. METHODS: A cohort of 143 people from Olmsted County, who were diagnosed with pituitary adenoma between 1933 and 2000, was studied. Only patients from Olmsted County were included because of the unique nature of medical care in Olmsted County, which allows the ascertainment of virtually all cases of pituitary adenoma for this community's residents and comparisons to the general population in the county. Surgical resection was performed in 76 patients, 29 patients underwent radiotherapy (with 21 undergoing both surgery and radiotherapy), 5 patients were reirradiated, and 59 patients were managed conservatively and observed. RESULTS: Median follow-up was 15.5 years. There was no difference in CVA-free survival between treatment groups. On univariate analysis age > 60 years (hazard ratio [HR], 11.93; 95% CI, 6.26-23.03; P < .001); male sex (HR, 3.67; 95% CI, 2.03-6.84; P < .001), and reirradiation (HR, 3.41; 95% CI, 1.05-9.68; P = .04) were associated with worse CVA-free survival. In multivariate analysis, only age > 60 years was associated with worse CVA-free survival. Compared with the general population, there was a 4-fold increase in the rate of CVAs in pituitary adenoma patients (HR, 4.2; 95% CI, 2.8-6.1). Two patients developed SBT (an irradiated patient and a surgically managed patient). CONCLUSION: CVA is a significant risk for patients with pituitary tumors, but treatment does not seem to impact the risk. Even with long-term follow-up, SBTs are a rare event regardless of treatment modality. PMID- 26034613 TI - Neuro-Oncology Practice: Consolidating A Good Beginning. PMID- 26034614 TI - Quality of surgical care and readmission in elderly glioblastoma patients. AB - BACKGROUND: Thirty-day readmissions post medical or surgical discharge have been analyzed extensively. Studies have shown that complex interactions of multiple factors are responsible for these hospitalizations. METHODS: A retrospective analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) Medicare database of newly diagnosed elderly glioblastoma multiforme (GBM) patients who underwent surgical resection between 1991 and 2007. Hospitals were classified into high- or low-readmission rate cohorts using a risk-adjusted methodology. Bivariate comparisons of outcomes were conducted. Multivariate analysis evaluated differences in quality of care according to hospital readmission rates. RESULTS: A total of 1,273 patients underwent surgery in 338 hospitals; 523 patients were treated in 228 high-readmission hospitals and 750 in 110 low-readmission hospitals. Patient characteristics for high-versus low readmission hospitals were compared. In a confounder-adjusted model, patients treated in high- versus low-readmission hospitals had similar outcomes. The hazard of mortality for patients treated at high- compared to low-readmission hospitals was 1.06 (95% CI, 0.095%-1.19%). While overall complications were comparable between high- and low-readmission hospitals (16.3% vs 14.3%; P = .33), more postoperative pulmonary embolism/deep vein thrombosis complications were documented in patients treated at high-readmission hospitals (7.5% vs 4.1%; P = .01). Adverse events and levels of resection achieved during surgery were comparable at high- and low-readmission hospitals. CONCLUSIONS: For patients undergoing GBM resection, quality of care provided by hospitals with the highest adjusted readmission rates was similar to the care delivered by hospitals with the lowest rates. These findings provide evidence against the preconceived notion that 30-day readmissions can be used as a metric for quality of surgical and postsurgical care. PMID- 26034615 TI - The association between cognitive functioning and health-related quality of life in low-grade glioma patients. AB - BACKGROUND: Glioma patients are not only confronted with the diagnosis and treatment of a brain tumor, but also with changes in cognitive and neurological functioning that can profoundly affect their daily lives. At present, little is known about the relationship between cognitive functioning and health-related quality of life (HRQOL) during the disease trajectory. We studied this association in low-grade glioma (LGG) patients with stable disease at an average of 6 years after diagnosis. METHODS: Patients and healthy controls underwent neuropsychological testing and completed self-report measures of generic (MOS SF36) and disease-specific (EORTC BN20) HRQOL. Associations were determined with Pearson correlations, and corrections for multiple testing were made. RESULTS: We analyzed data gathered from 190 LGG patients. Performance in all cognitive domains was positively associated with physical health (SF36 Physical Component Summary). Executive functioning, processing speed, working memory, and information processing were positively associated with mental health (SF36 Mental Component Summary). We found negative associations between a wide range of cognitive domains and disease-specific HRQOL scales. CONCLUSIONS: In stable LGG patients, poorer cognitive functioning is related to lower generic and disease specific HRQOL. This confirms that cognitive assessment of LGG patients should not be done in isolation from assessment of its impact on HRQOL, both in clinical and in research settings. PMID- 26034616 TI - Concordance of patient and caregiver reports in evaluating quality of life in patients with malignant gliomas and an assessment of caregiver burden. AB - BACKGROUND: Given the neurocognitive impairment experienced by many patients with malignant gliomas, caregiver reports can be critical in assessing the quality of life (QOL) of these patients. In this study, we explored whether assessment of patient QOL by the primary caregiver shows concordance with the patient's self reported QOL, and we quantified the burden faced by caregivers. METHODS: QOL of 45 patients was evaluated by both the patient and primary caregiver on 3 or more separate occasions using the Functional Assessment of Cancer Therapy-Brain (FACT Br) instrument, and concordance between the 2 reports was evaluated. Caregiver burden was measured using the Caregiver Quality of Life Index-Cancer (CQOL-C) instrument. RESULTS: Overall, good concordance was observed between the patient and caregiver FACT-Br reports (intraclass correlation coefficient = 0.74). Patient-reported FACT-Br scores were 4.75 (95% CI, 1.44-8.05) points higher than paired caregiver reports on the 200-point scale (P = .008); however, this difference did not achieve clinical significance. Caregiver burden, as measured by the CQOL-C, was significantly greater among caregivers in this study than those previously reported for caregivers of patients with lung, breast, or prostate cancer (P < .001). CONCLUSIONS: Despite minor discrepancies in caregiver assessments of patient QOL relative to patient self-reports, our results suggest that the caregiver assessments can serve as adequate proxies for patient reports. Our results also illustrate the particularly heavy burden faced by caregivers of patients with malignant glioma. Further research into both of these areas is warranted. PMID- 26034617 TI - Impact of recall period on primary brain tumor patient's self-report of symptoms. AB - BACKGROUND: Understanding the severity of symptoms is an integral part of patient care. The MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) was developed using a 24-hour recall period. The choice of recall period is dependent on the treatment and disease of interest. The aim of this study was to evaluate the congruence and equivalency of 24-hour and 7-day symptom reporting using the MDASI BT. METHOD: Adult brain tumor patients completed the MDASI-BT using 24-hour and 7 day recall periods and a tablet format. Equivalence and congruence were determined using equivalency testing and Bland-Altman analysis. Reliability and known group's validity were then assessed by use of Cronbach's alpha and evaluating differences based on performance status. RESULTS: One hundred patients (mean age, 48 y; range 19 y-77 y), who were primarily white (86%) males (62%) with a variety of brain tumors, most commonly glioblastoma (69%), participated. KPS scores ranged from 50%-100%, with 28% of participants scoring 80% or lower. Overall severity reporting using the 7-day recall was congruent and equivalent with the 24-hour rating, with difference scores of one point or less on the overall instrument and individual symptoms. The 7-day recall period instrument demonstrated psychometric properties similar to the established 24-hour recall instrument. CONCLUSION: This study supports the use of the 7-day recall period in addition to the 24-hour recall period for symptom reports of patients with primary brain tumors. Future studies should continue to explore the reliability and validity of this recall period and its utility in other central nervous system tumor populations. PMID- 26034618 TI - Personal health records, symptoms, uncertainty, and mood in brain tumor patients. AB - BACKGROUND: The advantages of patient access to the electronic medical record (EMR) through integrated personal health records (PHR) may be substantial, and foremost is the enhanced information flow between patient and practitioner. Because this is an emerging technology, the actualized benefits to complex patient groups remain largely unknown. MD Anderson Cancer Center provides web based PHR portal access to the EMR including clinic notes, MRI results, and pathology reports. This study sought to evaluate PHR use by glioma patients. METHODS: Cross-sectional survey and PHR-derived user data from 186 patients were analyzed using descriptive and inferential statistics. Logistic regression assessed disparities between users and nonusers. Dependence of PHR access on treatment stage was tested through linear regression. Path analysis evaluated PHR access, disease-related uncertainty, symptom experience, and mood. RESULTS: Patients averaged 44.2 years (range 19y-80y), 77% had a high-grade tumor, and 60% had accessed PHR at least one time (range 0-126). Strongest predictors of access included education level (college level or higher), low performance status, middle income, and in-state residency. Patients undergoing treatment were more active users. PHR access was associated with lower disease-related uncertainty and lower symptom severity. Mood was not directly related to PHR use but mediated an association between symptom severity and uncertainty. CONCLUSIONS: While many reports presume better disease and symptom understanding for patients with EMR access, this study is the first to correlate PHR use to lower patient uncertainty levels. Early examination of PHR provides an important basis for critical evaluation and optimization to better structure this benefit for brain tumor patients. PMID- 26034619 TI - Financial burden experienced by patients undergoing treatment for malignant gliomas. AB - BACKGROUND: Patients undergoing treatment for malignant gliomas (MGs) can encounter medical costs beyond what their insurance covers. The magnitude and type of costs experienced by patients are unknown. The purpose of this study was to have patients or their families report on the medical costs incurred during the patients MG treatment. METHODS: Patients with MG were eligible if they were within 6 months of diagnosis or tumor recurrence. Patients had to be >=18 years of age, fluent in English, and not aphasic. Weekly logbooks were issued to patients for recording associated costs for ~6 months or until tumor progression. "Out-of-pocket" (OOP) costs included medical and nonmedical expenses that were not reimbursed by insurance. Direct medical costs included hospital and physician bills. Direct nonmedical costs included transportation, parking, and other related items. Indirect medical costs included lost wages. Costs were analyzed to provide mean and medians with range of expenses. RESULTS: Forty-three patients provided cost data for a median of 12 weeks. There were 25 men and 18 women with a median age of 57 years (range, 24y-73y); 79% were married, and 49% reported annual income >$75 000. Health insurance coverage was preferred provider organizations for 58% of patients, and median deductible was $1 500. Median monthly OOP cost was $1 342 (mean, $2 451; range, $333.41-$17 267.16). The highest OOP median costs were medication copayments ($710; range, $0-13 611.20), transportation ($327; range, $0-$1 927), and hospital bill copayments ($403; range, $0-$4 000). Median lost wages were $7 500, and median lost days of work were 12.8. CONCLUSIONS: OOP costs for MG patients can be significant and comprise direct and indirect costs across several areas. Informing patients about expected costs could limit additional duress and allow financial support systems to be implemented. PMID- 26034621 TI - Neurocognitive functioning and quality of life in patients with recurrent malignant gliomas treated on a phase Ib trial evaluating topotecan by convection enhanced delivery. AB - BACKGROUND: Malignant gliomas are highly proliferative, invasive tumors that are resistant to conventional treatment, and disease progression is often accompanied by physical and mental debilitation. Neurocognitive functioning (NCF) and quality of life (QoL) were evaluated as part of a prospective phase Ib dose-escalation study of topotecan by convection-enhanced delivery (CED) for adult patients with recurrent malignant gliomas. METHODS: Sixteen patients were enrolled, and NCF and QoL were evaluated using the Cognitive Stability Index and SF-36 at baseline and monthly for 4 months post treatment. Descriptive analyses included the reliable change index for serial evaluations and correlations for associations between outcome variables and age, tumor volume, total topotecan dose, and treatment effect. RESULTS: Individual classifications of response to treatment indicated that a majority of patients reported stable scores over the follow-up period. Demographic and treatment-related variables were not associated with outcomes. Baseline processing speed scores were invalid for 6 subjects. Higher rates of valid scores were observed on subsequent administrations. CONCLUSIONS: As the first study to use CED of any kind to evaluate the impact of CED on NCF or QoL, there was no evidence of severe detriment to either outcome. Long-term evaluation is necessary to track changes in NCF and QoL related to disease progression. Invalid scores suggest that computer-based assessments may not be suitable for all patients with malignant gliomas, especially those with cognitive deficits secondary to their disease. Future trials should include a wider range of sensitive measures to assess the impact of CED on patient NCF and QoL. PMID- 26034622 TI - Culturally and linguistically diverse patient participation in glioma research. AB - Marginal communities, such as culturally and linguistically diverse (CALD) patients, have significantly lower rates of recruitment, accrual, and retention in cancer clinical trials. A combination of language and cultural barriers means that trial participation from CALD communities remains at suboptimal levels, which in turn favors research findings that are biased towards therapeutic effects or toxicities within the context of non-CALD populations. Here we outline some key challenges and implications for CALD patient participation in glioma research in countries such as Australia, where English is the language of governance and health services implementation. We highlight multistakeholder interventions to improve both investigator recruitment and participation of CALD communities in future glioma research, particularly in this era when global migration has come of age. Enhancing research participation of CALD communities ensures not only wider understanding of genetic heterogeneity to improve glioma outcomes but also equity in access to care. PMID- 26034625 TI - Neuro-Oncology Practice: Time Flies When You Are Having Fun! PMID- 26034623 TI - Child-related characteristics predicting subsequent health-related quality of life in 8- to 14-year-old children with and without cerebellar tumors: a prospective longitudinal study. AB - BACKGROUND: We identified child-related determinants of health-related quality of life (HRQoL) in children aged 8-14 years who were treated for 2 common types of pediatric brain tumors. METHODS: Questionnaire measures of HRQoL and psychometric assessments were completed by 110 children on 3 occasions over 24 months. Of these 110, 72 were within 3 years of diagnosis of a cerebellar tumor (37 standard risk medulloblastoma, 35 low-grade cerebellar astrocytoma), and 38 were in a nontumor group. HRQoL, executive function, health status, and behavioral difficulties were also assessed by parents and teachers as appropriate. Regression modeling was used to relate HRQoL z scores to age, sex, socioeconomic status, and 5 domains of functioning: Cognition, Emotion, Social, Motor and Sensory, and Behavior. RESULTS: HRQoL z scores were significantly lower after astrocytoma than those in the nontumor group and significantly lower again in the medulloblastoma group, both by self-report and by parent-report. In regression modeling, significant child-related predictors of poorer HRQoL z scores by self report were poorer cognitive and emotional function (both z scores) and greater age (years) at enrollment (B = 0.038, 0.098, 0.136, respectively). By parent report, poorer cognitive, emotional and motor or sensory function (z score) were predictive of lower subsequent HRQoL of the child (B = 0.043, 0.112, 0.019, respectively), while age at enrollment was not. CONCLUSIONS: Early screening of cognitive and emotional function in this age group, which are potentially amenable to change, could identify those at risk of poor HRQoL and provide a rational basis for interventions to improve HRQoL. PMID- 26034626 TI - Management of high-grade gliomas in the pediatric patient: Past, present, and future. AB - High-grade gliomas (HGGs) constitute ~15% of all primary brain tumors in children and adolescents. Routine histopathological diagnosis is based on tissue obtained from biopsy or, preferably, from the resected tumor itself. The majority of pediatric HGGs are clinically and biologically distinct from histologically similar adult malignant gliomas; these differences may explain the disparate responses to therapy and clinical outcomes when comparing children and adults with HGG. The recently proposed integrated genomic classification identifies 6 distinct biological subgroups of glioblastoma (GBM) throughout the age spectrum. Driver mutations in genes affecting histone H3.3 (K27M and G34R/V) coupled with mutations involving specific proteins (TP53, ATRX, DAXX, SETD2, ACVR1, FGFR1, NTRK) induce defects in chromatin remodeling and may play a central role in the genesis of many pediatric HGGs. Current clinical practice in pediatric HGGs includes surgical resection followed by radiation therapy (in children aged > 3 years) with concurrent and adjuvant chemotherapy with temozolomide. However, these multimodality treatment strategies have had a minimal impact on improving survival. Ongoing clinical trials are investigating new molecular targets, chemoradiation sensitization strategies, and immunotherapy. Future clinical trials of pediatric HGG will incorporate the distinction between GBM molecular subgroups and stratify patients using group-specific biomarkers. PMID- 26034627 TI - Sports and childhood brain tumors: Can I play? AB - BACKGROUND: It is unknown whether children with brain tumors have a higher risk of complications while participating in sports. We sought to estimate the prevalence of such events by conducting a systematic review of the literature, and we surveyed providers involved with pediatric central nervous system (CNS) tumor patients. METHODS: A systematic review of the literature in the PubMed, Scopus, and Cochrane databases was conducted for original articles addressing sport-related complications in the brain-tumor population. An online questionnaire was created to survey providers involved with pediatric CNS tumor patients about their current recommendations and experience regarding sports and brain tumors. RESULTS: We retrieved 32 subjects, including 19 pediatric cases from the literature. Most lesions associated with sport complications were arachnoid cysts (n = 21), followed by glioma (n = 5). The sports in which symptom onset most commonly occurred were soccer (n = 7), football (n = 5), and running (n = 5). We surveyed 111 pediatric neuro-oncology providers. Sport restriction varied greatly from none to 14 sports. Time to return to play in sports with contact also varied considerably between providers. Rationales for limiting sports activities were partly related to subspecialty. Responders reported 9 sport-related adverse events in patients with brain tumor. CONCLUSIONS: Sport related complications are uncommon in children with brain tumors. Patients might not be at a significantly higher risk and should not need to be excluded from most sports activities. PMID- 26034629 TI - Hypofractionated stereotactic radiosurgery with concurrent bevacizumab for recurrent malignant gliomas: the University of Alabama at Birmingham experience. AB - BACKGROUND: Nearly all patients with malignant glioma will have disease recurrence. Our purpose was to define the treatment toxicity and efficacy of concurrent bevazicumab (BVZ) with hypofractionated stereotactic radiosurgery (SRS) of relatively larger targets for patients with recurrent MG. METHODS: A retrospective review of 21 patients with recurrent malignant glioma (18 glioblastoma, 3 WHO grade III glioma), treated at initial diagnosis with surgery and standard chemoradiation, was performed. All patients had concurrent BVZ with hypofractionatedSRS, 30 Gy in 5 fractions, with or without concurrent chemotherapy (temozolomide or CCNU). RESULTS: Median patient age was 54 years, median Karnofsky Performance Status was 80, and median target size was 4.3 cm (range, 3.4-7.5 cm). Eleven patients (52%) had previously failed BVZ. One patient had grade 3 toxicities (seizures, dysphasia), which resolved with inpatient admission and intravenous steroids/antiepileptics. Treatment-related toxicities were grade 3 (n = 1), grade 2 (n = 9), and grade 0-1 (n = 11). Kaplan-Meier median progression-free survival and overall survival estimates (calculated from start of SRS) for GBM patients (n = 18) were 11.0 and 12.5 months, respectively. Concurrent chemotherapy did not appear to show any statistically significant efficacy benefit or have any propensity for toxicity. CONCLUSION: BVZ concurrent with hypofractionated SRS was well tolerated by this cohort of patients with relatively larger targets. Ongoing randomized trials with more moderate radiotherapy dosing may help establish the efficacy of this regimen, though intricacies of this approach, including patient selection, radiation target volume delineation/size, and optimal radiation dose, will need further evaluation. PMID- 26034630 TI - The management of lomustine overdose in malignant glioma patients. AB - Lomustine is an oral alkylating drug commonly used for brain tumor patients. Recently, the lomustine-containing PCV polychemotherapy regime (procarbazine, CCNU/lomustine, and vincristine) in combination with radiotherapy has become the standard of care for anaplastic oligodendroglioma with 1p/19q codeletion and high risk low-grade glioma. Here, we review the literature of all reported cases of lomustine overdose, highlight complications by exemplifying a case of inadvertent lomustine overdose, and outline the management of this potential complication of outpatient PCV therapy. PMID- 26034631 TI - Primary brain tumors and posterior reversible encephalopathy syndrome. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic encephalopathic state associated with reversible cerebral vasogenic edema. It is an increasingly recognized occurrence in the oncology population. However, it is very uncommon in patients with primary brain tumors (PBTs). The aim of this study was to analyze the clinicoradiological features and report the clinical outcomes of PRES in PBT patients. METHODS: We identified 4 cases with PBT who developed PRES at MD Anderson Cancer Center (MDACC) between 2012 and 2014. Clinical and radiological data were abstracted from their records. In addition, we also solicited 8 cases from the literature. RESULTS: The median age at PRES onset was 19 years, male-to-female ratio was 1:1, and the syndrome occurred in patients with ependymoma (n = 4), glioblastoma (n = 3), diffuse intrinsic pontine glioma (DIPG; n = 3), juvenile pilocytic astrocytoma (n = 1), and atypical meningioma (n = 1). Two glioblastomas and 2 DIPG cases received bevacizumab and vandetanib before the onset of symptoms, respectively. The most common clinical presentation was seizures (n = 7). Three MDACC patients recovered completely in 3-4 weeks after the onset of symptoms. One patient died due to active cancer and several comorbidities including PRES. CONCLUSIONS: Hypertension seems to be the most important coexisting risk factor for development of PRES; however, the potential effects of chemotherapeutic agents in the pathogenesis of PRES should also be examined. The clinicoradiological course of PRES in PBT patients did not vary from the classical descriptions of PRES found in other causes. PRES must be considered as part of the differential diagnosis in patients with PBTs presenting with seizures or acute encephalopathy. PMID- 26034628 TI - Pattern of care and effectiveness of treatment for glioblastoma patients in the real world: Results from a prospective population-based registry. Could survival differ in a high-volume center? AB - BACKGROUND: As yet, no population-based prospective studies have been conducted to investigate the incidence and clinical outcome of glioblastoma (GBM) or the diffusion and impact of the current standard therapeutic approach in newly diagnosed patients younger than aged 70 years. METHODS: Data on all new cases of primary brain tumors observed from January 1, 2009, to December 31, 2010, in adults residing within the Emilia-Romagna region were recorded in a prospective registry in the Project of Emilia Romagna on Neuro-Oncology (PERNO). Based on the data from this registry, a prospective evaluation was made of the treatment efficacy and outcome in GBM patients. RESULTS: Two hundred sixty-seven GBM patients (median age, 64 y; range, 29-84 y) were enrolled. The median overall survival (OS) was 10.7 months (95% CI, 9.2-12.4). The 139 patients <=aged 70 years who were given standard temozolomide treatment concomitant with and adjuvant to radiotherapy had a median OS of 16.4 months (95% CI, 14.0-18.5). With multivariate analysis, OS correlated significantly with KPS (HR = 0.458; 95% CI, 0.248-0.847; P = .0127), MGMT methylation status (HR = 0.612; 95% CI, 0.388 0.966; P = .0350), and treatment received in a high versus low-volume center (HR = 0.56; 95% CI, 0.328-0.986; P = .0446). CONCLUSIONS: The median OS following standard temozolomide treatment concurrent with and adjuvant to radiotherapy given to (72.8% of) patients aged <=70 years is consistent with findings reported from randomized phase III trials. The volume and expertise of the treatment center should be further investigated as a prognostic factor. PMID- 26034632 TI - Assessing the quality of life among caregivers of patients with gliomas. AB - BACKGROUND: The aim of the study was to analyze the impact of gliomas in caregivers' quality of life (QoL) and to compare this specific population to other oncology caregivers and the normative population in order to find differences and understand which aspects of QoL are more impacted. METHODS: The sample was composed of caregivers of patients with gliomas from the Neuro Oncology Department of Timone University Hospital of Marseilles, France. Control caregivers were selected from different oncology departments and were matched with caregivers of patients with brain cancer on age, sex, and relationship with the patients. We used the specific CareGiver Oncology Quality of Life questionnaire (CarGOQoL) to assess the impact of cancer and its treatment on caregivers' QoL. Caregivers also completed the Short Form 36 (SF36) for comparison with the French normative sample. RESULTS: The study sample included 50 caregivers of patients with gliomas, aged 30-77 years, 28% of whom were men. When comparing specific CarGOQoL scores with those of the control caregivers, brain cancer caregivers had significantly lower scores for the burden and leisure time dimensions, with an effect size of 0.4. No significant differences between cases and controls were observed with SF36. CONCLUSION: Caregivers of patients with gliomas showed increased burden scores and lower scores for the leisure time dimension. This could be explained by their unique care situation, in which patients become more limited physically and cognitively. PMID- 26034634 TI - New initiatives for Neuro-Oncology Practice-building on the success of the first year. PMID- 26034635 TI - Health-related quality of life and other clinical outcome assessments in brain tumor patients: challenges in the design, conduct and interpretation of clinical trials. PMID- 26034636 TI - Corticosteroid use in neuro-oncology: an update. AB - Because of the lack of curative approaches for most patients with malignant brain tumors, supportive therapy, which aims at maintaining quality of life and functional independence, has a central role in the treatment of many patients. Steroids are particularly important in the setting of supportive therapy. They are commonly used to treat tumor-associated edema, and their administration is typically associated with rapid symptom relief, such as the resolution of headaches. Besides their antiedema activity, corticosteroids are characterized by their potent antilymphoma properties and their effects against acute or delayed emesis caused by systemic chemotherapy in cancer patients. Accordingly, steroids are among the most frequently used drugs in oncology. These desirable properties of steroids are counterbalanced by cardiovascular, muscular, and psychiatric side effects. On the cellular level, corticosteroids exert various effects that translate into the desired clinical activity, but they also evoke significant toxicity that may outweigh the beneficial effects. The mode of action and the limitations of steroid treatment are summarized in this review article. Interactions between steroids and other drugs must be considered. A particular challenge to the ongoing use of glucocorticoids is that newer therapeutic approaches are being introduced in neuro-oncology for which concomitant steroids are likely to be contraindicated. These include the emergence of various immunotherapeutic approaches including vaccination strategies and treatment with immune checkpoint inhibitors. Since the administration of steroids may interfere with the activity of these novel therapies, an even more critical evaluation of their use will be required. PMID- 26034637 TI - Impairment of medical decisional capacity in relation to Karnofsky Performance Status in adults with malignant brain tumor. AB - BACKGROUND: We aimed to investigate the relationship between medical decisional capacity (MDC) and Karnofsky Performance Status (KPS) in adults with malignant brain tumors. METHODS: Participants were 71 adults with primary (n = 26) or metastatic (n = 45) brain tumors. Testing to determine KPS scores and MDC was performed as close together as possible for each patient. Participants were administered a standardized measure of medical decision-making capacity (Capacity to Consent to Treatment Instrument [CCTI]) to assess 3 treatment consent abilities (ie, appreciation, reasoning, and understanding). Capacity classifications (ie, capable, marginally capable, and incapable) were established using cut scores previously derived from healthy control CCTI performance. RESULTS: The majority of participants had KPS scores of 90-100 (n = 39), with the remainder divided between KPS scores of 70-80 (n = 26) and 50-60 (n = 6). Comparisons between persons with KPS scores of 90-100 or 70-80 revealed significant differences on the CCTI consent standards of understanding and appreciation. Participants with KPS ratings of 90-100 achieved 46% capable classifications across all CCTI standards, in contrast with 23% of participants with KPS ratings of 70-80, and 0% of participants with KPS ratings of 50-60. CONCLUSIONS: A substantial portion of brain-tumor patients with KPS scores reflecting only minimal disability nonetheless demonstrated impairments on standardized measures of MDC. Clinicians working with this adult population should carefully screen for capacity to make clinical treatment decisions regardless of functional/performance status. PMID- 26034638 TI - Predictors of subjective versus objective cognitive functioning in patients with stable grades II and III glioma. AB - BACKGROUND: Studies in cancer and noncancer populations demonstrate lower than expected correlations between subjective cognitive symptoms and cognitive functioning as determined by standardized neuropsychological tests. This paper systematically examines the association between subjective and objective cognitive functioning in patients with low-grade glioma and the associations of these indicators of cognitive function with clusters of sociodemographic, clinical, and self-reported physical and mental health factors. METHODS: Multiple regression analyses with the subjective and 2 objective indicators of cognitive functioning as dependent variables and 4 clusters of predictor variables were conducted in 169 patients with predominantly low-grade glioma. RESULTS: Correlations between the subjective and the 2 objective cognitive indicators were negligible (0.04) to low (0.24). Objective cognitive deficits were predominantly associated with sociodemographic (older age, lower education, male sex) and clinical (left hemisphere tumor) variables, while lower ratings of subjective cognitive function were more closely related to self-reported mental health symptoms (fatigue, lower mental well-being), physical (motor) dysfunction and female sex. Self-reported communication deficits were associated significantly with both subjective and objective dysfunction. CONCLUSIONS: We recommend that both subjective and objective measures of cognitive functioning, together with a measure of psychological distress, be used for comprehensive neuropsychological assessments of patients with glioma to determine which areas are most affected and which specific intervention strategies are most appropriate. PMID- 26034639 TI - The potential utility of parent-reported attention screening in survivors of childhood cancer to identify those in need of comprehensive neuropsychological evaluation. AB - BACKGROUND: Survivors of childhood cancer are at risk for neuropsychological late effects, yet identifying those in need of evaluation and obtaining needed services can be challenging for the medical team. Finding time- and cost effective screening measures that can be used to identify children in need of evaluation is a clinical priority. Our objective was to investigate the association between parent-rated attention problems and related neuropsychological impairments in childhood cancer survivors as a means of identifying those at high risk for difficulties. METHODS: Cognitive and psychosocial data of survivors who completed neuropsychological evaluations were retrospectively abstracted. Parents of 70 survivors of pediatric cancer (mean age, 11.6 years) completed the Conners Parent Rating Scale and the Child Behavior Checklist. Children also completed a measure of intellectual functioning. The 18 symptoms of inattention and hyperactivity were abstracted from the Conners questionnaire, and participants were classified according to whether or not they met attention deficit/hyperactivity disorder (ADHD) symptom criteria (>=6 inattentive symptoms). RESULTS: Survivors who met symptom criteria for ADHD (27%) demonstrated greater impairments in IQ and working memory, but not processing speed, than survivors who did not. Meeting ADHD symptom criteria was also associated with greater externalizing and social problems but not more internalizing symptoms. ADHD symptom screening was associated with low sensitivity (range = 26.3%-69.2%) but stronger specificity (range = 75.0%-82.7%) for neuropsychological difficulties. CONCLUSION: Parental ratings of attentional symptoms may be a useful way to screen survivors who may be in need of a full neuropsychological assessment. PMID- 26034640 TI - Gamma knife stereotactic radiosurgery in the treatment of brainstem metastases: The MD Anderson experience. AB - BACKGROUND: Brainstem metastases (BSMs) represent a significant treatment challenge. Stereotactic radiosurgery (SRS) is often used to treat BSM. We report our experience in the treatment of BSM with Gamma Knife SRS (GK_SRS). METHODS: The records of 1962 patients with brain metastases treated with GK_SRS between 2009 and 2013 were retrospectively reviewed. Seventy-four patients with 77 BSMs and follow-up brain imaging were identified. Local control (LC), overall survival (OS), progression-free survival (PFS), and toxicity were assessed. RESULTS: Median follow-up was 5.5 months (range, 0.2-48.5 months). Median tumor volume was 0.13 cm3 (range, 0.003-5.58 cm3). Median treatment dose was 16 Gy (range, 10-20 Gy) prescribed to 50% isodose line (range, 40%-86%). Crude LC was 94% (72/77). Kaplan-Meier estimate of median OS was 8.5 months (95% CI, 5.6-9.4 months). Symptomatic lesions and larger lesions, especially size >=2 cm3, were associated with worse LC (HR = 8.70, P = .05; HR = 14.55, P = .02; HR = 62.81, P < .001) and worse OS (HR = 2.00, P = .02; HR = 2.14, P = .03; HR = 2.81, P = .008). Thirty six percent of BSMs were symptomatic, of which 36% (10/28) resolved after SRS and 50% (14/28) had stable or improved symptoms. Actuarial median PFS was 3.9 months (95% CI, 2.7-4.9 months). Midbrain location was significant for worse PFS (HR = 2.29, P = .03). Toxicity was low (8%, 6/74), with size and midbrain location associated with increased toxicity (HR 1.57, P = .05; HR = 5.25, P = .045). CONCLUSIONS: GK_SRS is associated with high LC (94%) and low toxicity (8%) for BSMs. Presence of symptoms or lesion size >= 2 cm3 was predictive of worse LC and OS. PMID- 26034641 TI - Large volume re-irradiation with bevacizumab is a feasible salvage option for patients with refractory high-grade glioma. AB - BACKGROUND: Clinical studies of re-irradiation (ReRT) for relapsed high-grade glioma (HGG) have generally reported the use of small volume ReRT techniques such as stereotactic radiosurgery in selected patients with isolated focal relapse. This study reports the outcome with large-volume ReRT to manage the more common mescenario of extensive diffuse relapse of HGG. METHODS: All HGG patients managed with an overlapping second course of radiation therapy (RT) for refractory progression of HGG between October 2009 and April 2013 were included. ReRT was initially used with bevacizumab (BEV), then used when disease was refractory to BEV, and finally used upfront with BEV-naive patients. Tumor volume (GTV) and specific RT dosimetry factors, including the target volume treated (PTV), and cumulative RT dose maximum (Dmax), were analyzed. Median survival post ReRT was calculated using the Kaplan-Meier method and SPPS v19 software. RESULTS: Eighteen HGG participants with refractory, bulky contrast-enhancing disease received ReRT. Thirteen participants had a maximum tumor diameter >5 cm, and median GTV was 54 cm3. Seven participants had BEV-refractory disease, and 8 participants were BEV naive. ReRT dose was 35-40 Gy in 15 fractions; median PTV was 133 cm3, and median Dmax was 98.2 Gy. Median survival post ReRT for all participants was 8 months (95%CI, 5.8-10.2 months); with 10 months and 3 months for the BEV-naive and BEV refractory participants, respectively (P = .024). Two early participants, who were managed without BEV, were later salvaged with BEV, including one who required craniotomy for radiation necrosis at 6 weeks post RT. No other significant morbidity was reported. CONCLUSION: ReRT combined with BEV is a feasible salvage treatment option for diffuse refractory HGG. PMID- 26034643 TI - Musculoskeletal injuries in a resource-constrained environment: comparing diagnostic accuracy of on-the-spot ultrasonography and conventional radiography for bone fracture screening during the Paris-Dakar rally raid. AB - BACKGROUND: Ultrasound (US) is a good first-line alternative for the diagnosis of bone fractures in adults as well as children. Our study shows that, compared to X ray, in a resource-constrained environment, on-site US has a high sensitivity (98%) and specificity (96%) in the diagnosis of bone fractures. PURPOSE: To compare the accuracy of on-the-spot US with conventional radiography in the screening for bone fractures during the Paris-Dakar rally raid. MATERIAL AND METHODS: Eighty-three patients (81 men, 2 women) with clinically suspected bone fractures were included in 2013 and 2014. They underwent X-ray and US on the spot, blindly interpreted by two musculoskeletal radiologists. Using X-ray as gold standard, we calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for US, for each anatomic location. The accuracy of US and radiography were also assessed, as were the number of fragments and their degree of displacement (Student's t-test). RESULTS: Compared with X-ray, sensitivity, specificity, PPV, and NPV of on-site US were, respectively, for the presence (or absence) of fractures: 98%, 98%, 100%, and 95%. The accuracy of US was 99%. Only one radial styloid process fracture was misdiagnosed with US. There was no significant difference between US and X-ray (P > 0.93) concerning the number of fragments and their degree of displacement. CONCLUSION: Bedside musculoskeletal ultrasound performed by trained musculoskeletal radiologists is a useful method in determining and assessing bone fractures in a resource constrained environment. PMID- 26034644 TI - Usefulness of magnetic resonance angiography for the evaluation of varices at hepaticojejunostomy after liver transplantation. AB - A 7-year-old Japanese girl who had undergone living-donor liver transplantation (LT) at the age of 10 months for decompensated liver cirrhosis caused by biliary atresia presented with recurrent episodes of obscure gastrointestinal bleeding (GIB) with anemia. Over the following 6 years, she experienced five episodes of GIB requiring hospitalization. Subsequent evaluations including repeat esophagogastroduodenoscopy (EGD), colonoscopy (CS), contrast-enhanced computed tomography (CT), and Meckel's scan all failed to reveal a bleeding source. However, varices at the site of hepaticojejunostomy were detected on abdominal ultrasonography and magnetic resonance angiography (MRA) at the age of 7 years. MRA might be more helpful than contrast-enhanced CT for identifying such bleeding. PMID- 26034645 TI - Effects of erythropoietin on adipose tissue: a possible strategy in refilling. AB - BACKGROUND: The increased resorption and the difficulty of the fat graft take following autologous fat transplantation procedure are associated with reduced fat tissue revascularization and increased apoptosis of adipose cells. We suppose that the lipofilling procedure induces an inflammatory environment within the fat graft mass, whose evolution influences the efficacy of autologous fat graft survival. Erythropoietin (EPO) is a glycoprotein hormone known to exert angiogenetic and anti-inflammatory effects; therefore, our purpose was to investigate its reaction with adipose tissue used in lipofilling. METHODS: Fat masses were harvested using manual suction lipectomy and then seeded on dishes in appropriate culture and treated for 3 weeks with 3 doses of EPO. CD31 and CD68 immunohistochemistry was used to identify microvessels and several infiltrating leukocyte cells. RESULTS: Following EPO administration, we have detected an increase in the number of CD31-positive microvessel endothelium cells and CD31 positive small leukocytes and a reduction of CD68-positive cells. These effects were more conspicuous following higher EPO dose. CONCLUSIONS: Our findings evidence EPO treatment as a useful strategy to sustain the revascularization of grafted tissue and to reduce its inflammatory state. PMID- 26034646 TI - Aesthetic evaluation in oncoplastic and conservative breast surgery: a comparative analysis. AB - BACKGROUND: In conservative breast surgery, the achievement of a satisfactory cosmetic result could be challenging; oncoplastic techniques may be helpful in many cases. A comparative analysis was performed among 3 groups of patients undergoing oncoplastic techniques plus external radiation therapy or intraoperative radiotherapy (IORT) and breast conservative surgery plus external radiation therapy; long-term oncologic results in terms of disease relapse and aesthetic outcomes were compared. METHODS: Ninety-six patients were considered: 32 patients treated with oncoplastic surgery, 16 then subjected to radiotherapy (group 1) and another 16 treated with IORT (group 2); 64 patients treated by conservative surgery and radiotherapy formed the control group (group 3). Patients were asked to give a judgment on the cosmetic result considering the following parameters: breast symmetry, appearance of the residual scar, symmetry between the 2 nipple-areola complexes, global aesthetic judgment, and satisfaction about the result. RESULTS: With respect to the oncological and aesthetic outcome, the statistical significance of the results obtained in the 3 groups was calculated using the chi-square test. The results, processed by the chi-square test, were not statistically significant; however, the overall judgments expressed by the patients of all 3 groups were more than satisfactory (scores greater than or equal to 6). CONCLUSIONS: In our experience, when the inclusion criteria are satisfied and the equipment is available, oncoplastic techniques associated with IORT should be considered the treatment of choice for breast cancer in early stage. The excellent cosmetic results and patient's satisfaction encourage us to continue on this way. PMID- 26034647 TI - Versatility of capsular flaps in the salvage of exposed breast implants. AB - Breast implant exposure due to poor tissue coverage or previous irradiation represents a surgical challenge both in the reconstructive and aesthetic plastic surgery practice. In case of implant extrusion or incipient exposure, the commonly suggested strategies, such as targeted antibiotic therapy, drainage and lavage of the cavity, fistulectomy, and primary closure, may be ineffective leading the surgeon to an unwanted implant removal or to adopt more invasive flap coverage procedures. Breast implant capsule, in its physiological clinical behavior, can be considered as a new reliable source of tissue, which can be used in a wide range of clinical situations. In our hands, capsular flaps proved to be a versatile solution not only to treat breast contour deformities or inframammary fold malpositions but also to salvage exposed breast implants. In this scenario, the use of more invasive surgical techniques can be avoided or simply saved and delayed for future recurrences.(Plast Reconstr Surg Glob Open 2015;3:e340; doi:10.1097/GOX.0000000000000307; Published online 30 March 2015.). PMID- 26034648 TI - The use of acellular dermal matrix in the closure of oronasal fistulae after cleft palate repair. PMID- 26034649 TI - Endoscopic forehead muscle resection for nerve decompression: a modified procedure. PMID- 26034650 TI - Exposed subcutaneous implantable devices: an operative protocol for management and salvage. AB - BACKGROUND: Implantable venous and electrical devices are prone to exposure and infection. Indications for management are controversial, but-especially if infected-exposed devices are often removed and an additional operation is needed to replace the device, causing a delay in chemotherapy and prolonging healing time. We present our protocol for device salvage, on which limited literature is available. METHODS: Between 2007 and 2013, 17 patients were treated (12 venous access ports, 3 cardiac pacemakers, and 2 subcutaneous neural stimulators). Most patients were operated within 7 days from exposure. All patients received only a single perioperative dose of prophylactic antibiotic. In cases of gross infection (n = 1), the device was immediately replaced. In the absence of clinical signs of infection: Complete capsulectomy and aggressive cleaning with an n-acetylcysteine solution and saline solution.Primary exposure of venous ports with sufficient skin coverage (n = 10): the device was covered with local skin flaps.Recurrent cases, cases with insufficient skin coverage or big devices (n = 7): the device was moved to a subpectoral pocket.Mean follow-up was 19 months. RESULTS: Sixteen devices were saved. Only one grossly infected pacemaker was removed and replaced immediately. Only in 1 case, exposure of a venous port recurred after 18 months and was successfully moved to a subpectoral pocket. Chemotherapy was always restarted as scheduled and electrical devices remained functional. CONCLUSIONS: This protocol allows-with a straightforward operation and simple measures-to save exposed devices even several days after exposure. Submuscular placement or immediate replacement is indicated only in selected cases. PMID- 26034651 TI - Venous Graft for Full-thickness Palpebral Reconstruction. AB - Full-thickness palpebral reconstruction is a challenge for most surgeons. The complex structures composing the eyelid must be reconstructed with care both for functional and cosmetic reasons. It is possible to find in literature different methods to reconstruct either the anterior or posterior lamella, based on graft or flaps. Most patients involved in this kind of surgery are elderly. It is important to use easy and fast procedures to minimize the length of the operation and its complications. In our department, we used to reconstruct the anterior lamella by means of a Tenzel or a Mustarde flap, whereas for the posterior lamella, we previously utilized a chondromucosal graft, harvested from nasal septum. Thus, these procedures required general anesthesia and long operatory time. We started using a vein graft for the posterior lamella. In this article, we present a series of 9 patients who underwent complex palpebral reconstruction for oncological reasons. In 5 patients (group A), we reconstructed the tarsoconjunctival layer by a chondromucosal graft, whereas in 4 patients (group B), we used a propulsive vein graft. The follow-up was from 10 to 20 months. The patient satisfaction was high, and we had no relapse in the series. In group A, we had more complications, including ectropion and septal perforations, whereas in group B, the operation was faster and we noted minor complications. In conclusion, the use of a propulsive vein to reconstruct the tarsoconjunctival layer was a reliable, safe, and fast procedure that can be considered in complex palpebral reconstructions. PMID- 26034652 TI - FLiGS Score: A New Method of Outcome Assessment for Lip Carcinoma-Treated Patients. AB - BACKGROUND: Lip cancer and its treatment have considerable functional and cosmetic effects with resultant nutritional and physical detriments. As we continue to investigate new treatment regimens, we are simultaneously required to assess postoperative outcomes to design interventions that lessen the adverse impact of this disease process. We wish to introduce Functional Lip Glasgow Scale (FLiGS) score as a new method of outcome assessment to measure the effect of lip cancer and its treatment on patients' daily functioning. METHODS: Fifty patients affected by lip squamous cell carcinoma were recruited between 2009 and 2013. Patients were asked to fill the FLiGS questionnaire before surgery, 1 month, 6 months, and 1 year after surgery. The subscores were used to calculate a total FLiGS score of global oral disability. Statistical analysis was performed to test validity and reliability. RESULTS: FLiGS scores improved significantly from preoperative to 12 months postoperative values (P = 0.000). Statistical evidence of validity was provided through r s (Spearman correlation coefficient) that resulted >0.30 for all surveys and for which P < 0.001. FLiGS score reliability was shown through examination of internal consistency and test-retest reliability. CONCLUSIONS: FLiGS score is a simple way of assessing functional impairment related to lip cancer before and after surgery; it is sensitive, valid, reliable, and clinically relevant: it provides useful information to orient the physician in the postoperative management and in the rehabilitation program. PMID- 26034653 TI - Lower-pole Shaping of the Breast by Means of a Double Glandular and Cutaneous Advancement Flap: The "Arrow" Flap. AB - Lower-pole shaping of the breast is sometimes a difficult challenge when performing vertical mammoplasty. The problems mostly encountered are too large breast bases, persistent dog ears, which require long incision, and poor breast projection. We report a modification of the technique that we use in breast reduction so as to better shape the lower pole and to reduce revision surgery. PMID- 26034654 TI - Metabolic liver function measured in vivo by dynamic (18)F-FDGal PET/CT without arterial blood sampling. AB - BACKGROUND: Metabolic liver function can be measured by dynamic PET/CT with the radio-labelled galactose-analogue 2-[(18)F]fluoro-2-deoxy-D-galactose ((18)F FDGal) in terms of hepatic systemic clearance of (18)F-FDGal (K, ml blood/ml liver tissue/min). The method requires arterial blood sampling from a radial artery (arterial input function), and the aim of this study was to develop a method for extracting an image-derived, non-invasive input function from a volume of interest (VOI). METHODS: Dynamic (18)F-FDGal PET/CT data from 16 subjects without liver disease (healthy subjects) and 16 patients with liver cirrhosis were included in the study. Five different input VOIs were tested: four in the abdominal aorta and one in the left ventricle of the heart. Arterial input function from manual blood sampling was available for all subjects. K*-values were calculated using time-activity curves (TACs) from each VOI as input and compared to the K-value calculated using arterial blood samples as input. Each input VOI was tested on PET data reconstructed with and without resolution modelling. RESULTS: All five image-derived input VOIs yielded K*-values that correlated significantly with K calculated using arterial blood samples. Furthermore, TACs from two different VOIs yielded K*-values that did not statistically deviate from K calculated using arterial blood samples. A semicircle drawn in the posterior part of the abdominal aorta was the only VOI that was successful for both healthy subjects and patients as well as for PET data reconstructed with and without resolution modelling. CONCLUSIONS: Metabolic liver function using (18)F-FDGal PET/CT can be measured without arterial blood samples by using input data from a semicircle VOI drawn in the posterior part of the abdominal aorta. PMID- 26034656 TI - Phase II study of lapatinib in combination with vinorelbine, as first or second line therapy in women with HER2 overexpressing metastatic breast cancer. AB - BACKGROUND: Lapatinib in combination with capecitabine is approved for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress the human epidermal growth factor receptor 2 (HER2) and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Based on our phase I trial, we conducted a single arm, multicenter phase II study of lapatinib in combination with vinorelbine. PATIENT AND METHODS: Women with HER2-positive advanced breast cancer, who had received up to one prior regimen for metastatic disease, were eligible. Prior trastuzumab was allowed. Patients received daily lapatinib 1500 mg orally and vinorelbine 20 mg/m(2) intravenously on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall response rate (ORR). RESULTS: Forty-four patients received the combination treatment, including 48% as second-line therapy. The ORR was 41% (95% confidence interval [CI] 26-55%), including 9% with a complete response. Median progression-free survival was 24.1 weeks (95% CI 17-37 weeks) and median duration of response was 32 weeks (95% CI 18-42 weeks). Nearly 80% of patients did not require a dose reduction in lapatinib, although most patients required one dose reduction of vinorelbine secondary to neutropenia. The most common toxicities were grade 1 and 2 diarrhea, nausea, fatigue and rash, and grade 3 and 4 neutropenia. One case of grade 3 asymptomatic decreased left ventricular ejection fraction event was reported. CONCLUSION: The combination of lapatinib and vinorelbine was active, feasible and well tolerated in patients with HER2-positive advanced breast cancer. PMID- 26034655 TI - In vitro susceptibility to amphotericin B, itraconazole, voriconazole, posaconazole and caspofungin of Aspergillus spp. isolated from patients with haematological malignancies in Tunisia. AB - The resistance of Aspergillus species to antifungal is increasingly reported and the knowledge of the local epidemiology and antifungal susceptibility pattern is pivotal to define adequate treatment policies. Our study aimed to: 1) describe the in vitro antifungal susceptibility profile of the Aspergillus species isolated from patients with haematological malignancies in Tunisia; 2) compare the E-test and Sensititre Yeast-One assays for the detection of paradoxical growth and trailing effect, both phenotypes commonly exhibited by Aspergillus spp. upon exposure to caspofungin and 3) to evaluate the mortality rate in patients according to the causative Aspergillus species and the antifungal treatment. We tested amphotericin B, itraconazole, voriconazole, posaconazole and caspofungin against 48 Aspergillus isolates (17, A. niger; 18, A. flavus; 9, A. tubingensis; 1, A. westerdijkiae; and 1, A. ochraceus) with the E-test. Minimal inhibition concentrations were above the epidemiological cut-off values for amphotericin B in 67% of A. flavus strains; for caspofungin in 22% of A. flavus strains; and for itraconazole in 22% of A. tubingensis strains, voriconazole and posaconazole MICs were below the epidemiological cut-off values for all strains. When exposed to caspofungin, 42% of the strains exhibited trailing effect and 38% paradoxical growth. Trailing effect occurred in 61% of A. flavus strains and paradoxical growth in 62% of Aspergillus section Nigri strains. E-test and Sensititre Yeast-One assays were only fairly concordant for the detection of these phenotypes. Repeatability of both assays was high for trailing effect but poor for paradoxical growth. The relatively high frequency of amphotericin B resistant strains makes voriconazole best adapted as a first-line treatment of invasive aspergillosis from amphotericin B to voriconazole in this hospital. PMID- 26034657 TI - Feasibility of automated body trait determination using the SR4K time-of-flight camera in cow barns. AB - As herd sizes have increased in the last decades, computerized monitoring solutions, which provide fast, objective and accurate evaluations of the herd status, gain more and more importance. This study analyzes the feasibility of a Time-of-Flight-camera-based system for gathering body traits in dairy cows for use under cow barn conditions. Recording, determination of body condition score on a 5 point scale by visual and manual inspection, and measuring the backfat thickness with ultrasound took place from July 2011 to May 2012 at the dairy research farm Karkendamm of the Institute of Animal Breeding and Husbandry, Christian-Albrechts-University Kiel (Germany) and between August 2010 and July 2012 at the Institute for Agricultural Engineering and Animal Husbandry of Bavarian State Research Center for Agriculture in Grub (Germany). The two breeds Holstein Friesian cows (Karkendamm) and Fleckvieh (Grub) were considered in this study. Software for recording, image sorting and evaluation, determining the body parts needed, and extracting traits from the images was written and assembled to an automated system. Sorting the images and finding ischeal tuberosities, base of the tail, and dishes of the rump, backbone, and hips had error rates of 0.2%, 1.5%, 0.1%, and 2.6%, respectively. 13 traits were extracted and compared to backfat thickness and body condition score as well as between breeds. All traits depend significantly on the animal and showed very large effect sizes. Coefficients of determination restricted to individual animals were reaching up to 0.89. The precision in measuring the traits and gathering backfat thickness was comparable. Results indicated that the application of Time-Of-Flight in determination of body traits is feasible. PMID- 26034658 TI - The ClpS-like N-domain is essential for the functioning of Ubr11, an N-recognin in Schizosaccharomyces pombe. AB - Several Ubr ubiquitin ligases recognize the N-terminal amino acid of substrate proteins and promote their degradation via the Arg/N-end rule pathway. The primary destabilizing N-terminal amino acids in yeast are classified into type 1 (Arg, Lys, and His) and type 2 (Phe, Trp, Tyr, Leu, Ile, and Met-F) residues. The type 1 and type 2 residues bind to the UBR box and the ClpS/N-domain, respectively, in canonical Ubr ubiquitin ligases that act as N-recognins. In this study, the requirement for type 1 and type 2 amino acid recognition by Schizosaccharomyces pombe Ubr11 was examined in vivo. Consistent with the results of previous studies, the ubr11? null mutant was found to be defective in oligopeptide uptake and resistant to ergosterol synthesis inhibitors. Furthermore, the ubr11? mutant was also less sensitive to some protein synthesis inhibitors. A ubr11 ClpS/N-domain mutant, which retained ubiquitin ligase activity but could not recognize type 2 amino acids, phenocopied all known defects of the ubr11? mutant. However, the recognition of type 1 residues by Ubr11 was not required for its functioning, and no severe physiological abnormalities were observed in a ubr11 mutant defective in the recognition of type 1 residues. These results reinforce the fundamental importance of the ClpS/N domain for the functioning of the N-recognin, Ubr11. PMID- 26034659 TI - Women's preferences for selective estrogen reuptake modulators: an investigation using the time trade-off technique. AB - PURPOSE: Selective Estrogen Receptor Modulators (SERMs) reduce the risk of breast cancer for women at increased risk by 38%. However, uptake is extremely low and the reasons for this are not completely understood. The aims of this study were to utilize time trade-off methods to determine the degree of risk reduction required to make taking SERMs worthwhile to women, and the factors associated with requiring greater risk reduction to take SERMs. METHODS: Women at increased risk of breast cancer (N = 107) were recruited from two familial cancer clinics in Australia. Participants completed a questionnaire either online or in pen and paper format. Hierarchical multiple linear regression analysis was used to analyze the data. RESULTS: Overall, there was considerable heterogeneity in the degree of risk reduction required to make taking SERMs worthwhile. Women with higher perceived breast cancer risk and those with stronger intentions to undergo (or who had undergone) an oophorectomy required a smaller degree of risk reduction to consider taking SERMs worthwhile. CONCLUSION: Women at increased familial risk appear motivated to consider SERMs for prevention. A tailored approach to communicating about medical prevention is essential. Health professionals could usefully highlight the absolute (rather than relative) probability of side effects and take into account an individual's perceived (rather than objective) risk of breast cancer. PMID- 26034660 TI - A radiologic morphometric study of sellar, infrassellar and parasellar regions by magnetic resonance in adults. AB - OBJECTIVE: To evaluate variations of some anatomic structures of sellar and parasellar regions and their possible differences between genders and age groups. PATIENTS AND METHODS: Magnetic resonance images (MRI) of 380 patients were performed to analyze the dimensions of the sphenoid sinus, pituitary gland, optic chiasm, intra-cavernous carotid distances, distance between columella nasal - sphenoid sinus; and columella nasal-pituitary gland. The patients age ranged between 20 and 80 years (mean age 48 years). The study included 235 females (mean age 53 years) and 145 males (mean age 40 years). RESULTS: The transverse length of the pituitary, the inter-carotid distance and the height of the pituitary were similar between genders and age groups. The width and height of the optic chiasm showed differences only between females of different ages. Males presented greater distances between nasal columella and sphenoid sinus. The most common type of pneumatization of the sphenoid sinus was the sellar, and depending on the age group, sphenoid sinus was larger in males than females. CONCLUSION: The anatomy of the Sellar and parasellar regions is complex and varies widely within the normal range. They are a small area, rich in anatomical details affecting multiple physiological systems in the body and, therefore, have great importance in several medical fields. A better understanding of these complex structures is essential in clinical diagnosis and treatment of disease. PMID- 26034661 TI - A systematic review of gemcitabine and taxanes combination therapy randomized trials for metastatic breast cancer. AB - PURPOSE: Gemcitabine/taxanes-based combination shows anti-tumor activity for the treatment of metastatic breast cancer, but there is a debate regarding the advantages of gemcitabine and taxanes regimens as a first-line or second-line treatment for metastatic breast cancer. Here we conducted a systematic review and meta-analysis to compare the efficacy and toxicity for patients receiving chemotherapy with or without GT-based regimens. METHODS: The randomized controlled trials were performed by searching Pubmed, MEDLINE, EMBASE, and conference proceedings. We identified eight randomized controlled trials and then extracted and combined the data using to calculate hazard ratios (HR). The primary outcomes were progression-free survival (PFS) and time to progression (TTP). The secondary outcomes were overall survival (OS) and acute toxicity. A meta-analysis was performed using Review Manager Version 4.2. RESULTS: Eight eligible trails were identified. These studies involved 2234 patients with metastatic breast cancer, (1122 patients received GT-based combination regimen and 1112 patients received a regimen without the combination). A fixed-effects model meta-analysis showed that ORR and TTP are superior for GT-treated patients ORR (OR = 1.28, 95% CI 1.07-1.53), TTP (HR = 0.80; 95% CI 0.71-0.89). And GT based combination significantly improved OS in the first-line subgroup (HR = 0.84; 95% CI 0.71-0.99). However, there were significant differences regarding acute hematological toxicity, particularly thrombocytopenia. CONCLUSION: Gemcitabine/taxanes-treated patients with metastatic breast cancer showed a significant improvement in the ORR, TTP and OS (first-line background) compared to patients not treated with the combination regimen. PMID- 26034662 TI - Bio-ethanol production through simultaneous saccharification and co-fermentation (SSCF) of a low-moisture anhydrous ammonia (LMAA)-pretreated napiegrass (Pennisetum purpureum Schumach). AB - Efficient bio-ethanol production from napiegrass (Pennisetum purpureum Schumach) was investigated. A low-moisture anhydrous ammonia (LMAA)-pretreated napiegrass was subjected to simultaneous saccharification and co-fermentation (SSCF), which was performed at 36 degrees C using Escherichia coli KO11, Saccharomyces cerevisiae, cellulase, and xylanase. It was found that use of xylanase as well as the LMAA-pretreatment was effective for the SSCF. After the SSCF for 96 h, the ethanol yield reached 74% of the theoretical yield based on the glucan (397 mg g( 1)) and xylan (214 mg g(-1)) occurring in dry powdered LMAA-pretreated napiergrass. PMID- 26034663 TI - Willingness to pay to avoid metastatic breast cancer treatment side effects: results from a conjoint analysis. AB - PURPOSE: Metastatic breast cancer (MBC) patients are treated with a variety of regimens with differing side effects that can reduce the patients' quality of life. This study assessed the willingness to pay (WTP) to avoid side effects related to MBC treatment using conjoint analysis. METHODS: An online, self administered conjoint analysis survey of US adult female MBC patients was conducted to elicit preferences for MBC treatment side effects. Attributes included in the analysis were hair loss, diarrhea, fatigue, nausea, tingling in hands and feet, pain, risk of infection, and out-of-pocket costs. Fifteen choice based conjoint questions were presented where patients selected the most preferred therapy. A partial profile design was used to allow for each treatment description to be made with 3 instead of all 8 attributes. The attribute choices for each question included 2 side effects and a yearly out-of-pocket price. RESULTS: There were 298 respondents. MBC patients were willing to pay (US$) $3,894 to avoid severe diarrhea, $3,479 to avoid being hospitalized due to infection, $3,211 to avoid severe nausea, $2,764 to avoid severe tingling in hands and feet, $2,652 to avoid severe fatigue, $1,853 to avoid obvious hair loss, and $1,458 to avoid severe pain. The most important attributes when selecting a therapy for MBC in terms of average utility were risk of infection, diarrhea, and nausea. CONCLUSIONS: MBC patients were willing to pay significant amounts to avoid side effects associated with MBC treatment, with patients willing to pay the most to avoid diarrhea, risk of infection, and nausea. PMID- 26034664 TI - A novel low-complexity post-processing algorithm for precise QRS localization. AB - Precise localization of QRS complexes is an essential step in the analysis of small transient changes in instant heart rate and before signal averaging in QRS morphological analysis. Most localization algorithms reported in literature are either not robust to artifacts, depend on the sampling rate of the ECG recordings or are too computationally expensive for real-time applications, especially in low-power embedded devices. This paper proposes a localization algorithm based on the intersection of tangents fitted to the slopes of R waves detected by any QRS detector. Despite having a lower complexity, this algorithm achieves comparable trigger jitter to more complex localization methods without requiring the data to first be upsampled. It also achieves high localization precision regardless of which QRS detector is used as input. It is robust to clipping artifacts and to noise, achieving an average localization error below 2 ms and a trigger jitter below 1 ms on recordings where no additional artifacts were added, and below 8 ms for recordings where the signal was severely degraded. Finally, it increases the accuracy of template-based false positive rejection, allowing nearly all mock false positives added to a set of QRS detections to be removed at the cost of a very small decrease in sensitivity. The localization algorithm proposed is particularly well-suited for implementation in embedded, low-power devices for real-time applications. PMID- 26034665 TI - Numerical solution of a diffusion problem by exponentially fitted finite difference methods. AB - This paper is focused on the accurate and efficient solution of partial differential differential equations modelling a diffusion problem by means of exponentially fitted finite difference numerical methods. After constructing and analysing special purpose finite differences for the approximation of second order partial derivatives, we employed them in the numerical solution of a diffusion equation with mixed boundary conditions. Numerical experiments reveal that a special purpose integration, both in space and in time, is more accurate and efficient than that gained by employing a general purpose solver. PMID- 26034666 TI - Groundwater contamination in Ibadan, South-West Nigeria. AB - Groundwater is the main source of water for domestic use in Nigeria because it is perceived to be clean. The presence of geogenic contaminants (arsenic and fluoride), and the level of awareness of their presence in groundwater in Ibadan, Nigeria was examined in this study. A total of one hundred and twenty groundwater samples were collected from hand dug wells which tap into shallow aquifers and their location taken with the aid of a GPS. The concentration of arsenic was determined by Atomic Absorption Spectrophotometry (AAS) while concentration of fluoride was determined by single beam spectrophotometer. Three hundred and fifty semi structured questionnaires were also administered within the study area to determine the level of awareness of contamination problem. Simple summary statistics including mean (m) standard deviation (s) and minimum-maximum values of the hydro-chemical data was used in the data analyses, while spatial concentrations were mapped using ArcGIS. The results showed arsenic concentration exceeding the WHO (2011) recommended concentration for drinking water in 98% and 100% of the dry and wet season samples. Concentration of Fluoride exceeded the recommended limits in 13% and 100% of the dry and wet season samples. Questionnaire analyses revealed that 85% of respondents have never tested their wells, 55% have no knowledge of geogenic contamination, while 92% never heard of arsenic or fluoride (52%). The study recommends enlightenment on geogenic contamination and testing of wells for remediation purposes. PMID- 26034667 TI - Development of cereal and legume based food products for the elderly. AB - Diets for elderly must contain nutritious foods, fit their physiological limitations, and match with their food culture. Cereals and legumes are suggested food choices regardless of their cultures and beliefs. Ready-to-eat products containing suitable macronutrient patterns from cereals and legumes were developed. Energy distributions from carbohydrate (60 kcal/100 kcal), protein (15 kcal/100 kcal), and fat (25 kcal/100 kcal), protein quality, and percent energy from saturated fatty acid and free sugar were criteria for the formulation. Carbohydrate sources were rice flour, brown rice flour, mung bean starch, which carbohydrate in rice flour was the most digestible on in vitro test. Protein and fat sources were soybean flour, black sesame seed, and rice bran oil. Three products, i.e., flake snack, instant beverage, and instant soup were produced by drying basic ingredients as flakes on a double-roller drum dryer and directly used or dry-mixed with other ingredients. The products (Aw <0.3) had balanced energy distribution, good quality protein, and energy from saturated fat < 8 kcal/100 kcal and free sugar < 10 kcal/100 kcal. Results from sensory central location test in 219 elderly subjects indicated that the flake snacks from both carbohydrate sources were significantly more acceptable than the other two products. PMID- 26034668 TI - Feasibility and appropriateness of recommended sorghum production technologies. AB - Several initiatives were taken by the Directorate of Sorghum Research and concerned organizations to disseminate promising sorghum technologies. However, many of them were not accepted by the farmers at desired level due to several reasons. Therefore, it was felt necessary to assess the feasibility and appropriateness of recommended technologies as perceived primarily by the research system and followed by the extension personnel. These steps were felt to be a forerunner to screen the recommended technologies for their dissemination. The documentation of the sorghum production technologies/practices for both rainy and post-rainy season was made. The perception of 50 researchers regarding the feasibility of these technologies elucidated that out of 21 documented technologies, six were having feasibility scores of > 4.5 and < 2.2, while the rest of the nine technologies had a medium feasibility score in between 2.0 and 4.5 on a feasibility continuum ranging from 1.0 (not feasible) to 5.0 (highly feasible). Out of these six assessed technologies, extension personnel have perceived three each of technologies as highly appropriate and feasible. Correlation of eight indicators of appropriateness with feasibility of technologies was significant whereas, relative advantage had no correlation. Five indicators of appropriateness namely, simplicity, observability, physical compatibility, production sustainability and cost together explained 96.63 per cent of the total variation in feasibility. It stated that the five indicators are contributing significantly in feasibility of sorghum production technologies. These need to be taken into consideration while developing and disseminating the technologies. PMID- 26034669 TI - Reproductive biology and genetic diversity of the green turtle (Chelonia mydas) in Vamizi island, Mozambique. AB - INTRODUCTION: Vamizi, an Island located in the Western Indian Ocean, is visited by a small and not fully characterized green turtle (Chelonia mydas (L.)) population. This population is threatened by natural hazards and several human activities, which are used to identify conservation priorities for marine turtles. It was our aim to contribute to the knowledge of marine turtles that nest in Vamizi, with respect to its regional management, and to an area that may possibly be included on the UNESCO World Heritage List due to its potential Outstanding Universal Value. CASE DESCRIPTION: Here, we evaluate the nesting parameters (incubation period, clutch size, hatching and emergence successes rates) and patterns over an 8-year (2003 - 2010) conservation program. We also present the results of genetic diversity based on the analysis of approximately an 850 pb fragment of the mitochondrial DNA control region. DISCUSSION AND EVALUATION: We found that Vamizi beaches host a small number of nesting females, approximately 52 per year, but these have shown a reduction in their length. High hatching success (88.5 +/- SD 17.2%, N = 649), emergence success rates (84.5 +/- SD 20.4%, N = 649) were observed, and genetic diversity (N = 135), with 11 haplotypes found (7 new). It was also observed, in the later years of this study, a reduction in the incubation period, a dislocation of the nesting peak activity and an increase in the number of flooded nests and an increase of the number of nests in areas with lower human activity. CONCLUSIONS: Some resilience and behavioral plasticity seems to occur regarding human territory occupancy and climate changes. However, regardless of the results, aspects like what seems to be the reduction of some cohorts, the number of flooded nests and the diminishing of the incubation period (East and South facing beaches), show that conservation efforts have to be improved. PMID- 26034670 TI - Are parents really attached to their adopted children? AB - BACKGROUND: Psychological studies found that adopted children suffer from lack of attachment relationships in life. It is important for new parents to understand the underlying concepts before they begin to comprehend behavior issues arising out of different turbulent situations in an adopted child's life. Attachment theory facilitates in comprehending the frame of mind of these children, when they come from emotionally turbulent backgrounds and how some, if not all behavior issues can be attempted to be resolved to recognize children better and to create a nurturing relationship between adopted child and new parents. FINDINGS: Focus group method was deployed to collect the data via un-restricted non-probability sampling approach; data was quantified for evaluating the hypotheses via t-test of equality of means. Cross cultural findings suggested that parents-adopted children relationship in terms of secure attachment is revealed more in non-working parents, female parents, children of 11-14 years and female children across stated nations while, the ambivalent, avoidant and disorganized attachments are found more in practice if parents are working & male parents and if foster children are male at large & of 15-18 years. CONCLUSION: It is concluded that the task of creating an enriched attachment relationship with an adopted child depends more on parents, normally non working parents and female parents while quality time and care is given somehow the other to young and female kids by either of the parents for establishing quality attachment. Quality time being bestowed to kids translates the category and intensity of parents- children associations. PMID- 26034671 TI - Genetic analysis of resistance to Pseudomonas syringae pv. actinidiae (Psa) in a kiwifruit progeny test: an application of generalised linear mixed models (GLMMs). AB - Linear Mixed models (LMMs) that incorporate genetic and spatial covariance structures have been used for many years to estimate genetic parameters and to predict breeding values in animal and plant breeding. Although the theoretical aspects for extending LMM to generalised linear mixed models (GLMMs) have been around for some time, suitable software has been developed only within the last decade or so. The GLIMMIX procedure in SAS(r) is becoming popular for fitting GLMMs in various disciplines. Applications of GLMMs to genetic analysis have been limited, probably because of the complexity of the models used. This is particularly so for Proc GLIMMIX because, unlike ASReml software, it is not specifically tailored for analysis of breeding data and some pre-procedure coding is necessary. Binary data that fits the GLMM framework is commonly encountered in breeding experiments, such as when evaluating individuals for resistance by observing the presence or absence of disease. Bacterial canker (Psa) caused by Pseudomonas syringae pv. actinidiae is a serious disease of kiwifruit in New Zealand and other kiwifruit-producing countries. Data from a progeny test trial was available to identify parents with high breeding values for resistance. We successfully applied the GLIMMIX procedure for this purpose. Heritability for resistance was moderate, and we identified two parents and their family as having high potential for Psa resistance breeding. There are several potential pitfalls when using GLMMs with binary data and these are briefly discussed. PMID- 26034672 TI - Endoglin (CD105) expression differentiates between aseptic loosening and periprosthetic joint infection after total joint arthroplasty. AB - The differentiation between aseptic loosening and periprosthetic joint infection (PJI) after total joint arthroplasty is essential for successful therapy. A better understanding of pathogenesis of aseptic loosening and PJI may help to prevent or treat these complications. Previous investigations revealed an increased vascularization in the periprosthetic membrane in cases of PJI via PET signals. Based on these findings our hypothesis was that PJI is associated with an increased neovascularization in the periprosthetic membrane. Tissue samples from periprosthetic membranes of the bone-implant interface were investigated histologically for inflammation, wear particles, vascularization and fibrosis. To identify vascular structures antibodies against CD 31, CD 34, factor VIII and CD 105 (endoglin) were applied for immunohistochemical investigations. According to a consensus classification of Morawietz the tissue samples were divided into four types: type I (wear particle induced type, n = 11), type II (infectious type, n = 7), type III (combined type, n = 7) and type IV (indeterminate type, n = 7). Patients with PJI (type II) showed a pronounced infiltration of neutrophil granulocytes in the periprosthetic membrane and an enhanced neovascularization indicated by positive immunoreaction with antibodies against CD 105 (endoglin). Tissue samples classified as type I, type III and type IV showed significantly less immune reaction for CD 105. In cases of aseptic loosening and PJI vascularization is found in different expression in periprosthetic membranes. However, in aseptic loosening, there is nearly no neovascularization with CD 105 positive immune reaction. Therefore, endoglin (CD 105) expression allows for differentiation between aseptic loosening and PJI. PMID- 26034673 TI - El Nino Southern Oscillation (ENSO) impact on tuna fisheries in Indian Ocean. AB - El Nino Southern Oscillation (ENSO) is an important driver of interannual variations in climate and ecosystem productivity in tropical regions. However, detailed information about this important phenomenon of the Indian Ocean is scarce. Consequently, the objective of this study is to improve understanding of the impact of warm event El Nino and cool event La Nina on annual tuna landings from the Indian Ocean from 1980 to 2010. In this study, maximum tuna landings were recorded during a weak El Nino year (1456054 t in 2006) and during a weak La Nina year (1243562 t in 2000), although the lowest tuna catch was followed during the strong El Nino year (1204119 t in 2009) and during a strong La Nina year (706546 t in 1988). Validation of predicted tuna landings and SST were showing a significant positive correlation (p < 0.01) was observed all the major tuna species except Southern Bluefin Tuna. Whereas the other relationships such as sea level pressure, Wind actions; Zonal Wind (U), Meridonial Wind (V), and Scalar Wind (W) are less well-defined. In contrast with principal component analysis we find that Principal Components 1 explains 75.5% of the total variance and suggest that sea surface temperature plays a major role in determining tuna availability in the region especially during warm event El Nino years; landings in Indian Ocean tend to be optimum SST 25 to 26 degrees C in ENSO event. Our results confirm the ENSO impact on climate, tuna abundance and production in the Indian Ocean. However, among the oceanic variables SST explained the highest deviance in generalized additive models and therefore considered the best habitat predictor in the Indian Ocean followed by sea level pressure and Winds (U, V, W). PMID- 26034674 TI - An assessment of the predictors of the dynamics in arable production per capita index, arable production and permanent cropland and forest area based on structural equation models. AB - This study sets out to verify the key predictors of the dynamics of the arable production per capita index, the arable production and permanent crop land and forest area at a national scale in Cameroon. To achieve this objective, data for twelve time series data variables spanning the period 1961-2000 were collected from Oxford University, the United Nations Development program, the World Bank, FAOSTAT and the World Resource Institute. The data were analysed using structural equation models (SEM) based on the two stage least square approach (2SLS). To optimize the results, variables that showed high correlations were dropped because they will not add any new information into the models. The results show that the arable production per capita index is impacted more by population while the influence of rainfall on the arable production per capita index is weak. Arable production and permanent cropland on its part has as the main predictor arable production per capita index. Forest area is seen to be more vulnerable to trade in forest products and logging than any other variable. The models presented in this study are quite reliable because the p and t values are consistent and overall, these results are consistent with previous studies. PMID- 26034675 TI - Address allocation for MANET merge and partition using cluster based routing. AB - Network merges and partitions occur quite often in MANET wherein address auto configuration is a critical requirement. There are various approaches for address auto-configuration in MANETs which allocate address to the nodes in a dynamic and distributed manner in which HOST ID and MANET ID are assigned on the basis of their Base value. MANET merges and partitions employing Cluster Based Routing Protocol require a node to be assigned as the Cluster Head (CH). This paper presents the Election Algorithm which assigns a node as the Cluster Head on the basis of its weight. Through simulation using the NS-2, it has been shown that the Election Algorithm improves the packet delivery ratio (PDR) significantly and decreases the packet delay to a great extent in comparison to the existing AODV protocol. PMID- 26034676 TI - A framework to observe and evaluate the sustainability of human-natural systems in a complex dynamic context. AB - This paper aims to explore the prominent implications of the process of observing complex dynamics linked to sustainability in human-natural systems and to propose a framework for sustainability evaluation by introducing the concept of sustainability boundaries. Arguing that both observing and evaluating sustainability should engage awareness of complex dynamics from the outset, we try to embody this idea in the framework by two complementary methods, namely, the layer view- and dimensional view-based methods, which support the understanding of a reflexive and iterative sustainability process. The framework enables the observation of complex dynamic sustainability contexts, which we call observation metastructures, and enable us to map the contexts to sustainability boundaries. PMID- 26034677 TI - miRNAs in Sera of Tunisian patients discriminate between inflammatory breast cancer and non-inflammatory breast cancer. AB - In recent years, circulating miRNAs have attracted interest as stable, non invasive biomarkers for various pathological conditions. Here, we investigated their potential to serve as minimally invasive, early detection markers for inflammatory breast cancer (IBC) and non-inflammatory breast cancer (non-IBC) in serum. miRNA profiling was performed on serum from 20 patients with non-IBC, 20 with IBC, and 20 normal control subjects. Real-time reverse transcription polymerase chain reaction (qRT-PCR) was applied to measure the level of 12 candidate miRNAs previously identified in other research(miR-342-5p, miR-342--3p, miR-320, miR-30b, miR-29a, miR-24, miR-15a, miR-548d-5p, miR-486-3p, miR-451, miR 337-5p, miR-335).We found that 4 miRNAs (miR-24, miR-342-3p, miR-337-5p and miR 451) were differentially expressed in serum of IBC patients compared to non-IBC, and 3 miRNAs (miR-337-5p ,miR-451and miR-30b) were differentially expressed in IBC and non-IBC patients combined compared to healthy controls. miR-24, miR-342 3p, miR-337-5p and miR-451 were found to be significantly down-regulated in IBC patients compared to non-IBC. Likewise, the expression level of mir-451 showed significant down-regulation in IBC serum, while mir-30b and miR-337-5p were up regulated in non-IBC serum comparatively to normal controls. Using receiver operational curve (ROC) analysis, we show that dysregulated miRNAs can discriminate patients with IBC and non-IBC from healthy controls with sensitivity ranging from 76 to 81% and specificity from 66 to 80%, for three separate miRNAs. In conclusion, our data suggest that circulating miRNAs are potential biomarkers for classifying IBC and non-IBC, and may also be candidates for early detection of breast cancer. PMID- 26034678 TI - Ecotone analysis: assessing the impact of vehicle transit on saltmarsh crab population and ecosystem. AB - The frequent transit of vehicles (recreational or not) through saltpans and saltmarsh fields has been recorded as one of the major causes of physical and ecological damage for these environments. While several studies have been carried out to assess the consequence of this anthropogenic activity on the different local plant species, little is known on its long-term impact on the faunal community. Invertebrates, such as crabs, provide several essential ecological services, and their presence and abundance are tightly connected to that of the saltmarsh plants. Decrease of vegetative cover due to vehicle transit is likely to cause alterations in the morphology and the composition of the saltmarsh ecosystem. In this study we evaluate presence and distribution of the main crustacean species in several impacted sites in Townsville area (Queensland, Australia), to determine possible correlation between vehicle tracks alterations and crab distribution, as well as investigate any possible habitat shift in the mid- and long-term. Results indicate that reduction of plant cover affects species composition and distribution, with different effects based on the unique characteristics of each crab species analysed, resulting in an overall alteration of the assemblage structure. PMID- 26034679 TI - Liquid film condensation along a vertical surface in a thin porous medium with large anisotropic permeability. AB - The problems of steady film condensation on a vertical surface embedded in a thin porous medium with anisotropic permeability filled with pure saturated vapour are studied analytically by using the Brinkman-Darcy flow model. The principal axes of anisotropic permeability are oriented in a direction that non-coincident with the gravity force. On the basis of the flow permeability tensor due to the anisotropic properties and the Brinkman-Darcy flow model adopted by considering negligible macroscopic and microscopic inertial terms, boundary-layer approximations in the porous liquid film momentum equation is solved analytically. Scale analysis is applied to predict the order-of-magnitudes involved in the boundary layer regime. The first novel contribution in the mathematics consists in the use of the anisotropic permeability tensor inside the expression of the mathematical formulation of the film condensation problem along a vertical surface embedded in a porous medium. The present analytical study reveals that the anisotropic permeability properties have a strong influence on the liquid film thickness, condensate mass flow rate and surface heat transfer rate. The comparison between thin and thick porous media is also presented. PMID- 26034680 TI - Arylamine N-acetyl Transferase (NAT) in the blue secretion of Telescopium telescopium: xenobiotic metabolizing enzyme as a biomarker for detection of environmental pollution. AB - Telescopium telescopium, a marine mollusc collected from Sundarban mangrove, belongs to the largest mollusca phylum in the world and exudes a blue secretion when stimulated mechanically. The blue secretion was found to metabolize (preferentially) para-amino benzoic acid, a substrate for N-acetyl transferase (NAT), thereby indicating acetyl transferase like activity of the secretion. Attempts were also made to characterise bioactive fraction of the blue secretion and to further use this as a biomarker for monitoring of marine pollution. NAT like enzyme from marine mollusc is a potential candidate for detoxification of different harmful chemicals. A partially purified extract of blue secretion was obtained by fractional precipitation with (NH4)2SO4. From different fractions obtained by precipitation, the 0-30% fraction (30S) displayed NAT like activity (using para amino benzoic acid as a substrate with para nitrophenyl phosphate or acetyl coenzyme A as acetyl group donors). Maximum NAT like enzyme activity was attained at 25 degrees C and at a pH of 6. The enzyme activity was found to be inhibited by 5 mM phenyl methyl sulfonyl fluoride. The divalent metal ions reduced NAT like activity of 30S. Moreover, Cu(2+) and Zn(2+) (at concentration of 1 mM) completely inhibited NAT activity. The thermal stability and bench-top stability studies were performed and it was found that the enzyme was stable at room temperature for more than 24 hours. Results from the present study further indicate that heavy metal content in blue secretion gradually decreased from pre monsoon to post-monsoon season, which also corresponded to the change in NAT like activity. Therefore, this article stresses the importance of biomarker research for monitoring pollution. PMID- 26034681 TI - HAV in fresh vegetables: a hidden health risk in district Mardan, Pakistan. AB - Hepatitis A is an acute inflammation of the liver caused by the hepatitis A virus (HAV) in human. The path of entry of HAV to the bloodstream is the epithelium of the intestine. Liver inflammation occurs when HAV multiplies within the hepatocytes and Kupffer cells of the liver. HAV is mostly transmitted by contaminated water, fruits and vegetables. The purpose of the current study was to evaluate fresh vegetables raised on the fecal contaminated water for the detection of HAV by PCR method. Twenty nine samples were collected from 13 different locations of district Mardan and screened for the presence of HAV. Village Bajowro near Takht Bhai was the most contaminated site having HAV in all vegetables grown over there. Water samples collected from this area proved to be contaminated with HAV. It may be concluded that fecal contaminated water is unsafe for irrigation because of the health risk associated with such practices. PMID- 26034682 TI - Protomers of protein hetero-oligomers tend to resemble each other more than expected. AB - A large fraction of the proteome is made by proteins that are not permanently monomeric but form oligomeric assemblies, which can be either homo- or hetero oligomeric. Here it is described that protomers of hetero-oligomeric proteins tend to resemble each other more than expected. This is verified by comparing the level of similarity of pairs of hetero-oligomeric protein protomers and of pairs of proteins that do not interact with each other. This observation, interesting per se, might reflect the evolution of hetero-oligomers from ancestral homo oligomers, through gene duplication and paralogs divergence. However, other hypotheses cannot be excluded and the observed structural similarity might result from several causes. PMID- 26034684 TI - Indigenous students transitioning to school: responses to pre-foundational mathematics. AB - Australian Indigenous students' mathematics performance continues to be below that of non-Indigenous students. This occurs from the early years of school, due largely to knowledge and social differences on entry to formal schooling. This paper reports on a mathematics research project conducted in one Aboriginal community school in New South Wales, Australia. The project aimed to identify and explain the ways that young Australian Indigenous students (age 2-4 years) learn number language and processes, specifically attribute language, sorting, 1-1 correspondence and, counting. The project adopted a mixed methods approach. That is, the methodology was decolonising (Smith 1999) in that it collaborated with and gave benefit back to the Indigenous community and school being researched. It was qualitative and interpretative (Burns 2000) and incorporated an action research teaching-experiment approach where and teachers collaborated with the researchers to try new teaching methods. This paper draws on data pertaining to students' response to diagnostic interview questions, the pre- and post-test results of the interview and photographic evidence as observations during mathematics learning time. Participants referred to in this paper include one female principal (N = 1), and the transition class of students' pre- (N = 6) and post-test (N = 3) results of the pre-foundational processes (also referred to as attributes). The results were encouraging with improvements in colour (34%), patterns (33%) and capacity (38%). As a result of this project, our epistemology regarding the importance of finding out about students' pre-foundational knowledge and understandings and providing a culturally appropriate learning environment with resources has been built upon. PMID- 26034683 TI - Leptin receptor polymorphism Gln223Arg (rs1137101) in oral squamous cell carcinoma and potentially malignant oral lesions. AB - The purpose of this study was to assess the LEPR gene Gln223Arg polymorphism (rs1137101) in oral squamous cell carcinoma (OSCC) and in potentially malignant oral lesions (PMOL) in comparison to normal oral mucosa in a Brazilian population. Smokers (n = 89) were selected from a representative sample of 471 individuals from the general population of Montes Claros, Brazil. Participants were age and gender matched to patients with OSCC (n = 25) and oral epithelial dysplasia (n = 25). We investigated the LEPR Gln223Arg polymorphism (A>G; rs1137101) in these groups. Genotype variants were assessed by RFLP-PCR, using MspI (HPAII) restriction endonuclease. The institutional review board of the Universidade Estadual de Montes Claros approved the study (process number 2667/2011). Written informed consent for this study was obtained from all participants. The GG genotype (Arg223Arg) appears to be the more relevant polymorphic variant in OSCC. It occurred, approximately, twice as frequently in OSCC patients than in the general population. In contrast, the A allele in its homozygosis form (Gln223Gln) is significantly associated with the development of PMOL; 80% of the samples from the PMOL group exhibit AA genotype. Our findings suggest new insights regarding LEPR gene variations in the development of OSCC and PMOL. PMID- 26034685 TI - High frequency input impedance modeling of low-voltage residential installations influence on lightning overvoltage simulations results. AB - The overvoltage level of a system is strongly dependent on the connected loads and with more precise models, better and more reliable simulation results are obtained. This paper presents the input impedance characteristics, measured over a wide range of frequencies, of various actual low-voltage residential installations. The measured frequency responses were fitted by effective RLC models and a general model was also developed. The range of frequencies considered in the study, nearly d.c. up to 5 MHz, allows the use of these models for lightning or switching studies. It is also presented overvoltage simulations, using different residential installations models presented in the paper, of a distribution network subjected to lightning surges on the medium voltage circuit. PMID- 26034686 TI - Statistical design and optimization of single cell oil production from sugarcane bagasse hydrolysate by an oleaginous yeast Rhodotorula sp. IIP-33 using response surface methodology. AB - Single cell oil production from sugarcane bagasse hydrolysate by oleaginous yeast Rhodotorula sp. IIP-33 was analyzed using a two stage statistical design approach based on Response Surface Methodology. Variables like pentose sugar, (NH4)2SO4, KH2PO4, yeast extract, pH and temperature were found to influence lipid production significantly. Under optimized condition in a shake flask, yield of lipid was 2.1199 g with fat coefficient of 7.09 which also resembled ~99% similarity to model predicted lipid production. In this paper we are presenting optimized results for production of non polar lipid which could be later deoxygenated into hydrocarbon. A qualitative analyses of selective lipid samples yielded a varying distribution of free acid ranging from C6 to C18, majoring C16:0, C18:0 and C18:1 under different fermentation conditions. PMID- 26034687 TI - Investigation of Solitary wave solutions for Vakhnenko-Parkes equation via exp function and Exp(-phi(xi))-expansion method. AB - In this paper, we have described two dreadfully important methods to solve nonlinear partial differential equations which are known as exp-function and the exp(-phi(xi)) -expansion method. Recently, there are several methods to use for finding analytical solutions of the nonlinear partial differential equations. The methods are diverse and useful for solving the nonlinear evolution equations. With the help of these methods, we are investigated the exact travelling wave solutions of the Vakhnenko- Parkes equation. The obtaining soliton solutions of this equation are described many physical phenomena for weakly nonlinear surface and internal waves in a rotating ocean. Further, three-dimensional plots of the solutions such as solitons, singular solitons, bell type solitary wave i.e. non topological solitons solutions and periodic solutions are also given to visualize the dynamics of the equation. PMID- 26034688 TI - Isotretinoin-induced skeletal hyperostosis. AB - We describe a case of skeletal hyperostosis in a 29 year old man presenting with non-inflammatory back pain with a past history of isotretinoin therapy for acne. The development of skeletal hyperostosis, predominantly of the spine, has been reported in association with isotretinoin use and has a radiographic picture similar to diffuse idiopathic skeletal hyperostosis. The prevalence and severity of this condition appears to correlate with duration of therapy. Isotretinoin is a well-established treatment for severe acne. It is important for the rheumatologist be aware of this phenomenon when assessing young patients with musculoskeletal symptoms and evidence of radiological abnormalities. PMID- 26034689 TI - Expression of a manganese peroxidase isozyme 2 transgene in the ethanologenic white rot fungus Phlebia sp. strain MG-60. AB - BACKGROUND: The white-rot fungus Phlebia sp. strain MG-60 was proposed as a candidate for integrated fungal fermentation process (IFFP), which unifies aerobic delignification and semi-aerobic consolidated biological processing by a single microorganism based on its ability to efficiently degrade lignin and ferment the sugars from cellulose. To improve IFFP, the development of a molecular breeding method for strain MG-60 is necessary. The purpose of this study is to establish the transformation method for the strain MG-60 and to obtain the over-expressing transformants of lignin-degrading enzyme, manganese peroxidase. FINDINGS: In the present study, the expression vector regulated by Phlebia brevispora glyceraldehyde-3-phosphate dehydrogenase promoter and terminator was constructed. A polyethylene glycol transformation method for the ethanol-fermenting white-rot fungus Phlebia sp. MG-60 was established with high transformation efficiency, and the manganese peroxidase isozyme 2 gene (MGmnp2) transformants were obtained, showing higher MnP activity than control transformants. MGmnp2 transformants showed higher selective lignin degradation on Quercus wood powder. CONCLUSIONS: This first report of MG-60 transformation provides a useful methodology for widely accessible to interested researches. These results indicate the possibility of metabolic engineering of strain MG-60 for improving IFFP. PMID- 26034690 TI - Population, diversity and characteristics of cellulolytic microorganisms from the Indo-Burma Biodiversity hotspot. AB - Forest ecosystem harbour a large number of biotic components where cellulolytic microorganisms participate actively in the biotransformation of dead and decaying organic matter and soil nutrient cycling. This study explores the aerobic culturable cellulolytic microorganisms in the forest soils of North East India. Soil samples rich in dead and decaying organic matter were collected from eight conserved forests during the season when microbes were found to be most active. Cellulolytic microorganisms were isolated using selective media in which cellulose was the sole carbon source. Population of culturable, aerobic, cellulolytic microorganisms were found to be higher at the incubation temperature that corresponds to the natural ambient temperature of the site of sample collection. Bacterial population was higher in all of the sites than fungal population. Bacterial population ranged from 1.91 * 10(5) to 3.35 * 10(6) CFU g( 1) dry soil while actinomycetes and fungal population ranged from 9.13 * 10(2) to 3.46 * 10(4) CFU g(-1) dry soil and 9.36 * 10(2) to 4.31 * 10(4) CFU g(-1) dry soil, respectively. It was observed that though many isolates showed activity on the CMC plate assay, very few isolates showed significant filter paper activity. Three cellulolytic fungal isolates showing high FPase activity were characterised, identified and submitted to GenBank as Talaromyces verruculosus SGMNPf3 (KC937053), Trichoderma gamsii SGSPf7 (KC937055) and Trichoderma atroviride SGBMf4 (KC937054). PMID- 26034691 TI - Vibrational spectroscopic, NMR parameters and electronic properties of three 3 phenylthiophene derivatives via density functional theory. AB - Quantum chemistry calculations have been performed to compute the optimized geometries, vibrational frequencies, and Mulliken Charges at B3LYP/6-31G(d) and B3LYP/6-311++G(d,p) levels for 3-(4-fluorophenyl)thiophene (FPT), 3-(4 nitrophenyl)thiophene (NPT) and 3-(4-cyanophenyl) thiophene (CPT) in the ground state. In addition, the (13)C and (1)H NMR are calculated by B3LYP/6-311++G(d,p) and B3LYP/6-311++G(2d,2p) methods. The singlet electronic excited state properties of the three compounds were investigated using the time-dependent density functional method (TD-DFT) at the B3LYP/6-311++G(d,p)//TD- B3LYP/6 311++G(d,p) level of theory. The influence of the substituted groups on C9 atom is discussed. PMID- 26034692 TI - Land cover transformation in two post-mining landscapes subjected to different ages of reclamation since dumping of spoils. AB - Transformation of natural land cover (LC) into modified LC has become inevitable due to growing human needs. Nevertheless, landscape transformational patterns during reclamation of mine damaged lands remain vague. Our hypothesis was that post-mining landscapes with different ages since dumping become more diverse in LC transformation over time. The aim was to study the impact of landscape reclamation on land cover changes (LCC) in two post-mining landscapes. Land cover maps of 1988, 1991, 1995, 1998, 2000 and 2003 were produced from LANDSAT TM images of Schlabendorf Nord and Schlabendorf Sud and used to survey the changing landscape. Change detection extension was used to identify changes among land cover types (LCTs). Detrended correspondence analyses (DCA) ordination technique (CANOCO) aided study of similarity among LC distribution. Soil pH analysis was carried out to study effect of soil and climate conditions on LCC. The results show that visible patterns of increase and decrease in the LCTs occurred in both landscapes. Given two post-mining landscapes subjected to different ages of reclamation, clear differences in vegetation growth and LCC pattern would occur. At early stages of restoration, LCTs often have unstable conditions and experience more acute transformation depending on the level of land use intensity in space and time. LCCs were mostly due to progressive and reversed succession. Due to variation in post-mining landscape soil conditions, soil treatment during reclamation should be site specific. The comparative analysis of LCCs in Schlabendorf provides a framework for prioritizing land use planning options for sustainable management of post-mining landscapes in temperate ecosystems. PMID- 26034693 TI - Decomposition of multivariate function using the Heaviside step function. AB - Whereas the Dirac delta function introduced by P. A. M. Dirac in 1930 to develop his theory of quantum mechanics has been well studied, a not famous formula related to the delta function using the Heaviside step function in a single variable form, also given by Dirac, has been poorly studied. Following Dirac's method, we demonstrate the decomposition of a multivariate function into a sum of integrals in which each integrand is composed of a derivative of the function and a direct product of Heaviside step functions. It is an extension of Dirac's single-variable form to that for multiple variables. PMID- 26034694 TI - Fast digital zooming system using directionally adaptive image interpolation and restoration. AB - This paper presents a fast digital zooming system for mobile consumer cameras using directionally adaptive image interpolation and restoration methods. The proposed interpolation algorithm performs edge refinement along the initially estimated edge orientation using directionally steerable filters. Either the directionally weighted linear or adaptive cubic-spline interpolation filter is then selectively used according to the refined edge orientation for removing jagged artifacts in the slanted edge region. A novel image restoration algorithm is also presented for removing blurring artifacts caused by the linear or cubic spline interpolation using the directionally adaptive truncated constrained least squares (TCLS) filter. Both proposed steerable filter-based interpolation and the TCLS-based restoration filters have a finite impulse response (FIR) structure for real time processing in an image signal processing (ISP) chain. Experimental results show that the proposed digital zooming system provides high-quality magnified images with FIR filter-based fast computational structure. PMID- 26034695 TI - Clinicopathologic characteristics of SALL4-immunopositive hepatocellular carcinoma. AB - The aim of this study was to investigate the clinicopathologic characteristics of sal-like protein 4 (SALL4)-immunopositive hepatocellular carcinoma (HCC). Solitary HCCs that were surgically treated at the University of Tokyo Hospital between 2000 and 2008 were the subject of this study. Diffuse, non-punctate nuclear immunoreactivity to SALL4 was observed in 47 of 337 HCCs (13.9%). Compared to patients with SALL4-negative HCC, patients with SALL4-positive HCC were younger (mean 59.2 years vs. 65.2 years), more frequently female (44.7% vs. 18.3%) and positive for hepatitis B virus angigen (42.6% vs. 18.6%). They had much higher serum levels of alpha-fetoprotein (median 3976.5 ng/ml vs. 14.0 ng/ml) (P < 0.001). Liver function tended to be favourable, as was shown by less indocyanine green retention at 15 minutes (ICG15), in patients with SALL4 positive HCCs (P < 0.001). Histologically, SALL4-positive HCCs exhibited less histological differentiation (P < 0.001) and had a higher frequency of micro- or macrovascular invasion (72.3% vs. 54.1%, P = 0.019) and intrahepatic metastasis (34.0% vs. 19.3%, P = 0.022) than SALL4-negative HCCs. SALL4-positive HCCs were more frequently immunoreactive for cytokeratin 19 (42.6% vs. 11.7%, P < 0.001) and EpCAM (51.1% vs. 8.3%, P < 0.001). The log-rank test indicated short-term disease-free survival (< 1 year) of patients with SALL4-positive HCC was worse than those with SALL4-negative HCC (P = 0.019). Multivariate analyses, however, failed to show the prognostic significance of SALL4 immunoreactivity in HCCs. In conclusion, SALL4-immunopositive HCCs constitute a subset with characteristic patient backgrounds and somewhat aggressive behavior, as was manifested by frequent vascular invasion and intrahepatic metastasis. There was little prognostic significance of SALL4 immunoreactivity in HCCs. PMID- 26034696 TI - Construction of the membership surface of imprecise vector. AB - In this article, a method has been developed to construct the membership surface of imprecise vector based on Randomness-Impreciseness Consistency Principle. The Randomness-Impreciseness Consistency Principle leads to define a normal law of impreciseness using two different laws of randomness. The Dubois-Prade left and right reference functions of an imprecise number are distribution function and complementary distribution function respectively. In this article, based on the Randomness-Impreciseness Consistency Principle we have successfully obtained the membership surface of imprecise vector and demonstrated with the help of numerical examples. PMID- 26034697 TI - On the average temperature of airless spherical bodies and the magnitude of Earth's atmospheric thermal effect. AB - The presence of atmosphere can appreciably warm a planet's surface above the temperature of an airless environment. Known as a natural Greenhouse Effect (GE), this near-surface Atmospheric Thermal Enhancement (ATE) as named herein is presently entirely attributed to the absorption of up-welling long-wave radiation by greenhouse gases. Often quoted as 33 K for Earth, GE is estimated as a difference between planet's observed mean surface temperature and an effective radiating temperature calculated from the globally averaged absorbed solar flux using the Stefan-Boltzmann (SB) radiation law. This approach equates a planet's average temperature in the absence of greenhouse gases or atmosphere to an effective emission temperature assuming ATE = GE. The SB law is also routinely employed to estimating the mean temperatures of airless bodies. We demonstrate that this formula as applied to spherical objects is mathematically incorrect owing to Holder's inequality between integrals and leads to biased results such as a significant underestimation of Earth's ATE. We derive a new expression for the mean physical temperature of airless bodies based on an analytic integration of the SB law over a sphere that accounts for effects of regolith heat storage and cosmic background radiation on nighttime temperatures. Upon verifying our model against Moon surface temperature data provided by the NASA Diviner Lunar Radiometer Experiment, we propose it as a new analytic standard for evaluating the thermal environment of airless bodies. Physical evidence is presented that Earth's ATE should be assessed against the temperature of an equivalent airless body such as the Moon rather than a hypothetical atmosphere devoid of greenhouse gases. Employing the new temperature formula we show that Earth's total ATE is ~90 K, not 33 K, and that ATE = GE + TE, where GE is the thermal effect of greenhouse gases, while TE > 15 K is a thermodynamic enhancement independent of the atmospheric infrared back radiation. It is concluded that the contribution of greenhouse gases to Earth's ATE defined as GE = ATE - TE might be greater than 33 K, but will remain uncertain until the strength of the hereto identified TE is fully quantified by future research. PMID- 26034698 TI - Exact solutions for (1 + 1)-dimensional nonlinear dispersive modified Benjamin Bona-Mahony equation and coupled Klein-Gordon equations. AB - ABSTRACT: In this work, recently developed modified simple equation (MSE) method is applied to find exact traveling wave solutions of nonlinear evolution equations (NLEEs). To do so, we consider the (1 + 1)-dimensional nonlinear dispersive modified Benjamin-Bona-Mahony (DMBBM) equation and coupled Klein Gordon (cKG) equations. Two classes of explicit exact solutions-hyperbolic and trigonometric solutions of the associated equations are characterized with some free parameters. Then these exact solutions correspond to solitary waves for particular values of the parameters. PACS NUMBERS: 02.30.Jr; 02.70.Wz; 05.45.Yv; 94.05.Fg. PMID- 26034699 TI - A class of Fourier integrals based on the electric potential of an elongated dipole. AB - In the present paper the closed expressions of a class of non tabulated Fourier integrals are derived. These integrals are associated with a group of functions at space domain, which represent the electric potential of a distribution of elongated dipoles which are perpendicular to a flat surface. It is shown that the Fourier integrals are produced by the Fourier transform of the Green's function of the potential of the dipole distribution, times a definite integral in which the distribution of the polarization is involved. Therefore the form of this distribution controls the expression of the Fourier integral. Introducing various dipole distributions, the respective Fourier integrals are derived. These integrals may be useful in the quantitative interpretation of electric potential anomalies produced by elongated dipole distributions, at spatial frequency domain. PMID- 26034700 TI - Case of arthritis secondary to leprosy. AB - INTRODUCTION: Leprosy is a chronic granulomatous infectious disease, which is caused by Mycobacterium leprae. High numbers of people are still affected by this disease in some of the developing countries however, it is rarely seen in non endemic regions. Cutaneous and neurological manifestations are the common and classical presentations of leprosy. Musculoskeletal involvement is the third most common manifestation but is less frequently reported. Joint involvement can present as acute symmetrical polyarthritis or chronic polyarthritis resembling rheumatoid arthritis. Leprosy can also present with tenosynovitis, either isolated or associated with arthritis. CASE PRESENTATION: We report a case of 29 year-old man who developed tenosynovitis and acute symmetrical polyarthritis including small joints of hands and feet three weeks after appearance of typical cutaneous lesion of leprosy. Patient improved with steroid and anti leprosy treatment. Patient had another acute episode with symmetrical polyarthritis four months later while on treatment. DISCUSSION AND EVALUATION: In the modern era, there is increase movement of population from developing countries to developed countries, it is likely that patient suffering from leprosy with arthritis may present to rheumatology clinic in those countries where leprosy is not endemic. Exact pathogenesis for musculoskeletal manifestations is still not fully known. Our patient presented with symmetrical polyarthritis, enthesitis and systemic involvement, which was secondary to lepra reaction. Having good knowledge of musculoskeletal manifestation of leprosy, will help narrow differential diagnosis and will prevent unnecessary diagnostic workup. CONCLUSION: Leprosy can present with different rheumatologic manifestation including tenosynovitis and acute symmetrical polyarthritis. Type 2 lepra reaction (Erythema nodosum leprosum ENL) can present with systemic manifestation and can involve skin, nerves, joints, kidneys and liver. PMID- 26034702 TI - Diagnostic challenge of paroxysmal sympathetic hyperactivity (PSH) associated with diffuse axonal injury (DAI) in head trauma. PMID- 26034701 TI - Association of the TP53 codon 72 polymorphism and breast cancer risk: a meta analysis. AB - This study was conducted in order to investigate the implications of the R72P polymorphism in the TP53 gene in breast cancer risk. The enlightenment of this matter might provide a piece of information about the potential implications of this polymorphism in patient risk. A meta-analysis was conducted considering a large sample size from studies with conflicting results on the R72P polymorphism in breast cancer patients. Relevant studies were selected from PubMed and SciELO databases for data extraction and statistical analysis. Database was built according to the continent and considering the genotype frequencies, sample size and genotyping methodology. The dominant models (RR vs RP + PP and RR + RP vs. PP), homozygous (RR vs. PP), heterozygous (RR vs. RP and RP vs. PP) and the allele (R vs. P) were used. Genotype frequencies were summarized and evaluated by chi(2) test of heterogeneity in 2*2 contingency tables with 95% CIs. Odds Ratios (OR) were calculated with a fixed-effect model (Mantel-Haenszel) or a random effect model (DerSimonian-Laird) if the studies were considered homogeneous (P > 0.05) or heterogeneous (P < 0.05), respectively, using BioEstat(r) 5.0 software. Supported by a large sample size composed by 25,629 cases and 26,633 controls from 41 studies, we found significant association between the R72P polymorphism in the TP53 gene and the breast cancer risk. The overall data shows an increased risk due to the P allele dominant model, but not in Asia where the risk was associated with the R allele and R dominant model. PMID- 26034703 TI - Symbiotic effectiveness of inoculation with Bradyrhizobium isolates on soybean [Glycine max (L.) Merrill] genotypes with different maturities. AB - The influence of soybean genotypes with different maturity groups on the symbiotic effectiveness of Bradyrhizobium spp under high native soil N is not well known. Therefore, the objective of this work was to evaluate the influence of maturity time of soybean genotypes on the symbiotic effectiveness of Bradyrhizobium spp. at higher soil N. Three isolates of Bradyrhizobium spp. (UK isolate, TAL-379 isolate and local-isolate) and six soybean genotypes, three late maturing (Wogayen, TGx-1336424 and Belsa) and three medium maturing (GIZA, Afgat and Gishame) were used for greenhouse experiment. Only GIZA and TGx-1336424 were selected for field experiment. The result of the experiments showed that significantly (P < 0.05) differences in all investigated traits, except total plant tissue N, was observed in TGx-1336424 with UK-Isolate and Local-Isolate.TAL 379 inoculation performed better in all investigated traits of GIZA genotype than other inoculation treatments. N-fertilization in the greenhouse experiment significantly (P < 0.05) improved the shoot biomass of Wogayen and Belsa-95, but did not observe in GIZA and Gishame. The regression analysis obtained between nodule number and nodule dry weight with that of grain yield indicated generally higher R(2) value for late maturing than that of the medium maturing genotypes. This indicates high importance of nodulation for improving the GY of late maturing genotypes. Hence, this study proves the need for inoculation to improve the production and productivity of soybean sustainably in Ethiopia, with particularly pronounced effect on late maturing genotypes of soybean. PMID- 26034704 TI - Gene expression in the liver of female, but not male mice treated with rapamycin resembles changes observed under dietary restriction. AB - It is well known that in mice the extension in lifespan by rapamycin is sexually dimorphic, in that it has a larger effect in females than males. In a previous study we showed that in male C57BL6 mice, rapamycin had less profound effects in both gene expression and liver metabolites when compared to dietary restriction (DR), but no data was available in females. Because recent studies showed that rapamycin increases longevity in a dose dependent manner and at every dose tested the effect remains larger in females than in males, we hypothesized that rapamycin should have a stronger effect on gene expression in females, and this effect could be dose dependent. To test this hypothesis, we measured the changes in liver gene expression induced by rapamycin (14 ppm) with a focus on several genes involved in pathways known to play a role in aging and that are altered by DR. To investigate whether any effects are dose dependent, we also analyzed females treated with two additional doses of rapamycin (22 and 42 ppm). We observed striking differences between male and female in gene expression at 14 ppm, where females have a larger response to rapamycin than males, and the effects of rapamycin in females resemble what we observed under DR. However, these effects were generally not dose dependent. These data support the notion that female mice respond better to rapamycin, and at least with the set of genes studied here, the effect of rapamycin in females resemble the effect of DR. PMID- 26034705 TI - RNA interference-mediated antiviral defense in insects. AB - Small interfering RNA (siRNA)-mediated RNA interference (RNAi) pathways are critical for the detection and inhibition of RNA virus replication in insects. Recent work has also implicated RNAi pathways in the establishment of persistent virus infections and in the control of DNA virus replication. Accumulating evidence suggests that diverse double-stranded RNAs produced by RNA and DNA viruses can trigger RNAi responses yet many viruses have evolved mechanisms to inhibit RNAi defenses. Therefore, an evolutionary arms race exists between host RNAi pathways and invading viral pathogens. Here we review recent advances in our knowledge of how insect RNAi pathways are elicited upon infection, the strategies used by viruses to counter these defenses, and discuss recent evidence implicating Piwi-interacting RNAs in antiviral defense. PMID- 26034706 TI - Neurodevelopmental outcome of infants with gastroschisis at one-year follow-up. AB - OBJECTIVE: Gastroschisis is a congenital malformation of the abdominal wall and may be associated with significant neonatal mortality and morbidity. The primary objective of this study was to describe the neurodevelopmental outcomes of neonates with this condition. METHODS: Medical records of all neonates admitted with a diagnosis of gastroschisis to a tertiary surgical unit from October 2006 to August 2011 were retrospectively reviewed. Demographic and clinical variables were collated along with developmental assessment results at one-year follow-up. Developmental assessment results were compared with case matched healthy control neonates of similar gestational age and birth weight. RESULTS: Of 20 patients in the study, 16 had simple and four had complex gastroschisis. Mean birth weight was 2.29 kg with a mean gestational age of 35.7 weeks. The majority of neonates underwent primary surgical repair, while 15% had a silo followed by surgical repair. Neonates with gastroschisis did not significantly differ from the control group in neurodevelopmental outcomes. Receptive and expressive language delay was found in gastroschisis is attributable to small for gestational age rather than the malformation per se. CONCLUSIONS: These data suggest that neurodevelopmental outcomes at one year of age in children with gastroschisis were associated with being small for gestational age rather than the malformation. PMID- 26034707 TI - Neonatal tracheostomy - issues and solutions. AB - AIMS: To record and analyse the technical aspects of neonatal tracheostomy and to suggest some solutions. MATERIALS AND METHODS: This is a retrospective observational cohort of 37 cases of neonatal tracheostomies performed over 30 years (1985-2014). RESULTS: Thirty-three of the 37 tracheostomies were done as an elective procedure and four done emergently. Eighteen neonatal tracheostomies were done with a low transverse cervical incision and 19 were done with low vertical cervical incision. Three patients had bleeding while exposing the trachea. Trachea could not easily be identified in 2 cases. Commercial tracheostomy tubes were used in only 20 cases. In 17 patients, the conventional endotracheal tubes 2.5 or 3fr size were used. There were 3 instances of wound infection out of which one has peri-tracheostomy necrotizing cellulitis and the neonate succumbed to sepsis. Two cases had surgical emphysema. No case had pneumothorax. CONCLUSION: We described tracheostomy in neonates in a resource constrained centre. Various makeshift arrangements can be used in absence of standard supplies. PMID- 26034708 TI - Spontaneous intestinal perforation in neonates. AB - BACKGROUND: The term Spontaneous Intestinal Perforation (SIP) suggests a perforation in the gastrointestinal tract of a newborn with no demonstrable cause. METHODS: Four neonates presenting with spontaneous bowel perforation were analyzed with respect to clinical presentation, management and outcome. RESULTS: The mean age at presentation was 11.4 days. There were three males and one female. One of the neonates was preterm, very low birth weight and the other three were full term. Two neonates underwent emergency exploratory laparotomy and two were initially managed by peritoneal drainage in view of poor general condition; one of them improved and did not require further operative intervention. The preterm very low birth weight neonate was stabilized and explored after 48 hours. Intra-operatively, two of them had two ileal perforations each which required ileostomy; one had single perforation in the transverse colon which was primarily repaired. All four had an uneventful recovery. CONCLUSION: SIP is a distinct clinical entity and has better outcome than neonates with intestinal perforation secondary to Necrotizing Enterocolitis (NEC). PMID- 26034709 TI - Neonatal Appendicitis (Part 2): A Review of 24 cases with Inguinoscrotal Manifestation. PMID- 26034710 TI - Hernia of umbilical cord: report of three unusual cases. AB - Congenital hernia of umbilical cord is a less frequent entity in newborns and occasionally associated with other maladies. Herein, we report three unusual cases of hernia of umbilical cord. First case was associated with in-utero evisceration of entire small bowel through the presumably ruptured hernia of umbilical cord and other two cases had associated patent vitellointestinal duct (PVID). All of the cases were managed successfully. PMID- 26034711 TI - Congenital granular cell tumor - a rare entity. AB - Congenital granular cell tumor is a rare benign neoplastic growth affecting the gingival mucosa of neonates. Prenatal ultrasound diagnosis has recently come to focus and in spite of several reports on immune-histochemical and other advanced marker studies, the cause and origin of the lesion remains debatable till date. Review of literature on prenatal diagnosis and histopathology along with immunohistochemistry is discussed. PMID- 26034712 TI - The EXIT for Prenatally Diagnosed Cervical Cystic Teratoma: A Case Report. AB - The Ex-utero intrapartum treatment (EXIT) is a procedure performed during caesarean section while on fetal-placental circulation. We present a prenatally diagnosed cervical cystic mass causing tracheal compression which was managed successfully with the EXIT procedure. PMID- 26034713 TI - Duodenal perforation in a neonate: an unusual presentation and analysis of the cause. AB - Duodenal perforation in neonates is a rare surgical emergency. In the cases reported, most perforations are localised to the anterior duodenum and a few at posterior aspect. We present a case of duodenal perforation in the second part of the duodenum in a 26-day-old healthy male neonate. PMID- 26034714 TI - Congenital diaphragmatic hernia in a case of patau syndrome: a rare association. AB - Congenital diaphragmatic hernia (CDH) occurs in 5-10% associated with chromosomal abnormalities like, Pallister Killian syndrome, Trisomy 18, and certain deletions.. Association of CDH with trisomy 13 (Patau syndromes) is very rare. Here, we report such an unusual association, where surgical repair was done, but eventually the case succumbed as a result of multiple fatal co-morbidities. PMID- 26034715 TI - Unusual Gross Pneumocephalus and Pneumoperitoneum after VP Shunt Surgery: A Case Report. AB - We report an unusual case where a two-month infant developed a simultaneous and spontaneous pneumocephalus and gross pneumoperitoneum along with progressive surgical emphysema after VP shunt procedure. PMID- 26034716 TI - Athena's Pages on Neonatal Appendicitis. PMID- 26034717 TI - Athena's Reply. PMID- 26034718 TI - Umbilicus: A Site for Stoma in Hirschsprung's Disease. PMID- 26034719 TI - Anorectal malformations (part 2). PMID- 26034721 TI - Cervical and ocular vestibular evoked myogenic potentials in multiple sclerosis participants. AB - BACKGROUND: Multiple sclerosis (MS) is a chronic neurological disease that affects brain and spinal cord. The infratentorial region contains the cerebellum and brainstem. Vestibular evoked myogenic potentials (VEMPs) are short-latency myogenic responses. Cervical vestibular evoked myogenic potential (cVEMP) is a manifestation of vestibulocolic reflex and ocular vestibular evoked myogenic potential (oVEMP) contributes to the linear vestibular-ocular reflex. The aim of this study was to evaluate cVEMP and oVEMP in MS patients with and without infratentorial plaques and compare the findings with normal controls. METHODS: In this cross-sectional study, latency and amplitude of cVEMP and oVEMP were recorded in 15 healthy females with mean age of 31.13+/-9.27 years, 17 female MS patients with infratentorial plaque(s) and mean age of 29.88+/-8.93 years, and 17 female MS patients without infratentorial plaque(s) and mean age of 30.58+/-8.02 years. All patients underwent a complete clinical neurological evaluation and brain MRI scanning. Simple random sampling method was used in this study and data were analyzed using one way ANOVA through SPSS v22. RESULTS: The latency of N1-P1 and P13 in MS participants with and without infratentorial plaques were significantly prolonged compared to normal controls (p<0.001). Additionally latency of P13- N23-N1 and P1 in MS patients with infratentorial plaques were significantly prolonged compared to patients without infratentorial plaques subjects (p<0.001). CONCLUSION: Abnormality of both cVEMP and oVEMP in MS patient with infratentorial plaque are more than that of MS patient without infratentorial plaque. Recording both ocular and cervical VEMPs are appropriate electrophysiologic methods assessing the function of both ascending and descending central vestibular pathways. PMID- 26034722 TI - Computed Tomographic measurement of distal femor rotation in Iranian population. AB - BACKGROUND: Proper rotation of components in total knee arthroplasty (TKA) will largely affect the postoperative outcome. Ethnical variation may affect rotational profile. We aimed to evaluate distal femur rotation in Iranian population using transepicondylar axes. METHODS: From a total of 450 knee CT scans and via consecutive sampling, 150 qualified subjects with normal lower extremities alignment were selected comprising 96 (64%) males and 54 (36%) females aging 17-80 years. The posterior condylar angle and condylar twist angles were defined as angles between either surgical epicondylar axis (line connecting lateral epicondylar prominence and the medial sulcus) or clinical epicondylar axis (line connecting most prominent points of both epicondyle) and posterior conylar line. Data were compared among genders. RESULTS: Average age of our samples was 43 years (ranging 11-80). Mean (+/-sd) values for posterior condylar angle and condylar twist angles were 2.35o (+/-1.34) and 5.77o (+/-1.70), respectively. The former variable was not discernible in twenty of our subjects because of obscure medial sulcus. Our findings were totally appeared similar to studies from other ethnicities and the observed minor differences may have originated from amount of osteoarthritis and malalignment. CONCLUSION: Overall, Iranian distal femur rotational profile was similar to other reports. Some minor observed differences may be partially due to samples' age and different amount of knee osteoarthritis. It is proposed to rely on several methods for determining rotational profile while performing TKA. Moreover, preoperative computed tomography should be fully scrutinized especially in severely osteoarthitic knees. PMID- 26034720 TI - Markers of adiposity among children and adolescents: implications of the isotemporal substitution paradigm with sedentary behavior and physical activity patterns. AB - BACKGROUND: The purpose of this study was to examine the association between daily movement patterns and dual energy X-ray absorptiometry-determined body fat percent (DXA-BF%) among children and adolescents while applying both traditional and novel analytical procedures. METHODS: Using data from the cross-sectional 2003-2006 National Health and Nutrition Examination Survey (n = 5607), physical activity was assessed via accelerometry, with the following movement patterns assessed: 1) meeting moderate-to-vigorous physical activity (MVPA) guidelines and engaging in more light-intensity physical activity (LIPA) than sedentary behavior (SB); 2) meeting MVPA guidelines, but engaging in less LIPA than SB; 3) not meeting MVPA guidelines, but engaging in more LIPA than SB; and 4) not meeting MVPA guidelines and engaging in less LIPA than SB. Various markers of adiposity (e.g., DXA-BF%) were assessed. RESULTS: Children in movement pattern 1 (52 %), compared to those in movement pattern 4, had significantly lower levels of BMI (? 2.2 kg/m(2)), waist circumference (? 6.5 cm), tricep skinfold (? 4.2 mm), subscapularis skinfold (? 2.6 mm), android BF% (? 7.6 %), gynoid BF% (? 5.1 %), and total BF% (? 5.2 %). Substituting 60 min/day of SB with MVPA resulted in a 4.6 % decreased estimate of total DXA-BF%. No findings were significant for adolescents. CONCLUSIONS: The low proportion of children engaging in >= 60 min/day of MVPA and accumulating relatively more LIPA than SB had the lowest DXA BF%. PMID- 26034723 TI - Preparation of factor VII concentrate using CNBr-activated Sepharose 4B immunoaffinity chromatography. AB - BACKGROUND: Factor VII concentrates are used in patients with congenital or acquired factor VII deficiency or treatment of hemophilia patients with inhibitors. In this research, immunoaffinity chromatography was used to purify factor VII from prothrombin complex (Prothrombin- Proconvertin-Stuart Factor Antihemophilic Factor B or PPSB) which contains coagulation factors II, VII, IX and X. The aim of this study was to improve purity, safety and tolerability as a highly purified factor VII concentrate. METHODS: PPSB was prepared using DEAE Sephadex and was used as the starting material for purification of coagulation factor VII. Prothrombin complex was treated by solvent/detergent at 24 degrees C for 6 h with constant stirring. The mixture of PPSB in the PBS buffer was filtered and then chromatographed using CNBr-activated Sepharose 4B coupled with specific antibody. Factors II, IX, VII, X and VIIa were assayed on the fractions. Fractions of 48-50 were pooled and lyophilized as a factor VII concentrate. Agarose gel electrophoresis was performed and Tween 80 was measured in the factor VII concentrate. RESULTS: Specific activity of factor VII concentrate increased from 0.16 to 55.6 with a purificationfold of 347.5 and the amount of activated factor VII (FVIIa) was found higher than PPSB (4.4-fold). RESULTS of electrophoresis on agarose gel indicated higher purity of Factor VII compared to PPSB; these finding revealed that factor VII migrated as alpha-2 proteins. In order to improve viral safety, solvent-detergent treatment was applied prior to further purification and nearly complete elimination of tween 80 (2 MUg/ml). CONCLUSION: It was concluded that immuonoaffinity chromatography using CNBr activated Sepharose 4B can be a suitable choice for large-scale production of factor VII concentrate with higher purity, safety and activated factor VII. PMID- 26034725 TI - Don't underestimate fournier's gangrene: report of 8 cases in 10 month survey. AB - BACKGROUND: Fourniers gangrene caused by synergic aerobic and anaerobic organism is a life threatening disorder. METHODS: The medical records of 8 among 839 patients admitted to imam ali general hospital Zahedan university of Medical Sciences with fourniers gangrene during the 10 months period between 2012 and 2013 were reviewed. RESULTS: The most common etiology and presentation were abscess and perianal pain respectively. Mixed bacterial flora was common finding in patient. Single debridement was carried out in 2 patients and repeated procedure was needed in 6. CONCLUSION: This disease is characterized with high mortality of up to 75% but in our study the rate was 37.5%. In other studies diabetes mellitus was found to be the common condition related to fourniers gangrene but in our study the common etiology was perianal abscess. Fourniers gangrene should be rule out in any patient with perianal pain and flulike, swelling skin. PMID- 26034726 TI - Clinical learning environments (actual and expected): perceptions of Iran University of Medical Sciences nursing students. AB - BACKGROUND: Educational clinical environment has an important role in nursing students' learning. Any difference between actual and expected clinical environment will decrease nursing students' interest in clinical environments and has a negative correlation with their clinical performance. METHODS: This descriptive cross-sectional study is an attempt to compare nursing students' perception of the actual and expected status of clinical environments in medical surgical wards. Participants of the study were 127 bachelor nursing students of Iran University of Medical Sciences in the internship period. Data gathering instruments were a demographic questionnaire (including sex, age, and grade point average), and the Clinical Learning Environment Inventory (CLEI) originally developed by Professor Chan (2001), in which its modified Farsi version (Actual and Preferred forms) consisting 42 items, 6 scales and 7 items per scale was used. Descriptive and inferential statistics (t-test, paired t-test, ANOVA) were used for data analysis through SPSS version 16. RESULTS: The results indicated that there were significant differences between the preferred and actual form in all six scales. In other word, comparing with the actual form, the mean scores of all items in the preferred form were higher. The maximum mean difference was in innovation and the highest mean difference was in involvement scale. CONCLUSION: It is concluded that nursing students do not have a positive perception of their actual clinical teaching environment and this perception is significantly different from their perception of their expected environment. PMID- 26034727 TI - Intimate partner violence and risky sexual behaviors among Iranian women with substance use disorders. AB - BACKGROUND: Intimate partner violence (IPV) and risky sexual behaviors are serious and overlapping public health problems that disproportionately affect drug-involved women. Despite the fact that drug-using women experience extensive IPV, to date, no studies have investigated the association of IPV and risky sexual behaviors among drug-using women in Iran. METHODS: Drug-using women (N =120) were recruited from a rehabilitation center in Tehran from March to October, 2009. The Revised Conflict Tactics Scale (CTS2), a standardized questionnaire, was used to collect data regarding violence. We used t-test and logistic regression models to explore the relationship between IPV domains and specific sexual risk behavior outcomes using SPSS 21. RESULTS: The means (sd) for CTS2 domains were as follows: negotiation 4.29 (1.55), psychological violence 2.55 (1.51), sexual violence 0.37 (1.00), physical abuse 1.17 (1.49), injury 2.18 (1.97), and the mean total score was 1.69 (0.96). We found significantly higher injury scores, but lower sexual abuse scores among women with sexually transmitted infection (STI) compared to women without STI (p-values 0.030 and <0.0001, respectively). In addition, we found that psychological abuse was positively associated with STI (p-value 0.03) and increased condom use (p = 0.010), possibly mediated through an increased likelihood of having multiple partners. CONCLUSION: The findings revealed that in Iran drug-involved women experience high rates of IPV and that IPV is associated with increased risky sexual behavior. IMPLICATION: Preventive interventions for violence that are integrated within drug treatment programs, as well as harm reduction programs are highly recommended. PMID- 26034724 TI - Rectal cancer: a review. AB - Rectal cancer is the second most common cancer in large intestine. The prevalence and the number of young patients diagnosed with rectal cancer have made it as one of the major health problems in the world. With regard to the improved access to and use of modern screening tools, a number of new cases are diagnosed each year. Considering the location of the rectum and its adjacent organs, management and treatment of rectal tumor is different from tumors located in other parts of the gastrointestinal tract or even the colon. In this article, we will review the current updates on rectal cancer including epidemiology, risk factors, clinical presentations, screening, and staging. Diagnostic methods and latest treatment modalities and approaches will also be discussed in detail. PMID- 26034728 TI - The effect of group mindfulness - based stress reduction program and conscious yoga on the fatigue severity and global and specific life quality in women with breast cancer. AB - BACKGROUND: Cancer is not merely an event with a certain end, but it is a permanent and vague situation that is determined by delayed effects due to the disease, its treatment and its related psychological issues. The aim of this study was to examine the effectiveness of the mindfulness-based stress reduction program and conscious yoga on the mental fatigue severity and life quality of women with breast cancer. METHODS: This was a quasi-experimental study with a pre test, post-test and control group. In this study, 24 patients with the diagnosis of breast cancer were selected among the patients who referred to the Division of Oncology and Radiotherapy of Imam Hossein hospital in Tehran using available sampling method, and were randomly assigned into the experimental and control groups. All the participants completed the Fatigue Severity Scale, Global Life Quality of Cancer Patient and Specific Life Quality of Cancer Patient questionnaires. Data were analyzed by multivariate repeated measurement variance analysis model. RESULTS: Findings revealed that the mindfulness-based stress reduction treatment significantly improved the overall quality of life, role, cognitive, emotion, social functions and pain and fatigue symptoms in global life quality in the experimental group. It also significantly improved the body image, future functions and therapy side effects in specific life quality of the experimental group compared to the control group. In addition, fatigue severity caused by cancer was reduced significantly. CONCLUSION: The results showed that the mindfulness - based stress reduction treatment can be effective in improving global and specific life quality and fatigue severity in women with breast cancer. PMID- 26034729 TI - Does routine repeat testing of critical laboratory values improve their accuracy? AB - BACKGROUND: Routine repeat testing of critical laboratory values is very common these days to increase their accuracy and to avoid reporting false or infeasible results. We figure that repeat testing of critical laboratory values has any benefits or not. METHODS: We examined 2233 repeated critical laboratory values in 13 different hematology and chemistry tests including: hemoglobin, white blood cell, platelet, international normalized ratio, partial thromboplastin time, glucose, potassium, sodium, phosphorus, magnesium, calcium, total bilirubin and direct bilirubin. The absolute difference and the percentage of change between the two tests for each critical value were calculated and then compared with the College of American Pathologists/Clinical Laboratory Improvement Amendments allowable error. RESULTS: Repeat testing yielded results that were within the allowable error on 2213 of 2233 specimens (99.1%). There was only one outlier (0.2%) in the white blood cell test category, 9 (2.9%) in the platelet test category, 5 (4%) in the partial thromboplastin time test category, 5 (4.8%) in the international normalized ratio test category and none in other test categories. CONCLUSION: Routine, repeat testing of critical hemoglobin, white blood cell, platelet, international normalized ratio, partial thromboplastin time, glucose, potassium, sodium, phosphorus, magnesium, calcium, total bilirubin and direct bilirubin results does not have any benefits to increase their accuracy. PMID- 26034730 TI - Quality measurement indicators for Iranian Health Centers. AB - BACKGROUND: Recently, quality is a serious concern in development of organizations. There are various indicators to assess quality and the purpose of this study was to identify the main indicators for quality measurement of Iranian health centers. METHODS: This qualitative study was conducted in three stages: first, review of the literature was performed to identify different indicators for quality measurement in health centers; second, a tworound Delphi process was used with participation of 18 experts in both rounds; third, Analytical Hierarchy Process (AHP) method was applied to give weights to each indicator. RESULTS: Twenty-seven indicators were identified from the literature review stage. The Delphi method reduced the list to 4 indicators. Developing a quality plan in the health center had the highest weight (38%) and percentage of followed complaints the lowest (12%). The consistency rate was 7.2% indicating appropriateness of the data. CONCLUSION: This list of indicators can be used as a template for measuring quality of health centers in Iran and possibly in other developing countries. PMID- 26034731 TI - The prevalence of adulthood overweight and obesity in Tehran: findings from Urban HEART-2 study. AB - BACKGROUND: To estimate and compare prevalence of overweight and obesity among adult people across the 22 districts of Tehran in 2011. METHODS: This was a cross sectional study using data on 47,406 women and 47,525 men aged>= 15 years from a large population-based survey (Urban HEART-2). Age-standardized prevalence (ASP) of overweight (25<=BMI<30) and obesity (BMI>=30) were estimated for the Tehran's districts. Pearson Chi2 tests and logistic regression were used to examine any significant differences in prevalence of these disorders across sociodemographic groups. RESULTS: ASPs of overweight were 36.5% and 32.0 % among men and women, respectively (p<0.001). These figures for obesity were 10.7% and 15.3% among men and women, respectively (p<0.001). Crude prevalence of overweight and obesity rose with age up to the age of 54 years and decreased thereafter. Across education groups, the lowest prevalence of overweight/obesity was seen among most educated people. The results showed that being young, single and student were associated with lower odds of overweight/obesity. CONCLUSION: This study showed a high prevalence of overweight and obesity among adult in Tehran. There were significant associations between sociodemographic characteristics and prevalence of overweight/obesity among adults in Tehran. The results of this study might be used in identifying high risk groups of overweight and obesity in Tehran. PMID- 26034733 TI - The effect of depression and anxiety on expression levels of toll like receptor signaling molecules in chronic HBV infected patients. AB - BACKGROUND: Toll- like receptors (TLRs) play an important role in the recognition of DAMPs and PAMPs and induction of inflammation. Previous studies demonstrated that depression and anxiety can influence the expression levels of immune related molecules. Our previous study revealed that mRNA levels of IRAKIRAK4, TRAF3 and IRF7 were significantly decreased in chronic HBV infected (CHB) patients when compared to healthy controls. Therefore, the aim of this study was to evaluate the effects of depression and anxiety on the expression levels of these molecules in CHB patients. METHODS: Sixty CHB patients participated in this study and filled out the standard questionnaires; and the expression of IRAK4, TRAF3 and IRF7 were examined using Real-Time PCR techniques. RESULTS: The results of this study demonstrated that expression of IRAK4, TRAF3 and IRF7 did not differ between patients with various stages of depression and anxiety (all p>0.05). CONCLUSION: According to the results, it seems that declined expression of IRAK4, TRAF3 and IRF7 in CHB patients were not related to depression and anxiety, and other factors including genetic and immunoregulatory effects of HBV may be responsible for the declined expression of these molecules. PMID- 26034732 TI - The meaning of work in people with severe mental illness (SMI) in Iran. AB - BACKGROUND: Work is the key component for most people in regard to financial, social and wellbeing matters. Employment is an important factor underpinning mental health disorders. However, unemployment remains an unsolved issue worldwide. Numerous studies have focused on employment outcomes in people with severe mental illness (SMI) but, only a few have explored their perspective on employment. Therefore, this study aimed to clarify the meaning of work among clients with SMI in Iran. METHODS: A qualitative research approach was used to conduct this research. Ten participants who were consumers of mental health services took part in this study. Data were analyzed by inductive content analysis approach. RESULTS: Four themes emerged from data including: acquiring identity, work as a drive, passing the time and financial independence. CONCLUSION: Meaning of work in studied people with SMI was probably similar to the general population. The different finding in this study refers to the dominancy of family relationships and spiritual believes which could cover some problems and in turn affect the meaning of work. Highlighting these meanings could direct mental health professionals to better planning for their clients have better understanding of their clients' work future and in turn provide more precise plan for them. PMID- 26034734 TI - Attention deficit hyperactivity disorder in children with early stages of chronic kidney disease. AB - BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) is the most common childhood neurological disorder. This disorder is more prevalent in some chronic diseases. The aim of this study was to investigate ADHD in children with early stages of chronic kidney disease (CKD) and to compare it with healthy children. METHODS: Seventy five 5-16-year-old children with early stages of CKD (stage 1, 2 and 3) and 75 healthy children without CKD were included in this case - control study as case and control groups, respectively. The participants were selected from those children who were referred to the pediatric clinic of Amir Kabir Hospital of Arak (Iran) in the form of simple probability and based on inclusion and exclusion criteria. ADHD was diagnosed using Conner's Parent Rating Scale - 48 (CPRS-48) and DSM-IV criteria and was confirmed by a psychologist consultant. Data were analyzed by Binomial test in SPSS18. RESULTS: ADHD inattentive type was observed in 8 cases (10.6%) with CKD and 2 controls (2.6%) (p= 0.109). Moreover, in the case and control groups, 7 (9.3%) and 6 (8%) children were affected by ADHD hyperactiveimpulsive type (p= 0.997), and 9 (12%) and 12 (16%) children were affected by ADHD mixed type (p= 0.664), respectively. CONCLUSION: No differences were found between the prevalence of ADHD in the children with early stages of CKD and the control group. However, due to the importance of the relationships between different types of psychiatric disorders and CKD and lack of enough evidence concerning the relationship between ADHD and different stages of CKD in children, conducting further studies in this field is recommended. PMID- 26034735 TI - Nurses' experiences of humour in clinical settings. AB - BACKGROUND: Providing holistic nursing care when there is a shortage of personnel and equipment exposes nurses to stress and a higher risk of occupational burnout. Humour can promote nurses' health and influence nursing care. The aim of this study was to describe nurses' experiences of humour in clinical settings and factors affecting it. METHODS: This qualitative study investigated nurses' experiences of humour. Five hospitals affiliated to Tehran University of Medical Sciences provided the setting for this study. The participants comprised of 17 nurses with master's and Baccalaureate degrees (BSN) in nursing. These nurses worked at educational hospitals affiliated to Tehran University of Medical Sciences and had minimum work experience of 12 months in various clinical wards. Nurses from all wards were invited to participate in this study. The data were collected through semi structure interviews using guides comprising probing questions. Telephonic interviews were used to further supplement the data. The data were analysed using conventional content analysis. RESULTS: The data were classified into five themes including the dynamics of humour, condition enforcement, Risk making probability, Instrumental use and Change: opportunities and threats. CONCLUSION: Understanding nurses' perceptions and experiences of humour helps identify its contributing factors and provides valuable guidelines for enhancing nurses and patients' mental, emotional and physical health. Spreading a culture of humour through teaching methods can improve workplace cheerfulness and highlights the importance of humour in patient care in nurses and nursing students. PMID- 26034736 TI - The effect of education on improvement of intake of fruits and vegetables aiming at preventing cardiovascular diseases. AB - BACKGROUND: Cardiovascular diseases refer to a group of diseases that affect the cardiovascular system; principally cardiac diseases, vascular diseases of the brain and kidney and peripheral arterial diseases which are caused by various factors. Considering the importance of nutrition education, especially the intake of fruits and vegetables, this study was performed to determine the effect of health education, Based on the Health Belief Model, on the improvement of intake of fruits and vegetables aiming at preventing cardiovascular diseases among high school girls in the city of Shahre- Kord, Iran. METHODS: This was a quasi experimental intervention study, in which 120 female students of high schools in Isfahan were selected through convenient sampling and were divided into two groups of experimental (60) and control (60). The instruments for data collection were the Health Belief Model and FFQ questionnaires. The HBM questionnaire was completed three times (before, immediately and two months after the intervention) and the FFQ questionnaire was completed two times (before and two months after the intervention) by the students. After the pre-test, six educational sessions were provided for the experimental group. Finally, data were collected and analyzed by SPSS 16 (ttest, paired t-test and repeated measure ANOVA). RESULTS: There were no differences between the two groups in terms of demographic variables. Before the intervention, there were not any significant differences between the scores of different structures of this model between the two groups (p>0.05); however, after the intervention, significant differences were found between the experimental and control groups in the levels of knowledge, perceived susceptibility, perceived severity, perceived benefits, perceived barriers, perceived efficacy and performance (p<0.001). CONCLUSION: According to the results, the intervention had a positive impact on the improvement of intake of fruits and vegetables among the students. PMID- 26034737 TI - A computer-based selective visual attention test for first-grade school children: design, development and psychometric properties. AB - BACKGROUND: Visual attention is known as a critical base for learning. The purpose of the present study was to design, develop and evaluate the test-retest and internal consistency reliability as well as face, content and convergent validity of the computer- based selective visual attention test (SeVAT) for healthy first-grade school children. METHODS: In the first phase of this study, the computer-based SeVAT was developed in two versions of original and parallel. Ten experts in occupational therapy helped to measure the content validity using the CVR and CVI methods. Face validity was measured through opinions collected from 10 first-grade children. The convergent validity of the test was examined using the Spearman correlation between the SeVAT and Stroop test. In addition, test-retest reliability was determined by measuring the intra-class correlation (ICC) between the original and parallel versions of the SeVAT in a single session. The internal consistency was calculated by Cronbach's alpha coefficients. Sixty first grade children (30 girls/30boys) participated in this study. RESULTS: The developed test was found to have good content and face validity. The SeVAT showed an excellent test-retest reliability (ICC= 0.778, p<0.001) and internal consistency (Cronbach's Alpha of original and parallel tests were 0.857 and 0.831, respectively). SeVAT and Stroop test demonstrated a positive correlation upon the convergent validity testing. CONCLUSION: Our results suggested an acceptable reliability and validity for the computer-based SeVAT in the assessment of selective attention in children. Further research may warrant the differential validity of such a test in other age groups and neuro cognitively disordered populations. PMID- 26034738 TI - Protective role of Proanthocyanidin in experimental ovarian torsion. AB - BACKGROUND: Proanthocyanidin is a potent bioactive antioxidant naturally occurring in grape seed and acts as reactive oxygen species (ROS) scavenger. The aim of this study was to investigate the effects of proanthocyanidinin in experimental ovarian torsion injury. METHODS: Twenty four rats were randomly divided into three groups (n=8). Group 1: the laparotomy group, group 2: ovarian torsion group, and group 3: intervention group administered proanthocyanidinin of 50 mg/kg before bilateral ovarian ischemia and reperfusion. Histologic examination and scoring was done at the end of the experiment. Statistical analyses were performed using the SPSS v. 19. RESULTS: Ovarian histopathologic findings of all three groups were significantly different in terms of hemorrhage (p<0.001), edema (p=0.001) and vascular dilatation (p< 0.001). Pathologic changes induced by I/R were reduced in ovaries of rats administered proanthocyanidin, in particular, hemorrhage, edema and vascular dilatation. CONCLUSION: Proanthocyanidin, known as free radical scavenger and antioxidant, is protective against tissue damage induced by ischemia and/or ischemia/reperfusion in rat ovaries. PMID- 26034739 TI - The effect of exercise therapy on knee osteoarthritis: a randomized clinical trial. AB - BACKGROUND: Knee osteoarthritis (OA) is the most common musculoskeletal disease among old individuals which affects ability for sitting on the chair, standing, walking and climbing stairs. Our objective was to investigate the short and long term effects of the most simple and the least expensive exercise protocols in combination to conventional conservative therapy for knee OA. METHODS: It was a single blind RCT study with a 12-months follow-up. Totally, 56 patients with knee OA were assigned into 2 random groups. The patients in exercise group received exercise for knee muscles in combination with non-steroid anti-inflammatory drugs (NSAIDs) and 10 sessions acupuncture and physiotherapy modalities. Non-exercise group received similar treatments except exercise program. The changes in patients' pain and functional status were evaluated by visual analog scale (VAS), knee and osteoarthritis outcome score (KOOS) questionnaire and functional tests (4 steps, 5 sit up, and 6 min walk test) before and after treatment (1 and 3 months after intervention), and 1 year later at the follow-up. RESULTS: The results showed that the patients with knee OA in exercise group had significant improvement in pain, disability, walking, stair climbing, and sit up speed after treatment at first and second follow-up when compared with their initial status and when compared with non-exercise group. At third follow up (1 year later) there was significant difference between groups in VAS and in three items of KOOS questionnaire in functional status. CONCLUSION: Non aerobic exercises for muscles around knee can augment the effect of other therapeutic interventions like medical therapy, acupuncture, and modalities for knee OA. PMID- 26034740 TI - The effect of rosemary extract on spatial memory, learning and antioxidant enzymes activities in the hippocampus of middle-aged rats. AB - BACKGROUND: The Rosemary extract (RE) possesses various antioxidant, cytoprotective and cognition- improving bioactivities. In this study, we postulated which doses of RE have a more effect on the hippocampus of middle-aged rats. METHODS: In this experimental study, thirty-two middle-aged male Wistar rats were fed by different doses (50,100 and 200 mg/kg/day) of RE (containing 40% carnosic acid) or distilled water for 12 weeks. The effects of different RE doses on learning and spatial memory scores, hippocampal neuronal survival, antioxidant enzymes and lipid peroxidation amount were evaluated by one and two way analysis of variance (ANOVA). RESULTS: It seemed that RE (100mg/kg) could recover the spatial memory retrieval score (p< 0.05). The amount of activity of SOD, GPx and CAT enzymes in the hippocampus of animals of the RE (100mg/kg) group showed a significant increase compared to the normal group (p< 0.01), (p< 0.01) and (p< 0.05), respectively. Also, the amount of activity of GPx in the RE (50 mg/kg) group of animals showed a significant increase compared to the normal group (p< 0.05). No significant difference was found between the groups in the MDA level. CONCLUSION: The results revealed that rosemary extract (40% carnosic acid) may improve the memory score and oxidative stress activity in middle aged rats in a dose dependent manner, especially in 100mg/kg. PMID- 26034741 TI - MR defecography: a diagnostic test for the evaluation of pelvic floor motion in patients with dyssynergic defecation after biofeedback therapy. AB - BACKGROUND: Dyssynergic defecation is a major cause of chronic functional constipation as a common digestive complaint. We clinically evaluated the effects of biofeedback therapy on the pelvic floor motion indices through magnetic resonance (MR) defecography, quality of life and depression in patients with dyssynergic defecation. METHODS: In this clinical trial study, among patients referring to the Colorectal Clinic of Hazrat Rasoul Hospital, 22 subjects were randomly assigned into two equal groups (n= 11) to receive either standard only or biofeedback and standard therapy. Dynamic changes of the pelvic floor were measured by MR defecography. During the simulated defecation, two MR defecography dynamic indices including abnormal anorectal angle change and perineal descent were measured before and after treatment. The effects of biofeedback therapy on patients' symptoms, quality of life and severity of depression were assessed and compared with the standard therapy. Statistical analysis was carried out using independent _t-test and Mann-Whitney test. RESULTS: Paradox index (p< 0.001), perineal descent index (p< 0.001), depression (p< 0.1), physical function (p< 0.001), vitality (p< 0.001) and role emotion (p< 0.001) significantly improved in the biofeedback therapy group in contrast to the standard therapy SDT group. CONCLUSION: Biofeedback therapy appears to be effective in improving symptoms of functional constipation and dysfunction of pelvic floor motion as well as patient's quality of life and depression state. MR defecography is able to show the changes in dynamic indices of the pelvic floor through biofeedback therapy. PMID- 26034742 TI - A systematic review of the effectiveness of catheter ablation NavX mapping system for treatment of the cardiac arrhythmia. AB - BACKGROUND: Catheter ablation is widely used for treatment of atrial fibrillation. The use of fluoroscopic and non-fluoroscopic mapping systems in catheter ablation is common. This study conducted to investigate the safety and effectiveness of Navx non-fluoroscopic mapping system. METHODS: In this study, the appropriate electronic databases including Cochrane Library and Ovid Medline searched until August 2013 using free text and MeSH. Systematic reviews, health technology assessment reports in which systematic review was conducted and controlled trials with the sample size of 100 patients and more were included into the study. RESULTS of included studies were analyzed qualitatively. RESULTS: Seven papers were included in this study. According to these studies, non fluoroscopic guidance systems may reduce the exposure to radiation compared to fluoroscopic system. NavX system has minimum exposure time. Non-fluoroscopic guidance systems are safer than fluoroscopic guidance system. NavX system reduces the procedure and fluoroscopy time. There was no significant difference between two systems, NavX and Carto, based on their safety and effectiveness. CONCLUSION: Ensite NavX system is relatively safer and more effective than fluoroscopic guidance systems for treating the cardiac arrhythmia. PMID- 26034743 TI - The role of ergonomic training interventions on decreasing neck and shoulders pain among workers of an Iranian automobile factory: a randomized trial study. AB - BACKGROUND: Ergonomic training had been implemented for prevention or reduction of neck and shoulder complaints among workers. The purpose of the present study was to assess the role of ergonomic training intervention on decreasing the prevalence of neck and shoulder complaints among workers of an automobile factory. METHODS: Within the present randomized clinical trial, the role of three ergonomic training methods on the prevalence of neck and shoulders pain among 503 workers of an automobile factory (Response rate: 94.23%) was assessed. The eligible workers were randomly allocated into the following three interventional (pamphlet, lecture, workshop) groups and one control group. The Nordic questionnaire was used to assess the prevalence of neck and shoulder complaints. We followed and assessed the prevalence of neck and shoulders complaints among the study employees before and one year after the intervention. We used chi square and Mann-Whitney tests to compare the prevalence of neck and shoulder complaints between the trial and control groups. A two-tailed P-value less than or equal to 0.05 was considered statistically significant. RESULTS: The prevalence of neck and shoulders complaints among the study employees at the recent week (p= 0.002) and year (p= 0.02) had been significantly decreased in the study employees after participating in the study workshop. The prevalence of neck and shoulders complaints at the recent week and year did not significantly changed in the study employees after receiving the pamphlet and lecture as ergonomic trainings. CONCLUSION: Workshop as an ergonomic training method had an effective and powerful role on decreasing the prevalence of neck and shoulders complaints among workers. PMID- 26034744 TI - Surgical results of anderson-hynes dismembered pyeloplasty without internal drainage in adults with ureteroplevic junction obstruction. AB - BACKGROUND: Anderson-Hynes dismembered pyeloplasty is the gold standard therapeutic approach to ureteropelvic junction obstruction (UPJO). Use of a drainage method to protect the suture line from leakage is a matter of controversy. OBJECTIVES: We have compared the surgical outcome of Anderson-Hynes dismembered pyeloplasty for UPJO repair, with or without internal stenting. PATIENTS AND METHODS: Eighty-two patients with UPJO were evaluated from 1996 to 2002. Complicated or emergent cases were excluded. Classic standard dismembered pyeloplasty was performed. Internal drainage, with a double j catheter, was performed in several patients, randomly. Another drain was also placed in the retroperitoneal space. The follow-up of patients was planned weekly, with patient visits and urine analysis and intravenous pyelography (IVP) and diethylene triamine-pentaacetate (DTPA) scan after one month. RESULTS: The study group consisted of 51 male and 31 female patients, who were mostly in the age range of 20 - 40 years. Comparing the two techniques of pyeloplasty with or without internal drainage, there was no significant difference between groups regarding extravasation and anastomosis complications, such as leakage, stenosis, urinoma formation or evidence of obstruction on postoperative IVP or DTPA scan. However, a higher incidence of catheter related urinary symptoms and flank pain was reported among those with internal stent. CONCLUSIONS: Pyeloplasty, with adequate spatulation, hemostasis and a watertight anastomosis, represents the mainstay of successful pyeloplasty and there may be no significant benefit for urethral stenting, especially in non-complicated cases. PMID- 26034745 TI - Adrenal cystic lymphangioma presented with hypertension: a case report. AB - INTRODUCTION: Adrenal cystic lymphangioma is a rare benign tumor, which is nearly always asymptomatic and incidentally discovered during routine imaging work-ups or investigating other pathologies. CASE REPORT: A 43-year-old female presented hypertension, which during routine work-up of her newly diagnosed hypertension an adrenal mass was discovered and after operation the pathologic diagnosis was lymphangioma of adrenal. CONCLUSIONS: In evaluation of adrenal masses cystic lymphangioma should be considered as a differential diagnosis. PMID- 26034746 TI - Effectiveness of Intravenous Immunoglobulin Plus Plasmapheresis on Antibody mediated Rejection or Thrombotic Microangiopathy in Iranian Kidney Transplant Recipient. AB - BACKGROUND: Antibody mediated rejection (AMR) and thrombotic microangiopathy (TMA) after kidney transplantation are difficult to differentiate most of the times and both play important roles in kidney allograft loss. Common treatment strategies of these two conditions include plasmapheresis, intravenous immunoglobulin (IVIG) and rituximab. OBJECTIVES: This study was designed to assess the efficacy of routine treatment of AMR/TMA in Iranian kidney transplant recipients, which comprises of plasmapheresis and IVIG. PATIENTS AND METHODS: This one-year cross-sectional study was performed in the Kidney Transplantation Ward of Imam-Khomeini Hospital Complex, Tehran, Iran. All kidney transplant recipients who were administered plasmapheresis and IVIG to treat definite or suggested AMR or TMA were assessed clinically and also evaluated on laboratory data. RESULTS: During 2014, we encountered five patients with suspicious AMR or TMA at our kidney transplant center. Renal biopsy was performed for two of them, suggesting AMR for one patient and TMA for another patient. All patients were treated with plasmapheresis plus IVIG. In this center, as a routine practice, the cumulative dose of 2 g/kg of IVIG was divided to 300 - 400 mg/kg after each plasmapheresis. Only one out of the five patients showed response, albeit not completely. CONCLUSIONS: Due to daily plasmapheresis within the first several days after AMR or TMA, administering high amounts of the cumulative dose of IVIG after plasmapheresis may result in high amounts of IVIG withdrawal by plasmapheresis and response failure. Our suggestion is to reduce the IVIG dose after each plasmapheresis to 100 mg/kg (i.e. replacement dose) to reach a cumulative dose of 2 g/Kg. If plasmapheresis treatment is initiated sooner than the completion of the IVIG cumulative dose of 2 g/kg, the remaining dose can be administered during one injection. PMID- 26034747 TI - Malnutrition-inflammation score and quality of life in hemodialysis patients: is there any correlation? AB - BACKGROUND: Malnutrition, inflammation and poor quality of life are prevalent among hemodialysis (HD) patients. Health-related quality of life is an important determinant of hospitalization and mortality in HD patients. OBJECTIVES: The aim of this study was to assess the correlation between quality of life and malnutrition-inflammation status according to subjective global assessment (SGA) and malnutrition-inflammation scores (MIS) in HD patients. PATIENTS AND METHODS: We randomly selected 87 of 180 stable HD patients from two HD centers. Those on hemodialysis for at least three months and with malnutrition according to the SGA scores were included in this study. They were divided into two groups of mild to moderate malnutrition (n = 39) and severe malnutrition (n = 49) based on the SGA scores. Serum levels of transferrin, albumin, blood urea nitrogen, creatinine, kt/v, body mass index and malnutrition-inflammation scores were measured in all patients. Health-related quality of life was assessed by validated short form-12 (SF-12) questionnaire for each patient. These values were compared between the two groups of patients by independent sample t-test and Mann-Whitney U test. The correlations of nutritional variables with SGA and MIS scores were determined by Pearson and Spearman correlation tests. RESULTS: There were no differences in measured parameters between the two groups except for MIS scores. Those with severe malnutrition showed higher MIS scores. All quality of life aspects and total scores (PCS, MCS) (rather than social functioning (SF) aspect) were significantly different between the two groups, which showed lower physical and mental scores in severely-malnourished patients. Physical functioning (PF), role limitations due to physical heath (RP), general health (GH), mental health (MH), SF, role limitation due to emotional health (RE), vitality (VT) aspects and total scores (PCS and MCS) had negative significant correlations with MIS and SGA scores (All P values < 0.05). No correlation was found between MIS and SGA scores and other measured variables. CONCLUSIONS: This study focused on important effects of malnutrition and inflammation on health-related quality of life aspects, both physically and mentally in HD patients. SGA and MIS are highly correlated with quality of life in HD patients. PMID- 26034748 TI - Radical improvement of signs and symptoms in systemic lupus erythematosus when treated with hemodiafiltration with endogenous reinfusion dialysis. AB - Lupus nephritis is one of the most serious complications of systemic lupus erythematosus (SLE). In the kidney, immune complexes and autoantibodies activate mesangial cells that secrete cytokines that can further amplify inflammatory processes. We present the case of a 42-year-old woman with lupus nephritis accompanied by periods of exacerbation of SLE, with necrotic-like skin lesions, psoriatic arthritis without skin psoriasis, purpura of the lower limb, petechial rash, joint pain, fever, eyelid edema with bilateral conjunctival hyperemia and itching. The patient underwent a dialytic treatment of hemodiafiltration with endogenous reinfusion. The technique uses the super-high-flux membrane Synclear 02 (SUPRA treatment) coupled with an adsorbent cartridge that has affinity for many toxins and mediators. Fever and joint pain were immediately reduced after treatment and, subsequently, there was a notable reduction of the skin damage. Prednisone and immunosuppressive drugs were gradually reduced until complete suspension. High-performance liquid chromatography coupled with quadrupole time of-flight mass spectrometer was performed for identification of proteins captured by a resin bed during a dialysis session of the patient. This technique identified several biomarkers of kidney injuries, uremic toxins, fragments of immunoglobulins, antigens involved in antiphospholipid syndrome and a new marker (alpha-defensin) that correlated significantly with disease activity. The removal of these different proteins could possibly provide an explanation of the improvement in the patient's symptoms and the normalization of her SLE. SUPRA coupled with an adsorption may be a promising new technique for the treatment of lupus nephritis. PMID- 26034749 TI - Fourier Transform Infrared Spectroscopic Imaging of Fracture Healing in the Normal Mouse. AB - Fourier transform infrared spectroscopic imaging (FTIRI) was used to study bone healing with spatial analysis of various callus tissues in wild type mice. Femoral fractures were produced in 28 male C57BL mice by osteotomy. Animals were sacrificed at 1, 2, 4, and 8 weeks to obtain callus tissue at well-defined healing stages. Following microcomputerized tomography, bone samples were cut in consecutive sections for FTIRI and histology, allowing for spatial correlation of both imaging methods in different callus areas (early calcified cartilage, woven bone, areas of intramembranous and endochondral bone formation). Based on FTIRI, mineral/matrix ratio increased significantly during the first 4 weeks of fracture healing in all callus areas and correlated with bone mineral density measured by micro-CT. Carbonate/phosphate ratio was elevated in newly formed calcified tissue and at week 2 attained values comparable to cortical bone. Collagen maturity and mineral crystallinity increased during weeks 1-8 in most tissues while acid phosphate substitution decreased. Temporal and callus area dependent changes were detected throughout the healing period. These data assert the usefulness of FTIRI for evaluation of fracture healing in the mouse and its potential to evaluate pathologic fracture healing and the effects of therapeutic interventions. PMID- 26034750 TI - Histoplasmosis in Patients With Cell-Mediated Immunodeficiency: Human Immunodeficiency Virus Infection, Organ Transplantation, and Tumor Necrosis Factor-alpha Inhibition. AB - Background. Histoplasmosis causes severe disease in patients with defects of cell-mediated immunity. It is not known whether outcomes vary related to the type of immunodeficiency or class of antifungal treatment. Methods. We reviewed cases of active histoplasmosis that occurred at Vanderbilt University Medical Center from July 1999 to June 2012 in patients with human immunodeficiency virus (HIV) infection, a history of transplantation, or tumor necrosis factor (TNF)-alpha inhibitor use. These groups were compared for differences in clinical presentation and outcomes. In addition, outcomes were related to the initial choice of treatment. Results. Ninety cases were identified (56 HIV, 23 transplant, 11 TNF-alpha inhibitor). Tumor necrosis factor-alpha patients had milder disease, shorter courses of therapy, and fewer relapses than HIV patients. Histoplasma antigenuria was highly prevalent in all groups (HIV 88%, transplant 95%, TNF-alpha 91%). Organ transplant recipients received amphotericin B formulation as initial therapy less often than other groups (22% vs 57% HIV vs 55% TNF-alpha; P = .006). Treatment failures only occurred in patients with severe disease. The failure rate was similar whether patients received initial amphotericin or triazole therapy. Ninety-day histoplasmosis-related mortality was 9% for all groups and did not vary significantly with choice of initial treatment. Conclusions. Histoplasmosis caused milder disease in patients receiving TNF-alpha inhibitors than patients with HIV or solid organ transplantation. Treatment failures and mortality only occurred in patients with severe disease and did not vary based on type of immunosuppression or choice of initial therapy. PMID- 26034751 TI - Risk factors for developing active tuberculosis after the treatment of latent tuberculosis in adults infected with human immunodeficiency virus. AB - Tuberculosis is the leading cause of death among adults infected with human immunodeficiency virus (HIV), and rates of tuberculosis remain high even after preventive therapy. Among 908 HIV-infected adults in a trial of preventive treatment, we found self-reported alcohol consumption, low baseline CD4 count, high baseline viral load, and tuberculin skin test size >15 mm as independent risk factors for incident tuberculosis. PMID- 26034752 TI - Trends in hospitalizations with primary varicella and herpes zoster during the prevaricella and initial postvaricella and herpes zoster vaccine eras, connecticut, 1994-2012. AB - Background. The introductions of the varicella vaccine in 1995 and herpes zoster (HZ) vaccine in 2006 have an ongoing potential to modify the epidemiology of both diseases. Analysis of data on hospitalizations can be conducted to examine trends in the occurrence of severe disease over time and to assess the possible impact of vaccination on the incidence of hospitalization. Methods. Statewide hospital discharge data 1994-2012 in Connecticut were used to identify individuals discharged with a diagnosis of varicella and the initial admissions of persons with a discharge diagnosis of HZ in the first or second diagnostic position. Trends in overall age-standardized and age group-specific hospitalization rates for preselected time intervals before and after the introduction of vaccines were examined using Poisson regression models or Mantel-Haenszel chi(2) tests. Results. Beginning in 2001, 5 years after the introduction of varicella vaccine, HZ hospitalization rates decreased significantly in individuals <15 years at an average rate of 19.4% per year through 2012. Among individuals >=60 years, HZ hospitalization rates increased by 5.1% per year from 2001 to 2006 but decreased by 4.2% per year from 2007 to 2012. Primary varicella hospitalization rates declined 82.9% from the prevaccine era (1994-1995) to the 1-dose era (2001-2005) (P < .001). Rates further decreased significantly in the 2-dose era (2010-2012) among 5 to 9 year olds (100% decrease). Conclusions. Varicella vaccine seems to have had an impact on both varicella and HZ hospitalizations, and introduction of the HZ vaccine may be having an impact on HZ hospitalizations. PMID- 26034753 TI - Transrectal prostate biopsy-associated prophylaxis and infectious complications: report of a query to the emerging infections network of the infectious diseases society of america. AB - Background. Fluoroquinolone-resistant infections after transrectal prostate biopsy (TRPB) are increasing. Methods. Members of the Emerging Infections Network, a consortium of adult infectious diseases physicians sponsored by the Centers for Disease Control and Prevention and the Infectious Diseases Society of America, were administered an electronic 9-question survey regarding post-TRPB infections and associated prophylaxis. Results were compared with respondent characteristics. Results. The overall response rate was 47% (552 of 1180). Of the 552 respondents, 234 (42%) reported that this problem was not applicable to their practice. The remaining 318 (58%) reported that, despite widespread recent changes in prophylactic regimens, fluoroquinolone monotherapy still was most common, but diverse alternate or supplemental oral and parenteral antibiotics (including imipenem) also were used. Reports of culture-guided prophylaxis were rare (9%). The most common duration of prophylaxis was a single prebiopsy antibiotic dose. However, 16%-23% of respondents reported prophylaxis continuing for >=24 hours postbiopsy. Post-TRPB infections were reported as being more frequent now than 4 years ago, with sepsis and genitourinary presentations predominating, but with osteomyelitis, endocarditis, and epidural abscess also occurring. Infection isolates reportedly were usually resistant to the prophylactic regimen. Conclusions. Emerging Infections Network members perceive post-TRPB infections as increasingly frequent, caused by resistant strains, and involving serious illness. Prophylactic approaches, although in flux, still usually entail ciprofloxacin monotherapy, which often is given for excessive durations. Multiple opportunities exist for infectious diseases specialists to partner with proceduralists in devising, studying, and implementing improved prophylaxis regimens for TRPB. PMID- 26034754 TI - Screening for Schistosoma mansoni and Strongyloides stercoralis Infection Among Brazilian Immigrants in the United States. AB - The prevalence of schistosomiasis and strongyloidiasis among Brazilian immigrants in the United States is unknown. We performed a retrospective chart review of serologic screening of asymptomatic Brazilian immigrants during routine physicals. Of 208 eligible patients, 189 were screened: 27.7% (n = 52) had elevated Schistosoma antibodies and 5.8% (n = 11) had elevated Strongyloides stercoralis antibodies. PMID- 26034755 TI - Weight gain after fecal microbiota transplantation. AB - Fecal microbiota transplantation (FMT) is a promising treatment for recurrent Clostridium difficile infection. We report a case of a woman successfully treated with FMT who developed new-onset obesity after receiving stool from a healthy but overweight donor. This case may stimulate further studies on the mechanisms of the nutritional-neural-microbiota axis and reports of outcomes in patients who have used nonideal donors for FMT. PMID- 26034756 TI - Fecal microbiota transplant: benefits and risks. PMID- 26034757 TI - Seroprevalence of measles, mumps, rubella and varicella antibodies in the United States population, 2009-2010. AB - Background. In the United States, measles, mumps, rubella, and varicella immunity is now primarily achieved through vaccination. Monitoring population immunity is necessary. Methods. We evaluated seroprevalence of antibodies to measles, mumps, rubella, and varicella using the National Health and Nutrition Examination Survey during 2009-2010. Results. Measles, mumps, rubella, and varicella seroprevalence was 92.0% (95% confidence interval [CI], 90.9%-93.0%), 87.6% (CI, 85.8%-89.2%), 95.3% (CI, 94.3%-96.2%), and 97.8% (CI, 97.1%-98.3%), respectively. United States (US)-born persons had lower mumps seroprevalence and higher varicella seroprevalence than non-US born persons. Conclusions. Seroprevalence was high (88%-98%) for all 4 viruses in the US population during 2009-2010. PMID- 26034758 TI - Cephalosporin side chain idiosyncrasies: a case report of ceftriaxone-induced agranulocytosis and review of literature. PMID- 26034759 TI - A 19 year old with Fever, rash, and conjunctivitis: a connection with the heart. PMID- 26034760 TI - Appropriateness of gram-negative agent use at a tertiary care hospital in the setting of significant antimicrobial resistance. AB - Background. Practicing antimicrobial stewardship in the setting of widespread antimicrobial resistance among gram-negative bacilli, particularly in urban areas, is challenging. Methods. We conducted a retrospective cross-sectional study at a tertiary care hospital with an established antimicrobial stewardship program in New York, New York to determine appropriateness of use of gram negative antimicrobials and to identify factors associated with suboptimal antimicrobial use. Adult inpatients who received gram-negative agents on 2 dates, 1 June 2010 or 1 December 2010, were identified through pharmacy records. Clinical data were collected for each patient. Use of gram-negative agents was deemed optimal or suboptimal through chart review and according to hospital guidelines. Data were compared using chi(2) or Fischer's exact test for categorical variables and Student t test or Mann-Whitney U test for continuous variables. Results. A total of 356 patients were included who received 422 gram negative agents. Administration was deemed suboptimal in 26% of instances, with the most common reason being spectrum of activity too broad. In multivariable analysis, being in an intensive care unit (adjusted odds ratio [aOR], .49; 95% confidence interval [CI], .29-.84), having an infectious diseases consultation within the previous 7 days (aOR, .52; 95% CI, .28-.98), and having a history of multidrug-resistant gram-negative bacilli within the past year (aOR, .24; 95% CI, .09-.65) were associated with optimal gram-negative agent use. Beta-lactam/beta lactamase inhibitor combination drug use (aOR, 2.6; 95% CI, 1.35-5.16) was associated with suboptimal use. Conclusions. Gram-negative agents were used too broadly despite numerous antimicrobial stewardship program activities. PMID- 26034761 TI - Comparative effectiveness of induction therapy for human immunodeficiency virus associated cryptococcal meningitis: a network meta-analysis. AB - Background. Multiple international treatment guidelines recommend amphotericin based combination regimens for induction therapy of cryptococcal meningitis. Yet, only 1 trial has reported a mortality benefit for combination amphotericin flucytosine, and none have reported a mortality benefit for combination amphotericin-fluconazole. Methods. We conducted a Bayesian network meta-analysis to estimate the comparative effectiveness of recommended induction therapies for HIV-associated cryptococcal meningitis. We searched PubMed and Cochrane CENTRAL for clinical reports of induction therapy for HIV-associated cryptococcal meningitis. We extracted or calculated early (two-week) and late (six to 12-week) mortality by treatment arm for the following induction regimens: amphotericin B alone, amphotericin B + flucytosine, amphotericin B + triazoles, amphotericin B + flucytosine +triazoles, triazoles alone, triazoles + flucytosine, liposomal amphotericin B, and amphotericin B + other medicines. Results. In the overall sample (35 studies, n = 2483), we found no evidence of decreased mortality from addition of flucytosine or triazoles to amphotericin B, compared with amphotericin B alone. Although we did find a nonsignificant benefit for addition of flucytosine to amphotericin B in studies including participants with altered levels of consciousness, we did not identify a benefit for combination therapy in restricted analyses in either resource-rich or resource-limited settings, studies conducted before or after 2004, and studies restricted to a high dose of amphotericin B and fluconazole. Conclusions. Given considerations of drug availability and toxicity, there is an important need for additional data to clarify which populations are most likely to benefit from combination therapies for human immunodeficiency virus-associated cryptococcal meningitis. PMID- 26034762 TI - Long-Term Care Facilities Are Reservoirs for Antimicrobial-Resistant Sequence Type 131 Escherichia coli. AB - Background. Emerging data implicate long-term care facilities (LTCFs) as reservoirs of fluoroquinolone-resistant (FQ-R) Escherichia coli of sequence type 131 (ST131). We screened for ST131 among LTCF residents, characterized isolates molecularly, and identified risk factors for colonization. Methods. We conducted a cross-sectional study using a single perianal swab or stool sample per resident in 2 LTCFs in Olmsted County, Minnesota, from April to July 2013. Confirmed FQ-R E. coli isolates underwent polymerase chain reaction-based phylotyping, detection of ST131 and its H30 and H30-Rx subclones, extended virulence genotyping, and pulsed-field gel electrophoresis (PFGE) analysis. Epidemiological data were collected from medical records. Results. Of 133 fecal samples, 33 (25%) yielded FQ-R E. coli, 32 (97%) of which were ST131. The overall proportion with ST131 intestinal colonization was 32 of 133 (24%), which differed by facility: 17 of 41 (42%) in facility 1 vs 15 of 92 (16%) in facility 2 (P = .002). All ST131 isolates represented the H30 subclone, with virulence gene and PFGE profiles resembling those of previously described ST131 clinical isolates. By PFGE, certain isolates clustered both within and across LTCFs. Multivariable predictors of ST131 colonization included inability to sign consent (odds ratio [OR], 4.16 [P = .005]), decubitus ulcer (OR, 4.87 [ P = .04]), and fecal incontinence (OR, 2.59 [P = .06]). Conclusions. Approximately one fourth of LTCF residents carried FQ-R ST131 E. coli resembling ST131 clinical isolates. Pulsed-field gel electrophoresis suggested intra- and interfacility transmission. The identified risk factors suggest that LTCF residents who require increased nursing care are at greatest risk for ST131 colonization, possibly due to healthcare-associated transmission. PMID- 26034763 TI - Determinants of infant susceptibility to malaria during the first year of life in South Western cameroon. AB - Background. Falciparum malaria is an important pediatric infectious disease that frequently affects pregnant women and alters infant morbidity. However, the impact of some prenatal and perinatal risk factors such as season and intermittent preventive treatment during pregnancy (IPTp) on neonatal susceptibility has not been fully elucidated. Methods. A cohort of 415 infants born to women who were positive and negative for malaria was monitored in a longitudinal study in Southwestern Cameroon. The clinical and malaria statuses were assessed throughout, whereas paired maternal-cord and 1-year-old antimalarial antibodies were assayed by enzyme-linked immunosorbent assay. Infant susceptibility to malaria was ascertained after accounting for IPTp and season in the statistical analysis. Results. Malaria prevalence was higher in women (P = .039) who delivered during the rainy season and their infants (P = .030) compared with their dry season counterparts. Infants born to women who were positive for malaria (6.40 +/- 2.83 months) were older (P = .028) than their counterparts who were negative for malaria (5.52 +/- 2.85 months) when they experienced their first malaria episode. Infants born in September-November (adjusted odds ratio [OR] = 0.31, 95% confidence interval [CI] = 0.13-0.72) and to mothers on 1 or no IPTp-sulfadoxine/pyrimethamine (SP) dose (adjusted OR = 0.51, 95% CI = 0.28-0.91) were protected, whereas those born in the rainy season (adjusted OR = 2.82, 95% CI = 1.21-6.55) were susceptible to malaria. Conclusions. Intermittent preventive treatment during pregnancy and month of birth have important implications for infant susceptibility to malaria, with 2 or more IPTp-SP dosage possibly reducing immunoglobulin M production. PMID- 26034764 TI - Impact of Decentralized Care and the Xpert MTB/RIF Test on Rifampicin-Resistant Tuberculosis Treatment Initiation in Khayelitsha, South Africa. AB - Background. Globally, case detection and treatment access are poor for rifampicin-resistant tuberculosis (RR-TB). The Xpert MTB/RIF test has the potential to increase detection and reduce time to treatment (TTT). However, these benefits are dependent on health system capacity to provide treatment. Methods. We retrospectively assessed the impact of Xpert on treatment initiation and TTT in the context of decentralized RR-TB care in Khayelitsha, Cape Town, using routine programmatic data. Community-based treatment was introduced progressively from 2008. Before 2007, diagnosis relied on phenotypic resistance (culture). During 2007-2008, the line probe assay (LPA) was introduced, followed by Xpert in 2012. Results. Before decentralization (2003-2006), median TTT was 71 days (interquartile range [IQR], 49-134; n = 158). The LPA introduction during 2007-2008 was associated with reduced median TTT from 76 to 50 days (P < .0001, n = 257). Between January 2009 and June 2013, 938 RR-TB cases were diagnosed (74% human immunodeficiency virus [HIV]-infected). Decentralization during 2008-2011 was associated with declining TTT (P < .0001, test for trend), a decline to 28 days in 2011 (IQR, 16-40; n = 173). Xpert was associated with a further reduction to 8 days in 2013 (IQR, 5-25; n = 89; P < .0001). Treatment initiation remained unchanged with Xpert and was lower among HIV-infected (2010-2013); 87.9% (445 of 506) compared with 96.9% (188 of 194) for HIV-uninfected (P < .0001) patients. Conclusions. Improved case detection and rapid treatment initiation are required to interrupt transmission and reduce mortality. In this setting, decentralization was associated with high treatment initiation and reduced TTT. Xpert implementation significantly enhanced the reduction in TTT and has the potential to reduce transmission. PMID- 26034766 TI - Knowledge and awareness of acute human immunodeficiency virus infection among mobile app-using men who have sex with men: a missed public health opportunity. AB - In a national online survey, we assessed awareness and knowledge of acute human immunodeficiency virus (HIV) infection manifestation among 1748 men who have sex with men (MSM). Only 39% of respondents were aware that acute HIV infection may be accompanied by symptoms. Education and increased access to acute HIV testing may facilitate MSM to appropriately seek acute HIV testing. PMID- 26034765 TI - Incidence and predictors of hepatic steatosis and fibrosis by serum biomarkers in a large cohort of human immunodeficiency virus mono-infected patients. AB - Background. Longitudinal data on liver disease in human immunodeficiency virus (HIV) mono-infection are scarce. We used noninvasive serum biomarkers to study incidence and predictors of hepatic steatosis and fibrosis. Methods. Hepatic steatosis was diagnosed by hepatic steatosis index >=36. Advanced liver fibrosis was diagnosed by fibrosis-4 index >3.25. Kaplan-Meier analysis was used to estimate incidences. Cox regression analysis was used to explore predictors of hepatic steatosis and fibrosis development. Results. In this retrospective observational study, 796 consecutive HIV mono-infected patients were observed for a median of 4.9 (interquartile range, 2.2-6.4) years. Incidence of hepatic steatosis was 6.9 of 100 per person-years (PY) (95% confidence interval [CI], 5.9 7.9). Incidence of advanced liver fibrosis was 0.9 of 100 PY (95% CI, 0.6-1.3). Development of hepatic steatosis was predicted by black ethnicity (adjusted hazard ratio [aHR] = 2.18; 95% CI, 1.58-3; P < .001) and lower albumin (aHR = 0.94; 95% CI, 0.91-0.97; P < .001). Development of advanced liver fibrosis was predicted by higher glucose (aHR = 1.22; 95% CI, 1.2-1.3; P < .001) and lower albumin (aHR = 0.89; 95% CI, 0.84-0.93; P < .001). Conclusions. Incident hepatic steatosis is frequent in HIV mono-infected patients, particularly in those of black ethnicity. These patients can also develop advanced liver fibrosis. Identification of at-risk individuals can help early initiation of hepatological monitoring and interventions, such as targeting euglycemia. PMID- 26034767 TI - Disinfection of syringes contaminated with hepatitis C virus by rinsing with household products. AB - Background. Hepatitis C virus (HCV) transmission among people who inject drugs (PWID) is associated with the sharing of injection paraphernalia. People who inject drugs often "disinfect" used syringes with household products when new syringes are unavailable. We assessed the effectiveness of these products in disinfecting HCV-contaminated syringes. Methods. A genotype-2a reporter virus assay was used to assess HCV infectivity in syringes postrinsing. Hepatitis C virus-contaminated 1 mL insulin syringes with fixed needles and 1 mL tuberculin syringes with detachable needles were rinsed with water, Clorox bleach, hydrogen peroxide, ethanol, isopropanol, Lysol, or Dawn Ultra at different concentrations. Syringes were either immediately tested for viable virus or stored at 4 degrees C, 22 degrees C, and 37 degrees C for up to 21 days before viral infectivity was determined. Results. Most products tested reduced HCV infectivity to undetectable levels in insulin syringes. Bleach eliminated HCV infectivity in both syringes. Other disinfectants produced virus recovery ranging from high (5% ethanol, 77% +/- 12% HCV-positive syringes) to low (1:800 Dawn Ultra, 7% +/- 7% positive syringes) in tuberculin syringes. Conclusions. Household disinfectants tested were more effective in fixed-needle syringes (low residual volume) than in syringes with detachable needles (high residual volume). Bleach was the most effective disinfectant after 1 rinse, whereas other diluted household products required multiple rinses to eliminate HCV. Rinsing with water, 5% ethanol (as in beer), and 20% ethanol (as in fortified wine) was ineffective and should be avoided. Our data suggest that rinsing of syringes with household disinfectants may be an effective tool in preventing HCV transmission in PWID when done properly. PMID- 26034768 TI - Switch to Rilpivirine/Emtricitabine/Tenofovir Single-Tablet Regimen of Human Immunodeficiency Virus-1 RNA-Suppressed Patients, Agence Nationale de Recherches sur le SIDA et les Hepatites Virales CO3 Aquitaine Cohort, 2012-2014. AB - Background. The purpose of this study was to assess the efficacy and tolerability of combined antiretroviral therapy (cART) in human immunodeficiency virus (HIV)-1 virologically suppressed patients who switched to rilpivirine (RPV)/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) as a single-tablet regimen (STR). Methods. A retrospective multicenter cohort study was performed between September 2012 and February 2014 in Bordeaux University Hospital affiliated clinics. Patients with a plasma HIV viral load (VL) lower than 50 copies/mL and switching to STR were evaluated at baseline, 3, 6, 9, and 12 months from switch time (M3, M6, M9, M12) for VL and other biological parameters. Change from baseline in CD4 cell counts was evaluated at M6 and M12. Virological failure (VF) was defined as 2 consecutive VL >50 copies/mL. Results. Three hundred four patients were included in the analysis. Single-tablet regimen switch was proposed to 116 patients with adverse events, mostly efavirenz (EFV)-based (n = 59), and to 224 patients for cART simplification. Thirty of 196 patients with available genotype resistance test results displayed virus with >=1 drug resistance mutation on reverse-transcriptase gene. After 12 months of follow-up, 93.4% (95.5% confidence interval, 89.9-96.2) of patients remained virologically suppressed. There was no significant change in CD4 cell count. During the study period, 5 patients experienced VF, one of them harboring RPV resistance mutation. Clinical cART tolerability improved in 79 patients overall (29.9%) at M6, especially neurological symptoms related to EFV. Fasting serum lipid profiles improved, but a significant estimated glomerular function rate decrease (-11 mL/min/1.73 m(2); P < 10(-4)) was observed. Conclusions. Overall, virologic suppression was maintained in patients after switching to RPV/TDF/ FTC. This STR strategy was associated with improved tolerability. PMID- 26034769 TI - CD4 recovery on antiretroviral therapy is associated with decreased progression to liver disease among hepatitis C virus-infected injecting drug users. AB - Background. Human immunodeficiency virus (HIV) coinfection accelerates liver disease progression in individuals with chronic hepatitis C. We evaluated the associations of CD4, HIV RNA, and antiretroviral therapy (ART)-induced CD4 recovery with liver diagnoses in a prospective cohort of injecting drug users (IDUs). Methods. We evaluated 383 coinfected IDUs in the Boston area, prospectively observed for a median of 1.8 years. Liver disease progression included the first occurrence of hepatocellular carcinoma, variceal bleeding, ascites, encephalopathy, or death due to hepatic failure. Multivariable-adjusted extended Cox models were specified to estimate hazard ratios (HRs) for comparisons of CD4, change in CD4 (from nadir), and HIV RNA with respect to liver disease progression events. Results. Twenty-four persons experienced a liver disease progression event over 1155 person-years (2.1 per 100 person-years), including 20 deaths attributed to end-stage liver disease (1.7 per 100 person years). CD4 at baseline and over follow-up strongly predicted liver disease progression (baseline CD4 <200 vs >=200: HR = 5.23, 95% confidence interval [CI], 2.30-11.92; time-updated CD4 <200 vs >=200: HR = 11.79, 95% CI, 4.47-31.07). Nadir CD4 was also a strong indicator (<100 vs >=100: HR = 3.52, 95% CI, 1.54 8.06). A lack of CD4 recovery (failure to increase 100 cells over nadir) among ART initiators was associated with increased risk (HR = 7.69; 95% CI, 2.60 22.69). Human immunodeficiency virus RNA was not significantly associated with liver disease progression. Conclusions. Impaired immune function was highly predictive of liver disease progression in this cohort of IDUs, and a lack of CD4 recovery on ART was associated with increased risk of progression to HCV associated liver disease. PMID- 26034770 TI - Rethinking risk for pneumococcal disease in adults: the role of risk stacking. AB - Using data from 3 private healthcare claims repositories, we evaluated the incidence of pneumococcal disease among adults with US Advisory Committee on Immunization Practices (ACIP) defined at-risk conditions or rheumatoid arthritis, lupus, Crohn's disease, and neuromuscular disorder/seizures and those with traditional high-risk conditions. We observed that adults with >=2 concurrent comorbid conditions had pneumococcal disease incidence rates that were as high as or higher than rates observed in those with traditional high-risk conditions. PMID- 26034771 TI - Mycoplasma pneumoniae Pneumonia Associated With Methemoglobinemia and Anemia: An Overlooked Association? AB - We report a case of acute methemoglobinemia and anemia in a patient with Mycoplasma pneumoniae pneumonia. We suggest that M. pneumoniae secretes a putative protein that can induce methemoglobin in red blood cells. Thus, Mycoplasma pneumoniae may induce methemoglobinemia in patients who have low oxygen saturation and anemia. PMID- 26034772 TI - Acinetobacter infections and outcomes at an academic medical center: a disease of long-term care. AB - Background. Our study aims to describe the epidemiology, microbial resistance patterns, and clinical outcomes of Acinetobacter infections at an academic university hospital. This retrospective study analyzed all inpatient clinical isolates of Acinetobacter collected at an academic medical center over 4 years. The data were obtained from an Academic tertiary referral center between January 2008 and December 2011. All consecutive inpatients during the study period who had a clinical culture positive for Acinetobacter were included in the study. Patients without medical records available for review or less than 18 years of age were excluded. Methods. Records were reviewed to determine source of isolation, risk factors for acquisition, drug resistance patterns, and clinical outcomes. Repetitive sequence-based polymerase chain reaction of selected banked isolates was used to determine patterns of clonal spread in and among institutions during periods of higher infection rates. Results. Four hundred eighty-seven clinical isolates of Acinetobacter were found in 212 patients (in 252 admissions). Patients with Acinetobacter infections were frequently admitted from healthcare facilities (HCFs) (59%). One hundred eighty-three of 248 (76%) initial isolates tested were resistant to meropenem. One hundred ninety-eight of 249 (79.5%) initial isolates were multidrug resistant (MDR). Factors associated with mortality included bacteremia (odds ratio [OR] = 1.93, P = .024), concomitant steroid use (OR = 2.87, P < .001), admission from a HCF (OR = 6.34, P = .004), and chronic obstructive pulmonary disease (OR = 3.17, P < .001). Conclusions. Acinetobacter isolates at our institution are frequently MDR and are more common among those who reside in HCFs. Our findings underline the need for new strategies to prevent and treat this pathogen, including stewardship efforts in long-term care settings. PMID- 26034773 TI - Similarity-based codes sequentially assigned to ebolavirus genomes are informative of species membership, associated outbreaks, and transmission chains. AB - Background. Developing a universal standardized microbial typing and nomenclature system that provides phylogenetic and epidemiological information in real time has never been as urgent in public health as it is today. We previously proposed to use genome similarity as the basis for immediate and precise typing and naming of individual organisms or viruses. In this study, we tested the validity of the proposed system and applied it to the epidemiology of infectious diseases using Ebola virus disease (EVD) outbreaks as the example. Methods. One hundred twenty-eight publicly available ebolavirus genomes were compared with each other, and average nucleotide identity (ANI) was calculated. The ANI was then used to assign unique codes, hereafter referred to as Life Identification Numbers (LINs), to every viral isolate, whereby each LIN consisted of a series of positions reflecting increasing genome similarity. Congruence of LINs with phylogenetic and epidemiological relationships was then determined. Results. Assigned LINs correlate with phylogeny at the species and infraspecies level and can even identify some individual transmission chains during the 2014-2015 EVD epidemic in West Africa. Conclusions. Life Identification Numbers can provide a fast, automated, standardized, and scalable approach to precisely identify and name viral isolates upon genome sequence submission, facilitating unambiguous communication during disease epidemics among clinicians, epidemiologists, and governments. PMID- 26034774 TI - Challenges in the management of disseminated progressive histoplasmosis in human immunodeficiency virus-infected patients in resource-limited settings. AB - The diagnosis of histoplasmosis in patients with human immunodeficiency virus in southern Africa is complicated by the nonspecific presentation of the disease in this patient group and the unavailability of sensitive diagnostics including antigen assays. Treatment options are also limited due to the unavailability of liposomal amphotericin and itraconazole, and the inability to perform therapeutic drug monitoring further confounds management. We present 3 clinical cases to illustrate the limits of diagnosis and management in the southern African context, and we highlight the need for additional diagnostic tools and treatment options in resource-limited settings. PMID- 26034776 TI - Ceftaroline desensitization procedure in a pregnant patient with multiple drug allergies. AB - Validated skin testing is lacking for many drugs, including ceftaroline. The cross-reactivity between ceftaroline and other beta-lactam antibiotics is unknown. We report a case of a pregnant patient with cystic fibrosis and multiple drug allergies who required ceftaroline for methicillin-resistant Staphylococcus aureus pneumonia and underwent an uncomplicated empiric desensitization procedure. PMID- 26034775 TI - Incident Hepatitis C Virus Infections in the Swiss HIV Cohort Study: Changes in Treatment Uptake and Outcomes Between 1991 and 2013. AB - Background. The hepatitis C virus (HCV) epidemic is evolving rapidly in patients infected with human immunodeficiency virus (HIV). We aimed to describe changes in treatment uptake and outcomes of incident HCV infections before and after 2006, the time-point at which major changes in HCV epidemic became apparent. Methods. We included all adults with an incident HCV infection before June 2012 in the Swiss HIV Cohort Study, a prospective nationwide representative cohort of individuals infected with HIV. We assessed the following outcomes by time period: the proportion of patients starting an HCV therapy, the proportion of treated patients achieving a sustained virological response (SVR), and the proportion of patients with persistent HCV infection during follow-up. Results. Of 193 patients with an HCV seroconversion, 106 were diagnosed before and 87 after January 2006. The proportion of men who have sex with men increased from 24% before to 85% after 2006 (P < .001). Hepatitis C virus treatment uptake increased from 33% before 2006 to 77% after 2006 (P < .001). Treatment was started during early infection in 22% of patients before and 91% after 2006 (P < .001). An SVR was achieved in 78% and 29% (P = .01) of patients treated during early and chronic HCV infection. The probability of having a detectable viral load 5 years after diagnosis was 0.67 (95% confidence interval [CI], 0.58-0.77) in the group diagnosed before 2006 and 0.24 (95% CI, 0.16-0.35) in the other group (P < .001). Conclusions. In recent years, increased uptake and earlier initiation of HCV therapy among patients with incident infections significantly reduced the proportion of patients with replicating HCV. PMID- 26034777 TI - Statin treatment and mortality: propensity score-matched analyses of 2007-2008 and 2009-2010 laboratory-confirmed influenza hospitalizations. AB - Background. Annual influenza epidemics are responsible for substantial morbidity and mortality. The use of immunomodulatory agents such as statins to target host inflammatory responses in influenza virus infection has been suggested as an adjunct treatment, especially during pandemics, when antiviral quantities are limited or vaccine production can be delayed. Methods. We used population-based, influenza hospitalization surveillance data, propensity score-matched analysis, and Cox regression to determine whether there was an association between mortality (within 30 days of a positive influenza test) and statin treatment among hospitalized cohorts from 2 influenza seasons (October 1, 2007 to April 30, 2008 and September 1, 2009 to April 31, 2010). Results. Hazard ratios for death within the 30-day follow-up period were 0.41 (95% confidence interval [CI], .25 .68) for a matched sample from the 2007-2008 season and 0.77 (95% CI, .43-1.36) for a matched sample from the 2009 pandemic. Conclusions. The analysis suggests a protective effect against death from influenza among patients hospitalized in 2007-2008 but not during the pandemic. Sensitivity analysis indicates the findings for 2007-2008 may be influenced by unmeasured confounders. This analysis does not support using statins as an adjunct treatment for preventing death among persons hospitalized for influenza. PMID- 26034778 TI - Rapid improvement in passive tuberculosis case detection and tuberculosis treatment outcomes after implementation of a bundled laboratory diagnostic and on site training intervention targeting mid-level providers. AB - Background. Tuberculosis (TB) control is a public health priority with 3 million cases unrecognized by the public health system each year. We assessed the impact of improved TB diagnostics and on-site training on TB case detection and treatment outcomes in rural healthcare facilities. Methods. Fluorescence microscopy, Xpert MTB/RIF, and on-site training were introduced at 10 healthcare facilities. Using quasi-experimental methods, these 10 intervention healthcare facilities were compared with 2 controls and their own performance the previous year. Results. From January to October 2012, 186 357 and 32 886 outpatients were seen in the 10 intervention and 2 control facilities, respectively. The intervention facilities had a 52.04% higher proportion of presumptive TB cases with a sputum examination (odds ratio [OR] = 12.65; 95% confidence interval [CI], 5.60-28.55). After adjusting for age group and gender, the proportion of smear positive patients initiated on treatment was 37.76% higher in the intervention than in the control facilities (adjusted OR [AOR], 7.59; 95% CI, 2.19-26.33). After adjusting for the factors above, as well as human immunodeficiency virus and TB retreatment status, the proportion of TB cases who completed treatment was 29.16% higher (AOR, 4.89; 95% CI, 2.24-10.67) and the proportion of TB cases who were lost to follow-up was 66.98% lower (AOR, 0.04; 95% CI, 0.01-0.09). When compared with baseline performance, the intervention facilities had a significantly higher proportion of presumptive TB cases with a sputum examination (64.70% vs 3.44%; OR, 23.95; 95% CI, 12.96-44.25), and these facilities started 56.25% more smear-positive TB cases on treatment during the project period (AOR, 15.36; 95% CI, 6.57-35.91). Conclusions. Optimizing the existing healthcare workforce through a bundled diagnostics and on-site training intervention for nonphysician healthcare workers will rapidly improve TB case detection and outcomes towards global targets. PMID- 26034779 TI - Activation of latent human immunodeficiency virus by the histone deacetylase inhibitor panobinostat: a pilot study to assess effects on the central nervous system. AB - In a substudy of a clinical trial, we assessed whether activation of latent human immunodeficiency virus (HIV) by the histone deacetylase inhibitor panobinostat had detrimental effects on the central nervous system (CNS). Adults infected with HIV received oral panobinostat 20 mg 3 times per week every other week for 8 weeks. In cerebrospinal fluid (CSF), we assayed panobinostat concentration, HIV RNA, and the level of neuroinflammatory or degenerative biomarkers in 11 individuals before and during study therapy. Neither panobinostat nor HIV RNA was detected in CSF. In addition, there was no change from baseline in CSF biomarkers. Thus, panobinostat administration was not associated with CNS adverse effects as assessed by CSF biomarkers. PMID- 26034780 TI - Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study. AB - BACKGROUND: Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. METHODS: We did a retrospective cohort study of patients registered in the US Veterans Health Administration database and diagnosed with MGUS between Oct 1, 1999, and Dec 31, 2009. We included patients (aged >18 years) with at least one International Classification of Diseases (9th revision) code for diabetes mellitus and one treatment for their diabetes before MGUS diagnosis. We reviewed patient-level clinical data to verify diagnoses and extract any available data for size of baseline M-protein and type of MGUS. We defined metformin users as patients with diabetes who were given metformin consistently for 4 years after their diabetes diagnosis and before multiple myeloma development, death, or censorship. Our primary outcome was time from MGUS diagnosis to multiple myeloma diagnosis. We used Kaplan-Meier curves and Cox models to analyse the association between metformin use and MGUS progression. FINDINGS: We obtained data for 3287 patients, of whom 2003 (61%) were included in the final analytical cohort. Median follow-up was 69 months (IQR 49-96). 463 (23%) participants were metformin users and 1540 (77%) participants were non-users. 13 (3%) metformin users progressed to multiple myeloma compared with 74 (5%) non-users. After adjustment, metformin use was associated with a reduced risk of progression to multiple myeloma (hazard ratio 0.47, 95% CI 0.25-0.87). INTERPRETATION: For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple myeloma. Prospective studies are needed to establish whether this association is causal and whether these results can be extrapolated to non-diabetic individuals. FUNDING: Barnes-Jewish Hospital Foundation, National Institutes of Health, Agency for Healthcare Research and Quality, American Cancer Society. PMID- 26034781 TI - Resident bacteria-stimulated IL-10-secreting B cells ameliorate T cell-mediated colitis by inducing Tr-1 cells that require IL-27-signaling. AB - BACKGROUND & AIMS: Regulatory roles of IL-10-producing B cells in colitis are not fully understood. The aim of this study is to explore the molecular mechanisms by which these cells modulate mucosal homeostasis. METHODS: CD4+ T cells from WT, Il10-/- or Il27ra-/- mice were co-transferred with B cells from specific pathogen free (SPF) or germ-free (GF) WT or Il10-/- mice into Rag2-/-Il10-/- (DKO) mice and the severity of colitis and intestinal regulatory T cell populations were characterized. In vitro, WT or Il10-/- B cells were co-cultured with unfractionated, naive or regulatory T cells plus Il10-/- antigen-presenting cells and stimulated with cecal bacterial lysate (CBL) with or without IL-27 or anti-IL 10R blockade. Gene expressions, cytokines in the supernatant and cell populations were assessed. RESULTS: WT but not Il10-/- B cells attenuate Th1/Th17-mediated colitis in DKO mice that also received WT but not Il10-/- T cells. In vitro, CBL stimulated WT B cells secrete abundant IL-10 and suppress IFNgamma and IL-17a production by T cells without requiring cell contact. Although both WT and Il10-/ B cells induce Foxp3+CD4+ Tregs, only WT B cells induce IL-10-producing (Foxp3 negative) T regulatory-1 (Tr-1) cells both in vivo and in vitro. However, IL-10 producing B cells did not attenuate colitis or induce Tr-1 cells in the absence of T cell IL-27-signaling in vivo. WT B cell-dependent Tr-1 induction and concomitant decreased IFNgamma-secretion were also mediated by T-cell IL-27 signaling in vitro. CONCLUSIONS: IL-10-secreting B cells activated by physiologically-relevant bacteria ameliorate T cell-mediated colitis and contribute to intestinal homeostasis by suppressing effector T cells and inducing Tr-1 cells via IL-27-signaling on T cells. PMID- 26034782 TI - Agricultural livelihoods in coastal Bangladesh under climate and environmental change--a model framework. AB - Coastal Bangladesh experiences significant poverty and hazards today and is highly vulnerable to climate and environmental change over the coming decades. Coastal stakeholders are demanding information to assist in the decision making processes, including simulation models to explore how different interventions, under different plausible future socio-economic and environmental scenarios, could alleviate environmental risks and promote development. Many existing simulation models neglect the complex interdependencies between the socio economic and environmental system of coastal Bangladesh. Here an integrated approach has been proposed to develop a simulation model to support agriculture and poverty-based analysis and decision-making in coastal Bangladesh. In particular, we show how a simulation model of farmer's livelihoods at the household level can be achieved. An extended version of the FAO's CROPWAT agriculture model has been integrated with a downscaled regional demography model to simulate net agriculture profit. This is used together with a household income expenses balance and a loans logical tree to simulate the evolution of food security indicators and poverty levels. Modelling identifies salinity and temperature stress as limiting factors to crop productivity and fertilisation due to atmospheric carbon dioxide concentrations as a reinforcing factor. The crop simulation results compare well with expected outcomes but also reveal some unexpected behaviours. For example, under current model assumptions, temperature is more important than salinity for crop production. The agriculture-based livelihood and poverty simulations highlight the critical significance of debt through informal and formal loans set at such levels as to persistently undermine the well-being of agriculture-dependent households. Simulations also indicate that progressive approaches to agriculture (i.e. diversification) might not provide the clear economic benefit from the perspective of pricing due to greater susceptibility to climate vagaries. The livelihood and poverty results highlight the importance of the holistic consideration of the human-nature system and the careful selection of poverty indicators. Although the simulation model at this stage contains the minimum elements required to simulate the complexity of farmer livelihood interactions in coastal Bangladesh, the crop and socio-economic findings compare well with expected behaviours. The presented integrated model is the first step to develop a holistic, transferable analytic method and tool for coastal Bangladesh. PMID- 26034783 TI - Lentinula edodes-derived polysaccharide enhances systemic and mucosal immunity by spatial modulation of intestinal gene expression in mice. AB - Mushroom polysaccharides have been reported to possess significant biological activities. However, their molecular mechanisms are not fully elucidated. In this study, the immunostimulating activity of a newly purified heteropolysaccharide L2 from Lentinula edodes is evaluated in Caco-2 cells and a Caco-2/RAW264.7 co culture system, as well as in mice. Subsequently, the customized RT-PCR array containing 112 genes is employed to investigate the effects of L2 on gene expressions in the small intestine, cecum and colon. The results show that L2 significantly enhances immune responses by differentially affecting the gene expressions of small intestine, cecum and colon, in which 55, 26 and 25 genes are markedly changed, respectively. In particular, 3 core regulation networks are identified for various parts of gut. These data demonstrate the potential of L2 as a potent immune stimulator and for the first time provide a detailed landscape of tissue-specific gene expressions and core regulation networks in response to L. edodes-derived heteropolysaccharide treatment. PMID- 26034784 TI - A palm-size MUNMR relaxometer using a digital microfluidic device and a semiconductor transceiver for chemical/biological diagnosis. AB - Herein, we describe a micro-nuclear magnetic resonance (MUNMR) relaxometer miniaturized to palm-size and electronically automated for multi-step and multi sample chemical/biological diagnosis. The co-integration of microfluidic and microelectronic technologies enables an association between the droplet managements and MUNMR assays inside a portable sub-Tesla magnet (1.2 kg, 0.46 Tesla). Targets in unprocessed biological samples, captured by specific probe decorated magnetic nanoparticles (NPs), can be sequentially quantified by their spin-spin relaxation time (T2) via multiplexed MUNMR screening. Distinct droplet samples are operated by a digital microfluidic device that electronically manages the electrowetting-on-dielectric effects over an electrode array. Each electrode (3.5 * 3.5 mm(2)) is scanned with capacitive sensing to locate the distinct droplet samples in real time. A cross-domain-optimized butterfly-coil-input semiconductor transceiver transduces between magnetic and electrical signals to/from a sub-10 MUL droplet sample for high-sensitivity MUNMR screening. A temperature logger senses the ambient temperature (0 to 40 degrees C) and a backend processor calibrates the working frequency for the transmitter to precisely excite the protons. In our experiments, the MUNMR relaxometer quantifies avidin using biotinylated Iron NPs (Phi: 30 nm, [Fe]: 0.5 mM) with a sensitivity of 0.2 MUM. Auto-handling and identification of two targets (avidin and water) are demonstrated and completed within 2.2 min. This MUNMR relaxometer holds promise for combinatorial chemical/biological diagnostic protocols using closed-loop electronic automation. PMID- 26034785 TI - Highly sensitive determination of reduced glutathione based on a cobalt nanoparticle implanted-modified indium tin oxide electrode. AB - Cobalt nanoparticle modified indium tin oxide (CoNP/ITO) electrodes fabricated by ion implantation were applied for the detection of reduced glutathione (GSH). The CoNP/ITO electrode was characterized by scanning electron microscopy (SEM), energy dispersive X-ray (EDX) detector and X-ray photoelectron spectroscopy (XPS). The assay performance with regard to GSH were evaluated by cyclic voltammetry (CV) and chronoamperometry (I-t). The proposed sensor exhibited a much higher electrocatalytic activity toward the oxidation of GSH than the bare ITO electrode, with a detection limit of 5 nM. The CoNP/ITO electrode showed enhanced electrocatalytic properties, high sensitivity, good long-term stability and reproducibility as well as a rapid response to detect GSH. In addition, the CoNP/ITO electrode was also used to analyse the GSH concentration in eye drop samples, and the results were in good agreement with the labelled values. PMID- 26034787 TI - Gene therapy and gene transfer approaches to prevent or treat chronic virus infections. PMID- 26034786 TI - Plasmonic sensors for the competitive detection of testosterone. AB - The ability to detect small molecules in a rapid and sensitive manner is of great importance in the field of clinical chemistry, and the advancement of novel biosensors is key to realising point-of-care analysis for essential targets. Testosterone is an example of such a small molecule, the detection of which is important in both clinical analysis, and in the sporting industry to prevent doping. As such, a portable, rapid and sensitive test for testosterone would be of great use across a variety of analytical fields. Here we report on a novel method of testosterone analysis, based on a competitive inhibition assay utilising functionalized gold nanoparticles. Two sensing platforms are directly compared for the detection of testosterone based on both classical SPR and LSPR. We provide an in-depth discussion on the optimum surface chemistries needed to create a stable detection conjugate before successfully detecting testosterone using our newly developed portable 4-channel SPR instrument. We provide the first detailed study into the comparison of SPR and LSPR for the analysis of a small molecule, and provide a simple and effective method of testosterone detection that could potentially be extended to a variety of different analytes. PMID- 26034788 TI - Supporting the cardiologists of tomorrow at the European Society of Cardiology. PMID- 26034789 TI - Stem cells for heart failure: the experience of writing a Cochrane systematic review. PMID- 26034790 TI - Mediterranean diet linked to improved cardiovascular function in erectile dysfunction patients. PMID- 26034791 TI - [Short sleepers who are overweight are at particular risk]. PMID- 26034792 TI - [Less illness and death through computer support?]. PMID- 26034793 TI - [Epidemiology meets intersectionality]. PMID- 26034794 TI - [More daring (direct) democracy]. PMID- 26034795 TI - An optimized method to extract poplar leaf proteins for two-dimensional gel electrophoresis guided by analysis of polysaccharides and phenolic compounds. AB - Commonly used methods for protein extraction from plant leaves, such as extraction with phenol or a combination of TCA and acetone, were ineffective for four tested cultivars of poplar. Moreover, multiple protocols for 2DE of the extracted proteins gave different results when protein profiles of relatively closely related plants were compared. Given that polycyclic compounds strongly hinder 2DE, we analyzed the impact of polyphenols and polysaccharides present in the plant tissues used for protein extraction, on the quality of 2DE protein profiles. Analysis of content of polyphenols and polysaccharides in leaves of poplar cultivars showed that even small differences in concentrations of analyzed metabolites accompany large differences between poplar cultivars when considering the susceptibility of samples to protein extraction for 2DE. High-quality 2DE results were correlated with decreased amounts of polyphenols. Additional analysis using MS/MS suggested that only levels of total phenolics affected the results of 2DE. Soluble total nonstructural carbohydrates also had a negative effect, but the level of starch was not important. Finally, we present an optimized method (OPTI) for extraction of proteins from poplar leaves, which enables reliable comparative analysis of four different poplar cultivars i.e. 'Eridano', 'Villafranca', 'NE-42' and 'Luisa Avanzo', which have not yet been used for the proteomic studies. PMID- 26034796 TI - The role of tracers in hydrogeology. PMID- 26034797 TI - [Hygienic evaluation of working conditions and working process of fire rescue employees]. AB - As a result of complex hygienic evaluation of working conditions of various professional groups ofpersonnel of State Emergency Service of Ukraine the labor activity of fire-rescues was found to occur in more hazardous conditions than appeared in fire trucks drivers and fire safety inspectors. The work in the area of fire extinguishing was shown to significantly affect on professionally important physiological functions of firemen, causing a decline in attention, memory, accuracy, reactions, increasing of the level of anxiety. Results of the study of the functional state of the cardiovascular system show a decrease in its functional reserves and adaptive capabilities in groups of firefighters and fire trucks drivers, compared with the inspectors. There was revealed the accelerated biological aging of firefighters--biological age appears to be significantly higher than the calendar one in average by 3.2 years, which is much more similar to the difference in other occupational groups (p < 0.01). In the mechanisms offunctional disregulatory disorders in fire-rescues the important role was established to belong to significant changes in the activity of the sympathetic adrenal system, which exhibits a high secretory activity with a predominance of hormonal level response and the relative increase of the free forms of catecholamines on the background of a relative decrease in its reserve possibilities and metabolic uncoupling processes. The data obtained were hygienic prerequisitesfor the development of the complex psycho-hygienic prevention and medical and psychological rehabilitation of fire-rescue workers admitted in the Specialized center for medical and psychological rehabilitation of the State Service of Ukraine for emergencies, working at the base of the sanatorium "Odessa". PMID- 26034799 TI - Being pragmatic. PMID- 26034798 TI - [On the occasion of the 75th anniversary of the birth of V.A. Kaptsov]. PMID- 26034800 TI - Blurred vision. PMID- 26034802 TI - Common stem--pamide. PMID- 26034801 TI - Ioxapine (Adasuve) for inhalation. A dangerous gadget. AB - No comparative trials versus well-established drugs; worrisome risk of bronchospasm; unsuitable mode of administration for agitated, often uncooperative patients. PMID- 26034803 TI - Eculizumab (Soliris) and paroxysmal nocturnal haemoglobinuria in children. When transfusions are too frequent. AB - Many uncertainties; assessment based on extrapolation of adult data. PMID- 26034804 TI - Human papillomavirus vaccines: 2014 safety review. AB - The efficacy of HPV vaccines has still not been adequately determined as of late 2014, apart from a preventive effect on precancerous cervical lesions in the years following vaccination.This makes it all the more important to thoroughly assess the adverse effects of HPV vaccination. PMID- 26034805 TI - Efficacy HPV vaccine in late 2014. AB - Initial evaluation of the HPV 6, 11, 16, 18 vaccine showed about a 40% reduction in high-grade cervical dysplasia due to all virus genotypes among young women aged 16 to 23 years who were not yet sexually active. These results were obtained after 4 years of follow-up and were confirmed after an additional 3 years. Clinical assessment of the HPV 16, 18 vaccine yielded similar results. The interval between initial HPV infection and diagnosis of cervical cancer seems to be at least 20 years. Comparisons of vaccinated and unvaccinated cohorts are consistent with the results of clinical trials, but follow-up is still too short because most of the women studied have not reached the age at which the incidence of high-grade dysplasia peaks. The available evidence shows no replacement of HPV vaccine genotypes by other highly oncogenic genotypes but, once again, follow-up is relatively short. In late 2014, follow-up is still too short to show whether HPV vaccination prevents cervical cancer in young women before they become sexually active. Earlier clinical trials showing efficacy in preventing high grade dysplasia have not been challenged by epidemiological data. Overall, it will be several more years before conclusive evidence is obtained. In 2015, screening remains the cornerstone for reducing the incidence of invasive cervical cancer. PMID- 26034806 TI - Glucose-lowering treatment of type 2 diabetes. Part II--Glucose-lowering drugs after metformin: a choice based largely on adverse effects. AB - Metformin alone is the glucose-lowering drug of first choice for patients with type 2 diabetes. None of the other glucose-lowering drugs available in 2014 have any proven efficacy in preventing diabetes complications. How important are adverse effects in the choice of glucose-lowering alternatives to metformin for patients with type 2 diabetes? What about their effects on HbA1c levels? To answer these questions, we conducted a review of the literature using the standard Prescrire methodology. Sulphonylureas have been in use for many years. These drugs lower HbA1c levels by an average of 1.5% when used alone, and by 0.8% to 1% when added to metformin. All sulphonylureas can cause dose-related hypoglycaemia. Available data do not rule out a tangible increase or decrease in cardiovascular mortality among patients treated with sulphonylureas. Comparative data suggest that the combination of metformin + sulphonylurea increases overall mortality. Human insulins have also been in use for many years. A daily injection of long-acting insulin, added to on-going oral glucose-lowering therapy, lowers HbA1c by 0.7% to 2.5% on average but causes weight gain and increases the risk of hypoglycaemia. It cannot be ruled out that insulin may increase the risk of certain cancers. Alpha-glucosidase inhibitors have a weak glucose-lowering effect. The average decline in HbA1c is about 0.7%, which is not sufficient to offset the gastrointestinal disorders caused by these drugs. The glucose-lowering effect of repaglinide is similar to that of sulphonylureas. Repaglinide can cause hypoglycaemia, particularly when co-administered with inhibitors of some cytochrome P450 isoenzymes. Glitazones have a clearly unfavourable harm-benefit balance, potentially causing fractures, heart failure, other cardiovascular events, bladder cancer. Gliptins lower HbA1c by 0.7% on average but can provoke anaphylactic reactions, Stevens-Johnson syndrome, and infections. Saxagliptin may increase the risk of fractures and heart failure. The long-term adverse effects of gliptins are poorly documented and may include an increased risk of pancreatic cancer. These risks are not offset by any proven clinical efficacy; patients should therefore not be exposed to these drugs. When they are combined with metformin, two injectable GLP-1 analogues, exenatide and liraglutide, have a glucose-lowering potency similar to one or two daily insulin injections. They have the advantage of inducing weight loss, without increasing the risk of hypoglycaemia. Gastrointestinal adverse effects such as nausea are frequent at the beginning of treatment. A possible increase in the risk of pancreatitis, pancreatic cancer and thyroid cancer has not been ruled out. Gliflozins reduce HbA1c by 0.6-0.7% on average. These drugs are already known to have a burdensome adverse effect profile despite their relatively recent market introduction. There are also safety signals concerning serious long-term adverse effects. Patients should not be exposed to these risks. PMID- 26034807 TI - Type 2 diabetes: which glucose-lowering drug, if any, after metformin? PMID- 26034808 TI - Drug packaging in 2014: authorities should direct more efforts towards medication safety. AB - In 2014, Prescrire examined the packaging quality of about 250 drugs. A few advances stand out, mainly involving recent drugs, but on the whole, the situation is worrisome in terms of medication safety. Although pharmaceutical companies and drug regulatory agencies seem to be taking more account of the risk of accidental poisoning in children, the level of protection remains low overall in the absence of stringent measures on the part of the authorities. New drugs too often have poor-quality or even dangerous packaging at the time of their market introduction. And the packaging quality of older drugs is disturbing. Pharmaceutical companies no longer invest in the packaging of these products, and agencies often fail to take advantage of the opportunities provided by their reassessment to improve the situation. The inappropriate labelling of certain injectable drugs remains a source of medication errors, sometimes resulting in very serious consequences. In 2014, signs of progress in the packaging of several drugs show that its role in medication safety is better appreciated. But the persistence of dangers in the pharmaceuticals market, created by "unfinished", overly complex or poor-quality packaging, raises the question of the responsibility of pharmaceutical companies and agencies for past and present accidents. PMID- 26034809 TI - Access to data: EMA in key position. AB - The European Medicines Agency must fulfil its transparency obligations and resist industry pressure. PMID- 26034810 TI - Resistance to Ditylenchus destructor Infection in Sweet Potato by the Expression of Small Interfering RNAs Targeting unc-15, a Movement-Related Gene. AB - Stem nematode (Ditylenchus destructor) is one of most serious diseases that limit the productivity and quality of sweet potato (Ipomoea batatas), a root crop with worldwide importance for food security and nutrition improvement. Hence, there is a global demand for developing sweet potato varieties that are resistant to the disease. In this study, we have investigated the interference of stem nematode infectivity by the expression of small interfering RNAs (siRNAs) in transgenic sweet potato that are homologous to the unc-15 gene, which affects the muscle protein paramyosin of the pathogen. The production of double-stranded RNAs and siRNAs in transgenic lines with a single transgene integration event was verified by Northern blot analysis. The expression of unc-15 was reduced dramatically in stem nematodes collected from the inoculated storage roots of transgenic plants, and the infection areas of their storage roots were dramatically smaller than that of wild-type (WT). Compared with the WT, the transgenic plants showed increased yield in the stem nematode-infested field. Our results demonstrate that the expression of siRNAs targeting the unc-15 gene of D. destructor is an effective approach in improving stem nematode resistance in sweet potato, in adjunct with the global integrated pest management programs. PMID- 26034811 TI - The gut microbiome and childhood obesity: connecting the dots. PMID- 26034812 TI - Re: Estrada et al., "Children's Hospital Association Consensus Statements for Comorbidities of Childhood Obesity". PMID- 26034813 TI - QSAR study of some anti-hyperglycaemic sulphonylurea drugs. AB - Sulphonylureas are widely used anti-hyperglycaemic drugs for the treatment of type 2 diabetes. The only published quantitative structure-activity relationship (QSAR) models for sulphonylurea drugs have been found to be questionable, for a number of reasons. We have re-analysed the human anti-hyperglycaemic potencies, acute mouse intraperitoneal toxicities (LD50) and plasma protein-binding abilities of the 15 drugs using multiple linear regression and obtained good QSAR models for each endpoint. The obtained QSARs all comply well with the Organisation for Economic Co-operation and Development (OECD) Guidelines for the Validation of (Q)SARs. We could not carry out external validation of our models for acute toxicity and plasma protein-binding because of the very small datasets available. PMID- 26034814 TI - Atomically crafted spin lattices as model systems for quantum magnetism. AB - Low-dimensional quantum magnetism presents a seemingly unlimited source of rich, intriguing physics. Yet, because realistic experimental representations are difficult to come by, the field remains predominantly theoretical. In recent years, artificial spin structures built through manipulation of magnetic atoms in a scanning tunnelling microscope have developed into a promising testing ground for experimental verification of theoretical models. Here, we present an overview of available tools and discuss recent achievements as well as future avenues. Moreover, we show new observations on magnetic switching in a bistable bit that can be used to extrapolate information on the magnetisation of the microscope tip. PMID- 26034815 TI - A synthesis of alsmaphorazine B demonstrates the chemical feasibility of a new biogenetic hypothesis. AB - An N-oxide fragmentation/hydroxylamine oxidation/intramolecular 1,3-dipolar cycloaddition cascade efficiently converted an oxidized congener of akuammicine into the complex, hexacyclic architecture of the alsmaphorazine alkaloids. This dramatic structural change shows the chemical feasibility of our novel proposal for alsmaphorazine biogenesis. Critical to these endeavors was a marked improvement in our previously reported Zincke aldehyde cycloaddition approach to indole alkaloids, which permitted the gram-scale synthesis of akuammicine. The chemoselective oxidations of akuammicine leading up to the key rearrangement also generated several biogenetically related alkaloids of the alstolucine and alpneumine families. PMID- 26034816 TI - Role of Capsular Polysaccharides in Biofilm Formation: An AFM Nanomechanics Study. AB - Bacteria form biofilms to facilitate colonization of biotic and abiotic surfaces, and biofilm formation on indwelling medical devices is a common cause of hospital acquired infection. Although it is well-recognized that the exopolysaccharide capsule is one of the key bacterial components for biofilm formation, the underlying biophysical mechanism is poorly understood. In the present study, nanomechanical measurements of wild type and specific mutants of the pathogen, Klebsiella pneumoniae, were performed in situ using atomic force microscopy (AFM). Theoretical modeling of the mechanical data and static microtiter plate biofilm assays show that the organization of the capsule can influence bacterial adhesion, and thereby biofilm formation. The capsular organization is affected by the presence of type 3 fimbriae. Understanding the biophysical mechanisms for the impact of the structural organization of the bacterial polysaccharide capsule on biofilm formation will aid the development of strategies to prevent biofilm formation. PMID- 26034818 TI - Medication safety. PMID- 26034817 TI - Gated Luminescence Imaging of Silicon Nanoparticles. AB - The luminescence lifetime of nanocrystalline silicon is typically on the order of microseconds, significantly longer than the nanosecond lifetimes exhibited by fluorescent molecules naturally present in cells and tissues. Time-gated imaging, where the image is acquired at a time after termination of an excitation pulse, allows discrimination of a silicon nanoparticle probe from these endogenous signals. Because of the microsecond time scale for silicon emission, time-gated imaging is relatively simple to implement for this biocompatible and nontoxic probe. Here a time-gated system with ~10 ns resolution is described, using an intensified CCD camera and pulsed LED or laser excitation sources. The method is demonstrated by tracking the fate of mesoporous silicon nanoparticles containing the tumor-targeting peptide iRGD, administered by retro-orbital injection into live mice. Imaging of such systemically administered nanoparticles in vivo is particularly challenging because of the low concentration of probe in the targeted tissues and relatively high background signals from tissue autofluorescence. Contrast improvements of >100-fold (relative to steady-state imaging) is demonstrated in the targeted tissues. PMID- 26034822 TI - Optimizing medication safety in the home. AB - Medication safety among community-dwelling older adults in the United States is an ongoing health issue impacting health outcomes, chronic disease management, and aging in place at home. This article describes a medication safety improvement project that aimed to: (1) Increase the ability of participants to manage medications, (2) Identify and make necessary medication changes, (3) Create an accurate up-to-date medication list to be available in the home, and (4) Provide communication between the primary care provider, participant, and case manager. An in-home medication assessment was completed for 25 participants using an evidence-based medication management software system. This process was used to review medications; identify medication-related problems; create a shared medication list; and convey this information to the primary care provider, case manager, and client while addressing needed medication changes. Educational interventions on management and understanding of medications were provided to participants to emphasize the correct use of medications and use of a personal medication record. Outcome improvements included provision of an accurate medication list, early identification of medication-related problems, identification of drug duplication, and identification of medication self management challenges that can be useful for optimizing medication safety-related home healthcare and inform future interventions. PMID- 26034820 TI - Type 2 diabetes drugs: a review. AB - Diabetes is a common diagnosis for home care patients. Diabetes drugs are now available that target the multiple defects of metabolism that characterize Type 2 diabetes. Understanding the wide variety of medications available will assist clinicians in guiding their patients through the complexities of diabetes self care to promote optimal glucose control. PMID- 26034823 TI - Loss and Loneliness: Audrey's Story. AB - Loneliness is a concept recently capturing the attention of nursing and other healthcare professionals due to its unfavorable effects on health outcomes. The purpose of this article is to convey the story of one widow named Audrey (pseudonym) and to describe her experiences of profound loneliness. Narratives from this single case study are reported as part of a larger qualitative, phenomenological study on loneliness in community-dwelling older adults. Findings from Audrey's story reveal intense periods of loneliness, longing and loss primarily resulting from the death of her spouse. Excerpts from these narratives uncover Audrey's coping strategies for loneliness, which included watching television, telephoning her children, reading the paper, and finding comfort in her faith. Audrey's story is essential for all home healthcare professionals to understand, as it illustrates the powerful impact of loneliness on the quality of life and health of an older adult. PMID- 26034824 TI - Professional boundary violations: a literature review. AB - The purpose of this article is to review the nursing literature related to professional boundary violations in nursing. A search was conducted using CINAHL, MEDLINE, Ebscohost, and NCSBN. The key words searched were professional boundaries, boundary violation, boundary crossings, nurse, home health nurses, and home nursing. The search returned over 40 publications related specifically to boundary violations and nursing although only four of them are published research studies and one as a dissertation. Seven common characteristics emerged from the nonresearch nursing articles on professional boundaries: (1) Dual relations/role reversal, (2) Gifts and money, (3) Excessive self-disclosure, (4) Secretive behavior, (5) Excessive attention/overinvolvement, (6) Sexual behavior, and (7) Social media. Additional nursing research is greatly needed in the area of professional boundaries. The nurse-patient relationship should always be maintained for the benefit of the patient and not the personal gain of the nurse. Ongoing education in nursing practice regarding professional boundaries is needed. Nurses need to be mindful of state practice acts, codes of conduct, and employer policies. PMID- 26034825 TI - Co-morbid Depression and Cardiovascular Disease in the Older Adult Homecare Patient. AB - Depression and cardiovascular disease are leading causes of morbidity and mortality in the United States and globally. Depression significantly increases the risk of fatal and nonfatal cardiovascular disease and increases the risk of mortality in patients with cardiovascular disease. Patients receiving home healthcare are disproportionally affected by depression. Comorbid depression can occur in two time frames: precardiac and postcardiac. It is imperative that home care patients be adequately screened and monitored for depressive symptoms. Home care patients with cardiac disease who are under treatment for depression should be carefully monitored for adherence to their medical care, drug efficacy, and safety with respect to their cardiovascular as well as mental health. PMID- 26034826 TI - Diabetes and weight loss. PMID- 26034827 TI - Misidentification of alphanumeric symbols in both handwritten and computer generated information. PMID- 26034828 TI - Hand hygiene and Clostridium difficile infections. PMID- 26034829 TI - A day in the life of a telehealth nurse. PMID- 26034830 TI - The teach back method. PMID- 26034831 TI - Ghost authorship. PMID- 26034833 TI - Mechanistic Insights into the Cu(I)- and Cu(II)-Catalyzed Cyclization of o Alkynylbenzaldehydes: The Solvent DMF and Oxidation State of Copper Affect the Reaction Mechanism. AB - A computational study with the BhandHLYP density functional is conducted to elucidate the mechanisms of Cu(I)- and Cu(II)-catalyzed reactions of o alkynylbenzaldehydes with a nucleophile (MeOH). Our calculations suggest the following. (a) The use of CuCl as a catalyst deceases significantly the energy barrier and promotes intramolecular cyclization. (b) Solvent DMF is critical in the stepwise hydrogen-transport process involved in an intermolecular nucleophilic addition because it can greatly reduce the free energy barrier of the hydrogen-transfer process as a proton shuttle. In addition, we find that substrate MeOH also plays a role similar to that of DMF in the hydrogen-transport reaction. (c) The 6-endo product P1 is formed exclusively using a catalytic system consisting of CuCl and DMF, whereas a mixture of 6-endo product P1 and 5 exo product P2 in a ratio of ~1:1 is produced using CuCl2 and DMF as a catalytic system. Our theoretical calculations reproduce the experimental results very well. This study is expected to improve our understanding of Cu(I)- and Cu(II) catalyzed reactions involving Lewis base solvents and to provide guidance for the future design of new catalysts and new reactions. PMID- 26034832 TI - Of mice and monkeys: can animal models be utilized to study neurological consequences of pediatric HIV-1 infection? AB - Pediatric human immunodeficiency virus (HIV-1) infection remains a global health crisis. Children are much more susceptible to HIV-1 neurological impairments than adults, which can be exacerbated by coinfections. Neurological characteristics of pediatric HIV-1 infection suggest dysfunction in the frontal cortex as well as the hippocampus; limited MRI data indicate global cerebral atrophy, and pathological data suggest accelerated neuronal apoptosis in the cortex. An obstacle to pediatric HIV-1 research is a human representative model system. Host species specificity of HIV-1 limits the ability to model neurological consequences of pediatric HIV-1 infection in animals. Several models have been proposed including neonatal intracranial injections of HIV-1 viral proteins in rats and perinatal simian immunodeficiency virus (SIV) infection of infant macaques. Nonhuman primate models recapitulate the complexity of pediatric HIV-1 neuropathogenesis while rodent models are able to elucidate the role specific viral proteins exert on neurodevelopment. Nonhuman primate models show similar behavioral and neuropathological characteristics to pediatric HIV-1 infection and offer a stage to investigate early viral mechanisms, latency reservoirs, and therapeutic interventions. Here we review the relative strengths and limitations of pediatric HIV-1 model systems. PMID- 26034834 TI - Consequences of metabolic and oxidative modifications of cartilage tissue. AB - A hallmark of chronic metabolic diseases, such as diabetes and metabolic syndrome, and oxidative stress, as occurs in chronic inflammatory and degenerative conditions, is the presence of extensive protein post-translational modifications, including glycation, glycoxidation, carbonylation and nitrosylation. These modifications have been detected on structural cartilage proteins in joints and intervertebral discs, where they are known to affect protein folding, induce protein aggregation and, ultimately, generate microanatomical changes in the proteoglycan-collagen network that surrounds chondrocytes. Many of these modifications have also been shown to promote oxidative cleavage as well as enzymatically-mediated matrix degradation. Overall, a general picture starts to emerge indicating that biochemical changes in proteins constitute an early event that compromises the anatomical organization and viscoelasticity of cartilage, thereby affecting its ability to sustain pressure and, ultimately, impeding its overall bio-performance. PMID- 26034835 TI - Immune cell profiling to guide therapeutic decisions in rheumatic diseases. AB - Biomarkers are needed to guide treatment decisions for patients with rheumatic diseases. Although the phenotypic and functional analysis of immune cells is an appealing strategy for understanding immune-mediated disease processes, immune cell profiling currently has no role in clinical rheumatology. New technologies, including mass cytometry, gene expression profiling by RNA sequencing (RNA-seq) and multiplexed functional assays, enable the analysis of immune cell function with unprecedented detail and promise not only a deeper understanding of pathogenesis, but also the discovery of novel biomarkers. The large and complex data sets generated by these technologies--big data--require specialized approaches for analysis and visualization of results. Standardization of assays and definition of the range of normal values are additional challenges when translating these novel approaches into clinical practice. In this Review, we discuss technological advances in the high-dimensional analysis of immune cells and consider how these developments might support the discovery of predictive biomarkers to benefit the practice of rheumatology and improve patient care. PMID- 26034841 TI - PET Tracers To Study Clinically Relevant Hepatic Transporters. AB - Transporter proteins expressed on the cell membranes of hepatocytes are directly involved in the hepatic clearance, mediating the transport of drugs and metabolites through the hepatocyte, from the bloodstream into the bile. Reduction of hepatic transporter activity (due to chemical inhibition, genetic polymorphism, or low expression) can increase systemic or liver exposure to potentially toxic compounds, causing adverse effects. Many clinically used drugs have been associated with inhibition of hepatic transporters in vitro, suggesting the potential involvement of liver transporters in drug-drug interactions (DDIs). Recently, radiolabeled hepatic transporter substrates have been successfully employed in positron emission tomography (PET) imaging to demonstrate inhibition of clinically relevant hepatic transporters. The present article briefly describes the clinical relevance of hepatic transporters followed by a review of the application of PET imaging for the determination of pharmacokinetic parameters useful to describe the transporter activity and the design, accessibility, and preclinical and clinical applications of available radiotracers. Finally, based on the analysis of the strengths and limitations of the available tracers, some criteria for the development of novel PET probes for hepatic transporters and new potential applications are suggested. PMID- 26034840 TI - Prenatal Exposure to Perfluoroalkyl Acids and Serum Testosterone Concentrations at 15 Years of Age in Female ALSPAC Study Participants. AB - BACKGROUND: Exposure to perfluorooctane sulfonic acid (PFOS) or to perfluorooctanoic acid (PFOA) increases mouse and human peroxisome proliferator activated receptor alpha (PPARalpha) subtype activity, which influences lipid metabolism. Because cholesterol is the substrate from which testosterone is synthesized, exposure to these substances has the potential to alter testosterone concentrations. OBJECTIVES: We explored associations of total testosterone and sex hormone-binding globulin (SHBG) concentrations at age 15 years with prenatal exposures to PFOS, PFOA, perfluorohexane sulfonic acid (PFHxS), and perfluoronanoic acid (PFNA) in females. METHODS: Prenatal concentrations of the perfluoroalkyl acids (PFAAs) were measured in serum collected from pregnant mothers at enrollment (1991-1992) in the Avon Longitudinal Study of Parents and Children (ALSPAC). The median gestational age when the maternal blood sample was obtained was 16 weeks (interquartile range, 11-28 weeks). Total testosterone and SHBG concentrations were measured in serum obtained from their daughters at 15 years of age. Associations between prenatal PFAAs concentrations and reproductive outcomes were estimated using linear regression models (n = 72). RESULTS: Adjusted total testosterone concentrations were on average 0.18-nmol/L (95% CI: 0.01, 0.35) higher in daughters with prenatal PFOS in the upper concentration tertile compared with daughters with prenatal PFOS in the lower tertile. Adjusted total testosterone concentrations were also higher in daughters with prenatal concentrations of PFOA (beta = 0.24; 95% CI: 0.05, 0.43) and PFHxS (beta = 0.18; 95% CI: 0.00, 0.35) in the upper tertile compared with daughters with concentrations in the lower tertile. We did not find evidence of associations between PFNA and total testosterone or between any of the PFAAs and SHBG. CONCLUSIONS: Our findings were based on a small study sample and should be interpreted with caution. However, they suggest that prenatal exposure to some PFAAs may alter testosterone concentrations in females. PMID- 26034836 TI - The anti-DNA antibody: origin and impact, dogmas and controversies. AB - The inclusion of 'the anti-DNA antibody' by the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) as a criterion for systemic lupus erythematosus does not convey the diverse origins of these antibodies, whether their production is transient or persistent (which is heavily influenced by the nature of the inducing antigens), the specificities exerted by these antibodies or their clinical impact-or lack thereof. A substantial amount of data not considered in clinical medicine could be added from basic immunology evidence, which could change the paradigms linked to what 'the anti-DNA antibody' is, in a pathogenic, classification or diagnostic context. PMID- 26034842 TI - From T2,2@Bmmim to Alkali@T2,2@Bmmim Ivory Ball-like Clusters: Ionothermal Syntheses, Precise Doping, and Photocatalytic Properties. AB - Presented here are the syntheses, structures, and properties of an In-Sn-Se compound based on a ternary super-supertetrahedral T2,2 cluster nested by Bmmim cations and two of its alkali-doped quaternary analogues. By means of a one-pot ionothermal method, an alkali metal ion (Cs(+) or Rb(+)) could be precisely doped into the central cavity of the cluster, forming an alkali@T2,2@Bmmim quaternary cluster. Remarkably, the undoped compound exhibited excellent stability and visible light photodegradation ability over a wide range of pH, especially in acidic conditions. PMID- 26034845 TI - Correction. PMID- 26034843 TI - Reversible Nanoparticle-Micelle Transformation of Ionic Liquid Sulfonatocalix[6]arene Aggregates. AB - The effect of temperature and NaCl concentration variations on the self-assembly of 1-methyl-3-tetradecylimidazolium (C14mim(+)) and 4-sulfonatocalix[6]arene (SCX6) was studied by dynamic light scattering and isothermal calorimetric methods at pH 7. Inclusion complex formation promoted the self-assembly to spherical nanoparticles (NP), which transformed to supramolecular micelles (SM) in the presence of NaCl. Highly reversible, temperature-responsive behavior was observed, and the conditions of the NP-SM transition could be tuned by the alteration of C14mim(+):SCX6 mixing ratio and NaCl concentration. The association to SM was always exothermic with enthalpy independent of the amount of NaCl. In contrast, NPs were produced in endothermic process at low temperature, and the enthalpy change became less favorable upon increase in NaCl concentration. The NP formation was accompanied by negative molar heat capacity change, which further diminished when NaCl concentration was raised. PMID- 26034847 TI - Physician groups urge CMS to preserve Medicare beneficiaries' continuity of care. PMID- 26034846 TI - Employment accommodation assessments for pregnant patients. PMID- 26034848 TI - Advice for protection against mosquitoes and ticks. PMID- 26034849 TI - Osteopathic schools are producing more graduates, but fewer are practicing in primary care. PMID- 26034850 TI - Shifting sources of U.S. Primary care physicians. PMID- 26034851 TI - Colchicine for acute gout. PMID- 26034852 TI - Aclidinium for Stable COPD. PMID- 26034853 TI - Atypical moles: diagnosis and management. AB - Atypical moles are benign pigmented lesions. Although they are benign, they exhibit some of the clinical and histologic features of malignant melanoma. They are more common in fair-skinned individuals and in those with high sun exposure. Atypical moles are characterized by size of 6 mm or more at the greatest dimension, color variegation, border irregularity, and pebbled texture. They are associated with an increased risk of melanoma, warranting enhanced surveillance, especially in patients with more than 50 moles and a family history of melanoma. Because an individual lesion is unlikely to display malignant transformation, biopsy of all atypical moles is neither clinically beneficial nor cost-effective. The ABCDE (asymmetry, border irregularity, color unevenness, diameter of 6 mm or more, evolution) mnemonic is a valuable tool for clinicians and patients to identify lesions that could be melanoma. Also, according to the "ugly duckling" concept, benign moles tend to have a similar appearance, whereas an outlier with a different appearance is more likely to be undergoing malignant change. Atypical moles with changes suggestive of malignant melanoma should be biopsied, using an excisional method, if possible. PMID- 26034854 TI - Nonpharmacologic management of hypertension: what works? AB - Hypertension is one of the most common conditions encountered in primary care. Nonpharmacologic strategies have been shown to help lower blood pressure. Lifestyle modifications are recommended for all patients with hypertension. The American Heart Association/American College of Cardiology lifestyle management guideline recommends a diet emphasizing vegetables, fruits, and whole grains; limiting sodium intake to less than 2,400 mg per day; and exercising three or four times per week for an average of 40 minutes per session. Other nonpharmacologic strategies include weight loss, tobacco cessation, decreased alcohol consumption, biofeedback, and self-measured blood pressure monitoring. For patients with obstructive sleep apnea, the use of continuous positive airway pressure has been shown to improve blood pressure. Dietary supplements such as garlic, cocoa, vitamin C, coenzyme Q10, omega-3 fatty acids, and magnesium have been suggested for lowering blood pressure, but evidence is lacking. PMID- 26034855 TI - Sudden infant death syndrome. AB - Sudden infant death syndrome (SIDS) is the sudden unexpected death of a child younger than one year during sleep that cannot be explained after a postmortem evaluation including autopsy, a thorough history, and scene evaluation. The incidence of SIDS has decreased more than 50% in the past 20 years, largely as a result of the Back to Sleep campaign. The most important risk factors relate to the sleep environment. Prone and side sleeping positions are significantly more dangerous than the supine position. Bed sharing with a parent is strongly correlated with an increased risk of SIDS, especially in infants younger than 12 weeks. Apparent life-threatening events are not a risk factor for SIDS. Parents should place infants on their backs to sleep, should not share a bed, and should avoid exposing the infant to tobacco smoke. Other risk-reducing measures include using a firm crib mattress, breastfeeding, keeping vaccinations up to date, avoiding overheating due to overbundling, avoiding soft bedding, and considering the use of a pacifier during sleep once breastfeeding is established. One consequence of the Back to Sleep campaign is a significant increase in the incidence of occipital flattening. Infants who develop a flat spot should be placed with the head facing alternating directions each time he or she is put to bed. Supervised prone positioning while the infant is awake, avoiding excessive use of carriers, and upright positioning while awake are also recommended. PMID- 26034857 TI - Diffuse, bright-red rash with desquamation and scaling in an adult. PMID- 26034858 TI - FPIN's Clinical Inquiries. Management of acute achilles tendon rupture. PMID- 26034860 TI - Tight glycemic control for type 2 diabetes mellitus (over five years). PMID- 26034862 TI - How to lower your blood pressure without medicines. PMID- 26034863 TI - Sudden Infant Death Syndrome (SIDS). PMID- 26034864 TI - Spatial analysis of the effect of the 2010 heat wave on stroke mortality in Nanjing, China. AB - To examine the spatial variation of stroke mortality risk during heat wave, we collected 418 stroke mortality cases with permanent addresses for a severe heat wave (July 28-August 15, 2010) and 624 cases for the reference period (July 29 August 16, 2009 and July 27-August 14, 2011) in Nanjing, China. Generalized additive models were used to explore the association between location and stroke mortality risk during the heat wave while controlling individual-level risk factors. Heat wave vulnerability was then applied to explain the possible spatial variations of heat-wave-related mortality risk. The overall risk ratio (95% confidence intervals) of stroke mortality due to the heat wave in Nanjing was 1.34 (1.21 to 1.47). Geolocation was found to be significantly associated with the heat-wave-related stroke mortality risk. Using alternative reference periods generated similar results. A district-level risk assessment revealed similar spatial patterns. The highest stroke mortality risk observed in Luhe district was due to the combination of high heat exposure and high vulnerability. Our findings provide evidence that stroke mortality risk is higher in rural areas during heat waves and that these areas require future interventions to reduce vulnerability. PMID- 26034865 TI - "Mass-forming" variant of ischemic colitis is a distinct entity with predilection for the proximal colon. AB - We systematically evaluated the clinicopathologic features and outcome of a rare, unusual variant of ischemic colitis that presents as a mass lesion mimicking malignancy on imaging or colonoscopy. A retrospective search was performed for cases with a histologic diagnosis of ischemic colitis and a clinical impression of malignancy. Of the 23 patients initially identified, 4 were excluded because clinical and histologic review showed mucosal prolapse (n=1), discrete colon polyp (n=2), and a diverticular mass (n=1) without concern for malignancy. The mass-forming variant of ischemic colitis (n=19) was seen predominantly in elderly (mean age 71.8 y) women (63.2%) with a striking predilection for the right colon (13/19), particularly the cecum (n=6). Abdominal pain (52.6%) and hematochezia (26.3%) were the most common presenting symptoms. A computed tomography scan showed segmental thickening suspicious for malignancy in 6/8 patients. Colonoscopy revealed an exophytic (n=16) or stricturing (n=3) mass with a mean size of 4.67 cm. Mucosal biopsies showed features typical for ischemic colitis in all cases. A colectomy was performed in 4 cases. In 2, the mass-like appearance was due to marked submucosal and mural edema, whereas in the other 2 cases, with a malignant stricture-like lesion, marked submucosal fibrosis and cholesterol emboli were present. No malignancy was identified on follow-up in any patient (mean 39.9 mo). Follow-up colonoscopy was performed in 7 patients 1 to 32 weeks after initial presentation and showed resolution of the mass in all cases. Awareness of this rare variant of ischemic colitis will prevent unnecessary resections in these patients. PMID- 26034866 TI - Ipilimumab-associated Hepatitis: Clinicopathologic Characterization in a Series of 11 Cases. AB - Ipilimumab is a monoclonal antibody that inhibits the CTLA4 receptor on cytotoxic T lymphocytes, resulting in immune-mediated tumor cell death. Ipilimumab is most often used in the treatment of metastatic melanoma, and rarely liver toxicity necessitating cessation of treatment occurs. The aim of this study was to characterize the histologic features and clinical course of ipilimumab-associated hepatitis. Eleven patients with clinical suspicion of ipilimumab-induced hepatitis, due to the development of abnormal liver function tests (LFTs) while receiving treatment, and who underwent liver biopsy, were identified over a 6 year period. Ten patients were male and 1 female (median age 58 y), and all received 1 to 4 doses of ipilimumab. None had known preexisting liver disease. Two patients were obese, and another had a history of alcohol abuse. Viral and autoimmune serologies were negative in all patients except 1 who had a mildly elevated ANA titer. Nine biopsies showed active hepatitis with 2 distinct histologic patterns: panlobular hepatitis in 6 cases and zone 3 hepatitis in 3. The inflammatory infiltrate was similar in composition in both patterns, composed predominantly of CD8+ T lymphocytes, admixed histiocytes, scattered plasma cells, and eosinophils. Prominent histiocytic sinusoidal infiltrates were present in 7 cases and frequently formed loose histiocytic aggregates. Central vein endothelialitis was present in 8 cases. Patients in this group tended to have markedly elevated ALT, AST, and total bilirubin. Two cases did not fit into the above 2 histologic groups: 1 showed portal inflammation with cholangitis, and the other showed morphologic features indistinguishable from nonalcoholic steatohepatitis. Discontinuation of ipilimumab and administration of immunosuppressives resulted in resolution or marked improvement of LFTs in all patients within 3 months of presentation. Ipilimumab may potentially unmask previously subclinical liver disease, for example, fatty liver disease, and the diagnosis of ipilimumab-induced liver injury may only be recognized with certainty after cessation of the drug leads to normalization of LFTs. Overall, ipilimumab-associated hepatitis most often presents with a panlobular active hepatitis that resembles autoimmune hepatitis. Prominent sinusoidal histiocytic infiltrates and central vein damage with endothelialitis may be helpful histologic clues to the diagnosis of ipilimumab-associated hepatitis. PMID- 26034867 TI - Skin Involvement of Mantle Cell Lymphoma May Mimic Primary Cutaneous Diffuse Large B-cell Lymphoma, Leg Type. AB - Mantle cell lymphoma (MCL) is a B-cell neoplasm with a variable and generally aggressive clinical course. So far our knowledge of skin involvement of MCL is limited. To understand the clinical and histopathologic features of MCL with skin involvement, the files of the Lymph Node Registry Kiel were screened for MCL diagnosed in the skin. Over a period of 13 years, 1321 biopsy specimens were diagnosed as MCL; among them, 14 patients (1%) showed skin involvement. Of these, skin was the initial site of manifestation in 6/11 (55%) cases. One patient presented with a skin-limited lymphoma. Furthermore, 7/12 (58%) patients presented with lesions on the leg. The lymphomas were highly proliferative with blastoid cytology in 12/14 (86%) cases. Moreover, the immunophenotype with expression of BCL2 (100%), MUM-1/IRF4 (83%), and IgM (82%) and lack of CD10 (25%) and BCL6 (0%) closely resembled the features of primary cutaneous diffuse large B cell lymphoma, leg type. Solely the expression of cyclin D1 (100%) and the presence of t(11;14) (100%) allowed a distinction from cases of primary cutaneous diffuse large B-cell lymphoma, leg type. Only 2 MCL cases with skin involvement presented with classical cytology. Interestingly, in these 2 cases skin involvement occurred simultaneously in a lesion of coexisting primary cutaneous marginal zone lymphoma. Our data suggest that clinical presentation on the leg and blastoid cytology along with high proliferation and expression of Bcl2, Mum 1/IRF4, and IgM are typical for MCL involving the skin. Lymphomas with these features might be erroneously diagnosed as diffuse large B-cell lymphoma, leg type, if cyclin D1 staining is not performed. PMID- 26034868 TI - Nuclear Localization of beta-Catenin in Sertoli Cell Tumors and Other Sex Cord Stromal Tumors of the Testis: An Immunohistochemical Study of 87 Cases. AB - The diagnosis and subclassification of Sertoli cell tumors (SCT) of the testis are often challenging to general surgical pathologists because of the rarity of the tumors. Immunohistochemical study to date has limited diagnostic value. Nuclear localization of beta-catenin, which correlated closely with CTNNB1 gene mutation, was recently reported in SCTs. We investigated the utility of beta catenin nuclear localization in diagnosing SCTs and differentiating them from other testicular sex cord-stromal tumors. Immunohistochemical staining for beta catenin was evaluated in 87 cases of testicular sex cord-stromal tumor: 33 SCTs, not otherwise specified (SCT-NOS) (15 with benign and 18 with malignant features), 10 sclerosing SCTs (SSCT), 5 large cell calcifying SCTs (LCCSCT), 6 Sertoli-stromal cell tumors, 10 Leydig cell tumors, 7 juvenile granulosa cell tumors, 4 adult granulosa cell tumors, and 12 sex cord-stromal tumors, unclassified. Twenty-one of 33 (64%) SCT-NOS, 6 of 10 (60%) SSCTs, and 4 of 6 (67%) Sertoli-stromal cell tumors showed strong, diffuse beta-catenin nuclear staining. Nuclear beta-catenin positivity was more frequent in SCTs-NOS with benign features than in those with malignant features (93% and 39%, respectively, P=0.13) and, in the Sertoli-stromal cell tumors, occurred only in the Sertoli component. All 5 LCCSCTs and all other types of sex cord-stromal tumor were negative for beta-catenin nuclear staining. In conclusion, SCT-NOS and SSCT frequently show beta-catenin nuclear localization. Positive nuclear staining of beta-catenin is specific for SCT-NOS, SSCT, and Sertoli-stromal cell tumor among testicular sex cord-stromal tumors but has limited sensitivity (63%) in this group. The similar reactivity of SCT-NOS and SSCT provides additional support that these 2 variants are not distinct entities. PMID- 26034870 TI - Judicial bypass of parental consent for abortion: characteristics of pregnant minor "Jane Doe's". AB - Pregnant minors can obtain an abortion without parental consent through a judicial bypass procedure in 38 states. To grant such a petition in Ohio, the Court must determine that the young woman is either "sufficiently mature and well enough informed to intelligently decide whether to have an abortion," or that notification of her parents is "not in her best interest," usually due to abuse. For the sake of anonymity in these emotionally and politically charged cases, the evaluee is referred to as "Jane Doe." This project sought to describe characteristics of teenagers seeking judicial bypass for abortion, which have not been well described in the scientific literature. Data were collected from Jane Doe evaluations completed at a metropolitan juvenile court psychiatric clinic, over 3 years. The mean age of the evaluees (N = 55) was 16.4 years. The vast majority (95%) were granted a judicial bypass. They usually had long-term boyfriends of comparable age. They had often told trusted adults about their pregnancy, though not their parents, due to concerns of violence or being excluded from the family. This study presents the first comprehensive description of characteristics of minors seeking judicial bypasses for abortion. Psychiatrists may apply general principles of informed consent in such evaluations, including ascertaining whether the decision is being made voluntarily, knowingly, and with sufficient decision-making capacity. PMID- 26034869 TI - Adamantinoma-like Ewing family tumors of the head and neck: a pitfall in the differential diagnosis of basaloid and myoepithelial carcinomas. AB - Ewing sarcoma family tumors (EFTs) of the head and neck are rare and may be difficult to diagnose, as they display significant histologic overlap with other more common undifferentiated small blue round cell malignancies. Occasionally, EFTs may exhibit overt epithelial differentiation in the form of diffuse cytokeratin immunoexpression or squamous pearls, resembling the so-called adamantinoma-like EFTs and being challenging to distinguish from bona fide carcinomas. Furthermore, the presence of EWSR1 gene rearrangement correlated with strong keratin expression may suggest a myoepithelial carcinoma. Herein, we analyze a series of 7 adamantinoma-like EFTs of the head and neck, most of them being initially misdiagnosed as carcinomas because of their anatomic location and strong cytokeratin immunoexpression, and subsequently reclassified as EFT by molecular techniques. The tumors arose in the sinonasal tract (n=2), parotid gland (n=2), thyroid gland (n=2), and orbit (n=1), in patients ranging in age from 7 to 56 years (mean, 31 y). Microscopically, they departed from the typical EFT morphology by growing as nests with peripheral nuclear palisading and prominent interlobular fibrosis, imparting a distinctly basaloid appearance. Moreover, 2 cases exhibited overt keratinization in the form of squamous pearls, and 1 sinonasal tumor demonstrated areas of intraepithelial growth. All cases were positive for CD99, pancytokeratin, and p40. A subset of cases showed synaptophysin, S100 protein, and/or p16 reactivity, further confounding the diagnosis. Fluorescence in situ hybridization assays showed EWSR1 and FLI1 rearrangements in all cases. Our results reinforce that a subset of head and neck EFTs may show strong cytokeratin expression or focal keratinization, and are therefore histologically indistinguishable from more common true epithelial neoplasms. Thus, CD99 should be included in the immunopanel of a round cell malignancy regardless of strong cytokeratin expression or anatomic location, and a strong and diffuse CD99 positivity should prompt molecular testing for the presence of EWSR1 gene rearrangements. PMID- 26034871 TI - The symptoms of posttraumatic stress disorder and depression among adult earthquake survivors in China. AB - The objective of the study was to examine the relationships between mental health conditions (posttraumatic stress disorder [PTSD] only, depression only, and PTSD and depression) and related factors. A cross-sectional survey was conducted among 1362 adults from two severely affected townships at 6 months after the earthquake. The results of the analyses showed that the prevalence of depression and PTSD were 31.4% and 22.1%, respectively, 6 months after the earthquake. When PTSD and depression were treated as two separate dependent variables, PTSD and depression share almost similar sets of predictive factors. After its four categories (none, PTSD only, depression only, and PTSD and depression) were used as categorical dependent variables, there are different predictive factors. The findings suggest that there are two different groups of individuals, those who develop depression only in response to earthquake exposure and those who develop both depression and PTSD. PMID- 26034872 TI - Cigarette smoking and interest in quitting among overweight and obese adults with serious mental illness enrolled in a fitness intervention. AB - This study explored cigarette smoking, health status, and interest in quitting among overweight and obese adults with serious mental illness enrolled in a fitness intervention. Baseline data from two studies of the In SHAPE fitness intervention were combined. A total of 341 overweight or obese adults with serious mental illness were assessed on smoking, interest in quitting, cardiovascular fitness, lipids, body mass index, readiness to change diet, and psychiatric symptoms. Thirty-six percent (n = 122) of participants were categorized as current smokers. The majority of smokers (84%) were interested in quitting. Smokers were more likely to be younger, male, and less educated than non-smokers. Smokers had lower high-density lipoprotein cholesterol and were less ready to reduce dietary fat, after adjusting for age, gender, and education. Findings highlight the potential to address both fitness and smoking to reduce cardiovascular risk in individuals with serious mental illness. PMID- 26034873 TI - Paranoid delusional disorder follows social anxiety disorder in a long-term case series: evolutionary perspective. AB - Social anxiety disorder (SAD) patients may have self-referential ideas and share other cognitive processes with paranoid delusional disorder (PDD) patients. From an evolutionary perspective, SAD may derive from biologically instinctive social hierarchy ranking, thus causing an assumption of inferior social rank, and thus prompting concerns about mistreatment from those of perceived higher rank. This naturalistic longitudinal study followed four patients with initial SAD and later onset of PDD. These four patients show the same sequence of diagnosed SAD followed by diagnosed PDD, as is often retrospectively described by other PDD patients. Although antipsychotic medication improved psychotic symptoms in all patients, those who also had adjunctive serotonin-specific reuptake inhibitors for SAD had much more improvement in both psychosis and social functioning. From an evolutionary perspective, it can be conjectured that when conscious modulation of the SAD social rank instinct is diminished due to hypofrontality (common to many psychotic disorders), then unmodulated SAD can lead to paranoid delusional disorder, with prominent ideas of reference. Non-psychotic SAD may be prodromal or causal for PDD. PMID- 26034874 TI - Controversies about the use of antidepressants in pregnancy: response to Dr. Casper, Dr. Osborne, and Dr. Payne. PMID- 26034875 TI - Comment on The dangers of gastritis: a case of clarithromycin-associated brief psychotic episode. PMID- 26034876 TI - State of the Science: Taxane-Induced Musculoskeletal Pain. AB - BACKGROUND: Cancer survival rates are improving, but this increased survivorship is offset by persistent treatment-related symptoms. Taxane-induced musculoskeletal pain (TIMP) is 1 treatment-related symptom likely undermining cancer survivors' health-related quality of life. OBJECTIVE: The specific aims of this review were to evaluate (1) the conceptual clarity of TIMP, (2) descriptions of the TIMP symptom experience, (3) contextual variables influencing TIMP, and (4) the impact of TIMP on selected outcomes. METHODS: A systematic approach conducted in PubMed yielded 688 articles, and 12 articles included evaluable data related to TIMP. RESULTS: On average, 2 to 4 terms signifying TIMP were used; among the terms arthralgia, myalgia, and bone pain, the range of TIMP prevalence estimates varied from 1.3% to 94%. Intensity was measured in all studies, most commonly (50% of studies) using the National Cancer Institute Common Toxicity Criteria. Contextual variables and the impact of TIMP on outcomes were addressed in only 17% and 42% of studies, respectively. CONCLUSIONS: Research to date has involved inconsistent use of terms signifying TIMP. Assessment of TIMP has been largely limited to intensity, with few studies evaluating contextual variables influencing TIMP or the impact of TIMP on outcomes. More comprehensive TIMP assessment is necessary in future research. IMPLICATIONS FOR PRACTICE: In order to improve patient-reported outcomes in cancer care, control of treatment-related symptoms is essential. Further research about TIMP will address national priorities for generating new knowledge to advance symptom science and will be directly relevant to the care of cancer survivors undergoing taxane-based chemotherapy. PMID- 26034877 TI - Canadian Nurses' Perspectives on Prostate Cancer Support Groups: A Survey Study. AB - BACKGROUND: Prostate cancer support groups (PCSGs) are community-based organizations that offer information and psychosocial support to men who experience prostate cancer and their families. Nurses are well positioned to refer men to a range of psychosocial resources to help them adjust to prostate cancer; however, little is known about nurses' perspectives on PCSGs. OBJECTIVE: The aim of this study was to describe nurses' views about PCSGs as a means to making recommendations for advancing the effectiveness of PCSGs. METHODS: A convenience sample of 101 Canadian nurses completed a 43-item Likert-scale questionnaire with the additional option of providing comments in response to an open-ended question. Univariate descriptive statistics and content analysis were used to analyze the quantitative and qualitative data, respectively. RESULTS: Participants held positive views about the roles and potential impact of PCSGs. Participants strongly endorsed the benefits of support groups in disseminating information and providing support to help decrease patient anxiety. Online support groups were endorsed as a practical alternative for men who are reluctant to participate in face-to-face groups. CONCLUSIONS: Findings suggest that nurses support the value of Canadian face-to-face and online PCSGs. This is important, given that nurses can help connect individual patients to community-based sources providing psychosocial support. IMPLICATIONS FOR PRACTICE: Many men benefit from participating in PCSGs. Aside from positively endorsing the work of PCSGs, nurses are important partners for raising awareness of these groups among potential attendees and can directly contribute to information sharing in face-to-face and online PCSGs. PMID- 26034878 TI - Integrin alpha4 is involved in the regulation of glioma-induced motility of bone marrow mesenchymal stem cells. AB - Bone marrow mesenchymal stem cells (BMSCs) have the ability of migrating towards glioma tissue. However, this migratory behavior remains to be elucidated. The aim of this study was to define the role of integrin alpha4 in the motility of BMSCs towards glioma. The role of integrin alpha4 in the migration of BMSCs towards glioma was evaluated using an in vitro migration assay with the application of a specific integrin alpha4-blocking antibody. The effect of glioma conditioned medium (CM) on the integrin alpha4 expression level of BMSCs was assessed by RT PCR, immunocytochemistry and western blot analysis. BAY11-7082, LY294002, SB203580, PD98059 and SP600125 were used to investigate the role of NF-kappaB, PI3K, p38 MAPK, MEK and JNK in the above process. In addition, the role of NF kappaB in the tropism of BMSCs towards glioma was also evaluated using the in vitro model. The migration of BMSCs towards glioma CM was attenuated by blocking integrin alpha4. The stimulation of glioma CM increased integrin alpha4 expression of BMSCs. Furthermore, the inhibition of NF-kappaB and PI3K decreased the glioma-induced integrin alpha4 upregulation on BMSCs. Inhibition of NF-kappaB decreased the number of migrating BMSCs towards gliomas. Glioma cells induced the migration of BMSCs by promoting the expression of integrin alpha4. NF-kappaB and PI3K contributed to the signal transduction of this process. Similar to PI3K, NF kappaB is associated with the regulation of BMSCs migration toward glioma. Thus, these results may be useful to elucidate the mechanism involved in the glioma induced migration of BMSCs. PMID- 26034879 TI - Life Cycle Payback Estimates of Nanosilver Enabled Textiles under Different Silver Loading, Release, And Laundering Scenarios Informed by Literature Review. AB - Silver was utilized throughout history to prevent the growth of bacteria in food and wounds. Recently, nanoscale silver has been applied to consumer textiles (nAg textiles) to eliminate the prevalence of odor-causing bacteria. In turn, it is proposed that consumers will launder these items less frequently thus, reducing the life cycle impacts. While previous studies report that laundering processes are associated with the greatest environmental impacts of these textiles, there is no data available to support the proposed shift in consumer laundering behavior. Here, the results from a comprehensive literature review of nAg-textile life cycle studies are used to inform a cradle-to-grave life cycle impact assessment. Rather than assuming shifts in consumer behavior, the impact assessment is conducted in such a way that considers all laundering scenarios to elucidate the potential for reduced laundering to enable realization of a net life cycle benefit. In addition to identifying the most impactful stages of the life cycle across nine-midpoint categories, a payback period and uncertainty analysis quantifies the reduction in lifetime launderings required to recover the impacts associated with nanoenabling the textile. Reduction of nAg-textile life cycle impacts is not straightforward and depends on the impact category considered. PMID- 26034880 TI - Phase 1 Safety, Pharmacokinetics, and Pharmacodynamics of Dapivirine and Maraviroc Vaginal Rings: A Double-Blind Randomized Trial. AB - BACKGROUND: Variable adherence limits effectiveness of daily oral and intravaginal tenofovir-containing pre-exposure prophylaxis. Monthly vaginal antiretroviral rings are one approach to improve adherence and drug delivery. METHODS: MTN-013/IPM 026, a multisite, double-blind, randomized, placebo controlled trial in 48 HIV-negative US women, evaluated vaginal rings containing dapivirine (DPV) (25 mg) and maraviroc (MVC) (100 mg), DPV only, MVC only, and placebo used continuously for 28 days. Safety was assessed by adverse events. Drug concentrations were quantified in plasma, cervicovaginal fluid (CVF), and cervical tissue. Cervical biopsy explants were challenged with HIV ex vivo to evaluate pharmacodynamics. RESULTS: There was no difference in related genitourinary adverse events between treatment arms compared with placebo. DPV and MVC concentrations rose higher initially before falling more rapidly with the combination ring compared with relatively stable concentrations with the single drug rings. DPV concentrations in CVF were 1 and 5 log10 greater than cervical tissue and plasma for both rings. MVC was consistently detected only in CVF. DPV and MVC CVF and DPV tissue concentrations dropped rapidly after ring removal. Cervical tissue showed a significant inverse linear relationship between HIV replication and DPV levels. CONCLUSIONS: In this first study of a combination microbicide vaginal ring, all 4 rings were safe and well tolerated. Tissue DPV concentrations were 1000 times greater than plasma concentrations and single drug rings had more stable pharmacokinetics. DPV, but not MVC, demonstrated concentration-dependent inhibition of HIV-1 infection in cervical tissue. Because MVC concentrations were consistently detectable only in CVF and not in plasma, improved drug release of MVC rings is needed. PMID- 26034881 TI - Tissue Distribution, Excretion and Pharmacokinetics of the Environmental Pollutant Dibenzo[def,p]chrysene in Mice. AB - Dibenzo[def,p]chrysene (DBP), a representative example of the class of polycyclic aromatic hydrocarbon (PAH), is known to induce tumors in multiple organ sites including the ovary, lung, mammary glands, and oral cavity in rodents. The goal of this study was to test the hypothesis that the levels of DBP and its metabolites that reach and retain the levels for an extended time in the target organs as well as the capacity of these organs to metabolize this carcinogen to active metabolites that can damage DNA may account for its tissue selective tumorigenicity. Therefore, we used the radiolabeled [(3)H] DBP to accurately assess the tissue distribution, excretion, and pharmacokinetics of this carcinogen. We also compared the levels of DBPDE-DNA adducts in a select target organ (ovary) and nontarget organs (kidney and liver) in mice treated orally with DBP. Our results showed that after 1 week, 91.40 +/- 7.23% of the radioactivity was recovered in the feces; the corresponding value excreted in the urine was less than 2% after 1 week. After 24 h, the stomach had the highest radioactivity followed by the intestine and the liver; however, after 1 week, levels of the radioactivity in these organs were the lowest among tissues examined including the ovary and liver; the pharmacokinetic analysis of DBP was conducted using a one compartment open model. The level of (-)-anti-trans-DBPDE-dA in the ovaries (8.91 +/- 0.08 adducts/10(7) dA) was significantly higher (p < 0.01) than the levels of adducts in kidneys (0.69 +/- 0.09 adducts/10(7) dA) and livers (0.63 +/ 0.11 adducts/10(7) dA). Collectively, the results of the tissue distribution and pharmacokinetic analysis may not fully support our hypothesis, but the capacity of the target organs vs nontarget organs to metabolize DBP to active intermediates that can damage DNA may account for its tissue selective tumorigenicity. PMID- 26034882 TI - The influence of performance level, age and gender on pacing strategy during a 100-km ultramarathon. AB - The aim of this study is to analyse the influence of performance level, age and gender on pacing during a 100-km ultramarathon. Results of a 100-km race incorporating the World Masters Championships were used to identify differences in relative speeds in each 10-km segment between participants finishing in the first, second, third and fourth quartiles of overall positions (Groups 1, 2, 3 and 4, respectively). Similar analyses were performed between the top and bottom 50% of finishers in each age category, as well as within male and female categories. Pacing varied between athletes achieving different absolute performance levels. Group 1 ran at significantly lower relative speeds than all other groups in the first three 10-km segments (all P < 0.01), and significantly higher relative speeds than Group 4 in the 6th and 10th (both P < 0.01), and Group 2 in the 8th (P = 0.04). Group 4 displayed significantly higher relative speeds than Group 2 and 3 in the first three segments (all P < 0.01). Overall strategies remained consistent across age categories, although a similar phenomenon was observed within each category whereby 'top' competitors displayed lower relative speeds than 'bottom' competitors in the early stages, but higher relative speeds in the later stages. Females showed lower relative starting speeds and higher finishing speeds than males. 'Top' and 'bottom' finishing males displayed differing strategies, but this was not the case within females. Although pacing remained consistent across age categories, it differed with level of performance within each, possibly suggesting strategies are anchored on direct competitors. Strategy differs between genders and differs depending on performance level achieved in males but not females. PMID- 26034883 TI - Treatment of Silk Fibroin with Poly(ethylene glycol) for the Enhancement of Corneal Epithelial Cell Growth. AB - A silk protein, fibroin, was isolated from the cocoons of the domesticated silkworm (Bombyx mori) and cast into membranes to serve as freestanding templates for tissue-engineered corneal cell constructs to be used in ocular surface reconstruction. In this study, we sought to enhance the attachment and proliferation of corneal epithelial cells by increasing the permeability of the fibroin membranes and the topographic roughness of their surface. By mixing the fibroin solution with poly(ethylene glycol) (PEG) of molecular weight 300 Da, membranes were produced with increased permeability and with topographic patterns generated on their surface. In order to enhance their mechanical stability, some PEG-treated membranes were also crosslinked with genipin. The resulting membranes were thoroughly characterized and compared to the non-treated membranes. The PEG treated membranes were similar in tensile strength to the non-treated ones, but their elastic modulus was higher and elongation lower, indicating enhanced rigidity. The crosslinking with genipin did not induce a significant improvement in mechanical properties. In cultures of a human-derived corneal epithelial cell line (HCE-T), the PEG treatment of the substratum did not improve the attachment of cells and it enhanced only slightly the cell proliferation in the longer term. Likewise, primary cultures of human limbal epithelial cells grew equally well on both non-treated and PEG-treated membranes, and the stratification of cultures was consistently improved in the presence of an underlying culture of irradiated 3T3 feeder cells, irrespectively of PEG-treatment. Nevertheless, the cultures grown on the PEG-treated membranes in the presence of feeder cells did display a higher nuclear-to-cytoplasmic ratio suggesting a more proliferative phenotype. We concluded that while the treatment with PEG had a significant effect on some structural properties of the B. mori silk fibroin (BMSF) membranes, there were minimal gains in the performance of these materials as a substratum for corneal epithelial cell growth. The reduced mechanical stability of freestanding PEG treated membranes makes them a less viable choice than the non-treated membranes. PMID- 26034884 TI - Biomimetic Hybrid Nanofiber Sheets Composed of RGD Peptide-Decorated PLGA as Cell Adhesive Substrates. AB - In biomedical applications, there is a need for tissue engineering scaffolds to promote and control cellular behaviors, including adhesion, proliferation and differentiation. In particular, the initial adhesion of cells has a great influence on those cellular behaviors. In this study, we concentrate on developing cell-adhesive substrates applicable for tissue engineering scaffolds. The hybrid nanofiber sheets were prepared by electrospinning poly(lactic-co glycolic acid) (PLGA) and M13 phage, which was genetically modified to enhance cell adhesion thru expressing RGD peptides on their surface. The RGD peptide is a specific motif of extracellular matrix (ECM) for integrin receptors of cells. RGD peptide-decorated PLGA (RGD-PLGA) nanofiber sheets were characterized by scanning electron microscopy, immunofluorescence staining, contact angle measurement and differential scanning calorimetry. In addition, the initial adhesion and proliferation of four different types of mammalian cells were determined in order to evaluate the potential of RGD-PLGA nanofiber sheets as cell-adhesive substrates. Our results showed that the hybrid nanofiber sheets have a three dimensional porous structure comparable to the native ECM. Furthermore, the initial adhesion and proliferation of cells were significantly enhanced on RGD PLGA sheets. These results suggest that biomimetic RGD-PLGA nanofiber sheets can be promising cell-adhesive substrates for application as tissue engineering scaffolds. PMID- 26034885 TI - Antibacterial Labdane Diterpenoids from Vitex vestita. AB - A large-scale in vitro screening of tropical plants using an antibacterial assay permitted the selection of several species with significant antibacterial activities. Bioassay-guided purification of the dichloromethane extract of the leaves of the Malaysian species Vitex vestita, led to the isolation of six new labdane-type diterpenoids, namely, 12-epivitexolide A (2), vitexolides B and C (3 and 4), vitexolide E (8), and vitexolins A and B (5 and 6), along with six known compounds, vitexolides A (1) and D (7), acuminolide (9), 3beta-hydroxyanticopalic acid (10), 8alpha-hydroxyanticopalic acid (11), and 6alpha-hydroxyanticopalic acid (12). Their structures were elucidated on the basis of 1D and 2D NMR analyses and HRMS experiments. Both variable-temperature NMR spectroscopic studies and chemical modifications were performed to investigate the dynamic epimerization of the gamma-hydroxybutenolide moiety of compounds 1-4. Compounds were assayed against a panel of 46 Gram-positive strains. Vitexolide A (1) exhibited the most potent antibacterial activity with minimal inhibitory concentration values ranging from 6 to 96 MUM, whereas compounds 2 and 6-9 showed moderate antibacterial activity. The presence of a beta-hydroxyalkyl-gamma hydroxybutenolide subunit contributed significantly to antibacterial activity. Compounds 1-4 and 6-9 showed cytotoxic activities against the HCT-116 cancer cell line (1 < IC50s < 10 MUM) and human fetal lung fibroblast MRC5 cell line (1 < IC50s < 10 MUM for compounds 1, 2, 7, 8, and 9). PMID- 26034887 TI - It seems like only yesterday. AB - I spent my childhood and adolescence in North and South Carolina, attended Duke University, and then entered Duke Medical School. One year in the laboratory of George Schwert in the biochemistry department kindled my interest in biochemistry. After one year of residency on the medical service of Duke Hospital, chaired by Eugene Stead, I joined the group of Arthur Kornberg at Stanford Medical School as a postdoctoral fellow. Two years later I accepted a faculty position at Harvard Medical School, where I remain today. During these 50 years, together with an outstanding group of students, postdoctoral fellows, and collaborators, I have pursued studies on DNA replication. I have experienced the excitement of discovering a number of important enzymes in DNA replication that, in turn, triggered an interest in the dynamics of a replisome. My associations with industry have been stimulating and fostered new friendships. I could not have chosen a better career. PMID- 26034888 TI - The Balbiani Ring Story: Synthesis, Assembly, Processing, and Transport of Specific Messenger RNA-Protein Complexes. AB - Eukaryotic gene expression is the result of the integrated action of multimolecular machineries. These machineries associate with gene transcripts, often already nascent precursor messenger RNAs (pre-mRNAs). They rebuild the transcript and convey properties allowing the processed transcript, the mRNA, to be exported to the cytoplasm, quality controlled, stored, translated, and degraded. To understand these integrated processes, one must understand the temporal and spatial aspects of the fate of the gene transcripts in relation to interacting molecular machineries. Improved methodology is necessary to study gene expression in vivo for endogenous genes. A complementary approach is to study biological systems that provide exceptional experimental possibilities. We describe such a system, the Balbiani ring (BR) genes in polytene cells in the dipteran Chironomus tentans. The BR genes, along with their pre-mRNA-protein complexes (pre-mRNPs) and mRNA-protein complexes (mRNPs), allow the visualization of intact cell nuclei and enable analyses of where and when different molecular machineries associate with and act on the BR pre-mRNAs and mRNAs. PMID- 26034886 TI - Fatal H5N6 Avian Influenza Virus Infection in a Domestic Cat and Wild Birds in China. AB - H5N6 avian influenza viruses (AIVs) may pose a potential human risk as suggested by the first documented naturally-acquired human H5N6 virus infection in 2014. Here, we report the first cases of fatal H5N6 avian influenza virus (AIV) infection in a domestic cat and wild birds. These cases followed human H5N6 infections in China and preceded an H5N6 outbreak in chickens. The extensive migration routes of wild birds may contribute to the geographic spread of H5N6 AIVs and pose a risk to humans and susceptible domesticated animals, and the H5N6 AIVs may spread from southern China to northern China by wild birds. Additional surveillance is required to better understand the threat of zoonotic transmission of AIVs. PMID- 26034889 TI - Regulation of alternative splicing through coupling with transcription and chromatin structure. AB - Alternative precursor messenger RNA (pre-mRNA) splicing plays a pivotal role in the flow of genetic information from DNA to proteins by expanding the coding capacity of genomes. Regulation of alternative splicing is as important as regulation of transcription to determine cell- and tissue-specific features, normal cell functioning, and responses of eukaryotic cells to external cues. Its importance is confirmed by the evolutionary conservation and diversification of alternative splicing and the fact that its deregulation causes hereditary disease and cancer. This review discusses the multiple layers of cotranscriptional regulation of alternative splicing in which chromatin structure, DNA methylation, histone marks, and nucleosome positioning play a fundamental role in providing a dynamic scaffold for interactions between the splicing and transcription machineries. We focus on evidence for how the kinetics of RNA polymerase II (RNAPII) elongation and the recruitment of splicing factors and adaptor proteins to chromatin components act in coordination to regulate alternative splicing. PMID- 26034890 TI - Mechanisms of Methicillin Resistance in Staphylococcus aureus. AB - Staphylococcus aureus is a major human and veterinary pathogen worldwide. Methicillin-resistant S. aureus (MRSA) poses a significant and enduring problem to the treatment of infection by such strains. Resistance is usually conferred by the acquisition of a nonnative gene encoding a penicillin-binding protein (PBP2a), with significantly lower affinity for beta-lactams. This resistance allows cell-wall biosynthesis, the target of beta-lactams, to continue even in the presence of typically inhibitory concentrations of antibiotic. PBP2a is encoded by the mecA gene, which is carried on a distinct mobile genetic element (SCCmec), the expression of which is controlled through a proteolytic signal transduction pathway comprising a sensor protein (MecR1) and a repressor (MecI). Many of the molecular and biochemical mechanisms underlying methicillin resistance in S. aureus have been elucidated, including regulatory events and the structure of key proteins. Here we review recent advances in this area. PMID- 26034891 TI - Structural Biology of Bacterial Type IV Secretion Systems. AB - Type IV secretion systems (T4SSs) are large multisubunit translocons, found in both gram-negative and gram-positive bacteria and in some archaea. These systems transport a diverse array of substrates from DNA and protein-DNA complexes to proteins, and play fundamental roles in both bacterial pathogenesis and bacterial adaptation to the cellular milieu in which bacteria live. This review describes the various biochemical and structural advances made toward understanding the biogenesis, architecture, and function of T4SSs. PMID- 26034892 TI - Gating mechanisms of voltage-gated proton channels. AB - Hv1 is a voltage-gated proton-selective channel that plays critical parts in host defense, sperm motility, and cancer progression. Hv1 contains a conserved voltage sensor domain (VSD) that is shared by a large family of voltage-gated ion channels, but it lacks a pore domain. Voltage sensitivity and proton conductivity are conferred by a unitary VSD that consists of four transmembrane helices. The architecture of Hv1 differs from that of cation channels that form a pore in the center among multiple subunits (as in most cation channels) or homologous repeats (as in voltage-gated sodium and calcium channels). Hv1 forms a dimer in which a cytoplasmic coiled coil underpins the two protomers and forms a single, long helix that is contiguous with S4, the transmembrane voltage-sensing segment. The closed-state structure of Hv1 was recently solved using X-ray crystallography. In this article, we discuss the gating mechanism of Hv1 and focus on cooperativity within dimers and their sensitivity to metal ions. PMID- 26034895 TI - Therapeutic Drug Monitoring of Mycophenolic Acid in Lupus Nephritis: A Review of Current Literature. AB - In recent years, mycophenolate mofetil (MMF)-based immunosuppressive regimen was recommended in induction and in maintenance therapy in lupus nephritis (LN), one of the most severe and common manifestations of systemic lupus erythematosus. However, no recommendations were made so far regarding monitoring of mycophenolic acid (MPA) plasma concentrations. Therapeutic drug monitoring (TDM) constitutes a practical tool to ensure optimal posology. In renal transplantation, it was proved that acute allograft rejection incidences decreased when the recommended MPA target exposure has been maintained (30-60 mg.h.L). The results obtained in the field of transplant medicine indicate the potential benefit of carrying out TDM in LN. To date, the correlation of MPA exposure and clinical outcomes in the population of LN patients was the objective of just a few studies. The aim of this review was therefore to present TDM studies in LN patients on MMF therapy and to compare their results. Based on the conclusions drawn from TDM studies in LN, it can be suggested that the area under the concentration-time curve threshold values of 30-45 mg.h.L can potentially be associated with favorable treatment outcome. Moreover, the majority of the analyzed studies indicate relatively good correlation between trough concentration and the area under the concentration-time curve in patients treated with MMF that constitutes an important implication for TDM approach in routine setting. The threshold of 3 mg/L can potentially be recommended as a target trough value. PMID- 26034896 TI - Identification and analysis of the resorcinomycin biosynthetic gene cluster. AB - Resorcinomycin (1) is composed of a nonproteinogenic amino acid, (S)-2-(3,5 dihydroxy-4-isopropylphenyl)-2-guanidinoacetic acid (2), and glycine. A biosynthetic gene cluster was identified in a genome database of Streptoverticillium roseoverticillatum by searching for orthologs of the genes responsible for biosynthesis of pheganomycin (3), which possesses a (2) derivative at its N-terminus. The cluster contained a gene encoding an ATP-grasp ligase (res5), which was suggested to catalyze the peptide bond formation between 2 and glycine. A res5-deletion mutant lost 1 productivity but accumulated 2 in the culture broth. However, recombinant RES5 did not show catalytic activity to form 1 with 2 and glycine as substrates. Moreover, heterologous expression of the cluster resulted in accumulation of only 2 and no production of 1 was observed. These results suggested that a peptide with glycine at its N-terminus may be used as a nucleophile and then maturated by a peptidase encoded by a gene outside of the cluster. PMID- 26034894 TI - A molecular description of cellulose biosynthesis. AB - Cellulose is the most abundant biopolymer on Earth, and certain organisms from bacteria to plants and animals synthesize cellulose as an extracellular polymer for various biological functions. Humans have used cellulose for millennia as a material and an energy source, and the advent of a lignocellulosic fuel industry will elevate it to the primary carbon source for the burgeoning renewable energy sector. Despite the biological and societal importance of cellulose, the molecular mechanism by which it is synthesized is now only beginning to emerge. On the basis of recent advances in structural and molecular biology on bacterial cellulose synthases, we review emerging concepts of how the enzymes polymerize glucose molecules, how the nascent polymer is transported across the plasma membrane, and how bacterial cellulose biosynthesis is regulated during biofilm formation. Additionally, we review evolutionary commonalities and differences between cellulose synthases that modulate the nature of the cellulose product formed. PMID- 26034893 TI - Chemical approaches to discovery and study of sources and targets of hydrogen peroxide redox signaling through NADPH oxidase proteins. AB - Hydrogen peroxide (H2O2) is a prime member of the reactive oxygen species (ROS) family of molecules produced during normal cell function and in response to various stimuli, but if left unchecked, it can inflict oxidative damage on all types of biological macromolecules and lead to cell death. In this context, a major source of H2O2 for redox signaling purposes is the NADPH oxidase (Nox) family of enzymes, which were classically studied for their roles in phagocytic immune response but have now been found to exist in virtually all mammalian cell types in various isoforms with distinct tissue and subcellular localizations. Downstream of this tightly regulated ROS generation, site-specific, reversible covalent modification of proteins, particularly oxidation of cysteine thiols to sulfenic acids, represents a prominent posttranslational modification akin to phosphorylation as an emerging molecular mechanism for transforming an oxidant signal into a dynamic biological response. We review two complementary types of chemical tools that enable (a) specific detection of H2O2 generated at its sources and (b) mapping of sulfenic acid posttranslational modification targets that mediate its signaling functions, which can be used to study this important chemical signal in biological systems. PMID- 26034898 TI - The Effect of Acute Exercise on Neutrophil Reactive Oxygen Species Production and Inflammatory Markers in Healthy Prepubertal and Adult Males. AB - The adaptive effects of exercise-induced inflammation and reactive oxygen species production has been well studied in adults, but not in children. Characterizing the exercise responses in children compared with adults will start clarifying the transition from the child phenotype to that of an adult. Ten children aged 8-10 and 12 adults aged 19-21 performed 2 * 30-min bouts of continuous cycling, separated by a 6-min rest period, at a target work rate of 60% of their maximum aerobic capacity. Blood samples were collected pre- and immediately postexercise, and analyzed for neutrophil count, systemic oxidative and inflammatory markers, and intracellular neutrophil-derived reactive oxygen species. Although postexercise absolute neutrophils increased by approximately twofold in men (2.72 +/- 0.49 * 109/L to 4.85 +/- 2.05 * 109/L; p = .007), boys showed no such change (3.18 +/- 0.67 * 109/L to 3.57 +/- 0.73 * 109/L; p = .52). Contrary to these findings, boys did show an increase in overall intracellular neutrophil ROS production, whereas men did not. Boys also demonstrated higher overall protein carbonyl levels (0.07 nmol/mg vs 0.04 nmol/mg; boys vs men respectively), whereas men showed higher overall malondialdehyde (0.24 MUM vs 0.67 MUM; boys vs men respectively). The differences observed in the exercise-induced inflammatory and oxidative stress response may indicate growth-mediated adaptive responses to exercise during childhood development. PMID- 26034897 TI - Treatment of multifocal breast cancer by systemic delivery of dual-targeted adeno associated viral vectors. AB - Adeno-associated viral (AAV) vectors yield high potential for clinical gene therapy but, like for other vectors systems, they frequently do not sufficiently transduce the target tissue and their unspecific tropism prevents their application for multifocal diseases such as disseminated cancer. Targeted AAV vectors have been obtained from random AAV display peptide libraries but so far, all vector variants selected from AAV libraries upon systemic administration in vivo retained some collateral tropism, frequently the heart. Here we explored, if this impediment can be overcome by microRNA-regulated transgene cassettes as the combination of library-derived capsid targeting and micro-RNA control has not been evaluated so far. We used a tumor-targeted AAV capsid variant (ESGLSQS) selected from random AAV-display peptide libraries in vivo with remaining off target tropism toward the heart and regulated targeted transgene expression in vivo by complementary target elements for heart-specific microRNA (miRT-1d). Although this vector still maintained its strong transduction capacity for tumor target tissue after intravenous injection, transgene expression in the heart was almost completely abrogated. This strong and completely tumor-specific transgene expression was used for therapeutic gene transfer in an aggressive multifocal, transgenic, polyoma middle T-induced, murine breast cancer model. A therapeutic suicide gene, delivered systemically by this dual-targeted AAV vector to multifocal breast cancer, significantly inhibited tumor growth after one single vector administration while avoiding side effects compared with untargeted vectors. PMID- 26034899 TI - Mini Vortex Mixer: A Simple Way to Prevent Sculptra Needle Clogging. PMID- 26034900 TI - Understanding the Economic Value of Plastic Surgery to a Health Care System. PMID- 26034901 TI - Cell Phones Can Be Hazardous to Your Free Flap: Fact or Myth? PMID- 26034902 TI - Does Combining Abdominoplasty and Liposuction Really Increase the Risk of Venous Thromboembolism? PMID- 26034903 TI - Minimally Invasive Breast Augmentation: Where Is the Evidence? PMID- 26034904 TI - ? PMID- 26034906 TI - Critically appraising noninferiority randomized controlled trials: a primer for emergency physicians. AB - Noninferiority (NI) trials aim to show that a new treatment or drug is not inferior to a standard, accepted treatment. The rapid proliferation of NI trials within the literature makes it imperative for emergency physicians to be able to read, interpret, and appraise critically this type of research study. Using several emergency medicine examples from the recent literature, this article outlines the key differences between traditional, superiority randomized controlled trials and NI trials. We summarize four important points that an emergency physician should consider when critically appraising an NI trial: 1) Does the new treatment have tangible benefits over the standard treatment? 2) Was the choice of the NI margin appropriate? 3) Was the effect of the standard treatment preserved? Does the trial have assay sensitivity? and 4) What type of analysis strategy was employed: intention-to-treat (ITT) or per protocol (PP)? PMID- 26034907 TI - A note on non-inferiority margins. PMID- 26034905 TI - TFH cells accumulate in mucosal tissues of humanized-DRAG mice and are highly permissive to HIV-1. AB - CD4(+) T follicular helper cells (TFH) in germinal centers are required for maturation of B-cells. While the role of TFH-cells has been studied in blood and lymph nodes of HIV-1 infected individuals, its role in the mucosal tissues has not been investigated. We show that the gut and female reproductive tract (FRT) of humanized DRAG mice have a high level of human lymphocytes and a high frequency of TFH (CXCR5(+)PD-1(++)) and precursor-TFH (CXCR5(+)PD-1(+)) cells. The majority of TFH-cells expressed CCR5 and CXCR3 and are the most permissive to HIV-1 infection. A single low-dose intravaginal HIV-1 challenge of humanized DRAG mice results in 100% infectivity with accumulation of TFH-cells mainly in the Peyer's patches and FRT. The novel finding of TFH-cells in the FRT may contribute to the high susceptibility of DRAG mice to HIV-1 infection. This mouse model thus provides new opportunities to study TFH-cells and to evaluate HIV-1 vaccines. PMID- 26034908 TI - Re: a note on non-inferiority margins. PMID- 26034909 TI - Effect of prehospital initiation of therapeutic hypothermia in adults with cardiac arrest on time-to-target temperature. AB - OBJECTIVE: Despite growing adoption, the impact of prehospital initiation of therapeutic hypothermia on outcomes of cardiac arrest patients is unknown. The objective of this study was to determine if prehospital administration of cold intravenous fluids improved the time-to-target temperature. METHODS: All patients enrolled in an institutional post- cardiac arrest treatment pathway were prospectively registered into a quality assurance database. Patients undergoing cooling induction on hospital arrival were compared to those receiving a new treatment protocol initiated during the study period involving prehospital cooling with 4 degrees C (39.2 degrees F) normal saline. The primary outcome was the time-to-target temperature. Secondary outcomes included emergency medicine system transport time metrics, mortality, and neurologic status at discharge and 1 year. RESULTS: One hundred thirty-two patients were enrolled during the study period. The initial rhythm was ventricular fibrillation/tachycardia in 63% and asystole/pulseless electrical activity in 36%. Eighty patients received prehospital cooling and 52 patients did not and comprised the historical control group. Time-to-target temperatures were not significantly different between prehospital and hospital cooled groups (256 v. 271 minutes, respectively, p=0.64), nor was there any improvement in hospital survival (54% v. 50%, p=0.67), good neurologic outcome (49% v. 44%, p=0.61), or 1- year survival (49% v. 42%, p=0.46) between the two groups. Transport times were longer in the prehospital cooled group. CONCLUSIONS: Out-of-hospital cardiac arrest patients treated with prehospital cooling before arrival at our urban hospital did not have faster time to-target temperature or improvement in outcomes compared to patients cooled immediately on emergency department arrival. Further research is needed to determine if any benefits exist from prehospital cooling prior to its widespread adoption. PMID- 26034910 TI - Rates of elastic compression stockings prescription following the diagnosis of deep venous thrombosis among Canadian emergency physicians and trainees. AB - Introduction Postthrombotic syndrome (PTS) is a complication of deep vein thrombosis (DVT) characterized by chronic pain, swelling, and heaviness, and may result in ulceration. Elastic compression stockings (ECS) worn daily after DVT have been shown to reduce the incidence and severity of PTS. The aim of our study was to investigate practices and perceptions of physicians regarding adjunct therapies to anticoagulation in patients diagnosed with lower extremity DVT. METHODS: A national online survey was conducted of Canadian emergency medicine staff physicians and residents (n=471) to investigate their attitudes toward the prescription of ECS post-diagnosis of DVT. A paper survey of patients in a thrombosis clinic (n=58) was also administered to better understand the patient experiences with ECS. RESULTS: The majority of staff physician (62%) and resident (69%) respondents were unsure of whether ECS were effective in preventing PTS and managing venous symptoms. Only 6% of staff physicians and 7% of residents routinely prescribed ECS for above-knee DVTs. More than 78% of respondents were unsure about the optimal timing of initiation of ECS and duration of therapy. Although all patients noted symptomatic relief with ECS, only 50% were prescribed stockings by an emergency or family doctor, and 69% of those patients wore the stockings on a daily basis. Staff physicians most frequently identified poor fit as the reason for lack of patient compliance, whereas patients most frequently cited cost. CONCLUSIONS: Our findings suggest that there is variability in practice among Canadian emergency medicine physicians and trainees and a need for widespread education regarding the latest evidence of the benefit of ECS after DVT. PMID- 26034911 TI - Better performance on length-of-stay benchmarks associated with reduced risk following emergency department discharge: an observational cohort study. AB - Introduction Emergency department (ED) crowding is associated with adverse outcomes. Several jurisdictions have established benchmarks and targets for length-of-stay (LOS) to reduce crowding. An evaluation has been conducted on whether performance on Ontario's ED LOS benchmarks is associated with reduced risk of death or hospitalization. METHODS: A retrospective cohort study of discharged ED patients was conducted using population-based administrative data from Ontario (April 2008 to February 2012). For each ED visit, the proportion of patients seen during the same shift that met ED LOS benchmarks was determined. Performance was categorized as <80%, 80% to <90%, 90% to <95%, and 95%-100% of same-shift ED patients meeting the benchmark. Logistic regression models analysed the association between performance on ED LOS benchmarks and 7-day death or hospitalization, controlled for patient and ED characteristics and stratified by patient acuity. RESULTS: From 122 EDs, 2,295,256 high-acuity and 1,626,629 low acuity visits resulting in discharge were included. Deaths and hospitalizations within 7 days totalled 1,429 (0.062%) and 49,771 (2.2%) among high-acuity, and 220 (0.014%) and 9,005 (0.55%) among low-acuity patients, respectively. Adverse outcomes generally increased among patients seen during shifts when a lower proportion of ED patients met ED LOS benchmarks. The adjusted odds ratios (and 95% confidence intervals) among high- and low-acuity patients seen on shifts when <80% met ED benchmarks (compared with >=95%) were, respectively, 1.32 (1.05-1.67) and 1.84 (1.21-2.81) for death, and 1.13 (1.08-1.17) and 1.40 (1.31-1.49) for hospitalization. CONCLUSIONS: Better performance on Ontario's ED LOS benchmarks for each shift is associated with a 10%-45% relative reduction in the odds of death or admission 7 days after ED discharge. PMID- 26034912 TI - Effect of a point-of-care ultrasound protocol on the diagnostic performance of medical learners during simulated cardiorespiratory scenarios. AB - BACKGROUND: Goal-directed point-of-care ultrasound (PoCUS) protocols have been shown to improve the diagnostic accuracy of the initial clinical assessment of the critically ill patient. The diagnostic impact of the Abdominal and Cardiac Evaluation with Sonography in Shock (ACES) protocol was assessed in simulated emergency medical scenarios. METHODS: Following a focused PoCUS training program, the diagnostic accuracy, confidence, and precision of 12 medical learners participating in standardized scenarios were tested using high-fidelity clinical and ultrasound simulators. Participants were assessed during 72 simulated cardiorespiratory scenarios. Differential diagnoses were collected from participants before and after PoCUS in each scenario, and confidence surveys were completed. Data were analysed using R software. RESULTS: Prior to PoCUS, 45 (62.5%) correct primary diagnoses were made compared with 64 (88.9%) following PoCUS (chi2=14, 1df, p=0.0002). PoCUS was also shown to increase participants' confidence in their diagnoses. The mean confidence in diagnosis score pre-PoCUS was 52.2 (SD=14.7), whereas post-PoCUS it was 81.7 (SD=9.5). The estimated difference in means (-28.36) was significant (t=-7.71, p<0.0001). Using PoCUS, participants were further able to narrow their differential diagnoses. The median number of diagnoses for each patient pre-PoCUS was 3.5 (interquartile range [IQR]=3.8, 3.0) with a median of 2.3 (IQR=2.9,1.5) diagnoses post-PoCUS. The difference was significant (W=0, p<0.001). CONCLUSION: This pilot study suggests that, in medical learners newly competent in PoCUS, the addition of an ACES PoCUS protocol to standard clinical assessment improves diagnostic accuracy, confidence, and precision in simulated cardiorespiratory scenarios. This is consistent with clinical studies and supports the use of ultrasound during medical simulation. PMID- 26034913 TI - Ambulatory vital signs in the workup of pulmonary embolism using a standardized 3 minute walk test. AB - OBJECTIVE: Diagnosing pulmonary embolism can be difficult given its highly variable clinical presentation. Our objective was to determine whether a decrease in oxygen saturation or an increase in heart rate while ambulating could be used as an objective tool in the diagnosis of pulmonary embolism. METHODS: This was a two-site tertiary-care-centre prospective cohort study that enrolled adult emergency department or thrombosis clinic patients with suspected or newly confirmed pulmonary embolism. Patients were asked to participate in a standardized 3-minute walk test, which assessed ambulatory heart rate and ambulatory oxygen saturation. The primary outcome was pulmonary embolism. RESULTS: We enrolled 114 patients, including 30 with pulmonary embolism (26.3%). A >=2% absolute decrease in ambulatory oxygen saturation and an ambulatory change in heart rate >10 beats per minute (BPM) were significantly associated with pulmonary embolism. An ambulatory heart rate change of >10 BPM had a sensitivity of 96.6% (95% confidence interval [CI] 83.3 to 99.4) and a specificity of 31.0% (95% CI 22.1 to 45.0) for pulmonary embolism. A >=2% absolute decrease ambulatory oxygen saturation had a sensitivity of 80.2% (95% CI 62.7 to 90.5) and a specificity of 39.3% (95% CI 29.5 to 50.0) for pulmonary embolism. The combination of both variables yielded a sensitivity of 100.0% (95% CI 87.0 to 100.0) and a specificity of 11.0% (95% CI 6.6 to 21.0). CONCLUSION: In summary, our study found that an ambulatory heart rate change of >10 BPM or a >=2% absolute decrease in ambulatory oxygen saturation from baseline during a standardized 3-minute walk test are highly correlated with pulmonary embolism. Although the findings appear promising, neither of these variables can currently be recommended as a screening tool for pulmonary embolism until larger prospective studies examine their performance either alone or with pre-existing rules. PMID- 26034914 TI - Applying hospital evidence to paramedicine: issues of indirectness, validity and knowledge translation. AB - The practice of emergency medicine (EM) has been intertwined with emergency medical services (EMS) for more than 40 years. In this commentary, we explore the practice of translating hospital based evidence into the prehospital setting. We will challenge both EMS and EM dogma-bringing hospital care to patients in the field is not always better. In providing examples of therapies championed in hospitals that have failed to translate into the field, we will discuss the unique prehospital environment, and why evidence from the hospital setting cannot necessarily be translated to the prehospital field. Paramedicine is maturing so that the capability now exists to conduct practice-specific research that can inform best practices. Before translation from the hospital environment is implemented, evidence must be evaluated by people with expertise in three domains: critical appraisal, EM, and EMS. Scientific evidence should be assessed for: quality and bias; directness, generalizability, and validity to the EMS population; effect size and anticipated benefit from prehospital application; feasibility (including economic evaluation, human resource availability in the mobile environment); and patient and provider safety. PMID- 26034915 TI - Does location matter? A proposed methodology to evaluate neighbourhood effects on cardiac arrest survival and bystander CPR. AB - BACKGROUND: Traditional variables used to explain survival following out-of hospital cardiac arrest (OHCA) account for only 72% of survival, suggesting that other unknown factors may influence outcomes. Research on other diseases suggests that neighbourhood factors may partly determine health outcomes. Yet, this approach has rarely been used for OHCA. This work outlines a methodology to investigate multiple neighbourhood factors as determinants of OHCA outcomes. METHODS: A retrospective, observational cohort study design will be used. All adult non-emergency medical service witnessed OHCAs of cardiac etiology within the city of Toronto between 2006 and 2010 will be included. Event details will be extracted from the Toronto site of the Resuscitation Outcomes Consortium Epistry Cardiac Arrest, an existing population-based dataset of consecutive OHCA patients. Geographic information systems technology will be used to assign patients to census tracts. Neighbourhood variables to be explored include the Ontario Marginalization Index (deprivation, dependency, ethnicity, and instability), crime rate, and density of family physicians. Hierarchical logistic regression analysis will be used to explore the association between neighbourhood characteristics and 1) survival-to-hospital discharge, 2) return-of-spontaneous circulation at hospital arrival, and 3) provision of bystander cardiopulmonary resuscitation (CPR). Receiver operating characteristics curves will evaluate each model's ability to discriminate between those with and without each outcome. Discussion This study will determine the role of neighbourhood characteristics in OHCA and their association with clinical outcomes. The results can be used as the basis to focus on specific neighbourhoods for facilitating educational interventions, CPR awareness programs, and higher utilization of automatic defibrillation devices. PMID- 26034916 TI - Hemodynamically stable wide-complex tachycardia in a young patient. PMID- 26034917 TI - Clopidogrel with aspirin versus aspirin alone in prevention of stroke following transient ischemic attack or acute minor stroke. AB - Clinical question Following transient ischemic attack or acute minor stroke, does the combination of clopidogrel and aspirin reduce the risk of stroke greater than aspirin alone? Article chosen Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013;369:11-9. OBJECTIVE: The primary outcome measured in this study was ischemic or hemorrhagic stroke at 90 days of follow-up in groups assigned to treatment with a combination of aspirin and clopidogrel or aspirin alone following transient ischemic attack or acute minor stroke. The secondary outcomes were new clinical vascular events, including vascular death. PMID- 26034918 TI - An unusual presentation of small bowel intussusception. AB - A previously healthy 2-year-old boy presented to the emergency department with a decreased level of consciousness. A physical examination was unremarkable except for miosis and atypical limb movements. The patient underwent an extensive workup, including the search for metabolic, infectious, neurologic, and toxicologic etiologies. An abdominal ultrasound was performed because the child continued to remain neurologically impaired with no cause identified on other investigations. The ultrasound revealed a persistent uncomplicated ileoileal intussusception. The patient was taken to the operating room for surgical reduction. The child recovered fully postoperatively. This case illustrates the rare presentation of intussusception encephalopathy, which can be a diagnostic dilemma, especially when none of the symptoms of intussusception are present. Endogenous opioid poisoning is hypothesized to be the cause of the miosis and may hint at the diagnosis and aid in early management. PMID- 26034919 TI - Fault lines. PMID- 26034920 TI - Executive summary of the CAEP 2014 Academic Symposium: How to make research succeed in your department. AB - The vision of the recently created Canadian Association of Emergency Physicians (CAEP) Academic Section is to promote high-quality emergency patient care by conducting world-leading education and research in emergency medicine. The Academic Section plans to achieve this goal by enhancing academic emergency medicine primarily at Canadian medical schools and teaching hospitals. It seeks to foster and develop education, research, and academic leadership amongst Canadian emergency physicians, residents, and students. In this light, the Academic Section began in 2013 to hold the annual Academic Symposia to highlight best practices and recommendations for the three core domains of governance and leadership, education scholarship, and research. Each year, members of three panels are asked to review the literature, survey and interview experts, achieve consensus, and present their recommendations at the Symposium (2013, Education Scholarship; 2014, Research; and 2015, Governance and Funding). Research is essential to medical advancement. As a relatively young specialty, emergency medicine is rapidly evolving to adapt to new diagnostic tools, the challenges of crowding in emergency departments, and the growing needs of emergency patients. There is significant variability in the infrastructure, support, and productivity of emergency medicine research programs across Canada. All Canadians benefit from an investigation of the means to improve research infrastructure, training programs, and funding opportunities. Such an analysis is essential to identify areas for improvement, which will support the expansion of emergency medicine research. To this end, physician-scientist leaders were gathered from across Canada to develop pragmatic recommendations on the improvement of emergency medicine research through a comprehensive analysis of current best practices, systematic literature reviews, stakeholder surveys, and expert interviews. PMID- 26034921 TI - CAEP 2014 Academic Symposium: "How to make research succeed in your emergency department: How to develop and train career researchers in emergency medicine". AB - OBJECTIVES: We sought to 1) identify best practices for training and mentoring clinician researchers, 2) characterize facilitators and barriers for Canadian emergency medicine researchers, and 3) develop pragmatic recommendations to improve and standardize emergency medicine postgraduate research training programs to build research capacity. METHODS: We performed a systematic review of MEDLINE and Embase using search terms relevant to emergency medicine research fellowship/graduate training. We conducted an email survey of all Canadian emergency physician researchers. The Society for Academic Emergency Medicine (SAEM) research fellowship program was analysed, and other similar international programs were sought. An expert panel reviewed these data and presented recommendations at the Canadian Association of Emergency Physicians (CAEP) 2014 Academic Symposium. We refined our recommendations based on feedback received. RESULTS: Of 1,246 potentially relevant citations, we included 10 articles. We identified five key themes: 1) creating training opportunities; 2) ensuring adequate protected time; 3) salary support; 4) infrastructure; and 5) mentorship. Our survey achieved a 72% (67/93) response rate. From these responses, 42 (63%) consider themselves clinical researchers (i.e., spend a significant proportion of their career conducting research). The single largest constraint to conducting research was funding. Factors felt to be positive contributors to a clinical research career included salary support, research training (including an advanced graduate degree), mentorship, and infrastructure. The SAEM research fellowship was the only emergency medicine research fellowship program identified. This 2 year program requires approval of both the teaching centre and each applying fellow. This program requires training in 15 core competencies, manuscript preparation, and submission of a large grant to a national peer-review funding organization. CONCLUSIONS: We recommend that the CAEP Academic Section create a process to endorse research fellowship/graduate training programs. These programs should include two phases: Phase I: Research fellowship/graduate training would include an advanced research university degree and 15 core learning areas. Phase II: research consolidation involves a further 1-3 years with an emphasis on mentorship and scholarship production. It is anticipated that clinician scientists completing Phase I and Phase II training at a CAEP Academic Section endorsed site(s) will be independent researchers with a higher likelihood of securing external peer-reviewed funding and be able to have a meaningful external impact in emergency medicine research. PMID- 26034922 TI - Proteome of Soybean Seed Exudates Contains Plant Defense-Related Proteins Active against the Root-Knot Nematode Meloidogyne incognita. AB - Several studies have described the effects of seed exudates against microorganisms, but only few of them have investigated the proteins that have defensive activity particularly against nematode parasites. This study focused on the proteins released in the exudates of soybean seeds and evaluated their nematicidal properties against Meloidogyne incognita. A proteomic approach indicated the existence of 63 exuded proteins, including beta-1,3-glucanase, chitinase, lectin, trypsin inhibitor, and lipoxygenase, all of which are related to plant defense. The presence of some of these proteins was confirmed by their in vitro activity. The soybean exudates were able to reduce the hatching of nematode eggs and to cause 100% mortality of second-stage juveniles (J2). The pretreatment of J2 with these exudates resulted in a 90% reduction of the gall number in tobacco plants. These findings suggest that the exuded proteins are directly involved in plant defense against soil pathogens, including nematodes, during seed germination. PMID- 26034923 TI - Toxicity of a dental adhesive compared with ionizing radiation and zoledronic acid. AB - BACKGROUND: To determine the toxicity of aqueous dilutions of a universal self priming dental adhesive (DA) and comparing these with those elicited by exposure to ionizing radiation (IR), Zoledronic acid (Z) treatment and the synergic effects of the combined treatment with IR+Z. MATERIAL AND METHODS: The genotoxic effect of DA was determined by the increase in the frequency of micronuclei in cytokinesis-blocked in cultured human lymphocytes before and after exposure to 2Gy of X-rays. The cytotoxic effect was studied by using the MTT cell viability test in normal prostate cell lines (PNT2) after exposure to different X-ray doses (0Gy-20Gy). The cell lines divided into different groups and treated with different test substances: DA in presence of O2, DA in absence of O2, Z-treated and control. RESULTS: An in vitro dose-dependent and time-dependent cytotoxic effect of DA, Z and IR on PNT2 cells (p>0.001) was demonstrated. DA without-O2, following the recommendations of manufacturers, had a more pronounced effect of increasing cell death than DA with-O2 (p<0.001). In the genotoxicity assay, DA at 25% of its original concentration significantly increased chromosome damage (p<0.001). The samples studied were found to be toxic, and the samples photo polymerized in absence of O2 showed a bigger cytotoxic effect comparable to the additive toxic effect showed by the combined treatment of IR+Z. CONCLUSIONS: Additional effort should be carried out to develop adhesives, which would reduce the release of hazardous substances; since toxic effects are similar to that reported by other agents whose clinical use is controlled by the health authorities. PMID- 26034925 TI - Incidence and prevalence of salivary gland tumours in Valparaiso, Chile. AB - BACKGROUND: To determine the incidence and prevalence of salivary gland tumours in the province of Valparaiso, Chile. MATERIAL AND METHODS: Retrospective review of salivary gland tumours diagnosed between the years 2000 and 2011 from four local pathology services. Information on demographics and histopathology were retrieved from the medical records. RESULTS: The study sample consisted of 279 salivary gland tumours. Prevalence and incidence rates per 100.000 persons were 15.4 and 2.51, respectively. Most of the neoplasms corresponded to benign tumours (70.3%). The most affected gland was the parotid gland. Pleomorphic adenoma was the most common benign tumour (53.8%) and mucoepidermoid carcinoma was the most common malignant tumour (7.2%). CONCLUSIONS: Salivary gland tumours are uncommon neoplasms that usually arise in the parotid gland. Pleomorphic adenoma and mucoepidermoid carcinoma were the most common benign and malignant tumours reported in this series. PMID- 26034924 TI - Repair of bone defect by nano-modified white mineral trioxide aggregates in rabbit: A histopathological study. AB - BACKGROUND: Many researchers have tried to enhance materials functions in different aspects of science using nano-modification method, and in many cases the results have been encouraging. To evaluate the histopathological responses of the micro-/nano-size cement-type biomaterials derived from calcium silicate-based composition with addition of nano tricalcium aluminate (3CaO.Al2O3) on bone healing response. MATERIAL AND METHODS: Ninety mature male rabbits were anesthetized and a bone defect was created in the right mandible. The rabbits were divided into three groups, which were in turn subdivided into five subgroups with six animals each based on the defect filled by: white mineral trioxide aggregate (WMTA), Nano-WMTA, WMTA without 3CaO.Al2O3, Nano-WMTA with 2% Nano 3CaO.Al2O3, and empty as control. Twenty, forty and sixty days postoperatively the animals were sacrificed and the right mandibles were removed for histopathological evaluations. Kruskal-Wallis test with post-hoc comparisons based on the LSMeans procedure was used for data analysis. RESULTS: All the experimental materials provoked a moderate to severe inflammatory reaction, which significantly differed from the control group (p< 0.05). Statistical analysis of bone formation and bone regeneration data showed significant differences between groups at 40- and 60- day intervals in all groups. Absence of 3CaO.Al2O3 leads to more inflammation and foreign body reaction than other groups in all time intervals. CONCLUSIONS: Both powder nano-modification and addition of 2% Nano 3CaO.Al2O3 to calcium silicate-based cement enhanced the favorable tissue response and osteogenesis properties of WMTA based materials. PMID- 26034926 TI - Survival of immediately versus delayed loaded short implants: A prospective case series study. AB - BACKGROUND: To assess and compare survival rates of immediately and delayed loaded short implants (7 mm) in free ends of a partially edentulous jaw with moderate-severe alveolar bone resorption. MATERIAL AND METHODS: 24 patients with atrophic edentulous free-ends were included in this prospective study. Four study groups were monitored monthly and their behavior was evaluated: bridges supported only by short implants and mixed short and long implant bridge groups, both with immediate and delayed loading. Failures, bone loss, probing depth and bleeding on probing were evaluated. RESULTS: 54 Mk III Shorty TiU and 15 Branemark System(r)MK III TiU implants with a length longer than 7mm were included in the study. Twenty-eight implants were inserted following the immediate loading protocol and 26 according a two-stage procedure, depending on the torque value. The cumulative survival rate of short implants was 87% (n=54) after a mean time of 47.72 months (range 33-62 months), showing statistically significant differences related to loading protocol (p=0.047). Short implants immediately loaded had a higher long-term survival rate (96.4%) compared to the other study group (76.9%). Besides, short implants splinted to longer immediately loaded implants presented the highest survival rate (100%). Twenty-five (53.19%) short implants showed a bone loss of less than one millimeter after the follow-up period. Statistically significant differences were found between bleeding on probing, presence of plaque or suppuration and a higher bone loss in both loading protocols (p=0.001). CONCLUSIONS: Immediate loading of short implants placed on free ends can be considered an option in the treatment protocol of patients with severe bone resorption especially if implants are splinted to others of greater length. PMID- 26034927 TI - Alpha lipoic acid efficacy in burning mouth syndrome. A controlled clinical trial. AB - BACKGROUND: A double-blind placebo-controlled trial was conducted in order to evaluate the efficacy of alpha lipoic acid (ALA) and determine the statistical significance of the outcome variables. Burning mouth syndrome (BMS) is defined as an oral burning sensation in the absence of clinical signs which could justify the syndrome. Recent studies suggest the existence of neurological factors as a possible cause of the disease. MATERIAL AND METHODS: 60 patients with BMS, in two groups: case group with 600 mg/day and placebo as control group; with follow up of 2 months. RESULTS: 64% of ALA patients reported some level of improvement, with a level of maintenance of 68.75% one month after treatment. 27.6% of the placebo group also demonstrated some reduction in BMS symptoms. CONCLUSIONS: Long term evolution and the intensity of symptoms are variables that reduce the probability of improvement with ALA treatment. PMID- 26034929 TI - Is the Erich arch bar the best intermaxillary fixation method in maxillofacial fractures? A systematic review. AB - BACKGROUND: Intermaxillary fixation is used to achieve proper occlusion during and after oral and maxillofacial fracture surgery. The aim of this systematic review was to compare Erich arch bar fixation with other intermaxillary fixation methods in terms of the operating time, safety during installation, oral health maintenance and occlusal stability. MATERIAL AND METHODS: An electronic online search was conducted of the Scirus, PubMed, Ovid, Cochrane Library and VHL databases. A clinical trial dating from the inception of the data bases until August 2013 was selected. Studies that compared Erich arch bars with other intermaxillary fixation methods in patients older than 18 years-old were included. The studies were assessed by two independent reviewers. The methodological quality of each article was analyzed. RESULTS: Nine hundred and twenty-five manuscripts were found. Seven relevant articles were analyzed in this review. The risk of bias was considered moderate for four studies and high for three clinical trials. CONCLUSIONS: There is not enough evidence to conclude that the Erich arch bar is the best intermaxillary fixation method in cases of oral and maxillofacial fractures. PMID- 26034928 TI - Intermittent administration of parathyroid hormone improves the repairing process of rat calvaria defects: A histomorphometric and radiodensitometric study. AB - BACKGROUND: The aim of this study was to evaluate the effects of intermittent treatment of parathyroid hormone (PTH (1-34)) on the bone regeneration of critically-sized rat calvarial bone defects. MATERIAL AND METHODS: Thirty-two male rats were trephined (4mm full-thickness diameter), in the central part of the parietal bones and divided into 2 groups of 16. The PTH group received subcutaneous injections of PTH (1-34) at 40ug/kg, 3 times a week and the control (CTL) group received the vehicle in the same regimen. The rats were sacrificed at 4 weeks post-treatment regimen, the parietal bones were extracted and samples were evaluated through histomorphometry and radiodensitometry. RESULTS: The histological observations showed that the PTH group presented more "island-like" new bone between the defect margins with fibrous tissues than did the CTL group. The PTH group significantly exhibited greater histologic bone formation than did the CTL group (1.5mm +/-0.7; 1.9 mm +/- 0.6, p<0.05/ for residual bone defect). The radiodensitometry analysis revealed significant differences among the PTH and CTL groups (2.1 Al eq. +/-0.04; 1.8Al eq. +/-0.06, p<0.05), demonstrating an increase in bone mineral density. The PTH treatment contributed to the bone formation with a higher amount of mineral and/or fibrous tissue when compared with the CTL group. CONCLUSIONS: The results suggest that it was possible to increase the process of bone regeneration by accelerating the healing process in rat calvarial defects through intermittent administration of the PTH treatment. PMID- 26034930 TI - Oral health-related quality of life of implant-supported overdentures versus conventional complete prostheses: Retrospective study of a cohort of edentulous patients. AB - BACKGROUND: This work aims to confirm if implant-supported overdentures are a good treatment option for edentulous patients and offer an improvement in quality of life compared with traditional complete prostheses (dentures). MATERIAL AND METHODS: This retrospective clinical descriptive study included three evaluation groups: validation group (n=57); control group of patients with complete removeable prostheses (n=56); study group of patients with implant-supported overdentures retained with the Locator(r) system (n=80). The study also validated the Oral Health Impact Profile-20 questionnaire. Individual protocols were created that included socio-demographic data, the Oral Health Impact Profile-20 (OHIP-20) questionnaire and Oral Satisfaction Scale (OSS). Descriptive and bivariate statistical analysis was carried out applying chi2, Pearson, Kruskal Wallis, and Student t tests, transferring data into SPSS-Windows(r) software from a Microsoft(r) Excel spreadsheet. RESULTS: The OHIP-20 proved to be a valid instrument and provided reliable assessment of health-related quality of life among both the Spanish general population and edentulous patients. The control and study groups proved comparable, showing socio-demographic homogeneity. For patients with overdentures retained by means of the Locator(r) system, these restorations had significantly lower impact on quality of life (19 vs 33), both generally and for each individual questionnaire item, and much higher satisfaction with the state of their oral cavities (8.3 vs 5.3) than patients wearing dentures; both sets of data showed a direct linear relationship, so that as the level of impact on quality of life increased, perceived oral satisfaction worsened. CONCLUSIONS: Patients rehabilitated with implant supported overdentures retained by the Locator(r) system, presented significantly lower levels of impact on their quality of life and significantly higher oral satisfaction than patients with conventional complete prostheses. PMID- 26034931 TI - Systemic moxifloxacin vs amoxicillin/metronidazole adjunct to non-surgical treatment in generalized aggressive periodontitis. AB - BACKGROUND: The objective of this randomized clinical study was to evaluate the effect of systemic administration of moxifloxacin compared to amoxicillin and metronidazole, combined with non-surgical treatment in patients with generalized aggressive periodontitis (GAgP) in a 6-month follow-up. MATERIAL AND METHODS: A total of 39 systemically healthy patients with GAgP were evaluated in this randomized clinical trial. Periodontal parameters were recorded at the baseline during the 1st, 3rd and 6th month. Patients received either 400 mg of moxifloxacin per os once daily or 500 mg of metronidazole and 500 mg amoxicillin per os three times daily for 7 days consecutively. RESULTS: No significant differences between groups were found in any parameters at the baseline. Both groups led to a statistically significant decrease in all clinical periodontal parameters compared to the baseline (PI; p<0.001 and GI, PD, BOP, CAL, p<0.01). There were no differences between the 1st and 3rd months or the 3rd and 6th months for clinical parameters in the groups. Also, no intergroup difference was observed in any parameters at any time, except the gingival index at 6th months. CONCLUSIONS: Systemic administration of moxifloxacin as an adjunct to non surgical treatment significantly improves clinical outcomes and provides comparable clinical improvement with less adverse events to that of combination of amoxicillin and metronidazole in the treatment of GAgP. PMID- 26034933 TI - Dropping the ball. PMID- 26034934 TI - Unmasking nonmotor symptoms of Parkinson disease. PMID- 26034932 TI - Repair of complete bilateral cleft lip with severely protruding premaxilla performing a premaxillary setback and vomerine ostectomy in one stage surgery. AB - BACKGROUND: The authors present a technique for selected cases of CBCL. The primary repair of the CBCL with a severely protruding premaxilla in one stage surgery is very difficult, essentially because a good muscular apposition is difficult, forcing synchronously to do a premaxillary setback to facilitate subsequent bilateral lip repair and, thus, achieving satisfactory results. We achieve this by a reductive ostectomy on the vomero-premaxillary suture. MATERIAL AND METHODS: 4 patients with CBCL and severely protruding premaxilla underwent premaxillary setback by vomerine ostectomy at the same time of lip repair in the past 24 months. The extent of premaxillary setback varied between 9 and 16 mm. The required amount of bone was removed anterior to the vomero-premaxillary suture. The authors did an additional simultaneous gingivoperiosteoplasty in all patients, achieving an enough stability of the premaxilla in its new position, to be able to close the alveolar gap bilaterally. The authors have examined the position of premaxilla and dental arch between 6 and 24 months. We did not do the primary nose correction, because this increased the risk of impairment of the already compromised vascularity of the philtrum and premaxilla. RESULTS: The follow-up period ranged between 6 and 24 months. None of the patients had any major complication. During follow-up, the premaxilla was minimally mobile. We achieved a good lip repair in all cases: adequate muscle repair, symmetry of the lip, prolabium and Cupid's bow, as well as good scars. Conclusions: To our knowledge, there are few reports of one stage surgery with vomerine ostectomy to repair CBCL with severely protruding premaxilla. Doing this vomerine ostectomy, we don't know how it will affect the subsequent growth of the premaxila and restrict the natural maxillary growth. Applying this alternative treatment for children with CBCL and protruded premaxilla without any preoperative orthopedic, we can successfully perform, in a single-stage surgery, a good primary lip repair at our center. Further confirmations of this surgery with follow up and anthropometric studies of these patients during childhood and adolescence are required. PMID- 26034935 TI - Referral to a Commercial Weight Management Program in Patients With Coronary Heart Disease: A PILOT STUDY IN THE NETHERLANDS. AB - PURPOSE: To quantify the impact of a commercial weight management program on weight change in obese patients with coronary heart disease. METHODS: An observational, single-center pilot study in the Netherlands. Forty-five patients diagnosed with a recent acute coronary syndrome and a body mass index of >30 kg/m2 were recruited. The commercial weight management intervention (Weight Watchers) promotes a hypoenergetic and balanced diet, increased physical activity, and group support. The program included weekly 30-minute in-hospital meetings with an experienced coach. The program was offered in parallel with a cardiac rehabilitation program. RESULTS: Thirty-five patients completed the program. Of these patients, 32 patients (91%) decreased body weight. Mean weight change was -5.8 kg (range: +0.6 kg to -15.4 kg), and 20 patients (57%) achieved the target of 5% weight loss of their initial weight. Twenty-seven patients continued the commercial weight loss program after 14 weeks, the mean followup of these patients was 34 weeks and their mean weight change was -9.1 kg (range: 0.0 23.0 kg). CONCLUSIONS: Obese patients, discharged after an acute coronary syndrome, who were referred to a commercial weight management program, achieved significant weight loss. Although this is a nonrandomized pilot study with patients who were selected by motivation and by the ability to participate in the program, the proportion of weight loss is significant and promising. PMID- 26034936 TI - Decreased tidal volume may limit cardiopulmonary performance during exercise in subacute stroke. AB - PURPOSE: The aim of this retrospective study was to determine whether pulmonary function was reduced at submaximal and peak exercise in subacute stroke (SG) when compared with sedentary adults (CON). METHODS: Ten individuals with subacute stroke and 10 sedentary, age- and gender-matched adults performed cardiopulmonary exercise testing (CPET), using a recumbent stepper. We used independent t tests to determine between-group differences at peak effort. We used repeated-measures analysis of variance with Test Minute (minutes 1-6) as the within-subject factor and Group (SG, CON) as the between-subject factor to assess cardiopulmonary submaximal performance. RESULTS: The SG had significantly lower values (P < .05) for oxygen uptake, minute ventilation ((Equation is included in full-text article.)E), and tidal volume (VT) than CON at peak effort of the CPET. During CPET submaximal effort, we report a significant main effect for Test Minute and Group for VT and respiratory rate but no main effect of Group for (Equation is included in full-text article.)E. To maintain adequate (Equation is included in full-text article.)E during submaximal effort and decreased VT, higher respiratory rate was observed. CONCLUSIONS: These results suggest that diminished VT in subacute stroke patients may limit performance during submaximal and peak effort of CPET. Rehabilitation professionals should consider methods for improving pulmonary function during stroke rehabilitation. PMID- 26034937 TI - A Systematic Review of the Effects of Telerehabilitation in Patients With Cardiopulmonary Diseases. AB - PURPOSE: To examine the effects of telerehabilitation compared with other delivery models for improving physical or functional outcomes in patients with cardiopulmonary diseases. METHODS: A search was completed for English language publications from 1990 to August 2013 across 4 electronic databases and gray literature. Inclusion criteria were: (1) home-based telerehabilitation as a core component; (2) at least 2 exercise sessions; (3) randomized controlled trials; and (4) reporting of physical or functional outcome measures in adult patients with coronary heart disease, chronic heart failure, and chronic respiratory disease. Studies were independently screened by 2 reviewers and graded by a reviewer according to the Downs and Black checklist. A narrative synthesis of the included studies was undertaken. RESULTS: Eleven studies were analyzed. It appears that telerehabilitation is no different to other delivery models for patients with cardiopulmonary diseases, in terms of exercise capacity expressed as distance on the 6-minute walk test and peak oxygen consumption and quality of life. Telerehabilitation appears to have higher adherence rates compared with center-based exercise. There has been similar or no adverse events reported in telerehabilitation compared with center-based exercise. CONCLUSIONS: Although telerehabilitation shows promise in patients with cardiopulmonary diseases, compelling evidence is still limited. There is a need for more detailed, high quality studies and for studies on the use of video-based telerehabilitation. PMID- 26034938 TI - Interventions for drug-using offenders with co-occurring mental illness. AB - BACKGROUND: This is an updated version of an original Cochrane review published in Issue 3 2006 (Perry 2006). The review represents one from a family of four reviews focusing on interventions for drug-using offenders. This specific review considers interventions aimed at reducing drug use or criminal activity, or both for drug-using offenders with co-occurring mental illness. OBJECTIVES: To assess the effectiveness of interventions for drug-using offenders with co-occurring mental illness in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases up to May 2014 and 5 Internet resources (searched between 2004 and 11 November 2009). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials designed to reduce, eliminate, or prevent relapse of drug use and criminal activity, or both in drug-using offenders with co-occurring mental illness. We also reported data on the cost and cost-effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Eight trials with 2058 participants met the inclusion criteria. The methodological quality of the trials was generally difficult to rate due to a lack of clear reporting. On most 'Risk of bias' items, we rated the majority of studies as unclear. Overall, we could not statistically combine the results due to the heterogenous nature of the different study interventions and comparison groups. A narrative summary of the findings identified that the interventions reported limited success with reducing self report drug use, but did have some impact on re-incarceration rates, but not re-arrest. In the single comparisons, we found moderate-quality evidence that therapeutic communities determine a reduction in re-incarceration but reported less success for outcomes of re-arrest, moderate quality of evidence and self report drug use. Three single studies evaluating case management via a mental health drug court (very low quality of evidence), motivational interviewing and cognitive skills (low and very low quality of evidence) and interpersonal psychotherapy (very low quality of evidence) did not report significant reductions in criminal activity and self report drug use respectively. Quality of evidence for these three types of interventions was low to very low. The trials reported some cost information, but it was not sufficient to be able to evaluate the cost-effectiveness of the interventions. AUTHORS' CONCLUSIONS: Two of the five trials showed some promising results for the use of therapeutic communities and aftercare, but only in relation to reducing subsequent re-incarceration. Overall, the studies showed a high degree of variation, warranting a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. More evaluations are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems. PMID- 26034939 TI - Direct growth of freestanding GaN on C-face SiC by HVPE. AB - In this work, high quality GaN crystal was successfully grown on C-face 6H-SiC by HVPE using a two steps growth process. Due to the small interaction stress between the GaN and the SiC substrate, the GaN was self-separated from the SiC substrate even with a small thickness of about 100 MUm. Moreover, the SiC substrate was excellent without damage after the whole process so that it can be repeatedly used in the GaN growth. Hot phosphoric acid etching (at 240 degrees C for 30 min) was employed to identify the polarity of the GaN layer. According to the etching results, the obtained layer was Ga-polar GaN. High-resolution X-ray diffraction (HRXRD) and electron backscatter diffraction (EBSD) were done to characterize the quality of the freestanding GaN. The Raman measurements showed that the freestanding GaN film grown on the C-face 6H-SiC was stress-free. The optical properties of the freestanding GaN layer were determined by photoluminescence (PL) spectra. PMID- 26034942 TI - Texas windstorm: Charles T. Bowling. PMID- 26034943 TI - Improving the quality of life at the end of life. PMID- 26034944 TI - The other physician payment problem. PMID- 26034952 TI - A public health perspective on a national precision medicine cohort: balancing long-term knowledge generation with early health benefit. PMID- 26034953 TI - A piece of my mind. Penny wise. PMID- 26034954 TI - Bundled approaches for surgical site infection prevention: the continuing quest to get to zero. PMID- 26034955 TI - Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. AB - IMPORTANCE: The association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial since the US Food and Drug Administration issued a public health advisory in 2006. OBJECTIVE: To examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy. DESIGN AND SETTING: Cohort study nested in the 2000 2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow up date was December 31, 2010. PARTICIPANTS: A total of 3,789,330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES: SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use. MAIN OUTCOMES AND MEASURES: Recorded diagnosis of PPHN during the first 30 days after delivery. RESULTS: A total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01 1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74). CONCLUSIONS AND RELEVANCE: Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies. PMID- 26034957 TI - Increasing support for the treatment of complicated grief in adults of all ages. PMID- 26034956 TI - Association of a bundled intervention with surgical site infections among patients undergoing cardiac, hip, or knee surgery. AB - IMPORTANCE: Previous studies suggested that a bundled intervention was associated with lower rates of Staphylococcus aureus surgical site infections (SSIs) among patients having cardiac or orthopedic operations. OBJECTIVE: To evaluate whether the implementation of an evidence-based bundle is associated with a lower risk of S. aureus SSIs in patients undergoing cardiac operations or hip or knee arthroplasties. DESIGN, SETTING, AND PARTICIPANTS: Twenty hospitals in 9 US states participated in this pragmatic study; rates of SSIs were collected for a median of 39 months (range, 39-43) during the preintervention period (March 1, 2009, to intervention) and a median of 21 months (range, 14-22) during the intervention period (from intervention start through March 31, 2014). INTERVENTIONS: Patients whose preoperative nares screens were positive for methicillin-resistant S. aureus (MRSA) or methicillin-susceptible S. aureus (MSSA) were asked to apply mupirocin intranasally twice daily for up to 5 days and to bathe daily with chlorhexidine-gluconate (CHG) for up to 5 days before their operations. MRSA carriers received vancomycin and cefazolin or cefuroxime for perioperative prophylaxis; all others received cefazolin or cefuroxime. Patients who were MRSA-negative and MSSA-negative bathed with CHG the night before and morning of their operations. Patients were treated as MRSA-positive if screening results were unknown. MAIN OUTCOMES AND MEASURES: The primary outcome was complex (deep incisional or organ space) S. aureus SSIs. Monthly SSI counts were analyzed using Poisson regression analysis. RESULTS: After a 3-month phase in period, bundle adherence was 83% (39% full adherence; 44% partial adherence). Overall, 101 complex S. aureus SSIs occurred after 28,218 operations during the preintervention period and 29 occurred after 14,316 operations during the intervention period (mean rate per 10,000 operations, 36 for preintervention period vs 21 for intervention period, difference, -15 [95% CI, -35 to -2]; rate ratio [RR], 0.58 [95% CI, 0.37 to 0.92]). The rates of complex S. aureus SSIs decreased for hip or knee arthroplasties (difference per 10,000 operations, -17 [95% CI, -39 to 0]; RR, 0.48 [95% CI, 0.29 to 0.80]) and for cardiac operations (difference per 10,000 operations, -6 [95% CI, -48 to 8]; RR, 0.86 [95% CI, 0.47 to 1.57]). CONCLUSIONS AND RELEVANCE: In this multicenter study, a bundle comprising S. aureus screening, decolonization, and targeted prophylaxis was associated with a modest, statistically significant decrease in complex S. aureus SSIs. PMID- 26034958 TI - Enlarged thymus in a patient with dyspnea and weight loss. PMID- 26034959 TI - An inhaled insulin (Afrezza). PMID- 26034960 TI - Appropriateness of advanced diagnostic imaging ordering before and after implementation of clinical decision support systems. PMID- 26034961 TI - Lowering blood pressure in patients with diabetes. PMID- 26034962 TI - Lowering blood pressure in patients with diabetes. PMID- 26034963 TI - Lowering blood pressure in patients with diabetes--reply. PMID- 26034964 TI - Treatment for hospitalized patients with severe community-acquired pneumonia. PMID- 26034965 TI - Treatment for hospitalized patients with severe community-acquired pneumonia- reply. PMID- 26034967 TI - Incorrect age data in table. PMID- 26034966 TI - Incorrect representation of analyses. PMID- 26034969 TI - New clues to a second genetic system. PMID- 26034970 TI - JAMA patient page. Medications for weight loss: indications and usage. PMID- 26034972 TI - The tailored inner space of TiO2 electrodes via a 30 second wet etching process: high efficiency solid-state perovskite solar cells. AB - We fabricated a perovskite solar cell with enhanced device efficiency based on the tailored inner space of the TiO2 electrode by utilizing a very short chemical etching process. It was found that the mesoporous TiO2 photoanode treated with a HF solution exhibited remarkably enhanced power conversion efficiencies under simulated AM 1.5G one sun illumination. The controlled inner space and morphology of the etched TiO2 electrode provide an optimized space for perovskite sensitizers and infiltration of a hole transport layer without sacrificing its original electron transport ability, which resulted in higher JSC, FF and VOC values. This simple platform provides new opportunities for tailoring the microstructure of the TiO2 electrode and has great potential in various optoelectronic devices utilizing metal oxide nanostructures. PMID- 26034971 TI - The role of basic residues in the adsorption of blood proteins onto the graphene surface. AB - With its many unique properties, graphene has shown great potential in various biomedical applications, while its biocompatibility has also attracted growing concerns. Previous studies have shown that the formation of protein-graphene corona could effectively reduce its cytotoxicity; however, the underlying molecular mechanism remains not well-understood. Herein, we use extensive molecular dynamics simulations to demonstrate that blood proteins such as bovine fibrinogen (BFG) can absorb onto the graphene surface quickly and tightly to form a corona complex. Aromatic residues contributed significantly during this adsorption process due to the strong pi-pi stacking interactions between their aromatic rings and the graphene sp(2)-carbons. Somewhat surprisingly, basic residues like arginine, also played an equally or even stronger role during this process. The strong dispersion interactions between the sidechains of these solvent-exposed basic residues and the graphene surface provide the driving force for a tight binding of these basic residues. To the best of our knowledge, this is the first study with blood proteins to show that, in addition to the aromatic residues, the basic residues also play an important role in the formation of protein-graphene corona complexes. PMID- 26034973 TI - Early access to vocational rehabilitation for spinal cord injury inpatients. AB - OBJECTIVES: To describe a novel early vocational rehabilitation programme (In Voc) for inpatients with spinal cord injury and to report early vocational outcomes. DESIGN: Observational longitudinal cohort study. SUBJECTS: One hundred adults with spinal cord injury admitted to spinal units in Sydney, Australia within a 24-month period. METHODS: In-Voc was offered to all inpatients within the first 6 months of acquired spinal cord injury and was provided by trained vocational consultants. Baseline demographics, opinions about work readiness, details of the vocational services provided and preliminary employment outcomes were documented. RESULTS: The In-Voc programme was relatively short in duration (median 11 weeks, range 3-39 weeks) with a median total of 9.1 h (range 1-75.2 h) of service delivered per participant. At case closure (median 3 weeks post discharge), 29/84 (34.5%) of participants were in paid employment (7% full-time, 8% part-time, 7% on sick leave, and 12% working with hours unknown), 36% were unemployed (6% seeking work, 16% not seeking work, 14% job seeking status unknown), 13% were students or in-training, and 17% were in vocational rehabilitation. CONCLUSION: Our research suggests that implementing an early vocational rehabilitation programme with individuals in the hospital setting is feasible and has good potential for enhancing post-injury labour-force participation. PMID- 26034977 TI - Matrine-induced autophagy regulated by p53 through AMP-activated protein kinase in human hepatoma cells. AB - Matrine, one of the main extract components of Sophora flavescens, has been shown to exhibit inhibitory effects on some tumors through autophagy. However, the mechanism underlying the effect of matrine remains unclear. The cultured human hepatocellular carcinoma cell line HepG2 and SMMC-7721 were treated with matrine. Signal transduction and gene expression profile were determined. Matrine stimulated autophagy in SMMC-7721 cells in a mammalian target of rapamycin (mTOR) dependent manner, but in an mTOR-independent manner in HepG2 cells. Next, in HepG2 cells, autophagy induced by matrine was regulated by p53 inactivation through AMP-activated protein kinase (AMPK) signaling transduction, then AMPK suppression switched autophagy to apoptosis. Furthermore, the interferon (IFN) inducible genes, including interferon alpha-inducible protein 27 (IFI27) and interferon induced transmembrane protein 1 (IFITM1), which are downstream effector of p53, might be modulated by matrine-induced autophagy. In addition, we found that the p53 protein isoforms, p53beta, p53gamma, ?133p53, and ?133p53gamma, due to alternative splicing of intron 9, might be regulated by the p53-mediated autophagy. These results show that matrine induces autophagy in human hepatoma cells through a novel mechanism, which is p53/AMPK signaling pathway involvement in matrine-promoted autophagy. PMID- 26034979 TI - Endogenous hydrogen sulfide is associated with angiotensin II type 1 receptor in a rat model of carbon tetrachloride-induced hepatic fibrosis. AB - The present study aimed to investigate the effects of endogenous hydrogen sulfide (H2S) on the expression levels of angiotensin II type 1 receptor (AGTR1) in a rat model of carbon tetrachloride (CCl4)-induced hepatic fibrosis. A total of 56 Wistar rats were randomly divided into four groups: Normal control group, model group, sodium hydrosulfide (NaHS) group, and DL-propargylglycine (PAG) group. Hepatic fibrosis was induced by CCl4. The rats in the PAG group were intraperitoneally injected with PAG, an inhibitor of cystathionine-gamma-lyase (CSE). The rats in the NaHS group were intraperitoneally injected with NaHS. An equal volume of saline solution was intraperitoneally injected into both the control and model groups. All rats were sacrificed at week three or four following treatment. The serum levels of hyaluronidase (HA), laminin protein (LN), procollagen III (PcIII), and collagen IV (cIV) were detected using ELISA. The serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and albumin (ALB) were detected using an automatic biochemical analyzer. The liver mRNA expression levels of CSE were detected by reverse transcription-quantitative polymerase chain reaction. The liver expression levels of AGTR1 and the plasma expression levels of H2S were detected using western blot analyses. The results indicated that the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly higher in the PAG group, as compared with the model group (P<0.05). Conversely, the expression levels of ALB were significantly lower in the PAG group, as compared with the model group. In addition, the severity of hepatic fibrosis, the serum expression levels of HA, LN, PcIII, cIV, ALT, and AST, the liver expression levels of CSE and AGTR1, and the plasma expression levels of H2S were significantly lower in the NaHS group, as compared with the model group (P<0.05). These results suggest that endogenous H2S is associated with CCl4-induced hepatic fibrosis in rats, and may exhibit anti-fibrotic effects. Furthermore, H2S reduced the liver expression levels of AGTR1, which may be associated with the delayed progression of hepatic fibrosis. PMID- 26034978 TI - B cells Using Calcium Signaling for Specific and Rapid Detection of Escherichia coli O157:H7. AB - A rapid and sensitive detection technology is highly desirable for specific detection of E. coli O157:H7, one of the leading bacterial pathogens causing foodborne illness. In this study, we reported the rapid detection of E. coli O157:H7 by using calcium signaling of the B cell upon cellular membrane anchors anti-E. coli O157:H7 IgM. The binding of E. coli O157:H7 to the IgM on B cell surface activates the B cell receptor (BCR)-induced Ca(2+) signaling pathway and results in the release of Ca(2+) within seconds. The elevated intracellular Ca(2+) triggers Fura-2, a fluorescent Ca(2+) indicator, for reporting the presence of pathogens. The Fura-2 is transferred to B cells before detection. The study demonstrated that the developed B cell based biosensor was able to specifically detect E. coli O157:H7 at the low concentration within 10 min in pure culture samples. Finally, the B cell based biosensor was used for the detection of E. coli O157:H7 in ground beef samples. With its short detection time and high sensitivity at the low concentration of the target bacteria, this B cell biosensor shows promise in future application of the high throughput and rapid food detection, biosafety and environmental monitoring. PMID- 26034981 TI - Tuning photochemistry: substituent effects on pisigma* state mediated bond fission in thioanisoles. AB - We report a combination of experimental (velocity map imaging measurements of the methyl (Me) radical products) and ab initio electronic structure studies that explore the influence of substituents (Y) on the dynamics of S-Me bond fission following excitation to the first excited S1 states of thioanisole and three 4 substituted thioanisoles (4-YPhSMe, with Y = H, Me, MeO and CN). In all bar the case that Y = CN, the resulting 4-YPhS products are found to be formed predominantly in their excited (A) electronic state. In all cases, the relative yield of X state products increases upon tuning to shorter excitation wavelengths and, in the specific case of bare thioanisole (as found previously by Lim and Kim, Nat. Chem., 2010, 2, 627), jumps when exciting on the parent resonance assigned to the S1(v7a = 1) level. Two conical intersections (CIs) in the RS-Me stretch coordinate are crucial to rationalising all of the observed dynamics. The first, (CI-1, between the diabatic (1)pipi* and dissociative (1)pisigma* potential energy surfaces (PESs) at RS-Me~ 2 A) lies above the S1(v = 0) level in energy, and the calculated minimum energy path through this barrier involves substantial deviations from planarity in all bar 4-CNPhSMe. Beyond this barrier, the potential is quite steeply repulsive, and Me + 4-YPhS(A) products are the inevitable products if the molecular framework is unable to re-planarise within the time it takes for the dissociating molecules to pass through the region of CI 2 (between the diabatic (1)pisigma* and ground (S0) states) where the product electronic branching is determined. The gradual increase in the yield of 4 YPhS(X) radicals upon tuning to shorter photolysis wavelengths, the much increased branching into PhS(X) products when exciting the PhSMe (S1, v7a = 1) level and the dominance of 4-CNPhS(X) products in the specific case that Y = CN can all be understood in terms of a (relative) lowering of the effective barrier associated with CI-1, thereby allowing access to the dissociative region of the PES at closer-to-planar geometries. PMID- 26034980 TI - Selective enhancement of hypoxic cell killing by tempol-regulated suicide gene expression. AB - The presence of hypoxic regions within solid tumors is caused by an imbalance between cell proliferation and angiogenesis. Such regions may facilitate the onset of recurrence after radiation therapy and chemotherapy, as hypoxic cells show resistance to these treatments. We found that tempol, a nitroxide, strongly induces the accumulation of hypoxia-inducible factor (HIF)-1alpha, particularly under conditions of hypoxia. We, therefore, evaluated whether tempol enhances the gene expression via HIF-1alpha, potentially leading to various applications for cancer gene therapy targeting hypoxic cells. Consequently, following treatment with tempol under hypoxia, the luciferase (Luc) activity in the cells transfected with the plasmid containing the luc gene with the oxygen-dependent degradation domain and a promoter composed of hypoxia-responsive elements increased up to approximately 10-fold compared to that observed in cells treated identically with the exception of tempol. The plasmid constructed by replacing the luc gene with the fcy::fur fusion gene as a suicide gene, strongly induced the accumulation of the Fcy::Fur fusion protein, only when incubated in the presence of the hypoxic mimic CoCl2 and tempol. The transfected cells were successfully killed with the addition of 5-fluorocytosine to the cell culture according to the fcy::fur fusion gene expression. As similar but lesser enhancement of the Luc activity was also observed in solid tumor tissues in nude mice, this strategy may be applied for hypoxic cancer eradication. PMID- 26034982 TI - The Forkhead Transcription Factor FOXP2 Is Required for Regulation of p21WAF1/CIP1 in 143B Osteosarcoma Cell Growth Arrest. AB - Mutations of the forkhead transcription factor FOXP2 gene have been implicated in inherited speech-and-language disorders, and specific Foxp2 expression patterns in neuronal populations and neuronal phenotypes arising from Foxp2 disruption have been described. However, molecular functions of FOXP2 are not completely understood. Here we report a requirement for FOXP2 in growth arrest of the osteosarcoma cell line 143B. We observed endogenous expression of this transcription factor both transiently in normally developing murine osteoblasts and constitutively in human SAOS-2 osteosarcoma cells blocked in early osteoblast development. Critically, we demonstrate that in 143B osteosarcoma cells with minimal endogenous expression, FOXP2 induced by growth arrest is required for up regulation of p21WAF1/CIP1. Upon growth factor withdrawal, FOXP2 induction occurs rapidly and precedes p21WAF1/CIP1 activation. Additionally, FOXP2 expression could be induced by MAPK pathway inhibition in growth-arrested 143B cells, but not in traditional cell line models of osteoblast differentiation (MG-63, C2C12, MC3T3-E1). Our data are consistent with a model in which transient upregulation of Foxp2 in pre-osteoblast mesenchymal cells regulates a p21-dependent growth arrest checkpoint, which may have implications for normal mesenchymal and osteosarcoma biology. PMID- 26034983 TI - Experience sampling-based personalized feedback and positive affect: a randomized controlled trial in depressed patients. AB - OBJECTIVES: Positive affect (PA) plays a crucial role in the development, course, and recovery of depression. Recently, we showed that a therapeutic application of the experience sampling method (ESM), consisting of feedback focusing on PA in daily life, was associated with a decrease in depressive symptoms. The present study investigated whether the experience of PA increased during the course of this intervention. DESIGN: Multicentre parallel randomized controlled trial. An electronic random sequence generator was used to allocate treatments. SETTINGS: University, two local mental health care institutions, one local hospital. PARTICIPANTS: 102 pharmacologically treated outpatients with a DSM-IV diagnosis of major depressive disorder, randomized over three treatment arms. INTERVENTION: Six weeks of ESM self-monitoring combined with weekly PA-focused feedback sessions (experimental group); six weeks of ESM self-monitoring combined with six weekly sessions without feedback (pseudo-experimental group); or treatment as usual (control group). MAIN OUTCOME: The interaction between treatment allocation and time in predicting positive and negative affect (NA) was investigated in multilevel regression models. RESULTS: 102 patients were randomized (mean age 48.0, SD 10.2) of which 81 finished the entire study protocol. All 102 patients were included in the analyses. The experimental group did not show a significant larger increase in momentary PA during or shortly after the intervention compared to the pseudo-experimental or control groups (chi2(2) = 0.33, p = .846). The pseudo-experimental group showed a larger decrease in NA compared to the control group (chi2(1) = 6.29, p =.012). CONCLUSION: PA-focused feedback did not significantly impact daily life PA during or shortly after the intervention. As the previously reported reduction in depressive symptoms associated with the feedback unveiled itself only after weeks, it is conceivable that the effects on daily life PA also evolve slowly and therefore were not captured by the experience sampling procedure immediately after treatment. TRIAL REGISTRATION: Trialregister.nl/trialreg/index.asp. NTR1974. PMID- 26034984 TI - A linear city model with asymmetric consumer distribution. AB - The article analyzes a linear-city model where the consumer distribution can be asymmetric, which is important because in real markets this distribution is often asymmetric. The model yields equilibrium price differences, even though the firms' costs are equal and their locations are symmetric (at the two endpoints of the city). The equilibrium price difference is proportional to the transportation cost parameter and does not depend on the good's cost. The firms' markups are also proportional to the transportation cost. The two firms' prices will be equal in equilibrium if and only if half of the consumers are located to the left of the city's midpoint, even if other characteristics of the consumer distribution are highly asymmetric. An extension analyzes what happens when the firms have different costs and how the two sources of asymmetry - the consumer distribution and the cost per unit - interact together. The model can be useful as a tool for further development by other researchers interested in applying this simple yet flexible framework for the analysis of various topics. PMID- 26034985 TI - The efficacy of combining antiangiogenic agents with chemotherapy for patients with advanced non-small cell lung cancer who failed first-line chemotherapy: a systematic review and meta-analysis. AB - BACKGROUND: The clinical outcomes of patients with NSCLC who progressed after first-line treatments remain poor. The purpose of this study was to assess the advantage of antiangiogenic therapy plus standard treatment versus standard treatment alone for this population of patients. METHODS: We conducted a rigorous search using electronic databases for eligible studies reporting antiangiogenic therapy combined with standard second-line chemotherapy versus standard second line treatment for patient who progressed after front-line treatment. Pooled risk ratio and 95% confidence intervals were calculated using proper statistical method. Predefined subgroup analyses were conducted to identify the potential proper patients. RESULTS: Thirteen phase II/III RCTs which involved a total of 8358 participants were included. Overall, there was significant improvement in OS (HR 0.94, 95%CI: 0.89-0.99, p=0.03), PFS (HR 0.80, 95%CI: 0.76-0.84, p<0.00001), ORR (RR 1.75, 95%CI: 1.55-1.98, p<0.00001) and DCR (RR 1.23, 95%CI: 1.18-1.28, p<0.00001) in the group with antiangiogenic therapy plus standard treatment versus the group with standard treatment alone. Subgroup analysis showed that OS benefit was presented only in patients treated with docetaxel plus antiangiogenic agents (HR 0.92, 95%CI: 0.86-0.99, p=0.02) and patients with non-squamous NSCLC (HR for OS 0.92, 95%CI: 0.86-0.99, p=0.02). CONCLUSIONS: This study revealed that the addition of antiangiogenic agents to the standard treatments could provide clinical benefit to NSCLC patients who failed their first-line therapy. Furthermore, proper selection of the combined standard cytotoxic agent, as well as the patient population by tumor histology, is warranted for future studies and clinical application of antiangiogenic therapy. PMID- 26034986 TI - Proximity Ligation In situ Assay is a Powerful Tool to Monitor Specific ATG Protein Interactions following Autophagy Induction. AB - Macroautophagy is a highly regulated intracellular degradation process which has been extensively studied over the last decade. This pathway has been initially described as a non selective process inducing the degradation of parts of the cytoplasm as well as organelles at random. Nevertheless, over the last few years, new research highlighted the existence of a more selective autophagy pathway specifically recruiting some organelles or aggregates to the autophagosomes in order to induce their degradation. These selective autophagy pathways such as aggrephagy, mitophagy, pexophagy or xenophagy, involve the intervention of a cargo, the material to be degraded, cargo adapters, the molecules allowing the recruitment of the cargo to the autophagosome, and the proteins of the ATG8 family which link the cargo adapters to the autophagosome. One of the main questions which now remain is to develop new techniques and protocols able to discriminate between these different types of induced autophagy. In our work, we studied the possibility to use the P-LISA technique, which has been recently developed to study endogenous in vivo protein interactions, as a new technique to characterize the ATG proteins specifically involved in bulk or selective autophagy. In this manuscript, we indeed demonstrate that this technique allows the study of endogenous ATG protein interactions in cells following autophagy induction, but more interestingly that this technique might be used to characterize the ATG proteins involved in selective autophagy. PMID- 26034987 TI - Accuracy and feasibility of point-of-care white blood cell count and C-reactive protein measurements at the pediatric emergency department. AB - BACKGROUND: Several point-of-care (POC) tests are available for evaluation of febrile patients, but the data about their performance in acute care setting is sparse. We investigated the analytical accuracy and feasibility of POC tests for white blood cell (WBC) count and C-reactive protein (CRP) at the pediatric emergency department (ED). METHODS: In the first part of the study, HemoCue WBC and Afinion AS100 CRP POC analyzers were compared with laboratory's routine WBC (Sysmex XE-2100) and CRP (Modular P) analyzers in the hospital central laboratory in 77 and 48 clinical blood samples, respectively. The POC tests were then adopted in use at the pediatric ED. In the second part of the study, we compared WBC and CRP levels measured by POC and routine methods during 171 ED patient visits by 168 febrile children and adolescents. Attending physicians performed POC tests in capillary fingerprick samples. RESULTS: In parallel measurements in the laboratory both WBC and CRP POC analyzers showed good agreement with the reference methods. In febrile children at the emergency department (median age 2.4 years), physician performed POC determinations in capillary blood gave comparable results with those in venous blood analyzed in the laboratory. The mean difference between POC and reference test result was 1.1 E9/L (95% limits of agreement from -6.5 to 8.8 E9/L) for WBC and -1.2 mg/L (95% limits of agreement from -29.6 to 27.2 mg/L) for CRP. CONCLUSIONS: POC tests are feasible and relatively accurate methods to assess CRP level and WBC count among febrile children at the ED. PMID- 26034988 TI - Effects of assimilable organic carbon and free chlorine on bacterial growth in drinking water. AB - Assimilable organic carbon (AOC) is one of the most important factors affecting the re-growth of microorganisms in drinking water. High AOC concentrations result in biological instability, but disinfection kills microbes to ensure the safety of drinking water. Free chlorine is an important oxidizing agent used during the disinfection process. Therefore, we explored the combined effects of AOC and free chlorine on bacterial growth in drinking water using flow cytometry (FCM). The initial AOC concentration was 168 MUg.L(-1) in all water samples. Without free chlorine, the concentrations of intact bacteria increased but the level of AOC decreased. The addition of sodium hypochlorite caused an increase and fluctuation in AOC due to the oxidation of organic carbon. The concentrations of intact bacteria decreased from 1.1 * 10(5) cells.mL(-1) to 2.6 * 10(4) cells.mL(-1) at an initial free chlorine dose of 0.6 mg.L(-1) to 4.8 * 10(4) cells.mL(-1) at an initial free chlorine dose of 0.3 mg.L(-1) due to free chlorine originating from sodium hypochlorite. Additionally, free chlorine might be more obviously affected AOC concentrations than microbial growth did. These results suggested that AOC and free chlorine might have combined effects on microbial growth. In this study, our results showed concentrations determined by FCM were higher than those by HPC, which indicated that some E. coli detected by FCM might not be detected using HPC in drinking water. The level of free chlorine might restrain the consumption of AOC by inhibiting the growth of E. coli; on the other hand, chlorination might increase the level of AOC, thereby increase the potential for microbial growth in the drinking water network. PMID- 26034989 TI - Response of the cholesterol metabolism to a negative energy balance in dairy cows depends on the lactational stage. AB - The response of cholesterol metabolism to a negative energy balance (NEB) induced by feed restriction for 3 weeks starting at 100 days in milk (DIM) compared to the physiologically occurring NEB in week 1 postpartum (p.p.) was investigated in 50 dairy cows (25 control (CON) and 25 feed-restricted (RES)). Blood samples, liver biopsies and milk samples were taken in week 1 p.p., and in weeks 0 and 3 of feed restriction. Plasma concentrations of total cholesterol (C), phospholipids (PL), triglycerides (TAG), very low density lipoprotein-cholesterol (VLDL-C) and low density lipoprotein-cholesterol (LDL-C) increased in RES cows from week 0 to 3 during feed restriction and were higher in week 3 compared to CON cows. In contrast, during the physiologically occurring NEB in week 1 p.p., C, PL, TAG and lipoprotein concentrations were at a minimum. Plasma phospholipid transfer protein (PLTP) and lecithin:cholesterol acyltransferase (LCAT) activities did not differ between week 0 and 3 for both groups, whereas during NEB in week 1 p.p. PLTP activity was increased and LCAT activity was decreased. Milk C concentration was not affected by feed restriction in both groups, whereas milk C mass was decreased in week 3 for RES cows. In comparison, C concentration and mass in milk were elevated in week 1 p.p. Hepatic mRNA abundance of sterol regulatory element-binding factor-2 (SREBF-2), 3-hydroxy-3-methylglutaryl coenzyme A synthase 1 (HMGCS1), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), and ATP-binding cassette transporter (ABCA1) were similar in CON and RES cows during feed restriction, but were upregulated during NEB in week 1 p.p. compared to the non-lactating stage without a NEB. In conclusion, cholesterol metabolism in dairy cows is affected by nutrient and energy deficiency depending on the stage of lactation. PMID- 26034990 TI - The Role of Inducible Hsp70, and Other Heat Shock Proteins, in Adaptive Complex of Cold Tolerance of the Fruit Fly (Drosophila melanogaster). AB - BACKGROUND: The ubiquitous occurrence of inducible Heat Shock Proteins (Hsps) up regulation in response to cold-acclimation and/or to cold shock, including massive increase of Hsp70 mRNA levels, often led to hasty interpretations of its role in the repair of cold injury expressed as protein denaturation or misfolding. So far, direct functional analyses in Drosophila melanogaster and other insects brought either limited or no support for such interpretations. In this paper, we analyze the cold tolerance and the expression levels of 24 different mRNA transcripts of the Hsps complex and related genes in response to cold in two strains of D. melanogaster: the wild-type and the Hsp70- null mutant lacking all six copies of Hsp70 gene. PRINCIPAL FINDINGS: We found that larvae of both strains show similar patterns of Hsps complex gene expression in response to long-term cold-acclimation and during recovery from chronic cold exposures or acute cold shocks. No transcriptional compensation for missing Hsp70 gene was seen in Hsp70- strain. The cold-induced Hsps gene expression is most probably regulated by alternative splice variants C and D of the Heat Shock Factor. The cold tolerance in Hsp70- null mutants was clearly impaired only when the larvae were exposed to severe acute cold shock. No differences in mortality were found between two strains when the larvae were exposed to relatively mild doses of cold, either chronic exposures to 0 degrees C or acute cold shocks at temperatures down to -4 degrees C. CONCLUSIONS: The up-regulated expression of a complex of inducible Hsps genes, and Hsp70 mRNA in particular, is tightly associated with cold-acclimation and cold exposure in D. melanogaster. Genetic elimination of Hsp70 up-regulation response has no effect on survival of chronic exposures to 0 degrees C or mild acute cold shocks, while it negatively affects survival after severe acute cold shocks at temperatures below -8 degrees C. PMID- 26034992 TI - Resistivity coefficients for body composition analysis using bioimpedance spectroscopy: effects of body dominance and mixture theory algorithm. AB - Body composition is commonly predicted from bioelectrical impedance spectroscopy using mixture theory algorithms. Mixture theory algorithms require the input of values for the resistivities of intra-and extracellular water of body tissues. Various derivations of these algorithms have been published, individually requiring resistivity values specific for each algorithm. This study determined apparent resistivity values in 85 healthy males and 66 healthy females for each of the four published mixture theory algorithms. The resistivity coefficients determined here are compared to published values and the inter-individual (biological) variation discussed with particular reference to consequential error in prediction of body fluid volumes. In addition, the relationships between the four algorithmic approaches are derived and methods for the inter-conversion of coefficients between algorithms presented. PMID- 26034993 TI - Variability in Use of Health Services and Its Association with Self-Management Skills: A Population-Based Exploratory Analysis. AB - Self-management skills are helpful in making appropriate health-related decisions; however, improvements in self-management skills do not always translate into changes in health services utilization. Therefore, to assess associations between self-management skills and health services use, a randomly selected sample of 984 residents was drawn from South East Queensland, Australia. This cross-sectional study collected self-reported data on respondents' use of health services, health-related behaviors, demographics, and 3 self-management skills: self-monitoring, health services navigation, and social mobilization. The results indicate that the ability to navigate the health system was associated with greater use of health services while the ability to mobilize one's social supports was associated with reduced use of allied health services. Being able to navigate the health system appeared to be driven by necessity, in that those with higher navigation skills were unemployed, financially stressed, or had a chronic condition. This pattern of results confirms the socioeconomic gradient that exists in health. PMID- 26034991 TI - Investigating the Association between Flowering Time and Defense in the Arabidopsis thaliana-Fusarium oxysporum Interaction. AB - Plants respond to pathogens either by investing more resources into immunity which is costly to development, or by accelerating reproductive processes such as flowering time to ensure reproduction occurs before the plant succumbs to disease. In this study we explored the link between flowering time and pathogen defense using the interaction between Arabidopsis thaliana and the root infecting fungal pathogen Fusarium oxysporum. We report that F. oxysporum infection accelerates flowering time and regulates transcription of a number of floral integrator genes, including FLOWERING LOCUS C (FLC), FLOWERING LOCUS T (FT) and GIGANTEA (GI). Furthermore, we observed a positive correlation between late flowering and resistance to F. oxysporum in A. thaliana natural ecotypes. Late flowering gi and autonomous pathway mutants also exhibited enhanced resistance to F. oxysporum, supporting the association between flowering time and defense. However, epistasis analysis showed that accelerating flowering time by deletion of FLC in fve-3 or fpa-7 mutants did not alter disease resistance, suggesting that the effect of autonomous pathway on disease resistance occurs independently from flowering time. Indeed, RNA-seq analyses suggest that fve-3 mediated resistance to F. oxysporum is most likely a result of altered defense-associated gene transcription. Together, our results indicate that the association between flowering time and pathogen defense is complex and can involve both pleiotropic and direct effects. PMID- 26034994 TI - MicroRNA-491-5p suppresses cervical cancer cell growth by targeting hTERT. AB - MicroRNAs (miRNAs) are small non-coding RNAs that have been shown to regulate a variety of biological processes by targeting messenger RNA. MicroRNA-491-5p (miR 491-5p), an important miRNA, has been demonstrated to be involved in the processes of initiation and progression in several tumors. However, the precise biological function of miR-491-5p and its molecular mechanism in cervical cancer cells remain elusive. The present study was carried out to investigate the clinical significance and prognostic value of miR-491-5p expression in cervical cancer, and to evaluate the role of miR-491-5p and the underlying molecular mechanisms involved in cervical cancer. The results showed that miR-491-5p expression was significantly downregulated in cervical cancer tissues when compared with the corresponding adjacent normal tissues (P<0.001), and the value was negatively associated with advanced International Federation of Gynecology and Obstetrics (FIGO) stage, high histological grading and lymph node metastasis (P<0.01). The enforced expression of miR-491-5p in cervical cancer cells significantly inhibited proliferation, migration and invasion, induced cell apoptosis, and suppressed the tumor growth of the mouse model of HeLa cells. In addition, the dual-luciferase reporter assay revealed that human telomerase reverse transcriptase (hTERT) was identified as a novel target gene of miR-491 5p. Notably, it was found that miR-491-5p regulated the PI3K/AKT signaling pathway. These results suggested that targeting miR-491-5p is a strategy for blocking the development of cervical cancer. PMID- 26034996 TI - Air-Stable Gold Nanoparticles Ligated by Secondary Phosphine Oxides as Catalyst for the Chemoselective Hydrogenation of Substituted Aldehydes: a Remarkable Ligand Effect. AB - Air-stable and homogeneous gold nanoparticles (AuNPs, 1a-5a) ligated by various secondary phosphine oxides (SPOs), [R(1)R(2)P(O)H] (R(1) = Naph, R(2) = (t)Bu, L1; R(1) = R(2) = Ph, L2; R(1) = Ph, R(2) = Naph, L3; R(1) = R(2) = Et, L4; R(1) = R(2) = Cy, L5; R(1) = R(2) = (t)Bu, L6), with different electronic and steric properties were synthesized via NaBH4 reduction of the corresponding Au(I)-SPO complex. These easily accessible ligands allow the formation of well dispersed and small nanoparticles (size 1.2-2.2 nm), which were characterized by the use of a wide variety of techniques, such as transmission electron microscopy, thermogravimetric analysis, UV-vis, energy-dispersive X-ray, X-ray photoelectron spectroscopy (XPS), attenuated total reflectance Fourier transform infrared spectroscopy (ATR FT-IR), and cross polarization magic angle spinning (CP MAS) NMR spectroscopy. A pronounced ligand effect was found, and CP MAS NMR experiments enabled us to probe important differences in the polarity of the P-O bond of the SPOs coordinated to the nanoparticle surface depending on the type of substituents in the ligand. AuNPs containing aryl SPOs carry only SPO anions and are highly selective for aldehyde hydrogenation. AuNPs of similar size made with alkyl SPOs contain also SPOH, hydrogen bonded to SPO anions. As a consequence they contain less Au(I) and more Au(0), as is also evidenced by XPS. They are less selective and active in aldehyde hydrogenation and now show the typical activity of Au(0)NPs in nitro group hydrogenation. PMID- 26034997 TI - A possible molecular mechanism of hearing loss during cerebral ischemia in mice. AB - Ischemic brain stroke is a leading cause of disability and includes hearing loss. Clinical reports have also suggested that there is hearing loss in stroke patients but the mechanism was not determined. Therefore, we hypothesized that hearing loss after cerebral ischemia may be associated with changes to the synapse, gap junction, and sodium channel (NaC) proteins. Ischemia-reperfusion injury was induced in wild-type mice (I/R group). The lesion volume was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining of the brain sections. BBB disruption was confirmed by Evans blue staining and leakage of bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC). We found that brain edema, infarct size, and permeability were increased in ischemic mice as compared with the sham-operated group. Caspase-3, caspase-9, and TUNEL positive cells were increased in I/R mice, indicating neuronal apoptosis. Moreover, there were increased expressions of matrix metalloprotease's (MMP-2, 3, -9, and -13), interleukin (IL)-6, and decreased expressions of tight junction proteins (TJP) in the I/R group, as compared with the sham group, which signifies inflammation and BBB disruption. We also observed decreased levels of post synaptic density protein-95 (PSD-95), synapse-associated protein 97 (SAP-97), connexin-43, NaC-alpha, and NaC-beta, and increased expression of connexin-45, whereas no substantial change was observed in connexin-26 expression in the I/R group. Interestingly, auditory response was reduced in the I/R mice, indicating hearing loss. These data suggest that hearing loss in ischemic mice was primarily due to alterations in connexin, synapses, and NaC channels. PMID- 26034998 TI - Functionalized Collagen Scaffold Neutralizing the Myelin-Inhibitory Molecules Promoted Neurites Outgrowth in Vitro and Facilitated Spinal Cord Regeneration in Vivo. AB - Research has demonstrated that many myelin-associated inhibitory molecules jointly contribute to the failure of adult spinal cord regeneration. Therapies comprehensively targeting the multiple inhibitory nature of the injured spinal cord are being concerned. Here, two collagen-binding proteins, CBD-EphA4LBD and CBD-PlexinB1LBD, were constructed, respectively, to neutralize the axon guidance molecules ephrinB3 and sema4D that inhibit the regeneration of nerve fibers. The two neutralizing proteins have proven their ability to specifically bind collagen and to continuously release from collagen scaffolds. They could also promote neurites outgrowth of cerebellar granular neurons and dorsal root ganglion neurons in vitro. Subsequently, the functionalized collagen scaffolds by physically absorbing NEP1-40 and immobilizing CBD-EphA4LBD and CBD-PlexinB1LBD were transplanted into a rat T10 complete spinal cord transection model. Our results showed that rats that received the treatment of transplanting the functionalized collagen scaffold exhibited great advantage on axonal regeneration and locomotion recovery after spinal cord injury. PMID- 26034999 TI - Nanoalloy Printed and Pulse-Laser Sintered Flexible Sensor Devices with Enhanced Stability and Materials Compatibility. AB - While conformal and wearable devices have become one of the most desired formats for printable electronics, it is challenging to establish a scalable process that produces stable conductive patterns but also uses substrates compatible with widely available wearable materials. Here, we describe findings of an investigation of a nanoalloy ink printed and pulsed-laser sintered conductive patterns as flexible functional devices with enhanced stability and materials compatibility. While nanoparticle inks are desired for printable electronics, almost all existing nanoparticle inks are based on single-metal component, which, as an electronic element, is limited by its inherent stabilities of the metal such as propensity of metal oxidation and mobility of metal ions, especially in sintering processes. The work here has demonstrated the first example in exploiting plasmonic coupling of nanoalloys and pulsed-laser energy with controllable thermal penetration. The experimental and theoretical results have revealed clear correlation between the pulsed laser parameters and the nanoalloy structural characteristics. The superior performance of the resulting flexible sensor device, upon imparting nanostructured sensing materials, for detecting volatile organic compounds has significant implications to developing stable and wearable sensors for monitoring environmental pollutants and breath biomarkers. This simple "nanoalloy printing-laser sintering-nanostructure printing" process is entirely general to many different sensor devices and nanostructured sensing materials, enabling the ability to easily construct sophisticated sensor array. PMID- 26035000 TI - Crystalline Bis-urea Nanochannel Architectures Tailored for Single-File Diffusion Studies. AB - Urea is a versatile building block that can be modified to self-assemble into a multitude of structures. One-dimensional nanochannels with zigzag architecture and cross-sectional dimensions of only ~3.7 A * 4.8 A are formed by the columnar assembly of phenyl ether bis-urea macrocycles. Nanochannels formed by phenylethynylene bis-urea macrocycles have a round cross-section with a diameter of ~9.0 A. This work compares the Xe atom packing and diffusion inside the crystalline channels of these two bis-ureas using hyperpolarized Xe-129 NMR. The elliptical channel structure of the phenyl ether bis-urea macrocycle produces a Xe-129 powder pattern line shape characteristic of an asymmetric chemical shift tensor with shifts extending to well over 300 ppm with respect to the bulk gas, reflecting extreme confinement of the Xe atom. The wider channels formed by phenylethynylene bis-urea, in contrast, present an isotropic dynamically average electronic environment. Completely different diffusion dynamics are revealed in the two bis-ureas using hyperpolarized spin-tracer exchange NMR. Thus, a simple replacement of phenyl ether with phenylethynylene as the rigid linker unit results in a transition from single-file to Fickian diffusion dynamics. Self assembled bis-urea macrocycles are found to be highly suitable materials for fundamental molecular transport studies on micrometer length scales. PMID- 26035002 TI - Bimodal Phonon Scattering in Graphene Grain Boundaries. AB - Graphene has served as the model 2D system for over a decade, and the effects of grain boundaries (GBs) on its electrical and mechanical properties are very well investigated. However, no direct measurement of the correlation between thermal transport and graphene GBs has been reported. Here, we report a simultaneous comparison of thermal transport in supported single crystalline graphene to thermal transport across an individual graphene GB. Our experiments show that thermal conductance (per unit area) through an isolated GB can be up to an order of magnitude lower than the theoretically anticipated values. Our measurements are supported by Boltzmann transport modeling which uncovers a new bimodal phonon scattering phenomenon initiated by the GB structure. In this novel scattering mechanism, boundary roughness scattering dominates the phonon transport in low mismatch GBs, while for higher mismatch angles there is an additional resistance caused by the formation of a disordered region at the GB. Nonequilibrium molecular dynamics simulations verify that the amount of disorder in the GB region is the determining factor in impeding thermal transport across GBs. PMID- 26035001 TI - Modeling Protein-Micelle Systems in Implicit Water. AB - Several membrane proteins and numerous membrane-active peptides have been studied in detergent micelles by solution NMR. However, the detailed structure of these complexes remains unknown. We propose a modeling approach that treats the protein and detergent in atomistic detail and the solvent implicitly. The model is based on previous work on dodecylphosphocholine micelles, adapted for use with the CHARMM36 force field and extended to sodium dodecyl sulfate micelles. Solvation parameters were slightly adjusted to reproduce experimental data on aggregation numbers and critical micelle concentrations. To test the approach, several membrane-active peptides and three beta-barrel membrane proteins were subjected to molecular dynamics simulations in the presence of a large number of detergent molecules. Their experimentally determined secondary structure was maintained and the RMSD values were less than 2 A. Deformations were commonly observed in the N or C termini. The atomistic view of the protein-micelle systems that this approach provides could be useful in interpreting biophysical experiments carried out in the presence of detergent. PMID- 26035003 TI - Synthesis of B,O,N-Doped Adamantanes and Diamantanes by Condensation of Oximes with Boronic Acids. AB - Condensation of oximes with boronic acids RB(OH)2 or B(OH)3 affords remarkably stable 2,4,10-trioxa-1,5,7-triaza-3-boroadamantanes via an unprecedented multicomponent process. The mechanism involves the reversible generation of unstable oxime cyclotrimers, which are readily intercepted by boronic acids. PMID- 26035004 TI - 2014 review, 2015 preview. PMID- 26035005 TI - Resilience of oocyte germinal vesicles to microwave-assisted drying in the domestic cat model. AB - The ability to compact and inject the cat germinal vesicle (GV) into a recipient cytoplast allows exploration of a new fertility preservation strategy that avoids whole oocyte freezing. The objective of the present study was to understand the impact of water loss and storage time on GV DNA integrity. Immature cat oocytes were exposed to 1.5 M trehalose for 10 min before microwave-assisted dehydration for 0, 5, 10, 15, 20, 25, 30, or 40 min. Oocytes then were rehydrated to assess chromatin configuration and the incidence of DNA fragmentation (TUNEL assay). The moisture content progressively decreased (p<0.05) from 1.7 to 0.1 gH2O/gDW over the first 30 min, but did not decrease further (p>0.05) after 40 min. Chromatin configuration was unaffected (p>0.05) over time. The percentage of GVs with DNA fragmentation was unaltered (p>0.05) from 0 to 30 min of treatment (range, 6.1% 12%), but increased (p<0.05) to 32.5% after 40 min. Next, the influence of storage at two different supra-zero temperatures after 30 min of drying was investigated. Oocyte-loaded, microwave-treated filters were individually sealed in Dri-Shield moisture barrier bags and stored at 4 degrees C or ambient temperature for 0 to 8 weeks. Moisture contents gradually decreased (p<0.05) from 0.12 to 0.10 gH2O/gDW after 8 weeks of storage at 4 degrees C or ambient temperature. The percentage of GVs with DNA fragmentation more than doubled (p<0.05) from 0 (14.3%) to 2 days (30.0%-33.0%), but remained stable (p>0.05) thereafter (1 through 4 weeks, 25.0%-35.0%). Collective results demonstrate the feasibility of using microwave processing to dehydrate the mammalian GV to a moisture content that is nonlethal and enables nonfrozen storage, an alternative approach for preserving the maternal genome at cool or ambient temperature. PMID- 26035006 TI - The importance of biobanking in cancer research. AB - BACKGROUND: Establishing the importance of biobanking in cancer research is important for research funders and for planning health research infrastructure. This study delineates the importance of biobanking to the cancer research landscape in Canada and relative to other forms of health research infrastructure. METHODS: The Cancer Research Society (CRS) is a Canadian organization with a broad mission and national portfolio that funds studies across the spectrum of cancer research. We selected all 35 investigators who received CRS grants in the 2010/11 competition and then analyzed their publications from 2010 to 2014. Articles were categorized by overall research area, acknowledged source of funding, specific scientific focus, and the presence of any data that involved an 'indicator' (human biospecimens, cell lines, animal models, advanced microscopy, flow cell sorters, and next generation sequencing) of dependence on different kinds of health research infrastructures. Publications involving biobanking and utilizing biospecimens were further classified by biospecimen provenance and type of biospecimen used. RESULTS: These investigators generated 502 (from a total of 749) papers that were related to the field of cancer research. Amongst 445 papers that contained primary data, we found no significant differences between CRS funded and 'other funded' papers in terms of biospecimen use, which occurred in 38% of articles. Overall biospecimens were mostly obtained directly from patients (17%), or indirectly from biorepositories (31%) and hospitals (46%). The proportions of studies using other tools was as follows: 54% cell lines, 32% animal models, 14% advanced microscopy, 14% flow sorters, and 8% next generation sequencing. The spectrum of research was very similar to the overall profile of cancer research in Canada in 2010. CONCLUSIONS: This study suggests that biorepositories that coordinate the activity of biobanking rank amongst the most important of established health research infrastructures as contributors to research publications. PMID- 26035007 TI - The hybrid synthetic microdata platform: a method for statistical disclosure control. AB - Owners of biobanks are in an unfortunate position: on the one hand, they need to protect the privacy of their participants, whereas on the other, their usefulness relies on the disclosure of the data they hold. Existing methods for Statistical Disclosure Control attempt to find a balance between utility and confidentiality, but come at a cost for the analysts of the data. We outline an alternative perspective to the balance between confidentiality and utility. By combining the generation of synthetic data with the automated execution of data analyses, biobank owners can guarantee the privacy of their participants, yet allow the analysts to work in an unrestricted manner. PMID- 26035008 TI - Quality management of biorepositories. AB - Biomedical investigators require high quality human tissue to support their research; thus, an important aspect of the provision of tissues by biorepositories is the assurance of high quality and consistency of processing specimens. This is best accomplished by a quality management system (QMS). This article describes the basis of a QMS program designed to aid biorepositories that want to improve their operations. In 1983, the UAB Tissue Collection and Biobanking Facility (TCBF) introduced a QMS program focused on providing solid tissues to support a wide range of research; this QMS included a quality control examination of the specific specimens provided for research. Similarly, the Division of Laboratory Sciences at the Centers for Disease Control and Prevention (CDC) introduced a QMS program for their laboratory analyses, focused primarily on bodily fluids. The authors of this article bring together the experience of the QMS programs at these two sites to facilitate the development or improvement of quality management systems of a wide range of biorepositories. PMID- 26035009 TI - Establishment and cryopreservation of a giant panda skeletal muscle-derived cell line. AB - The giant panda Ailuropoda melanoleuca is an endangered species and is a symbol for wildlife conservation. Although efforts have been made to protect this rare and endangered species through breeding and conservative biology, the long-term preservation of giant panda genome resources (gametes, tissues, organs, genomic libraries, etc.) is still a practical option. In this study, the giant panda skeletal muscle-derived cell line was successfully established via primary explants culture and cryopreservation techniques. The population doubling time of giant panda skeletal cells was approximately 33.8 h, and this population maintained a high cell viability before and after cryopreservation (95.6% and 90.7%, respectively). The two skeletal muscle-specific genes SMYD1 and MYF6 were expressed and detected by RT-PCR in the giant panda skeletal muscle-derived cell line. Karyotyping analysis revealed that the frequencies of giant panda skeletal muscle cells showing a chromosome number of 2n=42 ranged from 90.6~94.2%. Thus, the giant panda skeletal muscle-derived cell line provides a vital resource and material platform for further studies and is likely to be useful for the protection of this rare and endangered species. PMID- 26035010 TI - The influence of tissue procurement procedures on RNA integrity, gene expression, and morphology in porcine and human liver tissue. AB - The advent of molecular characterization of tissues has brought an increasing emphasis on the quality of biospecimens, starting with the tissue procurement process. RNA levels are particularly affected by factors in the collection process, but the influence of different pre-analytical factors is not well understood. Here we present the influence of tissue specimen size, as well as the transport and freezing protocols, on RNA quality. Large, medium, and smaller porcine liver samples were stored either dry, on moist gauze, or in salt solution for various times, and then frozen in either liquid nitrogen or in pre-cooled isopentane. Large and small human liver samples were frozen in pre-cooled isopentane either immediately or after one hour at room temperature. The small samples were stored dry, on moist gauze, or in salt solution. RNA was isolated and RIN values were measured. The RNA for six standard reference genes from human liver was analyzed by RT-qPCR, and tissue morphology was assessed for artifacts of freezing. Experiments using porcine liver samples showed that RNA derived from smaller samples was more degraded after one hour of cold ischemia, and that cooled transport is preferable. Human liver samples showed significant RNA degradation after 1 h of cold ischemia, which was more pronounced in smaller samples. RNA integrity was not significantly influenced by the transport or freezing method, but changes in gene expression were observed in samples either transported on gauze or in salt solution. Based on observations in liver samples, smaller samples are more subject to gene expression variability introduced by post-excision sample handling than are larger samples. Small biopsies should be transported on ice and snap frozen as soon as possible after acquisition from the patient. PMID- 26035011 TI - Specific legislation on biobanks in Spain. AB - Spain has enacted specific legislation concerning biobanks. This legislation regulates how biobanks should be set up, how they should operate, and the requirements they need to comply with. The main objective of this legislation is to keep a good balance between scientific progress and respect for the rights and freedom of individuals participating in research. Therefore, this legislation lays down a series of basic principles, for instance, the principle to inform donors accurately i) on the deposit of samples in terms of the objectives and implications of their donation and on the need to obtain written consents; ii) on the obligation to establish consistent procedures to guarantee the confidentiality of personal data associated with and obtained from biological samples; iii) on the concept of free sample donation either by donors or by biobanks; iv) on the need for consistent procedures to deposit samples and data in biobanks; and v) for acts of donation and data for research projects to be performed correctly. Although this Spanish legislation fulfills its objectives, it has some drawbacks; mainly it overprotects research participants. This issue should be analyzed in future revisions of the legislation. PMID- 26035012 TI - Biobank classification in an Australian setting. AB - In 2011, Watson and Barnes proposed a schema for classifying biobanks into 3 groups (mono-, oligo-, and poly-user), primarily based upon biospecimen access policies. We used results from a recent comprehensive survey of cancer biobanks in New South Wales, Australia to assess the applicability of this biobank classification schema in an Australian setting. Cancer biobanks were identified using publically available data, and by consulting with research managers. A comprehensive survey was developed and administered through a face-to-face setting. Data were analyzed using Microsoft ExcelTM 2010 and IBM SPSS StatisticsTM version 21.0. The cancer biobank cohort (n=23) represented 5 mono user biobanks, 7 oligo-user biobanks, and 11 poly-user biobanks, and was analyzed as two groups (mono-/oligo- versus poly-user biobanks). Poly-user biobanks employed significantly more full-time equivalent staff, and were significantly more likely to have a website, share staff between biobanks, access governance support, utilize quality control measures, be aware of biobanking best practice documents, and offer staff training. Mono-/oligo-user biobanks were significantly more likely to seek advice from other biobanks. Our results further delineate a biobank classification system that is primarily based on access policy, and demonstrate its relevance in an Australian setting. PMID- 26035013 TI - Evaluation of cross-sample contamination in tissue microarrays by polymerase chain reaction. AB - In the past decade, the popularity and power of Tissue Microarray (TMA) technology has increased since it provides a method to detect diagnostic and prognostic markers in an array of clinical tissue specimens collected for translational research. TMAs allow for rapid and cost-effective analysis of hundreds of molecular markers at the nucleic acid and protein levels. This technology is particularly useful in the realization of the Human Protein Atlas Project, since it aims to create a reference database of non-redundant human proteins. In this context, it is important to assure the lack of cross-sample contamination due to the repeated use of the same needle in consecutive coring. Here we show that carry-over contamination from one tissue core to another does not occur, reinforcing the accuracy of the TMA technology in the simultaneous testing of multiple bio-samples. PMID- 26035014 TI - The biobank at the University of Texas Health Science Center at Houston. PMID- 26035015 TI - Road Map for the Future: The ISBER Strategic Plan. PMID- 26035016 TI - Force Balance Model for Bubble Rise, Impact, and Bounce from Solid Surfaces. AB - A force balance model for the rise and impact of air bubbles in a liquid against rigid horizontal surfaces that takes into account effects of buoyancy and hydrodynamic drag forces, bubble deformation, inertia of the fluid via an added mass force, and a film force between the bubble and the rigid surface is proposed. Numerical solution of the governing equations for the position and velocity of the center of mass of the bubbles is compared against experimental data taken with ultraclean water. The boundary condition at the air-water interface is taken to be stress free, which is consistent for bubbles in clean water systems. Features that are compared include bubble terminal velocity, bubbles accelerating from rest to terminal speed, and bubbles impacting and bouncing off different solid surfaces for bubbles that have already or are yet to attain terminal speed. Excellent agreement between theory and experiments indicates that the forces included in the model constitute the main physical ingredients to describe the bouncing phenomenon. PMID- 26035017 TI - Modeling Nonlinear Adsorption with a Single Chemical Parameter: Predicting Chemical Median Langmuir Binding Constants. AB - Procedures for accurately predicting linear partition coefficients onto various sorbents (e.g., organic carbon, soils, clay) are reliable and well established. However, similar procedures for the prediction of sorption parameters of nonlinear isotherm models are not. The purpose of this paper is to present a procedure for predicting nonlinear isotherm parameters, specifically the median Langmuir binding constants, KL, obtained utilizing the single-chemical parameter log-normal Langmuir isotherm developed in the accompanying work. A reduced poly parameter linear free energy relationship (pp-LFER) is able to predict median Langmuir binding constants for graphite, charcoal, and Darco granular activated carbon (GAC) adsorption data. For the larger F400 GAC data set, a single pp-LFER model was insufficient, as a plateau is observed for the median Langmuir binding constants of larger molecular volume sorbates. This volumetric cutoff occurs in proximity to the median pore diameter for F400 GAC. A log-linear relationship exists between the aqueous solubility of these large compounds and their median Langmuir binding constants. Using this relationship for the chemicals above the volumetric cutoff and the pp-LFER below the cutoff, the median Langmuir binding constants can be predicted with a root-mean square error for graphite (n = 13), charcoal (n = 11), Darco GAC (n = 14), and F400 GAC (n = 44) of 0.129, 0.307, 0.407, and 0.424, respectively. PMID- 26035018 TI - Soudanones A-G: Antifungal Isochromanones from the Ascomycetous Fungus Cadophora sp. Isolated from an Iron Mine. AB - One new isochromane (pseudoanguillosporin C, 2), seven isochromanones (soudanones A-G, 3-9), and six known analogues including 10 and 11 were isolated from a culture of the fungus Cadophora sp. 10-5-2 M, collected from the subterranean 10th level of the Soudan Underground Iron Mine in Minnesota. All of the compounds were tested against a panel of microbial pathogens, and 2, 3, 10, and 11 were found to have activity against Cryptococcus neoformans (MIC = 35, 40, 20, and 30 MUg/mL, respectively). Compound 11 was also active against Candida albicans, with an MIC of 40 MUg/mL. PMID- 26035019 TI - Synthesis of double-fluorescent labeled prion protein for FRET analysis. AB - An abnormal form of prion protein (PrP) is considered to be the pathogen in prion diseases. However, the structural details of this abnormal form are not known. To characterize the non-native structure of PrP, we synthesized position-specific double-fluorescent labeled PrP for a fluorescence resonance energy transfer (FRET) experiment. Using FRET, we observed a conformational change in the labeled PrP associated with amyloid fibril formation. The FRET analysis indicated that the distance between fluorescent labeled N- and C-terminal sites of PrP increased upon the formation of amyloid fibrils compared with that of the native state. This approach using FRET analysis is useful for elucidating the structure of abnormal PrP. PMID- 26035020 TI - The antihyperlipidemic mechanism of high sulfate content ulvan in rats. AB - Numerous studies have suggested that hyperlipidemia is closely linked to cardiovascular disease. The aim of this study was to investigate the possible antihyperlipidemia mechanism of HU (high sulfate content of ulvan) in high cholesterol fed rats. Wistar rats were made hyperlipidemic by feeding with a high cholesterol diet. HU was administered to these hyperlipidemia rats for 30 days. Lipid levels and the mRNA expressions of FXR, LXR and PPARgamma in liver were measured after 30 days of treatment. In the HU-treated groups, the middle dosage group of male rats (total cholesterol (TC): p < 0.01) and the low-dosage group of female rats (TC, LDL-C: p < 0.01) showed stronger activity with respect to antihyperlipidemia. Moreover, some HU groups could upregulate the mRNA expression of FXR and PPARgamma and downregulate the expression of LXR. For the male rats, compared with the hyperlipidemia group, the middle dosage HU had the most pronounced effect on increasing the mRNA levels of FXR (p < 0.01); low- and high dosage HU showed a significant inhibition of the mRNA levels of LXR (p < 0.01). All HU female groups could upregulate the mRNA expression of PPARgamma in a concentration-dependent manner. In summary, HU could improve lipid profiles through upregulation of FXR and PPARgamma and downregulation of LXR. PMID- 26035021 TI - Biological Properties of Fucoxanthin in Oil Recovered from Two Brown Seaweeds Using Supercritical CO2 Extraction. AB - The bioactive materials in brown seaweeds hold great interest for developing new drugs and healthy foods. The oil content in brown seaweeds (Saccharina japonica and Sargassum horneri) was extracted by using environmentally friendly supercritical CO2 (SC-CO2) with ethanol as a co-solvent in a semi-batch flow extraction process and compared the results with a conventional extraction process using hexane, ethanol, and acetone mixed with methanol (1:1, v/v). The SC CO2 method was used at a temperature of 45 degrees C and pressure of 250 bar. The flow rate of CO2 (27 g/min) was constant for the entire extraction period of 2 h. The obtained oil from the brown seaweeds was analyzed to determine their valuable compounds such as fatty acids, phenolic compounds, fucoxanthin and biological properties including antioxidant, antimicrobial, and antihypertension effects. The amounts of fucoxanthin extracted from the SC-CO2 oils of S. japonica and S. horneri were 0.41 +/- 0.05 and 0.77 +/- 0.07 mg/g, respectively. High antihypertensive activity was detected when using mixed acetone and methanol, whereas the phenolic content and antioxidant property were higher in the oil extracted by SC-CO2. The acetone-methanol mix extracts exhibited better antimicrobial activities than those obtained by other means. Thus, the SC-CO2 extraction process appears to be a good method for obtaining valuable compounds from both brown seaweeds, and showed stronger biological activity than that obtained by the conventional extraction process. PMID- 26035022 TI - New Anti-Inflammatory Cembranes from the Cultured Soft Coral Nephthea columnaris. AB - Two new cembranes, columnariols A (1) and B (2), were isolated from the cultured soft coral Nephthea columnaris. The structures of cembranes 1 and 2 were elucidated by spectroscopic methods. In the anti-inflammatory effects test, cembranes 1 and 2 were found to significantly inhibit the accumulation of the pro inflammatory iNOS and COX-2 protein of the lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. Compound 1 exhibited moderate cytotoxicity toward LNCaP cells with an IC50 value of 9.80 MUg/mL. PMID- 26035024 TI - Microfluidic Superheating for Peptide Sequence Elucidation. AB - Herein, we introduce microfluidic superheating as a new method for peptide fragmentation prior to mass spectrometric analysis. The superheating conditions were found to be stable up to 240 degrees C for more than 30 min without elevated pressure or boiling of the aqueous sample. As proof of principle, we exposed the peptides ACTH1-10 and OVA257-264 to various superheating conditions, causing different degrees of decomposition. Optimized superheating conditions resulted in the entire peptide ladder sequence of the y-ions, allowing the amino acid sequence to be deduced from a single-stage mass spectrum. Thus, obtaining information in the same quality as from tandem mass spectrometry can be achieved by a single superheating step. PMID- 26035023 TI - Entry Inhibition of Influenza Viruses with High Mannose Binding Lectin ESA-2 from the Red Alga Eucheuma serra through the Recognition of Viral Hemagglutinin. AB - Lectin sensitivity of the recent pandemic influenza A virus (H1N1-2009) was screened for 12 lectins with various carbohydrate specificity by a neutral red dye uptake assay with MDCK cells. Among them, a high mannose (HM)-binding anti HIV lectin, ESA-2 from the red alga Eucheuma serra, showed the highest inhibition against infection with an EC50 of 12.4 nM. Moreover, ESA-2 exhibited a wide range of antiviral spectrum against various influenza strains with EC50s of pico molar to low nanomolar levels. Besides ESA-2, HM-binding plant lectin ConA, fucose binding lectins such as fungal AOL from Aspergillus oryzae and AAL from Aleuria aurantia were active against H1N1-2009, but the potency of inhibition was of less magnitude compared with ESA-2. Direct interaction between ESA-2 and a viral envelope glycoprotein, hemagglutinin (HA), was demonstrated by ELISA assay. This interaction was effectively suppressed by glycoproteins bearing HM-glycans, indicating that ESA-2 binds to the HA of influenza virus through HM-glycans. Upon treatment with ESA-2, no viral antigens were detected in the host cells, indicating that ESA-2 inhibited the initial steps of virus entry into the cells. ESA-2 would thus be useful as a novel microbicide to prevent penetration of viruses such as HIV and influenza viruses to the host cells. PMID- 26035025 TI - Feasibility of energy medicine in a community teaching hospital: an exploratory case series. AB - BACKGROUND: Energy medicine (EM) derives from the theory that a subtle biologic energy can be influenced for therapeutic effect. EM practitioners may be trained within a specific tradition or work solo. Few studies have investigated the feasibility of solo-practitioner EM in hospitals. OBJECTIVE: This study investigated the feasibility of EM as provided by a solo practitioner in inpatient and emergent settings. DESIGN: Feasibility study, including a prospective case series. SETTINGS: Inpatient units and emergency department. OUTCOME MEASURES: To investigate the feasibility of EM, acceptability, demand, implementation, and practicality were assessed. Short-term clinical changes were documented by treating physicians. PARTICIPANTS: Patients, employees, and family members were enrolled in the study only if study physicians expected no or slow improvement in specific symptoms. Those with secondary gains or who could not communicate perception of symptom change were excluded. RESULTS: EM was found to have acceptability and demand, and implementation was smooth because study procedures dovetailed with conventional clinical practice. Practicality was acceptable within the study but was low upon further application of EM because of cost of program administration. Twenty-four of 32 patients requested relief from pain. Of 50 reports of pain, 5 (10%) showed no improvement; 4 (8%), slight improvement; 3 (6%), moderate improvement; and 38 (76%), marked improvement. Twenty-one patients had issues other than pain. Of 29 non-pain-related problems, 3 (10%) showed no, 2 (7%) showed slight, 1 (4%) showed moderate, and 23 (79%) showed marked improvement. Changes during EM sessions were usually immediate. CONCLUSIONS: This study successfully implemented EM provided by a solo practitioner in inpatient and emergent hospital settings and found that acceptability and demand justified its presence. Most patients experienced marked, immediate improvement of symptoms associated with their chief complaint. Substantial practicality issues must be addressed to implement EM clinically in a hospital, however. PMID- 26035026 TI - [Autoantibodies in systemic sclerosis]. AB - Systemic sclerosis (SSc) is a rare connective tissue disorder, which leads to progressive fibrosis of many organs. Its course is characterized by the presence of two classical autoantibodies: anti-topoisomerase I (ATA, Scl-70) and anti centromere (ACA). In recent years, the presence of antibodies against a wider range of antigens was demonstrated, namely: RNA polymerase III, fibrillarin, NOR90, Th/To, PM-Scl-100, PM-Scl-75, Ku, PDGFR, but their clinical significance is relatively little known and until recently the methods of their assessment were available only in specialized laboratories. More and more reports in the literature indicate existence of links between the presence of selected autoantibodies with clinical correlations i.e. anti-RNA polymerase III with scleroderma renal crisis or anti-Ku and myositis, arthritis and joint contractures. The importance of autoantibodies in the diagnostic process was underlined by their inclusion into the new ACR/EULAR 2013 classification criteria for systemic sclerosis. This work reviews the current knowledge on the clinical significance of autoantibodies in systemic sclerosis. PMID- 26035027 TI - Role of Alumina and Montmorillonite in Changing the Sorption of Herbicides to Biochars. AB - The influence of biochars on the fate of herbicides in soil depends mostly on environmental factors among which the role of soil minerals is not clear. Two wood-derived biochars produced at 400 degrees C (BC400) and 600 degrees C (BC600) were treated with alumina and montmorillonite to investigate their interaction with biochars and the influence of herbicide sorption. Both minerals exhibited a pore-expanding effect that was likely relative to the removal of authigenic organic matter away from the biochars' surface. Alumina brought more remarkable pore expansion by doubling the surface area of the BC400 biochar and the mesopore area of the BC600 biochar. Consequently, more adsorption sites were accessible for herbicide molecules, which resulted in higher sorption of herbicides (acetochlor and metribuzin) to the mineral-treated biochars than to the untreated biochars. The results are useful for understanding the change of surface and sorption properties of biochars with soil applications. PMID- 26035029 TI - Education Emergencies: A Plan for Success. AB - Although atypical, there are urgent situations in which education must be developed and deployed quickly to a large number of people. This article describes a strategy to guide rapid deployment of staff education based on lessons learned by educators who were recently faced with such a situation. PMID- 26035028 TI - All Those Liver Masses are not Necessarily from the Liver: A Case of a Giant Adrenal Pseudocyst Mimicking a Hepatic Cyst. AB - BACKGROUND: Most abdominal cysts, including adrenal pseudocysts, are benign and asymptomatic. Rapid enlargement, hemorrhage, infection, rupture with leakage of cyst contents, or pressure on adjacent organs can cause symptoms. Although usually diagnosed incidentally on imaging, determining the origin of a cyst can sometimes be challenging. In these situations, surgical excision and pathological analysis is crucial to diagnosis and management. We report here a case of a giant symptomatic adrenal pseudocyst that closely mimicked a hepatic cyst at presentation. CASE REPORT: A 50-year-old man, with a history of an incidentally detected hepatic cyst, presented with severe abdominal pain, fevers, leukocytosis, and mildly abnormal liver function tests. CT scan revealed a large well defined cystic space-occupying lesion within the liver, with findings suggesting cyst rupture and possible infection. Early laparotomy was performed, and the origin was determined intraoperatively to be right adrenal, which was later confirmed by pathology. CONCLUSIONS: Contrast-enhanced CT scan is the criterion standard for evaluation for abdominal cystic masses. Precise diagnosis of a giant abdominal cyst can be challenging. Surgery is both diagnostic and curative in such situations. We also discuss the specific situations in which surgery should be considered in cases of adrenal cystic masses. PMID- 26035030 TI - Spontaneous, Life-Threatening Hemorrhagic Cardiac Tamponade Secondary to Rivaroxaban. AB - Bleeding is the most feared complication of anticoagulants. Rivaroxaban is a newer oral anticoagulant with a favorable regimen due to lack of frequent blood monitoring and fewer drug interactions. We report a case of spontaneous pericardial hemorrhage associated with rivaroxaban. Within 10 days of starting rivaroxaban for atrial fibrillation, the patient developed a life-threatening cardiac tamponade leading to shock and multiorgan failure. After urgent pericardiocentesis/drainage, the patient recovered. This case highlights the necessity of larger clinical trials and consensus guideline on monitoring the effects of novel oral anticoagulants and development of an antidote for reversal in cases of major bleeding events. PMID- 26035031 TI - Epidural Injection With or Without Steroid in Managing Chronic Low-Back and Lower Extremity Pain: A Meta-Analysis of 10 Randomized Controlled Trials. AB - Chronic low-back and lower extremity pain is mainly caused by lumbar disc herniation and radiculitis. Various surgery and nonsurgical modalities, including epidural injections, have been used to treat lumbar disc herniation or radiculitis. Therefore, we conducted this meta-analysis to assess the effects of the 2 interventions in managing various chronic low and lower extremity pain. A systematic literature search was conducted to identify randomized controlled trials, which compared the effect of local anesthetic with or without steroids. The outcomes included pain relief, functional improvement, opioid intake, and therapeutic procedural characteristics. Pooled estimates were calculated using a random-effects or fixed-effects model, depending on the heterogeneity between the included studies. Ten randomized controlled trials (involving 1111 patients) were included in this meta-analysis. The pooled results showed that 41.7% of patients who received local anesthetic with steroid (group 1) and 40.2% of patients who received local anesthetic alone (group 2) had significant improvement in pain relief, and the Numeric Rating Scale pain scales were significantly reduced by 4.09 scores [95% confidence interval (CI), -4.26 to -3.91] and 4.12 (95% CI, 4.35 to -3.89) scores, respectively. Similarly, 39.8% of patients in group 1 and 40.7% in group 2 achieved significantly improved functional status. The Oswestry Disability Indices in the 2 groups were reduced by 14.5 (95% CI, -15.24 to 13.75) and 12.37 (95% CI, -16.13 to -8.62), respectively. The average procedures per year in group 1 were 3.68 +/- 1.17 and 3.68 +/- 1.26 in group 2, with an average total relief per year of 31.67 +/- 13.17 and 32.64 +/- 13.92 weeks, respectively. The opioid intake decreased from baseline by 8.81 mg (95% CI, 12.24 to -5.38) and 16.92 mg (95% CI: -22.71 to -11.12) in the 2 groups, respectively. This meta-analysis confirms that epidural injections of local anesthetic with or without steroids have beneficial but similar effects in the treatment of patients with chronic low-back and lower extremity pain. PMID- 26035032 TI - Protective Effects of Tirofiban on Myocardial Ischemia-Reperfusion Injury in Rabbits. AB - We aimed to explore the different protective effects of tirofiban on myocardial ischemia-reperfusion (IR) injury in New Zealand white rabbits by comparing the results from different administration methods. Fifty New Zealand white rabbits were randomly divided into a sham group (group A, n = 10) and four IR groups (group B, IR group with injection of physiological saline; group C, tirofiban administered through marginal ear vein after reperfusion; group D, tirofiban injected through coronary ostia before reperfusion; group E, tirofiban injected through coronary artery after blood flow restoration; all n = 10). Myocardial IR injury models were prepared in IR groups. An automatic biochemical analyzer (HITACHI 7020, Japan) was applied for testing serum creatine kinase-MB levels. The myeloperoxidase activity, malondialdehyde levels, nitric oxide synthase activity, and nitric oxide (NO) volume were detected 180 minutes after reperfusion. The myocardial apoptosis was identified using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling technique, and the protein expressions of B-cell lymphoma-2, Bcl-2 associated X, and aquaporin-1 were measured through Western blot. The highest and lowest ST-segment resolution among the IR groups was observed in groups E and B, respectively. The creatine kinase-MB levels at 60, 120, and 180 minutes in group E was greatly decreased than in groups B, C, and D. Compared with the sham group, the IR groups demonstrated evidently elevated myeloperoxidase activity, malondialdehyde levels, inducible NOS activity, NO volume, myocardial apoptotic index, and aquaporin-1 expressions; among the IR groups, these indicators were increased and decreased most in groups B and E, respectively. The B-cell lymphoma-2/Bcl-2 associated X ratio in the IR groups were evidently higher than the sham group, with the highest and lowest rate in groups E and B, respectively. Tirofiban injection through coronary artery after blood flow restoration has a better protective effect against myocardial IR injury than tirofiban administration through coronary ostia before reperfusion and tirofiban injection through the auricular vein after reperfusion. PMID- 26035033 TI - Combination Therapies of Diacerein and Febuxostat Inhibit IL-1beta Responses and Improve Clinical Symptoms in Patients With Refractory Gout. AB - There are several therapeutic strategies available for the treatment of an acute gout attack and the prevention of recurrent gout flares, and they include nonsteroid anti-inflammatory drugs. This prospective study was aimed at evaluating the efficiency and safety of diacerein in combination with febuxostat on urate control, global assessments of disease activity, self-monitored gouty acute flare times, inflammatory markers, and clinical symptoms associated with their life quantity in patients with refractory gout. A total of 64 patients with refractory gout were sequentially recruited and prescribed with oral febuxostat alone or febuxostat plus diacerein daily for 12 weeks. The intensity of joint pain, numbers of acute flare, disease activity and the levels of serum amyloid A, mature IL-1beta, IL-18, C-reactive protein, and urate in individual subjects were routine analyzed. In comparison with that treatment with febuxostat alone, treatment with both drugs for 12 weeks had a better therapeutic effect on reducing the values of visual analog scales, acute flares, and healthy assessment questionnaire scores in these gout patients. Furthermore, treatment with both drugs also significantly reduced the mean daily dose of etoricoxib and the levels of serum IL-1beta and serum amyloid A. There was no significant difference in the frequency of patients with adverse effect between these 2 groups of patients. In conclusion, combination of diacerein and febuxostat had better therapeutic effect on reducing acute gout flares, inflammation, and clinical symptoms in patients with refractory gout. PMID- 26035034 TI - Acute Kidney Injury Associated With Vancomycin When Laxity Leads to Injury and Findings on Kidney Biopsy. AB - The issue of vancomycin-induced acute kidney injury (AKI) has resurged with the use of intravenous vancomycin as a first-line antibiotic, often for prolonged periods of time for the management of serious methicillin-resistant Staphylococcus aureus infections, and with a higher recommended trough level (15 20 MUg/mL). We have observed 3 patients on intravenous vancomycin who developed very high trough levels (>40 MUg/mL) and severe (stage 3) AKI. Those 3 patients underwent kidney biopsy for unresolving AKI, which revealed findings compatible with acute tubular necrosis. The first patient initially developed asymptomatic acute interstitial nephritis because of a concomitant antibiotic that caused worsening of kidney function, and the dose of vancomycin was not properly adjusted while staying at the nursing home. The second was an emaciated patient (BMI, 14) whose serum creatinine level was a deceptive marker of kidney function for the proper dosing of vancomycin, resulting in a toxic level. The third patient developed vancomycin-related AKI on an initially high therapeutic level, which then contributed to further rising in vancomycin level and subsequently causing severe AKI. One patient required hemodialysis, but all 3 patients ultimately recovered their kidney function significantly. A regular monitoring (preferably twice weekly) of serum creatinine and vancomycin trough level is advisable to minimize vancomycin-associated AKI, primarily acute tubular necrosis, for patients requiring prolonged administration of vancomycin (>2 weeks) on the currently recommended higher therapeutic trough levels (>15 MUg/mL). PMID- 26035035 TI - Incision and Curettage Versus Steroid Injection for the Treatment of Chalazia: A Meta-Analysis. AB - PURPOSE: To compare the efficacy of the chalazia treatment modalities of incision and curettage (I&C) and intralesional steroid injections (SI). METHODS: Full publications of randomized controlled trials that compared I&C with SI were identified. Aggregated success rate, weighted summary proportions, and weighted pooled relative risk for success were calculated for each method. RESULTS: Data were extracted from 8 publications that met these criteria, between 1984 and 2013. There were 288 patients treated by SI with aggregate success rate of 60.4% with 1 injection and 72.5% with 1 or 2 injections. The range of the success rate was 8.7 to 86.7% for 1 injection. The success rate for the second SI was 19.0%, with a range of 0% to 53.8%. There were 264 patients treated by I&C with a larger aggregate success rate of 78.0% with 1 procedure and 86.7% with 1 or 2 procedures (p < 0.05 for both comparisons). The range of the success rates was 60.0% to 92.0% for 1 I&C. The success rate for the second I&C was 90.65%, with a range of 83.3% to 100%. Compared with I&C, the overall relative risk for SI with 1 procedure was 0.77 (p = 0.05), while the overall relative risk for 1 or 2 procedures was 0.89 (p = 0.002). CONCLUSIONS: This analysis shows that I&C is more effective than SI with 1 procedure. This benefit is reduced when comparing 1 or 2 attempts of I&C and SI. Studies failed to show a difference in the incidence of complications with either procedure. PMID- 26035037 TI - Immature platelet fraction measurement is influenced by platelet size and is a useful parameter for discrimination of macrothrombocytopenia. AB - BACKGROUND: Reticulated platelets (RPs) as measured using flow cytometry are useful parameters of thrombopoiesis; however, difficulties remain with standardization between laboratories. On the other hand, immature platelet fraction (IPF) measurement, as determined using an automated hematology analyzer, is simple, reproducible, and displays a good correlation with RP, although specific factors may affect its value. We previously noticed that a small proportion of patients exhibit extremely high IPF values that do not correlate with flow cytometrically measured RP. OBJECTIVES: We investigated the mechanism of the aberrant increase in IPF values of different types of macrothrombocytopenia. PATIENTS/METHODS: IPF, RP, and other platelet indexes were analyzed using samples from 15 congenital macrothrombocytopenic patients from 12 families, 150 immune thrombocytopenic patients, and 27 normal individuals. We further monitored the change in IPF values and morphology during platelet agglutination. RESULTS: IPF values were about five times higher in MYH9 disorders (IPF 48.6 +/- 1.9%) and about twice as high in other macrothrombocytopenias (IPF 18.4 +/- 2.1%) than in immune thrombocytopenic patients with similar platelet counts (IPF 9.2 +/- 0.3%). We then examined changes in IPF values during ethylenediaminetetraacetic acid- and macroglobulinemia-induced platelet agglutination. The IPF value significantly increased in a time-dependent manner along with the formation of platelet clumps and was strongly influenced by a few tiny platelet aggregates. CONCLUSIONS: These results suggested that IPF values are influenced by platelet size. Furthermore, IPF could be a useful and convenient parameter for screening of macrothrombocytopenia, which presents with a disproportionately high IPF value. PMID- 26035038 TI - Current versus lifetime depression, APOE variation, and their interaction on cognitive performance in younger and older adults. AB - OBJECTIVE: An interaction effect of depressive symptoms and APOE e4 allele status on cognitive decline has been shown in old age: e4 allele carriers with more depressive symptoms have faster cognitive decline than those with either depression or the e4 allele. We test this interaction effect on four cognitive domains, using a clinical depression measure comparing current versus lifetime depression. METHODS: 14,379 individuals aged 18 to 59 years, and 3944 individuals aged 60 to 94 years from the Generation Scotland: Scottish Family Health Study participated. Linear-mixed models-accounting for participant relatedness and demographic and health indices-tested for effects of depression and APOE on cognitive abilities. RESULTS: There was no interaction between depression and APOE on cognition (p > .05). Current depression was associated with poorer speed (in both groups) and memory (18- to 59-year-olds); differences ranged from 0.01 to 0.03 standard deviation [SD]. For lifetime depression, cognitive performance was lower for digit symbol in younger adults, but higher for vocabulary in both younger (0.03 SD) and older (0.05 SD) adults. A negative effect of the APOE e4 allele on speed and memory was found in the group 60 years and older (effect sizes of 0.04 SD). CONCLUSIONS: The absence of a depression by APOE interaction on cognitive abilities suggests that these synergistic effects only operate at the level of cognitive decline. This implies that it is those biological pathways especially affected by aging that become compromised further by the combined presence of depression and APOE e4 in an individual. PMID- 26035039 TI - ? PMID- 26035040 TI - ? PMID- 26035036 TI - Use of Humanized Mice to Study the Pathogenesis of Autoimmune and Inflammatory Diseases. AB - Animal models of disease have been used extensively by the research community for the past several decades to better understand the pathogenesis of different diseases and assess the efficacy and toxicity of different therapeutic agents. Retrospective analyses of numerous preclinical intervention studies using mouse models of acute and chronic inflammatory diseases reveal a generalized failure to translate promising interventions or therapeutics into clinically effective treatments in patients. Although several possible reasons have been suggested to account for this generalized failure to translate therapeutic efficacy from the laboratory bench to the patient's bedside, it is becoming increasingly apparent that the mouse immune system is substantially different from the human. Indeed, it is well known that >80 major differences exist between mouse and human immunology; all of which contribute to significant differences in immune system development, activation, and responses to challenges in innate and adaptive immunity. This inconvenient reality has prompted investigators to attempt to humanize the mouse immune system to address important human-specific questions that are impossible to study in patients. The successful long-term engraftment of human hematolymphoid cells in mice would provide investigators with a relatively inexpensive small animal model to study clinically relevant mechanisms and facilitate the evaluation of human-specific therapies in vivo. The discovery that targeted mutation of the IL-2 receptor common gamma chain in lymphopenic mice allows for the long-term engraftment of functional human immune cells has advanced greatly our ability to humanize the mouse immune system. The objective of this review is to present a brief overview of the recent advances that have been made in the development and use of humanized mice with special emphasis on autoimmune and chronic inflammatory diseases. In addition, we discuss the use of these unique mouse models to define the human-specific immunopathological mechanisms responsible for the induction and perpetuation of chronic gut inflammation. PMID- 26035041 TI - Dried Blood Spot Self-Sampling at Home for the Individualization of Tamoxifen Treatment: A Feasibility Study. PMID- 26035042 TI - Yoga in the Management of Chronic Disease: A Systematic Review and Meta-analysis. AB - BACKGROUND: Heart disease, stroke, and chronic obstructive pulmonary disease (COPD) are the leading causes of death and disability worldwide. Although individuals with these conditions have been reported to benefit from yoga, its effectiveness remains unclear. OBJECTIVE: To perform a systematic review of the effectiveness of yoga on exercise capacity, health related quality of life (HRQL), and psychological well-being for individuals with chronic disease and describe the structure and delivery of programs. RESEARCH DESIGN: We performed a systematic review of randomized controlled trials examining yoga programs for individuals with heart disease, stroke, and COPD compared with usual care. Quality was assessed using the Cochrane risk of bias tool. Meta-analyses were conducted using Review Manager 5.3. The protocol was registered on PROSPERO (CRD42014014589). RESULTS: Ten studies (431 individuals, mean age 56+/-8 y) were included and were comparable in their design and components, irrespective of the chronic disease. The standardized mean difference for the mean change in exercise capacity was 2.69 (95% confidence interval, 1.39-3.99) and for HRQL it was 1.24 (95% confidence interval, -0.37 to 2.85). Symptoms of anxiety were reduced after yoga in individuals with stroke, although this was not observed in individuals with COPD. The effect of yoga on symptoms of depression varied across studies with no significant effects compared with usual care. CONCLUSIONS: Yoga programs have similar designs and components across chronic disease populations. Compared with usual care, yoga resulted in significant improvements in exercise capacity and a mean improvement in HRQL. Yoga programs may be a useful adjunct to formal rehabilitation programs. PMID- 26035043 TI - Provider Differences in Use of Implanted Ports in Older Adults With Cancer. AB - BACKGROUND: Identifying unwarranted variation in health care can highlight opportunities to reduce harm. One often discretionary process in oncology is use of implanted ports to administer intravenous chemotherapy. While there are benefits, ports carry risks. This study's objective was to assess provider-driven variation in port use among cancer patients receiving chemotherapy. RESEARCH DESIGN: Retrospective assessment using population-based SEER-Medicare data to assess differences in port use across health care providers of older adults with cancer. Participants included over 18,000 patients ages 66 and older diagnosed with breast, colorectal, lung, or pancreatic cancer in 2005-2007, treated by approximately 2900 providers. We identified port use for patients receiving treatment from hospital outpatient facilities versus physicians' offices. Our main analysis assessed the likelihood of a patient receiving a port given port use by the provider's last patient. For a subset of high-use providers, we examined individual provider-level variation by estimating the risk-adjusted likelihood of insertion. RESULTS: Patients receiving chemotherapy in hospital outpatient facilities were significantly less likely to receive a port than those treated in physicians' offices, with adjusted odds ratios (AOR) varying from 0.50 to 0.75 across cancer sites. Implanting a port was associated with increased likelihood of port insertion in the provider's next patient (AOR varied from 1.71 to 2.25). Significant between-provider variation was found among providers with at least 10 patients. CONCLUSIONS: Our findings support the idea that there is provider-driven variation in the use of ports for chemotherapy administration. This variation highlights an opportunity to standardize practice and reduce unnecessary use. PMID- 26035044 TI - Quality of Care for Chronic Conditions Among Disabled Medicaid Enrollees: An Evaluation of a 1915 (b) and (c) Waiver Program. AB - IMPORTANCE: Examining the impact of Medicaid-managed care home-based and community-based service (HCBS) alternatives to institutional care is critical given the recent rapid expansion of these models nationally. OBJECTIVE: We analyzed the effects of STAR+PLUS, a Texas Medicaid-managed care HCBS waiver program for adults with disabilities on the quality of chronic disease care. DESIGN, SETTING, AND PARTICIPANTS: We compared quality before and after a mandatory transition of disabled Medicaid enrollees older than 21 years from fee for-service (FFS) or primary care case management (PCCM) to STAR+PLUS in 28 counties, relative to enrollees in counties remaining in the FFS or PCCM models. MEASURES AND ANALYSIS: Person-level claims and encounter data for 2006-2010 were used to compute adherence to 6 quality measures. With county as the independent sampling unit, we employed a longitudinal linear mixed-model analysis accounting for administrative clustering and geographic and individual factors. RESULTS: Although quality was similar among programs at baseline, STAR+PLUS enrollees experienced large and sustained improvements in use of beta-blockers after discharge for heart attack (49% vs. 81% adherence posttransition; P<0.01) and appropriate use of systemic corticosteroids and bronchodilators after a chronic obstructive pulmonary disease event (39% vs. 68% adherence posttransition; P<0.0001) compared with FFS/PCCM enrollees. No statistically significant effects were identified for quality measures for asthma, diabetes, or cardiovascular disease. CONCLUSION: In 1 large Medicaid-managed care HCBS program, the quality of chronic disease care linked to acute events improved while that provided during routine encounters appeared unaffected. PMID- 26035045 TI - Commentary on Evolution of Facial Aesthetic Treatment Over Five or More Years. PMID- 26035046 TI - Muir-Torre Syndrome and Central Nervous System Malignancy: Highlighting an Uncommon Association. PMID- 26035047 TI - Density and Polarization States of Tumor-Associated Macrophages in Human Cutaneous Squamous Cell Carcinomas Arising in Solid Organ Transplant Recipients. AB - BACKGROUND: Solid organ transplant recipients (SOTRs) are 100 times more likely to develop cutaneous squamous cell carcinoma (SCC) with greater metastatic propensity compared with the general population, likely due to chronic immunosuppression and adverse drug effects on keratinocytes. Tumor-associated macrophages (TAMs) play critical roles in malignancies, either aiding in eradication of malignant cells or promoting tumor growth. OBJECTIVE: The authors examined whether TAM density and polarization states differ between SOTRs and nontransplant individuals. MATERIALS AND METHODS: The authors obtained normal skin, SCC in situ (SCCis), and SCC from SOTRs and nontransplant patients (N = 45) and stained with macrophage marker CD68, M1 marker CD40, and M2 marker arginase 1. RESULTS: The authors report a significantly higher density of TAMs in both SCCis and SCC. The intratumoral macrophage infiltration in SCCis from SOTR was significantly decreased compared with nontransplant patients. Tumor-associated macrophages in SCCis and SCC displayed both M1 and M2 polarization, and M2 activation levels were significantly lower in SCC from SOTR. CONCLUSION: Tumor associated macrophages are present in early carcinogenesis and may play a critical role in the transition from SCCis to SCC, before invasion of the basement membrane by tumor cells. The intratumoral macrophage density in early stages of tumor development is significantly affected in SOTR. PMID- 26035048 TI - Topical Brimonidine Gel as a Hemostatic Agent After Dermatologic Surgery. PMID- 26035049 TI - Utility of MRI in the Diagnosis and Post-Treatment Evaluation of Anogenital Hidradenitis Suppurativa. PMID- 26035050 TI - Impact of APOBEC Mutations on CD8+ T Cell Recognition of HIV Epitopes Varies Depending on the Restricting HLA. AB - We previously showed that APOBEC-mediated mutations in HIV CD8 T-cell epitopes generally reduce recognition by CD8 T cells. Here, we examined this effect in the context of histocompatibility-linked leukocyte antigen (HLA) alleles differentially associated with disease progression rates. For HLA-B57-restricted epitopes, APOBEC mutations generally diminished CD8 T cell recognition. Conversely, recognition of HLA-B35-restricted epitopes was consistently enhanced. For epitopes that can be presented by either HLA-A2 or A3, the same APOBEC mutation had differential effects on CD8 T cell recognition, depending on the individual's HLA genotype. The pattern of HLA dependence provides additional evidence that APOBEC action is channeled toward cytotoxic CD8 T-cell escape. PMID- 26035051 TI - Acute Dystonia After Stimulant Discontinuation in 2 ADHD Children Receiving Aripiprazole. PMID- 26035052 TI - Anisocoria Associated With Escitalopram. PMID- 26035053 TI - Off-Label Prescriptions of Low-Dose Quetiapine and Mirtazapine for Insomnia in The Netherlands. PMID- 26035054 TI - Increase of Heart Rate and QTc by Amitriptyline, But Not by Venlafaxine, Is Correlated to Serum Concentration. AB - Electrocardiographic pathologies are a common problem during antidepressant treatment. The authors investigated the association of serum concentrations of antidepressants and heart rate, QT, and QTc. Polymorphisms of NOS1AP (nitric oxide synthase 1 adaptor protein) rs10494366 and rs12143842 as potential influence factors also were considered. In the amitriptyline sample (n = 59), significant Spearman rho correlations were found between serum concentration and QTc (r = 0.333, P = 0.010), as well as heart rate (r = 0.407, P = 0.001). Patients with a serum concentration greater than the therapeutic range (>200 ng/mL) exhibit significantly higher heart rates (87.0 +/- 13.3 vs 80.0 +/- 13.9, U test P = 0.011) and higher QTc values (443.8 +/- 28.8 vs 427.9 +/- 20.6, U test P = 0.022). Excluding the 26 patients with a serum concentration greater than the therapeutic range, patients with rs12143842 risk alleles exhibit higher heart rates and as a trend lower QT intervals with no difference in QTc. In the venlafaxine sample (n = 81), no significant association between serum concentration and heart rate, QT, or QTc was revealed. In summary, the risk for relevant electrocardiographic alterations induced by tricyclic antidepressants, such as amitriptyline, is dependent on serum concentrations. NOS1AP polymorphisms may be a genetic vulnerability factor. PMID- 26035055 TI - Age-dependent variation in cytokines, chemokines, and biologic analytes rinsed from the surface of healthy human skin. AB - In the skin, aging is associated with overall epidermal thinning, decreased barrier function, and gradual deterioration of the epidermal immune response. However, the presence and role of cytokines, chemokines, and biologic analytes (CCBAs) in immunosenescence are not known. Here we identified age-related changes in skin properties and CCBAs from stratum corneum of healthy human subjects, providing a means to utilize CCBAs as benchmarks for aging skin health. Transepidermal water loss and a(*) (skin redness) decreased in an age-dependent manner, and were significantly lower (p < 0.05) in Groups 2 (56.6 +/- 4.6 years) and 3 (72.9 +/- 3.0 years) vs. Group 1 (24.3 +/- 2.8 years). In skin wash fluid, 48 CCBAs were detected; seven were significantly lower (p < 0.05) in Groups 2 and 3: EGF, FGF-2, IFNalpha2, IL-1RA, HSA, keratin-6, and involucrin; cortisol was significantly higher (p < 0.05) in Groups 2 and 3. Our results correspond with the pro-inflammatory shift that occurs with immunosenescence and also provides basis for understanding the inflammatory changes in normal aging skin. PMID- 26035056 TI - Tritagonist as a new term for uncharacterised microorganisms in environmental systems. PMID- 26035057 TI - Dynamic mode coupling in terahertz metamaterials. AB - The near and far field coupling behavior in plasmonic and metamaterial systems have been extensively studied over last few years. However, most of the coupling mechanisms reported in the past have been passive in nature which actually fail to control the coupling mechanism dynamically in the plasmonic metamaterial lattice array. Here, we demonstrate a dynamic mode coupling between resonators in a hybrid metal-semiconductor metamaterial comprised of metallic concentric rings that are physically connected with silicon bridges. The dielectric function of silicon can be instantaneously modified by photodoped carriers thus tailoring the coupling characteristics between the metallic resonators. Based on the experimental results, a theoretical model is developed, which shows that the optical responses depend on mode coupling that originates from the variation of the damping rate and coupling coefficient of the resonance modes. This particular scheme enables an in-depth understanding of the fundamental coupling mechanism and, therefore, the dynamic coupling enables functionalities and applications for designing on-demand reconfigurable metamaterial and plasmonic devices. PMID- 26035058 TI - Genome-wide copy-number variation study of psychosis in Alzheimer's disease. AB - About 40-60% of patients with late-onset Alzheimer's disease (AD) develop psychosis, which represents a distinct phenotype of more severe cognitive and functional deficits. The estimated heritability of AD+P is ~61%, which makes it a good target for genetic mapping. We performed a genome-wide copy-number variation (CNV) study on 496 AD cases with psychosis (AD+P), 639 AD subjects with intermediate psychosis (AD intermediate P) and 156 AD subjects without psychosis (AD-P) who were recruited at the University of Pittsburgh Alzheimer's Disease Research Center using over 1 million single-nucleotide polymorphisms (SNPs) and CNV markers. CNV load analysis found no significant difference in total and average CNV length and CNV number in the AD+P or AD intermediate P groups compared with the AD-P group. Our analysis revealed a marginally significant lower number of duplication events in AD+P cases compared with AD-P controls (P=0.059) using multivariable regression model. The most interesting finding was the presence of a genome-wide significant duplication in the APC2 gene on chromosome 19, which was protective against developing AD+P (odds ratio=0.42; P=7.2E-10). We also observed suggestive associations of duplications with AD+P in the SET (P=1.95E-06), JAG2 (P=5.01E-07) and ZFPM1 (P=2.13E-07) genes and marginal association of a deletion in CNTLN (P=8.87E-04). We have identified potential novel loci for psychosis in Alzheimer's disease that warrant follow-up in large scale independent studies. PMID- 26035059 TI - Altered functional connectivity of the cingulate subregions in schizophrenia. AB - Schizophrenia patients have shown altered resting-state functional connectivity (rsFC) of the cingulate cortex; however, it is unknown whether rsFCs of the cingulate subregions are differentially affected in this disorder. We aimed to clarify the issue by comparing rsFCs of each cingulate subregion between healthy controls and schizophrenia patients. A total of 102 healthy controls and 94 schizophrenia patients underwent resting-state functional magnetic resonance imaging with a sensitivity-encoded spiral-in imaging sequence to reduce susceptibility-induced signal loss and distortion. The cingulate cortex was divided into nine subregions, including the subgenual anterior cingulate cortex (ACC), areas 24 and 32 of the pregenual ACC, areas 24 and 32 of the anterior mid cingulate cortex (aMCC), posterior MCC (pMCC), dorsal (dPCC) and ventral (vPCC) posterior cingulate cortex (PCC) and retrosplenial cortex (RSC). The rsFCs of each cingulate subregion were compared between the two groups and the atrophy effect was considered. Results with and without global signal regression were reported. Most cingulate subregions exhibited decreased rsFCs in schizophrenia after global signal regression (GSR). Without GSR, only increased rsFC was found in schizophrenia, which primarily restricted to the aMCC, PCC and RSC. Some of these increased rsFCs were also significant after GSR. These findings suggest that GSR can greatly affect between-group differences in rsFCs and the consistently increased rsFCs may challenge the functional disconnection hypothesis of schizophrenia. PMID- 26035061 TI - Effect of dilution of stool soluble component on growth and development of Strongyloides stercoralis. AB - Dispersion or dilution of stool by water from heavy rainfall may affect Strongyloides stercoralis free-living development producing infective filariform larvae (FL). This study examined effect of water dilution of stool on survival of S. stercoralis free-living development. One g of stool was prepared in water so that its soluble component was diluted sequentially from 1:2 to 1:480. Three dishes were used to compare FL production in three culture conditions: stool suspension, stool sediment deposited in soil, and isolated rhabditiform larvae (RhL) deposited in soil. The fourth dish was for developmental observation of RhL into free-living stages. Numerous FL were generated from undiluted or 1:2 diluted stool and stool sediment placed on soil. However, starting from dilution 1:5, FL production continuously decreased in both stool suspensions and stool sediments placed on soil. RhL isolated from stool dilutions placed on soil gave rise to few FL. Worm mating were seen at 24-30 hours in dilutions 1:20-1:120 only. Highest numbers of FL from indirect free-living cycle were 1/3 of those from control. FL production decreased as stool dilution increased, and reached zero production at 1:160 dilution. Rainfall may disperse or dilute stool so that nutritional supplement for S. stercoralis free-living development is insufficient. PMID- 26035060 TI - Chronic administration of anticonvulsants but not antidepressants impairs bone strength: clinical implications. AB - Major depression and bipolar disorder are associated with decreased bone mineral density (BMD). Antidepressants such as imipramine (IMIP) and specific serotonin reuptake inhibitors (SSRIs) have been implicated in reduced BMD and/or fracture in older depressed patients. Moreover, anticonvulsants such as valproate (VAL) and carbamazepine (CBZ) are also known to increase fracture rates. Although BMD is a predictor of susceptibility to fracture, bone strength is a more sensitive predictor. We measured mechanical and geometrical properties of bone in 68 male Sprague Dawley rats on IMIP, fluoxetine (FLX), VAL, CBZ, CBZ vehicle and saline (SAL), given intraperitoneally daily for 8 weeks. Distinct regions were tested to failure by four-point bending, whereas load displacement was used to determine stiffness. The left femurs were scanned in a MicroCT system to calculate mid diaphyseal moments of inertia. None of these parameters were affected by antidepressants. However, VAL resulted in a significant decrease in stiffness and a reduction in yield, and CBZ induced a decrease in stiffness. Only CBZ induced alterations in mechanical properties that were accompanied by significant geometrical changes. These data reveal that chronic antidepressant treatment does not reduce bone strength, in contrast to chronic anticonvulsant treatment. Thus, decreased BMD and increased fracture rates in older patients on antidepressants are more likely to represent factors intrinsic to depression that weaken bone rather than antidepressants per se. Patients with affective illness on anticonvulsants may be at particularly high risk for fracture, especially as they grow older, as bone strength falls progressively with age. PMID- 26035062 TI - Genetically Engineered Ascorbic acid-deficient Live Mutants of Leishmania donovani induce long lasting Protective Immunity against Visceral Leishmaniasis. AB - Visceral leishmaniasis caused by Leishmania donovani is the most severe systemic form of the disease. There are still no vaccines available for humans and there are limitations associated with the current therapeutic regimens for leishmaniasis. Recently, we reported functional importance of Arabino-1, 4 lactone oxidase (ALO) enzyme from L. donovani involved in ascorbate biosynthesis pathway. In this study, we have shown that DeltaALO parasites do not affect the ability of null mutants to invade visceral organs but severely impair parasite persistence beyond 16 week in BALB/c mice and hence are safe as an immunogen. Both short term (5 week) and long term (20 week) immunization with DeltaALO parasites conferred sustained protection against virulent challenge in BALB/c mice, activated splenocytes and resulted in induction of pro-inflammatory cytokine response. Protection in immunized mice after challenge correlated with the stimulation of IFN-gamma producing CD4(+) and CD8(+) T cells. Antigen mediated cell immunity correlated with robust nitrite and superoxide generation, macrophage-derived oxidants critical in controlling Leishmania infection. Our data shows that live attenuated DeltaALO parasites are safe, induce protective immunity and can provide sustained protection against Leishmania donovani. We further conclude that the parasites attenuated in their anti-oxidative defence mechanism can be exploited as vaccine candidates. PMID- 26035063 TI - A comparative analysis of high-throughput platforms for validation of a circulating microRNA signature in diabetic retinopathy. AB - MicroRNAs are now increasingly recognized as biomarkers of disease progression. Several quantitative real-time PCR (qPCR) platforms have been developed to determine the relative levels of microRNAs in biological fluids. We systematically compared the detection of cellular and circulating microRNA using a standard 96-well platform, a high-content microfluidics platform and two ultra high content platforms. We used extensive analytical tools to compute inter- and intra-run variability and concordance measured using fidelity scoring, coefficient of variation and cluster analysis. We carried out unprejudiced next generation sequencing to identify a microRNA signature for Diabetic Retinopathy (DR) and systematically assessed the validation of this signature on clinical samples using each of the above four qPCR platforms. The results indicate that sensitivity to measure low copy number microRNAs is inversely related to qPCR reaction volume and that the choice of platform for microRNA biomarker validation should be made based on the abundance of miRNAs of interest. PMID- 26035065 TI - Protective effects of hepatic stellate cells against cisplatin-induced apoptosis in human hepatoma G2 cells. AB - The effects of hepatic stellate cells (HSCs) on tumorigenicity of HCC have been previously reported. However, the detailed mechanisms responsible for these effects remain unclear. In this study, we investigated the effects of HSCs on cisplatin-induced apoptosis in human hepatoma HepG2 cell lines. HepG2 cells were treated with cisplatin alone or co-cultured with LX-2 cells 3 days before incubation with cisplatin. Cisplatin causes apoptosis in HepG2 cells and LX-2 cells protect HepG2 cells from death. The protection of LX-2 cells against cisplatin-induced cytotoxicity in HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by cytotoxicity assay and nuclear staining analysis. p53 and Bax mRNA levels were elevated, and cell cycle arrest was produced after cisplatin treatment. LX-2 cells suppressed this elevation of p53 and Bax as well as the cell cycle arrest induced by cisplatin, when compared with those of the treated cells with cisplatin alone. The LX-2 cells pretreatment inhibited the cisplatin-induced apoptosis, which was related with the incomplete blockage in p53 activation. In summary, the results of our present study demonstrate that HSCs protect HepG2 cells against cisplatin-induced apoptosis and its protective effects occur via inhibiting the activation of p53, which is of critical importance for enhanced understanding of fundamental cancer biology. PMID- 26035064 TI - Childhood abuse and neglect may induce deficits in cognitive precursors of psychosis in high-risk children. AB - BACKGROUND: Millions of children are born to parents affected by major psychoses. Cognitive dysfunctions seen in patients are already detectable in these children. In parallel, childhood maltreatment increases the risk of adult psychoses through unknown mechanisms. We investigated whether high-risk offspring exposed to abuse/neglect displayed more cognitive precursors of adult psychoses in childhood and adolescence than nonexposed offspring. METHODS: We used a stepwise selection strategy from a 25-year follow-up of 48 densely affected kindreds including 1500 adults (405 patients with schizophrenia or bipolar disorder) to select high-risk offspring aged 6-22 years for inclusion in our study. All offspring were assessed for childhood trauma from direct interviews with the offspring, parents and relatives and from the review of lifetime medical records of parents and children and administered a neuropsychological battery including IQ and 4 of the most impaired neuropsychological domains in psychoses. RESULTS: Our study included 66 high-risk offspring. Those who were exposed to abuse/neglect had significantly lower IQ (effect size [ES] = 0.61) than nonexposed offspring and displayed poorer cognitive performance in visual episodic memory (ES = 0.67) and in executive functions of initiation (ES = 1.01). Moreover, exposed offspring presented more combinations of cognitive deficits that were associated with lower Global Assessment of Functioning scores. LIMITATIONS: Exposure to abuse/neglect was not assessed in the control group, thus the study could not test whether the effect of childhood maltreatment occurred only in a high-risk setting and not in the general population. CONCLUSION: In high-risk youths, maltreatment in childhood/adolescence may negatively impact cognitive domains known to be impaired in adults with psychoses, suggesting an early mediating effect in the association between abuse/neglect and adult psychoses. This finding provides a target for future developmental and preventive research. PMID- 26035066 TI - A novel characterization of amalgamated networks in natural systems. AB - Densely-connected networks are prominent among natural systems, exhibiting structural characteristics often optimized for biological function. To reveal such features in highly-connected networks, we introduce a new network characterization determined by a decomposition of network-connectivity into low rank and sparse components. Based on these components, we discover a new class of networks we define as amalgamated networks, which exhibit large functional groups and dense connectivity. Analyzing recent experimental findings on cerebral cortex, food-web, and gene regulatory networks, we establish the unique importance of amalgamated networks in fostering biologically advantageous properties, including rapid communication among nodes, structural stability under attacks, and separation of network activity into distinct functional modules. We further observe that our network characterization is scalable with network size and connectivity, thereby identifying robust features significant to diverse physical systems, which are typically undetectable by conventional characterizations of connectivity. We expect that studying the amalgamation properties of biological networks may offer new insights into understanding their structure-function relationships. PMID- 26035068 TI - Enhancement of SOX-2 expression and ROS accumulation by culture of A172 glioblastoma cells under non-adherent culture conditions. AB - More efficient isolation and identification of cancer stem cells (CSCs) would help in determining their fundamental roles in tumor biology. The classical tool for this purpose is anchorage-independent tumorsphere culture. We compared the effects of differently textured culture plates and serum deprivation on the acquisition of CSC properties of A172 glioblastoma cells. Cells were cultured on standard polystyrene-treated plates, ultra-low attachment, poly (2-hydroxyethyl methacrylate)-coated plates, and 1% agar-coated plates with 10% serum or in serum free glioblastoma sphere medium (GBM). Based on mitochondrial reductase activity and subG1 proportions, non-adherent conditions had a greater impact on A172 cell viability than serum deprivation. Among the stemness-related genes, SOX-2 expression was significantly upregulated by serum deprivation under non-adherent conditions, while several epithelial-to-mesenchymal transition (EMT)-related genes were less dependent on serum. In addition, reactive oxygen species (ROS) accumulation in A172 cells was significantly increased in GBM under non-adherent conditions. Despite the correlation between SOX-2 induction and ROS accumulation, treatment with the ROS scavenger N-acetyl-l-cysteine did not prevent SOX-2 expression, suggesting that ROS accumulation is not an essential requirement for induction of SOX-2. Our results suggested that cultivation of cancer cells under conditions of serum deprivation in an anchorage-independent manner may enrich SOX 2-expressing CSC-like cells in vitro. PMID- 26035067 TI - Protective effect of hydrogen-rich medium against high glucose-induced apoptosis of Schwann cells in vitro. AB - Diabetic peripheral neuropathy (DPN) is considered to be one of the most prevalent and life threatening microvascular diabetic complications. DPN affects up to 50% of patients with diabetes mellitus and there are currently no efficacious therapeutic strategies available for its treatment. Previous studies have reported that oxidative stress and poly(ADP-ribose) polymerase-1 (PARP-1) may be unifying factors for hyperglycemic injury. The aim of the present study was to investigate the protective effects of hydrogen-rich medium (HM) on high glucose (HG)-mediated oxidative stress, PARP-1 activation and the apoptosis of Schwann cells (SCs) in vitro. The cells were divided into different groups, and were treated for 48 h. Cell viability and apoptosis were evaluated using Cell Counting kit-8 and annexin V/propidium iodide assays, respectively. The concentrations of 8-hydroxy-2-deoxyguanosine (8-OHdG) and peroxynitrite (ONOO-) were detected using an enzyme-linked immunosorbent assay. The presence of intracellular oxygen free radicals was confirmed using flow cytometric analysis. Colorimetric assays were performed to determine the activity of caspase-3, and western blotting was performed to detect the protein expression levels of PARP-1, cleaved PARP-1, PAR, apoptosis-inducing factor (AIF), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein. HG was found to induce severe oxidative stress and promote the caspase-dependent and caspase-independent apoptosis of SCs. Treatment with HM inhibited HG-induced oxidative stress by suppressing hydroxyl and ONOO- production, levels of 8-OHdG, caspase-3 activity and apoptosis in the SCs. Furthermore, treatment with HM downregulated the HG-induced release of PAR, the activation of PARP-1 and nuclear translocation of AIF, and upregulated the expression of Bcl-2 in the SCs. These results indicated that HM inhibited the HG induced-oxidative stress-associated caspase-dependent and caspase-independent apoptotic pathways in SCs. Therefore, HM may have potential as a treatment for DPN. PMID- 26035069 TI - What Is Culinary Medicine and What Does It Do? PMID- 26035070 TI - Interaction prolonged DNA translocation through solid-state nanopores. AB - An interesting smooth blocked nanopore and corresponding "current ladder" phenomenon was observed in DNA translocation experiments through solid-state nanopores. The ionic current shows several drop steps (current levels in the current ladder) with an identical drop interval, which corresponds to an individual unfolded DNA translocation event. This indicates that multiple anchored DNA molecules have one end inside the nanopore to cause such a current ladder. On each current level, normal DNA translocation events were detected. The event duration time increases as the level number increases, which means DNA translocates more slowly when more DNA molecules are inside the nanopore due to DNA-DNA interactions. The Langevin dynamic model was used to explain the experimental observations. This finding strongly suggests that DNA-DNA interactions greatly impact the translocation dynamics when DNA passes through the nanopores. PMID- 26035071 TI - Density Functional Theory Study of BF3-Mediated Additions of Enols and [(Trimethylsilyl)oxy]alkenes to an Oxyallyl Cation: Homologous Mukaiyama Reactions. AB - The addition of enols and [(trimethylsilyl)oxy]alkenes, bearing methyl substituents at various positions, to a cyclic, BF3-complexed oxyallyl cation has been studied at the M06/6-311G(d)//B3LYP/6-31G(d) level of theory. The reactions with the [(trimethylsilyl)oxy]alkenes are homologous Mukaiyama reactions, which have not been examined computationally previously. In most instances a number of transition states were located, and the difference in energy between these transition states was not large, which pointed to low levels of diastereoselectivity in the reactions of the oxyallyl cation model compound. The lowest energy transition states were those with a synclinal geometry in which the alkene was positioned over the cyclic oxyallyl cation, and the relative orientation of the alkene and the oxyallyl cation was rationalized in terms of stabilizing intermolecular interactions, revealed by NBO analysis, between one or more fluorines of the complexed BF3 and hydrogens on the alkene moiety, and between the oxygen on the alkene and the pi-system of the oxyallyl cation. Because, in most instances with these simple models, two or more transition states of relatively low energy were located, predictions of diastereoselectivity in more complex examples that are based on simple models cannot be recommended. PMID- 26035072 TI - Exploring the nature of the excitation energies in [Re6(MU3-Q8)X6](4-) clusters: a relativistic approach. AB - This contribution is a relativistic theoretical study to characterize systematically the main electronic transitions in a series of hexarhenium chalcogenide [Re6(MU3-Q8)X6](4-) clusters with the aim of understanding: (i) the terminal ligand substitution effect, (ii) the substitution effect of the chalcogenide ion on the [Re6(MU3-Q8)](2+)core, and finally (iii) the significance of the spin-orbit coupling (SOC) effect on the optical selection rules. In all the cases, we found characteristic bands at around 300-550 nm, where the band positions are directly determined by the terminal ligand. However, SCN(-)/NCS(-) presents a different nature of the orbitals involved in the electronic transitions, in comparison with the other studied terminal ligands, located in the near-infrared (NIR) region. All the bands are red-shifted as a consequence of the ligand contribution in the composition of the orbitals involved in the electronic excitations. PMID- 26035073 TI - SASS6 overexpression is associated with mitotic chromosomal abnormalities and a poor prognosis in patients with colorectal cancer. AB - Spindle assembly abnormal protein 6 homolog (SASS6) plays an important role in the regulation of centriole duplication. To date, the genetic alteration of SASS6 has not been reported in human cancers. In the present study, we examined whether SASS6 expression is abnormally regulated in colorectal cancers (CRCs). Increased SASS6 mRNA and protein expression levels were observed in 49 (60.5%) of the 81 primary CRCs and 11 (57.9%) of the 19 primary CRCs, respectively. Moreover, the upregulation of SASS6 mRNA expression was statistically significant (P=0.0410). Next, using DLD-1 colon cancer cells inducibly expressing SASS6, SASS6 overexpression was shown to induce centrosome amplification, mitotic abnormalities such as chromosomal misalignment and lagging chromosome, and chromosomal numerical changes. Furthermore, SASS6 overexpression was associated with anaphase bridge formation, a type of mitotic structural abnormality, in primary CRCs (P<0.01). SASS6 upregulation in colon cancer was also revealed in the Cancer Genome Atlas (TCGA) data and was shown to be an independent predictor of poor survival (multivariate analysis: hazard ratio, 2.805; 95% confidence interval, 1.244-7.512; P=0.0112). Finally, further analysis of the TCGA data demonstrated SASS6 upregulation in a modest manner in 8 of 11 cancer types other than colon cancer, and SASS6 upregulation was found to be associated with a poor survival outcome in patients with kidney renal cell carcinoma and lung adenocarcinoma. Our present findings revealed that the upregulation of SASS6 expression is involved in the pathogenesis of CRC and is associated with a poor prognosis among patients with colon cancer. They also suggest that SASS6 upregulation is a genetic abnormality relatively common in human cancer. PMID- 26035074 TI - Orientation-Dependent London-van der Waals Interaction Energy between Macroscopic Bodies. AB - The aim of this work is to derive formulas for numerical calculations of the orientation-dependent London-van der Waals (vdW) interaction energy (V(A)) between two rectangular bodies with arbitrary dimensions, arranged at arbitrary relative angles (theta) and separations in twisted and coplanar rotational modes. The formulation is made using a simple volume-element-integration method in the framework of the microscopic approach, in which V(A) is the sum of the local vdW energy (Vp) between body 1 and each thin plate constituting body 2. Examples of the calculation results are the following: (1) The theta values that give maximal and minimal values of V(A) depend on their shapes and relative positions. (2) As the bodies come close to each other, the variations of V(A) with theta and thus vdW dispersion torques generated are drastically intensified. (3) Upon increasing the length of crossing rods in twisted configurations, the V(A) values become constant beyond a critical length (depending on theta and separation), where the length effect on V(A) disappears. (4) The distribution curves of Vp show that the region in body 2 which interacts effectively with body 1 (i.e., the effective interaction region) is more sharply localized in the vicinity of the surface (closest to body 1) as the separation is decreased. PMID- 26035076 TI - Evaluation of multisyllabic word production in Canadian English- or French speaking children within a non-linear phonological framework. AB - Currently, there is no theoretically justified, evidence-based metric for evaluating segmental and prosodic components of multisyllabic words (MSWs). A pilot study evaluated a MSW metric embedded in non-linear phonological- and language-processing frameworks. Six MSWs were analyzed in 10 Canadian English speaking 5-year-olds with typically developing speech, and eight French-speaking children, ages 3-4 years, with protracted phonological development (PPD). Mismatches were tallied (with and without vowels), with totals ranked by word and participant, then compared with ranks from Phonological Mean Length of Utterance (PMLU) and Percent Consonants Correct (PCC) tallies. For both groups, the number of different ranks was significant in comparisons of MSW metrics with PMLU and PCC. Rank orderings were systematically higher for English-speaking children using the MSW metric, with/without vowels, and for French-speaking children using the MSW metric with vowels. Overall, the MSW metric was particularly suitable for fine-grained differentiation of phonological accuracy in MSW production. PMID- 26035077 TI - Enhanced enzymatic hydrolysis of cellulose in microgels. AB - A cellulose-based microgel, where an individual microgel contains approximately one cellulose chain on average, is synthesized via free radical polymerization of a difunctional small-molecule N,N'-methylenebisacrylamide in cellulose solution. This microgelation leads to a low-ordered cellulose, favoring enzymatic hydrolysis of cellulose to generate glucose. PMID- 26035078 TI - Monodisperse Aluminosilicate Spheres with Tunable Al/Si Ratio and Hierarchical Macro-Meso-Microporous Structure. AB - While tremendous success has been seen in the development of ordered mesoporous silica by soft-templated methods, synthesis of hierarchical structures with controllable multiscale pore networks has remained a challenging topic. On the other hand, introduction of heteroatoms as an effective method of chemically functionalizing silica leads to difficulties in morphological control of the product, and multistep synthesis has been necessary for functionalized silica particles with hierarchical pore structure and uniform size. The present work demonstrates that the conflict between morphological control and heteroatom incorporation can be resolved in a CTAB-stabilized toluene-water-ethanol microemulsion system. For the first time, monodisperse macro-meso-microporous aluminosilicate spheres (MASS) are synthesized in one step at room temperature. Simultaneous tuning of Al/Si ratio (0-0.35) and the hierarchical pore structure is realized by Hofmeister anion effects of the Al source itself, [Al(OH)4](-), which change the geometry of CTAB micelles and giant vesicles. The Al is incorporated purely in a tetrahedrally coordinated status, and preliminary results from catalytic experiments show improved acidity of MASS as a catalyst support. PMID- 26035079 TI - DNA Translocation in Nanometer Thick Silicon Nanopores. AB - Solid-state nanopores are single-molecule sensors that detect changes in ionic conductance (DeltaG) when individual molecules pass through them. Producing high signal-to-noise ratio for the measurement of molecular structure in applications such as DNA sequencing requires low noise and large DeltaG. The latter is achieved by reducing the nanopore diameter and membrane thickness. While the minimum diameter is limited by the molecule size, the membrane thickness is constrained by material properties. We use molecular dynamics simulations to determine the theoretical thickness limit of amorphous Si membranes to be ~1 nm, and we designed an electron-irradiation-based thinning method to reach that limit and drill nanopores in the thinned regions. Double-stranded DNA translocations through these nanopores (down to 1.4 nm in thickness and 2.5 nm in diameter) provide the intrinsic ionic conductance detection limit in Si-based nanopores. In this regime, where the access resistance is comparable to the nanopore resistance, we observe the appearance of two conductance levels during molecule translocation. Considering the overall performance of Si-based nanopores, our work highlights their potential as a leading material for sequencing applications. PMID- 26035080 TI - Exciton Localization in Extended pi-Electron Systems: Comparison of Linear and Cyclic Structures. AB - We employ five pi-conjugated model materials of different molecular shape oligomers and cyclic structures-to investigate the extent of exciton self trapping and torsional motion of the molecular framework following optical excitation. Our studies combine steady state and transient fluorescence spectroscopy in the ensemble with measurements of polarization anisotropy on single molecules, supported by Monte Carlo simulations. The dimer exhibits a significant spectral red shift within ~100 ps after photoexcitation which is attributed to torsional relaxation. This relaxation mechanism is inhibited in the structurally rigid macrocyclic analogue. However, both systems show a high degree of exciton localization but with very different consequences: while, in the macrocycle, the exciton localizes randomly on different parts of the ring, scrambling polarization memory, in the dimer, localization leads to a deterministic exciton position with luminescence characteristics of a dipole. Monte Carlo simulations allow us to quantify the structural difference between the emitting and absorbing units of the pi-conjugated system in terms of disorder parameters. PMID- 26035081 TI - In-Plane Si Nanowire Growth Mechanism in Absence of External Si Flux. AB - We report on a new mechanism of nanowire formation: during Au deposition on Si(110) substrates, Au-Si droplets grow, move spontaneously, and fabricate a Si nanowire behind them in the absence of Si external flux. Nanowires are formed by Si dissolved from the substrate at the advancing front of the droplets and transported backward to the crystallization front. The droplet shape is determined by the Si etching anisotropy. The nanowire formation can be tuned by changing experimental parameters like substrate temperature and Au deposition rate. PMID- 26035082 TI - A Forty Year Odyssey in Metallo-Organic Chemistry. AB - In this invited Perspective, I provide a personal account highlighting several of my group's research contributions in metallo-organic chemistry over the past 40 years. Our early work focused primarily in stoichiometric structure/reactivity of transition metal-organic compounds and their use in organic synthesis. More recent efforts have centered on the discovery and development of new metal catalyzed organic reactions via reactive metal-organic intermediates. The major research findings that are described here include (1) propargyl-cobalt complexes as electrophilic agents for C-C and C-Nu coupling; (2) the activation of carbon dioxide by metal complexes; (3) metal-promoted C-H nitrogenation reactions; (4) oxo-metal catalyzed deoxygenation reactions; and (5) catalyst discovery via dynamic templating with substrate- and transition-state analogues. PMID- 26035083 TI - Stereocontrolled Synthesis of a Potential Transition-State Inhibitor of the Salicylate Synthase MbtI from Mycobacterium tuberculosis. AB - Mycobactins are small-molecule iron chelators (siderophores) produced by Mycobacterium tuberculosis (Mtb) for iron mobilization. The bifunctional salicylate synthase MbtI catalyzes the first step of mycobactin biosynthesis through the conversion of the primary metabolite chorismate into salicylic acid via isochorismate. We report the design, synthesis, and biochemical evaluation of an inhibitor based on the putative transition state (TS) for the isochorismatase partial reaction of MbtI. The inhibitor mimics the hypothesized charge buildup at C-4 of chorismate in the TS as well as C-O bond formation at C-6. Another important design element of the inhibitor is replacement of the labile pyruvate side chain in chorismate with a stable C-linked propionate isostere. We developed a stereocontrolled synthesis of the highly functionalized cyclohexene inhibitor that features an asymmetric aldol reaction using a titanium enolate, diastereoselective Grignard addition to a tert-butanesulfinyl aldimine, and ring closing olefin metathesis as key steps. PMID- 26035084 TI - Pharmacological interventions for drug-using offenders. AB - BACKGROUND: The review represents one in a family of four reviews focusing on a range of different interventions for drug-using offenders. This specific review considers pharmacological interventions aimed at reducing drug use or criminal activity, or both, for illicit drug-using offenders. OBJECTIVES: To assess the effectiveness of pharmacological interventions for drug-using offenders in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched Fourteen electronic bibliographic databases up to May 2014 and five additional Web resources (between 2004 and November 2011). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials assessing the efficacy of any pharmacological intervention a component of which is designed to reduce, eliminate or prevent relapse of drug use or criminal activity, or both, in drug-using offenders. We also report data on the cost and cost-effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: Fourteen trials with 2647 participants met the inclusion criteria. The interventions included in this review report on agonistic pharmacological interventions (buprenorphine, methadone and naltrexone) compared to no intervention, other non-pharmacological treatments (e.g. counselling) and other pharmacological drugs. The methodological trial quality was poorly described, and most studies were rated as 'unclear' by the reviewers. The biggest threats to risk of bias were generated through blinding (performance and detection bias) and incomplete outcome data (attrition bias). Studies could not be combined all together because the comparisons were too different. Only subgroup analysis for type of pharmacological treatment were done. When compared to non pharmacological, we found low quality evidence that agonist treatments are not effective in reducing drug use or criminal activity, objective results (biological) (two studies, 237 participants (RR 0.72 (95% CI 0.51 to 1.00); subjective (self-report), (three studies, 317 participants (RR 0.61 95% CI 0.31 to 1.18); self-report drug use (three studies, 510 participants (SMD: -0.62 (95% CI -0.85 to -0.39). We found low quality of evidence that antagonist treatment was not effective in reducing drug use (one study, 63 participants (RR 0.69, 95% CI 0.28 to 1.70) but we found moderate quality of evidence that they significantly reduced criminal activity (two studies, 114 participants, (RR 0.40, 95% CI 0.21 to 0.74).Findings on the effects of individual pharmacological interventions on drug use and criminal activity showed mixed results. In the comparison of methadone to buprenorphine, diamorphine and naltrexone, no significant differences were displayed for either treatment for self report dichotomous drug use (two studies, 370 participants (RR 1.04, 95% CI 0.69 to 1.55), continuous measures of drug use (one study, 81 participants, (mean difference (MD) 0.70, 95% CI -5.33 to 6.73); or criminal activity (one study, 116 participants, (RR 1.25, 95% CI 0.83 to 1.88) between methadone and buprenorphine. Similar results were found for comparisons with diamorphine with no significant differences between the drugs for self report dichotomous drug use for arrest (one study, 825 participants, (RR 1.25, 95% CI 1.03 to 1.51) or naltrexone for dichotomous measures of reincarceration (one study, 44 participants, (RR 1.10, 95% CI 0.37 to 3.26), and continuous outcome measure of crime, (MD -0.50, 95% CI 8.04 to 7.04) or self report drug use (MD 4.60, 95% CI -3.54 to 12.74). AUTHORS' CONCLUSIONS: When compared to non-pharmacological treatment, agonist treatments did not seem effective in reducing drug use or criminal activity. Antagonist treatments were not effective in reducing drug use but significantly reduced criminal activity. When comparing the drugs to one another we found no significant differences between the drug comparisons (methadone versus buprenorphine, diamorphine and naltrexone) on any of the outcome measures. Caution should be taken when interpreting these findings, as the conclusions are based on a small number of trials, and generalisation of these study findings should be limited mainly to male adult offenders. Additionally, many studies were rated at high risk of bias. PMID- 26035085 TI - Interventions for female drug-using offenders. AB - BACKGROUND: This is an updated version of a Cochrane review first published in Issue 3, 2006 (Perry 2006). The review represents one in a family of four reviews focusing on the effectiveness of interventions in reducing drug use and criminal activity for offenders. This specific review considers interventions for female drug-using offenders. OBJECTIVES: To assess the effectiveness of interventions for female drug-using offenders in reducing criminal activity, or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases up to May 2014 and five additional Website resources (between 2004 and November 2011). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials (RCTs) designed to reduce, eliminate or prevent relapse of drug use or criminal activity in female drug-using offenders. We also reported data on the cost and cost-effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: Nine trials with 1792 participants met the inclusion criteria. Trial quality and risks of bias varied across each study. We rated the majority of studies as being at 'unclear' risk of bias due to a lack of descriptive information. We divided the studies into different categories for the purpose of meta-analyses: for any psychosocial treatments in comparison to treatment as usual we found low quality evidence that there were no significant differences in arrest rates, (two studies; 489 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.45 to 1.52) or drug use (one study; 77 participants; RR 0.65, 95% CI 0.20 to 2.12), but we found moderate quality evidence that there was a significant reduction in reincarceration, (three studies; 630 participants; RR 0.46, 95% CI 0.34 to 0.64). Pharmacological intervention using buprenorphine in comparison to a placebo did not significantly reduce self reported drug use (one study; 36 participants; RR 0.58, 95% CI 0.25 to 1.35). No cost or cost-effectiveness evidence was reported in the studies. AUTHORS' CONCLUSIONS: Three of the nine trials show a positive trend towards the use of any psychosocial treatment in comparison to treatment as usual showing an overall significant reduction in subsequent reincarceration, but not arrest rates or drug use. Pharmacological interventions in comparison to a placebo did not significantly reduce drug use and did not measure criminal activity. Four different treatment comparisons showed varying results and were not combined due to differences in the intervention and comparison groups. The studies overall showed a high degree of heterogeneity for types of comparisons and outcome measures assessed, which limited the possibility to pool the data. Descriptions of treatment modalities are required to identify the important elements for treatment success in drug-using female offenders. More trials are required to increase the precision of confidence with which we can draw conclusions about the effectiveness of treatments for female drug-using offenders. PMID- 26035086 TI - Preventing aggression and other secondary features of dementia in elderly persons: Three case studies. AB - Dementia and Alzheimer's disease are associated with behavioral symptoms that can be costly and troublesome to caregivers. Behavioral strategies to prevent aggression in people with dementia (PWDs) are necessary to decrease caregiver burden and relieve other behavioral disturbances in PWDs, such as depression. On the basis of their previous study that identified pain as a possible cause of aggression, the authors developed a behavioral in-home intervention designed to teach caregiver(s) how to recognize signs of pain and distress in PWDs. The authors present a description of the Preventing Aggression in Veterans with Dementia (PAVeD) intervention and illustrate its use and results with three case studies. Results indicate that this intervention may help prevent the development of aggression and pain in PWDs, reduce caregiver burden, and help manage other behavioral symptoms associated with dementia. PMID- 26035087 TI - Effects of therapeutic relationship, expectancy, and credibility in breathing therapies for anxiety. AB - The authors investigated the effects of the quality of the therapeutic alliance, expectancy of improvement, and credibility of treatment on the outcome of two breathing therapies for anxiety and panic. Data were collected during a randomized clinical trial evaluating the efficacy of two theoretically opposing, end-tidal pCO2 feedback-assisted breathing therapies for patients experiencing anxiety attacks. In this study, five weekly individual breathing therapy sessions were administered for the patients who were experiencing anxiety attacks as symptoms of various anxiety disorders. The outcome of this trial indicated that regardless of the opposing breathing instructions (raise or lower pCO2) used in the two breathing therapies, patients in both treatment groups improved equally after treatment. Nonspecific factors rather than the different directions of pCO2 changes could have played a role in the improvement. Regression analyses showed that for both therapies patient-rated therapeutic alliance was predictive of improvement at the 1-month follow-up, and that patient-rated confidence that the therapy would produce improvement, an aspect of its credibility, accounted for almost half of the variance in improvement at the 6-month follow-up. Thus, two factors usually considered nonspecific were identified to be potent predictors of treatment outcome. PMID- 26035088 TI - Exploring the dynamic nature of "us": An integrative approach to relationship cognition. AB - Most psychiatric disorders are associated with problems in interpersonal relationships. This is not surprising because people's relationships with others are an influential and integral component of their lives. The cognitive representations of these relationships can be important in understanding these relationships, and both the attachment and relational schema approaches have helped to better understand the nature of these cognitions. The attachment approach is widely researched and established, but it struggles to fully assess the content of relationship knowledge. The relational schema approach provides a strong framework for assessing the content of relationship knowledge, but it does not currently have established measures for this content. In this article, the authors suggest that these two approaches may be particularly suited for integration, and they propose a comprehensive model of relationship cognition. Issues involving the measurement of relational knowledge and future research directions are discussed. Finally, the clinical utility of the proposed model is discussed. PMID- 26035089 TI - An analysis of successful outcomes and associated contributing factors in veterans' court. AB - This study aims to examine the extent to which a veteran's propensity for arrest following separation from veterans' court is associated with that veteran's length of stay within the program, type of discharge, or number of judicial sanctions issued. This is a retrospective chart review that focuses on the first 100 participants in the Harris County Veterans' Court Program. After controlling for a number of demographic factors, both arrests during enrollment in the veterans' court program (p = .031) and Factor Score 1 (unsuccessful discharge, fewer months in the veterans' court program, and more months of follow up) (p = .042) were predictive of arrest following separation from the veterans' court program. In addition, a prior diagnosis of opiate misuse was also predictive of arrest following separation (p < .001). Given these findings, veterans' court judges and program administrators might examine ways of continuing enrollment for veterans at highest risk for recidivism. PMID- 26035090 TI - The place of the body in young adults' use of the new technologies: Virtual bodies? AB - This research was initiated by the remark that new technologies allow young adults (from 18 to 25 years old) to have a faster and more direct access to the world, as well as a social life that is both broader and hidden from parental view. The aim of this research is therefore to understand better the role of new technologies in young adults' life, especially how they perceive their body through both images and others' eyes. Also, we intended to study the impact of new technologies on the psychical links and psychical functioning during the transition to adulthood. From a methodological point of view, we obtained qualitative results from semi-directive interviews. PMID- 26035091 TI - Optimization of Magnetic Inks Made of L1(0)-Ordered FePt Nanoparticles and Polystyrene-block-Poly(ethylene oxide) Copolymers. AB - The preparation of magnetic inks stable over time made of L10-ordered FePt nanoparticles, thiol-ended poly(ethylene glycol) methyl ether (mPEO-SH) compatibilizing macromolecules and asymmetric polystyrene-block-poly(ethylene oxide) copolymers (BCP) as a subsequent self-organizing medium was optimized. It was demonstrated that the use of sacrificial MgO shells as physical barriers during the annealing stage for getting the L10-ordered state makes easier and more efficient the anchoring of compatibilizing PEO macromolecules onto the nanoparticles surface. L10-FePt grafted nanoparticles have shown a good colloidal stability and affinity with the PEO domains of the BCP leading to L10-FePt/BCP composite thin layers with individual magnetic dots dispersed in the BCP matrix. PMID- 26035092 TI - Modeling Nonlinear Adsorption to Carbon with a Single Chemical Parameter: A Lognormal Langmuir Isotherm. AB - Predictive models for linear sorption of solutes onto various media, e.g., soil organic carbon, are well-established; however, methods for predicting parameters for nonlinear isotherm models, e.g., Freundlich and Langmuir models, are not. Predicting nonlinear partition coefficients is complicated by the number of model parameters to fit n isotherms (e.g., Freundlich (2n) or Polanyi-Manes (3n)). The purpose of this paper is to present a nonlinear adsorption model with only one chemically specific parameter. To accomplish this, several simplifications to a log-normal Langmuir (LNL) isotherm model with 3n parameters were explored. A single sorbate-specific binding constant, the median Langmuir binding constant, and two global sorbent parameters; the total site density and the standard deviation of the Langmuir binding constant were employed. This single-solute specific (ss-LNL) model (2 + n parameters) was demonstrated to fit adsorption data as well as the 2n parameter Freundlich model. The LNL isotherm model is fit to four data sets composed of various chemicals sorbed to graphite, charcoal, and activated carbon. The RMS errors for the 3-, 2-, and 1-chemical specific parameter models were 0.066, 0.068, 0.069, and 0.113, respectively. The median logarithmic parameter standard errors for the four models were 1.070, 0.4537, 0.382, and 0.201 respectively. Further, the single-parameter model was the only model for which there were no standard errors of estimated parameters greater than a factor of 3 (0.50 log units). The surprising result is that very little decrease in RMSE occurs when two of the three parameters, sigmakappa and qmax, are sorbate independent. However, the large standard errors present in the other models are significantly reduced. This remarkable simplification yields the single sorbate-specific parameter (ss-LNL) model. PMID- 26035093 TI - Isolation and Synthetic Diversification of Jadomycin 4-Amino-l-phenylalanine. AB - Streptomyces venezuelae ISP5230 was grown in the presence of phenylalanine analogues to observe whether they could be incorporated into novel jadomycin structures. It was found that the bacteria successfully produced jadomycins incorporating 4-aminophenylalanine enantiomers. Upon isolation and characterization of jadomycin 4-amino-l-phenylalanine (1), it was synthetically derivatized, using activated succinimidyl esters, to yield a small jadomycin amide library. These are the first examples of oxazolone-ring-containing jadomycins that have incorporated an amino functionality subsequently used for derivatization. PMID- 26035094 TI - Trajectory of substance use after an HIV risk reduction intervention. AB - BACKGROUND: Research assessments can confound the results of treatment outcome studies and can be themselves an intervention or form of aftercare. OBJECTIVE: To determine the trajectory of substance use and substance severity in a sample of African American cocaine users participating in a community-based sexual risk reduction trial. METHODS: Out-of-treatment participants were recruited using Respondent-Driven Sampling in two African American majority counties in rural Arkansas. They participated in either the sexual risk reduction condition or an active control focused on access to social services. They were interviewed at baseline, post-intervention, and 6 and 12 months post-intervention. Substance use outcome measures were use of crack cocaine, powder cocaine, marijuana, alcohol, and the Addiction Severity Index Alcohol and Drug Severity composites. A random sample of participants completed qualitative interviews post-12-month interview. RESULTS: 251 were enrolled. Substance use outcomes did not differ among the two conditions at any point in the study. Use of measured substances and the ASI composites significantly decreased between baseline and post-intervention (p < 0.01), decreases that persisted at the 12-month assessment period compared to baseline. Qualitative findings suggested that many participants identified increased awareness of their drug use and need to control it through the programs. Participants also noted strong bonding with interviewers. CONCLUSION: Clinical trials may have positive unexpected outcomes in terms of reduced substance use even though the trial is not substance use focused. Behavioral interventions for drug users that are not focused specifically on reducing drug use may nonetheless have unanticipated positive associations with reductions in drug use. PMID- 26035095 TI - Potential amoebicidal activity of hydrazone derivatives: synthesis, characterization, electrochemical behavior, theoretical study and evaluation of the biological activity. AB - Four new hydrazones were synthesized by the condensation of the selected hydrazine and the appropriate nitrobenzaldehyde. A complete characterization was done employing 1H- and 13C-NMR, electrochemical techniques and theoretical studies. After the characterization and electrochemical analysis of each compound, amoebicidal activity was tested in vitro against the HM1:IMSS strain of Entamoeba histolytica. The results showed the influence of the nitrobenzene group and the hydrazone linkage on the amoebicidal activity. meta-Nitro substituted compound 2 presents a promising amoebicidal activity with an IC50 = 0.84 MUM, which represents a 7-fold increase in cell growth inhibition potency with respect to metronidazole (IC50 = 6.3 MUM). Compounds 1, 3, and 4 show decreased amoebicidal activity, with IC50 values of 7, 75 and 23 uM, respectively, as a function of the nitro group position on the aromatic ring. The observed differences in the biological activity could be explained not only by the redox potential of the molecules, but also by their capacity to participate in the formation of intra- and intermolecular hydrogen bonds. Redox potentials as well as the amoebicidal activity can be described with parameters obtained from the DFT analysis. PMID- 26035096 TI - Microwave-Assisted Resolution of alpha-Lipoic Acid Catalyzed by an Ionic Liquid Co-Lyophilized Lipase. AB - The combination of the ionic liquid co-lyophilized lipase and microwave irradiation was used to improve enzyme performance in enantioselective esterification of alpha-lipoic acid. Effects of various reaction conditions on enzyme activity and enantioselectivity were investigated. Under optimal condition, the highest enantioselectivity (E = 41.2) was observed with a high enzyme activity (178.1 MUmol/h/mg) when using the ionic liquid co-lyophilized lipase with microwave assistance. Furthermore, the ionic liquid co-lyophilized lipase exhibited excellent reusability under low power microwave. PMID- 26035097 TI - Interplay between Beryllium Bonds and Anion-pi Interactions in BeR2:C6X6:Y- Complexes (R = H, F and Cl, X = H and F, and Y = Cl and Br). AB - A theoretical study of the beryllium bonds in BeR2:C6X6 (R = H, F, Cl and X = H and F) has been carried out by means of MP2/aug'-cc-pVDZ computational methods. In addition, the ternary complexes BeR2:C6X6:Y- (Y = Cl and Br) have been analyzed. Geometric, energetic and electronic aspects of the complexes have been taken into account. All the parameters analyzed provide a clear indication of favorable cooperativity in both interactions observed, beryllium bond and aromatic ring:anion interaction. PMID- 26035098 TI - DockBench: An Integrated Informatic Platform Bridging the Gap between the Robust Validation of Docking Protocols and Virtual Screening Simulations. AB - Virtual screening (VS) is a computational methodology that streamlines the drug discovery process by reducing costs and required resources through the in silico identification of potential drug candidates. Structure-based VS (SBVS) exploits knowledge about the three-dimensional (3D) structure of protein targets and uses the docking methodology as search engine for novel hits. The success of a SBVS campaign strongly depends upon the accuracy of the docking protocol used to select the candidates from large chemical libraries. The identification of suitable protocols is therefore a crucial step in the setup of SBVS experiments. Carrying out extensive benchmark studies, however, is usually a tangled task that requires users' proficiency in handling different file formats and philosophies at the basis of the plethora of existing software packages. We present here DockBench 1.0, a platform available free of charge that eases the pipeline by automating the entire procedure, from docking benchmark to VS setups. In its current implementation, DockBench 1.0 handles seven docking software packages and offers the possibility to test up to seventeen different protocols. The main features of our platform are presented here and the results of the benchmark study of human Checkpoint kinase 1 (hChk1) are discussed as validation test. PMID- 26035099 TI - Three New Sesquiterpene Aryl Esters from the Mycelium of Armillaria mellea. AB - Three new sesquiterpene aryl esters and eight known compounds were isolated from the EtOH extract of the mycelium of Armillaria mellea. The structures of new compounds were established by analysis of their spectroscopic data. Some of the isolates showed cytotoxicity to a variety of cancer cell lines, including MCF-7, H460, HT-29, and CEM. PMID- 26035100 TI - Synthesis and physicochemical characterization of the impurities of pemetrexed disodium, an anticancer drug. AB - A physicochemical characterization of the process-related impurities associated with the synthesis of pemetrexed disodium was performed. The possibility of pemetrexed impurities forming has been mentioned in literature, but no study on their structure has been published yet. This paper describes the development of the synthesis methods for these compounds and discusses their structure elucidation on the basis of two-dimensional NMR experiments and MS data. The identification of these impurities should be useful for the quality control during the production of the pemetrexed disodium salt. PMID- 26035101 TI - Computational Study of Symmetric Methylation on Histone Arginine Catalyzed by Protein Arginine Methyltransferase PRMT5 through QM/MM MD and Free Energy Simulations. AB - Protein arginine methyltransferases (PRMTs) catalyze the transfer of the methyl group from S-adenosyl-l-methionine (AdoMet) to arginine residues. There are three types of PRMTs (I, II and III) that produce different methylation products, including asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and monomethylarginine (MMA). Since these different methylations can lead to different biological consequences, understanding the origin of product specificity of PRMTs is of considerable interest. In this article, the quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed to study SDMA catalyzed by the Type II PRMT5 on the basis of experimental observation that the dimethylated product is generated through a distributive fashion. The simulations have identified some important interactions and proton transfers during the catalysis. Similar to the cases involving Type I PRMTs, a conserved Glu residue (Glu435) in PRMT5 is suggested to function as general base catalyst based on the result of the simulations. Moreover, our results show that PRMT5 has an energetic preference for the first methylation on Neta1 followed by the second methylation on a different omega guanidino nitrogen of arginine (Neta2).The first and second methyl transfers are estimated to have free energy barriers of 19-20 and 18-19 kcal/mol respectively. The computer simulations suggest a distinctive catalytic mechanism of symmetric dimethylation that seems to be different from asymmetric dimethylation. PMID- 26035102 TI - A 1H-NMR-Based Metabonomic Study on the Anti-Depressive Effect of the Total Alkaloid of Corydalis Rhizoma. AB - Corydalis Rhizoma, named YuanHu in China, is the dried tuber of Corydalis yanhusuo W.T. Wang which is used in Traditional Chinese Medicine for pain relief and blood activation. Previous pharmacological studies showed that apart from analgesics, the alkaloids from YuanHu may be useful in the therapy of depression by acting on the GABA, dopamine and benzodiazepine receptors. In this study, the antidepressive effect of the total alkaloid of YuanHu (YHTA) was investigated in a chronic unpredictable mild stress (CUMS) rat model using 1H-NMR-based metabonomics. Plasma metabolic profiles were analyzed and multivariate data analysis was applied to discover the metabolic biomarkers in CUMS rats. Thirteen biomarkers of CUMS-introduced depression were identified, which are myo-inositol, glycerol, glycine, creatine, glutamine, glutamate, beta-glucose, alpha-glucose, acetoacetate, 3-hydroxybutyrate, leucine and unsaturated lipids (L7, L9). Moreover, a metabolic network of the potential biomarkers in plasma perturbed by CUMS was detected. After YHTA treatment, clear separation between the model group and YHTA-treated group was achieved. The levels of all the abnormal metabolites mentioned above showed a tendency of restoration to normal levels. The results demonstrated the therapeutic efficacy of YHTA against depression and suggested that NMR-based metabolomics can provide a simple and easy tool for the evaluation of herbal therapeutics. PMID- 26035104 TI - PLS-Prediction and Confirmation of Hydrojuglone Glucoside as the Antitrypanosomal Constituent of Juglans Spp. AB - Naphthoquinones (NQs) occur naturally in a large variety of plants. Several NQs are highly active against protozoans, amongst them the causative pathogens of neglected tropical diseases such as human African trypanosomiasis (sleeping sickness), Chagas disease and leishmaniasis. Prominent NQ-producing plants can be found among Juglans spp. (Juglandaceae) with juglone derivatives as known constituents. In this study, 36 highly variable extracts were prepared from different plant parts of J. regia, J. cinerea and J. nigra. For all extracts, antiprotozoal activity was determined against the protozoans Trypanosoma cruzi, T. brucei rhodesiense and Leishmania donovani. In addition, an LC-MS fingerprint was recorded for each extract. With each extract's fingerprint and the data on in vitro growth inhibitory activity against T. brucei rhodesiense a Partial Least Squares (PLS) regression model was calculated in order to obtain an indication of compounds responsible for the differences in bioactivity between the 36 extracts. By means of PLS, hydrojuglone glucoside was predicted as an active compound against T. brucei and consequently isolated and tested in vitro. In fact, the pure compound showed activity against T. brucei at a significantly lower cytotoxicity towards mammalian cells than established antiprotozoal NQs such as lapachol. PMID- 26035103 TI - Comparison of Fruits of Forsythia suspensa at Two Different Maturation Stages by NMR-Based Metabolomics. AB - Forsythiae Fructus (FF), the dried fruit of Forsythia suspensa, has been widely used as a heat-clearing and detoxifying herbal medicine in China. Green FF (GF) and ripe FF (RF) are fruits of Forsythia suspensa at different maturity stages collected about a month apart. FF undergoes a complex series of physical and biochemical changes during fruit ripening. However, the clinical uses of GF and RF have not been distinguished to date. In order to comprehensively compare the chemical compositions of GF and RF, NMR-based metabolomics coupled with HPLC and UV spectrophotometry methods were adopted in this study. Furthermore, the in vitro antioxidant and antibacterial activities of 50% methanol extracts of GF and RF were also evaluated. A total of 27 metabolites were identified based on NMR data, and eight of them were found to be different between the GF and RF groups. The GF group contained higher levels of forsythoside A, forsythoside C, cornoside, rutin, phillyrin and gallic acid and lower levels of rengyol and beta glucose compared with the RF group. The antioxidant activity of GF was higher than that of RF, but no significant difference was observed between the antibacterial activities of GF and RF. Given our results showing their distinct chemical compositions, we propose that NMR-based metabolic profiling can be used to discriminate between GF and RF. Differences in the chemical and biological activities of GF and RF, as well as their clinical efficacies in traditional Chinese medicine should be systematically investigated in future studies. PMID- 26035105 TI - FDG PET/CT dataset for navigation on femoral bone: a feasibility study. AB - FDG PET/CT has become a valuable tool in the diagnosis of the activity of chronic osteomyelitis. The surgical strategy in the treatment of chronic osteomyelitis is the identification of the bone focus and radical debridement of sequesters. The aim of the current study was the registration and use of the FDG PET/CT imaging datasets on a navigation system to provide diagnostic imaging based feedback during surgical procedures. For the present study, FDG PET/CT scans were acquired from artificial bones and cadaver bones with a local focus of activity. The DICOM data sets were merged using a navigation system. The referenced regions of interest were matched with fluoroscopic pictures to register the PET/CT DICOM datasets to the bone and direct visual control. Navigated targeting led to accurate results when verified with fluoroscopic images by targeting previously inserted reference points in artificial and cadaver bone. FDG PET/CT datasets are suitable for navigation and compatible with conventional planning and navigation software. The combination of diagnostic FDG PET/CT imaging with surgical navigation techniques could be a valuable tool for the accurate treatment of chronic osteomyelitis. PMID- 26035106 TI - Degradation of magnetic nanoparticles mimicking lysosomal conditions followed by AC susceptibility. AB - BACKGROUND: A deeper knowledge on the effects of the degradation of magnetic nanoparticles on their magnetic properties is required to develop tools for the identification and quantification of magnetic nanoparticles in biological media by magnetic means. METHODS: Citric acid and phosphonoacetic acid-coated magnetic nanoparticles have been degraded in a medium that mimics lysosomal conditions. Magnetic measurements and transmission electron microscopy have been used to follow up the degradation process. RESULTS: Particle size is reduced significantly in 24 h at pH 4.5 and body temperature. These transformations affect the magnetic properties of the compounds. A reduction of the interparticle interactions is observed just 4 h after the beginning of the degradation process. A strong paramagnetic contribution coming from the degradation products appears with time. CONCLUSIONS: A model for the in vivo degradation of magnetic nanoparticles has been followed to gain insight on the changes of the magnetic properties of iron oxides during their degradation. The degradation kinetics is affected by the particle coating, in our case being the phosphonoacetic acid coated particles degraded faster than the citric acid-coated ones. PMID- 26035108 TI - Does ethnicity have an effect on fetal behavior? A comparison of Asian and Caucasian populations. AB - AIM: This study aimed to evaluate the ethnic difference in fetal behavior between Asian and Caucasian populations. METHODS: Fetal behavior was assesed by Kurjak's antenatal neurodevelopmental test (KANET) using four-dimensional (4D) ultrasound between 28 and 38 weeks of gestation. Eighty-nine Japanese (representative of Asians) and seventy-eight Croatian (representative of Caucasians) pregnant women were studied. The total value of KANET score and values of each parameter (eight parameters) were compared. RESULTS: The total KANET score was normal in both populations, but there was a significant difference in total KANET scores between Japanese (median, 14; range, 10-16) and Croatian fetuses (median, 12; range, 10 15) (P<0.0001). When individual KANET parameters were compared, we found significant differences in four fetal movements (isolated head anteflexion, isolated eye blinking, facial alteration or mouth opening, and isolated leg movement). No significant differences were noted in the four other parameters (cranial suture and head circumference, isolated hand movement or hand to face movements, fingers movements, and gestalt of general movements). CONCLUSION: Our results suggest that ethnicity should be considered when evaluating fetal behavior, especially during assessment of fetal facial expressions. Although there was a difference in the total KANET score between Japanese and Croatian populations, all the scores in both groups were within normal range. Our results indicate that ethnical differences in fetal behaviour do not affect the total KANET score, but close follow-up should be continued in some borderline cases. PMID- 26035107 TI - Magnetic relaxometry as applied to sensitive cancer detection and localization. AB - BACKGROUND: Here we describe superparamagnetic relaxometry (SPMR), a technology that utilizes highly sensitive magnetic sensors and superparamagnetic nanoparticles for cancer detection. Using SPMR, we sensitively and specifically detect nanoparticles conjugated to biomarkers for various types of cancer. SPMR offers high contrast in vivo, as there is no superparamagnetic background, and bones and tissue are transparent to the magnetic fields. METHODS: In SPMR measurements, a brief magnetizing pulse is used to align superparamagnetic nanoparticles of a discrete size. Following the pulse, an array of superconducting quantum interference detectors (SQUID) sensors detect the decaying magnetization field. NP size is chosen so that, when bound, the induced field decays in seconds. They are functionalized with specific biomarkers and incubated with cancer cells in vitro to determine specificity and cell binding. For in vivo experiments, functionalized NPs are injected into mice with xenograft tumors, and field maps are generated to localize tumor sites. RESULTS: Superparamagnetic NPs developed here have small size dispersion. Cell incubation studies measure specificity for different cell lines and antibodies with very high contrast. In vivo animal measurements verify SPMR localization of tumors. Our results indicate that SPMR possesses sensitivity more than 2 orders of magnitude better than previously reported. PMID- 26035109 TI - Preservation of urine free catecholamines and their free O-methylated metabolites with citric acid as an alternative to hydrochloric acid for LC-MS/MS-based analyses. AB - BACKGROUND: Measurements of urinary fractionated metadrenalines provide a useful screening test to diagnose phaeochromocytoma. Stability of these compounds and their parent catecholamines during and after urine collection is crucial to ensure accuracy of the measurements. Stabilisation with hydrochloric acid (HCl) can promote deconjugation of sulphate-conjugated metadrenalines, indicating a need for alternative preservatives. METHODS: Urine samples with an intrinsically acidic or alkaline pH (5.5-6.9 or 7.1-8.7, respectively) were used to assess stability of free catecholamines and their free O-methylated metabolites over 7 days of room temperature storage. Stabilisation with HCl was compared with ethylenediaminetetraacetic acid/metabisulphite and monobasic citric acid. Catecholamines and metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Free catecholamines and their O-methylated metabolites were stable in acidic urine samples over 7 days of room temperature storage, independent of the presence or absence of any stabilisation method. In contrast, free catecholamines, but not the free O-methylated metabolites, showed rapid degradation within 24 h and continuing degradation over 7 days in urine samples with an alkaline pH. Adjustment of alkaline urine samples to a pH of 3-5 with HCl or 4.8-5.4 with citric acid completely blocked degradation of catecholamines. Ethylenediaminetetraacetic acid/metabisulphite, although reducing the extent of degradation of catecholamines in alkaline urine, was largely ineffectual as a stabiliser. CONCLUSIONS: Citric acid is equally effective as HCl for stabilisation of urinary free catecholamines and minimises hazards associated with use of strong inorganic acids while avoiding deconjugation of sulphate conjugated metabolites during simultaneous LC-MS/MS measurements of free catecholamines and their free O-methylated metabolites. PMID- 26035110 TI - Two novel haemoglobin variants that affect haemoglobin A1c measurement by ion exchange chromatography. AB - BACKGROUND: Haemoglobin (Hb) variants are well-known factors interfering with accurate HbA1c testing. This report describes two novel Hb variants leading to inappropriate quantification of HbA1c by ion-exchange chromatography. METHODS: Glycated forms of novel Hb variants were recognised in the blood of two patients with diabetes mellitus screened by HbA1c ion-exchange chromatography. Dedicated high-resolution cation-exchange chromatography and subsequent DNA sequencing revealed the exact nature of the variants. Other common techniques for quantifying HbA1c were applied on both samples and haematological parameters were determined to judge possible pathology associated with the novel Hb variants. RESULTS: A fraction of 15% of abnormal Hb was observed in a 37-year-old female. DNA sequencing revealed a heterozygous mutation in the alpha1-globin gene, resulting in a leucine-to-phenylalanine amino-acid substitution (HBA1: c.301C>T, p.Leu101Phe). We named this variant Hb Weesp. The other novel variant, Hb Haelen, presented as a 40% fraction in a 63-year-old male and resulted from a heterozygous amino acid substitution in the beta-globin gene (HBB: c.335T>C, p.Val112Gly). The presence of both Hb variants resulted in aberrant separation of the Hb components, leading to an inadequate quantification of HbA1c. CONCLUSIONS: Close examination of HbA1c chromatograms revealed two novel, clinically silent Hb variants that interfere with HbA1c quantification. Healthcare providers need to be aware of the potential of such Hb variants when interpreting HbA1c results. PMID- 26035111 TI - Screening non-deletion alpha-thalassaemia mutations in the HBA1 and HBA2 genes by high-resolution melting analysis. AB - BACKGROUND: Screening for "non-deletion" alpha-chain haemoglobin variants resulting from point mutations or short deletions/insertions has attracted an increased interest during recent years, especially in areas where alpha thalassaemia is prevalent. We describe a method utilising high resolution melting analysis for detecting the 13 most common "non-deletion" alpha-thalassaemia mutations in populations around the Mediterranean and Middle East. METHODS: The method comprises: (1) amplification of a 1087 bp fragment for each of the duplicated alpha-globin genes (HBA1 and HBA2) flanking all 13 mutations using a common forward primer and different reverse primers specific for HBA1 and HBA2, respectively; (2) nested amplification of three fragments in HBA2 flanking 10 mutations and two fragments in HBA1 flanking 5 mutations; (3) High resolution melting analysis of the amplicons using a LightScanner Instrument and LC Green. RESULTS: All 13 "non-deletion" alpha-chain haemoglobin variants were successfully detected by high resolution melting analysis. All heterozygote samples and eight out of 10 available homozygotes were clearly differentiated from each other and from wild type in the same amplicon. Although not all homozygote samples were distinguishable from wild type samples, this should not present a problem in a clinical setting since all DNA results should be evaluated alongside the haematological and (if relevant) clinical findings in each case. CONCLUSIONS: The 13 "non-deletion" alpha-chain haemoglobin variants were successfully genotyped by high resolution melting analysis using LightScanner instrument and LCGreen Plus saturating dye. High resolution melting analysis is an accurate mutation scanning tool, advantageous as a closed-tube method, involving no post-PCR manipulations and requiring only around 5 min post-PCR analysis. PMID- 26035112 TI - The ratio of calprotectin to total protein as a diagnostic and prognostic marker for spontaneous bacterial peritonitis in patients with liver cirrhosis and ascites. AB - BACKGROUND: Diagnosis of spontaneous bacterial peritonitis (SBP) is based on a differential ascites leukocyte count which does not provide prognostic information. We performed a pilot study to assess calprotectin in ascites as an alternative diagnostic and prognostic marker. METHODS: We collected ascites from patients with liver cirrhosis from March 2012 to July 2013. Routine clinical and laboratory data of the patients were recorded. Ascites calprotectin levels were determined by ELISA. RESULTS: Overall, we collected 120 ascites samples from 100 patients with liver cirrhosis and from eight patients with malignant peritoneal effusion as disease control. Samples without infection had significantly lower calprotectin levels (median 34 ng/mL, range 5-795) than SBP samples (median 928 ng/mL, range 21-110,480; p<0.001) and malignant effusions (median 401, range 47 2596 ng/mL; p<0.001). In non-infected ascites, calprotectin levels were higher in Child-Pugh stage B versus C (median 57 ng/mL vs. 17 ng/mL; p<0.001) and in alcoholic versus viral cirrhosis (median 37 ng/mL vs. 10 ng/mL; p=0.015). The ratio of ascites calprotectin to total protein was a better marker for SBP than calprotectin alone (AUROC=0.93; p<0.001; sensitivity 93%, specificity 79%; positive predictive value 60%; negative predictive value 97%). In addition, high levels of the ratio to total protein were associated with poor 30-day survival (p=0.042). CONCLUSIONS: The ratio of ascites calprotectin to total protein may be a promising new diagnostic and prognostic marker in patients with liver cirrhosis and SBP and should be evaluated further. PMID- 26035113 TI - The diagnostic value of serum fucosylated fetuin A in hepatitis B virus-related liver diseases. AB - BACKGROUND: Some changes of glycoproteins have been identified in the serum of patients with different liver diseases, which provided potential glycan biomarkers for diagnosis, prognosis and monitoring of disease progression. METHODS: We established a lectin-antibody sandwich ELISA method to detect fucosylated fetuin A (fuc-fetuin A) level in serum, in which biotinylated Aleuria aurantia lectin (AAL) was used for specific recognition. Then serum fuc-fetuin A level was detected in 108 healthy controls and 548 hepatitis B virus (HBV) infected patients, including 232 hepatocellular carcinoma (HCC) patients, 114 liver cirrhosis (LC) patients, 86 liver fibrosis (LF) patients, and 116 asymptomatic HBV carriers, to assess its diagnostic and prognostic value in HBV related liver diseases. RESULTS: Serum fetuin A level decreased in LC patients as compared to HCC patients or healthy controls, while it decreased further according to the increasing Child-Pugh grades. The fuc-fetuin A level was in a decreasing order in LC, HCC, LF, HBV-carriers and healthy controls. For distinguishing LC and HCC patients from LF, HBV-carriers and healthy controls, the area under the receiver operating characteristic (ROC) curve is 0.871, with a sensitivity of 0.818 and specificity of 0.819. The survival analysis revealed that higher fuc-fetuin A level was significantly associated with worse recurrence free survival in HCC patients (p=0.018). CONCLUSIONS: The results indicated that the serum fuc-fetuin A might serve as a potential glycan biomarker for distinguishing LC and HCC from LF, HBV-carriers and healthy controls. Furthermore, the preoperative fuc-fetuin A level could be a useful prognostic biomarker for HCC patients. PMID- 26035114 TI - Considerations in parathyroid hormone testing. AB - Parathyroid hormone (PTH) is a major player in phosphocalcic metabolism and its measurement is very important for the correct diagnosis and treatment of several diseases. PTH determination represents the paradigm of quality in laboratory medicine as many variables in the pre-, intra-, and post-analytical phases strongly affect the value of the clinical information. Analytical determination of PTH has been rendered difficult by the presence, in the circulation, of truncated fragments that can cross-react with the antibodies used for its determination. In addition, pre-analytical phase is complicated by the lack of stability of the peptide and the best sample to use for its determination remains controversial, as well as sample handling and storage. PTH secretion is also affected by circadian and seasonal rhythms and by physical exercise. Finally, from the post-analytical perspective, establishment of reliable reference ranges requires further efforts as the selection criteria for reference subjects should take into consideration new variables such as gender, race and vitamin D levels. Finally, clinical guidelines have recently revised and improved the criteria for a correct interpretation of PTH values. PMID- 26035115 TI - Adjustment of serum potassium for age and platelet count. A simple step forward towards personalized medicine. PMID- 26035116 TI - The economic burden of hemolysis. PMID- 26035117 TI - Effect of storage time and temperature on the generation of reactive oxygen species in peripheral blood leukocytes. PMID- 26035118 TI - New trends in the long and puzzling history of HbA1c. PMID- 26035119 TI - New 1H NMR-Based Technique To Determine Epoxide Concentrations in Oxidized Oil. AB - A new method to determine epoxide concentrations in oxidized oils was developed and validated using (1)H NMR. Epoxides derived from lipid oxidation gave signals between 2.90 and 3.24 ppm, well separated from the signals of other lipid oxidation products. To calibrate, soybean oils with a range of epoxide concentrations were synthesized and analyzed using (1)H NMR by taking the sn-1,3 glycerol protons (4.18, 4.33 ppm) as internal references. The (1)H NMR signals were compared to the epoxide content determined by titration with hydrogen bromide (HBr)-acetic acid solution. As expected, the signal response increased with concentration linearly (R(2) = 99.96%), and validation of the method gave results comparable to those of the HBr method. A study of the oxidative stability of soybean oil was performed by applying this method to monitor epoxides during thermal lipid oxidation. The epoxide content increased over time and showed a different trend compared to peroxide value (PV). A phenomenological model was suggested to model epoxides derived from lipid oxidation. PMID- 26035120 TI - Use of Accelerometers to Examine Sedentary Time on an Acute Stroke Unit. AB - BACKGROUND AND PURPOSE: Observational studies demonstrate low levels of physical activity during inpatient stroke rehabilitation. There are no prior studies that have objectively measured sedentary time on the acute stroke unit and whether sedentary time is related to functional outcomes. The purpose of this study was to characterize sedentary time after acute stroke and determine whether there is a relationship to functional performance at discharge. METHODS: Thirty-two individuals (18 men; 56.5 +/- 12.7 years) with acute stroke were enrolled within 48 hours of hospital admission. An accelerometer was placed on the stroke affected ankle to measure 24-hour activity and was worn for 4 days or until discharge from the hospital. Performance of activities of daily living, walking endurance, and functional mobility were assessed using the Physical Performance Test, Six-Minute Walk Test, and Timed Up and Go, respectively. RESULTS: Mean percent time spent sedentary was 93.9 +/- 4.1% and percent time in light activity was 5.1 +/- 2.4%. When controlling for baseline performance, the mean time spent sedentary per day was significantly related to Physical Performance Test performance at discharge (r = -0.37; P = .05), but not the Six-Minute Walk Test or Timed Up and Go. DISCUSSION AND CONCLUSIONS: Patients with acute stroke were sedentary most of their hospital stay. To minimize the potential negative effects of inactivity, our data suggest that there should be greater emphasis on increasing physical activity during the hospital stay.Video Abstract Available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A101). PMID- 26035121 TI - Assessing the Response to Inhaled Albuterol by Monitoring Patient Effort-Related Trends With a Servo-I Ventilator in Neurally Adjusted Ventilatory Assist Mode: A Case Presentation. AB - BACKGROUND: Infants with chronic lung disease tend to be difficult to care for due to the heterogeneous nature of both their disease and the treatments required. Multiple types of medications, treatments, and nursing interventions are often needed to attain clinical success, and it is frequently difficult to discern which are effective versus the ones that offer no benefit. This article presents a case study that chronicles the care of an infant with chronic lung disease treated with albuterol. An innovative form of ventilation with monitoring of the electrical activity of the diaphragm with a special sensor-embedded catheter is used to assess the effectiveness of albuterol administration. PURPOSE: This case study presents the monitoring of the effectiveness of albuterol in an infant with chronic lung disease measuring the electrical activity of the diaphragm catheter (Edi) and the various monitoring systems on the Servo-i ventilator in Neurally Adjusted Ventilatory Assist (NAVA) Mode. CASE FINDINGS/RESULTS: The clinicians followed various respiratory trends monitored by the Servo-i ventilator after albuterol dosing to document the clinical utility of using albuterol in this infant. The monitoring provided by NAVA showed an improvement in both lung mechanics and clinical condition immediately after albuterol administration. IMPLICATIONS FOR PRACTICE: The infant had a positive response to albuterol dosing that subsequently led to reduced length of stay, reduced costs, and reduced family anxiety. This type of monitoring could help nurses and clinicians discern whether a given treatment or medication was effective. IMPLICATIONS FOR RESEARCH: This method of clinical monitoring could provide a means to assess clinical utility of respiratory medications, treatments, and nursing interventions in certain populations of neonates and infants. The impact of objective monitoring on required sedation, weight gain, ventilator days, length of hospitalization, and overall hospital costs are other possible areas for future research. PMID- 26035122 TI - Retinoic Acid Reduces Stem Cell-Like Features in Pancreatic Cancer Cells. AB - OBJECTIVES: Retinoic acid (RA) has important functions during embryonic development being involved in cell growth and differentiation. Although approved for the treatment of acute promyelocytic leukemia, it is still under investigation for different solid tumors including pancreatic cancer. The objective of this study was to analyze how RA affects pancreatic cancer stem cells and how its combination with chemotherapy could impact cell growth. METHODS: Using different pancreatic cancer cell lines, we evaluated the effect of RA alone or in combination with chemotherapy regulating cancer stem cells properties and pathways. RESULTS: Retinoic acid treatment reduces the expression of pancreatic stem cell markers CD24, CD44, CD133, and aldehyde dehydrogenase 1 but not c-Met. Although gemcitabine treatment increases the expression of some of these markers especially CD44 when it is combined with RA, a notable reduction in all of them is observed. Retinoic acid induces a G0/G1 arrest and combined with gemcitabine increases the apoptotic effect produced by chemotherapy probably as a consequence of a regulation of specific stem cell transcription factors. CONCLUSIONS: Retinoic acid regulates self-renewal capacity of cells in pancreatic tumors and should be further investigated in combination with chemotherapy as therapeutic strategy in pancreatic cancer. PMID- 26035123 TI - Mucin 1 Regulates Cox-2 Gene in Pancreatic Cancer. AB - OBJECTIVE: Eighty percent of pancreatic ductal adenocarcinomas (PDAs) overexpress mucin 1 (MUC1), a transmembrane mucin glycoprotein. MUC1(high) PDA patients also express high levels of cyclooxygenase 2 (COX-2) and show poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) partakes in oncogenic signaling, resulting in accelerated cancer progression. Our aim was to understand the regulation of Cox-2 expression by MUC1. METHODS: Levels of COX-2 and MUC1 were determined in MUC1(-/ ), MUC1(low), and MUC1(high) PDA cells and tumors using reverse transcriptase polymerase chain reaction, Western blot, and immunohistochemistry. Proliferative and invasive potential was assessed using MTT and Boyden chamber assays. Chromatin immunoprecipitation was performed to evaluate binding of MUC1-CT to the promoter of COX-2 gene. RESULTS: Significantly higher levels of COX-2 mRNA and protein were detected in MUC1(high) versus MUC1(low/null) cells, which were recapitulated in vivo. In addition, deletion of MUC1 gene and transient knockdown of MUC1 led to decreased COX-2 level. Also, MUC1-CT associated with the COX-2 promoter at ~1000 base pairs upstream of the transcription start site, the same gene locus where nuclear factor kappaB p65 associates with the COX-2 promoter. CONCLUSIONS: Data supports a novel regulation of COX-2 gene by MUC1 in PDA, the intervention of which may lead to a better therapeutic targeting in PDA patients. PMID- 26035124 TI - Should All Cases of High-Grade Serous Ovarian, Tubal, and Primary Peritoneal Carcinomas Be Reclassified as Tubo-Ovarian Serous Carcinoma? AB - INTRODUCTION: The dualistic theory of ovarian carcinogenesis proposes that epithelial "ovarian" cancer is not one entity with several histological subtypes but a collection of different diseases arising from cells of different origin, some of which may not originate in the ovarian surface epithelium. METHODS: All cases referred to the Pan-Birmingham Gynaecological Cancer Centre with an ovarian, tubal, or primary peritoneal cancer between April 2006 and April 2012 were identified from the West Midlands Cancer Registry. Tumors were classified into type I (low-grade endometrioid, clear cell, mucinous, and low-grade serous) and type II (high-grade serous, high-grade endometrioid, carcinosarcoma, and undifferentiated) cancers. RESULTS: Ovarian (83.5%), tubal (4.3%), or primary peritoneal carcinoma (12.2%) were diagnosed in a total of 583 woman. The ovarian tumors were type I in 134 cases (27.5%), type II in 325 cases (66.7%), and contained elements of both type I and type II tumors in 28 cases (5.7%). Most tubal and primary peritoneal cases, however, were type II tumors: 24 (96.0%) and 64 (90.1%), respectively. Only 16 (5.8%) of the ovarian high-grade serous carcinomas were stage I at diagnosis, whereas 240 (86.6%) were stage III+. Overall survival varied between the subtypes when matched for stage. Stage III low-grade serous and high-grade serous carcinomas had a significantly better survival compared to clear cell and mucinous cases, P = 0.0134. There was no significant difference in overall survival between the high-grade serous ovarian, tubal, or peritoneal carcinomas when matched for stage (stage III, P = 0.3758; stage IV, P = 0.4820). CONCLUSIONS: Type II tumors are more common than type I and account for most tubal and peritoneal cancers. High-grade serous carcinomas, whether classified as ovarian/tubal/peritoneal, seem to behave as one disease entity with no significant difference in survival outcomes, therefore supporting the proposition of a separate classification of "tubo-ovarian serous carcinoma". PMID- 26035125 TI - Vulvar Reconstruction by Perforator Flaps: Algorithm for Flap Choice Based on the Topography of the Defect. AB - OBJECTIVE: Many techniques have been proposed to reconstruct acquired vulvar defects. In our experience, every type of vulvar defect can be repaired with 2 pedicled flaps, namely, the pedicle deep inferior epigastric perforator (DIEP) flap and the lotus petal flap (LPF). MATERIALS AND METHODS: We report our reconstructive algorithm for vulvar reconstruction, based on the topography of the defect, applied in 22 consecutive patients from 2000 to 2012. According to the proposed algorithm, DIEP flap and LPF (monolateral or bilateral type) can repair all kinds of wide vulvar defects. Surgical defects were classified as type I (IA and IB) and type II in relation to the anatomy of the defect. RESULTS: No major complications were reported in our series. All patients reported satisfactory results, both functionally and aesthetically. CONCLUSIONS: We propose an easy classification of acquired vulvar defects separating the ones consequent only to the vulvar resection, with preservation of vagina (type I), by the wider defects after vaginal and vulvar resection (type II); type I can be subclassified into defects consequent to half-vulvar resection (type IA) or to total vulvar resection (type IB). Type I defects (IA and IB) can be reconstructed with monolateral or bilateral LPF; in type II resections, we have a great wound that required more tissue to fill the pelvic dead space, so we prefer pedicle DIEP flap. PMID- 26035126 TI - Differences in Clinical and Biological Features Between Type I and Type II Tumors in FIGO Stages I-II Epithelial Ovarian Carcinoma. AB - OBJECTIVE: The objective of this study was to compare immunohistochemical profile for the apoptosis regulators p53, C-MYC, bax, PUMA, and PTEN and the cell cycle regulatory proteins p21 and p27, as well as clinical factors between types I and II tumors. METHODS: In total, 131 patients in FIGO (International Federation of Gynecology and Obstetrics) stages I-II were divided into 2 groups of patients after type I tumors (n = 79) and type II tumors (n = 52). Differences in the immunohistochemical profile for the cell cycle-related proteins, detected by tissue microarrays and immune-histochemistry, were compared. For statistical tests, the Pearson chi test and the logistic regression model were used. All tests were 2-sided, and the level of statistical significance was P <= 0.05. RESULTS: In multivariate logistic regression analysis with recurrent disease as endpoint, FIGO stage (odds ratio [OR], 4.7), type I/II tumors (OR, 3.8), body mass index (BMI) (OR, 3.5), and p53 status (OR, 4.2) all were found to be independent predictive factors. In 2 different multivariate logistic regression analyses with type I/II tumors as endpoint, both p53p21 (OR, 2.9) and p27 status (OR, 3.0) were associated with type II tumors. Differently, C-MYC status (OR, 0.4) was associated with type I tumors. Furthermore, age (OR, 1.04), BMI (OR, 0.4), and recurrent disease (OR, 4.3) all were associated to type II tumors. In survival analysis, there was a trend (P = 0.054) toward better disease-free survival for patients with type I tumors. CONCLUSIONS: Concomitant positivity for p53 and negativity for p21, positivity for p27, and negativity for C-MYC in an epithelial ovarian tumor might strengthen the diagnostic option of type II tumor ovarian carcinoma. Patients with type II tumors were older, had lower BMI, and had more often recurrent disease than patients with type I tumors. PMID- 26035127 TI - Comparative Genomics Within the Bacillus Genus Reveal the Singularities of Two Robust Bacillus amyloliquefaciens Biocontrol Strains. AB - Bacillus amyloliquefaciens CECT 8237 and CECT 8238, formerly known as Bacillus subtilis UMAF6639 and UMAF6614, respectively, contribute to plant health by facing microbial pathogens or inducing the plant's defense mechanisms. We sequenced their genomes and developed a set of ad hoc scripts that allowed us to search for the features implicated in their beneficial interaction with plants. We define a core set of genes that should ideally be found in any beneficial Bacillus strain, including the production of secondary metabolites, volatile compounds, metabolic plasticity, cell-to-cell communication systems, and biofilm formation. We experimentally prove that some of these genetic elements are active, such as i) the production of known secondary metabolites or ii) acetoin and 2-3-butanediol, compounds that stimulate plant growth and host defense responses. A comparison with other Bacillus genomes permits us to find differences in the cell-to-cell communication system and biofilm formation and to hypothesize variations in their persistence and resistance ability in diverse environmental conditions. In addition, the major protection provided by CECT 8237 and CECT 8238, which is different from other Bacillus strains against bacterial and fungal melon diseases, permits us to propose a correlation with their singular genetic background and determine the need to search for additional blind biocontrol-related features. PMID- 26035128 TI - Linking Jasmonic Acid Signaling, Root Exudates, and Rhizosphere Microbiomes. AB - Jasmonic acid (JA) is an essential hormone in plant development and defense responses in Arabidopsis thaliana. Exogenous treatment with JA has recently been shown to alter root exudate profiles and the composition of root-associated bacterial communities. However, it is currently unknown whether disruptions of the JA in the rhizosphere affect root exudation profiles and the relative abundance of bacteria and archaea in the rhizosphere. In the present study, two Arabidopsis mutants that are disrupted in different branches of the jasmonate pathway, namely myc2 and med25, were cultivated in nutrient solution and soil to profile root exudates and bacterial and archaeal communities, respectively. Compared with the wild type, both mutants showed distinct exudation patterns, including lower amounts of asparagine, ornithine, and tryptophan, as well as distinct bacterial and archaeal community composition, as illustrated by an increased abundance of Streptomyces, Bacillus, and Lysinibacillus taxa in the med25 rhizosphere and an Enterobacteriaceae population in myc2. Alternatively, the Clostridiales population was less abundant in the rhizosphere of both mutants. Similarities between plant genotypes were highly correlated, as determined by operational taxonomic units in the rhizosphere and metabolites in root exudates. This strongly suggests that root exudates play a major role in modulating changes in microbial community composition upon plant defense responses. PMID- 26035129 TI - Loss of bcbrn1 and bcpks13 in Botrytis cinerea Not Only Blocks Melanization But Also Increases Vegetative Growth and Virulence. AB - Botrytis cinerea is a necrotrophic pathogen that causes gray mold disease in a broad range of plants. Dihydroxynaphthalene (DHN) melanin is a major component of the extracellular matrix of B. cinerea, but knowledge of the exact role of melanin biosynthesis in this pathogen is unclear. In this study, we characterize two genes in B. cinerea, bcpks13 and bcbrn1, encoding polyketide synthase and tetrahydroxynaphthalene (THN) reductases, respectively, and both have predicted roles in DHN melanin biosynthesis. The ?bcpks13 and ?bcbrn1 mutants show white and orange pigmentation, respectively, and the mutants are also deficient in conidiation in vitro but show enhanced growth rates and virulence on hosts. Moreover, the mutants display elevated acidification of the complete medium (CM), probably due to oxalic acid secretion and secretion of cell wall-degrading enzymes, and preferably utilize plant cell-wall components as carbon sources for mycelium growth in vitro. In contrast, overexpression of bcbrn1 (OE::bcbrn1 strain) results in attenuated hydrolytic enzyme secretion, acidification ability, and virulence. Taken together, these results indicate that bcpks13 and bcbrn1 participate in diverse cellular and developmental processes, such as melanization and conidiation in B. cinerea in vitro, but they negatively regulate the virulence of this pathogen. PMID- 26035130 TI - Stable Fluorescent and Enzymatic Tagging of Bradyrhizobium diazoefficiens to Analyze Host-Plant Infection and Colonization. AB - Bradyrhizobium diazoefficiens USDA 110 (formerly named Bradyrhizobium japonicum) can fix dinitrogen when living as an endosymbiont in root nodules of soybean and some other legumes. Formation of a functional symbiosis relies on a defined developmental program mediated by controlled gene expression in both symbiotic partners. In contrast to other well-studied Rhizobium-legume model systems that have been thoroughly examined by means of genetically tagged strains, analysis of B. diazoefficiens host infection has been impaired due to the lack of suitable tagging systems. Here, we describe the construction of B. diazoefficiens strains constitutively expressing single-copy genes for fluorescent proteins (eBFP2, mTurquoise2, GFP+, sYFP2, mCherry, HcRed) and enzymes (GusA, LacZ). For stable inheritance, the constructs were recombined into the chromosome. Effectiveness and versatility of the tagged strains was demonstrated in plant infection assays. (i) The infection process was followed from root-hair attachment to colonization of nodule cells with epifluorescent microscopy. (ii) Monitoring mixed infections with two strains producing different fluorescent proteins allowed rapid analysis of nodule occupancy and revealed that the majority of nodules contained clonal populations. (iii) Microscopic analysis of nodules induced by fluorescent strains provided evidence for host-dependent control of B. diazoefficiens bacteroid morphology in nodules of Aeschynomene afraspera and Arachis hypogaea (peanut), as deduced from their altered morphology compared with bacteroids in soybean nodules. PMID- 26035131 TI - ? PMID- 26035132 TI - ? PMID- 26035133 TI - A UNIQUE CASE OF ACUTE MACULAR NEURORETINOPATHY ASSOCIATED WITH COTTON WOOL SPOTS AND INTRARETINAL FLUID. AB - PURPOSE: To discuss the clinical findings in a unique case of acute macular neuroretinopathy with a focus on the pathophysiology of this rare entity. METHODS: The patient's clinical course was documented with color fundus photography and spectral domain ocular coherence tomography registered to infrared reflectance imaging. The visual field was assessed using the Amsler grid testing and Humphrey visual field 24-2. RESULTS: Initial fundus photography showed cotton wool spots and slight darkening of the central macula in each eye. Optical coherence tomography showed initial hyperreflective plaques at the level of the outer plexiform layer/outer nuclear layer junction with subsequent thinning of the outer nuclear layer and corresponding disruption of the ellipsoid and outer segment/retinal pigment epithelium. Infrared reflectance imaging revealed perifoveal hyporeflective lesions in each eye with corresponding visual field defects on the Amsler grid and visual field testing. The hyporeflective infrared lesions became more discreet during the ensuing weeks and remained stable beyond 11 weeks. CONCLUSION: The authors present the case of a 15-year-old girl diagnosed with acute macular neuroretinopathy. This case is notable in that she presented with cotton wool spots and intraretinal fluid, both of which are unusual for acute macular neuroretinopathy. The authors suggest that the presence of cotton wool spots and several small foci of intraretinal fluid seen in their patient may lend support to the ischemic hypothesis described by Sarraf et al. The optical coherence tomography images obtained in this case have the typical wedge-shaped or petaloid configuration, and the authors suggest that the shape of the lesions themselves also lends support to a vascular mechanism. PMID- 26035134 TI - SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CONVALESCENT PHASE OF TREATED SARCOID CHOROIDAL GRANULOMAS. AB - PURPOSE: To report swept-source optical coherence tomography findings of sarcoid choroidal granulomas in the posttreatment convalescent stage of disease. PATIENTS/METHODS: The authors retrospectively reviewed charts from patients with sarcoid-related choroidal granulomas and recorded pertinent examination and imaging findings. Swept-source optical coherence tomography was performed using the DRI 3D-OCT-1 Atlantis (Topcon) over the areas of previous choroidal granulomas after the patients had been treated. RESULTS: Three patients with sarcoid choroidal granulomas were imaged with swept-source optical coherence tomography. Findings included loss or alteration of choroidal architecture, subretinal fibrosis, and outer retinal tubulations in the areas of the sarcoid granulomas after treatment. In one case with an associated choroidal neovascular membrane, there was also disruption of Bruch membrane and loss of normal choroidal vascular network in the area of the lesion. CONCLUSION: Swept-source optical coherence tomography demonstrated significant anatomical sequelae that persisted after treatment of sarcoid granulomas. To the best of the authors' knowledge, this is the first report of outer retinal tubulations over healed sarcoid granulomas. PMID- 26035135 TI - ENHANCED DEPTH IMAGING FEATURES OF A CHOROIDAL MACROVESSEL. AB - PURPOSE: To report a case of a choroidal macrovessel imaged using enhanced depth imaging spectral domain optical coherence tomography (EDI-OCT) and describe the choroidal features. METHODS: CASE REPORT: a 42-year-old man presented with metamorphopsia. Multimodal imaging, including color fundus photography, near infrared reflectance, and EDI-OCT was used to describe a choroidal macrovessel. RESULTS: Initial ophthalmic examination revealed a serpentine-shaped subretinal pattern deep to the retina near the fovea. When the color image was subjected to a red filter, a large diameter vessel could be seen coursing from the fovea to the temporal macula. EDI-OCT of the choroidal macrovessel revealed a thickened choroid and mild deformation of both the ellipsoid zone and the choroidal-scleral junction. En face spectral domain optical coherence tomography at the level of the choroid demonstrated the anomalous vessel. CONCLUSION: EDI-OCT and en face optical coherence tomography, used in conjunction with other imaging modalities, can be used to demonstrate the presence and pattern of a choroidal macrovessel. A thickened choroid and overlying outer retinal indentation was observed in association of the choroidal macrovessel. These imaging tools can help distinguish this condition from other diagnoses with a similar appearance, such as ophthalmomyiasis. PMID- 26035136 TI - MACULAR HOLE FORMATION AFTER VITREOMACULAR DETACHMENT WITH AN OPERCULUM. AB - PURPOSE: To report the detailed changes in the macular morphology documented by spectral domain optical coherence tomography in a 74-year-old woman with macular hole (MH) formation after vitreomacular detachment with an operculum. METHODS: History and clinical examinations included slit-lamp biomicroscopy, best corrected visual acuity, color fundus photography, and spectral domain optical coherence tomography. RESULTS: The patient was referred for decreased vision in the left eye (visual acuity, right eye, 20/20; left eye, 20/50). Spectral domain optical coherence tomography showed a full-thickness MH in the left eye. The right eye had a lamellar MH, and the photoreceptor inner/outer segment line was uninterrupted beneath the central fovea. The right eye had vitreomacular detachment with a small round operculum suggestive of an elevated inner foveal retina. Thirty-seven months after the initial visit, the patient returned with visual acuity in the right eye that had decreased to 20/50 and a full-thickness MH had developed in the presence of vitreomacular detachment. An epiretinal membrane appeared nasal to the fovea, and the macular surface had a triangular dimple beneath the membrane. A large retinal schisis developed nasal to the hole. A tightrope-like structure bridged the MH edges. CONCLUSION: In this case, the MH resulted from the tangential traction caused by the epiretinal membrane after vitreomacular detachment developed; the MH was accompanied by a small round operculum, a retinal dimple beneath the membrane, and a tightrope-like structure that bridged the hole edges. The operculum likely comprised a detached inner foveal retina alone and did not include retinal photoreceptor cells. PMID- 26035137 TI - The Influence of Plasma Albumin Concentration on the Analysis Methodology of Free Valproic Acid by Ultrafiltration and Its Application to Therapeutic Drug Monitoring. AB - BACKGROUND: Free drug analysis is increasingly becoming popular in therapeutic drug monitoring (TDM). Centrifugal ultrafiltration (CF-UF) is the primary method to separate free drug from that of bound drug. However, the volume ratio of ultrafiltrate to sample solution (Vu/Vs) affects the accuracy of CF-UF, which highly depends on the different plasma conditions. Plasma protein concentrations in patients are different from those observed in healthy subjects, and there are also significant differences among patients with different diseases. Only very few studies have reported on the effect of protein concentration on the analysis methodology of free drug by CF-UF. METHODS: In this study, valproic acid was used as the representative drug, and plasma samples with different albumin concentrations were analyzed by CF-UF and hollow fiber centrifugal ultrafiltration (HFCF-UF). RESULTS: There was no significant difference of free drug concentrations by HFCF-UF and CF-UF when plasma albumin concentrations ranged 40-60 g/L. However, at low albumin concentrations (<40 g/L), a considerable difference was detected, and the difference was increased with the decrease of plasma albumin concentration. When the albumin concentration was as low as 10 g/L, the free drug concentration was 17.3 mcg/mL by CF-UF, whereas it was 10.2 mcg/mL by HFCF-UF. CONCLUSIONS: The accuracy of free drug measurement by CF-UF was albumin concentration dependent. However, such an effect was not observed when samples were prepared by HFCF-UF, which was more suitable for TDM of plasma samples from different patients. Therefore, this method could be readily applied to the measurement of free valproic acid plasma concentrations for TDM in patients. PMID- 26035138 TI - Drug-induced hepatotoxicity and tuberculosis in a hospital from the Argentinian northeast: cross-sectional study. AB - INTRODUCTION: Hepatotoxicity is a serious adverse effect of tuberculosis treatment. OBJECTIVES: The aim of this study was to estimate the prevalence, forms of presentation and clinical course of patients with hepatotoxicity secondary to antituberculosis drugs. METHODS: We performed a descriptive and observational study using medical records from patients older than 16 years between Jaunary 1, 2011 and June 30, 2014 in the Medical Clinic of the Hospital Angela I. de Llano, Corrientes, Argentina. RESULTS: During the study period 118 patients were diagnosed with tuberculosis; 7.6% (nine patients: six men and three women) developed hepatotoxicity. Six had hepatocellular characteristics and three had cholestatic characteristics. The mean age was 34.6 +/- 14.3 years. All patients received triple-association medication plus ethambutol on a daily basis. They were hospitalized for an average of 16 days (range: 4-37). Four were asymptomatic, three had anorexia, nausea and vomiting, and two were jaundiced. The interval between the beginning of treatment and the appearance of clinical manifestations was on average 9.6 days (range 2-23). The interval between the onset and cessation of treatment was on average 15.2 days (range 3-48). No patients required liver transplantation and no deaths were recorded. CONCLUSIONS: Hepatotoxicity of antituberculosis drugs has been associated with factors such as age over 35 years, female gender, pregnancy, malnutrition, alcoholism, human immunodeficiency virus, preexisting liver disease, daily treatment, diabetes, renal failure, and combined treatment. Since we lack a regional registry, this casuistry could be the kickoff for the creation of regional and/or national records of anti-tuberculosis drugs adverse effects and pharmacologic vigilance. Also, there is a need for programs to actively seek this complication, and the development of guidelines for unifying concepts and treatment protocols. PMID- 26035139 TI - Video Evidence That London Infants Can Resettle Themselves Back to Sleep After Waking in the Night, as well as Sleep for Long Periods, by 3 Months of Age. AB - OBJECTIVE: Most infants become settled at night by 3 months of age, whereas infants not settled by 5 months are likely to have long-term sleep-waking problems. We assessed whether normal infant development in the first 3 months involves increasing sleep-period length or the ability to resettle autonomously after waking in the night. METHODS: One hundred one infants were assessed at 5 weeks and 3 months of age using nighttime infrared video recordings and parental questionnaires. RESULTS: The clearest development was in sleep length; 45% of infants slept continuously for >=5 hours at night at 3 months compared with 10% at 5 weeks. In addition, around a quarter of infants woke and resettled themselves back to sleep in the night at each age. Autonomous resettling at 5 weeks predicted prolonged sleeping at 3 months suggesting it may be a developmental precursor. Infants reported by parents to sleep for a period of 5 hours or more included infants who resettled themselves and those with long sleeps. Three-month olds fed solely breast milk were as likely to self-resettle or have long sleep bouts as infants fed formula or mixed breast and formula milk. CONCLUSIONS: Infants are capable of resettling themselves back to sleep in the first 3 months of age; both autonomous resettling and prolonged sleeping are involved in "sleeping through the night" at an early age. Findings indicate the need for physiological studies of how arousal, waking, and resettling develop into sustained sleeping and of how environmental factors support these endogenous and behavioral processes. PMID- 26035141 TI - Psychotropic Medication Use in Children and Adolescents With Down Syndrome. AB - OBJECTIVE: To estimate the rate of psychotropic medication use in children and adolescents with Down syndrome (DS) and to describe age-related trends. METHODS: Data were obtained from electronic health records from 2010 to 2013 for a retrospective cohort of 832 children with DS, aged 5 to 21 years, including 5324 visits. The following medication classes: central nervous system (CNS) stimulants, selective serotonin reuptake inhibitors, atypical antipsychotics, and alpha adrenergic agonists were examined. The distribution of rates of medication use across ages was assessed graphically and with the Cochran-Armitage trend test. Between-group comparisons of medication classes were conducted using chi. Repeated measures models with generalized estimating equations were used to assess changes in rates of medication use over time. RESULTS: Children aged 12 to 21 years were more likely to be on any medication at some point compared with children aged 5 to 11 years (25% vs 17%, respectively, p = .003). For 5 to 11 year olds, the odds of being on a psychotropic medication increased with age for all medication classes studied. For 12 to 18 year olds, the odds of being on a CNS stimulant significantly decreased with increasing age (odds ratio: 0.73, 95% confidence intervals, 0.58-0.91), whereas the odds of being on a medication from one of the other classes was stable. CONCLUSION: Changes in psychotropic medication use across the age span in children with DS suggest that the type and severity of neurobehavioral problems in this population likely also change over time. These findings will inform future research on the common mental health conditions and treatments for children with DS. PMID- 26035140 TI - Patient-Centered Medical Home and Family Burden in Attention-Deficit Hyperactivity Disorder. AB - OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) can impair child health and functioning, but its effects on the family's economic burden are not well understood. The authors assessed this burden in US families of children with ADHD, and the degree to which access to a patient-centered medical home (PCMH) might reduce this burden. METHODS: We conducted cross-sectional analyses of 2005 2006 and 2009-2010 National Surveys of Children with Special Health Care Needs, focusing on families of children with ADHD. They defined family economic burden as (1) family financial problems (annual expenses for the child's health care or illness-related financial problems for the family) and/or (2) family employment problems (job loss, work time loss, or failure to change jobs to avoid insurance loss). Relative risk models assessed associations between PCMH and family economic burden, adjusted for child age, sex, ethnicity, ADHD severity, poverty status, caregiver education, and insurance. RESULTS: In 2009, 26% of families reported financial problems because of the child's ADHD, 2.1% reported out-of pocket expenses >5% of income, and 36% reported employment problems. Only 38% reported care that met all 5 criteria for a PCMH (similar to rates in 2005-2006). In multivariable analysis, care in a PCMH was associated with 48% lower relative risk (RR) of financial problems (RR = 0.52, p < .001) and 36% lower relative risk of employment problems (RR = 0.64, p < .001). Among PCMH components, family centered care and care coordination were more strongly associated with lower burden. CONCLUSIONS: The economic burdens of families with ADHD are significant but may be alleviated by family-centered care and care coordination in a medical home. PMID- 26035142 TI - Auditory Perception and Production of Speech Feature Contrasts by Pediatric Implant Users. AB - OBJECTIVE: The aim of the present research is to examine the relations between auditory perception and production of specific speech contrasts by children with cochlear implants (CIs) who received their implants before 3 years of age and to examine the hierarchy of abilities for perception and production for consonant and vowel features. The following features were examined: vowel height, vowel place, consonant place of articulation (front and back), continuance, and consonant voicing. DESIGN: Fifteen children (mean age = 4;0 and range 3;2 to 5;11) with a minimum of 18 months of experience with their implants and no additional known disabilities served as participants. Perception of feature contrasts was assessed using a modification of the Online Imitative Speech Pattern Contrast test, which uses imitation to assess speech feature perception. Production was examined by having the children name a series of pictures containing consonant and vowel segments that reflected contrasts of each feature. RESULTS: For five of the six feature contrasts, production accuracy was higher than perception accuracy. There was also a significant and positive correlation between accuracy of production and auditory perception for each consonant feature. This correlation was not found for vowels, owing largely to the overall high perception and production scores attained on the vowel features. The children perceived vowel feature contrasts more accurately than consonant feature contrasts. On average, the children had lower perception scores for Back Place and Continuance feature contrasts than for Anterior Place and Voicing contrasts. For all features, the median production scores were 100%; the majority of the children were able to accurately and consistently produce the feature contrasts. The mean production scores for features reflect greater score variability for consonant feature production than for vowel features. Back Place of articulation for back consonants and Continuance contrasts appeared to be the most difficult features to produce, as reflected in lower mean production scores for these features. CONCLUSIONS: The finding of greater production than auditory perception accuracy for five of the six features examined suggests that the children with CIs were able to produce articulatory contrasts that were not readily perceived through audition alone. Factors that are likely to play a role in the greater production accuracy in addition to audition include the lexical and phonetic properties of the words elicited, a child's phonological representation of the words and motor abilities, and learning through oro-tactile, visual, proprioceptive, and kinesthetic perception. The differences among the features examined, and between perception and production, point to the clinical importance of evaluating these abilities in children with CIs. The present findings further point to the utility of picture naming to establish a child's production accuracy, which in turn is necessary if using imitation as a measure of auditory capacity. PMID- 26035143 TI - Pediatric Cochlear Implantation: Why Do Children Receive Implants Late? AB - OBJECTIVES: Early cochlear implantation has been widely promoted for children who derive inadequate benefit from conventional acoustic amplification. Universal newborn hearing screening has led to earlier identification and intervention, including cochlear implantation in much of the world. The purpose of this study was to examine age and time to cochlear implantation and to understand the factors that affected late cochlear implantation in children who received cochlear implants. DESIGN: In this population-based study, data were examined for all children who underwent cochlear implant surgery in one region of Canada from 2002 to 2013. Clinical characteristics were collected prospectively as part of a larger project examining outcomes from newborn hearing screening. For this study, audiologic details including age and severity of hearing loss at diagnosis, age at cochlear implant candidacy, and age at cochlear implantation were documented. Additional detailed medical chart information was extracted to identify the factors associated with late implantation for children who received cochlear implants more than 12 months after confirmation of hearing loss. RESULTS: The median age of diagnosis of permanent hearing loss for 187 children was 12.6 (interquartile range: 5.5, 21.7) months, and the age of cochlear implantation over the 12-year period was highly variable with a median age of 36.2 (interquartile range: 21.4, 71.3) months. A total of 118 (63.1%) received their first implant more than 12 months after confirmation of hearing loss. Detailed analysis of clinical profiles for these 118 children revealed that late implantation could be accounted for primarily by progressive hearing loss (52.5%), complex medical conditions (16.9%), family indecision (9.3%), geographical location (5.9%), and other miscellaneous known (6.8%) and unknown factors (8.5%). CONCLUSIONS: This study confirms that despite the trend toward earlier implantation, a substantial number of children can be expected to receive their first cochlear implant well beyond their first birthday because they do not meet audiologic criteria of severe to profound hearing loss for cochlear implantation at the time of identification of permanent hearing loss. This study underscores the importance of carefully monitoring all children with permanent hearing loss to ensure that optimal intervention including cochlear implantation occurs in a timely manner. PMID- 26035144 TI - Social Support Predicts Hearing Aid Satisfaction. AB - OBJECTIVES: The goals of the current research were to determine: (1) whether there is a relationship between perceived social support and hearing aid satisfaction, and (2) how well perceived social support predicts hearing aid satisfaction relative to other correlates previously identified in the literature. DESIGN: In study 1, 173 adult ((Equation is included in full-text article.)age = 68.9 years; SD = 13.4) users of hearing aids completed a survey assessing attitudes toward health, hearing, and hearing aids, as well as a questionnaire assessing Big-Five personality factors (Openness to Experience, Conscientiousness, Extraversion, Agreeableness, and Neuroticism) either using paper and pencil or the Internet. In a follow-up study designed to replicate and extend the results from study 1, 161 adult ((Equation is included in full-text article.)age = 32.8 years; SD = 13.3) users of hearing aids completed a similar survey on the Internet. In study 2, participants also completed a measure of hearing aid benefit and reported the style of their hearing aid. RESULTS: In studies 1 and 2, perceived social support was significantly correlated with hearing aid satisfaction (respectively, r = 0.34, r = 0.51, ps < 0.001). The results of a regression analysis revealed that in study 1, 22% of the variance in hearing aid satisfaction scores was predicted by perceived social support, satisfaction with one's hearing health care provider, duration of daily hearing aid use, and openness. In study 2, 43% of the variance in hearing aid satisfaction was predicted by perceived social support, hearing aid benefit, neuroticism, and hearing aid style. Overall, perceived social support was the best predictor of hearing aid satisfaction in both studies. After controlling for response style (i.e., acquiescence or the tendency to respond positively), the correlation between perceived social support and hearing aid satisfaction remained the same in study 1 (r = 0.34, p < 0.001) and was lower in study 2 (r = 0.39, p < 0.001), although the change in correlation was not significant. CONCLUSIONS: The results from study 1 provide evidence to suggest that perceived social support is a significant predictor of satisfaction with hearing aids, a finding that was replicated in a different sample of participants investigated in study 2. A significant relationship between perceived social support and hearing aid satisfaction was observed in both studies, even though the composition of the two samples differed in terms of age, relationship status, income, proportion of individuals with unilateral versus bilateral hearing impairment, and lifetime experience with hearing aids. The results from both studies 1 and 2 provide no support for the claim that participant response style accounts for the relationship between hearing aid satisfaction and perceived social support. PMID- 26035145 TI - Lipid Rescue in a Pediatric Burn Patient. AB - Pain control is a major concern for patients suffering burns. The addition of bupivacaine to the donor site infiltration solution containing epinephrine could offer a safe and effective means to treat postanesthesia pain. Despite the addition of epinephrine to localize the effects, systemic absorption occurs, and there exists the possibility of inadvertent intravascular injection, with potential CNS and cardiac toxicity. The patient is a 6-year-old boy who sustained flame burns to bilateral lower extremities and buttocks. A Pitkin's solution containing 2 mg epinephrine/L of normosol and a 0.5% bupivacaine at 3 mg/kg was injected. Shortly after the patient became bradycardic with decreasing end tidal CO2. Pediatric advanced life support protocol was begun. He underwent 30 minutes of cardiopulmonary resuscitation. At this time, intralipid therapy was initiated with a 1.5 mg/kg bolus. Shortly after therapy, a pulse was regained. It had been previously demonstrated that the addition of bupivacaine to a subcutaneous infiltrating solution for donor site harvesting was a safe and effective treatment of pain for skin graft harvesting. Care must be taken to stay within the therapeutic allotted dose. Inadvertent intravascular injection is a rare complication. Early recognition of clinical signs of local anesthetic toxicity is a key to the management and treatment. A lipid protocol should be in place, given the many positive case reports of local anesthetic toxicity. Surgeon judgment must be used when weighing the risks and benefits of pain control during skin harvesting vs the potential cardiac effects with local anesthetics. PMID- 26035146 TI - Further Concerns About Glutamine: A Case Report on Hyperammonemic Encephalopathy. AB - OBJECTIVE: We report a case of a woman with hyperammonemic encephalopathy following glutamine supplementation. DESIGN: Case report. INTERVENTIONS: Plasma amino acid analysis suggestive of a urea cycle defect and initiation of a treatment with lactulose and the two ammonia scavenger drugs sodium benzoate and phenylacetate. Together with a restricted protein intake ammonia and glutamine plasma levels decreased with subsequent improvement of the neurological status. MEASUREMENTS AND MAIN RESULTS: Massive catabolism and exogenous glutamine administration may have contributed to hyperammonemia and hyperglutaminemia in this patient. CONCLUSION: This case adds further concerns regarding glutamine administration to critically ill patients and implies the importance of monitoring ammonia and glutamine serum levels in such patients. PMID- 26035147 TI - An Observational Study of Decision Making by Medical Intensivists. AB - OBJECTIVES: The ICU is a place of frequent, high-stakes decision making. However, the number and types of decisions made by intensivists have not been well characterized. We sought to describe intensivist decision making and determine how the number and types of decisions are affected by patient, provider, and systems factors. DESIGN: Direct observation of intensivist decision making during patient rounds. SETTING: Twenty-four-bed academic medical ICU. SUBJECTS: Medical intensivists leading patient care rounds. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: During 920 observed patient rounds on 374 unique patients, intensivists made 8,174 critical care decisions (mean, 8.9 decisions per patient daily, 102.2 total decisions daily) over a mean of 3.7 hours. Patient factors associated with increased numbers of decisions included a shorter time since ICU admission and an earlier slot in rounding order (both p < 0.05). Intensivist identity explained the greatest proportion of variance in number of decisions per patient even when controlling for all other factors significant in bivariable regression. A given intensivist made more decisions per patient during days later in the 14-day rotation (p < 0.05). Female intensivists made significantly more decisions than male intensivists (p < 0.05). CONCLUSIONS: Intensivists made over 100 daily critical care decisions during rounds. The number of decisions was influenced by a variety of patient- and system-related factors and was highly variable among intensivists. Future work is needed to explore effects of the decision-making burden on providers' choices and on patient outcomes. PMID- 26035148 TI - Panax notoginseng saponins mitigate ovariectomy-induced bone loss and inhibit marrow adiposity in rats. AB - OBJECTIVE: Previous data have suggested that Panax notoginseng saponins (PNS) can prevent estrogen deficiency-induced bone loss by dual action: stimulation of new bone formation and inhibition of bone resorption. Marrow adipogenesis has been identified as a negative indicator of skeletal strength and integrity. This study assessed the effects of early PNS supplementation on bone microarchitecture preservation and marrow fat content in an ovariectomized rat model. METHODS: Forty adult female Sprague-Dawley rats were randomly assigned to four equal groups for 12 weeks of treatment: (1) sham operation (SHAM) + vehicle; (2) ovariectomy (OVX) + vehicle; (3) OVX + 17beta-estradiol (25 MUg/kg); (4) OVX + PNS (300 mg/kg/d, PO). Marrow fat content of the femur was determined, using fat/water magnetic resonance imaging (MRI), at baseline and 6 and 12 weeks after operation. At the end of the experiment, bone turnover, trabecular microarchitecture, and marrow adipocytes were assessed by serum biomarkers, micro computed tomography (micro-CT), and histopathology, respectively. The effects of PNS on adipocytic differentiation were reflected by expression levels of the adipogenic genes PPARgamma2 and C/EBPalpha, as determined by reverse transcription-polymerase chain reaction. RESULTS: Ovariectomized rats experienced remarkable increases in marrow fat content across time points, which were accompanied by elevated rate of bone turnover, global volumetric bone density, and trabecular microarchitecture deterioration. These OVX-induced pathological changes are reversible in that most of them could be mostly corrected upon 17beta estradiol treatment. PNS treatment significantly reduced marrow adipogenesis (adipocyte density, -27.2%; size, -22.7%; adipocyte volume-to-tissue volume ratio, -53.3%; all P < 0.01) and adipocyte marker gene expression, and prevented bone mass loss and microarchitecture deterioration. Moreover, PNS enhanced osteoblast activity but suppressed osteoclast turnover, as evidenced by decreased levels of serum C-terminal telopeptides of type I collagen and elevated levels of alkaline phosphatase. CONCLUSIONS: PNS mitigates estrogen deficiency-induced deterioration of trabecular microarchitecture and suppresses marrow adipogenesis. PMID- 26035149 TI - Compounded bioidentical hormone therapy: time for a reality check? PMID- 26035150 TI - The North American Menopause Society Statement on Continuing Use of Systemic Hormone Therapy After Age 65. PMID- 26035151 TI - NAMS supports judicious use of systemic hormone therapy for women aged 65 years and older. PMID- 26035152 TI - Lack of Evidence From a Transgenic Mouse Model that the Activation and Migration of Melanocytes to the Epidermis after Neonatal UVR Enhances Melanoma Development. PMID- 26035153 TI - Direct measurements of magnetic interaction-induced cross-correlations of two microparticles in Brownian motion. AB - The effect of magnetic interactions on the Brownian motion of two magnetic microparticles is investigated. The cross-correlations of the thermal fluctuations of the two magnetic microbeads are directly measured using double trap optical tweezers. It is experimentally demonstrated that the cross correlation function is governed by the gradient of the magnetic force between the microparticles. The magnetic forces are measured with femtonewton precision, and the magnetic dipole moments of individual microparticles are determined within an accuracy on the order of fA-m(2). PMID- 26035154 TI - Probing the Effect of Two Heterozygous Mutations in Codon 723 of SLC26A4 on Deafness Phenotype Based on Molecular Dynamics Simulations. AB - A Chinese family was identified with clinical features of enlarged vestibular aqueduct syndrome (EVAS). The mutational analysis showed that the proband (III-2) had EVAS with bilateral sensorineural hearing loss and carried a rare compound heterozygous mutation of SLC26A4 (IVS7-2A>G, c.2167C>G), which was inherited from the same mutant alleles of IVS7-2A>G heterozygous father and c.2167C>G heterozygous mother. Compared with another confirmed pathogenic biallelic mutation in SLC26A4 (IVS7-2A>G, c.2168A>G), these two biallelic mutations shared one common mutant allele and the same codon of the other mutant allele, but led to different changes of amino acid (p.H723D, p.H723R) and both resulted in the deafness phenotype. Structure-modeling indicated that these two mutant alleles changed the shape of pendrin protein encoded by SLC26A4 with increasing randomness in conformation, and might impair pendrin's ability as an anion transporter. The molecular dynamics simulations also revealed that the stability of mutant pendrins was reduced with increased flexibility of backbone atoms, which was consistent with the structure-modeling results. These evidences indicated that codon 723 was a hot-spot region in SLC26A4 with a significant impact on the structure and function of pendrin, and acted as one of the genetic factors responsible for the development of hearing loss. PMID- 26035155 TI - [Status report of Hungarian radiotherapy based on treatment data, available infrastucture, and human resources]. AB - The purpose of the study is to report the status of Hungarian radiotherapy (RT) based on the assessment of treatment data in years 2012 to 2014, available infrastructure, and RT staffing. Between December 2014 and January 2015, a RT questionnaire including 3 parts (1. treatment data; 2. infrastructure; 3. staffing) was sent out to all Hungarian RT centers (n=12). All RT centers responded to all questions of the survey. 1. Treatment data: In 2014, 33,162 patients were treated with RT: 31,678 (95.5%) with teletherapy, and 1484 (4.5%) with brachytherapy (BT). Between 2012 and 2014, the number of patients treated with radiotherapy increased with 6.6%, but the number of BT patients decreased by 11%. Forty-two percent of all patients were treated in the two centers of the capital: 9235 patients (28%) at the National Institute of Oncology (NIO), and 4812 (14%) at the Municipial Oncoradiology Center (MOC). Out of the patients treated on megavoltage RT units (n=22,239), only 901 (4%) were treated with intensity-modulated RT (IMRT), and 2018 (9%) with image-guided RT (IGRT). In 2014, 52% of all BT treatments were performed in Budapest: NIO - 539 patients (36%); MOC - 239 patients (16%); and BT was not available in 3 RT centers. Prostate I-125 seed implants and interstitial breast BT was utilized in one, prostate HDR BT in two, and head&neck implants in three centers. 2. Infrastructure: Including ongoing development projects funded by the European Union, by the end of year 2015, 39 megavoltage teletherapy units, and 12 HDR BT units will be in use in 13 available Hungarian RT centers. 3. Staffing: Actually, 92 radiation oncologists (RO), 29 RT residents, 61 medical physicists, and 229 radiation therapy technologists are working in 12 RT centers. There are 23 vacant positions (including 11 RO positions) available at the Hungarian RT centers. According to the professional minimal requirements and WHO guidelines, the implementation of 11 new linear accelerators, and 1 BT units are needed in Hungary. Further resources for the development and upgrade of RT infrastructure and capacity should be allocated to RT centers in Budapest. Brachytherapy and modern teletherapy (e.g. IMRT and IGRT) are underutilized in Hungary compared to other European countries. Implementation of continuous education and practical training programs in leading Hungarian and international RT centers are suggested in an effort to a wider implementation of modern RT techniques in Hungarian RT centers. PMID- 26035156 TI - [Dosimetry analysis of intensity-modulated and conformal radiation therapy for head and neck tumors]. AB - The aim of the study was to compare different treatment plans - intensity modulated and conformal - for head and neck cancer patients. Treatment plans were developed for ten head and neck cancer patients by applying four different techniques: two conventional 3D conformal plans (forward treatment planning, with two opposing fields 90o-270o and one asymmetric anterior field, matching in isocenter /Conv/, conformal parotis sparing plans /ConPas/), 3D conformal plans with inverse treatment planning techniques /INVCRT/ and intensity-modulated radiation therapy plans /IMRT/. The plans were made for the same target volumes PTV50 (elective) and PTV66 (boost-16 Gy). The cumulative dose was 66 Gy, and the Philips Pinnacle3 v8.0m TPS was used for treatment planning. The organs at risk (OAR) were as follows: spinal cord, brain stem, left and right parotis and oral cavity. The dose constrains and conditions for optimization were determined for IMRT techniques with 7 fields. During the optimization we applied two different protocols: in one case the plans were made by 40 segments for "step and shoot" IMRT techniques and by 14 segments for INVCRT, which were converted into static fields. The homogeneity (HI) and conformity (COIN) indices were calculated for planning target volumes and the comparisons were assessed on several dosimetric parameters for OARs. The IMRT, INVCRT, Conv and ConPas techniques for PTV50 planning target volume gave the following values for homogeneity index: 0.13, 0.18, 0.22, 0.19, and for conformity index: 0.76, 0.68, 0.13, 0.09. The spinal cord received a maximum of 38 Gy, 42 Gy, 45 Gy and 44 Gy for the PTV66. Mean doses of the oral cavity outside the target volume were 33 Gy, 36 Gy, 30 Gy and 48 Gy. When the 16 Gy boost treatment was applied on one side only, the mean dose for the parotis on the contralateral side was 28 Gy, 31 Gy, 49 Gy and 43 Gy, while 39 Gy, 41 Gy, 59 Gy and 53 Gy on the same side. The objectives of adequate target coverage and sparing of critical structures were fulfilled only with IMRT technique. Although the sparing of the oral cavity was the most effectively provided by the traditional technique - due to the arrangement of the fields - it gave the worst results regarding the parotis and the target volume. The highest dose for the oral cavity was given by the ConPas technique, which can cause serious early and late side effects. By increasing the number of segments for IMRT at a reasonable level, the dose for OARs can be reduced. PMID- 26035157 TI - [Role of 18FDG-PET/CT in the management and gross tumor volume definition for radiotherapy of head and neck cancer; single institution experiences based on long-term follow-up]. AB - The purpose of our work is evaluation of the impact of 18FDG-PET/CT on the complex management of locoregionally advanced (T3-4N1-3) head and neck squamous cell cancer (LAHNSC), and on the target definition for 3D conformal (3DCRT) and intensity-modulated radiotherapy (IMRT). 18FDG-PET/CT were performed on 185 patients with LAHNSC prior to radiotherapy/chemoradiation in the treatment position between 2006 and 2011. Prior to it 91 patients received induction chemotherapy (in 20 cases of these, baseline PET/CT was also available). The independently delineated CT-based gross tumor volume (GTVct) and PET/CT based ones (GTVpet) were compared. Impact of PET/CT on the treatment strategy, on tumor response evaluation to ICT, on GTV definition furthermore on overall and disease specific survival (OS, DSS) was analysed. PET/CT revealed 10 head and neck, 2 lung cancers for 15 patients with carcinoma of unknown primary (CUP) while 3 remained unknown. Second tumors were detected in 8 (4.4%), distant metastasis in 15 (8.2%) cases. The difference between GTVct and GTVpet was significant (p=0.001). In 16 patients (14%) the GTVpet were larger than GTVct due to multifocal manifestations in the laryngo-pharyngeal regions (4 cases) or lymph node metastases (12 cases). In the majority of the cases (82 pts, 72%) PET/CT based conturing resulted in remarkable decrease in the volume (15-20%: 4 cases, 20-50%: 46 cases, >50%: 32 cases). On the basis of the initial and post-ICT PET/CT comparison in 15/20 patients more than 50% volume reduction and in 6/20 cases complete response were achieved. After an average of 6.4 years of follow-up the OS (median: 18.3+/-2.6 months) and DSS (median: 25.0+/-4.0 months) exhibited close correlation (p=0.0001) to the GTVpet. In cases with GTVpet <10 cm3 prior to RT, DSS did not reach the median, the mean is 82.1+/-6.1 months, while in cases with GTVpet 10-40 cm3 the median of the DSS was 28.8+/-4.9 months (HR = 3.57; 95% CI: 1.5-8.3), and in those with GTVpet >40 cm3 the median DSS was 8.4+/-0.96 months (HR= 11.48; 95% CI: 5.3-24.9). Our results suggest that 18FDG-PET/CT plays an important role for patient with LAHNSC, by modifying the treatment concept and improving the target definition for selective RT modalities. Volumetric PET/CT based assessment of the tumor response after ICT gives valuable contribution to further therapy planning. PMID- 26035158 TI - [Accelerated partial breast irradiation with image-guided intensity-modulated radiotherapy following breast-conserving surgery - preliminary results of a phase II clinical study]. AB - The purpose of the study was to implement accelerated partial breast irradiation (APBI) by means of image-guided intensity-modulated radiotherapy (IG-IMRT) following breast-conserving surgery (BCS) for low-risk early invasive breast cancer. Between July 2011 and March 2014, 60 patients with low-risk early invasive (St I-II) breast cancer who underwent BCS were enrolled in our phase II prospective study. Postoperative APBI was given by means of step and shoot IG IMRT using 4 to 5 fields to a total dose of 36.9 Gy (9*4.1 Gy) using a twice-a day fractionation. Before each fraction, series of CT images were taken from the region of the target volume using a kV CT on-rail mounted in the treatment room. An image fusion software was used for automatic image registration of the planning and verification CT images. Patient set-up errors were detected in three directions (LAT, LONG, VERT), and inaccuracies were adjusted by automatic movements of the treatment table. Breast cancer related events, acute and late toxicities, and cosmetic results were registered and analysed. At a median follow up of 24 months (range 12-44) neither locoregional nor distant failure was observed. Grade 1 (G1), G2 erythema, G1 oedema, and G1 and G2 pain occurred in 21 (35%), 2 (3.3%), 23 (38.3%), 6 (10%) and 2 (3.3%) patients, respectively. No G3-4 acute side effects were detected. Among late radiation side effects G1 pigmentation, G1 fibrosis, and G1 fat necrosis occurred in 5 (8.3%), 7 (11.7%), and 2 (3.3%) patients, respectively. No >=G2 late toxicity was detected. Excellent and good cosmetic outcome was detected in 45 (75%) and 15 (25%) patients. IG-IMRT is a reproducible and feasible technique for the delivery of APBI following conservative surgery for the treatment of low-risk, early-stage invasive breast carcinoma. Preliminary results are promising, early radiation side effects are minimal, and cosmetic results are excellent. PMID- 26035159 TI - [Measurement of peak correction factor of Farmer chamber for calibration of flattening filter free (FFF) clinical photon beams]. AB - Farmer-type ionization chambers are considered the most reliable detectors and for this reason they are most frequently used for the calibration of photon beams of medical linear accelerators. Flattening filter free (FFF) photon beams of linear accelerators have recently started to be used in radiotherapy. The dose profile of FFF beams is peaked in the center of the field and the dose distribution will be inhomogeneous along the axis of the 2.3 cm long measuring volume of the Farmer chamber. The peaked radiation field will result in volume averaging effects in the large Farmer chamber, therefore this chamber will underestimate the true central axis dose. Our objective was to determine the value of the peak correction factor (Kp) of Farmer-type chamber with measurements to avoid the underestimation of the central axis dose during the calibration of FFF radiation fields. Measurements were made with 6 MV and 10 MV flattened (6X and 10X) and FFF beams (6XFFF and 10XFFF) of a Varian TrueBeam medical linear accelerator in a solid water phantom at 10 cm depth. The source surface distance (SSD) was 100 cm, the field size was 10*10 cm and the dose rate was always 400 MU/min during the measurements. We delivered 100 MU in each measurement and the absorbed dose to water was calculated according to the IAEA TRS-398 dosimetry protocol. The measured signals of the ionization chambers were always corrected for the ion recombination loss. The ion recombination correction factors (Kr) were determined with the two-voltage method separately for the used ion chambers and for flattened and unflattened beams. First, we measured the dose to water with PTW TM30012 Farmer chamber in 6XFFF and 6X beams, then calculated the ratio of doses of 6XFFF and 6X beams (R6,Farmer). Immediately after this we repeated the above measurements with PTW TM31010 Semiflex chamber and determined the ratio of doses of 6XFFF and 6X beams again (R6,Semiflex). The length of the sensitive volume of the Semiflex chamber is only 6.5 mm. According to our dose profile measurements the peak correction factor of this chamber equals to unity for both photon energies. As a consequence R6,Semiflex is larger than R6,Farmer and Kp6XFFF = R6,Semiflex / R6,Farmer, where Kp6XFFF is the peak correction factor of the Farmer chamber in 6XFFF beam. The advantage of this method is that we have to calculate ratio of doses, so it is not necessary to know the calibration factors of the chambers. Repeating the above measurements with 10X and 10XFFF beams we determined the peak correction factor of Farmer chamber for 10XFFF beam, too (Kp10XFFF). According to our measurements Kp6XFFF = 1.0025 and Kp10XFFF = 1.009. The bigger peak correction factor for 10XFFF beam is in accordance with the fact that the peak of dose profile is steeper for higher photon energy. The above described method for the determination of Kp can be used for other photon energies and other large volume ionization chambers. PMID- 26035160 TI - [Implementation of cone beam CT-guided volumetric modulated arc therapy and establishment of related institutional quality assurance protocols]. AB - We intend to present the process of implementation of kilovoltage CT-guided volumetric modulated arc therapy (VMAT), and related quality assurance (QA). An Elekta SynergyTM linear accelerator has been installed recently in our institution, equipped with Agility(c) head, kilovoltage cone-beam CT image guidance and ability of arc therapy. The major steps of the implementation of these techniques and the background of physics QA will be described. Specific dynamic tests have been performed to verify intensity-modulated radiation delivery and the accuracy of on board imaging. Systematic daily, weekly and monthly physics QA protocols have been worked out and applied in the clinical practice. As a result, cone beam CT based image-guided radiotherapy (IGRT) and volumetric modulated arc therapy was introduced in our institution. PMID- 26035161 TI - [Imaging protocols for the management of respiratory motions in the radiotherapy planning for early stage lung cancer patients]. AB - The aim of our work is to present the imaging techniques used at the National Institute of Oncology for taking into consideration the breathing motion at radiation therapy treatment planning. Internationally recommended imaging techniques, such as 4D CT, respiratory gating and ITV (Internal Target Volume) definition were examined. The different imaging techniques were analysed regarding the delivered dose during imaging, the required time to adapt the technique, and the necessary equipment. The differences in size of PTVs (Planning Target Volume) due to diverse volume defining methods were compared in 5 cases. For 4D CT breath monitoring is crucial, which requires special equipment. To decrease the relatively high exposure of 4D CT it is possible to scan only a few predefined breathing phases. The possible positions of the tumour can be well approximated with CT scans taken in the inhale maximum, the exhale maximum and in intermediate phase. The intermediate phase can be exchanged with an ordinary CT image set, and the extreme phase CT images can be ensured by given verbal instructions for the patient. This way special gating equipment is not required. Based on these 3 breathing phases an ITV can be defined. Using this ITV definition method the margin between the CTV (Clinical Target Volume) and the PTV can be reduced by 1 cm. Using this imaging protocol PTV can be reduced by 30%. A further 10% PTV reduction can be achieved with respiratory gating. In the routine clinical practice respiratory motion management with a 3-phase CT-imaging protocol the PTV for early-stage lung cancer can be significantly reduced without the use of 4D CT and/or respiratory gating. For special, high precision treatment techniques 4D CT is recommended. PMID- 26035162 TI - [Historical overview and the current practice of intracavitary treatment of cervical and endometrial cancer in the Oncoradiology Center of Budapest]. AB - The aims of our study were to describe the history and development of intracavitary brachytherapy in the treatment of gynecological tumors, to introduce our current practice for intracavitary brachytherapy treatments based on CT planning. Gynecological intracavitary brachytherapy has been applied in our department since the early 1930s. After a long development it has been completely renewed by 2014. In our center definitive and/or preoperative gynecological HDR AL brachytherapy treatments were given to 25 patients (13 corpus uterine cancer patients and 12 cervical cancer patients) during the period of 01. 01. 2014-31. 01. 2015. In each case, target volumes were planned by CT images, DVH (dose volume histogram) analysis was performed in order to calculate the radiation tolerance dose of rectum and urinary bladder. Evaluation was performed by the EclipseTM 11.0.47. brachytherapy treatment planning system. During the definitive treatments of the 13 uterine cancer patients the D2cc value related to rectum tolerance was 66.3 GyEQD2 (46-91 Gy). The average D2cc value of urinary bladder tolerance was 76.5 GyEQD2 (30-112 Gy). CI was 0.72 (0.6-0.95). Average value of COIN was 0.57 (0.35-0.78). Compared to the prescribed dose D100 and D90 values were given in ratios. Compared to the volume which receives 100% of reference dose V150 and V200 values were also given in ratios. D100 and D90 were calculated to be 0.66 (0.47-0.97) and 0.91 (0.8-1.25). V150 and V200 volumes were 0.11 (0.04 0.18) and 0.06 (0.02-0.1). During the definitive treatments of 12 cervical cancer patients the D2cc value related to rectum tolerance calculated by DVH was 75.2 GyEQD2 (60-82 Gy). The average D2cc value of urinary bladder tolerance was 85 GyEQD2 based on DVH. CI was 0.66 (0.42-0.76). Average value of COIN was 0.52 (0.32-0.78). Mean value of DHI was 0.46 (0.27-0.54). D100 and D90 were calculated to be 0.72 (0.57-0.89) and 0.91 (0.84-1.11). V150 and V200 volumes were 0.057 (0.02-0.13) and 0.02 (0.002-0.06). During treatments no severe side effects were found. During gynecological intracavitary HDR therapies the calculated dose of the target volume can be given safely using the EclipseTM 11.0.47. brachytherapy planning system and CT-based planning. CT-based treatment planning provides optimal safety for organs at risk, acceptable doses for rectum and urinary bladder while the target volume receives the proper prescribed dose. PMID- 26035163 TI - [Intraoperative and post-implant dosimetry in patients treated with permanent prostate implant brachytherapy]. AB - The purpose of our work was to compare intraoperative and four-week post-implant dosimetry for loose and stranded seed implants for permanent prostate implant brachytherapy. In our institute low-dose-rate (LDR) prostate brachytherapy is performed with encapsulated I-125 isotopes (seeds) using transrectal ultrasound guidance and metal needles. The SPOT PRO 3.1 (Elekta, Sweden) system is used for treatment planning. In this study the first 79 patients were treated with loose seed (LS) technique, the consecutive patients were treated with stranded seed (SS) technique. During intraoperative planning the dose constraints were the same for both techniques. All LSs were placed inside the prostate capsule, while with SS a 2 mm margin around the prostate was allowed for seed positioning. The prescribed dose for the prostate was 145 Gy. This study investigated prostate dose coverage in 30-30 randomly selected patients with LS and SS. Four weeks after the implantation native CT and MRI were done and CT/MRI image fusion was performed. The target was contoured on MRI and the plan was prepared on CT data. To assess the treatment plan dose-volume histograms were used. For the target coverage V100, V90, D90, D100, for the dose inhomogeneity V150, V200, and the dose-homogeneity index (DHI), for dose conformality the conformal index (COIN) were calculated. Intraoperative and postimplant plans were compared. The mean V100 values decreased at four-week plan for SS (97% vs. 84%) and for LS (96% vs. 80%) technique, as well. Decrease was observed for all parameters except for the DHI value. The DHI increased for SS (0.38 vs. 0.41) and for LS (0.38 vs. 0.47) technique, as well. The COIN decreased for both techniques at four-week plan (SS: 0.63 vs. 0.57; LS: 0.67 vs. 0.50). All differences were significant except for the DHI value at SS technique. The percentage changes were not significant, except the COIN value. The dose coverage of the target decreased significantly at four-week plans for both techniques. The decrease was larger for LS technique, but the difference between techniques was not significant at this patient number. The dose distribution was more homogenous, but the conformality was worse at four week plans. PMID- 26035164 TI - [Clinical experience in image-guided ultra-conformal hypofractionated radiotherapy in case of metastatic diseases at the University of Pecs]. AB - With the development of radiation therapy technology, the utilization of more accurate patient fixation, inclusion of PET/CT image fusion into treatment planning, 3D image-guided radiotherapy, and intensity-modulated dynamic arc irradiation, the application of hypofractionated stereotactic radiotherapy can be extended to specified extracranial target volumes, and so even to the treatment of various metastases. Between October 2012 and August 2014 in our institute we performed extracranial, hypofractionated, image-tobbguided radiotherapy with RapidArc system for six cases, and 3D conformal multifield technique for one patient with Novalis TX system in case of different few-numbered and slow-growing metastases. For the precise definition of the target volumes we employed PET/CT during the treatment planning procedure. Octreotid scan was applied in one carcinoid tumour patient. Considering the localisation of the metastases and the predictable motion of the organs, we applied 5 to 20 mm safety margin during the contouring procedure. The average treatment volume was 312 cm3. With 2.5-3 Gy fraction doses we delivered 39-45 Gy total dose, and the treatment duration was 2.5 to 3 weeks. The image guidance was carried out via ExacTrac, and kV-Cone Beam CT equipment based on an online protocol, therefore localisation differences were corrected before every single treatment. The patients tolerated the treatments well without major (Gr>2) side effects. Total or near total regression of the metastases was observed at subsequent control examinations in all cases (the median follow-up time was 5 months). According to our first experience, extracranial, imageguided hypofractionated radiotherapy is well-tolerated by patients and can be effectively applied in the treatment of slow-growing and few numbered metastases. PMID- 26035165 TI - Impact of Antiretroviral Therapy on HIV-1 Persistence: The Case for Early Initiation. AB - Combination antiretroviral therapy suppresses HIV-1 replication, but is not curative because of the persistence of both residual viremia and long-lived cells carrying latent, intact proviruses. Recent data, however, have highlighted the substantial impact of early initiation of combination antiretroviral therapy on the number of HIV-1-infected cells that persist after treatment and on the possibility of post-treatment control of viral replication. The well-publicized case of the "Mississippi baby" has fueled great interest in outcomes following immediate initiation of combination antiretroviral therapy in both infants and adults. Here, we review current knowledge of the impact of combination antiretroviral therapy on HIV-1 reservoirs, with specific focus on the timing of treatment initiation. We propose that early initiation of combination antiretroviral therapy is likely to promote the efficacy of strategies to achieve long-term, therapy-free remission of HIV-1 and that this possibility should be considered in decisions about when to initiate the therapy. PMID- 26035166 TI - Burden, Determinants, and Pharmacological Management of Hypertension in HIV Positive Patients and Populations: A Systematic Narrative Review. AB - Hypertension among HIV-positive populations has emerged as a new threat to the health and well being of people living with HIV, particularly among those receiving antiretroviral therapy. We reviewed the global evidence on the burden of disease (including prevalence and incidence), determinants of hypertension among HIV-positive populations, and the pharmacological management of hypertension in HIV-positive patients. We systematically searched PubMed-MEDLINE and EMBASE from January 2000 through February 2015 for relevant studies and traced their citations through the ISI Web of Science. We also searched the websites of the World Health Organisation, the International Society of Hypertension, and the International AIDS Society and constructed a narrative data synthesis. Hypertension is common in HIV-positive populations, with prevalence estimates ranging from 4.7 to 54.4% in high-income countries, and from 8.7 to 45.9% in low- and middle-income countries. The role of HIV-specific factors including disease severity, duration of disease, and treatments on the presence of hypertension in HIV-positive patients is reported, but patterns remain unclear. The clinical management of hypertension in HIV-positive patients is similar to those with hypertension in the general population; however, additional considerations should be given to potential drug interactions between antihypertensive agents and antiretroviral drugs to inform the clinician's selection of these therapies. Hypertension is common in HIV-positive populations and remains an important comorbidity affecting mortality outcomes. Further research examining the development of hypertension and its associated care in HIV positive patients is required to optimize management of the dual conditions. PMID- 26035167 TI - Clinical Relevance of Kynurenine Pathway in HIV/AIDS: An Immune Checkpoint at the Crossroads of Metabolism and Inflammation. AB - Tryptophan degradation along the kynurenine pathway is associated with a wide variety of pathophysiological processes, of which tumor tolerance and immune dysfunction in several chronic viral infections including HIV are well known. The kynurenine pathway is at the crossroads of metabolism and immunity and plays an important role in inflammation while also playing an opposing role in the control of acute and chronic infections. In this review we have summarized findings from recent studies reporting modulation of tryptophan degrading the kynurenine pathway in the context of HIV infection. This immuno-metabolic pathway is modulated by three distinct inducible enzymes: indoleamine 2,3-dioxygenase 1 and 2 and tryptophan 2,3-dioxygenase. Increased expression of these enzymes by antigen-presenting cells leads to local or systemic tryptophan depletion, resulting in a mechanism of defense against certain microorganisms. Conversely, it can also lead to immunosuppression by antigen-specific T-cell exhaustion and recruitment of T regulatory cells. Recently, among these enzymes, indoleamine 2,3 dioxygenase 1 has been recognized to be an immune response checkpoint that plays an important role in HIV immune dysfunction, even in the context of antiretroviral therapy. In addition to the activation of the kynurenine pathway by HIV proteins Tat and Nef, the tryptophan-degrading bacteria present in the intestinal flora have been associated with dysfunction of gut mucosal CD4 Th17/Th22 cells, leading to microbial translocation and creating a systemic kynurenine pathway activation cycle. This self-sustaining feedback loop has deleterious effects on disease progression and on neurocognitive impairment in HIV-infected patients. Therapy designed to break the vicious cycle of induced tryptophan degradation is warranted to revert immune exhaustion in HIV-infected persons. PMID- 26035168 TI - Catch Me If You Can--The Race Between HIV and Neutralizing Antibodies. AB - Broadly neutralizing antibodies represent the major protective mechanism of vaccines targeting pathogenic microbes in humans and animals. For HIV, broadly neutralizing antibodies have also been shown to be protective in experimental animal models. However, despite the identification of a respectable number of broadly neutralizing antibodies from chronically infected HIV-positive persons in recent years, attempts to induce such antibodies by vaccines have generally failed over the last decades. Though unsuccessful in view of achieving a protective vaccine against HIV, many of these studies have contributed significantly to the understanding of the generation of broadly neutralizing antibodies against HIV-1 as well as to the vulnerable sites they target on the surface of the virus. Here we review the most important features of patient derived broadly neutralizing antibodies, the long and complex B-cell maturation pathways required for their production, and the resulting consequences for vaccine development. We further address characteristics of the epitopes targeted by broadly neutralizing antibodies on the virus surface as well as mechanisms of viral escape. Taken together, the identification of vaccine candidates able to induce broadly neutralizing antibodies against HIV-1 is the major challenge in HIV vaccine development. Mutual coevolution of rationally designed HIV vaccine candidates, with affinity maturation pathways of antibodies they induce upon vaccination, may best mimic the natural situation of chronically HIV-infected patients who are able to generate broadly neutralizing antibodies. PMID- 26035169 TI - Rezolsta(r) (Darunavir/Cobicistat): First Boosted Protease Inhibitor Co formulated with Cobicistat. AB - Rezolsta(r) (darunavir/cobicistat) is the first boosted protease inhibitor in a fixed-dose combination to be approved for the treatment of HIV infection. It contains darunavir, a protease inhibitor with a well-known safety and efficacy profile, and the new pharmacokinetic enhancer cobicistat. The convenience of this combination makes boosted darunavir easier to take, thus improving adherence. Exposure to darunavir is equivalent when it is administered with cobicistat or with ritonavir. Darunavir/cobicistat-based antiretroviral therapy has shown considerable efficacy and good tolerability in several clinical trials. Data from the single-arm, open-label, phase III GS-US-216-130 trial showed virological efficacy rates comparable to those from ARTEMIS and ODIN. Darunavir/cobicistat was well tolerated; most adverse events were mild and consisted of gastrointestinal disturbances. Cobicistat inhibits transporters of creatinine in kidney tubules, thus causing a minimal and reversible reduction in estimated glomerular filtration rate. Like ritonavir, cobicistat is a strong CYP3A4 inhibitor and, as such, shares most of its drug interactions. However, inhibition by cobicistat seems to be more specific than with ritonavir, and cobicistat has no inducer effect; therefore, differences in its drug interaction profile may be observed. PMID- 26035170 TI - Caution with new oral hepatitis C drugs. AB - The hepatitis C field is living a revolution following the introduction of all oral therapies that can cure most patients with short courses of direct-acting antiviral (DAA) combinations. Given that chronic hepatitis C affects globally around 20% of HIV persons, major attention has been focused on the HIV/HCV coinfected population. Current evidence suggests that these patients depict cure rates of over 90%, similar to HCV-monoinfected individuals. Accordingly, current guidelines for hepatitis C therapy no longer separate mono- and coinfected subjects. PMID- 26035171 TI - New update of the DHHS guidelines for adults and children. AB - On April 2015, the U.S. Department of Health and Human Services (DHHS) released an updated version of its antiretroviral treatment guidelines for adults. The new guidelines include revised recommendations for first-line antiretroviral therapy as well as management of treatment-experienced patients. PMID- 26035172 TI - Pannexin1 channels dominate ATP release in the cochlea ensuring endocochlear potential and auditory receptor potential generation and hearing. AB - Pannexin1 (Panx1) is a gap junction gene in vertebrates whose proteins mainly function as non-junctional channels on the cell surface. Panx1 channels can release ATP under physiological conditions and play critical roles in many physiological and pathological processes. Here, we report that Panx1 deficiency can reduce ATP release and endocochlear potential (EP) generation in the cochlea inducing hearing loss. Panx1 extensively expresses in the cochlea, including the cochlear lateral wall. We found that deletion of Panx1 in the cochlear lateral wall almost abolished ATP release under physiological conditions. Positive EP is a driving force for current through hair cells to produce auditory receptor potential. EP generation requires ATP. In the Panx1 deficient mice, EP and auditory receptor potential as measured by cochlear microphonics (CM) were significantly reduced. However, no apparent hair cell loss was detected. Moreover, defect of connexin hemichannels by deletion of connexin26 (Cx26) and Cx30, which are predominant connexin isoforms in the cochlea, did not reduce ATP release under physiological conditions. These data demonstrate that Panx1 channels dominate ATP release in the cochlea ensuring EP and auditory receptor potential generation and hearing. Panx1 deficiency can reduce ATP release and EP generation causing hearing loss. PMID- 26035174 TI - Predicting the Spatial Distribution of Wolf (Canis lupus) Breeding Areas in a Mountainous Region of Central Italy. AB - Wolves (Canis lupus) in Italy represent a relict west European population. They are classified as vulnerable by IUCN, though have increased in number and expanded their range in recent decades. Here we use 17 years of monitoring data (from 1993 to 2010) collected in a mountainous region of central Italy (Arezzo, Tuscany) in an ecological niche-based model (MaxEnt) to characterize breeding sites (i.e. the areas where pups were raised) within home ranges, as detected from play-back responses. From a suite of variables related to topography, habitat and human disturbance we found that elevation and distance to protected areas were most important in explaining the locality of wolf responses. Rendezvous sites (family play-back response sites) typically occurred between 800 and 1200 m a.s.l., inside protected areas, and were usually located along mountain chains distant from human settlements and roads. In these areas human disturbance is low and the densities of ungulates are typically high. Over recent years, rendezvous sites have occurred closer to urban areas as the wolf population has continued to expand, despite the consequent human disturbance. This suggests that undisturbed landscapes may be reaching their carrying capacity for wolves. This, in turn, may lead to the potential for increased human-wolf interactions in future. Applying our model, both within and beyond the species' current range, we identify sites both within the current range and also further afield, that the species could occupy in future. Our work underlines the importance of the present protected areas network in facilitating the recolonisation by wolves. Our projections of suitability of sites for future establishment as the population continues to expand could inform planning to minimize future wolf-human conflicts. PMID- 26035173 TI - Identification, phylogeny, and transcript of chitinase family genes in sugarcane. AB - Chitinases are pathogensis-related proteins, which play an important role in plant defense mechanisms. The role of the sugarcane chitinase family genes remains unclear due to the highly heterozygous and aneuploidy chromosome genetic background of sugarcane. Ten differentially expressed chitinase genes (belonging to class I~VII) were obtained from RNA-seq analysis of both incompatible and compatible sugarcane genotypes during Sporisorium scitamineum challenge. Their structural properties and expression patterns were analyzed. Seven chitinases (ScChiI1, ScChiI2, ScChiI3, ScChiIII1, ScChiIII2, ScChiIV1 and ScChiVI1) showed more positive with early response and maintained increased transcripts in the incompatible interaction than those in the compatible one. Three (ScChiII1, ScChiV1 and ScChiVII1) seemed to have no significant difference in expression patterns between incompatible and compatible interactions. The ten chitinases were expressed differentially in response to hormone treatment as well as having distinct tissue specificity. ScChiI1, ScChiIV1 and ScChiVII1 were induced by various abiotic stresses (NaCl, CuCl2, PEG and 4 degrees C) and their involvement in plant immunity was demonstrated by over-expression in Nicotiana benthamiana. The results suggest that sugarcane chitinase family exhibit differential responses to biotic and abiotic stress, providing new insights into their function. PMID- 26035175 TI - Paraquat prohibition and change in the suicide rate and methods in South Korea. AB - The annual suicide rate in South Korea is the highest among the developed countries. Paraquat is a highly lethal herbicide, commonly used in South Korea as a means for suicide. We have studied the effect of the 2011 paraquat prohibition on the national suicide rate and method of suicide in South Korea. We obtained the monthly suicide rate from 2005 to 2013 in South Korea. In our analyses, we adjusted for the effects of celebrity suicides, and economic, meteorological, and seasonal factors on suicide rate. We employed change point analysis to determine the effect of paraquat prohibition on suicide rate over time, and the results were verified by structural change analysis, an alternative statistical method. After the paraquat prohibition period in South Korea, there was a significant reduction in the total suicide rate and suicide rate by poisoning with herbicides or fungicides in all age groups and in both genders. The estimated suicide rates during this period decreased by 10.0% and 46.1% for total suicides and suicides by poisoning of herbicides or fungicides, respectively. In addition, method substitution effect of paraquat prohibition was found in suicide by poisoning by carbon monoxide, which did not exceed the reduction in the suicide rate of poisoning with herbicides or fungicides. In South Korea, paraquat prohibition led to a lower rate of suicide by paraquat poisoning, as well as a reduction in the overall suicide rate. Paraquat prohibition should be considered as a national suicide prevention strategy in developing and developed countries alongside careful observation for method substitution effects. PMID- 26035176 TI - Theoretical predictions on the electronic structure and charge carrier mobility in 2D phosphorus sheets. AB - We have investigated the electronic structure and carrier mobility of four types of phosphorous monolayer sheet (alpha-P, beta-P,gamma-P and delta-P) using density functional theory combined with Boltzmann transport method and relaxation time approximation. It is shown that alpha-P, beta-P and gamma-P are indirect gap semiconductors, while delta-P is a direct one. All four sheets have ultrahigh carrier mobility and show anisotropy in-plane. The highest mobility value is ~3 * 10(5) cm(2)V(-1)s(-1), which is comparable to that of graphene. Because of the huge difference between the hole and electron mobilities, alpha-P, gamma-P and delta-P sheets can be considered as n-type semiconductors, and beta-P sheet can be considered as a p-type semiconductor. Our results suggest that phosphorous monolayer sheets can be considered as a new type of two dimensional materials for applications in optoelectronics and nanoelectronic devices. PMID- 26035177 TI - Streptococcus thermophilus Biofilm Formation: A Remnant Trait of Ancestral Commensal Life? AB - Microorganisms have a long history of use in food production and preservation. Their adaptation to food environments has profoundly modified their features, mainly through genomic flux. Streptococcus thermophilus, one of the most frequent starter culture organisms consumed daily by humans emerged recently from a commensal ancestor. As such, it is a useful model for genomic studies of bacterial domestication processes. Many streptococcal species form biofilms, a key feature of the major lifestyle of these bacteria in nature. However, few descriptions of S. thermophilus biofilms have been reported. An analysis of the ability of a representative collection of natural isolates to form biofilms revealed that S. thermophilus was a poor biofilm producer and that this characteristic was associated with an inability to attach firmly to surfaces. The identification of three biofilm-associated genes in the strain producing the most biofilms shed light on the reasons for the rarity of this trait in this species. These genes encode proteins involved in crucial stages of biofilm formation and are heterogeneously distributed between strains. One of the biofilm genes appears to have been acquired by horizontal transfer. The other two are located in loci presenting features of reductive evolution, and are absent from most of the strains analyzed. Their orthologs in commensal bacteria are involved in adhesion to host cells, suggesting that they are remnants of ancestral functions. The biofilm phenotype appears to be a commensal trait that has been lost during the genetic domestication of S. thermophilus, consistent with its adaptation to the milk environment and the selection of starter strains for dairy fermentations. PMID- 26035178 TI - Regulation of Nav1.7: A Conserved SCN9A Natural Antisense Transcript Expressed in Dorsal Root Ganglia. AB - The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception yet the transcriptional and post-transcriptional mechanisms that regulate this gene are still incompletely understood. Here, we describe a novel natural antisense transcript (NAT) for SCN9A that is conserved in humans and mice. The NAT has a similar tissue expression pattern to the sense gene and is alternatively spliced within dorsal root ganglia. The human and mouse NATs exist in cis with the sense gene in a tail-to-tail orientation and both share sequences that are complementary to the terminal exon of SCN9A/Scn9a. Overexpression analyses of the human NAT in human embryonic kidney (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines show that it can function to downregulate Nav1.7 mRNA, protein levels and currents. The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene. Our results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man. PMID- 26035179 TI - Instruments measuring blunted affect in schizophrenia: a systematic review. AB - Blunted affect, also referred to as emotional blunting, is a prominent symptom of schizophrenia. Patients with blunted affect have difficulty in expressing their emotions. The work of Abrams and Taylor and their development of the Rating Scale for Emotional Blunting in the late 1970's was an early indicator that blunted affect could indeed be assessed reliably. Since then, several new instruments assessing negative symptoms with subscales measuring blunted affect have been developed. In light of this, we aim to provide researchers and clinicians with a systematic review of the different instruments used to assess blunted affect by providing a comparison of the type, characteristics, administration and psychometric properties of these instruments. Studies reporting on the psychometric properties of instruments assessing blunted affect in patients with schizophrenia were included. Reviews and case studies were excluded. We reviewed 30 full-text articles and included 15 articles and 10 instruments in this systematic review. On average the instruments take 15-30 minutes to administer. We found that blunted affect items common across all instruments assess: gestures, facial expressions and vocal expressions. The CAINS Self-report Expression Subscale, had a low internal consistency score. This suggests that this sub-scale does not reliably assess patients' self-reported blunted affect symptoms and is likely due to the nature of blunted affect. Instruments correlated minimally with instruments measuring positive symptoms and more importantly with depression suggesting that the instruments distinguish between seemingly similar symptoms. PMID- 26035180 TI - Depression and Anxiety Disorders among Hospitalized Women with Breast Cancer. AB - PURPOSE: To document the prevalence of depression and anxiety disorders, and their associations with mortality among hospitalized breast cancer patients. METHODS: We examined the associations between breast cancer diagnosis and the diagnoses of anxiety or depression among 4,164 hospitalized breast cancer cases matched with 4,164 non-breast cancer controls using 2006-2009 inpatient data obtained from the Nationwide Inpatient Sample database. Conditional logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CI) for the associations between breast cancer diagnosis and diagnoses of anxiety or depression. We also used binary logistic regression models to examine the association between diagnoses of depression or anxiety, and in hospital mortality among breast cancer patients. RESULTS: We observed that breast cancer cases were less likely to have a diagnosis of depression (OR=0.63, 95% CI: 0.52-0.77), and less likely to have a diagnosis of anxiety (OR=0.68, 95% CI: 0.52 0.90) compared with controls. This association remained after controlling for race/ethnicity, residential income, insurance and residential region. Breast cancer patients with a depression diagnosis also had lower mortality (OR=0.69, 95% CI: 0.52-0.89) compared with those without a depression diagnosis, but there was no significant difference in mortality among those with and without anxiety diagnoses. CONCLUSION: Diagnoses of depression and anxiety in breast cancer patients were less prevalent than expected based on our analysis of hospitalized breast cancer patients and matched non-breast cancer controls identified in the NIS dataset using ICD-9 diagnostic codes. Results suggest that under-diagnosis of mental health problems may be common among hospitalized women with a primary diagnosis of breast cancer. Future work may fruitfully explore reasons for, and consequences of, inappropriate identification of the mental health needs of breast cancer patients. PMID- 26035181 TI - Improving the efficacy of therapeutic angiogenesis by UTMD-mediated Ang-1 gene delivery to the infarcted myocardium. AB - This study aimed to verify the feasibility and efficacy of ultrasound-targeted microbubble destruction (UTMD)-mediated angiopoietin-1 (Ang-1) gene delivery into the infarcted myocardium. Microbubbles carrying anti-intercellular adhesion molecule-1 (ICAM-1) antibody were prepared and identified. The microbubbles carrying anti-ICAM-1 antibody selectively adhered to the interleukin (IL)-1beta stimulated ECV304 cells and to the ischemic vascular endothelium, and the infarct area was examined to evaluate the targeting ability of ICAM-1 microbubbles in vitro and in vivo. The intravenous administration of the Ang-1 gene was carried out by UTMD in rabbits with acute myocardial infarction (AMI). The rabbits were divided into the control (no treatment), non-targeted microbubble destruction (non-TMB) and the ICAM-1 TMB (TMB) group. Gene delivery by direct intramyocardial injection (IMI) served as a reference. Two weeks later, regional myocardial perfusion and cardiac function were evaluated by echocardiography, and Ang-1 gene mediated angiogenesis was assessed histologically and biochemically. The results revealed that the ICAM-1-targeted microbubbles selectively adhered to the IL 1beta-stimulated ECV304 cells in vitro and to the ischemic vascular endothelium in the infarct area of the rabbits with AMI. Two weeks after the delivery of the Ang-1 gene, compared with the non-TMB group, left ventricular function and myocardial perfusion at the infarct area had improved in the TMB and IMI group (p<0.01). Ang-1 gene expression was detectable in the non-TMB, TMB and IMI group, while its expression was higher in the latter 2 groups (all p<0.01). The microvascular density (MVD) of the infarct area in the non-TMB, TMB and IMI group was 65.6 +/- 4.4, 96.7 +/- 2.1 and 100.7 +/- 3.6, respectively (p<0.01). The findings of our study indicate that UTMD-mediated gene delivery may be used to successfully deliver the Ang-1 gene to the infarcted myocardium, thus improving the efficacy of therapeutic angiogenesis. This may provide a novel strategy for future gene therapy. PMID- 26035182 TI - Influence of fatty acid synthase inhibitor orlistat on the DNA repair enzyme O6 methylguanine-DNA methyltransferase in human normal or malignant cells in vitro. AB - Tetrahydrolipstatin (orlistat), an inhibitor of lipases and fatty acid synthase, is used orally for long-term treatment of obesity. Although the drug possesses striking antitumor activities in vitro against human cancer cells and in vitro and in vivo against animal tumors, it also induces precancerous lesions in rat colon. Therefore, we tested the in vitro effect of orlistat on the expression of O6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme that plays an essential role in the control of mutagenesis and carcinogenesis. Western blot analysis demonstrated that 2-day continuous exposure to 40 uM orlistat did not affect MGMT levels in a human melanoma cell line, but downregulated the repair protein by 30-70% in human peripheral blood mononuclear cells, in two leukemia and two colon cancer cell lines. On the other hand, orlistat did not alter noticeably MGMT mRNA expression. Differently from lomeguatrib (a false substrate, strong inhibitor of MGMT) orlistat did not reduce substantially MGMT function after 2-h exposure of target cells to the agent, suggesting that this drug is not a competitive inhibitor of the repair protein. Combined treatment with orlistat and lomeguatrib showed additive reduction of MGMT levels. More importantly, orlistat-mediated downregulation of MGMT protein expression was markedly amplified when the drug was combined with a DNA methylating agent endowed with carcinogenic properties such as temozolomide. In conclusion, even if orlistat is scarcely absorbed by oral route, it is possible that this drug could reduce local MGMT-mediated protection against DNA damage provoked by DNA methylating compounds on gastrointestinal tract epithelial cells, thus favoring chemical carcinogenesis. PMID- 26035183 TI - Associations between Depressive State and Impaired Higher-Level Functional Capacity in the Elderly with Long-Term Care Requirements. AB - Depressive state has been reported to be significantly associated with higher level functional capacity among community-dwelling elderly. However, few studies have investigated the associations among people with long-term care requirements. We aimed to investigate the associations between depressive state and higher level functional capacity and obtain marginal odds ratios using propensity score analyses in people with long-term care requirements. We conducted a cross sectional study based on participants aged >= 65 years (n = 545) who were community dwelling and used outpatient care services for long-term preventive care. We measured higher-level functional capacity, depressive state, and possible confounders. Then, we estimated the marginal odds ratios (i.e., the change in odds of impaired higher-level functional capacity if all versus no participants were exposed to depressive state) by logistic models using generalized linear models with the inverse probability of treatment weighting (IPTW) for propensity score and design-based standard errors. Depressive state was used as the exposure variable and higher-level functional capacity as the outcome variable. The all absolute standardized differences after the IPTW using the propensity scores were < 10% which indicated negligible differences in the mean or prevalence of the covariates between non-depressive state and depressive state. The marginal odds ratios were estimated by the logistic models with IPTW using the propensity scores. The marginal odds ratios were 2.17 (95%CI: 1.13 4.19) for men and 2.57 (95%CI: 1.26-5.26) for women. Prevention of depressive state may contribute to not only depressive state but also higher-level functional capacity. PMID- 26035184 TI - Cognitive-behavioral therapy for 2 youths with misophonia. PMID- 26035185 TI - A randomized, double-blind, placebo-controlled study of the efficacy and safety of vortioxetine 10 mg and 20 mg in adults with major depressive disorder. AB - CONTEXT: Vortioxetine (Lu AA21004) is an antidepressant with a mechanism of action thought to be related to a combination of 2 pharmacologic actions: direct modulation of several receptors and inhibition of the serotonin transporter. OBJECTIVE: To evaluate the efficacy of vortioxetine 10 and 20 mg once daily in outpatients with major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: This 8-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study was conducted from July 2010 to January 2012 among adults with a primary diagnosis of recurrent major depressive disorder (DSM-IV-TR). INTERVENTION: Eligible subjects were randomized in 1:1:1 ratio to 1 of 3 treatment arms: vortioxetine 10 mg, vortioxetine 20 mg, or placebo once daily for 8 weeks. Subjects who completed the 8-week trial entered a 2-week blinded discontinuation period to assess potential discontinuation symptoms. MAIN OUTCOME MEASURE: The primary endpoint was the least squares mean change in Montgomery Asberg Depression Rating Scale (MADRS) total score from baseline. Key secondary outcomes were analyzed in the following prespecified sequential order: MADRS response (>= 50% decrease from baseline in total score), Clinical Global Impressions-Improvement score, change from baseline in MADRS total score in subjects with baseline Hamilton Anxiety Rating Scale score >= 20, MADRS remission (total score <= 10), and change from baseline in Sheehan Disability Scale total score (all at week 8). RESULTS: A total of 462 subjects were randomized to placebo (n = 157), vortioxetine 10 mg (n = 155), and vortioxetine 20 mg (n = 150). Mean (SE) reductions from baseline in MADRS total score (week 8) were 10.77 (+/- 0.807), -12.96 (+/- 0.832), and -14.41 (+/- 0.845) for the placebo, vortioxetine 10 mg (P = .058 vs placebo), and vortioxetine 20 mg (P = .002 vs placebo) groups. MADRS response/remission was achieved in 28.4%/14.2%, 33.8%/21.4%, and 39.2%/22.3% of subjects, respectively, in the 3 groups. Only MADRS response for vortioxetine 20 mg significantly separated from placebo (P = .044). Treatment was well tolerated, with the most frequently reported adverse events consisting of nausea, headache, diarrhea, and dizziness. CONCLUSIONS: Vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in this study population. Overall, vortioxetine was well tolerated in this study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01163266. PMID- 26035187 TI - Culturally competent strategies for assessing and treating ADHD in African American adults. AB - Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with symptoms of inattention, hyperactivity, and impulsivity. When ADHD persists into adulthood, patients often experience occupational and social impairments and may present with mood, anxiety, or substance use disorders. Despite the deleterious effects of ADHD, many adults, especially minority patients, remain undiagnosed and untreated. PMID- 26035186 TI - A randomized, double-blind, placebo-controlled study of the efficacy and safety of 2 doses of vortioxetine in adults with major depressive disorder. AB - BACKGROUND: This 8-week, randomized, double-blind, placebo-controlled study, conducted August 2010-May 2012 in the United States, evaluated the safety and efficacy of vortioxetine 10 mg and 15 mg in patients with major depressive disorder (MDD). The mechanism of action of vortioxetine is thought to be related to direct modulation of serotonin (5-HT) receptor activity and inhibition of the serotonin transporter. METHOD: Adults aged 18-75 years with MDD (DSM-IV-TR) and Montgomery-Asberg Depression Rating Scale (MADRS) total score >= 26 were randomized (1:1:1) to receive vortioxetine 10 mg or 15 mg or placebo once daily, with the primary efficacy end point being change from baseline at week 8 in MADRS analyzed by mixed model for repeated measures. Adverse events were recorded during the study, suicidal ideation and behavior were assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), and sexual dysfunction was assessed using the Arizona Sexual Experience (ASEX) scale. RESULTS: Of the 1,111 subjects screened, 469 subjects were randomized: 160 to placebo, 157 to vortioxetine 10 mg, and 152 to vortioxetine 15 mg. Differences from placebo in the primary efficacy end point were not statistically significant for vortioxetine 10 mg or vortioxetine 15 mg. Nausea, headache, dry mouth, constipation, diarrhea, vomiting, dizziness, and flatulence were reported in >= 5% of subjects receiving vortioxetine. Discontinuation due to adverse events occurred in 7 subjects (4.4%) in the placebo group, 8 (5.2%) in the vortioxetine 10 mg group, and 12 (7.9%) in the vortioxetine 15 mg group. ASEX total scores were similar across groups. There were no clinically significant trends within or between treatment groups on the C SSRS, laboratory values, electrocardiogram, or vital sign parameters. CONCLUSIONS: In this study, vortioxetine did not differ significantly from placebo on MADRS total score after 8 weeks of treatment in MDD subjects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01179516. PMID- 26035188 TI - Introduction. PMID- 26035189 TI - Longitudinal trajectories of ADHD symptomatology in offspring of parents with bipolar disorder and community controls. AB - OBJECTIVE: To compare the psychopathology and longitudinal course of attention deficit/hyperactivity disorder (ADHD) symptomatology and global functioning between the offspring with ADHD of parents with bipolar disorder and the offspring with ADHD of community control parents. METHOD: One hundred twenty-two offspring with ADHD of parents with bipolar disorder and 48 offspring with ADHD of control parents from the Pittsburgh Bipolar Offspring Study (BIOS) were included. DSM-IV lifetime psychiatric disorders were ascertained through the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children Present and Lifetime version (K-SADS-PL). The outcome measures of ADHD symptoms were ascertained at intake and every other year for a period of 6 years using the ADHD section of the K-SADS-PL and the Disruptive Behavior Disorder rating scale (DBD). Global functioning was assessed using the Children's Global Assessment Scale (CGAS). RESULTS: The offspring with ADHD of parents with bipolar disorder showed higher lifetime prevalence of mood and anxiety disorders relative to the offspring with ADHD of control parents (P values <= .03). For both groups of offspring with ADHD, the hyperactivity, impulsivity, and total K-SADS-PL ADHD scores decreased over time (P values < .001) without differences between the 2 groups. There were no between- or within-group differences in the inattention scores over time. The DBD ADHD scores decreased with age in both groups (P values < .002) without differences between the 2 groups. For both groups of offspring with ADHD, the global functioning did not improve over time. CONCLUSIONS: Offspring with ADHD of parents with bipolar disorder have more psychopathology relative to offspring with ADHD of control parents. However, there were no differences in the developmental courses of ADHD symptomatology between these 2 groups of ADHD youth. PMID- 26035190 TI - Longitudinal examination of the skeletal effects of selective serotonin reuptake inhibitors and risperidone in boys. AB - OBJECTIVE: In a previous cross-sectional study, we found lower bone mass during treatment with selective serotonin reuptake inhibitors (SSRIs) and risperidone in youths. Here, we evaluate the skeletal effects of these psychotropics at follow up. METHOD: Between April 2005 and July 2011, medically healthy 7- to 17-year-old males treated with risperidone for 6 months or more were enrolled through child psychiatry outpatient clinics and returned for follow-up 1.5 years later. Treatment history was extracted from the medical and pharmacy records. Anthropometric, laboratory, and bone mass measurements were obtained. Multivariable linear regression analyses compared participants who remained on risperidone at follow-up to those who had discontinued risperidone treatment as well as SSRI-treated versus SSRI-unexposed participants. RESULTS: The sample consisted of 94 boys with a mean age of 11.8 +/- 2.7 years at study entry. The majority had an externalizing disorder and had received risperidone and SSRIs for 2.5 +/- 1.7 years and 1.6 +/- 1.9 years, respectively, at study entry. By follow up, 26% (n = 24) had discontinued risperidone. Compared to discontinuing risperidone, continuing it was associated with a decline in participants' age-sex height-race-specific areal bone mineral density (BMD) z score at the lumbar spine (P < .04) and failure to increase radius trabecular volumetric BMD (P < .03), after accounting for significant covariates. In addition, receiving an SSRI was associated with reduced lumbar spine areal BMD z score and radius trabecular volumetric BMD at both study entry (P < .02 and P < .03, respectively) and follow up (P < .06 and P < .03, respectively), but without further decline between the 2 visits. CONCLUSIONS: Chronic SSRI treatment in children and adolescents is associated with reduced, albeit stable, bone mass for age, while chronic risperidone treatment is associated with failure to accrue bone mass. PMID- 26035191 TI - Precursors of bipolar disorders: a systematic literature review of prospective studies. AB - OBJECTIVE: To evaluate the presence of affective signs and symptoms as precursors of bipolar disorder in prospective studies, including assessment of their prevalence, duration, and predictive value. DATA SOURCES: We followed PRISMA guidelines to search PubMed, CINAHL, PsycINFO, EMBASE, SCOPUS, and ISI Web of Science databases to May 31, 2013, using the terms bipolar disorder AND (antecedent* OR predict* OR prodrom* OR prospect*) AND (diagnosis OR development). Hand searching of identified reports led to additional relevant references. STUDY SELECTION: We included only English-language articles containing (1) prospective, longitudinal studies with at least 2 structured clinical assessments (intake and follow-up); (2) no previous DSM-III or DSM-IV diagnoses of bipolar I or bipolar II; and (3) diagnostic outcome of bipolar I or bipolar II. Studies of subjects at familial risk of bipolar disorder were excluded, as these have been reviewed elsewhere. DATA EXTRACTION: We tabulated details of study design, outcomes, precursors, and predictive value. Only studies reporting a positive predictive association were included. RESULTS: In 26 published reports meeting selection criteria, methods varied widely in terms of design, duration of follow-up, ages, and populations investigated. Despite such heterogeneity in methods, findings were notably consistent. Precursors of bipolar disorder include mood lability, subsyndromal and major depression, subsyndromal hypomanic symptoms with or without major depression, cyclothymia and bipolar not otherwise specified, major depression with psychotic features, and other psychotic disorders. Bipolar disorder was also predicted by juvenile onset of major depression as well as frequency and loading of hypomanic or depressive symptoms. CONCLUSIONS: Despite the limitations of published reports, prospectively identified precursors of bipolar disorder typically arose years prior to syndromal onset, often with significant early morbidity and disability. Prospectively identified precursors of bipolar disorder are generally consistent with findings in retrospective and family-risk studies. Combining precursors and other risk factors may increase predictive value, support earlier diagnosis, improve treatment, and limit disability in bipolar disorder. PMID- 26035192 TI - Varenicline for smoking cessation in the bipolar patient. PMID- 26035193 TI - Dr Chengappa and colleagues reply. PMID- 26035194 TI - Overview of sleep: the neurologic processes of the sleep-wake cycle. AB - Sleep problems are common in adults and should be treated to improve overall health and safety. To choose the best treatment for patients with sleep problems, clinicians should understand the sleep-wake cycle and the stages of rapid eye movement and non-rapid eye movement sleep as well as the neurologic pathways of sleep and wake systems. The sleep- and wake-promoting systems are mutually inhibitory, with the predominantly active system determining if a person is awake or asleep. The orexin system also plays an important role in the stabilization of the sleep-wake cycle. PMID- 26035195 TI - Culturally competent approaches to diagnosing ADHD in Hispanic adults and overcoming cultural issues with patients and families. AB - Hispanics in the United States are a diverse population with different countries of origin and a wide range of English language proficiency, socioeconomic and immigration status, values, and traditions. Clinicians must combine what they know about treating adult ADHD in general with a culturally competent understanding of the special needs of Hispanic patients in order to provide effective and accessible treatment. Strategies to treat Hispanic adults may include clear communication during the patient's interview, assessment of comorbid conditions, and affordable treatment options. PMID- 26035196 TI - Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. AB - Intranasal drug delivery (INDD) systems offer a route to the brain that bypasses problems related to gastrointestinal absorption, first-pass metabolism, and the blood-brain barrier; onset of therapeutic action is rapid, and the inconvenience and discomfort of parenteral administration are avoided. INDD has found several applications in neuropsychiatry, such as to treat migraine, acute and chronic pain, Parkinson disease, disorders of cognition, autism, schizophrenia, social phobia, and depression. INDD has also been used to test experimental drugs, such as peptides, for neuropsychiatric indications; these drugs cannot easily be administered by other routes. This article examines the advantages and applications of INDD in neuropsychiatry; provides examples of test, experimental, and approved INDD treatments; and focuses especially on the potential of intranasal ketamine for the acute and maintenance therapy of refractory depression. PMID- 26035197 TI - Improvement in health-related quality of life among adults with serious mental illness receiving inpatient treatment: a prospective cohort study. AB - OBJECTIVE: This study examined changes in health-related quality of life in adult inpatients with serious mental illness engaged in a 6- to 8-week intensive treatment program. METHOD: Admission and discharge assessment with the MOS 36 item Short-Form Health Survey was completed (June 2010-June 2012) for 410 adults aged 18-68 years. Paired t tests and effect size estimates were calculated for the overall sample, and reliable change index scores and clinical significance were calculated to estimate individual-level response and recovery rates. Hierarchical stepwise regression analyses were conducted to explore patient pretreatment characteristics, including total number of DSM-IV-TR diagnoses, that influence treatment response. RESULTS: Large effect size improvements were demonstrated for the Mental Component Summary score (Cohen d = 1.5), including subjective ratings of vitality (Cohen d = 1.1), social functioning (Cohen d = 1.3), role-emotional functioning (Cohen d = 1.3), and mental health (Cohen d = 1.3). Equivocal findings for change in physical health were demonstrated, with the majority of patients demonstrating no significant change in function (t409 = 0.14, P = .89) but approximately equal numbers of patients demonstrating improvement and deterioration. The pretreatment characteristic of a tendency to be interpersonally distant, cold, and disengaged was predictive of a poorer outcome on Mental Component Summary treatment response (P < .001). CONCLUSIONS: In light of a heavy burden of illness and high psychiatric comorbidity of this sample, treatment response was generally positive for improvement in mental health functioning. This study adds to a growing body of evidence indicating robust treatment response even for those with serious mental illness when treatment is intensive and multimodal. PMID- 26035198 TI - Early discontinuation and suboptimal dosing of prazosin: a potential missed opportunity for veterans with posttraumatic stress disorder. AB - OBJECTIVE: Clinical Practice Guidelines issued by the US Department of Veterans Affairs (VA) and the Department of Defense recommend prazosin for sleep/nightmares for veterans with posttraumatic stress disorder (PTSD). As existing literature suggests this novel treatment option to be underutilized, we examined a cohort of veterans with PTSD initiating prazosin to characterize their typical duration of use and dosing patterns. METHOD: Administrative data from fiscal year 2010 were used to identify veterans with PTSD according to ICD-9 codes extracted from inpatient and outpatient encounters. The longitudinal course of prazosin use following initiation was examined using refill data, and estimated prazosin doses were calculated based upon total milligrams and the day's supply dispensed. RESULTS: A total of 12,844 veterans with PTSD initiated prazosin during 2010. Twenty percent of veterans never refilled the initial prescription, and 37.6% persisted on the drug for at least 1 year. Patients more likely to remain on prazosin for at least 1 year were older (ages 40-59 years [OR = 1.28; 95% CI, 1.15-1.45] and ages >= 60 years [OR = 1.25; 95% CI, 1.12-1.40]) relative to younger patients and taking more medications (4-6 [OR = 1.40; 95% CI, 1.27-1.55], 7-9 [OR = 1.73; 95% CI, 1.56-1.94], and >= 10 [OR = 2.04; 95% CI, 1.83-2.29]) relative to 0-3 medications. The mean maximum prazosin dose reached in the first year of treatment was 3.6 mg/d, and only 14.1% of patients reached the minimum guideline recommended dose of 6 mg/d. CONCLUSIONS: Of patients with PTSD newly initiated on prazosin in 2010, < 40% were still taking the drug 1 year later, and < 20% received the minimum recommended dose according to current VA guidelines. Further investigation is required to determine the precise clinical factors underlying these prescribing patterns and overcome barriers to guideline concordant treatment. PMID- 26035199 TI - Comparison of venlafaxine alone versus venlafaxine plus bright light therapy combination for severe major depressive disorder. AB - OBJECTIVE: Phototherapy, ie, bright light therapy, is an effective and safe treatment of major depressive disorder (MDD). It exerts rapid mood-elevating activity, similar to antidepressant medications, most likely mediated through both monoaminergic and circadian system melatonergic mechanisms. We assessed the efficiency of bright light therapy as an adjuvant treatment to antidepressant pharmacotherapy in patients with severe MDD randomized by Hamilton Depression Rating Scale (HDRS) score to either (1) 150 mg venlafaxine hydrochloride daily at 7:00 AM or (2) 150 mg venlafaxine plus 60-minute light of 7000 lux the initial week of clinical management (venlafaxine + bright light therapy) daily at 7:00 AM. METHOD: 50 inpatients with severe MDD at the Psychiatry Clinic of Yuzuncu Yil University Training and Education Hospital participated. The study, which was conducted from January 2013 through June 2014, entailed patients diagnosed with severe MDD based on DSM-IV-TR for the first time. Mood states were assessed by the HDRS, Profile of Mood States (POMS), and Beck Depression Inventory (BDI) before treatment and at 1, 2, 4, and 8 weeks of treatment. RESULTS: On the basis of the HDRS score as the primary outcome variable, both strategies significantly improved depression and negative mood states already at the first treatment week (P < .001). Differences in therapeutic effects by treatment strategy were remarkable at the second and fourth weeks of clinical management (P = .018 and P = .011, respectively), with beneficial effects continuing until trial conclusion. Those treated with venlafaxine + bright light therapy evidenced significantly lower HDRS depression scores (P < .05) as well as BDI scores (P < .05) and POMS negative mood states scores (depression-dejection, tension-anxiety, anger hostility, fatigue-inertia, and confusion-bewilderment subscales; all P < .05) after the second week. At week 4 of the trial, 19 (76%) of the 25 venlafaxine + bright light therapy patients versus just 11 (44%) of the 25 venlafaxine patients (P < .05) attained the target goal of treatment, a HDRS score <= 13, indicative of mild depression, and, although not statistically significant in our small sample study (P = .36), at week 8, 76% of venlafaxine + bright light therapy patients (n = 19) versus just 64% of the venlafaxine patients (n = 16) experienced complete remission of depression (HDRS score <= 7). CONCLUSIONS: Both venlafaxine and venlafaxine + bright light therapy treatment strategies significantly reversed the depressive mood of patients with severe MDD; however, the latter induced significantly stronger and more rapid beneficial effects. Future longer-term studies with large sample sizes, nonetheless, are required to confirm and generalize these results to patients of diverse ethnicities and cultures with both severe and mild MDD. TRIAL REGISTRATION: ANZCTR.org.au registration number: ACTRN12614001061628. PMID- 26035200 TI - Is there validity to the bipolar prodrome? PMID- 26035201 TI - Antidepressant signal detection in the clinical trials vortex. PMID- 26035202 TI - A breakthrough treatment for major depression. PMID- 26035203 TI - Circadian rhythms and mood disorders: a guide for the perplexed. PMID- 26035204 TI - Effects of N-Acetyl cysteine on suicidal ideation in bipolar depression. PMID- 26035205 TI - Correction: Postprandial oxytocin secretion is associated with severity of anxiety and depressive symptoms in anorexia nervosa. PMID- 26035206 TI - Tunable bistability in hybrid Bose-Einstein condensate optomechanics. AB - Cavity-optomechanics, a rapidly developing area of research, has made a remarkable progress. A stunning manifestation of optomechanical phenomena is in exploiting the mechanical effects of light to couple the optical degree of freedom with mechanical degree of freedom. In this report, we investigate the controlled bistable dynamics of such hybrid optomechanical system composed of cigar-shaped Bose-Einstein condensate (BEC) trapped inside high-finesse optical cavity with one moving-end mirror and is driven by a single mode optical field. The numerical results provide evidence for controlled optical bistability in optomechanics using transverse optical field which directly interacts with atoms causing the coupling of transverse field with momentum side modes, exited by intra-cavity field. This technique of transverse field coupling is also used to control bistable dynamics of both moving-end mirror and BEC. The report provides an understanding of temporal dynamics of moving-end mirror and BEC with respect to transverse field. Moreover, dependence of effective potential of the system on transverse field has also been discussed. To observe this phenomena in laboratory, we have suggested a certain set of experimental parameters. These findings provide a platform to investigate the tunable behavior of novel phenomenon like electromagnetically induced transparency and entanglement in hybrid systems. PMID- 26035207 TI - PD-1 and Tim-3 Pathways Regulate CD8+ T Cells Function in Atherosclerosis. AB - T cell-mediated immunity plays a significant role in the development of atherosclerosis (AS). There is increasing evidence that CD8+ T cells are also involved in AS but their exact roles remain unclear. The inhibitory receptors programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim 3) are well known inhibitory molecules that play a crucial role in regulating CD8+ T cell activation or tolerance. Here, we demonstrate that the co-expression of PD-1 and Tim-3 on CD8+ T cells is up-regulated in AS patients. PD-1+ Tim-3+ CD8+ T cells are enriched for within the central T (TCM) cell subset, with high proliferative activity and CD127 expression. Co-expression of PD-1 and Tim-3 on CD8+ T cells is associated with increased anti-atherogenic cytokine production as well as decreased pro-atherogenic cytokine production. Blockade of PD-1 and Tim-3 results in a decrease of anti-atherogenic cytokine production by PD-1+ Tim-3+ CD8+ T cells and in an augmentation of TNF-alpha and IFN-gamma production. These findings highlight the important role of the PD-1 and Tim-3 pathways in regulating CD8+ T cells function in human AS. PMID- 26035208 TI - Screening currency notes for microbial pathogens and antibiotic resistance genes using a shotgun metagenomic approach. AB - Fomites are a well-known source of microbial infections and previous studies have provided insights into the sojourning microbiome of fomites from various sources. Paper currency notes are one of the most commonly exchanged objects and its potential to transmit pathogenic organisms has been well recognized. Approaches to identify the microbiome associated with paper currency notes have been largely limited to culture dependent approaches. Subsequent studies portrayed the use of 16S ribosomal RNA based approaches which provided insights into the taxonomical distribution of the microbiome. However, recent techniques including shotgun sequencing provides resolution at gene level and enable estimation of their copy numbers in the metagenome. We investigated the microbiome of Indian paper currency notes using a shotgun metagenome sequencing approach. Metagenomic DNA isolated from samples of frequently circulated denominations of Indian currency notes were sequenced using Illumina Hiseq sequencer. Analysis of the data revealed presence of species belonging to both eukaryotic and prokaryotic genera. The taxonomic distribution at kingdom level revealed contigs mapping to eukaryota (70%), bacteria (9%), viruses and archae (~1%). We identified 78 pathogens including Staphylococcus aureus, Corynebacterium glutamicum, Enterococcus faecalis, and 75 cellulose degrading organisms including Acidothermus cellulolyticus, Cellulomonas flavigena and Ruminococcus albus. Additionally, 78 antibiotic resistance genes were identified and 18 of these were found in all the samples. Furthermore, six out of 78 pathogens harbored at least one of the 18 common antibiotic resistance genes. To the best of our knowledge, this is the first report of shotgun metagenome sequence dataset of paper currency notes, which can be useful for future applications including as bio-surveillance of exchangeable fomites for infectious agents. PMID- 26035210 TI - Apigenin inhibits the proliferation and invasion of osteosarcoma cells by suppressing the Wnt/beta-catenin signaling pathway. AB - Osteosarcoma (OS) is the most common type of bone cancer. Even with early diagnosis and aggressive treatment, the prognosis for OS is poor. In the present study, we investigated the proliferation and invasion inhibitory effect of apigenin on human OS cells and the possible molecular mechanisms involved. The cell viability of U2OS and MG63 human OS cell lines was detected by MTT assay. Cell cycle progression and invasion were assessed by flow cytometry and the Matrigel Boyden chamber assay, respectively, and the involvement of molecular mechanisms was examined by western blot analysis. We demonstrated that apigenin inhibited proliferation and reduced invasion in human OS cells, and downregulated the expression of beta-catenin in OS cells. Furthermore, the inhibitory effect of apigenin on OS cells was reversed by overexpression of beta-catenin, but enhanced by knockdown of beta-catenin. Collectively, our results showed that apigenin inhibits the tumor growth of OS cells by inactivating Wnt/beta-catenin signaling. Therefore, apigenin is a promising chemotherapeutic agent that may be used in the treatment of human OS. PMID- 26035209 TI - Effects of oestrogen deficiency on the alveolar bone of rats with experimental periodontitis. AB - Periodontitis is an inflammatory disease characterized by loss of connective tissue and alveolar bone, and osteoporosis is a common disease characterized by a systemic impairment of bone mass and microarchitecture. To date, the association between periodontitis and osteoporosis has remained to be fully elucidated. In the present study, an experimental rat model of periodontitis was used to explore the effects of oestrogen deficiency-induced osteoporosis on the maxillary alveolar bone. Forty-four female, six-month-old Sprague-Dawley rats were randomly divided into four groups: Control, ligature, ovariectomized (OVX), and OVX + ligature. One month after ovariectomy, rats in the ligature and OVX + ligature groups received ligatures on their first and second maxillary molars for 1 month. Fluorescent labelling was performed prior to sacrificing the animals. At the end of the experiment, the maxillae and serum were collected and subjected to micro computed tomography analysis, confocal laser-scanning microscopic observation, Van Gieson's fuchsin staining, tartrate-resistant acid phosphatase staining and ELISA. Ligatures slightly reduced the alveolar bone mineral density (BMD) and bone formation rate, but significantly reduced alveolar crest height (ACH). Ovariectomy reduced the alveolar BMD, impaired the trabecular structure, reduced the bone formation rate and increased the serum levels of bone resorption markers. Animals in the OVX + ligature group exhibited a lower alveolar BMD, a poorer trabecular structure, a reduced ACH, a lower bone formation rate and higher serum levels of bone resorption markers compared with those in the control group. The results of the present study showed that ovariectomy enhanced alveolar bone loss and reduced the ACH of rats with experimental periodontitis. Thus, post menopausal osteoporosis may influence the progression of periodontitis. PMID- 26035211 TI - Do future thoughts reflect personal goals? Current concerns and mental time travel into the past and future. AB - Our overriding hypothesis was that future thinking would be linked with goals to a greater extent than memories; conceptualizing goals as current concerns (i.e., uncompleted personal goals). We also hypothesized that current-concern-related events would differ from non-current-concern-related events on a set of phenomenological characteristics. We report novel data from a study examining involuntary and voluntary mental time travel using an adapted laboratory paradigm. Specifically, after autobiographical memories or future thoughts were elicited (between participants) in an involuntary and voluntary retrieval mode (within participants), participants self-generated five current concerns and decided whether each event was relevant or not to their current concerns. Consistent with our hypothesis, compared with memories, a larger percentage of involuntary and voluntary future thoughts reflected current concerns. Furthermore, events related to current concerns differed from non-concern-related events on a range of cognitive, representational, and affective phenomenological measures. These effects were consistent across temporal direction. In general, our results agree with the proposition that involuntary and voluntary future thinking is important for goal-directed cognition and behaviour. PMID- 26035212 TI - Effect of Self-Association on the Phase Stability of Triphenylamine Derivatives. AB - The self-association equilibrium, i.e. formation of noncovalent dimers, in two triphenylamine derivatives, TPD (N,N'-bis(3-methylphenyl)-N,N'-diphenylbenzidine) and mMTDAB (1,3,5-tris[(3-methylphenyl)phenylamino]benzene), in solution was evaluated by (1)H NMR spectroscopy. The gas-phase energetics of the respective dimerization processes was explored by computational quantum chemistry. The results indicate that self-association is significantly more extensive in TPB than in TDAB. It is proposed that this fact helps to explain why TPB presents a stability higher than expected in the liquid phase, which is reflected in a lower melting temperature, a less volatile liquid, and possibly a higher tendency to form a glass. These results highlight the influence of self-association on the phase equilibria and thermodynamic properties of pure organic substances. PMID- 26035213 TI - Temperature-dependent energy levels and size-independent thermodynamics. AB - We show that, by properly adopting the notion of temperature-dependent energy levels, the standard tools of differential thermodynamics can be used for a consistent thermostatistical description irrespective of system size. In this framework the paradigmatic (yet not always descriptive) large-system limit is no longer a necessary assumption for differential thermodynamics. We present a generalized relation between temperature and internal energy which extends thermodynamics all the way to isolated quantum systems. PMID- 26035214 TI - Tailored gold nanostructure arrays as catalysts for oxygen reduction in alkaline media and a single molecule SERS platform. AB - Although plenty of functional nanomaterials are widely applied in science and technology, cost-efficient, controlled and reproducible fabrication of metallic nanostructures is a considerable challenge. Automated electrorefining by scanning electrochemical microscopy (SECM) provides an effective approach to circumvent some drawbacks of traditional homogeneous syntheses of nanoparticles, providing precise control over the amount, time and place of reactant delivery. The precursor is just a raw metal, which is the most economically viable source. This approach ensures reproducibility and the opportunity for fabrication of micropatterns, which can be rapidly analyzed by scanning probe techniques. Here, a cost-effective methodology for the preparation of naked (ligand-free) metallic nanostructures, from polycrystalline gold using a moving microelectrode, is presented. Automated micropatterning of bare gold on indium tin oxide (ITO) demonstrates the versatility of this method to tune the size and shape of the nanostructures. The morphology of the obtained materials and thus their catalytic and plasmonic properties can be tuned using the electrorefining parameters. Programmable fabrication of sample microarrays by microprinting followed by comparative SECM studies or spectroscopic analysis allows quick optimization and characterization for specific purposes. Electrocatalytic oxygen reduction in alkaline media and surface-enhanced Raman spectroscopy (SERS) of single porphycene molecules are presented as model examples. PMID- 26035216 TI - Reduced expression of semaphorin 4D and plexin-B in breast cancer is associated with poorer prognosis and the potential linkage with oestrogen receptor. AB - Involvement of semaphorin 4D (Sema4D) and the receptor proteins of the plexins B family (plexin-B1, -B2 and -B3) in solid tumours suggests they play a role in breast cancer. In the present study, the expression of Sema4D and plexin-Bs was examined in a breast cancer cohort. The expression of Sema4D and plexin-Bs was examined in 147 tumours together with 22 normal mammary tissues using quantitative PCR along with clinicopathological patient data, as well as in MCF-7 and MDA-MB-231 cell lines treated with selective oestrogen receptor modulators (SERMs). The expression of Sema4D, plexin-B1 and -B2 was markedly reduced in tumours with local recurrence, compared to the patients that remained disease free. The reduced Sema4D expression was associated with poorer disease-free survival (median, 111.6 months, 95% CI, 96.5-126.7), compared to the patients with a higher expression (median, 144.0 months; 95% CI, 130.8-157.3; p=0.033). A reduced expression of plexin-B1 was observed in tumours with poorer differentiation and was associated with poorer overall and disease-free survival. No similar association was identified in relation to plexin-B2 and -B3. A higher expression of Sema4D and plexin-B1 was observed in the ERalpha-positive tumours compared to the ERalpha-negative tumours. The expression of these molecules was largely regulated in breast cancer cells exposed to SERMs. A decreased expression of Sema4D, plexin-B1 and -B2 was associated with local recurrence and poor prognosis. Response to SERMs indicated potential perspectives of these molecules in clinical assessment and management of diseases. PMID- 26035217 TI - Multivalent-Counterion-Induced Surfactant Multilayer Formation at Hydrophobic and Hydrophilic Solid-Solution Interfaces. AB - Surface multilayer formation from the anionic-nonionic surfactant mixture of sodium dodecyl dioxyethylene sulfate, SLES, and monododecyl dodecaethylene glycol, C12E12, by the addition of multivalent Al(3+) counterions at the solid solution interface is observed and characterized by neutron reflectivity, NR. The ability to form surface multilayer structures on hydrophobic and hydrophilic silica and cellulose surfaces is demonstrated. The surface multilayer formation is more pronounced and more well developed on the hydrophilic and hydrophobic silica surfaces than on the hydrophilic and hydrophobic cellulose surfaces. The less well developed multilayer formation on the cellulose surfaces is attributed to the greater surface inhomogeneities of the cellulose surface which partially inhibit lateral coherence and growth of the multilayer domains at the surface. The surface multilayer formation is associated with extreme wetting properties and offers the potential for the manipulation of the solid surfaces for enhanced adsorption and control of the wetting behavior. PMID- 26035219 TI - Neuraxial anesthesia for labor and delivery in a parturient with unstable cervical spine fracture. AB - We report the successful anesthetic management of labor and passive second-stage delivery in a parturient requiring cervical spine stabilization with a halo. A 25 year-old, Gravida 1, Para 0 at 37 weeks of gestation, admitted for observation after a recent motor vehicle collision, required induction of labor for preeclampsia. The mode of delivery was dependent on a successful anesthetic technique for a passive second stage of labor. The injury and halo presented concerns for access to her airway and preservation of neurologic status. An epidural placed early in labor allowed for adequate analgesia, as well as sacral extension for a forceps-assisted delivery. PMID- 26035220 TI - Emergence delirium with transient associative agnosia and expressive aphasia reversed by flumazenil in a pediatric patient. AB - Multiple factors may contribute to the development of emergence delirium in a child. We present the case of a healthy 12-year-old girl who received preoperative midazolam with the desired anxiolytic effect, underwent a brief general anesthetic, and then exhibited postoperative delirium, consisting of a transient associative agnosia and expressive aphasia. Administration of flumazenil led to immediate and lasting resolution of her symptoms. We hypothesize that gamma-aminobutyric acid type A receptor-mediated effects, most likely related to an atypical offset of midazolam, are an important subset of emergence delirium that is amenable to pharmacologic therapy with flumazenil. PMID- 26035221 TI - Favorable outcome of rivaroxaban-associated intracerebral hemorrhage reversed by 4-factor prothrombin complex concentrate: impact on thrombin generation. AB - The management of life-threatening bleeding associated with rivaroxaban remains a challenge for physicians due to the lack of evidence about clinically effective options for anticoagulation reversal. We report a favorable outcome in a patient receiving rivaroxaban prophylaxis, who developed a spontaneous subdural hematoma treated by a surgical evacuation and administration of 4-factor prothrombin complex concentrate. Classical coagulation variables were associated with impaired thrombin generation. Reversal with prothrombin complex concentrates improved all thrombin generation measures. Thrombin generation tests may be suitable for assessing the clinical utility of reversal drugs on rivaroxaban induced coagulopathy. PMID- 26035222 TI - Continuous positive airway pressure with pressure support ventilation is effective in treating acute-onset bilateral recurrent laryngeal nerve palsy. AB - Acute bilateral recurrent laryngeal nerve injury leading to acute vocal cord paralysis (VCP) is a serious complication of head and neck surgery, often requiring emergent surgical intervention. Although well documented, its presentation may be sudden and unexpected, occurring despite lack of obvious intraoperative nerve injury. There is limited literature on airway management strategies for patients with acute bilateral VCP before attaining a secure airway. We report a case of acute VCP that was successfully treated with continuous positive airway pressure via facemask ventilation. This effective temporizing strategy allowed clinicians to plan and prepare for tracheostomy, minimizing potential complications. PMID- 26035223 TI - Using PhonBank and Phon in studies of phonological development and disorders. AB - The goal of this paper is to present an overview of new tools that can be used to further our understanding of phonological development and disorders. We begin with a summary of the field of child phonology with a focus on databases and methods of analysis and then move to a description of PhonBank, a shared database for the study of phonology, and Phon, a specialised software system capable of performing various types of phonological analyses based on both phonetic transcriptions and acoustic analyses of speech productions. We provide a detailed example of using PhonBank and Phon to examine the use of velar fronting using longitudinal data from one child with typical development and three children with phonological disorder. We conclude with an emphasis on data sharing and its central relevance to further advances in our field. PMID- 26035224 TI - Chemical probes reveal an extraseptal mode of cross-linking in Staphylococcus aureus. AB - Staphylococcus aureus is an important human pathogen and a model organism for studying cell wall synthesis in Gram-positive cocci. The prevailing model of cell wall biogenesis in cocci holds that peptidoglycan synthesis (i.e., transglycosylation and cross-linking) is restricted spatially to the septal cross wall and temporally to cell division. Previously, we developed a method for visualizing cross-linking in S. aureus using fluorescently tagged mimics of the endogenous substrate of penicillin-binding proteins (PBPs). These probes are incorporated into the cell wall of S. aureus specifically by PBP4, allowing localization of the enzyme's cross-linking activity in vivo with precise spatial and temporal resolution. Here, using this methodology, we have discovered that PBP4 is active not only at the septum, but unexpectedly at the peripheral wall as well. These results challenge the long-held belief that peptidoglycan synthesis is restricted to the septum in spherical bacteria, and instead indicate the presence of two spatiotemporally distinct modes of cross-linking in S. aureus: one at the septum during cell division, and another at the peripheral wall between divisions. PMID- 26035225 TI - Influence of the interactions between tea (Camellia sinensis) extracts and ascorbic acid on their antioxidant activity: analysis with interaction indexes and isobolograms. AB - Products containing natural additives, including antioxidants, are usually perceived by consumers as safer than those with synthetic ones. Natural antioxidants, besides having a preservative activity, may exert beneficial health effects. Interactions between antioxidants may significantly change their antioxidant activity, thus in designing functional foods or food/cosmetic ingredients knowledge about the type of interactions could be useful. In the present study, the interactions between ascorbic acid (AA; vitamin C) and different black and green tea extracts and the influence on their antioxidant activities were investigated. The antioxidant activities of tea extracts and their mixtures with AA prepared in several different weight ratios were measured using the trolox equivalent antioxidant capacity (TEAC), 1,1-diphenyl-2 picrylhydrazyl (DPPH), and ferric-reducing antioxidant power (FRAP) methods. The type of interaction was determined by interaction indexes and isobolograms. It was found that the weight ratio of extracts to AA significantly influenced the antioxidant activity of a mixture and the type of interaction between these components. The weight ratio of tea extract to AA can cause the change of interaction, e.g. from antagonism to additivism or from additivism to synergism. The observed differences in the type of interactions were probably also a result of different extracts' polyphenol composition and content. The type of interaction may also be affected by the medium in which extracts and AA interact, especially its pH and the solvent used. To obtain the best antioxidant effect, all these factors should be taken into account during the design of a tea extract AA mixture. PMID- 26035226 TI - Screen Printing of Highly Loaded Silver Inks on Plastic Substrates Using Silicon Stencils. AB - Screen printing is a potential technique for mass-production of printed electronics; however, improvement in printing resolution is needed for high integration and performance. In this study, screen printing of highly loaded silver ink (77 wt %) on polyimide films is studied using fine-scale silicon stencils with openings ranging from 5 to 50 MUm wide. This approach enables printing of high-resolution silver lines with widths as small as 22 MUm. The printed silver lines on polyimide exhibit good electrical properties with a resistivity of 5.5*10(-6) Omega cm and excellent bending tolerance for bending radii greater than 5 mm (tensile strains less than 0.75%). PMID- 26035227 TI - Cross over from 3D variable range hopping to the 2D weak localization conduction mechanism in disordered carbon with the extent of graphitization. AB - The changes in the electrical transport properties and mechanism of conduction in disordered carbon, with the extent of graphitization, are studied and discussed. With heat treatment induced graphitic ordering, the electrical properties are considerably modified, inducing a crossover from strong localization to weak localization behavior. Accordingly, the conduction mechanism is modified from the 3-dimensional variable range hopping (3D VRH) model to the 2-dimensional weak localization (2D WL) model. Results show that carrier-carrier and carrier-phonon interactions play major roles in developing the weak localization behavior with the extent of graphitization. PMID- 26035229 TI - Transient Structures and Possible Limits of Data Recording in Phase-Change Materials. AB - Phase-change materials (PCMs) represent the leading candidates for universal data storage devices, which exploit the large difference in the physical properties of their transitional lattice structures. On a nanoscale, it is fundamental to determine their performance, which is ultimately controlled by the speed limit of transformation among the different structures involved. Here, we report observation with atomic-scale resolution of transient structures of nanofilms of crystalline germanium telluride, a prototypical PCM, using ultrafast electron crystallography. A nonthermal transformation from the initial rhombohedral phase to the cubic structure was found to occur in 12 ps. On a much longer time scale, hundreds of picoseconds, equilibrium heating of the nanofilm is reached, driving the system toward amorphization, provided that high excitation energy is invoked. These results elucidate the elementary steps defining the structural pathway in the transformation of crystalline-to-amorphous phase transitions and describe the essential atomic motions involved when driven by an ultrafast excitation. The establishment of the time scales of the different transient structures, as reported here, permits determination of the possible limit of performance, which is crucial for high-speed recording applications of PCMs. PMID- 26035228 TI - Peptidoglycan Modifications Tune the Stability and Function of the Innate Immune Receptor Nod2. AB - Natural modifications of peptidoglycan modulate the innate immune response. Peptidoglycan derivatives activate this response via the intracellular innate immune receptor, Nod2. To probe how these modifications alter the response, a novel and efficient carbohydrate synthesis was developed to allow for late-stage modification of the amine at the 2-position. Modification of the carbohydrate was found to be important for stabilizing Nod2 and generating the proper response. The native Nod2 ligands demonstrate a significant increase in the cellular stability of Nod2. Moreover, changing the identity of the natural ligands at the carbohydrate 2-position allows for the Nod2-dependent immune response to be either up-regulated or down-regulated. The ligand structure can be adjusted to tune the Nod2 response, suggesting that other innate immune receptors and their ligands could use a similar strategy. PMID- 26035230 TI - Lysosomal pH Decrease in Inflammatory Cells Used To Enable Activatable Imaging of Inflammation with a Sialic Acid Conjugated Profluorophore. AB - Inflammation causes significant morbidity and mortality, necessitating effective in vivo imaging of inflammation. Prior approaches often rely on combination of optical agents with entities specific for proteinaceous biomarkers overexpressed in inflammatory tissues. We herein report a fundamentally new approach to image inflammation by targeting lysosomes undergoing acidification in inflammatory cells with a sialic acid (Sia) conjugated near-infrared profluorophore (pNIR). Sia-pNIR contains a sialic acid domain for in vivo targeting of inflamed tissues and a pNIR domain which isomerizes into fluorescent and optoacoustic species in acidic lysosomes. Sia-pNIR displays high inflammation-to-healthy tissue signal contrasts in mice treated with Escherichia coli, Staphylococcus aureus, or lipopolysaccharide. In addition, inflammation-associated fluorescence is switched off upon antibiotics treatment in mice. This report shows the potentials of Sia pNIR for activatable dual-modality inflammation imaging, and particularly the use of lysosomes of inflamed cells as a previously unappreciated biomarker for inflammation imaging. PMID- 26035232 TI - Correction to "Pregnancy-Induced Metabolic Phenotype Variations in Maternal Plasma". PMID- 26035231 TI - Polyelectrolyte Multilayers Assembled Entirely from Immune Signals on Gold Nanoparticle Templates Promote Antigen-Specific T Cell Response. AB - Materials that allow modular, defined assembly of immune signals could support a new generation of rationally designed vaccines that promote tunable immune responses. Toward this goal, we have developed the first polyelectrolyte multilayer (PEM) coatings built entirely from immune signals. These immune-PEMs (iPEMs) are self-assembled on gold nanoparticle templates through stepwise electrostatic interactions between peptide antigen and polyanionic toll-like receptor (TLR) agonists that serve as molecular adjuvants. iPEMs do not require solvents or mixing, offer direct control over the composition and loading of vaccine components, and can be coated on substrates at any scale. These films also do not require other structural components, eliminating the potentially confounding effects caused by the inherent immune-stimulatory characteristics of many synthetic polymers. iPEM loading on gold nanoparticle substrates is tunable, and cryoTEM reveals iPEM shells coated on gold cores. These nanoparticles are efficiently internalized by primary dendritic cells (DCs), resulting in activation, selective triggering of TLR signaling, and presentation of the antigens used to assemble iPEMs. In coculture, iPEMs drive antigen-specific T cell proliferation and effector cytokines but not cytokines associated with more generalized inflammation. Compared to mice treated with soluble antigen and adjuvant, iPEM immunization promotes high levels of antigen-specific CD8(+) T cells in peripheral blood after 1 week. These enhancements result from increased DC activation and antigen presentation in draining lymph nodes. iPEM-immunized mice also exhibit a potent recall response after boosting, supporting the potential of iPEMs for designing well-defined vaccine coatings that provide high cargo density and eliminate synthetic film components. PMID- 26035233 TI - Hydrogen Bonded Squaramide-Based Foldable Module Induces Both beta- and alpha Turns in Hairpin Structures of alpha-Peptides in Water. AB - A novel tertiary squaramido-based reverse-turn module SQ is reported, and its conformational properties are evaluated. This module is easily incorporated into a alpha-peptide sequence by conventional solid-phase peptide synthesis. The structure characterization of the hybrid squaramido-peptide 4 is described, showing that the turn segment induces the formation of hairpin structures in water through the formation of both alphaSQ- and betaSQ-turns. PMID- 26035234 TI - CaCl2, Bisoxazoline, and Malonate: A Protocol for an Asymmetric Michael Reaction. AB - A mild protocol for the asymmetric Michael addition of dimethyl malonate to various alpha,beta-unsaturated carbonyl compounds was developed. The salient feature of this methodology is that a cheap and environmentally friendly Lewis acid, CaCl2, was used as a catalyst. An aminoindanol- and pyridine-derived ligand provided in the presence of CaCl2 Michael adducts in moderate to high enantioselectivities. The scope of the reaction was demonstrated. PMID- 26035235 TI - WITHDRAWN: Interventions for photodamaged skin. PMID- 26035236 TI - Emulsions Stabilized by Silica Rods via Arrested Demixing. AB - A binary liquid-liquid mixture with a lower critical solution temperature (LCST) when heated above a critical temperature undergoes demixing. During the initial phase of demixing process, high-energy liquid-liquid interfaces are created before both liquids eventually phase separate. By incorporating well characterized colloidal silica rods in a homogeneous one-phase liquid-liquid mixture of lutidine/water (L/W) before inducing phase separation, we show that colloidal rod stabilized Pickering emulsions can be obtained. We show that the droplet size of Pickering emulsions can be tuned by varying particle concentration, and the droplet size distribution follows the prediction of the limited coalescence model. PMID- 26035237 TI - Ni(II)20 "Bowls" from the Use of Tridentate Schiff Bases. AB - The reactions of N-salicylidene-o-aminophenol or its derivatives and excess of nickel(II) acetate in alcohols have led to Ni(II)20 clusters with an unprecedented "bowl" metal topology. PMID- 26035238 TI - Cross-sectional and longitudinal relationship between neuroticism and cognitive ability in advanced old age: the moderating role of severe sensory impairment. AB - OBJECTIVES: Gaining a comprehensive picture of the network of constructs in which cognitive functioning is embedded is crucial across the full lifespan. With respect to personality, previous findings support a relationship between neuroticism and cognitive abilities. However, findings regarding old age are inconsistent. In particular, little is known about potentially moderating variables which might explain some of the inconsistency. Our aim was to examine the moderating effect of severe sensory impairment on cross-sectional and longitudinal associations between neuroticism and cognitive functioning. METHOD: The study sample consisted of 121 visually impaired (VI), 116 hearing impaired (HI), and 150 sensory unimpaired older adults (UI). Mean age was 82.50 years (SD = 4.71 years). Neuroticism was assessed by the NEO Five Factor Inventory, and multiple established tests were used for the assessment of cognitive performance (e.g., subtests of the revised Wechsler Adult Intelligence Scale). RESULTS: Bivariate correlations and multi-group structural equation models indicated stronger relationships between cognitive abilities and neuroticism in both sensory impaired groups (VI and HI) compared to UI older individuals. This relationship was attenuated but still significant in both sensory impaired groups when controlling for age, education and health (number of chronic conditions). In cross-lagged panel models, higher baseline neuroticism was significantly associated with lower cognitive performance four years later in VI and HI individuals. CONCLUSION: Our results suggest that sensory impairment moderates both cross-sectional and longitudinal associations between neuroticism and cognitive function in advanced old age. PMID- 26035239 TI - Natural Product Primary Sulfonamides and Primary Sulfamates. AB - Primary sulfonamide and primary sulfamate functional groups feature prominently in the structures of U.S. FDA-approved drugs. However, the natural product chemical space contains few examples of these well-known zinc-binding chemotypes, with just two primary sulfonamide and five primary sulfamate natural products isolated and characterized to date. One of these natural products was isolated from a marine sponge, with the remainder isolated from Streptomyces species. In this review are outlined for the first time the discovery, isolation, striking breadth of bioactivity, and total synthesis (where available) for this rare group of natural products. PMID- 26035242 TI - The role of vitamin D in reproductive health--a Trojan Horse or the Golden Fleece? AB - In the last decade, vitamin D was in the spotlight in many fields of research. Despite numerous publications, its influence on reproductive health remains ambiguous. This paper presents an up-to-date review of current knowledge concerning the role of cholecalciferol in human reproduction. It covers various infertility issues, such as polycystic ovary syndrome, endometriosis, myoma induced infertility, male infertility, premature ovary failure and in vitro fertilization techniques. Vitamin D deficiency, defined as serum concentration of 25-hydroxycalciferol of less than 50 nmol/L, is commonly noted more frequently than only in fertility clinic patients. It is a global trend that is observed in all age groups. The results of original publications dated up to 2015 have been summarized and discussed in a critical manner. Most experts agree that vitamin D supplementation is a necessity, particularly in women suffering from obesity, insulin resistance or small ovarian reserve, as well as in men with oligo- and asthenozoospermia if serum concentration should fall below 50 nmol/L (normal range up to 125 nmol/L). High concentration of vitamin D and its metabolites in decidua during the 1st trimester suggests its important role in the implantation process and a local immunological embryo-protection. On the other hand, evidence based research did not prove a significant difference so far in ovulation stimulation or embryo development depending on vitamin D level. In one of the publications, it was also found that vitamin D binding protein (VDBP) has a molecular similarity to anti-sperm antibodies, and another one concluded that both low (<50 nmol/L) and high (>125 nmol/L) concentration of vitamin D are associated with decreased number and quality of spermatozoa in semen. Vitamin D is definitely not a Trojan Horse in reproductive health, since there were no adverse effects reported for vitamin D intake of up to 10,000 IU/day, but to proclaim it the Golden Fleece, more evidence is needed. PMID- 26035243 TI - Dietary Patterns Derived by Cluster Analysis are Associated with Cognitive Function among Korean Older Adults. AB - The objective of this study was to investigate major dietary patterns among older Korean adults through cluster analysis and to determine an association between dietary patterns and cognitive function. This is a cross-sectional study. The data from the Korean Multi-Rural Communities Cohort Study was used. Participants included 765 participants aged 60 years and over. A quantitative food frequency questionnaire with 106 items was used to investigate dietary intake. The Korean version of the MMSE-KC (Mini-Mental Status Examination-Korean version) was used to assess cognitive function. Two major dietary patterns were identified using K means cluster analysis. The "MFDF" dietary pattern indicated high consumption of Multigrain rice, Fish, Dairy products, Fruits and fruit juices, while the "WNC" dietary pattern referred to higher intakes of White rice, Noodles, and Coffee. Means of the total MMSE-KC and orientation score of the participants in the MFDF dietary pattern were higher than those of the WNC dietary pattern. Compared with the WNC dietary pattern, the MFDF dietary pattern showed a lower risk of cognitive impairment after adjusting for covariates (OR 0.64, 95% CI 0.44-0.94). The MFDF dietary pattern, with high consumption of multigrain rice, fish, dairy products, and fruits may be related to better cognition among Korean older adults. PMID- 26035241 TI - Dietary Inflammatory Index and Incidence of Cardiovascular Disease in the PREDIMED Study. AB - Previous studies have reported an association between a more pro-inflammatory diet profile and various chronic metabolic diseases. The Dietary Inflammatory Index (DII) was used to assess the inflammatory potential of nutrients and foods in the context of a dietary pattern. We prospectively examined the association between the DII and the incidence of cardiovascular disease (CVD: myocardial infarction, stroke or cardiovascular death) in the PREDIMED (Prevencion con Dieta Mediterranea) study including 7216 high-risk participants. The DII was computed based on a validated 137-item food frequency questionnaire. Multivariate-adjusted hazard ratios (HR) and 95% confidence intervals of CVD risk were computed across quartiles of the DII where the lowest (most anti-inflammatory) quartile is the referent. Risk increased across the quartiles (i.e., with increasing inflammatory potential): HR(quartile2) = 1.42 (95%CI = 0.97-2.09); HR(quartile3) = 1.85 (1.27 2.71); and HR(quartile4) = 1.73 (1.15-2.60). When fit as continuous the multiple adjusted hazard ratio for each additional standard deviation of the DII was 1.22 (1.06-1.40). Our results provide direct prospective evidence that a pro inflammatory diet is associated with a higher risk of cardiovascular clinical events. PMID- 26035245 TI - Iodized salt in Cambodia: trends from 2008 to 2014. AB - Though the consequences of nutritional iodine deficiency have been known for a long time, in Cambodia its elimination has only become a priority in the last 18 years. The Royal Government of Cambodia initiated the National Sub-Committee for Control of Iodine Deficiency Disorders in 1996 to fight this problem. Using three different surveys providing information across all provinces, we examined the compliance of salt iodization in Cambodia over the last 6 years. Salt samples from the 24 provinces were collect at the household level in 2008 (n = 566) and 2011 (n = 1275) and at the market level in 2014 (n = 1862) and analysed through a wavelength spectrophotometer for iodine content. According to the samples collected, the median iodine content significantly dropped from 22 mg/kg (25th/75th percentile: 2/37 mg/kg) in 2011 to 0 mg/kg in 2014 (25th/75th percentile: 0/8.9 mg/kg) (p < 0.001). The proportion of non-iodized salt within our collected salt drastically increased from 22% in 2011 to 62% in 2014 (p < 0.001). Since the international organizations ceased to support the procurement of iodine, the prevalence of salt compliant with the Cambodian declined within our samples. To date, the current levels of iodine added to tested salt are unsatisfactory as 92% of those salts do not meet the government requirements (99.6% of the coarse salt and 82.4% of the fine salt). This inappropriate iodization could illustrate the lack of periodic monitoring and enforcement from government entities. Therefore, government quality inspection should be reinforced to reduce the quantity of salt not meeting the national requirement. PMID- 26035244 TI - Vitamin D every day to keep the infection away? AB - Within the last decade, vitamin D has emerged as a central regulator of host defense against infections. In this regard, vitamin D triggers effective antimicrobial pathways against bacterial, fungal and viral pathogens in cells of the human innate immune system. However, vitamin D also mediates potent tolerogenic effects: it is generally believed that vitamin D attenuates inflammation and acquired immunity, and thus potentially limits collateral tissue damage. Nevertheless, several studies indicate that vitamin D promotes aspects of acquired host defense. Clinically, vitamin D deficiency has been associated with an increased risk for various infectious diseases in epidemiological studies; yet, robust data from controlled trials investigating the use of vitamin D as a preventive or therapeutic agent are missing. In this review, we summarize the current knowledge regarding the effect of vitamin D on innate and acquired host defense, and speculate on the difficulties to translate the available molecular medicine data into practical therapeutic or preventive recommendations. PMID- 26035246 TI - Selenium cycling across soil-plant-atmosphere interfaces: a critical review. AB - Selenium (Se) is an essential element for humans and animals, which occurs ubiquitously in the environment. It is present in trace amounts in both organic and inorganic forms in marine and freshwater systems, soils, biomass and in the atmosphere. Low Se levels in certain terrestrial environments have resulted in Se deficiency in humans, while elevated Se levels in waters and soils can be toxic and result in the death of aquatic wildlife and other animals. Human dietary Se intake is largely governed by Se concentrations in plants, which are controlled by root uptake of Se as a function of soil Se concentrations, speciation and bioavailability. In addition, plants and microorganisms can biomethylate Se, which can result in a loss of Se to the atmosphere. The mobilization of Se across soil-plant-atmosphere interfaces is thus of crucial importance for human Se status. This review gives an overview of current knowledge on Se cycling with a specific focus on soil-plant-atmosphere interfaces. Sources, speciation and mobility of Se in soils and plants will be discussed as well as Se hyperaccumulation by plants, biofortification and biomethylation. Future research on Se cycling in the environment is essential to minimize the adverse health effects associated with unsafe environmental Se levels. PMID- 26035249 TI - Tuning the SERS Response with Ag-Au Nanoparticle-Embedded Polymer Thin Film Substrates. AB - Development of facile routes to the fabrication of thin film substrates with tunable surface enhanced Raman scattering (SERS) efficiency and identification of the optimal conditions for maximizing the enhancement factor (EF) are significant in terms of both fundamental and application aspects of SERS. In the present work, polymer thin films with embedded bimetallic nanoparticles of Ag-Au are fabricated by a simple two-stage protocol. Ag nanoparticles are formed in the first stage, by the in situ reduction of silver nitrate by the poly(vinyl alcohol) (PVA) film through mild thermal annealing, without any additional reducing agent. In the second stage, aqueous solutions of chloroauric acid spread on the Ag-PVA thin film under ambient conditions, lead to the galvanic displacement of Ag by Au in situ inside the film, and the formation of Ag-Au particles. Evolution of the morphology of the bimetallic nanoparticles into hollow cage structures and the distribution of Au on the nanoparticles are revealed through electron microscopy and energy dispersive X-ray spectroscopy. The localized surface plasmon resonance (LSPR) extinction of the nanocomposite thin film evolves with the Ag-Au composition; theoretical simulation of the extinction spectra provides insight into the observed trends. The Ag-Au-PVA thin films are found to be efficient substrates for SERS. The EF follows the variation of the LSPR extinction vis-a-vis the excitation laser wavelength, but with an offset, and the maximum SERS effect is obtained at very low Au content; experiments with Rhodamine 6G showed EFs on the order of 10(8) and a limit of detection of 0.6 pmol. The present study describes a facile and simple fabrication of a nanocomposite thin film that can be conveniently deployed in SERS investigations, and the utility of the bimetallic system to tune and maximize the EF. PMID- 26035250 TI - Human Ether-a-go-go Related Gene (hERG) Channel Blocking Aporphine Alkaloids from Lotus Leaves and Their Quantitative Analysis in Dietary Weight Loss Supplements. AB - Blockage of the human ether-a-go-go related gene (hERG) channel can result in life-threatening ventricular tachyarrhythmia. In an in vitro screening of herbal materials for hERG blockers using an automated two-microelectrode voltage clamp assay on Xenopus oocytes, an alkaloid fraction of Nelumbo nucifera Gaertn. (lotus) leaves induced ~50% of hERG current inhibition at 100 MUg/mL. Chromatographic separation resulted in the isolation and identification of (-) asimilobine, 1, nuciferine, 2, O-nornuciferine, 3, N-nornuciferine, 4, and liensinine, 5. In agreement with in silico predicted ligand-target interactions, 2, 3, and 4 revealed distinct in vitro hERG blockages measured in HEK293 cells with IC50 values of 2.89, 7.91, and 9.75 MUM, respectively. Because lotus leaf dietary weight loss supplements are becoming increasingly popular, the identified hERG-blocking alkaloids were quantitated in five commercially available products. Results showed pronounced differences in the content of hERG-blocking alkaloids ranging up to 992 MUg (2) in the daily recommended dose. PMID- 26035251 TI - Assessment of Cerebral Autoregulation Patterns with Near-infrared Spectroscopy during Pharmacological-induced Pressure Changes. AB - BACKGROUND: Previous work has demonstrated paradoxical increases in cerebral oxygen saturation (ScO2) as blood pressure decreases and paradoxical decreases in ScO2 as blood pressure increases. It has been suggested that these paradoxical responses indicate a functional cerebral autoregulation mechanism. Accordingly, the authors hypothesized that if this suggestion is correct, paradoxical responses will occur exclusively in patients with intact cerebral autoregulation. METHODS: Thirty-four patients undergoing elective cardiac surgery were included. Cerebral autoregulation was assessed with the near-infrared spectroscopy-derived cerebral oximetry index (COx), computed by calculating the Spearman correlation coefficient between mean arterial pressure and ScO2. COx less than 0.30 was previously defined as functional autoregulation. During cardiopulmonary bypass, 20% change in blood pressure was accomplished with the use of nitroprusside for decreasing pressure and phenylephrine for increasing pressure. Effects on COx were assessed. Data were analyzed using two-way ANOVA, Kruskal-Wallis test, and Wilcoxon and Mann-Whitney U test. RESULTS: Sixty-five percent of patients had a baseline COx less than 0.30, indicating functional baseline autoregulation. In 50% of these patients (n = 10), COx became highly negative after vasoactive drug administration (from -0.04 [-0.25 to 0.16] to -0.63 [-0.83 to -0.26] after administration of phenylephrine, and from -0.05 [-0.19 to 0.17] to -0.55 [-0.94 to -0.35] after administration of nitroprusside). A negative COx implies a decrease in ScO2 with increase in pressure and, conversely, an increase in ScO2 with decrease in pressure. CONCLUSIONS: In this study, paradoxical changes in ScO2 after pharmacological-induced pressure changes occurred exclusively in patients with intact cerebral autoregulation, corroborating the hypothesis that these paradoxical responses might be attributable to a functional cerebral autoregulation. PMID- 26035247 TI - Modulation of the immune response to respiratory viruses by vitamin D. AB - BACKGROUND: Vitamin D deficiency has been shown to be independently associated with increased risk of viral acute respiratory infection (ARI) in a number of observational studies, and meta-analysis of clinical trials of vitamin D supplementation for prevention of ARI has demonstrated protective effects. Several cellular studies have investigated the effects of vitamin D metabolites on immune responses to respiratory viruses, but syntheses of these reports are lacking. SCOPE: In this article, we review the literature reporting results of in vitro experiments investigating immunomodulatory actions of vitamin D metabolites in human respiratory epithelial cells infected with respiratory viruses. KEY FINDINGS: Vitamin D metabolites do not consistently influence replication or clearance of rhinovirus, respiratory syncytial virus (RSV) or influenza A virus in human respiratory epithelial cell culture, although they do modulate expression and secretion of type 1 interferon, chemokines including CXCL8 and CXCL10 and pro-inflammatory cytokines, such as TNF and IL-6. FUTURE RESEARCH: More studies are needed to clarify the effects of vitamin D metabolites on respiratory virus-induced expression of cell surface markers mediating viral entry and bacterial adhesion to respiratory epithelial cells. PMID- 26035248 TI - The potential for zinc stable isotope techniques and modelling to determine optimal zinc supplementation. AB - It is well recognised that zinc deficiency is a major global public health issue, particularly in young children in low-income countries with diarrhoea and environmental enteropathy. Zinc supplementation is regarded as a powerful tool to correct zinc deficiency as well as to treat a variety of physiologic and pathologic conditions. However, the dose and frequency of its use as well as the choice of zinc salt are not clearly defined regardless of whether it is used to treat a disease or correct a nutritional deficiency. We discuss the application of zinc stable isotope tracer techniques to assess zinc physiology, metabolism and homeostasis and how these can address knowledge gaps in zinc supplementation pharmacokinetics. This may help to resolve optimal dose, frequency, length of administration, timing of delivery to food intake and choice of zinc compound. It appears that long-term preventive supplementation can be administered much less frequently than daily but more research needs to be undertaken to better understand how best to intervene with zinc in children at risk of zinc deficiency. Stable isotope techniques, linked with saturation response and compartmental modelling, also have the potential to assist in the continued search for simple markers of zinc status in health, malnutrition and disease. PMID- 26035252 TI - Pulse Photoplethysmographic Analysis Estimates the Sympathetic Activity Directed to Heart and Vessels. AB - BACKGROUND: Novel pulse photoplethysmographic-derived indices have been proposed as tools to measure autonomic nervous system (ANS) modulation in anesthetized and awake patients, but nowadays their experimental validation is lacking. The authors aimed to investigate the ability of pulse photoplethysmographic amplitude (PPGA), ANS state (ANSS), and ANSS index (ANSSi) to measure changes of ANS modulation in response to sympathetic stimulation. METHODS: Ten awake healthy volunteers underwent two passive head-up tilts at 45 degrees and 90 degrees . The heart rate variability (HRV) and systolic arterial pressure variability were analyzed in the frequency domain as a measure of ANS modulation directed to the heart and the vessels. HRV, baroreflex sensitivity, and pulse photoplethysmographic indices were measured at baseline and after tilt maneuvers. The agreement between HRV-derived indices and pulse photoplethysmographic indices was assessed using Bland-Altman plots. RESULTS: PPGA, ANSS, and ANSSi changed significantly during the study protocol. Head-up tilt decreased PPGA and ANSS and increased ANNSi. There was a good agreement between ANSSi and baroreflex sensitivity explored in the high-frequency band (bias, 0.23; 95% CI, -22.7 to 23.2 normalized units) and between ANSSi and the sympathovagal modulation directed to the heart (bias, 0.96; 95% CI, -8.7 to 10.8 normalized units). CONCLUSIONS: In controlled experimental conditions, novel pulse plethysmographic indices seem to estimate the changes of the sympathetic outflow directed to the vessels and the sympathovagal balance modulating heart rate. These indices might be useful in the future to monitor the fluctuation of sympathetic activity in anesthetized patients. PMID- 26035253 TI - Effects of a T-type calcium channel blocker, ABT-639, on spontaneous activity in C-nociceptors in patients with painful diabetic neuropathy: a randomized controlled trial. AB - T-type calcium channels are a potential novel target for treatment of neuropathic pain such as painful diabetic neuropathy. ABT-639 is a peripherally acting highly selective T-type Ca(v)3.2 calcium channel blocker that has demonstrated analgesic efficacy in preclinical models and may have the potential to reduce spontaneous fiber activity. Microneurography is a unique technique that directly assesses the function of peripheral sensory afferents and measures abnormal spontaneous activity in single peripheral nociceptive C fibers. Abnormal spontaneous activity in C-nociceptors functions as a marker for spontaneous pain, as reduction of this activity could indicate analgesic efficacy. This randomized, double-blind controlled study evaluated the effects of a single 100-mg oral dose of ABT-639, compared with placebo, on abnormal spontaneous activity in peripheral C nociceptors, measured for the first time by microneurography in adult patients with painful diabetic neuropathy. Lidocaine was included in this study and compared with placebo. Pharmacokinetics and safety of ABT-639 were evaluated. Thirty-nine patients were randomized, and a total of 56 analyzable C-nociceptors with spontaneous activity were identified in 34 patients. There were no significant differences in C-nociceptor activities after ABT-639 treatment vs placebo. Similar findings were observed for lidocaine vs placebo. There were no clinically significant findings in the safety of ABT-639. Further research of T type Ca(v)3.2 calcium channels as potential treatment targets for painful diabetic neuropathy is warranted. The utilization of microneurography as a means to measure abnormal activity in C-nociceptors in human clinical studies opens new possibilities for future studies of compounds targeting peripheral nerve hyperexcitability. ClinicalTrials.gov identifier: NCT01589432. PMID- 26035254 TI - Distinct temporal filtering mechanisms are engaged during dynamic increases and decreases of noxious stimulus intensity. AB - Physical stimuli are subject to pronounced temporal filtering during afferent processing such that changes occurring at certain rates are amplified and others are diminished. Temporal filtering of nociceptive information remains poorly understood. However, the phenomenon of offset analgesia, where a disproportional drop in perceived pain intensity is caused by a slight drop in noxious heat stimulation, indicates potent temporal filtering in the pain pathways. To develop a better understanding of how dynamic changes in a physical stimulus are constructed into an experience of pain, a transfer function between the skin temperature and the perceived pain intensity was modeled. Ten seconds of temperature-controlled near-infrared (970 nm) laser stimulations above the pain threshold with a 1 degrees C increment, decrement, or constant temperature were applied to the dorsum of the hand of healthy human volunteers. The skin temperature was assessed by an infrared camera. Offset analgesia was evoked by laser heat stimulation. The estimated transfer functions showed shorter latencies when the temperature was increased by 1 degrees C (0.53 seconds [0.52-0.54 seconds]) than when decreased by 1 degrees C (1.15 seconds [1.12-1.18 seconds]) and smaller gains (increase: 0.89 [0.82-0.97]; decrease: 2.61 [1.91-3.31]). The maximal gain was observed at rates around 0.06 Hz. These results show that temperature changes occurring around 0.06 Hz are best perceived and that a temperature decrease is associated with a larger but slower change in pain perception than a comparable temperature increase. These psychophysical findings confirm the existence of differential mechanisms involved in temporal filtering of dynamic increases and decreases in noxious stimulus intensity. PMID- 26035256 TI - The "alpha" and "attending" case managers. AB - Case management has gone from episodic, to coordinating central arenas, to fragmentation, and back again. We must now-at least for complex, selected patients-look at a new (or old) method of case management. This column talks about traditional case management, use of an "alpha" case manager, and the "attending" case manager. PMID- 26035255 TI - Elotuzumab Therapy for Relapsed or Refractory Multiple Myeloma. AB - BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival. RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients. CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.). PMID- 26035257 TI - The new age of bullying and violence in health care: the interprofessional impact. AB - PURPOSE/OBJECTIVES: This article: 1. Explores the incidence, scope, and organizational impact of workplace bullying and violence. 2. Discusses implications for the industry's emerging interprofessional practice culture and case management are addressed, including the emergence of a new dimension of trauma for health care sector victims. 3. Reviews current initiatives and recommendations to empower professionals on their own journey to overturn this dangerous reality for the workforce. PRIMARY PRACTICE SETTINGS(S): Applicable to all health care sectors where case management is practiced. FINDINGS/CONCLUSION: Despite glaring improvements in how care is rendered and an enhanced focus on quality delivery of care, a glaring issue has emerged for immediate resolution: the elimination of workplace bullying and violence. The emerging regulatory and organizational initiatives to reframe the delivery of care will become meaningless if the continued level of violence among and against the health care workforce is allowed to continue. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Professionals who hesitate to confront and address incidents of disruptive and oppressive behavior in the health care workplace potentially practice unethically. Bullying has fostered a dangerous culture of silence in the industry, one that impacts patient safety, quality care delivery plus has longer term behavioral health implications for the professionals striving to render care. Add the escalating numbers specific to workplace violence and the trends speak to an atmosphere of safety and quality in the health care workplace, which puts patients and professionals at risk. PMID- 26035259 TI - Hearing the Veteran's Voice in Congestive Heart Failure Readmissions. AB - PURPOSE/OBJECTIVE: Our purpose was to examine congestive heart failure (CHF) readmissions from the veterans' perspective. The use of health care provider interventions, such as standardized education materials, home telehealth, and a CHF clinic, was able to reduce readmissions rates from 35% to 23%. Our objective was to use input from the veterans to fine-tune our efforts and achieve readmission rates for patients with CHF below the national average of 21%. We wanted to identify factors that result in CHF readmissions, including disease education, self-care management, and barriers to self-care. This study was directed toward answering two questions: 1. What is the veteran's explanation for readmission? 2. According to the veteran, what are the barriers to following their treatment regimen? PRIMARY PRACTICE SETTING: It was a rural 84-bed Veterans Health Administration hospital in the Western United States. FINDINGS: Before this study, our efforts to reduce CHF readmissions were one-sided, all from the health care professionals' viewpoint. We wanted to hear what the veteran had to say; so, we interviewed 25 veterans. Four veterans were excluded due to issues with their consents. Ninety percent (n = 19/21) responded that they knew their CHF was worse by a change in their breathing (shortness of breath). They identified 48 signs/symptoms that indicated worsening CHF. Weight gain was noted as an indication of worsening CHF symptoms (n = 6/48) in 12.5% of the responses. Twenty-five percent (n = 12/48) of the veterans stated they recognized the early symptoms of worsening CHF. Thirty-eight percent (n = 8/21) of the veterans stated they had early symptoms of worsening CHF, but only two of them contacted their doctor. It is interesting to note that only 29% (n = 6/21) of the veterans recognized weight gain as a sign of worsening CHF and all of these veterans listed other symptoms (such as shortness of breath) along with weight gain. Weighing on a daily basis was practiced by only 30% of the group (n = 7/21); all but two of the veterans had no problems with weighing themselves. More than 71% of the veterans responded that they had no problems following their diet or taking their medications. More than half of the veterans did not need help with meals, transportation, or daily grooming/dressing/toileting. CONCLUSIONS: We were concerned about the evident delays in seeking medical care for worsening CHF. All veterans who did need help with the activities of daily living, medications, or diet had their needs met through their support systems. They did not perceive any barriers to seeking care. However, there remain many unanswered questions. Does the patient understand their discharge education and know how to use this information from daily weights or recognition of early symptoms, to indicate their need for urgent and emergency medical interventions? Or is it a problem that the education is not sufficient? Is it a question of the burden of care from multiple comorbid conditions or of taking too many medications? Do social issues drive readmissions? These questions are further explored in a second study, which is in the data analysis stage. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: There are three key findings from our study. 1. Veterans think in terms of symptoms that increase the impact of CHF on their life. 2. The relationship between daily weight and controlling CHF is not clear to veterans. 3. Hospital discharge instructions should clearly associate symptoms that are associated with worsening CHF. PMID- 26035261 TI - Do collaborative case management models decrease hospital readmission rates among high-risk patients? AB - BACKGROUND: Case management provides a process and structure in health care systems that influence and control quality of care while reducing costs. A quality indicator of widespread concern is 30-day readmission of patients. There is significant initiative to drive down hospital readmission rates through development and/or redesign of case management models. PURPOSE: To examine the relationship of a collaborative case management model on hospital readmission rates among patients aged 65 years and older. METHODOLOGY AND SAMPLE: A retrospective chart review of patients discharged alive (n = 978) was conducted to evaluate and compare 2 care management models on hospital readmission rates. Demographic data, diagnosis, insurance carrier, admission source, discharge disposition, and incidence of readmission were collected using a structured data extraction tool. Logistic regression was used to identify predictors of readmission within 30 days of hospital discharge. RESULTS: The sample was elderly (mean age = 79.5 years), White (88.8%), and primarily female (60%). Mean length of stay between pre- and postmodel groups was not statistically different (p = .2). The model contained 6 independent variables (gender, payer, admission source, discharge disposition, diagnosis, and length of stay) and none were statistically significant, chi2 (1, n = 978) = 1.97, p = .58. The analysis indicates that group characteristics did not distinguish who would get readmitted on the basis of independent variables measured. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Age, gender, admit source, diagnosis, length of stay, and discharge disposition are not significant predictors of readmissions. Hospital case management programs may want to consider structuring processes to support patient adherence. Additional research is needed in this area. PMID- 26035262 TI - Kindness in a big business environment. PMID- 26035263 TI - Mandatory Reporting: Let's Clear Up the Confusion. PMID- 26035264 TI - Giving "holistic" answers to the question of "why": educating and empowering individuals at care transitions. PMID- 26035265 TI - E-ACTS: A Framework for Difficult Decision-Making. PMID- 26035266 TI - ? PMID- 26035267 TI - ? PMID- 26035268 TI - A Prognosis System for Periimplant Diseases. AB - INTRODUCTION: Periimplant diseases have slowly become a common complication in implant patients. Here, we present a prognosis system to aid clinicians and researchers in the evaluation and treatment of periimplant diseases. This prognosis system divides periimplant disease into favorable, questionable, unfavorable, and hopeless cases based on the level of bone loss, pocket depth, mobility, bleeding on probing, and suppuration. MATERIALS AND METHODS: To test the accuracy of our prognostic scale, the authors designed and conducted a database search to compile articles allowing for testing of the proposed prognostic scale. DISCUSSION: The literature search returned 101 articles, of which two reported all relevant values for the prognostic system and were used to evaluate its reliability and accuracy. The prognostic system correctly predicted the likely outcome of periimplant disease up to 1 year posttreatment for all examined implants. CONCLUSIONS: The proposed prognostic system can be used as a tool for clinicians as they develop a treatment plan for all stages of periimplant disease. PMID- 26035270 TI - Heart transplantation from donation after circulatory death donors. PMID- 26035271 TI - Somatic Cell-based Therapy. PMID- 26035272 TI - Nancy L. Ascher, MD, PhD: Professor and Chair, Department of Surgery, UCSF; Past President, ASTS; President-elect, The Transplantation Society. PMID- 26035273 TI - Program-specific Reports: A Guide to the Debate. PMID- 26035274 TI - Mesenchymal stromal cell therapy: different sources exhibit different immunobiological properties. PMID- 26035275 TI - Simultaneous liver-kidney transplantation from donation after cardiac death donors: is there a better way to use these organs? PMID- 26035276 TI - Utilization of donors after cardiac death organs for simultaneous liver and kidney transplantation. PMID- 26035277 TI - Can patients maintain their use of everolimus until lung transplantation? PMID- 26035278 TI - Effectiveness of the Middle East respiratory syndrome-coronavirus protocol in enhancing the function of an Emergency Department in Qatar. AB - OBJECTIVE: This study aimed to investigate the effectiveness of a Middle East respiratory syndrome coronavirus (MERS-CoV) surveillance protocol in the Emergency Department (ED) at Hamad General Hospital. Effectiveness was measured by: (a) reduction in the number of patients admitted into the MERS-CoV tracking system; (b) identification of positive MERS-CoV cases; (c) containment of cross infectivity; and (d) increased efficiency in ED functioning. METHODS: A retrospective chart review was carried out of all ED patients suspected of MERS CoV during the height of the epidemic (August to October 2013). An algorithm was created on the basis of international guidelines to screen and triage suspected MERS-CoV patients. Once identified, patients were isolated, had a chest roentgenogram [chest radiography (CXR)] taken, and a nasopharyngeal swab for polymerase chain reaction (PCR) was sent with sputum samples for testing. Patients with normal CXR and mild respiratory symptoms were discharged with home isolation instructions until nasopharyngeal and sputum PCR results were available. Patients with fever and acute respiratory distress, with or without abnormal CXR, were treated in the hospital until tests proved negative for MERS CoV. RESULTS: The protocol successfully reduced the number of patients who needed to be tested for MERS-CoV from 12,563 to 514, identified seven positive cases, and did not lead to apparent cross infectivity that resulted in serious illness or death. The protocol also increased the efficiency of ED and cut the turnaround time for nasopharyngeal swab and sputum results from 3 days to 1 day. CONCLUSION: A highly protocolized surveillance system limited the impact of MERS-CoV on ED functioning by identifying and prioritizing high-risk patients. The emergence of new infectious diseases requires constant monitoring of interventions to reduce the impact of epidemics on population health and health services. PMID- 26035279 TI - A Case Study of the Environmental Experience of a Hospitalized Newborn Infant With Complex Congenital Heart Disease. AB - BACKGROUND: Infants with complex congenital heart disease are at high risk for developmental delays. Although the etiology of these delays is multifactorial, the physical environment may be a contributory factor. Extensive studies have been conducted in neonatal intensive care units measuring environmental influences on development, resulting in policy and practice changes. Cardiothoracic intensive care units and cardiac step-down units are new environments in which newborns with heart disease receive care. No environmental studies have been conducted in units caring for newborn infants recovering from cardiac surgery. OBJECTIVE: The aim of this study is to examine the environmental experience of a newborn infant with heart disease after surgical intervention within the first month of life. METHODS: Measurements of illumination, sound levels, and sleep were recorded on 1 infant for 2 consecutive postoperative days in the cardiothoracic intensive care unit and 2 consecutive days in the step-down unit. RESULTS: Although average daily noise exposure remained below recommended guidelines on 3 of 4 days, the infant experienced intermittent periods of excessive noise (>=55 dBA) during 59 of 87 hours and 110 episodes of acute noise events greater than 70 dBA. Average daily light exposure was below the recommended guidelines. However, light levels were more than twice the recommended levels at multiple points daily. For each of the 4 observation days, the infant experienced 66 to 102 awakenings during sleep, and sleep durations were less than 30 minutes 90% of the time. CONCLUSIONS: This study provides the first report of potential environmental stressors in newborn infants cared for in cardiac specialty units. Excessive levels of light and noise as well as frequent interruptions for medical and nursing care may contribute to disorganized sleep and increased patient distress and may impact subsequent neurodevelopment. Studies are needed to identify potentially adverse aspects of the intensive caregiving environment for newborn infants who have undergone cardiac surgery. PMID- 26035281 TI - Quantitative electroencephalography analysis in university students with hazardous alcohol consumption, but not alcohol dependence. AB - Hazardous alcohol consumption is a pattern of consumption that leads to a higher risk of harmful consequences either for the user or for others. This pattern of alcohol consumption has been linked to risky behaviors, accidents, and injuries. Individuals with hazardous alcohol consumption do not necessarily present alcohol dependence; thus, a study of particular neurophysiological correlates of this alcohol consumption pattern needs to be carried out in nondependent individuals. Here, we carried out a quantitative electroencephalography analysis in health sciences university students with hazardous alcohol consumption, but not alcohol dependence (HAC), and control participants without hazardous alcohol consumption or alcohol dependence (NHAC). We analyzed Absolute Power (AP), Relative Power (RP), and Mean Frequency (MF) for beta and theta frequency bands under both eyes closed and eyes open conditions. We found that participants in the HAC group presented higher beta AP at centroparietal region, as well as lower beta MF at frontal and centroparietal regions in the eyes closed condition. Interestingly, participants did not present any change in theta activity (AP, RP, or MF), whereas previous reports indicate an increase in theta AP in alcohol-dependent individuals. Our results partially resemble those found in alcohol-dependent individuals, although are not completely identical, suggesting a possible difference in the underlying neuronal mechanism behind alcohol dependence and hazardous alcohol consumption. Similarities could be explained considering that both hazardous alcohol consumption and alcohol dependence are manifestations of behavioral disinhibition. PMID- 26035280 TI - New Insights Into Multicenter PICU Mortality Among Pediatric Hematopoietic Stem Cell Transplant Patients. AB - OBJECTIVES: Over 2,500 children undergo hematopoietic stem cell transplantation in the United States each year, and up to 35% require PICU support for life threatening complications. PICU mortality has dropped from 85% to 44%, but interpretation is confounded by significant cohort heterogeneity. Reports conflict regarding outcomes for patients with different underlying hematopoietic stem cell transplantation indications, and the burden of infectious complications for these patients has not been evaluated. We aim to describe infections, critical care interventions, and mortality for pediatric hematopoietic stem cell transplantation patients requiring PICU admission. DESIGN: A retrospective multicenter cohort analysis. SETTING: One hundred twelve centers in the Virtual PICU Systems database, January 1, 2009, to June 30, 2012. PATIENTS: A total of 1,782 admissions for patients who are 21 years old or younger with prior hematopoietic stem cell transplantation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Pediatric Index of Mortality-2, Pediatric Risk of Mortality-3, transplant indication, infections, interventions, and mortality were recorded from admission through PICU death or discharge. Pediatric hematopoietic stem cell transplantation patients comprised 0.7% of all PICU admissions (1,782/246,346), which resulted in 16.2% mortality compared with 2.4% mortality for non hematopoietic stem cell transplantation admissions (odds ratio, 7.8; 95% CI, 6.8 8.8; p < 0.001). Mortality for admissions with underlying hematologic malignancy (22.7%) was similar to that of admissions with primary immunodeficiency (19.4%; p = 0.41) but significantly greater than admissions with underlying nonmalignant non-primary immunodeficiency hematologic disease (15.4%; p = 0.020), metabolic disorder (8.1%; p < 0.001), or solid malignancy (5.7%; p < 0.001). Infection was documented in 45.7% of admissions with 22.2% mortality; viral and fungal mortality were 28.5% and 33.7%, respectively. Invasive positive pressure ventilation and renal replacement therapy were used in only 34.6% and 11.9% of admissions, with mortality of 42.5% and 51.9%, respectively. CONCLUSIONS: PICU mortality for pediatric hematopoietic stem cell transplantation patients may be as low as 16.2% but higher for those receiving intubation (42.5%) or replacement therapy (51.9%). Hematologic malignancy and primary immunodeficiency had greater risk for mortality than other transplant indications. Greater understanding of other risk factors affecting mortality and the need for critical care support is needed. PMID- 26035282 TI - Well-temperate phage: optimal bet-hedging against local environmental collapses. AB - Upon infection of their bacterial hosts temperate phages must chose between lysogenic and lytic developmental strategies. Here we apply the game-theoretic bet-hedging strategy introduced by Kelly to derive the optimal lysogenic fraction of the total population of phages as a function of frequency and intensity of environmental downturns affecting the lytic subpopulation. "Well-temperate" phage from our title is characterized by the best long-term population growth rate. We show that it is realized when the lysogenization frequency is approximately equal to the probability of lytic population collapse. We further predict the existence of sharp boundaries in system's environmental, ecological, and biophysical parameters separating the regions where this temperate strategy is optimal from those dominated by purely virulent or dormant (purely lysogenic) strategies. We show that the virulent strategy works best for phages with large diversity of hosts, and access to multiple independent environments reachable by diffusion. Conversely, progressively more temperate or even dormant strategies are favored in the environments, that are subject to frequent and severe temporal downturns. PMID- 26035284 TI - Body image in persons with gender dysphoria. AB - BACKGROUND: For subjects with gender dysphoria, body image is an important aspect of their condition. These people sometimes exhibit a strong desire to change their primary and secondary sexual characteristics. In addition, idealization of beauty has grown in importance and it may increase body dissatisfaction. The aim of this paper is to analyze whether body dissatisfaction in people with gender dysphoria is similar to that in clinical population or if it is more similar to that which may appear in general population. We also looked at gender differences in body dissatisfaction. METHODS: A set of questionnaires was administered to patients with gender dysphoria: Eating Attitudes Test (EAT- 26), body dissatisfaction sub-scale of Eating disorder inventory-two (EDI-2) and IMAGEN questionnaire. RESULTS: In the case of body dissatisfaction subscale of Eating disorder inventory-two with a cut-off 11; body dissatisfaction in our sample was close to the level presented in clinical population. However, using cut-off points 14 and 16, they exhibited a body dissatisfaction level that was similar to the general population. The same occurred for the IMAGEN questionnaire. No gender differences were found when looking at the level of dissatisfaction. CONCLUSIONS: The data seem to indicate that people with gender dysphoria would be at an intermediate point in relation to body dissatisfaction between general population and clinical population; in both female and male transsexuals. It seems that some level of body dissatisfaction may be perceived in relation to the ideal of beauty, but this dissatisfaction is significantly lower than in clinical populations. PMID- 26035283 TI - CRISPR/Cas9 cleavage of viral DNA efficiently suppresses hepatitis B virus. AB - Chronic hepatitis B virus (HBV) infection is prevalent, deadly, and seldom cured due to the persistence of viral episomal DNA (cccDNA) in infected cells. Newly developed genome engineering tools may offer the ability to directly cleave viral DNA, thereby promoting viral clearance. Here, we show that the CRISPR/Cas9 system can specifically target and cleave conserved regions in the HBV genome, resulting in robust suppression of viral gene expression and replication. Upon sustained expression of Cas9 and appropriately chosen guide RNAs, we demonstrate cleavage of cccDNA by Cas9 and a dramatic reduction in both cccDNA and other parameters of viral gene expression and replication. Thus, we show that directly targeting viral episomal DNA is a novel therapeutic approach to control the virus and possibly cure patients. PMID- 26035285 TI - A Mesozoic bird from Gondwana preserving feathers. AB - The fossil record of birds in the Mesozoic of Gondwana is mostly based on isolated and often poorly preserved specimens, none of which has preserved details on feather anatomy. We provide the description of a fossil bird represented by a skeleton with feathers from the Early Cretaceous of Gondwana (NE Brazil). The specimen sheds light on the homology and 3D structure of the rachis dominated feathers, previously known from two-dimensional slabs. The rectrices exhibit a row of rounded spots, probably corresponding to some original colour pattern. The specimen supports the identification of the feather scapus as the rachis, which is notably robust and elliptical in cross-section. In spite of its juvenile nature, the tail plumage resembles the feathering of adult individuals of modern birds. Documentation of rachis-dominated tail in South American enantiornithines broadens the paleobiogeographic distribution of basal birds with this tail feather morphotype, up to now only reported from China. PMID- 26035286 TI - Short-wavelength infrared photodetector on Si employing strain-induced growth of very tall InAs nanowire arrays. AB - One-dimensional crystal growth enables the epitaxial integration of III-V compound semiconductors onto a silicon (Si) substrate despite significant lattice mismatch. Here, we report a short-wavelength infrared (SWIR, 1.4-3 MUm) photodetector that employs InAs nanowires (NWs) grown on Si. The wafer-scale epitaxial InAs NWs form on the Si substrate without a metal catalyst or pattern assistance; thus, the growth is free of metal-atom-induced contaminations, and is also cost-effective. InAs NW arrays with an average height of 50 MUm provide excellent anti-reflective and light trapping properties over a wide wavelength range. The photodetector exhibits a peak detectivity of 1.9 * 10(8) cm . Hz(1/2)/W for the SWIR band at 77 K and operates at temperatures as high as 220 K. The SWIR photodetector on the Si platform demonstrated in this study is promising for future low-cost optical sensors and Si photonics. PMID- 26035287 TI - Psychological distress and stressful life events in pediatric complex regional pain syndrome. AB - BACKGROUND: There is little knowledge regarding the association between psychological factors and complex regional pain syndrome (CRPS) in children. Specifically, it is not known which factors precipitate CRPS and which result from the ongoing painful disease. OBJECTIVES: To examine symptoms of depression and anxiety as well as the experience of stressful life events in children with CRPS compared with children with chronic primary headaches and functional abdominal pain. METHODS: A retrospective chart study examined children with CRPS (n=37) who received intensive inpatient pain treatment between 2004 and 2010. They were compared with two control groups (chronic primary headaches and functional abdominal pain; each n=37), who also received intensive inpatient pain treatment. Control groups were matched with the CRPS group with regard to admission date, age and sex. Groups were compared on symptoms of depression and anxiety as well as stressful life events. RESULTS: Children with CRPS reported lower anxiety and depression scores compared with children with abdominal pain. A higher number of stressful life events before and after the onset of the pain condition was observed for children with CRPS. CONCLUSIONS: Children with CRPS are not particularly prone to symptoms of anxiety or depression. Importantly, children with CRPS experienced more stressful life events than children with chronic headaches or abdominal pain. Prospective long-term studies are needed to further explore the potential role of stressful life events in the etiology of CRPS. PMID- 26035288 TI - Temperature dependence of electrical and thermal conduction in single silver nanowire. AB - In this work, the thermal and electrical transport in an individual silver nanowire is characterized down to 35 K for in-depth understanding of the strong structural defect induced electron scattering. The results indicate that, at room temperature, the electrical resistivity increases by around 4 folds from that of bulk silver. The Debye temperature (151 K) of the silver nanowire is found 36% lower than that (235 K) of bulk silver, confirming strong phonon softening. At room temperature, the thermal conductivity is reduced by 55% from that of bulk silver. This reduction becomes larger as the temperature goes down. To explain the opposite trends of thermal conductivity (kappa) ~ temperature (T) of silver nanowire and bulk silver, a unified thermal resistivity (Theta ~ T/k ) is used to elucidate the electron scattering mechanism. A large residual Theta is observed for silver nanowire while that of the bulk silver is almost zero. The same Theta ~ T trend proposes that the silver nanowire and bulk silver share the similar phonon-electron scattering mechanism for thermal transport. Due to phonon assisted electron energy transfer across grain boundaries, the Lorenz number of the silver nanowire is found much larger than that of bulk silver and decreases with decreasing temperature. PMID- 26035289 TI - Understanding the role of work in socioeconomic health inequalities. PMID- 26035290 TI - The role of Hurst exponent on cold field electron emission from conducting materials: from electric field distribution to Fowler-Nordheim plots. AB - This work considers the effects of the Hurst exponent (H) on the local electric field distribution and the slope of the Fowler-Nordheim (FN) plot when considering the cold field electron emission properties of rough Large-Area Conducting Field Emitter Surfaces (LACFESs). A LACFES is represented by a self affine Weierstrass-Mandelbrot function in a given spatial direction. For 0.1 <= H < 0.5, the local electric field distribution exhibits two clear exponential regimes. Moreover, a scaling between the macroscopic current density (JM) and the characteristic kernel current density (JkC), JM ~ [JkC]betaH, with an H-dependent exponent betaH > 1, has been found. This feature, which is less pronounced (but not absent) in the range where more smooth surfaces have been found (0.5 <= H <= 0.9), is a consequence of the dependency between the area efficiency of emission of a LACFES and the macroscopic electric field, which is often neglected in the interpretation of cold field electron emission experiments. Considering the recent developments in orthodox field emission theory, we show that the exponent betaH must be considered when calculating the slope characterization parameter (SCP) and thus provides a relevant method of more precisely extracting the characteristic field enhancement factor from the slope of the FN plot. PMID- 26035291 TI - Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study. AB - BACKGROUND: Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. METHODS AND FINDINGS: KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 MUg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was -5.36 * 10(-2) (95% CI, -8.27 * 10(-2) to -2.44 * 10(-2); ES = 0.49, p < 0.001) and for the anxiety subscale was -3.01 * 10(-2) (95% CI, -5.09 * 10(-2) to -9.34 * 10(-3); ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. CONCLUSIONS: The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. TRIAL REGISTRATION: ClinicalTrials.gov NCT00154180 and NCT00623311. PMID- 26035293 TI - Amorphastilbol exerts beneficial effects on glucose and lipid metabolism in mice consuming a high-fat-diet. AB - In the present study, the anti-diabetic effects of amorphastilbol (APH) from Amorpha fruticosa (AF) were evaluated in high-fat-diet (HFD) mice. HFD-induced blood glucose and insulin levels are significantly reduced in AF extract or APH treatment groups. HFD-induced weight gain was reduced by AF treatment, which is accompanied by reduction of fat mass and adipocyte size and number in white adipose tissues. Furthermore, total cholesterol and low-density lipoprotein cholesterol levels are decreased in AF- or APH-treated mice. In addition, AF and APH are able to improve insulin sensitivity through inhibition of protein tyrosine phosphatase 1B, a negative regulator of the insulin-signaling pathway. Taken together, the data suggest that AF has beneficial effects on glucose and lipid metabolism and its pharmacological effects are driven, in part, by its active component, APH. Therefore, AF and APH can be used as potential therapeutic agents against type 2 diabetes and associated metabolic disorders, including obesity, by enhancing glucose and lipid metabolism. PMID- 26035294 TI - How are physical activity behaviors and cardiovascular risk factors associated with characteristics of the built and social residential environment? AB - BACKGROUND: The aim of our study was to identify perceptions of built and social residential characteristics and their association with behaviors such as physical activity (PA), nutrition and smoking and with cardiovascular risk factors (elevated BMI and fasting blood glucose). METHODS: Among participants of a preventive medical checkup at an Austrian District Health Insurance Fund (n=904, response rate = 82.2%, 42% women, 18-91 years) self-reported and measured data were collected. RESULTS: Total PA was positively associated with the presence of trees along the streets and high levels of pro-physical activity social modeling (SM) and it was negatively related to perceived safety from crime. More leisure time PA was associated with higher levels of cycling/walking infrastructure and high levels of SM. PA for transportation was positively related to high levels of connectivity and high levels of SM. Better behavioral cardiovascular risk factor profiles (smoking and nutrition) were associated with high levels of SM and high levels of total PA. Lower BMI values were associated with high levels of infrastructure and high levels of SM. CONCLUSIONS: Both built and social residential characteristics are important correlates of PA as well as of major cardiovascular risk factors besides PA. PMID- 26035295 TI - To Be or Not to Be a Pseudogene: A Molecular Epidemiological Approach to the mclx Genes and Its Impact in Tuberculosis. AB - Tuberculosis presents a myriad of symptoms, progression routes and propagation patterns not yet fully understood. Whereas for a long time research has focused solely on the patient immunity and overall susceptibility, it is nowadays widely accepted that the genetic diversity of its causative agent, Mycobacterium tuberculosis, plays a key role in this dynamic. This study focuses on a particular family of genes, the mclxs (Mycobacterium cyclase/LuxR-like genes), which codify for a particular and nearly mycobacterial-exclusive combination of protein domains. mclxs genes were found to be pseudogenized by frameshift-causing insertion(s)/deletion(s) in a considerable number of M. tuberculosis complex strains and clinical isolates. To discern the functional implications of the pseudogenization, we have analysed the pattern of frameshift-causing mutations in a group of M. tuberculosis isolates while taking into account their microbial-, patient- and disease-related traits. Our logistic regression-based analyses have revealed disparate effects associated with the transcriptional inactivation of two mclx genes. In fact, mclx2 (Rv1358) pseudogenization appears to be primarily driven by the microbial phylogenetic background, being mainly related to the Euro American (EAm) lineage; on the other hand, mclx3 (Rv2488c) presents a higher tendency for pseudogenization among isolates from patients born on the Western Pacific area, and from isolates causing extra-pulmonary infections. These results contribute to the overall knowledge on the biology of M. tuberculosis infection, whereas at the same time launch the necessary basis for the functional assessment of these so far overlooked genes. PMID- 26035292 TI - Regulation of expression of O6-methylguanine-DNA methyltransferase and the treatment of glioblastoma (Review). AB - O-6-methylguanine-DNA methyltransferase (MGMT) is an abundantly expressed nuclear protein dealkylating O6-methylguanine (O6-MG) DNA residue, thus correcting the mismatches of O6-MG with a thymine residue during DNA replication. The dealkylating effect of MGMT is relevant not only in repairing DNA mismatches produced by environmental alkylating agents promoting tumor pathogenesis, but also when alkylating molecules are applied in the chemotherapy of different cancers, including glioma, the most common primary tumor of the central nervous system. Elevated MGMT gene expression is known to confer resistance to the treatment with the alkylating drug temozolomide in patients affected by gliomas and, on the contrary, methylation of MGMT gene promoter, which causes reduction of MGMT protein expression, is known to predict a favourable response to temozolomide. Thus, detecting expression levels of MGMT gene is crucial to indicate the option of alkylating agents or to select patients directly for a second line targeted therapy. Further study is required to gain insights into MGMT expression regulation, that has attracted growing interest recently in MGMT promoter methylation, histone acetylation and microRNAs expression. The review will focus on the epigenetic regulation of MGMT gene, with translational applications to the identification of biomarkers predicting response to therapy and prognosis. PMID- 26035296 TI - Detection and identification of pathogenic trypanosome species in tsetse flies along the Comoe River in Cote d'Ivoire. AB - In order to identify pathogenic trypanosomes responsible for African trypanosomiasis, and to better understand tsetse-trypanosome relationships, surveys were undertaken in three sites located in different eco-climatic areas in Cote d'Ivoire during the dry and rainy seasons. Tsetse flies were caught during five consecutive days using biconical traps, dissected and microscopically examined looking for trypanosome infection. Samples from infected flies were tested by PCR using specific primers for Trypanosoma brucei s.l., T. congolense savannah type, T. congolense forest type and T. vivax. Of 1941 tsetse flies caught including four species, i.e. Glossina palpalis palpalis, G. p. gambiensis, G. tachinoides and G. medicorum, 513 (26%) were dissected and 60 (12%) were found positive by microscopy. Up to 41% of the infections were due to T. congolense savannah type, 30% to T. vivax, 20% to T. congolense forest type and 9% due to T. brucei s.l. All four trypanosome species and subgroups were identified from G. tachinoides and G. p. palpalis, while only two were isolated from G. p. gambiensis (T. brucei s.l., T. congolense savannah type) and G. medicorum (T. congolense forest, savannah types). Mixed infections were found in 25% of cases and all involved T. congolense savannah type with another trypanosome species. The simultaneous occurrence of T. brucei s.l., and tsetse from the palpalis group may suggest that human trypanosomiasis can still be a constraint in these localities, while high rates of T. congolense and T. vivax in the area suggest a potential risk of animal trypanosomiasis in livestock along the Comoe River. PMID- 26035297 TI - Disease Containment Strategies based on Mobility and Information Dissemination. AB - Human mobility and social structure are at the basis of disease spreading. Disease containment strategies are usually devised from coarse-grained assumptions about human mobility. Cellular networks data, however, provides finer grained information, not only about how people move, but also about how they communicate. In this paper we analyze the behavior of a large number of individuals in Ivory Coast using cellular network data. We model mobility and communication between individuals by means of an interconnected multiplex structure where each node represents the population in a geographic area (i.e., a sous-prefecture, a third-level administrative region). We present a model that describes how diseases circulate around the country as people move between regions. We extend the model with a concurrent process of relevant information spreading. This process corresponds to people disseminating disease prevention information, e.g., hygiene practices, vaccination campaign notices and other, within their social network. Thus, this process interferes with the epidemic. We then evaluate how restricting the mobility or using preventive information spreading process affects the epidemic. We find that restricting mobility does not delay the occurrence of an endemic state and that an information campaign might be an effective countermeasure. PMID- 26035298 TI - Integrated analysis of DNA methylation and microRNA regulation of the lung adenocarcinoma transcriptome. AB - Lung adenocarcinoma, as a common type of non-small cell lung cancer (40%), poses a significant threat to public health worldwide. The present study aimed to determine the transcriptional regulatory mechanisms in lung adenocarcinoma. Illumina sequence data GSE 37764 including expression profiling, methylation profiling and non-coding RNA profiling of 6 never-smoker Korean female patients with non-small cell lung adenocarcinoma were obtained from the Gene Expression Omnibus (GEO) database. Differentially methylated genes, differentially expressed genes (DEGs) and differentially expressed microRNAs (miRNAs) between normal and tumor tissues of the same patients were screened with tools in R. Functional enrichment analysis of a variety of differential genes was performed. DEG specific methylation and transcription factors (TFs) were analyzed with ENCODE ChIP-seq. The integrated regulatory network of DEGs, TFs and miRNAs was constructed. Several overlapping DEGs, such as v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) were screened. DEGs were centrally modified by histones of tri-methylation of lysine 27 on histone H3 (H3K27me3) and di acetylation of lysine 12 or 20 on histone H2 (H2BK12/20AC). Upstream TFs of DEGs were enriched in different ChIP-seq clusters, such as glucocorticoid receptors (GRs). Two miRNAs (miR-126-3p and miR-30c-2-3p) and three TFs including homeobox A5 (HOXA5), Meis homeobox 1 (MEIS1) and T-box 5 (TBX5), played important roles in the integrated regulatory network conjointly. These DEGs, and DEG-related histone modifications, TFs and miRNAs may be important in the pathogenesis of lung adenocarcinoma. The present results may indicate directions for the next step in the study of the further elucidation and targeted prevention of lung adenocarcinoma. PMID- 26035299 TI - DBC1 promotes anoikis resistance of gastric cancer cells by regulating NF-kappaB activity. AB - Deleted in breast cancer 1 (DBC1) has been known to be overexpressed and serves as a poor prognostic indicator of several human cancers. In this study, we examined DBC1 expression in a total of 142 gastric cancer tissues by immunohistochemistry and revealed that DBC1 was overexpressed in gastric cancer and significantly associated with TNM stage and lymph node metastasis. The in vitro experiments showed that DBC1 expression correlated with the ability of anoikis resistance in gastric cancer cells, which has been defined as critical to metastasis. Furthermore, the results showed that the IKK-beta/NF-kappaB signaling pathway was involved in the regulation of anoikis resistance by DBC1 in gastric cancer cells. Taken together, the results indicated that DBC1 promotes anoikis resistance in gastric cancer cells by regulating NF-kappaB activity and may thus be a new therapeutic target for preventing potential metastasis. PMID- 26035300 TI - Rapid evolution of parasite resistance in a warmer environment: insights from a large scale field experiment. AB - Global climate change is expected to have major effects on host-parasite dynamics, with potentially enormous consequences for entire ecosystems. To develop an accurate prognostic framework, theoretical models must be supported by empirical research. We investigated potential changes in host-parasite dynamics between a fish parasite, the eyefluke Diplostomum baeri, and an intermediate host, the European perch Perca fluviatilis, in a large-scale semi-enclosed area in the Baltic Sea, the Biotest Lake, which since 1980 receives heated water from a nuclear power plant. Two sample screenings, in two consecutive years, showed that fish from the warmer Biotest Lake were now less parasitized than fish from the Baltic Sea. These results are contrasting previous screenings performed six years after the temperature change, which showed the inverse situation. An experimental infection, by which perch from both populations were exposed to D. baeri from the Baltic Sea, revealed that perch from the Baltic Sea were successfully infected, while Biotest fish were not. These findings suggest that the elevated temperature may have resulted, among other outcomes, in an extremely rapid evolutionary change through which fish from the experimental Biotest Lake have gained resistance to the parasite. Our results confirm the need to account for both rapid evolutionary adaptation and biotic interactions in predictive models, and highlight the importance of empirical research in order to validate future projections. PMID- 26035301 TI - Genetic Structure and Relationship Analysis of an Association Population in Jute (Corchorus spp.) Evaluated by SSR Markers. AB - Population structure and relationship analysis is of great importance in the germplasm utilization and association mapping. Jute, comprised of white jute (C. capsularis L) and dark jute (C. olitorius L), is second to cotton in its commercial significance in the world. Here, we assessed the genetic structure and relationship in a panel of 159 jute accessions from 11 countries and regions using 63 SSRs. The structure analysis divided the 159 jute accessions from white and dark jute into Co and Cc group, further into Co1, Co2, Cc1 and Cc2 subgroups. Out of Cc1 subgroup, 81 accessions were from China and the remaining 10 accessions were from India (2), Japan (5), Thailand, Vietnam (2) and Pakistan (1). Out of Cc2 subgroup, 35 accessions were from China, and the remaining 3 accessions were from India, Pakistan and Thailand respectively. It can be inferred that the genetic background of these jute accessions was not always correlative with their geographical regions. Similar results were found in Co1 and Co2 subgroups. Analysis of molecular variance revealed 81% molecular variation between groups but it was low (19%) within subgroups, which further confirmed the genetic differentiation between the two groups. The genetic relationship analysis showed that the most diverse genotypes were Maliyeshengchangguo and Changguozhongyueyin in dark jute, BZ-2-2, Aidianyehuangma, Yangjuchiyuanguo, Zijinhuangma and Jute 179 in white jute, which could be used as the potential parents in breeding programs for jute improvement. These results would be very useful for association studies and breeding in jute. PMID- 26035302 TI - Proteomic Analysis of Drug-Resistant Mycobacteria: Co-Evolution of Copper and INH Resistance. AB - Tuberculosis, caused by the pathogen Mycobacterium tuberculosis, is a worldwide public health threat. Mycobacterium tuberculosis is capable of resisting various stresses in host cells, including high levels of ROS and copper ions. To better understand the resistance mechanisms of mycobacteria to copper, we generated a copper-resistant strain of Mycobacterium smegmatis, mc2155-Cu from the selection of copper sulfate treated-bacteria. The mc2155-Cu strain has a 5-fold higher resistance to copper sulfate and a 2-fold higher resistance to isoniazid (INH) than its parental strain mc2155, respectively. Quantitative proteomics was carried out to find differentially expressed proteins between mc2155 and mc2155 Cu. Among 345 differentially expressed proteins, copper-translocating P-type ATPase was up-regulated, while all other ABC transporters were down-regulated in mc2155-Cu, suggesting copper-translocating P-type ATPase plays a crucial role in copper resistance. Results also indicated that the down-regulation of metabolic enzymes and decreases in cellular NAD, FAD, mycothiol, and glutamine levels in mc2155-Cu were responsible for its slowing growth rate as compared to mc2155. Down-regulation of KatG2 expression in both protein and mRNA levels indicates the co-evolution of copper and INH resistance in copper resistance bacteria, and provides new evidence to understanding of the molecular mechanisms of survival of mycobacteria under stress conditions. PMID- 26035303 TI - Handheld lasers allow efficient detection of fluorescent marked organisms in the field. AB - Marking organisms with fluorescent dyes and powders is a common technique used in ecological field studies that monitor movement of organisms to examine life history traits, behaviors, and population dynamics. External fluorescent marking is relatively inexpensive and can be readily employed to quickly mark large numbers of individuals; however, the ability to detect marked organisms in the field at night has been hampered by the limited detection distances provided by portable fluorescent ultraviolet lamps. In recent years, significant advances in LED lamp and laser technology have led to development of powerful, low-cost ultraviolet light sources. In this study, we evaluate the potential of these new technologies to improve detection of fluorescent-marked organisms in the field and to create new possibilities for tracking marked organisms in visually challenging environments such as tree canopies and aquatic habitats. Using handheld lasers, we document a method that provides a fivefold increase in detection distance over previously available technologies. This method allows easy scouting of tree canopies (from the ground), as well as shallow aquatic systems. This novel detection method for fluorescent-marked organisms thus promises to significantly enhance the use of fluorescent marking as a non destructive technique for tracking organisms in natural environments, facilitating field studies that aim to document otherwise inaccessible aspects of the movement, behavior, and population dynamics of study organisms, including species with significant economic impacts or relevance for ecology and human health. PMID- 26035304 TI - Is there a threshold concentration of cat allergen exposure on respiratory symptoms in adults? AB - BACKGROUND AND OBJECTIVE: Cat allergen concentrations higher than 8 MUg/g in settled house dust, have been suggested to provoke exacerbation of allergic respiratory symptoms. However, whether the 8 MUg/g of indoor cat allergen concentration is indeed the minimal exposure required for triggering the asthma related respiratory symptoms or the development of sensitization has not yet been confirmed. We studied the associations between domestic cat allergen concentrations and allergic symptoms in the European Community Respiratory Health Survey II, with the aim of confirming this suggested threshold. METHODS: Cat allergen concentrations were measured in the mattress dust of 3003 participants from 22 study centres. Levels of specific immunoglobulin E to cat allergens were measured in serum samples using an immunoassay. Information on allergic symptoms, medication use, home environment and smoking was obtained from a face-to-face interview. RESULTS: Domestic cat allergen concentrations were not associated with allergic/ asthmatic symptoms in the entire study population, nor in the subset sensitized to cat allergen. We also found no association among individuals exposed to concentrations higher than 8 MUg/g. However, exposure to medium cat allergen concentrations (0.24-0.63 MUg/g) was positively associated with reported asthmatic respiratory symptoms in subjects who have experienced allergic symptoms when near animals. CONCLUSIONS: The proposed 8 MUg/g threshold of cat allergen concentrations for the exacerbation of allergic/ respiratory symptoms was not confirmed in a general European adult population. Potential biases attributable to avoidance behaviours and an imprecise exposure assessment cannot be excluded. PMID- 26035305 TI - Magnetic criteria of aromaticity. AB - This review describes the current state of magnetic criteria of aromaticity. The introduction contains the fundamentals of ring currents in aromatic and antiaromatic systems, followed by a brief description of experimental and computational tools: NMR, diamagnetic susceptibility exaltation, current density analyses (CDA) and nucleus independent chemical shifts (NICS). This is followed by more comprehensive chapters: NMR - focusing on the work of R. Mitchell - NICS and CDA - describing the progress and development of the methods to their current state and presenting some examples of representative work. PMID- 26035306 TI - Genetic variants in DNA double-strand break repair genes and risk of salivary gland carcinoma: a case-control study. AB - DNA double strand break (DSB) repair is the primary defense mechanism against ionizing radiation-induced DNA damage. Ionizing radiation is the only established risk factor for salivary gland carcinoma (SGC). We hypothesized that genetic variants in DSB repair genes contribute to individual variation in susceptibility to SGC. To test this hypothesis, we conducted a case-control study in which we analyzed 415 single nucleotide polymorphisms (SNPs) in 45 DSB repair genes in 352 SGC cases and 598 controls. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Rs3748522 in RAD52 and rs13180356 in XRCC4 were significantly associated with SGC after Bonferroni adjustment; ORs (95% CIs) for the variant alleles of these SNPs were 1.71 (1.40-2.09, P = 1.70 * 10(-7)) and 0.58 (0.45-0.74, P = 2.00 * 10(-5)) respectively. The genetic effects were modulated by histological subtype. The association of RAD52-rs3748522 with SGC was strongest for mucoepidermoid carcinoma (OR = 2.21, 95% CI: 1.55-3.15, P = 1.25 * 10(-5), n = 74), and the association of XRCC4-rs13180356 with SGC was strongest for adenoid cystic carcinoma (OR = 0.60, 95% CI: 0.42-0.87, P = 6.91 * 10(-3), n = 123). Gene-level association analysis revealed one gene, PRKDC, with a marginally significant association with SGC risk in non-Hispanic whites. To our knowledge, this study is the first to comprehensively evaluate the genetic effect of DSB repair genes on SGC risk. Our results indicate that genetic variants in the DSB repair pathways contribute to inter-individual differences in susceptibility to SGC and show that the impact of genetic variants differs by histological subtype. Independent studies are warranted to confirm these findings. PMID- 26035308 TI - Seek, and ye shall find: Differences between spontaneous and voluntary analogical retrieval. AB - The present study tackles two overlooked aspects of analogical retrieval: (a) whether argumentation activities elicit a spontaneous search for analogical sources, and (b) whether strategic search can relax the superficial bias typically obtained in experimental studies of analogical retrieval. In Experiment 1, participants had to generate arguments for a target situation under three conditions: without indication to use analogies, with indication to use analogies, and with indication to search for sources within domains provided by the experimenters. Results showed that while voluntary search yields analogical retrievals reliably, the argumentation activity seldom elicits spontaneous remindings. A second set of results demonstrated that the superficial bias can be strategically relaxed, leading to a majority of distant retrievals. Experiment 2 replicated this result with the instruction to search within domains different from that of the target, and without providing a list of specific domains. The theoretical and educational implications of these findings are discussed. PMID- 26035307 TI - Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women. AB - BACKGROUND: Fructose, unlike glucose, promotes feeding behavior in rodents and its ingestion exerts differential effects in the human brain. However, plasma fructose is typically 1/1000 th of glucose levels and it is unclear to what extent fructose crosses the blood-brain barrier. We investigated whether local endogenous central nervous system (CNS) fructose production from glucose via the polyol pathway (glucose -> sorbitol -> fructose) contributes to brain exposure to fructose. METHODS: In this observational study, fasting glucose, sorbitol and fructose concentrations were measured using gas-chromatography-liquid mass spectroscopy in cerebrospinal fluid (CSF), maternal plasma, and venous cord blood collected from 25 pregnant women (6 lean, 10 overweight/obese, and 9 T2DM/gestational DM) undergoing spinal anesthesia and elective cesarean section. RESULTS: As expected, CSF glucose was ~ 60% of plasma glucose levels. In contrast, fructose was nearly 20-fold higher in CSF than in plasma (p < 0.001), and CSF sorbitol was ~ 9-times higher than plasma levels (p < 0.001). Moreover, CSF fructose correlated positively with CSF glucose (rho 0.45, p = 0.02) and sorbitol levels (rho 0.75, p < 0.001). Cord blood sorbitol was also ~ 7-fold higher than maternal plasma sorbitol levels (p = 0.001). There were no differences in plasma, CSF, and cord blood glucose, fructose, or sorbitol levels between groups. CONCLUSIONS: These data raise the possibility that fructose may be produced endogenously in the human brain and that the effects of fructose in the human brain and placenta may extend beyond its dietary consumption. PMID- 26035309 TI - Intersystem Crossing Pathway in Quinoline-Pyrazole Isomerism: A Time-Dependent Density Functional Theory Study on Excited-State Intramolecular Proton Transfer. AB - The dynamics of the excited-state intramolecular proton-transfer (ESIPT) reaction of quinoline-pyrazole (QP) isomers, designated as QP-I and QP-II, has been investigated by means of time-dependent density functional theory (TDDFT). A lower barrier has been found in the potential energy curve for the lowest singlet excited state (S1) along the proton-transfer coordinate of QP-II compared with that of QP-I; however, this is at variance with a recent experimental report [J. Phys. Chem. A 2010, 114, 7886-7891], in which the authors proposed that the ESIPT reaction would only proceed in QP-I due to the absence of a PT emission for QP II. Therefore, several deactivating pathways have been investigated to determine whether fluorescence quenching occurs in the PT form of QP-II (PT-II). The S1 state of PT-II has npi* character, which is a well-known dark state. Moreover, the energy gap between the S1 and T2 states is only 0.29 eV, implying that an intersystem crossing (ISC) process would occur rapidly following the ESIPT reaction. Therefore, it is demonstrated that the ESIPT could successfully proceed in QP-II and that the PT emission would be quenched by the ISC process. PMID- 26035311 TI - Synthesis of Co-based bimetallic nanocrystals with one-dimensional structure for selective control on syngas conversion. AB - Co-based bimetallic nanocrystals with one-dimensional (1D) branches were synthesized by the heterogeneous nucleation of Co atoms onto prenucleated seeds, such as Pd or Cu, through a facile wet-chemical route. The peripheral branches (rod-like) of the Co-Pd and Co-Cu nanocrystals were outspread along the (001) direction and were enclosed by (101) facets. By switching the prenucleated metals to form robust Co-Pd or Co-Cu bimetallic nanocatalysts, the selectivity of CO hydrogenation could be adjusted purposely towards heavy paraffins, light olefins or oxygenates. The Anderson-Schulz-Flory chain-lengthening probabilities for products were up to 0.9 over Co-Pd nanocrystals, showing that long-chain hydrocarbons can be formed with high selectivity using the targeted design of Co Pd nanocrystal catalysts. These Co-based bimetallic nanocrystals with a 1D structure exhibited superior catalytic activities over the corresponding Co-based nanoparticles for synthesis gas conversion. PMID- 26035312 TI - Brownian Dynamics of a Suspension of Particles with Constrained Voronoi Cell Volumes. AB - Solvent-free polymer-grafted nanoparticle fluids consist of inorganic core particles fluidized by polymers tethered to their surfaces. The attachment of the suspending fluid to the particle surface creates a strong penalty for local variations in the fluid volume surrounding the particles. As a model of such a suspension we perform Brownian dynamics of an equilibrium system consisting of hard spheres which experience a many-particle potential proportional to the variance of the Voronoi volumes surrounding each particle (E = alpha(Vi-V0)(2)). The coefficient of proportionality alpha can be varied such that pure hard sphere dynamics is recovered as alpha -> 0, while an incompressible array of hairy particles is obtained as alpha -> infinity. As alpha is increased the distribution of Voronoi volumes becomes narrower, the mean coordination number of the particle increases and the variance in the number of nearest neighbors decreases. The nearest neighbor peaks in the pair distribution function are suppressed and shifted to larger radial separations as the constraint acts to maintain relatively uniform interstitial regions. The structure factor of the model suspension satisfies S(k=0) -> 0 as alpha -> infinity in accordance with expectation for a single component (particle plus tethered fluid) incompressible system. The tracer diffusivity of the particles is reduced by the volume constraint and goes to zero at phi ~ 0.52, indicating an earlier glass transition than has been observed in hard sphere suspensions. The total pressure of the suspension grows in proportion to (alphakBT)(1/2) as the strength of the volume constraint potential grows. This stress arises primarily from the interparticle potential forces, while the hard-sphere collisional contribution to the stress is suppressed by the volume constraint. PMID- 26035313 TI - HtrA1: Its future potential as a novel biomarker for cancer. AB - HtrA1 appears to be involved in several physiological processes as well as in the pathogenesis of conditions such as Alzheimer's disease and osteoarthritis. It has also been hypothesized to play a role as a tumor suppressor. This manuscript reviews the current cancer-related HtrA1 research from the methodological and clinical standpoints including studies regarding its potential role as a tumor marker and/or prognostic factor. PRISMA method was used for study selection. The articles thus collected were examined and selected by two independent reviewers; any disagreement was resolved by a methodologist. A laboratory researcher reviewed the methods and laboratory techniques. Fifteen studies met the inclusion criteria and concerned the following cancer sites: the nervous system, bladder, breast, esophagus, stomach, liver, endometrium, thyroid, ovaries, pleura, lung and skin. Most articles described in vivo studies using a morphological approach and immunohistochemistry, whereas protein expression was quantified as staining intensity scored by two raters. Often the results were not comparable due to the different rating scales and study design. Current research on HtrA1 does not conclusively support its role as a tumor suppressor. PMID- 26035315 TI - Men's heightened risk of AIDS-related death: the legacy of gendered HIV testing and treatment strategies. PMID- 26035317 TI - A new model for post-integration latency in macroglial cells to study HIV-1 reservoirs of the brain. AB - OBJECTIVE: Macroglial cells like astrocytes are key targets for the formation of HIV-1 reservoirs in the brain. The 'shock-and-kill' HIV-1 cure strategy proposes eradication of reservoirs by clinical treatment with latency reversing agents (LRAs). However, virus activation may endanger the brain, due to limited cell turnover, viral neurotoxicity and poor penetration of antiretroviral drugs. Since the brain is not accessible to clinical sampling, we established an experimental model to investigate the LRA effects on HIV-1 latency in macroglial reservoirs. DESIGN: Human neural stem cells (HNSC.100) were used to generate a system that models HIV-1 transcriptional latency in proliferating progenitor, as well as differentiated macroglial cell populations and latency-modulating effects of LRAs and compounds targeting HIV-1 transcription were analysed. METHODS: HNSCs were infected with pseudotyped Env-defective HIV-1 viruses. HIV-1 DNA and RNA levels were quantified by qPCR. Expression of latent GFP-reporter viruses was analysed by confocal microscopy and flow cytometry. NF-kappaB signalling was investigated by confocal microscopy and chromatin immunoprecipitation. RESULTS: Two of the eight well known LRAs (tumour necrosis factor-alpha, suberoylanilide hydroxamic acid) reactivated HIV-1 in latently infected HNSCs. Tumour necrosis factor-alpha reactivated HIV-1 in progenitor and differentiated populations, whereas suberoylanilide hydroxamic acid was more potent in progenitors. Pre-treatment with inhibitors of key HIV-1 transcription factors (NF-kappaB, Cdk9) suppressed HIV-1 reactivation. CONCLUSION: We conclude that latent HIV-1 in macroglial reservoirs can be activated by selected LRAs. Identification of small molecules that suppress HIV-1 reactivation supports functional cure strategies. We propose using the HNSC model to develop novel strategies to enforce provirus quiescence in the brain. PMID- 26035316 TI - Medroxyprogesterone acetate increases HIV-1 infection of unstimulated peripheral blood mononuclear cells in vitro. AB - OBJECTIVE: Several observational studies suggest that medroxyprogesterone acetate (MPA) injectable contraceptives may increase a woman's risk of sexual HIV-1 acquisition. In-vitro studies are conflicting, mainly due to differences in the type of progestin studied or activation status of the primary cells. We sought to determine whether MPA increases infection of unstimulated peripheral blood mononuclear cells (PBMCs). METHODS: Freshly isolated PBMCs from normal blood donors were treated with physiologic MPA concentrations ranging from 0.003 to 5 ng/ml and infected with GFP-tagged R5-tropic or X4-tropic HIV-1 pseudoviruses by spinoculation. The infection was limited to a single cycle. Cells were stained with CD3, CD8 and CD14. Infection was quantified as the percentage of GFP cells by flow cytometry. RESULTS: Absolute infection was greater among unstimulated MPA treated CD3+CD8- T cells vs. untreated cells across MPA concentrations of 0.003-3 ng/ml using R5 (P < 0.003) and 0.03-0.3 ng/ml using X4 (P < 0.005) pseudovirus. There was increased relative infection of CD3+CD8- T cells in MPA-treated whole PBMC cultures but not after monocytes were depleted (P < 0.02). HIV-1 infection of stimulated PBMC showed no differences in R5 or X4 infection across all MPA concentrations (P > 0.5). CONCLUSION: The CD3+CD8- T-cell population of MPA treated unstimulated PBMCs were more susceptible to HIV-1 infection than untreated cells. The increased infection was partly due to monocytes and was lost when PBMC were exogenously stimulated. These data provide confirmation of a biological association between MPA exposure and increased susceptibility to HIV-1 infection, particularly among women who inject drugs. PMID- 26035318 TI - Association between gp120 envelope V1V2 and V4V5 variable loop profiles in a defined HIV-1 transmission cluster. AB - OBJECTIVE: Variations in the HIV-1 gp120 Env variable loop sequences correlate with virus phenotypes associated with transmission and/or disease progression. We aimed to identify whether signature sequences could be identified in the gp120 Env between acute infection and chronic infection viruses obtained from a group of individuals infected with closely related viruses. METHODS: To analyse acute infection versus chronic infection viruses, we studied a transmission cluster of 11 individuals, in which six presented during acute infection and five during chronic infection. Multiple HIV-1 gp120 Env clones were sequenced from each patient with predicted amino acid sequences compared between the groups. RESULTS: Cluster analysis of V1V5 Env sequences (n = 215) identified that acute infection viruses had lower potential N-linked glycosylation site (PNGS) densities than viruses from chronic infection, with a higher amino acid length/PNGS ratio. We found a negative correlation between the V1V2 and V4V5 regions for both amino acid length (Pearson P < 0.01) and PNGS numbers (Pearson P < 0.01) during HIV-1 transmission. This association was lost following seroconversion. These findings were confirmed by analysing sequences from the Los Alamos database that were selected and grouped according to timing of transmission. This included acute infection sequences collected 0-10 days (n = 400) and chronic infection sequences 0.5-3 years postseroconversion (n = 394). CONCLUSION: Our observations are consistent with a structural association between the V1V2 and V4V5 gp120 regions that is lost following viral transmission. These structural considerations should be taken into consideration when devising HIV-1 immunogens aimed at inducing protective antibody responses targeting transmitted viruses. PMID- 26035320 TI - Serum-free light chains in HIV-associated lymphoma: no correlation with histology or prognosis. AB - OBJECTIVES: Serum-free light chains (sFLCs) are a biomarker of B-cell proliferation. Two case-control studies found elevated levels of polyclonal sFLCs predict the development of HIV-associated lymphomas (HALs) in people living with HIV. This effect appears greater for non-Hodgkin's lymphomas than Hodgkin's lymphoma. In this study, we measured sFLCs at diagnosis of HALs, and correlated levels with histology and survival. METHODS: The clinic database of the National Centre for HIV Malignancy was used to identify HAL patients, in the antiretroviral treatment era. Levels of sFLCs were measured using stored sera (cases from 1996 to 2008) and prospectively from 2008 to 2014. Serum immunoglobulins were available for 201 patients. We assessed correlations between sFLCs, serum immunoglobulins, and histological subtypes and overall survival. RESULTS: Two hundred and sixty-four patients were identified and 70% had polyclonal sFLC, 8% monoclonal sFLC (90% kappa sFLC), and 22% normal sFLC levels. No significant difference in sFLCs was observed between the three major histological subtypes of HAL (Hodgkin's lymphoma, diffuse large B-cell lymphoma, and Burkitt lymphoma). Elevated sFLCs did not influence overall survival in HAL or for the three subtypes individually. DISCUSSION: Whilst these data confirm the finding of elevated sFLC in HAL, there was no significant difference in sFLC measurements between histological subtypes despite differences in pathogenesis. sFLC did not predict survival in HAL overall or by histological subtype. Elevated sFLCs may predict HAL, but measurement of sFLCs has limited utility in the classification and prognostication of these cases. PMID- 26035321 TI - Epidemiology of Kaposi's sarcoma-associated herpesvirus in HIV-1-infected US persons in the era of combination antiretroviral therapy. AB - OBJECTIVE: To determine the effect of the introduction of combination antiretroviral treatment (cART) in the HIV-1-infected US population on the epidemiology of Kaposi's sarcoma-associated herpesvirus (KSHV). DESIGN, SETTING AND PARTICIPANTS: We investigated the epidemiology of KSHV in 5022 HIV-1 infected, antiretroviral-naive US persons participating in six AIDS Clinical Trials Group (ACTG)-randomized clinical trials, and followed in a long-term cohort study. We tested the first and last available sera of each participant for antibodies to KSHV K8.1 and ORF73. MAIN OUTCOME MEASURES: We studied prevalence and incidence of KSHV infection, incidence of Kaposi's sarcoma, and overall survival. RESULTS: KSHV prevalence was 38.1% [95% confidence interval (CI) 36.8 39.5%]. Male sex, Caucasian race, age between 30 and 49 years, residence in north eastern or western United States, and enrolment after 2001 were independently associated with prevalent infection. KSHV incidence was 4.07/100 person-years (95% CI 3.70-4.47). Male sex, Caucasian race, age below 30, and enrolment after 2001 were associated with incident infection. CD4 cell count increase following cART was associated with lower risk. Kaposi's sarcoma incidence was 104.05/100 000 person-years (95% CI 71.17-146.89). Higher baseline CD4 cell count, but not increase in CD4 cell count after cART, was associated with lower hazard of Kaposi's sarcoma. Randomized assignment of protease inhibitors was not associated with better KSHV outcomes. CONCLUSIONS: HIV-1-infected individuals, in particular Caucasian men, remain at a significant risk for KSHV co-infection and Kaposi's sarcoma. Thus, optimal management of HIV-1 infection should continue to include vigilance for manifestations of KSHV co-infection, including Kaposi's sarcoma. PMID- 26035319 TI - Comparison of HBV-active HAART regimens in an HIV-HBV multinational cohort: outcomes through 144 weeks. AB - OBJECTIVES: To explore factors associated with short and long-term hepatitis B virus (HBV) DNA suppression in a multinational cohort of HIV-HBV co-infected patients receiving HBV-active antiretrovirals. METHODS: One hundred and fifteen HIV-HBV co-infected patients participating in one of the two global randomized clinical trials conducted by the Adult AIDS Clinical Trials Group of different antiretroviral regimens received either HBV monotherapy with either lamivudine or emtricitabine (N = 56), or HBV dual therapy with tenofovir disoproxil fumarate (TDF) + lamivudine or emtricitabine (N = 59). Associations of pretreatment characteristics with the primary (HBV DNA <200 IU/ml at 24 weeks) and longitudinal outcomes through 144 weeks were explored using logistic regression. HBV drug-resistance mutations were determined by pol sequencing in those with viral rebound. RESULTS: The proportion with HBV DNA below 200 IU/ml was 60% (95% confidence interval 50-69%) at 24 weeks and 79% (95% confidence interval 69-88%) at 144 weeks. Pretreatment factors associated with the primary outcome were HBV DNA, CD4 T-cell count, and aspartate aminotransferase, but only pretreatment HBV DNA remained associated with long-term suppression (P < 0.0001). HBV therapy group was not significantly associated with the primary outcome at 24 weeks; however, longitudinally, a greater proportion in the dual-therapy group achieved HBV DNA below 200 IU/ml (P = 0.007). A higher proportion of hepatitis B e antigen negative patients (n = 57) achieved HBV DNA below 200 IU/ml at any point, regardless of the therapy group. All 12 patients with emergence of lamivudine resistant mutants were in the monotherapy group. CONCLUSIONS: TDF-based dual HBV active antiretroviral therapy is preferred to treat HIV-HBV co-infected patients. In resource-limited settings in which TDF may not be universally available, lamivudine or emtricitabine HBV monotherapy is a reasonable option in patients with low HBV replication. PMID- 26035324 TI - First-line antiretroviral therapy for HIV-infected children. PMID- 26035323 TI - Hidden from health: structural stigma, sexual orientation concealment, and HIV across 38 countries in the European MSM Internet Survey. AB - OBJECTIVE: Substantial country-level variation exists in prejudiced attitudes towards male homosexuality and in the extent to which countries promote the unequal treatment of MSM through discriminatory laws. The impact and underlying mechanisms of country-level stigma on odds of diagnosed HIV, sexual opportunities, and experience of HIV-prevention services, needs and behaviours have rarely been examined, however. DESIGN: Data come from the European MSM Internet Survey (EMIS), which was administered between June and August 2010 across 38 European countries (N = 174 209). METHODS: Country-level stigma was assessed using a combination of national laws and policies affecting sexual minorities and a measure of attitudes held by the citizens of each country. We also assessed concealment, HIV status, number of past 12-month male sex partners, and eight HIV-preventive services, knowledge, and behavioural outcomes. RESULTS: MSM living in countries with higher levels of stigma had reduced odds of diagnosed HIV and fewer partners but higher odds of sexual risk behaviour, unmet prevention needs, not using testing services, and not discussing their sexuality in testing services. Sexual orientation concealment mediated associations between country-level stigma and these outcomes. CONCLUSION: Country-level stigma may have historically limited HIV transmission opportunities among MSM, but by restricting MSM's public visibility, it also reduces MSM's ability to access HIV preventive services, knowledge and precautionary behaviours. These findings suggest that MSM in European countries with high levels of stigma are vulnerable to HIV infection. Although they have less opportunity to identify and contact other MSM, this might change with emerging technologies. PMID- 26035322 TI - Psychiatric symptoms and antiretroviral nonadherence in US youth with perinatal HIV: a longitudinal study. AB - OBJECTIVES: The relationship of specific psychiatric conditions to adherence has not been examined in longitudinal studies of youth with perinatal HIV infection (PHIV). We examined associations between psychiatric conditions and antiretroviral nonadherence over 2 years. DESIGN: Longitudinal study in 294 PHIV youth, 6-17 years old, in the United States and Puerto Rico. METHODS: We annually assessed three nonadherence outcomes: missed above 5% of doses in the past 3 days, missed a dose within the past month, and unsuppressed viral load (>400 copies/ml). We fit multivariable logistic models for nonadherence using Generalized Estimating Equations, and evaluated associations of psychiatric conditions (attention deficit hyperactivity disorder, disruptive behavior, depression, anxiety) at entry with incident nonadherence using multivariable logistic regression. RESULTS: Nonadherence prevalence at study entry was 14% (3 day recall), 32% (past month nonadherence), and 38% (unsuppressed viral load), remaining similar over time. At entry, 38% met symptom cut-off criteria for at least one psychiatric condition. Greater odds of 3-day recall nonadherence were observed at week 96 for those with depression [adjusted odds ratio (aOR) 4.14, 95% confidence interval (CI) 1.11-15.42] or disruptive behavior (aOR 3.36, 95% CI 1.02-11.10], but not at entry. Those with vs. without attention deficit hyperactivity disorder had elevated odds of unsuppressed viral load at weeks 48 (aOR 2.46, 95% CI 1.27-4.78) and 96 (aOR 2.35, 95% CI 1.01-5.45), but not at entry. Among 232 youth adherent at entry, 16% reported incident 3-day recall nonadherence. Disruptive behavior conditions at entry were associated with incident 3-day recall nonadherence (aOR 3.01, 95% CI 1.24-7.31). CONCLUSION: In PHIV youth, comprehensive adherence interventions that address psychiatric conditions throughout the transition to adult care are needed. PMID- 26035326 TI - Sustained virological failure in Cameroonese patient infected by HIV-1 group N evidenced by sequence-based genotyping assay. PMID- 26035325 TI - Soluble CD14 is a nonspecific marker of monocyte activation. AB - Soluble CD14 is associated with morbidity and mortality in HIV disease. It is a co-receptor for lipopolysaccharide (LPS) that is released from monocytes upon activation. We demonstrate here, that inflammatory cytokines can induce the release of sCD14 in peripheral blood mononuclear cell cultures from healthy donors, and that TLR ligands other than LPS can cause a decrease in the monocyte cell surface expression of CD14. Thus, sCD14 is a marker of monocyte activation, not restricted to activation by LPS. PMID- 26035327 TI - Dolutegravir: successful experience in a challenging patient. PMID- 26035328 TI - HIV-1 group O resistance pathway with raltegravir is similar to HIV-1 group M. PMID- 26035330 TI - Updated European paediatric guidelines focus on long-term health consequences of HIV-1 infection and treatment. PMID- 26035329 TI - Fast disease progression in simian HIV-infected female macaque is accompanied by a robust local inflammatory innate immune and microbial response. AB - OBJECTIVE: Gender differences in immune response and the rate of disease progression in HIV-infected individuals have been reported but the underlying mechanism remains unclear, in part because of the lack of relevant animal models. Here, we report a novel nonhuman primate model for investigation of sex disparity in HIV disease progression. DESIGN/METHODS: Viral load and rate of disease progression were evaluated in rhesus macaques infected intrarectally with lineage related subtype C R5 simian HIVs. Cytokine/chemokine levels in rectal swab eluates, and bacterial species adherent to the swabs and in the feces were determined. RESULTS: Simian HIV-infected female rhesus macaques progressed faster to AIDS than male macaques, recapitulating the sex bias in HIV-1 disease in humans. There were no significant differences in the levels of soluble immune mediators in the rectal mucosa of naive female and male macaques. However, an exploratory longitudinal study in six infected macaques indicates that the female macaques mounted an earlier and more robust proinflammatory skewed rectal immune response to infection. Moreover, expansion of Proteobacteria that increase in other intestinal inflammatory disorders was significantly higher in the rectal mucosa of female than male macaques during acute infection. CONCLUSION: These findings suggest that sex differences in local innate immune activation and compositional shifts in the gut microbiota could be the drivers of increased disease susceptibility in female macaques. Further studies with this novel nonhuman primate model of HIV infection could lead to innovative research on gender differences, which may have important therapeutic implications for controlling disease in infected men as well as women. PMID- 26035331 TI - Sustained release of diltiazem HCl tableted after co-spray drying and physical mixing with PVAc and PVP. AB - In this work, aqueous diltiazem HCl and polyvinyl-pyrrolidone (PVP) solutions were mixed with Kollicoat SR 30D and spray dried to microparticles of different drug:excipient ratio and PVP content. Co-spray dried products and physical mixtures of drug, Kollidon SR and PVP were tableted. Spray drying process, co spray dried products and compressibility/compactability of co-spray dried and physical mixtures, as well as drug release and water uptake of matrix-tablets was evaluated. Simple power equation fitted drug release and water uptake (R(2) > 0.909 and 0.938, respectively) and correlations between them were examined. Co spray dried products with PVP content lower than in physical mixtures result in slower release, while at equal PVP content (19 and 29% w/w of excipient) in similar release (f2 > 50). Increase of PVP content increases release rate and co spray drying might be an alternative, when physical mixing is inadequate. Co spray dried products show better compressibility/compatibility but higher stickiness to the die-wall compared to physical mixtures. SEM observations and comparison of release and swelling showed that distribution of tableted component affects only the swelling, while PVP content for both co-spray dried and physical mixes is major reason for release alterations and an aid for drug release control. PMID- 26035332 TI - Phytantriol based liquid crystal provide sustained release of anticancer drug as a novel embolic agent. AB - Phytantriol has received increasing amount of attention in drug delivery system, however, the ability of the phytantriol based liquid crystal as a novel embolic agent to provide a sustained release delivery system is yet to be comprehensively demonstrated. The purpose of this study was to prepare a phytantriol-based cubic phase precursor solution loaded with anticancer drug hydroxycamptothecine (HCPT) and evaluate its embolization properties, in vitro drug release and cytotoxicity. Phase behavior of the phytantriol-solvent-water system was investigated by visual inspection and polarized light microscopy, and no phase transition was observed in the presence of HCPT within the studied dose range. Water uptake by the phytantriol matrices was determined gravimetrically, suggesting that the swelling complied with the second order kinetics. In vitro evaluation of embolic efficacy indicated that the isotropic solution displayed a satisfactory embolization effect. In vitro drug release results showed a sustained-release up to 30 days and the release behavior was affected by the initial composition and drug loading. Moreover, the in vitro cytotoxicity and anticancer activity were evaluated by MTT assay. No appreciable mortality was observed for NIH 3T3 cells after 48 h exposure to blank formulations, and the anticancer activity of HCPT loaded formulations to HepG2 and SMMC7721 cells was strongly dependent on the drug loading and treatment time. Taken together, these results indicate that phytantriol-based cubic phase embolic gelling solution is a promising potential carrier for HCPT delivery to achieve a sustained drug release by vascular embolization, and this technology may be potential for clinical applications. PMID- 26035333 TI - Synthesis of N-vinylindoles through copper catalyzed cyclization reaction of N-(2 alkynylphenyl)imine. AB - A copper(II)-catalyzed cyclization reaction of N-(2-alkynylphenyl)imine was developed. This strategy provided an effective procedure for the synthesis of substituted N-vinylindoles in moderate to good yields. PMID- 26035334 TI - Role of Cellulose Nanocrystals on the Microstructure of Maleic Anhydride Plasma Polymer Thin Films. AB - Recently, it was shown that the microstructure of a maleic anhydride plasma polymer (MAPP) could be tailored ab initio by adjusting the plasma process parameters. In this work, we aim to investigate the ability of cellulose nanocrystals (CNCs) to induce topographical structuration. Thus, a new approach was designed based on the deposition of MAPP on CNCs model surfaces. The nanocellulosic surfaces were produced by spin-coating the CNC suspension on a silicon wafer substrate and on a hydrophobic silicon wafer substrate patterned with circular hydrophilic microsized domains (diameter of 86.9 +/- 4.9 MUm), resulting in different degrees of CNC aggregation. By depositing the MAPP over these surfaces, it was possible to observe that the surface fraction of nanostructures increased from 20% to 35%. This observation suggests that CNCs can act as nucleation points resulting in more structures, although a critical density of the CNCs is required. PMID- 26035335 TI - On-Demand Lensless Single Cell Imaging Activated by Differential Resistive Pulse Sensing. AB - We present an on-demand single cell imaging technique activated by differential resistive pulse sensing in a portable system integrating a microfluidic differential coulter counter and a lensless complementary metal-oxide semiconductor (CMOS) imaging sensor. Dual parametric single cell analysis and on demand single cell imaging have been demonstrated by microbeads of different sizes and a cell mixture including red blood cells (RBCs) and tumor cell line HepG2 cells. The on-demand imaging capability could avoid generating useless images without cells and enable selective imaging of single cells within a specific size range. PMID- 26035336 TI - Proteomic Analysis of Phosphoproteins in the Rice Nucleus During the Early Stage of Seed Germination. AB - The early stage of seed germination is the first step in the plant life cycle without visible morphological change. To investigate the mechanism controlling the early stage of rice seed germination, we performed gel-and label-free nuclear phosphoproteomics. A total of 3467 phosphopeptides belonging to 102 nuclear phosphoproteins from rice embryos were identified. Protein-synthesis-related proteins were mainly phosphorylated. During the first 24 h following imbibition, 115 nuclear phosphoproteins were identified, and significant changes in the phosphorylation level over time were observed in 29 phosphoproteins. Cluster analysis indicated that nucleotide-binding proteins and zinc finger CCCH- and BED type proteins increased in abundance during the first 12 h of imbibition and then decreased. The in silico protein-protein interactions for 29 nuclear phosphoproteins indicated that the Sas10/Utp3 protein, which functions in snoRNA binding and gene silencing, was the center of the phosphoprotein network in nuclei. The germination rate of seeds was significantly slowed with phosphatase inhibitor treatment. The mRNA expression of the zinc finger CCCH-type protein did not change, and the zinc finger BED-type protein was upregulated in rice embryos during the early stage of germination with phosphatase inhibitor treatment. These results suggest that the phosphorylation and dephosphorylation of nuclear proteins are involved in rice seed germination. Furthermore, transcription factors such as zinc finger CCCH- and BED-type proteins might play a key role through nuclear phosphoproteins, and Sas10/Utp3 protein might interact with nuclear phosphoproteins in rice embryos to mediate the early stage of seed germination. PMID- 26035337 TI - Focused Electron and Ion Beam Induced Deposition on Flexible and Transparent Polycarbonate Substrates. AB - The successful application of focused electron (and ion) beam induced deposition techniques for the growth of nanowires on flexible and transparent polycarbonate films is reported here. After minimization of charging effects in the substrate, sub-100 nm-wide Pt, W, and Co nanowires have been grown and their electrical conduction is similar compared to the use of standard Si-based substrates. Experiments where the substrate is bent in a controlled way indicate that the electrical conduction is stable up to high bending angles, >50 degrees , for low resistivity Pt nanowires grown by the ion beam. On the other hand, the resistance of Pt nanowires grown by the electron beam changes significantly and reversibly with the bending angle. Aided by the substrate transparency, a diffraction grating in transmission mode has been built based on the growth of an array of Pt nanowires that shows sharp diffraction spots. The set of results supports the large potential of focused beam deposition as a high-resolution nanolithography technique on transparent and flexible substrates. The most promising applications are expected in flexible nano-optics and nanoplasmonics, flexible electronics, and nanosensing. PMID- 26035338 TI - Direct Annulation of Hydrazides to 1,3,4-Oxadiazoles via Oxidative C(CO) C(Methyl) Bond Cleavage of Methyl Ketones. AB - A new strategy for the synthesis of 1,3,4-oxadiazoles was established through direct annulation of hydrazides with methyl ketones. It was found that the use of K2CO3 as a base achieves an unexpected and highly efficient C-C bond cleavage. This reaction is proposed to go through oxidative cleavage of Csp(3)-H bonds, followed by cyclization and deacylation. PMID- 26035339 TI - Acyloxylation of 1,4-Dioxanes and 1,4-Dithianes Catalyzed by a Copper-Iron Mixed Oxide. AB - The use of a copper-iron mixed oxide as a heterogeneous catalyst for the efficient synthesis of alpha-acyloxy-1,4-dioxanes and 1,4-dithianes employing t butyl peroxyesters is reported. The preparation and characterization of the catalyst are described. The effect of the heteroatoms and a plausible mechanism are discussed. The method is operationally simple and involves low-cost starting materials affording products in good to excellent yields. PMID- 26035341 TI - Patient controlled opioid analgesia versus non-patient controlled opioid analgesia for postoperative pain. AB - BACKGROUND: This is an updated version of the original Cochrane review published in Issue 4, 2006. Patients may control postoperative pain by self administration of intravenous opioids using devices designed for this purpose (patient controlled analgesia or PCA). A 1992 meta-analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia, but disclosed no differences in analgesic consumption or length of postoperative hospital stay. Although Ballantyne's meta-analysis found that PCA did have a small but statistically significant benefit upon pain intensity, a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia. OBJECTIVES: To evaluate the efficacy and safety of patient controlled intravenous opioid analgesia (termed PCA in this review) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief. SEARCH METHODS: We ran the search for the previous review in November 2004. For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 12), MEDLINE (1966 to 28 January 2015), and EMBASE (1980 to 28 January 2015) for randomized controlled trials (RCTs) in any language, and reference lists of reviews and retrieved articles. SELECTION CRITERIA: We selected RCTs that assessed pain intensity as a primary or secondary outcome. These studies compared PCA without a continuous background infusion with non-patient controlled opioid analgesic regimens. We excluded studies that explicitly stated they involved patients with chronic pain. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, which included demographic variables, type of surgery, interventions, efficacy, and adverse events. We graded each included study for methodological quality by assessing risk of bias and employed the GRADE approach to assess the overall quality of the evidence. We performed meta-analysis of outcomes that included pain intensity assessed by a 0 to 100 visual analog scale (VAS), opioid consumption, patient satisfaction, length of stay, and adverse events. MAIN RESULTS: Forty-nine studies with 1725 participants receiving PCA and 1687 participants assigned to a control group met the inclusion criteria. The original review included 55 studies with 2023 patients receiving PCA and 1838 patients assigned to a control group. There were fewer included studies in our updated review due to the revised exclusion criteria. For the primary outcome, participants receiving PCA had lower VAS pain intensity scores versus non-patient controlled analgesia over most time intervals, e.g., scores over 0 to 24 hours were nine points lower (95% confidence interval (CI) -13 to -5, moderate quality evidence) and over 0 to 48 hours were 10 points lower (95% CI -12 to -7, low quality evidence). Among the secondary outcomes, participants were more satisfied with PCA (81% versus 61%, P value = 0.002) and consumed higher amounts of opioids than controls (0 to 24 hours, 7 mg more of intravenous morphine equivalents, 95% CI 1 mg to 13 mg). Those receiving PCA had a higher incidence of pruritus (15% versus 8%, P value = 0.01) but had a similar incidence of other adverse events. There was no difference in the length of hospital stay. AUTHORS' CONCLUSIONS: Since the last version of this review, we have found new studies providing additional information. We reanalyzed the data but the results did not substantially alter any of our previously published conclusions. This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control. PMID- 26035340 TI - Synthesis and Biological Evaluation of Novel Homoisoflavonoids for Retinal Neovascularization. AB - Eye diseases characterized by excessive angiogenesis such as wet age-related macular degeneration, proliferative diabetic retinopathy, and retinopathy of prematurity are major causes of blindness. Cremastranone is an antiangiogenic, naturally occurring homoisoflavanone with efficacy in retinal and choroidal neovascularization models and antiproliferative selectivity for endothelial cells over other cell types. We undertook a cell-based structure-activity relationship study to develop more potent cremastranone analogues, with improved antiproliferative selectivity for retinal endothelial cells. Phenylalanyl incorporated homoisoflavonoids showed improved activity and remarkable selectivity for retinal microvascular endothelial cells. A lead compound inhibited angiogenesis in vitro without inducing apoptosis and had efficacy in the oxygen-induced retinopathy model in vivo. PMID- 26035342 TI - Deep absorbing porphyrin small molecule for high-performance organic solar cells with very low energy losses. AB - We designed and synthesized the DPPEZnP-TEH molecule, with a porphyrin ring linked to two diketopyrrolopyrrole units by ethynylene bridges. The resulting material exhibits a very low energy band gap of 1.37 eV and a broad light absorption to 907 nm. An open-circuit voltage of 0.78 V was obtained in bulk heterojunction (BHJ) organic solar cells, showing a low energy loss of only 0.59 eV, which is the first report that small molecule solar cells show energy losses <0.6 eV. The optimized solar cells show remarkable external quantum efficiency, short circuit current, and power conversion efficiency up to 65%, 16.76 mA/cm(2), and 8.08%, respectively, which are the best values for BHJ solar cells with very low energy losses. Additionally, the morphology of DPPEZnP-TEH neat and blend films with PC61BM was studied thoroughly by grazing incidence X-ray diffraction, resonant soft X-ray scattering, and transmission electron microscopy under different fabrication conditions. PMID- 26035343 TI - Dynamic Layer-by-Layer Films: A Platform for Zero-Order Release. AB - Zero-order release is the ultimate goal of controlled drug release systems, however, it still remains a big challenge despite of numerous previous efforts. Here we show that the release of P(AAm-3-AAPBA) from P(AAm-3-AAPBA)/PVA film, a dynamic layer-by-layer (LBL) film, follows a perfect zero-order kinetics, provided that both polymers in the film have a narrow molecular weight distribution. Instead of releasing via diffusion or degradation, P(AAm-3-AAPBA) is released from the film via the dissociation of the interpolymer complex. The release rate is determined by molecular weight of the polymers. One could also tune the release rate via various external environmental stimuli, including pH, temperature, and glucose. The results suggest dynamic LBL film could serve as a new drug release platform that allows for not only zero-order release, but also intelligent release. PMID- 26035344 TI - NaF-KF-AlF3 System: Phase Transition in K2NaAl3F12 Ternary Fluoride. AB - Phase formation in the NaF-KF-AlF3 system, in the vicinity of the K2NaAl3F12 composition, has been studied. The samples have been prepared by melting the starting components at 650 degrees C. A new phase has been revealed, which appeared to be a low-temperature form of the well-known K2NaAl3F12 ternary fluoride obtained by the hydrothermal synthesis method. The high-temperature form melts at 598 degrees C and is stable in a narrow temperature region of about 15 deg below the melting point. Thermal analysis, high temperature X-ray diffraction, IR-spectroscopy, X-ray fluorescence, and X-ray powder diffraction crystal structure analysis have been applied to study the composition, crystal structure, and thermal properties of the low-temperature phase. The crystal structure consists of trigonal-hexagonal two-dimensional (2D) grids built from the [AlF6] octahedra connected via vertices. The 2D grids have a specific wave like conformation with a wavelength of 11.88 A and an amplitude of 0.46 A. There is a shift of the adjacent grids relative to each other. Because of this shift, the space between the grids changes. The shift leads to the formation of pores adapted to potassium and sodium ions. The reasons for the wave-like structure of layers are discussed. It is shown that the two polymorphic forms differ in the order of cation occupations. PMID- 26035345 TI - Decoding the attended speech stream with multi-channel EEG: implications for online, daily-life applications. AB - OBJECTIVE: Recent studies have provided evidence that temporal envelope driven speech decoding from high-density electroencephalography (EEG) and magnetoencephalography recordings can identify the attended speech stream in a multi-speaker scenario. The present work replicated the previous high density EEG study and investigated the necessary technical requirements for practical attended speech decoding with EEG. APPROACH: Twelve normal hearing participants attended to one out of two simultaneously presented audiobook stories, while high density EEG was recorded. An offline iterative procedure eliminating those channels contributing the least to decoding provided insight into the necessary channel number and optimal cross-subject channel configuration. Aiming towards the future goal of near real-time classification with an individually trained decoder, the minimum duration of training data necessary for successful classification was determined by using a chronological cross-validation approach. MAIN RESULTS: Close replication of the previously reported results confirmed the method robustness. Decoder performance remained stable from 96 channels down to 25. Furthermore, for less than 15 min of training data, the subject-independent (pre-trained) decoder performed better than an individually trained decoder did. SIGNIFICANCE: Our study complements previous research and provides information suggesting that efficient low-density EEG online decoding is within reach. PMID- 26035346 TI - Death ideation in older adults: psychological symptoms of depression, thwarted belongingness, and perceived burdensomeness. AB - Death ideation is commonly reported by older adults in the United States; however, the factors contributing to death ideation in older adults are not fully understood. Depressive symptoms, as well as components of the interpersonal theory of suicide, perceived burden, and thwarted belonging may contribute to death ideation. OBJECTIVES: The purpose of this study was to investigate the moderating relationship of the psychological symptoms of depression on the relation between perceived burdensomeness and death ideation, and thwarted belongingness and death ideation. METHOD: A sample of 151 older adults completed questionnaires assessing numerous covariates, as well as perceived burdensomeness, thwarted belongingness, death ideation, and the psychological symptoms of depression. RESULTS: The results of this study indicated that the proposed moderating relationship was supported for the relationship between perceived burdensomeness and death ideation, but was not supported for the relationship between thwarted belongingness and death ideation when covariates (loneliness and hopelessness) were controlled. CONCLUSION: This suggests that the psychological symptoms of depression are significantly associated with death ideation in older adults experiencing feelings of perceived burdensomeness. Additionally, the findings suggest that loneliness and hopelessness are also important factors to consider when assessing death ideation in older adults. PMID- 26035348 TI - Cyclopropyl-methoxycarbonyl Metomidate: Studies in a Lipopolysaccharide Inflammatory Model of Sepsis. AB - BACKGROUND: Cyclopropyl-methoxycarbonyl metomidate (CPMM) is a rapidly metabolized etomidate analog that is currently in clinical trials. The goal of this study is to assess CPMM's potential value as an anesthetic agent for use in patients with sepsis by defining its actions in an acute inflammatory model of sepsis. METHODS: Escherichia coli lipopolysaccharide (1 mg/kg) was injected intravenously into Sprague-Dawley rats. Thirty minutes later, CPMM, etomidate, or vehicle (n = 8 per group) was infused for 1 h. Plasma adrenocorticotropic hormone, corticosterone, and cytokine (interleukin-1beta, interleukin-6, interleukin-10, and tumor necrosis factor-alpha) concentrations were measured before, during, and after infusion. RESULTS: After lipopolysaccharide injection, adrenocorticotropic hormone concentrations changed similarly over time in all three groups. Compared with vehicle group rats, CPMM group rats had significantly lower corticosterone concentrations at only a single study time point during infusion and no significant differences in cytokine concentrations at any time during the study period. Compared with etomidate group rats, CPMM group rats had significantly higher corticosterone concentrations (up to nine-fold) during and after hypnotic infusion. Cytokine concentrations in CPMM group rats and vehicle group rats were not significantly different, but they were significantly lower than those in etomidate group rats. Postinfusion mortality was 40% in etomidate group rats and 0% in CPMM and vehicle group rats. CONCLUSION: Compared with etomidate, CPMM produces less adrenocortical suppression, lower plasma cytokine concentrations, and improved survival in a lipopolysaccharide inflammatory model of sepsis. These results suggest that CPMM may be a safer alternative to etomidate in patients with sepsis. PMID- 26035347 TI - Extracellular Calcium Modulates Chondrogenic and Osteogenic Differentiation of Human Adipose-Derived Stem Cells: A Novel Approach for Osteochondral Tissue Engineering Using a Single Stem Cell Source. AB - We have previously shown that elevating extracellular calcium from a concentration of 1.8 to 8 mM accelerates and increases human adipose-derived stem cell (hASC) osteogenic differentiation and cell-mediated calcium accretion, even in the absence of any other soluble osteogenic factors in the culture medium. However, the effects of elevated calcium on hASC chondrogenic differentiation have not been reported. The goal of this study was to determine the effects of varied calcium concentrations on chondrogenic differentiation of hASC. We hypothesized that exposure to elevated extracellular calcium (8 mM concentration) in a chondrogenic differentiation medium (CDM) would inhibit chondrogenesis of hASC when compared to basal calcium (1.8 mM concentration) controls. We further hypothesized that a full osteochondral construct could be engineered by controlling local release of calcium to induce site-specific chondrogenesis and osteogenesis using only hASC as the cell source. Human ASC was cultured as micromass pellets in CDM containing transforming growth factor-beta1 and bone morphogenetic protein 6 for 28 days at extracellular calcium concentrations of either 1.8 mM (basal) or 8 mM (elevated). Our findings indicated that elevated calcium induced osteogenesis and inhibited chondrogenesis in hASC. Based on these findings, stacked polylactic acid nanofibrous scaffolds containing either 0% or 20% tricalcium phosphate (TCP) nanoparticles were electrospun and tested for site specific chondrogenesis and osteogenesis. Histological assays confirmed that human ASC differentiated locally to generate calcified tissue in layers containing 20% TCP, and cartilage in the layers with no TCP when cultured in CDM. This is the first study to report the effects of elevated calcium on chondrogenic differentiation of hASC, and to develop osteochondral nanofibrous scaffolds using a single cell source and controlled calcium release to induce site-specific differentiation. This approach holds great promise for osteochondral tissue engineering using a single cell source (hASC) and single scaffold. PMID- 26035349 TI - Reaction diffusion Voronoi diagrams: from sensors data to computing. AB - In this paper, a new method to solve computational problems using reaction diffusion (RD) systems is presented. The novelty relies on the use of a model configuration that tailors its spatiotemporal dynamics to develop Voronoi diagrams (VD) as a part of the system's natural evolution. The proposed framework is deployed in a solution of related robotic problems, where the generalized VD are used to identify topological places in a grid map of the environment that is created from sensor measurements. The ability of the RD-based computation to integrate external information, like a grid map representing the environment in the model computational grid, permits a direct integration of sensor data into the model dynamics. The experimental results indicate that this method exhibits significantly less sensitivity to noisy data than the standard algorithms for determining VD in a grid. In addition, previous drawbacks of the computational algorithms based on RD models, like the generation of volatile solutions by means of excitable waves, are now overcome by final stable states. PMID- 26035350 TI - Provisioning vehicular services and communications based on a bluetooth sensor network deployment. AB - It is very common to rule out Bluetooth as a suitable technology for vehicular communications. The reasons behind this decision usually result from misconceptions such as accepting that Bluetooth has a short application range, or assuming its connection setup is not fast enough to allow communication which involves high speed moving nodes. This paper refutes those assertions and proposes the use of Bluetooth not only for Infrastructure-to-Vehicle (I2V) or Road-to-Vehicle (R2V) communications, but also for Vehicle-to-Vehicle (V2V) or Vehicle-to-Infrastructure (V2I) communications. This novel proposal is based on using the remote name request procedure of the standard, combined with an adjustment and optimization of the parameters present in the inquiry and page procedures. The proposed modifications reduce the information exchange delay, thus making Bluetooth a suitable technology for high-speed vehicle communications. The feasibility of the proposed scheme has been validated through experimental tests conducted in different scenarios: laboratory, a real highway and a racing test circuit. There, the communication system was installed in a vehicle circulating at speeds of up to 250 km/h, whereas autonomous devices were disseminated throughout the road path to communicate with the on board devices obtaining satisfying results. PMID- 26035351 TI - Solitary cystic tuberculosis of the distal femur and proximal tibia in children. AB - Pediatric skeletal (extraspinal) tuberculosis may mimic pyogenic infections and bone tumors. The aim of this study was to show a multimodality approach to the correct diagnosis and to evaluate the long-term clinical and radiological results of curettage and antituberculosis treatment. Between 2004 and 2012, we treated eight children (five boys, three girls) with histologically proven solitary cystic tuberculosis of the proximal tibia and distal femur. The average age at presentation was 4 years (range, 2-6 years). Except for one case with metadiaphyseal involvement, all lesions were located in the metaphysis and crossed the physis in three. The patients were managed by curettage without bone grafting, followed by antituberculosis therapy. The average follow-up was 4 years (range, 2-7 years). All children achieved complete clinical and radiological healing without any residual lesion or recurrence. In three cases with epiphyseal involvement, the growth plate maintained its function and gradually remodeled within 24 months, without any deformity. No surgical complication was observed. The diagnosis of pediatric skeletal tuberculosis can be made with a good correlation of clinical, radiological, and histological findings. High healing rates can be achieved with surgical debridement and chemotherapy. PMID- 26035352 TI - Reconstruction of the lateral malleolus in a type-Ib fibular hemimelia with a microvascular proximal fibular flap: a case report. AB - Fibular hemimelia, or fibular hypoplasia-aplasia, is the most frequent congenital long-bone deficiency. There is still some debate on reconstruction versus amputation for the severe type Ib and type II cases. Limb-length discrepancy can be corrected with Ilizarov methods, but ankle stability remains a problem. The absence of the lateral malleolus destabilizes the mortise in valgus and ankle fusion is usually needed. A case of lateral malleolus reconstruction in a teenage patient with severe type-Ib fibular hemimelia using a contralateral free proximal fibular epiphyseal transfer is reported. PMID- 26035353 TI - Comment on the article 'Dysplasia epiphysealis hemimelica of the knee: an unusual presentation with intra-articular loose bodies and literature review' by Wheeldon and Altiok. PMID- 26035354 TI - Novel HER3/MUC4 oncogenic signaling aggravates the tumorigenic phenotypes of pancreatic cancer cells. AB - Several studies have demonstrated that MUC4 is involved in progression and metastasis of pancreatic cancer (PC). Here, we report that HER3/MUC4 interaction in HER2 low cells is critical in driving pancreatic tumorigenesis. Upon HER2 knockdown, we observed elevated expression of HER3 and MUC4 and their interactions, which was confirmed by immunoprecipitation and bioinformatics analyses. In paired human PC tissues, higher percentage of HER3 positivity (10/33, 30.3%; p = 0.001) was observed than HER2 (5/33, 15.1%; p = 0.031), which was further confirmed in spontaneous mice (KPC; KrasG12D; Trp53R172H/+; Pdx-Cre) tumors of different weeks. Mechanistically, increased phosphorylation of ERK and expression of PI3K and c-Myc were observed in HER2 knockdown cells, suggesting a positive role for HER3/MUC4 in HER2 low cells. Further, HER2 knockdown resulted in increased proliferation, motility and tumorigenicity of PC cells. Consistently, transient knockdown of HER3 by siRNA in HER2 knockdown cells led to decreased proliferation. These observations led us to conclude that HER3 interacts with MUC4 to promote proliferation in HER2 low PC cells. Further, deficiency of both HER2 and HER3 leads to decreased proliferation of PC cells. Hence targeting these newly identified HER3/MUC4 signals would improve the PC patients survival by intercepting MUC4 mediated oncogenic signaling. PMID- 26035355 TI - Tensin4 is up-regulated by EGF-induced ERK1/2 activity and promotes cell proliferation and migration in hepatocellular carcinoma. AB - The focal adhesion protein Tensin4, also known as cten (c-terminal tensin like), is structurally distinct from the three other members in the Tensin family. Its expression and potential functions in cancers including hepatocellular carcinoma (HCC) are not well understood. With immunohistochemistry, 43% (13/30) of our human HCC cases showed up-regulation of Tensin4 as compared with their corresponding non-tumorous livers. In HCC cells, treatment with epidermal growth factor (EGF) significantly induced Tensin4 transcript and protein expression, while treatment with pharmacological inhibitors against the MEK1/2 kinases abolished such induction, suggesting that Tensin4 expression was dependent on Ras/MAPK signaling. With immunofluorescence microscopy, the focal adhesion localization of Tensin4 was confirmed in HCC cells. Significantly, detailed examination using a panel of Tensin4 deletion constructs revealed that this specific focal adhesion localization required the N-terminal region together with the C-terminal SH2 domain. Up-regulation of ERK signaling by EGF in the HCC cells resulted in a change to a mesenchymal cell-like morphology through modulation of the actin cytoskeleton. Functionally, stable Tensin4 knockdown in SMMC-7721 HCC cells resulted in reduced cell proliferation and migration in vitro. Taken together, our data suggest that Tensin4 may play a pro-oncogenic role in HCC, possibly functioning as a downstream effector of Ras/MAPK signaling. PMID- 26035356 TI - Overexpression of MAPK15 in gastric cancer is associated with copy number gain and contributes to the stability of c-Jun. AB - This study was aimed at understanding the functional and clinicopathological significance of MAPK15 alteration in gastric cancer. Genome-wide copy number alterations (CNAs) were first investigated in 40 gastric cancers using Agilent aCGH-244K or aCGH-400K, and copy number gains of MAPK15 found in aCGH were validated in another set of 48 gastric cancer tissues. The expression of MAPK15 was analyzed using immunohistochemistry in concurrent lesions of normal, adenoma, and carcinoma from additional 45 gastric cancer patients. The effects of MAPK15 on cell cycle, c-Jun phosphorylation, and mRNA stability were analyzed in gastric cancer cells. Copy number gains of MAPK15 were found in 15 (17%) of 88 tumor tissues. The mRNA levels of MAPK15 were relatively high in the gastric cancer tissues and gastric cancer cells with higher copy number gains than those without. Knockdown of MAPK15 using siRNA in gastric cancer cells significantly suppressed cell proliferation and resulted in cell cycle arrest at G1-S phase. Reduced c-Jun phosphorylation and c-Jun half-life were observed in MAPK15 knockdowned cells. In addition, transient transfection of MAPK15 into AGS gastric cancer cells with low copy number resulted in an increase of c-Jun phosphorylation and stability. The overexpression of MAPK15 occurred at a high frequency in carcinomas (37%) compared to concurrent normal tissues (2%) and adenomas (21%). In conclusion, the present study suggests that MAPK15 overexpression may contribute to the malignant transformation of gastric mucosa by prolonging the stability of c-Jun. And, patients with copy number gain of MAPK15 in normal or premalignant tissues of stomach may have a chance to progress to invasive cancer. PMID- 26035357 TI - Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over expression, impacting on signalling and cellular phenotypes in prostate cancer. AB - Monocarboxylate Transporter 2 (MCT2) is a major pyruvate transporter encoded by the SLC16A7 gene. Recent studies pointed to a consistent overexpression of MCT2 in prostate cancer (PCa) suggesting MCT2 as a putative biomarker and molecular target. Despite the importance of this observation the mechanisms involved in MCT2 regulation are unknown. Through an integrative analysis we have discovered that selective demethylation of an internal SLC16A7/MCT2 promoter is a recurrent event in independent PCa cohorts. This demethylation is associated with expression of isoforms differing only in 5'-UTR translational control motifs, providing one contributing mechanism for MCT2 protein overexpression in PCa. Genes co-expressed with SLC16A7/MCT2 also clustered in oncogenic-related pathways and effectors of these signalling pathways were found to bind at the SLC16A7/MCT2 gene locus. Finally, MCT2 knock-down attenuated the growth of PCa cells. The present study unveils an unexpected epigenetic regulation of SLC16A7/MCT2 isoforms and identifies a link between SLC16A7/MCT2, Androgen Receptor (AR), ETS related gene (ERG) and other oncogenic pathways in PCa. These results underscore the importance of combining data from epigenetic, transcriptomic and protein level changes to allow more comprehensive insights into the mechanisms underlying protein expression, that in our case provide additional weight to MCT2 as a candidate biomarker and molecular target in PCa. PMID- 26035358 TI - Pediatric acute respiratory distress syndrome: definition, incidence, and epidemiology: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVES: Although there are similarities in the pathophysiology of acute respiratory distress syndrome in adults and children, pediatric-specific practice patterns, comorbidities, and differences in outcome necessitate a pediatric specific definition. We sought to create such a definition. DESIGN: A subgroup of pediatric acute respiratory distress syndrome investigators who drafted a pediatric-specific definition of acute respiratory distress syndrome based on consensus opinion and supported by detailed literature review tested elements of the definition with patient data from previously published investigations. SETTINGS: International PICUs. SUBJECTS: Children enrolled in published investigations of pediatric acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Several aspects of the proposed pediatric acute respiratory distress syndrome definition align with the Berlin Definition of acute respiratory distress syndrome in adults: timing of acute respiratory distress syndrome after a known risk factor, the potential for acute respiratory distress syndrome to coexist with left ventricular dysfunction, and the importance of identifying a group of patients at risk to develop acute respiratory distress syndrome. There are insufficient data to support any specific age for "adult" acute respiratory distress syndrome compared with "pediatric" acute respiratory distress syndrome. However, children with perinatal related respiratory failure should be excluded from the definition of pediatric acute respiratory distress syndrome. Larger departures from the Berlin Definition surround 1) simplification of chest imaging criteria to eliminate bilateral infiltrates; 2) use of pulse oximetry-based criteria when PaO2 is unavailable; 3) inclusion of oxygenation index and oxygen saturation index instead of PaO2/FIO2 ratio with a minimum positive end-expiratory pressure level for invasively ventilated patients; 4) and specific inclusion of children with preexisting chronic lung disease or cyanotic congenital heart disease. CONCLUSIONS: This pediatric-specific definition for acute respiratory distress syndrome builds on the adult-based Berlin Definition, but has been modified to account for differences between adults and children with acute respiratory distress syndrome. We propose using this definition for future investigations and clinical care of children with pediatric acute respiratory distress syndrome and encourage external validation with the hope for continued iterative refinement of the definition. PMID- 26035359 TI - Methodology of the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: This article describes the methodology used for the Pediatric Acute Lung Injury Consensus Conference. DESIGN: Consensus conference of international experts in pediatric acute respiratory distress syndrome using the Research ANd Development/University of California, Los Angeles appropriateness method and an expert recommendations process developed by the French-speaking intensive care society. Topics related to pediatric acute respiratory distress syndrome were divided into nine subgroups with a review of the literature. SETTING: A group of 27 experts met three times over the course of 2 years and collaborated in their respective subgroups to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and future research priorities. MAIN RESULTS: The consensus conference resulted in summary of recommendations published in Pediatric Critical Care Medicine, the present Pediatric Acute Lung Injury Consensus Conference methodology article, articles on the nine pediatric acute respiratory distress syndrome subtopics, and a review of pediatric acute respiratory distress syndrome pathophysiology published in this supplement of Pediatric Critical Care Medicine. CONCLUSIONS: The methodology described involved experts from around the world and the use of modern information technology. This resulted in recommendations for pediatric acute respiratory distress syndrome management, the identification of current research gaps, and future priorities. PMID- 26035360 TI - Noninvasive support and ventilation for pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: Despite the widespread use of noninvasive ventilation in children and in children with acute lung injury and pediatric acute respiratory distress syndrome, there are few scientific data on the utility of this therapy. In this review, we examine the literature regarding noninvasive positive pressure ventilation and use the Research ANd Development/University of California, Los Angeles appropriateness methodology to provide strong or weak recommendations for the use of noninvasive positive pressure ventilation in children with pediatric acute respiratory distress syndrome. DATA SOURCES: Electronic searches were made in PubMed, EMBASE, Web of Science, Cochrane Library, and Scopus with the following specific keywords: noninvasive ventilation, noninvasive positive pressure ventilation, continuous positive airway pressure, and high-flow nasal cannula. STUDY SELECTION: Studies were eligible for inclusion if they included 10 or more children between 1 month and 18 years old. Randomized and nonrandomized controlled trials, controlled before-and-after studies, concurrent cohort studies, interrupted time series studies, historically controlled studies, cohort studies, cross-sectional studies, and uncontrolled longitudinal studies were included for data synthesis. DATA SYNTHESIS: The literature provides a solid physiological rationale for the use of noninvasive positive pressure ventilation in children with pediatric acute respiratory distress syndrome. The addition of noninvasive positive pressure ventilation can improve gas exchange and potentially prevent intubation and mechanical ventilation in some children with mild pediatric acute respiratory distress syndrome. Noninvasive positive pressure ventilation is not indicated in severe pediatric acute respiratory distress syndrome. Noninvasive positive pressure ventilation should be performed only in acute care setting with experienced team, and patient-ventilator synchrony is crucial for success. An oronasal interface provides superior support, but close monitoring of children is required due to the risk of progressive respiratory failure and the potential need for intubation. The use of high-flow nasal cannula is a promising treatment for respiratory disease; however, at this time, the efficacy of high-flow nasal cannula compared with noninvasive positive pressure ventilation is unknown. CONCLUSION: Noninvasive positive pressure ventilation can be beneficial in children with pediatric acute respiratory distress syndrome, particularly in those with milder disease. However, further research is needed into the use of noninvasive positive pressure ventilation in children. PMID- 26035361 TI - Extracorporeal support in children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: Extracorporeal life support has undergone a revolution in the past several years with the advent of new, miniaturized equipment and success in supporting patients with a variety of illnesses. Most experience has come with the use of extracorporeal membrane oxygenation, a modified form of cardiopulmonary bypass that can support the heart, lungs, and circulation for days to months at a time. To describe the recommendations for the use of extracorporeal membrane oxygenation in children with pediatric acute respiratory distress syndrome based on a review of the literature and expert opinion. DESIGN: Consensus conference of experts in pediatric acute lung injury. METHODS: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The extracorporeal support subgroup comprised two international experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used. RESULTS: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, 11 of which related to extracorporeal support. All recommendations had agreement, with 10 recommendations (91%) achieving strong agreement. These recommendations included the utilization of extracorporeal support for reversible causes of pediatric acute respiratory distress syndrome, consideration of quality of life when making the decision to use extracorporeal support, and the use of the Extracorporeal Life Support Organization registry to report all extracorporeal support activity, among others. CONCLUSIONS: Pediatric extracorporeal membrane oxygenation for pediatric acute respiratory distress syndrome could benefit from more specific data collection and collaboration of focused investigators to establish validated criteria for optimal application of extracorporeal membrane oxygenation and patient management protocols. Until that time, consensus opinion offers some insight into guidelines. PMID- 26035362 TI - The outcomes of children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: To provide additional details and evidence behind the recommendations for outcomes assessment of patients with pediatric acute respiratory distress syndrome from the Pediatric Acute Lung Injury Consensus Conference. DESIGN: Consensus conference of experts in pediatric acute lung injury. METHODS: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The outcomes subgroup comprised four experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used. RESULTS: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, seven of which related to outcomes after pediatric acute respiratory distress syndrome. All seven recommendations had strong agreement. Children with acute respiratory distress syndrome continue to have a high mortality, specifically, in relation to certain comorbidities and etiologies related to pediatric acute respiratory distress syndrome. Comorbid conditions, such as an immunocompromised state, increase the risk of mortality even further. Likewise, certain etiologies, such as non-pulmonary sepsis, also place children at a higher risk of mortality. Significant long-term effects were reported in adult survivors of acute respiratory distress syndrome: diminished lung function and exercise tolerance, reduced quality of life, and diminished neurocognitive function. Little knowledge of long-term outcomes exists in children who survive pediatric acute respiratory distress syndrome. Characterization of the longer term consequences of pediatric acute respiratory distress syndrome in children is vital to help identify opportunities for improved therapeutic and rehabilitative strategies that will lessen the long-term burden of pediatric acute respiratory distress syndrome and improve the quality of life in children. CONCLUSIONS: The Consensus Conference developed pediatric-specific recommendations for pediatric acute respiratory distress syndrome regarding outcome measures and future research priorities. These recommendations are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation. PMID- 26035364 TI - Ventilatory support in children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: To describe the recommendations of the Pediatric Acute Lung Injury Consensus Conference for mechanical ventilation management of pediatric patients with acute respiratory distress syndrome. DESIGN: Consensus Conference of experts in pediatric acute lung injury. METHODS: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 27 recommendations focused on the optimal mechanical ventilation approach of the patient with pediatric acute respiratory distress syndrome. Topics included ventilator mode, tidal volume delivery, inspiratory plateau pressure, high-frequency ventilation, cuffed endotracheal tubes, and gas exchange goals. When experimental data were lacking, a modified Delphi approach emphasizing the strong professional agreement was used. RESULTS: There were 17 recommendations with strong agreement and 10 recommendations with weak agreement. There were no recommendations with equipoise or disagreement. There was weak agreement on recommendations concerning approach to tidal volume and inspiratory pressure limitation (88% to 72% agreement, respectively), whereas strong agreement could be achieved for accepting permissive hypercapnia. Using positive end-expiratory pressure levels greater than 15 cm H2O in severe pediatric acute respiratory distress syndrome, under the condition that the markers of oxygen delivery, respiratory system compliance, and hemodynamics are closely monitored as positive end-expiratory pressure is increased, is strongly recommended. The concept of exploring the effects of careful recruitment maneuvers during conventional ventilation met an agreement level of 88%, whereas the use of recruitment maneuvers during rescue high frequency oscillatory ventilation is highly recommended (strong agreement). CONCLUSIONS: The Consensus Conference developed pediatric-specific recommendations regarding mechanical ventilation of the patient with pediatric acute respiratory distress syndrome as well as future research priorities. These recommendations are intended to initiate discussion regarding optimal mechanical ventilation management for children with pediatric acute respiratory distress syndrome and identify areas of controversy requiring further investigation. PMID- 26035363 TI - Comorbidities and assessment of severity of pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVES: To determine the impact of patient-specific and disease-related characteristics on the severity of illness and on outcome in pediatric patients with acute respiratory distress syndrome with the intent of guiding current medical practice and identifying important areas for future research. DESIGN: Electronic searches of PubMed, EMBASE, Web of Science, Cochrane, and Scopus were conducted. References were reviewed for relevance and features included in the following section. SETTINGS: Not applicable. SUBJECTS: PICU patients with evidence of acute lung injury, acute hypoxemic respiratory failure, and acute respiratory distress syndrome. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: The comorbidities associated with outcome in pediatric acute respiratory distress syndrome can be divided into 1) patient-specific factors and 2) factors inherent to the disease process. The primary comorbidity associated with poor outcome is preexisting congenital or acquired immunodeficiency. Severity of disease is often described by factors identifiable at admission to the ICU. Many measures that are predictive are influenced by the underlying disease process itself, but may also be influenced by nutritional status, chronic comorbidities, or underlying genetic predisposition. Of the measures available at the bedside, both PaO2/FIO2 ratio and oxygenation index are fairly consistent and robust predictors of disease severity and outcomes. Multiple organ system dysfunction is the single most important independent clinical risk factor for mortality in children at the onset of acute respiratory distress syndrome. CONCLUSIONS: The assessment of oxygenation and ventilation indices simultaneously with genetic and biomarker measurements holds the most promise for improved risk stratification for pediatric acute respiratory distress syndrome patients in the very near future. The next phases of pediatric acute respiratory distress syndrome pathophysiology and outcomes research will be enhanced if 1) age group differences are examined, 2) standardized datasets with adequately explicit definitions are used, 3) data are obtained at standardized times after pediatric acute respiratory distress syndrome onset, and 4) nonpulmonary organ failure scores are created and implemented. PMID- 26035365 TI - Pathobiology of acute respiratory distress syndrome. AB - The unique characteristics of pulmonary circulation and alveolar-epithelial capillary-endothelial barrier allow for maintenance of the air-filled, fluid-free status of the alveoli essential for facilitating gas exchange, maintaining alveolar stability, and defending the lung against inhaled pathogens. The hallmark of pathophysiology in acute respiratory distress syndrome is the loss of the alveolar capillary permeability barrier and the presence of protein-rich edema fluid in the alveoli. This alteration in permeability and accumulation of fluid in the alveoli accompanies damage to the lung epithelium and vascular endothelium along with dysregulated inflammation and inappropriate activity of leukocytes and platelets. In addition, there is uncontrolled activation of coagulation along with suppression of fibrinolysis and loss of surfactant. These pathophysiological changes result in the clinical manifestations of acute respiratory distress syndrome, which include hypoxemia, radiographic opacities, decreased functional residual capacity, increased physiologic deadspace, and decreased lung compliance. Resolution of acute respiratory distress syndrome involves the migration of cells to the site of injury and re-establishment of the epithelium and endothelium with or without the development of fibrosis. Most of the data related to acute respiratory distress syndrome, however, originate from studies in adults or in mature animals with very few studies performed in children or juvenile animals. The lack of studies in children is particularly problematic because the lungs and immune system are still developing during childhood and consequently the pathophysiology of pediatric acute respiratory distress syndrome may differ in significant ways from that seen in acute respiratory distress syndrome in adults. This article describes what is known of the pathophysiologic processes of pediatric acute respiratory distress syndrome as we know it today while also presenting the much greater body of evidence on these processes as elucidated by adult and animal studies. It is also our expressed intent to generate enthusiasm for larger and more in-depth investigations of the mechanisms of disease and repair specific to children in the years to come. PMID- 26035366 TI - Pulmonary specific ancillary treatment for pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: To provide an overview of the current literature on pulmonary-specific therapeutic approaches to pediatric acute respiratory distress syndrome to determine recommendations for clinical practice and/or future research. DATA SOURCES: PubMed, EMBASE, CINAHL, SCOPUS, and the Cochrane Library were searched from inception until January 2013 using the following keywords in various combinations: ARDS, treatment, nitric oxide, heliox, steroids, surfactant, etanercept, prostaglandin therapy, inhaled beta adrenergic receptor agonists, N acetylcysteine, ipratroprium bromide, dornase, plasminogen activators, fibrinolytics or other anticoagulants, and children. No language restrictions were applied. References from identified articles were searched for additional publications. STUDY SELECTION: All clinical studies pertaining to pulmonary specific therapeutic approaches to pediatric acute respiratory distress syndrome were reviewed. If clinical pediatric data were sparse or unavailable, the findings from studies of adult acute respiratory distress syndrome and animal models that might be relevant to pediatric acute respiratory distress syndrome were examined. DATA EXTRACTION: All relevant studies were reviewed and pertinent data abstracted. DATA SYNTHESIS: Over the course of three international meetings, the pertinent findings of the literature review were discussed by a panel of 24 experts in the field representing 21 academic institutions and 8 countries. Recommendations developed and the supporting literature were distributed to all panel members without a conflict of interest and were scored by using the Research ANd Development/University of California, Los Angeles Appropriateness method. The modified Delphi approach was used as the methodology to achieve consensus among the panel. CONCLUSIONS: Overall, the routine use of surfactant, inhaled nitric oxide, glucocorticoids, prone positioning, endotracheal suctioning, and chest physiotherapy cannot be recommended. Inhaled nitric oxide should only be used for patients with documented pulmonary hypertension and/or right ventricular failure. Prone positioning may be considered in patients with severe pediatric acute respiratory distress syndrome. Future studies are definitely warranted to establish the role, if any, of these ancillary treatment modalities in pediatric acute respiratory distress syndrome. PMID- 26035367 TI - Nonpulmonary treatments for pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: To describe the recommendations from the Pediatric Acute Lung Injury Consensus Conference on nonpulmonary treatments in pediatric acute respiratory distress syndrome. DESIGN: Consensus conference of experts in pediatric acute lung injury. METHODS: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The nonpulmonary subgroup comprised three experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was utilized. RESULTS: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, 30 of which related to nonpulmonary treatment. All 30 recommendations had strong agreement. Patients with pediatric acute respiratory distress syndrome should receive 1) minimal yet effective targeted sedation to facilitate mechanical ventilation; 2) neuromuscular blockade, if sedation alone is inadequate to achieve effective mechanical ventilation; 3) a nutrition plan to facilitate their recovery, maintain their growth, and meet their metabolic needs; 4) goal-directed fluid management to maintain adequate intravascular volume, end-organ perfusion, and optimal delivery of oxygen; and 5) goal-directed RBC transfusion to maintain adequate oxygen delivery. Future clinical trials in pediatric acute respiratory distress syndrome should report sedation, neuromuscular blockade, nutrition, fluid management, and transfusion exposures to allow comparison across studies. CONCLUSIONS: The Consensus Conference developed pediatric-specific definitions for pediatric acute respiratory distress syndrome and recommendations regarding treatment and future research priorities. These recommendations for nonpulmonary treatment in pediatric acute respiratory distress syndrome are intended to promote optimization and consistency of care for patients with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation. PMID- 26035368 TI - Monitoring of children with pediatric acute respiratory distress syndrome: proceedings from the Pediatric Acute Lung Injury Consensus Conference. AB - OBJECTIVE: To critically review the potential role of monitoring technologies in the management of pediatric acute respiratory distress syndrome, and specifically regarding monitoring of the general condition, respiratory system mechanics, severity scoring parameters, imaging, hemodynamic status, and specific weaning considerations. DESIGN: Consensus conference of experts in pediatric acute lung injury. METHODS: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The monitoring subgroup comprised two experts. When published data were lacking a modified Delphi approach, emphasizing strong professional agreement was used. RESULTS: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, 21 of which related to monitoring of a child with pediatric acute respiratory distress syndrome. All 21 recommendations had agreement, with 19 (90%) reaching strong agreement. CONCLUSIONS: The Consensus Conference developed pediatric-specific recommendations related to monitoring children with pediatric acute respiratory distress syndrome. These include interpreting monitored values such as tidal volume using predicted body weight, monitoring tidal volume at the end of the endotracheal tube in small children, and continuous monitoring of exhaled carbon dioxide in intubated children with pediatric acute respiratory distress syndrome, among others. These recommendations for monitoring in pediatric acute respiratory distress syndrome are intended to promote optimization and consistency of care for children with pediatric acute respiratory distress syndrome and identify areas of uncertainty requiring further investigation. PMID- 26035369 TI - ? PMID- 26035370 TI - ? PMID- 26035371 TI - ? PMID- 26035372 TI - ? PMID- 26035373 TI - ? PMID- 26035375 TI - Learning Curve of a Minimally Invasive Technique for Transcrestal Sinus Floor Elevation: A Split-Group Analysis in a Prospective Case Series With Multiple Clinicians. AB - AIMS: To assess the learning curve of a minimally invasive procedure for maxillary sinus floor elevation with a transcrestal approach (tSFE) and evaluate the influence of clinician's experience in implant surgery on its outcomes. MATERIALS AND METHODS: Patients were treated by clinicians with different levels of experience in implant surgery and inexperienced with respect to the investigated tSFE technique. The initial (n = 13) and final (n = 13) groups treated by the expert clinician were compared for tSFE outcomes. Additionally, the high, moderate, and low groups (n = 20 each) treated by the expert, moderately experienced, and low experienced clinician, respectively, were compared. RESULTS: (1) No significant differences in clinical and radiographic outcomes were observed between initial and final groups; (2) high, moderate, and low groups showed substantial vertical augmentation in limited operation time with treatment outcomes being influenced by the level of experience in implant surgery. CONCLUSIONS: The investigated technique allows for a substantial vertical augmentation at limited operation times when used by different clinicians. The extent of sinus lift (as radiographically assessed) seems to be influenced by the clinician's level of experience in implant dentistry. PMID- 26035374 TI - Regulation of transcription elongation and termination. AB - This article will review our current understanding of transcription elongation and termination in E. coli. We discuss why transcription elongation complexes pause at certain template sites and how auxiliary host and phage transcription factors affect elongation and termination. The connection between translation and transcription elongation is described. Finally we present an overview indicating where progress has been made and where it has not. PMID- 26035376 TI - Oral Rehabilitation With Orthognathic Surgery After Dental Implant Placement for Class III Malocclusion With Skeletal Asymmetry and Posterior Bite Collapse. AB - Increasing numbers of older patients are seeking orthognathic surgery to treat jaw deformity. However, orthodontic and orthognathic surgical treatment is difficult in cases without occlusal vertical stop. A 55-year-old man presented with Class III malocclusion and mandibular protrusion including esthetic problems and posterior bite collapse. He underwent dental implant treatment to reconstruct an occlusal vertical stop before orthognathic surgery. His occlusal function and esthetic problems improved after surgery, and his skeletal and occlusal stability has been maintained for 6 years. Dental implant placement at appropriate positions could help to determine the position of the proximal segment at orthognathic surgery and could shorten the time required to restore esthetic and occlusal function. This case demonstrates how skeletal and dental stability can be maintained long after surgery in a patient with jaw deformity and posterior bite collapse. PMID- 26035377 TI - High-Performance Polymers and Their Potential Application as Medical and Oral Implant Materials: A Review. AB - PURPOSE: To review the literature on high-performance polymeric (HPP) materials used as medical and oral implants and make comparisons with the commonly used titanium. MATERIAL AND METHODS: Original scientific articles published in English in MEDLINE (PubMed-NCBI) and Picarta literature databases between January 01, 1995 and June 01, 2013 were included in this review. Additional information was derived from scientific reports, medical and chemical textbooks, handbooks, product information, manufacturers' instructions, and Internet web sites of the manufacturers. RESULTS: Based on the 7 animal studies and 1 clinical study, HPP polyetheretherketone (PEEK) consisting of a single monomer and featuring a low Young modulus may be advantageous. PEEK seems to lead to less osteolyses and healing problems and no scattering in radiation was observed. Some animal studies showed direct contact between PEEK and the bone with high biocompatibility and no evidence for cytotoxicity, mutagenicity, carcinogenicity, and immunogenicity to the present day. CONCLUSION: The HPPs (ie, PEEK) may carry some potential to be an alternative material for titanium as medical and dental implants. Yet, clinical and animal studies are limited in the field of implantology with such materials. PMID- 26035378 TI - Molecular characterization of hepatocarcinogenesis using mouse models. AB - Hepatocellular carcinoma (HCC) is a deadly disease, often unnoticed until the late stages, when treatment options become limited. Thus, there is a crucial need to identify biomarkers for early detection of developing HCC, as well as molecular pathways that would be amenable to therapeutic intervention. Although analysis of human HCC tissues and serum components may serve these purposes, inability of early detection also precludes possibilities of identification of biomarkers or pathways that are sequentially perturbed at earlier phases of disease progression. We have therefore explored the option of utilizing mouse models to understand in a systematic and longitudinal manner the molecular pathways that are progressively deregulated by various etiological factors in contributing to HCC formation, and we report the initial findings in characterizing their validity. Hepatitis B surface antigen transgenic mice, which had been exposed to aflatoxin B1 at various stages in life, were used as a hepatitis model. Our findings confirm a synergistic effect of both these etiological factors, with a gender bias towards males for HCC predisposition. Time-based aflatoxin B1 treatment also demonstrated the requirement of non quiescent liver for effective transformation. Tumors from these models with various etiologies resemble human HCCs histologically and at the molecular level. Extensive molecular characterization revealed the presence of an 11-gene HCC expression signature that was able to discern transformed human hepatocytes from primary cells, regardless of etiology, and from other cancer types. Moreover, distinct molecular pathways appear to be deregulated by various etiological agents en route to formation of HCCs, in which common pathways converge, highlighting the existence of etiology-specific as well as common HCC-specific molecular perturbations. This study therefore highlights the utility of these mouse models, which provide a rich resource for the longitudinal analysis of molecular changes and biomarkers associated with HCC that could be exploited further for therapeutic targeting. PMID- 26035379 TI - Phenotypic and functional characterization of Bst+/- mouse retina. AB - The belly spot and tail (Bst(+/-)) mouse phenotype is caused by mutations of the ribosomal protein L24 (Rpl24). Among various phenotypes in Bst(+/-) mice, the most interesting are its retinal abnormalities, consisting of delayed closure of choroid fissures, decreased ganglion cells and subretinal vascularization. We further characterized the Bst(+/-) mouse and investigated the underlying molecular mechanisms to assess the feasibility of using this strain as a model for stem cell therapy of retinal degenerative diseases due to retinal ganglion cell (RGC) loss. We found that, although RGCs are significantly reduced in retinal ganglion cell layer in Bst(+/-) mouse, melanopsin(+) RGCs, also called ipRGCs, appear to be unchanged. Pupillary light reflex was completely absent in Bst(+/-) mice but they had a normal circadian rhythm. In order to examine the pathological abnormalities in Bst(+/-) mice, we performed electron microscopy in RGC and found that mitochondria morphology was deformed, having irregular borders and lacking cristae. The complex activities of the mitochondrial electron transport chain were significantly decreased. Finally, for subretinal vascularization, we also found that angiogenesis is delayed in Bst(+/-) associated with delayed hyaloid regression. Characterization of Bst(+/-) retina suggests that the Bst(+/-) mouse strain could be a useful murine model. It might be used to explore further the pathogenesis and strategy of treatment of retinal degenerative diseases by employing stem cell technology. PMID- 26035380 TI - IKKalpha is involved in kidney recovery and regeneration of acute ischemia/reperfusion injury in mice through IL10-producing regulatory T cells. AB - The recovery phase after kidney ischemia/reperfusion (IR) injury is often associated with the suppression of inflammation and the proliferation of tubular epithelial cells (TECs). The duration of this phase is often determined by the suppression of inflammation and the proliferation of TECs. Several lines of evidence suggest that IkappaB kinase alpha (IKKalpha) not only promotes the production of anti-inflammatory factors and/or prevents the production of inflammatory factors, but also induces the accompanying cell differentiation and regeneration, and suppresses inflammation. We therefore hypothesized that IKKalpha could participate in the kidney repair after IR injury and have used a mouse model of acute kidney injury (AKI) to test this. We found that IKKalpha mediated the repair of the kidney via infiltrated regulatory T (Treg) cells, which can produce anti-inflammatory cytokine IL10, and that IKKalpha also increased the proliferation of the surviving TECs and suppressed of inflammation. In addition, the expression of indoleamine 2,3-dioxygenase (IDO) in TECs is consistent with the infiltration of IL10-producing Treg cells. We conclude that IKKalpha is involved in kidney recovery and regeneration through the Treg cells that can produce IL10, which might be a potential therapeutic target that can be used to promote kidney repair after IR injury. PMID- 26035381 TI - Cx3cr1 deficiency in mice attenuates hepatic granuloma formation during acute schistosomiasis by enhancing the M2-type polarization of macrophages. AB - Acute schistosomiasis is characterized by pro-inflammatory responses against tissue- or organ-trapped parasite eggs along with granuloma formation. Here, we describe studies in Cx3cr1(-/-) mice and demonstrate the role of Cx3cr1 in the pathoetiology of granuloma formation during acute schistosomiasis. Mice deficient in Cx3cr1 were protected from granuloma formation and hepatic injury induced by Schistosoma japonicum eggs, as manifested by reduced body weight loss and attenuated hepatomegaly along with preserved liver function. Notably, S. japonicum infection induced high levels of hepatic Cx3cr1 expression, which was predominantly expressed by infiltrating macrophages. Loss of Cx3cr1 rendered macrophages preferentially towards M2 polarization, which then led to a characteristic switch of the host immune defense from a conventional Th1 to a typical Th2 response during acute schistosomiasis. This immune switch caused by Cx3cr1 deficiency was probably associated with enhanced STAT6/PPAR-gamma signaling and increased expression of indoleamine 2,3-dioxygenase (IDO), an enzyme that promotes M2 polarization of macrophages. Taken together, our data provide evidence suggesting that CX3CR1 could be a viable therapeutic target for treatment of acute schistosomiasis. PMID- 26035382 TI - Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1 mutant mice. AB - Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best-defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here, we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal-to-epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models with human tumour material of mutant or wild-type WT1 datasets identified the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin. PMID- 26035383 TI - Targeting tubulointerstitial remodeling in proteinuric nephropathy in rats. AB - Proteinuria is an important cause of tubulointerstitial damage. Anti-proteinuric interventions are not always successful, and residual proteinuria often leads to renal failure. This indicates the need for additional treatment modalities by targeting the harmful downstream consequences of proteinuria. We previously showed that proteinuria triggers renal lymphangiogenesis before the onset of interstitial inflammation and fibrosis. However, the interrelationship of these interstitial events in proteinuria is not yet clear. To this end, we specifically blocked lymphangiogenesis (anti-VEGFR3 antibody), monocyte/macrophage influx (clodronate liposomes) or lymphocyte and myofibroblast influx (S1P agonist FTY720) separately in a rat model to investigate the role and the possible interaction of each of these phenomena in tubulointerstitial remodeling in proteinuric nephropathy. Proteinuria was induced in 3-month old male Wistar rats by adriamycin injection. After 6 weeks, when proteinuria has developed, rats were treated for another 6 weeks by anti-VEGFR3 antibody, clodronate liposomes or FTY720 up to week 12. In proteinuric rats, lymphangiogenesis, influx of macrophages, T cells and myofibroblasts, and collagen III deposition and interstitial fibrosis significantly increased at week 12 vs week 6. Anti-VEGFR3 antibody prevented lymphangiogenesis in proteinuric rats, however, without significant effects on inflammatory and fibrotic markers or proteinuria. Clodronate liposomes inhibited macrophage influx and partly reduced myofibroblast expression; however, neither significantly prevented the development of lymphangiogenesis, nor fibrotic markers and proteinuria. FTY720 prevented myofibroblast accumulation, T-cell influx and interstitial fibrosis, and partially reduced macrophage number and proteinuria; however, it did not significantly influence lymphangiogenesis and collagen III deposition. This study showed that proteinuria-induced interstitial fibrosis cannot be halted by blocking lymphangiogenesis or the influx of macrophages. On the other hand, FTY720 treatment did prevent T-cell influx, myofibroblast accumulation and interstitial fibrosis, but not renal lymphangiogenesis and proteinuria. We conclude that tubulointerstitial fibrosis and inflammation are separate from lymphangiogenesis, at least under proteinuric conditions. PMID- 26035384 TI - Iron is a specific cofactor for distinct oxidation- and aggregation-dependent Abeta toxicity mechanisms in a Drosophila model. AB - Metals, including iron, are present at high concentrations in amyloid plaques in individuals with Alzheimer's disease, where they are also thought to be cofactors in generating oxidative stress and modulating amyloid formation. In this study, we present data from several Drosophila models of neurodegenerative proteinopathies indicating that the interaction between iron and amyloid beta peptide (Abeta) is specific and is not seen for other aggregation-prone polypeptides. The interaction with iron is likely to be important in the dimerisation of Abeta and is mediated by three N-terminal histidines. Transgenic fly lines systematically expressing all combinations of His>Ala substitutions in Abeta were generated and used to study the pathological role of these residues. Developmental eye phenotypes, longevity and histological examinations indicate that the N-terminal histidines have distinct position-dependent and -independent mechanisms. The former mediate the toxic effects of metals and Abeta aggregation under non-oxidising conditions and the latter are relevant under oxidising conditions. Understanding how Abeta mediates neurotoxic effects in vivo will help to better target pathological pathways using aggregation blockers and metal modifying agents. PMID- 26035385 TI - Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/beta-catenin-driven trans-differentiation of murine alveolar epithelial cells. AB - The alveolar epithelium represents a major site of tissue destruction during lung injury. It consists of alveolar epithelial type I (ATI) and type II (ATII) cells. ATII cells are capable of self-renewal and exert progenitor function for ATI cells upon alveolar epithelial injury. Cell differentiation pathways enabling this plasticity and allowing for proper repair, however, are poorly understood. Here, we applied proteomics, expression analysis and functional studies in primary murine ATII cells to identify proteins and molecular mechanisms involved in alveolar epithelial plasticity. Mass spectrometry of cultured ATII cells revealed a reduction of carbonyl reductase 2 (CBR2) and an increase in enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) protein expression during ATII-to-ATI cell trans-differentiation. This was accompanied by increased Wnt/beta-catenin signaling, as analyzed by qRT-PCR and immunoblotting. Notably, ENO1 and PDIA3, along with T1alpha (podoplanin; an ATI cell marker), exhibited decreased protein expression upon pharmacological and molecular Wnt/beta-catenin inhibition in cultured ATII cells, whereas CBR2 levels were stabilized. Moreover, we analyzed primary ATII cells from mice with bleomycin-induced lung injury, a model exhibiting activated Wnt/beta-catenin signaling in vivo. We observed reduced CBR2 significantly correlating with surfactant protein C (SFTPC), whereas ENO1 and PDIA3 along with T1alpha were increased in injured ATII cells. Finally, siRNA-mediated knockdown of ENO1, as well as PDIA3, in primary ATII cells led to reduced T1alpha expression, indicating diminished cell trans-differentiation. Our data thus identified proteins involved in ATII-to-ATI cell trans-differentiation and suggest a Wnt/beta-catenin-driven functional role of ENO1 and PDIA3 in alveolar epithelial cell plasticity in lung injury and repair. PMID- 26035386 TI - Chronic administration of recombinant IL-6 upregulates lipogenic enzyme expression and aggravates high-fat-diet-induced steatosis in IL-6-deficient mice. AB - Interleukin-6 (IL-6) has emerged as an important mediator of fatty acid metabolism with paradoxical effects in the liver. Administration of IL-6 has been reported to confer protection against steatosis, but plasma and tissue IL-6 concentrations are elevated in chronic liver diseases, including fatty liver diseases associated with obesity and alcoholic ingestion. In this study, we further investigated the role of IL-6 on steatosis induced through a high-fat diet (HFD) in wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice. Additionally, HFD-fed IL-6(-/-) mice were also chronically treated with recombinant IL-6 (rIL 6). Obesity in WT mice fed a HFD associated with elevated serum IL-6 levels, fatty liver, upregulation of carnitine palmitoyltransferase 1 (CPT1) and signal transducer and activator of transcription-3 (STAT3), increased AMP kinase phosphorylation (p-AMPK), and downregulation of the hepatic lipogenic enzymes fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1). The HFD-fed IL-6( /-) mice showed severe steatosis, no changes in CPT1 levels or AMPK activity, no increase in STAT3 amounts, inactivated STAT3, and marked downregulation of the expression of acetyl-CoA carboxylase (ACCalpha/beta), FAS and SCD1. The IL-6 chronic replacement in HFD-fed IL-6 -/-: mice restored hepatic STAT3 and AMPK activation but also increased the expression of the lipogenic enzymes ACCalpha/beta, FAS and SCD1. Furthermore, rIL-6 administration was associated with aggravated steatosis and elevated fat content in the liver. We conclude that, in the context of HFD-induced obesity, the administration of rIL-6 might contribute to the aggravation of fatty liver disease through increasing lipogenesis. PMID- 26035387 TI - Sun1 deficiency leads to cerebellar ataxia in mice. AB - Migration and organization of the nucleus are essential for the proliferation and differentiation of cells, including neurons. However, the relationship between the positioning of the nucleus and cellular morphogenesis remains poorly understood. Inherited recessive cerebellar ataxia has been attributed to mutations in SYNE1, a component of the linker of nucleoskeleton and cytoskeleton (LINC) complex. Regardless, Syne1-mutant mice present with normal cerebellar development. The Sad1-Unc-84 homology (SUN)-domain proteins are located at the inner nuclear membrane and recruit Syne proteins through the KASH domain to the outer nuclear membrane. Here, we report an unrecognized contribution of Sun1 and Sun2 to the postnatal development of murine cerebellum. Mice depleted of Sun1 showed a marked reduction in the cerebellar volume, and this phenotype is exacerbated with additional loss of a Sun2 allele. Consistent with these histological changes, Sun1(-/-) and Sun1(-/-)Sun2(+/-) mice exhibited defective motor coordination. Results of immunohistochemical analyses suggested that Sun1 is highly expressed in Purkinje cells and recruits Syne2 to the periphery of the nucleus. Approximately 33% of Purkinje cells in Sun1(-/-) mice and 66% of Purkinje cells in Sun1(-/-)Sun2(+/-) mice were absent from the surface of the internal granule layer (IGL), whereas the proliferation and migration of granule neurons were unaffected. Furthermore, the Sun1(-/-)Sun2(+/-) Purkinje cells exhibited retarded primary dendrite specification, reduced dendritic complexity and aberrant patterning of synapses. Our findings reveal a cell-type-specific role for Sun1 and Sun2 in nucleokinesis during cerebellar development, and we propose the use of Sun-deficient mice as a model for studying cerebellar ataxia that is associated with mutation of human SYNE genes or loss of Purkinje cells. PMID- 26035388 TI - A Drosophila model for mito-nuclear diseases generated by an incompatible interaction between tRNA and tRNA synthetase. AB - Communication between the mitochondrial and nuclear genomes is vital for cellular function. The assembly of mitochondrial enzyme complexes, which produce the majority of cellular energy, requires the coordinated expression and translation of both mitochondrially and nuclear-encoded proteins. The joint genetic architecture of this system complicates the basis of mitochondrial diseases, and mutations both in mitochondrial DNA (mtDNA)- and nuclear-encoded genes have been implicated in mitochondrial dysfunction. Previously, in a set of mitochondrial nuclear introgression strains, we characterized a dual genome epistasis in which a naturally occurring mutation in the Drosophila simulans simw(501) mtDNA-encoded transfer RNA (tRNA) for tyrosine (tRNA(Tyr)) interacts with a mutation in the nuclear-encoded mitochondrially localized tyrosyl-tRNA synthetase from Drosophila melanogaster. Here, we show that the incompatible mitochondrial-nuclear combination results in locomotor defects, reduced mitochondrial respiratory capacity, decreased oxidative phosphorylation (OXPHOS) enzyme activity and severe alterations in mitochondrial morphology. Transgenic rescue strains containing nuclear variants of the tyrosyl-tRNA synthetase are sufficient to rescue many of the deleterious phenotypes identified when paired with the simw(501) mtDNA. However, the severity of this defective mito-nuclear interaction varies across traits and genetic backgrounds, suggesting that the impact of mitochondrial dysfunction might be tissue specific. Because mutations in mitochondrial tRNA(Tyr) are associated with exercise intolerance in humans, this mitochondrial nuclear introgression model in Drosophila provides a means to dissect the molecular basis of these, and other, mitochondrial diseases that are a consequence of the joint genetic architecture of mitochondrial function. PMID- 26035389 TI - Glycoprotein A33 deficiency: a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease. AB - The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33(-/-) mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33(-/-) mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33(-/-) mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33(-/-) mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33(-/-) mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33(-/-) mice provide a valuable model to study the mechanisms linking intestinal permeability and multiple inflammatory pathologies. Moreover, this model could facilitate preclinical studies aimed at identifying drugs that restore barrier function. PMID- 26035390 TI - ALS mutant FUS proteins are recruited into stress granules in induced pluripotent stem cell-derived motoneurons. AB - Patient-derived induced pluripotent stem cells (iPSCs) provide an opportunity to study human diseases mainly in those cases for which no suitable model systems are available. Here, we have taken advantage of in vitro iPSCs derived from patients affected by amyotrophic lateral sclerosis (ALS) and carrying mutations in the RNA-binding protein FUS to study the cellular behavior of the mutant proteins in the appropriate genetic background. Moreover, the ability to differentiate iPSCs into spinal cord neural cells provides an in vitro model mimicking the physiological conditions. iPSCs were derived from FUS(R514S) and FUS(R521C) patient fibroblasts, whereas in the case of the severe FUS(P525L) mutation, in which fibroblasts were not available, a heterozygous and a homozygous iPSC line were raised by TALEN-directed mutagenesis. We show that aberrant localization and recruitment of FUS into stress granules (SGs) is a prerogative of the FUS mutant proteins and occurs only upon induction of stress in both undifferentiated iPSCs and spinal cord neural cells. Moreover, we show that the incorporation into SGs is proportional to the amount of cytoplasmic FUS, strongly correlating with the cytoplasmic delocalization phenotype of the different mutants. Therefore, the available iPSCs represent a very powerful system for understanding the correlation between FUS mutations, the molecular mechanisms of SG formation and ALS ethiopathogenesis. PMID- 26035391 TI - A mitochondrial therapeutic reverses visual decline in mouse models of diabetes. AB - Diabetic retinopathy is characterized by progressive vision loss and the advancement of retinal micoraneurysms, edema and angiogenesis. Unfortunately, managing glycemia or targeting vascular complications with anti-vascular endothelial growth factor agents has shown only limited efficacy in treating the deterioration of vision in diabetic retinopathy. In light of growing evidence that mitochondrial dysfunction is an independent pathophysiology of diabetes and diabetic retinopathy, we investigated whether selectively targeting and improving mitochondrial dysfunction is a viable treatment for visual decline in diabetes. Measures of spatial visual behavior, blood glucose, bodyweight and optical clarity were made in mouse models of diabetes. Treatment groups were administered MTP-131, a water-soluble tetrapeptide that selectively targets mitochondrial cardiolipin and promotes efficient electron transfer, either systemically or in eye drops. Progressive visual decline emerged in untreated animals before the overt symptoms of metabolic and ophthalmic abnormalities were manifest, but with time, visual dysfunction was accompanied by compromised glucose clearance, and elevated blood glucose and bodyweight. MTP-131 treatment reversed the visual decline without improving glycemic control or reducing bodyweight. These data provide evidence that visuomotor decline is an early complication of diabetes. They also indicate that selectively treating mitochondrial dysfunction with MTP 131 has the potential to remediate the visual dysfunction and to complement existing treatments for diabetic retinopathy. PMID- 26035392 TI - A new cellular model to follow Friedreich's ataxia development in a time-resolved way. AB - Friedreich's ataxia (FRDA) is a recessive autosomal ataxia caused by reduced levels of frataxin (FXN), an essential mitochondrial protein that is highly conserved from bacteria to primates. The exact role of frataxin and its primary function remain unclear although this information would be very valuable to design a therapeutic approach for FRDA. A main difficulty encountered so far has been that of establishing a clear temporal relationship between the different observations that could allow a distinction between causes and secondary effects, and provide a clear link between aging and disease development. To approach this problem, we developed a cellular model in which we can switch off/on in a time controlled way the frataxin gene partially mimicking what happens in the disease. We exploited the TALEN and CRISPR methodologies to engineer a cell line where the presence of an exogenous, inducible FXN gene rescues the cells from the knockout of the two endogenous FXN genes. This system allows the possibility of testing the progression of disease and is a valuable tool for following the phenotype with different newly acquired markers. PMID- 26035393 TI - A natural human IgM that binds to gangliosides is therapeutic in murine models of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neurological disease that primarily affects spinal cord anterior horn cells and their axons for which there is no treatment. Here we report the use of a recombinant natural human IgM that binds to the surface of neurons and supports neurite extension, rHIgM12, as a therapeutic strategy in murine models of human ALS. A single 200 ug intraperitoneal dose of rHIgM12 increases survival in two independent genetic based mutant SOD1 mouse strains (SOD1G86R and SOD1G93A) by 8 and 10 days, delays the onset of neurological deficits by 16 days, delays the onset of weight loss by 5 days, and preserves spinal cord axons and anterior horn neurons. Immuno-overlay of thin layer chromatography and surface plasmon resonance show that rHIgM12 binds with high affinity to the complex gangliosides GD1a and GT1b. Addition of rHIgM12 to neurons in culture increases alpha-tubulin tyrosination levels, suggesting an alteration of microtubule dynamics. We previously reported that a single peripheral dose of rHIgM12 preserved neurological function in a murine model of demyelination with axon loss. Because rHIgM12 improves three different models of neurological disease, we propose that the IgM might act late in the cascade of neuronal stress and/or death by a broad mechanism. PMID- 26035395 TI - RETINAL ANGIOMATOUS PROLIFERATION: A Quantitative Analysis of the Fundoscopic Features of the Fellow Eye. AB - PURPOSE: To quantitatively analyze and compare the fundoscopic features between fellow eyes of retinal angiomatous proliferation and typical exudative age related macular degeneration and to identify possible predictors of neovascularization. METHODS: Retrospective case-control study. Seventy-nine fellow eyes of unilateral retinal angiomatous proliferation (n = 40) and typical exudative age-related macular degeneration (n = 39) were included. Fundoscopic features of the fellow eyes were assessed using digital color fundus photographs taken at the time of diagnosis of neovascularization in the first affected eye. Grading was performed by two independent graders using RetmarkerAMD, a computer assisted grading software based on the International Classification and Grading System for age-related macular degeneration. RESULTS: Baseline total number and area (square micrometers) of drusen in the central 1,000, 3,000, and 6,000 MUm were considerably inferior in the fellow eyes of retinal angiomatous proliferation, with statistically significant differences (P < 0.05) observed in virtually every location (1,000, 3,000, and 6,000 MUm). A soft drusen (>=125 MUm) area >510,196 MUm2 in the central 6,000 MUm was associated with an increased risk of neovascularization (hazard ratio, 4.35; 95% confidence interval [1.56-12.15]; P = 0.005). CONCLUSION: Baseline fundoscopic features of the fellow eye differ significantly between retinal angiomatous proliferation and typical exudative age related macular degeneration. A large area (>510,196 MUm2) of soft drusen in the central 6,000 MUm confers a significantly higher risk of neovascularization and should be considered as a phenotypic risk factor. PMID- 26035394 TI - Phospholamban overexpression in mice causes a centronuclear myopathy-like phenotype. AB - Centronuclear myopathy (CNM) is a congenital myopathy that is histopathologically characterized by centrally located nuclei, central aggregation of oxidative activity, and type I fiber predominance and hypotrophy. Here, we obtained commercially available mice overexpressing phospholamban (Pln(OE)), a well-known inhibitor of sarco(endo)plasmic reticulum Ca(2+)-ATPases (SERCAs), in their slow twitch type I skeletal muscle fibers to determine the effects on SERCA function. As expected with a 6- to 7-fold overexpression of phospholamban, SERCA dysfunction was evident in Pln(OE) muscles, with marked reductions in rates of Ca(2+) uptake, maximal ATPase activity and the apparent affinity of SERCA for Ca(2+). However, our most significant discovery was that the soleus and gluteus minimus muscles from the Pln(OE) mice displayed overt signs of myopathy: they histopathologically resembled human CNM, with centrally located nuclei, central aggregation of oxidative activity, type I fiber predominance and hypotrophy, progressive fibrosis and muscle weakness. This phenotype is associated with significant upregulation of muscle sarcolipin and dynamin 2, increased Ca(2+) activated proteolysis, oxidative stress and protein nitrosylation. Moreover, in our assessment of muscle biopsies from three human CNM patients, we found a significant 53% reduction in SERCA activity and increases in both total and monomeric PLN content compared with five healthy subjects, thereby justifying future studies with more CNM patients. Altogether, our results suggest that the commercially available Pln(OE) mouse phenotypically resembles human CNM and could be used as a model to test potential mechanisms and therapeutic strategies. To date, there is no cure for CNM and our results suggest that targeting SERCA function, which has already been shown to be an effective therapeutic target for murine muscular dystrophy and human cardiomyopathy, might represent a novel therapeutic strategy to combat CNM. PMID- 26035396 TI - INCIDENCE OF SUSTAINED OCULAR HYPERTENSION USING PREPACKAGED VERSUS FRESHLY PREPARED INTRAVITREAL BEVACIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION. AB - PURPOSE: To compare the incidence of sustained ocular hypertension (OHT) after intravitreal injections of prepackaged versus freshly prepared bevacizumab monotherapy for the treatment of neovascular age-related macular degeneration. METHODS: Charts of 1,216 patients with neovascular age-related macular degeneration receiving intravitreal bevacizumab monotherapy at 2 retina practices using different preparations of bevacizumab between January 1, 2009, and December 31, 2011, were reviewed. Primary outcome was incidence of sustained OHT, defined as intraocular pressure > 25 mmHg with an increase >= 6 from baseline on >= 2 consecutive visits or requiring treatment. RESULTS: A total of 6,479 injections in 740 eyes of 634 patients were included and 14 eyes (0.81% incidence per eye year) developed sustained OHT. For eyes receiving prepackaged bevacizumab, 10 of 339 eyes (1.39% incidence per eye-year) developed sustained OHT compared with 4 of 401 eyes (0.39% incidence per eye-year) receiving freshly prepared bevacizumab, giving an incidence rate ratio of 3.55 (95% confidence interval, 0.93-13.49; P = 0.063). All eyes that developed sustained OHT achieved intraocular pressure control with observation or topical therapy alone. CONCLUSION: Incidence of sustained OHT after intravitreal bevacizumab is low. We found a trend toward higher rates of sustained OHT with prepackaged bevacizumab although this difference was not statistically or clinically significant. PMID- 26035397 TI - MACULAR DETACHMENT ASSOCIATED WITH INTRACHOROIDAL CAVITATION IN NONPATHOLOGICAL MYOPIC EYES. AB - PURPOSE: To report the characteristics of a macular detachment associated with peripapillary intrachoroidal cavitation (ICC) and the outcomes of vitrectomy. METHODS: The medical records of 69 eyes of 61 patients who underwent vitrectomy for macular detachment or macular retinoschisis but without vitreomacular traction or optic disc pit were reviewed. Optical coherence tomography was used to determine the morphology of the ICC. The outcomes of vitrectomy including the creation of a posterior vitreous detachment and internal limiting membrane peeling were evaluated. RESULTS: An ICC was detected in 3 of 3 eyes without pathologic myopia but none in 66 eyes with pathologic myopia (P < 0.0001). Myopic peripapillary conus was present in all 3 eyes, tilted disc in 2 eyes (67%), posterior staphyloma in 1 eye (33%), and no preoperative posterior vitreous detachment in all eyes. Optical coherence tomography detected a connection between the vitreous cavity and the ICC in two eyes with pit-like splitting and between the subretinal space and the ICC in two eyes. The macular detachment was resolved 5 months to 6 months postoperatively with improvement of vision. CONCLUSION: A macular detachment with ICC can be present in nonpathological myopic eyes. Vitreous surgery to create a posterior vitreous detachment with internal limiting membrane peeling may help resolve the macular detachment. PMID- 26035398 TI - COMPARISON OF HALVING THE IRRADIATION TIME OR THE VERTEPORFIN DOSE IN PHOTODYNAMIC THERAPY FOR CHRONIC CENTRAL SEROUS CHORIORETINOPATHY. AB - PURPOSE: To compare the efficacy and safety of photodynamic therapy using reduced irradiation time or reduced verteporfin dose for chronic central serous chorioretinopathy. METHODS: Between April 2011 and December 2013, 45 eyes with chronic central serous chorioretinopathy (43 consecutive patients) were treated with photodynamic therapy, using either half the irradiation time (18 eyes) or half the verteporfin dose (27 eyes). Outcome measures at follow-up, over at least 3 months, were complete resolution of serous retinal detachment, best-corrected visual acuity, and central retinal thickness. RESULTS: After 3 months, serous retinal detachment had completely resolved in 88.8% of eyes in both treatment groups, which were therefore not significantly different. The logarithm of the minimal angle of resolution best-corrected visual acuity (Snellen equivalent) improved from 0.245 (20/35) to 0.130 (20/27) (P < 0.05, paired t-test) in the reduced time group and from 0.283 (20/38) to 0.138 (20/27) (P < 0.05) in the reduced verteporfin group. Final best-corrected visual acuities in the 2 groups were not significantly different. Central retinal thicknesses dropped from 337.0 MUm to 146.6 MUm (P < 0.05) in the reduced time group and from 343.5 MUm to 166.9 MUm (P < 0.05) in the reduced verteporfin group. No ocular or systemic side effects were observed. CONCLUSION: Reduced irradiation time and reduced verteporfin dose were equally effective and safe in photodynamic therapy for chronic central serous chorioretinopathy. PMID- 26035399 TI - NEWLY DIAGNOSED ACTIVE RETINOBLASTOMA IN ADULTS. AB - PURPOSE: To describe the clinical features, treatment, and outcome of retinoblastoma in adults. METHODS: Retrospective case series. RESULTS: The mean age at initial presentation of retinoblastoma was 30 years (median, 26 years; range, 22-48 years). There were four males and four females, and all manifested unilateral retinoblastoma. The mean duration of symptoms was 22 months (median, 12 months; range, 1-100 months). Six patients had intraocular retinoblastoma, and 2 had secondary orbital involvement. The eyes with intraocular retinoblastoma were classified according to the International Classification of Retinoblastoma as Group D (n = 3) or Group E (n = 3). The primary treatment for intraocular retinoblastoma (n = 6) included systemic chemotherapy (n = 1), external beam radiotherapy (n = 2), and enucleation (n = 3). Secondary treatment for tumor recurrence included enucleation (n = 2), and combination of intraarterial chemotherapy, intravitreal chemotherapy, and plaque radiotherapy (n = 1). The eyes with orbital extension of retinoblastoma were classified according to the International Retinoblastoma Staging System as Stage 3a (n = 2). The primary treatment for those with orbital extension of retinoblastoma included multimodality treatment (combination of systemic chemotherapy, orbital exenteration, and external beam radiotherapy). Systemic metastasis and related death occurred in one case. CONCLUSION: Retinoblastoma in adults is uncommon. Active tumor in this age group is usually advanced, necessitating enucleation and/or orbital exenteration. PMID- 26035400 TI - FACTORS INFLUENCING NEED FOR RETREATMENT AND LONG-TERM VISUAL OUTCOME AFTER INTRAVITREAL BEVACIZUMAB FOR MYOPIC CHOROIDAL NEOVASCULARIZATION. AB - PURPOSE: To evaluate the efficacy and the predictive factors associated with the need for retreatment and long-term visual outcome after intravitreal bevacizumab for myopic choroidal neovascularization (CNV). METHODS: Retrospective cohort study of 93 eyes with subfoveal or juxtafoveal myopic CNV treated initially with either 3-monthly or single intravitreal bevacizumab injections followed by pro re nata retreatment. The efficacy was evaluated by the best-corrected visual acuity (BCVA) during follow-up visits. Backward stepwise multiple linear regression analyses were performed to evaluate the potential predictive factors on final BCVA, change in BCVA, and number of injections. Multiple logistic regression was performed to evaluate the potential predictive factors for retreatment. RESULTS: The mean follow-up duration was 25.12 +/- 11.18 (SD) months. The mean logMAR BCVA at baseline was 0.72 +/- 0.58 logMAR (20/100 Snellen equivalent) and was maintained at 0.39 +/- 0.46 logMAR (20/50 Snellen equivalent) at the last follow up (P < 0.001). The mean number of injections was 3.53 +/- 1.70 (range, 3-10), and a total of 25 eyes (26.9%) received retreatment. Patients who received single loading injection had significantly lower mean total number of injections (1.50 +/- 0.73 vs. 3.96 +/- 1.53). Both subfoveal and juxtafoveal myopic CNV eyes had significant improvement in BCVA (0.28 +/- 0.43 vs. 0.22 +/- 0.32 [20/40 vs 20/30 Snellen equivalent], P = 0.506), and juxtafoveal myopic CNV eyes had significantly better BCVA at baseline and at the last follow-up than the subfoveal group. Treatment-naive eyes had significant improvement from baseline BCVA, and the amount of improvement was significantly more than those who received previous photodynamic therapy (0.31 +/- 0.43 vs. 0.06 +/- 0.11 [20/40 vs 20/25 Snellen equivalent], P < 0.001). Multivariate stepwise regression analysis showed that the baseline CNV size (P < 0.05), baseline BCVA (P < 0.001), and duration of symptoms (P < 0.05) were significant predictive factors for final BCVA, and BCVA improvement. Multiple logistic regression analysis identified that CNV size (P = 0.014) and follow-up duration (P = 0.017) were significant predictive factors for retreatment. No significant association was found for number of injections. CONCLUSION: Intravitreal bevacizumab seems to be an effective treatment for both subfoveal and juxtafoveal myopic CNV in the long term. Patients presented with shorter duration of symptoms and smaller CNV size before treatment as significant prognostic factors that predict better visual outcome. Eyes with longer follow-up duration and larger baseline CNV size may have higher risk for retreatment. PMID- 26035401 TI - INTRAVITREAL DEXAMETHASONE IMPLANT FOR RADIATION MACULOPATHY SECONDARY TO PLAQUE BRACHYTHERAPY IN CHOROIDAL MELANOMA. AB - PURPOSE: To evaluate the efficacy of intravitreal dexamethasone implant 0.7 mg (Ozurdex) in radiation maculopathy secondary to plaque brachytherapy in choroidal melanoma. METHODS: Twelve eyes diagnosed of radiation maculopathy secondary to plaque brachytherapy and treated with intravitreal dexamethasone implant were included. Visual acuity, foveal thickness using spectral domain optical coherence tomography, and grade of macular edema, using Horgan classification, were evaluated. RESULTS: Mean age was 65.5 +/- 28 years (range, 40-82 years). Mean follow-up was 8.2 +/- 7.8 months (range, 2-28 months). Mean visual acuity before treatment was, in logarithm of the minimum angle of resolution scale, 1 +/- 0.58 (range, 0.4-2) and mean final visual acuity 0.8 +/- 0.58 (range, 0.2-2), showing a nonsignificant trend to improvement (P = 0.091; Wilcoxon's test). Foveal thickness before treatment was 416 +/- 263 MUm (range, 222-725 MUm) and final foveal thickness 254 +/- 170 MUm (range, 145-750), showing a significant decrease (P = 0.016; Wilcoxon's test). Referring to Horgan classification, a significant reduction in grades before and after treatment was demonstrated (P = 0.007; Wilcoxon's test). CONCLUSION: Ozurdex is a useful treatment for radiation maculopathy associated to plaque brachytherapy for uveal melanoma, with a significant decrease in foveal thickness and a significant improvement in Horgan classification. This anatomical improvement was correlated with a moderate improvement in visual acuity. PMID- 26035402 TI - CHARACTERISTICS AND LONG-TERM OUTCOME OF PATIENTS WITH NONINFECTIOUS RETINAL VASCULITIS. AB - PURPOSE: To investigate the characteristics and long-term outcome of patients with noninfectious retinal vasculitis. METHODS: This was a retrospective multicenter study. Main outcome measures included patients' characteristics, ocular findings, treatment modalities, and best-corrected visual acuity. All patients had at least 12-month follow-up time. RESULTS: Eighty-two eyes (45 patients) were included. Median follow-up was 46 months (range, 12-210 months). At presentation, 12 of the 45 patients (26.6%) had a known associated systemic or ocular disease. A diagnosis of a new systemic disease was found in additional 14 of 33 patients (42.5%) and birdshot chorioretinopathy in 3 of 33 patients (9.1%). The most common systemic disease was Behcet disease (17/24 patients; 70.8%). Laboratory tests had a low diagnostic value. The most common clinical findings were vitritis (58.5%) and perivascular sheathing (50.5%). Most patients were treated with immunosuppressive medications. Mean best-corrected visual acuity improved significantly during follow-up, patients with Behcet disease and worse visual acuity at baseline were more likely to have visual acuity improvement (P < 0.001). CONCLUSION: A new systemic or ocular disease associated with retinal vasculitis was found in more than half of the patients. Behcet disease was the most common newly diagnosed disease. Specific diagnosis leading to proper management is important to maintain favorable long-term visual outcome. PMID- 26035403 TI - INTRAOPERATIVE OPTICAL COHERENCE TOMOGRAPHY DURING VITREORETINAL SURGERY FOR DENSE VITREOUS HEMORRHAGE IN THE PIONEER STUDY. AB - PURPOSE: To evaluate the feasibility and utility of intraoperative optical coherence tomography (OCT) during pars plana vitrectomy surgery for dense vitreous hemorrhage. METHODS: The Prospective Assessment of Intraoperative and Perioperative OCT for Ophthalmic Surgery study examined the utility of intraoperative OCT in ophthalmic surgery. Intraoperative scanning was performed with a microscope-mounted spectral domain OCT system. This report is a case series of those eyes undergoing pars plana vitrectomy for dense central vitreous hemorrhage that precluded preoperative OCT assessment. Intraoperative OCT images were qualitatively evaluated for retinal abnormalities that might impact intraoperative or perioperative management. Clinical variables were collected and assessed. Surgeon assessment of intraoperative OCT utility was also evaluated. RESULTS: Twenty-three eyes were identified and included. The etiology for the vitreous hemorrhage was proliferative diabetic retinopathy (19 eyes, 82.6%), horseshoe retinal tear (1 eye, 4.3%), retinal vein occlusion with neovascularization (1 eye, 4.3%), presumed polypoid choroidal vasculopathy (1 eye, 4.3%), and presumed retinal arterial macroaneurysm (1 eye, 4.3%). Intraoperative OCT revealed epiretinal membrane (14 eyes, 60.9%), macular edema (14 eyes, 60.9%), posterior hyaloid traction (1 eye, 4.3%), and retinal detachment (1 eye, 4.3%). Surgeon feedback suggested that intraoperative OCT impacted surgical decision making in eyes where membrane peeling was performed. CONCLUSION: Intraoperative OCT during pars plana vitrectomy for vitreous hemorrhage may provide physicians with clinically relevant information that may impact surgical management, perioperative management, and patient outcomes. PMID- 26035404 TI - Locating and Outlining the Cortical Motor Representation Areas of Facial Muscles With Navigated Transcranial Magnetic Stimulation. AB - BACKGROUND: Navigated transcranial magnetic stimulation (nTMS) has become established as an accurate noninvasive technique for mapping the functional motor cortex for the representation areas of upper and lower limb muscles but not yet for facial musculature. OBJECTIVE: To characterize the applicability and clinical impact of using nTMS to map cortical motor areas of facial muscles in healthy volunteers and neurosurgical tumor patients. METHODS: Eight healthy volunteers and 12 patients with tumor were studied. The motor threshold (MT) was determined for the abductor pollicis brevis and mentalis muscles. The lateral part of the motor cortex was mapped with suprathreshold stimulation intensity, and motor evoked potentials were recorded from several facial muscles. The patient protocol was modified according to the clinical indication. RESULTS: In all healthy subjects, motor evoked potentials were elicited in the mentalis (mean latency, 13.4 milliseconds) and orbicularis oris (mean latency, 12.6 milliseconds) muscles. At 110% of MT of the mentalis, the motor evoked potentials of facial muscles were elicited mainly in the precentral gyrus but also from one gyrus anterior and posterior to it. The cortical areas applicable for mapping were limited by an artifact attributable to direct peripheral nerve stimulation. The mapping protocol was successful in 10 of 12 tumor patients at locating the representation area of the lower facial muscles. The MT of the facial muscles was significantly higher than that of the abductor pollicis brevis. CONCLUSION: nTMS is an applicable and clinically beneficial noninvasive method to preoperatively map the cortical representation areas of the facial muscles in the lower part of the face. Instead of using the MT of the abductor pollicis brevis, the stimulus intensity during mapping should be proportioned to the MT of a facial muscle. PMID- 26035405 TI - Prediction of Adrenal Adenomas With Hypercortisolism by Using Adrenal Computed Tomography: Emphasis on Contralateral Adrenal Thinning. AB - PURPOSE: To analyze computed tomography (CT) characteristics of adrenal adenomas with hypercortisolism on adrenal CT compared to adenomas with hyperaldosteronism. MATERIALS AND METHODS: Thirty-two adrenal adenomas, consisting of group A (hypercortisolism, n = 16) and group B (hyperaldosteronism, n = 16), were evaluated with adrenal CT. Thirty-four patients without adrenal nodule on CT and hormonal abnormality (group C) were selected for comparison. In adenomas, lesion size, attenuation value, and absolute and relative washout were compared between groups A and B. The mean adrenal thickness was compared quantitatively and qualitatively between groups. RESULTS: All of adenomas satisfied absolute (>=60%) or relative (>=40%) washout criteria of adrenal CT. The mean adrenal thickness was 1.6 +/- 0.3 mm in group A, 2.9 +/- 0.5 mm in group B, and 3.0 +/- 0.4 mm in group C (group A versus B or C, P < 0.001; group B versus C, P = 0.775). For differentiating group A from B, the area under the curve of quantitative and qualitative analyses for contralateral adrenal thickness was 0.982 and 0.934, respectively. Both sensitivity and specificity with cutoff of 2.0 mm or less in thickness and probably thin or more in visual score were 93.7% and 93.7%, and 87.5% and 93.7%, respectively, for predicting group A. CONCLUSIONS: Contralateral adrenal thinning on CT helps predict adrenal adenomas with hypercortisolism. PMID- 26035406 TI - Residual Anatomical Disease in Diffuse Large B-Cell Lymphoma Patients With FDG PET-Based Complete Response After First-Line R-CHOP Therapy: Does It Have Any Prognostic Value? AB - OBJECTIVE: This study aimed to determine the prognostic value of residual anatomical disease, including its size and reduction relative to baseline, in diffuse large B-cell lymphoma patients who have F-fluoro-2-deoxy-d-glucose positron emission tomography-based complete response after first-line R-CHOP therapy. METHODS: This retrospective study included 47 patients. In patients with computed tomography (CT)-based residual disease, the size of the largest residual lesion (Resmax) and the sum of the sizes of all residual lesions (Restotal) were measured, and their reductions relative to baseline (DeltaResmax and DeltaRestotal) were calculated. RESULTS: Patients with high-risk National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) scores had significantly lower progression-free survival (PFS) and overall survival (OS) than patients with low-risk NCCN-IPI scores (P = 0.032 and P = 0.022). In contrast, patients with residual lesions at CT had no significantly lower PFS and OS than those without (P = 0.531 and P = 0.801). In the subpopulation with CT based residual disease, patients with high Resmax, high Restotal, low DeltaResmax, and low DeltaRestotal had no significantly different PFS and OS than those with low Resmax, low Restotal, high DeltaResmax, and high DeltaRestotal (P = 0.980 and P = 0.790, P = 0.423 and P = 0.229, P = 0.923 and P = 0.893, and P = 0.923 and P = 0.893, respectively). CONCLUSIONS: The NCCN-IPI retains its prognostic value in diffuse large B-cell lymphoma patients with F-fluoro-2-deoxy d-glucose positron emission tomography-based complete response after first-line R CHOP therapy. However, the presence of residual anatomical disease, including its size and reduction relative to baseline, has no prognostic value in these patients. PMID- 26035407 TI - High-Pitch Dual-Source Computed Tomography Renal Angiography Comparison With Conventional Low-Pitch Computed Tomography Angiography: Image Quality, Contrast Medium Volume, and Radiation Dose. AB - OBJECTIVE: The objective of this study was to compare the image quality (IQ), contrast medium (CM) volume, and radiation dose of the high-pitch renal computed tomography angiography (CTA) with low-pitch protocol. METHODS: Fifty patients underwent renal CTA on a dual-source 128-slice scanner via a high-pitch mode (pitch = 2.05) with 0.5-mL/kg CM injection, whereas 50 patients were also scanned on the same scanner with low-pitch (pitch = 0.6) and 1.0 mL/kg CM injection. Subjective IQ was evaluated. Objective IQ was determined by the signal-to-noise ratio and contrast-to-noise ratio. Effective radiation dose was also evaluated. RESULTS: The contrast-to-noise ratio and signal-to-noise ratio values as well as the IQ scores between the 2 groups had no significant differences (P > 0.05). The effective radiation dose of the high-pitch group was significantly lower (P < 0.05). CONCLUSIONS: High-pitch scan can provide similar subjective and objective IQ compared with low-pitch protocol for renal CTA, whereas CM volume and radiation exposure were significantly reduced. PMID- 26035408 TI - With-No-Lysine Kinase 4 Mediates Alveolar Fluid Regulation in Hyperoxia-Induced Lung Injury. AB - OBJECTIVES: To investigate mechanisms involved in the regulation of epithelial ion channels and alveolar fluid clearance in hyperoxia-induced lung injury. DESIGN: Laboratory animal experiments. SETTING: Animal care facility procedure room in a medical center. SUBJECTS: Wild-type, STE20/SPS1-related proline/alanine rich kinase knockout (SPAK(-/-)), and with-no-lysine kinase 4 knockin (WNK4(D561A/+)) mice. INTERVENTIONS: Mice were exposed to room air or 95% hyperoxia for 60 hours. MEASUREMENTS AND MAIN RESULTS: Exposure to hyperoxia for 60 hours increased the lung expression of with-no-lysine kinase 4 and led to STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation, which resulted in the suppression of alveolar fluid clearance and increase of lung edema. WNK4(D561A/+) mice at the baseline presented an abundance of epithelium sodium channel and high levels of STE20/SPS1 related proline/alanine-rich kinase and sodium-potassium-chloride cotransporter phosphorylation. Compared with the wild-type group, hyperoxia caused greater epithelium sodium channel expression in WNK4(D561A/+) mice, but no significant difference in STE20/SPS1-related proline/alanine-rich kinase and sodium-potassium chloride cotransporter phosphorylation. The functional inactivation of sodium potassium-chloride cotransporter by gene knockout in SPAK(-/-) mice yielded a lower severity of lung injury and longer animal survival, whereas constitutive expression of with-no-lysine kinase 4 exacerbated the hyperoxia-induced lung injury. Pharmacologic inhibition of sodium-potassium-chloride cotransporter by inhaled furosemide improved animal survival in WNK4(D561A/+) mice. By contrast, inhibition of epithelium sodium channel exacerbated the hyperoxia-induced lung injury and animal death. CONCLUSIONS: With-no-lysine kinase 4 plays a crucial role in the regulation of epithelial ion channels and alveolar fluid clearance, mainly via phosphorylation and activation of STE20/SPS1-related proline/alanine rich kinase and sodium-potassium-chloride cotransporter. PMID- 26035409 TI - Spatial resolution versus data acquisition efficiency in mapping an inhomogeneous system with species diffusion. AB - Traditionally, spatially-resolved photoluminescence (PL) has been performed using a point-by-point scan mode with both excitation and detection occurring at the same spatial location. But with the availability of high quality detector arrays like CCDs, an imaging mode has become popular for performing spatially-resolved PL. By illuminating the entire area of interest and collecting the data simultaneously from all spatial locations, the measurement efficiency can be greatly improved. However, this new approach has proceeded under the implicit assumption of comparable spatial resolution. We show here that when carrier diffusion is present, the spatial resolution can actually differ substantially between the two modes, with the less efficient scan mode being far superior. We apply both techniques in investigation of defects in a GaAs epilayer - where isolated singlet and doublet dislocations can be identified. A superposition principle is developed for solving the diffusion equation to extract the intrinsic carrier diffusion length, which can be applied to a system with arbitrarily distributed defects. The understanding derived from this work is significant for a broad range of problems in physics and beyond (for instance biology) - whenever the dynamics of generation, diffusion, and annihilation of species can be probed with either measurement mode. PMID- 26035410 TI - Dietary fiber intake and pancreatic cancer risk: a meta-analysis of epidemiologic studies. AB - Evidence on the association between dietary fiber intake and pancreatic cancer risk has been controversial. Therefore, we carried out this meta-analysis to summarize available evidence from epidemiologic studies on this point. Relevant studies were identified by searching PubMed, Embase and Web of Science databases as well as by reviewing the rence lists of relevant articles. Random or fixed effects model was used to calculate the summary risk estimates and 95% confidence intervals (CIs). This meta-analysis included one cohort and thirteen case-control studies which involving a total of 3287 subjects with pancreatic cancer. After summarizing the risk estimates of these studies, we yielded a significant association between dietary fiber intake and pancreatic cancer risk among case control studies (odds ratio = 0.54; 95%CI = 0.44-0.67; I(2) = 41.4%; P = 0.043) but a non-significant result in cohort study (hazard ratio = 1.01; 95%CI = 0.59 1.74). Additionally, significant inverse associations were observed when we carried out the stratify analyses by the study characteristics and adjustment for potential confounders among case-control studies. Given only one cohort study included in the present meta-analysis, further prospective-designed studies should validate our findings and report more detail results, including those for subtypes of fiber, the risk estimates which corrected the impact of measurement errors and fully adjust for the potential confounders. PMID- 26035411 TI - Optogenetic control of contractile function in skeletal muscle. AB - Optogenetic stimulation allows activation of cells with high spatial and temporal precision. Here we show direct optogenetic stimulation of skeletal muscle from transgenic mice expressing the light-sensitive channel Channelrhodopsin-2 (ChR2). Largest tetanic contractions are observed with 5-ms light pulses at 30 Hz, resulting in 84% of the maximal force induced by electrical stimulation. We demonstrate the utility of this approach by selectively stimulating with a light guide individual intralaryngeal muscles in explanted larynges from ChR2 transgenic mice, which enables selective opening and closing of the vocal cords. Furthermore, systemic injection of adeno-associated virus into wild-type mice provides sufficient ChR2 expression for optogenetic opening of the vocal cords. Thus, direct optogenetic stimulation of skeletal muscle generates large force and provides the distinct advantage of localized and cell-type-specific activation. This technology could be useful for therapeutic purposes, such as restoring the mobility of the vocal cords in patients suffering from laryngeal paralysis. PMID- 26035412 TI - Decoupling the role of stiffness from other hydroxyapatite signalling cues in periosteal derived stem cell differentiation. AB - Bone extracellular matrix (ECM) is a natural composite made of collagen and mineral hydroxyapatite (HA). Dynamic cell-ECM interactions play a critical role in regulating cell differentiation and function. Understanding the principal ECM cues promoting osteogenic differentiation would be pivotal for both bone tissue engineering and regenerative medicine. Altering the mineral content generally modifies the stiffness as well as other physicochemical cues provided by composite materials, complicating the "cause-effect" analysis of resultant cell behaviour. To isolate the contribution of mechanical cues from other HA-derived signals, we developed and characterised composite HA/gelatin scaffolds with different mineral contents along with a set of stiffness-matched HA-free gelatin scaffolds. Samples were seeded with human periosteal derived progenitor cells (PDPCs) and cultured over 7 days, analysing their resultant morphology and gene expression. Our results show that both stiffness and HA contribute to directing PDPC osteogenic differentiation, highlighting the role of stiffness in triggering the expression of osteogenic genes and of HA in accelerating the process, particularly at high concentrations. PMID- 26035413 TI - Bounded rationality alters the dynamics of paediatric immunization acceptance. AB - Interactions between disease dynamics and vaccinating behavior have been explored in many coupled behavior-disease models. Cognitive effects such as risk perception, framing, and subjective probabilities of adverse events can be important determinants of the vaccinating behaviour, and represent departures from the pure "rational" decision model that are often described as "bounded rationality". However, the impact of such cognitive effects in the context of paediatric infectious disease vaccines has received relatively little attention. Here, we develop a disease-behavior model that accounts for bounded rationality through prospect theory. We analyze the model and compare its predictions to a reduced model that lacks bounded rationality. We find that, in general, introducing bounded rationality increases the dynamical richness of the model and makes it harder to eliminate a paediatric infectious disease. In contrast, in other cases, a low cost, highly efficacious vaccine can be refused, even when the rational decision model predicts acceptance. Injunctive social norms can prevent vaccine refusal, if vaccine acceptance is sufficiently high in the beginning of the vaccination campaign. Cognitive processes can have major impacts on the predictions of behaviour-disease models, and further study of such processes in the context of vaccination is thus warranted. PMID- 26035414 TI - Formation of carbonatite-related giant rare-earth-element deposits by the recycling of marine sediments. AB - Carbonatite-associated rare-earth-element (REE) deposits are the most significant source of the world's REEs; however, their genesis remains unclear. Here, we present new Sr-Nd-Pb and C-O isotopic data for Cenozoic carbonatite-hosted giant REE deposits in southwest China. These REE deposits are located along the western margin of the Yangtze Craton that experienced Proterozoic lithospheric accretion, and controlled by Cenozoic strike-slip faults related to Indo-Asian continental collision. The Cenozoic carbonatites were emplaced as stocks or dykes with associated syenites, and tend to be extremely enriched in Ba, Sr, and REEs and have high (87)Sr/(86)Sr ratios (>0.7055). These carbonatites were likely formed by melting of the sub-continental lithospheric mantle (SCLM), which had been previously metasomatized by high-flux REE- and CO2-rich fluids derived from subducted marine sediments. The fertility of these carbonatites depends on the release of REEs from recycled marine sediments and on the intensity of metasomatic REE refertilization of the SCLM. We suggest that cratonic edges, particularly along ancient convergent margins, possess the optimal configuration for generating giant REE deposits; therefore, areas of metamorphic basement bounded or cut by translithospheric faults along cratonic edges have a high potential for such deposits. PMID- 26035415 TI - Aerobic and cardiovascular autonomic adaptations to moderate intensity endurance exercise in patients with fibromyalgia. AB - OBJECTIVE: To investigate whether moderate intensity endurance exercise has similar effects on cardiovascular fitness and autonomic function in patients with fibromyalgia and healthy controls. DESIGN: Case-control intervention study. SUBJECTS: Twenty-five female patients with fibromyalgia and 25 age- and sex matched healthy controls (age range 40-64 years) were recruited to the study. Fifteen patients and 19 controls participated at both pre- and post-test. METHODS: Supervised spinning workouts of moderate intensity (~75% of age predicted maximum heart rate) were performed twice a week for 12 weeks. Cardiovascular fitness was evaluated by an incremental ergometer cycling test to anaerobic threshold. Autonomic function was assessed by heart rate recovery after exercise, resting blood pressure, and resting heart rate variability. Pain was scored on a visual analogue scale, while overall symptom level was assessed by the Fibromyalgia Impact Questionnaire. RESULTS: Linear regression analysis with adjustments for baseline level and attendance rate showed a similar dose dependent increase in patients and controls in oxygen uptake and workload after the 12-week intervention. Indices of autonomic function remained unchanged in both groups. Neck/shoulder pain decreased in patients, while overall symptom level remained unchanged. CONCLUSIONS: Female patients with fibromyalgia have similar cardiovascular adaptations to moderate intensity endurance exercise as healthy controls. PMID- 26035416 TI - GSK1904529A, an insulin-like growth factor-1 receptor inhibitor, inhibits glioma tumor growth, induces apoptosis and inhibits migration. AB - Malignant gliomas are the most common type of primary malignancy of the central nervous system, with a poor prognosis. The therapeutic options for malignant gliomas are limited and far from satisfactory, and novel treatment strategies are urgently required to improve the outcome of the disease. Insulin-like growth factor (IGF)/IGF-1 receptor (IGF-1R) signaling pathway regulates cell proliferation, motility and survival. The dysregulation of this signaling pathway has been implicated in the development of malignant gliomas. In the present study, GSK1904529A, a small molecule inhibitor of IGF-1R, suppressed glioma cell viability, induced glioma cell apoptosis and inhibited glioma cell migration in vitro. In addition, GSK1904529A inhibited glioma tumor growth and induced tumor cell apoptosis in vivo. In conclusion, the results of the present study suggested GSK1904529A as a promising agent for the treatment of malignant glioma. PMID- 26035417 TI - Elemol from Chamaecyparis obtusa ameliorates 2,4-dinitrochlorobenzene-induced atopic dermatitis. AB - Chamaecyparis obtusa has been traditionally used as an antibiotic agent and in cosmetics for the prevention of microorganism infection and skin troubles. Atopic dermatitis (AD) is a chronic inflammatory skin disease that encompasses immunologic responses, susceptibility factors and compromised skin-barrier function. Use of plant medicines in therapeutic treatment of AD has recently been suggested as an alternative therapeutic option. The present study examined the effect of elemol, an active component of Chamaecyparis obtusa, on AD using in vivo and in vitro models. RBL-2H3 cells were stimulated with concanavalin A and dinitrophenyl human serum albumin, and atopic dermatitis was induced in BALB/c mice by topical application of 2,4-dinitrochlorobenzene (DNCB) prior to elemol treatment. The mRNA expression was evaluated by reverse transcription quantitative polymerase chain reaction, and the levels of beta-hexosaminidase and serum immunoglobulin E (IgE) were examined by ELISA. Histological changes were also performed by microscopy. Elemol attenuated the onset of AD-like skin lesions, reduced serum IgE levels and decreased mast cell infiltration into the dermis and hypodermis. In addition, elemol downregulated the transcriptional expression of several pro-inflammatory cytokines, including TNF-alpha, IL-1beta, IL-6 and IkappaBalpha, in the skin of the DNCB-induced animal models of AD. In the RBL-2H3 mast cell line, elemol significantly inhibited the mRNA expression of IL-4 and IL-13, and further attenuated the release of beta-hexosaminidase from mast cells. Histological examination revealed that elemol significantly ameliorated the DNCB-induced dermal destruction in mice. The results of the present study suggested that elemol may have therapeutic potential in the treatment of AD due to its immunosuppressive effects. PMID- 26035418 TI - Histologic RNFL Thickness in Glaucomatous Versus Normal Human Eyes. AB - PURPOSE: To compare the retinal nerve fiber layer (RNFL) thickness in histologic sections of glaucomatous eyes to nonglaucomatous eyes, to ascertain whether RNFL thinning can be confirmed histologically in human eyes. MATERIALS AND METHODS: Seven postmortem glaucomatous eyes were compared with 17 normal postmortem eyes. The eyes were sectioned using the "umbrella technique" and measurements were performed on 4 concentric peripapillary rings with diameters of 3.0, 3.5, 4.0, and 4.5 mm. An overall average thickness, as well as an average for each of the temporal, superior, nasal, and inferior quadrants was obtained. The RNFL thickness of both groups in each of the quadrants in each of the rings were compared. RESULTS: The overall average thickness (MUm+/-SD) of the glaucomatous eyes for the 3.5-mm diameter rings was 36.5+/-10.6 compared with an average thickness of 60.3+/-19.5 in the nonglaucomatous eyes (P=0.006). The average sectorial thickness of the 3.5-mm diameter rings for the glaucomatous and normal eyes, respectively, was: temporal 30.9+/-10.6, 49.2+/-26.4 (P=0.080); superior 41.0+/-13.2, 75.3+/-26.5 (P=0.003); nasal 32.7+/-7.8, 48.1+/-15.0 (P=0.023); and inferior 41.6+/-14.4, 69.4+/-22.4 (P=0.012). The overall physiological "double hump" pattern was less preserved in the glaucomatous eyes. CONCLUSIONS: In this study a statistically significant loss of RNFL tissue was demonstrated when comparing glaucomatous to normal postmortem human eyes. These findings strengthen data obtained using imaging techniques that quantify RNFL thickness. PMID- 26035419 TI - The Relationship Between Choroidal Expansion and Intraocular Pressure Rise During the Water Drinking Test in Healthy Subjects and Patients With Exfoliation Syndrome. AB - PURPOSE: To evaluate the changes in choroidal thickness (ChT) and intraocular pressure (IOP) during the water drinking test (WDT) in patients with exfoliation syndrome (XFS). MATERIALS AND METHODS: In this prospective study, 20 eyes of 20 patients with XFS and 20 eyes of 20 healthy subjects underwent measurements of subfoveal ChT, IOP, systolic and diastolic blood pressure before and 30 and 60 minutes after the WDT. WDT involved ingestion of 1 L of water within 5 minutes. chi test and analysis of variance were used for the statistical analysis. RESULTS: There were no significant differences between the 2 groups with respect to age (P = 0.238), sex (P = 1.000), central corneal thickness (P = 0.714), axial length (P = 1.000), diastolic blood pressure (P = 0.350), systolic blood pressure (P = 0.064), and IOP (P = 0.234) before water ingestion. Baseline ChT was lower in the XFS group (285.1 +/- 69.1 MUm) as compared with that of controls (339.4 +/ 81.2 MUm) (P = 0.028). ChT was found to be significantly increased at 30 and 60 minutes after water ingestion in the XFS group (P < 0.001), whereas in the control group an increase was found only at the 60-minute time-point (P = 0.028). Independent of baseline ChT, at 60-minute endpoint, the magnitude of choroidal expansion was higher in XFS eyes (13.2 +/- 14.3%) compared with control eyes (6.2 +/- 3.5%) (P = 0.028). The mean IOP was higher at all time-points with respect to their respective baseline values in both XFS (P = 0.002, P < 0.001) and control (P = 0.038, P = 0.002) eyes. CONCLUSIONS: Choroidal expansion during WDT does not seem to be an important mechanism for IOP elevation in healthy eyes or those with XFS. Furthermore, the similarity of IOP increase to controls suggests that trabecular outflow facility is not impaired in eyes with XFS. PMID- 26035420 TI - Correlation of Macular Ganglion Cell Complex Thickness With Frequency-doubling Technology Perimetry in Open-angle Glaucoma With Hemifield Defects. AB - PURPOSE: To understand better the relationship between the macular ganglion cell complex (mGCC) thickness and visual field sensitivity assessed by frequency doubling technology (FDT) perimetry in the standard automated perimetry (SAP) normal hemifields of glaucomatous eyes, a model of preperimetric stage of glaucoma. PATIENTS AND METHODS: Thirty-four eyes of 34 patients with glaucomatous visual field defects restricted to the superior or inferior hemifield were included. Patients underwent the mGCC and circumpapillary retinal nerve fiber layer (cpRNFL) thickness measurements using spectral domain optical coherence tomography and the FDT testing with N-30 full-threshold protocol. SAP and FDT sensitivity values were averaged in the area corresponding to thickness measurements and the thickness sensitivity relationships were assessed in the SAP normal and SAP abnormal halves (Spearman's rank correlation coefficient). RESULTS: FDT sensitivity was significantly correlated with both the cpRNFL and mGCC thicknesses either in the SAP normal (rho=0.384 and 0.462, respectively) or in the SAP abnormal (rho=0.402 and 0.717, respectively) halves. Correlation between the FDT sensitivity and the mGCC thickness was significantly (P=0.016) stronger than that with the cpRNFL thickness in the SAP abnormal half. SAP sensitivity was correlated significantly (rho=0.570) only with the mGCC thickness in the SAP abnormal half. CONCLUSIONS: Similarly strong correlations of the mGCC thickness with the FDT sensitivity in the SAP normal and SAP abnormal halves, but not with the SAP sensitivity, indicates that the mGCC thickness and the FDT sensitivity may be more optimal structure-function indicator in preperimetric stage of glaucoma. PMID- 26035421 TI - Novel Parameter of Corneal Biomechanics That Differentiate Normals From Glaucoma. AB - PURPOSE: To identify novel corneal biomechanical parameters differentiating glaucomatous from normal eyes. PATIENTS AND METHODS: Sixty subjects with varying degrees of glaucoma severity and 61 normal controls underwent corneal biomechanical measurements including corneal deformation amplitude, inward and outward applanation length and velocity, and highest concavity time in 1 eye per subject at Queen Mary Hospital, Hong Kong. Measurements were taken with the Corvis ST device, a noncontact tonometer coupled with a high-speed Scheimpflug camera. The intraocular pressure (IOP) and central corneal thickness (CCT) were also measured. RESULTS: Significant findings included differences in outward applanation velocity (glaucoma: -0.37+/-0.01 m/s; control: -0.32+/-0.01 m/s; P=0.001), peak distance (glaucoma: 2.37+/-0.03 mm; control: 2.30+/-0.02 mm; P=0.005), and highest concavity time (glaucoma: 16.75+/-0.08 ms; control: 17.05+/ 0.07 ms; P=0.002) between the 2 groups, after correcting for IOP, CCT, and age. Both outward applanation velocity and peak distance were moderately correlated with IOP and CCT. However, highest concavity time was not correlated with either IOP or CCT (R(2)=0.0140 and 0.000055, respectively). Age was not correlated with any of the 3 parameters. CONCLUSIONS: Glaucomatous eyes have a greater mean outward applanation velocity and peak distance, but shorter time to highest concavity than eyes without glaucoma. The difference in time to highest concavity does not correlate with age, IOP, or CCT, suggesting that this parameter may be a marker of increased pressure susceptibility that is independently associated with glaucoma risk. PMID- 26035422 TI - Iridocorneal Endothelial Syndrome in a 14-Year-Old Male. AB - The iridocorneal endothelial syndrome is a rare cause of unilateral glaucoma that is almost never seen in children. We report a case of iridocorneal endothelial in a 14-year-old boy who did not yet have ocular hypertension or glaucoma. PMID- 26035423 TI - Tumor-specific Th2 responses inhibit growth of CT26 colon-cancer cells in mice via converting intratumor regulatory T cells to Th9 cells. AB - The abnormality of immune regulation plays a critical role in the pathogenesis of cancer; the underlying mechanism has not been fully understood yet. This study aims to investigate the role of cancer specific T helper (Th)2 response in the inhibition of colon cancer (Cca) cell growth. The results showed that with Cca cell (CT26 cell) extracts as an antigen, the Cca-extract specific Th2 response was induced in the Cca-bearing mice. The Cca mass size was significantly reduced, or radically disappeared (5 out of 10; or 50%); the survival rate was markedly improved in mice immunized with Cca-extract, but not in those immunized with another tumor cell (U87 cell) extracts or to bovine serum albumin. The immunization with Cca-extract also induced Cca cell apoptosis and converted the intra-Cca Tregs to T helper (Th) 9 cells. In conclusion, Cca-specific Th2 responses inhibit Cca growth in a mouse model via inducing Cca cell apoptosis and converting intra-Cca Tregs to Th9 cells. PMID- 26035424 TI - The emerging role of astrocyte-elevated gene-1 in hepatocellular carcinoma (Review). AB - Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide, yet effective treatment for this disease is lacking. Thus, there is an urgent need to identify novel therapeutic targets for this dreadful disease. Numerous studies have established that overexpression of astrocyte-elevated gene-1 (AEG-1) is frequently observed in multiple types of cancers including HCC, and its expression levels are correlated with the stage and grade of the disease. Further studies revealed that AEG-1 plays a key role in several crucial aspects of HCC progression, including growth, transformation, cell survival, invasion, metastasis and chemoresistance. Moreover, AEG-1 overexpression activates the Wnt/beta-catenin, mitogen-actived protein kinase (MAPK), nuclear factor (NF) kappaB, and PI3K/Akt signaling pathways, and promotes its downstream gene expression to facilitate malignant potential. Recently, transgenic mice with hepatocyte-specific expression of AEG-1 (Alb/AEG-1) and AEG-1-knockout mouse both revealed novel aspects of the functions of AEG-1 in an in vivo context. This review evaluates the multi-functions of AEG-1 and describes the major signaling pathways and molecular alterations regulated by AEG-1 in HCC, indicating its key roles and potential as a biomarker or significant target for the therapy of HCC. PMID- 26035425 TI - Consistent global structures of complex RNA states through multidimensional chemical mapping. AB - Accelerating discoveries of non-coding RNA (ncRNA) in myriad biological processes pose major challenges to structural and functional analysis. Despite progress in secondary structure modeling, high-throughput methods have generally failed to determine ncRNA tertiary structures, even at the 1-nm resolution that enables visualization of how helices and functional motifs are positioned in three dimensions. We report that integrating a new method called MOHCA-seq (Multiplexed *OH Cleavage Analysis with paired-end sequencing) with mutate-and-map secondary structure inference guides Rosetta 3D modeling to consistent 1-nm accuracy for intricately folded ncRNAs with lengths up to 188 nucleotides, including a blind RNA-puzzle challenge, the lariat-capping ribozyme. This multidimensional chemical mapping (MCM) pipeline resolves unexpected tertiary proximities for cyclic-di GMP, glycine, and adenosylcobalamin riboswitch aptamers without their ligands and a loose structure for the recently discovered human HoxA9D internal ribosome entry site regulon. MCM offers a sequencing-based route to uncovering ncRNA 3D structure, applicable to functionally important but potentially heterogeneous states. PMID- 26035427 TI - miR-153 inhibits epithelial-to-mesenchymal transition in hepatocellular carcinoma by targeting Snail. AB - Epithelial-to-mesenchymal transition (EMT) has been implicated as a dynamic cellular process in embryonic development and invasion of human cancers. Snail1 is a critical convergence hub in EMT regulation which transcriptionally represses E-cadherin expression. Currently, published data indicate that upregulation of Snail is mainly due to transcriptional activation and regulation of protein stability and cellular location. However, whether there is an alternative regulatory mechanism remains unclear. Our study showed that the expression of miR 153 was noticeably downregulated in hepatocellular carcinoma (HCC) cell lines and tissues, compared with normal liver epithelial cells (NLCs) and matched adjacent normal HCC tissues. Ectopic expression of miR-153 inhibited the migration and invasion ability of HCC cells, while suppression of miR-153 rescued this inhibitory effect. In addition, upregulation of miR-153 in HCC cells resulted in a decrease in epithelial markers, E-cadherin and alpha-catenin, and an increase in mesenchymal markers, N-cadherin and vimentin, and vice versa. Moreover, we demonstrated that miR-153 downregulated Snail expression by directly targeting the 3'-untranslated region (3'UTR) of Snail. Taken together, our results suggest that miR-153 plays a critical role in suppressing EMT and HCC progression by direct suppression of Snail expression. PMID- 26035426 TI - Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism. AB - Dangerous damage to mitochondrial DNA (mtDNA) can be ameliorated during mammalian development through a highly debated mechanism called the mtDNA bottleneck. Uncertainty surrounding this process limits our ability to address inherited mtDNA diseases. We produce a new, physically motivated, generalisable theoretical model for mtDNA populations during development, allowing the first statistical comparison of proposed bottleneck mechanisms. Using approximate Bayesian computation and mouse data, we find most statistical support for a combination of binomial partitioning of mtDNAs at cell divisions and random mtDNA turnover, meaning that the debated exact magnitude of mtDNA copy number depletion is flexible. New experimental measurements from a wild-derived mtDNA pairing in mice confirm the theoretical predictions of this model. We analytically solve a mathematical description of this mechanism, computing probabilities of mtDNA disease onset, efficacy of clinical sampling strategies, and effects of potential dynamic interventions, thus developing a quantitative and experimentally supported stochastic theory of the bottleneck. PMID- 26035428 TI - Are statins beneficial for chronic heart failure? AB - There is controversy about the role of statins in chronic heart failure. Even though it is clear they decrease inflammatory markers and probably improve some echocardiographic parameters, it is not clear if they impact clinically important outcomes. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified six systematic reviews including 21 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded statins in chronic heart failure do not decrease mortality, and might lead to little or no decrease in hospitalizations for heart failure or other clinical outcomes. PMID- 26035429 TI - Assessing development assistance for mental health in developing countries: 2007 2013. PMID- 26035430 TI - The Mechanism of Environmental Endocrine Disruptors (DEHP) Induces Epigenetic Transgenerational Inheritance of Cryptorchidism. AB - Discussion on the role of DEHP in the critical period of gonadal development in pregnant rats (F0), studied the evolution of F1-F4 generation of inter generational inheritance of cryptorchidism and the alteration of DNA methylation levels in testis. Pregnant SD rats were randomly divided into two groups: normal control group and DEHP experimental group. From pregnancy 7 d to 19 d, experimental group was sustained to gavage DEHP 750 mg/kg bw/day, observed the incidence of cryptorchidism in offspring and examined the pregnancy rate of female rats through mating experiments. Continuous recording the rat's weight and AGD value, after maturation (PND80) recording testis and epididymis' size and weight, detected the sperm number and quality. Subsequently, we examined the evolution morphological changes of testicular tissue for 4 generation rats by HE staining and Western Blot. Completed the MeDIP-sequencing analysis of 6 samples (F1 generation, F4 generation and Control). DEHP successfully induced cryptorchidism occurrence in offspring during pregnancy. The incidence of cryptorchidism in F1 was 30%, in F2 was 12.5%, and there was no cryptorchidism coming up in F3 and F4. Mating experiment shows conception rate 50% in F1, F2 generation was 75%, the F3 and F4 generation were 100%. HE staining showed that the seminiferous epithelium of F1 generation was atrophy and with a few spermatogenic cell, F2 generation had improved, F3 and F4 generation were tend to be normal. The DNA methyltransferase expression was up-regulated with the increase of generations by Real Time-PCR, immunohistochemistry and Western Blot. MeDIP-seq Data Analysis Results show many differentially methylated DNA sequences between F1 and F4. DEHP damage male reproductive function in rats, affect expression of DNA methyltransferase enzyme, which in turn leads to genomic imprinting methylation pattern changes and passed on to the next generation, so that the offspring of male reproductive system critical role in the development of imprinted genes imbalances, and eventually lead to producing offspring cryptorchidism. This may be an important mechanism of reproductive system damage. PMID- 26035431 TI - Adipocytokines, C-reactive protein, and cardiovascular disease: a population based prospective study. AB - BACKGROUND: Being overweight or obese is associated with a greater risk of coronary heart disease and stroke compared with normal weight. The role of the specific adipose tissue-derived substances, called adipocytokines, in overweight- and obesity-related cardiovascular disease (CVD) is still unclear. OBJECTIVE: To investigate the associations of three adipose tissue-derived substances: adiponectin, leptin, and interleukin-6 with incident CVD in a longitudinal population-based study, including extensive adjustments for traditional and metabolic risk factors closely associated with overweight and obesity. C-reactive protein (CRP) was used as a proxy for interleukin-6. METHODS: Prospective population-based study of 6.502 participants, 51.9% women, aged 30-60 years, free of CVD at baseline, with a mean follow-up time of 11.4 years, equivalent to 74,123 person-years of follow-up. As outcome, we defined a composite outcome comprising of the first event of fatal and nonfatal coronary heart disease and fatal and nonfatal stroke. RESULTS: During the follow-up period, 453 composite CV outcomes occurred among participants with complete datasets. In models, including gender, age, smoking status, systolic blood pressure, treatment for hypertension, diabetes, body mass index (BMI), total cholesterol, high-density-lipoprotein cholesterol, homeostasis model assessment of insulin resistance, estimated glomerular filtration rate, adiponectin, leptin, and CRP, neither adiponectin (hazard ratio [HR] with 95% confidence interval [CI]: 0.97 [0.87-1.08] per SD increase, P = 0.60) nor leptin (0.97 [0.85-1.12] per SD increase, P = 0.70) predicted the composite outcome, whereas CRP was significantly associated with the composite outcome (1.19 [1.07-1.35] per SD increase, P = 0.002). Furthermore, in mediation analysis, adjusted for age and sex, CRP decreased the BMI-associated CV risk by 43% (95%CI 29-72). CONCLUSIONS: In this study, neither adiponectin nor leptin were independently associated with CVD, raising questions over their role in CVD. The finding that CRP was significantly associated with an increased risk of CVD and decreased the BMI-associated CVD risk substantially, could imply that interleukin-6-related pathways may play a role in mediating overweight- and obesity-related CVD. PMID- 26035432 TI - Multi-pathway cellular analysis on crude natural drugs/herbs from Japanese Kampo formulations. AB - Kampo formulations comprise a number of crude natural drugs/herbs as constituents. The crude drugs/herbs have been traditionally classified by their traditional classifications or efficacies in Kampo medicines; however, it has been difficult to establish the scientific link between experimental evidence and traditional classifications in Kampo medicine. To clarify such traditional conceptions, we tested 112 crude drugs/herbs that are major components of Kampo formulations, in the multi-pathway analysis of 10 well-studied transcriptional activities including CREB, ERSF, HIF-1alpha, IRFs, MYC, NF-kappaB, p53, SMAD, SOX2, and TCF/LEF in A549 human lung cancer cells. By clustering the results of multi-pathway analysis with the Spearman rank-correlation coefficient and Ward linkage, three distinct traditional categories were significantly enriched in the major groupings, which are heat-clearing and dampness-drying herbs, acrid and warm exterior-resolving herbs, and acrid and cool exterior-resolving herbs. These results indicate that these crude drugs/herbs have similar effects on intracellular signaling and further imply that the traditional classifications of those enriched crude drugs/herbs can be supported by such experimental evidence. Collectively, our new in vitro multi-pathway analysis may be useful to clarify the mechanism of action of crude drugs/herbs and Kampo formulations. PMID- 26035433 TI - Systematic review and meta-analysis of the impact of carer stress on subsequent institutionalisation of community-dwelling older people. AB - BACKGROUND: In the caregiving literature there is a common assertion that a higher level of carer stress is a critical determinant of premature ending of homecare. However, this contention has not been systematically assessed. We therefore systematically reviewed and meta-analysed the prospective association between various forms of carer stress and subsequent institutionalisation of community-dwelling older people. METHODS: Systematic literature search of prospective studies measuring carer stress at baseline and institutionalisation at follow-up. Given substantial interchangeability in the measurement of carer stress, we included a wide number of exposure measures, namely: carer stress, burden, depression, distress, anxiety, burnout, and strain. Institutionalisation included both acute and long-term care utilisation. The standardised mean difference between stressed and non-stressed carers was the primary measure of effect. We assessed study quality with the Crowe Critical Appraisal Tool (CCAT). Pre-planned sensitivity analysis included examination of estimates according to study size; decade published; study quality according to quartiles of CCAT scores; population; follow-up period; study design and impact of adjusted or unadjusted estimates. RESULTS: The search yielded 6,963 articles. After exclusions, we analysed data from 54 datasets. The meta-analysis found that while carer stress has a significant effect on subsequent institutionalisation of care recipients, the overall effect size was negligible (SMD = 0 . 05, 95% CI = 0 . 04 0 . 07). Sensitivity analyses found that, the effect size was higher for measurements of stress than for other measures, though still relatively small (SMD = 0 . 23, 95% CI = 0 . 09-0 . 38). Thus, whether analysing the association between carer stress, burden, distress, or depression with either acute or long term care, the effect size remains small to negligible. Concurrently, we found estimates reduce over time and were smaller with larger studies and those of higher quality, according to the CCAT scores. CONCLUSION: Despite strong statements to the contrary, it appears that the effect of carer stress on subsequent care recipient institutionalisation is small to negligible. The current findings point to a biased literature, with significant small study effects. The results suggest a need to re-evaluate the degree to which carer stress predicts premature ending of home care. Concurrently, other factors may be more crucial in institutional placement than carer stress and should be investigated. PMID- 26035434 TI - Mitotic slippage and expression of survivin are linked to differential sensitivity of human cancer cell-lines to the Kinesin-5 inhibitor monastrol. AB - The mitotic Kinesin-5 motor proteins crosslink and slide apart antiparallel spindle microtubules, thus performing essential functions in mitotic spindle dynamics. Specific inhibition of their function by monastrol-like small molecules has been examined in clinical trials as anticancer treatment, with only partial success. Thus, strategies that improve the efficiency of monastrol-like anticancer drugs are required. In the current study, we examined the link between sensitivity to monastrol and occurrence of mitotic slippage in several human cell lines. We found that the rank of sensitivity to monastrol, from most sensitive to least sensitive, is: AGS > HepG2 > Lovo > Du145 >= HT29. We show correlation between the sensitivity of a particular cell-line to monastrol and the tendency of the same cell-line to undergo mitotic slippage. We also found that in the monastrol resistant HT29 cells, prolonged monastrol treatments increase mRNA and protein levels of the chromosomal passenger protein survivin. In contrast, survivin levels are not increased by this treatment in the monastrol-sensitive AGS cells. We further show that over-expression of survivin in the monastrol sensitive AGS cells reduces mitotic slippage and increases resistance to monastrol. Finally, we show that during short exposure to monastrol, Si RNA silencing of survivin expression reduces cell viability in both AGS and HT29 cells. Our data suggest that the efficiency of anti-cancer treatment with specific kinesin-5 inhibitors may be improved by modulation of expression levels of survivin. PMID- 26035435 TI - Label-Free Quantitative Proteomics of Embryogenic and Non-Embryogenic Callus during Sugarcane Somatic Embryogenesis. AB - The development of somatic cells in to embryogenic cells occurs in several stages and ends in somatic embryo formation, though most of these biochemical and molecular changes have yet to be elucidated. Somatic embryogenesis coupled with genetic transformation could be a biotechnological tool to improve potential crop yields potential in sugarcane cultivars. The objective of this study was to observe somatic embryo development and to identify differentially expressed proteins in embryogenic (E) and non-embryogenic (NE) callus during maturation treatment. E and NE callus were cultured on maturation culture medium supplemented with different concentrations (0.0, 0.75, 1.5 and 2.0 g L(-1)) of activated charcoal (AC). Somatic embryo formation and differential protein expression were evaluated at days 0 and 21 using shotgun proteomic analyses. Treatment with 1.5 g L(-1) AC resulted in higher somatic embryo maturation rates (158 somatic embryos in 14 days) in E callus but has no effect in NE callus. A total of 752 co-expressed proteins were identified through the SUCEST (The Sugarcane EST Project), including many housekeeping proteins. E callus showed 65 exclusive proteins on day 0, including dehydrogenase, desiccation-related protein, callose synthase 1 and nitric oxide synthase. After 21 days on maturation treatment, 14 exclusive proteins were identified in E callus, including catalase and secreted protein. NE callus showed 23 exclusive proteins on day 0 and 10 exclusive proteins after 21 days on maturation treatment, including many proteins related to protein degradation. The induction of maturation leads to somatic embryo development, which likely depends on the expression of specific proteins throughout the process, as seen in E callus under maturation treatment. On the other hand, some exclusive proteins can also specifically prevent of somatic embryos development, as seen in the NE callus. PMID- 26035436 TI - Coronary Plaque Burden at Coronary CT Angiography in Asymptomatic Men and Women. AB - Purpose To assess the relationship between total, calcified, and noncalcified coronary plaque burdens throughout the entire coronary vasculature at coronary computed tomographic (CT) angiography in relationship to cardiovascular risk factors in asymptomatic individuals with low-to-moderate risk. Materials and Methods This HIPAA-compliant study had institutional review board approval, and written informed consent was obtained. Two hundred two subjects were recruited to an ongoing prospective study designed to evaluate the effect of HMG-CoA reductase inhibitors on atherosclerosis. Eligible subjects were asymptomatic individuals older than 55 years who were eligible for statin therapy. Coronary CT angiography was performed by using a 320-detector row scanner. Coronary wall thickness and plaque were evaluated in all epicardial coronary arteries greater than 2 mm in diameter. Images were analyzed by using dedicated software involving an adaptive lumen attenuation algorithm. Total plaque index (calcified plus noncalcified plaque) was defined as plaque volume divided by vessel length. Multivariable regression analysis was performed to determine the relationship between risk factors and plaque indexes. Results The mean age of the subjects was 65.5 years +/- 6.9 (standard deviation) (36% women), and the median coronary artery calcium (CAC) score was 73 (interquartile range, 1-434). The total coronary plaque index was higher in men than in women (42.06 mm(2) +/- 9.22 vs 34.33 mm(2) +/- 8.35; P < .001). In multivariable analysis controlling for all risk factors, total plaque index remained higher in men than in women (by 5.01 mm(2); P = .03) and in those with higher simvastatin doses (by 0.44 mm(2)/10 mg simvastatin dose equivalent; P = .02). Noncalcified plaque index was positively correlated with systolic blood pressure (beta = 0.80 mm(2)/10 mm Hg; P = .03), diabetes (beta = 4.47 mm(2); P = .03), and low-density lipoprotein (LDL) cholesterol level (beta = 0.04 mm(2)/mg/dL; P = .02); the association with LDL cholesterol level remained significant (P = .02) after additional adjustment for the CAC score. Conclusion LDL cholesterol level, systolic blood pressure, and diabetes were associated with noncalcified plaque burden at coronary CT angiography in asymptomatic individuals with low-to-moderate risk. ((c)) RSNA, 2015 Online supplemental material is available for this article. PMID- 26035438 TI - Probing the Hydrogen Bonding of the Ferrous-NO Heme Center of nNOS by Pulsed Electron Paramagnetic Resonance. AB - Oxidation of L-arginine (L-Arg) to nitric oxide (NO) by NO synthase (NOS) takes place at the heme active site. It is of current interest to study structures of the heme species that activates O2 and transforms the substrate. The NOS ferrous NO complex is a close mimic of the obligatory ferric (hydro)peroxo intermediate in NOS catalysis. In this work, pulsed electron-nuclear double resonance (ENDOR) spectroscopy was used to probe the hydrogen bonding of the NO ligand in the ferrous-NO heme center of neuronal NOS (nNOS) without a substrate and with L-Arg or N-hydroxy-L-arginine (NOHA) substrates. Unexpectedly, no H-bonding interaction connecting the NO ligand to the active site water molecule or the Arg substrate was detected, in contrast to the results obtained by X-ray crystallography for the Arg-bound nNOS heme domain [Li et al. J. Biol. Inorg. Chem. 2006, 11, 753 768]. The nearby exchangeable proton in both the no-substrate and Arg-containing nNOS samples is located outside the H-bonding range and, on the basis of the obtained structural constraints, can belong to the active site water (or OH). On the contrary, in the NOHA-bound sample, the nearby exchangeable hydrogen forms an H-bond with the NO ligand (on the basis of its distance from the NO ligand and a nonzero isotropic hfi constant), but it does not belong to the active site water molecule because the water oxygen atom (detected by (17)O ENDOR) is too far. This hydrogen should therefore come from the NOHA substrate, which is in agreement with the X-ray crystallography work [Li et al. Biochemistry 2009, 48, 10246 10254]. The nearby nonexchangeable hydrogen atom assigned as H(epsilon) of Phe584 was detected in all three samples. This hydrogen atom may have a stabilizing effect on the NO ligand and probably determines its position. PMID- 26035439 TI - Lack of Association between Interleukin-10 Gene Polymorphisms and Graft Rejection Risk in Kidney Transplantation Recipients: A Meta-Analysis. AB - BACKGROUND: Interleukin-10 (IL-10) is an important immunomodulatory cytokine. Several studies focused the association between IL-10 promoter gene polymorphisms and graft rejection risk in kidney transplantation recipients. However, the results of these studies remain inconclusive. The aim of this study was to conduct a meta-analysis to further assess the associations. METHODS: The PubMed, Embase, and Ovid Medline databases were searched. Two independent authors extracted data, and the effects were estimated from an odds ratio (OR) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses identified sources of heterogeneity. RESULTS: A total of 16 studies including 595 rejection patients and 1239 stable graft patients were included in order to study the IL-10 -1082 (rs1800896 G/A), -819 (rs1800871 C/T), -592 (rs1800872 C/A) and IL-10 (-1082, 819,-592) polymorphisms. The -1082 G/A polymorphism was not associated with an increased graft rejection risk (OR = 1.03; 95%CI, 0.85-1.25, P = 0.74 for GA+AA vs. GG model). Moreover, all of the -819 C/T (OR = 1.06, 95%CI, 0.79-1.42, P = 0.70 for TA+TT vs. CC model), -592 C/A (OR = 1.10, 95% CI, 0.85-1.42, P = 0.47 for AC+AA vs. CC model) and IL-10 (-1082,-819,-592) polymorphisms (OR = 1.00, 95%CI, 0.79-1.27, P = 0.98 for I+L vs. H model) did not increase the graft rejection risk. In addition, we also performed subgroup analysis by ethnic group (mainly in Europeans or Asians) and rejection type (acute or chronic). There was also lack of evidence of a significant association between the IL-10 gene polymorphism and graft rejection risk. The present meta-analysis indicated that the IL-10 gene polymorphism was not associated with graft rejection risk in kidney transplantation recipients. CONCLUSION: This meta-analysis found evidence that the IL-10 polymorphism does not increase the risk of graft rejection in kidney transplantation recipients. Further chronic rejection and other ethnic population studies are needed to confirm our results. PMID- 26035440 TI - Heterogeneous core/shell fluoride nanocrystals with enhanced upconversion photoluminescence for in vivo bioimaging. AB - We report on heterogeneous core/shell CaF2:Yb(3+)/Ho(3+)@NaGdF4 nanocrystals of 17 nm with efficient upconversion (UC) photoluminescence (PL) for in vivo bioimaging. Monodisperse core/shell nanostructures were synthesized using a seed mediated growth process involving two quite different approaches of liquid-solid solution and thermal decomposition. They exhibit green emission with a sharp band around 540 nm when excited at ~980 nm, which is about 39 times brighter than the core CaF2:Yb(3+)/Ho(3+) nanoparticles. PL decays at 540 nm revealed that such an enhancement arises from efficient suppression of surface-related deactivation from the core nanocrystals. In vivo bioimaging employing water-dispersed core/shell nanoparticles displayed high contrast against the background. PMID- 26035441 TI - Mesogenic Structures, Lyotropic and Thermotropic Phase Transitions in Demethyl Ionene Alkyl Sulfonate Complexes. AB - Linear [B,10]-polyamines [(CH2)BN(CH3)(CH2)10N(CH3)] were prepared (B = 3 or 6). Protonated by stoichiometric amounts of n-alkylsulfonic acids, they form demethyl ionene sulfonate complexes, which proved thermally stable up to 220 degrees C. Salt free complexes were investigated by polarized microscopy, thermogravimetry, and X-ray diffraction. Except the heptyl sulfonate, which crystallized, all complexes bearing longer alkyl chains formed mesogenic phases. Being isotropic in dry state, they became optically anisotropic when exposed to humidity due to a lyotropic transition (mediated by the gas phase) to a hexagonal phase, mostly. A cubic phase containing less water was also observed. Anisotropic complexes again were converted to an isotropic state upon heating under controlled humidity. The clearing temperatures distinctly depend on humidity and rise with increasing length of the alkyl sulfonate. This may allow the use of the complexes as humidity sensors. Oriented liquid crystalline samples are formed upon fast cooling in flat capillaries. PMID- 26035442 TI - Proposal of a Mediterranean Diet Serving Score. AB - BACKGROUND AND AIMS: Numerous studies have demonstrated a relationship between Mediterranean Diet (MD) adherence and the prevention of cardiovascular diseases, cancer, and diabetes, etc. The study aim was to validate a novel instrument to measure MD adherence based on the consumption of food servings and food groups, and apply it in a female population from southern Spain and determining influential factors. METHODS AND RESULTS: The study included 1,155 women aged 12 83 yrs, classified as adolescents, adults, and over-60-yr-olds. All completed a validated semi-quantitative food frequency questionnaire (FFQ). The Mediterranean Dietary Serving Score (MDSS) is based on the latest update of the Mediterranean Diet Pyramid, using the recommended consumption frequency of foods and food groups; the MDSS ranges from 0 to 24. The discriminative power or correct subject classification capacity of the MDSS was analyzed with the Receiver Operating Characteristic (ROC) curve, using the MDS as reference method. Predictive factors for higher MDSS adherence were determined with a logistic regression model, adjusting for age. According to ROC curve analysis, MDSS evidenced a significant discriminative capacity between adherents and non-adherents to the MD pattern (optimal cutoff point=13.50; sensitivity=74%; specificity=48%). The mean MDSS was 12.45 (2.69) and was significantly higher with older age (p<0.001). Logistic regression analysis showed highest MD adherence by over 60-year-olds with low BMI and no habit of eating between meals. CONCLUSIONS: The MDSS is an updated, easy, valid, and accurate instrument to assess MD adherence based on the consumption of foods and food groups per meal, day, and week. It may be useful in future nutritional education programs to prevent the early onset of chronic non transmittable diseases in younger populations. PMID- 26035443 TI - Clinical significance and therapeutic potential of prostate cancer antigen 1/ALKBH3 in human renal cell carcinoma. AB - Prostate cancer antigen-1 (PCA-1)/ALKBH3 has been recently identified in human prostate cancer and its expression is correlated with disease progression and prognosis. However, the precise role and function of PCA-1/ALKBH3 in human malignancies are largely unknown. In the present study, we investigated the clinical significance and therapeutic potential of PCA-1/ALKBH3 in renal cell carcinoma (RCC). PCA-1/ALKBH3 expression was examined by immunohistochemistry in 101 RCC patients who underwent radical or partial nephrectomy. Its expression was positively correlated with advanced pathological T- and M-factors and TNM stage (T, P<0.05; M, P<0.01; TNM, P<0.01, respectively). In the prognostic analysis, PCA-1/ALKBH3-negative patients with RCC had a significantly better prognosis than PCA-1/ALKBH3-positive patients (5-year survival rate, 92.9 vs. 75.9%, respectively; P<0.05). Next, the therapeutic potential of targeting PCA-1/ALKBH3 was further evaluated by small interfering RNA method using a human RCC cell line (CAKI-1). We found that PCA-1/ALKBH3 knockdown significantly inhibited the growth of CAKI-1 cells compared with the control (P<0.001). Furthermore, knockdown of PCA-1 induced apoptosis in CAKI-1 cells, as assessed by poly(ADP-ribose) polymerase-cleavage assays. We demonstrated for the first time that PCA-1/ALKBH3 expression has a significant prognostic impact on patient prognosis in RCC. Furthermore, its knockdown has a therapeutic efficacy on RCC. Taken together, both our clinical and experimental data strongly suggest that PCA-1/ALKBH3 may be functionally important and a novel molecular target for human RCC. PMID- 26035444 TI - Arbuscular mycorrhizal fungi community structure, abundance and species richness changes in soil by different levels of heavy metal and metalloid concentration. AB - Arbuscular Mycorrhizal Fungi (AMF) play major roles in ecosystem functioning such as carbon sequestration, nutrient cycling, and plant growth promotion. It is important to know how this ecologically important soil microbial player is affected by soil abiotic factors particularly heavy metal and metalloid (HMM). The objective of this study was to understand the impact of soil HMM concentration on AMF abundance and community structure in the contaminated sites of South Korea. Soil samples were collected from the vicinity of an abandoned smelter and the samples were subjected to three complementary methods such as spore morphology, terminal restriction fragment length polymorphism (T-RFLP) and denaturing gradient gel electrophoresis (DGGE) for diversity analysis. Spore density was found to be significantly higher in highly contaminated soil compared to less contaminated soil. Spore morphological study revealed that Glomeraceae family was more abundant followed by Acaulosporaceae and Gigasporaceae in the vicinity of the smelter. T-RFLP and DGGE analysis confirmed the dominance of Funneliformis mosseae and Rhizophagus intraradices in all the study sites. Claroideoglomus claroideum, Funneliformis caledonium, Rhizophagus clarus and Funneliformis constrictum were found to be sensitive to high concentration of soil HMM. Richness and diversity of Glomeraceae family increased with significant increase in soil arsenic, cadmium and zinc concentrations. Our results revealed that the soil HMM has a vital impact on AMF community structure, especially with Glomeraceae family abundance, richness and diversity. PMID- 26035448 TI - Influence of cone beam CT parameters on the output of an automatic edge-detection based endodontic segmentation. AB - OBJECTIVES: To determine the optimal cone beam computed tomography settings for an automatic edge-detection based endodontic segmentation procedure by assessing the accuracy of the root canal measurements. METHODS: Twelve intact teeth with closed apexes were cut perpendicular to the root axis, at predetermined levels to the reference plane (first section made before acquisition). Acquisitions of each specimen were performed with the "9000 3D(r)" (76um, 14 bits) by using different combinations of milliamps and kilovolts. 3 dimensional images were displayed and root canals were segmented with the MeVisLab software (edge-detection based method). Histological root canal sections were then digitized with a 0,5 to 1um resolution and compared with equivalent 2 dimensional cone-beam reconstructions for each pair of settings using Pearson correlation coefficient, regression analysis and Bland-Altman method for the canal area and Feret's diameter. After a ranking process, a Wilcoxon paired test was done to compare the pair of settings. RESULTS: The best pair of acquisition settings was: 3.2mA/60kV. Significant differences were found between 3.2mA/60kV and other settings (p <0.05) for root canal area and for Feret's diameter. CONCLUSIONS: The quantitative analyses of the root canal system with edge-detection based method could depend on acquisition parameters. Improvements in segmentation still need to be done to ensure the quality of the reconstructions when we have to deal with closer outlines and because of the low spatial resolution. PMID- 26035445 TI - Photochemical degradation of the UV filter octyl methoxycinnamate in solution and in aggregates. AB - The photodegradation of the ultraviolet (UV) filter octyl methoxycinnamate (OMC) is investigated in both dilute solution and in aggregated form. In dilute solution, the ratio of trans and cis isomers achieved at the photostationary state is solvent-dependent because of variations in the isomerization quantum yield. The two isomeric forms at the photostationary state are highly resistant to further photodegradation and no other UVA-absorbing species are formed. Aggregation of OMC, either in a neat film or in aqueous colloidal suspensions, leads to irreversible photodegradation of the molecule and the formation of multiple photoproducts. In addition to previously identified photoproducts like the UVB-absorbing cis and trans isomers and photodimers, we find photoproduct species whose absorption extends into the UVA. Characterization of the photophysical properties of these species indicates that they have long-lived excited-states (tauf > 1 ns, 400 nm), unlike the isomeric forms of OMC (tauf < 30 ps, 266 nm), and that excitation at 405 nm can sensitize the formation of singlet oxygen. These results show that the environment of OMC affects the photochemistry of the molecule and that the environmental conditions must be taken into account when considering the molecule's stability. In particular, aggregation of OMC molecules results in complex photochemistry that can produce species whose absorption extends into UVA and are capable of generating reactive oxygen species. PMID- 26035449 TI - Evaluation of the effective dose of cone beam computed tomography and multi-slice computed tomography for temporomandibular joint examinations at optimized exposure levels. AB - OBJECTIVES: To compare the effective dose to patients from temporomandibular joint examinations using a dental cone-beam CT device and a multi-slice CT device, both before and after dose optimization. METHODS: A Promax3D (Planmeca, Helsinki, Finland) dental cone-beam CT and a Lightspeed VCT (GE, Fairfield, USA) multi-slice CT were used. Organ doses and effective doses were estimated from thermoluminescent dosimeters at 61 positions inside an anthropomorphic phantom at the exposure settings in clinical use. Optimized exposure protocols were obtained through an optimization study using a dry skull phantom, where four observers rated image quality taken at different exposure levels. The optimal exposure level was obtained when all included criteria were rated as acceptable or better by all observers. RESULTS: The effective dose from a bilateral examination was 184 uSv for Promax3D and 113 uSv for Lightspeed VCT before optimization. Post optimization the bilateral effective dose was 92 uSv for Promax3D and 124 uSv for Lightspeed VCT. CONCLUSIONS: At optimized exposure levels, the effective dose from cone-beam CT was comparable to MSCT. PMID- 26035450 TI - Allosteric supramolecular coordination constructs. AB - Coordination chemistry is regularly used to generate supramolecular constructs with unique environments around embedded components to affect their intrinsic properties. In certain cases, it can also be used to effect changes in supramolecular structure reminiscent of those that occur within stimuli responsive biological structures, such as allosteric enzymes. Indeed, among a handful of general strategies for synthesizing such supramolecular systems, the weak-link approach (WLA) uniquely allows one to toggle the frameworks' structural state post-assembly via simple reactions involving hemilabile ligands and transition metal centers. This synthetic strategy, when combined with dynamic ligand sorting processes, represents one of the few sets of general reactions in inorganic chemistry that allow one to synthesize spatially defined, stimuli responsive, and multi-component frameworks in high to quantitative yields and with remarkable functional group tolerance. The WLA has thus yielded a variety of functional systems that operate similarly to allosteric enzymes, toggling activity via changes in the frameworks' steric confinement or electronic state upon the recognition of small molecule inputs. In this Perspective we present the first full description of the fundamental inorganic reactions that provide the foundation for synthesizing WLA complexes. In addition, we discuss the application of regulatory strategies in biology to the design of allosteric supramolecular constructs for the regulation of various catalytic properties, electron-transfer processes, and molecular receptors, as well as for the development of sensing and signal amplification systems. PMID- 26035451 TI - An asymmetric naphthalimide derivative for n-channel organic field-effect transistors. AB - A new naphthalene diimide (NDI) derivative with an asymmetric aromatic backbone of 2-tetradecylbenzo[lmn]benzo[4,5]imidazo[2,1-b][3,8]phenanthroline-1,3,6(2H) trione (IZ0) was designed and synthesized. Low LUMO level, large energy gap, and high thermal stability are characterized for this IZ0 compound. The OFET devices based on an IZ0 semiconductor exhibit typical n-type behavior. Through continuously optimizing the fabrication conditions, high performance n-channel OFETs were fabricated based on IZ0 films and single crystals, with the highest carrier mobility of 0.072 cm(2) V(-1) s(-1) and 0.22 cm(2) V(-1) s(-1), respectively. PMID- 26035452 TI - Laser-Induced Hydrothermal Growth of Heterogeneous Metal-Oxide Nanowire on Flexible Substrate by Laser Absorption Layer Design. AB - Recent development of laser-induced hydrothermal growth enabled direct digital growth of ZnO nanowire array at an arbitrary position even on 3D structures by creating a localized temperature field through a photothermal reaction in liquid environment. However, its spatial size was generally limited by the size of the focused laser spot and the thermal diffusion, and the target material has been limited to ZnO. In this paper, we demonstrated a next generation laser-induced hydrothermal growth method to grow nanowire on a selected area that is even smaller than the laser focus size by designing laser absorption layer. The control of laser-induced temperature field was achieved through adjusting the physical properties of the substrate (dimension and thermal conductivity), and it enabled a successful synthesis of smaller nanowire array without changing any complex optics. Through precise localized temperature control with laser, this approach could be extended to various nanowires including ZnO and TiO2 nanowires even on heat sensitive polymer substrate. PMID- 26035454 TI - Proteomics of Important Food Crops in the Asia Oceania Region: Current Status and Future Perspectives. AB - In the rapidly growing economies of Asia and Oceania, food security has become a primary concern. With the rising population, growing more food at affordable prices is becoming even more important. In addition, the predicted climate change will lead to drastic changes in global surface temperature and changes in rainfall patterns that in turn will pose a serious threat to plant vegetation worldwide. As a result, understanding how plants will survive in a changing climate will be increasingly important. Such challenges require integrated approaches to increase agricultural production and cope with environmental threats. Proteomics can play a role in unraveling the underlying mechanisms for food production to address the growing demand for food. In this review, the current status of food crop proteomics is discussed, especially in regard to the Asia and Oceania regions. Furthermore, the future perspective in relation to proteomic techniques for the important food crops is highlighted. PMID- 26035456 TI - [In Process Citation]. PMID- 26035455 TI - Single Cell Real-Time miRNAs Sensing Based on Nanomotors. AB - A nanomotor-based strategy for rapid single-step intracellular biosensing of a target miRNA, expressed in intact cancer cells, at the single cell level is described. The new concept relies on the use of ultrasound (US) propelled dye labeled single-stranded DNA (ssDNA)/graphene-oxide (GO) coated gold nanowires (AuNWs) capable of penetrating intact cancer cells. Once the nanomotor is internalized into the cell, the quenched fluorescence signal (produced by the pi pi interaction between GO and a dye-labeled ssDNA) is recovered due to the displacement of the dye-ssDNA probe from the motor GO-quenching surface upon binding with the target miRNA-21, leading to an attractive intracellular "OFF-ON" fluorescence switching. The faster internalization process of the US-powered nanomotors and their rapid movement into the cells increase the likelihood of probe-target contacts, leading to a highly efficient and rapid hybridization. The ability of the nanomotor-based method to screen cancer cells based on the endogenous content of the target miRNA has been demonstrated by measuring the fluorescence signal in two types of cancer cells (MCF-7 and HeLa) with significantly different miRNA-21 expression levels. This single-step, motor-based miRNAs sensing approach enables rapid "on the move" specific detection of the target miRNA-21, even in single cells with an extremely low endogenous miRNA-21 content, allowing precise and real-time monitoring of intracellular miRNA expression. PMID- 26035453 TI - Single-Cell Analysis of [18F]Fluorodeoxyglucose Uptake by Droplet Radiofluidics. AB - Radiolabels can be used to detect small biomolecules with high sensitivity and specificity without interfering with the biochemical activity of the labeled molecule. For instance, the radiolabeled glucose analogue, [18F]fluorodeoxyglucose (FDG), is routinely used in positron emission tomography (PET) scans for cancer diagnosis, staging, and monitoring. However, despite their widespread usage, conventional radionuclide techniques are unable to measure the variability and modulation of FDG uptake in single cells. We present here a novel microfluidic technique, dubbed droplet radiofluidics, that can measure radiotracer uptake for single cells encapsulated into an array of microdroplets. The advantages of this approach are multiple. First, droplets can be quickly and easily positioned in a predetermined pattern for optimal imaging throughput. Second, droplet encapsulation reduces cell efflux as a confounding factor, because any effluxed radionuclide is trapped in the droplet. Last, multiplexed measurements can be performed using fluorescent labels. In this new approach, intracellular radiotracers are imaged on a conventional fluorescence microscope by capturing individual flashes of visible light that are produced as individual positrons, emitted during radioactive decay, traverse a scintillator plate placed below the cells. This method is used to measure the cell-to-cell heterogeneity in the uptake of tracers such as FDG in cell lines and cultured primary cells. The capacity of the platform to perform multiplexed measurements was demonstrated by measuring differential FDG uptake in single cells subjected to different incubation conditions and expressing different types of glucose transporters. This method opens many new avenues of research in basic cell biology and human disease by capturing the full range of stochastic variations in highly heterogeneous cell populations in a repeatable and high-throughput manner. PMID- 26035457 TI - [In Process Citation]. PMID- 26035458 TI - [In Process Citation]. PMID- 26035459 TI - [In Process Citation]. PMID- 26035460 TI - [In Process Citation]. PMID- 26035461 TI - [In Process Citation]. PMID- 26035462 TI - Diastereoselective Synthesis of Biheterocyclic Tetrahydrothiophene Derivatives via Base-Catalyzed Cascade Michael-Aldol [3 + 2] Annulation of 1,4-Dithiane-2,5 diol with Maleimides. AB - A highly diastereoselective intermolecular [3 + 2] annulation of 1,4-dithiane-2,5 diol to maleimides has been developed by using DABCO as a catalyst, which provides a series of highly functionalized biheterocyclic tetrahydrothiophene derivatives containing tetrahydrothiophene and pyrolidine backbones in excellent yields and diastereoselectivities (up to 98% yield and >20:1 d.r.). The cascade Michael-aldol reaction is capable of tolerating organic solvents as well as water. PMID- 26035463 TI - Miltirone Induces G2/M Cell Cycle Arrest and Apoptosis in CCRF-CEM Acute Lymphoblastic Leukemia Cells. AB - Miltirone (1) is a diterpene quinone extracted from a well-known Chinese traditional herb (Salvia miltiorrhiza). We investigated the cytotoxic effects of miltirone toward sensitive and multidrug-resistant acute lymphoblastic leukemia cell lines. Miltirone inhibited multidrug-resistant P-glycoprotein (P-gp) overexpressing CEM/ADR5000 cells better than drug-sensitive CCRF-CEM wild-type cells, a phenomenon termed collateral sensitivity. Flow cytometric analyses revealed that miltirone induced G2/M arrest and apoptosis. Furthermore, miltirone stimulated reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) disruption, which in turn induced DNA damage and activation of caspases and poly ADP-ribose polymerase (PARP). Downregulation of CCNB1 (cyclin B1) and CDC2 mRNA and upregulation of CDKN1A (p21) mRNA were in accord with miltirone-induced G2/M arrest. Moreover, miltirone decreased cell adherence to fibronectin. Molecular docking revealed that miltirone bound to the ATP-binding site of IKK-beta. In conclusion, miltirone was collateral sensitive in multidrug resistant P-gp-overexpressing cells, induced G2/M arrest, and triggered apoptosis via ROS-generated breakdown of MMP and DNA damage. Therefore, miltirone may be a promising candidate for cancer chemotherapy. PMID- 26035464 TI - Acid-Sensitive Peptide-Conjugated Doxorubicin Mediates the Lysosomal Pathway of Apoptosis and Reverses Drug Resistance in Breast Cancer. AB - The extended use of doxorubicin (DOX) could be limited because of the emergence of drug resistance associated with its treatment. To reverse the drug resistance, two thiol-modified peptide sequences HAIYPRHGGC and THRPPMWSPVWPGGC were, respectively, conjugated to DOXO-EMCH, forming a maleimide bridge in this study (i.e., T10-DOX and T15-DOX). The structures and properties of peptide-DOX conjugates were characterized using (1)H NMR, (13)C NMR, mass spectrometry, and high-performance liquid chromatography. Their stability was also evaluated. By using MCF-7/ADR cells as an in vitro model system and nude mice bearing MCF-7/ADR xenografts as an in vivo model, the ability of these novel peptide-DOX conjugates to reverse drug resistance was accessed as compared with free DOX. As a result, the IC50 values for T10-DOX and T15-DOX significantly decreased (31.6 +/- 1.6 MUM and 27.2 +/- 0.8 MUM), whereas the percentage of apoptotic cell population increased (35.4% and 39.3%). The in vivo extent of inhibition was more evident in the mice groups treated with peptide-DOX conjugates (59.6 +/- 8.99% and 46.4 +/- 6.63%), which had DOX primarily accumulated in tumor. These conjugates also showed a longer half-life in plasma and cleared much more slowly from the body. Furthermore, T10-DOX may be more effective than T15-DOX with a higher efficacy and a lower side effect. Most importantly, evidence was provided to support the enhanced intracellular drug accumulation and the induction of lysosomal pathway of apoptosis underlying the drug resistance. As an endosomal/lysosomal marker, cathepsin D permealized the destabilized organelle membrane and was detected in the cytoplasm, leading to the activation of the effector caspase-3 in cell apoptosis. This report is among the first to demonstrate that peptide-DOX-like conjugates promote apoptosis through the initiation of the lysosomal pathway. PMID- 26035466 TI - A conversation with Joseph Lau. AB - Dr. Joseph Lau is a world-leading expert in meta-analysis and systematic reviews. Currently a professor in the Department of Health Services, Policy and Practice and co-director of the Center for Evidence-based Medicine at Brown University, Professor Lau has applied evidence-based methods to a variety of clinical, biomedical and healthcare topics; has developed reliable and efficient methods and tools to conduct systematic reviews and meta-analyses; and has advanced an understanding on the impact of factors that may contribute to differences of results in scientific studies. His past research includes cumulative meta analysis of randomized controlled trials, comparison of results from large trials and meta-analyses of small trials, effect of baseline risk in the interpretation of clinical trial results, and empirical evaluation of existing methods of combining data. His current focus is on a Web-based repository of systematic review data, reviews of diagnostic tests, nutrition, clinical practice guidelines, and dissemination of evidence-based methods to varied health-care disciplines. This report is a conversation from an adapted version of an interview, more or less chronologically arranged, between Joseph C. Cappelleri as interviewer and Joseph Lau as interviewee, with Meghan Ingerick recording and transcribing the interview. PMID- 26035467 TI - Inaccuracy of regression results in replacing bivariate correlations. AB - This manuscript considers discrepancies between the bivariate correlation and several indices of association estimated from regression results. These indices can be estimated from results typically reported in primary studies. In recent years, many researchers conducting meta-analyses have used these indices in place of, or together with, the bivariate correlation. I illustrate the differences among these indices and the bivariate correlation. I demonstrate the inaccuracy of these indices as replacements for bivariate effects. Thus, I recommend discontinuing the use of these indices and partial effect sizes as replacement for the bivariate correlation. PMID- 26035468 TI - A Bayesian nonparametric meta-analysis model. AB - In a meta-analysis, it is important to specify a model that adequately describes the effect-size distribution of the underlying population of studies. The conventional normal fixed-effect and normal random-effects models assume a normal effect-size population distribution, conditionally on parameters and covariates. For estimating the mean overall effect size, such models may be adequate, but for prediction, they surely are not if the effect-size distribution exhibits non normal behavior. To address this issue, we propose a Bayesian nonparametric meta analysis model, which can describe a wider range of effect-size distributions, including unimodal symmetric distributions, as well as skewed and more multimodal distributions. We demonstrate our model through the analysis of real meta analytic data arising from behavioral-genetic research. We compare the predictive performance of the Bayesian nonparametric model against various conventional and more modern normal fixed-effects and random-effects models. PMID- 26035469 TI - Combining randomized and non-randomized evidence in clinical research: a review of methods and applications. AB - Researchers may have multiple motivations for combining disparate pieces of evidence in a meta-analysis, such as generalizing experimental results or increasing the power to detect an effect that a single study is not able to detect. However, while in meta-analysis, the main question may be simple, the structure of evidence available to answer it may be complex. As a consequence, combining disparate pieces of evidence becomes a challenge. In this review, we cover statistical methods that have been used for the evidence-synthesis of different study types with the same outcome and similar interventions. For the methodological review, a literature retrieval in the area of generalized evidence synthesis was performed, and publications were identified, assessed, grouped and classified. Furthermore real applications of these methods in medicine were identified and described. For these approaches, 39 real clinical applications could be identified. A new classification of methods is provided, which takes into account: the inferential approach, the bias modeling, the hierarchical structure, and the use of graphical modeling. We conclude with a discussion of pros and cons of our approach and give some practical advice. PMID- 26035470 TI - The use of meta-analytic statistical significance testing. AB - Meta-analysis multiplicity, the concept of conducting multiple tests of statistical significance within one review, is an underdeveloped literature. We address this issue by considering how Type I errors can impact meta-analytic results, suggest how statistical power may be affected through the use of multiplicity corrections, and propose how meta-analysts should analyze multiple tests of statistical significance. The context for this study is a meta-review of meta-analyses published in two leading review journals in education and psychology. Our review of 130 meta-analyses revealed a strong reliance on statistical significance testing without consideration of Type I errors or the use of multiplicity corrections. In order to provide valid conclusions, meta analysts must consider these issues prior to conducting the review. PMID- 26035471 TI - Finding your way out of the forest without a trail of bread crumbs: development and evaluation of two novel displays of forest plots. AB - Research has shown that forest plots are a gold standard in the visualization of meta-analytic results. However, research on the general interpretation of forest plots and the role of researchers' meta-analysis experience and field of study is still unavailable. Additionally, the traditional display of effect sizes, confidence intervals, and weights have repeatedly been criticized. The current work presents an online statistical cognition experiment in which a total of 279 researchers with experience in meta-analysis from 36 countries evaluated conventional forest plots and two novel versions of forest plots, namely, thick forest plots and rainforest plots. The results indicate certain biases in the interpretation of forest plots, especially with regard to heterogeneity, the distribution of weights, and the theoretical concept of confidence intervals. Although the two novel displays (thick forest plots and rainforest plots) are associated with slightly longer viewing times, they are at least as well-suited and esthetically and perceptively pleasing as the conventional displays while facilitating the correct and exhaustive interpretation of the meta-analytic information. Furthermore, it is advisable to combine conventional forest plots with distribution information of the individual effects, make confidence lines more visually striking, and to display a background grid in the graph. PMID- 26035472 TI - Reporting standards for literature searches and report inclusion criteria: making research syntheses more transparent and easy to replicate. AB - A complete description of the literature search, including the criteria used for the inclusion of reports after they have been located, used in a research synthesis or meta-analysis is critical if subsequent researchers are to accurately evaluate and reproduce a synthesis' methods and results. Based on previous guidelines and new suggestions, we present a set of focused and detailed standards for reporting the methods used in a literature search. The guidelines cover five search strategies: reference database searches, journal and bibliography searches, searches of the reference lists of reports, citation searches, and direct contact searches. First, we bring together all the unique recommendations made in existing guidelines for research synthesis. Second, we identify gaps in reporting standards for search strategies. Third, we address these gaps by providing new reporting recommendations. Our hope is to facilitate successful evaluation and replication of research synthesis results. PMID- 26035473 TI - Simultaneous synthesis of treatment effects and mapping to a common scale: an alternative to standardisation. AB - OBJECTIVE: Trials often may report several similar outcomes measured on different test instruments. We explored a method for synthesising treatment effect information both within and between trials and for reporting treatment effects on a common scale as an alternative to standardisation STUDY DESIGN: We applied a procedure that simultaneously estimates a pooled treatment effect and the "mapping" ratios between the treatment effects on test instruments in a connected network. Standardised and non-standardised treatment effects were compared. The methods were illustrated in a dataset of 22 trials of selective serotonin reuptake inhibitors against placebo for social anxiety disorder, each reporting treatment effects on between one and six of a total nine test instruments. RESULTS: Ratios of treatment effects on different test instruments varied from trial to trial, with a coefficient of variation of 18% (95% credible interval 11 29%). Standardised effect models fitted the data less well, and standardised treatment effects were estimated with less relative precision than non standardised effects and with greater relative heterogeneity. CONCLUSION: Simultaneous synthesis of treatment effects and mapping to a common scale make fewer assumptions than standardising by dividing effects by the sample standard deviation, allow results to be reported on a common scale, and deliver estimates with superior relative precision. PMID- 26035474 TI - Porous, Water-Resistant Multifilament Yarn Spun from Gelatin. AB - Sustainability, renewability, and biodegradability of polymeric material constantly gain in importance. A plausible approach is the recycling of agricultural waste proteins such as keratin, wheat gluten, casein or gelatin. The latter is abundantly available from animal byproducts and may well serve as building block for novel polymeric products. In this work, a procedure for the dry-wet spinning of multifilament gelatin yarns was developed. The process stands out as precipitated gelatin from a ternary mixture (gelatin/solvent/nonsolvent) was spun into porous filaments. About 1000 filaments were twisted into 2-ply yarns with good tenacity (4.7 cN tex(-1)). The gelatin yarns, per se susceptible to water, were cross-linked by different polyfunctional epoxides and examined in terms of free lysyl amino groups and swelling degree in water. Ethylene glycol diglycidyl ether exhibited the highest cross-linking efficiency. Further post treatments with gaseous formaldehyde and wool grease (lanolin) rendered the gelatin yarns water-resistant, allowing for multiple swelling cycles in water or in detergent solution. However, the swelling caused a decrease in filament porosity from ~30% to just below 10%. To demonstrate the applicability of gelatin yarn in a consumer good, a gelatin glove with good thermal insulation capacity was fabricated. PMID- 26035475 TI - A Series of [Co(Mabiq)Cl2-n] (n = 0, 1, 2) Compounds and Evidence for the Elusive Bimetallic Form. AB - The synthesis and characterization of a series of cobalt compounds, coordinated by the redox-active macrocyclic biquinazoline ligand, Mabiq [2-4:6-8-bis(3,3,4,4 tetramethyldihydropyrrolo)-10-15-(2,2'-biquinazolino)-[15]-1,3,5,8,10,14-hexaene 1,3,7,9,11,14-N6], is presented. The series includes the monometallic Co(Mabiq)Cl2 (1), Co(Mabiq)Cl (2), and Co(Mabiq) (4), with formal metal oxidation states of 3+ -> 1+. A binuclear cobaltous compound, Co2(Mabiq)Cl3 (3), also was obtained, providing the first evidence for the ability of the Mabiq ligand to coordinate two metal ions. The electronic structures of the paramagnetic 2 and 3 were examined by electron paramagnetic resonance spectroscopy and magnetic susceptibility studies. The Co(II) ion that resides in the N4-macrocylic cavity of 2 and 3 adopts a low-spin S = (1)/2 configuration. The bypirimidine functionality in 3 additionally coordinates a high-spin S = (3)/2 cobaltous ion in a tetrahedral environment. The two metal ions in 3 are weakly coupled by magnetometry. The square-planar, low-valent 4 offers one of a limited number of examples of structurally characterized N4-macrocyclic Co(I) compounds. Spectroscopic and density functional theory computational data suggest that a Co(II)(Mabiq(*)) description may be a reasonable alternative to the Co(I) formalism for this compound. PMID- 26035476 TI - Filter bank canonical correlation analysis for implementing a high-speed SSVEP based brain-computer interface. AB - OBJECTIVE: Recently, canonical correlation analysis (CCA) has been widely used in steady-state visual evoked potential (SSVEP)-based brain-computer interfaces (BCIs) due to its high efficiency, robustness, and simple implementation. However, a method with which to make use of harmonic SSVEP components to enhance the CCA-based frequency detection has not been well established. APPROACH: This study proposed a filter bank canonical correlation analysis (FBCCA) method to incorporate fundamental and harmonic frequency components to improve the detection of SSVEPs. A 40-target BCI speller based on frequency coding (frequency range: 8-15.8 Hz, frequency interval: 0.2 Hz) was used for performance evaluation. To optimize the filter bank design, three methods (M1: sub-bands with equally spaced bandwidths; M2: sub-bands corresponding to individual harmonic frequency bands; M3: sub-bands covering multiple harmonic frequency bands) were proposed for comparison. Classification accuracy and information transfer rate (ITR) of the three FBCCA methods and the standard CCA method were estimated using an offline dataset from 12 subjects. Furthermore, an online BCI speller adopting the optimal FBCCA method was tested with a group of 10 subjects. MAIN RESULTS: The FBCCA methods significantly outperformed the standard CCA method. The method M3 achieved the highest classification performance. At a spelling rate of ~33.3 characters/min, the online BCI speller obtained an average ITR of 151.18 +/- 20.34 bits min(-1). SIGNIFICANCE: By incorporating the fundamental and harmonic SSVEP components in target identification, the proposed FBCCA method significantly improves the performance of the SSVEP-based BCI, and thereby facilitates its practical applications such as high-speed spelling. PMID- 26035477 TI - Transient EPR Reveals Triplet State Delocalization in a Series of Cyclic and Linear pi-Conjugated Porphyrin Oligomers. AB - The photoexcited triplet states of a series of linear and cyclic butadiyne-linked porphyrin oligomers were investigated by transient Electron Paramagnetic Resonance (EPR) and Electron Nuclear DOuble Resonance (ENDOR). The spatial delocalization of the triplet state wave function in systems with different numbers of porphyrin units and different geometries was analyzed in terms of zero field splitting parameters and proton hyperfine couplings. Even though no significant change in the zero-field splitting parameters (D and E) is observed for linear oligomers with two to six porphyrin units, the spin polarization of the transient EPR spectra is particularly sensitive to the number of porphyrin units, implying a change of the mechanism of intersystem crossing. Analysis of the proton hyperfine couplings in linear oligomers with more than two porphyrin units, in combination with density functional theory calculations, indicates that the spin density is localized mainly on two to three porphyrin units rather than being distributed evenly over the whole pi-system. The sensitivity of the zero field splitting parameters to changes in geometry was investigated by comparing free linear oligomers with oligomers bound to a hexapyridyl template. Significant changes in the zero-field splitting parameter D were observed, while the proton hyperfine couplings show no change in the extent of triplet state delocalization. The triplet state of the cyclic porphyrin hexamer has a much decreased zero-field splitting parameter D and much smaller proton hyperfine couplings with respect to the monomeric unit, indicating complete delocalization over six porphyrin units in this symmetric system. This surprising result provides the first evidence for extensive triplet state delocalization in an artificial supramolecular assembly of porphyrins. PMID- 26035478 TI - Diurnal emotional reactivity: Ultradian changes at neural and behavioral levels in men. AB - The aim of this study was to examine the ultradian dynamic of emotional processing in men. Event-related potentials were recorded while participants watched different sets of unpleasant and neutral pictures every 15 min for 3 h. Emotional feelings induced by unpleasant pictures were also assessed with self rating scales at the end of each picture set. Whereas brain processing of neutral pictures remained stable over time, a late positive component elicited by unpleasant pictures presented ultradian oscillations varying between 65 and 110 min in 77% of the participants, mainly in the right centro-posterior area. Ultradian rhythms were also observed for values self-rating the intensity of unpleasant feelings. Correlative analyses performed between brain and behavioral ultradian oscillations indicated that these rhythms follow a temporal opposite pattern. For the first time, these results raise questions regarding the modulating role of ultradian oscillations when the brain computes the significance of unpleasant stimuli and produces the final emotional feelings. Overall, these findings open new perspectives on the temporal regulation of emotional reactivity in healthy individuals and in those with affective disorders. PMID- 26035479 TI - Leptin modulates the daily rhythmicity of blood glucose. AB - Leptin may affect central and/or peripheral timing, in addition to its well-known regulatory effects on metabolism. Here, we investigated whether leptin can impact rhythmicity of blood glucose and lipids. For that purpose, daily variations of blood glucose and lipids were compared between mice lacking functional leptin receptor (db/db) or deficient for leptin (ob/ob) and controls (db/+ and ob/+, respectively). Next, we investigated whether timed treatment with exogenous leptin in ob/ob mice could modulate blood glucose rhythm. Mice with defective leptin signaling (db/db and ob/ob) have the same phase-opposed timing in glycemia (11 and 9 h shift, respectively) compared to respective controls. By contrast, the phase of plasma lipids rhythms (e.g. triglycerides, non-esterified fatty acid - NEFA, high density lipoprotein - HDL, low density lipoprotein - LDL) remained essentially unchanged, whatever the genotype. Daily injections of leptin (1 mg/kg) in ob/ob mice during nighttime or daytime led to 1-2 h phase-advances of blood glucose rhythm and glucose arrhythmicity, respectively. These injections induced additional phase-dependent shifts of feeding rhythm (ranging from 2.6 h phase-delays to 2.6 h advances). The present study reveals a chronomodulatory role of leptin, and highlights that rhythmic leptin can be a determinant of daily variations of blood glucose and food intake, though not for lipids. PMID- 26035480 TI - Day and night shift schedules are associated with lower sleep quality in Evening types. AB - Eveningness has been suggested as a facilitating factor in adaptation to shift work, with several studies reporting evening chronotypes (E-types) as better sleepers when on night shifts. Conversely, eveningness has been associated with more sleep complaints during day shifts. However, sleep during day shifts has received limited attention in previous studies assessing chronotypes in shift workers. Environmental light exposure has also been reported to differ between chronotypes in day workers. Activity is also known to provide temporal input to the circadian clock. Therefore, the aim of this study was to compare objective sleep, light exposure and activity levels between chronotypes, both during the night and day shifts. Thirty-nine patrol police patrol officers working on a fast rotating shift schedule (mean age +/- SD: 28.9 +/- 3.2 yrs; 28 males) participated in this study. All subjects completed the Morningness-Eveningness Questionnaire (MEQ). Sleep and activity were monitored with actigraphy (Actiwatch L; Mini-Mitter/Respironics, Bend, OR) for four consecutive night shifts and four consecutive day shifts (night work schedule: 00:00 h-07:00 h; day work schedule: 07:00 h-15:00 h). Sleep and activity parameters were calculated with Actiware software. MEQ scores ranged from 26 to 56; no subject was categorized as Morning type. E-types (n = 13) showed significantly lower sleep efficiency, longer snooze time and spent more time awake after sleep onset than Intermediate-types (I types, n = 26) for both the night and day shifts. E-types also exhibited shorter and more numerous sleep bouts. Furthermore, when napping was taken into account, E-types had shorter total sleep duration than I-types during the day shifts. E types were more active during the first hours of their night shift when compared to I-types. Also, all participants spent more time active and had higher amount of activity per minute during day shifts when compared to night shifts. No difference was found regarding light exposure between chronotypes. In conclusion, sleep parameters revealed poorer sleep quality in E-types for both the night and day shifts. These differences could not be explained by sleep opportunity, light exposure or activity levels. This study challenges the notion that E-types adapt better to night shifts. Further studies must verify whether E-types exhibit lower sleep quality than Morning-types. PMID- 26035481 TI - Eating meals before wheel-running exercise attenuate high fat diet-driven obesity in mice under two meals per day schedule. AB - Mice that exercise after meals gain less body weight and visceral fat compared to those that exercised before meals under a one meal/exercise time per day schedule. Humans generally eat two or three meals per day, and rarely have only one meal. To extend our previous observations, we examined here whether a "two meals, two exercise sessions per day" schedule was optimal in terms of maintaining a healthy body weight. In this experiment, "morning" refers to the beginning of the active phase (the "morning" for nocturnal animals). We found that 2-h feeding before 2-h exercise in the morning and evening (F-Ex/F-Ex) resulted in greater attenuation of high fat diet (HFD)-induced weight gain compared to other combinations of feeding and exercise under two daily meals and two daily exercise periods. There were no significant differences in total food intake and total wheel counts, but feeding before exercise in the morning groups (F-Ex/F-Ex and F-Ex/Ex-F) increased the morning wheel counts. These results suggest that habitual exercise after feeding in the morning and evening is more effective for preventing HFD-induced weight gain. We also determined whether there were any correlations between food intake, wheel rotation, visceral fat volume and skeletal muscle volumes. We found positive associations between gastrocnemius muscle volumes and morning wheel counts, as well as negative associations between morning food intake volumes/body weight and morning wheel counts. These results suggest that morning exercise-induced increase of muscle volume may refer to anti-obesity. Evening exercise is negatively associated with fat volume increases, suggesting that this practice may counteract fat deposition. Our multifactorial analysis revealed that morning food intake helps to increase exercise, and that evening exercise reduced fat volumes. Thus, exercise in the morning or evening is important for preventing the onset of obesity. PMID- 26035482 TI - Daily activity patterns of 2316 men and women from five countries differing in socioeconomic development. AB - Daily rhythmicity in the locomotor activity of laboratory animals has been studied in great detail for many decades, but the daily pattern of locomotor activity has not received as much attention in humans. We collected waist-worn accelerometer data from more than 2000 individuals from five countries differing in socioeconomic development and conducted a detailed analysis of human locomotor activity. Body mass index (BMI) was computed from height and weight. Individual activity records lasting 7 days were subjected to cosinor analysis to determine the parameters of the daily activity rhythm: mesor (mean level), amplitude (half the range of excursion), acrophase (time of the peak) and robustness (rhythm strength). The activity records of all individual participants exhibited statistically significant 24-h rhythmicity, with activity increasing noticeably a few hours after sunrise and dropping off around the time of sunset, with a peak at 1:42 pm on average. The acrophase of the daily rhythm was comparable in men and women in each country but varied by as much as 3 h from country to country. Quantification of the socioeconomic stages of the five countries yielded suggestive evidence that more developed countries have more obese residents, who are less active, and who are active later in the day than residents from less developed countries. These results provide a detailed characterization of the daily activity pattern of individual human beings and reveal similarities and differences among people from five countries differing in socioeconomic development. PMID- 26035483 TI - Specific role of dietary fat in modifying cardiovascular and locomotor activity 24-h rhythms. AB - Meal-fed conscious rabbits normally exhibit postprandial elevation in blood pressure, heart rate (HR) and locomotor activity, which is abolished by consumption of a high-fat diet (HFD). Here, we assessed whether the cardiovascular changes are attributable to the increased caloric intake due to greater fat content or to hyperphagia. Rabbits were meal-fed during the baseline period then maintained on either an ad libitum normal fat diet (NFD) or ad libitum HFD for 2 weeks. Blood pressure, HR and locomotor activity were measured daily by radio-telemetry alongside food intake and body weight. Caloric intake in rabbits given a NFD ad libitum rose 50% from baseline but there were no changes in cardiovascular parameters. By contrast, HR increased by 10% on the first day of the ad libitum HFD (p < 0.001) prior to any change in body weight while blood pressure increased 7% after 4 d (p < 0.01) and remained elevated. Baseline 24-h patterns of blood pressure and HR were closely associated with mealtime, characterised by afternoon peaks and morning troughs. When the NFD was changed from meal-fed to ad libitum, blood pressure and HR did not change but afternoon activity levels decreased (p < 0.05). By contrast, after 13 d ad libitum HFD, morning HR, blood pressure and activity increased by 20%, 8% and 71%, respectively. Increased caloric intake specifically from fat, but not as a result of hyperphagia, appears to directly modulate cardiovascular homeostasis and circadian patterns, independent of white adipose tissue accumulation. PMID- 26035485 TI - Perinatal low-protein diet alters brainstem antioxidant metabolism in adult offspring. AB - BACKGROUND AND OBJECTIVES: Studies in humans and animal models have established a close relationship between early environment insult and subsequent risk of development of non-communicable diseases, including the cardiovascular. Whereas experimental evidences highlight the early undernutrition and the late cardiovascular disease relation, the central mechanisms linking the two remain unknown. Owing to the oxidative balance influence in several pathologies, the aim of the present study was to evaluate the effects of maternal undernutrition (i.e. a low-protein (LP) diet) on oxidative balance in the brainstem. METHODS AND RESULTS: Male rats from mothers fed with an LP diet (8% casein) throughout the perinatal period (i.e. gestation and lactation) showed 10* higher lipid peroxidation levels than animals treated with normoprotein (17% casein) at 100 days of age. In addition, we observed the following reductions in enzymatic activities: superoxide dismutase, 16%; catalase, 30%; glutathione peroxidase, 34%; glutathione-S-transferase, 51%; glutathione reductase, 23%; glucose-6 phosphate dehydrogenase, 31%; and in non-enzymatic glutathione system, 46%. DISCUSSION: This study is the first to focus on the role of maternal LP nutrition in oxidative balance in a central nervous system structure responsible for cardiovascular control in adult rats. Our data observed changes in oxidative balance in the offspring, therefore, bring a new concept related to early undernutrition and can help in the development of a new clinical strategy to combat the effects of nutritional insult. Wherein the central oxidative imbalance is a feasible mechanism underlying the hypertension risk in adulthood triggered by maternal LP diet. PMID- 26035484 TI - Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering. AB - The presentation and controlled release of bioactive signals to direct cellular growth and differentiation represents a widely used strategy in tissue engineering. Historically, work in this field has primarily focused on the delivery of large cytokines and growth factors, which can be costly to manufacture and difficult to deliver in a sustained manner. There has been a marked increase over the past decade in the pursuit of lipid mediators due to their wide range of effects over multiple cell types, low cost, and ease of scale up. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two bioactive lysophospholipids (LPLs) that have gained attention for use as pharmacological agents in tissue engineering applications. While these lipids can have similar effects on cellular response, they possess distinct chemical backbones, mechanisms of synthesis and degradation, and signaling pathways using a discrete set of G-protein-coupled receptors (GPCRs). LPA and S1P predominantly act extracellularly on their GPCRs and can directly regulate cell survival, differentiation, cytokine secretion, proliferation, and migration--each of the important functions that must be considered in regenerative medicine. In addition to these potent physiological functions, these LPLs play pivotal roles in a number of pathophysiological processes. To capitalize on the promise of these molecules in tissue engineering, these lipids have been incorporated into biomaterials for in vivo delivery. Here, we survey the effects of LPA and S1P on both cellular- and tissue-level phenotypes, with an eye toward regulating stem/progenitor cell growth and differentiation. In particular, we examine work that has translational applications for cell-based tissue engineering strategies in promoting cell survival, bone and cartilage engineering, and therapeutic angiogenesis. PMID- 26035486 TI - Monoclonal Antibody Combinations that Present Synergistic Neutralizing Activity: A Platform for Next-Generation Anti-Toxin Drugs. AB - Monoclonal antibodies (MAbs) are among the fastest-growing therapeutics and are being developed for a broad range of indications, including the neutralization of toxins, bacteria and viruses. Nevertheless, MAbs potency is still relatively low when compared to conventional polyclonal Ab preparations. Moreover, the efficacy of an individual neutralizing MAb may significantly be hampered by the potential absence or modification of its target epitope in a mutant or subtype of the infectious agent. These limitations of individual neutralizing MAbs can be overcome by using oligoclonal combinations of several MAbs with different specificities to the target antigen. Studies conducted in our lab and by others show that such combined MAb preparation may present substantial synergy in its potency over the calculated additive potency of its individual MAb components. Moreover, oligoclonal preparation is expected to be better suited to compensating for reduced efficacy due to epitope variation. In this review, the synergistic neutralization properties of combined oligoclonal Ab preparations are described. The effect of Ab affinity, autologous Fc fraction, and targeting a critical number of epitopes, as well as the unexpected contribution of non-neutralizing clones to the synergistic neutralizing effect are presented and discussed. PMID- 26035488 TI - Anti-fibrotic effect of natural toxin bee venom on animal model of unilateral ureteral obstruction. AB - Progressive renal fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure. Bee venom (BV) has been widely used as a traditional medicine for various diseases. However, the precise mechanism of BV in ameliorating the renal fibrosis is not fully understood. To investigate the therapeutic effects of BV against unilateral ureteral obstruction (UUO)-induced renal fibrosis, BV was given intraperitoneally after ureteral ligation. At seven days after UUO surgery, the kidney tissues were collected for protein analysis and histologic examination. Histological observation revealed that UUO induced a considerable increase in the number of infiltrated inflammatory cells. However, BV treatment markedly reduced these reactions compared with untreated UUO mice. The expression levels of TNF-alpha and IL-1beta were significantly reduced in BV treated mice compared with UUO mice. In addition, treatment with BV significantly inhibited TGF-beta1 and fibronectin expression in UUO mice. Moreover, the expression of alpha-SMA was markedly withdrawn after treatment with BV. These findings suggest that BV attenuates renal fibrosis and reduces inflammatory responses by suppression of multiple growth factor-mediated pro-fibrotic genes. In conclusion, BV may be a useful therapeutic agent for the prevention of fibrosis that characterizes progression of chronic kidney disease. PMID- 26035489 TI - Effects of Wheat Naturally Contaminated with Fusarium Mycotoxins on Growth Performance and Selected Health Indices of Red Tilapia (Oreochromis niloticus * O. mossambicus). AB - An 8-week feeding trial was conducted to examine effects of wheat naturally contaminated with Fusarium mycotoxins (deoxynivalenol, DON 41 mg.kg(-1)) on growth performance and selected health indices of red tilapia (Oreochromis niloticus * O. mossambicus; initial weight = 4.3 g/fish). Five experimental diets were formulated by replacement of clean wheat with naturally contaminated wheat resulting in graded levels of DON and zearalenone (ZEN) (Diet 1 0.07/0.01, Diet 2 0.31/0.09, Diet 3 0.50/0.21, Diet 4 0.92/0.37 and Diet 5 1.15/0.98 mg.kg(-1)). Groups of 50 fish were randomly allocated into each of 20 aquaria and fed to near satiety for eight weeks. Growth rate, feed intake and feed efficiency of fish fed the experimental diets decreased linearly with increasing levels of Fusarium mycotoxins (p < 0.05). Although growth depression was associated with feeding diets naturally contaminated with Fusarium mycotoxins, especially DON, no biochemical and histopathological parameters measured in blood and liver appeared affected by Fusarium mycotoxin concentrations of diets (p > 0.05). Though there was no clear evidence of overt DON toxicity to red tilapia, it is recommended that feed ingredients should be screened for Fusarium mycotoxin contamination to ensure optimal growth performance. PMID- 26035487 TI - Treatment of gastrointestinal sphincters spasms with botulinum toxin A. AB - Botulinum toxin A inhibits neuromuscular transmission. It has become a drug with many indications. The range of clinical applications has grown to encompass several neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum toxin A provides benefit in diseases of the gastrointestinal tract. Although toxin blocks cholinergic nerve endings in the autonomic nervous system, it has also been shown that it does not block non-adrenergic non-cholinergic responses mediated by nitric oxide. This has promoted further interest in using botulinum toxin A as a treatment for overactive smooth muscles and sphincters. The introduction of this therapy has made the treatment of several clinical conditions easier, in the outpatient setting, at a lower cost and without permanent complications. This review presents current data on the use of botulinum toxin A in the treatment of pathological conditions of the gastrointestinal tract. PMID- 26035490 TI - Nivalenol has a greater impact than deoxynivalenol on pig jejunum mucosa in vitro on explants and in vivo on intestinal loops. AB - The mycotoxins deoxynivalenol (DON) and nivalenol (NIV), worldwide cereal contaminants, raise concerns for animal and human gut health, following contaminated food or feed ingestion. The impact of DON and NIV on intestinal mucosa was investigated after acute exposure, in vitro and in vivo. The histological changes induced by DON and NIV were analyzed after four-hour exposure on pig jejunum explants and loops, two alternative models. On explants, dose-dependent increases in the histological changes were induced by DON and NIV, with a two-fold increase in lesion severity at 10 uM NIV. On loops, NIV had a greater impact on the mucosa than DON. The overall proliferative cells showed 30% and 13% decrease after NIV and DON exposure, respectively, and NIV increased the proliferative index of crypt enterocytes. NIV also increased apoptosis at the top of villi and reduced by almost half the proliferative/apoptotic cell ratio. Lamina propria cells (mainly immune cells) were more sensitive than enterocytes (epithelial cells) to apoptosis induced by NIV. Our results demonstrate a greater impact of NIV than DON on the intestinal mucosa, both in vitro and in vivo, and highlight the need of a specific hazard characterization for NIV risk assessment. PMID- 26035492 TI - Food contaminant zearalenone and its metabolites affect cytokine synthesis and intestinal epithelial integrity of porcine cells. AB - The intestinal epithelium is the first barrier against food contaminants. Zearalenone (ZEN) is an estrogenic mycotoxin that was identified as a common contaminant of cereal grains and food and feedstuffs. In the present study, we have investigated the in vitro effects of ZEN and some of its metabolites (alpha ZOL, beta-ZOL) in concentrations of 10-100 uM on a swine epithelial cell line: Intestinal porcine epithelial cells (IPEC-1). We demonstrated that both ZEN metabolites were more toxic for IPEC cells as resulted from the XTT test, while for doses lower than 10 uM, only beta-ZOL showed a more pronounced cytotoxicity versus epithelial cells as resulted from neutral red assay. ZEN has no effect on TER values, while alpha-ZOL significantly decreased the TER values, starting with day 4 of treatment. beta-ZOL had a dual effect, firstly it induced a significant increase of TER, and then, starting on day 6, it induced a dramatic decrease of TER values as compared with on day 0. Concerning the cytokine synthesis, our results showed that ZEN has a tendency to increase the synthesis of IL-8 and IL 10. By contrast, alpha- and beta-ZOL decreased the expression of both IL-8 and IL 10, in a dose dependent manner. In conclusion, our results showed that ZEN and its metabolites differently affected porcine intestinal cell viability, transepithelial resistance and cytokine synthesis with important implication for gut health. PMID- 26035491 TI - Chronic Sublethal Effects of Cantharidin on the Diamondback Moth Plutella xylostella (Lepidoptera: Plutellidae). AB - The diamondback moth, Plutella xylostella (Linnaeus) (Lepidoptera: Plutellidae), is a major pest of cruciferous vegetables worldwide. Cantharidin, a natural toxin isolated from blister beetles, has been reported to be toxic to P. xylostella. However, little is known on the chronic sublethal effects of cantharidin on this species. In this study, we assessed the changes of susceptibility, development, reproduction and other demographic parameters in both the selected P. xylostella strain (Sub, selected by LC25 cantharidin for consecutive 12 generations) and the revertant strain (SubR, derived from the Sub strain without being exposed to cantharidin for 12 generations). Results revealed that the two strains maintained a relatively high-level susceptibility to cantharidin. Severe adverse effects on the population dynamics and fitness in Sub strain were observed. In addition, repeated exposure of P. xylostella to sublethal concentration of cantharidin resulted in negative effects on adult performance and deformities in adults. Although morphologically normal for individuals, the SubR strain exhibited a disadvantage in population growth rate. Our results showed that sublethal concentration of cantharidin exhibited severe negative effects on population growth for longtime. These findings would be useful for assessing the potential effects and risk of cantharidin on P. xylostella and for developing effective integrated pest management. PMID- 26035493 TI - ProPairs: A Data Set for Protein-Protein Docking. AB - ProPairs is a data set of crystal structures of protein complexes defined as biological assemblies in the protein data bank (PDB), which are classified as legitimate protein-protein docking complexes by also identifying the corresponding unbound protein structures in the PDB. The underlying program selecting suitable protein complexes, also called ProPairs, is an automated method to extract structures of legitimate protein docking complexes and their unbound partner proteins from the PDB which fulfill specific criteria. In this way a total of 5,642 protein complexes have been identified with 11,600 different decompositions in unbound protein pairs yielding legitimate protein docking partners. After removing sequence redundancy (requiring a sequence identity of the residues in the interface of less than 40%), 2,070 different legitimate protein docking complexes remain. For 810 of these protein docking complexes, both docking partners possess corresponding unbound structures in the PDB. From the 2,070 nonredundant protein docking complexes there are 417 which possess a cofactor at the interface. From the 176 protein docking complexes of the Protein Protein Docking Benchmark 4.0 (DB4.0) data set, 13 differ from the ProPairs data set. Twelve of them differ with respect to the composition of the unbound structures but are contained in the large redundant ProPairs data set. One protein docking complex of the DB4.0 data set is not contained in ProPairs since the biological assembly specified in the PDB is wrong (PDB id 1d6r ). For one protein complex (PDB id 1bgx ) the DB4.0 data set uses a fabricated unbound structure. For public use interactive online access is provided to the ProPairs data set of nonredundant protein docking complexes along with the source code of the underlying method [ http://propairs.github.io]. PMID- 26035494 TI - Variability of the Anterior Humeral Line in Normal Pediatric Elbows. AB - BACKGROUND: The anterior humeral line (AHL) is considered a valuable radiographic tool in the assessment of pediatric elbow sagittal plane alignment following injury. However, few studies exist that examine the validity of the AHL. The purpose of this study is to report the variability of the AHL in skeletally immature children with normal elbows. METHODS: A total of 124 true lateral elbow radiographs of normal pediatric elbows were retrospectively identified and examined for the relationship of the AHL to the capitellum. The percentage of AHLs falling outside the middle third of the capitellum was compared among different age and sex groups using Fisher exact tests. RESULTS: In 100% of patients, the AHL touched the ossific nucleus of the capitellum. In 100% (52/52) of patients >=5 years the AHL goes through the middle third of the capitellum, but this is significantly different from patients less than 5 years of age in whom 25% (18/72) of patients the AHL fell outside of the middle third of the capitellum (P<0.001). In children less than 2 years of age, the AHL was in the anterior third in 30% of the cases. CONCLUSIONS: Traditional teaching that the AHL touches the capitellum on a lateral radiograph of a normal elbow in a child is correct, so if the AHL does not touch the capitellum it is appropriate to look for pathology. Similarly, in children 5 years and older the AHL goes through the middle third of the capitellum in all patients, so if it does not, it is appropriate to look for pathology. However, with decreasing age variability increases, with the AHL touching the anterior third of the capitellum in almost 1/3 of children. LEVEL OF EVIDENCE: Level III. PMID- 26035495 TI - A floppy baby. AB - Pompe disease is a rare inherited disorder of glycogen metabolism. We present a case of a 9-month-old infant who presented to the emergency department with generalized hypotonia and respiratory distress and was found to have Pompe disease. In this article, we will review the differential diagnosis of hypotonia in the infant, presentations of hypotonia that are relevant to the emergency department physician, as well as the diagnosis, management, and prognosis of Pompe disease. PMID- 26035496 TI - Fatal and near-fatal grape aspiration in children. AB - Choking remains an important cause of morbidity and mortality in young children. Whole seedless grapes are a popular fruit snack to give to young children.We present 3 cases of grape aspiration, discussing the emergency care from basic life support to specialist treatment.The lessons learned will be applicable to a wide range of health professionals from frontline emergency medical service personnel to physicians and nurses working in a hospital. PMID- 26035497 TI - A swollen hand with blisters: a case of compartment syndrome in a child. AB - The accurate identification of compartment syndrome in the emergency department is essential to timely treatment and prevention of long-term sequela. Recognizing compartment syndrome is not straightforward, especially in the pediatric population. In addition to communication barriers that exist with children, the classic signs of pain, pallor, paresthesia, paralysis, and pulselessness are not always present, making its diagnosis a challenge. We report a case of a child with compartment syndrome to the left hand due to compression from an ACE wrap. The existing literature on compartment syndrome in children is reviewed. PMID- 26035498 TI - Toe tourniquet syndrome caused by cable tie. AB - BACKGROUND: Tourniquet syndrome clinically presents as pain, discoloration, paresthesias, and swelling distal to a constricting band. If left untreated or unrecognized, it may induce ischemia, resulting in tissue necrosis or auto amputation of the appendage. Treatment involves removal of all constricting bands and monitoring of the neurovascular status of the digit after constriction removal. RESULTS: A healthy 7-year-old female had tied a cable tie around her toe for an unknown amount of time before evaluation. After examination of the toe and concern for ischemia, the cable tie was removed. Once the cable tie was removed, the area of necrotic tissue at the dorsal proximal phalanx was gently debrided taking special care to avoid the extensor tendon, which was exposed but appeared to be intact. Tetanus prophylaxis was updated, she was sent home on oral antibiotics and she went home with dressing changes. The patient was referred for a psychiatric consultation due to the unique nature of the self-injury and concern for possible underlying disorder. CONCLUSIONS: This case is the first in the literature to describe toe tourniquet syndrome caused by a cable tie. This case highlights the importance of treatment of the offending structure with release and to monitor the digit for signs of ischemia. A thorough history should be sought from both the patient and, in this case, the patient's caregiver to seek any additional clues of depression, anxiety, or anger. If warranted, appropriate consultation of a psychiatrist may be warranted. PMID- 26035499 TI - Radiographic evaluation of pediatric cerebrospinal fluid shunt malfunction in the emergency setting. AB - Children with ventricular cerebrospinal fluid shunts for treatment of hydrocephalus require frequent evaluation for potential shunt malfunction. Current practice relies heavily on neuroimaging, particularly cranial computed tomography, which repeatedly exposes children to ionizing radiation. Rapid cranial magnetic resonance imaging is a new radiation-sparing alternative to CT for evaluation of potential shunt malfunction. We review the diagnostic test performance, radiation exposure, advantages, and limitations of the major neuroimaging modalities available to providers caring for children with possible shunt malfunction in the emergent setting. PMID- 26035501 TI - Intravenous acetaminophen use in pediatrics. AB - Acetaminophen is a commonly used pediatric medication that has recently been approved for intravenous use in the United States. The purpose of this article was to review the pharmacodynamics, indications, contraindications, and precautions for the use of intravenous acetaminophen in pediatrics. PMID- 26035503 TI - False-positive focused abdominal sonography in trauma in a hypotensive child: case report. AB - We report a case of a false-positive focused abdominal sonography in trauma (FAST) examination in a persistently hypotensive pediatric trauma patient, performed 12 hours after the trauma, suspected to be caused by massive fluid resuscitation leading to ascites. While a positive FAST in a hypotensive trauma patient usually indicates hemoperitoneum, this case illustrates that the timing of the FAST examination relative to the injury, as well as clinical evolution including the volume of fluid resuscitation, need to be considered when interpreting the results of serial and/or late FAST examinations. PMID- 26035504 TI - Head trauma and intracranial hemorrhage in children with idiopathic thrombocytopenic purpura. AB - BACKGROUND: The current guidelines for management of idiopathic thrombocytopenic purpura (ITP) does not address head trauma and the current emergency pediatric head trauma management guidelines do not address children with ITP. The characteristics of patients who develop intracranial hemorrhage (ICH) as a result of head trauma or the management of head trauma in patients with ITP are not clear. OBJECTIVES: Review the literature to identify and describe the characteristics and outcomes of intracranial haemorrhage as a result of head trauma in children with ITP. METHODS: We reviewed literature using Medline, Embase, and PUBMED databases from inception until December 2013. Articles were included if they described patients with head trauma and intracranial bleeding in children with ITP. Nine relevant articles met inclusion criteria and were included. Three case reports, 3 institution survey studies, and 5 retrospective chart reviews. RESULTS: There were 114 cases of ICH reported in children with ITP, and 26% (n = 30) were identified to have ICH due to head trauma. Of the 30 children with ITP who had an ICH in the context of head injury, 23% (7 patients) died as a result of ICH and 13% (4 patients) suffered significant neurological sequelae. Twenty-seven percent were 3 years or younger when the age was reported CONCLUSIONS: Intracranial haemorrhage after head trauma in children with ITP leads to significant morbidity and mortality. As such, more thorough investigations, including radiological imaging and aggressive treatment, are recommended for children with ITP presenting with head injuries. PMID- 26035505 TI - An 8-year-old girl with abdominal pain and mental status changes. PMID- 26035507 TI - ? PMID- 26035506 TI - ECGs in the ED. PMID- 26035508 TI - ? PMID- 26035509 TI - Quality of Life in Patients with NSCLC Receiving Maintenance Therapy. AB - INTRODUCTION: In the past few years many trials have evaluated the use of maintenance therapy in the treatment of NSCLC stage IV. Both switch as well as continuation maintenance show an improved PFS and overall survival. HRQoL data was only partially published. The aim of this article is to review the published effects of maintenance therapy on HRQoL. METHODS: Two PubMed searches were performed using the terms: "maintenance therapy and NSCLC" and "maintenance therapy and NSCLC and HRQoL". The published data was compared, analysed and evaluated. RESULTS: 272 articles were found dealing with maintenance therapy, and of these 85 articles were found regarding maintenance therapy and HRQoL in NSCLC. Maintenance therapy showed no negative impact on HRQoL but failed to show a real benefit. Some symptoms showed positive trends during maintenance therapy. HRQoL can be used to select patients for maintenance therapy. CONCLUSIONS: Maintenance therapy is very safe, improves PFS and OS without impairing HRQoL. Although a positive impact on general QoL could not be demonstrated this is possibly due to the mode of evaluating HRQoL. Patient reported outcomes should be simplified and examined for a longer period of time. PMID- 26035511 TI - LONG-TERM FOLLOW-UP OF INTRAOCULAR PRESSURE AFTER VITRECTOMY IN EYES WITHOUT PREEXISTING GLAUCOMA. AB - PURPOSE: To identify whether vitrectomy is associated with an increased risk of elevated intraocular pressure (IOP) and to report the incidence of open-angle glaucoma after vitrectomy. METHODS: In this retrospective case series of 234 consecutive patients without a history of glaucoma or diabetes undergoing primary unilateral vitrectomy for an idiopathic epiretinal membrane or macular hole with a minimum of 2 years follow-up, mean IOP in operative and fellow eyes were compared at baseline and multiple postoperative times. Eyes were also assessed for the development of open-angle glaucoma. RESULTS: The mean baseline IOP was 14.91 mmHg, and the mean final IOP was 14.6 (P = 0.278) in the operative eyes. Linear regression analysis of IOP in operative eyes from baseline to the final visit found an increase of 0.000047 mmHg per year compared with -0.00027 mmHg per year in the fellow eyes with no significant difference in the slope of the 2 regression lines (P = 0.27). Six vitrectomy eyes were diagnosed with new-onset open-angle glaucoma during a mean follow-up of 4.4 years; however, only one was not also diagnosed with glaucoma or ocular hypertension in the fellow unoperated eye. CONCLUSION: Vitrectomy does not seem to be correlated with increased risk of IOP elevation or glaucoma development in comparison with fellow control eyes. PMID- 26035510 TI - RANIBIZUMAB PLUS PROMPT OR DEFERRED LASER FOR DIABETIC MACULAR EDEMA IN EYES WITH VITRECTOMY BEFORE ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY. AB - BACKGROUND: The approach to managing diabetic macular edema in eyes with previous vitrectomy is based on limited evidence. Therefore, an exploratory post hoc assessment of 3-year data from eyes with and without vitrectomy before randomization in a DRCR.net trial that evaluated ranibizumab + prompt or deferred laser for diabetic macular edema is presented. METHODS: Visual acuity and optical coherence tomography outcomes were compared between eyes with and without previous vitrectomy. RESULTS: At baseline, eyes with previous vitrectomy (n = 25) had longer duration of diabetes, worse visual acuity, less thickened central subfield measurements on optical coherence tomography and were more apt to have worse diabetic retinopathy severity level or previous treatment for macular edema or cataract surgery than eyes without a history of vitrectomy (n = 335). Analyses adjusted for these baseline imbalances did not identify substantial differences between eyes with and without previous vitrectomy at each annual visit through 3 years for the favorable visual acuity, optical coherence tomography central subfield thickness, or volume outcomes, although optical coherence tomography improvement appeared slower in vitrectomy eyes during the first year. CONCLUSION: This study provides little evidence that the beneficial clinical outcomes for patients with center-involved diabetic macular edema treated with anti-vascular endothelial growth factor are affected in the long term by previous vitrectomy. PMID- 26035512 TI - VARIATIONS IN CHOROIDAL THICKNESS AFTER HIGH-DOSE SYSTEMIC CORTICOSTEROID TREATMENT IN CHILDREN WITH CHRONIC GLOMERULONEPHRITIS. AB - PURPOSE: To study changes in choroidal thickness (CT) after high-dose systemic corticosteroid treatment using spectral domain optical coherence tomography. METHODS: The authors reviewed medical records for 64 eyes of 32 children who receiving high-dose corticosteroid therapy with chronic glomerulonephritis and no ocular disease. Choroidal thickness was measured in a prospective manner in the same subfoveal area using an enhanced depth imaging technique with spectral domain optical coherence tomography at the same time daily. The possible correlation between CT and various factors was evaluated. RESULTS: Choroidal thickness decreased significantly during methylprednisolone pulse treatment. Mean decrease in CT was 15.42 +/- 8.86 MUm (range, 14-30 MUm). In 10 eyes of 5 children with multiple hospitalizations and pulse treatments, a temporary decrease in CT was observed with methylprednisolone pulse treatment and after recovery without methylprednisolone pulse treatment. In multiple regression analysis, the number of previous methylprednisolone pulse treatments was the only factor associated with the mean amplitude of CT decrease (P = 0.011). CONCLUSION: High-dose systemic corticosteroid treatment significantly reduces CT. The effect of reducing the CT does not last after cessation of the treatment. The relation of central serous chorioretinopathy with corticosteroid treatment may not be based on the effect of corticosteroid treatment on CT. PMID- 26035513 TI - WIDE-FIELD SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY. AB - PURPOSE: To describe wide-field spectral domain optical coherence tomography morphologic relationships of the vitreous, retina, and choroid in healthy and pathologic eyes. METHODS: Standardized horizontal, vertical, and two oblique (supertemporal to inferonasal and supranasal to inferotemporal) spectral domain optical coherence tomography sections were collected for each patient. For extramacular imaging, images were obtained from 8 locations: (1) nasal to the optic disk, (2) extreme nasal periphery, (3) superior to the superotemporal vascular arcade, (4) extreme superior periphery, (5) inferior to the inferotemporal vascular arcade, (6) extreme inferior periphery, (7) temporal to the macula, and (8) extreme temporal periphery. Wide-angle montage images of optical coherence tomography from equator-to-equator were composed with a montaging software. RESULTS: Wide-field spectral domain optical coherence tomography scans were obtained in 10 healthy subjects, in 7 patients with central serous chorioretinopathy, in 5 patients with wet age-related macular degenerations, in 5 patients with dry age-related macular degenerations, in 4 patients with retinitis pigmentosa, and in 1 patient with acute exudative polymorphous vitelliform maculopathy. CONCLUSION: The novel approach of montaging spectral domain optical coherence tomography images to examine relationships between the choroid, retina, and associated structures adjacent to and outside of the macula may have a number of relevant applications in the study of vitreoretinal interface, paramacular and macular pathologic features. PMID- 26035514 TI - VARIABLE EXPRESSION OF RETINOPATHY IN A PEDIGREE OF PATIENTS WITH INCONTINENTIA PIGMENTI. AB - PURPOSE: To characterize the varied ocular manifestations of incontinentia pigmenti (IP) in a large pedigree. METHODS: All available members of the kindred who were affected with IP were examined with ophthalmoscopy, wide-field color photos, and fluorescein angiography. RESULTS: Individual family members demonstrated variable expression of retinopathy characteristic of IP. There was severe retinopathy in two eyes: one associated with concurrent persistent fetal vasculature and another with rhegmatogenous retinal detachment. Another individual with biopsy-confirmed IP demonstrated no retinopathy in either eye. When present, retinopathy manifested asymmetrically between eyes of the same individual. CONCLUSION: Cutaneous manifestations of IP are irregular and nonuniform due to lyonization of the X chromosome. In this report, we identify asymmetric retinal disease between eyes in the same individual and variable retinal findings within the kindred. These differences may be explained by random inactivation of the X chromosome or other epigenetic modifications. PMID- 26035515 TI - FLUCTUATION OF INFUSION PRESSURE DURING MICROINCISION VITRECTOMY USING THE CONSTELLATION VISION SYSTEM. AB - PURPOSE: To measure fluctuations in infusion pressure and intraocular pressure (IOP) during vitrectomy performed using a flow-based IOP control system. METHODS: Using 3 vitrectomized porcine eyes, the authors simultaneously measured infusion pressure and IOP during vitreous cutting and aspiration and after extraction of operative instruments in 23-gauge and 25-gauge system. The measurements were performed with the "IOP control" setting turned on or off. The efficacy of valved cannula and a built-in "IOP control limit" module in attenuation of infusion pressure fluctuation was evaluated. RESULTS: At set pressure of 30 mmHg and 60 mmHg, the mean infusion pressure levels were 43.7 mmHg and 78.7 mmHg in the vitreous cutting mode, 67.4 mmHg and 101.2 mmHg in the aspiration mode, and 72.8 mmHg and 115.8 mmHg after extraction of the operative instrument, respectively, when the 23-gauge system was used. Use of valved cannulas effectively attenuated fluctuations in both infusion pressure and IOP. When the IOP control limit setting was "on," the compensatory infusion pressure increase was markedly limited and similar to the set pressure level when the IOP control limit was set at Level 2. Similar results were obtained when a 25-gauge system was used. CONCLUSION: Infusion pressure increased markedly during vitrectomy using a flow based IOP control system. PMID- 26035516 TI - Cardiac applications of PET. AB - Routine use of cardiac positron emission tomography (PET) applications has been increasing but has not replaced cardiac single-photon emission computerized tomography (SPECT) studies yet. The majority of cardiac PET tracers, with the exception of fluorine-18 fluorodeoxyglucose (18F-FDG), are not widely available, as they require either an onsite cyclotron or a costly generator for their production. 18F-FDG PET imaging has high sensitivity for the detection of hibernating/viable myocardium and has replaced Tl-201 SPECT imaging in centers equipped with a PET/CT camera. PET myocardial perfusion imaging with various tracers such as Rb-82, N-13 ammonia, and O-15 H2O has higher sensitivity and specificity than myocardial perfusion SPECT for the detection of coronary artery disease (CAD). In particular, quantitative PET measurements of myocardial perfusion help identify subclinical coronary stenosis, better define the extent and severity of CAD, and detect ischemia when there is balanced reduction in myocardial perfusion due to three-vessel or main stem CAD. Fusion images of PET perfusion and CT coronary artery calcium scoring or CT coronary angiography provide additional complementary information and improve the detection of CAD. PET studies with novel 18F-labeled perfusion tracers such as 18F-flurpiridaz and 18F-FBnTP have yielded high sensitivity and specificity in the diagnosis of CAD. These tracers are still being tested in humans, and, if approved for clinical use, they will be commercially and widely available. In addition to viability studies, 18F-FDG PET can also be utilized to detect inflammation/infection in various conditions such as endocarditis, sarcoidosis, and atherosclerosis. Some recent series have obtained encouraging results for the detection of endocarditis in patients with intracardiac devices and prosthetic valves. PET tracers for cardiac neuronal imaging, such as C-11 HED, help assess the severity of heart failure and post-transplant cardiac reinnervation, and understand the pathogenesis of arrhytmias. The other uncommon applications of cardiac PET include NaF imaging to identify calcium deposition in atherosclerotic plaques and beta-amyloid imaging to diagnose cardiac amyloid involvement. 18F-FDG imaging with a novel PET/MR camera has been reported to be very sensitive and specific for the differentiation between malignant and nonmalignant cardiac masses. The other potential applications of PET/MR are cardiac infectious/inflammatory conditions such as endocarditis. PMID- 26035517 TI - Local validation of the use of Evolution for Bone for bone SPECT imaging. AB - PURPOSE: In order to locally validate the technique, a retrospective review of a cohort of randomly selected single-photon emission computed tomography (SPECT) bone scans reconstructed with ordered subsets expectation maximization (OSEM) and Evolution for Bone was undertaken. MATERIALS AND METHODS: Thirty consecutive bone SPECT patient data sets (17 spine, nine pelvis, and four spine and pelvis) were chosen. Poisson resampling was used to simulate reduced count data at 50, 75, and 100% of the original number of counts. Evolution for Bone applied resolution recovery to the reduced count images. All images were compared with the original OSEM images, currently used as the standard for clinical use. A qualitative blinded assessment was made by two independent observers, who assessed for noise, contrast, and resolution. RESULTS: Both radiologists saw an improvement in resolution (P = 0.776), noise (P = 0.007), and image quality with all data sets, compared with images processed purely with OSEM and viewed in Volumetrix. However, they completely disagreed on contrast, as the two radiologists scored contrast differently; however, the results are understandable. CONCLUSION: Images with 50, 75, and 100% of the original counts viewed using Evolution for Bone have improved image quality compared with images processed purely with OSEM and viewed in Volumetrix. Evolution for Bone therefore has great potential in departments for reducing either patient doses, waiting lists, or both. PMID- 26035518 TI - Estimation of the Adenoma Detection Rate From the Polyp Detection Rate by Using a Conversion Factor in a Predominantly Hispanic Population. AB - BACKGROUND: Calculating the adenoma detection rate (ADR) is a complex process in contrast to the polyp detection rate (PDR) that can be easily calculated. The average adenoma to polyp detection rate quotient (APDRQ) was proposed as a conversion factor to estimate the ADR for individual endoscopists from the endoscopist's PDR. However, this conversion factor was not validated in different practice settings. GOAL: To validate the use of the proposed conversion factor in a practice setting with a predominantly Hispanic population. STUDY: We conducted a retrospective, cross-sectional study (December 2007 to November 2012) of screening colonoscopies at a university practice setting with an 86.9% Hispanic population. The actual ADR and PDR were calculated for all endoscopists. The weighted average of ADR to PDR ratio for each endoscopist was used to obtain APDRQ. The APDRQ was used as a conversion multiplier to estimate each endoscopist's ADR using the single endoscopist's PDR. RESULTS: A total of 2148 screening colonoscopies were included. The average PDR for the whole group was 36.9% (range, 11% to 49%). The actual ADR was estimated as 25.5% (range, 11% to 37%). The average APDRQ for our group was 0.68. The estimated ADR was 25.48% (range, 8% to 33%). There was a high correlation between actual ADR and the estimated ADR (Pearson correlation=0.92). CONCLUSIONS: In a practice setting with a predominantly Hispanic population, a conversion factor can be used to estimate ADR from PDR providing a high degree of correlation with the actual ADR. PMID- 26035519 TI - Biological invasion and biological control select for different life histories. AB - Biological invaders have long been hypothesized to exhibit the fast end of the life-history spectrum, with early reproduction and a short lifespan. Here, we examine the rapid evolution of life history within the harlequin ladybird Harmonia axyridis. The species, once used as a biological control agent, is now a worldwide invader. We show that biocontrol populations have evolved a classic fast life history during their maintenance in laboratories. Invasive populations also reproduce earlier than native populations, but later than biocontrol ones. Invaders allocate more resources to reproduction than native and biocontrol individuals, and their reproduction is spread over a longer lifespan. This life history is best described as a bet-hedging strategy. We assert that invasiveness cannot be explained only by invoking faster life histories. Instead, the evolution of life history within invasive populations can progress rapidly and converge to a fine-tuned evolutionary match between the invaded environment and the invader. PMID- 26035520 TI - Maskless inverted pyramid texturization of silicon. AB - We discovered a technical solution of such outstanding importance that it can trigger new approaches in silicon wet etching processing and, in particular, photovoltaic cell manufacturing. The so called inverted pyramid arrays, outperforming conventional pyramid textures and black silicon because of their superior light-trapping and structure characteristics, can currently only be achieved using more complex techniques involving lithography, laser processing, etc. Importantly, our data demonstrate a feasibility of inverted pyramidal texturization of silicon by maskless Cu-nanoparticles assisted etching in Cu(NO3)2 / HF / H2O2 / H2O solutions and as such may have significant impacts on communities of fellow researchers and industrialists. PMID- 26035521 TI - A Critical Review of Neurobiological Factors Involved in the Interactions Between Chronic Pain, Depression, and Sleep Disruption. AB - AIMS/OBJECTIVES/BACKGROUND: A significant number of people who experience chronic pain also complain of depression and sleep problems. The comorbidities and bidirectional relationships that exist between these ailments are well recognized clinically. Further, all 3 disorders involve similar alterations in structural and functional neurobiology and share common pathophysiological mechanisms. We sought to comprehensively review the research literature regarding common neurobiological factors associated with these complex clinical disorders in order to better understand how they are related and provide further rationale for future clinical and research efforts to appropriately understand and manage them. METHODS: A comprehensive review of the existing research literature was conducted in the domains of chronic pain, depression, and sleep. RESULTS: Although the neurobiological underpinnings of these factors are complex and require further investigation, comparable changes are seen in levels of serotonin (5 hydroxytryptamine), proinflammatory cytokines, brain-derived neurotrophic factor, and other transmitters in these disorders. CONCLUSIONS: This review is unique as it attempts to cast a broader net over the common neurobiological correlates that exist across these 3 conditions. It highlights the complexity of the interrelationships between these disorders and the importance of increasing our understanding of neurobiological factors associated with them. PMID- 26035522 TI - Is the Nociception Coma Scale-Revised a Useful Clinical Tool for Managing Pain in Patients With Disorders of Consciousness? AB - OBJECTIVES: Our objective was to assess the clinical usefulness of the Nociception Coma Scale-revised (NCS-R) in pain management of patients with disorders of consciousness. MATERIALS AND METHODS: Thirty-nine patients with potential painful conditions (eg, due to fractures, decubitus ulcers, or spasticity) were assessed during nursing cares before and after the administration of an analgesic treatment tailored to each patient's clinical status. In addition to the NCS-R, the Glasgow Coma Scale (GCS) was used before and during treatment to observe fluctuations in consciousness. Twenty-three of them had no analgesic treatment before the assessment, whereas the analgesic treatment has been adapted in the other 16 patients. We performed nonparametric Wilcoxon tests to investigate the difference in the NCS-R and GCS total scores but also in the NCS-R subscores before versus during treatment. The effect of the level of consciousness and the etiology were assessed using a Mann-Whitney U test. RESULTS: NCS-R total scores were statistically lower during treatment when compared with the scores obtained before treatment. We also found that the motor, verbal, and facial expression subscores were lower during treatment than before treatment. In contrast, we found no difference between the GCS total scores obtained before versus during treatment. DISCUSSION: Our results suggest that the NCS-R is an interesting clinical tool for pain management. Besides, this tool seems useful when a balance is needed between reduced pain and preserved level of consciousness in patients with disorders of consciousness. PMID- 26035523 TI - Pregabalin Improves Fibromyalgia-related Sleep Disturbance. AB - OBJECTIVE: To investigate the effect of pregabalin on wake and sleep bout parameters. MATERIALS AND METHODS: A post hoc analysis of polysomnography data from a randomized, placebo-controlled, crossover study investigating the effect of pregabalin (150 to 450 mg/d) and placebo on sleep in fibromyalgia (FM). Eligible patients had FM and sleep-maintenance problems, including wake after sleep onset >=45 minutes and total sleep time (TST) 3.0 to 6.5 hours, but no other sleep/circadian rhythm disorders. Polysomnography was performed for 2 consecutive nights (screening, post-treatment). Wake and sleep bout duration and frequency were derived; a "bout"=consecutive 30-s epochs of sleep or wake. RESULTS: Of 119 patients randomized (103 [87%] female), data were available for 103 treated with pregabalin and 106 with placebo. Pregabalin versus placebo treatment decreased mean+/-SD number of wake/sleep bouts (33.24+/-1.33 vs. 36.85+/-1.32; difference: -3.61 [95% confidence interval, -6.03, -1.18]; P=0.0039) and increased sleep bout duration (15.25+/-0.63 vs. 11.58+/-0.62 min; +3.67 min [2.22, 5.12 min]; P<0.0001). Pregabalin decreased mean duration of wake bouts versus placebo (3.41+/-0.55 vs. 3.94+/-0.55 min; -0.53 min [-1.06, -0.002 min]; P=0.0493). An exploratory correlation analysis of treatment effects found stage 1 sleep was negatively correlated with wake and sleep bout duration and positively with wake/sleep bout number; slow wave sleep (%total sleep time) was positively correlated with wake and sleep bout duration and negatively with wake/sleep bout number. CONCLUSIONS: Pregabalin improved sleep parameters characteristic of disturbed sleep in FM, by preventing awakenings and increasing sleep bout duration. These effects are reflected in, and correlated with, a decrease in "light sleep" (stage 1) and an increase in "deep sleep" (slow wave sleep). PMID- 26035524 TI - Characteristics of Disturbed Sleep in Patients With Fibromyalgia Compared With Insomnia or With Pain-Free Volunteers. AB - OBJECTIVE: To investigate the differential nature of disturbed sleep in patients with fibromyalgia (FM) reporting sleep difficulties versus patients with primary insomnia (PI) and patients who do not report disturbed sleep (pain-free controls). MATERIALS AND METHODS: Patients (FM: n=132; PI: n=109; normals: n=52) were recruited for different studies. FM and PI patients were preselected to meet the sleep disturbance criteria. Patients with sleep or circadian disorders were excluded from all groups. Polysomnography was conducted at screening, during 2 consecutive nights. For this post hoc analysis of polysomnographies, length and frequency (duration, number) of wake and sleep bouts were analyzed, together with traditional sleep measures; a "bout"=consecutive 30-second epochs of sleep or wake. Data are mean+/-SD. RESULTS: FM and PI patients had decreased total sleep time and slow-wave sleep (SWS), and increased latency to persistent sleep (LPS) and wake time after sleep onset (WASO) versus controls (P<0.05 for each). FM versus PI patients had more SWS (48.1+/-32.4 vs. 27.2+/-23.6 min; P<0.0001) and shorter LPS (58.2+/-29.8 vs. 70.7+/-31.3 min; P=0.0055), but comparable WASO (107.7+/-32.8 vs. 108.6+/-31.5 min). Despite comparable WASO, FM patients had shorter (4.64+/-2.42 vs. 5.87+/-3.15 min; P=0.0016) but more frequent wake bouts versus PI patients (41.6+/-16.7 vs. 35.7+/-12.6; P=0.0075). Sleep bout duration was similar for FM (9.32+/-0.35 min) and PI patients (10.1+/-0.37 min); both populations had shorter sleep bout duration versus controls (15.7+/-0.7 min; P<0.0001 both). CONCLUSIONS: Increased frequency of wake and sleep bouts and decreased wake bout duration, together with decreased LPS and increased SWS, suggests that sleep in FM is characterized by an inability to maintain continuous sleep but a greater sleep drive compared with PI. PMID- 26035526 TI - Black metal thin films by deposition on dielectric antireflective moth-eye nanostructures. AB - Although metals are commonly shiny and highly reflective, we here show that thin metal films appear black when deposited on a dielectric with antireflective moth eye nanostructures. The nanostructures were tapered and close-packed, with heights in the range 300-600 nm, and a lateral, spatial frequency in the range 5 7 MUm(-1). A reflectance in the visible spectrum as low as 6%, and an absorbance of 90% was observed for an Al film of 100 nm thickness. Corresponding experiments on a planar film yielded 80% reflectance and 20% absorbance. The observed absorbance enhancement is attributed to a gradient effect causing the metal film to be antireflective, analogous to the mechanism in dielectrics and semiconductors. We find that the investigated nanostructures have too large spatial frequency to facilitate efficient coupling to the otherwise non-radiating surface plasmons. Applications for decoration and displays are discussed. PMID- 26035528 TI - Effects of straw mulch on soil water and winter wheat production in dryland farming. AB - The soil water supply is the main factor that limits dryland crop production in China. In a three-year field experiment at a dryland farming experimental station, we evaluated the effects of various straw mulch practices on soil water storage, grain yield, and water use efficiency (WUE) of winter wheat (Triticum aestivum). Field experiments were conducted with six different mulch combinations (two different mulch durations and three different mulch amounts): high (SM1; 9000 kg ha(-1)), medium (SM2; 6000 kg ha(-1)), and low (SM3; 3000 kg ha(-1)) straw mulch treatments for the whole period; and high (SM4), medium (SM5) and low (SM6) straw mulch treatments during the growth period only, where the control was the whole period without mulch (CK). Throughout the whole growth period of the three-year experiment, the average soil water content in the 0-200 cm soil layer increased by 0.7-22.5% compared with CK, while the WUE increased significantly by 30.6%, 32.7% and 24.2% with SM1, SM2, and SM3, respectively (P < 0.05). The yield increased by 13.3-23.0% when mulch was provided during the growth period, while the WUE increased by 15.2%, 17.2% and 18.0% with SM4, SM5, and SM6, respectively, compared with CK. PMID- 26035527 TI - A core-shell-shell nanoplatform upconverting near-infrared light at 808 nm for luminescence imaging and photodynamic therapy of cancer. AB - Upconversion nanoparticles (UCNPs) have been extensively explored for photodynamic therapy (PDT) and imaging due to their representative large anti Stokes shifts, deep penetration into biological tissues, narrow emission bands, and high spatial-temporal resolution. Conventional UCNP-based PDT system, however, utilizes exitation at 980 nm, at which water has significant absorption, leading to a huge concern that the cell killing effect is from the irradiation due to overheating effect. Here we report an efficient nanoplatform using 808-nm excited NaYbF4:Nd@NaGdF4:Yb/Er@NaGdF4 core-shell-shell nanoparticles loaded with Chlorin e6 and folic acid for simultaneous imaging and PDT. At this wavelength, the absorption of water is minimized. High energy transfer efficiency is achieved to generate cytotoxic singlet oxygen. Our nanoplatform effectively kills cancer cells in concentration-, time-, and receptor-dependent manners. More importantly, our nanoplatform is still able to efficiently generate singlet oxygen beneath 15 mm thickness of muscle tissue but 980 nm excitation cannot, showing that a higher penetration depth is achieved by our system. These results imply that our nanoplatform has the ability to effectively kill intrinsic tumor or the center of large tumors through PDT, which significantly improves the anticancer efficacy using UCNP-based PDT system and broadens the types of tumors that could be cured. PMID- 26035530 TI - GPS tracking for mapping seabird mortality induced by light pollution. AB - Light pollution and its consequences on ecosystems are increasing worldwide. Knowledge on the threshold levels of light pollution at which significant ecological impacts emerge and the size of dark refuges to maintain natural nocturnal processes is crucial to mitigate its negative consequences. Seabird fledglings are attracted by artificial lights when they leave their nest at night, causing high mortality. We used GPS data-loggers to track the flights of Cory's shearwater Calonectris diomedea fledglings from nest-burrows to ground, and to evaluate the light pollution levels of overflown areas on Tenerife, Canary Islands, using nocturnal, high-resolution satellite imagery. Birds were grounded at locations closer than 16 km from colonies in their maiden flights, and 50% were rescued within a 3 km radius from the nest-site. Most birds left the nests in the first three hours after sunset. Rescue locations showed radiance values greater than colonies, and flight distance was positively related to light pollution levels. Breeding habitat alteration by light pollution was more severe for inland colonies. We provide scientific-based information to manage dark refuges facilitating that fledglings from inland colonies reach the sea successfully. We also offer methodological approaches useful for other critically threatened petrel species grounded by light pollution. PMID- 26035529 TI - The anatomy of urban social networks and its implications in the searchability problem. AB - The appearance of large geolocated communication datasets has recently increased our understanding of how social networks relate to their physical space. However, many recurrently reported properties, such as the spatial clustering of network communities, have not yet been systematically tested at different scales. In this work we analyze the social network structure of over 25 million phone users from three countries at three different scales: country, provinces and cities. We consistently find that this last urban scenario presents significant differences to common knowledge about social networks. First, the emergence of a giant component in the network seems to be controlled by whether or not the network spans over the entire urban border, almost independently of the population or geographic extension of the city. Second, urban communities are much less geographically clustered than expected. These two findings shed new light on the widely-studied searchability in self-organized networks. By exhaustive simulation of decentralized search strategies we conclude that urban networks are searchable not through geographical proximity as their country-wide counterparts, but through an homophily-driven community structure. PMID- 26035531 TI - Influence of balance surface on ankle stabilizing muscle activity in subjects with chronic ankle instability. AB - OBJECTIVE: To evaluate the effect of balance surface type on muscle activity of ankle stabilizing muscles in subjects with chronic ankle instability. DESIGN: Case-controlled, repeated-measures study design. SUBJECTS: Twenty-eight subjects with chronic ankle instability and 28 healthy controls. METHODS: Subjects performed a barefooted single-legged stance on uniaxial and multidirectional unstable surfaces. Muscle activity of the mm. peroneus longus/brevis, tibialis anterior, gastrocnemius medialis were registered using surface electromyography. Mixed model analysis was used to explore differences in muscle activity between subjects with chronic ankle instability and controls, and the effect of surface type on muscle activity levels within subjects with chronic ankle instability. RESULTS: No differences were found between subjects with chronic ankle instability and healthy controls. Within subjects with chronic ankle instability, balancing along a frontal axis and on the Both Sides Up evoked overall highest muscle activity level, and the firm surface the least. Balancing on the firm surface showed the lowest tibialis anterior/peroneus longus muscle ratio, followed by balancing along a frontal axis and on the Airex pad. CONCLUSION: Clinicians can use these findings to improve the focus of balance training programmes by gradually progressing in difficulty level based on muscle activation levels taking co-contraction ratios into account. PMID- 26035533 TI - [Waiting time in lung cancer care. Patient guides provided faster flow]. AB - The work-up process for lung cancer patients consists of several steps from suspicion of malignant disease to start of treatment. Delays between these steps should be minimized. Data in the Swedish National Lung Cancer Register show that the work-up times for lung cancer patients vary greatly between different counties in central Sweden. In order to reduce delays, a trial of implementing patient guides (Sw: patientlotsar) for patients referred to the hospital was conducted. When comparing the work-up times before and after implementation of patient guides the median waiting time from suspicion of lung cancer to start of treatment in the region was reduced from 71 to 45 days. Furthermore, the duration of most of the steps in the work-up process were shortened despite more complex investigation procedures, e.g. increased use of PET/CT in the guided patient group. PMID- 26035534 TI - [Patient safety require rules and procedures that are both followed and disregarded]. AB - Modern health-care is a complex socio-technical system, and as such variability is normal and necessary. The ability of a complex system such as health-care to quickly and correctly adapt to varying circumstances is crucial to how well the system works. Both increased compliance to guidelines, and a concurrent ability in individuals to deviate from these guidelines in certain situations, can be expected to increase safety. Today, we know too little about these adaptations, and how they affect safety. New knowledge is needed to describe and understand complexity and variability in health-care. FRAM (Functional Resonance Analysis Method) is one such method. PMID- 26035532 TI - Nicorandil protects mesenchymal stem cells against hypoxia and serum deprivation induced apoptosis. AB - Nicorandil, an adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel opener, has been shown to exert a significant protective effect against ischemic heart injury. In the present study, we investigated the anti-apoptotic effects of nicorandil on rat mesenchymal stem cells (MSCs) subjected to hypoxia and serum deprivation (H/SD), as well as the potential underlying mechanisms. Apoptosis was induced in the MSCs by exposure to H/SD, and the apoptotic rates and reactive oxygen species (ROS) levels were determined by flow cytometry. The mitochondrial inner membrane potential was measured using the membrane-permeable dye, JC-1. Western blot analysis was used to measure the levels of Akt, Bcl-2, Bax, cytochrome c and cleaved caspase-3. The cell proliferative ability was assessed using the cell counting kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assay. The results revealed that H/SD-induced apoptosis was significantly attenuated by treatment with nicorandil in a concentration-dependent manner. Moreover, nicorandil markedly reduced the levels of ROS which were induced by exposure to H/SD, and increased the stability of mitochondrial membrane potential and the Bcl 2/Bax ratio, while it concomitantly decreased the H/SD-induced cleavage of caspase-3 and the release of cytochrome c. Treatment with the phosphoinositide 3 kinase (PI3K) inhibitor, LY294002, abolished the beneficial effects of nicorandil on the MSCs. In conclusion, the findings of the present study indicate that nicorandil exerts protective effects against MSC apoptosis induced by H/SD and that these effects are mediated through the PI3K/Akt, mitochondrial and ROS signaling pathways. PMID- 26035535 TI - [Vitamin D intoxication caused by drugs bought online. Sky high daily dosage for six months resulted in severe hypercalcemia]. AB - Intoxication with vitamin D may lead to severe hypercalcemia, renal failure and occasionally to death. An increasing amount of vitamin D supplement is sold over the-counter (OTC) or over the internet. Here we present a case were a person obtained vitamin D over the internet and administered 50 000 IE daily to his father for a period of six months, in the pursuit to stop or reverse the progression of a vascular dementia. The treatment resulted in a severe hypercalcemia and recurrent hospitalizations. In cases with an unexplained hypercalcemia, being associated with high levels of 25(OH)-vitamin D3 the possibility of intake of D-vitamin sold without a doctor's prescription should be investigated. PMID- 26035536 TI - [Underlying dysbiosis may be the cause of some forms of IBS. Patients were free of symptoms after the administration of microbiota]. AB - Two cases of post-infectious IBS were successfully treated with transplantation of an anaerobic cultivated human intestinal microbiota. This suggests that a dysbiosis of the intestinal microbiota could be the culprit at least in some cases of IBS. Resetting the gut microbiota might be a possible solution for these patients that otherwise may face a life-long reduction in quality of life. Studies have suggested that conditions as varied as chronic constipation, metabolic syndrome, autoimmunity, asthma, cardiovascular disease and Crohn's disease may be caused by intestinal dysbiosis. If this is the case we would like to suggest a new term: Dysbiotic Bowel Syndrome (DBS). PMID- 26035537 TI - [Vitamin D supplementation may do more harm than good. Evidence-based threshold values for vitamin D status are still lacking]. PMID- 26035538 TI - [Soup for 120 000 children--every day. Swedish humanitarian efforts in the war damaged Europe]. PMID- 26035539 TI - [Good corporate governance is important in the fight against antibiotic resistance. Physicians and veterinarians should work together with economists and political scientists]. PMID- 26035540 TI - [Heart attacks and appendicitis: To examine the cost is difficult]. PMID- 26035541 TI - [Expensive new drugs requires reflection and revision: Narrow interpretation of ethical platform]. PMID- 26035542 TI - ["The news" about nonspecific effects of vaccination: Alone must be strong]. PMID- 26035543 TI - [Forward-looking physicians can regain the initiative]. PMID- 26035544 TI - [Certainly there are problems with NPM]. PMID- 26035545 TI - [We welcome a discussion about DRG codes and CPP]. PMID- 26035546 TI - [Control instruments, manipulation and the future of Swedish health care]. PMID- 26035547 TI - [Not Available]. PMID- 26035548 TI - [Not Available]. PMID- 26035549 TI - [Swedish perinatal care in the forefront--yet it still needs improvement]. PMID- 26035550 TI - [Not Available]. PMID- 26035551 TI - [The parliamentary ethical platform applies]. PMID- 26035552 TI - [Ferrotoxicity--too early to "cry wolf"?]. PMID- 26035553 TI - Implementation of an Exercise Program in an Assisted Living Facility. AB - This quality improvement project was designed to implement a sit-to-stand exercise program delivered by nursing assistants in an assisted living facility. The primary outcome was for residents to either improve or maintain function in activities of daily living. The findings of this program have implications for nursing and the role that nursing assistants can play in promoting exercise and thus preventing avoidable decline in institutionalized residents. PMID- 26035554 TI - Implication of urinary complement factor H in the progression of immunoglobulin A nephropathy. AB - BACKGROUND: After activation, the complement system is involved in the pathogenesis of Immunoglobulin A nephropathy (IgAN). Complement factor H (CFH) is a crucial inhibitory factor of the alternative pathway of the complement system. The study investigated the effects of urinary CFH levels on IgAN progression. METHODS: A total of 351 patients with IgAN participated in this study. They were followed up for an average of 51.8 +/- 26.6 months. Renal outcome was defined as a composite endpoint, that included instances of end-stage renal disease (ESRD), >= 50% decline in estimated glomerular filtration rate (eGFR) or doubling of plasma creatinine levels. Urinary CFH levels were measured by enzyme-linked immunosorbent assay and calculated as the ratio of urinary CFH over creatinine (uCFH/uCr). RESULTS: In the whole cohort, uCFH/uCr values were associated with disease progression either as continuous [log(uCFH/uCr)] or categorical traits (dichotomous and quartile variables) after adjusting for eGFR, proteinuria, mean arterial blood pressure, histological grading and immunosuppressive therapy in the Cox proportional hazard model. Kaplan-Meier analysis showed that higher uCFH/uCr values at baseline predicted worse renal outcome during follow-up (log rank, P < 0.001). Receiver operating characteristic curve (ROC) analysis showed that log(uCFH/uCr) had predictive value for renal outcome (area under curve [AUC] = 0.745), and the AUC increased to 0.805 after being incorporated into baseline eGFR and proteinuria. In subgroup analysis with eGFR >= 60 mL/min/1.73 m2, log(uCFH/uCr) had better predictive value (AUC = 0.724, P = 0.002) for renal outcome compared to eGFR (AUC = 0.582, P = 0.259) and proteinuria (AUC = 0.615, P = 0.114). CONCLUSIONS: Urinary CFH levels are associated with renal function decline and increased urinary CFH levels are a risk factor for progression of IgA nephropathy. PMID- 26035555 TI - Paeoniflorin ameliorates acute myocardial infarction of rats by inhibiting inflammation and inducible nitric oxide synthase signaling pathways. AB - Paeoniflorin (PF) is the main active component of the commonly used Traditional Chinese Medicine peony, Paeonia Suffruticosa. PF has diverse biological functions and exhibits anti-oxidative, anti-inflammatory and anti-apoptotic activity. Inducible nitric oxide synthase (iNOS) is a catalyzing enzyme that is involved in the synthesis of nitric oxide (NO). NO has an important regulatory role in the cardiovascular, immune and nervous systems. PF has previously been demonstrated to inhibit the gene expression of iNOS. The present study aimed to identify a potentially novel cytoprotective function of PF, and to elucidate its effects against myocardial ischemic damage in a rat model of acute myocardial infarction (AMI). PF was able to significantly decrease the myocardial infarct size as well as the activities of creatine kinase (CK), the MB isoenzyme of CK, lactate dehydrogenase and cardiac troponin T. In addition, in the PF-treated groups, the expression levels of tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and nuclear factor-kappaB were markedly inhibited. Furthermore, treatment with PF inhibited the activities and protein expression levels of iNOS. Decreased caspase 3 and caspase-9 activities were also observed in the AMI rat model treated with various doses of PF. The results of the present study indicated that the cardioprotective effects of PF may be associated with the inhibition of inflammation and iNOS signaling pathways. PMID- 26035556 TI - Knockdown of RhoA expression alters ovarian cancer biological behavior in vitro and in nude mice. AB - RhoA regulates cell proliferation, migration, angiogenesis and gene expression. Altered RhoA activity contributes to cancer progression. The present study investigated the effects of RhoA knockdown on the regulation of ovarian cancer biological behavior in vitro and in nude mice. The expression of RhoA was knocked down using a lentivirus carrying RhoA short hairpin RNA (shRNA) in ovarian cancer cells and was confirmed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. The altered ovarian cancer biological behaviors were assayed by cell viability, terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL), migration, invasion, and nude mice tumorigenicity assays, while the altered gene expression was detected by RT-qPCR and western blot analysis. The results showed that lentivirus-carrying RhoA shRNA significantly suppressed RhoA expression in ovarian cancer cells, which suppressed tumor cell viability, migration, invasion and adhesion in vitro. RhoA silencing also inhibited the tumorigenicity of ovarian cancer cells in nude mice, which was characterized by the suppression of tumor xenograft formation and growth and induction of tumor cell apoptosis. The results of the present study demonstrated that knockdown of RhoA expression had a significant antitumor effect on ovarian cancer cells in vitro and in nude mice, suggesting that RhoA may be a target for the development of a novel therapeutic strategy in the control of ovarian cancer. PMID- 26035559 TI - [Genetic engineering technologies of stimulating angiogenesis as an innovation trend in angiology and vascular surgery]. AB - Presented herein is a review of the principles, fundamental concepts, and possibilities of genetic engineering technologies of stimulating angiogenesis for treatment of patients with lower limb chronic ischaemia. This is followed by a detailed discussion of the structure and results of Russian and foreign studies on this direction, also considering the causes of differences of their results. Outlined is a circle of clinical situations in relation to which these technologies may be regarded as most promising. PMID- 26035557 TI - Exposure to second-hand smoke and the risk of tuberculosis in children and adults: a systematic review and meta-analysis of 18 observational studies. AB - BACKGROUND: According to WHO Global Health Estimates, tuberculosis (TB) is among the top ten causes of global mortality and ranks second after cardiovascular disease in most high-burden regions. In this systematic review and meta-analysis, we investigated the role of second-hand smoke (SHS) exposure as a risk factor for TB among children and adults. METHODS AND FINDINGS: We performed a systematic literature search of PubMed, Embase, Scopus, Web of Science, and Google Scholar up to August 31, 2014. Our a priori inclusion criteria encompassed only original studies where latent TB infection (LTBI) and active TB disease were diagnosed microbiologically, clinically, histologically, or radiologically. Effect estimates were pooled using fixed- and random-effects models. We identified 18 eligible studies, with 30,757 children and 44,432 adult non-smokers, containing SHS exposure and TB outcome data for inclusion in the meta-analysis. Twelve studies assessed children and eight studies assessed adult non-smokers; two studies assessed both populations. Summary relative risk (RR) of LTBI associated with SHS exposure in children was similar to the overall effect size, with high heterogeneity (pooled RR 1.64, 95% CI 1.00-2.83). Children showed a more than 3 fold increased risk of SHS-associated active TB (pooled RR 3.41, 95% CI 1.81 6.45), which was higher than the risk in adults exposed to SHS (summary RR 1.32, 95% CI 1.04-1.68). Positive and significant exposure-response relationships were observed among children under 5 y (RR 5.88, 95% CI 2.09-16.54), children exposed to SHS through any parent (RR 4.20, 95% CI 1.92-9.20), and children living under the most crowded household conditions (RR 5.53, 95% CI 2.36-12.98). Associations for LTBI and active TB disease remained significant after adjustment for age, biomass fuel (BMF) use, and presence of a TB patient in the household, although the meta-analysis was limited to a subset of studies that adjusted for these variables. There was a loss of association with increased risk of LTBI (but not active TB) after adjustment for socioeconomic status (SES) and study quality. The major limitation of this analysis is the high heterogeneity in outcomes among studies of pediatric cases of LTBI and TB disease. CONCLUSIONS: We found that SHS exposure is associated with an increase in the relative risk of LTBI and active TB after controlling for age, BMF use, and contact with a TB patient, and there was no significant association of SHS exposure with LTBI after adjustment for SES and study quality. Given the high heterogeneity among the primary studies, our analysis may not show sufficient evidence to confirm an association. In addition, considering that the TB burden is highest in countries with increasing SHS exposure, it is important to confirm these results with higher quality studies. Research in this area may have important implications for TB and tobacco control programs, especially for children in settings with high SHS exposure and TB burden. PMID- 26035560 TI - [Effect of a vascular event on drug regimen compliance in patients with coronary atherosclerosis]. AB - In order to assess the effect of a vascular event on adherence to treatment we examined a total of 68 patients presenting with coronary atherosclerosis. The patients' age varied from 31 to 84 years (mean 57.1+/-8.7). There were 55 (81.1%) men and 13 (18.9%) women. Drug regimen compliance was evaluated by means of the Morisky-Green Medication Adherence Questionnaire before and after the vascular event. Of the 68 examined patients, 15 (22.1%) had not taken any therapeutic agents before the vascular event occurred, despite existing arterial hypertension. Drug regimen compliance prior to the vascular event was low in 82.4% of cases. The number of patients with coronary atherosclerosis and low compliance to treatment before the vascular event decreased significantly thereafter (p=0.0012). After the vascular event, the number of patients adhering to the doctor's recommendations on medicamentous therapy increases considerably. At the same time, a sufficiently great number of patients [about 30% of patients after endured myocardial infarction (MI) and 18% after transcutaneous coronary intervention (TCI)] still remain in the category of those "having low drug regimen compliance" and, accordingly, have high risk for the development of recurrent vascular events. Endured TCI increases patient compliance more significantly than MI, which requires additional study of a psychological component of the given fact. PMID- 26035561 TI - [Factor XIII-A subunit Val34Leu polymorphism and risk of venous thromboembolism in young adults]. AB - Factor XIII (FXIII) plays an important role in formation and stabilization of the fibrin clot. It is known that FXIII-A gene G163T (Val34Leu) polymorphism leads to increased activation of this factor, however participation of the 34Leu variant in thrombogenesis remains disputable. The present work was aimed at studying peculiarities of distribution of variants of FXIII-A polymorphisms in patients with early onset of venous thromboembolism (VTE), as well as revealing associative links between the carrier state of this mutation and the character of clinical course of the disease. We examined a total of 250 patients with VTE. Of these, there were 119 (47.6%) men and 131 (52.4%) women, mean age 37.42 years (range 10-45 years). In the group of patients with VTE, the proportion of homozygous carriers of allele 163T (Leu34) turned out to be more than 1.5-fold higher as compared with the corresponding parameter in the control group (OR=1.8, 95% CI: 0.9-4.0; p=0.14). Analysing FXIII-A G163T polymorphism depending on gender revealed a considerable increase in the incidence rate (IR) of 163TT genotype in women with VTE as compared to male patients (13.0% versus 5.1 %, respectively, OR=2.8, 95% CI: 1.1-7.4; p=0.047) and to the control group (OR=2.7; 95% CI: 1.2-6.1; p=0.023). Analysing gene FXIII-A polymorphism in the groups of patients with various clinical manifestations of VTE revealed a decrease in the proportion of heterozygotes in the group of deep vein thrombosis + pulmonary artery thromboembolism (PATE) and, vice versa, an increase in the proportion of homozygotes by the Leu34 variant in patients with signs of PATE. The obtained findings make it possible to consider the genotype 163TT of FXIII-A gene as a new independent risk factor for the development of VTE in young women living in the North-West region of Russia, which is observed for the first time. Additional studies are necessary. PMID- 26035562 TI - [Use of dabigatran etexilate for treatment of deep vein thrombosis and pulmonary artery thromboembolism]. AB - The authors present herein their experience in oral administration of dabigatran etexilate for treatment of lower-limb deep vein thrombosis and pulmonary thromboembolism in patients with thrombophilia, as well as assessment of its efficacy and safety. The study included a total of nineteen 20-to-79-year-old patients (11 men and 8 women) with venous thromboembolic complications. An inclusion criterion was the presence of lower-limb deep vein thrombosis documented in the B-mode in ultrasonography alone or in a combination with pulmonary thromboembolism confirmed by angiopulmonography end echocardiography. The exclusion criteria were as follow: oncological diseases, a history of surgical interventions, acute infections, skeletal injuries and fractures, long term immobilization, age under 20 and over 79 years. For 6 months the authors evaluated patients' tolerance of dabigatran, its efficacy, as well as the profile of safety concerning the development of major and clinically significant haemorrhage. It was determined that administration of dabigatran in patients with confirmed thrombophilia at a fixed dose (150 mg twice daily) during 6 months for treatment of lower-limb venous thromboses and pulmonary thromboembolism turned out to be effective and safe, with the drug possessing a good profile of safety and its administration requiring no routine laboratory monitoring. PMID- 26035563 TI - [Review of the proceedings of the congress "Controversies and updates in vascular surgery" (Paris, France, January 22-24, 2015)]. AB - The article is a brief review of the papers presented at the Congress "Controversies and Updates in Vascular Surgery - CACVS) held in Paris (France) on January 22-24, 2015. An emphasis is placed upon the problems of open and endovascular interventions for aortic aneurysms, lower-limb ischaemia, infection in vascular surgery, pathology of the venous system, choosing an approach for endovascular operations and a vascular access for haemodialysis. PMID- 26035564 TI - Deformity of subclavian artery as a cause of formation of vertebral subclavian steal syndrome. AB - Presented herein are 3 clinical case reports concerning formation of vertebral subclavian steal syndrome in deformities of subclavian arteries. By means of duplex scanning, angiography and multispiral computed tomography it was shown that deformities of subclavian arteries in the first segment (proximal to the origin of the vertebral artery) with septal stenosing are accompanied by a typical dopplerographic picture_pattern of steal syndrome. PMID- 26035565 TI - [Remote results of implantation of cava filters: analysis of errors and complications]. AB - The authors carried out comparative assessment of efficacy of cava filters (CF) for prevention of pulmonary artery thromboembolism in patients presenting with iliofemoral thrombosis with flotation of thrombi, as well as analysed complications in the remote postimplantation period. A total of 266 patients were examined within the terms from 1 month to 10 years after CF implantation. Depending on the type of the implanted device, all patients were subdivided into 3 groups: group 1 (n=65) consisted of patients with one-level CF, group 2 (n=112) comprised those with "sandglass" and "shuttle" type two-level cava filters, and group 3 (n=89) was composed of patients with the implanted CF "TrapEase" and "OptEase". In the remote period relapsed PATE was revealed in 5.2% of cases. Embolism in the CF was noted in 9.3% of cases, with the incidence rate of this complication not depending on the type of the implanted device. However, total occlusion of the inferior vena cava after embolism was observed 2 times more often in patients of the 2nd and 3rd group. In the first group recanalization of the intrafilter space occurred in one third of cases. Chronic occlusion of the inferior vena cava was revealed in 13.9% of cases, most frequently in group 2. Total occlusion of the inferior vena cava with the development of inferior vena cava syndrome was diagnosed in 24.1% of patients with thrombotic lesion below the level of renal veins confluence. This complication was associated with both characteristics of CF and technical errors of implantation, and was also encountered more frequently in group 2. PMID- 26035566 TI - [Results of endovascular treatment of abdominal aortic aneurysms]. AB - OBJECTIVE: Studying the results of endovascular prosthetic repair in patients with abdominal aortic aneurysms. MATERIAL AND METHODS: A retrospective study of 34 elderly and aged patients (mean age 67.4+/-1.24 years) with severe concomitant pathology and the risk of Euroscore averagely amounting to 13.16+/-0.19, subjected to endoprosthetic repair for the presence of AAA. RESULTS: In all 34 cases we obtained good immediate results of endoprosthetic repair of the infrarenal portion of the abdominal aorta: positioning of stent grafts was adequate, expansion complete, with no sign of endoleak. Hospital lethality rate was 0%. The intra- and postoperative periods were not accompanied by the development of neither cardiological nor neurological complications. Analysing by the McNemar criterion showed that there was a statistically significant trend towards elevation of leukocytosis and ESR after surgery (p=0.074), and for other indices the shifts were statistically insignificant or absent. Since no signs of an inflammatory process were revealed, in all cases the postoperative wounds healed with fist intension, the alterations in the blood formula were associated with resorption of thrombotic masses in the paraprosthesis space. CONCLUSION: In all cases, implantation of the stent graft resulted in achieving the main objective, i. e. adequate isolation of the aneurysmatic sac in AAA. Dynamic follow up did not reveal any cases of stent graft dislocation, aneurysm rupture, thrombosis of endograft branches, or type 1a leaks. PMID- 26035567 TI - [Endovascular interventions in true and false aneurysms of hepatic, splenic and renal arteries]. AB - A false aneurysm of visceral arteries is a life-threatening pathology sufficiently difficult to treat. Open operations are characterised by a large scope, considerable surgical injury and accompanied by a high rate of serious complications. The development of the technology of superselective catheterization of blood vessels, creation of specialized microcatheters, glue composites and various types of spirals made it possible to treat this severe pathology without resorting to open operations. The work deals with a brief literature review concerning epidemiology, methods of diagnosis and treatment of pseudoaneurysms of visceral arteries, followed by presenting three clinical case reports concerning successful treatment of posttraumatic false aneurysms of the right hepatic and splenic arteries, as well as an aneurysm of the renal artery. Both immediate and remote results of endovascular interventions in these patients are followed up, demonstrably showing possibilities of endovascular technologies in treatment of the pathology involved. PMID- 26035568 TI - [Peculiarities of treatment of chronic venous diseases in Russia. Preliminary results of the "VEIN ACT Program"]. AB - Presented herein are the results of the Russian part of the International Research Program "VEIN ACT" aimed at studying the structure of variants of conservative treatment for chronic venous diseases in the Russian Federation, assessing its efficacy and safety, as well as monitoring of patient compliance. The obtained findings demonstrated high popularity, among both physicians and patients, of phlebotrophic drugs, determining high patient's adherence thereto. Recommendations on correction of the lifestyle were complied with by more than 80% of patients, however frequently not in the full scale. Noted was sufficiently low compliance to compression therapy, manifesting itself as a decrease in the class of compression and irregular use thereof in more than 30% of patients. Usefulness of conservative therapy was objectively proved, consisting in satisfaction with treatment and a statistically significant decrease in severity of symptoms of chronic venous diseases in the overwhelming majority of patients. PMID- 26035569 TI - [Minimally invasive method of correction of valvular insufficiency of the femoral vein in various causes of its origin genesis]. AB - Presented herein are the results of treatment of patients with chronic venous insufficiency and trophic ulcers of lower limbs on the background of varicose disease and postthrombophlebitic syndrome. The treatment consisted in removal of pathological deep vertical venous reflux by means of a modified method of dosed narrowing of the femoral vein according to P.G. Shvalb's technique [1]. The obtained outcomes confirmed the necessity of influencing the pathological vertical deep venous reflux in patients with severe forms of chronic venous insufficiency and pronounced retrograde shunt along deep veins. PMID- 26035570 TI - [Thrombosis of muscle veins of the crus in patients operated on for varicose disease]. AB - The necessity of preventing venous thromboembolic complications in patients after endured surgical interventions for varicose disease remains a debatable problem. The study was aimed at assessing the incidence of deep vein thrombosis after phlebectomy and determining its clinical significance. MATERIAL AND METHODS: The authors carried out a prospective cohort study comprising a total of 86 patients (73 women and 13 men, aged from 16 to 64 years, the mean age 39.1+/-11.8 years) presenting with class C2-C4 varicose disease. All patients under conduction and tumescent anaesthesia were subjected to crossectomy, stripping, and miniphlebectomy. The operations lasted from 60 minutes to 3 hours 30 min (average duration--123+/-23 min). According to the Caprini score, in 58 patients the risk of thromboembolic complications was assessed as moderate (3-4 points), and in 28 patients as high (5 points and greater). In the postoperative period elastic compression was used in all patients, the activation began 1-2 hours after the operation. Anticoagulants in preventive doses were indicated in 6 patients due to the presence of additional risk factors. RESULTS: Ultrasonographic examination in the postoperative period revealed 3 (3.5%) cases of crural muscle vein thrombosis. Anticoagulation therapy was not indicated in these patients. Detecting thrombosis was followed by dynamic follow up. Ultrasonographic study revealed complete recanalization of thrombosed veins by the end of the second month of follow up. The incidence rate of thrombosis in the group with the moderate baseline risk of thrombosis amounted to 1.7% and in the group with high risk of thrombosis to 9.1% (p>0.1). CONCLUSION: Crossectomy, stripping of subcutaneous veins, and miniphlebectomy carried out under conduction and local anaesthesia are not significant risk factors for the development of thromboembolic complications. PMID- 26035571 TI - [Lesion of pelvic organs in secondary varicose veins of the small pelvis]. AB - The authors studied peculiarities of pelvic organs lesions in patients presenting with secondary small pelvic varicose veins (SPVV) induced by endured thrombosis of iliac veins. The study included a total of 70 patients after endured thrombosis of iliac veins verified by radiodiagnostic methods. The average duration of thrombosis amounted to 3.8 years. The patients were subdivided into two groups. The Study Group comprised 48 patients presenting with small pelvic varicose veins revealed by duplex scanning; the Control Group was composed of 22 patients with no varicose pelvic veins. It was determined that characteristic features of patients with secondary SPVV having developed after iliac veins thrombosis included chronic pelvic pain, dilatation of cavernous veins of the rectum, inguinal vein varicosity and varicose veins of the groin and anterior abdominal wall. Formation of secondary SPVV after endured iliac vein thrombosis leads to disorders of pelvic organs, similar to those in primary varicosity, but more often being functional. Endured iliac veins thrombosis in formation of secondary SPVV leads to urination impairments with prevalence of moderately pronounced symptomatology. Small pelvic organs dysfunction in women with secondary SPVV due to endured iliac veins thrombosis manifests itself in dyspareunia, leukorrhea, and dysmenorrhea. PMID- 26035572 TI - [Fifth EVF HOW: Hands-on Workshop on Venous Disease (Limassol, Cyprus) 30 October - 1 November 2014]. AB - The fifth Hands-on Workshop on Venous Diseases of the European Venous Forum was held from October 30 to November 1, 2014 in Limassol, Cyprus. Leading specialists from European countries for three days delivered reports concerning modern trends in diagnosis and treatment of venous diseases. The participants of the hands-on workshop had a unique possibility to learn first-hand the latest recommendations concerning diagnosis and treatment of varicose disease, acute venous thromboses, post-thrombotic disease, to know about advanced technologies being just introduced into clinical practice. PMID- 26035573 TI - [Prevention of wound infection in cardiac surgery: how much is topical use of antibiotics justified?]. AB - The authors studied efficacy of preventing wound infection of a sternotomic wound with and without conventional use of topical antibiotics, also determining predictors of the development of infectious complications after cardiosurgical interventions. Our retrospective study included a total of 1,593 patients subdivided into two groups. In Group One patients (n=951) sternal infection was prevented according to the P. Vogt technique; Group two patients (n=642) were also subjected to the same methodology, but with the exception of topical use of antibiotics. By the frequency of re-sternotomies performed, cases of superficial and deep wound infection, as well as by the average duration of operation, hospital and ICU stay there were no statistically significant differences between the groups (p<0.05). The average cost of antibacterial agents as calculated per one patient in Group One turned out substantially higher than in Group Two (amounting to 8.1+/-3.9 and 3.3+/-1.4 thousand roubles, respectively, p<0.001). Analysing possible predictors of the risk for the development of wound infection showed that the body mass index, duration of the operation, and performing re sternotomy exerted a statistically significant influence on probability of infections complications. It was determined that using the methodology of preventing sternal infection with topical application of antibiotics led to predominance of Gram-negative flora in the wound discharge (p=0.02). Exclusion of topical use of antibiotics does not lead to an increase in the incidence rate of wound complications (p=0.78) and normalizes the ratio of Gram-negative and Gram positive strains. PMID- 26035574 TI - Analysis of the efficiency of external carotid surgery. AB - The authors confirmed efficacy of external carotid artery plasty in occlusion of the internal carotid artery. The findings of triplex scanning and transcranial dopplerography demonstrated a considerable increment in the blood flow through the middle cerebral artery in the operated zone, amounting to approximately 30% one year after surgical treatment. Twenty-two patients before and after surgery were subjected to single-photon emission computed tomography. The majority of patients after surgery were found to have improved perfusion of the previously ischaemized zone of the brain on the side of operation according to the data of single-photon emission computed tomography. PMID- 26035575 TI - Spontaneous recanalization of chronic occlusion of the internal carotid artery. AB - Described in the article is a rare case concerning spontaneous recanalization of the extracranial portion of the internal carotid artery (ICA) eleven months after occlusion. Only few publications have been dedicated to recanalization of ICA chronic occlusion. Spontaneous recanalization of the ICA is more common than it is generally understood. The authors have analysed all available articles about this problem from PubMed (1957 to 2013), reviewing the mechanisms of recanalization of the ICA, methods of diagnosis and treatment. The purpose of this case report is to emphasize the importance of ICA spontaneous recanalization and consequences thereof. PMID- 26035576 TI - [Study of patency of vascular grafts manufactured by means of electrospinning]. AB - In vivo experiments were carried out to study functioning of vascular grafts manufactured by means of electrospinning from solutions of polycaprolactone (PCL) and hexafluoroisopropanol (HFIP), PCL with 10% gelatine and a low-permeability inner layer (LPIL) 10 MUm thick and PCL with 10% gelatine and LPIL (10 MUm) wherein as polymeric base instead of PCL copolymer of lactic and hydroxyacetic acids (polylactide-co-glycolide, PLGA) was used. The grafts were implanted into the infrarenal portion of the aorta to 45 rats, 15 rats for each type of the graft. Patency of artificial vessels was assessed by means of magnetic resonance tomography and diagnostic ultrasound Dopplerography at 2, 4 and 20 weeks (5 animals for each time point). The state of the graft and surrounding tissues was analysed by means of intraoperative assessment, survey microscopy and survey fluorescent microscopy. CONCLUSION: The obtained findings demonstrated that vascular grafts made by electrospinning technique with a low-permeability inner layer are less prone to formation of the neointima and stenosing as compared with grafts having no such layer. PMID- 26035577 TI - [Remote results of combined treatment of thoracoabdominal aneurysms resulting from dissection]. AB - Analysed herein are remote results of treatment at terms of 3 and 19 years in two patients with a complicated course of chronic thoracoabdominal aortic dissection. Each of them was subjected to 3 interventions, twice by emergency indications. Surgical corrections: resection of the abdominal aortic aneurysm (2), thoracoabdominal bypass grafting (1). Endovascular interventions: implantation of stent grafts into the descending aorta for a ruptured pseudoaneurysm (1) and in the subrenal segment of the abdominal aorta (1), embolization of the visceral artery for a ruptured aneurysm. The outcomes of treatment were considered good based on clinical and angiographic examinations. Revascularization in the segments of intervention and optimal quality of life of patients were achieved. The scope and choice of the method of correction are discussed with due regard for real clinical possibilities at specific terms of follow up. PMID- 26035578 TI - [Choosing the method of reconstruction for lower-limb critical ischemia]. AB - Presented herein are long-term outcomes of surgical treatment of 74 patients with atherosclerotic occlusive-stenotic lesions of the femoral-popliteal-tibial segment and critical ischaemia. 51 (68.92%) patients underwent femoropopliteal shunting into the isolated segment of the reversed great saphenous vein. Of these, three patients were subjected to a hybrid operation consisting of femoropopliteal bypass grafting and balloon angioplasty of the popliteal and one tibial artery. 23 (31.08%) patients endured percutaneous balloon angioplasty with stenting of the superficial femoral artery and balloon angioplasty of one tibial artery. Two-year patency of the zone of reconstruction of the femoropopliteal segment in these groups was identical, amounting to 64.71 and 56.52%, respectively. However, the group of patients with endovascular intervention demonstrated rather a high rate of intraoperative complications--21.74%, technical success in balloon angioplasty of arteries of the crus amounted to 65.22%. Once the method of operative treatment is chosen, preference is given to shunting in the isolated popliteal artery with sufficient collateral blood flow. Further studies are required to determine angiographic indications for endovascular intervention on tibial arteries. PMID- 26035579 TI - [Experience in treatment of combined osteovascular limb injuries in children]. AB - The article is dedicated to one of the currently important problems of present day traumatology and angiosurgery, i. e. possibility of performing primary reconstructive operations in children with complete and incomplete amputations, open and closed bone fractures in the conditions of circulatory impairment. The authors share their experience in treatment of 92 patients presenting with such injuries, describing the main indications for carrying out repair operations, and drawing appropriate conclusions. The main stages of reconstructions are demonstrated by a series of clinical examples. PMID- 26035580 TI - [Endovascular surgery in the war]. AB - Rapid growth of medical technologies has led to implementation of endovascular methods of diagnosis and treatment into rapidly developing battlefield surgery. This work based on analysing all available current publications generalizes the data on using endovascular surgery in combat vascular injury. During the Korean war (1950-1953) American surgeons for the first time performed endovascular balloon occlusion of the aorta - the first intravascular intervention carried out in a zone of combat operations. Half a century thereafter, with the beginning of the war in Afghanistan (2001) and in Iraq (2003) surgeons of central hospitals of the USA Armed Forces began performing delayed endovascular operations to the wounded. The development of technologies, advent of mobile angiographs made it possible to later on implement high-tech endovascular interventions in a zone of combat operations. At first, more often they performed implantation of cava filters, somewhat afterward - angioembolization of damaged accessory vessels, stenting and endovascular repair of major arteries. The first in the theatre of war endovascular prosthetic repair of the thoracic aorta for severe closed injury was performed in 2008. Russian experience of using endovascular surgery in combat injuries is limited to diagnostic angiography and regional intraarterial perfusion. Despite the advent of stationary angiographs in large hospitals of the RF Ministry of Defence in the early 1990s, endovascular operations for combat vascular injury are casuistic. Foreign experience in active implementation of endovascular technologies to treatment of war-time injuries has substantiated feasibility of using intravascular interventions in tertiary care military hospitals. Carrying out basic training courses on endovascular surgery should become an organic part of preparing multimodality general battlefield surgeons rendering care on the theatre of combat operations. PMID- 26035581 TI - [Hybrid surgical intervention in a patient with an aortic arch aneurysm and coronary artery disease]. AB - Presented herein is a clinical case report regarding the use of hybrid technology in surgical treatment of a patient with an aneurysm of the distal portion of the aortic arch and coronary artery disease. The patient underwent a hybrid operation, i.e. debranching of the aortic arch branches, exoprosthetic repair of the ascending aorta, autovenous prosthetic coronary bypass grafting of the branch of the blunt edge of the anterior interventricular artery, stenting of the ascending portion, arch and descending portion of the aorta (stent graft "Medtronic Valiant"). In doing so, we used a non-standard approach to connecting the artificial circulation unit and to choosing the place for establishing proximal anastomoses of autovenous coronary bypass grafts. The early postoperative period was complicated by the development of respiratory insufficiency requiring continuation artificial pulmonary ventilation. The duration of the hospital stay of the patient amounted to 15 days. The check-up multispiral computed tomography showed normal functioning of the reconstruction zones, the stent graft is expanded, with no leak observed. The conclusion was made that hybrid interventions may be considered as an alternative to the classical surgical treatment associated in patients of older age group with a severe course of the postoperative period and high lethality. PMID- 26035582 TI - [Surgical treatment of a female patient with non-specific aortoarteritis]. AB - Presented herein is a case report of successful surgical treatment of a female patient with non-specific aortoarteritis. In 2004 she was endured single-stage simultaneous autovenous ileorenal prosthetic repair on the right and autovenous aortorenal prosthetic reconstruction on the left for critical stenosis of the left renal artery and occlusion of the right one. In 2007 she underwent balloon dilatation of the aorta for abdominal aortic stenosis with a good favourable therapeutic outcome. In 2013 due to lesions of the aortic arch branches she was subjected to endarterectomy from the common carotid artery on the left, autovenous carotid-subclavian shunting on the right with a favourable outcome. Presented herein are the results of check-up multislice CT-angiography (MSCT) 9 years after operation on renal arteries. Multislice CT-angiography and duplex scanning of aortic arch branches made it possible to choose an optimal surgical policy in this woman. Simultaneous endarterectomy from the common carotid artery on the left with autovenous carotid-subclavian shunting on the right in a patient with non-specific aortoarteritis was used by us for the first time. This operation made it possible to restore patency of the carotid artery and to use it as a donor artery for carotid-subclavian shunting in order to eliminate vertebral subclavian steal syndrome. PMID- 26035583 TI - [Surgical treatment of a patient with occlusion of the main trunk of the renal artery of the solitary kidney]. AB - Presented herein is a clinical case report of successful stagewise surgical treatment of a patient with atherosclerotic occlusion of the main trunk of the renal artery of the single kidney. Clinically, the patient had signs of ischaemic renal disease in the form of pronounced azotemia being characteristic of the terminal stage of renal insufficiency, as well as malignant arterial hypertension. Besides, the patient had previously endured ischaemic stroke in the vertebrobaslar basin. The patient was subjected to stagewise surgical intervention, i.e., stenting of the upper-pole renal artery followed by open operation--prosthetic repair of the left renal artery with a synthetic prosthesis. Three months thereafter, the patient underwent carotid endarterectomy and operation of transposition of the subclavian artery. The postoperative period turned out uneventful. Currently, no progression of azotemia is observed, neither are there any indications for carrying out restorative therapy of the renal function. PMID- 26035584 TI - Host tissue and glycan binding specificities of avian viral attachment proteins using novel avian tissue microarrays. AB - The initial interaction between viral attachment proteins and the host cell is a critical determinant for the susceptibility of a host for a particular virus. To increase our understanding of avian pathogens and the susceptibility of poultry species, we developed novel avian tissue microarrays (TMAs). Tissue binding profiles of avian viral attachment proteins were studied by performing histochemistry on multi-species TMA, comprising of selected tissues from ten avian species, and single-species TMAs, grouping organ systems of each species together. The attachment pattern of the hemagglutinin protein was in line with the reported tropism of influenza virus H5N1, confirming the validity of TMAs in profiling the initial virus-host interaction. The previously believed chicken specific coronavirus (CoV) M41 spike (S1) protein displayed a broad attachment pattern to respiratory tissues of various avian species, albeit with lower affinity than hemagglutinin, suggesting that other avian species might be susceptible for chicken CoV. When comparing tissue-specific binding patterns of various avian coronaviral S1 proteins on the single-species TMAs, chicken and partridge CoV S1 had predominant affinity for the trachea, while pigeon CoV S1 showed marked preference for lung of their respective hosts. Binding of all coronaviral S1 proteins was dependent on sialic acids; however, while chicken CoV S1 preferred sialic acids type I lactosamine (Gal(1-3)GlcNAc) over type II (Gal(1 4)GlcNAc), the fine glycan specificities of pigeon and partridge CoVs were different, as chicken CoV S1-specific sialylglycopolymers could not block their binding to tissues. Taken together, TMAs provide a novel platform in the field of infectious diseases to allow identification of binding specificities of viral attachment proteins and are helpful to gain insight into the susceptibility of host and organ for avian pathogens. PMID- 26035585 TI - Manipulating Excited-State Dynamics of Individual Light-Harvesting Chromophores through Restricted Motions in a Hydrated Nanoscale Protein Cavity. AB - Manipulating the photophysical properties of light-absorbing units is a crucial element in the design of biomimetic light-harvesting systems. Using a highly tunable synthetic platform combined with transient absorption and time-resolved fluorescence measurements and molecular dynamics simulations, we interrogate isolated chromophores covalently linked to different positions in the interior of the hydrated nanoscale cavity of a supramolecular protein assembly. We find that, following photoexcitation, the time scales over which these chromophores are solvated, undergo conformational rearrangements, and return to the ground state are highly sensitive to their position within this cavity and are significantly slower than in a bulk aqueous solution. Molecular dynamics simulations reveal the hindered translations and rotations of water molecules within the protein cavity with spatial specificity. The results presented herein show that fully hydrated nanoscale protein cavities are a promising way to mimic the tight protein pockets found in natural light-harvesting complexes. We also show that the interplay between protein, solvent, and chromophores can be used to substantially tune the relaxation processes within artificial light-harvesting assemblies in order to significantly improve the yield of interchromophore energy transfer and extend the range of excitation transport. Our observations have implications for other important, similarly sized bioinspired materials, such as nanoreactors and biocompatible targeted delivery agents. PMID- 26035586 TI - Differentiation of Low- and High-Grade Pediatric Brain Tumors with High b-Value Diffusion-weighted MR Imaging and a Fractional Order Calculus Model. AB - PURPOSE: To demonstrate that a new set of parameters (D, beta, and MU) from a fractional order calculus (FROC) diffusion model can be used to improve the accuracy of MR imaging for differentiating among low- and high-grade pediatric brain tumors. MATERIALS AND METHODS: The institutional review board of the performing hospital approved this study, and written informed consent was obtained from the legal guardians of pediatric patients. Multi-b-value diffusion weighted magnetic resonance (MR) imaging was performed in 67 pediatric patients with brain tumors. Diffusion coefficient D, fractional order parameter beta (which correlates with tissue heterogeneity), and a microstructural quantity MU were calculated by fitting the multi-b-value diffusion-weighted images to an FROC model. D, beta, and MU values were measured in solid tumor regions, as well as in normal-appearing gray matter as a control. These values were compared between the low- and high-grade tumor groups by using the Mann-Whitney U test. The performance of FROC parameters for differentiating among patient groups was evaluated with receiver operating characteristic (ROC) analysis. RESULTS: None of the FROC parameters exhibited significant differences in normal-appearing gray matter (P >= .24), but all showed a significant difference (P < .002) between low (D, 1.53 MUm(2)/msec +/- 0.47; beta, 0.87 +/- 0.06; MU, 8.67 MUm +/- 0.95) and high-grade (D, 0.86 MUm(2)/msec +/- 0.23; beta, 0.73 +/- 0.06; MU, 7.8 MUm +/- 0.70) brain tumor groups. The combination of D and beta produced the largest area under the ROC curve (0.962) in the ROC analysis compared with individual parameters (beta, 0.943; D,0.910; and MU, 0.763), indicating an improved performance for tumor differentiation. CONCLUSION: The FROC parameters can be used to differentiate between low- and high-grade pediatric brain tumor groups. The combination of FROC parameters or individual parameters may serve as in vivo, noninvasive, and quantitative imaging markers for classifying pediatric brain tumors. PMID- 26035587 TI - Skeletal Muscle in Healthy Subjects versus Those with GNE-Related Myopathy: Evaluation with Shear-Wave US--A Pilot Study. AB - PURPOSE: To determine whether quantitative differences in shear-wave velocity (SWV) exist between normal skeletal muscle and those affected by GNE-related myopathy and to examine the effects of muscle anisotropy, depth, and axial preload on SWV in a healthy control group. MATERIALS AND METHODS: This study was approved by the institutional review board and compliant with HIPAA. Informed consent was obtained from all study volunteers. Eight patients (four women and four men aged 30-50 years) with genetically and biopsy-proved GNE-related myopathy and five healthy volunteers (three women and two men aged 27-33 years) underwent SWV imaging with use of a 9-MHz linear transducer. The gastrocnemius muscles were evaluated in the patients with GNE-related myopathy, and the gastrocnemius, vastus lateralis, and rectus femoris muscles were evaluated in the healthy cohort. The effect of muscle anisotropy, axial preload, and sample volume depth were examined in the healthy cohort. The effect of anisotropy at a fixed depth and preload were examined in the patients with GNE-related myopathy. RESULTS: Irrespective of the muscle, the mean SWV was significantly higher with the transverse orientation than with the longitudinal orientation (P < .001). In the healthy cohort, the mean SWV for superficial measurements was significantly lower than that for deep measurements (P < .02). The mean SWV with preload was significantly higher with compression (P < .001) for the rectus femoris only. The mean SWV was significantly lower in patients with GNE-related myopathy than in control subjects (P < .02). CONCLUSION: SWV parametric imaging may provide a useful quantitative adjunct in the assessment of disease activity in patients with GNE-related myopathy. There is diminished SWV and muscle anisotropy in GNE related myopathy. PMID- 26035588 TI - Prognostic Value of FDG PET/CT before Allogeneic and Autologous Stem Cell Transplantation for Aggressive Lymphoma. AB - PURPOSE: To determine the prognostic value of performing fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) before allogeneic and autologous stem cell transplantation (SCT) in patients with aggressive lymphoma. MATERIALS AND METHODS: A HIPAA-compliant retrospective review was performed under institutional review board waiver. Patients with aggressive lymphoma underwent allogeneic or autologous SCT between January 2005 and December 2010. FDG PET/CT was performed within the 3 months prior to transplantation. PET/CT images were evaluated for lesions with FDG avidity greater than that of the background liver. The relationship between pretransplantation PET and progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) was assessed with Kaplan-Meier curves and a corresponding log-rank test for categorical variables and Cox regression for continuous variables. RESULTS: A total of 175 patients were identified, of whom 73 underwent FDG PET/CT before allogeneic SCT and 102 underwent FDG PET/CT before autologous SCT. Before allogeneic SCT, 23 of 73 patients (32%) had FDG avid lesions, and before autologous SCT, 11 of 102 patients (11%) had FDG-avid lesions. For allogeneic SCT, the 2-year PFS estimate was 68% (95% confidence interval [CI]: 56%, 82%) in patients without FDG-avid lesions, but only 35% (95% CI: 20%, 61%) for patients with FDG-avid lesions (P = .014). For autologous SCT, the 2-year PFS was 72% (95% CI: 64%, 82%) in patients without FDG-avid lesions, but only 18% (95% CI: 5%, 64%) for patients with FDG-avid lesions (P < .0001). Similar differences were seen in OS and DSS. The risk for posttransplantation recurrence correlated with higher lesional maximum standardized uptake values: for PFS, P < .0001 to P = .01; for DSS, P < .0001 to P = .002; and for OS, P < .0001 to P = .015. CONCLUSION: Performing FDG PET/CT before SCT in patients with aggressive lymphoma has prognostic value. For patients with aggressive lymphomas, the presence of FDG-avid lesions at PET/CT performed before allogeneic and autologous SCT indicates a lower likelihood of SCT success. PMID- 26035589 TI - EETs Attenuate Ox-LDL-Induced LTB4 Production and Activity by Inhibiting p38 MAPK Phosphorylation and 5-LO/BLT1 Receptor Expression in Rat Pulmonary Arterial Endothelial Cells. AB - Cytochrome P-450 epoxygenase (EPOX)-derived epoxyeicosatrienoic acids (EETs), 5 lipoxygenase (5-LO), and leukotriene B4 (LTB4), the product of 5-LO, all play a pivotal role in the vascular inflammatory process. We have previously shown that EETs can alleviate oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation in primary rat pulmonary artery endothelial cells (RPAECs). Here, we investigated whether ox-LDL can promote LTB4 production through the 5-LO pathway. We further explored how exogenous EETs influence ox-LDL-induced LTB4 production and activity. We found that treatment with ox-LDL increased the production of LTB4 and further led to the expression and release of both monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 (ICAM-1). All of the above ox-LDL-induced changes were attenuated by the presence of 11,12-EET and 14,15-EET, as these molecules inhibited the 5-LO pathway. Furthermore, the LTB4 receptor 1 (BLT1 receptor) antagonist U75302 attenuated ox LDL-induced ICAM-1 and MCP-1/CCL2 expression and production, whereas LY255283, a LTB4 receptor 2 (BLT2 receptor) antagonist, produced no such effects. Moreover, in RPAECs, we demonstrated that the increased expression of 5-LO and BLT1 following ox-LDL treatment resulted from the activation of nuclear factor-kappaB (NF-kappaB) via the p38 mitogen-activated protein kinase (MAPK) pathway. Our results indicated that EETs suppress ox-LDL-induced LTB4 production and subsequent inflammatory responses by downregulating the 5-LO/BLT1 receptor pathway, in which p38 MAPK phosphorylation activates NF-kappaB. These results suggest that the metabolism of arachidonic acid via the 5-LO and EPOX pathways may present a mutual constraint on the physiological regulation of vascular endothelial cells. PMID- 26035590 TI - Carotid Stiffness and Physical Activity in Elderly--A Short Report of the SAPALDIA 3 Cohort Study. AB - INTRODUCTION: Regular physical activity has been shown to reduce cardiovascular disease risk in the general population. While smaller studies in specified groups (highly trained versus untrained individuals) indicate a certain dose-dependent effect of physical activity on the reduction of carotid stiffness (an indicator of subclinical vascular disease), it is unclear whether this association is present in a representative sample. Thus, we investigated this question cross sectionally in participants from the population-based Swiss Cohort Study on Air Pollution And Lung and Heart Diseases In Adults (SAPALDIA). METHODS: Self reported total, moderate and vigorous physical activity and distensibility as a measure of local arterial stiffness among 1636 participants aged 50 to 81 years without clinically manifest diseases were evaluated. Mixed regression models were used to examine associations of physical activity intensity with distensibility. RESULTS: Vigorous physical activity, but not total nor moderate physical activity, was significantly associated with increased distensibility (= reduced carotid stiffness) in univariate analyses (percent change in the geometric mean and 95% confidence interval per 1 standard deviation increment in vigorous physical activity = 2.54 (0.69; 4.43), p < 0.01; in total physical activity = 1.62 (-0.22; 3.50), p = 0.08; in moderate physical activity = 0.70 (-1.12; 2.56), p = 0.45). These associations disappeared when we additionally adjusted for age. CONCLUSION: After adjustment for the most important confounders and risk factors, we found no evidence for an association of physical activity with carotid stiffness in the general middle aged to elderly population. PMID- 26035592 TI - Direct Effects of Microalgae and Protists on Herring (Clupea harengus) Yolk Sac Larvae. AB - This study investigated effects of microalgae (Rhodomonas baltica) and heterotrophic protists (Oxyrrhis marina) on the daily growth, activity, condition and feeding success of Atlantic herring (Clupea harengus) larvae from hatch, through the end of the endogenous (yolk sac) period. Yolk sac larvae were reared in the presence and absence of microplankton and, each day, groups of larvae were provided access to copepods. Larvae reared with microalgae and protists exhibited precocious (2 days earlier) and >= 60% increased feeding incidence on copepods compared to larvae reared in only seawater (SW). In the absence and presence of microalgae and protists, life span and growth trajectories of yolk sac larvae were similar and digestive enzyme activity (trypsin) and nutritional condition (RNA-DNA ratio) markedly declined in all larvae directly after yolk sac depletion. Thus, microplankton promoted early feeding but was not sufficient to alter life span and growth during the yolk sac phase. Given the importance of early feeding, field programs should place greater emphasis on the protozooplankton-ichthyoplankton link to better understand match-mismatch dynamics and bottom-up drivers of year class success in marine fish. PMID- 26035593 TI - Toward the 2015 white house conference on aging: creating an aging policy vision for the decade ahead. PMID- 26035591 TI - Overexpression of an AP2/ERF Type Transcription Factor OsEREBP1 Confers Biotic and Abiotic Stress Tolerance in Rice. AB - AP2/ERF-type transcription factors regulate important functions of plant growth and development as well as responses to environmental stimuli. A rice AP2/ERF transcription factor, OsEREBP1 is a downstream component of a signal transduction pathway in a specific interaction between rice (Oryza sativa) and its bacterial pathogen, Xoo (Xanthomonas oryzae pv. oryzae). Constitutive expression of OsEREBP1 in rice driven by maize ubiquitin promoter did not affect normal plant growth. Microarray analysis revealed that over expression of OsEREBP1 caused increased expression of lipid metabolism related genes such as lipase and chloroplastic lipoxygenase as well as several genes related to jasmonate and abscisic acid biosynthesis. PR genes, transcription regulators and Aldhs (alcohol dehydrogenases) implicated in abiotic stress and submergence tolerance were also upregulated in transgenic plants. Transgenic plants showed increase in endogenous levels of alpha-linolenate, several jasmonate derivatives and abscisic acid but not salicylic acid. Soluble modified GFP (SmGFP)-tagged OsEREBP1 was localized to plastid nucleoids. Comparative analysis of non-transgenic and OsEREBP1 overexpressing genotypes revealed that OsEREBP1 attenuates disease caused by Xoo and confers drought and submergence tolerance in transgenic rice. Our results suggest that constitutive expression of OsEREBP1 activates the jasmonate and abscisic acid signalling pathways thereby priming the rice plants for enhanced survival under abiotic or biotic stress conditions. OsEREBP1 is thus, a good candidate gene for engineering plants for multiple stress tolerance. PMID- 26035594 TI - The neoliberal political economy and erosion of retirement security. AB - The origins and trajectory of the crisis in the United States retirement security system have slowly become part of the discussion about the social, political, and economic impacts of population aging. Private sources of retirement security have weakened significantly since 1980 as employers have converted defined benefits precisions to defined contribution plans. The Center for Retirement Research (CRR) now estimates that over half of boomer generation retirees will not receive 70-80% of their wages while working. This erosion of the private retirement security system will likely increase reliance on the public system, mainly Social Security and Medicare. These programs, however, have increasingly become the targets of critics who claim that they are not financially sustainable in their current form and must be significantly modified. This article will focus on an analysis of these trends in the erosion of the United States retirement security system and their connection to changes in the United States political economy as neoliberal, promarket ideology, and policies (low taxes, reduced spending, and deregulation) have become dominant in the private and public sectors. The neoliberal priority on reducing labor costs and achieving maximum shareholder value has created an environment inimical to maintain the traditional system of pension and health care benefits in both the private and public sectors. This article explores the implications of these neoliberal trends in the United States economy for the future of retirement security. PMID- 26035595 TI - Age-friendly community initiatives: conceptual issues and key questions. AB - Public policy and programs for older adults traditionally have focused on the delivery of benefits to targeted individuals. Over the past decade, age-friendly community initiatives (AFCIs) have developed as a paradigm shift in contrast to this predominant focus. AFCIs engage stakeholders from multiple sectors within a typically local geographic area to make social and/or physical environments more conducive to older adults' health, well-being, and ability to age in place and in the community. We describe three general categories of AFCIs, including community planning approaches, support-focused approaches, and cross-sector partnership approaches. Following from this conceptual overview, we posit four key policy relevant questions with implications for the expansion of AFCIs, including what public policy supports are necessary for the implementation of AFCIs across diverse communities, how entities outside of aging can be engaged to collaborate, to what extent advocates for various models can work together, and how the outcomes of these initiatives can be rigorously evaluated. We conclude by discussing how AFCIs are germane to the primary issues highlighted by the 2015 White House Conference on Aging. PMID- 26035596 TI - Policies to protect persons with dementia in assisted living: deja vu all over again? AB - Continued growth in the number of individuals with dementia residing in assisted living (AL) raises concerns about their safety and protection. In this Forum, we review current AL practices relevant to residents with dementia and present a rationale for examining the government role in protecting these individuals within this context. Since public oversight of AL is currently a state prerogative, we assess states' regulatory activity across 3 domains closely related to safety and protection of persons with dementia: environmental features, staffing, and use of chemical restraints. We then step back to consider the state policymaking environment and assess the feasibility of developing a minimum standard of regulations from one state to the next. This Forum concludes with a historical comparison between the contemporary AL market and the nursing home care market prior to the Nursing Home Reform Act of 1987, and we discuss how an increased amount of federal interest could improve existing state efforts to protect persons with dementia residing in AL. PMID- 26035598 TI - Mental health disorders among an invisible minority: depression and dementia among american Indian and alaska native elders. AB - According to the 2010 Census, 5.2 million people identified themselves as American Indian or Alaska Native (AIAN) in the United States. This was an increase of 39% from the prior Census, making AIANs one of the nation's fastest growing populations. The health and social programs reaching them, however, have experienced documented devastating shortfalls. Decades of inadequate resources have resulted in significant health and socioeconomic disparities. AIANs are often considered an "invisible minority." In 2012, there were 266,000 AIAN elders 65 or older who claimed one race alone. That number is projected to almost triple by 2030-when the nation's baby boomers move into the ranks of the older population. This article provides an overview of two primary mental health issues depression and dementia-that will confront this emerging AIAN elder population. Although other health and social issues exist, this article addresses depression and dementia because they are hidden from the community and from health care agencies. This paper focuses both on the unique characteristics of the AIAN population and why it is important to address depression and dementia. The conclusion explores pragmatic policy recommendations for improving the health and long-term mental health care status of AIAN elders. PMID- 26035597 TI - Translating Evidence-Based Dementia Caregiving Interventions into Practice: State of-the-Science and Next Steps. AB - Over the past 3 decades, more than 200 dementia caregiver interventions have been tested in randomized clinical trials and found to be efficacious. Few programs have been translated for delivery in various service contexts, and they remain inaccessible to the 15+ million dementia family caregivers in the United States. This article examines translational efforts and offers a vision for more rapid advancement in this area. We summarize the evidence for caregiver interventions, review published translational efforts, and recommend future directions to bridge the research-practice fissure in this area. We suggest that as caregiver interventions are tested external to service contexts, a translational phase is required. Yet, this is hampered by evidentiary gaps, lack of theory to understand implementation challenges, insufficient funding and unsupportive payment structures for sustaining programs. We propose ways to advance translational activities and future research with practical applications. PMID- 26035599 TI - Dementia friendly, dementia capable, and dementia positive: concepts to prepare for the future. AB - With an aging global population, the number of dementia cases is growing exponentially. To address the upcoming dementia crisis, the World Health Organization and Alzheimer's Disease International (2012) collaborated on an extensive report, Dementia: A Public Health Priority. In the United Kingdom, Prime Minster David Cameron initiated a national challenge on dementia, forming 3 dementia challenge champion groups aimed at improving health and care, creating dementia-friendly communities, and promoting dementia research. In the U.S., President Obama signed the National Alzheimer's Project Act, which led to the formation of the Advisory Council on Alzheimer's Research, Care, and Services and the launch of the first National Plan to Address Alzheimer's Disease. The term "dementia capable" was introduced in the 2012 Recommendations of the Public Members of the Advisory Council and has since been adopted in both the recommendations and annual updates of the national plan. This paper will first compare and contrast government usage of the concepts dementia friendly and dementia capable, along with another valuable concept, dementia positive, that was added after reviewing the literature. Finally, a new vision statement for the U.S.' national plan will be proposed and recommendations incorporating these 3 concepts in policy, research, and practice will be made. PMID- 26035600 TI - Public health imperative of the 21st century: innovations in palliative care systems, services, and supports to improve health and well-being of older americans. AB - A primary aim of federal aging and health policy must be promoting innovations in palliative care systems, services, and supports that improve the experience of growing old in America. Older adults must contend today with increasing burden over the life course often as the result of life-limiting chronic pain and chronic illnesses as well as social and economic factors beyond their control. These burdens are frequently shared with unpaid family caregivers who provide significant uncompensated medical care and social support to their loved ones. Enjoyment of the highest attainable standard of physical and mental health, recognized as a fundamental human right under international law, remains a goal for all older adults and encompasses the right to palliative care. For many older Americans, especially vulnerable subgroups who face health and pain disparities, however, this goal remains elusive. A public health strategy for implementing palliative care policy interventions will help to build age-friendly environments, assure the availability and accessibility of palliative systems of care, essential medicines, and an adequate generalist-level workforce, and sustain diffusion of innovation across all levels of health and social provision. The 2015 White House Conference on Aging must make these realignments a policy priority in order to foster social and economic development for all older Americans. PMID- 26035601 TI - Increasing opportunities for the productive engagement of older adults: a response to population aging. AB - "Productive aging" puts forward the fundamental view that the capacity of older adults must be better developed and utilized in activities that make economic contributions to society-working, caregiving, volunteering. It is suggested that productive engagement can lead to multiple positive ends: offsetting fiscal strains of a larger older population, contributing to the betterment of families and civil society, and maintaining the health and economic security of older adults. Advocates claim that outdated social structures and discriminatory behaviors limit participation of older adults in these important social roles as well as prevent the optimization of outcomes for older adults, families, and society. We ask two important questions: (a) How can we shape policies and programs to optimally engage the growing resources of an aging population for the sake of society and older adults themselves? and (b) How can policies pertaining to productive engagement reduce health and economic disparities? We answer these questions by first describing the current state of engagement in each of the three productive activities and summarize some current policies and programs that affect engagement. Next we highlight challenges that cross-cut productive engagement. Finally, we provide policy recommendations to address these challenges. PMID- 26035602 TI - Workplace-based health and wellness programs: the intersection of aging, work, and health. AB - Workplace-based health and wellness programs (HWPs) may be an obvious yet under utilized strategy for promoting positive health-related behaviors among older workers and for increasing their ability to continue to work. Given the unprecedented number of older adults who extend their labor force attachment beyond traditional retirement ages, a new vision of older adults' economic security and overall quality-of-life should take into account the intersections of aging, work, and health. The purpose of this article is to: (a) discuss the workplace as an increasingly important setting that can expand the reach and effectiveness of health promotion efforts; (b) examine current knowledge of barriers and facilitators that can affect older workers' participation in workplace-based HWPs; and (c) suggest new incentive structures that may increase older workers' engagement in these programs. We develop a rationale for our proposition that sustained participation in HWPs may improve the health status of older workers and reduce health care costs. It is our conclusion that there is significant potential for workplace-based HWPs to support older adults who want to or need to work. PMID- 26035603 TI - The arts, health, and aging in america: 2005-2015. AB - In advance of the White House Conference on Aging (WHCoA) in 1981, 1995, and 2005, the arts and aging communities held mini-conferences to ensure that arts, culture, and livability were part of larger public policy discussions. This article takes a historical look at recommendations from the 2005 WHCoA Mini Conference on Creativity and Aging in America, including arts in health care, lifelong learning, and livability through universal design. Overarching recommendations in 2005 requested investments in research, including cost-benefit analyses; identification of best practices and model programs; program dissemination to broaden the availability of arts programs. The "Arts" is a broad term encompassing all forms of arts including music, theater, dance, visual arts, literature, multimedia and design, folk, and traditional arts to engage the participation of all older Americans; promotion of innovative public and private partnerships to support arts program development, including workforce development (e.g., artists, social workers, and health care providers); and public awareness of the importance of arts participation to healthy aging. Through the leadership of the National Endowment for the Arts and U.S. Department of Health and Human Services, thinking about the arts and aging has broadened to include greater emphasis on a whole-person approach to the health and well-being of older adults. This approach engages older adults in arts participation not only as audience members, but as vital members of their community through creative expression focusing on life stories for intergenerational as well as interprofessional collaboration. This article reviews progress made to date and identifies critical gaps in services for future consideration at a 2015 Mini-Conference on Creativity and Aging related to the WCHoA area of emphasis on healthy aging. PMID- 26035604 TI - Creating a comprehensive care system for frail elders in "age boom" america. AB - Current options being discussed by policymakers cannot yield the highly reliable, highly efficient service delivery system-inclusive of both health care and community-based supportive services-that the nation's upcoming and transformative "age wave" will require. More far-reaching and rapid innovations in policy and health care delivery are essential. The MediCaring Accountable Care Community initiative is a comprehensive model that can deliver higher quality care for frail elderly Medicare beneficiaries at a lower per capita cost. The savings generated by adhering to established geriatric principles in the delivery of medical care would help fund community-based long-term services and supports (LTSS), using a modified Accountable Care Organization (ACO) known as an Accountable Care Community (ACC). A Community Board would monitor the quality and supply of services for frail elders, the most expensive phase of most lives. The constellation of improvements that form the basis of this model are congruent with the goal of improving access to LTSS, which is one of the 4 areas targeted by the Sixth White House Conference on Aging. PMID- 26035605 TI - Re-imagining long-term services and supports: towards livable environments, service capacity, and enhanced community integration, choice, and quality of life for seniors. AB - In the half century since enactment of the 1965 Great Society programs, accomplishments were gradually made to improve access to and quality of long-term services and supports (LTSS), including: mitigation of financial and care abuses in nursing facilities (NFs); substantial rebalancing of LTSS towards consumer preferred home-and-community-based services (HCBS); increasing flexible consumer centered HCBS including payment to family caregivers; and more assisted-living and housing options for seniors with heavy care needs. A unified planning and advocacy agenda across age and disability type and greater consumer transparency fueled progress. Nonetheless, LTSS is a broken system; persistent problems interfere with substantial and necessary change. These include; over-emphasis on safety for LTSS consumers; inattention to physical environments in all settings; regulatory and professional rigidity; and poor communication and information. Our recommendations are aimed at builders and designers, LTSS professionals, regulators, and educators/trainers; the last may be crucial in forging new consensus and over-coming entrenched beliefs. Policy recommendations include relatively narrow steps-for example, requiring single occupancy in all NFs and assisted living settings financed with public dollars-to broad reworking of the prerequisites for livable age-friendly (and dementia-friendly) communities and for a capable, flexible LTSS workforce. PMID- 26035606 TI - A new long-term care manifesto. AB - This article argues for a fresh look at how we provide long-term care (LTC) for older persons. Essentially, LTC offers a compensatory service that responds to frailty. Policy debate around LTC centers on costs, but we are paying for something we really don't want. Building societal enthusiasm (or even support) for LTC will require re-inventing and re-branding. LTC has three basic components: personal care, housing, and health care (primarily chronic disease management). They can be delivered in a variety of settings. It is rare to find all three done well simultaneously. Personal care (PC) needs to be both competent and compassionate. Housing must provide at least minimal amenities and foster autonomy; when travel time for PC raises costs dramatically, some form of clustered housing may be needed. Health care must be proactive, aimed at preventing exacerbations of chronic disease and resultant hospitalizations. Enhancing preferences means allowing taking informed risks. Payment incentives should reward both quality of care and quality of life, but positive outcomes must be defined as slowing decline. Paying for services but not for housing under Medicaid would automatically level the playing field between nursing homes (NH) and community-based services. Regulations should achieve greater parity between NH and community care and include both positive and negative feedback. Providing post-acute care should be separate from LTC. Using the tripartite LTC framework, we can create innovative flexible approaches to providing needed services for frail older persons in formats that are both desirable and affordable. Such care will be more socially desirable and hence worth paying for. PMID- 26035607 TI - Improving policies for caregiver respite services. AB - This paper provides a template for the decade ahead regarding the delivery, supply, and funding of caregiver respite services. Policy changes are needed to address these issues as concerns about our country's ability to meet future caregiving needs are growing along with our aging population. Federal initiatives and state-level policies and programs affecting respite are reviewed and directions for policy advancement are highlighted. Much more work is needed to educate caregivers and the general public about the necessity for respite beginning early in the caregiving career to prevent burnout and other adverse effects. Because it is unlikely that there will be a sufficient number of direct care workers to replace unpaid caregivers, improved policies are needed to ensure that their situation is sustainable through increased availability of high quality respite and other services vital to caregiver health and well-being. Among the 2015 White House Conference on Aging's priorities in the next decade, policies on long-term services and supports will require focused attention on family caregivers and the direct-care workforce to strengthen their ability to give care now and support their own physical, emotional, and financial needs in the future. PMID- 26035608 TI - Informal caregiving and its impact on health: a reappraisal from population-based studies. AB - Considerable research and public discourse on family caregiving portrays it as a stressful and burdensome experience with serious negative health consequences. A landmark study by Schulz and Beach that reported higher mortality rates for strained spouse caregivers has been widely cited as evidence for the physical health risks of caregiving and is often a centerpiece of advocacy for improved caregiver services. However, 5 subsequent population-based studies have found reduced mortality and extended longevity for caregivers as a whole compared with noncaregiving controls. Most caregivers also report benefits from caregiving, and many report little or no caregiving-related strain. Policy reports, media portrayals, and many research reports commonly present an overly dire picture of the health risks associated with caregiving and largely ignore alternative positive findings. As the pool of traditional family caregivers declines in the coming years, a more balanced and updated portrayal of the health effects of caregiving is needed to encourage more persons to take on caregiving roles, and to better target evidence-based services to the subgroup of caregivers who are highly strained or otherwise at risk. Recommendations are discussed for research that will better integrate and clarify both the negative and potential positive health effects of informal caregiving. PMID- 26035610 TI - Still alice. PMID- 26035611 TI - The elders: everyone is a story. PMID- 26035619 TI - A Case of Comorbid Persistent Genital Arousal Disorder and Premature Ejaculation: Killing Two Birds With One Stone. PMID- 26035609 TI - Elder mistreatment: priorities for consideration by the white house conference on aging. AB - Elder mistreatment is recognized internationally as a prevalent and growing problem, meriting the attention of policymakers, practitioners, and the general public. Studies have demonstrated that elder mistreatment is sufficiently widespread to be a major public health concern and that it leads to a range of negative physical, psychological, and financial outcomes. This article provides an overview of key issues related to the prevention and treatment of elder mistreatment, focusing on initiatives that can be addressed by the White House Conference on Aging. We review research on the extent of mistreatment and its consequences. We then propose 3 challenges in preventing and treating elder mistreatment that relate to improving research knowledge, creating a comprehensive service system, and developing effective policy. Under each challenge, examples are provided of promising initiatives that can be taken to eliminate mistreatment. To inform the recommendations, we employed recent data from the Elder Justice Roadmap Project, in which 750 stakeholders in the field of elder mistreatment were surveyed regarding research and policy priorities. PMID- 26035620 TI - The novel herbal cocktail MA128 suppresses tumor growth and the metastatic potential of highly malignant tumor cells. AB - MA128, a novel herbal medicine, was previously identified and its effectiveness in the treatment of asthma and atopic dermatitis (AD) was demonstrated. In particular, post-inflammatory hyperpigmentation (PIH) in AD mice was improved by treatment with MA128. In addition, MA128 exhibited anti-melanogenic activity by inhibiting tyrosinase activity via the p38 MAPK and protein kinase A signaling pathways in B16F10 cells. In the present study, we examined whether oral administration of MA128 suppressed the in vivo tumor growth of HT1080 cells in athymic nude mice. The results showed that the daily oral administration of 75 and 150 mg/kg MA128 suppressed the tumorigenic growth of HT1080 cells efficiently. Since metastasis is a major cause of cancer-associated mortality and the greatest challenge during cancer treatment, we investigated the effect of non toxic concentrations of MA128 on the metastatic potential of HT1080 cells. MA128 inhibited anchorage-independent colony formation, migration and invasion. Matrix metalloproteinase-9 (MMP-9) activity under resting and PMA-stimulated conditions was decreased in a dose-dependent manner by MA128 in HT1080 cells. In addition, the daily oral administration of MA128 at doses of 75 and 150 mg/kg efficiently blocked the lung metastasis of B16F10 cells that had been injected into the tail veins of C57BL/6 mice. In particular, none of the mice treated with MA128 exhibited systemic toxicity, such as body weight loss or liver and kidney dysfunction. MA128 also inhibited tumor-induced angiogenesis. Taken together, the results suggest that MA128 is a potential therapeutic agent and a safe herbal medicine for controlling malignant and metastatic cancer. PMID- 26035621 TI - Multifunctional inverse opal particles for drug delivery and monitoring. AB - Particle-based delivery systems have a demonstrated value for drug discovery and development. Here, we report a new type of particle-based delivery system that has controllable release and is self-monitoring. The particles were composed of poly(N-isopropylacrylamide) (pNIPAM) hydrogel with an inverse opal structure. The presence of macropores in the particles provides channels for active drug loading and release from the materials. PMID- 26035622 TI - Clinical development of curcumin in neurodegenerative disease. AB - Curcumin, a polyphenolic antioxidant derived from the turmeric root has undergone extensive preclinical development, showing remarkable efficacy in wound repair, cancer and inflammatory disorders. This review addresses the rationale for its use in neurodegenerative disease, particularly Alzheimer's disease. Curcumin is a pleiotropic molecule, which not only directly binds to and limits aggregation of the beta-sheet conformations of amyloid characteristic of many neurodegenerative diseases but also restores homeostasis of the inflammatory system, boosts the heat shock system to enhance clearance of toxic aggregates, scavenges free radicals, chelates iron and induces anti-oxidant response elements. Although curcumin corrects dysregulation of multiple pathways, it may exert many effects via a few molecular targets. Pharmaceutical development of natural compounds like curcumin and synthetic derivatives have strong scientific rationale, but will require overcoming various hurdles including; high cost of trials, concern about profitability and misconceptions about drug specificity, stability, and bioavailability. PMID- 26035623 TI - Combination drug therapy for the treatment of status epilepticus. AB - Status epilepticus (SE) is a common neurological emergent disease with high mortality and disability rates. Rapidly and effectively controlling seizures is key to saving the lives of patients and improving their prognoses. Traditional antiepileptic drugs for SE are ineffective in 30-40% of cases. In light of the diverse etiology and complex pathogenesis of SE, combination drug therapy for SE might be more conducive for the treatment of all patients because the combined use of drugs can produce synergistic effects via different mechanisms. This review summarizes combination drug therapies used for SE in animal experiments and clinical practice, the potential advantages of combination drug therapy and specific combination drug therapies using different antiepileptic drugs. The aim is to help researchers seek better treatments for early termination of SE. PMID- 26035624 TI - Fibromyalgia diagnosis: a review of the past, present and future. AB - Diagnosis of fibromyalgia (FM) remains controversial even though diverse diagnostic criteria have been developed. This review looks at the history, evolution of diagnostic criteria, endless controversy, recent trends and future perspectives regarding FM diagnosis. Some have criticized that diagnosis of FM could lead to medicalization, whereas others have raised concerns of under diagnosing FM. With the evolution of diagnosis criteria from American College of Rheumatology 1990 to modified American College of Rheumatology 2010, diagnosis of FM has become simpler. The recent trend of applying patient-reported questionnaires has also increased a simpler FM diagnosis. Reliable biomarkers will not be available for the foreseeable future, so diverse assessment tools will have to be used more pro-actively. After initial diagnosis, multiple and comprehensive assessment measures are needed during the course of treatment in order to better understand type and severity of FM symptoms. These, in turn, could help classify FM based on symptom domain, symptom severity, and comorbidity which would enable more personalized treatment. PMID- 26035626 TI - Stability of C(12)E(j) Bilayers Probed with Adhesive Droplets. AB - The stability of model surfactant bilayers from the poly(ethylene glycol) mono-n dodecyl ether (C12Ej) family was probed. The surfactant bilayers were formed by the adhesion of emulsion droplets. We generated C12Ej bilayers by forming water in-oil (w/o) emulsions with saline water droplets, covered by the surfactant, in a silicone and octane oil mixture. Using microfluidics, we studied the stability of those bilayers. C12E1 allowed only short-lived bilayers whereas C12E2 bilayers were stable over a wide range of oil mixtures. At high C12E2 concentration, a two phase region was displayed in the phase diagram: bilayers formed by the adhesion of two water droplets and Janus-like particles consisting of adhering aqueous and amphiphilic droplets. C12E8 and C12E25 did not mediate bilayer formation and caused phase inversion leading to o/w emulsion. With intermediate C12E4 and C12E5 surfactants, both w/o and o/w emulsions were unstable. We provided the titration of the C12E2 bilayer with C12E4 and C12E5 to study and predict their stability behavior. PMID- 26035625 TI - Selective Small Molecule Induced Degradation of the BET Bromodomain Protein BRD4. AB - The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1alpha. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4. PMID- 26035627 TI - The Protective Mechanism of Fluorofenidone in Renal Interstitial Inflammation and Fibrosis. AB - BACKGROUND: Deregulated inflammation has been implicated in the development of renal interstitial fibrosis and progressive renal failure. Previous work has established that fluorofenidone, a pyridone agent, attenuates renal fibrosis. However, the mechanism by which fluorofenidone prevents renal fibrosis remains unclear. The aim of this study was to investigate the in vivo effects of fluorofenidone on unilateral ureteral obstruction-induced fibrosis and the involved molecular mechanism in mouse peritoneal macrophages. METHODS: Renal fibrosis was induced in rat by unilateral ureteral obstruction for 3, 7 or 14 days. Ipsilateral kidneys were harvested for morphologic analysis. Leukocyte infiltration was assessed by immunohistochemistry staining. The expression of chemokines (MCP-1, RANTAS, IP-10, MIP-1alpha and MIP-1beta) and pro-inflammatory cytokines (TNF-alpha and IL-1beta) was measured by enzyme-linked immunosorbent assay and real-time polymerase chain reaction. Mouse peritoneal macrophages and HK-2 cells were incubated with necrotic MES-13 cells or TNF-alpha in the presence or absence of fluorofenidone. The production of MCP-1 was measured by enzyme linked immunosorbent assay, and phosphorylation of ERK1/2, p38 and JNK was quantified by Western blot. RESULTS: Fluorofenidone treatment hampered renal pathologic change and interstitial collagen deposition. Leukocyte infiltration and the expression of chemokines (MCP-1, RANTES, IP-10, MIP-1alpha and MIP-1beta) and pro-inflammatory cytokines (IL-1alpha) in kidney were significantly reduced by fluorofenidone treatment. Mechanistically, fluorofenidone significantly inhibited TNF-alpha or necrotic cell-induced activation of MAP kinase pathways in vitro. CONCLUSIONS: Fluorofenidone serves as a novel anti-inflammatory agent that attenuates ureteral obstruction-induced renal interstitial inflammation and fibrosis, possibly through the inhibition of the microtubule-associated protein kinase pathways. PMID- 26035628 TI - Nanothermometer Based on Resonant Tunneling Diodes: From Cryogenic to Room Temperatures. AB - Sensor miniaturization together with broadening temperature sensing range are fundamental challenges in nanothermometry. By exploiting a large temperature dependent screening effect observed in a resonant tunneling diode in sequence with a GaInNAs/GaAs quantum well, we present a low dimensional, wide range, and high sensitive nanothermometer. This sensor shows a large threshold voltage shift of the bistable switching of more than 4.5 V for a temperature raise from 4.5 to 295 K, with a linear voltage-temperature response of 19.2 mV K(-1), and a temperature uncertainty in the millikelvin (mK) range. Also, when we monitor the electroluminescence emission spectrum, an optical read-out control of the thermometer is provided. The combination of electrical and optical read-outs together with the sensor architecture excel the device as a thermometer with the capability of noninvasive temperature sensing, high local resolution, and sensitivity. PMID- 26035629 TI - Quasi-Spherical Cell Clusters Induced by a Polyelectrolyte Multilayer. AB - Fibroblasts cultured on polyelectrolyte multilayers, PEMUs, made from poly(diallyldimethylammonium), PDADMA, and poly(styrene sulfonate), PSS, showed a variety of attachment modes, depending on the charge of the last layer and deposition conditions. PEMUs terminated with PDADMA (cationic) were cytotoxic when built in 1.0 M NaCl but cytophilic when built in 0.15 M NaCl. Cells adhered poorly to all PSS-capped (anionic) films. PEMUs built in 0.15 M NaCl but terminated with a layer of PSS in 1.0 M NaCl induced most cells to form spherical clusters after about 48 h of culture. These clusters still interrogated the surface, and when they were replated on control tissue culture plastic, cells emerged with close to 100% viability. Differences between the various surfaces were probed in an effort to identify the mechanism responsible for this unusual behavior, which did not follow accepted correlations between substrate stiffness and cell adhesion. No significant differences in roughness or wetting were observed between cluster-inducing PSS-capped multilayers and those that did not produce clusters. When the surface charge was assayed with radiolabeled ions a strong increase in negative surface charge was revealed. Viewing the multilayer as a zwitterionic solid and comparing its surface charge density to that of a cell membrane yields similarities that suggest a mechanism for preventing protein adhesion to the surface, a necessary step in the integrin-mediated mechanotransduction properties of a cell. PMID- 26035630 TI - Probing Yeast Polarity with Acute, Reversible, Optogenetic Inhibition of Protein Function. AB - We recently developed a technique for rapidly and reversibly inhibiting protein function through light-inducible sequestration of proteins away from their normal sites of action. Here, we adapt this method for inducible inactivation of Bem1, a scaffold protein involved in budding yeast polarity. We find that acute inhibition of Bem1 produces profound defects in cell polarization and cell viability that are not observed in bem1Delta. By disrupting Bem1 activity at specific points in the cell cycle, we demonstrate that Bem1 is essential for the establishment of polarity and bud emergence but is dispensable for the growth of an emerged bud. By taking advantage of the reversibility of Bem1 inactivation, we show that pole size scales with cell size, and that this scaling is dependent on the actin cytoskeleton. Our experiments reveal how rapid reversible inactivation of protein function complements traditional genetic approaches. This strategy should be widely applicable to other biological contexts. PMID- 26035631 TI - Measured capillary forces on spheres at particle-laden interfaces. AB - We measure capillary forces on particles at fluid interfaces in order to assess the key parameters that yield effective stabilizing particles. In our experiments, a millimeter-scale particle is attached to a cantilever, which is used to pull the particle perpendicular to the interface. Simultaneously, we image from the side to measure the cantilever's deflection and thus the pulling force, as well as the height of the particle and the shape of the interface. We find that the peak force on a particle at an interface crowded with other particles is consistently smaller than the force at a clean interface. This result is independent of the difference in fluid mass densities, the material of the target sphere, and the capillary charge of the free particles. We attribute the force reduction to the perturbation of interface shape due to the constraints at the boundaries of the free particles. The results should be helpful in designing particles to stabilize droplets in new oil dispersants or in other applications. PMID- 26035632 TI - Structural differences between the active sites of the Ni-A and Ni-B states of the [NiFe] hydrogenase: an approach by quantum chemistry and single crystal ENDOR spectroscopy. AB - The two resting forms of the active site of [NiFe] hydrogenase, Ni-A and Ni-B, have significantly different activation kinetics, but reveal nearly identical spectroscopic features which suggest the two states exhibit subtle structural differences. Previous studies have indicated that the states differ by the identity of the bridging ligand between Ni and Fe; proposals include OH(-), OOH( ), H2O, O(2-), accompanied by modified cysteine residues. In this study, we use single crystal ENDOR spectroscopy and quantum chemical calculations within the framework of density functional theory (DFT) to calculate vibrational frequencies, (1)H and (17)O hyperfine coupling constants and g values with the aim to compare these data to experimental results obtained by crystallography, FTIR and EPR/ENDOR spectroscopy. We find that the Ni-A and Ni-B states are constitutional isomers that differ in their fine structural details. Calculated vibrational frequencies for the cyano and carbonyl ligands and (1)H and (17)O hyperfine coupling constants indicate that the bridging ligand in both Ni-A and Ni-B is indeed an OH(-) ligand. The difference in the isotropic hyperfine coupling constants of the beta-CH2 protons of Cys-549 is sensitive to the orientation of Cys-549; a difference of 0.5 MHz is observed experimentally for Ni A and 1.9 MHz for Ni-B, which results from a rotation of 7 degrees about the Calpha-Cbeta-Sgamma-Ni dihedral angle. Likewise, the difference of the intermediate g value is correlated with a rotation of Cys-546 of about 10 degrees. PMID- 26035633 TI - Development of a method for detecting trace metals in aqueous solutions based on the coordination chemistry of hexahydrotriazines. AB - The detection of trace amounts (<10 ppb) of heavy metals in aqueous solutions is described using 1,3,5-hexahydro-1,3,5-triazines (HTs) as chemical indicators and a low cost fluorimeter-based detection system. This method takes advantage of the inherent properties of HTs to coordinate strongly with metal ions in solution, a fundamental property that was studied using a combination of analytical tools (UV Vis titrations, (1)H-NMR titrations and computational modeling). Based on these fundamental studies that show significant changes in the HT UV signature when a metal ion is present, HT compounds were used to prepare indicator strips that resulted in significant fluorescence changes when a metal was present. A portable and economical approach was adopted to test the concept of utilizing HTs to detect heavy metals using a fluorimeter system that consisted of a low-pressure mercury lamp, a photo-detector, a monolithic photodiode and an amplifier, which produces a voltage proportional to the magnitude of the visible fluorescence emission. Readings of the prepared HT test strips were evaluated by exposure to two different heavy metals at the safe threshold concentration described by the U.S. Environmental Protection Agency (EPA) for Cr(3+) and Ag(2+) (100 MUg L(-1) and 6.25, respectively). This method of detection could be used to the presence of either metal at these threshold concentrations. PMID- 26035634 TI - Differentiating Ferroelectric and Nonferroelectric Electromechanical Effects with Scanning Probe Microscopy. AB - Ferroelectricity in functional materials remains one of the most fascinating areas of modern science in the past several decades. In the last several years, the rapid development of piezoresponse force microscopy (PFM) and spectroscopy revealed the presence of electromechanical hysteresis loops and bias-induced remnant polar states in a broad variety of materials including many inorganic oxides, polymers, and biosystems. In many cases, this behavior was interpreted as the ample evidence for ferroelectric nature of the system. Here, we systematically analyze PFM responses on ferroelectric and nonferroelectric materials and demonstrate that mechanisms unrelated to ferroelectricity can induce ferroelectric-like characteristics through charge injection and electrostatic forces on the tip. We will focus on similarities and differences in various PFM measurement characteristics to provide an experimental guideline to differentiate between ferroelectric material properties and charge injection. In the end, we apply the developed measurement protocols to an unknown ferroelectric material. PMID- 26035635 TI - Flavonoids from Perovskia atriplicifolia and Their in Vitro Displacement of the Respective Radioligands for Human Opioid and Cannabinoid Receptors. AB - Bioassay-guided fractionation of the leaves of Perovskia atriplicifolia (Russian sage) resulted in the isolation of four previously known flavonoid derivatives, 5 hydroxy-6,7,3',4'-tetramethoxyflavone (1), 5,7-dihydroxy-6,3',4' trimethoxyflavone (2), 5-hydroxy-6,7,4'-trimethoxyflavone (3), and 5,7-dihydroxy 6,4'-dimethoxyflavone (4). Compounds 1, 3, and 4 showed displacement of the radioligand for the cloned human delta opioid receptor with Ki values ranging from 3.1 to 26.0 MUM. In addition, the binding mode of the compounds in the active site of the delta opioid receptor was investigated through molecular modeling algorithms. This study may have implications in better understanding non nitrogenous delta opioid receptor ligands. PMID- 26035636 TI - Precise Ratiometric Control of Dual Drugs through a Single Macromolecule for Combination Therapy. AB - A major challenge of combinatorial therapy is the unification of the pharmacokinetics and cellular uptake of various drug molecules with precise control of the dosage thereby maximizing the combined effects. To realize ratiometric delivery and synchronized release of different drugs from a single carrier, a novel approach was designed in this study to load dual drugs onto the macromolecular carrier with different molar ratio by covalently preconjugating dual drugs through peptide linkers to form drug conjugates. In contrast to loading individual types of drugs separately, these drug conjugates enable the loading of dual drugs onto the same carrier in a precisely controllable manner to reverse multidrug resistance (MDR) of human hepatoma (HepG2) cells. As a proof of concept, the synthesis and characterization of xyloglucan-mitomycin C/doxorubicin (XG-MMC/DOX) conjugates were demonstrated. This approach enabled MMC and DOX to be conjugated to the same polymeric carrier with precise control of drug dosage. The cytotoxicity and combinatorial effects were significantly improved compared to the cocktail mixtures of XG-MMC and XG-DOX as well as the individual conjugate of the mixture. Moreover, the results also showed that there was an optimum ratio of dual drugs showing the best cytotoxicity effect and greatest synergy among other tested polymeric conjugate formulations. PMID- 26035637 TI - Generating Active "L-Pd(0)" via Neutral or Cationic pi-Allylpalladium Complexes Featuring Biaryl/Bipyrazolylphosphines: Synthetic, Mechanistic, and Structure Activity Studies in Challenging Cross-Coupling Reactions. AB - Two new classes of highly active yet air- and moisture-stable pi-R-allylpalladium complexes containing bulky biaryl- and bipyrazolylphosphines with extremely broad ligand scope have been developed. Neutral pi-allylpalladium complexes incorporated a range of biaryl/bipyrazolylphosphine ligands, while extremely bulky ligands were accommodated by a cationic scaffold. These complexes are easily activated under mild conditions and are efficient for a wide array of challenging C-C and C-X (X = heteroatom) cross-coupling reactions. Their high activity is correlated to their facile activation to a 12-electron-based "L Pd(0)" catalyst under commonly employed conditions for cross-coupling reactions, noninhibitory byproduct release upon activation, and suppression of the off-cycle pathway to form dinuclear (MU-allyl)(MU-Cl)Pd2(L)2 species, supported by structural (single crystal X-ray) and kinetic studies. A broad scope of C-C and C X coupling reactions with low catalyst loadings and short reaction times highlight the versatility and practicality of these catalysts in organic synthesis. PMID- 26035639 TI - Iodoarene-Catalyzed Stereospecific Intramolecular sp(3) C-H Amination: Reaction Development and Mechanistic Insights. AB - A new strategy is reported for intramolecular sp(3) C-H amination under mild reaction conditions using iodoarene as catalyst and m-CPBA as oxidant. This C-H functionalization involving iodine(III) reagents generated in situ occurs readily at sterically hindered tertiary C-H bonds. DFT (M06-2X) calculations show that the preferred pathway involves an iodonium cation intermediate and proceeds via an energetically concerted transition state, through hydride transfer followed by the spontaneous C-N bond formation. This leads to the experimentally observed amination at a chiral center without loss of stereochemical information. PMID- 26035638 TI - Insertion of linear 8.4 MUm diameter 16 channel carbon fiber electrode arrays for single unit recordings. AB - OBJECTIVE: Single carbon fiber electrodes (d = 8.4 MUm) insulated with parylene-c and functionalized with PEDOT: pTS have been shown to record single unit activity but manual implantation of these devices with forceps can be difficult. Without an improvement in the insertion method any increase in the channel count by fabricating carbon fiber arrays would be impractical. In this study, we utilize a water soluble coating and structural backbones that allow us to create, implant, and record from fully functionalized arrays of carbon fibers with ~150 MUm pitch. APPROACH: Two approaches were tested for the insertion of carbon fiber arrays. The first method used a poly(ethylene glycol) (PEG) coating that temporarily stiffened the fibers while leaving a small portion at the tip exposed. The small exposed portion (500 MUm-1 mm) readily penetrated the brain allowing for an insertion that did not require the handling of each fiber by forceps. The second method involved the fabrication of silicon support structures with individual shanks spaced 150 MUm apart. Each shank consisted of a small groove that held an individual carbon fiber. MAIN RESULTS: Our results showed that the PEG coating allowed for the chronic implantation of carbon fiber arrays in five rats with unit activity detected at 31 days post-implant. The silicon support structures recorded single unit activity in three acute rat surgeries. In one of those surgeries a stacked device with three layers of silicon support structures and carbon fibers was built and shown to readily insert into the brain with unit activity on select sites. SIGNIFICANCE: From these studies we have found that carbon fibers spaced at ~150 MUm readily insert into the brain. This greatly increases the recording density of chronic neural probes and paves the way for even higher density devices that have a minimal scarring response. PMID- 26035640 TI - Efficient Visible to Near-UV Photochemical Upconversion Sensitized by a Long Lifetime Cu(I) MLCT Complex. AB - The current investigation compares the photochemical upconversion sensitization properties of two long lifetime Cu(I) metal-to-ligand charge transfer (MLCT) chromophores to 3 distinct anthryl-based triplet acceptors. The sensitizers [Cu(dsbtmp)2](PF6) (1, dsbtmp = 2,9-di(sec-butyl)-3,4,7,8-tetramethyl-1,10 phenanthroline) and [Cu(dsbp)2](PF6) (2, dsbp = 2,9-di(sec-butyl-1,10 phenanthroline) were selectively excited in the presence of anthracene, 9,10 diphenylanthracene (DPA), and 9,10-dimethylanthracene (DMA) in degassed dichloromethane solutions. In all instances, triplet energy transfer was observed from selective excitation of the Cu(I) MLCT chromophore to each respective anthryl species. The bimolecular triplet-triplet energy transfer quenching rate constants were extracted from dynamic Stern-Volmer analyses in each case, yielding values below the diffusion limit in dichloromethane. However, the Stern Volmer quenching constants (KSV's) were sizable enough (up to ~2300 M(-1) with 1 as a sensitizer) to support efficient photochemical upconversion. As such, visible to near-UV photochemical upconversion was observed in every instance, along with the anticipated quadratic-to-linear incident light power dependence when pumping at 488 nm. The latter verified that it is indeed sensitized triplet triplet annihilation responsible for the generation of the anthryl-based singlet fluorescence. Photochemical upconversion quantum efficiencies were evaluated using a relative actinometric method as both a function of incident light power density as well as anthryl acceptor/annihilator concentration. When 1 was used as the sensitizer, upconversion quantum yields as large as 9.2% and 17.8% were observed for DMA and DPA, respectively. Finally, the combination of 1 with DMA was shown to be quite robust, showing no obvious signs of decomposition during 12 h of continuous 488 nm photolysis. PMID- 26035643 TI - Investigation of laboratory testing issues in the context of the Salmonella National Control Programme in Great Britain. AB - 1. The objective of this study was to identify any issues arising during the laboratory testing of samples collected under the National Control Programme for Salmonella. 2. A questionnaire-based survey was conducted among Defra (Department for Environment, Food and Rural Affairs)-approved testing laboratories in order to identify any complicating factors that the laboratories may encounter during the processing of samples. 3. Samples were reported to arrive in good condition and within the specified time frame after collection. The only concern was that new clients may be unaware of the procedure or correct sampling consumables to use. 4. There was evidence of variability between laboratories regarding the sample testing procedure used, with deviation from the guidelines in some cases. 5. This finding suggests that further guidance for laboratories on methodology is likely to be beneficial as this could help improve the detection of low levels of Salmonella. PMID- 26035641 TI - Bi-module sensing device to in situ quantitatively detect hydrogen peroxide released from migrating tumor cells. AB - Cell migration is one of the key cell functions in physiological and pathological processes, especially in tumor metastasis. However, it is not feasible to monitor the important biochemical molecules produced during cell migrations in situ by conventional cell migration assays. Herein, for the first time a device containing both electrochemical sensing and trans-well cell migration modules was fabricated to sensitively quantify biochemical molecules released from the cell migration process in situ. The fully assembled device with a multi-wall carbon nanotube/graphene/MnO2 nanocomposite functionalized electrode was able to successfully characterize hydrogen peroxide (H2O2) production from melanoma A375 cells, larynx carcinoma HEp-2 cells and liver cancer Hep G2 under serum established chemotaxis. The maximum concentration of H2O2 produced from A375, HEp 2 and Hep G2 in chemotaxis was 130 +/- 1.3 nM, 70 +/- 0.7 nM and 63 +/- 0.7 nM, respectively. While the time required reaching the summit of H2O2 production was 3.0, 4.0 and 1.5 h for A375, HEp-2 and Hep G2, respectively. By staining the polycarbonate micropore membrane disassembled from the device, we found that the average migration rate of the A375, HEp-2 and Hep G2 cells were 98 +/- 6%, 38 +/- 4% and 32 +/- 3%, respectively. The novel bi-module cell migration platform enables in situ investigation of cell secretion and cell function simultaneously, highlighting its potential for characterizing cell motility through monitoring H2O2 production on rare samples and for identifying underlying mechanisms of cell migration. PMID- 26035642 TI - Conformational Changes in the Orai1 C-Terminus Evoked by STIM1 Binding. AB - Store-operated CRAC channels regulate a wide range of cellular functions including gene expression, chemotaxis, and proliferation. CRAC channels consist of two components: the Orai proteins (Orai1-3), which form the ion-selective pore, and STIM proteins (STIM1-2), which form the endoplasmic reticulum (ER) Ca2+ sensors. Activation of CRAC channels is initiated by the migration of STIM1 to the ER-plasma membrane (PM) junctions, where it directly interacts with Orai1 to open the Ca2+-selective pores of the CRAC channels. The recent elucidation of the Drosophila Orai structure revealed a hexameric channel wherein the C-terminal helices of adjacent Orai subunits associate in an anti-parallel orientation. This association is maintained by hydrophobic interactions between the Drosophila equivalents of human Orai1 residues L273 and L276. Here, we used mutagenesis and chemical cross-linking to assess the nature and extent of conformational changes in the self-associated Orai1 C-termini during STIM1 binding. We find that linking the anti-parallel coiled-coils of the adjacent Orai1 C-termini through disulfide cross-links diminishes STIM1-Orai1 interaction, as assessed by FRET. Conversely, prior binding of STIM1 to the Orai1 C-terminus impairs cross-linking of the Orai1 C-termini. Mutational analysis indicated that a bend of the Orai1 helix located upstream of the self-associated coils (formed by the amino acid sequence SHK) establishes an appropriate orientation of the Orai1 C-termini that is required for STIM1 binding. Together, our results support a model wherein the self associated Orai1 C-termini rearrange modestly to accommodate STIM1 binding. PMID- 26035644 TI - A Nucleotomy Model with Intact Annulus Fibrosus to Test Intervertebral Disc Regeneration Strategies. AB - INTRODUCTION: New cells/hydrogel-based treatments for intervertebral disc (IVD) regeneration need to be tested on animal models before clinical translation. Ovine IVD represents a good model but does not allow the injection of a significant volume into intact IVD. The aim of this study was to compare different methods to create a cavity into ovine nucleus pulposus (NP) by enzymatic digestion (E), mechanical nucleotomy (N), or a combining technique (E+N), as a model to study IVD regeneration strategies with intact annulus fibrosus (AF) in functional spinal units (FSUs) in vitro. METHODS: The transpedicular approach via the endplate route (2 mm tunnel) was performed on ovine FSU (IVD and superior and inferior endplate) to access the NP. FSUs were treated by N (Arthroscopic shaver), E (Trypsin/Collagenase), or E+N. Treatments were evaluated macro- and microscopically. The degradation of proteoglycan (PG) around the cavity was assessed by gel electrophoresis. Cell viability was evaluated using the lactate dehydrogenase (LDH) assay. Cavity volume was quantified through computerized tomography after injection of agarose gel/contrast agent. RESULTS: A cavity with intact AF was successfully created with all three methods. The N group showed high reproducibility, low PG degradation, and no endplate thinning. Histological analysis demonstrated NP matrix degradation in enzyme-treated groups, while the PG content was homogenous using mechanical discectomy. Cell viability was affected only in the E group. The cavity volume normalized to the total IVD volume was 5.2% +/- 1.6% in E, 5.0% +/- 1.4% in E+N, and 4.2% +/- 0.1% in N. CONCLUSIONS: Mechanical nucleotomy leads to a more reproducible and less destructive cavity in the NP. Enzymatic methods perform better in terms of cavity volume; however, the cells and PG of the surrounding tissue may be affected. The mechanical nucleotomy enables the creation of a cavity into the IVD while keeping the AF intact, allowing the injection of reproducible volumes of hydrogel and tissue engineering construct for preclinical tests. PMID- 26035645 TI - Non-Contrast Enhanced MR Angiography (NCE-MRA) of the Calf: A Direct Comparison between Flow-Sensitive Dephasing (FSD) Prepared Steady-State Free Precession (SSFP) and Quiescent-Interval Single-Shot (QISS) in Patients with Diabetes. AB - OBJECTIVES: To compare the image quality and diagnostic performance of two non contrast enhanced MR angiography (NCE-MRA) techniques using flow-sensitive dephasing (FSD) prepared steady-state free precession (SSFP) and quiescent interval single-shot (QISS) for the calf arteries in patients with diabetes. MATERIALS AND METHODS: Twenty six patients underwent the two NCE-MRA techniques followed by contrast-enhanced MRA (CE-MRA) of lower extremity on a 1.5T MR system. Image quality scores, arterial stenosis scores, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), vessel sharpness, and diagnostic accuracy for detecting more than 50% arterial stenosis were evaluated and statistically compared using CE-MRA as the reference standard. RESULTS: All examinations were performed successfully. Of the total 153 calf arterial segments obtained in the 26 patients, FSD and QISS showed no significant difference in the number of diagnostic arterial segments (151 [98%] vs. 147 [96%], respectively, P>0.05). The image quality of FSD was higher than that of QISS in the peroneal artery and posterior tibial artery (P<0.05), but no significant difference in the anterior tibial artery (P>0.05). SNR and CNR of FSD were higher than those of QISS (P<0.01), while FSD showed comparable vessel sharpness compared with QISS (P>0.05). The time efficiency of SNR and CNR between FSD and QISS showed no significant difference when taking into account the times for FSD-related scout scans. There was no difference in sensitivity (95% vs. 93%, P>0.05) and negative predictive value (98% vs. 97%, P>0.05) between FSD and QISS for detecting stenosis greater than 50%. However, FSD showed higher specificities (99% vs. 92%, P<0.05) and diagnostic accuracy (98% vs. 92%, P<0.05) compared to QISS. CONCLUSION: Both FSD and QISS had similar high sensitivity and negative predictive value for detecting calf arteries with over 50% stenosis, but FSD showed slightly higher diagnostic specificity and better depiction of arterial lesions due to its isotropic submillimeter spatial resolution. QISS, being an easier to use and less time-consuming technique, could be a method of choice for rapid screening of arterial disease of the lower extremity. PMID- 26035646 TI - RBANS Norms based on the Relationship of Age, Gender, Education, and WRAT-3 Reading to Performance within an Older African American Sample. AB - OBJECTIVE: Due to factors including differences in educational opportunity, African Americans and Caucasians frequently differ on cognitive tests creating diagnostic error risks. Such differences have been found on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and preliminary norms based on a small sample of African Americans have been generated. In a larger sample of community-dwelling older African Americans, we explored sources of variance including age, gender, common medical conditions, years of education, and reading level to generate norms stratified on the most relevant bases. METHOD: Three hundred and fifty-five African Americans aged 55+ and living independently completed the RBANS and health, education, and psychosocial interviews. RESULTS: Hypertension and type 2 diabetes were unrelated to overall RBANS performance once age and education were accounted for. Age, education, and WRAT-3 Reading score (a proxy for scholastic attainment) were independent predictors of RBANS performance. Females performed better on List Learning, Story Memory, Fluency, Coding, List Recall, and List Recognition; males were superior on Line Orientation and Picture Naming. CONCLUSIONS: In addition to generating norms stratified by age, we provide descriptive statistics grouped by age and education, and by age and WRAT-3 Reading grade level, to provide clinicians with the opportunity to tailor their interpretation of scores based upon perceived best fit for their patient. Regression formulas are provided to address gender differences. To complement the standard index norms, we provide norms for alternative indexes representing additional an factor structure of cognitive domains. PMID- 26035649 TI - Leaderless Leaders: Leaders in Title Only. PMID- 26035648 TI - Human Papillomavirus Vaccination Among Adults and Children in 5 US States. AB - CONTEXT: The Centers for Disease Control and Prevention Advisory Committee for Immunization Practices has recommended human papillomavirus (HPV) vaccines for use in children and young adults for preventing HPV-related diseases, but HPV vaccine coverage is low in the United States. OBJECTIVE: To assess HPV vaccination among US adults and children and to identify characteristics associated with HPV vaccination. METHODS: We used the 2010 Behavioral Risk Factors Surveillance System data to examine HPV vaccine initiation and completion among adults aged 18 to 26 years and children aged 9 to 17 years in 5 US states. We performed a multivariate logistic regression to evaluate factors associated with HPV vaccination. RESULTS: We assessed the HPV vaccination status of 706 women and 560 men and 2201 girls and 2292 boys. In 2010, a total of 258 (41.6%) women and 21 (4.3%) men had initiated HPV vaccination. Of those vaccinated women, 182 (75%) completed the 3-dose vaccine series. Rural residence (adjusted odds ratio [aOR] = 0.37) and not having a Papanicolaou test (aOR = 0.44) were negatively associated with HPV vaccine initiation among women. Women who were aged 18 to 20 years (aOR = 2.93) were more likely to complete HPV vaccination. A total of 612 (24.6%) girls and 86 (5.2%) boys received 1 or more doses of HPV vaccines; 308 (50.3%) vaccinated girls and 14 (10.8%) vaccinated boys completed the vaccine series. Younger age (9-12 years: aOR = 0.09) and not receiving a seasonal influenza vaccine (aOR = 0.44) were negatively related to HPV vaccine initiation in girls. Girls were less likely to initiate and complete HPV vaccination if their parents did not have a routine checkup within 1 year. CONCLUSION: HPV vaccination in the United States remains below the Healthy People 2020 objective (80%). To increase HPV vaccination, strategies still need to focus on improving access to HPV vaccines and utilization of health services. PMID- 26035647 TI - HCV core protein uses multiple mechanisms to induce oxidative stress in human hepatoma Huh7 cells. AB - Hepatitis C virus (HCV) infection is accompanied by the induction of oxidative stress, mediated by several virus proteins, the most prominent being the nucleocapsid protein (HCV core). Here, using the truncated forms of HCV core, we have delineated several mechanisms by which it induces the oxidative stress. The N-terminal 36 amino acids of HCV core induced TGF?(?upbeta?)1-dependent expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4, both of which independently contributed to the production of reactive oxygen species (ROS). The same fragment also induced the expression of cyclo-oxygenase 2, which, however, made no input into ROS production. Amino acids 37-191 of HCV core up-regulated the transcription of a ROS generating enzyme cytochrome P450 2E1. Furthermore, the same fragment induced the expression of endoplasmic reticulum oxidoreductin 1?(?upalpha?). The latter triggered efflux of Ca2+ from ER to mitochondria via mitochondrial Ca2+ uniporter, leading to generation of superoxide anions, and possibly also H2O2. Suppression of any of these pathways in cells expressing the full-length core protein led to a partial inhibition of ROS production. Thus, HCV core causes oxidative stress via several independent pathways, each mediated by a distinct region of the protein. PMID- 26035650 TI - Effectiveness of Community-Based Minigrants to Increase Physical Activity and Decrease Sedentary Time in Youth. AB - OBJECTIVE: To determine the effectiveness of targeted grant funding for the implementation of multilevel community interventions to increase moderate to vigorous physical activity (MVPA) and decrease time spent sedentary among a large sample of youth in North Carolina. DESIGN: A repeated, cross-sectional, group randomized controlled trial design with a delayed treatment group. SETTING: Twenty counties in North Carolina. PARTICIPANTS: Analyses were conducted on 2138 youth, grades 4 to 8, who provided complete data across the 3 waves. INTERVENTION: The North Carolina Eat Smart, Move More Community Grants program consisted of 20 separate community interventions implemented by grantees that targeted increasing physical activity and/or decreasing sedentary time in youth. County grantees were pair-matched and randomized to receive funding for implementation in year 1 (2010-2011) or year 2 (2011-2012). MVPA/sedentary time was assessed via accelerometer with demographics assessed via self-report in 3 waves of data collection (fall 2010, 2011, and 2012). MAIN OUTCOME MEASURE: MVPA and sedentary time measured via accelerometry. RESULTS: After adjusting for covariates, there was no difference in MVPA between counties implementing in year 1 (2010-2011) and those implementing in year 2 (2011-2012; ie, waitlist controls) comparing data collection wave 1 to wave 2 (fall 2010-2011). A significant increase of 2.32 minutes per day of MVPA was observed following the implementation year across all counties as compared with the baseline year. Differences were largely driven by increased MVPA in elementary school youth (fourth and fifth grades). No significant changes in sedentary time were observed. CONCLUSIONS: Low-cost, high-reach mini-grants can have a small, but meaningful effect on children's MVPA, with greater effects seen in younger children. Future studies should examine characteristics of mini-grants projects that are associated with the greatest increases in MVPA among youth. PMID- 26035651 TI - Commentary on: "Comparison of 2 Orthotic Approaches in Children With Cerebral Palsy". PMID- 26035652 TI - Comparison of 2 Orthotic Approaches in Children With Cerebral Palsy. AB - PURPOSE: To compare dynamic ankle-foot orthoses (DAFOs) and adjustable dynamic response (ADR) ankle-foot orthoses (AFOs) in children with cerebral palsy. METHODS: A total of 10 children with cerebral palsy (4-12 years; 6 at Gross Motor Function Classification System level I, 4 at Gross Motor Function Classification System level III) and crouch and/or equinus gait wore DAFOs and ADR-AFOs, each for 4 weeks, in randomized order. Laboratory-based gait analysis, walking activity monitor, and parent-reported questionnaire outcomes were compared among braces and barefoot conditions. RESULTS: Children demonstrated better stride length (11-12 cm), hip extension (2 degrees -4 degrees ), and swing-phase dorsiflexion (9 degrees -17 degrees ) in both braces versus barefoot. Push-off power (0.3 W/kg) and knee extension (5 degrees ) were better in ADR-AFOs than in DAFOs. Parent satisfaction and walking activity (742 steps per day, 43 minutes per day) were higher for DAFOs. CONCLUSIONS: ADR-AFOs produce better knee extension and push-off power; DAFOs produce more normal ankle motion, greater parent satisfaction, and walking activity. Both braces provide improvements over barefoot. PMID- 26035653 TI - ? PMID- 26035654 TI - ? PMID- 26035655 TI - ? PMID- 26035656 TI - ? PMID- 26035657 TI - Evaluation of Quality of Life of Those Living near a Wind Farm. AB - OBJECTIVES: Health-related quality of life (HRQoL) can serve as a multidimensional means of evaluating the relationship between the presence of wind turbines in residential areas and their consequence for health. The purpose of this study was to determine whether a relationship exists between the presence of wind farms at different stages of development and the HRQoL of people living in their vicinity in Poland. METHOD: The instruments employed in this study were the SF-36v2, a questionnaire measuring self-reported health problems, and a sociodemographic questionnaire. The study involved 1277 people who lived within 2 km from a wind turbine. RESULTS: The highest overall QoL scores were obtained by respondents living the closest to wind turbines. The mental health, role emotional, and social functioning scores were significantly higher among respondents living near wind farms and wind-farm construction sites than among those living close to locations where wind farms were planned but where construction had not yet begun. Positive correlations were found between physical and mental component scores and reactions to the news of plans to construct a wind farm. Significant differences in physical and mental component scores were observed between residents who reacted calmly and those who responded with apprehension. Residents who expected the improvement of their financial standing as a result of the wind farm assessed their general health higher than those who did not expect to receive any economic benefits. The lowest QoL scores corresponded to frequent headaches, stomach aches, and back pain over the previous three months, as well as recurrent problems with falling asleep, anxiety, and a lack of acceptance of the project. CONCLUSION: The lowest overall QoL and general health scores were noted among residents of places where wind farm developments were either at the stage of planning or under construction. In order to find ways of reducing environmental stress and its adverse effects on health, it is necessary to conduct research on residents of places where a wind farm is either planned or under construction, or has just been completed. PMID- 26035658 TI - An ICF-Based Model for Implementing and Standardizing Multidisciplinary Obesity Rehabilitation Programs within the Healthcare System. AB - INTRODUCTION/OBJECTIVE: In this study, we aimed to design an ICF-based individual rehabilitation project for obese patients with comorbidities (IRPOb) integrated into the Rehab-CYCLE to standardize rehabilitative programs. This might facilitate the different health professionals involved in the continuum of care of obese patients to standardize rehabilitation interventions. METHODS: After training on the ICF and based on the relevant studies, ICF categories were identified in a formal consensus process by our multidisciplinary team. Thereafter, we defined an individual rehabilitation project based on a structured multi-disciplinary approach to obesity. RESULTS: the proposed IRPOb model identified the specific intervention areas (nutritional, physiotherapy, psychology, nursing), the short-term goals, the intervention modalities, the professionals involved and the assessment of the outcomes. Information was shared with the patient who signed informed consent. CONCLUSIONS: The model proposed provides the following advantages: (1) standardizes rehabilitative procedures; (2) facilitates the flow of congruent and updated information from the hospital to outpatient facilities, relatives, and care givers; (3) addresses organizational issues; (4) might serve as a benchmark for professionals who have limited specific expertise in rehabilitation of comorbid obese patients. PMID- 26035659 TI - Favourable changes of the risk-benefit ratio in alpine skiing. AB - During the past five decades recreational alpine skiing has become increasingly safer. The numerous annual media reports on ski injuries have to be interpreted on the basis of the tremendous numbers of skiers. These favourable changes seem primarily be due to the introduction of short carving skis, more rigid and comfortable ski boots, the use of protective gear like helmets, and the optimized preparation of ski slopes. The associated health benefits from skiing, especially arising from its association with a healthier life style, and possibly also from effects related to hypoxia preconditioning and increasing subjective vitality by natural elements clearly outweigh the health hazards. Technical improvements will likely help further reducing the injury risk. At least hypothetically, each individual skier could help to prevent injuries by the development of an appropriate physical fitness and responsible behaviour on ski slopes thereby optimizing the risk-benefit ratio of alpine skiing. PMID- 26035661 TI - Does treatment impact health outcomes for patients after acute coronary syndrome? AB - BACKGROUND: Mortality rates for acute coronary syndrome (ACS) patients are still very high all over the world. Our study aimed to investigate the impact of ACS treatment on cardiovascular (CV) mortality eight years following ACS. METHODS: A retrospective cohort study with a total of 613 patients was used. The data was collected from databases and medical records. An evidence-based treatment (EBT) algorithm was used based on the ESC guidelines. Logistic regression analysis and standardized odds ratios with 95% confidence interval (CI) were used for the risk assessment, with a p level<0.05 considered as significant. RESULTS: The median follow-up time in this study was 7.6 years. During follow-up 48.9% of the patients (n=300) died from CV and 207 (69%) for a relevant reason. For monotherapy ACE inhibitors and beta-blockers, and for fixed dose combined drugs ACE inhibitors and diuretics, were most frequently used. EBT was provided to 37.8% of patients. The EBT use (HR 0.541, CI 0.394-0.742, p<0.001) during follow up period was important for reducing CV mortality in ACS patients. CONCLUSIONS: The combined use of EBT significantly improved outcomes. The recurrent myocardial infarction and percutaneous coronary intervention patients were more frequent in EBT and it was beneficial for reducing CV mortality. PMID- 26035660 TI - Serum Biomarkers of Exposure to Perfluoroalkyl Substances in Relation to Serum Testosterone and Measures of Thyroid Function among Adults and Adolescents from NHANES 2011-2012. AB - Perfluoroalkyl substances (PFASs) are a group of environmentally-persistent chemicals that have been widely used in many industrial applications. There is human and animal evidence that PFASs may alter levels of reproductive and thyroid related hormones. However, human studies on the potential age-related effects of PFASs on these outcomes among males and females are limited. We explored the relationship between serum PFASs and serum total testosterone (T), thyroid stimulating hormone (TSH), and free and total triiodothyronine (FT3, TT3) and thyroxine (FT4, TT4) among males and females 12 to 80 years of age from the 2011 2012 cycle of the National Health and Nutrition Examination Survey. Associations were assessed using multiple linear regression models that were stratified on sex and age categories. Effect estimates from the majority of the adjusted models were not statistically significant. However, exposure to PFASs may be associated with increases in FT3, TT3, and FT4 among adult females, but during adolescence, PFASs may be related to increases in TSH among males and decreases in TSH among females. No significant relationships were observed between PFASs and T in any of the models. These findings suggest that exposure to PFASs may disrupt thyroid hormone homeostasis. PMID- 26035662 TI - Isolation, Virulence, and Antimicrobial Resistance of Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin Sensitive Staphylococcus aureus (MSSA) Strains from Oklahoma Retail Poultry Meats. AB - Staphylococcus aureus is one the top five pathogens causing domestically acquired foodborne illness in the U.S. Only a few studies are available related to the prevalence of S. aureus and MRSA in the U.S. retail poultry industry. The objectives of this study were to determine the prevalence of S. aureus (MSSA and MRSA) in retail chicken and turkey meats sold in Tulsa, Oklahoma and to characterize the recovered strains for their antimicrobial resistance and possession of toxin genes. A total of 167 (114 chicken and 53 turkey) retail poultry samples were used in this study. The chicken samples included 61 organic samples while the rest of the poultry samples were conventional. The overall prevalence of S. aureus was 57/106 (53.8%) in the conventional poultry samples and 25/61 (41%) in the organic ones. Prevalence in the turkey samples (64.2%) was higher than in the chicken ones (42.1%). Prevalence of S. aureus did not vary much between conventional (43.4%) and organic chicken samples (41%). Two chicken samples 2/114 (1.8%) were positive for MRSA. PFGE identified the two MRSA isolates as belonging to PFGE type USA300 (from conventional chicken) and USA 500 (from organic chicken) which are community acquired CA-MRSA suggesting a human based source of contamination. MLST and spa typing also supported this conclusion. A total of 168 Staphylococcus aureus isolates (101 chicken isolates and 67 turkey isolates) were screened for their antimicrobial susceptibility against 16 antimicrobials and their possession of 18 different toxin genes. Multidrug resistance was higher in the turkey isolates compared to the chicken ones and the percentage of resistance to most of the antimicrobials tested was also higher among the turkey isolates. The hemolysin hla and hld genes, enterotoxins seg and sei, and leucocidins lukE-lukD were more prevalent in the chicken isolates. The PVL gene lukS-lukF was detected only in chicken isolates including the MRSA ones. In conclusion, S. aureus is highly prevalent in poultry retail meats sold in Oklahoma with a very low presence of human-originated MRSA. Multidrug resistance is not only prevalent in the MRSA isolates, but also in many MSSA poultry strains, particularly turkey. PMID- 26035663 TI - Assessment of Industry-Induced Urban Human Health Risks Related to Benzo[a]pyrenebased on a Multimedia Fugacity Model: Case Study of Nanjing, China. AB - Large amounts of organic pollutants emitted from industries have accumulated and caused serious human health risks, especially in urban areas with rapid industrialization. This paper focused on the carcinogen benzo[a]pyrene (BaP) from industrial effluent and gaseous emissions, and established a multi-pathway exposure model based on a Level IV multimedia fugacity model to analyze the human health risks in a city that has undergone rapid industrialization. In this study, GIS tools combined with land-use data was introduced to analyze smaller spatial scales so as to enhance the spatial resolution of the results. An uncertainty analysis using a Monte Carlo simulation was also conducted to illustrate the rationale of the probabilistic assessment mode rather than deterministic assessment. Finally, the results of the case study in Nanjing, China indicated the annual average human cancer risk induced by local industrial emissions during 2002-2008 (lowest at 1.99x10(-6) in 2008 and highest at 3.34x10(-6) in 2004), which was lower than the USEPA prescriptive level (1x10(-6)-1x10(-4)) but cannot be neglected in the long term. The study results could not only instruct the BaP health risk management but also help future health risk prediction and control. PMID- 26035664 TI - Body Image and Nutritional Status Are Associated with Physical Activity in Men and Women: The ELSA-Brasil Study. AB - The association of body image dissatisfaction and obesity with physical activity is likely to differ according to gender. To investigate this hypothesis, we conducted a cross-sectional study among the ELSA-Brasil cohort members aged 34-65 years (n=13,286). The body image dissatisfaction was present even among normal weight individuals of both sexes and was associated with lesser chances of practicing moderate physical activity in women and intense physical activity in men. Men and women with central obesity were less prone to practice physical activity of high or moderate intensity. Overweight and obese men were more likely to report vigorous physical activity while obese women were less likely to report this level of physical activity. Body images as well as nutritional status are related to physical activity in both sexes, but the association with physical activity differs by gender. PMID- 26035665 TI - Water, sanitation, and hygiene in schools in low socio-economic regions in Nicaragua: a cross-sectional survey. AB - Water, sanitation, and hygiene (WaSH) in schools contributes to better health and educational outcomes among school-aged children. In 2012, UNICEF Nicaragua and partners conducted a cross-sectional survey of WaSH in 526 schools in 12 low socio-economic status municipalities in Nicaragua. The survey gathered information on: school characteristics; teacher and community participation; water and sanitation infrastructure; and hygiene education and habits. Survey results were analyzed for associations between variables. WaSH coverage was significantly higher in urban than rural areas. Presence of drinking water infrastructure (43%) was lower than sanitation infrastructure (64%). Eighty-one percent of schools had no hand washing stations and 74% of schools lacked soap. Sanitation facilities were not in use at 28% of schools with sanitation infrastructure and 26% of schools with water infrastructure had non-functional systems. Only 8% of schools had budgets to purchase toilet-cleaning supplies and 75% obtained supplies from students' families. This study generates transferable WaSH sector learnings and new insights from monitoring data. Results can be used by donors, service providers, and policy makers to better target resources in Nicaraguan schools. PMID- 26035667 TI - Disparities in Children's Blood Lead and Mercury Levels According to Community and Individual Socioeconomic Positions. AB - We aimed to examine the associations between blood lead and mercury levels and individual and community level socioeconomic positions (SEPs) in school-aged children. A longitudinal cohort study was performed in 33 elementary schools in 10 cities in Korea. Among a total of 6094 children included at baseline, the final study population, 2281 children followed-up biennially, were analyzed. The geometric mean (GM) levels of blood lead were 1.73 MUg/dL (range 0.02-9.26) and 1.56 MUg/dL (range 0.02-6.83) for male and female children, respectively. The blood lead levels were significantly higher in males, children living in rural areas, and those with lower individual SEP. The GM levels of blood mercury were 2.07 MUg/L (range 0.09-12.67) and 2.06 MUg/L (range 0.03-11.74) for males and females, respectively. Increased blood mercury levels were significantly associated with urban areas, higher individual SEP, and more deprived communities. The risk of high blood lead level was significantly higher for the lower individual SEP (odds ratio (OR) 2.18, 95% confidence interval (CI) 1.36 3.50 in the lowest educational attainment of the father), with a significant dose response relationship observed after adjusting for the community SEP. The association between high blood lead levels and lower individual SEP was much stronger in the more deprived communities (OR 2.88, 95% CI 1.27-6.53) than in the less deprived communities (OR 1.40, 95% CI 0.76-2.59), and showed a significant decreasing trend during the follow-up only in the less deprived communities. The risk of high blood mercury levels was higher in higher individual SEP (OR 0.64, 95% CI 0.40-1.03 in the lowest educational attainment of the father), with a significant dose-response relationship noted. Significant decreasing trends were observed during the follow-up both in the less and more deprived communities. From a public health point-of-view, community level intervention with different approaches for different metals is warranted to protect children from environmental exposure. PMID- 26035669 TI - Home-Based Exercise in Older Adults Recently Discharged From the Hospital for Cardiovascular Disease in China: Randomized Clinical Trial. AB - BACKGROUND: Exercise is important for fitness and recovery of older adults after hospitalization for treatment of cardiovascular disease. Home-based, nurse-led exercise programs may be beneficial. OBJECTIVE: The aim of this study was to test the effects of a low-intensity, home-based exercise protocol led by an advanced practice nurse on health-related quality of life (HRQOL), physical fitness, and left ventricular ejection fraction (LVEF) in older adults after hospital discharge with a cardiovascular disease diagnosis. METHODS: The study was randomized and single blinded. Seventy-seven older adults (>=75 years old, mean = 80.68 years old) were included; 32 subjects in the intervention and 29 in the control group completed the study. The low-intensity, home-based exercise protocol is composed of 14-type joint exercises and walking for 12 weeks. The main outcome measures were assessments on the Medical Outcomes Study Short-Form 36, the Senior Fitness Test, and LVEF at baseline and 12 weeks after hospital discharge. RESULTS: After 12 weeks, the intervention group showed significant improvements in HRQOL (physical functioning, role-physical, bodily pain, and vitality; p < .05) as well as on the Senior Fitness Test (chair stands, arm curls, Timed Up and Go, and 6-minute walk distance; p < .05); there was no significant improvement in LVEF (p = .56). CONCLUSIONS: The low-intensity, home based exercise led by an advanced practice nurse was effective in improving HRQOL and physical fitness. Adherence was high, and there were no adverse events related to exercise. PMID- 26035666 TI - Petroleum coke in the urban environment: a review of potential health effects. AB - Petroleum coke, or petcoke, is a granular coal-like industrial by-product that is separated during the refinement of heavy crude oil. Recently, the processing of material from Canadian oil sands in U.S. refineries has led to the appearance of large petcoke piles adjacent to urban communities in Detroit and Chicago. The purpose of this literature review is to assess what is known about the effects of petcoke exposure on human health. Toxicological studies in animals indicate that dermal or inhalation petcoke exposure does not lead to a significant risk for cancer development or reproductive and developmental effects. However, pulmonary inflammation was observed in long-term inhalation exposure studies. Epidemiological studies in coke oven workers have shown increased risk for cancer and chronic obstructive pulmonary diseases, but these studies are confounded by multiple industrial exposures, most notably to polycyclic aromatic hydrocarbons that are generated during petcoke production. The main threat to urban populations in the vicinity of petcoke piles is most likely fugitive dust emissions in the form of fine particulate matter. More research is required to determine whether petcoke fine particulate matter causes or exacerbates disease, either alone or in conjunction with other environmental contaminants. PMID- 26035670 TI - A Novel Direct Factor Xa Inhibitory Peptide with Anti-Platelet Aggregation Activity from Agkistrodon acutus Venom Hydrolysates. AB - Snake venom is a natural substance that contains numerous bioactive proteins and peptides, nearly all of which have been identified over the last several decades. In this study, we subjected snake venom to enzymatic hydrolysis to identify previously unreported bioactive peptides. The novel peptide ACH-11 with the sequence LTFPRIVFVLG was identified with both FXa inhibition and anti-platelet aggregation activities. ACH-11 inhibited the catalytic function of FXa towards its substrate S-2222 via a mixed model with a Ki value of 9.02 MUM and inhibited platelet aggregation induced by ADP and U46619 in a dose-dependent manner. Furthermore, ACH-11 exhibited potent antithrombotic activity in vivo. It reduced paralysis and death in an acute pulmonary thrombosis model by 90% and attenuated thrombosis weight in an arterio-venous shunt thrombosis model by 57.91%, both at a dose of 3 mg/kg. Additionally, a tail cutting bleeding time assay revealed that ACH-11 did not prolong bleeding time in mice at a dose of 3 mg/kg. Together, our results reveal that ACH-11 is a novel antithrombotic peptide exhibiting both FXa inhibition and anti-platelet aggregation activities, with a low bleeding risk. We believe that it could be a candidate or lead compound for new antithrombotic drug development. PMID- 26035671 TI - Seizure Prediction 6: [LINE SEPARATOR]From Mechanisms to Engineered Interventions for Epilepsy. PMID- 26035672 TI - Future of seizure prediction and intervention: closing the loop. AB - The ultimate goal of epilepsy therapies is to provide seizure control for all patients while eliminating side effects. Improved specificity of intervention through on-demand approaches may overcome many of the limitations of current intervention strategies. This article reviews the progress in seizure prediction and detection, potential new therapies to provide improved specificity, and devices to achieve these ends. Specifically, we discuss (1) potential signal modalities and algorithms for seizure detection and prediction, (2) closed-loop intervention approaches, and (3) hardware for implementing these algorithms and interventions. Seizure prediction and therapies maximize efficacy, whereas minimizing side effects through improved specificity may represent the future of epilepsy treatments. PMID- 26035675 TI - The role of inhibition in epileptic networks. AB - Inhibition plays many roles in cortical circuits, including coordination of network activity in different brain rhythms and neuronal clusters, gating of activity, gain control, and dictating the manner in which activity flows through the network. This latter is particularly relevant to epileptic states, when extreme hypersynchronous discharges can spread across cortical territories. We review these different physiological and pathological roles and discuss how inhibition can be compromised and why this predisposes the network to seizures. PMID- 26035674 TI - Role of multiple-scale modeling of epilepsy in seizure forecasting. AB - Over the past three decades, a number of seizure prediction, or forecasting, methods have been developed. Although major achievements were accomplished regarding the statistical evaluation of proposed algorithms, it is recognized that further progress is still necessary for clinical application in patients. The lack of physiological motivation can partly explain this limitation. Therefore, a natural question is raised: can computational models of epilepsy be used to improve these methods? Here, we review the literature on the multiple scale neural modeling of epilepsy and the use of such models to infer physiologic changes underlying epilepsy and epileptic seizures. The authors argue how these methods can be applied to advance the state-of-the-art in seizure forecasting. PMID- 26035673 TI - Conundrums of high-frequency oscillations (80-800 Hz) in the epileptic brain. AB - Pathological high-frequency oscillations (HFOs) (80-800 Hz) are considered biomarkers of epileptogenic tissue, but the underlying complex neuronal events are not well understood. Here, we identify and discuss several outstanding issues or conundrums in regards to the recording, analysis, and interpretation of HFOs in the epileptic brain to critically highlight what is known and what is not about these enigmatic events. High-frequency oscillations reflect a range of neuronal processes contributing to overlapping frequencies from the lower 80 Hz to the very fast spectral frequency bands. Given their complex neuronal nature, HFOs are extremely sensitive to recording conditions and analytical approaches. We provide a list of recommendations that could help to obtain comparable HFO signals in clinical and basic epilepsy research. Adopting basic standards will facilitate data sharing and interpretation that collectively will aid in understanding the role of HFOs in health and disease for translational purpose. PMID- 26035676 TI - Collaborating and sharing data in epilepsy research. AB - Technological advances are dramatically advancing translational research in Epilepsy. Neurophysiology, imaging, and metadata are now recorded digitally in most centers, enabling quantitative analysis. Basic and translational research opportunities to use these data are exploding, but academic and funding cultures prevent this potential from being realized. Research on epileptogenic networks, antiepileptic devices, and biomarkers could progress rapidly if collaborative efforts to digest this "big neuro data" could be organized. Higher temporal and spatial resolution data are driving the need for novel multidimensional visualization and analysis tools. Crowd-sourced science, the same that drives innovation in computer science, could easily be mobilized for these tasks, were it not for competition for funding, attribution, and lack of standard data formats and platforms. As these efforts mature, there is a great opportunity to advance Epilepsy research through data sharing and increase collaboration between the international research community. PMID- 26035677 TI - Nerve conduction studies after decompression in painful diabetic polyneuropathy. AB - PURPOSE: To investigate the influence of nerve decompression at potential entrapment sites in the lower extremity in painful diabetic polyneuropathy on nerve conduction study variables. METHODS: Forty-two patients with painful diabetic polyneuropathy were included in this prospective randomized controlled trial. Preoperative nerve conduction studies were performed bilaterally. Each patient underwent unilateral surgical decompression of the tibial nerve and common, superficial, and deep peroneal nerves. The contralateral side was used as a control: within-patient comparison. One year postoperatively, the nerve conduction studies were repeated. Univariate paired sample T-tests and a multivariate analysis of variance were performed to compare data. RESULTS: In univariate analysis of the peroneal nerve, the distal compound muscle action potential amplitude measured at the extensor digitorum brevis muscle of the intervention legs decreased significantly, as did the area drop measured at the extensor digitorum brevis muscle of the control legs. The distal motor latency measured at the extensor digitorum brevis muscle of the intervention legs increased significantly, as did the distal compound muscle action potential amplitude measured at the anterior tibial muscle of the control legs. For the tibial nerve, the distal compound muscle action potential duration decreased significantly in the control legs. The multivariate analysis showed no significance overall. CONCLUSIONS: Decompression of nerves of the lower extremity in patients with painful diabetic polyneuropathy has no beneficial effect on nerve conduction study variables 12 months after surgery. PMID- 26035679 TI - Pancreatitis: Alternatively activated macrophages mediate fibrosis. PMID- 26035680 TI - Pancreatic cancer: Pancreatic cancer exosomes prime the liver for metastasis. PMID- 26035681 TI - High School Football Players' Knowledge and Attitudes About Concussions. AB - OBJECTIVES: To assess high school (HS) football players' knowledge of concussions and to determine whether increased knowledge is correlated with better attitudes toward reporting concussion symptoms and abstaining from play. DESIGN: Two survey tools were used to assess athletes' knowledge and attitudes about concussions. Surveys collected information about demographics, knowledge about concussions, and attitudes about playing sports after a concussion. All athletes present completed one of the 2 surveys. A knowledge and attitude score for each survey was calculated. Frequencies and mean values were used to characterize the population; regression analysis, analysis of variance, and t tests were used to look for associations. SETTING: A football camp for HS athletes in the Cincinnati area. PARTICIPANTS: Male HS football players from competitive football programs in the Cincinnati area. INTERVENTION: None. MAIN OUTCOME MEASURE: Scores on knowledge and attitude sections; responses to individual questions. RESULTS: One hundred twenty (100%) athletes were enrolled although not every athlete responded to every question. Thirty (25%) reported history of a concussion; 82 (70%) reported receiving prior concussion education. More than 75% correctly recognized all concussion symptoms that were asked, except "feeling in a fog" [n = 63 (53%)]. One hundred nine (92%) recognized a risk of serious injury if they return to play too quickly. Sixty-four (54%) athletes would report symptoms of a concussion to their coach; 62 (53%) would continue to play with a headache from an injury. There was no association between knowledge score and attitude score (P = 0.08). CONCLUSIONS: Despite having knowledge about the symptoms and danger of concussions, many HS football athletes in our sample did not have a positive attitude toward reporting symptoms or abstaining from play after a concussion. CLINICAL RELEVANCE: Physicians should be aware that young athletes may not report concussion symptoms. PMID- 26035678 TI - Peroral endoscopic myotomy: an evolving treatment for achalasia. AB - Peroral endoscopic myotomy (POEM) was first performed in Japan in 2008 for uncomplicated achalasia. With excellent results, it was adopted by highly skilled endoscopists around the world and the indications for POEM were expanded to include advanced sigmoid achalasia, failed surgical myotomy, patients with previous endoscopic treatments and even other spastic oesophageal motility disorders. With increased uptake and performance of POEM, variations in technique and improved management of adverse events have been developed. Now, 6 years since the first case and with >3,000 procedures performed worldwide, long-term data has shown the efficacy of POEM to be long-lasting. A growing body of literature also exists pertaining to the learning curve, application of novel technologies, extended indications and physiologic changes with POEM. Ultimately, this once experimental procedure is evolving towards becoming the preferred treatment for achalasia and other spastic oesophageal motility disorders. PMID- 26035682 TI - Effect of Ankle Positioning During Hamstring Stretches for Improving Straight Leg Hip Flexion Motion. AB - OBJECTIVE: To compare the effects of stretching the hamstrings with the ankle in either a plantar-flexed (PF) or dorsiflexed (DF) position for improving straight leg hip flexion range of motion (ROM) over a 4-week period. DESIGN: Randomized, single-blinded, pretest, posttest design. SETTING: Athletic training facility. PARTICIPANTS: Each limb of 34 asymptomatic individuals (15 males, 19 females) was randomly assigned to one of the 3 groups. Twenty-four limbs received hamstring stretches with the ankle in DF, 24 limbs received hamstring stretches with the ankle in PF, and 20 limbs received no stretch (control). INDEPENDENT VARIABLES: Ankle position (PF, DF) during hamstring stretching. MAIN OUTCOME MEASURES: We measured pretest and posttest passive straight leg hip flexion ROM with the test ankle in a neutral position. For the intervention groups, the test limb was passively stretched with the ankle held in end range DF or PF for their respective group. Each stretch was held for 30 seconds for a total of 3 applications. Two treatment sessions were completed per week for a total of 4 weeks. The control limbs received no stretching during the 4-week period. We conducted 1-way analyses of covariance to determine significant changes in ROM between groups (P < 0.05). RESULTS: There was no significant difference between treatment groups (P = 0.90), but a significant difference was found for both the PF (P = 0.04) and DF (P = 0.01) groups when compared with the control group. CONCLUSIONS: Our findings indicate that both stretching the hamstrings in either PF or DF improve straight leg hip ROM compared with a control group. CLINICAL RELEVANCE: The results of this study should be considered by clinicians when determining the optimal stretching techniques aimed at increasing hamstring length. PMID- 26035683 TI - Dietary Supplements: Knowledge and Adverse Event Reporting Among American Medical Society for Sports Medicine Physicians. AB - OBJECTIVE: Certain dietary supplements (DSs) used by military populations pose a threat to overall readiness. This study assessed members of the American Medical Society for Sports Medicine (AMSSM) regarding their knowledge of DS use among their patients and reporting of suspected adverse events. DESIGN: A thirteen question retrospective, cross-sectional, Web-based survey sought data on practices regarding DSs and adverse event reporting. SETTING: Anonymous Web-based survey. PARTICIPANTS: Military and civilian sports medicine physicians. MAIN OUTCOME MEASURES: The primary finding of the study was how frequently practitioners report adverse events associated with DS use. RESULTS: A total of 311 physicians responded to the survey. Only 51% of respondents had a reliable source for information on DS safety and 58% routinely discussed DS use with their patients. Although a majority (71%) of respondents had encountered adverse events associated with DS use, few of those (10%) confirmed reporting such events. Reasons that physicians did not report adverse events were lack of knowledge regarding where to report (68%), how to report (61%), and availability of time (9%). CONCLUSIONS: Our results indicate that some AMSSM physicians are familiar with DSs and have encountered adverse events associated with their use. However, reporting of these adverse events to the appropriate agency is minimal at best. The significant gaps in physician knowledge regarding how and where to report such events indicate a need to educate physicians on this subject. CLINICAL RELEVANCE: The findings of this survey indicate the need for provider education on reporting adverse events associated with DS use. Although reporting of adverse events is essential for removing harmful DSs from the market, a majority of physicians have limited knowledge on this issue. Moreover, the survey provides insight into the barriers to physician reporting of adverse events. PMID- 26035684 TI - Decision-making and cognitive strategies. PMID- 26035685 TI - Nutrition regulation of male accessory gland growth and maturation in Tribolium castaneum. AB - Insulin/IGF-1 signaling (IIS) pathway is known to control growth, development and reproduction. Insulin-like peptide mediated body size plasticity in Drosophila melanogaster has been reported. Here, our studies showed that IIS pathway and nutrition regulate growth and maturation of the male accessory gland (MAG) in the red flour beetle, Tribolium castaneum. The size of MAG increased from day 1 to day 5 post-adult emergence (PAE). This increase in the size of MAG is contributed by an increase in cell size, but not cell number. The growth of MAG was impaired after double-stranded RNA (dsRNA)-mediated knockdown in the expression of genes coding for ILP3, InR, Chico, PI3k, AKT, and GATA1 involved in IIS pathway. Interestingly, starvation showed similar effects on the growth and maturation of MAG. The phenotypes observed in animals where IIS signaling pathway genes were knocked down are similar to the phenotypes observed after starving beetles for 5 days PAE. These data suggest that nutrition signals working through IIS pathway regulate maturation of MAG by promoting the growth of MAG cells. PMID- 26035686 TI - Mediators of First- Versus Second-generation Antipsychotic-related Mortality in Older Adults. AB - BACKGROUND: Observational studies of older adults showed higher mortality for first-generation antipsychotics than their second- generation counterparts, which led to US Food and Drug Administration warnings, but the actual mechanisms involved remain unclear. METHODS: A cohort of 9,060 initiators of first generation antipsychotics and 17,137 of second-generation antipsychotics enrolled in New Jersey and Pennsylvania Medicare were followed for 180 days. Medical events were assessed using diagnostic and procedure codes on inpatient billing claims. For the individual and joint set of medical events (mediators), we estimated the total, direct, and indirect effects of antipsychotic type (first versus second generation) on mortality on the risk ratio scale and the proportion mediated on the risk difference scale, obtaining 95% confidence intervals through bootstrapping. We performed bias analyses for false-negative mediator misclassification in claims data, with sensitivity ranging from 0.25 to 0.75. RESULTS: There were 3,199 deaths (outcomes), 862 cardiovascular events, 675 infectious events, and 491 hip fractures (potential mediators). Mortality was higher for first- than second-generation antipsychotic initiators (adjusted risk ratio: 1.14; 95% confidence interval: 1.06, 1.22). In naive analyses, that ignored potential misclassification, less than 4% of this difference was explained by any particular medical event. In bias analyses, the proportion mediated ranged from 6% to 16% for stroke, 3% to 9% for ventricular arrhythmia, 3% to 11% for myocardial infarction, 0% venous thromboembolism, 3% to 9% for pneumonia, 0% to 1% for other bacterial infection, and 1% to 3% for hip fracture. CONCLUSIONS: Acute cardiovascular events and pneumonia may explain part of the mortality difference between first- and second-generation antipsychotic initiators in this analysis. PMID- 26035687 TI - Adaptive sampling dual terahertz comb spectroscopy using dual free-running femtosecond lasers. AB - Terahertz (THz) dual comb spectroscopy (DCS) is a promising method for high accuracy, high-resolution, broadband THz spectroscopy because the mode-resolved THz comb spectrum includes both broadband THz radiation and narrow-line CW-THz radiation characteristics. In addition, all frequency modes of a THz comb can be phase-locked to a microwave frequency standard, providing excellent traceability. However, the need for stabilization of dual femtosecond lasers has often hindered its wide use. To overcome this limitation, here we have demonstrated adaptive sampling THz-DCS, allowing the use of free-running femtosecond lasers. To correct the fluctuation of the time and frequency scales caused by the laser timing jitter, an adaptive sampling clock is generated by dual THz-comb-referenced spectrum analysers and is used for a timing clock signal in a data acquisition board. The results not only indicated the successful implementation of THz-DCS with free-running lasers but also showed that this configuration outperforms standard THz-DCS with stabilized lasers due to the slight jitter remained in the stabilized lasers. PMID- 26035688 TI - The protective effect of lactoferrin on ventral mesencephalon neurons against MPP + is not connected with its iron binding ability. AB - Lactoferrin (Lf) can bind to lactoferrin receptor (LfR), leading to iron transport through the plasma membrane. Besides iron transportation, Lf also has antioxidant and anti-inflammatory properties. In the brain, Lf is only synthesized by activated microglia. LfR is present in blood vessels and nigral dopaminergic neurons. Both nigral iron accumulation and microglia activation is believed to be involved in Parkinson's disease (PD), moreover, increased Lf and LfR in dopaminergic neurons were found in PD cases and MPTP-intoxicated mice. How iron influences microglia to release Lf? Does Lf tend to transport iron to dopaminergic neurons leading to cell death or to protect dopaminergic neuron from neurotoxin? In this study, we observed that iron increased Lf synthesis in activated microglia. In ventral mesencephalon neurons, both iron-free Lf (apo-Lf) and iron-saturated Lf (holo-Lf) exerted neuroprotective effects against MPP(+) by mechanisms, believed to enhance the mitochondrial transmembrane potential, improve Cu/Zn-superoxide dismutase activity, increase Bcl-2 expression. Although apo-Lf but not holo-Lf chelated cellular iron, there was no difference between the two types of Lf in the neuroprotection. Our data indicate that iron overload increases the activated microglia releasing Lf. Lf plays protective role on ventral mesencephalon neurons against MPP(+), which is iron-chelating independent. PMID- 26035689 TI - Ovarian cancer stem cells induce the M2 polarization of macrophages through the PPARgamma and NF-kappaB pathways. AB - Increasing evidence suggests an association between cancer stem cells and the tumor microenvironment. Ovarian cancer stem cell (OCSC) factors can influence the tumor microenvironment and prognosis. However, the effects of OCSCs on macrophage M1/M2 polarization are not yet completely understood. In the present study, we evaluated the effects of OCSCs on macrophage M1/M2 polarization. In addition, we investigated whether the activation of the peroxisome proliferator-activated receptor gamma (PPARgamma)/nuclear factor-kappaB (NF-kappaB) pathway is involved in these effects, thus modulating the M1/M2 differentiation of monocytes into macrophages. The expression levels of markers of the M1 state, such as tumor necrosis factor (TNF)-alpha, inducible nitric oxide synthase (iNOS) and CD86, as well as those of markers of M2 activation, such as mannose receptor (MR), interleukin (IL)-10 and arginase-1 (Arg-1), were measured by RT-qPCR. We found that the OCSCs promoted the M2 polarization of Raw264.7 macrophages by upregulating the expression of MR, IL-10 and Arg-1, while the expression levels of M1 macrophages markers, including TNF-alpha, iNOS and CD86 were suppressed. In addition, treatment with OCSCs activated PPARgamma and suppressed NF-kappaB in the Raw264.7 cells. Furthermore, the PPARgamma, antagonist GW9662, attenuated the promoting effects of OCSCs on the M2 polarization of macrophages. To the best of our knowledge, the findings of the present study, provide the first evidence that OCSCs promote the M2 polarization of macrophages through the PPARgamma/NF-kappaB pathway. PMID- 26035690 TI - Uranium triamidoamine chemistry. AB - Triamidoamine (Tren) complexes of the p- and d-block elements have been well studied, and they display a diverse array of chemistry of academic, industrial and biological significance. Such in-depth investigations are not as widespread for Tren complexes of uranium, despite the general drive to better understand the chemical behaviour of uranium by virtue of its fundamental position within the nuclear sector. However, the chemistry of Tren-uranium complexes is characterised by the ability to stabilise otherwise reactive, multiply bonded main group donor atom ligands, construct uranium-metal bonds, promote small molecule activation, and support single molecule magnetism, all of which exploit the steric, electronic, thermodynamic and kinetic features of the Tren ligand system. This Feature Article presents a current account of the chemistry of Tren-uranium complexes. PMID- 26035691 TI - Depletion of histone deacetylase 1 inhibits metastatic abilities of gastric cancer cells by regulating the miR-34a/CD44 pathway. AB - Overexpression of histone deacetylases (HDACs) is associated with higher metastatic rates and a poor prognosis in gastric cancer. However, the underlying mechanisms involved remain unclear. The present study aimed to investigate the molecular pathways that are involved in HDAC1-mediated metastatic activities in gastric cancer cells. First we used a microRNA (miRNA or miR) microarray to screen potential miRNAs whose expression can be altered by HDAC1 depletion. Of these miRNAs, miR-34a is important as it is often inactivated in cancer cells and acts as a tumor suppressor for various types of cancer. The reverse transcription quantitative polymerase chain reaction (RT-qPCR) results confirmed that miR-34a was upregulated by HDAC1 knockdown. Cells depleted of HDAC1 had lower abilities to migrate, invade and adhere, which were restored by a miR-34a antagomiR. Depletion of HDAC1 also resulted in impaired microfilaments and microtubules, while co-transfection of the miR-34a antagomiR attenuated these changes in the cellular cytoskeleton. The HDAC1/miR-34a axis regulated the expression and activation of CD44 and its downstream factors including Bcl-2, Ras homolog family member A (RhoA), LIM domain kinase 1 (LIMK-1) and matrix metalloproteinase (MMP) 2. The latter three proteins were responsible for the organization of tubulin and actin cytoskeleton and the formation of cellular pseudopodia. In conclusion, results of the present study indicated that HDAC1 depletion inhibits the metastatic abilities of gastric cancer cells by regulating the miRNA-34a/CD44 pathway, which may be a potential target for the treatment of gastric cancer. PMID- 26035692 TI - Computerized training improves verbal working memory in patients with myalgic encephalomyelitis/chronic fatigue syndrome: A pilot study. AB - OBJECTIVE: Patients with myalgic encephalomyelitis/chronic fatigue syndrome experience cognitive difficulties. The aim of this study was to evaluate the effect of computerized training on working memory in this syndrome. DESIGN: Non randomized (quasi-experimental) study with no-treatment control group and non equivalent dependent variable design in a myalgic encephalomyelitis/chronic fatigue syndrome-cohort. SUBJECTS: Patients with myalgic encephalomyelitis/chronic fatigue syndrome who participated in a 6-month outpatient rehabilitation programme were included in the study. Eleven patients who showed signs of working memory deficit were recruited for additional memory training and 12 patients with no working memory deficit served as controls. METHODS: Cognitive training with computerized working memory tasks of increasing difficulty was performed 30-45 min/day, 5 days/week over a 5-week period. Short term and working memory tests (Digit Span - forward, backward, total) were used as primary outcome measures. Nine of the 11 patients were able to complete the training. RESULTS: Cognitive training increased working memory (p = 0.003) and general attention (p = 0.004) to the mean level. Short-term memory was also improved, but the difference was not statistically significant (p = 0.052) vs prior training. The control group did not show any significant improvement in primary outcome measures. CONCLUSION: Cognitive training may be a new treatment for patients with myalgic encephalomyelitis/chronic fatigue syndrome. PMID- 26035693 TI - Identifying enhanced cortico-basal ganglia loops associated with prolonged dance training. AB - Studies have revealed that prolonged, specialized training combined with higher cognitive conditioning induces enhanced brain alternation. In particular, dancers with long-term dance experience exhibit superior motor control and integration with their sensorimotor networks. However, little is known about the functional connectivity patterns of spontaneous intrinsic activities in the sensorimotor network of dancers. Our study examined the functional connectivity density (FCD) of dancers with a mean period of over 10 years of dance training in contrast with a matched non-dancer group without formal dance training using resting-state fMRI scans. FCD was mapped and analyzed, and the functional connectivity (FC) analyses were then performed based on the difference of FCD. Compared to the non-dancers, the dancers exhibited significantly increased FCD in the precentral gyri, postcentral gyri and bilateral putamen. Furthermore, the results of the FC analysis revealed enhanced connections between the middle cingulate cortex and the bilateral putamen and between the precentral and the postcentral gyri. All findings indicated an enhanced functional integration in the cortico-basal ganglia loops that govern motor control and integration in dancers. These findings might reflect improved sensorimotor function for the dancers consequent to long-term dance training. PMID- 26035695 TI - Hot Topics VII. PMID- 26035694 TI - CSN5 silencing reverses sorafenib resistance of human hepatocellular carcinoma HepG2 cells. AB - Hepatocellular carcinoma (HCC) is one of the most common tumor types, and is the third leading cause of cancer mortalities worldwide. A large number of patients with HCC are diagnosed at a late stage when the curative treatment of surgical resection and liver transplantation are no longer applicable. Sorafenib has been proved to improve overall survival in advanced HCC; however, drug resistance is common. The present study reported that the CSN5 is correlated with sorafenib resistance of the HCC cell line HepG2/S. Following silencing of CSN5, resistance to sorafenib was reversed, and multi-drug-resistance proteins, including as adenosine triphosphate binding cassette (ABC)B1, ABCC2 and ABCG2 as well as CDK6, cyclin D1 and B-cell lymphoma 2 were downregulated. In addition, it was demonstrated that the integrin beta-1, transforming growth factor-beta1 and nuclear factor-kappaB pathways were modified by CSN5. PMID- 26035696 TI - Procoagulant platelets and the pathways leading to cell death. AB - Platelets are critical mediators of thrombosis and hemostasis. In response to agonist, platelets aggregate to form a thrombus via ligand binding of the glycoprotein IIb/IIIa receptor. However, activated platelets are heterogeneous in nature and a subset of platelets stimulated by strong agonists support the assembly of the coagulation complexes. It is proposed that these "procoagulant" platelets have a unique role in hemostasis and thrombosis as the link between primary and secondary hemostasis, localizing the thrombin burst required for fibrin formation to micro-domains within the platelet thrombus. Loss of procoagulant potential leads to bleeding while an increase is linked with propensity to thrombosis. While many features of the procoagulant platelet are known, the exact nature of the procoagulant platelet remains controversial. It is noted that many of the morphological and biochemical features of procoagulant platelets are also features of the cyclophilin D necrosis pathway. This review will focus on the distinct roles of platelet subpopulations, the identity of the procoagulant platelet, and the potential role of the cell death pathways in regulating platelet procoagulant response. PMID- 26035697 TI - Centrifugal microfluidic platforms: advanced unit operations and applications. AB - Centrifugal microfluidics has evolved into a mature technology. Several major diagnostic companies either have products on the market or are currently evaluating centrifugal microfluidics for product development. The fields of application are widespread and include clinical chemistry, immunodiagnostics and protein analysis, cell handling, molecular diagnostics, as well as food, water, and soil analysis. Nevertheless, new fluidic functions and applications that expand the possibilities of centrifugal microfluidics are being introduced at a high pace. In this review, we first present an up-to-date comprehensive overview of centrifugal microfluidic unit operations. Then, we introduce the term "process chain" to review how these unit operations can be combined for the automation of laboratory workflows. Such aggregation of basic functionalities enables efficient fluidic design at a higher level of integration. Furthermore, we analyze how novel, ground-breaking unit operations may foster the integration of more complex applications. Among these are the storage of pneumatic energy to realize complex switching sequences or to pump liquids radially inward, as well as the complete pre-storage and release of reagents. In this context, centrifugal microfluidics provides major advantages over other microfluidic actuation principles: the pulse free inertial liquid propulsion provided by centrifugal microfluidics allows for closed fluidic systems that are free of any interfaces to external pumps. Processed volumes are easily scalable from nanoliters to milliliters. Volume forces can be adjusted by rotation and thus, even for very small volumes, surface forces may easily be overcome in the centrifugal gravity field which enables the efficient separation of nanoliter volumes from channels, chambers or sensor matrixes as well as the removal of any disturbing bubbles. In summary, centrifugal microfluidics takes advantage of a comprehensive set of fluidic unit operations such as liquid transport, metering, mixing and valving. The available unit operations cover the entire range of automated liquid handling requirements and enable efficient miniaturization, parallelization, and integration of assays. PMID- 26035698 TI - MiR-320e is a novel prognostic biomarker in colorectal cancer. AB - BACKGROUND: Advances in early detection and treatment have improved outcomes in patients with colorectal cancer (CRC). However, there remains a need for robust prognostic and predictive biomarkers. We conducted a systematic discovery and validation of microRNA (miRNA) biomarkers in two clinical trial cohorts of CRC patients. METHODS: We performed an initial 'discovery' phase using Affymetrix miRNA expression arrays to profile stage III CRC patients with and without tumour recurrence (n=50 per group) at 3-years of follow-up. All patients received adjuvant 5-fluorouracil (5-FU) plus oxaliplatin, that is, FOLFOX, treatment. During 'validation', we analysed miRNAs using qRT-PCR in an independent cohort of 237 stage II-IV CRC patients treated with 5-FU-based chemotherapy, as well as in normal colonic mucosa from 20 healthy subjects. Association with disease recurrence, disease-free survival (DFS) and overall survival (OS) was examined using Cox proportional hazard models. RESULTS: In the discovery cohort, miR-320e expression was significantly elevated in stage III colon cancers from patients with vs without recurrence (95% confidence interval (CI)=1.14-1.42; P<0.0001). These results were then independently validated in stage II and III tumours. Specifically, increased miR-320e expression was associated with poorer DFS (hazard ratio (HR)=1.65; 95% CI=1.27-2.13; P=0.0001) and OS (HR=1.78; 95% CI=1.31 2.41; P=0.0003) in stage III CRC patients. CONCLUSIONS: In two clinical trial cohorts, a systematic biomarker discovery and validation approach identified miR 320e to be a novel prognostic biomarker that is associated with adverse clinical outcome in stage III CRC patients treated with 5-FU-based adjuvant chemotherapy. These findings have important implications for the personalised management of CRC patients. PMID- 26035699 TI - The von Hippel-Lindau tumour suppressor gene: uncovering the expression of the pVHL172 isoform. AB - BACKGROUND: The von Hippel-Lindau (VHL) gene encodes two mRNA variants. Variant 1 encodes two protein isoforms, pVHL213 and pVHL160, that have been extensively documented in the literature. Variant 2 is produced by alternative splicing of exon 2 and encodes a pVHL isoform of 172 amino acids with a theoretical molecular weight of 19 kDa (pVHL172), the expression of which has never been demonstrated so far due to the absence of suitable antibodies. METHODS: We have generated an anti-pVHL monoclonal antibody (JD-1956) using pVHL172 recombinant protein. We tested the antibody against exogenous or endogenous expressed proteins in different cell lines. We identified the pVHL172 using a silencing RNA strategy. The epitope of the antibody was mapped using a peptide array. RESULTS: We efficiently detected the three different isoforms of pVHL in cell lines and tumorigenic tissues by western blotting and immunohistochemistry and confirmed for the first time the endogenous expression of pVHL172. CONCLUSIONS: The endogenous expression of the three isoforms and particularly the pVHL172 has never been shown before due to a lack of a highly specific antibody since none of the available commercial antibodies distinguish the three isoforms of pVHL in cells or in both normal and cancerous human tissues. Evidence of pVHL172 expression emphasises the need to further study its implication in renal tumorigenesis and VHL disease. PMID- 26035700 TI - Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC driven neuroblastoma: a Children's Oncology Group study. AB - BACKGROUND: MYCN amplification with subsequent MYCN protein overexpression is a powerful indicator of poor prognosis of neuroblastoma patients. Little is known regarding the prognostic significance of the homologous MYC protein expression in neuroblastoma. METHODS: Immunostaining for MYCN and MYC protein was performed on 357 undifferentiated/poorly differentiated neuroblastomas. Results were analysed with other prognostic markers. RESULTS: Sixty-seven (19%) tumours were MYCN(+), 38 (11%) were MYC(+), and one(0.3%) had both proteins(+). MYCN(+) tumours and MYC(+) tumours were more likely diagnosed in children>18months with stage4 disease. MYCN(+) tumours were associated with amplified MYCN, Unfavourable Histology (UH), and High-MKI (Mitosis-Karyorrhexis Index). MYC(+) tumours were also frequently UH but not associated with MYCN amplification, and more likely to have low-/intermediate-MKI. Favourable Histology patients without MYC/MYCN expressions exhibited the best survival (N=167, 89.7+/-5.5% 3-year EFS, 97.0+/ 3.2% 3-year OS), followed by UH patients without MYC/MYCN expressions (N=84, 63.1+/-13.6% 3-year EFS, 83.5+/-9.4% 3-year OS). MYCN(+)patients and MYC(+)patients had similar and significantly low (P<0.0001) survivals (46.2+/ 12.0% 3-year EFS, 63.2+/-12.1% 3-year OS and 43.4+/-23.1% 3-year EFS, 63.5+/ 19.2% 3-year OS, respectively). Notably, the prognostic impact imparted by MYC expression was independent from other markers. CONCLUSIONS: In this series, ~30% of neuroblastomas had augmented MYCN or MYC expression with dismal survivals. Prospective study of MYC/MYCN protein expression signature as a new biomarker for high-risk neuroblastomas should be conducted. PMID- 26035702 TI - Survival, quality-adjusted survival, and other clinical end points in older advanced non-small-cell lung cancer patients treated with albumin-bound paclitaxel. AB - BACKGROUND: This analysis compared the quality-adjusted survival and clinical outcomes of albumin-bound paclitaxel+carboplatin (nab-PC) vs solvent-based paclitaxel+carboplatin (sb-PC) as first-line therapy in advanced non-small-cell lung cancer (NSCLC) in older patients. METHODS: Using age-based subgroup data from a randomised Phase-3 clinical trial, nab-PC and sb-PC were compared with respect to overall response rate (ORR), overall survival (OS), progression-free survival (PFS), quality of life (QoL), safety/toxicity, and quality-adjusted time without symptoms or toxicity (Q-TWiST) with ages ?60 and ?70 years as cut points. RESULTS: Among patients aged ?60 years (N=546), nab-PC (N=265) significantly increased ORR and prolonged OS, despite a non-significant improvement in PFS, vs sb-PC (N=281). Nab-PC improved QoL and was associated with less neuropathy, arthralgia, and myalgia but resulted in more anaemia and thrombocytopenia. Nab-PC yielded significant Q-TWiST benefits (11.1 vs 9.8 months; 95% CI of gain: 0.2 2.6), with a relative Q-TWiST gain of 10.8% (ranging from 6.4% to 15.1% in threshold analysis). In the ?70 years age group, nab-PC showed similar, but non significant, ORR, PFS, and Q-TWiST benefits and significantly improved OS and QoL. CONCLUSION: Nab-PC as first-line therapy in older patients with advanced NSCLC increased ORR, OS, and QoL and resulted in quality-adjusted survival gains compared with standard sb-PC. PMID- 26035701 TI - Background risk of breast cancer influences the association between alcohol consumption and mammographic density. AB - BACKGROUND: Alcohol consumption has been suggested to increase risk of breast cancer through a mechanism that also increases mammographic density. Whether the association between alcohol consumption and mammographic density is modified by background breast cancer risk has, however, not been studied. METHODS: We conducted a population-based cross-sectional study of 53 060 Swedish women aged 40-74 years. Alcohol consumption was assessed using a web-based self-administered questionnaire. Mammographic density was measured using the fully-automated volumetric Volpara method. The Tyrer-Cuzick prediction model was used to estimate risk of developing breast cancer in the next 10 years. Linear regression models were used to evaluate the association between alcohol consumption and volumetric mammographic density and the potential influence of Tyrer-Cuzick breast cancer risk. RESULTS: Overall, increasing alcohol consumption was associated with higher absolute dense volume (cm(3)) and per cent dense volume (%). The association between alcohol consumption and absolute dense volume was most pronounced among women with the highest (?5%) Tyrer-Cuzick 10-year risk. Among high-risk women, women consuming 5.0-9.9, 10.0-19.9, 20.0-29.9, and 30.0-40.0 g of alcohol per day had 2.6 cm(3) (95% confidence interval (CI), 0.2-4.9), 2.9 cm(3) (95% CI, -0.6 to 6.3), 4.6 cm(3) (95% CI, 1.5-7.7), and 10.8 cm(3) (95% CI, 4.8-17.0) higher absolute dense volume, respectively, as compared with women abstaining from alcohol. A trend of increasing alcohol consumption and higher absolute dense volume was seen in women at low (?3%) risk, but not in women at moderate (3.0 4.9%) risk. CONCLUSION: Alcohol consumption may increase breast cancer risk through increasing mammographic density, particularly in women at high background risk of breast cancer. PMID- 26035703 TI - Evaluation of serum CEA, CYFRA21-1 and CA125 for the early detection of colorectal cancer using longitudinal preclinical samples. AB - BACKGROUND: Blood-borne biomarkers for early detection of colorectal cancer (CRC) could markedly increase screening uptake. The aim of this study was to evaluate serum carcinoembryonic antigen (CEA), CYFRA21-1 and CA125 for the early detection of CRC in an asymptomatic cohort. METHODS: This nested case-control study within UKCTOCS used 381 serial serum samples from 40 women subsequently diagnosed with CRC, 20 women subsequently diagnosed with benign disease and 40 matched non cancer controls with three to four samples per subject taken annually up to 4 years before diagnosis. CEA, CYFRA21-1 and CA125 were measured using validated assays and performance of markers evaluated for different pre-diagnosis time groups. RESULTS: CEA levels increased towards diagnosis in a third of all cases (half of late-stage cases), whereas longitudinal profiles were static in both benign and non-cancer controls. At a threshold of >5 ng ml(-1) the sensitivities for detecting CRC up to 1 and 4 years before clinical presentation were 25% and 13%, respectively, at 95% specificity. At a threshold of >2.5 ng ml(-1), sensitivities were 57.5% and 38.4%, respectively, with specificities of 81% and 83.5%. CYFRA21-1 and CA125 had no utility as screening markers and did not enhance CEA performance when used in combination. CEA gave average lead times of 17-24 months for test-positive cases. CONCLUSIONS: CEA is elevated in a significant proportion of individuals with preclinical CRC, but would not be useful alone as a screening tool. This work sets a baseline from which to develop panels of biomarkers which combine CEA for improved early detection of CRC. PMID- 26035704 TI - MTHFR C677T polymorphism interaction with heavy alcohol consumption increases head and neck carcinoma risk. AB - MTHFR C677T polymorphism has been indicated to be a risk factor for cancers, but its association with head and neck cancer (HNC) risk remains inconclusive. In the present study, we aimed to get a more precise estimation by performing a quantitative meta-analysis. Published papers up to Jun 2014 was searched and screened. Necessary information was rigorously extracted for data pooling and analyzing, and then, subgroup analyses on ethnicity, source of controls, sample size, tumor type, smoking and drinking status were also carried out. As a result, twenty-three case-control studies including 14298 subjects were included. The overall data failed to reveal a significant association between MTHFR C677T polymorphism and HNC risk (homozygote comparison model: OR = 1.16; 95%CI = 0.93 1.45; dominant model: OR = 1.05; 95%CI = .90-1.21; recessive model: OR = 1.14; 95%CI = 0.93-1.38). However, in the subgroup analysis about drinking status, increase risk was shown in the heavy drinking subgroup (TT vs CC: OR = 3.11; 95%CI = 1.52-3.02). In conclusion, the results of the present study suggest that Homozygous TT alleles of MTHFR C677T polymorphism might be a risk factor for HNC among individuals who have a heavy drinking history. Further studies are needed to get a more definitive conclusion. PMID- 26035705 TI - Impact of INICC Multidimensional Hand Hygiene Approach in ICUs in Four Cities in Argentina. AB - We evaluated the impact of the International Nosocomial Infection Control Consortium multidimensional approach to hand hygiene in 11 intensive care units in 4 cities in Argentina and analyzed predictors of poor hand hygiene compliance. We had a baseline period and a follow-up period. We observed 21 100 hand hygiene opportunities. Hand hygiene compliance increased from 28.3% to 64.8% (P = .0001). Males versus females (56.8% vs 66.4%; P < .001) and physicians versus nurses (46.6% vs 67.8%; P < .001) were significantly associated with poor hand hygiene compliance. PMID- 26035706 TI - Just-in-Time Training for High-Risk Low-Volume Therapies: An Approach to Ensure Patient Safety. AB - High-risk low-volume therapies are those therapies that are practiced infrequently and yet carry an increased risk to patients because of their complexity. Staff nurses are required to competently manage these therapies to treat patients' unique needs and optimize outcomes; however, maintaining competence is challenging. This article describes implementation of Just-in-Time Training, which requires validation of minimum competency of bedside nurses managing high-risk low-volume therapies through direct observation of a return demonstration competency checklist. PMID- 26035707 TI - Rates of Nursing Errors and Handoffs-Related Errors in a Medical Unit Following Implementation of a Standardized Nursing Handoff Form. AB - A standardized nursing handoff form was designed and implemented to improve handoff process, and rates of nursing errors were measured to determine the effectiveness of the intervention. This study was a prospective intervention study, using 1-group pretest-posttest quasi-experimental design, conducted on an inpatient medical unit. The rates of nursing errors decreased from 9.2 (95% confidence interval, 8.0-10.3) to 5.7 (95% confidence interval, 5.1-6.9) per 100 admissions (P < .001), comparing the pre- and postintervention periods. PMID- 26035708 TI - Using a Systems Engineering Initiative for Patient Safety to Evaluate a Hospital wide Daily Chlorhexidine Bathing Intervention. AB - We undertook a systems engineering approach to evaluate housewide implementation of daily chlorhexidine bathing. We performed direct observations of the bathing process and conducted provider and patient surveys. The main outcome was compliance with bathing using a checklist. Fifty-seven percent of baths had full compliance with the chlorhexidine bathing protocol. Additional time was the main barrier. Institutions undertaking daily chlorhexidine bathing should perform a rigorous assessment of implementation to optimize the benefits of this intervention. PMID- 26035709 TI - Pegfilgrastim Improves Survival of Lethally Irradiated Nonhuman Primates. AB - Leukocyte growth factors (LGF), such as filgrastim, pegfilgrastim and sargramostim, have been used to mitigate the hematologic symptoms of acute radiation syndrome (ARS) after radiation accidents. Although these pharmaceuticals are currently approved for treatment of chemotherapy-induced myelosuppression, such approval has not been granted for myelosuppression resulting from acute radiation exposure. Regulatory approval of drugs used to treat radiological or nuclear exposure injuries requires their development and testing in accordance with the Animal Efficacy Rule, set forth by the U.S. Food and Drug Administration. To date, filgrastim is the only LGF that has undergone efficacy assessment conducted under the Animal Efficacy Rule. To confirm the efficacy of another LGF with a shorter dosing regimen compared to filgrastim, we evaluated the use of pegfilgrastim (Neulasta((r))) in a lethal nonhuman primate (NHP) model of hematopoietic acute radiation syndrome (H-ARS). Rhesus macaques were exposed to 7.50 Gy total-body irradiation (the LD(50/60)), delivered at 0.80 Gy/min using linear accelerator 6 MV photons. Pegfilgrastim (300 MUg/kg, n = 23) or 5% dextrose in water (n = 23) was administered on day 1 and 8 postirradiation and all animals received medical management. Hematologic and physiologic parameters were evaluated for 60 days postirradiation. The primary, clinically relevant end point was survival to day 60; secondary end points included hematologic-related parameters. Pegfilgrastim significantly (P = 0.0014) increased 60 day survival to 91.3% (21/23) from 47.8% (11/23) in the control. Relative to the controls, pegfilgrastim also significantly: 1. decreased the median duration of neutropenia and thrombocytopenia; 2. improved the median time to recovery of absolute neutrophil count (ANC) >=500/MUL, ANC >=1,000/MUL and platelet (PLT) count >=20,000/MUL; 3. increased the mean ANC at nadir; and 4. decreased the incidence of Gram-negative bacteremia. These data demonstrate that pegfilgrastim is an additional medical countermeasure capable of increasing survival and neutrophil-related parameters when administered in an abbreviated schedule to a NHP model of lethal H-ARS. PMID- 26035710 TI - Formulation and in vitro, in vivo evaluation of effervescent floating sustained release imatinib mesylate tablet. AB - INTRODUCTION: Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets. METHODOLOGY: Floating sustained-release Imatinib mesylate tablets were prepared using the wet granulation method. Tablets were formulated using Hydroxypropyl Methylcellulose (HPMC K4M), with Sodium alginate (SA) and Carbomer 934P (CP) as release-retarding polymers, sodium bicarbonate (NaHCO3) as the effervescent agent and lactose as a filler. Floating behavior, in vitro drug release, and swelling index studies were conducted. Initial and total drug release duration was compared with a commercial tablet (Gleevec) in 0.1 N HCl (pH 1.2) at 37 +/- 0.5 degrees C for 24 hours. Tablets were then evaluated for various physical parameters, including weight variation, thickness, hardness, friability, and drug content. Consequently, 6 months of physical stability studies and in vitro gastro-retentive studies were conducted. RESULTS AND DISCUSSION: Statistical data analysis revealed that tablets containing a composition of 14.67% w/w HPMC K4M, 10.67%, w/w Na alginate, 1.33%, w/w Carbomer 934P and 9.33%, w/w NaHCO3 produced the most favorable formulation to develop 24-hour sustained-release tablets with optimum floating behavior and satisfactory physicochemical characteristics. Furthermore, in vitro release study revealed that the formulated SR tablet had significantly lower Cmax and higher Tmax compared to the conventional tablet (Gleevec). Thus, formulated SR tablets preserved persistent concentration of plasma up to 24 hours. CONCLUSION: In conclusion, in order to suggest a better drug delivery system with constant favorable release, resulting in optimized absorption and less side effects, formulated CP-HPMC-SA based imatinib mesylate floating sustained-release tablets can be a promising candidate for cancer chemotherapy. PMID- 26035711 TI - Genome and Transcriptome of Clostridium phytofermentans, Catalyst for the Direct Conversion of Plant Feedstocks to Fuels. AB - Clostridium phytofermentans was isolated from forest soil and is distinguished by its capacity to directly ferment plant cell wall polysaccharides into ethanol as the primary product, suggesting that it possesses unusual catabolic pathways. The objective of the present study was to understand the molecular mechanisms of biomass conversion to ethanol in a single organism, Clostridium phytofermentans, by analyzing its complete genome and transcriptome during growth on plant carbohydrates. The saccharolytic versatility of C. phytofermentans is reflected in a diversity of genes encoding ATP-binding cassette sugar transporters and glycoside hydrolases, many of which may have been acquired through horizontal gene transfer. These genes are frequently organized as operons that may be controlled individually by the many transcriptional regulators identified in the genome. Preferential ethanol production may be due to high levels of expression of multiple ethanol dehydrogenases and additional pathways maximizing ethanol yield. The genome also encodes three different proteinaceous bacterial microcompartments with the capacity to compartmentalize pathways that divert fermentation intermediates to various products. These characteristics make C. phytofermentans an attractive resource for improving the efficiency and speed of biomass conversion to biofuels. PMID- 26035712 TI - Interaction between the Natural Components in Danhong Injection (DHI) with Serum Albumin (SA) and the Influence of the Coexisting Multi-Components on the SaB-BSA Binding System: Fluorescence and Molecular Docking Studies. AB - Danhong injection (DHI) is a widely used Chinese Materia Medica standardized product for the clinical treatment of ischemic encephalopathy and coronary heart disease. The bindings of eight natural components in DHI between bovine serum albumin (BSA) were studied by fluorescence spectroscopy technology and molecular docking. According to the results, the quenching process of salvianolic acid B and hydroxysafflor yellow A was a static quenching procedure through the analysis of quenching data by the Stern-Volmer equation, the modified Stern-Volmer equation, and the modified Scatchard equation. Meanwhile, syringin (Syr) enhanced the fluorescence of BSA, and the data were analyzed using the Lineweaver-Burk equation. Molecular docking suggested that all of these natural components bind to serum albumin at the site I location. Further competitive experiments of SaB confirmed the result of molecular docking studies duo to the displacement of warfarin by SaB. Base on these studies, we selected SaB as a research target because it presented the strongest binding ability to BSA and investigated the influence of the multi-components coexisting in DHI on the interaction between the components of the SaB-BSA binding system. The participation of these natural components in DHI affected the interaction between the components of the SaB-BSA system. Therefore, when DHI is used in mammals, SaB is released from serum albumin more quickly than it is used alone. This work would provide a new experiment basis for revealing the scientific principle of compatibility for Traditional Chinese Medicine. PMID- 26035714 TI - Marital Satisfaction Trends in Hong Kong Between 2002 and 2012. AB - Macrosocial changes may generate influences on marital quality. This study used data from the 2002-2012 Knowledge, Attitude, and Practice surveys conducted by the Family Planning Association of Hong Kong to track the trends of marital satisfaction of both husbands and wives over a 10-year period in Hong Kong, with associated factors. Results indicated that 85% of the husbands and around 80% of the wives reported that they were satisfied with their marital relationships, and no significant changes in general were observed for them between 2002 and 2012 except for some subgroups. Husbands aged 45-49 years, in employment and whose monthly household income between 25,000 HKD and 39,999 HKD, reported marital satisfaction decreased over the past 10 years and wives with primary education or below also reported a decreasing trend during this period. Education and family income had positive influences on the husbands' and wives' marital satisfaction, and husbands were more likely to be sensitive to the unemployment. Less than one third of couples needed professional counseling on family-related issues, and couple conflicts and work-family conflicts were the urgent needs that should be given priority in delivering services. The implications of this study are discussed in the Chinese context of Hong Kong. PMID- 26035713 TI - Nuclear Receptor 4A1 (NR4A1) as a Drug Target for Renal Cell Adenocarcinoma. AB - The orphan nuclear receptor NR4A1 exhibits pro-oncogenic activity in cancer cell lines. NR4A1 activates mTOR signaling, regulates genes such as thioredoxin domain containing 5 and isocitrate dehydrogenase 1 that maintain low oxidative stress, and coactivates specificity protein 1 (Sp1)-regulated pro-survival and growth promoting genes. Transfection of renal cell carcinoma (RCC) ACHN and 786-O cells with oligonucleotides that target NR4A1 results in a 40-60% decrease in cell proliferation and induction of apoptosis. Moreover, knockdown of NR4A1 in RCC cells decreased bcl-2, survivin and epidermal growth factor receptor expression, inhibited of mTOR signaling, induced oxidative and endoplasmic reticulum stress, and decreased TXNDC5 and IDH1. We have recently demonstrated that selected 1,1 bis(3'-indolyl)-1-(p-substituted phenyl)methane (C-DIM) compounds including the p hydroxyphenyl (DIM-C-pPhOH) and p-carboxymethyl (DIM-C-pPhCO2Me) analogs bind NR4A1 and act as antagonists. Both DIM-C-pPhOH and DIM-C-pPhCO2Me inhibited growth and induced apoptosis in ACHN and 786-O cells, and the functional and genomic effects of the NR4A1 antagonists were comparable to those observed after NR4A1 knockdown. These results indicate that NR4A1 antagonists target multiple growth promoting and pro-survival pathways in RCC cells and in tumors (xenograft) and represent a novel chemotherapy for treating RCC. PMID- 26035715 TI - U0126 inhibits pancreatic cancer progression via the KRAS signaling pathway in a zebrafish xenotransplantation model. AB - Pancreatic cancer is one of the most aggressive human cancers, and the pharmaceutical outcomes for its treatment remain disappointing. Proper animal models will provide an efficient platform for investigating novel drugs, and the zebrafish has become one of the most promising and comprehensive model animal in cancer research. In the present study, we used a novel xenograft model in zebrafish by transplanting human pancreatic cancer cells to study the progression and metastasis of pancreatic cancer cells and to assay the pharmacological effects of new drug U0126 in vivo. We first established a primary xenograft model of pancreatic cancer by injecting human pancreatic cancer cells into both live larval and adult zebrafish, and then investigated the behaviors of CM-DiI-labeled human pancreatic cancer cells. Subsequently, we tested the potential of this model for drug screening by evaluating a known small-molecule inhibitor, U0126, which targets the KRAS signaling pathway. Cells with KRAS mutations exhibited significant proliferative and migratory behaviors and invaded the zebrafish vasculature system. In contrast, the proliferation and migration of Mia PaCa-2 cells in zebrafish larvae were substantially repressed following U0126 treatment. These results suggest that zebrafish xenotransplantation can be used as a simple and efficient tool to screen and identify new anti-pancreatic cancer compounds. PMID- 26035717 TI - Measuring graphene adhesion using atomic force microscopy with a microsphere tip. AB - Van der Waals adhesion between graphene and various substrates has an important impact on the physical properties, device applications and nanomanufacturing processes of graphene. Here we report a general, high-throughput and reliable method that can measure adhesion energies between ultraflat graphene and a broad range of materials using atomic force microscopy with a microsphere tip. In our experiments, only van der Waals force between the tip and a graphene flake is measured. The Maugis-Dugdale theory is employed to convert the measured adhesion force using AFM to the adhesion energy. The ultraflatness of monolayer graphene on mica eliminates the effect of graphene surface roughness on the adhesion, while roughness of the microsphere tip is addressed by the modified Rumpf model. Adhesion energies of monolayer graphene to SiO2 and Cu are obtained as 0.46 and 0.75 J m(-2), respectively. This work provides valuable insight into the mechanism of graphene adhesion and can readily extend to the adhesion measurement for other 2D nanomaterials. PMID- 26035718 TI - Ramucirumab as second-line treatment for patients with metastatic esophagogastric adenocarcinoma. AB - Ramucirumab is a fully humanized monoclonal antibody targeting the extracellular domain of the VEGF receptor 2. It prevents ligand binding to VEGF receptor 2 and receptor-mediated pathway activation in endothelial cells. After promising Phase I trial results in a variety of tumor types, two pivotal placebo-controlled Phase III trials conducted in patients with pretreated metastatic esophagogastric adenocarcinoma demonstrated significant clinical activity regarding the prolongation of overall survival both as monotherapy (REGARD study) and in combination with paclitaxel (RAINBOW study). Currently, ramucirumab is being investigated in the first-line treatment of esophagogastric adenocarcinoma in combination with capecitabine and cisplatin in a Phase III trial (RAINFALL). PMID- 26035716 TI - Immobilization of FLAG-Tagged Recombinant Adeno-Associated Virus 2 onto Tissue Engineering Scaffolds for the Improvement of Transgene Delivery in Cell Transplants. AB - The technology of virus-based genetic modification in tissue engineering has provided the opportunity to produce more flexible and versatile biomaterials for transplantation. Localizing the transgene expression with increased efficiency is critical for tissue engineering as well as a challenge for virus-based gene delivery. In this study, we tagged the VP2 protein of type 2 adeno-associated virus (AAV) with a 3*FLAG plasmid at the N-terminus and packaged a FLAG-tagged recombinant AAV2 chimeric mutant. The mutant AAVs were immobilized onto the tissue engineering scaffolds with crosslinked anti-FLAG antibodies by N succinimidyl-3-(2-pyridyldithiol) propionate (SPDP). Cultured cells were seeded to scaffolds to form 3D transplants, and then tested for viral transduction both in vitro and in vivo. The results showed that our FLAG-tagged AAV2 exerted similar transduction efficiency compared with the wild type AAV2 when infected cultured cells. Following immobilization onto the scaffolds of PLGA or gelatin sponge with anti-FLAG antibodies, the viral mediated transgene expression was significantly improved and more localized. Our data demonstrated that the mutation of AAV capsid targeted for antibody-based immobilization could be a practical approach for more efficient and precise transgene delivery. It was also suggested that the immobilization of AAV might have attractive potentials in applications of tissue engineering involving the targeted gene manipulation in 3D tissue cultures. PMID- 26035719 TI - Tivantinib (ARQ197) in hepatocellular carcinoma. AB - Here we review the development of tivantinib, a selective oral inhibitor of c MET. The initially identified dose and schedule for clinical use was 360 mg twice daily. Biological considerations and early results suggested its activity against hepatocellular carcinoma after progression on sorafenib. The results of randomized Phase II study in this setting have already been reported; while in the overall population, the risk of progression was reduced by 36% (HR: 0.64; 90% CI: 0.43-0.94; p = 0.04), in the pre-defined MET-high population median overall survival (7.2 vs 3.8 months; p = 0.01), median time to progression (2.7 vs 1.4 months; p = 0.03) as well as disease control rate (50 vs 20%), were increased by tivantinib. During study conduction, tivantinib dose was amended to 240 mg twice daily, due to a high incidence of neutropenia, without losing clinical efficacy. Presently, a global Phase III trial is being conducted. PMID- 26035720 TI - Colorectal cancer: using blood samples and tumor tissue to detect K-ras mutations. AB - We performed a meta-analysis to assess whether blood can be substituted for tumor tissue in K-ras mutation testing. PubMed, EMBASE, MEDLINE, and BIOSIS databases were searched. Twenty-three studies including 1261 patients were included. The pooled overall sensitivity, specificity, and concordance rate were 0.69 (95% CI: 0.59-0.78), 0.96 (95% CI: 0.93-0.97), and 0.86 (95% CI: 0.82-0.89), respectively. Subgroup analysis indicated that plasma (sensitivity: 0.74; mutation rate: 0.34) exhibited superior sensitivity compared with serum (sensitivity: 0.45; mutation rate: 0.24). We conclude that blood is a suitable substitute for tumor tissue in K-ras mutation testing. K-ras mutation positivity in blood can be used to identify patients who should not receive EGFR monoclonal antibody therapy, but the absence of blood positivity does not necessarily imply negativity. PMID- 26035721 TI - Controlling Bimetallic Nanostructures by the Microemulsion Method with Subnanometer Resolution Using a Prediction Model. AB - We present a theoretical model to predict the atomic structure of Au/Pt nanoparticles synthesized in microemulsions. Excellent concordance with the experimental results shows that the structure of the nanoparticles can be controlled at subnanometer resolution simply by changing the reactant concentration. The results of this study not only offer a better understanding of the complex mechanisms governing reactions in microemulsions, but open up a simple new way to synthesize bimetallic nanoparticles with ad hoc controlled nanostructures. PMID- 26035723 TI - Capsaicin 8% Patch for Central and Peripheral Neuropathic Pain of Persons with Incomplete Spinal Cord Injury: Two Case Reports. AB - Neuropathic pain after spinal cord injury is common and often refractory to standard treatments. The capsaicin 8% patch is a Food and Drug Administration approved treatment of neuropathic pain in postherpetic neuralgia and has demonstrated significant efficacy in human immunodeficiency virus-autonomic neuropathy. The patch defunctionalizes transient receptor potential vanilloid 1 receptors, impairing cutaneous nociceptors for a prolonged period (i.e., 8-12 wks) with no systemic side effects. A retrospective review was conducted on the effects of the patch in two patients with spinal cord injury and neuropathic pain refractory to standard treatments. Two weeks after application, both patients reported complete pain relief. Average onset of relief of 4 days and average duration of relief of 197 days, requiring only one to four applications per year, paralleled findings reported in postherpetic neuralgia and human immunodeficiency virus-autonomic neuropathy trials. Upregulation of capsaicin-sensitive transient receptor potential vanilloid 1 receptors after spinal cord injury has been reported. The capsaicin 8% patch is a promising therapeutic agent for neuropathic pain in spinal cord injury. PMID- 26035722 TI - Identification of Putative ORF5 Protein of Porcine Circovirus Type 2 and Functional Analysis of GFP-Fused ORF5 Protein. AB - Porcine circovirus type 2 (PCV2) is the essential infectious agent responsible for causing porcine circovirus-associated diseases in pigs. To date, eleven RNAs and five viral proteins of PCV2 have been detected. Here, we identified a novel viral gene within the PCV2 genome, termed ORF5, that exists at both the transcriptional and translational level during productive infection of PCV2 in porcine alveolar macrophages 3D4/2 (PAMs). Northern blot analysis was used to demonstrate that the ORF5 gene measures 180 bp in length and overlaps completely with ORF1 when read in the same direction. Site-directed mutagenesis was used to show that the ORF5 protein is not essential for PCV2 replication. To investigate the biological functions of the novel protein, we constructed a recombinant eukaryotic expression plasmid capable of expressing PCV2 ORF5. The results show that the GFP-tagged PCV2 ORF5 protein localizes to the endoplasmic reticulum (ER), is degraded via the proteasome, inhibits PAM growth and prolongs the S phase of the cell cycle. Further studies show that the GFP-tagged PCV2 ORF5 protein induces ER stress and activates NF-kappaB, which was further confirmed by a significant upregulation in IL-6, IL-8 and COX-2 expression. In addition, five cellular proteins (GPNMB, CYP1A1, YWHAB, ZNF511 and SRSF3) were found to interact with ORF5 via yeast two-hybrid assay. These findings provide novel information on the identification and functional analysis of the PCV2 ORF5 protein and are likely to be of benefit in elucidating the molecular mechanisms of PCV2 pathogenicity. However, additional experiments are needed to validate the expression and function of the ORF5 protein during PCV2 infection in vitro before any definitive conclusion can be drawn. PMID- 26035724 TI - Effect of Whole-Body Vibration on Balance Using Posturography and Balance Tests in Postmenopausal Women. AB - OBJECTIVE: The authors examined the impacts of whole-body vibration (WBV) applications on balance control in postmenopausal women using clinical balance tests and computerized static posturography. DESIGN: Patients were randomly divided into two groups and treated with WBV and/or home-based balance coordination exercises (BCEs). Patients in the WBV-BCE group were asked to stand on the platform in standing, squat, and deep squat positions. During each position, 30-sec vibration (30-35 Hz) and 60-sec rest periods were applied twice (20 sessions in total). The BCE program was performed by subjects twice per day. All subjects were evaluated before and after treatment using the Timed Up and Go test and the Berg Balance Scale (BBS). The fall index and the Fourier index were assessed via computerized static posturography. RESULTS: Sixty patients were recruited for the study, but only 42 patients (21 in each group) completed it. Fall index and the total values of the Fourier index 2-4 and Fourier index 5-6 frequencies indicated a significant improvement in the WBV-BCE group (P < 0.05). Both groups showed significant improvements in the Berg Balance Scale and Timed Up and Go test (P < 0.05). CONCLUSIONS: The ease of applying WBV furthermore supports its inclusion in daily treatment protocols for age-related decline in balance performance in women and improved balance and mobility measures associated with increased fall risk. PMID- 26035725 TI - Peroneal Stimulation for Foot Drop After Stroke: A Systematic Review. AB - The purpose of this systematic review was to summarize the effect of daily use of single-channel foot drop stimulation among persons with stroke. Randomized controlled trials were searched using electronic databases through May 2014. Six randomized controlled trials were included, involving 820 participants. Gait speed was the most common outcome measured. Other common outcomes included Timed Up and Go, modified Emory Functional Ambulation Profile, Berg Balance Scale, Physiologic Cost Index, Six-Minute Walk Test, quality-of-life, and lower extremity Fugl-Meyer. In summary, foot drop stimulation and ankle foot orthoses seem effective and "equivalent" for increasing gait speed. Other outcomes that consistently improved in both groups were the Timed Up and Go and Six-Minute Walk Test. Foot drop stimulation was more effective compared with ankle foot orthosis for decreasing Physiologic Cost Index and seemed to be preferred by participants. Physical therapy may facilitate improvement in both foot drop stimulation and ankle foot orthosis groups. PMID- 26035726 TI - Importance of an Optimal Fluoroscopic View When Performing Cervical Transforaminal Epidural Injections: RE: Pneumocephalus During Cervical Transforaminal Epidural Steroid Injections: A Case Report. PMID- 26035727 TI - Handheld dynamometry for plantar flexors? PMID- 26035728 TI - Selective injury of fornical column in a patient with mild traumatic brain injury. PMID- 26035729 TI - Influence of various acidic beverages on tooth erosion. Evaluation by a new method. AB - MATERIAL & METHODS: We have analyzed the loss of enamel and dentine after exposure to different non-alcoholic drinks with a simple new method using bovine teeth. 100 enamel and 100 dentine specimens from freshly extracted bovine incisors were randomly attributed to 10 groups (n=10 for enamel and dentine each). Prior to the start of the experiment all specimens were weighed using a precision balance. The mean initial masses (SD) were 35.8 mg (7.2) for enamel and 24.7 mg (7.0) for dentine. No statistically significant differences were found between groups for initial masses (p>0.05, ANOVA with Bonferroni post hoc test). Thereafter, all specimens of one group were simultaneously placed in 200 ml of the following fluids: Coca-Cola, Coca-Cola light, Sprite, apple juice, Red Bull, orange juice, Bonaqua Fruits (Mango-Acai), tap water, chlorinated swimming pool water, and lemon juice. Fluids were continuously ventilated at 37 degrees C for 7 days. Thereafter the specimens were weighed again and the mean mass loss was calculated. RESULTS: The values were (enamel/dentine): Coca-Cola 7.5 mg/6.6 mg; Coca-Cola light 5.2 mg/3.5 mg, Sprite 26.1 mg/17.7 mg, apple juice 27.1 mg/15.2 mg, Red Bull 16.6 mg/17.0 mg, orange juice 24.3 mg/20.2 mg, Bonaqua Fruits (Mango Acai) 17.8 mg/16.2 mg, tap water -0.2 mg/-0.3 mg, swimming pool water -0.3 mg/ 0.2 mg, and lemon juice 32.0 mg/28.3 mg. From all drinks, Cola and Cola light showed the least erosivity (p<0.001, ANOVA with Bonferroni post hoc test) whereas lemon juice showed statistically significant higher erosivity than all other drinks except Sprite and apple juice (p<0.01, ANOVA with Bonferroni post hoc test). CONCLUSIONS: In conclusion, erosivity of common non-alcoholic drinks varies widely. For example, Sprite, apple juice, and orange juice are about five times more erosive than Coca-Cola light. The findings from the present study should be taken into account in choosing a diet that provides satisfactory nutrition while minimizing tooth erosion. PMID- 26035730 TI - Dual-Enzyme-Loaded Multifunctional Hybrid Nanogel System for Pathological Responsive Ultrasound Imaging and T2-Weighted Magnetic Resonance Imaging. AB - A dual-enzyme-loaded multifunctional hybrid nanogel probe (SPIO@GCS/acryl/biotin CAT/SOD-gel, or SGC) has been developed for dual-modality pathological responsive ultrasound (US) imaging and enhanced T2-weighted magnetic resonance (MR) imaging. This probe is composed of functionalized superparamagnetic iron oxide particles, a dual enzyme species (catalase and superoxide dismutase), and a polysaccharide cationic polymer glycol chitosan gel. The dual-modality US/MR imaging capabilities of the hybrid nanogel for responsive US imaging and enhanced T2 weighted MR imaging have been evaluated both in vitro and in vivo. These results show that the hybrid nanogel SGC can exhibit efficient dual-enzyme biocatalysis with pathological species for responsive US imaging. SGC also demonstrates increased accumulation in acidic environments for enhanced T2-weighted MR imaging. Further research on these nanogel systems may lead to the development of more efficient US/MR contrast agents. PMID- 26035731 TI - Multi-particle collision dynamics algorithm for nematic fluids. AB - Research on transport, self-assembly and defect dynamics within confined, flowing liquid crystals requires versatile and computationally efficient mesoscopic algorithms to account for fluctuating nematohydrodynamic interactions. We present a multi-particle collision dynamics (MPCD) based algorithm to simulate liquid crystal hydrodynamic and director fields in two and three dimensions. The nematic MPCD method is shown to successfully reproduce the features of a nematic liquid crystal, including a nematic-isotropic phase transition with hysteresis in 3D, defect dynamics, isotropic Frank elastic coefficients, tumbling and shear alignment regimes and boundary condition-dependent order parameter fields. PMID- 26035732 TI - Colloidal properties and behaviors of 3 nm primary particles of detonation nanodiamonds in aqueous media. AB - This study was aimed to reveal the principal colloidal properties of the aqueous dispersion of extremely small primary single-crystalline diamond particles in water. Together with the non-diamond layer, the size of the colloidal species is 2.8 +/- 0.6 nm as found via DLS of the initial 5.00 wt/vol% hydrosol. Anionic dyes are readily adsorbed on the colloidal species. This is in line with the positive zeta-potential. The critical coagulation concentrations of the 0.19 wt/vol% nanodiamond hydrosol were determined with a set of inorganic electrolytes and anionic surfactants. The data are in line with the Schulze-Hardy rule for "positive" sols. The fulfillment of the lyotropic (Hofmeister) series was also observed for single-charged anions. The abnormal influence of alkali gives evidence of the acidic nature of the positive charge of the nanodiamond species. Application of acid-base indicators allows estimating the value of the interfacial electrical potential of the nanodiamond particles. Upon dilution from 5.00% to 0.01%, the colloidal system under study exhibits unusual changes. The average size increases ca. ten-fold as determined by DLS. The TEM images support this observation. At the same time, the viscosity drops. This phenomenon was explained in terms of the so-called periodic colloidal structures (colloidal crystals) in concentrated solutions. PMID- 26035733 TI - Pyridine Nucleosides Neopetrosides A and B from a Marine Neopetrosia sp. Sponge. Synthesis of Neopetroside A and Its beta-Riboside Analogue. AB - Neopetrosides A (1) and B (2), new naturally occurring ribosides of nicotinic acid with extremely rare alpha-N-glycoside linkages and residues of p hydroxybenzoic and pyrrole-2-carboxylic acids attached to C-5', were isolated from a marine Neopetrosia sp. sponge. Structures 1 and 2 were determined by NMR and MS methods and confirmed by the synthesis of 1 and its beta-riboside analogue (3). Neopetroside A (1) upregulates mitochondrial functions in cardiomyocytes. PMID- 26035736 TI - Ohmic Heating-Assisted Synthesis of 3-Arylquinolin-4(1H)-ones by a Reusable and Ligand-Free Suzuki-Miyaura Reaction in Water. AB - Potential bioactive 3-arylquinolin-4(1H)-ones were synthesized under ohmic heating using an efficient, reusable, and ligand-free protocol developed for the Suzuki-Miyaura coupling of 1-substituted-3-iodoquinolin-4(1H)-ones with several boronic acids in water using Pd(OAc)2 as a catalyst and tetrabutylammonium bromide (TBAB) as the phase transfer catalyst. Good substrate generality, ease of execution, short reaction time, and practicability make this method exploitable for the generation of libraries of B ring-substituted 3-arylquinolin-4(1H)-ones. After a simple workup, the Pd/catalyst-H2O-TBAB system could be reused for at least seven cycles without significant loss of activity. PMID- 26035734 TI - Controlled Dissolution of Griseofulvin Solid Dispersions from Electrosprayed Enteric Polymer Micromatrix Particles: Physicochemical Characterization and in Vitro Evaluation. AB - The oral bioavailability of a poorly water-soluble drug is often inadequate for the desired therapeutic effect. The bioavailability can be improved by enhancing the physicochemical properties of the drug (e.g., dissolution rate, permeation across the gastrointestinal tract). Other approach include shielding the drug from the gastric metabolism and targeted drug release to obtain optimal drug absorption. In this study, a poorly water-soluble model drug, griseofulvin, was encapsulated as disordered solid dispersions into Eudragit L 100-55 enteric polymer micromatrix particles, which were produced by electrospraying. Similar micromatrix particles were also produced with griseofulvin-loaded thermally oxidized mesoporous silicon (TOPSi) nanoparticles dispersed to the polymer micromatrices. The in vitro drug dissolution at pH 1.2 and 6.8, and permeation at pH 7.4 across Caco-2/HT29 cell monolayers from the micromatrix particles, were investigated. The micromatrix particles were found to be gastro-resistant, while at pH 6.8 the griseofulvin was released very rapidly in a fast-dissolving form. Compared to free griseofulvin, the permeability of encapsulated griseofulvin across the intestinal cell monolayers was greatly improved, particularly for the TOPSi-doped micromatrix particles. The griseofulvin solid dispersions were stable during storage for 6 months at accelerated conditions. Overall, the method developed here could prove to be a useful oral drug delivery solution for improving the bioavailability of poorly water-soluble or otherwise problematic drugs. PMID- 26035737 TI - microRNA regulatory mechanism by which PLLA aligned nanofibers influence PC12 cell differentiation. AB - OBJECTIVE: Aligned nanofibers (AFs) are regarded as promising biomaterials in nerve tissue engineering. However, a full understanding of the biocompatibility of AFs at the molecular level is still challenging. Therefore, the present study focused on identifying the microRNA (miRNA)-mediated regulatory mechanism by which poly-L-lactic acid (PLLA) AFs influence PC12 cell differentiation. APPROACH: Firstly, the effects of PLLA random nanofibers (RFs)/AFs and PLLA films (control) on the biological responses of PC12 cells that are associated with neuronal differentiation were examined. Then, SOLiD sequencing and cDNA microarray were employed to profile the expressions of miRNAs and mRNAs. The target genes of the misregulated miRNAs were predicted and compared with the mRNA profile data. Functions of the matched target genes (the intersection between the predicted target genes and the experimentally-determined, misregulated genes) were analyzed. MAIN RESULTS: The results revealed that neurites spread in various directions in control and RF groups. In the AF group, most neurites extended in parallel with each other. The glucose consumption and lactic acid production in the RF and AF groups were higher than those in the control group. Compared with the control group, 42 and 94 miRNAs were significantly dysregulated in the RF and AF groups, respectively. By comparing the predicted target genes with the mRNA profile data, five and 87 matched target genes were found in the RF and AF groups, respectively. Three of the matched target genes in the AF group were found to be associated with neuronal differentiation, whereas none had this association in the RF group. The PLLA AFs induced the dysregulation of miRNAs that regulate many biological functions, including axonal guidance, lipid metabolism and long-term potentiation. In particular, two miRNA-matched target gene-biological function modules associated with neuronal differentiation were identified as follows: (1) miR-23b, miR-18a, miR-107 and miR-103 regulate the Rras2 and Nf1 gene and thereby, affect cytoskeleton regulation and MAPK pathway; (2) miR-92a, miR-339-5p, miR-25, miR-125a-5p, miR-351 and miR-19b co-regulate the Pafah1b1 gene, affecting PC12 cell migration and differentiation. SIGNIFICANCE: This work demonstrates a bioinformatic approach to accomplish miRNA-mRNA profile integrative analysis and provides more insights for understanding the regulatory mechanism of miRNA in AFs affecting neuronal differentiation. These findings will be greatly beneficial for the application and design of AFs in nerve tissue engineering. PMID- 26035738 TI - Asymmetric Synthesis of Triarylmethanes by Rhodium-Catalyzed Enantioselective Arylation of Diarylmethylamines with Arylboroxines. AB - The reaction of racemic diarylmethylamines, (Ar(1)Ar(2)CHNR2), where Ar(1) is substituted with a 2-hydroxy group, with arylboroxines (Ar(3)BO)3 in the presence of a chiral diene-rhodium catalyst gave high yields of chiral triarylmethanes (Ar(1)Ar(2)CH*Ar(3)) with high enantioselectivity (up to 97% ee). The reaction is assumed to proceed through o-quinone methide intermediates which undergo Rh catalyzed asymmetric 1,4-addition of the arylboron reagents. PMID- 26035739 TI - Hydrothermal Synthesis and Dehydration of CaTeO3(H2O): An Original Route to Generate New CaTeO3 Polymorphs. AB - CaTeO3(H2O) was obtained from microwave-assisted hydrothermal synthesis as a polycrystalline sample material. The dehydration reaction was followed by thermal analysis (thermogravimetric/differential scanning calorimetry) and temperature dependent powder X-ray diffraction and leads to a new delta-CaTeO3 polymorph. The crystal structures of CaTeO3(H2O) and delta-CaTeO3 were solved ab initio from PXRD data. CaTeO3(H2O) is non-centrosymmetric: P21cn; Z = 8; a = 14.785 49(4) A; b = 6.791 94(3) A; c = 8.062 62(3) A. This layered structure is related to the ones of MTeO3(H2O) (M = Sr, Ba) with layers built of edge-sharing [CaO6(H2O)] polyhedra and are capped of each side by [Te(IV)O3E] units. Adjacent layers are stacked along the a-axis and are held together by H-bonds via the water molecules. The dehydration reaction starts above 120 degrees C. The transformation of CaTeO3(H2O) into delta-CaTeO3 (P21ca; Z = 8; a = 13.3647(6) A; b = 6.5330(3) A; c = 8.1896(3) A) results from topotactic process with layer condensation along the a-axis and the 1/2b? translation of intermediate layers. Thus, delta-CaTeO3 stays non-centrosymmetric. The characteristic layers of CaTeO3(H2O) are also maintained in delta-CaTeO3 but held together via van der Waals bonds instead of H-bonds through water molecules. Electron localization function and dipole moment calculations were also performed. For both structures and over each unit cell, the dipole moments are aligned antiparallel with net dipole moments of 3.94 and 0.47 D for CaTeO3(H2O) and delta-CaTeO3, respectively. The temperature-resolved second harmonic generation (TR-SHG) measurements, between 30 and 400 degrees C, show the decreasing of the SHG intensity response from 0.39 to 0.06 * quartz for CaTeO3(H2O) and delta-CaTeO3, respectively. PMID- 26035740 TI - Carbohydrate mouth rinse and caffeine improves high-intensity interval running capacity when carbohydrate restricted. AB - We tested the hypothesis that carbohydrate mouth rinsing, alone or in combination with caffeine, augments high-intensity interval (HIT) running capacity undertaken in a carbohydrate-restricted state. Carbohydrate restriction was achieved by performing high-intensity running to volitional exhaustion in the evening prior to the main experimental trials and further refraining from carbohydrate intake in the post-exercise and overnight period. On the subsequent morning, eight males performed 45-min steady-state (SS) exercise (65% [Formula: see text]) followed by HIT running to exhaustion (1-min at 80% [Formula: see text]interspersed with 1 min walking at 6 km/h). Subjects completed 3 trials consisting of placebo capsules (administered immediately prior to SS and immediately before HIT) and placebo mouth rinse at 4-min intervals during HIT (PLACEBO), placebo capsules but 10% carbohydrate mouth rinse (CMR) at corresponding time-points or finally, caffeine capsules (200 mg per dose) plus 10% carbohydrate mouth rinse (CAFF + CMR) at corresponding time-points. Heart rate, capillary glucose, lactate, glycerol and NEFA were not different at exhaustion during HIT (P > 0.05). However, HIT capacity was different (P < 0.05) between all pair-wise comparisons such that CAFF + CMR (65 +/- 26 min) was superior to CMR (52 +/- 23 min) and PLACEBO (36 +/- 22 min). We conclude that carbohydrate mouth rinsing and caffeine ingestion improves exercise capacity undertaken in carbohydrate-restricted states. Such nutritional strategies may be advantageous for those athletes who deliberately incorporate elements of training in carbohydrate-restricted states (i.e. the train-low paradigm) into their overall training programme in an attempt to strategically enhance mitochondrial adaptations of skeletal muscle. PMID- 26035741 TI - Effects of Scriptaid on the Histone Acetylation, DNA Methylation and Development of Buffalo Somatic Cell Nuclear Transfer Embryos. AB - The present study was undertaken to examine the effect of Scriptaid treatment on histone acetylation, DNA methylation, expression of genes related to histone acetylation, and development of buffalo somatic cell nuclear transfer (SCNT) embryos. Treatment of buffalo SCNT embryos with 500 nM Scriptaid for 24 h resulted in a significant increase in the blastocyst formation rate (28.2% vs. 13.6%, p<0.05). Meanwhile, treatment of buffalo SCNT embryos with Scriptaid also resulted in higher acetylation levels of H3K18 and lower methylation levels of global DNA at the blastocyst stage, which was similar to fertilized counterparts. The expression levels of CBP, p300, HAT1, Dnmt1, and Dnmt3a in SCNT embryos treated with Scriptaid were significantly lower than the control group at the eight-cell stage (p<0.05), but the expression of HAT1 and Dnmt1a was higher than the control group at the blastocyst stage (p<0.05). When 96 blastocysts developed from Scriptaid-treated SCNT embryos were transferred into 48 recipients, 11 recipients (22.9%) became pregnant, whereas only one recipient (11.1%) became pregnant following transfer of 18 blastocysts developed from untreated SCNT embryos into nine recipients. These results indicate that treatment of buffalo SCNT embryos with Scriptaid can improve their developmental competence, and this action is mediated by resulting in a similar histone acetylation level and global DNA methylation level compared to in vitro-fertilized embryos through regulating the expression pattern of genes related to histone acetylation and DNA methylation. PMID- 26035743 TI - Impact of withholding breastfeeding at the time of vaccination on the immunogenicity of oral rotavirus vaccine--a randomized trial. AB - BACKGROUND: Breast milk contains anti-rotavirus IgA antibodies and other innate immune factors that inhibit rotavirus replication in vitro. These factors could diminish the immunogenicity of oral rotavirus vaccines, particularly if breastfeeding occurs close to the time of vaccine administration. METHODS: Between April 2011 and November 2012, we conducted an open label, randomized trial to compare the immunogenicity of Rotarix (RV1) in infants whose breastfeeding was withheld one hour before through one hour after vaccination with that in infants breastfed at the time of vaccination. The trial was conducted in the peri-urban area of Ibrahim Hyderi in Karachi, Pakistan. Both groups received three doses of RV1 at 6, 10 and 14 weeks of age. Seroconversion (anti-rotavirus IgA antibodies >= 20 U/mL in subjects seronegative at 6 weeks of age) following three vaccine doses (6, 10 and 14 weeks) was determined at 18 weeks of age (primary objective) and seroconversion following two doses (6 and 10 weeks) was determined at 14 weeks of age (secondary objective). RESULTS: Four hundred eligible infants were randomly assigned in a 1:1 ratio between the withholding breastfeeding and immediate breastfeeding arms. Overall, 353 (88.3%) infants completed the study according to protocol; 181 in the withholding breastfeeding group and 172 in the immediate breastfeeding group. After three RV1 doses, anti-rotavirus IgA antibody seroconversion was 28.2% (95% CI: 22.1; 35.1) in the withholding arm and 37.8% (95% CI: 30.9; 45.2) in the immediate breastfeeding arm (difference: -9.6% [95% CI: -19.2; 0.2] p = 0.07). After two doses of RV1, seroconversion was 16.6% (95% CI: 11.9; 22.7) in the withholding arm and 29.1% (95% CI: 22.8, 36.3) in the immediate breastfeeding arm (difference: -12.5% [95% CI: -21.2,-3.8] p = 0.005). CONCLUSIONS: Withholding breastfeeding around the time of RV1 vaccine administration did not lead to increased anti-rotavirus IgA seroconversion compared with that seen with a breastfeed at the time of vaccination. On the contrary, IgA seroconversion in infants immediately breastfed tended to be higher than in those withheld from a feeding. Our findings suggest that breastfeeding should be continued adlib around the time of rotavirus vaccination and withholding breastfeeding at that time is unlikely to improve the vaccine immunogenicity. TRIAL REGISTRATION: ClinicalTrials.gov NCT01199874. PMID- 26035746 TI - Drugs for psoriasis. PMID- 26035744 TI - Prognostic Value and Clinicopathology Significance of MicroRNA-200c Expression in Cancer: A Meta-Analysis. AB - MiR-200c has been shown to be related to cancer formation and progression. However, the prognostic and clinicopathologic significance of miR-200c expression in cancer remain inconclusive. We carried out this systematic review and meta analysis to investigate the prognostic value of miR-200c expression in cancer. Pooled hazard ratios (HRs) of miR-200c for overall survival (OS) and progression free survival (PFS) were calculated to measure the effective value of miR-200c expression on prognosis. The association between miR-200c expression and clinical significance was measured by odds ratios (ORs). Twenty-three studies were included in our meta-analysis. We found that miR-200c was not significantly correlated with OS (HR = 1.41, 95%Cl: 0.95-2.10; P = 0.09) and PFS (HR = 1.12, 95%Cl: 0.68-1.84; P = 0.67) in cancer. In our subgroup analysis, higher expression of miR-200c was significantly associated with poor OS in blood (HR = 2.10, 95%CI: 1.52-2.90, P<0.00001). Moreover, in clinicopathology analysis, miR 200c expression in blood was significantly associated with TNM stage, lymph node metastasis and distant metastasis. MiR-200c may have the potential to become a new blood biomarker to monitor cancer prognosis and progression. PMID- 26035745 TI - Effects of Inhaled Corticosteroids on the Growth Plates of Infant Rats. AB - The most significant adverse effect of inhaled steroid administration in children is suppression of hypothalamic-pituitary-adrenal axis responsiveness and suppression of growth. This study evaluates the effects of inhaled corticosteroids on the growth plates in infant rats. Rats aged 10 days were divided into five groups. Low and high doses of budesonide and fluticasone propionate (50-200-250 mcg/day) were applied with a modified spacer for 10 days. The rat's tibias were then removed and the effects of the steroids on the growth plates were compared. Growth cartilage chondrocyte proliferation and apoptosis rates; IGF-1 and glucocorticoid receptor levels; and resting, proliferative, hypertrophic, and total zone (TZ) measurements were compared using immunohistochemical-staining methods. With high doses of fluticasone, growth plates were affected much more than with high doses of budesonide (p = 0.01). Fluticasone, particularly at a dose of 250 mcg, inhibited the growth plate with an intensive negative impact on all parameters. PMID- 26035747 TI - Nivolumab (Opdivo) for metastatic melanoma and metastatic NSCLC. PMID- 26035748 TI - Recombinant human parathyroid hormone (Natpara). PMID- 26035749 TI - Drugs for psoriatic arthritis. PMID- 26035751 TI - ? PMID- 26035750 TI - Increased Intrinsic Connectivity of the Default Mode Network in Temporal Lobe Epilepsy: Evidence from Resting-State MEG Recordings. AB - The electrophysiological signature of resting state oscillatory functional connectivity within the default mode network (DMN) during spike-free periods in temporal lobe epilepsy (TLE) remains unclear. Using magnetoencephalographic (MEG) recordings, this study investigated how the connectivity within the DMN was altered in TLE, and we examined the effect of lateralized TLE on functional connectivity. Sixteen medically intractable TLE patients and 22 controls participated in this study. Whole-scalp 306-channel MEG epochs without interictal spikes generated from both MEG and EEG data were analyzed using a minimum norm estimate (MNE) and source-based imaginary coherence analysis. With this processing, we obtained the cortical activation and functional connectivity within the DMN. The functional connectivity was increased between DMN and the right medial temporal (MT) region at the delta band and between DMN and the bilateral anterior cingulate cortex (ACC) regions at the theta band. The functional change was associated with the lateralization of TLE. The right TLE showed enhanced DMN connectivity with the right MT while the left TLE demonstrated increased DMN connectivity with the bilateral MT. There was no lateralization effect of TLE upon the DMN connectivity with ACC. These findings suggest that the resting-state functional connectivity within the DMN is reinforced in temporal lobe epilepsy during spike-free periods. Future studies are needed to examine if the altered functional connectivity can be used as a biomarker for treatment responses, cognitive dysfunction and prognosis in patients with TLE. PMID- 26035752 TI - Effect of Chronic Pioglitazone Treatment on Hepatic Gene Expression Profile in Obese C57BL/6J Mice. AB - Pioglitazone, a selective ligand of peroxisome proliferator-activated receptor gamma (PPARgamma), is an insulin sensitizer drug that is being used in a number of insulin-resistant conditions, including non-alcoholic fatty liver disease (NAFLD). However, there is a discrepancy between preclinical and clinical data in the literature and the benefits of pioglitazone treatment as well as the precise mechanism of action remain unclear. In the present study, we determined the effect of chronic pioglitazone treatment on hepatic gene expression profile in diet-induced obesity (DIO) C57BL/6J mice in order to understand the mechanisms of NAFLD induced by PPARgamma agonists. DIO mice were treated with pioglitazone (25 mg/kg/day) for 38 days, the gene expression profile in liver was evaluated using Affymetrix Mouse GeneChip 1.0 ST array. Pioglitazone treatment resulted in exacerbated hepatic steatosis and increased hepatic triglyceride and free fatty acids concentrations, though significantly increased the glucose infusion rate in hyperinsulinemic-euglycemic clamp test. The differentially expressed genes in liver of pioglitazone treated vs. untreated mice include 260 upregulated and 86 downregulated genes. Gene Ontology based enrichment analysis suggests that inflammation response is transcriptionally downregulated, while lipid metabolism is transcriptionally upregulated. This may underlie the observed aggravating liver steatosis and ameliorated systemic insulin resistance in DIO mice. PMID- 26035753 TI - The Arginine/ADMA Ratio Is Related to the Prevention of Atherosclerotic Plaques in Hypercholesterolemic Rabbits When Giving a Combined Therapy with Atorvastatine and Arginine. AB - Supplementation with arginine in combination with atorvastatin is more efficient in reducing the size of an atherosclerotic plaque than treatment with a statin or arginine alone in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits. We evaluated the mechanism behind this feature by exploring the role of the arginine/asymmetric dimethylarginine (ADMA) ratio, which is the substrate and inhibitor of nitric oxide synthase (NOS) and thereby nitric oxide (NO), respectively. METHODS: Rabbits were fed either an arginine diet (group A, n = 9), standard rabbit chow plus atorvastatin (group S, n = 8), standard rabbit chow plus an arginine diet with atorvastatin (group SA, n = 8) or standard rabbit chow (group C, n = 9) as control. Blood was sampled and the aorta was harvested for topographic and histological analysis. Plasma levels of arginine, ADMA, cholesterol and nitric oxide were determined and the arginine/ADMA ratio was calculated. RESULTS: The decrease in ADMA levels over time was significantly correlated to fewer aortic lesions in the distal aorta and total aorta. The arginine/ADMA ratio was correlated to cholesterol levels and decrease in cholesterol levels over time in the SA group. A lower arginine/ADMA ratio was significantly correlated to lower NO levels in the S and C group. DISCUSSION: A balance between arginine and ADMA is an important indicator in the prevention of the development of atherosclerotic plaques. PMID- 26035754 TI - Human Papillomavirus E6/E7-Specific siRNA Potentiates the Effect of Radiotherapy for Cervical Cancer in Vitro and in Vivo. AB - The functional inactivation of TP53 and Rb tumor suppressor proteins by the HPV derived E6 and E7 oncoproteins is likely an important step in cervical carcinogenesis. We have previously shown siRNA technology to selectively silence both E6/E7 oncogenes and demonstrated that the synthetic siRNAs could specifically block its expression in HPV-positive cervical cancer cells. Herein, we investigated the potentiality of E6/E7 siRNA candidates as radiosensitizers of radiotherapy for the human cervical carcinomas. HeLa and SiHa cells were transfected with HPV E6/E7 siRNA; the combined cytotoxic effect of E6/E7 siRNA and radiation was assessed by using the cell viability assay, flow cytometric analysis and the senescence-associated beta-galactosidase (SA-beta-Gal) assay. In addition, we also investigated the effect of combined therapy with irradiation and E6/E7 siRNA intravenous injection in an in vivo xenograft model. Combination therapy with siRNA and irradiation efficiently retarded tumor growth in established tumors of human cervical cancer cell xenografted mice. In addition, the chemically-modified HPV16 and 18 E6/E7 pooled siRNA in combination with irradiation strongly inhibited the growth of cervical cancer cells. Our results indicated that simultaneous inhibition of HPV E6/E7 oncogene expression with radiotherapy can promote potent antitumor activity and radiosensitizing activity in human cervical carcinomas. PMID- 26035755 TI - Ecotoxicogenomic approaches for understanding molecular mechanisms of environmental chemical toxicity using aquatic invertebrate, Daphnia model organism. AB - Due to the rapid advent in genomics technologies and attention to ecological risk assessment, the term "ecotoxicogenomics" has recently emerged to describe integration of omics studies (i.e., transcriptomics, proteomics, metabolomics, and epigenomics) into ecotoxicological fields. Ecotoxicogenomics is defined as study of an entire set of genes or proteins expression in ecological organisms to provide insight on environmental toxicity, offering benefit in ecological risk assessment. Indeed, Daphnia is a model species to study aquatic environmental toxicity designated in the Organization for Economic Co-operation and Development's toxicity test guideline and to investigate expression patterns using ecotoxicology-oriented genomics tools. Our main purpose is to demonstrate the potential utility of gene expression profiling in ecotoxicology by identifying novel biomarkers and relevant modes of toxicity in Daphnia magna. These approaches enable us to address adverse phenotypic outcomes linked to particular gene function(s) and mechanistic understanding of aquatic ecotoxicology as well as exploration of useful biomarkers. Furthermore, key challenges that currently face aquatic ecotoxicology (e.g., predicting toxicant responses among a broad spectrum of phytogenetic groups, predicting impact of temporal exposure on toxicant responses) necessitate the parallel use of other model organisms, both aquatic and terrestrial. By investigating gene expression profiling in an environmentally important organism, this provides viable support for the utility of ecotoxicogenomics. PMID- 26035756 TI - Effect of oral taurine on morbidity and mortality in elderly hip fracture patients: a randomized trial. AB - Hip fracture patients represent a large part of the elderly surgical population and face severe postoperative morbidity and excessive mortality compared to adult surgical hip fracture patients. Low antioxidant status and taurine deficiency is common in the elderly, and may negatively affect postoperative outcome. We hypothesized that taurine, an antioxidant, could improve clinical outcome in the elderly hip fracture patient. A double blind randomized, placebo controlled, clinical trial was conducted on elderly hip fracture patients. Supplementation started after admission and before surgery up to the sixth postoperative day. Markers of oxidative status were measured during hospitalization, and postoperative outcome was monitored for one year after surgery. Taurine supplementation did not improve in-hospital morbidity, medical comorbidities during the first year, or mortality during the first year. Taurine supplementation lowered postoperative oxidative stress, as shown by lower urinary 8-hydroxy-2-deoxyguanosine levels (Generalized estimating equations (GEE) analysis average difference over time; regression coefficient (Beta): -0.54; 95% CI: -1.08--0.01; p = 0.04), blunted plasma malondialdehyde response (Beta: 1.58; 95% CI: 0.00-3.15; p = 0.05) and a trend towards lower lactate to pyruvate ratio (Beta: -1.10; 95% CI: -2.33-0.12; p = 0.08). We concluded that peri-operative taurine supplementation attenuated postoperative oxidative stress in elderly hip fracture patients, but did not improve postoperative morbidity and mortality. PMID- 26035757 TI - A Combined Pharmacophore Modeling, 3D QSAR and Virtual Screening Studies on Imidazopyridines as B-Raf Inhibitors. AB - B-Raf kinase is an important target in treatment of cancers. In order to design and find potent B-Raf inhibitors (BRIs), 3D pharmacophore models were created using the Genetic Algorithm with Linear Assignment of Hypermolecular Alignment of Database (GALAHAD). The best pharmacophore model obtained which was used in effective alignment of the data set contains two acceptor atoms, three donor atoms and three hydrophobes. In succession, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 39 imidazopyridine BRIs to build three dimensional quantitative structure-activity relationship (3D QSAR) models based on both pharmacophore and docking alignments. The CoMSIA model based on the pharmacophore alignment shows the best result (q(2) = 0.621, r(2)(pred) = 0.885). This 3D QSAR approach provides significant insights that are useful for designing potent BRIs. In addition, the obtained best pharmacophore model was used for virtual screening against the NCI2000 database. The hit compounds were further filtered with molecular docking, and their biological activities were predicted using the CoMSIA model, and three potential BRIs with new skeletons were obtained. PMID- 26035758 TI - Advances in the management of acute retinal necrosis. PMID- 26035759 TI - Ocular sarcoidosis. PMID- 26035760 TI - Intraocular Sustained-release Steroids for Uveitis. PMID- 26035761 TI - Local therapeutic options for uveitic cystoid macular edema. PMID- 26035762 TI - Inflammatory Mechanisms of Age-related Macular Degeneration. PMID- 26035763 TI - Clinical trials in noninfectious uveitis. PMID- 26035765 TI - Cataract surgery in patients with uveitis. PMID- 26035766 TI - Current management approaches for uveitic glaucoma. PMID- 26035768 TI - Preface: Advances in the Management of Uveitis Part II. PMID- 26035769 TI - Antenatal Microbiome: Potential Contributor to Fetal Programming and Establishment of the Microbiome in Offspring. AB - BACKGROUND: Endogenous and exogenous exposures during fetal development have potential to impact birth and health outcomes of offspring. Accumulating evidence suggests exposures may alter the antenatal microbiome and subsequently alter the microbiome and health of offspring. OBJECTIVES: The purpose of this integrative review is to summarize and critically evaluate the current state of knowledge regarding the assessment of the antenatal microbiome on the health of human offspring. The article provides a brief summary of the known factors affecting the human microbiome and studies that assessed relationships between the antenatal microbiome and health outcomes of the offspring. METHODS: An integrative review was conducted to examine human research studies that focused on the antenatal microbiome and the health of the offspring using the electronic databases PubMed/MEDLINE and CINAHL from 2004 to the present. RESULTS: In addition to the known individual factors that are associated with establishment of the microbiome, the results of the integrative review suggest that medications (including antibiotics) and comorbidities (including infectious diseases, diet, socioeconomic status, and exposure to pollutants) should also be measured. DISCUSSION: The composition of the antenatal microbiome at various time points and body sites may be important mediators of short- and long-term health outcomes in offspring. In order to advance our understanding of the role of the antenatal microbiome on health and disease risk of the offspring, it will be important to further elucidate the composition of a healthy microbiome and specific mechanisms that contribute to altered health in later life. PMID- 26035764 TI - The role of sex in uveitis and ocular inflammation. PMID- 26035771 TI - Symptomatic Spinal Cord Bending After Meningioma Resection: A Technical Case Report. AB - Resection of intradural tumors is often followed by bending of the spinal cord within the surgical cave. This event is known to be innocuous. The authors report a case where the position assumed by the spinal cord at the end of surgery was associated with significant motor evoked potential decline. The patient, a 44 year-old woman with a meningioma of the craniocervical junction, underwent tumor resection aided by intraoperative neurophysiological monitoring. At the time of dural closure, the motor evoked potentials were completely lost on the left side and reduced on the right side. Intraoperative maneuvers showed that worsening was related to the spinal cord position. Motor evoked potentials were restored by tethering the cord posteriorly, back to its original site. This report underlines the usefulness of maintaining intraoperative monitoring until the end of surgery and provides a technical nuance to manage a rare complication. PMID- 26035770 TI - Structures, stabilities, and electronic properties of defects in monolayer black phosphorus. AB - The structures, stabilities, and electronic properties of monolayer black phosphorus (M-BP) with different kinds of defects are investigated within the frame of density-functional theory. All the possible configurations of defects in M-BP are explored, and the calculated results suggest that the stabilities of the configurations with different kinds of defects are greatly related to broken bonds, structural deformation and the character of the bonding. The configurations with two or three vacancies are energetically more favorable than the ones with a single vacancy. Meanwhile, the doping of two foreign atoms, such as sulfur, silicon or aluminum, is more stable than that of the corresponding single dopant. The electronic properties of M-BP are greatly affected by the types of defects. The single S-doped M-BP not only retains the character of a direct semiconductor, but it also can enlarge the band gap by 0.24 eV relative to the perfect one. Such results reveal that the defects not only greatly affect the electronic properties, but they also can be used as an effective way to modulate the band gap for the different applications of M-BP in electronic devices. PMID- 26035772 TI - Growth and development: Determinants of kidney size. PMID- 26035774 TI - Advanced aqueous rechargeable lithium battery using nanoparticulate LiTi2(PO4)3/C as a superior anode. AB - Poor cycling performance arising from the instability of anode is still a main challenge for aqueous rechargeable lithium batteries (ARLB). In the present work, a high performance LiTi2(PO4)3/C composite has been achieved by a novel and facile preparation method associated with an in-situ carbon coating approach. The LiTi2(PO4)3/C nanoparticles show high purity and the carbon layer is very uniform. When used as an anode material, the ARLB of LiTi2(PO4)3/C//LiMn2O4 delivered superior cycling stability with a capacity retention of 90% after 300 cycles at 30 mA g(-1) and 84% at 150 mA g(-1) over 1300 cycles. It also demonstrated excellent rate capability with reversible discharge capacities of 115 and 89 mAh g(-1) (based on the mass of anode) at 15 and 1500 mA g(-1), respectively. The superior electrochemical properties should be mainly ascribed to the high performance of LiTi2(PO4)3/C anode, benefiting from its nanostructure, high-quality carbon coating, appropriate crystal structure and excellent electrode surface stability as verified by Raman spectra, electrochemical impedance spectroscopy (EIS), X-ray diffraction (XRD) and scanning electron microscopy (SEM) measurements. PMID- 26035775 TI - Superior mesenteric artery syndrome. AB - Superior mesenteric artery (SMA) syndrome is an uncommon and potentially fatal cause of small bowel obstruction where the third portion of the duodenum is compressed between the abdominal aorta and the superior mesenteric artery. This is most frequently seen after sudden and significant weight loss, but other etiologies can also cause this duodenal compression. This syndrome can lead to food aversion, poor intake, and weight loss that exacerbate symptoms in a vicious cycle. SMA syndrome is often a diagnosis of exclusion due to nonspecific symptoms, including abdominal pain and distention, feelings of fullness after meals, and bilious emesis. Diagnosis may be assisted with radiography, tomography, endoscopy, and ultrasound imaging. Once SMA syndrome is identified, treatment is directed toward symptom management and nutritional support. If conservative measures fail, symptoms are severe, or the duodenum is compromised, several effective surgical procedures are routinely considered. This article provides an overview of SMA syndrome including history, pathophysiology, signs and symptoms, diagnostic testing, medical and surgical treatment, and implications for nursing staff. PMID- 26035773 TI - Kidney diseases associated with haematological cancers. AB - Advances in chemotherapy for haematological malignancies, resulting from a greater understanding of the complex pathophysiology of these diseases, have improved the survival of patients with these disorders. Clinicians must now, therefore, be more aware of the issues related to fluid, electrolyte, and acid base disorders, as well as acute and chronic kidney injuries that can develop in such patients as a result of the underlying malignancy and its treatment. Patients with acute kidney injury associated with haematological malignancy have a worse prognosis than do other patients with acute kidney injury. Glomerular diseases associated with haematological malignancies are thought to be paraneoplastic syndromes with variable histological presentations. Some of the newest therapeutic agents used to treat haematological malignancies have adverse renal effects that can preclude continuation of treatment, often leading to difficult clinical decisions when patients have advanced disease and alternative treatment options are limited. Haematopoietic stem cell transplantation has an expanding role as a therapy for haematological malignancies but is also associated with important renal complications. Here, we review the literature that examines the incidences, aetiologies, mechanisms and treatment options for renal disorders associated with haematological malignancies. PMID- 26035776 TI - Enhanced communication performance improvement and patient satisfaction in an endoscopy/ambulatory surgery unit. AB - A nursing incentive directed toward enhanced communication, performance improvement, patient safety, and patient satisfaction was initiated by the staff nurses in an endoscopy unit of a 714-bed specialized teaching hospital. Data were collected from approximately 1,800 ambulatory patients using a hands-off communication tool. The population was evenly divided between males and females. The goals of the data collection focused on the utilization of a medical questionnaire given to patients prior to elective procedures. The purpose of this initial study was to ascertain whether the questionnaires contributed to patients' communication regarding their health record while facilitating the admission/assessment phase of undergoing an elective endoscopy procedure. The medical questionnaire also served as a patient education tool whereby staff promoted the importance of safe medication administration. The initiative will remain ongoing and future studies will monitor and identify areas needed for performance improvement, patient safety, and enhanced communication. Patient satisfaction is measured using Press Ganey results. PMID- 26035777 TI - Symptom distress in patients with end-stage liver disease toward the end of life. AB - Research on symptom distress experienced by patients with end-stage liver disease at the end of life is limited. The aims of the study were to describe presence, frequency, severity, and distress of symptoms in patients with end-stage liver disease toward the end of life and to describe the variability in psychological and physical symptom distress between and within patients over time. This study used a prospective, longitudinal descriptive design. Data were collected from 20 patients once a month for up to 6 months. Participants completed the Memorial Symptom Assessment Scale, which reports a total score, a Global Distress Index score, and a psychological and a physical distress score. Patients reported lack of energy, pain, difficulty sleeping, and feeling drowsy as the most frequent, severe, and distressing symptoms. Global Distress Index mean scores (measured on a 1-4 scale) ranged from 2.6 to 2.9 across time. There was notable variability in psychological and physical distress scores between and within patients across time. Gaining knowledge about the prevalent symptoms experienced by patients with end-stage liver disease and the trajectory of these symptoms is crucial for designing interventions that optimize well-being in patients with end-stage liver disease as they are approaching death. PMID- 26035778 TI - Mesh-related complications after hiatal hernia repair: two case reports. PMID- 26035779 TI - A Review of the American Cancer Society's 2015 Colorectal Cancer Screening Recommendations. PMID- 26035780 TI - Local proliferation is the main source of rod microglia after optic nerve transection. AB - Microglia are the resident phagocytic cells with various functions in the central nervous system, and the morphologies of microglia imply the different stages and functions. In optical nerve transection (ONT) model in the retina, the retrograde degeneration of retinal ganglion cells (RGCs) induces microglial activations to a unique morphology termed "rod" microglia. A few studies described the "rod" microglia in the cortex and retina; however, the function and origin of "rod" microglia are largely unknown. In the present study, we firstly studied the temporal appearance of "rod" microglia after ONT, and found the "rod" microglia emerge at approximately 7 days after ONT and peak during 14 to 21 days. Interestingly, the number of "rod" microglia remarkably decays after 6 weeks. Secondly, the "rod" microglia eliminate the degenerating RGC debris by phagocytosis. Moreover, we found the major source of "rod" microgliosis is local proliferation rather than the infiltration of peripheral monocytes/hematopoietic stem cells. We for the first time described the appearance of "rod" retinal microglia following optic nerve transection. PMID- 26035781 TI - Linear lichen planus along the lines of Blaschko in three adult women: gene environment interactions. PMID- 26035782 TI - Ajuba proteins. AB - Schimizzi and Longmore summarise what we know about Ajuba LIM-domain proteins and their various subcellular roles. PMID- 26035783 TI - Facultative parthenogenesis in a critically endangered wild vertebrate. AB - Facultative parthenogenesis - the ability of sexually reproducing species to sometimes produce offspring asexually - is known from a wide range of ordinarily sexually reproducing vertebrates in captivity, including some birds, reptiles and sharks [1-3]. Despite this, free-living parthenogens have never been observed in any of these taxa in the wild, although two free-living snakes were recently discovered each gestating a single parthenogen - one copperhead (Agkistrodon contortrix) and one cottonmouth (Agkistrodon piscivorus) [1]. Vertebrate parthenogens are characterized as being of the homogametic sex (e.g., females in sharks, males in birds) and by having elevated homozygosity compared to their mother [1-3], which may reduce their viability [4]. Although it is unknown if either of the parthenogenetic snakes would have been carried to term or survived in the wild, facultative parthenogenesis might have adaptive significance [1]. If this is true, it is reasonable to hypothesize that parthenogenesis would be found most often at low population density, when females risk reproductive failure because finding mates is difficult [5]. Here, we document the first examples of viable parthenogens living in a normally sexually reproducing wild vertebrate, the smalltooth sawfish (Pristis pectinata). We also provide a simple approach to screen any microsatellite DNA database for parthenogens, which will enable hypothesis-driven research on the significance of vertebrate parthenogenesis in the wild. PMID- 26035784 TI - Neuroscience: teleporting mind into body and space. AB - Brain imaging and a novel 'body-swop' illusion reveals distinct parietal-premotor and parietal-hippocampal networks involved in constructing a sense of body ownership and self-location, with the posterior cingulate mediating between them. PMID- 26035785 TI - Actin-filament disassembly: it takes two to shrink them fast. AB - Actin-filament disassembly is indispensable for replenishing the pool of polymerizable actin and allows continuous dynamic remodelling of the actin cytoskeleton. A new study now reveals that ADF/cofilin preferentially dismantles branched networks and provides new insights into the collaborative work of ADF/cofilin and Aip1 on filament disassembly at the molecular level. PMID- 26035786 TI - Paleoanthropology: how old is the oldest human? AB - A 2.8 Ma old mandible unearthed in Ethiopia fills the gap between ape-like australopithecines and representatives of the genus Homo. It pushes the origin of large-brained hominins further back in time and highlights the complexity of the human evolutionary tree. PMID- 26035787 TI - Behavioral genetics: of mice, men, and internal bliss. AB - A mutation in the FAAH gene that enhances endocannabinoid signaling has been difficult to decipher, as it exists only in humans. A new study reports a knock in mouse expressing an identical mutation, bridging an important translational gap. PMID- 26035788 TI - Evolution: a turn up for the worms. AB - Extensive sequencing of transcriptomes reveals the evolutionary relationships among the major flatworm lineages, suggesting new roots and conflicting routes to parasitism. PMID- 26035789 TI - Root system patterning: auxin synthesis at the root periphery. AB - Plasticity in plant form is achieved through differential elaboration of developmental pre-patterns during postembryonic organ development. A new report links the output of the root clock, an oscillatory transcriptional pre-patterning mechanism, with cell-type-specific production of the plant hormone auxin, and identifies a downstream component required for elaboration of the pre-pattern. PMID- 26035790 TI - Heterochromatin: dark matter or variation on a theme? AB - Heterochromatin contributes to the dynamic range of eukaryotic gene expression. In yeast, its ability to suppress transcription is inversely proportional to activator strength. A recent study reveals that Sir silencing proteins enhance the avidity with which nucleosomes assemble, endowing heterochromatin with both repressive and dynamic characteristics. PMID- 26035791 TI - Evolution: a genomic guide to bird population history. AB - How species responded to the climatic oscillations during the past few million years is debated. A new study analyzing the genomes of 38 bird species finds variable patterns of population growth and declines that broadly correlate with global environmental change. PMID- 26035792 TI - Group behavior: social context modulates behavioral responses to sensory stimuli. AB - A new study reveals an unanticipated role for social context in driving group behavior of a solitary species to a sensory stimulus and is mediated by mechanosensory neurons signaling touch interactions among individuals. PMID- 26035794 TI - TM4SF1 as a prognostic marker of pancreatic ductal adenocarcinoma is involved in migration and invasion of cancer cells. AB - The cell surface protein Transmembrane 4 L6 family member 1 (TM4SF1) has been detected in various tumors, and its expression on tumor cells is implicated in cancer cell metastasis and patient prognosis. The role of TM4SF1 in malignant tumors remains poorly understood, particularly in pancreatic cancer. We performed immunohistochemical staining to analyze the expression of TM4SF1 in resected pancreatic tissues and investigated the correlation between TM4SF1 expression and prognosis. The function of TM4SF1 in the invasion and migration of pancreatic cancer cells was analyzed in vitro using an RNA interference technique. In pancreatic cancer tissues, TM4SF1 expression was detected in cancer cells, and patients with high tumor levels of TM4SF1 showed longer survival times than those with low TM4SF1 levels (P=0.0332). In vitro, reduced TM4SF1 expression enhanced the migration (P<0.05) and invasion (P<0.05) of pancreatic cancer cells partially via decreased E-cadherin expression. TM4SF1 protein levels were also reduced after TGF-beta1-induced epithelial-mesenchymal transition (EMT).TM4SF1 expression is associated with better prognosis in pancreatic cancer. Loss of TM4SF1 contributes to the invasion and migration of pancreatic cancer cells. PMID- 26035793 TI - Expanding roles for lipid droplets. AB - Lipid droplets are the intracellular sites for neutral lipid storage. They are critical for lipid metabolism and energy homeostasis, and their dysfunction has been linked to many diseases. Accumulating evidence suggests that the roles lipid droplets play in biology are significantly broader than previously anticipated. Lipid droplets are the source of molecules important in the nucleus: they can sequester transcription factors and chromatin components and generate the lipid ligands for certain nuclear receptors. Lipid droplets have also emerged as important nodes for fatty acid trafficking, both inside the cell and between cells. In immunity, new roles for droplets, not directly linked to lipid metabolism, have been uncovered, with evidence that they act as assembly platforms for specific viruses and as reservoirs for proteins that fight intracellular pathogens. Until recently, knowledge about droplets in the nervous system has been minimal, but now there are multiple links between lipid droplets and neurodegeneration: many candidate genes for hereditary spastic paraplegia also have central roles in lipid-droplet formation and maintenance, and mitochondrial dysfunction in neurons can lead to transient accumulation of lipid droplets in neighboring glial cells, an event that may, in turn, contribute to neuronal damage. As the cell biology and biochemistry of lipid droplets become increasingly well understood, the next few years should yield many new mechanistic insights into these novel functions of lipid droplets. PMID- 26035795 TI - Comparative study reveals better far-red fluorescent protein for whole body imaging. AB - Genetically encoded far-red and near-infrared fluorescent proteins enable efficient imaging in studies of tumorigenesis, embryogenesis, and inflammation in model animals. Here we report comparative testing of available GFP-like far-red fluorescent proteins along with a modified protein, named Katushka2S, and near infrared bacterial phytochrome-based markers. We compare fluorescence signal and signal-to-noise ratio at various excitation wavelength and emission filter combinations using transiently transfected cell implants in mice, providing a basis for rational choice of optimal marker(s) for in vivo imaging studies. We demonstrate that the signals of various far-red fluorescent proteins can be spectrally unmixed based on different signal-to-noise ratios in different channels, providing the straightforward possibility of multiplexed imaging with standard equipment. Katushka2S produced the brightest and fastest maturing fluorescence in all experimental setups. At the same time, signal-to-noise ratios for Katushka2S and near-infrared bacterial phytochrome, iRFP720 were comparable in their optimal channels. Distinct spectral and genetic characteristics suggest this pair of a far-red and a near-infrared fluorescent protein as an optimal combination for dual color, whole body imaging studies in model animals. PMID- 26035796 TI - Hypoxia-induced apoptosis is blocked by adrenomedullin via upregulation of Bcl-2 in human osteosarcoma cells. AB - Adrenomedullin (ADM), a multifunctional regulatory peptide, is potentially induced by hypoxia in physiological and pathological tissues, including many types of malignant tumors. Recent research has demonstrated that ADM expression is highly associated with the prognosis and disease severity of human osteosarcoma. However, the effect of ADM on the apoptosis of osteosarcoma cells and its possible mechanism remain to be elucidated. In the present study, we observed that mRNA and protein levels of ADM were increased in human osteosarcoma SOSP-F5M2 cells under a hypoxic microenvironment induced by cobalt chloride (CoCl2) in a time-dependent manner. Treatment with ADM significantly blunted hypoxic-induced apoptosis, evaluated by Hoechst 33342 staining and Annexin V FITC/PI labeling. The expression of B-cell lymphoma-2 (Bcl-2) was increased by administration of ADM; meanwhile, this effect was reversed by exogenously adding U0126, a selective inhibitor of MEK or ADM22-52 (ADM-specific receptor antagonist). These results demonstrated that ADM acted as a survival factor to inhibit hypoxic-induced apoptosis via interacting with its receptors CRLR-RAMP (2,3) in osteosarcoma cells. The anti-apoptotic function of ADM was found to be mediated by upregulation of the expression of Bcl-2 partially through activation of the MEK/ERK1/2 signaling pathway. Therefore, targeting of the ADM/ADM acceptors/ERK1/2/Bcl-2 pathway may provide a potential strategy through which to induce the apoptosis of osteosarcoma cells. PMID- 26035799 TI - The challenge of defining pathogenicity: the example of AHI1. PMID- 26035800 TI - Response to Heller and Bolz. PMID- 26035801 TI - The cost-effectiveness of routine testing for Lynch syndrome in newly diagnosed patients with colorectal cancer in the United States: corrected estimates. PMID- 26035802 TI - Reproducing genetics. PMID- 26035803 TI - ERRATUM: A genome sequencing program for novel undiagnosed diseases. PMID- 26035804 TI - CORRIGENDUM: Too much, too soon?: Commercial provision of noninvasive prenatal screening for subchromosomal abnormalities and beyond. PMID- 26035805 TI - CO2-Selective Nanoporous Metal-Organic Framework Microcantilevers. AB - Nanoporous anodic aluminum oxide (AAO) microcantilevers are fabricated and MIL-53 (Al) metal-organic framework (MOF) layers are directly synthesized on each cantilever surface by using the aluminum oxide as the metal ion source. Exposure of the MIL53-AAO cantilevers to various concentrations of CO2, N2, CO, and Ar induces changes in their deflections and resonance frequencies. The results of the resonance frequency measurements for the different adsorbed gas molecules are almost identical when the frequency changes are normalized by the molecular weights of the gases. In contrast, the deflection measurements show that only CO2 adsorption induces substantial bending of the MIL53-AAO cantilevers. This selective deflection of the cantilevers is attributed to the strong interactions between CO2 and the hydroxyl groups in MIL-53, which induce structural changes in the MIL-53 layers. Simultaneous measurements of the resonance frequency and the deflection are performed to show that the diffusion of CO2 into the nanoporous MIL-53 layers occurs very rapidly, whereas the binding of CO2 to hydroxyl groups occurs relatively slowly, which indicates that the adsorption of CO2 onto the MIL 53 layers and the desorption of CO2 from the MIL-53 layers are reaction limited. PMID- 26035806 TI - Corresponding Ganglion Cell Atrophy in Patients With Postgeniculate Homonymous Visual Field Loss. AB - BACKGROUND: The goal of our study was to look for the presence of homonymous ganglion cell layer-inner plexiform layer complex (GCL-IPL) thinning using spectral-domain optical coherence tomography (SD-OCT) in patients with a history of adult-onset injury to the postgeniculate pathways with rigorous radiological exclusion of geniculate and pregeniculate pathology. METHODS: We performed a retrospective review of twenty-two patients (ages 24-75 y, 6 men, 16 women) with homonymous visual field (VF) defects secondary to postgeniculate injury examining the GCL-IPL with SD-OCT. An additional fifteen patients (ages 28-85 y, 5 men, 10 women) with no visual pathway pathology served as controls. Using segmentation analysis software applied to the macular scan, a normalized asymmetry score was calculated for each eye comparing GCL-IPL thickness ipsilateral vs contralateral to the patient's brain lesions. RESULTS: We found that 15 of the twenty-two subjects had a relative thinning of the GCL-IPL ipsilateral to the postgeniculate lesion in both eyes (represented by a positive normalized asymmetry score in both eyes), whereas a similar pattern of right/left asymmetry was found in 4 controls (P = 0.0498). The magnitude of asymmetry was much greater in subjects compared with controls (P = 0.0004). There was no association between the degree of GCL IPL thinning and the mean deviation on automated VF testing. A moderate correlation (R = 0.782, P = 0.004) between the magnitude of thinning and latency from onset of retrogeniculate injury was observed only after excluding patients beyond a cutoff point of 150 months. CONCLUSIONS: This data provides compelling new evidence of retrograde transsynaptic degeneration causing retinal ganglion cell loss after postgeniculate visual pathway injury. PMID- 26035807 TI - Square-Wave Ocular Oscillation and Ataxia in an Anti-GAD-Positive Individual With Hypothyroidism. AB - Cerebellar ataxia is an uncommon manifestation of hypothyroidism with unknown pathomechanism. The few descriptions of the clinical phenotype range from limb, gait, and trunk ataxia to various ocular motor abnormalities. We evaluated a 62 year-old woman with previously undetected severe hypothyroidism who presented with prominent saccadic intrusions and gait ataxia. She had high titers of antithyroid autoantibodies and anti-glutamic acid decarboxylase (anti-GAD) antibodies. Horizontal eye movement recordings revealed a series of nearly continuous pseudoharmonic square wave jerks (SWJs) constituting a square wave oscillation. Amplitudes reached maximum values of about 4, and wave frequency approached 100 cycles per minute. Thyroxine substitution and corticosteroid administration had little effect on SWJ parameters. The square wave oscillation nearly completely resolved after a single treatment session with intravenous immunoglobulin suggesting a causal link between an autoimmune process and the cerebellar dysfunction. Current concepts of the genesis of saccadic intrusions favor a role for anti-GAD antibodies in the etiology of SWJs. PMID- 26035808 TI - Relationship Between Age, Gender, and Race in Patients Presenting With Myasthenia Gravis With Only Ocular Manifestations. AB - BACKGROUND: The demographic associations among patients presenting with myasthenia gravis with only ocular manifestations (OMG) is not clear. METHODS: In this 5-center case series, we collected the race, gender, and age at diagnosis of patients diagnosed with myasthenia gravis who had no signs or symptoms of generalized myasthenia gravis (GMG). An a priori sample size calculation determined that 140 patients were required to accept that there was a <=10-year difference in mean age (equivalence testing: power 90%, alpha = 0.05). Robust Bayesian analysis and linear regression were applied to evaluate whether age differed by gender or race. RESULTS: Of 433 patients included, 258 (60%) were men. Mean age among men was 57 years (SD = 19) and 52 years (SD = 21) among women. The 95% credible interval (CI) (Bayesian equivalent of confidence interval) was 0.8-8.7 years for mean age, and there was a 99.6% probability that the mean difference in age between sexes was <10 years. Race was documented in 376 (68 [18%] non-Caucasian). Caucasians were 17.3 years older than non Caucasians at diagnosis (95% CI, 12.2-22.3 y; P < 0.001) controlling for gender. There was no additive interaction of gender and race (P = 0.74). There was a bimodal distribution for women peaking around 30 and 60 years. Men had a left skewed unimodal age distribution peaking at age 70. CONCLUSIONS: The distribution of age at presentation in patients with OMG is different between men and women, similar to GMG. Non-Caucasian patients tend to develop OMG at a younger age. PMID- 26035809 TI - Determination of whether screening tests for chronic atrophic gastritis really has a positive predictive value. AB - Intestinal-type gastric adenocarcinomas are preceded by precancerous lesions, which begin with chronic atrophic gastritis. Over the last few years, multiple serological screening techniques have been performed and commercialized for the diagnosis of chronic atrophic gastritis. In the present study, 123 patients were recruited at the International Cancer Institute 'G. Pascale' Foundation (Naples, Italy) to test commercial kits for the serological determination of chronic atrophic gastritis, supported by histological analysis, according to the International Group of Gastroenterologists 'Operative Link for Gastritis Assessment Staging System'. The results revealed a significant discrepancy between serological screening and histological evaluation in 10.6% of patients, which highlighted the dubious positive predictive value of commercial serological screening kits. PMID- 26035810 TI - The Quality and Completeness of 2008 Perinatal and Under-five Mortality Data from Vital Registration, Jamaica. AB - OBJECTIVE: To evaluate the completeness and timeliness of registration of stillbirths and under-five deaths and the validity of the certification and coding process. SUBJECTS AND METHODS: Registered stillbirths and under-five deaths occurring in 2008 were compared to hospital, police, forensic pathologist and coroner's records. Missed cases and new information such as birthweight, gestation and date of birth were added to the database. A 10% random sample was evaluated to measure the quality of certification and coding. RESULTS: Of 646 stillbirths [>= 1000 g] and 933 under-five deaths, 69% and 79%, respectively were registered by December 31, 2009, for inclusion in the 2008 final demographic returns. Non-reporting of stillbirths was associated with infant gender, region and place of death (seven of 21 public hospitals accounted for 96% of unregistered stillbirths). Among under-five deaths, age at death, region, place and cause of death were important. Injury and community deaths increased with age. Registration delays including non-registration were associated with coroner's inquests. Most [80%] stillbirth certificates lacked usable cause of death data. Neonatal deaths due to prematurity and perinatal asphyxia were often misclassified by coders. The stillbirth [>= 1000 g], infant and under-five mortality rates were 15, 20 and 22/1000 births/live births, respectively. CONCLUSIONS: While registration of stillbirths and under-five deaths improved between 1998 and 2008, persistent under-reporting reduced official rates by 20 31%. A new perinatal death certificate documenting maternal and fetal causes of death and risk factors such as birthweight, gestation and age at death would improve stillbirth and neonatal death (0-28 days) data quality. PMID- 26035811 TI - The Prevalence of Elevated Blood Pressure in Adolescents in Nassau, The Bahamas. AB - OBJECTIVE: To determine the prevalence of elevated blood pressure (EBP) in Bahamian adolescents. METHODS: A cross-sectional survey employing a self administered questionnaire, and concurrently obtaining anthropometric measurements, was conducted involving selected grades 9, 10 and 11 students of all targeted public high schools in The Bahamas. RESULTS: The mean age of the 785 participants was 14.6 (+/- 1.153) years, and 87.6% were Bahamian. The prevalence of elevated systolic blood pressure (SBP) was 4.7% and 6.6% for elevated diastolic blood pressure (DBP). Elevated blood pressure prevalence was 8.9%. Elevated blood pressure was more common among grade 9 students (12-14-year olds) who had the largest proportion of EBP (55.7%). Both SBP and DBP increased with age in the males. Overall, students' prevalence of overweight/obesity was 32.2% (14.4% overweight, 17.8% obese). Body mass index (BMI), number of days per week eating fast food and perception of body weight were predictive of EBP. Body mass index, age and perception of body weight were found to be predictive of SBP (betaBMI = 0.25, p < 0.001; betaAge = 0.14, p < 0.001; betaWeight = 0.08, p < 0.037) and DBP (betaDBP = 0.192, p < 0.001). Overweight/obese students were 2.7 times more likely to have EBP. Elevated blood pressure was markedly associated with BMI, family history of hypertension and parents' overweight/obese status. CONCLUSION: The estimated prevalence of EBP in adolescent school children in New Providence, Bahamas, was comparable with neighbouring nations. PMID- 26035812 TI - What Is in the Caribbean Baby? Assessing Prenatal Exposures and Potential Health Outcomes to Environmental Contaminants in 10 Caribbean Countries. AB - OBJECTIVE: To assess prenatal exposures and potential health outcomes to environmental toxicants such as persistent organic pollutants (POPs), commonly used pesticides, and two heavy metals--mercury (Hg) and lead (Pb)--in 10 Caribbean countries. SUBJECTS AND METHODS: For each participating Caribbean island, approximately 50 maternal blood and urine samples were collected and analysed for POPs such as polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), other common classes of pesticides used in the Caribbean such as organophosphates (OP), carbamates, chlorophenols and pyrethroids, and for Hg and Pb. Data obtained from the participating countries were compared with those from the United States of America and Canada. RESULTS: A total of 438 samples were analysed from 10 Caribbean countries. Persistent organic pollutants was detected in almost all samples, however, these were generally low compared with comparable North American results. Evidence of exposure to PBDEs, OPs, carbamates and chlorophenols was also established. Caribbean pyrethroid concentrations were generally much higher than those recorded for North American women. Caribbean Pb maternal blood levels were generally lower than in North America, whereas Hg blood levels were two to three times higher. In almost all of the samples taken in this study, exposures to multiple chemicals were taking place at the same time. CONCLUSIONS: This first Caribbean-wide exploratory biomonitoring study on the concentrations of several toxicants in maternal samples taken from 10 Caribbean countries clearly reinforces the need for Caribbean primary care physicians and other public health officials to encourage their patients, and in particular pregnant women, to reduce their exposures to these environmental contaminants as far as it is feasible to do so. PMID- 26035813 TI - Nutritional Knowledge and Practices, Lifestyle Characteristics and Anthropometric Status of Turks and Caicos Islands Elementary School Children. AB - OBJECTIVES: To assess nutritional status, knowledge, practices and lifestyle characteristics of Turks and Caicos Islands (TCI) primary school children. SUBJECTS AND METHODS: Sociodemographic, nutrition knowledge and lifestyle information were collected via an interviewer-assisted questionnaire from grade 5 to 6 participants in a cross-sectional survey; anthropometrics were collected by trained interviewers. RESULTS: Two hundred and ninety-seven students (mean age = 10.91 +/- 1.01 years; female = 162 [54.5%]; overweight/obese = 121 [40.8%]) participated. Most were born (61.8%) or resided in TCI for more than five years (76.1%). Dietary patterns of breakfast (75.8%); >= 2 meals/day (81.2%); >= 1 snack/day (65%) and consumption of vegetables (14.5%) and fruits (27.3%) >= 2/day were reported. Multinomial regression examined lifestyle and sociodemographic characteristics among body mass index (BMI) categories. Breakfast-eaters were 54% less likely (OR = 0.46; p = 0.025) to be obese; consumers of < 3 meals/day were approximately twice more likely to be obese (OR = 2.074; p = 0.02); participants who "ate out" < 2 times/day (including lunch) were less likely to be overweight (OR = 0.365; p = 0.02). More boys reported strenuous activity (p = 0.05) while more girls reported moderate activity (p = 0.004). No vigorous exercise for >= 4 days/week was associated with obesity (OR = 2.0; p = 0.03). Most (> 80%) knew the food groups and that non-communicable diseases were related to diet and obesity (> 70%). CONCLUSION: Findings should inform policy, via the "Health in All" policy initiatives, to develop multisectoral interventions to positively impact children's nutritional status and ultimately eliminate obesogenic environments. PMID- 26035814 TI - Epidemiological Trend and Clinical Observations among Children and Adults with Dengue in Barbados. AB - OBJECTIVE: To describe the epidemiological characteristics and the clinical manifestations of the confirmed dengue cases over a ten-year period in Barbados, one of the English-speaking Caribbean countries. METHODS: All the cases of confirmed dengue from 2000 to 2009 were retrospectively studied. Long-term trends in incidence rate, demographic characteristics such as age, gender and seasonal distribution; clinical manifestations, immunological characteristics, need for hospitalization and mortality were studied. RESULTS: There were 3413 confirmed cases of dengue including 778 (22.8%) children and 2635 (77.2%) adults. The mean annual incidence rate of dengue was 1.36/1000 population. The median age of the persons with confirmed dengue was 27 years. The largest number of cases was seen in the 11 to 16-year age group. Hospitalization was required in 13.1% of dengue cases; 72.5% and 84% of all dengue were secondary infections among the children and adults, respectively. Dengue haemorrhagic fever accounted for 2.2% and 6% of all confirmed dengue among children and adults, respectively. The overall case fatality rate in this study was 0.35%. CONCLUSIONS: Dengue is a significant health problem primarily in adolescents and young adults. It is characterized by less severe cases and lower mortality rate. PMID- 26035816 TI - Outcome of HIV-infected Pregnant Women and Their Offspring in Barbados: A Five year Study. AB - OBJECTIVES: To describe the outcome of HIV-infected pregnant women and their offspring during a five-year period. METHODS: The medical records of HIV-infected pregnant women who delivered between January 2007 and December 2011 and their HIV exposed infants were reviewed. Demographics, outcome of pregnancy and infants, and clinic attendance were analysed. Data were entered on a Microsoft Excel spreadsheet. RESULTS: One hundred and forty-three women, aged 17-45 years (mean 27.3 years), were included in the study with 143 pregnancies and 142 pregnancy outcomes being recorded. One woman migrated before delivery. There were 122 live births and 18 (13%) terminations: 13 (9%) elective and five (4%) spontaneous. There was one ectopic pregnancy and one stillbirth. One hundred and twenty-two (85%) women were unmarried. Women were prescribed highly active antiretroviral therapy for prevention of mother-to-child transmission from the time of booking, apart from those opting for terminations or those who had spontaneous abortions. For clinic follow-up, 105 (73%) had regular attendance, 30 (21%) defaulted and could not be located despite intense tracking, four attended irregularly, and one refused to attend clinic. Four (3%) migrated after delivery. Two (1%) mothers died during the period of study. Two successive DNA polymerase chain reaction tests done within four months of age did not substantiate any cases of infant infection. CONCLUSION: This study revealed that there was a good outcome and compliance with follow-up of HIV-infected pregnant women and their offspring. PMID- 26035815 TI - Knowledge and Perceptions of HPV and the HPV Vaccine among Pre-adolescent Girls and Their Guardians in Georgetown, Guyana. AB - OBJECTIVES: To examine the knowledge and perceptions of 11-year old girls and their guardians toward the human papillomavirus (HPV), HPV (mandatory) vaccination and cervical cancer and to determine their main sources of health information. METHODS: A cross-sectional study was done by interviewing two separate study populations ie 11-year old girls from five primary schools in Georgetown and their guardians. Questions were designed to assess level of knowledge as well as perceptions about mandatory vaccination and sources of health information. RESULTS: A total of 87 girls participated, of whom 10 (11%) had already received the HPV vaccine. Overall, when asked whether they knew of HPV, the HPV vaccine, cervical cancer or the Pap smear, more than half of the girls, in every instance, did not know. Seventy-four guardians took part and most (> 80%) of them claimed that they knew about these parameters except for HPV transmission (40%) and the cause of cervical cancer (30%). Both girls and guardians responded poorly to questions about the detection of cervical cancer. Furthermore, only two of the 14 girls who stated that they knew how HPV was transmitted, actually answered correctly that it was sexual transmission. Girls were almost twice as likely to be in favour of mandatory vaccination as guardians (OR 1.8, 95% CI: 0.9, 3.6) but the difference was not significant (p > 0.05). The girls indicated health centres/clinics (58%), whilst TV/radio (66%) was the preference for the guardians as their most popular health information sources. CONCLUSIONS: These findings point to a necessity for educational programmes and activities in which children and their guardians can meaningfully participate and be informed about the different aspects of HPV vaccination. PMID- 26035817 TI - Analysis of [Gossypium capitis-viridis * (G.hirsutum * G.australe)2] Trispecific Hybrid and Selected Characteristics. AB - Speciation is always a contentious and challenging issue following with the presence of gene flow. In Gossypium, there are many valuable resources and wild diploid cotton especially C and B genome species possess some excellent traits which cultivated cotton always lacks. In order to explore character transferring rule from wild cotton to upland tetraploid cotton, the [G. capitis-viridis * (G. hirsutum * G. australe)2] triple hybrid was synthesized by interspecies hybridization and chromosome doubling. Morphology comparisons were measured among this hybrid and its parents. It showed that trispecific hybrid F1 had some intermediate morphological characters like leaf style between its parents and some different characters from its parents, like crawl growth characteristics and two kind flower color. It is highly resistant to insects comparing with other cotton species by four year field investigation. By cytogenetic analysis, triple hybrid was further confirmed by meiosis behavior of pollen mother cells. Comparing with regular meiosis of its three parents, it was distinguished by the occurrence of polyads with various numbers of unbalanced microspores and finally generating various abnormal pollen grains. All this phenomenon results in the sterility of this hybrid. This hybrid was further identified by SSR marker from DNA molecular level. It showed that 98 selected polymorphism primers amplified effective bands in this hybrids and its parents. The genetic proportion of three parents in this hybrid is 47.8% from G. hirsutum, 14.3% from G. australe, 7.0% from G. capitis-viridis, and 30.9% recombination bands respectively. It was testified that wild genetic material has been transferred into cultivated cotton and this new germplasm can be incorporated into cotton breeding program. PMID- 26035818 TI - Intravascular ultrasound observation of the mechanism of no-reflow phenomenon in acute myocardial infarction. AB - OBJECTIVE: To study the mechanism of the no-reflow phenomenon using coronary angiography (CAG) and intravascular ultrasound (IVUS). METHODS: A total of 120 patients with acute myocardial infarction (AMI) who successfully underwent indwelling intracoronary stent placement by percutaneous coronary intervention (PCI). All patients underwent pre- and post-PCI CAG and pre-IVUS. No-reflow was defined as post-PCI thrombolysis in myocardial infarction (TIMI) grade 0, 1, or 2 flow in the absence of mechanical obstruction. Normal reflow was defined as TIMI grade 3 flow. The pre-operation reference vascular area, minimal luminal cross sectional area, plaque cross-sectional area, lesion length, plaque volume and plaque traits were measured by IVUS. RESULTS: The no-reflow group was observed in 14 cases (11.6%) and normal blood-flow group in 106 cases (89.4%) based on CAG results. There was no statistically significant difference in the patients' medical history, reference vascular area (no-flow vs. normal-flow; 15.5 +/- 3.2 vs. 16.2 +/- 3.3, p > 0.05) and lesion length (21.9 +/- 5.1 vs. 19.5 +/- 4.8, p > 0.05) between the two groups. No-reflow patients had a longer symptom onset to reperfusion time compared to normal blood-flow group [(6.6 +/- 3.1) h vs (4.3 +/- 2.7) h; p < 0.05] and higher incidence of TIMI flow grade < 3 (71.4% vs 49.0%, p < 0.05). By IVUS examination, the no-reflow group had a significantly increased coronary plaque area and plaque volume compared to normal blood-flow group [(13.7 +/- 3.0) mm2 vs (10.2 +/- 2.9) mm2; (285.4 +/- 99.8) mm3 vs (189.7 +/- 86.4) mm3; p < 0.01]. The presence of IVUS-detected soft plaque (57.1% vs. 24.0%, p < 0.01), eccentric plaque (64.2% vs. 33.7%, p < 0.05), plaque rupture (50.0% vs. 21.2%, p < 0.01), and thrombosis (42.8% vs. 15.3%) were significantly more common in no reflow group. CONCLUSION: There was no obvious relationship between the coronary risk factors and no-reflow phenomenon. The symptom onset to reperfusion time, TIMI flow grade before stent deployment, plaque area, soft plaques, eccentric plaques, plaque rupture and thrombosis may be risk factors for the no-reflow phenomenon after PCI. PMID- 26035819 TI - Prior Hydrologic Disturbance Affects Competition between Aedes Mosquitoes via Changes in Leaf Litter. AB - Allochthonous leaf litter is often the main resource base for invertebrate communities in ephemeral water-filled containers, and detritus quality can be affected by hydrologic conditions. The invasive mosquito Aedes albopictus utilizes container habitats for its development where it competes as larvae for detritus and associated microorganisms with the native Aedes triseriatus. Different hydrologic conditions that containers are exposed to prior to mosquito utilization affect litter decay and associated water quality. We tested the hypothesis that larval competition between A. albopictus and A. triseriatus would be differentially affected by prior hydrologic conditions. Experimental microcosms provisioned with Quercus alba L. litter were subjected to one of three different hydrologic treatments prior to the addition of water and mosquito larvae: dry, flooded, and a wet/dry cycle. Interspecific competition between A. albopictus and A. triseriatus was mediated by hydrologic treatment, and was strongest in the dry treatment vs. the flooded or wet/dry treatments. Aedes triseriatus estimated rate of population change (lambda') was lowest in the dry treatment. Aedes albopictus lambda' was unaffected by hydrologic treatment, and was on average always increasing (i.e., > 1). Aedes triseriatus lambda' was affected by the interaction of hydrologic treatment with interspecific competition, and was on average declining (i.e., < 1.0), at the highest interspecific densities in the dry treatment. Dry treatment litter had the slowest decay rate and leached the highest concentration of tannin-lignin, but supported more total bacteria than the other treatments. These results suggest that dry conditions negatively impact A. triseriatus population performance and may result in the competitive exclusion of A. triseriatus by A. albopictus, possibly by reducing microbial taxa that Aedes species browse. Changing rainfall patterns with climate change are likely to affect competition between A. triseriatus and A. albopictus, probably enhancing negative competitive effects of A. albopictus on A. triseriatus in areas that experience drought. PMID- 26035820 TI - Simultaneous recordings of human microsaccades and drifts with a contemporary video eye tracker and the search coil technique. AB - Human eyes move continuously, even during visual fixation. These "fixational eye movements" (FEMs) include microsaccades, intersaccadic drift and oculomotor tremor. Research in human FEMs has grown considerably in the last decade, facilitated by the manufacture of noninvasive, high-resolution/speed video oculography eye trackers. Due to the small magnitude of FEMs, obtaining reliable data can be challenging, however, and depends critically on the sensitivity and precision of the eye tracking system. Yet, no study has conducted an in-depth comparison of human FEM recordings obtained with the search coil (considered the gold standard for measuring microsaccades and drift) and with contemporary, state of-the art video trackers. Here we measured human microsaccades and drift simultaneously with the search coil and a popular state-of-the-art video tracker. We found that 95% of microsaccades detected with the search coil were also detected with the video tracker, and 95% of microsaccades detected with video tracking were also detected with the search coil, indicating substantial agreement between the two systems. Peak/mean velocities and main sequence slopes of microsaccades detected with video tracking were significantly higher than those of the same microsaccades detected with the search coil, however. Ocular drift was significantly correlated between the two systems, but drift speeds were higher with video tracking than with the search coil. Overall, our combined results suggest that contemporary video tracking now approaches the search coil for measuring FEMs. PMID- 26035821 TI - Seed size, fecundity and postfire regeneration strategy are interdependent in Hakea. AB - Seed size is a key functional trait that affects plant fitness at the seedling stage and may vary greatly with species fruit size, growth form and fecundity. Using structural equation modelling (SEM) and correlated trait evolution analysis, we investigated the interaction network between seed size and fecundity, postfire regeneration strategy, fruit size, plant height and serotiny (on-plant seed storage) among 82 species of the woody shrub genus, Hakea, with a wide spectrum of seed sizes (2-500 mg). Seed size is negatively correlated with fecundity, while fire-killed species (nonsprouters) produce more seeds than resprouters though they are of similar size. Seed size is unrelated to plant height and level of serotiny while it scales allometrically with fruit size. A strong phylogenetic signal in seed size revealed phylogenetic constraints on seed size variation in Hakea. Our analyses suggest a causal relationship between seed size, fecundity and postfire regeneration strategy in Hakea. These results demonstrate that fruit size, fecundity and evolutionary history have had most control over seed size variation among Hakea species. PMID- 26035822 TI - Spatiotemporal stability of neonatal rat cardiomyocyte monolayers spontaneous activity is dependent on the culture substrate. AB - In native conditions, cardiac cells must continuously comply with diverse stimuli necessitating a perpetual adaptation. Polydimethylsiloxane (PDMS) is commonly used in cell culture to study cellular response to changes in the mechanical environment. The aim of this study was to evaluate the impact of using PDMS substrates on the properties of spontaneous activity of cardiomyocyte monolayer cultures. We compared PDMS to the gold standard normally used in culture: a glass substrate. Although mean frequency of spontaneous activity remained unaltered, incidence of reentrant activity was significantly higher in samples cultured on glass compared to PDMS substrates. Higher spatial and temporal instability of the spontaneous rate activation was found when cardiomyocytes were cultured on PDMS, and correlated with decreased connexin-43 and increased CaV3.1 and HCN2 mRNA levels. Compared to cultures on glass, cultures on PDMS were associated with the strongest response to isoproterenol and acetylcholine. These results reveal the importance of carefully selecting the culture substrate for studies involving mechanical stimulation, especially for tissue engineering or pharmacological high throughput screening of cardiac tissue analog. PMID- 26035824 TI - Pushing the limits of radiofrequency (RF) neuronal telemetry. AB - In a previous report it was shown that the channel capacity of an in vivo communication link using microscopic antennas at radiofrequency is severely limited by the requirement not to damage the tissue surrounding the antennas. For dipole-like antennas the strong electric field dissipates too much power into body tissues. Loop-type antennas have a strong magnetic near field and so dissipate much less power into the surrounding tissues but they require such a large current that the antenna temperature is raised to the thermal damage threshold of the tissue. The only solution was increasing the antenna size into hundreds of microns, which makes reporting on an individual neuron impossible. However, recently demonstrated true magnetic antennas offer an alternative not covered in the previous report. The near field of these antennas is dominated by the magnetic field yet they don't require large currents. Thus they combine the best characteristics of dipoles and loops. By calculating the coupling between identical magnetic antennas inside a model of the body medium we show an increase in the power transfer of up to 8 orders of magnitude higher than could be realized with the loops and dipoles, making the microscopic RF in-vivo transmitting antenna possible. PMID- 26035823 TI - Association between Aspirin Therapy and Clinical Outcomes in Patients with Non Obstructive Coronary Artery Disease: A Cohort Study. AB - BACKGROUND: Presence of non-obstructive coronary artery disease (CAD) is associated with increased prescription of cardiovascular preventive medications including aspirin. However, the association between aspirin therapy with all cause mortality and coronary revascularization in this population has not been investigated. METHODS AND FINDINGS: Among the cohort of individuals who underwent coronary computed tomography angiography (CCTA) from 2007 to 2011, 8372 consecutive patients with non-obstructive CAD (1-49% stenosis) were identified. Patients with statin or aspirin prescription before CCTA, and those with history of revascularization before CCTA were excluded. We analyzed the differences of all-cause mortality and a composite of mortality and late coronary revascularization (> 90 days after CCTA) between aspirin users (n = 3751; 44.8%) and non-users. During a median of 828 (interquartile range 385-1,342) days of follow-up, 221 (2.6%) mortality cases and 295 (3.5%) cases of composite endpoint were observed. Annualized mortality rates were 0.97% in aspirin users versus 1.28% in non-users, and annualized rates of composite endpoint were 1.56% versus 1.48%, respectively. Aspirin therapy was associated with significantly lower risk of all-cause mortality (adjusted HR 0.649; 95% CI 0.492-0.857; p = 0.0023), but not with the composite endpoint (adjusted HR 0.841; 95% CI 0.662-1.069; p = 0.1577). Association between aspirin and lower all-cause mortality was limited to patients with age >= 65 years, diabetes, hypertension, decreased renal function, and higher levels of coronary artery calcium score, low-density lipoprotein cholesterol and high-sensitivity C-reactive protein. CONCLUSIONS: Among the patients with non-obstructive CAD documented by CCTA, aspirin is associated with lower all-cause mortality only in those with higher risk. PMID- 26035825 TI - An efficient phase-selective gelator for aromatic solvents recovery based on a cyanostilbene amide derivative. AB - Two novel low molecular weight organogelators (LMOGs) 1 and 2 composed of a cholesteryl group, an amide group and various terminal cyanostilbene moieties were synthesized. They could form stable gels in p-xylene. In particular, 2 with more extended pi-conjugation length showed remarkable gelation ability in many aromatic solvents, chloroform and chloroform-containing mixed solvents at a relatively low concentration. FT-IR and XRD spectra indicated that the difference between 1 and 2 in the gelation properties may result from the deviation of the intermolecular hydrogen bonding and pi-pi stacking as driving forces for the formation of the gels. Significantly, 2 can function as an efficient room temperature phase-selective gelator (PSG) for potential application in the separation and recovery of various aromatic solvents from its mixture with water. Meanwhile, the gelator can be easily recovered and reused several times. Furthermore, the phase-selective gelation properties of 2 can provide a simple and feasible approach for the removal of the rhodamine B (RhB) dye from water. PMID- 26035826 TI - Unusual hydroxyl migration in the fragmentation of beta-alanine dication in the gas phase. AB - We present a combined experimental and theoretical study of the fragmentation of doubly positively charged beta-alanine molecules in the gas phase. The dissociation of the produced dicationic molecules, induced by low-energy ion collisions, is analysed by coincidence mass spectrometric techniques; the coupling with ab initio molecular dynamics simulations allows rationalisation of the experimental observations. The present strategy gives deeper insights into the chemical mechanisms of multiply charged amino acids in the gas phase. In the case of the beta-alanine dication, in addition to the expected Coulomb explosion and hydrogen migration processes, we have found evidence of hydroxyl-group migration, which leads to unusual fragmentation products, such as hydroxymethyl cation, and is necessary to explain some of the observed dominant channels. PMID- 26035827 TI - Immune-modulatory effects of bu-zhong-yi-qi-tang in ovalbumin-induced murine model of allergic asthma. AB - BACKGROUND: Bu-zhong-yi-qi-tang (BZYQT), an herbal formula of traditional Chinese medicine, has been an effective regimen of allergic diseases for nearly 800 years. Our previous report has demonstrated its anti-inflammatory effects in patients with perennial allergic rhinitis, and the aim of this study is to investigate the anti-asthmatic effect of BZYQT. METHODS: Female BALB/cByJNarl mice were sensitized with normal saline (control group) or OVA. Mice sensitized by OVA were fed with distilled water (OVA group), oral 0.5 g/Kg (low-dose group) or 1 g/Kg (high-dose group) of BZYQT solution once daily on days 36-40 besides their routine diet. Airway hyper-responsiveness (AHR), eosinophil infiltration, levels of cytokines and total immunoglobulin E (IgE) in broncho-alveolar lavage fluid (BALF) were determined. The lungs and tracheas were removed, and histopathologic examination was subsequently performed. RESULTS: AHR was significantly reduced in both low- and high-dose BZYQT groups compared with the OVA group after inhalation of the highest dose of methacholine (50 mg/ml). The levels of eotaxin, Th2-related cytokines (IL-4, IL-5, IL-13), IgE, and eosinophil infiltration in BALF were significantly decreased in both BZYQT groups compared with the OVA group. Histopathologic examination revealed that eosinophil infiltration of the lung and trachea tissues was remarkably attenuated in both BZYQT groups. CONCLUSIONS: Oral administration of BZYQT solution may exert anti asthmatic effect by relieving AHR in OVA-sensitized mice, which is compatible with our clinical experience. Although detailed mechanism is to be determined, we surmise that it may be correlated with the immune-modulatory effects of inhibiting Th2 responses on the basis of our limited results. PMID- 26035828 TI - Study on Environmental Causes and SNPs of MTHFR, MS and CBS Genes Related to Congenital Heart Disease. AB - PURPOSE: Congenital heart diseases (CHD) are among the most common birth defects in China. Environmental causes and folate metabolism changes may alter susceptibility to CHD. The aim of this study is to evaluate the relevant risk factors of children with CHD and their mothers. METHODS: 138 children with CHD and 207 normal children for controls were recruited. Their mothers were also enlisted in this study and interviewed following a questionnaire about their pregnant history and early pregnancy situation. Five single nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MS) and cystathionine beta-synthase (CBS) of mothers and children were genotyped. RESULTS: There were significant differences in the gender of children, occupation of mothers, family history with CHD, history of abortion, history of adverse pregnancy, early pregnancy health, fetus during pregnancy, pesticide exposure and drug exposure in CHD group and control group ( P < 0.05). Logistic regression analyses showed that after adjustment for above factors, MTHFR rs1801131 were significantly associated with their offspring CHD risk in mothers. Compared with the mothers whose MTHFR were rs1801131 AA and AC genotypes, the mothers who got a mutation of MTHFR rs1801131 CC genotypes had a 267% increase in risk of given birth of a CHD children (OR = 3.67,95%CI = 1.12-12.05). Meanwhile, MTHFR rs1801131 were significantly associated with CHD susceptibility in children (OR = 1.42, 95% CI = 1.00-2.44 in additive model). CONCLUSIONS: Besides mothers' social and fertility characteristics, our results suggested that the genetic variants in folate metabolism pathway might be one of the most related risk factors of CHD. MTHFR rs1801131 were identified as loci in Chinese population that were involved in CHD. PMID- 26035829 TI - MCL-1, BCL-XL and MITF Are Diversely Employed in Adaptive Response of Melanoma Cells to Changes in Microenvironment. AB - Melanoma cells can switch their phenotypes in response to microenvironmental insults. Heterogeneous melanoma populations characterized by long-term growth and a high self-renewal capacity can be obtained in vitro in EGF(+)bFGF(+) medium whilst invasive potential of melanoma cells is increased in serum-containing cultures. In the present study, we have shown that originally these patient derived melanoma populations exhibit variable expression of pro-survival genes from the BCL-2 family and inhibitors of apoptosis (IAPs), and differ in the baseline MCL-1 transcript stability as well. While being transferred to serum containing medium, melanoma cells are well protected from death. Immediate adaptive response of melanoma cells selectively involves a temporary MCL-1 increase, both at mRNA and protein levels, and BCL-XL can complement MCL-1, especially in MITFlow populations. Thus, the extent of MCL-1 and BCL-XL contributions seems to be cell context-dependent. An increase in MCL-1 level results from a transiently enhanced stability of its transcript, but not from altered protein turnover. Inhibition of MCL-1 preceding transfer to serum containing medium caused the induction of cell death in a subset of melanoma cells, which confirms the involvement of MCL-1 in melanoma cell survival during the rapid alteration of growth conditions. Additionally, immediate response to serum involves the transient increase in MITF expression and inhibition of ERK 1/2 activity. Uncovering the mechanisms of adaptive response to rapid changes in microenvironment may extend our knowledge on melanoma biology, especially at the stage of dissemination. PMID- 26035831 TI - Sites of peripheral artery occlusive disease as a predictor for all-cause and cardiovascular mortality in chronic hemodialysis. AB - BACKGROUND: The ankle-brachial blood pressure (BP) index (ABI) not only indicates the presence of peripheral artery occlusive disease (PAOD) but predicts mortality in patients undergoing hemodialysis (HD). However, whether the site of PAOD can provide additional contribution to predicting mortality have not been investigated yet. Our primary objective was to determine the associations between the site of PAOD and all-cause and cardiovascular mortality in chronic HD (CHD) patients. METHODS: A retrospective cohort study was conducted to evaluate 444 Taiwanese CHD patients between December 2006 and June 2013. The site of PAOD together with other explanatory variables such as demographic data, body mass index, a history of cardiovascular diseases, HD vintage, biochemical data, and cardiothoracic ratio (CTR) were assessed by the Cox proportional hazards regression model. RESULTS: The frequency of PAOD was 14.6% in both legs, 4.9% in the right side only, and 5.1% in the left side only. During the study period, 127 all-cause and 93 cardiovascular deaths occurred. PAOD site was found to have significant predictive power for all-cause mortality with the order of 3.04 (95% CI: 1.56-5.90) hazard ratio on the right side, 2.48 (95% CI: 1.27-4.82) on the left side, and 4.11 (95% CI: 2.76-6.13) on both sides. The corresponding figures for cardiovascular mortality were 3.81 (95% CI: 1.87-7.76) on the right side, 2.76 (95% CI: 1.30-5.82) on the left side, and 3.95 (95% CI: 2.45-6.36) on both sides. After adjustment for other explanatory variables, only right-sided PAOD still remained to have significant predictive power for all-cause and cardiovascular mortality and bilateral PAOD kept the significant association with all-cause mortality. CONCLUSIONS: The site of PAOD revealed various predictive powers for all-cause and cardiovascular mortality in CHD patients and only right sided PAOD remained an independent predictor for both types of mortality making allowance for relevant confounding factors. PMID- 26035830 TI - Inflammatory and repair pathways induced in human bronchoalveolar lavage cells with ozone inhalation. AB - BACKGROUND: Inhalation of ambient levels of ozone causes airway inflammation and epithelial injury. METHODS: To examine the responses of airway cells to ozone induced oxidative injury, 19 subjects (7 with asthma) were exposed to clean air (0ppb), medium (100ppb), and high (200ppb) ambient levels of ozone for 4h on three separate occasions in a climate-controlled chamber followed by bronchoscopy with bronchoalveolar lavage (BAL) 24h later. BAL cell mRNA expression was examined using Affymetrix GeneChip Microarray. The role of a differentially expressed gene (DEG) in epithelial injury was evaluated in an in vitro model of injury [16HBE14o- cell line scratch assay]. RESULTS: Ozone exposure caused a dose dependent up-regulation of several biologic pathways involved in inflammation and repair including chemokine and cytokine secretion, activity, and receptor binding; metalloproteinase and endopeptidase activity; adhesion, locomotion, and migration; and cell growth and tumorigenesis regulation. Asthmatic subjects had 1.7- to 3.8-fold higher expression of many DEGs suggestive of increased proinflammatory and matrix degradation and remodeling signals. The most highly up regulated gene was osteopontin, the protein level of which in BAL fluid increased in a dose-dependent manner after ozone exposure. Asthmatic subjects had a disproportionate increase in non-polymerized osteopontin with increasing exposure to ozone. Treatment with polymeric, but not monomeric, osteopontin enhanced the migration of epithelial cells and wound closure in an alpha9beta1 integrin dependent manner. CONCLUSIONS: Expression profiling of BAL cells after ozone exposure reveals potential regulatory genes and pathways activated by oxidative stress. One DEG, osteopontin, promotes epithelial wound healing in an in vitro model of injury. PMID- 26035832 TI - Modulation of Gene Expression by Polymer Nanocapsule Delivery of DNA Cassettes Encoding Small RNAs. AB - Small RNAs, including siRNAs, gRNAs and miRNAs, modulate gene expression and serve as potential therapies for human diseases. Delivery to target cells remains the fundamental limitation for use of these RNAs in humans. To address this challenge, we have developed a nanocapsule delivery technology that encapsulates small DNA molecules encoding RNAs into a small (30 nm) polymer nanocapsule. For proof of concept, we transduced DNA expression cassettes for three small RNAs. In one application, the DNA cassette encodes an shRNA transcriptional unit that downregulates CCR5 and protects from HIV-1 infection. The DNA cassette nanocapsules were further engineered for timed release of the DNA cargo for prolonged knockdown of CCR5. Secondly, the nanocapsules provide an efficient means for delivery of gRNAs in the CRISPR/Cas9 system to mutate integrated HIV-1. Finally, delivery of microRNA-125b to mobilized human CD34+ cells enhances survival and expansion of the CD34+ cells in culture. PMID- 26035833 TI - Curcumin Treatment Improves Motor Behavior in alpha-Synuclein Transgenic Mice. AB - The curry spice curcumin plays a protective role in mouse models of neurodegenerative diseases, and can also directly modulate aggregation of alpha synuclein protein in vitro, yet no studies have described the interaction of curcumin and alpha-synuclein in genetic synucleinopathy mouse models. Here we examined the effect of chronic and acute curcumin treatment in the Syn-GFP mouse line, which overexpresses wild-type human alpha-synuclein protein. We discovered that curcumin diet intervention significantly improved gait impairments and resulted in an increase in phosphorylated forms of alpha-synuclein at cortical presynaptic terminals. Acute curcumin treatment also caused an increase in phosphorylated alpha-synuclein in terminals, but had no direct effect on alpha synuclein aggregation, as measured by in vivo multiphoton imaging and Proteinase K digestion. Using LC-MS/MS, we detected ~5 ng/mL and ~12 ng/mL free curcumin in the plasma of chronic or acutely treated mice, with a glucuronidation rate of 94% and 97%, respectively. Despite the low plasma levels and extensive metabolism of curcumin, these results show that dietary curcumin intervention correlates with significant behavioral and molecular changes in a genetic synucleinopathy mouse model that mimics human disease. PMID- 26035834 TI - Cancer genetics education in a low- to middle-income country: evaluation of an interactive workshop for clinicians in Kenya. AB - BACKGROUND: Clinical genetic testing is becoming an integral part of medical care for inherited disorders. While genetic testing and counseling are readily available in high-income countries, in low- and middle-income countries like Kenya genetic testing is limited and genetic counseling is virtually non existent. Genetic testing is likely to become widespread in Kenya within the next decade, yet there has not been a concomitant increase in genetic counseling resources. To address this gap, we designed an interactive workshop for clinicians in Kenya focused on the genetics of the childhood eye cancer retinoblastoma. The objectives were to increase retinoblastoma genetics knowledge, build genetic counseling skills and increase confidence in those skills. METHODS: The workshop was conducted at the 2013 Kenyan National Retinoblastoma Strategy meeting. It included a retinoblastoma genetics presentation, small group discussion of case studies and genetic counseling role play. Knowledge was assessed by standardized test, and genetic counseling skills and confidence by questionnaire. RESULTS: Knowledge increased significantly post workshop, driven by increased knowledge of retinoblastoma causative genetics. One year post-workshop, participant knowledge had returned to baseline, indicating that knowledge retention requires more frequent reinforcement. Participants reported feeling more confident discussing genetics with patients, and had integrated more genetic counseling into patient interactions. CONCLUSION: A comprehensive retinoblastoma genetics workshop can increase the knowledge and skills necessary for effective retinoblastoma genetic counseling. PMID- 26035836 TI - Automated multi-lesion detection for referable diabetic retinopathy in indigenous health care. AB - Diabetic Retinopathy (DR) is a complication of diabetes mellitus that affects more than one-quarter of the population with diabetes, and can lead to blindness if not discovered in time. An automated screening enables the identification of patients who need further medical attention. This study aimed to classify retinal images of Aboriginal and Torres Strait Islander peoples utilizing an automated computer-based multi-lesion eye screening program for diabetic retinopathy. The multi-lesion classifier was trained on 1,014 images from the Sao Paulo Eye Hospital and tested on retinal images containing no DR-related lesion, single lesions, or multiple types of lesions from the Inala Aboriginal and Torres Strait Islander health care centre. The automated multi-lesion classifier has the potential to enhance the efficiency of clinical practice delivering diabetic retinopathy screening. Our program does not necessitate image samples for training from any specific ethnic group or population being assessed and is independent of image pre- or post-processing to identify retinal lesions. In this Aboriginal and Torres Strait Islander population, the program achieved 100% sensitivity and 88.9% specificity in identifying bright lesions, while detection of red lesions achieved a sensitivity of 67% and specificity of 95%. When both bright and red lesions were present, 100% sensitivity with 88.9% specificity was obtained. All results obtained with this automated screening program meet WHO standards for diabetic retinopathy screening. PMID- 26035835 TI - Periodontal treatment for preventing adverse pregnancy outcomes: a meta- and trial sequential analysis. AB - OBJECTIVES: Periodontal treatment might reduce adverse pregnancy outcomes. The efficacy of periodontal treatment to prevent preterm birth, low birth weight, and perinatal mortality was evaluated using meta-analysis and trial sequential analysis. METHODS: An existing systematic review was updated and meta-analyses performed. Risk of bias, heterogeneity, and publication bias were evaluated, and meta-regression performed. Subgroup analysis was used to compare different studies with low and high risk of bias and different populations, i.e., risk groups. Trial sequential analysis was used to assess risk of random errors. RESULTS: Thirteen randomized clinical trials evaluating 6283 pregnant women were meta-analyzed. Four and nine trials had low and high risk of bias, respectively. Overall, periodontal treatment had no significant effect on preterm birth (odds ratio [95% confidence interval] 0.79 [0.57-1.10]) or low birth weight (0.69 [0.43 1.13]). Trial sequential analysis demonstrated that futility was not reached for any of the outcomes. For populations with moderate occurrence (< 20%) of preterm birth or low birth weight, periodontal treatment was not efficacious for any of the outcomes, and trial sequential analyses indicated that further trials might be futile. For populations with high occurrence (>= 20%) of preterm birth and low birth weight, periodontal treatment seemed to reduce the risk of preterm birth (0.42 [0.24-0.73]) and low birth weight (0.32 [0.15-0.67]), but trial sequential analyses showed that firm evidence was not reached. Periodontal treatment did not significantly affect perinatal mortality, and firm evidence was not reached. Risk of bias, but not publication bias or patients' age modified the effect estimates. CONCLUSIONS: Providing periodontal treatment to pregnant women could potentially reduce the risks of perinatal outcomes, especially in mothers with high risks. Conclusive evidence could not be reached due to risks of bias, risks of random errors, and unclear effects of confounding. Further randomized clinical trials are required. PMID- 26035838 TI - Large-Scale SNP Discovery and Genotyping for Constructing a High-Density Genetic Map of Tea Plant Using Specific-Locus Amplified Fragment Sequencing (SLAF-seq). AB - Genetic maps are important tools in plant genomics and breeding. The present study reports the large-scale discovery of single nucleotide polymorphisms (SNPs) for genetic map construction in tea plant. We developed a total of 6,042 valid SNP markers using specific-locus amplified fragment sequencing (SLAF-seq), and subsequently mapped them into the previous framework map. The final map contained 6,448 molecular markers, distributing on fifteen linkage groups corresponding to the number of tea plant chromosomes. The total map length was 3,965 cM, with an average inter-locus distance of 1.0 cM. This map is the first SNP-based reference map of tea plant, as well as the most saturated one developed to date. The SNP markers and map resources generated in this study provide a wealth of genetic information that can serve as a foundation for downstream genetic analyses, such as the fine mapping of quantitative trait loci (QTL), map-based cloning, marker assisted selection, and anchoring of scaffolds to facilitate the process of whole genome sequencing projects for tea plant. PMID- 26035839 TI - Rasch analysis of the Chronic Pain Acceptance Questionnaire Revised in people with knee osteoarthritis. AB - OBJECTIVE: To examine the measurement properties of the Chronic Pain Acceptance Questionnaire Revised (CPAQ-R) and its subscales with people with knee osteoarthritis using Rasch analysis. DESIGN: Cross-sectional questionnaire study. PATIENTS: A total of 176 participants with radiographic evidence of osteoarthritis of the knee, as identified by a Kellgren-Lawrence grade >= 2, and pain on most days for at least the past month. METHODS: Participants completed the CPAQ-R at home within a set of measures covering different aspects of osteoarthritis pain. The questionnaires were returned by pre-paid envelope. Rasch analysis was conducted on the Activity Engagement and Pain Willingness subscales and the Total scale using Rasch Unidimensional Measurement Models (RUMM2020). RESULTS: The Activity Engagement and Pain Willingness subscales fit the Rasch model following minimal changes, including re-scoring and removal of item 14 due to misfit. Both subscales passed tests of unidimensionality. Although the Total scale could be adjusted to yield adequate fit statistics, it demonstrated multidimensionality. CONCLUSION: The Activity Engagement and Pain Willingness subscales have good measurement properties for 2 distinct factors relevant to pain acceptance. CPAQ-R is a valid measurement tool that may help target and evaluate response to treatments that address low activity engagement and pain willingness in people with osteoarthritis. PMID- 26035837 TI - Fecal Microbiota in Healthy Subjects Following Omnivore, Vegetarian and Vegan Diets: Culturable Populations and rRNA DGGE Profiling. AB - In this study, the fecal microbiota of 153 healthy volunteers, recruited from four different locations in Italy, has been studied by coupling viable counts, on different microbiological media, with ribosomal RNA Denaturing Gradient Gel Electrophoresis (rRNA-DGGE). The volunteers followed three different diets, namely omnivore, ovo-lacto-vegetarian and vegan. The results obtained from culture-dependent and -independent methods have underlined a high level of similarity of the viable fecal microbiota for the three investigated diets. The rRNA DGGE profiles were very complex and comprised a total number of bands that varied from 67 to 64 for the V3 and V9 regions of the 16S rRNA gene, respectively. Only a few bands were specific in/of all three diets, and the presence of common taxa associated with the dietary habits was found. As far as the viable counts are concerned, the high similarity of the fecal microbiota was once again confirmed, with only a few of the investigated groups showing significant differences. Interestingly, the samples grouped differently, according to the recruitment site, thus highlighting a higher impact of the food consumed by the volunteers in the specific geographical locations than that of the type of diet. Lastly, it should be mentioned that the fecal microbiota DGGE profiles obtained from the DNA were clearly separated from those produced using RNA, thus underlining a difference between the total and viable populations in the fecal samples. PMID- 26035840 TI - Reliability and validity of the modified sphygmomanometer test for the assessment of strength of upper limb muscles after stroke. AB - OBJECTIVE: To investigate the reliability (test-retest and inter-rater) and criterion-related validity of the modified sphygmomanometer test (MST) for the assessment of upper limb muscle strength in subjects with chronic stroke, and to determine whether the results are affected by the number of trials. PATIENTS AND METHODS: The strength of 11 upper limb muscle groups of 57 subjects with stroke was bilaterally assessed with portable dynamometers and the MST (measured in mmHg). To investigate whether the number of trials would affect the results, 1 way analysis of variance was applied. For the test-retest/inter-rater reliabilities and criterion-related validity of the MST, intra-class correlation coefficients (ICCs), Pearson's correlation coefficients, and coefficients of determination were calculated. RESULTS: Different numbers of trials provided similar values for all assessed muscles (0.01 <= F <= 0.18; 0.83 <= p <= 0.99) with adequate test-retest (0.83 <= ICC <= 0.97; p < 0.0001) and inter-rater reliabilities (0.79 <= ICC <= 0.97; p < 0.0001) and validity (0.61 <= r <= 0.95; p < 0.0001). The values obtained with the MST were good predictors of those obtained with portable dynamometers (0.60 <= r2 <= 0.86), except for pinch strength (0.39 <= r2 <= 0.54). CONCLUSION: The MST showed adequate measurement properties for the assessment of the strength of the upper limb muscles of subjects with chronic stroke. After familiarization a single trial provided adequate strength values. PMID- 26035845 TI - Prison terminal: the last days of private jack Hall. PMID- 26035841 TI - Advances in using MRI probes and sensors for in vivo cell tracking as applied to regenerative medicine. AB - The field of molecular and cellular imaging allows molecules and cells to be visualized in vivo non-invasively. It has uses not only as a research tool but in clinical settings as well, for example in monitoring cell-based regenerative therapies, in which cells are transplanted to replace degenerating or damaged tissues, or to restore a physiological function. The success of such cell-based therapies depends on several critical issues, including the route and accuracy of cell transplantation, the fate of cells after transplantation, and the interaction of engrafted cells with the host microenvironment. To assess these issues, it is necessary to monitor transplanted cells non-invasively in real time. Magnetic resonance imaging (MRI) is a tool uniquely suited to this task, given its ability to image deep inside tissue with high temporal resolution and sensitivity. Extraordinary efforts have recently been made to improve cellular MRI as applied to regenerative medicine, by developing more advanced contrast agents for use as probes and sensors. These advances enable the non-invasive monitoring of cell fate and, more recently, that of the different cellular functions of living cells, such as their enzymatic activity and gene expression, as well as their time point of cell death. We present here a review of recent advancements in the development of these probes and sensors, and of their functioning, applications and limitations. PMID- 26035842 TI - Genetically modified T cells in cancer therapy: opportunities and challenges. AB - Tumours use many strategies to evade the host immune response, including downregulation or weak immunogenicity of target antigens and creation of an immune-suppressive tumour environment. T cells play a key role in cell-mediated immunity and, recently, strategies to genetically modify T cells either through altering the specificity of the T cell receptor (TCR) or through introducing antibody-like recognition in chimeric antigen receptors (CARs) have made substantial advances. The potential of these approaches has been demonstrated in particular by the successful use of genetically modified T cells to treat B cell haematological malignancies in clinical trials. This clinical success is reflected in the growing number of strategic partnerships in this area that have attracted a high level of investment and involve large pharmaceutical organisations. Although our understanding of the factors that influence the safety and efficacy of these therapies has increased, challenges for bringing genetically modified T-cell immunotherapy to many patients with different tumour types remain. These challenges range from the selection of antigen targets and dealing with regulatory and safety issues to successfully navigating the routes to commercial development. However, the encouraging clinical data, the progress in the scientific understanding of tumour immunology and the improvements in the manufacture of cell products are all advancing the clinical translation of these important cellular immunotherapies. PMID- 26035843 TI - Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender. AB - Mutations in the CLN3 gene cause a fatal neurodegenerative disorder: juvenile CLN3 disease, also known as juvenile Batten disease. The two most commonly utilized mouse models of juvenile CLN3 disease are Cln3-knockout (Cln3(-/-)) and Cln3(Deltaex7/8)-knock-in mice, the latter mimicking the most frequent disease causing human mutation. To determine which mouse model has the most pronounced neurological phenotypes that can be used as outcome measures for therapeutic studies, we compared the exploratory activity, motor function and depressive-like behavior of 1-, 3- and 6-month-old Cln3(-/-) and Cln3(Deltaex7/8)-knock-in mice on two different genetic backgrounds (129S6/SvEv and C57BL/6J). Although, in many cases, the behavior of Cln3(-/-) and Cln3(Deltaex7/8) mice was similar, we found genetic-background-, gender- and age-dependent differences between the two mouse models. We also observed large differences in the behavior of the 129S6/SvEv and C57BL/6J wild-type strains, which highlights the strong influence that genetic background can have on phenotype. Based on our results, Cln3(-/-) male mice on the 129S6/SvEv genetic background are the most appropriate candidates for therapeutic studies. They exhibit motor deficits at 1 and 6 months of age in the vertical pole test, and they were the only mice to show impaired motor coordination in the rotarod test at both 3 and 6 months. Cln3(-/-) males on the C57BL/6J background and Cln3(Deltaex7/8) males on the 129S6/SvEv background also provide good outcome measures for therapeutic interventions. Cln3(-/-) (C57BL/6J) males had serious difficulties in climbing down (at 1 and 6 months) and turning downward on (at 1, 3 and 6 months) the vertical pole, whereas Cln3(Deltaex7/8) (129S6/SvEv) males climbed down the vertical pole drastically slower than wild type males at 3 and 6 months of age. Our study demonstrates the importance of testing mouse models on different genetic backgrounds and comparing males and females in order to find the most appropriate disease model for therapeutic studies. PMID- 26035846 TI - "Fumbling About with Alzheimer's": One Disease, Three Women and a Camera. PMID- 26035855 TI - Perceptions of Depression and Access to Mental Health Care Among Latino Immigrants: Looking Beyond One Size Fits All. AB - Compared with non-Latino Whites, Latino immigrants have a lower prevalence of depression. However, they are also less likely to seek professional mental health services. Our objective was to compare and contrast perceptions of depression and access to mental health care among four of the largest Latino immigrant subgroups in Florida (Puerto Rican, Cuban, Mexican, and Colombian). We conducted a total of 120 interviews (30 men and women from each subgroup). Thematic analysis of qualitative data revealed that participants across the four groups were aware of the signs and symptoms of depression and had similar perceptions of depression. However, notable differences by subgroup emerged with regard to perceptions of access to mental health care. We suggest that the variation stems from differences in life experiences and the immigration context. Understanding the variances and nuances of Latino immigrants' cultural construction of depression and immigration experience will enable practitioners to better serve this community. PMID- 26035856 TI - Anterior Cruciate Ligament Reconstruction Does Not Fully Restore Normal 3D Knee Kinematics at 12 Months During Walking and Walk-Pivoting: A Longitudinal Gait Analysis Study. AB - The purpose of the current study was to longitudinally evaluate how preoperative knee kinematics change after ACL reconstruction. Three-dimensional gait analysis using the point cluster method was undertaken on the same subjects preoperatively and at 3, 6, and 12 months after ACL reconstructive surgery. Thirteen subjects (7 males, 6 females) were examined while performing 2 different activities at self selected speeds: walking and walk-pivoting (walking, pivoting toward the landed limb side and walking away). The contralateral knees of subjects at 12 months postoperatively were selected as control knees. Flexion range in the stance phase increased with time after surgery, but remained lower than in the contralateral knee, even at 12 months postoperatively (P < .05) during walking and walk pivoting. The rotation pattern during walking and walk-pivoting showed an offset toward external rotation by 6 months postoperatively compared with control knees, while at 12 months postoperatively the offset had nearly disappeared and the movement pattern resembled that in control knees. These findings suggest that a return to sport participation by 6 months after ACL reconstruction requires careful consideration. Depending on the type of sport, activity restriction even after 12 months may need to be considered to allow complete kinematic restoration. PMID- 26035857 TI - Subtle Differences During Posturography Testing Can Influence Postural Sway Results: The Effects of Talking, Time Before Data Acquisition, and Visual Fixation. AB - The goal of this study was to examine the effects of 3 factors and their interactions on posturography: a period of time to become accustomed to the force platform before the initiation of data collection, presence of a visual fixation point, and participant talking during testing. The postural stability of 30 young adults and 30 older adults was evaluated to determine whether any observed effects were confounded with age. Analysis of variance techniques were used to test all possible combinations of the 3 factors. We hypothesized that all 3 factors would significantly affect postural stability. For both participant groups, the results suggest that a period of time to become accustomed to the force platform before the initiation of data collection and a visual fixation point significantly affect postural control measures, while brief participant talking does not. Despite this, no significant interactions existed suggesting that the effects of these factors, which may occur in clinical testing, do not depend on each other. Our results suggest that inconsistencies in posturography testing methods have the potential to significantly affect the results of posturography, underscoring the importance of developing a standardized testing methodology. PMID- 26035858 TI - Looking for a needle in a haystack--tackling rare diseases: an interview with Kym Boycott. PMID- 26035860 TI - The Interday Measurement Consistency of and Relationships Between Hamstring and Leg Musculo-articular Stiffness. AB - Hamstring stiffness (K(HAM)) and leg stiffness (K(LEG)) are commonly examined relative to athletic performance and injury risk. Given these may be modifiable, it is important to understand day-to-day variations inherent in these measures before use in training studies. In addition, the extent to which K(HAM) and K(LEG) measure similar active stiffness characteristics has not been established. We investigated the interday measurement consistency of K(HAM) and K(LEG), and examined the extent to which K(LEG) predicted K(HAM) in 6 males and 9 females. K(HAM) was moderately consistent day-to-day (ICC(2,5) = .71; SEM = 76.3 N.m(-1)), and 95% limits of agreement (95% LOA) revealed a systematic bias with considerable absolute measurement error (95% LOA = 89.6 +/- 224.8 N.m(-1)). Day to-day differences in procedural factors explained 59.4% of the variance in day to-day differences in K(HAM). Bilateral and unilateral K(LEG) was more consistent (ICC(2,3) range = .87-.94; SEM range = 1.0-2.91 kN.m(-1)) with lower absolute error (95% LOA bilateral= -2.0 +/- 10.3; left leg = -0.36 +/- 3.82; right leg = 1.05 +/- 3.61 kN.m(-1)). K(LEG) explained 44% of the variance in K(HAM) (P < .01). Findings suggest that procedural factors must be carefully controlled to yield consistent and precise K(HAM) measures. The ease and consistency of K(LEG), and moderate correlation with K(HAM), may steer clinicians toward K(LEG) when measuring lower-extremity stiffness for screening studies and monitoring the effectiveness of training interventions over time. PMID- 26035859 TI - Cellular models and therapies for age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a complex neurodegenerative visual disorder that causes profound physical and psychosocial effects. Visual impairment in AMD is caused by the loss of retinal pigmented epithelium (RPE) cells and the light-sensitive photoreceptor cells that they support. There is currently no effective treatment for the most common form of this disease (dry AMD). A new approach to treating AMD involves the transplantation of RPE cells derived from either human embryonic or induced pluripotent stem cells. Multiple clinical trials are being initiated using a variety of cell therapies. Although many animal models are available for AMD research, most do not recapitulate all aspects of the disease, hampering progress. However, the use of cultured RPE cells in AMD research is well established and, indeed, some of the more recently described RPE-based models show promise for investigating the molecular mechanisms of AMD and for screening drug candidates. Here, we discuss innovative cell-culture models of AMD and emerging stem-cell-based therapies for the treatment of this vision-robbing disease. PMID- 26035861 TI - Correlates of Physical Activity in Latino Preschool Children Attending Head Start. AB - BACKGROUND: Physical activity is associated with long-term benefits for health and tracks from early childhood into later adolescence. Limited information exists about factors influencing physical activity among Latino preschoolers. We aimed to identify correlates of objectively measured light-to-vigorous-intensity physical activity as a proportion of wear time (% PA) in Latino 3-5 year olds. METHODS: Latino preschoolers (n = 96) were recruited from Head Start centers in Houston, TX, USA, from 2009 to 2010. Sociodemographics, anthropometrics, acculturation, neighborhood disorder, and TV viewing were measured. Actigraph GT1M accelerometers measured physical activity. Block linear regression was used with % PA as the dependent variable. RESULTS: Children achieved 285.7 +/- 58.0 min/day of PA. In the final adjusted-model, child age, parental education and neighborhood disorder were positively associated with % PA (beta = 0.33, p = .002; beta = 0.25, p = .038; beta = 0.22, p = .039, respectively). TV viewing was inversely associated with % PA (beta=-0.23, p = .027). CONCLUSION: The majority of Latino preschoolers in our study exceeded US national and international guidelines of physical activity duration. Future interventions to sustain physical activity should focus on the influence of age, socioeconomic status, neighborhood disorder, and TV viewing on Latino preschoolers' attainment of physical activity. PMID- 26035863 TI - The Meckel-Gruber syndrome protein TMEM67 controls basal body positioning and epithelial branching morphogenesis in mice via the non-canonical Wnt pathway. AB - Ciliopathies are a group of developmental disorders that manifest with multi organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and cochlear hair cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the hair bundle, suggesting aberrant basal body migration, although planar cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extracellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/beta-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions. PMID- 26035864 TI - The lysyl oxidase inhibitor beta-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats. AB - Extracellular matrix (ECM) remodelling of the adipose tissue plays a pivotal role in the pathophysiology of obesity. The lysyl oxidase (LOX) family of amine oxidases, including LOX and LOX-like (LOXL) isoenzymes, controls ECM maturation, and upregulation of LOX activity is essential in fibrosis; however, its involvement in adipose tissue dysfunction in obesity is unclear. In this study, we observed that LOX is the main isoenzyme expressed in human adipose tissue and that its expression is strongly upregulated in samples from obese individuals that had been referred to bariatric surgery. LOX expression was also induced in the adipose tissue from male Wistar rats fed a high-fat diet (HFD). Interestingly, treatment with beta-aminopropionitrile (BAPN), a specific and irreversible inhibitor of LOX activity, attenuated the increase in body weight and fat mass that was observed in obese animals and shifted adipocyte size toward smaller adipocytes. BAPN also ameliorated the increase in collagen content that was observed in adipose tissue from obese animals and improved several metabolic parameters - it ameliorated glucose and insulin levels, decreased homeostasis model assessment (HOMA) index and reduced plasma triglyceride levels. Furthermore, in white adipose tissue from obese animals, BAPN prevented the downregulation of adiponectin and glucose transporter 4 (GLUT4), as well as the increase in suppressor of cytokine signaling 3 (SOCS3) and dipeptidyl peptidase 4 (DPP4) levels, triggered by the HFD. Likewise, in the TNFalpha-induced insulin resistant 3T3-L1 adipocyte model, BAPN prevented the downregulation of adiponectin and GLUT4 and the increase in SOCS3 levels, and consequently normalised insulin-stimulated glucose uptake. Therefore, our data provide evidence that LOX plays a pathologically relevant role in the metabolic dysfunction induced by obesity and emphasise the interest of novel pharmacological interventions that target adipose tissue fibrosis and LOX activity for the clinical management of this disease. PMID- 26035866 TI - Clueless, a protein required for mitochondrial function, interacts with the PINK1 Parkin complex in Drosophila. AB - Loss of mitochondrial function often leads to neurodegeneration and is thought to be one of the underlying causes of neurodegenerative diseases such as Parkinson's disease (PD). However, the precise events linking mitochondrial dysfunction to neuronal death remain elusive. PTEN-induced putative kinase 1 (PINK1) and Parkin (Park), either of which, when mutated, are responsible for early-onset PD, mark individual mitochondria for destruction at the mitochondrial outer membrane. The specific molecular pathways that regulate signaling between the nucleus and mitochondria to sense mitochondrial dysfunction under normal physiological conditions are not well understood. Here, we show that Drosophila Clueless (Clu), a highly conserved protein required for normal mitochondrial function, can associate with Translocase of the outer membrane (TOM) 20, Porin and PINK1, and is thus located at the mitochondrial outer membrane. Previously, we found that clu genetically interacts with park in Drosophila female germ cells. Here, we show that clu also genetically interacts with PINK1, and our epistasis analysis places clu downstream of PINK1 and upstream of park. In addition, Clu forms a complex with PINK1 and Park, further supporting that Clu links mitochondrial function with the PINK1-Park pathway. Lack of Clu causes PINK1 and Park to interact with each other, and clu mutants have decreased mitochondrial protein levels, suggesting that Clu can act as a negative regulator of the PINK1-Park pathway. Taken together, these results suggest that Clu directly modulates mitochondrial function, and that Clu's function contributes to the PINK1-Park pathway of mitochondrial quality control. PMID- 26035862 TI - Yeast as a system for modeling mitochondrial disease mechanisms and discovering therapies. AB - Mitochondrial diseases are severe and largely untreatable. Owing to the many essential processes carried out by mitochondria and the complex cellular systems that support these processes, these diseases are diverse, pleiotropic, and challenging to study. Much of our current understanding of mitochondrial function and dysfunction comes from studies in the baker's yeast Saccharomyces cerevisiae. Because of its good fermenting capacity, S. cerevisiae can survive mutations that inactivate oxidative phosphorylation, has the ability to tolerate the complete loss of mitochondrial DNA (a property referred to as 'petite-positivity'), and is amenable to mitochondrial and nuclear genome manipulation. These attributes make it an excellent model system for studying and resolving the molecular basis of numerous mitochondrial diseases. Here, we review the invaluable insights this model organism has yielded about diseases caused by mitochondrial dysfunction, which ranges from primary defects in oxidative phosphorylation to metabolic disorders, as well as dysfunctions in maintaining the genome or in the dynamics of mitochondria. Owing to the high level of functional conservation between yeast and human mitochondrial genes, several yeast species have been instrumental in revealing the molecular mechanisms of pathogenic human mitochondrial gene mutations. Importantly, such insights have pointed to potential therapeutic targets, as have genetic and chemical screens using yeast. PMID- 26035867 TI - Presence of multiple lesion types with vastly different microenvironments in C3HeB/FeJ mice following aerosol infection with Mycobacterium tuberculosis. AB - Cost-effective animal models that accurately reflect the pathological progression of pulmonary tuberculosis are needed to screen and evaluate novel tuberculosis drugs and drug regimens. Pulmonary disease in humans is characterized by a number of heterogeneous lesion types that reflect differences in cellular composition and organization, extent of encapsulation, and degree of caseous necrosis. C3HeB/FeJ mice have been increasingly used to model tuberculosis infection because they produce hypoxic, well-defined granulomas exhibiting caseous necrosis following aerosol infection with Mycobacterium tuberculosis. A comprehensive histopathological analysis revealed that C3HeB/FeJ mice develop three morphologically distinct lesion types in the lung that differ with respect to cellular composition, degree of immunopathology and control of bacterial replication. Mice displaying predominantly the fulminant necrotizing alveolitis lesion type had significantly higher pulmonary bacterial loads and displayed rapid and severe immunopathology characterized by increased mortality, highlighting the pathological role of an uncontrolled granulocytic response in the lung. Using a highly sensitive novel fluorescent acid-fast stain, we were able to visualize the spatial distribution and location of bacteria within each lesion type. Animal models that better reflect the heterogeneity of lesion types found in humans will permit more realistic modeling of drug penetration into solid caseous necrotic lesions and drug efficacy testing against metabolically distinct bacterial subpopulations. A more thorough understanding of the pathological progression of disease in C3HeB/FeJ mice could facilitate modulation of the immune response to produce the desired pathology, increasing the utility of this animal model. PMID- 26035865 TI - High-resolution live imaging reveals axon-glia interactions during peripheral nerve injury and repair in zebrafish. AB - Neural damage is a devastating outcome of physical trauma. The glia are one of the main effectors of neuronal repair in the nervous system, but the dynamic interactions between peripheral neurons and Schwann cells during injury and regeneration remain incompletely characterized. Here, we combine laser microsurgery, genetic analysis, high-resolution intravital imaging and lattice light-sheet microscopy to study the interaction between Schwann cells and sensory neurons in a zebrafish model of neurotrauma. We found that chronic denervation by neuronal ablation leads to Schwann-cell death, whereas acute denervation by axonal severing does not affect the overall complexity and architecture of the glia. Neuronal-circuit regeneration begins when Schwann cells extend bridging processes to close the injury gap. Regenerating axons grow faster and directionally after the physiological clearing of distal debris by the Schwann cells. This might facilitate circuit repair by ensuring that axons are guided through unoccupied spaces within bands of Bungner towards their original peripheral target. Accordingly, in the absence of Schwann cells, regenerating axons are misrouted, impairing the re-innervation of sensory organs. Our results indicate that regenerating axons use haptotaxis as a directional cue during the reconstitution of a neural circuit. These findings have implications for therapies aimed at neurorepair, which will benefit from preserving the architecture of the peripheral glia during periods of denervation. PMID- 26035868 TI - Heterogeneous disease progression and treatment response in a C3HeB/FeJ mouse model of tuberculosis. AB - Mice are the most commonly used species for non-clinical evaluations of drug efficacy against tuberculosis (TB). Unlike commonly used strains, C3HeB/FeJ mice develop caseous necrosis in the lung, which might alter the representation of drug efficacy in a way that is more like human TB. Because the development of such pathology requires time, we investigated the effect of infection incubation period on the activity of six drugs in C3HeB/FeJ and BALB/c mice. Mice were aerosol infected and held for 6, 10 or 14 weeks before receiving therapy with rifampin (RIF), rifapentine (RPT), pyrazinamide (PZA), linezolid (LZD), sutezolid (PNU) or metronidazole (MTZ) for 4-8 weeks. Outcomes included pathological assessments, pH measurements of liquefied caseum and assessment of colony-forming unit (CFU) counts from lung cultures. Remarkable heterogeneity in the timing and extent of disease progression was observed in C3HeB/FeJ mice, largely independent of incubation period. Likewise, drug efficacy in C3HeB/FeJ mice was not affected by incubation period. However, for PZA, LZD and PNU, dichotomous treatment effects correlating with the presence or absence of large caseous lesions were observed. In the case of PZA, its poor activity in the subset of C3HeB/FeJ mice with large caseous lesions might be explained by the pH of 7.36+/-0.09 measured in liquefied caseum. This study highlights the potential value of C3HeB/FeJ mice for non-clinical efficacy testing, especially for investigating the interaction of lesion pathology and drug effect. Careful use of this model could enhance the bridging of non-clinical results with clinical outcomes. PMID- 26035869 TI - Understanding the molecular mechanisms of human microtia via a pig model of HOXA1 syndrome. AB - Microtia is a congenital malformation of the outer ears. Although both genetic and environmental components have been implicated in microtia, the genetic causes of this innate disorder are poorly understood. Pigs have naturally occurring diseases comparable to those in humans, providing exceptional opportunity to dissect the molecular mechanism of human inherited diseases. Here we first demonstrated that a truncating mutation in HOXA1 causes a monogenic disorder of microtia in pigs. We further performed RNA sequencing (RNA-Seq) analysis on affected and healthy pig embryos (day 14.25). We identified a list of 337 differentially expressed genes (DEGs) between the normal and mutant samples, shedding light on the transcriptional network involving HOXA1. The DEGs are enriched in biological processes related to cardiovascular system and embryonic development, and neurological, renal and urological diseases. Aberrant expressions of many DEGs have been implicated in human innate deformities corresponding to microtia-associated syndromes. After applying three prioritizing algorithms, we highlighted appealing candidate genes for human microtia from the 337 DEGs. We searched for coding variants of functional significance within six candidate genes in 147 microtia-affected individuals. Of note, we identified one EVC2 non-synonymous mutation (p.Asp1174Asn) as a potential disease-implicating variant for a human microtia-associated syndrome. The findings advance our understanding of the molecular mechanisms underlying human microtia, and provide an interesting example of the characterization of human disease-predisposing variants using pig models. PMID- 26035870 TI - Deletion of the App-Runx1 region in mice models human partial monosomy 21. AB - Partial monosomy 21 (PM21) is a rare chromosomal abnormality that is characterized by the loss of a variable segment along human chromosome 21 (Hsa21). The clinical phenotypes of this loss are heterogeneous and range from mild alterations to lethal consequences, depending on the affected region of Hsa21. The most common features include intellectual disabilities, craniofacial dysmorphology, short stature, and muscular and cardiac defects. As a complement to human genetic approaches, our team has developed new monosomic mouse models that carry deletions on Hsa21 syntenic regions in order to identify the dosage sensitive genes that are responsible for the symptoms. We focus here on the Ms5Yah mouse model, in which a 7.7-Mb region has been deleted from the App to Runx1 genes. Ms5Yah mice display high postnatal lethality, with a few surviving individuals showing growth retardation, motor coordination deficits, and spatial learning and memory impairments. Further studies confirmed a gene dosage effect in the Ms5Yah hippocampus, and pinpointed disruptions of pathways related to cell adhesion (involving App, Cntnap5b, Lgals3bp, Mag, Mcam, Npnt, Pcdhb2, Pcdhb3, Pcdhb4, Pcdhb6, Pcdhb7, Pcdhb8, Pcdhb16 and Vwf). Our PM21 mouse model is the first to display morphological abnormalities and behavioural phenotypes similar to those found in affected humans, and it therefore demonstrates the major contribution that the App-Runx1 region has in the pathophysiology of PM21. PMID- 26035872 TI - Personal Life Approach: An Interactive Way of Understanding Older Adults' Participation in Activities Following Hospitalization. AB - PURPOSE: To explore factors that support or inhibit participation in daily activities amongst older adults who have returned home following hospitalization. DESIGN AND METHODS: An exploratory qualitative design was used to gather information from a sample of older adults. Participants were recruited during their hospital stay from acute and rehabilitation wards in Victoria, Australia. Semistructured interviews were carried out in the participants' home within 6 weeks of discharge. Data were analyzed through thematic analysis. RESULTS: Participants (n = 21) were aged >=65 years (mean 82 years [SD 8.5]), 57% were female (n = 11) and 76% with English as their first language (n = 16). Thematic analysis identified one primary theme (personal life approach) moderated by spirituality and two subthemes; interpretation of physical and mental abilities, and social interactions. The life approach acted as a filter through which participants interpreted their abilities and social interactions that either supported or inhibited their return to participation after a stay in hospital. IMPLICATIONS: The findings suggest that clinicians need to consider the individual's approach to life in their recovery following hospitalization. This approach can influence their return to participation in activities and potentially be supported (towards higher levels of optimism) by health professionals to enhance participation in activities postdischarge. PMID- 26035871 TI - Leiomodin-3-deficient mice display nemaline myopathy with fast-myofiber atrophy. AB - Nemaline myopathy (NM) is one of the most common forms of congenital myopathy, and affects either fast myofibers, slow myofibers, or both. However, an animal model for congenital myopathy with fast-myofiber-specific atrophy is not available. Furthermore, mutations in the leiomodin-3 (LMOD3) gene have recently been identified in a group of individuals with NM. However, it is not clear how loss of LMOD3 leads to NM. Here, we report a mouse mutant in which the piggyBac (PB) transposon is inserted into the Lmod3 gene and disrupts its expression. Lmod3(PB/PB) mice show severe muscle weakness and postnatal growth retardation. Electron microscopy and immunofluorescence studies of the mutant skeletal muscles revealed the presence of nemaline bodies, a hallmark of NM, and disorganized sarcomeric structures. Interestingly, Lmod3 deficiency caused muscle atrophy specific to the fast fibers. Together, our results show that Lmod3 is required in the fast fibers for sarcomere integrity, and this study offers the first NM mouse model with muscle atrophy that is specific to fast fibers. This model could be a valuable resource for interrogating myopathy pathogenesis and developing therapeutics for NM as well as other pathophysiological conditions with preferential atrophy of fast fibers, including cancer cachexia and sarcopenia. PMID- 26035873 TI - Care Preferences Among Middle-Aged and Older Adults With Chronic Disease in Europe: Individual Health Care Needs and National Health Care Infrastructure. AB - PURPOSE OF THE STUDY: The purpose of this study is to expand knowledge of care options for aging populations cross-nationally by examining key individual-level and nation-level predictors of European middle-aged and older adults' preferences for care. DESIGN AND METHODS: Drawing on data from the Survey of Health, Ageing and Retirement in Europe and the Organisation for Economic Co-operation and Development, we analyze old age care preferences of a sample of 6,469 adults aged 50 and older with chronic disease in 14 nations. Using multilevel modeling, we analyze associations between individual-level health care needs and nation-level health care infrastructure and preference for family-based (vs. state-based) personal care. RESULTS: We find that middle-aged and older adults with chronic disease whose health limits their ability to perform paid work, who did not receive personal care from informal sources, and who live in nations with generous long-term care funding are less likely to prefer family-based care and more likely to prefer state-based care. IMPLICATIONS: We discuss these findings in light of financial risks in later life and the future role of specialized health support programs, such as long-term care. PMID- 26035874 TI - Longitudinal and Reciprocal Relationships Between Depression and Disability in Older Women Caregivers and Noncaregivers. AB - PURPOSE OF THE STUDY: Depressive symptoms and disability each increase the risk of the other, yet few studies have examined reciprocal associations between these conditions in a single study, or over periods longer than 3 years. These associations may differ in older caregivers due to chronic stress, health characteristics, or factors related to caregiving. DESIGN AND METHODS: Structural equation models were used to investigate relationships between depressive symptoms and disability over 3 interviews spanning 6 years among 956 older women (M = 81.5 years) from the Caregiver Study of Osteoporotic Fractures. Results were evaluated separately for 611 noncaregivers and 345 caregivers to a relative or friend. RESULTS: In noncaregivers, more depressive symptoms significantly predicted greater disability, whereas greater disability predicted increased depressive symptoms at the next interview in age-adjusted models. In contrast, there was not a significant relationship between depression and disability in either direction for caregivers. Further adjustment for body mass index and medical condition variables did not change these relationships. IMPLICATIONS: Caregivers did not exhibit longitudinal or reciprocal relationships between depressive symptoms and disability observed in noncaregivers. It is possible that older women caregivers are buffered by better physical condition or social interactions related to caregiving activities. PMID- 26035875 TI - Caregiver Stress and Mental Health: Impact of Caregiving Relationship and Gender. AB - PURPOSE OF THE STUDY: This study compared the stress and mental health implications of caregiving to a spouse, children, siblings, other family members, friends, and others among middle-aged and older male and female caregivers. DESIGN AND METHODS: Multivariate regression analyses were conducted using 2007 Canadian General Social Survey data collected on a subsample of caregivers aged 45 and older. RESULTS: Our analyses revealed that for women, caring for a spouse or children was more stressful and detrimental to mental health than caring for parents or others. Similarly, for men, caring for a spouse and for children was more stressful than caring for others but did not adversely affect overall mental health. IMPLICATIONS: The findings suggest that spousal and child caregiving tend to be more rather than less stressful and detrimental to middle-aged and older caregivers' mental health than is caregiving to most others but that gender differences need to be considered. PMID- 26035876 TI - Turn Off the Music! Music Impairs Visual Associative Memory Performance in Older Adults. AB - PURPOSE OF THE STUDY: Whether we are explicitly listening to it or not, music is prevalent in our environment. Surprisingly, little is known about the effect of environmental music on concurrent cognitive functioning and whether young and older adults are differentially affected by music. Here, we investigated the impact of background music on a concurrent paired associate learning task in healthy young and older adults. DESIGN AND METHODS: Young and older adults listened to music or to silence while simultaneously studying face-name pairs. Participants' memory for the pairs was then tested while listening to either the same or different music. Participants also made subjective ratings about how distracting they found each song to be. RESULTS: Despite the fact that all participants rated music as more distracting to their performance than silence, only older adults' associative memory performance was impaired by music. These results are most consistent with the theory that older adults' failure to inhibit processing of distracting task-irrelevant information, in this case background music, contributes to their memory impairments. IMPLICATIONS: These data have important practical implications for older adults' ability to perform cognitively demanding tasks even in what many consider to be an unobtrusive environment. PMID- 26035877 TI - Affective Organizational Commitment in Swiss Nursing Homes: A Cross-Sectional Study. AB - PURPOSE OF THE STUDY: This substudy of the Swiss Nursing Homes Human Resources Project (SHURP) explored the relationships between affective organizational commitment (AOC) levels and organizational, situational, and care personnel characteristics, and between AOC and care personnel outcomes. DESIGNS AND METHODS: SHURP was a representative national cross-sectional study in 163 Swiss nursing homes. Its data sources were: (a) a care personnel questionnaire, (b) a facility questionnaire, (c) a unit questionnaire, and (d) administrative resident data. Generalized estimating equations (GEEs) were applied to examine AOC's relationships with selected antecedents and care personnel outcomes. RESULTS: Data were collected from 5,323 care personnel in 163 nursing homes (return rate: 76%). On a scale from 1 to 5, the mean level of AOC was 3.86 (standard deviation = 0.81). Variations in AOC regarding care personnel characteristics (age, education, and experience in nursing home) and organizational characteristics (size, profit status) were statistically significant with minimal effect sizes. The main factors positively related to AOC were leadership, job satisfaction, quality of care, and collaboration with the nursing home director. Care personnel outcomes significantly related to higher AOC were reduced intention to leave, health complaints, presenteeism, and absenteeism. IMPLICATIONS: As leadership is a crucial factor of AOC, its development might improve care personnel outcomes such as intention to leave or absenteeism. PMID- 26035878 TI - Unsustainable Home Telehealth: A Texas Qualitative Study. AB - PURPOSE: Telehealth has emerged as an innovative approach to aid older individuals in managing chronic diseases in their homes and avoid hospitalizations and institutionalization. However, the sustainability of home telehealth programs remains a major challenge. This qualitative study explored the reasons for the initial adoption and the eventual decline of a decade-long home telehealth program at a Texas home health agency (HHA). Barriers to and facilitators for sustaining home telehealth programs were also explored. DESIGN AND METHODS: Semistructured interviews of 13 HHA nursing staff and administrators, 1 physician, and 9 patients aged >55 years and their informal caregivers who used telehealth were conducted in summer 2013. Interview transcripts were analyzed using conventional content analysis. RESULTS: Data analysis generated 5 themes representing the decline of the Texas home telehealth program: its impact on patient-centered outcomes, its cost-effectiveness, patient clinician and interprofessional communication, technology usability, and home health management culture. Lack of significant impact on patient outcomes, in addition to financial, technical, management, and communication-related challenges, adversely affected the sustainability of this home telehealth program. IMPLICATIONS: A home telehealth program that attains patient-centered outcomes, improves cost-effectiveness of managing chronic diseases, improves quality of communication among patients and clinicians, is user-friendly for older adults, and involves end users in decision making is likely to be sustainable. PMID- 26035879 TI - Chamomile Consumption and Mortality: A Prospective Study of Mexican Origin Older Adults. AB - PURPOSE: Approximately 20% of adults use some kind of herbal; however, little data exists from population-based study or clinical trials to support effectiveness of most herbal products. Chamomile is a commonly used herb among older adults of Mexican origin. We examined the effects of herbal chamomile consumption on mortality among older adults of Mexican origin. METHODS AND DESIGN: A sample from the Hispanic Established Populations for Epidemiologic Study of the Elderly, a population-based study of noninstitutionalized Mexican Americans aged 65 and older from five Southwestern states (Texas, California, New Mexico, Colorado, and Arizona). We included all men and women from 2000 to 2007 (n = 1,677). RESULTS: Chamomile was used by 14% of the sample. Cox proportional hazards regression analyses showed that chamomile was associated with a decreased risk of mortality in the total sample (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.55-0.92) and for women (HR 0.67, 95% CI 0.49-0.92) but not for men. In models adjusted for sociodemographic variables, health behaviors, and chronic conditions, chamomile remained significantly associated with reduced mortality in women (HR 0.72, 95% CI 0.53-0.98). IMPLICATIONS: The use of chamomile shows protective effects against mortality in this sample of older adults of Mexican origin for women. Further research is warranted in other populations to determine if these effects are consistent. PMID- 26035881 TI - Motivators and Barriers to Reducing Sedentary Behavior Among Overweight and Obese Older Adults. AB - PURPOSE OF THE STUDY: To explore individual, social, environmental, and program related motivators, barriers, and impacts of sedentary behavior (SB) reduction among a group of overweight and obese older adults aged 60 and older. DESIGN AND METHODS: Semistructured interviews were conducted with 24 participants following a SB reduction intervention. Transcripts from these interviews were iteratively coded by a team, and key themes were defined and refined guided by the social ecological framework. RESULTS: Motivators included the desire to improve health, newly acquired awareness of SB, the ease of incorporating SB reduction into current lifestyle, an adaptable environment, and the use of reminders. Barriers included existing health conditions, enjoyment of sedentary activities, unadaptable environments, fatigue, and difficulty understanding SB reduction as distinct from physical activity (PA). Participants reported impacts on physical and mental health and changes in awareness, exercise, and daily activity. IMPLICATIONS: Although in many ways motivators and barriers to reducing SB are similar to those of PA, SB interventions have special considerations and may ultimately be easier for some individuals to incorporate into their lifestyle. PMID- 26035883 TI - "We Had a Beautiful Home . . . But I Think I'm Happier Here": A Good or Better Life in Residential Aged Care. AB - PURPOSE OF THE STUDY: This qualitative study investigates residents' perspectives on whether a "good life" is possible for older people living in residential aged care (RAC) and offers insight into the services and support needed to sustain their good life. DESIGN AND METHODS: Thirteen aged care residents (2 male, 11 female) ranging in age from 77 to 95 years, participated in semi-structured interviews in 2 RAC facilities in Adelaide, South Australia. Both facilities employed a model of aged care based on active aging and positive psychology principles called the partners in positive aging (PiPA) model. RESULTS: Interpretative phenomenological analysis showed that residents' perception of a good life was centred on the service providers' ability to enhance their physical, social, and psychological well-being while allowing them to maintain their sense of identity. Counter-stereotypically, findings suggest that the aged care environment can provide older people who are physically frail but cognitively intact with a better life than when they were living in their own homes. IMPLICATIONS: Psychological good life theory needs to be adapted and modified when considering the needs of cognitively intact older adults in residential care. PMID- 26035880 TI - An Examination of the Disablement Process Among Older American Indians: The Native Elder Care Study. AB - PURPOSE OF THE STUDY: Older American Indians disproportionately suffer from poorer physical and mental health and have greater disability compared to their racial and ethnic counterparts. The purpose of this study was to examine the disablement process among older American Indians. DESIGN AND METHODS: Data analyzed were from the Native Elder Care Study, which included in-person interviews with 505 community-dwelling American Indians aged >=55 years. We used structural equation modeling to examine the contributive direct and indirect effects of health, demographic, and psychosocial risk factors on disability. RESULTS: Pathology had direct and indirect effects through social support and depressive symptoms on chronic pain intensity. Pathology also had direct and indirect effects on disability. Chronic pain intensity was a significant mediator between pathology and functional limitations. With contributive effects of older age and female sex, greater functional limitations were associated with increased disability. IMPLICATIONS: Our results support the theorized main pathway of the Disablement Process Model with our sample of older American Indians. Our findings support the importance of taking into account intra and extraindividual factors in assessing the prevalence and incidence of disability for older American Indians. PMID- 26035882 TI - "It Was Very Rewarding for Me ...": Senior Volunteers' Experiences With Implementing a Reminiscence and Creative Activity Intervention. AB - PURPOSE OF THE STUDY: To describe the experience of recruiting, training, and retaining retired senior volunteers (RSVs) as interventionists delivering a successful reminiscence and creative activity intervention to community-dwelling palliative care patients and their caregivers. DESIGN AND METHODS: A community based participatory research framework involved Senior Corps RSV programs. Recruitment meetings and feedback groups yielded interested volunteers, who were trained in a 4-hr session using role plays and real-time feedback. Qualitative descriptive analysis identified themes arising from: (a) recruitment/feedback groups with potential RSV interventionists; and (b) individual interviews with RSVs who delivered the intervention. RESULTS: Themes identified within recruitment/feedback groups include questions about intervention process, concerns about patient health, positive perceptions of the intervention, and potential characteristics of successful interventionists. Twelve RSVs achieved 89.8% performance criterion in treatment delivery. Six volunteers worked with at least one family and 100% chose to work with additional families. Salient themes identified from exit interviews included positive and negative aspects of the experience, process recommendations, reactions to the Interventionist Manual, feelings arising during work with patient/caregiver participants, and personal reflections. Volunteers reported a strong desire to recommend the intervention to others as a meaningful volunteer opportunity. IMPLICATIONS: RSVs reported having a positive impact on palliative care dyads and experiencing personal benefit via increased meaning in life. Two issues require further research attention: (a) further translation of this cost-effective mode of treatment delivery for palliative dyads and (b) further characterization of successful RSVs and the long term impact on their own physical, cognitive, and emotional functioning. PMID- 26035884 TI - Introducing an Equal Rights Framework for Older Persons in Residential Care. AB - This article reconceptualizes residential care for older persons by introducing a framework developed from a rights-based principle of disability policies: the normalization principle. This principle is part of the social model and states that society should make available for people who have impairments living conditions that are as close as possible to those of "others." Using the framework on the case of eldercare in Sweden shows that although disability policies have used people without impairments as a comparative (external) reference group for claiming rights, eldercare policies use internal reference groups, basing comparisons on other care users. The article highlights the need for external comparisons in eldercare and suggests that the third age, which so far has been a normative reference group for older people, could be a comparative reference group when older persons in need of care claim rights to equal conditions. PMID- 26035885 TI - Holocaust Survivors' Memories of Past Trauma and the Functions of Reminiscence. AB - PURPOSE OF THE STUDY: Existing research suggests that specific ways of recalling autobiographical memories of one's past cluster in self-positive, self-negative, and prosocial reminiscence functions. We undertook the present qualitative study to gain understanding of reminiscence functions as described by 269 Israeli Holocaust survivors and to see whether groupings of themes that emerged would correspond to our tripartite model of the reminiscence functions. DESIGN AND METHODS: Participants (M = 80.4 years; SD = 6.87) were asked to describe memories that typify a reminiscence function in which they frequently or very frequently engage. Thematic analyses were conducted in English (translated) and Hebrew. RESULTS: Responses reflect the range of ways in which Holocaust survivors reminisce. The task of describing early life memories was difficult for some participants, while others' lived experiences enabled them to teach others to ensure that their collective memory remains in the consciousness of the next generation of Israelis and the Jewish state. Data are imbued with examples of horror, resilience, generativity, and gratitude. IMPLICATIONS: As hypothesized, survivors' memories cluster in self-positive, self-negative, and prosocial groupings consistent with the tripartite model of reminiscence functions. PMID- 26035886 TI - Support from Neighbors and Aging in Place: Can NORC Programs Make a Difference? AB - PURPOSE OF THE STUDY: There is growing enthusiasm for community-level efforts to strengthen supportive relationships among neighbors to enhance aging in place. However, there is little research on how older adults perceive support from neighbors in terms of helping them to remain in their own homes and communities safely and comfortably, particularly in the face of later life challenges. There also is little systematic study of ways in which community initiatives might influence these relationships. DESIGN AND METHODS: Qualitative interviews were conducted with 41 older adults from seven Naturally Occurring Retirement Community Supportive Service Program (NORC program) catchment areas in the greater New York City area. A grounded theory approach was used to identify themes and develop an empirically grounded account of NORC programs, support among neighbors, and aging in place. RESULTS: Participants identified several ways in which NORC programs influenced support among neighbors, such as by serving as a conduit for information sharing and helping older adults to broaden their private networks of social relationships. Overall, however, participants more consistently described limitations of the NORC programs' influence on support within these relationships. Participants also described how other sources of support were necessary in addition to support from neighbors to help people overcome major challenges to aging in place. IMPLICATIONS: Results suggest the importance of neighbors-helping-neighbors approaches to promote aging in place as a complement, rather than substitute, to other efforts, such as those that focus on enhancing access to formal providers and strengthening care within families. PMID- 26035887 TI - Stigma and Discontinuity in Multilevel Senior Housing's Continuum of Care. AB - PURPOSE OF THE STUDY: This article presents data from 2 qualitative studies, confirming what gerontologists observed 30 years ago. Multilevel senior housing residents experience stigma and distress in an environment where people are grouped by levels of functioning. DESIGN AND METHODS: Qualitative, interview based (N = 367) studies were conducted in senior housing settings offering multiple levels of care (N = 7). Analyses involved revisiting coded narrative data, ethnographers' field-based knowledge, and identification of pattern saturation. RESULTS: Residents and places reflecting the highest levels of care are stigmatized in a context where people are monitored for health changes and required to relocate. Consequently, residents self-isolate, develop a diminished sense of self, and hide health and cognitive conditions out of fear of relocation. IMPLICATIONS: Developers, operators, staff, and potential residents need to recognize the personal and social challenges typically experienced even in within-site relocation. It is important to rethink the predominant model of senior housing that requires residents with changing needs to move and adapt to the setting. PMID- 26035888 TI - Mobilizing Resources for Well-being: Implications for Developing Interventions in the Retirement Transition. AB - PURPOSE OF THE STUDY: Good health and well-being in later life are central issues for public health. Retirement presents an opportunity to intervene to improve health and well-being, as individuals may adjust associated lifestyle behaviors. However, there is little evidence about how well-being is experienced in the context of increasingly diverse retirement transitions. Our objectives were to explore (a) views on health and well-being through retirement transitions and (b) acceptability of intervening in this period. DESIGN AND METHODS: Qualitative study involving 48 workers/retirees, aged 53-77 years of diverse socioeconomic status, were recruited from urban and rural areas in North East England. Data were collected iteratively through focus groups (n = 6), individual interviews (n = 13), interviews with couples (n = 4), using the constant comparative method. Analysis was informed by theories of the Third Age and Sen's capabilities approach. RESULTS: Diverse retirement transitions were shaped by unanticipated events. Central to well-being was the "capability" to utilize resources to achieve desirable outcomes. Participants rejected a "later life" identity, associating it with decline, and an uncertain future. IMPLICATIONS: Lifestyle interventions that address challenges within the retirement transition may be acceptable. Inducements to change behavior based on possible long-term outcomes may be less appealing. Providing assistance to use resources to address personal goals may be central to effective interventions. PMID- 26035889 TI - The Significance of Sexuality and Intimacy in the Lives of Older African Americans With HIV/AIDS. AB - PURPOSE OF THE STUDY: Aging and HIV/AIDS research focuses primarily on standardized clinical, social, and behavioral measures, leaving unanswered questions about how this chronic and stigmatizing condition affects life course expectations and the meaning of aging with the disease. Utilizing Gaylene Becker's (1997) life course disruption theory, we explored older African Americans' experiences of living with HIV/AIDS. DESIGN AND METHODS: A purposive sample (N = 43) of seropositive African Americans aged 50 and older was selected from a parent study. Thirteen participants completed one semi-structured in-depth interview on life course expectations and experiences of living with HIV/AIDS. Interview transcripts were analyzed using standard qualitative coding and thematic analysis. RESULTS: Responding to broad, open-ended questions about the impact of HIV on life course expectations, participants emphasized how HIV limited their ability to experience sexuality and intimacy. Two major themes emerged, damaged sexuality and constrained intimacy. IMPLICATIONS: Older African Americans' discussions of living with HIV focused on the importance of and the challenges to sexuality and intimacy. Researchers and clinicians should be attentive to significant and ongoing HIV-related challenges to sexuality and intimacy facing older African Americans living with HIV/AIDS. PMID- 26035890 TI - The Meanings African American Caregivers Ascribe to Dementia-Related Changes: The Paradox of Hanging on to Loss. AB - PURPOSE OF THE STUDY: Using an interpretive phenomenological approach, this study explored the meaning African American (AA) caregivers ascribed to the dementia related changes in their care-recipients. DESIGN AND METHODS: Data were gathered in this qualitative study with 22 in-depth interviews. Eleven AA caregivers for persons with dementia, living in the Pacific Northwestern United States, were interviewed twice. Four caregivers participated in an optional observation session. RESULTS: Analysis based on the hermeneutic circle revealed that, for these caregivers, the dementia-related changes meant that they had to hang on to the care-recipients for as long as possible. Caregivers recognized that the valued care-recipients were changed, but still here and worthy of respect and compassion. Ancestral family values, shaped by historical oppression, appeared to influence these meanings. IMPLICATIONS: The results from this study suggest that AA caregivers tend to focus on the aspects of the care-recipients' personalities that remain, rather than grieve the dementia-related losses. These findings have the potential to deepen gerontologists' understanding of the AA caregiver experience. This, in turn, can facilitate effective caregiver decision making and coping. PMID- 26035891 TI - Implementation and Maintenance of a Community-Based Older Adult Physical Activity Program. AB - PURPOSE OF THE STUDY: We examine facilitators and barriers to the implementation and maintenance of Enhance(r)Fitness (EF), a group exercise program for older adults, at early-adopter YMCA-affiliated sites, and summarize strategies employed by EF instructors and staff to overcome challenges. DESIGN AND METHODS: This qualitative study used semi-structured phone interviews with 32 instructors, staff members, and master trainers from 24 different YMCA-affiliated sites. Interviews were digitally recorded, transcribed, and analyzed with a focus on the implementation and maintenance components of the RE-AIM framework. RESULTS: We identified a series of factors affecting the implementation and maintenance of EF at YMCA-affiliated sites, which can be categorized into program-specific (such as instructor training, the structure of the program, reporting requirements, and insurance coverage), and organizational (such as organizational support and infrastructure for program delivery, champions, and funding to cover the costs of program delivery). Strategies used to overcome challenges associated with these factors include identifying parts of the program that can be adapted, hiring staff and instructors that understand and support the program, and educating staff and instructors about the importance of evidence-based programs and of data collection for program evaluation. IMPLICATIONS: Assessing the readiness of organizations for program delivery and the match between program goals and the needs of organizations and participants would help facilitate the successful implementation and maintenance of physical activity programs in community settings. PMID- 26035893 TI - Access to Bridge Employment: Who Finds and Who Does Not Find Work After Retirement? AB - PURPOSE OF THE STUDY: Empirical studies on the determinants of bridge employment have often neglected the fact that some retirees may be unsuccessful in finding a bridge job. We present an integrative framework that emphasizes socioeconomic factors, health status, social context, and psychological factors to explain why some people fully retired after career exit, some participated in bridge jobs, while others unsuccessfully searched for one. DESIGN AND METHODS: Using Dutch panel data for 1,221 retirees, we estimated a multinomial logit model to explain participation in, and unsuccessful searches for, bridge employment. RESULTS: About 1 in 4 retirees participated in bridge employment after retirement, while 7% searched unsuccessfully for such work. Particularly those who experienced involuntary career exit were found to have a higher probability of being unsuccessful at finding bridge employment. IMPLICATIONS: The current study provides evidence for the impact of the social context on postretirement work and suggests a cumulative disadvantage in the work domain in later life. PMID- 26035892 TI - Intergenerational Support in a Daily Context. AB - PURPOSE OF THE STUDY: Using retrospective global reports, studies have found that middle-aged adults in the United States provide intermittent support to their aging parents and more frequent support to grown children. To date, studies have not examined support middle-aged adults provide to different generations on a daily basis. Daily support may include mundane everyday exchanges that may (or may not) affect well-being. DESIGN AND METHODS: Middle-aged adults (N = 191, mean age 55.93) completed a general interview regarding family ties, followed by interviews each day for 7 days (N = 1,261 days). Daily interviews assessed support (e.g., advice, emotional, practical help) participants provided each grown child (n = 454) and aging parent (n = 253). Participants also reported daily mood. RESULTS: Most participants provided emotional support (80%), advice (87%), and practical help (69%) to a grown child and also provided emotional support (61%) and advice (61%) or practical help (43%) to a parent that week. Multilevel models confirmed generational differences; grown children were more likely to receive everyday support than parents. Providing support to grown children was associated with positive mood, whereas providing support to parents was associated with more negative mood. IMPLICATIONS: Daily intergenerational support was more common than studies using global reports of support have found. Some daily support may be fleeting and not stand out in memory. The findings were consistent with the intergenerational stake hypothesis, which suggests middle aged adults are more invested in their grown children than in their parents. Nonetheless, middle-aged adults were highly involved with aging parents. PMID- 26035894 TI - Development and Pilot Evaluation of a Novel Dignity-Conserving End-of-Life (EoL) Care Model for Nursing Homes in Chinese Societies. AB - PURPOSE OF THE STUDY: The provision of end-of-life (EoL) care in long-term-care settings remains largely underdeveloped in most Chinese societies, and nursing home residents often fail to obtain good care as they approach death. This paper systematically describes the development and implementation mechanisms of a novel Dignity-Conserving EoL Care model that has been successfully adopted by three nursing homes in Hong Kong and presents preliminary evidence of its effectiveness on enhancing dignity and quality of life (QoL) of terminally ill residents. DESIGN AND METHODS: Nine terminally ill nursing home residents completed the McGill Quality of Life Questionnaire and the Nursing Facilities Quality of Life Questionnaire at baseline and 6 months post-EoL program enrollment. Wilcoxon signed rank test was used to detect significance changes in each QoL domains across time. RESULTS: Although significant deterioration was recorded for physical QoL, significant improvement was observed for social QoL. Moreover, a clear trend toward significant improvements was identified for the QoL domains of individuality and relationships. IMPLICATIONS: A holistic and compassionate caring environment, together with the core principles of family-centered care, interagency and interdisciplinary teamwork, as well as cultural-specific psycho socio-spiritual support, are all essential elements for optimizing QoL and promoting death with dignity for nursing home residents facing morality. This study provides a useful framework to facilitate the future development of EoL care in long-term-care settings in the Chinese context. PMID- 26035895 TI - "Make Me Feel at Ease and at Home": Differential Care Preferences of Nursing Home Residents. AB - PURPOSE OF THE STUDY: Assessing and honoring older adults' preferences is a fundamental step in providing person-centered care in long-term care facilities. Researchers and practitioners have begun to develop measures to assess nursing home (NH) residents' everyday preferences. However, little is known about how residents interpret and conceptualize their preferences and what specific clinical response may be needed to balance health and safety concerns with preferences. DESIGN AND METHODS: We used content analysis to examine interview responses on a subset of eight open-ended items from the Preferences of Every-day Living Inventory for Nursing Home (PELI-NH) residents with 337 NH residents (mean age 81). We considered how residents self-define various preferences of care and the associated importance of these preferences. RESULTS: Residents identified preferences for interpersonal interactions (greetings, staff showing care, and staff showing respect), coping strategies, personal care (bathroom needs, setting up bedding), and healthcare discussions. Respondents highlighted specific qualities and characteristics about care interactions that are necessary to fully meeting their everyday preferences. IMPLICATIONS: Results contribute to an emergent body of research that utilizes patient preferences to achieve the goals of person-centered care. The complexity of these responses substantiates the use of qualitative inquiry to thoroughly assess and integrate NH resident preferences into the delivery of person-centered care. PMID- 26035896 TI - Couples' Social Careers in Assisted Living: Reconciling Individual and Shared Situations. AB - PURPOSE OF THE STUDY: Despite important connections between relationships, health, and well-being, little is known about later-life couples' daily lives and experiences, especially those who are frail. Our aim was to advance knowledge by gaining an in-depth understanding of married and unmarried couples' intimate and social relationships in assisted living (AL) and by generating an explanatory theory. DESIGN AND METHODS: Using Grounded Theory Methods, we build on past research and analyze qualitative data from a 3-year mixed-methods study set in eight diverse AL settings located in the state of Georgia. Data collection included participant observation and informal and formal interviews yielding information on 29 couples, 26 married and 3 unmarried. RESULTS: Defined by their relationships with one another and those around them, couples' experiences were variable and involved a process of reconciling individual and shared situations. Analysis affirms and expands an existing typology of couples in AL. Our conceptual model illustrates the multilevel factors influencing the reconciliation process and leading to variation. Findings highlight the strengths and burdens of late-life couplehood and have implications for understanding these intimate ties beyond AL. IMPLICATIONS: Intimate and social relationships remain significant in later life. Strategies aimed at supporting couples should focus on individual and shared situations, particularly as couples' experience physical and cognitive decline across time. PMID- 26035897 TI - The Impact of Memory Change on Daily Life in Normal Aging and Mild Cognitive Impairment. AB - PURPOSE OF THE STUDY: Older adults with age-normal memory changes and those with amnestic mild cognitive impairment (aMCI) report mild memory difficulties with everyday problems such as learning new names or remembering past events. Although the type and extent of memory changes in these populations have been well documented, little is known about how memory changes impact their everyday lives. DESIGN AND METHODS: Using a qualitative research design, data were collected from three focus groups of older adults with normal memory changes (n = 23) and two focus groups of older adults with aMCI (n = 14). A thematic analysis using the constant comparative method was used to identify the impacts of memory change on key life domains. RESULTS: Four major themes emerged from the two groups, including changes in feelings and views of the self, changes in relationships and social interactions, changes in work and leisure activities, and deliberate increases in compensatory behaviors. Participants described both positive and negative consequences of memory change, and these were more substantial and generally more adverse for individuals with aMCI than for those with age-normal memory changes. IMPLICATIONS: There are similarities and important differences in the impact of mild memory change on the everyday lives of older adults with age normal memory changes and those with aMCI. Findings underscore the need for clinical interventions that aim to minimize the emotional impact of memory changes and that increase leisure and social activity in individuals with aMCI. PMID- 26035898 TI - Influences of Nationalism and Historical Traumatic Events on the Will-to-Live of Elderly Israelis. AB - PURPOSE OF THE STUDY: Existing research suggests that will-to-live (WTL) is an indicator of subjective well-being (SWB), and that similar personal variables including physical and mental health, quality-of-life, and sociodemographic characteristics influence elderly people's WTL. The purpose of this qualitative study was to explore additional factors which influence older persons' WTL. DESIGN AND METHODS: Twenty-five elderly Israelis across the country were interviewed about what weakens and strengthens their WTL. The grounded theory method guided the data collection and analysis. RESULTS: In addition to the previously reported aspects influencing WTL, analysis resulted in two new categories: nationalism and historical traumatic events. Negative influences of nationalism-related emotions on participants' WTL included themes of disappointment with the state, with children leaving the state, and with existential insecurity. Among the positive influences on WTL, participants mentioned pride in the state and in its development, personal security, and hope for a peaceful future. Under the category of historical traumatic events, participants reported posttraumatic stress and war anxieties, as well as satisfaction and revenge in continued existence, and appreciation for life in Israel compared with life before immigrating to Israel. IMPLICATIONS: Our findings indicate that nationalism and feelings of personal involvement in national developments play an important role in the lives of elderly Israelis to the degree that they contribute to their SWB and motivation to continue living. Practitioners and family members can intentionally arouse and strengthen positive nationalistic feelings in the elderly as a way to maintain and promote SWB and WTL. PMID- 26035899 TI - Caregivers' Willingness to Pay for Technologies to Support Caregiving. AB - PURPOSE OF THE STUDY: We report the results of a study designed to assess whether and how much informal caregivers are willing to pay for technologies designed to help monitor and support care recipients (CRs) in performing kitchen and personal care tasks. DESIGN AND METHODS: We carried out a web survey of a national sample of adult caregivers (age 18-64) caring for an older adult (N = 512). Respondents completed a 25min online survey that included questions about their caregiving situation, current use of everyday technology, use of specific caregiving technologies, general attitudes toward technology, and questions about technologies designed to help them monitor and provide assistance for CRs' kitchen and self-care activities. RESULTS: About 20% of caregivers were not willing to pay anything for kitchen and self-care technologies. Among those willing to pay something, the mean amount was approximately $50 per month for monitoring technologies and $70 per month for technologies that both monitored and provided some assistance. Younger caregivers, those caring for a person with Alzheimer's disease, and caregivers with more positive attitudes toward and experience with technology were willing to pay more. Most caregivers feel that the government or private insurance should help pay for these technologies. IMPLICATIONS: Caregivers are receptive and willing to pay for technologies that help them care for their CR, although the amount they are willing to pay is capped at around $70 per month. The combination of private pay and government subsidy may facilitate development and dissemination of caregiver technologies. PMID- 26035900 TI - Breathing Room in Monitored Space: The Impact of Passive Monitoring Technology on Privacy in Independent Living. AB - PURPOSE OF THE STUDY: This study examines articulations of the relationship between privacy and passive monitoring by users and former users of a sensor based remote monitoring system. A new conceptualization of privacy provides a framework for a constructive analysis of the study's findings with practical implications. DESIGN AND METHODS: Forty-nine in-depth semistructured interviews were conducted with elder residents, family members, and staff of 6 low-income independent living residence apartment buildings where the passive monitoring system had been offered for 6 years. Transcribed interviews were coded into the Dedoose software service and were analyzed using methods of grounded theory. RESULTS: Five diverse articulations of the relationship between privacy and passive monitoring emerged. The system produced new knowledge about residents and enabled staff to decide how much of that knowledge to disclose to residents. They chose not to disclose to residents their reason for following up on system generated alerts for 2 reasons: concern that feelings of privacy invasion may arise and cause dissatisfaction with the technology, and the knowledge that many resident users did not comprehend the extent of its features and would be alarmed. IMPLICATIONS: This research reveals the importance and challenges of obtaining informed consent. It identifies where boundary intrusion can occur in the use of passive monitoring as well as how changes to technology design and practice could create opportunities for residents to manage their own boundaries according to their privacy needs. The diversity of approaches to privacy supports the need for "opportunity for boundary management" to be employed as both a design and practice principle. PMID- 26035901 TI - Dyadic Analysis of Illness Perceptions Among Persons with Mild Cognitive Impairment and Their Family Members. AB - PURPOSE OF THIS STUDY: To characterize illness perceptions among persons with mild cognitive impairment (PWMCI) and their family care partners, and to examine whether PWMCI's and their family care partners' illness perceptions were associated with their own, as well as the other member of the dyad's, emotional reactions to MCI. DESIGN AND METHODS: This cross-sectional study of PWMCI and their family care partners (n = 60 dyads) used patient and relative versions of the Revised Illness Perception Questionnaire (IPQ-R) to assess metacognitive and emotional features of illness perception in MCI along 5 dimensions of perceived: seriousness of potential consequences, personal controllability, timeline, fluctuation (cycling) of symptoms, and illness coherence (clear vs. confusing). RESULTS: As compared to family members, PWMCI perceived MCI to be less potentially serious and to be more within their personal control, but dyads otherwise shared similar perceptions of MCI. Among PWMCI, perceived seriousness of the potential consequences of MCI was the only dimension to be significantly correlated with emotional distress. For family members, increased MCI-related emotional distress was significantly associated with perceptions of MCI as potentially serious, permanent, or confusing. A dyadic analysis using APIM showed that MCI-related emotional distress, in both PWMCI and family members, was linked to the PWMCI's perception of the seriousness of MCI. IMPLICATIONS: MCI-related education and support should be tailored for both the PWMCI and family member audiences, while acknowledging interdependence of illness perceptions within family units. Tailored information and support will be critical in managing MCI going forward, as illness perceptions are likely key factors on which individuals will plan for the future or base medical decisions. PMID- 26035902 TI - Volunteering and Cardiovascular Disease Risk: Does Helping Others Get "Under the Skin?". AB - PURPOSE OF THE STUDY: This study investigated whether volunteering was related to 5 risk factors for cardiovascular disease (CVD) and the metabolic syndrome (MetS) among middle-aged and older adults. DESIGN AND METHODS: Data from the 2004 and 2006 waves of the Health and Retirement Study (N = 7,803) were examined. Logistic regression was used to describe the relationships among volunteering and central adiposity, hypertension, lipid dysregulation, elevated blood glucose levels, and high inflammation, along with 2 indexes of the MetS. RESULTS: Among middle-aged adults, results showed that volunteers were less likely to have high central adiposity, lipid dysregulation, elevated blood glucose levels, and MetS compared with non-volunteers. For older adults, results showed volunteers were less likely to be hypertensive and more likely to have lipid dysregulation than their non volunteer counterparts. IMPLICATIONS: These results supported findings from other studies that formal volunteering is beneficial for middle-aged adults, and to a lesser degree, older adults. Further research is required to determine what factors may mediate the volunteer-CVD risk relationships. PMID- 26035903 TI - Nursing Home Residents' Preferences on Physician Orders for Life Sustaining Treatment. AB - PURPOSE OF THE STUDY: Previous studies examining preferences documented in Physician Orders for Life Sustaining Treatment (POLST) have found that most sampled POLSTs show a preference to limit care. These studies were conducted in states that are relatively ethnically homogeneous. This study investigated the POLST preferences of nursing home residents in an ethnically diverse state California-that requires nursing homes to document whether residents execute POLST. DESIGN AND METHODS: Data were collected from POLST forms executed by 941 residents in a convenience sample of 13 nursing homes in Southern California. The study analyzed data from 4 POLST form items: signatory (resident vs. surrogate decision-maker) and care preferences related to: (a) resuscitation; (b) medical intervention; and (c) artificially administered nutrition. Descriptive, comparative, and regression analyses are reported at both individual and facility levels. RESULTS: Of reviewed POLSTs, 46.8% documented a preference for "do not resuscitate" (DNR); 47.3% documented limits on medical intervention; and 52% documented limits on artificially administered nutrition. Residents in nursing homes serving comparatively larger populations of older residents and White residents had lower odds of electing the full care option for each of the POLST's 3 care items; those in nursing homes serving comparatively larger populations of Hispanic residents had higher odds of electing long-term artificially administered nutrition. IMPLICATIONS: This study found lower rates of POLST choices limiting care than previous studies, possibly because the sampled nursing homes served a more ethnically- and age-diverse population. California's requirement that nursing homes document whether residents execute POLST also may have indirectly influenced choice patterns. PMID- 26035905 TI - Successful aging: contentious past, productive future. PMID- 26035904 TI - Recruitment of Mobility Limited Older Adults Into a Facility-Led Exercise Nutrition Study: The Effect of Social Involvement. AB - PURPOSE OF THE STUDY: Older adults are among the most challenging population groups to enroll into health-related research. This article describes two methods used by investigators to recruit mobility limited older adults residing at assisted living or senior housing (SH) facilities into a facility-led exercise nutrition research study. DESIGN AND METHODS: Sedentary older adults were recruited from 42 different assisted living facilities (ALFs) or SH communities. Two different recruitment approaches were used: At 22 sites, investigators conducted heavily advertised informational sessions to recruit participants (Info only). At 20 locations, these sessions were preceded by attendance of a study team member at various activities offered by the facility over the preceding 2 weeks (activity attendance). Population reach, enrollment, personnel cost, and time required to recruit at least five participants at each facility was measured. Reasons for declining participation and withdrawal rate were also measured. RESULTS: Sixty percent more residents elected to be screened for eligibility when study personnel attended an activity offered by the facility. Activity attendance resulted in significantly less time, costs, and participant withdrawals compared with facilities with no activity attendance. IMPLICATIONS: Study team member attendance at activities offered by senior living facilities reduces cost and duration of recruitment and improves study retention. Interventions targeting this demographic are likely to benefit from deliberately building trust and familiarity among the resident population at senior living communities as part of the recruitment process. PMID- 26035911 TI - w-15:a new, potential opioid of abuse. PMID- 26035912 TI - Is there a paradox between opioid-prescribing by physicians and negative on-line ratings by patients? PMID- 26035913 TI - A case of physical and psychological dependence on butorphanol. PMID- 26035914 TI - Andrzej W. Lipkowski (1946-2014) - Obituary. PMID- 26035915 TI - [Complete skull-base reconstruction with a Galea Periost-Calvaria Split-Sandwich (GAP-CAS) technique]. AB - The frontal skull base represents an important barrier between the intracranial structures and the nasal sinuses preventing rhinoliquorrhea, ascending infections and brain prolaps.We reconstructed complete frontal skull base defects after interdisziplinary oncosurgery using a "Galea Periost - Calvaria Split - Sandwich (GAP-CAS) technique" with one half of the galea frontalis myofasccial flap torn to the nasal cavity, in-between the bone graft with the other half of the galea flap on top. By this technique it was possible to sufficiently cover the frontal skull base preventing cerebrospinal fluid leakage, meningitis and brain prolaps. PMID- 26035916 TI - [The fake lady on trial: transvestitism in psychiatry and the sexual sciences, or the regulation of public dress-code]. AB - With the publication of Carl Westphal's "die contrare Sexualempfindung" or "the Contrary Sexual Feeling" (1870), non-conform sexual/gender behavior, such as wearing clothing from the opposite gender, fell within psychiatry's field of activity; psychiatrists cooperated with law enforcement to maintain the public ordering of the sexes. On the basis of the Charite's medical records of a male patient, reported to have publically appeared in women's clothing and thereby making headlines in 1910 as the 'fake lady', the positions of psychiatrist Theodor Ziehen and sexual scientist Magnus Hirschfeld stand in contrast to one another--a development, which affected their forensic argumentation. As Hirschfeld had, in the same year 1910, introduced the concept of transvestitism to describe this very phenomenon, a transfer of competing interpretations out of sexual science and into psychiatry can be studied. The circulation of Magnus Hirschfeld's questionnaire to the vita sexualis allows for an investigation of the effects of such on the collective, biographical narration of sexual minorities, as well as on diagnostic capacity in psychiatry, in reference to transvestitism. An analysis of press-reports on the case and trials of the 'fake lady' approaches the question, how non-conform sexual behavior was to be recognized or identified in public and, for the sake of prevention, how it was explained. Such an analysis also investigates the role of the press in the popularization of Hirschfield's transvestitism concept. PMID- 26035917 TI - [Age and aging in Friedrich Hoffmann's medical practice]. AB - Our research uses medical case histories from the practice of Friedrich Hoffmann (1660-1742) in Halle (Saale) to explore the following key questions: what in Hoffmann's view constituted the beginning of 'old age', and what treatment he offered to these older patients. When examining the notion of what Hoffmann considered the start of 'old age' to be, it is apparent that in certain cases he deviated from his theoretical categorisation, when confronted with the disposition, or ill-health, of individual patients. It is also evident that Hoffmann pursued a differentiated approach to the treatment of those he viewed as older patients, avoiding the prescription of medication in favour of dietary measures to encourage blood circulation. Furthermore, whilst on the basis of Hoffmann's 'Iatromechanical Theory', the use of the intellect in 'old age' was considered detrimental to health, our findings suggest that Hoffmann did not advise his mainly upper class patients to avoid this entirely, as he appreciated that they had to conform to societal norms. PMID- 26035918 TI - [Medical dissertations during national socialism: a potential source inventory initial insight into "daily routine", ethics and mentality of university medical research up to (and after) 1945]. PMID- 26035920 TI - Prevalence of cavum septum pellucidum and/or cavum Vergae in brain computed tomographies of Taiwanese. AB - OBJECTIVE: The reported prevalence of cavum septum pellucidum (CSP) and cavum Vergae (CV) in brain computed tomography (CT) is 5.5% in Great Britain and 1.24% in China but unknown in Taiwan. Moreover, CSP and/or CV has generally been thought to decrease as age progresses, but the evidence of actual prevalence at different age levels is still limited in the literature. METHODS: A total of 19,031 patients with brain CT at a regional hospital in northern Taiwan from July 2008 to August 2010 were included in this study. Their radiological official reports were retrospectively reviewed to check for CSP and/or CV. An X2 test was used for statistical analysis (alpha = .05). RESULTS: The prevalence of CSP and/or CV in all brain CT was 0.93% (n = 177), which was lower. than that in the Chinese and British studies. Among them, 2.8% (n = 5) had only CSP, 1.7% (n = 3) had only CV, and 95.5% (n = 169) had coexistent CSP and CV. There is a significant difference in prevalence between the age groups (p = .009), and the prevalence is the highest in the group aged 20-29 years (1.56%) and lowest in the group aged above 80. After age 20-29, the prevalence tends to decrease with increasing age. CONCLUSION: This is not only the first study of CSP and CV in the Taiwanese population but the study population is also larger than those in the literature. The prevalence was found to approximately decrease as age progresses, but would reach the peak in the young adult group rather than the children or adolescent group. PMID- 26035919 TI - MAOA and TNF-beta gene polymorphisms are associated with photophobia but not osmophobia in patients with migraine. AB - PURPOSE: Photophobia and osmophobia are typical symptoms associated with migraine, but the contributions of gene polymorphisms to these symptoms are not fully elucidated. We investigated whether the gene polymorphisms are involved in photophobia and osmophobia in patients with migraine. METHODS: Ninety-one migraine patients and 119 non-headache healthy volunteers were enrolled. The 12 gene polymorphisms were determined by polymerase-chain-reaction (PCR) and PCR restriction-fragment-length polymorphism analysis. RESULTS: Photophobia and osmophobia were observed in 49 (54%) and 31 patients (34%), respectively. Distributions of monoamine oxidase A (MAOA) T941G and tumour necrosis factor-beta (TNF-beta) G252A polymorphisms were significantly different between patients with photophobia and controls. However, no gene polymorphism differences were observed between patients with osmophobia and controls. CONCLUSION: The MAOA T941G and TNF beta G252A gene polymorphisms appear to contribute to photophobia but not to osmophobia. We propose that different gene polymorphisms are responsible for photophobia and osmophobia symptoms during migraine. PMID- 26035921 TI - Late neurological sequelae due to brainstem irradiation for an assumed glioma. AB - PURPOSE: There is ongoing discussion whether radiotherapy might be beneficial in the treatment of intracranial cavernomas, however long-term sequelae due to brainstem irradiation may exist. CASE REPORT: The case of a 72-year-old female is reported who received radiotherapy in the pre-MRI era due to a suspected intra axial pontine lesion. Later on she developed severe trigeminal neuropathy and an MRI was performed 27 years after irradiation of the brainstem. On these images a large cavernous malformation with signs of multiple haemorrhages instead of the pontine glioma was seen accompanied by a substantial atrophy of brainstem structures. CONCLUSION: This case impressively demonstrates the long-term outcome of brainstem irradiation and reflects that cavernomas do not respond to radiotherapy. PMID- 26035922 TI - Acute severe headache associated with rapid tumor growth in a patient with vestibular schwannoma. AB - PURPOSE: Although headache in vestbibular schwannoma (VS) is uncommon as an initially presenting symptom, headache in VS is usually associated with tumor growth due to various factors, especially abrupt increase in size. We discuss various factors which influence rapid tumor growth including intratumoral hemorrhage and cystic change of tumor. CASE REPORT: A 68-years old female presented with sudden acute onset of occipital headache and severe dizziness. Brain MRI revealed 28 x 18 x 22 mm sized vestibular schwannoma with cystic change and heterogeneous enhancement (intratumoral hemorrhage) in the left cerebellopontine cistern with intracanalicular extension. CONCLUSION: This is a rare case of vestibular schwannoma with cystic change due to intratumoral hemorrhage with atypical apoplectic presentation on the background of hearing loss of 3 year duration. This highly unusual case highlights the need for careful clinical and radiological follow-up, in patients with vestibular schwannoma. In addition, although the predictive value may be limited, we must keep in mind that acute severe headache may be an alarming feature that predicts rapid tumor growth. PMID- 26035923 TI - [Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)]. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most prevalent monogenic cerebral small vessel diseases caused by a mutation in the NOTCH3 gene. The clinical manifestations of CADASIL range from single or multiple lacunar infarcts, transient ischemic attacks, dementia, migraine with aura to psychiatric disorders. The features of brain MRI of CADASIL include multiple lacunar infarcts and diffuse leukoencephalopathy, which frequently involves external capsules and anterior temporal regions. Almost all patients with CADASIL harbor cysteine involving mutations in NOTCH3. In Taiwan, two thirds of CADASIL patients carry NOTCH3 p.R544C mutations, and only approximately 56% of patients with CADASIL have leukoencephalopathy with anterior temporal regions involvement. PMID- 26035924 TI - Vertebrobasilar arterial fenestration detected by magnetic resonance angiography: pictorial neurological disease. PMID- 26035925 TI - Red ear syndrome. PMID- 26035926 TI - Atypical Ramsay Hunt syndrome. AB - Ramsay Hunt syndrome (RHS) is the reactivation of herpes zoster in the geniculate ganglion and typically presents the triad of ipsilateral peripheral type facial paralysis, ear pain, and erythematous vesicles in the external auditory canal and auricle. However, some unusual variants may occur. Here we present a patient of atypical RHS with uncommonly extensive dermatomal involvement of cranial nerve (CN) V2 and V3 and cervical roots, C2, C3 in addition to CN VII and VIII involvement. PMID- 26035927 TI - [Jean-Martin Charcot (1825-1893): a physician with multiple facets]. AB - This work is registered in the year (2013) commemorating the 120 years since Jean Martin Charcot's (1825-1893) death. Presently, the event takes place during 2013, in France, in Paris, at Hopital de la Salpetriere where Charcot practiced as medical chief of l'Hospice de la Vieillesse-Femmes, from 1862 until he died in 1893. The aim of the research is to show, from various examples and sources (printed and handwritten: fonds d'archives Charcot de la Salpetriere) how talented Charcot was as a clinician, pathologist and microscopist, researcher and experimenter, teacher, artist, designer, cartoonist, polyglot and traveller), how varied his medical career was and how innovative his scientific method was. All this permitted Charcot to make an impressive number of medical discoveries in various fields which are today known as geriatrics and rheumatology, internal medicine, cardiology, neurology, psychiatry and paranormal processes. PMID- 26035928 TI - Jewish physicians in the early life of Adolph Hitler. PMID- 26035929 TI - The alleged poisoning of Joseph Stalin: proof beyond reasonable doubt? AB - The name "Ioseb Besarionis dze Dzhugashvili" is as unassuming as it is unknown. It is the birth name of the brutal dictator who changed the face of Europe and whose actions still influence our lives today. Stalin, the man responsible for the slaughter of over twenty million of his own Soviet citizens and yet, the man who transformed the USSR from the feudalistic society of the Tsar's to a twentieth century military powerhouse that was instrumental in the defeat of Nazi Germany. Known as "Koba" to his friends, he cultivated a cult of personality where he was, and to a certain extent still is, admired in Russia and the former Soviet states. This paper will look at the following questions: why when he fell gravely ill did his comrades wait so long before seeking medical assistance? why were there omissions in the final post mortem report?, and why did one his closest lieutenants boast so openly about having murdered him. PMID- 26035930 TI - Iconography and provenance of versals in De humani corporis fabrica: Vesalius/Kalkar. AB - The most well known feature of Vesalius' De humani corporis fabrica (1543) are the ecorches (Fr. flayed human body) striding in the environs of Padua, Italy. These illustrations are the apex of an unsurpassed achievement in anatomical illustration. Not as obvious, striking or well known and oft neglected are the versals (the ornate capital letters at the beginning of a paragraph) in De fabrica. Not as well crafted, artistically, as the ecorches the versals transcend the realm of anatomy and science into mythological and iconographic interpretation. Did Vesalius have the artistic talent and was well versed in humanities to execute such ecorches and meaningful versals? Almost certainly there were other artists involved, well versed in art and humanities--more probably Johannes Stephanus Kalkar (c. 1499-1546). PMID- 26035931 TI - [Samuel Pozzi (1846-1918), flamboyant surgeon of la Belle Epoque]. AB - Samuel Pozzi was an outstanding in the Paris of nineteenth century, highly gifted and successful, but his real personality remains, after one hundred years, filled with mystery. He was born in the heart of Dordogne, Bergerac, in a family of Huguenots who had come from Geneva. After his first studies in Pau and Bordeaux, he came to Paris, while barely eighteen years old to reach the heights of the medical world of his time. Beginning as "Interne" then "Chirurgien des hopitaux", "professeur agrege", head Physician at Hopital Broca and, finally he was appointed Professor to the newly created Chair of Clinical Gynecology. He gained fame as a master of gynecological surgery but kept, during his career, a keen interest for all fields of surgery, including organ transplantation. PMID- 26035932 TI - Caucasian Medical Society and formation of modern medicine in Georgia. PMID- 26035933 TI - Zaza Phanaskerteli--an outstanding physician of the XVth century. PMID- 26035934 TI - Dr Ahmed Zaky Abushady: author, beekeeper, doctor and poet. AB - Ahmed Zaky Abushady, (1892-1955) was an author, beekeeper, doctor and poet. This paper follows his life from his upbringing in Egypt and his time as a medical student in England to his later life as a pathologist working in Alexandria and Cairo and finally his years in the United States of America. It emphasises his contributions in several fields not directly related to medicine and looks at his continuing influence. PMID- 26035935 TI - Existence of vimentin and GFAP protein expressions as a result of 2 Methoxyethanol administration in cerebral cortex tissue of Swiss Webster mice (Mus musculus): an immunohistochemical analysis. AB - Une of the plastic-based materials widely used in the plastics industry in various countries is ester phthalate. This compound will be oxidized in the body into 2-methoxyethanol (2-ME). The effect of 2-ME on human health and environment depends on the number, duration and the frequency of exposure. Recently, the incidence of brain damage tends to increase. In the last decade, it has been widely reported the negative effects of chemical pollutants to the environment. The aim of this study were to know the existence of the expression of Vimentin and GFAP proteins caused by 2-ME on the histological structure of the cerebral cortex of mice fetal during the prenatal period on gestation day 14 (GD 14) and day 18 (GD 18). The 2-ME compound was injected intraperitoneally with a dose of 7.5 mmol kg(-1) of body weight at GD-10. The result showed that there is a change in existence Vimentin protein in the cerebral cortex fetal of treated mice at GD 14, which is very conspicuous. Meanwhile, a change in existence of GFAP protein in cerebral cortex fetal of treated mice at GD 14, have relatively no difference from controls and no impact on histological structure changes of the cerebral corteks at GD 14. The change in existence of Vimentin protein in the cerebral cortex fetal of treated mice at GD 14 have an impact on histological structure of the cerebral cortex of mice treated at GD 18. It is believed that the impact is due to the effects of 2-methoxyethanol. PMID- 26035936 TI - Effect of media compositions on alpha-glucosidase inhibitory activity, growth and fatty acid content in mycelium extracts of Colletotrichum sp. TSC13 from Taxus Sumatrana (Miq.) de Laub. AB - The active alpha-glucosidase inhibitor compounds in the endophytic fungus Colletotrichum sp. TSC13 were found to be the unsaturated fatty acids (oleic, linoleic and linolenic acids). These compounds have potential as antidiabetic agents. The aim of the present study is to investigate the effects of various media composition on growth (mycelium dry weight) and the fatty acids content (MUg mg(-1) mycelium DW) of Colletotrichum sp. TSC13 in relation to its alpha glucosidase inhibitory activity. For that purpose, the experiments were set up by varying the carbon and nitrogen sources, metal ions and desaturase and fatty acid synthase inhibitors in the media. Colletotrichum sp. TSC13 grown on potato dextrose broth (PDB) was used as control. The alpha-glucosidase inhibitory activities were (range from 43.9 +/- 2.5 to 88.6 +/- 5.2%) at 10 MUg mL(-1). This activity seemed to correlate with the unsaturated fatty acids content of the samples. Different sugars as carbon source experiment showed that xylose gave the highest growth (938.7 +/- 141.6 mg). However, the highest fatty acids content was obtained from fructose medium which containing linoleic acid (38.8 +/- 4.9 MU g mg(-1) DW). Soluble starch gave better growth (672.5 +/- 62.3 mg) but very low fatty acids content (2.8 +/- 0.1 MUg mg(-1) DW) was obtained. Yeast extract was the best nitrogen source. Fatty acids production was better as compared to beef extract and soytone. This is the first report of various media compositions on fatty acids content in Colletotrichum sp. TSC13 in relation to its alpha glucosidase inhibitory activity. PMID- 26035937 TI - Detection p53 gene deletion in hematological malignancies using fluorescence in situ hybridization: a pilot study. . AB - P53 as a tumor suppressor gene plays a major role in cancer development, it is essential for cell growth regulation and apoptosis. The deletion of p53 is known to be associated with aggressive diseases in several hematological malignancies. The evidence indicated that p53 deletions can be acquired as a result of chemotherapy. Therefore, a follow-up study for p53 gene deletion by fluorescence in situ hybridization technique (FISH) was carried out for the patients group who affected with different hematological malignancies before and after chemotherapy. The main goals from screening of p53 deletion were to assess the correlation between p53 deletion and chemotherapy resistance, overall median survival and chromosomal abnormalities. It is concluded from the present study that p53 deletion has a cardinal effect on the clinical outcome (chemotherapy resistance, overall median survival) and outcome of chromosomal abnormalities (quality and quantity of chromosomal abnormalities) of the patients who were affected with hematological malignancies before and after chemotherapy. PMID- 26035938 TI - Dry matter yields and quality of forages derived from grass species and organic production methods (year 111). AB - This third year work was carried on at Khon Kaen University during the 2008-2009 to investigate dry matter yields of grass, grass plus legumes, grown on Korat soil series (Oxic Paleustults). The experiment consisted of twelve-treatment combinations of a 3x4 factorial arranged in a Randomized Complete Block Design (RCBD) with four replications. The results showed that Dry Matter Yields (DMY) of Ruzi and Guinea grass were similar with mean values of 6,585 and 6,130 kg ha(-1) whilst Napier gave the lowest (884 kg ha(-1)). With grass plus legume, grass species and production methods gave highly significant dry matter yields where Guinea and Ruzi gave dry matter yields of 7,165 and 7,181 kg ha(-1), respectively and Napier was the least (2,790 kg ha(-1)). The production methods with the use of cattle manure gave the highest DMY (grass alone) of 10,267 kg ha(-1) followed by Wynn and Verano with values of 6,064 and 3,623 kg ha(-1), respectively. Guinea plus cattle manure gave the highest DMY of 14,599 kg ha(-1) whilst Ruzi gave 12,977 kg ha(-1). Guinea plus Wynn gave DMY of 7,082 kg ha(-1). Ruzi plus Verano gave DMY of 6,501 kg ha(-1). Forage qualities of crude protein were highest with those grown with grass plus legumes. Some prospects in improving production were discussed. PMID- 26035939 TI - A comparative study about the influences of climatic factors on fertility rate among the healthy and infertile women in the North of Iran. AB - Fertility rate is an important health issue in the world which has been influenced by different factors and attracts the researchers' attention. In this study influences of climate factors on fertility rate were investigated. In this analytical correlational study, relationship between climate factors and fertility rate among the healthy and infertile women who referred to Imam educational hospital in Sari, North of Iran, during 2006-2012 was investigated. Results indicated that climatic factors such as: Temperature (r = -0.324, p = 0.005), air pressure (r = 0.2495, p = 0.031) and rainfall (r = 0.415, sig < 0.001) had relationship with healthy women' fertility rate, although, this relationship was not found in infertile women. Also, fecundity peak of infertile women similar to the fecundity peak of healthy women was during autumn. Considering influences of climate factors on fertility rate could be helpful for developing child birth strategies. PMID- 26035940 TI - Evaluation of effect of dietary supplementation with Dacryodes edulis G.Don pulp oil on serum lipid parameters in Wistar albino rats. AB - The pulp of Dacryodes edulis G.Don which is rich in oils is commonly consumed in Nigeria when in season. The effect of diet supplementation with edulis fruit pulp oil on body lipid parameters was evaluated in male Wistar albino rats. D. edulis oil was extracted in n-hexane. The test diet was.compounded using the oil extract (10%), whereas the control animals were kept on control diet formulated with groundnut oil (10%). After six weeks, the animals were anaesthetized with chloroform and blood samples collected through cardiac puncture for the determination of serum lipid profile. Results revealed that D. edulis fruit pulp oil did not cause any significant (p > 0.05) alterations in serum total cholesterol, LDL-cholesterol and triacylglycerol. The total amount of lipids present in the serum was increased by 33.3%, whereas the quantity of liver lipids decreased by the same factor (33.3%). Insignificant (p > 0.05) increases in the weights (g 100 g(-1) BW) of the liver (2.91 +/- 0.17 to 3.38 +/- 0.25), kidney (0.36 +/- 0.06 to 0.40 +/- 0.02) and heart (0.32 +/- 0.02 to 0.33 +/- 0.04) were observed in the test group. No significant change (p > 0.05) in the average body weight of the test animals was recorded. HPLC analysis of D. edulis oil showed that it contained palmitic acid (48.7%), linoleic acid (28.6%),oleic acid (12.9%), stearic acid (5.0%), lauric acid (2.2%), linolenic acid (1.7%) and myristic acid (0.9%). The peroxide value of the oil was 0.00. Prolonged intake of D. edulis fruit pulp oil may induce adverse effects on the body organs, even though the body lipid profile remains unaltered. PMID- 26035941 TI - Body weight changes during the menstrual cycle among university students in Ahvaz, Iran. AB - Weight changes during menstrual cycle may be a cause of concern about body weight among most women. Limited data are available linking menstrual cycle and body weight changes. The aim of this study was to examine the relationship between menstrual cycles and body weight changes among university students in Ahvaz, Iran. This cross-sectional study was conducted on 50 Iranian female students aged 18-24 years. Anthropometric indices were measured according to standard protocols. During a complete menstrual cycle, weights of participants were measured each morning. Seventy eight percent of participants had normal weight (Body Mass Index: 18.5-24.9 kg m(-2)). Body weight increased only slightly during the three days before beginning of the menstruation. By using repeated-measures ANOVA, no statistically significant differences were found in weigh during menstrual cycle (p-value = 0.301). No statistically significant changes were found in body weight during women's menstrual cycle in a group of healthy non obese Iranian young women. Further studies on overweight and obese women are suggested. PMID- 26035942 TI - Growth performance and survival rate of Macrobrachium rosenbergii (De Man, 1979) larvae using different doses of probiotics. AB - The efficiency of probiotics (Ecomarine) in rearing of Macrobrachium rosenbergii larvae was evaluated in a commercial prawn hatchery for five weeks. Stage-1 (zero age) larvae (of length: 2 mm; weight: 0.12 mg) were stocked at the rate of 100 L( 1). The experiment determined the growth rate, survival rate of the larvae for the both treatment and control groups. Final average weight were found 8.39 +/- 3.28E-04 and 8.18 +/- 2.86E-04 mg and length were found 9.08 +/- 0.649 and 9.02 +/- 0.081 mm for treatment and control group respectively. Comparatively higher growth performance was observed in treatment than control. Post Larvae (PL) was first observed 20th days of culture in treatment tanks whereas PL in control tanks was found 24th days of culture. Survival rate was found 58 and 46% in treatment and control group respectively. There was significant (p < 0.05) survival rate between two experiment groups. This study revealed that probiotics could be better in quality seed production of M. rosenbergii while significant changes were not noticed in the physic-chemical parameters i.e., water temperature, salinity, DO, pH, nitrate-NO2, hardness and alkalinity observed in both the treatments. PMID- 26035943 TI - Nitrogen level and physiological basis of yield of mungbean at varying plant population in High Ganges River Flood Plain soil of Bangladesh. AB - A field experiment was conducted at the Regional Agricultural Research Station of Bangladesh Agricultural Research Institute, Jessore during early kharif season of 2009 and 2010 to observe the effect of nitrogen on the physiological basis of yield of mungbean at varying plant population. In the experiment, four nitrogen levels (N0, N40, N60 and N80 kg ha(-1)) were assigned in the main plots and three plant population (P30, P35 and P40 m(-2)) in the sub plots. The results revealed that mungbean showed better growth in N60 and N80 kg ha(-1) representing higher values of CGR, TDM, LAI and plant height while N40 exhibited intermediate growth. Again, growth of mungbean was better in higher plant population (35-40 m(-2)) representing higher values of growth parameters. Seed yield of mungbean was obtained the highest (1908 kg ha(-1)) associated with the highest No. of pods plant(-1) (29.98), seeds pod(-1) (10.41) and 1000-seed weight (37.70 g) in N40 kg ha(-1). Further, seed yield of mungbean was the highest (1919 kg ha(-1)) in plant population of 40 m(-2). In interaction, seed yield was the highest (1963 kg ha( 1)) in N40 kg ha(-1) with plant population of 40 m(-2). The effect of applied nitrogen on the seed yield of mungbean can be explained 78% (R2 = 0.78) by this function (Y = 1540.70+16.069x-0.173x2). The optimum nitrogen level was 46 kg ha( 1) by using the developed functional model and then the predicted seed yield of mungbean would be 1944 kg ha(-1). PMID- 26035944 TI - Effects of epidermal growth factor, platelet derived growth factor and growth hormone on cultured rat keratinocytes cells in vitro. AB - Some growth factors, such as Epidermal Growth Factor (EGF), Growth Hormone (GH) and Platelet Derived Growth Factor (PDGF) have beneficial effects on keratinocyte proliferation and wound healing. Although the mechanism of these factors is unclear. In response to injury, growth factors are secreted by kinds of cutaneous cells. The goal of this project is to investigate the factors that could cause proliferate of the keratinocyte cells in vitro. The keratinocytes were removed from rat pups (10 days). Cultured in media with different concentration of GH, PDGF and EGF separately. The proliferation of cells was evaluated by the method of MTT and 3H-thymidine incorporation. Proliferation of keratinocytes was significantly higher in experimental groups than in control group. EGF maximally stimulated at 10 and 25 ng mL(-1). PDGF-BB maximally stimulated at 50 ng mL(-1), respectively. And maximal stimulation of GH was 2.5 IU L(-1). GH, PDGF-BB and EGF stimulate keratinocyte cells proliferation in different concentration. These growth factors could play in healing of the skin. PMID- 26035945 TI - Effect of testosterone undecanoate hormone on sperm and its level in the hemolymph of male mud spiny lobster, Panulirus polyphagus. AB - The present study aimed to determine the effect of testosterone undecanoate hormone on sperm quality (sperm viability) and sperm quantity (sperm counts) and its levels in the hemolymph of male mud spiny lobster, Panulirus polyphagus. Male P. polyphagus was injected laterally in fifth abdominal segment of pure hormone, Testosterone Undecanoate (TU) and ethanol at days 1, 8, 15, 22 and 29. Hemolymph of P. polyphagus was taken every two weeks and checked with Enzyme-linked immunosorbent assay (ELISA) to measure hormone levels. The mean sperm quality and quantity were increased due to increase the TU dose and TU levels also increase. The sperm quality, quantity and hormone levels were relevance each others. These findings indicate that TU injection should be evaluated as a practical way of improving sperm quality and quantity in commercial operations. PMID- 26035946 TI - Comparison of the volatile composition of Stachys pubescence oils obtained by hydro distillation and steam distillation. AB - The oils obtained by hydrodistillation and steam distillation of the aerial part of Stachys pubescence Ten. was analyzed by GC and GC/MS. Water distilled essential oil of the aerial part of S. pubescence, was rich in fatty acids like hexadecanoic acid and linoleic acid and also benzaldehyde and spathulenol whereas the steam distilled oil of the plant contained hexadecanoic acid, spathulenol and eugenol. Both of oils were rich in fatty acids (36.6 and 27.9%, respectively). Moreover, the content of oxygenated mono and sesquiterpenss were defined higher in steam distilled oil than hydrodistiledd oil (24.5, 17.2 and 6.1, 15.5%, respectively). In conclusion it seems that oxygenated terpenoids were trended to steam distillation method more than hydrodistillation, respectively. PMID- 26035947 TI - Fluctuation of diptera larvae in phytotelmata and relation with climate variation in West Sumatra Indonesia. AB - Research of fluctuations in Diptera's larvae in Phytotelmata had been conducted at three locations in West Sumatra, Indonesia; Padang, Bukittinggi and Payakumbuh; which aimed to determine the number and fluctuations Diptera larvae in Phytotelmata. The results obtained; the highest number of individual larvae Diptera in Phytotelmata was 7109 Aedes albopictus larvae (49.56%), followed by larvae of Culex tritaeniorhynchus with 2409 individuals (16.80%). Larvae fluctuated every month and tent to increase in November and December. There was no difference in the number of Diptera larvae individuals inhabiting pandan, taro, and pineapple, but there were significant differences between the three types of Phytotelmata (pandanus, taro and pineapple) with bamboo (p < 0.05). Number of individual larvae in Phytotelmata negatively correlated with temperature and rainfall, but positively correlated with humidity (r = 0.44: p < 0.05). PMID- 26035948 TI - Growth pattern for body weight, hip height and body length of Brakmas cattle. AB - The objective of this study was to determine the growth pattern for body weight, hip height and body length using non-linear model and the correlation between the parameters in Brakmas cows. Cross-sectional data of body weight, hip height and body length of 363 heads of Brakmas cows were collected to determine the growth pattern using Brody and Gompertz growth model. The results showed that Gompertz growth function had the best goodness of fit to describe the growth of Brakmas cattle for body weight, hip height and body length as shown by its high coefficient of determination (0.96, 0.99 and 0.99, respectively). Brody model estimated higher mature sizes compared to Gompertz model as the rate of maturing derived by Brody model are lower for the parameters as shown by negative correlation between mature size and maturing. Body length-body weight has the highest correlation coefficient (0.95) and hip height-body weight showed the lowest relationship (0.92). PMID- 26035949 TI - Emergence of Avian Infectious Bronchitis Virus and its variants need better diagnosis, prevention and control strategies: a global perspective. AB - Growth in poultry sector is being challenged due to increased incidence and re emergence of diseases caused due to evolution of several viral pathogens and use of live vaccines. Piles of economic losses are encountered due to these diseases. Avian Infectious Bronchitis (IB), caused by Corona virus, is OIE-listed disease and characterized by respiratory, renal and urogenital involvements, causing high mortality. Economic losses are encountered due to loss of productive performance of both egg and meat-type chickens. Variant viruses evolve due to spontaneous mutations and recombinations, causing disease in vaccinated flocks of all ages. Serotyping and genotyping are the common methods of classification of IBV strains. The virus has 4 clusters, grouped into 7 serotypes and the most important strains are Massachusetts, Connecticut, Arkansas, Gray, Holte and Florida along with numerous others, distributed round the globe. Several conventional and molecular diagnostic methods have been described for the diagnosis of IB in chickens. 'All-in/all-out' operations of rearing along with good biosafety measures forms the basis of prevention, whereas vaccination forms the backbone of IB control programme. Both live and inactivated (oil emulsified) conventional vaccines are available. The new generation vaccines (recombinant and vector-based) developed against locally prevailing IBV strains may be more helpful and avoid the reversion of virulence in live vaccine viruses. The present review deals with all these perspectives of this important emerging poultry pathogen. PMID- 26035950 TI - Ross River Virus (RRV) infection in horses and humans: a review. AB - A fascinating and important arbovirus is Ross River Virus (RRV) which is endemic and epizootic in nature in certain parts of the world. RRV is a member of the genus Alphavirus within the Semliki Forest complex of the family Togaviridae, which also includes the Getah virus. The virus is responsible for causing disease both in humans as well as horses. Mosquito species (Aedes camptorhynchus and Aedes vigilax; Culex annulirostris) are the most important vector for this virus. In places of low temperature as well as low rainfall or where there is lack of habitat of mosquito there is also limitation in the transmission of the virus. Such probability is higher especially in temperate regions bordering endemic regions having sub-tropical climate. There is involvement of articular as well as non-articular cells in the replication of RRV. Levels of pro-inflammatory factors viz., tumor necrosis factor-alpha (TNF-alpha); interferon-gamma (IFN-gamma); and macrophage chemo-attractant protein-1 (MAC-1) during disease pathogenesis have been found to be reduced. Reverse transcription-polymerase chain reaction (RT PCR) is the most advanced molecular diagnostic tool along with epitope-blocking enzyme-linked immunosorbent assay (ELISA) for detecting RRV infection. Treatment for RRV infection is only supportive. Vaccination is not a fruitful approach. Precise data collection will help the researchers to understand the RRV disease dynamics and thereby designing effective prevention and control strategy. Advances in diagnosis, vaccine development and emerging/novel therapeutic regimens need to be explored to their full potential to tackle RRV infection and the disease it causes. PMID- 26035951 TI - Distillery spentwash decolorization by a noval consortium of Pediococcus acidilactici and Candida tropicalis under static condition. AB - The aim of this study was to isolate a consortium of bacterium and yeast from natural resources for better decolorization of distillery spentwash. Consortium exhibited 82+/-1.5% decolorization within 24 h when incubated at 45 degrees C under static condition in effluent supplemented with 0.1%, glucose; 0.1%, peptone; 0.05%, MgSO4; 0.01%. The cultures were identified as Pediococcus acidilactici by 16S rDNA analysis and Candida tropicalis on the basis of phenotypic level. It is the first time when thermotolerant melanoidin decolorizing consortium (Pediococcus acidilactici and Candida tropicalis) isolated from distillery soil was capable to decolorizing melanoidin pigment of distillery effluent. Hence, it was observed that consortium has the ability to degrade the spentwash efficiently. This study could be an approach towards control of ecological pollution and health hazards of humans in and about the distillery location. PMID- 26035952 TI - Characterization and chromosome location of ADP-ribosylation factors (ARFs) in wheat. AB - In this study, the ARF genes were cloned, sequenced and located on the chromosomes. The gene expression of various stress conditions were analyzed through RT-PCR. Two important features of ARF in wheat were found: (1) High sequences homology among species in mammalian and plant and (2) Four exons and three introns were conserved in Poaceae. In this study the coding genes of ADP ribosylation Factors (ARF) were characterized and they were located on chromosomes 3AL and 2DL in common wheat and its diploid progenitors. Forty-seven candidate SNPs in ARF were detected which were located in exons (17 SNPs) and introns (30 SNPs), respectively. As expected, most of the SNPs (66.34%) in ARF were transitions and the rest (33.66%) were transversions. The expression difference of ARF under various environmental stresses (low-temperature, Abscisic Acid (ABA), Polyethylene Glycol (PEG), NaCl, stripe rust), in two stages (seedling and maturity) and in different tissues (root, stem, flag leaf and immature embryo) of 15 days post-flowering were investigated. The results revealed that the expression levels of ARF were affected by environmental stresses. PEG stress induced the highest level of ARF expression, followed by the stripe rust and ABA stresses. PMID- 26035953 TI - Experimental pathological studies of an Indian chicken anaemia virus isolate and its detection by PCR and FAT. AB - Chicken Infectious Anaemia Virus (CIAV) is one of the potent immunosuppressive and economically important agents affecting poultry industry worldwide. Recent reports indicate the emergence of this virus in the poultry flocks of the country. The present study aimed to investigate the pathogenic potential of a recent isolate of CIAV obtained from poultry flock of Uttaranchal State, India. Twenty first day-old age Specific Pathogen Free (SPF) chicks were inoculated intramuscularly with 10(4.5) median tissue culture infective dose (TCID50) of CIAV passaged in the Marek's disease virus transformed chicken splenic T lymphocyte (MDCC-MSB 1) cell line while 15 chicks were kept as control. The CIAV isolate produced consistent clinical signs, loss in body weight gain, anaemia, low haematocrit values, bone marrow aplasia and generalized lymphoid atrophy. Mean Packed Cell Volume (PCV) value of the infected chicks was significantly low (18.22+/-2.22) compared to control group (34.12+/-4.72) at 14 day post infection (dpi). The establishment of virus infection in chicks was confirmed both at molecular and antigenic levels by Polymerase Chain Reaction (PCR) and Indirect Immunofluorescent Test (IIFT), respectively. Characteristic apoptotic pattern was also detected in the affected organs and the virus was re-isolated successfully in MDCC-MSB1 cell cultures. The present results revealed that the virus circulating in poultry flocks of Uttaranchal state is both pathogenic and immunosuppressive in nature. Extensive epidemiological studies are suggested in the poultry flocks of the country along with adaptation of appropriate diagnostic, prevention and control strategies so as to prevent economic losses caused by this important poultry pathogen. PMID- 26035954 TI - Drying of sweet whey using drum dryer technique and utilization of the produced powder in French-type bread and butter cookies. AB - The objective of this study was to dry sweet liquid whey using drum dryer and to utilize the whey powder in French-type bread and cookies as a sugar substitute. The sweet whey powder was characterized chemically for ash, moisture, water activity, protein, salt, acidity and lactose contents. Optimization parameters including drying temperature, drum speed and starch addition for whey drying by drum dryer were tested to produce the best powder characteristics. The optimum temperature was 140 degrees C at a drum speed of 20 rpm with a corn starch level of 2% (weight per weight). Sweet whey powder produced was used as a sugar replacer in French-type bread and butter cookies at substitution levels of 25, 50 and 75% of total sugars. The developed products were analyzed chemically and sensorially. The two developed products were relatively high in protein, ash, lactose and salts compared to the control samples. Regarding the sensory evaluation, the results showed that the sugar substitution of 25 and 50% in bread and cookies were significantly (p<0.05) better than the control. It can be concluded that sweet whey powder can significantly improve the quality of the studied bakery items. PMID- 26035955 TI - Egg Drop Syndrome-76 (EDS-76) in Japanese quails (Coturnix coturnix japonica): an experimental study revealing pathology, effect on egg production/quality and immune responses. AB - Egg Drop Syndrome-76 (EDS-76) is a recognized disease of chickens and Japanese Quails, which is of high economic importance due to its drastic negative effects on egg production in laying birds. The aim of the present study was to better understand the EDS-76 viral disease process in Japanese quails (Coturnix coturnix japonica), since very limited studies have been conducted in this species of birds. For this purpose, an experimental study was conducted with infection of EDS-76 virus in laying Japanese quails to reveal pathology, effect on egg production/quality and immune responses of this virus in these birds. By 7, 9 and 13-15 Days Post Infection (DPI), drop as well as aberrant egg production and lower mean egg quality were observed compared to control birds. Significant histopathological changes were observed in genitalia and spleen. Haemagglutination Inhibition (HI) and Enzyme Linked Immunosorbent Assay (ELISA) titres rose rapidly by 2nd week when it became maximum; thereafter declined and maintained at low levels up to 10 week post infection. The mean total protein values in infected quail gradually increased to 4.10+/-0.05/100 mL without any change in mean albumen value at 12 DPI. In conclusion, the course of the EDS-76 is significant not only in chickens but also in quails even though it occurs occasionally in quails. Explorative pathological, blood biochemical and immunological studies are suggested during EDS-76 viral disease course in quails. This would aid in formulating effective disease prevention and control measures for this economically important disease of poultry. PMID- 26035956 TI - Study of antisickling and vasorelaxant activities and acute toxicity assessment of crude extracts of leaves of Ficus sycomorus L. (Moraceae). AB - The leaves of Ficus sycomorus are used in Burkina Faso folk medicine for the treatment of sickle cell disease. The present comparative study of crude extracts of leaves (decoction, macerated extract and a 95% ethanol extract) was performed with the aim to assess the efficiency of this traditional use and to determine the most active of the three extracts. Antisickling activity was assessed by the Emmel's test. Vasorelaxant effect on rat aortic rings precontracted by phenylephrine with and without N-nitro-L-arginine methyl ester chloride (L-NAME) was also evaluated. The 95% ethanol extract (20 mg mL(-1)) showed the most antisickling activity on sickle erythrocytes, by inhibiting completely sickling of double heterozygote SC cells in 60 min and that of homozygote SS cells in 90 min. On the aorta this extract exhibited a significant (p<0.05) vasorelaxant activity, better than that of the other extracts, with an IC50 value of 6.86+/ 0.13 mg mL(-1) against 18.78+/-0.38 and 28.56+/-1.27 mg mL(-1), respectively for the macerated extract and the decoction. When the aortic rings were pretreated with L-NAME, only the ethanolic extract conserved its vasorelaxant activity, up to 73% of relaxation. The acute toxicity of the decoction, assessed by intraperitoneal route and using the Litchfield and Wilcoxon method, led to an LD50 value of 1553.61 mg kg(-1) b.wt. This places the drug among those with low toxicity according to the WHO scale. These results confirm those previously obtained and provide a scientific basis supporting the use of this plant in folk medicine against sickle cell disease. They indicate the importance of Ficus sycomorus in the research of new antisickling molecules. PMID- 26035957 TI - Evaluation of the ex vivo antimalarial activity of organotin (IV) ethylphenyldithiocarbamate on erythrocytes infected with Plasmodium berghei NK 65. AB - Malaria is the most destructive and dangerous parasitic disease. The commonness of this disease is getting worse mainly due to the increasing resistance of Plasmodium falciparum against antimalarial drugs. Therefore, the search for new antimalarial drug is urgently needed. This study was carried out to evaluate the effects of dibutyltin (IV) ethylphenyldithiocarbamate (DBEP), diphenyltin (IV) ethylphenyldithiocarbamate (DPEP) and triphenyltin (IV) ethylphenyldithiocarbamate (TPEP) compounds as antimalarial agents. These compounds were evaluated against erythrocytes infected with Plasmodium berghei NK65 via ex vivo. Organotin (IV) ethylphenyldithiocarbamate, [R(n)Sn(C9H10NS2)(4 n)] with R = C4H9 and C6H5 for n = 2; R = C6H5 for n = 3 is chemically synthesised for its potential activities. pLDH assay was employed for determination of the concentration that inhibited 50% of the Plasmodium's activity (IC50) after 24 h treatment at concentration range of 10-0.0000001 mg mL(-1). Plasmodium berghei NK65 was cultured in vitro to determine the different morphology of trophozoite and schizont. Only DPEP and TPEP compounds have antimalarial activity towards P. berghei NK65 at IC50 0.094+/-0.011 and 0.892+/ 0.088 mg mL(-1), respectively. The IC50 of DPEP and TPEP were lowest at 30% parasitemia with IC50 0.001+/-0.00009 and 0.0009+/-0.0001 mg mL(-1), respectively. In vitro culture showed that TPEP was effective towards P. berghei NK65 in trophozoite and schizont morphology with IC50 0.0001+/-0.00005 and 0.00009+/-0.00003 MUg mL(-1), respectively. In conclusion, DPEP and TPEP have antimalarial effect on erythrocytes infected with P. berghei NK65 and have potential as antimalarial and schizonticidal agents. PMID- 26035958 TI - GIS-assisted dispersion of SO2 in the industrial regions. AB - Sulfur dioxide is one of the most important pollutants in urban areas which cause respiratory problems and acid rain. The aim of this research is to study the feasibility of using passive diffusive air sampling and GIS technique to determine the dispersion level of SO2 in the industrialized Zarghan area and assessing the contribution level of generating sources of SO2 in the urban areas. It is also essential to determine the contribution of other sources and dispersion radius of pollutants in the area as well. In this study, we used passive sampling method to measure the concentration of sulfur dioxide at 10 monitoring stations. Interpolation tools in ArcGIS technique create a continuous surface from measured values to predict SO2 concentration in other parts of the city. The concentrations of SO2 around Shiraz oil refinery and Dudej region located at 3 km from the oil refinery were 60 and 19 MUg m(-3), respectively. In conclusion the results indicated that SO2 concentration was not exceeded the standard limit in the residential area and the role of the local highway and industrial park was not significant. PMID- 26035959 TI - Analyses of the leaf, fruit and seed of Thaumatococcus daniefii (Benth.): exploring potential uses. AB - Thaumatococcus daniellii is an economic plant with versatile uses in Southern Nigeria. The arils attached to the seeds contain thaumatin, a non-sugar sweetener and taste modifier. This study examined the chemical constituents of the leaf, fruit and seed of T. daniellii. The fresh fruit, on weight basis, consists of 4.8% aril, 22.8% seed and 72.4% fleshy part. The leaf contained (per 100 g): 10.67 g moisture, 8.95 g ash, 17.21 g fat, 21.06 g protein, 24.61 g crude fiber 17.50 g carbohydrate, 0.10 g calcium, 0.08 g magnesium, 0.01 g iron and 0.37 g phosphorus. The fruit (fleshy part) contained 10.04 g moisture, 21.08 g ash, 0.93 g fat, 11.53 g protein, 18.43 g crude fiber, 37.27 g carbohydrate, 0.34 g calcium, 0.30 g magnesium, 0.01 g iron and 0.21 g phosphorus. The seed contained 15.15 g moisture, 11.30 g ash, 0.21 g fat, 10.36 g protein, 20.52 g crude fiber and 42.46 g carbohydrate. Terpenoids, flavonoids, alkaloids and cardiac glycosides were significantly present in both the leaf and fruit whereas phlobatannin, saponin, steroids, anthraquinones and ascorbic acid were absent. Tannin was present only in the leaf. The leaf and fruit of T. daniellii have significant nutritional and medicinal benefits. The leaf is rich in protein and fat. The fruit is a good source of minerals, particularly, calcium and magnesium; the leaf is also rich in phosphorus. PMID- 26035960 TI - Psychopharmacological potentials of methanol leaf extract of Securinega virosa Roxb (Ex Willd) Baill. in mice. AB - Schizophrenia is a highly disabling chronic psychiatric illness. The existing antipsychotic agents are associated with untoward effects and drug interactions leading to the intensification of search for newer agents with better efficacy and safety profile. Securinega virosa is a commonly used medicinal plant in African traditional medicine. The decoction of the leaves of the plant in combination with other plants is used in the management of mental illness. In this study, we evaluate the antipsychotic potential of the methanol leaf extract (25, 50 and 100 mg kg(-1)) of the plant using apomorphine-induced stereotypic climbing behavior and swim-induced grooming tests, all in mice. The CNS depressant effect was also evaluated using ketamine-induced sleep test mice. The extract at the highest dose tested (100 mg kg(-1)) significantly reduced the apomorphine (1 mg kg(-1))-induced stereotypic climbing behavior after 30 min. Similarly, haloperidol (2 mg kg(-1)), the standard agent significantly (p<0.001) decreased the mean climbing behavior. In the swim-induced grooming test, the extract significantly (p<0.01) and dose-dependently decreased the total grooming time. Similarly, haloperidol (2 mg kg(-1)) significantly (p<0.001) decreased the mean grooming activity. The extract significantly increased the total ketamine induced sleep duration at doses of 50 and 100 mg kg(-1). These findings suggest that the extract possesses antipsychotic and sedative potentials and lend credence to the ethnomedical use of the leaves of the plant in the management of mental illness. PMID- 26035961 TI - Liver function assessment in malaria, typhoid and malaria-typhoid co-infection in Aba, Abia State, Nigeria. AB - Malaria and typhoid fever are among the most endemic diseases in the tropics and are associated with poverty and underdevelopment with significant morbidity and mortality. Both diseases can lead to liver damage if not properly treated. The liver function assessment was therefore conducted on (90) volunteer patients; comprising (30) patients with malaria only, (30) with typhoid only and (30) with malaria-typhoid co-infection randomly selected from Abia State University Teaching Hospital, Aba, Abia State, Nigeria and (20) healthy individuals were used as control. Blood samples collected from these subjects were screened for malaria parasite and Staphylococcus typhi using standard methods. Mean serum levels of ALP (112.55+/-84.23), AST (31.33+/-12.80), ALT (23.10+/-11.84), TB (19.43+/-5.02), CB (5.91+/-3.03) and ALP (116.69+/-48.68), AST (28.33+/-11.72), ALT (22.8+/-5.94), TB (19.31+/-5.84),CB (5.60+/-2.50) were obtained for those subjects with malaria and typhoid respectively and subjects with malaria-typhoid co-infection recorded the following; ALP (134.33+/-56.62), AST (33.97+/-8.43), ALT (24.40+/-4.37),TB (21.27+/-2.96),CB (6.58+/-3.10) while the control subjects had mean serum levels ofALP (71.05+/-18.18), AST (16.65+/-7.45), ALT (13.85+/ 6.09), TB (10.05+/-4.85) and CB (3.00+/-1.67). These mean values were subjected to a statistical test using students t-test which revealed a significant increase (p<0.05).The results suggest that malaria, typhoid and malaria-typhoid co infection can elevate ALP, AST, ALT, TB and CB serum levels and can lead to liver damage if not properly treated. PMID- 26035962 TI - Effect of de cortication and roasting on trypsin inhibitors and tannin contents of cowpea (Vigna unguiculata L. Walp) seeds. AB - This study was carried out to evaluate the nutritive value of cowpea seeds. Also to minimize the presence of some anti nutritional factors such as tannin and trypsin inhibitors. It is aimed to determined the best method by which we can reduce the anti nutritional factors. Samples of raw, decorticated and decorticated roasted cowpea seeds were subjected to proximate analysis. The results show that for dry matter (93.63, 94.33 and 95.9), for crude protein (29.18, 31.80 and 29.73), for ash (4.60, 4.0 and 5.52) for fiber (6.22, 3.75 and 4.32) for ether extract (2.30, 2.50 and 1.60) for nitrogen free extract (51.33, 52.28 and 54.73), respectively for raw, decorticated and decorticated roasted seeds. Tannin content percentages were determined using method. The results were (0.76, 0.02 and 0.005), respectively. Trypsin inhibitors were determined using enzymatic method the results were (1.68, 0.74 and 1.36), respectively for raw, decorticated and decorticated roasted cowpea seeds. It is concluded that chemical composition was varied between the treatments. Decorticated seeds gives high level of protein followed by the others. De cortication significantly reduced tannin content by 85%. Roasting significantly decreased trypsin inhibitors by 65%. Processing of cowpea seeds either mechanically or by heat, significantly improve their nutritional value. PMID- 26035963 TI - Association between ABO blood/rhesus grouping and hepatitis B and C: a case control study. AB - During past decades, a connection between hepatitis and the host ABO/Rh blood groups has been always under dispute, with no appropriately designed study yet. This study aimed to investigate possible association between ABO blood/Rh groups with both hepatitis B and C. In this case-control setting, 200 healthy individuals (controls), 200 patients with chronic Hepatitis-B infection (HB) and 200 patients with chronic Hepatitis-C infection (HC) were recruited from 2010 to 2013 in Tabriz Sina Hospital. ABO blood and Rh grouping was performed and the results were compared between the case and control groups. Both pair of the control and HB groups and the control and HC groups were matched for their subjects' age and sex. In the control group, 178 subjects (89%) were Rh+ and 22 subjects (11%) were Rh-. In the HB group, there were 180 Rh+ (90%) and 20 Rh- (10%) patients. In the HC group there were 168 Rh+ (84%) and 32 Rh-negative (16%) patients. Both pair of the control and HB groups (p = 0.74), as well as the control and HC groups (p = 0.14) were comparable for the status of Rh. In the control group there were 84 (42%), 32 (16%), 66 (33%) and 18 (9%) subjects with A, B, O and AB blood groups, respectively. The corresponding figures were 84 (42%), 34 (17%), 58 (29%) and 24 (12%) for the HB patients; and 80 (40%), 29 (14.5%), 85 (42.5%) and 6 (3%) for the HC patients. Comparing between the control and HB groups showed no significant difference in terms of the frequency of ABO blood groups (p = 0.70). However, with comparing the control and HC groups, the rate of O blood group was significantly higher in the HC group and concomitantly, the rate of AB blood group was significantly higher in the control group (p = 0.04). Although, there is not a significant association between ABO blood groups and HB, this association is significant between certain ABO blood groups and HC. PMID- 26035964 TI - Association between Human Leukocyte Antigen class-I and hepatitis C: the first report in Azeri patients. AB - It has been suggested that host genetic diversity may be associated with Hepatitis C (HC). However, available data are tremendously heterogeneous due to the influence of ethnic and geographical differences. This study aimed to investigate possible association between certain Human Leukocyte Antigen (HLA) class-I alleles with HC in a group of Azeri patients for the first time in the literature. In a case-control study, 50 patients with confirmed HC (cases) and 50 healthy age- and sex-matched counterparts (controls) were evaluated in Tabriz Sina and Imam Reza Hospitals in a 2-year period of time (2011-2013). The investigated HLA alleles in the present study were: A2, A3, B35, B38, BW4, CW4 and CW7. The A2-positive cases were significantly more frequent in the case than in the control group (58 vs. 32%, p = 0.01, Odds Ratio (OR) = 2.9). Similar trend was documented for A3 (62 vs. 26%, p < 0.001, OR = 4.6), B35 (24 vs. 2%, p = 0.001, OR = 15.5) and BW4 (78 vs. 46%, p = 0.001, OR = 4.2). In contrast, the rate of B38-positive (34 vs. 8%, p = 0.001, OR = 0.2) and CW7-positive (38 vs. 14%, p = 0.01, OR = 0.3) cases was significantly higher in the hepatitis-C negative subjects. There was no significant difference in terms of the rate of CW4-positivity between the two groups (20% in the cases vs. 34% in the controls, p = 0.12, OR = 0.5). This study showed that there are significant associations between certain HLA-I alleles with hepatitis C in Azeri patients. While some alleles make the host prone to the disease, others may have a protective role in this regard. PMID- 26035965 TI - [Nucleosome fracton of extracellular dna as the index of apoptosis]. AB - Review is devoted to the analysis of changes of the extracellular DNA (excDNA) in pathological conditions involving the process of apoptosis, and the possibility of using of excDNA in the diagnosis and evaluation of course of various diseases. Apoptosis is the main mechanism of the appearance of the DNA in the circulation. ExcDNA found in the norm, its function is considered to be the part of the immune response. The excDNA content increases substantially during the induction of apoptosis. Dynamics of increase of excDNA content in stroke allows to diagnose the form of stroke and massiveness of destruction of brain tissue. Reduced content of excDNA is associated with the inhibition of apoptosis, it was shown that under such conditions there is a change of composition of excDNA. Investigation of excDNA character changes in the progression and treatment of cancer substantiates the possibility of early assessment the effectiveness of treatment. It is experimentally shown the immunosuppressive action of excDNA of tumor and its transforming effect on the cells. Ionizing radiation is an examples that demonstrated the association of induction of apoptosis and the release of excDNA. It is characterize some of the genome sequences of excDNA. Created on the basis of excDNA study tests of minimally invasive diagnostics are potentially useful in oncology and other areas of medicine. The study of tandem repeats, which are absent in the assembled genome, but there is a part of excDNA, will create tests for the diagnosis of cancer in the early stages. PMID- 26035966 TI - [Large tandem repeats of mesocricetus a uratus in silico and in situ]. AB - The class of tandemly repeated sequences exists only in eukaryotic genomes and absent in prokaryotes. The tens percent of eukaryotic genome are built up of the tandem repeats. The whole set of different tandem repeats is not revealed to any of the eukaryote species in spite of the half century history of its investigation by molecular biology methods. Previously we found the set of tandem repeats in the database of well assembled mouse genome with the bioinformatics methods. In the current work we applied the same methods to the poorly assembled hamster Mesocricetus auratus genome. 19 tandem repeats families have been found in hamster genome by bioinformatics (in silico). Only one of tandem repeats' families found have been cloned previously and exists in the Repbase, the database of all known repetitive fragments. The rest of the families are new and need the experimental verification by FISH (in situ). Oligo probes were designed at the base of in silico found sequences. Oligo probe for the known tandem repeat gives the same signal as the cloned probe, i.e., probes designed are suitable for oligo-FISH. All four oligo probes tested give signal at the heterochromatic centromeric region as expected, though with different intensities and at different number of chromosomes. The results show the power of the in silico methods for the mostly mysterious genome component, tandem repeats, investigation. PMID- 26035967 TI - [Tandem repeats in rodents genome and their mapping]. AB - Tandemly-repeated sequences represent a unique class of eukaryotic DNA. Their content in the genome of higher eukaryotes mounts to tens of percents. However, the evolution of this class of sequences is poorly-studied. In our paper, 62 families of Mus musculus tandem repeats are analyzed by bioinformatic methods, and 7 of them are analyzed by fluorescence in situ hybridization. It is shown that the same tandem repeat sets co-occure only in closely related species of mice. But even in such species we observe differences in localization on the chromosomes and the number of individual tandem repeats. With increasing evolutionary distance only some of the tandem repeat families remain common for different species. It is shown, that the use of a combination of bioinformatics and molecular biology techniques is very perspective for further studies of the evolution of tandem repeats. PMID- 26035968 TI - [The DDX5 protein is involved in cell proliferation and differentiation]. AB - The expression of DDX5 protein (RNA-helicase p68) correlates with processes of proliferation and differentiation. However there is no direct evidence of involvement of the protein in these processes. In present work, we studied the influence of DDX5 protein inactivation by si-RNA on the proliferation of Jurkat cells and dynamic of DDX5 expression during differentiation of U-937 cells induced by phorbol 12-myristate-13-acetate (PMA). We showed that the content of DDX5 in Jurkat cells is less in phases G0/G1 as compare to phases G2/M. The treatment of cells with the antisense LV-shDDX5 was followed by the increase of G0/G1 cells. It was also shown that the increase of expression of the DDX5 protein occurred during the initial stages of differentiation, and the peak of expression was registered during the first 2-3 hours after the induction of the cells, later the DDX5 content decreases. The increase of the number of macrophage surface marker CR3 on the membrane of cells occurred only in 24 hours after induction of the cells by PMA. Thus, these data confirm that: (1) the DDX5 protein is essential for normal cell proliferation; (2) the transition from G1 to S/G2 phase is accompanied by an increase of DDX5 protein concentration in the cells; (3) the concentration of the DDX5 protein increases on early stages of U 937 cells differentiation and after decreases. PMID- 26035969 TI - [Radiation preconditioning of mouse retina results in tolerance to MNU-induced degeneration and stimulates retinal recovery]. AB - Emerging body of data indicate protecting effect of low level of stress (preconditioning) on retina. Our previous studies have revealed a non-linear dose response relationship for cytotoxic effect of both ionizing radiation and N methyl-N-nitrosourea (MNU) on mouse retina. Moreover, non-cytotoxic dose of MNU increased tolerance of retina to following challenge dose of MNU. This result displays protection of retina through mechanism of recovery. In the present study we used the mouse model for MNU-induced retinal degeneration to evaluate the adaptive response of the retina to proton irradiation and implication of glial Muller cells in this response. In this paper, we have shown that the recovery of the retina after exposure to genotoxic agents is associated with an increased efficiency of DNA damage repair and lowered death of retinal photoreceptors. PMID- 26035970 TI - [Mechanisms of smooth endoplasmic reticulum aggregates creation in oocyte's cytoplasm in IVF cycles and its clinical relevance (literature review)]. AB - A large proportion of human oocytes received from exogenous gonadotropin stimulated cycles have different morphological attributes, or dysmorphisms. The presence of dysmorphism can affect the fertilization rate, the embryo quality and subsequently the frequency of occurrence of implantation and pregnancy. Special attention is paid to oocytes with cytoplasmic attributes such as alteration of cytoplasmic granularity, the appearance of vacuoles, lipofuscin bodies and visible (large) aggregates of smooth endoplasmic reticulum. Endoplasmic reticulum (ER) is a type of the organelle forming an interconnected network of flattened, membrane-enclosed sacs or tubes. One of the main functions of ER in the oocyte is storage and redistribution of calcium, which provides cell activation during fertilization. Furthermore, complex of ER and mitochondria is necessary for accumulation of energy, synthesis of lipids and triglycerides, as well as synthesis of cytosolic and nuclear membranes during the early stages of cleavage. The appearance of anomalously large aggregates of ER in oocytes correlates with a low fertilization rate, low embryo quality, and pregnancy rate. The aim of the manuscript is to summarize current understanding of the mechanism of formation of such pathology of oocytes, together with special aspects of their fertilization and embryo quality. PMID- 26035971 TI - [Antiapoptotic gene bcl-2 prevents cellular senescence program reactivation induced by histone deacetylase inhibitor sodium butyrate in E1A and cHa-ras transformed rat fibroblasts]. AB - We have investigated the role of apoptosis resistance gene bcl-2 in the activation of cellular senescence program induced by histone deacetylase inhibitor (HDACi) sodium butyrate (NaBut) in transformed rat fibroblasts. This study was conducted in a resistant to apoptosis induction cell line of rat embryo fibroblasts transfor- med by oncogenes E1A, cHa-ras and bcl-2 (ERasBcl). The parent cell line transformed with only EJA and cHa-ras (ERas) was used as a control. It has been found that NaBut reduces proliferation rate of ERasBcl cells significantly weaker than of ERas transformed cells, despite the fact that the G1 cell cycle arrest was observed in both cell lines. After NaBut treatment, hypertrophy of the apoptosis resistant transformants ERasBcl also was reduced compared to parent cell line ERas, due to less activation of mTORC1, which is known to control the synthesis of protein and ribosome biogenesis. The degree of mTORC1 activation was as.sessed by its target proteins phosphorylation: the ribosomal S6 protein and 4E-BP1--inhibitor of translation initiation factor eIF4E. Since cell senescence process may be associated with changes in autophagy regulation, we analyzed the dynamics of one of the main autophagosome formation markers--protein LC3. The accumulation of lipid-bound form LC3-II changes significantly in ERasBcl cells after NaBut treatment and has transient nature. The set of analyzed cellular senescence markers suggests that a high level of apoptosis resistance gene bcl-2 expression prevents the realization of tumor suppressor senescence program induced by HDACi sodium butyrate treatment. PMID- 26035972 TI - [The influence of dipole modifiers on the channel-forming activity of amyloid and amyloid-like peptides in lipid bilayers]. AB - We have studied the steady-state transmembrane current induced by amyloid and amyloid-like peptides in lipid bilayers in the presence of dipole modifiers. It has been shown that the addition of dipole modifier, phloretin, to the membrane bathing solutions leads to an increase in the multichannel activity of amyloid beta-peptide fragment 25-35, [Gly35]-amyloid beta-peptide fragment 25--35, prion protein fragment 106-126 and amyloid-like peptides myr-BASP1 (1--13), myr-BASP1(1 -19) and GAP-43(1--40). We have found that the effect of phloretin is not the result of dipole potential changes due to adsorption of this modifier on the membrane. Using the various fragments of amyloid beta-peptide, presenilin, prion protein and neuronal proteins BASP1 and GAP-43 allowes to conclude that the steady-state peptide-induced transmembrane current in the case of addition of phloretin is due to the electrostatic interaction between the positively charged channel-forming agents and negatively charged dipole modifier. The results obtained by electron microscopy have demonstrated that this interaction increases degree of peptide oligomerization. PMID- 26035973 TI - [Culture of mussel Mytiuls edulis I. mantle cells]. AB - To date, cell lines derived from marine invertebrates have not been available. Hence primary cell cultures serve as model systems for various experiments. In present study we established primary culture of mussel Mytilus edulis L. mantle cells. Cells were isolated by means of explant culture or enzymatic dissociation of mantle tissue. They maintained viability up to 22 months regardless of culture initiation method. In course of culturing, cells, which were transferred onto new plates, successfully attached to a new surface. Physiological activity of cultured cells was also confirmed by formation of crystals, which appeared after 4-6 months. After continuous time of culturing, mantle cells can be cryopreserved using 5 % DMSO with post-freezing survival up to 50%. These results demonstrate that M. edulis mantle cells can maintain viability and physiological activity for exceptionally long time and can be cryopreserved for further examination. PMID- 26035974 TI - [Vladimir Davidovich Zhestyanikov (1924-2014)]. PMID- 26035975 TI - President's message. PMID- 26035976 TI - Coronary levels of angiotensin-II and endothelin-I in diabetic patients with and without coronary artery disease. AB - Two groups of patients were studied to find out the levels of angiotensin-II and endothelin-I in the coronary and peripheral circulation. Group A consisted of eight patients with diabetes mellitus type 2 and coronary artery disease; and Group B with diabetes mellitus without coronary artery disease. Significant differences were found between Group A and B in the levels of both peptides peripherally and intracoronary. This shows the importance of these peptides in the origin of coronary artery disease and progression of the disease in diabetics with coronary artery disease. PMID- 26035977 TI - Interventional nephrology in Puerto Rico: a four year experience. AB - Puerto Rico is one of the most prevalent areas covered by Medicare in need of renal replacement therapy for which interventional procedures are performed. A cumulative analysis of this management is reported in patients during the period between June 2007 and August 2010. Experience accumulated with 3755 surgical patients revealed that 58% had intravascular catheters, 28% had arteriovenous fistulas, 15% had arteriovenous grafts, and 2% without vascular access. Procedures performed in these patients were: catheter introduction in 1990 cases (33%), angioplasty in 751 cases (20%), angiography in 450 cases (12%), thrombectomy in 413 cases (11%) and venous mapping in 151 cases (4%). The success rates of these procedures were evaluated by analysis of the Society of Interventional Radiology (SIR) criteria for Lifeline Vascular Access. Using SIR definition of success rate for at least one session that includes "declots", placement of catheters and angioplasty, our results revealed an average of 98.2% overall success rate greater than the standard value KDOQI/SIR (> 85% ). This study has documented for four years the success rate of Vascular Interventional Nephrology Center at Auxilio Mutuo Hospital. In order to maintain this success rate is necessary to further evaluate its effectiveness and, most importantly, the development of an educational program for vascular access in patients with chronic kidney disease prior to placement in dialysis units. PMID- 26035978 TI - Brugada syndrome in Puerto Rico: a case series. AB - Brugada syndrome is characterized by ST-segment changes in the right precordial ECG leads and a high incidence of sudden death in patients with strutural norm hearts. Life-threatening ventricular arrhythmias are the hallmark of Brugada syndrome whice incidence and prevalence of BrS in Puerto Rico, to our knowledge, has never been studied and there is only one case report of BrS in Puerto Rico in the literature. We review three cases of BrS in Puerto Rican patients who presented to our institution with syncope reviewing the literature. PMID- 26035979 TI - Primary venous and malignancy, is there any relationship? AB - Deep venous thrombosis and pulmonary embolism can be the first manifestation of cancer. In light of this association screening for cancer has been proposed in patients with primary VTE to identify an undiagnosed malignancy. METHOD: Descriptive, retrospective record review that includes 3244 patients from VA San Juan Caribbean system with diagnosis of lung (small and non-small cell), prostate, colon, rectum, liver, stomach, esophagus, pancreas and breast cancer, lymphoma or leukemia from 2005 to 2010 evaluated for primary VTE during five years prior to their malignancy diagnosis. Secondary outcomes evaluated were age and staging at the time of VTE diagnosis. The inclusion criteria were veterans with age 21 years old or more and with diagnosis of the above mentioned malignancies. The exclusion criteria were pregnancy five years to the diagnosis of malignancy, history of coagulopathy or use of anticoagulation at moment of the diagnosis of malignancy. RESULTS: 3244 records were reviewed. From the 2858 that met the inclusion criteria 22 (8%) had history of VTE five years before their malignancy, most of them (14%) with diagnosis of pancreatic malignancy. After we studied VTE by site of malignancy: 7% of pancreatic, 0.8% of prostate, 0.5% of colon, 0.6% of bladder, 0.8% of liver, 0.4% of lung, 1.1% of rectal cancer patients but none with leukemia, stomach, esophagus, breast cancer had VTE. Regarding patients with advanced metastatic cancer at the moment of their diagnosis, only 13% had a prior event of VTE. CONCLUSION: Although at this point there is no clear indication to screen for malignancy in patients presenting primary VTE our results point out an increased number of VTE in patients with subsequent pancreatic cancer. More research is needed before further recommendations on cancer screening in patients with VTE. PMID- 26035980 TI - Intravenous ascorbic acid and hydrogen peroxide in the management of patients with chikungunya. AB - Chikungunya is a viral illness characterized by severe joint pains, which may persist for months to years. There is no effective treatment for this disease. We treated 56 patients with moderate to severe persistent pains with a single infusion of ascorbic acid ranging from 25-50 grams and hydrogen peroxide (3 cc of a 3% solution) from July to October 2014. Patients were asked about their pain using the Verbal Numerical Rating Scale-11 immediately before and after treatment. The mean Pain Score before and after treatment was 8 and 2 respectively (60%) (p < 0.001); and 5 patients (9%) had a Pain Score of 0. The use of intravenous ascorbic acid and hydrogen peroxide resulted in a statistically significant reduction of pain in patients with moderate to severe pain from the Chikungunya virus immediately after treatment. PMID- 26035981 TI - Quality of life-in patients with differentiated thyroid cancer at the general endocrinology clinics of the University Hospital of Puerto Rico. AB - Differentiated thyroid cancer (DTC) can compromise the quality of life of patients. Our purpose is to investigate if the quality of life, in a cohort of patients in Puerto Rico, is affected by the diagnosis and/or treatment modalities received for DTC. METHODS: This is a cross-sectional study of 75 subjects with DTC. A Spanish version of the University of Washington Quality of Life Questionnaire was used, including multiple aspects of physical and social functioning. Descriptive and bivariate analysis between domain scores and variables of interest were performed. RESULTS: 82.7% of the patients reported that their health was the same or better than it was before treatment. The mean composite score obtained was 82.3, reflecting an overall little effect on quality of life. Patients diagnosed with DTC at an age of > or =45 years reported a significantly better score on the pain domain when compared with those diagnosed earlier (p < 0.05). Patient who received >150 mCi of radioiodine had a tendency towards a worse score on the same domain (p = 0.05). CONCLUSIONS: Our cohort reported an overall minimal effect on the quality of life of patients with DTC. Future treatment strategies should include periodic quality of life evaluations, in order to tailor therapy in this growing population. PMID- 26035982 TI - Clinical and radiological indicators of severity in patients with acute pancreatitis. AB - The purpose of this study was to estimate the degree of association between clinical (Ranson criteria) and radiological variables (Abdominal CT scan) with degree of severity in patients with a diagnosis of acute pancreatitis. METHOD: All patients discharged with the diagnosis of acute pancreatitis from January 1, 2010 through December 31, 2012 in a community hospital were selected (N=174). The following variables were studied: sex; age; weight; height; admission and discharge dates; presence of several chronic conditions; laboratory results included in Ranson criteria; abdominal CT category; outcome, including fatality surgery, and other complications. Analysis included descriptive statistics and Risk-Ratios for complications for different groups of subjects, using clinical and radiological criteria. RESULTS: The incidence rate of complications, including fatality, surgery and organ failure was 36.2%. Factors that showed significant associations with the risk of complication on crude analysis were gallbladder disease with a RR=1.78 ($95% CI: 1.22, 2.60) and abnormal abdominal CT with a RR=1.85 (95% CI: 1.11, 3.07). with multivariate analysis, gallbladder disease, abnormal abdominal CT, and presence of 3 or more Ranson's criteria showed increased risk for complications, but the results did not reach statistical significance. DISCUSSION: The factors that seemed to be associated with increased rate of complications in subjects with acute pancreatitis were gallbladder disease, abnormal abdominal CT, and 3 or more Ranson's criteria. The Results did not show statistical significance probably because of low statistical power of the study. PMID- 26035983 TI - Celiac trunk and branches dissection due to energy drink consumption and heavy resistance exercise: case report and review of literature. AB - Higher doses and consumption of energy drinks leads to cardiovascular effects and potential consequences. Principal components found in energy drinks such as caffeine, guarana and taurine has been related to dilatation, aneurysm formation, dissection and ruptures. There is no evidence showing an integration of these components and its effects in endothelium and aortic walls due to higher levels of pressure during exercises. We report a case of a 44 years male with celiac trunk and branches dissection due to long-term consumption of energy drinks and intense exercise routine. Our proposition relates cell and vessel walls alterations including elasticity in endothelial wall due to higher blood pressure, resistance by intense exercise routine and long-term consumption of energy drinks. PMID- 26035984 TI - Worsening gradient of aortic stenosis with treatment of pulmonary arterial hypertension in scleroderma. AB - Systemic sclerosis (SSc) can cause interstitial lung and pulmonary vascular disease that can induce pulmonary arterial hypertension (PAH). It is well known that severe PAH may reduce left ventricluar preload and decrease diastolic filling with the potential of reducing forward flow. We present a case in which a patient with SSc and symptomatic PAH required direct pulmonary vasodilator therapy for treatment of elevated pulmonary pressures. On follow-up echocardiogram, while improvement in right ventricular function and reduction in estimated pulmonary pressures were noted; worsening of aortic valve gradients was also found. Cardiac hemodynamics of pulmonary vasodilator therapy is discussed and the literature is reviewed. PMID- 26035985 TI - Uncommon cause of life-threatening retroperitoneal hemorrhage in a healthy young Hispanic patient: splenic artery aneurysm rupture. AB - Splenic artery aneurysms (SAA) are a rare life threatening clinical diagnosis. We present a case of a young Hispanic woman with an aneurysm of the middle branch of the splenic artery and active leakage. The defect was embolized with complete resolution of the retroperitoneal bleeding. Physicians should be aware of this rare entity especially when female patients presents complainiing of severe epigastric pain with associated hypovolemic shock. PMID- 26035986 TI - Atraumatic bilateral femoral neck fractures in a premenopausal female with hypovitaminosis D. AB - Bilateral femur neck fractures in young adult patients are very rare in atraumatic circumstances. We report a young premenopausal female with osteomalacia secondary to vitamin D deficiency and spontaneous bilateral femur neck fractures. Patients had no reported risk factors for osteomalacia but hypovitaminosis D was noted on laboratory evaluation. Osteomalacia secondary to low serum levels of vitamin D may lead to stress and fragility fractures. Identification and treatment of at risk patients may decrease the incidence of stress fractures and its possible complications. PMID- 26035987 TI - Small cell carcinoma of the uterine cervix: a case report and literature review. AB - Small cell carcinoma of the uterine cervix is a rare and aggressive extra pulmonary variant of small cell tumors. This carcinoma of the cervix comprises less than 5% of all cervical carcinomas and is know to be highly undifferentiated. It is associated with a poor prognosis and characterized by premature distant nodal involvement. The survival rate at all stages ranges from 17% to 67%. We describe the case of a 41 year old female patient with a rare, and aggressive, clinical stage IB1 small cell neuroendocrine carcinoma of the cervix. The goal of this case report is to describe this rare pathology and contribute information to the scant available data. PMID- 26035988 TI - Handlebar hernia: case report and literature review. AB - Handlebar hernia is a rare traumatic abdominal wall hernia occurring after blunt trauma. We report a case of an adolescent patient with a traumatic rectus muscle abdominal wall hernia produced by injury with the bicycle handlebar. The skin abrasion caused by the trauma and a swelling reproduced after a Valsalva maneuver suggested the diagnosis. Traumatic wall hernias after blunt trauma should be repaired primarily to avoid complications. PMID- 26035989 TI - Should we revisit anticoagulation guidelines during thyroid storm? AB - Thyroid storm is a rare but potentially catastrophic disease expression of thyrotoxicosis with well-recognized cardiovascular manifestations such as heart failure and atrial fibrillation. Even through some studies have found an increased risk of cardiac thrombus formation and subsequent thromboembolism in these patients, the use of anticoagulation to prevent thromboembolic sequelae of thyrotoxic atrial fibrillation remains unclear. We present a patient presenting with new onset dilated cardiomyopathy and resistant atrial fibrillation with thyroid storm that had a large left atrial appendage clot. Case particulars are discussed and the literature reviewed. PMID- 26035992 TI - [Changes in bone structure according to the results of investigations on biosatellites of the "BION" series]. AB - Noninvasive technologies of bone investigations measure largely the main skeletal sites and are not quite suitable to have a look at the bone internal organization in situ. However, there are data obtained noninvasively in experiments on board the space biosatellites. The review is dedicated to analysis and comparison of the evidence for the bone organic and mineral matrix restructuring due to microgravity. These changes have presumably evolved in the course of the system reaction of bone tissue and the whole skeleton. PMID- 26035993 TI - [Comparative evaluation of the effects of hypoxic gaseous mixtures varying in oxygen concentration on Japanese quail embryogenesis]. AB - The paper presents the results of comparative characterization of the effects of low oxygen levels (10 +/- 0.5 and 14.5 +/- 0.5%) on developing organism. Four-day old embryos of the Japanese quail (Coturnix coturnix japonica) were chosen for the object of investigation as this is the age when avians acquire their organs and systems. Acute hypoxia (10 +/- 0.5% oxygen) caused a general death of the embryos, and serious abnormalities of the eye and brain, and ectopy. Embryos that developed in the low-oxygen atmosphere (14.5 +/- 0.5%) did not exhibit many of these morphological abnormalities and yet their growth was retarded apparently. Such abnormalities in acute hypoxia are ascribed to disturbance in development of extra-embryonic membranes, amnion in particular, desynchronization of morphogenetic processes and movement of embryo's tissue layers. PMID- 26035994 TI - [Morphologic changes in mice trachea, bronchi and lungs after prolonged combined radiation and inhaled chemical exposure]. AB - Investigations of morphology and morphometry of the breathing organs (trachea, bronchi and lungs) and immunogenesis of mice subject to a combined sequential exposure to fractionated external gamma-irradiation by the total dose of 350 cGy and a mix of acetone, ethanol and acetaldehyde in MPCs for piloted spacecrafts simulating the estimated levels in crewed exploration missions were conducted. Morphologic changes in the breathing organs of animals after space missions point to immunogenesis activation and appearance of a "structural trace" as a chronic inflammation with the growth of fibrous connective tissue in tracheal, bronchial and lung walls, increase in volume fractions of glands and vessels and reduction in loose fibrous connective tissue. Formation of the fibrous connective tissue was particularly noticeable in respiratory parts of the breathing organs suggesting a high risk of long-term adverse effects. PMID- 26035995 TI - [Mitigation of mice radiation damage after acute and prolonged gamma-irradiation by a laser device]. AB - Effects of 7 Gy 60Co gamma-radiation (acute and prolonged exposure), and combined exposure to 650 nm laser and gamma-radiation on survival, peripheral blood, karyocyte count and mitotic index of bone marrow cells were studied in young C57BL/6 mice. All mice died following acute gamma-irradiation at the dose rate of 1.14 Gy/min for 5 days or combined exposure for 11 days. Thirty percent survival from prolonged exposure to the dose rate of 0.027 Gy/min was observed after 19 day gamma- and 38-day combined irradiation. Peripheral blood parameters did not differ significantly after acute and prolonged exposure; however, hyperchromemia was observed in mice after 24 hours of acute gamma-irradiation. The count of mitoses per 1000 nucleus-containing BM cells evidenced that BM was virtually collapsed after 72 hours since the acute gamma-exposure. It was demonstrated that laser can manage protection from a broad range of ionizing radiation doses and mitigate the adverse effects of equally acute and prolonged radiation exposure. PMID- 26035996 TI - [Gender differences in weather sensitivity of normal adult people registered on the rheoencephalogram and electroencephalogram]. AB - In the real-life environment the subjectively unperceived reactivity of rheoencephalogram (REG) and electroencephalogram (EEG) to ordinary geophysical factors (i.e. wind, atmospheric pressure, relative humidity and temperature) is gender-dependent. Correlations between REG and EEG values and weather fluctuations are more frequent and stronger in men. Dependence of EEG rhythms on weather factors increases as the rhythmic activity within the delta-theta-beta range becomes more rapid. This pattern is particularly evident in men but not women. Reactivity of neurodynamic parameters in female REG and EEG is responsive to the ovarian-menstrual cycle. Almost all cases of cerebral weather sensitivity of women were objectified in the post-ovulatory period, whereas in the preovulatory period episodes of weather sensitivity were only singular. PMID- 26035997 TI - [Use of the ion-exchange substrate to optimize mineral nutrition of plants within a bio-engineering life support system with a high level of closure]. AB - Purpose of the work was to test manageability of nutrient solutions containing mineralized human exometabolites by using an ion-exchange substrate (IES) for cultivating wheat in a bio-engineering life support system with a high level of closure. Object of the investigation was wheat Triticum aestivum L. (Lysovsky cv. l. 232). Crops were raised on clayite in a growth chamber of a hydroponic conveyor system under continuous light. Correction of nutrient solution was to lift the limits of crop supply with minerals. The experimental crop grew in nutrient solution with immersed IES "BIONA-312"; nutrient solution for the control crop was corrected by adding mineral salts. Solution correction did not have a noteworthy effect on the yield, CO2-gas exchange or mineral composition of wheat plants. IES makes simple the technology of plant cultivation on solutions enriched with human exometabolites. PMID- 26035998 TI - [Performance characteristics of root zone moisture and water potential sensors for greenhouses in the conditions of extended space flight]. AB - The investigation was performed using greenhouse Lada in the Russian segment of the International space station (ISS RS) as part of space experiment Plants-2 during ISS missions 5 through to 22. A set of 6 point moisture sensors embedded in the root zone (turface particles of 1-2 mm in diam.) and 4 tensiometers inside root modules (RM) were used to monitor moisture content and water potential in the root zone. The purpose was to verify functionality and to test performance of the sensors in the spacefight environment. It was shown that with the average RZ moisture content of 80% the measurement error of the sensors do not exceed +/- 1.5%. Dynamic analysis of the tensiometers measurements attests that error in water potential measurements does not exceed +/- 111 Pa. PMID- 26035999 TI - [Mechanisms of changes in the human spinal column in response to static and dynamic axial mechanic loading]. AB - The study was concerned with the human spinal column reaction to axial static and dynamic loading. Fresh segments of the column from dorsal vertebra XI to lumber vertebra II were exposed to axial static (20 mm/min) and dynamic (200 and 500 mm/min) loading. Measured variables included load value, whole segment deformation, anterior surfaces of intervertebral disk Th(XI)-Th(XII) and dorsal vertebra XII, and acoustic emission signals indicative of spongy bone microdestruction. It was found that vertebral body deformation augmented less in comparison with the intervertebral disk and that central parts of the spinal end plates compress greater than peripheral. This difference was more considerable due to static loading rather than dynamic. To produce deformation of a spinal segment by dynamic loading same as by the static one, it is necessary to overcome a stronger resistance of a larger number of trabecular bones. Herefrom it follows that, first, to cause an equal segment compression the dynamic load must be heavier than static and, which is of paramount practical significance, dynamic strength of the column is markedly higher than static. Secondly, spinal stiffness during impact is higher as compared with the static condition. Thirdly, same degree of deformation due to dynamic loading should result in a larger volume of microdestructions comparing with static loading, which is testified by a reliable difference in the number of AE signals accumulated prior to fracture. The number of AE signals amounts to 444.2 +/- 308.2 and 85.0 +/- 36.6 in case of the dynamic and static loading, respectively (p < 0.05 according to Student's t-criterion). PMID- 26036000 TI - [Calculation of the strain-deformation condition of the spinal motor segment during loading]. AB - A mathematical model is proposed to analyze the spinal strain-deformation condition resulting from axial and lateral g-loads generated by changes in the gravity field and/or pilot's maneuvering high-performance aircraft. The solution algorithm takes into account changes in the intervertebral disk pressure and the fibrous ring shape at the time of close-to-critical g values. Calculation of the spinal strain-deformation condition was implemented by the instrumentality of computer system SPLEN (KOMMEK ltd., Russia). Analysis of the spinal strain deformation condition was made for 2 types of external loads, i.e. normal and unilateral with a bending moment. Maximum permissible loads on a spinal segment were evaluated, as well as distribution of strain intensity, mean strains, spinal deformation and destruction field was described. The constructed computer models could be used as a basis for developing a technique of predicting characteristic spinal injuries in consequence of specific extreme loads and pathologies. PMID- 26036001 TI - [Practicing subnarcotic xenon dose inhalation in spa treatment of posttraumatic stress-induced disorders]. AB - Purpose of the investigation was to compare and contrast effectiveness of xenon therapy of stress-induced neurotic disorders and traditional spa-based therapy. Patients of the experimental and control groups were people of risky professions who received drug therapy, psychotherapy and physiotherapy. The experimental group was additionally treated by inhalation therapeutic doses of medical xenon. Comparative analysis of qualitative and quantitative parameters of electroencephalogram (EEG), blood oxygen level, heart rate and blood pressure were compared in the groups before and after treatment. Recovery of the central nervous system functions, activation of parasympathetic involvement, abatement of main psychopathological and somatovegetative disorders in the experimental group were considered as signs of psychic improvement and return to the gestalt behavior. PMID- 26036002 TI - [Topographic characteristics of the human electrodermal activity]. AB - The investigation with participation of 6 test-subjects provided the first evidence that two dermal areas far apart from each other may possess identical spontaneous electrodermal activity (EDA) (r = 0.98) and, on the contrary, adjacent dermal areas may differ in EDA (p = 0.001). Asymmetry in EDA distribution across the human body was demonstrated. Most often the left part of the body was negatively charged relative to the right part. This held true also to the upper body in 59.2% cases and the lower body in 87.3% cases. In the vast majority of cases (98.6-100%) the upper body was charged negatively relative to the lower body. PMID- 26036003 TI - [Academician Nikolai Pavlovich Kravkov: on his 150th birthday]. AB - The article outlines the life and activities of academician N. P. Kravkov (1865 1924), the founder of pharmacology in Russia. During his 25 years of service as Head of the Department of Pharmacology at the Military Medical Academy in St. Petersburg, N. P. Kravkov established a large national school of pharmacological science. He was the author of a number of fundamental discoveries, which enriched the Russian and world science. PMID- 26036004 TI - [Experimental comparative study of the analgesic activity of the diurnal anxiolytic mebicar, amitriptyline, and diazepam]. AB - It is established that mebicar, amitriptyline, and diazepam administered intraperitoneally at therapeutic doses increase the pain thresholds in mice as manifested in "hot plate" analgesia test. Mebicar was more effective than diazepam and not inferior to amitriptyline in increasing the pain thresholds at earlier time points. PMID- 26036005 TI - [Reactivity of the central nervous system influences the sensitivity of secretory cells of the stomach to carbacholine and glycyl-proline (Gly-Pro)]. AB - In experiments using cluster analysis of the behavioral activity of rats in the "open field" test, the animals were divided into three groups with different types of behavior and response to the first presentation of the test: (i) active search (all the studied reactions are expressed), (ii) intermediate, and (iii) passive-defensive (lowest level of activity). Differences in the indices of carbacholine-stimulated gastric secretion in rats of different groups were manifested by greater secretion of the stomach and lower digestive capacity of gastric juice observed in rats with active-search and intermediate types of behavior in the "open field" test in contrast to rats with passive-defensive type. Combined administration of cholinomimetic and glycyl-proline (Gly-Pro) lead to decreased proteolytic activity of gastric juice in rats with active-search behavior in the "open field" test, decreased volume of gastric secretion in rats with an intermediate type of behavior, and increased volume of juice and its decreased digestive ability in rats with passive-defensive behavior. PMID- 26036006 TI - [Metabolic therapy of nephrolithiasis in two different rat models of kidney disease]. AB - 108 albino male rats were used in two experimental rat models reproducing urolithiasis for the assessment of metabolic drug medicine Remaxol nephroprotective effect upon the development of this disease. "Ethyleneglycol" model consisted of adding 1% ethylene glycol solution in drinking water for 37 days and "fructose-induced" one--of adding 10% fructose solution in drinking water for the same period. Therapy included a 10-day course of daily i.v. injections of Remaxol (14 ml/kg). Both experimental models were successful in producing urolithiasis with considerable disturbances in the structure and functioning of kidneys up to revealing microconcrement formation. The "ethyleneglycol" model proved to cause maximum changes while the "Fructose induced" model--only moderate ones. Metabolic correction of these changes was successful in nephroprotection effectively normalizing kidney functions and the total protein concentration, eliminating hyperglycemia and reducing creatinine and urea blood plasma concentration in both rat experimental models. PMID- 26036007 TI - [Preclinical study of immunocorrection action of the sum of active substances of Coluria geoides (Pall.) Ledeb. (Rosaceae)]. AB - A preclinical study of the immunocorrection action of the sum of active substances isolated from ethereal-oil plants Coluria geoides (Pall.) Ledeb. (Rosaceae family) with respect to experimental immunodeficiency showed that preparations relieve symptoms of immunodeficiency caused by the administration of cyclophosphan: suppressed synthesis of anti-erythrocyte antibodies (agglutinine) and proliferative processes in the spleen. Under the influence of C. geoides preparations, the absolute numbers of cariocytes and antibody forming cells in spleen significantly increased (compared to the group of animals with experimental immunodeficiency) and in some cases reached the background level. The drugs studied produced a more pronounced stimulating effect on the synthesis of specific immunoglobulins and proliferation of antibody forming cells of spleen as compared to the effect of Echinacea tincture. Preparation C-2 (extract from underground organs and grass of C. geoides obtained by percolation method with 70% ethanol) is most promising for in-depth research and the development of new effective drugs with immunocorrecting properties. PMID- 26036008 TI - [Pharmacokinetic evaluation of afobazole pharmaceutical composition with modified release]. AB - The main pharmacokinetic parameters (AUC0-infinity, Tmax, Cmax, Cl/F, t1/2 el, MRT, Cmax/AUC0-I, Vd/F) of afobazole base in a new pharmaceutical composition and afobazole dihydrochloride substance after single peroral administration have been determined in rats. The availability of afobazole base pharmaceutical composition relative to that of the substance amounted to 153.2%. PMID- 26036009 TI - [Experimental study of the basic pharmacokinetic characteristics of dipeptide carnosine and its efficiency of penetration into brain tissues]. AB - We have used an original chromatography/mass spectrometry technique to study the pharmacokinetics of dipeptide carnosine in C57 Black/6 mice after intra peritoneal administration of the drug at a dose of 1 g/kg. The basic pharmacokinetic characteristics of carnosine were measured the in the blood and brain. The obtained concentration-time curve has a biexponential character. It is shown that the maximum concentration of carnosine in the blood plasma is Cmax = 1081.75 +/- 124.24 MUg/mL and it is achieved in a time interval of Tmax = 0.25 h. We showed that i.p. administration of exogenous carnosine could significantly increase the concentration of that substance in the brain. Tissue availability of dipeptide carnosine for brain tissue is relatively good and constitutes 59% from the total amount of blood carnosine. It was found that the maximum concentration of carnosine in the brain occurs at the sixth hour after i.p. administration when the concentration of drug in the blood is minimal. PMID- 26036011 TI - [Role of renin-angiotensin system in cardiovascular effects of melatonin]. AB - Pineal hormone melatonin shows therapeutic properties against various kinds of cardiovascular disturbances. The reviewed data show that an important role in the protective effects of melatonin is played by limitation of the renin-angiotensin system activity. PMID- 26036010 TI - [Kinetics of methyluracil release from bioresorbable polymeric carriers]. AB - Bioresorbable poly(lactic-co-glycolic) matrix-carriers containing 20 wt. % of 6 methyluracil (MU) have been prepared by supercritical fluid monolithization without organic solvents. Raman spectroscopy was used to analyze both the spatial distribution MU over polymer matrices and the MU release kinetics from the carrier into phosphate buffer solution. It was found that, during the first 24 h, the amount of released MU did not exceed 15-20% of its encapsulated content. After that, the MU release kinetics passed to almost linear regime with simultaneous retarding of the process. On the 40th day of observation, the MU content in solution reached up to 80% of its initial content in the carriers. Thus, using 6-methyluracil as a model, it was shown that the proposed bioresorbable and bioactive composites can be used as matrix-carriers for targeted and long-term drug release. PMID- 26036012 TI - [G. M. Pichkhadze (on his 70th birthday)]. PMID- 26036013 TI - [On Kazakhstan Republic Committee on Consumers Rights Protection in industrial hygiene and occupational diseases]. AB - The article covers major principles of activities performed by Kazakhstan Republic Committee on Consumers Rights Protection, its objectives, functions to achieve sanitary and epidemiologic well-being of the population. PMID- 26036014 TI - [State of lipid peroxidation in workers engaged into chrysotile-asbestos production]. AB - To study influence of chrysotile-asbestos dust on health of asbestos production workers, the authors conducted biochemical study of serum lipids peroxidation in workers of mining transport enterprise and ore-dressing complex, in accordance with length of service. According to comparative analysis of the resuts obtained, the workers of mining transport enterprise and ore-dressing complex demonstrate more active lipid peroxidation with longer length of service, more pronounced in ore-dressing complex workers. PMID- 26036015 TI - [Possiblity to forecast lung pathology via parameters of allowable length of exposure to chrysotile]. AB - Studies of allowable (safe) length of service in occuptions of mining transport enterprise "Kostanaiskie mineral" JSC were conducted to forecast occurrence of dust lung diseases in workers exposed to chrysotile-asbestos dust. To calculate allowable length of service, the authors used values of average shift concentration of chrysotile-asbestos dust. Based on the calculated data of the allowable length of service in chrysotile-asbestos production, the authors forecasted course of dust lung diseases. PMID- 26036016 TI - [Physical and chemical markers of chronic obstructive lung disease development in industrial workers]. AB - The article demonstrates that patients with chronic obstructive lung disease (COLD) of both mixed and bronchitis forms with medium severity grade appeared to have 2 types of changes in morphologic types of serum faces. Patients with various clinical forms of severe COLD presented unidirectional change in morphologic types of serum faces. Patients with various forms of moderate COLD had one variant of morphologic types of serum faces was close to that in the patients with more severe clinical course--so that face can be considered as a "transitional form" between moderate and severe COLD. These results are interesting in specifying diagnostic criteria of COLD severity and additional diagnostic criteria of the severity grade. PMID- 26036017 TI - [Cytologic study of buccal epithelium in various lengths of service in chrysotile asbestos production]. AB - Buccal epithelium cytograms were analyzed in workers of chrysotile-asbestos production "Kostanaiskiye mineraly" JSC. Findings are that 10-20 years of service are associated with increased number of 4th differentiation grade cells and correspondingly decreased number of 5th differentiation grade cells. Later, with 20 years of service, numbers of 4th and 5th grade epitheliocytes reach initial values. With 10-20 years of service, integral parameters of differentiation index, cornification index and intracellular relations decrease. Findings are that 10-20 years of service are connected with domination of proliferation over differentiation processes. Length of service over 20 years is with adaptive processess in the workers. These data are important in evaluation of mucosal system in variable length of occupational service. PMID- 26036019 TI - [Morbidity in draft military personnel]. AB - Military service activity appeared to influence health state of military personnel. Body strain at initial stages of the service, connected with stress situation, affects general body resistance and manifests in higher general morbidity level with transitory disablement that decreases with adaptation. Based on normalized intensity parameters, the equation enables to ease a procedure of evaluation and forecast of transitory disablement morbidity in draft military personnel. PMID- 26036018 TI - [Cytologic parameters of broncho-alveolar lavage state in experimental animals exposed to mechanical rubber aerosol]. AB - Cytologic studies covered broncho-alveolar lavage in animals exposed to mechanical rubber aerosol in subacute (2 months) and chronic (5 months) experiments. Under exposure to mechanical rubber aerosol the experimental animals developed disorders of lung protective mechanisms. Subacute dust inhalation in the experimental animals caused higher counts of neutrophils and degeneratively changed cells with increased functional activity of alveolar macrophages and neutrophils. Chronic dust inhalation in the experimental animals proved lower functional activity alveolar macrophages and neutrophils. PMID- 26036020 TI - [Evaluating work intensity in major and auxiliary occupations of by-product coke industry]. AB - The article covers evaluation of work strain in major and auxiliary occupations of by-product coke industry. The study results conclude that occupational activity of by-product coke industry workers, under exposure to occupational hazards, affects the workers' performance. Major occupations workers demonstrate higher level of functional strain of CNS, poor concentration of attention and lower ability to switch over, decreased general performance, vs. the auxiliary occupations workers who demonstrated increased cardiovascular and neuro-muscular strain due to occupational activity. PMID- 26036021 TI - [Influence of ecologic factors on respiratory diseases in urban residents of Kazakhstan Republic]. AB - The authors studied influence of ecologic factors on respiratory diseases development in urban residents of Kazakhstan Republic. Multivariate (correlation and regression) analysis demonstrates that chronic obstructive lung disease development is contributed by high concentration of nitrogen oxide in ambient air (r = -0.75; p = 0.005) in Temirtau, Kamenogorsk and Aktau cities, high lead content of sedimented dust (r = 0.64; p = 0.02) in Temirtau, Ust'-Kamenogorsk and Ekibastuz cities. PMID- 26036022 TI - [Influence of industrial pollution with mercury on levels of its accumulation in populated area objects and foods]. AB - The article deals with results of study covering influence of industrial pollution with mercury on its accumulation level in populated area objects and foods. Mercury content was measured in ambient air, snow, water, bed silt and regional foods of vegetable and animal origin--that is a potential health hazard for Central Kazakhstan population. The data obtained prove that high levels of mercury were detected in all the studied objects. PMID- 26036023 TI - [On new screening biomarker to evaluate health state in personnel engaged into chemical weapons extinction]. AB - The work was aimed to find new screeding parameters (biomarkers) for evaluation of health state of workers engaged into enterprises with hazardous work conditions, as exemplified by "Maradykovskyi" object of chemical weapons extinction. Analysis of 27 serum cytokines was conducted in donors and the object personnel with various work conditions. Findings are statistically significant increase of serum eotaxin in the personnel of "dirty" zone, who are regularly exposed to toxic agents in individual filter protective means over the working day. For screening detection of health disorders in the object personnel, the authors suggested new complex biomarker--ratio Eotaxin* IFNgamma/TNFalpha that demonstrates 67.9% sensitivity and 87.5% specificity in differentiating the "dirty" zone personnel and other staffers. PMID- 26036024 TI - [On necessity to modify biochemical methods for detecting organophosphorus componds in chemical weapons extinction objects (review of literature)]. AB - The article covers problems of biochemical methods assessing organophosphorus toxic compounds in objects of chemical weapons extinction. The authors present results of works developing new, more specific and selective biochemical methods. PMID- 26036025 TI - [To the memory of Vladimir Boleslavovich Smulevich (to the 90th birthday)]. PMID- 26036026 TI - [Destruction of oil in the presence of Cu2+ and surfactants of Acinetobacter calcoaceticus IMV B-7241, Rhodococcus erythropolis IMV Ac-5017 and Nocardia vaccinii IMV B-7405]. AB - The effect of copper cations (0.01-1.0 mM) and surface-active agents (surfactants) of Acinetobacter calcoaceticus IMV B-7241, Rhodococcus erythropolis IMV Alc-5017 and Nocardia vaccinii IMV B-7405 in the form of culture liquid on the destruction of oil in water (3.0-6.0 g/L) and soil (20 g/kg), including in the presence of Cd2+ and Pb2+ (0.01-0.5 mM), was investigated. It was shown that the degree of oil degradation in water and soil after 20 days in the presence of low concentrations of Cu2+ (0.01-0.05 mM) and culture liquid of strains IMV B 7241, IMV Ac-5017, and IMV B-7405 was 15 - 25% higher than without copper cations. The activating effect of Cu2+ on the decomposition of complex oil and Cd2+ and Pb2+ pollution was established: after treatment with surfactant of A. calcoacelicus IMV B-7241 and R. erythropolis IMV Ac-5017 destruction of oil in water and soil was 85-95%, and after removal of the copper cations decreased to 45-70%. Intensification of oil destruction in the presence of copper cations may be due to their stimulating effect on the activity of alkane hydroxylases as in surfactant-producing strains, and natural (autochthonous) oxidizing microbiota. PMID- 26036027 TI - [The taxonomic study of the strain Bacillus sp. UCM B-7404--phytopathogenic fungae antagonist]. AB - The polyphasic taxonomic analysis of strain Bacillus sp. UCM B-7404 active against phytopathogenic fungi and producing extracellular phytohormones, lytic enzymes and lipopeptide antifungal compounds has been carried out. The basic cell wall fatty acids presented by branched iso- and anteiso- C15:0 and C17:0 acids, contained 65-77% of the average pool. Phylogenetic assay of 16S rRNA gene nucleotide sequence, phenotypic and chemotaxonomic characteristics proved the attachment of strain Bacillus sp. UCM B-7404 to Bacillus amyloliquefaciens subsp. plantarum. PMID- 26036028 TI - [Physiological and biochemical activity of bacteria during germination of cucumber seeds and impact of ciliates Colpoda steinii on this process]. AB - It is shown that the bacteria Bacillus subtilis B-7023 IMV produce indole-3 acetic acid and amino acids in the liquid medium Knoop. Processing cucumber seed suspension containing 10(7) cfu/ml as bacilli, and Azotobacter vinelandii IMV V 7076, resulted in a decrease in the length of the roots of plants. Reduction of bacterial load bacilli to 10(6) cfu/ml followed by reduction of indole-3-acetic acid in the medium, and to an increase in the length of roots, shoots and total plant mass. During the cultivation of Bacillus subtilis IMV V-7023 with ciliates Colpoda steinii reduced the amount of free forms of auxin in the medium to 5.5 times, and the related--to trace amounts. The content of histidine, phenylalanine, tyrosine, methionine and lysine significantly reduced. PMID- 26036029 TI - [Probiotic features of carotene producing strains Bacillus sp. 1.1 and B. amyloliquefaciens UCM B-5113]. AB - Researched probiotic properties of carotinproducing strains Bacillus sp. 1.1 and B. amyloliquefaciens UCM B-5113. It was established that Bacillus sp. 1.1 characterized by high and middle antagonistic activity against museums and actual test cultures and B. amyloliquefaciens UCM B-5113 shown middle and low activity. They grew up and formed a pigment at pH 6.0 in the presence of 0.4% bile. Bacillus sp. 1.1 and B. amyloliquefaciens UCM B-5113 were avirulent, had low antagonistic activity and characterized by susceptibility to antimicrobial agents, excluding colistin. The results suggested the possibility to create based on Bacillus sp. 1.1 and B. amyloliquefaciens UCM B-5113 probiotic preparation. PMID- 26036030 TI - [Detection of pathogenic bacteria Rhizobium vitis in vineyards of the south of Ukraine]. AB - The total number of microbiota from grape crown gall tissues ranged from (2,3 +/- 0.8) x 10(3) to (7.3 +/- 0.4) x 10(5) CFU/g. The amount of bacteria from Rhizobium genus reached from (1.2 +/-0.2) x 10(2) to (2.1 +/- 0.2) x 10(4) CFU/g depending on a tested plant. It was found out that only a small percentage of the strains (3.1 - 4.9%) were oncogenic. New pathogenic strains (R. vitis ONU388, R. vitis ONU389 and R. vitis ONU390) possessing plasmid genes of pathogenicity virC, ipt and virD2 were isolated. PMID- 26036031 TI - [Featuring pathogenicity factors in biofilm-forming and no-biofilm forming strains of Staphylococcus epidermidis]. AB - A comparative study of the manifestation of pathogenicity factors: hemolytic, lipase, letsytinase activity and ability to adhere in 20 film-forming and 17 non film-forming strains of S. epidermidis. Studying pathogenicity factors of the film-forming strains it was found that complete hemolysis and lipase activity shown was by all the film-forming strains of S. epidermidis, letsytinase activity was observed in 80%. Among the non-film-forming strains complete hemolysis and lipase activity were observed in 89% and letsytinase - 71%. Researched non-film forming and film-forming strains of S. epidermidis showed the ability to adhere to buccal epithelial cells of humans. Found that all the film-forming strains of S. epidermidis were hight level adgesion, the highest IAM was equal to 11,84. It was found that among non-film-forming strains of S. epidermidis were low-, medium and hight level adgesion. IAM of non-film-forming strains of S. epidermidis is 3 times lower compared to the IAM of the film-forming strains of human epithelial cells and was 3.2. PMID- 26036032 TI - [A stereotype for men and women]. PMID- 26036033 TI - ["Positive discrimination" and with great approval]. PMID- 26036034 TI - [A man is good for a team of women]. PMID- 26036035 TI - ["Dialogue for 3 promotes trust]. PMID- 26036036 TI - [Communicating clearly what is important]. PMID- 26036037 TI - [What is the actual job description of nurse anesthetists?]. PMID- 26036038 TI - [Elevating the upper body and aspiration pneumonia]. PMID- 26036039 TI - [Working at the edge between life and death]. PMID- 26036040 TI - [Promoting a good work climate is central]. PMID- 26036041 TI - [Nurse and women advocate]. PMID- 26036042 TI - [I had to do difficult political work]. PMID- 26036043 TI - [Reducing loud breathing noises of dying persons]. PMID- 26036044 TI - [3 women in their mid fifties]. PMID- 26036045 TI - [Long live the men!]. PMID- 26036046 TI - [What is rare is precious]. PMID- 26036047 TI - [A decision aid]. PMID- 26036048 TI - [A review of the situation]. PMID- 26036049 TI - [A counter balance to the "alpha male" stereotype]. PMID- 26036050 TI - [A unique dispensary in Switzerland]. PMID- 26036051 TI - [Living differently after a myocardial infarct]. PMID- 26036052 TI - [Mirror, mirror, tell me...]. PMID- 26036053 TI - [The nurse and the physician]. PMID- 26036054 TI - Frommelt Attitudes Toward Care of the Dying Scale Form B: psychometric testing of the Italian version for students. AB - Nurses' attitudes toward caring for dying patients have an impact on the quality of the care provided. Education can improve knowledge and attitudes toward end-of life care. No validated tool that measures such attitudes is available for Italian nursing students. The aim of this study was to translate the Frommelt Attitudes Toward Care of the Dying Scale (FATCOD) Form B from English into Italian and to establish its validity and reliability within an Italian population of students. A two-stage design was used. Stage I adapted the original version of the tool and tested it for content validity through a multistep process. Stage 2 tested its psychometric properties by analyzing internal consistency, test-retest reliability, and construct validity. The convenience sample consisted of 465 nursing students from all the universities of one Italian region. Measures of stability showed a very good overall (0.87) intraclass correlation coefficient (ICC). The discriminating capacity of the scale was adequate with good values of asymmetry and kurtosis for most of the items. Good internal consistency was found. The six factors derived from the factor analysis are the following: Fear/Malaise, Communication, Relationship, Care of the family, Family as Caring, and Active Care. FATCOD Form B-I is a valid, reliable, and acceptable tool for evaluation of attitudes toward end-of-life care in Italian students. It measures six specific dimensions that should be highlighted during health care student education and training. PMID- 26036055 TI - Support for voluntary and nonvoluntary euthanasia: what roles do conditions of suffering and the identity of the terminally ill play? AB - This study investigated the level of support for voluntary and nonvoluntary euthanasia under three conditions of suffering (pain; debilitated nature of the body; burden on the family) experienced by oneself, a significant other, and a person in general. The sample consisted of 1,897 Thai adults (719 males, 1,178 females) who voluntarily filled in the study's questionnaire. Initial multivariate analysis of variance indicated significant group (oneself, significant other, person in general) differences in level of support for voluntary and nonvoluntary euthanasia and under the three conditions of suffering. Multigroup path analysis conducted on the posited euthanasia model showed that the three conditions of suffering exerted differential direct and indirect influences on the support of voluntary and nonvoluntary euthanasia as a function of the identity of the person for whom euthanasia was being considered. The implications of these findings are discussed. PMID- 26036056 TI - Nurses' Involvement in Patients' Dying and Death: Scale development and validation. AB - This study reports the development of a measurement scale, The Nurses' Involvement in Patients' Dying and Death Scale (NIPDYDS), which fully captures the experiences of nurses caring for patients' dying and death. Potential items were extracted from narrative data gathered systematically and comprehensively from in-depth interviews with nurses engaged in caring for patients' dying and death. Factor analyses revealed four factors, consisting of 40 total items, with two factors related to the positive aspects of the experience (Deep involvement in facing dying and death and Increased competence in facing dying and death) and two factors related to the negative aspects of the experience (Uncertainty and difficulty dealing with dying and death and Accustomed to dying and death). Validity and reliability of the scale were found to be acceptable. The factorial structure of the NIPDYDS was contrasted to Frommelt's (1991) FATCOD (The Frommelt Attitude Toward Care of the Dying Scale), and the usefulness and limitations of the NIPDYDS were discussed. PMID- 26036057 TI - Approaches to death and dying: a cultural comparison of Turkey and the United States. AB - Three principles that guide the bioethics movement in the United States and other Western societies apply to the approaches of death and dying in both the United States and Turkey. These three principles, Autonomy, Beneficence, and justice, are reflected in the practices of people in both countries. The issue of autonomy is of greater concern to those in the United States, while decisions are made entirely with family and physician involvement in Turkey. Beneficence and Justice can be identified as ethical issues in both countries. Similarities with end-of life experiences are linked by faith-based beliefs of Islam and Christianity. Differences in sociocultural influences, such as policies about advance directives in the United States, account for differences in end-of-life decision making. This article examines the spiritual, cultural, legal, and political factors that inform the experience of people in Turkey and in the United States when death is at hand. PMID- 26036058 TI - The multidimensional mortality awareness measure and model: development and validation of a new self-report questionnaire and psychological framework. AB - For each of eight literature-identified conceptual dimensions of mortality awareness, questionnaire items were generated, producing 89 in all. A total of 359 participants responded to these items and to questionnaires measuring health attitudes, risk taking, rebelliousness, and demographic variables. Multivariate correlational analyses investigated the underlying structure of the item pool and the construct validity as well as the reliability of the emergent empirically derived subscales. Five components, rather than eight, were identified. Given the item content of each, the associated mortality awareness subscales were labeled as legacy, fearfulness, acceptance, disempowerment, and disengagement. Each attained an acceptable level of internal reliability. Relationships with other variables supported the construct validity of these empirically derived subscales and more generally of this five-factor model. In conclusion, this new multidimensional measure and model of mortality awareness extends our understanding of this important aspect of human existence and supports a more integrative and optimistic approach to mortality awareness than previously available. PMID- 26036059 TI - Grief and risk of depression in context: the emotional outcomes of bereaved cancer caregivers. AB - We investigated the relationships of grief and depression to cancer caregiving in early bereavement. We began with three expectations: (a) each outcome would reflect different situational predictors, (b) grief would be more directly related to such predictors, and (c) components of grief would relate differently to the caregiving context and depressed mood. We conducted telephone interviews with family caregivers of incurable cancer patients from two hospitals. A total of 199 family caregivers were interviewed at the time of the patient's diagnosis and reinterviewed 3 months after the patient's death. Results showed grief severity was predicted by caregiving circumstances, but bereavement depressed mood was largely unrelated to caregiving. Grief was the main predictor of depressed mood and mediated almost all other effects. We conclude that while grief may trigger depression, the dissimilar connection to context means that the two emotional states should not be equated based purely on similarity of expression. PMID- 26036060 TI - Promoting collaboration between hospice and palliative care providers and adult day services for individuals with intellectual and developmental disabilities. AB - While end-of-life issues are increasingly gaining more attention, people with intellectual and developmental disabilities (IDD) continue to receive significantly less consideration in research, education, and clinical practice compared with the general population. This is a growing concern especially since the sheer number of persons aging with IDD is expected to double in the next 17 years. Furthermore, policies are shifting to reflect a preference for home and community-based services as an alternative to institutionalization, and it becomes evident that adult day services (ADS) may be ideal settings for receipt of end-of-life care, especially among individuals with IDD. However, end-of-life care and advance planning most commonly occur in long-term care settings for the general population and have historically been less of a priority in ADS and residential services for people with IDD. This article discusses the attitudes of, and collaboration between, ADS and end-of-life providers for aging adults including persons with IDD and explores how ADS may be a great pathway for delivering end-of-life care to the IDD population. Implications and recommendations will also be examined. PMID- 26036061 TI - Disenfranchised grief following African American Homicide loss: an inductive case study. AB - Disenfranchised grief is experienced when a mourner's grief response is socially invalidated, unacknowledged, or discouraged. When the circumstances of death or the emotional reactions of the griever violate social norms, empathic failures can occur within the bereaved individual's support systems. This study used conventional content analysis, an intensive and inductive qualitative research method, to analyze the experience of one African American woman who lost her only son to homicide, a particularly distressing and marginalized form of loss. Results elucidate both the empathic failings and resiliencies within the social systems of this griever and emerged from the perspectives offered by the bereaved mother and her primary supporter. Clinical implications and suggestions for future research are discussed. PMID- 26036062 TI - Cannibalism. AB - A dataset of 73 variables was complied on 345 serial killers, 31 of whom who engaged in cannibalism. A distinction was made between those who engaged only in cannibalism, those who engaged in necrophilia, and those who engaged in both or neither. Those who engaged in both cannibalism and necrophilia were the most psychiatrically disturbed and deviant, but those who engaged in only cannibalism were more disturbed and deviant in their actions than those who engaged in neither behavior. PMID- 26036063 TI - Children's cancer camps: a way to understand grief differently. AB - A philosophical hermeneutic study was conducted as part of the first author's doctoral research to understand the meaning of children's cancer camps for the child with cancer and the family. Twenty family members from six families were interviewed in order to bring understanding to this topic. This article will detail the finding related to the experience of grief that often accompanies a cancer diagnosis, and how camp seems to allow children and families to understand their grief differently. The interesting thing about this particular cancer camp is that families of children who have died continue to attend the camp yearly, and there are events to memorialize the many children known to all the campers who no longer attend camp. This is not a grief camp but a cancer camp where grief is allowed presence as it necessarily has to in the world of childhood cancer. PMID- 26036064 TI - [On the classification of the failure to render medical assistance to the patient]. AB - The authors propose the classification of the failure to render medical assistance to the patient. At present, much attention is given to the analysis of drawbacks in the provision of medical care to the victims of various human activities. A variety of classifications of these disadvantageous practices have been proposed. However, they either only casually deal the problem of failure to render medical assistance to the patient or totally disregard it. The necessity to develop the new classification of the failure to render medical assistance to the patient arises from the formulation of article 124 of the Criminal Code of the Russian Federation that requires to evaluate the severity of harm to the health of the patient resulting from the inaction of the person(s) obliged to provide the necessary medical aid. PMID- 26036065 TI - [The specific features of the damage to the non-biological and biological simulators of the human body inflicted by the shots from a 9.0 mm pneumatic rifle]. AB - The objective of the present work was to study the specific constructional features of a 9.0 mm pneumatic rifle designed to use three types of bullets differing in the head shape. Also, the morphological signs of the injuries inflicted by such bullets that can serve as the prerequisites for objective differentiation of the damages are considered. The study revealed peculiarities of experimental damage to the non-biological (plasticine blocks) and biological (bio-mannequins) simulators of homogeneous human tissues inflicted by the shots from the pneumatic rifle from different distances. PMID- 26036066 TI - [The forensic medical characteristics of the entrance bullet holes created by the shots from pneumatic rifles]. AB - The objective of the present study was to compare the injurious action of three types of the bullets for the pneumatic weapons shot from different distances using the Gamo pump air pistol and the BAM B22-1 pneumatic rifle. The following four kinds of the bullets were tested: "the fireball", "Luman cap 0.3", "Luman Field Target 0.68" and "DIABOLO". It was experimentally shown that the injurious action of the bullets fired from the same distance from the pneumatic weapons depends on the type of both the bullet and the weapon, as well as the properties of the target material. Specifically, the action of bullets fired from the piston pneumatic rifle remained stable whereas that of the bullets shot from the gas balloon air pistol decreased as the gas was exhausted. The studies by the contact diffusion method have demonstrated that the entrance bullet holes created by the shots from pneumatic weapons are surrounded by dispersed metal particles which makes it possible to estimate the shooting distance. Moreover, the bullets fired from the pneumatic weapons leave the muzzle face imprint on certain target materials. PMID- 26036067 TI - [The use of the sequential mathematical analysis for the determination of the driver's seat position inside the car passenger compartment from the injuries to the extremities in the case of a traffic accident]. AB - The objective of the present study was to determine the diagnostic coefficients (DC) for the injuries to the upper and lower extremities of the vehicle drivers inflicted inside the passenger compartment in the case of a traffic accident. We have analysed the archival expert documents collected from 45 regional bureaus of forensic medical expertise during the period from 1995 to 2014 that contained the results of examination of 200 corpses and 300 survivors who had suffered injuries in the traffic accidents. The statistical and mathematical treatment of these materials with the use of sequential mathematical analysis based on the Bayes and Wald formulas yielded diagnostic coefficients that make it possible to elucidate the most informative features characterizing the driver of a vehicle. In case of a lethal outcome, the most significant injuries include bleeding from the posterior left elbow region (DC +7.6), skin scratches on the palm surface of the right wrist (DC +7.6), bleeding from the postrerior region of the left lower leg (DC +7.6), wounds on the dorsal surface of the left wrist (DC +6.3), bruises at the anterior surface of the left knee (DC +6.3), etc. The most informative features in the survivals of the traffic accidents are bone fractures (DC +7.0), tension of ligaments and dislocation of the right talocrural joint (DC +6.5), fractures of the left kneecap and left tibial epiphysis (DC +5.4), hemorrhage and bruises in the anterior right knee region (DC + 5.4 each), skin scratches in the right posterior carpal region (DC +5.1). It is concluded that the use of the diagnostic coefficients makes it possible to draw the attention of the experts to the above features and to objectively determine the driver's seat position inside the car passenger compartment in the case of a traffic accident. Moreover such an approach contributes to the improvement of the quality of expert conclusions and the results of forensic medical expertise of the circumstance of traffic accidents. PMID- 26036068 TI - [The forensic medical characteristics and assessment of the neck injuries resulting from intubation]. AB - The objective of the present study was to detect injuries to the sublungual bone, larynx, and trachea resulting from intubation in the patients including those with the blunt neck trauma and to determine their character and localization. Another objective was the forensic medical evaluation of these injuries from the standpoint of harm to human health. A total of 80 cases of death from neck injuries were available for the analysis. These subjects underwent tracheal intubation prior to death that was performed either by an ambulance crew or in a hospital setting. Forty of these patients had the blunt neck trauma inflicted in the preceding period. It was shown that tracheal intubation leads in 60% of the patients to isolated or combined fractures of the sublingual bone, laryngeal and tracheal cartilages in the form of the injuries to the greater horns of the hyoid bone and the inferior horns of the thyroid cartilage, fissures in the arch of the cricoid cartilage, sometimes cracks and complete fractures of the tracheal cartilages, and breaks of the connections between the hyoid bone body and its greater horns. The scope of the injuries in the neck region is larger and their severity higher when intubation is performed in the patients with the blunt neck trauma compared with the subjects undergoing intubation in the absence of previous external injurious impacts. It is concluded that forensic medical expertise and examination of the corpses of the subjects who had undergone tracheal intubation prior to death coming should include the removal of the entire complex of the neck organs together with the unopened larynx and the cervical portion of the trachea. Differential diagnostics of the injuries inflicted by tracheal intubation following the blunt neck trauma should be performed only by means of the comprehensive assessment of the external defects and the fractures of the constituents of the hyoid-laryngeal-tracheal complex using the graphical and vector methods of analysis. PMID- 26036069 TI - [The peculiarities of coding and the determination of the primary cause of death from the diseases induced by the human immunodeficiency virus in accordance with ICD-10]. AB - The objective of the present study was to formulate the principles of coding and identification of the primary cause of death from the diseases induced by the human immunodeficiency virus in accordance with the 10th edition of the international classification of diseases (ICD-10) taking into consideration the official amendments introduced by WHO. The rules of formulation of medical death certificates and peculiarities of formulation of forensic medical diagnoses in the cases of death from the diseases induced by the human immunodeficiency virus are considered. The authors emphasize the importance to observe these rules in order to ensure obtaining the statistically significant information about the mortality caused by H IV infection. PMID- 26036070 TI - [The immunohistochemical study of the structures of the cardiac conduction system in the case of death from alcoholic cardiomyopathy]. AB - The objective of the present study was to study the morphological criteria for toxic cardiopathy with the use of histological and immunohistochemical methods. The results of immunohistochemical studies of the sinoatrial node---???---(SAN) and the working myocardium in the patients presenting with alcoholic cardiomyopathy (ACMP) are presented. It was shown that vimentin expression in the SAN structures and the contractile myocardium is slightly increased whereas the expression of sarcomeric actin is decreased and that of fibrinogen is increased too. The authors put forward an assumption about the role of lesions in the membrane apparatus of the pacemaker cells in the development of arrhythmia characteristic of tanatogenesis associated with alcoholic cardiomyopathy. PMID- 26036071 TI - [The specific morphological and biochemical features of inhalation poisoning with ammonia]. AB - This experimental study using the laboratory animals (rats and rabbits) has demonstrated the morphological and biochemical changes associated with inhalation poisoning with ammonia. Certain regular features of this form of intoxication were revealed. Specifically, the determination of the major biochemical characteristics of blood makes it possible to evaluate the performance of the hepatobiliary and cardiovascular systems. The results of blood pH measurement give evidence of its alkalinization. PMID- 26036072 TI - [The morphological features of a 20 mcl blood stain]. AB - The objective of this work was to study blood stains of small volume (20 mcl). It was shown that the fall of a blood droplet from the height of 5 to 200 cm at the angle of 90 degrees on a smooth non-absorbing surface (glass) leaves round stains. Their size increases with increasing height of the fall. The character of the stain edges also depends on the height of the fall. The edges are even when the drops fall from the height of less than 20 cm but become wave-shaped with blunt projections when the height of the fall is increased to 30-90 cm. The fall from the height of 100 to 200 cm gives rise to the stains with the scalloped edges having the rectangular or nearly rectangular protrusions. From one to three additional Plateau drops can be observed near the main one. PMID- 26036073 TI - [The chemico-toxicological determination of dilthiasem]. AB - The objective of the present study was to determine the optimal conditions for isolation of dilthiasem, its purification by the combination of the extraction and column chromatography techniques, and the development of the universal method for the detection of this compound in the biological material. Other research methods included thin layer chromatography (TLC), gas chromatography mass spectrometry (GH-MS), extraction, low-pressure column chromatography, and spectrophotometry. The effectiveness of dilthiasem isolation from the biological material with the use of 12 organic substances, water, and aqueous solutions was compared. The use of acetone as the universal solvent for dilthiasem isolation from the tissues and biological fluids of the cadaveric organs was substantiated. It was shown that dilthiasem can be purified from endogenous substances contained in the biological materials by means of combined liquid-liquid extraction and chromatography on the 30 mcm Silasorb C-18 column. The new modifications of thin layer chromatography and gas chromatography mass-spectrometry (GH-MS) are proposed for the identification and quantitative determination of dilthiasem isolated from cadaveric blood and hepatic tissue. PMID- 26036074 TI - [The possibilities for expert examination during of situational forensic medical expertises including the trasological investigation of the blood stains]. AB - The objective of the present study was to demonstrate the possibilities of trasological investigations of the blood stains for the purpose of situational forensic medical expertises. The potential of such investigations is exemplified by the case of the head wound inflicted by the shot from the Osa civil self defense handgun. The possibilities of comprehensive assessment of the injuries to the human body, analysis of blood stains on the clothes and the surrounding objects at the place of the accident for the detailed reconstruction of the event are illustrated. PMID- 26036075 TI - [Postmortem forensic medical diagnostics of fulminant sepsis caused by Gram negative bacterium (Capnocitophaga canimorsus) following a dog bite]. AB - This article provides the example of postmortem forensic medical diagnostics of fulminant sepsis caused by Gram-negative bacterium (Capnocitophaga canimorsus) following a dog bite. In order to identify the etiological factor of fulminant sepsis, the expert carried out the study of the autopsy materials with the use of polymerase chain reaction (PCR). This method has only recently been introduced into postmortem diagnostics of fulminant sepsis in this country; it has no analogs abroad and can be employed for the purpose of forensic medical expertise and pathological anatomic studies. PMID- 26036077 TI - [The Kazan department of forensic medicine: the history, development, and achievements]. PMID- 26036076 TI - [The characteristics of the notions used in forensic medicine and their logical basis]. AB - The authors briefly characterize the formerly poorly defined notions used by forensic medical experts for the completion of the conclusions based on the results of primary forensic medical examinations of the corpses. The main errors made in the use of these notions encountered in the materials of primary forensic medical expertises of the corpses, the recommendations to avoid these mistakes are proposed. The present paper continues the series of specialized articles dealing with the main types of logical fallacies encountered in the expert conclusions with a view to further publication of the results of the in-depth analysis of logical mistakes in these documents. PMID- 26036078 TI - [On the occasion of the 150th anniversary of the foundation of the Journal "Arkhiv sudebnoy meditsiny i obshestvennoy gigieny (The Archive of Forensic Medicine and Public Hygiene)"]. PMID- 26036079 TI - [The report about the scientific and practical conference "The topical problems of forensic medical expertise of the explosion injury". St. Petersburg, 9-10 October 2014]. PMID- 26036080 TI - [The application of invasive and non-invasive reflexotherapeutic methods for the improvement of tolerance to the influence of seasonal meteorological factors and correction of bronchial asthma]. AB - The present study included 94 patients presenting with bronchial asthma (BA) who underwent the controlled treatment during one year. The treatment consisted of basal anti-asthmatic therapy in combination with acupuncture reflexotherapy or a complex of non-invasive reflexotherapeutic methods (CNIRTM) designed to increase the effectiveness of correction of asthma, to improve the clinical status of the patients, to decrease by more than two-fold the frequency of unstable episodes of the disease showing the well-apparent seasonal dependence, and to diminish the consumption of pharmaceuticals (reduction of the mean daily dose of prednisolone by 31% and 37% in comparison with its 79% increase in the patients receiving the standard treatment). Moreover, it was shown that the achievement of clinical and preventive effect of the application of non-pharmacological methods may be associated with the activation of the mechanisms of adaptation to the stress factors (such as correction of the cortisol blood level and parameters of the immune status, etc.) and the increase of the patient's tolerance to their influence. PMID- 26036081 TI - [The influence of low-intensity laser irradiation of blood on the lactoferrin level in the patients presenting with community-acquired pneumonia]. AB - The objective of the present study was to estimate the influence of low-intensity laser irradiation of blood on the levels of lactoferrin in the patients presenting with community-acquired pneumonia. MATERIALS AND METHODS: All the patients were divided into two groups. Those comprising the control group received only medicamental therapy. The standard treatment of the patients in the second group was supplemented by intravenous laser irradiation of blood (IVLIB 405 technique). Each irradiation session performed in a continuous mode lasted 5 7 minutes, with the total treatment course consisting of 7 daily procedures. Lactoferrin was determined before and after the treatment by the enzyme immunoassay with the use of "Lactoferrin Strip" kits ("Vektor-Best- Yug" JSC, Russia). RESULTS: Analysis of the results of the study revealed a significant decrease in the blood lactoferrin level down to the normal range in the patients treated with the use of laser therapy. CONCLUSION: The application of intravenous laser irradiation of blood for the combined treatment of the patients with community-acquired pneumonia was accompanied by normalization of the blood lactoferrin level and the improvement of the clinical course of the disease. PMID- 26036082 TI - [The effectiveness of the application of dynamic electrical neurostimulation for the treatment of dorsalgias of the lumbar-sacral localization]. AB - Dynamic electrical neurostimulation (DENS) is a variant of transcutaneous electrical neurostimulation based on the use of biological feedback monitoring the surface impedance of the skin. The present study was designed to estimate the effectiveness of the application of dynamic electrical neurostimulation for the treatment of dorsalgias of the lumbar-sacral localization in comparison with the standard combined treatment including pharmacotherapy, massage, and therapeutic physical culture exercises. The data obtained indicate that the inclusion of DENS in the standard treatment protocol promotes the regression of pain and neurological symptoms; moreover, it accelerates the achievement of clinical remission. PMID- 26036083 TI - [The interference-electropuncture for the disordered vegetative maintenance of the vertebral-motor segments in the patients presenting with dorsopathies]. AB - Vegetative neuropathy of the vertebral component of the spinal nerve was identified based on the results of dynamic segmental diagnosis in the course of medical rehabilitation of 390 patients presenting with dorsopathies. 153 patients experienced segmental autonomous imbalance at the level of the vertebral-motor segments (VMS) of the spinal column. This neuropathy was characterized by the increased sympathetic influence on the tissues of VMS in 85 patients and the impaired sympathetic regulation of the VMS tissue in the remaining 68 patients. Interference-electropuncture (IFEP) as the method for the influence on the biologically active points by interference currents was included in the complex of rehabilitative measures in a group of 51 patients. IFEP parameters were selected on an individual basis taking into consideration the segmental mechanisms of vegetative regulation. The results of medical rehabilitation of these patients were substantially better and significantly different from the results of the treatment of other patients managed with the use of standard medicamental therapy and physiotherapy. At the same time, the patients with dorsopathies receiving IFEP reported a more pronounced alleviation of pain, regression of muscle-tonic manifestations, and improvement of the indicators of the quality of life associated with the improvement of vertebroneurological symptoms. PMID- 26036084 TI - [Diagnostics and rational therapy of mild neuro-orthopedic pathology in the children and adolescents]. AB - The objective of the present work was to study characteristics of mild neuro orthopedic pathology in the children and adolescents with special reference to its etiological, pathophysiological and clinical features and to develop the program for the differentiated treatment of this condition. MATERIAL AND METHODS: We have examined 100 children at the age from 3 to 15 years presenting with minor asymmetry of the lower extremity length, primary (idiopathic) pelvic obliquity, and pathology of the locomotor system of the known etiology (secondary). We have conducted topographical and electromyographic studies. In addition, the autonomic dysfunction has been evaluated. RESULTS: Mild neuro-orthopedic pathology develops in the process of the child's growth and development in association with the neuromuscular and autonomic disorders. The targeted conservative treatment in combination with the adequate clinical supervision may prevent the further progression of pathology in question. PMID- 26036085 TI - [The application of normobaric hypoxytherapy for the subclinical hypothyroidism]. AB - At present, there is no uniform approach to the treatment of subclinical hypothyroidism (SH). The objective of the present study was to estimate the influence of normobaric hypoxytherapy on the thyroid status and immunological characteristics of the patients presenting with subclinical hypothyroidism. MATERIAL AND METHODS: The study involved 140 patients at the age varying from 18 to 60 years suffering from SH associated with autoimmune thyroiditis: 75 of them underwent a course of hypoxytherapy, the remaining 65 patients comprised the control group. RESULTS: The changes in the immune status of the patients with SH were apparent as the depression of cellular immunity and activation of humoral immunity which confirmed the autoimmune nature of the disease. Hypoxytherapy caused positive changes in the immune status of the patients in the form of increased number of CD3+ and CD(8+)-cells, reduction of the number of CD(4+) cells, and the normalization of the immunoregulatory index. The evaluation of the parameters of humoral immunity has demonstrated normalization of the total B lymphocyte content along with the level of serum IgA, IgM, IgG, reduction of circulating immune complexes and anti-thyroid antibodies. These changes promoted the recovery of the thyroid function that manifested itself as the normalization of the blood thyroid-stimulating hormone level. CONCLUSION: It is concluded that hypoxytherapy can be recommended as monotherapy for the treatment of subclinical hypothyroidism as a tool for the influence on the key components of pathogenesis of this disease and prevention of the manifestation of its clinically expressed form. PMID- 26036086 TI - [The estimation of the effectiveness of the anesthetic techniques applied for the combined treatment of the patients presenting with chronic generalized periodontitis]. AB - The treatment of patients presenting with periodontitis is one of the most difficult tasks facing modern dentistry. Most periodontal manipulations are associated with pain sensation; therefore, pain relief is one of the most topical problems in dentistry. The objective of the present study was to enhance both the safety and the effectiveness of anesthetization procedures applied for the treat ment of patients suffering from moderately severe chronic generalized periodontitis. MATERIAL AND METHODS: The effectiveness of local anesthesia was estimated using the methods of functional diagnostics, such as the assessment of the threshold pain sensitivity and bioimpedance spectrometry of the periodontal tissues. RESULTS: The data on dynamics of the threshold pain sensitivity were used to estimate the effectiveness of local anesthesia during periodontal interventions. CONCLUSION: The results obtained by means of bio-impedance spectrometry made it possible to estimate the influence of anesthesia on extracellular hydration of thee periodontal tissues. PMID- 26036087 TI - [The neurophysiological basis of the effectiveness of transcranial methods for the treatment of neuropathic pain]. AB - The present article reports the data concerning the prevalence of chronic pain syndromes in clinical practice. The importance of addressing the problem of finding effective treatment modalities for the patients presenting with these conditions is emphasized. The mechanisms of neuropathic pain are analyzed. The possible pathogenetically sound substantiations for the pharmacological and non pharmacological treatment of chronic pain are discussed. The article highlights the results of recent meta-analyses of the comparative effectiveness of transcranial methods. The mail lines of further investigations in the field of monotherapy and combined treatment of neuropathic pain are outlined. PMID- 26036088 TI - [The application of stem together with visible and infrared light in regenerative medicine (Part 2)]. AB - The objective of the present study was to review the experimental studies concerned with in vitro and in vivo visible and infrared light irradiation of human and animal stem cells (SC) to assess the possibilities of using its photobiomodulatory effects for the purpose of regenerative medicine (RM). Despite the long history of photochromotherapy there is thus far no reliable theoretical basis for the choice of such irradiation parameters as power density, radiation dose and exposure time. Nor is there a generally accepted opinion on the light application for the purpose of regenerative medicine. Therefore, the clinical application of light irradiation remains a matter of controversy, in the first place due to the difficulty of the rational choice of irradiation parameters. In laboratory research, the theoretical basis for the choice of irradiation parameters remains a stumbling block too. RESULTS: A relationship between the increased radiation power density and the cell differentiation rate was documented. SC exposure to light in the absence of the factors causing their differentiation failed to induce it. On the contrary, it increased the features characteristic of undifferentiated cells. The maximum differentiation rate of the same cells was achieved by using irradiation parameters different from those needed to achieve the maxi- mum proliferation rate. The increase of SC differentiation rate upon a rise in radiation power density was induced by increasing ir- radiation energy density. CONCLUSION: The increase of power density and the reduction of either energy density or exposure time were needed to enhance the SC responsiveness to irradiation in the form of either proliferation or differentiation. The effectiveness of phototherapy at all stages of SC treatment was documented especially when it was applied to stimulate the reservoirs of bone marrow lying far from the site of the pathogenic process together with simultaneous light irradiation of the affected site and pre treatment of stem cells prior to their administration. Based on the results of this analysis we have proposed "a plot showing the dependence of cell response on the generalized photostimulus" and coined two new terms "photostress" and "photoshock". PMID- 26036089 TI - [The application of cardiorespiratory training in the framework of the comprehensive programs for the medical rehabilitation of the patients presenting with chronic obstructive pulmonary disease]. AB - This article is concerned with the modern concepts of chronic obstructive pulmonary disease. Also, it presents the international definition of "pulmonary rehabilitation". Especially much attention is given to the physical rehabilitation as one of the main and fundamental components of medical rehabilitation of the patients presenting with chronic obstructive pulmonary disease. The up-to-date approaches to the application of fitness gymnastics for the purpose of scientific research and clinical practice are considered with special reference to the combination of cyclic, static, and dynamic loads with the use of relevant modern equipment. The data on the effectiveness and safety of these rehabilitative technologies are discussed in the context of their application for further research in the field of rehabilitative medicine. Recommendations are proposed on the implementation of these methods in the current practical work. PMID- 26036090 TI - [From the Russian Balneological Society to innovative technologies of spa and health resort-based treatment. The 95th anniversary of the Pyatigorsk State Research Institute of Balneology]. AB - This article is dedicated to the 95th anniversary of the Federal state budgetary institution "Pyatigorsk State Research Institute of Balneology", Russian Federal Medico-Biological Agency. The main stages of the development of the institution are described with special reference to its scientific achievements and the principal lines of current activities. PMID- 26036091 TI - Healthcare system financing and profits: all that glitters is not gold. AB - The objective of this paper is an analysis of two main attributes of healthcare systems. First of the main attributes is the trend of ever growing expenditures of healthcare systems all across the world. Second attribute is the efficiency of chosen mixed healthcare systems, where mixed system is one which features involvement of both private and public sector. Countries chosen for analysis are USA as the country with high private sector influence on healthcare, France with its mediocre influence and Japan, where the private companies participate in health care but are very strictly regulated by a zero profit rule, and the Czech Republic, where public sector dominates the health care. The result is that the systems with higher influence of the private sector tend to have lesser occupancy, not significantly better performance and higher expenditures. This raise doubts whether the private sector brings anything of value for the patients within the healthcare system. However, more detailed analysis should be carried out to confirm or refuse this hypothesis. PMID- 26036092 TI - Educational inequalities in self-rated health: whether post-socialist Estonia and Russia are performing better than 'Scandinavian' Finland. AB - AIM: The aim of the study is to analyse relationship between self-rated health (SRH) and education in post-socialist countries (Estonia and Russia) and in Finland, a Scandinavian country. METHODS: Data from the 5th wave of the European Social Survey (ESS) carried out in 2010 were used. In particular, we used a sub sample of the 25-69 years old. Two-step analysis was carried out: descriptive overview of relationship between SRH and education to assess the knowledge related impact of education on SRH in pooled model for all three countries; and logistic regression analysis to evaluate separate models in each country. RESULTS: The prevalence of at-least-good health was the highest in Finland, Estonia occupied the second position and Russia the third. Knowledge-related educational inequalities were lower in Russia compared to Finland, while they were of similar magnitude in Estonia and Finland. CONCLUSIONS: Our expectations that knowledge-based inequalities are lower in post-socialist countries compared to a Scandinavian country turn to be true in case of Russia, not Estonia. Possible reasons for the expectations might be a lack of attention paid to educational inequalities in terms of access to social resources, competitiveness in the labour market and to what extent education provide a tool against uncertainty (preventing work- and unemployment-related stress). Series of comparative studies revealing links between certain institutional packages and (socio-economic and knowledge-related) educational inequalities seem to be of special relevance. PMID- 26036093 TI - Territorial differences in infant mortality in Latvia in the first decade of the third millennium. AB - OBJECTIVE: Infant and child mortality are some of the most substantial indicators of country welfare. Infant mortality (IM) in Latvia is constantly the highest among 25 Member States of the European Union. Since the regaining of independence in 1991, IM has decreased by almost 50%, however, it is still high enough to cause concern that the country will not be able to meet the UN Millennium Development Goals to decrease IM in Latvia by 2015. The Medical Faculty at the University of Latvia has conducted several studies identifying correlations between IM and GDP, total expenditure on health, unemployment and GINI coefficient. It is necessary to identify all IM causes and relationships which have not been studied, including the effect of social factors causing inequality between inhabitants of urban and rural areas: - The aim of the study was to determine the IM rate and the main death causes and their differences between rural and urban areas in Latvia (2000-2010). MATERIALS: This is a register-based study. The data of 1994 deceased infants was analyzed over the time period from 2000-2010. The studied population was divided into two groups - urban and rural areas by mothers' area of residence. Descriptive and analytical methods were used for analysis - frequency distribution, correlation and regression analysis. RESULTS: IM by maternal residence as well as IM indicators in the most common diagnostic subgroups have been higher in rural areas in the entire studied period (2000-2010). The decrease proportion of IM was more rapid in rural regions with a period average of 6.2% in comparison to urban regions - 2.6%. Annual decrease of IM from perinatal period conditions was 50% lower in rural than urban areas; annual decrease of IM from congenital malformations, deformations and chromosomal abnormalities was 20% lower in urban than rural areas; annual decrease in other diagnostic groups was 40% lower in urban than rural areas. During the study period, differences in infant mortality based on maternal socio- demographic factors, maternal health as well as pregnancy and obstetric history have been found, but the results of statistical analysis cannot be used to define these relationships as statistically significant in either areas. CONCLUSIONS: infant mortality in Latvia due to various conditions prevailing during perinatal period, external causes and sudden infant death syndrome can be substantially decreased - by improving the theoretical and technical capacity of obstetric departments in rural areas as well as educating society on preventable causes of death. PMID- 26036094 TI - Adolescent obesity and associated cardiovascular risk factors of rural and urban life (Eskisehir, Turkey). AB - INTRODUCTION: The purpose of this study is to determine the prevalence of obesity and to compare the associated risk factors between the adolescent children living in rural and urban areas. MATERIALS: This cross-sectional study conducted among 3,918 high school students getting education in the city centre and rural areas of Eskisehir. A specially designed questionnaire form included questions about socio-demographic characteristics as well as cardiovascular risk factors including smoking status, diet habits (breakfasting, consumption of sugar sweetened beverages and fruit and vegetable consumption), physical activity and time spent on computer and/or television. RESULTS: The prevalence of being overweight was 10.4% and 12.2% and the prevalence of obesity was 7.9% and 11.3% in rural and urban areas, respectively. In urban areas, being overweight was accompanied by prehypertension (OR=2.3, 95% Cl 1.6-3.3), hypertension (OR= 2.3, 95% CI 1.6-3.2), and family history of cardiovascular disease (OR =1.3, 95% CI 1 1.7), and obesity was accompanied by prehypertension (OR= 2.3, 95% CI 1.6-3.3), hypertension (OR=3.9, 95% Cl 2.9-5.3), excessive use of computer/TV (OR=1.3, 95% CI 1.1-1.7), having no breakfast (OR=1.3, 95% CI 1.1-1.7), physician-diagnosed diabetes mellitus (OR=4.2, 95% CI 1.3-14.1) and consumption of sugar-sweetened beverages (OR=0.6, 95% CI 0.5-0.8). In rural areas, although the variables accompanying being overweight were parallel with those in urban areas, obesity was only associated with prehypertension (OR=6.1, 95% CI 2.6-14.1), hypertension (OR=22.1, 95% Cl 9.9-49.3) and family history of cardiovascular disease (OR=1.6, 95% CI 1.1-2.6). CONCLUSION: Risk factors may differ in the adolescents from rural and urban areas. It is important in overweight and obese children to assess the family history of cardiovascular disease, blood pressure and blood glucose, to ask about the habit of regularly breakfasting, and to evaluate time spent on computer/TV. As in urban areas, environmental regulations also become important in rural areas. Appropriate social activities for children to spent more time outdoor, e.g. in parks or playgrounds, are important in urban as well as in rural areas. PMID- 26036095 TI - Breastfeeding and time of complementary food introduction as predictors of obesity in children. AB - Although obesity is a multifactorial disorder caused by various behavioural, genetic and environmental influences, early life factors affecting certain critical periods during childhood (prenatal period, adiposity rebound period at 3 5 years and around 5-7 years, as well as puberty) are important in promoting obesity in adulthood. The objective was to determine the association between the birth weight, birth length, breastfeeding and time of introduction of complementary food with obesity among 302 healthy Caucasian children 6-7 years old. Binary logistic regression analysis was used to assess the impact of a number of perinatal and socioeconomic confounding factors on the likelihood for overweight and obesity among children. The level of significance was set at p <0.05. Our findings indicate that duration of breastfeeding for at least 3 months, with introduction of complementary food after the age of 6 months have an important role in preventing obesity. This findings are crucial for planning preventive strategies to prevent further increases in the prevalence of overweight and obesity. PMID- 26036096 TI - Growth of Czech breastfed infants in comparison with the World Health Organization standards. AB - Growth references are important for paediatric health monitoring. It is critical to understand differences in growth interpretation and potential consequences when using available growth references. This study compares the growth of Czech breastfed children with the current WHO growth standards 2006 and the Czech references 1991, 2001. A total of 960 infant/parent pairs in the Czech Republic were recruited through paediatric practices. Anthropometric data were collected during infants' first 12 months of life and parent questionnaires were gathered during a preventive visit at 18 months. Czech breastfed infants were longer with a greater head circumference at all percentiles compared to the WHO standards and were similar to the national references. The percentile weight-for-age and weight for-length values of infants (: 6 months) were lower, and higher (6-12 months) compared to the WHO standards. The infant growth in the sample differed from both the WHO standards as well as the national references. Our findings indicate that the growth of Czech breastfed children differs from the current national references. These discrepancies were smaller compared to the WHO standards. The results of the study were used for new growth assessment guidelines to optimize feeding recommendations for Czech infants. The adoption of the WHO standards in the Czech Republic is not recommended. PMID- 26036097 TI - Immigrant status as important determinant of breastfeeding practice in southern Europe. AB - AIM: Breastfeeding is universally accepted as the optimal way to nourish infants. There is evidence that socio-demographic factors, including immigrant status, are related to infant feeding practices. The aim of the present study was to identify the factors which are associated with breastfeeding initiation and duration, with special focus on the role of immigrant status of the mother in breastfeeding practice. A sample of mothers giving birth and living in Athens, Greece, was investigated. METHODS: 428 mothers (438 infants) were recruited in the maternity ward of a Tertiary University Hospital, and were interviewed using a structured questionnaire. Monthly telephone interviews were subsequently conducted until the sixth postpartum month. Multivariate logistic regression models were used to quantify the association of socio-demographic parameters with breastfeeding initiation. Cox regression analysis was employed to assess related factors that might influence breastfeeding duration. RESULTS: Being an immigrant was positively associated with exclusive as well as partial breastfeeding initiation (OR 7.97, 95% CI 1.02-62.19). Immigrant mothers were also 0.35 times less likely (95% Ci 0.21-0.58) to stop breastfeeding earlier, compared to the native ones. Several other factors were deemed important either for breastfeeding initiation or its duration but not for both aspects of breastfeeding practice. CONCLUSION: Maternal immigrant status was found to be consistently associated with breastfeeding initiation and duration in this study sample. Health professionals, health policy makers and politicians should remain attuned to the cultural backgrounds which have created strong breastfeeding traditions, to further promote breastfeeding practice in Western countries. PMID- 26036098 TI - Self-perceived health in the czech population: recent evidence. AB - This article considers developing trends in self-perceptions of health among the Czech population. Its conclusions are based on data from the European Union Statistics on Income and Living Conditions (EU-SILC) conducted from 2005-2011. The data analysis suggests that the compression of morbidity is present, but the Czech Republic continues to lag behind Western Europe. In addition, among males the difference in health expectancies between the Czech Republic and the EU-15 is due to a change in mortality at higher ages, rather than in self-perceived health. Among females the opposite is true. Demographic categories, such as "attained education" and "age-group" proved to be significant factors in influencing self-perceived health in the Czech population for the year 2011. Gender and marital status seem to be less important. PMID- 26036099 TI - Adolescents' drinking and drunkenness more likely in one-parent families and due to poor communication with mother. AB - OBJECTIVES: Alcohol use is a relatively common behaviour, particularly among adolescents, and has become a major public health concern. This study explores the associations between family composition, the quality of adolescents' communication with parents and adolescents' recent frequent alcohol drinking and lifetime drunkenness. METHODS: Data were obtained from the Slovak part of the 2005-2006 Health Behaviour in School-aged Children (HBSC) study. The sample consisted of 3,882 students (46.3% males; mean age 13.3; +/- 1.6). Data on drinking alcohol in the past week, lifetime drunkenness, communication and family composition were collected via anonymous questionnaires stratified for ages 11, 13 and 15 years and following the methodology of the HBSC study. RESULTS: The results showed that living in an incomplete family increased the risk of frequent drinking and drunkenness among adolescents as well as a low quality of communication between mothers and their children. Risks were higher for drunkenness than for frequent alcohol use and strongly increased by age, with the communication with parents worsening at increasing age. CONCLUSIONS: Our findings show the importance of the quality of communication between parents and adolescents in preventing the hazardous alcohol use among adolescents. Preventive interventions to reduce adolescents' use of alcohol should therefore also target the quality of communication in the family. PMID- 26036100 TI - Prevalence of hypertension and pre-hypertension in 13-17 year old adolescents living in Mthatha - South Africa: a cross-sectional study. AB - BACKGROUND: Hypertension is one of the most common risk factors for cardiovascular diseases (CVDs), yet not much effort is being invested in early diagnosis and control of the condition in susceptible children. The aim of this study was to,investigate the prevalence of pre-hypertension and hypertension in peri-urban school-attending adolescents and explore the relationship between blood pressure and selected anthropometric measurements. METHODS: A cross sectional study of adolescents aged 13-17 years was performed. Data on height, weight, waist and hip circumferences as well as blood pressure were collected from all participants. Body mass index (BMI) and blood pressure percentiles were calculated. Results: The overall prevalence of obesity was 20.4% while the prevalence of hypertension and pre-hypertension was 21.2% and 12.3%, respectively. The prevalence of hypertension and pre-hypertension in males was 22.0% and 13.6% compared to 20.9% and 16.5% in females, respectively. Both conditions were associated with higher BMI in both girls and boys. While mean systolic blood pressure (SBP) was positively associated with higher BMI and waist circumference (WC) in males and females, it correlated negatively with hip circumference (HC) in males. On the other hand, mean diastolic blood pressure (DBP) correlated better with HC in males but only weakly in females. CONCLUSION: Adolescent learners in Mthatha had a high prevalence of hypertension and pre hypertension which were associated with overweight and obesity. Results highlight the urgent need for screening in view of early detection and implementation of intervention strategies to prevent a high incidence of CVDs in this country. PMID- 26036101 TI - Seroprevalence and risk factors of syphilis among HIV/AIDS patients in Istanbul, Turkey. AB - OBJECTIVE: Data on syphilis seroprevalence among human immunodeficiency virus (HIV)/Acquired immunodeficiency syndrome (AIDS) patients are unavailable in Turkey although they have common transmission routes. Our study is oriented towards the assessment of the seroprevalence of syphilis and the related risk factors in the HIV/AIDS patients followed in our outpatient clinic. MATERIALS: Newly diagnosed HIV/AIDS cases (n = 308) who attended our outpatient clinic between January 2006 and April 2013 were included in the study. Patient characteristics, medical history, physical examination findings, CD4+ T lymphocyte count, HIV RNA level, rapid plasma reagent (RPR) and Treponema pallidum hemagglutination (TPHA) test results were analyzed retrospectively. TPHA positivity was considered indicative of syphilis-causing T pallidum exposure. RESULTS: HIV infection was transmitted through heterosexual (n = 176) or homosexual (n =131) contact (266 male, 86.3%; age 38.3 +/- 11.7 years; CD4+ T lymphocyte count, 330.6 +/- 15.17/mm3). 50.7% of the patients attained only primary education. Out of the 245 cases, who were asked about the number of their sexual partners, 40 patients (26 women) lived in a monogamous relationship. Condom usage was not practiced (57.2%) or was only occasional (34.4% - particularly with their legal spouses and for contraception). Physical exam revealed no signs of syphilis or other STIs. TPHA (+/- RPR) positivity was determined in 40 patients (12.9%), indicating T pallidum exposure. All patients with positive syphilis serology were male (p= 0.0026). T pallidum exposure was determined in 21.3% of homosexual and 6.8% of heterosexual cases (p = 0.0003). CONCLUSION: Since sexual contact is the most common route of transmission for both infections, syphilis seroprevalence was relatively high in our HIV/AIDS patients. Male and homosexual HIV/AIDS patients constituted a group at the highest risk for syphilis. PMID- 26036102 TI - Norovirus infection in Belarus: occurrence and molecular epidemiology. AB - The objective of the study is to analyze molecular epidemiologic surveillance for norovirus infection in Belarus over the past five years (2009-2013). Laboratory diagnostics was carried out by RT-PCR in 684 patients. Two regions of norovirus genome, localized in RNA-polymerase and capsid protein genes, were used for phylogenetic analysis. Noroviruses were predominant causative agents in adults and second only to rotaviruses in children, they also prevailed among aetiological agents of outbreaks (66.7% of outbreaks). In 2009-2013, the major norovirus genotype was GII.4 (58.3% of all genotyped isolates). Genovariant GII.4 2006b circulated in 2009 and 2010, genovariant GII.4 2009 New Orleans - in 2010 and 2012. In addition to GII.4, genotypes GII.6 (16.6%), GII.2 (4.1%), GII.3 (2.2%), and recombinant genotypes GII.g-GII.12 and GII.g-GII.1 (10.4% and 8.3%, respectively) circulated in Belarus. The findings indicate a significant contribution of noroviruses in development of sporadic morbidity and outbreaks of acute gastroenteritis in Belarus. Outbreaks or prominent increases of sporadic morbidity were mostly due to the emergence of a new genotype, or an epidemic genovariant. PMID- 26036103 TI - Spatiotemporal analysis of ambient air pollution exposure and respiratory infections cases in Beijing. AB - BACKGROUND: Ambient air pollutants (PM2.5) are components of persistent haze in Beijing during the autumn and winter seasons. MATERIALS: We collected hourly PM2.5 monitoring data for 35 days from 35 sites in Beijing during 2012. We also identified patients developing respiratory infections during the same time period in the same locale. A BME model was used to simulate environmental exposure concentrations over the course of each day. A medical accessibility analysis was performed to exclude the impact of medical availability on the analysis. A spatial analysis was included in the evaluation of the relationship between exposure duration and concentration of PM2.5 with the development of acute respiratory disease. RESULTS: A low concentration of PM2.5 (greater than 35 ug/m3 and less than 115 ug/m3) for at least 3 days was associated with an increased risk of acute respiratory disease. A high concentration of PM2.5 (greater than 115 ug/m3) was associated with an increased risk of infection even after 1 day of exposure. PMID- 26036105 TI - Ebola virus disease: temperature checks for travelers? PMID- 26036104 TI - Prevention of taxi accidents in Xi'an, China: what matters most? AB - OBJECTIVES: Since the city of Xi'an has been extremely concerned with the serious problem of taxi involved crashes, injuries and fatalities, the primary purpose of this study is to identify the risk factors associated with the magnitude and nature of the problem and provide possible measures for enhancing the overall safety performance of taxi industry. METHODS: Using 726 crash samples from the original of 7,183 observations in Xi'an over the period from 2006 to 2012, comparative statistics and systematic analysis were employed to describe the distribution of taxi crashes by driver characteristics, roadway contributors and environmental factors and then determine the significant factors contributing to crash injuries and fatalities. RESULTS: The trend and pattern of taxi involved crashes vary significantly. Middle aged (77.27%) male (91.60%) drivers with limited education (68.59%) and less driving (31.27%) and job (82.50%) experience were much more likely to be involved in such a crash. Additionally, it is found that a large majority of taxi crashes occurred with the most frequent type of rear end collisions (30.72%), on six-lane segments without median (16.94%) or four legged intersections (15.29%), under adverse weather conditions (31.82%), at weekends (34.99%), and during winter days (34.72%), but fatal and serious crashes were more likely to happen at night (30.72%) or under wet road surface conditions (16.94%), due to driver's overspeeding, unbelted, disregarding signs or signals, or other types of risk driving behaviour. CONCLUSIONS: The risk of taxi related crashes varies by drivers, roadways and environment. To reduce the risk of potential crashes for taxi drivers, we recommend the targeted legislation and enforcement, stronger night and trip restrictions, awareness of risk behaviour, and periodical training requirement. Such proposals and measures are expected to help mitigate taxi crashes and promote road safety in China. PMID- 26036106 TI - The impact of the economic crisis on neonatal hearing screening in Greece. PMID- 26036108 TI - Step-by-step approach helps reduce specimen errors in the OR. PMID- 26036107 TI - Infections spur new guidelines for endoscope reprocessing. PMID- 26036109 TI - Research projects potential cost savings with wider use of MIS. PMID- 26036110 TI - Shared governance teaches staff to take ownership of decision making. PMID- 26036111 TI - Google Glass--seeing the benefits for clinicians and patients. PMID- 26036112 TI - Making the most of operational performance dashboards. PMID- 26036113 TI - Master five key concepts to sharpen financial management skills. PMID- 26036114 TI - Help is available for managing pharmaceutical waste safely and legally. PMID- 26036115 TI - Appointment of new assistant editor. PMID- 26036116 TI - Kathleen Mears Memorial Lecture: I can do that--skill building through volunteering. PMID- 26036117 TI - Multimodality intraoperative neurophysiological monitoring during Onyx embolization of cerebrovascular malformations. AB - General anesthesia prohibits neurological examination during embolization of cerebrovascular malformations when provocative testing prior to pedicle occlusion is needed. Intraoperative neurophysiological monitoring (IONM) has the potential to fill this gap but remains relatively unexplored. We conduct a retrospective review of consecutive patients with cerebrovascular malformations treated with Onyx (ethylene vinyl alcohol copolymer, dissolved in dimethyl sulfoxide) embolization under general anesthesia with IONM from 2009 to 2012. Somatosensory evoked potentials (SSEPs), transcranial motor evoked potentials (TcMEPs), visual evoked potential (VEPs), auditory brainstem response (ABR), and electroencephalography (EEG) were used selectively in all patients depending on the location of the malformation. Provocative testing combined with IONM was performed in 28 patients over 75 sessions. Three patients demonstrated changes in TcMEPs or ABR during provocative testing, which halted the planned embolization. Two patients demonstrated changes in baseline SSEPs after embolization, despite normal IONM during provocative testing, correlating with postprocedural contralateral weakness. Six patients developed visual deficits after arterial occlusion despite unchanged VEPs and occipital EEG during provocative testing and embolization. We therefore conclude that the sensitivity of TcMEPs and SSEPs is preferable to EEG, and we strongly caution against relying on occipital recorded VEPs to predict visual deficits. PMID- 26036118 TI - PartnerSHIPS: aligning your department with administration for smooth sailing. AB - Healthy partnerships with hospital administration are essential for any neurodiagnostics program to experience growth and development. The differing backgrounds of business-oriented administrators and clinically oriented technologists can result in challenges with various departmental initiatives and lead to ineffective outcomes when seeking to balance high-quality, patient oriented care with efficient and profitable operations. Over the course of a two year period, The University of Texas Medical Branch at Galveston (UTMB Health) implemented several changes that have led to better patient care outcomes. These changes were possible because of a remarkably effective collaboration between neurodiagnostic technologists and hospital administration. Proven business principles were combined with evidence-based healthcare and clinical-practice guidelines to facilitate the following initiatives: 1. Combining EEG, electromyogram and nerve conduction studies (EMG/ NCV), intraoperative neurophysiological monitoring (IONM), long-term monitoring (LTM), and epilepsy monitoring unit (EMU) into one department. 2. Cross-training of technologists. 3. Policy and procedure development. 4. Strategic planning and relationship building. a. Partnering with local community college neurodiagnostic program. b. Building a per diem nurse (PRN)/float pool for coverage. c. Contracting for IONM services. Implementing these changes has resulted in many improvements within the department, such as an overall increase in procedure volumes, professional development and growth opportunities for staff and the availability of additional services for improved patient care. PMID- 26036119 TI - Motor evoked potentials for femoral nerve protection in transpsoas lateral access surgery of the spine. AB - Detecting potential intraoperative injuries to the femoral nerve should be the main goal of neuromonitoring of lateral lumber interbody fusion (LLIF) procedures. We propose a theory and technique to utilize motor evoked potentials (MEPs) to protect the femoral nerve (a peripheral nerve), which is at risk in LLIF procedures. MEPs have been advocated and widely used for monitoring spinal cord function during surgical correction of spinal deformity and surgery of the cervical and thoracic spine, but have had limited acceptance for use in lumbar procedures. This is due to the theoretical possibility that MEP recordings may not be sensitive in detecting an injury to a single nerve root considering there is overlapping muscle innervation of adjacent root levels. However, in LLIF procedures, the surgeon is more likely to encounter lumbar plexus elements than nerve roots. Within the substance of the psoas muscle, the L2, L3, and L4 nerve roots combine in the lumbar plexus to form the trunk of the femoral nerve. At the point where the nerve roots become the trunk of the femoral nerve, there is no longer any alternative overlapping innervation to the quadriceps muscles. Insult to the fully formed femoral nerve, which completely blocks conduction in motor axons, should theoretically abolish all MEP responses to the quadriceps muscles. On multiple occasions over the past year, our neuro-monitoring groups have observed significantly degraded amplitudes of the femoral motor and/or sensory evoked potentials limited to only the surgical side. Most of these degraded response amplitudes rapidly returned to baseline values with a surgical intervention (i.e., prompt removal of surgical retraction). PMID- 26036120 TI - The use of neurodiagnostic technologies in the 21st century neuroscientific revolution. AB - Neuroscience is fascinating, mysterious, and truly medicine's "final frontier" but deciphering its marvels has historically been inhibited by its sheer complexity. The recent escalation of global neuroscientific endeavors and vast financial backing from governments, foundations, and industries, however are changing this perspective. The sequencing of the human genome, development of innovative tools for mapping neuronal connectivities, and enhanced resolution capabilities of imaging techniques have made landmark contributions toward advancing neurotechnologies. Nations all around the world have initiated and launched brain mapping projects on such a profound and financially immense scale that research in 2015 and beyond are highly anticipated to revolutionize medicine and our interaction with the technological world. Although neurodiagnostic technology is not the vanguard of research interest in the scientific community, it will certainly ride the coattails of these new neuroscientific endeavors. And, in turn, these advancements will greatly impact how we diagnose, treat, and care for our patients in the future. Therefore, the purpose of this article is not only to introduce current neuroscientific enterprises, but to also explore some of the most interesting and instrumental findings using neurodiagnostic technology over the past year. PMID- 26036121 TI - Waveform Window #29. Fact or Artifact? PMID- 26036122 TI - [A day for meeting and sharing]. PMID- 26036123 TI - [Chronic kidney disease, an often underestimated complication of diabetes]. AB - Diabetic kidney chronic kidney disease, an often underestimated complication of diabetes. Diabetic kidney disease is a serious complication which can evolve into severe chronic kidney disease (CKD), or even end-stage renal disease (ESRD). It impacts on the patient's quality of life and that of their family and significantly increases the cost of care. The development and progression of chronic kidney disease is prevented by strictly controlling blood sugar levels and cardiovascular risk factors as well as monitoring the markers of kidney disease. In the case of CKD, treatment may need to be adapted. PMID- 26036124 TI - [The kidney transplant patient's care pathway]. AB - The kidney transplant is the preferred treatment for end-stage chronic kidney disease. The pre-transplant assessment is readjusted when the doctor calls to inform the patient of the availability of an organ. After the operation and the follow-up in the day hospital, the patient must be regularly monitored. They will have to take immunosuppressant drugs for the rest of their lives. PMID- 26036125 TI - [Dialysis treatment for diabetic patients]. AB - Advanced-stage diabetic nephropathy requires multidisciplinary treatment for the patient. He/she must be informed, when necessary, of the possible dialysis methods and the assessment of the transplant options. Haemodialysis and peritoneal dialysis offer comparable survival rates. The enlightened choice of the patient is guided by the nephrology team. Survival on dialysis unfortunately remains uncertain due to numerous comorbidities, in particular cardiovascular conditions. PMID- 26036126 TI - [A blood glucose slide chart for improving diabetes patient education]. AB - A blood glucose slide chart has been developed in order to help patients with type 2 diabetes who do not speak French or who have comprehension difficulties. Combined with pictograms to help patients visualise the action they need to take depending on the recorded glucose level, it constitutes a therapeutic education tool which can be useful on a day-to-day basis both for patients as well as caregivers. PMID- 26036127 TI - [Mg2+, ATP-dependent plasma membrane calcium pump of smooth muscle cells. I. Structural organization and properties]. AB - Tight control of cytoplasm Ca2+ concentration is essential in cell functioning. Changing of Ca2+ concentration is thorough in smooth muscle cells, because it determines relaxation/constraint process. One of key proteins which control Ca2+ concentration in cytoplasm is Mg2+, ATP-dependent plasma membrane calcium pump. Thus, it is important to find compoumds which allowed one to change Mg2+, ATP dependent plasma membrane calcium pump activity, as long as this topic is of current interest in biochemical research which regards energy and pharmacomechanical coupling mechanism of muscle excitation and contraction. In this article we generalized literatute and own data about properties of smooth muscle cell plasma membrane Ca(2+)-pump. Stuctural oganization, kinetical properties and molecular biology are considered. PMID- 26036128 TI - Biochemical markers of bone collagen type I metabolism. AB - This review focuses on the analysis of diagnostic value of the major bone remodeling markers, in particular synthesis and degradation markers of collagen type I. These include carboxy- and aminoterminal telopeptide, carboxy- and aminoterminal propeptide of procollagen type I, hydroxyproline, hydroxylysine, pyridinoline and deoxypyridinoline. Their measurement allows evaluating the structural and functional conditions and also the rate of metabolic processes in the bone tissue. The advantages and disadvantages of determination of these markers in the condition of different bone diseases were examined. It is shown that determination of bone collagen type I metabolism markers is the most informative for assessment of bone resorption, formation and turnover. PMID- 26036129 TI - Modern fluorescent techniques to investigate the mechanisms of lymphocyte activation. AB - Fluorescent proteins are promising toolsfor studying intracellular signaling processes in lymphocytes. This brief review summarizes fluorescence-based imaging techniques developed in recent years and discusses new methodological advances, such as fluorescent photoswitches, fluorescence recovery after photobleaching (FRAP), fluorescent resonance energy transfer (FRET), fluorescence lifetime imaging microscopy (FLIM), photoactivated localization microscopy (PALM), stochastic optical reconstruction microscopy (STORM), stimulated emission depletion (STED), total internal reflection fluorescence (TIRF) and other techiques. This survey also highlights recent advances in vitro imaging of live tissues, novel applications of flow cytometry with genetically modifed fluorescent proteins, and future prospects for the development of new immunological test systems based on fluorescent protein technology. PMID- 26036130 TI - The effect of N-stearoylethanolamine on plasma lipid composition in rats with experimental insulin resistance. AB - A model of insulin resistance (IR), induced by prolonged high fat diet with high content of saturated fats was used to investigate the effect of N stearoylethanolamine (NSE) on the composition of free fatty acids (FFA), plasma lipoprotein spectrum and content of proinflammatory cytokine TNFalpha in rats. The results of this work showed a rise in the content of monounsaturated fatty acids (18:1 n-9) and a reduction in the level of polyunsaturated fatty acids (20:4 n-6) in plasma of rats with experimental IR. These findings are accompanied by the increased TNFalpha production and significant changes in plasma lipoprotein profile of rats with the fat overload. Particularly, a decreased high density lipoprotein (HDL) cholesterol level and increased low-density (LDL) and very low-density lipoprotein (VLDL) cholesterol level were detected. The NSE administration to obese rats with IR restored the content of mono- and polyunsaturated FFA, increased HDL cholesterol content and reduced LDL cholesterol level. In addition, the IR rats treated with NSE showed normalization in the serum TNFalpha level. Our results showed the restoration of plasma lipid profile under NSE administration in rats with obesity-induced IR. Considering the fact that plasma lipid composition displays the lipid metabolism in general, the NSE actions may play a significant role in the prevention of IR-associated complications. PMID- 26036131 TI - Synthesis, biological evaluation and docking of novel bisamidinohydrazones as non peptide inhibitors of furin. AB - A series of novel non-peptidicfurin inhibitors with values of inhibitory constants (Ki) in the range of 0.74-1.54 MUM was obtained by interactions of aminoguanidine hydrocarbonate with three diaryldicarbalde- hydes. Correspondingly p-hydroquinone, piperazine and adipic acid were used as linkers between their ben zene moieties. Docking studies of these new inhibitors into recently published 3D-structure of human furin (PDB code 4OMC) showed that they were able to interact with subsites S1 and S4 of the enzyme. The overall arrangement of bisamidinohydrazones into furin active site was similar to the position of the ligand co- crystallized with a protease. Observations obtained with molecular modeling allowed further guidance into chemical modifications of the synthesized inhibitors which improve their inhibitory activity. PMID- 26036132 TI - Effect of Pd(II) and Ni(II) coordination compounds with 4-amino-3-mercapto-5 methyl-1,2,4-triazole on the mitochondrial dehydrogenases activity. AB - Pd(I) and Ni(II) complex compounds: [Pd(AMMT)2]Cl2 (1), [Pd(AMMT)4]Cl2 (2) and [Ni(AMMT)2(H2O)](NO3)2 (3) with 4-amino-3-mercapto-5-methyl-1,2,4-triazole (AMMT) have been synthesized. The spectral characteristics of 1, 2 were studied by 1H (13C) NMR and UV-Vis spectroscopy. X-ray diffraction studies established that all complexes contain the AMMT molecule, which are coordinated to the central metal ion in the thione tautomeric form. At the ratio M: L = 1:2 ligand is coordinated in bidentate chelate manner by the nitrogen of amino- and sulfur of mercapto group (compounds 1, 3). But the molar ratio M: L = 1:4 leads to monodentate coordination of AMMT molecules only by sulfur of mercaptogroup (complex 2). Vacant coordination sites of the metal ion are occupied by water molecules (complex 3). The screening of complexes 1-3 and starting compounds [AMMT, K2PdCl4 (4), Ni(NO3)2 . 6H2O (5)] by their mitochondrial dehydrogenase activity have been performed by us for the first time, resulting in established that the Pd(II) complexes (1, 2), Pd(II) salt (4) and AMMT normalize the activity of mitochondrial dehydrogenases of cancer HeLa cells, identified by MTT-test. In contrast, the Ni(II) complex (3) and Ni(II) salt (5) do not stimulate the activity of mitochondrial dehydrogenases. It has been found, that all investigated compounds do not affect on the cell cycle and the level of apoptotic cells as well as do not show a toxic effect. Thus, these results indicate that AMMT and Pd(II) complexes may be used as modifiers of mitochondrial respiration, which dysfunction is particularly evident in the tumor cells. PMID- 26036133 TI - Analysis of creatine kinase activity with evaluation of protein expression under the effect of heat and hydrogen peroxide. AB - Protein oxidation has detrimental effects on the brain functioning, which involves inhibition of the crucial enzyme, brain type creatine kinase (CKBB), responsible for the CK/phosphocreatine shuttle system. Here we demonstrate a susceptibility of CKBB to several ordinary stressors. In our study enzymatic activity of purified recombinant brain-type creatine kinase was evaluated. We assayed 30 nMconcentration of CKBB under normal and stress conditions. In the direction of phosphocreatine formation hydrogen peroxide and heat treatments altered CKBB activity down to 26 and 14%, respectively. Also, examination of immunoblotted membrane patterns by SDS-PAGE electrophoresis and western blot analysis showed a decrease in expression levels of intrinsic CKBB enzyme in HeLa andA549 cells. Hence, our results clearly show that cytosolic CKBB is extremely sensitive to oxidative stress and heat induced inactivation. Therefore, due to its susceptibility, this enzyme may be defined as a potential target in brain damage. PMID- 26036134 TI - [The influence of iron ions on ATP-hydrolases activity of cell membranes of rat colon smooth muscle and kidney]. AB - To elucidate the specific features of the ATP-hydrolases structural resistance in the membrane under the action of the prooxidants: Fe2' and hydrogen peroxide, and N-ethylmaleimide (NEM) the colonic smooth muscle (CSM) Na+, K(+)-ATPase activity was compared with activities of the corresponding Mg(2+)-ATP-hydrolase and ATPases from kidney medullar layer of rats. The inhibition study of the CSM Na+, K(+)-ATPase by divalent iron shows the decrease of the activity by 30% at 0.1 MUM FeSO4 and in the range of 0.1-10 MUM--to 45% of residual activity. When comparing with kidney enzyme (rep- resents exclusively alpha1-isozyme) the CSM Na+, K(+) ATPase sensitivity to Fe2+ is reliably higher at its submicromolar concentration. CSM Mg2+-ATPase is much more resistant to iron ions effect, than kidney one. However for two tissues Mg2(+)-ATPase activity is always more resistant as compared with corresponding Na+, K(+)-ATPase activity. Against 1 mM EGTA Na+,K(+) ATPase and Mg2(+)-ATPase activities of GMOK and kidneys are equally insensitive to effect of hydrogen peroxide in concentration up to 1 mM. But in the presence of 20 MUM FeSO4 in the concentration range of 1 nM-1 mM of H2O2 the Na+, K(+) ATPase is inhibited to greater extent, than Mg2+-ATPase activity. NEM sensitivity of the two ATP-hydrolase systems corresponds to prooxidant sensitivity that indicates the distinct importance of SH-groups for their functioning. It is concluded that Na+, K+-ATPase can serve as a marker of membrane sensitivity to oxidation, Mg(2+)-ATPase is resistant to oxidation and can be considered as criterion of the oxidation resistance when comparing membrane enzyme complexes, es- pecially in GMOK. PMID- 26036135 TI - C60 fullerene prevents genotoxic effects of doxorubicin in human lymphocytes in vitro. AB - The self-ordering of C60 fullerene, doxorubicin and their mixture precipitated from aqueous solutions was investigated using atomic-force microscopy. The results suggest the complexation between the two compounds. The genotoxicity of doxorubicin in complex with C60 fullerene (C 60+Dox) was evaluated in vitro with comet assay using human lymphocytes. The obtained results show that the C60 fullerene prevents the toxic effect of Dox in normal cells and, thus, C60+Dox complex might be proposed for biomedical application. PMID- 26036136 TI - [Antioxidant properties of cluster rhenium compounds and their effect on erythropoiesis of rats with guerin carcinoma]. AB - Biochemical characteristics of kidneys, pe- ripheral blood and bone marrow of rats in model of tumor growth under introduction of cisplatin and cis tetrachlorodi-MU-isobutyratodirhenium(III), cis-Re2(i-C3H7COO)2Cl4 (I) have been investigated. It was shown that introduction of I alone and together with cisplatin led to decrease of biochemical markers of oxidation of lipids and proteins in tissue homogenates of the kidneys, change of enzyme activity in the urea and tissue homogenates of the kidneys, by a decrease of filtration function of kidneys. Introduction of nanoliposomal forms of the rhenium cluster compound led to a practically normal morphological picture of bone marrow and increase of the RBC (by 60%) with normalization of hematocrit counts, and decrease of quantities of destructed RBC (3.2 times) in comparison with the tumor-bearing animals. A tentative scheme of influence of cluster rhenium compound on erythropoiesis through regulation of synthesis of erythropoietin in kidneys has been proposed. PMID- 26036137 TI - [Application of the methods of molecular modeling to the search for new biologically active substances]. AB - The searching for new chemical compounds possessing specific biological activity is a complex problem that needs the usage of modern methods of molecular modeling. In particular, for the prupose of searching for potentially active compounds for whole class of SH2 domains, a comparison of all available structures, their cluster analysis, molecu- lar docking, selection of all possible pharmacophore models and GTM prediction were done. Obtained results testify to the considerable variability of binding of SH2 domains. PMID- 26036138 TI - [NADH:ubiquinone reductase and succinate dehydrogenase activity in the liver of rats with acetaminophen-induced toxic hepatitis on the background of alimentary protein deficiency]. AB - The ratio between the redox forms of the nicotinamide coenzymes and key enzymatic activity of the I and II respiratory chain complexes in the liver cells mitochondria of rats with acetaminophen-induced hepatitis under the conditions of alimentary deprivation of protein was studied. It was estimated, that under the conditions of acute acetaminophen-induced hepatitis of rats kept on a low-protein diet during 4 weeks a significant decrease of the NADH:ubiquinone reductase and succinate dehydrogenase activity with simultaneous increase of the ratio between redox forms of the nicotinamide coenzymes (NAD+/NADH) is observed compared to the same indices in the liver cells of animals with experimental hepatitis kept on the ration balanced by all nutrients. Results of research may become basic ones for the biochemical rationale for the approaches directed to the correction and elimination of the consequences of energy exchange in the toxic hepatitis, induced on the background of protein deficiency. PMID- 26036139 TI - [Role of Ca ions in the induction of heat-resistance of wheat coleoptiles by brassinosteroids]. AB - The involvement of Ca2+ into the signal transduction of exogenous brassinosteroids (BS) (24-epi-brassinolide-24-EBL and 24-epicastasterone-24-ECS) causing the increase of heat resistance of the cells of wheat (Triticum aestivum L.) coleoptiles was investigated using calcium chelator EGTA and inhibitor of phosphatidylinositol-specific phospholipase C--neomycin. Twenty-four-hour treatment of coleoptile segments with 10 nM solutions of 24-EBL and 24-ECS led to a transient increase in the generation of superoxide anion radical by cell surface and the subsequent activation of superoxide dismutase and catalase. Pretreatment of coleoptiles with EGTA and neomycin depressed to a considerable extent these effects and leveled the increase in heat resistance of wheat coleoptiles that were caused by BS. Possible mechanisms of involvement of calcium signaling into the formation of reactive oxygen species in plant cells and induction of heat resistance of plant cells by the action of exogenous BS have been discussed. PMID- 26036140 TI - [Laureates of the Palladin Prize of the National Academy of Sciences of Ukraine (2013)]. PMID- 26036142 TI - YAP in MAPK pathway targeted therapy resistance. PMID- 26036141 TI - Psychosocial factors associated with work disability in men and women with diabetes: a pooled analysis of three occupational cohort studies. AB - AIMS: To examine the extent to which adverse psychosocial factors, such as living alone, psychological distress, job strain and low support from supervisor, increase the risk of work disability (sickness absence and disability pension) among employees with diabetes. METHODS: In this pooled analysis of individual participant data from three occupational cohort studies (the Finnish Public Sector Study, the British Whitehall II study, and the French GAZEL study), 1088 women and 949 men with diabetes were followed up to determine the duration (number of days) and frequency (number of spells) of work disability. The mean follow-up periods were 3.2 years in the GAZEL study, 4.6 years in the Whitehall II study and 4.7 years in the Finnish Public Sector Study. Psychosocial factors and potential confounding factors were assessed at baseline using standard questionnaires. Study-specific estimates were pooled using fixed-effects meta analysis. RESULTS: In analysis adjusted for sociodemographic factors, health behaviours and comorbidities, participants with psychological distress had longer (rate ratio 1.66; 95% CI 1.31-2.09) and more frequent absences (rate ratio 1.33; 95% CI 1.19-1.49) compared with those with no psychological distress. Job strain was associated with slightly increased absence frequency (rate ratio 1.19 95% CI 1.05-1.35), but not with absence duration. Living alone and low supervisor support were not associated with absence duration or frequency. We observed no sex differences in these associations. CONCLUSIONS: Psychological distress was associated with increased duration and frequency of work disability among employees with diabetes. Job strain was associated with increased absence frequency but not with absence duration. PMID- 26036143 TI - Effects of Block Length and Membrane Processing Conditions on the Morphology and Properties of Perfluorosulfonated Poly(arylene ether sulfone) Multiblock Copolymer Membranes for PEMFC. AB - Perfluorosulfonated poly(arylene ether sulfone) multiblock copolymers have been shown to be promising as proton exchange membranes. The commonly used approach for preparation of the membrane is solvent casting; the properties of the resulting membranes are very dependent on the membrane processing conditions. In this paper, we study the effects of block length, selectivity of the solvent, and thermal treatment on the membrane properties such as morphology, water uptake, and ionic conductivity. DiMethylSulfOxide (DMSO), and DiMethylAcetamide (DMAc) were selected as casting solvents based on the Flory-Huggins parameter calculated by inversion gas chromatography (IGC). It was found that the solvent selectivity has a mild impact on the mean size of the ionic domains and the expansion upon swelling, while it dramatically affects the supramolecular ordering of the blocks. The membranes cast from DMSO exhibit more interconnected ionic clusters yielding higher conductivities and water uptake as compared to membranes cast from DMAc. A 10-fold increase in proton conductivity was achieved after thermal annealing of membranes at 150 degrees C, and the ionomers with longer block lengths show conductivities similar to Nafion at 80 degrees C and low relative humidity (30%). PMID- 26036144 TI - Confusion about the species richness of human gut microbiota. AB - A key message from a range of high profile next generation sequencing studies on the human microbiota is that it composes a tremendously rich community of more than 1000 species within each one of us. Although more recent studies have shown estimates of between 100 and 200 species per individual, this has not yet been made clear in the literature. Currently, the most widely accepted estimate of species richness is therefore five to ten times too high. Here, we will review the different estimates of species richness in the literature, address potential sources of artefacts, the reluctance to correct these, and provide suggestions for future directions. PMID- 26036145 TI - Use of T-RFLP and seven restriction enzymes to compare the faecal microbiota of obese and lean Japanese healthy men. AB - The composition of the intestinal microbiota of 92 healthy Japanese men was measured following consumption of identical meals for 3 days; terminal restriction fragment length polymorphisms were then used to analyse the DNA content of their faeces. The obtained operational taxonomic units (OTUs) were further analysed using seven restriction enzymes: 516f-BslI and -HaeIII, 27f-MspI and -AluI, and 35f-HhaI, -MspI and -AluI. Subjects were classified by their body mass index (BMI) as lean (<18.5) or obese (>25.0). OTUs were then analysed using data mining software. Pearson correlation coefficients on data mining results indicated only a weak relationship between BMI and OTU diversity. Specific OTUs attributed to lean and obese subjects were further examined by data mining with six groups of enzymes and closely related accession numbers for lean and obese subjects were successfully narrowed down. 16S rRNA sequences showed Bacillus spp., Erysipelothrix spp. and Holdemania spp. to be present among 30 bacterial candidates related to the lean group. Fifteen candidates were classified Firmicutes, one was classified as Chloroflexi, and the others were not classified. 45 Microbacteriaceae, 11 uncultured Actinobacterium, and 3 other families were present among the 119 candidate OTUs related to obesity. We conclude that the presence of Firmicutes and Actinobacteria may be related to the BMI of the subject. PMID- 26036146 TI - Impact of a yogurt matrix and cell microencapsulation on the survival of Lactobacillus reuteri in three in vitro gastric digestion procedures. AB - The goal of this study was to assess the interaction between microencapsulation and a yogurt food matrix on the survival of Lactobacillus reuteri NCIMB 30242 in four different in vitro systems that simulate a gastric environment. The four systems were: United States Pharmacopeia (USP) solutions, a static two-step (STS) procedure which included simulated food ingredients, a constantly dynamic digestion procedure (IViDiS), as well a multi-step dynamic digestion scheme (S'IViDiS). The pH profiles of the various procedures varied between systems with acidity levels being: USP > STS > IViDiS = S'IVIDiS. Addition of a food matrix increased the pH in all systems except for the USP methodology. Microencapsulation in alginate-based gels was effective in protecting the cells in model solutions when no food ingredients were present. The stability of the probiotic culture in the in vitro gastric environments was enhanced when (1) yoghurt or simulated food ingredient were present in the medium in sufficient quantity, (2) pH was higher. The procedure-comparison data of this study will be helpful in interpreting the literature with respect to viable counts of probiotics obtained from different static or dynamic in vitro gastric systems. PMID- 26036147 TI - What does the BJD now stand for? A position statement. PMID- 26036148 TI - The International Foundation for Dermatology. PMID- 26036150 TI - Do mutations in BRCA1/BRCA2 confer a higher risk of skin cancer? PMID- 26036149 TI - The global challenge for skin health. PMID- 26036151 TI - Smartphone diagnosis of skin cancer: there's not yet an app for that. PMID- 26036152 TI - Deficiency in barrier function and slow barrier recovery in atopic dermatitis does not depend only on the FLG mutation status. PMID- 26036153 TI - Automated Melasma Area and Severity Index scoring. PMID- 26036154 TI - Itch: challenges for clinicians and investigators. PMID- 26036155 TI - CD30-rich transformed mycosis fungoides or anaplastic large cell lymphoma? How to get it right. PMID- 26036156 TI - Pump up the hair follicle. PMID- 26036157 TI - Indolent CD8-positive lymphoid proliferation of acral sites: identifying the sheep in wolf's clothing. PMID- 26036158 TI - Treatment for erythropoietic protoporphyria. PMID- 26036159 TI - Tuberculosis risk and biological therapy for psoriasis. PMID- 26036160 TI - Long-term use of ciclosporin in a real-world setting. PMID- 26036161 TI - Revisiting antiseptic use in reducing post-surgical recurrence in mycetoma. PMID- 26036162 TI - The association between psoriasis and asthma. PMID- 26036166 TI - Characteristics of total gaseous mercury concentrations at a coastal area of the Yangtze Delta, China. AB - : In this study, we report on total gaseous mercury (TGM) field observations made in the rural area of Shanghai, Chongming Island, China, from September 2009 to April 2012. The average TGM was 2.65 +/- 1.73 ng m-3 in Chongming Island, which is higher than the TGM background value of the Northern Hemisphere (1.5-1.7 ng m 3); this indicates that to some extent, the Chongming area has been affected by anthropogenic mercury emissions. The observed TGM follows a seasonal pattern; concentrations are highest in winter, followed by autumn, summer, and spring. There is also a clear diurnal variation in TGM. All peak values appear between 7:00 and 9:00 in all four seasons; this appears to be the result of the height change in the atmospheric boundary layer that occurs between day and night. TGM concentrations in Chongming remain high in the westerly wind direction, especially in the southwest direction because of its low frequency, so the greatest source contribution to TGM in Chongming lies to the northwest. Wind speed is also a significant factor affecting TGM, and was negatively correlated with TGM concentrations. TGM is also closely related to carbon monoxide (CO) concentrations, indicating that TGM is impacted by human activities. The slope of the linear fitting of TGM and CO demonstrates that the contribution of noncoal source emissions to TGM in summer is greater than in autumn, mainly because the high temperature and intensive sunlight in summer increase mercury emissions from natural sources. IMPLICATIONS: Except for some studies in the coastal areas (e.g., Kang Hwa Island by Kim et al., 2006, An-Myun Island by Kim et al., 2002, and Okinawa by Chan et al., 2008), data specifically for coastal areas are lacking. Monitoring of total gaseous mercury (TGM) in the rural area of Shanghai, Chongming Island, can help us understand mercury distribution. PMID- 26036168 TI - Bone morbidity in chronic myeloproliferative neoplasms. AB - Patients with the classical Philadelphia chromosome-negative chronic myeloproliferative neoplasms including essential thrombocythemia, polycythemia vera and primary myelofibrosis often suffer from comorbidities, in particular, cardiovascular diseases and thrombotic events. Apparently, there is also an increased risk of osteoporotic fractures among these patients. However, the true prevalence, mechanisms involved and therapeutic implications are not well described. In this review, we summarize what is currently known about possible associations between bone disease and chronic myeloproliferative neoplasms. Chronic inflammation has been suggested to explain the initiation of clonal development and progression in chronic myeloproliferative neoplasms. Decreased bone mineral density and enhanced fracture risk are well-known manifestations of many chronic systemic inflammatory diseases. As opposed to systemic mastocytosis (SM) where pathogenic mechanisms for bone manifestations probably involve effects of mast cell mediators on bone metabolism, the mechanisms responsible for increased fracture risk in other chronic myeloproliferative neoplasms are not known. PMID- 26036167 TI - Enhanced E/Z Isomerization of (All-E)-lycopene by Employing Iron(III) Chloride as a Catalyst. AB - Catalytic isomerization of (all-E)-lycopene to Z-isomers using iron(III) chloride was investigated and optimized under various conditions of solvents, concentrations of iron(III) chloride, and reaction temperatures. The total contents of Z-isomers converted were higher in the order of CH2 Cl2 (78.4%) > benzene (61.4%) > acetone (51.5%) > ethyl acetate (50.8%) at 20 degrees C for 3 h using 1.0 * 10(-3) mg/mL iron(III) chloride for 0.1 mg/mL (all-E)-lycopene. However, the decomposition of lycopene was markedly accelerated in CH2 Cl2 : the remaining lycopene after the reaction for 3 h and 12 h was only 79.4% and 47.5%, respectively. As the concentration of catalyst increased in acetone, the Z isomerization ratio of lycopene increased to more than 80%, followed by rapid degradation of lycopene to undetectable levels using >4.0 * 10(-3) mg/mL iron(III) chloride with the above concentration of (all-E)-lycopene. Finally, greater isomerization (79.9%) was attained at 60 degrees C in acetone for 3 h in the presence of 1.0 * 10(-3) mg/mL iron(III) chloride, largely without decomposition of lycopene (remaining ratio of total amount of lycopene isomers after the reaction, 96.5%). As iron(III) chloride has found general use as a food additive for iron fortification and acetone is also widely used in the food field, this method can be applied to the food and beverage processing industry. PRACTICAL APPLICATION: The dietary intake of lycopene, a natural red pigment found in brightly colored vegetables and fruits such as tomatoes and watermelons, has been reported to lower the risk of some diseases, including cancer. Lycopene molecules occur naturally in a long and "straight" shape, but on the other hand lycopene molecules with "bent" forms are highly absorbed by living cells, and showed good antioxidant activity. This study has demonstrated the efficient production of the "bent" lycopene using ionic iron as an accelerator, which is often contained in nutritional supplements. PMID- 26036169 TI - Evaluation of neonatal circumcision training for resident doctors in a developing country. AB - BACKGROUND: There is a high prevalence of neonatal circumcision (NC) in Sub Saharan Africa. However, when providers do not have adequate training on the procedure, neonatal circumcision can result in complications. There are indications that the reported high complication rate of NC in the current setting might be a reflection of inadequate training of the providers. In order to establish a framework for better training of providers of NC, it may be necessary to evaluate the providers' opinions of their training and competence of the procedure. OBJECTIVE: The opinions of surgical, paediatric, and obstetrics gynaecology resident doctors were evaluated for their exposure to, training on and perceived competence of neonatal circumcision. STUDY DESIGN: The resident doctors in surgery, paediatrics and obstetrics-gynaecology (OBGYN) at two teaching hospitals in southeastern Nigeria were surveyed using a self-developed questionnaire. The self-assessment survey evaluated the residents' exposure and training on NC, and their perceived competence of the procedure. The responses from the different specialties were compared. Data were analysed using Statistical package for Social Sciences (SPSS). RESULTS: The summary of findings is shown in Table below: The confidence in the ability to perform the NC did not significantly differ between the sexes (male 53/87 vs female 6/15; P = 0.22) and the level of training (SHO, Senior house officer 7/17, Registrar 24/42, senior registrar 28/43; P = 0.24). DISCUSSION: A substantial proportion of residents who encountered neonatal circumcision considered their training in NC to be sub optimal, despite their perceived exposure to the procedure. Notwithstanding this deficiency of training, the majority of the residents planned to perform NC and this presaged an expectedly higher rate of complications. Well-thought-out and structured training, comprising lectures, workshops and hands-on training, for the resident doctors and the other providers of NC might address these shortcomings and minimise complications. This may further be strengthened with a government policy on circumcision. The limitations of the study included: (1) It was a self-assessment survey and this introduced bias in the assessment of competency; (2) There were no outcome measures in the survey for those who had practical exposure vs those who did not. CONCLUSION: The resident doctors perceived that their exposure, training and competence in NC might be sub optimal. Curriculum modification that incorporates appropriate hands-on training in NC might address these deficiencies. PMID- 26036171 TI - Epigenetic pathways regulating bone homeostasis. AB - Epigenetic control of the genome involves a complex series of unique, physiologically responsive and integrated pathways, each with distinct mechanisms. Insight into epigenetic regulation has transformed understanding of inheritance, development and a broad spectrum of biological processes as well as advances in mechanistic and clinical characterization of tissues and disease states. The dynamics of bone tissue undergoing continuous remodeling during growth and turnover in the adult skeleton, involves epigenetic mechanisms that have emerged as an important component to maintaining skeletal homeostasis. A series of four reviews are presented in the journal BONE covering different aspects of epigenetic control mechanisms that have impacted on the skeleton. Authorship on each of the reviews is shared by investigators from different institutions to present a consensus of emerging concepts and future directions for understanding regulation of the bone epigenome and skeletal pathologies. PMID- 26036170 TI - BMPs and the muscle-bone connection. AB - Muscle and bone are two intimately connected tissues. A coordinated interplay between these tissues at mechanical levels is required for their development, function and ageing. Evidence is emerging that several genes and molecular pathways exert a pleiotropic effect on both muscle and bone. Bone morphogenetic proteins (BMPs) are secreted signal factors belonging to the transforming growth factor beta (TGFbeta) superfamily. BMPs have an essential role during bone and cartilage formation and maintenance. Recently, we and others have demonstrated that the BMP pathway also has a role in controlling adult skeletal muscle mass. Thus, BMPs become crucial regulators of both bone and muscle formation and homeostasis. In this review we will discuss the signalling downstream BMP and its role in muscle-bone interaction. This article is part of a Special Issue entitled "Muscle Bone Interactions". PMID- 26036172 TI - Bone marrow ablation demonstrates that estrogen plays an important role in osteogenesis and bone turnover via an antioxidative mechanism. AB - To assess the effect of estrogen deficiency on osteogenesis and bone turnover in vivo, 8-week-old mice were sham-operated or bilaterally ovariectomized (OVX), and after 8 weeks, mechanical bone marrow ablation (BMX) was performed and newly formed bone tissue was analyzed from 6 days to 2 weeks after BMX. Our results demonstrated that OVX mice following BMX displayed 2 reversed phase changes, one phase observed at 6 and 8 days after BMX delayed osteogenesis accompanied by a delay in osteoclastogenesis, and the other phase observed at 12 and 14 days after BMX increased osteoblastic activity and osteoclastic activity. Furthermore, we asked whether impaired osteogenesis caused by estrogen deficiency was associated with increased oxidative stress, and oxidative stress parameters were examined in bone tissue from sham-operated and OVX mice and OVX mice were administrated with antioxidant N-acetyl-l-cysteine (NAC) or vehicle after BMX. Results demonstrated that estrogen deficiency induced oxidative stress in mouse bone tissue with reduced antioxidase levels and activity, whereas NAC administration almost rescued the abnormalities in osteogenesis and bone turnover caused by OVX. Results from this study indicate that estrogen deficiency resulted in primarily impaired osteogenesis and subsequently accelerated bone turnover by increasing oxidative stress and oxidative stress promises to be an effective target in the process of treatment of postmenopausal osteoporosis. PMID- 26036173 TI - Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly. AB - PURPOSE: ALOX12 and ALOX15 encode arachidonate lipoxygenases which produce lipid metabolites involved in inflammatory processes. Metabolites generated by ALOX12 and ALOX15 can activate the expression of the potent pro-inflammatory cytokine IL 6, and produce endogenous ligands for PPARG. In this study, polymorphisms in ALOX12, ALOX15, IL6 and PPARG were investigated for association with bone properties in young and elderly Swedish women. METHODS: Three SNPs in ALOX12, five in ALOX15, one each in IL6 and PPARG were genotyped in the cohorts PEAK-25 (n=1061 women; all 25y) and OPRA (n=1044 women; all 75y). Bone mineral density (BMD) and quantitative ultrasound (QUS) were analyzed in both cohorts; trabecular bone score (TBS) in PEAK-25; bone loss, fracture incidence and serum C-reactive protein (CRP) were assessed in OPRA. RESULTS: In the elderly women ALOX15 (rs2619112) was associated with CRP levels (p=0.004) and incident fracture of any type (p=0.014), although not with BMD or ultrasound. In young women, carrying the common T allele (ALOX 15 rs748694) was associated with lower QUS values (p=0.002 0.006). The IL6 SNP was associated with lower BMD in PEAK-25 (femoral neck p=0.034; hip p=0.012). TBS was not associated with variation in any gene. Variants in the ALOX12 and PPARgamma were not associated with BMD in either cohort. CONCLUSIONS: This study suggests that variation in inflammation related genes ALOX15 and IL6 was associated with bone microarchitecture and density in young adult women, but appears to be less important in the elderly, despite an observed association with CRP as a marker of inflammation and incident fracture. PMID- 26036174 TI - Local delivery of FTY720 in PCL membrane improves SCI functional recovery by reducing reactive astrogliosis. AB - FTY720 has recently been approved as an oral drug for treating relapsing forms of multiple sclerosis, and exerts its therapeutic effect by acting as an immunological inhibitor targeting the sphingosine-1-phosphate (S1P) receptor subtype (S1P1) of T cells. Recently studies demonstrated positive efficacy of this drug on spinal cord injury (SCI) in animal models after systemic administration, albeit with significant adverse side effects. We hereby hypothesize that localized delivery of FTY720 can promote SCI recovery by reducing pathological astrogliosis. The mechanistic functions of FTY720 were investigated in vitro and in vivo utilizing immunofluorescence, histology, MRI and behavioral analysis. The in vitro study showed that FTY720 can reduce astrocyte migration and proliferation activated by S1P. FTY720 can prolong internalization of S1P1 and exert antagonistic effects on S1P1. In vivo study of SCI animal models demonstrated that local delivery of FTY720 with polycaprolactone (PCL) membrane significantly decreased S1P1 expression and glial scarring compared with the control group. Furthermore, FTY720-treated groups exhibited less cavitation volume and neuron loss, which significantly improved recovery of motor function. These findings demonstrated that localized delivery of FTY720 can promote SCI recovery by targeting the S1P1 receptor of astrocytes, provide a new therapeutic strategy for SCI treatment. PMID- 26036175 TI - Pediatric tubular pulmonary heart valve from decellularized engineered tissue tubes. AB - Pediatric patients account for a small portion of the heart valve replacements performed, but a pediatric pulmonary valve replacement with growth potential remains an unmet clinical need. Herein we report the first tubular heart valve made from two decellularized, engineered tissue tubes attached with absorbable sutures, which can meet this need, in principle. Engineered tissue tubes were fabricated by allowing ovine dermal fibroblasts to replace a sacrificial fibrin gel with an aligned, cell-produced collagenous matrix, which was subsequently decellularized. Previously, these engineered tubes became extensively recellularized following implantation into the sheep femoral artery. Thus, a tubular valve made from these tubes may be amenable to recellularization and, ideally, somatic growth. The suture line pattern generated three equi-spaced leaflets in the inner tube, which collapsed inward when exposed to back pressure, per tubular valve design. Valve testing was performed in a pulse duplicator system equipped with a secondary flow loop to allow for root distention. All tissue-engineered valves exhibited full leaflet opening and closing, minimal regurgitation (<5%), and low systolic pressure gradients (<2.5 mmHg) under pulmonary conditions. Valve performance was maintained under various trans-root pressure gradients and no tissue damage was evident after 2 million cycles of fatigue testing. PMID- 26036176 TI - Percutaneous external fixator pins with bactericidal micron-thin sol-gel films for the prevention of pin tract infection. AB - Risk of infection is considerable in open fractures, especially when fracture fixation devices are used to stabilize the fractured bones. Overall deep infection rates of 16.2% have been reported. The infection rate is even greater, up to 32.2%, with external fixation of femoral fractures. The use of percutaneous implants for certain clinical applications, such as percutaneous implants for external fracture fixation, still represents a challenge today. Currently, bone infections are very difficult to treat. Very potent antibiotics are needed, which creates the risk of irreversible damage to other organs, when the antibiotics are administered systemically. As such, controlled, local release is being pursued, but no such treatments are in clinical use. Herein, the use of bactericidal micron-thin sol-gel films on metallic fracture fixation pins is reported. The data demonstrates that triclosan (2,4,4'-trichloro-2'-hydroxydiphenylether), an antimicrobial agent, can be successfully incorporated into micron-thin sol-gel films deposited on percutaneous pins. The sol-gel films continuously release triclosan in vitro for durations exceeding 8 weeks (longest measured time point). The bactericidal effect of the micron-thin sol-gel films follows from both in vitro and in vivo studies. Inserting percutaneous pins in distal rabbit tibiae, there were no signs of infection around implants coated with a micron-thin sol gel/triclosan film. Healing had progressed normally, bone tissue growth was normal and there was no epithelial downgrowth. This result was in contrast with the results in rabbits that received control, uncoated percutaneous pins, in which abundant signs of infection and epithelial downgrowth were observed. Thus, well-adherent, micron-thin sol-gel films laden with a bactericidal molecule successfully prevented pin tract infection. PMID- 26036177 TI - Assessments of radioactivity concentration of natural radionuclides and radiological hazard indices in sediment samples from the East coast of Tamilnadu, India with statistical approach. AB - This paper reports on the distribution of three natural radionuclides (238)U, (232)Th and (40)K in coastal sediments from Pattipulam to Devanampattinam along the East coast of Tamilnadu to establish baseline data for future environmental monitoring. Sediment samples were collected by a Peterson grab samples from 10m water depth parallel to the shore line. Concentration of natural radionuclides were determined using a NaI(Tl) detector based gamma-spectrometry. The mean activity concentration is ?2.21, 14.29 and 360.23Bqkg(-1) for (238)U, (232)Th and (40)K, respectively. The average activity of (232)Th, (238)U and (40)K is lower when compared to the world average value. Radiological hazard parameters were estimated based on the activity concentrations of (238)U, (232)Th and (40)K to find out any radiation hazard associated with the sediments. The radiological hazard parameters such as radium equivalent activity (Raeq), absorbed gamma dose rates in air (DR), the annual gonadal dose equivalent (AGDE), annual effective dose equivalent (AEDE), external hazard index (Hex) internal hazard index (Hin), activity utilization index (AUI) and excess lifetime cancer (ELCR) associated with the radionuclides were calculated and compared with internationally approved values and the recommended safety limits. Pearson correlation, principal component analysis (PCA) and hierarchical cluster analysis (HCA) have been applied in order to recognize and classify radiological parameters in sediments collected at 22 sites on East coast of Tamilnadu. The values of radiation hazard parameters were comparable to the world averages and below the recommended values. Therefore, coastal sediments do not to pose any significant radiological health risk to the people living in nearby areas along East coast of Tamilnadu. The data obtained in this study will serve as a baseline data in natural radionuclide concentration in sediments along the coastal East coast of Tamilnadu. PMID- 26036178 TI - A family empowerment program for families having children with thalassemia, Thailand. AB - The purpose of this quasi-experimental design study was to examine the effectiveness of a family empowerment program (FEP) on family functioning and empowerment among 56 families having children with thalassemia. The 26 families in the experimental group received the FEP and usual care, while 30 families in the control group received usual care. Data collection occurred through family functioning and empowerment questionnaires. Between-group differences were tested with t-tests and analysis of variance. The result revealed that family caregivers who participated in the FEP had significantly increased family functioning and empowerment scores over time. The FEP can be used as a powerful intervention for assisting families and children with thalassemia and the education of health professionals. PMID- 26036180 TI - Sodium in commonly consumed fast foods in New Zealand: a public health opportunity. AB - OBJECTIVE: (i) To determine the Na content of commonly consumed fast foods in New Zealand and (ii) to estimate Na intake from savoury fast foods for the New Zealand adult population. DESIGN: Commonly consumed fast foods were identified from the 2008/09 New Zealand Adult Nutrition Survey. Na values from all savoury fast foods from chain restaurants (n 471) were obtained from nutrition information on company websites, while the twelve most popular fast-food types from independent outlets (n 52) were determined using laboratory analysis. Results were compared with the UK Food Standards Agency 2012 sodium targets. Nutrient analysis was completed to estimate Na intake from savoury fast foods for the New Zealand population using the 2008/09 New Zealand Adult Nutrition Survey. SETTING: New Zealand. SUBJECTS: Adults aged 15 years and above. RESULTS: From chain restaurants, sauces/salad dressings and fried chicken had the highest Na content (per 100 g) and from independent outlets, sausage rolls, battered hotdogs and mince and cheese pies were highest in Na (per 100 g). The majority of fast foods exceeded the UK Food Standards Agency 2012 sodium targets. The mean daily Na intake from savoury fast foods was 283 mg/d for the total adult population and 1229 mg/d for fast-food consumers. CONCLUSIONS: Taking into account the Na content and frequency of consumption, potato dishes, filled rolls, hamburgers and battered fish contributed substantially to Na intake for fast-food consumers in New Zealand. These foods should be targeted for Na reduction reformulation. PMID- 26036179 TI - Defect-Engineered Metal-Organic Frameworks. AB - Defect engineering in metal-organic frameworks (MOFs) is an exciting concept for tailoring material properties, which opens up novel opportunities not only in sorption and catalysis, but also in controlling more challenging physical characteristics such as band gap as well as magnetic and electrical/conductive properties. It is challenging to structurally characterize the inherent or intentionally created defects of various types, and there have so far been few efforts to comprehensively discuss these issues. Based on selected reports spanning the last decades, this Review closes that gap by providing both a concise overview of defects in MOFs, or more broadly coordination network compounds (CNCs), including their classification and characterization, together with the (potential) applications of defective CNCs/MOFs. Moreover, we will highlight important aspects of "defect-engineering" concepts applied for CNCs, also in comparison with relevant solid materials such as zeolites or COFs. Finally, we discuss the future potential of defect-engineered CNCs. PMID- 26036181 TI - Effects of maternal subtotal nephrectomy on the development of the fetal kidney: A morphometric study. AB - The present study was designed to explore if maternal subtotal (5/6) nephrectomy affects the development of fetal rat kidneys using morphometric methods and examining whether there are any apoptotic changes in the fetal kidney. To generate 5/6 nephrectomized model rats, animals underwent 2/3 left nephrectomy on gestation day (GD) 5 and total right nephrectomy on GD 12. The fetal kidneys were examined on GDs 16 and 22. A significant decrease in fetal body weight resulting from maternal 5/6 nephrectomy was observed on GD 16, and a significant decrease in fetal renal weight and fetal body weight caused by maternal nephrectomy was observed on GD 22. Maternal 5/6 nephrectomy induced a significant increase in glomerular number, proximal tubular length, and total proximal tubular volume of fetuses on GD 22. Maternal 5/6 nephrectomy resulted in an increase in the number of apoptotic cells in the metanephric mesenchyme of the kidney on GD 16, and in the collecting tubules on GD 22. These findings suggest that maternal 5/6 nephrectomy stimulates the development of the fetal kidney while suppressing fetal growth. PMID- 26036182 TI - Abstracts 19th Annual Congress of Euroacademia Multidisciplinaria Neurotraumatologica (EMN) and 1st Committee Meeting of Military Neurosurgeons of the World Federation of Neurosurgical Societies (WFNS). PMID- 26036183 TI - Performance of a next generation sequencing SNP assay on degraded DNA. AB - Forensic DNA casework samples are often of insufficient quantity or quality to generate full profiles by conventional DNA typing methods. Polymerase chain reaction (PCR) amplification of short tandem repeat (STR) loci is inherently limited in samples containing degraded DNA, as the cumulative size of repeat regions, primer binding regions, and flanking sequence is necessarily larger than the PCR template. Additionally, traditional capillary electrophoresis (CE) assay design further inherently limits shortening amplicons because the markers must be separated by size. Non-traditional markers, such as single nucleotide polymorphisms (SNPs) and insertion deletion polymorphisms (InDels), may yield more information from challenging samples due to their smaller amplicon size. In this study, the performance of a next generation sequencing (NGS) SNP assay and CE-based STR, mini-STR, and InDel assays was evaluated with a series of fragmented, size-selected samples. Information obtained from the NGS SNP assay exhibited higher overall inverse random match probability (1/RMP) values compared to the CE-based typing assays, with particular benefit for fragment sizes <= 150 base pairs (bp). The InDel, mini-STR, and NGS SNP assays all had similar percentages of loci with reportable alleles at this level of degradation; however, the relatively fewer number of loci in the InDel and mini-STR assays results in the NGS SNP assay having at least nine orders of magnitude higher 1/RMP values. In addition, the NGS SNP assay and three CE-based assays (two STR and one InDel assay) were tested using a dilution series consisting of 0.5 ng, 0.1 ng, and 0.05 ng non-degraded DNA. All tested assays showed similar percentages of loci with reportable alleles at these levels of input DNA; however, due to the larger number of loci, the NGS SNP assay and the larger of the two tested CE-based STR assays both resulted in considerably higher 1/RMP values than the other assays. These results indicate the potential advantage of NGS SNP assays for forensic analysis of degraded DNA samples. PMID- 26036184 TI - Population genetic analysis of insertion-deletion polymorphisms in a Brazilian population using the Investigator DIPplex kit. AB - The aim of this study was to estimate the diversity of 30 insertion/deletion (INDEL) markers (Investigator((r)) DIPplex kit) in a sample of 519 individuals from six Brazilian states and to evaluate their applicability in forensic genetics. All INDEL markers were found to be highly polymorphic in the Brazilian population and were in Hardy-Weinberg equilibrium. To determine their forensic suitability in the Brazilian population, the markers were evaluated for discrimination power, match probability and exclusion power. The combined discrimination power (CDP), combined match power (CMP) and combined power of exclusion (CPE) were higher than 0.999999, 3.4 * 10(-13) and 0.9973, respectively. Further comparison of 29 worldwide populations revealed significant genetic differences between continental populations and a closer relationship between the Brazilian and European populations. PMID- 26036185 TI - Statistical and population genetics issues of two Hungarian datasets from the aspect of DNA evidence interpretation. AB - When the DNA profile from a crime-scene matches that of a suspect, the weight of DNA evidence depends on the unbiased estimation of the match probability of the profiles. For this reason, it is required to establish and expand the databases that reflect the actual allele frequencies in the population applied. 21,473 complete DNA profiles from Databank samples were used to establish the allele frequency database to represent the population of Hungarian suspects. We used fifteen STR loci (PowerPlex ESI16) including five, new ESS loci. The aim was to calculate the statistical, forensic efficiency parameters for the Databank samples and compare the newly detected data to the earlier report. The population substructure caused by relatedness may influence the frequency of profiles estimated. As our Databank profiles were considered non-random samples, possible relationships between the suspects can be assumed. Therefore, population inbreeding effect was estimated using the FIS calculation. The overall inbreeding parameter was found to be 0.0106. Furthermore, we tested the impact of the two allele frequency datasets on 101 randomly chosen STR profiles, including full and partial profiles. The 95% confidence interval estimates for the profile frequencies (pM) resulted in a tighter range when we used the new dataset compared to the previously published ones. We found that the FIS had less effect on frequency values in the 21,473 samples than the application of minimum allele frequency. No genetic substructure was detected by STRUCTURE analysis. Due to the low level of inbreeding effect and the high number of samples, the new dataset provides unbiased and precise estimates of LR for statistical interpretation of forensic casework and allows us to use lower allele frequencies. PMID- 26036186 TI - The Nipple is Just Another Margin. PMID- 26036187 TI - Neoadjuvant Chemotherapy Followed by Maintenance Therapy With or Without Bevacizumab in Unresectable High-Grade Serous Ovarian Cancer: A Case-Control Study. AB - OBJECTIVE: The aim of this study was to compare the toxicity, perioperative outcomes of interval debulking surgery (IDS), and duration of progression-free survival (PFS) in women with unresectable high-grade serous advanced ovarian cancer (AOC) receiving neoadjuvant chemotherapy (NACT) with or without bevacizumab. METHODS: Twenty-five patients with high-grade serous AOC treated with bevacizumab-based NACT (cases) were matched according to initial disease extension assessed by laparoscopy, and age, in a 1:2 ratio, with 50 high-grade serous AOC patients treated with standard NACT without bevacizumab (controls). RESULTS: Both groups received a median of four NACT cycles before IDS (p = 0.867), and the median time interval between NACT and IDS was 27 days in both groups (p = 0.547). Twenty-two cases (88.0 %) showed complete/partial radiologic response compared with 36 controls (72.3 %; p = 0.054). A higher percentage of cases showed complete serological response (48 vs. 35.1 %; p = 0.041). At IDS, complete cytoreduction was achieved in 20 cases (80.0 %) and 36 controls (72.3 %) [p = 0.260]. No differences were observed between groups in terms of surgical complexity score, perioperative outcomes, surgical complications, and chemotherapy-related adverse events. One death due to gastrointestinal perforation was observed among cases. Cases showed a longer median PFS compared with controls (18 months vs. 10 months; p = 0.001), and the administration of bevacizumab (hazard ratio 3.786; p = 0.001) retained a prognostic role for longer PFS at multivariate analysis. CONCLUSIONS: The incorporation of bevacizumab in NACT prolongs PFS without affecting the safety of IDS. The risk of gastrointestinal perforation should be considered prior to attempting bevacizumab based NACT in women with diffuse bowel involvement at initial laparoscopic evaluation. PMID- 26036188 TI - Overexpression of Transcription Termination Factor 1 is Associated with a Poor Prognosis in Patients with Colorectal Cancer. AB - BACKGROUND: RNA polymerase 1 transcription termination factor (TTF1) mediates the transcription of ribosomal RNA (rRNA). In the current study, we investigated the clinical and biological significance of the TTF1 gene in colorectal cancer (CRC). METHODS: The expression of TTF1 messenger RNA (mRNA) in tumor and normal tissues from 136 patients with CRC was examined by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). We also performed in vitro cell proliferation and migration assays in TTF1-expressing CRC cells. The biological role of TTF1 in CRC was further elucidated using gene set enrichment analysis (GSEA) with CRC samples. RESULTS: TTF1 expression was significantly higher in tumor tissues than in corresponding normal tissues (p = 0.016). In clinicopathological analysis, the high-TTF1 expression group showed a higher incidence of liver metastasis and lymphatic invasion than the low-TTF1 expression group (p < 0.05), and tended to have more frequent venous invasion than the low TTF1 expression group. Furthermore, the high-TTF1 expression group had a significantly poorer prognosis than the low-TTF1 expression group (p = 0.011). Moreover, overexpression of TTF1 enhanced the proliferation and migration capacity of CRC cells in vitro. GSEA revealed that TTF1 was significantly associated with the RAS and MYC pathways, and this observation was confirmed in samples from 136 patients with CRC. CONCLUSION: TTF1 was involved in cancer progression via the RAS and MYC pathways in CRC, suggesting that TTF1 may be a prognostic indicator and therapeutic target in CRC. PMID- 26036189 TI - Doppler Ultrasound Flow Evaluation of the Uterine Arteries Significantly Correlates with Tumor Size in Cervical Cancer Patients. AB - PURPOSE: The aim of this present study was to evaluate the sonographic correlation between Doppler flow characteristics of the uterine arteries and tumor size in patients with cervical cancer, in order to establish a new potential marker to monitor treatment response. METHODS: This was a retrospective cohort study of 25 patients who underwent a sonographic evaluation of Doppler flow characteristics of the uterine arteries before surgery or radiochemotherapy for early and locally advanced/advanced cervical cancer, respectively, was analyzed. The primary outcome was the correlation between Doppler flow characteristics of the uterine arteries and tumor size in patients with cervical cancer. RESULTS: Median age was 49 (range 26-85) years, and mean tumor size was 40.8 +/- 17 mm. A significant positive correlation was found between tumor diameter and the uterine artery end-diastolic velocity (r = 0.47, p < 0.05) as well as the peak systolic velocity (r = 0.41, p < 0.05). No correlation was found between tumor size and the pulsatility index or resistance index. CONCLUSIONS: In cervical cancer, uterine artery velocity parameters are associated with tumor size. This finding could become particularly useful in the follow-up of locally advanced cervical cancer patients undergoing radiochemotherapy or in corroborating the selection of women with more possibility of a high response rate during neoadjuvant chemotherapy before surgery. PMID- 26036190 TI - Does low-molecular-weight heparin influence fetal growth or uterine and umbilical arterial Doppler in women with a history of early-onset uteroplacental insufficiency and an inheritable thrombophilia? Secondary randomised controlled trial results. AB - OBJECTIVE: Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency? DESIGN: Secondary outcomes of the FRUIT-RCT. SETTING: Multicentre, international. POPULATION: The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestational-age infant and an inheritable thrombophilia. METHODS: After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22-24, 28-30 and 34-36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22-24 weeks) was examined using a chi square test. MAIN OUTCOME MEASURES: Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries. RESULTS: No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms. CONCLUSION: The addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity. TWEETABLE ABSTRACT: LMWH does not influence fetal growth or uterine or umbilical flow velocities. PMID- 26036191 TI - The implementation of national action program diabetes in the Netherlands: lessons learned. AB - BACKGROUND: Over the past decade, the National Action program Diabetes (NAD) was implemented in the Netherlands. Its aim was to introduce the Care Standard (CS) for diabetes by means of a specific implementation plan and piloting in several regions. This study aimed to provide insight into the implementation of the NAD as, coupled with the introduction of the CS, it may function as an example for similar approaches in other countries. METHODS: A series of quantitative studies (participants 2010: N = 1726, participants 2013: N = 1370 & participants pilot regions 2013: N = 168) and qualitative studies (participants 2010: N = 18 and participants 2013: N = 4) was conducted among health care professionals (HCPs). In addition, two quantitative studies were conducted among type 1 and 2 patients (participants 2010: N = 573; participants 2013: N = 5056). RESULTS: Overall, positive changes in diabetes care were detected in the period 2010 - 2013. In 2013 significantly more HCPs were familiar with the CS (43.7 versus 37.6 %) and more HCPs perceived themselves to be working largely or completely in accordance with the CS (89.2 versus 79.0 %) than in 2010. A comparison of the results in specific pilot regions with the rest of the country revealed that HCPs in these regions scored significantly more positively on implementation and appreciation of the CS. This positive trend was reflected by the high levels of reported patient satisfaction and involvement in treatment. HCPs who were in possession of the CS had significantly better scores on the implementation of several elements of the CS than HCPs who were not in possession of the CS. CONCLUSION: The CS has become more prominent and embedded in daily health care practice. In retrospect the CS has provided momentum for the realization of various processes relating to the wider implementation of standards to improve the care for people with other chronic diseases in the Netherlands. Experiences with the NAD and CS underline the need to move towards an integrated multidisciplinary approach of diabetes care worldwide. PMID- 26036192 TI - The subjective experience of young women with non-metastatic breast cancer: the Young Women with Breast Cancer Inventory. AB - BACKGROUND: The subjective experience of young women with breast cancer has some particular features linked to the impact of the disease and its treatment on their age-related issues (e.g. desire for a child, couple relationship, career management). Despite these specific concerns, no questionnaire currently targets the young breast cancer patient's quality of life, subjective experience or common problems when facing cancer. This study presents the psychometric validation of an inventory that aimed to measure the impact of breast cancer on the quality of life of young women (<45 years of age) with non-metastatic disease. METHODS: 546 women aged <45 years when diagnosed with a non-metastatic breast cancer were recruited in 27 French cancer research and treatment centers. They answered a self-reported questionnaire created from verbatim collected by non-directive interviews carried out with 69 patients in a first qualitative study. Exploratory and confirmatory analyses were conducted in order to obtain the final structure of the scale. Internal consistency, test-retest reliability and concurrent validity with quality of life questionnaires currently used (QLQ C30 and the QLQ-BR23 module) were then assessed. RESULTS: The YW-BCI36 contains 36 items and highlights 8 factors: 1) feeling of couple cohesion, 2) negative affectivity and apprehension about the future, 3) management of child(ren) and of everyday life, 4) sharing with close relatives, 5) body image and sexuality, 6) financial difficulties, 7) deterioration of relationships with close relatives, and 8) career management. Psychometric analyses indicated good internal consistency (Cronbach's alpha values ranging from 0.76 to 0.91) and temporal reliability (Bravais-Pearson correlations ranging from 0.66 to 0.85). As expected, there were quite strong correlations between the YW-BCI36 and the QLQ C30 and QLQ-BR23 scores (r ranging from 0.20 to -0.66), indicating adequate concurrent validity. CONCLUSIONS: The YW-BCI36 was confirmed as a valid scale for evaluating the subjective experience of breast cancer in young women. This instrument could help to identify the problems of these women more precisely, in order to respond to them better by an optimal care management. This scale may improve the medical, psychological and social care of breast cancer patients. PMID- 26036193 TI - Comparison of two protocols of periosteal distraction osteogenesis in a rabbit calvaria model. AB - The regenerative pathways during periosteal distraction osteogenesis may be influenced by the local environment composed by cells, growth factors, nutrition and mechanical load. The aim of the present study was to evaluate the influence of two protocols of periosteal distraction on bone formation. Custom made distraction devices were surgically fixed onto the calvariae of 60 rabbits. After an initial healing period of 7 days, two groups of animals were submitted to distraction rates of 0.25 and 0.5 mm/24 h for 10 days, respectively. Six animals per group were sacrificed 10 (mid-distraction), 17 (end-distraction), 24 (1-week consolidation), 31 (2-week consolidation) and 77 days (2-month consolidation) after surgery. Newly formed bone was assessed by means of micro-CT and histologically. Expression of transcripts encoding tissue-specific genes (BMP-2, RUNX2, ACP5, SPARC, collagen I alpha1, collagen II alpha1 and SOX9) was analyzed by quantitative PCR. Two patterns of bone formation were observed, originating from the old bone surface in Group I and from the periosteum in Group II. Bone volume (BV) and bone mineral density (BMD) significantly increased up to the 2 month consolidation period within the groups (p < 0.05). Significantly more bone was observed in Group II compared to Group I at the 2-month consolidation period (p < 0.001). Expression of transcripts encoding osteogenic genes in bone depended on the time-point of observation (p < 0.05). Low level of transcripts reveals an indirect role of periosteum in the osteogenic process. Two protocols of periosteal distraction in the present model resulted in moderate differences in terms of bone formation. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1121-1131, 2016. PMID- 26036194 TI - Safe anaesthetic care: further improvements require a focus on resilience. PMID- 26036195 TI - Isolation and characterization of monoclonal antibodies specific for chondroitin sulfate E. AB - Chondroitin sulfate E (CSE) is a polysaccharide containing mainly disaccharide units of D-glucuronic acid (GlcA) and 4,6-O-disulfated N-acetyl-D-galactosamine (GalNAc) residues (E-unit) in the amount of ~ 60%. CSE is involved in many biological and pathological processes. In this study, we established new monoclonal antibodies, termed E-12C and E-18H, by using CSE that contained more than 70% of E-units as an immunogen. These antibodies recognized CSE but not other CSs isomers or dermatan sulfate (DS). We evaluated the reactivities of the antibodies to 6-O-sulfated CSA (6S-CSA) and DS (6S-DS) that possessed ~ 60% of GalNAc (4S, 6S) moieties in their structures. Neither of the antibodies reacted with 6S-DS. The antibodies strictly distinguished the structural difference of GlcA and L-iduronic acid in the polysaccharide. Binding affinities of the antibodies were determined by a surface plasmon resonance assay using CSE and 6S CSA. The binding affinities were strongly associated with the molecular weight of CSE and the E-unit content of 6S-CSA. Moreover, we demonstrated that the antibodies are applicable to histochemical analysis. In conclusion, the new anti CSE monoclonal antibodies specifically recognize the E-unit of CSE. The antibodies will become useful tools for the investigation of the biological and pathological significance of CSE. PMID- 26036196 TI - Working together for women's empowerment: Strategies for interdisciplinary collaboration in perinatal care. AB - Women's experiences of pregnancy, birth, and postpartum adjustment are often characterized by feelings of disempowerment, trauma, and emotional pain. Psychosocial perinatal care has not kept up with medical advances in perinatal care. Access to psychosocial care appears to be inadequate because of the following: (a) perinatal health care providers are insufficiently prepared to address emotional aspects of maternal care and (b) traditional, compartmentalized psychological services benefit only a subsection of perinatal women, often in an untimely manner. Practical and innovative psychosocial services, integrated into routine perinatal care, can provide widespread access to psychosocial resources for mothers and supports providers in delivering optimal care. PMID- 26036197 TI - Pediatric central nervous system solitary fibrous tumor: case report. AB - INTRODUCTION: Solitary fibrous tumors are mesenchymally derived masses most commonly originating from the lung pleura. CASE REPORT: Herein, we report a 6 month-old presenting with syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a suprasellar mass. The mass proved to be a solitary fibrous tumor. This case and salient literature are reviewed. CONCLUSIONS: To our knowledge, this is the youngest patient to be described with a mass of this type within the central nervous system. PMID- 26036198 TI - Diffusion tensor imaging of the cervical spinal cord in children. AB - PURPOSE: Obtaining fast, reliable, high-resolution diffusion tensor imaging (DTI) of the pediatric cervical spinal cord (CSC) is challenging, given the multitude of technical limitations involved. Overcoming these limitations may further potentiate DTI as a valuable quantitative tool in evaluating the pediatric CSC. METHODS: Sixteen patients (9 girls and 7 boys) with hypoxic brain injury, craniocervical junction malformations, and head trauma were included in this retrospective study. Region of interests were placed from C1-C2 through C7-T1 consecutively at the cervical intervertebral disc levels. DTI metrics were compared with a pediatric DTI database of healthy controls. Clinical background and outcomes were tabulated. RESULTS: Patients with hypoxic brain injury, Chiari I and II malformations, and head trauma demonstrated lower fractional anisotropy values than that of healthy controls at certain cervical intervertebral disc levels. CONCLUSIONS: DTI may be a promising modality for providing additional information beyond that of conventional magnetic resonance imaging in pediatric central nervous system disorders. PMID- 26036199 TI - Comparison of fractionation strategies for offline two-dimensional liquid chromatography tandem mass spectrometry analysis of proteins from mouse adipose tissue. AB - In the frame of protein identification from mouse adipose tissue, two strategies were compared for the offline elution of peptides from a strong cation exchange (SCX) column in two-dimensional liquid chromatography tandem mass spectrometry (2D-LC-MS/MS) analyses. First, the salt gradient (using K(+) as displacing agent) was evaluated from 25 to 500mM KCl. Then, a less investigated elution mode using a pH gradient (using citric acid and ammonium hydroxide) was carried out from pH 2.5 to 9.0. Equal amounts of peptide digest derived from mouse adipose tissue were loaded onto the SCX column and fractionated according to the two approaches. A total of 15 fractions were collected in two independent experiments for each SCX elution strategy. Then, each fraction was analyzed on a nanoLC-MS/MS platform equipped with a column-switching unit for desalting and enrichment. No substantial differences in peptide quality characteristics (molecular weight, isoelectric point, or GRAVY [grand average of hydropathicity] index distributions) were observed between the two datasets. The pH gradient approach was found to be superior, with 27.5% more unique peptide identifications and 10% more distinct protein identifications compared with the salt-based elution method. In conclusion, our data imply that the pH gradient SCX fractionation is more desirable for proteomics analysis of entire adipose tissue. PMID- 26036200 TI - Overexpression of cryoglobulin-like single-chain antibody induces morular cell phenotype via liquid-liquid phase separation in the secretory pathway organelles. AB - Cryoprecipitation of immunoglobulins is often reported in association with B-cell lymphoproliferative disorders and plasma cell dyscrasias. However, the biochemical basis of such cryoglobulin behaviors is not well understood because of a general lack of suitable experimental systems. Here, we report the identification and characterization of a single-chain antibody (scFv-Fc) that recapitulates cryoglobulin-like properties. When model scFv-Fc protein was engineered to multimerize, by appending the secretory tailpiece (stp) of human immunoglobulin MU-chain to the C terminus, the resulting oligomeric scFv-Fc-stp protein acquired two unexpected properties: the induction of a morular cell phenotype during protein biosynthesis and the cryoprecipitation of secreted proteins in harvested cell culture media. The turbidity of the culture media and the inclusion bodies that gave morular appearances were attributed to microscopic spherical protein droplet formation, a hallmark characteristic of liquid-liquid phase separation (LLPS) event. Mutagenesis approaches revealed that these two phenomena were independent of covalent protein oligomerization induced by stp. Disruption of the N-linked glycosylation motif in the stp region enhanced morular phenotype propensity but reduced protein secretion. Intermolecular disulfide bonds that stabilize Fc dimers and oligomers were necessary for efficient induction of LLPS, but their simultaneous elimination could not abrogate the LLPS propensity completely. Noncovalent protein-protein interactions between scFv-Fc stp chains sufficiently established a basis for LLPS induction. Morular cell phenotypes and cryoprecipitation were clearly underpinned by intrinsic physicochemical properties embedded in the overexpressed cargo protein. Overproduction of condensation-prone secretory proteins that culminate in LLPS in the endoplasmic reticulum therefore serves as a path to produce morular Russell body phenotype. PMID- 26036201 TI - Study on the interactions between anti-cancer drug oxaliplatin and DNA by atomic force microscopy. AB - Oxaliplatin is one of the most important anticancer drugs at present. However, the mechanism of action of oxaliplatin is still controversial. In this study, the interactions between oxaliplatin and a plasmid DNA have been studied so as to reveal the structural basis of its activity. The structural characteristic of pUC19 DNA (2ng/MUL) incubated with 100MUmol/L and 1000MUmol/L of oxaliplatin for the different time on a freshly cleaved highly ordered pyrolytic graphite (HOPG) surface was investigated by atomic force microscopy (AFM). High resolution AFM observation indicated that oxaliplatin can induce pUC19 DNA molecules change from the extended conformation to the entangled structures with many nodes, and finally to the compact particles. The present AFM results provide structural evidence about the interactions between oxaliplatin and circular duplex DNA containing multiple targets. PMID- 26036203 TI - Meniscal Transplantation and its Effect on Osteoarthritis Risk: an abridged protocol for the MeTEOR study: a comprehensive cohort study incorporating a pilot randomised controlled trial. AB - OBJECTIVES: Subtotal or total meniscectomy in the medial or lateral compartment of the knee results in a high risk of future osteoarthritis. Meniscal allograft transplantation has been performed for over thirty years with the scientifically plausible hypothesis that it functions in a similar way to a native meniscus. It is thought that a meniscal allograft transplant has a chondroprotective effect, reducing symptoms and the long-term risk of osteoarthritis. However, this hypothesis has never been tested in a high-quality study on human participants. This study aims to address this shortfall by performing a pilot randomised controlled trial within the context of a comprehensive cohort study design. METHODS: Patients will be randomised to receive either meniscal transplant or a non-operative, personalised knee therapy program. MRIs will be performed every four months for one year. The primary endpoint is the mean change in cartilage volume in the weight-bearing area of the knee at one year post intervention. Secondary outcome measures include the mean change in cartilage thickness, T2 maps, patient-reported outcome measures, health economics assessment and complications. RESULTS: This study is expected to report its findings in 2016. Cite this article: Bone Joint Res 2015;4:93-8. PMID- 26036204 TI - Stress Tolerance of Antibody-Poly(Amino Acid) Complexes for Improving the Stability of High Concentration Antibody Formulations. AB - The stabilization of antibodies in aqueous solution against physical stress remains a problematic issue for pharmaceutical applications. Recently, protein polyelectrolyte complex (PPC) formation using poly(amino acids) was proposed to prepare antibody formulation in a salt-dissociable precipitated state without protein denaturation. Here, we investigated the stabilization effect of PPC of therapeutic antibodies with poly-l-glutamic acid on agitation and thermal stress as forms of mechanical and non-mechanical stress, respectively. The precipitated state of PPC prevented the inactivation and aggregation induced by agitation. Similar results were obtained using the suspension state of PPC, but the stabilizing effects were slightly inferior to those of the PPC precipitate. PPC precipitate and PPC suspension prevented heat-induced inactivation of the antibodies, but showed little effect on heat-induced aggregation. Thus, PPC is a new candidate as a simple storage method for antibodies in aqueous solution, as an alternative state for freeze-drying. PMID- 26036205 TI - Evaluating an outreach service for paediatric burns follow up. AB - Complications following paediatric burns are well documented and care needs to be taken to ensure the appropriate follow up of these patients. Historically this has meant follow up into adulthood however this is often not necessary. The centralisation of burns services in the UK means that patients and their parents may have to travel significant distances to receive this follow up care. To optimise our burns service we have introduced a burns outreach service to enable the patients to be treated closer to home. The aim of this study is to investigate the impact of the introduction of the burns outreach service and within this environment define the optimum length of time needed to follow up these patients. A retrospective analysis was carried out of 100 consecutive paediatric burns patients who underwent surgical management of their burn. During the follow up period there were 43 complications in 32 patients (32%). These included adverse scarring (either hypertrophic or keloid), delayed healing (taking >1 month to heal) and contractures (utilising either splinting or surgical correction). Fifty-nine percent of these complications occurred within 6 months of injury and all occurred within 18 months. Size of burn was directly correlated to the risk of developing a complication. The outreach service reduced the distance the patient needs to travel for follow up by more than 50%. There was also a significant financial benefit for the service as the follow up clinics were on average 50% cheaper with burns outreach than burns physician. Burns outreach is a feasible service that not only benefits the patients but also is cheaper for the burns service. The optimum length of follow up for paediatric burns in 18 months, after which if there have not been any complications they can be discharged. PMID- 26036206 TI - Independent general practice follows the same ethical standards as the NHS. PMID- 26036207 TI - Axon regeneration: Splicing up repair mechanisms. PMID- 26036208 TI - Neurodegenerative disease: Expanding neurodegeneration modelling. PMID- 26036209 TI - Effects of feedback-based balance and core resistance training vs. Pilates training on balance and muscle function in older women: a randomized-controlled trial. AB - BACKGROUND: Aging is associated with decline in physical function that could result in the development of physical impairment and disability. Hence, interventions that simultaneously challenge balance ability, trunk (core) and extremity strength of older adults could be particularly effective in preserving and enhancing these physical functions. OBJECTIVE: The purpose of this study was to compare the effects of feedback-based balance and core resistance training utilizing the a special computer-controlled device (Huber(r)) with the conventional Pilates training on balance ability, neuromuscular function and body composition of healthy older women. METHODS: Thirty-four older women (age: 70+/-4 years) were randomly assigned to a Huber group (n=17) or Pilates group (n=17). Both groups trained for 8 weeks, 3 times a week. Maximal isometric strength of the trunk flexors, extensors, and lateral flexors, leg power, upper-body strength, single- and dual-task static balance, and body composition were measured before and after the intervention programs. RESULTS: Significant group*time interactions and main effects of time (p<0.05) were found for body composition, balance ability in standard and dual-task conditions, all trunk muscle strength variables, and leg power in favor of the Huber group. The observed improvements in balance ability under both standard and dual-task conditions in the Huber group were mainly the result of enhanced postural control in medial-lateral direction (p<0.05). CONCLUSION: Feedback-based balance and core resistance training proved to be more effective in improving single- and dual task balance ability, trunk muscle strength, leg power, and body composition of healthy older women than the traditional Pilates training. PMID- 26036210 TI - Microparticles released from Mycobacterium tuberculosis-infected human macrophages contain increased levels of the type I interferon inducible proteins including ISG15. AB - Microparticles (MPs) are small membranous particles (100-1000 nm) released under normal steady-state conditions and are thought to provide a communication network between host cells. Previous studies demonstrated that Mycobacterium tuberculosis (M. tb) infection of macrophages increased the release of MPs, and these MPs induced a proinflammatory response from uninfected macrophages in vitro and in vivo following their transfer into uninfected mice. To determine how M. tb infection modulates the protein composition of the MPs, and if this contributes to their proinflammatory properties, we compared the proteomes of MPs derived from M. tb-infected (TBinf-MP) and uninfected human THP-1 monocytic cells. MP proteins were analyzed by GeLC-MS/MS with spectral counting revealing 68 proteins with statistically significant differential abundances. The 42 proteins increased in abundance in TBinf-MPs included proteins associated with immune function (7), lysosomal/endosomal maturation (4), vesicular formation (12), nucleosome proteins (4), and antigen processing (9). Prominent among these were the type I interferon inducible proteins, ISG15, IFIT1, IFIT2, and IFIT3. Exposure of uninfected THP-1 cells to TBinf-MPs induced increased gene expression of isg15, ifit1, ifit2, and ifit3 and the release of proinflammatory cytokines. These proteins may regulate the proinflammatory potential of the MPs and provide candidate biomarkers for M. tb infection. PMID- 26036212 TI - Estrogen and colorectal cancer incidence and mortality. AB - BACKGROUND: The preponderance of observational studies describe an association between the use of estrogen alone and a lower incidence of colorectal cancer. In contrast, no difference in the incidence of colorectal cancer was seen in the Women's Health Initiative (WHI) randomized, placebo-controlled trial with estrogen alone after a mean intervention of 7.1 years and cumulative follow-up of 13.2 years. This study extends these findings by providing detailed analyses of the effects of estrogen alone on the histology, grade, and stage of colorectal cancer, relevant subgroups, and deaths from and after colorectal cancer. METHODS: The WHI study was a randomized, double-blind, placebo-controlled trial involving 10,739 postmenopausal women with prior hysterectomy. Participants were assigned to conjugated equine estrogen at 0.625 mg/d (n = 5279) or a matching placebo (n = 5409). Rates of colorectal cancer diagnoses and deaths from and after colorectal cancer were assessed throughout the study. RESULTS: Colorectal cancer rates in the estrogen-alone and placebo groups were comparable: 0.14% and 0.12% per year, respectively (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.83-1.58; P = .43). Bowel screening examinations were comparable between the 2 groups throughout the study. The grade, stage, and location of colorectal cancer did not differ between the randomization groups. There were more colorectal cancer deaths in the estrogen-alone group (34 [0.05%] vs 24 [0.03%]; HR, 1.46, 95% CI, 0.86 2.46; P = .16), but the difference was not statistically significant. The colorectal cancer incidence was higher for participants with a history of colon polyp removal in the estrogen-alone group (0.23% vs 0.02%; HR, 13.47; nominal 95% CI, 1.76-103.0; P < .001). CONCLUSIONS: The use of estrogen alone in postmenopausal women with prior hysterectomy does not influence the incidence of colorectal cancer or deaths from or after colorectal cancer. A possibly higher risk of colorectal cancer in women with prior colon polyp removal who use estrogen alone requires confirmation. PMID- 26036211 TI - Identification and expression of SRF targeted by miR-133a during early development of Paralichthys olivaceus. AB - Serum response factor (SRF) is a MADS-box transcription factor that regulates the expression of genes involved in development, metabolism, cell proliferation, and differentiation. In the present study, we cloned the full-length SRF cDNA which includes the coding region of 1503 bp, a 573-bp 5'untranslated region (UTR) and a 400-bp 3'-UTR. The deduced 501 amino acid sequence of the SRF protein contained a MADS domain and NLS at the N terminus, similar to other organisms, and it also is highly phylogenetically conserved. SRF mRNA is ubiquitously expressed in various tissues, with the highest level in the kidneys, and it is also highly expressed during the embryonic and metamorphic stages. During metamorphosis, the SRF mRNA levels are down-regulated by exogenous thyroid hormone (TH) at 17 dph and by thiourea (TU) at 29, 36, and 41 dph, whereas SRF mRNA levels were significantly up-regulated by the added exogenous TH to the TU-treated larvae at 41 dph, which indicates that thyroid hormone is essential for expression of SRF mRNA, so, higher levels of TH did not result in changes of SRF mRNA levels, while TH deficiency or inhibited by the non-specific TU toxicity cause down-regulation of SRF mRNA, which indicated that TH can indirectly affect the SRF mRNA levels. Meanwhile, using a luciferase reporter assay, we verified that SRF is a common target gene of miR-133a which is a muscle-specific microRNA (miRNA), which indicated that SRF may be involved in the signaling pathway of miRNA that regulates muscle development. PMID- 26036213 TI - BlastNeuron for Automated Comparison, Retrieval and Clustering of 3D Neuron Morphologies. AB - Characterizing the identity and types of neurons in the brain, as well as their associated function, requires a means of quantifying and comparing 3D neuron morphology. Presently, neuron comparison methods are based on statistics from neuronal morphology such as size and number of branches, which are not fully suitable for detecting local similarities and differences in the detailed structure. We developed BlastNeuron to compare neurons in terms of their global appearance, detailed arborization patterns, and topological similarity. BlastNeuron first compares and clusters 3D neuron reconstructions based on global morphology features and moment invariants, independent of their orientations, sizes, level of reconstruction and other variations. Subsequently, BlastNeuron performs local alignment between any pair of retrieved neurons via a tree topology driven dynamic programming method. A 3D correspondence map can thus be generated at the resolution of single reconstruction nodes. We applied BlastNeuron to three datasets: (1) 10,000+ neuron reconstructions from a public morphology database, (2) 681 newly and manually reconstructed neurons, and (3) neurons reconstructions produced using several independent reconstruction methods. Our approach was able to accurately and efficiently retrieve morphologically and functionally similar neuron structures from large morphology database, identify the local common structures, and find clusters of neurons that share similarities in both morphology and molecular profiles. PMID- 26036214 TI - Corifollitropin alfa compared to daily FSH in controlled ovarian stimulation for in vitro fertilization: a meta-analysis. AB - The present study offers a meta-analysis of published randomized controlled trials (RCTs) evaluating the outcomes of in vitro fertilization (IVF) cycles using corifollitropin alfa for controlled ovarian stimulation (COS) in comparison with daily recombinant FSH (rFSH). The study examined seven RCTs including 2138 patients receiving corifollitropin alfa and 1788 women receiving daily rFSH for COS. As a novel aspect, this meta-analysis included two specific subpopulations of IVF patients, i.e. egg donors and poor responders. There were no significant differences between corifollitropin alfa and rFSH with respect to the majority of the clinical parameters considered, and comparable were the outcomes in terms of live birth rate, ongoing pregnancy rate, and clinical pregnancy rate. Women receiving corifollitropin alfa had a significantly higher number of metaphase II oocytes at ovum pick-up, and number of formed embryos, in comparison to rFSH. The risk of cycle cancellation due to overstimulation was significantly higher in the corifollitropin alfa group. Ovarian hyperstimulation syndrome (OHSS) incidence was statistically comparable between patients receiving long lasting or daily rFSH. Nevertheless, in view of the fact that corifollitropin alfa resulted in a higher number of metaphase II oocytes collected and a higher number of cycles cancelled due to overstimulation, corifollitropin alfa should be cautiously considered in women with the potential of being hyper responders. PMID- 26036215 TI - Titanium migration driven by Li vacancies in Li(1-x)Ti2O4 spinel. AB - Gentle oxidation of lithium titanate spinel (LiTi2O4) with water at room temperature gives Li-deficient Li0.33Ti2O4. Combined X-ray and neutron Rietveld analysis shows that 28% of the Ti cations are displaced to alternative octahedral sites, in keeping with a proposed model based on Ti-migration limited by Li vacancy concentration. PMID- 26036217 TI - Isotope-Filtered 4D NMR Spectroscopy for Structure Determination of Humic Substances. AB - Humic substances, the main component of soil organic matter, could form an integral part of green and sustainable solutions to the soil fertility problem. However, their global-scale application is hindered from both scientific and regulatory perspectives by the lack of understanding of the molecular make-up of these chromatographically inseparable mixtures containing thousands of molecules. Here we show how multidimensional NMR spectroscopy of isotopically tagged molecules enables structure characterization of humic compounds. We illustrate this approach by identifying major substitution patterns of phenolic aromatic moieties of a peat soil fulvic acid, an operational fraction of humic substances. Our methodology represents a paradigm shift in the use of NMR active tags in structure determination of small molecules in complex mixtures. Unlike previous tagging methodologies that focused on the signals of the tags, we utilize tags to directly probe the identity of the molecules they are attached to. PMID- 26036218 TI - Genotypes at rs2844682 and rs3909184 have no clinical value in identifying HLA B*15:02 carriers. PMID- 26036219 TI - Competitive apnea diving sessions induces an adaptative antioxidant response in mononucleated blood cells. AB - The aim was evaluating the effects of hypoxia/reoxygenation repetitive episodes during 5 days of apnea diving (3-day training/2-day competition) on peripheral blood mononuclear cells (PBMCs) antioxidant defenses, oxidative damage, and plasma xanthine oxidase activity. Blood samples, from seven professional apnea divers, were taken under basal conditions the previous morning to the first training session (pre-diving basal), 4 h after ending the competition (4 h post diving) and the following morning (15 h after last dive) in basal conditions (post-diving basal). Glucose levels significantly decreased whereas triglycerides increased at 4 h post-diving, both returning to basal values at post-diving basal. Glutathione reductase and catalase activity significantly increased after 4 h post-diving remaining elevated at post-diving basal. Glutathione peroxidase and superoxide dismutase activities and catalase protein levels progressively increased after diving with significant differences respect to initial values at post-diving basal. No significant differences were observed in circulating PBMCs and oxidative damage markers. Plasma xanthine oxidase activity and nitrite levels, but not the inducible nitric oxide synthetase, significantly increased 4 h post-diving, returning to the basal values after 15 h. In conclusion, chronic and repetitive episodes of diving apnea during five consecutive days increased plasma xanthine oxidase activity and nitric oxide production which could enhance the signalling role of reactive oxygen and nitrogen species for PBMCs antioxidant adaptation against hypoxia/reoxygenation. PMID- 26036220 TI - S-resistin, a non secretable resistin isoform, impairs the insulin signalling pathway in 3T3-L1 adipocytes. AB - S-resistin is a non-secretable resistin spliced variant, which is expressed mainly in the white adipose tissue from Wistar rats. Previous results confirmed that 3T3-L1 cells expressing s-resistin (3T3-L1-s-res) showed an inflammatory response and exhibited a decrease in glucose transport, both basal and insulin stimulated. Here we present evidences demonstrating for the first time that s resistin, like resistin, blocks insulin signalling pathway by inhibiting insulin receptor, insulin receptor substrate 1, protein kinase B/Akt and the mammalian target of rapamycin phosphorylation, and increasing the suppressor of cytokine signalling 3 levels being the later probably due to augmented of leptin expression. Thus, our data suggest that s-resistin could act by a still unknown intracrine pathway as an intracellular sensor, regulating the adipocyte insulin sensitivity. PMID- 26036221 TI - Single-incision laparoscopic cholecystectomy versus traditional laparoscopic cholecystectomy performed by a single surgeon: findings of a randomized trial. AB - PURPOSES: Traditional laparoscopic cholecystectomy (TLC) is performed widely; however, single-incision cholecystectomy (SILC) has been proposed as a better and less traumatic procedure. METHODS: In this prospective, double-blinded, randomized study, patients were randomized to undergo either elective SILC or TLC. The primary endpoint was the level of pain after surgery and the secondary endpoints were complications, cosmetic outcomes, and patient satisfaction. RESULTS: A total of 59 patients were enrolled (SILC, n = 30; TLC, n = 29). The median operative time was longer for the SILC group (55 vs. 40 min; P < 0.0001). Patients in the SILC group had a lower median VAS pain score 4 h after surgery (20 mm for the TLC group vs. 15 mm for the SILC group). Complications were distributed equally. Twenty-eight of the 30 patients in the SILC group vs. 23 of the 29 patients in the TLC group were very satisfied with their operation (P = 0.032). The cosmetic results of SILC were better than those of TLC, with visible scars in 21 patients from the TLC group vs. 3 patients from the SILC group (P = 0.0001). CONCLUSIONS: We found SILC to be a safe, feasible, and adaptable surgical technique. The pain scores at 4 h were significantly better for SILC than for TLC. PMID- 26036222 TI - Surgical intervention strategy for postoperative chylothorax after lung resection. AB - PURPOSE: The optimal surgical management of postoperative chylothorax has not been established. Thus, we evaluated the treatment strategy for postoperative chylothorax and identified associated predictors of surgical intervention. METHODS: The subjects of this retrospective study were 50 patients who suffered postoperative chylothorax, representing 4 % of 1235 patients who underwent pulmonary resection between 2008 and 2012. The chylothorax patients were classified into two groups based on their postoperative management: a conservative group and a surgical group. The following parameters were investigated to establish the predictors of surgical intervention for chylothorax: mode of surgery, preoperative complications, intraoperative management, and postoperative clinical status. RESULTS: Forty-one (82 %) patients were treated conservatively and 9 (18 %) underwent reoperation, as direct or concomitant ligation of the thoracic duct at the point of leakage. The frequency of postoperative chest tube drainage just after initial surgery was significantly greater in the surgical group than the conservative group before oral intake was restarted (448 +/- 189 vs. 296 +/- 117 ml/12 h, respectively; p = 0.003). Furthermore, it was a significant predictor of reoperation based on a multivariate analysis (p = 0.010). CONCLUSIONS: The amount of chest tube drainage just after surgery and before oral intake was a useful predictor to help us decide on the need for early surgical intervention for postoperative chylothorax. PMID- 26036224 TI - In vitro combinations containing Tegobuvir are highly efficient in curing cells from HCV replicon and in delaying/preventing the development of drug resistance. AB - Tegobuvir (GS-9190) is a non-nucleoside inhibitor of HCV RNA replication with proven antiviral activity in HCV-infected patients. The in vitro antiviral activity of Tegobuvir, when combined with one or two other direct acting antivirals (DAA) was assessed. When Tegobuvir was combined with either interferon alpha-2b, ribavirin, the protease inhibitor (PI) VX-950, the nucleoside polymerase inhibitor (NI) 2'-C-methylcytidine or various non-nucleoside polymerase inhibitors, an overall additive antiviral activity was observed. Adding Tegobuvir (at concentrations of 6, 30 or 150nM) to replicon-containing cells in the presence of suboptimal concentrations of the PI or of the various polymerase inhibitors either markedly delayed or completely prevented resistance development against these latter compounds. Tegobuvir (15nM), when combined with the PI, was able to cure replicon-containing cells from their replicon after a single passage, whereas either compound alone (at 2-fold higher concentration) was not. The triple combination of Tegobuvir (10nM), the PI and the NI resulted in clearance of replicon RNA after only two passages. In contrast, the inhibitors when used alone at 3-fold higher concentrations were not able to cure the cells from the replicon, after as long as 6 passages. Combinations containing low concentrations of Tegobuvir are thus highly effective in curing cells from HCV replicon and in delaying or preventing the development of resistance against other DAA. PMID- 26036225 TI - Correction: Atomic layer deposition of a MoS2 film. AB - Correction for 'Atomic layer deposition of a MoS2 film' by Lee Kheng Tan et al., Nanoscale, 2014, 6, 10584-10588. PMID- 26036226 TI - Is laboratory medicine ready for the era of personalized medicine? A survey addressed to laboratory directors of hospitals/academic schools of medicine in Europe. AB - Developments in "-omics" are creating a paradigm shift in laboratory medicine leading to personalized medicine. This allows the increase in diagnostics and therapeutics focused on individuals rather than populations. In order to investigate whether laboratory medicine is ready to play a key role in the integration of personalized medicine in routine health care and set the state-of the-art knowledge about personalized medicine and laboratory medicine in Europe, a questionnaire was constructed under the auspices of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the European Society of Pharmacogenomics and Personalised Therapy (ESPT). The answers of the participating laboratory medicine professionals indicate that they are aware that personalized medicine can represent a new and promising health model, and that laboratory medicine should play a key role in supporting the implementation of personalized medicine in the clinical setting. Participants think that the current organization of laboratory medicine needs additional/relevant implementations such as (i) new technological facilities in -omics; (ii) additional training for the current personnel focused on the new methodologies; (iii) incorporation in the laboratory of new competencies in data interpretation and counseling; and (iv) cooperation and collaboration among professionals of different disciplines to integrate information according to a personalized medicine approach. PMID- 26036223 TI - Neutrophil/lymphocyte ratio predicts the prognosis in esophageal squamous cell carcinoma patients. AB - PURPOSE: As cancer advances, changes in the systemic inflammatory response alter the relative levels of circulating white blood cell types and may contribute to the progression and outcomes of cancer. The aim of the current study is to clarify the impact of the preoperative neutrophil/lymphocyte ratio (NLR) on the prognosis and whether clinical and pathological features modify the influence of the NLR on the prognosis of esophageal squamous cell carcinoma (ESCC) patients. METHODS: We retrospectively analyzed the mortality hazard ratios (HRs), including the preoperative NLR, obtained from data for 283 ESCC patients undergoing resection in the period from 2005 to 2011, adjusting for clinical and pathological features. RESULTS: A high NLR was associated with a significantly shorter overall survival (p = 0.0018) and cancer-specific survival (p = 0.0097). In the multivariate Cox model, we confirmed that the NLR was an independent prognostic marker for both overall survival (p = 0.0081) and cancer-specific survival (p = 0.028). The outcomes were not significantly modified by other diagnostic factors, including the tumor stage, in the survival analysis. CONCLUSIONS: The preoperative NLR is significantly associated with a poor prognosis in patients with ESCC, suggesting the utility of NLR as a cost effective and broadly available independent prognostic marker of ESCC. PMID- 26036227 TI - Beyond hemostasis: the challenge of treating plasminogen deficiency. A report of three cases. AB - Congenital plasminogen deficiency is a rare autosomal recessive disorder, characterized by chronic mucosal membranous lesions. Although the most common clinical manifestation is eye involvement as ligneous conjunctivitis, extra ocular lesions affecting other mucosal surfaces indicates a systemic disease. In this report we describe two cases with atypical extra-ocular involvement that includes pericarditis and recurrent hematocolpos, and one with paradoxical correlation between ocular lesions and plasminogen levels. In ligneous conjunctivitis, although different treatment strategies have been tried with mild success, the only effective therapy is topical or systemic plasminogen concentrates that are not commercially available. Unfortunately there is not either effective management for cases with multisystemic disease. Hence, treatment for plasminogen deficiency is still a challenge and the variability of the clinical spectrum in this pathology makes necessary a multidisciplinary approach. PMID- 26036228 TI - Preoperative INR and postoperative major bleeding and mortality: A retrospective cohort study. AB - Little research has been done on the current cut-off international normalized ratio (INR) value of 1.5 for patients undergoing surgery. The objectives of this study are to assess the association between INR and postoperative major bleeding and mortality in patients undergoing surgery and to identify an ideal pre operative INR for surgical patients. We analyzed data from the American College of Surgeons' National Surgical Quality Improvement Program database between 2008 and 2011 (636,231 patients). The primary outcomes were major bleeding and mortality at 30 days postoperatively. Multivariate logistic regression analyses were carried out to assess these associations. Compared to an INR of <1, the adjusted odds ratio (aOR) for major bleeding was 1.22 (95 % CI 1.18-1.25) for INR 1-1.49, 1.48 (95 % CI 1.40-1.56) for INR 1.5-1.9, and 1.49 (95 % CI 1.39-1.60) for INR >=2. The aOR for mortality at 30 days post-operation compared to INR of <1 was 1.51 (95 % CI 1.41-1.62), 2.31 (95 % CI 2.12-2.52), and 2.81 (95 % CI 2.56 3.10) for INR 1-1.49, 1.5-1.9, and >=2, respectively. The ideal pre-operative INR value to predict an increased risk for major bleeding was 1.10 and 1.13 for mortality. In conclusion, preoperative INR is significantly and independently associated with postoperative major bleeding and mortality. PMID- 26036229 TI - Consequences of treating false positive heparin-induced thrombocytopenia. AB - Identification of patients with heparin-induced thrombocytopenia is encumbered by false positive enzyme-linked immuno assay (ELISA) antibody results, therefore a serotonin release assay (SRA) is used for confirmation. Recently, several studies have demonstrated that increasing the optical density (OD) threshold (currently at 0.4) of the antibody test enhances the positive predictive value. The purpose of this study was to determine the frequency of patients who were ELISA antibody positive but SRA negative, and the costs and bleeding events associated with alternative anticoagulant treatment. We hypothesized that treating patients with a positive ELISA antibody OD value of <1.0 would result in increased cost and bleeding risk. This retrospective chart review was conducted on adult hospitalized patients from 2011 to 2013. Patients with positive ELISA antibodies (OD of 0.4-1.0) and an SRA result were included. Eighty-five patients were identified with positive antibodies (average OD of 0.66), 100 % of which were found to be SRA negative. A total of 59 patients (69 %) received alternative anticoagulants. The average duration of treatment was 3.1 days, and 4 patients (4.7 %) experienced a bleeding event. The cost of testing and laboratory monitoring was $36,346 and the cost of the alternative anticoagulants totaled $47,179. The total cost was $83,525, with an average total cost per patient of $982. This study adds to the body of literature suggesting treatment should only be initiated if the OD is one or greater. The high false positive rate caused increased cost and some bleeding events. PMID- 26036230 TI - Tuning the threshold voltage of MoS2 field-effect transistors via surface treatment. AB - Controlling the threshold voltage (Vth) of a field-effect transistor is important for realizing robust logic circuits. Here, we report a facile approach to achieve bidirectional Vth tuning of molybdenum disulfide (MoS2) field-effect transistors. By increasing and decreasing the amount of sulfur vacancies in the MoS2 surface, the Vth of MoS2 transistors can be left- and right-shifted, respectively. Transistors fabricated on perfect MoS2 flakes are found to exhibit a two-fold enhancement in mobility and a very positive Vth (18.5 +/- 7.5 V). More importantly, our elegant hydrogen treatment is able to tune the large Vth to a small value (~0 V) without any performance degradation simply by reducing the atomic ratio of S : Mo slightly; in other words, it creates a certain amount of sulfur vacancies in the MoS2 surface, which generate defect states in the band gap of MoS2 that mediates conduction of a MoS2 transistor in the subthreshold regime. First-principles calculations further indicate that the defect band's edge and width can be tuned according to the vacancy density. This work not only demonstrates for the first time the ease of tuning the Vth of MoS2 transistors, but also offers a process technology solution that is critical for further development of MoS2 as a mainstream electronic material. PMID- 26036231 TI - In situ molecular elucidation of drug supersaturation achieved by nano-sizing and amorphization of poorly water-soluble drug. AB - Quantitative evaluation of drug supersaturation and nanoparticle formation was conducted using in situ evaluation techniques, including nuclear magnetic resonance (NMR) spectroscopy. We prepared a ternary complex of carbamazepine (CBZ) with hydroxypropyl methylcellulose (HPMC) and sodium dodecyl sulfate (SDS) to improve the drug concentration. Different preparation methods, including grinding and spray drying, were performed to prepare the ternary component products, ground mixture (GM) and spray-dried sample (SD), respectively. Although CBZ was completely amorphized in the ternary SD, CBZ was partially amorphized with the remaining CBZ crystals in the ternary GM. Aqueous dispersion of the ternary GM formed nanoparticles of around 150 nm, originating from the CBZ crystals in the ternary GM. In contrast, the ternary SD formed transparent solutions without a precipitate. The molecular-level evaluation using NMR measurements revealed that approximately half a dose of CBZ in the ternary GM dispersion was present as nanoparticles; however, CBZ in the ternary SD was completely dissolved in the aqueous solution. The characteristic difference between the solid states, followed by different preparation methods, induced different solution characteristics in the ternary GM and SD. The permeation study, using a dialysis membrane, showed that the CBZ concentration dissolved in the bulk water phase rapidly reduced in the ternary SD dispersion compared to the ternary GM dispersion; this demonstrated the advantage of ternary GM dispersion in the maintenance of CBZ supersaturation. Long-term maintenance of a supersaturated state of CBZ observed in the ternary GM dispersion rather than in the ternary SD dispersion was achieved by the inhibition of CBZ crystallization owing to the existence of CBZ nanoparticles in the ternary GM dispersion. Nanoparticle formation, combined with drug amorphization, could be a promising approach to improve drug concentrations. The detailed elucidation of solution characteristics using in situ evaluation techniques will lead to the formation of useful solid dispersion and nanoparticle formulations, resulting in improved drug absorption. PMID- 26036232 TI - Potential metal impurities in active pharmaceutical substances and finished medicinal products - A market surveillance study. AB - A market surveillance study has been established by using different atomic spectrometric methods for the determination of selected elemental impurities of particular interest, to gain an overview about the quality of presently marketed drug products and their bulk drug substances. The limit tests were carried out with respect to the existing EMA guideline on the specification limits for residuals of metal catalysts or metal reagents. Also attention was given to the future implementation of two new chapters of the United States Pharmacopoeia (USP) stating limit concentrations of elemental impurities. The methods used for determination of metal residues were inductively coupled plasma-mass spectrometry (ICP-MS), inductively coupled plasma-optical emission spectrometry (ICP-OES), and atomic absorption spectrometry technologies (GFAAS, CVAAS, HGAAS). This article presents the development and validation of the methods used for the determination of 21 selected metals in 113 samples from drug products and their active pharmaceutical ingredients. PMID- 26036233 TI - Development of (153) Sm-folate-polyethyleneimine-conjugated chitosan nanoparticles for targeted therapy. AB - The aim of this study was to develop biocompatible, water-soluble (153) Sm labeled chitosan nanoparticles (NPs) containing folate and polyethyleneimine functionalities i.e. chitosan-graft-PEI-folate (CHI-DTPA-g-PEI-FA), suitable for targeted therapy. The physicochemical properties of the obtained NPs were characterized by dynamic light-scattering analysis for their mean size, size distribution, and zeta potential; scanning electron microscopy for surface morphology; and (1) H-NMR, FT-IR analyses for molecular dispersity of folate in the NPs. NPs were spherical with mean diameter below 250 nm, polydispersity of below 0.15, and positive zeta potential values. The NP complex ((153) Sm-CHI-DTPA g-PEI-FA) was stable at 25 degrees C (6-8 h, >90% radiochemical purity, instant thin layer chromatography (ITLC)). Binding studies using fluorescent NPs for internalization also demonstrated significant uptake in MCF-7 cells. MCF-7 cell internalization was significantly greater for 4T1. In blocking studies, both MCF 7 and 4T1 cell lines demonstrated specific folate receptor (FR) binding (decreasing 45%). In vivo biodistribution studies indicated major excretion of NPs metabolites and/or free (153) Sm through the kidneys. The preliminary imaging studies in 4T1 tumor-bearing mice showed minor uptake up to 96 h. The present folic acid that functionalized chitosan NP is a candidate material for folate receptor therapy. PMID- 26036234 TI - Glycan biomarker discovery. PMID- 26036239 TI - Reply to Fiorelli et al. PMID- 26036240 TI - Management of postoperative pain as part of a successful multidisciplinary lung volume reduction surgery programme. PMID- 26036241 TI - Fangjiomics: revealing adaptive omics pharmacological mechanisms of the myriad combination therapies to achieve personalized medicine. PMID- 26036242 TI - Facile Self-Assembly of Quantum Plasmonic Circuit Components. AB - A facile and cost-effective self-assembly route to engineering of vital quantum plasmonic circuit components is reported. By modifying the surface energy of silver nanowires, the position and density of attached nanodiamonds can be maneuvered leading to silver nanowire/nanodiamond(s) hybrid nanostructures. These structures exhibit strong plasmonic coupling effects and thus hold promise to serve as quantum plasmonic components. PMID- 26036243 TI - Tetranuclear Uranyl Polyrotaxanes: Preferred Selectivity toward Uranyl Tetramer for Stabilizing a Flexible Polyrotaxane Chain Exhibiting Weakened Supramolecular Inclusion. AB - Introduction of mechanically interlocked components into actinide-based metal organic materials such as polyrotaxanes will generate an entirely new type of inorganic-organic hybrid materials showing more supramolecular encapsulation based dynamics. In this work, tetranuclear uranyl-directed polyrotaxanes (UO2 )4 O2 -C5A3-CB6 (1) and (UO2 )4 O2 -C6A3-CB6 (2), which are the first actinide pseudorotaxanes with high-nuclearity uranium centers, were obtained through systematic extension of the string spacer in pseudorotaxane ligands from 1,4 butylene (C4) to 1,5-pentylene (C5) and 1,6-hexylene (C6). Both of the as synthesized tetranuclear uranyl polyrotaxanes were structurally characterized and analyzed. Considering the structure of UO2 -C4A3-CB6 and the 1,4-butylene string spacer, the preference for the uranyl tetramer may be related to the configurational inversion of the pseudorotaxane ligands from trans mode to cis mode on coordination to the uranyl center. Detailed structural analysis suggests that the length of the stretched string molecules for CB6-encapsulated pseudorotaxanes has remarkable effect on the supramolecular inclusion interactions and the configurations of pseudorotaxanes, and should be responsible for the configurational inversion of pseudorotaxane spacers and subsequent distinct changes of the uranyl building units and geometric structures. PMID- 26036244 TI - Multivariate Analysis of Combined Fourier Transform Near-Infrared Spectrometry (FT-NIR) and Raman Datasets for Improved Discrimination of Drying Oils. AB - This work explores the application of chemometric techniques to the analysis of lipidic paint binders (i.e., drying oils) by means of Raman and near-infrared spectroscopy. These binders have been widely used by artists throughout history, both individually and in mixtures. We prepared various model samples of the pure binders (linseed, poppy seed, and walnut oils) obtained from different manufacturers. These model samples were left to dry and then characterized by Raman and reflectance near-infrared spectroscopy. Multivariate analysis was performed by applying principal component analysis (PCA) on the first derivative of the corresponding Raman spectra (1800-750 cm(-1)), near-infrared spectra (6000 3900 cm(-1)), and their combination to test whether spectral differences could enable samples to be distinguished on the basis of their composition. The vibrational bands we found most useful to discriminate between the different products we studied are the fundamental nu(C=C) stretching and methylenic stretching and bending combination bands. The results of the multivariate analysis demonstrated the potential of chemometric approaches for characterizing and identifying drying oils, and also for gaining a deeper insight into the aging process. Comparison with high-performance liquid chromatography data was conducted to check the PCA results. PMID- 26036245 TI - Integrative taxonomic approach to the cryptic diversity of Diplostomum spp. in lymnaeid snails from Europe with a focus on the 'Diplostomum mergi' species complex. AB - BACKGROUND: Recent molecular studies have discovered substantial unrecognised diversity within the genus Diplostomum in fish populations in Europe and North America including three species complexes. However, data from the first intermediate host populations are virtually lacking. This study addresses the application of an integrative taxonomic approach to the cryptic species diversity of Diplostomum spp. in natural lymnaeid snail populations in Europe with a focus on the 'D. mergi' species complex. METHODS: Totals of 1,909 Radix auricularia, 349 Radix peregra, 668 Stagnicola palustris and 245 Lymnaea stagnalis were sampled at five reservoirs of the Ruhr river system in Germany and screened for infections with Diplostomum spp. Cercariae were examined and identified alive, fixed and under scanning electron microscopy. Sequences from the barcode region of the cytochrome c oxidase subunit 1 (cox1) mitochondrial gene and from the internal transcribed spacer cluster (ITS1-5.8S-ITS2) of the rRNA gene were amplified for 51 and 13 isolates, respectively. RESULTS: Detailed morphological and molecular analyses provided evidence for three named species (Diplostomum spathaceum, D. pseudospathaceum and D. parviventosum), and a further four species level lineages ('D. mergi Lineages 2-4' and 'Diplostomum sp. Clade Q' in the lymnaeid snail populations from the Ruhr river basin. The paper provides the first descriptions of molecularly identified cercariae of D. spathaceum and of the cercariae of D. parviventosum, three lineages of the 'D. mergi' species complex and of 'Diplostomum sp. Clade Q'. CONCLUSION: The integration of molecular and morphological evidence for Diplostomum spp. achieved in this study will serve as a baseline for species identification of these important parasites of snail and fish populations and thus advance further studies on the distribution of Diplostomum spp. in Europe. PMID- 26036246 TI - Benefits of polidocanol endovenous microfoam (Varithena(r)) compared with physician-compounded foams. AB - OBJECTIVE: To compare foam bubble size and bubble size distribution, stability, and degradation rate of commercially available polidocanol endovenous microfoam (Varithena(r)) and physician-compounded foams using a number of laboratory tests. METHODS: Foam properties of polidocanol endovenous microfoam and physician compounded foams were measured and compared using a glass-plate method and a Sympatec QICPIC image analysis method to measure bubble size and bubble size distribution, TurbiscanTM LAB for foam half time and drainage and a novel biomimetic vein model to measure foam stability. Physician-compounded foams composed of polidocanol and room air, CO2, or mixtures of oxygen and carbon dioxide (O2:CO2) were generated by different methods. RESULTS: Polidocanol endovenous microfoam was found to have a narrow bubble size distribution with no large (>500 um) bubbles. Physician-compounded foams made with the Tessari method had broader bubble size distribution and large bubbles, which have an impact on foam stability. Polidocanol endovenous microfoam had a lower degradation rate than any physician-compounded foams, including foams made using room air (p < 0.035). The same result was obtained at different liquid to gas ratios (1:4 and 1:7) for physician-compounded foams. In all tests performed, CO2 foams were the least stable and different O2:CO2 mixtures had intermediate performance. In the biomimetic vein model, polidocanol endovenous microfoam had the slowest degradation rate and longest calculated dwell time, which represents the length of time the foam is in contact with the vein, almost twice that of physician compounded foams using room air and eight times better than physician-compounded foams prepared using equivalent gas mixes. CONCLUSION: Bubble size, bubble size distribution and stability of various sclerosing foam formulations show that polidocanol endovenous microfoam results in better overall performance compared with physician-compounded foams. Polidocanol endovenous microfoam offers better stability and cohesive properties in a biomimetic vein model compared to physician-compounded foams. Polidocanol endovenous microfoam, which is indicated in the United States for treatment of great saphenous vein system incompetence, provides clinicians with a consistent product with enhanced handling properties. PMID- 26036247 TI - Pharmacological adjuncts for chronic venous ulcer healing: a systematic review. AB - BACKGROUND: The aim of this study was to systematically review the current evidence and determine whether there is a clinical benefit for using pharmacological agents as adjunctive treatment for chronic venous ulcers. METHOD: A systematic review of the MEDLINE and EMBASE (from 1 January 1947 through 15 August 2013) and Cochrane databases (from inception through 15 August 2013) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria were all randomised controlled trials investigating pharmacological adjuncts for the treatment of venous ulcers with a minimum sample size of 20 patients for each treatment arm. RESULTS: Ten relevant articles were identified; one pilot randomised controlled trial and four Cochrane reviews were included. Pentoxifylline, aspirin, sulodexide, mesoglycan, flavonoids, thromboxane A2 antagonist (ifetroban), zinc, prostaglandin and prostacyclin analogues were the drugs reviewed. Pentoxifylline was found to be more effective than placebo in terms of complete ulcer healing or in causing a significant improvement (greater than 60% reduction in ulcer size) (RR 1.70, 95% CI 1.30 to 2.24). Aspirin and flavonoids show potential to be effective adjuncts but methodological shortcomings and issues with bias limit the validity of results from trials involving each of these drugs, respectively. There was no significant difference between placebo and Ifetroban and likewise pooled results from trials investigating sulodexide and zinc showed no benefit in comparison to placebo. CONCLUSION: Many systemic pharmacological agents have been investigated as adjuncts to venous ulcer healing; however, pentoxifylline (400 mg, three times a day) is currently the only drug that has promising evidence to support its use. Other compounds are in early stage research. PMID- 26036248 TI - The influence of age and gender on venous symptomatology. An epidemiological survey in Belgium and Luxembourg. AB - AIM: The aim of this study is to measure the incidence of the symptoms in patients with chronic venous disease (CVD) and to look for the influence of age on the severity of symptoms for both genders. MATERIALS AND METHODS: A survey was carried out in Belgium and Luxembourg between May and September 2013. Patient recruitment was done by 406 general practitioners (GPs). Each GP screened 10-20 consecutive patients older than 18 years. Inquiries were made regarding the presence of symptoms and possible signs of CVD. Patients with diagnosed CVD filled out a questionnaire including a quality of life score (CIVIQ-14). These data were converted into a CIVIQ Global Index Score (GIS). Statistical analysis was performed in order to calculate the effect of age and gender on the number of symptoms and the estimated probabilities of having CVD. RESULTS: Totally 6009 patients were included in this survey. The mean age was 53.4 years. Of all, 61.3% of the patients have CVD (C1-C6). Of all, 64.7% of patients were symptomatic. Age and female gender were major risk factors for developing CVD. Most common symptoms were 'heavy legs' (70.4%), pain (54.0%), and sensation of swelling (52.7%). The number of symptoms increases with age (p < 0.001). Female patients have significantly more symptoms in comparison with male patients in all age groups. In both females and males, age is negatively correlated with GIS score (p < 0.001). The estimated probability of having CVD was significantly higher for woman compared to men and increases with age for both gender. CONCLUSION: CVD is a very common progressive disease with age as a major risk factor. Increasing age results in a higher C-classification, more symptoms, and a lower GIS score (quality of life). Female gender interacts significantly with age and results in a more advanced stage of CVD. PMID- 26036249 TI - Impact of CCSVI on cerebral haemodynamics: a mathematical study using MRI angiographic and flow data. AB - BACKGROUND: The presence of abnormal anatomy and flow in neck veins has been recently linked to neurological diseases. The precise impact of extra-cranial abnormalities such as stenoses remains unexplored. METHODS: Pressure and velocity fields in the full cardiovascular system are computed by means of a global mathematical model that accounts for the relationship between pulsating cerebral blood flow and intracranial pressure. RESULTS: Our model predicts that extra cranial strictures cause increased pressure in the cerebral venous system. Specifically, there is a predicted pressure increase of about 10% in patients with a 90% stenoses. Pressure increases are related to significant flow redistribution with flow reduction of up to 70% in stenosed vessels and consequent flow increase in collateral pathways. CONCLUSIONS: Extra-cranial venous strictures can lead to pressure increases in intra-cranial veins of up to 1.3 mmHg, despite the shielding role of the Starling resistor. The long-term clinical implications of the predicted pressure changes are unclear. PMID- 26036251 TI - Feeding practices in early life and later intake of fruit and vegetables among Japanese toddlers: the Osaka Maternal and Child Health Study. AB - OBJECTIVE: A growing body of evidence from Western countries shows that infant feeding practices are associated with later childhood dietary habits, but little is known about these relationships in non-Western countries with different food cultures. We examined the association of breast-feeding duration and age at introduction of solid foods with later intake of fruit and vegetables among Japanese toddlers. DESIGN: Information on breast-feeding duration, age at introduction of solid foods and child's intake frequency of fruit and vegetables were collected with a self-administered questionnaire at 16-24 months postpartum. Logistic regression analysis was used to calculate odds ratios of low intake (<1 time/d) of fruit or vegetables for each infant feeding practice. SETTING: Japan. SUBJECTS: Japanese mother-child pairs (n 763) from a prospective birth cohort study. RESULTS: Neither breast-feeding duration nor age at introduction of solid foods was associated with fruit intake at 16-24 months of age. Breast-feeding duration, but not age at introduction of solid foods, was associated with later intake of vegetables. When breast-feeding duration was categorized into two groups with the cut-off at 6 months, children who were breast-fed for >=6 months had a significantly decreased risk of low intake of vegetables (OR=0.53; 95% CI 0.34, 0.84) than those breast-fed for <6 months. This association was independent of potential confounders including maternal education and maternal vegetable intake (OR=0.59; 95% CI 0.36, 0.97). CONCLUSIONS: This finding suggests that >=6 months of breast-feeding may prevent low intake of vegetables in early childhood among Japanese toddlers. PMID- 26036252 TI - The Elegant Simplicity of the Liverwort Marchantia polymorpha. PMID- 26036250 TI - Characterization of bursa subacromialis-derived mesenchymal stem cells. AB - INTRODUCTION: The bursa subacromialis (BS) provides the gliding mechanism of the shoulder and regenerates itself after surgical removal. Therefore, we explored the presence of mesenchymal stem cells (MSCs) within the human adult BS tissue and characterized the BS cells compared to MSCs from bone marrow (BMSCs) on a molecular level. METHODS: BS cells were isolated by collagenase digest from BS tissues derived from patients with degenerative rotator cuff tears, and BMSCs were recovered by adherent culture from bone-marrow of patients with osteoarthritis of the hip. BS cells and BMSCs were compared upon their potential to proliferate and differentiate along chondrogenic, osteogenic and adipogenic lineages under specific culture conditions. Expression profiles of markers associated with mesenchymal phenotypes were comparatively evaluated by flow cytometry, immunohistochemistry, and whole genome array analyses. RESULTS: BS cells and BMSCs appeared mainly fibroblastic and revealed almost similar surface antigen expression profiles, which was CD44(+), CD73(+), CD90(+), CD105(+), CD106(+), STRO-1(+), CD14(-), CD31(-), CD34(-), CD45(-), CD144(-). Array analyses revealed 1969 genes upregulated and 1184 genes downregulated in BS cells vs. BMSCs, indicating a high level of transcriptome similarity. After 3 weeks of differentiation culture, BS cells and BMSCs showed a similar strong chondrogenic, adipogenic and osteogenic potential, as shown by histological, immunohistochemical and RT-PCR analyses in contrast to the respective negative controls. CONCLUSIONS: Our in vitro characterizations show that BS cells fulfill all characteristics of mesenchymal stem cells, and therefore merit further attention for the development of improved therapies for various shoulder pathologies. PMID- 26036253 TI - Dynamic Changes in ANGUSTIFOLIA3 Complex Composition Reveal a Growth Regulatory Mechanism in the Maize Leaf. AB - Most molecular processes during plant development occur with a particular spatio temporal specificity. Thus far, it has remained technically challenging to capture dynamic protein-protein interactions within a growing organ, where the interplay between cell division and cell expansion is instrumental. Here, we combined high-resolution sampling of the growing maize (Zea mays) leaf with tandem affinity purification followed by mass spectrometry. Our results indicate that the growth-regulating SWI/SNF chromatin remodeling complex associated with ANGUSTIFOLIA3 (AN3) was conserved within growing organs and between dicots and monocots. Moreover, we were able to demonstrate the dynamics of the AN3 interacting proteins within the growing leaf, since copurified GROWTH-REGULATING FACTORs (GRFs) varied throughout the growing leaf. Indeed, GRF1, GRF6, GRF7, GRF12, GRF15, and GRF17 were significantly enriched in the division zone of the growing leaf, while GRF4 and GRF10 levels were comparable between division zone and expansion zone in the growing leaf. These dynamics were also reflected at the mRNA and protein levels, indicating tight developmental regulation of the AN3 associated chromatin remodeling complex. In addition, the phenotypes of maize plants overexpressing miRNA396a-resistant GRF1 support a model proposing that distinct associations of the chromatin remodeling complex with specific GRFs tightly regulate the transition between cell division and cell expansion. Together, our data demonstrate that advancing from static to dynamic protein protein interaction analysis in a growing organ adds insights in how developmental switches are regulated. PMID- 26036255 TI - Retraction. PMID- 26036254 TI - Uncovering DELLA-Independent Gibberellin Responses by Characterizing New Tomato procera Mutants. AB - Gibberellin (GA) regulates plant development primarily by triggering the degradation/deactivation of the DELLA proteins. However, it remains unclear whether all GA responses are regulated by DELLAs. Tomato (Solanum lycopersicum) has a single DELLA gene named PROCERA (PRO), and its recessive pro allele exhibits constitutive GA activity but retains responsiveness to external GA. In the loss-of-function mutant pro(DeltaGRAS), all examined GA developmental responses were considerably enhanced relative to pro and a defect in seed desiccation tolerance was uncovered. As pro, but not pro(DeltaGRAS), elongation was promoted by GA treatment, pro may retain residual DELLA activity. In agreement with homeostatic feedback regulation of the GA biosynthetic pathway, we found that GA20oxidase1 expression was suppressed in pro(DeltaGRAS) and was not affected by exogenous GA3. In contrast, expression of GA2oxidase4 was not affected by the elevated GA signaling in pro(DeltaGRAS) but was strongly induced by exogenous GA3. Since a similar response was found in Arabidopsis thaliana plants with impaired activity of all five DELLA genes, we suggest that homeostatic GA responses are regulated by both DELLA-dependent and -independent pathways. Transcriptome analysis of GA-treated pro(DeltaGRAS) leaves suggests that 5% of all GA-regulated genes in tomato are DELLA independent. PMID- 26036257 TI - Flavor, relative palatability and components of cow's milk hydrolysed formulas and amino acid-based formula. AB - BACKGROUND: Both extensively hydrolysed formulas (eHF) and amino acid-based formula (AAFs) have been demonstrated effective for the treatment of CMA. However, in clinical practice, parents complain that hydrolysates are rejected by children due to their bad taste. Flavor of hydrolysed formulas has been poorly investigated although it affects the acceptance of milk over all the other attributes. The aim of the present study was to understand the factors underlying the unpleasant flavor of hydrolysed 25 formulas and amino acid-based formula. SUBJECTS AND METHODS: One hundred and fifty trained panelists performed a randomized-double-blind test with different milks. The smell, texture, taste and aftertaste of each formula were evaluated on a scale ranging from -2 (worst) to 2 (best). RESULTS: Formulas showed significant difference, as compared to cow's milk, in smell, texture, taste and aftertaste. Overall, whey eHFs were judged of better palatability than casein eHF and the AAFs (p < 0.05). Whey eHF showed significant differences among them for sensory attributes, especially for taste and aftertaste. CONCLUSIONS: These results suggest that a broad range of flavor exists among the hydrolysed formulas. Further studies, adequately designed to investigate the relationship between milks' flavor and nutrient profile of hydrolysed formulas are warranted. PMID- 26036256 TI - Auxin Produced by the Indole-3-Pyruvic Acid Pathway Regulates Development and Gemmae Dormancy in the Liverwort Marchantia polymorpha. AB - The plant hormone auxin (indole-3-acetic acid [IAA]) has previously been suggested to regulate diverse forms of dormancy in both seed plants and liverworts. Here, we use loss- and gain-of-function alleles for auxin synthesis- and signaling-related genes, as well as pharmacological approaches, to study how auxin regulates development and dormancy in the gametophyte generation of the liverwort Marchantia polymorpha. We found that M. polymorpha possess the smallest known toolkit for the indole-3-pyruvic acid (IPyA) pathway in any land plant and that this auxin synthesis pathway mainly is active in meristematic regions of the thallus. Previously a Trp-independent auxin synthesis pathway has been suggested to produce a majority of IAA in bryophytes. Our results indicate that the Trp dependent IPyA pathway produces IAA that is essential for proper development of the gametophyte thallus of M. polymorpha. Furthermore, we show that dormancy of gemmae is positively regulated by auxin synthesized by the IPyA pathway in the apex of the thallus. Our results indicate that auxin synthesis, transport, and signaling, in addition to its role in growth and development, have a critical role in regulation of gemmae dormancy in M. polymorpha. PMID- 26036258 TI - The SIRT1/TP53 axis is activated upon B-cell receptor triggering via miR-132 up regulation in chronic lymphocytic leukemia cells. AB - The B-cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). By global microRNA profiling of CLL cells stimulated or not stimulated by anti-IgM, significant up-regulation of microRNAs from the miR-132~212 cluster was observed both in IGHV gene unmutated (UM) and mutated (M) CLL cells. Parallel gene expression profiling identified SIRT1, a deacetylase targeting several proteins including TP53, among the top-ranked miR-132 target genes down-regulated upon anti-IgM exposure. The direct regulation of SIRT1 expression by miR-132 was demonstrated using luciferase assays. The reduction of SIRT1 mRNA and protein (P = 0.001) upon anti IgM stimulation was associated with an increase in TP53 acetylation (P = 0.007), and the parallel up-regulation of the TP53 target gene CDKN1A. Consistently, miR 132 transfections of CLL-like cells resulted in down-regulation of SIRT1 and an induction of a TP53-dependent apoptosis. Finally, in a series of 134 CLL samples, miR-132, when expressed above the median value, associated with prolonged time-to first-treatment in patients with M CLL (HR = 0.41; P = 0.02). Collectively, the miR-132/SIRT1/TP53 axis was identified as a novel pathway triggered by BCR engagement that further increases the complexity of the interactions between tumor microenvironments and CLL cells. PMID- 26036259 TI - Epigenetically downregulated Semaphorin 3E contributes to gastric cancer. AB - Axon guidance protein Semaphorin 3E (Sema3E) promotes tumor metastasis and suppresses tumor cell death. Here, we demonstrated that Sema3E was decreased in gastric cancer. Its levels were inversely associated with tumor progression. Levels of Sema3E were associated with low p300 and high class I histone deacetylase (class I HDAC). Ectopic expression of Sema3E inhibited proliferation and colony formation of gastric cancer cell lines in vitro and xenografts in vivo. Sema3E overexpression inhibited migration and invasion of gastric cancer cells, which was associated with induction of E-cadherin and reduction of Akt and ERK1/2 phosphorylation. We suggest that silencing of Sema3E contributes to the pathogenesis of gastric cancer. PMID- 26036260 TI - RhoE is required for contact inhibition and negatively regulates tumor initiation and progression. AB - RhoE is a small GTPase involved in the regulation of actin cytoskeleton dynamics, cell cycle and apoptosis. The role of RhoE in cancer is currently controversial, with reports of both oncogenic and tumor-suppressive functions for RhoE. Using RhoE-deficient mice, we show here that the absence of RhoE blunts contact inhibition of growth by inhibiting p27Kip1 nuclear translocation and cooperates in oncogenic transformation of mouse primary fibroblasts. Heterozygous RhoE+/gt mice are more susceptible to chemically induced skin tumors and RhoE knock-down results in increased metastatic potential of cancer cells. These results indicate that RhoE plays a role in suppressing tumor initiation and progression. PMID- 26036261 TI - Intravesical administration of exogenous microRNA-145 as a therapy for mouse orthotopic human bladder cancer xenograft. AB - We previously reported that the level of microRNA (miR)-145 is attenuated in human bladder cancer cells. In this current study, we investigated whether intravesical administration of miR-145 could be a potential therapeutic strategy for controlling bladder cancer by using an orthotopic human bladder cancer xenograft model. Following transfection of 253J B-V cells with miR-145, the effects of the ectopic expression of miR-145 were examined by performing MTT, Western blotting analysis, Hoechst33342 staining, and wound healing assay in vitro. Also, a mouse orthotopic human bladder cancer model was established by inoculating 253J B-V cells into the bladder wall of mice. The anti-cancer effects of intravesical injections of miR-145 into these mice were then assessed. Transfection of 253J B-V cells with miR-145 induced apoptosis and suppression of cell migration in vitro. Western blotting showed that the levels of c-Myc, socs7, FSCN1, E-cadherin, beta-catenin, and catenin delta-1 were decreased and that the PI3K/Akt and Erk1/2 signaling pathways were increased in compensatory fashion. In vivo, mice treated with miR-145 showed 76% inhibition of tumor growth, with a significant prolongation of animal survival (p = 0.0183 vs. control). Western blotting showed that both apoptosis and cell motility-related genes were significantly decreased as seen in vitro. Furthermore, PI3k/Akt and Erk1/2 signaling pathways, which were activated in a compensatory manner in vitro, were decreased in vivo. Intravesical administration of exogenous miR-145 was thus concluded to be a valid therapy for bladder cancer in this human bladder cancer xenograft model. PMID- 26036262 TI - SOX9, a potential tumor suppressor in cervical cancer, transactivates p21WAF1/CIP1 and suppresses cervical tumor growth. AB - Sex-determining region Y-box 9 protein (SOX9) is a transcription factor that may act as both oncogene and tumor suppressor depending on tumor origin. Here we found that SOX9 expression was progressively decreased in cervical carcinoma in situ and especially in invasive cervical carcinoma, compared with normal cervix tissue. The effects of SOX9 on the proliferation, viability, and tumor formation of cervical carcinoma cells were assessed through the silencing and overexpression of SOX9. Overexpression of SOX9 in cervical carcinoma cells (SiHa and C33A) inhibited cell growth in vitro and tumor formation in vivo. In agreement, the silencing of SOX9 in HeLa cells promoted cell growth in culture and tumor formation in mice. Overexpression of SOX9 transactivated p21WAF1/CIP1 via a specific promoter region, thus blocking G1/S transition. The quantitative chromatin immunoprecipitation analysis revealed physical interaction between SOX9 and the specific region of the p21WAF1/CIP1 promoter. We suggest that SOX9 is a potential therapeutic target in cervical carcinoma, that specifically transactivates p21WAF1/CIP1. PMID- 26036263 TI - Electron Correlation Microscopy: A New Technique for Studying Local Atom Dynamics Applied to a Supercooled Liquid. AB - Electron correlation microscopy (ECM) is a new technique that utilizes time resolved coherent electron nanodiffraction to study dynamic atomic rearrangements in materials. It is the electron scattering equivalent of photon correlation spectroscopy with the added advantage of nanometer-scale spatial resolution. We have applied ECM to a Pd40Ni40P20 metallic glass, heated inside a scanning transmission electron microscope into a supercooled liquid to measure the structural relaxation time tau between the glass transition temperature T g and the crystallization temperature, T x . tau determined from the mean diffraction intensity autocorrelation function g 2(t) decreases with temperature following an Arrhenius relationship between T g and T g +25 K, and then increases as temperature approaches T x . The distribution of tau determined from the g 2(t) of single speckles is broad and changes significantly with temperature. PMID- 26036264 TI - Ensuring Health Care Worker Safety When Handling Hazardous Drugs: The Joint Position Statement From the Oncology Nursing Society, the American Society of Clinical Oncology, and the Hematology/Oncology Pharmacy Association. PMID- 26036265 TI - Choosing Wisely: Where's the Beef? PMID- 26036267 TI - Regarding "Models of Cancer Survivorship Care: Overview and Summary of Current Evidence". PMID- 26036268 TI - Role of the 340B Drug Discount Program in Recent Cancer Care Trends. AB - The 340B program, a drug discount program created by the US Congress, allows safety-net providers to access discounted drug pricing that helps low-income and vulnerable patients. This program has recently been the subject of significant discussions as to its potential implications. Herein we review the role of the 340B drug discount program and its relevance to recent trends in cancer care and to the access of safety-net providers and vulnerable patients to much-needed drug support. PMID- 26036266 TI - Breast Cancer Risk Assessment Among Low-Income Women of Color in Primary Care: A Pilot Study. AB - PURPOSE: The US Preventive Services Task Force recommends identifying candidates for breast cancer (BC) chemoprevention and referring them for genetic counseling as part of routine care. Little is known about the feasibility of implementing these recommendations or how low-income women of color might respond to individualized risk assessment (IRA) performed by primary care providers (PCPs). METHODS: Women recruited from a federally qualified health center were given the option to discuss BC risk status with their PCP. Comprehensive IRA was performed using a software tool designed for the primary care environment combining three assessment instruments and providing risk-adapted recommendations for screening, prevention, and genetic referral. Logistic regression models assessed factors associated with wanting to learn and discuss BC risk with PCP. RESULTS: Of 237 participants, only 12.7% (n = 30) did not want to discuss IRA results with their PCP. Factors associated with lower odds of wanting to learn results included having private insurance and reporting ever having had a mammogram. Factors associated with higher odds of wanting to learn results included older age (50 to 69 years) and increased BC worry. For all women wishing to learn results, IRA was successfully completed and delivered to the PCP immediately before the encounter for incorporation into the well-visit evaluation. CONCLUSION: Incorporation of US Preventive Services Task Force recommendations as part of routine primary care is feasible. Interest in IRA seems high among underserved women. This approach warrants further investigation as a strategy for addressing disparities in BC mortality. PMID- 26036269 TI - Reply to E. Grunfeld. PMID- 26036270 TI - Analysing chemical attraction of gravid Anopheles gambiae sensu stricto with modified BG-Sentinel traps. AB - BACKGROUND: Cues that guide gravid Anopheles gambiae sensu lato to oviposition sites can be manipulated to create new strategies for monitoring and controlling malaria vectors. However, progress towards identifying such cues is slow in part due to the lack of appropriate tools for investigating long-range attraction to putative oviposition substrates. This study aimed to develop a relatively easy-to use bioassay system that can effectively analyse chemical attraction of gravid Anopheles gambiae sensu stricto. METHODS: BG-SentinelTM mosquito traps that use fans to dispense odourants were modified to contain aqueous substrates. Choice tests with two identical traps set in an 80 m(2) screened semi-field system were used to analyse the catch efficacy of the traps and the effectiveness of the bioassay. A different batch of 200 gravid An. gambiae s.s. was released on every experimental night. Choices tested were (1) distilled versus distilled water (baseline) and (2) distilled water versus soil infusion. Further, comparisons were made of distilled water and soil infusions both containing 150 g/l of Sodium Chloride (NaCl). Sodium Chloride is known to affect the release rate of volatiles from organic substrates. RESULTS: When both traps contained distilled water, 45% (95 confidence interval (CI) 33-57%) of all released mosquitoes were trapped. The proportion increased to 84% (95 CI 73-91%) when traps contained soil infusions. In choice tests, a gravid female was twice as likely to be trapped in the test trap with soil infusion as in the trap with distilled water (odds ratio (OR) 1.8, 95% CI 1.3-2.6). Furthermore, the attraction of gravid females towards the test trap with infusion more than tripled (OR 3.4, 95% CI 2.4-4.8) when salt was added to the substrates. CONCLUSION: Minor modifications of the BG-SentinelTM mosquito trap turned it into a powerful bioassay tool for evaluating the orientation of gravid mosquitoes to putative oviposition substrates using olfaction. This study describes a useful tool for investigating olfactory attraction of gravid An. gambiae s.s. and provides additional evidence that gravid mosquitoes of this species are attracted to and can be baited with attractive substrates such as organic infusions over a distance of several metres. PMID- 26036271 TI - Comparison of coprological, immunological and molecular methods for the detection of dogs infected with Angiostrongylus vasorum before and after anthelmintic treatment. AB - Timely diagnosis of the nematode Angiostrongylus vasorum in dogs is important in view of severe and permanent lung and cardiovascular lesions that may occur. The performance of the classical Baermann coprological method was compared with ELISAs for the serological detection of circulating antigen and specific antibodies and with Polymerase chain reaction (PCR) performed on EDTA blood, feces and tracheal swabs of serial samples from experimentally inoculated dogs over 13 weeks post inoculation (wpi) (n = 16) and following anthelmintic treatment (n = 6). Patency was observed from 6.7 to 7.6 wpi in all dogs, Baermann results were then mostly positive (116/119, 97%) during the patent period, with wide variations in the numbers of first stage larvae numbers. Blood PCR was tested positive on 1-2 occasions in 11/16 dogs in the pre-patent period, while all tested positive by antibody-detection ELISA by 6 wpi. The proportion of dogs testing positive by fecal PCR and antigen-detection ELISA rose early in the patent period. Tracheal swabs were occasionally DNA-positive in 3/16 dogs starting from 10 wpi. Following treatment, larval excretion stopped within 3 weeks and blood PCR results became negative within 1 week (5/6 dogs), while 4/6 dogs were positive for parasite DNA in tracheal swabs. Parasite antigen and specific antibodies both persisted in the blood for 3-9 weeks after treatment, with average optical densities and the proportion of positive dogs falling gradually, while results using other tests were much more variable. Results indicate that the earliest and most consistent results are obtained by the ELISAs, which can also be used for monitoring dogs after anthelmintic treatment. PMID- 26036273 TI - Factors Related to Coital Frequency of Women in Their Thirties. AB - This cross-sectional study aimed to identify factors related to coital frequency (CF) among 254 women in their 30s using a semistructured interview to collect sociodemographic, anthropometric, reproductive, clinical, and relationship data. CF was characterized as (a) never, (b) rarely (<=1 times/month), (c) occasionally (<=1 times /week), (d) regularly (2-3 times/week), or (e) frequently (>3 times/week). The mean age was 34.38 +/- 0.43 years, mean body mass index (BMI) was 27.86 +/- 6.52 kg, mean family income was US$1,044.18 +/- 796.19, mean number of children was 1.71 +/- 0.89, and mean relationship duration was 8.87 +/- 5.11 years. Eighty-seven women (35.2%) were taking hormonal contraceptives, 143 (98.0%) were employed, 239 (96.48%) had a secondary or higher education, and 9 (3.62%) had primary schooling. CF was classified as >3 times/week in 22 (8.66%), 2-3 times/week for 98 (38.58%), <=1 times/week in 40 (15.75%), <=1 times/month in 14 (5.51%), and never in 5 (1.97%). Women who reported having coitus >3 times/week a week had significantly higher body mass index (BMI; 32.72 +/- 7.42 kg/m(2)) than those who had coitus 2-3 times/week (28.45 +/- 6.76 kg/m(2)) and <=1 times /week (26.81 +/- 5.39 kg/m(2)) (p < 0.01 for both comparisons). Thus, coital frequency varies in women in their 30s. Obese women had a higher CF than normal-weight and overweight women. PMID- 26036272 TI - Blood-based identification of non-responders to anti-TNF therapy in rheumatoid arthritis. AB - BACKGROUND: Faced with an increasing number of choices for biologic therapies, rheumatologists have a critical need for better tools to inform rheumatoid arthritis (RA) disease management. The ability to identify patients who are unlikely to respond to first-line biologic anti-TNF therapies prior to their treatment would allow these patients to seek alternative therapies, providing faster relief and avoiding complications of disease. METHODS: We identified a gene expression classifier to predict, pre-treatment, which RA patients are unlikely to respond to the anti-TNF infliximab. The classifier was trained and independently evaluated using four published whole blood gene expression data sets, in which RA patients (n = 116 = 44 + 15 + 30 + 27) were treated with infliximab, and their response assessed 14-16 months post treatment according to the European League Against Rheumatism (EULAR) response criteria. For each patient, prior knowledge was used to group gene expression measurements into disease-relevant biological signaling mechanisms that were used as the input features for regularized logistic regression. RESULTS: The classifier produced a substantial enrichment of non-responders (59 %, given by the cross validated test precision) compared to the full population (27 % non-responders), while identifying nearly a third of non-responders. Given this classifier performance, treatment of predicted non-responders with alternative biologics would decrease their chance of non-response by between a third and a half, substantially improving their odds of effective treatment and stemming further disease progression. The classifier consisted of 18 signaling mechanisms, which together indicated that higher inflammatory signaling mediated by TNF and other cytokines was present pre-treatment in the blood of patients who responded to infliximab treatment. In contrast, non-responders were classified by relatively higher levels of specific metabolic activities in the blood prior to treatment. CONCLUSIONS: We were able to successfully produce a classifier to identify a population of RA patients significantly enriched in anti-TNF non-responders across four different patient cohorts. Additional prospective studies are needed to validate and refine the classifier for clinical use. PMID- 26036274 TI - Solvent Control of Surface Plasmon-Mediated Chemical Deposition of Au Nanoparticles from Alkylgold Phosphine Complexes. AB - Bottom-up approaches to nanofabrication are of great interest because they can enable structural control while minimizing material waste and fabrication time. One new bottom-up nanofabrication method involves excitation of the surface plasmon resonance (SPR) of a Ag surface to drive deposition of sub-15 nm Au nanoparticles from MeAuPPh3. In this work we used density functional theory to investigate the role of the PPh3 ligands of the Au precursor and the effect of adsorbed solvent on the deposition process, and to elucidate the mechanism of Au nanoparticle deposition. In the absence of solvent, the calculated barrier to MeAuPPh3 dissociation on the bare surface is <20 kcal/mol, making it facile at room temperature. Once adsorbed on the surface, neighboring MeAu fragments undergo ethane elimination to produce Au adatoms that cluster into Au nanoparticles. However, if the sample is immersed in benzene, we predict that the monolayer of adsorbed solvent blocks the adsorption of MeAuPPh3 onto the Ag surface because the PPh3 ligand is large compared to the size of the exposed surface between adsorbed benzenes. Instead, the Au-P bond of MeAuPPh3 dissociates in solution (Ea = 38.5 kcal/mol) in the plasmon heated near-surface region followed by the adsorption of the MeAu fragment on Ag in the interstitial space of the benzene monolayer. The adsorbed benzene forces the Au precursor to react through the higher energy path of dissociation in solution rather than dissociatively adsorbing onto the bare surface. This requires a higher temperature if the reaction is to proceed at a reasonable rate and enables the control of deposition by the light induced SPR heating of the surface and nearby solution. PMID- 26036277 TI - Critical review of the influences of nanoparticles on biological wastewater treatment and sludge digestion. AB - Nanoparticles (NPs), with at least one dimension less than 100 nm, are substantially employed in consumer and industrial products due to their specific physical and chemical properties. The wide uses of engineered NPs inevitably cause their release into the environment, especially wastewater treatment plants. Therefore, it is essential to systematically assess their potential impact on biological wastewater treatment and subsequent sewage sludge digestion. This review aims to provide such support. First, this paper reviews the recent advances on the analytical developments and nano-bio interface of NPs in wastewater and sewage sludge treatment. The effects of NPs on biological wastewater treatment and sewage sludge digestion and related mechanisms are discussed in detail. Finally, the key questions that need to be answered in the future are pointed out, which include on-line revelation of the changes of NPs in sewage and sludge environments, in situ assessment of the variations of microorganisms involved in these biological systems after they are exposed to NPs. Differentiation of the contribution of individual toxicity mechanisms to these systems, and the identification of under what conditions the nanoparticle induced toxicity will be increased or decreased are also considered. PMID- 26036276 TI - Use of antidiabetic and antidepressant drugs is associated with increased risk of myocardial infarction: a nationwide register study. AB - AIMS: To explore the gender- and age-specific risk of developing a first myocardial infarction in people treated with antidiabetic and/or antidepressant drugs compared with people with no pharmaceutical treatment for diabetes or depression. METHODS: A cohort of all Swedish residents aged 45-84 years (n = 4 083 719) was followed for a period of 3 years. Data were derived from three nationwide registers. The prescription and dispensing of antidiabetic and antidepressant drugs were used as markers of disease. All study subjects were reallocated according to treatment and the treatment categories were updated every year. Data were analysed using a Cox regression model with a time-dependent variable. The outcome of interest was first fatal or non-fatal myocardial infarction. RESULTS: During follow-up, 42 840 people had a first myocardial infarction, 3511 of which were fatal. Women aged 45-64 years, receiving both antidiabetic and antidepressant drugs had a hazard ratio for myocardial infarction of 7.4 (95% CI 6.3-8.6) compared with women receiving neither. The corresponding hazard ratio for men was 3.1 (95% CI 2.8-3.6). CONCLUSIONS: The combined use of antidiabetic and antidepressant drugs was associated with a higher risk of myocardial infarction compared with use of either group of drugs alone. The increase in relative risk was greater in middle-aged women than in middle-aged men. PMID- 26036278 TI - Bioconjugation of therapeutic proteins and enzymes using the expanded set of genetically encoded amino acids. AB - The last decade has witnessed striking progress in the development of bioorthogonal reactions that are strictly directed towards intended sites in biomolecules while avoiding interference by a number of physical and chemical factors in biological environment. Efforts to exploit bioorthogonal reactions in protein conjugation have led to the evolution of protein translational machineries and the expansion of genetic codes that systematically incorporate a range of non-natural amino acids containing bioorthogonal groups into recombinant proteins in a site-specific manner. Chemoselective conjugation of proteins has begun to find valuable applications to previously inaccessible problems. In this review, we describe bioorthogonal reactions useful for protein conjugation, and biosynthetic methods that produce proteins amenable to those reactions through an expanded genetic code. We then provide key examples in which novel protein conjugates, generated by the genetic incorporation of a non-natural amino acid and the chemoselective reactions, address unmet needs in protein therapeutics and enzyme engineering. PMID- 26036275 TI - T-cell intracellular antigens in health and disease. AB - T-cell intracellular antigen 1 (TIA1) and TIA1-related/like protein (TIAR/TIAL1) are 2 proteins discovered in 1991 as components of cytotoxic T lymphocyte granules. They act in the nucleus as regulators of transcription and pre-mRNA splicing. In the cytoplasm, TIA1 and TIAR regulate and/or modulate the location, stability and/or translation of mRNAs. As knowledge of the different genes regulated by these proteins and the cellular/biological programs in which they are involved increases, it is evident that these antigens are key players in human physiology and pathology. This review will discuss the latest developments in the field, with physiopathological relevance, that point to novel roles for these regulators in the molecular and cell biology of higher eukaryotes. PMID- 26036279 TI - Palladium-Catalyzed One-Pot Reaction of Hydrazones, Dihaloarenes, and Organoboron Reagents: Synthesis and Cytotoxic Activity of 1,1-Diarylethylene Derivatives. AB - A new three-component assembly reaction between N-tosylhydrazones, dihalogenated arenes, and boronic acids or boronate esters was developed, producing highly substituted 1,1-diarylethylenes in good yields. The two C-C bonds formed through this coupling have been catalyzed by a single Pd-catalyst in a one-pot fashion. It is noted that the one-pot pinacol boronate cross-coupling reaction generally provides products in high yields, offers an expansive substrate scope, and can address a broad range of aryl, styrene, vinyl, and heterocyclic olefinic targets. The scope of this one-pot coupling has been also extended to the synthesis of the 1,1-diarylethylene skeleton of the natural product ratanhine. The new compounds were evaluated for their cytotoxic activity, and this allowed the identification of compound 4ab that exhibits excellent antiproliferative activity in the nanomolar concentration range against HCT116 cancer cell lines. PMID- 26036280 TI - Astrocytes: targets in obesity. PMID- 26036282 TI - Phase and Texture Characterizations of Scar Collagen Second-Harmonic Generation Images Varied with Scar Duration. AB - This work developed a phase congruency algorithm combined with texture analysis to quantitatively characterize collagen morphology in second-harmonic generation (SHG) images from human scars. The extracted phase and texture parameters of the SHG images quantified collagen directionality, homogeneity, and coarseness in scars and varied with scar duration. Phase parameters showed an increasing tendency of the mean of phase congruency with scar duration, indicating that collagen fibers are better oriented over time. Texture parameters calculated from local difference local binary pattern (LD-LBP) and Haar wavelet transform, demonstrated that the LD-LBP variance decreased and the energy of all subimages increased with scar duration. It implied that collagen has a more regular pattern and becomes coarser with scar duration. In addition, the random forest regression was used to predict scar duration, demonstrating reliable performance of the extracted phase and texture parameters in characterizing collagen morphology in scar SHG images. Results indicate that the extracted parameters using the proposed method can be used as quantitative indicators to monitor scar progression with time and can help understand the mechanism of scar progression. PMID- 26036281 TI - Structurally diverse c-Myc inhibitors share a common mechanism of action involving ATP depletion. AB - The c-Myc (Myc) oncoprotein is deregulated in a large proportion of diverse human cancers. Considerable effort has therefore been directed at identifying pharmacologic inhibitors as potential anti-neoplastic agents. Three such groups of small molecule inhibitors have been described. The first is comprised of so called "direct" inhibitors, which perturb Myc's ability to form productive DNA binding heterodimers in association with its partner, Max. The second group is comprised of indirect inhibitors, which largely function by targeting the BET domain protein BRD4 to prevent the proper formation of transcriptional complexes that assemble in response to Myc-Max DNA binding. Thirdly, synthetic lethal inhibitors cause the selective apoptosis of Myc over-expressing either by promoting mitotic catastrophe or altering Myc protein stability. We report here a common mechanism by which all Myc inhibitors, irrespective of class, lead to eventual cellular demise. This involves the depletion of ATP stores due to mitochondrial dysfunction and the eventual down-regulation of Myc protein. The accompanying metabolic de-regulation causes neutral lipid accumulation, cell cycle arrest, and an attempt to rectify the ATP deficit by up-regulating AMP activated protein kinase (AMPK). These responses are ultimately futile due to the lack of functional Myc to support the requisite anabolic response. Finally, the effects of Myc depletion on ATP levels, cell cycle arrest, differentiation and AMPK activation can be mimicked by pharmacologic inhibition of the mitochondrial electron transport chain without affecting Myc levels. Thus, all Myc inhibitors promote a global energy collapse that appears to underlie many of their phenotypic consequences. PMID- 26036283 TI - Mono-ethylhexyl phthalate stimulates prostaglandin secretion in human placental macrophages and THP-1 cells. AB - BACKGROUND: Diethylhexyl phthalate (DEHP) is widely used as a plasticizer in polyvinyl chloride products. DEHP exposure, which is widespread in the US, increases preterm birth risk; however, the mechanisms driving this relationship are unclear. Because cyclooxygenase-2 (COX-2) dependent prostaglandin synthesis is implicated in preterm birth, we evaluated effects of mono-2-ethylhexyl phthalate (MEHP), the active metabolite of DEHP, on prostaglandin E2 (PGE2) synthesis and COX expression in human placental macrophages (PM). In addition, responses in PM were compared to those in a human macrophage-like cell line, THP 1. METHODS: PM and THP-1 cells were treated for 2, 4, 8, or 24 h with MEHP concentrations ranging from 10 to 180 micromolar. PGE2 concentrations were assessed in culture medium using ELISA, and COX expression was determined by western blot. RESULTS: Treatment of PM and THP-1 cells with 180 micromolar MEHP for 24 h significantly increased PGE2 release. Co-treatment of PMs or THP-1 cells with 180 micromolar MEHP and the non-selective COX inhibitor indomethacin reduced MEHP-stimulated PGE2 production. Similarly, co-treatment of PM and THP-1 cells with the COX-2 selective inhibitor NS-398 resulted in a significant decrease in PGE2, suggesting that MEHP-stimulated PGE2 is dependent specifically on increased COX-2 expression. Western blot analysis revealed a significant increase in COX-2 expression in PM and THP-1 cells treated with 180 micromolar MEHP, and no changes in COX-1 expression, supporting the role of COX-2 in MEHP-stimulated PGE2 synthesis. CONCLUSIONS: The findings from this study are the first to demonstrate phthalate-stimulated PGE2 synthesis in PM and warrant future studies into COX-2 dependent prostaglandin synthesis as a mechanism of toxicant-associated preterm birth. PMID- 26036286 TI - Hyperhomocysteinemia: Impact on Neurodegenerative Diseases. AB - Neurodegenerative diseases are the diseases of the central nervous system with various aetiology and symptoms. Dementia, Alzheimer's disease (AD), Parkinson's disease (PD) and autism are some examples of neurodegenerative diseases. Hyperhomocysteinemia (Hhcy) is considered to be an independent risk factor for numerous pathological conditions under neurodegenerative diseases. Along with genetic factors that are the prime cause of homocysteine (Hcy) imbalance, the nutritional and hormonal factors are also contributing to high Hcy levels in the body. Numerous clinical and epidemiological data confirm the direct correlation of Hcy levels in the body and generation of different types of central nervous system disorders, cardiovascular diseases, cancer and others. Till now, it is difficult to say whether homocysteine is the cause of the disease or whether it is one of the impacts of the diseases. However, Hhcy is a surrogate marker of vitamin B deficiency and is a neurotoxic agent. This Mini Review will give an overview of how far research has gone into understanding the homocysteine imbalance with prognostic, causative and preventive measures in treating neurodegenerative diseases. PMID- 26036284 TI - Genomewide Association Study for Maximum Number of Alcoholic Drinks in European Americans and African Americans. AB - BACKGROUND: We conducted a genomewide association study (GWAS) for maximum number of alcoholic drinks consumed in a 24-hour period ("MaxDrinks"), in 2 independent samples comprised of over 9,500 subjects, following up on our GWAS for alcohol dependence (AD) in European Americans (EAs) and African Americans (AAs). METHODS: The samples included our GWAS samples (Yale-UPenn) recruited for studies of the genetics of drug or AD, and a publicly available sample: the Study of Addiction: Genetics and Environment (SAGE). Genomewide association analysis was performed for ~890,000 single nucleotide polymorphisms (SNPs) using linear association random effects models. EAs and AAs were separately analyzed. RESULTS: The results confirmed significant associations of the well-known functional loci at ADH1B with MaxDrinks in EAs (rs1229984 Arg48His p = 5.96 * 10(-15) ) and AAs (rs2066702 Arg370Cys, p = 2.50 * 10(-10) ). The region of significant association on chromosome 4 was extended to LOC100507053 in AAs but not EAs. We also identified potentially novel significant common SNPs for MaxDrinks in EAs in the Yale-UPenn sample: rs1799876 at SERPINC1 on chromosome 1 (4.00 * 10(-8) ) and rs2309169 close to ANKRD36 on chromosome 2 (p = 5.58 * 10(-9) ). After adjusting for the peak SNP rs1229984 on ADH1B, rs1799876 was nearly significant (p = 1.99 * 10(-7) ) and rs2309169 remained highly significant (2.12 * 10(-9) ). CONCLUSIONS: The results provide further support that ADH1B modulates alcohol consumption. Future replications of potential novel loci are warranted. This is the largest MaxDrinks GWAS to date, the first in AAs. PMID- 26036287 TI - Death and dying. PMID- 26036285 TI - c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target. AB - BACKGROUND: c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. METHODS: The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. RESULTS: Elevated expression of c Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. CONCLUSIONS: The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression. PMID- 26036288 TI - The eye examination. PMID- 26036289 TI - Diffuse small miliary red papules in an infant. Benign neonatal hemangiomatosis. PMID- 26036290 TI - Dual ectopic thyroid: A rare entity. Dual ectopic thyroid tissue. PMID- 26036297 TI - Abdominal examination. PMID- 26036298 TI - Early use of MRI for suspected pyomyositis. PMID- 26036299 TI - Neonatal hypernatraemic dehydration. PMID- 26036300 TI - Effectiveness of physical activity interventions on preventing gestational diabetes mellitus and excessive maternal weight gain: a meta-analysis. AB - BACKGROUND: It is commonly accepted that pregnancy-related physiological changes (circulatory, respiratory, and locomotor) negatively influence the daily physical activity of pregnant women. OBJECTIVES: The aim of this study is to conduct a meta-analysis of randomised controlled trials (RCTs) for assessing the effectiveness of physical exercise interventions during pregnancy to prevent gestational diabetes mellitus and excessive maternal weight gain. SEARCH STRATEGY: Keywords were used to conduct a computerised search in six databases: Cochrane Library Plus, Science Direct, EMBASE, PubMed, Web of Science, and ClinicalTrials.gov. SELECTION CRITERIA: Healthy pregnant women who were sedentary or had low levels of physical activity were selected for RCTs that included an exercise programme. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and assessed the quality of the included studies. Of 4225 articles retrieved, 13 RCTs (2873 pregnant women) met the inclusion criteria. Pooled relative risk (RR) or weighted mean differences (WMDs) (depending on the outcome measure) were calculated using a random-effects model. MAIN RESULTS: Overall, physical exercise programmes during pregnancy decreased the risk of gestational diabetes mellitus (RR = 0.69; P = 0.009), particularly when the exercise programme was performed throughout pregnancy (RR = 0.64; P = 0.038). Furthermore, decreases were also observed in maternal weight (WMD = -1.14 kg; 95% CI -1.50 to 0.78; P < 0.001). No serious adverse effects were reported. CONCLUSION: Structured moderate physical exercise programmes during pregnancy decrease the risk of gestational diabetes mellitus and diminish maternal weight gain, and seem to be safe for the mother and the neonate; however, further studies are needed to establish recommendations. PMID- 26036302 TI - Treatment of Female Sexual Pain Disorders: A Systematic Review. AB - Sexual pain disorders affect women's sexual and reproductive health and are poorly understood. Although many treatments have been evaluated, there is no one "gold standard" treatment. The aim of this systematic review was to investigate what treatments for female sexual pain have been evaluated in clinical studies and their effectiveness. The search strategy resulted in 65 papers included in this review. The articles were divided into the following categories: medical treatments; surgical treatments; physical therapies; psychological therapies; comparative treatment studies; and miscellaneous and combined treatments. Topical and systemic medical treatments have generally been found to lead to improvements in, but not complete relief of, pain, and side effects are quite common. Surgical procedures have demonstrated very high success rates, although there has been variability in complete relief of pain after surgery, which suggests less invasive treatments should be considered first. Physical therapies and psychological therapies have been shown to be promising treatments, supporting a biopsychosocial approach to sexual pain disorders. Although most of the interventions described have been reported as effective, many women still experience pain. A multidisciplinary team with active patient involvement may be needed to optimize treatment outcome. PMID- 26036303 TI - Sulforaphane attenuates EGFR signaling in NSCLC cells. AB - BACKGROUND: EGFR, a receptor tyrosine kinase (RTK), is frequently overexpressed and mutated in non-small cell lung cancer (NSCLC). Tyrosine kinase inhibitors (TKIs) have been widely used in the treatment of many cancers, including NSCLC. However, intrinsic and acquired resistance to TKI remains a common obstacle. One strategy that may help overcome EGFR-TKI resistance is to target EGFR for degradation. As EGFR is a client protein of heat-shock protein 90 (HSP90) and sulforaphane is known to functionally regulate HSP90, we hypothesized that sulforaphane could attenuate EGFR-related signaling and potentially be used to treat NSCLC. RESULTS: Our study revealed that sulforaphane displayed antitumor activity against NSCLC cells both in vitro and in vivo. The sensitivity of NSCLC cells to sulforaphane appeared to positively correlate with the inhibition of EGFR-related signaling, which was attributed to the increased proteasomal degradation of EGFR. Combined treatment of NSCLC cells with sulforaphane plus another HSP90 inhibitor (17-AAG) enhanced the inhibition of EGFR-related signaling both in vitro and in vivo. CONCLUSIONS: We have shown that sulforaphane is a novel inhibitory modulator of EGFR expression and is effective in inhibiting the tumor growth of EGFR-TKI-resistant NSCLC cells. Our findings suggest that sulforaphane should be further explored for its potential clinical applications against NSCLC. PMID- 26036304 TI - Egg-specific expression of protein with DNA methyltransferase activity in the biocarcinogenic liver fluke Clonorchis sinensis. AB - Despite recent reports regarding the biology of cytosine methylation in Schistosoma mansoni, the impact of the regulatory machinery remains unclear in diverse platyhelminthes. This ambiguity is reinforced by discoveries of DNA methyltransferase 2 (DNMT2)-only organisms and the substrate specificity of DNMT2 preferential to RNA molecules. Here, we characterized a novel DNA methyltransferase, named CsDNMT2, in a liver fluke Clonorchis sinensis. The protein exhibited structural properties conserved in other members of the DNMT2 family. The native and recombinant CsDNMT2 exhibited considerable enzymatic activity on DNA. The spatiotemporal expression of CsDNMT2 mirrored that of 5 methylcytosine (5 mC), both of which were elevated in the C. sinensis eggs. However, CsDNMT2 and 5 mC were marginally detected in other histological regions of C. sinensis adults including ovaries and seminal receptacle. The methylation site seemed not related to genomic loci occupied by progenies of an active long terminal-repeat retrotransposon. Taken together, our data strongly suggest that C. sinensis has preserved the functional DNA methylation machinery and that DNMT2 acts as a genuine alternative to DNMT1/DNMT3 to methylate DNA in the DNMT2-only organism. The epigenetic regulation would target functional genes primarily involved in the formation and/or maturation of eggs, rather than retrotransposons. PMID- 26036305 TI - AMPK-friend or foe for targeted therapy? PMID- 26036301 TI - Surface hydrolysis of sphingomyelin by the outer membrane protein Rv0888 supports replication of Mycobacterium tuberculosis in macrophages. AB - Sphingomyelinases secreted by pathogenic bacteria play important roles in host pathogen interactions ranging from interfering with phagocytosis and oxidative burst to iron acquisition. This study shows that the Mtb protein Rv0888 possesses potent sphingomyelinase activity cleaving sphingomyelin, a major lipid in eukaryotic cells, into ceramide and phosphocholine, which are then utilized by Mtb as carbon, nitrogen and phosphorus sources, respectively. An Mtb rv0888 deletion mutant did not grow on sphingomyelin as a sole carbon source anymore and replicated poorly in macrophages indicating that Mtb utilizes sphingomyelin during infection. Rv0888 is an unusual membrane protein with a surface-exposed C terminal sphingomyelinase domain and a putative N-terminal channel domain that mediated glucose and phosphocholine uptake across the outer membrane in an M. smegmatis porin mutant. Hence, we propose to name Rv0888 as SpmT (sphingomyelinase of Mycobacterium tuberculosis). Erythrocyte membranes contain up to 27% sphingomyelin. The finding that Rv0888 accounts for half of Mtb's hemolytic activity is consistent with its sphingomyelinase activity and the observation that Rv0888 levels are increased in the presence of erythrocytes and sphingomyelin by 5- and 100-fold, respectively. Thus, Rv0888 is a novel outer membrane protein that enables Mtb to utilize sphingomyelin as a source of several essential nutrients during intracellular growth. PMID- 26036306 TI - A fruitful decade from 2005 to 2014 for anthraquinone patents. AB - INTRODUCTION: Anthraquinones are aromatic compounds whose structures are related to anthracene (parent structure: 9,10-dioxoanthracene) for which various methods for their synthesis have been developed. In the past decade (2005 - 2014), much work has been done regarding anthraquinone chemistry in order to discover new compounds related to this scaffold as anticancer, antibacterial, antidiabetic, antiviral, anti-HCV, antifibrotic, fungicidal and anti-inflammatory agents. AREAS COVERED: This review covers the patents on therapeutic activities of anthraquinones and their derivatives in the years between 2005 and 2014. A large portion of the therapeutic applications that were reported in international patents will be presented and discussed. Although a large number of patents have been registered over the last decade, this review is focused on important patents related to cancer, inflammation, infectious diseases, diabetic conditions and hepatitis C. EXPERT OPINION: The tricyclic planar ring system of anthraquinones displays a wide range of important pharmaceutical properties. By linking active anthraquinone analogs to other important pharmacophores or conjugates such as oximes, N-heterocycles, benzodiazepines or glycosyl ethers, their anticancer potential is enhanced. The ability of anthraquinone analogs to become more prominent as novel pharmaceutical agents may further be enhanced by fusing functionalized heterocyclic rings onto established anthraquinone cores. PMID- 26036307 TI - Raman Spectroscopic Study on Phosphorous-Doped Silicon Nanoparticles. AB - The Raman spectra of films prepared from 8, 19, and 30 nm nanoparticles of silicon doped with phosphorous were measured with excitation at 514.5 nm. The observed spectra were analyzed by decomposing the observed Raman bands into three symmetric Voigt function bands, which were assigned to the Si-Si stretching modes of crystalline, boundary, and amorphous-like components. The fractions of crystalline, boundary, and amorphous-like regions were estimated from the obtained components. The obtained fractions can be explained as a sphere-like nanoparticle consisting of a crystalline core surrounded with boundary and amorphous-like shells, which is consistent with the transmission electron microscope images showing a sphere-like shape. The observed spectral shape of the 8 nm nanoparticle film showed significant changes upon light irradiation with a power density of 5.5 kW cm(-2), i.e., the amorphous-like region converted to a crystalline one. The temperature of the film under laser irradiation was estimated to be lower than 1041 degrees C from the anti-Stokes to the Stokes Raman bands due to the Si-Si stretching mode. The observed partial crystallization is probably induced by heating associated with light irradiation. PMID- 26036308 TI - Cochlear implantation in children with complex needs: the perceptions of professionals at cochlear implant centres. AB - OBJECTIVE: To explore the views of cochlear implant centre teams about the process of referral, assessment and rehabilitation for children with complex needs. METHODS: An on-line survey of cochlear implant centres in the UK and in the Netherlands was carried out, with both quantitative and qualitative questions. The survey was designed and piloted by four professionals in each country, experienced in working in cochlear implant services, and with complex children. The open qualitative responses were analysed independently for the emergent themes. RESULTS: Seven centres from Netherlands and eight from UK responded. The proportion of children reported with complex needs ranged from under 10% to between 40 and 60%. Children with complex needs were more likely to be later referred than the norm, and to take longer to assess. There was little agreement about the assessments used prior to implantation, or in follow-up. The most commonly seen additional disability was visual, followed by motor/physical challenges and autistic spectrum disorders. The most reported challenge was assessment, followed by parental expectations, and wearing the system. The least reported concern was educational management. The major goal was seen to be hearing and sensory input, rather than speech and language attainment. All centres commented on the importance of parental observation. CONCLUSION: There is a need for a consensus on the assessment of these children, with the development of more objective parent led observation measures to collect long-term data across centres. Closer collaboration with educators, particularly those with other expertise, would facilitate long-term management and asssessment. Data logging, now available, will help monitor wearing and use of system. PMID- 26036310 TI - Aza-[2,3]-Wittig Sigmatropic Rearrangement of Allylic Tertiary Amines: A Successful Example with High Chirality Transfer. AB - We report herein a successful example of an aza-[2,3]-Wittig rearrangement in an allylic tertiary N,N-dibenzyl amine derived from (S)-alaninol or (S)-isoleucinol. This reaction occurs upon metalation at the benzylic position with a mixture of butyllithium/diisopropylamine/potassium t-butoxide and proceeds with a high 1,3 transfer of chirality. PMID- 26036309 TI - The artificial pancreas: evaluating risk of hypoglycaemia following errors that can be expected with prolonged at-home use. AB - AIMS: Artificial pancreas systems show benefit in closely monitored at-home studies, but may not have sufficient power to assess safety during infrequent, but expected, system or user errors. The aim of this study was to assess the safety of an artificial pancreas system emulating the beta-cell when the glucose value used for control is improperly calibrated and participants forget to administer pre-meal insulin boluses. METHODS: Artificial pancreas control was performed in a clinic research centre on three separate occasions each lasting from 10 p.m. to 2 p.m. Sensor glucose values normally used for artificial pancreas control were replaced with scaled blood glucose values calculated to be 20% lower than, equal to or 33% higher than the true blood glucose. Safe control was defined as blood glucose between 3.9 and 8.3 mmol/l. RESULTS: Artificial pancreas control resulted in fasting scaled blood glucose values not different from target (6.67 mmol/l) at any scaling factor. Meal control with scaled blood glucose 33% higher than blood glucose resulted in supplemental carbohydrate to prevent hypoglycaemia in four of six participants during breakfast, and one participant during the night. In all instances, scaled blood glucose reported blood glucose as safe. CONCLUSIONS: Outpatient trials evaluating artificial pancreas performance based on sensor glucose may not detect hypoglycaemia when sensor glucose reads higher than blood glucose. Because these errors are expected to occur, in-hospital artificial pancreas studies using supplemental carbohydrate in anticipation of hypoglycaemia, which allow safety to be assessed in a controlled non-significant environment should be considered as an alternative. Inpatient studies provide a definitive alternative to model-based computer simulations and can be conducted in parallel with closely monitored outpatient artificial pancreas studies used to assess benefit. PMID- 26036311 TI - Bruton's tyrosine kinase (Btk) inhibitor ibrutinib suppresses stem-like traits in ovarian cancer. AB - According to a Prognoscan database, upregulation of Bruton's tyrosine kinase (Btk) is associated with low overall survival in ovarian cancer patients. We found that spheroids-forming ovarian cancer cell, which highly expressed cancer stem-like cell (CSC) markers and Btk, were cisplatin resistant. We next treated CSCs and non-CSCs by a combination of ibrutinib and cisplatin. We found that chemoresistance was dependent on Btk and JAK2/STAT3, which maintained CSC by inducing Sox-2 and prosurvival genes. We suggest that addition of ibrutinib to cisplatin may improve treatment outcome in ovarian cancer. PMID- 26036312 TI - Enhanced antitumor efficacy of ultrasonic cavitation with up-sized microbubbles in pancreatic cancer. AB - Ultrasonic cavitation is a novel potential approach for cancer treatment. We optimized the techniques of ultrasonic cavitation to enhance antitumor efficacy in a mouse model with human pancreatic cancer. A polydisperse MB contrast agent formulation (TS-P) with a mean number diameter of 1.9 MUm was depleted in small diameter particles by differential centrifugation, producing an "up-sized" size distribution (TS-PL) possessing a mean diameter of 2.9 MUm. Mice bearing the XPA 1-RFP pancreatic tumor were treated daily for 3 consecutive days with either up sized or standard MB. Both treatment cohorts exhibited a significant reduction in tumor volume relative to the untreated control cohort (P < 0.05), and TS-PL group has significantly reduction in tumor volume (1215.1+/- 324.7 mm3) compared with standard TS-P group (2131.2+/-753.4 mm3) (P < 0.05). The treatment with TS-PL resulted in more tumor cell necrosis and apoptosis than with TS-P. Decreased expression of CD31 and MVD was observed histologically in tumors treated with TS PL relative to TS-P. This study demonstrates that tuning the size distribution of existing contrast agent products, specifically to reduce the concentration of small MB, is required for enhanced anti-tumor cavitation activity. PMID- 26036313 TI - Increased resistance to proteasome inhibitors in multiple myeloma mediated by cIAP2--implications for a combinatorial treatment. AB - Despite the introduction of new treatment options for multiple myeloma (MM), a majority of patients relapse due to the development of resistance. Unraveling new mechanisms underlying resistance could lead to identification of possible targets for combinatorial treatment. Using TRAF3 deleted/mutated MM cell lines, we evaluated the role of the cellular inhibitor of apoptosis 2 (cIAP2) in drug resistance and uncovered the plausible mechanisms underlying this resistance and possible strategies to overcome this by combinatorial treatment. In MM, cIAP2 is part of the gene signature of aberrant NF-kappaB signaling and is heterogeneously expressed amongst MM patients. In cIAP2 overexpressing cells a decreased sensitivity to the proteasome inhibitors bortezomib, MG132 and carfilzomib was observed. Gene expression analysis revealed that 440 genes were differentially expressed due to cIAP2 overexpression. Importantly, the data imply that cIAPs are rational targets for combinatorial treatment in the population of MM with deleted/mutated TRAF3. Indeed, we found that treatment with the IAP inhibitor AT 406 enhanced the anti-MM effect of bortezomib in the investigated cell lines. Taken together, our results show that cIAP2 is an important factor mediating bortezomib resistance in MM cells harboring TRAF3 deletion/mutation and therefore should be considered as a target for combinatorial treatment. PMID- 26036315 TI - Recent advances in polymyalgia rheumatica. AB - Polymyalgia rheumatica (PMR) is a chronic inflammatory disorder of unknown cause characterised by the subacute onset of shoulder and pelvic girdle pain, and early morning stiffness in men and women over the age of 50 years. Due to the lack of a gold standard investigation, diagnosis is based on a clinical construct and laboratory evidence of inflammation. Heterogeneity in the clinical presentation and disease course of PMR has long been recognised. Aside from the evolution of alternative diagnoses, such as late-onset rheumatoid arthritis, concomitant giant cell arteritis is also recognised in 16-21% of cases. In 2012, revised classification criteria were released by the European League Against Rheumatism and American College of Rheumatology in order to identify a more homogeneous population upon which future studies could be based. In this article, we aim to provide an updated perspective on the pathogenesis and diagnosis of PMR, with particular focus on imaging modalities, such as ultrasound and whole body positron emission tomography/computed tomography, which have advanced our current understanding of this disease. Future treatment directions, based on recognition of the key cytokines involved in PMR, will also be explored. PMID- 26036314 TI - Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells. AB - Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl. PMID- 26036316 TI - [Potential and effectiveness of a telemedical rescue assistance system. Prospective observational study on implementation in emergency medicine]. AB - BACKGROUND: The demographic change and an increasing multimorbidity of patients represent increasing challenges for the adequate prehospital treatment of emergency patients. The incorporation of supplementary telemedical concepts and systems can lead to an improved guideline-conform treatment. Beneficial evidence of telemedical procedures is only known for isolated disease patterns; however, no mobile telemedical concept exists which is suitable for use in the wide variety of different clinical situations. AIM: This article presents a newly developed and evaluated total telemedical concept (TemRas) that encompasses organizational, medical and technical components. The use of intelligent and robust communication technology and the implementation of this add-on system allows the telemedical support of the rescue service for all emergencies. METHODS: After development of the telemedical rescue assistance system, which includes organizational, medical and technical components, a telemedical centre and six ambulances in five different districts in North-Rhine Westphalia were equipped with this new tool. During the evaluation phase of 1 year in the routine emergency medical service the rate of complications as well as differences between urban and rural areas were analyzed with respect to different target parameters. RESULTS: Between August 2012 and July 2013 a total of 401 teleconsultations were performed during emergency missions and 24 during secondary interhospital transfers. No complications due to teleconsultation were observed. The mean duration (+/-SD) of teleconsultations was longer in rural areas than in urban areas with 28.6+/-12.0 min vs. 25.5+/-11.1 min (p < 0.0001). In 63.2% of these missions administration of medications was delegated to the ambulance personnel (52.0% urban vs. 73.6% rural, p < 0.0001). The severity of ailments corresponded to scores of III and VI in the National Advisory Committee for Aeronautics (NACA) classification. CONCLUSION: Emergency medical care of patients with support by a telemedical system is technically feasible, safe for the patient and allows medical treatment independent of spatial availability of a physician in different emergency situations. PMID- 26036317 TI - [Tension pneumomediastinum and tension pneumothorax following tracheal perforation during cardiopulmonary resuscitation]. AB - Tension pneumothorax can occur at any time during cardiopulmonary resuscitation (CPR) with external cardiac massage and invasive ventilation either from primary or iatrogenic rib fractures with concomitant pleural or parenchymal injury. Airway injury can also cause tension pneumothorax during CPR. This article presents the case of a 41-year-old woman who suffered cardiopulmonary arrest after undergoing elective mandibular surgery. During CPR the upper airway could not be secured by orotracheal intubation due to massive craniofacial soft tissue swelling. A surgical airway was established with obviously unrecognized iatrogenic tracheal perforation and subsequent development of tension pneumomediastinum and tension pneumothorax during ventilation. Neither the tension pneumomediastinum nor the tension pneumothorax were decompressed and accordingly resuscitation efforts remained unsuccessful. This case illustrates the need for a structured approach to resuscitate patients with ventilation problems regarding decompression of tension pneumomediastinum and/or tension pneumothorax during CPR. PMID- 26036318 TI - Comment on "crystallographic snapshot of an arrested intermediate in the biomimetic activation of CO2 ". AB - Out of focus: A recent Communication published in this journal describes the synthesis of [nBu4 N]HCO3 . The authors performed a single-crystal X-ray study that revealed a putative species described as an incipient hydroxide ion engaging in a long, and presumably weak, interaction with CO2 . Our recent exploration of the coordination chemistry of CO2 with small ions leads us to believe that such an exceptional bonding situation is unlikely. Instead, we argue that the crystal structure is that of [nBu4 N]O2 CCH3 and therefore not representative of the bulk powder from the synthesis. PMID- 26036319 TI - Solution-Phase Conversion of Bulk Metal Oxides to Metal Chalcogenides Using a Simple Thiol-Amine Solvent Mixture. AB - A thiol-amine solvent mixture is used to dissolve ten inexpensive bulk oxides (Cu2O, ZnO, GeO2, As2O3, Ag2O, CdO, SnO, Sb2O3, PbO, and Bi2O3) under ambient conditions. Dissolved oxides can be converted to the corresponding sulfides using the thiol as the sulfur source, while selenides and tellurides can be accessed upon mixing with a stoichiometric amount of dissolved selenium or tellurium. The practicality of this method is illustrated by solution depositing Sb2Se3 thin films from compound inks of dissolved Sb2O3 and selenium that give high photoelectrochemical current response. The direct band gap of the resulting material can be tuned from 1.2-1.6 eV by modulating the ink formulation to give compositionally controlled Sb2Se(3-x)S(x) alloys. PMID- 26036320 TI - Genetic diversity and population structure of an Italian landrace of runner bean (Phaseolus coccineus L.): inferences for its safeguard and on-farm conservation. AB - The landraces are considered important sources of valuable germplasm for breeding activities to face climatic changes as well as to satisfy the requirement of new varieties for marginal areas. Runner bean (Phaseolus coccineus L.) is one of the most cultivated Phaseolus species worldwide, but few studies have been addressed to assess the genetic diversity and structure within and among landrace populations. In the present study, 20 different populations of a runner bean landrace from Central Italy named "Fagiolone," together with 41 accessions from Italy and Mesoamerica, were evaluated by using 14 nuclear SSRs to establish its genetic structure and distinctiveness. Results indicated that "Fagiolone" landrace can be considered as a dynamic evolving open-pollinated population that shows a significant level of genetic variation, mostly detected within populations, and the presence of two main genetic groups, of which one distinguished from other Italian runner bean landraces. Results highlighted also a relevant importance of farmers' management practices able to influence the genetic structure of this landrace, in particular the seed exchanges and selection, and the past introduction in cultivation of landraces/cultivars similar to seed morphology, but genetically rather far from "Fagiolone." The most suitable on-farm strategies for seed collection, conservation and multiplication will be defined based on our results, as a model for threatened populations of other allogamous crop species. STRUCTURE and phylogenetic analyses indicated that Mesoamerican accessions and Italian landraces belong to two distinct gene pools confirming the hypothesis that Europe could be considered a secondary diversification center for P. coccineus. PMID- 26036321 TI - The diagnostic challenge of pulmonary tumour thrombotic microangiopathy as a presentation for metastatic gastric cancer: a case report and review of the literature. AB - BACKGROUND: Pulmonary tumour thrombotic microangiopathy (PTTM) is a rare complication of metastatic cancer with a distinct histological appearance which presents with dyspnoea and pulmonary arterial hypertension and leads to death in hours to days. It is a challenging diagnosis to make ante mortem, in part due to the rapid clinical decline. Herein, we report a case of a young woman initially felt to have pulmonary sarcoidosis but who then died eight days later from what was found at post mortem to be PTTM. CASE PRESENTATION: A 41 year old Caucasian woman presented with progressive dyspnoea. Computed tomography of her thorax showed diffuse tiny centrilobular nodules in a tree-in-bud appearance along with small volume mediastinal lymphadenopathy. A presumptive diagnosis of pulmonary sarcoidosis was made; bronchoscopy with transbronchial lung biopsy was arranged to confirm the diagnosis. However, she rapidly deteriorated and died eight days later. Post mortem examination revealed metastatic poorly differentiated gastric adenocarcinoma with PTTM being the final cause of death. CONCLUSION: This case demonstrates the diagnostic difficulties in such a rare and rapidly fatal oncological complication; a greater awareness amongst clinicians may help make a positive diagnosis in the short window of time available. Little is known about its pathogenesis, and even less about optimal management strategies. We review the literature to demonstrate the clinical characteristics that might provide clues towards an ante mortem diagnosis, and highlight how imatinib may provide the key to treating PTTM. PMID- 26036322 TI - Timely thoracoscopic decortication promotes the recovery of paediatric parapneumonic empyema. AB - INTRODUCTION: Parapneumonic empyema is one of the most commonly encountered yet difficult to manage paediatric thoracic conditions. Conservative treatment with chest tube drainage and fibrinolytic agents had been proposed but operative decortication remains the gold standard for refractory cases. Thoracoscopic decortication has been advocated in recent years due to its superiority in terms of post-operative pain, cosmesis and other long-term results. However, few studies investigated the effect of timing on peri-operative outcomes. This study aims to explore the benefits of early decortication. METHODS: Retrospective study of all patients who underwent thoracoscopic decortication between 1999 and 2013 at a tertiary referral centre was performed. Data were extracted from respective medical records. Patients' demographics, peri-operative outcomes, length of hospitalization and post-operative complications were analysed. RESULTS: A total of 28 patients were identified, 12 males and 16 females. Average age of patients was 4.5 years (range 12 months-14 years). Right-sided empyema was involved in 14 of the patients. Patients who underwent operation within 2 weeks from symptom onset (n = 16) showed significant shorter post-operative hospital stay (mean 9.5 vs 20.4 days, p = 0.003) and total hospitalization duration (mean 19.3 vs 38.8 days, p < 0.001). Correlation study demonstrated a strong relation between delay in operation and prolonged hospitalization (r = 0.63, p = 0.001). The peri operative and post-operative outcomes were similar. No major post-operative complication was encountered except one patient who required a second decortication for residual empyema. CONCLUSION: Thoracoscopic decortication is a safe and feasible procedure for parapneumonic empyema. Timely surgery is recommended as it promotes early recovery and shorter hospitalization. PMID- 26036324 TI - The use of meta-analyses for benefit/risk re-evaluations of hydroxyethyl starch. PMID- 26036323 TI - An application of MeSH enrichment analysis in livestock. AB - An integral part of functional genomics studies is to assess the enrichment of specific biological terms in lists of genes found to be playing an important role in biological phenomena. Contrasting the observed frequency of annotated terms with those of the background is at the core of overrepresentation analysis (ORA). Gene Ontology (GO) is a means to consistently classify and annotate gene products and has become a mainstay in ORA. Alternatively, Medical Subject Headings (MeSH) offers a comprehensive life science vocabulary including additional categories that are not covered by GO. Although MeSH is applied predominantly in human and model organism research, its full potential in livestock genetics is yet to be explored. In this study, MeSH ORA was evaluated to discern biological properties of identified genes and contrast them with the results obtained from GO enrichment analysis. Three published datasets were employed for this purpose, representing a gene expression study in dairy cattle, the use of SNPs for genome wide prediction in swine and the identification of genomic regions targeted by selection in horses. We found that several overrepresented MeSH annotations linked to these gene sets share similar concepts with those of GO terms. Moreover, MeSH yielded unique annotations, which are not directly provided by GO terms, suggesting that MeSH has the potential to refine and enrich the representation of biological knowledge. We demonstrated that MeSH can be regarded as another choice of annotation to draw biological inferences from genes identified via experimental analyses. When used in combination with GO terms, our results indicate that MeSH can enhance our functional interpretations for specific biological conditions or the genetic basis of complex traits in livestock species. PMID- 26036325 TI - Management of stone disease in infants. AB - Evaluating and treating renal stone disease in infants are technically challenging. In this study, we evaluated the surgical treatment of renal stones in children under 1 year of age. We retrospectively reviewed the records of patients under 1 year old who were treated with ESWL, endourological or open surgical procedures for renal stone disease between January, 2009 and December, 2012. The patients' age, gender, stone size, stone location and number, complications, stone-free status, and postoperative complications were recorded. 19 of 121 infants with a mean age of 10.2 +/- 3.07 months were treated with surgical procedures. Six (75%) of eight cystinuria patients required a surgical intervention. Retrograde endoscopic management was performed in thirteen patients (63.4%) as an initial surgical approach. There were three major (15.7%) complications. The rate of open surgical procedures was 31.6% (6 of 19 infants). The cutoff value of stone size for open surgery was 10 mm. There was a significant relationship between the conversion to open procedures and stone size, stone location, and symptom presentation especially the presence of obstruction (p < 0.05). After repeated treatments, the stone clearance rate of RIRS reached 84.6%. Retrograde intrarenal surgery is an effective and safe treatment method for renal stones in infants and can be used as a first-line therapy in most patients under 1 year old. This is especially important if an associated ureteral stone or lower pole stone that requires treatment is present and for patients with cystinuria, which does not respond favorably to ESWL. PMID- 26036327 TI - Design and Application of Variable Temperature Setup for Scanning Electron Microscopy in Gases and Liquids at Ambient Conditions. AB - Scanning electron microscopy (SEM) of nanoscale objects in dry and fully hydrated conditions at different temperatures is of critical importance in revealing details of their interactions with an ambient environment. Currently available WETSEM capsules are equipped with thin electron-transparent membranes and allow imaging of samples at atmospheric pressure, but do not provide temperature control over the sample. Here, we developed and tested a thermoelectric cooling/heating setup for WETSEM capsules to allow ambient pressure in situ SEM studies with a temperature range between -15 and 100 degrees C in gaseous, liquid, and frozen conditions. The design of the setup also allows for correlation of the SEM with optical microscopy and spectroscopy. As a demonstration of the possibilities of the developed approach, we performed real time in situ microscopy studies of water condensation on a surface of Morpho sulkowskyi butterfly wing scales. We observed that initial water nucleation takes place on top of the scale ridges. These results confirmed earlier discovery of a preexisting polarity gradient of the ridges of Morpho butterflies. Our developed thermoelectric cooling/heating setup for environmental capsules meets the diverse needs for in situ nanocharacterization in material science, catalysis, microelectronics, chemistry, and biology. PMID- 26036326 TI - Genetic and antigenic characterization of H5 and H7 influenza viruses isolated from migratory water birds in Hokkaido, Japan and Mongolia from 2010 to 2014. AB - Migratory water birds are the natural reservoir of influenza A viruses. H5 and H7 influenza viruses are isolated over the world and also circulate among poultry in Asia. In 2010, two H5N1 highly pathogenic avian influenza viruses (HPAIVs) were isolated from fecal samples of water birds on the flyway of migration from Siberia, Russia to the south in Hokkaido, Japan. H7N9 viruses are sporadically isolated from humans and circulate in poultry in China. To monitor whether these viruses have spread in the wild bird population, we conducted virological surveillance of avian influenza in migratory water birds in autumn from 2010 to 2014. A total of 8103 fecal samples from migratory water birds were collected in Japan and Mongolia, and 350 influenza viruses including 13 H5 and 19 H7 influenza viruses were isolated. A phylogenetic analysis revealed that all isolates are genetically closely related to viruses circulating among wild water birds. The results of the antigenic analysis indicated that the antigenicity of viruses in wild water birds is highly stable despite their nucleotide sequence diversity but is distinct from that of HPAIVs recently isolated in Asia. The present results suggest that HPAIVs and Chinese H7N9 viruses were not predominantly circulating in migratory water birds; however, continued monitoring of H5 and H7 influenza viruses both in domestic and wild birds is recommended for the control of avian influenza. PMID- 26036328 TI - Neuroendocrine Carcinoma of the Gallbladder Masquerading as a Klatskin Tumor in a 74-Year-Old Male. PMID- 26036329 TI - Efficacy of topical resin lacquer, amorolfine and oral terbinafine for treating toenail onychomycosis: a prospective, randomized, controlled, investigator blinded, parallel-group clinical trial. AB - BACKGROUND: Norway spruce (Picea abies) produces resin to protect against decomposition by microbial pathogens. In vitro tests have shown that spruce resin has antifungal properties against dermatophytes known to cause nearly 90% of onychomycosis in humans. OBJECTIVES: To confirm previous in vivo observations that a topical resin lacquer provides mycological and clinical efficacy, and to compare this lacquer with topical amorolfine hydrochloride lacquer and systemic terbinafine for treating dermatophyte toenail onychomycosis. METHODS: In this prospective, randomized, controlled, investigator-blinded study, 73 patients with onychomycosis were randomized to receive topical 30% resin lacquer once daily for 9 months, topical 5% amorolfine lacquer once weekly for 9 months, or 250 mg oral terbinafine once daily for 3 months. The primary outcome measure was complete mycological cure at 10 months. Secondary outcomes were clinical efficacy, cost effectiveness and patient compliance. RESULTS: At 10 months, complete mycological cure rates with the resin, amorolfine and terbinafine treatments were 13% [95% confidence interval (CI) 0-28], 8% (95% CI 0-19) and 56% (95% CI 35-77), respectively (P <= 0.002). At 10 months, clinical responses were complete in four patients (16%) treated with terbinafine, and partial in seven (30%), seven (28%) and nine (36%) patients treated with resin, amorolfine and terbinafine, respectively (P < 0.05). Resin, amorolfine and terbinafine treatments cost ?41.6, ?56.3 and ?52.1, respectively, per patient (P < 0.001). CONCLUSIONS: Topical 30% resin lacquer and topical 5% amorolfine lacquer provided similar efficacy for treating dermatophyte toenail onychomycosis. However, orally administered terbinafine was significantly more effective in terms of mycological cure and clinical outcome than either topical therapy at the 10-month follow-up. PMID- 26036331 TI - Carbon Nanosheets: Synthesis and Application. AB - Carbon nanosheets (CNSs) with tunable sizes, morphologies, and pore structures have been synthesized through several chemical routes. Graphitized CNSs have been synthesized through exfoliation, chemical vapor deposition, or high-temperature carbonization. Porous CNSs have been synthesized by using various methods, including pyrolysis, self-assembly, or a solvothermal method in connection with carbonization. These CNSs have successfully been used as detectors for metal ions, as cathodes for field electron emissions, as electrodes for supercapacitors and fuel cells, and as supports for photocatalytic and catalytic oxygen reduction. Therefore, the synthesis and application of CNSs are receiving increasing levels of interest, particularly as application benefits, in the context of future energy/chemical industry, are becoming recognized. This review provides a summary of the most recent and important progress in the production of CNSs and highlights their application in environmental and energy-related fields. PMID- 26036332 TI - Visa refusal following compulsory hospital admission under the Mental Health Act 1983 (England and Wales): fact or fiction? AB - ACCESSIBLE SUMMARY: Historically, compulsory hospital admission led to discrimination for service users. For example, until recently detention under the Mental Health Act 1983 (England and Wales) would disqualify a person from being a Member of Parliament. There is a belief among mental health professionals that compulsory hospital admission will result in service users being refused a tourist visa. However, there is a paucity of literature on this topic, particularly from an international perspective. Based on the information reviewed in this study, there is no evidence to support this belief. Of 262 travel destinations, 96 (36.6%) require British citizens to obtain a tourist visa. Six (2.3%) destinations require applicants to declare a mental health condition in order to obtain a tourist visa. None of these destinations ask applicants to declare a history of compulsory hospital admission. However, the possibility exists that anyone declaring a mental health problem may be asked to provide further information about their condition before a visa is granted. Mental health nurses require education to ensure that their knowledge of mental health legislation is up to date. This education should include information on the potential consequences of compulsory hospital admission for the service user's social life following discharge. Service users and their families should be provided with written information on the potential social impact of detention along with a list of organizations that can provide advice on specific issues. ABSTRACT: This study sought to establish whether a history of compulsory hospital admission prevented a person from obtaining a tourist visa. A visa application form and/or other relevant information were obtained for 262 travel destinations visited by British citizens. Ninety-six (36.6%) destinations require British citizens to obtain a tourist visa. All visas are issued subject to travellers meeting a number of conditions, for example being in possession of travel insurance. Six (2.3%) destinations (Australia, China, Guam, Puerto Rico, Russia and the USA) ask applicants to declare a mental health condition. None of these destinations require applicants to disclose whether they have been admitted to hospital, either informal or under a section of the Mental Health Act 1983. However, the possibility exists that anyone declaring a mental health problem may be asked to provide further information about their condition before a visa is granted. Mental health professionals need to acquire accurate knowledge of the potential consequences of compulsory hospital admission. This will enable them to support service users more effectively. Similarly, service users need to be aware of the implications of detention for their social life following discharge from hospital. Further research is required in this area, particularly from an international perspective. PMID- 26036333 TI - Simulator training in fetoscopic laser surgery for twin-twin transfusion syndrome: a pilot randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of a newly developed training curriculum on the performance of fetoscopic laser surgery for twin-twin transfusion syndrome (TTTS) using an advanced high-fidelity simulator model. METHODS: Ten novices were randomized to receive verbal instructions and either skills training using the simulator (study group; n = 5) or no training (control group; n = 5). Both groups were evaluated with a pre-training and post-training test on the simulator. Performance was assessed by two independent observers and comprised a 52-item checklist for surgical performance (SP) score, measurement of procedure time and number of anastomoses missed. Eleven experts set the benchmark level of performance. Face validity and educational value of the simulator were assessed using a questionnaire. RESULTS: Both groups showed an improvement in SP score at the post-training test compared with the pre-training test. The simulator-trained group significantly outperformed the control group, with a median SP score of 28 (54%) in the pre-test and 46 (88%) in the post-test vs 25 (48%) and 36 (69%), respectively (P = 0.008). Procedure time decreased by 11 min (from 44 to 33 min) in the study group vs 1 min (from 39 to 38 min) in the control group (P = 0.69). There was no significant difference in the number of missed anastomoses at the post-training test between the two groups (1 vs 0). Subsequent feedback provided by the participants indicated that training on the simulator was perceived as a useful educational activity. CONCLUSIONS: Proficiency-based simulator training improves performance, indicated by SP score, for fetoscopic laser therapy. Despite the small sample size of this study, practice on a simulator is recommended before trainees carry out laser therapy for TTTS in pregnant women. PMID- 26036335 TI - Fusing Continuous-Valued Medical Labels Using a Bayesian Model. AB - With the rapid increase in volume of time series medical data available through wearable devices, there is a need to employ automated algorithms to label data. Examples of labels include interventions, changes in activity (e.g. sleep) and changes in physiology (e.g. arrhythmias). However, automated algorithms tend to be unreliable resulting in lower quality care. Expert annotations are scarce, expensive, and prone to significant inter- and intra-observer variance. To address these problems, a Bayesian Continuous-valued Label Aggregator (BCLA) is proposed to provide a reliable estimation of label aggregation while accurately infer the precision and bias of each algorithm. The BCLA was applied to QT interval (pro-arrhythmic indicator) estimation from the electrocardiogram using labels from the 2006 PhysioNet/Computing in Cardiology Challenge database. It was compared to the mean, median, and a previously proposed Expectation Maximization (EM) label aggregation approaches. While accurately predicting each labelling algorithm's bias and precision, the root-mean-square error of the BCLA was 11.78 +/- 0.63 ms, significantly outperforming the best Challenge entry (15.37 +/- 2.13 ms) as well as the EM, mean, and median voting strategies (14.76 +/- 0.52, 17.61 +/- 0.55, and 14.43 +/- 0.57 ms respectively with p < 0.0001). The BCLA could therefore provide accurate estimation for medical continuous-valued label tasks in an unsupervised manner even when the ground truth is not available. PMID- 26036334 TI - Approaches for estimating minimal clinically important differences in systemic lupus erythematosus. AB - A minimal clinically important difference (MCID) is an important concept used to determine whether a medical intervention improves perceived outcomes in patients. Prior to the introduction of the concept in 1989, studies focused primarily on statistical significance. As most recent clinical trials in systemic lupus erythematosus (SLE) have failed to show significant effects, determining a clinically relevant threshold for outcome scores (that is, the MCID) of existing instruments may be critical for conducting and interpreting meaningful clinical trials as well as for facilitating the establishment of treatment recommendations for patients. To that effect, methods to determine the MCID can be divided into two well-defined categories: distribution-based and anchor-based approaches. Distribution-based approaches are based on statistical characteristics of the obtained samples. There are various methods within the distribution-based approach, including the standard error of measurement, the standard deviation, the effect size, the minimal detectable change, the reliable change index, and the standardized response mean. Anchor-based approaches compare the change in a patient-reported outcome to a second, external measure of change (that is, one that is more clearly understood, such as a global assessment), which serves as the anchor. Finally, the Delphi technique can be applied as an adjunct to defining a clinically important difference. Despite an abundance of methods reported in the literature, little work in MCID estimation has been done in the context of SLE. As the MCID can help determine the effect of a given therapy on a patient and add meaning to statistical inferences made in clinical research, we believe there ought to be renewed focus on this area. Here, we provide an update on the use of MCIDs in clinical research, review some of the work done in this area in SLE, and propose an agenda for future research. PMID- 26036336 TI - Altered Flow Changes Thrombin Generation Rate of Circulating Platelets. AB - Shear stress affects platelet participation in coagulation. Many numerical models have been developed to describe coagulation kinetics. However, most of those models used rate constants determined under static conditions. Little is known about the effects of flow on coagulation rate constants. In the present study, platelets were exposed to constant or pulsatile shear stress/rate, with or without prothrombin, factor Xa, and factor Va. Thrombin generation was measured using a modified prothrombinase assay, and the overall thrombin generation rate was solved using typical Michaelis-Menten kinetics. Platelet surface P-selectin and phosphatidylserine (PS) expression was measured using flow cytometry. The results demonstrated that the concentration of factor Va had a dominant effect on thrombin generation rate under flow. In comparison, the expression of PS was less sensitive to altered flow. The lumped overall rate constant for prothrombin conversion to thrombin was significantly affected by the shear forces that were applied to the coagulation complex. Constant shear stress/rate induced faster thrombin generation compared to pulsatile shear stress/rate, but elevated shear stress/rate did not necessarily enhance thrombin generation. Therefore, the overall thrombin generation rate is dynamic and must be described as a function of shear stress/rate, shear exposure time and the immediate availability of coagulation proteins. PMID- 26036337 TI - Predictors of post-partum stress in Vietnamese immigrant women in Taiwan. AB - AIM: The post-partum period is a stressful time of change, particularly for immigrant women, but, to the best of the present authors' knowledge, the subject has not been explored. This study aimed to examine immigrant women's post-partum stress, depression, and levels of social support, and to determine the predictors of post-partum stress for Vietnamese immigrant women in Taiwan. METHODS: A cross sectional design was used. In this descriptive survey, 208 Vietnamese immigrant women were telephone interviewed by a trained Vietnamese research assistant during one of their 6 weeks post-partum. Data were collected through telephone interviews using three questionnaires, including the Hung Postpartum Stress Scale, Beck Depression Inventory, and Social Support Scale. RESULTS: The result shows that Vietnamese women had low level post-partum stress scores. Participants' family support rated higher than friend support. The incidence of depression was 0.5%. Social support, number of post-partum days, and family income were found to be predictors for post-partum stress, accounting for 26.6% of the variance. The Vietnamese immigrant women experienced significant stress regarding their maternal roles and received most of their support from their families rather than from friends. CONCLUSION: Nurses caring for this cohort should therefore consider these factors in order to help them cope with their post-partum stress. Healthcare providers should offer available resources to these immigrant women and their spouses during this critical period in their lives. For instance, antenatal education classes could be provided to help immigrant women manage and overcome post-partum issues. PMID- 26036339 TI - The evolution of oviparity in squamate reptiles: An adaptationist perspective. AB - Phylogenetically based analyses can suggest directions of evolutionary transitions, based on parsimony, but can never provide unambiguous answers. To clarify the relative frequency of phylogenetic shifts from oviparity to viviparity versus the reverse, we need additional sources of evidence. Adaptationist thinking (i.e., consideration of selective forces) has revealed a great deal about the transition from oviparity to viviparity, but has rarely been employed to consider the reverse transition. An evaluation of costs and benefits identifies major obstacles to the re-evolution of oviparity. For example, even a modest decrease in the degree of embryogenesis completed in utero (i.e., a shift from viviparity back toward "normal" oviparity) requires the mother to find a suitable nest-site (often, a risky endeavor), and a minor decrease in the duration of uterine retention of eggs may not substantially reduce maternal costs (because many of those costs are minimized by maternal behavioral adaptations to pregnancy). In many climates, a small decrease in the duration of uterine retention of eggs would not allow the female to produce a second clutch within the same season; and thus, would not reduce the fecundity disadvantage of viviparity. Life-history theory thus suggests an asymmetry in the fitness consequences of the intermediate stages between oviparity and viviparity. That asymmetry facilitates the "forward" transition (based on thermally driven benefits to offspring viability) but opposes the "reverse" transition (based on lower fitness of heavily burdened females that need to seek nest-sites). These factors should constrain the re-evolution of oviparity to specific conditions (e.g., where abundant nest-sites are available within a female's usual home range, rather than requiring extensive migration). PMID- 26036338 TI - Universal tumor screening for Lynch syndrome: Assessment of the perspectives of patients with colorectal cancer regarding benefits and barriers. AB - BACKGROUND: Universal tumor screening for Lynch syndrome, the most common form of hereditary colorectal cancer (CRC), has been recommended among all patients newly diagnosed with CRC. However, there is limited literature regarding patient perspectives of tumor screening for Lynch syndrome among patients with CRC who are not selected for screening based on family history criteria. METHODS: A total of 145 patients aged 39 to 87 years were administered surveys assessing perceived risk, patient perspectives, and potential benefits of and barriers to tumor screening for Lynch syndrome. Associations between patient-specific and cancer specific factors and survey responses were analyzed. RESULTS: The majority of participants perceived their risk of developing Lynch syndrome as being low, with 9 participants (6.2%) anticipating an abnormal screening result. However, most participants endorsed the potential benefits of screening for themselves and their families, with 84.8% endorsing >=6 benefits and 50.3% endorsing all 8 benefits. Participants also endorsed few potential barriers to screening, with 89.4% endorsing <=4 of 9 potential barriers. A common barrier was worry about the cost of additional testing and surveillance, which was endorsed by 54.5% of participants. The level of distress associated with tumor screening for Lynch syndrome, which was very low, was not associated with age or CRC stage. CONCLUSIONS: The results of the current study indicate that patients with CRC overall have a positive attitude toward tumor screening for Lynch syndrome, endorse the benefits of screening, and experience low levels of distress. These findings provide insight into patient attitudes toward tumor screening for Lynch syndrome among unselected patients with CRC to inform educational approaches that assist in patient decision-making and guide the successful implementation of screening programs. PMID- 26036340 TI - The use of ubiquitin lysine mutants to characterize E2-E3 linkage specificity: Mass spectrometry offers a cautionary "tail". AB - Oligomeric ubiquitin structures (i.e. ubiquitin "chains") may be formed through any of seven different lysine residues in the polypeptide, or via the amine group of Met 1. Different types of ubiquitin chains can confer very different biological outcomes to a protein substrate, yet the structural characteristics of E2s and E3s that determine ubiquitin linkage specificity remain poorly understood. In vitro autoubiquitylation assays combined with ubiquitin protein variants bearing individually mutated lysine residues ("K-to-R" mutants) have thus been widely used to characterize E2-E3 linkage specificity. However, how this type of assay compares to direct identification of ubiquitin linkage types using mass spectrometry (MS) has not been rigorously tested. Here, we characterize the linkage specificity of 12 different E2-E3 combinations using both approaches. The simple MS-based method described here is more robust, requires less material and is less prone to bias introduced by, e.g. the use of mutant proteins with unknown effects on E1, E2 or E3 recognition, antibodies with uncharacterized epitopes, the low dynamic range of X-ray film, and additional sources of experimental error. Indeed, our results suggest that the K-to-R assay be approached with some caution. PMID- 26036341 TI - Comparison of output-based approaches used to substantiate bovine tuberculosis free status in Danish cattle herds. AB - We compared two published studies based on different output-based surveillance models, which were used for evaluating the performance of two meat inspection systems in cattle and to substantiate freedom from bovine tuberculosis (bTB) in Denmark. The systems were the current meat inspection methods (CMI) vs. the visual-only inspection (VOI). In one study, the surveillance system sensitivity (SSe) was estimated to substantiate the bTB free status. The other study used SSe in the estimation of the probability of freedom (PFree), based on the epidemiological concept of negative predictive value to substantiate the bTB free status. Both studies found that changing from CMI to VOI would markedly decrease the SSe. However, the two studies reported diverging conclusions regarding the effect on the substantiation of Denmark as a bTB free country, if VOI were to be introduced. The objectives of this work were: (a) to investigate the reasons why conclusions based on the two models differed, and (b) to create a hybrid model based on elements from both studies to evaluate the impact of a change from CMI to VOI. The hybrid model was based on the PFree approach to substantiate freedom from bTB and was parametrized with inputs according to the newest available information. The PFree was updated on an annual basis for each of 42 years of test-negative surveillance data (1995-2037), while assuming a low (<1%) annual probability of introduction of bTB into Danish cattle herds. The most important reasons for the difference between the study conclusions were: the approach chosen to substantiate the bTB free status (SSe vs. PFree) and the number of years of surveillance data considered. With the hybrid model, the PFree reached a level >95% after the first year of surveillance and remained >=96% with both the CMI and VOI systems until the end of the analyzed period. It is appropriate to use the PFree of the surveillance system to substantiate confidence in bTB free status, when test-negative surveillance results can be documented over an extended period of time, while maintaining a low probability of introduction of bTB into the cattle population. For Denmark, the probability of introduction of bTB should be kept <1% on an annual basis to sustain the high confidence in freedom over time. The results could be considered when deciding if the CMI can be replaced by VOI in cattle abattoirs of countries for which bTB freedom can be demonstrated. PMID- 26036342 TI - Use of a modified Delphi panel to identify and weight criteria for prioritization of zoonotic diseases in Switzerland. AB - Zoonotic diseases have a significant impact on public health globally. To prevent or reduce future zoonotic outbreaks, there is a constant need to invest in research and surveillance programs while updating risk management strategies. However, given the limited resources available, disease prioritization based on the need for their control and surveillance is important. This study was performed to identify and weight disease criteria for the prioritization of zoonotic diseases in Switzerland using a semi-quantitative research method based on expert opinion. Twenty-eight criteria relevant for disease control and surveillance, classified under five domains, were selected following a thorough literature review, and these were evaluated and weighted by seven experts from the Swiss Federal Veterinary Office using a modified Delphi panel. The median scores assigned to each criterion were then used to rank 16 notifiable and/or emerging zoonoses in Switzerland. The experts weighted the majority of the criteria similarly, and the top three criteria were Severity of disease in humans, incidence and prevalence of the disease in humans and treatment in humans. Based on these weightings, the three highest ranked diseases were Avian Influenza, Bovine Spongiform Encephalitis, and Bovine Tuberculosis. Overall, this study provided a preliminary list of criteria relevant for disease prioritization in Switzerland. These were further evaluated in a companion study which involved a quantitative prioritization method and multiple stakeholders. PMID- 26036344 TI - Stress triggers mitochondrial biogenesis to preserve steroidogenesis in Leydig cells. AB - Adaptability to stress is a fundamental prerequisite for survival. Mitochondria are a key component of the stress response in all cells. For steroid-hormones producing cells, including also Leydig cells of testes, the mitochondria are a key control point for the steroid biosynthesis and regulation. However, the mitochondrial biogenesis in steroidogenic cells has never been explored. Here we show that increased mitochondrial biogenesis is the adaptive response of testosterone-producing Leydig cells from stressed rats. All markers of mitochondrial biogenesis together with transcription factors and related kinases are up-regulated in Leydig cells from rats exposed to repeated psychophysical stress. This is followed with increased mitochondrial mass. The expression of PGC1, master regulator of mitochondrial biogenesis and integrator of environmental signals, is stimulated by cAMP-PRKA, cGMP, and beta-adrenergic receptors. Accordingly, stress-triggered mitochondrial biogenesis represents an adaptive mechanism and does not only correlate with but also is an essential for testosterone production, being both events depend on the same regulators. Here we propose that all events induced by acute stress, the most common stress in human society, provoke adaptive response of testosterone-producing Leydig cells and activate PGC1, a protein required to make new mitochondria but also protector against the oxidative damage. Given the importance of mitochondria for steroid hormones production and stress response, as well as the role of steroid hormones in stress response and metabolic syndrome, we anticipate our result to be a starting point for more investigations since stress is a constant factor in life and has become one of the most significant health problems in modern societies. PMID- 26036343 TI - PAK1 modulates a PPARgamma/NF-kappaB cascade in intestinal inflammation. AB - P21-activated kinases (PAKs) are multifunctional effectors of Rho GTPases with both kinase and scaffolding activity. Here, we investigated the effects of inflammation on PAK1 signaling and its role in colitis-driven carcinogenesis. PAK1 and p-PAK1 (Thr423) were assessed by immunohistochemistry, immunofluorescence, and Western blot. C57BL6/J wildtype mice were treated with a single intraperitoneal TNFalpha injection. Small intestinal organoids from these mice and from PAK1-KO mice were cultured with TNFalpha. NF-kappaB and PPARgamma were analyzed upon PAK1 overexpression and silencing for transcriptional/translational regulation. PAK1 expression and activation was increased on the luminal intestinal epithelial surface in inflammatory bowel disease and colitis-associated cancer. PAK1 was phosphorylated upon treatment with IFNgamma, IL-1beta, and TNFalpha. In vivo, mice administered with TNFalpha showed increased p-PAK1 in intestinal villi, which was associated with nuclear p65 and NF-kappaB activation. p65 nuclear translocation downstream of TNFalpha was strongly inhibited in PAK1-KO small intestinal organoids. PAK1 overexpression induced a PAK1-p65 interaction as visualized by co-immunoprecipitation, nuclear translocation, and increased NF-kappaB transactivation, all of which were impeded by kinase-dead PAK1. Moreover, PAK1 overexpression downregulated PPARgamma and mesalamine recovered PPARgamma through PAK1 inhibition. On the other hand PAK1 silencing inhibited NF-kappaB, which was recovered using BADGE, a PPARgamma antagonist. Altogether these data demonstrate that PAK1 overexpression and activation in inflammation and colitis-associated cancer promote NF-kappaB activity via suppression of PPARgamma in intestinal epithelial cells. PMID- 26036345 TI - Augmented EGF receptor tyrosine kinase activity impairs vascular function by NADPH oxidase-dependent mechanism in type 2 diabetic mouse. AB - We previously determined that augmented EGFR tyrosine kinase (EGFRtk) impairs vascular function in type 2 diabetic mouse (TD2). Here we determined that EGFRtk causes vascular dysfunction through NADPH oxidase activity in TD2. Mesenteric resistance arteries (MRA) from C57/BL6 and db-/db- mice were mounted in a wired myograph and pre-incubated for 1h with either EGFRtk inhibitor (AG1478) or exogenous EGF. The inhibition of EGFRtk did not affect the contractile response to phenylephrine-(PE) and thromboxane-(U46619) or endothelium-dependent relaxation (EDR) to acetylcholine in MRA from control group. However, in TD2 mice, AG1478 reduced the contractile response to U46619, improved vasodilatation and reduced p22phox-NADPH expression, but had no effect on the contractile response to PE. The incubation of MRA with exogenous EGF potentiated the contractile response to PE in MRA from control and diabetic mice. However, EGF impaired the EDR and potentiated the vasoconstriction to U46619 only in the control group. Interestingly, NADPH oxidase inhibition in the presence of EGF restored the normal contraction to PE and improved the EDR but had no effect on the potentiated contraction to U46619. Vascular function improvement was associated with the rescue of eNOS and Akt and reduction in phosphorylated Rho kinase, NOX4 mRNA levels, and NADPH oxidase activity. MRA from p47phox-/- mice incubated with EGF potentiated the contraction to U46619 but had no effect to PE or ACh responses. The present study provides evidence that augmented EGFRtk impairs vascular function by NADPH oxidase-dependent mechanism. Therefore, EGFRtk and oxidative stress should be potential targets to treat vascular dysfunction in TD2. PMID- 26036346 TI - Micro-RNAs miR-29a and miR-330-5p function as tumor suppressors by targeting the MUC1 mucin in pancreatic cancer cells. AB - MUC1 is an oncogenic mucin overexpressed in several epithelial cancers, including pancreatic ductal adenocarcinoma, and is considered as a potent target for cancer therapy. To control cancer progression, miRNAs became very recently, major targets and tools to inhibit oncogene expression. Inhibiting MUC1 using miRNAs appears thus as an attractive strategy to reduce cancer progression. However, potent miRNAs and associated mechanisms regulating MUC1 expression remain to be identified. To this aim, we undertook to study MUC1 regulation by miRNAs in pancreatic cancer cells and identify those with tumor suppressive activity. MiRNAs potentially targeting the 3'-UTR, the coding region, or the 5'-UTR of MUC1 were selected using an in silico approach. Our in vitro and in vivo experiments indicate that miR-29a and miR-330-5p are strong inhibitors of MUC1 expression in pancreatic cancer cells through direct binding to MUC1 3'-UTR. MUC1 regulation by the other selected miRNAs (miR-183, miR-200a, miR-876-3p and miR-939) was found to be indirect. MiR-29a and miR-330-5p are also deregulated in human pancreatic cancer cell lines and tissues and in pancreatic tissues of Kras(G12D) mice. In vitro, miR-29a and miR-330-5p inhibit cell proliferation, cell migration, cell invasion and sensitize pancreatic cancer cells to gemcitabine. In vivo intra tumoral injection of these two miRNAs in xenografted pancreatic tumors led to reduced tumor growth. Altogether, we have identified miR-29a and miR-330-5p as two new tumor suppressive miRNAs that inhibit the expression of MUC1 oncogenic mucin in pancreatic cancer cells. PMID- 26036347 TI - Psychopharmacologic Management in Integrated Care: Challenges for Residency Education. AB - The integration of psychiatric care in primary care is becoming a reality. Psychiatric training programs are facing multiple challenges to accommodate this transition. We here present the perspectives of Group for the Advancement of Psychiatry Committee on Psychopharmacology. The members of the group respond to the concerns raised by a resident currently confronting this changing landscape. By discussing the training, clinical, and communicating challenges of integrated care, they shed light on many of the questions being tackled by residency training programs. This commentary on the timely discussion about integrated care seeks to provide insight on the future of training in psychiatry by outlining the core questions of this change. PMID- 26036348 TI - Integrated Care in Community Settings and Psychiatric Training. PMID- 26036349 TI - A Systematic Review of Reference Values in Pediatric Cardiopulmonary Exercise Testing. AB - Cardiopulmonary exercise testing (CPET) is used for the diagnosis and prognosis of cardiovascular and pulmonary conditions in children and adolescents. Several authors have published reference values for pediatric CPET, but evaluation of their validity is lacking. The aim of this study was to review pediatric CPET references values published between 1980 and 2014. We specifically assessed the adequacy of the normalization methods used to adjust for body size. Articles that proposed references values were reviewed. We abstracted information on exercise protocols, CPET measurements and normalization methods. We then evaluated the studies' methodological quality and assessed them for potential biases. Thirty four studies were included. We found important heterogeneity in the choice of exercise protocols and in the approach to adjustment for body size or other relevant confounding factors. Adjustment for body size was principally done using linear regression for age or weight. Assessment of potential biases (residual association, heteroscedasticity and departure from the normal distribution) was mentioned in only a minority of studies. Our study shows that contemporary pediatric reference values for CPET have been developed based on heterogeneous exercise protocols and variable normalization strategies. Furthermore, assessment of potential bias has been inconsistent and insufficiently described. High quality reference values with adequate adjustment for confounding variables are needed in order to optimize CPET's specificity and sensitivity to detect abnormal cardiopulmonary response to exercise. PMID- 26036350 TI - Predictors of Prolonged Hospital Length of Stay Following Stage II Palliation of Hypoplastic Left Heart Syndrome (and Variants): Analysis of the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) Database. AB - The objective of this study is to identify predictors of prolonged hospital length of stay (LOS) for single ventricle patients following stage 2 palliation (S2P), excluding patients who underwent a hybrid procedure. We explore the impact of demographic features, stage 1 palliation (S1P), interstage I (IS1) management, S2P, and post-surgical care on hospital LOS following S2P. We conducted a retrospective analysis of the National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) database. The NPC-QIC database is an established registry of patients with hypoplastic left heart syndrome (HLHS) and its variants. It contains detailed information regarding the demographic features, S1P, IS1, S2P, and interstage 2 (IS2) management of children with HLHS and related single ventricle cardiac malformations. Between 2008 and 2012, there were 477 participants with recorded LOS data in the NPC-QIC registry. Excluding the 29 patients who underwent hybrid procedure, there were 448 participants who underwent a Norwood (or Norwood-variant procedure) as S1P. In order to be included in the NPC-QIC database, participants were discharged to home following S1P and prior to S2P. We found that postoperative LOS among the 448 S2P procedure recipients is most strongly influenced by the need for reoperation following S2P, the need for an additional cardiac catheterization procedure following S2P, the use of non-oral methods of nutrition (e.g., nasogastric tube, total parental nutrition, gastrostomy tube), and the development of postoperative complications. Factors such as age at the time of S2P, the presence of a major non-cardiac anomaly, site participant volume, IS1 course, the type and number of vasoactive agents used following S2P, and the need for more than 1 intensive care unit (ICU) hospitalization (following discharge to the ward but prior to discharge to home) were significant predictors by univariate analysis but not by multivariate analysis. We excluded participants undergoing the hybrid procedure as S1P from this analysis given that the S2P following the initial hybrid is typically a more complicated procedure. Hospital LOS following S2P among children undergoing the Norwood or Norwood-variant procedure as S1P is most strongly influenced by events following S2P and not demographic or S1P factors. Factors most predictive of prolonged LOS include the need for reoperation, the need for an additional cardiac catheterization procedure following S2P, the need for non-oral methods of nutrition, and the development of postoperative complications. PMID- 26036351 TI - Identification of Copy Number Variations in Isolated Tetralogy of Fallot. AB - Tetralogy of Fallot (ToF) is one of the most common and severe congenital heart defects (CHD). Recently, unbalanced structural genomic variants or copy number variations (CNVs) were proposed to be involved in the etiology of many complex diseases, including CHDs. The aim of this study was to investigate the frequency of CNVs in a region with a high density of CNVs, 22q11.2, and other regions with CHD-related genes in a sample of 52 Mexican mestizo patients with isolated ToF and negative fluorescence in situ hybridization staining for 22q11. CNVs were studied using two multiplex ligation-dependent probe amplification (MLPA) kits, SALSA P250-B1(r) (DiGeorge gene region) and SALSA MLPA P311-A1(r) CHD-related gene regions (GATA4, NKX2-5, TBX5, BMP4, and CRELD1). The MLPA assay detected a de novo CNV deletion of the probes located in exons 2 and 7 of the TBX1 gene in one of the 52 patients studied; this result was confirmed by real-time quantitative polymerase chain reaction. This deletion was not present in the patient's parents and 104 chromosomes from healthy control subjects. Our results clearly suggest a possible etiologic association between the TBX1 deletion and the ToF in our patient. PMID- 26036352 TI - Outcomes of Patients After Arterial Switch Operation: 18 Years of Experience in a Single Medium-Volume Center. AB - The objective of this paper was to describe the outcomes in patients submitted to arterial switch operation and to analyze the predictors of in-hospital mortality and further need of re-operation at a single-center institution. Between September 1995 and January 2014, 128 consecutive arterial switch operations were performed. Surgical mortality during this period was analyzed retrospectively, and a follow-up analysis of the survivors was conducted. Surgical era, cardiopulmonary bypass time (p = 0.001), and diagnosis category (p = 0.025) influenced in-hospital mortality. The estimated overall survival for the 91 hospital survivors was 96.8, 96.4, and 96.2 % at 5, 10, and 15 years, respectively. The median follow-up time was 67 months (range 0.71-222 months). Three patients (5 %) presented severe aortic regurgitation. Right ventricle outflow tract systolic gradient by echocardiography was above 60 mmHg in 2 %. Late re-interventions occurred in 12 (13 %) patients with mean time of 64 +/- 34 months after the initial procedure. Actuarial freedom from re-interventions at 5, 10, and 15 years was 96.4, 69.7, and 61.9 %, respectively. Arterial switch operation remains the procedure of choice in patients with transposition of great arteries. It can be performed even in middle-volume institutions, leading to the same middle- and long-term outcomes of high-volume institutions. Early high mortality rate may occur due not only to learning curve, but also to cardiopulmonary bypass time and ventricular septal defect closure. PMID- 26036353 TI - Graphene oxide monolayers as atomically thin seeding layers for atomic layer deposition of metal oxides. AB - Graphene oxide (GO) was explored as an atomically-thin transferable seed layer for the atomic layer deposition (ALD) of dielectric materials on any substrate of choice. This approach does not require specific chemical groups on the target surface to initiate ALD. This establishes GO as a unique interface which enables the growth of dielectric materials on a wide range of substrate materials and opens up numerous prospects for applications. In this work, a mild oxygen plasma treatment was used to oxidize graphene monolayers with well-controlled and tunable density of epoxide functional groups. This was confirmed by synchrotron radiation photoelectron spectroscopy. In addition, density functional theory calculations were carried out on representative epoxidized graphene monolayer models to correlate the capacitive properties of GO with its electronic structure. Capacitance-voltage measurements showed that the capacitive behavior of Al2O3/GO depends on the oxidation level of GO. Finally, GO was successfully used as an ALD seed layer for the deposition of Al2O3 on chemically inert single layer graphene, resulting in high performance top-gated field-effect transistors. PMID- 26036355 TI - A Challenge Beyond Bottom Cells: Top-Illuminated Flexible Organic Solar Cells with Nanostructured Dielectric/Metal/Polymer (DMP) Films. AB - Top-illuminated flexible organic solar cells with a high power conversion efficiency (~6.75%) are fabricated using a dielectric/metal/polymer (DMP) electrode. Employing a polymer layer (n = 1.49) makes it possible to show the high transmittance, which is insensitive to film thickness, and the excellent haze induced by well-ordered nanopatterns on the DMP electrode, leading to a 28% of enhancement in efficiency compared to bottom cells. PMID- 26036354 TI - A Review of the Toxicity of HIV Medications II: Interactions with Drugs and Complementary and Alternative Medicine Products. AB - For many patients today, HIV has become a chronic disease. For those patients who have access to and adhere to lifelong antiretroviral (ARV) therapy, the potential for drug-drug interactions has become a real and life-threatening concern. It is known that most ARV drug interactions occur through the cytochrome P450 (CYP) pathway. Medications for comorbid medical conditions, holistic supplements, and illicit drugs can be affected by CYP inhibitors and inducers and have the potential to cause harm and toxicity. Protease inhibitors (PIs) tend to inhibit CYP3A4, while most non-nucleoside reverse transcriptase inhibitors (NNRTIs) tend to induce the enzyme. As such, failure to adjust the dose of co-administered medications, such as statins and steroids, may lead to serious complications including rhabdomyolysis and hypercortisolism, respectively. Similarly, gastric acid blockers can decrease several ARV absorption, and warfarin doses may need to be adjusted to maintain therapeutic concentrations. Illicit drugs such as methylenedioxymethamphetamine (MDMA, "ecstasy") in combination with PIs lead to increased toxicity, while the concomitant administration of sedative drugs such as midazolam and alprazolam in patients taking PIs can result in prolonged sedation, delayed recovery, and increased length of stay. Even supplements like St. John's Wort can alter PI concentrations. In theory, any drug that is metabolized by CYP has potential for a pharmacokinetic drug-drug interaction with all PIs, cobicistat, and most NNRTIs. When adding a new medication to an ARV regimen, use of a drug-drug interaction software and/or consultation with a clinical pharmacist/pharmacologist or HIV specialist is recommended. PMID- 26036356 TI - New molecular targets in non clear renal cell carcinoma: An overview of ongoing clinical trials. AB - Non-clear cell renal cell carcinomas (nccRCCs) are a heterogeneous group of tumors, characterized by different histological features, molecular alterations, clinical outcomes, and responses to treatment. According to the 2004 WHO classification, 50 different histotypes were recognized. In 2013, five new distinct epithelial tumors and three provisional entities have been added to this classification, relying on morphology, immunohistochemistry, cytogenetics, and molecular pathology advances. Targeted therapies against VEGF and mTOR pathways have become the cornerstones of the treatment for clear cell RCC, dramatically revolutionizing the patients' prognosis. Interestingly, other than mTOR and VEGF pathways, tumor proliferation of some nccRCC histotypes seems to depend on alternative signaling pathways, as demonstrated by the close correlation between papillary RCC and activation of the HGF/MET axis. Currently, several strategies are under evaluation in patients with nccRCC. These approaches include TKIs and mTOR inhibitors, MET-pathway antagonists and immunotherapy. The aim of this review is to analyze the rationale for the use of TKIs and mTOR inhibitors as treatment options for nccRCC and to describe the future therapeutic perspectives for these patients. PMID- 26036359 TI - Iron(III)-Mediated Radical Nitration of Bisarylsulfonyl Hydrazones: Synthesis of Bisarylnitromethyl Sulfones. AB - Iron(III)-mediated radical nitration of bisarylsulfonyl hydrazones is described. In this protocol, the nontoxic and inexpensive Fe(NO3)3.9H2O plays a dual role as catalyst as well as nitro source. The mild conditions, broad substrate scope, and the functional group compatibility are the significant features. The reaction pathway has been demonstrated using DFT calculations, and the products can be subsequently converted into oximes using SnCl2.2H2O in high yields. PMID- 26036357 TI - Toll like receptors and pancreatic diseases: From a pathogenetic mechanism to a therapeutic target. AB - Toll-like receptors (TLRs) mediate interactions between environmental stimuli and innate immunity. TLRs play a major role in the development of numerous pancreatic diseases, making these molecules attractive as potential therapeutic targets. TLR2, TLR7 and TLR9 are involved in the initiation of type 1 diabetes mellitus (T1DM), whereas TLR2 and TLR4 play a major role in the onset of type 2 diabetes mellitus (T2DM). Furthermore, TLRs cause derangements in several tumor suppressor proteins (such as p16, p21, p27, p53 and pRb), induce STAT3 activation and promote epithelial-mesenchymal transition as well as oncogene-induced senescence. In this review we will focus on the contribution of TLRs in pancreatic disease including cancer and we describe recent progress in TLR-modulation for the treatment of these patients. PMID- 26036358 TI - Expression of oncogenic BRAFV600E in melanocytes induces Schwannian differentiation in vivo. PMID- 26036361 TI - The NHS won't cope without non-EU nurses. PMID- 26036360 TI - Autoregulation of ZEB2 expression for zearalenone production in Fusarium graminearum. AB - Several Fusarium species produce the polyketide mycotoxin zearalenone (ZEA), a causative agent of hyperestrogenic syndrome in animals that is often found in F. graminearum-infected cereals in temperate regions. The ZEA biosynthetic cluster genes PKS4, PKS13, ZEB1 and ZEB2 encode a reducing polyketide synthase, a non reducing polyketide synthase, an isoamyl alcohol oxidase and a transcription factor respectively. In this study, the production of two isoforms (ZEB2L and ZEB2S) from the ZEB2 gene in F. graminearum via an alternative promoter was characterized. ZEB2L contains a basic leucine zipper (bZIP) DNA-binding domain at the N-terminus, whereas ZEB2S is an N-terminally truncated form of ZEB2L that lacks the bZIP domain. Interestingly, ZEA triggers the induction of both ZEB2L and ZEB2S transcription. ZEB2L and ZEB2S interact with each other to form a heterodimer that regulates ZEA production by reducing the binding affinity of ZEB2L for the ZEB2L gene promoter. Our study provides insight into the autoregulation of ZEB2 expression by alternative promoter usage and a feedback loop during ZEA production; this regulatory mechanism is similar to that observed in higher eukaryotes. PMID- 26036362 TI - Immigration legislation threatens 'crisis' in care home staff supply. PMID- 26036363 TI - New coin honours war heroine nurse. PMID- 26036364 TI - Queen's speech omission represents 'major setback' for nursing regulation. PMID- 26036365 TI - Students feel ignored, excluded and distressed. PMID- 26036366 TI - Human rights breaches found in Northern Ireland. PMID- 26036367 TI - Daily Mail headline sparks protest following abuse of Filipino nurses. PMID- 26036368 TI - Trust hires staff but CCG will not fund them. PMID- 26036370 TI - Safety alert over solutions mix-up. PMID- 26036371 TI - Antibiotic clinics provide 'incredible' community care. PMID- 26036372 TI - Slimmed down nurse wins award. PMID- 26036373 TI - New NICE guidelines recommend debriefing after violent incidents. PMID- 26036374 TI - Inpatient feedback highlights gulf in trust performance. PMID- 26036380 TI - Stroke. PMID- 26036381 TI - Ending the stigma of alcohol services. PMID- 26036382 TI - Nurses need a voice in community care. PMID- 26036383 TI - Using legislation to save patient lives. PMID- 26036392 TI - Consensus Action on Salt Health. PMID- 26036394 TI - Speed Anatomy. PMID- 26036396 TI - The NHS is already a seven-day service, prime minister. PMID- 26036397 TI - Entire NHS workforce needs to unite against this government. PMID- 26036398 TI - Results of inpatient survey show the case for safe staffing is undeniable. PMID- 26036399 TI - I was attacked for challenging the views of a medical minority. PMID- 26036402 TI - Victorino Chua's ex-colleagues deserve support for their ordeal. PMID- 26036404 TI - Action research: changing nursing practice. AB - This article describes action research as a methodology and gives two examples of its application to nursing and health services research. Action research is cyclical in nature and involves the development, evaluation and redefining of an action plan using four basic steps: planning, action, observation and reflection. These cycles of action continue until the research group is satisfied that its objectives have been met. Data generation and analysis are iterative processes that occur continuously throughout the project, which is usually time-limited. Factors that should be taken into account to ensure success include: engaging the community, consideration of 'insider' versus 'outsider' perspectives, competing agendas, expectations not being met and the integrity of the research methodology. PMID- 26036405 TI - Developing a collaborative research partnership. AB - This article details a collaborative research project undertaken in an acute NHS foundation trust, in partnership with a local higher education institution (HEI). The article identifies enablers and challenges to working in this type of collaboration and discusses the implications for the development of similar projects. PMID- 26036406 TI - Preventing amputation in adults with diabetes: identifying the risks. AB - Good management of diabetes can reduce the risk of complications of the disease. When not well managed, diabetes is associated with the complications of heart disease, stroke, blindness, kidney disease and amputations. Diabetes can reduce the blood supply to the feet and cause a loss of feeling. As a result, foot injuries do not heal well and the person may not realise that their foot is sore or injured. Damage to the foot may lead to the development of foot ulcers, which if left untreated may result in amputation of the limb. Preventive care is a priority, but when complications occur the next step is to halt progression. Therefore, effective foot care and timely treatment of foot ulcers are important in preserving foot function and mobility, and preventing amputation in adults with diabetes. PMID- 26036407 TI - Urinary continence. PMID- 26036408 TI - Promote exercise actively. PMID- 26036409 TI - A digital network of writers. PMID- 26036412 TI - Catalyst for ideas. PMID- 26036413 TI - Corrigendum. AB - Article title: The oncogene EVI1 enhances transcriptional and biological responses of human myeloid cells to all-trans retinoic acid. Authors: Birgit Steinmetz, Hubert Hackl, Eva Slabakova, Ilse Schwarzinger, Monika Smejova, Andreas Spittler, Itziar Arbesu, Medhat Shehata, Karel Soucek, and Rotraud Wieser. Journal: Cell Cycle. Bibliometrics: Volume 13, Issue 18, Pages 2931-43. DOI: 10.4161/15384101.2014.946869. The following information was missing from the Methods section in print and online: Microarray data described in this article were deposited in the gene expression omnibus, accession numbers GSE66837 and GSE66854. The authors apologize for any inconvenience caused. PMID- 26036414 TI - Erratum. AB - Article title: Autophagy is involved in high glucose-induced heart tube malformation. Authors: Guang Wang, Wen-qing Huang, Shu-dan Cui, Shuai Li, Xiao-yu Wang, Yan Li, Manli Chuai, Liu Cao, Jiang-chao Li,Da-xiang Lu, and Xuesong Yang. Journal: Cell Cycle. Bibliometrics: Volume 14, Issue 5, Pages 772-783. DOI: 10.1080/15384101.2014.1000170. The author affiliations appeared incorrectly in print and online. The correct affiliations are provided below. PMID- 26036415 TI - Critical care management of systemic mastocytosis: when every wasp is a killer bee. AB - Since the critical care physician will most likely be involved in a life threatening expression of systemic mastocytosis, recognition of this disease is of utmost importance in the critical care management of these patients. Mastocytosis is a severely under-recognized disease because it typically occurs secondary to another condition and thus may occur more frequently than assumed. In this article, we will review the current knowledge on the treatment of mastocytosis crises with an emphasis on critical care management. Mastocytosis is characterized by the clonal proliferation and accumulation of mast cells in different tissues. Mast cell mediators contain a wide range of biologically active substances that may lead to itching and hives but may ultimately lead to anaphylactic shock caused by the release of histamine and other mediators from mast cells. The mainstay of therapy is the avoidance of potential triggers of mast cell degranulation and, if unsuccessful, blocking the cascade of mast cell mediators. The critical care physician should be well aware of the special precautions which should be kept in mind throughout the management of a mastocytosis crisis to avoid massive mast cell degranulation. Histamine-releasing drugs and certain physical triggers like temperature change should be avoided. PMID- 26036416 TI - Nitric oxide mediated amelioration of arsenic toxicity which alters the alternative oxidase (Aox1) gene expression in Hordeum vulgare L. AB - The role of nitric oxide (NO) as a key molecule in the signal transduction pathway of a biotic stress response has already been described. Recent studies indicate that it also participate in the signaling of abiotic stresses. In the present study, we showed the altered expression of stress responsive gene alternative oxidase (Aox1) in seedlings of barley (Hordeum vulgare L.) in response to arsenic toxicity. Arsenic toxicity decreased the germination percentage, biomass, chlorophyll and carotenoid content whereas, arsenic toxicity enhanced the MDA content and proline content in a dose dependent manner. Other enzyme activities like catalase and superoxide dismutase increased with the increase in concentrations but it fell down at higher concentration of arsenic. Pretreatment of nitric oxide results in the enhanced expression of alternative oxidase which showed the adaptation of alternative pathway during the arsenic stress and it also enhances the growth ability and adaptability towards the arsenic stress. The results support the conclusion that nitric oxide ameliorates the arsenic toxicity not only at the level of antioxidant defense but also by affecting other mechanism of detoxification. PMID- 26036417 TI - Silicon alleviates cadmium toxicity by enhanced photosynthetic rate and modified bundle sheath's cell chloroplasts ultrastructure in maize. AB - Silicon was shown to alleviate the negative effects of various biotic and abiotic stresses on plant growth. Although the positive role of Si on toxic and heavy metal Cd has been already described, the mechanisms have been explained only partially and still remain unclear. In the present study we investigated the effect of Si on photosynthetic-related processes in maize exposed to two different levels of Cd via measurements of net photosynthetic rate (AN), chlorophyll a fluorescence and pigment analysis, as well as studies of leaf tissue anatomy and cell ultrastructure using bright-field and transmission electron microscopy. We found that Si actively alleviated the toxic syndromes of Cd by increasing AN, effective photochemical quantum yield of photosystem II (phiPSII) and content of assimilation pigments, although did not decrease the concentration of Cd in leaf tissues. Cadmium did not affect the leaf anatomy and ultrastructure of leaf mesophyll's cell chloroplasts; however, Cd negatively affected thylakoid formation in chloroplasts of bundle sheath cells, and this was alleviated by Si. Improved thylakoid formation in bundle sheath's cell chloroplasts may contribute to Si-induced enhancement of photosynthesis and related increase in biomass production in C4 plant maize. PMID- 26036418 TI - Active biomonitoring with the moss Pseudoscleropodium purum: Comparison between different types of transplants and bulk deposition. AB - Active biomonitoring with terrestrial mosses can be used to complement traditional air pollution monitoring techniques. Several studies have been carried out to compare the uptake capacity of different types of moss transplants. However, until now the relationship between the uptake of elements in devitalized moss bags and in irrigated transplants has not been explored. In this study, the final concentrations of Cd, Cu, Hg, Pb and Zn were determined in irrigated and devitalized moss transplants in the surroundings of a steelworks. The concentrations were also compared with those of the same elements in the bulk deposition to determine which type of moss transplant yields the closest correlations. Devitalized moss retained higher concentrations of all of the elements (except Hg) than the irrigated moss. Both irrigated and devitalized moss transplants appear to detect the same type of contamination (i.e. particulate matter and dissolved metals rather than gaseous forms) as significant correlations were found for Cu, Hg, Pb and Zn, whereas, neither type of the moss transplant was sensitive enough to detect changes in the soluble fraction load of bulk deposition. Further studies will be needed to a better understanding of the correlation between the concentrations of elements in moss transplants with the particulate fraction of the bulk deposition. This will enable the establishment of a more robust and accurate biomonitoring tool. PMID- 26036419 TI - Development of a lipovitellin-based sandwich ELISA for quantification of vitellogenin in surface mucus and plasma of goldfish (Carassius auratus). AB - Goldfish (Carassius auratus) vitellogenin (Vtg) is an efficient biomarker for estrogen contamination in aquatic environments. In this study, Vtg and lipovitellin (Lv) were purified from the plasma of 17beta-estradiol (E2)-induced male goldfish and unfertilized eggs of females, and were used to generate polyclonal antibodies against Vtg (anti-Vtg) and Lv (anti-Lv), respectively. SDS PAGE and Western blot were performed to confirm the specificity of the two antibodies and the immunological similarity between Vtg and Lv. As anti-Lv recognized more antigen epitopes than anti-Vtg, it was used to develop a sandwich enzyme-linked immunosorbent assay (ELISA) for goldfish Vtg with purified Lv as the standard. The detection limit of the assay was 1.82ng/mL, and the working range was 3.9-250ng/mL. The use of Lv instead of Vtg as the standard provided greater precision and strengthened the robustness of the sandwich ELISA. Western blot and the Lv-based ELISA were used to detect Vtg inductions in surface mucus and plasma of E2-induced goldfish. The surface mucus Vtg level in E2-induced males was significantly higher than that in the control males and E2-induced females, and was much closer to the plasma Vtg level in E2-induced males than that in E2-induced females. Therefore, the surface mucus Vtg level of male goldfish may be a reliable indicator of estrogenic activity in the aquatic environment. PMID- 26036420 TI - beta-N-methylamino-L-alanine (BMAA) metabolism in the aquatic macrophyte Ceratophyllum demersum. AB - The cyanobacterial neurotoxin, beta-N-methylamino-l-alanine (BMAA) bioaccumulates and biomagnifies within the environment. However, most reports on the environmental presence of BMAA focus on the presence of BMAA in animals rather than in plants. Various laboratory studies have reported that this neurotoxin, implicated in neurodegenerative disease, is rapidly taken up by various aquatic and terrestrial plants, including crop plants. In this study the metabolism of BMAA in the aquatic macrophyte, Ceratophyllum demersum, was investigated using stable isotopically labelled BMAA. Data show that the toxin is rapidly removed from the environment by the plant. However, during depuration cellular BMAA concentrations decrease considerably, without excretion of the toxin back into the environment and without catabolism of BMAA, evidenced by the absence of label transfer to other amino acids. This strongly suggests that BMAA is metabolised via covalent modification and sequestered inside the plant as a BMAA-derivative. This modification may be reversed in humans following consumption of BMAA containing plant material. These data therefore impact on the assessment of the risk of human exposure to this neurotoxin. PMID- 26036421 TI - Contingent attentional capture triggers the congruency sequence effect. AB - The congruency effect in distracter interference tasks is often reduced after incongruent as compared to congruent trials. Here, we investigated whether this congruency sequence effect (CSE) is triggered by (a) attentional adaptation resulting from perceptual conflict or (b) contingent attentional capture arising from distracters that possess target-defining perceptual features. To distinguish between these hypotheses, we varied the perceptual format in which a distracter (word or arrow) and a subsequent target (word or arrow) appeared in a prime-probe task. In Experiment 1, we varied these formats across four blocks of a factorial design, such that targets always appeared in a single perceptual format. Consistent with both hypotheses, we observed a CSE only when the distracter appeared in the same perceptual format as the target. In Experiment 2, we varied these formats randomly across trials within each block, such that targets appeared randomly in either format. Consistent with the attentional capture account but inconsistent with the perceptual conflict account, we observed equivalent CSEs in the same and different perceptual format conditions. These findings show for the first time that contingent attentional capture plays an important role in triggering the CSE. PMID- 26036422 TI - Scientific production and bibliometric impact of a representative group of Spanish internists with established research careers. AB - OBJECTIVE: To study the temporal evolution of the bibliometric indices of internists with established research experience in order to predict the future behavior of researchers and to assess whether output focused on a specific area of internal medicine helps obtain greater visibility than in general internal medicine. MATERIAL AND METHOD: We analyzed a representative group of members of the Spanish Society of Internal Medicine (SEMI) based on data obtained from the Web of Science. As an indicator of productivity, we analyzed the number of articles published. As impact indicators, we studied the impact factor (IF), the number of citations and the h-index. RESULTS: We analyzed 42 internists, with a mean experience of 30 years and a total of 6655 publications. The mean (SD) number of studies was 158 (96), the number of citations was 2,850 (2,865), the IF was 711 (549) and the h-index was 25 (11). These figures were higher for the specialist internists than for the general internists. There was a good relationship between the impact and productivity indicators (R(2)=.61-.89) and a poor relationship between these indicators and the years of experience (R(2)=.13 .19). The temporal evolution of these indicators for each individual researcher and for all researchers as a whole was adjusted to a second-degree polynomial model, with the h-index having the highest R(2) values. CONCLUSIONS: The h-index is the factor that had the best adjustment and least variability and could therefore help predict the future scientific output and impact of internists. The specialist researchers achieved greater visibility than the general internists. PMID- 26036423 TI - 81-year-old man with pain and swelling in the right side of the chest. PMID- 26036424 TI - Do we have consensus about consensus statements? PMID- 26036425 TI - 2015 SCAI/ACC/HFSA/STS Clinical Expert Consensus Statement on the Use of Percutaneous Mechanical Circulatory Support Devices in Cardiovascular Care (Endorsed by the American Heart Association, the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencion; Affirmation of Value by the Canadian Association of Interventional Cardiology-Association Canadienne de Cardiologie d'intervention). AB - Although historically the intra-aortic balloon pump has been the only mechanical circulatory support device available to clinicians, a number of new devices have become commercially available and have entered clinical practice. These include axial flow pumps, such as Impella((r)); left atrial to femoral artery bypass pumps, specifically the TandemHeart; and new devices for institution of extracorporeal membrane oxygenation. These devices differ significantly in their hemodynamic effects, insertion, monitoring, and clinical applicability. This document reviews the physiologic impact on the circulation of these devices and their use in specific clinical situations. These situations include patients undergoing high-risk percutaneous coronary intervention, those presenting with cardiogenic shock, and acute decompensated heart failure. Specialized uses for right-sided support and in pediatric populations are discussed and the clinical utility of mechanical circulatory support devices is reviewed, as are the American College of Cardiology/American Heart Association clinical practice guidelines. PMID- 26036426 TI - Appropriate use of echocardiography in an Australian regional centre. AB - BACKGROUND: The 2011 Appropriate Use Criteria (AUC) were developed by the American Society of Echocardiography (ASE) to provide guidance for referring physicians in response to growing concerns about unnecessary transthoracic echocardiogram (TTE) requests. When applied in multiple centres overseas, the rate of inappropriate referrals was as high as 22%. AIM: To assess the applicability of, and the level of adherence to the 2011 AUC in an Australian regional hospital where the AUC have not been tested systematically. METHODS: A retrospective analysis of 1000 inpatient and outpatient TTE referrals was conducted between January 2014 and June 2014 at Bendigo Hospital, a major regional referral hospital. RESULTS: Ninety-eight percent of the TTE referrals were classifiable. The most common indication for ordering TTE was to evaluate symptoms potentially related to a cardiac aetiology. Of the classifiable referrals, 77% were appropriate, 20.3% were inappropriate and 2.7% were uncertain. The most common inappropriate indications were routine surveillance of the left ventricular (LV) function in stable chronic cardiac conditions and routine perioperative evaluation of the LV function with no symptoms or signs of cardiovascular disease. Inappropriate referrals were significantly more frequent in outpatients compared with inpatients (24.4% vs 9.6%, P < 0.001). CONCLUSION: This study provides a novel insight into the ordering of TTEs in regional Australia. In this study, one in five referrals had an inappropriate indication and could be avoided. This may have significant implications for healthcare resources in regional centres, and strategies to reduce inappropriate echocardiography ordering need to be implemented. PMID- 26036428 TI - Controllable synthesis of hollow mesoporous silica particles by a facile one-pot sol-gel method. AB - A simple and facile one-pot sol-gel method is proposed for the fabrication of hollow mesoporous silica particles. Both the particle size and the shell thickness can be well controlled by moderately tuning some experimental parameters. PMID- 26036427 TI - Hysteroscopy and heavy menstrual bleeding (to cover TCRE and second-generation endometrial ablation). AB - Endometrial resection and ablation are an intermediate treatment for heavy menstrual bleeding (HMB). Many women do not like the continuous use of hormones, nor do they prefer a rigorous treatment as hysterectomy. The first generation of endometrial resection/ablation is now superseded by the second-generation endometrial ablation. Both seem to be equally effective in reducing HMB, and there was no evidence that rates of satisfaction differed significantly. Overall, second-generation techniques were often easier to perform with shorter surgery times and the ability to use local rather than general anaesthesia. Complications seem to be less after second-generation endometrial ablation; however, the easiness of use can be a pitfall. Prognostic parameters should be taken into account while counselling women who opt for an endometrial ablation. The most important prognostic parameters are age (satisfaction increases with age) and preoperative dysmenorrhoea (decreases satisfaction). PMID- 26036429 TI - Decrease of phosphorylated proto-oncogene CREB at Ser 133 site inhibits growth and metastatic activity of renal cell cancer. AB - OBJECTIVE: Cyclic-AMP-responsive element-binding protein (CREB) is a proto oncogenic transcription factor. The authors' previous reports showed that blocking the CREB binding site at Ser 133 inhibited the expression of target genes, which related to the progression of some tumors. In this study, the authors investigated the role of phosphorylated CREB (pCREB) at Ser133 in renal cell carcinoma (RCC) growth and metastases. METHODS: Immunohistochemistry, xenograft model in nude mice, cell proliferation assay, cell invasion/migration assay, fluorescent immunocytochemistry and Western analysis were performed in an immortalized proximal tubule epithelial cell line and clear-cell RCC. RESULTS: The authors' results showed that knockdown of pCREB inhibited kidney cancer cells growth in vivo. Furthermore, suppression of the pCREB level blunted the capabilities of cell migration and invasion in vitro and was accompanied with significantly decreased expression of MMP-2 and MMP-9, the filopodia formation and epithelial-mesenchymal transition-related proteins. Surprisingly, no changes of expression or location of vimentin were revealed in the experiment. Bioinformatic software explained the possible reason for this is that the promoter of vimentin does not contain the CRE sequence. CONCLUSIONS: These data suggest that decreasing the level of pCREB inhibits the growth and metastasis of RCC by targeting the Ser 133 site. PMID- 26036430 TI - People receiving unnecessary treatments: accurate diagnosis is key. PMID- 26036432 TI - Total Synthesis of Limonin. AB - Limonoids are highly oxygenated C13alpha-triterpenes and common secondary metabolites. Several hundred congeners have been isolated to date. The first total synthesis of (+/-)-limonin, the flagship congener of the limonoids, is now reported and features 1) a tandem radical cyclization generating the BCD ring system with the C13alpha configuration that is essential to the limonoids and a Robinson annulation to construct the limonoid androstane framework, 2) a singlet oxygen cycloaddition and a Baeyer-Villiger oxidation to synthesize the highly oxidized D ring, and 3) a Suarez reaction to construct the unique AA' ring system. PMID- 26036433 TI - Telemedicine as a tool to bring clinical ethics expertise to remote locations. AB - The American Society for Bioethics and Humanities promulgated standards for clinical ethics consultants and is currently developing a national Quality Attestation in Clinical Ethics Consultation to assist facilities in ensuring that those performing clinical ethics consultations meet minimum standards. As the field moves towards such professionalization, there is a need to provide access to qualified clinical ethicists at a broad range of medical facilities. Currently, however, there are insufficient numbers of trained clinical ethicists to staff all healthcare facilities, and many facilities lack the necessary resources to hire staff clinical ethicists. In this review, we describe several models for providing expert clinical ethics support to remote facilities that lack access to qualified clinical ethicists. Based on this analysis, we recommend telemedicine as the optimal model providing expert support to local ethics committee members tasked with providing clinical ethics consultation services. PMID- 26036434 TI - Melatonin improves bone mineral density at the femoral neck in postmenopausal women with osteopenia: a randomized controlled trial. AB - Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double-blind RCT, we randomized 81 postmenopausal osteopenic women to 1-yr nightly treatment with melatonin 1 mg (N = 20), 3 mg (N = 20), or placebo (N = 41). At baseline and after 1-yr treatment, we measured bone mineral density (BMD) by dual X-ray absorptiometry, quantitative computed tomography (QCT), and high-resolution peripheral QCT (HR pQCT) and determined calciotropic hormones and bone markers. Mean age of the study subjects was 63 (range 56-73) yr. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (P < 0.05) in a dose-dependent manner (P < 0.01), as BMD increased by 0.5% in the 1 mg/day group (P = 0.55) and by 2.3% (P < 0.01) in the 3 mg/day group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (P = 0.04), and volumetric bone mineral density (vBMD) in the spine, by 3.6% (P = 0.04) in the 3 mg/day. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers; however, 24-hr urinary calcium was decreased in response to melatonin by 12.2% (P = 0.02). In conclusion, 1-yr treatment with melatonin increased BMD at femoral neck in a dose dependent manner, while high-dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of nighttime melatonin will protect against fractures. PMID- 26036431 TI - Vascular Targeting of a Gold Nanoparticle to Breast Cancer Metastasis. AB - The vast majority of breast cancer deaths are due to metastatic disease. Although deep tissue targeting of nanoparticles is suitable for some primary tumors, vascular targeting may be a more attractive strategy for micrometastasis. This study combined a vascular targeting strategy with the enhanced targeting capabilities of a nanoparticle to evaluate the ability of a gold nanoparticle (AuNP) to specifically target the early spread of metastatic disease. As a ligand for the vascular targeting strategy, we utilized a peptide targeting alpha(v) beta(3) integrin, which is functionally linked to the development of micrometastases at a distal site. By employing a straightforward radiolabeling method to incorporate Technetium-99m into the AuNPs, we used the high sensitivity of radionuclide imaging to monitor the longitudinal accumulation of the nanoparticles in metastatic sites. Animal and histological studies showed that vascular targeting of the nanoparticle facilitated highly accurate targeting of micrometastasis in the 4T1 mouse model of breast cancer metastasis using radionuclide imaging and a low dose of the nanoparticle. Because of the efficient targeting scheme, 14% of the injected AuNP deposited at metastatic sites in the lungs within 60 min after injection, indicating that the vascular bed of metastasis is a viable target site for nanoparticles. PMID- 26036435 TI - Understanding Gaps Between the Risk Perceptions of Wildland-Urban Interface (WUI) Residents and Wildfire Professionals. AB - Research across a variety of risk domains finds that the risk perceptions of professionals and the public differ. Such risk perception gaps occur if professionals and the public understand individual risk factors differently or if they aggregate risk factors into overall risk differently. The nature of such divergences, whether based on objective inaccuracies or on differing perspectives, is important to understand. However, evidence of risk perception gaps typically pertains to general, overall risk levels; evidence of and details about mismatches between the specific level of risk faced by individuals and their perceptions of that risk is less available. We examine these issues with a paired data set of professional and resident assessments of parcel-level wildfire risk for private property in a wildland-urban interface community located in western Colorado, United States. We find evidence of a gap between the parcel level risk assessments of a wildfire professional and numerous measures of residents' risk assessments. Overall risk ratings diverge for the majority of properties, as do judgments about many specific property attributes and about the relative contribution of these attributes to a property's overall level of risk. However, overall risk gaps are not well explained by many factors commonly found to relate to risk perceptions. Understanding the nature of these risk perception gaps can facilitate improved communication by wildfire professionals about how risks can be mitigated on private lands. These results also speak to the general nature of individual-level risk perception. PMID- 26036437 TI - THERAPY OF ENDOCRINE DISEASE: Islet transplantation for type 1 diabetes: so close and yet so far away. AB - Over the past decades, tremendous efforts have been made to establish pancreatic islet transplantation as a standard therapy for type 1 diabetes. Recent advances in islet transplantation have resulted in steady improvements in the 5-year insulin independence rates for diabetic patients. Here we review the key challenges encountered in the islet transplantation field which include islet source limitation, sub-optimal engraftment of islets, lack of oxygen and blood supply for transplanted islets, and immune rejection of islets. Additionally, we discuss possible solutions for these challenges. PMID- 26036439 TI - Do physical activity interventions prevent gestational diabetes? PMID- 26036440 TI - Effects study on the thermal stresses in a LEU metal foil annular target. AB - The effects of fission gas pressure, uranium swelling and thermal contact conductance on the thermal-mechanical behavior of an annular target containing a low-enriched uranium foil (LEU) encapsulated in a nickel foil have been presented in this paper. The draw-plug assembly method is simulated to obtain the residual stresses, which are applied to the irradiation model as initial inputs, and the integrated assembly-irradiation process is simulated as an axisymmetric problem using the commercial finite element code Abaqus FEA. Parametric studies were performed on the LEU heat generation rate and the results indicate satisfactory irradiation performance of the annular target. The temperature and stress margins have been provided along with a discussion of the results. PMID- 26036443 TI - Self-organized materials for optoelectronic applications. PMID- 26036447 TI - Pulmonary delivery of pyrazinamide-loaded large porous particles. AB - We have improved the aerodynamic properties of pyrazinamide loaded large porous particles (PZA-LPPs) designed for pulmonary delivery. To overcome the segregation of the different components occurring during the spray drying process and to obtain homogeneous LPPs, spray drying parameters were modified to decrease the drying speed. As a result, good aerodynamic properties for lung delivery were obtained with a fine particle fraction (FPF) of 40.1+/-1.0%, an alveolar fraction (AF) of 29.6+/-3.1%, a mass median aerodynamic diameter (MMADaer) of 4.1+/-0.2MUm and a geometric standard deviation (GSD) of 2.16+/-0.16. Plasma and epithelial lining fluid (ELF) concentrations of pyrazinamide were evaluated after intratracheal insufflation of PZA-LPPs (4.22mgkg(-1)) into rats and compared to intravenous administration (iv) of a pyrazinamide solution (5.82mgkg(-1)). The in vivo pharmacokinetic evaluation of PZA-LPPs in rats reveals that intratracheal insufflation of PZA-LPPs leads to a rapid absorption in plasma with an absolute bioavailability of 66%. This proves that PZA-LPPs dissolve fast upon deposition and that PZA crosses efficiently the lung barrier to reach the systemic circulation. PZA concentrations were 1.28-fold higher in ELF after intratracheal administration than after iv administration and the ratio of ELF concentrations over plasma concentrations was 2-fold greater. Although these improvements are moderate, lung delivery of PZA appears an interesting alternative to oral delivery of the molecule and should now be tested in an infected animal model to evaluate its efficacy against Mycobacterium tuberculosis. PMID- 26036448 TI - Formulation to target delivery to the ciliary body and choroid via the suprachoroidal space of the eye using microneedles. AB - In this work, we tested the hypothesis that particles injected into the suprachoroidal space can be localized at the site of injection or broadly distributed throughout the suprachoroidal space by controlling polymeric formulation properties. Single hollow microneedles were inserted into the sclera of New Zealand White rabbits and injected non-biodegradable fluorescently tagged nanoparticles and microparticles suspended in polymeric formulations into the suprachoroidal space of the eye. When formulated in saline, the particles were distributed over 29-42% of the suprachoroidal space immediately after injection. To spread particles over larger areas of the choroidal surface, addition of hyaluronic acid to make moderately non-Newtonian solutions increased particle spread to up to 100% of the suprachoroidal space. To localize particles at the site of injection adjacent to the ciliary body, strongly non-Newtonian polymer solutions localized particles to 8.3-20% of the suprachoroidal space, which exhibited a small increase in area over the course of two months. This study demonstrates targeted particle delivery within the suprachoroidal space using polymer formulations that spread particles over the whole choroidal surface or localized them adjacent to the ciliary body after injection. PMID- 26036449 TI - Physical methods to quantify small antibiotic molecules uptake into Gram-negative bacteria. AB - The development of antibiotics against Gram-negative bacteria is a challenge: any active compound must cross the outer cell envelope composed of a hydrophilic highly charged lipopolysaccharide layer followed by a tight hydrophobic layer containing water filled gates called porins to reach the hydrophilic periplasmic space and depending on the target with the further need to cross the hydrophobic inner membrane. In addition to a possible rapid enzymatic deactivation efflux pumps shuffle compounds back outside. The resulting low permeability of cell envelope requires high dose and leads therefore to toxicity problems. Despite its relevance the permeability barrier in Gram-negative bacteria is not well understood partially caused by the lack of appropriate direct assays. Here we give a brief introduction on current available techniques to quantify passive diffusion of small hydrophilic molecules into Gram-negative bacteria. PMID- 26036450 TI - Hydrodeoxygenation of Guaiacol over Ceria-Zirconia Catalysts. AB - The hydrodeoxygenation of guaiacol is investigated over bulk ceria and ceria zirconia catalysts with different elemental compositions. The reactions are performed in a flow reactor at 1 atm and 275-400 degrees C. The primary products are phenol and catechol, whereas cresol and benzene are formed as secondary products. No products with hydrogenated rings are formed. The highest conversion of guaiacol is achieved over a catalyst containing 60 mol % CeO2 and 40 mol % ZrO2 . Pseudo-first-order activation energies of 97-114 kJ mol(-1) are observed over the mixed metal oxide catalysts. None of the catalysts show significant deactivation during 72 h on stream. The important physicochemical properties of the catalysts are characterized by X-ray diffraction (XRD), temperature programmed reduction, titration of oxygen vacancies, and temperature-programmed desorption of ammonia. On the basis of these experimental results, the reasons for the observed reactivity trends are identified. PMID- 26036451 TI - Fetal brain 11beta-hydroxysteroid dehydrogenase type 2 selectively determines programming of adult depressive-like behaviors and cognitive function, but not anxiety behaviors in male mice. AB - Stress or elevated glucocorticoids during sensitive windows of fetal development increase the risk of neuropsychiatric disorders in adult rodents and humans, a phenomenon known as glucocorticoid programming. 11beta-Hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which catalyses rapid inactivation of glucocorticoids in the placenta, controls access of maternal glucocorticoids to the fetal compartment, placing it in a key position to modulate glucocorticoid programming of behavior. However, the importance of the high expression of 11beta HSD2 within the midgestational fetal brain is unknown. To examine this, a brain specific knockout of 11beta-HSD2 (HSD2BKO) was generated and compared to wild type littermates. HSD2BKO have markedly diminished fetal brain 11beta-HSD2, but intact fetal body and placental 11beta-HSD2 and normal fetal and placental growth. Despite normal fetal plasma corticosterone, HSD2BKO exhibit elevated fetal brain corticosterone levels at midgestation. As adults, HSD2BKO show depressive-like behavior and have cognitive impairments. However, unlike complete feto-placental deficiency, HSD2BKO show no anxiety-like behavioral deficits. The clear mechanistic separation of the programmed components of depression and cognition from anxiety implies distinct mechanisms of pathogenesis, affording potential opportunities for stratified interventions. PMID- 26036452 TI - Chronobiological hypothalamic-pituitary-thyroid axis status and antidepressant outcome in major depression. AB - BACKGROUND: We previously demonstrated that the difference between 2300h and 0800h TSH response to protirelin (TRH) tests on the same day (DeltaDeltaTSH test) is an improved measure in detecting hypothalamic-pituitary-thyroid (HPT) axis dysregulation in depression. This chronobiological index (1) is reduced in about three quarters of major depressed inpatients, and (2) is normalized after successful antidepressant treatment. In the present study, we examined whether early changes in HPT axis activity during the first 2 weeks of antidepressant treatment could be associated with subsequent outcome. METHODS: The DeltaDeltaTSH test was performed in 50 drug-free DSM-IV euthyroid major depressed inpatients and 50 hospitalized controls. After 2 weeks of antidepressant treatment the DeltaDeltaTSH test was repeated in all inpatients. Antidepressant response was evaluated after 6 weeks of treatment. RESULTS: At baseline, DeltaDeltaTSH values were significantly lower in patients compared to controls and 38 patients (76%) showed reduced DeltaDeltaTSH values (i.e., <2.5mU/L). After 2 weeks of antidepressant treatment, 20 patients showed DeltaDeltaTSH normalization (among them 18 were subsequent remitters), while 18 patients did not normalize their DeltaDeltaTSH (among them 15 were non-remitters) (p<0.00001). Among the 12 patients who had normal DeltaDeltaTSH values at baseline, 8 out 9 who had still normal values after 2 weeks of treatment were remitters, while the 3 with worsening HPT axis function (i.e., reduced DeltaDeltaTSH value after 2 weeks of treatment) were non-remitters (p<0.02). A logistic regression analysis revealed that DeltaDeltaTSH levels after 2 weeks of treatment could predict the probability of remission (odds ratio [OR]=2.11, 95% confidence interval [CI]=1.31 3.41). CONCLUSIONS: Our results suggest that after 2 weeks of antidepressant treatment: (1) chronobiological restoration of the HPT axis activity precedes clinical remission, and (2) alteration of the HPT axis is associated with treatment resistance. PMID- 26036453 TI - Secretory IgA reactivity to social threat in youth: Relations with HPA, ANS, and behavior. AB - Although the role of immune marker secretory immunoglobulin A (SIgA) in stress related health outcomes is gaining recognition, SIgA responsiveness to acute stress has rarely been assessed in adults, and not at all in children. This study was designed to clarify developmental origins of differential immune function related health risks by investigating youth SIgA responses to psychosocial stressors, including both normative responses and variability related to behavioral problems. Children and adolescents from a larger study (n=82) gave 6 saliva samples during a laboratory session in which they were exposed to a series of performance or interpersonal stressors. Samples were assayed for SIgA, as well as cortisol (representing hypothalamic-pituitary-adrenal axis activity) and alpha amylase (sAA; representing autonomic nervous system activity). Behavioral problems were assessed with parent-report measures of youth internalizing and externalizing. Youth SIgA trajectories followed a normative pattern of reactivity and recovery around the stressors; however, these responses were blunted in youth with higher externalizing scores. SIgA showed differential associations with cortisol and sAA, and with positive and negative affect; whereas overall levels of SIgA related to cortisol output and positive affect, changes in SIgA over time synchronized with changes in sAA and negative affect. In contrast to SIgA, neither cortisol nor sAA related significantly to behavioral problems. Implications for the role of SIgA during psychosocial stress in the development of immune function-related health risks are discussed. PMID- 26036454 TI - DHEAS and cortisol/DHEAS-ratio in recurrent depression: State, or trait predicting 10-year recurrence? AB - BACKGROUND: Major depressive disorder (MDD) has been associated with low dehydroepiandrosterone-sulphate (DHEAS), - particularly relative to high cortisol - although conflicting findings exist. Moreover, it is unclear whether low DHEAS is only present during the depressive state, or manifests as a trait that may reflect vulnerability for recurrence. Therefore, we longitudinally tested whether low DHEAS and high cortisol/DHEAS-ratio in recurrent MDD (I) reflects a trait, and/or (II) varies with depressive state. In addition, we tested associations with (III) previous MDD-episodes, (IV) prospective recurrence, and (V) effects of cognitive therapy. METHODS: At study-entry, we cross-sectionally compared morning and evening salivary DHEAS and molar cortisol/DHEAS-ratio of 187 remitted recurrent MDD-patients with 72 matched controls. Subsequently, patients participated in an 8-week randomized controlled cognitive therapy trial. We repeated salivary measures after 3 months and 2 years. We measured clinical symptoms during a 10-year follow-up. RESULTS: Remitted patients showed steeper diurnal DHEAS-decline (p<.005) and a flatter diurnal profile of cortisol/DHEAS ratio (p<.001) than controls. We found no state-effect in DHEAS or cortisol/DHEAS ratio throughout follow-up and no association with number of previous episodes. Higher morning cortisol/DHEAS-ratio predicted shorter time till recurrence over the 10-year follow-up in interaction with the effects of cognitive therapy (p<.05). Finally, cognitive therapy did not influence DHEAS or cortisol/DHEAS ratio. CONCLUSIONS: Diurnal profiles of DHEAS and cortisol/DHEAS-ratio remain equally altered in between depressive episodes, and may predict future recurrence. This suggests they represent an endophenotypic vulnerability trait rather than a state-effect, which provides a new road to understand recurrent depression and its prevention. TRIAL REGISTRATION: www.isrctn.com/ISRCTN68246470. PMID- 26036455 TI - Thrombin generation assays for optimizing low molecular weight heparin dosing in pregnant women at risk of thrombosis--response to Ismail et al. PMID- 26036456 TI - Laparoscopic colostomy for acute left colon obstruction caused by diverticular disease in high risk patient: A case report. AB - INTRODUCTION: The colostomy is often necessary in complicated divertcular disease. The laparoscopic colostomy is not widely used for the treatment of complicated diverticular disease. Its use in patients with high operative risk is still on debate. The aim of this case report was to present the benefits of laparoscopic colostomy in patients with high peri-and postoperative risk factors. PRESENTATION OF CASE: We present a case of 76-year-old female admitted to emergency unit for left colonic obstruction. The patient had a past history of liver cirrhosis HCV-related with a severe malnutrition, hypertrophic cardiomyopathy, diverticular disease, hiatal ernia, previous appendectomy. Patient was classified according to their preoperative risk ASA 3 (classification of the American society of Anestesia-ASA score). Contrast-enhanced abdominal CT revealed a marked thickening in the sigmoid colon and a marked circumferential stenosis in the sigmoid colon in absence of neoplasm, and/or abscess. The laparoscopic procedure is proposed as first intention. DISCUSSION: The operation time was 50min, and the hospital stay was 4 days. Post operative complications grade I according to the Clavien Dindo Classification. CONCLUSIONS: Laparoscopic colostomy is safe and feasible procedure in experienced hands. It is associated with low morbidity and short stay in hospital and should be considered a good alternative to a laparotomy. PMID- 26036457 TI - Modified tension-free mesh repair used in rare case of Littre's hernia. AB - INTRODUCTION: Meckel's diverticulum is found at the antimesenteric border of the ileum, usually located from 30 to 90cm from the ileocecal valve. Meckel's diverticulum complications, such as bowel obstruction, diverticulitis, hemorrhage and rarely, hernias containing a Meckel's diverticulum (Littre's Hernia) required surgical intervention. CASE PRESENTATION: We introduce the case report of 77-year old man with inguinal hernia containing Meckel's diverticulum operated by the modified tension-free mesh repair. DISCUSSION: Although Meckel's diverticulum is a relatively common anomaly, herniation of these embryological remnants is an exceedingly rare event. It can be difficult to diagnose Littre's hernia before operation. CONCLUSION: The important thing is not to hesitate to perform diverticulectomy, to avoid complications of the patient in the future. PMID- 26036458 TI - A case report of abdominal compartment syndrome caused by malposition of a femoral venous catheter. AB - INTRODUCTION: Venous catheter malposition is a rare event with potential catastrophic consequences. To our knowledge we describe one of the first case reports of an adult presenting with a rare late complication of femoral venous catheter malposition: abdominal compartment syndrome. PRESENTATION OF CASE: A 39 year-old female sustained severe cerebral injury in a road traffic accident. During initial resuscitation a femoral venous catheter was inserted without ultrasound guidance with no immediate concerns. After 48h whilst in intensive care unit the patient developed progressive abdominal distension. Bedside investigations revealed raised intra-abdominal pressures associated with new organ failure. Subsequent an emergency laparotomy and on-table intravenous contrast radiographs revealed extravasation of contrast into the peritoneal space from the malposition of the catheter into the abdominal cavity. DISCUSSION: Complications of central venous catheterization are associated with adverse events with significant morbidity to the patient as well as having cost implications. Mechanical complications are underreported but are potentially preventable through ultrasound-guided insertion, in accordance with international guidelines. CONCLUSION: This case report highlights the importance of safe methods of catheter insertion, the need for increased awareness of late femoral catheter malposition and its potential catastrophic consequences. PMID- 26036459 TI - Pretreatment of gastric outlet obstruction with pancrelipase: Report of a case. AB - INTRODUCTION: Gastric outlet obstruction is characterized by the retention of gastric contents. Removal of gastric contents is an important part of the treatment strategy. The use of a nasogastric tube alone can result in inadequate removal of gastric contents. We treated a patient with advanced gastric cancer and gastric outlet obstruction with pancrelipase to aid in the removal of gastric contents. PRESENTATION OF CASE: The patient is an 81-year-old man with a Type 3 gastric cancer nearly circumferentially involving the antrum, resulting in gastric outlet obstruction. A nasogastric tube was placed for four days, but drainage of gastric contents was inadequate. Pancrelipase was then given orally for four days, and gastric contents were evacuated. The patient underwent distal gastrectomy with Roux-en-Y reconstruction and was discharged from the hospital on postoperative day 14. DISCUSSION: This report suggests that pancrelipase may be beneficial in the treatment of patients with gastric outlet obstruction. CONCLUSION: Pancrelipase allowed gastric contents to be evacuated in a short period of time in a patient with gastric outlet obstruction. PMID- 26036460 TI - A rare case of giant gastrointestinal stromal tumor of the stomach involving the serosal surface. AB - INTRODUCTION: Although rare, gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors affecting the gastrointestinal tract. PRESENTATION OF CASE: Here we report the case of a 43-year-old man complaining of abdominal pain along with a painless and palpable mass, which was confirmed on magnetic resonance and multislice computed tomography. Laparotomy revealed a nodular grayish-white firm noninfiltrative mass (39*27*14cm, 6109g) that was well localized within the extramuscular and peritoneal surface of the anterior wall of the stomach; complete tumor resection was performed. Histopathological examination revealed features typical of GIST, including increased cellularity, increased mitotic activity, and spindle shaped cells as well as positive immunoreactivity for KIT, CD34, and vimentin. DISCUSSION: A review of literature revealed that GISTs of the size and weight similar to the present case has been rarely reported. GIST most frequently involves the stomach. Although the etiopathogenesis of this disease remains unclear, few well-documented familial cases have been associated with GIST syndromes. CONCLUSION: The primary treatment preferred is complete surgical excision of the tumor. PMID- 26036461 TI - Right adrenal gland neuroblastoma infiltrating the liver and mimicking mesenchymal hamartoma: A case report. AB - INTRODUCTION: Neuroblastoma is the most common extracranial solid pediatric malignancy. The most common site is abdomen with predominance of suprarenal medulla. Infiltration of the tumour to the liver is rare. No cases were reported in the literature about the misdiagnosis of neuroblastoma as mesenchymal hamartoma in the liver. PRESENTATION OF CASE: We represent a rare case of neuroblastoma misdiagnosed as mesenchymal hamartoma in liver in a six-month-old female infant presented with fever and abdominal mass. Abdominal computed tomography (CT) revealed large cystic lesion occupying most of the right liver enchroaching upon right suprarenal region and displacing the right kidney inferior suggestive for mesenchymal hamartoma. Right adrenalectomy with en-bloc resection of the adjacent liver segments was done. Postoperative pathology revealed neuroblastoma with positive specific immunohistochemistry (IHC). DISCUSSION: Although neuroblastoma is the second most common pediatric abdominal malignancy with specific diagnostic modalities, a misdiagnosis of a case with neuroblastoma as mesenchymal hamartoma is rare. Histopathological diagnosis of neuroblastoma with positive IHC is essential as shown in our case. CONCLUSION: We represent a rare case of neuroblastoma which arose from the right adrenal gland and infiltrated the adjacent liver substance mimicking mesenchymal hamartoma of the liver. Neuroblastoma is rarely presented with pyrexia of unknown origin. Neuroblastoma should be considered in differential diagnosis of abdominal mass in all infants and children. PMID- 26036463 TI - Informal HIV Caregiver Proxy Reports of Care Recipients' Treatment Adherence: Relationship Factors Associated with Concordance with Recipients' Viral Suppression. AB - To explore the role of informal caregivers in adherence, we compared adherence reports by caregivers to those of care recipients. We identified individual-level and relationship factors associated with agreement between caregivers' reports of recipients' adherence and assessed viral suppression. Participants were care recipients, who were on ART and had ever injected drugs, and their caregivers (N = 258 dyads). Nearly three-fourths of caregivers' reports of recipients' ART adherence agreed with recipients' viral suppression status. Agreement was associated with recipient age and expressing affection or gratitude to the caregiver, caregiver's having been close to someone who died of HIV/AIDS, and caregiver's fear of caregiving-related HIV (re)infection, while it was negatively associated with recipient's limited physical functioning. Our findings support the utility of caregiver proxy reports of care recipients' ART adherence and suggest ways to identify and promote HIV caregiver attention to and support of this vulnerable population's ART adherence. PMID- 26036465 TI - Factors Influencing Uptake of Rapid HIV and Hepatitis C Screening Among Drug Misusing Adult Emergency Department Patients: Implications for Future HIV/HCV Screening Interventions. AB - In this randomized, controlled trial among 957 English- or Spanish-speaking drug misusing adult emergency department (ED) patients, we determined if a tailored brief intervention (BI) increased uptake of rapid HIV/HCV screening, and identified factors associated with greater screening uptake. Rapid HIV/HCV screening uptake was greater in the control than the BI arm (45 vs. 38 %; p < 0.04). Screening uptake depended on elapsed study time and which research staff member offered testing. In the control arm, uptake was lowest for those spending <30 or >=90 min in the study. In the BI arm, screening uptake generally increased over time. Tailored BI content specifically addressing participant HIV/HCV knowledge, HIV/HCV risk behaviors, or need for HIV/HCV screening was not associated with greater screening uptake. These study findings suggested factors that should be considered when designing future ED-based screening initiatives, such as elapsed study time, who offers testing, and the content of interventions. PMID- 26036467 TI - Hydrogen sulfide mediates the cardioprotective effects of gene therapy with PKG Ialpha. AB - Cyclic GMP-dependent protein kinase (PKG) is a serine-threonine kinase that mediates the cardioprotective effect of ischemic and pharmacologic preconditioning. Since hydrogen sulfide (H2S) has been implicated in mediating the cardioprotective effects of the cGMP modulators tadalafil and cinaciguat, we tested the hypothesis that myocardial gene therapy with PKG exerts cardioprotection against ischemia/reperfusion (I/R) injury through a mechanism involving H2S. Adult rat cardiomyocytes were infected with adenoviral vector encoding PKGIalpha or inactive mutant PKGIalphaK390A (K390A) for 24 h. Necrosis and apoptosis (n = 6/group) were determined after 90 min of simulated ischemia and 1 or 18 h of reoxygenation, respectively. To study the effect of PKGIalpha in vivo, mice received intramyocardial injections of adenoviral PKGIalpha or K390A. Four days later, the hearts were subjected to 30 min of ischemia followed by reperfusion for 24 h. The inhibitor of H2S-producing enzyme, cystathionine-gamma lyase (CSE), dl-propargylglycine (PAG, 50 mg/kg, ip) was given 30 min before ischemia. PKGIalpha overexpression induced CSE expression, whereas cystathionine beta-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase expression was not changed. PKGIalpha overexpression increased H2S in the heart and cardiomyocytes in relation to control and PKGIalphaK390A. Moreover, PAG abolished protection with PKGIalpha in vitro by increasing necrosis (35.2 +/- 1.7%, P < 0.05) and apoptosis (23.5 +/- 1.8 %, P < 0.05) as compared to PKGIalpha-overexpressing cells (necrosis: 17.2 +/- 0.9% and apoptosis: 13.2 +/- 0.8%). In vivo, PKGIalpha overexpression reduced infarct size and preserved left ventricular fractional shortening as compared with K390A (P < 0.05) and PAG abolished the cardioprotective effect of PKGIalpha. The protective effect of myocardial gene therapy with PKGIalpha against I/R injury is mediated through a mechanism involving H2S signaling. PMID- 26036466 TI - Randomized phase II study of S-1 dosing schedule for resected colorectal cancer. AB - BACKGROUND: Postoperative adjuvant chemotherapy for patients with stage III Colorectal cancer (CRC) is now internationally accepted as standard care for improving patient outcomes. The Adjuvant Chemotherapy Trial of S-1 for Colorectal Cancer (ACTS-CC) confirmed the non-inferiority of S-1 to tegafur/urcail/leucovorin in terms of overall survival and disease-free survival in patients with stage III CRC after curative surgery. However, the 6-month completion rate of S-1 treatment was 76.5% in the ACTS-CC. Therefore, treatment completion remains an unresolved problem. METHODS/DESIGN: A randomized phase II trial was designed to evaluate the efficacy and safety of oral daily administration and alternate-day administration of S-1 as adjuvant chemotherapy in curatively resected stage III CRC. Enrolled patients were assigned to either S 1 daily administration (Arm A) or alternate-day S-1 administration (Arm B). Assigned treatment will start within 8 weeks after surgery. In both arms, S-1 dosing (oral) will be based on body surface area (80 mg/day for body surface area<1.25 m2, 100 mg/day for 1.25-1.5 m2, or 60 mg/day for >1.5 m2). In Arm A, S 1 will be administered orally for 28 days, followed by a 14-day rest. Administration will be conducted for 24 weeks from the date of therapy start. In Arm B, S-1 will be administered orally on alternate days for 28 weeks from the date of the start of therapy. After treatment, all patients will be observed without additional therapy unless recurrent lesions or other cancer lesions occur. The primary endpoint is treatment completion rate. Secondary endpoints include 3-year disease-free survival, compliance, and adverse events. DISCUSSION: Previously, S-1 alternate-day intake maintained the efficacy of chemotherapy while reducing adverse effects for patients with R0-resected stage II/III gastric cancer. Improvement of chemotherapy completion rate for patients with colorectal cancer will lead to an improved patient prognosis. Therefore, a randomized phase II trial has been designed to examine the efficacy of alternate-day versus current standard daily S-1 administration as adjuvant chemotherapy for R0 resected stage III colorectal cancer. TRIAL REGISTRATION: This study was registered on 18 February 2014 with University Hospital Medical Information Network Clinical Trials Registry: UMIN000013185. PMID- 26036464 TI - HIV Stigma in Prisons and Jails: Results from a Staff Survey. AB - With numerous HIV service gaps in prisons and jails, there has been little research on HIV stigma attitudes among correctional staff. Such attitudes may undermine HIV services for inmates at risk of or infected with HIV. This HIV stigma attitudes survey among 218 correctional staff in 32 US facilities (1) provides an overview of staff's stigma attitudes, (2) reports psychometric analyses of domains in Earnshaw and Chaudoir's HIV Stigma Framework (HSF), and (3) explores differences in stigma attitudes among different staff types. Overall, correctional and medical staff expressed non stigmatizing attitudes toward people living with HIV/AIDS, but perceived that stigma and discrimination exist in others. Factor analyses revealed a three factor structure capturing two mechanisms of the HSF (prejudice, discrimination). Few factor score differences were found by staff type or setting. Implications for correctional HIV services and future research on HIV stigma attitudes are discussed. PMID- 26036468 TI - Attitudes towards mental illness of nursing students in a Baccalaureate programme in Jamaica: a questionnaire survey. AB - There is longstanding evidence of nurses demonstrating negative attitudes towards people with mental illness. Student nurses' fear or discomfort with mentally ill patients results in poorer outcomes for patients and students' dissatisfaction with their experience of mental health nursing. There is evidence of negative attitudes towards mental illness in the Jamaican society; however, no studies have explored whether these attitudes are held by nursing students. The aim of the study was to examine the attitudes of nursing students towards mental illness. A questionnaire survey was conducted with a convenience sample of 143 third-year nursing students who were enrolled in a baccalaureate programme. Data were collected using the Attitudes Towards Acute Mental Health Scale (ATAMHS). A response rate of 71% was achieved for the survey. The findings indicated that the student nurses held an overall negative attitude towards mental illness, with a general perception that mentally ill people are dangerous. The student nurses were divided in their opinions in a number of areas, suggesting a possible conflict of opinions. Negative attitudes towards mental illness impact client outcomes and the career choices made by nurses. This study provides baseline data within the Jamaican context that adds to the evidence on nursing students' attitude to mental illness. Further research is needed to explore whether nursing education and clinical experience enables student nurses in Jamaica to develop a more positive attitude towards mental illness and mental health nursing and whether cultural factors contribute to negative attitudes. PMID- 26036469 TI - Influences of dehydration and rehydration on the lubrication properties of phospholipid polymer-grafted cross-linked polyethylene. AB - Surface modification by grafting of biocompatible phospholipid polymer onto the surface of artificial joint material has been proposed to reduce the risk of aseptic loosening and improve the durability. Poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC)-grafted cross-linked polyethylene (CLPE) has shown promising results for reducing wear of CLPE. The main lubrication mechanism for the PMPC layer is considered to be the hydration lubrication. In this study, the lubrication properties of PMPC-grafted CLPE were evaluated in reciprocating friction test with rehydration process by unloading in various lubricants. The start-up friction of PMPC-grafted CLPE was reduced, and the damage of PMPC layer was suppressed by rehydration in water or hyaluronic acid solutions. In contrast, the start-up friction of PMPC-grafted CLPE increased in fetal bovine serum solution, and the damage for PMPC layer was quite noticeable. Interestingly, the start-up friction of PMPC-grafted CLPE was reduced in fetal bovine serum solution containing hyaluronic acid, and the damage of the PMPC layer was suppressed. These results indicate that the rehydration by unloading and hyaluronic acid are elemental in maximizing the lubrication effect of hydrated PMPC layer. PMID- 26036471 TI - Demystifying the night shift: learning beyond 9-5. PMID- 26036470 TI - Reduced Expression of P2Y2 Receptor and Acetylcholinesterase at Neuromuscular Junction of P2Y1 Receptor Knock-out Mice. AB - ATP is co-stored and co-released with acetylcholine (ACh) at the pre-synaptic vesicles in vertebrate neuromuscular junction (nmj). Several lines of studies demonstrated that binding of ATP to its corresponding P2Y1 and P2Y2 receptors in the muscle regulated post-synaptic gene expressions. To further support the notion that P2Y receptors are playing indispensable role in formation of post synaptic specifications at the nmj, the knock-out mice of P2Y1 receptor (P2Y1R ( /-)) were employed here for analyses. In P2Y1R (-/-) mice, the expression of P2Y2 receptor in muscle was reduced by over 50 %, as compared to P2Y1R (+/+) mice. In parallel, the expression of acetylcholinesterase (AChE) in muscle was markedly decreased. In the analysis of the expression of anchoring subunits of AChE in P2Y1R (-/-) mice, the proline-rich membrane anchor (PRiMA) subunit was reduced by 60 %; while the collagen tail (ColQ) subunit was reduced by 50 %. AChE molecular forms in the muscle were not changed, except the amount of enzyme was reduced. Immuno-staining of P2Y1R (-/-) mice nmj, both AChE and AChR were still co localized at the nmj, and the staining was diminished. Taken together our data demonstrated that P2Y1 receptor regulated the nmj gene expression. PMID- 26036472 TI - Familial haploidentical challenging unrelated donor Allo-SCT in advanced non Hodgkin lymphomas when matched related donor is not available. PMID- 26036473 TI - Are lifestyle behavioral factors associated with health-related quality of life in long-term survivors of non-Hodgkin lymphoma? AB - BACKGROUND: The objective of the current study was to determine whether survivors of non-Hodgkin lymphoma are meeting select American Cancer Society (ACS) health related guidelines for cancer survivors, as well as to examine relationships between these lifestyle factors and health-related quality of life (HRQoL) and posttraumatic stress (PTS). METHODS: A cross-sectional sample of 566 survivors of NHL was identified from the tumor registries of 2 large academic medical centers. Respondents were surveyed regarding physical activity, fruit and vegetable intake, body weight, tobacco use, HRQoL using the Medical Outcomes Study Short Form-36, and PTS using the Posttraumatic Stress Disorder CheckList-Civilian form. Lifestyle cluster scores were generated based on whether individuals met health guidelines and multiple linear regression analysis was used to evaluate relationships between lifestyle behaviors and HRQoL scores and PTS scores. RESULTS: Approximately 11% of participants met all 4 ACS health recommendations. Meeting all 4 healthy recommendations was related to better physical and mental QoL (standardized regression coefficient [beta], .57 [P<.0001] and beta, .47 [P = .002]) and to lower PTS scores (beta, -0.41; P = .01). CONCLUSIONS: Survivors of NHL who met more ACS health-related guidelines appeared to have better HRQoL and less PTS. Unfortunately, many survivors are not meeting these guidelines, which could impact their overall well-being and longevity. PMID- 26036474 TI - The Ins and Outs of Small GTPase Rac1 in the Vasculature. AB - The Rho family of small GTPases forms a 20-member family within the Ras superfamily of GTP-dependent enzymes that are activated by a variety of extracellular signals. The most well known Rho family members are RhoA (Ras homolog gene family, member A), Cdc42 (cell division control protein 42), and Rac1 (Ras-related C3 botulinum toxin substrate 1), which affect intracellular signaling pathways that regulate a plethora of critical cellular functions, such as oxidative stress, cellular contacts, migration, and proliferation. In this review, we describe the current knowledge on the role of GTPase Rac1 in the vasculature. Whereas most recent reviews focus on the role of vascular Rac1 in endothelial cells, in the present review we also highlight the functional involvement of Rac1 in other vascular cells types, namely, smooth muscle cells present in the media and fibroblasts located in the adventitia of the vessel wall. Collectively, this overview shows that Rac1 activity is involved in various functions within one cell type at distinct locations within the cell, and that there are overlapping but also cell type-specific functions in the vasculature. Chronically enhanced Rac1 activity seems to contribute to vascular pathology; however, Rac1 is essential to vascular homeostasis, which makes Rac1 inhibition as a therapeutic option a delicate balancing act. PMID- 26036476 TI - Organ and tissue donation for transplantation from fatal trauma victims. AB - INTRODUCTION: The aim of this study was to analyze multiple aspects of organ donation after mortality owing to trauma-related causes. METHODS: We completed a cross-sectional, retrospective, descriptive study that used data were extracted from monthly death reports and clinical records of fatal external injury victims 2-70 years of age who were assisted at 1 of 4 hospitals in the municipality of Maringa and the surrounding metropolitan area in Parana state, Brazil, in 2012. RESULTS: A total of 871 individuals within the age range for donation died, 15.4% owing to external causes of injury. Of these 134 cases, 80.6% were male and 52.23% were 18-40 years old. A total of 57% of deaths were owing to traffic accidents, 58% of which involved motorcycles. Aggression was a factor in 25% of deaths, with 55% owing to firearm wounds. Approximately 52% of families consented to organ donation when asked. A total of 58% of families who refused consent did not indicate a specific reason. At 62%, the majority of refusals involved brain dead patients. Approximately 58% of the families did not receive a request for consent. Out of these 78 cases, 83% showed contraindications, 44% had sepsis, 40% hemodilution, and 10% logistical/infrastructural problems. CONCLUSIONS: The highest proportion of non donor cases was owing to the lack of a formal request for consent from the family. Thus, continued training for health care professionals on the donation-transplantation process and early identification of potential donors and appropriate organ maintenance is necessary. PMID- 26036477 TI - What is organ donation and transplantation? Educating through the doubt. AB - BACKGROUND: Organ transplantation in Brazil is increasing, but one of its current obstacles is the negative response of the population to organ donation. Therefore, to make the process viable, it is essential that people are educated in organ donation and transplantation. The purpose of this research was to evaluate the main doubts on this subject and to clarify these issues by educating the respondents on the basis of their questions. METHODS: Handout questionnaires about organ donation and transplantation were distributed in public schools. The public targets were parents, teachers, and students. The interviewers were trained medical students. RESULTS: In this pilot study with 293 subjects, 97% of respondents had already heard about organ donation; 81% said they would donate their organs, whereas 76% said they would donate the organs of family members and 78% said they believe in the existence of organ trafficking in Brazil. CONCLUSIONS: The high percentage of respondents believing in the existence of an organ trade highlights the urgency in clarifying this topic. To do so, the population must be educated about the ethics of the process of donation, emphasizing the fact that there is no organ trade in Brazil. PMID- 26036478 TI - Clinical outcomes and genetic expression profile in human liver graft dysfunction during ischemia/reperfusion injury. AB - INTRODUCTION: This study aims to compare the molecular gene expression during ischemia reperfusion injury. Several surgical times were considered: in the beginning of the harvesting (T0), at the end of the cold ischemia period (T1), and after reperfusion (T2) and compared with graft dysfunction after liver transplant (OLT). METHODS: We studied 54 patients undergoing OLT. Clinical, laboratory data, and histologic data (Suzuki classification) as well as the Survival Outcomes Following Liver Transplantation (SOFT) score were used and compared with the molecular gene expression of the following genes: Interleukin (IL)-1b, IL-6, tumor necrosis factor-alpha, perforin, E-selectin (SELE), Fas ligand, granzyme B, heme oxygenase-1, and nitric oxide synthetase. RESULTS: Fifteen patients presented with graft dysfunction according to SOFT criteria. No relevant data were obtained by comparing the variables graft dysfunction and histologic variables. We observed a statistically significant relation between SELE at T0 (P = .013) and IL-1beta at T0 (P = .028) and early graft dysfunction. CONCLUSIONS: We conclude that several genetically determined proinflammatory expressions may play a critical role in the development of graft dysfunction after OLT. PMID- 26036479 TI - Comparison Between IGL-1 and HTK Preservation Solutions in Deceased Donor Liver Transplantation. AB - The effectiveness of liver preservation solutions remains in evidence. Cold ischemia time, steatosis, expanded criterion donors, operational cost, and survival represent important roles in its success. In a prospective cohort study between August 2009 and April 2014, 178 patients were allocated into an Institut Georges Lopez - 1 (IGL-1) solution group (63.5%) or histidine-tryptophan ketoglutarate (HTK) group (36.5%). There were no differences among recipient's characteristics including age, skin color, gender, Model for End-stage Liver Disease score, acute rejection, cholestasis, and reperfusion syndrome incidences. Also, donors, age average, skin color, donor risk index, time in intensive care unit, hemodynamic variables, infections, and steatosis incidences were similar. The average cold ischemia time was 494 minutes in the IGL-1 group and 489 minutes in the HTK group (P = .77). Alanine aminotransferase and aspartate aminotransferase serum levels on the first postoperative day were 707 and 1185 mg/dL, respectively, with IGL-1 and 1298 and 2291 mg/dL, respectively, with HTK (P = .016) and similar at day 15 (P > .88). The incidence of delayed graft function was 4.5% with IGL-1 and 4.6% with HTK (P = .90). The incidence primary nonfunction was 2.7% with IGL-1 and 3.1% with HTK (P = .71). The incidence of perioperative death was 11.5% with IGL-1 and 13.8% with HTK (P = .94). The survival in 30 months was 86% in IGL-1 group and 82% in HTK group (P = .66). Both preservation solutions are efficient to liver transplantations with deceased donors. Major prospective trials are necessary to evaluate each preservation solution's particularities. The preservation solution availability in each transplantation center must guide its use at the present moment. PMID- 26036480 TI - Effect of Different Sensitization Events on HLA Alloimmunization in Kidney Transplantation Candidates. AB - BACKGROUND: HLA alloimmunization is caused by sensitization events (SEs), such as transfusion, pregnancy, or previous organ transplantation, and the effects of particular SEs have not been thoroughly studied. Our aim was to evaluate how each SE affected HLA alloimmunization by considering Luminex assays. METHODS: Sera from 722 kidney transplantation candidates were screened per protocol by means of Luminex assays to determine the presence of anti-HLA class I/II antibodies; positive sera underwent single-antigen assay to determine the presence of specific antibodies against HLA A, B, C, DR, DQ, DP loci (positivity if median fluorescence intensity values were >1,000). The effect of each SE was analyzed considering only patients exposed to 1 kind of sensitization. RESULTS: In the 453 candidates with >=1 SE, anti-HLA class I positivity rates were significantly higher in patients with previous transfusion (18.9%; P = .014), pregnancy (38.3%; P < .001) or transplant (75%; P < .001) compared with those with no SE (similar results for class II). The strength (median fluorescence intensity) of specific antibodies was significantly higher in patients with previous transplantation than in those with previous transfusion for HLA-A (8,017 vs 2,302; P = .02), HLA B (7,765 vs 2,901; P = .018), and HLA-DR (9,835 vs 2,060; P = .003). Other anti HLA antibody strengths were similar between patients with previous pregnancy or transplantation. CONCLUSIONS: Presence of any SE analyzed was associated with a higher prevalence of anti-HLA antibodies for class I +/- II compared with nonsensitized patients. Transplantation had the strongest immunization effect on both classes, followed by pregnancy and then transfusion. PMID- 26036481 TI - Living kidney donor transplantation: an alternative with limitations. AB - BACKGROUND: The major issues involved in the decision to donate are the perioperative risk and the risk of chronic kidney disease or even end-stage renal disease. The usual glomerular filtration rate (GFR) in kidney donors after transplantation is approximately 70% of the predonation rate; however, some have a GFR <60 mL/min/1.73 m(2). So after kidney donation, mild to moderate renal insufficiency may occur. Thus, it is important to identify predictor factors of postdonation kidney function. OBJECTIVES: To evaluate the influence of predictor factors in the evolution of the remaining kidney function and to quantify nonpredictable and unexpected developments in GFR at 1 year post donation. METHODS: We performed a study of the evolution of renal function pre- and postnephrectomy of 55 living donors without perioperative comorbidities and a mean follow-up of 6.03 +/- 2.7 years. RESULTS: One year after nephrectomy donor function was 32% lower than the prenephrectomy value and 21% of donors had an eGFR <60 mL/min/1.73 m(2). In multivariate logistic regression a living donor with a predonation eGFR <100 but >80 mL/min/1.73 m(2) had 5.24 times a chance of having an eGFR <60 mL/min/1.73 m(2) at 1 year post donation than if he had an eGFR >=100 mL/min/1.73 m(2). Among 15 donors with prenephrectomy eGFR >=80 and <100 mL/min/1.73m(2), 8 (53%), RR = 3.26 (1.517-7.012) had eGFR <60 mL/min/ 1.73 m(2). CONCLUSIONS: The eGFR predonation and donor age influenced the first-year postnephrectomy eGFR. Some donors had a more accelerated eGFR fall, not always related to predonation eGFR and age. PMID- 26036482 TI - From Open to Laparoscopic Living-donor Nephrectomy: Changing the Paradigm in a High-volume Transplant Center. AB - In 1995, Ratner et al reported the first laparoscopic living-donor nephrectomy, and since then this approach is gradually replacing traditional open surgery. The learning curve of the procedure is still unclear and lessons taken from initial experience series are of utmost importance. We retrospectively analyzed our initial 50 living-donor laparoscopic nephrectomies, of which 90% were performed on the left side. Renal vascular variation occurred in 28% of donors. The median age and body mass index of the donors were 50 years (IQR 39-55) and 24.65 kg/m(2) (IQR 22.5-27.3), respectively. The median operative time and warm ischemia time were 160 minutes (IQR 141-178) and 240 seconds (IQR 210-280), respectively. Estimated blood loss was 60 mL (IQR 60-127.5). The serum creatinine of the receptors was 97.6 MUmol/L (IQR 87.5-139.6) 1 month after transplant. Overall, there were 5 complications, including 2 (4%) open conversions, 1 (2%) incisional hernia, 1 (2%) graft loss, and 1 (2%) reintervention. The body mass index and the multiple arteries did not influence the operative time and warm ischemia time or the recipient's serum creatinine level. Along the series, there was a significant reduction in the operative time (Spearman rho = -5.2; P < .001), but no significant differences were found for warm ischemia time, blood loss, or serum creatinine of the recipients (P > .05). Laparoscopic donor nephrectomy is a safe procedure in centers experienced in laparoscopic surgery; however, the learning curve plateau was not reached after the initial 50 cases. PMID- 26036483 TI - New Recipes With Known Ingredients: Combined Therapy of Everolimus and Low-dose Tacrolimus in De Novo Renal Allograft Recipients. AB - BACKGROUND: Calcineurin inhibitors (CNIs) are the cornerstones of immunosuppressive management in renal allograft recipients even though their nephrotoxicity may contribute to a reduced long-term graft survival. This has created a great interest in improving immunosuppressive strategies in the early post-transplantation period. Proliferation signal inhibitors (PSIs), such as everolimus, are promising alternatives, although their side effects may have a drawback in de novo renal transplant recipients, for instance, delaying renal function in the presence of renal ischemia/acute tubular necrosis and predisposing to lymphocele development. STUDY AND METHODS: A retrospective study was developed to compare the combined therapy of low-dose tacrolimus and everolimus (study group) with mycophenolate mofetil/mycophenolic acid and standard-dose tacrolimus (control group) in the first 3 months post transplantation. The study's end-points concerned renal graft function, proteinuria, incidence of biopsy-proven acute rejection, surgical complication rates, and incidence of new-onset diabetes after renal transplantation. RESULTS: There was no more delayed graft function in the study group and graft function distribution was similar between groups. Median serum creatinine and eGFR were comparable as well as proteinuria levels. Generally, adverse events were rare in both groups and there were no significant statistical differences between them in terms of biopsy-proven acute rejection, surgical complication, and new-onset diabetes after renal transplantation rates. CONCLUSION: Despite the slightly lower tendency for serum creatinine in the study group, renal allograft function wasn't statistically different between groups. Moreover, there weren't more metabolic or surgical complications in the study group. Everolimus may be a choice in tacrolimus-sparing strategies, but a larger study and a longer follow up are still required. PMID- 26036484 TI - Impact of conversion from Advagraf to twice-daily generic tacrolimus in kidney transplant recipients: a single-center study. AB - BACKGROUND: The conversion of twice-daily (Prograf) to once-daily tacrolimus (Advagraf) as well as from Prograf to a generic tacrolimus preparation was proved to be safe in kidney transplant patients. There are no published studies comparing the clinical outcomes of patients who were receiving Advagraf and were switched to generic preparations of tacrolimus. OBJECTIVES: To evaluate the impact, safety profile, side effects, and renal graft function after the conversion of Advagraf to a generic preparation of tacrolimus. POPULATION AND METHODS: This prospective study was conducted over a 9-month period. The conversion to twice-daily generic tacrolimus was performed on a 1 mg:1 mg basis, total daily dose. We included 123 kidney transplant recipients (55% male). The mean (+/- SD) age was 49.9 +/- 12 years. There were 100 (81%) Caucasian patients; the mean (+/- SD) time from transplantation to conversion was 4.6 +/- 4.4 years. RESULTS: A significant increase in blood levels (18%; P = .000) was reported. There was a necessary tacrolimus dose reduction of 17% (P = .000) and >= 3 blood trough levels to adjust the initial tacrolimus blood levels. The mean serum creatinine remained stable before conversion, at months 1 and 6 (1.40, 1.43, and 1.46 mg/dL, respectively). Significant adverse effects were reported in 9% of our patients. There were no episodes of acute rejection or graft loss during the study. CONCLUSIONS: The conversion proved to be safe. A drug reduction was necessary to ensure stable renal function and good tolerability. PMID- 26036485 TI - Kidney transplantation: which variables should be improved? AB - INTRODUCTION: Several factors have an impact on allograft survival but many are still controversial. In this study we investigated the effect of multiple factors on early renal graft function as an effort to find new tools to improve. MATERIAL AND METHODS: This was a transversal study of 64 patients who underwent kidney transplantation during the first semester of 2013. Demographic, clinical, and laboratory data were collected and analyzed. We used SPSS 20.0. Univariate analysis through nonparametric tests and multivariate analysis through linear regression were made. RESULTS: Regarding the donor, age (beta = 1.581; P = .003) and stroke as cause of death (P = .044) were associated with a higher creatinine level. Concerning the recipient, age (beta = 0.963; P = .001) as well as the difference between the candidate and the donor (beta = 1.203; P = .000), black race (P = .032/.000), male gender (P = .027/.046), vasculopathic end-stage renal disease (ESRD; P = .050), hemodialysis (HD) modality (P = .001/.033), HD session before surgery (P = .005), body mass index (BMI) >25 kg/m(2) (P = .043), hypoalbuminemia (beta = -0.280/-0.076; P = .029/.046), and anemia (beta = -0.361; P = .032) were also associated with a higher creatinine level. Living donor transplant (P = .000/.043), instant diuresis (P = .000/.021), and post transplantation higher blood pressure (BP; systolic BP [SBP] beta = -0.452; P = .021 and diastolic BP [DBP] beta = -0.318; P = .033) were associate with lower creatinine values. Overall, 87.6% of the renal function markers after the first semester were explained by the multiple factors above mentioned. CONCLUSIONS: Our findings are of practical clinical interest because nutritional status, hemoglobin, albumin, and BP are some of the objective measurable and modifiable parameters of which management may improve renal graft function. PMID- 26036486 TI - Small kidneys for large recipients: does size matter in renal transplantation? AB - BACKGROUND: Imbalance between transplanted renal mass and the metabolic demands of the recipient has been identified as a predictor of renal graft function. Multiple factors have been used to test this influence, but none of them is consensually accepted. The aim of this study is to evaluate the influence of the imbalance between transplanted renal mass and the metabolic needs of the recipient by analyzing the relationship between the ratio of the weight of the renal graft and the body weight of the recipient (Kw/Rw) on transplantation outcomes. METHODS: Prospective observational study of 236 first and single cadaveric renal transplants in non-hyperimmunized recipients was conducted. Grafts were orthogonally measured and weighed immediately before implantation, and these measures were correlated with donor and recipient data. According to the Kw/Rw ratio, patients were divided into three groups: Kw/Rw < 2.8 (P25), Kw/Rw = 2.8-4.2, and Kw/Rw > 4.2 (P75). After a mean follow-up of 5.2 years, transplant outcomes (delayed graft function; acute rejections; and estimated 1-, 6-, 12-, 36-, and 60-month renal function, graft, and patient survivals) were evaluated and correlated in uni- and multivariate analyses with the Kw/Rw ratio. RESULTS: Mean values for graft dimensions were 109.47 * 61.77 * 40.07 mm and the mean weight was 234.63 g. Mean calculated volume was 145.64 mL. The mean Kw/Rw ratio was 3.65 g/kg. These values were significantly lower for female grafts (3.91 vs 3.24, P < .001). According to the Kw/Rw ratio groups, there were no differences on delayed graft function, acute rejection episodes, and estimated graft function at the defined times. The increase in estimated glomerular filtration rate by a mean of 3.6 mL/min between 1 and 6 months for patients with Kw/Rw < 2.8 was not statistically relevant when compared to the higher ratio group with a mean variation of -0.91 mL/min (P = .222). Graft survival rate at 5 years after transplantation was 79% in the Kw/Rw < 2.8 group and 82% in the Kw/Rw > 4.2 group (P = .538). Patient survival rate at 5 years after transplantation was 85% in the Kw/Rw < 2.8 group and 92% in the high ratio group (P = .381). Kw/Rw ratio was not an independent risk factor for transplant failure at 5.2 years in a multivariate logistic regression analysis. Irrespective of recipient weight, graft survival was significantly higher for grafts with volume or weight above the 50 percentile (vol > 134 mL, P = .011 or weight > 226 g, P = .016). CONCLUSION: The imbalance between implanted renal mass and recipient metabolic demands does not seem to influence the functional outcomes and graft survival up to 60 months post-transplantation. Nevertheless, irrespective of recipient weight, graft survival is significantly higher for grafts with volume or weight above the 50 percentile. PMID- 26036488 TI - Deceased-donor Kidney Transplantation: Predictive Factors and Impact on Postoperative Outcome. AB - Kidney transplantation (KT) is the treatment of choice in end stage renal disease. Patients proposed for KT have multiple comorbidities, which makes KT a challenge. Our aim was to assess predictive factors for postoperative complications in deceased-donor KT. For data statistical analysis, logistic and linear regressions were used. Between 2012 and 2013, 113 KTs were performed in patients with a mean age 49.9 years. The most prevalent etiology was unknown (32.7%). All patients were in kidney replacement therapy (KRT), for an average of 5.7 years. Most had comorbidities before KT (84.1%), the most frequent hypertension (82.3%). Mean ischemia time (IT) was 1056 minutes. Complications occurred in 93.8% of cases. There were reinterventions in 12.4% of cases, and reinterventions in 13.3%. The time in KRT, IT, and ischemic heart disease had predictive power for the length of hospital stay. Diabetes mellitus before KT and IT were predictors for nephrourologic complications; anemia before KT for hematologic complications; and anemia before KT and time in KRT for cardiovascular complications. The morbidity associated with this disease points to the need to identify and improve the patient-dependent variables influencing its outcome, so as to improve short-term success. PMID- 26036487 TI - Lack of impact of hepatitis C virus infection on graft survival after kidney transplantation--a Portuguese single-center experience. AB - BACKGROUND: Hepatitis C virus infection (HCV) is a common problem among kidney transplant (KT) recipients. The long-term burden of HCV infection on graft survival after kidney transplantation is controversial. METHODS: We performed a retrospective study including all renal transplant recipients with HCV infection (n = 34) compared with a control group (n = 80). The prevalence of HCV infection was 2.7%. The median follow-up period was 134 months (11 years). Graft survival and associated risk factors were assessed by means of Cox proportional hazard analysis. RESULTS: We found that HCV-positive patients remained on dialysis for longer periods (P = .001) and received transplants at a younger age (P = .03). Actuarial graft survival rates at 1, 5, and 10 years after KT were, respectively, 94.1%, 78.1%, and 66.9%, in the HCV-positive group and 94.9%, 89.1%, and 80.4% in the HCV-negative group. Graft survival did not differ significantly between groups (P = .154). A higher incidence of major cardiovascular disease among HCV positive patients (P = .004) was noted. Multivariate analysis showed that HCV infection was not an important risk factor for graft loss (adjusted hazard ratio, 2.810; 95% confidence interval, 0.925-8.541; P = .069). Among the HCV-positive population, immunosuppression with cyclosporine or azathioprine conveyed better graft survival. CONCLUSIONS: Our findings suggest that the long-term impact of HCV infection on graft survival after KT is not significant. KT remains a safe and effective modality of renal replacement in HCV-infected patients with end stage renal disease. PMID- 26036489 TI - Living-donor Kidney Transplantation: Predictive Factors and Impact on Post transplant Outcome. AB - Renal transplantation from living donors represents a valuable opportunity for patients with end-stage renal disease due to short- and long-term outcomes. Nevertheless, it requires that a detailed set of conditions be considered for donor and recipient selection, with possible implications arising from these criteria in the post-transplant outcome. The present work aims to study demographic and clinical characteristics of donors and kidney recipients that predict post-transplantation outcomes after living donor kidney transplantation. With this aim, all patients who underwent donor nephrectomy and living donor transplantation between January 2012 and December 2013 were selected. Demographics, medical comorbidities, and postoperative outcomes were transcribed from electronic patient records. Linear and logistic regressions were applied for data analysis. The study sample consists of 40 patients who underwent living donor kidney transplantation. The presence of peripheral arterial disease and the etiology of end-stage renal disease were the only pretransplant variables that seem to independently predict hospitalization time. Simultaneously, the occurrence of urorenal and infectious complications had a statistically significant correlation with hospitalization time. Additionally, the incidence of cardiovascular complications was correlated with surgical reinterventions at a significant level. The results suggest that careful selection of the donor and the kidney recipient appears to be a prerequisite for a successful transplantation in vivo. PMID- 26036490 TI - Hepatitis B virus, hepatitis C virus, and kidney transplant acute rejection and survival. AB - The effect of hepatitis Bs-antigen (AgHBs) and anti-hepatitis C virus (HCV) positivity on renal transplant outcomes is still controversial. Some studies describe higher rates of acute rejection and allograft loss, and greater mortality in transplant recipients with hepatitis. We retrospectively evaluated data from 2284 allograft recipients who underwent transplantation at our hospital between July 1980 and December 2012. Statistical analysis was made using chi square and Student t tests, Kaplan-Meier curves, and survival analysis. We identified 62 AgHBs+ patients, 99 anti-HCV+ patients, and 14 AgHBs+/anti-HCV+ patients; 2109 patients had "no hepatitis." Mean follow-up time was 7.93 years. No statistical differences were identified on allograft acute rejection rate or patient survival between groups. AgHBs+ patients had, however, an inferior allograft survival, with statistical significance. According to our study, hepatitis B has a harmful impact on allograft survival, although it does not compromise the patient survival. PMID- 26036491 TI - Renal Transplantation in HIV-Infected Patients: The First Portuguese Review. AB - INTRODUCTION: With the introduction of combination antiretroviral therapy (cART), prognosis of human immunodeficiency virus (HIV) infection has been improved and kidney transplantation (KT) in HIV-positive patients became possible. METHODS: We reviewed the demographic, clinical, laboratory, and therapeutic data of all the HIV-infected patients who underwent KT between 2009 (first KT in Portugal in a HIV-infected patient) and May 2014. Case accrual was through all Portuguese KT centers where a KT in an HIV-infected patient was performed. Patients were transplanted following the American and Spanish guideline recommendations that included maintenance on cART, undetectable plasma HIV RNA copies, and absolute CD4 counts of >= 200 cells/MUL in the last 6 months. RESULTS: Fourteen KT were performed on men and 3 on women. The mean age of patients at the time of transplantation was 49.9 +/- 11.7 years. HIV status was known for 12 +/- 5 years. Eight patients had AIDS in the past and all patients received grafts from deceased donors. Twelve patients (64.7%) underwent induction therapy with basiliximab and 2 patients experienced early graft loss. In 2 patients, humoral rejection was diagnosed and in 3 patients, cellular rejection. Two patients died and an additional patient had early graft loss. CONCLUSION: KT is a possible, but challenging, renal replacement therapy in selected HIV-positive patients. Even in those with AIDS criteria in the past, when the disease is controlled, and after the reconstitution of the immune system with cART, KT can be performed. Nevertheless, the risk-benefit ratio for each patient needs to be taken in consideration. PMID- 26036493 TI - Pre-emptive pediatric kidney transplantation or not? AB - BACKGROUND: Kidney transplantation prior to dialysis (pre-emptive kidney transplantation, PKT) has been controversial because of the paucity of clinical evidence to clarify the risks and benefits of PKT. Several authors have confirmed a significant advantage of PKT in the treatment of patients with end-stage renal disease (ESRD). The aim of this study was to examine the characteristics of patients who received PKT or non-pre-emptive kidney transplant (NPKT). METHODS: We used a cohort of 323 consecutive kidney-transplanted children (53% boys) from Hospital da Crianca Santo Antonio, Porto Alegre, Brazil, who underwent transplantation between January 2000 and December 2010. RESULTS: The main causes of ESRD were congenital anomalies of the kidney and urinary tract (CAKUT) (39%) and glomerulopathies (27.5%). The 12-, 36-, 60-, and 90-months death-censored graft survival rates were 97%, 92%, 86%, and 76%, respectively, in the PKT group, and 87%, 79%, 72%, and 65% in the NPKT group (P < .05). CONCLUSIONS: The results of this study suggest that pre-emptive transplantation is beneficial (hazard ratio = 0.37; 95% confidence interval: 0.18-0.82). The main causes of graft loss (n = 67) were recurrence of primary disease (21%), chronic allograft injury (17%), and death with a functioning graft (16%). We recommend PKT as a better choice for transplantation whenever possible to minimize ESRD morbidity and provide better long-term patient and graft survival. PMID- 26036492 TI - Collaborative Brazilian Pediatric Renal Transplant Registry (CoBrazPed-RTx): A Report From 2004 to 2013. AB - BACKGROUND: The Collaborative Brazilian Pediatric Renal Transplant Registry started in 2004 as a multicenter initiative aiming to analyze, report, and share the results of pediatric kidney transplantation in Brazil. Data from all pediatric kidney transplants performed between January 2004 and December 2013 were recorded electronically and periodically updated. All patients under 18 years old from the participating centers were enrolled. Demographic data, etiology of chronic kidney disease, and patient and graft survival were analyzed. From a total of 2443 pediatric kidney transplants performed in Brazil during the study period, we report data from 1751 pediatric renal transplants performed in 13 centers enrolled in the collaborative study. Median age at transplantation was 12.4 years, and most of recipients were male (56%). The most common underlying renal etiologies were obstructive uropathy (31%) and glomerulopathy (26%). METHODS: According to donor source, 1155 (66%) of transplants were performed with deceased donors (DD). Initial immunosuppression consisted mainly of tacrolimus, mycophenolate, steroids, and induction therapy with anti-IL-2R antibodies. RESULTS: One-year graft survival (death-censored) was 93% and 90% (log rank test, P < .01), respectively, for living donor (LD) and DD. Graft losses (15%) were most frequently caused by vascular thrombosis, chronic allograft nephropathy, death with functioning kidney, acute rejection, and recurrent renal disease. Recipients of DD had 2.02 (95% confidence interval: 1.14-3.59) times the hazard of graft loss compared with those of LD (P = .015). Patient survival rates at 1 and 5 years were 98% and 97% for LD and 97% and 93% for DD, respectively. The mortality rate was 3.8%, mainly as the result of infection and cardiovascular disease. CONCLUSIONS: The results of this collaborative pediatric transplant study are comparable to international registries. Our effort has been able to maintain an exchange of information, both among the participating centers and with other international registries. PMID- 26036494 TI - Living-donor and Deceased-donor Renal Transplantation: Differences in Early Outcome--A Single-center Experience. AB - Living-donor renal transplant (LDRT) yields better long-term outcomes than cadaver-donor renal transplant (CDRT). The aim of the present study was to identify the differences in the early postoperative period between LDRT and CDRT recipients. A retrospective study was conducted including all patients receiving a LDRT and CDRT in this center in 2012 and 2013. A total of 153 recipients were identified (CDRT n = 113, LDRT n = 40). On average, LDRT recipients were younger by 12.7 years (P < .001) and had fewer comorbidities (P < .05). There were no differences in gender or primary kidney disease. Mean time on dialysis, dialytic technique, and ischemia time were different between groups (P < .001, P < .01, P < .001, respectively). On average the length of hospital stay for LDRT recipients was 7 days shorter (P < .001). We found significant differences in the occurrence of early complications (P < .001) and its subtypes, with the exception of neurologic and respiratory complications. There were no differences in reinterventions and readmissions between groups. Recipients' age was an independent risk factor for overall postoperative complications and infectious complications; hypertension before renal transplant and cold ischemia time were predictors for cardiovascular complications; and cold ischemia time also was a predictor of nephrourologic and endocrine complications. CDRT patients had more postoperative complications during hospital stay. The variables identified as predictors of early outcome were different for the 2 groups of patients. Modifiable risk factors for better early outcomes and the impact of immediate complications in long-term graft survival must be investigated. PMID- 26036495 TI - Kidney transplantation process in Brazil represented in business process modeling notation. AB - Kidney transplantation is considered to be the best treatment for people with chronic kidney failure, because it improves the patients' quality of life and increases their length of survival compared with patients undergoing dialysis. The kidney transplantation process in Brazil is defined through laws, decrees, ordinances, and resolutions, but there is no visual representation of this process. The aim of this study was to analyze official documents to construct a representation of the kidney transplantation process in Brazil with the use of business process modeling notation (BPMN). The methodology for this study was based on an exploratory observational study, document analysis, and construction of process diagrams with the use of BPMN. Two rounds of validations by specialists were conducted. The result includes the kidney transplantation process in Brazil representation with the use of BPMN. We analyzed 2 digital documents that resulted in 2 processes with 45 total of activities and events, 6 organizations involved, and 6 different stages of the process. The constructed representation makes it easier to understand the rules for the business of kidney transplantation and can be used by the health care professionals involved in the various activities within this process. Construction of a representation with language appropriate for the Brazilian lay public is underway. PMID- 26036496 TI - Long-term survival (>25 years) of deceased donor kidney transplant recipients: a single-center experience. AB - INTRODUCTION: The aim of this preliminary work is to analyze the clinical features of 52 patients with a functional transplanted kidney for >25 years (all first transplant and all deceased donor recipients) and to compare with a similar though more complete study from Hopital Necker-Paris 2012. METHODS: The mean graft survival at 25 years is 12.7% and at 30 years is 10%. The actual mean serum creatinine concentration is 1.3 mg/L. We analyzed recipient age (mean, 35.9 years) and gender (29 men and 23 women). Donor age was 26.7 +/- 10.3 years. Seven patients (13.4%) were transplanted with 1 HLA mismatch, 42.3% with 2 mismatches, and 44.2% with 3 mismatches. Mean cold ischemia time was 15.45 +/- 7.7 hours. Of the recipients, 76% had immediate graft function; 38% experienced 1 acute rejection episode and 4 patients had 2 rejection crises. The initial immunosuppressive regimen was azathioprine (AZA) + prednisolone (Pred) in 14 patients, cyclosporin (CSA) + Pred in 13 patients, and CSA + AZA + Pred in 25 patients. Of these patients, 19% maintained their initial regimen, and 54% (28 patients) were very stable on a mixed CSA regimen for >25 years. RESULTS: We present the major complications (diabetes, neoplasia, and hepatitis C virus positivity). CONCLUSION: Our results in deceased donor kidney recipients for >25 years are similar to the mixed population (deceased donors and living donors) presented by the Necker group, although 54% of our patients remain on CSA immunosuppression, contradicting the idea that its use is not compatible with good long-term kidney function in transplant recipients. PMID- 26036497 TI - Invasive Fungal Infections After Kidney Transplantation: A Single-center Experience. AB - INTRODUCTION: Invasive fungal infections (IFI) affecting transplant recipients are associated with increased mortality and graft dysfunction. OBJECTIVE: Describe the frequency, clinical features, and outcomes of IFI (except pneumocystis infection) in kidney transplant recipients. METHOD: Single-center descriptive study including every kidney transplant recipient with a culture proven or probable IFI between 2003 and 2013, according to the EORTC-MSG criteria. RESULTS: We identified 45 IFI. There were 13 cases of invasive candidiasis (C. albicans: 6 and non-C. albicans candidial spp.: 7), 11 cases of pulmonary aspergillosis (A. fumigatus: 9 and A. flavus: 2); 11 cases of subcutaneous mycosis (Alternaria spp.: 9, Paecilomyces spp.: 1, and Pseudallescheria spp.: 1); 7 cases of cryptococcosis; 2 cases of pneumonia by non Aspergillus molds (Mucor spp.: 1 and Cunninghamella spp.: 1); and 1 case of Geotrichum capitatum pneumonia. All patients were recipients from deceased donors. Six cases occurred in the first 3 months post-transplant, 15 cases between the third and twelfth months, and 21 cases after the twelfth month. Treatment options were fluconazole for Candida infections, voriconazole or caspofungin for aspergillosis, liposomal amphotericin for cryptococcosis, and itraconazole plus excision or cryotherapy for subcutaneous mycosis. Fifteen patients died (33%). Mortality rates were 15% for invasive candidiasis, 45% for aspergillosis, 71% for cryptococcosis, 100% for non-Aspergillus molds and G. capitatum pneumonia, and 0% for subcutaneous mycosis. Six patients who survived (14%) started regular hemodialysis. CONCLUSION: IFI still have a high mortality and morbidity in kidney transplant recipients, as verified in this report. We reinforce the need for a high index of suspicion and prompt treatment. PMID- 26036498 TI - Malignancy in Kidney Transplantation: A 25-Year Single-center Experience in Portugal. AB - It is known that the incidence of malignancy in transplant recipients is higher than in the general population, with a more aggressive behavior and a worse outcome. In fact, malignancy is the third most common cause of death among kidney transplant (KT) recipients, after cardiovascular events and infections. The aim of this study was to investigate the incidence and characteristics of malignancies after KT in a single center. A total of 2353 patients who underwent KT between 1987 and 2012 were retrospectively studied. The results were compared with a group without cancer. During the follow-up period leading to August 2014, which included a median duration of 126.3 +/- 81.8 months, 223 malignancies (9.4%) were diagnosed, which were the cause of death in 59 patients. Patients with cancer were older, had a longer duration of graft function, and had more episodes of acute rejection (AR), and a higher number of patients were treated with azathioprine and cyclosporine as initial immunosuppressive regime (P = .001). The most frequent malignancy was skin cancer (28.7%), followed by malignant lymphoma (12.1%) and kidney cancer (10.8%). The mean age of patients at diagnosis was 58.0 +/- 11.1 years. The average time for development of a cancer was 7.5 +/- 5.8 years, with 43.2% detected between 1 and 5 years. Patient survival was significantly lower among subjects with cancer, and censored graft survival was significantly higher in this group (P = .001). Multivariate logistic regression analysis showed that recipients' age and acute rejection episode are risk factors for development of post-kidney transplantation malignancy. PMID- 26036499 TI - Post-transplant Lymphoproliferative Disorder: A Single-Center Experience. AB - BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is the second most common neoplasia after adult kidney transplantation (KT). METHODS: We retrospectively analyzed 8 adult patients who underwent KT in our center, diagnosed with PTLD between 2001 and 2014. RESULTS: Six patients were men. The median age at presentation was 43 years and the median time since transplantation was 7.3 years. Three patients had previously received anti-thymocyte globulin/OKT3, and all were taking calcineurin inhibitors (CNI) at diagnosis. The monomorphic type was the most common, with diffuse large B-cell lymphoma as the origin. The most frequent presentation was fever. Four in five patients had Epstein-Barr-related PTLD. All patients received various regimens of immunosuppression reduction (IR), with 4 converting CNI to mTOR inhibitor (imTOR). Subsequent treatment (when needed) was chemotherapy, radiotherapy, and surgery. The maximum follow-up time was 6.7 years, with a 50% mortality rate that occurred at a median time of 3.5 months (2 died with functioning kidney). All 4 patients who were in remission at the end of follow-up had CNI conversion to imTOR, and none lost the allograft. CONCLUSIONS: Despite the small number of cases, our results confirm the high PTLD impact in overall and allograft survival. Our PTLD type distribution is in accord with the literature. First-line PTLD treatment is IR, but the best method is still unknown; our results may suggest a beneficial effect of CNI conversion to imTOR. PMID- 26036500 TI - Metabolic profile and cardiovascular risk in a population of renal transplant recipients. AB - INTRODUCTION: Cardiovascular disease is more common in renal transplant recipients (RTRs) than in the general population, and is the major cause of both graft loss and patient death in RTRs. OBJECTIVES: This study aimed to characterize the cardiovascular risk factors, calculate the 7-year risk for major adverse cardiac events and the 7-year risk for death in a population of RTRs using a cardiovascular risk calculator, and determine the main cardiovascular risk factors associated with increased prediction of major adverse cardiac event (MACE) and death. PATIENTS: This is a retrospective review of clinical data from 121 RTRs who are in follow-up programs at our institution, and who had a functioning and stable graft for longer than 6 months. RESULTS: Among 121 adult patients followed at our institution (59.5% males, mean age of 49.6 +/- 13.8 years, mean times for functioning grafts were 105 +/- 73.5 mo), 86.8% had hypertension, 19.8% had diabetes, 24.8% were current or former smokers, 61.9% had increased body mass index, and 71% had dyslipidemia. The 7-year risk for MACE was more than 10% in 38 (31.4%) patients with age, diabetes, and smoke being independent risk predictors. The 7-year risk for death was more than 10% in 56 (46.3%) patients with age, diabetes, blood pressure, smoking, and male gender being independent risk predictors. CONCLUSION: There is a high prevalence of cardiovascular risk factors in a population of RTRs, and there is increased risk for MACE and death. Accurate risk prediction is important for physician decision support and patient education, promoting improved cardiovascular health of RTRs, and thus prolonging the survival of both patients and graft. PMID- 26036501 TI - Female sexual function and depression after kidney transplantation: comparison between deceased- and living-donor recipients. AB - Disturbances in sexual function and depression are a common feature in women with chronic renal failure. Living-donor kidney transplantation seems to warrant better results than its cadaveric counterpart in many aspects but its impact on post-transplantation sexual function remains unknown. This study aimed to compare post-transplantation sexual function and depression in women receiving kidney grafts from living and deceased donors. From a single-center prospective database of 2016 renal transplantations between June 2011 and June 2013, we enrolled 50 sexually active women after kidney transplantation. Female sexual function was evaluated with the Female Sexual Function Index Questionnaire (FSFI) and depression was assessed using the Beck Depression Inventory-II (BDI-II) scale. Thirty-four patients referred the questionnaires. The sexual domains of satisfaction and desire were significantly better in living-donor receptors; in all other domains evaluated by FSFI no statistically significant difference was encountered between groups, although living-donor receptors tended to report better function. Total BDI-II was well correlated with total FSFI score in our study cohort (Spearman's rho = -0.80, P < .001). Only 34.6% of women referred to have discussed sexual issues with their physicians before transplantation, whereas 73.1% stated it would have been important. In conclusion, living-donor transplantation exerted a positive effect on women's sexual function. PMID- 26036502 TI - Allograft nephrectomy: a single-institution, 10-year experience. AB - INTRODUCTION: Allograft nephrectomy (AN) is associated with a high number of surgical complications. Some authors advocate that early nephrectomy (<1 year) is associated with fewer complications. Intracapsular (ICAN) and extracapsular AN (ECAN) might have a different impact on allosensitization and surgical outcomes. Our goal was to compare surgical outcomes between early and late AN in our institution and to compare ICAN and ECAN in terms of surgical outcomes and panel reactive antibodies (PRA) variation. MATERIALS AND METHODS: Between January 2000 and October 2012, we performed 104 AN at our institution (32 early and 72 late). Comparisons between early and late AN, and, within the latter, between the 2 different techniques were sought. Statistical analysis was performed for sample description, group comparison and %PRA variation. RESULTS: Among the 104 patients with a mean age of 47.9 +/- 14.2 years, 54 were men. Age, gender, body mass index, and number of previous transplants were similar between early and late AN and between ICAN and ECAN patients. Late AN was associated with less blood loss (293.4 +/- 229.0 vs 414.3 +/- 349.5 mL; P = .03), shorter hospital stay (12.8 +/- 14.5 vs 26.8 +/- 26.5; P < .05), and fewer complications (22.2% vs 59.3%; P < .05). The chance of being relisted for transplantation was similar (50.0% in early vs 59.7% in late AN; P = .7). When comparing ICAN and ECAN, there was no difference in surgical outcomes. The %PRA variation between the 2 techniques was comparable (-1.2 +/- 10.6 ICAN vs -0.5 +/- 15.9 ECAN; P = .8), as was the chance of being relisted for transplantation (60.5% ICAN vs 58.6% ECAN; P = .8). CONCLUSIONS: Early AN was associated with a greater number of surgical complications. Nevertheless, the number of AN patients returning to the active waiting list was similar between early and late AN groups. ICAN and ECAN had similar surgical and postoperative outcomes, although a bias may be present because some conversions from ECAN to ICAN occurred owing to technical issues. As in other studies, ICAN did not seem to affect allosensitization or jeopardize the chance of being relisted for transplant when compared with ECAN. PMID- 26036503 TI - Liver depurative techniques: a single liver transplantation center experience. AB - BACKGROUND: In a liver transplant (LT) center, treatments with Prometheus were evaluated. The main outcome considered was 1 and 6 months survival. METHODS: During the study period, 74 patients underwent treatment with Prometheus; 64 were enrolled, with a mean age of 51 +/- 13 years; 47 men underwent 212 treatments (mean, 3.02 per patient). The parameters evaluated were age, sex, laboratorial (liver enzymes, ammonia) and clinical (model for end-stage liver disease and Child-Turcotte-Pugh score) data. RESULTS: Death was verified in 23 patients (35.9%) during the hospitalization period, 20 patients (31.3%) were submitted to liver transplantation, and 21 were discharged. LT was performed in 4 patients with acute liver failure (ALF, 23.7%), in 7 patients with acute on chronic liver failure (AoCLF, 43.7%), and in 6 patients with liver disease after LT (30%). Seven patients who underwent LT died (35%). In the multivariate analysis, older age (P = .015), higher international normalized ratio (INR) (P = .019), and acute liver failure (P = .039) were independently associated with an adverse 1-month clinical outcome. On the other hand, older age (P = .011) and acute kidney injury (P = .031) at presentation were both related to worse 6-month outcome. For patients with ALF and AoCLF we did not observe the same differences. CONCLUSIONS: In this cohort, older age was the most important parameter defining 1- and 6 month survival, although higher INR and presence of ALF were important for 1 month survival and AKI for 6-month survival. No difference was observed between patients who underwent LT or did not have LT. PMID- 26036504 TI - Imaging screening of catastrophic neurological events using a software tool: preliminary results. AB - BACKGROUND: In Portugal, as in most countries, the most frequent organ donors are brain-dead donors. To answer the increasing need for transplants, donation programs have been implemented. The goal is to recognize virtually all the possible and potential brain-dead donors admitted to hospitals. The aim of this work was to describe preliminary results of a software application designed to identify devastating neurological injury victims who may progress to brain death and can be possible organ donors. METHODS: This was an observational, longitudinal study with retrospective data collection. The software application is an automatic algorithm based on natural language processing for selected keywords/expressions present in the cranio-encephalic computerized tomography (CE CT) scan reports to identify catastrophic neurological situations, with e-mail notification to the Transplant Coordinator (TC). The first 7 months of this application were analyzed and compared with the standard clinical evaluation methodology. RESULTS: The imaging identification tool showed a sensitivity of 77% and a specificity of 66%; predictive positive value (PPV) was 0.8 and predictive negative value (PNV) was 0.7 for the identification of catastrophic neurological events. CONCLUSION: The methodology proposed in this work seems promising in improving the screening efficiency of critical neurological events. PMID- 26036505 TI - Anxiety and depression symptoms in hepatic encephalopathy: are they psychiatric or organic? AB - BACKGROUND: Hepatic encephalopathy (HE) represents a broad continuum of neuropsychiatric abnormalities, from subtly altered mental status to deep coma, seen in patients with liver dysfunction. HE can mimic all of the major psychiatric syndromes. The distinction between HE and a psychiatric condition, namely depression, is sometimes difficult. Some liver patients end up being medicated with psychiatric drugs which might worsen their medical state. The main objective of this study was to try to find the correlations between anxiety and depression symptoms and the presence of HE to better diagnose and treat these patients. METHODS: Sixty consecutive liver transplant candidates, attending the outpatient clinics of a liver transplantation center were studied from January 1, 2012, to December 1, 2012. Each patient was assessed by means of Psychometric Hepatic Encephalopathy Score subtests and Hospital Anxiety and Depression Scale. RESULTS: We found a statistically significant relationship between HE and some of the depressive symptoms: anhedonia and loss of energy. CONCLUSIONS: These findings may indicate that when in the presence of an HE patient with depressive symptoms, HE-directed therapies should be attempted before antidepressant drugs. PMID- 26036506 TI - Variables associated with the risk of early death after liver transplantation at a liver transplant unit in a university hospital. AB - BACKGROUND: Graft dysfunction after liver transplantation is a serious complication that can lead to graft loss and patient death. This was a study to identify risk factors for early death (up to 30 days after transplantation). METHODS: It was an observational and retrospective analysis at the Liver Transplantation Unit, Hospital de Clinicas, State University of Campinas, Brazil. From July 1994 to December 2012, 302 patients were included (>18 years old, piggyback technique). Of these cases, 26% died within 30 days. For analysis, Student t tests and chi-square were used to analyze receptor-related (age, body mass index, serum sodium, graft dysfunction, Model for End-Stage Liver Disease score, renal function, and early graft dysfunction [EGD type 1, 2, or 3]), surgery (hot and cold ischemia, surgical time, and units of packed erythrocytes [pRBC]), and donor (age, hypotension, and brain death cause) factors. Risk factors were identified by means of logistic regression model adjusted by the Hosmer-Lemeshow test with significance set at P < .05. RESULTS: We found that hyponatremic recipients had a 6.26-fold higher risk for early death. There was a 9% reduced chance of death when the recipient serum sodium increased 1 unit. The chance of EGD3 to have early death was 18-fold higher than for EGD1 and there was a 13% increased risk for death for each unit of pRBC transfused. CONCLUSIONS: Donor total bilirubin, hyponatremia, massive transfusion, and EGD3 in the allocation graft should be observed for better results in the postoperative period. PMID- 26036508 TI - Evaluation of operative risk in de novo familial amyloid polyneuropathy retransplantation. AB - Familial amyloid polyneuropathy (FAP) is the most common hereditary amyloidosis, characterized by progressive peripheral sensory and motor neuropathy. The livers of patients with FAP are used in domino liver transplantation in selected cases to increase the number of grafts available. In our department 10 patients underwent liver retransplantation (ReLTx) in the absence of liver dysfunction by de novo FAP after domino liver transplantation. Our aim was to compare the differences in the consumption of blood products and intraoperative hemodynamic support among patients with FAP undergoing liver transplantation (LTx) and patients with de novo FAP undergoing ReLTx in the same time frame. The anesthetic records of all patients who underwent LTx for FAP and ReLTx for de novo FAP were analyzed, from January 2009 to May 2014. Patients were divided into 2 groups: group 1 patients with FAP, and group 2 patients with de novo FAP. Statistical differences in the value of preoperative creatinine were found. Hemoglobin levels, preoperative international normalized ratio (INR), use of blood products, aminergic support, and surgical time showed no statistical difference. Major bleeding rates would be expected in patients undergoing ReLTx. Changes in renal function, chronic immunosuppressive therapy, and age may contribute to the increase in intraoperative complications. We did not find statistically significant differences, leading us to the conclusion that de novo FAP does not seem to be a predictor of perioperative risk. PMID- 26036507 TI - Liver retransplantation in patients with acquired familial amyloid polyneuropathy: a Portuguese center experience. AB - In 1995 Furtado et al performed the first domino transplantation using a donor liver with familial amyloid polyneuropathy (FAP), thereby increasing the pool of donors. Our experience showed that the onset of FAP symptoms occurs earlier in some patients. Patients with FAP acquired by transplantation are candidates for liver retransplantation to minimize the progression of symptoms. Liver retransplantation is considered to be a high-risk procedure and has lower survival compared with the first transplantation. We evaluated the risk of liver retransplantation in patients with acquired FAP. We did a retrospective analysis of these patients based on the records of perioperative data. From 1995 to 2004 we carried out 81 domino transplantations, of which 10 were submitted to liver retransplantation because of acquired FAP. The better outcomes in this group lead us to think that the liver retransplantation in patients with acquired FAP is not associated with the same risks of liver retransplantation in candidates with graft failure. PMID- 26036509 TI - Infections After Liver Transplantation: A Retrospective, Single-center Study. AB - OBJECTIVE: To access the incidence of infectious problems after liver transplantation (LT). DESIGN: A retrospective, single-center study. MATERIALS AND METHODS: Patients undergoing LT from January 2008 to December 2011 were considered. Exclusion criterion was death occurring in the first 48 hours after LT. We determined the site of infection and the bacterial isolates and collected and compared recipient's variables, graft variables, surgical data, post-LT clinical data. RESULTS: Of the 492 patients who underwent LT and the 463 considered for this study, 190 (Group 1, 41%) developed at least 1 infection, with 298 infections detected. Of these, 189 microorganisms were isolated, 81 (51%) gram-positive bacteria (most frequently Staphylococcus spp). Biliary infections were more frequent (mean time of 160.4 +/- 167.7 days after LT); from 3 months after LT, gram-negative bacteria were observed (57%). Patients with infections after LT presented lower aminotransferase levels, but higher requirements in blood transfusions, intraoperative vasopressors, hemodialysis, and hospital stay. Operative and cold ischemia times were similar. CONCLUSION: We found a 41% incidence of all infections in a 2-year follow-up after LT. Gram positive bacteria were more frequent isolated; however, negative bacteria were commonly isolated later. Clinical data after LT were more relevant for the development of infections. Donors' variables should be considered in future analyses. PMID- 26036510 TI - Donor risk index does not predict graft survival after pancreas transplantation in Brazil. AB - BACKGROUND: Pancreas donor risk index (DRI) was developed by using large multicenter American data to predict the risk of adverse outcomes in pancreas transplantation based on donor and technical/logistical characteristics. AIM: The goal of this study was to evaluate the usefulness of the DRI in predicting graft survival in a Brazilian population of pancreas transplant recipients. METHOD: We conducted a retrospective analysis of the 570 procedures performed by the same surgical team between 1996 and 2011. Because of the lack of sufficient data for the calculation of DRI values, only 154 cases were studied (27%), of which 105 underwent simultaneous pancreas-kidney transplantation, 33 underwent pancreas after kidney transplantation, and 16 underwent pancreas transplantation alone. Donor cause of death was classified as cerebrovascular accident (CVA) and non CVA. Graft origin was divided into three groups: local, if the graft was obtained in the metropolitan area of the city of Sao Paulo; regional, if collected in other cities of the state of Sao Paulo; and national, if obtained outside the state. RESULTS: Logistic regression analysis did not find a statistically significant association between DRI values and 1-year graft survival (odds ratio = 0.676; 95% confidence interval 0.152 to 3.014; P = .60). One-year graft survival calculated by the Kaplan-Meier method was 89.8% in transplants with DRI <= 1, 77.9% in those with 1 < DRI < 1.5, and 93.3% in those with DRI >= 1.5 (P = .106). CONCLUSION: The pancreas DRI model did not prove effective in predicting pancreas graft survival in a Brazilian sample of recipients. PMID- 26036511 TI - Stents for bronchial stenosis after lung transplantation: should they be removed? AB - BACKGROUND: Airway complications after lung transplantation are the major cause of morbidity, affecting up to 33% of all cases. Bronchial stenosis is the most common complication. The use of stents has been established as the most effective therapy; however, their removal is recommended after 3-6 months of use. We have been using self-expandable stents as a definitive treatment and remove them only if necessary. For this report, we evaluated the use of self-expandable stents as a definitive treatment for bronchial stenosis after lung transplantation. METHODS: We performed a retrospective cohort study to evaluate patients with bronchial stenosis from August 2003 to April 2014. Clinical and pulmonary function test data were collected. RESULTS: Two hundred lung transplants were performed, 156 of which were bilateral. Sixteen patients experienced airway complications: 4 had dehiscence, 2 necrosis, and 10 bronchial stenosis. Of these patients, 7 had undergone bilateral procedures, and 2 patients developed stenosis in both sides. Twelve anastomotic stenoses were observed. The follow-up after stenting ranged from 1 to 7 years. All patients had increased lung function, and 4 remained stable with sustained increase in pulmonary function without episodes of infection. Three patients required removal of their prosthesis 6 months to 1 year after implantation because of complications. Two patients died owing to unrelated causes. CONCLUSIONS: Definitive treatment of bronchial stenosis with self-expandable stents is a viable option. The 1st year seems to be the most crucial for determining definitive treatment, because no patients required removal of their stent after 1 year. PMID- 26036512 TI - Liver regeneration model in growing rats with hepatic artery ligation: histologic and molecular studies. AB - BACKGROUND: Liver transplantation is an effective treatment for irreversible liver diseases. The incidence of hepatic artery thrombosis remains high. Our objective was to analyze the effect of ligature of the hepatic artery on liver regeneration in a growing animal model. METHODS: Seventy-five male Wistar rats were divided into the following 3 groups: group 1 (sham, G1): incision without intervention; group 2 (G2): 70% hepatectomy; group 3 (G3): 70% hepatectomy and ligation of the hepatic artery. Preceding the 70% hepatectomy, a hepatic artery ligature was performed with resection of a segment of the artery. The liver specimens were stained with hematoxylin-eosin, and immunohistochemical staining for Ki-67 was performed. The expression of the interleukin (IL) 6 gene was studied by means of reverse-transcription polymerase chain reaction. RESULTS: G2 and G3 demonstrated similar tendencies toward an increase in the gain weight ratio over time. The mitotic activity was significantly lower at 72 hours in G3 than in G2. There was no difference between Ki-67 staining between G2 and G3. The expression of the IL-6 gene was present in all of the groups, lower in G1, with no difference between G2 and G3. CONCLUSIONS: The experimental model was feasible and adequate for these investigations. Hepatectomy stimulated hepatocyte proliferation, and the obstruction of the arterial flow did not affect liver regeneration. PMID- 26036513 TI - No protective function found in Wistar rats submitted to long ischemia time and reperfusion after intermittent clamping of the total hepatic pedicle. AB - BACKGROUND: Although the intermittent Pringle maneuver is used for major transplant surgery, traumas, and hepatic protection, long ischemia time and reperfusion may limit some protection in Wistar rats. The aim of the study was to evaluate the protection effects of intermittent clamping in the total hepatic pedicle after a long period of ischemia and reperfusion in Wistar rats. METHODS: Forty-two male Wistar rats, weighing +/- 327.7 g, were anesthetized intravenously with sodium thiopental and given a U-shaped incision in the abdomen. The total hepatic pedicle was isolated and subjected to clamping with a microvascular clamp. Groups included were the continuous group (CG, n = 14, 40 minutes of ischemia/40 minutes of reperfusion); the intermittent group (IG, n = 14, 4 cycles a 10 minute ischemia/reperfusion 10 minutes); and the sham group (SG, n = 14, 80 minutes of observation time). Blood collection for transaminase dosage was carried out, and hepatic biopsy specimens were taken for mitochondrial respiration and histological evaluation. RESULTS: In groups CG and IG, aspartate aminotransferase and alanine aminotransferase enzymes were elevated in comparison to group SG (P < .008); mitochondrias, when stimulated by use of adenosine diphosphate or carbonylcyanide p-trifluoromethoxyphenylhydrazone, had a significant decrease in mitochondrial respiration (P < .05), and the respiratory control ratio in the ischemic groups was lower (P < .03) when compared with the GS. On histological examination, 100% of the GC had lesions: 33% focal hemorrhagic necrosis, 17% sinuzoidal congestion and/or vacuolization, and 50% venous congestion; in the IG, 100% had lesions: 43% sinusoidal congestion and/or vacuolization and 57% venous congestion. CONCLUSIONS: The intermittent total hepatic pedicle clamping for a long period of time in the Wistar rats had no efficacy in protection of liver injury. PMID- 26036514 TI - Renal transplantation in type 1 diabetes mellitus: an unusual case report. AB - Diabetes mellitus (DM) may progress to diabetic nephropathy (DN) in approximately 40% of cases and it accounts for one of the most common causes of end-stage of renal disease (ESRD). The pathogenesis of DN involves complex interactions between metabolic and hemodynamic factors. DM type 1 has a dominant impact on morbidity and mortality after renal transplantation. We report a kidney transplantation patient with DM and DN as the etiology of end-stage renal disease and whose post-transplantation evolution over 19 years was remarkably atypical. DM was diagnosed at the age of 7 years and the patient suffered a rapid and aggressive progression of her disease with early development of DN and diabetic retinopathy. Nineteen years post-transplantation, the patient shows neither deterioration of graft function nor clinical reactivation of DN. There seems to be two quite distinct answers to the same injury supported by a group of factors that led to micro- and macrovascular lesions, all present before transplantation and potentially aggravated through some immunosuppressive therapy. This clinical evolution suggests the hypothesis that not only the graft but also the donor may have inherent characteristics that enabled him to display the resistance to DN despite the genetic susceptibility of the receptor. The answers to these questions would help to explain why some patients with diabetes progress to macro and microvascular complications and others remain resistant to developing these vascular disorders. In this case, the resistance to DN is apparently a feature related to the donor. PMID- 26036515 TI - Chronic Q Fever in a renal transplant recipient: a case report. AB - Q fever is a zoonosis caused by Coxiella burnetii that presents with a wide spectrum of acute and chronic manifestations. Progression to chronic Q fever is frequently associated with valve and vascular prosthesis, aneurisms, pregnancy, immunosuppression, and advanced chronic kidney disease. We present a case of a kidney transplant recipient with persistent fever of unknown origin, negative blood cultures, anemia, and increased erythrocyte sedimentation rate (ESR) and C reactive protein (CRP). Q fever serological tests were suggestive of chronic Q fever and the patient was diagnosed with probable chronic Q fever according to the Dutch Fever Consensus Group Guidelines. Initiation of doxycycline 200 mg/d and hydroxychloroquine 600 mg/d resulted in clinical remission. Chronic Q fever is a high-morbidity and -mortality disease if untreated and special attention has to be given to high-risk patients, such as kidney transplant recipients. PMID- 26036516 TI - A rare paracoccidioidomycosis diagnosis in a kidney transplant receptor: case report. AB - INTRODUCTION: Paracoccidioidomycosis (PCM) is a systemic mycosis of chronic presentation more frequent in adults, which may lead to disseminated severe and lethal forms involving the lungs, skin, lymph nodes, spleen, liver, and lymphoid organs of the digestive tract. Common in Latin America, it is rare in transplanted patients, with few cases described in the literature. PURPOSE: To report a case of a patient who underwent kidney transplant 3 years ago with a pseudotumoral cervical PCM diagnosis. METHODS: A male patient, 45 years old, who underwent kidney transplantation 3 years ago presenting with diarrhea, severe weight loss, and anemia; no breathing complaints. Parasitological stool tests, fecal culture, urine culture, and abdomen USG were performed in order to assess the diarrhea, and were inconclusive. He was treated with antibiotics and antiparasitic drugs with no improvement and continued with weight loss of 15 kg within 3 months. Immunosuppression was changed, with the mycophenolic acid reduced until it was replaced by everolimus. The diarrhea returned to intensify, and there was an increase in the creatinine (from 1.5 to 3.4). He was empirically treated with sulfamethoxazole/trimethoprim, with total remission of the diarrhea. The patient underwent a kidney biopsy, anti-HIV examinations, PCR BK virus, and PCR for Mycobacterium tuberculosis-with no diagnostic conclusion. During his fifth hospitalization (6 months after the beginning of the diagnostic research), presenting a quite compromised general state, loss of 20 kg, anemia, kidney failure, and fever, he developed skin lesions on the legs and a voluminous and hard tumor in the right cervical region. Chest computed tomography was performed, and the tumoral lesions were removed from those regions. He was started on tuberculostatics and underwent a biopsy of the cervical tumoral lesion. RESULT: Biopsy of the cervical tumor showed a fungal infection by paracoccidioidomycosis. The BAAR test of the biopsy was negative. The patient died a few weeks after the diagnosis. CONCLUSION: The association between the organ transplant and PCM is rare and, in unusual clinical presentations, the diagnosis difficulty may compromise a successful treatment. PMID- 26036517 TI - Incidentally discovered hepatocellular carcinoma in explanted liver: clinical, histopathologic features and outcome. AB - BACKGROUND: Incidental hepatocellular carcinomas (iHCCs) are tumors discovered on the explanted liver that were not present on imaging before transplantation. The natural history, histopathologic characteristics, and prognosis are not clearly defined. METHODS: We compared the characteristics of iHCC and previously known hepatocellular carcinoma (pkHCC) in patients who underwent liver transplantation from 1998 to 2012 in a retrospective study. RESULTS: During this period a total of 675 patients were transplanted; 56 patients (9%) had pkHCC and 12 (2%) had iHCC. The sex and age distributions were similar. The median Model for End-Stage Liver Disease score in iHCC patients was 17.0 versus 13.0 in patients with pkHCC (P = .001). Thirty-three percent of iHCC patients had multiple tumors, and 25% had bilobar involvement. The median cumulative tumor size in iHCC was 1.8 cm, and 5.5 cm in pkHCC (P = .005). Incidence of microvascular invasion was not different (16.7% vs 38.9%; P = .191). American Joint Committee on Cancer T1 stage was found in 58.3% of patients with iHCC and in 22.2% of pkHCC patients. Patients with iHCC had 1-, 3-, and 5-year survivals, respectively, of 100%, 83% and 64%, compared with 80%, 66%, and 38% for patients with pkHCC (P = .138). None of the patients with iHCC had recurrence of HCC, whereas incidence of recurrence in pkHCC patients was 12.5%. CONCLUSIONS: iHCC occurred in patients with more advanced liver disease. The cumulative tumor size of iHCC was smaller but one-third were multifocal. Survival was similar to patients with pkHCC, and recurrence was not noted in patients with iHCC. PMID- 26036518 TI - Seventh-day syndrome: a catastrophic event after liver transplantation: case report. AB - Seventh-day syndrome (7DS) is an early serious complication of liver transplantation, characterized by sudden failure of a previously normally functioning liver graft ~1 week after the surgery. Although it is an uncommon event, it has major associated mortality. As its etiology is yet to be recognized, the only currently available treatment is retransplantation. We present 3 cases of orthotopic liver transplantation recipients who had an initial uneventful recovery after surgery followed by a dramatic rise of serum liver enzyme levels ~7 days later and hepatic failure with subsequent graft loss and death despite high-dose immunosuppressive therapy. Histologic findings showed massive centrolobular hemorrhage and hepatocellular necrosis with reduced inflammation. It is essential to review and accumulate more clinical and laboratory information to better understand this syndrome and to better prevent and treat it. PMID- 26036519 TI - Chronic Ocular Graft vs Host Disease as a Serious Complication of Allogeneic Hematopoietic Stem Cell Transplantation: Case Report. AB - Chronic graft-vs-host disease (cGVHD) is a serious systemic immunological complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Ocular GVHD (O-GVHD) is frequently associated with cGVHD. Secondary corneal epithelial changes can occur in the setting of advanced chronic O-GVHD-associated keratoconjunctivitis sicca (KCS), which generally has a stable course with conventional medical treatment. Bilateral corneal ulcers and ocular perforation, although not frequent, can occur in most extreme cases. The authors describe 2 clinical cases of ocular perforation (Clinical case 1) and bilateral simultaneous corneal ulcers (Clinical case 2) due to advanced chronic O-GVHD, which can rarely occur despite treatment. A close ophthalmological follow-up and good dialogue with the multidisciplinary transplantation team are essential after allo-HSCT. PMID- 26036521 TI - Intellectuality and attitudes of clergy about organ donation in Turkey: metasynthesis of observational studies. AB - INTRODUCTION: In Turkey, donation rates remained low despite the efforts of the Religious Affairs Supreme Council. We sought to determine theological perspectives and behaviors of clergy and theology students toward organ donation. METHODS: We conducted a systematic review and metaanalysis of observational studies. RESULTS: There were 2154 participants. Eighty-two percent stated Islam allows organ donation. Nineteen had organ donation card (<1%). Fifty-four percent were reluctant to donate organs themselves, 56% lacked sufficient knowledge. Twenty percent referred to school education and periodicals as the source of information. Sixty-nine percent were act as opinion leaders for organ donation. In curriculums of the Faculties of Theology, organ donation as a separate topic has not been found. No articles regarding organ donation have been published in theology journals in their 60-year publication history. CONCLUSIONS: A discrepancy exists between the resolutions of the Board of Religious Affairs and attitudes of clergy toward organ donation in Turkey. Theology faculties seem not to pay specific attention to this issue. The Directorate of Religious Affairs and the faculty of theology should meet at a common point immediately in terms of training programs and continuing education with strict audit in context of organ transplantation and donation. PMID- 26036522 TI - Mass media, online social network, and organ donation: old mistakes and new perspectives. AB - INTRODUCTION: Contrary to TV programs projecting awareness about organ donation in society, concrete evidence exists about adverse influence of negative broadcasts on organ donation rates. We sought to determine the effect of mass media on public opinion toward organ donation and the efficacy of public campaigns and novel social media attempts on donation rates. METHODS: We conducted a systematic review of relevant literature and national campaign results. RESULTS: Hoaxes about brain death and organ transplantation adversely affect organ donation rates in both Western and Eastern societies. Scientifically controversial and exaggerated press conferences and institutional advertisements create mistrust in doctors, thus reducing organ donation. The overall effect of public education campaigns in promoting organ donation is a temporary 5% gain. Increments in organ donation rates is expected with novel applications of social media (Facebook effect). CONCLUSION: Communication, based on mutual trust, must be established between medicine and the media. Continuing education programs with regard to public awareness on organ donation should be conducted over social media. PMID- 26036523 TI - 5,7-dihydroxy-3,4,6-trimethoxyflavone attenuates ischemic damage and apoptosis in mouse islets. AB - BACKGROUND: The transplantation of isolated pancreatic islets is a promising treatment for diabetes. 5,7-dihydroxy-3,4,6-trimethoxyflavone (Eupatilin), a pharmacologically active flavone derived from the Artemisia plant species, has been reported to have antioxidant and anti-inflammatory activities. This study examines the hypothesis that preoperative eupatilin treatment can attenuate ischemic damage and apoptosis before islet transplantation. METHODS: Islets isolated from Balb/c mice were randomly divided into 2 groups, and cultured in medium supplemented with or without eupatilin. In vitro islet viability and function were assessed. After treatment with a cytokine cocktail consisting of tumor necrosis factor (TNF)-alpha, interferon (INF)-gamma, and interleukin (IL) 1beta, islet cell viability, function, and apoptotic status were determined. The glutathione (GSH) and nitrous oxide (NO) levels were also measured. Proteins related to apoptosis were analyzed using Western blotting. RESULTS: There was no difference in cell viability between the 2 groups. Islets cultured in the medium supplemented with eupatilin showed 1.4-fold higher glucose-induced insulin secretion than the islets cultured in the medium without eupatilin. After treatment with a cytokine cocktail, glucose-induced insulin release and the total insulin content of the islets were significantly improved in eupatilin-pretreated islets compared with islets not treated with eupatilin. Apoptosis was significantly decreased, and GSH levels were elevated in the eupatilin-pretreated group. Cytokine-only treated islets produced significantly higher levels of NO, iNOS, and caspase-3 than islets pretreated with eupatilin before cytokine treatment. CONCLUSIONS: These results suggest that preoperative eupatilin administration enhances islet function before transplantation and attenuates the cytokine-induced damage associated with NO production and apoptosis. PMID- 26036524 TI - Niacin ameliorates kidney warm ischemia and reperfusion injury-induced ventricular dysfunction and oxidative stress and disturbance in mitochondrial metabolism in rats. AB - OBJECTIVE: Kidney ischemia and reperfusion (I/R) injury-associated acute and chronic kidney injury often leads to cardiac dysfunction, which may involve depletion of intracellular NAD(+) (the oxidized form of the nicotinamide adenine dinucleotide coenzyme) and reduction in intracellular adenosine triphosphate (ATP) levels, resulting in mitochondrial dysfunction. We examined whether treatment with niacin, an antioxidant and a component of NAD+, protects cardiac function and improves myocardial mitochondrial metabolism during kidney I/R injury. METHODS: Studies were performed in Sprague-Dawley male rats divided into sham-operated, kidney I/R, and niacin-treated kidney I/R groups. Niacin was administered 3 days before the ischemia through 7 days of reperfusion. Kidney ischemia was conducted by bilateral occlusion of renal pedicles for 45 minutes, followed by releasing the clamps and closing the abdominal incision. After 7 days of reperfusion, we measured the cardiac function using a simultaneous pressure volume catheter, cardiac biomarker (troponin T; cTnT), and kidney injury marker (creatinine and blood urea nitrogen). Myocardial malondialdehyde level and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha mRNA expression also were measured. RESULTS: Kidney I/R injury impairs cardiac function, induces myocardial and kidney injury, and markedly increases myocardial PGC-1alpha mRNA expression, suggesting utilizing more free fatty acid for ATP production. Niacin treatment improved cardiac function, reduced oxidative stress, and sustained PGC-1alpha expression (P < .05). CONCLUSIONS: Kidney I/R-associated cardiac dysfunction is likely associated with increases in myocardial lipid peroxidation and utilizing more free fatty acid for ATP production. Niacin improves mitochondrial metabolism and reduced myocardial oxidative stress. PMID- 26036525 TI - Intravenous superoxide dismutase administration reduces contralateral lung injury induced by unilateral lung ischemia and reperfusion in rats through suppression of activity and protein expression of matrix metalloproteases. AB - BACKGROUND: Ischemia and reperfusion (I/R) of the lungs induces massive superoxide radical production. On the other hand, matrix metalloproteases (MMPs) were shown to play an essential role in I/R-associated lung injury. We aimed to investigate the lung-protective efficacy of intravenous superoxide dismutase (SOD) administration and its relation with MMPs activity in the lungs subsequent to I/R injury. METHODS: Twenty-two male Sprague-Dawley rats were divided into a sham group (n = 6), a unilateral lung I/R group (n = 8), and a SOD-treated lung I/R group (n = 8). Unilateral lung ischemia was conducted by occluding the left lung hilum for 90 min, followed by 5 hours of reperfusion through release of the occlusion. In the SOD-treated group, SOD was administered intravenously during the first hour of reperfusion. We assessed the protein contents in the broncho alveolar lavage fluid (PCBAL) as a marker for protein permeability and lung wet to-dry weight ratio (W/D) for lung water content. We also measured levels of lipid peroxidation and MMP activity in the lungs, by tissue malonedealdehyde (MDA) level with the use of enzyme-linked immunoassay, and the gelatin zymography technique, respectively. RESULTS: Forty-eight hours of left-lung I/R significantly increased PCBAL (P < .001), W/D (P < .05), tissue MDA level (P < .05), and MMP-9 and MMP-2 activity. SOD treatment attenuated I/R-induced contralateral lung injury, reducing pulmonary permeability, lipid peroxidation, and MMP activities. CONCLUSIONS: I/R injury of the left lung induced increases in W/D, PCBAL, MDA level, and MMP-9 activity in the right lung. SOD treatment during the first hour of a 5-hour reperfusion protected the lung through suppressing MMP 9 activity and reducing tissue lipid peroxidation. PMID- 26036526 TI - Hepatic Warm Ischemia-Reperfusion-Induced Increase in Pulmonary Capillary Filtration Is Ameliorated by Administration of a Multidrug Resistance-Associated Protein 1 Inhibitor and Leukotriene D4 Antagonist (MK-571) Through Reducing Neutrophil Infiltration and Pulmonary Inflammation and Oxidative Stress in Rats. AB - BACKGROUND: Hepatopulmonary syndrome (HPS) is the major complication subsequent to liver ischemia and reperfusion (I/R) injury after resection or transplantation of liver. Hallmarks of HPS include increases in pulmonary leukotrienes and neutrophil recruitment and infiltrating across capillaries. We aimed to investigate the protective efficacy of MK-571, a multidrug resistance-associated protein 1 inhibitor and leukotriene D4 agonist, against hepatic I/R injury associated change in capillary filtration. METHODS: Eighteen Sprague-Dawley male rats were evenly divided into a sham-operated group, a hepatic I/R group, and an MK-571-treated I/R group. MK-571 was administered intraperitoneally 15 min before hepatic ischemia and every 12 hours during reperfusion. Ischemia was conducted by occluding the hepatic artery and portal vein for 30 min, followed by removing the clamps and closing the incision. Forty-eight hours after hepatic ischemia, we assessed the pulmonary capillary filtration coefficient (Kfc) through the use of in vitro-isolated, perfused rat lung preparation. We also measured the lung wet to-dry weight ratio (W/D) and protein concentration in broncho-alveolar lavage fluid (PCBAL). Lung inflammation and oxidative stress were evaluated by use of tissue tumor necrosis factor (TNF)-alpha and malondialdehyde levels and lavage differential macrophage and neutrophil cell count. RESULTS: Hepatic I/R injury markedly increased Kfc, W/D, PCBAL, tissue TNF-alpha level, and differential neutrophil cell count (P < .05). MK-571 treatment reduced neutrophil infiltration and lung inflammation and improved pulmonary capillary filtration, collectively suggesting lung protection. CONCLUSIONS: Treatment with MK-571 before and during hepatic ischemia and reperfusion protects lung against pulmonary capillary barrier function impairment through decreasing pulmonary lung inflammation and lavage neutrophils. PMID- 26036527 TI - Quality and Quantity of Health Evaluation and the Follow-up of Iranian Living Donors. AB - BACKGROUND: Shortage of donors is the main obstacle in organ transplantation. In renal transplantation living donation is the key solution for removing this barrier. The Iranian model of kidney transplantation has been faced with many challenges, but there are limited reports about the depth of evaluation and outcome of donors. This study was conducted to assess the quality and quantity of donors' health evaluation before donation and their follow-up afterward. METHODS: With assistance of the Iranian Kidney Foundation, we accessed the contact information of living donors through the years 2001-2012. We tried to contact donors who have donated at least 2 years before the survey. We interviewed these donors according to a questionnaire that was approved by the ethics committee of the research deputy of Tehran University of Medical Sciences. The collected data were analyzed using the SPSS software version 20. RESULTS: The contact data of 388 donors were available but we were able to contact only 60 donors. We found that 40% of donors had been informed about the risks and benefits of donation. Also, 11% of donors had not had a full physical examination and in 5% even blood pressure was not measured before donation by the transplantation team. The donors reported that 34% of them had not been educated on how they should follow up their health status and 50% of the donors did not have any follow-up after donation. CONCLUSION: In the Iranian model of transplantation the donors are the neglected victims of renal transplantation and this model should be revised immediately, concerning both the medical and ethical issues. PMID- 26036528 TI - Simultaneous pancreas-kidney transplantation from living donor using hand assisted laparoscopic donor surgery: single-center experience. AB - BACKGROUND: Simultaneous pancreas-kidney (SPK) transplantation has been the fundamental treatment and has shown significant results in selected patients diagnosed with type 1 diabetes with renal insufficiency. Most pancreas transplantations are dependent on deceased donors, yet the waiting time for SPK transplantation from deceased donors is significantly long in Asian countries. METHODS: In 3 cases, living-donor SPK transplantation was performed with the use of hand-assisted laparoscopic donor surgery (HALS). Three cases of patients who underwent SPK transplantation from living donors (LDSPK) with the use of HALS at Korea University Anam Hospital from 2012 to 2013 were retrospectively reviewed regarding patient characteristics and clinical outcomes of donors and recipients. For the donors, the pancreas and renal function had been well preserved postoperatively. RESULTS: One donor had a pancreatic fistula, which was controlled with conservative management. Of the 3 cases of recipient operation, 1 case was performed by ABO incompatibility donor. The levels of creatinine, serum insulin, and C-peptide of recipients were normalized and remained stable at the last follow-up. CONCLUSIONS: LDSPK can be an efficient alternative in cases in which the deceased donor is not present at the proper time, depending on the degree of completion in the operator's skill. PMID- 26036529 TI - Long-term study of steroid avoidance in renal transplant patients: a single center experience. AB - OBJECTIVES: Steroids have played a major role in renal transplantation for more than 4 decades. However, chronic use of steroids is associated with many comorbidities. This study aimed to assess the costs and benefits of a steroid free immunosuppression regimen in a prospective randomized controlled study of living-donor renal transplantation, which was lacking in the literature. MATERIALS AND METHODS: In our study, 428 patients were enrolled to receive tacrolimus (Tac), mycophenolic acid (MPA), basiliximab (Simulect, Novartis, Basel, Switzerland) induction and steroids only for 3 days (214 patients, study group) and steroid maintenance (214 patients, control group). Median follow-up was 66 +/- 41 months. RESULTS: We found that both groups showed comparable graft and patient survival, rejection episodes, and graft function. Posttransplantation hypertension was detected in 40% of the steroid-free group and 80% of the steroid maintenance group (P = .05), whereas posttransplantation diabetes mellitus was detected in 5% and 15% of these 2 groups, respectively (P = .3). CONCLUSIONS: Among low-immunological-risk recipients of living-donor renal transplants, steroid avoidance was feasible, safe, and had less morbidity outcome using Simulect induction, then Tac and MPA as maintenance immunosuppression. Steroid avoidance was associated with a lower total cost despite comparable immunosuppression cost, which was attributed to the lower cost of associated morbidities. PMID- 26036530 TI - Fibromyalgia and its clinical relevance in renal transplant recipients. AB - OBJECTIVE: Recent evidence suggests that fibromyalgia syndrome (FS) is associated with inflammation and endothelial dysfunction. Our aim was to determine the prevalence of FS in renal transplant recipients and to identify possible links between FS and clinical and laboratory parameters. METHODS: Ninety-nine kidney transplant recipients with normal graft functions (37.15 +/- 10.83 years old, 67 male) were enrolled in the study. All subjects completed the Fibromyalgia Impact Questionnaire (FIQ). The biochemical and clinical parameters in the 1st post transplantation year were retrospectively recorded. Cardiovascular parameters, including body composition analyses (Tanita), ambulatory blood pressure monitoring data, and pulse-wave velocity, were cross-sectionally analyzed. RESULTS: Mean FIQ score for the whole group was 21.4 +/- 14.7. Eight patients had FIQ score >50, and these patients had significantly higher left ventricular mass index than patients with lower FIQ score (P = .048). Patients were divided according to their physical impairment score (PIS): PIS >=5 (n = 50) and PIS <5 (n = 49). Patients with higher PIS had significantly higher serum creatinine (P = .047) and lower eGFR values (P = .008) than patients with lower PIS. Patients were also evaluated with the use of the stiffness score (SS): patients with (n = 41) and without (n = 58) stiffness. Patients with stiffness had significantly higher office systolic (P = .027) and diastolic (P = .044) blood pressure, body mass index (P = .033), and sagittal abdominal diameter (P = .05) than patients without stiffness. Decline in estimated glomerular filtration rate levels were significantly higher in patients with higher FIQ (7.6% vs 9.4%; P = .0001) than in other patients. CONCLUSIONS: FS in renal transplant recipients was strongly associated with hypertension, arterial stiffness, obesity, and renal allograft dysfunction. PMID- 26036531 TI - Pre- and Posttransplant IgA Anti-Fab Antibodies to Predict Long-term Kidney Graft Survival. AB - OBJECTIVES: Immunologic factors are reliable markers for allograft monitoring, because of their seminal role in rejection process. One of these factors is the immunoglobulin (Ig)A anti-Fab of the IgG antibody. This study aimed to evaluate the predictive value of pre- and posttransplant levels of this marker for kidney allograft function and survival. METHODS: Sera samples of 59 living unrelated donor kidney recipients were collected before and after transplantation (days 7, 14, and 30) and investigated for IgA anti-Fab of IgG antibody levels using enzyme linked immunosorbent assay in relation with allograft outcome. RESULTS: Among 59 patients, 15 cases (25%) including 10 with acute rejection and 5 with chronic rejection episodes showed graft failure during a mean of 5 years of follow-up. High posttransplant levels of IgA anti-Fab antibodies were observed more frequently in patients with stable graft function (SGF) compared with patients with graft failure (P = 2 * 10(-6)). None of patients with acute or chronic rejection episodes had high levels of IgA anti-Fab antibodies at day 30 posttransplant compared with the SGF group (P = 10(-6) and P = .01, respectively). In addition, high levels of IgA anti-Fab antibody correlated with lesser concentration of serum creatinine at 1 month posttransplantation (P = .01). Five-year graft survival was associated with high levels of pre- and posttransplant IgA anti-Fab antibodies (P = .02 and P = .003, respectively). CONCLUSIONS: Our findings indicate the protective effect of higher levels of IgA anti-Fab antibodies regarding to kidney allograft outcomes and long-term graft survival. PMID- 26036532 TI - Does lower urinary tract status affect renal transplantation outcomes in children? AB - BACKGROUND: Lower urinary tract dysfunction (LUTD), an important cause of end stage renal disease (ESRD) in children, can adversely affect renal graft survival. We compared renal transplant patients with LUTD as primary renal disease to those without LUTD. METHODS: The data of 60 children who underwent renal transplantation (RTx) between 2000 and 2012 were retrospectively reviewed. All patients with LUTD were evaluated with urodynamic tests preoperatively; 15 patients required clean intermittent catheterization and 9 patients underwent augmentation cystoplasty before RTx. RESULTS: There were 25 children with LUTD. The mean follow-up for LUTD (+) and LUTD (-) groups were 63 (22-155) and 101 months (14-124), and graft survival were 76% for LUTD (+) and 80% for LUTD (-), respectively (P = .711). On the other hand, creatinine levels at last follow-up were significantly higher in the LUTD (+) group (1.3 +/- 0.3 mg/dL vs 0.96 +/- 0.57 mg/dL, P < .001). Infectious complications and postoperative urinary tract infection incidences were also higher in the LUTD (+) group (68% vs 25.7%, P = .002 and 60% vs 11.4%, P < .01). CONCLUSION: UTI is significantly higher after kidney transplantation in patients with LUTD. Despite the higher risk of UTI, renal transplantation can be performed safely in those patients with careful patient selection, preoperative management, and close postoperative follow-up. Restoration of good bladder function is the key factor in the success of kidney transplantation in those patients. PMID- 26036533 TI - Evaluation of renal transplantations performed in the Transplantation Center at Sanko University Medical School. AB - INTRODUCTION: Renal transplantation is the optimum treatment to improve the quality and length of life in end-stage renal disease. The aim of this study is to evaluate patients who underwent renal transplantation in our transplantation center and to present our clinical experience. METHODS: Living donor and cadaveric renal transplants performed in the Transplantation Center of Sanko University Medical School between 2011 and 2014 were evaluated retrospectively. In our study, important parameters, such as delayed graft function, early and late phase infections and urologic complications after the operation, results of renal transplants with marginal donors with high creatinine levels, and increase in posttransplant body mass index were evaluated regarding to the living donor and cadaveric renal transplants performed in our transplantation center. RESULTS: We included 136 patients were (92 males [68%] and 44 females [32%]), with an average age of 38.9 +/- 9.8 years (range, 17-67). There were 63 living donor renal transplantations (43%) and 73 cadaveric renal transplantations (57%). The youngest cadaveric donor was 3 years old, and the oldest was 86. Fifteen of the cadaveric donors had blood creatinine levels around 1.5 g/dL. The highest level of creatinine from cadaveric donors was 5.1 g/dL. CONCLUSIONS: Living donor renal transplantations have higher success rate than cadaveric renal transplantations. Ureteroneocystostomy and native ureteropyelostomy seem to be safe and efficient treatment methods for ureteral complications. High creatinine levels in marginal donors do not affect graft function in early stages. PMID- 26036534 TI - Pharmacokinetics of mycophenolate mofetil in Omani patients on cyclosporine or tacrolimus. AB - BACKGROUND: Mycophenolate mofetil (MMF) reduces rejection in organ transplantation and is effective in controlling autoimmune diseases. Determining the area under the receiver operating characteristic curve (AUC) of MMF is not routine despite interindividual variability. The aim of this study was to look into MMF-AUC in Omani patients on cyclosporine (CsA) or tacrolimus (Tac). METHODS: We measured MMF-AUC in 27 stable Omani patients. We used the 4-time points-limited sampling strategy. RESULTS: Sixteen, 8, and 3 recipients were receiving Tac, CsA, and calcineurin inhibitor (CNI)-free regimens, respectively. The mean MMF dose was 1,685 +/- 442 mg/d. All except 3 patients were within or above the target AUC. The AUC was significantly higher in patients receiving Tac versus CsA. All patients on Tac were within or above the target AUC. Seven of the 8 patients with MMF-AUC above target were receiving Tac. Two of the 3 patients with MMF-AUC below target were on CsA. DISCUSSION: These preliminary results confirm the significant interindividual variability of MMF-AUC. None of the recipients on Tac had an AUC below target. Most patients above the target AUC were receiving Tac. Two of the 3 patients with MMF-AUC below target were on CsA and receiving 1 g/d MMF. Patients on Tac are at risk of having higher than the target AUC, exposing them to overimmunosuppression. Recipients on CsA seem to require >1 g/d MMF. CONCLUSIONS: These preliminary results encourage measuring the AUC of MMF. The fixed MMF dose regimen seems to be unreliable to predict the AUC. Preventing under- or overimmunosuppression offsets the burden. PMID- 26036535 TI - Dual kidney transplantation: a single-center experience. AB - BACKGROUND: Dual kidney transplantation (DKT) is an alternate approach to use marginal kidneys not suitable to be allocated for single kidney transplant. This retrospective study reviewed the short- and long-term outcomes regarding graft and patient survivals over a 9-year period at a single center. METHODS: From 2005 to 2013, 33 DKTs were performed in our unit, where allocation was guided by clinical parameters mainly. The mean ages for recipients and donors were 58.6 +/- 12.5 and 54.8 +/- 13.6 years, respectively. Cold ischemia time was 21.4 +/- 4 hours, and mean HLA mismatch for HLA-A, HLA-B, and HLA-DR was 3.06 +/- 1.07. Immunosuppression regime was tacrolimus based. RESULTS: Median follow-up time of 56 months showed patient and death-censored graft survivals at 1, 3, and 5 years to be 90% and 84%, 90% and 81%, and 84% and 81%, respectively. The rate of delayed graft function was 46.9% (n = 15), the rate of primary graft function was 46.9% (n = 15), the rate of and primary graft nonfunction was 6.2% (n = 2). Nineteen patients (59.4%) required biopsy: 12 of them showed acute tubular necrosis and 7 had rejection (1 needed graft removal, 4 were treated successfully with steroid and/or antithymocyte globulin, and 2 did not require treatment). CONCLUSIONS: Outcomes of DKT in our center were satisfactory and similar to those of other transplant centers regarding patient and graft survivals. PMID- 26036536 TI - Quality of life in renal transplant recipient and donor. AB - OBJECTIVES: Quality of life (QoL) assessment in renal transplant patients has become an important tool in evaluating outcomes. In this work the QoL of the renal transplant donor and recipient are compared to healthy, age- and BMI matched individuals. MATERIALS AND METHODS: The donors were all living related. The immunosuppression protocol was prednisolone, cyclosporine/tacrolimus, and mycophenolate mofetil/azathioprine. Renal function was stable. Quality of life was assessed by KDQOL-SF-36. It includes 36 items divided into 8 scales. RESULTS: Comparison among healthy subjects (n = 20), kidney donor (n = 20), vs recipients (n = 40) for age was 35 +/- 8, 40 +/- 11, vs 37 +/- 10 years (P = NS), and BMI was 23 +/- 5, 21 +/- 4, vs 21 +/- 4 kg/m(2) (P = NS). The mean duration of transplantation of donor and recipients was 22 +/- 11 vs 28 +/- 25 months (P = NS). Items in SF-36 among 3 groups, respectively, showed general health scores of 48 +/- 23, 60 +/- 20, vs 59 +/- 20; physical functioning 61 +/- 28, 84 +/- 23, vs 76 +/- 265; role physical 31 +/- 38, 70 +/- 44, vs 636 +/- 53; pain 79 +/- 36, 73 +/- 23, vs 69 +/- 25; emotional well-being 63 +/- 17, 74 +/- 14, vs 73 +/- 34; social function 83 +/- 20, 95 +/- 8, vs 91 +/- 15, and energy/fatigue 57 +/- 17, 62 +/- 16, vs 58 +/- 15; (P = NS) was similar in all groups. Correlation studies showed strong positive association of all the items with each other. CONCLUSIONS: This study finding is in accordance with the expected outcome that QoL improves significantly to near normal in renal transplant recipients. At the same time donors' QoL also is not compromised. Both donor and recipient have similar high quality scores to those of a healthy person. PMID- 26036537 TI - Antibiotic selective pressure and development of bacterial resistance detected in bacteriuria following kidney transplantation. AB - INTRODUCTION: Bacteriuria (symptomatic and asymptomatic) is the most common infectious complication after kidney transplantation. This study aimed to determine its prevalence among kidney transplant recipients hospitalized after transplantation, respective risk factors, and frequency of isolates and antibacterial susceptibility. METHODS: Retrospectively, we divided hospitalized patients into 3 groups. Groups 1 and 2 included 78 and 152 recipients with and without bacteriuria, respectively, and the potential risk factors were compared. Cefixime was prescribed as early postsurgical prophylaxis. Group 3 patients were 116 randomly selected nontransplantation patients with urinary tract infection. Frequency of uropathogens and their antibiotic susceptibility were compared in groups 1 and 3. RESULTS: In total, 103 bacteriuria episodes were detected in 15.2% of the patients. The frequency of risk factors in groups 1 and 2 was similar. Escherichia coli was the most common isolate in groups 1 (40.8%) and 3 (68.1%; P = .03). Streptococcus faecalis was the most common gram-positive isolate in groups 1 (17.5%) and 3 (6.9%; P = .03). Sensitivity rates in group 1 were 9% to trimethoprim-sulfamethoxazole, 20% to ciprofloxacin, and 38.4% to gentamicin, which was not significantly different from group 3. However, the sensitivity rates of gram-negative isolates to ceftriaxone were 9.5% and 28.4% (P = .004) in groups 1 and 3, respectively, and to cefixime 4.5% and 22% (P = .01). DISCUSSION: High antibacterial resistance of uropathogens isolated from kidney transplantation and nontransplantation patients is alarming. The higher resistance to third-generation cephalosporins in transplant recipients may be due to antibiotic selection pressure secondary to postsurgical prophylaxis with cefixime. PMID- 26036538 TI - Which CMV viral load threshold should be defined as CMV infection in kidney transplant patients? AB - BACKGROUND: Cytomegalovirus infection (CMV) is prevalent in kidney transplant patients. Which level of CMV viral load should be accepted as the gold standard for CMV infection diagnosis is a relatively unsettled issue. METHODS: Seventy three kidney transplant patients (mean age = 35.97 +/- 14.07 years, 39 male and 34 female) entered this retrospective study. The area under the curve (AUC) of the receiver operative curve (ROC) characteristics was used to define which level of CMV viral load results in the most sensitivity and specificity for different clinical and para clinical parameters differing infected and non-infected patients. Quantitative real-time polymerase chain reaction (TaqMan method) was used for measuring CMV viral load. Written consent was obtained from all patients. RESULTS: Platelets, compared with the other clinical and para-clinical parameters, had the strongest correlation with CMV viral load in kidney transplant patients (r = -.314, P = .007). There was no correlation between CMV viral load and other laboratory parameters including clinical manifestation. Choosing a threshold of more than 10,000 copies/mL of CMV viral load for defining CMV infection resulted in significance for differing in both white blood cell and platelet count between infected and non-infected patients (AUC = .68, P = .023; AUC = .70, P = .014, respectively). CONCLUSIONS: Accepting a CMV viral load threshold of more than 10,000 copies/mL as CMV infection has the most sensitivity and specificity for predicting both white blood cell and platelet counts in kidney transplant patients. No CMV viral load threshold as the gold standard for CMV infection diagnosis has the discriminatory power for differing clinical and para-clinical parameters other than platelet and white blood cell count between presumably infected kidney transplant patients and those not infected. PMID- 26036539 TI - Evaluation of ganciclovir resistance in cytomegalovirus infection of renal transplant recipients in Tehran. AB - BACKGROUND: Human cytomegalovirus (CMV) infection is a major issue in solid organ transplant recipients. Although development of prophylaxis and preemptive procedures have presented significantly improved consequences in CMV infection, increasing incidence of antiviral resistance has raised virologists' concern. METHODS: The present study focused on kidney transplant recipients with high quantities of CMV load after antiviral therapy. We collected 5 mL blood from each of 58 patients. DNA extraction was performed with the use of the QIAamp DNA Mini kit (Qiagen), in accordance with the manufacturer's instructions. RESULTS: Our population study was 38% female and 62% male. CMV DNA was observed in 50 specimens (86%) with the range of 1.9 * 10(3) to 11 * 10(7) copies/mL serum. All of these patients had received ganciclovir for >3 months. Sequencing showed 18 mutations in 10 patients. Among these, 16 mutations were associated with Ul97 and the rest with Ul54 gene. Forty CMV-positive patients did not show any mutations. CONCLUSIONS: The consequences of long-term ganciclovir resistance could not be determined. PMID- 26036540 TI - Prevalence of polyomavirus among United Arab Emirates kidney transplant recipients: results from a single center. AB - BACKGROUND: BK viremia and nephropathy are increasing problems in renal transplant recipients. The absence of a safe and effective antiviral therapy made screening-based prevention a recommended strategy. The prevalence of its reactivation among recipients of kidney transplants in the Middle East has not been well established. Our objective was to determine the prevalence of BK virus (BKV) infection for renal transplant recipients at our medical center. METHODS: All renal transplant recipients followed up in our transplantation clinic between 2012 and 2013 (n = 116) were screened. Urine and blood quantitative real-time polymerase chain reaction (PCR) for the BKV were performed in all of the study patients. Renal biopsy was performed only in patients with deteriorating renal function associated with positive PCR. Patients who showed positive BKV PCR were followed up for 6 to 12 months. This included clinical and kidney function assessment along with BKV PCR viral load. RESULTS: Among the 116 kidney transplant recipients studied, 65 (56%) were male, age 51 +/- 15 years, with a transplantation vintage of 131 +/- 61 months; 17 (14.7%) were positive for BKV PCR. Three (2.7%) showed viremia; 2 of them had deterioration of kidney function, renal biopsy confirmed the diagnosis of BK nephropathy (NP) in both cases. The 3 cases were managed by reducing the immunosuppressive treatment with stabilization of their kidney function. Cases with stable renal function and positive urine for BKV cleared the virus spontaneously during follow-up after minor reduction of the immunosuppressive treatment or without any intervention. None of our patients lost the graft due to BK NP. CONCLUSION: Our study suggests that BKV is not uncommon in our kidney transplant recipients. Routine screening suggested by the KDIGO Guidelines could help minimize its detrimental impact on the transplant outcome. PMID- 26036541 TI - Post-transplant Hyperuricemia as a Cardiovascular Risk Factor. AB - PURPOSE: Uric acid is known to impair endothelial cell function and to stimulate the development of renal interstitial fibrosis. The aim of this study was to evaluate the association between first-year hyperuricemia with graft dysfunction and the development of cardiovascular risk disorders in renal transplant recipients. METHODS: One hundred kidney transplant recipients (31 female, 45.9 +/ 9.6 post-transplantation months) with normal graft functions were enrolled. The clinical biochemical parameters in the first post-transplantation year were retrospectively recorded and searched for the predictive value in yearly determined graft function and association with cross-sectionally analyzed cardiovascular parameters, including body composition analyses, ambulatory blood pressure monitoring data, and pulse wave velocity. Hyperuricemia was defined as an uric acid level of >= 6.5 mg/dL that persisted for at least 2 consecutive tests. RESULTS: One year after transplantation, 37% of subjects had hyperuricemia. According to cross-sectional data, sagittal abdominal diameter (P = .002) and hip circumferences (P = .013) were significantly higher in hyperuricemic patients than in normouricemic ones. Hyperuricemic patients had higher fat (P = .014) and muscle mass (P = .016) than normouremic patients. Hyperuricemic patients had significantly higher mean systolic BP (P = .044) than normouremic patients. Hyperuricemic patients had significantly higher pulse wave velocity levels (P = .0001) and left ventricular mass index (P = .044) than normouremic patients. The yearly decline in estimated glomerular filtration rate levels was significantly higher in hyperuricemic patients (P = .0001) than in normouricemic ones. CONCLUSION: Post-transplantation hyperuricemia is associated with hypertension, arterial stiffness, and dyslipidemia; it should be accepted not only as a marker for renal allograft dysfunction but also as a cardiovascular risk factor in renal transplant recipients. PMID- 26036542 TI - Study of the risk factors and complications of diabetes mellitus after live kidney donation. AB - OBJECTIVES: Kidney donors, similar to the general population, are at risk for developing type 2 diabetes mellitus (T2DM). The course of donors who develop T2DM has not been well studied. This work estimates the incidence of diabetes after kidney donation, and some risk factors and complications of diabetes mellitus postdonation. MATERIALS AND METHODS: This study examined the records of 2267 donors who donated one of their kidneys between 1976 and 2014 at the Urology and Nephrology Center, Mansoura University, Egypt, and who were regularly followed up at its outpatient clinic. A total of 388 donors were included in the study, and their medical records were revised. RESULTS: Postdonation weight gain and family history of diabetes mellitus were statistically significant for the development of diabetes mellitus, high or very high albuminuria, and/or decreased creatinine clearance. Metformin and insulin use seemed to significantly reduce the protein excretion and creatinine clearance decline in the studied group. CONCLUSIONS: There is a significant impact of a family history of diabetes mellitus on the development of high or very high albuminuria and/or decreased creatinine clearance. PMID- 26036543 TI - Conversion from tacrolimus to cyclosporine in patients with new-onset diabetes after renal transplant: an open-label randomized prospective pilot study. AB - BACKGROUND: New-onset diabetes after transplant (NODAT) is associated with serious morbidity and mortality. The incidence of NODAT is higher with tacrolimus (Tac) compared with cyclosporine (CsA); however, the effects of switching from Tac to CsA in NODAT have not been studied well. MATERIALS AND METHODS: This was a single-center, open-label, prospective, randomized study, including renal transplant recipients who were on Tac-based immunosuppression and developed NODAT. Those with pretransplant diabetes, hypersensitivity to CsA or Tac, severe infections, and denying consent were excluded. Subjects were randomized to either switch to CsA or to continue on Tac. Fasting and postprandial plasma glucose, fasting insulin and C-peptide levels, insulin and oral hypoglycaemic agents (OHA) use were monitored monthly for 3 months, whereas glycosylated haemoglobin (HbA1c) was checked at baseline and 3 months. RESULTS: Sixty-seven subjects were randomized to switch to CsA (n = 32) or continuation of Tac (n = 35). Both groups had similar baseline characteristics. After randomization, there was significant improvement in fasting plasma glucose, fasting insulin levels, C-peptide levels, and insulin requirement in both groups, whereas HbA1c improved significantly only in the CsA group. The decline in fasting plasma glucose and insulin requirement was more significant in subjects on CsA. An equal number of subjects in each group (59.4% in CsA group and 40% in Tac group, P = ns) had resolution of NODAT. Weight gain was more significant in the CsA group; however, there was no difference in other side effects or rejection episodes. CONCLUSIONS: A switch from tacrolimus to cyclosporine is a safe and effective strategy in patients with NODAT. PMID- 26036544 TI - Sagittal abdominal diameter as an anthropometric measure of cardiovascular and graft loss risk in renal transplant recipients. AB - BACKGROUND: Sagittal abdominal diameter (SAD) has been presented as a stronger prognostic factor for all-cause and cardiovascular mortality in the general population. The aim of this study was to evaluate the relationship between SAD and its associated parameters in renal transplant recipients. METHODS: One hundred eighty-one renal transplant recipients were enrolled in the study. All patients were evaluated according to standard clinical and biochemical parameters. Anthropometric measurements were performed for all patients. Pulse wave velocity (PWV) was determined from pressure tracing over carotid and femoral arteries with the use of the Sphygmocor system. RESULTS: Patients were divided into 2 groups according to SAD measurements. Group 1 (n = 127) was defined as SAD <24.3 cm, and group 2 (n = 54) was defined as SAD >= 24.3 cm. Patients in group 2 had significantly higher triglycerides, C-reactive protein (CRP), uric acid, systolic blood pressure, PWV, and body mass index measurements compared with group 1 (P < .05 for all). In group 2, estimated glomerular filtration rate (eGFR) was significantly lower than group 1 (P = .022). SAD had positive correlation with PWV, systolic and diastolic blood pressure, body mass index, triglycerides, fasting glucose, CRP, and uric acid (P < .05 for all). On stepwise linear regression analyses, proteinuria (P = .005), SAD (P = .001), and CRP (P = .015) independently predicted the degree of percentage change of eGFR. CONCLUSIONS: Considering the significant association of visceral fat with inflammation and cardiovascular disease, estimating visceral fat by means of SAD could be a useful tool to stratify cardiovascular risk as well as graft function in renal transplant recipients. PMID- 26036545 TI - Hyperviscosity in renal transplant recipients. AB - OBJECTIVE: The resistance of blood to flow is called plasma viscosity. Increased blood viscosity has been described in patients with coronary and peripheral arterial disease. In this study, we evaluated the influence of clinical and laboratory findings on plasma viscosity in renal transplant recipients. METHODS: Eighty-one kidney transplant recipients (37.8 +/- 11.3 years old, 50.38 +/- 16.8 months post-transplantation period, 27 female) with normal graft functions were enrolled. The biochemical and clinical parameters in the 1st year after transplantation were retrospectively recorded, and graft function was evaluated by means of the yearly decline in eGFR. Plasma viscosity was measured and searched for the association with cross-sectionally analyzed cardiovascular parameters including body composition analyses, ambulatory blood pressure monitoring (ABPM) data, and pulse-wave velocity. RESULTS: Patients were divided into 2 groups according to the median value of serum viscosity. Patients with high viscosity had higher serum low-density lipoprotein (P = .042) and C-reactive protein (P = .046) levels than lower viscosity group. In ABPM, daytime (P = .047) and office systolic (P = .046) blood pressure levels and left ventricular mass index (LVMI; P = .012) were significantly higher in patients with hyperviscosity. Patients with high viscosity had higher hip circumference (P = .038) and fat mass (P = .048). Estimated glomerular filtration rate decline was significantly higher in high-viscosity patients than in patients with low viscosity levels (12.9% vs 17.2%; P = .001) at 2 years' follow-up. CONCLUSIONS: We suggest that the hyperviscous state of the renal transplant recipients may arise from the inflammatory state, hypertension, and increased fat mass and increased LVMI. Hyperviscosity is also closely related to renal allograft dysfunction. PMID- 26036546 TI - High-grade proteinuria as a cardiovascular risk factor in renal transplant recipients. AB - BACKGROUND: Proteinuria is a marker of graft damage and is closely associated with a higher risk of morbidity, mortality, and cardiovascular disease in kidney transplant recipients (KTRs). Arterial stiffness is a well-known predictor of vascular calcification and systemic arteriosclerosis. In our study, we aimed to investigate the association between proteinuria and graft/patient survival and to determine whether proteinuria may be a predictor for cardiovascular disease in our KTR population. METHODS: Ninety KTRs (31 women; age, 38.7 +/- 11 years, with 45.9 +/- 9.6 months post-transplantation period) with normal graft functions in the 3 to 5 years of the post-transplantation period were enrolled. All patients were evaluated for their standard clinical (age, sex, and duration of hemodialysis) parameters. High-grade proteinuria was defined as proteinuria >500 mg/day in the 24-hour urine collection. All patients were evaluated by means of pulse-wave velocity (PWV) measurement at the initiation of the study. RESULTS: Patients were divided into 2 groups: group 1 (high-grade proteinuria) patients with >=500 mg/24 hours (n = 30) and group 2 (low-grade proteinuria) patients with <500 mg/24 hours (n = 60). High-grade proteinuria was correlated with higher PWV measurements and lower estimated glomerular filtration levels. Proteinuria appears to precede the elevation of serum creatinine and thus may be a useful marker of renal injury and may also be a contributing factor on deterioration of the graft. CONCLUSIONS: High-grade (>500 mg/day) proteinuria in KTRs is strongly associated with poor graft survival and increased risk of cardiovascular events. In our study, we proved the significant difference between high-grade and low grade proteinuric patients, and we suggest 500 mg/day as the threshold of proteinuria in KTR population. PMID- 26036547 TI - Post-transplant C-reactive protein predicts arterial stiffness and graft function in renal transplant recipients. AB - BACKGROUND: The aim of this study was to evaluate the renal and cardiovascular outcomes of post-transplant c-reactive protein (CRP) levels. METHODS: One hundred fifty renal transplant recipients (113 men; median age, 38.9 +/- 10.8 years) were cross-sectionally analyzed. Mean pre-transplant and post-transplant CRP levels were analyzed by the 1(st), 3(rd), 6(th), 12(th), and 24(th) months of transplantation. Patients were divided into 3 groups according to mean post transplantation CRP levels: group 1 (CRP >20 mg/L and fluctuating levels; n = 34), group 2 (CRP, 6-20 mg/L; n = 40), and group 3 (CRP <6 mg/L; n = 76). Arterial stiffness was measured by means of carotid femoral pulse-wave velocity (PWv) by use of the SphygmoCor system. RESULTS: Patients in group 1 had significantly lower estimated glomerular filtration rate (eGFR) (P = .000) and left ventricular systolic function and higher duration of dialysis before transplantation, pulse-wave velocity (PWv), proteinuria, and left ventricular mass index when compared with the other two groups. In regression analysis, eGFR and PWv were detected as the predictors of post-transplantation CRP levels. CONCLUSIONS: Fluctuating and high stable (>20 mg/L) post-transplant CRP levels predict eGFR, proteinuria, left ventricular mass index, and PWv after transplantation. Thus, CRP levels may be a useful marker to anticipate graft survival and cardiovascular morbidity in renal transplant recipients. PMID- 26036548 TI - Post-transplantation Anemia Predicts Cardiovascular Morbidity and Poor Graft Function in Kidney Transplant Recipients. AB - OBJECTIVE: We aimed to investigate whether low post-transplantation-period hemoglobin levels are predictive of cardiovascular morbidity in terms of left ventricular (LV) hypertrophy and vascular stiffness and to determine the contributing factors of post-transplantation anemia in kidney transplant (KT) recipients. METHODS: One hundred fifty (mean age, 38.9 +/- 10.8 y; 113 male) KT recipients with functioning grafts were enrolled in the study. All subjects underwent clinical and laboratory evaluations (24-hour urinary protein loss, complete blood count) and transthoracic echocardiography to assess LV systolic function. Arterial stiffness was measured by means of carotid-femoral pulse-wave velocity (PWV). Mean hemoglobin levels were analyzed at the 1st, 6th, 12th, and 24th months after transplantation. Patients were divided into 2 groups according to presence of anemia: patients with anemia (group 1; n = 120) and normal (group 2; n = 30). RESULTS: PWV values (6.8 +/- 1.9 m/s vs 6.4 +/- 1.1 m/s in groups 1 and 2, respectively; P = .002) and LV mass index (LVMI; 252.1 +/- 93.7 g/m(2) vs 161.2 +/- 38.5 g/m(2) groups 1 and 2, respectively; P = .001) were significantly higher in group 1. Estimated glomerular filtration rate and (64 +/- 28.5 m/min vs 77.8 +/- 30 m/min in groups 1 and 2, respectively; P = .001) LV systolic function (57.2 +/- 5.8% vs 77.8 +/- 30% in groups 1 and 2, respectively; P < .005) were significantly lower in group 1. In regression analysis, LV systolic function and LVMI were predictors of post-transplantation hemoglobin levels. CONCLUSIONS: Post transplantation anemia contributes to cardiovascular morbidity by deteriorating LV function and increasing PWV and is therefore associated with poor prognosis for graft survival. Early correction of post-transplantation anemia, especially with the use of erythropoietin, may be beneficial for both graft and recipient survivals. PMID- 26036549 TI - Graft function and arterial stiffness: can bioimpedance analysis be useful in renal transplant recipients? AB - OBJECTIVE: We aimed to determine the total body water (TBW) by means of bioimpedance analysis (BIA) and to analyze the association of TBW, graft function, and arterial stiffness by means of pulse-wave velocity (PWV) and echocardiographic measurements in renal transplant (RT) recipients. METHODS: Eighty-two RT recipients (mean age, 38.7 +/- 11.5 y; 58 male) who were using >=1 antihypertensive treatment were enrolled in the study. Biochemical parameters, 24 hour urinary protein loss, estimated glomerular filtration rate (eGFR), transthoracic echocardiography, bioimpedance analysis according to systolic blood pressure, TBW, lean tissue index (LTI), extracellular water (ECW), intracellular water (ICW), lean tissue mass (LTM), phase angle (Phi50) levels, and renal resistive index (RRI) were evaluated. RESULTS: TBW and ECW were significantly correlated with systolic blood pressure. Urinary protein loss, pulmonary artery pressure, frequency of overhydration, systolic blood pressure, TBW, LTI, ECW, ICW, LTM, and Phi50 values were significantly higher in patients with estimated glomerular filtration rate (eGFR) 15-49 mL/min but similar in patients with eGFR 50-70 mL/min. CONCLUSIONS: Hypertensive RT recipients have increased TBW, LTI, ICW, FTI, LTM, and Phi50 values. Graft function is positively correlated with systolic blood pressure and BIA parameters. Therefore, hypertensive RT recipients should be closely followed with the use of BIA for an early diagnosis of loss of graft function. PMID- 26036550 TI - Pulmonary hypertension is closely related to arterial stiffness in renal transplant patients. AB - INTRODUCTION AND AIMS: Pulmonary hypertension (PH) is an independent predictor of increased mortality in patients on dialysis and those undergoing renal transplantation. We investigated PH and its association with vascular calcification and endothelial dysfunction in renal transplant patients. METHODS: The records of 300 consecutive patients who underwent renal transplant in our center between 2005 to 2012 were evaluated. PH was defined as systolic pulmonary artery pressure (sPAP) >= 35 mm Hg. Demographic information, clinical characteristics, pulse wave velocity (PWv), and renal recessive indices (RRI) were collected and compared among patients with and without PH. RESULTS: Eight patients in PH group (age 36 [19] years) and 87 subjects in nPH group (age 35 [9] years) were evaluated. Demographic and clinical characteristics and laboratory data of the 2 groups were similar. Additionally, sPAP was positively correlated with PWv (r = 0.263, P = .01). In multivariate analyses, RRI (P = .004), serum CRP (P = .025), and PWv (P = .001) were associated with pulmonary artery pressure. CONCLUSION: PH is significantly associated with arterial stiffness in renal transplant recipients who have a high risk for cardiovascular disease. Considering the common prevalence of cardiovascular diseases, including PH, we suggested that all patients with renal transplantation should be evaluated for regular echocardiographic examination in clinical practice. PMID- 26036551 TI - Effects of different positive end-expiratory pressure values on liver function and indocyanine green clearance test in liver transplantation donors: a prospective, randomized, double-blind study. AB - INTRODUCTION: The aim of this study was demonstrate the influence of different positive end-expiratory pressure (PEEP) values on blood flow of the liver by indocyanine green (ICG) clearance test in donor patients. METHODS: ICG clearance tests were conducted concurrently using a noninvasive monitor that tracks the plasma disappearance rate of ICG (PDR-ICG%/min) and 15-minute retention rate after administration of ICG (ICG-R15%). This study was performed in 40 patients who underwent right hepatectomy. RESULTS: The positive end-expiratory pressure (PEEP) was 0 cm H20 in the first (control) group (group K) and 10 mm Hg in the second study group (group P). ICG clearance test values before general anesthesia (T0), after induction of general anesthesia (T1), after transection (T2), 24 hours postoperative (T3), and 72 hours postoperative (T4) were recorded. Simultaneously, hemoglobin (Hgb), hematocrit (Hct), platelet count, plasma levels of prothrombin (PT), International Normalized Ratio (INR), total bilirubin, direct bilirubin, albumin, aspartate aminotransferase, and alanine aminotransferase values were analyzed. In terms of the plasma disappearance rate and retention rate of ICG 15 minutes after administration, significant difference was not observed between groups. PT and INR values were different within comparisons groups (P < .05). There were significant differences in Hgb and Hct values compared with the baseline values (T0) within group (T1, T2, T3, T4) measurements and between group comparisons at T0 and T4 (P < .05). Systemic arterial pressure, mean arterial pressure, and central venous pressure were significantly different between the groups (P < .05). CONCLUSIONS: Given the small magnitude and limited clinical significance of these changes, we conclude that PEEP values between 0 and 10 cm H2O have no effect on global liver function and liver-related liabilities tests in patients undergoing elective liver donor surgery. PMID- 26036552 TI - Optimal central venous pressure during the neohepatic phase to decrease peak portal vein flow velocity for the prevention of portal hyperperfusion in patients undergoing living donor liver transplantation. AB - BACKGROUND: The association between intraoperative systemic hemodynamic status and preventing portal hyperperfusion, which induces shear stress on the sinusoidal endothelial cells of liver grafts, resulting in poor graft function in live-donor recipients, has not been identified. This study evaluates the effects of systemic hemodynamic parameters (SHPs) during the neohepatic phase on changes in hepatic hemodynamic parameters (HHPs) between the neohepatic phase and the 1st postoperative day. METHODS: Thirty-eight patients undergoing living donor liver transplantation (LDLT) were enrolled in this study. HHPs (flow velocities of portal vein and hepatic artery) were measured immediately after hepatic artery and bile duct reconstruction and on the first postoperative day. SHPs (mean arterial pressure, central venous pressure [CVP], cardiac index, stroke volume variation, stroke volume index, systemic vascular resistance index, and central venous oxygen saturation) were recorded and averaged for 5 minutes after the measurement of HHPs. The relationships between the SHPs and HHPs were assessed using linear or quadratic regression analysis. RESULTS: Peak portal vein flow velocity (PVV) decreased on the 1st postoperative day in 24 patients (63%). There was an inverted-U relationship between CVP and the percentage change in PVV (R(2) = 0.241, P = .008). According to the quadratic regression model, the PVV maximally decreased at a CVP of 7.8 mm Hg. No significant correlations were found between the other SHPs and HHPs. CONCLUSIONS: Maintaining CVP (approximately 8 mm Hg) during the neohepatic phase was clinically beneficial in decreasing PVV to prevent portal hyperperfusion in the early postoperative period of LDLT. PMID- 26036553 TI - The evaluation of hemodynamic changes during the reperfusion phase in adult living donor liver transplantations: the role of cardiovascular problems. AB - OBJECTIVE: This study sought to evaluate the hemodynamic changes of and to analyze the effects of coronary artery disease (CAD) as well as its risk factors on hemodynamic parameters during the reperfusion phase (RP) in adult living donor liver transplantation (ALDLT). PATIENTS AND METHODS: This single-center retrospective study evaluated 154 adult patients being assessed from January 2001 to December 2013 for orthotopic liver transplantation (OLT). The patients were divided into separate groups according to the presence or absence of CAD and its risk factors, including diabetes, hypertension, dyslipidemia, smoking, sex, and age. The hemodynamic parameters were noted during the RP with respect to the patient files. The comparison of the groups and the effects of cardiovascular problems on hemodynamic parameters were statistically analyzed. RESULTS: A decrease of more than 20% in systolic arterial pressure was seen in 16 (16.7%), 7 (43.8%), and 17 (40.5%) patients without CAD, with CAD, and with its high risk factors (>2), respectively (P < .05). Moreover, diastolic hypotension was seen in 59 (38.3%) patients during RP; of those, 10 (62.5%) had CAD and 19 (45.2%) had CAD high-risk factors. The decline in both systolic and diastolic arterial pressure was significantly correlated with the increased number of risk factors (P < .05). CONCLUSIONS: RP in ALDLT remains an issue not only for the surgeons but also for the anesthesiologists. Clinicians should be aware of CAD and its risk factors before OLT and successful management of such problems are mandatory for hemodynamic stability during this formidable process. PMID- 26036554 TI - Effects of two different techniques of postoperative analgesia management in liver transplant donors: a prospective, randomized, double-blind study. AB - The aim of this study was the compare the donor patients who received intravenous (IV) morphine with patient-controlled analgesia (PCA) or epidural morphine during the early postoperative period who underwent liver transplantation. Forty patients were included in the study and randomly divided into 2 groups in a double-blinded manner. They were given IV morphine 5 mg (Group C), or epidural anesthesia adding morphine (2 mg; Group E) by epidural anesthesia technique starting 15 minutes before the estimated time of completion of surgery. All of the patients received PCA with IV morphine (Group C; PCA device was set to deliver 1 mg morphine with a lockout of 15 minutes and a 4-hour limit of 20 mg, and no continuous infusion) or epidural morphine (Group E; patient-controlled epidural analgesia [PCEA] device was set to deliver 0.5 mg morphine with a lockout of 30 minutes and a 4-hour limit of 10 mg, and no continuous infusion) and were followed up for 24 hours, and pain scores were evaluated by study nurses who were blinded to the study protocol. The visual analogue scale (VAS) scores at rest and at movement and morphine consumption at 12 and 24 hours after operation evaluation time points were significantly higher in Group E than those in Group C (P < .05). Furthermore, total morphine consumption in Group C was significantly higher than that in Group E (P < .05). Epidural morphine via PCEA was associated with decreased postoperative VAS scores and morphine consumption. These findings may be beneficial for managing postoperative analgesia protocols in liver transplant donor patients. PMID- 26036555 TI - Comparison of different scoring systems in predicting short-term mortality after liver transplantation. AB - BACKGROUND: Many scoring systems have been used in predicting the outcomes of liver transplantations. The aim of this study was to compare between 4 scoring systems-Sequential Organ Failure Assessment (SOFA), Model for End-Stage Liver Disease, Acute Physiology and Chronic Health Evaluation II, and Child Turcotte Pugh -among patients who underwent living-donor liver transplantation (LDLT) seeking to evaluate the best system to correlate with post-operative outcomes. METHODS: This study retrospectively reviewed the medical records of 53 patients who had received LDLT in a tertiary care hospital from January 2005 to December 2010. Demographic, clinical, and laboratory data were recorded. Each patient was assessed by use of 4 scoring systems before transplantation and on post-operative days 1 to 7 and at 3 months. RESULTS: The overall 3-month survival rate was 64%. The pre-transplant SOFA score had the best discriminatory power; moreover, the SOFA score on post-operative day 7 had the best Youden index (.875). The survival rate at 3-month follow-up after liver transplantation differed significantly (P = .00023, highest area under the receiver operator characteristic curve = .952) between patients who had SOFA scores <8 and those had SOFA score >8 on post-liver transplant day 7. This study also demonstrated that respiratory rate (P = .017) and serum bilirubin level (P = .048) and duration of intensive care unit stay (P = .04) are significant risk factors related to early mortality after LDLT. CONCLUSIONS: The pre-transplant SOFA score was a statistically significant predictor of 3-month mortality; SOFA score on post-liver transplant day 7 had the best discriminative power for predicting 3-month mortality. PMID- 26036556 TI - Living donor liver transplant versus cadaveric liver transplant survival in relation to model for end-stage liver disease score. AB - BACKGROUND: The Model for End-Stage Liver Disease (MELD) score is universally used to prioritize patients on the liver transplant waiting list. It is potentially used to predict survival as well. There has been conflicting evidence on the use of living donor liver transplantation (LDLT) in patients with high MELD scores. We reported retrospective data comparing survival between LDLT and deceased donor liver transplantation (DDLT) In relation to MELD score in a single center experience. METHODS: We retrospectively reviewed our records from 2001 to 2013 for LDLT and DDLT. Data reviewed include the numbers of patients for LDLT and DDLT, age, sex, MELD score, etiology of liver disease, hepatocellular carcinoma, re-transplantation, median follow-up, mortality (with 1 month, 1 year, or after 1 year), and cause of death. Only adults are included in this analysis. Patients were categorized into MELD scores above and below 25. Kaplan-Meier analysis was used for survival, and the log-rank chi(2) test was used for comparison, with a value of P < .05 used for significance. RESULTS: The total number of transplanted patients at King Faisal Specialist Hospital, Riyadh, Saudi Arabia, was 491. There were 222 patients for LDLT and 269 patients for DDLT. The median age was 53 years (15-80 years), and 292 were male (59.5%). The overall 1-, 3-, and 5-year Kaplan-Meier survival rates of LDLT and DDLT were 89%, 85%, and 84%, respectively, for MELD score below 25, and 80%,78%, and 77%, respectively, for MELD score greater than or equal to 25. CONCLUSIONS: Our data showed no difference between the survival rates of the two groups (DDLT versus LDLDT), nor that high MELD score has a negative impact on survival. A larger cohort of patients may be needed to confirm these findings. PMID- 26036557 TI - Early postoperative pulmonary complications after heart transplantation. AB - OBJECTIVE: The aim of this study was to determine the types, incidence, and risk factors for early postoperative pulmonary complications in heart transplant recipients. METHODS: We retrospectively collected data from the records of consecutive heart transplantations from January 2003 to December 2013. A total of 83 patients underwent heart transplantation. The data collected for each case were demographic features, duration of mechanical ventilation, respiratory problems that developed during the intensive care unit (ICU) stay, and early postoperative mortality (<30 d). RESULTS: Of the 72 patients considered, 52 (72.2%) were male. The overall mean age at the time of transplantation was 32.1 +/- 16.6 years. Twenty-five patients (34.7%) developed early postoperative respiratory complications. The most frequent problem was pleural effusion (n = 19; 26.4%), followed by atelectasis (n = 6; 8.3%), acute respiratory distress syndrome (n = 5; 6.9%), pulmonary edema (n = 4; 5.6%), and pneumonia (n = 3; 4.2%). Postoperative duration of mechanical ventilation (44.2 +/- 59.2 h vs 123.8 +/- 190.8 h; P = .005) and the length of postoperative ICU stay (10.1 +/- 5.8 h vs 19.8 +/- 28.9 h; P = .03) were longer among patients who had respiratory problems. Postoperative length of stay in the hospital (22.3 +/- 12.5 d vs 30.3 +/- 38.3 d; P = .75) was similar in the 2 groups. The overall mortality rate was 12.5% (n = 9). The patients who had respiratory problems did not show higher mortality than those who did not have respiratory problems (16.0% vs 10.6%; P = .71). CONCLUSIONS: Respiratory complications were relatively common in our cohort of heart transplant recipients. However, these complications were mostly self limiting and did not result in worse mortality. PMID- 26036558 TI - Effectiveness of fludarabine- and busulfan-based conditioning regimens in patients with acute myeloblastic leukemia: 8-year experience in a single center. AB - OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for acute myeloblastic leukemia (AML). Because the conditioning regimen of busulfan plus cyclophosphamide carries significant risks of toxicity, we evaluated the factors affecting survival after fludarabine replacement instead of cyclophosphamide. METHODS: The study included 55 patients who underwent allo-HSCT for AML and received busulfan, fludarabine, and antithymocyte globulin (ATG). RESULTS: Forty-eight patients received a myeloablative regimen; 7 patients received a reduced-intensity conditioning regimen. The neutrophil and platelet engraftment times were 12 days (range 9 to 20) and 12 days (range 7 to 19), respectively. Graft-vs-host disease (GvHD) developed in 10% and 50% of the patients, respectively. Seven patients received donor lymphocyte infusion. Of them, 5 patients developed grade I or II GvHD, one grade IV GvHD. The median follow-up period was 20.6 months. The predicted progression-free survival (PFS) at 1 and 3 years after transplantation was 78% and 74%, respectively. The overall survival (OS) at 1, 3, and 5 years was 76%, 74%, and 62%, respectively. Treatment-related mortality (infection in 1 patient, GvHD in 2 patients) occurred in 3 patients (5.5%). Multivariate analysis revealed that OS and PFS were not influenced by age, dose of busulfan or ATG, or presence of cytomegalovirus antigenemia. Acute GvHD and pretransplantation minimal residual disease positivity negatively affected the transplant outcome. The presence of active disease at the time of transplantation was found as an independent risk factor for AML. CONCLUSIONS: Busulfan- and fludarabine-based conditioning regimens are effective for AML, and have acceptable toxicity, morbidity, and mortality. PMID- 26036559 TI - Prospect of using decellularized human placenta and cow placentome for creation of new organs: targeting the liver (part I: anatomic study). AB - INTRODUCTION: This paper presents anatomic studies of decellularized human placenta and cow placentome and proves that there is a possibility to create a scaffold using the natural microvascular structure for growing organs and tissues. MATERIALS AND METHODS: The anatomic studies were conducted on 20 full term placentas from human donors, and placentomes collected from 8 cows. Before the anatomic studies of human placenta and cow placentome, decellularization was conducted. For visualization of vessels, 50% Latex in water (Nairit L3) through the umbilical cord artery and vein was injected. Corrosion casts were also prepared. RESULTS: An important feature in the transplantation of microfragments of the liver tissue is the blood supply system of the piled chorion, which consists of the main vascular trunks, and perivascular and superficial capillary network. Conditionally, based on the degree of difficulty, there are several types of grouping of the capillaries in terminal pile: simple capillary knot, coiled capillary knot, and complexly organized tangle-shaped capillary network with the richly anastomosing crimped microvessels. A similar pattern was observed in the terminal pile of the placentomes of the cow. For the creation of the auxiliary liver and connection of it into the systemic circulation of the recipient, we can use this exclusiveness of the angioarchitechtonics. CONCLUSIONS: Anatomic studies demonstrated that decellularized human placenta, as well as cow placentome, can be used as a scaffold for growth of organs and tissues in vitro and in vivo. PMID- 26036560 TI - Investigation of the biomechanical integrity of decellularized rat abdominal aorta. AB - OBJECTIVES: The loss or damage of an organ or tissue is one of the most common and devastating problems in healthcare today. Tissue engineering applies the principles of engineering and biology toward the development of functional biological replacements that are able to maintain, improve, or restore the function of pathological tissues. The aim of the overall project is to study an already existing method for the decellularization of homograft vascular grafts for use in vascular surgery. MATERIALS AND METHODS: The biomechanical integrity of native and decellularized rat aortas was assessed under uniaxial tension tests. For this purpose, 36 male rats (12 Wistar and 24 Dark Agouti [DA]) were used to excise their abdominal aortas. Twelve of the aortas were tested fresh (Wistar and DA rats), within 24 hours from euthanasia, and the rest were decellularized using a modified protocol (DA rats only). Fresh and decellularized samples (n = 12) were subjected to uniaxial tensile loading to failure, and the recorded stress-strain behaviour of each specimen was assessed in terms of 6 biomechanical parameters. RESULTS: No statistically significant differences were found in any of the biomechanical parameters studied between the decellularized DA rat aorta group and both the native DA and Wistar rat aorta groups (P > .05). Also, no significant difference was shown between the native DA and native Wistar rat aorta groups. CONCLUSIONS: The results from this study have shown that the decellularization protocol did not affect the mechanical properties of the native rat aorta. In addition to this, both native Wistar and native/decellularized DA rat aorta groups shared similar mechanical properties. PMID- 26036561 TI - Spontaneous clearance of hepatitis C genotype 4 after liver retransplantation. AB - BACKGROUND: Hepatitis C virus (HCV)-related cirrhosis remains the most common indication for liver transplantation worldwide. Graft reinfection with HCV is nearly universal, causing significant morbidity and mortality. Spontaneous clearance of HCV after liver transplantation and retransplantation is extremely rare. We report a case of spontaneous clearance of HCV genotype 4 that occurred shortly after 2nd liver transplantation. CASE REPORT: A 32-year-old female patient received a cadaveric liver transplant for HCV-related cirrhosis in 2007. She was not treated for HCV before transplantation. The patient developed biopsy proven HCV recurrence with elevated transaminases and 65,553 IU/mL HCV RNA, genotype 4. She could not tolerate interferon-based treatment. The patient's condition progressively worsened and required a 2nd cadaveric liver transplantation in March 2013. Immunosuppression initially included steroids and Prograf, which was then switched to cyclosporine after the patient developed seizure. She developed acute cellular rejection which was readily treated with immunosuppression adjustment. HCV RNA became negative in April, which was confirmed in May 2013. CONCLUSIONS: Spontaneous clearance of hepatitis C rarely occurs after liver transplantation and is extremely rare after retransplantation. This finding may be explained by alterations in the host immune responses to HCV after transplantation. To our knowledge, this is the first case of spontaneous clearance of HCV genotype 4 after liver retransplantation. PMID- 26036562 TI - High immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected Chinese rhesus macaques. AB - Chinese rhesus macaques (CRMs) are ideal experimental animals for studying the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and for vaccine research. SHIV89.6 has been reported to be an attenuated virus because, in most cases, SHIV89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. After two serial passages in vivo, SHIV (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. However, the pathogenic ability of SHIV89.6 is not well understood. In this study, we found that 6 of 14 SHIV89.6-infected CRMs died within 127 weeks after infection. We found especially high immune activation, low IFN-alpha expression, and distinctive cytokine expression profiles in the infected and dead (ID) group of monkeys, while there was only few change in the CD4(+) T counts and distribution of T cell subsets in the ID group monkeys. Also, there was a similar dynamic of viral load between infected and surviving (IS) and ID group monkeys. Furthermore, we found various correlations among immune activation, IFN-alpha expression, and frequencies of cytokine-secreting cells. These results suggest that SHIV89.6 infections have pathogenic potential in CRMs and that high immune activation and abnormal expression of cytokines contribute to death of SHIV89.6 infected CRMs. This also implies that high immune activation may be relevant to dysfunction of immune cells. It is proposed that high immune activation and dysfunction of immune cells may be good predictors for disease progression and markers for therapy. PMID- 26036563 TI - Recombinant expression of the alternate reading frame protein (ARFP) of hepatitis C virus genotype 4a (HCV-4a) and detection of ARFP and anti-ARFP antibodies in HCV-infected patients. AB - HCV is a single-stranded RNA virus with a single open reading frame (ORF) that is translated into a polyprotein that is then processed to form 10 viral proteins. An additional eleventh viral protein, the alternative reading frame protein (ARFP), was discovered relatively recently. This protein results from a translational frameshift in the core region during the expression of the viral proteins. Recombinant expression of different forms of ARFP was previously done for HCV genotypes 1 and 2, and more recently, genotype 3. However, none of the previous studies addressed the expression of ARFP of HCV genotype 4a, which is responsible for 80 % of HCV infections in the Middle East and Africa. Moreover, the direct detection of the ARFP antigen in HCV-infected patients was never studied before for any HCV genotype. In the present study, recombinant ARFP derived from HCV genotype 4a was successfully expressed in E. coli and purified using metal affinity chromatography. The recombinant ARFP protein and anti-ARFP antibodies were used for detection of ARFP antigen in patients' sera, employing competitive enzyme-linked immunosorbent assay (ELISA) procedures. Furthermore, the recombinant antigen was also used to detect and quantify anti-ARFP antibodies in HCV-infected Egyptian patients at different stages of pegylated interferon/ribavirin therapy, using an ELISA assay. The ARFP antigen was detectable in 69.4 % of RNA-positive sera, indicating that ARFP antigen is produced during the natural course of HCV infection. In addition, significant levels of anti-ARFP antibodies were present in 41 % of the serum samples tested. The important diagnostic value of the recombinant ARFP antigen was also demonstrated. PMID- 26036564 TI - A gyrovirus infecting a sea bird. AB - We characterized the genome of a highly divergent gyrovirus (GyV8) in the spleen and uropygial gland tissues of a diseased northern fulmar (Fulmarus glacialis), a pelagic bird beached in San Francisco, California. No other exogenous viral sequences could be identified using viral metagenomics. The small circular DNA genome shared no significant nucleotide sequence identity, and only 38-42 % amino acid sequence identity in VP1, with any of the previously identified gyroviruses. GyV8 is the first member of the third major phylogenetic clade of this viral genus and the first gyrovirus detected in an avian species other than chicken. PMID- 26036566 TI - Grab the wiggly tail: new insights into the dynamics of circadian clocks. PMID- 26036565 TI - NMR Exchange Format: a unified and open standard for representation of NMR restraint data. PMID- 26036568 TI - RGM co-receptors add complexity to BMP signaling. PMID- 26036567 TI - Exposing the secrets of sex determination. PMID- 26036572 TI - Heuristic model of depressive disorders as systemic chronic disease. PMID- 26036573 TI - Isolation of mitochondria by gentle cell membrane disruption, and their subsequent characterization. AB - Mitochondria play a key role in several physiological processes as in integrating signals in the cell. However, understanding of the mechanism by which mitochondria sense and respond to signals has been limited due to the lack of an appropriate model system. In this study, we developed a method to isolate and characterize mitochondria without cell homogenization. By gently pipetting cells treated with streptolysin-O, a pore-forming membrane protein, we disrupted the cell membrane and were able to isolate both elongated and spherical mitochondria. Fluorescence imaging combined with super resolution microscopy showed that both the outer and inner membranes of the elongated mitochondria isolated using the newly developed method were intact. In addition, a FRET-based ATP sensor expressed in the mitochondrial matrix demonstrated that ATP generation by FoF1 ATPase in the isolated elongated mitochondria was as high as that in intracellular mitochondria. On the other hand, some of the spherical mitochondria isolated with this method had the outer membrane that no longer encapsulated the inner membrane. In addition, all mitochondria isolated using conventional procedures involving homogenization were spherical, many of them had damaged membranes, and low levels of ATP generation. Our results suggest that elongated mitochondria isolated from cells through gentle cell membrane disruption using a pore-forming protein tend to be more similar to intracellular mitochondria, having an intact membrane system and higher activity than spherical mitochondria. PMID- 26036574 TI - Histamine inhibits differentiation of skin fibroblasts into myofibroblasts. AB - Histamine and TGF-beta, major mediators secreted by mast cells, are involved in skin inflammation and play critical roles in the pathogenesis of systemic sclerosis. However, the roles of signaling mechanisms in the development of skin fibrosis remain largely unclear. Here we show that histamine suppressed the expression of alpha smooth muscle actin (alphaSMA), a marker of myofibroblasts, induced by TGF-beta1 in skin fibroblasts. Histamine H1-receptor (H1R), but not H2 receptor (H2R) or H4-receptor (H4R), was expressed on skin fibroblasts at both mRNA and protein levels. Interestingly, an H1R antagonist, but not H2R or H4R antagonists, antagonized the histamine-mediated suppression of alphaSMA expression by TGF-beta1. Correspondingly, phosphorylated Smad2 was detected after treatment with TGF-beta1, whereas the addition of histamine inhibited this phosphorylation. Taken together, histamine-H1R decreased TGF-beta1-mediated Smad2 phosphorylation and inhibited differentiation of skin fibroblasts into myofibroblasts. PMID- 26036575 TI - Humanization of a phosphothreonine peptide-specific chicken antibody by combinatorial library optimization of the phosphoepitope-binding motif. AB - Detection of protein phosphorylation at a specific residue has been achieved by using antibodies, which have usually been raised by animal immunization. However, there have been no reports of the humanization of phosphospecific non-human antibodies. Here, we report the humanization of a chicken pT231 antibody specific to a tau protein-derived peptide carrying the phosphorylated threonine at residue 231 (pT231 peptide) as a model for better understanding the phosphoepitope recognition mechanism. In the chicken antibody, the phosphate group of the pT231 peptide antigen is exclusively recognized by complementarity determining region 2 of the heavy chain variable domain (VH-CDR2). Simple grafting of six CDRs of the chicken antibody into a homologous human framework (FR) template resulted in the complete loss of pT231-peptide binding. Using a yeast surface-displayed combinatorial library with permutations of 11 FR residues potentially affecting CDR loop conformations, we identified 5 critical FR residues. The back mutation of these residues to the corresponding chicken residues completely recovered the pT231-peptide binding affinity and specificity of the humanized antibody. Importantly, the back mutation of the FR 76 residue of VH (H76) (Asn to Ser) was critical in preserving the pT231-binding motif conformation via allosteric regulation of ArgH71, which closely interacts with ThrH52 and SerH52a residues on VH-CDR2 to induce the unique phosphate-binding bowl-like conformation. Our humanization approach of CDR grafting plus permutations of FR residues by combinatorial library screening can be applied to other animal antibodies containing unique binding motifs on CDRs specific to posttranslationally modified epitopes. PMID- 26036576 TI - Parkin induces G2/M cell cycle arrest in TNF-alpha-treated HeLa cells. AB - Parkin is a known tumor suppressor. However, the mechanism by which parkin acts as a tumor suppressor remains to be fully elucidated. Previously, we reported that parkin expression induces caspase-dependent apoptotic cell death in TNF alpha-treated HeLa cells. However, at that time, we did not consider the involvement of parkin in cell cycle control. In the current study, we investigated whether parkin is involved in cell cycle regulation and suppression of cancer cell growth. In our cell cycle analyses, parkin expression induced G2/M cell cycle arrest in TNF-alpha-treated HeLa cells. To elucidate the mechanism(s) by which parkin induces this G2/M arrest, we analyzed cell cycle regulatory molecules involved in the G2/M transition. Parkin expression induced CDC2 phosphorylation which is known to inhibit CDC2 activity and cause G2/M arrest. Cyclin B1, which is degraded during the mitotic transition, accumulated in response to parkin expression, thereby indicating parkin-induced G2/M arrest. Next, we established that Myt1, which is known to phosphorylate and inhibit CDC2, increased following parkin expression. In addition, we found that parkin also induces increased Myt1 expression, G2/M arrest, and reduced cell viability in TNF alpha-treated HCT15 cells. Furthermore, knockdown of parkin expression by parkin specific siRNA decreased Myt1 expression and phosphorylation of CDC2 and resulted in recovered cell viability. These results suggest that parkin acts as a crucial molecule causing cell cycle arrest in G2/M, thereby suppressing tumor cell growth. PMID- 26036577 TI - The regulation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase by autophagy in low-glycolytic hepatocellular carcinoma cells. AB - The glycolytic phenotype is a dominant metabolic phenomenon in cancer and is reflected in becoming aggressive. Certain hepatocellular carcinoma lack increased glycolysis and prefer to uptake acetate than glucose for metabolism. Autophagy plays a role in preserving energies and nutrients when there is limited external nutrient supply and maintains glucose level of blood though supporting gluconeogenesis in the liver. As the role of autophagy and gluconeogenesis in HCC following the glycolic activity was not clear, we cultured HCC cells with different glycolytic levels in Hank's balanced salt solution (HBSS) to induce autophagy and conducted the activity of gluconeogenesis. Both autophagy and gluconeogenesis were induced in low glycolytic HCC cells (HepG2). In glycolytic Hep3B cells, only autophagy without gluconeogenesis was induced upon starvation. When autophagy was blocked, the level of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was reduced in HepG2 cells and not in Hep3B. Altogether, we investigated contribution of hepatic gluconeogenesis to the metabolic phenotype of HCC cells and the role of autophagy as a potential mechanism regulating gluconeogenesis in low glycolytic HCC. PMID- 26036578 TI - A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non syndromic hearing loss. AB - Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A domain, which has an important role for protein tetramerization, and the B segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel. PMID- 26036579 TI - Sub-cellular force microscopy in single normal and cancer cells. AB - This work investigates the biomechanical properties of sub-cellular structures of breast cells using atomic force microscopy (AFM). The cells are modeled as a triple-layered structure where the Generalized Maxwell model is applied to experimental data from AFM stress-relaxation tests to extract the elastic modulus, the apparent viscosity, and the relaxation time of sub-cellular structures. The triple-layered modeling results allow for determination and comparison of the biomechanical properties of the three major sub-cellular structures between normal and cancerous cells: the up plasma membrane/actin cortex, the mid cytoplasm/nucleus, and the low nuclear/integrin sub-domains. The results reveal that the sub-domains become stiffer and significantly more viscous with depth, regardless of cell type. In addition, there is a decreasing trend in the average elastic modulus and apparent viscosity of the all corresponding sub cellular structures from normal to cancerous cells, which becomes most remarkable in the deeper sub-domain. The presented modeling in this work constitutes a unique AFM-based experimental framework to study the biomechanics of sub-cellular structures. PMID- 26036580 TI - Concentrations of trace elements in the kidney, liver, muscle, and skin of short sea snake (Lapemis curtus) from the Strait of Hormuz Persian Gulf. AB - To our knowledge, this is the first report into trace elements accumulation in tissues of the short sea snake (Lapemis curtus). Lead (Pb), cadmium (Cd), copper (Cu), vanadium (V), nickel (Ni), and zinc (Zn) were determined in the kidney, liver, skin, and muscle tissues of short sea snake, L. curtus, from the Strait of Hormuz during October 2011. Skins generally displayed the lowest trace element burdens. Kidneys displayed the highest Pb, Cd, V, Ni, and Cu mean concentrations (0.89, 0.04, 1.66, 6.22, and 20.23 MUg g(-1) dry weight, respectively), while muscle exhibited the highest Zn levels (493.32 MUg g(-1) dry weight). Concentration ranges of the selected trace elements were compared with those reported in other studies. Data presented here may be considered as a baseline for further ecotoxicological studies in sea snakes. PMID- 26036581 TI - Insecticides induced biochemical changes in freshwater microalga Chlamydomonas mexicana. AB - The effect of insecticides (acephate and imidacloprid) on a freshwater microalga Chlamydomonas mexicana was investigated with respect to photosynthetic pigments, carbohydrate and protein contents, fatty acids composition and induction of stress indicators including proline, superoxide dismutase (SOD) and catalase (CAT). C. mexicana was cultivated with 1, 5, 10, 15, 20 and 25 mg L(-1) of acephate and imidacloprid. The microalga growth increased with increasing concentrations of both insecticides up to 15 mg L(-1), beyond which the growth declined compared to control condition (without insecticides). C. mexicana cultivated with 15 mg L(-1) of both insecticides for 12 days was used for further analysis. The accumulation of photosynthetic pigments (chlorophyll and carotenoids), carbohydrates and protein was decreased in the presence of both insecticides. Acephate and imidacloprid induced the activities of superoxide dismutase (SOD) and catalase (CAT) and increased the concentration of proline in the microalga, which play a defensive role against various environmental stresses. Fatty acid analysis revealed that the fraction of polyunsaturated fatty acids decreased on exposure to both insecticides. C. mexicana also promoted 25 and 21% removal of acephate and imidacloprid, respectively. The biochemical changes in C. mexicana on exposure to acephate and imidacloprid indicate that the microalga undergoes an adaptive change in response to the insecticide-induced oxidative stress. PMID- 26036582 TI - Radiolytic decomposition of ciprofloxacin using gamma irradiation in aqueous solution. AB - Gamma irradiation-induced decomposition of ciprofloxacin (CIP) was elucidated with different additives, such as CO3 (2-), NO3 (-), NO2 (-), humic acid, methanol, 2-propanol, and tert-butanol. The results show that low initial concentration and acidic condition were favorable for CIP removal during gamma irradiation. By contrast, radiolytic decomposition of CIP was inhibited with the addition of anions and organic additives. As a strong carcinogen, Cr(6+) was especially mixed with CIP to produce combined pollution. It is noteworthy that the removal of the mixture of CIP and Cr(6+) presented a synergistic effect; the degradation efficiency of the two pollutants was markedly improved compared to that of the single pollutant during gamma irradiation. Based on the results of quantum chemical calculations and LC-MS analysis, we determined seven kinds of degradation intermediates and presented the CIP degradation pathways, which were mainly attributed to the oxidation process of hydroxyl radicals OH. and the direct decomposition of CIP molecules. PMID- 26036583 TI - Nitrogen and phosphorus associating with different size suspended solids in roof and road runoff in Beijing, China. AB - Roofs and roads, accounting for a large portion of the urban impervious land surface, have contributed significantly to urban nonpoint pollution. In this study, in Beijing, China, roof and road runoff are sampled to measure the suspended solids (SS), nitrogen (N), and phosphorus (P) contained in particles with different sizes. The SS content in the road runoff (151.59 mg/L) was sevenfold that in the roof runoff (21.13 mg/L, p < 0.05). The SS contained more coarse particulates in the roof runoff than in road runoff. The small particulates in the range of 0.45-50 MUm consisted of 59 % SS in the roof runoff and 94 % SS in the road runoff. P was mainly attached to particle sizes of 10-50 MUm in the roof (73 %) and road (48 %) runoffs, while N was mainly in a dissolved phase state in both runoffs. So, the different associations of N and P raise a challenge in preventing stormwater pollution in urban environments. PMID- 26036584 TI - Effects of different warming patterns on the translocations of cadmium and copper in a soil-rice seedling system. AB - Heavy-metal-polluted rice poses potential threats to food security and has received great attention in recent years, while how elevated temperature affects the translocation of heavy metals in soil-rice system is unclear. In this study, potting experiments were conducted in plant growth chambers for 24 days to evaluate the effects of different warming patterns on cadmium (Cd) and copper (Cu) migrations in soil-rice seedling system. Rice seedlings were cultivated under four different day/night temperature patterns: 25/18 degrees C (CK), 25/23 degrees C (N5), 30/18 degrees C (D5), and 30/23 degrees C (DN5), respectively. Non-contaminated soil (CS), Cd/Cu lightly polluted soil (LS), and highly polluted soil (HS) were chosen for experiments. The results showed that different warming patterns decreased soil pH and elevated available soil Cd/Cu concentrations. The shoot and root biomass were increased by 39.0-320 and 28.6-348 %, respectively. Warming induced significant (p < 0.05) increase of Cd/Cu uptake and translocation in rice seedlings, especially for the Cd concentration in shoot. The Cd concentrations of shoot increased by 5-12 times and up to 8 times for LS and HS, respectively. Meanwhile, the Cd concentration of shoot increased with warming while that of root kept unchanged, indicating that warming promoted cadmium translocation from root to shoot (about -four to nine times of CK), while warming changed the Cu concentration of shoot similarly to that of root and had no significant effects on Cu translocations in rice seedlings. Our study may provide improved understanding for Cd/Cu fates in soil-rice system by warming and imply that heavy metals had the higher environmental risk under the future global warming. PMID- 26036585 TI - Electrochemical impedance immunosensor for rapid detection of stressed pathogenic Staphylococcus aureus bacteria. AB - In this work, we report the adaptation of bacteria to stress conditions that induce instability of their cultural, morphological, and enzymatic characters, on which the identification of pathogenic bacteria is based. These can raise serious issues during the characterization of bacteria. The timely detection of pathogens is also a subject of great importance. For this reason, our objective is oriented towards developing an immunosensing system for rapid detection and quantification of Staphylococcus aureus. Polyclonal anti-S. aureus are immobilized onto modified gold electrode by self-assembled molecular monolayer (SAM) method. The electrochemical performances of the developed immunosensor were evaluated by impedance spectroscopy through the monitoring of the charge transfer resistance at the modified solid/liquid interface using ferri-/ferrocyanide as redox probe. The developed immunosensor was applied to detect stressed and resuscitate bacteria. As a result, a stable and reproducible immunosensor with sensitivity of 15 kOmega/decade and a detection limit of 10 CFU/mL was obtained for the S. aureus concentrations ranging from 10(1) to 10(7) CFU/mL. A low deviation in the immunosensor response (+/-10 %) was signed when it is exposed to stressed and not stressed bacteria. PMID- 26036587 TI - Carbon and energy fixation of great duckweed Spirodela polyrhiza growing in swine wastewater. AB - The ability to fix carbon and energy in swine wastewater of duckweeds was investigated using Spirodela polyrhiza as the model species. Cultures of S. polyrhiza were grown in dilutions of both original swine wastewater (OSW) and anaerobic digestion effluent (ADE) based on total ammonia nitrogen (TAN). Results showed that elevated concentrations of TAN caused decreased growth, carbon fixation, and energy production rates, particularly just after the first rise in two types of swine wastewater. Also, OSW was more suitable for S. polyrhiza cultivation than ADE. Maximum carbon and energy fixation were achieved at OSW-TAN concentrations of 12.08 and 13.07 mg L(-1), respectively. Photosynthetic activity of S. polyrhiza could be inhibited by both nutrient stress (in high-concentration wastewater) and nutrient limitation (in low-concentration wastewater), affecting its growth and ability for carbon-energy fixation. PMID- 26036586 TI - Pilot study testing a European human biomonitoring framework for biomarkers of chemical exposure in children and their mothers: experiences in the UK. AB - Exposure to a number of environmental chemicals in UK mothers and children has been assessed as part of the European biomonitoring pilot study, Demonstration of a Study to Coordinate and Perform Human Biomonitoring on a European Scale (DEMOCOPHES). For the European-funded project, 17 countries tested the biomonitoring guidelines and protocols developed by COPHES. The results from the pilot study in the UK are presented; 21 school children aged 6-11 years old and their mothers provided hair samples to measure mercury and urine samples, to measure cadmium, cotinine and several phthalate metabolites: mono(2-ethyl-5 hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxo-hexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP), mono-ethyl phthalate (MEP), mono-iso butyl phthalate (MiBP), mono-benzyl phthalate (MBzP) and mono-n-butyl phthalate (MnBP). Questionnaire data was collected on environment, health and lifestyle. Mercury in hair was higher in children who reported frequent consumption of fish (geometric mean 0.35 MUg/g) compared to those that ate fish less frequently (0.13 MUg/g, p = 0.002). Cadmium accumulates with age as demonstrated by higher levels of urinary cadmium in the mothers (geometric mean 0.24 MUg/L) than in the children(0.14 MUg/L). None of the mothers reported being regular smokers, and this was evident with extremely low levels of cotinine measured (maximum value 3.6 MUg/L in mothers, 2.4 MUg/L in children). Very low levels of the phthalate metabolites were also measured in both mothers and children (geometric means in mothers: 5OH-MEHP 8.6 MUg/L, 5oxo-MEHP 5.1 MUg/L, MEHP 1.2 MUg/L, MEP 26.8 MUg/L, MiBP 17.0 MUg/L, MBzP 1.6 MUg/L and MnBP 13.5 MUg/L; and in children: 5OH-MEHP 18.4 MUg/L, 5oxo-MEHP 11.4 MUg/L, MEHP 1.4 MUg/L, MEP 14.3 MUg/L, MiBP 25.8 MUg/L, MBzP 3.5 MUg/L and MnBP 22.6 MUg/L). All measured biomarker levels were similar to or below population-based reference values published by the US National Health and Nutrition Examination Survey (NHANES) and Germany's GerES surveys. No results were above available health guidance values and were of no concern with regards to health. The framework and techniques learnt here will assist with future work on biomonitoring in the UK. PMID- 26036588 TI - Enhanced hydroxyl radical generation in the combined ozonation and electrolysis process using carbon nanotubes containing gas diffusion cathode. AB - Combination of ozone together with electrolysis (ozone-electrolysis) is a promising wastewater treatment technology. This work investigated the potential use of carbon nanotube (CNT)-based gas diffusion cathode (GDC) for ozone electrolysis process employing hydroxyl radicals (.OH) production as an indicator. Compared with conventional active carbon (AC)-polytetrafluoroethylene (PTFE) and carbon black (CB)-PTFE cathodes, the production of .OH in the coupled process was improved using CNTs-PTFE GDC. Appropriate addition of acetylene black (AB) and pore-forming agent Na2SO4 could enhance the efficiency of CNTs-PTFE GDC. The optimum GDC composition was obtained by response surface methodology (RSM) analysis and was determined as CNTs 31.2 wt%, PTFE 60.6 wt%, AB 3.5 wt%, and Na2SO4 4.7 wt%. Moreover, the optimized CNT-based GDC exhibited much more effective than traditional Ti and graphite cathodes in Acid Orange 7 (AO7) mineralization and possessed the desirable stability without performance decay after ten times reaction. The comparison tests revealed that peroxone reaction was the main pathway of .OH production in the present system, and cathodic reduction of ozone could significantly promote .OH generation. These results suggested that application of CNT-based GDC offers considerable advantages in ozone-electrolysis of organic wastewater. PMID- 26036589 TI - Musca domestica laboratory susceptibility to three ethnobotanical culinary plants. AB - Throughout history, synanthropic Musca domestica had remained a worldwide problem whenever poor sanitation and bad hygienic conditions exists. Houseflies growing resistance to chemical insecticides are a rising environmental problem that necessitates search for alternatives. Mentha cervina, Ocimum basilicum, and Coriandrum sativum were tested for bioactivity on M. domestica adults and larvae. They are culinary Mediterranean plants. In adulticidal bioassay, using both CDC bottles and fumigation techniques, basil was the most effective extract with LC50 1.074 and 34.996 g/L, respectively. Concerning larvicidal bioassay by fumigation technique, coriander had the highest toxicity index with LC50 29.521 g/L. In both dipping and feeding technique, basil had the highest toxicity with LC50 32.643 and 0.749 g/L, respectively. Basil showed the highest toxicity results in four out of the five models tested followed by coriander then mint; this result highlights the potentiality of basil as a green insecticide in management of flies and opens new insight in the industrialization of basil-based fly control products. PMID- 26036590 TI - Viviparous placentotrophy in reptiles and the parent-offspring conflict. AB - In placentotrophic viviparous reptiles, pregnant females deliver nutrients to their developing fetuses by diverse morphological specializations that reflect independent evolutionary origins. A survey of these specializations reveals a major emphasis on histotrophy (uterine secretion and fetal absorption) rather than hemotrophy (transfer between maternal and fetal blood streams). Of available hypotheses for the prevalence of histotrophic transfer, the most promising derives insights from the theoretical parent-offspring conflict over nutrient investment. I suggest that histotrophy gives pregnant females greater control over nutrient synthesis, storage, and delivery than hemotrophic transfer, reflecting maternal preeminence in any potential parent-offspring competition over nutrient investment. One lizard species shows invasive ovo-implantation and direct contact between fetal tissues and maternal blood vessels, potentially conferring control over nutrient transfer to the embryo. Future research on squamates will benefit from application of parent-offspring conflict theory to the transition from incipient to substantial matrotrophy, as well as by testing theory-derived predictions on both facultatively and highly placentotrophic forms. PMID- 26036591 TI - Delusional disorder and schizophrenia: a comparison of the neurocognitive and clinical characteristics in first-episode patients. AB - BACKGROUND: Delusional disorder (DD) is thought to be distinct from schizophrenia (SZ). However, few systematic investigations have been conducted on DD because of the difficulty in ascertaining a representative sample size. Existing knowledge has been mostly generated from inpatient cohorts, which may be biased towards a more severe sample. METHOD: We compared the demographic, clinical and cognitive differences between 71 patients with first-episode DD and 71 age-matched patients with first-episode SZ. Participants were consecutively recruited from a population-based territory-wide study of early psychosis in Hong Kong targeting first-episode psychosis. Basic demographic information, premorbid functioning, duration of untreated psychosis, pathways to care, symptomatology, social, occupational, and cognitive functioning were comprehensively assessed using standardized measurements. RESULTS: Patients with DD had less premorbid schizoid and schizotypal traits compared to patients with SZ. More patients with DD were married compared to patients with SZ. However, at first episode, there were no significant differences between the two groups in regards to the duration of untreated psychosis, pathways to care, symptom severity, neurocognitive performance, treatment, and functioning. CONCLUSIONS: Our findings challenge previous thinking that patients with DD had better functioning than patients with SZ. This study not only provides an updated perspective into conceptualizing the clinical differences between DD and SZ, but also expands the descriptive account of the two disorders to include the neurocognitive dimension. PMID- 26036593 TI - Photodegradation in Micellar Aqueous Solutions of Erythrosin Esters Derivatives. AB - Strong light absorption and high levels of singlet oxygen production indicate erythrosin B as a viable candidate as a photosensitizer in photodynamic therapy or photodynamic inactivation of microorganisms. Under light irradiation, erythrosin B undergoes a photobleaching process that can decrease the production of singlet oxygen. In this paper, we use thermal lens spectroscopy to investigate photobleaching in micellar solutions of erythrosin ester derivatives: methyl, butyl, and decyl esters in low concentrations of non-ionic micellar aqueous solutions. Using a previously developed thermal lens model, it was possible to determine the photobleaching rate and fluorescence quantum efficiency for dye micelle solutions. The results suggest that photobleaching is related to the intensity of the dye-micelle interaction and demonstrate that the thermal lens technique can be used as a sensitive tool for quantitative measurement of photochemical properties in very diluted solutions. PMID- 26036594 TI - Impacts of visitor number on Kangaroos housed in free-range exhibits. AB - Free range exhibits are becoming increasingly popular in zoos as a means to enhance interaction between visitors and animals. However very little research exists on the impacts of visitors on animal behaviour and stress in free range exhibits. We investigated the effects of visitor number on the behaviour and stress physiology of Kangaroo Island (KI) Kangaroos, Macropus fuliginosus fuliginosus, and Red Kangaroos, Macropus rufus, housed in two free range exhibits in Australian zoos. Behavioural observations were conducted on individual kangaroos at each site using instantaneous scan sampling to record activity (e.g., vigilance, foraging, resting) and distance from the visitor pathway. Individually identifiable faecal samples were collected at the end of each study day and analysed for faecal glucocorticoid metabolite (FGM) concentration. When visitor number increased, both KI Kangaroos and Red Kangaroos increased the time spent engaged in visitor-directed vigilance and KI Kangaroos also increased the time spent engaged in locomotion and decreased the time spent resting. There was no effect of visitor number on the distance kangaroos positioned themselves from the visitor pathway or FGM concentration in either species. While there are limitations in interpreting these results in terms of fear of visitors, there was no evidence of adverse effects animal welfare in these study groups based on avoidance behaviour or stress physiology under the range of visitor numbers that we studied. PMID- 26036592 TI - Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tacrolimus. AB - INTRODUCTION: In rheumatoid arthritis (RA) patients receiving immunosuppressive treatments, vaccination against Streptococcus pneumoniae is recommended. The objective of the study was to evaluate the effects of tacrolimus (TAC) on immune response following administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) in patients with established RA. METHODS: Patients with RA (n = 133) were vaccinated with PPSV23. Patients were classified into TAC (n = 29), methotrexate (MTX) (n = 55), control (n = 35), and TAC/MTX (n = 14) treatment groups. We measured the concentrations of pneumococcal serotypes 6B and 23F by using an enzyme-linked immunosorbent assay and determined antibody functionality by using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI), before and 4 to 6 weeks after vaccination. A positive antibody response was defined as at least a twofold increase in the IgG concentration or as at least a 10-fold increase in the OI. RESULTS: IgG concentrations and OIs were significantly increased in all treatment groups after PPSV23 vaccination. The TAC treatment group appears to respond in a manner similar to that of the RA control group in terms of 6B and 23F serotype concentration and function. In contrast, the MTX group had the lowest immune response. Patients who received a combination of TAC and MTX (TAC/MTX) also had a diminished immune response compared with those who received TAC alone. CONCLUSIONS: TAC monotherapy does not appear to impair PPSV23 immunogenicity in patients with RA, whereas antibody production and function may be reduced when TAC is used with MTX. Thus, PPSV23 administration during ongoing TAC treatment should be encouraged for infection-prone TAC-treated patients with rheumatic diseases. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012. PMID- 26036595 TI - Differences between pulmonologists, thoracic surgeons and radiation oncologists in deciding on the treatment of stage I non-small cell lung cancer: A binary choice experiment. AB - BACKGROUND AND PURPOSE: Surgery is the standard of care in stage I non-small cell lung cancer (NSCLC), but stereotactic ablative radiotherapy (SABR) is increasingly used to treat patients at high-risk for surgical complications. We studied which patient- and clinician-related characteristics influenced treatment recommendations. MATERIAL AND METHODS: A binary choice experiment with hypothetical cases was conducted. Cases varied on five patient-related characteristics: patient age, Chronic Obstructive Pulmonary Disease Global Initiative for Chronic Obstructive Lung Disease (COPD GOLD) score, Charlson co morbidity index, World Health Organization performance status (WHO-PS) and patient treatment preference (surgery/SABR). Clinician characteristics were recorded. Responses were analyzed using generalized linear mixed models. RESULTS: 126 clinicians completed the survey. All patient-related characteristics, the clinician speciality, and whether clinicians considered outcomes of surgery comparable to SABR, significantly influenced treatment recommendations. Pulmonologists were most influenced by WHO-PS and comorbidity, whereas comorbidity and age had greatest influence on radiation oncologists and surgeons. Clinicians were less influenced by stated patient preference and COPD GOLD score. Limited consistency was observed in treatment recommendations. CONCLUSIONS: This study suggests that more efforts are needed to develop uniform approaches for making treatment recommendations, and also to incorporate patient preferences when making treatment decisions for stage I NSCLC. PMID- 26036596 TI - MALDI-TOF mass spectrometry fingerprinting: A diagnostic tool to differentiate dematiaceous fungi Stachybotrys chartarum and Stachybotrys chlorohalonata. AB - Stachybotrys chartarum and Stachybotrys chlorohalonata are two closely related species. Unambiguous identification of these two species is a challenging task if relying solely on morphological criteria and therefore smarter and less labor intensive approaches are needed. Here we show that even such closely related species of fungi as S. chartarum and S. chlorohalonata are unequivocally discriminated by their highly reproducible MALDI-TOF-MS fingerprints (matrix assisted laser desorption/ionization time-of-flight mass spectrometry fingerprints). We examined 19 Stachybotrys and one Aspergillus isolate by MALDI TOF-MS. All but one isolate produced melanin containing conidia on malt extract agar. Mass spectra were obtained in good quality from the analysis of hyaline and darkly pigmented conidia by circumventing the property of melanin which causes signal suppression. MALDI-TOF fingerprint analysis clearly discriminated not only the two morphologically similar species S. chartarum and S. chlorohalonata from each other but separated them precisely from Stachybotrys bisbyi and Aspergillus versicolor isolates. Furthermore, even S. chartarum chemotypes A and S could be differentiated into two distinct groups by their MALDI-TOF fingerprints. The chemotypes of S. chartarum isolates were identified by trichodiene synthase 5 (tri5) sequences prior to mass spectra analysis. Additionally, species identities of all isolates were verified by their 18S rRNA and tri5 gene sequences. PMID- 26036597 TI - A tactile sensor translating texture and sliding motion information into electrical pulses. AB - An electric pulse output by a nanogenerator upon a strain-and-release event resembles a neural impulse. Cutaneous receptors imbedded in skin transduce mechanical forces impinging the skin into neural impulses and the tactile information is encoded into the firing rates of the neural impulses. Here, we report a nanogenerator-type tactile sensor, which records the texture and sliding motion by outputting a sequence of electric pulses. The sensitive component of the device is an NG embedded in a polydimethylsiloxane package. An artificial finger-print serving as a strain introducer mimicking finger prints is integrated over the NG. The electric pulses outputted by the device transmit the texture and sliding motion information. The device demonstrates a capability of detecting punch holes with depth less than 200 MUm on a nonwoven cloth. It also shows a perfect reproducibility of the electric pulses as it scans the same area of a band wire and a piece of nonwoven cloth. The artificial finger-print is the key element in transferring the strain direction, which allows the active sensor (a nanogenerator) beneath to detect the bumpy structure during a touch and sliding motion. PMID- 26036598 TI - Expression of somatostatin receptor subtype 2 in growth hormone-secreting pituitary adenoma and the regulation of miR-185. AB - INTRODUCTION: Long-acting somatostatin analogs (SSAs) are most widely used to treat growth hormone (GH)-secreting pituitary adenoma. However, approximately 30 % of treated patients show resistance to SSAs, which may be associated with the reduction of somatostatin receptor subtype 2 (SSTR2) mRNA and protein expression. MATERIALS AND METHODS: The present study used immunohistochemistry to detect the expression of SSTR2 and SSTR5 in twenty human GH-secreting adenoma samples treated with SSAs and seven normal pituitary samples. RESULTS: The staining intensities of SSTR2 and SSTR5 were stronger in most adenoma samples than in normal pituitary. The expression of SSTR2 tended to be lower in the SSA non responder group than in responders. A search of the Bioinformatics data bank and the miRCURYTM LNA array confirmed miR-185 as the putative mircoRNA (miRNA) regulating the expression of SSTR2. An in vitro study using Dual Luciferase reporter assay demonstrated that miR-185 likely targets the 3'-UTR of SSTR2 mRNA in the rat pituitary adenoma GH3 cell line. MiR-185 also downregulated or upregulated the expression of SSTR2 mRNA and SSTR2 protein, following transfection with miR-185 mimics or inhibitors, respectively. CONCLUSION: MiR-185 enhanced the cell proliferation and inhibited the apoptosis of GH3 cells. PMID- 26036599 TI - A review on the effects of Allium sativum (Garlic) in metabolic syndrome. AB - The metabolic syndrome is a common problem world-wide and includes abdominal obesity, hypertension, dyslipidemia, and hyperglycemia disorders. It leads to insulin resistance and the development of diabetes mellitus or cardiovascular disease. Allium sativum (garlic) has been documented to exhibit anti-diabetic, hypotensive, and hypolipidemic properties. This suggests a potential role of A. sativum in the management of metabolic syndrome; however, more studies should be conducted to evaluate its effectiveness. In this review, we discussed the most relevant articles to find out the role of A. sativum in different components of metabolic syndrome and cardiovascular disease risk factors. Because human reports are rare, further studies are required to establish the clinical value of A. sativum in metabolic syndrome. PMID- 26036600 TI - Predictors of incomplete response to therapy among Filipino patients with papillary thyroid cancer in a tertiary hospital. AB - BACKGROUND: Although survival rate in papillary thyroid cancer (PTC) is high, the risk of persistence and recurrence together with the dramatic rise in its incidence cannot be overemphasized. Filipinos are considered to be at greater risk for negative outcomes. A paradigm shift in the management of PTC introduces re-stratification based on response to therapy which was reported to have better correlation with long-term outcome. The study aimed to identify predictors of incomplete response after thyroidectomy and radioiodine therapy among patients with PTC. The results of the study may have important implications in our understanding of the disease process allowing more aggressive treatment and monitoring of certain subgroups of patients. METHODOLOGY: Retrospective review of 225 patients with PTC (59% ATA low risk, 30 % ATA intermediate risk and 11% ATA high risk) who underwent thyroidectomy and radioiodine therapy was performed. Thirteen variables were considered (age, gender, histopathological variant, stage, extent of disease, MACIS score, AMES score, primary tumour size, lymph node, lymphovascular invasion, bilaterality, multifocality and preoperative TSH level). Logistic regression analysis using Backward Wald algorithm was used to identify independent predictors of incomplete response to therapy after 24 months. RESULTS: Of the 225 patients, 69 (31%) had incomplete response. Biochemical and structural (predominantly thyroid bed, lung and bone) incomplete response was observed in 6 and 63 patients, respectively. Incomplete response was documented in 8, 54 and 92% of low-, intermediate- and high-risk patients based on ATA recommendation. Incomplete response was significantly dependent on gender, lymph node involvement and location, extent of malignancy and multifocality taking into account the size of concurrent tumours (p < 0.05). The model was found to have high sensitivity (71%) and specificity (96%). CONCLUSION: A significant fraction of PTC patients experienced incomplete response to therapy. Our data suggest that male gender, lateral or mediastinal lymph node involvement, class III extent of disease by De Groot and multifocality with concurrent tumour or tumours more than 1 cm are major predictors of incomplete response. Not all predictors of recurrence and mortality are consistent predictors of treatment response which may be equally important in a disease with low mortality but significant morbidity like PTC. PMID- 26036601 TI - Cardiothoracic ratio on chest radiograph in pediatric heart disease: How does it correlate with heart volumes at magnetic resonance imaging? AB - BACKGROUND: The cardiothoracic ratio by chest radiograph is widely used as a marker of cardiac size. OBJECTIVE: The purpose of this study is to correlate cardiothoracic ratio and cardiac volumes as measured by cardiovascular magnetic resonance (MR) in common structural and myopathic heart disease with increased cardiac size due to volume overload or hypertrophy. MATERIAL AND METHODS: A retrospective single center study was performed in all patients between 2007 and 2013 with repaired tetralogy of Fallot (TOF), aortic regurgitation, isolated left to-right shunt and hypertrophic cardiomyopathy (HCM) who underwent cardiovascular MR and chest radiograph within 6 months of each other. Cardiothoracic ratios by chest radiograph (frontal and lateral) were compared to cardiac volumes (indexed for body surface area) by cardiovascular MR. RESULTS: One hundred twenty-seven patients (mean age: 11.2 +/- 5.5 years) were included in this study (76 with TOF, 23 with isolated left-to-right shunt, 16 with aortic regurgitation and 12 with HCM). Frontal cardiothoracic ratio of all groups correlated with indexed right ventricular (RV) end-diastolic volume (EDVI) (r = 0.40, P < 0.01) and indexed total heart volume (THVI) (r = 0.27, P < 0.01). In TOF patients, frontal cardiothoracic ratio correlated with RVEDVI (r = 0.34, P < 0.01; coefficient of variation = 27.6%), indexed RV end-systolic volume (ESVI) (r = 0.44, P < 0.01; coefficient of variation = 33.3%) and THVI (r = 0.35, P < 0.01; coefficient of variation = 19.6%), although RV volumes and THVI showed widespread variation given the high coefficients of variation. In patients with aortic regurgitation, frontal cardiothoracic ratio correlated with left ventricular (LV) EDVI (r = 0.50, P = 0.047), but not with THVI and aortic regurgitant fraction, and widespread variation for LV EDVI (coefficient of variation = 19.2%), LV ESVI (coefficient of variation = 32.5%) and THVI (coefficient of variation = 13.6%) was also observed. Frontal cardiothoracic ratio was not correlated with cardiac volumes or mass in patients with a left-to-right shunt or HCM. Lateral cardiothoracic ratio showed no correlation with any cardiac volume in all four groups. CONCLUSION: Although increased cardiothoracic ratio on frontal chest radiograph is associated with increased biventricular volumes in patients with pulmonary and aortic regurgitation, significant variation in ventricular volumes and total heart volume for any given frontal cardiothoracic ratio limits the use of cardiothoracic ratio in monitoring the individual patient's heart size. Frontal cardiothoracic ratio did not correlate with cardiac chamber volumes in patients with a left-to-right shunt or HCM and lateral cardiothoracic ratio offered no additional value for cardiac size assessment. PMID- 26036602 TI - Factors associated with smoking frequency among current waterpipe smokers in the United States: Findings from the National College Health Assessment II. AB - BACKGROUND: Some waterpipe smokers exhibit nicotine dependent behaviors such as increased use over time and inability to quit, placing them at high risk of adverse health outcomes. This study examines the determinants of dependence by measuring frequency of use among current waterpipe smokers using a large national U.S. METHODS: Data were drawn from four waves (Spring/Fall 2009 and Spring/Fall 2010) of the American College Health Association-National College Health Assessment datasets. The sample was restricted to students who smoked a waterpipe at least once in the past 30 days (N=19,323). Ordered logistic regression modeled the factors associated with higher frequency of waterpipe smoking. RESULTS: Among current waterpipe smokers, 6% used a waterpipe daily or almost daily (20-29 days). Daily cigarette smokers were at higher odds of smoking a waterpipe at higher frequencies compared with non-smokers of cigarettes (OR=1.81; 95% CI=1.61 2.04). There was a strong association between daily cigar smoking and higher frequency of waterpipe smoking (OR=7.77; 95% CI=5.49-11.02). Similarly, students who used marijuana had higher odds of smoking a waterpipe at higher frequencies (OR=1.57; 95% CI=1.37-1.81). CONCLUSIONS: Daily consumers of other addictive substances are at a higher risk of intensive waterpipe smoking and thus higher risk of waterpipe dependence. Intervention programs must incorporate methods to reduce waterpipe dependence and subsequently prevent its deleterious health effects. PMID- 26036604 TI - Drying-Mediated Self-Assembled Growth of Transition Metal Dichalcogenide Wires and their Heterostructures. PMID- 26036603 TI - Alcohol problem recognition and help seeking in adolescents and young adults at varying genetic and environmental risk. AB - INTRODUCTION: Alcohol use disorder symptoms frequently occur in adolescents and younger adults who seldom acknowledge a need for help. We identified sociodemographic, clinical, and familial predictors of alcohol problem recognition and help seeking in an offspring of twin sample. METHOD: We analyzed longitudinal data from the Children of Alcoholics and Twins as Parents studies, which are combinable longitudinal data sources due to their equivalent design. We analyzed respondents (n=1073, 56.0% of the total sample) with alcohol use disorder symptoms at the baseline interview. Familial characteristics included perceptions of alcohol problems and help seeking for alcohol problems within the immediate family and a categorical variable indicating genetic and environmental risk. We used logistic regression to examine predictors of alcohol problem recognition and help seeking. RESULTS: Approximately 25.9% recognized their alcohol problems and 26.7% sought help for drinking. In covariate-adjusted analyses, help seeking among family members predicted problem recognition, several clinical characteristics predicted both problem recognition and help seeking, and familial risk predicted help seeking. Alcohol problem recognition mediated the association between alcohol use disorder symptoms and incident help seeking. CONCLUSIONS: Facilitating the self-recognition of alcohol use disorder symptoms, and perhaps the awareness of family members' help seeking for alcohol problems, may be potentially promising methods to facilitate help seeking. PMID- 26036606 TI - Electronic and Chemical State of Aluminum from the Single- (K) and Double Electron Excitation (KLII&III, KLI) X-ray Absorption Near-Edge Spectra of alpha Alumina, Sodium Aluminate, Aqueous Al(3+).(H2O)6, and Aqueous Al(OH)4(-). AB - We probe, at high energy resolution, the double electron excitation (KLII&II) X ray absorption region that lies approximately 115 eV above the main Al K-edge (1566 eV) of alpha-alumina and sodium aluminate. The two solid standards, alpha alumina (octahedral) and sodium aluminate (tetrahedral), are compared to aqueous species that have the same Al coordination symmetries, Al(3+).6H2O (octahedral) and Al(OH)4(-) (tetrahedral). For the octahedral species, the edge height of the KLII&III-edge is approximately 10% of the main K-edge; however, the edge height is much weaker (3% of K-edge height) for Al species with tetrahedral symmetry. For the alpha-alumina and aqueous Al(3+).6H2O the KLII&III spectra contain white line features and extended absorption fine structure (EXAFS) that mimics the K edge spectra. The KLII&III-edge feature interferes with an important region in the EXAFS spectra of the crystalline and aqueous standards. The K-edge spectra and K-edge energy positions are predicted using time-dependent density functional theory (TDDFT). The TDDFT calculations for the K-edge X-ray absorption near-edge spectra (XANES) reproduce the observed transitions in the experimental spectra of the four Al species. The KLII&II and KLI onsets and their corresponding chemical shifts for the four standards are estimated using the delta self-consistent field (DeltaSCF) method. PMID- 26036605 TI - Indication for cataract surgery. Do we have evidence of who will benefit from surgery? A systematic review and meta-analysis. AB - The need for cataract surgery is expected to rise dramatically in the future due to the increasing proportion of elderly citizens and increasing demands for optimum visual function. The aim of this study was to provide an evidence-based recommendation for the indication of cataract surgery based on which group of patients are most likely to benefit from surgery. A systematic literature search was performed in the MEDLINE, CINAHL, EMBASE and COCHRANE LIBRARY databases. Studies evaluating the outcome after cataract surgery according to preoperative visual acuity and visual complaints were included in a meta-analysis. We identified eight observational studies comparing outcome after cataract surgery in patients with poor (<20/40) and fair (>20/40) preoperative visual acuity. We could not find any studies that compared outcome after cataract surgery in patients with few or many preoperative visual complaints. A meta-analysis showed that the outcome of cataract surgery, evaluated as objective and subjective visual improvement, was independent on preoperative visual acuity. There is a lack of scientific evidence to guide the clinician in deciding which patients are most likely to benefit from surgery. To overcome this shortage of evidence, many systems have been developed internationally to prioritize patients on waiting lists for cataract surgery, but the Swedish NIKE (Nationell Indikationsmodell for Katarakt Ekstraktion) is the only system where an association to the preoperative scoring of a patient has been related to outcome of cataract surgery. We advise that clinicians are inspired by the NIKE system when they decide which patients to operate to ensure that surgery is only offered to patients who are expected to benefit from cataract surgery. PMID- 26036607 TI - Nutritional status and eating habits of the institutionalised elderly in Turkey: a follow-up study. AB - BACKGROUND: As the elderly population increases in Turkey, so do the associated health and nutritional problems. The main purpose of the present study was to determine the nutritional status of elderly individuals who live in institutions. METHODS: A total of 102 elderly volunteers was recruited from seven residential homes of the Ministry of Family and Social Policies in Ankara. In the consecutive years of 2007, 2008 and 2009, dietary intake was assessed using a 24-h food recall. Nutritional status was screened using a questionnaire from the Mini Nutritional Assessment, basic characteristics were determined and anthropometric measurements were assessed. RESULTS: The percentage of elderly participants who were malnourished or at risk for malnutrition increased by the completion of the follow-up (P < 0.05). It was found that energy, total protein, animal proteins, carbohydrates, niacin, vitamin C, vitamin E and zinc intake of men decreased significantly over the years studied (P < 0.05). A significant decrease occurred among women in animal protein, vitamin B1 , niacin and the percentage of energy from proteins (P < 0.05); however, an increase in energy from fat (P < 0.05) was determined. Within the years studied, the percentage of nutrients meeting the Turkish recommended daily allowances decreased from 2007 to 2009 both in men and women. During the years 2007 to 2009, the percentage of waist circumferences >102 cm for men was 46.4%, 45.6% and 48.1%, respectively, and the percentage of waist circumferences for women >88 cm was 75.6%, 75.6% and 81.8%, respectively. CONCLUSIONS: During the follow-up, significant nutritional changes were determined. To prevent malnutrition, periodical screening of nutritional status should be a priority and a standard policy for elderly people, especially for those institutionalised. PMID- 26036608 TI - Internal fixation of fragility fractures of the femoral neck. PMID- 26036609 TI - A systematic study of normalization methods for Infinium 450K methylation data using whole-genome bisulfite sequencing data. AB - DNA methylation plays an important role in disease etiology. The Illumina Infinium HumanMethylation450 (450K) BeadChip is a widely used platform in large scale epidemiologic studies. This platform can efficiently and simultaneously measure methylation levels at ~480,000 CpG sites in the human genome in multiple study samples. Due to the intrinsic chip design of 2 types of chemistry probes, data normalization or preprocessing is a critical step to consider before data analysis. To date, numerous methods and pipelines have been developed for this purpose, and some studies have been conducted to evaluate different methods. However, validation studies have often been limited to a small number of CpG sites to reduce the variability in technical replicates. In this study, we measured methylation on a set of samples using both whole-genome bisulfite sequencing (WGBS) and 450K chips. We used WGBS data as a gold standard of true methylation states in cells to compare the performances of 8 normalization methods for 450K data on a genome-wide scale. Analyses on our dataset indicate that the most effective methods are peak-based correction (PBC) and quantile normalization plus beta-mixture quantile normalization (QN.BMIQ). To our knowledge, this is the first study to systematically compare existing normalization methods for Illumina 450K data using novel WGBS data. Our results provide a benchmark reference for the analysis of DNA methylation chip data, particularly in white blood cells. PMID- 26036610 TI - The power of the context map: Designing realistic outcome evaluation strategies and other unanticipated benefits. AB - Developing a feasible evaluation plan is challenging when multiple activities, often sponsored by multiple agencies, work together toward a common goal. Often, resources are limited and not every agency's interest can be represented in the final evaluation plan. The article illustrates how the Antecedent Target Measurement (ATM) approach to logic modeling was adapted to meet this challenge. The key adaptation is the context map generated in the first step of the ATM approach. The context map makes visually explicit many of the underlying conditions contributing to a problem as possible. The article also shares how a prioritization matrix can assist the evaluator in filtering through the context map to prioritize the outcomes to be included in the final evaluation plan as well as creating realistic outcomes. This transparent prioritization process can be especially helpful in managing evaluation expectations of multiple agencies with competing interests. Additional strategic planning benefits of the context map include pinpointing redundancies caused by overlapping collaborative efforts, identifying gaps in coverage, and assisting the coordination of multiple stakeholders. PMID- 26036611 TI - Training and capacity building evaluation: Maximizing resources and results with Success Case Method. AB - This article describes the use of Success Case Method (Brinkerhoff, 2003) to evaluate health promotion and public health training programs. The goal of the Office Community Research and Engagement (OCRE) of the Puerto Rico Clinical and Translational Research Consortium (PRCTRC) is to establish a stable and sustainable translational research capacity. Early efforts toward achieving this goal included sponsoring two independent research training programs. A description of the implementation of the five step Success Case Method is presented. Results reveal that SCM would deem both trainings as highly successful, based upon the overall impact of a low number of success cases. However, a traditional summative evaluation would consider this disappointing. Strengths of SCM are discussed. It was concluded that the Success Case Method is a useful and valuable evaluative method for measuring the success of health promotion and public health training initiatives and provides sufficient information for decision-making processes. PMID- 26036612 TI - The Father Friendly Initiative within Families: Using a logic model to develop program theory for a father support program. AB - The transition to fatherhood, with its numerous challenges, has been well documented. Likewise, fathers' relationships with health and social services have also begun to be explored. Yet despite the problems fathers experience in interactions with healthcare services, few programs have been developed for them. To explain this, some authors point to the difficulty practitioners encounter in developing and structuring the theory of programs they are trying to create to promote and support father involvement (Savaya, R., & Waysman, M. (2005). Administration in Social Work, 29(2), 85), even when such theory is key to a program's effectiveness (Chen, H.-T. (2005). Practical program evaluation. Thousand Oaks, CA: Sage Publications). The objective of the present paper is to present a tool, the logic model, to bridge this gap and to equip practitioners for structuring program theory. This paper addresses two questions: (1) What would be a useful instrument for structuring the development of program theory in interventions for fathers? (2) How would the concepts of a father involvement program best be organized? The case of the Father Friendly Initiative within Families (FFIF) program is used to present and illustrate six simple steps for developing a logic model that are based on program theory and demonstrate its relevance. PMID- 26036613 TI - Prevalence of mood disturbance in Australian adults with chronic spinal cord injury. AB - BACKGROUND: There is little understanding of the prevalence of mental health issues in people with spinal cord injury (SCI) after they leave rehabilitation or how mental health issues can alter over time. AIM: The aims were to (i) determine the prevalence of mood disturbance in adults with chronic SCI living in the community, (ii) ascertain whether the prevalence of mood disturbance had changed since a previous study in 2004-2005 and (iii) establish whether people with chronic SCI remain vulnerable to mood disturbance, irrespective of time since injury. METHODS: Prospective, open-cohort case series. Participants were 573 community-based adults with a chronic SCI. The depression, anxiety and stress scale - short version was used. Analyses included simple descriptors, Chi-squared and repeated measures t-tests. RESULTS: Nearly half of participants (n = 263/573; 46%) reported symptoms indicating mood disturbance, which was similar to the level found in the previous study. While the presence of mood disturbance persisted in 23% of adults (n = 26) and 46 (41%) were in the 'below threshold' category, just over a third of the adults who participated in both studies (n = 111) experienced a change (n = 21, 19% mood disturbance resolved and n = 18, 16% mood disturbance developed). CONCLUSION: Both resilience and change are common. At no time after SCI is the risk of mental health problems considered reduced or even stable. These results highlight the importance of regular mental health reviews even in those who have previously displayed good resilience. PMID- 26036616 TI - Seeded on-surface supramolecular growth for large area conductive donor-acceptor assembly. AB - Charge transport features of organic semiconductor assemblies are of paramount importance. However, large-area extended supramolecular structures of donor acceptor combinations with controlled self-assembly pathways are hardly accessible. In this context, as a representative example, seeded on-surface supramolecular growth of tetrathiafulvalene and tetracyano-p-quinodimethane (TTF TCNQ) using active termini of solution-formed sheaves has been introduced to form an extended assembly. We demonstrate for the first time, the creation of a large area donor-acceptor assembly on the surface, which is practically very tedious, using a seeded, evaporation-assisted growth process. The excellent molecular ordering in this assembly is substantiated by its good electrical conductivity (~10-2 S cm-1). The on-surface assembly via both internally formed and externally added sheaf-like seeds open new pathways in supramolecular chemistry and device applications. PMID- 26036615 TI - Cellulose-Pectin Spatial Contacts Are Inherent to Never-Dried Arabidopsis Primary Cell Walls: Evidence from Solid-State Nuclear Magnetic Resonance. AB - The structural role of pectins in plant primary cell walls is not yet well understood because of the complex and disordered nature of the cell wall polymers. We recently introduced multidimensional solid-state nuclear magnetic resonance spectroscopy to characterize the spatial proximities of wall polysaccharides. The data showed extensive cross peaks between pectins and cellulose in the primary wall of Arabidopsis (Arabidopsis thaliana), indicating subnanometer contacts between the two polysaccharides. This result was unexpected because stable pectin-cellulose interactions are not predicted by in vitro binding assays and prevailing cell wall models. To investigate whether the spatial contacts that give rise to the cross peaks are artifacts of sample preparation, we now compare never-dried Arabidopsis primary walls with dehydrated and rehydrated samples. One-dimensional (13)C spectra, two-dimensional (13)C (13)C correlation spectra, water-polysaccharide correlation spectra, and dynamics data all indicate that the structure, mobility, and intermolecular contacts of the polysaccharides are indistinguishable between never-dried and rehydrated walls. Moreover, a partially depectinated cell wall in which 40% of homogalacturonan is extracted retains cellulose-pectin cross peaks, indicating that the cellulose-pectin contacts are not due to molecular crowding. The cross peaks are observed both at -20 degrees C and at ambient temperature, thus ruling out freezing as a cause of spatial contacts. These results indicate that rhamnogalacturonan I and a portion of homogalacturonan have significant interactions with cellulose microfibrils in the native primary wall. This pectin cellulose association may be formed during wall biosynthesis and may involve pectin entrapment in or between cellulose microfibrils, which cannot be mimicked by in vitro binding assays. PMID- 26036614 TI - Ethylene Biosynthesis Is Promoted by Very-Long-Chain Fatty Acids during Lysigenous Aerenchyma Formation in Rice Roots. AB - In rice (Oryza sativa) roots, lysigenous aerenchyma, which is created by programmed cell death and lysis of cortical cells, is constitutively formed under aerobic conditions, and its formation is further induced under oxygen-deficient conditions. Ethylene is involved in the induction of aerenchyma formation. reduced culm number1 (rcn1) is a rice mutant in which the gene encoding the ATP binding cassette transporter RCN1/OsABCG5 is defective. Here, we report that the induction of aerenchyma formation was reduced in roots of rcn1 grown in stagnant deoxygenated nutrient solution (i.e. under stagnant conditions, which mimic oxygen-deficient conditions in waterlogged soils). 1-Aminocyclopropane-1 carboxylic acid synthase (ACS) is a key enzyme in ethylene biosynthesis. Stagnant conditions hardly induced the expression of ACS1 in rcn1 roots, resulting in low ethylene production in the roots. Accumulation of saturated very-long-chain fatty acids (VLCFAs) of 24, 26, and 28 carbons was reduced in rcn1 roots. Exogenously supplied VLCFA (26 carbons) increased the expression level of ACS1 and induced aerenchyma formation in rcn1 roots. Moreover, in rice lines in which the gene encoding a fatty acid elongase, CUT1-LIKE (CUT1L; a homolog of the gene encoding Arabidopsis CUT1, which is required for cuticular wax production), was silenced, both ACS1 expression and aerenchyma formation were reduced. Interestingly, the expression of ACS1, CUT1L, and RCN1/OsABCG5 was induced predominantly in the outer part of roots under stagnant conditions. These results suggest that, in rice under oxygen-deficient conditions, VLCFAs increase ethylene production by promoting 1-aminocyclopropane-1-carboxylic acid biosynthesis in the outer part of roots, which, in turn, induces aerenchyma formation in the root cortex. PMID- 26036617 TI - Patterns of Food Consumption are Associated with Obesity, Self-Reported Diabetes and Cardiovascular Disease in Five American Indian Communities. AB - The relationship between dietary patterns and chronic disease is underexplored in indigenous populations. We assessed diets of 424 American Indian (AI) adults living in 5 rural AI communities. We identified four food patterns. Increased prevalence for cardiovascular disease was highly associated with the consumption of unhealthy snacks and high fat-food patterns (OR 3.6, CI=1.06, 12.3; and OR 6.0, CI=1.63, 22.1), respectively. Moreover, the food-consumption pattern appeared to be different by community setting (p<.05). We recommend culturally appropriate community-intervention programs to promote healthy behavior and to prevent diet-related chronic diseases in this high-risk population. PMID- 26036618 TI - Practical mental health screening in pediatric epilepsy. PMID- 26036619 TI - Thoughts from the clinic: Marijuana, is it medicine or recreational drug? PMID- 26036620 TI - An Evaluation of the Identification and Management of Overweight and Obesity in a Pediatric Clinic. AB - With the rise in overweight and obesity in children, it is imperative for health care providers to routinely address appropriate body mass index for children during primary care visits. The purposes of this project were to determine if overweight and obese children are accurately being identified and to evaluate provider adherence to American Academy of Pediatrics guidelines for the management of obesity. A retrospective chart review was completed for all children ages 2, 6, and 10 years who presented for a well-child visit from January 1, 2011, through June 30, 2011. Based on a review of 255 charts, 21.6% of patients were overweight and 18.4% were obese according to standards of the Centers for Disease Control and Prevention. Of these children, 34% were properly documented as being either overweight or obese, and documentation was lacking for the remaining 66%. Of the children correctly identified as being overweight or obese, only 11% and 26%, respectively, were counseled on therapeutic lifestyle changes, including diet and exercise. This review provides evidence that providers have opportunities to intervene early with well-child examinations and that providers have great room for improvement on counseling overweight and obese children. PMID- 26036622 TI - Curcumin Inhibits Invasiveness and Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma Through Reducing Matrix Metalloproteinase 2, 9 and Modulating p53-E-Cadherin Pathway. AB - HYPOTHESES: Epithelial-mesenchymal transition (EMT) and invasion play a critical role in cancer progression and metastasis. We have shown that low E-cadherin and high Twist expression are significantly correlated with prognostic survival prediction in oral squamous cell carcinoma (OSCC). This study aimed to determine the anti-invasive effect of curcumin on the expression of matrix metalloproteinases (MMPs) and of EMT regulators in OSCC. METHODS: SCC-25 cells were treated with curcumin, and cell proliferation, invasion, and expression of MMPs and EMT regulators were assessed for cell viability by trypan blue exclusion, for invasion by Matrigel invasion chamber, and for EMT regulators and MMP changes in the levels of proteins by immunoblotting. RESULTS: Our data showed that curcumin treatment not only decreased the expression of MMP-2 and MMP-9 to inhibit invasiveness in oral cancer but also modulated the expression of EMT markers, such as Snail, Twist, and E-cadherin, and induced p53 expression that is crucial to EMT repression. CONCLUSION: Curcumin has the potential to become an adjunctive regimen for the prevention of cancer progression and metastasis in oral cancer. PMID- 26036621 TI - Stress and Quality of Life in Urban Caregivers of Children With Poorly Controlled Asthma: A Longitudinal Analysis. AB - INTRODUCTION: The intent of this analysis was to examine the longitudinal effects of risk and protective factors on quality of life (QOL) in caregivers of minority children with asthma. METHOD: Caregivers (n = 300) reported on demographics, child asthma characteristics, daily asthma caregiving stress, general life stress, social support, and QOL. Latent growth curve modeling examined changes in QOL across 12 months as a function of stress, asthma control, and social support. RESULTS: Caregivers were primarily the biological mother (92%), single (71%), unemployed (55%), and living in poverty. Children were African American (96%), Medicaid eligible (92%), and had poorly controlled asthma (93%). Lower QOL was associated with higher life stress, greater asthma caregiving stress, and lower asthma control over time. DISCUSSION: Findings underscore the importance of assessing objective and subjective measures of asthma burden and daily life stress in clinical encounters with urban, low-income caregivers of children with poorly controlled asthma. PMID- 26036623 TI - A Randomized Controlled Study to Determine the Efficacy of Garlic Compounds in Patients With Hematological Malignancies at Risk for Chemotherapy-Related Febrile Neutropenia. AB - BACKGROUND: Patients receiving chemotherapy for hematological malignancies are at high risk for febrile neutropenia (FN). Garlic extracts (GEs) are natural food substances showing antimicrobial effects in vivo. OBJECTIVES: We explored whether adding GE may be efficacious in reducing the risk or severity of infections. DESIGN: This was a placebo-controlled double-blind randomized study. RESULTS: Of 95 patients randomized to receive GE or placebo following chemotherapy, a febrile episode was documented in 50% of patients receiving GE and 63.3% receiving placebo (P = .89). There was a higher risk of developing a third and fourth febrile episode in the GE group (P = .01). However, among those at a lower risk for FN, those receiving GE developed fewer FN episodes (P = .075), especially those with severe neutropenia (P = .05). Major adverse events were distributed equally, but nonadherence was more common in the GE than in the placebo group: 19.5% versus 4%, respectively (P = .05). CONCLUSIONS: GE was safe and did not reduce FN risk in the entire cohort, but yet appeared to exert a protective effect in the lower-risk subgroup. We do not recommend the use of GE for FN prevention in higher-risk patients. A larger-scale clinical trial for the lower risk subgroup of patients is advocated. (This trial was registered at www.clinicaltrials.gov as NCT00247039.). PMID- 26036624 TI - Antitumor Effects of Purified Protosappanin B Extracted From Lignum Sappan. AB - HYPOTHESIS: To assess the antitumor effects of protosappanin B extracted from Lignum Sappan. STUDY DESIGN: Lignum Sappan was sequentially extracted by boiling water and ethyl acetate. The resulting extract was separated by column chromatography, to yield protosappanin B. The compound was then identified by thin-layer chromatography, high-performance liquid chromatography, elemental analysis, and spectrometry (infrared and ultraviolet). The effects on tumor cell viability and growth of purified protosappanin B were evaluated in vitro by trypan blue exclusion and MTT assays, respectively. And the effects of protosappanin B were assessed in vivo, on H22 mouse liver cancer cell invasion and the survival of tumor-bearing mice. RESULTS: Protosappanin B (2 mg/mL) reduced the viability of human bladder cancer T24 cells and mouse bladder cancer BTT cells in a time-dependent manner (P < .05) and significantly inhibited the growth of the human colon cancer cell lines HCT-116 and SW-480. IC50 values of 21.32, 26.73, and 76.53 ug/mL were obtained for SW-480, HCT-116, and BTT cells, respectively, after 48 hours of treatment with protosappanin B. In addition, pretreatment of H22 cells with protosappanin B (final concentration = 6.25 mg/mL) resulted in complete inhibition of tumor formation in KM mice. Furthermore, protosappanin B (200 and 300 mg/kg) significantly increased the survival of BTT tumor-bearing T739 mice, at a rate comparable to that of 1 mg/kg mitomycin. CONCLUSION: Protosappanin B extracted from Lignum Sappan exerts marked antitumor effects both in vitro and in vivo. PMID- 26036625 TI - Necrosis targeted radiotherapy with iodine-131-labeled hypericin to improve anticancer efficacy of vascular disrupting treatment in rabbit VX2 tumor models. AB - A viable rim of tumor cells surrounding central necrosis always exists and leads to tumor recurrence after vascular disrupting treatment (VDT). A novel necrosis targeted radiotherapy (NTRT) using iodine-131-labeled hypericin (131I-Hyp) was specifically designed to treat viable tumor rim and improve tumor control after VDT in rabbit models of multifocal VX2 tumors. NTRT was administered 24 hours after VDT. Tumor growth was significantly slowed down by NTRT with a smaller tumor volume and a prolonged tumor doubling time (14.4 vs. 5.7 days), as followed by in vivo magnetic resonance imaging over 12 days. The viable tumor rims were well inhibited in NTRT group compared with single VDT control group, as showed on tumor cross sections at day 12 (1 vs. 3.7 in area). High targetability of 131I Hyp to tumor necrosis was demonstrated by in vivo SPECT as high uptake in tumor regions lasting over 9 days with 4.26 to 98 times higher radioactivity for necrosis versus the viable tumor and other organs by gamma counting, and with ratios of 7.7-11.7 and 10.5-13.7 for necrosis over peri-tumor tissue by autoradiography and fluorescence microscopy, respectively. In conclusion, NTRT improved the anticancer efficacy of VDT in rabbits with VX2 tumors. PMID- 26036627 TI - Down regulation of Akirin-2 increases chemosensitivity in human glioblastomas more efficiently than Twist-1. AB - The Twist-1 transcription factor and its interacting protein Akirin-2 regulate apoptosis. We found that in glioblastomas, highly malignant brain tumors, Akirin 2 and Twist-1 were expressed in glial fibrillary acidic protein positive tumor regions as well as in tumor endothelial cells and infiltrating macrophages / microglia. Temozolomide (TMZ) induced the expression of both molecules, partly shifting their nuclear to cytosolic localization. The knock-down (kd) of Akirin-2 increased the activity of cleaved (c)Caspase-3/-7, the amounts of cCaspases-3, -7 and cPARP-1 and resulted in an increased number of apoptotic cells after TMZ exposure. Glioblastoma cells containing decreased amounts of Akirin-2 after kd contained increased amounts of cCaspase-3 as determined by the ImageStreamx Mark II technology. For Twist-1, similar results were obtained with the exception that the combination of TMZ treatment and Twist-1 kd failed to significantly reduce chemoresistance compared with controls. This could be attributed to a cell population containing only slightly increased cCaspase-3 together with decreased Twist-1 levels, which was clearly larger than the respective population observed under Akirin-2 kd. Our results showed that, compared with Twist-1, Akirin-2 is the more promising target for RNAi strategies antagonizing Twist-1/Akirin-2 facilitated glioblastoma cell survival. PMID- 26036626 TI - Identification of novel genes that regulate androgen receptor signaling and growth of androgen-deprived prostate cancer cells. AB - Prostate cancer progression to castration refractory disease is associated with anomalous transcriptional activity of the androgen receptor (AR) in an androgen depleted milieu. To identify novel gene products whose downregulation transactivates AR in prostate cancer cells, we performed a screen of enzymatically-generated shRNA lenti-libraries selecting for transduced LNCaP cells with elevated expression of a fluorescent reporter gene under the control of an AR-responsive promoter. The shRNAs present in selected populations were analyzed using high-throughput sequencing to identify target genes. Highly enriched gene targets were then validated with siRNAs against selected genes, testing first for increased expression of luciferase from an AR-responsive promoter and then for altered expression of endogenous androgen-regulated genes in LNCaP cells. We identified 20 human genes whose silencing affected the expression of exogenous and endogenous androgen-responsive genes in prostate cancer cells grown in androgen-depleted medium. Knockdown of four of these genes upregulated the expression of endogenous AR targets and siRNAs targeting two of these genes (IGSF8 and RTN1) enabled androgen-independent proliferation of androgen-dependent cells. The effects of IGSF8 appear to be mediated through its interaction with a tetraspanin protein, CD9, previously implicated in prostate cancer progression. Remarkably, homozygous deletions of IGSF8 are found almost exclusively in prostate cancers but not in other cancer types. Our study shows that androgen independence can be achieved through the inhibition of specific genes and reveals a novel set of genes that regulate AR signaling in prostate cancers. PMID- 26036628 TI - Honokiol abrogates leptin-induced tumor progression by inhibiting Wnt1-MTA1-beta catenin signaling axis in a microRNA-34a dependent manner. AB - Obesity greatly influences risk, progression and prognosis of breast cancer. As molecular effects of obesity are largely mediated by adipocytokine leptin, finding effective novel strategies to antagonize neoplastic effects of leptin is desirable to disrupt obesity-cancer axis. Present study is designed to test the efficacy of honokiol (HNK), a bioactive polyphenol from Magnolia grandiflora, against oncogenic actions of leptin and systematically elucidate the underlying mechanisms. Our results show that HNK significantly inhibits leptin-induced breast-cancer cell-growth, invasion, migration and leptin-induced breast-tumor xenograft growth. Using a phospho-kinase screening array, we discover that HNK inhibits phosphorylation and activation of key molecules of leptin-signaling network. Specifically, HNK inhibits leptin-induced Wnt1-MTA1-beta-catenin signaling in vitro and in vivo. Finally, an integral role of miR-34a in HNK mediated inhibition of Wnt1-MTA1-beta-catenin axis was discovered. HNK inhibits Stat3 phosphorylation, abrogates its recruitment to miR-34a promoter and this release of repressor-Stat3 results in miR-34a activation leading to Wnt1-MTA1 beta-catenin inhibition. Accordingly, HNK treatment inhibited breast tumor growth in diet-induced-obese mouse model (exhibiting high leptin levels) in a manner associated with activation of miR-34a and inhibition of MTA1-beta-catenin. These data provide first in vitro and in vivo evidence for the leptin-antagonist potential of HNK revealing a crosstalk between HNK and miR34a and Wnt1-MTA1-beta catenin axis. PMID- 26036629 TI - Functional role of DNA mismatch repair gene PMS2 in prostate cancer cells. AB - DNA mismatch repair (MMR) enzymes act as proofreading complexes that maintains genomic integrity and MMR-deficient cells show an increased mutation rate. MMR has also been shown to influence cell signaling and the regulation of tumor development. MMR consists of various genes and includes post-meiotic segregation (PMS) 2 which is a vital component of mutL-alpha. In prostate, the functional role of this gene has never been reported and in this study, our aim was to investigate the effect of PMS2 on growth properties of prostate cancer (PCa) cells. Previous studies have shown PMS2 to be deficient in DU145 cells and this lack of expression was confirmed by Western blotting whereas normal prostatic PWR 1E and RWPE-1 cells expressed this gene. PMS2 effects on various growth properties of DU145 were then determined by creating stable gene transfectants. Interestingly, PMS2 caused decreased cell proliferation, migration, invasion, and in vivo growth; and increased apoptosis as compared to vector control. We further analyzed genes affected by PMS2 expression and observe the apoptosis-related TMS1 gene to be significantly upregulated whereas anti-apoptotic BCL2A1 was downregulated. These results demonstrate a functional role for PMS2 to protect against PCa progression by enhancing apoptosis of PCa cells. PMID- 26036630 TI - Absolute quantification of cell-free microRNAs in cancer patients. AB - The hypothesis to use microRNAs (miRNAs) circulating in the blood as cancer biomarkers was formulated some years ago based on promising initial results. After some exciting discoveries, however, it became evident that the accurate quantification of cell-free miRNAs was more challenging than expected. Difficulties were linked to the strong impact that many, if not all, pre- and post- analytical variables have on the final results. In this study, we used currently available high-throughput technologies to identify miRNAs present in plasma and serum of patients with breast, colorectal, lung, thyroid and melanoma tumors, and healthy controls. Then, we assessed the absolute level of nine different miRNAs (miR-320a, miR-21-5p, miR-378a-3p, miR-181a-5p, miR-3156-5p, miR 2110, miR-125a-5p, miR-425-5p, miR-766-3p) in 207 samples from healthy controls and cancer patients using droplet digital PCR (ddPCR) technology. We identified miRNAs specifically modulated in one or more cancer types, according to tissue source. The significant reduction of miR-181a-5p levels in breast cancer patients serum was further validated using two independent cohorts, one from Italy (n = 70) and one from US (n = 90), with AUC 0.66 and 0.73 respectively. This study finally powers the use of cell-free miRNAs as cancer biomarkers and propose miR 181a-5p as a diagnostic breast cancer biomarker. PMID- 26036631 TI - The 14-3-3sigma/GSK3beta/beta-catenin/ZEB1 regulatory loop modulates chemo sensitivity in human tongue cancer. AB - Here we demonstrated that chemotherapy induced 14-3-3sigma expression in tongue cancer (TC) cells and overexpressed 14-3-3sigma sensitized TC cells to chemotherapy especially in multidrug resistant TC (MDR-TC) cells. In agreement, 14-3-3sigma knockdown enhanced resistance of TC cells to chemotherapy. Mechanically, we found 14-3-3sigma physically bound to GSK3beta in protein level and the binding inhibited beta-catenin signaling. Coincidentally, chemotherapy as well as 14-3-3sigma overexpression led to increase of GSK3beta protein level. Increased GSK3beta protein sensitized TC cells to chemotherapy. Moreover, deregulation of 14-3-3sigma/GSK3beta/beta-catenin axis led to overexpressed ZEB1 in TC cells, especially in MDR-TC cells. As a negative feedback loop, ZEB1 bond to 14-3-3sigma promoter to enhance promoter hypermethylation in TC cells. Promoter hypermethylation resulted into the decrease of 14-3-3sigma expression. Importantly, a positive correlation was observed between 14-3-3sigma and GSK3beta protein expression in TC tissues from patients receiving chemotherapy. High levels of 14-3-3sigma and GSK3beta were associated with better prognosis in TC patients. PMID- 26036632 TI - Exploiting the potential of autophagy in cisplatin therapy: A new strategy to overcome resistance. AB - Resistance to cisplatin is a major challenge in the current cancer therapy. In order to explore new therapeutic strategies to cisplatin resistance, we evaluated, in a model of lung cancer (H1299 and H460 cell lines), the nature of the pathways leading to cell death. We observed that H1299 displayed a natural resistance to cisplatin due to an inability to trigger an apoptotic response that correlates with the induction of autophagy. However, pharmacological and genetic approaches showed how autophagy was a mechanism associated to cell death rather than to resistance. Indeed, pro-autophagic stimuli such as mTOR or Akt inhibition mediate cell death in both cell lines to a similar extent. We next evaluated the response to a novel platinum compound, monoplatin, able to promote cell death in an exclusive autophagy-dependent manner. In this case, no differences were observed between both cell lines. Furthermore, in response to monoplatin, two molecular hallmarks of cisplatin response (p53 and MAPKs) were not implicated, indicating the ability of this pro-autophagic compound to overcome cisplatin resistance. In summary, our data highlight how induction of autophagy could be used in cisplatin resistant tumours and an alternative treatment for p53 mutated patient in a synthetic lethally approach. PMID- 26036633 TI - MiR-1 downregulation correlates with poor survival in clear cell renal cell carcinoma where it interferes with cell cycle regulation and metastasis. AB - MicroRNAs (miRNA) that are strongly implicated in carcinogenesis have recently reshaped our understanding of the role of noncoding RNAs. Here, we focused on the function and molecular mechanism of miR-1 and its potential clinical application in clear cell renal cell carcinoma (ccRCC). First, miR-1 was significantly downregulated in 87.8% renal cancer samples compared with corresponding noncancerous tissues (NCT), which was significantly associated with clinical stage, T classification and poor overall survival. Functional study demonstrated that enforced overexpression of miR-1 in renal cancer cells inhibited proliferation and metastasis in vitro and in vivo. Conversely, miR-1 inhibitor silencing miR-1 expression promoted cell proliferation and metastasis in ccRCC. CDK4, CDK6, Caprin1 and Slug were each directly targeted for inhibition by miR-1 and restoring their expression reversed miR-1-mediated inhibition of cell cycle progression and metastasis. Taken together, our findings established a tumor suppressive role for miR-1 in the progression of ccRCC by targeting CDK4, CDK6, Caprin1 and Slug and suggested miR-1 can be served as a novel potential therapeutic target for ccRCC. PMID- 26036634 TI - Lapatinib promotes the incidence of hepatotoxicity by increasing chemotherapeutic agent accumulation in hepatocytes. AB - Lapatinib has been used in combination with capecitabine or paclitaxel to treat patients with progressive HER2-overexpressing metastatic breast cancer (MBC). Unfortunately, an increased incidence of hepatotoxicity had been reported in the combinational therapy. The aim of this study was to investigate the potential mechanisms of this combinational therapy. We found that the patients receiving lapatinib and paclitaxel treatment showed a higher incidence of hepatobiliary system disorders than those receiving paclitaxel alone. Lapatinib was shown to increase the accumulation of doxorubicin in ABCB1-overexpressing hepatocellular cancer cells and normal liver tissues without altering the protein level of ABCB1. Pharmacokinetic studies revealed that lapatinib could increase the systematic exposure of paclitaxel and doxorubicin. Moreover, the in vivo experiments showed that the levels of alanine aminotransferase and serious hepatocyte injury in the group of lapatinib plus chemotherapeutic agent were significantly higher than those in the group of single chemotherapeutic agent such as paclitaxel or doxorubicin. Our study thus revealed for the first time that the higher incidence of hepatotoxicity during this combinational treatment was due to the increased drug accumulation in hepatocytes mediated by the inhibition of ABCB1 by lapatinib. Appropriate dose adjustment may be needed to optimize the combination therapy. PMID- 26036635 TI - Tanshinones suppress AURKA through up-regulation of miR-32 expression in non small cell lung cancer. AB - Tanshinone is the liposoluble constituent of Salia miltiorrhiza, a root used in traditional herbal medicine which is known to possess certain health benefits. Although it is known that tanshinones, including tanshinone I (T1), tanshinone IIA (T2A), and cryptotanshinone (CT), can inhibit the growth of lung cancer cells in vitro, the mechanism under which they act is still unclear. AURKA, an oncogene, encodes a serine-threonine kinase which regulates mitotic processes in mammalian cells. Here, we reported that tanshinones mediate AURKA suppression partly through up-regulating the expression of miR-32. We found that tanshinones could inhibit cell proliferation, promote apoptosis, and impede cell-cycle progression, thus performing an antineoplastic function in non-small cell lung cancer (NSCLC). Additionally, we demonstrated that tanshinones attained these effects in part by down-regulating AURKA, corroborating previous reports. Our results showed that in NSCLC, similar effects were obtained with knock-down of the AURKA gene by siRNA. We also verified that AURKA was the direct target of miR 32. Collectively, our results demonstrated that tanshinones could inhibit NSCLC by suppressing AURKA via up-regulating the expressions of miR-32 and other related miRNAs. PMID- 26036636 TI - Effect of tumor size on breast cancer-specific survival stratified by joint hormone receptor status in a SEER population-based study. AB - BACKGROUND & AIMS: The prognostic value of tumor size is variable. We aimed to characterize the interaction between tumor size and hormone receptor (HoR) status to determine breast cancer-specific mortality (BCSM). METHODS: We used the Surveillance, Epidemiology and End Results (SEER) registry to identify 328, 870 female patients diagnosed with invasive breast cancer from 1990 through 2010. Primary study variables included tumor size, joint HoR status and their corresponding relationship. Kaplan-Meier and adjusted Cox proportional hazards models with interaction terms were utilized. RESULTS: The multivariable analysis revealed a significant interaction between tumor size and HoR status (P < 0.001). Using tumors 61-70 mm in size as the reference for estrogen receptor-negative (ER ) and progesterone receptor-negative (PR-) disease, the hazard ratio (HR) for BCSM increased with increasing tumor size across nearly all categories. In the ER positive (ER+) and PR-positive (PR+) group, however, patients with tumors > 50 mm had nearly identical BCSM rates (P = 0.127, P = 0.099 and P = 0.370 for 51-60 mm, 71-80 mm and > 80 mm tumors, respectively), whereas BCSM was positively correlated with tumors < 51 mm. CONCLUSIONS: The observation of identical HRs for BCSM among patients with ER+ and PR+ tumors >50 mm underscores the importance of individualized treatment. Our findings may contribute to a better understanding of breast cancer biology. PMID- 26036637 TI - EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging therapy. AB - The combination of time and order-dependent chemotherapeutic strategies has demonstrated enhanced efficacy in killing cancer cells while minimizing adverse effects. However, the precise mechanism remains elusive. Our results showed that pre-treatment of MCF-7 and MDA-MB-468 cells with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib or lapatinib significantly enhanced the cytotoxic effects of DNA-damaging agents compared to coadministration of the EGFR inhibitor and DNA-damaging agent. Sequential application of erlotinib and doxorubicin increased activated caspase-8 by promoting pro-caspase-8 homodimerization and autocatalytical cleavage, whereas coadministration did not. We found that EGFR inhibitors promoted pro-caspase-8 homodimerization by inhibiting ERK pathway signaling, while doxorubicin promoted it. Our data highlight that ERK has the potential to inhibit the formation of pro-caspase-8 homodimers by phosphorylating pro-caspase-8 at S387. In conclusion, the pretreatment of EGFR tyrosine kinase inhibitors promote pro-caspase-8 dimerization that sensitizes cancer cells to DNA-damaging agents. Our findings provide rationale for novel strategies for the implementation of combined targeted and cytotoxic chemotherapy within a new framework of time and order dependent therapy. PMID- 26036638 TI - MicroRNA-101 inhibits cell progression and increases paclitaxel sensitivity by suppressing MCL-1 expression in human triple-negative breast cancer. AB - Triple-negative breast cancer is the most aggressive breast cancer subtype. The aim of our study was to investigate the functional role of both miR-101 and MCL-1 in the sensitivity of human triple-negative breast cancer (TNBC) to paclitaxel. We found that the expression of miR-101 was strongly decreased in triple-negative breast cancer tissues and cell lines. The expression of miR-101 was not associated with clinical stage or lymph node infiltration in TNBC. Ectopic overexpression of miR-101 inhibit growth and induced apoptosis in vitro and suppressed tumorigenicity in vivo. MCL-1 was significantly overexpressed in most of the TNBC tissues and cell lines. Luciferase assay results confirmed MCL-1 as a direct target gene of miR-101. MiR-101 inhibited MCL-1 expression in TNBC cells and transplanted tumors. There was a negative correlation between the level of expression of miR-101 and MCL-1 in TNBC tissues. Suppression of MCL-1 enhanced the sensitivity of MDA-MB-435 cells to paclitaxel. Furthermore, miR-101 increased paclitaxel sensitivity by inhibiting MCL-1 expression. Our findings provide significant insight into the molecular mechanisms of TNBC carcinogenesis and may have clinical relevance for the development of novel, targeted therapies for TNBC. PMID- 26036639 TI - FGFR2 is overexpressed in myxoid liposarcoma and inhibition of FGFR signaling impairs tumor growth in vitro. AB - Myxoid liposarcomas account for more than one third of liposarcomas and about 10% of all adult soft tissue sarcomas. The tumors are characterized by specific chromosomal translocations leading to the chimeric oncogenes FUS-DDIT3 or EWS1R DDIT3. The encoded fusion proteins act as aberrant transcription factors. Therefore, we implemented comparative expression analyses using whole-genome microarrays in tumor and fat tissue samples. We aimed at identifying differentially expressed genes which may serve as diagnostic or prognostic biomarkers or as therapeutic targets. Microarray analyses revealed overexpression of FGFR2 and other members of the FGF/FGFR family. Overexpression of FGFR2 was validated by qPCR, immunohistochemistry and western blot analysis in primary tumor samples. Treatment of the myxoid liposarcoma cell lines MLS 402 and MLS 1765 with the FGFR inhibitors PD173074, TKI258 (dovitinib) and BGJ398 as well as specific siRNAs reduced cell proliferation, induced apoptosis and delayed cell migration. Combination of FGFR inhibitors with trabectedin further increased the effect. Our study demonstrates overexpression of FGFR2 and a functional role of FGFR signaling in myxoid liposarcoma. As FGFR inhibition showed effects on proliferation and cell migration and induced apoptosis in vitro, our data indicate the potential use of FGFR inhibitors as a targeted therapy for these tumors. PMID- 26036641 TI - A Second Anti-CD20 Drug for NHL. PMID- 26036640 TI - IPP51, a chalcone acting as a microtubule inhibitor with in vivo antitumor activity against bladder carcinoma. AB - We previously identified 1-(2,4-dimethoxyphenyl)-3-(1-methylindolyl) propenone (IPP51), a new chalcone derivative that is capable of inducing prometaphase arrest and subsequent apoptosis of bladder cancer cells. Here, we demonstrate that IPP51 selectively inhibits proliferation of tumor-derived cells versus normal non-tumor cells. IPP51 interfered with spindle formation and mitotic chromosome alignment. Accumulation of cyclin B1 and mitotic checkpoint proteins Bub1 and BubR1 on chromosomes in IPP51 treated cells indicated the activation of spindle-assembly checkpoint, which is consistent with the mitotic arrest. The antimitotic actions of other chalcones are often associated with microtubule disruption. Indeed, IPP51 inhibited tubulin polymerization in an in vitro assay with purified tubulin. In cells, IPP51 induced an increase in soluble tubulin. Furthermore, IPP51 inhibited in vitro capillary-like tube formation by endothelial cells, indicating that it has anti-angiogenic activity. Molecular docking showed that the indol group of IPP51 can be accommodated in the colchicine binding site of tubulin. This characteristic was confirmed by an in vitro competition assay demonstrating that IPP51 can compete for colchicine binding to soluble tubulin. Finally, in a human bladder xenograft mouse model, IPP51 inhibited tumor growth without signs of toxicity. Altogether, these findings suggest that IPP51 is an attractive new microtubule-targeting agent with potential chemotherapeutic value. PMID- 26036642 TI - Palbociclib Extends Survival in Advanced Breast Cancer. PMID- 26036644 TI - On the Biopharmaceutics Classification System Biowaiver of Ibuprofen. PMID- 26036645 TI - Organic Crystals with Near-Infrared Amplified Spontaneous Emissions Based on 2' Hydroxychalcone Derivatives: Subtle Structure Modification but Great Property Change. AB - A series of highly efficient deep red to near-infrared (NIR) emissive organic crystals 1-3 based on the structurally simple 2'-hydroxychalcone derivatives were synthesized through a simple one-step condensation reaction. Crystal 1 displays the highest quantum yield (Phif) of 0.32 among the reported organic single crystals with an emission maximum (lambdaem) over 710 nm. Comparison between the bright emissive crystals 1-3 and the nearly nonluminous compounds 4-7 clearly gives evidence that a subtle structure modification can arouse great property changes, which is instructive in designing new high-efficiency organic luminescent materials. Notably, crystals 1-3 exhibit amplified spontaneous emissions (ASE) with extremely low thresholds. Thus, organic deep red to NIR emissive crystals with very high Phif have been obtained and are found to display the first example of NIR fluorescent crystal ASE. PMID- 26036643 TI - Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer. AB - Irreversible pyrimidine-based EGFR inhibitors, including WZ4002, selectively inhibit both EGFR-activating and EGFR inhibitor-resistant T790M mutations more potently than wild-type EGFR. Although this class of mutant-selective EGFR inhibitors is effective clinically in lung cancer patients harboring EGFR(T790M), prior preclinical studies demonstrate that acquired resistance can occur through genomic alterations that activate ERK1/2 signaling. Here, we find that ERK1/2 reactivation occurs rapidly following WZ4002 treatment. Concomitant inhibition of ERK1/2 by the MEK inhibitor trametinib prevents ERK1/2 reactivation, enhances WZ4002-induced apoptosis, and inhibits the emergence of resistance in WZ4002 sensitive models known to acquire resistance via both T790M-dependent and T790M independent mechanisms. Resistance to WZ4002 in combination with trametinib eventually emerges due to AKT/mTOR reactivation. These data suggest that initial cotargeting of EGFR and MEK could significantly impede the development of acquired resistance in EGFR-mutant lung cancer. SIGNIFICANCE: Patients with EGFR mutant lung cancer develop acquired resistance to EGFR and mutant-selective EGFR tyrosine kinase inhibitors. Here, we show that cotargeting EGFR and MEK can prevent the emergence of a broad variety of drug resistance mechanisms in vitro and in vivo and may be a superior therapeutic regimen for these patients. PMID- 26036646 TI - Managing repetitive behaviours in young children with autism spectrum disorder (ASD): pilot randomised controlled trial of a new parent group intervention. AB - Early intervention for autism spectrum disorder (ASD) tends to focus on enhancing social-communication skills. We report the acceptability, feasibility and impact on child functioning of a new 8 weeks parent-group intervention to manage restricted and repetitive behaviours (RRB) in young children with ASD aged 3-7 years. Forty-five families took part in the pilot RCT. A range of primary and secondary outcome measures were collected on four occasions (baseline, 10, 18 and 24 weeks) to capture both independent ratings and parent-reported changes in RRB. This pilot established that parents were willing to be recruited and randomised, and the format and content of the intervention was feasible. Fidelity of delivery was high, and attendance was 90 %. A fully powered trial is now planned. PMID- 26036647 TI - The right to appropriate and meaningful education for children with ASD. AB - This paper will explore from a 'child's rights perspective' the 'right' of children with autistic spectrum disorder (ASD) to appropriate and meaningful education. Human 'rights' principles within international law will be evaluated in relation to how they have been interpreted and applied in relation to achieving this 'right'. The International Convention of the Rights of the Child (United Nations in Convention on the rights of the child, office of the high commissioner, United Nations, Geneva, 1989) and the convention on the rights of the person with disability (United Nations in Convention on the rights of person's with disabilities and optional protocol, office of the high commissioner, United Nations, Geneva, 2006) amongst others will be utilised to argue the case for 'inclusive' educational opportunities to be a 'right' of every child on the autistic spectrum. The efficacy of mainstream inclusion is explored, identifying the position that a 'one size fits all' model of education is not appropriate for all children with ASD. PMID- 26036648 TI - The association between autism spectrum disorders and congenital anomalies by organ systems in a Finnish national birth cohort. AB - The aim of this study was to evaluate the association between autism spectrum disorders (ASD) with and without intellectual disability (ID) and congenital anomalies (CAs) by organ system. The sample included all children diagnosed with ASD (n = 4441) from the Finnish Hospital Discharge Register during 1987-2000 and a total of four controls per case (n = 17,695). CAs of the eye, central nervous system, and specific craniofacial anomalies were most strongly associated with ASD. Children with ASD and co-occurring ID were more likely to have CAs compared to ASD children without ID. The results suggest that some cases of ASD may originate during organogenesis, in the early first trimester of pregnancy. The results of this study may be useful for identifying prenatal etiological factors and elucidating the molecular pathogenesis of ASD. PMID- 26036649 TI - Reliability and validity of parent- and child-rated anxiety measures in autism spectrum disorder. AB - Autism spectrum disorder (ASD) and anxiety frequently co-occur. Research on the phenomenology and treatment of anxiety in ASD is expanding, but is hampered by the lack of instruments validated for this population. This study evaluated the self- and parent-reported Revised Child Anxiety and Depression Scale and the Multidimensional Anxiety Scale in Children-2 among 46 youth with ASD. Internal consistency and test-retest reliability were acceptable, but inter-rater reliability was poor. Parent-child agreement was better for youth with higher IQs, less severe ASD symptoms, or more social cognitive skills. Convergent and divergent validity were acceptable. Demographic characteristics were considered as predictors of anxiety: they were unrelated to parent-report, but younger age and more severe ASD were related to increased self-reported anxiety. PMID- 26036651 TI - Gender disparities in German home-care arrangements. AB - An ageing population correlates with rising needs for long-term care (LTC). Support programmes should consider the specific needs of the various subgroups of care dependents and family caregivers. The objective of this study was to analyse the gender-specific disparities in home-care arrangements in Germany, and for this purpose, survey and insurance claims data were used. A survey of 2545 insured care recipients with high-level care needs was conducted in 2012 with the Barmer GEK, a major German statutory healthcare insurance. Insurance claims data were provided for a follow-up, focussing on the group aged 60 years and older. For statistical comparison, chi-squared test and t-tests were used, and a p-value < 0.05 was considered statistically significant. Most care recipients are female, and they are on average 2 years older than males. Men receive family care mostly from their wives, whereas widows frequently live alone and receive care from daughters, sons, other relatives, neighbours and friends, as well as from professional nursing services. Furthermore, women more often anticipate the need for (further) professional assistance and move in with a relative or to an assisted living facility or a nursing home in good time. The desired rate for relocation to a nursing home was higher than the anticipated, and during the 6 month follow-up, the actual rate of relocations was in between both. In summary, the caring situation of men and women is different. Care-receiving men are most often cared for by their wives. Widowed women need a social network and their children in order to remain in their own home. To provide better home-care arrangements for women in this situation, the family and social networks need a stronger focus in politics and research. To stabilise the home-care situation of men with high-level care needs, their wives need more support. PMID- 26036652 TI - Co-delivery of rapamycin- and piperine-loaded polymeric nanoparticles for breast cancer treatment. AB - P-glycoprotein (P-gp) efflux is the major cause of multidrug resistance (MDR) in tumors when using anticancer drugs, moreover, poor bioavailability of few drugs is also due to P-gp efflux in the gut. Rapamycin (RPM) is in the clinical trials for breast cancer treatment, but its P-gp substrate property leads to poor oral bioavailability and efficacy. The objective of this study is to formulate and evaluate nanoparticles of RPM, along with a chemosensitizer (piperine, PIP) for improved oral bioavailability and efficacy. Poly(d,l-lactide-co-glycolide) (PLGA) was selected as polymer as it has moderate MDR reversal activity, which may provide additional benefits. The nanoprecipitation method was used to prepare PLGA nanoparticles with particle size below 150 nm, loaded with both drugs (RPM and PIP). Prepared nanoparticles showed sustained in vitro drug release for weeks, with initial release kinetics of zero order with non-Fickian transport, subsequently followed by Higuchi kinetics with Fickian diffusion. An everted gut sac method was used to study the effect of P-gp efflux on drug transport. This reveals that the uptake of the RPM (P-gp substrate) has been increased in the presence of chemosensitizer. Pharmacokinetic studies showed better absorption profile of RPM from polymeric nanoparticles compared to its suspension counterpart and improved bioavailability of 4.8-folds in combination with a chemosensitizer. An in vitro cell line study indicates higher efficacy of nanoparticles compared to free drug solution. Results suggest that the use of a combination of PIP with RPM nanoparticles would be a promising approach in the treatment of breast cancer. PMID- 26036653 TI - Claudin-binder C-CPE mutants enhance permeability of insulin across human nasal epithelial cells. AB - OBJECTIVE: Intranasal insulin administration has therapeutic potential for Alzheimer's disease and in intranasal administration across the nasal mucosa, the paracellular pathway regulated by tight junctions is important. The C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE) binds the tight junction protein claudin and disrupts the tight junctional barrier without a cytotoxic effect. The C-CPE mutant called C-CPE 194 binds only to claudin-4, whereas the C CPE 194 mutant called C-CPE m19 binds not only to claudin-4 but also to claudin 1. METHODS: In the present study, to investigate the effects of C-CPE mutants on the tight junctional functions of human nasal epithelial cells (HNECs) and on the permeability of human recombinant insulin across the cells, HNECs were treated with C-CPE 194 and C-CPE m19. RESULTS: C-CPE 194 and C-CPE m19 disrupted the barrier and fence functions without changes in expression of claudin-1, -4, -7, and occludin or cytotoxicity, whereas they transiently increased the activity of ERK1/2 phosphorylation. The disruption of the barrier function caused by C-CPE 194 and C-CPE m19 was prevented by pretreatment with the MAPKK inhibitor U0126. Furthermore, C-CPE 194 and C-CPE m19 significantly enhanced the permeability of human recombinant insulin across HNECs and the permeability was also inhibited by U0126. CONCLUSION: These findings suggest that C-CPE mutants 194 and m19 can regulate the permeability of insulin across HNECs via the MAPK pathway and may play a crucial role in therapy for the diseases such as Alzheimer's disease via the direct intranasal insulin administration. PMID- 26036654 TI - [The most frequent electrolyte disorders in the emergency department : what must be done immediately?]. AB - Hyponatremia is the most common form of electrolyte disorder in the emergency room. The symptoms are unspecific and include nausea, dizziness and often falls. Typical symptoms of severe hypernatremia are vomiting, cerebral seizures, somnolence and even coma. The specific initial laboratory diagnostics include measurement of serum electrolytes, serum glucose, serum and urine osmolarity and sodium in urine. The main aim of the clinical examination is to estimate the volume status. If a patient has hypovolemia an infusion of isotonic sodium chloride solution (0.9 %) is the method of choice. If the patient is euvolemic the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or (neurotropic) drugs might be the cause. In these cases the primary measure is restriction of fluid intake. As a rapid correction of sodium levels can lead to pontine myelinolysis, the increase in sodium concentration must not be less than 10 mmol/l within the first 24 h and 18 mmol/l within the first 48 h. Clinical symptoms of hyperkalemia include neurological (e.g. muscle weakness, paresis, hyperreflexia, cramps and dysesthesia), gastrointestinal (e.g. nausea, vomiting and diarrhea) and cardiac symptoms (e.g. dysrhythmia and conductance disorders). Calcium injection stabilizes cardiac rhythm disorders immediately. For a rapid drop in potassium by shifting the potassium to the intracellular space, administration of glucose with insulin and high-dose inhalative administration of betamimetics can be used. Potassium elimination is achieved by infusion of isotonic sodium choride (0.9 %) with i.v. administration of furosemide, ion exchange resins and hemodialysis. PMID- 26036655 TI - [Iatrogenic electrolyte disorders]. AB - The maintenance of water and electrolyte homeostasis is of enormous importance for the functioning of cells and tissues. A number of therapeutic procedures intentionally or unintentionally influence important regulatory mechanisms of these interdependent balanced systems. Excessive salt intake doesn't only expand the extracellular volume; it can also cause a considerable increase in tonicity. Owing to its insulin-dependent duality of action, glucose can represent an effective or an ineffective osmolyte. This fact has to be considered in patients with diabetic ketoacidosis. Diuretics reduce the volume expansion via renal excretion of sodium (and water); however, in addition to hypokalemia, diuretics can also cause severe alkalosis. Nowadays, hemodialysis is a routine procedure but even routine procedures can deliver undesirable surprises. Can dialysis cause an increase in calcium levels, or does the procedure remove therapeutically administered radioactive iodine? The current article presents a series of cases we have come across in recent years. These case reports illustrate common, but also rare iatrogenic situations. The discussion of these cases is aimed at raising awareness of the issues involved in a pathophysiological approach to clinical problems. PMID- 26036656 TI - [A 61-year-old man with jaundice following stomach cancer]. AB - A 61-year-old man with occlusion of the common bile duct due to metachronous metastases after surgery for adenocarcinoma of the stomach underwent a bile drainage intervention using endoscopic ultrasound (EUS). A self-expanding metal stent was inserted into the common bile duct of the liver via the esophagus. Successful drainage of the bile fluid into the duodenum was achieved for 14 months until the death of the patient. EUS interventions are becoming increasingly common. Although many questions such as the methodological details still remain, EUS interventions have the potential to become standard procedures especially in the situation of malignant stenoses of the bile or pancreatic duct. PMID- 26036657 TI - Transition between stunted and nonstunted status: both occur from birth to 15 years of age in Malawi children. AB - AIM: The timing and frequency of stunting and possible catch-up growth are ambiguous in low-income settings. This study explored the timing and extent of becoming stunted and nonstunted between birth and 15 years of age in a resource poor area of Malawi, south-east Africa. METHODS: We followed 767 children from the foetal period until 15 years of age and examined the transition between stunted and nonstunted status and the pubertal stage at 15 years of age. We also plotted smoothed curves for the mean absolute deficits in centimetres and height for-age standard deviation scores (HAZ) according to the World Health Organization's 2006 and 2007 references. RESULTS: Most two-year olds (80%) were stunted (HAZ < -2 SD), but this had declined to 37% at 15 years of age. During the three five-year intervals, new stunting cases ranged from 3.9 to 21.3% and the percentage who became nonstunted was 9.1 to 15%. The majority (85%) of the children, who were moderately stunted at two years of age, became nonstunted during the follow-up period. Only, 9% of boys and 20% of girls had reached advanced puberty by the age of 15. CONCLUSION: Becoming stunted and nonstunted status both occurred throughout the period from birth to 15 years of age in Malawi children. The small percentage who had reached advanced puberty by the age of 15 suggests significant further growth potential. PMID- 26036658 TI - Interactions of an anticancer drug Formestane with single and double stranded DNA at physiological conditions. AB - Mode of interactions of anticancer drug Formestane (FMT) with single and double stranded DNA has been investigated at different temperatures and at two physiological pH values i.e. 7.4 (human blood pH) and 4.7 (stomach pH). Fluorescence spectroscopy, UV-Vis spectroscopy, cyclic voltammetry and square wave voltammetry were employed to probe the interaction between FMT and DNA. The observed fluorescence quenching of dsDNA-ethidium bromide system by the anticancer drug FMT confirmed the intercalative mode of binding between the FMT and dsDNA. The absorption spectra and voltammetric results indicate FMT gets intercalated between dsDNA bases and the strength of interaction is independent on the ionic strength. Comparison of the mode of interaction of FMT with dsDNA and ssDNA was discussed. The calculated binding constants for FMT-dsDNA and FMT ssDNA complexes at pH 7.4 were found to be 1.52*10(5)M(-1) and 1.24*10(6)M(-1), respectively. Stoichiometric coefficients and thermodynamic parameters of FMT dsDNA and FMT-ssDNA complexes were evaluated. The association between the anticancer drug FMT with DNA is maximum at pH 7.4 which depicts the most stable complexes are formed at human blood pH. The decrease in peak current of FMT resulting from its interaction with DNA was employed for determination of dsDNA and ssDNA concentration at physiological conditions. PMID- 26036659 TI - Kinetics of bacterial inactivation by 405nm and 520nm light emitting diodes and the role of endogenous coproporphyrin on bacterial susceptibility. AB - Photodynamic inactivation studies of microbial pathogens have focused on the use of an external photosensitizer or a precursor compound to eliminate bacteria. The present study investigated the inactivation kinetics of six bacterial pathogens by a 405nm light emitting diode (LED) without the addition of any external compound. The role of endogenous coproporphyrin on the bacterial susceptibility to LEDs was also examined. Pathogens were illuminated with LEDs at 25, 10 and 4 degrees C for 9h and the inactivation curves were modeled using six different equations. Endogenous coproporphyrin was quantified using an HPLC system equipped with a fluorescence detector. At a dose of 306J/cm(2), the 405nm LED brought about 4.0, 2.1 and 1.9 log reductions in the populations of Staphylococcus aureus at 25, 10 and 4 degrees C, respectively. At all three temperatures, the population of Bacillus cereus and Listeria monocytogenes reduced by approximately 2.3 and 1.9 log respectively. Salmonella Typhimurium and Escherichia coli O157:H7 showed moderate susceptibility to 405nm LED while Pseudomonas aeruginosa was most resistant. Of the six models tested, Hom model proved most suitable. This study demonstrated that 405nm LEDs can be useful in the inactivation of bacterial pathogens with the aid of endogenous coproporphyrin alone. PMID- 26036660 TI - Magnesium sulfate, chorioamnionitis, and neurodevelopment after preterm birth. AB - OBJECTIVE: To assess the neuroprotective effect of magnesium sulfate (MgSO4 ) in preterm children exposed to chorioamnionitis. DESIGN: A secondary analysis of a multicentre randomised controlled trial of antenatal MgSO4 administered to women at risk of preterm birth for the prevention of cerebral palsy (CP). Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at >=24 weeks of gestation, were selected. Cases were exposed to antepartum MgSO4 ; controls received placebo. SETTING: Multicentre randomised controlled trial. POPULATION: Singleton, non-anomalous pregnancies with clinical chorioamnionitis, delivering at >=24 weeks of gestation. METHODS: All data were analysed by intention to treat. Univariate and multivariate analyses were performed. MAIN OUTCOME MEASURES: Primary outcome was a composite of stillbirth, death by the age of 1 year, or moderate or severe CP by the age of 2 years. Secondary outcomes included a composite neonatal outcome as well as neurodevelopmental delay, defined as Bayley II mental and psychomotor developmental indices <70 at the age of 2 years. Subgroup analysis assessed these outcomes in children born at <28 weeks of gestation. RESULTS: A total of 396 children were included, with 192 (48.5%) randomised to MgSO4 . Maternal and delivery characteristics were similar between the groups. The primary outcome occurred in 14.1% of children exposed to MgSO4 and 12.7% of children exposed to placebo (relative risk, RR 1.29; 95% CI 0.70-2.38). Rates of stillbirth, death, moderate-severe CP, and neurodevelopmental delay did not differ between groups. In the subgroup analysis of children born at <28 weeks of gestation, there was no difference in the rates of the primary outcome, nor in the secondary outcomes assessed. [Correction added on 02 March 2016 after online publication: There were errors in statistical data analysis and these have been corrected throughout the article.] CONCLUSIONS: Among children at risk for early preterm delivery exposed to chorioamnionitis, antenatal administration of MgSO4 was not associated with improved neurodevelopmental outcome. We do not recommend any change in the guidelines on the administration of MgSO4 for neuroprotection based on this study. TWEETABLE ABSTRACT: MgSO4 was not associated with improved neurodevelopmental outcome in setting of chorioamnionitis. PMID- 26036661 TI - Self-Assembly-Driven Electrospinning: The Transition from Fibers to Intact Beaded Morphologies. AB - Polymer beads have attracted considerable interest for use in catalysis, drug delivery, and photonics due to their particular shape and surface morphology. Electrospinning, typically used for producing nanofibers, can also be used to fabricate polymer beads if the solution has a sufficiently low concentration. In this work, a novel approach for producing more uniform, intact beads is presented by electrospinning self-assembled block copolymer (BCP) solutions. This approach allows a relatively high polymer concentration to be used, yet with a low degree of entanglement between polymer chains due to microphase separation of the BCP in a selective solvent system. Herein, to demonstrate the technology, a well-studied polystyrene-poly(ethylene butylene)-polystyrene triblock copolymer is dissolved in a co-solvent system. The effect of solvent composition on the characteristics of the fibers and beads is intensively studied, and the mechanism of this fiber to-bead is found to be dependent on microphase separation of the BCP. PMID- 26036662 TI - Patients' right to choose private medicine. PMID- 26036663 TI - Immunocytochemical localization of V-H(+) -ATPase, Na(+) /K(+) -ATPase, and carbonic anhydrase in gill lamellae of adult freshwater euryhaline shrimp Macrobrachium acanthurus (Decapoda, Palaemonidae). AB - Physiological (organismal), biochemical, and molecular biological contributions to the knowledge of the osmoregulatory plasticity of palaemonid freshwater shrimps has provided a fairly complete model of transporter localization in their branchial epithelium. Direct immunological demonstration of the main enzymes in the gill epithelia of adult palaemonids is, however, still incipient. The diadromous freshwater shrimp Macrobrachium acanthurus was exposed to increased salinity (250/00 for 24 hr), and its responses at the systemic level were evaluated through the assays of hemolymph osmolality and muscle hydration, and at cellular and subcellular levels through the activity and localization of the V H(+) -ATPase, the Na(+) /K(+) -ATPase, and the carbonic anhydrase. Results showed an increase in hemolymph osmolality (629 +/- 5.3 mOsm/kg H2 O) and a decrease in muscle hydration (73.8 +/- 0.5%), comparing values after 24 hr in 250/00 with control shrimps in freshwater (respectively 409.5 +/- 15.8 mOsm/kg H2 O and 77.5 +/- 0.4%). V-H(+) -ATPase was localized in pillar cells, whereas Na(+) /K(+) ATPase in the septal cells. The main novelty of this study was that carbonic anhydrase was localized in the whole branchial tissue, in pillar and septal cells. Exposure to high salinity for 24 hr led to no detectable changes in their localization or in vitro activity. Immunolocalization data corroborated the literature and current models of palaemonid gill ion transport. The absence of changes reinforces the need for the constant expression of these enzymes to account for the euryhalinity of these shrimps. PMID- 26036664 TI - The effect of exposure to media campaign messages on adult cessation. AB - INTRODUCTION: Numerous studies have examined the relationship between antitobacco mass-media campaigns and quit attempts. However, less is known about the effect of these campaigns on relapse. This paper evaluates the effect of media exposure on smokers' quit attempts and relapse. METHODS: We used data from the Florida Adult Cohort Survey, a telephone follow-up survey of adult smokers and recent quitters, who completed the Florida Adult Tobacco Survey. For this study, 1823 unique smokers and recent quitters from baseline first observed between July 2008 and October 2012 were surveyed through up to seven follow-up interviews between October 2009 and October 2013. Media exposure during this period primarily represents exposure to Florida's Tobacco Free Florida (TFF) campaign, although it also includes exposure to the Centers for Disease Control and Prevention's Tips From Former Smokers media campaign in 2012-2013. A multiple-spell discrete-time survival model was estimated using logistic regression. Each spell represents a quit attempt or relapse event. RESULTS: The odds of the first observed quit attempt are higher at higher levels of target rating points (TRPs) (aOR=1.02, p=0.023). The odds ratio for relapse and second quit and second relapse was not statistically significant. CONCLUSIONS: The results suggest that exposure to media campaign messages in Florida has led to increases in quit attempts. Although the estimates were not statistically significant for relapse or the second spell of quit attempts or relapse, the results suggest that media messages might also influence subsequent quit attempts or relapses after an initial quit attempt. PMID- 26036665 TI - Gender differences influence overweight smokers' experimentation with electronic nicotine delivery systems. AB - INTRODUCTION: Overweight and obese tobacco users possess increased risk of cancer, diabetes, heart disease and chronic tobacco-related disease. Efforts to prevent tobacco-related health risk in this comorbid population would be informed by better understanding and monitoring of trends in the concurrent use of electronic nicotine delivery systems (ENDS) among smokers in the US marketplace. METHOD: The California Longitudinal Smokers Study (CLSS) established a cohort of current cigarette smokers in 2011 who were surveyed for tobacco use and health behavior at baseline and again in 2012 at follow-up. RESULTS: We observed a large increase in reported experimentation with ENDS. As hypothesized, overweight or obese smokers were more likely to report experimentation with ENDS, an increase that was also observed among women. Experimentation with ENDS was not associated with a reduction in use of cigarettes or a decrease in cigarette dependence in this high risk population of smokers. CONCLUSIONS: Continued surveillance of this vulnerable population is needed to better understand how experimentation with new ENDS products may impact health, facilitate switching to non-combustible tobacco or facilitate persistent cigarette dependence. PMID- 26036666 TI - Assessing the overlap between tobacco and marijuana: Trends in patterns of co-use of tobacco and marijuana in adults from 2003-2012. AB - BACKGROUND: As marijuana legalization and acceptability increase in the U.S., it is important to understand the potential impact on tobacco use. Accordingly, we assessed prevalence, correlates, and ten-year trends in co-use of marijuana and tobacco among U.S. adults. METHODS: Data came from 378,459 adults participating in the 2003-2012 National Survey on Drug Use and Health, an annual, cross sectional, household survey. Data from 2011-2012 were used to compute the most recent prevalence of past 30-day marijuana and tobacco use (co-use). Data from 2003-2012 were used to compute demographic correlates of co-use, overall trends in co-use, and trends by age, race, and sex. We also assessed trends in tobacco use among marijuana users and marijuana use among tobacco users. RESULTS: From 2011 to 2012, 5.2% of participants were past month co-marijuana and tobacco users, 24.0% were tobacco-only users, and 2.3% were marijuana-only users. From 2003 to 2012, prevalence of co-use increased overall (p<.0001), and among males and females (p<.001, p<.05), those ages 26-34 (p<.001) and 50+years (p<.0001), and Whites (p<.01), Blacks (p<.05), and Hispanics (p<.01); there were no changes among adults 18-25 years. Tobacco use among marijuana users decreased between 2003 and 2012 (from 74.3% to 69.6%, p<.0001), while marijuana use increased among tobacco users (from 14.2% to 17.8, p<.0001). CONCLUSIONS: Co-use of tobacco and marijuana increased from 2003-2012, with marijuana use increasing among past month tobacco users and tobacco use declining among past-month marijuana users. Improved surveillance of co-use is needed as marijuana legalization policies expand and become more integrated in communities. PMID- 26036667 TI - Gender differences in the associations among marijuana use, cigarette use, and symptoms of depression during adolescence and young adulthood. AB - INTRODUCTION: As prevalence of marijuana use increases, it is important that we better understand how factors like gender, cigarette use, and depression are related to marijuana use during adolescence and young adulthood. We examined longitudinal relationships among these variables in adolescents moving into young adulthood who were studied longitudinally for six years. METHODS: 1263 individuals were included in the study. Participants were oversampled for ever smoking a cigarette at baseline, when they were 15-16 years old. Frequency of cigarette smoking and marijuana use, as well as depression symptoms, were assessed at baseline, 6, 15, 24, 60 and 72 months. RESULTS: Cigarette use frequency and depression symptoms were associated with frequency of marijuana use (p-values<.001), particularly in adolescence, but there were important gender differences in these relationships. Specifically, symptoms of depression were related to marijuana use frequency among males (p<.001), but not females (p=.62). In addition, frequency of marijuana use was associated with increased cigarette use frequency, especially among males who had higher symptoms of depression (p<.001). However, this effect was not seen among females. Exploratory analyses suggested that relationships between frequency of use and depression are specific to marijuana, not cigarettes. CONCLUSIONS: Marijuana use is strongly related to depression symptoms and cigarette use frequency in males, indicating that in males these detrimental factors converge, whereas in females they do not. Gender differences in the factors related to marijuana use may mean that there are different risks for and consequences from use and have implications for prevention and intervention efforts. PMID- 26036668 TI - Nse1 and Nse4, subunits of the Smc5-Smc6 complex, are involved in Dictyostelium development upon starvation. AB - The Smc5-Smc6 complex contains a heterodimeric core of two SMC proteins and non Smc elements (Nse1-6), and plays an important role in DNA repair. We investigated the functional roles of Nse4 and Nse1 in Dictyostelium discoideum. Nse4 and Nse3 expressed as Flag-tagged fusion proteins were highly enriched in nuclei, while Nse1 was localized in whole cells. Using yeast two-hybrid assays, only the interaction between Nse3 and Nse1 was detected among the combinations. However, all of the interactions among these three proteins were recognized by co immunoprecipitation assay using cell lysates prepared from the cells expressing green fluorescent protein (GFP)- or Flag-tagged fusion proteins. GFP-tagged Nse1, which localized in whole cells, was translocated to nuclei when co-expressed with Flag-tagged Nse3 or Nse4. RNAi-mediated Nse1 and Nse4 knockdown cells (Nse1 KD and Nse4 KD cells) were generated and found to be more sensitive to UV-induced cell death than control cells. Upon starvation, Nse1 and Nse4 KD cells had increases in the number of smaller fruiting bodies that formed on non-nutrient agar plates or aggregates that formed under submerged culture. We found a reduction in the mRNA level of pdsA, in vegetative and 8 h-starved Nse4 KD cells, and pdsA knockdown cells displayed effects similar to Nse4 KD cells. Our results suggest that Nse4 and Nse1 are involved in not only the cellular DNA damage response but also cellular development in D. discoideum. PMID- 26036669 TI - Automated Detection of HONcode Website Conformity Compared to Manual Detection: An Evaluation. AB - BACKGROUND: To earn HONcode certification, a website must conform to the 8 principles of the HONcode of Conduct In the current manual process of certification, a HONcode expert assesses the candidate website using precise guidelines for each principle. In the scope of the European project KHRESMOI, the Health on the Net (HON) Foundation has developed an automated system to assist in detecting a website's HONcode conformity. Automated assistance in conducting HONcode reviews can expedite the current time-consuming tasks of HONcode certification and ongoing surveillance. Additionally, an automated tool used as a plugin to a general search engine might help to detect health websites that respect HONcode principles but have not yet been certified. OBJECTIVE: The goal of this study was to determine whether the automated system is capable of performing as good as human experts for the task of identifying HONcode principles on health websites. METHODS: Using manual evaluation by HONcode senior experts as a baseline, this study compared the capability of the automated HONcode detection system to that of the HONcode senior experts. A set of 27 health-related websites were manually assessed for compliance to each of the 8 HONcode principles by senior HONcode experts. The same set of websites were processed by the automated system for HONcode compliance detection based on supervised machine learning. The results obtained by these two methods were then compared. RESULTS: For the privacy criterion, the automated system obtained the same results as the human expert for 17 of 27 sites (14 true positives and 3 true negatives) without noise (0 false positives). The remaining 10 false negative instances for the privacy criterion represented tolerable behavior because it is important that all automatically detected principle conformities are accurate (ie, specificity [100%] is preferred over sensitivity [58%] for the privacy criterion). In addition, the automated system had precision of at least 75%, with a recall of more than 50% for contact details (100% precision, 69% recall), authority (85% precision, 52% recall), and reference (75% precision, 56% recall). The results also revealed issues for some criteria such as date. Changing the "document" definition (ie, using the sentence instead of whole document as a unit of classification) within the automated system resolved some but not all of them. CONCLUSIONS: Study results indicate concordance between automated and expert manual compliance detection for authority, privacy, reference, and contact details. Results also indicate that using the same general parameters for automated detection of each criterion produces suboptimal results. Future work to configure optimal system parameters for each HONcode principle would improve results. The potential utility of integrating automated detection of HONcode conformity into future search engines is also discussed. PMID- 26036671 TI - Endophytic Streptomyces in the traditional medicinal plant Arnica montana L.: secondary metabolites and biological activity. AB - Arnica montana L. is a medical plant of the Asteraceae family and grows preferably on nutrient poor soils in mountainous environments. Such surroundings are known to make plants dependent on symbiosis with other organisms. Up to now only arbuscular mycorrhizal fungi were found to act as endophytic symbiosis partners for A. montana. Here we identified five Streptomyces strains, microorganisms also known to occur as endophytes in plants and to produce a huge variety of active secondary metabolites, as inhabitants of A. montana. The secondary metabolite spectrum of these strains does not contain sesquiterpene lactones, but consists of the glutarimide antibiotics cycloheximide and actiphenol as well as the diketopiperazines cyclo-prolyl-valyl, cyclo-prolyl isoleucyl, cyclo-prolyl-leucyl and cyclo-prolyl-phenylalanyl. Notably, genome analysis of one strain was performed and indicated a huge genome size with a high number of natural products gene clusters among which genes for cycloheximide production were detected. Only weak activity against the Gram-positive bacterium Staphylococcus aureus was revealed, but the extracts showed a marked cytotoxic activity as well as an antifungal activity against Candida parapsilosis and Fusarium verticillioides. Altogether, our results provide evidence that A. montana and its endophytic Streptomyces benefit from each other by completing their protection against competitors and pathogens and by exchanging plant growth promoting signals with nutrients. PMID- 26036672 TI - Halomonas heilongjiangensis sp. nov., a novel moderately halophilic bacterium isolated from saline and alkaline soil. AB - A moderately halophilic bacterium, designated strain 9-2(T), was isolated from saline and alkaline soil collected in Lindian county, Heilongjiang province, China. The strain was observed to be strictly aerobic, Gram-negative, rod-shaped, oxidase-positive, catalase-positive and motile. It was found to require NaCl for growth and to grow at NaCl concentrations of 0.5-14 % (w/v) (optimum, 7-10 %, w/v), at temperatures of 10-45 degrees C (optimum 25-30 degrees C) and at pH 5.0-10.0 (optimum pH 8.0). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain 9-2(T) is a member of the genus Halomonas and is closely related to Halomonas desiderata DSM 9502(T) (96.68 %), Halomonas campaniensis DSM 1293(T) (96.46 %), Halomonas ventosae DSM 15911(T) (96.27 %) and Halomonas kenyensis DSM 17331(T) (96.27 %). The DNA-DNA hybridization value was 38.9 +/- 0.66 % between the novel isolate 9-2(T) and H. desiderata DSM 9502(T). The predominant ubiquinones were identified as Q9 (75.1 %) and Q8 (24.9 %). The major fatty acids were identified as C16:0 (22.0 %), Summed feature 8 (C18:1 omega6c/C18:1 omega7c, 19.6 %), Summed feature 3 (C16:1 omega6c/C16:1 omega7c, 12.6 %), C12:0 3-OH (12.0 %) and C10:0 (11.7 %). The DNA G+C content was determined to be 69.7 mol%. On the basis of the evidence presented in this study, strain 9-2(T) is considered to represent a novel species of the genus Halomonas, for which the name Halomonas heilongjiangensis sp. nov. is proposed. The type strain is 9-2(T) (=DSM 26881(T) = CGMCC 1.12467(T)). PMID- 26036674 TI - Cross-Couplings Using Aryl Ethers via C-O Bond Activation Enabled by Nickel Catalysts. AB - Arene synthesis has been revolutionized by the invention of catalytic cross coupling reactions, wherein aryl halides can be coupled with organometallic and organic nucleophiles. Although the replacement of aryl halides with phenol derivatives would lead to more economical and ecological methods, success has been primarily limited to activated phenol derivatives such as triflates. Aryl ethers arguably represent one of the most ideal substrates in terms of availability, cost, safety, and atom efficiency. However, the robust nature of the C(aryl)-O bonds of aryl ethers renders it extremely difficult to use them in catalytic reactions among the phenol derivatives. In 1979, Wenkert reported a seminal work on the nickel-catalyzed cross-coupling of aryl ethers with Grignard reagents. However, it was not until 2004 that the unique ability of a low-valent nickel species to activate otherwise unreactive C(aryl)-O bonds was appreciated with Dankwardt's identification of the Ni(0)/PCy3 system, which significantly expanded the efficiency of the Wenkert reaction. Application of the nickel catalyst to cross-couplings with other nucleophiles was first accomplished in 2008 by our group using organoboron reagents. Later on, several other nucleophiles, including organozinc reagents, amines, hydrosilane, and hydrogen were shown to be coupled with aryl ethers under nickel catalysis. Despite these advances, progress in this field is relatively slow because of the low reactivity of benzene derivatives (e.g., anisole) compared with polyaromatic substrates (e.g., methoxynaphthalene), particularly when less reactive and synthetically useful nucleophiles are used. The "naphthalene problem" has been overcome by the use of N-heterocyclic carbene (NHC) ligands bearing bulky N-alkyl substituents, which enables a wide range of aryl ethers to be coupled with organoboron nucleophiles. Moreover, the use of N-alkyl-substituted NHC ligands allows the use of alkynylmagnesium reagents, thereby realizing the first Sonogashira-type reaction of anisoles. From a mechanistic perspective, nickel-catalyzed cross couplings of aryl ethers are at a nascent stage, in particular regarding the mode of activation of C(aryl)-O bonds. Oxidative addition is one plausible pathway, although such a process has not been fully verified experimentally. Nickel catalyzed reductive cleavage of aryl ethers in the absence of an external reducing agent provides strong support for this oxidative addition process. Several other mechanisms have also been proposed. For example, Martin demonstrated a new possibility of the involvement of a Ni(I) species, which could mediate the cleavage of the C(aryl)-O bond via a redox-neutral pathway. The tolerance of aryl ethers under commonly used synthetic conditions enables alkoxy groups to serve as a platform for late-stage elaboration of complex molecules without any tedious protecting group manipulations. Aryl ethers are therefore not mere economical alternatives to aryl halides but also enable nonclassical synthetic strategies. PMID- 26036673 TI - Catenovulum maritimus sp. nov., a novel agarolytic gammaproteobacterium isolated from the marine alga Porphyra yezoensis Ueda (AST58-103), and emended description of the genus Catenovulum. AB - A novel agarolytic, Gram-stain negative, heterotrophic, facultatively anaerobic and pale-white pigmented bacterial strain, designated Q1(T), was isolated from the marine alga Porphyra yezoensis Ueda (AST58-103) collected from the coastal area of Weihai, China. The cells are motile by means of peritrichous flagella. The isolate requires NaCl for growth, while seawater is not necessary, and growth occurs optimally at about 30-33 degrees C, in 1-3 % (w/v) NaCl and at pH 7-7.5. Strain Q1(T) shows oxidase-positive and catalase-negative activities, and possesses the ability to hydrolyse starch and alginate, but not cellulose, gelatin, urea or Tween-80. Phylogenetic analysis based on 16S rRNA gene sequence indicated that strain Q1(T) is affiliated with the family Alteromonadaceae within the class Gammaproteobacteria. The isolate, strain Q1(T), is most closely related to Catenovulum agarivorans YM01(T) (94.85 %), with less than 91.2 % sequence similarity to other close relatives with validly published names. The draft genome sequence of strain Q1(T) consists of 62 contigs (>200 bp) of 4,548,270 bp. The genomes of Q1(T) and YM01(T) have an ANI value of 70.7 %, and the POCP value between the two genomes is 64.4 %. The genomic DNA G+C content of strain Q1(T) is 37.9 mol% as calculated from the draft genome sequence. The main isoprenoid quinone is ubiquinone-8. The predominant cellular fatty acids are summed feature 3 (C16:1 omega7c and/or iso-C15:0 2-OH), C16:0 and C18:1 omega7c. The major polar lipids are phosphatidylethanolamine and phosphatidylglycerol. Based on data from a polyphasic chemotaxonomic, physiological and biochemical study, strain Q1(T) should be classified as a novel species of the genus Catenovulum, for which the name Catenovulum maritimus sp. nov. is proposed. The type strain is Q1(T) (=CICC 10836(T)=DSM 28813(T)). PMID- 26036675 TI - Economic evaluation favours physiotherapy but not corticosteroid injection as a first-line intervention for chronic lateral epicondylalgia: evidence from a randomised clinical trial. AB - AIM: To determine the cost-effectiveness of corticosteroid injection, physiotherapy and a combination of these interventions, compared to a reference group receiving a blinded placebo injection. METHODS: 165 adults with unilateral lateral epicondylalgia of longer than 6 weeks duration from Brisbane, Australia, were randomised for concealed allocation to saline injection (placebo), corticosteroid injection, saline injection plus physiotherapy (eight sessions of elbow manipulation and exercise) or corticosteroid injection plus physiotherapy. Costs to society and health-related quality of life (estimated by EuroQol-5D) over the 1 year follow-up were used to generate incremental cost per quality adjusted life year (QALY) ratios for each intervention relative to placebo. RESULTS: Intention-to-treat analysis was possible for 154 (93%) of trial participants. Physiotherapy was more costly, but was the only intervention that produced a statistically significant improvement in quality of life relative to placebo (MD, 95% CI 0.035, 0.003 to 0.068). Similar cost/QALY ratios were found for physiotherapy ($A29 343; GBP18 962) and corticosteroid injection ($A31 750; GBP20 518); however, the probability of being more cost-effective than placebo at values above $A50 000 per quality-adjusted life year was 81% for physiotherapy and 53% for corticosteroid injection. Cost/QALY was far greater for a combination of corticosteroid injection and physiotherapy ($A228 000; GBP147 340). SUMMARY: Physiotherapy was a cost-effective treatment for lateral epicondylalgia. Corticosteroid injection was associated with greater variability, and a lower probability of being cost-effective if a willingness to pay threshold of $A50 000 is assumed. A combination of corticosteroid injection and physiotherapy was ineffective and cost-ineffective. Physiotherapy, not corticosteroid injection, should be considered as a first-line intervention for lateral epicondylalgia. TRIAL REGISTRATION NUMBER: anzctr.org Trial identifier: ACTRN12609000051246. PMID- 26036676 TI - Structured exercise improves mobility after hip fracture: a meta-analysis with meta-regression. AB - OBJECTIVES: To determine the effect of structured exercise on overall mobility in people after hip fracture. To explore associations between trial-level characteristics and overall mobility. DESIGN: Systematic review, meta-analysis and meta-regression. DATA SOURCES: MEDLINE, EMBASE, CINAHL, the Cochrane Central Register of Controlled Trials, the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register and the Physiotherapy Evidence Database to May 2014. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Randomised controlled trials of structured exercise, which aimed to improve mobility compared with a control intervention in adult participants after surgery for hip fracture were included. DATA EXTRACTION AND SYNTHESIS: Data were extracted by one investigator and checked by an independent investigator. Standardised mean differences (SMD) of overall mobility were meta-analysed using random effects models. Random effects meta-regression was used to explore associations between trial-level characteristics and overall mobility. RESULTS: 13 trials included in the meta analysis involved 1903 participants. The pooled Hedges' g SMD for overall mobility was 0.35 (95% CI 0.12 to 0.58, p=0.002) in favour of the intervention. Meta-regression showed greater treatment effects in trials that included progressive resistance exercise (change in SMD=0.58, 95% CI 0.17 to 0.98, p=0.008, adjusted R2=60%) and delivered interventions in settings other than hospital alone (change in SMD=0.50, 95% CI 0.08 to 0.93, p=0.024, adjusted R2=49%). CONCLUSIONS AND IMPLICATIONS: Structured exercise produced small improvements on overall mobility after hip fracture. Interventions that included progressive resistance training and were delivered in other settings were more effective, although the latter may have been confounded by duration of interventions. PMID- 26036677 TI - Higher shoe-surface interaction is associated with doubling of lower extremity injury risk in football codes: a systematic review and meta-analysis. AB - BACKGROUND: Turning or cutting on a planted foot may be an important inciting event for lower limb injury, particularly when shoe-surface traction is high. We systematically reviewed the relationship between shoe-surface interaction and lower-extremity injury in football sports. METHODS: A systematic literature search of four databases was conducted up to November 2014. Prospective studies investigating the relationship between rotational traction and injury rate were included. Two researchers independently extracted outcome data and assessed the quality of included studies using a modified Downs and Black index. Effect sizes (OR+95% CIs) were calculated using RevMan software. Where possible, data were pooled using the fixed effect model. RESULTS: Three prospective studies were included (4972 male athletes). The methodological quality was generally good with studies meeting 68-89% of the assessment criteria. All studies categorised athletes into low (lowest mean value 15 nm) or high traction groups (highest mean value 74 nm) based on standardised preseason testing. In all cases, injury reporting was undertaken prospectively over approximately three seasons, with verification from a medical practitioner. Injury data focused on: all lower limb injuries, ankle/knee injuries or ACL injury only. There was a clear relationship between rotational traction and injury and the direction and magnitude of effect sizes were consistent across studies. The pooled data from the three studies (OR=2.73, 95% CI 2.13 to 3.15; chi(2)=3.19, df=2, p=0.21; I(2)=36.5%) suggest that the odds of injury are approximately 2.5 times higher when higher levels of rotational traction are present at the shoe-surface interface. SUMMARY AND CONCLUSIONS: Higher levels of rotational traction influence lower limb injury risk in American Football athletes. We conclude that this warrants considerable attention from clinicians and others interested in injury prevention across all football codes. PMID- 26036678 TI - Strategic Assessment of Risk and Risk Tolerance (StARRT) framework for return-to play decision-making. AB - The sport medicine clinician is faced with return-to-play (RTP) decisions for every patient who wants to return to activity. The complex interaction of factors related to history, physical examination, testing, activity and baseline characteristics can make RTP decision-making challenging. Further, when reasoning is not explicit, unnecessary conflict can arise among clinicians themselves, or among clinicians and patients. This conflict can have negative health consequences for the patient. In 2010, a transparent framework for RTP decisions was proposed. However, some have identified limitations to the framework and found difficulties in its implementation. This paper presents a revised framework that addresses the limitations, and provides concrete examples of how to apply it in simple and complex cases. PMID- 26036680 TI - Delayed recurrent bleeding from central venous catheter track after catheter removal in a haemophilia patient. PMID- 26036679 TI - [ICD leads]. AB - Implantable cardioverter-defibrillator (ICD) leads have to fulfill particular requirements: safe pacing and sensing, detection, and termination of ventricular tachyarrhythmias, if necessary by (multiple) high-energy shocks. At the same time, their implantation has to be simple, they need to provide excellent long term stability and they must be completely and safely extractable. Numerous technical developments have enabled currently available ICD leads to fulfill these expectations to a high extent. However, some changes of lead design, materials, and manufacturing processes have led to increased lead failure, especially in two lead models (Medtronic Sprint Fidelis(r), St. Jude Medical Riata(r)). The high rate of lead failure was identified only several years after market release, in part because there are no appropriate registries of ICD leads. This review presents background and developments of ICD lead technology and their association with the clinical usage of ICD therapy. To also benefit patients with only slightly-to-moderately increased risk of ventricular tachyarrhythmia, optimum ICD therapy requires optimal leads and sufficiently experienced implanters. PMID- 26036681 TI - Virtual patient activity patterns for clinical learning. AB - BACKGROUND: Virtual patients are software tools that present learners with patient case situations and tasks. Some virtual patients take the learner through a guided case scenario, whereas others require learners to make diagnostic and therapeutic decisions. Much attention has been paid to the design of virtual patients and their use as standalone activities, but rather less attention has been paid to their use in broader educational activities. This article describes a series of activity patterns that make use of virtual patients. CONTEXT: The article describes five patterns of clinical teaching activities that make use of virtual patients: independent study activities; collaborative group activities; blended activities; bridging activities; and reference activities. These patterns were developed inductively from the authors' teaching practices over a number of years. These are not the only activity patterns and designs that can make use of virtual patients but they are ones that have been found to be particularly useful over time and in many different contexts. INNOVATION: Although the design of educational artifacts such as virtual patients is important, clinical teachers also need to consider the ways in which they are used. Different kinds of activity can employ different kinds of virtual patients of varying levels of complexity. An activity focus can allow clinical teachers to make more effective and broader use of virtual patients. IMPLICATIONS: Virtual patients can be used for more than independent study. Clinical teachers are encouraged to explore the multitude of uses that virtual patients can be put to, and the ways in which activities can be constructed around them. Different kinds of activity can employ different kinds of virtual patients, of varying levels of complexity. PMID- 26036682 TI - The oncogenic role of EIF3D is associated with increased cell cycle progression and motility in prostate cancer. AB - EIF3 is the largest multi-protein complex, and several studies have revealed the oncogenic roles of its subunits in many human cancers. However, the roles of EIF3D in the development and progression of PCa remain uncovered. In the present study, the expression of EIF3D in prostate cancer and paracarcinoma tissues, as well as PCa cell lines, was examined. In PCa tissues, the expression of EIF3D was up-regulated compared to that in paracarcinoma tissues. In order to investigate whether EIF3D could serve as potential therapeutic target for prostate cancer, EIF3D was knocked down to verify its functional role in prostate cancer cells. After EIF3D knockdown in PC-3 and DU145 cells, cell proliferation, invasion and colony formation were significantly inhibited; meanwhile, cell cycle analysis revealed cell cycle arrest at G2/M phase. EIF3D is associated with PCa, and silencing EIF3D will result in decreased proliferation, and migration, as well as G2/M arrest in DU145 and PC-3 cells. These results suggest that EIF3D plays an oncogenic role in PCa development and progression. PMID- 26036683 TI - Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus. AB - The principles of allelic exclusion state that each B cell expresses a single light and heavy chain pair. Here, we show that B cells with both kappa and lambda light chains (Igkappa and Iglambda) are enriched in some patients with the systemic autoimmune disease systemic lupus erythematosus (SLE), but not in the systemic autoimmune disease control granulomatosis with polyangiitis. Detection of dual Igkappa and Iglambda expression by flow cytometry could not be abolished by acid washing or by DNAse treatment to remove any bound polyclonal antibody or complexes, and was retained after two days in culture. Both surface and intracytoplasmic dual light chain expression was evident by flow cytometry and confocal microscopy. We observed reduced frequency of rearrangements of the kappa deleting element (KDE) in SLE and an inverse correlation between the frequency of KDE rearrangement and the frequency of dual light chain expressing B cells. We propose that dual expression of Igkappa and Iglambda by a single B cell may occur in some patients with SLE when this may be a consequence of reduced activity of the KDE. PMID- 26036684 TI - Epithelial-mesenchymal transition in keloid tissues and TGF-beta1-induced hair follicle outer root sheath keratinocytes. AB - Keloid is a skin fibrotic disease with the characteristics of recurrence and invasion, its pathogenesis still remains unrevealed. The epithelial-mesenchymal transition (EMT) is critical for wound healing, fibrosis, recurrence, and invasion of cancer. We sought to investigate the EMT in keloid and the mechanism through which the EMT regulates keloid formation. In keloid tissues, the expressions of EMT-associated markers and transforming growth factor (TGF) beta1/Smad3 signaling were examined by immunohistochemistry. In the keloid epidermis and dermal tissue, the expressions of genes related to the regulation of skin homeostasis, fibroblast growth factor receptor 2 (FGFR2) and p63, were analyzed using quantitative real-time polymerase chain reaction. The results showed that accompanying the loss of the epithelial marker E-cadherin and the gain of the mesenchymal markers fibroblast-specific protein 1 (FSP1) and vimentin in epithelial cells from epidermis and skin appendages, and in endothelial cells from dermal microvessels, enhanced TGF-beta1 expression and Smad3 phosphorylation were noted in keloid tissues. Moreover, alternative splicing of the FGFR2 gene switched the predominantly expressed isoform from FGFR2-IIIb to -IIIc, concomitant with the decreased expression of DeltaNp63 and TAp63, which changes might partially account for abnormal epidermis and appendages in keloids. In addition, we found that TGF-beta1-induced hair follicle outer root sheath keratinocytes (ORSKs) and normal skin epithelial cells underwent EMT in vitro with ORSKs exhibiting more obvious EMT changes and more similar expression profiles for EMT-associated and skin homeostasis-related genes as in keloid tissues, suggesting that ORSKs might play crucial roles in the EMT in keloids. Our study provided insights into the molecular mechanisms mediating the EMT pathogenesis of keloids. PMID- 26036685 TI - Use of the guanidination reaction for determining reactive lysine, bioavailable lysine and gut endogenous lysine. AB - Determining the bioavailability of lysine in foods and feedstuffs is important since lysine is often the first limiting indispensable amino acid in diets for intensively farmed livestock (pigs and poultry) and also in many cereal-based diets consumed by humans. When foods or feedstuffs are heat processed, lysine can undergo Maillard reactions to produce nutritionally unavailable products. The guanidination reaction, the reaction of O-methylisourea with the side chain amino group of lysine that produces homoarginine, has been used to determine the unmodified lysine (reactive lysine) in processed foods and feedstuffs and also true ileal digestible reactive lysine (bioavailable lysine). The advantages of the guanidination method in comparison with other reactive lysine methods such as the fluorodinitrobenzene, trinitrobenzenesulphonic acid and dye-binding methods are that it is very specific for reactive lysine and also that the method is relatively straightforward to conduct. The specificity of the guanidination reaction for the lysine side chain amino group is particularly important, since ileal digesta will contain N-terminal groups in the form of free amino acids and peptides. The main disadvantage is that complete conversion of lysine to homoarginine is required, yet it is not straightforward to test for complete guanidination in processed foods and feedstuffs. Another disadvantage is that the guanidination reaction conditions may vary for different food types and sometimes within the same food type. Consequently, food-specific guanidination reaction conditions may be required and more work is needed to optimise the reaction conditions across different foods and feedstuffs. PMID- 26036686 TI - Hydrolysis with Cucurbita ficifolia serine protease reduces antigenic response to bovine whey protein concentrate and alphas-casein. AB - In the present study the effect of hydrolysis with non-commercial Cucurbita ficifolia serine protease on a reduction of the IgE and IgG binding capacity of whey protein concentrate and alphas-casein was investigated. The intensity of the protein degradation was analyzed by the degree of hydrolysis, the free amino groups content and RP-HPLC. The ability to bind the antibodies by native proteins and their hydrolysates was determined using a competitive ELISA test. Deep hydrolysis contributed to a significant reduction of immunoreactive epitopes present in WPC. In the case of IgE and IgG present in the serum pool of children with CMA, the lowest binding capacity was detected in the 24 h WPC hydrolysate, where the inhibition of the reaction with native WPC was <=23 and <=60 %, respectively. The analysis of the IgG reactivity in the antiserum of the immunized goat showed that the lowest antibody binding capacity was exhibited also by 24 h WPC hydrolysate at a concentration of 1000 MUg/ml where the inhibition of the reaction with nWPC was <=47 %. One-hour hydrolysis of alpha casein was sufficient to significant reduction of the protein antigenicity, while the longer time (5 h) of hydrolysis probably lead to the appearance of new epitopes reactive with polyclonal. PMID- 26036687 TI - Ionic transport through sub-10 nm diameter hydrophobic high-aspect ratio nanopores: experiment, theory and simulation. AB - Fundamental understanding of ionic transport at the nanoscale is essential for developing biosensors based on nanopore technology and new generation high performance nanofiltration membranes for separation and purification applications. We study here ionic transport through single putatively neutral hydrophobic nanopores with high aspect ratio (of length L = 6 MUm with diameters ranging from 1 to 10 nm) and with a well controlled cylindrical geometry. We develop a detailed hybrid mesoscopic theoretical approach for the electrolyte conductivity inside nanopores, which considers explicitly ion advection by electro-osmotic flow and possible flow slip at the pore surface. By fitting the experimental conductance data we show that for nanopore diameters greater than 4 nm a constant weak surface charge density of about 10(-2) C m(-2) needs to be incorporated in the model to account for conductance plateaus of a few pico siemens at low salt concentrations. For tighter nanopores, our analysis leads to a higher surface charge density, which can be attributed to a modification of ion solvation structure close to the pore surface, as observed in the molecular dynamics simulations we performed. PMID- 26036688 TI - Home care by general practitioners for cancer patients in the last 3 months of life: An epidemiological study of quality and associated factors. AB - BACKGROUND: Stronger generalist end-of-life care at home for people with cancer is called for but the quality of end-of-life care delivered by general practitioners has been questioned. AIM: To determine the degree of and factors associated with bereaved relatives' satisfaction with home end-of-life care delivered by general practitioners to cancer patients. DESIGN: Population-based mortality followback survey. SETTING/PARTICIPANTS: Bereaved relatives of people who died of cancer in London, United Kingdom (identified from death registrations in 2009-2010), were invited to complete a postal questionnaire surveying the deceased's final 3 months of life. RESULTS: Questionnaires were completed for 596 decedents of whom 548 spent at least 1 day at home in the last 3 months of life. Of the respondents, 55% (95% confidence interval: 51%-59%) reported excellent/very good home care by general practitioners, compared with 78% (95% confidence interval: 74%-82%) for specialist palliative care providers and 68% (95% confidence interval: 64%-73%) for district/community/private nurses. The odds of high satisfaction (excellent/very good) with end-of-life care by general practitioners doubled if general practitioners made three or more compared with one or no home visits in the patient's last 3 months of life (adjusted odds ratio: 2.54 (95% confidence interval: 1.52-4.24)) and halved if the patient died at hospital rather than at home (adjusted odds ratio: 0.55 (95% confidence interval: 0.31-0.998)). CONCLUSION: There is considerable room for improvement in the satisfaction with home care provided by general practitioners to terminally ill cancer patients. Ensuring an adequate offer of home visits by general practitioners may help to achieve this goal. PMID- 26036689 TI - Global gene expression profile of normal and regenerating liver in young and old mice. AB - The ability of the liver to regenerate and adjust its size after two/third partial hepatectomy (PH) is impaired in old rodents and humans. Here, we investigated by microarray analysis the expression pattern of hepatic genes in young and old untreated mice and the differences in gene expression profile following PH. Of the 10,237 messenger RNAs that had detectable expression, only 108 displayed a greater than 2-fold modification in gene expression levels between the two groups. These genes were involved in inflammatory and immune response, xenobiotics, and lipid and glucose metabolism. To identify the genes responsible for the different regenerative response, 10-week and 18-month-old mice subjected to PH were sacrificed at different time intervals after surgery. The results showed that 2463 transcripts had significantly different expression post PH between the two groups. However, in spite of impaired liver regeneration in old mice, cell cycle genes were similarly modified in both groups, the only exception being cyclin D1 gene which was up-regulated soon after PH in young mice, but mostly down-regulated in aged animals. Surprisingly, while in young hepatectomized mice, Yap messenger RNA (mRNA) expression was not significantly enhanced and protein expression essentially reflected the progression into cell cycle, its mRNA and protein levels were robustly increased in the liver of aged animals. Furthermore, a significant change of the age-related expression of the size regulator Yes-associated protein (YAP) was observed. Unexpectedly, while in young hepatectomized mice, Yap mRNA expression was not significantly enhanced and protein expression essentially reflected the progression into cell cycle, its mRNA and protein levels were robustly increased in the liver of aged animals. Moreover, when PH was performed on mitogen-induced enlarged livers, the earlier restoration of the original liver mass compared to animals subjected to PH only led to YAP down-regulation concomitantly with cyclin D1 up-regulation. Our data suggest that YAP activation is a size-dependent homeostatic mechanism that does not necessarily reflect cell cycle progression. PMID- 26036690 TI - Febuxostat ameliorates doxorubicin-induced cardiotoxicity in rats. AB - The clinical use of doxorubicin is associated with dose limiting cardiotoxicity. This is a manifestation of free radical production triggered by doxorubicin. Therefore, we evaluated the efficacy of febuxostat, a xanthine oxidase inhibitor and antioxidant, in blocking cardiotoxicity associated with doxorubicin in rats. Male albino Wistar rats were divided into four groups: control (normal saline 2.5mL/kg/dayi.p. on alternate days, a total of 6 doses); Doxorubicin (2.5mg/kg/dayi.p. on alternate days, a total of 6 doses), Doxorubicin+Febuxostat (10mg/kg/day oral) and Doxorubicin+Carvedilol (30mg/kg/day oral) for 14days. Febuxostat significantly ameliorated the doxorubicin-induced deranged cardiac functions as there was significant improvement in arterial pressures, left ventricular end diastolic pressure and inotropic and lusitropic states of the myocardium. These changes were well substantiated with biochemical findings, wherein febuxostat prevented the depletion of non-protein sulfhydryls level, with increased manganese superoxide dismutase level and reduced cardiac injury markers (creatine kinase-MB and B-type natriuretic peptide levels) and thiobarbituric acid reactive substances level. Febuxostat also exhibited significant anti inflammatory (decreased expression of NF-kappaBp65, IKK-beta and TNF-alpha) and anti-apoptotic effect (increased Bcl-2 expression and decreased Bax and caspase-3 expression and TUNEL positivity). Hematoxylin and Eosin, Masson Trichome, Picro Sirius Red and ultrastructural studies further corroborated with hemodynamic and biochemical findings showing that febuxostat mitigated doxorubicin-induced increases in inflammatory cells, edema, collagen deposition, interstitial fibrosis, perivascular fibrosis and mitochondrial damage and better preservation of myocardial architecture. In addition, all these changes were comparable to those produced by carvedilol. Thus, our results suggest that the antioxidant and anti-apoptotic effect of febuxostat contributes to its protective effects against doxorubicin-induced cardiotoxicity. PMID- 26036691 TI - Exceedingly Facile Ph-X Activation (X = Cl, Br, I) with Ruthenium(II): Arresting Kinetics, Autocatalysis, and Mechanisms. AB - [(Ph3P)3Ru(L)(H)2] (where L = H2 (1) in the presence of styrene, Ph3P (3), and N2 (4)) cleave the Ph-X bond (X = Cl, Br, I) at RT to give [(Ph3P)3RuH(X)] (2) and PhH. A combined experimental and DFT study points to [(Ph3P)3Ru(H)2] as the reactive species generated upon spontaneous loss of L from 3 and 4. The reaction of 3 with excess PhI displays striking kinetics which initially appears zeroth order in Ru. However mechanistic studies reveal that this is due to autocatalysis comprising two factors: 1) complex 2, originating from the initial PhI activation with 3, is roughly as reactive toward PhI as 3 itself; and 2) the Ph-I bond cleavage with the just-produced 2 gives rise to [(Ph3P)2RuI2], which quickly comproportionates with the still-present 3 to recover 2. Both the initial and onward activation reactions involve PPh3 dissociation, PhI coordination to Ru through I, rearrangement to a eta(2)-PhI intermediate, and Ph-I oxidative addition. PMID- 26036692 TI - The role of physical activity and psychological coping strategies in the management of painful diabetic neuropathy--A systematic review of the literature. AB - BACKGROUND: Diabetes is rising in prevalence; painful diabetic neuropathy (PDN) is one complication of diabetes. PDN is primarily managed with medication but analgesic failure is common and people remain in pain and distress. It is unclear whether pain management strategies are appropriate for PDN. OBJECTIVES: To establish the effectiveness of physical activity and psychological coping strategies for PDN. DESIGN: Systematic literature review. DATA SOURCES: Ten online databases. ELIGIBILITY CRITERIA (PARTICIPANTS AND INTERVENTIONS): Controlled trials reporting specific results for PDN, investigating, (a) physical activity or (b) psychological coping strategies and measuring pain as an outcome. The search was restricted to published research with no restriction on language or date of publication. STUDY APPRAISAL METHODS: Methodological quality and risk of bias assessed with Cochrane collaboration and NICE checklist for randomised controlled trials. RESULTS: Of 1306 titles identified, four studies met the inclusion criteria. Two trials investigated physical activity and two investigated psychological coping interventions. Studies showed pain measures improved or did not worsen compared to controls, but methodological quality was moderate and results need cautious interpretation. LIMITATIONS: The studies were of small sample size and used a diverse range of outcome measures. There is high risk of bias from lack of blinding and attrition at follow up. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: The research literature in this area is sparse and inconsistent, despite the pressing clinical challenge of PDN. Firm conclusions cannot be drawn from the studies included. Further high quality research is required to match treatment provision to patient requirements. PMID- 26036694 TI - Entrainment of prosody in the interaction of mothers with their young children. AB - Caregiver speech is not a static collection of utterances, but occurs in conversational exchanges, in which caregiver and child dynamically influence each other's speech. We investigate (a) whether children and caregivers modulate the prosody of their speech as a function of their interlocutor's speech, and (b) the influence of the initiator of the conversation on durational characteristics of the exchange. We analyzed naturalistic conversations from 13 mother infant/toddler dyads aged 12-30 months across full-day recordings of 3-5 days per dyad using LENA and automated analytic tools. We found small, but significant, effects of mothers and their children influencing each other's speech, particularly in pitch measures. We also found longer utterances and shorter response latencies for the initiator of a conversation. While mothers show more mature conversational capabilities (more entrainment, shorter response latencies), our findings converge with prior research to highlight the active role of young children in the conversational exchange. PMID- 26036693 TI - The histology of Nanomia bijuga (Hydrozoa: Siphonophora). AB - The siphonophore Nanomia bijuga is a pelagic hydrozoan (Cnidaria) with complex morphological organization. Each siphonophore is made up of many asexually produced, genetically identical zooids that are functionally specialized and morphologically distinct. These zooids predominantly arise by budding in two growth zones, and are arranged in precise patterns. This study describes the cellular anatomy of several zooid types, the stem, and the gas-filled float, called the pneumatophore. The distribution of cellular morphologies across zooid types enhances our understanding of zooid function. The unique absorptive cells in the palpon, for example, indicate specialized intracellular digestive processing in this zooid type. Though cnidarians are usually thought of as mono epithelial, we characterize at least two cellular populations in this species which are not connected to a basement membrane. This work provides a greater understanding of epithelial diversity within the cnidarians, and will be a foundation for future studies on N. bijuga, including functional assays and gene expression analyses. PMID- 26036695 TI - The Evolving Position of the American Psychiatric Association on Firearm Policy (1993-2014). AB - Before the Supreme Court's 2008 decision in District of Columbia v. Heller, the American Psychiatric Association's position on gun policy reflected the strong gun control perspective championed by the nation's public health establishment. After Heller declared that an individual's right to bear arms is constitutionally protected, the APA refocused its attention on the specific aspects of firearm policy that implicate the interests and rights of persons with mental illness. Psychiatrists are mindful of the need to curtail firearm access by persons with mental disorders that elevate the risk of suicide or violence to others, but they are also opposed to stigmatization, discrimination, and unfair treatment of individuals based on mental illness. Although civil commitment is an acceptable basis for prohibiting access to firearms, other adjudications of conduct indicative of elevated risk should also be included. Every state should provide a fair and reasonable process for restoring firearm rights after a suitable waiting period based on individualized assessment of whether the person remains at an elevated risk. However, restricting firearm rights of persons solely on the basis of a diagnosis of a mental disorder or voluntary treatment, whether in-patient or outpatient, discourages treatment and would be counterproductive. PMID- 26036696 TI - Fast Analysis of Complete Macroscopic Gunshot Residues on Substrates Using Raman Imaging. AB - Raman spectroscopy has emerged as a viable technique for the organic analysis of gunshot residues (GSRs), offering additional information to the well-established analysis using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDX). In this article, a Raman imaging system with an electron multiplying coupled-charged device (EMCCD) camera was used to analyze complete GSR particles from both conventional and nontoxic ammunition fired at different cloth targets. The same cloths were then stained with blood to mimic real evidence and measured. The direct analysis using Raman imaging of the GSR particles collected with the stubs used for SEM-EDX analysis (the frequent method used for GSR collection) was evaluated. Multivariate curve-resolution and chemical-mapping methods were applied to the spectroscopic data to identify and highlight the signal corresponding to the GSR particles and differentiate them from the substrates. It was confirmed that both measurement approaches (on the targets and the stubs) could be used for the identification of GSR particles, even under unfavorable conditions such as the presence of blood. The results obtained demonstrate the huge potential of Raman imaging for the fast analysis of complete GSR particles and prove its complementary usefulness in the analysis of the stubs used by the well-established SEM-EDX technique. PMID- 26036697 TI - Detection of Brucella abortus DNA in aborted goats and sheep in Egypt by real time PCR. AB - BACKGROUND: Brucellosis is a major zoonoses affects wide range of domesticated as well as wild animals. Despite the eradication program of brucellosis in Egypt, the disease is still endemic among cattle, buffaloes, sheep, goats, and camels. RESULTS: In the present study, abortion occurred naturally among 25 animals (10 cows, 5 buffaloes, 9 Egyptian Baladi goats and 1 ewe) shared the same pasture were investigated by real-time polymerase chain reaction (RT-PCR). DNA of Brucella (B.) abortus was detected in serum of goats and sheep which has aborted recently by species-specific RT-PCR. The results suggest cross-species infection of B. abortus from cattle to non-preferred hosts raised in close contact. CONCLUSION: This article will renew our knowledge about the Brucella agent causing abortion in small ruminants in Egypt. Information provided in this study is important for surveillance program, because eradication programs and vaccination strategies may have to be adapted accordingly. PMID- 26036698 TI - Selection of Antibodies Interfering with Cell Surface Receptor Signaling Using Embryonic Stem Cell Differentiation. AB - Antibodies able to bind and modify the function of cell surface signaling components in vivo are increasingly being used as therapeutic drugs. The identification of such "functional" antibodies from within large antibody pools is, therefore, the subject of intense research. Here we describe a novel cell based expression and reporting system for the identification of functional antibodies from antigen-binding populations preselected with phage display. The system involves inducible expression of the antibody gene population from the Rosa-26 locus of embryonic stem (ES) cells, followed by secretion of the antibodies during ES cell differentiation. Target antigens are cell-surface signaling components (receptors or ligands) with a known effect on the direction of cell differentiation (FGFR1 mediating ES cell exit from self renewal in this particular protocol). Therefore, inhibition or activation of these components by functional antibodies in a few elite clones causes a shift in the differentiation outcomes of these clones, leading to their phenotypic selection. Functional antibody genes are then recovered from positive clones and used to produce the purified antibodies, which can be tested for their ability to affect cell fates exogenously. Identified functional antibody genes can be further introduced in different stem cell types. Inducible expression of functional antibodies has a temporally controlled protein-knockdown capability, which can be used to study the unknown role of the signaling pathway in different developmental contexts. Moreover, it provides a means for control of stem cell differentiation with potential in vivo applications. PMID- 26036699 TI - Inverse problem analysis of pluripotent stem cell aggregation dynamics in stirred suspension cultures. AB - The cultivation of stem cells as aggregates in scalable bioreactor cultures is an appealing modality for the large-scale manufacturing of stem cell products. Aggregation phenomena are central to such bioprocesses affecting the viability, proliferation and differentiation trajectory of stem cells but a quantitative framework is currently lacking. A population balance equation (PBE) model was used to describe the temporal evolution of the embryonic stem cell (ESC) cluster size distribution by considering collision-induced aggregation and cell proliferation in a stirred-suspension vessel. For ESC cultures at different agitation rates, the aggregation kernel representing the aggregation dynamics was successfully recovered as a solution of the inverse problem. The rate of change of the average aggregate size was greater at the intermediate rate tested suggesting a trade-off between increased collisions and agitation-induced shear. Results from forward simulation with obtained aggregation kernels were in agreement with transient aggregate size data from experiments. We conclude that the framework presented here can complement mechanistic studies offering insights into relevant stem cell clustering processes. More importantly from a process development standpoint, this strategy can be employed in the design and control of bioreactors for the generation of stem cell derivatives for drug screening, tissue engineering and regenerative medicine. PMID- 26036700 TI - Curcumin Targeted, Polymalic Acid-Based MRI Contrast Agent for the Detection of Abeta Plaques in Alzheimer's Disease. AB - Currently, there is no gadolinium-based contrast agent available for conventional magnetic resonance imaging (MRI) detection of amyloidal beta (Abeta) plaques in Alzheimer's disease (AD). Its timely finding would be vital for patient survival and quality of life. Curcumin (CUR), a common Indian spice effectively binds to Abeta plaques which is a hallmark of AD. To address this binding, we have designed a novel nanoimaging agent (NIA) based on nature-derived poly(beta-l malic acid) (PMLA) containing covalently attached gadolinium-DOTA(Gd-DOTA) and nature-derived CUR. The all-in-one agent recognizes and selectively binds to Abeta plaques and is detected by MRI. It efficiently detected Abeta plaques in human and mouse samples by an ex vivo staining. The method can be useful in clinic for safe and noninvasive diagnosis of AD. PMID- 26036701 TI - Exploring equity in uptake of the NHS Health Check and a nested physical activity intervention trial. AB - BACKGROUND: Socio-demographic factors characterizing disadvantage may influence uptake of preventative health interventions such as the NHS Health Check and research trials informing their content. METHODS: A cross-sectional study examining socio-demographic characteristics of participants and non-participants to the NHS Health Check and a nested trial of very brief physical activity interventions within this context. Age, gender, Index of Multiple Deprivation (IMD) and ethnicity were extracted from patient records of four General Practices (GP) in England. RESULTS: In multivariate analyses controlling for GP surgery, the odds of participation in the Health Check were higher for older patients (OR 1.05, 95% CI 1.04-1.07) and lower from areas of greater deprivation (IMD Quintiles 4 versus 1, OR 0.37, 95% CI 0.18-0.76, 5 versus 1 OR 0.42, 95% CI 0.20 0.88). Older patients were more likely to participate in the physical activity trial (OR 1.04, 95% CI 1.02-1.06). CONCLUSIONS: Younger patients and those living in areas of greater deprivation may be at risk of non-participation in the NHS Health Check, while younger age also predicted non-participation in a nested research trial. The role that GP-surgery-specific factors play in influencing participation across different socio-demographic groups requires further exploration. PMID- 26036702 TI - Body mass index relates weight to height differently in women and older adults: serial cross-sectional surveys in England (1992-2011). AB - BACKGROUND: Body mass index (BMI) tends to be higher among shorter adults, especially women. The dependence of BMI-height correlation on age and calendar time may inform us about temporal determinants of BMI. METHODS: Series of cross sectional surveys: Health Survey for England, 1992-2011. We study the Benn Index, which is the coefficient in a regression of log(weight) on log(height). This is adjusted for age, gender and calendar time, allowing for non-linear terms and interactions. RESULTS: By height quartile, mean BMI decreased with increasing height, more so in women than in men (P < 0.001). The decrease in mean BMI in the tallest compared with the shortest height quartile was 0.77 in men (95% CI 0.69, 0.86) and 1.98 in women (95% CI 1.89, 2.08). Regression analysis of log(weight) on log(height) revealed that the inverse association between BMI and height was more pronounced in older adults and stronger in women than in men, with little change over calendar time. CONCLUSIONS: Unlike early childhood, where taller children tend to have higher BMI, adults, especially women and older people, show an inverse BMI-height association. BMI is a heterogeneous measure of weight-for height; height may be an important and complex determinant of BMI trajectory over the life course. PMID- 26036703 TI - The role of public law-based litigation in tobacco companies' strategies in high income, FCTC ratifying countries, 2004-14. AB - BACKGROUND: Tobacco companies use a host of strategies to undermine public health efforts directed to reduce and eliminate smoking. The success, failure and trends in domestic litigation used by tobacco companies to undermine tobacco control are not well understood, with commentators often assuming disputes are trade related or international in nature. We analyse domestic legal disputes involving tobacco companies and public health actors in high-income countries across the last decade to ascertain the types of action and the success or failure of cases, develop effective responses. METHODS: WorldLii, a publicly available online law repository, was used to identify domestic court cases involving tobacco companies from 2004 to 2014, while outcome data from LexisNexis and Westlaw databases were used to identify appeals and trace case history. RESULTS: We identified six domestic cases in the UK, Australia and Canada, noting that the tobacco industry won only one of six cases; a win later usurped by legislative reform and a further court case. Nevertheless, we found cases involve significant resource costs for governments, often progressing across multiple jurisdictional levels. DISCUSSION: We suggest that, in light of our results, while litigation takes up significant time and incurs legal costs for health ministries, policymakers must robustly fend off suggestions that litigation wastes taxpayers' money, pointing to the good prospects of winning such legal battles. PMID- 26036704 TI - The role of paraffin oil on the interaction between denitrifying anaerobic methane oxidation and Anammox processes. AB - Methane is sparingly soluble in water, resulting in a slow reaction rate in the denitrifying anaerobic methane oxidation (DAMO) process. The slow rate limits the feasibility of research to examine the interaction between the DAMO and the anaerobic ammonium oxidation (Anammox) process. In this study, optimized 5 % (v/v) paraffin oil was added as a second liquid phase to improve methane solubility in a reactor containing DAMO and Anammox microbes. After just addition, methane solubility was found to increase by 25 % and DAMO activity was enhanced. After a 100-day cultivation, the paraffin reactor showed almost two times higher consumption rates of NO3 (-) (0.2268 mmol/day) and NH4 (+) (0.1403 mmol/day), compared to the control reactor without paraffin oil. The microbes tended to distribute in the oil-water interface. The quantitative (q) PCR result showed the abundance of gene copies of DAMO archaea, DAMO bacteria, and Anammox bacteria in the paraffin reactor were higher than those in the control reactor after 1 month. Fluorescence in situ hybridization revealed that the percentages of the three microbes were 55.5 and 77.6 % in the control and paraffin reactors after 100 days, respectively. A simple model of mass balance was developed to describe the interactions between DAMO and Anammox microbes and validate the activity results. A mechanism was proposed to describe the possible way that paraffin oil enhanced DAMO activity. It is quite clear that paraffin oil enhances not only DAMO activity but also Anammox activity via the interaction between them; both NO3 (-) and NH4 (+) consumption rates were about two times those of the control. PMID- 26036705 TI - Heterologous expression of tyrosinase (MelC2) from Streptomyces avermitilis MA4680 in E. coli and its application for ortho-hydroxylation of resveratrol to produce piceatannol. AB - Recombinant tyrosinase from Streptomyces avermitilis MA4680, MelC2 (gi:499291317), was heterologously expressed in Escherichia coli BL21 (DE3). The expression level of active MelC2 was increased by the codon-optimized MelC1 caddie protein (KP198295.1). By performing saturation mutagenesis of the Y91 residue of MelC1, it was found that aromatic residues such as Y, F, and W at the 91st position help produce a correctly folded conformation of MelC2. The recombinant MelC2 was utilized as a biocatalyst to convert trans-resveratrol into piceatannol. In order to improve the product yield through suppression of the formation of melanin, a by-product, an increase in the ratio of monooxygenation (k 1) to dioxygenation (k 2) of MelC2 is desirable. This was achieved by a combination of protein engineering and regeneration of NADH with glucose dehydrogenase (GDH). Saturation mutagenesis was performed at 15 residues within 8 A radius from copper ions of MelC2. A total of 2760 mutants were examined (99.7 % probability for NNK codon) and I41Y, a mutant, was screened. The ratio of k 1 to k 2 of the mutant increased sevenfold on tyrosine and fivefold on resveratrol, when compared to wild-type MelC2. As a result, the overall product yield from 500 MUM resveratrol in 50-mL reaction was 15.4 % (77.4 MUM piceatannol), 1.7 times higher than wild type. When I41Y was incorporated with the NADH regeneration system, the total product yield was 58.0 %, an eightfold increase (290.2 MUM of piceatannol). PMID- 26036706 TI - Utilization of secondary-treated wastewater for the production of freshwater microalgae. AB - In this work, we studied the potential use of secondary-treated wastewater as nutrient source in the production of freshwater microalgae strains. Experiments were performed indoors in a semicontinuous mode, at 0.3 day(-1), simulating outdoor conditions. We demonstrated that all the tested strains can be produced by using only secondary-treated wastewater as the nutrient source. The utilization of secondary-treated wastewater imposes nutrient-limiting conditions, with maximal biomass productivity dropping to 0.5 g l(-1) day(-1) and modifies the biochemical composition of the biomass by increasing the amount of lipids and carbohydrates while reducing the biomass protein content. We measured fatty acid content and productivity of up to 25 %d.wt. and 110 mg l(-1) day(-1), respectively. We demonstrated that all the tested strains were capable of completely removing the nitrogen and phosphorus contained in the secondary treated wastewater, and while the use of this effluent reduced the cells' photosynthetic efficiency, the nitrogen and phosphorus coefficient yield increased. Muriellopsis sp. and S. subpicatus were selected as the most promising strains for outdoor production using secondary-treated wastewater as the culture medium; this was not only because of their high productivity but also their photosynthetic efficiency, of up to 2.5 %, along with nutrient coefficient yields of up to 96 gbiomass gN (-1) and 166 gbiomass gP (-1). Coupling microalgae production processes to tertiary treatment in wastewater treatment plants make it possible to recover nutrients contained in the water and to produce valuable biomass, especially where nutrient removal is required prior to wastewater discharge. PMID- 26036707 TI - Direct Coexistence Methods to Determine the Solubility of Salts in Water from Numerical Simulations. Test Case NaCl. AB - The solubility of NaCl, an equilibrium between a saturated solution of ions and a solid with a crystalline structure, was obtained from molecular dynamics simulations using the SPC/E and TIP4P-Ew water models. Four initial setups on supersaturated systems were tested on sodium chloride (NaCl) solutions to determine the equilibrium conditions and computational performance: (1) an ionic solution confined between two crystal plates of periodic NaCl, (2) a solution with all the ions initially distributed randomly, (3) a nanocrystal immersed in pure water, and (4) a nanocrystal immersed in an ionic solution. In some cases, the equilibration of the system can take several microseconds. The results from this work showed that the solubility of NaCl was the same, within simulation error, for the four setups, and in agreement with previously reported values from simulations with the setup (1). The system of a nanocrystal immersed in supersaturated solution was found to equilibrate faster than others. In agreement with laser-Doppler droplet measurements, at equilibrium with the solution the crystals in all the setups had a slight positive charge. PMID- 26036708 TI - Current intravitreal pharmacologic therapies for diabetic macular edema. AB - INTRODUCTION: Diabetic retinopathy is the leading cause of vision loss in working age adults; it is a highly prevalent cause of vision loss overall and has a potent impact on the quality of life in those with diabetes mellitus and public health in general. Diabetic macular edema (DME) is the most common cause of vision loss from diabetic retinopathy. In patients with diabetes mellitus, chronic hyperglycemia leads to activation of the inflammatory cascade and retinal capillary damage that result in microaneurysm formation in the retina. In addition to the possibility of associated ischemia, microaneurysms are hyperpermeable; the resultant loss of the blood-retinal barrier leads to vision loss if consequent edema involves the center of the fovea. The standard of DME therapy for >25 years was focal laser photocoagulation applied to or near the microaneurysms. However, results from clinical trials of intravitreal vascular endothelial growth factor (VEGF) blockers and corticosteroids for the treatment of DME have led to a dramatic paradigm shift away from laser therapy to primary treatment with these pharmacologic agents. METHODS: Medline literature search of approaches for treating DME. RESULTS: Intravitreal pharmacologic treatments with anti-VEGF agents and corticosteroids have recently been shown to be superior to laser treatment of DME. CONCLUSION: The existence of pharmacologic treatment of DME, shown to be superior to laser monotherapy, has created a seismic change in the approach of treatment of these patients. This review provides a summary of the therapies and the rationale regarding the current pharmacologic therapy of DME. PMID- 26036709 TI - Concentration-dependent activation of dopamine receptors differentially modulates GABA release onto orexin neurons. AB - Dopamine (DA) and orexin neurons play important roles in reward and food intake. There are anatomical and functional connections between these two cell groups: orexin peptides stimulate DA neurons in the ventral tegmental area and DA inhibits orexin neurons in the hypothalamus. However, the cellular mechanisms underlying the action of DA on orexin neurons remain incompletely understood. Therefore, the effect of DA on inhibitory transmission to orexin neurons was investigated in rat brain slices using the whole-cell patch-clamp technique. We found that DA modulated the frequency of spontaneous and miniature IPSCs (mIPSCs) in a concentration-dependent bidirectional manner. Low (1 MUM) and high (100 MUM) concentrations of DA decreased and increased IPSC frequency, respectively. These effects did not accompany a change in mIPSC amplitude and persisted in the presence of G-protein signaling inhibitor GDPbetaS in the pipette, suggesting that DA acts presynaptically. The decrease in mIPSC frequency was mediated by D2 receptors whereas the increase required co-activation of D1 and D2 receptors and subsequent activation of phospholipase C. In summary, our results suggest that DA has complex effects on GABAergic transmission to orexin neurons, involving cooperation of multiple receptor subtypes. The direction of dopaminergic influence on orexin neurons is dependent on the level of DA in the hypothalamus. At low levels DA disinhibits orexin neurons whereas at high levels it facilitates GABA release, which may act as negative feedback to curb the excitatory orexinergic output to DA neurons. These mechanisms may have implications for consummatory and motivated behaviours. PMID- 26036710 TI - Meningococcal serogroup Y disease in Europe: Continuation of high importance in some European regions in 2013. AB - Neisseria meningitidis or meningococcus is divided into 12 distinct serogroups of which A, B, C, W, X, and Y are medically most important and cause health problems in different parts of the world. The epidemiology of N. meningitidis is unpredictable over time and across geographic regions. Globally, serogroup A has been prevalent in the African "meningitis belt" whereas serogroup B and C have predominated in Europe. In a paper published earlier in this journal (1) , an increase in serogroup Y invasive meningococcal disease (IMD) in some European countries was reported based on the epidemiological data for 2010, 2011 and 2012. Here, we report additional data from 30 European countries indicating that high or increased serogroup Y disease levels have continued in 2013 in certain regions of Europe. In the Western and Central Europe, there were no major changes in the proportion of serogroup Y IMD cases in 2013 compared to 2012. In the Scandinavian countries, proportion of serogroup Y disease remained high, ranging from 26% to 51% in 2013. This was in contrast to Baltic, Eastern and most Southern European countries, where the proportion of serogroup Y IMD was low similarly to previous years. For the last 2 decades, the mean age of patients affected by serogroup Y was 41 y for 7 countries from which data was available and 50% of cases were in patients aged 45 to 88 y. The age distribution of serogroup Y was bimodal and did not change significantly despite the increase of the total number and the proportion of serogroup Y IMD in some European regions. PMID- 26036711 TI - Metacommunity speciation models and their implications for diversification theory. AB - The emergence of new frameworks combining evolutionary and ecological dynamics in communities opens new perspectives on the study of speciation. By acknowledging the relative contribution of local and regional dynamics in shaping the complexity of ecological communities, metacommunity theory sheds a new light on the mechanisms underlying the emergence of species. Three integrative frameworks have been proposed, involving neutral dynamics, niche theory, and life history trade-offs respectively. Here, we review these frameworks of metacommunity theory to emphasise that: (1) studies on speciation and community ecology have converged towards similar general principles by acknowledging the central role of dispersal in metacommunities dynamics, (2) considering the conditions of emergence and maintenance of new species in communities has given rise to new models of speciation embedded in the metacommunity theory, (3) studies of diversification have shifted from relating phylogenetic patterns to landscapes spatial and ecological characteristics towards integrative approaches that explicitly consider speciation in a mechanistic ecological framework. We highlight several challenges, in particular the need for a better integration of the eco evolutionary consequences of dispersal and the need to increase our understanding on the relative rates of evolutionary and ecological changes in communities. PMID- 26036713 TI - Recent advances in purely organic phosphorescent materials. AB - Luminescent organic materials have attracted significant attention in recent times owing to their opportunities in various functional applications. Interestingly, unlike fluorescence, opportunities hidden within the phosphorescence properties of organic compounds have received considerably less attention even until last few years. It is only in the second decade of the 21st century, within a time span of less than last 5 years, that the concepts and prospects of organic compounds as phosphorescent materials have evolved rapidly. The previously perceived limitations of organic compounds as phosphorescent materials have been overcome and several molecules have been designed using old and new concepts, such as heavy atom effects, matrix assisted isolation, hydrogen bonding and halogen bonding, thereby gaining access to a significant number of materials with efficient phosphorescent features. In addition, significant improvements have been made in the development of RTP (room temperature phosphorescent) materials, which can be used under ambient conditions. In this review, we bring together the vastly different approaches developed by various researchers to understand and appreciate this recent revolution in organic luminescent materials. PMID- 26036712 TI - How do infants recognize joint attention? AB - The emergence of joint attention is still a matter of vigorous debate. It involves diverse hypotheses ranging from innate modules dedicated to intention reading to more neuro-constructivist approaches. The aim of this study was to assess whether 12-month-old infants are able to recognize a "joint attention" situation when observing such a social interaction. Using a violation-of expectation paradigm, we habituated infants to a "joint attention" video and then compared their looking time durations between "divergent attention" videos and "joint attention" ones using a 2 (familiar or novel perceptual component)*2 (familiar or novel conceptual component) factorial design. These results were enriched with measures of pupil dilation, which are considered to be reliable measures of cognitive load. Infants looked longer at test events that involved novel speaker and divergent attention but no changes in infants' pupil dilation were observed in any conditions. Although looking time data suggest that infants may appreciate discrepancies from expectations related to joint attention behavior, in the absence of clear evidence from pupillometry, the results show no demonstration of understanding of joint attention, even at a tacit level. Our results suggest that infants may be sensitive to relevant perceptual variables in joint attention situations, which would help scaffold social cognitive development. This study supports a gradual, learning interpretation of how infants come to recognize, understand, and participate in joint attention. PMID- 26036714 TI - Expression of gonadal steroid receptors in the ovaries of post-menopausal women with malignant or benign endometrial pathology: a pilot study. AB - This pilot study aimed to investigate the expression of estrogen (ER) and progesterone receptors (PR), as well as their subtypes [alpha (ERalpha), beta (ERbeta)], in the ovaries of postmenopausal women with benign or malignant endometrial pathology. Twenty postmenopausal women (age 66.2 +/- 7.4 years) were included, diagnosed with benign (n = 10) or malignant [(serous/papillary (n = 4), endometrioid (n = 6)] endometrial lesions. Higher ERbeta and PR ovarian expressions were observed comparing women with endometrioid versus non endometrioid endometrial carcinoma (p = 0.022 and p = 0.029, respectively). Age, age at menarche and presence of hypertension were negatively associated with ERs and PR expression. The expression of ERalpha and ERbeta was inversely correlated with menopausal age, which was not verified for PR. No significant association was observed between ERs or PR expression and benign or malignant endometrial pathology. Higher expression of ERbeta and PR in the postmenopausal ovary is associated with the presence of a less aggressive type of endometrial cancer, comparing women with endometrioid versus non-endometrioid lesions. The expression pattern of ovarian receptors did not differ regarding the development of benign or malignant endometrial lesions. Larger observational studies are necessary to confirm the significance of our findings. PMID- 26036715 TI - Term pregnancy and live birth subsequent to immediate uterine transfer of sperm microinjected oocyte in a natural cycle. AB - It has been reported that it is possible to achieve a pregnancy after immediate uterine transfer of oocyte and sperm, before fertilization and cleavage were known to have occurred; there is an enormous amount of work about the optimal timing of embryo transfer, with no conclusive evidence of a gold standard satisfying patient age, endometrial receptivity, hormonal levels and embryological parameters. We hereby report a case of one 35-year-old nulligravid woman with longstanding tubal factor infertility and 3 previous failed ICSI cycles, treated with ICSI and immediate transfer of the oocyte microinjected with a spermatozoon in a natural cycle. A single oocyte was retrieved, injected with a spermatozoon and transferred 40 min after injection, resulting in an uneventful pregnancy and delivery of a healthy female infant weighing 3320 g at 40 weeks' estimated gestational age. This case, certainly novel, should be interpreted with caution. Whether confirmed for efficacy and safeness in appropriate controlled clinical trials, our present observation could offer a simple, practical and cost effective approach in ART programs in selected patients. PMID- 26036716 TI - Polymorphisms of the methylenetetrahydrofolate reductase gene (C677T and A1298C) in the placenta of pregnancies complicated with preeclampsia. AB - BACKGROUND: Preeclampsia has been related to single-nucleotide polymorphisms (SNPs) of the methylenetetrahydrofolate reductase (MTHFR) gene; however, data regarding the placenta are still lacking. OBJECTIVE: To determine the frequency of C677T and A1298C SNPs of the MTHFR gene in the placenta of preeclamptic pregnancies and healthy controls. METHODS: Genotyping of C677T and A1298C polymorphisms of the MTHFR gene using RFLP-PCR was performed to the placenta of 100 gestations (n = 50 complicated with preeclampsia and n = 50 normal controls matched for parity and maternal age). RESULTS: Gestational age at birth and neonatal and placental weight were significantly lower in women with preeclampsia as compared to controls. The TT genotype of the C677T polymorphism was threefold more prevalent in preeclamptic placentas as compared to the placenta of controls (24.0% versus 8.0%, p = 0.001). Upon pooled analysis (n = 100), placental and neonatal weights were significantly lower in placentas displaying this genotype (TT, C677T) as compared with the CC genotype. CONCLUSION: This study found that the frequency of the TT mutant genotype of the C677T polymorphism was higher in the placenta of pregnancies complicated with preeclampsia. There is a need for further research in this matter. PMID- 26036717 TI - How can we better predict the risk of spontaneous miscarriage among women experiencing threatened miscarriage? AB - This study seeks to establish progesterone and progesterone-induced blocking factor (PIBF) levels as predictors of subsequent completed miscarriage among women presenting with threatened miscarriage between 6 and 10 weeks of gestation. Our secondary objective was to assess the known maternal risk factors, toward development of a parsimonious and clinician-friendly risk assessment model for predicting completed miscarriage. In this article, we present a prospective cohort study of 119 patients presenting with threatened miscarriage from gestation weeks 6 to 10 at a tertiary women's hospital emergency unit in Singapore. Thirty (25.2%) women had a spontaneous miscarriage. Low progesterone and PIBF levels are similarly predictive of subsequent completed miscarriage. Study results (OR, 95% CI) showed that higher levels of progesterone (0.91, 95% CI 0.88-0.94) and PIBF (0.99, 95% CI 0.98-0.99) were associated with lower risk of miscarriage. Low progesterone level was a very strong predictor of miscarriage risk in our study despite previous concerns about its pulsatile secretion. Low serum progesterone and PIBF levels predicted spontaneous miscarriage among women presenting with threatened miscarriage between gestation weeks 6 to 10. Predictive models to calculate probability of spontaneous miscarriage based on serum progesterone, together with maternal BMI and fetal heart are proposed. PMID- 26036718 TI - Association of estrogen receptor gene polymorphisms with human precocious puberty: a systematic review and meta-analysis. AB - This study aims to estimate the association between ESR1 polymorphisms (PvuII and XbaI) and ESR2 polymorphisms (RsaI and AluI) with precocious puberty. Relevant studies published before March 2014 were retrieved by a electronic search among nine databases. Meta-analysis of the pooled odds ratios (ORs) with 95% confidence intervals (CIs) was calculated. Four eligible case-control studies including 491 precocious puberty patients and 370 healthy controls were identified. Three studies reported ESR1 PvuII and XbaI polymorphism and one study reported ESR2 RsaI and AluI polymorphism. Increment of precocious puberty risk was associated with PvuII polymorphism in the heterosis model ((CT) versus TT: OR 1.42, 95% CI: 1.05-1.91, p = 0.02). Risk of precocious puberty was associated with XbaI polymorphism in the dominant model (GG + GA versus AA: OR 1.48, 95% CI: 1.11 1.97, p = 0.007) and the heterosis model (GA versus AA: OR 1.68, 95% CI: 1.23 2.29, p = 0.001). This meta-analysis suggests that ESR1 XbaI and PvuII polymorphisms are associated with precocious puberty susceptibility, and the relationship between ESR2 RsaI and AluI polymorphism with precocious puberty remains to be further investigated. Well-designed studies with large sample size among different polymorphisms and ethnicities are in urgent need to provide and update reliable data for comprehensive and definite conclusion. PMID- 26036719 TI - Results from the International Consensus Conference on myo-inositol and D-chiro inositol in Obstetrics and Gynecology--assisted reproduction technology. AB - A substantial body of research on mammalian gametogenesis and human reproduction has recently investigated the effect of myo-inositol (MyoIns) on oocyte and sperm cell quality, due to its possible application to medically assisted reproduction. With a growing number of both clinical and basic research papers, the meaning of several observations now needs to be interpreted under a solid and rigorous physiological framework. The 2013 Florence International Consensus Conference on Myo- and D-chiro-inositol in obstetrics and gynecology has answered a number of research questions concerning the use of the two stereoisomers in assisted reproductive technologies. Available clinical trials and studies on the physiological and pharmacological effects of these molecules have been surveyed. Specifically, the physiological involvement of MyoIns in oocyte maturation and sperm cell functions has been discussed, providing an answer to the following questions: (1) Are inositols physiologically involved in oocyte maturation? (2) Are inositols involved in the physiology of spermatozoa function? (3) Is treatment with inositols helpful within assisted reproduction technology cycles? (4) Are there any differences in clinical efficacy between MyoIns and D-chiro inositol? The conclusions of this Conference, drawn depending on expert panel opinions and shared with all the participants, are summarized in this review paper. PMID- 26036720 TI - Biomarkers for pediatric pulmonary arterial hypertension: challenges and recommendations. AB - Pediatric pulmonary arterial hypertension (PAH) is an uncommon disease that can occur in neonates, infants, and children, and is associated with high morbidity and mortality. Despite advances in treatment strategies over the last two decades, the underlying structural and functional changes to the pulmonary arterial circulation are progressive and lead eventually to right heart failure. The management of PAH in children is complex due not only to the developmental aspects but also because most evidence-based practices derive from adult PAH studies. As such, the pediatric clinician would be greatly aided by specific characteristics (biomarkers) objectively measured in children with PAH to determine appropriate clinical management. This review highlights the current state of biomarkers in pediatric PAH and looks forward to potential biomarkers, and makes several recommendations for their use and interpretation. PMID- 26036721 TI - Coronary artery calcium: 0.5 mm slice-thickness reconstruction with adjusted attenuation threshold outperforms 3.0 mm by validating against spatially registered intravascular ultrasound with radiofrequency backscatter. AB - RATIONALE AND OBJECTIVES: Coronary artery calcium (CAC) images can be reconstructed with thinner slice thickness on some modern multidetector-row computed tomography scanners without additional radiation. We hypothesized that the isotropic 0.5-mm CAC reconstruction outperforms the conventional 3.0-mm reconstruction in detecting and quantifying coronary calcium, and we proposed to compare them by validating against spatially registered intravascular ultrasound with radiofrequency backscatter-virtual histology (IVUS-VH). MATERIALS AND METHODS: Twenty-seven patients were enrolled, and 5976 mm of coronary arteries were analyzed. A semiautomatic software was developed to coregister CAC and IVUS VH on a detailed slice-by-slice basis. Calcium detection and calcium volume quantification were evaluated and compared using varying calcium attenuation thresholds. Algorithms for deriving individualized optimal threshold and comparable Agatston score on the 0.5-mm reconstruction were developed. RESULTS: The isotropic 0.5-mm reconstruction achieved significantly higher area under receiver-operating curve than the conventional 3.0-mm reconstruction (0.9 vs. 0.74, P < .001). Using the optimal threshold, the 0.5-mm reconstruction had higher sensitivity (0.79 vs. 0.65), specificity (0.85 vs. 0.77), positive predictive value (0.42 vs. 0.29), and negative predictive value (0.97 vs. 0.94) than the 3.0 mm. Individualized optimal threshold was significantly correlated with the image noise (r = 0.66, P < .001) in the 0.5-mm reconstruction. CONCLUSIONS: By optimizing the calcium threshold, the 0.5-mm reconstruction is superior to the conventional 3.0-mm in detecting and quantifying calcium, which may improve the clinical value of CAC without additional radiation. PMID- 26036723 TI - Patients' perceptions of participation in nursing care on medical wards. AB - BACKGROUND: Patient participation benefits the patient and is a core concept of patient-centred care. Patients believe in their ability to prevent errors; thus, they may play a vital role in combating adverse event rates in hospitals. AIMS AND OBJECTIVES: To explore hospitalised medical patients' perceptions of participating in nursing care, including the barriers and facilitators for this activity. RESEARCH METHODS: This interpretive study was conducted on four medical wards, in two hospitals. Purposeful maximum variation sampling was operationalised to recruit patients that differed in areas such as age, gender and mobility status. In-depth semi-structured audiotaped interviews were undertaken and analysed using inductive content analysis. RESULTS: Twenty patients participated in the study. Four categories were uncovered in the data. First, valuing participation showed patients' willingness to participate, viewing it as a worthwhile task. Second, exchanging intelligence was a way of participating where patients' knowledge was built and shared with health professionals. Third, on the lookout was a type of participation where patients monitored their care, showing an attentive approach towards their own safety. Fourth, power imbalance was characterised by patients feeling their opportunities for participation were restricted. CONCLUSIONS: Patients were motivated to participate and valued participation. Cultivating this motivation may be crucial to patient empowerment and practices of safety monitoring, a fundamental strategy to addressing patient safety issues in hospitals. Engaging nurse-patient relationships, inclusive of knowledge sharing, is required in practice to empower patients to participate. Educating patients on the consequences of non participation may motivate them, while nurses may benefit from training on patient-centred approaches. Future research should address ways to increase patient motivation and opportunities to participate. PMID- 26036722 TI - A tale of two CLCs: biophysical insights toward understanding ClC-5 and ClC-7 function in endosomes and lysosomes. AB - The CLC protein family comprises both Cl(-) channels and H(+) -coupled anion transporters. The understanding of the critical role of CLC proteins in a number of physiological functions has greatly contributed to a revision of the classical paradigm that attributed to Cl(-) ions only a marginal role in human physiology. The endosomal ClC-5 and the lysosomal ClC-7 are the best characterized human CLC transporters. Their dysfunction causes Dent's disease and osteopetrosis, respectively. It had been originally proposed that they would provide a Cl(-) shunt conductance allowing efficient acidification of intracellular compartments. However, this model seems to conflict with the transport properties of these proteins and with recent physiological evidence. Currently, there is no consensus on their specific physiological role. CLC proteins present also a number of peculiar biophysical properties, such as the dimeric architecture, the co existence of intrinsically different thermodynamic modes of transport based on similar structural principles, and the gating mechanism recently emerging for the transporters, just to name a few. This review focuses on the biophysical properties and physiological roles of ClC-5 and ClC-7. PMID- 26036724 TI - Targeted delivery of transferrin and TAT co-modified liposomes encapsulating both paclitaxel and doxorubicin for melanoma. AB - The purpose of this study was to develop an efficient dual-ligand based liposomal drug delivery system with targeting specificity as well as properties that would kill melanoma cells. Liposomes modified with transferrin (Tf) and cell penetrating peptide TAT was prepared, which encapsulated two kinds of chemotherapy drugs, paclitaxel and doxorubicin (Tf/TAT-PTX/DOX-LP). The Tf ligands specifically bind to the overexpressed Tf receptors on the surface of melanoma cells, while the TAT ligands functioned as a classical cell penetrating peptide, helping dual-ligand liposomes be internalized by melanoma cells. The effect of dual-targeting system and "double-drug" combination therapy were evaluated both in vitro and in vivo. In vitro, cellular uptake, intracellular distribution and tumor spheroids penetration studies demonstrated that the system could not only be selectively and efficiently penetrate melanoma cells. Besides, apoptosis staining assay and cytotoxicity showed effective anti-tumor capability and obvious synergistic effect of combination therapy of PTX and DOX. In vivo imaging and fluorescent images of tumor section further demonstrated that Tf/TAT PTX/DOX-LP had the highest tumor distribution. The results of these experiments demonstrated that double-drug liposomal drug delivery systems (DDS) had both enhanced targeting efficiency and increased therapeutic efficacy. PMID- 26036725 TI - Incidence, risk factors and hospital burden in children under five years of age hospitalised with respiratory syncytial virus infections. AB - AIM: Respiratory syncytial virus (RSV) infections are among the most common lower respiratory tract infections in infants, but few studies have determined the age specific incidence of hospitalisation in defined populations. This study gathered Swedish data on RSV in Gothenburg and its 10 surrounding municipalities from 2004 to 2011. METHODS: Information was obtained from hospital databases of all patients up to five years of age who had a discharge diagnosis of an RSV infection and had a positive antigen detection or polymerase chain reaction test. RESULTS: A total of 1764 children fulfilled the inclusion criteria and 238 of these were preterm. The incidence under one year of age was 17.4/1000/year, and in children aged one to four years it was 0.6/1000/year. RSV patients occupied a mean of 1141 hospital beds per year: 65 were treated in the intensive care unit, 27 needed ventilator support, 19 needed continuous positive airway pressure, 408 (23%) received antibiotics, 399 (23%) received steroids, and all but four patients received a bronchodilator. All children survived. CONCLUSION: The incidence of RSV infections was high, medication use was high, and complications were low. Preterm infants had a higher risk, but most infants needing hospitalisation for RSV are full term and have no known risk factors. PMID- 26036726 TI - Collective dynamics of non-coalescing and coalescing droplets in microfluidic parking networks. AB - We study the complex collective dynamics mediated by flow resistance interactions when trains of non-coalescing and coalescing confined drops are introduced into a microfluidic parking network (MPN). The MPN consists of serially connected loops capable of parking arrays of drops. We define parking modes based on whether drops park without breakage or drop fragments are parked subsequent to breakage or drops park after coalescence. With both non-coalescing and coalescing drops, we map the occurrence of these parking modes in MPNs as a function of system parameters including drop volume, drop spacing and capillary number. We find that the non-coalescing drops can either park or break in the network, producing highly polydisperse arrays. We further show that parking due to collision induced droplet break-up is the main cause of polydispersity. We discover that collisions occur due to a crowding instability, which is a natural outcome of the network topology. In striking contrast, with coalescing drops we show that the ability of drops to coalesce rectifies the volume of parked polydisperse drops, despite drops breaking in the network. We find that several parking modes act in concert during this hydrodynamic self-rectification mechanism, producing highly monodisperse drop arrays over a wide operating parameter space. We demonstrate that the rectification mechanism can be harnessed to produce two-dimensional arrays of microfluidic drops with highly tunable surface-to-volume ratios, paving the way for fundamental investigations of interfacial phenomena in emulsions. PMID- 26036727 TI - [Priorities in epidemiological research]. PMID- 26036728 TI - [Prevention between evidence of efficacy and ineffectiveness]. PMID- 26036729 TI - [Tuberculosis and immigration: the answers that epidemiology can provide (and society is waiting for)]. PMID- 26036730 TI - [Epidemiology to support prevention and health promotion in the reorganization of the Italian National Institute of Health]. PMID- 26036731 TI - [Registries and surveillances: lacks and perspectives]. PMID- 26036732 TI - [Epidemiology in troublesome scenarios]. PMID- 26036733 TI - [Epidemiological study on the health status of residents in Manfredonia (Italy). The beginning of the study told by the researchers]. PMID- 26036734 TI - [Epidemiological study on the health status of residents in Manfredonia (Italy). The beginning of the study told by the citizens]. AB - In Manfredonia (Southern Italy) an epidemiological study on the health status of the residents, based on a new perspective of a research shared by researchers and citizens, has been launched. The design of the study considered the previous history of Manfredonia, whose management of environmental issues produced distrust and suspicion towards institutions; these feelings are still alive in the civil society. In this article the beginning of the study is framed by means of a double narration: from the point of view of the researchers and of the citizens. After two public meetings, a citizen coordination group, a website and a public relation office have been created. During the next meetings, researchers and population will set the objectives of the survey, and the public health implications of different possible scenarios will be discussed. PMID- 26036735 TI - [A New Year scientific meteor]. PMID- 26036736 TI - [Stem cell division is necessary for oncogenesis, primary prevention is necessary to fight cancer]. PMID- 26036737 TI - [Antenatal course attendance among primiparous mothers, with physiological pregnancy and birth at term in Trentino (Northern Italy): characteristics of non attender women and benefits among attender women in pregnancy behaviours, type of birth delivery and neonatal outcomes]. AB - OBJECTIVE: to outline the attendance rate of antenatal classes (ANCs) among women resident in Trentino Region (North-Eastern Italy) during the period 2000-2012; to identify the main sociodemographic characteristics of women who do not attend ANCs and to measure the effectiveness of ANCs attendance. DESIGN: cohort study with a retrospective data collection. SETTING AND PARTICIPANTS: by the computerised database of Trentino Certificates of delivery care, primiparous mothers living in Trentino presenting a physiological pregnancy and birth at term (>=37 weeks of gestation) were selected. Temporal trends of ANCs attendance were also studied for all mothers living in Trentino, all primiparous residents, all multiparous residents and all residents with foreign citizenship. MAIN OUTCOME MEASURES: possible associations between the probability of not attending ANCs and sociodemographic variables concerning mothers were analysed: age, professional status, educational level, marital status, citizenship and residence in an area served by a maternal and child health (MCH) clinic or not. Significant relationships between ANCs attendance and variables related to course of pregnancy, childbirth and neonatal outcomes were identified. RESULTS: ANCs coverage has a statistically significant increasing trend over time for each group of women living in Trentino. Among the selected primiparous pregnant women, the principal barriers to ANCs access are being foreign, having an age <=30 years, in particular <=20 years, being housewives or unemployed, presenting a medium-low educational level, and residing in an area not served by a MCH clinic. ANCs-not-attending women show a lower awareness of the importance of performing serological tests for Syphilis and Cytomegalo-virus and they declare smoking in pregnancy. Benefits of ANCs attendance do not affect neonatal outcomes, but they concern a higher probability of vaginal birth and a higher breastfeeding predisposition. CONCLUSION: data about ANCs attendance in Trentino Region appear higher than other national-regional studies. However, there are significant differences in access to ANCs regarding women's sociodemographic characteristics and resources distribution and MCH clinics measurement. In Italy, an evaluation about the accessibility of MCH clinics and their functioning criteria is desirable, focusing on marketing practices towards lower classes women. In Trentino, virtuosos MCH clinics have introduced elastic times in the ANCs planning and they have involved cultural mediators and private gynaecologists. Younger pregnant women are included in the ANCs after a preliminary meeting or by individual paths. PMID- 26036738 TI - [Meta-analysis or pooled analysis? A comparison based on time-series used for the analysis of short-term effects of air pollution on human health]. AB - OBJECTIVES: to compare the meta-analysis and the pooled analysis approach to study short-term effects of air pollution on human health in Emilia-Romagna Region (Central Italy) cities, characterised by strong homogeneity of environmental and sociodemographic features. METHODS: application of fixed effects meta-analysis and fixed-effects pooled analysis on time-series data of seven cities in Emilia-Romagna in the period 2006-2010. The relationship among adverse health events (deaths due to natural causes, cardiovascular disease, cerebrovascular disease and respiratory disease) and concentrations of PM10, PM2.5 and NO2 was investigated by means of GAM models, using the EpiAir protocol. RESULTS: the pooled analysis application entailed a gain in terms of precision of effect estimates in respect to meta-analysis approach. The interval widths of pooled analysis are lower than those of meta-analytic estimates, with percentage reductions between 7% and 43%. This power increase led to a major number of statistically significant pooled analysis estimates. It has been a generally good correspondence between the two methods in terms of direction and strength of the association among health outcomes and the various pollutants. An exception is the PM10 effect estimate on respiratory mortality, where the meta-analytic estimate was significantly higher and not in line with literature data. CONCLUSIONS: the study highlighted the increase in accuracy and stability of effect estimates obtained from a pooled analysis compared to a meta-analysis in a regional context such as the Emilia-Romagna Region, characterised by the absence of heterogeneity in exposure to pollutants and other confounders. In this context, the pooled approach is to be considered preferable to meta-analysis. PMID- 26036739 TI - [Organisational determinants of adherence to secondary prevention medications after acute myocardial infarction]. AB - OBJECTIVES: to identify organisational determinants of adherence to evidence based drug treatments after acute myocardial infarction (AMI), under the hypothesis that low adherence is associated with higher mortality and risk of reinfarction. In particular, we investigated the effect of group vs. single handed practice and multi-professional practice characteristics on patients' adherence to polytherapy after AMI. DESIGN: retrospective cohort study. SETTING AND PARTICIPANTS: residents in the Local Health Authority of Bologna (Italy) who were discharged from any Italian hospital between 2008 and 2011 with a diagnosis of AMI, and followed-up for a year. MAIN OUTCOME MEASURES: adherence to at least three out of the four drug therapies recommended for secondary prevention of AMI (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta blockers, antiplatelet agents, statins). Patients who had at least 80% of days of follow-up covered by drug doses were considered adherent. RESULTS: of the 4,828 post-AMI patients, 31.6% were adherent to polytherapy. General practice characteristics were unrelated to adherence, whereas discharge from cardiology hospital wards was significantly associated with higher patients' adherence (OR 1.97; 95%CI 1.56-2.48). CONCLUSION: general practice organisational models are not associated with higher adherence to evidence-based medications after AMI, whereas cardiologists seem to play a key role in improving patient adherence to polytherapy. Healthcare delivery models should be designed; in them, general practitioners are responsible for the provision of patient-centred care pathways and for care co-ordination with other primary care professionals and specialists, and take an advocacy role for the patient when needed. PMID- 26036740 TI - [Tuberculosis among children and young adults in Emilia-Romagna Region (Northern Italy): surveillance system and integration with socioeconomic data]. AB - OBJECTIVES: to characterise the cases of tuberculosis (TB) aged 0-24 years reported in Emilia-Romagna (Northern Italy) Region between 2001 and 2010 through an ecological approach and from a sociodemographic perspective. DESIGN: observational study on notified TB cases, with data integration and subsequent location through geocoding and ecological deprivation index. SETTING AND PARTICIPANTS: notification records of TB cases identified by the current surveillance system. Cases were geocoded where address details were available and, through spatial intersection with census block polygons, the related deprivation index (DI) was attributed to them. MAIN OUTCOME MEASURES: deprivation index distribution of the observed cases. RESULTS: in the considered decade, 686 cases of tuberculosis in the age group 0-24 years were reported, 14.5% of the overall number of cases in the Emilia-Romagna Region. The DI was attributed to the 90.4% of cases. Notified TB cases were more frequently located in the most deprived areas. CONCLUSIONS: as other TB international surveillance systems, this study shows that it is possible to locate TB cases, to link them with census data and, therefore, to characterise with socioeconomic information. Looking ahead, the extension of the analysis to all age classes, the updating of socioeconomic data and the use of qualitative methodologies can integrate surveillance system data to better describe the social disadvantage among TB cases. PMID- 26036741 TI - [Impact of the abolition of food handler certification on notification rates of foodborne diseases in Italy]. AB - OBJECTIVES: to assess the trends of foodborne diseases in respect of the abolition of food handler certification by Italian Regions. DESIGN: rates of foodborne diseases recorded before and after the abolition of food handler certification were compared. SETTING AND PARTICIPANTS: the study included notifications collected in Italy through the national infectious disease surveillance system between 1996 and 2009. MAIN OUTCOME MEASURES: annual rates of seven main foodborne diseases. RESULTS: a significant reduction in notifications of foodborne diseases occurred in most Italian Regions in the years after the abolition of the food handler certification. CONCLUSIONS: the abolition of food handler certification coincided with no increase in the overall estimated incidence of foodborne diseases in the Italian population. Furthermore, the temporal and spatial patterns of notification rates suggest the possibility that other key factors have contributed to this result, including the heterogeneity of the surveillance system performance. PMID- 26036742 TI - [The mortality rate for homicide among women in Italy: a historical and geographical analysis as a contribution to the study of femicide]. AB - As 70% of the killings of women takes place in the context of relational dynamics and in 80% of the cases the perpetrator is a man, we can presume that femicide constitutes much of the homicide mortality among women. Epidemiological surveillance of the killings of women can, therefore, provide indicators on the trends and geographical distribution of femicide and, indirectly, of the more general phenomenon of harassment and violence against women. The analysis of 40 years of mortality shows only a slight decrease of the murders of women nationwide. This suggests that the factors that underline this phenomenon are deeply rooted in the relationship between men and women. The decrease has taken place mainly in the South and Islands and the percentage SMRs point to a reversal of the relationship between geographic areas: thus, at the end of the observation period the North-West assumes a greater weight than the South and Islands. So we cannot exclude that part of the decrease in murders of women can be attributed to the overall decrease in homicides related to criminal activity, most pronounced in the South and Islands. PMID- 26036743 TI - [SENTIERI studies: scientific evidence and lack of use for prevention]. AB - Studies from SENTIERI project have been crucial to show high-risk levels (mortality and morbidity) in communities living close to polluted sites. Despite the presence of some methodological limits, these studies represent a strong invitation towards primary prevention, also considering a possible underestimation of the health risk. The same pollutants responsible for the results showed in the SENTIERI studies are able to induce diseases (i.e., endocrine-metabolic diseases, spontaneous abortion, foetal malformations, autism, neurologic diseases) still unevaluated or not evaluable considering the actually available tools. SENTIERI illustrated only part of the health risk involving about 6 millions of Italians exposed since decades to environmental toxics, generated by legally approved plants. The well-documented health effects (avoidable since years) should be wider if a more extensive concept of "polluted site" was considered, according to the European Environment Agency (EEA) indications. It is ethically unacceptable to drive a model of public health based on damage recording in large communities living since decades in risky areas, absolutely neglecting preventive risk analysis. The clear results from SENTIERI did not induce great attention in politicians, who should be the main drivers of primary prevention measures. Our Country is not structured to act primary prevention actions, an unfeasible target in the short-medium term. Remediation measures were not effectively started or concluded in any of the examined sites; in some of these, additional polluting plants were realised, delaying the risk reduction. Health and environmental policies have not travelled on capable ways, until now. It is crucial to open collaborative and participative path to epidemiologists and experts skilled in environmental medicine to draw plans for prevention, which could be rapidly and effectively useful. PMID- 26036744 TI - [Unhealthy eating habits among children aged 8-9 are still common in Italy]. PMID- 26036746 TI - [The risk of cancer is slightly higher among Italian cancer patients than in the general population]. PMID- 26036747 TI - [The target of the National Prevention Plan]. PMID- 26036748 TI - Refinement of Protein Structure Predicted Models Using Minimum Spanning Tree. AB - The protein structure prediction is of three categories: homology modeling, fold recognition and ab initio modeling, and this division into categories depends on whether similar protein structures were previously determined using X-ray crystallography or NMR or not. Protein structure models predicted by the free modeling (ab initio modeling) are considered as low-resolution models. Progress has recently been made in refining low-resolution models (ab initio modeling) closer to the native ones; this can be done by minimizing the energy funnel of physics-based force fields. In this paper, we present a new refinement method based on applying minimum spanning tree to produce a connected graph from the atoms forming the protein. This connected graph represents the minimum van der Waals energy path. The new refinement method causes supplementary execution time (about 55.83486 sec. in the average for a protein sequence of length 166 amino acids) but enhance the predicted model of low resolution. We used a small set of 18 different targets got from CASP10. The results show the improvement in about (83.333%) of the cases. We compare our results with state-of-art algorithms results. PMID- 26036745 TI - [In Italy the prevalence of sedentary habits among children is decreasing]. PMID- 26036749 TI - Molecular characterization and expression profiles of neuropeptide precursors in the migratory locust. AB - Neuropeptides serve as the most important regulatory signals in insects. Many neuropeptides and their precursors have been identified in terms of the contig sequences of whole genome information of the migratory locust (Locusta migratoria), which exhibits a typical phenotypic plasticity in morphology, behavior and physiology. However, functions of these locust neuropeptides are largely unknown. In this study, we first revised the 23 reported neuropeptide precursor genes and identified almost all the neuropeptide precursors and corresponding products in L. migratoria. We further revealed the significant expansion profiles (such as AKH) and alternative splicing of neuropeptide genes (Lom-ITP, Lom-OK and Lom-NPF1). Transcriptomic analysis indicated that several neuropeptides, such as Lom-ACP and Lom-OK, displayed development-specific expression patterns. qRT-PCR data confirmed that most neuropeptide precursors were strongly expressed in the central nervous system. Fifteen neuropeptide genes displayed different expression levels between solitarious and gregarious locusts. These findings provide valuable clues to understand neuropeptide evolution and their functional roles in basic biology and phase transition in locusts. PMID- 26036750 TI - Cardiac resynchronization therapy and cardiac sympathetic function. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an established therapy for advanced congestive heart failure, improving both survival and hospitalization. The mechanism beneath these improvements still needs to be defined as about one third of the patients do not benefit from resynchronization. Restoration of sympatho-vagal function can play a significant role in the process, but available data are limited. In this scenario, positron emission tomography scans with (11) C-hydroxyephedrine, a noradrenaline analogous, has the potential to characterize the modifications of the sympathetic nervous system induced by CRT in decompensated patients. MATERIALS AND METHODS: Ten patients (six males, age 68 +/ 10 years) with primary dilated cardiomyopathy were studied before and after resynchronization (acutely and after 3 months), from a clinical and echocardiographic point of view. Their cardiac sympathetic nerve activity was evaluated by (11) C-hydroxyephedrine positron emission tomography before resynchronization, at short and medium term after resynchronization. RESULTS: Responders to CRT (patients showing >= 15% decrease in left ventricular end systolic volume) showed a higher level of left ventricular radiotracer uptake both at baseline and after resynchronization with respect to nonresponders. This was coupled with a progressive improvement in homogeneity in left ventricular tracer uptake mainly in responders. CONCLUSIONS: Cardiac resynchronization therapy improves cardiac sympathetic nerve activity in responders since its activation, while nonresponders do not show any significant change at any time of evaluation. CRT seems to be more effective in those patients with a still structurally preserved, yet functionally impaired, neuroautonomic system. PMID- 26036751 TI - The pharmacokinetic study on the mechanism of toxicity attenuation of rhubarb total free anthraquinone oral colon-specific drug delivery system. AB - Rhubarb is commonly used as laxatives in Asian countries, of which anthraquinones are the major active ingredients, but there are an increased number of concerns regarding the nephrotoxicity of anthraquinones. In this study, we compared the pharmacokinetic characteristics of rhubarb anthraquinones in rats after orally administered with rhubarb and rhubarb total free anthraquinone oral colon specific drug delivery granules (RTFA-OCDD-GN), and then explained why these granules could reduce the nephrotoxicity of anthraquinones when they produced purgative efficacy. A sensitive and reliable high performance liquid chromatography (HPLC) method has been fully validated for simultaneous determination of the five active components of rhubarb, and successfully applied to investigate and compare the remarkable differences in pharmacokinetic study of rhubarb anthraquinones after orally administered with rhubarb and RTFA-OCDD-GN. The results showed that, compared with rhubarb group, the AUC, Cmax, t1/2z and Vz/F of aloe-emodin, rhein, emodin and chrysophanol in rats receiving the RTFA OCDD-GN were significantly decreased, and the Tmax of the four analytes was prolonged. Moreover, the Tmax of rhein, the Cmax of chrysophanol and emodin all have significant differences (P<0.05). Simultaneously, anthraquinone prototype excretion rates in urine and feces of aloe-emodin, rhein, emodin, chrysophanol and physcion were all increased. These findings suggested that oral colon specific drug delivery technology made anthraquinone aglycone to colon-specific release after oral administration. This allowed anthraquinones to not only play the corresponding purgative effect but also avoid intestinal absorption and promote excretion. And thereby greatly reduced the nephrotoxicity of rhubarb. The result is a new breakthrough in rhubarb toxicity attenuated research. PMID- 26036753 TI - Integrating mHealth and Systems Science: A Combination Approach to Prevent and Treat Chronic Health Conditions. AB - Chronic health conditions are a growing global health concern and account for over half of all deaths worldwide. Finding ways to decrease the burden of and resources allotted to chronic health conditions is of primary importance. Recent advances in technology and insights into modeling techniques offer promising approaches, which if combined, represent a novel direction that would further advance the prevention and treatment of chronic health conditions. PMID- 26036752 TI - Changes in the concentrations of four maternal steroids during embryonic development in the threespined stickleback (Gasterosteus aculeatus). AB - Embryonic exposure to steroids often leads to long-term phenotypic effects. It has been hypothesized that mothers may be able to create a steroid environment that adjusts the phenotypes of offspring to current environmental conditions. Complicating this hypothesis is the potential for developing embryos to modulate their early endocrine environment. This study utilized the threespined stickleback (Gasterosteus aculeatus) to characterize the early endocrine environment within eggs by measuring four steroids (progesterone, testosterone, estradiol, and cortisol) of maternal origin. We then examined how the concentrations of these four steroids changed over the first 12 days post fertilization (dpf). Progesterone, testosterone, estradiol, and cortisol of maternal origin could be detected within unfertilized eggs and levels of all four steroids declined in the first 3 days following fertilization. While levels of progesterone, testosterone, and estradiol remained low after the initial decline, levels of cortisol rose again by 8 dpf. These results demonstrate that G. aculeatus embryos begin development in the presence of a number of maternal steroids but levels begin to change quickly following fertilization. This suggests that embryonic processes change the early endocrine environment and hence influence the ability of maternal steroids to affect development. With these findings, G. aculeatus becomes an intriguing system in which to study how selection may act on both maternal and embryonic processes to shape the evolutionary consequence of steroid-mediated maternal effects. PMID- 26036754 TI - Developing a Quality Assurance System for Multiple Evidence Based Practices in a Statewide Service Improvement Initiative. AB - Efforts to implement evidence based practices (EBP) are increasingly common in child-serving systems. However, public systems undertaking comprehensive improvement efforts that aim to increase availability of multiple practices at the same time may struggle to build comprehensive and user-friendly strategies to develop the workforce and encourage adoption, faithful implementation, and sustainability of selected EBPs. Given that research shows model adherence predicts positive outcomes, one critical EBP implementation support is systematic quality, fidelity, and compliance monitoring. This paper describes the development and initial implementation of a quality assurance framework for a statewide EBP initiative within child welfare. This initiative aimed to improve provider practice and monitor provider competence and compliance across four different EBPs, and to inform funding and policy decisions. The paper presents preliminary data as an illustration of lessons learned during the quality monitoring process and concludes with a discussion of the promise and challenges of developing and applying a multi-EBP quality assurance framework for use in public systems. PMID- 26036755 TI - Combinatorial Characterization of TiO2 Chemical Vapor Deposition Utilizing Titanium Isopropoxide. AB - The combinatorial characterization of the growth kinetics in chemical vapor deposition processes is challenging because precise information about the local precursor flow is usually difficult to access. In consequence, combinatorial chemical vapor deposition techniques are utilized more to study functional properties of thin films as a function of chemical composition, growth rate or crystallinity than to study the growth process itself. We present an experimental procedure which allows the combinatorial study of precursor surface kinetics during the film growth using high vacuum chemical vapor deposition. As consequence of the high vacuum environment, the precursor transport takes place in the molecular flow regime, which allows predicting and modifying precursor impinging rates on the substrate with comparatively little experimental effort. In this contribution, we study the surface kinetics of titanium dioxide formation using titanium tetraisopropoxide as precursor molecule over a large parameter range. We discuss precursor flux and temperature dependent morphology, crystallinity, growth rates, and precursor deposition efficiency. We conclude that the surface reaction of the adsorbed precursor molecules comprises a higher order reaction component with respect to precursor surface coverage. PMID- 26036756 TI - Should anti-inhibitor coagulant complex and tranexamic acid be used concomitantly? AB - Inhibitor development in haemophilia patients is challenging especially when undergoing surgical procedures. The development of an inhibitor precludes using factor VIII (FVIII) therapy thereby requiring a bypassing agent (BPA) for surgical bleeding prophylaxis if the FVIII inhibitor titre >5 BU. Concomitant use of anti-inhibitor coagulant complex (AICC) and tranexamic acid has been reported in the literature as a beneficial treatment for this population. Anti-inhibitor coagulant complex is known to cause an increase in thrombin generation and tranexamic acid inhibits fibrinolysis. Hence, the combined used of AICC and tranexamic acid has been limited due to safety concerns over possibilities of increased risk of thrombotic events and disseminated intravascular coagulation. However, the rationale for concomitant therapy is to obtain a potential synergistic effect and to increase clot stability. We conducted a literature review of past studies and individual case reports of concomitant use of AICC and tranexamic acid, which was extensively used during dental procedures. Evidence also exists for concomitant use of the combined therapy in orthopaedic procedures, control of gastrointestinal bleeding, epistaxis and cerebral haemorrhages. Some patients who received the combined therapy had failed monotherapy with a single BPA prior to combined therapy. There were no reports of thrombotic complications related to the concomitant therapy and haemostasis was achieved in all cases. Anti-inhibitor coagulant complex and tranexamic acid therapy was found to be safe, well-tolerated and effective therapy in haemophilia patients with inhibitors. Additional randomized controlled studies should be performed to confirm these findings. PMID- 26036757 TI - Correction: Exploring the origins of the apparent "electrocatalytic" oxidation of kojic acid at graphene modified electrodes. AB - Correction for 'Exploring the origins of the apparent "electrocatalytic" oxidation of kojic acid at graphene modified electrodes' by Luiz C. S. Figueiredo Filho et al., Analyst, 2013, 138, 4436-4442. PMID- 26036759 TI - Clinical significance of CUL4A in human prostate cancer. AB - Aberrant expression of the Cullin 4A (CUL4A) is found in many tumor types, but the functions and mechanism of CUL4A in prostate cancer (PCa) development and progression remain largely unknown. The aim of this study was to investigate the possible role of CUL4A in prostate tumorigenesis. Immunohistochemistry was used to examine CUL4A expression in human PCa tissues and BPH tissues. Cell proliferation was assessed by MTT, and migration and invasion were analyzed by Transwell and Matrigel assays after CUL4A knockdown in PCa in vitro. The results showed that CUL4A protein was overexpressed in 86.21 % of PCa tissues. CUL4A knockdown with siRNA in PCa cells decreased cell proliferation, migration, and invasion. Mechanistically, CUL4A could modulate the expression of P53 in PCa cells. Our results indicate that CUL4A overexpression play an oncogenic role in the pathogenesis of PCa, and CUL4A may be a potential therapeutic target for PCa. PMID- 26036758 TI - Posttranslational modifications of FOXO1 regulate epidermal growth factor receptor tyrosine kinase inhibitor resistance for non-small cell lung cancer cells. AB - Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are effective clinical therapies for advanced non-small cell lung cancer (NSCLC) patients, while resistance to TKIs remains a serious problem in clinical practice. Recently, it has been proposed that targeting mTOR could overcome TKI resistance in NSCLC cells. Forkhead box class O1 (FOXO1) has emerged as an important rheostat that modulates the activity of Akt and mTOR signaling pathway. However, the role of FOXO1 and related regulatory mechanism in TKI resistance in NSCLC remain largely unknown. Here, we find that mTOR-AKT-FOXO1 signaling cascade is deregulated in TKI-resistant NSCLC cells and that FOXO1 was highly phosphorylated and lowly acetylated upon erlotinib treatment. Combination of mTOR or PI3K inhibitor and erlotinib overcomes TKI resistance to inhibit cell growth and induce apoptosis in TKI-resistant NSCLC cells. Furthermore, the phosphorylation and acetylation of FOXO1 are reversely modulated by mTORC2-AKT signaling pathway. FOXO1 mutation analyses reveal that FOXO1 acetylation inhibits cell proliferation and promotes NSCLC cell apoptosis, while the phosphorylation of FOXO1 plays opposite roles in NSCLC cells. Importantly, increasing FOXO1 acetylation by a HDAC inhibitor, depsipeptide, overcomes TKI resistance to effectively induce TKI resistant NSCLC cell apoptosis. Together, FOXO1 plays dual roles in TKI resistance through posttranslational modifications in NSCLC and this study provides a possible strategy for treatment of TKI-resistant NSCLC patients. PMID- 26036760 TI - Expression of long noncoding RNA-HOX transcript antisense intergenic RNA in oral squamous cell carcinoma and effect on cell growth. AB - The aim of this study was to analyze the correlation between long noncoding RNA HOX transcript antisense intergenic RNA (HOTAIR) and the clinical pathological characteristics and prognosis of oral squamous cell carcinoma (OSCC) and to evaluate the effect on cell growth. HOTAIR expressions in 50 surgically resected samples (including tumor and paracancerous tissues) collected from OSCC patients treated in our hospital from January 2009 to December 2010 were detected by real time quantitative reverse transcription-PCR, and the relationship with clinical pathological characteristics and prognosis was analyzed. The effect of small interfering RNA treatment on cell growth (Tca8113, UM-1, and CAL-27 cells) was evaluated by MTT assay, and those on apoptosis and cell cycle were assessed by flow cytometry. HOTAIR was positively expressed in 45 samples (90 %). The expression level in tumor tissues was significantly higher than that in paracancerous tissues (t = 5.459, P < 0.01). Relative expression level of HOTAIR was correlated with tumor size and clinical stage (P < 0.05). More HOTAIR was expressed in OSCC cell lines than in normal oral epithelial cells. Interfering with HOTAIR expression in Tca8113 cells significantly decelerated cell growth, arrested cell cycle, and promoted apoptosis (P < 0.01). HOTAIR was highly expressed in OSCC tissues and facilitated the growth of OSCC cells, thus probably being an eligible molecular marker for OSCC diagnosis and prognosis determination. PMID- 26036761 TI - MicroRNA-375 functions as a tumor suppressor in osteosarcoma by targeting PIK3CA. AB - Osteosarcoma has become one of the most common primary malignant bone tumors in childhood and adult. Numerous studies have demonstrated that aberrant microRNA (miRNA) expression is involved in human disease including cancer. To date, the potential miRNAs regulating osteosarcoma growth and progression are not fully identified yet. Herein, we showed that miR-375 was frequently downregulated in osteosarcoma tissue and cell lines compared to normal human colon tissues. Overexpression of miR-375 resulted in decreased expression of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) at both mRNA and protein levels. We found that miR-375 overexpression markedly suppressed cell proliferation in vitro. And inhibition of miR-375 promotes osteosarcoma growth. Mechanistic studies showed that PIK3CA was a potential target of miR-375 and it mediated reduction of PIK3CA resulted in suppression of PI3K/Akt pathway. Taken together, our results demonstrate that miR-375 functions as a growth suppressive miRNA and plays an important role in inhibiting the tumorigenesis through targeting PIK3CA in osteosarcoma. PMID- 26036763 TI - Teaching medical students the art of the 'write-up'. AB - BACKGROUND: The creation of a complete 'write-up' continues to be essential to the clinical learning experience for medical students. The ability to document a clinical encounter is a key communication skill and Core Entrustable Professional Activity for entering residency. METHODS: We developed a guide to the comprehensive write-up, a grading rubric, and a videotaped encounter with a standardised doctor and patient. Second-year medical students created a write-up based upon this encounter, which was then peer-reviewed in a small group writer's workshop session. The students were later required to submit a write-up, based upon a real patient encounter, to the course directors for a grade. All write-ups (n = 185) were graded by the course director. Fifty-one were independently graded by a second course director. These grades were compared with the 175 student write-ups from the previous year. The ability to document a clinical encounter is a key communication skill ... for entering residency RESULTS: The average grade for student write-ups was 86 with a standard deviation of 9, compared with an average of 75 with a standard deviation of 17 for the year prior to the introduction of this session (p < 0.001). The average score given by a second rater was 83 with a standard deviation of 11, indicating a high level of agreement and internal consistency. DISCUSSION: These tools were easy to use and well received by faculty members and students, and the quality of student write ups significantly improved after the introduction of the session. The grading rubric demonstrated high inter-rater reliability, indicating that this can be adapted and used by others for instruction and assessment. PMID- 26036762 TI - Metallothionein 2A core promoter region genetic polymorphism and its impact on the risk, tumor behavior, and recurrences of sinonasal inverted papilloma (Schneiderian papilloma). AB - Inverted papillomas are a unique group of locally aggressive benign epithelial neoplasms in the nasal cavity and paranasal sinuses arising from the Schneiderian mucosa. Metallothioneins are sulfhydryl-rich heavy metal-binding proteins required for metal toxicity protection and regulation of biological mechanisms including proliferation and invasion. The goal of this study was to identify three SNPs at loci -5 A/G (rs28366003) and -209 A/G (rs1610216) in the core promoter region and at locus +838 C/G (rs10636) in 3'UTR region of the MT2A gene with IP risk and with tumor invasiveness according to Krouse staging. Genotyping was performed using the PCR restriction fragment length polymorphism technique in 130 genetically unrelated IP individuals, and 418 randomly selected healthy volunteers. The presence of the rs28366003 SNP was significantly related to the risk of IP within the present population-based case-control study. Compared to homozygous common allele carriers, heterozygosity and homozygosity for the G variant had a significantly increased risk of IP (adjusted odds ratio [OR] = 7.71, 95% confidence interval [CI]: 4.01-14.91, p(dominant) < 0.001). Moreover, risk allele carriers demonstrated higher Krouse stage (pT1 vs. pT2-4) (OR = 19.32; 95% CI, 2.30-173.53; p < 0.0001), diffuse tumor growth (OR = 4.58; 95% CI, 1.70-12.11; p = 0.0008), bone destruction (OR = 4.13; 95% CI, 1.50-11.60; p = 0.003), and higher incidence of tumor recurrences (OR = 5.11; 95% CI, 1.68-15.20; p = 0.001). The findings suggest that MT2A gene variation rs28366003 may be implicated in the etiology of sinonasal inverted papilloma in a Polish population. PMID- 26036764 TI - The BMJ was inconsiderate when publishing personal view on private practice. PMID- 26036765 TI - Absolute or relative measures of height and weight? An Editorial. PMID- 26036766 TI - Non-cooperative game theory in biology and cooperative reasoning in humans. AB - The readiness for spontaneous cooperation together with the assumptions that others share this cooperativity has been identified as a fundamental feature that distinguishes humans from other animals, including the great apes. At the same time, cooperativity presents an evolutionary puzzle because non-cooperators do better in a group of cooperators. We develop here an analysis of the process leading to cooperation in terms of rationality concepts, game theory and epistemic logic. We are, however, not attempting to reconstruct the actual evolutionary process. We rather want to provide the logical structure underlying cooperation in order to understand why cooperation is possible and what kind of reasoning and beliefs would lead to cooperative decision-making. Game theory depends on an underlying common belief in non-cooperative rationality of the players, and cooperativity similarly can utilize a common belief in cooperative rationality as its basis. We suggest a weaker concept of rational decision-making in games that encompasses both types of decision-making. We build this up in stages, starting from simple optimization, then using anticipation of the reaction of others, to finally arrive at reflexive and cooperative reasoning. While each stage is more difficult than the preceding, importantly, we also identify a reduction of complexity achieved by the consistent application of higher stage reasoning. PMID- 26036768 TI - A new cell-free bandage-type artificial skin for cutaneous wounds. AB - Engineered skin substitutes are widely used in skin wound management. However, no currently available products satisfy all the criteria of usability in emergency situations, easy handling, and minimal scar formation. To overcome these shortcomings, we designed a cell-free bandage-type artificial skin, named "VitriBand" (VB), using adhesive film dressing, silicone-coated polyethylene terephthalate film, and collagen xerogel membrane defined as a dried collagen vitrigel membrane without free water. We analyzed its advantages over in-line products by comparing VB with hydrocolloid dressing and collagen sponge. For evaluation, mice inflicted with full-thickness skin defects were treated with VB, hydrocolloid dressing, and collagen sponge. A plastic film group treated only with adhesive film dressing and silicone-coated polyethylene terephthalate film, and a no treatment group were also compared. VB promoted epithelization while inhibiting the emergence of myofibroblasts and inflammation in the regenerating tissue more effectively than the plastic film, hydrocolloid dressing, and collagen sponge products. We have succeeded in establishing a cell-free bandage type artificial skin that could serve as a promising first-line medical biomaterial for emergency treatment of skin injuries in various medical situations. PMID- 26036767 TI - Soluble flagellin coimmunization attenuates Th1 priming to Salmonella and clearance by modulating dendritic cell activation and cytokine production. AB - Soluble flagellin (sFliC) from Salmonella Typhimurium (STm) can induce a Th2 response to itself and coadministered antigens through ligation of TLR5. These properties suggest that sFliC could potentially modulate responses to Th1 antigens like live STm if both antigens are given concurrently. After coimmunization of mice with sFliC and STm there was a reduction in Th1 T cells (T bet(+) IFN-gamma(+) CD4 T cells) compared to STm alone and there was impaired clearance of STm. In contrast, there was no significant defect in the early extrafollicular B-cell response to STm. These effects are dependent upon TLR5 and flagellin expression by STm. The mechanism for these effects is not related to IL 4 induced to sFliC but rather to the effects of sFliC coimmunization on DCs. After coimmunization with STm and sFliC, splenic DCs had a lower expression of costimulatory molecules and profoundly altered kinetics of IL-12 and TNFalpha expression. Ex vivo experiments using in vivo conditioned DCs confirmed the effects of sFliC were due to altered DC function during a critical window in the coordinated interplay between DCs and naive T cells. This has marked implications for understanding how limits in Th1 priming can be achieved during infection induced, Th1-mediated inflammation. PMID- 26036769 TI - The role of Syk signaling in antifungal innate immunity of human corneal epithelial cells. AB - BACKGROUND: Fungal keratitis is a kind of intractable and sight-threatening diseases. Spleen-tyrosine kinase (Syk) is a non-receptor tyrosine kinase, which plays an important role in the signaling pathway of the receptors. In the current study, we investigate the expression and function of Syk in human corneal epithelial cells with Aspergillus fumigatus (A. fumigatus) infection. METHODS: Cultured telomerase-immortalized human corneal epithelial cells (THCEs) were treated with A. fumigatus hyphae with or without treatment of Syk inhibitors. Activation of Syk and the role of Syk in regulating inflammatory cytokines and chemokines expression were evaluated. The mRNA expression was determined by real time PCR, and protein activation was measured by western blotting. RESULTS: Syk protein was detected in THCEs, and its activation was enhanced after treatment of A. fumigatus hyphae. Expression of inflammatory cytokines (IL-1beta and IL-6) and chemokines (IL-8 and CXCL1) mRNA were significantly increased after stimulation of A. fumigatus hyphae in THCEs. Activation of Syk and expression of IL-1beta, IL 6, IL-8 and CXCL1 by A. fumigatus hyphae were blocked by Syk inhibitors. CONCLUSION: These findings demonstrate that normal human corneal epithelial cells produce Syk, and Syk activation plays an important role in regulating A. fumigatus hyphae-induced inflammatory responses in THCEs. PMID- 26036771 TI - Quantum Discord for d?2 Systems. AB - We present an analytical solution for classical correlation, defined in terms of linear entropy, in an arbitrary system when the second subsystem is measured. We show that the optimal measurements used in the maximization of the classical correlation in terms of linear entropy, when used to calculate the quantum discord in terms of von Neumann entropy, result in a tight upper bound for arbitrary d?2 systems. This bound agrees with all known analytical results about quantum discord in terms of von Neumann entropy and, when comparing it with the numerical results for 10(6) two-qubit random density matrices, we obtain an average deviation of order 10(-4). Furthermore, our results give a way to calculate the quantum discord for arbitrary n-qubit GHZ and W states evolving under the action of the amplitude damping noisy channel. PMID- 26036770 TI - Effect of passive ultrasonic irrigation on diffusion of hydroxyl ion through radicular dentine. AB - OBJECTIVE: This study investigated the effect of passive ultrasonic irrigation (PUI) on diffusion of hydroxyl ions through radicular dentine. MATERIALS AND METHODS: After chemomechanical preparation of root canals in 60 human teeth, the cementoenamel junction and the apical 3 mm of each root were covered with fast setting adhesive. Four final irrigation protocols were applied (n = 10): group (G)1: irrigation with EDTA + NaOCl; G2: EDTA + PUI + NaOCl; G3: EDTA+(NaOCl + PUI); G4: (EDTA + PUI) + (NaOCl + PUI). Ten teeth irrigated with distilled water followed by PUI (G5) served as the negative control. After drying, the canals were filled with calcium hydroxide paste (CH), sealed and kept in individual vials containing 10 mL of distilled water with known pH values. At 7, 14, and 21 days, the pH of the water in the vials was measured. The pH values in various groups were analyzed with two-way ANOVA (irrigation protocol and time period as factors) and Holm-Sidak multiple comparison test (alpha = 0.05). RESULTS: Changes in pH was not significantly different among groups (P = 0.651) but was significant different among different time periods (P < 0.0001). For all groups, ion diffusion was higher at 14 and 21 days than at 7 days. CONCLUSIONS: PUI has no effect on diffusion of hydroxyl ions through radicular dentine. When CH is used as temporary filling material, a waiting period of at least 14 days is required to create an alkaline environment within the radicular dentine. CLINICAL RELEVANCE: The use of PUI during final irrigation phase does not improve the action of CH when it is used as temporary filling material. PMID- 26036773 TI - Response to commentary: biventricular non-compaction hypertrophic cardiomyopathy in association with congenital complete heart block and type I mitochondrial complex deficiency. PMID- 26036774 TI - Occult obstructive sleep apnea and clinical outcomes of radiofrequency catheter ablation in patients with atrial fibrillation. AB - BACKGROUND: Recurrent atrial fibrillation (AF) after successful cardioversion can be predicted by obstructive sleep apnea (OSA) diagnosed by polysomnography. However, it is not known whether the validated STOP-BANG questionnaire can predict AF recurrence after radiofrequency ablation (RFA). Our objective is to determine the prevalence of unrecognized OSA in patients with AF and its relation to freedom from AF after RFA. METHODS: Validated surveys were administered to 247 consecutive AF patients following radiofrequency ablation from January to October 2011. OSA status was assessed at baseline RFA. Clinical follow up occurred at 3-6 month intervals. RESULTS: OSA had been previously diagnosed in 94/247 (38%). Among 153 patients without prior diagnosis of OSA, 121 (79%) had high risk STOP BANG scores for OSA. Probability of maintaining sinus rhythm after RFA was similar among patients with known OSA (66/94, 70%) and high risk OSA scores (95/124, 77%) and higher than among patients with low risk OSA scores (29/32, 91%, P=0.03). Among patients without prior OSA, a high risk STOP-BANG score did predict recurrent AF (OR = 3.7, 95 % CI 1.4-11.4, P = 0.0005). Multivariate analysis showed a higher risk of atrial arrhythmia recurrence for non-paroxysmal AF patients (OR = 3.1, +/- 95 % CI 1.4-7.1, P = 0.005). CONCLUSIONS: The majority of AF patients undergoing RFA have high risk OSA scores, suggesting that OSA is vastly underdiagnosed in this population. STOP-BANG independently predicted recurrent AF in patients without a prior diagnosis of OSA. PMID- 26036775 TI - Evaluation of a new impedancemeter to independently measure extracellular, intracellular and total body water volumes: application to the measurement of hydration. AB - The objective of this study was to evaluate the accuracy of independent hydric data for the quantification of total body water (V t), extracellular water (V e) and intracellular water (V i), obtained by a multifrequency impedancemeter Z Metrix((r)) (ZM), in standing and lying position, with respect to the Xitron reference. In a second step, the aim was to consider whether it is possible to quantify daily hydration. The average repeatability error of the ZM impedancemeter is less than 0.5 %. For total body water (V t), we note a low R (2) dispersion with an average of 0.9 for men and 0.6 for women. The estimation of extracellular water is equivalent to a maximum error of 3.1 % in standing position for women against 2.97 % for men in the same position. The estimation of the total body water by direct measurement and by summing the volumes of extracellular and intracellular water obtained by the Z-Metrix((r)) shows very low dispersions with R (2) = 0.89 and average error from 1.3 % for healthy women in lying position to 3.9 % for healthy women in standing position. Finally, despite the impact of events on the daily measurements, it is viable to track a subject's overall hydration. PMID- 26036776 TI - Temporal bone fracture under lateral impact: biomechanical and macroscopic evaluation. AB - This work was conducted to study biomechanical properties and macroscopic analysis of petrous fracture by lateral impact. Seven embalmed intact human cadaver heads were tested to failure using an electrohydraulic testing device. Dynamic loading was done at 2 m/s on temporal region with maximal deflection to 12 mm. Anthropometric and pathological data were determined by pretest and posttest computed tomography images, macroscopic evaluation, and anatomical dissection. Biomechanical data were obtained. Results indicated the head to have nonlinear structural response. The overall mean values of failure forces, deflections, stiffness, occipital, and frontal peak acceleration were 7.1 kN (+/ 1.1), 9.1 mm (+/-1.8), 1.3 kN/mm (+/-0.4), 90.5 g (+/-22.5), and 65.4 g (+/-16), respectively. The seven lateral impacts caused fractures, temporal fractures in six cases. We observed very strong homogeneity for the biomechanical and pathological results between different trials in our study and between data from various experiments and our study. No statistical correlation was found between anthropometric, biomechanical, and pathological data. These data will assist in the development and validation of finite element models of head injury. PMID- 26036777 TI - Next-Generation o-Nitrobenzyl Photolabile Groups for Light-Directed Chemistry and Microarray Synthesis. AB - Light as an external trigger is a valuable and easily controllable tool for directing chemical reactions with high spatial and temporal accuracy. Two o nitrobenzyl derivatives, benzoyl- and thiophenyl-NPPOC, undergo photo deprotection with significantly improved efficiency over that of the commonly used NPPOC group. The two- and twelvefold increase in photo-deprotection efficiency was proven using photolithograph synthesis of microarrays. PMID- 26036778 TI - Lipid-protein interplay and lateral organization in biomembranes. AB - The distribution of lipids and membrane proteins within and between cellular membranes is carefully regulated. This sorting of lipids and proteins results in compositional differences between membrane compartments, bilayer leaflets, and lateral domains in the bilayer plane. The lateral organization of lipids and proteins has proven challenging to investigate, and the driving mechanisms remains unclear. Lipid self-organization has an essential role in the formation of lateral membrane structure, but the role of transmembrane proteins is not well known. This review focuses on how lateral lipid structure can affect the lateral distribution of proteins and how proteins could influence the organization of lipids in biomembranes. PMID- 26036779 TI - The effect of MRI contrast agents on hepatic and splenic uptake in the rabbit during (99m) Tc-MDP bone scintigraphy. AB - The objective of this study was to investigate the effects of Omniscan(r) and Magnevist(r) on (99m) Tc-MDP uptake in rabbits during (99m) Tc-MDP bone scintigraphy. In Experiment Group 1, 30 healthy adult rabbits were randomized into six subgroups (n = 5); each subgroup experienced a different time interval between injections (30 min, 60 min, 120 min, 240 min, 360 min, 24 h). All six subgroups were injected first with Omniscan(r), then with (99m) Tc-MDP. After 7 days, the same six subgroups were injected with normal saline followed by (99m) Tc-MDP at the same time intervals. In Experiment Group 2, 20 healthy adult rabbits were allocated randomly to four subgroups (n = 5); each subgroup experienced a different time interval between injections (30 min, 60 min, 120 min, 240 min). All four subgroups were injected first with Magnevist(r), then with (99m) Tc-MDP. After 7 days, the same four subgroups were injected with normal saline followed by (99m) Tc-MDP. In all experiments, whole-body skeletal imaging was performed. Liver, spleen, and background were delineated to determine the target-to-background (T/B) ratio. Diffusely increased intake of the imaging agent was seen in the liver and spleen when the injection-time interval between Omniscan(r) and (99m) Tc-MDP varied from 30 min to 240 min and when the time interval between Magnevist(r) and (99m) Tc-MDP was 30 min-60 min. The imaging findings are consistent with the results of L/B and S/B ratios in each experiment group. Both Omniscan(r) and Magnevist(r) have an effect on (99m) Tc-MDP uptake during bone scanning; the main effect is diffusely increased hepatic and splenic activity. PMID- 26036780 TI - BRILMA methylene blue in cadavers. Anatomical dissection. PMID- 26036781 TI - GLU298ASP and 4G/5G Polymorphisms and the Risk of Ischemic Stroke in Young Individuals. AB - BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase (eNOS) and in the plasminogen activator inhibitor -1 (PAI-1) genes have been implicated in stroke pathogenesis but results are still controversial. The aim of this study was to examine the possible contribution of Glu298Asp in the eNOS and 4G/5G in the PAI-1polymorphisms with ischemic stroke in a young Mexican population. MATERIALS AND METHODS: In a case-control study, conducted between January 2006 and June 2010, 204 patients <=45 years of age with ischemic stroke and 204 controls matched by age and gender, were recruited. The Glu298Asp and 4G/5G polymorphisms were determined in all participants by polymerase chain reaction restriction fragment length polymorphism. RESULTS: There was a significant difference in the Glu298Asp genotype distribution (P=0.001) and allele frequency between the two groups (P=0.001). The 4G/5G genotype distribution (P=0.40) and the allele frequency was similar between groups; (P=0.13). There were independent factors for ischemic stroke: Asp carriage (GluAsp+AspAsp) (P=0.02); smoking (P=0.01); hypertension (P=0.03), and familial history of atherothrombotic disease (P=0.04). CONCLUSIONS: The Asp allele from the Gu298Asp gene represents an independent risk factor for ischemic stroke in a young Mexican population. In contrast, the 4G/5G was not associated with an increased risk for this disease in the same group of patients, as previously has been demonstrated in other populations. PMID- 26036782 TI - Systematic study of cell isolation from bovine nucleus pulposus: Improving cell yield and experiment reliability. AB - Differences in matrix compositions in human nucleus pulposus (NP) clinical samples demand different cell isolation protocols for optimal results but there is no clear guide about this to date. Sub-optimal protocols may result in low cell yield, limited reliability of results or even failure of experiments. Cell yield, viability and attachment of cells isolated from bovine NP tissue with different protocols were estimated by cell counting, Trypan blue staining and cell culturing respectively. RNA was extracted from isolated cells and quantified by Nanodrop spectrometry and RT-qPCR. Higher collagenase concentration, longer digestion duration and pronase pre-treatment increased the cell yield. Cell viability remained high (<5% dead cells) even after 0.2% collagenase treatment for overnight. NP cells remained to have high ACAN, COL2A1, CDH2, KRT18, and KRT19 expression compared to muscle cells for different cell isolation conditions tested. Digestion by collagenase alone without the use of pronase could isolate cells from human degenerated NP tissue but clusters of cells were observed. We suggest the use of the disappearance of tissue as an indirect measure of cells released. This study provides a guide for researchers to decide the parameters involved in NP cell isolation for optimal outcome. PMID- 26036783 TI - Interaction of the transforming growth factor-beta and Notch signaling pathways in the regulation of granulosa cell proliferation. AB - The Notch and transforming growth factor (TGF)-beta signalling pathways play an important role in granulosa cell proliferation. However, the mechanisms underlying the cross-talk between these two signalling pathways are unknown. Herein we demonstrated a functional synergism between Notch and TGF-beta signalling in the regulation of preantral granulosa cell (PAGC) proliferation. Activation of TGF-beta signalling increased hairy/enhancer-of-split related with YRPW motif 2 gene (Hey2) expression (one of the target genes of the Notch pathway) in PAGCs, and suppression of TGF-beta signalling by Smad3 knockdown reduced Hey2 expression. Inhibition of the proliferation of PAGCs by N-[N-(3,5 difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butylester (DAPT), an inhibitor of Notch signalling, was rescued by both the addition of ActA and overexpression of Smad3, indicating an interaction between the TGF-beta and Notch signalling pathways. Co-immunoprecipitation (CoIP) and chromatin immunoprecipitation (ChIP) assays were performed to identify the point of interaction between the two signalling pathways. CoIP showed direct protein-protein interaction between Smad3 and Notch2 intracellular domain (NICD2), whereas ChIP showed that Smad3 could be recruited to the promoter regions of Notch target genes as a transcription factor. Therefore, the findings of the present study support the idea that nuclear Smad3 protein can integrate with NICD2 to form a complex that acts as a transcription factor to bind specific DNA motifs in Notch target genes, such as Hey1 and Hey2, and thus participates in the transcriptional regulation of Notch target genes, as well as regulation of the proliferation of PAGCs. PMID- 26036784 TI - Recent advances in noble metal based composite nanocatalysts: colloidal synthesis, properties, and catalytic applications. AB - This Review article provides a report on progress in the synthesis, properties and catalytic applications of noble metal based composite nanomaterials. We begin with a brief discussion on the categories of various composite materials. We then present some important colloidal synthetic approaches to the composite nanostructures; here, major attention has been paid to bimetallic nanoparticles. We also introduce some important physiochemical properties that are beneficial from composite nanomaterials. Finally, we highlight the catalytic applications of such composite nanoparticles and conclude with remarks on prospective future directions. PMID- 26036785 TI - Reconstruction of Extensive Soft-Tissue Defects with Concomitant Bone Defects in the Lower Extremity with the Latissimus Dorsi-Serratus Anterior-Rib Free Flap. AB - BACKGROUND: The combined latissimus dorsi-serratus anterior-rib (LD-SA-rib) free flap provides a large soft-tissue flap with a vascularized bone flap through a solitary vascular pedicle in a one-stage reconstruction. METHODS: Seven LD-SA-rib free flaps were performed in seven patients to reconstruct concomitant bone and extensive soft-tissue defects in the lower extremity (tibia, five; femur, one; foot, one). The patients were all male, with an average age of 34 years (range, 20-48 years). These defects were secondary to trauma in five patients and posttraumatic osteomyelitis in two patients. RESULTS: All flaps survived and achieved bony union. The average time to bony union was 9.4 months. Bone hypertrophy of at least 20% occurred in all flaps. All patients achieved full weight-bearing ambulation without aid at an average duration of 23.7 months. Two patients developed stress fractures of the rib flap. There was no significant donor site morbidity, except for two patients who had pleural tears during harvesting of the flap. CONCLUSION: The LD-SA-rib flap provides a large soft tissue component and a vascularized bone flap for reconstruction of composite large soft-tissue defects with concomitant bone defects of the lower extremity in a one-stage procedure. PMID- 26036787 TI - Prediction and biochemical analysis of putative cleavage sites of the 3C-like protease of Middle East respiratory syndrome coronavirus. AB - Coronavirus 3C-like protease (3CLpro) is responsible for the cleavage of coronaviral polyprotein 1a/1ab (pp1a/1ab) to produce the mature non-structural proteins (nsps) of nsp4-16. The nsp5 of the newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) was identified as 3CLpro and its canonical cleavage sites (between nsps) were predicted based on sequence alignment, but the cleavability of these cleavage sites remains to be experimentally confirmed and putative non-canonical cleavage sites (inside one nsp) within the pp1a/1ab awaits further analysis. Here, we proposed a method for predicting coronaviral 3CLpro cleavage sites which balances the prediction accuracy and false positive outcomes. By applying this method to MERS-CoV, the 11 canonical cleavage sites were readily identified and verified by the biochemical assays. The Michaelis constant of the canonical cleavage sites of MERS-CoV showed that the substrate specificity of MERS-CoV 3CLpro is relatively conserved. Interestingly, nine putative non-canonical cleavage sites were predicted and three of them could be cleaved by MERS-CoV nsp5. These results pave the way for identification and functional characterization of new nsp products of coronaviruses. PMID- 26036786 TI - Consequences of high-sensitivity troponin T testing applied in a primary care population with chest pain compared with a commercially available point-of-care troponin T analysis: an observational prospective study. AB - BACKGROUND: There is a demand for a highly sensitive and specific point-of care test to detect acute myocardial infarction (AMI). It is unclear if a high sensitivity troponin assay will have enough discriminative power to become a decision support in primary care. The aim of this study was to evaluate a high sensitivity troponin T assay performed in three primary health care centres in southeast Sweden and to compare the outcome with a point-of-care troponin T test. METHODS: This study included 115 patients who consulted their general practitioner for chest pain, dyspnoea on exertion, unexplained weakness and/or fatigue in the last 7 days. Troponin T was analysed by a point-of-care test and a high-sensitivity method together with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and creatinine. All patients were checked for AMI or unstable angina (UA) within 30 days of study enrolment. Univariate and multivariate logistic regression was carried out to examine possible connections between troponin T >= 15 ng/L, clinical variables and laboratory findings at baseline. In addition, 21 patients with troponin T >= 15 ng/L and no signs of AMI or UA were followed up for 2-3 years. RESULTS: Three patients were diagnosed with AMI and three with UA. At the >= 15 ng/L cut-off, the troponin T method had 100% sensitivity, 75% specificity for AMI and a positive predictive value of 10%. The troponin T point of-care test missed one case of AMI and the detection limit was 50 ng/L. Troponin T >= 15 ng/L was correlated to age >=65 years (odds ratio (OR), 10.9 95% CI 2.28 51.8) and NT-proBNP in accordance with heart failure (OR 8.62 95% CI 1.61-46.1). Fourteen of the 21 patients, without signs of AMI or UA at baseline, still had increased troponin T at follow-up after 2-3 years. CONCLUSIONS: A high sensitivity troponin T assay could become useful in primary care as a point-of care test for patients <65 years. For patients older than 65-70 years, a higher decision limit than >=15 ng/L should be considered and used in conjunction with clinical parameters and possibly with NT-proBNP. PMID- 26036788 TI - Biodegradable Nanotopography Combined with Neurotrophic Signals Enhances Contact Guidance and Neuronal Differentiation of Human Neural Stem Cells. AB - Biophysical cues provided by nanotopographical surfaces have been used as stimuli to guide neurite extension and regulate neural stem cell (NSC) differentiation. Here, we fabricated biodegradable polymer substrates with nanoscale topography for enhancing human NSC (hNSC) differentiation and guided neurite outgrowth. The substrate was constructed from biodegradable poly(lactic-co-glycolic acid) (PLGA) using solvent-assisted capillary force lithography. We found that precoating with 3,4-dihydroxy-l-phenylalanine (DOPA) facilitated the immobilization of poly-l lysine and fibronectin on PLGA substrates via bio-inspired catechol chemistry. The DOPA-coated nanopatterned substrates directed cellular alignment along the patterned grooves by contact guidance, leading to enhanced focal adhesion, skeletal protein reorganization, and neuronal differentiation of hNSCs as indicated by highly extended neurites from cell bodies and increased expression of neuronal markers (Tuj1 and MAP2). The addition of nerve growth factor further enhanced neuronal differentiation of hNSCs, indicating a synergistic effect of biophysical and biochemical cues on NSC differentiation. These bio-inspired PLGA nanopatterned substrates could potentially be used as implantable biomaterials for improving the efficacy of hNSCs in treating neurodegenerative diseases. PMID- 26036789 TI - Treatment of experimental pythiosis with essential oils of Origanum vulgare and Mentha piperita singly, in association and in combination with immunotherapy. AB - This study investigated the in vivo antimicrobial activity of the essential oils of Origanum vulgare and Mentha piperita both singly, associated and in combination with immunotherapy to treat experimental pythiosis. The disease was reproduced in 18 rabbits divided into six groups (n=3): group 1, control; group 2, treated with essential oil of Mentha piperita; group 3, treated with essential oil of Origanum vulgare; group 4, treated with commercial immunotherapic; group 5, treated with a association of oils of M. piperita and O. vulgare and group 6, treated with a combination of both oils plus immunotherapy. Essential oils were added in a topical cream base formula, and lesions were treated daily for 45 days. The animals in groups 4 and 6 received a dose of immunotherapeutic agent every 14 days. The results revealed that the evolution of lesions in groups 5 and 6 did not differ from one another but differed from the other groups. The lesions of group 5 increased 3.16 times every measurement, while those of group 6 increased 1.83 times, indicating that the smallest growth of the lesions occurred when the combination of therapies were used. A rabbit from group 5 showed clinical cure at day 20 of treatment. This research is the pioneer in the treatment of experimental pythiosis using essential oils from medicinal plants and a combination of therapies. This study demonstrated that the use of essential oils can be a viable alternative treatment to cutaneous pythiosis, particularly when used in association or combination with immunotherapy. PMID- 26036790 TI - Phylogenetic analysis and genetic diversity of 3' region of rtxA gene from geographically diverse strains of Moraxella bovis, Moraxella bovoculi and Moraxella ovis. AB - The cytotoxin A (MbxA) is one of the main virulence factors of Moraxella bovis involved in the pathogenesis of infectious bovine keratoconjunctivitis (IBK). Moraxella ovis and Moraxella bovoculi, suspected to be associated with infectious keratitis in sheep and cattle respectively, also have a gene that encodes the cytotoxin A (movA and mbvA, respectively). The aim of this study was to determine the molecular sequence of the 3' region of the cytotoxin gene of Moraxella spp. strains isolated from clinical cases to establish phylogenetic and evolutionary comparisons. PCR amplification, nucleotide sequencing (nt) and amino acid (aa) sequence prediction were performed, followed by the sequences comparison, identity level calculation and selective pressure analysis. The phylogenetic reconstruction based on nt and aa sequences clearly differentiate M. bovis (n=15), M. bovoculi (n=11) and M. ovis (n=7) and their respective reference strains. An alignment of 843nt revealed high similarity within bacterial species (MbxA=99.9% nt and aa; MbvA=99.3% nt and 98.8% aa; MovA=99.5% nt and 99.3% aa). The similarity of partial sequences (nt 1807-2649) of MbxA in relation to MbvA and MovA ranged from 76.3 to 78.5%; similarity between MbvA and MovA ranged from 95.7 to 97.5%. A negative selection on mbvA and movA sequences was revealed by the molecular evolution analysis. The phylogenetic analysis of movA and mbvA allowed different strains of Moraxella spp. to be grouped according to the period of isolation. Sequence analysis of cytotoxin may provide insights into genetic and evolutionary relationships and into the genetic/molecular basis of Moraxella spp. PMID- 26036791 TI - Assessing splenic enlargement on CT by unidimensional measurement changes in patients with colorectal liver metastases. AB - PURPOSE: The aim of this study was to assess splenic volume and to correlate unidimensional measurements with reference volumetric changes in chemotherapy treated patients with colorectal cancer (CRC) liver metastases. METHODS: Forty consecutive patients were selected from the cohort of a previously reported study of chemotherapy-related morbidity following major hepatectomy for CRC liver metastases. Patients were treated for 6 months prior to resection, with imaging performed at baseline and after 6 months of chemotherapy. Three unidimensional spleen measurements were recorded-width, thickness, and height (W, T, and H). Reference splenic volume was measured at baseline and after chemotherapy. The best unidimensional splenic measurement was determined by regression analysis. The 95% CI for the predicted values and R (2) values was calculated for each regression. The percentage of volume increase at 6 months was calculated. RESULTS: W and H showed the highest correlation with splenic volume prior to and following chemotherapy (R (2) = 0.65-0.74, p < 0.001), while T showed a low correlation (R (2) = 0.11 and 0.18, p < 0.05). The mean reference splenic volume increased after 6 months of chemotherapy compared to baseline (326 vs. 278 mL). Splenic volume changes showed the highest correlation with changes in W (R (2) = 0.56, p < 0.001), then H (R (2) = 0.40, p < 0.001), but were not significantly correlated with changes in T (R (2) = 0.01, p = 0.055). CONCLUSIONS: Our results show the potential utility of measuring changes in splenic width to predict clinically significant changes in splenic volume in chemotherapy-treated patients with CRC liver metastases. PMID- 26036792 TI - Imaging of adrenal and renal hemorrhage. AB - Hemorrhage of the kidneys and adrenal glands has many etiologies. In the adrenal glands, trauma, anticoagulation, stress, sepsis, surgery, and neoplasms are common causes of hemorrhage. In the kidneys, reasons for hemorrhage include trauma, bleeding diathesis, vascular diseases, infection, infarction, hemorrhagic cyst rupture, the Antopol-Goldman lesion, and neoplasms. Angiomyolipoma and renal cell carcinoma are the neoplasms most commonly associated with hemorrhage in the kidneys and adrenal cortical carcinoma, metastases, and pheochromocytoma are associated with hemorrhage in the adrenal glands. Understanding the computed tomography and magnetic resonance imaging features, and causes of hemorrhage in the kidneys and adrenal glands is critical. It is also important to keep in mind that mimickers of hemorrhage exist, including lymphoma in both the kidneys and adrenal glands, and melanoma metastases in the adrenal glands. Appropriate imaging follow-up of renal and adrenal hemorrhage should occur to exclude an underlying malignancy as the cause. If there is suspicion for malignancy that cannot be definitively diagnosed on imaging, surgery or biopsy may be warranted. Angiography may be indicated when there is a suspected underlying vascular disease. Unnecessary intervention, such as nephrectomy, may be avoided in patients with benign causes or no underlying disease. Appropriate management is dependent on accurate diagnosis of the cause of renal or adrenal hemorrhage and it is incumbent upon the radiologist to determine the etiology. PMID- 26036793 TI - The initial experience of the upper abdominal CT angiography using low concentration contrast medium on dual energy spectral CT. AB - OBJECTIVE: To investigate the feasibility of using Spectral CT imaging with low contrast medium in abdominal CT angiography (CTA). SUBJECTS AND METHODS: 70 consecutive patients (40 men, 42.6 +/- 20.4 years; 30 women, 46.7 +/- 18.8 years) with suspected abdominal focal lesions were referred to CTA exam. They were randomly assigned into two groups. Group A: 35 patients underwent conventional CT scan of Tube voltage 120 kVp, automatic current modulation with a Noise Index of 12, ASIR 30%, and injected with Iohexol (350 mgI/ml). Group B: 35 patients underwent Spectral CT Imaging, with Tube current of 600 mA, injected with Iodixanol (270 mgI/ml). The optimal mono-energy keV was achieved using the optimal contrast noise ratio in abdominal aorta at the renal artery level relative to the erector spine muscle. Both groups were injected with an injection rate of 3.5 ml/s, and a contrast volume of 1.5 ml/kg body weight. The Hounsfield units (HU) and noise of the bilateral renal arteries and muscle of both groups, as well as the optimal monochromatic image set of Group B were measured. Two radiologists assessed all images with a 5-points scale. CTDIvol and DLP were recorded. Data were analyzed using student t test. RESULTS: The total iodine intake of Group B was 28% lower than that of Group A. The CNR of abdomen artery, celiac trunk, superior mesenteric artery, and renal artery in spectral group (at the best mono-energy of 53.0 keV) were higher than those in conventional CTA group (p < 0.001). The subjective image quality score of spectral CTA group was also rated higher than conventional CTA group (p < 0.001). CTDIvol, DLP, and effective dose of spectral group were all lower than conventional group, but there were no significant differences (p > 0.05). CONCLUSION: With 28% contrast medium reduction and reduced radiation dose, CT angiography using spectral imaging and lower concentration contrast agent provided better image quality than conventional CTA. PMID- 26036794 TI - Quantitative assessment of solid renal masses by contrast-enhanced ultrasound with time-intensity curves: how we do it. AB - PURPOSE: To discuss the evaluation of the enhancement curve over time of the major renal cell carcinoma (RCC) subtypes, oncocytoma, and lipid-poor angiomyolipoma, to aid in the preoperative differentiation of these entities. Differentiation of these lesions is important, given the different prognoses of the subtypes, as well as the desire to avoid resecting benign lesions. METHODS: We discuss findings from CT, MR, and US, but with a special emphasis on contrast enhanced ultrasound (CEUS). CEUS technique is described, as well as time intensity curve analysis. RESULTS: Examples of each of the major RCC subtypes (clear cell, papillary, and chromophobe) are shown, as well as examples of oncocytoma and lipid-poor angiomyolipoma. For each lesion, the time-intensity curve of enhancement on CEUS is reviewed, and correlated with the enhancement curve over time reported for multiphase CT and MR. CONCLUSIONS: Preoperative differentiation of the most common solid renal masses is important, and the time intensity curves of these lesions show some distinguishing features that can aid in this differentiation. The use of CEUS is increasing, and as a modality it is especially well suited to the evaluation of the time-intensity curve. PMID- 26036795 TI - Alterations in Human Liver Metabolome during Prolonged Cryostorage. AB - Tissue metabolomics requires high sample quality that crucially depends on the biobanking storage protocol. Hence, we systematically analyzed the influence of realistic storage scenarios on the liver metabolome with different storage temperatures and repeated transfer of samples between storage and retrieval environments, simulating the repeated temperature changes affecting unrelated samples stored in the same container as the sample that is to be retrieved. By cycling between storage (-80 degrees C freezer, liquid nitrogen, cold nitrogen gas) and retrieval (room temperature, -80 degrees C), assuming three cycles per day and sample, we simulated biobank storage between 3 months and 10 years. Liver tissue metabolome was analyzed by liquid chromatography/mass spectrometry. Most metabolite concentrations changed <5% for the first "year" of time-compressed biobanking simulation, predominantly due to hydrolysis of peptides and lipids. Interestingly, storage temperature affected metabolite concentrations only little, while there was a linear dependence on the number of temperature change cycles. Elevated sample temperature during (prolonged) retrieval time led to a distinctly different signature of metabolite changes that were induced by cycling. Our findings allow giving recommendations for optimized storage protocols and provide signatures that allow detection of deviations from protocol. PMID- 26036796 TI - Tumor necrosis factor enhances the sleep-like state and electrical stimulation induces a wake-like state in co-cultures of neurons and glia. AB - We characterise sleep-like states in cultured neurons and glia during development in vitro as well as after electrical stimulation, the addition of tumor necrosis factor alpha (TNF), and the combination of TNF plus electrical stimulation. We also characterise optogenetic stimulation-induced ATP release and neuronal interleukin-1 and TNF expression in vitro demonstrating the activity dependence of these putative sleep-regulatory substances. Action potential (AP) burstiness, expressed as the burstiness index (BI), synchronization of slow electrical potentials between recording electrodes (SYN), and slow wave (SW) power (0.25 3.75 Hz) determined using fast Fourier analyses emerged as network properties, maturing after 2 weeks in culture. Homologous in vivo measures are used to characterise sleep. Electrical stimulation reduced the BI, SYN and SW power values during and/or after the stimulus period. One day later, homeostasis was evident from rebounds of SYN and SW power values to above baseline levels; the magnitude of the rebound was stimulus pattern-dependent. The addition of TNF enhanced BI, SYN and SW power values, suggesting the induction of a deeper sleep like state. Electrical stimulation reversed these TNF effects, suggesting the network state was more wake-like. The day after TNF plus electrical stimulation, the changes in SYN and SW power values were dependent upon the stimulus patterns the cells received the day before. We conclude that sleep and wake states in cultured in vitro networks can be controlled and they share molecular regulatory mechanisms with local in vivo networks. Further, sleep is an activity-dependent emergent local network property. PMID- 26036797 TI - A chimeric protein comprising the glucosyltransferase and cysteine proteinase domains of toxin B and the receptor binding domain of toxin A induces protective immunity against Clostridium difficile infection in mice and hamsters. AB - Clostridium difficile is the major cause of hospital-acquired infectious diarrhea and colitis in developed countries. The pathogenicity of C. difficile is mainly mediated by the release of 2 large potent exotoxins, toxin A (TcdA) and toxin B (TcdB), both of which require neutralization to prevent disease occurrence. We have generated a novel chimeric protein, designated mTcd138, comprised of the glucosyltransferase and cysteine proteinase domains of TcdB and the receptor binding domain of TcdA and expressed it in Bacillus megaterium. To ensure that mTcd138 is atoxic, 2 point mutations were introduced to the glucosyltransferase domain of TcdB, which essentially eliminates toxicity of mTcd138. Parenteral immunizations of mice and hamsters with mTcd138 induced protective antibodies to both toxins and provided protection against infection with the hyper-virulent C. difficile strain UK6. PMID- 26036799 TI - Fine-scale spatial genetic structure analysis of the black truffle Tuber aestivum and its link to aroma variability. AB - Truffles are symbiotic fungi in high demand by food connoisseurs. Improving yield and product quality requires a better understanding of truffle genetics and aroma biosynthesis. One aim here was to investigate the diversity and fine-scale spatial genetic structure of the Burgundy truffle Tuber aestivum. The second aim was to assess how genetic structuring along with fruiting body maturation and geographical origin influenced single constituents of truffle aroma. A total of 39 Burgundy truffles collected in two orchards were characterized in terms of aroma profile (SPME-GC/MS) and genotype (microsatellites). A moderate genetic differentiation was observed between the populations of the two orchards. An important seasonal and spatial genetic structuring was detected. Within one orchard, individuals belonging to the same genet were generally collected during a single season and in the close vicinity from each other. Maximum genet size nevertheless ranged from 46 to 92 m. Geographical origin or maturity only had minor effects on aroma profiles but genetic structuring, specifically clonal identity, had a pronounced influence on the concentrations of C8 - and C4 -VOCs. Our results highlight a high seasonal genetic turnover and indicate that the aroma of Burgundy truffle is influenced by the identity of single clones/genets. PMID- 26036798 TI - Cardiospecific CD36 suppression by lentivirus-mediated RNA interference prevents cardiac hypertrophy and systolic dysfunction in high-fat-diet induced obese mice. AB - BACKGROUND: Fatty acid (FA) catabolism abnormality has been proved to play an important role in obesity-related cardiomyopathy. We hypothesized that cardiospecific suppression of CD36, the predominant membrane FA transporter, would protect against obesity-related cardiomyopathy. METHODS: Four-wk-old male C57BL/6 J mice were fed with either high-fat-diet (HFD) or control-normal-diet for 2 wk. Then they were subjected to intramyocardial injection with recombinant lentiviral vectors containing short hairpin RNAs to selectively downregulate the expression of either cardiac CD36 or irrelevant gene by RNA interference. After a 10-wk continuation of the diet, biochemical, functional, morphological, histological, metabolic and molecular profiles were assessed. RESULTS: HFD administration elicited obesity, cardiac hypertrophy and systolic dysfunction accompanied with elevated serum levels of blood urea nitrogen (BUN), creatinine, fasting serum glucose (FSG), total cholesterol (TC) and triglyceride. Additionally, HFD consumption promoted lipid accumulation and reactive oxygen species (ROS) generation in the cardiomyocytes. Cardiospecific CD36 inhibition protected against HFD induced cardiac remodeling by decreasing heart/body weight ratio, increasing left ventricular (LV) ejection fraction and fractional shortening as well as normalizing LV diameter, without influencing body weight gain. Inhibition of cardiac CD36 also mitigated obesity induced alteration in BUN, creatinine and triglyceride, but had no effect on FSG or TC. Moreover, cardiospecific CD36 deficiency corrected myocardial lipid overaccumulation and intracellular ROS overproduction that were induced by HFD feeding. CONCLUSIONS: Cardiospecific CD36 inhibition protects against the aggravation of cardiac functional and morphological changes associated with HFD induced obesity. CD36 represents a potential therapeutic target for obesity cardiomyopathy. PMID- 26036800 TI - Dual photonic-bandgap optical films towards the generation of photonic crystal derived 2-dimensional chemical codes. AB - Chemical-oriented 2-dimensional (2D) optical codes were constructed for the first time by integrating bi-layer or bistriate-structure responsive photonic crystals (RPCs), which not only presents high information capacity in encoding processes, but offers a facile route to the detection of high performance sensors along with accurate analysis and anti-jamming performances. PMID- 26036801 TI - Chronic transfusion therapy improves but does not normalize systemic and pulmonary vasculopathy in sickle cell disease. AB - Tricuspid regurgitant (TR) jet velocity and its relationship to pulmonary hypertension has been controversial in sickle cell disease (SCD). Plasma free hemoglobin is elevated in SCD patients and acutely impairs systemic vascular reactivity. We postulated that plasma free hemoglobin would be negatively associated with both systemic and pulmonary endothelial function, assessed by flow-mediated dilation (FMD) of the brachial artery and TR jet velocity, respectively. Whole blood viscosity, plasma free hemoglobin, TR jet, and FMD were measured in chronically transfused SCD pre- and posttransfusion (N = 25), in nontransfused SCD (N = 26), and in ethnicity-matched control subjects (N = 10). We found increased TR jet velocity and decreased FMD in nontransfused SCD patients compared with the other 2 groups. TR jet velocity was inversely correlated with FMD. There was a striking nonlinear relationship between plasma free hemoglobin and both TR jet velocity and FMD. A single transfusion in the chronically transfused cohort improved FMD. In our patient sample, TR jet velocity and FMD were most strongly associated with plasma free hemoglobin and transfusion status (transfusions being protective), and thus consistent with the hypothesis that intravascular hemolysis and increased endogenous erythropoiesis damage vascular endothelia. PMID- 26036803 TI - Polycomb repressive complex 2 component Suz12 is required for hematopoietic stem cell function and lymphopoiesis. AB - Polycomb repressive complex 2 (PRC2) is a chromatin modifier that regulates stem cells in embryonic and adult tissues. Loss-of-function studies of PRC2 components have been complicated by early embryonic dependence on PRC2 activity and the partial functional redundancy of enhancer of zeste homolog 1 (Ezh1) and enhancer of zeste homolog 2 (Ezh2), which encode the enzymatic component of PRC2. Here, we investigated the role of PRC2 in hematopoiesis by conditional deletion of suppressor of zeste 12 protein homolog (Suz12), a core component of PRC2. Complete loss of Suz12 resulted in failure of hematopoiesis, both in the embryo and the adult, with a loss of maintenance of hematopoietic stem cells (HSCs). In contrast, partial loss of PRC2 enhanced HSC self-renewal. Although Suz12 was required for lymphoid development, deletion in individual blood cell lineages revealed that it was dispensable for the development of granulocytic, monocytic, and megakaryocytic cells. Collectively, these data reveal the multifaceted role of PRC2 in hematopoiesis, with divergent dose-dependent effects in HSC and distinct roles in maturing blood cells. Because PRC2 is a potential target for cancer therapy, the significant consequences of modest changes in PRC2 activity, as well as the cell and developmental stage-specific effects, will need to be carefully considered in any therapeutic context. PMID- 26036802 TI - CD8+ T cells are predominantly protective and required for effective steroid therapy in murine models of immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is a common autoimmune bleeding disorder characterized by autoantibodies targeting platelet surface proteins, most commonly GPIIbIIIa (alphaIIbbeta3 integrin), leading to platelet destruction. Recently, CD8(+) cytotoxic T-lymphocytes (CTLs) targeting platelets and megakaryocytes have also been implicated in thrombocytopenia. Because steroids are the most commonly administered therapy for ITP worldwide, we established both active (immunized splenocyte engraftment) and passive (antibody injection) murine models of steroid treatment. Surprisingly, we found that, in both models, CD8(+) T cells limited the severity of the thrombocytopenia and were required for an efficacious response to steroid therapy. Conversely, CD8(+) T-cell depletion led to more severe thrombocytopenia, whereas CD8(+) T-cell transfusion ameliorated thrombocytopenia. CD8(+) T-regulatory cell (Treg) subsets were detected, and interestingly, dexamethasone (DEX) treatment selectively expanded CD8(+) Tregs while decreasing CTLs. In vitro coculture studies revealed CD8(+) Tregs suppressed CD4(+) and CD19(+) proliferation, platelet-associated immunoglobulin G generation, CTL cytotoxicity, platelet apoptosis, and clearance. Furthermore, we found increased production of anti-inflammatory interleukin-10 in coculture studies and in vivo after steroid treatment. Thus, we uncovered subsets of CD8(+) Tregs and demonstrated their potent immunosuppressive and protective roles in experimentally induced thrombocytopenia. The data further elucidate mechanisms of steroid treatment and suggest therapeutic potential for CD8(+) Tregs in immune thrombocytopenia. PMID- 26036804 TI - Single platelets seal neutrophil-induced vascular breaches via GPVI during immune complex-mediated inflammation in mice. AB - Platelets protect vascular integrity during inflammation. Recent evidence suggests that this action is independent of thrombus formation and requires the engagement of glycoprotein VI (GPVI), but it remains unclear how platelets prevent inflammatory bleeding. We investigated whether platelets and GPVI act primarily by preventing detrimental effects of neutrophils using models of immune complex (IC)-mediated inflammation in mice immunodepleted in platelets and/or neutrophils or deficient in GPVI. Depletion of neutrophils prevented bleeding in thrombocytopenic and GPVI(-/-) mice during IC-mediated dermatitis. GPVI deficiency did not modify neutrophil recruitment, which was reduced by thrombocytopenia. Neutrophil cytotoxic activities were reduced in thrombocytopenic and GPVI(-/-) mice during IC-mediated inflammation. Intravital microscopy revealed that in this setting, intravascular binding sites for platelets were exposed by neutrophils, and GPVI supported the recruitment of individual platelets to these spots. Furthermore, the platelet secretory response accompanying IC-mediated inflammation was partly mediated by GPVI, and blocking of GPVI signaling impaired the vasculoprotective action of platelets. Together, our results show that GPVI plays a dual role in inflammation by enhancing neutrophil-damaging activities while supporting the activation and hemostatic adhesion of single platelets to neutrophil-induced vascular breaches. PMID- 26036805 TI - In vitro-assessment of putative antiprogestin activities of phytochemicals and synthetic UV absorbers in human endometrial Ishikawa cells. AB - Critical steps of embryo implantation are controlled by progesterone. These processes can be interrupted by progesterone receptor (PR) antagonists, e.g. drugs used for abortion. Antiprogestin effects induced by natural compounds and environmental chemicals have been rarely addressed. In our in vitro study, we investigated putative antiprogestin activities of the plant compounds apigenin (API) and trans-ferulic acid (t-FA) as well as the UV absorbers octyl methoxycinnamate (OMC) and 4-methylbenzylidene camphor (4-MBC). They were compared with the selective progesterone receptor modulators (SPRMs) mifepristone (RU486) and ulipristal acetate (UPA) as well as the full PR-antagonist ZK137316. Effects of test compounds in combination with progesterone on the progesterone sensitive target gene estrogen sulfotransferase (SULT1E1) were characterized by sigmoidal concentration-response curves obtained by RT-qPCR. The agonistic effect of progesterone on SULT1E1 mRNA levels was concentration-dependently antagonized by RU486, UPA and ZK137316 as well as, with lower potency, apigenin. t-FA, OMC and 4-MBC had no effect on SULT1E1 mRNA levels. We demonstrated that apigenin, although at higher concentrations, exerts a similar effect as the well characterized SPRMs RU486 and UPA or the progesterone antagonist ZK137316 in this model. Our endometrium-specific Ishikawa cell assay is a useful complement to artificial transactivation assays for the identification of environmental substances with antiprogestin activities. PMID- 26036806 TI - Osteoporosis and cardiovascular disease: an update. AB - Osteoporosis (OP) and cardiovascular diseases (CVD) are the most important causes of mortality and morbility in the elderly. Lots of studies showed a correlation between bone loss and cardiovascular risk mediated by the vascular calcification. The relationship between OP and CVD could be firstly explained by their common risk factors such as age, smoking, alcohol consumption, physical activity and menopause. However, other different hypotheses were proposed to clarify this link. Multiple factors, for example bone morphogenetic proteins, osteoprotegerin, receptor activator of nuclear factor kappaB ligand, parathyroid hormone, phosphate, oxidized lipids and vitamins D and K seemed to be involved in both conditions, indicating a possible common pathophysiologic mechanism. We review and discuss the available data describing this association. Further studies are necessary to better investigate similarities between OP and CVD. PMID- 26036807 TI - Editorial. PMID- 26036808 TI - Magnetic Resonance Imaging with a Weak Albumin Binding Contrast Agent can Reveal Additional Endoleaks in Patients with an Enlarging Aneurysm after EVAR. AB - OBJECTIVES/BACKGROUND: To examine the additional diagnostic value of magnetic resonance imaging (MRI) after administration of a weak albumin binding contrast agent in post-endovascular aneurysm repair (EVAR) patients with aneurysm growth with no or uncertain endoleak after computed tomography angiography (CTA). METHODS: This was a prospective diagnostic cross sectional study carried out between April 2011 and August 2013. MRI was performed in all patients with aneurysm growth>=5 mm after EVAR implantation and no or uncertain endoleak on CTA, or the inability, on CTA, to identify the source of a visible endoleak. All MRI scans were performed on a 1.5 T clinical MRI scanner after administration of a weak albumin binding contrast agent. The presence of endoleaks was assessed by visually comparing pre- and post-contrast T1-weighted images with fat suppression. Post-contrast images were acquired 5 and 15 minutes after contrast administration. RESULTS: Twenty-nine patients (26 men; 90%) with a median age of 74 years (interquartile range [IQR] 67-76) were included. The median interval between EVAR and MRI was 39 months (IQR 20-50). The median increase in maximum aneurysm diameter during total follow up after EVAR was 11 mm (IQR 6-17). At CTA, 16 patients (55%) had no detectable endoleak, five patients (17%) had suspected but uncertain endoleak, and eight patients had a definite endoleak (28%). On the post-contrast MRI images, endoleak was observed in 24 patients (83%). In all patients with uncertain endoleak on CTA, endoleak was detected with MRI. For type II endoleaks, feeding vessels were detected in 22/23 patients (96%) and these were all, except one, lumbar arteries. CONCLUSION: In patients with enlarging aneurysms of unknown origin after EVAR, MRI with a weak albumin binding contrast agent has additional value for both the detection and determination of the origin of the endoleak. PMID- 26036809 TI - One year health status benefits following treatment for new onset or exacerbation of peripheral arterial disease symptoms: the importance of patients' baseline health status. AB - OBJECTIVE/BACKGROUND: Limited information is available on expected health status gains following invasive treatment in peripheral arterial disease (PAD). One year health status outcomes following invasive treatment for PAD were compared, and whether pre-procedural health status was indicative of 1 year health status gains was evaluated. METHODS: Pre-procedural and 1 year health status (Short Form-12, Physical Component Score [PCS]) was prospectively assessed in a cohort of 474 patients, enrolled from 2 Dutch vascular clinics (March 2006-August 2011), with new or exacerbation of PAD symptoms. One year treatment strategy (invasive vs. non-invasive) and clinical information was abstracted. Quartiles of baseline health status scores and mean 1 year health status change scores were compared by invasive treatment for PAD. The numbers needed to treat (NNT) to obtain clinically relevant changes in 1 year health status were calculated. A propensity weight adjusted linear regression analysis was constructed to predict 1 year PCS scores. RESULTS: Invasive treatment was performed in 39% of patients. Patients with baseline health status scores in the lowest quartile undergoing invasive treatment had the greatest improvement (mean invasive 11.3 +/- 10.3 vs. mean non invasive 5.3 +/- 8.5 [p = .001, NNT = 3]), whereas those in the highest quartile improved less (.8 +/- 6.3 vs. -3.0 +/- 8.2 [p = .025, NNT = 90]). Undergoing invasive treatment (p < .0001) and lower baseline health status scores (p < .0001) were independently associated with greater 1 year health status gains. CONCLUSION: Substantial improvements were found in patients presenting with lower pre-procedural health status scores, whereas patients with higher starting health status levels had less to gain by an invasive strategy. PMID- 26036810 TI - Risk Factor Analysis of Bird Beak Occurrence after Thoracic Endovascular Aortic Repair. AB - OBJECTIVES: The aim was to analyze the role played by anatomy and stent graft in the incidence of incomplete apposition to aortic arch. METHODS: Between 2007 and 2014 data including available and suitable computed tomographic angiography (CTA) imaging of patients who had undergone thoracic endovascular aortic repair were reviewed. The study included 80 patients (65 men, 54 +/- 21 years) treated for traumatic aortic rupture (n = 27), thoracic aortic aneurysm (n = 15), type B aortic dissection (n = 24), penetrating aortic ulcer (n = 5), intramural hematoma (n = 2), aorto-oesophageal fistula (n = 2), and aortic mural thrombus (n = 5). Pre- and post-operative CTA images were analyzed to characterize bird beak in terms of length and angle, and to calculate aortic angulation within a 30 mm range at the proximal deployment zone. RESULTS: Bird beak configuration was detected in 46 patients (57%): mean stent protrusion length was 16 mm (range: 8 29 mm) and mean bird beak angle was 20 degrees (range: 7-40 degrees ). The bird beak effect was significantly more frequent after traumatic aortic rupture treatment (p = .05) and in landing zone 2 (p = .01). No influence of either stent graft type or generation, or degree of oversizing was observed (p = .29, p = .28, p = .81 respectively). However, the mean aortic angle of patients with bird beak was higher in the Pro-form group than that in the Zenith TX2 group (62 degrees vs. 48 degrees , p = .13). Multivariate analysis identified the aortic angle of the deployment zone as the unique independent risk factor of malapposition (HR = 1.05, 95% CI 1-1.10, p = .005). The cutoff value of 51 degrees was found to be predictive of bird beak occurrence with a sensitivity of 58% and a specificity of 85%. CONCLUSIONS: Assessment of proximal landing zone morphology to avoid deployment zones generating an aortic angle of over 50 degrees can be recommended to improve aortic curvature apposition with the current available devices. PMID- 26036812 TI - Hyponatremia and mortality risk: a Danish cohort study of 279 508 acutely hospitalized patients. AB - OBJECTIVE: We aimed to investigate the impact of hyponatremia severity on mortality risk and assess any evidence of a dose-response relation, utilizing prospectively collected data from population-based registries. DESIGN: Cohort study of 279 ,508 first-time acute admissions to Departments of Internal Medicine in the North and Central Denmark Regions from 2006 to 2011. METHODS: We used the Kaplan-Meier method (1 - survival function) to compute 30-day and 1-year mortality in patients with normonatremia and categories of increasing hyponatremia severity. Relative risks (RRs) with 95% CIs, adjusted for age, gender and previous morbidities, and stratified by clinical subgroups were estimated by the pseudo-value approach. The probability of death was estimated treating serum sodium as a continuous variable. RESULTS: The prevalence of admission hyponatremia was 15% (41,803 patients). Thirty-day mortality was 3.6% in normonatremic patients compared to 7.3, 10.0, 10.4 and 9.6% in patients with serum sodium levels of 130-134.9, 125-129.9, 120-124.9 and <120 mmol/l, resulting in adjusted RRs of 1.4 (95% CI: 1.3-1.4), 1.7 (95% CI: 1.6-1.8), 1.7 (95% CI: 1.4 1.9) and 1.3 (95% CI: 1.1-1.5) respectively. Mortality risk was increased across virtually all clinical subgroups, and remained increased by 30-40% 1 year after admission. The probability of death increased when serum sodium decreased from 139 to 132 mmol/l. No clear increase in mortality was observed for lower concentrations. CONCLUSIONS: Hyponatremia is highly prevalent among patients admitted to Departments of Internal Medicine and is associated with increased 30 day and 1-year mortality risk, regardless of underlying disease. This risk seems independent of hyponatremia severity. PMID- 26036811 TI - The effects of insulin and liraglutide on osteoprotegerin and vascular calcification in vitro and in patients with type 2 diabetes. AB - OBJECTIVE: Vascular calcification (VC) is inhibited by the glycoprotein osteoprotegerin (OPG). It is unclear whether treatments for type 2 diabetes are capable of promoting or inhibiting VC. The present study examined the effects of insulin and liraglutide on i) the production of OPG and ii) the emergence of VC, both in vitro in human aortic smooth muscle cells (HASMCs) and in vivo in type 2 diabetes. DESIGN/METHODS: HASMCs were exposed to insulin glargine or liraglutide, after which OPG production, alkaline phosphatase (ALP) activity and levels of Runx2, ALP and bone sialoprotein (BSP) mRNA were measured. A prospective, nonrandomised human subject study was also conducted, in which OPG levels and coronary artery calcification (CAC) were measured in a type 2 diabetes population before and 16 months after the commencement of either insulin or liraglutide treatment and in a control group that took oral hypoglycemics only. RESULTS: Exposure to insulin glargine, but not liraglutide, was associated with significantly decreased OPG production (11 913+/-1409 pg/10(4) cells vs 282+/-13 pg/10(4) cells, control vs 10 nmol/l insulin, P<0.0001), increased ALP activity (0.82+/-0.06 IU/10(4) cells vs 2.40+/-0.16 IU/10(4) cells, control vs 10 nmol/l insulin, P<0.0001) and increased osteogenic gene expression by HASMCs. In the clinical study (n=101), insulin treatment was associated with a significant reduction in OPG levels and, despite not achieving full statistical significance, a trend towards increased CAC in patients. CONCLUSION: Exogenous insulin down regulated OPG in vitro and in vivo and promoted VC in vitro. Although neither insulin nor liraglutide significantly affected CAC in the present pilot study, these data support the establishment of randomised trials to investigate medications and VC in diabetes. PMID- 26036813 TI - MANAGEMENT OF ENDOCRINE DISEASE: Paediatric Cushing's disease. AB - Cushing's disease (CD) is the commonest form of ACTH-dependent Cushing's syndrome and is a rare clinical diagnosis in paediatric and adolescent patients. CD is caused by an ACTH-secreting pituitary corticotroph adenoma and is associated with significant morbidity in children; therefore, early diagnosis and treatment are critical for optimal therapeutic outcome. This review highlights the key clinical and biochemical features of paediatric CD and appraises current practices in diagnosis and management. A close liaison with adult endocrinology colleagues, particularly, for interpretation of investigations and definition of therapeutic strategy is strongly advised. PMID- 26036814 TI - Stigma as a stressor and transition to schizophrenia after one year among young people at risk of psychosis. AB - According to stress-vulnerability models, social stressors contribute to the onset of schizophrenia. Stigma and discrimination associated with mental illness may be a stressor for young people at risk of psychosis even prior to illness onset, but quantitative longitudinal data on this issue are lacking. We examined the cognitive appraisal of stigma-related stress as predictor of transition to schizophrenia among young people at risk of psychosis. In Zurich, Switzerland, 172 participants between 13 and 35years old and with either high or ultra-high risk of psychosis or risk of bipolar disorder were included. With 71 dropouts, transition was assessed during 12months among 101 participants of whom 13 converted to schizophrenia. At baseline, the cognitive appraisal of stigma as a stressor was measured by self-report, based on the primary appraisal of stigma as harmful and the secondary appraisal of resources to cope with stigma. Positive and negative symptoms were examined using the Positive and Negative Syndrome Scale. Compared with participants who did not convert to schizophrenia, converters had significantly more positive (p<.001) and negative (p<.001) symptoms and reported higher levels of stigma-related harm (p=.003) and stress (p=.009) at baseline. More perceived harm due to stigma at baseline predicted transition to schizophrenia (odds ratio 2.34, 95%-CI 1.19-4.60) after adjusting for age, gender, symptoms and functioning. Stigma stress may increase the risk of transition to schizophrenia. Research is needed on interventions that reduce public negative attitudes towards young people at risk and that support individuals at risk to cope with stigma-related stress. PMID- 26036815 TI - The dimensional structure of short forms of the Wisconsin Schizotypy Scales. AB - The Wisconsin Schizotypy Scales (WSS) are widely used for assessing schizotypy. Confirmatory factor analysis (CFA) indicates that a two-factor structure, positive and negative schizotypy, underlies these scales. Recently developed 15 item short forms of the WSS demonstrated good reliability and validity. This study examined the factor structure underlying the short-form WSS. Consistent with the original scales, CFA on three large samples (n=6137, 2171, and 2292, respectively) indicated that a two-factor model with positive and negative dimensions provided better fit than a generic schizotypy model for the short-form WSS. The short-form dimensions correlated highly with the original scale dimensions and displayed good stability across 10weeks. Preliminary construct validity was demonstrated through associations with interview and questionnaire measures of psychopathology, functioning, and personality comparable to those found with the original WSS. This is the first study examining the dimensional structure of the short WSS and the validity of these dimensions. The findings support the multidimensional nature of schizotypy and the appropriateness of dimensions derived from the short-form WSS. PMID- 26036816 TI - Self reported rates of criminal offending and victimization in young people at risk for psychosis. AB - A significant relationship exists between experiencing psychosis and both engaging in criminal offending and being a victim of crime. A substantial proportion of violence and offending occurs during the first episode of psychosis, but it is unclear whether such behaviour is also evident in the earlier pre-psychotic stage of illness. As part of a prospective study of young people who were seeking help for mental health problems, we enquired about participants' experiences of being charged and/or convicted of a criminal offence and being a victim of crime. This paper uses cross-sectional baseline data to compare the rates of these forensic outcomes in participants at-risk of psychosis (n=271) with those not at-risk (n=440). Univariate logistic regression showed that the at-risk for psychosis group was significantly more likely than the not at-risk participants to report having been charged by police (11.1% vs 5.9%; p=.015) and convicted by the courts (4.4% vs. 1.6%; p=0.028) with a non-violent offence, as well as to have been convicted of any criminal offence (6.3% vs. 3.0%; p=0.037). The at-risk were also more likely to report having been a victim of crime (23.7% vs 14.0%; p=.002), particularly violent victimization (16.5% vs 8.2%; p=.001). In multivariate logistic regression analyses, being at-risk for psychosis remained a significant predictor of three of the four outcome measures after controlling for other known covariates such as gender, age, substance misuse and unemployment. This is the first study to demonstrate that, relative to their non-psychotic help-seeking counterparts, young people at-risk for psychosis are at higher risk of forensic outcomes, particularly violent crime victimization. PMID- 26036818 TI - In Situ Detection of Particle Aggregation on Electrode Surfaces. AB - Partially blocked electrodes (PBEs) are important; many applications use non conductive nanoparticles (NPs) to introduce new electrode functionalities. As aggregation is a problem in NP immobilization, developing an in situ method to detect aggregation is vital to characterise such modified electrodes. We present chronoamperometry as a method for detection of NP surface aggregation and semi quantitative sizing of the formed aggregates, based on the diffusion limited current measured at PBEs as compared with the values calculated numerically for different blocking feature sizes. In contrast to voltammetry, no approximations on electrode kinetics are needed, making chronoamperometry a more general and reliable method. Sizing is shown for two modification methods. Upon drop casting, significant aggregation is observed, while it is minimized in electrophoretic NP deposition. The aggregate sizes determined are in semi-quantitative agreement with ex situ microscopic analysis of the PBEs. PMID- 26036817 TI - Participation of alpha2 -adrenoceptors in sodium appetite inhibition during sickness behaviour following administration of lipopolysaccharide. AB - Sickness behaviour, a syndrome characterized by a general reduction in animal activity, is part of the active-phase response to fight infection. Lipopolysaccharide (LPS), an effective endotoxin to model sickness behaviour, reduces thirst and sodium excretion, and increases neurohypophysial secretion. Here we review the effects of LPS on thirst and sodium appetite. Altered renal function and hydromineral fluid intake in response to LPS occur in the context of behavioural reorganization, which manifests itself as part of the syndrome. Recent data show that, in addition to its classical effect on thirst, non-septic doses of LPS injected intraperitoneally produce a preferential inhibition of intracellular thirst versus extracellular thirst. Moreover, LPS also reduced hypertonic NaCl intake in sodium-depleted rats that entered a sodium appetite test. Antagonism of alpha2 -adrenoceptors abolished the effect of LPS on sodium appetite. LPS and cytokine transduction potentially recruit brain noradrenaline and alpha2 -adrenoceptors to control sodium appetite and sickness behaviour. PMID- 26036820 TI - Personal resurrection: female childhood sexual abuse survivors' experience of the Wellness-Program. AB - BACKGROUND: Childhood sexual abuse (CSA) survivors deal with complex mental, physical and relationship problems in adulthood which negatively affects their well-being and health. The aim of the present paper was to present a description of the Wellness-Program for female CSA survivors, the participating women's evaluation of the different therapies in the program as well as a qualitative study on their experience of the program's effects on their life, health and well being. METHOD: The Wellness-Program lasted for 10 weeks with organised schedule 20 hours per week. A team of health professionals used a holistic approach and provided traditional and complementary individual and group therapy focusing on both mind and body. In-depth phenomenological interviews with ten women, 22-53 years old, were conducted 1 week before and 1 week after the program as well as 15 months later. Data collection and data analysis were guided by the Vancouver School of doing phenomenology. RESULTS: Prior to participating in the program, the women were unable to work or attend school, were on disability allowance, were socially isolated and had complex health problems. After the Wellness Program, all the women, except one, were back to work, school or in further rehabilitation. Furthermore, the in-depth interviews showed that their health and well-being, personal life and relationship with partners, family and friends improved. They felt empowered, more in control and had developed increased trust towards others. Six themes were constructed from the in-depth interviews. They were: feeling totally lost, releasing experiences, developing trusting relationships, gaining control, experiencing positive changes in physical and mental health and, finally, feeling of empowerment. The overriding theme of the study was personal resurrection. CONCLUSIONS: The Wellness-Program contributed considerably to improved health and well-being of the women. However, further assessment of the program is recommended before making it available within the healthcare system. PMID- 26036821 TI - Bending the curve: force health protection during the insertion phase of the Ebola outbreak response. AB - After >10 years of enduring operations in Iraq and Afghanistan, Defence Strategic Direction is returning to a contingency posture. As the first post-Afghanistan operation, in September 2014, a UK Joint Inter-Agency Task Force deployed to Sierra Leone in response to the Ebola virus disease (EVD) epidemic in West Africa. The aims were expanding treatment capacity, assisting with training and supporting host nation resilience. The insertion phase of this deployment created a unique set of challenges for force health protection. In addition to the considerable risk of tropical disease and trauma, deployed personnel faced the risks of working in an EVD epidemic. This report explores how deployed medical assets overcame the difficulties of mounting a short-notice contingent operation in a region of the world with inherent major climatic and health challenges. PMID- 26036819 TI - Programmed death-1 checkpoint blockade in acute myeloid leukemia. AB - INTRODUCTION: Immune checkpoints are regulatory pathways induced in activated T lymphocytes that regulate antigen responsiveness. These immune checkpoints are hijacked by tumors to promote dysfunction of anti-tumor effector cells and consequently of tumor escape from the host immune system. AREAS COVERED: Programmed death-1/programmed death ligand (PD-1/PDL-1), a checkpoint pathway, has been extensively investigated in leukemia mouse models. Expression of PD-1 on the surface of activated immune cells and of its ligands, PD-L1 and PD-L2, on leukemic blasts has been documented. Clinical trials with PD-1 inhibitors in patients with hematological malignancies are ongoing with promising clinical responses. EXPERT OPINION: Therapy of hematological cancers with antibodies blocking inhibitory receptors is expected to be highly clinically effective. Checkpoint inhibitory receptors and their ligands are co-expressed on hematopoietic cells found in the leukemic milieu. Several distinct immunological mechanisms are likely to be engaged by antibody-based checkpoint blockade. Co expression of multiple inhibitory receptors on hematopoietic cells offers an opportunity for combining blocking antibodies to achieve more effective therapy. Up-regulation of receptor/ligand expression in the leukemic milieu may provide a blood marker predictive of response. Finally, chemotherapy-induced up-regulation of PD-1 on T cells after conventional leukemia therapy creates a solid rationale for application of checkpoint blockade as a follow-up therapy. PMID- 26036823 TI - Tracing the origin of the panda's thumb. AB - We investigate the relative development of the carnivoran radial sesamoids to untangle the evolution of this iconic structure. In the pandas (both giant and red), this 'false thumb' is known to perform a grasping role during bamboo feeding in both the red and giant pandas. An original locomotor role has been inferred for ailurids, but this remains to be ascertained for ursids. A large sample of radial sesamoids of Indarctos arctoides from the Miocene of Batallones 3 (Spain) indicates that this early ailuropodine bear displayed a relatively hypertrophied radial sesamoid, with a configuration more similar to that of the red panda and other carnivorans than to that of giant pandas. This false thumb is the first evidence of this feature in the Ursidae, which can be linked to a more herbivorous diet. Moreover, in the two extant pandas, the false thumb should not be interpreted as an anatomical convergence, but as an exaptive convergence regarding its use during the bamboo feeding, which changes the evolutionary view of this singular structure. PMID- 26036822 TI - Risk factors for heat illness among British soldiers in the hot Collective Training Environment. AB - BACKGROUND: Heat illness is a preventable disorder in military populations. Measures that protect vulnerable individuals and contribute to effective Immediate Treatment may reduce the impact of heat illness, but depend upon adequate understanding and awareness among Commanders and their troops. OBJECTIVE: To assess risk factors for heat illness in British soldiers deployed to the hot Collective Training Environment (CTE) and to explore awareness of Immediate Treatment responses. METHODS: An anonymous questionnaire was distributed to British soldiers deployed in the hot CTEs of Kenya and Canada. Responses were analysed to determine the prevalence of individual (Intrinsic) and Command-practice (Extrinsic) risk factors for heat illness and the self-reported awareness of key Immediate Treatment priorities (recognition, first aid and casualty evacuation). RESULTS: The prevalence of Intrinsic risk factors was relatively low in comparison with Extrinsic risk factors. The majority of respondents were aware of key Immediate Treatment responses. The most frequently reported factors in each domain were increased risk by body composition scoring, inadequate time for heat acclimatisation and insufficient briefing about casualty evacuation. CONCLUSIONS: Novel data on the distribution and scale of risk factors for heat illness are presented. A collective approach to risk reduction by the accumulation of 'marginal gains' is proposed for the UK military. This should focus on limiting Intrinsic risk factors before deployment, reducing Extrinsic factors during training and promoting timely Immediate Treatment responses within the hot CTE. PMID- 26036825 TI - Risk factors for outbreaks of infectious pancreatic necrosis (IPN) and associated mortality in Norwegian salmonid farming. AB - Infectious pancreatic necrosis (IPN) has for many years been considered one of the most important restraints to the production of salmonids in European aquaculture. In Norway, the disease is responsible for high losses in post-smolts in the first few weeks after sea transfer. Despite the importance of IPN, there are few epidemiological studies on risk factors and mitigation strategies. In this paper, we present analyses of data from all cohorts put to sea in 2009 to 2012 on Norwegian marine salmonid farms. The data used were obtained from national registers on salmonid production and disease outbreaks. The results showed that the risk of IPN outbreak was higher for spring versus autumn cohorts, Atlantic salmon versus rainbow trout and for cohorts on farms with previous history of IPN. The risk increased with increasing cohort size and infection pressure, whereas increasing temperature and weight at sea transfer decreased the risk. Estimations from a model of cumulative mortality within the first 6 mo after sea transfer showed that mortality in cohorts with IPN increased to approximately 7.2% as compared to a 'baseline' cohort with a mortality of 3.4%. If the cohort had both IPN and pancreas disease (PD), the estimated mortality increased to 12.9%, and cohorts with both IPN, PD and heart and skeletal muscle inflammation (HSMI) had an estimated mortality of 16.6%, when all other significant factors were kept constant (these were cohort type, year, temperature at sea transfer and weight at sea transfer). Our results provide valuable inputs for mitigation strategies and for economic modelling of consequences of disease. PMID- 26036826 TI - Saprolegnia species in Norwegian salmon hatcheries: field survey identifies S. diclina sub-clade IIIB as the dominating taxon. AB - Saprolegnia isolates within the recognized clades encompassing the taxa S. parasitica and S. diclina act as opportunist and aggressive pathogens to both fish and their eggs. They are responsible for significant economic losses in aquaculture, particularly in salmonid hatcheries. However, the identity, distribution and pathogenic significance of involved species often remain unexplored. In this study, 89 Saprolegnia isolates were recovered from water, eggs and salmon tissue samples that originated from salmon (Salmo salar) hatcheries along the coast of Norway. The cultures were characterized morphologically and molecularly in order to provide an overview of the species composition of Saprolegnia spp. present in Norwegian salmon hatcheries. We demonstrate that S. diclina clearly dominated and contributed to 79% of the recovered isolates. Parsimony analyses of the nuclear ribosomal internal transcribed spacer (ITS) region split these isolates into 2 strongly supported sub-clades, S. diclina sub-clade IIIA and IIIB, where sub-clade IIIB accounted for 66% of all isolates. A minor portion of the isolates constituted other taxa that were either conspecific or showed strong affinity to S. parasitica, S. ferax, S. hypogyna and Scoliolegnia asterophora. The unique sub-clade IIIB of S. diclina was most prevalent in water and salmon eggs, while S. parasitica isolates were more frequently isolated from post hatching stages. The study demonstrated that morphological criteria in many cases were insufficient for species delimitation due to lack of sexual structures or incoherent morphological expression of such features within the tested replicates. PMID- 26036827 TI - Risk factors for development of internal neoplasms in koi carp Cyprinus carpio koi. AB - Fish, like mammals, can be affected by neoplastic proliferations. As yet, there are only a very small number of studies reporting on the occurrence of tumours in koi carp Cyprinus carpio koi and only sporadic reports on the nature of the tumours or on risk factors associated with their development. Between 2008 and 2012, koi with abdominal swelling were examined pathologically: neoplastic lesions were diagnosed and classified histologically. We evaluated possible risk factors for the development of these internal neoplasms in koi carp in Switzerland, using an online 2-part questionnaire sent to fish keepers with koi affected by internal tumours and to fish keepers who had not previously reported any affected koi. Part 1 addressed all participants and focused on general information about koi husbandry and pond technical data; Part 2 addressed participants that had one or several case(s) of koi with internal tumour(s) between 2008 and 2012, and consisted of specific questions about affected koi. A total of 112 internal tumours were reported by the 353 koi keepers participating in the survey. Analysis of the obtained data revealed that tumour occurrence was significantly associated with the location (indoors vs. outdoors) and volume of the pond, frequency of water changes, origin of the koi, number of koi kept in a pond and the use of certain pond disinfectant/medication products. Our results contribute to the identification of possible risk factors, which in turn could help to establish prophylactic measures in order to reduce the occurrence of internal neoplasms in koi. PMID- 26036828 TI - Trichlorfon-induced haematological and biochemical changes in Cyprinus carpio: ameliorative effect of propolis. AB - Trichlorfon is among the most commonly used products to treat fish parasites in aquaculture. We investigated the effectiveness of propolis in alleviating the toxicity of trichlorfon on haematological and oxidant/antioxidant parameters in carp Cyprinus carpio. Fish were exposed to sublethal concentrations (11 and 22 mg l-1) of trichlorfon, and propolis (10 mg kg-1 of fish weight) was simultaneously administered. At the end of 14 d administration, blood and tissue (liver, kidney, gill) samples were collected. Haematological changes (red and white blood cell count, haemoglobin concentration, haematocrit level and erythrocyte indices: mean corpuscular volume, mean corpuscular haemoglobin and mean corpuscular haemoglobin concentration) were determined in the blood samples, while antioxidant parameters (malondialdehyde and reduced glutathione levels and superoxide dismutase, catalase and glutathione peroxidase activities) were evaluated in the liver, kidney and gill samples. Trichlorfon led to negative alterations in the haematological and antioxidant parameters investigated. The administration of propolis alleviated this effect and suggests that fish treated with trichlorfon improve their physiological status when fed a propolis-supplemented diet. PMID- 26036829 TI - Morphological and molecular characterization of actinosporeans infecting oligochaete Branchiura sowerbyi from Chinese carp ponds. AB - We surveyed the actinosporean stages of fish myxosporeans at fish farms in Jiangsu Province, China, from 2011 to 2014. During the surveys, we identified 7 actinosporean types from 4 collective groups: echinactinomyxon (1 type), triactinomyxon (1 type), aurantiactinomyxon (1 type), and neoactinomyxum (4 types), released by the oligochaete Branchiura sowerbyi. The morphological characteristics and DNA sequences of these types are described here. Based on 18S rDNA sequence analysis, the actinosporean of echinactinomyxon type CZ with 4 branches at the end of the caudal processes was identified as Myxobolus wulii, and the neoactinomyxum type JD was identified as Thelohanellus wangi Yuan, Xi, Wang, Xie, Zhang, 2015 (JX458816), a recently nominated species from the gills of allogynogenetic gibel carp Carassius auratus gibelio. In addition, actinosporeans of aurantiactinomyxon type JD, neoactinomyxum type CZ-1, neoactinomyxum type CZ 2, and neoactinomyxum type CZ-3 showed high genetic similarity to T. wuhanensis (96.3-96.5%), T. nikolskii (98.0-99.1%), T. wuhanensis (97.8-98.9%), and T. hovorkai (98.7-98.9%), respectively. Phylogenetic analyses showed that these actinosporeans were robustly clustered in the Thelohanellus spp. clade. PMID- 26036830 TI - Characterization of Chinese giant salamander iridovirus tissue tropism and inflammatory response after infection. AB - The Chinese giant salamander iridovirus (GSIV), belonging to the genus Ranavirus in the family Iridoviridae, causes severe hemorrhagic lesions and nearly 100% mortality in naturally infected Chinese giant salamanders Andrias davidiamus. However, the replication and distribution of the virus has not been well characterized in vivo. Using in situ hybridization, the expression of the GSIV major capsid protein (MCP) was detected in the cytoplasm of cells of the spleen, kidney, liver and gut tissues. MCP expression in the spleen and kidney appeared to fluctuate significantly during the acute phase of infection. Using an immunofluorescence assay, GSIV antigens were abundant in the spleen and kidney tissues but appeared to be at relatively low levels in the liver and gut. Additionally, there were significant changes in the expression of the pro inflammatory cytokines macrophage migration inhibitory factor (MIF), tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) in different tissues in response to infection with GSIV. The expression of MIF, TNF-alpha and IL-1beta had significantly increased in the spleen at 3 d post-infection; this correlated with a decrease in virus replication in the spleen. These results suggest that the spleen and kidney are the major target tissues of GSIV, and the increased expression of MIF, TNF-alpha and IL-1beta may contribute to a reduction of virus replication in the spleen. PMID- 26036831 TI - Novel quantitative TaqMan(r) MGB real-time PCR for sensitive detection of Vibrio aestuarianus in Crassostrea gigas. AB - Validation of a novel quantitative real-time PCR using TaqMan(r) minor groove binder (MGB) chemistry is described for sensitive and rapid detection of Vibrio aestuarianus, an increasingly important pathogen of Pacific cupped oyster Crassostrea gigas aquaculture. Primers and TaqMan(r) MGB hydrolysis probe were designed to specifically amplify a 58bp DNA fragment of the V. aestuarianus dnaJ gene. Real-time PCR selectivity was empirically tested using DNA extracted from isolates of V. aestuarianus and a selection of different aquatic bacterial species, including other Vibrio spp. Theoretical selectivity was assessed through sequence comparison using the NCBI BLAST similarity tool. Quantitative PCR plasmid standards were generated to test assay linearity, amplification efficiency and the limit of quantitation (LOQ), according to International Organisation for Standardisation ISO 16140 validation recommendations. LOQ ranged between 5 and 10 PCR copies, although the detection range extended beyond this with reduced precision. Applied performance was tested using C. gigas samples taken from a selection of Irish aquaculture sites. Increasing levels of V. aestuarianus, accompanied by the development of tissue pathology in examined oysters, were found at 1 site that was sampled repeatedly in 2013. Rapid, sensitive and reproducible detections of V. aestuarianus from C. gigas tissue samples were attained during this validation study with a small sample size, and a practical application for disease management is described. PMID- 26036832 TI - Identification and prevalence of coral diseases on three Western Indian Ocean coral reefs. AB - Coral diseases have caused a substantial decline in the biodiversity and abundance of reef-building corals. To date, more than 30 distinct diseases of scleractinian corals have been reported, which cause progressive tissue loss and/or affect coral growth, reproductive capacity, recruitment, species diversity and the abundance of reef-associated organisms. While coral disease research has increased over the last 4 decades, very little is known about coral diseases in the Western Indian Ocean. Surveys conducted at multiple sites in Reunion, South Africa and Mayotte between August 2010 and June 2012 revealed the presence of 6 main coral diseases: black band disease (BBD), white syndrome (WS), pink line syndrome (PLS), growth anomalies (GA), skeleton eroding band (SEB) and Porites white patch syndrome (PWPS). Overall, disease prevalence was higher in Reunion (7.5 +/- 2.2%; mean +/- SE) compared to South Africa (3.9 +/- 0.8%) and Mayotte (2.7 +/- 0.3%). Across locations, Acropora and Porites were the genera most susceptible to disease. Spatial variability was detected in both Reunion and South Africa, with BBD and WS more prevalent on shallow than deep reefs. There was also evidence of seasonality in 2 diseases: the prevalence of BBD and WS was higher in summer than winter. This was the first study to investigate the ecology of coral diseases, providing both qualitative and quantitative data, on Western Indian Ocean reefs, and surveys should be expanded to confirm these patterns. PMID- 26036833 TI - Histological evaluation of sodium percarbonate exposure on the gills of rainbow trout. AB - Ichthyophthirius multifiliis is a recurring problem in Australian rainbow trout Oncorhynchus mykiss farms and requires strategically timed, repeat treatments for effective management. Sodium percarbonate (SPC) is permitted for use in Australia, with host safety margins based on the toxicity of acute exposures to hydrogen peroxide (HP), the active product released when SPC is added to water. The effects of exposure to HP released by SPC, of repeated doses and of doses exceeding 100 mg l-1 on rainbow trout are unknown. We exposed juvenile rainbow trout (mean weight: 30.5 +/- 9 g) to repeated doses of 50, 150 and 250 mg l-1 SPC for 1 h on Days 1, 2, 7 and 8 of a treatment regime. The effect of SPC was assessed by histological evaluation of structural changes in gill tissue. Survival was 100% in all groups, but some fish exposed to 250 mg l-1 SPC displayed impaired swimming performance, and on Day 9 after the final treatment, oedema was present in 9.8% of lamella, which was significantly higher than the mean occurrence of 1.7, 4.2 and 1.3% in fish treated with 0, 50 and 150 mg l-1 SPC, respectively. These changes resolved within 24 h of the cessation of treatment. We conclude that SPC is safe to use on rainbow trout in doses of <=150 mg l-1 at 17 degrees C, however caution is advised at doses approaching 250 mg l 1. Water temperature, fish age, fish size and maturity, intensity of parasite infection and stocking density could alter the sensitivity of rainbow trout to SPC treatments. PMID- 26036834 TI - Zapping the gap: Reducing the multisensory temporal binding window by means of transcranial direct current stimulation (tDCS). AB - Synchrony among the senses lies at the heart of our possession of a unified conscious perception of the world. However, due to discrepancies in physical and neural information processing from different senses, the brain accommodates a limited range of temporal asynchronies between sensory inputs, i.e. the multisensory temporal binding window (TBW). Using non-invasive brain stimulation, we sought to modulate the audio-visual TBW and to identify cortical areas implicated in the conscious perception of multisensory synchrony. Participants performed a simultaneity judgment task while experiencing anodal (Experiment 1) or cathodal (Experiment 2) transcranial direct current stimulation (tDCS) over parietal and frontal regions. The results demonstrate that stimulating the right posterior parietal cortex significantly reduces the audio-visual TBW by approximately 30%, thereby causally linking this region to the plasticity of the TBW. This highlights a potential interventional technique for populations with a wider TBW, such as in autism and dyslexia. PMID- 26036835 TI - The Mozart Effect: A quantitative EEG study. AB - The aim of this study is to investigate the influence of Mozart's music on brain activity through spectral analysis of the EEG in young healthy adults (Adults), in healthy elderly (Elderly) and in elderly with Mild Cognitive Impairment (MCI). EEG recording was performed at basal rest conditions and after listening to Mozart's K448 or "Fur Elise" Beethoven's sonatas. After listening to Mozart, an increase of alpha band and median frequency index of background alpha rhythm activity (a pattern of brain wave activity linked to memory, cognition and open mind to problem solving) was observed both in Adults and in Elderly. No changes were observed in MCI. After listening to Beethoven, no changes in EEG activity were detected. This results may be representative of the fact that said Mozart's music is able to "activate" neuronal cortical circuits related to attentive and cognitive functions. PMID- 26036836 TI - Reply to Bachmann and Aru. AB - A reply to the Bachmann and Aru (2015) critique of our paper (Mack, Erol, & Clarke, 2015) in which we rebut their criticisms and argue once again that our results support our view that iconic memory requires attention. PMID- 26036837 TI - The neural correlates of movement intentions: A pilot study comparing hypnotic and simulated paralysis. AB - The distinct feeling of wanting to act and thereby causing our own actions is crucial to our self-perception as free human agents. Disturbances of the link between intention and action occur in several disorders. Little is known, however, about the neural correlates of wanting or intending to act. To investigate these for simple voluntary movements, we used a paradigm involving hypnotic paralysis and functional magnetic resonance imaging. Eight healthy women were instructed to sequentially perform left and right hand movements during a normal condition, as well as during simulated weakness, simulated paralysis and hypnotic paralysis of the right hand. Right frontopolar cortex was selectively hypoactivated for attempted right hand movement during simulated paralysis while it was active in all other conditions. Since simulated paralysis was the only condition lacking an intention to move, the activation in frontopolar cortex might be related to the intention or volition to move. PMID- 26036838 TI - Origin and compensation of imaging artefacts in localization-based super resolution microscopy. AB - Interpretation of high resolution images provided by localization-based microscopy techniques is a challenge due to imaging artefacts that can be categorized by their origin. They can be introduced by the optical system, by the studied sample or by the applied algorithms. Some artefacts can be eliminated via precise calibration procedures, others can be reduced only below a certain value. Images studied both theoretically and experimentally are qualified either by pattern specific metrics or by a more general metric based on fluorescence correlation spectroscopy. PMID- 26036839 TI - Low bone mineral density and fat-free mass in younger patients with a femoral neck fracture. AB - BACKGROUND: Reduced bone mineral density (BMD) together with muscle wasting and dysfunction, that is sarcopenia, emerges as a risk factor for hip fracture. The aim of this study was to examine body composition and BMD and their relationship with trauma mechanisms in young and middle-aged patients with femoral neck fracture. MATERIALS AND METHODS: Altogether, 185 patients with femoral neck fracture aged 20-69 were included. BMD, body composition and fat-free mass index (FFMI) were determined by dual-X-ray absorptiometry (DXA), and trauma mechanisms were registered. RESULTS: Ninety per cent of the whole study population had a femoral neck BMD below the mean for age. In the young patients (< 50 years), 27% had a Z-score of BMD <= -2 SD. More than half of the middle-aged patients (50-69 years) had osteopenia, that is T-score -1 to -2.5, and 35% had osteoporosis, that is T-score < -2.5, at the femoral neck. Patients with low-energy trauma, sport injury or high-energy trauma had a median standardised BMD of 0.702, 0.740 vs. 0.803 g/cm(2) (P = 0.03), and a median FFMI of 15.9, 17.7 vs. 17.5 kg/m(2) (P < 0.001), respectively. FFMI < 10th percentile of an age- and gender-matched reference population was observed in one-third. CONCLUSIONS: A majority had low BMD at the femoral neck, and one-third had reduced FFMI (i.e. sarcopenia). Patients with fracture following low-energy trauma had significantly lower femoral neck BMD and FFMI than patients with other trauma mechanisms. DXA examination of both BMD and body composition could be of value especially in those with low-energy trauma. PMID- 26036840 TI - Molecular and transcriptional characterization of GTHs and mPRalpha during ovarian maturation in rock bream Oplegnathus fasciatus. AB - The membrane progestin receptor alpha (mPRalpha) plays an important role in the regulation of oocyte meiotic maturation in fish. However, the endocrine regulation of multiple spawning in fish with asynchronous ovarian development remains to be determined. We identified four genes (FSHbeta, LHbeta, CGalpha and mPRalpha) that are widely expressed in both the reproductive and non-reproductive tissues of rock bream Oplegnathus fasciatus and examined their expression during ovarian maturation. The level of FSHbeta transcripts in the pituitary remained high during vitellogenic stages, when the plasma levels of estradiol-17beta reached maximum levels and oocyte development was stimulated. LHbeta expression in the pituitary and ovary reached maximum levels during oocyte maturation when the plasma levels of testosterone also reached a maximum. A significant correlation between mPRalpha transcript levels and the gonadosomatic index was observed during vitellogenesis and final maturation. Brain gonadotropin (FSHbeta and LHbeta) and mPRalpha were continuously expressed at different stages of ovarian development. The dynamic and diverse nature of gonadotropins and mPRalpha gene expression patterns suggests that these genes might jointly regulate ovarian development and maturation through the brain-pituitary-ovary axis in the rock bream endocrine system. PMID- 26036841 TI - Delivering a "dose of hope": a faith-based program to increase older african americans' participation in clinical trials. AB - BACKGROUND: Underrepresentation of older-age racial and ethnic minorities in clinical research is a significant barrier to health in the United States, as it impedes medical research advancement of effective preventive and therapeutic strategies. OBJECTIVE: The objective of the study was to develop and test the feasibility of a community-developed faith-based intervention and evaluate its potential to increase the number of older African Americans in clinical research. METHODS: Using a cluster-randomized design, we worked with six matched churches to enroll at least 210 persons. We provided those in the intervention group churches with three educational sessions on the role of clinical trials in addressing health disparity topics, and those in the comparison group completed surveys at the same timepoints. All persons enrolled in the study received ongoing information via newsletters and direct outreach on an array of clinical studies seeking participants. We evaluated the short-, mid-, and longer-term effects of the interventional program on clinical trial-related outcomes (ie, screening and enrollment). RESULTS: From 2012 to 2013, we enrolled a balanced cohort of 221 persons in the program. At a 3-month follow-up, mean intention to seek information about clinical trials was higher than baseline in both treatment (mu=7.5/10; sigma=3.1) and control arms (mu=6.6/10; sigma=3.3), with the difference more pronounced in the treatment arm. The program demonstrated strong retention at 3-month (95.4%, 211/221) and 6-month timepoints (94.1%, 208/221). CONCLUSIONS: The "Dose of Hope" program addressed an unmet need to reach an often overlooked audience of older African Americans who are members of churches and stimulate their interest in clinical trial participation. The program demonstrated its appeal in the delivery of effective messages and information about health disparities, and the role of clinical research in addressing these challenges. PMID- 26036842 TI - Identification of two novel mammographic density loci at 6Q25.1. AB - INTRODUCTION: Mammographic density (MD) is a strong heritable and intermediate phenotype for breast cancer, but much of its genetic variation remains unexplained. We performed a large-scale genetic association study including 8,419 women of European ancestry to identify MD loci. METHODS: Participants of three Swedish studies were genotyped on a custom Illumina iSelect genotyping array and percent and absolute mammographic density were ascertained using semiautomated and fully automated methods from film and digital mammograms. Linear regression analysis was used to test for SNP-MD associations, adjusting for age, body mass index, menopausal status and six principal components. Meta-analyses were performed by combining P values taking sample size, study-specific inflation factor and direction of effect into account. RESULTS: Genome-wide significant associations were observed for two previously identified loci: ZNF365 (rs10995194, P = 2.3 * 10(-8) for percent MD and P = 8.7 * 10(-9) for absolute MD) and AREG (rs10034692, P = 6.7 * 10(-9) for absolute MD). In addition, we found evidence of association for two variants at 6q25.1, both of which are known breast cancer susceptibility loci: rs9485370 in the TAB2 gene (P = 4.8 * 10(-9) for percent MD and P = 2.5 * 10(-8) for absolute MD) and rs60705924 in the CCDC170/ESR1 region (P = 2.2 * 10(-8) for absolute MD). Both regions have been implicated in estrogen receptor signaling with TAB2 being a potential regulator of tamoxifen response. CONCLUSIONS: We identified two novel MD loci at 6q25.1. These findings underscore the importance of 6q25.1 as a susceptibility region and provide more insight into the mechanisms through which MD influences breast cancer risk. PMID- 26036843 TI - Design of Cationic Multiwalled Carbon Nanotubes as Efficient siRNA Vectors for Lung Cancer Xenograft Eradication. AB - Polo-Like Kinase (PLK1) has been identified as a potential target in cancer gene therapy via chemical or genetic inhibitory approaches. The biomedical applications of chemically functionalized carbon nanotubes (f-CNTs) in cancer therapy have been studied due to their ability to efficiently deliver siRNA intracellularly. In this study, we established the capacity of cationic MWNT NH3(+) to deliver the apoptotic siRNA against PLK1 (siPLK1) in Calu6 tumor xenografts by direct intratumoral injections. A direct comparison with cationic liposomes was made. This study validates the PLK1 gene as a potential target in cancer gene therapy including lung cancer, as demonstrated by the therapeutic efficacy of siPLK1:MWNT-NH3(+) complexes and their ability to significantly improve animal survival. Biological analysis of the siPLK1:MWNT-NH3(+) treated tumors by qRT-PCR and Western blot, in addition to TUNEL staining confirmed the biological functionality of the siRNA intratumorally, suggesting that tumor eradication was due to PLK1 knockdown. Furthermore, by using a fluorescently labeled, noncoding siRNA sequence complexed with MWNT-NH3(+), we established for the first time that the improved therapeutic efficacy observed in f-CNT-based siRNA delivery is directly proportional to the enhanced siRNA retention in the solid tumor and subsequent uptake by tumor cells after local administration in vivo. PMID- 26036844 TI - Side effects of desmopressin in patients with bleeding disorders. AB - INTRODUCTION: Desmopressin is frequently used in patients with bleeding disorders because of its prohaemostatic effects. In recent years desmopressin use increased due to reported high incidence of inhibitors in mild haemophilia after clotting factor infusion and the rising costs of clotting factor concentrates. The safety and frequency of side effects have hardly been assessed in well-designed studies. AIM: We therefore prospectively evaluated side effects of desmopressin in a large unselected cohort of bleeding disorder patients, who received a desmopressin test dose. METHODS: Blood was drawn prior to, one, three, six and 24 h after desmopressin. Primary outcome was change in serum sodium, haematocrit, serum- and urine osmolality, body weight and vital signs. Self-reported side effects were evaluated as secondary outcome. RESULTS: In total, 108 patients were included, median age 30 years, the majority of whom had von Willebrand disease type 1 (76%). A significant change in water balance parameters was observed. Four patients (4%) had hyponatraemia (<=135 mmol L(-1) ) after 24 h but no severe hyponatraemia occurred (<=125 mmol L(-1) ). After infusion, 41 (38%) patients were hypotensive (<=90 mmHg SBP and/or <=60 mmHg DBP) and 10 (9%) presented with tachycardia (>100 min(-1) ). However, none of these effects sustained at 24 h. Infusion was discontinued in one patient because of tachycardia, nausea and malaise. Self-reported side effects included: headache, fatigue, flush and dizziness. CONCLUSION: Observed side effects correspond with the known antidiuretic and vasomotor effects of desmopressin. Changes in parameters were temporary and not clinically relevant. In conclusion, our study supports desmopressin use as a safe treatment option in patients with various bleeding disorders. PMID- 26036845 TI - Infringement of the barriers of cancer via dietary phytoconstituents capsaicin through novel drug delivery system. AB - Cancer is the major cause of fatality and the number of new cases is increasing incessantly. Conventional therapies and existing anticancer agents cause serious side effects and expand the patient's lifespan by a few years. There is the need to exploit alternative anticancer agents and novel drug delivery system to deliver these agents to the tumor site for the prevention of cancer. Recently, biologically active compounds isolated from plants used for the management of cancer have been the heart of interest. Capsaicin is a major pungent agent present in the chili peppers that is heavily consumed in the world. Capsaicin has demonstrated effectiveness as an anticancer agent, but a restraining factor is its pungency, extremely low aqueous solubility, and poor oral bioavailability which impede its use as an anticancer agent. Many technologies have been developed and applied to conquer this drawback. We bring to light the benefits of this phytoconstituent for treating different types of cancer. We also discussed some of the delivery approaches that have already made an impact by either delivering a drug to target tissue or increasing its bioavailability by many folds. PMID- 26036846 TI - Traditional fire-use, landscape transition, and the legacies of social theory past. AB - Fire-use and the scale and character of its effects on landscapes remain hotly debated in the paleo- and historical-fire literature. Since the second half of the nineteenth century, anthropology and geography have played important roles in providing theoretical propositions and testable hypotheses for advancing understandings of the ecological role of human-fire-use in landscape histories. This article reviews some of the most salient and persistent theoretical propositions and hypotheses concerning the role of humans in historical fire ecology. The review discusses this history in light of current research agendas, such as those offered by pyrogeography. The review suggests that a more theoretically cognizant historical fire ecology should strive to operationalize transdisciplinary theory capable of addressing the role of human variability in the evolutionary history of landscapes. To facilitate this process, researchers should focus attention on integrating more current human ecology theory into transdisciplinary research agendas. PMID- 26036847 TI - I-C-SEA Change: A participatory tool for rapid assessment of vulnerability of tropical coastal communities to climate change impacts. AB - We present a synoptic, participatory vulnerability assessment tool to help identify the likely impacts of climate change and human activity in coastal areas and begin discussions among stakeholders on the coping and adaptation measures necessary to minimize these impacts. Vulnerability assessment tools are most needed in the tropical Indo-Pacific, where burgeoning populations and inequitable economic growth place even greater burdens on natural resources and support ecosystems. The Integrated Coastal Sensitivity, Exposure, and Adaptive Capacity for Climate Change (I-C-SEA Change) tool is built around a series of scoring rubrics to guide non-specialists in assigning scores to the sensitivity and adaptive capacity components of vulnerability, particularly for coral reef, seagrass, and mangrove habitats, along with fisheries and coastal integrity. These scores are then weighed against threat or exposure to climate-related impacts such as marine flooding and erosion. The tool provides opportunities for learning by engaging more stakeholders in participatory planning and group decision-making. It also allows for information to be collated and processed during a "town-hall" meeting, facilitating further discussion, data validation, and even interactive scenario building. PMID- 26036849 TI - Expanding aged care clinical education. PMID- 26036850 TI - Newborn hearing screening outcomes during the first decade of the program in a reference hospital from Turkey. AB - In this study, the authors report the results of a three-stage newborn hearing screening (NHS) program for well babies at the Gazi University Hospital (GUH) in Ankara between 2003 and 2013. GUH-NHS was performed by automated transient evoked otoacoustic emission (a-TEOAE) at the first and second steps and by automated brainstem audiometry (a-ABR) at the third step. The data were analysed to assess not only rate of congenital permanent hearing loss (CPHL), but also the effectiveness of the program during the years. A total of 18,470 well babies were tested. The data showed that coverage ratio for the GUH-born babies was increased and more outside-born babies (OBB) were admitted by time (means 84.31 and 11.28 %, respectively). Mean CPHL was found to be 0.26 %. Mean referral rate was decreased to 0.81 % by a-ABR from 2.16 % by a-TEOAE. Mean of missed cases in any stage of GUH-NHS was 4.88 %. It was seen that neither CPHL nor referral rate, but only ratio of missed ones presented increase in parallel to increment in OBB. This paper first presents that clinically acceptable screening procedures developed in GUH by time, and secondly higher rate of CPHL in Turkey than in the Western countries, and benefits of third stage screening by a-ABR because it prevented referral of 251 children (1.29 %) to the clinical tests. We think that this number is reasonably important regarding not only economical point of view, but also waiting lists in the audiology departments in a developing country, in which audiological service is still limited. PMID- 26036851 TI - Nomenclature proposal to describe vocal fold motion impairment. AB - The terms used to describe vocal fold motion impairment are confusing and not standardized. This results in a failure to communicate accurately and to major limitations of interpreting research studies involving vocal fold impairment. We propose standard nomenclature for reporting vocal fold impairment. Overarching terms of vocal fold immobility and hypomobility are rigorously defined. This includes assessment techniques and inclusion and exclusion criteria for determining vocal fold immobility and hypomobility. In addition, criteria for use of the following terms have been outlined in detail: vocal fold paralysis, vocal fold paresis, vocal fold immobility/hypomobility associated with mechanical impairment of the crico-arytenoid joint and vocal fold immobility/hypomobility related to laryngeal malignant disease. This represents the first rigorously defined vocal fold motion impairment nomenclature system. This provides detailed definitions to the terms vocal fold paralysis and vocal fold paresis. PMID- 26036852 TI - TMPRSS3 mutations in autosomal recessive nonsyndromic hearing loss. AB - Nonsyndromic genetic deafness is highly heterogeneous in its clinical presentation, pattern of inheritance and underlying genetic causes. Mutations in TMPRSS3 gene encoding transmembrane serine protease account for <1 % of autosomal recessive nonsyndromic hearing loss (ARNSHL) in Caucasians. Targeted next generation sequencing in the index family with profound deaf parents and a son, and Sanger sequencing of selected TMPRSS3 gene regions in a cohort of thirty-five patients with suspected ARNSHL was adopted. A son and his mother in the index family were homozygous for TMPRSS3 c.208delC (p.His70Thrfs*19) variant. Father was digenic compound heterozygote for the same variant and common GJB2 c.35delG variant. Three additional patients from the ARNSHL cohort were homozygous for TMPRSS3 c.208delC. TMPRSS3 defects seem to be an important cause of ARNSHL in Slovenia resulting in uniform phenotype with profound congenital hearing loss, and satisfactory hearing and speech recognition outcome after cochlear implantation. Consequently, TMPRSS3 gene analysis should be included in the first tier of genetic investigations of ARNSHL along with GJB2 and GJB6 genes. PMID- 26036853 TI - Obesity as a risk factor in cancer: A national consensus of the Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology. AB - In the last few years, many prospective studies have demonstrated a clear association between obesity and cancers of the colon and rectum, breast in post menopausal women, endometrium, kidney, oesophagus and pancreas. Obesity is also associated with a high risk of recurrence and cancer-related death. The pathophysiology of obesity involves various changes that may be implicated in the relationship between obesity and cancer, such as excess inflammatory cytokines and chronic inflammation, hyperinsulinaemia, insulin resistance, and raised leptin and oestrogens. The Spanish Society for the Study of Obesity and the Spanish Society of Medical Oncology have signed a cooperation agreement to work together towards reducing the impact of obesity in cancer. Preventing obesity prevents cancer. PMID- 26036854 TI - A retrospective analysis of lung metastasis in 64 patients with alveolar soft part sarcoma. AB - OBJECTIVES: To analyse the lung metastasis and possible factors influencing lung metastasis in alveolar soft part sarcoma (ASPS) patients. METHODS: The medical records of 64 consecutive ASPS patients were reviewed to analyse their treatments, features of lung metastasis, and possible factors influencing lung metastasis. RESULTS: Thirty-six females and 28 males with a median age of 27 years were included. The primary disease sites were the extremities in 51 patients and other locations in 13 patients. The median primary tumour size was 5 cm. Wide local excision of the primary tumour was performed on 56 patients (87.5 %). Thirteen patients (20.3 %) received postoperative adjuvant radiotherapy, and nine patients (14.1 %) underwent adjuvant chemotherapy. Twelve patients (18.8 %) presented with metastatic lung disease. Twenty-nine patients (45.3 %) developed metastatic lung disease during follow-up. Lung metastasis occurred in 64.1 % of the patients. Lung metastasis was detected at a median interval of 20 months after primary ASPS diagnosis. Being male, >20 years of age, having a primary tumour size >= 5 cm, and local recurrence were associated with a greater rate of lung metastasis. Median survival after the diagnosis of lung metastasis was 34 months. The 5-year survival rates were 64.1 and 95.2 % for patients with and without lung metastasis (P < 0.001). Thirty-seven patients with metastatic lung disease received anthracycline- and ifosfamide-based chemotherapy. One patient experienced a partial remission. CONCLUSIONS: ASPS patients have a high prevalence of lung metastasis. Sex, age, primary tumour size, and local recurrence are major factors influencing lung metastasis. Chemotherapy is not efficacious in ASPS patients with lung metastasis. PMID- 26036855 TI - SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies. AB - SCN5A mutations involving the alpha-subunit of the cardiac voltage-gated muscle sodium channel (NaV1.5) result in different cardiac channelopathies with an autosomal-dominant inheritance such as Brugada syndrome. On the other hand, mutations in SCN4A encoding the alpha-subunit of the skeletal voltage-gated sodium channel (NaV1.4) cause non-dystrophic myotonia and/or periodic paralysis. In this study, we investigated whether cardiac arrhythmias or channelopathies such as Brugada syndrome can be part of the clinical phenotype associated with SCN4A variants and whether patients with Brugada syndrome present with non dystrophic myotonia or periodic paralysis and related gene mutations. We therefore screened seven families with different SCN4A variants and non dystrophic myotonia phenotypes for Brugada syndrome and performed a neurological, neurophysiological and genetic work-up in 107 Brugada families. In the families with an SCN4A-associated non-dystrophic myotonia, three patients had a clinical diagnosis of Brugada syndrome, whereas we found a remarkably high prevalence of myotonic features involving different genes in the families with Brugada syndrome. One Brugada family carried an SCN4A variant that is predicted to probably affect function, one family suffered from a not genetically confirmed non-dystrophic myotonia, one family was diagnosed with myotonic dystrophy (DMPK gene) and one family had a Thomsen disease myotonia congenita (CLCN1 variant that affects function). Our findings and data suggest a possible involvement of SCN4A variants in the pathophysiological mechanism underlying the development of a spontaneous or drug-induced type 1 electrocardiographic pattern and the occurrence of malignant arrhythmias in some patients with Brugada syndrome. PMID- 26036856 TI - Motivations, concerns and preferences of personal genome sequencing research participants: Baseline findings from the HealthSeq project. AB - Whole exome/genome sequencing (WES/WGS) is increasingly offered to ostensibly healthy individuals. Understanding the motivations and concerns of research participants seeking out personal WGS and their preferences regarding return-of results and data sharing will help optimize protocols for WES/WGS. Baseline interviews including both qualitative and quantitative components were conducted with research participants (n=35) in the HealthSeq project, a longitudinal cohort study of individuals receiving personal WGS results. Data sharing preferences were recorded during informed consent. In the qualitative interview component, the dominant motivations that emerged were obtaining personal disease risk information, satisfying curiosity, contributing to research, self-exploration and interest in ancestry, and the dominant concern was the potential psychological impact of the results. In the quantitative component, 57% endorsed concerns about privacy. Most wanted to receive all personal WGS results (94%) and their raw data (89%); a third (37%) consented to having their data shared to the Database of Genotypes and Phenotypes (dbGaP). Early adopters of personal WGS in the HealthSeq project express a variety of health- and non-health-related motivations. Almost all want all available findings, while also expressing concerns about the psychological impact and privacy of their results. PMID- 26036857 TI - Towards a European consensus for reporting incidental findings during clinical NGS testing. AB - In 2013, the American College of Medical Genetics (ACMG) examined the issue of incidental findings in whole exome and whole genome sequencing, and introduced recommendations to search for, evaluate and report medically actionable variants in a set of 56 genes. At a debate held during the 2014 European Society for Human Genetics Conference (ESHG) in Milan, Italy, the first author of that paper presented this view in a debate session that did not end with a conclusive vote from the mainly European audience for or against reporting back actionable incidental findings. In this meeting report, we elaborate on the discussions held during a special meeting hosted at the ESHG in 2013 from posing the question 'How to reach a (European) consensus on reporting incidental findings and unclassified variants in diagnostic next generation sequencing'. We ask whether an European consensus exists on the reporting of incidental findings in genome diagnostics, and present a series of key issues that require discussion at both a national and European level in order to develop recommendations for handling incidental findings and unclassified variants in line with the legal and cultural particularities of individual European member states. PMID- 26036858 TI - High acceptance of an early dyslexia screening test involving genetic analyses in Germany. AB - Dyslexia is a developmental disorder characterized by severe problems in the acquisition of reading and writing skills. It has a strong neurobiological basis. Genetic influence is estimated at 50-70%. One of the central problems with dyslexia is its late diagnosis, normally not before the end of the 2nd grade, resulting in the loss of several years for early therapy. Currently, research is focusing on the development of early tests for dyslexia, which may be based on EEG and genetics. Our aim was to determine the acceptance of such a future test among parents. We conducted a representative survey in Germany with 1000 parents of children aged 3-7 years, with and without experience of dyslexia. 88.7% of the parents supported the introduction of an early test for dyslexia based on EEG and genetics; 82.8% would have their own children tested, and 57.9% were willing to pay for the test if health insurance did not cover the costs. Test acceptance was significantly higher if parents had prior experience with dyslexia. The perceived benefits of such a test were early recognition and remediation and, preventing deficits. Concerns regarded the precision of the test, its potentially stigmatizing effect and its costs. The high overall support for the test leads to the conclusion that parents would accept a test for dyslexia based on EEG and genetics. PMID- 26036859 TI - Systematic analysis of variants related to familial hypercholesterolemia in families with premature myocardial infarction. AB - Familial hypercholesterolemia (FH) is an oligogenic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDLC) levels. Variants in four genes have been reported to cause the classical autosomal-dominant form of the disease. FH is largely under-diagnosed in European countries. As FH increases the risk for coronary artery disease (CAD) and myocardial infarction (MI), it might be specifically overlooked in the large number of such patients. Here, we systematically examined the frequency of potential FH-causing variants by exome sequencing in 255 German patients with premature MI and a positive family history for CAD. We further performed co-segregation analyses in an average of 5.5 family members per MI patient. In total, we identified 11 potential disease-causing variants that co-segregate within the families, that is, 5% of patients with premature MI and positive CAD family history had FH. Eight variants were previously reported as disease-causing and three are novel (LDLR.c.811G>A p.(V271I)), PCSK9.c.610G>A (p.(D204N)) and STAP1.c.139A>G (p.(T47A))). Co segregation analyses identified multiple additional family members carrying one of these FH variants and the clinical phenotype of either FH (n=2) or FH and premature CAD (n=15). However, exome sequencing also revealed that some variants in FH genes, which have been reported to cause FH, do not co-segregate with FH. The data reveal that a large proportion of FH patients escape the diagnosis, even when they have premature MI. Hence, systematic molecular-genetic screening for FH in such patients may reveal a substantial number of cases and thereby allow a timely LDLC-lowering in both FH/MI patients as well as their variant-carrying family members. PMID- 26036860 TI - Preferences for genetic testing for colorectal cancer within a population-based screening program: a discrete choice experiment. AB - This study explored individuals' preferences for genetic testing for colorectal cancer (CRC) in a screening situation and their willingness to participate in genetic testing for Lynch syndrome, familial adenomatous polyposis (FAP), and familial colorectal cancer (FCC). For that purpose, 532 respondents aged 55-65 years completed a Discrete Choice Experiment. Using panel latent class models, the preferences for two screening situation characteristics (the probability of being genetically predisposed and the probability of developing CRC) and screening test characteristics (the frequency of preventive colonoscopies and CRC survival) were estimated. Based on these preferences, respondents' willingness to participate in the three screening initiatives was estimated. Lower-educated respondents and respondents who express serious anxiety and worries found colonoscopy frequency and the probability of developing CRC relatively more important and survival relatively less important compared with higher-educated respondents and respondents who express no anxiety and worries. These differences in preferences resulted in opposite preferences for participation in FCC and FAP screening. In conclusion, the general population is willing to participate in genetic screening for CRC. If individuals are suspected of genetic or familial CRC, they should at least be informed about their increased risk of being genetically predisposed and about the importance of participating in all preventive follow-up colonoscopies in order to maximize survival. PMID- 26036861 TI - A comprehensive scoping review of ability and disability in ADHD using the International Classification of Functioning, Disability and Health-Children and Youth Version (ICF-CY). AB - This is the first in a series of four empirical investigations to develop International Classification of Functioning, Disability and Health (ICF) Core Sets for Attention Deficit Hyperactivity Disorder (ADHD). The objective here was to use a comprehensive scoping review approach to identify the concepts of functional ability and disability used in the scientific ADHD literature and link these to the nomenclature of the ICF-CY. Systematic searches were conducted using Medline/PubMed, PsycINFO, ERIC and Cinahl, to extract the relevant concepts of functional ability and disability from the identified outcome studies of ADHD. These concepts were then linked to ICF-CY by two independent researchers using a standardized linking procedure. Data from identified studies were analysed until saturation of ICF-CY categories was reached. Eighty studies were included in the final analysis. Concepts contained in these studies were linked to 128 ICF-CY categories. Of these categories, 68 were considered to be particularly relevant to ADHD (i.e., identified in at least 5 % of the studies). Of these, 32 were related to Activities and participation, 31 were related to Body functions, and five were related to environmental factors. The five most frequently identified categories were school education (53 %), energy and drive functions (50 %), psychomotor functions (50 %), attention functions (49 %), and emotional functions (45 %). The broad variety of ICF-CY categories identified in this study underlines the necessity to consider ability and disability in ADHD across all dimensions of life, for which the ICF-CY provides a valuable and universally applicable framework. These results, in combination with three additional preparatory studies (expert survey, focus groups, clinical study), will provide a scientific basis to define the ICF Core Sets for ADHD for multi-purpose use in basic and applied research, and every day clinical practice. PMID- 26036863 TI - Malignant hyperthermia in the early days of pediatric anesthesia: an interview with anesthesiology pioneer, Dr. John F. Ryan. AB - Dr. John F. Ryan (1935 - ), Associate Professor of Anaesthesia at the Harvard Medical School, influenced the careers of hundreds of residents and fellows-in training while instilling in them his core values of resilience, hard work, and integrity. His authoritative textbook, A Practice of Anesthesia for Infants and Children, remains as influential today as it did when first published decades ago. Although he had had many accomplishments, he identified his experiences caring for patients with malignant hyperthermia and characterizing the early discovery of this condition as his defining contribution to medicine. Based on a series of interviews with Dr. Ryan, this article reviews a remarkable career that coincides with the dawn of modern pediatric anesthetic practice. PMID- 26036862 TI - New evidence of factor structure and measurement invariance of the SDQ across five European nations. AB - The main purpose of the present study was to analyse the internal structure and to test the measurement invariance of the Strengths and Difficulties Questionnaire (SDQ), self-reported version, in five European countries. The sample consisted of 3012 adolescents aged between 12 and 17 years (M = 14.20; SD = 0.83). The five-factor model (with correlated errors added), and the five factor model (with correlated errors added) with the reverse-worded items allowed to cross-load on the Prosocial subscale, displayed adequate goodness of-fit indices. Multi-group confirmatory factor analysis showed that the five-factor model (with correlated errors added) had partial strong measurement invariance by countries. A total of 11 of the 25 items were non-invariant across samples. The level of internal consistency of the Total difficulties score was 0.84, ranging between 0.69 and 0.78 for the SDQ subscales. The findings indicate that the SDQ's subscales need to be modified in various ways for screening emotional and behavioural problems in the five European countries that were analysed. PMID- 26036865 TI - Government should monitor quality of medical education. PMID- 26036866 TI - Enantioselective Synthesis of Pyrrole-Based Spiro- and Polycyclic Derivatives by Iridium-Catalyzed Asymmetric Allylic Dearomatization and Controllable Migration Reactions. AB - The first highly diastereo- and enantioselective synthesis of five-membered spiro 2H-pyrroles was achieved using an Ir-catalyzed asymmetric allylic dearomatization reaction. The spiro-2H-pyrrole derivatives readily undergo a controllable and stereospecific allylic migration under acid catalysis, providing polycyclic pyrrole derivatives in excellent yields and ee values. Additionally, the novel Ir complex K1, derived from [Ir(cod)Cl]2 (cod = 1,5-cyclooctadiene) and N-benzhydryl N-phenyldinaphthophosphoramidite (BHPphos), showed excellent control of both diastereo- and enantioselectivities. PMID- 26036864 TI - Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes. AB - Exosomes are approximately 100-nm vesicles that consist of a lipid bilayer of cellular membranes secreted in large quantities from various types of normal and disease-related cells. Endocytosis has been reported as a major pathway for the cellular uptake of exosomes; however, the detailed mechanisms of their cellular uptake are still unknown. Here, we demonstrate the active induction of macropinocytosis (accompanied by actin reorganisation, ruffling of plasma membrane, and engulfment of large volumes of extracellular fluid) by stimulation of cancer-related receptors and show that the epidermal growth factor (EGF) receptor significantly enhances the cellular uptake of exosomes. We also demonstrate that oncogenic K-Ras-expressing MIA PaCa-2 cells exhibit intensive macropinocytosis that actively transports extracellular exosomes into the cells compared with wild-type K-Ras-expressing BxPC-3 cells. Furthermore, encapsulation of the ribosome-inactivating protein saporin with EGF in exosomes using our simple electroporation method produces superior cytotoxicity via the enhanced cellular uptake of exosomes. Our findings contribute to the biological, pharmaceutical, and medical research fields in terms of understanding the macropinocytosis-mediated cellular uptake of exosomes with applications for exosomal delivery systems. PMID- 26036867 TI - Evaluation of a new automated assay for the measurement of circulating 1,25 dihydroxyvitamin D levels in daily practice. AB - BACKGROUND AND OBJECTIVE: 1,25-dihydroxyvitamin D [1,25(OH)2D] is the most important vitamin D metabolite in regulating calcium and phosphorus metabolism and bone resorption. It is measured in plasma for diagnosis and management of patients with disorders influencing vitamin D metabolism. The most common methods for 1,25(OH)2D quantification are competitive isotopic I(125) immunoassays. The purpose of this work is to compare the IDS isotopic immunoassay (IDS RIA) and the nonisotopic iSYS immunoassay (IDS iSYS) for 1,25(OH)2D measurement in human serum and in control samples obtained from the Vitamin D External Quality Assessment Scheme (DEQAS). METHODS: 1,25(OH)2D concentrations in 180 serum samples (87 females and 93 males) and in 25 samples from the DEQAS were assayed using IDS RIA and IDS iSYS methods. Both assays were performed after delipidation and immunoextraction steps. Measurement range was 9.0-348.0pmol/L and 15.6 504.0pmol/L for IDS RIA and IDS iSYS assay, respectively. 'Normal adult' reference ranges of 1,25(OH)2D were 43-168pmol/L for IDS RIA and 63-228pmol/L for IDS iSYS. RESULTS: The equation of the Deming regression analysis demonstrated that IDS iSYS tended to give lower 1,25(OH)2D concentrations by a mean of 20% over the tested concentration range when compared to IDS RIA. Both assays would easily meet the DEQAS goal of 80% of survey samples within 30% of the All Laboratory Trimmed Mean "ALTM". Results of 1,25(OH)2D obtained using IDS iSYS in samples distributed by DEQAS were closely related to those by LC-MS/MS method. CONCLUSIONS: The concentrations of 1,25(OH)2D measured by the IDS iSYS tended to be lower than those of IDS RIA in patients, but quite comparable to those of LC MS/MS and ALTM in DEQAS samples. PMID- 26036868 TI - Mechanisms of immunological tolerance. AB - There is increasing interest in establishing diagnostic markers of immunological tolerance applicable to efforts to minimize drug immunosuppression in transplantation and chronic immunological diseases. It is hoped that an understanding of the diverse mechanisms that can contribute to tolerance will guide efforts to establish diagnostic tolerance biomarkers. Not only would these be valuable for management of autoimmune diseases, transplants and allergies, but they might also guide efforts to override tolerance processes in cancer and vaccine development. Where tolerance is generated by deletion or inactivation of antigen reactive lymphocytes, it is unlikely that any long-term-valid blood biomarkers might be found. Where tolerance is mediated by active regulatory mechanisms, indicators that can be usefully measured may emerge, but these would likely show significant heterogeneity reflecting the diversity of active tolerance processes operating in different individuals. Given this, the most useful "kits" might be those "smart" enough to detect this diversity of tolerance players. PMID- 26036869 TI - A novel double heterozygous Hb Fontainebleau/HbD Punjab hemoglobinopathy. AB - OBJECTIVES: To report the finding of a novel double heterozygous hemoglobinopathy, the coinheritance of Hb Fontainebleau (alpha-chain variant) with HbD-Punjab (beta-chain variant) discovered upon investigation of unexplained microcytosis in an infant. DESIGN AND METHODS: Hemoglobinopathy investigation was performed by high performance liquid chromatography (HPLC) using the beta thalassemia Short Program on the Bio-Rad Variant II(TM) followed by gel electrophoresis at alkaline and acid pH (Sebia Hydrasys 2 Electrophoresis System) and molecular diagnostic testing. This study complied with our institutional board ethics requirements. RESULTS: HPLC and electrophoresis suggested a complex alpha- and beta-chain hemoglobinopathy with presumptive identification of the beta Hb variant as Hb D-Punjab. DNA sequencing analysis revealed the presence of a double heterozygous status for Hb Fontainebleau/Hb D-Punjab. CONCLUSIONS: In this paper we report the coinheritance of Hb Fontainebleau with Hb D-Punjab. PMID- 26036870 TI - Detection of Pesticides and Metabolites Using Surface-Enhanced Raman Spectroscopy (SERS): Acephate. AB - A protocol created for acephate detection on particulates and vapors surrounding farmworkers as well as in urine samples is reported. Acephate is detected to the low parts-per-billion (ppb) range using surface-enhanced Raman spectroscopy (SERS). Optimal SERS sensor metal choice and post-production treatments to improve sensor stability in aqueous solutions containing acephate are presented. Acephate is detected in the vapor phase and can be differentiated from urine components and structurally similar pesticides, including the acephate metabolite degradation product methamidophos. Protocol evaluation and preliminary field tests from North Carolina farms are discussed. PMID- 26036871 TI - Mydriasert pupillary dilation for cataract surgery: an economic and clinical study. AB - BACKGROUND: Mydriasert is an insoluble ophthalmic insert indicated for mydriasis prior to cataract surgery, which gradually releases the active ingredients: tropicamide (0.25 mg) and phenylephrine (5.38 mg). This study aimed to evaluate the cost of Mydriasert compared with conventional mydriatic eye drops to induce pupil dilation prior to cataract surgery using a budget impact model. METHODS: A cohort-based, decision tree, budget impact model was developed to estimate the drug, consumable and staff costs for achieving mydriasis with Mydriasert compared to mydriatic eye drops (tropicamide [1%] plus phenylephrine [10%]). Insights from structured interviews with clinicians (n = 5) experienced in using both Mydriasert and mydriatic eye drops and results from the current clinical study of patients undergoing cataract surgery (n = 144) at a Greater London district general hospital were used to obtain key input parameters for the model, and to validate the model approach. RESULTS: The base case analysis in a cohort of 1763 patients undergoing cataract surgery showed that when Mydriasert substituted mydriatic eye drops, annual total costs decreased by 18% and annual total nurse time decreased from 235.1 hours to 44.1 hours over one year (2012-2013). CONCLUSIONS: This study demonstrated that despite its higher unit cost than mydriatic eye drops, Mydriasert resulted in overall savings in health-care costs, mainly associated with reduced nursing time. The economic model developed could assist National Health Service managers and local payers to estimate the budget impact of the introduction of Mydriasert into different clinical settings. PMID- 26036873 TI - Comparative proteomic analysis using 2DE-LC-MS/MS reveals the mechanism of Fuzhuan brick tea extract against hepatic fat accumulation in rats with nonalcoholic fatty liver disease. AB - Fuzhuan brick tea has received increasing attention in recent years owing to its benefits for nonalcoholic fatty liver disease (NAFLD) and associated metabolic syndrome. For exploring the ameliorative mechanism, the liver proteomes from three groups of rats fed either a normal control diet (NCD), a high fat diet (HFD), or a HFD supplemented with high-dose Fuzhuan brick tea extract (FTE) (HFD + HFTE) were comprehensively compared by quantitative proteomics using 2DE-LC MS/MS. This is the first study of the effects of tea aqueous extract on the liver proteome of rats suffering from metabolic syndrome. The results showed that 57 proteins displayed more than 1.5-fold differences in at least one of two comparisons of HFD versus NCD and HFD versus HFD + HFTE due to HFD feeding and FTE treatment, respectively. Of them, over 75% of proteins exhibited a similar tendency of expression in the two comparisons, meaning FTE was able to correct HFD effects on rat livers. By function analyses, an extensive list of proteins was involved in sugar and lipid metabolism. Compared with HFD-fed rats, the reduced lipogenesis and enhanced beta-oxidation, tricarboxylic acid cycle and respiratory chain in HFD + HFTE-fed rats, which mainly contributed to ameliorate hepatic fat accumulation and associated NAFLD. Additionally, some putative drug targets were also revealed such as COX2, PGAM1, ACACB, FAS, and ECHS1. PMID- 26036872 TI - Immunosuppressive potential of human amnion epithelial cells in the treatment of experimental autoimmune encephalomyelitis. AB - BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS). In recent years, it has been found that cells such as human amnion epithelial cells (hAECs) have the ability to modulate immune responses in vitro and in vivo and can differentiate into multiple cell lineages. Accordingly, we investigated the immunoregulatory effects of hAECs as a potential therapy in an MS-like disease, EAE (experimental autoimmune encephalomyelitis), in mice. METHODS: Using flow cytometry, the phenotypic profile of hAECs from different donors was assessed. The immunomodulatory properties of hAECs were examined in vitro using antigen-specific and one-way mixed lymphocyte proliferation assays. The therapeutic efficacy of hAECs was examined using a relapsing-remitting model of EAE in NOD/Lt mice. T cell responsiveness, cytokine secretion, T regulatory, and T helper cell phenotype were determined in the peripheral lymphoid organs and CNS of these animals. RESULTS: In vitro, hAECs suppressed both specific and non-specific T cell proliferation, decreased pro inflammatory cytokine production, and inhibited the activation of stimulated T cells. Furthermore, T cells retained their naive phenotype when co-cultured with hAECs. In vivo studies revealed that hAECs not only suppressed the development of EAE but also prevented disease relapse in these mice. T cell responses and production of the pro-inflammatory cytokine interleukin (IL)-17A were reduced in hAEC-treated mice, and this was coupled with a significant increase in the number of peripheral T regulatory cells and naive CD4+ T cells. Furthermore, increased proportions of Th2 cells in the peripheral lymphoid organs and within the CNS were observed. CONCLUSION: The therapeutic effect of hAECs is in part mediated by inducing an anti-inflammatory response within the CNS, demonstrating that hAECs hold promise for the treatment of autoimmune diseases like MS. PMID- 26036877 TI - Incidence of Surgical Site Infection Following Mastectomy With and Without Immediate Reconstruction Using Private Insurer Claims Data. AB - OBJECTIVE: The National Healthcare Safety Network classifies breast operations as clean procedures with an expected 1%-2% surgical site infection (SSI) incidence. We assessed differences in SSI incidence following mastectomy with and without immediate reconstruction in a large, geographically diverse population. DESIGN: Retrospective cohort study. PATIENTS: Commercially insured women aged 18-64 years with ICD-9-CM procedure or CPT-4 codes for mastectomy from January 1, 2004 through December 31, 2011 METHODS: Incident SSIs within 180 days after surgery were identified by ICD-9-CM diagnosis codes. The incidences of SSI after mastectomy with and without immediate reconstruction were compared using the chi2 test. RESULTS: From 2004 to 2011, 18,696 mastectomy procedures among 18,085 women were identified, with immediate reconstruction in 10,836 procedures (58%). The incidence of SSI within 180 days following mastectomy with or without reconstruction was 8.1% (1,520 of 18,696). In total, 49% of SSIs were identified within 30 days post-mastectomy, 24.5% were identified 31-60 days post-mastectomy, 10.5% were identified 61-90 days post-mastectomy, and 15.7% were identified 91 180 days post-mastectomy. The incidences of SSI were 5.0% (395 of 7,860) after mastectomy only, 10.3% (848 of 8,217) after mastectomy plus implant, 10.7% (207 of 1,942) after mastectomy plus flap, and 10.3% (70 of 677) after mastectomy plus flap and implant (P<.001). The SSI risk was higher after bilateral compared with unilateral mastectomy with immediate reconstruction (11.4% vs 9.4%, P=.001) than without (6.1% vs 4.7%, P=.021) immediate reconstruction. CONCLUSIONS: SSI incidence was twice that after mastectomy with immediate reconstruction than after mastectomy alone. Only 49% of SSIs were coded within 30 days after operation. Our results suggest that stratification by procedure type facilitates comparison of SSI rates after breast operations between facilities. PMID- 26036878 TI - Papillary-like main pancreatic duct invaginated pancreaticojejunostomy versus duct-to-mucosa pancreaticojejunostomy after pancreaticoduodenectomy: A prospective randomized trial. AB - BACKGROUND: Development of a postoperative pancreatic fistula (POPF) is the single most significant complication of pancreatic anastomosis, which is a key procedure in pancreaticoduodenectomy. We previously reported a new papillary-like pancreaticojejunostomy, and a retrospective study showed a benefit in reducing the incidence of grade B/C POPF compared with duct-to-mucosa pancreaticojejunostomy. The aim of this study was to reassess whether the new pancreaticojejunostomy would decrease the POPF rate. METHODS: A prospective, randomized, controlled trial (NCT01731821 registered at http://ClinicalTrials.gov) involving 308 patients who underwent pancreaticoduodenectomy was conducted. RESULTS: The overall POPF rate was significantly lower in the papillary-like group compared with the duct-to-mucosa group (14/155 [9.0%] vs 31/153 [20.3%]; P = .005), and the grade B/C POPF rate of the papillary-like group was significantly decreased compared with the duct-to mucosa group. Multivariable analyses identified higher body mass index (odds ratio [OR], 3.520; P = .000), longer operative time (OR, 2.587; P = .041), soft texture and nondilated main pancreatic duct (OR, 0.365; P = .014), and the duct to-mucosa pancreaticojejunostomy (OR, 0.405; P = .013) as significant risk factors for POPF. Further stratified analyses showed that, for patients with soft texture and nondilated main pancreatic duct, the POPF rate in the papillary-like group (9.6%) was significantly lower than that in the duct-to-mucosa group (27.3%). However, for patients with hard texture or dilated main pancreatic duct, there was no difference between the 2 groups (7.8% vs 8.6%; P > 0.999). CONCLUSION: The new papillary-like pancreaticojejunostomy may provide a better option for patients with soft texture and nondilated main pancreatic duct. PMID- 26036879 TI - Reply "Modified D2 lymphadenectomy is effective in patients with node-positive gastric cancers undergoing potentially curative total gastrectomy". PMID- 26036880 TI - The pitfalls of inguinal herniorrhaphy: Surgeon volume matters. AB - BACKGROUND: There is currently little information regarding the impact of procedure volume on outcomes after open inguinal hernia repair in the United States. Our hypothesis was that increasing procedure volume is associated with lesser rates of reoperation and resource use. METHODS: The database of the Statewide Planning and Research Cooperative System was queried for elective open initial inguinal hernia repairs performed in New York State from 2001 to 2008 via the use of International Classification of Diseases, 9th Revision and Current Procedural Terminology codes. Surgeon and hospital procedure volumes were grouped into tertiles based on the number of open inguinal hernia repairs performed per year. Bivariate, hierarchical mixed effects Cox proportional-hazards, and negative binomial regression analyses were performed assessing for factors associated with reoperation for recurrence, procedure time, and downstream total charges. RESULTS: Among 151,322 patients who underwent open inguinal hernia repair, the overall rate of reoperation for recurrence within 5 years was 1.7% with a median time to reoperation of 1.9 years. An inverse relationship was seen between surgeon volume and reoperation rate, procedure time, and health care costs (P < .001). After we controlled for surgeon, facility, operative and patient characteristics, low-volume surgeons (<25 repairs/year) had greater rates of reoperation (hazard ratio 1.23,95% confidence interval [95% CI] 1.11-1.36), longer procedure times (incidence rate ratio 1.22, 95% CI 1.21-1.24), and greater downstream costs (incidence rate ratio 1.13,95% CI 1.10-1.17) than high-volume surgeons (>=25 repairs/year). CONCLUSION: Surgeon volume <25 cases per year for open inguinal hernia repair was independently associated with greater rates of reoperation for recurrence, worse operative efficiency, and greater health care costs. Referral to surgeons who perform >=25 inguinal hernia repairs per year should be considered to decrease reoperation rates and resource use. PMID- 26036881 TI - Frailty is associated with a history with more falls in elderly hospitalised patients. AB - INTRODUCTION: When elderly people are admitted to hospital, their risk of falling may often not be recognised. The risk of falling in the elderly is linked to frailty. In a Danish study, it was found that the "Identification of Seniors at Risk" screen (ISAR) predicted the patients' amount of health problems, days in hospital and readmission. It may therefore also be a predictor of frailty. This study aimed to evaluate how many elderly patients were admitted to an emergency department (ED) because of a fall and to examine if there was a correlation between these patients and their ISAR score. METHODS: A descriptive cohort study was conducted including patients aged 65 years or older admitted to the ED, n = 198. The following data were collected: ISAR screen, cause of admittance. Furthermore, a retrospective journal review was performed by a specialist in geriatrics. RESULTS: Prior to admission, 31% had experienced a fall. Of those, 67% were not referred for further fall assessment. Patients who had experienced falls had more health problems than patients without falls (mean 5.7 versus mean 4.4 (p = 0.00)) and more had cognitive impairment (31% versus 14% (p = 0.00)). A positive correlation was found between patients' ISAR score and falls (p = 0.03). CONCLUSION: To prevent further falls and readmissions, it is crucial not only to focus on elderly people's presenting problems, but also on their dizziness and falls, especially in cognitively impaired elderly patients, and to make a plan for further assessment and follow-up. We suggest the ISAR screen as a supplement to measurement of vital signs as it may predict frailty and falls. FUNDING: not relevant. PMID- 26036882 TI - Telephone reminders reduced the non-attendance rate in a gastroenterology outpatient clinic. AB - INTRODUCTION: Non-attendance is a global health-care problem. The aim of the present study was 1) to investigate if a telephone reminder could reduce the non attendance rate, 2) to study reasons for non-attendance and 3) to evaluate if a permanent implementation would be economically advantageous in a gastroenterology outpatient clinic like ours. METHODS: This was a comparative intervention study with a historical control group in a gastroenterology outpatient clinic. The study lasted six months. Patients with a scheduled appointment in the first three month period received no reminder (control group, n = 2,705). Patients in the following three-month period were reminded by telephone one weekday in advance of their appointment, when possible (intervention group, n = 2,479). Non-attending patients in the intervention group received a questionnaire. Based on the results, a financial cost-benefit analysis was made. RESULTS: In the intervention group, 1,577 (64%) patients answered the reminder telephone call. The non attendance rate was significantly lower in the intervention group (6.1%) than in the control group (10.5%) (p < 0.00001). Only 1.3% of the patients who answered the reminder turned out to be non-attendees. The most common explanation for non attendance in the intervention group was forgetfulness (39%). The reminder telephone call was cost-effective. CONCLUSION: In this outpatient clinic, telephone reminders were cost-effective and significantly reduced the non attendance rate by 43%. PMID- 26036883 TI - Season is an unreliable predictor of Lyme neuroborreliosis. AB - INTRODUCTION: Lyme neuroborreliosis (LNB) is a tick-borne infection of the nervous system caused by the spirochete Borrelia burgdorferi sensu lato. The primary symptoms are usually painful radiculitis, facial palsy and lymphocytic meningitis. The aim of this study was to provide data on the seasonal variation, anamnesis, symptoms, laboratory data and course of the disease in adults (>= 16 years). METHODS: The medical records of 69 patients with confirmed LNB who attended the Department of Neurology, Lillebaelt Hospital, Vejle, Denmark, were analysed. The diagnosis was confirmed by the presence of leucocytosis in the cerebrospinal fluid and intrathecal production of immunoglobulin M and/or G anti B. burgdorferi antibodies. RESULTS: Onset of neurological symptoms in LNB occurred year round in the Region of Southern Denmark. Only half of the patients had a history of a tick bite or erythema migrans (EM). Half of the patients who observed a tick bite subsequently reported EM. The duration from the onset of neurological symptoms to referral to hospital was remarkably long for patients with radiculoneuritis, whereas the onset of facial palsy led to a swift referral. Patients who were >= 50 years old had a significantly lower age-related risk of facial palsy without radicular symptoms. CONCLUSION: In this study, winter as a low-risk season was not a reliable factor in ruling out LNB. This finding may be relevant when investigating the cause of facial palsy and radicular symptoms. PMID- 26036885 TI - Attention to cancer patients' safety after primary treatment is needed. AB - INTRODUCTION: Knowledge about patient safety issues after primary treatment of cancer is sparse. METHODS: The present article is a retrospective analysis of adverse events (AEs) after primary cancer treatment to characterise the types of AEs and their consequences. A total of 724 AEs reported from 2010 to 2013 were identified via the Danish Patient Safety Database. The International Classification for Patient Safety was used to characterise event types. Consequences were characterised as either psychical harm or delay. We focused on AEs in care transitions. RESULTS: Common event types were administrative processes (58%), communication and documentation (56%), clinical processes (42%) and medication (27%). 46% of AEs led to physical harm. 4% resulted in severe physical harm or death. 18% resulted in delay in diagnosis of relapse or new cancer, treatment or referral. 50% of all AEs were related to care transitions. The AEs in care transitions carry great potential for prevention as they often relate to inadequate administrative practices, poor communication and documentation, or to unclear transferal of responsibility for the patient. CONCLUSION: Attention to patient safety after primary cancer treatment is required. The identification of a substantial number of AEs in care transitions stresses a need for increased continuity and clear transfer of responsibility in cancer care after primary treatment. To support learning from AEs, the AE reports should provide more details on the contextual factors. PMID- 26036884 TI - Poor quality of referral from mental to somatic hospitals. AB - INTRODUCTION: Concomitant somatic and mental illness is associated with excess mortality compared with the general population. To prevent this, a number of health initiatives relating to somatic illness in psychiatric patients have recently been introduced. One of the means used to screen for and treat somatic disease in psychiatric patients is highly qualified referral for somatic specialist assessment. The aim of this study was to assess the quality of referral of psychiatric patients to specialists in internal medicine. METHODS: A total of 110 consecutive referrals were collected from August to November in 2012 and 2013. Regional guidelines define the requirement for the satisfactory referral scheme and using these guidelines as a reference, each referral was rated based on indexation and an overall assessment. A report about the 2012 results was presented to the hospital management. The management of the hospital was not informed about the 2013 replication of the study. RESULTS: Half of the topics assessed were inadequately completed. Information about somatic co morbidity was missing in 76% of the referrals. Description of relevant tests and physical examinations was missing in 53%. By overall assessment, 40% of the referrals were rated as being insufficient. The resident physicians stand out by producing the most informative referrals. The 2013 results improved compared with 2012. CONCLUSION: We call for improvement in the quality of the referrals among psychiatric in-patients to somatic specialists. We propose an expansion of the use of standardised schemes and a strengthening of the skills needed to write a good referral. PMID- 26036886 TI - High prevalence of ulcer bleeding risk factors in dual antiplatelet-treated patients after percutaneous coronary intervention. AB - INTRODUCTION: Dual antiplatelet therapy is standard treatment following percutaneous coronary intervention (PCI) and stenting. However, such therapy increases the risk of upper gastrointestinal bleeding (UGIB). The risk factors of UGIB are well-documented and proton pump inhibitor (PPI) treatment reduces the risk. The aim was to describe the prevalence of risk factors of UGIB in dual antiplatelet-treated patients. METHODS: A questionnaire was used to assess the prevalence of risk factors of upper gastrointestinal bleeding among dual antiplatelet-treated first-time PCI patients in Western Denmark. The following characteristics were considered risk factors: increasing age (age 60-69 years and >= 70 years); dyspepsia; previous peptic ulcer; use of non-steroidal anti inflammatory drugs (NSAIDs) (weekly or daily), corticosteroids, selective serotonin reuptake inhibitors (SSRIs) and anticoagulants. RESULTS: A total of 1,358 patients with a mean age of 64.1 years (range: 33-92 years) were included. The distribution of risk factors was as follows: dyspepsia: 681 patients (50.1%); previous ulcer: 110 (8.1%; 2.3% with bleeding); use of NSAIDs: 214 (15.8%); corticosteroids (2.9%), SSRIs (5.8%) and anticoagulants (6.3%). Defined high-risk patients: 886 (65.2%). PPI treatment prior to PCI was found in 248 (18.3%), of whom 86% were at high risk of UGIB. CONCLUSION: This study demonstrates a high prevalence of risk factors among PCI patients treated with dual antiplatelet therapy, many of whom were not in PPI treatment. PMID- 26036887 TI - High risk of neonatal complications in children of mothers with gestational diabetes mellitus in their first pregnancy. AB - INTRODUCTION: THE study presents the neonatal outcome from a cohort of women with gestational diabetes mellitus (GDM) in their first pregnancy. METHODS: During a five-year period (2009-2013), a prospective follow-up study was performed at the Department of Gynaecology and Obstetrics, Lillebaelt Hospital - Kolding. The study included 535 pregnant women diagnosed with GDM. A study population of nulliparous GDM patients was sampled, and during the period from 1 January 2010 to 1 March 2013, a total of 137 women delivered for the first time. The present study population considers the 131 offspring, excluding six pairs of twins. RESULTS: The overwhelming majority of the offspring had a birth weight within the normal range and only six (4.6%) were large for gestational age. There were 95 (72.5%) vaginal deliveries, whereas 36 (27.5%) were born by caesarean section (CS). Nearly half of the 25 nulliparous GDM patients with a body mass index >= 35 kg/m2 delivered by CS - six by emergency CS and three by planned CS. A total of 20 neonates (15.3%) developed neonatal hypoglycaemia and four (3.1%) had an Apgar score < 7 after 5 min. A total of 25 (19.1%) among the offspring were admitted to the neonatal intensive care unit. CONCLUSION: The present study supports the notion of high-risk pregnancy among GDM patients. Compared with nulliparous in general, the offspring were more likely to be delivered by emergency CS. Despite the prophylactic procedures, one in six had neonatal hypoglycaemia. PMID- 26036888 TI - The management of diabetic foot ulcers in Danish hospitals is not optimal. AB - INTRODUCTION: The diabetic foot is a complicated health issue which ideally involves several different specialists to ensure the most effective treatment. The Danish Health and Medicines Authority recently published a national guideline to address the implementation of multidisciplinary teams in the treatment. The objective of this study was to describe the treatment practices at the time the guidelines were launched. METHODS: A questionnaire-based survey was conducted among Danish hospital departments working with diabetic feet. All public departments were invited by e-mail to participate and the participant answering the questionnaire was identified as knowledgeable about the department's procedures on treatment of diabetic feet. Only one questionnaire per department was allowed. RESULTS: A total of 62 questionnaires were sent out. We achieved a response rate of ~37% (n = 23). Respondents (n = 13) were mostly orthopaedic surgeons. A classification system of the diabetic foot was rarely or never used, and eight respondents (42%) reported having a multidisciplinary team in accordance with the national guidelines. 73% of the respondents performed some form of surgical intervention on diabetic feet, mainly minor procedures. CONCLUSION: The study demonstrated that several areas of treatment practices relating to the diabetic foot had potential for improvement as they did not adhere to national Danish guidelines. A follow-up survey, allowing time for local implementation, seems warranted. PMID- 26036889 TI - Computed tomography in forensic medicine. PMID- 26036890 TI - The long-term consequences of previous hyperthyroidism. A register-based study of singletons and twins. PMID- 26036891 TI - Cognition and neuroplasticity in the remitted state of unipolar depressive disorder. PMID- 26036892 TI - Circadian variation in endotoxaemia and modulatory effects of melatonin. PMID- 26036893 TI - Antiarrhythmic principle of SK channel inhibition in atrial fibrillation. PMID- 26036894 TI - Multiscale strain analysis of tendon subjected to shear and compression demonstrates strain attenuation, fiber sliding, and reorganization. AB - The manner in which strains are passed down the hierarchical length scales of tendons dictates how cells within the collagen network regulate the tissue response to loading. How tendons deform in different hierarchical levels under shear and compression is unknown. The aims of this study were: (i) to evaluate whether specific regions of bovine deep digital flexor tendons exhibited different strain attenuation from macro to micro length scales, and (ii) to elucidate mechanisms responsible for tendon deformation under shear and compression. Samples from distal and proximal regions of flexor tendons were subjected to three-step incremental stress-relaxation tests. Images of tissue markers, photobleached lines on collagen fibers, and nuclei locations were collected before and after loading. Results showed that strain transfer was attenuated from tissue to local matrix under both shear and compression. Nuclear aspect ratios exhibited smaller changes for distal samples, suggesting that cells are more shielded from deformation in the distal region. Collagen fiber sliding was observed to contribute significantly in response to shear, while uncrimping and fiber reorganization were the predominant mechanisms under compression. This study provides insight into microscale mechanisms responsible for multiscale strain attenuation of tendons under non-tensile macroscale loading. PMID- 26036895 TI - Ultra-fast electron capture by electrosterically-stabilized gold nanoparticles. AB - Ultra-fast pre-solvated electron capture has been observed for aqueous solutions of room-temperature ionic liquid (RTIL) surface-stabilized gold nanoparticles (AuNPs; ~9 nm). The extraordinarily large inverse temperature dependent rate constants (k(e)~ 5 * 10(14) M(-1) s(-1)) measured for the capture of electrons in solution suggest electron capture by the AuNP surface that is on the timescale of, and therefore in competition with, electron solvation and electron-cation recombination reactions. The observed electron transfer rates challenge the conventional notion that radiation induced biological damage would be enhanced in the presence of AuNPs. On the contrary, AuNPs stabilized by non-covalently bonded ligands demonstrate the potential to quench radiation-induced electrons, indicating potential applications in fields ranging from radiation therapy to heterogeneous catalysis. PMID- 26036896 TI - Innovations in reproductive endocrinology: a tribute to Bruce Carr, MD. PMID- 26036897 TI - Novel strategies for the management of recurrent pregnancy loss. AB - This article discusses the current trends in the diagnosis and treatment of recurrent pregnancy loss. Genetic testing of the miscarriage tissue by 23 chromosome microarray and the ability to identify maternal cell contamination have increased our awareness of the role of aneuploidy as a cause of recurrent pregnancy loss. This increasing influence and the role of genetic testing in developing a strategy for the evaluation of recurrent pregnancy loss are described and discussed. The most common questions that practicing physicians ask about recurrent pregnancy loss include how many losses are needed to make the diagnosis, what counts as a pregnancy loss, what constitutes a full workup, should we get karyotypes on the parents and the miscarriage, and what is the prognosis for a live birth? This review attempts to answer those questions based on current research and clinical experience to expand our current understanding of recurrent pregnancy loss. PMID- 26036898 TI - Shifting paradigms in diminished ovarian reserve and advanced reproductive age in assisted reproduction: customization instead of conformity. AB - As women are increasingly delaying childbearing into their 30s and beyond, diminished ovarian reserve (DOR) and advanced reproductive age (ARA) patients are bound to become a large proportion of all assisted reproductive technology practices. Traditional controlled ovarian stimulation (COS) protocols for DOR and/or ARA have had some limited success, but pregnancy rates are lower and cycle cancellation rates are higher than their younger counterparts with normal ovarian reserve. Though many physicians have a selection of favorite standard protocols that they use, patients with DOR may require closer monitoring and customization of the treatment cycle to address the common problems that come with low ovarian reserve. Frequent issues that surface in women with DOR and/or ARA include poor follicular response, premature luteinizing hormone surge, and poor embryo quality. Limited published evidence exists to guide treatment for DOR. However, use of minimal or mild doses of gonadotropins, avoidance of severe pituitary suppression, and consideration for luteal phase stimulation and a "freeze all" approach are possible customized treatment options that can be considered for such patients who have failed more traditional COS protocols. PMID- 26036899 TI - Regulators of ovarian preantral follicle development. AB - Preantral follicle development has become an increasingly recognized area of study in the last two decades. Factors that regulate the growth survival and differentiation of these small, yet complex structures have been identified. The field of fertility preservation and a need for increased numbers of mature oocytes for stem cell research revealed how little we knew of how follicles got from the primordial stage to the antral stage with a healthy and competent oocyte inside. This work discusses the role of gonadotropins in regulating preantral follicles and also the role of the TGF-beta family members and their associated Smad signaling molecules in preantral follicle development. Preantral follicle development is a necessary step to fertility in females and further understanding of this process is essential for progress in both infertility care and the enlarging field of in vitro folliculogenesis. PMID- 26036900 TI - The Role of a Mitochondrial Progesterone Receptor (PR-M) in Progesterone Action. AB - Historically, progesterone functions to regulate gene expression via two nuclear progesterone receptors (PR-B and PR-A). Yet, actions of progesterone independent of gene regulation have been observed for decades. These are based on progesterone induced cellular events that occur too rapidly to involve gene transcription or in cells lacking active gene transcription such as mature spermatozoa. Understanding of these "nongenomic" effects has been slowed by the lack of identification of specific receptors. Previous discovery of a mitochondrial progesterone receptor, PR-M, has opened up the possibility of direct, ligand-dependent modulation of mitochondrial activity. In this article, we review the current knowledge of PR-M and speculate on possible physiologic and pathophysiologic actions. PMID- 26036901 TI - The emerging role of angiogenic factor dysregulation in the pathogenesis of polycystic ovarian syndrome. AB - Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in reproductive age affecting 5 to 7% of women. It is characterized by anovulatory infertility, hyperandrogenism, and polycystic ovaries. Angiogenesis in the ovary is critical for follicular growth, ovulation, and the subsequent development and regression of the corpus luteum. Accumulating evidence suggests that multiple angiogenic factors are dysregulated in PCOS, including vascular endothelial growth factor, angiopoietins, platelet-derived growth factor, transforming growth factor-beta, and basic fibroblast growth factor. This angiogenic factor imbalance likely underlies the increased stromal vascularity observed in PCOS. Angiogenic factor dysregulation may play an important role in the pathophysiology of PCOS and may contribute to ovulatory dysfunction, subfertility, and ovarian hyperstimulation syndrome, which are commonly seen in women with PCOS. Further experimental studies are needed to gain a better understanding of the growth factors that are involved in normal and pathological ovarian angiogenesis, and to assess the potential of angiogenesis-based treatment strategies in PCOS. PMID- 26036902 TI - Estrogens, obesity, inflammation, and breast cancer-what is the link? AB - It gives me great pleasure to contribute to this special issue of Seminars which honors the career of Bruce Carr. As it happens, Bruce was my first Fellow upon my arrival at the Green Center for Reproductive Biology Sciences at UT Southwestern Medical Center in 1977. At that time, the Center was filled with luminaries of Reproductive Endocrinology, such as John Porter, Jack Johnston, Norman Gant, and of course the Director, Paul MacDonald, so to be given the responsibility of mentoring a new Fellow was a daunting responsibility. However, Bruce quickly rolled up his sleeves and plunged straight in, and we forged a relationship which led to some 36 manuscripts in 4 years. The first of these was entitled "The Role of Serum Lipoproteins in Steroidogenesis by the Human Fetal Adrenal Cortex," published in the Journal of Clinical Endocrinology and Metabolism, volume 49, pages 146-148, in 1979, and the authors were Simpson ER, Carr BR, Parker CR Jr, Milewich L, Porter JC, and MacDonald PC. Bruce quickly moved up the ranks of the Obstetrics/Gynecology Department to become full Professor and we went our separate ways professionally, but we remain close friends to this day. This special issue is indeed a worthy tribute to an outstanding career and especially to Bruce's role as editor-in-chief of Seminars which he has guided through the rapid evolution of the specialty, always maintaining a strong research focus and thus carrying on the rich tradition of the Green Center and the Obstetrics/Gynecology Department. PMID- 26036903 TI - Pregnancy in polycystic ovary syndrome I: lessons from a pragmatic explanatory with repository clinical trial. AB - This article reports results from a multicenter pragmatic study, with explanatory components and also with a repository, the Pregnancy in Polycystic Ovary Syndrome I study (Clinicaltrials.gov: NCT00068861), which we label with the acronym PERCT. This was a study conceived and conducted by the Steering Committee of the Reproductive Medicine Network. We discuss the publication structure from the study, including concept, protocol baseline, primary and secondary outcome papers, as well as ancillary papers related to studies conducted using biosamples from the study repository. We demonstrate that the primary outcome paper remains far and away the most impactful publication from this study. However, we note also that other related publications, including the baseline paper and some papers related to secondary hypotheses, such as prediction models, can still be relatively impactful. However, the most impactful ancillary publications arose from utilizing specimens in the repository to test post hoc hypotheses. Therefore, establishing a repository of serum and DNA samples, and potentially other biological specimens (i.e., semen, urine, biome samples, etc.) and making these specimens and data available to investigators may provide further meaningful productivity to a large pragmatic multicenter trial known here as PERCT. PMID- 26036904 TI - Molecular biology of endometriosis: from aromatase to genomic abnormalities. AB - Endometriosis has been initially described as the presence of ectopic endometrial tissue on pelvic organs or in extrapelvic sites; and this has been used as its key pathologic feature ever since. Endometriosis responds to fluctuations in estrogen and progesterone by growth and inflammation, leading to pain aggravated by menses. It was proposed that pelvic endometriosis primarily originate from retrograde menstruation of a critical number of eutopic endometrial cells with stem characteristics. This postulate is supported by the molecular defects found in ectopic endometriotic tissue. Genome-wide differences in CpG methylation between eutopic endometrial and endometriotic stromal cells are present. Defective CpG methylation affecting several genes that encode key transcription factors such as GATA6, steroidogenic factor-1, and estrogen receptor-beta in endometriosis gives rise to overproduction of local estrogen and prostaglandins and suppression of progesterone receptor. Progesterone receptor deficiency leads to progesterone resistance, resulting in decreased retinol uptake and retinoic acid production and altered retinoic acid action. These molecular defects collectively give rise to poor cellular differentiation, enhanced survival, and increased inflammation, which are the biological hallmarks of endometriotic tissue. PMID- 26036906 TI - Novel therapeutic approaches for pulmonary arterial hypertension: Unique molecular targets to site-specific drug delivery. AB - Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder characterized by increased blood pressure in the small arterioles supplying blood to lungs for oxygenation. Advances in understanding of molecular and cellular biology techniques have led to the findings that PAH is indeed a cascade of diseases exploiting multi-faceted complex pathophysiology, with cellular proliferation and vascular remodeling being the key pathogenic events along with several cellular pathways involved. While current therapies for PAH do provide for amelioration of disease symptoms and acute survival benefits, their full therapeutic potential is hindered by patient incompliance and off-target side effects. To overcome the issues related with current therapy and to devise a more selective therapy, various novel pathways are being investigated for PAH treatment. In addition, inability to deliver anti-PAH drugs to the disease site i.e., distal pulmonary arterioles has been one of the major challenges in achieving improved patient outcomes and improved therapeutic efficacy. Several novel carriers have been explored to increase the selectivity of currently approved anti-PAH drugs and to act as suitable carriers for the delivery of investigational drugs. In the present review, we have discussed potential of various novel molecular pathways/targets including RhoA/Rho kinase, tyrosine kinase, endothelial progenitor cells, vasoactive intestinal peptide, and miRNA in PAH therapeutics. We have also discussed various techniques for site-specific drug delivery of anti PAH therapeutics so as to improve the efficacy of approved and investigational drugs. This review will provide gainful insights into current advances in PAH therapeutics with an emphasis on site-specific drug payload delivery. PMID- 26036905 TI - Cell-based assays for screening androgen receptor ligands. AB - The androgen receptor (AR, NR3C4) mediates the majority of androgen effects on target cells. The AR is activated following ligand binding that result is enhanced of target gene transcription. Several cell-based model systems have been developed that allow sensitive detection and monitoring of steroids or other compounds with AR bioactivity. Most cell-based AR reporter models use transgenic gene constructs that include an androgen response element that controls reporter gene expression. The DNA cis-regulatory elements that respond to AR share sequence similarity with cis-regulatory elements for glucocorticoid (GR, NR3C1), mineralocorticoid (MR, NR3C2), and progesterone (PGR, NR3C3) receptors, which has compromised AR selectivity for some models. In recent years, the sensitivity and selectivity of AR bioassays have been significantly improved through careful selection of cell models, utilization of improved reporter genes, and the use of yeast two-hybrid AR systems. This review summarizes and compares the currently available androgen-responsive cell model systems. PMID- 26036907 TI - Protein-Resistant Biodegradable Amphiphilic Graft Copolymer Vesicles as Protein Carriers. AB - The protein adsorption and self-assembly behavior of biocompatible graft copolymer, poly(lactide-co-diazidomethyl trimethylene carbonate)-g-poly(ethylene glycol) [P(LA-co-DAC)-g-PEG], were systematically studied. The graft copolymers showed enhanced resistance to non-specific protein adsorption compared with their block copolymer counterparts, indicative of the increased effect of PEG density beyond PEG length. Diverse nanostructures including vesicles can be assembled from the amphiphilic graft copolymers with well-defined nano-sizes. Hemoglobin (Hb), as a model protein, can be entrapped in the formed vesicles and keep the gas-binding capacity. The reduced release rate of Hb from graft copolymer vesicles indicated the relatively stable membrane packing compared with block copolymer counterpart. PMID- 26036908 TI - L-Arginine supplementation 0.5% of diet during the last 90 days of gestation and 14 days postpartum reduced uterine fluid accumulation in the broodmare. AB - L-Arginine is an essential amino acid in many species that has been shown to influence reproduction. However, in horses a dose of 1% L-arginine of total dietary intake impaired absorption of other amino acids, whereas a dose of 0.5% did not. The objectives of this experiment were to evaluate postpartum parameters on mares supplemented with 0.5% L-arginine through the last 90d of gestation and 14d postpartum. Sixteen light-horse mares were randomly divided in two groups: 8 mares supplemented with 0.5% L-arginine and 8 mares fed an isonitrogenous equivalent. Gestation length, days to uterine clearance and days to first ovulation were compared. Uterine body depth, diameter of uterine horns, and length of largest pocket of uterine fluid were recorded daily via transrectal ultrasound. Measurements of foal weight, height, and cannon bone circumference were recorded for 9 weeks. Arginine treatment had no effect on gestation length (P=0.58). Supplemented mares cleared fluid quicker postpartum (6.8+/-0.53d; P=0.026) compared to control (9.0+/-0.38d). Mares supplemented with L-arginine had smaller diameter of fluid present in the postpartum uterus (P<=0.05). Days to first postpartum ovulation were not affected by treatment nor any influence on uterine involution. Finally, treatment had no effect on any foal's measured parameters. L-Arginine supplementation fed at 0.5% of daily intake during the last 90d of gestation and early postpartum in mares decreased uterine fluid accumulation, yet did not appear to have any effect on any other parameters measured. PMID- 26036909 TI - The TLR-2/TLR-6 agonist macrophage-activating lipopeptide-2 augments human NK cell cytotoxicity when PGE2 production by monocytes is inhibited by a COX-2 blocker. AB - Macrophage-activating lipopeptide-2 (MALP-2) is a potent inducer of proinflammatory cytokine secretion by macrophages, monocytes, and dendritic cells. MALP-2 was reported to be involved in natural killer (NK) cell activation and ensuing tumor rejection. However, the mechanism of MALP-2-mediated NK cell activation remained unclear. Therefore, we studied the effects of MALP-2 on cultured human NK cells. We found that MALP-2 had no direct effect on NK cells. Instead, MALP-2 acted on monocytes and triggered the release of different molecules such as interleukin (IL)-1beta, IL-6, IL-10, IL-12, IL-15, interferon gamma-induced protein (IP-10), and prostaglandin (PG)-E2. Our data show that monocyte-derived IP-10 could significantly induce NK cell cytotoxicity as long as the immunosuppression by PGE2 is specifically inhibited by cyclooxygenase (COX)-2 blockade. In summary, our results show that MALP-2-mediated stimulation of monocytes results in the production of several mediators which, depending on the prevailing conditions, affect the activity of NK cells in various ways. Hence, MALP-2 administration with concurrent blocking of COX-2 can be considered as a promising approach in MALP-2-based adjuvant tumor therapies. PMID- 26036910 TI - Identification of Plasma Metabolites Prognostic of Acute Kidney Injury after Cardiac Surgery with Cardiopulmonary Bypass. AB - Acute kidney injury (AKI) is a frequent complication after cardiopulmonary bypass, but early detection of postoperative AKI remains challenging. Protein biomarkers predict AKI excellently in homogeneous cohorts but are less reliable in patients suffering from various comorbidities. We employed nuclear magnetic resonance spectroscopy in a prospective study of 85 adult cardiac surgery patients to identify metabolites prognostic of AKI in plasma specimens collected 24 h after surgery. Postoperative AKI of stages 1-3, as defined by the Acute Kidney Injury Network (AKIN), developed in 33 cases. A random forests classifier trained on the NMR spectra prognosticated AKI across all stages, with an average accuracy of 80 +/- 0.9% and an area under the receiver operating characteristic curve of 0.87 +/- 0.01. Prognostications were based, on average, on 24 +/- 2.8 spectral features. Among the set of discriminative ions and molecules identified were Mg(2+), lactate, and the glucuronide conjugate of propofol. Using creatinine, Mg(2+), and lactate levels to derive an AKIN index score, we found AKIN 1 disease to be largely indistinguishable from AKIN 0, in concordance with the rather mild nature of AKIN 1 disease. PMID- 26036911 TI - Antimicrobial resistance profile of Enterococcus species isolated from intestinal tracts of hospitalized patients in Jimma, Ethiopia. AB - BACKGROUND: Multi-drug-resistant Enterococci colonizing the intestinal tract of hospitalized patients are the major source of infection as well as nosocomial spread. Despite worldwide increasing rate of multidrug resistant Enterococci colonization and infection among hospitalized patients, there is scarcity of data from resource limited setting. The present study aimed at determining the antimicrobial resistance profile of Enterococcus species from intestinal tracts of hospitalized patients in Jimma, Ethiopia. METHODS: The study was conducted among hospitalized patients at Jimma University Specialized Hospital, from January to July 2013. Fecal samples were collected and processed for bacterial isolation and susceptibility testing to antimicrobial agents. Stool samples were inoculated onto enterococcus selective media (Bile Esculin azide agar plate) with and without 6 ug/ml of vancomycin. The isolates were identified to genus and species level by cultural characteristics, Gram's stain, catalase test, growth in 6.5% NaCl broth, growth at 45 degrees C, motility test and by using API 20 Streptococcus system. Sensitivity testing was done using Kirby-Bauer disk diffusion method. Minimum inhibitory concentrations for vancomycin were determined using E-test strips. RESULT: Overall, Enterococci were isolated from 114 (76%) of the study subjects. The isolates were Enterococcus faecium (35.1%) followed by Enterococcus faecalis (29.8%), Enterococcus gallinarum (17.5%), Enterococcus casseliflavus (8.8%) and Enterococcus durans (8.8%). Among 114 tested Enterococci isolates, 41 (36%) were resistant to ampicillin, 62 (54.4%) to streptomycin and 39 (34.2%) to gentamycin. Other alternative antibiotics to treat mixed nosocomial infection caused by Enterococci also showed high rate of resistance in vitro: ciprofloxacin (50% of resistance), norfloxacin (49.1%), erythromycin (63.2%), tetracycline (64.9%), chloramphenicol (34.2%), and nitrofrantoin (32.4%). Multiple drug resistance was observed among 89.5% of E. faecium and E. faecalis. Vancomycin resistant Enterococci were observed in 5% of E. faecium isolates. CONCLUSION: This study reveals high rate of fecal colonization by multidrug-resistant Enterococci and prevalence of vancomycin resistance strains. Thus periodic surveillance of antibacterial susceptibilities is recommended to detect emerging resistance and to prevent the spread of antibacterial-resistant strains. PMID- 26036915 TI - Topological organization of CA3-to-CA1 excitation. AB - The CA1-projecting axons of CA3 pyramidal cells, called Schaffer collaterals, constitute one of the major information flow routes in the hippocampal formation. Recent anatomical studies have revealed the non-random structural connectivity between CA3 and CA1, but little is known regarding the functional connectivity (i.e. how CA3 network activity is functionally transmitted downstream to the CA1 network). Using functional multi-neuron calcium imaging of rat hippocampal slices, we monitored the spatiotemporal patterns of spontaneous CA3 and CA1 burst activity under pharmacological GABAergic blockade. We found that spatially clustered CA3 activity patterns were transformed into layered CA1 activity sequences. Specifically, synchronized bursts initiated from multiple hot spots in CA3 ensembles, and CA1 neurons located deeper in the pyramidal cell layer were recruited during earlier phases of the burst events. The order of these sequential activations was maintained across the bursts, but the sequence velocity varied depending on the inter-burst intervals. Thus, CA3 axons innervate CA1 neurons in a highly topographical fashion. PMID- 26036917 TI - A FRET-based ratiometric redox probe for detecting oxidative stress by confocal microscopy, FLIM and flow cytometry. AB - Understanding the role of oxidative stress in disease requires real time monitoring of redox status within a cell. We report a FRET-based, ratiometric redox probe which can be applied to monitor cellular oxidative capacity using three different modalities - confocal microscopy, fluorescence lifetime imaging and flow cytometry. PMID- 26036918 TI - Stand during working day to prevent health risks of sedentary jobs, says guidance. PMID- 26036916 TI - Immunogenicity and protective efficacy of an EV71 virus-like particle vaccine against lethal challenge in newborn mice. AB - Enterovirus 71(EV71) has caused severe epidemics of hand, foot and mouth disease (HFMD) in the Asia Pacific in recent years, particularly in infants and pre school children. It has become a serious public health threat, as currently there are no approved vaccines or antiviral drugs for EV71 infection. Many EV71 vaccines have been under development worldwide, however the main focus is inactivated EV71 vaccines. For example, the inactivated EV71 vaccine has recently finished phase III clinical trial in Mainland China. There have been very few studies on EV71 virus like particles (VLPs). In this study, the immunogenicity and protective potency of the EV71 VLPs produced in insect cells were evaluated in mice with different dosages. Our results showed that EV71 VLPs could elicit high titers of neutralizing antibodies (NTAbs) in a dose-dependent manner and NTAbs were sustained after the second injection with an average GMT (geometric mean titer) level from 19 to 2960 in immunized mice. Survival rates were 100%, 100%, 85%, and 40% after challenge with 15 LD50 (median lethal dose) of EV71 in these newborn mice, respectively. ED50 (50% effective dose) of VLPs was 0.20 MUg/dose in newborn mice, while NTAb titer under this dosage was about 50. Passive protection was determined with 2 methods and demonstrated that the survival rates were positively correlated with NTAb titers, which at 24 and 54 induced 50% survival rates in experimental animals. The ED50 of VLP vaccines and the passive NTAb titers were also analyzed. The maternal NTAb titer was similar as the passive NTAb titer in the mouse model challenged with our lethal mouse EV71 strain. Hence, our work has provided preliminary data on the protection potency of VLPs as a vaccine candidate and would facilitate future VLP vaccine development. PMID- 26036919 TI - The Incidence Rate of Acute Transfusion Reactions in Thalassemia Patients Referred to the Shiraz Thalassemia Centre, Shiraz, Iran, Before and After the Establishment of the Hemovigilance System. AB - This study aimed to investigate the incidence rate of acute transfusion reactions in thalassemia patients before and after the establishment of the hemovigilance system. This prospective descriptive study was conducted at the Dastgheyb Hospital, Shiraz, Iran, from 2009 to 2012. The incidence rate, type, imputability and severity of acute transfusion reactions were compared in thalassemia patients before and after the establishment of the hemovigilance system. A total of 741 thalassemia patients were referred to the Dastgheyb Hospital for transfusions during the study period. The incidence rates of acute transfusion reactions were reported as 0.06% (11 out of 16,214), 0.11% (23 out of 19,660), 0.10% (28 out of 26,129) and 0.2% (50 out of 24,121), respectively, from 2009 to 2012. The most frequent were major allergic reactions and febrile non hemolytic transfusion reactions (FNHTR). The transfusion reactions were increasingly reported after the establishment of the hemovigilance system in 2011 (p < 0.05). The establishment of the hemovigilance system can improve reporting of transfusion reactions. Moreover, evaluation of the incidence rate of transfusion reactions is necessary to design preventive measures to reduce transfusion risks. PMID- 26036920 TI - Phage-bacteria interaction network in human oral microbiome. AB - Although increasing knowledge suggests that bacteriophages play important roles in regulating microbial ecosystems, phage-bacteria interaction in human oral cavities remains less understood. Here we performed a metagenomic analysis to explore the composition and variation of oral dsDNA phage populations and potential phage-bacteria interaction. A total of 1,711 contigs assembled with more than 100 Gb shotgun sequencing data were annotated to 104 phages based on their best BLAST matches against the NR database. Bray-Curtis dissimilarities demonstrated that both phage and bacterial composition are highly diverse between periodontally healthy samples but show a trend towards homogenization in diseased gingivae samples. Significantly, according to the CRISPR arrays that record infection relationship between bacteria and phage, we found certain oral phages were able to invade other bacteria besides their putative bacterial hosts. These cross-infective phages were positively correlated with commensal bacteria while were negatively correlated with major periodontal pathogens, suggesting possible connection between these phages and microbial community structure in oral cavities. By characterizing phage-bacteria interaction as networks rather than exclusively pairwise predator-prey relationships, our study provides the first insight into the participation of cross-infective phages in forming human oral microbiota. PMID- 26036921 TI - Understanding the molecular mechanism and regioselectivity in the synthesis of celecoxib via a domino reaction: A DFT study. AB - The molecular mechanism and energetic of the domino reaction involved in the synthesis of celecoxib, a well-known anti-inflammatory drug, were theoretically studied at the DFT-B3LYP/6-31G(*) level. The first reaction in this domino process, which is also the rate-determining step, is a complete regioselective [3+2] cycloaddition (32CA) reaction associated with the nucleophilic attack of C5 carbon atom of enamine 7 on the C3 carbon atom of nitrile imine 6, leading to cycloadduct 8. The second reaction is a rapid acid/base catalysed stepwise elimination reaction of the morpholine 9 from cycloadduct 8 affording celecoxibe 3. The results also show that neither molecular mechanism of reaction nor activation barriers are considerably affected by the inclusion of solvent. The calculated relative Gibbs free energies as well as local reactivity indices obtained using the calculated Parr functions explain the complete regioselective fashion provided by the 32CA reaction under consideration in excellent agreement with the experimental findings. PMID- 26036923 TI - Individual differences in spatial cognition influence mental simulation of language. AB - The factors that contribute to perceptual simulation during sentence comprehension remain underexplored. Extant research on perspective taking in language has largely focused on linguistic constraints, such as the role of pronouns in guiding perspective adoption. In the present study, we identify preferential usage of egocentric and allocentric reference frames in individuals, and test the two groups on a standard sentence-picture verification task. Across three experiments, we show that individual biases in spatial reference frame adoption observed in non-linguistic tasks influence visual simulation of perspective in language. Our findings suggest that typically reported grand averaged effects may obscure important between-subject differences, and support proposals arguing for representational pluralism, where perceptual information is integrated dynamically and in a way that is sensitive to contextual and especially individual constraints. PMID- 26036922 TI - Evidence for capacity sharing when stopping. AB - Research on multitasking indicates that central processing capacity is limited, resulting in a performance decrement when central processes overlap in time. A notable exception seems to be stopping responses. The main theoretical and computational accounts of stop performance assume that going and stopping do not share processing capacity. This independence assumption has been supported by many behavioral studies and by studies modeling the processes underlying going and stopping. However, almost all previous investigations of capacity sharing between stopping and going have manipulated the difficulty of the go task while keeping the stop task simple. In the present study, we held the difficulty of the go task constant and manipulated the difficulty of the stop task. We report the results of four experiments in which subjects performed a selective stop-change task, which required them to stop and change a go response if a valid signal occurred, but to execute the go response if invalid signals occurred. In the consistent-mapping condition, the valid signal stayed the same throughout the whole experiment; in the varied-mapping condition, the valid signal changed regularly, so the demands on the rule-based system remained high. We found strong dependence between stopping and going, especially in the varied-mapping condition. We propose that in selective stop tasks, the decision to stop or not will share processing capacity with the go task. This idea can account for performance differences between groups, subjects, and conditions. We discuss implications for the wider stop-signal and dual-task literature. PMID- 26036924 TI - How distinct is the coding of face identity and expression? Evidence for some common dimensions in face space. AB - Traditional models of face perception emphasize distinct routes for processing face identity and expression. These models have been highly influential in guiding neural and behavioural research on the mechanisms of face perception. However, it is becoming clear that specialised brain areas for coding identity and expression may respond to both attributes and that identity and expression perception can interact. Here we use perceptual aftereffects to demonstrate the existence of dimensions in perceptual face space that code both identity and expression, further challenging the traditional view. Specifically, we find a significant positive association between face identity aftereffects and expression aftereffects, which dissociates from other face (gaze) and non-face (tilt) aftereffects. Importantly, individual variation in the adaptive calibration of these common dimensions significantly predicts ability to recognize both identity and expression. These results highlight the role of common dimensions in our ability to recognize identity and expression, and show why the high-level visual processing of these attributes is not entirely distinct. PMID- 26036926 TI - Justifying conflicts of interest in medical journals: a very bad idea. PMID- 26036925 TI - Learning from gesture: How early does it happen? AB - Iconic gesture is a rich source of information for conveying ideas to learners. However, in order to learn from iconic gesture, a learner must be able to interpret its iconic form-a nontrivial task for young children. Our study explores how young children interpret iconic gesture and whether they can use it to infer a previously unknown action. In Study 1, 2- and 3-year-old children were shown iconic gestures that illustrated how to operate a novel toy to achieve a target action. Children in both age groups successfully figured out the target action more often after seeing an iconic gesture demonstration than after seeing no demonstration. However, the 2-year-olds (but not the 3-year-olds) figured out fewer target actions after seeing an iconic gesture demonstration than after seeing a demonstration of an incomplete-action and, in this sense, were not yet experts at interpreting gesture. Nevertheless, both age groups seemed to understand that gesture could convey information that can be used to guide their own actions, and that gesture is thus not movement for its own sake. That is, the children in both groups produced the action displayed in gesture on the object itself, rather than producing the action in the air (in other words, they rarely imitated the experimenter's gesture as it was performed). Study 2 compared 2-year olds' performance following iconic vs. point gesture demonstrations. Iconic gestures led children to discover more target actions than point gestures, suggesting that iconic gesture does more than just focus a learner's attention, it conveys substantive information about how to solve the problem, information that is accessible to children as young as 2. The ability to learn from iconic gesture is thus in place by toddlerhood and, although still fragile, allows children to process gesture, not as meaningless movement, but as an intentional communicative representation. PMID- 26036927 TI - Repetitive manual acupuncture increases markers of innate immunity in mice subjected to restraint stress. AB - OBJECTIVE: To study the effects of repetitive manual acupuncture treatment on acute stress in mice and to explore its impact on the immune system. METHODS: Thirty-six mice were randomly allocated to one of four groups: control, acupuncture, stress and acupuncture+stress (n=9 each). Mice in the two acupuncture groups were given daily acupuncture treatment superficially (to skin depth) at CV6, CV12 and bilateral ST25, LR14, GB20, GB21, BL10, BL11, BL13, BL14, BL19, BL23 and BL25 for 7 days. On the eighth day mice in the stress and acupuncture+stress groups were exposed to acute stress for 2 h by confinement in a 50 mL centrifuge tube. Body temperature, blood glucose, the number and subpopulation ratios of leucocytes in the liver, spleen and thymus, natural killer (NK) cell percentage cytotoxicity and serum corticosterone and interferon gamma IFNgamma were quantified. RESULTS: Mice exposed to stress (irrespective of acupuncture treatment) exhibited hypothermia and hyperglycaemia. However, the increase in glucose level was mitigated by repetitive acupuncture treatment (p<0.05). Percentage cytotoxicity and the level of corticosterone were significantly increased after stress but were unaffected by acupuncture. IFNgamma levels did not differ between the groups. Hepatic innate immunity in the liver appeared to be stimulated by repetitive acupuncture treatment as proportions of extrathymic T cells, NK cells and NKT cells in the liver were greatest in the acupuncture+stress group and significantly increased relative to the control group. CONCLUSIONS: Repetitive manual acupuncture mitigated stress-induced hyperglycaemia and enhanced markers of innate immunity in the liver within the range of normal homoeostasis. As long as acupuncture stimuli were appropriately applied, they did not appear to be stressful to the mice. PMID- 26036929 TI - Feasibility of a patient-centred nutrition intervention to improve oral intakes of patients at risk of pressure ulcer: a pilot randomised control trial. AB - AIM: Nutrition is important for pressure ulcer prevention. This randomised control pilot study assessed the feasibility of conducting a larger trial to test the effectiveness of a patient-centred intervention for improving the dietary intakes of patients at risk of pressure ulcer in hospital. METHODS: A 3-day intervention targeting patients at risk of pressure ulcer was developed, based on three main foundations: patient education, patient participation and guided goal setting. The intervention was piloted in three wards in a metropolitan hospital in Queensland, Australia. Participants were randomised into control or intervention groups and had their oral intakes monitored. A subset of intervention patients was interviewed on their perceptions of the intervention. Feasibility was tested against three criteria: >=75% recruitment; >=80% retention; and >=80% intervention fidelity. Secondary outcomes related to effects on energy and protein intakes. RESULTS: Eighty patients participated in the study and 66 were included in final analysis. The recruitment rate was 82%, retention rate was 88%, and 100% of intervention patients received the intervention. Patients viewed the intervention as motivating and met significantly more of their estimated energy and protein requirements over time. CONCLUSION: This pilot study indicates that the intervention is feasible and acceptable by patients at risk of pressure ulcer. A larger trial is needed to confirm the effectiveness of the intervention in the clinical setting. PMID- 26036928 TI - Enterovirus 71 infection in children with hand, foot, and mouth disease in Shanghai, China: epidemiology, clinical feature and diagnosis. AB - BACKGROUND: In 2012 a large outbreak of hand, foot, and mouth disease (HFMD) widely spread over China, causing more than 2 million cases and 567 deaths. Our purpose was to characterize the major pathogens responsible for the 2012 HFMD outbreak and analyze the genetic characterization of the enterovirus 71 (EV71) strains in Shanghai; also, to analyze the dynamic patterns of neutralizing antibody (NAb) against EV71 and evaluate the diagnostic value of several methods for clinical detection of EV71. METHODS: Clinical samples including stool, serum and CSF were collected from 396 enrolled HFMD inpatients during the peak seasons in 2012. We analyzed the molecular epidemiology, clinical feature, and diagnostic tests of EV71 infection. RESULTS: EV71 was responsible for 60.35 % of HFMD inpatients and 88.46 % of severe cases. The circulating EV71 strains belonged to subgenogroup C4a. The nucleotide sequences of VP1 between severe cases and uncomplicated cases shared 99.2 ~ 100 % of homology. Among 218 cases with EV71 infection, 211 (96.79 %) serum samples showed NAb positive against EV71 and NAb titer reached higher level 3 days after disease onset. Of 92 cases with EV71 associated meningitis or encephalitis, 5 (5.43 %) of 92 had EV71 RNA detected in CSF samples. The blood anti-EV71 IgM assay showed a sensitivity of 93.30 % and a specificity of 50 %. CONCLUSIONS: EV71 C4a remained the predominant subgenotype circulating in Shanghai. The severity of the EV71 infection is not associated with the virulence determinants in VP1. RT-PCR together with IgM detection can enhance the early diagnosis of severe EV71-associated HFMD. PMID- 26036930 TI - Automated estimation of salvageable tissue: Comparison with expert readers. AB - PURPOSE: To assess the performance of an automatic perfusion-diffusion mismatch outlining algorithm, in a cohort of acute ischemic stroke patients imaged as part of a multicenter study. MATERIALS AND METHODS: Magnetic resonance imaging (MRI) from 167 patients with anterior circulation strokes scanned at either 3T or 1.5T systems were analyzed retrospectively through an automatic perfusion-diffusion mismatch detection algorithm. In addition, four expert raters manually outlined perfusion lesions on time-to-peak (TTP) maps and diffusion lesions on diffusion weighted images (DWI), and reference perfusion-diffusion mismatch masks were obtained as the areas where at least three experts were in agreement that tissue was part of the perfusion-weighted imaging (PWI) lesion, but not the diffusion lesion. Per-subject analyses of mismatch volumes and mismatch overlap were subsequently performed. RESULTS: The use of the automatic perfusion-diffusion mismatch detection algorithm resulted in a 4.0 ml mean (standard deviation 28.7 ml) difference in mismatch volume compared to the reference expert consensus (Pearson correlation, r = 0.91, P < 0.0001). The median spatial agreement was 0.71, with an interquartile range of 0.28. CONCLUSION: We demonstrated excellent agreement between the perfusion-diffusion mismatch masks estimated by our proposed automatic algorithm and those achieved by expert consensus. PMID- 26036931 TI - [Image-guided pain therapy]. PMID- 26036932 TI - [Cerebrospinal fluid leakage. Indications, technique and results of treatment with a blood patch]. AB - BACKGROUND: In most cases cerebrospinal fluid (CSF) leaks are iatrogenic and caused by medical interventions, such as lumbar puncture, peridural anesthesia and surgical interventions on the spine, However, spontaneous cerebral hypotension is currently detected more frequently due to improvements in diagnostic possibilities but often the cause cannot be clarified with certainty. METHODS: There are various diagnostic tools for confirming the diagnosis and searching for the site of CSF leakage, such as postmyelography computed tomography (postmyelo-CT), indium(111) radioisotope cisternography and (myelo) magnetic resonance imaging (MRI), which show different sensitivities. In accordance with own experience native MRI with fat-saturated T2-weighted sequences is often sufficient for diagnosing CSF leakage and the site. For the remaining cases an additional postmyelo-CT or alternatively myelo-MRI is recommended. In some patients with spontaneous cranial hypotension multiple CSF leaks are found at different spinal levels. The main symptom in most cases is an orthostatic headache. While post-puncture syndrome is self-limiting in many cases, spontaneous CSF leakage usually requires blood patch therapy. A lumbar blood patch can be safely carried out under guidance by fluoroscopy. In the case of a cervical or dorsal blood patch, CT guidance is recommended, which ensures epidural application of the blood patch and minimizes the risk of damaging the spinal cord. Despite a high success rate at the first attempt with a blood patch of up to 85%, some cases require repeating the blood patch. A targeted blood patch of a CSF leak should generally be favoured over a blindly placed blood patch; nevertheless, if a CSF leak cannot be localized by CT or MRI a therapeutic attempt with a lumbar blood patch can be carried out. After a successful blood patch intracranial hygromas and pachymeningeal enhancement in the head show fast regression; however, epidural hygromas of the spine can persist for a period of several months, even though patients are already free of symptoms. CONCLUSION: In total, blood patch therapy is a safe and technically relative simple method with a high success rate. Therefore, it represents the therapy of choice in patients with spontaneous cerebrospinal fluid leakage as well as in cases of post-lumbar puncture syndrome refractory to conservative therapy. PMID- 26036933 TI - Cardiovascular risk factors and small vessel disease of the brain: Blood pressure, white matter lesions, and functional decline in older persons. AB - Several potential vascular risk factors exist for the development and accumulation of subcortical white matter disease in older people. We have reported that in older people followed for up to 4 years white matter hyperintensity (WMH) lesions on magnetic resonance imaging nearly doubled in volume and were associated with alterations in mobility and cognitive function. Herein we review the genetic, metabolic, and vascular risk factors that have been evaluated in association with the development and pathogenesis of WMH in older persons. Our research efforts have focused on systemic hypertension, particularly in the out-of-office setting as 24-hour ambulatory blood pressure (BP) has proven to be a stronger indicator of the progression of WMH in older people and the associated functional decline than doctor's office BP. Based on relations between 24-hour systolic BP levels, the accrual of WMH, and functional decline, we have designed the INFINITY trial, the first interventional study to use ambulatory BP to guide antihypertensive therapy to address this problem in the geriatric population. PMID- 26036934 TI - Hippocampal complex atrophy in poststroke and mild cognitive impairment. AB - To investigate putative interacting or distinct pathways for hippocampal complex substructure (HCS) atrophy and cognitive affection in early-stage Alzheimer's disease (AD) and cerebrovascular disease (CVD), we recruited healthy controls, patients with mild cognitive impairment (MCI) and poststroke patients. HCSs were segmented, and quantitative white-matter hyperintensity (WMH) load and cerebrospinal fluid (CSF) amyloid-beta concentrations were determined. The WMH load was higher poststroke. All examined HCSs were smaller in amyloid-positive MCI than in controls, and the subicular regions were smaller poststroke. Memory was reduced in amyloid-positive MCI, and psychomotor speed and executive function were reduced in poststroke and amyloid-positive MCI. Size of several HCS correlated with WMH load poststroke and with CSF amyloid-beta concentrations in MCI. In poststroke and amyloid-positive MCI, neuropsychological function correlated with WMH load and hippocampal volume. There are similar patterns of HCS atrophy in CVD and early-stage AD, but different HCS associations with WMH and CSF biomarkers. WMHs add to hippocampal atrophy and the archetypal AD deficit delayed recall. In line with mounting evidence of a mechanistic link between primary AD pathology and CVD, these additive effects suggest interacting pathologic processes. PMID- 26036935 TI - Parkinson's disease-related spatial covariance pattern identified with resting state functional MRI. AB - In this study, we sought to identify a disease-related spatial covariance pattern of spontaneous neural activity in Parkinson's disease using resting-state functional magnetic resonance imaging (MRI). Time-series data were acquired in 58 patients with early to moderate stage Parkinson's disease and 54 healthy controls, and analyzed by Scaled Subprofile Model Principal Component Analysis toolbox. A split-sample analysis was also performed in a derivation sample of 28 patients and 28 control subjects and validated in a prospective testing sample of 30 patients and 26 control subjects. The topographic pattern of neural activity in Parkinson's disease was characterized by decreased activity in the striatum, supplementary motor area, middle frontal gyrus, and occipital cortex, and increased activity in the thalamus, cerebellum, precuneus, superior parietal lobule, and temporal cortex. Pattern expression was elevated in the patients compared with the controls, with a high accuracy (90%) to discriminate the patients from the controls. The split-sample analysis produced a similar pattern but with a lower accuracy for group discrimination in both the derivation (80%) and the validation (73%) samples. Our results showed that resting-state functional MRI can be potentially useful for identification of Parkinson's disease-related spatial covariance patterns, and for differentiation of Parkinson's disease patients from healthy controls at an individual level. PMID- 26036936 TI - Association between the perfusion/diffusion and diffusion/FLAIR mismatch: data from the AXIS2 trial. AB - The perfusion-/diffusion-weighted imaging (PWI/DWI) mismatch and the diffusion/fluid attenuated inversion recovery (DWI/FLAIR) mismatch are magnetic resonance imaging (MRI) markers of evolving brain ischemia. We examined whether the DWI/FLAIR mismatch was independently associated with the PWI/DWI mismatch. Furthermore, we determined whether the presence of the DWI/FLAIR mismatch in patients with the PWI/DWI mismatch would provide additional information regarding last seen normal time (LTM). We used data from the 'AX200 for ischemic stroke' trial (AXIS 2 study NCT00927836). We studied the association between the presence of the DWI/FLAIR and PWI/DWI mismatch, baseline National Institute of Health Stroke Scale (NIHSS), age, ischemic-core volume, gender, intravenous (IV) tissue plasminogen activator (tPA), and perfusion-mismatch volume in univariate analysis. Significant variables (P<0.05) were added into the final multivariate model. We analyzed 197 patients. Seventy-two (37%) had both the PWI/DWI and the DWI/FLAIR mismatch. Patients with the double mismatch pattern had a shorter LTM than patients with the PWI/DWI mismatch alone (Median difference 90 minutes, P<0.01). Multivariate analysis confirmed the independent association between the two mismatch patterns (odds ratio (OR) 2.6, 95% confidence interval (CI) 1.2 to 5.4). Our study implies that the DWI/FLAIR mismatch and PWI/DWI mismatch are strongly associated, independent from LTM. Furthermore, in the presence of the PWI/DWI mismatch, the DWI/FLAIR pattern indicates a shorter LTM. This could have implications in selecting patients for reperfusion therapy. PMID- 26036937 TI - A method for reducing the effects of motion contamination in arterial spin labeling magnetic resonance imaging. AB - Arterial spin labeling (ASL) is a noninvasive method to measure cerebral blood flow (CBF). Arterial spin labeling is susceptible to artifact generated by head motion; this artifact is propagated through the subtraction procedure required to calculate CBF. We introduce a novel strategy for mitigating this artifact based on weighting tag/control volumes according to a noise estimate. We evaluated this strategy (DVARS weighting) in application to both pulsed ASL (PASL) and pseudo continuous ASL (pCASL) in a cohort of normal adults (N=57). Application of DVARS weighting significantly improved test-retest repeatability as assessed by the intra-class correlation coefficient. Before the application of DVARS weighting, mean gray matter intra-class correlation (ICC) between subsequent ASL runs was 0.48 and 0.51 in PASL and pCASL, respectively. With weighting, ICC was significantly improved to 0.63 and 0.58. PMID- 26036938 TI - Region-specific cerebral metabolic alterations in streptozotocin-induced type 1 diabetic rats: an in vivo proton magnetic resonance spectroscopy study. AB - Clinical and experimental in vivo (1)H-magnetic resonance spectroscopy ((1)H-MRS) studies have demonstrated that type 1 diabetes mellitus (T1DM) is associated with cerebral metabolic abnormalities. However, less is known whether T1DM induces different metabolic disturbances in different brain regions. In this study, in vivo (1)H-MRS was used to measure metabolic alterations in the visual cortex, striatum, and hippocampus of streptozotocin (STZ)-induced uncontrolled T1DM rats at 4 days and 4 weeks after induction. It was observed that altered neuronal metabolism occurred in STZ-treated rats as early as 4 days after induction. At 4 weeks, T1DM-related metabolic disturbances were clearly region specific. The diabetic visual cortex had more or less normal-appearing metabolic profile; while the striatum and hippocampus showed similar abnormalities in neuronal metabolism involving N-acetyl aspartate and glutamate; but only the hippocampus exhibited significant changes in glial markers such as taurine and myo-inositol. It is concluded that cerebral metabolic perturbations in STZ-induced T1DM rats are region specific at 4 weeks after induction, perhaps as a manifestation of varied vulnerability among the brain regions to sustained hyperglycemia. PMID- 26036939 TI - Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials. AB - Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George's Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used (n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required. PMID- 26036940 TI - The fatty acid amide hydrolase C385A variant affects brain binding of the positron emission tomography tracer [11C]CURB. AB - The common functional single-nucleotide polymorphism (rs324420, C385A) of the endocannabinoid inactivating enzyme fatty acid amide hydrolase (FAAH) has been associated with anxiety disorder relevant phenotype and risk for addictions. Here, we tested whether the FAAH polymorphism affects in vivo binding of the FAAH positron emission tomography (PET) probe [(11)C]CURB ([(11)C-carbonyl]-6-hydroxy [1,10-biphenyl]-3-yl cyclohexylcarbamate (URB694)). Participants (n=24) completed one [(11)C]CURB/PET scan and were genotyped for rs324420. Relative to C/C (58%), A-allele carriers (42%) had 23% lower [(11)C]CURB binding (lambdak3) in brain. We report evidence that the genetic variant rs324420 in FAAH is associated with measurable differences in brain FAAH binding as per PET [(11)C]CURB measurement. PMID- 26036941 TI - A probable dual mode of action for both L- and D-lactate neuroprotection in cerebral ischemia. AB - Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non astrocytic (most likely neuronal) cells as well as an energy substrate. PMID- 26036944 TI - Factors associated with influenza vaccination in middle and older aged Australian adults according to eligibility for the national vaccination program. AB - BACKGROUND: In Australia, influenza vaccination is recommended and provided free of charge for all adults aged >=65 years and those aged <65 years with specific risk factors. Other than age, there is limited information on characteristics associated with vaccine uptake. METHODS: We used the 45 and Up Study, a large cohort of adults aged >=45 years, who completed a questionnaire in 2012 asking about influenza vaccination. We compared characteristics of those reporting influenza vaccination in those aged <65 and >=65 years using a log binomial model to estimate relative rates (RRs), adjusted for age and other factors. RESULTS: Among 27,036 participants, the proportion reporting influenza vaccination in the last year increased steadily with age from 24.6% in those <54 years to 67.2% in those 75-79 years; of those eligible for universal free vaccine, (>=65 years) 57.3% had an influenza vaccination in the previous year. Many characteristics associated with higher vaccination rates in adults aged <65 years (mean 60.7) and those >=65 years (mean 73.7) were similar. These included sex (women versus men: <65 years, aRR=1.14[95% CI 1.08-1.20]; >=65 years, aRR=1.04[1.02-1.07]), higher BMI (>=30 kg/m(2) versus >18.5 to <25 kg/m(2): <65 years, aRR=1.16[1.09-1.24]; >=65 years, aRR=1.06[1.03-1.09]), requiring assistance with daily tasks versus not (<65 years, aRR=1.27[1.15-1.40]; >=65 years, aRR=1.05[1.02-1.09]) and reporting versus not reporting specific chronic illnesses (<65 years, aRR=1.55 [1.48-1.63]; >=65 years, aRR=1.08[1.06-1.10]). Current smokers had lower vaccination rates (<65 years, aRR=0.78[0.69-0.90]; >=65 years, aRR=0.91[0.84 0.99]). Among those aged <65 years only, being a carer, higher income, and education were associated with influenza vaccination (aRR=1.32[1.19-1.47], 1.17[1.10-1.24] and 1.12[1.10-1.22] respectively). Non-English speaking country of birth was associated with lower vaccination rates in >=65 years (aRR 0.86[0.81 0.92]). CONCLUSIONS: Factors most strongly associated with vaccination were age and among those aged <65 years, having a medical indication recommended for influenza vaccination, suggesting higher uptake among those who can access free vaccine. Among those eligible for free vaccination, interventions could be targeted towards men, smokers, those from non-English speaking backgrounds and those <65 years with a medical indication. PMID- 26036942 TI - Genetic characterization of measles virus in the Philippines, 2008-2011. AB - BACKGROUND: Large outbreaks of measles occurred in the Philippines in 2010 and 2011. Genetic analysis was performed to identify the genotype of measles virus (MeV) that was responsible for the large outbreaks. METHODS: A total of 114 representative MeVs that were detected in the Philippines from 2008 to 2011 were analyzed by sequencing the C-terminal region of nucleocapsid (N) gene and partial hemagglutinin (H) gene and by inferring the phylogenetic trees. RESULTS: Genetic analysis showed that genotype D9 was the predominant circulating strain during the 4-year study period. Genotype D9 was detected in 23 samples (92%) by N gene sequencing and 93 samples (94%) by H gene analysis. Sporadic cases of genotype G3 MeV were identified in 2 samples (8%) by N gene sequencing and 6 samples (6%) by H gene analysis. Genotype G3 MeV was detected mainly in Panay Island in 2009 and 2010. Molecular clock analysis of N gene showed that the recent genotype D9 viruses that caused the big outbreaks in 2010 and 2011 diverged from a common ancestor in 2005 in one of the neighboring Southeast Asian countries, where D9 was endemic. These big outbreaks of measles resulted in a spillover and were associated with genotype D9 MeV importation to Japan and the USA. CONCLUSION: Genotype D9 MeV became endemic and caused two big outbreaks in the Philippines in 2010 and 2011. Genotype G3 MeV was detected sporadically with limited geographic distribution. This study highlights the importance of genetic analysis not only in helping with the assessment of measles elimination program in the country but also in elucidating the transmission dynamics of measles virus. PMID- 26036945 TI - Immunogenicity and safety of the human papillomavirus vaccine in patients with autoimmune diseases: A systematic review. AB - Whereas safety and efficacy of HPV vaccines in healthy women have been shown in several randomised controlled clinical trials and in post marketing analyses, only few data exist in patients affected by autoimmune diseases. These issues are significant as autoimmune conditions are recognised as a risk factor for the persistence of HPV infection. Herein we review and systematise the existing literature to assess immunogenicity and safety of HPV vaccination in patients with autoimmune diseases, including systemic lupus erythematosus and juvenile idiopathic arthritis. The results of our literature revision suggest that the HPV vaccines are efficacious and safe in most of the patients affected by autoimmune diseases. Yet, some points of concern remain to be tackled, including the effects of concomitant therapies, the risk of disease exacerbation and the cost effectiveness of such immunisation programmes in these populations. PMID- 26036946 TI - Exploring the presentation of HPV information online: A semantic network analysis of websites. AB - CONTEXT: Negative vaccination-related information online leads some to opt out of recommended vaccinations. OBJECTIVE: To determine how HPV vaccine information is presented online and what concepts co-occur. METHODS: A semantic network analysis of the words in first-page Google search results was conducted using three negative, three neutral, and three positive search terms for 10 base concepts such as HPV vaccine, and HPV immunizations. In total, 223 of the 300 websites retrieved met inclusion requirements. Website information was analyzed using network statistics to determine what words most frequently appear, which words co occur, and the sentiment of the words. RESULTS: High levels of word interconnectivity were found suggesting a rich set of semantic links and a very integrated set of concepts. Limited number of words held centrality indicating limited concept prominence. This dense network signifies concepts that are well connected. Negative words were most prevalent and were associated with describing the HPV vaccine's side-effects as well as the negative effects of HPV and cervical cancer. A smaller cluster focuses on reporting negative vaccine side effects. Clustering shows the words women and girls closely located to the words sexually, virus, and infection. DISCUSSION: Information about the HPV vaccine online centered on a limited number of concepts. HPV vaccine benefits as well as the risks of HPV, including severity and susceptibility, were centrally presented. Word cluster results imply that HPV vaccine information for women and girls is discussed in more sexual terms than for men and boys. PMID- 26036947 TI - Persistence of antibodies six years after booster vaccination with inactivated vaccine against Japanese encephalitis. AB - BACKGROUND: Japanese Encephalitis (JE) virus occurs in wide regions of Asia with over 3 billion people living in areas at risk for JE. An estimated 68,000 clinical cases of JE occur every year, and vaccination is the most effective prophylactic measure. One internationally licensed vaccine containing the inactivated JE virus strain SA14-14-2 is Ixiaro (Valneva, Austria). According to recommendations, basic immunization consists of vaccinations on day 0, day 28, and a booster dose 12-24 months later. Protection in terms of neutralizing antibody titers has been assessed up to 12 months after the third dose of the vaccine. The current investigation was designed to evaluate antibody decline over time and to predict long-term duration of seroprotection after a booster dose. METHOD: In a preceding trial, volunteers received basic immunization (day 0, day 28) and one booster dose against JE 15 months later. A follow up blood draw 6 years following their booster dose was carried out in 67 subjects. For antibody testing, a 50% plaque reduction neutralization test (PRNT50-test) was used. PRNT50 values of 10 and above are surrogate levels of protection according to WHO standards. RESULT: Seventy-six months following the booster dose, 96% of the tested subjects had PRNT50 titers of 10 or higher. Geometric mean titer (GMT) was 148 (95% CI confidence interval: 107-207). Antibody titers were lower in volunteers 50 years of age and older. Vaccination history against other flaviviruses (yellow fever or tick borne encephalitis) did not significantly influence PRNT50 titers. A two-step log-linear decline model predicted protection against JE of approximately 14 years after the booster dose. CONCLUSION: Six years after a booster dose against JE, long-term protection could be demonstrated. According to our results, further booster doses should be scheduled 10 years following the first booster dose. PMID- 26036948 TI - A broad protection provided by matrix protein 2 (M2) of avian influenza virus. AB - To prevent a future influenza A virus subtype pandemic outbreak, developing a broad-spectrum vaccine would be highly beneficial. The ion channel protein M2 is highly conserved in a diverse number of influenza A virus subtypes. This distinguishing characteristic makes M2 an attractive vaccine target for a broadly protective vaccine. We expressed a full-length M2 protein which was C-terminally fused to a small peptide in Escherichia coli. Because this recombinant M2 (rM2) protein forms multimeric complexes with high molecular weight, it serves as a potential immunogen. Antibodies induced by the rM2 protein prevented the replication of different subtypes of influenza A virus both in vitro and in vivo. Animal study demonstrated that rM2 immunization protected mice against influenza A virus infection via limiting replication of virus progeny in vivo and attenuating lung damage. As such, the M2 protein is a highly potential candidate for next generation vaccine development with the capability of protecting against various influenza A virus subtypes. PMID- 26036949 TI - Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. AB - BACKGROUND: Identifying genetic variants that lead to discernible phenotypes is the core of Mendelian genetics. An approach that considers embryonic lethality as a bona fide Mendelian phenotype has the potential to reveal novel genetic causes, which will further our understanding of early human development at a molecular level. Consanguineous families in which embryonic lethality segregates as a recessive Mendelian phenotype offer a unique opportunity for high throughput novel gene discovery as has been established for other recessive postnatal phenotypes. RESULTS: We have studied 24 eligible families using autozygosity mapping and whole-exome sequencing. In addition to revealing mutations in genes previously linked to embryonic lethality in severe cases, our approach revealed seven novel candidate genes (THSD1, PIGC, UBN1, MYOM1, DNAH14, GALNT14, and FZD6). A founder mutation in one of these genes, THSD1, which has been linked to vascular permeability, accounted for embryonic lethality in three of the study families. Unlike the other six candidate genes, we were able to identify a second mutation in THSD1 in a family with a less severe phenotype consisting of hydrops fetalis and persistent postnatal edema, which provides further support for the proposed link between this gene and embryonic lethality. CONCLUSIONS: Our study represents an important step towards the systematic analysis of "embryonic lethal genes" in humans. PMID- 26036950 TI - PEGylated IFNbeta-1a in the treatment of multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic immune-mediated disease of the CNS characterized in most cases by a relapsing and remitting disease course, often followed by a progressive course. There are many available injectable therapies for the relapsing-remitting form of MS (RRMS); however, efficacy can be affected by poor adherence and compliance, and an increased frequency of side effects as a result of frequent injections is seen. AREAS COVERED: This review focuses on the use of subcutaneous PEGylated IFNbeta-1a (PEGIFN beta-1a) in RRMS. The pharmacological data in addition to clinical safety and tolerability are analyzed. The clinical efficacy is assessed by evaluating results of various end points used in the ADVANCE Phase III study and the differences between treatment groups over 2 years. EXPERT OPINION: We discuss the significance of the ADVANCE trial results and how the results compare to other products on the market. Due to a lack of head-to-head comparison of PEGIFN beta-1a with other types of drugs for RRMS, it is difficult to draw conclusion about the superiority of the drug. We also discuss whether the results can be applied to patients with more severe forms of the disease. Overall, PEGIFN beta-1a is a promising addition to the repertoire of emerging drugs for the treatment of RRMS. PMID- 26036951 TI - Functional display of heterotetrameric human protein kinase CK2 on Escherichia coli: a novel tool for drug discovery. AB - BACKGROUND: Human protein kinase CK2 represents a novel therapeutic target for neoplastic diseases. Inhibitors are in need to explore the druggability and the therapeutic options of this enzyme. A bottleneck in the search for new inhibitors is the availability of the target for testing. Therefore an assay was developed to provide easy access to CK2 for discovery of novel inhibitors. RESULTS: Autodisplay was used to present human CK2 on the surface of Escherichia coli. Heterotetrameric CK2 consists of two subunits, alpha and beta, which were displayed individually on the surface. Co-display of CK2alpha and CK2beta on the cell surface led to the formation of functional holoenzyme, as demonstrated by NaCl dependency of enzymatic activity, which differs from that of the catalytic subunit CK2alpha without beta. In addition interaction of CK2alpha and CK2beta at the cell surface was confirmed by co-immunoprecipitation assays. Surface displayed CK2 holoenzyme enabled an easy IC50 value determination. The IC50 values for the known CK2 inhibitors TBB and Silmitasertib were determined to be 50 and 3.3 nM, respectively. CONCLUSION: Surface-displayed CK2alpha and CK2beta assembled on the cell surface of E. coli to an active tetrameric holoenzyme. The whole-cell CK2 autodisplay assay as developed is suitable for inhibition studies. Furthermore, it can be used to determine quantitative CK2 inhibition data such as IC50 values. In summary, this is the first report on the functional surface display of a heterotetrameric enzyme on E. coli. PMID- 26036952 TI - Suprascarpal fat pad thickness may predict venous drainage patterns in abdominal wall flaps. AB - BACKGROUND: Abdominal wall flaps are routinely used in reconstructive procedures. In some patients inadequate venous drainage from the deep vein may cause fat necrosis or flap failure. Occasionally the superficial inferior epigastric vessels (SIEV) are of sufficient size to allow for microvascular revascularization. This study looked at the ratio of the sub- and suprascarpal fat layers, the number of deep system perforators, and SIEV diameter to determine any correlation of the fat topography and SIEV. METHODS: 50 abdominal/pelvic CT angiograms (100 hemiabdomens) were examined in women aged 34-70 years for number of perforators, SIEV diameter, and fat pad thickness above and below Scarpa's fascia. Data was analyzed using multivariate model. RESULTS: The average suprascarpal and subscarpal layers were 18.6 +/- 11.5 mm and 6.2 +/- 7.2 mm thick, respectively. The average SIEV diameter was 2.06 +/- 0.81 mm and the average number of perforators was 2.09 +/- 1.03 per hemiabdomen. Hemiabdomens with suprascarpal thickness>23 mm had greater SIEV diameter [2.69 mm vs. 1.8 mm (P < 0.0001)] The fat layer thickness did not correlate with the number of perforators. Neither subscarpal fat thickness nor suprascarpal-to-subscarpal fat layer thickness correlated significantly with SIEV caliber or number of perforators in multivariate model. CONCLUSIONS: Suprascarpal fat pad thicker than 23 mm had larger SIEVs irrespective of the number of deep system perforators. This may indicate a cohort of patients at risk of venous congestion from poor venous drainage if only the deep system is revascularized. We recommend harvesting the SIEV in patients with suprascarpal fat pad >23 mm to aid in superficial drainage. PMID- 26036953 TI - Eucapnic Voluntary Hyperventilation to Detect Exercise-Induced Bronchoconstriction in Cystic Fibrosis. AB - BACKGROUND: Exercise-induced bronchoconstriction (EIB) has not been well studied in cystic fibrosis (CF), and eucapnic voluntary hyperventilation (EVH) testing has not been used as an objective assessment of EIB in CF to date. METHODS: A prospective cohort pilot study was completed where standard EVH testing was completed by 10 CF patients with forced expiratory volume in 1 s (FEV1) >=70% of predicted. All patients also completed a cardiopulmonary exercise test (CPET) with pre- and post-CPET spirometry as a comparative method of detecting EIB. RESULTS: No adverse events occurred with EVH testing. A total of 20% (2/10) patients were diagnosed with EIB by means of EVH. Both patients had clinical symptoms consistent with EIB. No patient had a CPET-based exercise challenge consistent with EIB. CONCLUSIONS: EVH testing was safe and effective in the objective assessment for EIB in patients with CF who had well-preserved lung function. It may be a more sensitive method of detecting EIB then exercise challenge. PMID- 26036954 TI - Changes in the prognosis of Japanese patients who developed type 1 diabetes before the age of 30 years. AB - AIMS: We investigated changes in vital prognosis according to the year at diagnosis of type 1 diabetes mellitus (T1DM) in a hospital-based survey. METHODS: Of 1054 Japanese subjects diagnosed as T1DM between 1952 and 1999 before the age of 30 and consulted the diabetes center between 1962 and 1999, the survival status up to 2010 or 20 years of follow-up was investigated. Subjects were divided by the year at diagnosis of T1DM: before 1979 (Group A: n = 359), 1980 to 1989 (Group B: n = 400), and 1990 to 1999 (Group C: n = 295). The mortality (/100,000 person years) and standardized mortality ratio (SMR) were calculated, and the effect of year at diagnosis of T1DM was explored by the Cox proportional hazard model. RESULTS: The survival status was confirmed in 90.0%. The mortality rate (95%CI) and age and sex adjusted SMR (95%CI) were 457 (288-627) and 3.0 (1.9 4.2) in Group A, 265 (143-387) and 2.2 (1.2-3.2) in Group B, and 144 (29-259) and 1.6 (0.3-2.9) in Group C, respectively. The cumulative survival rate was significantly different according to the year at diagnosis of T1DM (p = 0.0239). Cox's proportional hazard model revealed that Groups B and C had significantly lower risks of death than Group A after adjustment for gender and age at diagnosis of T1DM (HR 0.48 [95%CI 0.26-0.87] for Group B and HR 0.25 [95%CI 0.09 0.60] for Group C). CONCLUSION: This study indicated that vital prognosis is improving according to the year at diagnosis of T1DM and suggested the need of a nationwide survey. PMID- 26036955 TI - Cardiovascular autonomic tone relation to metabolic parameters and hsCRP in normoglycemia and prediabetes. AB - AIMS: The aim of the study was to evaluate cardiovascular autonomic function (CAF) at different stages of obesity and in the presence of metabolic syndrome (MetS), and its association with metabolic parameters and hsCRP in subjects with normal glucose tolerance (NGT) and prediabetes. METHODS: A total of 259 subjects (mean age 47.1 +/- 14.6 years, mean BMI 31.4 +/- 8.1 kg/m(2)), divided in 2 groups: NGT and prediabetes, and subdivided according to glucose tolerance, BMI and MetS, were enrolled. Anthropometric indices, glucose tolerance, blood pressure, serum lipids and hsCRP were measured. Body composition was estimated by impedance analysis. CAF was assessed by ANX-3.0 method. RESULTS: Sympathetic and parasympathetic activity were decreased in severe obesity and MetS as compared to controls in NGT. Negative correlation was observed between sympathetic and parasympathetic tone and BMI, waist circumference, total body fat, visceral fat area (VFA), blood pressure, total and LDL cholesterol, and hsCRP in NGT; and VFA, HbA1c and glycemia in prediabetes. CONCLUSION: Obesity and MetS seem to be associated with CAF deterioration, and metabolic parameters and hsCRP correlate with CAF and probably increase cardiovascular risk in NGT, whilst VFA, HbA1c and glycemia significantly influence CAF alterations in prediabetes. PMID- 26036956 TI - Anti-inflammatory effect of water extracts of Graptopetalum paraguayense supplementation in subjects with metabolic syndrome: a preliminary study. AB - BACKGROUND: Many studies have demonstrated that Graptopetalum paraguayense has good antioxidant ability; however, few studies have examined its anti inflammatory effect. The study aimed to investigate the anti-inflammatory effects of water extracts of G. paraguayense (WGP, 4 g day(-1)) in subjects with metabolic syndrome (MS). Intervention was administered for 12 weeks. Levels of inflammatory markers [high sensitivity C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6)] and antioxidant enzymes activities were measured. RESULTS: Forty-two subjects completed the 12 week intervention study (placebo, n = 19; WGP, n = 23). After 12 weeks supplementation, subjects in WGP group had significantly lower levels of inflammatory markers than the baseline (P < 0.05) and the placebo group (CRP, P = 0.07; TNF-alpha, P = 0.04; IL-6, P = 0.03). The changes in levels of the inflammatory markers were significantly decreased in WGP group (CRP, P = 0.04; TNF-alpha, P = 0.06; IL-6, P = 0.01) compared to the placebo group. Levels of inflammatory markers were significantly negatively correlated with the antioxidant enzymes activities after supplementation. CONCLUSION: This study demonstrated a significant reduction in inflammatory status in MS after WGP supplementation. WGP may exert an anti-inflammatory effect on MS in addition to its antioxidant ability. PMID- 26036959 TI - Effects of temperature and oxygen on growth and differentiation of embryos of the ground skink, Scincella lateralis. AB - Development of reptile embryos is dependent upon adequate oxygen availability to meet embryonic metabolic demand. Metabolic rate of embryos is temperature dependent, with oxygen consumption increasing exponentially as a function of temperature. Because metabolic rate is more temperature sensitive than diffusion, developmental processes are predicted to be oxygen-limited at high temperatures. We tested the hypothesis that the amount of development lizard embryos achieve in the oviduct is dependent upon both temperature and oxygen availability. We evaluated the effect of temperature (23, 33 degrees C) and oxygen concentration (9%, 15%, 21% O2 ) on survival and development of embryos of the oviparous skink Scincella lateralis. We predicted that incubation at 33 degrees C under hypoxic conditions would result in higher embryo mortality due to mismatch between embryo oxygen demand and oxygen supply compared to eggs incubated at 23 degrees C under hypoxic conditions. Embryo mortality was highest at 33 degrees C/9% O2 (86%) compared to 23 degrees C/9% O2 (14%), however, mortality did not differ among any other oxygen-temperature treatment combination. Both temperature and oxygen affected differentiation, but the interaction between temperature and oxygen was not significant. Embryo growth in mass and hatchling mass were affected by oxygen concentration independent of temperature treatment. Differing responses of growth and differentiation to temperature and oxygen treatments suggests that somatic growth may be more sensitive to oxygen availability than differentiation. Results indicate that embryo mortality can occur both via the direct effect of high temperature on cellular function as well as indirectly through thermally induced oxygen diffusion limitation. PMID- 26036960 TI - The Use of Channel-Purge Storage for Gastrointestinal Endoscopes Reduces Microbial Contamination. AB - Storage cabinets for heat-sensitive endoscopes (SCHEs) are designed to store gastrointestinal (GI) endoscopes in a clean, dry and well-ventilated cupboard to prevent microbiological proliferation. The use of SCHEs in a GI endoscopy unit has significally reduced the rate of contaminated endoscopes (13.0% vs 45.0%, P<.001). PMID- 26036961 TI - Changing undergraduate attitudes to mental illness. AB - BACKGROUND: Promoting positive experiences of patient contact during psychiatry clerkships may be important in influencing medical students' attitudes to people with mental illness. Here we report findings from a focus group study that explored the impact on undergraduate attitudes of participation in a novel social interaction programme for people with mental illness and their carers, provided by a non-governmental organisation (NGO). METHOD: An audio-taped focus group interview was undertaken with 14 medical students using a semi-structured interview guide. The recorded discussion was transcribed verbatim and thematic analysis was performed. RESULTS: Initial apprehension about interacting with patients lessened as the students engaged in shared activities. Students described their increased awareness of the normality and competence of psychiatric patients. As future doctors, they reported a greater understanding of the benefits of social inclusion for patients and carers alike. Promoting positive experiences of patient contact ... may be important in influencing medical students' attitudes to people with mental illness DISCUSSION: Medical students' joint participation in a group activity programme for people with mental illness in non-hospital settings may have advantages in promoting positive attitudinal change. Clinical teachers could usefully incorporate this type of experience into the undergraduate psychiatry curriculum. PMID- 26036957 TI - Behavioral and Neuroanatomical Phenotypes in Mouse Models of Autism. AB - In order to understand the consequences of the mutation on behavioral and biological phenotypes relevant to autism, mutations in many of the risk genes for autism spectrum disorder have been experimentally generated in mice. Here, we summarize behavioral outcomes and neuroanatomical abnormalities, with a focus on high-resolution magnetic resonance imaging of postmortem mouse brains. Results are described from multiple mouse models of autism spectrum disorder and comorbid syndromes, including the 15q11-13, 16p11.2, 22q11.2, Cntnap2, Engrailed2, Fragile X, Integrinbeta3, MET, Neurexin1a, Neuroligin3, Reelin, Rett, Shank3, Slc6a4, tuberous sclerosis, and Williams syndrome models, and inbred strains with strong autism-relevant behavioral phenotypes, including BTBR and BALB. Concomitant behavioral and neuroanatomical abnormalities can strengthen the interpretation of results from a mouse model, and may elevate the usefulness of the model system for therapeutic discovery. PMID- 26036962 TI - Identification of genomic regions associated with female fertility in Danish Jersey using whole genome sequence data. AB - BACKGROUND: Female fertility is an important trait in cattle breeding programs. In the Nordic countries selection is based on a fertility index (FTI). The fertility index is a weighted combination of four female fertility traits estimated breeding values for number of inseminations per conception (AIS), 56 day non-return rate (NRR), number of days from first to last insemination (IFL), and number of days between calving and first insemination (ICF). The objective of this study was to identify associations between sequence variants and fertility traits in Jersey cattle based on 1,225 Jersey sires from Denmark with official breeding values for female fertility traits. The association analyses were carried out in two steps: first the cattle genome was scanned for quantitative trait loci using a sire model for FTI using imputed whole genome sequence variants; second the significant quantitative trait locus regions were re analyzed using a linear mixed model (animal model) for both FTI and its component traits AIS, NRR, IFL and ICF. The underlying traits were analyzed separately for heifers (first parity cows) and cows (later parity cows) for AIS, NRR, and IFL. RESULTS: In the first step 6 QTL were detected for FTI: one QTL on each of BTA7, BTA20, BTA23, BTA25, and two QTL on BTA9 (QTL9-1 and QTL9-2). In the second step, ICF showed association with the QTL regions on BTA7, QTL9-2 QTL2 on BTA9, and BTA25, AIS for cows on BTA20 and BTA23, AIS for heifers on QTL9-2 on BTA9, IFL for cows on BTA20, BTA23 and BTA25, IFL for heifers on BTA7 and QTL9-2 on BTA9, NRR for heifers on BTA7 and BTA23, and NRR for cows on BTA23. CONCLUSION: The genome wide association study presented here revealed 6 genomic regions associated with FTI. Screening these 6 QTL regions for the underlying female fertility traits revealed that different female fertility traits showed associations with different subsets of the individual FTI QTL peaks. The result of this study contributed to a better insight into the genetic control of FTI in the Danish Jersey. PMID- 26036963 TI - Young peoples' experience and self-management in the six months following major injury: A qualitative study. AB - PURPOSE: The aim of this qualitative study was to explore how young people aged 16-24 years' experience, perceive and manage the effects of major traumatic injury during the initial six months following major traumatic injury. Specifically: (1) how do young people manage the physical and emotional effects of major injury within the trauma system of care? (2) What are young peoples' perceived needs for healthcare and how are these met within the trauma system of care? (3) What do young people perceive as the role of family in supporting them? METHODS: This study forms part of the qualitative follow-up phase of an explanatory sequential mixed methods study investigating the characteristics and experience of major traumatic injury for young people 16-24 years, and the role of family in supporting them, in the initial six months following injury. The paper reports on young peoples' (aged 16-24 years) experiences of being admitted with major traumatic injury to two Australian Level 1 Trauma Centres. Twelve injured young people aged 17-23 years (mean=19 years) participated in the study. Two semi-structured in-depth interviews with young people were conducted and transcribed verbatim; the first prior to hospital discharge (n=12), and the second (n=7) within 3 months of hospital discharge. Data were managed using NVivo software, and thematically analysed. FINDINGS: During the initial 6 months following injury, young people experienced a complex process of adaptation involving feelings of vulnerability and loss of control over their physicality, environment and life-course. Self-management strategies included use of Information technology as a form of distraction; family and friends to create a sense of familiarity and normality; and information and validation-seeking from health care professionals as a means of understanding and regaining a sense of self. CONCLUSION: Key elements of resilience theory applicable to the findings such as problem-based coping, self-efficacy and strong social support offer a useful framework for anticipatory guidance that is responsive to the psychosocial needs of injured young people and facilitates a strength-based patient-centred approach to managing major traumatic injury. PMID- 26036964 TI - N-3 polyunsaturated fatty acids in animal models with neuroinflammation: An update. AB - Neuroinflammation is a characteristic of a multitude of neurological and psychiatric disorders. Modulating inflammatory pathways offers a potential therapeutic target in these disorders. Omega-3 polyunsaturated fatty acids have anti-inflammatory and pro-resolving properties in the periphery, however, their effect on neuroinflammation is less studied. This review summarizes 61 animal studies that tested the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory outcomes in vivo in various models including stroke, spinal cord injury, aging, Alzheimer's disease, Parkinson's disease, lipopolysaccharide and IL-1beta injections, diabetes, neuropathic pain, traumatic brain injury, depression, surgically induced cognitive decline, whole body irradiation, amyotrophic lateral sclerosis, N-methyl-D-aspartate-induced excitotoxicity and lupus. The evidence presented in this review suggests anti-neuroinflammatory properties of omega-3 polyunsaturated fatty acids, however, it is not clear by which mechanism omega-3 polyunsaturated fatty acids exert their effect. Future research should aim to isolate the effect of omega-3 polyunsaturated fatty acids on neuroinflammatory signaling in vivo and elucidate the mechanisms underlying these effects. PMID- 26036966 TI - Dual Stimuli-Responsive Poly(beta-amino ester) Nanoparticles for On-Demand Burst Release. AB - We designed poly(beta-amino esters) (PBAEs) bearing both UV light- and pH sensitive groups and used PBAEs to prepare nanoparticles (NPs) that can be utilized for on-demand burst release of guest molecules in response to multiple triggers. Due to the presence of the photo-cleavable group in each repeating unit of PBAE, rapid release of encapsulated model drug could be achieved even with exposures to low intensity UV (10 mW . cm(-2) ). Especially, the burst release was further accelerated by additional UV treatments in the acidic condition showing the combinatory effect of dual stimuli. We believe these PBAE-based NPs can potentially be used to design intelligent controlled release device and nanomedicines. PMID- 26036965 TI - A cluster randomised controlled trial to investigate the effectiveness and cost effectiveness of the 'Girls Active' intervention: a study protocol. AB - BACKGROUND: Despite the health benefits of physical activity, data from the UK suggest that a large proportion of adolescents do not meet the recommended levels of moderate-to-vigorous physical activity (MVPA). This is particularly evident in girls, who are less active than boys across all ages and may display a faster rate of decline in physical activity throughout adolescence. The 'Girls Active' intervention has been designed by the Youth Sport Trust to target the lower participation rates observed in adolescent girls. 'Girls Active' uses peer leadership and marketing to empower girls to influence decision making in their school, develop as role models and promote physical activity to other girls. Schools are provided with training and resources to review their physical activity, sport and PE provision, culture and practices to ensure they are relevant and attractive to adolescent girls. METHODS/DESIGN: This study is a two arm cluster randomised controlled trial (RCT) aiming to recruit 20 secondary schools. Clusters will be randomised at the school level (stratified by school size and proportion of Black and Minority Ethnic (BME) pupils) to receive either the 'Girls Active' intervention or carry on with usual practice (1:1). The 20 secondary schools will be recruited from state secondary schools within the Midlands area. We aim to recruit 80 girls aged 11-14 years in each school. Data will be collected at three time points; baseline and seven and 14 months after baseline. Our primary aim is to investigate whether 'Girls Active' leads to higher objectively measured (GENEActiv) moderate-to-vigorous physical activity in adolescent girls at 14 months after baseline assessment compared to the control group. Secondary outcomes include other objectively measured physical activity variables, adiposity, physical activity-related psychological factors and the cost-effectiveness of the 'Girls Active' intervention. A thorough process evaluation will be conducted during the course of the intervention delivery. DISCUSSION: The findings of this study will provide valuable information on whether this type of school-based approach to increasing physical activity in adolescent girls is both effective and cost-effective in the UK. TRIAL REGISTRATION: ISRCTN10688342. Registered 12 January 2015. PMID- 26036967 TI - Brg1 Controls the Expression of Pax7 to Promote Viability and Proliferation of Mouse Primary Myoblasts. AB - Brg1 (Brahma-related gene 1) is a catalytic component of the evolutionarily conserved mammalian SWI/SNF ATP-dependent chromatin remodeling enzymes that disrupt histone-DNA contacts on the nucleosome. While the requirement for the SWI/SNF enzymes in cell differentiation has been extensively studied, its role in precursor cell proliferation and survival is not as well defined. Muscle satellite cells constitute the stem cell pool that sustains and regenerates myofibers in adult skeletal muscle. Here, we show that deletion of Brg1 in primary mouse myoblasts derived from muscle satellite cells cultured ex vivo leads to a cell proliferation defect and apoptosis. We determined that Brg1 regulates cell proliferation and survival by controlling chromatin remodeling and activating transcription at the Pax7 promoter, which is expressed during somite development and is required for controlling viability of the satellite cell population. Reintroduction of catalytically active Brg1 or of Pax7 into Brg1 deficient satellite cells rescued the apoptotic phenotype and restored proliferation. These data demonstrate that Brg1 functions as a positive regulator for cellular proliferation and survival of primary myoblasts. Therefore, the regulation of gene expression through Brg1-mediated chromatin remodeling is critical not just for skeletal muscle differentiation but for maintaining the myoblast population as well. PMID- 26036968 TI - Ultrasound-guided spinal injections: a feasibility study of a guidance system. AB - PURPOSE: Facet joint injections of analgesic agents are widely used to treat patients with lower back pain. The current standard-of-care for guiding the injection is fluoroscopy, which exposes the patient and physician to significant radiation. As an alternative, several ultrasound guidance systems have been proposed, but have not become the standard-of-care, mainly because of the difficulty in image interpretation by the anesthesiologist unfamiliar with the complex spinal sonography. METHODS: We introduce an ultrasound-based navigation system that allows for live 2D ultrasound images augmented with a patient specific statistical model of the spine and relating this information to the position of the tracked injection needle. The model registration accuracy is assessed on ultrasound data obtained from nine subjects who had prior CT images as the gold standard for the statistical model. The clinical validity of our method is evaluated on four subjects (of an ongoing in vivo study) which underwent facet joint injections. RESULTS: The statistical model could be registered to the bone structures in the ultrasound volume with an average RMS accuracy of 2.3+/-0.4 mm. The shape of the individual vertebrae could be estimated from the US volume with an average RMS surface distance error of 1.5+/ 0.4 mm. The facet joints could be identified by the statistical model with an average accuracy of 5.1 +/- 1.5 mm. CONCLUSIONS: The results of this initial feasibility assessment suggest that this ultrasound-based system is capable of providing information sufficient to guide facet joint injections. Further clinical studies are warranted. PMID- 26036969 TI - Characterization and evolutionary analysis of duplicated C7 in miiuy croaker. AB - The complement system, as one of the most sophisticated innate immune system, plays an important role in defense against invading microorganisms. The complement component C7 participates in the cytolytic phase of complement activation through a series of polymerization reactions with other terminal complement components. In this study, we derived two C7 genes from the whole genome of miiuy croaker which were the consequence of the fish-specific genome duplication. Our data showed that miiuy croaker C7-1 and C7-2 genes shared same structure domains. The analysis of gene synteny showed that high degree conserved of synteny was retained between miiuy croaker and other teleosts, and miiuy croaker had a relatively closer relationship with fugu. The expression of C7-1 and C7-2 in miiuy croaker healthy tissues revealed that they were ubiquitously expressed in all ten tested tissues. Besides, the immune response of C7-1 and C7 2 were different in spleen with Vibrio anguillarum, Staphylococcus aureus, poly I:C and LPS at 24 h post-injection, respectively. Furthermore, the expression patterns of C7-1 and C7-2 were different in liver, spleen and kidney after infected with V. anguillarum at different time-point. Evolutionary analysis showed that all the ancestral lineages underwent positive selection except for the ancestral lineages of fish C7-2, indicated that the ancestral lineages of fish C7-1 genes undertook more pressures than C7-2 in defense against the invading microorganisms. Meanwhile, a series of maximum likelihood methods were used to explore the evolutionary patterns on extant vertebrates' C7 genes. Three and one positive selection sites were found in extant mammalian C7 genes and fish C7-2 genes, but no positive selection site was found in extant fishes C7-1 genes. The result showed that extant fish C7-2 genes undertook more pressures compared with C7-1. In conclusion, fish C7-1 and C7-2 gene underwent different evolutionary patterns. PMID- 26036970 TI - Taxane modulation of anesthetic sensitivity in surgery for nonmetastatic breast cancer. AB - STUDY OBJECTIVE AND DESIGN: The mechanism of action of commonly used general anesthetics is largely unknown. One hypothesized mechanism is through modulation of microtubule stability. Taxanes, a subset of chemotherapeutic drugs known to alter microtubule stability and commonly used to treat breast cancer, offer a natural experiment to test our hypothesis that patients exposed to taxanes prior to surgery, as compared to after surgery, would have a partial resistance to general anesthetics. SETTING, PATIENTS, AND MEASUREMENTS: The anesthetic record of adult women with nonmetastatic breast cancer was used to obtain changes in heart rate and blood pressure surrounding incision, and the amount of inhaled anesthetic agent, induction, and rescue drugs administered. MAIN RESULTS: Change in blood pressure in response to incision was significantly higher in the neoadjuvant group (P = .03), whereas change in heart rate was not (P = .53). A greater amount of morphine was administered in the neoadjuvant group (26.3 vs 15.5 mg, P = .02), although not a higher concentration of inhaled anesthetics (P = .15). CONCLUSION: These results suggest that the alteration of microtubule stability is one of a number of mechanisms of inhaled anesthetics. PMID- 26036971 TI - Short term ex vivo storage of kidneys cause progressive nuclear ploidy changes of renal tubular epitheliocytes. AB - In renal transplantation, there has been considerable success, mainly in term of post-transplant graft function. However, upon closer scrutiny, it is known that severe dysfunction, including persistence of renal failure is seen after transplantation. The major condition that potentially cause significant lesion may be hypothesized to be related to the hypothermic approach to storage. To systematically examine these issues, we stored mammalian (sheep) kidneys in UWS at 4 degrees C for four different time points (0, 1, 3 and 6 hours). We obtained renal histological sections and examined tubular architecture as well as nuclear characteristics of tubular epitheliocytes. The results of our preliminary investigations suggest that there are temporal changes of tubular epitheliocytes, as well as genomic changes. These changes were also seen in tissues stored at room temperature. Our observations suggest the need for additional studies for redesigning of improvised storage solutions. Pilot studies using Celsior also revealed similar kind of nuclear changes, suggesting that storage conditions are contributory, including perfusion versus static conditions. The results may explain persistence of tubular injury several days after orthotopic transplantation, and may potentially be contributory to delayed graft function (DGF). PMID- 26036972 TI - VEGF Signaling Regulates Cofilin and the Arp2/3-complex within the Axonal Growth Cone. AB - Over the last decade, our understanding of the vascular endothelial growth factor (VEGF) has rapidly increased, becoming the focus of many investigations the world over. Besides its classical role in the vascular system, VEGF was also identified as a factor affecting the nervous system. One structure that responds to VEGF signaling is the axonal growth cone, the correct behavior of which is essential for the development of a properly working neuronal network. It navigates growing axons to their final destination and helps to create proper synapses at predetermined locations. Recent data concerning the impact of VEGF on the actin cytoskeleton of neuronal growth cones are discussed and new findings of VEGF signaling in regard to actin dynamics are specified. Overall, we describe the role of VEGF regulation of cofilin and the Arp2/3-complex in axonal growth cones. PMID- 26036973 TI - Acute and Chronic Treatments with Quetiapine Increase Mitochondrial Respiratory Chain Complex Activity in the Rat Brain. AB - Several studies have found that the molecular mechanisms of mitochondrial energy metabolism are impaired in major depressive disorder (MDD). Classic antidepressants and atypical antipsychotics can alter the function of enzymes involved in adenosine triphosphate (ATP) metabolism. Quetiapine is an atypical antipsychotic that, in addition to having a therapeutic benefit in treating MDD, appears to exert antioxidant and neuroprotective effects. Therefore, we aimed to evaluate the acute and chronic effects of quetiapine on the activity of enzyme complexes I to IV of the mitochondrial respiratory chain and creatine kinase (CK) in brain regions involved with MDD. After a single dose or serial injections over 14 days of quetiapine (20, 40, and 80 mg) were administered, isolates from the pre- frontal cortex, hippocampus, amygdala and nucleus accumbens were analyzed for enzyme activity levels. The enzyme activity varied according to the dose, brain region, and acute or chronic dosing protocols. In general, complexes I-III activity was increased, especially after acute administration. Acute administration also increased the activity of complex IV and CK in the amygdala while complex I was inhibited in the prefrontal cortex and nucleus accumbens. These results suggest that quetiapine produces an increase in respiratory chain complex activity, which may be underlying its efficacy against psychiatric disorders and neuronal damage. PMID- 26036974 TI - Outcome Prediction after Non-aneurysmal Non-traumatic Subarachnoid Hemorrhage. AB - Contrary to aneurysmal bleeding, non-aneurysmal non-traumatic subarachnoid hemorrhage (NASAH) is rarely associated with unfavorable clinical outcome, cerebral infarction and vasospasm. We aimed to identify independent predictors for a poor clinical course and outcome after NASAH. All patients with NASAH treated at our institution between January 2005 and December 2012 were retrospectively analyzed. Collected demographic, clinical and radiographic variables were divided into primary (admission) and secondary (follow-up) parameters. Independent predictors of unfavorable outcome (defined as modified Rankin scale=3-6), cerebral infarction and development of vasospasm were identified. In addition, a risk score for the estimation of clinical outcome was designed. Out of population with 157 NASAH patients, unfavorable outcome was documented in 57 cases (36.3%) at discharge and in 17 cases (10.8%) after 6 months. Cerebral infarction(s) were found in 7 patients (4.3%). In multivariate analyses, higher age (>=65 years), poorer initial clinical condition measured by Hunt & Hess grade and diffuse basal bleeding pattern were independent outcome predictors and therefore included in the risk score (1-8 points). The risk score correlated with outcome at discharge (p<0.0001) and clinical improvement after 6 months (p=0.0238). A diffuse basal bleeding pattern predicted the detection of vasospasm by transcranial Doppler (p=0.001). Poor initial clinical condition (p=0.028) and vasospasm (p=0.031) were associated with the occurrence of cerebral infarction. NASAH patients with higher age, bad clinical condition on admission and diffuse bleeding pattern are prone to unfavorable outcome. The proposed risk score helps to identify patients with poor prognosis after NASAH. PMID- 26036975 TI - Rufinamide Improves Functional and Behavioral Deficits via Blockade of Tetrodotoxin-Resistant Sodium Channels in Diabetic Neuropathy. AB - Rufinamide is a structurally novel, antiepileptic drug approved for the treatment of Lennox-Gastaut syndrome. Its mechanism of action involves inhibition of voltage-gated Na+ channels (VGSCs) with possible membrane-stabilizing effects. VGSCs play a significant role in the pathogenesis of neuropathic pain. Therefore, we investigated the effects of rufinamide on tetrodotoxin-resistant sodium current (TTX-R I(Na)) in acutely dissociated rat dorsal root ganglion (DRG) neurons isolated from streptozotocin-induced diabetic rats by using whole-cell voltage-clamp configuration. In addition, the functional and behavioural nociceptive parameters were evaluated to assess its potential in diabetic neuropathy. Diabetic rats demonstrated the mechanical allodynia and thermal hyperalgesia with reduced nerve perfusion and conduction velocity as compared to control. Rufinamide treatments (3 and 10 mg/kg) significantly improved these functional and nociceptive deficits. Diabetic rat DRG neurons exhibited increased TTX-R I(Na) density as compared to control. The voltage-dependent activation and steady-state inactivation curves for TTX-R I(Na) in DRG neurons from diabetic rats were shifted negatively as compared to control. Rufinamide treatments significantly blocked the TTX-R Na+ channel activity as evident from significant reduction in I(Na) density and hyperpolarizing shift in activation and inactivation curves as compared to diabetic control. This suggests that rufinamide acts on TTX-R Na+ channels, reduces channel activity and attenuates nerve functional and behavioral parameters in diabetic rats. Altogether, these results indicate therapeutic potential of rufinamide in the treatment of diabetic neuropathy. PMID- 26036976 TI - Neuroprotective Effects of Agomelatine and Vinpocetine Against Chronic Cerebral Hypoperfusion Induced Vascular Dementia. AB - Chronic cerebral hypoperfusion (CCH) has been considered as a critical cause for the development of cognitive decline and dementia of vascular origin. Melatonin receptors have been reported to be beneficial in improving memory deterioration. Phosphodiesterase-1 (PDE1) enzyme offers protection against cognitive impairments and cerebrovascular disorders. Aim of this study is to explore the role of agomelatine (a dual MT1 and MT2 melatonin receptor agonist) and vinpocetine (selective PDE1 inhibitor) in CCH induced vascular dementia (VaD). Two vessel occlusion (2VO) or bilateral common carotid arteries ligation method was performed to initiate a phase of chronic hypoperfusion in mice. 2VO animals have shown significant cognitive deficits (Morris water maze), cholinergic dysfunction (increased acetyl cholinesterase -AChE) activity alongwith increased brain oxidative stress (decreased brain catalase, glutathione, as well as superoxide dismutase with an increase in malondialdehyde levels), and significant increase in brain infarct size (2,3,5- triphenylterazolium chloride-TTC staining). Treatment of agomelatine and vinpocetine reduced CCH induced learning and memory deficits and limited cholinergic dysfunction, oxidative stress, and tissue damage, suggesting that agomelatine and vinpocetine may provide benefits in CCH induced VaD. PMID- 26036977 TI - Radix Angelica Sinensis Promotes Synaptic Plasticity During Cognitive Recovery in Chronically Stressed Rats. AB - The accumulation of chronic stress is associated with cognitive dysfunction. Radix Angelica Sinensis (RAS) has been shown to have neuroprotective potential for treating Alzheimer's disease and vascular dementia. However, the impact of RAS on cognitive impairment induced by chronic stress has not been studied. In the present study, RAS significantly alleviated cognitive deficits in rats subjected to chronic restraint stress. This neuroprotective effect was associated with enhancement of synaptic efficacy by improving field excitatory postsynaptic potential amplitudes, alleviating adverse alterations in the structure of synapses and neurons in the hippocampus, and increasing the levels of brain derived neurotrophic factor, microtubule-associated protein-2, and synaptophysin in the hippocampus. These findings provide initial evidence for the therapeutic potential of RAS for the treatment of neuronal deterioration caused by chronic stress. PMID- 26036978 TI - Computer simulations of sample preconcentration in carrier-free systems and isoelectric focusing in microchannels using simple ampholytes. AB - In this work, electrophoretic preconcentration of protein and peptide samples in microchannels was studied theoretically using the 1D dynamic simulator GENTRANS, and experimentally combined with MS. In all configurations studied, the sample was uniformly distributed throughout the channel before power application, and driving electrodes were used as microchannel ends. In the first part, previously obtained experimental results from carrier-free systems are compared to simulation results, and the effects of atmospheric carbon dioxide and impurities in the sample solution are examined. Simulation provided insight into the dynamics of the transport of all components under the applied electric field and revealed the formation of a pure water zone in the channel center. In the second part, the use of an IEF procedure with simple well defined amphoteric carrier components, i.e. amino acids, for concentration and fractionation of peptides was investigated. By performing simulations a qualitative description of the analyte behavior in this system was obtained. Neurotensin and [Glu1]-Fibrinopeptide B were separated by IEF in microchannels featuring a liquid lid for simple sample handling and placement of the driving electrodes. Component distributions in the channel were detected using MALDI- and nano-ESI-MS and data were in agreement with those obtained by simulation. Dynamic simulations are demonstrated to represent an effective tool to investigate the electrophoretic behavior of all components in the microchannel. PMID- 26036979 TI - Combined immunotherapy improves survival in metastatic melanoma. PMID- 26036980 TI - The development of the TNM classification of gastric cancer. AB - The first tumor, node, metastasis (TNM) classification for stomach tumors was published in the second edition of the TNM classification of malignant tumors in 1974 and was followed by additional editions up to the seventh edition published in 2010. In the Buffalo Meeting 2008 a harmonization between the Eastern (Japanese) and Western stomach tumor classification was achieved with only minor remaing differences. The present TNM classification of stomach tumors has been criticized but it can be considered generally accepted worldwide. For generating data based on this new TNM classification it is important to correctly use TNM and pTNM. The decions on therapy and the estimation of prognosis are based on TNM. New molecular factor studies will be correlated and based on the results of the TNM classification. PMID- 26036981 TI - More reasons why private practice is unethical. PMID- 26036982 TI - Venous thrombosis in afibrinogenemia: a successful use of rivaroxaban. PMID- 26036983 TI - Use of monitoring data to support conservation management and policy decisions in Micronesia. AB - Adaptive management implies a continuous knowledge-based decision-making process in conservation. Yet, the coupling of scientific monitoring and management frameworks remains rare in practice because formal and informal communication pathways are lacking. We examined 4 cases in Micronesia where conservation practitioners are using new knowledge in the form of monitoring data to advance marine conservation. These cases were drawn from projects in Micronesia Challenge jurisdictions that received funding for coupled monitoring-to-management frameworks and encompassed all segments of adaptive management. Monitoring in Helen Reef, Republic of Palau, was catalyzed by coral bleaching and revealed evidence of overfishing that led to increased enforcement and outreach. In Nimpal Channel, Yap, Federated States of Micronesia (FSM), monitoring the recovery of marine food resources after customary restrictions were put in place led to new, more effective enforcement approaches. Monitoring in Laolao Bay, Saipan, Commonwealth of the Northern Mariana Islands, was catalyzed by observable sediment loads from poor land-use practices and resulted in actions that reduced land-based threats, particularly littering and illegal burning, and revealed additional threats from overfishing. Pohnpei (FSM) began monitoring after observed declines in grouper spawning aggregations. This data led to adjusting marine conservation area boundaries and implementing market-based size class restrictions. Two themes emerged from these cases. First, in each case monitoring was conducted in a manner relevant to the social and ecological systems and integrated into the decision-making process. Second, conservation practitioners and scientists in these cases integrated culturally appropriate stakeholder engagement throughout all phases of the adaptive management cycle. More broadly, our study suggests, when describing adaptive management, providing more details on how monitoring and management activities are linked at similar spatial scales and across similar time frames can enhance the application of knowledge. PMID- 26036984 TI - Luminescence switching of a persistent room-temperature phosphorescent pure organic molecule in response to external stimuli. AB - 4-(Carbazol-9-yl)benzaldehyde could emit yellow RTP, which could last for 3 s because of efficient intersystem crossing. Moreover, multicolor luminescent switches could be realized by simply applying a mechanical force stimulus. PMID- 26036985 TI - Alanine aminotransferase and gamma-glutamyl transferase have different dose response relationships with risk of mortality by age. AB - BACKGROUND & AIMS: It remains unclear whether the respective dose-response relationships between serum alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) levels and risk of mortality are consistent by age. METHODS: We used sampled cohort data from the National Health Insurance Corporation to conduct a retrospective cohort study. A total of 313 252 participants who received medical health check-ups from 2002 to 2008 were assessed for risk of death according to serum ALT and GGT levels over an average of 6 years. The hazard ratios (HRs) for mortality were analysed with Cox proportional hazard model. RESULTS: The crude mortality rate increased linearly with increasing serum ALT and GGT levels in adults aged <60 years. However, the all-cause mortality rate showed a J-shaped relationship with increasing serum ALT levels whereas all cause mortality rate showed a linear relationship with increasing serum GGT levels in adults aged >=60 years. The HR of death showed U-shaped relationships with increasing serum ALT levels in adults aged >=60 years. On the contrary, the HR of death from any cause had a linear association with increasing serum GGT levels among all age groups. CONCLUSIONS: In this study, U-shaped relationship patterns were demonstrated between serum ALT levels and risk for all-cause mortality in adults aged >=60 years while serum GGT levels showed a linear relationship with risk for all-cause death. Very low levels of serum ALT in elderly patients suggest that they are at high risk of mortality. PMID- 26036986 TI - Local Control Theory in Trajectory Surface Hopping Dynamics Applied to the Excited-State Proton Transfer of 4-Hydroxyacridine. AB - The application of local control theory combined with nonadiabatic ab initio molecular dynamics to study the photoinduced intramolecular proton transfer reaction in 4-hydroxyacridine was investigated. All calculations were performed within the framework of linear-response time-dependent density functional theory. The computed pulses revealed important information about the underlying excited state nuclear dynamics highlighting the involvement of collective vibrational modes that would normally be neglected in a study performed on model systems constrained to a subset of the full configuration space. This study emphasizes the strengths of local control theory for the design of pulses that can trigger chemical reactions associated with the population of a given molecular excited state. In addition, analysis of the generated pulses can help to shed new light on the photophysics and photochemistry of complex molecular systems. PMID- 26036988 TI - Sugar sweetened beverages and fatty liver disease: Rising concern and call to action. PMID- 26036987 TI - Home-based community health worker intervention to reduce pesticide exposures to farmworkers' children: A randomized-controlled trial. AB - We conducted a randomized-controlled trial of a home-based intervention to reduce pesticide exposures to farmworkers' children in Monterey County, California (n=116 families). The intervention consisted of three home-based educational sessions delivered by community health workers in Spanish. Measurements of organophosphate (OP) insecticide metabolites in child urine (n=106) and pesticides in home floor wipes (n=103) were collected before and after the intervention. Median child urinary dialkyl phosphate (DAP) metabolite levels were slightly lower among the intervention group children at follow-up compared with baseline, albeit nonsignificantly. DAP metabolite levels in the control group children were markedly higher at follow-up compared with baseline. In adjusted models, intervention participation was associated with a 51% decrease in total DAP metabolite levels. Carbaryl, chlorpyrifos, cypermethrin, dacthal, diazinon, malathion, and trans-permethrin were commonly detected in the floor wipes. In adjusted models, intervention participation was significantly associated with a 37% decrease in trans-permethrin floor wipe levels in homes, but not OP or other agricultural pesticides. In summary, intervention group children had slightly reduced pesticide exposures, whereas child exposures were higher among the control group. Additional intervention studies evaluating methods to reduce pesticide exposures to farmworker families and children are needed. PMID- 26036989 TI - Involvement of Long-Lived Intermediate States in the Complex Folding Pathway of the Human Telomeric G-Quadruplex. AB - The energy landscapes of human telomeric G-quadruplexes are complex, and their folding pathways have remained largely unexplored. By using real-time NMR spectroscopy, we investigated the K(+)-induced folding of the human telomeric DNA sequence 5'-TTGGG(TTAGGG)3 A-3'. Three long-lived states were detected during folding: a major conformation (hybrid-1), a previously structurally uncharacterized minor conformation (hybrid-2), and a partially unfolded state. The minor hybrid-2 conformation is formed faster than the more stable hybrid-1 conformation. Equilibration of the two states is slow and proceeds via a partially unfolded intermediate state, which can be described as an ensemble of hairpin-like structures. PMID- 26036991 TI - Diagnostic value of Thallium-201 scintigraphy in differentiating malignant bone tumors from benign bone lesions. AB - OBJECTIVE: This retrospective study aims to evaluate the diagnostic capacity of thallium-201 (201Tl) scintigraphy for differentiating malignant bone tumors from benign bone lesions. METHODS: Between January 2006 and December 2012, 279 patients with bone lesions (51 malignant and 228 benign) underwent 201Tl scintigraphy before treatment. To evaluate 201Tl uptake, we investigated tumor-to background contrast (TBC) as well as TBC washout rate (WR). The differences of TBC on early and delayed images and WR were estimated by the Mann-Whitney U test. Receiver operating characteristic (ROC) analyses were used to determine the cut off TBC values for differentiating malignant bone tumors from benign bone lesions. RESULTS: There were statistically significant differences in median TBC between malignant tumors and benign lesions. These differences occurred for early imaging (1.57 vs. 0.09, p < 0.001) as well as for delayed imaging (0.83 vs. 0.07, p < 0.001). However, there was no statistical difference in WR between malignant tumors and benign lesions (44 vs. 43 %, NS). The chosen TBC cut-off value was 0.68 for early imaging and 0.38 for delayed imaging. Using these cut-off values, the prediction of malignancy had a 77 % sensitivity, 74 % specificity, and 75 % accuracy for early imaging and an 80 % sensitivity, 76 % specificity, and 77 % accuracy for delayed imaging. CONCLUSIONS: 201Tl scintigraphy may have the ability to distinguish malignant bone tumors from benign bone lesions. PMID- 26036990 TI - The opioid peptide dynorphin A induces leukocyte responses via integrin Mac-1 (alphaMbeta2, CD11b/CD18). AB - BACKGROUND: Opioid peptides, including dynorphin A, besides their analgesic action in the nervous system, exert a broad spectrum of effects on cells of the immune system, including leukocyte migration, degranulation and cytokine production. The mechanisms whereby opioid peptides induce leukocyte responses are poorly understood. The integrin Mac-1 (alphaMbeta2, CD11b/CD18) is a multiligand receptor which mediates numerous reactions of neutrophils and monocyte/macrophages during the immune-inflammatory response. Our recent elucidation of the ligand recognition specificity of Mac-1 suggested that dynorphin A and dynorphin B contain Mac-1 recognition motifs and can potentially interact with this receptor. RESULTS: In this study, we have synthesized the peptide library spanning the sequence of dynorphin AB, containing dynorphin A and B, and showed that the peptides bound recombinant alphaMI-domain, the ligand binding region of Mac-1. In addition, immobilized dynorphins A and B supported adhesion of the Mac-1-expressing cells. In binding to dynorphins A and B, Mac-1 cooperated with cell surface proteoglycans since both anti-Mac-1 function blocking reagents and heparin were required to block adhesion. Further focusing on dynorphin A, we showed that its interaction with the alphaMI-domain was activation independent as both the alpha7 helix-truncated (active conformation) and helix-extended (nonactive conformation) alphaMI-domains efficiently bound dynorphin A. Dynorphin A induced a potent migratory response of Mac-1-expressing, but not Mac-1-deficient leukocytes, and enhanced Mac-1-mediated phagocytosis of latex beads by murine IC-21 macrophages. CONCLUSIONS: Together, the results identify dynorphins A and B as novel ligands for Mac-1 and suggest a role for the Dynorphin A-Mac-1 interactions in the induction of nonopiod receptor-dependent effects in leukocytes. PMID- 26036992 TI - Estimation of Genetic Relationships Between Individuals Across Cohorts and Platforms: Application to Childhood Height. AB - Combining genotype data across cohorts increases power to estimate the heritability due to common single nucleotide polymorphisms (SNPs), based on analyzing a Genetic Relationship Matrix (GRM). However, the combination of SNP data across multiple cohorts may lead to stratification, when for example, different genotyping platforms are used. In the current study, we address issues of combining SNP data from different cohorts, the Netherlands Twin Register (NTR) and the Generation R (GENR) study. Both cohorts include children of Northern European Dutch background (N = 3102 + 2826, respectively) who were genotyped on different platforms. We explore imputation and phasing as a tool and compare three GRM-building strategies, when data from two cohorts are (1) just combined, (2) pre-combined and cross-platform imputed and (3) cross-platform imputed and post-combined. We test these three strategies with data on childhood height for unrelated individuals (N = 3124, average age 6.7 years) to explore their effect on SNP-heritability estimates and compare results to those obtained from the independent studies. All combination strategies result in SNP-heritability estimates with a standard error smaller than those of the independent studies. We did not observe significant difference in estimates of SNP-heritability based on various cross-platform imputed GRMs. SNP-heritability of childhood height was on average estimated as 0.50 (SE = 0.10). Introducing cohort as a covariate resulted in ~2 % drop. Principal components (PCs) adjustment resulted in SNP-heritability estimates of about 0.39 (SE = 0.11). Strikingly, we did not find significant difference between cross-platform imputed and combined GRMs. All estimates were significant regardless the use of PCs adjustment. Based on these analyses we conclude that imputation with a reference set helps to increase power to estimate SNP-heritability by combining cohorts of the same ethnicity genotyped on different platforms. However, important factors should be taken into account such as remaining cohort stratification after imputation and/or phenotypic heterogeneity between and within cohorts. Whether one should use imputation, or just combine the genotype data, depends on the number of overlapping SNPs in relation to the total number of genotyped SNPs for both cohorts, and their ability to tag all the genetic variance related to the specific trait of interest. PMID- 26036993 TI - Cross-Lagged Associations Between Adolescents' Depressive Symptoms and Negative Cognitive Style: The Role of Negative Life Events. AB - Previous research has established that cognitive theory-based depression prevention programs aiming change in negative cognitive style in early adolescents do not have strong effects in universal settings. Although theories suggest that a negative cognitive style precedes depressive symptoms, empirical findings are mixed. We hypothesized that negative cognitive style may not predict depressive symptoms in adolescents with normative depressive symptoms. Depressive symptoms, negative cognitive style and dependent negative life events were assessed in young adolescents (N = 1343; mean age = 13.4 years, SD = 0.77; 52.3 % girls) at four time points over an 18-month period. Using a cross-lagged panel design, results revealed that depressive symptoms predicted a negative cognitive style but not vice versa. However, when including dependent negative life events as a variable, depressive symptoms did not prospect a negative cognitive style consistently. When dependent negative life events were used as a time-varying covariate, depressive symptoms and a negative cognitive style were not related. We concluded that negative cognitive style is not predictive of depressive symptoms in a community sample of young adolescents. Moreover, the findings suggest that longitudinal relationships between depressive symptoms and a negative cognitive style are not meaningful when dependent negative life events are not considered. PMID- 26036994 TI - Transitions in Current Substance Use from Adolescence to Early-Adulthood. AB - Substance use behaviors do not occur in isolation of one another and are not static over time. As adolescents age into early adulthood, there may be dynamic changes in their substance use behaviors, and these changes may be influenced by family and school factors. The current study uses Latent Transition Analysis to examine these changes by measuring transitions among different substance use profiles based on past 30-day alcohol, tobacco and marijuana use, and by estimating associations with demographic, family and school factors. Data were from youth (n = 850; 80% African American, 17% white, 3% mixed race, 50% female and 50% male) in grade 10 (Time 1), with 24- (Time 2) and 48-month (Time 3) follow-ups. Substance use profiles included Non-users (54%), Alcohol and Marijuana Users (20%), and Alcohol, Tobacco and Marijuana Users (26%). There were considerable transitions among profiles from Time 1 to Time 2, and fewer transitions from Time 2 to Time 3. At Time 1, African American race and positive school attitudes were negatively associated with being an Alcohol and Marijuana User, and being an Alcohol, Tobacco and Marijuana User. Family conflict, parental school involvement, female gender and African American race were associated with transitions among substance use profiles. Implications are discussed for a better understanding of transitions in substance use profiles, and for promoting maintenance of non-use and transitions from substance using profiles to non-use. PMID- 26036996 TI - Cancer Is Essentially Due to Bad Luck ... But Not So Much If You Don't Exercise or Are Overweight. PMID- 26036997 TI - The Role of EBPs in Behavioral Health Treatment. PMID- 26036995 TI - Gender Differences in the Effect of Depressive Symptoms on Prospective Alcohol Expectancies, Coping Motives, and Alcohol Outcomes in the First Year of College. AB - Problematic alcohol use and risk for dependence peak during late adolescence, particularly among first-year college students. Although students matriculating into college with depressive symptoms experience elevated risk for alcohol problems, few studies have examined the intervening mechanisms of risk. In this study, we examined depressed mood at college entry on prospective alcohol expectancies, drinking motives, and alcohol outcomes during the first year of college, adjusting for pre-college factors. Participants (N = 614; 59% female, 33% non-White) were incoming college students from three universities who completed online self-report surveys prior to matriculating into college and at the end of their first year in college. We utilized path analysis to test our hypotheses. In women, the path that linked depressive symptoms to consequences was primarily attributable to the effect of pre-college drinking to cope on drinking to cope in college, which in turn was associated with alcohol consequences. In men, the effect of depressive symptoms on alcohol consequences in college was independent of pre-college and college factors, thus indicating the need for research that identifies mechanisms of risk in males. Interventions that address coping deficits and motivations for drinking may be particularly beneficial for depressed adolescent females during this high-risk developmental period. PMID- 26037000 TI - Law & Psychiatry: Has the ADA Been Reborn as a Tool of Broad Community Change for People With Mental Disabilities? AB - Twenty-five years after enactment of the Americans with Disabilities Act (ADA), the U.S. Justice Department has begun to aggressively use the law to compel states to reform community care of individuals with mental disabilities. In this month's Law & Psychiatry column, the author highlights settlement agreements between Justice and the states of New York and Rhode Island that will produce sweeping changes in housing and employment for thousands of individuals with mental disabilities. Is the ADA's original promise finally being realized? The Americans with Disabilities Act (ADA) was enacted with the hope that it would result in the end of segregation based on disability. That promise has been only partially met. However, two recent settlement agreements between the U.S. Department of Justice and the states of New York and Rhode Island promise sweeping change in housing and employment for thousands of individuals with mental disabilities. This column describes the agreements, which adopt best practices as the foundation for community change and which suggest that the ADA may be reaching its full promise. PMID- 26036999 TI - Case studies in public-sector leadership: residency training transformation: a view from the frontline. AB - Psychiatrists of the future will be called upon to lead teams of clinicians in increasingly complex medical care systems, but will they be prepared for those roles? The authors of this column asked alumni of the Columbia University Public Psychiatry Fellowship (PPF) to identify important skills and knowledge that were not stressed in general residency education. "Silos are rampant in our work," complained one respondent, reflecting a common concern that not enough time was spent teaching residents to collaborate. PMID- 26037001 TI - Economic grand rounds: experience with mandated use of generic medications for patients covered by the mental health safety net. AB - Reducing pharmacy costs without increasing adverse outcomes would relieve some pressure on mental health budgets. This column describes the experience of a publicly funded provider network in a Michigan county that mandated generic use of psychotropic medications to address financial challenges. The percentage of brand-name medications and cost per prescription declined with the policy change, resulting in lower total pharmacy expenditures. No increase was noted in prescriptions per patient or psychiatric hospitalizations. Changes were sustained after the initial implementation period. Mandating generic use may be feasible as a tool for constraining pharmacy costs in mental health budgets. PMID- 26037002 TI - Commentary: not just variation in estimates: deinstitutionalization of the justice system. PMID- 26037003 TI - Correction. PMID- 26037004 TI - Infrastructure Change Is Not Enough: An Evaluation of SAMHSA's Mental Health Transformation State Incentive Grants. AB - OBJECTIVE: The authors evaluated the Substance Abuse and Mental Health Services Administration's mental health transformation state incentive grant program, which provided more than $100 million to nine states to make infrastructure changes designed to improve services and outcomes. METHODS: The authors measured infrastructure changes, service changes, and consumer outcomes in the nine programs. Although the federal program had no logic model, the authors adopted a model that hypothesized positive, but small, correlations between the program elements. RESULTS: There were few statistically significant correlations and a number of negative correlations between infrastructure changes, service changes, and consumer outcomes. CONCLUSIONS: Federal investments should take into account evidence that infrastructure changes alone do not necessarily contribute to better consumer outcomes, support operationally defined infrastructure improvements, require that service improvements accompany infrastructure changes, and provide sufficient resources to oversee grantee behaviors. In addition, future evaluation should support evaluation best practices. PMID- 26037005 TI - Potentially preventable medical hospitalizations among Maryland residents with mental illness, 2005-2010. AB - OBJECTIVE: The goal of this study was to assess the association between mental illness and potentially preventable ambulatory care-sensitive (ACS) hospitalizations among children, adults, and older adults. METHODS: This was a retrospective, cross-sectional study that used 2005-2010 Maryland hospital discharge data (N=508,142 hospitalizations). Logistic regression was used to assess the associations between mental illness and ACS hospitalizations. RESULTS: Any mental illness diagnosis was associated with heightened odds of ACS hospitalization in all three age groups. Any mental illness diagnosis was associated with 84% higher odds of ACS hospitalization among children, 32% higher odds of ACS hospitalization among adults, and 30% higher odds of ACS hospitalization among older adults. CONCLUSIONS: Mental illness was associated with increased odds of ACS hospitalization across the life span. Future research should examine the potential for integrated medical and behavioral health care models to address the poorly controlled somatic conditions that lead to ACS hospitalizations among persons with mental illness. PMID- 26037006 TI - Use of Software for Tablet Computers to Promote Engagement With Supported Employment: Results From an RCT. AB - OBJECTIVE: Information technology is opening up new ways to engage people who may benefit from psychiatric services. This study examined an intervention to promote engagement in supported employment for use with a tablet computer. METHODS: In a randomized controlled trial, 45 clients at an urban community mental health agency received a software application for use with a computer tablet and a brochure to promote engagement with supported employment services (N=22) or only the brochure (N=23). Engagement was defined as requesting and attending an in person meeting with an employment specialist within 30 days postintervention. RESULTS: Engagement was reported for 11 (50%) participants who received the tablet-based application and one participant (4%) who received only the brochure (odds ratio=22.95, 95% confidence interval=2.51-193.38). CONCLUSIONS: Mobile computer-based engagement interventions can promote initial contact between clients and employment specialists. PMID- 26037007 TI - Smoking cessation among people seeking mental health treatment. AB - OBJECTIVE: This study examined smoking cessation characteristics of smokers who reported seeking mental health treatment. METHODS: Data for adult current smokers (N=18,939) were combined from the 2000, 2005, and 2010 National Health Interview Survey. Multivariate regressions were used to assess associations between smoking cessation behaviors, cessation-related social norms, and mental health treatment. RESULTS: Smokers (N=1,897) who reported seeing mental health professionals for mental health problems had higher odds of having made attempts to quit in the past year (odds ratio [OR]=1.17), of having used nicotine replacement therapy (OR=1.28), and of using face-to-face counseling (OR=2.40), telephone quit lines (OR=1.81), and support groups (OR=1.63) to assist smoking cessation. They were more likely to have been advised by health professionals to quit smoking (OR=1.62) but less likely to live in a smoke-free home (OR=.78). Use of smoking cessation treatments and prevalence of smoke-free homes increased over the sampling period. CONCLUSIONS: Findings highlight the need for tailored efforts to reduce tobacco use among people with mental health problems. PMID- 26037008 TI - Bias blaster: a game to beat interpretation bias in psychosis. PMID- 26037009 TI - Psychiatric advance directives in traditional health systems. PMID- 26037010 TI - Stigma, race, and culture. PMID- 26037011 TI - Stigma, race, and culture: in reply. PMID- 26037013 TI - MIL-100 derived nitrogen-embodied carbon shells embedded with iron nanoparticles. AB - The use of metal-organic frameworks (MOFs) as templates and precursors to synthesize new carbon materials with controllable morphology and pre-selected heteroatom doping holds promise for applications as efficient non-precious metal catalysts. Here, we report a facile pyrolysis pathway to convert MIL-100 into nitrogen-doped carbon shells encapsulating Fe nanoparticles in a comparative study involving multiple selected nitrogen sources. The hierarchical porous architecture, embedded Fe nanoparticles, and nitrogen decoration endow this composite with a superior oxygen reduction activity. Furthermore, the excellent durability and high methanol tolerance even outperform the commercial Pt-C catalyst. PMID- 26037014 TI - Psychosocial factors impacting on life transitions among young adults with type 2 diabetes: an Australian - Danish qualitative study. AB - BACKGROUND: Type 2 diabetes (T2DM) prevalence is increasing rapidly worldwide with a significant increase in young adults. There is limited information about psychosocial and service needs of this group. AIM: To explore similarities and differences in how psychosocial factors impact on Australian and Danish young adults with T2DM and to identify unmet support needs during life transitions. METHOD: A qualitative approach was adopted using thematic content analysis of 26 in-depth semi-structured interviews. An inductive descriptive content analysis was undertaken using a comparative coding system. FINDINGS: Eligible participants were from Australia (12) and Denmark (14), aged 19-42 years who had T2DM for more than 10 months. In general, they reported diabetes management was difficult during transitions and diabetes self-care routines had to change to accommodate life changes. The underpinning sense of 'uncertainty' initiated by life transitions caused guilt that often resulted in low self-worth, anxiety and depression, which in turn had a negative impact on social and professional relationships. The participants emphasised the importance of connectedness to social networks, particularly with T2DM peers, and the need for flexible access to health professionals, age-specific tailored support and lower costs for Australians. Australian participants were more concerned than Danish participants about the cost associated with diabetes care and their ability to stay employed; hence, they were reluctant to disclose diabetes at work. CONCLUSION: T2DM had a similar impact on life transitions of Australian and Danish young adults with T2DM, suggesting health care needs to encompass managing life transitions. Participants had to cope with uncertainty and the impact of people's responses to diabetes, particularly at work and in relationships. Health professionals are urged to integrate these factors in care plans and education, which must be individualised and focus on the psychosocial aspects that operate during life transitions. PMID- 26037015 TI - Acyclovir-related kidney injury during alemtuzumab infusion. PMID- 26037016 TI - Deep brain stimulation for movement disorders: update on recent discoveries and outlook on future developments. AB - Modern deep brain stimulation (DBS) has become a routine therapy for patients with movement disorders such as Parkinson's disease, generalized or segmental dystonia and for multiple forms of tremor. Growing numbers of publications also report beneficial effects in other movement disorders such as Tourette's syndrome, various forms of chorea and DBS is even being studied for Parkinson's related dementia. While exerting remarkable effects on many motor symptoms, DBS does not restore normal neurophysiology and therefore may also have undesirable side effects including speech and gait deterioration. Furthermore, its efficacy might be compromised in the long term, due to progression of the underlying disease. Various programming strategies have been studied to try and address these issues, e.g., the use of low-frequency rather than high-frequency stimulation or the targeting of alternative brain structures such as the pedunculopontine nucleus. In addition, further technical developments will soon provide clinicians with an expanded choice of hardware such as segmented electrodes allowing for a steering of the current to optimize beneficial effects and reduce side effects as well as the possibility of adaptive stimulation systems based on closed-loop concepts with or without accompanying advances in programming and imaging software. In the present article, we will provide an update on the most recent achievements and discoveries relevant to the application of DBS in the treatment of movement disorder patients and give an outlook on future clinical and technical developments. PMID- 26037019 TI - Correction: Modifying a known gelator scaffold for nitrite detection. AB - Correction for 'Modifying a known gelator scaffold for nitrite detection' by Danielle M. Zurcher et al., Chem. Commun., 2014, 50, 7813-7816. PMID- 26037017 TI - Monogenic causes of stroke: now and the future. AB - Most stroke is multifactorial with multiple polygenic risk factors each conferring small increases in risk interacting with environmental risk factors, but it can also arise from mutations in a single gene. This review covers single gene disorders which lead to stroke as a major phenotype, with a focus on those which cause cerebral small vessel disease (SVD), an area where there has been significant recent progress with findings that may inform us about the pathogenesis of SVD more broadly. We also discuss the impact that next generation sequencing technology (NGST) is likely to have on clinical practice in this area. The most common form of monogenic SVD is cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, due to the mutations in the NOTCH3 gene. Several other inherited forms of SVD include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, retinal vasculopathy with cerebral leukodystrophy, collagen type IV alpha1 and alpha2 gene-related arteriopathy and FOXC1 deletion related arteriopathy. These monogenic forms of SVD, with overlapping clinical phenotypes, are beginning to provide insights into how the small arteries in the brain can be damaged and some of the mechanisms identified may also be relevant to more common sporadic SVD. Despite the discovery of these disorders, it is often challenging to clinically and radiologically distinguish between syndromes, while screening multiple genes for causative mutations that can be costly and time-consuming. The rapidly falling cost of NGST may allow quicker diagnosis of these rare causes of SVD, and can also identify previously unknown disease-causing variants. PMID- 26037018 TI - Cocaine self-administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine. AB - Dopaminergic projections from the ventral midbrain to the nucleus accumbens (NAc) have long been implicated in encoding associations between reward availability and environmental stimuli. As such, this circuit is instrumental in guiding behaviors towards obtaining maximal rewards based on previous experience. Cocaine acts on the dopamine system to exert its reinforcing effects and it is thought that cocaine-induced dysregulation of dopamine neurotransmission contributes to the difficulty that cocaine addicts exhibit in selecting environmentally appropriate behaviors. Here we used cocaine self-administration combined with in vivo fast scan cyclic voltammetry in anesthetised rats to examine the function of the ventral tegmental area to NAc projection neurons. Over 5 days of cocaine self administration (fixed-ratio 1; 1.5 mg/kg/injection; 40 injections/day), animals increased their rate of intake. Following cocaine self-administration, there was a marked reduction in ventral tegmental area-stimulated NAc dopamine release. Additionally, there was a decreased augmentation of stimulated dopamine overflow in response to a cocaine challenge. These findings demonstrate that cocaine induces a hypodopaminergic state, which may contribute to the inflexible drug taking and drug-seeking behaviors observed in cocaine abusers. Additionally, tolerance to the ability of cocaine to elevate dopamine may lead to increased cocaine intake in order to overcome decreased effects, another hallmark of cocaine abuse. PMID- 26037020 TI - Thermodynamic Study of Interactions Between ZnO and ZnO Binding Peptides Using Isothermal Titration Calorimetry. AB - While material-specific peptide binding sequences have been identified using a combination of combinatorial methods and computational modeling tools, a deep molecular level understanding of the fundamental principles through which these interactions occur and in some instances modify the morphology of inorganic materials is far from being fully realized. Understanding the thermodynamic changes that occur during peptide-inorganic interactions and correlating these to structural modifications of the inorganic materials could be the key to achieving and mastering control over material formation processes. This study is a detailed investigation applying isothermal titration calorimetry (ITC) to directly probe thermodynamic changes that occur during interaction of ZnO binding peptides (ZnO BPs) and ZnO. The ZnO-BPs used are reported sequences G-12 (GLHVMHKVAPPR), GT-16 (GLHVMHKVAPPR-GGGC), and alanine mutants of G-12 (G-12A6, G-12A11, and G-12A12) whose interaction with ZnO during solution synthesis studies have been extensively investigated. The interactions of the ZnO-BPs with ZnO yielded biphasic isotherms comprising both an endothermic and an exothermic event. Qualitative differences were observed in the isothermal profiles of the different peptides and ZnO particles studied. Measured DeltaG values were between -6 and 8.5 kcal/mol, and high adsorption affinity values indicated the occurrence of favorable ZnO-BP-ZnO interactions. ITC has great potential in its use to understand peptide-inorganic interactions, and with continued development, the knowledge gained may be instrumental for simplification of selection processes of organic molecules for the advancement of material synthesis and design. PMID- 26037021 TI - [Epigenetic regulation of urological tumors. Importance for prognosis and metastasis]. PMID- 26037022 TI - Colorimetric Detection of Creatinine Based on Plasmonic Nanoparticles via Synergistic Coordination Chemistry. AB - A simple and portable colorimetric assay for creatinine detection is fabricated based on the synergistic coordination of creatinine and uric acid with Hg(2+) on the surface of gold nanoparticles, which exhibits good selectivity and sensitivity. Point-of-care clinical creatinine monitoring can be supported for monitoring renal function and diagnosing corresponding renal diseases at home. PMID- 26037023 TI - Protozoal infections of the cornea and conjunctiva in dogs associated with chronic ocular surface disease and topical immunosuppression. AB - OBJECTIVE: To describe five cases of protozoal keratitis or conjunctivitis in dogs with chronic preexisting ocular surface disease treated with long-term immunosuppression. ANIMALS STUDIED: Five dogs that developed corneal or conjunctival mass lesions. PROCEDURES: The database of the Comparative Ocular Pathology Laboratory of Wisconsin was searched for canine cases diagnosed with corneal or conjunctival protozoal infection. Five cases were identified, and tissues were examined using routine and special histochemical stains: immunohistochemical labels for Neospora caninum, Toxoplasma gondii, and Leishmania spp., and tissue sample PCR for Leishmania spp., Trypanosoma cruzi, tissue coccidia (i.e., T. gondii/Sarcocystis/Neospora), piroplasms, trichomonads, and Acanthamoeba. Electron microscopy was performed for two cases, and serology for N. caninum and T. gondii was available for three cases. RESULTS: Preexisting ocular diseases included keratoconjunctivitis sicca and pigmentary keratitis (n = 4) and pyogranulomatous meibomian adenitis (n = 1). All dogs were treated with tacrolimus or cyclosporine for at least 1.2 years. Dogs were presented with fleshy corneal or conjunctival masses that were clinically suspected to be neoplastic (n = 4) or immune mediated (n = 1). Histologic examination revealed granulomatous inflammation with intralesional protozoal organisms. Amoeba (n = 2), T. gondii (n = 2), or Leishmania mexicana (n = 1) were identified using molecular techniques. Serological tests were negative. CONCLUSIONS: Protozoal keratitis and conjunctivitis without systemic involvement appears rare and may be associated with chronic preexisting ocular surface disease treated with long-term immunosuppression. Based upon clinical appearance, lesions could be confused with neoplasia. This is the first report of amoebic keratoconjunctivitis in dogs and of L. mexicana in dogs in the United States. PMID- 26037024 TI - Quality of Life and Late Complications After Minimally Invasive Compared to Open Esophagectomy: Results of a Randomized Trial. AB - BACKGROUND: The minimally invasive esophagectomy (MIE) is widely being implemented for esophageal cancer in order to reduce morbidity and improve quality of life. Non-randomized studies investigating the mid-term quality of life after MIE show conflicting results at 1-year follow-up. Therefore, the aim of this study is to determine whether MIE has a continuing better mid-term 1-year quality of life than open esophagectomy (OE) indicating both a faster recovery and less procedure-related symptoms. METHODS: A one-year follow-up analysis of the quality of life was conducted for patients participating in the randomized trial in which MIE was compared with OE. Late complications as symptomatic stenosis of anastomosis are also reported. RESULTS: Quality of life at 1 year was better in the MIE group than in the OE group for the physical component summary SF36 [50 (6; 48-53) versus 45 (9; 42-48) p .003]; global health C30 [79 (10; 76 83) versus 67 (21; 60-75) p .004]; and pain OES18 module [6 (9; 2-8) versus 16 (16; 10-22) p .001], respectively. Twenty six patients (44%) in the MIE and 22 patients (39%) in the OE group were diagnosed and treated for symptomatic stenosis of the anastomosis. CONCLUSIONS: This first randomized trial shows that MIE is associated with a better mid-term one-year quality of life compared to OE. PMID- 26037025 TI - Systematic Review of Surgical Literature from Resource-Limited Countries: Developing Strategies for Success. AB - BACKGROUND: Injuries and surgical diseases are leading causes of global mortality. We sought to identify successful strategies to augment surgical capacity and research endeavors in low-income countries (LIC's) based on existing peer-reviewed literature. METHODS: A systematic review of literature from or pertaining to LIC's from January 2002 to December 2011 was performed. Variables analyzed included type of intervention performed, research methodology, and publication demographics such as surgical specialty, partnerships involved, authorship contribution, place and journal of publication. FINDINGS: A total of 2049 articles met the inclusion criteria between 2002 and 2011. The two most common study methodologies performed were case series (44%) and case reports (18%). A total of 43% of publications were without outcome measures. Only 21% of all publications were authored by a collaboration of authors from low-income countries and developed country nationals. The five most common countries represented were Nepal (429), United States (408), England (170), Bangladesh (158), and Kenya (134). Furthermore, of countries evaluated, Nepal and Bangladesh were the only two with a specific national journal. INTERPRETATION: Based on the results of this research, the following recommendations were made: (1) Describe, develop, and stimulate surgical research through national peer-reviewed journals, (2) Foster centers of excellence to promote robust research competencies, (3) Endorse partnerships across regions and institutions in the promotion of global surgery, and (4) Build on outcome-directed research. PMID- 26037026 TI - Quantifying the Disability from Congenital Anomalies Averted Through Pediatric Surgery: A Cross-Sectional Comparison of a Pediatric Surgical Unit in Kenya and Canada. AB - BACKGROUND: Pediatric surgical practice is different in low- and middle-income countries as compared to North America. While resources are limited, the impact of pediatric surgical procedures is significant. The objective of this study was to calculate and compare disability-adjusted life years (DALYs) averted in a Kenyan and Canadian surgical unit for a subset of pediatric congenital anomalies. METHODS: Medical records of children having undergone surgical procedures for 13 congenital conditions in both surgical units were collected over 12 months. DALYs for each condition were calculated using previously obtained disability weights derived in each country. Age-adjusted life expectancy rates from the WHO were used to determine years of life lost. Risk of permanent disability without surgery and probability of successful treatment values were obtained from the literature and included in the DALY calculation. RESULTS: The conditions accounting for the largest total number of averted DALYs in Kenya were hydrocephalus (60.8%) and spina bifida (18.1%), whereas in Canada they were hydrocephalus (24.2%) and undescended testes (19.2%). A total of 23,169 DALYs were averted through 1042 surgical procedures (22.2 DALYs per procedure) during the study period in Kenya, compared to 5497 DALYs through 373 procedures (14.7 DALYs per procedure) in Canada. CONCLUSIONS: Using recent developments in burden of disease measurement, the results point to the significant impact of pediatric surgical centers in addressing the global burden of congenital surgical disease. The study carries significant implications for resource allocation and training. PMID- 26037027 TI - Adipose-derived stem cells for wound repair and regeneration. AB - INTRODUCTION: The use of undifferentiated cells for cell-based tissue repair and regeneration strategies represents a promising approach for chronic wound healing. Multipotent adult stem cells isolated from adipose tissue, termed adipose-derived stem cells (ASCs), appear to be an ideal population of stem cells because they are autologous, non-immunogenic, plentiful, and easily obtained. Both preclinical and clinical studies have revealed that ASCs have potential for wound healing due to the mechanisms described below. AREAS COVERED: Both in vitro and in vivo studies demonstrated that ASCs not only differentiate into keratinocytes, fibroblasts, and endothelial cells, as evidenced by their morphology, expression of cell surface markers, and gene expression, but also secrete several soluble factors, which positively contribute to wound healing in a paracrine manner. Clinical trials have been conducted using autologous ASCs with great success. EXPERT OPINION: There remain many concerns regarding the use of ASCs, including how these cells act as precursors of keratinocytes, fibroblasts, and endothelial cells, or as a secretion vehicle of soluble factors. Further studies are necessary to establish the optimal strategy for the treatment of chronic wounds in patients with different disease backgrounds. PMID- 26037029 TI - Proposition, identification, and experimental evaluation of an inverse dynamic neuromusculoskeletal model for the human finger. AB - PURPOSE: The purpose of this study is to develop an inverse dynamic model of the human middle finger in order to identify the muscle activation, muscle force, and neural activation of the muscles involved during motion. Its originality comes from the coupling of biomechanical and physiological models and the proposition of a dedicated optimization procedure and cost function for identifying the model unknowns. METHODS: Three sub-models work in interaction: the first is the biomechanical model, primarily consisting of the dynamic equations of the middle finger system; the second is the muscle model, which helps to identify the muscle force from muscle activation and dynamic deformation for six involved muscles. The third model allows one to link muscle activation to neural intent from the Central Nervous System (CNS). This modeling procedure leads to a complex analytical nonlinear system identified using multi-step energy minimization procedure and a specific cost function. RESULTS: Numerical simulations with different articulation velocities are presented and discussed. Then, experimental evaluation of the proposed model is performed following a protocol combining electromyography and motion capture during a hand opening-closing paradigm. After comparison, several results from the simulation and experiments were found to be in accordance. The difficulty in evaluating such complex dynamic models is also demonstrated. CONCLUSIONS: Despite the model simplifications, the obtained preliminary results are promising. Indeed, the proposed model, once correctly validated in future works, should be a relevant tool to simulate and predict deficiencies of the middle finger system for rehabilitation purposes. PMID- 26037030 TI - Practical use of medical terminology in curriculum mapping. AB - BACKGROUND: Various information systems for medical curriculum mapping and harmonization have been developed and successfully applied to date. However, the methods for exploiting the datasets captured inside the systems are rather lacking. METHOD: We reviewed the existing medical terminologies, nomenclatures, coding and classification systems in order to select the most suitable one and apply it in delivering visual analytic tools and reports for the benefit of medical curriculum designers and innovators. RESULTS: A formal description of a particular curriculum of general medicine is based on 1347 learning units covering 7075 learning outcomes. Two data-analytical reports have been developed and discussed, showing how the curriculum is consistent with the MeSH thesaurus and how the MeSH thesaurus can be used to demonstrate interconnectivity of the curriculum through association analysis. CONCLUSION: Although the MeSH thesaurus is designed mainly to index medical literature and support searching through bibliographic databases, we have proved its use in medical curriculum mapping as being beneficial for curriculum designers and innovators. The presented approach can be followed wherever needed to identify all the mandatory components used for transparent and comprehensive overview of medical curriculum data. PMID- 26037031 TI - Evidence for the relationship between the regulatory effects of microRNAs and attack robustness of biological networks. AB - It has been previously suggested that microRNAs (miRNAs) have a tendency to regulate the important components of biological networks. The goal of the present study was to systematically test if one can establish a relationship between miRNA targets and the important components of biological networks (including human protein-protein interaction network, signaling network and metabolic network). For this analysis, we have studied the attack robustness of these networks. It has been previously shown that deletion of network vertices in descending order of their importance (e.g., in decreasing order of vertex degrees) can affect the network structure much more considerably. In the current study, we introduced three miRNA-based measures of importance: "miRNA count" (i.e., the number of miRNAs that regulate a given network component); average adjacent miRNA count, "AAmiC" (i.e., the average number of miRNAs regulating the targeted components adjacent to a given component); and total adjacent miRNA count, "TAmiC" (i.e., the total number of miRNAs regulating the targeted components adjacent to a given component). Our results suggest that "miRNA count" is only marginally capable of locating the important components of the networks, while TAmiC was the most relevant measure. By comparing TAmiC with the classical centrality measures (which are solely based on the network structure) when simultaneously removing vertices, we show that this measure is correlated to degree and betweenness centrality measures, while its performance is generally better than that of closeness and eigenvector centrality measures. The results of this study suggest that TAmiC which represents a measure based on both network structure and biological knowledge, can successfully determine the important network components indicating that miRNA regulation and network robustness are related. PMID- 26037032 TI - Identifying brain functional alterations in postmenopausal women with cognitive impairment. AB - INTRODUCTION: Gender differences and menopause are associated with the cognitive decline and pathogenesis of Alzheimer's disease (AD). Although deficits of subcortical-cortical loops have been implicated in AD, no study has directly examined the resting-state brain functional alterations in postmenopausal women with mild cognitive impairment (MCI). METHODOLOGY: Forty-eight subjects were recruited, including 15 older females with MCI, 13 older females without MCI, 10 older males with MCI and 10 older males without MCI. Full-scale neuropsychological tests were used to evaluate cognitive function. Resting-state fMRI and the amplitude of low-frequency fluctuation (ALFF) approach were used to investigate changes in the brain function in these subjects. A voxel-wise analysis of variance (ANOVA: gender * disease) was performed, and gender-brain behavior relationships were further examined. RESULTS: First, older females with MCI showed cognitive dysfunction in multiple domains compared to normal controls. Second, the brain function of subcortical-cortical loops was disrupted in older females with MCI. Finally, regional resting-state function of the left precuneus was significantly associated with altered episodic memory in these female patients. CONCLUSIONS: This study revealed the patterns of neural networks in older females with cognitive disorders, and may provide new ideas and evidence regarding the mechanism of cognitive impairment in postmenopausal women. PMID- 26037033 TI - Cation-Specific Conformations in a Dual-Function Ion-Pumping Microbial Rhodopsin. AB - A recently discovered rhodopsin ion pump (DeNaR, also known as KR2) in the marine bacterium Dokdonia eikasta uses light to pump protons or sodium ions from the cell depending on the ionic composition of the medium. In cells suspended in a KCl solution, DeNaR functions as a light-driven proton pump, whereas in a NaCl solution, DeNaR conducts light-driven sodium ion pumping, a novel activity within the rhodopsin family. These two distinct functions raise the questions of whether the conformations of the protein differ in the presence of K(+) or Na(+) and whether the helical movements that result in the canonical E -> C conformational change in other microbial rhodopsins are conserved in DeNaR. Visible absorption maxima of DeNaR in its unphotolyzed (dark) state show an 8 nm difference between Na(+) and K(+) in decyl maltopyranoside micelles, indicating an influence of the cations on the retinylidene photoactive site. In addition, electronic paramagnetic resonance (EPR) spectra of the dark states reveal repositioning of helices F and G when K(+) is replaced with Na(+). Furthermore, the conformational changes assessed by EPR spin-spin dipolar coupling show that the light-induced transmembrane helix movements are very similar to those found in bacteriorhodopsin but are altered by the presence of Na(+), resulting in a new feature, the clockwise rotation of helix F. The results establish the first observation of a cation switch controlling the conformations of a microbial rhodopsin and indicate specific interactions of Na(+) with the half-channels of DeNaR to open an appropriate path for ion translocation. PMID- 26037034 TI - Genetic moderation of the association between adolescent romantic involvement and depression: Contributions of serotonin transporter gene polymorphism, chronic stress, and family discord. AB - Studies support a link between adolescent romantic involvement and depression. Adolescent romantic relationships may increase depression risk by introducing chronic stress, and genetic vulnerability to stress reactivity/emotion dysregulation may moderate these associations. We tested genetic moderation of longitudinal associations between adolescent romantic involvement and later depressive symptoms by a polymorphism in the serotonin transporter linked polymorphic region gene (5-HTTLPR) and examined contributory roles of chronic stress and family discord. Three hundred eighty-one youth participated at ages 15 and 20. The results indicated that 5-HTTLPR moderated the association between age 15 romantic involvement and age 20 depressive symptoms, with strongest effects for short homozygotes. Conditional process analysis revealed that chronic stress functioned as a moderated mediator of this association, fully accounting for the romantic involvement-depression link among short/short genotypes. Also, romantic involvement predicted later depressive symptoms most strongly among short-allele carriers with high family discord. The results have important implications for understanding the romantic involvement-depression link and the behavioral and emotional correlates of the 5-HTTLPR genotype. PMID- 26037035 TI - Intradermal insulin infusion achieves faster insulin action than subcutaneous infusion for 3-day wear. AB - Rapid uptake previously demonstrated by intradermal (ID) drug administration indicates compound delivery within the dermis may have clinical and pharmacological advantages for certain drug therapies. This study is the first clinical trial to evaluate continuous microneedle-based drug infusion, device wearability, and intradermal microneedle insulin kinetics over a multi-day (72 h) wear period. This was a single center, open-label, two-period crossover study in T1DM patients on continuous subcutaneous insulin infusion (CSII). Patients received treatment during interventional visits: one SC and one ID basal/bolus infusion of insulin aspart (NovoRapid(r) U-100) administered over 3 days in a randomized order. Twenty-eight patients were randomized and exposed to trial product, and 23 completed the study. Bolus insulin infusions were given prior to standardized breakfast and lunch test meals on each of the three treatment days. Blood samples were drawn at predefined time points for measurements of insulin aspart and blood glucose in serum. The primary endpoint insulin Tmax demonstrated that ID bolus infusion was associated with a significantly shorter Tmax with statistically significantly smaller intra-subject variability, compared to SC infusion, and this difference was maintained over three treatment days. Analyses of secondary PK endpoints corresponded with the primary endpoint findings. Postprandial glycemic response was significantly less pronounced after ID bolus: For most endpoints ID vs. SC, differences were statistically significant within the 0-1.5 or 0-2 h time period. Intradermal delivery of insulin is a viable delivery route alternative providing reduced time for insulin absorption with less intra-subject variability and lower glycemic response. PMID- 26037036 TI - Renal insufficiency is the leading cause of double maintenance (bevacizumab and pemetrexed) discontinuation for toxicity to advanced non-small cell lung cancer in real world setting. AB - OBJECTIVES: In advanced non-small cell lung cancer (NSCLC), maintenance therapy has emerged as a novel therapeutic reference for patients with non-progressive disease after platinum-based induction chemotherapy. However, the use of double maintenance (DM) with pemetrexed and bevacizumab is still being evaluated in terms of its clinical benefits and safety profile. The objective of this retrospective study was to describe the reasons for DM discontinuation in a real world setting. MATERIALS AND METHODS: Patients with advanced non-squamous NSCLC were eligible if they had received at least 4 cycles of induction chemotherapy, followed by at least 1 cycle of DM. They were identified by using the oncology pharmacy database of 17 French centers. RESULTS: Eighty-one patients who began a DM after induction chemotherapy were identified from September 2009 to April 2013. Among the 78 patients who had stopped DM at the time of the analysis, the main reasons for discontinuation were disease progression (42%), adverse events (33%), and personal preference (8%). The most frequent toxicity responsible for DM discontinuation was renal insufficiency (54%). CONCLUSION: For patients with advanced NSCLC eligible for DM therapy, a particular attention should be paid to potential renal failure. Kidney function should be monitored carefully before and during DM to detect and manage early this adverse event. PMID- 26037037 TI - Contrasting developmental axon regrowth and neurite sprouting of Drosophila mushroom body neurons reveals shared and unique molecular mechanisms. AB - The molecular mechanisms regulating intrinsic axon growth potential during development or following injury remain largely unknown despite their vast importance. Here, we have established a neurite sprouting assay of primary cultured mushroom body (MB) neurons. We used the MARCM technique to both mark and manipulate MB neurons, enabling us to quantify the sprouting abilities of single WT and mutant neurons originating from flies at different developmental stages. Sprouting of dissociated MB neurons was dependent on wnd, the DLK ortholog, a conserved gene that is required for axon regeneration. Next, and as expected, we found that the sprouting ability of adult MB neurons was significantly decreased. In contrast, and to our surprise, we found that pupal-derived neurons exhibit increased sprouting compared with neurons derived from larvae, suggesting the existence of an elevated growth potential state. We then contrasted the molecular requirements of neurite sprouting to developmental axon regrowth of MB gamma neurons, a process that we have previously shown requires the nuclear receptor UNF acting via the target of rapamycin (TOR) pathway. Strikingly, we found that while TOR was required for neurite sprouting, UNF was not. In contrast, we found that PTEN inhibits sprouting in adult neurons, suggesting that TOR is regulated by the PI3K/PTEN pathway during sprouting and by UNF during developmental regrowth. Interestingly, the PI3K pathway as well as Wnd were not required for developmental regrowth nor for initial axon outgrowth suggesting that axon growth during circuit formation, remodeling, and regeneration share some molecular components but differ in others. PMID- 26037038 TI - Complex abdominal wall defect reconstruction using a latissimus dorsi free flap with mesh after malignant tumor resection. AB - PURPOSE: Extended and full-thickness abdominal wall defects are commonly reconstructed using free flaps. Published surgical outcomes involving the latissimus dorsi (LD) free flap procedure are limited and are less numerous than those with free flaps involving the thigh. The aim of this report was to describe the immediate and long-term evaluation of complex abdominal wall reconstruction using a LD free flap with mesh. PATIENTS AND METHODS: Between 2005 and 2013, nine patients with extended malignant tumors of the abdominal wall underwent surgeries. After the surgical resection, the mean defect size was 385 cm2 (range: 190-650 cm2 ). Full-thickness abdominal wall reconstruction was performed with a combination of LD free flaps and meshes. The immediate and long-term outcomes were assessed regarding the complications, sustainable strength of the abdominal wall and cancer recurrence. RESULTS: The meshes measured 927 cm2 in average (range: 500-1036 cm2 ). Eight Parietex Composite(r) and 1 Bard Collamend Implant(r) were used. No donor site complications occurred, and complete LD flap survival was achieved without partial necrosis or thrombosis. One obese patient who received a porcine dermis mesh developed an eventration four days postoperatively and exhibited a limited amount of abdominal skin necrosis around the flap. Two patients died from cancer evolution. After a mean follow-up of 60.4 months (range: 29-94 months), clinical evaluation of the abdomen revealed 2 patients without anomalies, 4 cases of abdominal bulging without functional discomfort and 1 case of major abdominal distension. CONCLUSIONS: Complex abdominal reconstruction with LD free flap and mesh allows extended satisfactory coverage with a low incidence of flap and donor site complications. However, patients should be advised of the significant risk of abdominal bulging. (c) 2014 Wiley Periodicals, Inc. Microsurgery 37:38-43, 2017. PMID- 26037039 TI - Fatty acid composition of the ovine longissimus dorsi muscle: effect of feed restriction in three breeds of different origin. AB - BACKGROUND: Muscle fatty acid profile reflects the body condition of animals and has a noticeable effect on meat quality. Herein, longissimus dorsi muscle of three different sheep breeds, Damara (a fat-tailed breed), Dorper and Australian Merino sheep, was analysed for fatty acid composition. The three breeds were subjected to two distinctive feeding levels (ad libitum and restricted feeding) over 42 days. RESULTS: The Damara sheep revealed several differences compared to the other two breeds, namely a higher concentration of polyunsaturated fatty acids, which can be related to being a fat-tailed breed. Even in restricted feeding conditions, this breed revealed the highest levels compared to Merino and Dorper sheep respectively, of linoleic acid (+31% and +28%), linolenic acid (+97% and +51%), eicosapentaenoic acid (EPA) (+65% and +37%), docosapentanenoic acid (DPA) (+31% Merino) and dodosahexanenoic acid (DHA) (+63% and +77%). EPA, DPA and DHA are three omega-3 fatty acids, with described beneficial characteristics. CONCLUSION: With this work we show other qualities (higher levels of the omega-3 fatty acids, EPA, DPA and DHA) of Damara meat that might present this breed as an interesting alternative for animal production in semi-arid climates. PMID- 26037040 TI - Application of Photoreactive Barium Titanate (BaTiO3) Beam Fanning to the Photothermal Mirror Technique: An Experimental Analysis. AB - An adaptive spatial filter is used as an optical novelty filter to detect photothermal mirror (PM) signals in high absorbing materials using continuous wave laser excitation. The optical novelty filter uses an optical beam-fanning limiter based on single domain barium titanate (BaTiO3), cut and poled 45 degrees relative to the c-axis. The optical novelty filter approach relaxes the requirement for high sample surface smoothness because the effect aperture adapts to the surface, reducing the stationary background from the optical signal and provides a means of developing the photothermal mirror signal. Time-dependent probe laser phase shifts due to photothermal surface deformation pass through the optical novelty filter and are detected as an intensity increase over the stationary or "mundane" signal. Experimental studies are performed using four well-characterized metals using both the conventional photothermal mirror and optical novelty filter apparatuses in order to understand the complicated signal behavior. Signal behavior is analyzed in different excitation intervals using pseudo-chopped sample excitation with different duty cycles. Optical novelty filter signals show fast response for changes in the spatial beam profile followed by long relaxation time. Reasons for the optical novelty filter response are described. PMID- 26037041 TI - Factors that hinder community participation in developing and implementing comprehensive council health plans in Manyoni District, Tanzania. AB - BACKGROUND: Decentralization of public health planning is proposed to facilitate public participation in health issues. Health Sector Reform in Tanzania places emphasis on the participation of lower level health facilities and community in health planning process. Despite availability of policies, guidelines, and community representative organs, actual implementation of decentralization strategies is poorly achieved. This study intended to find out factors that hinder community participation in developing and implementing Comprehensive Council Health Plan (CCHP). MATERIALS AND METHODS: A qualitative approach was conducted in this study with key informants from Health Facility Governing Committees (HFGC), Council Health Service Board (CHSB), and Council Health Management Team (CHMT). Data were collected using in-depth interviews. Data generated were analyzed for themes and patterns. RESULTS: Factors that hindered community participation included lack of awareness on the CCHP among HFGC members, poor communication and information sharing between CHMT and HFGC, unstipulated roles and responsibilities of HFGC, lack of management capacity among HFGC members, and lack of financial resources for implementing HFGC activities. CONCLUSIONS: The identified challenges call for policy makers to revisit the decentralization by devolution policy by ensuring that local governance structures have adequate resources as well as autonomy to participate in planning and managing CCHP in general and health facility plans in particular. PMID- 26037042 TI - Test anxiety and United States Medical Licensing Examination scores. AB - BACKGROUND: Many medical students experience test anxiety, which may impair their performance in examinations. We examined the relationship between test anxiety and United States Medical Licensing Examination (USMLE) step-1 scores and determined the effect of a test-taking course on anxiety and USMLE scores. METHODS: We randomly chose second-year students to take a test-taking strategies course (cases) from among volunteers. The remainder of the class served as controls. We measured test anxiety with the Westside Test Anxiety Scale (with possible scores of 1-5). The cases completed the Westside Test Anxiety scale at baseline, after completing the course (4 weeks) and again after taking the USLME step 1 (10 weeks). The controls completed the instrument at baseline and after taking the USMLE step 1 (10 weeks). RESULTS: Ninety-three of 101 (92%) students participated in the study. The baseline test anxiety score for all students was 2.48 (SD 0.63). Test anxiety was inversely correlated with USMLE step 1 (beta = 0.24, p = 0.01), adjusting for Medical College Admission Test (MCAT) scores. The test anxiety score of the participants decreased from 2.79 to 2.61 after the course (p = 0.09), and decreased further to 2.53 after the USMLE (p = 0.02), whereas the scores of the controls increased. The mean USMLE step-1 score was 234 for the cases and 243 for the controls (p = 0.03). Many medical students experience test anxiety, which may impair their performance in examinations DISCUSSION: Test anxiety is modestly inversely correlated with USMLE step-1 scores. A test-taking strategy course modestly reduced anxiety, but did not improve USMLE scores. More robust interventions that achieve greater reductions in text anxiety may improve test scores. PMID- 26037044 TI - Theory for STM images of resonances in the near-field regime: application to adsorbates and local defects on graphene. AB - We analyze the STM current through electronic resonances on a substrate as a function of tip-surface distance. We show that when the tip approaches the surface a maximum of the density of states of the electronic resonance at some energy can lead to a dip of the STM signal dI/dV. This phenomenon is a Fano effect resulting from the coupling of the electronic states of the STM tip with the resonance. In graphene such resonances can be produced by local defects or adsorbates and we analyze the cases of top and hollow configurations of adsorbates. PMID- 26037043 TI - NLX-112, a novel 5-HT1A receptor agonist for the treatment of L-DOPA-induced dyskinesia: Behavioral and neurochemical profile in rat. AB - L-DOPA is the gold-standard treatment for Parkinson's disease (PD), but induces troublesome dyskinesia after prolonged treatment. This is associated with the 'false neurotransmitter' conversion of L-DOPA to dopamine by serotonin neurons projecting from the raphe to the dorsal striatum. Reducing their activity by targeting pre-synaptic 5-HT1A receptors should thus be an attractive therapeutic strategy, but previous 5-HT1A agonists have yielded disappointing results. Here, we describe the activity of a novel, highly selective and potent 5-HT1A agonist, NLX-112 (also known as befiradol or F13640) in rat models relevant to PD and its associated affective disorders. NLX-112 (0.16 mg/kg, i.p.) potently and completely reversed haloperidol-induced catalepsy in intact rats and abolished L DOPA-induced Abnormal Involuntary Movements (AIMs) in hemiparkinsonian rats, an effect that was reversed by the selective 5-HT1A antagonist, WAY100635. In microdialysis experiments, NLX-112 profoundly decreased striatal 5-HT extracellular levels, indicative of inhibition of serotonergic function. NLX-112 also blunted the L-DOPA-induced surge in dopamine levels on the lesioned side of the brain, an action that likely underlies its anti-dyskinetic effects. NLX-112 (0.16 mg/kg, i.p.) robustly induced rotations in hemiparkinsonian rats, suggesting that it has a motor facilitatory effect. Rotations were abolished by WAY100635 and were ipsilateral to the lesioned side, suggesting a predominant stimulation of the dopamine system on the non-lesioned side of the brain. NLX-112 also efficaciously reduced immobility time in the forced swim test (75% reduction at 0.16 mg/kg, i.p.) and eliminated stress-induced ultrasonic vocalization at 0.08 mg/kg, i.p., effects consistent with potential antidepressant- and anxiolytic-like properties. In other tests, NLX-112 (0.01-0.16 mg/kg, i.p.) did not impair the ability of L-DOPA to rescue forepaw akinesia in the cylinder test but decreased rotarod performance, probably due to induction of flat body posture and forepaw treading which are typical of 5-HT1A agonists upon acute administration. However, upon repeated administration of NLX-112 (0.63 mg/kg, i.p., twice a day), flat body posture and forepaw treading subsided within 4 days of treatment. Taken together, these observations suggest that NLX-112 could exhibit a novel therapeutic profile, combining robust anti-dyskinetic properties without impairing the therapeutic properties of L-DOPA, and with additional beneficial effects on non-motor (affective) symptoms. PMID- 26037045 TI - Establishment of Immortalized Mouse Bmp2 Knock-Out Dental Papilla Mesenchymal Cells Necessary for Study of Odontoblastic Differentiation and Odontogenesis. AB - Bmp2 is essential for dentin formation. Bmp2 cKO mice exhibited similar phenotype to dentinogenesis imperfecta, showing dental pulp exposure, hypomineralized dentin, and delayed odontoblast differentiation. As it is relatively difficult to obtain lot of primary Bmp2 cKO dental papilla mesenchymal cells and to maintain a long-term culture of these primary cells, availability of immortalized deleted Bmp2 dental papilla mesenchymal cells is critical for studying the underlying mechanism of Bmp2 signal in odontogenesis. In this study, our goal was to generate an immortalized deleted Bmp2 dental papilla mesenchymal (iBmp2(ko/ko)dp) cell line by introducing Cre recombinase and green fluorescent protein (GFP) into the immortalized mouse floxed Bmp2 dental papilla mesenchymal (iBmp2(fx/fx)dp) cells. iBmp2(ko/ko)dp cells were confirmed by GFP and PCR. The deleted Bmp2 cells exhibited slow cell proliferation rate and cell growth was arrested in G2 phase. Expression of tooth-related marker genes and cell differentiation were decreased in the deleted cells. Importantly, extracellular matrix remodeling was impaired in the iBmp2(ko/ko)dp cells as reflected by the decreased Mmp-9 expression. In addition, with exogenous Bmp2 induction, these cell differentiation and mineralization were rescued as well as extracellular matrix remodeling was enhanced. Therefore, we for the first time described establishment of iBmp(ko/ko) cells that are useful for study of mechanisms in regulating dental papilla mesenchymal cell lineages. PMID- 26037046 TI - An analysis of apparent diffusion coefficient in the myometrium of normal uterus between the menopausal and premenopausal phases. AB - OBJECTIVE: To investigate the apparent diffusion coefficients (ADCs) of normal uterine myometrium between menopausal phase and premenopausal phases (menstrual, proliferating and secretory phases). MATERIALS AND METHODS: Magnetic resonance images of 96 healthy women were obtained with a 3.0T MRI device. According to their physiological cycles, they were further divided into four groups: group A (menopausal phase), group B (menstrual phase), group C (proliferating phase), and group D (secretory phase). The ADC values were measured using a GE post processing workstation. Variations of the ADC values were compared among the four groups by statistical analysis. RESULTS: The ADC values of normal uterine myometrium were significantly different among the four groups [menopausal phase, (1.15 +/- 0.20) * 10(-3) mm(2)/s; menstrual phase, (1.89 +/- 0.35) * 10(-3) mm(2)/s; proliferative phase, (1.70 +/- 0.18) * 10(-3) mm(2)/s; secretory phase, (1.86 +/- 0.12) * 10(-3) mm(2)/s] (P < 0.001). The ADC values of myometrium in the menopausal phase were significantly lower than those in the premenopausal phase (P < 0.001). The ADC values of myometrium in the secretory phase were significantly greater than those in the proliferative phase (P < 0.05). No statistically significant differences were observed between the menstrual and secretory phase and between the menstrual and proliferating phase (P > 0.05). CONCLUSION: A wide variation of ADC values of normal myometrium was observed during four different physiological phases, and it should be taken into account by radiologists for diagnosis of uterine diseases, particularly in the menopausal phase. PMID- 26037047 TI - Long Noncoding RNAs in Lung Cancer. AB - Despite great progress in research and treatment options, lung cancer remains the leading cause of cancer-related deaths worldwide. Oncogenic driver mutations in protein-encoding genes were defined and allow for personalized therapies based on genetic diagnoses. Nonetheless, diagnosis of lung cancer mostly occurs at late stages, and chronic treatment is followed by a fast onset of chemoresistance. Hence, there is an urgent need for reliable biomarkers and alternative treatment options. With the era of whole genome and transcriptome sequencing technologies, long noncoding RNAs emerged as a novel class of versatile, functional RNA molecules. Although for most of them the mechanism of action remains to be defined, accumulating evidence confirms their involvement in various aspects of lung tumorigenesis. They are functional on the epigenetic, transcriptional, and posttranscriptional level and are regulators of pathophysiological key pathways including cell growth, apoptosis, and metastasis. Long noncoding RNAs are gaining increasing attention as potential biomarkers and a novel class of druggable molecules. It has become clear that we are only beginning to understand the complexity of tumorigenic processes. The clinical integration of long noncoding RNAs in terms of prognostic and predictive biomarker signatures and additional cancer targets could provide a chance to increase the therapeutic benefit. Here, we review the current knowledge about the expression, regulation, biological function, and clinical relevance of long noncoding RNAs in lung cancer. PMID- 26037048 TI - The Past, Present, and Future of NK Cells in Hematopoietic Cell Transplantation and Adoptive Transfer. AB - Hematopoietic cell transplantation (HCT) has been used as a part of cancer therapy for over half a decade. Beyond the necessity for donor-derived cells to reconstitute hematopoiesis after radiation and chemotherapy, immunologic reconstitution from allogeneic cells is important for the elimination of residual tumor cells. Natural killer (NK) cells are first among lymphocytes to reconstitute post-transplant and protect against cancer relapse. In this review, we provide a historical perspective on the role of NK cells in cancer control in the transplant setting and focus on current research aimed at improving NK cell responses for therapeutic benefit. PMID- 26037049 TI - Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy. AB - Protein disulfide isomerase (PDI) family members including PDI and ERp57 emerge as novel targets for anti-thrombotic treatments, but chemical agents with selectivity remain to be explored. We previously reported a novel derivative of danshensu (DSS), known as ADTM, displayed strong cardioprotective effects against oxidative stress-induced cellular injury in vitro and acute myocardial infarct in vivo. Herein, using chemical proteomics approach, we identified ERp57 as a major target of ADTM. ADTM displayed potent inhibitory effects on the redox activity of ERp57, inhibited the adenosine diphosphate (ADP)-induced expressions of P selectin and alphaIIbbeta3 integrin, and disrupted the interaction between ERp57 and alphaIIbbeta3. In addition, ADTM inhibited both arachidonic acid (AA)-induced and ADP-induced platelet aggregation in vitro. Furthermore, ADTM significantly inhibited rat platelet aggregation and thrombus formation in vivo. Taken together, ADTM represents a promising candidate for anti-thrombotic therapy targeting ERp57. PMID- 26037051 TI - Development and validation of a brain maturation index using longitudinal neuroanatomical scans. AB - BACKGROUND: Major psychiatric disorders are increasingly being conceptualized as 'neurodevelopmental', because they are associated with aberrant brain maturation. Several studies have hypothesized that a brain maturation index integrating patterns of neuroanatomical measurements may reliably identify individual subjects deviating from a normative neurodevelopmental trajectory. However, while recent studies have shown great promise in developing accurate brain maturation indices using neuroimaging data and multivariate machine learning techniques, this approach has not been validated using a large sample of longitudinal data from children and adolescents. METHODS: T1-weighted scans from 303 healthy subjects aged 4.88 to 18.35years were acquired from the National Institute of Health (NIH) pediatric repository (http://www.pediatricmri.nih.gov). Out of the 303 subjects, 115 subjects were re-scanned after 2years. The least absolute shrinkage and selection operator algorithm (LASSO) was 'trained' to integrate neuroanatomical changes across chronological age and predict each individual's brain maturity. The resulting brain maturation index was developed using first visit scans only, and was validated using second-visit scans. RESULTS: We report a high correlation between the first-visit chronological age and brain maturation index (r=0.82, mean absolute error or MAE=1.69years), and a high correlation between the second-visit chronological age and brain maturation index (r=0.83, MAE=1.71years). The brain maturation index captured neuroanatomical volume changes between the first and second visits with an MAE of 0.27years. CONCLUSIONS: The brain maturation index developed in this study accurately predicted individual subjects' brain maturation longitudinally. Due to its strong clinical potentials in identifying individuals with an abnormal brain maturation trajectory, the brain maturation index may allow timely clinical interventions for individuals at risk for psychiatric disorders. PMID- 26037050 TI - N-acetyl-aspartate levels correlate with intra-axonal compartment parameters from diffusion MRI. AB - Diffusion MRI combined with biophysical modeling allows for the description of a white matter (WM) fiber bundle in terms of compartment specific white matter tract integrity (WMTI) metrics, which include intra-axonal diffusivity (Daxon), extra-axonal axial diffusivity (De||), extra-axonal radial diffusivity (De?), axonal water fraction (AWF), and tortuosity (alpha) of extra-axonal space. Here we derive these parameters from diffusion kurtosis imaging to examine their relationship to concentrations of global WM N-acetyl-aspartate (NAA), creatine (Cr), choline (Cho) and myo-Inositol (mI), as measured with proton MR spectroscopy ((1)H-MRS), in a cohort of 25 patients with mild traumatic brain injury (MTBI). We found statistically significant (p<0.05) positive correlations between NAA and Daxon, AWF, alpha, and fractional anisotropy; negative correlations between NAA and De,? and the overall radial diffusivity (D?). These correlations were supported by similar findings in regional analysis of the genu and splenium of the corpus callosum. Furthermore, a positive correlation in global WM was noted between Daxon and Cr, as well as a positive correlation between De|| and Cho, and a positive trend between De|| and mI. The specific correlations between NAA, an endogenous probe of the neuronal intracellular space, and WMTI metrics related to the intra-axonal space, combined with the specific correlations of De|| with mI and Cho, both predominantly present extra axonally, corroborate the overarching assumption of many advanced modeling approaches that diffusion imaging can disentangle between the intra- and extra axonal compartments in WM fiber bundles. Our findings are also generally consistent with what is known about the pathophysiology of MTBI, which appears to involve both intra-axonal injury (as reflected by a positive trend between NAA and Daxon) as well as axonal shrinkage, demyelination, degeneration, and/or loss (as reflected by correlations between NAA and De?, AWF, and alpha). PMID- 26037052 TI - Co-activation Probability Estimation (CoPE): An approach for modeling functional co-activation architecture based on neuroimaging coordinates. AB - Recent progress in functional neuroimaging has prompted studies of brain activation during various cognitive tasks. Coordinate-based meta-analysis has been utilized to discover the brain regions that are consistently activated across experiments. However, within-experiment co-activation relationships, which can reflect the underlying functional relationships between different brain regions, have not been widely studied. In particular, voxel-wise co-activation, which may be able to provide a detailed configuration of the co-activation network, still needs to be modeled. To estimate the voxel-wise co-activation pattern and deduce the co-activation network, a Co-activation Probability Estimation (CoPE) method was proposed to model within-experiment activations for the purpose of defining the co-activations. A permutation test was adopted as a significance test. Moreover, the co-activations were automatically separated into local and long-range ones, based on distance. The two types of co-activations describe distinct features: the first reflects convergent activations; the second represents co-activations between different brain regions. The validation of CoPE was based on five simulation tests and one real dataset derived from studies of working memory. Both the simulated and the real data demonstrated that CoPE was not only able to find local convergence but also significant long-range co activation. In particular, CoPE was able to identify a 'core' co-activation network in the working memory dataset. As a data-driven method, the CoPE method can be used to mine underlying co-activation relationships across experiments in future studies. PMID- 26037054 TI - Quantification of voxel-wise total fibre density: Investigating the problems associated with track-count mapping. AB - A biological parameter that would be valuable to be able to extract from diffusion MRI data is the local white matter axonal density. Track-density imaging (TDI) has been used as if it could provide such a measure; however, this has been the subject of controversy, primarily due to the fact that track-count quantitation is highly sensitive to tracking biases and errors. The spherical deconvolution informed filtering of tractograms (SIFT) post-processing method was recently introduced to minimise tractography biases, and thus provides a more biologically meaningful measure that could be used in track-count mapping (i.e. TDI following SIFT). The TDI intensity following SIFT ideally corresponds to the orientational average of the fibre orientation distribution (FOD), which corresponds to the total Apparent Fibre Density (AFDtotal) within the AFD framework; in fact, AFDtotal provides a direct measure of local fibre density at native resolution that does not rely on fibre-tracking. In this study, we demonstrate problems associated with quantitative TDI investigations, which can be avoided by using SIFT processing or directly by using AFDtotal maps. We also characterise the intra- and inter-subject reproducibility of TDI maps (with and without SIFT pre-processing) and AFDtotal maps. It is shown that SIFT improves the quantitative characteristics of TDI, but is still vastly inferior to the properties of the AFDtotal parameter itself, because the latter does not require tracking. While standard TDI might be preferable in applications when high anatomical contrast is required, particularly when combined with super resolution, for voxel-wise quantitation of total tract density (i.e. without tract orientation information) at native resolution, the total AFD maps are preferable to TDI or other related track-count maps. Regardless of the track count measure, it should be noted that all of these voxel-averaged approaches discard important information that is retained in fibre-specific approaches such as AFD. PMID- 26037053 TI - 4D MEMRI atlas of neonatal FVB/N mouse brain development. AB - The widespread use of the mouse as a model system to study brain development has created the need for noninvasive neuroimaging methods that can be applied to early postnatal mice. The goal of this study was to optimize in vivo three- (3D) and four-dimensional (4D) manganese (Mn)-enhanced MRI (MEMRI) approaches for acquiring and analyzing data from the developing mouse brain. The combination of custom, stage-dependent holders and self-gated (motion-correcting) 3D MRI sequences enabled the acquisition of high-resolution (100-MUm isotropic), motion artifact-free brain images with a high level of contrast due to Mn-enhancement of numerous brain regions and nuclei. We acquired high-quality longitudinal brain images from two groups of FVB/N strain mice, six mice per group, each mouse imaged on alternate odd or even days (6 3D MEMRI images at each day) covering the developmental stages between postnatal days 1 to 11. The effects of Mn-exposure, anesthesia and MRI were assessed, showing small but significant transient effects on body weight and brain volume, which recovered with time and did not result in significant morphological differences when compared to controls. Metrics derived from deformation-based morphometry (DBM) were used for quantitative analysis of changes in volume and position of a number of brain regions. The cerebellum, a brain region undergoing significant changes in size and patterning at early postnatal stages, was analyzed in detail to demonstrate the spatiotemporal characterization made possible by this new atlas of mouse brain development. These results show that MEMRI is a powerful tool for quantitative analysis of mouse brain development, with great potential for in vivo phenotype analysis in mouse models of neurodevelopmental diseases. PMID- 26037055 TI - Dual-echo fMRI can detect activations in inferior temporal lobe during intelligible speech comprehension. AB - The neural basis of speech comprehension has been investigated intensively during the past few decades. Incoming auditory signals are analysed for speech-like patterns and meaningful information can be extracted by mapping these sounds onto stored semantic representations. Investigation into the neural basis of speech comprehension has largely focused on the temporal lobe, in particular the superior and posterior regions. The ventral anterior temporal lobe (vATL), which includes the inferior temporal gyrus (ITG) and temporal fusiform gyrus (TFG) is consistently omitted in fMRI studies. In contrast, PET studies have shown the involvement of these ventral temporal regions. One crucial factor is the signal loss experienced using conventional echo planar imaging (EPI) for fMRI, at tissue interfaces such as the vATL. One method to overcome this signal loss is to employ a dual-echo EPI technique. The aim of this study was to use intelligible and unintelligible (spectrally rotated) sentences to determine if the vATL could be detected during a passive speech comprehension task using a dual-echo acquisition. A whole brain analysis for an intelligibility contrast showed bilateral superior temporal lobe activations and a cluster of activation within the left vATL. Converging evidence implicates the same ventral temporal regions during semantic processing tasks, which include language processing. The specific role of the ventral temporal region during intelligible speech processing cannot be determined from this data alone, but the converging evidence from PET, MEG, TMS and neuropsychology strongly suggest that it contains the stored semantic representations, which are activated by the speech decoding process. PMID- 26037056 TI - A diffusion tensor MRI atlas of the postmortem rhesus macaque brain. AB - The rhesus macaque (Macaca mulatta) is the most widely used nonhuman primate for modeling the structure and function of the brain. Brain atlases, and particularly those based on magnetic resonance imaging (MRI), have become important tools for understanding normal brain structure, and for identifying structural abnormalities resulting from disease states, exposures, and/or aging. Diffusion tensor imaging (DTI)-based MRI brain atlases are widely used in both human and macaque brain imaging studies because of the unique contrasts, quantitative diffusion metrics, and diffusion tractography that they can provide. Previous MRI and DTI atlases of the rhesus brain have been limited by low contrast and/or low spatial resolution imaging. Here we present a microscopic resolution MRI/DTI atlas of the rhesus brain based on 10 postmortem brain specimens. The atlas includes both structural MRI and DTI image data, a detailed three-dimensional segmentation of 241 anatomic structures, diffusion tractography, cortical thickness estimates, and maps of anatomic variability among atlas specimens. This atlas incorporates many useful features from previous work, including anatomic label nomenclature and ontology, data orientation, and stereotaxic reference frame, and further extends prior analyses with the inclusion of high-resolution multi-contrast image data. PMID- 26037057 TI - First-in-human PET quantification study of cerebral alpha4beta2* nicotinic acetylcholine receptors using the novel specific radioligand (-) [(18)F]Flubatine. AB - alpha4beta2* nicotinic receptors (alpha4beta2* nAChRs) could provide a biomarker in neuropsychiatric disorders (e.g., Alzheimer's and Parkinson's diseases, depressive disorders, and nicotine addiction). However, there is a lack of alpha4beta2* nAChR specific PET radioligands with kinetics fast enough to enable quantification of nAChR within a reasonable time frame. Following on from promising preclinical results, the aim of the present study was to evaluate for the first time in humans the novel PET radioligand (-)-[(18)F]Flubatine, formerly known as (-)-[(18)F]NCFHEB, as a tool for alpha4beta2* nAChR imaging and in vivo quantification. Dynamic PET emission recordings lasting 270min were acquired on an ECAT EXACT HR+ scanner in 12 healthy male non-smoking subjects (71.0+/ 5.0years) following the intravenous injection of 353.7+/-9.4MBq of (-) [(18)F]Flubatine. Individual magnetic resonance imaging (MRI) was performed for co-registration. PET frames were motion-corrected, before the kinetics in 29 brain regions were characterized using 1- and 2-tissue compartment models (1TCM, 2TCM). Given the low amounts of metabolite present in plasma, we tested arterial input functions with and without metabolite corrections. In addition, pixel-based graphical analysis (Logan plot) was used. The model's goodness of fit, with and without metabolite correction was assessed by Akaike's information criterion. Model parameters of interest were the total distribution volume VT (mL/cm(3)), and the binding potential BPND relative to the corpus callosum, which served as a reference region. The tracer proved to have high stability in vivo, with 90% of the plasma radioactivity remaining as untransformed parent compound at 90min, fast brain kinetics with rapid uptake and equilibration between free and receptor bound tracer. Adequate fits of brain TACs were obtained with the 1TCM. VT could be reliably estimated within 90min for all regions investigated, and within 30min for low-binding regions such as the cerebral cortex. The rank order of VT by region corresponded well with the known distribution of alpha4beta2* receptors (VT [thalamus] 27.4+/-3.8, VT [putamen] 12.7+/-0.9, VT [frontal cortex] 10.0+/ 0.8, and VT [corpus callosum] 6.3+/-0.8). The BPND, which is a parameter of alpha4beta2* nAChR availability, was 3.41+/-0.79 for the thalamus, 1.04+/-0.25 for the putamen and 0.61+/-0.23 for the frontal cortex, indicating high specific tracer binding. Use of the arterial input function without metabolite correction resulted in a 10% underestimation in VT, and was without important biasing effects on BPND. Altogether, kinetics and imaging properties of (-) [(18)F]Flubatine appear favorable and suggest that (-)-[(18)F]Flubatine is a very suitable and clinically applicable PET tracer for in vivo imaging of alpha4beta2* nAChRs in neuropsychiatric disorders. PMID- 26037058 TI - Anaerobic digestion of paunch in a CSTR for renewable energy production and nutrient mineralization. AB - A laboratory study investigated the anaerobic digestion of paunch in a continuous stirred tank reactor (CSTR) for the recovery of biogas and mineralization of nutrients. At an organic loading rate (OLR) of 2.8gVSL(-1)day(-1) with a 30-day hydraulic retention time (HRT), a CH4 yield of 0.213Lg(-1)VS and CH4 production rate of 0.600LL(-1)day(-1) were obtained. Post-anaerobic digestion of the effluent from the CSTR for 30days at 40 degrees C recovered 0.067Lg(-1)VS as CH4, which was 21% of the batch CH4 potential. Post-digestion of the effluent from the digestate obtained at this OLR is needed to meet the stable effluent criteria. Furthermore, low levels of soluble ions such as K(+), Ca(2+) and Mg(2+) were found in the liquid fraction of the digestate and the remainder could have been retained in the solid digestate fraction. This study demonstrates the potential of biogas production from paunch in providing renewable energy. In addition, recovery of plant nutrients in the digestate is important for a sustainable agricultural system. PMID- 26037059 TI - High-grade epithelial-myoepithelial carcinoma of the parotid gland with mucous cell differentiation. AB - Epithelial-myoepithelial carcinoma (EMC) is a rare salivary gland tumor with a low-grade malignancy, and EMC with high-grade histopathological features is exceedingly rare. Furthermore, EMC with intracellular mucin is also extremely rare. We report an uncommon case of a high-grade EMC of the parotid gland with mucous cell differentiation in a 66-year old Japanese woman who noticed a right palpable parotid mass increasing in size within a one-year period. The cytological specimen showed a focally biphasic structure and included isolated or discohesive piled-up clusters with hyaline globules surrounded by neoplastic cells with nuclear atypia. The gross examination revealed a relatively well demarcated, multinodular gray-whitish and solid mass. Histologically, the tumor consisted of variably sized solid nests or trabeculae with central necrosis and increased mitotic activity, and invaded into adjacent skeletal muscles. Immunohistochemically, the biphasic ductal and myoepithelial differentiation of this tumor confirmed the diagnosis of high-grade EMC. Furthermore, numerous small nests with d-PAS and alcian blue-positive mucous cells predominated in about 5% of the whole tumor, and these mucous cells were encompassed by neoplastic myoepithelial cells. We should recognize this variant of EMC because we can't rule out the possibility of EMC even in the presence of mucous cells. PMID- 26037060 TI - A hierarchical algorithm for molecular similarity (H-FORMS). AB - A new hierarchical method to determine molecular similarity is introduced. The goal of this method is to detect if a pair of molecules has the same structure by estimating a rigid transformation that aligns the molecules and a correspondence function that matches their atoms. The algorithm firstly detect similarity based on the global spatial structure. If this analysis is not sufficient, the algorithm computes novel local structural rotation-invariant descriptors for the atom neighborhood and uses this information to match atoms. Two strategies (deterministic and stochastic) on the matching based alignment computation are tested. As a result, the atom-matching based on local similarity indexes decreases the number of testing trials and significantly reduces the dimensionality of the Hungarian assignation problem. The experiments on well known datasets show that our proposal outperforms state-of-the-art methods in terms of the required computational time and accuracy. PMID- 26037062 TI - Why we should help people understand our scientific literature. PMID- 26037061 TI - Investigating the origin and global dispersal history of hepatitis E virus genotype 4 using phylogeographical analysis. AB - BACKGROUND & AIMS: Hepatitis E virus (HEV) genotype 4 has mainly been isolated from sporadic hepatitis cases and swine in Asian countries. We analysed the origin and global dispersal history of genotype 4 using a Bayesian phylogeographical approach. METHODS: The 412-nucleotide sequences of open reading frame 2 of genotype 4 (47 Japanese, 40 Chinese, 1 Indian, 8 Indonesian, 1 Korean, 1 Taiwanese, 2 Danish and 2 Italian), of which sampling date and location were known, were collected. Evolutionary rate, divergence time, demographic growth and phylogeography were co-estimated in the Bayesian statistical inference framework implemented in the BEAST package to model spatial dispersal on a time-scaled genealogy. RESULTS: The most probable origin of genotype 4 was Japan and the time of origin was 1909 (95% highest posterior density, 1871-1940). Seven lineages of genotype 4 migrated from Japan to China. The analysis also showed the migration of genotype 4 from Japan or China to India and Indonesia and from China to Indonesia, Taiwan, Korea and a few European countries. CONCLUSIONS: Swine trade between countries coincided with the migration time and direction of genotype 4 in some cases and was considered the primary cause of dispersal. However, there was no clear cause of dispersal for some cases, for which no records of pig trade were found. Future research should analyse additional nucleotide sequences paired with epidemiological data from various countries to improve our understanding of HEV dispersal. PMID- 26037063 TI - The association between microRNA-323b polymorphism and hepatitis B virus persistent infection - some problems should be addressed. PMID- 26037064 TI - The association between microRNA-323b polymorphism and hepatitis B virus persistent infection - some problems should be addressed. PMID- 26037066 TI - [3+2] Redox-Neutral Cycloaddition of Nitrocyclopropanes with Styrenes by Visible Light Photocatalysis. AB - The first nitro-group-initiated redox-neutral [3+2] cycloaddition of nitrocyclopropanes with alkenes by using visible-light-absorbing transition-metal complexes was reported. High diastereoselectivities were observed for two quaternary carbon centers on the ring and validated by DFT calculations. Spiro- or polycyclic structures can be constructed smoothly. Cyclic gamma-amino acid derivatives and polysubstituted cyclic amino alcohols can be obtained easily through reduction of the nitro group. PMID- 26037065 TI - Apoptosis associated with Wnt/beta-catenin pathway leads to steroid-induced avascular necrosis of femoral head. AB - BACKGROUND: The objective of the current study was to establish a rat model to investigate apoptosis in steroid-induced femoral head osteonecrosis occurring via the Wnt/beta-catenin pathway. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into a control group (group A), model group (group B) and sFRP1 group (group C), each consisting of 24 rats, and the rats were intravenously injected with LPS (10 MUg/kg body weight). After 24 h, three injections of MPS (20 mg/kg body weight) were administered intramuscularly at 24-h intervals. The rats in group C were injected intramuscularly with 1 MUg/kg sFRP1 protein per day for 30 days, beginning at the time of the first MPS administration. The group A rats were fed and housed under identical conditions but received saline injection. All animals were sacrificed at weeks 2, 4 and 8 from the first MPS injection. Histopathological staining was preformed to evaluated osteonecrosis. Apoptosis was detected via quantitative terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate nick-end labelling (TUNEL) staining, caspase-3 activity assay, and detection of Bcl-2 and Bax protein expression by immunohistochemistry and Western blotting. Wnt/beta-catenin pathway signalling molecules, including activated beta-catenin and c-Myc, were detected by immunohistochemistry and Western blotting. RESULTS: Typical osteonecrosis was observed in groups B and C. Apoptosis gradually increased with increasing time in both groups B and C. More severe osteonecrosis and apoptosis were observed in group C compared with group B. The expression levels of caspase-3 and Bax were higher while that of Bcl-2 was lower in group C compared with group B. The expression levels of activated beta-catenin and c-Myc gradually decreased with increasing time in both groups B and C, and they were lower in group C compared with group B. CONCLUSIONS: The Wnt/beta-catenin pathway is involved in the pathogenesis of early stage SANFH, as we have demonstrated in an SANFH rat model, and it may act through the regulation of c-Myc, which affects the cell cycle and cell apoptosis. PMID- 26037067 TI - Dumbbell stanane: a large-gap quantum spin hall insulator. AB - A quantum spin Hall (QSH) effect is quite promising for applications in spintronics and quantum computations, but at present, can only be achieved at ultralow temperatures. The determination of large-gap QSH insulators is critical to increase the operating temperature. By using first-principles calculations, we demonstrate that the stable hydrogenated stanene with a dumbbell-like structure (DB stanane) has large topological nontrivial band gaps of 312 meV (Gamma point) and 160 meV for the bulk, characterized by a topological invariant of Z2 = 1 because of s-pxy band inversion. Helical gapless edge states appear in the nanoribbon structures with high Fermi velocity comparable to that of graphene. The nontrivial topological states are robust against the substrate effects. The realization of this material is a feasible solution for the applications of QSH effects at room temperature and can be beneficial in the fabrication of high speed spintronics devices. PMID- 26037068 TI - Recent progresses in the exploration of machine learning methods as in-silico ADME prediction tools. AB - In-silico methods have been explored as potential tools for assessing ADME and ADME regulatory properties particularly in early drug discovery stages. Machine learning methods, with their ability in classifying diverse structures and complex mechanisms, are well suited for predicting ADME and ADME regulatory properties. Recent efforts have been directed at the broadening of application scopes and the improvement of predictive performance with particular focuses on the coverage of ADME properties, and exploration of more diversified training data, appropriate molecular features, and consensus modeling. Moreover, several online machine learning ADME prediction servers have emerged. Here we review these progresses and discuss the performances, application prospects and challenges of exploring machine learning methods as useful tools in predicting ADME and ADME regulatory properties. PMID- 26037069 TI - Are EGF and TLR-4 crucial to understanding the link between milk and NEC? PMID- 26037071 TI - Influence of Aromatic Residues on the Material Characteristics of Abeta Amyloid Protofibrils at the Atomic Scale. AB - Amyloid fibrils, which cause a number of degenerative diseases, are insoluble under physiological conditions and are supported by native contacts. Recently, the effects of the aromatic residues on the Abeta amyloid protofibril were investigated in a ThT fluorescence study. However, the relationship between the material characteristics of the Abeta protofibril and its aromatic residues has not yet been investigated on the atomic scale. Here, we successfully constructed wild-type (WT) and mutated types of Abeta protofibrils by using molecular dynamics simulations. Through principle component analysis, we established the structural stability and vibrational characteristics of F20L Abeta protofibrils and compared them with WT and other mutated models such as F19L and F19LF20L. In addition, structural stability was assessed by calculating the elastic modulus, which showed that the F20L model has higher values than the other models studied. From our results, it is shown that aromatic residues influence the structural and material characteristics of Abeta protofibrils. PMID- 26037070 TI - A critical role for cellular inhibitor of protein 2 (cIAP2) in colitis-associated colorectal cancer and intestinal homeostasis mediated by the inflammasome and survival pathways. AB - Cellular inhibitors of apoptosis proteins (cIAPs) are critical arbiters of cell death and key mediators of inflammation and innate immunity. cIAP2 is frequently overexpressed in colorectal cancer and in regenerating crypts of ulcerative colitis patients. However, its corresponding functions in intestinal homeostasis and underlying mechanisms in disease pathogenesis are poorly understood. We found that mice deficient in cIAP2 exhibited reduced colitis-associated colorectal cancer tumor burden but, surprisingly, enhanced susceptibility to acute and chronic colitis. The exacerbated colitis phenotype of cIAP2-deficient mice was mediated by increased cell death and impaired activation of the regenerative inflammasome-interleukin-18 (IL-18) pathway required for tissue repair following injury. Accordingly, administration of recombinant IL-18 or pharmacological inhibition of caspases or the kinase RIPK1 protected cIAP2-deficient mice from colitis and restored intestinal epithelial barrier architecture. Thus, cIAP2 orchestrates intestinal homeostasis by exerting a dual function in suppressing cell death and promoting intestinal epithelial cell proliferation and crypt regeneration. PMID- 26037072 TI - Design, synthesis, and functional evaluation of CO-releasing molecules triggered by Penicillin G amidase as a model protease. AB - Protease-triggered CO-releasing molecules (CORMs) were developed. The viability of the approach was demonstrated through the synthesis of compounds consisting of an eta(4) -oxydiene-Fe(CO)3 moiety connected to a penicillin G amidase (PGA) cleavable unit through a self-immolative linker. The rate of PGA-induced hydrolysis was investigated by HPLC analysis and the subsequent CO release was quantitatively assessed through headspace gas chromatography. In an in vitro assay with human endothelial cells, typical biological effects of CO, that is, inhibition of the inflammatory response and the induction of heme oxygenase-1 expression, were observed only upon co-administration of the CORM and PGA. This work forms a promising basis for the future development of protease-specific CORMs for potential medicinal applications. PMID- 26037073 TI - The relationship between body mass index and uric acid: a study on Japanese adult twins. AB - OBJECTIVES: The present study aimed to investigate the association between body mass index (BMI) and uric acid (UA) using the twin study methodology to adjust for genetic factors. METHODS: The association between BMI and UA was investigated in a cross-sectional study using data from both monozygotic and dizygotic twins registered at the Osaka University Center for Twin Research and the Osaka University Graduate School of Medicine. From January 2011 to March 2014, 422 individuals participated in the health examination. We measured height, weight, age, BMI, lifestyle habits (Breslow's Health Practice Index), serum UA, and serum creatinine. To investigate the association between UA and BMI with adjustment for the clustering of a twin within a pair, individual-level analyses were performed using generalized linear mixed models (GLMMs). To investigate an association with adjustment for genetic and family environmental factors, twin-pair difference values analyses were performed. RESULTS: In all analysis, BMI was associated with UA in men and women. Using the GLMMs, standardized regression coefficients were 0.194 (95 % confidence interval: 0.016-0.373) in men and 0.186 (95 % confidence interval: 0.071-0.302) in women. Considering twin-pair difference value analyses, standardized regression coefficients were 0.333 (95 % confidence interval: 0.072 0.594) in men and 0.314 (95 % confidence interval: 0.151-0.477) in women. CONCLUSIONS: The present study shows that BMI was significantly associated with UA, after adjusting for both genetic and familial environment factors in both men and women. PMID- 26037074 TI - AP4 activates cell migration and EMT mediated by p53 in MDA-MB-231 breast carcinoma cells. AB - Tumor metastasis is the primary cause of mortality in most cancer patients. Before disassociation from the tumors, most of malignant tumor cells undergo the epithelial-mesenchymal transition to break away from the adhesions between the cells and the surrounding extracellular matrix. Recently, activating enhancer binding protein (AP4) has been shown to be a mediator of EMT in colorectal cancer and high level of AP4 correlates with poor prognosis in cancer patients. It has been found that AP4 upregulates the genes involved in EMT and cell proliferation in colorectal cancer cells and that the aggressive human breast cancer cells MDA MB-231 are highly metastatic. Therefore, we tested the hypothesis that AP4 may also affect cell migration and EMT in this cell type. Three different assays, including the wound-healing assay, the Boyden chamber assay, and the cell tracking assay, were employed to confirm that AP4 activated both cell migration and invasion. Immunofluorescence staining and Western blot analysis revealed that the cells underwent EMT when AP4 was upregulated. In contrast, overexpression of dominant-negative AP4, lacking the DNA-binding domain, inactivated the DNA binding ability of endogenous AP4 and led to lower cell motility. Furthermore, we found that AP4 enhanced p53 expression at both transcriptional and translational levels. Knockdown of p53 by siRNA significantly diminished the activation of cell migration by AP4, indicating that AP4 can regulate cell migration via the activity of p53. PMID- 26037075 TI - Anti-inflammatory effect of procyanidin B1 on LPS-treated THP1 cells via interaction with the TLR4-MD-2 heterodimer and p38 MAPK and NF-kappaB signaling. AB - Anti-inflammatory effects of procyanidin B1 have been documented; however, the molecular mechanisms that are involved have not been fully elucidated. Molecular docking models were applied to evaluate the binding capacity of lipopolysaccharide (LPS) and procyanidin B1 with the toll-like receptor (TLR)4/myeloid differentiation factor (MD)-2 complex. LPS-induced production of the proinflammatory cytokine tumor necrosis factor (TNF)-alpha in a human monocyte cell line (THP1) was measured by ELISA. mRNA expression of MD-2, TLR4, TNF receptor-associated factor (TRAF)-6, and nuclear factor (NF)-kappaB was measured by real-time PCR with or without an 18-h co-treatment with procyanidin B1. In addition, protein expression of phosphorylated p38 mitogen-activated protein kinase (MAPK) and NF-kappaB was determined by Western blotting. Structural modeling studies identified Tyr296 in TLR4 and Ser120 in MD-2 as critical sites for hydrogen bonding with procyanidin B1, similar to the sites occupied by LPS. The production of TNF-alpha was significantly decreased by procyanidin B1 in LPS-treated THP1 cells (p < 0.05). Procyanidin B1 also significantly suppressed levels of phosphorylated p38 MAPK and NF-kappaB protein, as well as mRNA levels of MD-2, TRAF-6, and NF-kappaB (all p < 0.05). Procyanidin B1 can compete with LPS for binding to the TLR4-MD-2 heterodimer and suppress downstream activation of p38 MAPK and NF-kappaB signaling pathways. PMID- 26037076 TI - Aerobic biodegradation of organic compounds in hydraulic fracturing fluids. AB - Little is known of the attenuation of chemical mixtures created for hydraulic fracturing within the natural environment. A synthetic hydraulic fracturing fluid was developed from disclosed industry formulas and produced for laboratory experiments using commercial additives in use by Marcellus shale field crews. The experiments employed an internationally accepted standard method (OECD 301A) to evaluate aerobic biodegradation potential of the fluid mixture by monitoring the removal of dissolved organic carbon (DOC) from an aqueous solution by activated sludge and lake water microbial consortia for two substrate concentrations and four salinities. Microbial degradation removed from 57 % to more than 90 % of added DOC within 6.5 days, with higher removal efficiency at more dilute concentrations and little difference in overall removal extent between sludge and lake microbe treatments. The alcohols isopropanol and octanol were degraded to levels below detection limits while the solvent acetone accumulated in biological treatments through time. Salinity concentrations of 40 g/L or more completely inhibited degradation during the first 6.5 days of incubation with the synthetic hydraulic fracturing fluid even though communities were pre-acclimated to salt. Initially diverse microbial communities became dominated by 16S rRNA sequences affiliated with Pseudomonas and other Pseudomonadaceae after incubation with the synthetic fracturing fluid, taxa which may be involved in acetone production. These data expand our understanding of constraints on the biodegradation potential of organic compounds in hydraulic fracturing fluids under aerobic conditions in the event that they are accidentally released to surface waters and shallow soils. PMID- 26037077 TI - Use and risks of surgical mesh for pelvic organ prolapse surgery in women in New York state: population based cohort study. AB - OBJECTIVE: To assess the use of mesh in pelvic organ prolapse surgery, and compare short term outcomes between procedures using and not using mesh. DESIGN: All inclusive, population based cohort study. SETTING: Statewide surgical care captured in the New York Statewide Planning and Research Cooperative System. PARTICIPANTS: Women who underwent prolapse repair procedures in New York state from 2008 to 2011. MAIN OUTCOMES MEASURES: 90 day safety events and reinterventions within one year, after propensity score matching. Categorical, time to event, and subgroup analyses (<65 and >= 65 year age groups) were conducted. RESULTS: Of 27,991 patients in total, 7338 and 20, 653 underwent prolapse repair procedures with and without mesh, respectively. Mesh use increased by 44.7%, from 1461 procedures in 2008 to 2114 procedures in 2011. Most patients in the cohort were younger than 65 years (62.3% (n=17,424/27, 991)). However, more patients were aged 65 years and older in the mesh group than in the non-mesh group (44.3% (n=3249) v 35.4% (n=7318)). Complications after surgery were not common, irrespective of the use or non-use of mesh. After propensity score matching, patients who received the surgery with mesh had a higher chance of having a reintervention within one year (mesh 3.3% v no mesh 2.2%, hazard ratio 1.47 (95% confidence interval 1.21 to 1.79)) and were more likely to have urinary retention within 90 days (mesh 7.5% v no mesh 5.6%, risk ratio 1.33 (95% confidence interval 1.18 to 1.51)), compared with those who received surgery without mesh. In subgroup analyses based on age, mesh use was associated with an increased risk of reintervention within one year in patients under age 65 years, and increased risk of urinary retention in patients aged 65 years and over. CONCLUSIONS: Despite multiple warnings released by the US Food and Drug Administration since 2008, use of mesh in pelvic organ prolapse surgery continues to grow. In this statewide comprehensive study, mesh procedures were associated with an increased risk of reinterventions within one year and urinary retention after surgery. PMID- 26037078 TI - An exploratory study of dietary intake patterns among adults diagnosed with cardiovascular risk factors. AB - The objective of the present exploratory study was to assess compliance with the nutrient recommendations among a convenience sample of adults diagnosed with cardiovascular risk factors in northern Greece and evaluate their dietary intake patterns. Ninety-two people participated in this cross-sectional study. Dietary assessment was carried out using a semi-quantitative food frequency questionnaire. Principal components analysis (PCA) and hierarchical cluster analysis (HCA) were adopted to obtain dietary patterns and classify individuals with similar dietary behaviour. HCA, performed on the factorial scores obtained from PCA, revealed a 4-group interpretable and statistically significant clustering of participants. For all clusters, the mean daily intake for saturated fatty acids was more than 10% of total calories, while the mean sodium intake was above 1500 mg; additionally, a relatively low mean Mediterranean diet score was recorded. Dietary interventions should be considered to raise awareness and expand knowledge on the nutritional and functional benefits of heart-healthy foods. PMID- 26037079 TI - Pharmacokinetics of Oral Combination Contraceptive Drugs Containing Ethinyl Estradiol and Levonorgestrel in Healthy Female Chinese Volunteers. AB - BACKGROUND AND OBJECTIVE: A new combination contraceptive tablet containing 0.02 mg ethinyl estradiol (EE) and 0.10 mg levonorgestrel (LNG) with potential advantages has been developed in China. This study was aimed to describe the pharmacokinetic characteristics of this new combination contraceptive tablet in female Chinese volunteers. METHODS: This study was designed as phase I, open label, and one-sequence clinical trial. 12 healthy nonpregnant female Chinese volunteers received a single dose (1 tablet) and multiple dose (1 tablet per day) administration for 21 consecutive days under fasting condition. Blood samples were analyzed with 2 validated LC-MS/MS methods for EE and LNG, respectively. RESULTS AND CONCLUSION: After the single dose administration, the C max of EE and LNG were 44.76+/-18.64 pg/mL and 2.256+/-1.008 ng/mL, respectively. The steady state condition of EE was achieved on the 6(th) day after the beginning of the multiple dose administration, while the steady-state condition of LNG was achieved on the 21(st) day. For EE, the mean MRT 0-72 and t 1/2 increased by 40.2 and 30.6%, meanwhile the mean Cl/F and Vd/F decreased by 18.5 and 29.1%, respectively from Day 1 to Day 24. For LNG, the mean MRT 0-72 increased by 27.1%, while the mean Cl/F and Vd/F decreased by 62.4 and 86.3%, respectively from Day 1 to Day 24. The t 1/2 remained unchanged for LNG. The exposure of LNG significantly increased with repeated dosing, but that of EE just slightly increased. PMID- 26037080 TI - Contributions of medicinal plants to the Gross National Happiness and Biodiscovery in Bhutan. AB - BACKGROUND: The medicinal plants and the associated Bhutanese traditional medicine (BTM) are protected by the country's constitution and receive both government support and acceptance by the wider public. More than 1000 medicinal plants are described in the BTM but currently collects only 300 species for daily formulations of BTM. These medicinal plants have been one of the drivers of the 'Gross National Happiness (GNH)' and biodiscovery projects in Bhutan. However, no review covering the systematic evaluations of the contributions of medicinal plants and the BTM to the GNH and biodiscovery exist till date. METHODS: This paper, therefore addresses this information gap. It is based on the review of the existing traditional and scientific literature, government websites and policy documents. The descriptions and discussions of the paper is straightened, authenticated and enhanced by the data collected through the informal discussions with the BTM practitioners and also through the authors' many years of practical observations of the impact of the medicinal plants programs and the BTM practices in Bhutan. RESULTS: This paper found the following: a) the medicinal plants generates income to the farmers elevating their living standard and the economic status, b) it serves as the bulk ingredients of the BTM facilitating the provision of free traditional health care services to the patients, c) helps the conservation of medicinal plants and their pristine environment through recognition of their spiritual, social and economic values, d) preserves the rich BTM cultural heritage, and e) guides the biodiscovery projects based on their ethnobotanical information. The paper also identified the challenges and research gaps, and recommends appropriate strategies that can help secure the sustainable future of the medicinal plants, the BTM and the biodiscovery projects. CONCLUSIONS: The medicinal plants play significant role in the country's biodiscovery projects and the internationally renowned development policy of 'Gross National Happiness'. PMID- 26037081 TI - Solvent engineering towards controlled grain growth in perovskite planar heterojunction solar cells. AB - We report an effective solvent engineering process to enable controlled perovskite crystal growth and a wider window for processing uniform and dense methyl ammonium lead iodide (MAPbI3) perovskite films. Planar heterojunction solar cells fabricated with this method demonstrate hysteresis-free performance with a power conversion efficiency around 10%. The crystal structure of an organic-based Pb iodide intermediate phase is identified for the first time, which is critical in controlling the crystal growth and optimizing thin film morphology. PMID- 26037082 TI - Necrotic myocardial cells release damage-associated molecular patterns that provoke fibroblast activation in vitro and trigger myocardial inflammation and fibrosis in vivo. AB - BACKGROUND: Tissue injury triggers inflammatory responses that promote tissue fibrosis; however, the mechanisms that couple tissue injury, inflammation, and fibroblast activation are not known. Given that dying cells release proinflammatory "damage-associated molecular patterns" (DAMPs), we asked whether proteins released by necrotic myocardial cells (NMCs) were sufficient to activate fibroblasts in vitro by examining fibroblast activation after stimulation with proteins released by necrotic myocardial tissue, as well as in vivo by injecting proteins released by necrotic myocardial tissue into the hearts of mice and determining the extent of myocardial inflammation and fibrosis at 72 hours. METHODS AND RESULTS: The freeze-thaw technique was used to induce myocardial necrosis in freshly excised mouse hearts. Supernatants from NMCs contained multiple DAMPs, including high mobility group box-1 (HMGB1), galectin-3, S100beta, S100A8, S100A9, and interleukin-1alpha. NMCs provoked a significant increase in fibroblast proliferation, alpha-smooth muscle actin activation, and collagen 1A1 and 3A1 mRNA expression and significantly increased fibroblast motility in a cell-wounding assay in a Toll-like receptor 4 (TLR4)- and receptor for advanced glycation end products-dependent manner. NMC stimulation resulted in a significant 3- to 4-fold activation of Akt and Erk, whereas pretreatment with Akt (A6730) and Erk (U0126) inhibitors decreased NMC-induced fibroblast proliferation dose-dependently. The effects of NMCs on cell proliferation and collagen gene expression were mimicked by several recombinant DAMPs, including HMGB1 and galectin-3. Moreover, immunodepletion of HMGB1 in NMC supernatants abrogated NMC-induced cell proliferation. Finally, injection of NMC supernatants or recombinant HMGB1 into the heart provoked increased myocardial inflammation and fibrosis in wild-type mice but not in TLR4-deficient mice. CONCLUSIONS: These studies constitute the initial demonstration that DAMPs released by NMCs induce fibroblast activation in vitro, as well as myocardial inflammation and fibrosis in vivo, at least in part, through TLR4-dependent signaling. PMID- 26037083 TI - Age and sex differences in long-term outcomes following implantable cardioverter defibrillator placement in contemporary clinical practice: findings from the Cardiovascular Research Network. AB - BACKGROUND: Patient sex and age may influence rates of death after receiving an implantable cardioverter-defibrillator for primary prevention. Differences in outcomes other than mortality and whether these differences vary by heart failure symptoms, etiology, and left ventricular ejection fraction are not well characterized. METHODS AND RESULTS: We studied 2954 patients with left ventricular ejection fraction <=0.35 undergoing first-time implantable cardioverter-defibrillator for primary prevention within the Cardiovascular Research Network; 769 patients (26%) were women, and 2827 (62%) were aged >65 years. In a median follow-up of 2.4 years, outcome rates per 1000 patient-years were 109 for death, 438 for hospitalization, and 111 for heart failure hospitalizations. Procedure-related complications occurred in 8.36%. In multivariable models, women had significantly lower risks of death (hazard ratio 0.67, 95% CI 0.56 to 0.80) and heart failure hospitalization (hazard ratio 0.82, 95% CI 0.68 to 0.98) and higher risks for complications (hazard ratio 1.38, 95% CI 1.01 to 1.90) than men; patients aged >65 years had higher risks of death (hazard ratio 1.55, 95% CI 1.30 to 1.86) and heart failure hospitalization (hazard ratio 1.25, 95% CI 1.05 to 1.49) than younger patients. Age and sex differences were generally consistent in strata according to symptoms, etiology, and severity of left ventricular systolic dysfunction, except the higher risk of complications in women, which differed by New York Heart Association classification (P=0.03 for sex-New York Heart Association interaction), and the risk of heart failure hospitalization in older patients, which differed by etiology of heart failure (P=0.05 for age-etiology interaction). CONCLUSIONS: The burden of adverse outcomes after receipt of an implantable cardioverter defibrillator for primary prevention is substantial and varies according to patient age and sex. These differences in outcome generally do not vary according to baseline heart failure characteristics. PMID- 26037085 TI - Correction: Peptide-catalyzed kinetic resolution of planar-chiral metallocenes. AB - Correction for 'Peptide-catalyzed kinetic resolution of planar-chiral metallocenes' by Midori Akiyama et al., Chem. Commun., 2014, 50, 7893-7896. PMID- 26037084 TI - Randomized, double-blinded, placebo-controlled trial of fibrinogen concentrate supplementation after complex cardiac surgery. AB - BACKGROUND: Postoperative bleeding after heart operations is still a common finding, leading to allogeneic blood products transfusion. Fibrinogen and coagulation factors deficiency are possible determinants of bleeding. The experimental hypothesis of this study is that a first-line fibrinogen supplementation avoids the need for fresh frozen plasma (FFP) and reduces the need for any kind of transfusions. METHODS AND RESULTS: This was a single-center, prospective, randomized, placebo-controlled, double-blinded study. One-hundred sixteen patients undergoing heart surgery with an expected cardiopulmonary bypass duration >90 minutes were admitted to the study. Patients in the treatment arm received fibrinogen concentrate after protamine administration; patients in the control arm received saline solution. In case of ongoing bleeding, patients in the treatment arm could receive prothrombin complex concentrates (PCCs) and those in the control arm saline solution. The primary endpoint was avoidance of any allogeneic blood product. Patients in the treatment arm had a significantly lower rate of any allogeneic blood products transfusion (odds ratio, 0.40; 95% confidence interval, 0.19 to 0.84, P=0.015). The total amount of packed red cells and FFP units transfused was significantly lower in the treatment arm. Postoperative bleeding was significantly (P=0.042) less in the treatment arm (median, 300 mL; interquartile range, 200 to 400 mL) than in the control arm (median, 355 mL; interquartile range, 250 to 600 mL). CONCLUSIONS: Fibrinogen concentrate limits postoperative bleeding after complex heart surgery, leading to a significant reduction in allogeneic blood products transfusions. No safety issues were raised. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01471730. PMID- 26037087 TI - Development of co-dominant SCAR markers linked to resistant gene against the Fusarium oxysporum f. sp. radicis-lycopersici. AB - We developed highly reliable co-dominant SCAR markers linked to the Frl gene. FORL testing is difficult. The marker is expected to be quickly adapted for MAS by tomato breeders. Fusarium oxysporum f. sp. radicis-lycopersici causes Fusarium crown and root rot (FCR), an economically important soil-borne disease of tomato. The resistance against FCR is conferred by a single dominant gene (Frl) located on chromosome 9. The aim of this study was to develop molecular markers linked to the Frl gene for use in marker-assisted breeding (MAS) programs. The FCR resistant 'Fla. 7781' and susceptible 'B560' lines were crossed, and F1 was both selfed and backcrossed to 'B560' to generate segregating F2 and BC1 populations. The two conserved set II (COSII) markers were found linked to the Frl gene, one co-segregated with FCR resistance in both F2 and BC1 populations and the other was 8.5 cM away. Both COSII markers were converted into co-dominant SCAR markers. SCARFrl marker produced a 950 and a 1000 bp fragments for resistant and susceptible alleles, respectively. The linkage of SCARFrl marker was confirmed in BC2F3 populations developed by backcrossing the resistant 'Fla. 7781' to five different susceptible lines. The SCARFrl marker has been in use in the tomato breeding programs in BATEM, Antalya, Turkey, since 2012 and has proved highly reliable. The SCARFrl marker is expected to aid in the development of FCR resistant lines via marker-assisted selection (MAS). PMID- 26037086 TI - A genetic linkage map of black raspberry (Rubus occidentalis) and the mapping of Ag(4) conferring resistance to the aphid Amphorophora agathonica. AB - KEY MESSAGE: We have constructed a densely populated, saturated genetic linkage map of black raspberry and successfully placed a locus for aphid resistance. Black raspberry (Rubus occidentalis L.) is a high-value crop in the Pacific Northwest of North America with an international marketplace. Few genetic resources are readily available and little improvement has been achieved through breeding efforts to address production challenges involved in growing this crop. Contributing to its lack of improvement is low genetic diversity in elite cultivars and an untapped reservoir of genetic diversity from wild germplasm. In the Pacific Northwest, where most production is centered, the current standard commercial cultivar is highly susceptible to the aphid Amphorophora agathonica Hottes, which is a vector for the Raspberry mosaic virus complex. Infection with the virus complex leads to a rapid decline in plant health resulting in field replacement after only 3-4 growing seasons. Sources of aphid resistance have been identified in wild germplasm and are used to develop mapping populations to study the inheritance of these valuable traits. We have constructed a genetic linkage map using single-nucleotide polymorphism and transferable (primarily simple sequence repeat) markers for F1 population ORUS 4305 consisting of 115 progeny that segregate for aphid resistance. Our linkage map of seven linkage groups representing the seven haploid chromosomes of black raspberry consists of 274 markers on the maternal map and 292 markers on the paternal map including a morphological locus for aphid resistance. This is the first linkage map of black raspberry and will aid in developing markers for marker-assisted breeding, comparative mapping with other Rubus species, and enhancing the black raspberry genome assembly. PMID- 26037088 TI - Impact of the D genome and quantitative trait loci on quantitative traits in a spring durum by spring bread wheat cross. AB - The impact of the D genome and QTL in the A and B genomes on agronomic performance of hexaploid wheat and tetraploid durum was determined using novel recombinant inbred line populations derived from interploid crosses. Genetic differences between common hexaploid (6X) bread wheat (Triticum aestivum, 2n = 6x = 42, genome, AABBDD) and tetraploid (4X) durum wheat (T. turgidum subsp. durum, 2n = 4x = 28, genome, AABB) may exist due to effects of the D genome and allelic differences at loci in the A and B genomes. Previous work allowed identification of a 6X by 4X cross combination that resulted in a large number of fertile recombinant progeny at both ploidy levels. In this study, interspecific recombinant inbred line populations at both 4X and 6X ploidy with 88 and 117 individuals, respectively, were developed from a cross between Choteau spring wheat (6X) and Mountrail durum wheat (4X). The presence of the D genome in the 6X population resulted in increased yield, tiller number, kernel weight, and kernel size, as well as a decrease in stem solidness, test weight and seed per spike. Similar results were found with a second RIL population containing 152 lines from 18 additional 6X by 4X crosses. Several QTL for agronomic and quality traits were identified in both the 4X and 6X populations. Although negatively impacted by the lack of the D genome, kernel weight in Mountrail (4X) was higher than Choteau (6X) due to positive alleles from Mountrail on chromosomes 3B and 7A. These and other favorable alleles may be useful for introgression between ploidy levels. PMID- 26037089 TI - Nanoparticle-Structured Highly Sensitive and Anisotropic Gauge Sensors. AB - The ability to tune gauge factors in terms of magnitude and orientation is important for wearable and conformal electronics. Herein, a sensor device is described which is fabricated by assembling and printing molecularly linked thin films of gold nanoparticles on flexible microelectrodes with unusually high and anisotropic gauge factors. A sharp difference in gauge factors up to two to three orders of magnitude between bending perpendicular (B(?)) and parallel (B(||)) to the current flow directions is observed. The origin of the unusual high and anisotropic gauge factors is analyzed in terms of nanoparticle size, interparticle spacing, interparticle structure, and other parameters, and by considering the theoretical aspects of electron conduction mechanism and percolation pathway. A critical range of resistivity where a very small change in strain and the strain orientation is identified to impact the percolation pathway in a significant way, leading to the high and anisotropic gauge factors. The gauge anisotropy stems from molecular and nanoscale fine tuning of interparticle properties of molecularly linked nanoparticle assembly on flexible microelectrodes, which has important implication for the design of gauge sensors for highly sensitive detection of deformation in complex sensing environment or on complex curved surfaces such as wearable electronics and skin sensors. PMID- 26037090 TI - The metabolic syndrome and cancer: Is the metabolic syndrome useful for predicting cancer risk above and beyond its individual components? AB - AIMS: The metabolic syndrome (MetS) is a risk factor for cancer. However, it is not known if the MetS confers a greater cancer risk than the sum of its individual components, which components drive the association, or if the MetS predicts future cancer risk. MATERIALS AND METHODS: We linked 20,648 participants from the Australian and New Zealand Diabetes and Cancer Collaboration with complete data on the MetS to national cancer registries and used Cox proportional hazards models to estimate associations of the MetS, the number of positive MetS components, and each of the five MetS components separately with the risk for overall, colorectal, prostate and breast cancer. Hazard ratios (HR) and 95% confidence intervals (95%CI) are reported. We assessed predictive ability of the MetS using Harrell's c-statistic. RESULTS: The MetS was inversely associated with prostate cancer (HR 0.85; 95% CI 0.72-0.99). We found no evidence of an association between the MetS overall, colorectal and breast cancers. For those with five positive MetS components the HR was 1.12 (1.02-1.48) and 2.07 (1.26 3.39) for overall, and colorectal cancer, respectively, compared with those with zero positive MetS components. Greater waist circumference (WC) (1.38; 1.13-1.70) and elevated blood pressure (1.29; 1.01-1.64) were associated with colorectal cancer. Elevated WC and triglycerides were (inversely) associated with prostate cancer. MetS models were only poor to moderate discriminators for all cancer outcomes. CONCLUSIONS: We show that the MetS is (inversely) associated with prostate cancer, but is not associated with overall, colorectal or breast cancer. Although, persons with five positive components of the MetS are at a 1.2 and 2.1 increased risk for overall and colorectal cancer, respectively, and these associations appear to be driven, largely, by elevated WC and BP. We also demonstrate that the MetS is only a moderate discriminator of cancer risk. PMID- 26037091 TI - Endovascular Repair of Renal Artery Anastomotic Pseudoaneurysm Following Living Donor Kidney Transplant. AB - Renal artery anastomotic pseudoaneurysms, an uncommon complication of transplantation, may result in aneurysm rupture and loss of allograft. We report the case of 50-year-old female with back pain 3 weeks post renal transplantation. CT scan revealed transplant renal artery anastomotic pseudoaneurysm arising from anastomosis of two renal arteries joined together to form a single renal artery that was joined to the aorta. Successful endovascular treatment was achieved with covered stents, resulting in preserved renal function. Follow-up ultrasound at one-day post procedure and CT at 2 months revealed satisfactory renal perfusion with no pseudoaneurysm. Endovascular treatment of transplant renal artery pseudoaneurysms with covered stent and ostial flare balloon technology may be preferred in patients with extensive prior pelvic surgery, as illustrated in this case. PMID- 26037092 TI - In Vitro Assessment of a New Extension Set Intended to Reduce Occupational Exposure to Antineoplastic Drugs During Hepatic Chemoembolisation. PMID- 26037093 TI - Intense Adrenal Enhancement: A CT Feature of Cardiogenic Shock. AB - In this report, images of intense adrenal enhancement in a 79-year-old female patient with right-sided heart failure and severe tricuspid insufficiency are presented. Only two cases of intense adrenal enhancement as a sign of cardiogenic shock were previously reported in the literature. Intense adrenal enhancement could be one of the earliest CT signs of cardiogenic shock. Its presence should be immediately reported to the referring physician as a sign of significant hemodynamic instability warranting early critical-care management. PMID- 26037094 TI - Mixed response and time-to-event endpoints for multistage single-arm phase II design. AB - BACKGROUND: The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. METHODS: We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. RESULTS: Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. CONCLUSIONS: The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design. PMID- 26037095 TI - Single and combined exposure to MC-LR and BMAA confirm suitability of Aegagropila linnaei for use in green liver systems((r))-A case study with cyanobacterial toxins. AB - The filamentous green algae Aegagropila linnaei was tested for its uptake capacity of the cyanobacterial toxins microcystin-LR (MC-LR) and beta-N methylamino-l-alanine (BMAA) in order to approve the suitability of its use in the Green Liver System((r)). Uptake into the algae and toxin reduction in the medium were analyzed by LC-MS/MS after static exposure for one week to 20MUgL(-1) MC-LR, 80MUgL(-1) BMAA, and 20MUgL(-1) MC-LR together with 80MUgL(-1) BMAA, respectively. BMAA was effectively removed by A. linnaei within 5 days compared to only around 35% removal of the initial exposure concentration in the case of MC-LR, independent of the application mode, in single or in a mixture. However, differences were found for BMAA amounts taken up into the tissue in that it was higher if applied in combination with MC-LR. Additionally, physiological responses such as the activity of biotransformation enzyme glutathione S transferase (GST), antioxidant enzymes peroxidase (POD) and catalase (CAT) as well as the development of the reactive oxygen species hydrogen peroxide (H2O2) were compared between the different treatment groups in order to determine possible harmful effects of the toxin exposure on the algae. In contrast to the toxin exposure to a single toxin with no significant enzymatic response, exposure to the toxin mixture provoked an immediate increase in GST and CAT activity after one day as well as after longer exposure for one week, hinting on an enhanced need for prevention against exposure derived reactive oxygen species as well as putative biotransformation attempts in a mixture exposure scenario. PMID- 26037096 TI - Toxic effects of two sources of dietborne cadmium on the juvenile cobia, Rachycentron canadum L. and tissue-specific accumulation of related minerals. AB - In the present study, juvenile cobia, Rachycentron canadum L. were fed diets contaminated by two different sources of cadmium: squid viscera meal (SVM-Cd, organic form) and cadmium chloride (CdCl2-Cd, inorganic form). The Cd concentrations in fish diet were approximate 3.0, 5.0 and 10.0mg Cd kg(-1) for both inorganic and organic forms. In the control diet (0.312mg Cd kg(-1) diet, Cd mainly come from fish meal), no cadmium was added. The experiment lasted for 16 weeks and a statistically significant inverse relationship was observed between specific growth rate (SGR) and the concentration of dietary Cd. The SGR of cobia fed a diet with SVM-Cd increased at the lowest doses and decreased with the increasing level of dietary SVM. Fish fed diet contaminated SVM-Cd had significantly higher SGR than those fed diets contaminated CdCl2-Cd among the high Cd level diets treatments. The dietary Cd levels also significantly affected the survival rate of the fish. Among the hematological characteristics and plasma constituents, glutamic-pyruvic transaminase activities and alkaline phosphatase activities in serum and liver increased and hepatic superoxide dismutase activity decreased with the increasing dietary Cd levels. The cobia fed diet contaminated by high level of CdCl2-Cd had significantly higher ALP activity than cobia fed diet contaminated by high level of SVM-Cd. The results from these studies indicate no differences in toxicity response to dietborne SVM-Cd and CdCl2-Cd at a low level of Cd. However, at a higher level, cobia was more sensitive to dietborne CdCl2-Cd than SVM-Cd. Based on quadratic regression of SGR, The Cd concentrations was 3.617mg kg(-1) in the optimal diet, Cd source was SVM (126mg Cd kg(-1) in SVM) which stimulate the growth of cobia and the added level was determined to be 26.7g kg(-1) diet in the present study. Cd accumulations in the kidney of cobia fed both types of Cd were higher than other tissues, and the order of Cd accumulation in tissues were kidney>liver>intestine>gill>muscle. Iron accumulation in liver and kidney and calcium accumulation in vertebra and scale were also significantly affected by dietary Cd levels. PMID- 26037097 TI - Application of isotope dilution method for measuring bioavailability of organic contaminants sorbed to dissolved organic matter (DOM). AB - Natural waters such as surface water and sediment porewater invariably contain dissolved organic matter (DOM). Association of strongly hydrophobic contaminants (HOCs) with DOM leads to decreased toxicity and bioavailability, but bioavailability of DOM-sorbed HOCs is difficult to measure. Current methods to estimate bioavailability of HOCs in water are based on only the freely dissolved concentration (Cfree). The ignorance of the exchangeable fraction of HOCs sorbed on DOM may result in an underestimation of the toxicity potential of HOCs to aquatic organisms. Here we explore the applicability of an isotope dilution method (IDM) to measuring the desorption fraction of DOM-sorbed pyrene and bifenthrin and determining their exchangeable pool (E) as an approximation of bioavailability. E values, expressed as percentage of the total concentration, ranged between 0.80 and 0.92% for pyrene and 0.74 and 0.85% for bifenthrin, depending primarily on the amount of chemical in the freely dissolved form. However, between 34 and 78% of the DOM-sorbed pyrene was exchangeable. This fraction ranged between 23% and 82% for bifenthrin. The ability of IDM to predict bioavailability was further shown from a significant relationship (r(2)>0.72, P<0.0001) between E and bioaccumulation into Daphnia magna. Therefore, IDM may be used to improve the bioavailability measurement and risk assessment of HOCs in aquatic systems. PMID- 26037098 TI - Developmental retardation, reduced fecundity, and modulated expression of the defensome in the intertidal copepod Tigriopus japonicus exposed to BDE-47 and PFOS. AB - 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) and perfluorooctane sulfonate (PFOS) are widely dispersed persistent organic pollutants (POPs) in the marine ecosystem. However, their toxic effects on marine organisms are still poorly understood. In this study, we investigated the effects of BDE-47 and PFOS on development and reproduction at the organismal level and reactive oxygen species (ROS) production and gene expression patterns of the defensome at the cellular level in the intertidal copepod Tigriopus japonicus. In copepods exposed to BDE 47 and PFOS, we observed developmental retardation and reduced fecundity, suggesting repercussions on in vivo endpoints through alterations to the normal molting and reproduction system of T. japonicus. BDE-47 and PFOS increased levels of ROS in T. japonicus in a concentration-dependent manner, indicating that POPs can induce oxidative stress through the generation of ROS. Additionally, transcript profiles of genes related to detoxification (e.g., CYPs), antioxidant functions (e.g., GST- sigma, catalase, MnSOD), apoptosis (e.g., p53, Rb), and cellular proliferation (e.g., PCNA) were modulated over 72h in response to BDE-47 (120MUg/L) and PFOS (1000MUg/L). These findings indicate that BDE-47 and PFOS can induce oxidative stress-mediated DNA damage repair systems with transcriptional regulation of detoxification, antioxidant, and apoptosis-related genes, resulting in developmental retardation and reduced fecundity in the copepod T. japonicus. PMID- 26037099 TI - Toxicological aspects of photocatalytic degradation of selected xenobiotics with nano-sized Mn-doped TiO2. AB - The toxic effects of two selected xenobiotics, bisphenol A (BPA) and atrazine (ATZ), were evaluated after photocatalytic degradation using nano-sized, Mn-doped TiO2. Undoped and Mn-doped TiO2 nanoparticles were synthesized. The samples were characterized by X-ray diffractometry (XRD), scanning electron microscopy (SEM), UV-vis-diffuse reflectance spectra (DRS), X-ray fluorescence spectroscopy (XRF), and BET surface area. The photocatalytic efficiency of the undoped and Mn-doped TiO2 was evaluated for BPA and ATZ. The toxicity of the synthesized photocatalysts and photocatalytic by-products of BPA and ATZ was determined using frog embryos and tadpoles, zebrafish embryos, and bioluminescent bacteria. Possible toxic effects were also evaluated using selected enzyme biomarkers. The results showed that Mn-doped TiO2 nanoparticles did not cause significant lethality in Xenopus laevis embryos and tadpoles, but nonfiltered samples caused lethality in zebrafish. Furthermore, Mn-doping of TiO2 increased the photocatalytic degradation capability of nanoparticles, and it successfully degraded BPA and AZT, but degradation of AZT caused an increase of the lethal effects on both tadpoles and fish embryos. Degradation of BPA caused a significant reduction of lethal effects, especially after 2-4h of degradation. However, biochemical assays showed that both Mn-doped TiO2 and the degradation by products caused a significant change of selected biomarkers on X. laevis tadpoles; thus, the ecological risks of Mn-doped TiO2 should be considered due to nanomaterial applications and for spilled nanoparticles in an aquatic ecosystem. Also, the risk of nanoparticles should be considered using indicator reference biochemical markers to verify the environmental health impacts. PMID- 26037100 TI - Does the presence of titanium dioxide nanoparticles reduce copper toxicity? A factorial approach with the benthic amphipod Gammarus fossarum. AB - In aquatic ecosystems, titanium dioxide nanoparticles (nano-TiO2) may adsorb co occurring chemical stressors, such as copper (Cu). This interaction has the potential to reduce the concentration of dissolved Cu due to surface binding to the nanoparticles. The subsequent sedimentation of nano-TiO2 agglomerates may increase the exposure of benthic species towards the associated Cu. This scenario was assessed by employing the amphipod Gammarus fossarum as model species and taking advantage of a 2*2-factorial design investigating absence and presence of 2mg nano-TiO2/L and 40MUg Cu/L (n=45; t=24d) in darkness, respectively. Nano-TiO2 alone did not affect mortality and leaf consumption, whereas Cu alone caused high mortality (>70%), reduced leaf consumption (25%) and feces production (30%) relative to the control. In presence of nano-TiO2, Cu-induced toxicity was largely eliminated. However, independent of Cu, nano-TiO2 decreased the gammarids' assimilation and weight. Hence, nano-TiO2 may be applicable as Cu remediation agent, while its potential long-term effects need further attention. PMID- 26037102 TI - Complete revascularisation in ST-elevation myocardial infarction and multivessel disease: meta-analysis of randomised controlled trials. AB - BACKGROUND: Current guidelines recommend culprit-only revascularisation (COR) in haemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel (MV) disease. Contrarily, growing body of evidence available from recent randomised controlled trials (RCTs) demonstrates improved outcomes with complete MV-percutaneous coronary intervention (PCI). METHODS AND RESULTS: We performed a meta-analysis of RCTs comparing complete MV-PCI with non complete MV-PCI in STEMI and MV disease. Complete MV-PCI was defined as revascularisation to non-infarct-related artery lesions during index procedure, non-complete MV-PCI-encompassed COR and staged approaches. Multiple databases and congress proceedings from major cardiovascular societies' meetings were screened for relevant studies. Primary endpoint was the composite of major adverse cardiac events (MACE) typically defined as death, recurrent myocardial infarction (MI) and repeat revascularisation. Secondary endpoints were cardiovascular mortality, recurrent MI and repeat revascularisation. Outcomes were analysed at longest available follow-up with differences accounted for with adjusted models by person years. Seven RCTs (N=1303) were included. The median follow-up was 12 months. Complete MV-PCI reduced the odds of MACE compared with non-complete MV-PCI (OR (95% CIs) 0.59 (0.36 to 0.97), p=0.04) driven by reduction in recurrent MI (0.48 (0.27 to 0.85), p=0.01) and repeat revascularisation (0.51 (0.31 to 0.84), p=0.008). Complete MV-PCI was associated with a non-significant trend towards reduced cardiovascular mortality (0.54 (0.26 to 1.10), p=0.09) as well. In a sensitivity analysis, none of the baseline clinical variables significantly influenced overall estimates. CONCLUSIONS: In STEMI and MV disease, complete MV PCI as compared with non-complete strategy reduces MACE by 41%, driven by a 52% reduction in recurrent MI and 49% reduction in repeat revascularisation. PMID- 26037103 TI - Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis. AB - OBJECTIVE: Non-vitamin K antagonist oral anticoagulants (NOACs) are efficacious and safe antithrombotic drugs but the non-availability of an antidote for potential fatal haemorrhagic events is clinically perceived as a strong limitation. We aimed at evaluating the risk of haemorrhage-related fatalities associated with NOACs in patients requiring long-term anticoagulation. METHODS: MEDLINE, Cochrane Library and Web of Science databases were searched in November 2014 for atrial fibrillation (AF) or venous thromboembolism (VTE) phase III randomised controlled trials (RCT) comparing NOACs with vitamin K antagonists (VKAs) or low molecular weight heparin (LMWH) followed by VKAs. Pooled OR and 95% CIs were estimated through meta-analysis. Heterogeneity was assessed with the I(2) test. RESULTS: Eleven studies were included: 5 on AF and 6 on VTE. A total of 100 324 patients were evaluated in 4 rivaroxaban, 3 dabigatran, 2 apixaban and 2 edoxaban studies. NOAC-treated patients had a 47% odds reduction compared with VKA (OR 0.53; 95% CI 0.42 to 0.68; I(2)=0%; 3 events avoided per 1000 patients) and 64% odds reduction compared with LMWH-VKA (OR 0.36; 95% CI 0.15 to 0.84; I(2)=0%; 1 event avoided per 1000 patients) regarding fatal bleeding risk. Case fatality due to major bleeding was lower in NOAC-treated patients both in AF (OR 0.68; 95% CI 0.48 to 0.96; I(2)=37%; 1 death avoided per 39 major bleedings) and VTE (OR 0.54; 95% CI 0.22 to 1.32; I(2)=0%) patients. AF survivors of major bleeding events treated with NOACs had lower mortality compared with patients treated with VKAs (OR 0.57; 95% CI 0.45 to 0.73; I(2)=0%; 78 events avoided per 1000 survivors to major bleeding). CONCLUSIONS: These data suggest that NOACs decrease the risk of fatality cases related to major bleeding events, particularly in AF patients. These results support the safety profile of NOACs even without having a widely available drug-specific antidote. PMID- 26037104 TI - Prognostic utility of novel biomarkers of cardiovascular stress in patients with aortic stenosis undergoing valve replacement. AB - OBJECTIVE: In heart failure populations without aortic stenosis (AS), the prognostic utility of multiple biomarkers in addition to clinical factors has been demonstrated. We aimed to determine whether multiple biomarkers of cardiovascular stress are associated with mortality in patients with AS undergoing aortic valve replacement (AVR) independent of clinical factors. METHODS: From a prospective registry of patients with AS, 345 participants who were referred for and treated with AVR (transcatheter (n=183) or surgical (n=162)) were included. Eight biomarkers were measured on blood samples obtained prior to AVR: growth differentiation factor 15 (GDF15), soluble ST2 (sST2), amino terminal pro-B-type natriuretic peptide (NTproBNP), galectin-3, high-sensitivity cardiac troponin T, myeloperoxidase, high-sensitivity C reactive protein and monocyte chemotactic protein-1. Biomarkers were evaluated based on median value (high vs low) in a Cox proportional hazards model for all-cause mortality and a parsimonious group of biomarkers selected. Mean follow-up was 1.9+/-1.2 years; 91 patients died. RESULTS: Three biomarkers (GDF15, sST2 and NTproBNP) were retained in the model. One-year mortality was 5%, 12%, 18% and 33% for patients with 0 (n=79), 1 (n=96), 2 (n=87) and 3 (n=83) biomarkers elevated, respectively (p<0.001). After adjustment for the Society of Thoracic Surgeons (STS) risk score, a greater number of elevated biomarkers was associated with increased mortality (referent: 0 elevated): 1 elevated (HR 1.47, 95% CI 0.60 to 3.63, p=0.40), 2 elevated (HR 2.89, 95% CI 1.24 to 6.74, p=0.014) and 3 elevated (HR 4.59, 95% CI 1.97 to 10.71, p<0.001). Among patients at intermediate or high surgical risk (STS score >=4), 1-year and 2-year mortality rates were 34% and 43% for patients with three biomarkers elevated versus 4% and 4% for patients with 0 biomarkers elevated. When added to the STS score, the number of biomarkers elevated provided a category-free net reclassification improvement of 64% at 1 year (p<0.001). The association between a greater number of elevated biomarkers and increased mortality after valve replacement was similar in the transcatheter and surgical AVR populations. CONCLUSIONS: These findings demonstrate the potential utility of multiple biomarkers to aid in risk stratification of patients with AS. Further studies are needed to evaluate their utility in clinical decision-making in specific AS populations. PMID- 26037105 TI - Sigma-1 receptors and animal studies centered on pain and analgesia. AB - INTRODUCTION: Neuropathic pain is difficult to relieve with standard analgesics and tends to be resistant to opioid therapy. Sigma-1 receptors activated during neuropathic injury may sustain pain. Neuropathic injury activates sigma-1 receptors, which results in activation of various kinases, modulates the activity of multiple ion channels, ligand activated ion channels and voltage-gated ion channels; alters monoamine neurotransmission and dampens opioid receptors G protein activation. Activation of sigma-1 receptors tonically inhibits opioid receptor G-protein activation and thus dampens analgesic responses. Therefore, sigma-1 receptor antagonists are potential analgesics for neuropathic and adjuvants to opioid therapy. AREAS COVERED: This article reviews the importance of sigma-1 receptors as pain generators in multiple animal models in order to illustrate both the importance of these unique receptors in pathologic pain and the potential benefits to sigma-1 receptor antagonists as analgesics. EXPERT OPINION: Sigma-1 receptor antagonists have a great potential as analgesics for acute neuropathic injury (herpes zoster, acute postoperative pain and chemotherapy induced neuropathy) and may, as an additional benefit, prevent the development of chronic neuropathic pain. Antagonists are potentially effective as adjuvants to opioid therapy when used early to prevent analgesic tolerance. Drug development is complicated by the complexity of sigma-1 receptor pharmacodynamics and its multiple targets, the lack of a specific sigma-1 receptor antagonist, and potential side effects due to on-target toxicities (cognitive impairment, depression). PMID- 26037106 TI - Associations of daily levels of PM10 and NO2 with emergency hospital admissions and mortality in Switzerland: Trends and missed prevention potential over the last decade. AB - BACKGROUND: In most regions of the world, levels and constituents of the air pollution mixture have substantially changed over the last decades. AIMS: To evaluate if the effects of PM10 and NO2 on daily emergency hospital admissions and mortality have changed during a ~10 year period in Switzerland; to retrospectively estimate prevention potential of different policy choices. METHODS: Thirteen Poisson-regression models across Switzerland were developed using daily PM10 and NO2 levels from central monitors and accounting for several temporal and seasonal confounders. Time trends of effects were evaluated with an interaction variable. Distributed lag models with 28 days exposure window were used to retrospectively predict missed prevention potential for each region. RESULTS: Overall, emergency hospitalizations and mortality from any medical cause increased by 0.2% (95% Confidence Interval [95% CI]: 0.01, 0.33) and 0.2% (95% CI: -0.1, 0.6) for a 10 ug/m(3) increment of PM10, and 0.7% (95% CI: 0.1, 1.3) for NO2 and mortality. Over the study period, the association between respiratory emergencies and PM10 changed by a factor of 1.017 (95% CI: 1.001, 1.034) and by a factor of 0.977 [95% CI: 0.956, 0.998]) for respiratory mortality among the elderly for NO2. During the study period, abatement strategies targeting a 20% lower overall mean would have prevented four times more cases than abating days exceeding daily standards. CONCLUSION: During the last decade, the short term effects of PM10 and NO2 on hospitalizations and mortality in Switzerland have almost not changed. More ambitious strategies of air pollutant reduction in Switzerland would have had non negligible public health benefits. PMID- 26037107 TI - Assessment of sociodemographic and geographic disparities in cancer risk from air toxics in South Carolina. AB - Populations of color and low-income communities are often disproportionately burdened by exposures to various environmental contaminants, including air pollution. Some air pollutants have carcinogenic properties that are particularly problematic in South Carolina (SC), a state that consistently has high rates of cancer mortality for all sites. The purpose of this study was to assess cancer risk disparities in SC by linking risk estimates from the U.S. Environmental Protection Agency's 2005 National Air Toxics Assessment (NATA) with sociodemographic data from the 2000 US Census Bureau. Specifically, NATA risk data for varying risk categories were linked by tract ID and analyzed with sociodemographic variables from the 2000 census using R. The average change in cancer risk from all sources by sociodemographic variable was quantified using multiple linear regression models. Spatial methods were further employed using ArcGIS 10 to assess the distribution of all source risk and percent non-white at each census tract level. The relative risk (RR) estimates of the proportion of high cancer risk tracts (defined as the top 10% of cancer risk in SC) and their respective 95% confidence intervals (CIs) were calculated between the first and latter three quartiles defined by sociodemographic factors, while the variance in the percentage of high cancer risk between quartile groups was tested using Pearson's chi-square. The average total cancer risk for SC was 26.8 people/million (ppl/million). The risk from on-road sources was approximately 5.8 ppl/million, higher than the risk from major, area, and non-road sources (1.8, 2.6, and 1.3 ppl/million), respectively. Based on our findings, addressing on road sources may decrease the disproportionate cancer risk burden among low income populations and communities of color in SC. PMID- 26037108 TI - Fingerprint analysis of brominated flame retardants and Dechloranes in North Sea sediments. AB - 53 brominated and chlorinated flame retardants were investigated in sediment samples from the German rivers Elbe and Weser, the German Bight, Jadebusen, East Frisian Coast as well as the UK East coast. The aim of the presented study was to investigate the prevalence of different halogenated flame retardant groups as contaminants in North Sea sediments, identify determining factors for the distribution and levels as well as to identify area specific fingerprints that could help identify sources. In order to do that a fast and effective ASE extraction method with an on-line clean-up was developed as well as a GC-EI-MSMS and LC-ESI-MSMS method to analyse PBDEs, MeOBDEs, alternate BFRs, Dechloranes as well as TBBPA and HBCDD. A fingerprinting method was adopted to identify representative area-specific patterns based on detection frequency as well as concentrations of individual compounds. Concentrations in general were low, with<1 ng g(-1) dw for most compounds. Exceptions were the comparably high concentrations of BDE-209 with up to 7 ng g(-1) dw in selected samples and TBBPA in UK samples with 2.7+/-1.5 ng g(-1) dw. Apart from BDE-209 and TBBPA, alternate BFRs and Dechloranes were predominant in all analysed samples, displaying the increasing relevance of these compounds as environmental contaminants. PMID- 26037109 TI - Mexico City normal weight children exposed to high concentrations of ambient PM2.5 show high blood leptin and endothelin-1, vitamin D deficiency, and food reward hormone dysregulation versus low pollution controls. Relevance for obesity and Alzheimer disease. AB - Millions of Mexico, US and across the world children are overweight and obese. Exposure to fossil-fuel combustion sources increases the risk for obesity and diabetes, while long-term exposure to fine particulate matter (PM2.5) and ozone (O3) above US EPA standards is associated with increased risk of Alzheimer's disease (AD). Mexico City Metropolitan Area children are chronically exposed to PM2.5 and O3 concentrations above the standards and exhibit systemic, brain and intrathecal inflammation, cognitive deficits, and Alzheimer disease neuropathology. We investigated adipokines, food reward hormones, endothelial dysfunction, vitamin D and apolipoprotein E (APOE) relationships in 80 healthy, normal weight 11.1+/-3.2 year olds matched by age, gender, BMI and SES, low (n: 26) versus high (n:54) PM2.5 exposures. Mexico City children had higher leptin and endothelin-1 (p<0.01 and p<0.000), and decreases in glucagon-like peptide-1 (GLP 1), ghrelin, and glucagon (<0.02) versus controls. BMI and leptin relationships were significantly different in low versus high PM2.5 exposed children. Mexico City APOE 4 versus 3 children had higher glucose (p=0.009). Serum 25-hydroxyvitamin D<30 ng/mL was documented in 87% of Mexico City children. Leptin is strongly positively associated to PM 2.5 cumulative exposures. Residing in a high PM2.5 and O3 environment is associated with 12h fasting hyperleptinemia, altered appetite-regulating peptides, vitamin D deficiency, and increases in ET-1 in clinically healthy children. These changes could signal the future trajectory of urban children towards the development of insulin resistance, obesity, type II diabetes, premature cardiovascular disease, addiction-like behavior, cognitive impairment and Alzheimer's disease. Increased efforts should be made to decrease pediatric PM2.5 exposures, to deliver health interventions prior to the development of obesity and to identify and mitigate environmental factors influencing obesity and Alzheimer disease. PMID- 26037110 TI - Effects of prenatal substance exposure on infant temperament vary by context. AB - This was a prospective longitudinal multisite study of the effects of prenatal cocaine and/or opiate exposure on temperament in 4-month-olds of the Maternal Lifestyle Study (N = 958: 366 cocaine exposed, 37 opiate exposed, 33 exposed to both drugs, 522 matched comparison). The study evaluated positivity and negativity during The Behavior Assessment of Infant Temperament (Garcia Coll et al., 1988). Parents rated temperament (Infant Behavior Questionnaire; Rothbart, 1981). Cocaine-exposed infants showed less positivity overall, mainly during activity and threshold items, more negativity during sociability items, and less negativity during irritability and threshold items. Latent profile analysis indicated individual temperament patterns were best described by three groups: low/moderate overall reactivity, high social negative reactivity, and high nonsocial negative reactivity. Infants with heavy cocaine exposure were more likely in high social negative reactivity profile, were less negative during threshold items, and required longer soothing intervention. Cocaine- and opiate exposed infants scored lower on Infant Behavior Questionnaire smiling and laughter and duration of orienting scales. Opiate-exposed infants were rated as less respondent to soothing. By including a multitask measure of temperament we were able to show context-specific behavioral dysregulation in prenatally cocaine exposed infants. The findings indicate flatter temperament may be specific to nonsocial contexts, whereas social interactions may be more distressing for cocaine-exposed infants. PMID- 26037111 TI - Biochar reduces the bioavailability of di-(2-ethylhexyl) phthalate in soil. AB - A pot experiment was conducted to evaluate the effect of biochars on the bioavailability of di-(2-ethylhexyl) phthalate (DEHP) in two soils using Brassica chinensis L. as an indicator plant. The residual concentrations of DEHP tended to be higher in the biochar-amended soils than in the control soils. They were lower (p<0.05) in the high organic carbon content soil (HOC; 2.2%C) than in the low organic carbon content soil (LOC; 0.35%C). The DEHP concentrations in plant shoots grown in the HOC soils were lower than those in the LOC soils (p<0.05). Compared to the control, the biochar addition decreased the DEHP concentrations in shoots grown in the LOC soils; whereas there was no significant difference in the HOC soils. Our results showed that soil OC content as well as biochar properties are the key factors influencing the bioavailability of DEHP in soils. PMID- 26037112 TI - Acute disseminated encephalomyelitis: current knowledge and open questions. AB - Acute disseminated encephalomyelitis (ADEM) is usually an acute, multi-focal, and monophasic immune-mediated disease of the central nervous system. The disorder is mainly a condition of the pediatric age group, but neurologists are also involved in the management of adult patients. The lack of defined diagnostic criteria for ADEM underlies the limited understanding of its epidemiology, etiology, pathogenesis, course, prognosis, therapy, as well as the association with, and distinction from, multiple sclerosis. The present review summarizes current knowledge and outlines unanswered questions the answers to which should be eventually provided through a synergistic combination of clinical and basic research. PMID- 26037113 TI - Inhibition of catechol-O-methyl transferase (COMT) by tolcapone restores reductions in microtubule-associated protein 2 (MAP2) and synaptophysin (SYP) following exposure of neuronal cells to neurotropic HIV. AB - This investigation aimed to assess whether inhibition of cathecol-O-methyl transferase (COMT) by tolcapone could provide neuroprotection against HIV associated neurodegenerative effects. This study was conducted based on a previous work, which showed that a single nucleotide polymorphism (SNP) at position 158 (val158met) in COMT, resulted in 40 % lower COMT activity. Importantly, this reduction confers a protective effect against HIV-associated neurocognitive disorders (HAND), which have been linked to HIV-associated brain changes. SH-SY5Y-differentiated neurons were exposed to macrophage-propagated HIV (neurotropic MACS2-Br strain) in the presence or absence of tolcapone for 6 days. RNA was extracted, and qPCR was performed using Qiagen RT2 custom array consisting of genes for neuronal and synaptic integrity, COMT and pro inflammatory markers. Immunofluorescence was conducted to validate the gene expression changes at the protein level. Our findings demonstrated that HIV significantly increased the messenger RNA (mRNA) expression of COMT while reducing the expression of microtubule-associated protein 2 (MAP2) (p = 0.0015) and synaptophysin (SYP) (p = 0.012) compared to control. A concomitant exposure of tolcapone ameliorated the perturbed expression of MAP2 (p = 0.009) and COMT (p = 0.024) associated with HIV. Immunofluorescence revealed a trend reduction of SYP and MAP2 with exposure to HIV and that concomitant exposure of tolcapone increased SYP (p = 0.016) compared to HIV alone. Our findings demonstrated in vitro that inhibition of COMT can ameliorate HIV-associated neurodegenerative changes that resulted in the decreased expression of the structural and synaptic components MAP2 and SYP. As HIV-associated dendritic and synaptic damage are contributors to HAND, inhibition of COMT may represent a potential strategy for attenuating or preventing some of the symptoms of HAND. PMID- 26037114 TI - Chronic SIV and morphine treatment increases heat shock protein 5 expression at the synapse. AB - The abuse of opiates such as morphine in synergy with HIV infection accelerates neurocognitive impairments and neuropathology in the CNS of HIV-infected subjects, collectively referred to as HAND. To identify potential pathogenic markers associated with HIV and morphine in perturbing the synaptic architecture, we performed quantitative mass spectrometry proteomics on purified synaptosomes isolated from the caudate of two groups of rhesus macaques chronically infected with SIV differing by one regimen-morphine treatment. The upregulation of heat shock 70-kDa protein 5 in the SIV + morphine group points to increased cellular stress during SIV/morphine interaction thus leading to CNS dysfunction. PMID- 26037115 TI - Patient stratification and therapy in atypical haemolytic uraemic syndrome (aHUS). AB - Approximately 50% of aHUS patients have an underlying inherited and/or acquired abnormality of complement which predisposes to excessive activation of the alternative pathway. Use of complement inhibitors such as eculizumab to treat aHUS is therefore logical. Anecdotal reports and subsequent open-label trials demonstrated the efficacy of eculizumab in aHUS leading to approval by both the FDA and EMA. NHS England established in 2013 an interim national service for aHUS including funding for eculizumab for both new patients and those undergoing transplantation. NICE guidance now also recommends eculizumab for funding within the NHS in England under the coordination of an expert centre. The investigation and response to treatment in this cohort provides a unique resource for patient stratification. PMID- 26037116 TI - Fatty acid binding protein 7 and n-3 poly unsaturated fatty acid supply in early rat brain development. AB - Fatty acid binding protein 7 (FABP7), abundant in the embryonic brain, binds with the highest affinity to docosahexaenoic acid (DHA) and is expressed in the early stages of embryogenesis. Here, we have examined the consequences of the exposure to different DHA levels and of the in utero depletion of FABP7 on early rat brain development. Neurodevelopment was evaluated through the contents of two proteins, connexin 43 (Cx43) and cyclin-dependent kinase 5 (CDK5), both involved in neuroblast proliferation, differentiation, and migration. The dams were fed with diets presenting different DHA contents, from deficiency to supplementation. DHA brain embryos contents already differed at embryonic day 11.5 and the differences kept increasing with time. Cx43 and CDK5 contents were positively associated with the brain DHA levels. When FABP7 was depleted in vivo by injections of siRNA in the telencephalon, the enhancement of the contents of both proteins was lost in supplemented animals, but FABP7 depletion did not modify phospholipid compositions regardless of the diets. Thus, FABP7 is a necessary mediator of the effect of DHA on these proteins synthesis, but its role in DHA uptake is not critical, although FABP7 is localized in phospholipid-rich areas. Our study shows that high contents of DHA associated with FABP7 are necessary to promote early brain development, which prompted us to recommend DHA supplementation early in pregnancy. PMID- 26037117 TI - Choosing Together: encouraging person centred care and shared decision making. PMID- 26037118 TI - Lifestyle evolution in cyanobacterial symbionts of sponges. AB - The "Candidatus Synechococcus spongiarum" group includes different clades of cyanobacteria with high 16S rRNA sequence identity (~99%) and is the most abundant and widespread cyanobacterial symbiont of marine sponges. The first draft genome of a "Ca. Synechococcus spongiarum" group member was recently published, providing evidence of genome reduction by loss of genes involved in several nonessential functions. However, "Ca. Synechococcus spongiarum" includes a variety of clades that may differ widely in genomic repertoire and consequently in physiology and symbiotic function. Here, we present three additional draft genomes of "Ca. Synechococcus spongiarum," each from a different clade. By comparing all four symbiont genomes to those of free-living cyanobacteria, we revealed general adaptations to life inside sponges and specific adaptations of each phylotype. Symbiont genomes shared about half of their total number of coding genes. Common traits of "Ca. Synechococcus spongiarum" members were a high abundance of DNA modification and recombination genes and a reduction in genes involved in inorganic ion transport and metabolism, cell wall biogenesis, and signal transduction mechanisms. Moreover, these symbionts were characterized by a reduced number of antioxidant enzymes and low-weight peptides of photosystem II compared to their free-living relatives. Variability within the "Ca. Synechococcus spongiarum" group was mostly related to immune system features, potential for siderophore-mediated iron transport, and dependency on methionine from external sources. The common absence of genes involved in synthesis of residues, typical of the O antigen of free-living Synechococcus species, suggests a novel mechanism utilized by these symbionts to avoid sponge predation and phage attack. IMPORTANCE: While the Synechococcus/Prochlorococcus-type cyanobacteria are widely distributed in the world's oceans, a subgroup has established its niche within marine sponge tissues. Recently, the first genome of sponge associated cyanobacteria, "Candidatus Synechococcus spongiarum," was described. The sequencing of three representatives of different clades within this cyanobacterial group has enabled us to investigate intraspecies diversity, as well as to give a more comprehensive understanding of the common symbiotic features that adapt "Ca. Synechococcus spongiarum" to its life within the sponge host. PMID- 26037119 TI - Fungal Inositol Pyrophosphate IP7 Is Crucial for Metabolic Adaptation to the Host Environment and Pathogenicity. AB - Inositol pyrophosphates (PP-IPs) comprising inositol, phosphate, and pyrophosphate (PP) are essential for multiple functions in eukaryotes. Their role in fungal pathogens has never been addressed. Cryptococcus neoformans is a model pathogenic fungus causing life-threatening meningoencephalitis. We investigate the cryptococcal kinases responsible for the production of PP-IPs (IP7/IP8) and the hierarchy of PP-IP importance in pathogenicity. Using gene deletion and inositol polyphosphate profiling, we identified Kcs1 as the major IP6 kinase (producing IP7) and Asp1 as an IP7 kinase (producing IP8). We show that Kcs1 derived IP7 is the most crucial PP-IP for cryptococcal drug susceptibility and the production of virulence determinants. In particular, Kcs1 kinase activity is essential for cryptococcal infection of mouse lungs, as reduced fungal burdens were observed in the absence of Kcs1 or when Kcs1 was catalytically inactive. Transcriptome and carbon source utilization analysis suggested that compromised growth of the KCS1 deletion strain (Deltakcs1 mutant) in the low-glucose environment of the host lung is due to its inability to utilize alternative carbon sources. Despite this metabolic defect, the Deltakcs1 mutant established persistent, low-level asymptomatic pulmonary infection but failed to elicit a strong immune response in vivo and in vitro and was not readily phagocytosed by primary or immortalized monocytes. Reduced recognition of the Deltakcs1 cells by monocytes correlated with reduced exposure of mannoproteins on the Deltakcs1 mutant cell surface. We conclude that IP7 is essential for fungal metabolic adaptation to the host environment, immune recognition, and pathogenicity. IMPORTANCE: Cryptococcus neoformans is responsible for 1 million cases of AIDS associated meningitis and ~600,000 deaths annually. Understanding cellular pathways responsible for pathogenicity might have an impact on new drug development. We characterized the inositol polyphosphate kinases Kcs1 and Asp1, which are predicted to catalyze the production of inositol pyrophosphates containing one or two diphosphate moieties (PP-IPs). Using gene deletion analysis and inositol polyphosphate profiling, we confirmed that Kcs1 and Asp1 are major IP6 and IP7 kinases, respectively. Kcs1-derived IP7, but not Asp1-derived IP8, is crucial for pathogenicity. Global expression profiling and carbon source utilization testing suggest that IP7-deficient cryptococci cannot adapt their metabolism to allow growth in the glucose-poor environment of the host lung, and consequently, fungal burdens are significantly reduced. Persistent asymptomatic Deltakcs1 mutant infection correlated with decreased mannoprotein exposure on the Deltakcs1 mutant surface and reduced phagocytosis. We conclude that IP7 is crucial for the metabolic adaptation of C. neoformans to the host environment and for pathogenicity. PMID- 26037120 TI - Genomic Context of Azole Resistance Mutations in Aspergillus fumigatus Determined Using Whole-Genome Sequencing. AB - A rapid and global emergence of azole resistance has been observed in the pathogenic fungus Aspergillus fumigatus over the past decade. The dominant resistance mechanism appears to be of environmental origin and involves mutations in the cyp51A gene, which encodes a protein targeted by triazole antifungal drugs. Whole-genome sequencing (WGS) was performed for high-resolution single nucleotide polymorphism (SNP) analysis of 24 A. fumigatus isolates, including azole-resistant and susceptible clinical and environmental strains obtained from India, the Netherlands, and the United Kingdom, in order to assess the utility of WGS for characterizing the alleles causing resistance. WGS analysis confirmed that TR34/L98H (a mutation comprising a tandem repeat [TR] of 34 bases in the promoter of the cyp51A gene and a leucine-to-histidine change at codon 98) is the sole mechanism of azole resistance among the isolates tested in this panel of isolates. We used population genomic analysis and showed that A. fumigatus was panmictic, with as much genetic diversity found within a country as is found between continents. A striking exception to this was shown in India, where isolates are highly related despite being isolated from both clinical and environmental sources across >1,000 km; this broad occurrence suggests a recent selective sweep of a highly fit genotype that is associated with the TR34/L98H allele. We found that these sequenced isolates are all recombining, showing that azole-resistant alleles are segregating into diverse genetic backgrounds. Our analysis delineates the fundamental population genetic parameters that are needed to enable the use of genome-wide association studies to identify the contribution of SNP diversity to the generation and spread of azole resistance in this medically important fungus. IMPORTANCE: Resistance to azoles in the ubiquitous ascomycete fungus A. fumigatus was first reported from clinical isolates collected in the United States during the late 1980s. Over the last decade, an increasing number of A. fumigatus isolates from the clinic and from nature have been found to show resistance to azoles, suggesting that resistance is emerging through selection by the widespread usage of agricultural azole antifungal compounds. Aspergillosis is an emerging clinical problem, with high rates of treatment failures necessitating the development of new techniques for surveillance and for determining the genome-wide basis of azole resistance in A. fumigatus. PMID- 26037121 TI - Defining the Roles of TcdA and TcdB in Localized Gastrointestinal Disease, Systemic Organ Damage, and the Host Response during Clostridium difficile Infections. AB - Clostridium difficile is a leading cause of antibiotic-associated diarrhea, a significant animal pathogen, and a worldwide public health burden. Most disease causing strains secrete two exotoxins, TcdA and TcdB, which are considered to be the primary virulence factors. Understanding the role that these toxins play in disease is essential for the rational design of urgently needed new therapeutics. However, their relative contributions to disease remain contentious. Using three different animal models, we show that TcdA(+) TcdB(-) mutants are attenuated in virulence in comparison to the wild-type (TcdA(+) TcdB(+)) strain, whereas TcdA( ) TcdB(+) mutants are fully virulent. We also show for the first time that TcdB alone is associated with both severe localized intestinal damage and systemic organ damage, suggesting that this toxin might be responsible for the onset of multiple organ dysfunction syndrome (MODS), a poorly characterized but often fatal complication of C. difficile infection (CDI). Finally, we show that TcdB is the primary factor responsible for inducing the in vivo host innate immune and inflammatory responses. Surprisingly, the animal infection model used was found to profoundly influence disease outcomes, a finding which has important ramifications for the validation of new therapeutics and future disease pathogenesis studies. Overall, our results show unequivocally that TcdB is the major virulence factor of C. difficile and provide new insights into the host response to C. difficile during infection. The results also highlight the critical nature of using appropriate and, when possible, multiple animal infection models when studying bacterial virulence mechanisms. IMPORTANCE: Clostridium difficile is a leading cause of antibiotic-associated diarrhea and an important hospital pathogen. TcdA and TcdB are thought to be the primary virulence factors responsible for disease symptoms of C. difficile infections (CDI). However, the individual contributions of these toxins to disease remain contentious. Using three different animal models of infection, we show for the first time that TcdB alone causes severe damage to the gut, as well as systemic organ damage, suggesting that this toxin might be responsible for MODS, a serious but poorly understood complication of CDI. These findings provide important new insights into the host response to C. difficile during infection and should guide the rational development of urgently required nonantibiotic therapeutics for the treatment of CDI. PMID- 26037122 TI - Bacteriophages limit the existence conditions for conjugative plasmids. AB - Bacteriophages are a major cause of bacterial mortality and impose strong selection on natural bacterial populations, yet their effects on the dynamics of conjugative plasmids have rarely been tested. We combined experimental evolution, mathematical modeling, and individual-based simulations to explain how the ecological and population genetics effects of bacteriophages upon bacteria interact to determine the dynamics of conjugative plasmids and their persistence. The ecological effects of bacteriophages on bacteria are predicted to limit the existence conditions for conjugative plasmids, preventing persistence under weak selection for plasmid accessory traits. Experiments showed that phages drove faster extinction of plasmids in environments where the plasmid conferred no benefit, but they also revealed more complex effects of phages on plasmid dynamics under these conditions, specifically, the temporary maintenance of plasmids at fixation followed by rapid loss. We hypothesized that the population genetic effects of bacteriophages, specifically, selection for phage resistance mutations, may have caused this. Further mathematical modeling and individual based simulations supported our hypothesis, showing that conjugative plasmids may hitchhike with phage resistance mutations in the bacterial chromosome. IMPORTANCE: Conjugative plasmids are infectious loops of DNA capable of transmitting DNA between bacterial cells and between species. Because plasmids often carry extra genes that allow bacteria to live in otherwise-inhospitable environments, their dynamics are central to understanding bacterial adaptive evolution. The plasmid-bacterium interaction has typically been studied in isolation, but in natural bacterial communities, bacteriophages, viruses that infect bacteria, are ubiquitous. Using experiments, mathematical models, and computer simulations we show that bacteriophages drive plasmid dynamics through their ecological and evolutionary effects on bacteria and ultimately limit the conditions allowing plasmid existence. These results advance our understanding of bacterial adaptation and show that bacteriophages could be used to select against plasmids carrying undesirable traits, such as antibiotic resistance. PMID- 26037123 TI - Erratum for "Dynamic remodeling of microbial biofilms by functionally distinct exopolysaccharides". PMID- 26037124 TI - Internalization of Pseudomonas aeruginosa Strain PAO1 into Epithelial Cells Is Promoted by Interaction of a T6SS Effector with the Microtubule Network. AB - Invasion of nonphagocytic cells through rearrangement of the actin cytoskeleton is a common immune evasion mechanism used by most intracellular bacteria. However, some pathogens modulate host microtubules as well by a still poorly understood mechanism. In this study, we aim at deciphering the mechanisms by which the opportunistic bacterial pathogen Pseudomonas aeruginosa invades nonphagocytic cells, although it is considered mainly an extracellular bacterium. Using confocal microscopy and immunofluorescence, we show that the evolved VgrG2b effector of P. aeruginosa strain PAO1 is delivered into epithelial cells by a type VI secretion system, called H2-T6SS, involving the VgrG2a component. An in vivo interactome of VgrG2b in host cells allows the identification of microtubule components, including the gamma-tubulin ring complex (gammaTuRC), a multiprotein complex catalyzing microtubule nucleation, as the major host target of VgrG2b. This interaction promotes a microtubule-dependent internalization of the bacterium since colchicine and nocodazole, two microtubule-destabilizing drugs, prevent VgrG2b-mediated P. aeruginosa entry even if the invasion still requires actin. We further validate our findings by demonstrating that the type VI injection step can be bypassed by ectopic production of VgrG2b inside target cells prior to infection. Moreover, such uncoupling between VgrG2b injection and bacterial internalization also reveals that they constitute two independent steps. With VgrG2b, we provide the first example of a bacterial protein interacting with the gammaTuRC. Our study offers key insight into the mechanism of self-promoting invasion of P. aeruginosa into human cells via a directed and specific effector-host protein interaction. IMPORTANCE: Innate immunity and specifically professional phagocytic cells are key determinants in the ability of the host to control P. aeruginosa infection. However, among various virulence strategies, including attack, this opportunistic bacterial pathogen is able to avoid host clearance by triggering its own internalization in nonphagocytic cells. We previously showed that a protein secretion/injection machinery, called the H2 type VI secretion system (H2-T6SS), promotes P. aeruginosa uptake by epithelial cells. Here we investigate which H2-T6SS effector enables P. aeruginosa to enter nonphagocytic cells. We show that VgrG2b is delivered by the H2-T6SS machinery into epithelial cells, where it interacts with microtubules and, more particularly, with the gamma-tubulin ring complex (gammaTuRC) known as the microtubule-nucleating center. This interaction precedes a microtubule- and actin-dependent internalization of P. aeruginosa. We thus discovered an unprecedented target for a bacterial virulence factor since VgrG2b constitutes, to our knowledge, the first example of a bacterial protein interacting with the gammaTuRC. PMID- 26037125 TI - Secretory Aspartyl Proteinases Cause Vaginitis and Can Mediate Vaginitis Caused by Candida albicans in Mice. AB - Vaginal inflammation (vaginitis) is the most common disease caused by the human pathogenic fungus Candida albicans. Secretory aspartyl proteinases (Sap) are major virulence traits of C. albicans that have been suggested to play a role in vaginitis. To dissect the mechanisms by which Sap play this role, Sap2, a dominantly expressed member of the Sap family and a putative constituent of an anti-Candida vaccine, was used. Injection of full-length Sap2 into the mouse vagina caused local neutrophil influx and accumulation of the inflammasome dependent interleukin-1beta (IL-1beta) but not of inflammasome-independent tumor necrosis factor alpha. Sap2 could be replaced by other Sap, while no inflammation was induced by the vaccine antigen, the N-terminal-truncated, enzymatically inactive tSap2. Anti-Sap2 antibodies, in particular Fab from a human combinatorial antibody library, inhibited or abolished the inflammatory response, provided the antibodies were able, like the Sap inhibitor Pepstatin A, to inhibit Sap enzyme activity. The same antibodies and Pepstatin A also inhibited neutrophil influx and cytokine production stimulated by C. albicans intravaginal injection, and a mutant strain lacking SAP1, SAP2, and SAP3 was unable to cause vaginal inflammation. Sap2 induced expression of activated caspase-1 in murine and human vaginal epithelial cells. Caspase-1 inhibition downregulated IL-1beta and IL-18 production by vaginal epithelial cells, and blockade of the IL-1beta receptor strongly reduced neutrophil influx. Overall, the data suggest that some Sap, particularly Sap2, are proinflammatory proteins in vivo and can mediate the inflammasome-dependent, acute inflammatory response of vaginal epithelial cells to C. albicans. These findings support the notion that vaccine-induced or passively administered anti-Sap antibodies could contribute to control vaginitis. IMPORTANCE: Candidal vaginitis is an acute inflammatory disease that affects many women of fertile age, with no definitive cure and, in its recurrent forms, causing true devastation of quality of life. Unraveling the fungal factors causing inflammation is important to be able to devise novel tools to fight the disease. In an experimental murine model, we have discovered that aspartyl proteinases, particularly Sap2, may cause the same inflammatory signs of vaginitis caused by the fungus and that anti-Sap antibodies and the protease inhibitor Pepstatin A almost equally inhibit Sap- and C. albicans-induced inflammation. Sap-induced vaginitis is an early event during vaginal infection, is uncoupled from fungal growth, and requires Sap and caspase-1 enzymatic activities to occur, suggesting that Sap or products of Sap activity activate an inflammasome sensor of epithelial cells. Our data support the notion that anti Sap antibodies could help control the essence of candidal vaginitis, i.e., the inflammatory response. PMID- 26037126 TI - Inhibiting the Mammalian target of rapamycin blocks the development of experimental cerebral malaria. AB - Malaria is an infectious disease caused by parasites of several Plasmodium spp. Cerebral malaria (CM) is a common form of severe malaria resulting in nearly 700,000 deaths each year in Africa alone. At present, there is no adjunctive therapy for CM. Although the mechanisms underlying the pathogenesis of CM are incompletely understood, it is likely that both intrinsic features of the parasite and the human host's immune response contribute to disease. The kinase mammalian target of rapamycin (mTOR) is a central regulator of immune responses, and drugs that inhibit the mTOR pathway have been shown to be antiparasitic. In a mouse model of CM, experimental CM (ECM), we show that the mTOR inhibitor rapamycin protects against ECM when administered within the first 4 days of infection. Treatment with rapamycin increased survival, blocked breakdown of the blood-brain barrier and brain hemorrhaging, decreased the influx of both CD4(+) and CD8(+) T cells into the brain and the accumulation of parasitized red blood cells in the brain. Rapamycin induced marked transcriptional changes in the brains of infected mice, and analysis of transcription profiles predicted that rapamycin blocked leukocyte trafficking to and proliferation in the brain. Remarkably, animals were protected against ECM even though rapamycin treatment significantly increased the inflammatory response induced by infection in both the brain and spleen. These results open a new avenue for the development of highly selective adjunctive therapies for CM by targeting pathways that regulate host and parasite metabolism. IMPORTANCE: Malaria is a highly prevalent infectious disease caused by parasites of several Plasmodium spp. Malaria is usually uncomplicated and resolves with time; however, in about 1% of cases, almost exclusively among young children, malaria becomes severe and life threatening, resulting in nearly 700,000 deaths each year in Africa alone. Among the most severe complications of Plasmodium falciparum infection is cerebral malaria with a fatality rate of 15 to 20%, despite treatment with antimalarial drugs. Cerebral malaria takes a second toll on African children, leaving survivors at high risk of debilitating neurological defects. At present, we have no effective adjunctive therapies for cerebral malaria, and developing such therapies would have a large impact on saving young lives in Africa. Here we report results that open a new avenue for the development of highly selective adjunctive therapies for cerebral malaria by targeting pathways that regulate host and parasite metabolism. PMID- 26037127 TI - Small and inconsistent effects of whole body vibration on athletic performance: a systematic review and meta-analysis. AB - PURPOSE: We quantified the acute and chronic effects of whole body vibration on athletic performance or its proxy measures in competitive and/or elite athletes. METHODS: Systematic literature review and meta-analysis. RESULTS: Whole body vibration combined with exercise had an overall 0.3 % acute effect on maximal voluntary leg force (-6.4 %, effect size = -0.43, 1 study), leg power (4.7 %, weighted mean effect size = 0.30, 6 studies), flexibility (4.6 %, effect size = 0.12 to 0.22, 2 studies), and athletic performance (-1.9 %, weighted mean effect size = 0.26, 6 studies) in 191 (103 male, 88 female) athletes representing eight sports (overall effect size = 0.28). Whole body vibration combined with exercise had an overall 10.2 % chronic effect on maximal voluntary leg force (14.6 %, weighted mean effect size = 0.44, 5 studies), leg power (10.7 %, weighted mean effect size = 0.42, 9 studies), flexibility (16.5 %, effect size = 0.57 to 0.61, 2 studies), and athletic performance (-1.2 %, weighted mean effect size = 0.45, 5 studies) in 437 (169 male, 268 female) athletes (overall effect size = 0.44). CONCLUSIONS: Whole body vibration has small and inconsistent acute and chronic effects on athletic performance in competitive and/or elite athletes. These findings lead to the hypothesis that neuromuscular adaptive processes following whole body vibration are not specific enough to enhance athletic performance. Thus, other types of exercise programs (e.g., resistance training) are recommended if the goal is to improve athletic performance. PMID- 26037128 TI - Multicomponent T2 relaxation studies of the avian egg. AB - PURPOSE: To investigate the tissue-like multiexponential T2 signal decays in avian eggs. METHODS: Transverse relaxation studies of raw, soft-boiled and hard boiled eggs were performed at 3 Tesla using a three-dimensional Carr-Purcell Meiboom-Gill imaging sequence. Signal decays over a TE range of 11 to 354 ms were fitted assuming single- and multicomponent signal decays with up to three separately decaying components. Fat saturation was used to facilitate spectral assignment of observed decay components. RESULTS: Egg white, yolk and the centrally located latebra all demonstrate nonmonoexponential T2 decays. Specifically, egg white exhibits two-component decays with intermediate and long T2 times. Meanwhile, yolk and latebra are generally best characterized with triexponential decays, with short, intermediate and very long T2 decay times. Fat saturation revealed that the intermediate component of yolk could be attributed to lipids. Cooking of the egg profoundly altered the decay curves. CONCLUSION: Avian egg T2 decay curves cover a wide range of decay times. Observed T2 components in yolk and latebra as short as 10 ms, may prove valuable for testing clinical sequences designed to measure short T2 components, such as myelin associated water in the brain. Thus we propose that the egg can be a versatile and widely available MR transverse relaxation phantom. PMID- 26037129 TI - Past five-year trend, current prevalence and household knowledge, attitude and practice of malaria in Abeshge, south-central Ethiopia. AB - BACKGROUND: In Ethiopia malaria remains a leading cause of outpatient consultation despite massive control efforts. This study was aimed at analysing 5 year retrospective trend and current prevalence of malaria as well as community knowledge, attitude and practice (KAP) in Walga Health Centre (WHC) catchment area in Abeshge District, south-central Ethiopia. METHODS: A cross-sectional, household survey was conducted to determine malaria prevalence and KAP in December 2013. Further, malaria cases reported from WHC in 2008-2012 were extracted. A multi-stage, random sampling technique was used to select study participants from four kebeles. Of 800 participants, 400 were interviewed to assess their KAP about malaria and the other half were recruited for malaria microscopy. RESULTS: Overall, 11,523 (33.8%) slide-confirmed malaria cases were reported (no fatalities) among 34,060 outpatients diagnosed in 2008-2012. There was successively significant decline in malaria prevalence from 2009 onwards although a significant rise was noticed in 2009 compared to 2008 (p<0.0001). Male malaria suspects (17,626) were significantly higher than of females (16,434) (p=0.0127) but malaria prevalence was not significantly variable between sexes. Individuals who were >=15 years constituted 44.9% of the patients. Although most participants (78.8%) associated mosquito bites with malaria, the remaining mentioned exposure to rain or body contact with malaria patients as causes of malaria. Mosquito nets, draining stagnant water and indoor residual spraying were the most frequently mentioned malaria preventive measures. In the parasitological survey, a single individual (0.25%) with mixed Plasmodium falciparum-Plasmodium vivax infections was found. CONCLUSION: Although malaria remains a primary cause of outpatient admission in WHC, the retrospective data showed a significantly declining trend. This together with the very low prevalence in the current parasitological survey suggests the effectiveness of ongoing control interventions in the locality. PMID- 26037130 TI - Optimised extraction of beta-carotene from Spirulina platensis and hypoglycaemic effect in streptozotocin-induced diabetic mice. AB - BACKGROUND: Spirulina platensis is rich in beta-carotene, which possesses many important biological activities. This study investigated the ultrasound-assisted extraction and purification of beta-carotene from Spirulina platensis by using response surface methodology (RSM), determined its antioxidant capacity in vitro and explored its hypoglycaemic effect in diabetic mice. RESULTS: The raw beta carotene extract with a concentration of 1942.14 +/- 10.03 ug mL(-1) was obtained at the optimised condition by RSM (0.40 of the solid-liquid ratio, 51% of the extraction power, and 17 min of the extraction time), and the purity of evaporated beta-carotene extract reached 816.32 +/- 10.57 mg g(-1) after purified by a NKA-9 resin with a sampling and elution rate of 1 mL min(-1) . The beta carotene extract scavenged 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radicals with the highest ratios of 44 +/- 0.26% and 35 +/- 0.45% respectively, and exhibited strong inhibiting capacity on anti-lipid peroxidation. The blood glucose level of streptozotocin-induced diabetic mice was significantly reduced from 15.81 +/- 1.71 mmol L(-1) to 8.10 +/- 0.88 mmol L(-1) after 10 d administration of the beta-carotene extract [100 mg kg(-1) body weight (BW)], and the increased food and water intakes in the diabetic mice were also significantly relieved after beta-carotene treatment. CONCLUSION: Our results suggested that extraction of beta-carotene from Spirulina platensis had potential prospects in scaled-up industrialisation and healthcare applications. PMID- 26037131 TI - Reply: To PMID 25631867. PMID- 26037132 TI - Evaluation of Factors To Determine Platelet Compatibility by Using Self-Assembled Monolayers with a Chemical Gradient. AB - Intercorrelation among surface chemical composition, packing structure of molecules, water contact angles, amounts and structures of adsorbed proteins, and blood compatibility was systematically investigated with self-assembled monolayers (SAMs) with continuous chemical composition gradients. The SAMs were mixtures of two thiols: n-hexanethiol (hydrophobic and protein-adsorbing) and hydroxyl-tri(ethylene glycol)-terminated alkanethiol (hydrophilic and protein resistant) with continuously changing mixing ratios. From the systematic analyses, we found that protein adsorption is governed both by sizes of proteins and hydrophobic domains of the substrate. Furthermore, we found a clear correlation between adsorption of fibrinogen and adhesion of platelets. Combined with the results of surface force measurements, we found that the interfacial behavior of water molecules is profoundly correlated with protein resistance and antiplatelet adhesion. On the basis of these results, we conclude that the structuring of water at the SAM-water interface is a critical factor in this context. PMID- 26037133 TI - Rapid Detection of Rare Deleterious Variants by Next Generation Sequencing with Optional Microarray SNP Genotype Data. AB - Autozygosity mapping is a powerful technique for the identification of rare, autosomal recessive, disease-causing genes. The ease with which this category of disease gene can be identified has greatly increased through the availability of genome-wide SNP genotyping microarrays and subsequently of exome sequencing. Although these methods have simplified the generation of experimental data, its analysis, particularly when disparate data types must be integrated, remains time consuming. Moreover, the huge volume of sequence variant data generated from next generation sequencing experiments opens up the possibility of using these data instead of microarray genotype data to identify disease loci. To allow these two types of data to be used in an integrated fashion, we have developed AgileVCFMapper, a program that performs both the mapping of disease loci by SNP genotyping and the analysis of potentially deleterious variants using exome sequence variant data, in a single step. This method does not require microarray SNP genotype data, although analysis with a combination of microarray and exome genotype data enables more precise delineation of disease loci, due to superior marker density and distribution. PMID- 26037134 TI - A (15)N CPMG relaxation dispersion experiment more resistant to resonance offset and pulse imperfection. AB - Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion is a powerful NMR method to study protein dynamics on the microsecond-millisecond time scale. J-coupling, resonance offset, radio frequency field inhomogeneity, and pulse imperfection often introduce systematic errors into the measured transverse relaxation rates. Here we proposed a modified continuous wave decoupling CPMG experiment, which is more unaffected by resonance offset and pulse imperfection. We found that it is unnecessary to match the decoupling field strength with the delay between CPMG refocusing pulses, provided that decoupling field is strong enough. The performance of the scheme proposed here was shown by simulations and further demonstrated experimentally on a fatty acid binding protein. PMID- 26037135 TI - Effect of magnetic field fluctuation on ultra-low field MRI measurements in the unshielded laboratory environment. AB - Magnetic field fluctuations in our unshielded urban laboratory can reach hundreds of nT in the noisy daytime and is only a few nT in the quiet midnight. The field fluctuation causes the Larmor frequency fL to drift randomly for several Hz during the unshielded ultra-low field (ULF) nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI) measurements, thus seriously spoiling the averaging effect and causing imaging artifacts. By using an active compensation (AC) technique based on the spatial correlation of the low-frequency magnetic field fluctuation, the field fluctuation can be suppressed to tens of nT, which is a moderate situation between the noisy daytime and the quiet midnight. In this paper, the effect of the field fluctuation on ULF MRI measurements was investigated. The 1D and 2D MRI signals of a water phantom were measured using a second-order low-Tc superconducting quantum interference device (SQUID) in three fluctuation cases: severe fluctuation (noisy daytime), moderate fluctuation (daytime with AC) and minute fluctuation (quiet midnight) when different gradient fields were applied. When the active compensation is applied or when the frequency encoding gradient field Gx reaches a sufficiently strong value in our measurements, the image artifacts become invisible in all three fluctuation cases. Therefore it is feasible to perform ULF-MRI measurements in unshielded urban environment without imaging artifacts originating from magnetic fluctuations by using the active compensation technique and/or strong gradient fields. PMID- 26037137 TI - Polarization of core orbitals and computation of nuclear quadrupole coupling constants using Gaussian basis sets. AB - Most standard Gaussian basis sets for first row atoms, even large sets designed to converge on a 'complete basis set' limit, systematically overestimate the electric field gradient at nuclear sites for first row atoms, resulting in errors of up to 15% in the computation of nuclear quadrupole coupling constants. This error results from a failure to include tight d functions, which permit the core 1s orbitals to distort under the influence of the field of the nuclear quadrupole. Augmentation of standard basis sets with a single set of single exponent d functions, matched to the reciprocal square of the nominal 1s radius, reduces these errors by up to 90%. PMID- 26037136 TI - Nuclear spin hyperpolarization of the solvent using signal amplification by reversible exchange (SABRE). AB - Here we report the polarization of the solvent OH protons by SABRE using standard iridium-based catalysts under slightly acidic conditions. Solvent polarization was observed in the presence of a variety of structurally similar N-donor substrates while no solvent enhancement was observed in the absence of substrate or para-hydrogen (p-H2). Solvent polarization was sensitive to the polarizing field and catalyst:substrate ratio in a manner similar to that of substrate protons. SABRE experiments with pyridine-d5 suggest a mechanism where hyperpolarization is transferred from the free substrate to the solvent by chemical exchange while measured hyperpolarization decay times suggest a complimentary mechanism which occurs by direct coordination of the solvent to the catalytic complex. We found the solvent hyperpolarization to decay nearly 3 times more slowly than its characteristic spin-lattice relaxation time suggesting that the hyperpolarized state of the solvent may be sufficiently long lived (~20s) to hyperpolarize biomolecules having exchangeable protons. This route may offer future opportunities for SABRE to impact metabolic imaging. PMID- 26037138 TI - Association between apolipoprotein A-IV concentrations and chronic kidney disease in two large population-based cohorts: results from the KORA studies. AB - BACKGROUND: Apolipoprotein A-IV (apoA-IV) is an anti-atherogenic and antioxidative glycoprotein. Plasma apoA-IV levels are elevated in patients with primary chronic kidney disease (CKD) or renal failure. The association between apoA-IV and kidney function has not been investigated in the general population; therefore, we analysed this relationship in two large population-based cohorts. METHODS: Plasma apoA-IV concentrations were measured in the Cooperative Health Research in the Region of Augsburg (KORA) F3 (n = 3159) and KORA F4 (n = 3061) studies. CKD was defined by the serum creatinine-estimated glomerular filtration rate (eGFR) and/or urine albumin-to-creatinine ratio. RESULTS: Mean (+/-SD) apoA IV concentration was 17.3 +/- 4.7 mg dL(-1) in KORA F3 and 15.3 +/- 4.3 mg dL(-1) in KORA F4. Fully adjusted linear mixed models revealed a significant association between apoA-IV concentration and lower eGFR in the third and fourth versus the first quartile of apoA-IV (beta = -1.78 mL min(-1) /1.73 m2, P = 0.0003 and beta = -5.09 mL min(-1) /1.73 m2, P = 2.83 * 10(-23) , respectively). ApoA-IV was significantly associated with an eGFR of <60 mL min(-1) /1.73 m2, which was observed in 601 of the 6220 study participants [odds ratio (OR) 1.46, P = 0.03 and OR 3.47, P = 6.84 * 10(-15) for the third and fourth vs. the first quartile of apoA-IV, respectively]. Adding apoA-IV (fourth vs. first quartile) to the fully adjusted model significantly improved discrimination of eGFR <60 mL min(-1) /1.73 m2 in KORA F3 [integrated discrimination improvement (IDI) 0.03, P = 1.30 * 10(-7) ] and KORA F4 (IDI 0.04, P = 1.32 * 10(-9) ) beyond classical risk factors for CKD. CONCLUSION: The present analysis in two population-based cohorts revealed that high plasma apoA-IV concentrations are strongly associated with low kidney function defined by eGFR independent of major CKD risk factors. ApoA-IV appears to be an early marker of impaired kidney function. PMID- 26037140 TI - Leadership development in undergraduate education. PMID- 26037139 TI - Erratum to: Clostridium Difficile Infection from a Surgical Perspective. PMID- 26037141 TI - Prefibrillar huntingtin oligomers isolated from HD brain potently seed amyloid formation. AB - Many neurodegenerative diseases are associated with deposits of aggregated protein in the brain. The molecular pathways through which soluble proteins misfold to form amyloids and large protein aggregates often include diverse oligomeric species, only some of which progress to the amyloid state. Here we show that prefibrillar huntingtin (HTT) oligomers, isolated from Huntington's disease (HD) affected human brain samples or mouse models, stimulate polyglutamine amyloid formation. Fibrillar HTT oligomers have been shown to be unstable under denaturing conditions and appear not to lead to amyloid formation. Here we show that prefibrillar HTT oligomers are remarkably stable and are potent seeds of polyglutamine amyloid formation. Therefore, our findings help to dissect the complex molecular pathway of HTT misfolding. PMID- 26037142 TI - Hyperproduction of IL-6 caused by aberrant TDP-43 overexpression in high-fat diet induced obese mice. AB - Inclusion of Tat-activating regulatory DNA-binding protein-43 (TDP-43) due to hyperphosphorylation or hyperubiquitination is a cause of neurodegenerative disease. Cellular TDP-43 expression is tightly controlled through a negative feedback loop involving its mRNA. Recently, we reported that the TDP-43-mediated sub-nuclear body is an essential site of interleukin-6 (IL-6) pre-mRNA processing. Here we show that mice fed on a high-fat diet exhibit increased TDP 43 expression in the liver and adipose tissue with a prominent increase in IL-6. TDP-43 depletion in vivo reduces IL-6 production in the liver. Overexpression or depletion of TDP-43 in pre-adipose and adipose cells causes reciprocal alteration of IL-6 expression and RNA processing. Our findings provide evidence for a link between homeostasis of TDP-43 expression and the risk of developing obesity. PMID- 26037143 TI - Kindlin-2 phosphorylation by Src at Y193 enhances Src activity and is involved in Migfilin recruitment to the focal adhesions. AB - Kindlin-2 regulates external to internal cell signaling by interaction with integrins in a process that involves the tyrosine kinase, Src. However, the underlying mechanisms remain elusive. Here we report that Src binds to and phosphorylates Kindlin-2 at Y193. Reciprocally, Kindlin-2-Y193 phosphorylation activates and maintains Src kinase activity. Kindlin-2-Y193 phosphorylation is also involved in its binding capacity with Migfilin and the recruitment of Migfilin to the focal adhesions. Functionally, we demonstrate that Kindlin-2-Y193 phosphorylation regulates Kindlin-2-mediated cell spreading and migration. These findings suggest that Src, Kindlin-2 and Migfilin together constitute a positive feedback loop that controls Src activity and regulates integrin-mediated cellular functions. PMID- 26037144 TI - Secretin receptor involvement in prion-infected cells and animals. AB - The cellular mechanisms behind prion biosynthesis and metabolism remain unclear. Here we show that secretin signaling via the secretin receptor regulates abnormal prion protein formation in prion-infected cells. Animal studies demonstrate that secretin receptor deficiency slightly, but significantly, prolongs incubation time in female but not male mice. This gender-specificity is consistent with our finding that prion-infected cells are derived from females. Therefore, our results provide initial insights into the reasons why age of disease onset in certain prion diseases is reported to occur slightly earlier in females than males. PMID- 26037145 TI - A coefficient average approximation towards Gutzwiller wavefunction formalism. AB - Gutzwiller wavefunction is a physically well-motivated trial wavefunction for describing correlated electron systems. In this work, a new approximation is introduced to facilitate the evaluation of the expectation value of any operator within the Gutzwiller wavefunction formalism. The basic idea is to make use of a specially designed average over Gutzwiller wavefunction coefficients expanded in the many-body Fock space to approximate the ratio of expectation values between a Gutzwiller wavefunction and its underlying noninteracting wavefunction. To check with the standard Gutzwiller approximation (GA), we test its performance on single band systems and find quite interesting properties. On finite systems, we noticed that it gives superior performance over GA, while on infinite systems it asymptotically approaches GA. Analytic analysis together with numerical tests are provided to support this claimed asymptotical behavior. Finally, possible improvements on the approximation and its generalization towards multiband systems are illustrated and discussed. PMID- 26037146 TI - Linear Polarized Transmission Resonance Raman Studies in Fruits: Experimental Versus Model Calculations. AB - A linear polarized transmission resonance Raman spectroscopic technique was developed to measure the depolarization ratio of different beta-carotene Raman bands in carrot roots and mangos. Basically, this optical property was measured as a function of the vegetal tissue thickness and fruit postharvest lifetime. In general, the depolarization ratio increases as the sample optical thickness does and decreases as the fruit postharvest lifetime increases. In addition, a previous theoretical model was extended by considering the light state of polarization to obtain the depolarization ratio as a function of the sample absorption and scattering coefficient. It was shown how the reported theoretical model is able to satisfactorily describe the fruit optical parameter dependence on both the sample thickness and its postharvest time. Finally, the advantages and limitations of the present technique and theoretical mode are discussed. PMID- 26037147 TI - Flexure-based Roll-to-roll Platform: A Practical Solution for Realizing Large area Microcontact Printing. AB - A continuous roll-to-roll microcontact printing (MCP) platform promises large area nanoscale patterning with significantly improved throughput and a great variety of applications, e.g. precision patterning of metals, bio-molecules, colloidal nanocrystals, etc. Compared with nanoimprint lithography, MCP does not require a thermal imprinting step (which limits the speed and material choices), but instead, extreme precision with multi-axis positioning and misalignment correction capabilities for large area adaptation. In this work, we exploit a flexure-based mechanism that enables continuous MCP with 500 nm precision and 0.05 N force control. The fully automated roll-to-roll platform is coupled with a new backfilling MCP chemistry optimized for high-speed patterning of gold and silver. Gratings of 300, 400, 600 nm line-width at various locations on a 4-inch plastic substrate are fabricated at a speed of 60 cm/min. Our work represents the first example of roll-to-roll MCP with high reproducibility, wafer scale production capability at nanometer resolution. The precision roll-to-roll platform can be readily applied to other material systems. PMID- 26037148 TI - Insights into the unfolding pathway and identification of thermally sensitive regions of phytase from Aspergillus niger by molecular dynamics simulations. AB - Thermal stability is of great importance in the application of commercial phytases. Phytase A (PhyA) is a monomeric protein comprising twelve alpha-helices and ten beta-sheets. Comparative molecular dynamics (MD) simulations (at 310, 350, 400, and 500 K) revealed that the thermal stability of PhyA from Aspergillus niger (A. niger) is associated with its conformational rigidity. The most thermally sensitive regions were identified as loops 8 (residues 83-106), 10 (161 174), 14 (224-230), 17 (306-331), and 24 (442-444), which are present on the surface of the protein. It was observed that solvent-exposed loops denature before or show higher flexibility than buried residues. We observed that PhyA begins to unfold at loops 8 and 14, which further extends to loop 24 at the C terminus. The intense movement of loop 8 causes the helix H2 and beta-sheet B3 to fluctuate at high temperature. The high flexibility of the H2, H10, and H12 helices at high temperature resulted in complete denaturation. The high mobility of loop 14 easily transfers to the adjacent helices H7, H8, and H9, which fluctuate and partially unfold at high temperature (500 K). It was also observed that the salt bridges Asp110-Lys149, Asp205-Lys277, Asp335-Arg136, Asp416-Arg420, and Glu387-Arg400 are important influences on the structural stability but not the thermostability, as the lengths of these salt bridges did not increase with rising temperature. The salt bridges Glu125-Arg163, Asp299-Arg136, Asp266-Arg219, Asp339-Lys278, Asp335-Arg136, and Asp424-Arg428 are all important for thermostability, as the lengths of these bridges increased dramatically with increasing temperature. Here, for the first time, we have computationally identified the thermolabile regions of PhyA, and this information could be used to engineer novel thermostable phytases. Numerous homologous phytases of fungal as well as bacterial origin are known, and these homologs show high sequence similarity. Our findings could prove useful in attempts to increase the thermostability of homologous phytases via protein engineering. PMID- 26037149 TI - Structural-topological preferences and protonation sequence of aliphatic polyamines: a theoretical case study of tetramine trien. AB - A large set of lowest and medium energy conformers of aliphatic tetramine trien was used to uncover structural-topological preferences of poliamines. Numerous common structural features among HL and H 2 L tautomers were identified, e.g., H atoms of protonated functional groups are always involved in intramolecular NH***N interactions and they result in as large and as many as possible rings in lowest energy conformers. Largest, 11-membered, molecular rings stabilize a molecule most and they appeared to be strain free whereas 5-memebred intramolecular rings were most strained (all formed due to NH***N interactions). The CH***HC interactions with QTAIM-defined atomic interaction lines were also found but, surprisingly, mainly in the lowest energy conformers of HL tautomers. According to the non-covalent interaction-based (NCI) analysis, 5-memebered rings formed by CH***HC interactions are not strained and, in general, 3D NCI isosurfaces mimic those obtained for weaker NH***N interactions. Also, 3D NCI isosurfaces found for NH***N and CH***HC interactions, regardless whether linked or not by an atomic interaction line, appeared to be indistinguishable. Using lowest energy conformers, theoretically predicted mixture of primary (HL p ) and secondary (HL s ) forms of trien was found to be in accord with the literature reports; using linear conformers resulted in predicting HL s as the only tautomer formed. In contrast to HF, the overall performance of B3LYP was found satisfactory for the purpose of the study. PMID- 26037150 TI - Simulation and experimental analysis of nanoindentation and mechanical properties of amorphous NiAl alloys. AB - This paper used numerical and experimental methods to investigate the mechanical properties of amorphous NiAl alloys during the nanoindentation process. A simulation was performed using the many-body tight-binding potential method. Temperature, plastic deformation, elastic recovery, and hardness were evaluated. The experimental method was based on nanoindentation measurements, allowing a precise prediction of Young's modulus and hardness values for comparison with the simulation results. The indentation simulation results showed a significant increase of NiAl hardness and elastic recovery with increasing Ni content. Furthermore, the results showed that hardness and Young's modulus increase with increasing Ni content. The simulation results are in good agreement with the experimental results. Adhesion test of amorphous NiAl alloys at room temperature is also described in this study. PMID- 26037151 TI - Perception of sexuality and fertility in women living with HIV: a questionnaire study from two Nordic countries. AB - INTRODUCTION: As the human immunodeficiency virus (HIV)-positive population ages, issues concerning sexuality and fertility, among others, are becoming relevant. HIV is still surrounded by stigma and taboos, and there have been few studies conducted in industrialized settings concerning these questions. We therefore wanted to investigate the perception of sexuality and fertility in women living with HIV (WLWH) in an industrialized setting, using a questionnaire. METHODS: WLWH were recruited at their regular outpatient clinic visits, at the major Departments of Infectious Diseases in Denmark and Finland, from January 2012 to October 2013. A questionnaire was developed, study participants were informed of the nature of study and, if they agreed to participate and signed a consent form, they filled in the questionnaire. Demographic information on the participants was obtained from patient files (in Finland) or from a national HIV cohort (in Denmark). Statistical analysis was performed using STATA, version 11. RESULTS: In total, 560 women were included in the study. The median age was 44 years. The majority were of white European origin, with fully suppressed HIV viral load, CD4 cell count >350 uL and mild or no symptoms of their HIV infection. A total of 62% were sexually active, stating condom use as their sole form of contraception. Of the sexually inactive women, one-third were in steady relationships. Eighty percent reported prior pregnancies, of which the majority had one or more children. Most children were born prior to the women's HIV diagnosis and the mode of conception was predominantly natural. One-quarter of the participating women desired pregnancy, while more than half did not. The remaining quarter either stated that they already had the desired number of children or chose not to answer the question. Fourteen percent stated that their HIV diagnosis ended their wish for children; of these women, the median time of diagnosis was between 1995 and 1996. Pregnancy had been attempted unsuccessfully in one-quarter of study participants. The final question inquired what the risk of mother-to-child transmission was, with all precautions taken. Fifteen percent estimated the risk to be above two percent. CONCLUSIONS: In conclusion, the majority of WLWH in industrialized settings in Denmark and Finland have few HIV-related symptoms, are sexually active and have a strong desire for children. PMID- 26037152 TI - MED12 and uterine smooth muscle oncogenesis: State of the art and perspectives. AB - MED12 is a subunit of the multiprotein complex Mediator, an evolutionary conserved regulator of transcription. Oncogenic mutations in exon 2 of MED12 occur in nearly 70% of uterine leiomyomas, and together with HMGA, represent the most common genetic anomalies in leiomyoma. This mutational anomaly represents a driver mutation. MED12 mutations are restricted to benign smooth muscle tumours (leiomyomas) of the uterus or of the Mullerian system, but decreased protein expression has also been observed in uterine leiomyosarcomas independently of mutational status, suggesting a possible epigenetic mechanism. The discovery of MED12 involvement in leiomyoma genesis has dramatically contributed to increasing our knowledge on leiomyomas, but many questions remain. Here we summarise the current state of knowledge and perspectives on the role of MED12 in the genesis of uterine smooth muscle tumours. PMID- 26037153 TI - Guilt by Association--A Closer Look at Calcium, Heart Failure, and Mortality. PMID- 26037154 TI - Screening of BCOR-CCNB3 sarcoma using immunohistochemistry for CCNB3: A clinicopathological report of three pediatric cases. AB - BCOR-CCNB3 sarcoma is a recently recognized tumor morphologically and clinically simulating Ewing sarcoma. We herein retrospectively collected clinicopathologic data on BCOR-CCNB3 sarcoma in the Kyoto University Hospital over the last 10 years. Three (20%) bone sarcomas were revealed to be diffusely positive for CCNB3 immunohistochemistry among 15 pediatric cases of undifferentiated sarcoma morphologically similar to Ewing sarcoma, while the other cases showed completely negative staining. The three patients with immunohistochemically CCNB3-positive tumors were all male, aged between 11 and 17, and confirmed to have the BCOR CCNB3 fusion transcript by RT-PCR. Radiologically, all cases had well-demarcated solid masses with bone destruction. Although the tumors were basically small round cell tumors, less monomorphic histological patterns such as short spindle cells, a myxoid matrix, and hemangiopericytoma-like pattern were also observed in both biopsy and resected specimens. Two patients achieved a complete response after chemotherapy for Ewing sarcoma and osteosarcoma, respectively. These results demonstrated that the application of CCNB3 immunostaining was useful for differentiating BCOR-CCNB3 from a group of 'Ewing-like sarcomas' and may contribute to the evaluation of treatment strategies for bone sarcomas. PMID- 26037155 TI - Small heterodimer partner (SHP) links hepatitis C and liver fibrosis: a small protein on the big stage. PMID- 26037156 TI - Acute effects of cocaine and cannabis on response inhibition in humans: an ERP investigation. AB - Substance abuse has often been associated with alterations in response inhibition in humans. Not much research has examined how the acute effects of drugs modify the neurophysiological correlates of response inhibition, or how these effects interact with individual variation in trait levels of impulsivity and novelty seeking. This study investigated the effects of cocaine and cannabis on behavioural and event-related potential (ERP) correlates of response inhibition in 38 healthy drug using volunteers. A double-blind placebo-controlled randomized three-way crossover design was used. All subjects completed a standard Go/NoGo task after administration of the drugs. Compared with a placebo, cocaine yielded improved accuracy, quicker reaction times and an increased prefrontal NoGo-P3 ERP. Cannabis produced opposing results; slower reaction times, impaired accuracy and a reduction in the amplitude of the prefrontal NoGo-P3. Cannabis in addition decreased the amplitude of the parietally recorded P3, while cocaine did not affect this. Neither drugs specifically affected the N2 component, suggesting that pre-motor response inhibitory processes remain unaffected. Neither trait impulsivity nor novelty seeking interacted with drug-induced effects on measures of response inhibition. We conclude that acute drug effects on response inhibition seem to be specific to the later, evaluative stages of response inhibition. The acute effects of cannabis appeared less specific to response inhibition than those of cocaine. Together, the results show that the behavioural effects on response inhibition are reflected in electrophysiological correlates. This study did not support a substantial role of vulnerability personality traits in the acute intoxication stage. PMID- 26037157 TI - Development of a sensitive UPLC-ESI-MS/MS method for quantification of sofosbuvir and its metabolite, GS-331007, in human plasma: Application to a bioequivalence study. AB - A rapid and simple LC-MS/MS method was developed and validated for the simultaneous estimation of sofosbuvir (SF) and its metabolite GS-331007 (GS) using famotidine as an internal standard (IS). The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Extraction with ethyl acetate was used in sample preparation. The prepared samples were chromatographed on Acquity UPLC HSS C18 (50 mm * 2.1 mm, 1.8 MUm) column by pumping 0.1% formic acid and acetonitrile (50:50, v/v) in an isocratic mode at a flow rate of 0.3 ml/min. Method validation was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 10 2500 ng/ml for both SF and its metabolite. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A very short run time of 1.2 min made it possible to analyze more than 300 human plasma samples per day. The developed assay method was successfully applied to a bioequivalence study in human volunteers. PMID- 26037158 TI - Development and validation of a bioanalytical method for the simultaneous determination of heroin, its main metabolites, naloxone and naltrexone by LC MS/MS in human plasma samples: Application to a clinical trial of oral administration of a heroin/naloxone formulation. AB - A bioanalytical method using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification of heroin, its main metabolites and naloxone. In addition, naltrexone was detected qualitatively. This method was used to analyse human plasma samples from a clinical trial after oral administration of a heroin/naloxone formulation in healthy volunteers. O-methylcodeine was used as an internal standard. Samples were kept in an ice-bath during their processing to minimize the degradation of heroin. A short methodology based on protein precipitation with methanol was used for sample preparation. After protein precipitation, only the addition of a formic acid solution was needed to elute heroin, 6-monoacetylmorphine, morphine, naloxone and naltrexone. Morphine metabolites were evaporated to dryness and reconstituted in a formic acid solution. Chromatographic separation was achieved at 35 degrees C on an X-Bridge Phenyl column (150 * 4.6 mm, 5 MUm) using a gradient elution with a mobile phase of ammonium formate buffer at pH 3.0 and formic acid in acetonitrile. The run time was 8 min. The analytes were monitored using a triple quadrupole mass spectrometer with positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode. The method was found to be linear in a concentration range of 10-2000 ng/mL for M3G and 10-1000 ng/mL for the rest of compounds. Quality controls showed accurate values between -3.6% and 4.0% and intra- and inter-day precisions were below 11.5% for all analytes. The overall recoveries were approximately 100% for all analytes including the internal standard. A rapid, specific, precise and simple method was developed for the determination of heroin, its metabolites, naloxone and naltrexone in human plasma. This method was successfully applied to a clinical trial in 12 healthy volunteers. PMID- 26037159 TI - Metabolomic quality control of commercial Asian ginseng, and cultivated and wild American ginseng using (1)H NMR and multi-step PCA. AB - Ginseng, mainly Asian ginseng and American ginseng, is the most widely consumed herbal product in the world . However, the existing quality control method is not adequate: adulteration is often seen in the market. In this study, 31 batches of ginseng from Chinese stores were analyzed using (1)H NMR metabolite profiles together with multi-step principal component analysis. The most abundant metabolites, sugars, were excluded from the NMR spectra after the first principal component analysis, in order to reveal differences contributed by less abundant metabolites. For the first time, robust, distinctive and representative differences of Asian ginseng from American ginseng were found and the key metabolites responsible were identified as sucrose, glucose, arginine, choline, and 2-oxoglutarate and malate. Differences between wild and cultivated ginseng were identified as ginsenosides. A substitute cultivated American ginseng was noticed. These results demonstrated that the combination of (1)H NMR and PCA is effective in quality control of ginseng. PMID- 26037160 TI - A novel HPLC-MS/MS method for the simultaneous determination of astemizole and its major metabolite in dog or monkey plasma and application to pharmacokinetics. AB - Astemizole (AST), a second-generation antihistamine, is metabolized to desmethyl astemizole (DEA), and although it has been removed from the market for inducing QT interval prolongation, it has reemerged as a potential anticancer and antimalarial agent. This report describes a novel high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneously determining the concentrations of AST and DEA in beagle dog and cynomolgus monkey plasma with simple preparation method and short retention time. Prior to HPLC analyses, the plasma samples were extracted with simple liquid-liquid extraction method. The isocratic mobile phase was 0.025% trifluoroacetic acid (TFA dissolved in acetonitrile) and 20 mM ammonium acetate (94:6) at a flow rate of 0.25 mL/min and diphenhydramine used as internal standard. In MS/MS analyses, precursor ions of the analytes were optimized as protonated molecular ions: [M+H](+). The lower limit of quantification of astemizole was 2.5 ng/mL in both species and desmethyl astemizole were 7.5 ng/mL and 10 ng/mL in dog and monkey plasma, respectively. The accuracy, precision, and stability of the method were in accordance with FDA guidelines for the validation of bioanalytical methods. Finally this validated method was successfully applied to a pharmacokinetic study in dogs and monkeys after oral administration of 10 mg/kg AST. PMID- 26037161 TI - UPLC-MS/MS method for the simultaneous quantification of anti-HBV nucleos(t)ides analogs: Entecavir, lamivudine, telbivudine and tenofovir in plasma of HBV infected patients. AB - Hepatitis B infection affects two billion people worldwide and 350 million of these are chronically infected. Chronic hepatitis B virus is one of the most important cause of mortality and morbidity worldwide. If it is left untreated, about one-third of affected people will develop progressive and possibly fatal liver disease, like hepatic cirrhosis and primary hepatocellular carcinoma. Currently, five nucleos(t)ide analogs are approved for the treatment of chronic HBV infection. They are: lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. In this work, we developed and validated an UPLC-Tandem mass spectrometry assay method capable of monitoring lamivudine, telbivudine, tenofovir and entecavir plasma concentrations. Both standards and quality controls (high, medium and low) were prepared in human plasma. Each sample was added with internal standard (5'amino-5'deoxy-thymidine) and then drugs were extracted through a protein precipitation protocol with acetonitrile+0.1% formic acid and then dried. The extracts were resuspended in water and then injected into the chromatographic system. The chromatographic separation was performed on an Acquity UPLC HSS T3 1.8 MUm 2.1 * 150 mm column, with a gradient of water and acetonitrile, both added with formic acid (0.05%). Accuracy, intra-day and inter-day precision at quality controls levels fitted all FDA guidelines for all analytes, while matrix effects and recoveries resulted stable between samples for each analyte. Finally, we tested this method by monitoring plasma concentrations in 30 HBV+ patients with good results. This simple analytical method could represent a useful tool for the management of anti HBV therapy. PMID- 26037162 TI - New approach of validation using internal normalization technique for quantification of related substances in raw material, intermediates and pharmaceutical substances by HPLC. AB - Internal normalization (IN) serves as a quantitative tool in gas chromatography. Nevertheless, its utilization in liquid chromatography is not widely employed, as several requirements need to be taken into account. However, IN can be used in case of relative amounts estimation when the absolute concentration is not the crucial factor. This suits very well in pharmaceutical analysis when the relative amount of active pharmaceutical ingredient (API) impurities is to be estimated with a limited knowledge of statistics, such as t-test and linear regression. The determination of three prasugrel impurities in the real sample by means of IN and the comparison of these results with external standard calibration was presented. The IN method was validated by test of population means and variances agreement and the agreement of external calibration and IN was performed by Student t-test. The influence of impurities concentration above and below is also discussed as well as the validation parameters, LOD and LOQ. It was found that the results achieved by external calibration and IN are statistically the same and, therefore, IN is a proper method for relative amount estimation of API impurities. PMID- 26037163 TI - Molecularly imprinted polymer for chlorogenic acid by modified precipitation polymerization and its application to extraction of chlorogenic acid from Eucommia ulmodies leaves. AB - Molecularly imprinted polymers (MIPs) for chlorogenic acid (CGA) were prepared by modified precipitation polymerization using methacrylic acid as a functional monomer, divinylbenzene as a crosslinker and methanol or dimethylsulfoxide as a co-solvent. The prepared MIPs were microspheres with a narrow particle size distribution. Binding experiments and Scatchard analyses revealed that two classes of binding sites, high and low affinity sites, were formed on the MIP. The retention and molecular-recognition properties of the prepared MIP were evaluated using a mixture of water and acetonitrile as a mobile phase in hydrophilic interaction chromatography. With an increase of acetonitrile content, the retention factor of CGA was increased on the MIP. In addition to shape recognition, hydrophilic interactions seem to work for the recognition of CGA on the MIP. The MIP had a specific molecular-recognition ability for CGA, while other related compounds, such as caffeic acid, gallic acid, protocatechuic acid and vanillic acid, could not be recognized by the MIP. Furthermore, the MIP for CGA was successfully applied for extraction of CGA in the leaves of Eucommia ulmodies. PMID- 26037165 TI - Self-(Un)rolling Biopolymer Microstructures: Rings, Tubules, and Helical Tubules from the Same Material. AB - We have demonstrated the facile formation of reversible and fast self-rolling biopolymer microstructures from sandwiched active-passive, silk-on-silk materials. Both experimental and modeling results confirmed that the shape of individual sheets effectively controls biaxial stresses within these sheets, which can self-roll into distinct 3D structures including microscopic rings, tubules, and helical tubules. This is a unique example of tailoring self-rolled 3D geometries through shape design without changing the inner morphology of active bimorph biomaterials. In contrast to traditional organic-soluble synthetic materials, we utilized a biocompatible and biodegradable biopolymer that underwent a facile aqueous layer-by-layer (LbL) assembly process for the fabrication of 2D films. The resulting films can undergo reversible pH-triggered rolling/unrolling, with a variety of 3D structures forming from biopolymer structures that have identical morphology and composition. PMID- 26037164 TI - Total synthesis of tetraacylated phosphatidylinositol hexamannoside and evaluation of its immunomodulatory activity. AB - Tuberculosis, aggravated by drug-resistant strains and HIV co-infection of the causative agent Mycobacterium tuberculosis, is a global problem that affects millions of people. With essential immunoregulatory roles, phosphatidylinositol mannosides are among the cell-envelope components critical to the pathogenesis and survival of M. tuberculosis inside its host. Here we report the first synthesis of the highly complex tetraacylated phosphatidylinositol hexamannoside (Ac2PIM6), having stearic and tuberculostearic acids as lipid components. Our effort makes use of stereoelectronic and steric effects to control the regioselective and stereoselective outcomes and minimize the synthetic steps, particularly in the key desymmetrization and functionalization of myo-inositol. A short synthesis of tuberculostearic acid in six steps from the Roche ester is also described. Mice exposed to the synthesized Ac2PIM6 exhibit increased production of interleukin-4 and interferon-gamma, and the corresponding adjuvant effect is shown by the induction of ovalbumin- and tetanus toxoid-specific antibodies. PMID- 26037166 TI - Origin of the Regioselectivity in the Gas-Phase Aniline+CH3 (+) Electrophilic Aromatic Substitution. AB - Nonadiabatic ab initio molecular dynamics simulations are carried out to monitor the attack of CH3 (+) on aniline in the gas phase to form the corresponding sigma complexes. The reaction is ultrafast and is governed by a single electron transfer within 30 fs, which involves two sequential conical intersections and finally produces a radical pair. Positive-charge allocation in the aromatic compound is found to govern the substitution pattern in ortho, meta, or para position. Although the major products in the first step of the electrophilic aromatic substitution are the ortho and para sigma complexes, initially 26 % of the simulated trajectories also form meta complexes, which then undergo H shifts, mainly to the para position. PMID- 26037167 TI - Expression of the Chemokine Receptors CXCR3, CXCR4, CXCR7 and Their Ligands in Rhabdomyosarcoma. AB - Rhabdomyosarcomas (RMS) are soft tissue malignant tumors of childhood and adolescents. The mechanisms underlying their aggressiveness are still poorly understood. Chemokines are chemotactic proteins involved in pathological processes that have been intensely studied in several types of cancers because of their influence in migration, angiogenesis, or metastases. We analyzed the expression of the chemokine receptors CXCR3, CXCR4 and CXCR7 and their ligands CXCL9, CXCL10, CXCL11 and CXCL12, in 15 RMS samples derived from nine patients. Expression was measured in tumors and primary cultures of RMS by Real-Time Polymerase Chain Reaction, immunostaining and flow cytometry. Our results show that these receptors are widely expressed in RMS. A significant difference between CXCL12/CXCR4, CXCL12/CXCR7, CXCL11/CXCR7 expression ratios was found in alveolar versus embryonal RMS and similarly between CXCL12/CXCR4 and CXCL11/CXCR3 ratios in primary versus recurrent tumors. These findings suggest a possible association between the interrelation of chemokine/chemokine-receptor and an aggressive biological behavior in RMS. PMID- 26037168 TI - Serine Protease Inhibitor Kazal Type 1 (SPINK1) Promotes Proliferation of Colorectal Cancer Through the Epidermal Growth Factor as a Prognostic Marker. AB - Serine protease inhibitor Kazal type-1 (SPINK1), a trypsin kinase inhibitor, is involved in inflammation, cell proliferation and carcinogenesis. The role and association between SPINK1, EGFR and Ki-67 in colorectal adenoma (CRA) and colorectal cancer (CRC) are still unknown. In this study, we used immunohistochemical stain to evaluate expression of SPINK1, EGFR and Ki-67 proteins in 30 CRA and 53 CRC patients semiquantitatively, and then analyzed their correlation with clinicopathologic parameters. Our results revealed that SPINK1 expression was noted in the upper and basal parts of the crypts in CRA and was more intensely related with cellular atypia. EGFR expression was found in 13 out of 30 adenomas, including 9 out of 15 adenomas with dysplasia or synchronous CRC (60 %), and 4 out of 15 adenomas without dysplasia (26.7 %). In CRC, high SPINK1 expression was significantly associated with males (p = 0.041) and advanced disease stage (p = 0.015). EGFR positivity was significantly correlated with higher T stage (p = 0.004) and disease stage (stage I-IV, p = 0.017; early vs. late, p = 0.015). Pearson's correlation showed positive correlation between the SPINK1 intensity and EGFR immunoreactivity (p = 0.011), and Ki-67 and SPINK1 intensity or percentage (p = 0.017 and p = 0.039 respectively). In Kaplan-Meier analyses, patients with high SPINK1 intensity tended to have shorter overall survival (p = 0.03). Concomitant expression of high SPINK1 intensity and EGFR was also identified as being associated with poor prognosis (p = 0.015). In conclusion, high SPINK1 expression is associated with advanced stage and poor prognosis. There is positive correlation between high SPINK1 expression, EGFR immunoreactivity, and high Ki-67 labeling index. The SPINK1 protein seems to play a role in tumor proliferation and malignant transformation through the EGFR pathway. SPINK1 may serve as a prognostic biomarker in therapeutic targeting in the future. PMID- 26037169 TI - Epithelial-Mesenchymal Transition Markers beta-catenin, Snail, and E-Cadherin do not Predict Disease Free Survival in Prostate Adenocarcinoma: a Prospective Study. AB - Current methods for diagnosis and staging of prostate adenocarcinoma are not sensitive enough to distinguish between patients with indolent disease and those that should receive radical treatment. Epithelial-mesenchymal transition (EMT) is a well-characterized process involved in tumor invasion and metastasis. The aim of this study is to analyze the expression of beta-catenin, Snail, and E-cadherin in prostate cancer patients with prospective evaluation of their value in predicting disease-free survival (DFS). One-hundred-and-three consecutive prostate carcinoma patients who underwent radical prostatectomy and 35 patients with benign prostate hyperplasia (BPH) were enrolled. Age, initial PSA level, tumor size and clinical stage were documented for adenocarcinoma patients and they were enrolled in active surveillance with serum PSA levels. Recurrence was defined as PSA level of >= 0.2 ng/ml on at least 2 occasions over a 2-month period. Immunohistochemical staining intensity was scored as negative, weakly positive, moderately positive, and strongly positive. For Snail and beta-catenin immunoreaction, the tumors were considered nuclear positive when more than 5 % of the nuclei of tumor cells were positively stained. Patients with prostate cancer had weaker beta-catenin (p < 0.0001), Snail (p = 0.006), and E-cadherin (p = 0.02) staining when compared to BPH patients and the frequency of nuclear positivity for beta-catenin and Snail were higher in adenocarcinoma group (p < 0.0001). Increased expression and nuclear positivity of beta-catenin were associated with advanced stage (p = 0.012 and p = 0.003) and higher tumor volume (p = 0.013 and p = 0.002). Additionally, patients with increased Snail expression had higher Gleason scores and tumor volume at presentation (p = 0.008 and p = 0.004). However, there were no significant DFS differences in adenocarcinoma patients who did and did not have beta-catenin, Snail, and E-cadherin expression as assessed with log-rank test. Expressions of beta-catenin, Snail, and E cadherin were significantly lower in prostate cancer patients compared to BPH patients and both beta-catenin and Snail had nuclear staining pattern in patients with adenocarcinoma. However, none of these markers predicted DFS in 36-month follow up of our cohort. PMID- 26037170 TI - The joint evolution of traits and habitat: ontogenetic shifts in leaf morphology and wetland specialization in Lasthenia. AB - The interplay between functional traits and habitat associations drives species' evolutionary responses to environmental heterogeneity, including processes such as adaptation, ecological speciation, and niche evolution. Seasonal variation is an aspect of the environment that varies across habitats, and could result in adaptive shifts in trait values across the life cycle of a plant. Here, we use phylogenetic comparative methods to evaluate the joint evolution of plant traits and habitat associations in Lasthenia (Asteraceae), a small clade of predominantly annual plants that have differentiated into an ecologically diverse range of habitats, including seasonal ephemeral wetlands known as vernal pools. Our results support the hypothesis that there is a link between the evolution of leaf morphology and the ecohydrological niche in Lasthenia, and, in the formation of aerenchyma (air space), differentiation between vernal pool and terrestrial taxa is fine-tuned to specific stages of plant ontogeny that reflects the evolution of heterophylly. Our findings demonstrate how the relationships between traits and habitat type can vary across the development of an organism, while highlighting a carefully considered comparative approach for examining correlated trait and niche evolution in a recently diversified and ecologically diverse plant clade. PMID- 26037171 TI - Novel imaging findings in two cases of biotinidase deficiency-a treatable metabolic disorder. AB - Biotinidase deficiency is one of the few treatable inborn errors of metabolism. We describe unique MRI features in two patients with biotinidase deficiency. Brain MRI in case one demonstrated symmetrical diffusion restriction in bilateral hippocampi, parahippocampal gyri, central tegmental tracts, and cerebellar white matter besides other structures that have been reported previously. The second patient was noted to have bilateral symmetrical T2 hyperintensities involving the anterior, lateral and posterior columns of the entire spinal cord on MRI. Knowledge of the varied MRI features of biotinidase deficiency will aid the prompt diagnosis and treatment of a potentially disabling illness, especially in countries where newborn screening is not routinely performed. PMID- 26037173 TI - Neurosurgery in Turkish poetry: three poets, two poems and two neurosurgeons. AB - Poems are essential in art and vital organs in literature. Similarly, surgery (and neurosurgery) is also regarded to be an art in medicine. From Hippocrates to nowadays, there is a debate on whether medicine -especially surgery- is a kind of an art or a field of science or a combination of both. This close relation becomes clearer during the practice of surgery, especially in neurosurgery. Herein, the relation between Turkish poetry and Turkish neurosurgery is being presented by researching the interesting and exciting stories about three poets (Can Yucel, Hasan Huseyin Korkmazgil, Nazim Hikmet), their poems; and two Turkish neurosurgeons (Gazi Yasargil, Yucel Kanpolat). PMID- 26037172 TI - Very high resolution single pass HLA genotyping using amplicon sequencing on the 454 next generation DNA sequencers: Comparison with Sanger sequencing. AB - Compared to Sanger sequencing, next-generation sequencing offers advantages for high resolution HLA genotyping including increased throughput, lower cost, and reduced genotype ambiguity. Here we describe an enhancement of the Roche 454 GS GType HLA genotyping assay to provide very high resolution (VHR) typing, by the addition of 8 primer pairs to the original 14, to genotype 11 HLA loci. These additional amplicons help resolve common and well-documented alleles and exclude commonly found null alleles in genotype ambiguity strings. Simplification of workflow to reduce the initial preparation effort using early pooling of amplicons or the Fluidigm Access ArrayTM is also described. Performance of the VHR assay was evaluated on 28 well characterized cell lines using Conexio Assign MPS software which uses genomic, rather than cDNA, reference sequence. Concordance was 98.4%; 1.6% had no genotype assignment. Of concordant calls, 53% were unambiguous. To further assess the assay, 59 clinical samples were genotyped and results compared to unambiguous allele assignments obtained by prior sequence based typing supplemented with SSO and/or SSP. Concordance was 98.7% with 58.2% as unambiguous calls; 1.3% could not be assigned. Our results show that the amplicon-based VHR assay is robust and can replace current Sanger methodology. Together with software enhancements, it has the potential to provide even higher resolution HLA typing. PMID- 26037174 TI - Minimally invasive approaches in metastatic spinal tumor surgery. AB - The surgical treatment of spinal metastases is still controversial. Due to developments in diagnostic imaging there has been a great evolution in minimally invasive surgical techniques for the spinal surgery. Most of the patients with spinal metastases are debilitated and under high risk of major surgical morbidity and mortality. Less perioperative pain, less blood loss, less hospitalization time, protection of the spine biomechanics, fast recovery and less morbidity in medically debilitated patients are the advantages of minimally invasive surgical techniques. Radiotherapy, chemotherapy or combining both treatments are the standard treatment options for spinal tumors following surgery. Standard open approaches are not suitable for some patients due to limited life expectancies, high surgical complication rates and decrease in quality of life. Minimal invasive techniques represent major advance in minimizing approach related morbidity in the treatment of spinal tumors. Because of the evolution of minimally invasive surgical techniques for the spinal surgery, minimally invasive techniques are alternative treatment to standard open approaches for the treatment of metastatic spinal tumors. Due to less complication rates there has been a trend toward the minimalization of spine surgery. PMID- 26037175 TI - Management of colloid cyst of third ventricle. AB - Colloid cysts are usually located in third ventricle and are believed to be derived from either primitive neuroepithelium or endoderm. Patients may remain asymptomatic for long time while some can present with paroxysmal headache, gait disturbance, nausea, vomiting, behavioral changes, weaknesses of lower limbs, impaired memory, new learning disability and sudden death. Computed tomography usually reveals a well-defined round or oval nonenhancing lesion. Although magnetic resonance imaging (MRI) signal intensity of colloid cysts is variable, the most common appearance is hyperintensity in T1-weighted sequences and iso to hypointensity in T2-weighted sequences. Observation, stereotactic aspiration, microscopic or endoscopic approaches and shunt surgery are various management options. Transcallosal and transcortical microscopic (with or without tubular retractor) approaches are mainly useful in normal-sized and dilated ventricles respectively. Endoscopic technique is an effective alternative to microsurgical technique but total resection and long-term recurrence remains a concern. Utilization of two instruments, the bi port technique and tubular retractor can be helpful in selected patients to overcome limitations. Although total excision should be aimed, subtotal excision and coagulation of residual cyst wall usually results in good long-term results without any growth of remnant wall. Conversion to an open procedure may be required in some patients. PMID- 26037176 TI - Effectiveness of physical therapy and rehabilitation programs starting immediately after lumbar disc surgery. AB - AIM: The aim of this randomized study was to compare exercise program to control group regarding pain, back disability, behavioural outcomes, global health measures and back mobility who underwent microdiscectomy operation. MATERIAL AND METHODS: Thirty patients who underwent lumbar microdiscectomy were randomized into exercise and control groups. After surgery, patients in the exercise group undertook a 12-week home based exercise program, started immediately postsurgery and concentrated on improving strength and endurance of the back, abdominal muscles, lower extremities and mobility of the spine and hips. Outcome measures were: Oswestry Disability Index (ODI), Beck Depression scale, lumbar schober, Visual Analogue Scale (VAS), return to work (return-to-work status), generic functional status (SF-36). RESULTS: Treatment compliance was high in both groups. Surgery improved pain, disability, general health status, lumbar mobility and behavioural status. After the exercise program, the exercise group showed further improvements in these measures at 12 week after surgery. CONCLUSION: A 12-week postoperative exercise program starting immediately after surgery can improve pain, disability, and spinal function in patients who have undergone microdiscectomy. PMID- 26037177 TI - Cavernous sinus invasion and effect of immunohistochemical features on remission in growth hormone secreting pituitary adenomas. AB - AIM: We examined the cavernous sinus invasion and tumor biological markers that influence the remission rate. Cavernous sinus (CS) invasion was evaluated radiologically. Tumor biological markers consisting of the tumor cell growth parameter Ki-67 and the cancer cell vasculature marker of vascular endothelial growth factor (VEGF) were evaluated. MATERIAL AND METHODS: We examined 28 immunohistochemically proven GH secreting pituitary adenoma patients who had been operated via endoscopic transsphenoidal surgery at Department of Neurosurgery, Kocaeli University Hospital between 2003 and 2008. Pathology preparations were stained with Ki-67 and VEGF. We evaluated remission at the postoperative 6th week. The basal GH level, nadir GH level and IGF-1 levels were evaluated to determine remission. RESULTS: Remission was achieved in 6 of 18 patients (33%) who had cavernous sinus invasion. Remission was achieved in 7 of 10 patients (70%) who did not have cavernous sinus invasion. There was no correlation between the Ki-67 proliferation index and cavernous sinus invasion (p=0.593). There was a positive correlation between VEGF expression and cavernous sinus invasion (p=0.03). CONCLUSION: The remission rate found less in the cavernous sinus invasion group. No association was found between Ki 67 proliferation index and cavernous sinus invasion. We found that a positive correlation between VEGF expression and cavernous sinus invasion. VEGF expression can therefore indirectly affect remission via cavernous sinus invasion. PMID- 26037178 TI - Why do the patients reject spinal operations? A preliminary study. AB - AIM: Cases of failed back and spine surgery have increased significantly recently, which leads to patient hesitation in deciding about whether to be operated on. In this article, we present a survey investigating refusal reasons for spinal surgery, and we emphasize the effect of failed back surgery. MATERIAL AND METHODS: A survey was conducted among 100 patients who were admitted to the outpatient clinic of neurosurgery at the Elazig Training and Research Hospital. All of the patients were recommended spinal surgery for various reasons, but did not want to be operated on. Demographic data for the patients, indication of the recommended surgery, the reason for the patient's refusal of the operation, information about previous neurosurgical operations and the history of dissatisfaction with the surgery of an acquaintance were recorded. The data obtained were evaluated statistically and analyzed by percentage. RESULTS: 46 patients stated they had distrust of surgery, and 54 patients did not want to be operated on for personal reasons. When the two groups were compared, neurosurgical operations and the history of dissatisfaction of the patient or an acquaintance was significantly higher in the first group (p < 0.001). It was found that 40% of all the patients (n = 40) had a past unpleasant neurosurgical experience that was either personal or relevant. CONCLUSION: Spinal surgery is a preferred subspecialty of neurosurgery. However, patients' discontent with spinal surgery has been rising gradually in recent years. An accurate indication and proper surgical technique is essential for increasing satisfaction with spinal surgery. Minimally invasive interventions must be considered if necessary. The postoperative expectations of the physician and the patient must also be carefully defined. PMID- 26037180 TI - The analysis of long-term follow-up screening in patients with surgically treated intracranial aneurysms. AB - AIM: To understand the late anatomical results of surgically treated intracranial aneurysms (IA's) and to investigate the incidence of recurrent, de novo aneurysms, the natural history of residual aneurysms, and the morphological changes in temporarily clipped vascular segments. MATERIAL AND METHODS: A total of 117 patients underwent screening with digital subtraction angiography (DSA) or computed tomographic angiography (CTA) in a range of 3 - 13 years. Late angiographies were evaluated in terms of recurrence, change in known residua, the presence of de novo aneurysms and the morphological changes in temporarily clipped vessels. We also analysed the cumulative data including previously published results. RESULTS: In the long-term DSA, three residual aneurysms were observed to be enlarged while four remnants showed no morphological change. In one patient, spontaneous obliteration was seen. No recurrent aneurysm was detected. One de novo aneurysm was observed. We did not find any morphological change in 71 temporarily clipped vascular segments. CONCLUSION: Our data demonstrates that completely occluded aneurysms could remain stable even years later. Most of the small neck residues appeared to remain unchanged or even be thrombosed but they should be carefully followed. The incidence of de novo aneurysms might be expected to be lower. PMID- 26037179 TI - A modified technique for the treatment of isthmic spondylolisthesis. AB - AIM: To describe a modified technique for the treatment of single level, isthmic spondylolisthesis (IS) MATERIAL and METHODS: Forty-two patients who underwent posterior lumbar interbody fusion (PLIF) with spinolaminar autologous bone graft for the treatment of isthmic spondylolisthesis between May 2007 and November 2011, were retrospectively reviewed. All patients underwent total removal of the spinolaminar process, total discectomy and endplate decortication, and proper size spinolaminar autologous bone graft was sequentially inserted into the disc space with posterior instrumentation. Outcomes of the study included visual analogue scale (VAS), Oswestry disability index (ODI), and radiographic fusion. RESULTS: The average duration of follow-up was 3.5 years. Neither has implant failure been observed nor has revision been required so far. The mean Oswestry Disability Index improved from 53% to 9.5%, and visual analog scale for back pain from 8.5 to 3.8 at the first month and 1.3 at the sixth month postoperatively. Visual analog scale for leg pain from 8.3 to 1.4 at the first month and 0.8 at the sixth month postoperatively. All patients had clinical and radiographic evidence of solid fusion without any need for revision. CONCLUSION: The modified posterior lumbar interbody fusion and posterior instrumentation technique is a safe and effective treatment for isthmic spondylolisthesis. PMID- 26037181 TI - Detection and Evaluation of Intracranial Aneurysms with 3D-CT Angiography and Compatibility of Simulation View with Surgical Observation. AB - AIM: The aim of this study was to report our experience with a 64-channel computerized tomography (CT) scanner as the primary choice on the detection of intracranial aneurysms. Comparison of intracranial aneurysms with the simulated images obtained via three-dimensional computed tomography angiography (3D-CTA) in pterional approach was also aimed. MATERIAL AND METHODS: Among 288 consecutive patients who had intracranial aneurysms detected on 64-slice CTA, a total of 337 aneurysms were detected. CTA simulation images and intraoperative images were compared with regards to size, shape, and orientation. RESULTS: In one of the 22 CTA-negative cases, one aneurysm was detected in DSA and an additional aneurysm was detected in a patient operated with CTA. Aneurysm size, shape and direction were error free except a few cases. However, CTA was found to be insufficient to show particularly perforating arteries that were smaller than 2 mm in size. CONCLUSION: As a fast and noninvasive technique, CTA can be used as an initial examination in subarachnoid hemorrhage. Keeping the fact that there can be insufficiency in showing particularly small aneurysms in mind, DSA should be performed on CTA-negative cases and required cases. PMID- 26037182 TI - Comparison of the Surgical Results for Foramen Magnum Decompression with and without Duraplasty in Chiari Malformation Type 1. AB - AIM: The surgical results for foramen magnum decompression (FMD) with and without duraplasty in Chiari Malformation type 1 (CM-1) were compared retrospectively. MATERIAL AND METHODS: Thirty-nine cases of CM-1 with and without syringomyelia (SM) were included. There were 18 patients in the nonduraplasty and 21 in the duraplasty group. Syringomyelia, tonsillar herniation (TH), preoperative symptom duration, and postoperative SM size were compared. RESULTS: No significant difference was found between improvement in the duraplasty group (81%) and the non-duraplasty group (61.1%). In cases whose symptom duration was 0-36 months, improvement in the duraplasty group (93%) was significantly better than in the nonduraplasty group (50%) (p < 0.01). The rate of syrinx regression was 92.3% in the duraplasty group and 12.5% in the non-duraplasty group (p < 0.05). In cases with SM, the improvement was 21.4% in the non-duraplasty group compared to 78.6% in the duraplasty group (p=0.056). In cases with TH greater than 10 mm, the improvement was 66.7% in the non-duraplasty group, whereas all six cases (100%) in the duraplasty group had improved. CONCLUSION: In SM associated cases, cases with TH greater than 10 mm, and whose symptom duration is less than 36 months, duraplasty is a more reliable choice despite a slightly higher rate of complications. PMID- 26037183 TI - Effects of Acorus calamus Rhizome Extract on the Neuromodulatory System in Restraint Stress Male Rats. AB - AIM: Prolonged exposure to stress mainly affects the cognitive functions of the brain by inducing neuronal damage mediated through oxidative stress. Acorus calamus (AC) has long been used in Indian folk medicine for various central nervous system (CNS) abnormalities. Hence the present study investigates the effect AC on learning and memory in rats. MATERIAL AND METHODS: Adult Wistar male rats were subjected to restrained stress for 21 days (6 hr/day) and the animals were concurrently administered AC for 21 days orally. The Hebb-Williams maze and elevated plus maze served as standard behavioural models for testing memory. The rats were sacrificed on 22nd day and the brain homogenate was taken for various biochemical assessments. RESULTS: Sodium potassium ATPase activity and TBARS levels showed a significant decrease in the stress group compared to control. After administration of AC, the activity of Na- K- ATPase and levels of TBARS showed a tendency to revert back to normal. However there was no effect on AOPP levels, even after the treatment, which remained high. CONCLUSION: The present study shows the preventive action of AC rhizome powder on stress induced cognitive functions and modulatory effect on antioxidants and Na-K-ATPase activity. PMID- 26037184 TI - Surgical management of midline anterior skull base meningiomas: experience of 30 cases. AB - AIM: Midline anterior skull base meningiomas include olfactory groove meningiomas (OGMs), Tuberculum Sellae meningiomas (TSMs), and planum sphenoidale meningiomas (PSMs). The main surgical challenge in treating these lesions is to excise the tumor totally without causing mortality or morbidity. Studying the clinical patterns and the surgical outcomes of these lesions. MATERIAL AND METHODS: Thirty cases of midline anterior skull base lesions were included in our study. Patients were operated upon by four routes: (i) unilateral subfrontal, (ii) bilateral subfrontal, (iii) frontotemporal approach, and (iv) bifrontal basal interhemispheric. Extent of resection was classified according to the Simpson grading system. The functional outcome of the patients was assessed by comparing the preoperative and the postoperative neurological examination, as well as the Karnofsky performance scale. RESULTS: We had 14 OGMs (46.7%), 9 TSMs (30%), and 7 PSMs (23.3%). The most commonly utilized approach was the subfrontal approach (unilateral or bilateral) in 80% of the cases, followed by the pterional approach in 16.6% of the cases. Total removal was achieved in 86.7% of the cases; subtotal excision was achieved in 13.3% of the cases. 41.2% of our cases showed postoperative clinical improvement. We had two mortalities in our study, representing 6.7%. We did not detect any tumor recurrences in our follow up. The median preoperative Karnofsky scale was 85, while the median postoperative Karnofsky scale was 90. CONCLUSION: Midline anterior skull base lesions are becoming amenable for total surgical excision with minimal morbidities and mortalities. Most preferred surgical routes are the subfrontal and the pterional approaches. PMID- 26037185 TI - Functional outcome of surgery for glioma directly adjacent to pyramidal tract depicted by diffusion-tensor based fiber tracking. AB - AIM: To investigate the outcome of glioma resection surgery and changes of pyramidal tract (PT) for patients where PT is immediately adjacent to the tumors, which were revealed by diffusion tensor imaging (DTI) based fiber tracking (FT) technique. MATERIAL AND METHODS: 40 patients enrolled. Preoperative and intraoperative tractography of the PT was performed before and after glioma resection. Motor function was recorded before surgery and 1 week, three to six months after surgery. Distances (D) between intraoperative tractography of the PT and the resection cavity were measured. RESULTS: 14 patients had transient aggravated or newly motor deficits 1 week after surgery. After 3 to 6 months follow up, only 3 (7.5%) patients had permanent deficits. In 12 (30%) patients, the intraoperative PT tractogram adjoined the resection cavity after tumor removal (D=0). They all had transient aggravated motor deficits after surgery and 3 were permanent. In 19 patients with preoperative motor deficits, 11 (57.90%) had zero D value. In other 21 patients, 1 (4.76%) had zero D value. There was significant difference between these two ratio (p < 0.01). CONCLUSION: DTI based FT is helpful in protection for the PT during glioma surgery, even if the PT is directly adjacent to the glioma. Patients with preoperative motor deficits faced more risk of persistent aggravated deficits after surgery. PMID- 26037186 TI - Comparison of the Toxicities of Ethylene Vinyl Alcohol Copolymer (EVOH) Preparations, Dimethyl Sulphoxide and N-Butyl 2-Cyanoacrylate on Cerebral Parenchyma in an Experimental Rabbit Model. AB - AIM: Ethylene vinyl alcohol copolymer (EVOH), its organic solvent dimethyl sulfoxide (DMSO), and N-Butyl 2-Cyanoacrylate (NBCA) are widely used in neurovascular embolization procedures and yet with potential risk of cytotoxicity. The aim of this study was to evaluate the toxic effect of EVOH DMSO, its solvent DMSO and NBCA on cerebral parenchyma in a rabbit model. MATERIAL AND METHODS: Forty-eight albino male rabbits were divided into 6 groups based on the substance injected into the parenchyma; normal saline, DMSO, NBCA, 6% EVOH-DMSO and 20% EVOH-DMSO and control group. At 72 hours the subjects were sacrificed and brain samples were harvested for histopathological examination and lipid peroxidase measurements. RESULTS: Neuronal degeneration and inflammatory reaction in the brain parenchyma was prominent especially in DMSO group and EVOHDMSO groups. Furthermore, the extent of degeneration and inflammatory reaction was related to the concentration of the embolic agent in the EVOH group. Lipid peroxidase activity was significantly increased in the NBCA group as compared to all but to 20 % EVOH-DMSO group. CONCLUSION: EVOH and its solvent DMSO cause degeneration and inflammatory reaction in brain parenchyma and for EVOH this reaction was appeared to be dose dependent. PMID- 26037187 TI - Biochemical and histopathological effects of catechin on experimental peripheral nerve injuries. AB - AIM: Catechin is a type of polyphenol, along with epicatechin, epigallocatechin, and epigallocatechin-gallate (EGCG). This study aims to investigate the effect of EGCG, a major metabolite of catechin, which is the principle bioactive compound in green tea, on rats with peripheral nerve injury. MATERIAL AND METHODS: A total of 74 rats were divided into six groups, namely the control, the trauma, the normal saline, a 25mg/kg EGCG, a 50mg/kg EGCG and a daily consumption group (10mg/kg EGCG was given intraperitoneally for 14 days before the trauma). Except the first group, the other groups underwent a 1-minute sciatic nerve compression by clip with 50gr/cm2 pressure. Nerve samples were obtained at 28 day after trauma for the biochemical and histopathological analysis. RESULTS: Our study showed that the Daily consumption, 25mg/kg EGCG and 50mg/kg EGCG groups demonstrated statistically significant decreased lipid peroxidation levels and particularly daily consumption, and the 25mg/kg EGCG group showed a favourable reduction of degeneration and edema histologically. CONCLUSION: This study shows that Catechin and its derivatives have a protective effect on peripheral nerve injury. PMID- 26037188 TI - Pain perception differences between patients and physicians: a pain severity study in patients with low back pain. AB - AIM: Perception, definition and tolerance of pain vary individually because of its subjective character. This study aimed to determine the perception differences between patients with mechanical low back pain (MLBP) and their physicians regarding the assessments of the patients' pain severity. MATERIAL AND METHODS: 181 patients with MLBP and 2 physicians took part in the study. Before the initial examination, the patients filled out a questionnaire consisting of demographic data, pain characteristics, Modified Oswestry Disability Questionnaire (MODQ) and Visual Analog Scale (VAS). The patients' forms were concealed from the physicians. Then physicians examined their patients and rated their pain severity using a different VAS form. RESULTS: The mean age of the patients was 36.2 +/- 12.3 years. 64.6% (n:117) were female, 71.9% (n:13) were highly educated and 57.1% (n:103) were obese. Physicians always rated the patients' pain severity significantly lower than the patients rated their own pain regardless of all demographic data (p < 0.001). Correlation between the VAS scores of patients and physicians were detected as 0.41 (p < 0.001) and the power of the study was calculated as 91.5%. The mean MODQ score of the patients was calculated as 54.4 +/- 21.1. Reliability of the questions in MODQ was calculated as alpha:0.87. A moderate correlation between VAS ratings and MODQ was observed (r:0.52, p < 0.001). CONCLUSION: As a main factor directly affecting many outcomes, good communication between patient and physician, is essential to assess the patients' pain more accurately. PMID- 26037189 TI - Pituitary macroadenoma coexistent with a posterior circulation aneurysm leading to subarachnoidal hemorrhage during transsphenoidal surgery. AB - The coexistence of cerebral aneurysm and pituitary adenoma has been described previously. Most of such cases harbor functional tumors and anterior circulation aneurysms, with very rare cases of posterior circulation aneurysms. In this report, we present a case of subarachnoidal hemorrhage due to rupture of an undetected basilar apex aneurysm during microscopic transsphenoidal surgery for a nonfunctional pituitary adenoma. Subarachnoidal hemorrhage following transsphenoidal surgery is a rare event. The concurrence of posterior circulation aneurysm and nonfunctional adenoma is uncommon too. Neuroimaging of cerebrovascular circulation before surgical treatment of pituitary adenoma, although controversial, would be helpful to evaluate vascular involvement and rule out any potential concurrent cerebrovascular diseases. Open or endovascular treatment of unruptured intracranial aneurysms carries relatively low morbidity and may be considered prior to other elective intracranial procedures like transsphenoidal surgery. PMID- 26037190 TI - Giant cell tumor of the sixth thoracic vertebra: case report. AB - Giant cell tumor is an uncommon but most aggressive benign tumour of the spine with unpredictable outcome and challenging treatment. Spinal giant cell tumors located above the sacrum are rare and treatment recommendations are still unclear. We report a rare case of this lesion in an adult and discuss the management and outcome of such uncommon tumors. A 31-year-old woman presented with progressive motor weakness of both lower limbs with back pain during the past month, associated with sphincter disturbances for the past two days. She was diagnosed with a lytic heterogeneously enhancing mass depending mainly on the T6 posterior arch with small vertebral body involvement. The tumor extent reached surrounding soft tissue and the spinal canal with marked spinal cord compression. A posterior approach was realized as an emergency. Histological examination showed evidence of a giant cell tumor and a complementary irradiation was used. The patient improved well post operatively. There was no recurrence or metastasis over 5 years of follow-up. PMID- 26037191 TI - Embolization in the treatment of an intraosseous glomus tumor in the upper thoracic spine complicating compression myelopathy: a case report and a literature review. AB - Glomus tumors are very infrequent in the spine. The lesions can grow intraosseously along the entire spinal axis. A single female presenting with back pain from the upper thoracic spine is reported on. Removal of this lesion may require reconstruction of the anterior column with posterior fixation resulting in significant blood loss. The current report describes an embolization procedure prior to removal in order to reduce the significant blood loss that occurs with removal of this lesion, and summarizes the clinical and pathological characteristics of this rare tumor. A single, recent case and removal of an intraosseous tumor arising from the upper thoracic vertebra of T2-T4 is described. A 45-year-old female presenting with symptoms secondary to a glomus tumor of the upper thoracic vertebra of T2-T4 underwent resection of the lesion followed by reconstruction of the anterior column following preoperative emobolization. She had neurological symptoms for 3 years, and an irregular crescent-shaped lesion was seen going through the foramen at T3 to the chest cavity in the MRI scans. The operation was performed with a posterior approach in a single stage. The use of preoperative embolization of the T2-T4 segmental arteries resulted in significantly less blood loss as compared to without an embolization procedure. It was confirmed by histopathological examination that the glomus tumor rose from the smooth muscle cells in the right paravertebral muscles of T2. The glomus tumor has not recurred in the MRI during the five-year follow-up. Intraosseous glomus tumors are rare lesions that may extend into the epidural space and through the neural foramina and chest compartments resulting in neurological compromise. Over time, they may grow very large. Radiotherapy can be useful for eradication of this rare lesion. However, it can reoccur requiring extensive surgery resulting in significant blood loss. Preoperative embolization results in a reduction of blood loss and can be a very useful technique when performing the resection of large lesions suspected to be glomus tumors. PMID- 26037192 TI - Subarachnoid and intracerebral hemorrhage after alcohol ingestion and illicit use of sildenafil. AB - Sildenafil is a drug used in the treatment of male impotence. Few cases of spontaneous intracerebral hemorrhage following the use of sildenafil have been cited in the literature. A 42-year-old man was admitted to the emergency outpatient clinic of Istanbul Educational and Research Hospital after sudden loss of consciousness. He had ingested alcohol, taken 50mg sildenafil and had sexual intercourse. Non-contrast cranial tomography revealed an intracerebral hematoma with extension to the ventricles. Sildenafil is a selective phosphodiesterase-5 enzyme inhibitor. With the inhibition of PDE-5, the amount of cyclic-guanosine monophosphate (c-GMP) in the smooth vascular muscle cells in the corpus cavernosum increases, leading to a relaxation of muscles and vasodilatation. Studies have shown that the NO-c-GMP pathway leads to cerebral vasodilatation with a similar mechanism. The literature has shown that the effect of PDE-1 and PDE-2 on cerebral bleeding control is affected by sildenafil. This increased blood flow increases the risk of intracranial haemorrhage. Although data concerning the presentation of intracerebral hematoma in connection with the combined use of alcohol ingestion and use of sildenafil is inadequate, it can nevertheless be thought that the combined use increases the risk of spontaneous intracerebral hemorrhage and caution is in order concerning the matter. PMID- 26037193 TI - Endoscopic transaqueductal removal of fourth ventricular neurocysticercosis: report of three cases. AB - In this study, we try to present our experience of transaqueductal removal of the fourth ventricular neurocysticercosis (FVNCC) with a flexible neuroendoscope. Three cases of the fourth ventricular cysticercosis were transaqueductally removed with FUJINON EB-270P flexible neuroendoscope through a frontal precoronal burr hole. The diagnosis was established on imaging and confirmed on histology in all of the cases. Complete excision of cysts in the fourth ventricle was performed in all cases with no significant intraoperative or postoperative complications. The shunt and the string-of-beads multiple cysts in the basal cistern were removed simultaneously through the orificium fistulae of the third ventricle floor with the flexible neuroendoscope. Satisfactory postoperative CSF flow around foramen magnum was detected by cine phase-contrast magnetic resonance imaging. All of the patients were asymptomatic, with an average follow-up of 6 months. The whole ventricular system can be explored easily with electrical flexible neuroendoscope. Endoscopic transaqueductal removal of the fourth ventricular cysticercosis with a flexible neuroendoscope should be recommended as the optimal choice of the disease due to its minimal invasion, fewer complications, shorter length of stay and cheaper treatment costs. PMID- 26037194 TI - Multifocal lateral and fourth ventricular primary central nervous system lymphoma: case report and literature review. AB - We report a 66-year-old man with 2-month history of dizziness and 1-month history of diplopia. Cranial magnetic resonance imaging (MRI) disclosed two solid masses, one in the right lateral ventricle and another in the fourth ventricle. A surgical biopsy was performed on the basis of safety. The diagnosis of large B cell lymphoma was made postoperatively. The patient recovered without additional deficits and was then commenced on chemotherapy and remained well 6 months after the diagnosis. Primary B-cell lymphomas should always be included in the list of differential diagnosis of intraventricular tumors. Here we report an extremely rare case of primary central nervous system lymphoma with multifocal ventricular involvement. PMID- 26037195 TI - Co-occurrence of intracranial Rosai-Dorfman disease and Langerhans histiocytosis of the skull: case report and review of literature. AB - Rosai-Dorfman Disease involves histiocytic proliferation of the lymphatic system. Extranodal disease involving the central nervous system is uncommon. Furthermore, the combination of this disease entity with Langerhans cell histiocytosis is an even rarer phenomenon that has only recently been highlighted. A young male, who had previously undergone surgical excision of a skull lesion that was reported as Langerhans histiocytosis presented with an intracranial lesion mimicking a meningioma. Histopathology of the lesion was reported as being consistent with Rosai-Dorfman disease and the patient is currently undergoing chemotherapy. This is only the second report of the co-occurrence of Langerhans histiocytosis and Rosai-Dorfman disease in the cranium and intracranial cavity. The possibility that the diseases represent different spectra of the same underlying pathology is one that merits more detailed analysis, especially at the genomic level. PMID- 26037196 TI - Sciatic nerve hypertrophy with Klippel-Trenaunay syndrome: a case report. AB - A 73-year-old female patient who had severe neuropathic pain due to sciatic nerve hypertrophy with the Klippel-Trenaunay Syndrome has been presented. Localized hypertrophic neuropathy is in one region and characterized by concentric proliferation of Schwann cells around the axon. It is very rare in the absence of generalized hypertrophic neuropathy. Very little is known about the etiology and the course of this neuropathy. Klippel-Trenaunay-Syndrome (KTS) is a rare syndrome characterized by hemangioma, abnormalities of the venous and lymphatic systems, and limb enlargement due to soft tissue and bone hypertrophy. PMID- 26037197 TI - Extended endoscopic endonasal surgery using three-dimensional endoscopy in the intra-operative MRI suite for supra-diaphragmatic ectopic pituitary adenoma. AB - We describe a supra-diaphragmatic ectopic pituitary adenoma that was safely removed using the extended endoscopic endonasal approach, and discuss the value of three-dimensional (3D) endoscopy and intra-operative magnetic resonance imaging (MRI) to this type of procedure. A 61-year-old-man with bitemporal hemianopsia was referred to our hospital, where MRI revealed an enhanced suprasellar tumor compressing the optic chiasma. The tumor extended on the planum sphenoidale and partially encased the right internal carotid artery. An endocrinological assessment indicated normal pituitary function. The extended endoscopic endonasal approach was taken using a 3D endoscope in the intraoperative MRI suite. The tumor was located above the diaphragma sellae and separated from the normal pituitary gland. The pathological findings indicated non-functioning pituitary adenoma and thus the tumor was diagnosed as a supra diaphragmatic ectopic pituitary adenoma. Intra-operative MRI provided useful information to minimize dural opening and the supra-diaphragmatic ectopic pituitary adenoma was removed from the complex neurovascular structure via the extended endoscopic endonasal approach under 3D endoscopic guidance in the intra operative suite. Safe and effective removal of a supra-diaphragmatic ectopic pituitary adenoma was accomplished via the extended endoscopic endonasal approach with visual information provided by 3D endoscopy and intra-operative MRI. PMID- 26037198 TI - Aretaeus of Cappadocia and his treatises on diseases. AB - Aretaeus of Cappadocia is considered as one of the greatest medical scholars of Greco-Roman antiquity after Hippocrates. He presumably was a native or at least a citizen of Cappadocia, a Roman province in Asia Minor (Turkey), and most likely lived around the middle of the second century (A.D.) His eight volume treatise, written in Ionic Greek, entitled On the Causes, Symptoms and Cure of Acute and Chronic Diseases remained unknown until the middle of the 16th century when, in 1552, the first Latin edition was published. In this work, Aretaeus offered clinical descriptions of a number of diseases among which he gave classic accounts of asthma, epilepsy, pneumonia, tetanus, uterus cancer and different kinds of insanity. He differentiated nervous diseases and mental disorders and described hysteria, headaches, mania and melancholia. He also rendered the earliest clear accounts on coeliac disease, diphtheria and heart murmur, and gave diabetes its name. PMID- 26037199 TI - A 12-week randomized double-blind parallel pilot trial of Sinetrol XPur on body weight, abdominal fat, waist circumference, and muscle metabolism in overweight men. AB - Overweight and obesity are associated to increased risk of developing non communicable diseases that might dramatically affect life expectancy according World Health Organization. Overweight, obesity, and decline in physical activity are correlated to a significant propensity to lose skeletal muscle mass as a result of prolonged inflammation and oxidative stress whereas cohort surveys and clinical investigations have demonstrated health benefits of Citrus-based polyphenols to reverse such regression. Overweight men were included in a double blind, randomized, parallel pilot trial where they received daily for a 12-week period 900 mg of a Citrus-based polyphenol extract, Sinetrol(r) XPur. Body composition, anthropometric, and blood parameters were assessed before and at the end of the intervention period. After 12 weeks, while the silhouette slimmed down, metabolic parameters were significantly improved and skeletal muscle catabolism held back. These data suggest that over a 12-week period, the efficacy of the supplement improve both overweight process and correlated skeletal muscle mass metabolism. PMID- 26037200 TI - The orphan estrogen-related receptor alpha and metabolic regulation: new frontiers. AB - Metabolic homeostasis during long-term adaptation in animals is primarily achieved by controlling the expression of metabolic genes by a plethora of cellular transcription factors. The nuclear receptor (NR) superfamily in eukaryotes is an assembly of diverse receptors working as transcriptional regulators of multiple genes. The orphan estrogen-related receptor alpha (ERRalpha) is one such receptor of the NR superfamily with significant influence on numerous metabolic and other genes. Although it is presently unknown as to which endogenous hormones or ligands activate ERRalpha, nevertheless it regulates a host of genes whose products participate in various metabolic pathways. Studies over the years show new and interesting data that add to the growing knowledge on ERRalpha and metabolic regulation. For instance, novel findings indicate existence of mTOR/ERRalpha regulatory axis and also that ERRalpha control PGC 1alpha expression which potentially have significant impact on cellular metabolism. Data show that ERRalpha exerts its metabolic control by regulating the expression of SIRT5 that influences oxygen consumption and ATP generation. Moreover, ERRalpha has a role in creatine and lactate uptake in skeletal muscle which is important towards energy generation and contraction. This review is focused on the new insights gained into ERRalpha regulation of metabolism, networks and pathways that have important consequences in maintaining metabolic homeostasis including development of cancer. PMID- 26037201 TI - Intestinal mTOR regulates GLP-1 production in mouse L cells. AB - AIMS/HYPOTHESIS: Glucagon-like peptide (GLP-1), an intestinal incretin produced in L cells through proglucagon processing, is released in response to meal intake. The intracellular mechanism by which L cells sense the organism energy level to coordinate the production of GLP-1 remains unclear. Mechanistic target of rapamycin (mTOR) is an intracellular fuel sensor critical for energy homeostasis. In this study, we investigated whether intestinal mTOR regulates GLP 1 production in L cells. METHODS: The effects of mTOR on GLP-1 production were examined in lean- or high-fat diet (HFD) induced diabetic C57/BL6, db/db, Neurog3 Tsc1(-/-) mice, and STC-1 cells. GLP-1 expression was investigated by real-time PCR and western blotting. Plasma GLP-1 and insulin were detected by enzyme immunoassay and radioimmunoassay, respectively. RESULTS: Fasting downregulated mTOR activity, which was associated with a decrement of intestinal proglucagon and circulating GLP-1. Upon re-feeding, these alterations returned to the levels of fed animals. In HFD induced diabetic mice, ileal mTOR signalling, proglucagon and circulating GLP-1 were significantly decreased. Inhibition of mTOR signalling by rapamycin decreased levels of intestinal and plasma GLP-1 in both normal and diabetic mice. Activation of the intestinal mTOR signalling by L-leucine or Tsc1 gene deletion increased levels of intestinal proglucagon and plasma GLP-1. Overexpression of mTOR stimulated proglucagon promoter activity and GLP-1 production, whereas inhibition of mTOR activity by overexpression of tuberous sclerosis 1 (TSC1) or TSC2 decreased proglucagon promoter activity and GLP-1 production in STC-1 cells. CONCLUSIONS/INTERPRETATION: mTOR may link energy supply with the production of GLP-1 in L cells. PMID- 26037202 TI - Involvement of long non-coding RNAs in beta cell failure at the onset of type 1 diabetes in NOD mice. AB - AIMS/HYPOTHESIS: Exposure of pancreatic beta cells to cytokines released by islet infiltrating immune cells induces alterations in gene expression, leading to impaired insulin secretion and apoptosis in the initial phases of type 1 diabetes. Long non-coding RNAs (lncRNAs) are a new class of transcripts participating in the development of many diseases. As little is known about their role in insulin-secreting cells, this study aimed to evaluate their contribution to beta cell dysfunction. METHODS: The expression of lncRNAs was determined by microarray in the MIN6 beta cell line exposed to proinflammatory cytokines. The changes induced by cytokines were further assessed by real-time PCR in islets of control and NOD mice. The involvement of selected lncRNAs modified by cytokines was assessed after their overexpression in MIN6 cells and primary islet cells. RESULTS: MIN6 cells were found to express a large number of lncRNAs, many of which were modified by cytokine treatment. The changes in the level of selected lncRNAs were confirmed in mouse islets and an increase in these lncRNAs was also seen in prediabetic NOD mice. Overexpression of these lncRNAs in MIN6 and mouse islet cells, either alone or in combination with cytokines, favoured beta cell apoptosis without affecting insulin production or secretion. Furthermore, overexpression of lncRNA-1 promoted nuclear translocation of nuclear factor of kappa light polypeptide gene enhancer in B cells 1 (NF-kappaB). CONCLUSIONS/INTERPRETATION: Our study shows that lncRNAs are modulated during the development of type 1 diabetes in NOD mice, and that their overexpression sensitises beta cells to apoptosis, probably contributing to their failure during the initial phases of the disease. PMID- 26037204 TI - Challenging behaviour and learning disabilities: summary of NICE guidance. PMID- 26037205 TI - Efficacy of perifosine alone and in combination with sorafenib in an HrasG12V plus shp53 transgenic mouse model of hepatocellular carcinoma. AB - PURPOSE: Perifosine has shown antitumor activity via inhibition of Akt phosphorylation in many advanced solid tumors. This study investigated the efficacy of perifosine alone and in combination with sorafenib in a transgenic mouse model of HCC. METHODS: The mouse model of HCC was generated by hydrodynamic injection of transposons encoding HrasG12V and short-hairpin RNA downregulating p53. The transgenic mice were treated with perifosine alone and in combination with sorafenib to evaluate efficacy of drugs on tumor growth and survival. RESULTS: Treatment with perifosine for 5 weeks, alone and in combination with sorafenib, strongly inhibited tumor growth and increased survival. Perifosine inhibited HCC cell proliferation, induced apoptosis, and decreased tumor angiogenesis. Furthermore, its combination with sorafenib enhanced these effects. In addition, Akt phosphorylation was decreased by perifosine and further decreased by combination treatment. Although perifosine alone did not appear to activate the caspase pathway, combination treatment increased the cleavage of caspase-3, caspase-9, and poly (ADP-ribose) polymerase. CONCLUSIONS: The preclinical effect that current study showed represents a strong rationale for clinical trials using perifosine alone and in combination with sorafenib in the treatment of HCC patients. PMID- 26037206 TI - Impact of body surface area on survival in EGFR-mutant non-small cell lung cancer patients treated with gefitinib monotherapy: observational study of the Okayama Lung Cancer Study Group 0703. AB - BACKGROUND: The approved dose of gefitinib is fixed, without adjustment for physical size. We demonstrated previously that its efficacy was affected by body surface area (BSA) in patients with EGFR-mutant non-small cell lung cancer (NSCLC). To validate these observations, we assessed the association between BSA and the efficacy of gefitinib using a different patient cohort. METHODS: Prospective cohort data from 115 NSCLC patients with EGFR-mutant tumours, who received gefitinib monotherapy between 2007 and 2012, were analysed. RESULTS: Gefitinib was less effective in individuals with a high BSA (>=1.5 m(2)) in EGFR mutant NSCLC compared with those with a low BSA (<1.5 m(2)). The median progression-free survival (PFS) in the high- and low-BSA groups was 4.2 and 8.5 months, respectively, although there was no difference in survival among the whole NSCLC cohort. Multivariate analysis also showed a significant effect of BSA on PFS (hazard ratio 1.72; 95 % confidence interval 1.08-2.74; p = 0.021). Sensitivity analysis revealed that the use of the BSA cut-off level around 1.50 m(2) was robust for detecting subpopulations that would benefit less from gefitinib monotherapy. CONCLUSION: We found in the prospective cohort data that BSA could affect the efficacy of gefitinib monotherapy in patients with EGFR mutant NSCLC, suggesting that BSA-based dose setting of gefitinib monotherapy might be further investigated, despite the fact that no molecular-targeted agent described to date undergoes dose adjustment according to BSA. PMID- 26037207 TI - Financing and funding health care: Optimal policy and political implementability. AB - Health care financing and funding are usually analyzed in isolation. This paper combines the corresponding strands of the literature and thereby advances our understanding of the important interaction between them. We investigate the impact of three modes of health care financing, namely, optimal income taxation, proportional income taxation, and insurance premiums, on optimal provider payment and on the political implementability of optimal policies under majority voting. Considering a standard multi-task agency framework we show that optimal health care policies will generally differ across financing regimes when the health authority has redistributive concerns. We show that health care financing also has a bearing on the political implementability of optimal health care policies. Our results demonstrate that an isolated analysis of (optimal) provider payment rests on very strong assumptions regarding both the financing of health care and the redistributive preferences of the health authority. PMID- 26037208 TI - Tibial plateau levelling osteotomy in 69 small breed dogs using conically coupled 1.9/2.5 mm locking plates. A clinical and radiographic retrospective assessment. AB - OBJECTIVE: To report clinical experiences with the tibial plateau levelling osteotomy (TPLO) procedure in small breed dogs with cranial cruciate ligament (CCL) disease using specific, conically coupled, 1.9/2.5 mm locking plates and evaluating short-term complications and outcome. METHODS: Medical records of small breed dogs (<15 kg) that underwent TPLO using 1.9/2.5 mm locking plates were reviewed retrospectively. The preoperative, postoperative and six to eight weeks postoperative tibial plateau angle (TPA) measurements were determined from the radiographic images. Lameness evaluation was assessed subjectively preoperatively and six to eight weeks postoperatively. RESULTS: Sixty-nine small breed dogs (n = 79 stifles) were included in the study. Mean (+/- SD) preoperative TPA was 29.0 +/- 3.4 degrees , postoperative TPA was 5.8 +/- 2.5 degrees , and six to eight weeks postoperative TPA was 7.3 +/- 4.1 degrees . Sixteen complications occurred in 12 out of 79 TPLO procedures: three were intra operative (intra-articular screw placement) and 13 were postoperative complications, of which nine were identified as minor complications not requiring surgical reintervention, and four as major complications requiring additional surgical intervention, including tibial tuberosity fracture (n = 1), osteomyelitis (n = 1), screw failure (n = 1), and plate breakage (n = 1). Lameness scores by clinical assessment reduced from a median value of 3/4 preoperatively to 1/4 at six to eight weeks postoperatively. CLINICAL SIGNIFICANCE: 1.9/2.5 mm locking plates appear to be a valid choice of implant for the stabilization of unilateral TPLO in small breed dogs. PMID- 26037209 TI - Investigational sigma-1 receptor antagonists for the treatment of pain. AB - INTRODUCTION: The sigma-1 receptor (sigma1R) is a ligand-regulated molecular chaperone that interacts with other proteins, including NMDA and opioid receptors, to modulate their activity. Convergent evidence indicates that sigma1R antagonists exert inhibitory effects (and agonists stimulatory effects) on pain by stepping down the intracellular signaling cascades involved in transduction of noxious stimuli and plastic changes (i.e., sensitization phenomena) associated with chronic pain states. AREAS COVERED: This review addresses three primary domains. The first focuses on mechanisms underlying the antinociceptive effects of sigma1R antagonists. The second addresses evidence gained using pharmacological tools and experimental drugs in the discovery phase and clinical development. Finally, the article outlines the potential benefits of sigma1R antagonists, alone or in combination, in the context of available pain therapeutics. EXPERT OPINION: There is a critical need for new analgesics based on new mechanisms of action. Target identification requires convincing evidence relating targets to function. In turn, target validation requires confirmation of therapeutic benefits, ideally in humans. Current preclinical evidence provides strong rationale for sigma1R antagonists in pain. The outcome of clinical studies with the most advanced investigational sigma1R antagonist, S1RA (E-52862), will be of great interest to ascertain the potential of this new therapeutic approach to pain management. PMID- 26037210 TI - Death in the "microwave oven": A form of execution by carbonization. AB - Death in the "microwave oven" has nothing to do with microwaves energy. It is the jargon name given to a criminal form of execution by carbonization that has been adopted by drug dealers in Rio de Janeiro (Brazil). The goal is to torture and intimidate victims, in an attempt of corpse occultation and to make identification harder or impossible. This paper brings to attention of the forensic international community an unusual and very cruel form of execution as a way to document these situations. PMID- 26037211 TI - The persistence of the attentional bias to regularities in a changing environment. AB - The environment often is stable, but some aspects may change over time. The challenge for the visual system is to discover and flexibly adapt to the changes. We examined how attention is shifted in the presence of changes in the underlying structure of the environment. In six experiments, observers viewed four simultaneous streams of objects while performing a visual search task. In the first half of each experiment, the stream in the structured location contained regularities, the shapes in the random location were randomized, and gray squares appeared in two neutral locations. In the second half, the stream in the structured or the random location may change. In the first half of all experiments, visual search was facilitated in the structured location, suggesting that attention was consistently biased toward regularities. In the second half, this bias persisted in the structured location when no change occurred (Experiment 1), when the regularities were removed (Experiment 2), or when new regularities embedded in the original or novel stimuli emerged in the previously random location (Experiments 3 and 6). However, visual search was numerically but no longer reliably faster in the structured location when the initial regularities were removed and new regularities were introduced in the previously random location (Experiment 4), or when novel random stimuli appeared in the random location (Experiment 5). This suggests that the attentional bias was weakened. Overall, the results demonstrate that the attentional bias to regularities was persistent but also sensitive to changes in the environment. PMID- 26037213 TI - Plasmons in supported size-selected silver nanoclusters. AB - The plasmonic behavior of size-selected supported silver clusters is studied by surface second harmonic generation spectroscopy for the first time. A blue shift of ~0.2 eV in the plasmon resonance is observed with decreasing cluster size from Ag55 to Ag9. In addition to the general blue shift, a nonscalable size-dependence is also observed in plasmonic behavior of Ag nanoclusters, which is attributed to varying structural properties of the clusters. The results are in quantitative agreement with a hybrid theoretical model based on Mie theory and the existing DFT calculations. PMID- 26037212 TI - Comparing the Performance of the HADS and the GDS-15 in the AIBL Study. PMID- 26037214 TI - An optimization-based method for prediction of lumbar spine segmental kinematics from the measurements of thorax and pelvic kinematics. AB - Given measurement difficulties, earlier modeling studies have often used some constant ratios to predict lumbar segmental kinematics from measurements of total lumbar kinematics. Recent imaging studies suggested distribution of lumbar kinematics across its vertebrae changes with trunk rotation, lumbar posture, and presence of load. An optimization-based method is presented and validated in this study to predict segmental kinematics from measured total lumbar kinematics. Specifically, a kinematics-driven biomechanical model of the spine is used in a heuristic optimization procedure to obtain a set of segmental kinematics that, when prescribed to the model, were associated with the minimum value for the sum of squared predicted muscle stresses across all the lower back muscles. Furthermore, spinal loads estimated using the predicted kinematics by the present method were compared with those estimated using constant ratios. Predicted segmental kinematics were in good agreement with those obtained by imaging with an average error of ~10%. Compared with those obtained using constant ratios, predicted spinal loads using segmental kinematics obtained here were in general smaller. In conclusion, the proposed method offers an alternative tool for improving model-based estimates of spinal loads where image-based measurement of lumbar kinematics is not feasible. PMID- 26037215 TI - Severe hydrocephalus caused by diffuse leptomeningeal and neurocutaneous melanocytosis of antenatal onset: a clinical, pathologic, and molecular study of 2 cases. AB - Diffuse leptomeningeal melanocytosis (DLM) is a rare nevomelanocytic proliferation arising in the meninges. Despite their lack of morphological features of malignancy, these clonal nevomelanocytic cells are capable of extensive invasion and of malignant behavior. When associated with congenital melanocytic nevi, the disorder is named neurocutaneous melanocytosis (NCM). When symptomatic, DLM is usually revealed during childhood, but some cases remain clinically silent. The aim of this study was to analyze melanocytic proliferation in 2 rare and severe cases of isolated DLM and NCM of prenatal onset by neuropathologic and molecular analysis. We performed neuropathologic examination, comparative genomic hybridization arrays, fluorescence in situ hybridization, BRAF and NRAS pyrosequencing in the 2 cases, and next-generation sequencing in the case of isolated DLM. The neuropathologic examination showed diffuse meningeal melanocytic proliferation involving the whole central nervous system with multiple areas of intraneural invasion, associated with large nevi in 1 case. We did not find any chromosomal imbalances. A NRAS(Q61K) mutation was found in the cutaneous and meningeal lesions from the NCM. No mutation was found within a panel of oncogenes including BRAF, NRAS, HRAS, KIT, GNAQ, and GNA11 concerning the isolated DLM. We report 2 exceptional cases of hydrocephalus of prenatal onset related to DLM and NCM. The molecular mechanisms underlying our case of DLM remain unsolved despite the panel of analysis applied. PMID- 26037216 TI - Non-contraceptive benefits of hormonal and intrauterine reversible contraceptive methods. AB - BACKGROUND: Most contraceptive methods present benefits beyond contraception; however, despite a large body of evidence, many healthcare professionals (HCPs), users and potential users are unaware of those benefits. This review evaluates the evidence for non-contraceptive benefits of hormonal and non-hormonal contraceptive methods. METHODS: We searched the medical publications in PubMed, POPLINE, CENTRAL, EMBASE and LILACS for relevant articles, on non-contraceptive benefits of the use of hormonal and intrauterine reversible contraceptive methods, which were published in English between 1980 and July 2014. Articles were identified using the following search terms: 'contraceptive methods', 'benefits', 'cancer', 'anaemia', 'heavy menstrual bleeding (HMB)', 'endometrial hyperplasia', 'endometriosis' and 'leiomyoma'. RESULTS: We identified, through the literature search, evidence that some combined oral contraceptives have benefits in controlling HMB and anaemia, reducing the rate of endometrial, ovarian and colorectal cancer and ectopic pregnancy as well as alleviating symptoms of premenstrual dysphoric disorder. Furthermore, the use of the levonorgestrel-releasing intrauterine system also controls HMB and anaemia and endometrial hyperplasia and cancer, reduces rates of endometrial polyps in users of tamoxifen and alleviates pain associated with endometriosis and adenomyosis. Depot medroxyprogesterone acetate controls crises of pain associated with sickle cell disease and endometriosis. Users of the etonogestrel-releasing contraceptive implant have the benefits of a reduction of pain associated with endometriosis, and users of the copper intrauterine device have reduced rates of endometrial and cervical cancer. CONCLUSIONS: Despite the high contraceptive effectiveness of many hormonal and intrauterine reversible contraceptive methods, many HCPs, users and potential users are concerned mainly about side effects and safety of both hormonal and non-hormonal contraceptive methods, and there is scarce information about the many benefits that these methods offer beyond contraception. PMID- 26037217 TI - Dysplastic nevus: Fact and fiction. AB - The term "dysplastic nevus" (DN) implies that this nevus exists as a distinct and defined entity of potential detriment to its host. We examine the current data, which suggest that this entity exists as histologically and possibly genetically different from common nevus, with some overlapping features. Studies show that a melanoma associated with a nevus is just as likely to arise in a common nevus as in DN. Furthermore, there is no evidence that a histologically defined DN evolves into a melanoma or that the presence of 1 or more DN on an individual patient confers any increased melanoma risk. We suggest that the term "dysplastic nevus" be abandoned so that the focus can shift to confirmed and relevant indicators of melanoma risk, including high nevus counts and large nevus size. PMID- 26037218 TI - Genetic fine mapping and candidate gene analysis of the Gossypium hirsutum Ligon lintless-1 (Li1) mutant on chromosome 22(D). AB - Ligon lintless-1 (Li1) is a Gossypium hirsutum mutant that is controlled by a dominant gene that arrests the development of cotton fiber after anthesis. Two F2 mapping populations were developed from mutant (Li1 * H7124) F1 plants in 2012 and 2013; each was composed of 142 and 1024 plants, respectively. Using these populations, Li1 was mapped to a 0.3-cM region in which nine single-strand conformation polymorphism markers co-segregated with the Li1 locus. In the published G. raimondii genome, these markers were mapped to a region of about 1.2 Mb (the Li1 region) and were separated by markers that flanked the Li1 locus in the genetic map, dividing the Li1 region into three segments. Thirty-six genes were annotated by the gene prediction software FGENESH (Softberry) in the Li1 region. Twelve genes were candidates of Li1, while the remaining 24 genes were identified as transposable elements, DNA/RNA polymerase superfamily or unknown function genes. Among the 12 candidate genes, those encoding ribosomal protein s10, actin protein, ATP synthase, and beta-tubulin 5 were the most-promising candidates of the Li1 mutant because the function of these genes is closely related to fiber development. High-throughput RNA sequencing and quantitative PCR revealed that these candidate genes had obvious differential gene expression between mutant and wild-type plants at the fiber elongation stage, strengthening the inference that they could be the most likely candidate gene of the Li1 mutant phenotype. PMID- 26037219 TI - Identification and characterization of NF-YB family genes in tung tree. AB - The NF-YB transcription factor gene family encodes a subunit of the CCAAT box binding factor (CBF), a highly conserved trimeric activator that strongly binds to the CCAAT box promoter element. Studies on model plants have shown that NF-YB proteins participate in important developmental and physiological processes, but little is known about NF-YB proteins in trees. Here, we identified seven NF-YB transcription factor-encoding genes in Vernicia fordii, an important oilseed tree in China. A phylogenetic analysis separated the genes into two groups; non-LEC1 type (VfNF-YB1, 5, 7, 9, 11, 13) and LEC1-type (VfNF-YB 14). A gene structure analysis showed that VfNF-YB 5 has three introns and the other genes have no introns. The seven VfNF-YB sequences contain highly conserved domains, a disordered region at the N terminus, and two long helix structures at the C terminus. Phylogenetic analyses showed that VfNF-YB family genes are highly homologous to GmNF-YB genes, and many of them are closely related to functionally characterized NF-YBs. In expression analyses of various tissues (root, stem, leaf, and kernel) and the root during pathogen infection, VfNF-YB1, 5, and 11 were dominantly expressed in kernels, and VfNF-YB7 and 9 were expressed only in the root. Different VfNF-YB family genes showed different responses to pathogen infection, suggesting that they play different roles in the pathogen response. Together, these findings represent the first extensive evaluation of the NF-YB family in tung tree and provide a foundation for dissecting the functions of VfNF YB genes in seed development, stress adaption, fatty acid synthesis, and pathogen response. PMID- 26037221 TI - Pedicle-in-a-trench technique for lower extremity reconstruction. PMID- 26037220 TI - Fat-suppressed alternating-SSFP for whole-brain fMRI using breath-hold and visual stimulus paradigms. AB - PURPOSE: To achieve artifact-suppressed whole-brain pass-band-balanced steady state free precession functional MRI from a single functional magnetic resonance imaging (fMRI) scan. METHODS: A complete and practical data acquisition sequence for alt-SSFP fMRI was developed. First, multishot flyback-echo-planar imaging (EPI) and echo-time shifting were used to achieve data acquisition that was robust against eddy currents, gradient delays, and ghosting artifacts. Second, a steady-state catalyzation scheme was implemented to reduce oscillations in the transient signal when catalyzing in and out of alternate steady states. Next, a short spatial-spectral radiofrequency (RF) pulse was designed to achieve excellent fat-suppression while maintaining a repetition time <15 ms to sensitize functional activation toward smaller vessels and capillaries. Lastly, parallel imaging was used to achieve whole-brain coverage and sufficiently high temporal resolution. RESULTS: Breath-hold experiments showed excellent fat-suppression and alt-SSFP's capability to recover functional sensitivity from signal dropout regions of conventional gradient-echo and banding artifacts from conventional pass-band-balanced steady-state free precession. Applying fat-suppression resulted in improved activation maps and increased temporal SNR. Visual stimulus functional studies verify the proposed method's excellent functional sensitivity to neuronal activation. CONCLUSION: Artifact-suppressed images are demonstrated, showing a practical pass-band-balanced steady-state free precession fMRI method that permits whole-brain imaging with excellent blood oxygen level-dependent sensitivity and fat suppression. PMID- 26037222 TI - Keeping it simple: Improving dental outcomes with osseointegrated implants after "single barrel" free fibula reconstruction of the mandible. PMID- 26037223 TI - Highly Regioselective Halogenation of Pyridine N-Oxide: Practical Access to 2 Halo-Substituted Pyridines. AB - A highly efficient and regioselective halogenation reaction of unsymmetrical pyridine N-oxide under mild conditions is described. The methodology provides a practical access to various 2-halo-substituted pyridines, which are pharmaceutically important intermediates. PMID- 26037225 TI - Human IgG is produced in a pro-form that requires clipping of C-terminal lysines for maximal complement activation. AB - Human IgG is produced with C-terminal lysines that are cleaved off in circulation. The function of this modification was unknown and generally thought not to affect antibody function. We recently reported that efficient C1q binding and complement-dependent cytotoxicity (CDC) requires IgG hexamerization at the cell surface. Here we demonstrate that C-terminal lysines may interfere with this process, leading to suboptimal C1q binding and CDC of cells opsonized with C terminal lysine-containing IgG. After we removed these lysines with a carboxypeptidase, maximal complement activation was observed. Interestingly, IgG1 mutants containing either a negative C-terminal charge or multiple positive charges lost CDC almost completely; however, CDC was fully restored by mixing C terminal mutants of opposite charge. Our data indicate a novel post-translational control mechanism of human IgG: human IgG molecules are produced in a pro-form in which charged C-termini interfere with IgG hexamer formation, C1q binding and CDC. To allow maximal complement activation, C-terminal lysine processing is required to release the antibody's full cytotoxic potential. PMID- 26037227 TI - Author's reply to Tovey and colleagues. PMID- 26037226 TI - Characterization of the infectious reservoir of malaria with an agent-based model calibrated to age-stratified parasite densities and infectiousness. AB - BACKGROUND: Elimination of malaria can only be achieved through removal of all vectors or complete depletion of the infectious reservoir in humans. Mechanistic models can be built to synthesize diverse observations from the field collected under a variety of conditions and subsequently used to query the infectious reservoir in great detail. METHODS: The EMOD model of malaria transmission was calibrated to prevalence, incidence, asexual parasite density, gametocyte density, infection duration, and infectiousness data from nine study sites. The infectious reservoir was characterized by age and parasite detectability with diagnostics of varying sensitivity over a range of transmission intensities with and without case management and vector control. Mass screen-and-treat drug campaigns were tested for likelihood of achieving elimination. RESULTS: The composition of the infectious reservoir is similar over a range of transmission intensities, and higher intensity settings are biased towards infections in children. Recent ramp-ups in case management and use of insecticide-treated bed nets (ITNs) reduce the infectious reservoir and shift the composition towards sub microscopic infections. Mass campaigns with anti-malarial drugs are highly effective at interrupting transmission if deployed shortly after ITN campaigns. CONCLUSIONS: Low-density infections comprise a substantial portion of the infectious reservoir. Proper timing of vector control, seasonal variation in transmission intensity and mass drug campaigns allows lingering population immunity to help drive a region towards elimination. PMID- 26037228 TI - Absent AB isoagglutinins: a clue to immunodeficiency. PMID- 26037229 TI - A functional tracking task to assess frontal plane motor control in post stroke gait. AB - The ability to execute appropriate medio-lateral foot placements during gait is thought to require active frontal plane control and to be critical in maintaining upright posture during gait. The aggregate frontal plane metrics of step width and step width variability have been assessed for post-stroke populations, but only under normal walking conditions. However, in the case of stroke, limb specific differences in sensory-motor control are likely. Thus, an investigation of limb specific motor control characteristics under tracking task conditions is needed to appropriately characterize frontal plane sensory-motor control post stroke. Chronic stroke subjects (n=15) and age matched control subjects (n=10) tracked static, bilateral foot placement targets at self-selected walking speeds and completed a free walking trial. Variability and error of tracking performance were analyzed for step width and foot placement. Stroke subjects demonstrated reduced ability to control step width variability and foot placement variability, compared to control subjects. Step width variability and affected limb foot placement variability were sensitive to task complexity, increasing significantly in response to a decrease in step width target size. These results show that stroke mediated changes in the sensory-motor integration processes are manifested as inter-limb differences in frontal plane motor variability during a gait tracking task, with an additional sensitivity to task complexity. Additionally, the proposed step width tracking paradigm presents a clinically reproducible motor control metric that can be used for diagnostic assessment or as a potential outcome for a gait training regimen. PMID- 26037230 TI - Genetic improvement for disease resistance in oysters: A review. AB - Oyster species suffer from numerous disease outbreaks, often causing high mortality. Because the environment cannot be controlled, genetic improvement for disease resistance to pathogens is an attractive option to reduce their impact on oyster production. We review the literature on selective breeding programs for disease resistance in oyster species, and the impact of triploidy on such resistance. Significant response to selection to improve disease resistance was observed in all studies after two to four generations of selection for Haplosporidium nelsoni and Roseovarius crassostrea in Crassostrea virginica, OsHV 1 in Crassostrea gigas, and Martelia sydneyi in Saccostrea glomerata. Clearly, resistance in these cases was heritable, but most of the studies failed to provide estimates for heritability or genetic correlations with other traits, e.g., between resistance to one disease and another. Generally, it seems breeding for higher resistance to one disease does not confer higher resistance or susceptibility to another disease. For disease resistance in triploid oysters, several studies showed that triploidy confers neither advantage nor disadvantage in survival, e.g., OsHV-1 resistance in C. gigas. Other studies showed higher disease resistance of triploids over diploid as observed in C. virginica and S. glomerata. One indirect mechanism for triploids to avoid disease was to grow faster, thus limiting the span of time when oysters might be exposed to disease. PMID- 26037231 TI - Electronic and magnetic properties of epitaxial perovskite SrCrO3(0 0 1). AB - We have investigated the intrinsic properties of SrCrO3 epitaxial thin films synthesized by molecular beam epitaxy. We find compelling evidence that SrCrO3 is a correlated metal. X-ray photoemission valence band and O K-edge x-ray absorption spectra indicate a strongly hybridized Cr3d-O2p state crossing the Fermi level, leading to metallic behavior. Comparison between valence band spectra near the Fermi level and the densities of states calculated using density functional theory (DFT) suggests the presence of coherent and incoherent states and points to strong electron correlation effects. The magnetic susceptibility can be described by Pauli paramagnetism at temperatures above 100 K, but reveals antiferromagnetic behavior at lower temperatures, possibly resulting from orbital ordering. PMID- 26037233 TI - Ethical issues relating to trainee publication requirements. PMID- 26037232 TI - Usual Primary Care Provider Characteristics of a Patient-Centered Medical Home and Mental Health Service Use. AB - BACKGROUND: The benefits of the patient-centered medical home (PCMH) over and above that of a usual source of medical care have yet to be determined, particularly for adults with mental health disorders. OBJECTIVE: To examine qualities of a usual provider that align with PCMH goals of access, comprehensiveness, and patient-centered care, and to determine whether PCMH qualities in a usual provider are associated with the use of mental health services (MHS). DESIGN: Using national data from the Medical Expenditure Panel Survey, we conducted a lagged cross-sectional study of MHS use subsequent to participant reports of psychological distress and usual provider and practice characteristics. PARTICIPANTS: A total of 2,358 adults, aged 18-64 years, met the criteria for serious psychological distress and reported on their usual provider and practice characteristics. MAIN MEASURES: We defined "usual provider" as a primary care provider/practice, and "PCMH provider" as a usual provider that delivered accessible, comprehensive, patient-centered care as determined by patient self-reporting. The dependent variable, MHS, included self-reported mental health visits to a primary care provider or mental health specialist, counseling, and psychiatric medication treatment over a period of 1 year. RESULTS: Participants with a usual provider were significantly more likely than those with no usual provider to have experienced a primary care mental health visit (marginal effect [ME] = 8.5, 95 % CI = 3.2-13.8) and to have received psychiatric medication (ME = 15.5, 95 % CI = 9.4-21.5). Participants with a PCMH were additionally more likely than those with no usual provider to visit a mental health specialist (ME = 7.6, 95 % CI = 0.7-14.4) and receive mental health counseling (ME = 8.5, 95 % CI = 1.5-15.6). Among those who reported having had any type of mental health visit, participants with a PCMH were more likely to have received mental health counseling than those with only a usual provider (ME = 10.0, 95 % CI = 1.0-19.0). CONCLUSIONS: Access to a usual provider is associated with increased receipt of needed MHS. Patients who have a usual provider with PCMH qualities are more likely to receive mental health counseling. PMID- 26037234 TI - Structural Basis for Polymer Packing and Solvation Properties of the Organogermanium Crystalline Polymer Propagermanium and Its Derivatives. AB - Of organogermanium compounds known to have an immunostimulatory action, propagermanium [PGe; 3-oxygermylpropionic acid polymer, (C3 H5 GeO3.5 )n] is the only one used as a pharmaceutical agent, to treat the hepatitis B virus in Japan. However, because of lack of information about its structure, PGe has been confused with a polymeric solid, repagermanium (RGe, Ge-132, poly-trans-[(2 carboxyethyl) germasesquioxane], (C18 H30 Ge6 O21 )n), which has the same essential formula as PGe. To clarify this issue, the structure of PGe was analyzed using X-ray diffraction (XRD). PGe has a polymeric ladder-shaped structure of a concatenated eight-membered ring composed of Ge-O bonds, which is clearly distinguished from the infinite sheet structure in RGe. Moreover, we observed temperature or moisture-dependent transformations among these compounds using powder XRD. For instance, PGe was easily dissolved in water, and transformed to RGe by exposure to water vapor, but transformed into another straight-chain structure when exposed to aqueous solution. As a result of these findings, PGe was indicated to have labile polymer packing against RGe. These characteristics of PGe may affect pharmaceutical properties such as respective stability and solubility, which indicate its unique impact on physiological activity. PMID- 26037236 TI - Application of Micro-Raman Spectroscopy to the Study of Yttria-Stabilized Tetragonal Zirconia Polycrystal (Y-TZP) Phase Transformation. AB - The aim of this study was to perform micro-Raman spectroscopy as an alternative and nondestructive method to identify the phase transformation of zirconia after mechanical stress. The groups evaluated were experimental zirconia, zirconcad, IPS e.max ZirCad, and In Ceram YZ. Ten specimens were constructed for each group (n = 30) and subjected to a three-point bending test with a crosshead speed of 0.5 mm/min. The fractured surfaces were analyzed by micro-Raman spectroscopy. The laser power was kept at 10 mW, and scanning was performed in three regions of the fractured surface: (i) near the source of the failure (region of tensile stress), (ii) central to the fractured surface, and (iii) far from the source of failure. All materials showed the characteristic bands of tetragonal and monoclinic phases of zirconia. All zirconia studied showed a monoclinic phase in the tensile stress region. Micro-Raman spectroscopy was effective in detecting the presence of crystalline phases in polycrystals ceramics. PMID- 26037235 TI - A novel brain partition highlights the modular skeleton shared by structure and function. AB - Elucidating the intricate relationship between brain structure and function, both in healthy and pathological conditions, is a key challenge for modern neuroscience. Recent progress in neuroimaging has helped advance our understanding of this important issue, with diffusion images providing information about structural connectivity (SC) and functional magnetic resonance imaging shedding light on resting state functional connectivity (rsFC). Here, we adopt a systems approach, relying on modular hierarchical clustering, to study together SC and rsFC datasets gathered independently from healthy human subjects. Our novel approach allows us to find a common skeleton shared by structure and function from which a new, optimal, brain partition can be extracted. We describe the emerging common structure-function modules (SFMs) in detail and compare them with commonly employed anatomical or functional parcellations. Our results underline the strong correspondence between brain structure and resting-state dynamics as well as the emerging coherent organization of the human brain. PMID- 26037237 TI - Transformation of dissolved organic matters in landfill leachate bioelectrochemical system. AB - A membraneless bioelectrochemical system (BES) reactor and an anoxic/oxic (A/O) reactor of identical configurations were applied to treat the landfill leachate (20,100 mg l(-1) chemical oxygen demand (COD) and 1330 mg l(-1) NH4(+)-N) at 24-h hydraulic retention time and 3 kg chemical oxygen demand m(-3) d(-1) volume loading. The BES with maximum power density of 2.77+/-0.26 W m(-3) and internal resistance of 47.5+/-1.4 Omega removed 84-89% COD and 94-98% NH4(+)-N, 11% and 47%, respectively, higher than the A/O reactor. The dissolved organic matters (DOM) in effluents from the BES and the A/O reactor were for the first time characterized and compared. The MFC preferentially degraded hydrophilic fraction (HPI) of the fed DOM and yielded excess humin with high aromaticity. The electric fields by bioelectrochemical reactions occurred at cathode stimulate the activities of COD degraders and nitrifiers in biofilms to enhance ammonium removals by BES reactor. PMID- 26037224 TI - Rich club analysis in the Alzheimer's disease connectome reveals a relatively undisturbed structural core network. AB - Diffusion imaging can assess the white matter connections within the brain, revealing how neural pathways break down in Alzheimer's disease (AD). We analyzed 3-Tesla whole-brain diffusion-weighted images from 202 participants scanned by the Alzheimer's Disease Neuroimaging Initiative-50 healthy controls, 110 with mild cognitive impairment (MCI) and 42 AD patients. From whole-brain tractography, we reconstructed structural brain connectivity networks to map connections between cortical regions. We tested whether AD disrupts the "rich club" - a network property where high-degree network nodes are more interconnected than expected by chance. We calculated the rich club properties at a range of degree thresholds, as well as other network topology measures including global degree, clustering coefficient, path length, and efficiency. Network disruptions predominated in the low-degree regions of the connectome in patients, relative to controls. The other metrics also showed alterations, suggesting a distinctive pattern of disruption in AD, less pronounced in MCI, targeting global brain connectivity, and focusing on more remotely connected nodes rather than the central core of the network. AD involves severely reduced structural connectivity; our step-wise rich club coefficients analyze points to disruptions predominantly in the peripheral network components; other modalities of data are needed to know if this indicates impaired communication among non rich club regions. The highly connected core was relatively preserved, offering new evidence on the neural basis of progressive risk for cognitive decline. PMID- 26037238 TI - IgG4-related disease initially presented as an orbital mass lesion mimicking optic nerve sheath meningioma. AB - We report a case of an optic nerve mass lesion associated with IgG4-related disease. A 39-year-old man presented with right blurred vision and proptosis 8 years before admission. Magnetic resonance imaging showed a mass lesion in the center of the right orbit, which was diagnosed as optic nerve sheath meningioma by neuroradiologists and neurosurgeons. Irradiation was selected for treatment of the lesion on the basis of the radiological diagnosis; subsequently, the lesion gradually reduced in size. However, regrowth of an optic nerve mass lesion observed during the previous 2 years caused remarkable exophthalmos, and removal of the orbital mass lesion was performed via a transcranial orbital approach. Pathological examinations resulted in a diagnosis of IgG4-related disease, and hematological tests revealed an elevated level of serum IgG4. Additional radiological examinations showed mass lesions in the left maxillary nerve, bilateral inferior alveolar nerves, paravertebral tissue, and left kidney. Treatment with oral steroids has produced a reduction in the size of these lesions. PMID- 26037239 TI - Hydrolyzable and condensed tannins resistance in Clostridium perfringens. AB - Tannins added in the diet are being used to improve nutrition and health in farm animals as an alternative to antibiotic growth promoters and to control enteric clostridial diseases. However, the capacity of Clostridium perfringens to develop resistance under the selective pressure of tannins is unknown. The purpose of this study was to determine if C. perfringens possess the ability to develop resistance against tannins in comparison with antimicrobial agents. Susceptibility for 7 AGPs (antimicrobial growth promoters), 9 therapeutic antimicrobials and 2 tannin based extracts was determined for 30 C. perfringens strains isolated from poultry and cattle. Two susceptible strains were selected and cultured in presence of sub-inhibitory concentrations of tannins and AGPs for resistant sub-populations selection. Tannin resistance of C. perfringens isolates from both animal species revealed no statistically significant differences in MICs (minimum inhibitory concentration). Poultry isolates showed higher MICs to several AGPs compared with cattle isolates. All isolates were susceptible to the therapeutic antimicrobials tested, but avian isolates showed a significantly lower susceptibility to these antimicrobials which was highly correlated with an increased resistance to bacitracin and others AGPs. In-vitro selection of resistant clones suggests that C. perfringens was unable to develop resistance against tannins at least compared to AGPs like bacitracin and avilamycin. Avian origin strains, which were previously exposed to antibiotics showed higher resistance, compared to cattle origin strains. These results suggest that the evolution of resistance against tannins in C. perfringens would be more difficult and slower than to the determined AGPs. PMID- 26037240 TI - The oral mucosal and salivary microbial community of Behcet's syndrome and recurrent aphthous stomatitis. AB - BACKGROUND: Behcet's syndrome (BS) is a multisystem immune-related disease of unknown etiology. Recurrent aphthous stomatitis (RAS) is characterized by the presence of idiopathic oral ulceration without extraoral manifestation. The interplay between the oral microbial communities and the immune response could play an important role in the etiology and pathogenesis of both BS and RAS. OBJECTIVE: To investigate the salivary and oral mucosal microbial communities in BS and RAS. METHODS: Purified microbial DNA isolated from saliva samples (54 BS, 25 healthy controls [HC], and 8 RAS) were examined by the human oral microbe identification microarray. Cultivable salivary and oral mucosal microbial communities from ulcer and non-ulcer sites were identified by matrix-assisted laser desorption/ionization time-of-flight analysis. Mycobacterium spp. were detected in saliva and in ulcer and non-ulcer oral mucosal brush biopsies following culture on Lowenstein-Jensen slopes and Mycobacterial Growth Indicator Tubes. RESULTS: There was increased colonization with Rothia denticariosa of the non-ulcer sites of BS and RAS patients (p<0.05). Ulcer sites in BS were highly colonized with Streptococcus salivarius compared to those of RAS (p<0.05), and with Streptococcus sanguinis compared to HC (p<0.0001). Oral mucosa of HC were more highly colonized with Neisseria and Veillonella compared to all studied groups (p<0.0001). CONCLUSIONS: Despite the uncertainty whether the reported differences in the oral mucosal microbial community of BS and RAS are of causative or reactive nature, it is envisaged that restoring the balance of the oral microbial community of the ulcer sites may be used in the future as a new treatment modality for oral ulceration. PMID- 26037241 TI - Comparison of the in vitro effects of saline, hypertonic hydroxyethyl starch, hypertonic saline, and two forms of hydroxyethyl starch on whole blood coagulation and platelet function in dogs. AB - OBJECTIVE: To compare the in vitro effects of hypertonic solutions and colloids to saline on coagulation in dogs. DESIGN: In vitro experimental study. SETTING: Veterinary teaching hospital. ANIMALS: Twenty-one adult dogs. INTERVENTIONS: Blood samples were diluted with saline, 7.2% hypertonic saline solution with 6% hydroxyethylstarch with an average molecular weight of 200 kDa and a molar substitution of 0.4 (HH), 7.2% hypertonic saline (HTS), hydroxyethyl starch (HES) 130/0.4 or hydroxyethyl starch 600/0.75 at ratios of 1:22 and 1:9, and with saline and HES at a ratio of 1:3. MEASUREMENTS AND MAIN RESULTS: Whole blood coagulation was analyzed using rotational thromboelastometry (extrinsic thromboelastometry-cloting time (ExTEM-CT), maximal clot firmness (MCF) and clot formation time (CFT) and fibrinogen function TEM-CT (FibTEM-CT) and MCF) and platelet function was analyzed using a platelet function analyzer (closure time, CTPFA ). All parameters measured were impaired by saline dilution. The CTPFA was prolonged by 7.2% hypertonic saline solution with 6% hydroxyethylstarch with an average molecular weight of 200 kDa and a molar substitution of 0.4 (HH) and HTS but not by HES solutions. At clinical dilutions equivalent to those generally administered for shock (saline 1:3, HES 1:9, and hypertonic solutions 1:22), CTPFA was more prolonged by HH and HTS than other solutions but more by saline than HES. No difference was found between the HES solutions or the hypertonic solutions. ExTEM-CFT and MCF were impaired by HH and HTS but only mildly by HES solutions. At clinically relevant dilutions, no difference was found in ExTEM-CFT between HTS and saline or in ExTEM-MCF between HH and saline. No consistent difference was found between the 2 HES solutions but HH impaired ExTEM-CFT and MCF more than HTS. At high dilutions, FibTEM-CT and -MCF and ExTEM-CT were impaired by HES. CONCLUSIONS: Hypertonic solutions affect platelet function and whole blood coagulation to a greater extent than saline and HES. At clinically relevant dilutions, only CTPFA was markedly more affected by hypertonic solutions than by saline. At high dilutions, HES significantly affects coagulation but to no greater extent than saline at clinically relevant dilutions. PMID- 26037242 TI - Synthesis and Characterization of Cationic Low-Valent Gallium Complexes of Cryptand[2.2.2]. AB - The synthesis and characterization of two bimetallic, cationic low-valent gallium cryptand[2.2.2] complexes is reported. The reaction of cryptand[2.2.2] with Ga2Cl4 gave two different cations, [Ga3Cl4 (crypt-222)](+) (1) or [Ga2Cl2 (crypt 222)](2+) (2), depending on whether or not trimethylsilyl triflate (Me3SiOTf) was added as a co-reagent. Complexes 1 and 2 are the first examples of bimetallic cryptand[2.2.2] complexes, as well as the first low-valent gallium cryptand[2.2.2] complexes. Computational methods were used to evaluate the bonding in the gallium cores. PMID- 26037243 TI - Corrigendum: The mitochondrial uniporter controls fight or flight heart rate increases. PMID- 26037244 TI - A Single-Step Synthesis of Electroactive Mesoporous ProDOT-Silica Structures. AB - The single-step preparation of highly ordered mesoporous silica hybrid nanocomposites with conjugated polymers was explored using a novel cationic 3,4 propylenedioxythiophene (ProDOT) surfactant (PrS). The method does not require high-temperature calcination or a washing procedure. The combination of self assembly of the silica surfactant and in situ polymerization of the ProDOT tail is responsible for creation of the mesoporosity with ultralarge pores, large pore volume, and electroactivity. As this novel material exhibits excellent textural parameters together with electrical conductivity, we believe that this could find potential applications in various fields. This novel concept of creating mesoporosity without a calcination process is a significant breakthrough in the field of mesoporous materials and the method can be further generalized as a rational preparation of various mesoporous hybrid materials having different structures and pore diameters. PMID- 26037245 TI - Role of the alpha1 blocker doxazosin in alcoholism: a proof-of-concept randomized controlled trial. AB - Evidence suggests that the norepinephrine system represents an important treatment target for alcohol dependence (AD) and the alpha1 -blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The alpha1 -blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was conducted in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators. Forty-one AD individuals were randomized, 30 (doxazosin = 15) completed the treatment phase and 28 (doxazosin = 14) also completed the follow-up. There were no significant differences between groups on DPW and HDD per week. With FHDA as a moderator, there were significant FHDA * medication interactions for both DPW (pcorrected = 0.001, d = 1.18) and HDD (pcorrected = 0.00009, d = 1.30). Post hoc analyses revealed that doxazosin significantly reduced alcohol drinking in AD patients with high FHDA and by contrast increased drinking in those with low FHDA. Doxazosin may be effective selectively in AD patients with high FHDA. This study provides preliminary evidence for personalized medicine using alpha1 -blockade to treat AD. However, confirmatory studies are required. PMID- 26037246 TI - A simple and efficient seamless DNA cloning method using SLiCE from Escherichia coli laboratory strains and its application to SLiP site-directed mutagenesis. AB - BACKGROUND: Seamless ligation cloning extract (SLiCE) is a simple and efficient method for DNA assembly that uses cell extracts from the Escherichia coli PPY strain, which expresses the components of the lambda prophage Red/ET recombination system. This method facilitates restriction endonuclease cleavage site-free DNA cloning by performing recombination between short stretches of homologous DNA (>= 15 base pairs). RESULTS: To extend the versatility of this system, I examined whether, in addition to bacterial extracts from the PPY strain, other E. coli laboratory strains were suitable for the SLiCE protocol. Indeed, carefully prepared cell extracts from several strains exhibited sufficient cloning activity for seamless gene incorporation into vectors with short homology lengths (approximately 15-20 bp). Furthermore, SLiCE was applied to the polymerase chain reaction (PCR)-based site-directed mutagenesis method, in a process termed "SLiCE-mediated PCR-based site-directed mutagenesis (SLiP site directed mutagenesis)". SLiP site-directed mutagenesis simplifies the steps of PCR-based site-directed mutagenesis, as it exploits the capability of the SLiCE method to insert multiple fragments. CONCLUSIONS: SLiCE can be performed in the laboratory with no requirement for a special E. coli strain, and the technique is easily established. This method increases the cloning efficiency, shortens the time for DNA manipulation, and greatly reduces the cost of seamless DNA cloning. PMID- 26037247 TI - Contractile function and energy metabolism of skeletal muscle in rats with secondary carnitine deficiency. AB - The consequences of carnitine depletion upon metabolic and contractile characteristics of skeletal muscle remain largely unexplored. Therefore, we investigated the effect of N-trimethyl-hydrazine-3-propionate (THP) administration, a carnitine analog inhibiting carnitine biosynthesis and renal reabsorption of carnitine, on skeletal muscle function and energy metabolism. Male Sprague-Dawley rats were fed a standard rat chow in the absence (CON; n = 8) or presence of THP (n = 8) for 3 wk. Following treatment, rats were fasted for 24 h prior to excision of their soleus and EDL muscles for biochemical characterization at rest and following 5 min of contraction in vitro. THP treatment reduced the carnitine pool by ~80% in both soleus and EDL muscles compared with CON. Carnitine depletion was associated with a 30% decrease soleus muscle weight, whereas contractile function (expressed per gram of muscle), free coenzyme A, and water content remained unaltered from CON. Muscle fiber distribution and fiber area remained unaffected, whereas markers of apoptosis were increased in soleus muscle of THP-treated rats. In EDL muscle, carnitine depletion was associated with reduced free coenzyme A availability (-25%, P < 0.05), impaired peak tension development (-44%, P < 0.05), and increased glycogen hydrolysis (52%, P < 0.05) during muscle contraction, whereas PDC activation, muscle weight, and water content remained unaltered from CON. In conclusion, myopathy associated with carnitine deficiency can have different causes. Although muscle atrophy, most likely due to increased apoptosis, is predominant in muscle composed predominantly of type I fibers (soleus), disturbance of energy metabolism appears to be the major cause in muscle composed of type II fibers (EDL). PMID- 26037248 TI - Mitochondrial respiratory capacity and coupling control decline with age in human skeletal muscle. AB - Mitochondrial health is critical to physiological function, particularly in tissues with high ATP turnover, such as striated muscle. It has been postulated that derangements in skeletal muscle mitochondrial function contribute to impaired physical function in older adults. Here, we determined mitochondrial respiratory capacity and coupling control in skeletal muscle biopsies obtained from young and older adults. Twenty-four young (28 +/- 7 yr) and thirty-one older (62 +/- 8 yr) adults were studied. Mitochondrial respiration was determined in permeabilized myofibers from the vastus lateralis after the addition of substrates oligomycin and CCCP. Thereafter, mitochondrial coupling control was calculated. Maximal coupled respiration (respiration linked to ATP production) was lower in muscle from older vs. young subjects (P < 0.01), as was maximal uncoupled respiration (P = 0.06). Coupling control in response to the ATP synthase inhibitor oligomycin was lower in older adults (P < 0.05), as was the mitochondria flux control ratio, coupled respiration normalized to maximal uncoupled respiration (P < 0.05). Calculation of respiratory function revealed lower respiration linked to ATP production (P < 0.001) and greater reserve respiration (P < 0.01); i.e., respiratory capacity not used for phosphorylation in muscle from older adults. We conclude that skeletal muscle mitochondrial respiratory capacity and coupling control decline with age. Lower respiratory capacity and coupling efficiency result in a reduced capacity for ATP production in skeletal muscle of older adults. PMID- 26037250 TI - Transorgan fluxes in a porcine model reveal a central role for liver in acylcarnitine metabolism. AB - Acylcarnitines are derived from mitochondrial acyl-CoA metabolism and have been associated with diet-induced insulin resistance. However, plasma acylcarnitine profiles have been shown to poorly reflect whole body acylcarnitine metabolism. We aimed to clarify the individual role of different organ compartments in whole body acylcarnitine metabolism in a fasted and postprandial state in a porcine transorgan arteriovenous model. Twelve cross-bred pigs underwent surgery where intravascular catheters were positioned before and after the liver, gut, hindquarter muscle compartment, and kidney. Before and after a mixed meal, we measured acylcarnitine profiles at several time points and calculated net transorgan acylcarnitine fluxes. Fasting plasma acylcarnitine concentrations correlated with net hepatic transorgan fluxes of free and C2- and C16-carnitine. Transorgan acylcarnitine fluxes were small, except for a pronounced net hepatic C2-carnitine production. The peak of the postprandial acylcarnitine fluxes was between 60 and 90 min. Acylcarnitine production or release was seen in the gut and liver and consisted mostly of C2-carnitine. Acylcarnitines were extracted by the kidney. No significant net muscle acylcarnitine flux was observed. We conclude that liver has a key role in acylcarnitine metabolism, with high net fluxes of C2-carnitine both in the fasted and fed state, whereas the contribution of skeletal muscle is minor. These results further clarify the role of different organ compartments in the metabolism of different acylcarnitine species. PMID- 26037249 TI - Short-term diabetic hyperglycemia suppresses celiac ganglia neurotransmission, thereby impairing sympathetically mediated glucagon responses. AB - Short-term hyperglycemia suppresses superior cervical ganglia neurotransmission. If this ganglionic dysfunction also occurs in the islet sympathetic pathway, sympathetically mediated glucagon responses could be impaired. Our objectives were 1) to test for a suppressive effect of 7 days of streptozotocin (STZ) diabetes on celiac ganglia (CG) activation and on neurotransmitter and glucagon responses to preganglionic nerve stimulation, 2) to isolate the defect in the islet sympathetic pathway to the CG itself, and 3) to test for a protective effect of the WLD(S) mutation. We injected saline or nicotine in nondiabetic and STZ-diabetic rats and measured fos mRNA levels in whole CG. We electrically stimulated the preganglionic or postganglionic nerve trunk of the CG in nondiabetic and STZ-diabetic rats and measured portal venous norepinephrine and glucagon responses. We repeated the nicotine and preganglionic nerve stimulation studies in nondiabetic and STZ-diabetic WLD(S) rats. In STZ-diabetic rats, the CG fos response to nicotine was suppressed, and the norepinephrine and glucagon responses to preganglionic nerve stimulation were impaired. In contrast, the norepinephrine and glucagon responses to postganglionic nerve stimulation were normal. The CG fos response to nicotine, and the norepinephrine and glucagon responses to preganglionic nerve stimulation, were normal in STZ-diabetic WLD(S) rats. In conclusion, short-term hyperglycemia's suppressive effect on nicotinic acetylcholine receptors of the CG impairs sympathetically mediated glucagon responses. WLD(S) rats are protected from this dysfunction. The implication is that this CG dysfunction may contribute to the impaired glucagon response to insulin-induced hypoglycemia seen early in type 1 diabetes. PMID- 26037251 TI - AdipoRon, the first orally active adiponectin receptor activator, attenuates postischemic myocardial apoptosis through both AMPK-mediated and AMPK-independent signalings. AB - Adiponectin (APN) is a cardioprotective molecule. Its reduction in diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury. Although APN administration in animals attenuates MI/R injury, multiple factors limit its clinical application. The current study investigated whether AdipoRon, the first orally active molecule that binds APN receptors, may protect the heart against MI/R injury, and if so, to delineate the involved mechanisms. Wild-type (WT), APN knockout (APN-KO), and cardiomyocyte specific-AMPK dominant negative (AMPK-DN) mice were treated with vehicle or AdipoRon (50 mg/kg, 10 min prior to MI) and subjected to MI/R (30 min/3-24 h). Compared with vehicle, oral administration of AdipoRon to WT mice significantly improved cardiac function and attenuated postischemic cardiomyocyte apoptosis, determined by DNA ladder formation, TUNEL staining, and caspase-3 activation (all P < 0.01). MI/R-induced apoptotic cell death was significantly enhanced in mice deficient in either APN (APN-KO) or AMPK (AMPK-DN). In APN-KO mice, AdipoRon attenuated MI/R injury to the same degree as observed in WT mice. In AMPK-DN mice, AdipoRon's antiapoptotic action was partially inhibited but not lost. Finally, AdipoRon significantly attenuated postischemic oxidative stress, as evidenced by reduced NADPH oxidase expression and superoxide production. Collectively, these results demonstrate for the first time that AdipoRon, an orally active APN receptor activator, effectively attenuated postischemic cardiac injury, supporting APN receptor agonists as a promising novel therapeutic approach treating cardiovascular complications caused by obesity-related disorders such as type 2 diabetes. PMID- 26037254 TI - An unusual case of severe anaemia and lymphocytosis. PMID- 26037253 TI - Grassland species differentially regulate proline concentrations under future climate conditions: an integrated biochemical and modelling approach. AB - Proline (Pro) is a versatile metabolite playing a role in the protection of plants against environmental stresses. To gain a deeper understanding of the regulation of Pro metabolism under predicted future climate conditions, including drought stress, elevated temperature and CO2 , we combined measurements in contrasting grassland species (two grasses and two legumes) at multiple organisational levels, that is, metabolite concentrations, enzyme activities and gene expression. Drought stress (D) activates Pro biosynthesis and represses its catabolism, and elevated temperature (DT) further elevated its content. Elevated CO2 attenuated the DT effect on Pro accumulation. Computational pathway control analysis allowed a mechanistic understanding of the regulatory changes in Pro metabolism. This analysis indicates that the experimentally observed coregulation of multiple enzymes is more effective in modulating Pro concentrations than regulation of a single step. Pyrroline-5-carboxylate synthetase (P5CS) and pyrroline-5-carboxylate reductase (P5CR) play a central role in grasses (Lolium perenne, Poa pratensis), and arginase (ARG), ornithine aminotransferase (OAT) and P5CR play a central role in legumes (Medicago lupulina, Lotus corniculatus). Different strategies in the regulation of Pro concentrations under stress conditions were observed. In grasses the glutamate pathway is activated predominantly, and in the legumes the ornithine pathway, possibly related to differences in N-nutritional status. PMID- 26037255 TI - Serum 25-hydroxyvitamin D deficiency and increased risk of breast cancer among Korean women: a case-control study. AB - Despite the emerging literature supporting the beneficial role of vitamin D on various health outcomes including carcinogenesis, current evidence on the association between vitamin D and breast cancer is still largely inconsistent. Furthermore, this relationship is particularly under explored among Asian population. We conducted a large case-control study with Korean women. We obtained and compared serum 25-hydroxyvitamin D (25(OH)D) between breast cancer patients (N = 3634) and general population (N = 17,133). Moreover, we further examined the association between serum 25(OH)D and breast cancer risk stratified by menopausal status and hormone receptor (HR) status of the tumor. Adjusted odds ratio (OR) for breast cancer comparing women with deficient level of serum 25(OH)D to women with sufficient level of serum 25(OH)D was 1.27 [95 % confidence interval (CI) 1.15-1.39]. This association did not significantly vary by menopausal status [pre-menopause: 1.26 (95 % CI 1.09-1.45) vs. post-menopause: 1.25 (95 % CI 1.10-1.41)]. When stratified by HR status, the inverse association remained significant in both positive and negative statuses. However, this association was more pronounced in HR-negative breast cancer, particularly with triple-negative breast cancer patients (1.45, 95 % CI 1.15-1.82). Given the growing burden of breast cancer in Asia and dearth of studies examining the association between vitamin D and breast cancer risk in Asian women thus far, this study provides a meaningful evidence for potential preventive effect of vitamin D on breast cancer for this particular population. PMID- 26037256 TI - Tumour characteristics and survival in familial breast cancer prospectively diagnosed by annual mammography. AB - Women from breast cancer families without a demonstrable BRCA1/2 mutation were subjected to annual mammography from age 30 years onwards. One-hundred and ninety eight patients were diagnosed prospectively with invasive breast cancer and followed for a total of 1513 years. Overall 10-year survival was 88 %. Together with our previous report that women in such kindreds had about twice the population risk of breast cancer, the combined conclusion was that the overall chances of developing breast cancer causing death within 10 years before 50 years of age was 1 % or less when subjected to annual mammography and current treatment. These are empirical prospective observations which may be used for genetic counselling. The majority (160/194 = 84 %) of patients had ER+ and/or low grade tumours with 92 % 10-year survival. One minor group of the patients had ER- tumours, another small group had high grade tumours with nodal spread, both groups were associated with worse prognosis, but the two groups were not mutually associated. PMID- 26037257 TI - Renal injury during hip fracture surgery: an exploratory study. AB - BACKGROUND: The present observational study was undertaken to identify potential markers of poor outcome, such as renal failure and mortality, after hip fracture surgery. METHODS: Forty-three patients, with a mean age of 78 years, were studied having undergone acute hip fracture surgery. Analysis included the urinary excretion of cortisol, albumin and sodium. The degree of fluid retention was evaluated based on the urinary excretion of metabolic end products. Fluid retention and the excretion of albumin and neutrophil gelatinase-associated lipocalin (NGAL) were measured repeatedly in a sub-group of 15 patients who also underwent haemodynamic monitoring. The perioperative change in serum creatinine and a 30-day mortality served as outcome measures. RESULTS: Although serum creatinine increased by > 25% in 21% of the patients, only a high preoperative creatinine concentration correlated with a 30-day mortality. The subgroup analysis revealed that fluid retention was pronounced and remained essentially unchanged up to the first postoperative day. A rise in serum creatinine was always preceded by increased urinary excretion of NGAL that, in turn, was associated with preoperative fluid retention. The only perioperative event that correlated with a higher 30-day mortality was perioperative aggravation of albuminuria (67% vs 0%, P < 0.01), which became more common with advanced age and a low cardiac index. CONCLUSIONS: Two different mechanisms seem to affect the kidneys during hip fracture surgery. The first elevates the serum creatinine concentration while the second increases the albuminuria. Only the second mechanism had a bearing on mortality. PMID- 26037258 TI - Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma--a review. AB - Multiple trauma patients require extremely good management and thus, the trauma team needs to be prepared and to be up to date with the new standards of intensive therapy. Oxidative stress and free radicals represent an extremely aggressive factor to cells, having a direct consequence upon the severity of lung inflammation. Pulmonary tissue is damaged by oxidative stress, leading to biosynthesis of mediators that exacerbate inflammation modulators. The subsequent inflammation spreads throughout the body, leading most of the time to multiple organ dysfunction and death. In this paper, we briefly present an update of biochemical effects of oxidative stress and free radical damage to the pulmonary tissue in patients in critical condition in the intensive care unit. Also, we would like to present a series of active substances that substantially reduce the aggressiveness of free radicals, increasing the chances of survival. PMID- 26037259 TI - Bilingualism, Language Disorders and Intercultural Families in Contemporary Italy: Family Relations, Transmission of Language and Representations of Otherness. AB - This study aims to show how language disorders in children affect language transmission and the mixedness experience in intercultural families. To this end, it adopts a qualitative method of study based on the administration of ad hoc interviews to intercultural couples who consulted our Child Neuropsychiatry Service because of language disorders in their children. One of the main consequences, when the child of an intercultural couple presents a language disorder and a diagnostic process has to be initiated, may be interruption of the transmission of the second language, especially if it is the mother's language. The decision to do this, which may be taken on the advice of teachers and health professionals, but also because the parents themselves often attribute their child's language disorder to his bilingual condition, affects not only the relationship between the mother and her child, but also processes in the construction of parenthood and in the structuring of the child's personality and the plurality of his affiliations. A clear understanding of how the dialectic between the categories of "alien" and "familiar" is managed in these contemporary families, which have to reckon with the condition of otherness, is crucial for psychiatrists and psychotherapists working in settings in which cultural difference is an issue to consider. PMID- 26037261 TI - Methods: for studying pharmacogenetic profiles of combination chemotherapeutic drugs. AB - INTRODUCTION: Molecular and genetic analysis of tumors and individuals has led to patient-centered therapies, through the discovery and identification of genetic markers predictive of drug efficacy and tolerability. Present therapies often include a combination of synergic drugs, each of them directed against different targets. Therefore, the pharmacogenetic profiling of tumor masses and patients is becoming a challenge, and several questions may arise when planning a translational study. AREAS COVERED: The review presents the different techniques used to stratify oncology patients and to tailor antineoplastic treatments according to individual pharmacogenetic profiling. The advantages of these methodologies are discussed as well as current limits. EXPERT OPINION: Facing the rapid technological evolution for genetic analyses, the most pressing issues are the choice of appropriate strategies (i.e., from gene candidate up to next generation sequencing) and the possibility to replicate study results for their final validation. It is likely that the latter will be the major obstacle in the future. However, the present landscape is opening up new possibilities, overcoming those hurdles that have limited result translation into clinical settings for years. PMID- 26037262 TI - Modified One-layer Duct-to-mucosa Pancreaticojejunostomy Reduces Pancreatic Fistula After Pancreaticoduodenectomy. AB - Postoperative pancreatic fistula (POPF) is a major source of morbidity after pancreaticoduodenectomy (PD). The purpose of this retrospective study comparing one-layer pancreaticojejunostomy (PJ) with two-layer PJ after PD was to evaluate whether the one-layer duct-to-mucosa PJ after PD can reduce the incidence of POPF.A total of 194 consecutive patients who underwent PD by one surgeon (Y. Miao) from January 2011 to February 2014 were included in this study. Among those patients, 104 underwent one-layer PJ (one-layer group) and 90 patients underwent two-layer PJ (two-layer group), respectively. Preoperative clinicopathologic features, intraoperative parameters, postoperative morbidity with focus on POPF, were compared between the two groups.The overall incidence of POPF was 19.6% (38/194), and clinically relevant grade B/C POPF rates were 8.6% (16/194) and 3.1% (6/194), respectively. There were no differences in patients' demographics and operation related factors between the two groups. However, the incidence of POPF in the one-layer group was significantly lower than in two-layer group (13.5% [14/104 patients] and 26.7% [24/90 patients] respectively; p=0.021). The median postoperative hospital stay was also significantly lower in the one-layer group compared to the two-layer group (13 days vs. 15 days, p=0.035). One patient in two-layer group died due to postoperative hemorrhage.One-layer duct-to-mucosa pancreaticojejunostomy is a simple and easy technique for pancreaticojejunal anastomosis after PD, and can reduce the POPF rate in comparison to the two-layer technique. PMID- 26037263 TI - Comparison of double locking plate constructs with single non-locking plate constructs in single cycle to failure in bending and torsion. AB - OBJECTIVE: To evaluate the biomechanical properties of single 3.5 mm broad dynamic compression plate (DCP) and double 3.5 mm String-of-Pearls (SOP) plate constructs in single-cycle bending and torsion. We hypothesized that the double SOP construct would outperform the broad DCP in both bending and torsional testing. METHODS: Broad DCP plates and double 3.5 mm SOP plates were secured to a previously validated bone model in an effort to simulate bridging osteosynthesis. Constructs were tested in both four-point bending and torsional testing. RESULTS: The double SOP constructs had significantly greater bending stiffness, bending strength, bending structural stiffness, and torsional stiffness when compared to the broad DCP constructs. The single broad DCP constructs had significantly higher yield torque and yield angles during torsional testing. CLINICAL RELEVANCE: Although the in vitro mechanical performance of the double SOP construct was significantly greater than the single broad DCP constructs under bending loads, the actual differences were small. Various patient, fracture, and implant factors must be considered when choosing an appropriate implant for fracture fixation. PMID- 26037264 TI - Chronic postnatal stress induces voluntary alcohol intake and modifies glutamate transporters in adolescent rats. AB - Postnatal stress alters stress responses for life, with serious consequences on the central nervous system (CNS), involving glutamatergic neurotransmission and development of voluntary alcohol intake. Several drugs of abuse, including alcohol and cocaine, alter glutamate transport (GluT). Here, we evaluated effects of chronic postnatal stress (CPS) on alcohol intake and brain glutamate uptake and transporters in male adolescent Wistar rats. For CPS from postnatal day (PD) 7, pups were separated from their mothers and exposed to cold stress (4 degrees C) for 1 h daily for 20 days; controls remained with their mothers. Then they were exposed to either voluntary ethanol (6%) or dextrose (1%) intake for 7 days (5-7 rats per group), then killed. CPS: (1) increased voluntary ethanol intake, (2) did not affect body weight gain or produce signs of toxicity with alcohol exposure, (3) increased glutamate uptake by hippocampal synaptosomes in vitro and (4) reduced protein levels (Western measurements) in hippocampus and frontal cortex of glial glutamate transporter-1 (GLT-1) and excitatory amino-acid transporter-3 (EAAT-3) but increased glutamate aspartate transporter (GLAST) levels. We propose that CPS-induced decrements in GLT-1 and EAAT-3 expression levels are opposed by activation of a compensatory mechanism to prevent excitotoxicity. A greater role for GLAST in total glutamate uptake to prevent enlarged extracellular glutamate levels is inferred. Although CPS strongly increased intake of ethanol, this had little impact on effects of CPS on brain glutamate uptake or transporters. However, the impact of early life adverse events on glutamatergic neurotransmission may underlie increased alcohol consumption in adulthood. PMID- 26037265 TI - Factors affecting the lung perfused blood volume in patients with intrapulmonary clots after anti-coagulation therapy. AB - OBJECTIVES: Factors affecting the improvement in the lung perfused blood volume (LPBV) were evaluated based on the presence of intrapulmonary clots (IPCs) after anti-coagulation therapy using 64-slice dual-energy CT. MATERIALS AND METHODS: 96 patients exhibiting venous thromboembolism underwent initial and repeated LPBV examinations between December 2008 and July 2014. Fifteen patients were excluded due to pulmonary comorbidities, and a total of 81 patients were included in this study. Acute pulmonary embolism (PE) was diagnosed in 46 of the patients (56.7%). LPBV images were three-dimensionally reconstructed with two threshold ranges: 1 120 HU (V120) and 1-5 HU (V5), and the relative value of V5 per V120 expressed as %V5. These values were subsequently compared with indicators of the severity of PE, such as the D-dimer level, heart rate and CT measurements. This study was approved by the local ethics committee. RESULTS: In patients with IPCs, the D dimer, V5 and %V5values were significantly larger (p<=0.01) in the initial LPBV, although these differences disappeared in subsequent LPBV after treatment. The right ventricular (RV) diameter, RV/left ventricular (RV/LV) diameter ratio and %V5 values were also significantly reduced, whereas the V5 value did not significantly decrease (p=0.07), but V120 value significantly increased (p<0.001) after treatment. However, in patients with IPCs the change rate in %V5 [(subsequent-initial)/initial %V5] showed a better correlation with that in V5 (r=0.94, p<0.001) rate than that in V120 (r=0.19, p=0.19) after treatment. CONCLUSIONS: Increased whole lung perfusion (V120) and a decreased low perfusion volume (V5) affect the improvement in the %V5 values after treatment. PMID- 26037266 TI - Clinical evaluation of image quality and radiation dose reduction in upper abdominal computed tomography using model-based iterative reconstruction; comparison with filtered back projection and adaptive statistical iterative reconstruction. AB - PURPOSE: To evaluate the image quality of upper abdominal CT images reconstructed with model-based iterative reconstruction (MBIR) in comparison with filtered back projection (FBP) and adaptive statistical iterative reconstruction (ASIR) on scans acquired with various radiation exposure dose protocols. MATERIALS AND METHODS: This prospective study was approved by our institutional review board, and informed consent was obtained from all 90 patients who underwent both control dose (CD) and reduced-dose (RD) CT of the upper abdomen (unenhanced: n=45, contrast-enhanced: n=45). The RD scan protocol was randomly selected from three protocols; Protocol A: 12.5% dose, Protocol B: 25% dose, Protocol C: 50% dose. Objective image noise, signal-to-noise (SNR) ratio for the liver parenchyma, visual image score and lesion conspicuity were compared among CD images of FBP and RD images of FBP, ASIR and MBIR. RESULTS: RD images of MBIR yielded significantly lower objective image noise and higher SNR compared with RD images of FBP and ASIR for all protocols (P<.01) and CD images of FBP for Protocol C (P<.05). Although the subjective image quality of RD images of MBIR was almost acceptable for Protocol C, it was inferior to that of CD images of FBP for Protocols A and B (P<.0083). The conspicuity of the small lesions in RD images of MBIR tended to be superior to that in RD images of FBP and ASIR and inferior to that in CD images for Protocols A and B, although the differences were not significant (P>.0083). CONCLUSION: Although 12.5%-dose MBIR images (mean size specific dose estimates [SSDE] of 1.13mGy) yielded objective image noise and SNR comparable to CD-FBP images, at least a 50% dose (mean SSDE of 4.63mGy) would be needed to maintain the subjective image quality and the lesion conspicuity. PMID- 26037267 TI - Imaging of posterior tibial tendon dysfunction--Comparison of high-resolution ultrasound and 3T MRI. AB - PURPOSE: Posterior tibial tendon dysfunction is the most common cause of acquired asymmetric flatfoot deformity. The purpose of this study was to determine and compare the diagnostic value of MRI and high-resolution ultrasound (HR-US) in posterior tibial tendon dysfunction (PTTD), and assess their correlation with intraoperative findings. MATERIALS AND METHODS: We reviewed 23 posterior tibial tendons in 23 patients with clinical findings of PTTD (13 females, 10 males; mean age, 50 years) with 18MHz HR-US and 3T MRI. Surgical intervention was performed in nine patients. RESULTS: HR-US findings included 2 complete tears, 6 partial tears, 10 tendons with tendinosis, and 5 unremarkable tendons. MRI demonstrated 2 complete tears, 7 partial tears, 10 tendons with tendinosis, and 4 unremarkable tendons. HR-US and MRI were concordant in 20/23 cases (87%). Image findings for HR-US were confirmed in six of nine patients (66.7%) by intraoperative inspection, whereas imaging findings for MRI were concordant with five of nine cases (55.6%). CONCLUSION: Our results indicate that HR-US can be considered slightly more accurate than MRI in the detection of PTTD. PMID- 26037268 TI - Asymmetric capillary bridges between contacting spheres. AB - When a drop of liquid wets two identical solid spheres, the liquid forms a capillary bridge between the spheres to minimize surface energy. In the absence of external forces, these bridges are typically assumed to be axisymmetric, and the shape that minimizes surface energy can be calculated analytically. However under certain conditions, the bridge is axisymmetrically unstable, and migrates to a non-axisymmetric configuration. The goal of this paper is to characterize these non-axisymmetric capillary bridges. Specifically, we numerically calculate the shape of the capillary bridge between two contacting spheres that minimizes the total surface energy for a given volume and contact angle and compare to experiments. When the bridge is asymmetric, finite element calculations demonstrate that the shape of the bridge is spherical. In general, the bridge shape depends on both volume and contact angle, yet we find the degree of asymmetry is controlled by a single parameter. PMID- 26037269 TI - Fast dye removal from water by starch-based nanocomposites. AB - Robust and efficient methylene blue (MB) adsorbent was prepared based on starch/cellulose nanowhiskers hydrogel composite. Maximum MB adsorption capacity of ~2050mgperg of dried hydrogel was obtained with the composite at 5wt.% of cellulose nanowhiskers and at pH 5. Adsorption capacity varied from 1450mg/g to 2050mg/g with increasing the initial MB concentration from 1500mg/L to 2500mg/L, respectively. For all the concentrations studied ca. 90% of MB was removed by the adsorbent. Optimal conditions were obtained at pH?5 due to the generation of negatively charged groups (COO(-)) in the adsorbent, which can strongly interact with the positive charges from MB. The main advantage of this system over other reported adsorbents, besides the fact of being synthesized from biodegradable polymers (starch and cellulose), is its fast adsorption kinetics that follows the pseudo-second order model, which is based on chimisorption phenomenon. Saturation condition was reached as fast as 1h of experiments owing to the formation of an adsorbed MB monolayer as suggested by the Langmuir isotherm model. Desorption experiments showed 60wt.% of MB loaded can be removed from the adsorbent by immersing it in a pH 1 solution, showing its feasibility to be reused. Therefore, starch/cellulose nanowhiskers hydrogel composite presents outstanding capacity to be employed in the remediation of MB contaminated wastewaters. PMID- 26037270 TI - CoTiO3/Ag3VO4 composite: A study on the role of CoTiO3 and the active species in the photocatalytic degradation of methylene blue. AB - The role of CoTiO3 and the possible active species in the methylene blue (MB) degradation over the visible-light-driven CoTiO3/Ag3VO4 catalyst have firstly been investigated in this work. CoTiO3 is found to play important roles in enhancing the visible light-harvesting ability of the composite and increasing electron-hole separation efficiency due to the hybrid effect between Ag3VO4 and CoTiO3. The indirect probe experiments reveal that CoTiO3/Ag3VO4 heterostructure provides large amount of active species, therefore a high photocatalytic activity could be obtained. The results clearly suggest that the photocatalytic MB degradation over this hybrid catalyst is mainly governed by direct hole oxidation. PMID- 26037271 TI - Anionic starch-induced Cu-based composite with flake-like mesostructure for gas phase propanal efficient removal. AB - Highly crystalline flake-like CuCeO2-delta composites (strCCx) with large specific surface area and developed mesoporosity were prepared using an economic and effective bio-template route. Modified starch with abundant surface carboxyl groups was adopted as the chelating agent and template for metal cations immobilization via electrostatic attraction predominately based on the process of -COO(-)?Cu(2+) and -COO(-)?Ce(3+). Physicochemical properties of prepared materials were systematically explored by FT-IR, XRD, TG, N2 adsorption/desorption, FE-SEM, TEM, H2-TPR, O2-TPD, XPS, DRUV-Vis, and XAFS techniques. Propanal as a typical oxygen-contained VOC was adopted as the probe pollutant to evaluate the catalytic performance of synthesized materials. Characterization results reveal that plenty of copper ions in composite oxides are incorporated into CeO2 lattice, which produces oxygen vacancies and enhances metal reducibility. Both specific surface area and pore volume of strCCx samples decreased with the increasing of Cu loading. The flake-like CuCeO2-delta sample (Cu/(Cu+Ce)=0.15) with highest specific surface area (108.2m(2)/g) and surface oxygen concentration is indentified as the most active catalyst with propanal totally destructed at 230 degrees C. The introduction of H2O has a negative effect on propanal removal, and the synthesized catalyst has high tolerance to moisture. In conclusion, the specific surface area and surface oxygen density are two vital factors governing the catalytic activity of composite catalysts. PMID- 26037272 TI - Measurement of surface and interfacial tension using pendant drop tensiometry. AB - Pendant drop tensiometry offers a simple and elegant solution to determining surface and interfacial tension - a central parameter in many colloidal systems including emulsions, foams and wetting phenomena. The technique involves the acquisition of a silhouette of an axisymmetric fluid droplet, and iterative fitting of the Young-Laplace equation that balances gravitational deformation of the drop with the restorative interfacial tension. Since the advent of high quality digital cameras and desktop computers, this process has been automated with high speed and precision. However, despite its beguiling simplicity, there are complications and limitations that accompany pendant drop tensiometry connected with both Bond number (the balance between interfacial tension and gravitational forces) and drop volume. Here, we discuss the process involved with going from a captured experimental image to a fitted interfacial tension value, highlighting pertinent features and limitations along the way. We introduce a new parameter, the Worthington number, Wo, to characterise the measurement precision. A fully functional, open-source acquisition and fitting software is provided to enable the reader to test and develop the technique further. PMID- 26037273 TI - Metastable gamma-Bi2O3 tetrahedra: Phase-transition dominated by polyethylene glycol, photoluminescence and implications for internal structure by etch. AB - Metastable gamma-Bi2O3 tetrahedra have been fabricated by a facile polyethylene glycol-assistance (PEG, Mw=400) one-step precipitation method at 70 degrees C. The tetrahedra of 8MUm are built up of ultrathin nanosheets via layer-by-layer self-assembly. X-ray powder diffraction, scanning electron microscopy, UV-visible spectrometer and fluorescence spectrophotometer were employed to characterize the obtained gamma-Bi2O3. The morphology of the gamma-Bi2O3 is significantly influenced by the feeding concentration of NaOH solution. Tetrahedra and incomplete tetrahedra whose edges are clipped in various degrees of gamma-Bi2O3 can be obtained with different concentrations of NaOH solution. The uniform and ordered chains of PEG play a crucial role not only in the morphology, even more important in phase-transition of Bi2O3. The photoluminescence (PL) characteristic of the sample was investigated. PMID- 26037274 TI - A randomized clinical trial on arresting dentine caries in preschool children by topical fluorides--18 month results. AB - OBJECTIVES: This study aimed to compare the effectiveness of three topical fluoride application protocols in arresting dentine caries in primary teeth of preschool children in a fluoridated area. METHODS: Children aged 3-4 years who had at least one active dentine caries lesion were randomly allocated into three intervention groups: Group 1-application of 30% silver diammine fluoride (SDF) solution every 12 months; Group 2-three applications of 30% SDF solution at weekly interval at baseline; and Group 3-three applications of 5% sodium fluoride (NaF) varnish at weekly interval at baseline. A masked examiner carried out follow-up examinations every 6 months to assess whether the treated lesions had become arrested. RESULTS: A total of 304 children with 1670 tooth surfaces with dentine caries received treatment at baseline. After 18 months, 275 children (91%) remained in the study. The caries arrest rates at tooth surface level were 40%, 35% and 27% for Groups 1, 2 and 3, respectively (p<0.001). Result of the multi-level survival analysis showed that the two SDF application protocols could shorten the time to arrest of dentine caries compared with the NaF application protocol. Presence of plaque on lesion surface, tooth type and tooth surface all had significant effects on caries arrest rates. CONCLUSIONS: Annual or three consecutive weekly applications of SDF solution is more effective in arresting dentine caries in primary teeth than three consecutive weekly applications of NaF varnish. CLINICAL SIGNIFICANCE: In a water fluoridated area, application of SDF solution, either three weekly applications at baseline or annually, can arrest active dentine caries lesions in primary teeth faster than three weekly applications of NaF varnish at baseline. PMID- 26037275 TI - Ethnic inequalities in severe mental disorders: where is the harm? PMID- 26037276 TI - A crossover randomised and controlled trial of the impact of active video games on motor coordination and perceptions of physical ability in children at risk of Developmental Coordination Disorder. AB - BACKGROUND: Impaired motor development can significantly affect a child's life and may result in an increased risk of a range of physical and psychological disorders. Active video game (AVG) interventions have been demonstrated to enhance motor skills in children with Developmental Coordination Disorder (DCD); however a home-based intervention has not been assessed. OBJECTIVES: The primary aim of this study was to compare the changes in motor coordination between a 16 week period of AVG use, with 16 weeks of normal activities (NAG). The secondary aim was to compare the child and parent perceptions of their physical performance between the AVG and NAG conditions. METHODS: Twenty-one 9-12 year olds (10 males) were confirmed to be at risk of DCD (? 16th percentile Movement Assessment Battery for Children-2nd edition (MABC-2) and ? 15th percentile Developmental Coordination Disorder Questionnaire (DCDQ)) and participated in this crossover randomised and controlled trial. Data was collected at study entry, after the first 16 week condition and following the final 16 week condition, including; (1) the MABC-2, (2) three-dimensional motion analysis of single leg balance and finger-nose tasks, and (3) parent perception of physical skills. Participant perception of physical skills was collected only after the first and second conditions. RESULTS: There was no significant difference between AVG and NAG for any of the primary variables including the MABC-2, balance centre-of-mass path distance and finger-nose path distance. There was no significant intervention effect for secondary measures of motor coordination; however the children perceived their motor skills to be significantly enhanced as a result of the AVG intervention in comparison to the period of no intervention. CONCLUSION: A 16 week home based AVG intervention did not enhance motor skills in children with DCD, although they perceived their physical skills to be significantly improved. TRIAL REGISTRATION: Australia and New Zealand Clinical trials Registry (ACTRN 12611000400965). PMID- 26037277 TI - Dyslexic children fail to comply with the rhythmic constraints of handwriting. AB - In this study, we sought to demonstrate that deficits in a specific motor activity, handwriting, are associated to Developmental Dyslexia. The linguistic and writing performance of children with Developmental Dyslexia, with and without handwriting problems (dysgraphia), were compared to that of children with Typical Development. The quantitative kinematic variables of handwriting were collected by means of a digitizing tablet. The results showed that all children with Developmental Dyslexia wrote more slowly than those with Typical Development. Contrary to typically developing children, they also varied more in the time taken to write the individual letters of a word and failed to comply with the principles of isochrony and homothety. Moreover, a series of correlations was found among reading, language measures and writing measures suggesting that the two abilities may be linked. We propose that the link between handwriting and reading/language deficits is mediated by rhythm, as both reading (which is grounded on language) and handwriting are ruled by principles of rhythmic organization. PMID- 26037278 TI - A polytomous rasch analysis of the english version of health-related quality of life for drug abusers test. AB - The specific aim of this study was to analyze the psychometric properties of the English version of the Health-Related Quality of Life for Drug Abusers Test (HRQoLDA Test) applying the Rasch model, and emphasizing fit between empirical data and theoretical Rasch model assumptions; item(s) category probability curve; and precision in terms of information function. In this study, the authors present the results of the translation and adaptation of the original Spanish version to English, as applied to a sample of substance users in Australia. The authors evaluated 121 adults recruited from inpatient and outpatient treatment facilities in Sydney, Australia. The Rating Scale Model was used in the psychometric analysis of the English version of the HRQoLDA Test. The items and persons revealed a fit between the reported data and the model. It was also demonstrated that respondents did not discriminate among the five response categories, which led to a reduction to three response categories. The adaptation of the TECVASP to the English language, renamed the HRQoLDA test, as developed with an Australian sample revealed adequate psychometric properties. PMID- 26037279 TI - Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status. AB - A multianalyte algorithmic assay (MAAA) identifies circulating neuroendocrine tumor (NET) transcripts (n=51) with a sensitivity/specificity of 98%/97%. We evaluated whether blood measurements correlated with tumor tissue transcript analysis. The latter were segregated into gene clusters (GC) that defined clinical 'hallmarks' of neoplasia. A MAAA/cluster integrated algorithm (CIA) was developed as a predictive activity index to define tumor behavior and outcome. We evaluated three groups. Group 1: publically available NET transcriptome databases (n=15; GeneProfiler). Group 2: prospectively collected tumors and matched blood samples (n=22; qRT-PCR). Group 3: prospective clinical blood samples, n=159: stable disease (SD): n=111 and progressive disease (PD): n=48. Regulatory network analysis, linear modeling, principal component analysis (PCA), and receiver operating characteristic analyses were used to delineate neoplasia 'hallmarks' and assess GC predictive utility. Our results demonstrated: group 1: NET transcriptomes identified (92%) genes elevated. Group 2: 98% genes elevated by qPCR (fold change >2, P<0.05). Correlation analysis of matched blood/tumor was highly significant (R(2)=0.7, P<0.0001), and 58% of genes defined nine omic clusters (SSTRome, proliferome, signalome, metabolome, secretome, epigenome, plurome, and apoptome). Group 3: six clusters (SSTRome, proliferome, metabolome, secretome, epigenome, and plurome) differentiated SD from PD (area under the curve (AUC)=0.81). Integration with blood-algorithm amplified the AUC to 0.92+/ 0.02 for differentiating PD and SD. The CIA defined a significantly lower SD score (34.1+/-2.6%) than in PD (84+/-2.8%, P<0.0001). In conclusion, circulating transcripts measurements reflect NET tissue values. Integration of biologically relevant GC differentiate SD from PD. Combination of GC data with the blood algorithm predicted disease status in >92%. Blood transcript measurement predicts NET activity. PMID- 26037280 TI - Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer. AB - Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined >200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four- to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour autotaxin, LPA levels and inflammatory mediators including IL1beta, IL6, IL8, GMCSF, TNFalpha, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased autotaxin secretion. We confirmed that this autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities. PMID- 26037282 TI - Paternal age bioethics. AB - Modern genetic sequencing studies have confirmed that the sperm of older men contain a greater number of de novo germline mutations than the sperm of younger men. Although most of these mutations are neutral or of minimal phenotypic impact, a minority of them present a risk to the health of future children. If demographic trends towards later fatherhood continue, this will likely lead to a more children suffering from genetic disorders. A trend of later fatherhood will accelerate the accumulation of paternal-origin de novo mutations in the gene pool, gradually reducing human fitness in the long term. These risks suggest that paternal age is of ethical importance. Children affected by de novo mutations arising from delayed fatherhood can be said to be harmed, in the sense of 'impersonal' harm or 'non-comparative' harm. Various strategies are open at societal and individual levels towards reducing deleterious paternal age effects. Options include health education to promote earlier fatherhood, incentives for young sperm donors and state-supported universal sperm banking. The latter approach would likely be of the greatest benefit and could in principle be implemented immediately. More futuristically, human germline genetic modification offers the potential to repair heritable mutational damage. PMID- 26037281 TI - Growth characteristics and expression of CD73 and CD146 in cells cultured from dental pulp. AB - AIM: Dental pulp stem cells (DPSCs) in permanent teeth and stem cells from human exfoliated deciduous (SHED) teeth are unique sources of mesenchymal stem cells. The aim of this study was to compare the growth characteristics and morphology of DPSCs and SHED and their immuno-phenotype using CD73 and CD146 in the 1st, 3rd, and 5th passage of cell culture. METHODS: Growth characteristics, morphology, and colony forming efficiency were assessed for SHED and DPSCs. Immunocytochemistry and flow cytometry using CD146 and CD73 was performed for SHED and DPSCs in the 1st, 3rd and 5th passage of culture. Data was analyzed using SPSSTM software (version 17.0.0). RESULTS: The seeding efficiency and colony forming unit efficiency was higher in SHED than in DPSCs. Flow cytometry analysis using CD73 and CD146 showed an increase in CD73 expression with increase in passage number in SHED and a decrease in CD73 expression with increase in passage number in DPSCs. There was a decrease in CD146 expression from passage one through five in SHED and DPSCs. CONCLUSION: Cells isolated from the pulp of deciduous teeth and permanent teeth show difference in their growth characteristics and phenotype and are a viable source of stem cells. PMID- 26037283 TI - Opt-out and consent. AB - A chief objection to opt-out organ donor registration policies is that they do not secure people's actual consent to donation, and so fail to respect their autonomy rights to decide what happens to their organs after they die. However, scholars have recently offered two powerful responses to this objection. First, Michael B Gill argues that opt-out policies do not fail to respect people's autonomy simply because they do not secure people's actual consent to donation. Second, Ben Saunders argues that opt-out policies do secure people's actual-if not explicit-consent, provided that certain conditions are satisfied. I argue that Gill and Saunders' arguments are not successful. My conclusion does not imply that jurisdictions should not implement opt-out policies-their failure to secure people's actual consent may be outweighed by other considerations. But, my conclusion does imply that Gill and Saunders are mistaken to claim that opt-out policies are respectful of people's autonomy. PMID- 26037284 TI - Circulating microparticles in umbilical cord blood in normal pregnancy and pregnancy with preeclampsia. AB - INTRODUCTION: Placenta microthrombi being one of the prevalent recurrent histological findings in women with preeclampsia (PE), it is reasonable to think that the study of coagulation alterations in cord blood could be more informative than that observed in maternal blood. The aim of the present study was to measure different subtypes of microparticles (MP) plasma levels in the maternal peripheral blood at labour and in the venous cord blood of pregnant women with PE compared to those in a group of women without PE. MATERIALS AND METHODS: Thirty two pregnant women in labour, 16 with and 16 without PE, were enrolled. Blood samples were collected immediately after delivery from cord blood and from maternal peripheral blood. Total, cellular-derived and tissue factor- bearing MP were analyzed using flow-cytometry. Procoagulant activity of MP was assessed using the STA(r) Procoag PPL assay. RESULTS: Total MP, platelet activated-derived (P-Selectin+), leukocyte-derived and TF+MP were higher in pregnancies complicated by PE as compared with normotensive women (p<0.05). Platelet-derived MP (CD61+) levels were lower in PE than in healthy women and no difference was found in endothelial-derived MP levels between the two groups. The PPL clotting time was significantly shorter in PE compared with controls. When only venous cord blood was analysed, all MP detected were significantly higher in PE than in healthy normotensive women (p<0.05). CONCLUSIONS: MP are very likely involved in the hypercoagulable and pro-inflammatory intravascular reactions during PE. Prospective studies in a larger population are needed to define the clinical meaning of MP measurement in the PE setting. PMID- 26037285 TI - Physicochemical characterisation of rVIII-SingleChain, a novel recombinant single chain factor VIII. AB - rVIII-SingleChain is a novel recombinant single-chain factor VIII (FVIII) construct, comprising covalently bonded heavy and light chains. Post translational modifications of FVIII affect physicochemical parameters, including hydrophobicity and charge. The most relevant post-translational modifications of FVIII products are N-glycosylation of asparagine residues and tyrosine sulphations. Here, the physicochemical properties, thrombin cleavage products and post-translational modifications of rVIII-SingleChain were investigated and compared against commercially available recombinant FVIII (rFVIII) products with a predominant two-chain structure (B-domain deleted rFVIII and full-length rFVIII). rVIII-SingleChain was expressed in Chinese hamster ovary (CHO) cells and purified by chromatographic methods. Physicochemical properties of rVIII SingleChain or thrombin-derived cleavage products were assessed using size exclusion chromatography, reversed-phase chromatography and sodium dodecyl sulphate polyacrylamide gel electrophoresis. Analysis of the respective carbohydrate structures was performed after release of N-glycans by PNGase F followed by fluorescence labelling and high-performance liquid chromatography. Proteolysis by trypsin generated the corresponding peptides, which were analysed for sulphated tyrosines by liquid chromatography-electrospray ionisation time of flight-mass spectrometry. rVIII-SingleChain was shown to be of high purity and homogeneity, and presented a well-defined single-chain molecule with predominant beta-sheet conformation. The coagulation-relevant thrombin-activation products of rVIII-SingleChain were comparable with those obtained by activation of commercially available rFVIII products. rVIII-SingleChain post-translational modifications were similar to other CHO cell-derived rFVIII products for N glycopattern and tyrosine sulphation. In conclusion, rVIII-SingleChain is of high homogeneity and purity, and provides an expected cleavage pattern on activation, setting the basis for optimal efficacy in the patient. PMID- 26037286 TI - Risk and benefit of direct oral anticoagulants or PAR-1 antagonists in addition to antiplatelet therapy in patients with acute coronary syndrome. AB - BACKGROUND: The overall risk-benefit profile of direct oral anticoagulants (DOACs) or PAR-1 antagonists in addition to antiplatelet therapy for patients with acute coronary syndrome (ACS) has not been clearly established. METHODS: Studies evaluating clinical outcomes of DOACs (including direct Xa inhibitors and direct thrombin inhibitors) or PAR-1 antagonists in addition to standard antiplatelet therapy in patients with recent ACS, published before Nov 2014, were screen. Eleven double blind, placebo-controlled, randomized clinical studies including 46782 patients were identified. RESULTS: The study revealed an up to 3 fold increased risk of hemorrhagic stroke in patients receiving DOACs (OR 3.45, 95% CI 1.62 to 7.37, P=0.001, and I(2)=0%) or PAR-1 antagonists (OR 2.60, 95% CI 1.18 to 5.69, P=0.02, and I(2)=0%) in addition to antiplatelet therapy compared to those with antiplatelet therapy alone. Despite a moderate but significant reduction of composite death/MI/stroke was observed in patients with additional DOACs (OR 0.86, 95% CI 0.78 to 0.94, P=0.002, and I(2)=0%) or PAR-1 antagonists (OR 0.89, 95% CI 0.80 to 0.98, P=0.02, and I(2)=0%), due to the remarkably increased major bleeding risks, overall net clinical outcomes (death/MI/stroke/major bleeding) did not differ between patients with or without additional DOACs (OR 0.99, 95% CI 0.91 to 1.09, P=0.88, and I(2)=0%) or PAR-1 antagonists (OR 0.98, 95% CI 0.91 to 1.05, P=0.55, and I(2)=0%). CONCLUSIONS: In patients with ACS, the addition of DOACs or PAR-1 antagonists to antiplatelet therapy led to a modest but significant reduction in composite efficacy outcome at the cost of a substantial increase in hemorrhagic stroke and major bleeding events. PMID- 26037287 TI - A narrow heritability evaluation of gestational age at birth. PMID- 26037288 TI - Perioperative Monitoring of Heart Rate and Rhythm. AB - Perioperative disorders of heart rate and rhythm are common and can contribute to patient morbidity and mortality. Management of perioperative arrhythmias is facilitated by understanding the basic mechanisms of arrhythmia formation and the role of transient imbalances. The decisions of when and how to treat perioperative arrhythmias are based on whether or not hemodynamic signs are present and the assumed risk of sudden arrhythmic death. Perioperative arrhythmias warrant careful monitoring and consideration of potential complications associated with antiarrhythmic therapy. PMID- 26037289 TI - Development of a Novel Urine Alzheimer-Associated Neuronal Thread Protein ELISA Kit and Its Potential Use in the Diagnosis of Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease (AD) is an age-related chronic degenerative disease that damages the nervous system. A noninvasive and simple method for early detection of AD is extremely important for the diagnosis and prognosis of AD. Thus, we aimed to develop an enzyme-linked immunosorbent assay (ELISA) kit to detect urine Alzheimer-associated neuronal thread protein (AD7C-NTP), and to evaluate its clinical value for the diagnosis of AD. METHODS: Immunogenic AD7C NTP peptide fragments were synthesized by the solid-phase method and used for immunizing mice or rabbits to generate anti-AD7C-NTP antibodies. The urine AD7C NTP ELISA kit was then established; the generated mouse anti-AD7C-NTP antibody was used as a capture antibody, the biotin-labeled rabbit anti-AD7C-NTP antibody was used as a detection antibody, and avidin labeled by horseradish peroxidase was used as a substrate. The first morning urine specimens of 121 AD patients and 118 age-matched controls were collected, and the urine AD7C-NTP levels were detected by the above ELISA kit. RESULTS: Mouse and rabbit anti-AD7C-NTP antibody ELISA titer was found to be 1:8,000 and 1:32,000, respectively. A single band with a relative molecular mass of 41 kDa was found in human brain specimens by Western blot assay, which was identified as AD7C-NTP antibody. The urine AD7C-NTP concentration of the AD patients was higher than that of the age-matched controls, the sensitivity was 89.3% and the specificity was 84.7%. CONCLUSIONS: Our study demonstrated that our newly developed urine AD7C-NTP ELISA kit has suggested potential for diagnosing AD in a Chinese population, suggesting it may be a useful diagnostic kit for detecting early AD. PMID- 26037290 TI - Trends in income-related inequality in untreated caries among children in the United States: findings from NHANES I, NHANES III, and NHANES 1999-2004. AB - OBJECTIVE: The goal of this analysis was to describe income-related inequality in untreated caries among children in the United States over time. METHODS: The analysis focuses on children ages 2-12 years in three nationally representative U.S. surveys: the National Health and Nutrition Examination Survey (NHANES) 1971 1974, NHANES 1988-1994, and NHANES 1999-2004. The outcome of interest is untreated dental caries. Various methods are employed to measure absolute and relative inequality within each survey such as pair-wise comparisons, measures of association (odds ratios), and three summary measures of overall inequality: the slope index of inequality, the relative index of inequality, and the concentration index. Inequality trends are then assessed by comparing these estimates across the three surveys. RESULTS: Inequality was present in each of the three surveys analyzed. Whether measured on an absolute or relative scale, untreated caries disproportionately affected those with lower income. Trend analysis shows that, despite population-wide reductions in untreated caries between NHANES I and NHANES III, overall absolute inequality slightly increased, while overall relative inequality significantly increased. Between NHANES III and NHANES 1999-2004, both absolute and relative inequality tended to decrease; however, these changes were not statistically significant. CONCLUSIONS: Socioeconomic inequality in oral health is an important measure of progress in overall population health and a key input to inform health policies. This analysis shows the presence of socioeconomic inequality in oral health in the American child population, as well as changes in its magnitude over time. Further research is needed to determine the factors related to these changes and their relative contribution to inequality trends. PMID- 26037292 TI - Comparison of Ticagrelor Versus Prasugrel to Prevent Periprocedural Myonecrosis in Acute Coronary Syndromes. AB - Guidelines recommend a ticagrelor loading dose (LD) before PCI or a prasugrel LD at the time of percutaneous coronary intervention (PCI) in intermediate and high risk non-ST-elevation acute coronary syndrome (NSTE-ACS). However, achieving an optimal PR inhibition at the time of PCI is critical to prevent adverse events and depends on the timing of LD intake in relation to PCI. We aimed to compare the rate of myonecrosis related to PCI in patients with NSTE-ACS receiving ticagrelor pretreatment versus prasugrel at the time of intervention. We prospectively randomized 213 patients with NSTE-ACS to a 180 mg of ticagrelor LD given as soon as possible after admission and before PCI or to a 60 mg LD of prasugrel given at the time of PCI. The primary end point was the rate of periprocedural myonecrosis as defined by an increase of >5 times the ninety-ninth percentiles in troponin-negative patients or a 20% increase in troponin-positive patients. The 2 groups were similar regarding baseline characteristics including clinical setting (p = 0.2). Procedural characteristics were also identical including the number of treated vessels and stenting procedures. Patients in the prasugrel group more often required emergent PCI (p = 0.001). Patients in the ticagrelor group had less periprocedural myonecrosis compared with those in the prasugrel group (19.8% vs 38.3%; p = 0.03). The rate of major adverse cardiovascular events and Bleeding Academic Research Consortium >=2 at 1-month follow-up was low and similar between the 2 groups. In conclusion, a ticagrelor LD as soon as possible before PCI is superior to prasugrel at the time of PCI to prevent periprocedural myonecrosis in NSTE-ACS. PMID- 26037291 TI - Murine IL-17+ Vgamma4 T lymphocytes accumulate in the lungs and play a protective role during severe sepsis. AB - BACKGROUND: Lung inflammation is a major consequence of the systemic inflammatory response caused by severe sepsis. Increased migration of gammadelta T lymphocytes into the lungs has been previously demonstrated during experimental sepsis; however, the involvement of the gammadelta T cell subtype Vgamma4 has not been previously described. METHODS: Severe sepsis was induced by cecal ligation and puncture (CLP; 9 punctures, 21G needle) in male C57BL/6 mice. gammadelta and Vgamma4 T lymphocyte depletion was performed by 3A10 and UC3-10A6 mAb i.p. administration, respectively. Lung infiltrating T lymphocytes, IL-17 production and mortality rate were evaluated. RESULTS: Severe sepsis induced by CLP in C57BL/6 mice led to an intense lung inflammatory response, marked by the accumulation of gammadelta T lymphocytes (comprising the Vgamma4 subtype). gammadelta T lymphocytes present in the lungs of CLP mice were likely to be originated from peripheral lymphoid organs and migrated towards CCL2, CCL3 and CCL5, which were highly produced in response to CLP-induced sepsis. Increased expression of CD25 by Vgamma4 T lymphocytes was observed in spleen earlier than that by alphabeta T cells, suggesting the early activation of Vgamma4 T cells. The Vgamma4 T lymphocyte subset predominated among the IL-17(+) cell populations present in the lungs of CLP mice (unlike Vgamma1 and alphabeta T lymphocytes) and was strongly biased toward IL-17 rather than toward IFN-gamma production. Accordingly, the in vivo administration of anti-Vgamma4 mAb abrogated CLP-induced IL-17 production in mouse lungs. Furthermore, anti-Vgamma4 mAb treatment accelerated mortality rate in severe septic mice, demonstrating that Vgamma4 T lymphocyte play a beneficial role in host defense. CONCLUSIONS: Overall, our findings provide evidence that early-activated Vgamma4 T lymphocytes are the main responsible cells for IL-17 production in inflamed lungs during the course of sepsis and delay mortality of septic mice. PMID- 26037293 TI - Comparison of Coronary Computed Tomographic Angiographic Findings in Asymptomatic Subjects With Versus Without Diabetes Mellitus. AB - There are limited data on the impact of diabetes mellitus (DM) on the risk of subclinical atherosclerosis. Therefore, we sought to investigate the impact of DM on the risk of subclinical atherosclerosis in asymptomatic subjects. We analyzed 2,034 propensity score-matched asymptomatic subjects who underwent coronary computed tomographic angiography (mean age 55.9 +/- 8.2 years; men 1,725 [84.8%]). Coronary artery calcium score, degree and extent of coronary artery disease (CAD), and clinical outcomes were assessed. High-risk CAD was defined as at least 2-vessel coronary disease with proximal left anterior descending artery involvement, 3-vessel disease, or left main disease. Compared with subjects without DM, those matched with DM had higher coronary artery calcium score (89.9 +/- 240.4 vs 62.8 +/- 179.5, p = 0.004) and more significant CAD (>=50% diameter stenosis, 15.2% vs 10.2%, p = 0.001), largely in the form of 1-vessel disease (10.8% vs 7.3%, p = 0.007). However, there were no significant differences between matched pairs in significant CAD in the left main or proximal left anterior descending artery (5.3% vs 3.8%, p = 0.138), multivessel disease (4.4% vs 2.9%, p = 0.101), and high-risk CAD (4.3% vs 2.7%, p = 0.058). During the follow-up period (median 21.8, interquartile range 15.2 to 33.4 months), there was no significant difference in the composite of all-cause death, myocardial infarction, acute coronary syndrome, and coronary revascularization between 2 groups (hazard ratio 1.438, 95% confidence interval 0.844 to 2.449, p = 0.181). In asymptomatic subjects, those matched with DM have more subclinical atherosclerosis, mainly confined to non-high-risk CAD, than those matched without DM, and there are no differences in high-risk CAD and clinical outcomes. PMID- 26037295 TI - Relation of Acute Heart Failure Hospital Length of Stay to Subsequent Readmission and All-Cause Mortality. AB - Heart failure (HF) hospitalization length of stay (LOS) has been associated with the risk of subsequent readmission and mortality. We identified 19,927 hospitalized patients with HF who were discharged alive from 2008 to 2011 from 3 Kaiser Permanente regions. In adjusted Cox models using LOS 3 to 4 days as the reference category, shorter LOS was not significantly associated with hospital readmissions. LOS of 5 to 10 days was associated with 17% greater risk of readmission within 30 days (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.07 to 1.28) and 9% greater risk within 1 year (HR 1.09, 95% CI 1.03 to 1.15). LOS of 11 to 29 days was associated with increased readmission risk of 52% at 30 days (HR 1.52, 95% CI 1.30 to 1.76) and 25% at 1 year (HR 1.25, 95% CI 1.16 to 1.35). Mortality risk within 30 days among those with LOS of 1 day was 47% lower (HR 0.53, 95% CI 0.43 to 0.65) and 32% lower at 1 year (HR 0.68, 95% CI 0.62 to 0.74). LOS of 2 days was associated with lower mortality risk of 17% (HR 0.83, 95% CI 0.76 to 0.90) at 1 year. At LOS 5 to 10 days, 30-day and 1-year risk of mortality was increased by 52% (HR 1.52, 95% CI 1.30 to 1.76) and 25% (HR 1.25, 95% CI 1.16 to 1.35), respectively. LOS of 11 to 29 days was associated with 171% higher mortality risk at 30 days (HR 2.71, 95% CI 2.19 to 3.35) and 73% at 1 year (HR 1.73, 95% CI 1.53 to 1.97). Longer LOS during the index HF hospitalization was associated with readmission and mortality within 30 days and 1 year independent of co-morbidities and cardiovascular risk factors. These results suggest that LOS may be a proxy for the severity of HF during the index hospitalization. PMID- 26037294 TI - Prevalence and Impact of Co-morbidity Burden as Defined by the Charlson Co morbidity Index on 30-Day and 1- and 5-Year Outcomes After Coronary Stent Implantation (from the Nobori-2 Study). AB - Co-morbidities have typically been considered as prevalent cardiovascular risk factors and cardiovascular diseases rather than systematic measures of general co morbidity burden in patients who underwent percutaneous coronary intervention (PCI). Charlson co-morbidity index (CCI) is a measure of co-morbidity burden providing a means of quantifying the prognostic impact of 22 co-morbid conditions on the basis of their number and prognostic impact. The study evaluated the impact of the CCI on cardiac mortality and major adverse cardiovascular events (MACE) after PCI through analysis of the Nobori-2 study. The prognostic impact of CCI was studied in 3,067 patients who underwent PCI in 4,479 lesions across 125 centers worldwide on 30-day and 1- and 5-year cardiac mortality and MACE. Data were adjusted for potential confounders using stepwise logistic regression; 2,280 of 3,067 patients (74.4%) had >=1 co-morbid conditions. CCI (per unit increase) was independently associated with an increase in both cardiac death (odds ratio [OR] 1.47 95% confidence interval [CI] 1.20 to 1.80, p = 0.0002) and MACE (OR 1.29 95% CI 1.14 to 1.47, p <=0.0011) at 30 days, with similar observations recorded at 1 and 5 years. CCI score >=2 was independently associated with increased 30-day cardiac death (OR 4.25, 95% CI 1.24 to 14.56, p = 0.02) at 1 month, and this increased risk was also observed at 1 and 5 years. In conclusion, co-morbid burden, as measured using CCI, is an independent predictor of adverse outcomes in the short, medium, and long term. Co-morbidity should be considered in the decision-making process when counseling patients regarding the periprocedural risks associated with PCI, in conjunction with traditional risk factors. PMID- 26037296 TI - Stereo- and Regioselective Formation of Silyl-Dienyl Boronates. AB - The intramolecular trans-silylruthenation of internal alkynes and subsequent insertion of vinyl boronates is described. This approach provides complete regiocontrol through a stereoselective trans-5-exo-dig cyclization which affords a tetrasubstituted olefin as a vinylsilane and a highly functionalized Z,E diene motif. PMID- 26037297 TI - Social Transitions Cause Rapid Behavioral and Neuroendocrine Changes. AB - In species that form dominance hierarchies, there are often opportunities for low ranking individuals to challenge high-ranking ones, resulting in a rise or fall in social rank. How does an animal rapidly detect, process, and then respond to these social transitions? This article explores and summarizes how these social transitions can rapidly (within 24 h) impact an individual's behavior, physiology, and brain, using the African cichlid fish, Astatotilapia burtoni, as a model. Male A. burtoni form hierarchies in which a few brightly-colored dominant males defend territories and spawn with females, while the remaining males are subordinate, more drab-colored, do not hold a territory, and have minimal opportunities for reproduction. These social phenotypes are plastic and reversible, meaning that individual males may switch between dominant and subordinate status multiple times within a lifetime. When the social environment is manipulated to create males that either ascend (subordinate to dominant) or descend (dominant to subordinate) in rank, there are rapid changes in behavior, circulating hormones, and levels of gene expression in the brain that reflect the direction of transition. For example, within minutes, males ascending in status show bright coloration, a distinct eye-bar, increased dominance behaviors, activation of brain nuclei in the social behavior network, and higher levels of sex steroids in the plasma. Ascending males also show rapid changes in levels of neuropeptide and steroid receptors in the brain, as well as in the pituitary and testes. To further examine hormone-behavior relationships in this species during rapid social ascent, the present study also measured levels of testosterone, 11 ketotestosterone, estradiol, progestins, and cortisol in the plasma during the first week of social ascent and tested for correlations with behavior. Plasma levels of all steroids were rapidly increased at 30 min after social ascent, but were not correlated with behavior during the initial rise in rank, suggesting that behavior is dissociated from endocrine status. These changes during social ascent are then compared with our current knowledge about males descending in rank, who rapidly show faded coloration, decreased dominance behaviors, increased subordinate behaviors, and higher circulating levels of cortisol. Collectively, this work highlights how the perception of similar social cues that are opposite in value are rapidly translated into adaptive behavioral and neuroendocrine changes that promote survival and reproductive fitness. Finally, future directions are proposed to better understand the mechanisms that govern these rapid changes in social position. PMID- 26037298 TI - Abundance and Localization of Progesterone Receptor Isoforms in Endometrium in Women With and Without Endometriosis and in Peritoneal and Ovarian Endometriotic Implants. AB - BACKGROUND: Several studies suggest that resistance to progesterone may contribute to the pathophysiology of endometriosis. Progesterone mediates its biological activity via the 2 progesterone receptor (PR) isoforms (PR-A and PR B). Effects of progesterone are determined by the PR-A:PR-B ratio such that a PR B-dominant state promotes progesterone signaling, whereas a PR-A-dominant state decreases progesterone responsiveness. Our objective was to compare the abundance and cellular localization of the PR isoforms in endometrium and endometriotic lesions from women with and without peritoneal and ovarian endometriosis. METHODS: This in vitro study was conducted in a tertiary care facility. Reproductive-age women with surgically diagnosed endometriosis (n = 18) and asymptomatic control individuals (n = 20) were prospectively recruited at the late proliferative and the early secretory phases. At laparoscopy, samples of eutopic endometrium, peritoneal and ovarian endometriosis, and disease-free peritoneum were obtained for subsequent immunohistochemical and immunoblot analysis of PR-B and total PR localization and PR-A and PR-B abundance, respectively. RESULTS: The PR-A and PR-B were detected in eutopic endometrium and in peritoneal and ovarian endometriosis but not in disease-free peritoneum from patients with and without endometriosis. In peritoneal endometriosis, PR-A was the predominant isoform detected, whereas both receptors were detected in ovarian endometriosis and eutopic endometrium. In eutopic endometrium, levels of PR-A were significantly elevated in women with endometriosis compared with women without disease, regardless of menstrual phase. The PR-A levels were significantly elevated in ovarian endometriosis compared with peritoneal endometriosis. CONCLUSIONS: Endometriotic lesions and eutopic endometrium from women with endometriosis are uniform in a PR-A-dominant state. The data suggest that menstrual efflux of a PR-A-dominant endometrial tissue into the peritoneal cavity may play a role in the pathophysiology of endometriosis. PMID- 26037299 TI - Resveratrol Protects Against Pathological Preterm Birth by Suppression of Macrophage-Mediated Inflammation. AB - Inflammatory cytokines play a major role in spontaneous preterm birth. Resveratrol has strong anti-inflammatory effects, but its effect on preterm birth in vivo is unknown. We investigated whether resveratrol protects against preterm birth in the lipopolysaccharide (LPS)-induced preterm mouse model. Twelve-day-old pregnant mice were fed 20 to 40 mg/kg resveratrol daily. On day 15, 10 MUg of LPS was injected into uterine cervices. Resveratrol administration significantly decreased the rate of preterm birth. Resveratrol administration abolished LPS induced elevation of tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 1beta but not IL-6 levels. The TNF-alpha messenger RNA levels were decreased in the cervices of resveratrol-administered mice compared with controls. Resveratrol treatment suppressed the elevation in TNF-alpha and IL-1beta levels in LPS exposed peritoneal macrophages. Further resveratrol treatment eradicated the proinflammatory cytokine-mediated elevation in cyclooxygenase 2 (COX-2) in peritoneal macrophages. Resveratrol may protect against pathological preterm birth by suppression of elevated proinflammatory cytokines and consequent elevation of COX-2 in macrophages. PMID- 26037300 TI - Progesterone Metabolites Produced by Cytochrome P450 3A Modulate Uterine Contractility in a Murine Model. AB - OBJECTIVE: We seek to characterize the effect of progesterone metabolites on spontaneous and oxytocin-induced uterine contractility. STUDY DESIGN: Spontaneous contractility was studied in mouse uterine horns after treatment with progesterone, 2alpha-hydroxyprogesterone, 6beta-hydroxyprogesterone (6beta-OHP), 16alpha-hydroxyprogesterone (16alpha-OHP), or 17-hydroxyprogesterone caproate (17 OHPC) at 10(-9) to 10(-6) mol/L. Uterine horns were exposed to progestins (10(-6) mol/L), followed by increasing concentrations of oxytocin (1-100 nmol/L) to study oxytocin-induced contractility. Contraction parameters were compared for each progestin and matched vehicle control using repeated measures 2-way analysis of variance. In vitro metabolism of progesterone by recombinant cytochrome P450 3A (CYP3A) microsomes (3A5, 3A5, and 3A7) identified major metabolites. RESULTS: Oxytocin-induced contractile frequency was decreased by 16alpha-OHP (P = .03) and increased by 6beta-OHP (P = .05). Progesterone and 17-OHPC decreased oxytocin induced contractile force (P = .02 and P = .04, respectively) and frequency (P = .02 and P = .03, respectively). Only progesterone decreased spontaneous contractile force (P = .02). Production of 16alpha-OHP and 6beta-OHP metabolites were confirmed in all CYP3A isoforms tested. CONCLUSION: Progesterone metabolites produced by maternal or fetal CYP3A enzymes influence uterine contractility. PMID- 26037301 TI - The Stage- and Cell Type-Specific Localization of Fragile X Mental Retardation Protein in Rat Ovaries. AB - Premutations of the fragile X mental retardation 1 (FMR1) gene are associated with increased risk of primary ovarian insufficiency. Here we examined the localization of the Fmr1 gene protein product, fragile X mental retardation protein (FMRP), in rat ovaries at different stages, including fetus, neonate, and old age. In ovaries dissected from 19 days postcoitum embryos, the germ cells were divided into 2 types: one with decondensed chromatin in the nucleus was FMRP positive in the cytoplasm, but the other with strongly condensed chromatin in the nucleus was FMRP negative in the cytoplasm. The FMRP was predominantly localized to the cytoplasm of oocytes in growing ovarian follicles. Levels of FMRP in oocytes from elderly (9 or 14 months of age) ovaries were lower than in those from younger ovaries. These results suggest that FMRP is associated with the activation of oogenesis and oocyte function. Especially, FMRP is likely to be implicated in germline development during oogenesis. PMID- 26037303 TI - Disentangling the relation between left temporoparietal white matter and reading: A spherical deconvolution tractography study. AB - Diffusion tensor imaging (DTI) studies have shown that left temporoparietal white matter is related to phonological aspects of reading. However, DTI lacks the sensitivity to disentangle whether phonological processing is sustained by intrahemispheric connections, interhemispheric connections, or projection tracts. Spherical deconvolution (SD) is a nontensor model which enables a more accurate estimation of multiple fiber directions in crossing fiber regions. Hence, this study is the first to investigate whether the observed relation with reading aspects in left temporoparietal white matter is sustained by a particular pathway by applying a nontensor model. Second, measures of degree of diffusion anisotropy, which indirectly informs about white matter organization, were compared between DTI and SD tractography. In this study, 71 children (5-6 years old) participated. Intrahemispheric, interhemispheric, and projection pathways were delineated using DTI and SD tractography. Anisotropy indices were extracted, that is, fractional anisotropy (FA) in DTI and quantitative hindrance modulated orientational anisotropy (HMOA) in SD. DTI results show that diffusion anisotropy in both the intrahemispheric and projection tracts was positively correlated to phonological awareness; however, the effect was confounded by subjects' motion. In SD, the relation was restricted to the left intrahemispheric connections. A model comparison suggested that FA was, relatively to HMOA, more confounded by fiber crossings; however, anisotropy indices were highly related. In sum, this study shows the potential of SD to quantify white matter microstructure in regions containing crossing fibers. More specifically, SD analyses show that phonological awareness is sustained by left intrahemispheric connections and not interhemispheric or projection tracts. PMID- 26037302 TI - Convergence of eicosanoid and integrin biology: 12-lipoxygenase seeks a partner. AB - BACKGROUND: Integrins and enzymes of the eicosanoid pathway are both well established contributors to cancer. However, this is the first report of the interdependence of the two signaling systems. In a screen for proteins that interacted with, and thereby potentially regulated, the human platelet-type 12 lipoxygenase (12-LOX, ALOX12), we identified the integrin beta4 (ITGB4). METHODS: Using a cultured mammalian cell model, we have demonstrated that ITGB4 stimulation leads to recruitment of 12-LOX from the cytosol to the membrane where it physically interacts with the integrin to become enzymatically active to produce 12(S)-HETE, a known bioactive lipid metabolite that regulates numerous cancer phenotypes. RESULTS: The net effect of the interaction was the prevention of cell death in response to starvation. Additionally, regulation of beta4 mediated, EGF-stimulated invasion was shown to be dependent on 12-LOX, and downstream Erk signaling in response to ITGB4 activation also required 12-LOX. CONCLUSIONS: This is the first report of an enzyme of the eicosanoid pathway being recruited to and regulated by activated beta4 integrin. Integrin beta4 has recently been shown to induce expansion of prostate tumor progenitors and there is a strong correlation between stage/grade of prostate cancer and 12-LOX expression. The 12-LOX enzymatic product, 12(S)-HETE, regulates angiogenesis and cell migration in many cancer types. Therefore, disruption of integrin beta4 12LOX interaction could reduce the pro-inflammatory oncogenic activity of 12-LOX. This report on the consequences of 12-LOX and ITGB4 interaction sets a precedent for the linkage of integrin and eicosanoid biology through direct protein-protein association. PMID- 26037304 TI - Meckel Gruber syndrome, A case report. AB - INTRODUCTION: Meckel-Gruber Syndrome was first described by J R Meckel in 1822. It is an autosomal recessive disorder, and is caused by the failure of mesodermal induction. The typical triad of Meckel-Gruber Syndrome (MGS) involves meningo encephalocele, polycystic kidneys and postaxial polydactyly. The worldwide incidence varies from 1 in 1.300 to 1 in 140.000 live births. CASE: In this report, we present a case of MGS in which the diagnosis was made at 19 weeks of gestation based on ultrasonographic findings of the typical triad of the disease (encephalocele, polycystic kidneys, and polydactyly) These features were suggestive of the diagnosis of Meckel Gruber Syndrome (MGS). She had also placenta previa totalis. The patient was counselled regarding the lethal outcome of MGS. Unfortunately, the family did not approve the termination of pregnancy. At the 32nd week, she referred to hospital with complaints of vaginal bleeding and uterine contractions. An emergency cesarean section was perfomed due to plasental malposition. A 1380 gr, female fetus was delivered. First and 5th minute Apgar scores were 1 and 0, respectively. Consequently, the baby died after 45 minutes of neonatal resuscitation. CONCLUSION: MGS is a lethal disorder. One cannot speak about survival of the fetus because of the pulmonary hypoplasia. The parents should be counseled about prognosis of the fetus and the outcome. Counselers should strictly give information about the recurrence risk for the next pregnancies. PMID- 26037305 TI - BMA calls for action over rise in consultant vacancies in Scotland. PMID- 26037306 TI - Internal Hernia After Laparoscopic Antecolic Roux-en-Y Gastric Bypass. AB - BACKGROUND: We evaluated the incidence and presentations of internal hernias (IH) after laparoscopic antecolic Roux-en-Y gastric bypass (RYGB) at our institution. METHODS: We retrospectively reviewed the records of 594 patients who underwent laparoscopic antecolic RYGB at our institution between December 2004 and December 2010. RESULTS: Five hundred ninety-four patients underwent laparoscopic antecolic RYGB with a mean follow-up of 50.5 months. Thirty-six patients developed 37 IH (6.2 %) requiring surgical intervention. Mean age of IH patients was 36.9 years. Thirty-one out of 36 were female. Mean preoperative BMI was 44.3 Kg/m(2). The mean time of presentation after their RYGB was 25.9 months. The mean % excess body weight loss at time of presentation was 54.0 %. Twenty-five out of 37 of IH occurred at Petersen's space; 9/37 IH occurred under the jejunojejunostomy; three patients had hernias at both locations. Mesenteric swirling was the most common CT scan finding in 20/36 (55.6 %). Six out of 36 CT were initially read as normal; however, on retrospective review by a radiologist, abnormalities indicating IH were found in 4/6. Patients presented with different degrees of acuity: 6/37 with chronic abdominal pain and 28/37 with acute abdominal pain. Bowel necrosis was found in 3/37. CONCLUSION: IH is a serious and potentially fatal complication of RYGB. Presentation can vary from chronic abdominal pain to bowel necrosis. CT is helpful in providing diagnosis; however, careful attention to the specific signs of small bowel volvulus, such as mesenteric swirl sign, should be given. IH should be considered in RYGB patients who present with even vague symptoms. PMID- 26037307 TI - RNA secondary structure prediction based on SHAPE data in helix regions. AB - RNA molecules play important and fundamental roles in biological processes. Frequently, the functional form of single-stranded RNA molecules requires a specific tertiary structure. Classically, RNA structure determination has mostly been accomplished by X-Ray crystallography or Nuclear Magnetic Resonance approaches. These experimental methods are time consuming and expensive. In the past two decades, some computational methods and algorithms have been developed for RNA secondary structure prediction. In these algorithms, minimum free energy is known as the best criterion. However, the results of algorithms show that minimum free energy is not a sufficient criterion to predict RNA secondary structure. These algorithms need some additional knowledge about the structure, which has to be added in the methods. Recently, the information obtained from some experimental data, called SHAPE, can greatly improve the consistency between the native and predicted RNA secondary structure. In this paper, we investigate the influence of SHAPE data on four types of RNA substructures, helices, loops, base pairs from the start and end of helices and two base pairs from the start and end of helices. The results show that SHAPE data in helix regions can improve the prediction. We represent a new method to apply SHAPE data in helix regions for finding RNA secondary structure. Finally, we compare the results of the method on a set of RNAs to predict minimum free energy structure based on considering all SHAPE data and only SHAPE data in helix regions as pseudo free energy and without SHAPE data (without any pseudo free energy). The results show that RNA secondary structure prediction based on considering only SHAPE data in helix regions is more successful than not considering SHAPE data and it provides competitive results in comparison with considering all SHAPE data. PMID- 26037308 TI - Sufficient conditions of endemic threshold on metapopulation networks. AB - In this paper, we focus on susceptible-infected-susceptible dynamics on metapopulation networks, where nodes represent subpopulations, and where agents diffuse and interact. Recent studies suggest that heterogeneous network structure between elements plays an important role in determining the threshold of infection rate at the onset of epidemics, a fundamental quantity governing the epidemic dynamics. We consider the general case in which the infection rate at each node depends on its population size, as shown in recent empirical observations. We first prove that a sufficient condition for the endemic threshold (i.e., its upper bound), previously derived based on a mean-field approximation of network structure, also holds true for arbitrary networks. We also derive an improved condition showing that networks with the rich-club property (i.e., high connectivity between nodes with a large number of links) are more prone to disease spreading. The dependency of infection rate on population size introduces a considerable difference between this upper bound and estimates based on mean-field approximations, even when degree-degree correlations are considered. We verify the theoretical results with numerical simulations. PMID- 26037309 TI - Adsorption of Polyvinylpyrrolidone and its Impact on Maintenance of Aqueous Supersaturation of Indomethacin via Crystal Growth Inhibition. AB - This study explored the adsorption and crystal growth inhibitory effects of polyvinylpyrrolidone (PVP) on indomethacin crystals in an aqueous medium. A solution depletion method was used to construct adsorption isotherms of PVPs with different molecular weights and N-vinylpyrrolidone onto indomethacin crystals. The affinity for and extent of maximum adsorption of PVP on indomethacin crystals were significantly higher than that of N-vinylpyrrolidone, which was attributed to cooperative interactions between PVP and the surface of indomethacin. The extent of PVP adsorption onto indomethacin crystals in terms of mg/m(2) was greater for higher molecular weight PVP but less on a molar basis indicating an increased percentage of loops and tails for the higher molecular weight PVP. PVP significantly inhibited the crystal growth of indomethacin at a high degree of supersaturation as compared with N-vinylpyrrolidone, which was attributed to a change in indomethacin crystal growth mechanism leading to a change in the rate limiting step from bulk diffusion to surface integration. Higher molecular weight PVPs are better inhibitors of the crystal growth of indomethacin than lower molecular weight PVPs, which was attributed in part to a greater barrier for surface diffusion of indomethacin provided by a thicker adsorption layer of PVP. PMID- 26037310 TI - Fbxl11 Is a Novel Negative Element of the Mammalian Circadian Clock. AB - In mammals, molecular circadian rhythms are generated by autoregulatory transcriptional-translational feedback loops with PERIOD/CRYPTOCHROME containing complexes inhibiting the transcription of their own genes. Although the major circadian oscillator components seem to be identified, an increasing number of additional factors modulating core clock component functions are being discovered. In a systematic screen using short hairpin RNA in human clock reporter cells, we identified FBXL11 (also known as KDM2A), a histone demethylase, whose gene dosage is crucial for a correct circadian period. Knockdown of FBXL11 leads to period shortening and overexpression to period lengthening. In addition, altering FBXL11 gene dosage modulates clock gene transcript levels, most prominently that of Nr1d1. FBXL11 exercises its role in the mammalian circadian clock by acting as a negative element on CLOCK/BMAL1 and RORalpha-induced transcription. It binds directly to the promoter regions of CLOCK/BMAL1-regulated genes via a CXXC-type zinc finger motif in a circadian phase-dependent manner; however, the histone-demethylase activity of FBXL11 is not required for transcriptional repression. Therefore, we propose FBXL11 as a novel component of the circadian clock that regulates the circadian gene expression by a so far unknown mechanism. PMID- 26037311 TI - Gene profile of soluble growth factors involved in angiogenesis, in an adipose derived stromal cell/endothelial cell co-culture, 3D gel model. AB - OBJECTIVES: The aim of this study was to investigate gene expressions of growth factors for angiogenesis, in a three-dimensional (3D) gel populated with adipose derived stromal cells (ASCs) and endothelial cells (ECs) in co-culture. MATERIALS AND METHODS: The 3D gel, mixed with green fluorescent protein (GFP)-positive ASCs and DsRed-Express-positive ECs, 1:1 ratio, was established in vitro. The phenomenon of angiogenesis was observed using confocal microscopy. To detect gene expressions for growth factor proteins in both ASCs and ECs, transwell co-culture was used, and cell lysate samples were collected at 1, 3, 5 and 7 days. Semi quantitative polymerase chain reaction (PCR) was conducted to quantify mRNA expressions of the growth factors. RESULTS: Angiogenesis was first observed in the gels by 7 days post-implantation. Over this time in ECs, genes coding for VEGFA/B, IGF-1, HIF-1alpha, FGF-1/-2 and BMP-5/-7 significantly increased. Meanwhile in ASCs, genes coding for VEGFA/B, IGF-1, HIF-1alpha, FGF-1/-2 and BMP 6 also were significantly enhanced. In particular, increased amounts of IGF-1 and HIF-1alpha in both ECs and ASCs were prominent relative to other factors. CONCLUSIONS: Contact co-culture with ASCs and ECs at 1:1 ratio, in the 3D gel promoted angiogenesis; non-contact co-culture further confirmed gene expressions for growth factors, VEGFA/B, IGF-1, HIF-1alpha and FGF-1/-2 in both ASCs and ECs; BMP-5/-7 in ECs and BMP-6 in ASCs were also confirmed. This establishment of growth factor expression seemed to be responsible for enhancement of angiogenesis. This indicates that these factors could be utilized as targets for engineered angiogenesis. PMID- 26037313 TI - Towards a full ab initio theory of strong electronic correlations in nanoscale devices. AB - In this paper I give a detailed account of an ab initio methodology for describing strong electronic correlations in nanoscale devices hosting transition metal atoms with open d- or f-shells. The method combines Kohn-Sham density functional theory for treating the weakly interacting electrons on a static mean field level with non-perturbative many-body methods for the strongly interacting electrons in the open d- and f-shells. An effective description of the strongly interacting electrons in terms of a multi-orbital Anderson impurity model is obtained by projection onto the strongly correlated subspace properly taking into account the non-orthogonality of the atomic basis set. A special focus lies on the ab initio calculation of the effective screened interaction matrix U for the Anderson model. Solution of the effective Anderson model with the one-crossing approximation or other impurity solver techniques yields the dynamic correlations within the strongly correlated subspace giving rise e.g. to the Kondo effect. As an example the method is applied to the case of a Co adatom on the Cu(0 0 1) surface. The calculated low-bias tunnel spectra show Fano-Kondo lineshapes similar to those measured in experiments. The exact shape of the Fano-Kondo feature as well as its width depend quite strongly on the filling of the Co 3d shell. Although this somewhat hampers accurate quantitative predictions regarding lineshapes and Kondo temperatures, the overall physical situation can be predicted quite reliably. PMID- 26037312 TI - Residual force depression in single sarcomeres is abolished by MgADP-induced activation. AB - The mechanisms behind the shortening-induced force depression commonly observed in skeletal muscles remain unclear, but have been associated with sarcomere length non-uniformity and/or crossbridge inhibition. The purpose of this study was twofold: (i) to evaluate if force depression is present in isolated single sarcomeres, a preparation that eliminates sarcomere length non-uniformities and (ii) to evaluate if force depression is inhibited when single sarcomeres are activated with MgADP, which biases crossbridges into a strongly-bound state. Single sarcomeres (n = 16) were isolated from rabbit psoas myofibrils using two micro-needles (one compliant, one rigid), piercing the sarcomere externally adjacent to the Z-lines. The sarcomeres were contracted isometrically and subsequently shortened, in both Ca(2+)- and MgADP-activating solutions. Shortening in Ca(2+)-activated samples resulted in a 27.44 +/- 9.04% force depression when compared to isometric contractions produced at similar final sarcomere lengths (P < 0.001). There was no force depression in MgADP-activated sarcomeres (force depression = -1.79 +/- 9.69%, P = 0.435). These results suggest that force depression is a sarcomeric property, and that is associated with an inhibition of myosin-actin interactions. PMID- 26037314 TI - A time-tested procedure. PMID- 26037315 TI - Potential and limitations of on-line comprehensive reversed phase liquid chromatography*supercritical fluid chromatography for the separation of neutral compounds: An approach to separate an aqueous extract of bio-oil. AB - On-line comprehensive Reversed Phase Liquid Chromatography*Supercritical Fluid Chromatography (RPLCxSFC) was investigated for the separation of complex samples of neutral compounds. The presented approach aimed at overcoming the constraints involved by such a coupling. The search for suitable conditions (stationary phases, injection solvent, injection volume, design of interface) are discussed with a view of ensuring a good transfer of the compounds between both dimensions, thereby allowing high effective peak capacity in the second dimension. Instrumental aspects that are of prime importance in on-line 2D separations, were also tackled (dwell volume, extra column volume and detection). After extensive preliminary studies, an on-line RPLCxSFC separation of a bio-oil aqueous extract was carried out and compared to an on-line RPLCxRPLC separation of the same sample in terms of orthogonality, peak capacity and sensitivity. Both separations were achieved in 100min. For this sample and in these optimized conditions, it is shown that RPLCxSFC (with Hypercarb and Acquity BEH-2EP as stationary phases in first and second dimension respectively) can generate a slightly higher peak capacity than RPLCxRPLC (with Hypercarb and Acquity CSH phenyl-hexyl as stationary phases in first and second dimension respectively) (620 vs 560). Such a result is essentially due to the high degree of orthogonality between RPLC and SFC which may balance for lesser peak efficiency obtained with SFC as second dimension. Finally, even though current limitations in SFC instrumentation (i.e. large extra-column volume, large dwell volume, no ultra-high pressure) can be critical at the moment for on-line 2D-separations, RPLCxSFC appears to be a promising alternative to RPLCxRPLC for the separation of complex samples of neutral compounds. PMID- 26037316 TI - Effects of a malfunctional column on conventional and FeedCol-simulated moving bed chromatography performance. AB - The effects of a malfunctional column on the performance of a simulated moving bed (SMB) process were studied experimentally and theoretically. The experimental results of conventional four-zone SMB (2-2-2-2 configuration) and FeedCol operation (2-2-2-2 configuration with one feed column) with one malfunctional column were compared with simulation results of the corresponding SMB processes with a normal column configuration. The malfunctional column in SMB processes significantly deteriorated raffinate purity. However, the extract purity was equivalent or slightly improved compared with the corresponding normal SMB operation because the complete separation zone of the malfunctional column moved to a lower flow rate range in zones II and III. With the malfunctional column configuration, FeedCol operation gave better experimental performance (up to 7%) than conventional SMB operation because controlling product purity with FeedCol operation was more flexible through the use of two additional operating variables, injection time and injection length. Thus, compared with conventional SMB separation, extract with equivalent or slightly better purity could be produced from FeedCol operation even with a malfunctional column, while minimizing the decrease in raffinate purity (less than 2%). PMID- 26037317 TI - Least absolute shrinkage and selection operator and dimensionality reduction techniques in quantitative structure retention relationship modeling of retention in hydrophilic interaction liquid chromatography. AB - The objective of this study was to model the retention of nucleosides and pterins in hydrophilic interaction liquid chromatography (HILIC) via QSRR-based approach. Two home-made (Amino-P-C18, Amino-P-C10) and one commercial (IAM.PC.DD2) HILIC stationary phases were considered. Logarithm of retention factor at 5% of acetonitrile (logkACN) along with descriptors obtained for 16 nucleosides and 11 pterins were used to develop QSRR models. We used and compared the predictive performance of three regression techniques: partial least square (PLS), the least absolute shrinkage and selection operator (LASSO), and the LASSO followed by stepwise multiple linear regression. The highest predictive squared correlation coefficient (QLOOCV(2)) in PLS analysis was found for Amino-P-C10 (QLOOCV(2)=0.687) and IAM.PC.DD2 (QLOOCV(2)=0.506) and the lowest for IAM.PC.DD2 (QLOOCV(2)=-0.01). Much higher values were obtained for the LASSO model. The QLOOCV(2) equaled 0.9 for Amino-P-C10, 0.66 for IAM.PC.DD2 and 0.59 for Amino-P C18. The combination of LASSO with stepwise regression provided models with comparable predictive performance as the LASSO, however with possibility of calculating the standard error of estimates. The use of LASSO itself and in combination with classical stepwise regression may offer greater stability of the developed models thanks to more smooth change of coefficients and reduced susceptibility towards chance correlation. Application of QSRR-based approach, along with the computational methods proposed in this work, may offer a useful approach in the modeling of retention of nucleoside and pterin compounds in HILIC. PMID- 26037318 TI - Argentation high performance liquid chromatography on-line coupled to gas chromatography for the analysis of monounsaturated polyolefin oligomers in packaging materials and foods. AB - Multidimensional chromatography based on two-dimensional high performance liquid chromatography on-line coupled to gas chromatography (on-line HPLC-HPLC-GC) enables the separate analysis of saturated, monounsaturated and aromatic hydrocarbons in packaging materials like polyolefins or paperboard and their migrates into foods. Since normal-phase HPLC on silica gel did not preseparate saturated from monounsaturated hydrocarbons, a separation step on a normal-phase HPLC column treated in the laboratory with an optimized amount of silver nitrate was added. The preparation of this HPLC column and the instrumental set-up are described, followed by examples showing the potential of the method. In a preliminary investigation of 11 polyolefin granulates for food contact up to 40% monounsaturated hydrocarbons among the oligomers C16-35 were determined. PMID- 26037319 TI - N-Substituted pyrazole-3-carboxamides as inhibitors of human 15-lipoxygenase. AB - High-throughput screening was used to find selective inhibitors of human 15 lipoxygenase-1 (15-LOX-1). One hit, a 1-benzoyl substituted pyrazole-3 carboxanilide (1a), was used as a starting point in a program to develop potent and selective 15-LOX-1 inhibitors. PMID- 26037320 TI - Syntheses and evaluation of substituted aromatic hydroxamates and hydroxamic acids that target Mycobacterium tuberculosis. AB - Tuberculosis (TB) continues to remain one of the most threatening diseases in the world. With the emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) strains, the need to develop new therapies is dire. The syntheses of a focused library of hydroxamates and hydroxamic acids is described, as well as anti-TB activity in the microplate alamar blue assay (MABA). A number of compounds exhibited good activity against Mtb, with notable compounds exhibiting MIC values in the range of 20-0.71 MUM. This work suggests that both hydroxamates and their free acids may be incorporated into more complex scaffolds and serve as potential leads for the development of anti-TB agents. PMID- 26037321 TI - Synthesis and biological evaluation of quinones derived from natural product komaroviquinone as anti-Trypanosoma cruzi agents. AB - Current chemotherapy drugs for Chagas' disease are insufficient due to their limited efficacy; however, anti-trypanosomal agents have recently shown promise. As such, synthetic intermediates of komaroviquinone were evaluated for anti trypanosomal activity. Based on the results, a series of novel quinone derivatives were screened for anti-trypanosomal activity and mammalian cytotoxicity. Several quinone derivatives displayed higher antiprotozoal activity against Trypanosoma cruzi trypomastigotes than the reference drug benznidazole, without concomitant toxicity toward the host cell. PMID- 26037322 TI - 3-Substituted pyrazoles and 4-substituted triazoles as inhibitors of human 15 lipoxygenase-1. AB - Investigation of 1N-substituted pyrazole-3-carboxanilides as 15-lipoxygenase-1 (15-LOX-1) inhibitors demonstrated that the 1N-substituent was not essential for activity or selectivity. Additional halogen substituents on the pyrazole ring, however, increased activity. Further development led to triazole-4-carboxanilides and 2-(3-pyrazolyl) benzoxazoles, which are potent and selective 15-LOX-1 inhibitors. PMID- 26037323 TI - Accuracy assessment of 3D bone reconstructions using CT: an intro comparison. AB - Computed tomography provides high contrast imaging of the joint anatomy and is used routinely to reconstruct 3D models of the osseous and cartilage geometry (CT arthrography) for use in the design of orthopedic implants, for computer assisted surgeries and computational dynamic and structural analysis. The objective of this study was to assess the accuracy of bone and cartilage surface model reconstructions by comparing reconstructed geometries with bone digitizations obtained using an optical tracking system. Bone surface digitizations obtained in this study determined the ground truth measure for the underlying geometry. We evaluated the use of a commercially available reconstruction technique using clinical CT scanning protocols using the elbow joint as an example of a surface with complex geometry. To assess the accuracies of the reconstructed models (8 fresh frozen cadaveric specimens) against the ground truth bony digitization-as defined by this study-proximity mapping was used to calculate residual error. The overall mean error was less than 0.4 mm in the cortical region and 0.3 mm in the subchondral region of the bone. Similarly creating 3D cartilage surface models from CT scans using air contrast had a mean error of less than 0.3 mm. Results from this study indicate that clinical CT scanning protocols and commonly used and commercially available reconstruction algorithms can create models which accurately represent the true geometry. PMID- 26037327 TI - Reconstruction of the Alveolar Buccal Bone Plate in Compromised Fresh Socket after Immediate Implant Placement Followed by Immediate Provisionalization. AB - OBJECTIVE: The aim of this clinical report was to reestablish the buccal bone wall after immediate implant placement. The socket defect was corrected with autogenous bone, and a connective tissue graft was removed from the maxillary tuberosity to increase the thickness, height, and width of the buccal bone and gingival tissue followed by immediate provisionalization of the crown during the same operation. CLINICAL CONSIDERATIONS: A 66-year-old patient presented with a hopeless maxillary left central incisor with loss of the buccal bone wall. Atraumatic, flapless extraction was performed, and an immediate implant was placed in the extraction socket followed by preparation of an immediate provisional restoration. Subsequently, immediate reconstruction of the buccal bone plate was performed, using the tuberosity as the donor site, to obtain block bone and connective tissue grafts, as well as particulate bone. Finally, immediate provisionalization of the crown followed by simple sutures was performed. Cone-beam computed tomography and periapical radiographs were taken before and after surgery. After 4 months, the final prosthetic crown was made. After a 2-year follow-up, a satisfactory aesthetic result was achieved with lower treatment time and morbidity. CONCLUSION: This case demonstrates the effective use of immediate reconstruction of the buccal bone wall for the treatment of a hopeless tooth in the maxillary aesthetic area. This procedure efficiently promoted harmonious gingival and bone architecture, recovered lost anatomical structures with sufficient width and thickness, and maintained the stability of the alveolar bone crest in a single procedure. CLINICAL SIGNIFICANCE: If appropriate clinical conditions exist, immediate dentoalveolar restoration may be the most conservative means of reconstructing the buccal bone wall after immediate implant placement followed by immediate provisionalization with predictable healing and lower treatment time. PMID- 26037324 TI - Effect of person-centred care on antipsychotic drug use in nursing homes (EPCentCare): study protocol for a cluster-randomised controlled trial. AB - BACKGROUND: The majority of nursing home residents with dementia experience behavioural and psychological symptoms like apathy, agitation, and anxiety. According to analyses of prescription prevalence in Germany, antipsychotic drugs are regularly prescribed as first-line treatment of neuropsychiatric symptoms in persons with dementia, although guidelines clearly prioritise non-pharmacological interventions. Frequently, antipsychotic drugs are prescribed for inappropriate reasons and for too long without regular reviewing. The use of antipsychotics is associated with adverse events like increased risk of falling, stroke, and mortality. The aim of the study is to investigate whether a person-centred care approach, successfully evaluated in nursing homes in the United Kingdom, can be implemented in German nursing homes and, in comparison with a control group, can result in a clinically relevant reduction of the proportion of residents with antipsychotic prescriptions. METHODS/DESIGN: The study is a cluster-randomised controlled trial comparing an intervention group (two-day initial training on person-centred care and ongoing training and support programme) with a control group. Both study groups will receive, as optimised usual care, a medication review by an experienced psychiatrist/geriatrician providing feedback to the prescribing physician. Overall, 36 nursing homes in East, North, and West Germany will be randomised. The primary outcome is the proportion of residents receiving at least one antipsychotic prescription (long-term medication) after 12 months of follow-up. Secondary outcomes are residents' quality of life, agitated behaviour, as well as safety parameters like falls and fall-related medical attention. A health economic evaluation and a process evaluation will be performed alongside the study. DISCUSSION: To improve care, a reduction of the current high prescription rate of antipsychotics in nursing homes by the intervention programme is expected. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02295462. PMID- 26037328 TI - Biochemical responses over time in common carp Cyprinus carpio (Teleostei, Cyprinidae) during fed supplementation with alpha-lipoic acid. AB - The current study aimed to evaluate the influence of lipoic acid (LA) supplementation (439.84+/-6.71 mg LA/kg feed) on antioxidants responses throughout the time in intestine, liver and muscle of juvenile common carp Cyprinus carpio. Two experimental groups were fed during four weeks with a diet with or without LA. Glutathione-S-transferase (GST) activity, glutathione (GSH) content, antioxidant capacity against peroxyl radicals (ACAP) and lipid peroxidation (TBARS) were evaluated in these organs. Also, a technique to measure protein disulfide bonds and sulfhydryl groups was optimized for intestine samples. GST activity was significantly higher (p<0.05) in intestine after two weeks of supplementation. GSH content was also significantly higher (p<0.05) in intestine, liver and muscle of fish fed with LA after two and three weeks, respectively. Total capacity antioxidant against peroxyl radicals was significantly increased (p<0.05) in the muscle of animals fed with LA after the fourth week. Concentration of disulfide bonds was higher in the intestine of fish fed with LA but this group also showed higher concentration of sulfhydryl groups (p<0.05). It is concluded that supplementation with LA is a safe strategy to induce antioxidant responses and improves the antioxidant status in different organs of common carp. Two week of supplementation are required to induce antioxidant responses in intestine and liver and three week for muscle. PMID- 26037329 TI - CUL4 forms an E3 ligase with COP1 and SPA to promote light-induced degradation of PIF1. AB - Plants undergo contrasting developmental programs in dark and light. Photomorphogenesis, a light-adapted programme is repressed in the dark by the synergistic actions of CUL4(COP1-SPA) E3 ubiquitin ligase and a subset of basic helix-loop-helix transcription factors called phytochrome interacting factors (PIFs). To promote photomorphogenesis, light activates the phytochrome family of sensory photoreceptors, which inhibits these repressors by poorly understood mechanisms. Here, we show that the CUL4(COP1-SPA) E3 ubiquitin ligase is necessary for the light-induced degradation of PIF1 in Arabidopsis. The light induced ubiquitylation and subsequent degradation of PIF1 is reduced in the cop1, spaQ and cul4 backgrounds. COP1, SPA1 and CUL4 preferentially form complexes with the phosphorylated forms of PIF1 in response to light. The cop1 and spaQ seeds display strong hyposensitive response to far-red light-mediated seed germination and light-regulated gene expression. These data show a mechanism by which an E3 ligase attenuates its activity by degrading its cofactor in response to light. PMID- 26037330 TI - Handheld X-ray Fluorescence Spectrometers: Radiation Exposure Risks of Matrix Specific Measurement Scenarios. AB - This study investigates X-ray intensity and dispersion around handheld X-ray fluorescence (XRF) instruments during the measurement of a range of sample matrices to establish radiation exposure risk during operation. Four handheld XRF instruments representing three manufacturers were used on four smooth, flat-lying materials of contrasting matrix composition. Dose rates were measured at 10, 20, 30, and 40 cm intervals every 30 degrees around the instrument at 0 and 45 degrees from the horizontal, as well as vertically from the instrument screen. The analysis of polyethylene recorded dose rates 156 times higher (on average) than steel measurements and 34 times higher than both quartz sand and quartz sandstone. A worst-case exposure scenario was assumed where a user analyses a polyethylene material at arms reach for 1 h each working day for one year. This scenario resulted in an effective body dose of 73.5 MUSv, equivalent to three to four chest X-rays (20 MUSv) a year, 20 times lower than the average annual background radiation exposure in Australia and well below the annual exposure limit of 1 mSv for non-radiation workers. This study finds the advantages of using handheld XRF spectrometers far outweighs the risk of low radiation exposure linked to X-ray scattering from samples. PMID- 26037331 TI - Optical Absorption and Magnetic Field Effect Based Imaging of Transient Radicals. AB - Short-lived radicals generated in the photoexcitation of flavin adenine dinucleotide (FAD) in aqueous solution at low pH are detected with high sensitivity and spatial resolution using a newly developed transient optical absorption detection (TOAD) imaging microscope. Radicals can be studied under both flash photolysis and continuous irradiation conditions, providing a means of directly probing potential biological magnetoreception within sub-cellular structures. Direct spatial imaging of magnetic field effects (MFEs) by magnetic intensity modulation (MIM) imaging is demonstrated along with transfer and inversion of the magnetic field sensitivity of the flavin semiquinone radical concentration to that of the ground state of the flavin under strongly pumped reaction cycling conditions. A low field effect (LFE) on the flavin semiquinone adenine radical pair is resolved for the first time, with important implications for biological magnetoreception through the radical pair mechanism. PMID- 26037333 TI - The experience of daily life of acutely admitted frail elderly patients one week after discharge from the hospital. AB - INTRODUCTION: Frail elderly are at higher risk of negative outcomes such as disability, low quality of life, and hospital admissions. Furthermore, a peak in readmission of acutely admitted elderly patients is seen shortly after discharge. An investigation into the daily life experiences of the frail elderly shortly after discharge seems important to address these issues. The aim of this study was to explore how frail elderly patients experience daily life 1 week after discharge from an acute admission. METHODS: The qualitative methodological approach was interpretive description. Data were gathered using individual interviews. The participants were frail elderly patients over 65 years of age, who were interviewed at their home 1 week after discharge from an acute admission to a medical ward. RESULTS: Four main categories were identified: "The system," "Keeping a social life," "Being in everyday life," and "Handling everyday life." These categories affected the way the frail elderly experienced daily life and these elements resulted in a general feeling of well-being or non-well-being. The transition to home was experienced as unsafe and troublesome especially for the more frail participants, whereas the less frail experienced this less. CONCLUSION AND DISCUSSION: Several elements and stressors were affecting the well-being of the participants in daily life 1 week after discharge. In particular, contact with the health care system created frustrations and worries, but also physical disability, loneliness, and inactivity were issues of concern. These elements should be addressed by health professionals in relation to the transition phase. Future interventions should incorporate a multidimensional and bio-psycho-social perspective when acutely admitted frail elderly are discharged. Stakeholders should evaluate present practice to seek to improve care across health care sectors. PMID- 26037334 TI - What are the risks? PMID- 26037332 TI - Role of the satiety factor oleoylethanolamide in alcoholism. AB - Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in rodents, which in turn reduces alcohol consumption by engaging peroxisome proliferator-activated receptor-alpha (PPAR-alpha). This effect appears to rely on peripheral signaling mechanisms as alcohol self-administration is unaltered by intracerebral PPAR-alpha agonist administration, and the lesion of sensory afferent fibers (by capsaicin) abrogates the effect of systemically administered OEA on alcohol intake. Additionally, OEA is shown to block cue-induced reinstatement of alcohol-seeking behavior (an animal model of relapse) and reduce the severity of somatic withdrawal symptoms in alcohol-dependent animals. Collectively, these findings demonstrate a homeostatic role for OEA signaling in the behavioral effects of alcohol exposure and highlight OEA as a novel therapeutic target for alcohol use disorders and alcoholism. PMID- 26037335 TI - Diagnostic performance of (18)F-fluorodeoxyglucose PET/CT and bone scintigraphy in breast cancer patients with suspected bone metastasis. AB - BACKGROUND: We prospectively compared the diagnostic accuracies of PET/CT and BS in patients with suspected bone metastases from breast cancer. METHODS: This single-institution prospective study included consecutive patients with suspected bone metastases from biopsy-proven breast cancer seen at Tokai University Hospital between September 2011 and March 2014. Inclusion criteria included suspicions for bone metastases (bone pain, elevated alkaline phosphatase, elevated tumor markers, or suspected bone metastases by BS). Two nuclear medicine physicians evaluated PET/CT and BS images. RESULTS: Thirty patients were initially enrolled in this study. Two were excluded from the analyses because they declined to undergo imaging during follow-up. PET/CT successfully detected bone metastases in all 10 patients finally diagnosed with the condition, whereas BS identified 2. The two methods were not highly concordant in detecting osseous metastases. In 19 of 28 paired studies (68 %), 2 (10 %) were positive for metastasis, and 17 (90 %) were negative. Nine occurrences (32 %) were discordant; of these, 2 were PET/CT positive and BS negative; 5 were PET/CT positive and BS equivocal; one was PET/CT negative and BS equivocal, and one was PET/CT equivocal and BS negative. CONCLUSIONS: Our results indicated that PET/CT was superior to BS for the diagnosis of bone metastases. On the basis of the results of previous studies as well as ours, PET/CT could replace BS as the initial modality to detect bone metastases in patients suspected for the condition. PMID- 26037337 TI - The impact of Polycomb group (PcG) and Trithorax group (TrxG) epigenetic factors in plant plasticity. AB - Current advances indicate that epigenetic mechanisms play important roles in the regulatory networks involved in plant developmental responses to environmental conditions. Hence, understanding the role of such components becomes crucial to understanding the mechanisms underlying the plasticity and variability of plant traits, and thus the ecology and evolution of plant development. We now know that important components of phenotypic variation may result from heritable and reversible epigenetic mechanisms without genetic alterations. The epigenetic factors Polycomb group (PcG) and Trithorax group (TrxG) are involved in developmental processes that respond to environmental signals, playing important roles in plant plasticity. In this review, we discuss current knowledge of TrxG and PcG functions in different developmental processes in response to internal and environmental cues and we also integrate the emerging evidence concerning their function in plant plasticity. Many such plastic responses rely on meristematic cell behavior, including stem cell niche maintenance, cellular reprogramming, flowering and dormancy as well as stress memory. This information will help to determine how to integrate the role of epigenetic regulation into models of gene regulatory networks, which have mostly included transcriptional interactions underlying various aspects of plant development and its plastic response to environmental conditions. PMID- 26037338 TI - [Preimplantation genetic diagnosis of infantile malignant osteopetrosis in a Chinese family]. AB - OBJECTIVE: To explore the application of preimplantation genetic diagnosis (PGD) for infantile malignant osteopetrosis (IMO). METHODS: For a family affected with IMO, PGD was provided using combined parental mutation detection and haplotype constructions with microsatellite markers spanning the TCIRG1 gene. Prenatal diagnosis was performed on the chorionic villus and amniocentesis samples by direct sequencing. RESULTS: Prenatal diagnosis showed that the fetus by the third pregnancy has carried the parental mutations [c.242delC (p.Pro81Argfs*85) and c.1114C>T (p.Gln372*)], and the pregnancy was terminated. PGD was subsequently performed through mutations detection and haplotype analyses following whole genome amplification (WGA) of each of 13 cells. The results showed that 6 of the 13 embryos were unaffected, 3 were carriers and 4 were affected. Well developed unaffected/carrier embryos were selected and transferred into the uterus. A single pregnancy was confirmed. Subsequently pre- and post-natal diagnoses have confirmed development of a healthy child. CONCLUSION: The study demonstrated the advantage of PGD over prenatal diagnosis when natural pregnancies have repeatedly produced IMO children/fetuses. PMID- 26037339 TI - [The value of blastocyst culture on preimplantation genetic diagnosis]. AB - OBJECTIVE: To estimate the value of blastocyst culture for preimplantation genetic diagnosis (PGD). METHODS: Day 3 embryos were biopsied and analyzed with fluorescence in situ hybridization (FISH) technique. Embryos with normal FISH results were cultured into blastocysts, and the ones with better morphology scores were transferred. Fourteen embryos with abnormal FISH results were cultured into blastocysts. Part of the cells taken from the blastocysts were amplified by whole genomic amplification (WGA) and assessed by array-based comparative genomic hybridization (array-CGH) analysis. RESULTS: Six blastocysts with normal FISH results were transferred in 5 cycles. Four healthy babies of 3 cycles were delivered. Another one was a singleton pregnancy but with embryo growth arrest, whose villus karyotype was normal. Fourteen embryos with abnormal FISH results were cultured into blastocysts and analyzed by array-CGH. Six blastocysts were normal by array-CGH. CONCLUSION: FISH combined with blastocyst culture may further ensure the accuracy of PGD result. Detection at the blastocyst stage can avoid false positive results and mosaic interferences on Day 3 stage and are therefore more authentic. PMID- 26037340 TI - [A novel indel NF1 mutation identified in a patient with neurofibromatosis type 1]. AB - OBJECTIVE: To identify the genetic etiology in a Chinese patient with neurofibromatosis type 1 (NF-1). METHODS: All coding exons and the flanking sequences of neurofibromin 1 (NF1) gene from the patient were captured, individually barcoded and subjected to HiSeq2000 high-throughput sequencing. Suspected mutation was validated in the nuclear family members with Sanger sequencing. RESULTS: A novel indel mutation, c.789_790delAGinsT, was identified in the exon 8 of the NF1 gene in the patient but not in her asymptomatic parents. The mutation was predicted to have caused shifting of the reading frame and a premature downstream stop codon (p.K263Nfs*18). Two known polymorphisms, c.888+108 C>T (rs2953000) and c.888+118 G>T (rs2952999), was detected in the flanking of the indel mutation in the patient and her father. Sequencing chromatogram for the family indicates that above changes are located on the same chromosome. CONCLUSION: The c.789_790delAGinsT, as a de novo mutation occurring on the paternally derived chromosome, is most likely to be causative for the disease. Compared with Sanger sequencing, targeted next-generation sequencing is more efficient and can dramatically reduce the cost for the genetic testing of NF 1. PMID- 26037341 TI - [Kniest dysplasia due to mutation of COL2A1 gene]. AB - OBJECTIVE: To detect potential mutation of COL2A1 gene in two children suspected for Kniest dysplasia. METHODS: The 54 exons and splicing regions of the COL2A1 gene were amplified with PCR and the product was subjected to direct sequencing. RESULTS: A missense mutation (c.905C>T, p.Ala302Val) was found in the coding region of the COL2A1 gene, which has been previously reported in abroad. The patients appeared to have short trunk dwarfism, enlarged joints and midface hypoplasia. CONCLUSION: The probands are the first cases of Kniest dysplasia described in China, and so was the p.Ala302Val mutation. PMID- 26037342 TI - [Identification of novel compound heterozygous mutations of USH2A gene in a family with Usher syndrome type II]. AB - OBJECTIVE: To identify potential mutations in a Chinese family with Usher syndrome type II. METHODS: Genomic DNA was obtained from two affected and four unaffected members of the family and subjected to amplification of the entire coding sequence and splicing sites of USH2A gene. Mutation detection was conducted by direct sequencing of the PCR products. A total of 100 normal unrelated individuals were used as controls. RESULTS: The patients were identified to be a compound heterozygote for two mutations: c.8272G>T (p.E2758X) in exon 42 from his mother and c.12376-12378ACT>TAA(p.T4126X) in exon 63 of the USH2A gene from his father. Both mutations were not found in either of the two unaffected family members or 100 unrelated controls, and had completely co segregated with the disease phenotype in the family. Neither mutation has been reported in the HGMD database. CONCLUSION: The novel compound heterozygous mutations c.8272G>T and c.12376-12378ACT>TAA within the USH2A gene may be responsible for the disease. This result may provide new clues for molecular diagnosis of this disease. PMID- 26037343 TI - [Congenital hypofibrinogenemia associated with a novel mutation in FGG gene]. AB - OBJECTIVE: To identify the genetic mutation underlying congenital hypofibrinogenamia in a Chinese pedigree. METHODS: Standard coagulation tests including the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), plasminogen activity (PLG:A), D-Dimer (DD) and fibrin degradation products (FDP) were tested with fresh plasma using a STA-R analyzer. The activity of fibrinogen (Fg:C) and fibrinogen antigen (Fg:Ag) were measured respectively with the Clauss method and immunoturbidimetry. All exons and exon intron boundaries of the fibrinogen Aalpha-, Bbeta-, and gamma-chain genes (FGA, FGB and FGG) were amplified by PCR followed by direct sequencing. Suspected mutation was confirmed by reverse sequencing and analyzed with a Swiss-PdbViewer. RESULTS: The PT level in the proband was normal, while the APTT and TT were slightly prolonged. The functional and antigen fibrinogen levels were both significantly reduced (0.91 g/L and 0.95 g/L, respectively). Similar abnormalities were also found in her father, elder sister, son and niece. The coagulant parameters of her mother were all within the normal range. Genetic analysis has reveled a heterozygous A>C change at nucleotide 5864 in exon 7 of gamma gene in the proband, predicting a novel Lys232Thr mutation. The proband's father, elder sister, son and niece were all carriers of the same mutation. Protein model analysis indicated that the Lys232Thr mutation did not disrupt the native network of hydrogen bonds, but has changed the mutual electrostatic forces, resulting in increased instability of the protein. CONCLUSION: The heterozygous Lys232Thr mutation identified in the FGG gene probably underlies the hypofibrinogenemia in this pedigree. PMID- 26037344 TI - [Analysis of common mutations of deafness-related genes in 2725 newborns]. AB - OBJECTIVE: To screen for common mutations of deafness-related genes in order to determine the carrier rate, types of mutation, and their relevance to hearing loss. METHODS: For 4 deafness-related genes GJB2, GJB3, 12S rRNA and SLC26A4, 20 common mutations were screened among 2725 newborns from Shaoxing, Zhejiang by matrix-assisted laser desorption ionization-time of flight-mass spectrometry. RESULTS: Among the 2725 newborns,149 (5.47%) were diagnosed with mutations, which included 84 (3.08%) with GJB2 mutations, 13 (0.48%) with GJB3 mutations, 49 (1.80%) with SLC26A4 mutations and 3 (0.11%) with 12S rRNA mutations. Fourteen mutational hotspots were identified. The most common mutations have included GJB2 c.235delC (65 cases), SLC26A4 IVS7-2A>G (34 cases), GJB2 c.299_300delAT (13 cases), GJB3 c.538C>T (7 cases), GJB2 c.176_191del16 (6 cases) and GJB3 c.547G>A (6 cases). CONCLUSION: The detecting rate for deafness-related gene mutations has been relatively high. To broaden the screening spectrum may improve such rate. Besides GJB2, 12S rRNA, SLC26A4, GJB3 also features a high mutation rate in the region. PMID- 26037345 TI - [Screening of common deaf genes in pregnant women and prevention of deafness at birth]. AB - OBJECTIVE: To determine the carrier rate for common mutations causing deafness among pregnant women in order to prevent births of deaf children. METHODS: For 893 pregnant women, 2 mL peripheral venous blood was taken and DNA was extracted. A deafness DNA microarray screening was applied to such samples, and DNA sequencing was applied to husbands of women with positive screening results. RESULTS: A total of 40 carriers were detected, with the overall mutation rate being 4.48%. Among such carriers, GJB2 235delC was the most common heterozygous mutation (18 cases) and the mutation rate was 2.02%. GJB2 299A-T heterozygous mutation was detected in 7 cases with a mutation rate of 0.78%. IVS7-2A to G heterozygous mutation was detected in 9 cases with a mutation rate of 1.02%. There were 2 cases carrying GJB3 heterozygous mutation and 2 cases of mitochondrial 12S rRNA heterozygous mutation, with a mutation rate of 0.22%. IVS7 2A>G with GJB3 538C>T double heterozygous mutation was detected in 1 case, and IVS7-2A>G with GJB2 299A-T double heterozygous mutation was detected in another case, with the mutation rate of each being 0.11%. DNA sequencing has failed to find presence of mutations in the same gene in the husbands. The results of neonatal hearing follow-up were all normal. CONCLUSION: Applications of the deaf genes screening in pregnant women may play prove to be valuable for the early detection for neonatal deafness. PMID- 26037346 TI - [Identification of a novel heterozygous mutation in a pedigree with hereditary coagulation factor XII deficiency]. AB - OBJECTIVE: To identify potential mutation underlying hereditary coagulation factor XII (FXII) deficiency in a pedigree and explore its molecular pathogenesis. METHODS: Activated partial thromboplastin time (APTT), FXII activity (FXII:C) and FXII antigen(FXII:Ag) and other coagulant parameters of the proband and 5 family members were measured. Potential mutations in the 14 exons and intron-exon boundaries of the FXII gene were screened with polymerase chain reaction (PCR) and direct DNA sequencing. Suspected mutations were confirmed with reverse sequencing. Corresponding PCR fragments from other family members were also sequenced. RESULTS: APPT of the proband and his son were significantly prolonged to 121.5 s and 98.5 s, respectively. FXII:C and FXII:Ag of the proband and his son have reduced to 5%, 6.8% and 9%, 12.2%, respectively. Plasma plasminogen activity (PLG:A) in both individuals was slightly higher than the normal reference range. FXII:C of his second daughter and grandson were slightly reduced to 64% and 60%. FXII:C of the other family members were all in the normal range (72%-113%). A heterozygous missense mutation, g.8597G>A, was identified in exon 13 of the FXII gene in the proband, which resulted in an p.Asp538Asn substitution. For the promoter regions of the FXII gene, the genotype of the proband was 46TT. The same mutations and 46T/T were also found in the proband's son but not in other members of the family. The genotypes of the proband's spouse, eldest daughter and grandson were 46CT, and his second daughter was 46TT. CONCLUSION: The heterozygous mutation of g.8597G>A identified in exon 13 of FXII gene is a novel mutation. Heterozygous p.Asp538Asn mutation and 46TT in the FXII gene can cause hereditary FXII deficiency, which was probably responsible for the low FXII concentrations in this pedigree. PMID- 26037347 TI - [Six cases of benign recurrent vertigo from a family]. PMID- 26037348 TI - [Detection for chromosomal aberrations in 43 fetuses with spontaneous abortion and stillbirth by array-based comparative genomic hybridization]. AB - OBJECTIVE: To assess the value of array-based comparative genomic hybridization (array-CGH) for analyzing tissues derived from spontaneous abortion and stillbirth. METHODS: Agilent Human Genome CGH Microarray 4*44 K chip and Affymetrix Cytoscan 750 K Array were utilized to detect genome-wide copy number variations (CNV) in 43 fetuses with spontaneous abortion and stillbirth. All identified CNV were analyzed with references from Database of Genomic variants (DGV), database of DECIPHER, ISCA and OMIM, as well as comprehensive literature review to determine whether the identified CNVs were pathogenic. Parental DNA of two cases was also analyzed with the same arrays for pathogenic or unknown significant CNVs. RESULTS: All of the 43 specimens were successfully analyzed. Clinically significant chromosomal aberrations were identified in 32 (74.4%) of the samples, which included 26 aneuploidies and 10 pathogenic CNV. CONCLUSION: Array-CGH is a fast and effective method for analyzing tissues derived from spontaneous abortions and stillbirths which may be difficult to culture for karyotype analysis. PMID- 26037349 TI - [Subcellular localization of ataxin-3 and its effect on the morphology of cytoplasmic organoids]. AB - OBJECTIVE: To explore the subcellular localization of ataxin-3 and the effect of polyglutamine (polyQ) expansion mutation on the morphology of mitochondrion, golgi apparatus and endoplasmic reticulum. METHODS: Transient transfection was employed to build cell models expressing wild-type or mutant ataxin-3 proteins. Indirect immunofluorescence was applied to identify markers of organelle membrane. The results were observed under a laser scanning confocal microscope. RESULTS: No co-localization was observed for ataxin-3 protein and mitochondrial marker TOM20, but the percentage of cells with mitochondrial fragmentation has increased in cells expressing mutant ataxin-3 (P<0.05). No co-localization was observed for ataxin-3 protein and golgi marker GM130, and mutant ataxin-3 did not cause golgi fragmentation. Wide type and polyQ-expanded ataxin-3 both showed partial co-localization with ER marker calnexin. The latter showed more overlap with calnexin, and the overlapping signals were mostly located in the places where aggregates were situated. CONCLUSION: PolyQ-expanded ataxin-3 protein may indirectly affect the integrity of mitochondria, but may cause no effect on the structure and functions of golgi apparatus. Endoplasmic reticulum may be another place where extended ataxin-3 protein can induce cytotoxicity in addition to the nucleus. PMID- 26037350 TI - [Molecular genetic analysis and clinical phenotype of a pedigree with familial dominant drusen]. AB - OBJECTIVE: To analyze clinical features and mutations of EFEMP1 gene in a Chinese pedigree with familial dominant drusen. METHODS: Clinical features of the pedigree were studied with fundus photography, fundus fluorescein angiography and optical coherence tomography. Molecular genetic analysis was performed on the patients and unaffected individuals from the family. All coding exons of the EFEMP1 gene were amplified by polymerase chain reaction (PCR) and sequenced. The results were compared with wild-type sequences from NCBI. The proband who had suffered from choroidal neovascularization and preretinal hemorrhage received an intravitreal injection of an anti-vascular endothelial growth factor (VEGF) preparation. RESULTS: A heterozygous mutation C>T (R345W) was identified in exon 10 of the EFEMP1 gene in two affected individuals from the family. The same mutation was not detected in unaffected family members and 100 healthy individuals. Postoperative follow-up of the patient receiving intravitreal injection of anti-VEGF drug showed that visual acuity was improved and fundus appeared to be stable. CONCLUSION: The R345W mutation in EFEMP1 is responsible for the dominant drusen in this family. Intravitreal injection of anti-VEGF drug is a promising treatment for the improvement in vision. PMID- 26037351 TI - [Genetic testing and prenatal diagnosis for eight families affected with Duchenne muscular dystrophy]. AB - OBJECTIVE: To optimize the methods for genetic detection and prenatal diagnosis of Duchenne muscular dystrophy (DMD). METHODS: Denaturing high-performance liquid chromatography (DHPLC), multiplex PCR (mPCR), sequencing and other molecular techniques were used in combination for molecular diagnosis of 8 cases diagnosed as DMD. RESULTS: Among the 8 cases, 4 have carried large deletions, 3 have point mutations, among which 6 were of de novo type. Prenatal diagnosis were offered for 5 families, the results showed that none of the fetuses had carried large deletions or point mutations. The pregnancies had continued and healthy babies were born. CONCLUSION: Combined use of short tandem repeat, DHPLC, mPCR and sequencing can improve the detection of DMD gene mutations. By establishing and optimizing genetic and prenatal diagnostic methods, accurate genetic counseling can be provided for families affected with DMD. PMID- 26037352 TI - [Detection of ADAR1 gene mutation in a family with dyschromatosis symmetrica hereditaria]. AB - OBJECTIVE: To detect mutation of ADAR1 gene in a family affected with dyschromatosis symmetrica hereditaria. METHODS: Clinical data and blood samples of the family were collected. Potential mutation of the ADAR1 gene were scanned in 3 patients and 3 unaffected members by PCR amplification and direct sequencing. The coding sequences of the ADAR1 were also screened in 50 normal controls. RESULTS: A frameshift mutation (c.2252insG) of the ADAR1 gene was identified in all of the 3 patients. The same mutation was not found in the 3 unaffected members and 50 normal cases. CONCLUSION: The frameshift mutation of ADAR1 gene (c.2252insG) is probably responsible for the disease in this family. PMID- 26037353 TI - [Application of chromosome microarray analysis for fetuses with increased nuchal translucency and a normal karyotype]. AB - OBJECTIVE: To explore the genetic etiology for fetuses with increased nuchal translucency (NT) but a normal karyotype at whole genome level by chromosome microarray analysis (CMA). METHODS: Seventy-eight fetuses with increased NT (>= 3.0 mm) but a normal karyotype were collected between 11(+0) and 13(+6) gestational weeks. Genomic DNA was extracted, and microarray testing was performed using Affymetrix CytoScan(TM) HD arrays. The data was analyzed by CHAS software. All detected copy number variations (CNVs) were confirmed with real time quantitative polymerase chain reaction. RESULTS: The CMA assay has detected pathogenic CNVs in 6 fetuses (7.69%), which have ranged from 0.41 Mb to 15.87 Mb. Well-known microdeletion or microduplication syndromes including Wolf-Hirschhorn syndrome, 22q11 microdeletion syndrome and ATR-16 syndrome were identified in three cases. The detection rates in fetuses with or without structural abnormalities were 18.18% and 5.97%, respectively (P=0.198 with Fisher's Exact Test). The average NT in fetuses with pathogenic CNVs and non-pathogenic CNVs has measured 4.48 mm and 4.22 mm (P=0.735 by Mann-Whitney Test). CONCLUSION: For fetuses with increased NT, CMA can identify chromosomal microdeletion/microduplication unrecognizable by conventional karyotyping analysis. It may therefore play an important role in prenatal diagnosis and genetic counseling by improving the diagnostic rate. PMID- 26037354 TI - [Prenatal diagnosis of a fetus with partial trisomy 8p resulting from a balanced maternal translocation by array-based comparative genomic hybridization]. AB - OBJECTIVE: To determine the karyotype of a fetus with transverse aortic arch hypoplasia, and to investigate the feasibility of array-based comparative genomic hybridization (array-CGH) for molecular genetic diagnosis. METHODS: G-banding was performed to analyze the karyotypes of the fetus and its parents, and array-CGH was applied to identify the chromosomal abnormality of the fetus. RESULTS: G banding analysis revealed that the pregnant woman has carried a balanced translocation 46,XX, t(8;16)(p21;q24), while the fetus has carried an unbalanced translocation 46,XX,der(16)t(8;16)(p21;q24)mat. Array-CGH analysis suggested that the derivative chromosomal fragment has originated from 8p with breakpoints in 8p23.3-p21.3. CONCLUSION: Trisomy 8p23.3-p21.3 may have predisposed to transverse aortic arch hypoplasia in the fetus. Parental karyotype analysis could help to characterize the translocation and evaluate the recurrent risk. Compared with routine karyotype analysis, aCGH has a higher resolution and greater accuracy for mapping chromosomal aberrations. PMID- 26037355 TI - [Morphology and pathogenesis of 47, XYY/47, XY, +mar identified in patients with super male syndrome]. AB - OBJECTIVE: To explore the source and morphology of supernumerary markers from patients with 47,XYY/47,XY, +mar and supermale syndrome. METHODS: Conventional GTG banded karyotyping and dual-color fluorescence in situ hybridization (FISH) were performed on 21 such patients. RESULTS: Among these cases, 18 had their small supernumerary marker derived from the Y chromosome. Three were derived from autosomal chromosomes. Those derived from Y chromosome were small fragments with centromeres, while those derived from autosomes were in the ring form. CONCLUSION: In children with supermale syndrome and 47,XYY/47,XY,+ mar, the supernumerary marker chromosomes primarily derive from sex chromosomes. These small chromosomes mainly have the forms of small segments with centromeres or rings. For such children, molecular cytogenetic analysis can facilitate genetic counseling and prenatal diagnosis. PMID- 26037356 TI - [A rare Pk phenotype caused by a 433 C>T mutation of the beta-1,3-N acetylgalactosyltransferase gene]. AB - OBJECTIVE: To study the serological characteristics and molecular mechanism for a rare Pk phenotype of the P1Pk blood group system. METHODS: The blood group of the proband was identified by serological techniques. The coding region and flanking intronic sequences of the beta-1,3-N-acetylgalactosyltransferase gene (B3GALANT1) associated with the Pk phenotype were analyzed using polymerase chain reaction sequence-based typing. RESULTS: The proband was identified as having a rare Pk phenotype including anti-P in her serum. The blood group of her daughter and husband showed a P2 phenotype. The nucleotide sequences of the B3GALANT1 gene of her husband and two randomly-chosen individuals were the same as the reference sequence (GenBank AB050855). Nucleotide position 433 C>T homozygous mutation in the B3GALANT1 was found in the proband, which has resulted in a stop codon at amino acid position 145, which may produce a premature protein capable of decreasing or inhibiting the activity of the beta -1,3-N acetylgalactosyltransferase. The nucleotide position 433 C/T heterozygous in the B3GALANT1 was found in her daughter. CONCLUSION: The Pk phenotype resulted from 433 C>T mutation in the B3GALANT1 gene has been identified. PMID- 26037357 TI - [Association of NEDD4 gene polymorphisms with schizophrenia and its clinical characteristics in Chinese Han population]. AB - OBJECTIVE: To assess the association of neural precursor cell expressed developmentally down-regulated 4 (NEDD4) with schizophrenia. METHODS: Five single nucleotide polymorphisms (SNPs) of the NEDD4 gene were genotyped by TaqMan SNP genotyping assay in an independent sample of 464 individuals with schizophrenia and 487 healthy controls from eastern Han Chinese population. Clinical data were collected with a general information questionnaire and Positive and Negative Syndrome Scale (PANSS). RESULTS: Frequencies of rs3088077 (allelic: chi2=18.024, P=0.000; genotypic: chi2=16.634, P=0.000), rs7162435 (allelic: chi2=6.771, P=0.009; genotypic: chi2=7.352, P=0.025) and rs2303579 (allelic: chi2=11.253, P=0.001; genotypic: chi2=12.248, P=0.002) were found to be significant different between the two groups. Moreover, TT of rs7162435 was significantly correlated with scores of factors of excitement and hostility (14.53+/-3.925, F=3.551, P=0.029). CONCLUSION: rs3088077, rs7162435 and rs2303579 of the NEDD4 gene may be associated with schizophrenia. Moreover, the TT genotype of rs7162435 may increase the severity of excitement and hostility. Our results may provide a clue for delineating the connection between the glutamate hypothesis of schizophrenia and ubiquitination. PMID- 26037358 TI - [Association of gender, age, education and polymorphism of DRD4 gene with cognitive functions in adults]. AB - OBJECTIVE: To assess the association of cognitive functions with gender, age, education and polymorphism of dopamine receptor D4 (DRD4) gene in healthy adults. METHODS: Four hundred and fifty-five healthy participants have completed 3 cognitive function tests including Tower of Hanoi (TOH), Wisconsin Card Sorting Test (WCST) and Trail Making Test (TMT). Peripheral blood samples were collected from all participants, and genomic DNA was extracted according to a standard phenol-chloroform procedure. Rs3758653 in the promoter region of the DRD4 gene was genotyped using Illumina GoldenGate genotyping assay. RESULTS: Males have performed better than females in terms of TOH executive time and TOH total score, but did worse in TOH planning time. Most of the measured cognitive domains were affected by age and education. Cognitive ability has decreased along with increased age and decline of educational years. The polymorphism of rs3758653 has mainly correlated with the TOH executive time. Compared with A allele carriers, G allele carriers did worse in TOH executive time. CONCLUSION: Gender, age, education and the rs3758653 polymorphism of the DRD4 gene play an important role in cognitive functions in healthy adults. PMID- 26037359 TI - [Association of MTHFR and MTRR genes polymorphisms with non-disjunctions of chromosomes 18 and 21]. AB - OBJECTIVE: To explore the effect of MTHFR and MTRR genes polymorphisms on chromosomes 18 and 21 non-disjunction through investigation of Henan Han Chinese young females with a gestational history of trisomy 21 (Down syndrome, DS) or trisomy 18 (Edwards syndrome, ES). METHODS: Polymorphisms of MTHFR 677C/T, MTHFR 1298A/C and MTRR 66A/G were analyzed in 73 healthy females (controls group), 78 females with a gestational history of DS (DS group) and 54 females with a gestational history of ES (ES group) by direct sequencing of PCR products from amplification of peripheral blood lymphocyte DNA. RESULTS: The frequency of MTHFR 677T allele was significantly different among the DS group, ES group and the control group (P<0.05). The frequency of MTRR 66G allele was significantly different only between the DS group and the control group (P<0.05). MTHFR 1298A/C polymorphisms were not associated with either ES or DS. Compared with the wild genotype MTHFR 677CC or MTRR 66AA, carriers of the MTHFR 677CT, 677TT, or MTRR 66GG genotypes had respectively 2.694 times (95%CI: 1.204-6.025, P<0.05), 5.451 times (95%CI: 2.211-13.435, P<0.05) and 9.618 times (95%CI: 2.085-44.365, P<0.05) risk of bearing a DS baby. Compared with the wild genotype MTHFR 677CC, carriers of the MTHFR 677CT and 677TT genotype had respectively 2.701 times (95%CI: 1.133 6.438, P<0.05) and 3.804 times (95%CI: 1.406-10.293, P<0.05) risk of bearing a ES baby. Neither MTRR 66AG or 66GG genotype was associated with the occurrence of ES. CONCLUSION: The MTHFR 677T and MTRR 66G may represent a risk factor for DS gestation, while MTHFR 677T may represent a risk factor for ES gestation for Chinese Han females. PMID- 26037360 TI - [A cancer family with six cases]. PMID- 26037361 TI - [Association of methylenetetrahydrofolate reductase gene polymorphisms with polycystic ovary syndrome]. AB - OBJECTIVE: To assess the association of C677T and A1298C polymorphisms of methylenetetrahydrofolate reductase (MTHFR) gene with the susceptibility to polycystic ovary syndrome (PCOS). METHODS: Blood samples of 115 PCOS patients and 58 fertile women (for whom PCOS has been excluded) were collected for DNA extraction. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used for determining the C677T and A1298C polymorphisms. A database has been set up with Epidata and a significance test was performed with a statistical analysis system. RESULTS: A significant difference has been found in the allele frequencies of MTHFR gene 677 C and T polymorphisms between the two groups (P<0.01), for which T allele has increased the risk for PCOS by 2.06 times. Heterozygous and homozygous genotypes at position 677 (CT and TT) were more common among PCOS cases than controls, with an OR of 3.91 (95%CI: 1.70-8.97) and 4.39 (95%CI: 1.77-10.89), respectively. There was no statistical difference in genotypic distribution of MTHFR gene A1298C polymorphism (P>0.05). In the PCOS group, there was a significant difference with an OR of 6.40 (95%CI: 1.71-23.95) for an increased risk of insulin resistance in homozygous C677T mutations (TT) compared with the wild genotype (CC, P<0.01). The PCOS group and the control group also differed significantly in their red blood cell folate levels (P<0.01), but not in serum vitamin B12 and homocysteine levels (P>0.05). CONCLUSION: MTHFR gene C677T polymorphism is associated with PCOS, for which CT and TT genotypes can increase the risk of PCOS. The TT genotype can also increase the risk of insulin resistance in PCOS patients. The A1298C polymorphism of the MTHFR gene is not associated with the occurrence of PCOS. The folate level in red blood cells of PCOS patients is lower, for whom folate should be supplemented. PMID- 26037362 TI - [Association of IFNgamma gene Tag single nucleotide polymorphisms and HBV infection in ethnic Dai and Hani populations from Yunnan]. AB - OBJECTIVE: To assess the association of interferon gamma gene (IFNgamma ) tag single nucleotide polymorphisms (Tag SNPs) with hepatitis B virus (HBV) infection in ethnic Dai and Hani minorities from Xishuangbanna, Yunnan. METHODS: Peripheral blood samples were collected from 300 Dai minorities and 300 Hani minorities, each included 100 healthy controls and 200 HBV infected individuals (including 100 spontaneous recovery subjects and 100 chronic HBV infected patients). Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDITOF MS) was used to determine the Tag SNPs of IFNgamma gene. Haplotypes were constructed. RESULTS: In Hani and Dai minorities, the frequencies of rs1861494 CC genotype in HBV infected group was significantly higher than the healthy group (Dai: chi2=10.017, P=0.001; Hani: chi2=6.515, P=0.039), and there was a significant difference between the HBV infected group and the control group under the C allele recessive mode (CC/TC+TT) (Dai: P=0.035, OR=9.567, 95%CI: 1.166 78.499; Hani: P=0.027, OR=5.484, 95%CI: 1.216-24.726). In Dai minorities, the frequencies of rs2069705 CC genotype and C allele in chronic HBV infected group was significantly higher than the spontaneous recovery group (genotype: chi2=8.112, P=0.017; allele: chi2=4.066, P=0.044), and there was a significant difference between chronic HBV infected group and spontaneous recovery group under the C allele recessive mode (CC/CT+TT) (P=0.013, OR=0.341, 95%CI: 0.146 0.796). CONCLUSION: Above results suggested that the rs1861494 CC genotype of the IFNgamma gene has conferred an increased risk for HBV susceptibility in both Dai and Hani minorities. In addition, the rs2069705 CC genotype may be a risky factor for Dai minorities to develop chronic HBV infection. PMID- 26037363 TI - [Genetic polymorphisms of 30 InDel loci in Chinese ethnic population residing in Tibet]. AB - OBJECTIVE: To analyze the genetic data of 30 insertion and deletion polymorphisms (InDel) loci included in an InvestigatorR DIPplex diagnostic kit, and to evaluate the forensic application in ethnic Tibetan population from China. METHODS: By detecting 226 unrelated individuals with the Investigator(R) DIPplex kit, allelic frequencies and population genetics parameters of the 30 InDels were statistically analyzed and compared with available data derived from other populations from various regions. RESULTS: After the Bonferroni correction at a 95% significance level (P=0.0017), no significant departures from the Hardy Weinberg equilibrium were observed except for the HLD114 locus. Linkage disequilibrium test showed no significant allelic association between all 30 loci after the Bonferroni's correction. The average heterozygosity (Ho) of all loci was 0.4125, the mean discrimination power (DP) was 0.5618, the mean polymorphism information content (PIC) was 0.3280, and the combined discrimination power (TDP) was 0.999999999990. The combined power of exclusion of all loci was 0.987 849 91 in trio cases and 0.94977125 in duo cases. Genetic distance between Tibetan and Han from Beijing was minimum (0.0068) in the 5 populations, while genetic distance between Tibetan and Uygur was maximal (0.0215). CONCLUSION: Multiplex detection has revealed that these 30 InDel loci have a moderate distribution of genetic polymorphism among ethnic Tibetan group residing in Tibet, China. PMID- 26037364 TI - [Identification of 3 novel HLA-A alleles A*24:224, A*24:225 and A*24:257 by sequence-based typing]. AB - OBJECTIVE: To verify 3 novel HLA-A alleles A*24:224, A*24:225 and A*24:257 identified in Chinese Han individuals. METHODS: No full matched results were obtained at HLA-A locus in HLA typing for China Marrow Donor Program (CMDP) using bi-allelic Sequence-Based Typing (SBT). The novel HLA alleles were identified with allele-specific amplification SBT. RESULTS: All of the three probands had a novel nucleotide sequence at HLA-A locus. All of the 3 new sequences are most close to HLA-A*24:02:01:01 except for 1 or 2 nucleotide substitution in exon 2, which resulted in different changes in corresponding codons and encoded amino acids. CONCLUSION: Three novel HLA-A alleles were confirmed and officially named as HLA-A*24:224, HLA-A*24:225 and HLA-A*24:257 under the GenBank accession numbers JQ899198, JQ924283 and HG003642 by the WHO Nomenclature Committee for Factors of the HLA System in November 2012 and November 2013, respectively. PMID- 26037365 TI - [Advance in genetic research on multiple system atrophy]. AB - Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. Widespread presence of glial cytoplasmic inclusions is the neuropathologic hallmark of MSA. The disease has long been considered as a sporadic disorder. However, in recent years, a few familial cases of MSA have been reported, and researches have verified certain genetic variants could increase the risk of MSA. These indicated genetic factors may play an imported role in the pathogenesis of MSA. In this review, the emerging evidence in favor of genetic players in MSA is discussed. PMID- 26037366 TI - [The role of calcium/calmodulin dependent serine protein kinase in embryonic development and related diseases]. AB - Calcium/calmodulin dependent serine protein kinase (CASK), which belongs to the family of membrane associated guanylate kinase (MAGUK) proteins, has several isoforms. CASK expresses differently in embryonic tissues and adult tissues. It can be modulated by phosphorylation and SUMOylation. CASK plays an important role in neural development, spermatozoal development and renal development. Dysfunction of CASK may lead to diseases. CASK is distributed extensively in the brain, regulating synapse formation. Mutation of CASK can lead to several neurologic diseases. CASK is also involved in the development and maturation of sperm and fertilization. It also can influence renal development through interaction with DLG1. PMID- 26037367 TI - [Advance in research on MECP2 [corrected] duplication syndrome]. AB - Methyl-CpG-binding protein 2 gene (MECP2; OMIM 300005) is located at chromosome Xq28. Mutations of the gene including point mutation, duplication and deletion can lead to severe neurodevelopmental disorders. The disease caused by duplication of the entire MECP2 gene, named as MECP2 duplication syndrome, is mostly seen in males. The clinical manifestation of this syndrome include mental retardation, hypotonia, poor speech development, recurrent infection, progressive spasticity, epilepsy, autism or autistic features with or without midface hypoplasia. Most patients have inherited the duplication from their unaffected mothers, with only a few cases having de novo mutation. Females with duplicated MECP2 gene are typically asymptomatic because of a skewed X chromosome inactivation (XCI) pattern. Proposed mechanisms of this genomic rearrangement include fork stalling and template switching (FoSTeS) and microhomology mediated break-induced replication (MMBIR). Since no effective treatment is available for this disease, proper genetic counseling and prenatal diagnosis for the high risk families are crucial. PMID- 26037368 TI - [Congenital cataract: three cases from a family]. PMID- 26037369 TI - [Onset of hemangioma in a consanguineous pedigree]. PMID- 26037370 TI - [25 cases with diffuse non-epidermolysis palmoplantar keratoderma from a family]. PMID- 26037371 TI - Does a Change Over All Equal a Change in All? Testing for Polarized Alcohol Use Within and Across Socio-Economic Groups in Germany. AB - AIMS: This study aimed at testing whether drinking volume and episodic heavy drinking (EHD) frequency in Germany are polarizing between consumption levels over time. Polarization is defined as a reduction in alcohol use among the majority of the population, while a subpopulation with a high intake level maintains or increases its drinking or its EHD frequency. The polarization hypothesis was tested across and within socio-economic subgroups. METHOD: Analyses were based on seven cross-sectional waves of the Epidemiological Survey of Substance Abuse (ESA) conducted between 1995 and 2012 (n = 7833-9084). Overall polarization was estimated based on regression models with time by consumption level interactions; the three-way interaction with socio-economic status (SES) was consecutively introduced to test the stability of effects over socio-economic strata. Interactions were interpreted by graphical inspection. RESULTS: For both alcohol use indicators, declines over time were largest in the highest consumption level. This was found within all SES groups, but was most pronounced at low and least pronounced at medium SES. CONCLUSION: The results indicate no polarization but convergence between consumption levels. Socio-economic status groups differ in the magnitude of convergence which was lowest in medium SES. The overall decline was strongest for the highest consumption level of low SES. PMID- 26037372 TI - Tolerability of High-dose Baclofen in the Treatment of Patients with Alcohol Disorders: A Retrospective Study. AB - AIMS: The aim of this study was to describe the tolerability of high-dose baclofen taken by patients with alcohol disorders during their first year of treatment. METHODS: The medical records of all patients prescribed baclofen by one general practitioner were examined and all patients who could be contacted were retrospectively interviewed about adverse effects. RESULTS: Of the 146 eligible patients, 116 (79%) could be interviewed. Ninety (78%) reported at least one adverse effect (mean number per patient: 2.8 +/- 2.7). The mean dosage of baclofen at the onset of the first adverse effect was 83 +/- 57 mg/day. The most frequent group of adverse effects involved disruption of the wake-sleep cycle and affected 73 patients (63%). Persistent adverse effects occurred in 62 patients (53%). Eight patients (7%) had adverse effects that led them to stop taking baclofen. Their dosages were <90 mg/day at that time. Alertness disorders and depression were the adverse effects that most frequently led to stopping baclofen. Bouts of somnolence and hypomanic episodes were the most potentially dangerous adverse effects. Women reported significantly more adverse effects than men. CONCLUSION: High-dose baclofen exposes patients with alcohol disorders to many adverse effects. Generally persistent, some adverse effects appear at low doses and may be dangerous. PMID- 26037373 TI - Oxidative N-Heterocyclic Carbene-Catalyzed gamma-Carbon Addition of Enals to Imines: Mechanistic Studies and Access to Antimicrobial Compounds. AB - The reaction mechanism of the gamma-carbon addition of enal to imine under oxidative N-heterocyclic carbene catalysis is studied experimentally. The oxidation, gamma-carbon deprotonation, and nucleophilic addition of gamma-carbon to imine were found to be facile steps. The results of our study also provide highly enantioselective access to tricyclic sulfonyl amides that exhibit interesting antimicrobial activities against X. oryzae, a bacterium that causes bacterial disease in rice growing. PMID- 26037375 TI - CYP2C9 polymorphisms and phenytoin metabolism: implications for adverse effects. AB - INTRODUCTION: Phenytoin, a widely prescribed old-generation antiepileptic drug, requires careful individualization of dosage to compensate for its prominent pharmacokinetic variability. This article reviews the contribution of genetic polymorphisms affecting the activity of CYP2C9, the main enzyme responsible for phenytoin metabolism, to the variation in phenytoin clearance and susceptibility to adverse effects. AREAS COVERED: Comprehensive and critical review of available evidence concerning the influence of CYP2C9 genetic polymorphism on phenytoin pharmacokinetic and safety profile. EXPERT OPINION: There is extensive evidence that CYP2C9 polymorphisms are an important determinant of the rate of phenytoin metabolism, although other factors including expression of other enzymes such as CYP2C19 and the influence of drug interactions, physiological and disease-related factors may also play a role. Patients carrying CYP2C9 genotypes associated with reduced phenytoin clearance are at greater risk of developing CNS adverse effects as well as serious cutaneous adverse reactions when given usual dosages of phenytoin. The clinical value and cost-effectiveness of CYP2C9 genotyping in improving the safety of phenytoin therapy, however, have not been clearly established and require formal testing in well-designed prospective studies. PMID- 26037376 TI - Commitment in different relationships statuses: validation study of the personal commitment scale. AB - This study presents the validation process of the Portuguese version of the short form Dedication Scale (Rhoades, Stanley, & Markman, 2006; Stanley, 1986), with a sample of 924 participants in different relationship statutes. With 14 items, this short version is recommended by the authors for its simple use, when wanting to measure commitment in romantic relationships. Confirmatory factor analysis showed that the instrument did not have a totally acceptable fit with the data so an exploratory factor analysis was conducted. This revealed a one-dimensional structure of the scale, and led to the exclusion of two items, which relate to a distinct meta-commitment dimension. In sum, the Portuguese version (ECP - Personal Commitment Scale) has 12 items, with good internal consistency (alpha = .82), correlations item-total between .36 and .60, and good criteria validity (p < .001). Its use for research is therefore appropriate. In a second study, significant differences were found between the participants' four relationship statuses (dating non-cohabiting and cohabiting relationships, formal unions and marriage) (p < .001; eta2 p = .03). Results showed that married participants were more committed than those in a formal union, even when controlling for several relational and socio-demographic variables. No differences were found between cohabiting and non-cohabiting dating participants. Men reported higher levels of commitment than women (p < .001; eta2 p = .02). Implications and suggestions for future research are discussed. PMID- 26037377 TI - THE OFFENDER PERSONALITY DISORDER PATHWAY: RISKING REHABILITATION? AB - Following over a decade of treatment refusal by 'risky' offenders preventively detained in Dangerous and Severe Personality Disorder hospital and prison units, the coalition government now aims to improve treatment engagement in high secure prisons by clarifying pathways out of detention. This article asks whether the reconfiguration will end reliance upon preventive detention for public protection. Drawing on original empirical data collected by the author, it is argued that the government is unaware that offenders with 'severe personality disorder' appear to engage with treatment only if it increases their chances of achieving expedited parole. Hitherto, this incentive was provided by the Indeterminate Sentence for Public Protection; its replacement with determinate sentences under the Legal Aid, Sentencing and Punishment of Offenders Act 2012 will worsen treatment engagement, because they provide offenders with a prison release date. The troubling result may be increased reliance by the Secretary of State for Justice on his inherent jurisdiction under the Mental Health Act 1983 to transfer offenders due for prison release to secure psychiatric hospitals. To counter this limitation of risk-focused decision-making, it is proposed that judges be able to impose a new hybrid order combining a custodial term with a subsequent community mental health treatment requirement. PMID- 26037378 TI - Oxygen-transfer performance of a newly designed, very low-volume membrane oxygenator. AB - OBJECTIVES: Oxygenation of blood and other physiological solutions are routinely required in fundamental research for both in vitro and in vivo experimentation. However, very few oxygenators with suitable priming volumes (<2-3 ml) are available for surgery in small animals. We have designed a new, miniaturized membrane oxygenator and investigated the oxygen-transfer performance using both buffer and blood perfusates. METHODS: The mini-oxygenator was designed with a central perforated core-tube surrounded by parallel-oriented microporous polypropylene hollow fibres, placed inside a hollow shell with a lateral-luer outlet, and sealed at both extremities. With this design, perfusate is delivered via the core-tube to the centre of the mini-oxygenator, and exits via the luer port. A series of mini-oxygenators were constructed and tested in an in vitro perfusion circuit by monitoring oxygen transfer using modified Krebs-Henseleit buffer or whole porcine blood. Effects of perfusion pressure and temperature over flows of 5-60 ml * min(-1) were assessed. RESULTS: Twelve mini-oxygenators with a mean priming volume of 1.5 +/- 0.3 ml were evaluated. With buffer, oxygen transfer reached a maximum of 14.8 +/- 1.0 ml O2 * l(-1) (pO2: 450 +/- 32 mmHg) at perfusate flow rates of 5 ml * min(-1) and decreased with an increase in perfusate flow to 7.8 +/- 0.7 ml ml O2 * l(-1) (pO2: 219 +/- 24 mmHg) at 60 ml * min(-1). Similarly, with blood perfusate, oxygen transfer also decreased as perfusate flow increased, ranging from 33 +/- 5 ml O2 * l(-1) at 5 ml * min(-1) to 11 +/- 2 ml O2 * l(-1) at 60 ml * min(-1). Furthermore, oxygen transfer capacity remained stable with blood perfusion over a period of at least 2 h. CONCLUSIONS: We have developed a new miniaturized membrane oxygenator with an ultra-low priming volume (<2 ml) and adequate oxygenation performance. This oxygenator may be of use in overcoming current limitations in equipment size for effective oxygenation in low-volume perfusion circuits, such as small animal extracorporeal circulation and ex vivo organ perfusion. PMID- 26037379 TI - Analysis of yeh Fimbrial Gene Cluster in Escherichia coli O157:H7 in Order to Find a Genetic Marker for this Serotype. AB - yeh fimbrial gene cluster encodes a type of putative fimbrial complex belonging to chaperone-usher assembly pathway. Recent studies have shown that yeh fimbrial gene cluster is present in 94 % of Escherichia coli isolates and responsible for adhesion to some abiotic surfaces. Our preliminary comparative genomic analysis of 96 complete genomes of different E. coli strains revealed that the major region of this gene cluster is unique to E. coli O157:H7 strains. To investigate the detail of the analysis, we BLAST the sequence of this gene cluster against the existing complete and draft genome sequences of different E. coli strains and other genera belonging to Enterobacteriaceae family in NCBI database. The results showed that this gene cluster is properly unique to E. coli O157:H7 strains and could be used as a stable and specific genetic signature for the identification of this serotype. In this respect, we also experimentally validated the specificity of this gene cluster for the identification of E. coli O157:H7 strains by loop-mediated isothermal amplification method. PMID- 26037380 TI - Molecular Phylogeny and Taxonomy of Yamadazyma dushanensis f.a., sp. nov., a Cellobiose-Fermenting Yeast Species from China. AB - Three yeast strains of Yamadazyma dushanensis f.a., sp. nov. were isolated from rotten wood samples collected in the Dushan Forest Park, Nanyang, Henan Province, China. Sequence analyses of the D1/D2 domains of the large subunit rRNA gene and the internal transcribed spacer (ITS) regions revealed that this new species is located in the Yamadazyma clade (Debaryomycetaceae and Saccharomycetales), with three closely related species, namely, Yamadazyma terventina, Yamadazyma mexicana and Candida trypodendroni. The novel species differed from these three described species by 5-6 nt substitutions in the D1/D2 sequences. However, the ITS sequences of the new species were quite divergent from those of Y. terventina, Y. mexicana and C. trypodendroni with 12-18 nt substitutions. This new yeast species could assimilate cellobiose and other compounds related to rotting wood. The fermentation of cellobiose in Durham tubes was observed for the strains of this new yeast. The new species could also be distinguished from its closely related species, Y. terventina, Y. mexicana and C. trypodendroni, based on a number of morphological and physiological characteristics. The type strain is Y. dushanensis sp. nov. NYNU 14668 (T) (=CICC 33051(T) = CBS 13914(T)). PMID- 26037381 TI - New Comparative Analysis Based on the Secondary Structure of SSU-rRNA Gene Reveals the Evolutionary Trend and the Family-Genus Characters of Mobilida (Ciliophora, Peritrichia). AB - In order to reveal the structural evolutionary trend of Mobilida ciliates, twenty six SSU-rRNA sequences of mobilid species, including seven ones newly sequenced in the present work, were used for comparative phylogenic analysis based on the RNA secondary structure. The research results indicate that all the secondary structures except domains Helix 10, Helix 12, and Helix 37 could be regarded as the criterions in classification between the family Trichodinidae and Urceolariida, and four regions including Helix E10-1, Helix 29, Helix 43, and Helix 45-Helix 46 could be as criterions in classification between the genus Trichodinella and Trichodina in family Trichodinidae. After the analysis of common structural feature within the Mobilida, it was found that the secondary structure of V6 could prove the family Urceolariidae primitive status. This research has further suggested that the genus Trichodina could be divergent earlier than Trichodinella in the family Trichodinidae. In addition, the relationship between the secondary structure and topology of phylogenic tree that the branching order of most clades corresponds with the secondary structure of species within each clade of phylogenetic tree was first uncovered and discussed in the present study. PMID- 26037382 TI - Fluid Management Dilemma in Patients with Severe Sepsis and Septic Shock. PMID- 26037385 TI - Catheter specimen urines: are they worth culturing? AB - Urinary tract infections are the most commonly acquired bacterial infections, but the significance of growths from catheter-related specimens, particularly heavy mixed growths, is uncertain and can pose a dilemma for the clinical laboratory responsible for processing and authorising reports, as well as a diagnostic dilemma for clinicians. Furthermore, inappropriate processing and reporting of samples may lead to inappropriate treatment of patients, which can result in adverse effects as well as increased laboratory and clinical costs. This short communication summarises recent evidence and guidelines on the matter. PMID- 26037383 TI - Modulation of extracellular matrix in cancer is associated with enhanced tumor cell targeting by bacteriophage vectors. AB - BACKGROUND: Gene therapy has been an attractive paradigm for cancer treatment. However, cancer gene therapy has been challenged by the inherent limitation of vectors that are able to deliver therapeutic genes to tumors specifically and efficiently following systemic administration. Bacteriophage (phage) are viruses that have shown promise for targeted systemic gene delivery. Yet, they are considered poor vectors for gene transfer. Recently, we generated a tumor targeted phage named adeno-associated virus/phage (AAVP), which is a filamentous phage particle whose genome contains the adeno-associated virus genome. Its effectiveness in delivering therapeutic genes to tumors specifically both in vitro and in vivo has been shown in numerous studies. Despite being a clinically useful vector, a multitude of barriers impede gene transduction to tumor cells. We hypothesized that one such factor is the tumor extracellular matrix (ECM). METHODS: We used a number of tumor cell lines from different species and histological types in 2D monolayers or 3D multicellular tumor spheroid (MCTS) models. To assess whether the ECM is a barrier to tumor cell targeting by AAVP, we depleted the ECM using collagenase, hyaluronidase, or combination of both. We employed multiple techniques to investigate and quantify the effect of ECM depletion on ECM composition (including collagen type I, hyaluronic acid, fibronectin and laminin), and how AAVP adsorption, internalisation, gene expression and therapeutic efficacy are subsequently affected. Data were analyzed using a student's t test when comparing two groups or one-way ANOVA and post hoc Tukey tests when using more than two groups. RESULTS: We demonstrate that collagenase and hyaluronidase-mediated degradation of tumor ECM affects the composition of collagen, hyaluronic acid and fibronectin. Consequently, AAVP diffusion, internalisation, gene expression and tumor cell killing were enhanced after enzymatic treatment. Our data suggest that enhancement of gene transfer by the AAVP is solely attributed to ECM depletion. We provide substantial evidence that ECM modulation is relevant in clinically applicable settings by using 3D MCTS, which simulates in vivo environments more accurately. CONCLUSION: Our findings suggest that ECM depletion is an effective strategy to enhance the efficiency of viral vector-guided gene therapy. PMID- 26037384 TI - Synthesis of 24-h soluble gelatin sponge particles and their effect on liver necrosis following hepatic artery embolization: Results of in vitro and in vivo studies. AB - AIM: To synthesize 24-h soluble gelatin sponge particles (SGSP) of 200-500 and 500-1000 um, and to investigate their ischemic potency following hepatic artery embolization (HAE). METHODS: Low-endotoxin gelatin was freeze-dried and heated at 110, 115, 118, 120, 122 and 125 degrees C to form cross-linked gelatin sponge. We prepared 200-500- and 500-1000-um SGSP by pulverizing and sieving the gelatin sponge. The dissolution times in saline were measured. Eight healthy pigs underwent HAE of the right and left hepatic arteries with either 200-500- or 500 1000-um SGSP (n = 4/group). RESULTS: The particles prepared at 110-122 degrees C were soluble whereas particles prepared at 125 degrees C or more were insoluble. The mean dissolution time of the particles increased with increasing temperature. In each pig, sequential arteriography confirmed that recanalization was complete 24 h after embolization. Pathological tests 48 h after HAE revealed coagulation necrosis but least damage to the biliary tract. The liver necrosis rate (mean +/- standard deviation) was significantly greater in the 200-500-um group than in the 500-1000-um group (9.89 +/- 4.04% vs 4.44 +/- 0.67%, respectively; P = 0.0027). A significantly greater proportion of arteries with a diameter of 100-200 um had residual SGSP in the 200-500-um group than in the 500-1000-um group (P < 0.002). CONCLUSION: HAE with 200-500-um SGSP had greater effects on promoting liver necrosis without biliary damage than did HAE with 500-1000-um SGSP. PMID- 26037386 TI - Influence of chronic illnesses and underlying risk conditions on the incidence of pneumococcal pneumonia in older adults. AB - OBJECTIVE: To investigate hospitalizations from pneumococcal pneumonia in older adults with specific underlying chronic conditions, evaluating the influence of these conditions in developing pneumonia. METHODS: Population-based cohort study involving 27,204 individuals >= 60 years old in Southern Catalonia, Spain. All cases of hospitalization from pneumococcal pneumonia (bacteremic and nonbacteremic) were collected since 01/12/2008 until 30/11/2011. Cox regression was used to calculate hazards ratio (HR) and estimate the association between baseline conditions and the risk of developing pneumococcal pneumonia. RESULTS: Maximum incidences (per 1000 person-years) appeared among patients with history of prior pneumonia (14.6), nursing home residents (12.8), persons with immunodeficiency/asplenia (7.7) and patients with chronic pulmonary disease (7.6). In multivariable analysis, age (HR: 1.05), nursing home residence (HR: 4.59), history of prior pneumonia (HR: 3.58), stroke (HR: 2.50), chronic heart disease (HR: 1.53), chronic pulmonary disease (HR: 4.09), diabetes mellitus (HR: 1.66), smoking (HR: 1.69) and immunosuppressive medication (HR: 1.87) appeared significantly associated with an increased risk of pneumococcal pneumonia. CONCLUSION: Our data support that nursing home residence, chronic pulmonary disease and immunocompromising conditions are the underlying conditions most strongly associated with an increasing risk of pneumococcal pneumonia in older adults. This data underline the need for better prevention strategies among these persons. PMID- 26037387 TI - Use of oral trazodone for sedation in cats: a pilot study. AB - OBJECTIVES: Resistance to transportation and stressful veterinary visits are major causes for a decrease in feline veterinary care. Few options exist for oral sedatives to reduce cats' anxiety prior to veterinary visits. The purpose of this study was to evaluate the safety and efficacy of oral trazodone for use as a single dose agent for sedation in cats. METHODS: Six laboratory cats were given single 50, 75 and 100 mg doses of trazodone and placebo. Trazodone 100 mg and placebo treatments were randomized. Pre- and post-study laboratory values and physical examinations were compared. During each 4 h period post-treatment, sedation was measured via accelerometers and video observations scored by an observer blinded to treatment. Examinations were performed on the cats 90 mins after treatment, and their behavioral responses scored by the same blinded observer. RESULTS: No adverse effects or changes in physical examinations or laboratory values were detected as a result of trazodone administration. Accelerometer data showed trazodone 50, 75 and 100 mg caused sedation as measured by activity reduction (83%, 46% and 66%, respectively). In contrast, there was a 14% activity increase after placebo. There was a significant reduction in video observation scores when cats were given trazodone 100 mg compared with placebo. Mean latency to peak sedation for trazodone 100 mg occurred at 2 h. Scores for behavioral response to examination, performed at 90 mins post-treatment, were not significantly different between cats receiving trazodone 100 mg and placebo. CONCLUSIONS AND RELEVANCE: Trazodone was well tolerated in this population of cats and caused appreciable sedation at all doses. Behavior during examination was not significantly different when cats received trazodone 100 mg compared with placebo. Further studies are recommended to investigate the use of oral trazodone in cats for the purpose of decreasing anxiety assocaited with transportation and examination. PMID- 26037388 TI - HIF-1alpha-induced microRNA-210 reduces hypoxia-induced osteoblast MG-63 cell apoptosis. AB - To better understand the ischemic-hypoxia-induced fracture healing impairment, we determined in this study the microRNA-210 expression in broken bone specimens and in osteoblasts under hypoxia and then determined the influence of microRNA-210 overexpression on the osteoblast cell proliferation and apoptosis. Results demonstrated that microRNA-210 expression was upregulated with an association with HIF-1alpha overexpression in clinical human catagmatic tissues and was upregulated HIF-1alpha-dependently in response to hypoxia in osteoblast MG-63 cells. CCK-8 assay indicated that microRNA-210 upregulation by microRNA-210 mimics reduced the chemotherapeutic 5-FU-induced osteoblast cell death, and colony formation assay demonstrated that microRNA-210 mimics promoted osteoblast cells growth. Moreover, the microRNA-210 mimics transfection inhibited the hypoxia-induced MG-63 cell apoptosis via inhibiting the activation of caspase 3 and caspase 9. Therefore, our research indicated a protective role of microRNA 210 in response to hypoxia. And microRNA-210 might serve as a protective role in bone fracture healing. PMID- 26037389 TI - Paradigm shift in plant growth control. AB - For plants to grow they need resources and appropriate conditions that these resources are converted into biomass. While acknowledging the importance of co drivers, the classical view is still that carbon, that is, photosynthetic CO2 uptake, ranks above any other drivers of plant growth. Hence, theory and modelling of growth traditionally is carbon centric. Here, I suggest that this view is not reflecting reality, but emerged from the availability of methods and process understanding at leaf level. In most cases, poorly understood processes of tissue formation and cell growth are governing carbon demand, and thus, CO2 uptake. Carbon can only be converted into biomass to the extent chemical elements other than carbon, temperature or cell turgor permit. PMID- 26037390 TI - Plant nitrogen assimilation and its regulation: a complex puzzle with missing pieces. AB - Nitrogen (N) is an essential element for plants that is available in agricultural soils mainly as macronutrients in the form of nitrate and ammonium. Interplay between high-affinity and low-affinity transporters ensures efficient uptake from the soil even under highly fluctuating N availability. After uptake, N assimilation comprises the reduction of nitrate to ammonium and its subsequent incorporation into amino acids. Amino acids, but also nitrate, are transported from root to shoot and vice versa. Most steps of N transport and assimilation are tightly controlled by a regulatory network acting both cell-autonomously and systemically. N sensors, transcription factors and further regulatory players have been identified during recent years, elucidating parts of the huge puzzle that represents the efficient use of N by plants. PMID- 26037391 TI - Unexpected roles of plastoglobules (plastid lipid droplets) in vitamin K1 and E metabolism. AB - Tocopherol (vitamin E) and phylloquinone (vitamin K1) are lipid-soluble antioxidants that can only be synthesized by photosynthetic organisms. These compounds function primarily at the thylakoid membrane but are also present in chloroplast lipid droplets, also known as plastoglobules (PG). Depending on environmental conditions and stage of plant development, changes in the content, number and size of PG occur. PG are directly connected to the thylakoid membrane via the outer lipid leaflet. Apart from storage, PG are active in metabolism and likely trafficking of diverse lipid species. This review presents recent advances on how plastoglobules are implicated in the biosynthesis and metabolism of vitamin E and K. PMID- 26037392 TI - New mechanistic links between sugar and hormone signalling networks. AB - Plant growth and development must be coordinated with metabolism, notably with the efficiency of photosynthesis and the uptake of nutrients. This coordination requires local connections between hormonal response and metabolic state, as well as long-distance connections between shoot and root tissues. Recently, several molecular mechanisms have been proposed to explain the integration of sugar signalling with hormone pathways. In this work, DELLA and PIF proteins have emerged as hubs in sugar-hormone cross-regulation networks. PMID- 26037393 TI - Evaluation of differences in carotid intima-media thickness in patients affected by systemic rheumatic diseases. AB - The objective of this study is to investigate whether rheumatic autoimmune diseases, systemic sclerosis (SSc) in particular, are associated with increased carotid intima-media thickness (C-IMT). A total of 108 clinical outpatients (93 females), mean age 51 +/- 14 years suffering from CTD were consecutively enrolled. Patients were subdivided into the following two groups: (1) Systemic Sclerosis (SSc, 60 patients); (2) non-Systemic Sclerosis (NoSSc, 48 patients). No randomization was managed. All patients underwent structured clinical interview, physical examination, laboratory evaluation and two-dimensional echo-color Doppler of the carotid arteries to measure C-IMT and atherosclerotic plaques. Framingham risk score was also calculated. We also enrolled 108 healthy controls (HC), matched by sex and age. The primary outcome was to stratify cardiovascular risk of CTD patients. There were no significant differences between SSc and NoSSc patients regarding any of the demographics and traditional cardiovascular risk factors. Mean C-IMT was not significantly different between the whole CTD patients (0.86 +/- 0.13 mm) and HC (0.83 +/- 0.13 mm). C-IMT was significantly higher in SSc than in NoSSc group (0.91 +/- 0.1 mm vs 0.80 +/- 0.14 mm, p < 0.001). Furthermore, C-IMT in SSc group was significantly higher than C-IMT in controls (0.91 +/- 0.1 mm vs 0.83 +/- 0.13 mm, p < 0.001). C-IMT did correlate neither with disease activity nor with drug intake. SSc patients had a significant increase in C-IMT as compared to NoSSc patients and healthy controls. PMID- 26037395 TI - Clinical pharmacists help prescribers and patients make informed decisions. PMID- 26037394 TI - Blood urea nitrogen to creatinine ratio is associated with congestion and mortality in heart failure patients with renal dysfunction. AB - Renal dysfunction (RD) and venous congestion are related and common in heart failure (HF). Studies suggest that venous congestion may be the primary driver of RD in HF. In this study, we sought to investigate retrospectively the relationship between common measures of renal function with caval congestion and mortality among outpatients with HF and RD. We reviewed data from 103 HF outpatients (45 males, mean age 74 years, ejection fraction 41.8 +/- 11.6 %) with estimated glomerular filtration rate (eGFR) of < 60 ml/min in a single centre. During an ambulatory visit, all patients underwent blood test and ultrasonography of the inferior vena cava (IVC). Caval congestion was defined as IVC with both dilatation and impaired collapsibility. The best values of renal metrics in predicting caval congestion were determined with receiver-operating characteristic analysis. The BUN/Cr ratio is moderately correlated with IVC expiratory maximum diameter (r = 0.31, p < 0.0007). In a multiple logistic regression model, BUN/Cr > 25.5 (adjusted OR 2.98, p 0.015) and eGFR <= 45.8 (adjusted OR 5.38, p 0.002) identify patients at risk for caval congestion; a BUN/Cr > 23.7 was the best predictor of impaired collapsibility (adjusted OR 4.41, p 0.001). a BUN/Cr > 25.5 (HR 2.19, 95 % CI 1.21-3.94, p < 0.001) and NYHA class 3 (HR 2.91, 95 % CI 1.60-5.31, p < 0.0005) were independent risk factors associated with all-cause death during a median follow-up of 31 months. In outpatients with HF and RD, a higher BUN/Cr and lower eGFR are reliable renal biomarkers for caval congestion. The BUN/Cr is associated with long-term mortality and may help to stratify HF severity. PMID- 26037396 TI - Evaluation of inhaler technique, adherence to therapy and their effect on disease control among children with asthma using metered dose or dry powder inhalers. AB - OBJECTIVE: To address the problems about correct use of inhaler devices, adherence to inhaler corticosteroid treatment and the effects of these problems on the control of asthma. METHODS: Children with asthma were evaluated for the correct use of inhaler devices and adherence to therapy using a questionnaire. Effect of these on control of asthma was defined. RESULTS: A hundred and seventy one patients and/or their families were interviewed. The mean age was 8.29 +/- 4.65 years (1-19) and 62.6% were male. Metered dose inhaler (MDI) with spacer was used by 119 (69.5%) patients and 52 (30.5%) used dry powder inhalers (DPIs). The devices were used correctly by 68.1% of patients using MDI and 34.6% of patients using DPI (p < 0.001). The most common improper step was "breathe in from the spacer 5-6 times or 10 s" for MDI (24.4%) and "exhale to residual volume" for DPI (51.9%). Frequency of correct use was higher in patients trained 3 times (p < 0.001). Asthma was controlled more frequently among correct users (p < 0.001). Partial or poor adherence was showed 22.8% of patients. Patients with mothers who had lower educational status had higher frequency of incorrect use of inhaler device (p = 0.007). CONCLUSION: It was found that asthma control was better among correct users. Repetitive training about using devices may contribute improving inhaler technique. Especially children whose mothers had low education level and patients using DPI should be evaluated more carefully. PMID- 26037397 TI - "I just forget to take it": asthma self-management needs and preferences in adolescents. AB - BACKGROUND: Medication adherence rates often decline as children become teenagers. Effective adherence-enhancing interventions for adolescents are lacking. The objective of this study was to assess adolescent asthmatics needs and preferences regarding medication counseling and support, with focus on new media. METHODS: Three focus groups including 21 asthmatic adolescents recruited from both primary and secondary care were held to explore needs and preferences regarding asthma-self management. Questions concerned adherence behavior and needs and preferences in adherence support with focus on new media (mobile technology, social media, health games). RESULTS: Forgetting was mentioned as major reason for not using medication as prescribed. Adolescents also mentioned lack of perceived need or beneficial effects. Parents mainly play a role in reminding to take medication and collecting refills. The suggested strategies to support self-management included smartphone applications with a reminder function and easy access to online information. Participants were positive about sharing of experiences with other teenagers. CONCLUSION: Forgetfulness is a major reason for non-adherence in adolescents. Furthermore, our results suggest use of peer support may be helpful in promoting good medication use. Future interventions should be aimed at providing practical reminders and should be modifiable to individual preferences. PMID- 26037398 TI - Curcumin inhibits Ec109 cell growth via an AMPK-mediated metabolic switch. AB - AIMS: Glycolytic enzymes are always greatly increased in cancer cells. Whether metabolic reprogramming is involved in curcumin-mediated inhibition of cancer cell growth is unknown. MAIN METHODS: In this study, cell viability was assayed with MTS analysis; cell cycle was measured with flow cytometry analysis. RT-PCR and western blotting were used to analyse the mRNA and protein expression, respectively. KEY FINDINGS: Here we demonstrated that curcumin inhibited cancer cell growth, especially for Ec109 cells. Curcumin induced cell cycle arrest at G2/M phase. Curcumin caused a significant down-regulation of glycolytic enzymes expressions in a dose-dependent manner. Our results further indicated that the AMPK was required for curcumin-mediated down-regulation of glycolytic enzymes. AMPK-mediated down-regulation of glycolytic enzymes blocked Ec109 cell growth. SIGNIFICANCE: Taken together, our results revealed that the AMPK-mediated metabolic switch plays an important role in esophageal cancer cell growth. PMID- 26037399 TI - NALP3 inflammasome activation in protein misfolding diseases. AB - Protein-misfolding diseases, such as Alzheimer's disease, type 2 diabetes, Prion diseases, and Parkinson's disease, are characterized by inflammatory reactions. In all these diseases, IL-1beta (Interlukine-1beta) has been shown to be an important regulator, and the misfolded proteins are proved to be triggers of the release of IL-1beta. Recently, several reports demonstrated that the inflammasome activation is involved in the progress of the misfolded protein diseases, and that the inflammasome can recognize pathogenic proteins leading to the release of IL-1beta. In this review, we discuss the role of inflammasome in the pathogenesis of misfolded protein diseases and the potential of inflammasome-targeting therapeutic interventions in the management of these diseases. PMID- 26037400 TI - Vitamin D levels in multiple sclerosis patients: Association with TGF-beta2, TGF betaRI, and TGF-betaRII expression. AB - AIM: A variety of evidence suggests that vitamin D can prevent the development of multiple sclerosis (MS). TGF-beta pathway genes also play important roles in MS. Here, we aim to study whether vitamin D affects TGF-beta pathway gene expression and Expanded Disability Status Scale (EDSS) scores in MS patients. MAIN METHODS: A randomized clinical trial was conducted on 31 relapsing-remitting (RR) MS patients. Using real-time RT-PCR, we tested the levels of TGF-beta2, TGF-betaRI and TGF-betaRII mRNAs in the RRMS patients before and after 8 weeks of supplementation with vitamin D. KEY FINDINGS: Expression of TGF-beta2 mRNA increased 2.84-fold, while TGF-betaRI and TGF-betaRII mRNA levels did not change after vitamin D treatment. In addition, these results revealed no correlation between the normalized expression of TGF-beta2, TGF-betaRI, or TGF-betaRII and EDSS scores. SIGNIFICANCE: Here, we demonstrate new evidence for the complex role of vitamin D in the pathogenesis, activity and progression of MS through the TGF beta signaling pathway. PMID- 26037401 TI - Electro-acupuncture up-regulates astrocytic MCT1 expression to improve neurological deficit in middle cerebral artery occlusion rats. AB - AIMS: Cerebral ischemia is one of the common diseases treated by electro acupuncture (EA). Although the clinical efficacy has been widely affirmed, the mechanisms of action leading to the health benefits are not understood. In this study, the role of EA in modulating the lactate energy metabolism and lactate transportation was explored on the middle cerebral artery occlusion (MCAO) ischemic rat model. MAIN METHODS: Repeated EA treatments once daily for 7 days were applied to the MCAO rats and neurological function evaluation was performed. Brain tissues were harvested for lactate concentration examination, immunohistochemical staining, Western blot and qRT-PCR analyses for the expressions of lactate transporter (monocarboxylate transporter 1, MCT1) and glial fibrillary acidic protein (GFAP). KEY FINDINGS: The animal behavioral tests showed that the 7-day EA treatments significantly promoted the recovery of neurological deficits in the MCAO rats, which correlated with the enhanced lactate energy metabolism in the ischemic brain. In the cortical ischemic area of the MCAO rats, EA treatments led to the activation of astrocytes, and induced a further increase of lactate transporter (monocarboxylate transporter 1, MCT1) expression in astrocytes at both protein and mRNA levels. SIGNIFICANCE: Our results suggest that the EA treatments activated lactate metabolism in the resident astrocytes around the ischemic area and up-regulated the expression of MCT1 in these astrocytes which facilitated the transfer of intracellular lactate to extracellular domain to be utilized by injured neurons to improve the neurological deficit. PMID- 26037402 TI - The development of reasoning about the temporal and causal relations among past, present, and future events. AB - Children's capacity to reason about temporal and causal relations among past, present, and future events was investigated. In two studies, 4- and 6-year-olds (N=160) received structurally analogous search and planning tasks that required retrospective or prospective temporal-causal reasoning, respectively. The search task was compared with a closely matched control task that did not require temporal-causal reasoning. Results revealed that (a) both age groups solved the control task, (b) 6-year-olds mastered both retrospective and prospective tasks, and (c) 4-year-olds showed limited competence in both retrospective and prospective tasks. The current study, thus, suggests that flexible temporal causal reasoning develops in parallel for past- and future-directed reasoning, is qualitatively different from simpler forms of temporal cognition, and develops during the late preschool years. PMID- 26037403 TI - Young children heed advice selectively. AB - A rational strategy to update and revise one's uncertain beliefs is to take advice by other agents who are better informed. Adults routinely engage in such advice taking in systematic and selective ways depending on relevant characteristics such as reliability of advisors. The current study merged research in social and developmental psychology to examine whether children also adjust their initial judgment to varying degrees depending on the characteristics of their advisors. Participants aged 3 to 6 years played a game in which they made initial judgments, received advice, and subsequently made final judgments. They systematically revised their judgments in light of the advice, and they did so selectively as a function of advisor expertise. They made greater adjustments to their initial judgment when advised by an apparently knowledgeable informant. This suggests that the pattern of advice taking studied in social psychology has its roots in early development. PMID- 26037404 TI - Simple arithmetic development in school age: The coactivation and selection of arithmetic facts. AB - We evaluated the possible inhibitory mechanism responsible for selecting arithmetic facts in children from 8 or 9 years to 12 or 13 years of age. To this end, we used an adapted version of the negative priming paradigm (NP paradigm) in which children received additions and they decided whether they were correct or not. When an addition was incorrect but the result was that of multiplying the operands (e.g., 2 + 4 = 8), only children from 10 or 11 years of age onward took more time to respond compared with control additions with unrelated results, suggesting that they coactivated arithmetic knowledge of multiplications even when it was irrelevant to perform the task. Furthermore, children from 10 or 11 years of age onward were slower to respond when the result of multiplying the operands was presented again in a correct addition problem (e.g., 2 + 6 = 8). This result showed the development of an inhibitory mechanism involved in the selection of arithmetic facts through formal education. PMID- 26037405 TI - MiR-2 family targets awd and fng to regulate wing morphogenesis in Bombyx mori. AB - MicroRNAs (miRNAs) are post-transcriptional regulators that target specific mRNAs for repression and thus play key roles in many biological processes, including insect wing morphogenesis. miR-2 is an invertebrate-specific miRNA family that has been predicted in the fruit fly, Drosophila melanogaster, to be involved in regulating the Notch signaling pathway. We show here that miR-2 plays a critical role in wing morphogenesis in the silkworm, Bombyx mori, a lepidopteran model insect. Transgenic over-expression of a miR-2 cluster using a Gal4/UAS system results in deformed adult wings, supporting the conclusion that miR-2 regulates functions essential for normal wing morphogenesis. Two genes, abnormal wing disc (awd) and fringe (fng), which are positive regulators in Notch signaling, are identified as miR-2 targets and validated by a dual-luciferase reporter assay. The relative abundance of both awd and fng expression products was reduced significantly in transgenic animals, implicating them in the abnormal wing phenotype. Furthermore, somatic mutagenesis analysis of awd and fng using the CRISPR/Cas9 system and knock-out mutants also resulted in deformed wings similar to those observed in the miR-2 overexpression transgenic animals. The critical role of miR-2 in Bombyx wing morphogenesis may provide a potential target in future lepidopteran pest control. PMID- 26037406 TI - Ex vivo biomechanical comparison of barbed suture and standard polypropylene suture for acute tendon laceration in a canine model. AB - OBJECTIVES: Evaluate performance and resistance to gap formation of a non absorbable, barbed, monofilament suture, in comparison with a non-absorbable, smooth, monofilament polypropylene suture, in two different suture patterns: three-loop pulley (3LP) and modified Bunnell-Mayer (BM). SAMPLE SIZE: Seventy-two medium-sized cadaveric superficial digital flexor muscle tendon units. METHODS: After manual transection and suture repair, individual specimens were placed in an electromechanical tensile testing machine and tested to monotonic failure using tensile ramp loading. Video data acquisition allowed evaluation of failure mode and quantification of gap formation. RESULTS: Incidence of gap formation between tendon ends was significantly greater in tenorrhaphies repaired with barbed suture compared to those repaired with smooth polypropylene. Use of a 3LP suture pattern caused significantly less gapping between tendon ends when compared to the BM pattern. CONCLUSION: Smooth polypropylene suture was consistently superior in load performance than a unidirectional barbed suture. The 3LP pattern was more resistant than a BM pattern at preventing gap formation. CLINICAL SIGNIFICANCE: Smooth polypropylene should be recommended over barbed unidirectional suture for use in canine tendinous repair to provide increased resistance to gap formation. The 3LP is superior to the BM suture pattern, requiring significantly more force to cause tenorrhaphy gap formation and failure, which may translate to increased accrual of repair site strength and tendinous healing in clinical situations. PMID- 26037408 TI - A family of Ru(II) complexes built on a novel sexipyridine building block: synthesis, photophysical properties and the rare structural characterization of a triruthenium species. AB - A new tris-2'',4'',6''-(2,2'-bipyridin-4-yl)-1'',3'',5''-triazine ligand and its family of ruthenium coordination complexes are described along with their characterization by electrochemical and photophysical methods as well as a rare single crystal X-ray analysis of a triruthenium polypyridine complex. PMID- 26037407 TI - Longitudinal mentorship to support the development of medical students' future professional role: a qualitative study. AB - BACKGROUND: Mentoring has been employed in medical education in recent years, but there is extensive variation in the published literature concerning the goals of mentoring and the role of the mentor. Therefore, there is still a need for a deeper understanding of the meaning of mentoring for medical students' learning and development. The aim of this qualitative study is to explore how formal and longitudinal mentoring can contribute to medical students' professional development. METHODS: Sixteen medical students at a Swedish university were interviewed individually about their experiences of combined group and one-to-one mentoring that is given throughout their studies. The mentoring programme was focused on the non-medical skills of the profession and used CanMEDS roles of a physician for students' self-assessment. Data were analysed using a latent, interpretive approach to content analysis. RESULTS: The results comprise three themes: Integrating oneself with one's future role as a physician, Experiencing clinical reality with the mentor creates incentives to learn and Towards understanding the professional competence of a physician. The mentorship enabled the students to create a view of their future professional role and to integrate it with their own personalities. The students' understanding of professional competence and behaviour evolved during the mentorship and they made advances towards understanding the wholeness of the profession. This approach to mentorship supported different components of the students' professional development; the themes Integrating oneself with one's future role and Towards understanding the professional competence of a physician can be regarded as two parallel processes, while the third theme, Experiencing clinical reality with the mentor creates incentives to learn, promotes these processes. CONCLUSIONS: Formalized and longitudinal mentoring focusing on the non-medical skills can be recommended to help medical students to integrate their professional role with themselves as individuals and promote understanding of professional competence in the process of becoming a physician. PMID- 26037409 TI - Epilepsy and Brugada syndrome. PMID- 26037410 TI - Green Phosphorescence and Electroluminescence of Sulfur Pentafluoride Functionalized Cationic Iridium(III) Complexes. AB - We report on four cationic iridium(III) complexes [Ir(C^N)2(dtBubpy)](PF6) that have sulfur pentafluoride-modified 1-phenylpyrazole and 2-phenylpyridine cyclometalating (C^N) ligands (dtBubpy = 4,4'-di-tert-butyl-2,2'-bipyridyl). Three of the complexes were characterized by single-crystal X-ray structure analysis. In cyclic voltammetry, the complexes undergo reversible oxidation of iridium(III) and irreversible reduction of the SF5 group. They emit bright green phosphorescence in acetonitrile solution and in thin films at room temperature, with emission maxima in the range of 482-519 nm and photoluminescence quantum yields of up to 79%. The electron-withdrawing sulfur pentafluoride group on the cyclometalating ligands increases the oxidation potential and the redox gap and blue-shifts the phosphorescence of the iridium complexes more so than the commonly employed fluoro and trifluoromethyl groups. The irreversible reduction of the SF5 group may be a problem in organic electronics; for example, the complexes do not exhibit electroluminescence in light-emitting electrochemical cells (LEECs). Nevertheless, the complexes exhibit green to yellow-green electroluminescence in doped multilayer organic light-emitting diodes (OLEDs) with emission maxima ranging from 501 nm to 520 nm and with an external quantum efficiency (EQE) of up to 1.7% in solution-processed devices. PMID- 26037412 TI - Statistics Notes: Bootstrap resampling methods. PMID- 26037411 TI - Sex differences in glia reactivity after cortical brain injury. AB - Several brain disorders associated with neuroinflammation show sex differences in their incidence, onset, progression and/or outcome. The different regulation of the neuroinflammatory response in males and females could underlie these sex differences. In this study, we have explored whether reactive gliosis after a penetrating cortical injury exhibits sex differences. Males presented a higher density of Iba1 immunoreactive cells in the proximity of the wound (0-220 MUm) than females. This sex difference was due to a higher number of Iba1 immunoreactive cells with nonreactive morphology. In addition microglia/macrophages in that region expressed arginase-1, marker of alternatively activated microglia, and the neuroprotective protein Neuroglobin, in a greater proportion in males than in females. No sex differences were found in the number of astrocytes around the lesion. However, the percentage of astrocytes expressing chemokine (C-C motif) ligand 2 (CCL2), involved in recruitment of immune cells and gliosis regulation, was higher in males. Males also presented a significantly higher density of neurons in the lesion edge than females. These findings indicate that male and female mice have different neuroinflammatory responses after a cortical stab wound injury and suggest that sex differences in reactive gliosis may contribute to sex differences in neuroinflammatory diseases. GLIA 2015;63:1966-1981. PMID- 26037413 TI - Evaluation of hypothermia on the in vitro metabolism and binding and in vivo disposition of midazolam in rats. AB - The effect of hypothermia on the in vivo pharmacokinetics of midazolam was evaluated, with a focus on altered metabolism in the liver and binding to serum proteins. Rat primary hepatocytes were incubated with midazolam (which is metabolized mainly by CYP3A2) at 37, 32 or 28 degrees C. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of midazolam were estimated using the Michaelis-Menten equation. The Km of CYP3A2 midazolam remained unchanged, but the Vmax decreased at 28 degrees C. In rats, whose temperature was maintained at 37, 32 or 28 degrees C by a heat lamp or ice pack, the plasma concentrations of midazolam were higher, whereas those in the brain and liver were unchanged at 28 degrees C. The tissue/plasma concentration ratios were, however, increased significantly. The unbound fraction of midazolam in serum at 28 degrees C was half that at 37 degrees C. These pharmacokinetic changes associated with hypothermic conditions were due to reductions in CYP3A2 activity and protein binding. PMID- 26037414 TI - Metabolic control, does it matter? PMID- 26037416 TI - Saturable Hepatic Extraction of Gemcitabine Involves Biphasic Uptake Mediated by Nucleoside Transporters Equilibrative Nucleoside Transporter 1 and 2. AB - Hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) is expected to be more effective and safer method to treat hepatic metastasis of pancreatic cancer compared with intravenous administration, because it affords higher tumor exposure with lower systemic exposure. Thus, a key issue for dose selection is the saturability of hepatic uptake of GEM. Therefore, we investigated GEM uptake in rat and human isolated hepatocytes. Hepatic GEM uptake involved high- and low affinity saturable components with Km values of micromolar and millimolar order, respectively. The uptake was inhibited concentration dependently by S-(4 nitrobenzyl)-6-thioinosine (NBMPR) and was sodium-ion-independent, suggesting a contribution of equilibrative nucleoside transporters (ENTs). The concentration dependence of uptake in the presence of 0.1 MUM NBMPR showed a single low affinity binding site. Therefore, the high- and low-affinity sites correspond to ENT1 and ENT2, respectively. Our results indicate hepatic extraction of GEM is predominantly mediated by the low-affinity site (hENT2), and at clinically relevant hepatic concentrations of GEM, hENT2-mediated uptake would not be completely saturated. This is critical for HAI, because saturation of hepatic uptake would result in a marked increase of GEM concentration in the peripheral circulation, abrogating the advantage of HAI over intravenous administration in terms of severe adverse events. PMID- 26037417 TI - Spinal 5-HT1A, not the 5-HT1B or 5-HT3 receptors, mediates descending serotonergic inhibition for late-phase mechanical allodynia of carrageenan induced peripheral inflammation. AB - Previous electrophysiological studies demonstrated a limited role of 5 hydroxytryptamine 3 receptor (5-HT3R), but facilitatory role of 5-HT1AR and 5 HT1BR in spinal nociceptive processing of carrageenan-induced inflammatory pain. The release of spinal 5-HT was shown to peak in early-phase and return to baseline in late-phase of carrageenan inflammation. We examined the role of the descending serotonergic projections involving 5-HT1AR, 5-HT1BR, and 5-HT3R in mechanical allodynia of early- (first 4h) and late-phase (24h after) carrageenan induced inflammation. Intrathecal administration of 5-HT produced a significant anti-allodynic effect in late-phase, but not in early-phase. Similarly, intrathecal 5-HT1AR agonist (8-OH-DPAT) attenuated the intensity of late-phase allodynia in a dose dependent fashion which was antagonized by 5-HT1AR antagonist (WAY-100635), but produced no effect on the early-phase allodynia. However, other agonists or antagonists of 5-HT1BR (CP-93129, SB-224289) and 5-HT3R (m-CPBG, ondansetron) did not produce any anti- or pro-allodynic effect in both early- and late- phase allodynia. These results suggest that spinal 5-HT1A, but not 5-HT1B or 5-HT3 receptors mediate descending serotonergic inhibition on nociceptive processing of late-phase mechanical allodynia in carrageenan-induced inflammation. PMID- 26037419 TI - Sex on show. Issues of privacy and dignity in a Forensic mental health hospital: Nurse and patient views. AB - AIMS AND OBJECTIVES: To explore perceptions of privacy and dignity for sexual relationships in a Forensic mental health hospital. BACKGROUND: The role of nurses in forensic mental health hospitals is frequently complicated by opposing expectations of therapeutic relationships and maintaining security. What can result is an over-emphasis on risk reduction by controlling patient behaviour, which can extend to patient intimacy and sexual relationships. DESIGN: An exploratory, qualitative approach. METHODS: Individual interviews were conducted with 12 nurses and 10 patients in a forensic mental health hospital. Thematic data analysis was undertaken to identify the main themes. RESULTS: The need for a private and dignified place for patient intimacy was one major theme to emerge from this research from both nurse and patient participants and is the focus of this article. A disparity is reported between the level of support reported by nurse participants with the experience of the patient participants. CONCLUSIONS: Sexual intimacy and sexual relationships are important components of normal human behaviour. Institutional rules and rule adherence create barriers for patients, forcing their intimacy and sexual relationships into secrecy. There is a need for further research to consider the benefits and risks of patient intimacy and sexual relationships for long-term patients in forensic mental health settings. RELEVANCE TO CLINICAL PRACTICE: Patients in forensic hospitals are sexually active and seek support from nurses. Nurses are in an ideal role to recognise the important part they can play in supporting the intimacy and sexual relationship needs of patients. Strategies to assist in developing confidence in responding to normal human behaviour is a matter of priority. PMID- 26037418 TI - Pharmacological stimulation of hypoxia inducible factor-1alpha facilitates the corticosterone response to a mild acute stressor. AB - While both glucocorticoids (the principal output of the hypothalamic-pituitary adrenal axis) and oxidative stress have been implicated in outcomes due to an excessive or prolonged stress response, the precise mechanisms linking these two systems remain poorly elucidated. One potential mediator between the hypothalamic pituitary-adrenal axis and oxidative stress is the hypoxia inducible factor-1 (HIF-1) pathway. HIF-1 is an oxygen-responsive transcription factor with diverse effects including changes in cellular metabolism. The experiments in this manuscript sought to determine if pharmacological stimulation of HIF-1alpha via administration of dimethyloxalylglycine (DMOG) would facilitate the corticosterone response to a mild acute stressor. DMOG administration significantly increased plasma corticosterone 5 min after an acute airpuff without changing baseline plasma corticosterone or plasma corticosterone level two hours post-startle. DMOG administration also reduced hippocampal gene expression of the pro-translocation co-chaperone for the glucocorticoid receptor, FKBP4, two hours after airpuff startle. At this same two-hour time point, hippocampal expression of FKBP5, an anti-translocation co-chaperone of the glucocorticoid receptor, in the DMOG-treated group was also positively correlated with plasma corticosterone levels. These data indicate that there is significant crosstalk between the hypothalamic-pituitary-axis and the HIF-1 pathway and extend the current knowledge of glucocorticoid and hypoxia interactions in an ethologically relevant stress model. PMID- 26037421 TI - Rotavirus vaccines at the threshold of implementation in India. AB - India is poised to introduce rotavirus vaccines into its routine childhood immunization programme. Substantial data ara available on disease and economic burden of rotavirus gastroenteritis and on circulating strains in India, which highlight the public health need for a rotavirus vaccine. A locally manufactured oral rotavirus vaccine has been licensed in India and it has been shown to be effective against severe rotavirus gastroenteritis in Indian children. The Government of India has announced that the vaccine will be included in the universal immunization n programme. Careful planning and preparation for post licensure impact and safety evaluations will ensure that additional high quality benefit-risk data will be available for India. PMID- 26037422 TI - Factoids and critical care. PMID- 26037423 TI - Undiagnosed mandibular condylar fractures causing temporomandibular joint ankylosis: A problem in northern India. AB - BACKGROUND: Temporomandibular joint (TMJ) ankylosis due to undiagnosed condylar fractures has a high incidence in India compared to western countries. We evaluated the demographics, injury pattern, hospital reporting and referral pattern of undiagnosed condylar fractures complicating TMJ ankylosis in northern India. METHODS: We did a retrospective analysis by retrieving medical records of patients with post-traumatic TMJ ankylosis reporting to the Department of Oral and Maxillofacial Surgery, All India Institute of Medical Sciences between 1 July 2012 and 30 June 2013. RESULTS: Of 90 patients with post-traumatic TMJ ankylosis, 74 (82.2%) resided in rural areas. Sixty-three (70%) patients were from the states of Uttar Pradesh, Bihar and Jharkhand. Only 8.8% had higher education and 10% had an annual income of more than '2 lakh. In 69 (84.4%) patients, fall was the aetiological factor. Primary health centres (42%) and private clinics (20.5%) received the major share of patients immediately following injury. Few patients (19.3%) had some radiographic examination done and only 17% were referred by the primary healthcare provider. Of those referred only 3 were examined by a dental practitioner. Only 10% of all were diagnosed with condylar fractures. CONCLUSION: Patients with TMJ ankylosis presenting to us have poor literacy and income levels. A missed diagnosis of condylar fractures by rural healthcare providers contributes to its high incidence in India. Improving awareness of clinicians and improved rural healthcare infrastructure can help prevent this complication. PMID- 26037424 TI - Detection of comorbid illnesses during pre-anaesthesia evaluation in a university teaching hospital: A prospective observational study. AB - BACKGROUND: Consultation for surgery and anaesthesia is often the first point of contact with a healthcare provider for a majority of patients in developing countries. In India, where patients have poor access to healthcare, they are likely to present with uncontrolled/untreated/undetected coexisting diseases. However, there is little published literature on this aspect. We hypothesized that many of our patients will present to our pre-anaesthesia evaluation clinic (PAC) with undetected comorbid illnesses and will require proper assessment, treatment and optimization before surgery. Thus, we aimed to assess the frequency and type of comorbid illnesses in patients attending the pre-anaesthesia clinic for elective surgery. METHODS: We did a prospective observational study on all patients evaluated in the PAC of our university teaching hospital over a 3-month period to assess the frequency and type of comorbid illnesses. The data recorded included demographic profile and presence of coexisting illness and was classified as preexisting or newly diagnosed at the time of the visit to the PAC. The data were then tabulated and analysed statistically using SPSS software version 14.0. The frequency and percentage of occurrence for each comorbid illness was determined. RESULTS: Of 3973 patients, 242 (6%) had 304 comorbid illnesses (135 cardiac, 54 endocrine, 15 respiratory, 12 others). Of these 88 (29%) were newly detected comorbid conditions (69 cardiac, 9 endocrine, 9 respiratory, 1 others). The most frequent comorbid illness both pre-existing and newly diagnosed were cardiac. Hypertension was the commonest problem in our study population (168 patients). CONCLUSION: We confirmed that a PAC can detect hitherto undetected comorbid illnesses which are likely to impact the perioperative process. PMID- 26037425 TI - Malignant hyperthermia in a young adolescent: A case report. AB - A 15-year-old girl developed symptoms suggestive of malignant hyperthermia during a laparoscopic appendicectomy for acute appendicitis. The triad of masseter spasm, hypercarbia and hyperthermia within 30 minutes of exposure to triggering factors was present and was treated successfully with dantrolene. She is among a handful of cases known locally. The problems faced in the post-acute phase included the development of thrombophlebitis due to dantrolene use in our patient, as well as paucity of testing centres for malignant hyperthermia both locally and in the region. This prevented us from making a definitive diagnosis in our patient. PMID- 26037426 TI - Bariatric surgery: An overview. PMID- 26037427 TI - Protocol-based care for early septic shock. PMID- 26037428 TI - Pasireotide for prevention of pancreatic leak: Is there light at the end of the tunnel? PMID- 26037429 TI - Is double-fortified salt a panacea for iron-deficiency anaemia in India? PMID- 26037430 TI - Student-centred learning in Community Medicine: An experience from Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry. AB - BACKGROUND: Student-centred learning (SCL) places the student at the centre of policies, practices and decision-making in the teaching-learning process. SCL methodology also advocates active involvement of students in the curriculum planning, selection of teaching-learning methods and assessment process. We planned an education innovation project to assess the perception of fifth semester undergraduate medical students towards implementation of an SCL methodology. METHODS: The study was done among 87 fifth semester undergraduate medical students (batch of 2010-11) in the noncommunicable disease epidemiology section of Community Medicine at the Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry. The students divided themselves into seven groups and developed the learning objectives, selected teaching-learning methods and assessment process for each session. The facilitators had 3-5 rounds of interaction with each group before the session. Qualitative analysis of feedback collected from students and external faculty after each session was done. The effect of implementing the SCL methodology was assessed by the reaction level of Kirkpatrick's training evaluation model by using a rating scale Results. Of the 87 eligible students, 73 (83.9%) returned the forms for evaluation. All seven groups were able to formulate the learning objectives. Most of the groups had used PowerPoint slides and videos as a teaching-learning tool. Innovative assessment methods such as crosswords and 'chocopati' were used by some groups. In general, the perception of students was favourable towards SCL compared to conventional methods and they felt that this methodology should be adopted more often. Time management and organization of sessions were the main problems encountered by the students. The mean (SD) score for the items 'sessions were useful', 'sessions were enjoyable' and 'sessions improved my knowledge' were 6.2 (1.8), 7.1 (1.8) and 6.3 (1.9), respectively. CONCLUSION: The majority of students found the sessions on innovative teaching-learning and assessment techniques enjoyable, useful and informative. The sessions showed that students took an active part in curriculum planning, execution and evaluation. PMID- 26037431 TI - Sensitizing undergraduate medical students to consultation skills: A pilot study. AB - BACKGROUND: Good consultation skills help physicians to diagnose the problems of the patient more accurately, and foster a therapeutic relationship. We describe a pilot study that used role-play with peers as a method to sensitize first clinical year medical students to consultation skills Methods. Students were divided into groups of three where one acted as a doctor, the second as a patient and the third as an observer. Students were asked to perform a role-play of a prepared clinical scenario where the patient had a hidden fear of malignancy. Observations were recorded in a simplified Calgary-Cambridge consultation checklist. Students' feedback and their emotions written after the role-play were analysed and discussed. Assessment of their learning was done with an objective structured clinical examination. RESULTS: Students' feedback revealed that they were sensitized to the importance of starting the consultation with an open question, listening to the opening statement, non-verbal. PMID- 26037432 TI - Maternal healthcare and perinatal mortality among brick kiln migrant workers: A case study. PMID- 26037433 TI - Surgeon Captain I.K. Indrajit. PMID- 26037435 TI - Letter from Bristol. PMID- 26037441 TI - Acquired generalized ichthyosis in chronic myeloid leukaemia. PMID- 26037442 TI - Letter from Ganiyari. PMID- 26037443 TI - Compact fluorescent lamps: Advantages and health issues. PMID- 26037444 TI - A handicap to the growth of quality radiology in India. PMID- 26037445 TI - Cardiac tamponade: A rare presenting manifestation of systemic lupus erythematosus. PMID- 26037446 TI - Why do we submit double-space manuscripts to medical journals? PMID- 26037447 TI - An innovative test for rapid diagnosis of malaria. PMID- 26037448 TI - Ebola virus outbreak, a 'Public Health Emergency of International Concern'. PMID- 26037449 TI - Japanese encephalitis, rotavirus, rubella and injectable polio vaccine: Four new tools in the immunization programme of India. PMID- 26037450 TI - Prophylactic use of aspirin can reduce the incidence of colonic and other cancers. PMID- 26037451 TI - Social structure and space use of Amur tigers (Panthera tigris altaica) in Southern Russian Far East based on GPS telemetry data. AB - To better understand the spatial structure of Amur tigers (Panthera tigris altaica) at the southern edge of their range we fitted 14 tigers (6?? and 8??) with 15 GPS-Argos collars between 2008 and 2011 in 2 study sites: the Ussuriskii Reserve of southern Sikhote-Alin and the Land of the Leopard National Park in southwest Primorye, Russian Far East. Fixed kernel estimates of male home ranges were larger than those of female home ranges (P < 0.05 [mean 95% fixed kernel(?) = 401 +/- 205 km(2) ; mean 95% fixed kernel(?) = 778 +/- 267 km(2)]). The home range size of females varied greatly, but on average was similar to estimates derived from earlier work further north. Low overlap of adjacent home ranges suggested that females retained exclusive territories. Real core areas of females overlapped only slightly, and remained stable over multiple years. The home ranges of adult males were smaller than those of males to the north, and in contrast to previous studies, high overlap among males indicated the absence of territoriality. Nonetheless, real core areas of males did not overlap, suggesting some spatial separation. In comparison to other tiger populations and other areas of the Russian Far East, the sex ratio in our 2 study areas was highly skewed towards males. We believe this skewed sex ratio resulted in the dissolution of territoriality of males due to an inability to defend individual females, with males resorting to scramble competition for mates. Continued monitoring of these sites to determine whether shifts in the sex ratio might result in a return to male territoriality would provide confirmation of our tentative hypothesis. PMID- 26037452 TI - Natriuretic peptide control of energy balance and glucose homeostasis. AB - Cardiac natriuretic peptides (NP) have recently emerged as metabolic hormones. Physiological stimulation of cardiac NP release as during exercise may contribute to increase fatty acid mobilization from adipose tissue and their oxidation by skeletal muscles. Clinical studies have shown that although very high plasma NP level characterizes cardiac dysfunction and heart failure, a consistently reduced plasma NP level is observed in metabolic diseases such as obesity and type 2 diabetes. A low circulating NP level also predicts the risk of new onset type 2 diabetes. It is unclear at this stage if the "natriuretic handicap" observed in obesity is causally associated with the incidence of type 2 diabetes. Recent work indicates that NP can activate a thermogenic program in brown and white fat, increase energy expenditure and inhibit food intake. Mouse studies also argue for a key role of NP in the regulation of energy balance and glucose homeostasis. This review will focus on recent human and mouse studies to highlight the metabolic roles of NP and their potential relevance in the context of obesity and type 2 diabetes. PMID- 26037453 TI - Accurate cortical tissue classification on MRI by modeling cortical folding patterns. AB - Accurate tissue classification is a crucial prerequisite to MRI morphometry. Automated methods based on intensity histograms constructed from the entire volume are challenged by regional intensity variations due to local radiofrequency artifacts as well as disparities in tissue composition, laminar architecture and folding patterns. Current work proposes a novel anatomy-driven method in which parcels conforming cortical folding were regionally extracted from the brain. Each parcel is subsequently classified using nonparametric mean shift clustering. Evaluation was carried out on manually labeled images from two datasets acquired at 3.0 Tesla (n = 15) and 1.5 Tesla (n = 20). In both datasets, we observed high tissue classification accuracy of the proposed method (Dice index >97.6% at 3.0 Tesla, and >89.2% at 1.5 Tesla). Moreover, our method consistently outperformed state-of-the-art classification routines available in SPM8 and FSL-FAST, as well as a recently proposed local classifier that partitions the brain into cubes. Contour-based analyses localized more accurate white matter-gray matter (GM) interface classification of the proposed framework compared to the other algorithms, particularly in central and occipital cortices that generally display bright GM due to their highly degree of myelination. Excellent accuracy was maintained, even in the absence of correction for intensity inhomogeneity. The presented anatomy-driven local classification algorithm may significantly improve cortical boundary definition, with possible benefits for morphometric inference and biomarker discovery. PMID- 26037454 TI - Teaching of clinical anatomy in rheumatology: a review of methodologies. AB - Clinical anatomy may be defined as anatomy that is applied to the care of the patient. It is the foundation of a well-informed physical examination that is so important in rheumatologic practice. Unfortunately, there is both documented and observed evidence of a significant deficiency in the teaching and performance of a competent musculoskeletal examination at multiple levels of medical education including in rheumatology trainees. At the Annual Meeting of the American College of Rheumatology in Boston, MA, that took place in November 2014, a Clinical Anatomy Study Group met to share techniques of teaching clinical anatomy to rheumatology fellows, residents, and students. Techniques that were reviewed included traditional anatomic diagrams, hands-on cross-examination, cadaver study, and musculoskeletal ultrasound. The proceedings of the Study Group section are described in this review. PMID- 26037455 TI - Who is holding the baby? Women's experiences of contact with their baby immediately after birth: An Australian population-based survey. AB - BACKGROUND: Seeing and holding their baby immediately after the birth is the pinnacle of the childbearing process for parents. Few studies have examined women's experiences of seeing and holding their baby immediately after birth. We investigated women's experiences of initial contact with their newborns using data from an Australian population-based survey. METHODS: All women who gave birth in September/October in 2007 in two Australian states were mailed questionnaires six months following the birth. Women were asked three questions about early newborn contact including where their baby was held in the first hour after birth and whether they were able to hold their baby as soon and for as long as they liked. We examined the association between model of maternity care and early newborn contact stratified by admission to SCN/NICU. RESULTS: The majority (92%) of women whose babies remained with them reported holding their babies as soon and for as long as they liked in the first hour after birth. However, for women whose babies were admitted to SCN/NICU only a minority (47%) reported this. Women in public models of care (with the exception of primary midwifery care) whose babies remained with them were less likely to report holding their babies as soon and for as long as they liked compared to women in private care. CONCLUSION: Our findings suggest that there is potential to increase the proportion of mothers and fathers who get to hold their baby immediately after the birth by modifying birth suite and operating room practices. PMID- 26037456 TI - Adjustment following chronic spinal cord injury: Determining factors that contribute to social participation. AB - OBJECTIVES: Spinal cord injury (SCI) is a catastrophic event that may result in diminished physical, social, and mental health. The main objective of this research was to establish inpatient factors that contribute to social participation following discharge into the community. DESIGN: Prospective longitudinal design with measures taken three times, soon after admission to rehabilitation (N = 88), at discharge from the inpatient phase (N = 81) and 6 months following discharge (N = 71). METHODS: Participants included adults with SCI admitted into three SCI units over a 33-month period. Assessment included demographic, injury, and psychosocial health measures. Adjustment was defined by the extent of social re-integration or participation post-discharge after 6 months in the community. Social participation was measured by the Impact on Participation and Autonomy Questionnaire (IPAQ). Logistic regression models were used to establish inpatient factors that significantly predicted social participation 6 months post-discharge. RESULTS: Six months after discharge, around 55% of the sample had difficulties with social participation. The odds against being employed for an adult with poor social participation was found to be 8.4 to 1. Factors that predicted social participation included a younger age, having less severe secondary medical complications like bladder and bowel dysfunction, having a higher cognitive capacity, perceiving one has control (self efficacy) over one's life and environment, and having greater perceived social support. CONCLUSIONS: These results provide direction for enhancing existing psychosocial health strategies within SCI rehabilitation, affording an opportunity for every person who sustains a permanent SCI to have optimal capacity for social participation. Statement of contribution What is already known on this subject? Spinal cord injury (SCI) is associated with significant challenges to wellbeing, including a high risk of secondary chronic illnesses, risk of co-morbid mental health problems, financial insecurity and social isolation. Research has shown poor social participation can lead to problems in re-integration into society following discharge from inpatient rehabilitation. Research to date has examined various factors related to poor social participation, but the majority of this research has been survey based with convenience samples. What does this study add? This study adds results of prospective longitudinal research on adjustment following SCI, where adjustment was defined by the rate of social participation when living in the community. About one-third of SCI participants were found to have very poor social participation, and only one-third had found some form of employment 6 months after discharge. Multiple factors were found to predict and contribute to poor social participation, including older age when injured, more severe medical complications, cognitive deficits, poor perceptions of control or self-efficacy, and poor social support. PMID- 26037457 TI - Antidepressive treatments for Parkinson's disease: A systematic review and meta analysis. AB - CONTEXT: Depression affects 50-70% of patients with Parkinson's disease resulting in significant comorbidity, executive dysfunction, and poorer quality of life. Divergent results from studies of different treatments preclude definite treatment recommendations. OBJECTIVE: To perform a systematic review and meta analysis of published randomized controlled trials (RCTS) evaluating the efficacy of pharmacologic and behavioral interventions, and repetitive transcranial magnetic stimulation (rTMS) for depression among patients with idiopathic Parkinson's disease. DATA SOURCES: Trial registers and the following databases were searched: PubMed, CINAHL, EMBASE, and PsycInfo. Bibliographies of relevant articles were cross-referenced. STUDY SELECTION AND DATA EXTRACTION: RCTs comparing pharmacologic, behavioral, or rTMS with a placebo/other drugs or methods with no restrictions on participant age, gender, and duration or setting of treatment were included. Eligibility assessment was performed independently. Identified records were sequentially screened according to eligibility criteria. Differences in mean depression score and 95% confidence intervals were calculated. RESULTS: A total of 893 idiopathic Parkinson's disease patients with clinical depression across 20 RCTs were included. The overall standard mean difference for all pharmacologic interventions was 0.30 (95% CI -0.00, 0.61, p = 0.054). On stratification, there was a distinct difference in effect between antidepressants (SMD of 0.54, 95%CI 0.24, 0.83, p = 0.000) and non antidepressants (SMD of -0.29, 95% CI -0.86, 0.29, p = 0.328). Behavioral interventions demonstrated significant efficacy with an effect size of 0.87 (95% CI 0.41, 1.33, p = 0.000). CONCLUSIONS: This meta-analysis demonstrates that pharmacologic treatment with antidepressant medications, specifically the selective serotonin reuptake inhibitors (SSRIs), and behavioral interventions (CBT) significantly improved depression among Parkinson's disease patients. PMID- 26037458 TI - Cognitive reserve and beta-amyloid pathology in Parkinson disease. AB - INTRODUCTION: Dementia in Parkinson disease (PD) is associated with abnormal accumulation of proteins, including beta-amyloid, in cortical regions. High cognitive reserve capacity may protect cognition from beta-amyloid and delay the onset of dementia. We tested the cognitive reserve theory in PD by determining whether educational attainment, a proxy for cognitive reserve, modifies the correlation between cortical beta-amyloid accumulation and cognitive impairment. METHODS: PD participants (N = 155) underwent MRI to quantify brain volume and [(11)C] PiB PET imaging to quantify fibrillar beta-amyloid deposition. Mean cortical binding potentials (MCBP) were calculated for each participant, with higher scores indicating more fibrillar beta-amyloid. Global cognitive function was assessed using the Clinical Dementia Rating (CDR) and Mini-Mental State Examination (MMSE). Multiple linear regression analysis was used to determine whether education modified the relationship between MCBP and cognitive function after controlling for brain volume. RESULTS: MCBP interacted with educational attainment to predict scores on each of the cognitive outcome measures (ps <= 0.02). Post-hoc analysis revealed that the effect of MCBP on cognitive function changed once the level of education reached 16 years. For participants with less than 16 years of education (n = 68), higher MCBP correlated with worse cognitive function, with MCBP accounting for 8-30% of the variance in MMSE and CDR scores (ps <= 0.02). For participants with at least 16 years of education (n = 87), MCBP did not correlate with MMSE or CDR scores (R(2)s < 0.02, ps >= 0.17). CONCLUSION: These findings provide support for the cognitive reserve theory in PD and suggest that education may protect PD patients' cognition against cortical beta-amyloid pathology. PMID- 26037459 TI - The association between infectious burden and Parkinson's disease: A case-control study. AB - INTRODUCTION: The etiology of Parkinson's disease (PD) remains unclear. The aim of this study was to examine the association between common pathogenic infections and PD. METHODS: Antibody titers to common infectious pathogens including cytomegalovirus (CMV), Epstein Barr virus (EBV),herpes simplex virus type-1 (HSV 1), Borrelia burgdorferi (B. burgdorferi), Chlamydophila pneumoniae (C. pneumoniae) and Helicobacter pylori (H. pylori) were measured by ELISA in serum of 131 PD patients and 141 normal controls. Infectious burden (IB) was defined as a composite serologic measure of exposure to these common pathogens. RESULTS: Seropositivities toward zero-two, three-four and five-six of these pathogens were found in 11%, 74% and 15% of normal controls while in 4%, 61% and 35% of PD patients, respectively. IB, bacterial burden and viral burden were independently associated with PD. Schwab and England (S&E) scores were negatively correlated with IB in patients with PD. Serum alpha-synuclein protein levels and inflammatory cytokines (interleukin-1beta and interleukin-6) in individuals with higher IB were also significantly higher. CONCLUSIONS: IB consisting of CMV, EBV, HSV-1, B. burgdorferi, C. pneumoniae and H. pylori is associated with PD. This study supports the role of infection in the etiology of PD. PMID- 26037460 TI - Is Reducing Dietary Sodium Helpful in Reducing Blood Pressure and Cardiovascular Disease Risk? An Argument Generated From the PURE Study. PMID- 26037461 TI - Paracoccus denitrificans possesses two BioR homologs having a role in regulation of biotin metabolism. AB - Recently, we determined that BioR, the GntR family of transcription factor, acts as a repressor for biotin metabolism exclusively distributed in certain species of alpha-proteobacteria, including the zoonotic agent Brucella melitensis and the plant pathogen Agrobacterium tumefaciens. However, the scenario is unusual in Paracoccus denitrificans, another closely related member of the same phylum alpha proteobacteria featuring with denitrification. Not only does it encode two BioR homologs Pden_1431 and Pden_2922 (designated as BioR1 and BioR2, respectively), but also has six predictive BioR-recognizable sites (the two bioR homolog each has one site, whereas the two bio operons (bioBFDAGC and bioYB) each contains two tandem BioR boxes). It raised the possibility that unexpected complexity is present in BioR-mediated biotin regulation. Here we report that this is the case. The identity of the purified BioR proteins (BioR1 and BioR2) was confirmed with LC-QToF-MS. Phylogenetic analyses combined with GC percentage raised a possibility that the bioR2 gene might be acquired by horizontal gene transfer. Gel shift assays revealed that the predicted BioR-binding sites are functional for the two BioR homologs, in much similarity to the scenario seen with the BioR site of A. tumefaciens bioBFDAZ. Using the A. tumefaciens reporter system carrying a plasmid-borne LacZ fusion, we revealed that the two homologs of P. denitrificans BioR are functional repressors for biotin metabolism. As anticipated, not only does the addition of exogenous biotin stimulate efficiently the expression of bioYB operon encoding biotin transport/uptake system BioY, but also inhibits the transcription of the bioBFDAGC operon resembling the de novo biotin synthetic pathway. EMSA-based screening failed to demonstrate that the biotin-related metabolite is involved in BioR-DNA interplay, which is consistent with our former observation with Brucella BioR. Our finding defined a complex regulatory network for biotin metabolism in P. denitrificans by two BioR proteins. PMID- 26037462 TI - Paradoxical role of PKA inhibitor on amyloidbeta-induced memory deficit. AB - In spite of characterizing the role of protein kinase A (PKA) in activating biochemical mechanisms, few studies have investigated the effects of PKA inhibitors on memory functions. In the present study, we used Pavlovian fear conditioning paradigm to evaluate memory alterations caused by two doses of H89 (as a conditional inhibitor of PKA) alone and in combination with amyloid-beta (Abeta) in rats. Moreover, we used the Western blotting method to investigate the alterations in markers of transcription, oxidative stress, inflammation, and apoptosis pathways involved in memory impairment. Stereotaxic surgery was done to inject Abeta (30 ng/side) directly into the hippocampal CA1 area bilaterally and H89 (5 or 10 MUM) intracerebroventricular unilaterally. One series of rats were trained 7 days after injections, then contextual and tone tests were conducted on days 8 and 9, respectively. Second series of rats were trained 14 days after the injections and tests were carried out on days 15 and 16. Our behavioral results showed that H89 (5 MUM) not only has no destructive effect on memory, but also attenuates memory deficit caused by Abeta in combination groups. In contrast, H89 (10MUM) has a reversible destructive effect on memory. Our molecular findings indicated that low dose of H89 increases CREB phosphorylation, Nrf2 and HO-1 which results in survival resistance to the stress. On the contrary, H89 with higher concentration leads to substantial increase of NF-kappaB and caspase-3 levels, which impair memory functions. In conclusion, our data suggest that H89 as a PKA inhibitor influences memory process through a dose and time dependent manner. PMID- 26037463 TI - Functional expression of a heterologous nickel-dependent, ATP-independent urease in Saccharomyces cerevisiae. AB - In microbial processes for production of proteins, biomass and nitrogen containing commodity chemicals, ATP requirements for nitrogen assimilation affect product yields on the energy producing substrate. In Saccharomyces cerevisiae, a current host for heterologous protein production and potential platform for production of nitrogen-containing chemicals, uptake and assimilation of ammonium requires 1 ATP per incorporated NH3. Urea assimilation by this yeast is more energy efficient but still requires 0.5 ATP per NH3 produced. To decrease ATP costs for nitrogen assimilation, the S. cerevisiae gene encoding ATP-dependent urease (DUR1,2) was replaced by a Schizosaccharomyces pombe gene encoding ATP independent urease (ure2), along with its accessory genes ureD, ureF and ureG. Since S. pombe ure2 is a Ni(2+)-dependent enzyme and Saccharomyces cerevisiae does not express native Ni(2+)-dependent enzymes, the S. pombe high-affinity nickel-transporter gene (nic1) was also expressed. Expression of the S. pombe genes into dur1,2Delta S. cerevisiae yielded an in vitro ATP-independent urease activity of 0.44+/-0.01 umol min(-1) mg protein(-1) and restored growth on urea as sole nitrogen source. Functional expression of the Nic1 transporter was essential for growth on urea at low Ni(2+) concentrations. The maximum specific growth rates of the engineered strain on urea and ammonium were lower than those of a DUR1,2 reference strain. In glucose-limited chemostat cultures with urea as nitrogen source, the engineered strain exhibited an increased release of ammonia and reduced nitrogen content of the biomass. Our results indicate a new strategy for improving yeast-based production of nitrogen-containing chemicals and demonstrate that Ni(2+)-dependent enzymes can be functionally expressed in S. cerevisiae. PMID- 26037464 TI - A hierarchical (multicomponent) model of in-group identification: examining in Russian samples. AB - The aim of this study was to examine the validity and reliability of Leach et al.'s (2008) model of in-group identification in two studies using Russian samples (overall N = 621). In Study 1, a series of multi-group confirmatory factor analysis revealed that the hierarchical model of in-group identification, which included two second-order factors, self-definition (individual self stereotyping, and in-group homogeneity) and self-investment (satisfaction, solidarity, and centrality), fitted the data well for all four group identities (ethnic, religious, university, and gender) (CFI > .93, TLI > .92, RMSEA < .06, SRMR < .06) and demonstrated a better fit, compared to the alternative models. In Study 2, the construct validity and reliability of the Russian version of the in group identification measure was examined. Results show that these measures have adequate psychometric properties. In short, our results show that Leach et al.'s model is reproduced in Russian culture. The Russian version of this measure can be recommended for use in future in-group research in Russian-speaking samples. PMID- 26037465 TI - Erratum to: Disseminated oligodendroglial-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity. PMID- 26037466 TI - Dendritic cell immunotherapy for brain tumors. AB - Glioblastomas are characterized by immunosuppression, rapid proliferation, angiogenesis, and invasion into the surrounding brain parenchyma. Limitations in current therapeutic approaches have spurred the development of personalized, patient-specific treatments. Among these, active immunotherapy has emerged as a viable option for glioma treatment. The ability to generate an immune response utilizing patient-derived dendritic cells (DCs) (professional antigen-presenting cells) is especially attractive. This approach to glioma treatment allows for the immunologic targeting and destruction of malignant cells. Data acquired in multiple pre-clinical models and clinical trials have shown significant responses and prolonged survival. Here we provide an overview of the current status of DC vaccination for the treatment of gliomas. PMID- 26037467 TI - The treatment of simple elbow dislocation in adults. AB - BACKGROUND: Simple elbow dislocation is a complex soft-tissue injury that can cause permanent symptoms. Its incidence is 5 to 6 cases per 100 000 persons per year. Its proper treatment is debated; options range from immobilization in a cast to surgical intervention. METHODS: We systematically reviewed the literature on the treatment of simple elbow dislocation and performed a meta-analysis, primarily on the basis of clinical scores and secondarily with respect to pain, range of motion, and return to work. RESULTS: A randomized controlled trial (RCT) showed that clinical results at short-term follow-up were superior for early functional treatment compared to immobilization in a cast. Brief immobilization, however, reduced pain initially, and the long-term results of early mobilization and immobilization in a cast were the same. Our meta-analysis showed that early mobilization enables patients to return to work earlier (difference of mean values -2.91, 95% confidence interval [CI] -3.18 to -2.64), and that the extent of soft-tissue injury is correlated with the clinical outcome (inverse relationship; difference of mean values -12.07, 95% CI -23.88 to -0.26). Surgical and conservative treatment were compared in a single RCT, which revealed no significant difference in outcomes. A meta-analysis of two retrospective comparative studies showed no advantage of immediate ligament repair over delayed surgery. CONCLUSION: Early functional treatment is the evidence-based therapeutic standard for simple elbow dislocation. The past few years have seen further developments in surgery for simple elbow dislocation. Further study is needed to determine whether surgery for elbow dislocation with high-grade instability can prevent persistent pain, limitation of motion, and chronic instability. PMID- 26037468 TI - Secondary Malignancies Following Treatment for Hodgkin's Lymphoma in Childhood and Adolescence. AB - BACKGROUND: About 155 persons under age 18 develop Hodgkin's lymphoma (HL) in Germany every year. More than 90% survive at least 20 years. They may, however, suffer from late sequelae of treatment, including secondary malignant neoplasia (SMN). METHODS: 2548 patients from the German, Austrian, and Swiss pediatric Hodgkin's lymphoma studies that were conducted over the period 1978-2002 were asked every 2-3 years about possible late sequelae of treatment, either directly or through their physicians. The documented cases of SMN were analyzed for cumulative incidence, standardized incidence rates (SIR), and absolute excess risk (AER). RESULTS: 147 cases of SMN were diagnosed in 138 of the 2548 patients, including 47 cases of thyroid cancer, 37 of breast cancer, and 15 of hematopoietic neoplasia. The cumulative incidence of SMN at 20, 25, and 30 years was 7% , 11.2% , and 18.7% , respectively. These percentages are rather low compared to other international studies. For all types of SMN, the SIR was 9.1 and the AER was 16.8. Among the 123 patients with secondary solid tumors, 105 (85% ) had a tumor in the irradiated region. CONCLUSION: Survivors of pediatric HL must be informed about the risk of late sequelae of treatment for HL, including SMN in the irradiated region, and that they will need regular follow-up examinations. In the future, radiotherapy for children and adolescents should be further reduced or entirely avoided. PMID- 26037469 TI - Missing treatment option. PMID- 26037470 TI - In reply. PMID- 26037472 TI - Pre-augmentation soft tissue expansion: an overview. AB - OBJECTIVES: The aim of this study was to explore the development of soft tissue expanders, their different types and their potential applications prior to bone augmentation and implant placement. MATERIAL AND METHODS: A review of pertinent literature was performed using PubMed to comprehend the dynamics of soft tissue expanders and determine the current position of their pre-augmentation applications. RESULTS: There is promising, albeit preliminary information regarding the benefits of pre-augmentation soft tissue expansion. Findings cannot be generalised due to relatively small sample size. CONCLUSIONS: Further clinical trials with larger sample sizes and long-term follow-up are needed before soft tissue expanders can be confidently applied in everyday clinical practice. PMID- 26037473 TI - Efficient Visible-Light-Driven Z-Scheme Overall Water Splitting Using a MgTa2O(6 x)N(y)/TaON Heterostructure Photocatalyst for H2 Evolution. AB - An (oxy)nitride-based heterostructure for powdered Z-scheme overall water splitting is presented. Compared with the single MgTa2O(6-x)N(y) or TaON photocatalyst, a MgTa2O(6-x)N(y)/TaON heterostructure fabricated by a simple one pot nitridation route was demonstrated to effectively suppress the recombination of carriers by efficient spatial charge separation and decreased defect density. By employing Pt-loaded MgTa2O(6-x)N(y)/TaON as a H2-evolving photocatalyst, a Z scheme overall water splitting system with an apparent quantum efficiency (AQE) of 6.8% at 420 nm was constructed (PtO(x)-WO3 and IO3(-)/I(-) pairs were used as an O2-evolving photocatalyst and a redox mediator, respectively), the activity of which is circa 7 or 360 times of that using Pt-TaON or Pt-MgTa2O(6-x)N)y) as a H2 evolving photocatalyst, respectively. To the best of our knowledge, this is the highest AQE among the powdered Z-scheme overall water splitting systems ever reported. PMID- 26037474 TI - A case of a teenage boy with eosinophilic gastroenteritis with esophageal involvement developing a hemorrhagic duodenal ulcer. AB - A boy in his early teens visited our hospital with chief complaints of hematemesis and tarry stools. Upper gastrointestinal endoscopy identified a hemorrhagic duodenal ulcer, for which hemostasis was performed using a clip. Proton pump inhibitor (PPI) administration diminished the ulcer but relapse occurred after PPI discontinuation. The esophagus showed concentric rings and longitudinal linear furrows considered to be characteristic of eosinophilic esophagitis. Biopsies of the duodenal ulcer and the esophagus revealed marked infiltration of eosinophils, leading to a diagnosis of eosinophilic gastroenteritis with esophageal involvement. Steroid treatment was initiated, and the duodenal ulcer and esophagitis resolved. Endoscopic findings characteristic of eosinophilic esophagitis were key to the diagnosis of eosinophilic gastroenteritis. PMID- 26037475 TI - Switch-On Fluorescence of a Perylene-Dye-Functionalized Metal-Organic Framework through Postsynthetic Modification. AB - A perylene dye was introduced directly as a linker into a metal-organic framework (MOF) during synthesis. Depending on the dye concentration in the MOF synthesis mixture, different fluorescent materials were generated. The successful incorporation of the dye was proven by using (13) C and (27) Al MAS NMR spectroscopy, by solution NMR spectroscopy after digestion of the MOF sample, and by synthesizing a reference dye without connecting groups, which could coordinate on the metal-oxo cluster inside the MOF. Fluorescence quenching effects of the MOF linker, 2-aminoterephthalate, were observed and overcome by postsynthetic modification with acetic anhydride. We show here for the first time that amino groups, which can be used as anchoring points for covalent attachment of other molecules, are responsible for fluorescence quenching. Thus, a very promising strategy to implement switchable fluorescence into MOFs is shown here. PMID- 26037476 TI - Yield stress and elasticity influence on surface tension measurements. AB - We have performed surface tension measurements on carbopol gels of different concentrations and yield stresses. Our setup, based on the force exerted by a capillary bridge on two parallel plates, allows us to measure an apparent surface tension of the complex fluid and to investigate the influence of flow history. More precisely the apparent surface tension measured after stretching the bridge is always higher than after compressing it. The difference between the two values is due to the existence of a yield stress in the fluid. The experimental observations are successfully reproduced with a simple elasto-plastic model. The shape of successive stretching-compression cycles can be described by taking into account the yield stress and the elasticity of the gel. We show that the surface tension gammaLV of yield stress fluids is the mean of the apparent surface tension values only if the elastic modulus is high compared to the yield stress. This work highlights that measurements of thermodynamic quantities are challenged by the fluid out-of-equilibrium state implied by jamming, even at small scales where the shape of the bridge is driven by surface energy. Therefore setups allowing for deformation in opposite directions are relevant for surface tension measurements on yield stress fluids. PMID- 26037477 TI - Jumonji Domain Containing Protein 6: A Novel Oxygen Sensor in the Human Placenta. AB - Persistent low oxygen is implicated in the pathogenesis of placental-associated pathologies such as preeclampsia, a serious disorder of pregnancy. Emerging evidence implicates a novel family of Jumonji C catalytic domain proteins as mediators of hypoxic gene expression. Here, we investigated the regulatory relationship between Jumonji C domain containing protein 6 (JMJD6) and hypoxia inducible factor (HIF)1A in the human placenta at physiological and pathological conditions. JMJD6 expression inversely correlated with changes in oxygen tension during early placental development, ie, high at 7-9 weeks when-partial pressure of O2 is low and declining afterwards when-partial pressure of O2 increases. Moreover, JMJD6 protein was significantly elevated in early-onset preeclamptic placentae, localizing to the syncytiotrophoblast layer and syncytial knots. Exposure of primary isolated trophoblast cells, human villous explants, and JEG3 choriocarcinoma cells to low oxygen (3%) and sodium nitroprusside (inducer of oxidative stress) also resulted in elevated JMJD6 levels, which was abrogated by HIF1A knockdown. In normoxia, knockdown of JMJD6 in JEG3 cells stabilized HIF1A with a concomitant decrease in von Hippel-Lindau (VHL) tumor suppressor protein, a negative regulator of HIF1A stability. In contrast, overexpression of JMJD6 enhanced VHL expression and destabilized HIF1A. JMJD6 regulation of VHL stability did not involve the ubiquitin-proteasome system but likely occurred through lysyl hydroxylation and small ubiquitin-like modifier 1-dependent small ubiquitin-like modifierylation. In summary, our data signify a novel role for JMJD6 as an oxygen sensor in the human placenta, and alterations in the JMJD6-VHL-HIF1A feedback loop may indirectly contribute to elevated HIF1A found in preeclampsia. PMID- 26037478 TI - Effect of magnetic field on positron lifetimes of Fe, Co and Ni. AB - Positron lifetime spectra of Fe, Co and Ni were measured under magnetic field using a (22)Na source. Very small but distinguishable difference of positron lifetime upon magnetic field reversal was observed suggesting the existence of two bulk lifetimes associated with majority and minority spin electrons. Using two spin-dependent Fe bulk lifetimes, the difference Doppler broadening of annihilation radiation spectra between majority and minority spin electrons were also examined. Agreement between experiment and theory indicates that spin polarized positron annihilation spectroscopy may have potential in investigation of spin-aligned electron momentum distribution. PMID- 26037479 TI - Providers with Limited Experience Perform Better in Advanced Life Support with Assistance Using an Interactive Device with an Automated External Defibrillator Linked to a Ventilator. AB - BACKGROUND: Medical teams with limited experience in performing advanced life support (ALS) or with a low frequency of cardiopulmonary resuscitation (CPR) while on duty, often have difficulty complying with CPR guidelines. OBJECTIVE: This study evaluated whether the quality of CPR of trained medical students, who served as an example of teams with limited experience in ALS, could be improved with device assistance. The primary outcome was the hands-off time (i.e., the percentage of the entire CPR time without chest compressions). The secondary outcome was seven time intervals, which should be as short as possible, and the quality of ventilations and chest compressions on the mannequin. METHODS: We compared standard CPR equipment to an interactive device with visual and acoustic instructions for ALS workflow measures to guide briefly trained medical students through the ALS algorithm in a full-scale mannequin simulation study with a randomized crossover study design. The study equipment consisted of an automatic external defibrillator and ventilator that were electronically linked and communicating as a single system. Included were regular medical students in the third to sixth years of medical school of one class who provided written informed consent for voluntary participation and for the analysis of their CPR performance data. No exclusion criteria were applied. For statistical measures of evaluation we used an analysis of variance for crossover trials accounting for treatment effect, sequence effect, and carry-over effect, with adjustment for prior practical experience of the participants. RESULTS: Forty-two medical students participated in 21 CPR sessions, each using the standard and study equipment. Regarding the primary end point, the study equipment reduced the hands-off time from 40.1% (95% confidence interval [CI] 36.9-43.4%) to 35.6% (95% CI 32.4-38.9%, p = 0.031) compared with the standard equipment. Within the prespecified secondary end points, study equipment reduced the time interval until the first rescuer changeover from 273 s (95% CI 244-302 s) to 223 s (95% CI 194-253 s, p = 0.001) and increased the percentage of ventilations with a correct tidal volume of 400-600 mL from 34.3% (95% CI 19.0-49.6%) to 60.9% (95% CI 45.6-76.2%, p = 0.018). CONCLUSIONS: The assist device increased the rescuers' CPR quality. CPR providers with limited experience or a limited frequency of CPR performance (i.e., rural Emergency Medical Services crew) may potentially benefit from this assist device. PMID- 26037480 TI - Initial Low Oxygen Extraction Ratio Is Related to Severe Organ Dysfunction and High In-Hospital Mortality in Severe Sepsis and Septic Shock Patients. AB - BACKGROUND: In severe sepsis and septic shock, global tissue hypoxia is a key development preceding multi-organ failure and death. OBJECTIVE: Our aim was to find whether the initial low oxygen extraction ratio (OER) is related to the severity of organ dysfunction and to predict the in-hospital mortality in severe sepsis or septic shock patients. METHODS: This was a secondary analysis of 169 patients with severe sepsis or septic shock in an emergency department. We calculated OER with 1- central venous oxygen saturation (ScvO2)/arterial oxygen saturation and compared the data according to the level of OER (high > 0.3, 0.2 <= normal <= 0.3, lower < 0.2). RESULTS: A total 133 patients were selected for analysis. OER was inversely proportional to ScvO2 (r(2) = 0.878; p < 0.001). The sepsis-related organ failure assessment score and in-hospital mortality of each group were 6.2 +/- 3.7 and 37.0% for high OER, 5.7 +/- 3.0 and 11.8% for normal OER, and 7.7 +/- 3.9 and 41.7% for low OER, respectively (p = 0.034; p = 0.003). In patients with initial ScvO2 of >70%, in-hospital mortality of patients with low OER was significantly higher than patients with normal OER. CONCLUSIONS: Initial low OER was associated with severe organ dysfunction that resulted in high mortality with severe sepsis and septic shock. When patients had initial ScvO2 of > 70% but abnormally low OER, their in-hospital mortality was higher than in normal OER patients. Therefore, the OER should be considered when attempting to predict the outcome of septic patients using ScvO2 at an early stage of management for sepsis. PMID- 26037481 TI - Emergency Care of Children with Ambulatory Care Sensitive Conditions in the United States. AB - BACKGROUND: Ambulatory care sensitive (ACS) conditions are health problems that could be prevented or ameliorated with adequate access to primary care services. OBJECTIVES: To determine the extent to which ACS conditions account for care received by children in U.S. emergency departments (EDs) and the patient charges for this care. METHODS: A retrospective, cross-sectional analysis of the 2010 Nationwide Emergency Department Sample was performed. Patients 0-19 years of age were included and visits for ACS conditions were identified. Main outcome measures were the percentage of visits for ACS conditions, regression models predicting presentation for ACS conditions based on patient demographic characteristics, and ED charges for ACS ED visits. RESULTS: Of almost 30 million pediatric ED visits in the United States in 2010, 13.2% were for exclusively ACS conditions. Patients with public or no insurance were 1.2 times more likely than privately insured patients to present for an ACS condition. Lower household income (adjusted odds ratio [aOR] 1.49; 95% confidence interval [CI] 1.33-1.66) and younger patient age (aOR = 2.55; 95% CI 2.41-2.69) were also predictive of an ACS ED visit. The total of charges for ACS visits was almost $3 billion, of which publicly insured patients accounted for $1.5 billion. CONCLUSIONS: Almost one in seven U.S. pediatric ED visits may be preventable by quality primary care. Patients with public insurance and lower income are more likely than other groups to present with ACS conditions. Better access to and use of primary care services could reduce health care costs and relieve ED overcrowding. PMID- 26037482 TI - Deterioration of clinical features of a patient with autism spectrum disorder after anti-N-methyl-D-aspartate receptor encephalitis. PMID- 26037483 TI - Spaces of phylogenetic networks from generalized nearest-neighbor interchange operations. AB - Phylogenetic networks are a generalization of evolutionary or phylogenetic trees that are used to represent the evolution of species which have undergone reticulate evolution. In this paper we consider spaces of such networks defined by some novel local operations that we introduce for converting one phylogenetic network into another. These operations are modeled on the well-studied nearest neighbor interchange operations on phylogenetic trees, and lead to natural generalizations of the tree spaces that have been previously associated to such operations. We present several results on spaces of some relatively simple networks, called level-1 networks, including the size of the neighborhood of a fixed network, and bounds on the diameter of the metric defined by taking the smallest number of operations required to convert one network into another. We expect that our results will be useful in the development of methods for systematically searching for optimal phylogenetic networks using, for example, likelihood and Bayesian approaches. PMID- 26037485 TI - A functional comparison of the domestic cat bitter receptors Tas2r38 and Tas2r43 with their human orthologs. AB - BACKGROUND: Domestic cats (felis catus) have a reputation for being rather unpredictable in their dietary choices. While their appetite for protein or savory flavors is consistent with their nutritional needs, their preference among protein-sufficient dietary options may relate to differences in the response to other flavor characteristics. Studies of domestic cat taste perception are limited, in part, due to the lack of receptor sequence information. Several studies have described the phylogenetic relationship of specific cat taste receptor sequences as compared with other carnivores. For example, domestic cats are obligate carnivores and their receptor Tas1r2, associated with the human perception of sweet, is present only as a pseudogene. Similarly, the cat perception of bitter may differ from that of other mammals due to variations in their repertoire of bitter receptor (Tas2r) genes. This report includes the first functional characterization of domestic cat taste receptors. RESULTS: We functionally expressed two uncharacterized domestic sequences Tas2r38 and Tas2r43 and deorphanized the receptors using a cellular functional assay. Statistical significance was determined using an unpaired, two-tailed t-test. The cat sequence for Tas2r38 contains 3 major amino acid residues known to confer the taster phenotype (PAI), which is associated with sensitivity to the bitter compounds PROP and PTC. However, in contrast to human TAS2R38, cat Tas2r38 is activated by PTC but not by PROP. Furthermore, like its human counterpart, cat Tas2r43 is activated by aloin and denatonium, but differs from the human TAS2R43 by insensitivity to saccharin. The responses of both cat receptors to the bitter ligands were concentration-dependent and were inhibited by the human bitter blocker probenecid. CONCLUSIONS: These data demonstrate that the response profiles of the cat bitter receptors Tas2r38 and Tas2r43 are distinct from those of their orthologous human receptors. Results with cat Tas2r38 also demonstrate that additional residues beyond those classically associated with PROP sensitivity in humans influence the sensitivity to PROP and PTC. Functional studies of the human bitter receptor family are being applied to the development of food and medicinal products with more appealing flavor profiles. Our work lays the foundation for similar work applied to felines. PMID- 26037486 TI - The effects of idarubicin versus other anthracyclines for induction therapy of patients with newly diagnosed leukaemia. AB - BACKGROUND: Anthracycline combined with cytarabine has been the standard for induction therapy of newly diagnosed acute myeloid leukaemia (AML) for several decades. Due to theoretical advantages, idarubicin (IDA) might be the most effective and tolerable anthracycline. However, there is no evidence that would definitively prove the superiority of IDA over other anthracyclines. OBJECTIVES: To assess the efficacy and safety of IDA versus other anthracyclines in induction therapy of newly diagnosed AML. SEARCH METHODS: We identified relevant randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 8), MEDLINE (from 1946 to 3 August 2014), EMBASE (from 1974 to 3 August 2014), Chinese BioMedical Literature Database (1978 to 3 August 2014), relevant conference proceedings and databases of ongoing trials. SELECTION CRITERIA: RCTs that compared IDA with other anthracyclines in induction therapy of newly diagnosed AML. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of studies according to methodological standards of the Cochrane Collaboration. We estimated hazard ratios (HRs) for time-to-event data outcomes using the inverse variance method, and risk ratios (RRs) for dichotomous data outcomes using the Mantel-Haenszel method. We adopted a fixed-effect model and repeated the main meta-analysis by a random-effects model in a sensitivity analysis. MAIN RESULTS: We identified 2017 references. Ultimately, 27 RCTs (including 22 two-armed RCTs and five three-armed RCTs) involving 9549 patients were eligible. The consolidation treatments adopted in the studies were comparable and had no impact on the results. Overall, the risk of bias of the studies was unclear to high.Eighteen RCTs (N = 6755) assessed IDA versus daunorubicin (DNR). The main meta-analyses showed that IDA compared with DNR prolonged overall survival (OS) (12 studies, 5976 patients; HR 0.90, 95% confidence interval (CI) 0.84 to 0.96, P = 0.0008; high quality of evidence) and disease-free survival (DFS) (eight studies, 3070 patients; HR 0.88, 95% CI 0.81 to 0.96, P = 0.004; moderate quality of evidence), increased complete remission (CR) rate (18 studies, 6692 patients; RR 1.04, 95% CI 1.01 to 1.07, P = 0.009; moderate quality of evidence), and reduced relapse rate (four studies, 1091 patients; RR 0.88, 95% CI 0.80 to 0.98, P = 0.02; moderate quality of evidence), although increased the risks of death on induction therapy (14 studies, 6349 patients; RR 1.18, 95% CI 1.01 to 1.36, P = 0.03; moderate quality of evidence) and grade 3/4 mucositis (five studies, 2000 patients; RR 1.22, 95% CI 1.04 to 1.44, P = 0.02; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (six studies, 2795 patients; RR 0.98, 95% CI 0.70 to 1.37, P = 0.91; moderate quality of evidence) and other grade 3/4 adverse events (AEs). None of the studies reported on quality of life (QoL).Eight RCTs (N = 2419) evaluated IDA versus mitoxantrone (MIT). The main meta-analyses showed that there was no evidence for difference between arms in OS (six studies, 2171 patients; HR 0.98, 95% CI 0.89 to 1.08, P = 0.69; high quality of evidence), DFS (four studies, 249 patients; HR 0.88, 95% CI 0.70 to 1.10, P = 0.26; low quality of evidence), CR rate (eight studies, 2411 patients; RR 0.97, 95% CI 0.92 to 1.03, P = 0.32;moderate quality of evidence), the risks of death on induction therapy (five studies, 2055 patients; RR 1.10, 95% CI 0.88 to 1.38, P = 0.39; moderate quality of evidence) and relapse (three studies, 328 patients; RR 0.99, 95% CI 0.80 to 1.22, P = 0.89; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (one study, 160 patients; RR 0.67, 95% CI 0.11 to 3.88, P = 0.65; low quality of evidence) and other grade 3/4 AEs. None of the studies reported on QoL.Two RCTs (N = 211) compared IDA with doxorubicin (DOX). Neither study assessed OS. One study showed that there was no evidence for difference in DFS (63 patients; HR 0.62, 95% CI 0.34 to 1.14, P = 0.12; low quality of evidence). The main meta analysis for CR rate showed an improved CR rate with IDA (two studies, 187 patients; RR 1.28, 95% CI 1.03 to 1.59, P = 0.02; low quality of evidence). Neither study provided data for the risks of death on induction therapy and relapse. One trial showed that there was no evidence for difference in the risk of grade 3/4 cardiac toxicity (one study, 100 patients; RR 0.31, 95% CI 0.01 to 7.39, P = 0.47; very low quality of evidence). Neither study reported on QoL.Two RCTs (N = 1037) evaluated IDA versus zorubicin (ZRB). Neither study assessed OS. One trial showed that there was no evidence for difference in DFS (one study, 155 patients; HR 1.25, 95% CI 0.83 to 1.88, P = 0.29; low quality of evidence). The main meta-analyses for CR and death on induction therapy both showed that there was no evidence for difference (CR rate: two studies, 964 patients; RR 1.04, 95% CI 0.96 to 1.13, P = 0.31; low quality of evidence. risk of death on induction therapy: two studies, 964 patients; RR 0.75, 95% CI 0.50 to 1.13, P = 0.17; moderate quality of evidence). Neither study reported the risks of relapse and grade 3/4 cardiotoxicity. One trial showed that IDA reduced the risk of grade 3/4 mucositis. Neither study reported on QoL. AUTHORS' CONCLUSIONS: Compared with DNR in induction therapy of newly diagnosed AML, IDA prolongs OS and DFS, increases CR rate and reduces relapse rate, although increases the risks of death on induction therapy and grade 3/4 mucositis. The currently available evidence does not show any difference between IDA and MIT used in induction therapy of newly diagnosed AML. There is insufficient evidence regarding IDA versus DOX and IDA versus ZRB to make final conclusions. Additionally, there is no evidence for difference on the effect of IDA compared with DNR, MIT, DOX or ZRB on QoL. PMID- 26037484 TI - The Beyond Ageing Project Phase 2--a double-blind, selective prevention, randomised, placebo-controlled trial of omega-3 fatty acids and sertraline in an older age cohort at risk for depression: study protocol for a randomized controlled trial. AB - BACKGROUND: Late-life depression is associated with high rates of morbidity, premature mortality, disability, functional decline, caregiver burden and increased health care costs. While clinical and public health approaches are focused on prevention or early intervention strategies, the ideal method of intervention remains unclear. No study has set out to evaluate the role of neurobiological agents in preventing depressive symptoms in older populations at risk of depression. METHODS/DESIGN: Subjects with previously reported sub threshold depressive symptoms, aged 60 to 74 years, will be screened to participate in a single-centre, double-blind, randomised controlled trial with three parallel groups involving omega-3 fatty acid supplementation or sertraline hydrochloride, compared with matching placebo. Subjects will be excluded if they have current depression or suicide ideation; are taking antidepressants or any supplement containing omega-3 fatty acid; or have a prior history of stroke or other serious cerebrovascular or cardiovascular disease, neurological disease, significant psychiatric disease (other than depression) or neurodegenerative disease. The trial will consist of a 12 month treatment phase with follow-up at three months and 12 months to assess outcome events. At three months, subjects will undergo structural neuroimaging to assess whether treatment effects on depressive symptoms correlate with brain changes. Additionally, proton spectroscopy techniques will be used to capture brain-imaging markers of the biological effects of the interventions. The trial will be conducted in urban New South Wales, Australia, and will recruit a community-based sample of 450 adults. Using intention-to-treat methods, the primary endpoint is an absence of clinically relevant depression scores at 12 months between the omega-3 fatty acid and sertraline interventions and the placebo condition. DISCUSSION: The current health, social and economic costs of late-life depression make prevention imperative from a public health perspective. This innovative trial aims to address the long-neglected area of prevention of depression in older adults. The interventions are targeted to the pathophysiology of disease, and regardless of the effect size of treatment, the outcomes will offer major scientific advances regarding the neurobiological action of these agents. The main results are expected to be available in 2017. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12610000032055 (12 January 2010). PMID- 26037487 TI - Measuring the Physiologic Properties of Oral Lesions Receiving Fractionated Photodynamic Therapy. AB - Photodynamic therapy (PDT) can treat superficial, early-stage disease with minimal damage to underlying tissues and without cumulative dose-limiting toxicity. Treatment efficacy is affected by disease physiologic properties, but these properties are not routinely measured. We assessed diffuse reflectance spectroscopy (DRS) for the noninvasive, contact measurement of tissue hemoglobin oxygen saturation (St O2 ) and total hemoglobin concentration ([tHb]) in the premalignant or superficial microinvasive oral lesions of patients treated with 5 aminolevulinic acid (ALA)-PDT. Patients were enrolled on a Phase 1 study of ALA PDT that evaluated fluences of 50, 100, 150 or 200 J cm(-2) delivered at 100 mW cm(-2) . To test the feasibility of incorporating DRS measurements within the illumination period, studies were performed in patients who received fractionated (two-part) illumination that included a dark interval of 90-180 s. Using DRS, tissue oxygenation at different depths within the lesion could also be assessed. DRS could be performed concurrently with contact measurements of photosensitizer levels by fluorescence spectroscopy, but a separate noncontact fluorescence spectroscopy system provided continuous assessment of photobleaching during illumination to greater tissue depths. Results establish that the integration of DRS into PDT of early-stage oral disease is feasible, and motivates further studies to evaluate its predictive and dosimetric value. PMID- 26037488 TI - Association between depression and glycemic control among type 2 diabetes patients in Lima, Peru. AB - INTRODUCTION: There is limited and controversial information regarding the potential impact of depression on glycemic control. This study aims to evaluate the association between depression and poor glycemic control. In addition, the prevalence of depression and rates of poor glycemic control were determined. METHODS: Cross-sectional study performed in the endocrinology unit of two hospitals of ESSALUD in Peru. The outcome of interest was poor glycemic control, evaluated by glycated hemoglobin (HbA1c: <7% versus >=7%), whereas the exposure of interest was depression defined as 15 or more points in the Patient Health Questionnaire-9 tool. The association of interest was evaluated using Poisson regression models with robust standard errors reporting prevalence ratios (PR) and 95% confidence intervals (95% CI) adjusting for potential confounders. RESULTS: A total of 277 participants, 184 (66.4%) males, mean age 59.0 (SD: 4.8), and 7.1 (SD: 6.8) years of disease were analyzed. Only 31 participants (11.2%; 95% CI: 7.5%-14.9%) had moderately severe or severe depression, whereas 70 (25.3%; 95% CI 20.3%-30.8%) had good glycemic control. Depression increased the probability of having poor glycemic control (PR=1.32; 95% CI 1.15-1.51) after adjusting for several potential confounders. CONCLUSIONS: There is an association between depression and poor glycemic control among type 2 diabetes patients. Our results suggest that early detection of depression might be important to facilitate appropriate glycemic control and avoid further metabolic complications. PMID- 26037489 TI - Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to Ketamine in Sp4 Hypomorphic Mice. AB - BACKGROUND: Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Sp4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that Sp4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice. METHODS: In the present study, we used the Cre-LoxP system to restore Sp4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice. RESULTS: Restoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating. CONCLUSIONS: Our studies suggest that the Sp4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion. PMID- 26037490 TI - Quantification of glycated N-terminal peptide of hemoglobin using derivatization for multiple functional groups of amino acids followed by liquid chromatography/tandem mass spectrometry. AB - A novel method of amino acid analysis using derivatization of multiple functional groups (amino, carboxyl, and phenolic hydroxyl groups) was applied to measure glycated amino acids in order to quantify glycated peptides and evaluate the degree of glycation of peptide. Amino and carboxyl groups of amino acids were derivatized with 1-bromobutane so that the hydrophobicities and basicities of the amino acids, including glycated amino acids, were improved. These derivatized amino acids could be detected with high sensitivity using LC-MS/MS. In this study, 1-deoxyfructosyl-VHLTPE and VHLTPE, which are N-terminal peptides of the beta-chains of hemoglobin, were selected as target compounds. After reducing the peptide sample solution with sodium borohydride, the obtained peptides were hydrolyzed with hydrochloric acid. The released amino acids were then derivatized with 1-bromobutane and analyzed with LC-MS/MS. The derivatized amino acids, including glycated amino acids, could be separated using an octadecyl silylated silica column and good sharp peaks were detected. We show a confirmatory experiment that the proposed method can be applied to evaluate the degree of glycation of peptides, using mixtures of glycated and non-glycated peptide. PMID- 26037492 TI - Relations between common and specific factors of anxiety sensitivity and distress tolerance and fear, distress, and alcohol and substance use disorders. AB - Whereas it has been speculated that the psychopathology risk factors anxiety sensitivity (AS) and distress tolerance (DT) are highly overlapping, no studies have examined whether a core affect sensitivity construct explains this relation. It was hypothesized that, in a sample of 808 treatment-seeking individuals (M(age) = 35.11, SD = 14.94), the best-fitting confirmatory factor analysis model of AS and DT would comprise a common underlying affect sensitivity factor orthogonal to DT and lower-order AS factors (physical, cognitive, and social concerns). It was also hypothesized that specific relations between the factors and fear, distress, and alcohol/substance use disorders would emerge. The best fitting model comprised a common affect sensitivity factor orthogonal to DT and lower-order AS factors. Whereas the affect sensitivity and DT factors were associated with fear, distress, and alcohol/substance use disorders, AS cognitive concerns was only related to distress disorders and AS social concerns was only related to fear disorders. PMID- 26037491 TI - A sensitised RNAi screen reveals a ch-TOG genetic interaction network required for spindle assembly. AB - How multiple spindle assembly pathways are integrated to drive bipolar spindle assembly is poorly understood. We performed an image-based double RNAi screen to identify genes encoding Microtubule-Associated Proteins (MAPs) that interact with the highly conserved ch-TOG gene to regulate bipolar spindle assembly in human cells. We identified a ch-TOG centred network of genetic interactions which promotes centrosome-mediated microtubule polymerisation, leading to the incorporation of microtubules polymerised by all pathways into a bipolar structure [corrected]. Our genetic screen also reveals that ch-TOG maintains a dynamic microtubule population, in part, through modulating HSET activity. ch-TOG ensures that spindle assembly is robust to perturbation but sufficiently dynamic such that spindles can explore a diverse shape space in search of structures that can align chromosomes. PMID- 26037493 TI - Intolerance of uncertainty as a mediator of reductions in worry in a cognitive behavioral treatment program for generalized anxiety disorder. AB - Growing evidence suggests that intolerance of uncertainty (IU) is a cognitive vulnerability that is a central feature across diverse anxiety disorders, including generalized anxiety disorder (GAD). Although cognitive behavioral therapy (CBT) has been shown to reduce IU, it remains to be established whether or not reductions in IU mediate reductions in worry. This study examined the process of change in IU and worry in a sample of 28 individuals with GAD who completed CBT. Changes in IU and worry, assessed bi-weekly during treatment, were analyzed using multilevel mediation models. Results revealed that change in IU mediated change in worry (ab = -0.20; 95% CI [-.35, -.09]), but change in worry did not mediate change in IU (ab = -0.16; 95% CI [-.06, .12]). Findings indicated that reductions in IU accounted for 59% of the reductions in worry observed over the course of treatment, suggesting that changes in IU are not simply concomitants of changes in worry. Findings support the idea that IU is a critical construct underlying GAD. PMID- 26037494 TI - Energetic stabilities of thiolated pyrimidines on gold nanoparticles investigated by Raman spectroscopy and density functional theory calculations. AB - The adsorption structures of 2-thiocytosine (2TC) on gold surfaces were examined by means of vibrational Raman spectroscopy and quantum mechanical density functional theory calculations. The 1H-thione-amino form was calculated to be most stable among the six examined tautomers. The three plausible binding geometries of sulfur, pyrimidine nitrogen, and amino group binding modes were calculated to estimate the binding energies of the 1H-thione-amino form with six gold cluster atoms. Thiouracils including 2-thiouracil (2TU), 4-thiouracil (4TU), and 6-methyl-2-thiouracil (6M2TU) were also studied to compare their relative binding energies on gold atoms. The intracellular localization of a DNA base analog of 2TC on gold nanoparticles (AuNPs) in HeLa cells was identified by means of surface-enhanced Raman scattering. AuNPs were modified with 2TC by self assembly. Our dark-field microscopy and z-depth-dependent confocal Raman spectroscopy indicated that 2TC-assembled AuNPs could be found inside cancer cells. On the other hand, we did not observe noticeably strong Raman peaks in the cases of thiouracils including 2TU, 4TU, and 6M2TU. This may be due to the additional amino group of 2TC, which can lead to a stronger binding of adsorbates on AuNPs. PMID- 26037495 TI - Using different chemical methods for deposition of copper selenide thin films and comparison of their characterization. AB - Different chemical methods such as Successive Ionic Layer Adsorption and Reaction (SILAR), spin coating and spray pyrolysis methods were used to deposite of copper selenide thin films on the glass substrates. The films were characterized by X ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), energy dispersive X-ray analysis (EDX) spectroscopy and UV-vis spectrophotometry. The XRD and SEM studies showed that all the films exhibit polycrystalline nature and crystallinity of copper selenide thin films prepared with spray pyrolysis greater than spin coating and SILAR methods. From SEM and AFM images, it was observed copper selenide films were uniform on the glass substrates without any visible cracks or pores. The EDX spectra showed that the expected elements exist in the thin films. Optical absorption studies showed that the band gaps of copper selenide thin films were in the range 2.84-2.93 eV depending on different chemical methods. The refractive index (n), optical static and high frequency dielectric constants (epsilon0, epsiloninfinity) values were calculated by using the energy bandgap values for each deposition method. The obtained results from different chemical methods revealed that the spray pyrolysis technique is the best chemical deposition method to fabricate copper selenide thin films. This absolute advantage was lead to play key roles on performance and efficiency electrochromic and photovoltaic devices. PMID- 26037496 TI - Supramolecular effect of curcurbit[7]uril on the binding mode of 2-(4 (dimethylamino) styryl)-1-methylpyridinium iodide with Calf Thymus DNA: From minor groove to intercalative. AB - The effect of curcurbit[7]uril (CB[7]) in the binding mode of 2-(4 (dimethylamino) styryl)-1-methylpyridinium (DASPMI) with Calf Thymus DNA has been discussed in this paper. Red shift, intensity change in absorption and emission spectra and presence of isosbestic point with increasing concentration of CB[7] in groove bound DASPMI-DNA complex indicates a change in binding pattern. Appearance of a third slower component in lifetime decay in presence of CB[7] which gets more slow in high CB[7] concentration is indicative of a new type of binding. Major changes in ct-DNA bands in circular dichroism spectra with addition of CB[7] make a strong case for intercalative binding. Increased computed values of binding constant associated with diminishing quenching constant in presence of potassium iodide make a positive candidate for intercalative binding. Formation of big spherical condensate in DASPMI-DNA complex in presence of CB[7] which grows bigger in higher CB[7] concentration shows a morphological change. Molecular docking nicely portrays the intercalative nature of binding corroborating the experimental evidences. PMID- 26037497 TI - Anticancer activity studies of a ruthenium(II) polypyridyl complex against human hepatocellular (BEL-7402) cells. AB - A Ru(II) polypyridyl complex [Ru(bpy)2(HMSPIP)](ClO4)2 (1) (bpy=2,2'-bipyridine, HMSPIP=2-(4-methylsulfonyl)phenyl-1H-imidazo[4,5-f][1,10] phenanthroline) was synthesized. The IC50 value of the complex against human hepatocellular cell BEL 7402 is 21.6+/-2.7 MUM. The complex shows no cytotoxic activity toward human lung adenocarcinoma cell A549, human osteosarcoma cell MG-63 and human breast cancer cell SK-BR-3 cells. It is easily for complex 1 to be taken up by BEL-7402 cells. The complex can enhance the reactive oxygen species (ROS) levels and induce the decrease in the mitochondrial membrane potential. The complex inhibits the cell growth in BEL-7402 cells at G2/M phase. Complex 1 can regulate the expression of Bcl-2 family proteins. The results show that the complex induces apoptosis of BEL 7402 cells through a ROS-mediated mitochondrial dysfunction pathway. PMID- 26037498 TI - Investigation on the upconversion emission in 2D BiOBr:Yb(3+)/Ho(3+) nanosheets. AB - As lanthanide doped upconverting host, two dimensional (2D) nanostructure materials have remarkable advantages compare with the bulk materials, but excellent 2D upconversion nanohost is still few up to date. In this work, Yb(3+)/Ho(3+) co-doped BiOBr nanosheets have been successfully prepared via a facile hydrothermal method, which were characterized by X-ray diffraction, transmission electron microscopy, Atomic Force Microscope, Raman spectra, Fourier transform infrared absorption and UC luminescence spectra. Under excitation at 980 nm, bright green UC emission centered at 550 nm accompanied with weak red (663 nm) and near infrared (NIR) UC emissions (760 nm) were observed. Power dependence studies revealed that NIR and red UC emissions were both dominated by a two and one-photon process due to saturation effects that is related to the special crystal structure of BiOBr nanosheets, and a different UC mechanism of NIR emission from Ho(3+) was proposed accordingly. PMID- 26037499 TI - Development of normalized spectra manipulating spectrophotometric methods for simultaneous determination of Dimenhydrinate and Cinnarizine binary mixture. AB - Simultaneous determination of Dimenhydrinate (DIM) and Cinnarizine (CIN) binary mixture with simple procedures were applied. Three ratio manipulating spectrophotometric methods were proposed. Normalized spectrum was utilized as a divisor for simultaneous determination of both drugs with minimum manipulation steps. The proposed methods were simultaneous constant center (SCC), simultaneous derivative ratio spectrophotometry (S(1)DD) and ratio H-point standard addition method (RHPSAM). Peak amplitudes at isoabsorptive point in ratio spectra were measured for determination of total concentrations of DIM and CIN. For subsequent determination of DIM concentration, difference between peak amplitudes at 250 nm and 267 nm were used in SCC. While the peak amplitude at 275 nm of the first derivative ratio spectra were used in S(1)DD; then subtraction of DIM concentration from the total one provided the CIN concentration. The last RHPSAM was a dual wavelength method in which two calibrations were plotted at 220 nm and 230 nm. The coordinates of intersection point between the two calibration lines were corresponding to DIM and CIN concentrations. The proposed methods were successfully applied for combined dosage form analysis, Moreover statistical comparison between the proposed and reported spectrophotometric methods was applied. PMID- 26037500 TI - Ionization and tautomerism of methyl fluorescein and related dyes. AB - The protolytic equilibrium of methyl ether of fluorescein is studied in water, aqueous ethanol, and in other solvents. The constants of the two-step dissociation are determined by spectrophotometry. In water, the fractions of the zwitterionic, quinonoid, and lactonic tautomes are correspondingly 11%, 6%, and 83%, as deduced from the UV-visible spectra. Corresponding study of the ionization of the methyl ether ester of fluorescein, fluorescein ethyl ester, and sulfonefluorescein allows testing the correction of the attribution of the microscopic dissociation constants of methoxy fluorescein. The results of nuclear magnetic resonance and infrared spectroscopy, as well as the X-ray analysis confirm the predomination of the lactonic structure of the molecular species in solid state and in DMSO. Contrary to it, the spectroscopic studies in both hydrogen-donor bond (HDB) and non-HBD solvents confirm that the presence of lactonic monoanion is atypical for the dye under study and, with high probability, also for the mother compound fluorescein. PMID- 26037501 TI - The influence of TeO2 on thermal stability and 1.53 MUm spectroscopic properties in Er(3+) doped oxyfluorite glasses. AB - In this work, the thermal and spectroscopic properties of Er(3+)-doped oxyfluorite glass based on AMCSBYT (AlF3-MgF2-CaF2-SrF2-BaF2-YF3-TeO2) system for different TeO2 concentrations from 6 to 21 mol% is reported. After adding a suitable content of TeO2, the thermal ability of glass improves significantly whose DeltaT and S can reach to 118 degrees C and 4.47, respectively. The stimulated emission cross-section reaches to 7.80*10(-21) cm(2) and the fluorescence lifetime is 12.18 ms. At the same time, the bandwidth characteristics reach to 46.41*10(-21) cm(2) nm and the gain performance is 63.73*10(-21) cm(2) ms. These results show that the optical performances of this oxyfluorite glass are very well. Hence, AMCSBYT glass with superior performances might be a useful material for applications in optical amplifier around 1.53 MUm. PMID- 26037502 TI - Outreach clinical dental education: the Portsmouth experience - a 4-year follow up study. AB - BACKGROUND: The Portsmouth Dental Academy (UPDA) was opened in September 2010 and was a development from the highly successful School of Professionals Complementary to Dentistry (2004-2010). The aim of the Academy was to provide integrated team education for all dental professionals in a primary care setting. The dental students are on outreach from King's College London, and the dental care professional students are registered at the University of Portsmouth. OBJECTIVES: To evaluate the dental students response to the residential outreach educational experience at the UPDA. METHODS: A 49-item questionnaire divided into nine domains that provided both qualitative data and quantitative data were administered at the end of the longitudinal 10-week placement, to four successive cohorts of students in 2010-2014. RESULTS: A 95% return rate was achieved. Students valued highly the quality of the clinical teaching. Through their experience, they felt they understood fully the role of the dentist in care planning in primary care and felt well prepared for dental foundation training. This educational success is unpinned with successful maintenance factors including a well-organised induction period and giving the students a sense of belongingness, empowerment and autonomy for their personal development as new graduates. CONCLUSION: Within the limitations of the questionnaire study over the 4-year period, the students were very positive about all the aspects of this residential outreach education at the UPDA but particularly valued the immersion in clinical dentistry and the bridging from dental school to their dental foundation training. PMID- 26037504 TI - Synthesis and Isolation of Organogold Complexes through a Controlled 1,2-Silyl Migration. AB - During our efforts toward the synthesis of naturally occurring polyprenylated polycyclic acylphloroglucinol using a Au(I)-catalyzed 6-endo dig carbocyclization, we isolated stable vinyllic gold intermediates. Optimization lead to isolated yields of up to 98%, using 2-(di-tert-butylphosphino)biphenyl as the ligand. This transformation is derived from a silyl rearrangement that can be fully controlled according to the nature of the substituent on the ynone. This selective transformation does not require basic conditions to prevent protodeauration. These vinylgold complexes are the first isolated intermediates during a silyl migration with gold(I). More than 16 new organogold complexes were synthesized and characterized by single-crystal X-ray diffraction. Reactivity of these complexes is also presented. PMID- 26037505 TI - Side Effects of Culture Media Antibiotics on Cell Differentiation. AB - Besides the advance in scientific knowledge and the production of different compounds, cell culture can now be used to obtain cells for regenerative medicine. To avoid microbial contamination, antibiotics were usually incorporated into culture media. However, these compounds affect cell biochemistry and may modify the differentiation potential of cultured cells. To check this possibility, we grew human adipose tissue-derived stem cells and differentiated them to adipocyte with or without antibiotics commonly used in these culture protocols, such as a penicillin-streptomycin-amphotericin mix or gentamicin. We show that these antibiotics affect cell differentiation. Therefore, antibiotics should not be used in cell culture because aseptic techniques make these compounds unnecessary. PMID- 26037503 TI - Microtubule-associated protein 6 mediates neuronal connectivity through Semaphorin 3E-dependent signalling for axonal growth. AB - Structural microtubule associated proteins (MAPs) stabilize microtubules, a property that was thought to be essential for development, maintenance and function of neuronal circuits. However, deletion of the structural MAPs in mice does not lead to major neurodevelopment defects. Here we demonstrate a role for MAP6 in brain wiring that is independent of microtubule binding. We find that MAP6 deletion disrupts brain connectivity and is associated with a lack of post commissural fornix fibres. MAP6 contributes to fornix development by regulating axonal elongation induced by Semaphorin 3E. We show that MAP6 acts downstream of receptor activation through a mechanism that requires a proline-rich domain distinct from its microtubule-stabilizing domains. We also show that MAP6 directly binds to SH3 domain proteins known to be involved in neurite extension and semaphorin function. We conclude that MAP6 is critical to interface guidance molecules with intracellular signalling effectors during the development of cerebral axon tracts. PMID- 26037506 TI - Calibration Adjustment of the Mid-infrared Analyzer for an Accurate Determination of the Macronutrient Composition of Human Milk. AB - BACKGROUND: Human milk composition analysis seems essential to adapt human milk fortification for preterm neonates. The Miris human milk analyzer (HMA), based on mid-infrared methodology, is convenient for a unique determination of macronutrients. However, HMA measurements are not totally comparable with reference methods (RMs). OBJECTIVE: The primary aim of this study was to compare HMA results with results from biochemical RMs for a large range of protein, fat, and carbohydrate contents and to establish a calibration adjustment. METHODS: Human milk was fractionated in protein, fat, and skim milk by covering large ranges of protein (0-3 g/100 mL), fat (0-8 g/100 mL), and carbohydrate (5-8 g/100 mL). For each macronutrient, a calibration curve was plotted by linear regression using measurements obtained using HMA and RMs. RESULTS: For fat, 53 measurements were performed, and the linear regression equation was HMA = 0.79RM + 0.28 (R(2) = 0.92). For true protein (29 measurements), the linear regression equation was HMA = 0.9RM + 0.23 (R(2) = 0.98). For carbohydrate (15 measurements), the linear regression equation was HMA = 0.59RM + 1.86 (R(2) = 0.95). A homogenization step with a disruptor coupled to a sonication step was necessary to obtain better accuracy of the measurements. Good repeatability (coefficient of variation < 7%) and reproducibility (coefficient of variation < 17%) were obtained after calibration adjustment. CONCLUSION: New calibration curves were developed for the Miris HMA, allowing accurate measurements in large ranges of macronutrient content. This is necessary for reliable use of this device in individualizing nutrition for preterm newborns. PMID- 26037507 TI - Engaging with Community Advisory Boards (CABs) in Lusaka Zambia: perspectives from the research team and CAB members. AB - BACKGROUND: The use of a Community Advisory Board (CAB) is one method of ensuring community engagement in community based research. To identify the process used to constitute CABs in Zambia, this paper draws on the perspectives of both research team members and CAB members from research groups who used CABs in Lusaka. Enabling and restricting factors impacting on the functioning of the CAB were identified. METHODS: All studies approved by the University of Zambia Bioethics Research Committee (UBNZABREC) from 2008 - 2012 were reviewed to identify those studies that were likely to include a CAB. Eight teams with studies that included a CAB were identified. For each of these studies, consent was obtained to conduct an informal interview with a research team member and to obtain contact details for one CAB member. In total 14 interviews were conducted with 8 research team members and 6 CAB members from 12-30 August 2013. RESULTS: Identification of potential CAB members from the community and their participation in developing the terms of reference for CABs was perceived to have contributed to the success of the CAB. Due to the trust that the community had in members of their community the CABs were then in a stronger position to influence community participation in the research. Training of CAB members was identified as a factor that enhanced the functioning of a CAB. Lack of commitment and low literacy levels of CAB members posed a threat to the role of the CAB. Although compensation in the form of a stipend was not provided, CAB members were provided with transport reimbursements for attending meetings. CONCLUSIONS: Selection of CAB members from within the community contributed to community confidence in the CAB, enhancing its ability to act as an effective link between study team and community. This contributed positively to the conduct of the study and enhanced community awareness and acceptance of the research. However, establishment of study specific CABs has the potential to compromise CAB independence due to support provided by the research team in the form of transport reimbursements and other forms of support. Consideration should be given to establishing community wide Community Advisory Boards that could function across a range of studies to increase independent objective decision-making. PMID- 26037508 TI - Revisiting the commercial-academic interface in medical journals. PMID- 26037509 TI - Albumin Supplement Affects the Metabolism and Metabolism-Related Drug-Drug Interaction of Fenoprofen Enantiomers. AB - The influence of albumin towards the metabolism behavior of fenoprofen enantiomers and relevant drug-drug interaction was investigated in the present study. The metabolic behavior of fenoprofen enantiomers was compared in a phase II metabolic incubation system with and without bovine serum albumin (BSA). BSA supplement increased the binding affinity parameter (Km) of (R)-fenoprofen towards human liver microsomes (HLMs) from 148.3 to 214.4 MUM. In contrast, BSA supplement decreased the Km of (S)-fenoprofen towards HLMs from 218.2 to 123.5 MUM. For maximum reaction velocity (Vmax), the addition of BSA increased the Vmax of (R)-fenoprofen from 1.3 to 1.6 nmol/min/mg protein. In the contrast, BSA supplement decreased the Vmax value from 3.3 to 1.5 nmol/min/mg protein. Andrographolide-fenoprofen interaction was used as an example to investigate the influence of BSA supplement towards fenoprofen-relevant drug-drug interaction. The addition of 0.2% BSA in the incubation system significantly decreased the inhibition potential of andrographolide towards (R)-fenoprofen metabolism (P < 0.001). Different from (R)-fenoprofen, the addition of BSA significantly increased the inhibition potential of andrographolide towards the metabolism of (S)-fenoprofen. BSA supplement also changed the inhibition kinetic type and parameter of andrographolide towards the metabolism of (S)-fenoprofen. In conclusion, albumin supplement changes the metabolic behavior of fenoprofen enantiomers and the fenoprofen-andrographolide interaction. PMID- 26037510 TI - Proximo-distal patellar position in three small dog breeds with medial patellar luxation. AB - INTRODUCTION: Medial patellar luxation is thought to be associated with a high proximal position of the patella in the trochlear groove. OBJECTIVE: To determine whether the ratio of patellar ligament length and patellar length (L:P) is influenced by the stifle angle (75 degrees , 96 degrees , 113 degrees , 130 degrees , and 148 degrees ) in small dog breeds and to compare the L:P ratio in dogs of three small dog breeds with and without medial patellar luxation. METHODS: A mediolateral radiograph of the stifle joint was used to measure the L:P ratio in the stifle joints of dogs of three small breeds with and without medial patellar luxation. The L:P ratio was evaluated at five stifle angles (75 degrees , 96 degrees , 113 degrees , 130 degrees , and 148 degrees ) in 14 cadavers (26 stifle joints) of small dog breeds in order to identify the best stifle angle to measure the L:P ratio. Then the mean +/- SD L:P ratio was calculated for normal stifles and stifles with medial patellar luxation grades 1, 2, and 3 in 194 Pomeranians, 74 Chihuahuas, and 41 Toy or Standard Poodles. RESULTS: The L:P ratio was the same for all five stifle angles in the cadavers (p = 0.195). It was also not significantly different in the three breeds (p = 0.135), in normal and medial patellar luxation-affected stifles overall (p = 0.354), and in normal and medial patellar luxation-affected joints within each breed (p = 0.19). CLINICAL SIGNIFICANCE: We conclude that a proximo-distal patellar position is not associated with medial patellar luxation in Pomeranians, Chihuahuas, and Toy or Standard Poodles. Thus a longer patellar ligament length does not play a role in the pathophysiology of medial patellar luxation in these small dog breeds. PMID- 26037511 TI - Stochastic epidemic models featuring contact tracing with delays. AB - This paper is concerned with a stochastic model for the spread of an SEIR (susceptible -> exposed (=latent) -> infective -> removed) epidemic with a contact tracing scheme, in which removed individuals may name some of their infectious contacts, who are then removed if they have not been already after some tracing delay. The epidemic is analysed via an approximating, modified birth death process, for which a type-reproduction number is derived in terms of unnamed individuals, that is shown to be infinite when the contact rate is sufficiently large. We obtain explicit results under the assumption of either constant or exponentially distributed infectious periods, including the epidemic extinction probability in the former case. Numerical illustrations show that, while the distributions of latent periods and delays have an effect on the spread of the epidemic, the assumption of whether the delays experienced by individuals infected by the same individual are of the same or independent length makes little difference. PMID- 26037512 TI - A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone. AB - CONTEXT: RTHalpha is a recently discovered resistance to thyroid hormone (RTH) due to mutation of THRA, the gene encoding TRalpha1, the thyroid hormone receptor. It has been described in a few patients with growth retardation, short stature, and a low free T4/free T3 (FT4/FT3) ratio. OBJECTIVE: A 27-year-old patient presenting with dwarfism and a low FT4/FT3 ratio was investigated. DESIGN: Clinical, biochemical, and radiological data were collected. Whole exome sequencing was performed in the patient and her relatives. RESULTS: The patient exhibited congenital macrocytic anemia and severe bone malformation with growth retardation, dwarfism, clavicular agenesis, and abnormalities of the fingers, toes, and elbow joints. In adulthood, she presented with active behavior, chronic motor diarrhea, and hypercalcemia. Treatment with T3 led to heart rate acceleration, worsening of diarrhea, and TSH suppression. Low resting energy expenditure normalized on T3. rT3, SHBG, and IGF-1 remained normal. A de novo monoallelic missense mutation in THRA was discovered, the N359Y amino acid substitution (c.1075A>T), which affected both the TRalpha1 and the non-receptor isoform TRalpha2. The mutant TRalpha1 had a decrease in transcriptional activity related to decreased T3 binding and a dominant-negative effect on the wild-type receptor. CONCLUSIONS: This patient presents a new phenotype including more significant bone abnormalities, lower TSH, and higher FT3 levels, without certainty of all her symptoms with the TRalpha1(N359Y) mutation. This case suggests that patients with a low FT4/FT3 ratio should be screened for THRA mutations, even if clinical and biological features differ from previous reported cases of RTHalpha. PMID- 26037513 TI - Postprandial Protein Handling Is Not Impaired in Type 2 Diabetes Patients When Compared With Normoglycemic Controls. AB - CONTEXT: The progressive loss of muscle mass with aging is accelerated in type 2 diabetes patients. It has been suggested that this is attributed to a blunted muscle protein synthetic response to food intake. OBJECTIVE: The objective of the study was to test the hypothesis that the muscle protein synthetic response to protein ingestion is impaired in older type 2 diabetes patients when compared with healthy, normoglycemic controls. DESIGN: A clinical intervention study with two parallel groups was conducted between August 2011 and July 2012. SETTING: The study was conducted at the research unit of Maastricht University, The Netherlands. Intervention, Participants, and Main Outcome Measures: Eleven older type 2 diabetes males [diabetes; age 71 +/- 1 y, body mass index (BMI) 26.2 +/- 0.5 kg/m(2)] and 12 age- and BMI-matched normoglycemic controls (control; age 74 +/- 1 y, BMI 24.8 +/- 1.1 kg/m(2)) participated in an experiment in which they ingested 20 g intrinsically L-[1-(13)C]phenylalanine-labeled protein. Continuous iv L-[ring-(2)H5]phenylalanine infusion was applied, and blood and muscle samples were obtained to assess amino acid kinetics and muscle protein synthesis rates in the postabsorptive and postprandial state. RESULTS: Plasma insulin concentrations increased after protein ingestion in both groups, with a greater rise in the diabetes group. Postabsorptive and postprandial muscle protein synthesis rates did not differ between groups and averaged 0.029 +/- 0.003 vs 0.029 +/- 0.003%/h(1) and 0.031 +/- 0.002 vs 0.033 +/- 0.002%/h(1) in the diabetes versus control group, respectively. Postprandial L-[1-(13)C]phenylalanine incorporation into muscle protein did not differ between groups (0.018 +/- 0.001 vs 0.019 +/- 0.002 mole percent excess, respectively). CONCLUSIONS: Postabsorptive muscle protein synthesis and postprandial protein handling is not impaired in older individuals with type 2 diabetes when compared with age-matched, normoglycemic controls. PMID- 26037514 TI - Post-Gastric Bypass Hyperinsulinemic Hypoglycemia: Fructose is a Carbohydrate Which Can Be Safely Consumed. AB - CONTEXT: Postprandial hypoglycemia after gastric bypass surgery is a serious problem. Available treatments are often ineffective. OBJECTIVE: The objective was to test the hypotheses that injection of rapid-acting insulin before a high carbohydrate meal or replacement of other carbohydrates with fructose in the meal would prevent hypoglycemia. DESIGN: This was a randomized, crossover trial comparing a high-carbohydrate meal with premeal saline injection (control), a high-carbohydrate meal with premeal insulin injection, and a high-fructose meal with total carbohydrate content similar to the control meal. SETTING: The setting was an academic medical center. PATIENTS: Ten patients with post-gastric bypass hyperinsulinemic hypoglycemia participated. INTERVENTIONS: Interventions included lispro insulin injected before test meals and replacement of other carbohydrates with fructose in test meals. MAIN OUTCOME MEASURE: The main outcome measure was plasma glucose < 60 mg/dL after test meals. RESULTS: After the control meal, mean peak glucose and insulin were 173 +/- 47 mg/dL and 134 +/- 55 mU/L, respectively; mean glucose nadir was 44 +/- 15 mg/dL; and eight of 10 subjects demonstrated glucose < 60 mg/dL. Five subjects demonstrated a glucose nadir < 40 mg/dL. There were no significant differences in the corresponding values after premeal insulin treatment, except that the mean glucose nadir of 34 +/- 10 mg/dL was lower (P < .05). After the fructose meal, mean peak postprandial glucose and insulin were 117 +/- 20 mg/dL and 45 +/- 31 mU/L, respectively (both P < .001 for comparison with control), mean glucose nadir was 67 +/- 10 mg/dL (P < .001), and two of 10 subjects demonstrated glucose < 60 mg/dL (P < .05). CONCLUSIONS: People with post gastric bypass hypoglycemia can consume a meal sweetened with fructose with little risk of hypoglycemia. Treatment with rapid-acting insulin before a carbohydrate-containing meal did not prevent hypoglycemia. PMID- 26037516 TI - Quantitative Macro-Raman Spectroscopy on Microparticle-Based Pharmaceutical Dosage Forms. AB - Quantitative macro-Raman spectroscopy was applied to the analysis of the bulk composition of pharmaceutical drug powders. Powders were extracted from seven commercial lactose-carrier-based dry-powder inhalers: Flixotide 50, 100, 250, and 500 MUg/dose (four concentrations of fluticasone propionate) and Seretide 100, 250, and 500 MUg/dose (three concentrations of fluticasone propionate, each with 50 MUg/dose salmeterol xinafoate ). Also, a carrier-free pressurized metered-dose inhaler of the same combination product, Seretide 50 (50 MUg fluticasone propionate and 25 MUg salmeterol xinafoate per dose) was tested. The applicability of a custom-designed dispersive macro-Raman instrument with a large sample volume of 0.16 MUL was tested to determine the composition of the multicomponent powder samples. To quantify the error caused by sample heterogeneity, a Monte Carlo model was developed to predict the minimum sample volume required for representative sampling of potentially heterogeneous samples at the microscopic level, characterized by different particle-size distributions and compositions. Typical carrier-free respirable powder samples required a minimum sample volume on the order of 10(-4) MUL to achieve representative sampling with less than 3% relative error. In contrast, dosage forms containing non-respirable carriers (e.g., lactose) required a sample volume on the order of 0.1 MUL for representative measurements. Error analysis of the experimental results showed good agreement with the error predicted by the simulation. PMID- 26037515 TI - Adipose Tissue Redistribution and Ectopic Lipid Deposition in Active Acromegaly and Effects of Surgical Treatment. AB - CONTEXT: GH and IGF-I have important roles in the maintenance of substrate metabolism and body composition. However, when in excess in acromegaly, the lipolytic and insulin antagonistic effects of GH may alter adipose tissue (AT) deposition. OBJECTIVES: The purpose of this study was to examine the effect of surgery for acromegaly on AT distribution and ectopic lipid deposition in liver and muscle. DESIGN: This was a prospective study before and up to 2 years after pituitary surgery. SETTING: The setting was an academic pituitary center. PATIENTS: Participants were 23 patients with newly diagnosed, untreated acromegaly. MAIN OUTCOME MEASURES: We determined visceral (VAT), subcutaneous (SAT), and intermuscular adipose tissue (IMAT), and skeletal muscle compartments by total-body magnetic resonance imaging, intrahepatic and intramyocellular lipid by proton magnetic resonance spectroscopy, and serum endocrine, metabolic, and cardiovascular risk markers. RESULTS: VAT and SAT masses were lower than predicted in active acromegaly, but increased after surgery in male and female subjects along with lowering of GH, IGF-I, and insulin resistance. VAT and SAT increased to a greater extent in men than in women. Skeletal muscle mass decreased in men. IMAT was higher in active acromegaly and decreased in women after surgery. Intrahepatic lipid increased, but intramyocellular lipid did not change after surgery. CONCLUSIONS: Acromegaly may present a unique type of lipodystrophy characterized by reduced storage of AT in central depots and a shift of excess lipid to IMAT. After surgery, this pattern partially reverses, but differentially in men and women. These findings have implications for understanding the role of GH in body composition and metabolic risk in acromegaly and other clinical settings of GH use. PMID- 26037517 TI - Changes over time in callus formation caused by intermittently administering PTH in rabbit distraction osteogenesis models. AB - BACKGROUND: Changes over time in the callus during intermittent administration of parathyroid hormone (PTH) were studied in rabbit distraction osteogenesis models. METHOD: Models of distraction osteogenesis in Japanese white rabbits were created, and distraction osteogenesis (total length: 10.5 mm) was performed for 2 weeks. Simultaneously with the start of distraction, 30 rabbits received 4 weeks of subcutaneous administration of 30 MUg/kg of PTH(1-34), teriparatide, (P-group: n = 15) or saline (N-group: n = 15) every other day. The tibias of five rabbits were dissected at 6, 8, and 10 weeks after surgery to perform bone mineral density (BMD), peripheral quantitative computed tomography (pQCT), and mechanical testing. RESULTS: The mean BMD had no significant differences over time at 6, 8, and 10 weeks after surgery between the P-group and the N-group. On pQCT, the P group had significant increases in total bone cross-sectional area of the callus compared to the N-group at 8 and 10 weeks after surgery. On mechanical testing, the P-group's absorption energy had not changed at 6 weeks after surgery compared to the N-group, but it had significantly increased at 8 weeks. At 10 weeks after surgery, the N-group's absorption energy rapidly increased, and the difference between the two groups disappeared. CONCLUSION: The intermittent administration of PTH(1-34), teriparatide, for 4 weeks every other day from the start of distraction had the potential to shorten the callus maturation period in the rabbit distraction osteogenesis models. PMID- 26037518 TI - Lysophospholipids from the Guangxi Sponge Spirastrella purpurea. AB - Four known (1-4) and two new (5 and 6) lysophospholipids were isolated from the sponge Spirastrella purpurea from Weizhou Island, Guangxi Autonomous Region, China. The structures of the new compounds (5 and 6) were elucidated by detailed spectroscopic techniques, including 1D and 2D NMR ((1)H and (13)C NMR, (1)H-(1)H COSY, HSQC, and HMBC) as well as mass spectrometry and optical rotation experiments. The known compounds (1-4) were identified by comparison of their spectroscopic data and specific optical rotation with those reported in the literature. The isolated compounds displayed various moderate in vitro antifungal activities against four fungi (Cryptococcus neoformans, Candida glabrata, Trichophyton rubrum, and Aspergillus fumigatus), whereas they displayed no neuroprotective activity against Abeta25-35-induced SH-SY5Y cell damage. PMID- 26037519 TI - Occurrence of Hexacosapolyenoic Acids 26:7(n-3), 26:6(n-3), 26:6(n-6) and 26:5(n 3) in Deep-Sea Brittle Stars from Near the Kuril Islands. AB - Significant amounts of polyunsaturated fatty acids (PUFA) with a chain length of 26 carbon atoms were detected in lipids of five deep water species of Ophiuroidea besides common fatty acids with chain lengths between 14 and 24. By means of hydrogenation, GC-MS of the methyl esters, and 4,4-dimethyloxazoline (DMOX) derivatives of these C26 acids were characterized as 5,8,11,14,17,20,23 hexacosaheptaenoic [26:7(n-3)]; 8,11,14,17,20,23-hexacosahexaenoic [26:6(n-3)]; 5,8,11,14,17,20- hexacosahexaenoic [26:6(n-6)]; and 11,14,17,20,23 hexacosapentaenoic [26:5(n-3)]. Concentrations of these acids varied from 0.3 to 4.5 mol% of the total FA. In all the samples investigated, the main component of C26PUFA was hexacosaheptaenoic acid 26:7(n-3). These C26PUFA are localized mainly in polar lipids. The presence of the possible biosynthesis precursors suggests that the C26PUFA are produced by the brittle stars, and are not accumulated from food sources. This finding can also explain the presence of small amounts of the 26:7(n-3) acid detected earlier in flesh lipids of the roughscale sole Clidoderma asperrimum, which feeds on deep water brittle stars. We suggest a possible scheme of the biosynthesis of C26 PUFA. PMID- 26037520 TI - Reversed-Phase Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry for High-Throughput Molecular Profiling of Sea Cucumber Cerebrosides. AB - Usually, the chemical structures of cerebrosides in sea creatures are more complicated than those from terrestrial plants and animals. Very little is known about the method for high-throughput molecular profiling of cerebrosides in sea cucumbers. In this study, cerebrosides from four species of edible sea cucumbers, specifically, Apostichopus japonicas, Thelenota ananas, Acaudina molpadioides and Bohadschia marmorata, were rapidly identified using reversed-phase liquid chromatography-quadrupole-time-of-flight mass spectrometry (RPLC-QToF-MS). [M + H](+) in positive electrospray ionization (ESI) mode were used to obtain the product ion spectra. The cerebroside molecules were selected according to the neutral loss fragments of 180 Da and then identified according to pairs of specific products of long-chain bases (LCB) and their precursor ions. A typical predominant LCB was 2-amino-1,3-dihydroxy-4-heptadecene (d17:1), which was acylated to form saturated and monounsaturated non-hydroxy and monohydroxy fatty acids with 17-25 carbon atoms. Simultaneously, the occurrence of 2-hydroxy tricosenoic acid (C23:1h) was characteristic of sea cucumber cerebrosides, whereas this molecule was rarely discovered in plants, mammals, or fungi. The profiles of LCB and fatty acids (FA) distribution might be related to the genera of sea cucumber. These data will be useful for identification of cerebrosides using RPLC-QToF-MS. PMID- 26037522 TI - Time to revise the revised-International Prognostic Scoring System? PMID- 26037521 TI - Vitamin D3 supplementation: Response and predictors of vitamin D3 metabolites - A randomized controlled trial. AB - BACKGROUND & AIMS: Large parts of the population are insufficiently supplied with vitamin D, in particular when endogenous synthesis is absent. Therefore many health care providers recommend the use of vitamin D supplements. The current study aimed to investigate the efficacy of an once-daily oral dose of 20 MUg vitamin D3 to improve the vitamin D status and to evaluate predictors of response. METHODS: The study was conducted as a double-blind, randomized, placebo controlled parallel trial from January till April 2013. In total, 105 subjects (20-71 years) were allocated to receive either a vitamin D3 supplement (20 MUg/d) or a placebo for 12 weeks. Circulating levels of vitamin D3 metabolites such as the 25(OH)D3 and the 24,25(OH)2D3, and biomarkers of calcium and phosphate metabolism were quantified. RESULTS: The 25(OH)D3 serum concentrations in the placebo group decreased from 38 +/- 15 nmol/L at baseline to 32 +/- 14 nmol/L and 32 +/- 13 nmol/L at weeks 8 and 12 of the study, respectively (p < 0.01). In the vitamin D3 group, the serum 25(OH)D3 concentration increased from 38 +/- 14 nmol/L at baseline to 70 +/- 15 nmol/L and 73 +/- 16 nmol/L at weeks 8 and 12 of vitamin D3 supplementation (p < 0.001), respectively. As a result, 94% of the vitamin D3-supplemented participants reached 25(OH)D3 concentrations of >=50 nmol/L and thereof 46% attained 25(OH)D3 levels of >=75 nmol/L until the end of the study. The extent of the 25(OH)D3 increase upon vitamin D3 supplementation depended on 25(OH)D3 baseline levels, age, body weight and circulating levels of triglycerides. In contrast to 25(OH)D3, the response of 24,25(OH)2D3 to the vitamin D3 treatment was affected only by baseline levels of 24,25(OH)2D3 and age. CONCLUSIONS: The average improvement of 25(OH)D3 levels in individuals who received 20 MUg vitamin D3 per day during the winter months was 41 nmol/L compared to individuals without supplementation. As a result almost all participants with the vitamin D3 supplementation attained 25(OH)D3 concentrations of 50 nmol/L and higher. The suitability of 24,25(OH)2D3 as a marker of vitamin D status needs further investigation. Clinical trial registration number at clinicaltrials.gov: NCT01711905. PMID- 26037523 TI - Bacteria influence mountain pine beetle brood development through interactions with symbiotic and antagonistic fungi: implications for climate-driven host range expansion. AB - Bark beetles are associated with diverse communities of symbionts. Although fungi have received significant attention, we know little about how bacteria, and in particular their interactions with fungi, affect bark beetle reproduction. We tested how interactions between four bacterial associates, two symbiotic fungi, and two opportunistic fungi affect performance of mountain pine beetles (Dendroctonus ponderosae) in host tissue. We compared beetle performance in phloem of its historical host, lodgepole pine (Pinus contorta), and its novel host recently accessed through warming climate, jack pine (Pinus banksiana). Overall, beetles produced more larvae, and established longer ovipositional and larval galleries in host tissue predominantly colonized by the symbiotic fungi, Grosmannia clavigera, or Ophiostoma montium than by the opportunistic colonizer Aspergillus and to a lesser extent, Trichoderma. This occurred in both historical and naive hosts. Impacts of bacteria on beetle reproduction depended on particular fungus-bacterium combinations and host species. Some bacteria, e.g., Pseudomonas sp. D4-22 and Hy4T4 in P. contorta and Pseudomonas sp. Hy4T4 and Stenotrophomonas in P. banksiana, reduced antagonistic effects by Aspergillus and Trichoderma resulting in more larvae and longer ovipositional and larval galleries. These effects were not selective, as bacteria also reduced beneficial effects by symbionts in both host species. Interestingly, Bacillus enhanced antagonistic effects by Aspergillus in both hosts. These results demonstrate that bacteria influence brood development of bark beetles in host tissue. They also suggest that climate-driven range expansion of D. ponderosae through the boreal forest will not be significantly constrained by requirements of, or interactions among, its microbial associates. PMID- 26037524 TI - PBPK modeling of irbesartan: incorporation of hepatic uptake. AB - Physiological based pharmacokinetic (PBPK) modeling is now commonly used in drug development to integrate human or animal physiological data in order to predict pharmacokinetic profiles. The aim of this work was to construct and refine a PBPK model of irbesartan taking into account its active uptake via OATP1B1/B3 in order to predict more accurately its pharmacokinetic profile using Simcyp((r)). The activity and expression of the human hepatocyte transporters OATP1B1 and OATP1B3 were studied. The relative activity factors (RAFs) for OATP1B1 and OATP1B3 transporters were calculated from intrinsic clearances obtained by concentration dependent uptake experiments in human hepatocytes and HEK overexpressing cells: RAF1B1 using estrone-3-sulfate and pitavastatine clearances, and RAF1B3 using cholecystokinine octapeptide (CCK-8) clearances. The relative expression factor (REF) was calculated by comparing immunoblotting of hepatocytes (REFHH ) or tissues (REFtissue) with those of overexpressing HEK cells for each transporter. These scaling factors were applied in a PBPK model of irbesartan using the Simcyp(r) simulator. Pharmacokinetic simulation using REFHH (1.82 for OATP1B1, 8.03 for OATP1B3) as an extrapolation factor was the closest to the human clinical pharmacokinetic profile of irbesartan. These investigations show the importance of integrating the contribution of the active uptake of a drug in the liver to improve PBPK modeling. PMID- 26037525 TI - Bronchiolitis in children: summary of NICE guidance. PMID- 26037526 TI - Dissociation of Charge Transfer States and Carrier Separation in Bilayer Organic Solar Cells: A Time-Resolved Electroabsorption Spectroscopy Study. AB - Ultrafast optical probing of the electric field by means of Stark effect in planar heterojunction cyanine dye/fullerene organic solar cells enables one to directly monitor the dynamics of free electron formation during the dissociation of interfacial charge transfer (CT) states. Motions of electrons and holes is scrutinized separately by selectively probing the Stark shift dynamics at selected wavelengths. It is shown that only charge pairs with an effective electron-hole separation distance of less than 4 nm are created during the dissociation of Frenkel excitons. Dissociation of the coulombically bound charge pairs is identified as the major rate-limiting step for charge carriers' generation. Interfacial CT states split into free charges on the time-scale of tens to hundreds of picoseconds, mainly by electron escape from the Coulomb potential over a barrier that is lowered by the electric field. The motion of holes in the small molecule donor material during the charge separation time is found to be insignificant. PMID- 26037527 TI - An imputation-based solution to using mismeasured covariates in propensity score analysis. AB - Although covariate measurement error is likely the norm rather than the exception, methods for handling covariate measurement error in propensity score methods have not been widely investigated. We consider a multiple imputation based approach that uses an external calibration sample with information on the true and mismeasured covariates, multiple imputation for external calibration, to correct for the measurement error, and investigate its performance using simulation studies. As expected, using the covariate measured with error leads to bias in the treatment effect estimate. In contrast, the multiple imputation for external calibration method can eliminate almost all the bias. We confirm that the outcome must be used in the imputation process to obtain good results, a finding related to the idea of congenial imputation and analysis in the broader multiple imputation literature. We illustrate the multiple imputation for external calibration approach using a motivating example estimating the effects of living in a disadvantaged neighborhood on mental health and substance use outcomes among adolescents. These results show that estimating the propensity score using covariates measured with error leads to biased estimates of treatment effects, but when a calibration data set is available, multiple imputation for external calibration can be used to help correct for such bias. PMID- 26037529 TI - Two-stage phase II oncology designs using short-term endpoints for early stopping. AB - Phase II oncology trials are conducted to evaluate whether the tumour activity of a new treatment is promising enough to warrant further investigation. The most commonly used approach in this context is a two-stage single-arm design with binary endpoint. As for all designs with interim analysis, its efficiency strongly depends on the relation between recruitment rate and follow-up time required to measure the patients' outcomes. Usually, recruitment is postponed after the sample size of the first stage is achieved up until the outcomes of all patients are available. This may lead to a considerable increase of the trial length and with it to a delay in the drug development process. We propose a design where an intermediate endpoint is used in the interim analysis to decide whether or not the study is continued with a second stage. Optimal and minimax versions of this design are derived. The characteristics of the proposed design in terms of type I error rate, power, maximum and expected sample size as well as trial duration are investigated. Guidance is given on how to select the most appropriate design. Application is illustrated by a phase II oncology trial in patients with advanced angiosarcoma, which motivated this research. PMID- 26037528 TI - Bayesian multivariate augmented Beta rectangular regression models for patient reported outcomes and survival data. AB - Many longitudinal studies (e.g. observational studies and randomized clinical trials) have collected multiple rating scales at each visit in the form of patient-reported outcomes (PROs) in the close unit interval [0 ,1]. We propose a joint modeling framework to address the issues from the following data features: (1) multiple correlated PROs; (2) the presence of the boundary values of zeros and ones; (3) extreme outliers and heavy tails; (4) the PRO-dependent terminal events such as death and dropout. Our modeling framework consists of a multivariate augmented mixed-effects sub-model based on Beta rectangular distributions for the multiple longitudinal outcomes and a Cox model for the terminal events. The simulation studies suggest that in the presence of outliers, heavy tails, and dependent terminal event, our proposed models provide more accurate parameter estimates than the joint model based on Beta distributions. The proposed models are applied to the motivating Long-term Study-1 (LS-1 study, n = 1741) of Parkinson's disease patients. PMID- 26037530 TI - WT1 and interferon-beta-vitamin D association in MS: a longitudinal study. AB - BACKGROUND: It has been suggested that polymorphisms in the WT1 gene modulate the effect of IFN-beta treatment in multiple sclerosis (MS) through regulation of the relationship between IFN-beta and vitamin D. OBJECTIVE: To examine whether WT1 modulates the relationship between IFN-beta and vitamin D in a longitudinal study with repeated assessment of vitamin D before and after initiation of IFN-beta. METHODS: In a prospective study of 85 patients with relapsing remitting MS, 25 hydroxyvitamin D was measured at month 0, 1, 3, 6, 7, 9, 12, 18 and 24. None of the patients used any immunomodulatory treatment at inclusion, and all started IFN-beta treatment at month 6. RESULTS: The mean concentrations of seasonally adjusted 25-hydroxyvitamin increased slightly (3.1 +/- 1.2 nmol/l, P = 0.008) after initiation of IFN-beta. The association between IFN-beta treatment and 25 hydroxyvitamin D was similar in patients carrying any of the two alleles in the WT1 SNPs (rs10767935 and rs5030244) recently reported to modulate this relationship. CONCLUSIONS: In this prospective study with repeated measurements of 25-hydroxyvitamin D before and during treatment with IFN-beta, we did not find that genetic variation in WT1 plays any role in regulating the relationship between IFN-beta and serum 25-hydroxyvitamin D. PMID- 26037531 TI - An Assessment of the Oral Bioavailability of Three Ca-Channel Blockers Using a Cassette-Microdose Study: A New Strategy for Streamlining Oral Drug Development. AB - A cassette-microdose (MD) clinical study was performed to demonstrate its usefulness for identifying the most promising compound for oral use. Three Ca channel blockers (nifedipine, nicardipine, and diltiazem) were chosen as model drugs. In the MD clinical study, a cassette-dose method was employed in which three model drugs were administered simultaneously. Both intravenous (i.v.) and oral (p.o.) administration studies were conducted to calculate the oral bioavailability (BA). For comparison, p.o. studies with therapeutic dose (ThD) levels were also performed. In all studies, blood concentrations of each drug were successfully determined using liquid chromatography-mass spectrometry with the lower limit of quantification of 0.2-2.0 pg/mL. Oral BA of nifedipine in the MD study was approximately 50% and in the same range with that obtained in the ThD study, whereas other two drugs showed significantly lower BA in the MD study, indicating a dose-dependent absorption. In addition, compared with the ThD study, absorption of nicardipine was delayed in the MD study. As a result, nifedipine was considered to be most promising for oral use. In conclusion, a cassette-MD clinical study is of advantage for oral drug development that enables to identify the candidate having desired properties for oral use. PMID- 26037532 TI - Control methods against invasive Aedes mosquitoes in Europe: a review. AB - Five species of invasive Aedes mosquitoes have recently become established in Europe: Ae. albopictus, Ae. aegypti, Ae. japonicus japonicus, Ae. koreicus and Ae. atropalpus. These mosquitoes are a serious nuisance for people and are also competent vectors for several exotic pathogens such as dengue and chikungunya viruses. As they are a growing public health concern, methods to control these mosquitoes need to be implemented to reduce their biting and their potential for disease transmission. There is a crucial need to evaluate methods as part of an integrated invasive mosquito species control strategy in different European countries, taking into account local Aedes infestations and European regulations. This review presents the control methods available or in development against invasive Aedes mosquitoes, with a particular focus on those that can be implemented in Europe. These control methods are divided into five categories: environmental (source reduction), mechanical (trapping), biological (e.g. copepods, Bacillus thuringiensis var. israelensis, Wolbachia), chemical (insect growth regulators, pyrethroids) and genetic (sterile insect technique and genetically modified mosquitoes). We discuss the effectiveness, ecological impact, sustainability and stage of development of each control method. PMID- 26037533 TI - Tyrosinase inhibitor screening in traditional Chinese medicines by electrophoretically mediated microanalysis. AB - A capillary-electrophoresis-based method for the screening of tyrosinase inhibitors in traditional Chinese medicines was developed. The method integrated electrophoretically mediated microanalysis with sandwich mode injection, partial filling, and rapid polarity switching techniques, and carried out on-column enzyme reaction and the separation of substrate and product. The conditions were optimized including the background electrolyte, mixing voltage, and the incubation time. Finally, the screening of nine standard natural compounds of traditional Chinese medicines was carried out. The inhibitors can be directly identified from the reduced peak area of the product compared to that obtained without any inhibitor. Chlorogenic acid (100 MUM) showed inhibitory activity with the inhibitory percentage of 19.8%, while the other compounds showed no inhibitory activity. This method has great application potential in drug discovery from traditional Chinese medicines. PMID- 26037534 TI - Violence toward chronic pain care providers: A national survey. AB - INTRODUCTION: This study measured the following: violence rates against chronic pain care providers (CPCPs), character/context/risk factors for violence and CPCPs' mitigation strategies. METHOD: An e-mail survey was sent to members of the American Society of Interventional Pain Physicians (ASIIP) to collect demographics, rates/type of violence, injury, risk mitigation, and context of violence. Correlation with demographic factors calculated using one-way ANOVA and chi2 test (Fisher test). RESULTS: Security was called by 64.85% of CPCPs and 51.52% received threats. The threats involved a gun 7.05% of the time. Injury was reported by 2.73% of CPCPs. The most common risk mitigation was discharging patient (85.33%). Others used protective equipment (16.89%) of which a significant percentage carried a gun (54%). Opioid management was the highest context for violence (89.9%; P < 0.0001). Those who practiced part-time were more likely to be harmed (P = 0.0290). Females were less likely to be threatened (P = 0.0507). Anesthesiology was the most threatened vs other specialties (P = 0.0215). Urban practices were less likely to move or close the practice (P = 0.0292). CONCLUSION: CPCPs were at high risk for violence. Risk factors were older age, male, working part time, and anesthesiology. Risk was highest in the context of opioid management and disability. Discharging patient was the most common risk mitigation. A significant number of physicians carried firearms. PMID- 26037535 TI - Genomic Data from Extinct North American Camelops Revise Camel Evolutionary History. AB - Recent advances in paleogenomic technologies have enabled an increasingly detailed understanding of the evolutionary relationships of now-extinct mammalian taxa. However, a number of enigmatic Quaternary species have never been characterized with molecular data, often because available fossils are rare or are found in environments that are not optimal for DNA preservation. Here, we analyze paleogenomic data extracted from bones attributed to the late Pleistocene western camel, Camelops cf. hesternus, a species that was distributed across central and western North America until its extinction approximately 13,000 years ago. Despite a modal sequence length of only around 35 base pairs, we reconstructed high-coverage complete mitochondrial genomes and low-coverage partial nuclear genomes for each specimen. We find that Camelops is sister to African and Asian bactrian and dromedary camels, to the exclusion of South American camelids (llamas, guanacos, alpacas, and vicunas). These results contradict previous morphology-based phylogenetic models for Camelops, which suggest instead a closer relationship between Camelops and the South American camelids. The molecular data imply a Late Miocene divergence of the Camelops clade from lineages that separately gave rise to the extant camels of Eurasia. Our results demonstrate the increasing capacity of modern paleogenomic methods to resolve evolutionary relationships among distantly related lineages. PMID- 26037537 TI - Dopaminergic correlates of metabolic network activity in Parkinson's disease. AB - Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both (18) F-fluorodeoxyglucose (FDG) and (18) F-fluoro-L-dopa (FDOPA). Expression values for the PD motor- and cognition-related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel-by-voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel-wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel-wise correlations between caudate/putamen FDOPA uptake and whole-brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss. PMID- 26037536 TI - Recent Evolution in Rattus norvegicus Is Shaped by Declining Effective Population Size. AB - The brown rat, Rattus norvegicus, is both a notorious pest and a frequently used model in biomedical research. By analyzing genome sequences of 12 wild-caught brown rats from their presumed ancestral range in NE China, along with the sequence of a black rat, Rattus rattus, we investigate the selective and demographic forces shaping variation in the genome. We estimate that the recent effective population size (Ne) of this species = [Formula: see text], based on silent site diversity. We compare patterns of diversity in these genomes with patterns in multiple genome sequences of the house mouse (Mus musculus castaneus), which has a much larger Ne. This reveals an important role for variation in the strength of genetic drift in mammalian genome evolution. By a Pairwise Sequentially Markovian Coalescent analysis of demographic history, we infer that there has been a recent population size bottleneck in wild rats, which we date to approximately 20,000 years ago. Consistent with this, wild rat populations have experienced an increased flux of mildly deleterious mutations, which segregate at higher frequencies in protein-coding genes and conserved noncoding elements. This leads to negative estimates of the rate of adaptive evolution (alpha) in proteins and conserved noncoding elements, a result which we discuss in relation to the strongly positive estimates observed in wild house mice. As a consequence of the population bottleneck, wild rats also show a markedly slower decay of linkage disequilibrium with physical distance than wild house mice. PMID- 26037538 TI - Nodal Upstaging in Robotic and Video Assisted Thoracic Surgery Lobectomy for Clinical N0 Lung Cancer. AB - BACKGROUND: Recent multiinstitutional published data have demonstrated increased pathologic nodal upstaging by robotic lobectomy compared with historical video assisted thoracic surgery (VATS) lobectomy data. To eliminate potential variability from multiple surgical techniques, we compared the rate of nodal upstaging at a single institution where robotic and VATS lobectomy are both performed. METHODS: We retrospectively reviewed clinically node-negative patients with lung cancer undergoing VATS or robotic lobectomy. Clinical data were recorded in concordance with The Society of Thoracic Surgeons database elements. The rates of pathologic nodal upstaging as well as disease-free and overall survival were calculated. RESULTS: A total of 211 patients underwent anatomic lobectomy by VATS (n = 158) or robotics (n = 53) from 2009 to 2014. The two groups were statistically similar in their clinical stage, tumor size, location, and histologic evaluation. Within the VATS group, 24 patients experienced nodal upstaging (15.2%), with 13 patients having pN1 disease, and 11 patients having pN2 disease. The robotics group contained 7 patients (13.2%) with nodal upstaging, with 5 patients exhibiting pN1 disease and 2 patients with pN2 disease. When VATS and robotics were compared, there was no significant difference in pathologic upstaging (p = 0.72), 2-year overall survival (88% vs 95%, respectively; p = 0.40), or 2-year disease-free survival (83% vs 93%, respectively; p = 0.48). CONCLUSIONS: In this comparison of robotic and VATS lobectomy for clinically node-negative lung cancer that was managed with consistent surgical technique and pathologic evaluation, the rate of nodal upstaging achieved by robotics appears similar to VATS. In addition, there were no appreciable differences in disease-free or overall survival. PMID- 26037539 TI - Risk Score for Predicting Mortality in Flail Chest. AB - BACKGROUND: Flail chest injuries are associated with high mortality and morbidity. Despite evidence that operative repair of flail chest is beneficial, it is rarely done. We sought to create a simple risk score using available preoperative covariates to calculate individual risk of mortality in flail chest. METHODS: A logistic regression model was trained on Ontario Trauma Registry data to generate a mortality risk score. The final model was validated for calibration and discrimination and corrected for optimism. RESULTS: The model uses five risk factors that are readily obtained during the initial assessment of the trauma patient: age, Glasgow Coma Score, ventilation, cardiopulmonary resuscitation, and number of comorbidities. It was determined that less than 6 points is consistent with 1% observed mortality, 6 to 10 points predicts 5% mortality, 11 to 15 points predicts 22% mortality, and 16 or more points predicts 46% mortality. CONCLUSIONS: We have developed a simple model that can be easily applied at bedside to predict mortality in patients with flail chest by accessing a spreadsheet program in an application or other handheld computer device. This model has the potential to be a useful tool for surgeons considering operative repair of flail chest. PMID- 26037540 TI - A Modified Model for Preoperatively Predicting Malignancy of Solitary Pulmonary Nodules: An Asia Cohort Study. AB - BACKGROUND: With the recent widespread use of computed tomography, interest in ground glass opacity pulmonary lesions has increased. We aimed to develop a model for predicting the probability of malignancy in solitary pulmonary nodules. METHODS: We assessed 846 patients with newly discovered solitary pulmonary nodules referred to Fujian Medical University Union Hospital. Data on 18 clinical and 13 radiologic variables were collected. Two thirds of the patients were randomly selected to derive the prediction model (derivation set); the remaining one third provided a validation set. The lesions were divided according to proportion of ground glass opacity (less than 50% or 50% or greater). Univariate analysis of significant covariates for their relationship to the presence of malignancy was performed. An equation expressing the probability of malignancy was derived from these findings and tested on data from the validation group. Receiver-operating characteristic curves were constructed using the prediction model and the Mayo Clinic model. RESULTS: In lesions with less than 50% ground glass opacity, three clinical characteristics (age, presence of symptoms, total protein) and three radiologic characteristics (diameter, lobulation, calcified nodes) were independent predictors of malignancy. In lesions with 50% or more ground glass opacity, two clinical characteristics (sex, percent of forced expiratory volume in 1 second accounting for expected value) and two radiologic characteristics (diameter, calcified nodes) were independent predictors of malignancy. Our prediction model was better than the Mayo Clinic model to distinguish between benign and malignant solitary pulmonary nodules (p < 0.05). CONCLUSIONS: Our prediction model could accurately identify malignancy in patients with solitary pulmonary nodules, especially in lesions with 50% or more ground glass opacity. PMID- 26037542 TI - Enhanced Raman Scattering from Vibro-Polariton Hybrid States. AB - Ground-state molecular vibrations can be hybridized through strong coupling with the vacuum field of a cavity optical mode in the infrared region, leading to the formation of two new coherent vibro-polariton states. The spontaneous Raman scattering from such hybridized light-matter states was studied, showing that the collective Rabi splitting occurs at the level of a single selected bond. Moreover, the coherent nature of the vibro-polariton states boosts the Raman scattering cross-section by two to three orders of magnitude, revealing a new enhancement mechanism as a result of vibrational strong coupling. This observation has fundamental consequences for the understanding of light-molecule strong coupling and for molecular science. PMID- 26037543 TI - Population dynamics of Amur tigers (Panthera tigris altaica) in Sikhote-Alin Biosphere Zapovednik: 1966-2012. AB - In 2010, the world's tiger (Panthera tigris) range countries agreed to the goal of doubling tiger numbers over 12 years, but whether such an increase is biologically feasible has not been assessed. Long-term monitoring of tigers in Sikhote-Alin Biosphere Zapovednik (SABZ), Russia provided an opportunity to determine growth rates of a recovering population. A 41-year growth phase was followed by a rapid decline in tiger numbers. Annual growth rates during the growth phase averaged 4.6%, beginning near 10% in the earliest years but quickly dropping below 5%. Sex ratio (females per male) mirrored growth rates, declining as population size increased. The rapid decline from 2009 to 2012 appeared to be tied to multiple factors, including poaching, severe winters and disease. Reproductive indicators of this population are similar to those of Bengal tiger populations, suggesting that growth rates may be similar. These results suggest that, first, tiger populations likely in general grow slowly: 3-5% yearly increases are realistic and larger growth rates are likely only when populations are highly depressed, mortality rates are low and prey populations are high relative to numbers of adult females. Second, while more research is needed, it should not be assumed that tiger populations with high prey densities will necessarily grow more quickly than populations with low prey densities. Third, while growth is slow, decline can be rapid. Fourth, because declines can happen so quickly, there is a constant need to monitor populations and be ready to respond with appropriate and timely conservation interventions if tiger populations are to remain secure. Finally, an average annual growth rate across all tiger populations of 6%, required to reach the Global Tiger Initiative's goal of doubling tiger numbers in 12 years, is a noble but unlikely scenario. PMID- 26037544 TI - Using the Effects of Youngsters' Eyesight on Quality of Life Questionnaire to Measure Visual Outcomes in Children With Uveitis. AB - OBJECTIVE: The Effects of Youngsters' Eyesight on Quality of Life (EYE-Q) is a novel measure of vision-related quality of life (QOL) and function in children. We aim to determine the validity of the EYE-Q in childhood uveitis. METHODS: We abstracted medical record data on arthritis and uveitis in a convenience sample of children with juvenile idiopathic arthritis (JIA) and/or uveitis. In addition to the EYE-Q, parents and patients completed questionnaires on overall QOL (Pediatric Quality of Life Inventory [PedsQL]), and physical functioning (Childhood Health Assessment Questionnaire [C-HAQ]). RESULTS: Among 57 children (8 JIA, 24 JIA and uveitis, 25 uveitis alone), 102 ocular examinations were performed within 1 month of completing questionnaires. Uveitis patients had bilateral disease (69%), anterior involvement (78%), synechiae (51%), and cataracts (49%). Children with vision loss in their better eye (visual acuity [VA] 20/50 or worse) had worse EYE-Q (P = 0.006) and PedsQL (P = 0.028) scores, but not C-HAQ scores. The EYE-Q moderately correlated with logMAR VA (rs = 0.43), PedsQL (rs = 0.43), and C-HAQ (rs = -0.45), but was not correlated with anterior chamber cells or intraocular pressure. The PedsQL and C-HAQ did not correlate with VA or cells. There were strong correlations between the parent and child EYE-Q (rs = 0.62). Cronbach's alpha for the child report was 0.91. The EYE Q had strong test-retest reliability (rs = 0.75). CONCLUSION: The EYE-Q may be an important tool in the assessment of visual outcomes in childhood uveitis and an improvement over general measures in detecting changes in vision-related function. PMID- 26037545 TI - Knee laxity modifications after ACL rupture and surgical intra- and extra articular reconstructions: intra-operative measures in reconstructed and healthy knees. AB - PURPOSE: Quantifying the effects of anterior cruciate ligament (ACL) deficiency on knee joint laxity is fundamental for understanding the outcomes of its reconstruction techniques. The general aim of this study was to determine intra operatively the main modifications in knee laxity before and after standard isolated intra-articular and additional extra-articular anterolateral reinforcement. Our main hypothesis was that laxity abnormalities, particularly axial rotation, can still result from these ACL reconstruction techniques. METHODS: Thirty-two patients with primary ACL deficiency were analysed by a navigation system immediately before and after each of the two reconstructions. Laxity measurements in terms of knee translations and rotations were taken during the anteroposterior drawer test, with internal-external rotation at 20 degrees and 90 degrees of flexion, and varus-valgus and pivot-shift tests. All these laxity measures were also taken originally from the contralateral healthy knee. RESULTS: With respect to the contralateral healthy knee, in the ACL-deficient knee significantly increased laxity (expressed in %) was found in the medial compared with that of the lateral compartment, respectively, 115 and 68 % in the drawer test at 20 degrees flexion, and 55 and 46 % at 90 degrees flexion. In the medial compartment, a significant 35 % increment was also observed for the coupled tibial anteroposterior translation during axial knee rotation at 20 degrees of flexion. After isolated intra-articular reconstruction, normal values of anteroposterior laxity were found restored in the pivot-shift and drawer tests in the lateral compartment, but not fully in the medial compartment. After the reinforcement, laxity in the medial compartment was also found restored in the axial rotation test at 20 degrees flexion. CONCLUSION: In ACL reconstruction, with respect to the contralateral knee, intra-articular plus additional anterolateral reinforcement procedures do not restore normal joint laxity. This combined procedure over-constrained the lateral compartment, while excessive laxity still persists at the medial one. LEVEL OF EVIDENCE: III. PMID- 26037546 TI - Higher forgotten joint score for fixed-bearing than for mobile-bearing total knee arthroplasty. AB - PURPOSE: To compare the postoperative subjective outcome for fixed- and mobile bearing total knee arthroplasty (TKA) by using the forgotten joint score (FJS 12), a new patient-reported outcome score of 12 questions evaluating the potential of a patient to forget about his operated joint. The hypothesis of this study was that a mobile-bearing TKA would have a higher level of forgotten joint than a fixed-bearing model of the same design. METHODS: A retrospective cohort study was conducted in 100 patients who underwent TKA at least 1 year [mean (SD) 18 (5) months] before with either a fixed-bearing (N = 50) or a mobile-bearing (N = 50) TKA from the same implant family. Clinical outcome was evaluated with the knee society score and patient-reported outcome with the forgotten joint score. RESULTS: No difference was observed for demographics in between both study groups. The mean (SD) postoperative FJS-12 for the fixed-bearing TKA was 71 (28) compared to a mean (SD) of 56.5 (30) for the mobile-bearing TKA. DISCUSSION: The clinical relevance of the present retrospective study is that it shows for the first time a significant difference between fixed- and mobile-bearing TKA by using a new patient-reported outcome score. The hypothesis that mobile-bearing TKA would have a higher degree of forgotten joint than a fixed-bearing TKA could not be confirmed. A level I prospective study should be set up to objectivise these findings. LEVEL OF EVIDENCE: IV. PMID- 26037547 TI - The challenge of treating complex knee instability. PMID- 26037548 TI - Fixed combination of cinnarizine and dimenhydrinate in the prophylactic therapy of vestibular migraine: an observational study. AB - Vestibular migraine (VM) is one of the most frequent causes of episodic vertigo, with a lifetime prevalence of 0.98%. Prophylactic therapy includes calcium channel blockers, beta-blockers, antiepileptic drugs and antidepressants. We studied the association of cinnarizine 20 mg and dimenhydrinate 40 mg (Arlevertan) in a group of 22 patients affected by definite VM. Proposed therapy included one tablet twice a day for 1 month, which was repeated three times with 1 month of interval between drug intake; results were compared with those of a control group of 11 VM patients who asked to observe only lifestyle measures for migraine. The main outcome was the number of vertigo and headache crises in the 6 months before therapy and in the 6 months of follow-up. Subjects performing Arlevertan presented during the 6 months of therapy a decrease of vertigo attacks from 5.3 to 2.1 and of headaches from 4.3 to 1.7 (p < 0.0001); 68% of these subjects reported a decrease of at least 50% of vertigo attacks, while 63% of headaches. Conversely, vertigo attacks decreased from 3.5 to 2.2 and headaches from 2.6 to 2 in patients observing only lifestyle; 18% of these subjects reported a decrease of at least 50% of vertigo crises and 27% of headaches. Our data do not differ from those of previous works assessing efficacy of different prophylactic therapies for VM and reporting consistent reduction of vertigo spells in a rate of patients ranging from 60 and 80%. PMID- 26037549 TI - TREM2 variants and risk of Alzheimer's disease: a meta-analysis. AB - Recent studies show that heterozygous variant of triggering receptor expressed on myeloid cells 2 (TREM2) increase the risk of Alzheimer's disease (AD) but with inconclusive results. Here, we conducted a meta-analysis to summarize and clarify the association between TREM2 variants and AD, and examined the relationship between TREM2 genetic variant and the etiology of AD. Relevant case-control studies were retrieved and collected according to established inclusion criteria. Odds ratio (OR) and 95% confidence interval (95% CI) were used to estimate the associations between three TREM2 variants (rs75932628, rs104894002, and rs143332484) and AD. In overall meta-analysis, the summary ORs for rs75932628, rs104894002, and rs143332484 were 2.70 [95% CI: 2.24, 3.24; P < 0.001], 7.21 (95% CI: 1.28, 40.78; P = 0.025), and 1.65 (95% CI: 1.24, 2.21; P = 0.001), respectively, indicating that the TREM2 rs75932628, rs104894002, and rs143332484 may contribute to AD risk. However, sensitivity analysis showed that the results of rs104894002 and rs143332484 should be interpreted with caution, and larger sample size, particularly in different ethnicities, are needed to validate the two variants. The current meta-analysis demonstrates that TREM2 is a candidate gene for AD susceptibility, and TREM2 variant rs75932628 may be a risk factor for AD. PMID- 26037550 TI - Alternate methods of nasal epithelial cell sampling for airway genomic studies. PMID- 26037551 TI - Peanut defensins: Novel allergens isolated from lipophilic peanut extract. AB - BACKGROUND: Peanut is one of the most hazardous sources of food allergens. Unknown allergens are still hidden in the complex lipophilic matrix. These allergens need to be discovered to allow estimation of the allergenic risk for patients with peanut allergy and to further improve diagnostic measures. OBJECTIVE: We performed detection, isolation, and characterization of novel peanut allergens from lipophilic peanut extract. METHODS: Extraction of roasted peanuts were performed under defined extraction conditions and examined by means of 2-dimensional PAGE. Subsequently, chromatographic methods were adapted to isolate low-molecular-weight components. Proteins were studied by using SDS-PAGE and immunoblotting with sera from patients with peanut allergy. For allergen identification protein sequencing, homology search and mass spectrometry were applied. Functional characterization for allergenicity was performed by using the basophil activation assay and for antimicrobial activity by using inhibition assays of different bacteria and fungi. RESULTS: IgE-reactive proteins of 12, 11, and 10 kDa were first detected after chloroform/methanol extraction in the flow through of hydrophobic interaction chromatography. The proteins were able to activate basophils of patients with peanut allergy. N-terminal sequencing and homology search in the expressed sequence tag database identified the allergens as peanut defensins, which was confirmed by using mass spectrometry. On microbial cell cultures, the peanut defensins showed inhibitory effects on the mold strains of the genera Cladosporium and Alternaria but none on bacteria. CONCLUSIONS: We identified defensins as novel peanut allergens (Ara h 12 and Ara h 13) that react in particular with IgE of patients with severe peanut allergy. Their antimicrobial activity is solely antifungal. PMID- 26037555 TI - [Proceedings book]. PMID- 26037553 TI - Brain Glycogen Decreases During Intense Exercise Without Hypoglycemia: The Possible Involvement of Serotonin. AB - Brain glycogen stored in astrocytes, a source of lactate as a neuronal energy source, decreases during prolonged exercise with hypoglycemia. However, brain glycogen dynamics during exercise without hypoglycemia remain unknown. Since intense exercise increases brain noradrenaline and serotonin as known inducers for brain glycogenolysis, we hypothesized that brain glycogen decreases with intense exercise not accompanied by hypoglycemia. To test this hypothesis, we employed a well-established acute intense exercise model of swimming in rats. Rats swam for fourteen 20 s bouts with a weight equal to 8 % of their body mass and were sacrificed using high-power (10 kW) microwave irradiation to inactivate brain enzymes for accurate detection of brain glycogen and monoamines. Intense exercise did not alter blood glucose, but did increase blood lactate levels. Immediately after exercise, brain glycogen decreased and brain lactate increased in the hippocampus, cerebellum, cortex, and brainstem. Simultaneously, serotonin turnover in the hippocampus and brainstem mutually increased and were associated with decreased brain glycogen. Intense swimming exercise that does not induce hypoglycemia decreases brain glycogen associated with increased brain lactate, implying an importance of glycogen in brain energetics during intense exercise even without hypoglycemia. Activated serotonergic regulation is a possible underlying mechanism for intense exercise-induced glycogenolysis at least in the hippocampus and brainstem. PMID- 26037554 TI - Detection of pulseless electric activity using regional cerebral saturation monitoring. PMID- 26037556 TI - [In Process Citation]. PMID- 26037557 TI - [In Process Citation]. PMID- 26037552 TI - Single-cell systems-level analysis of human Toll-like receptor activation defines a chemokine signature in patients with systemic lupus erythematosus. AB - BACKGROUND: Activation of Toll-like receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in patients with systemic lupus erythematosus (SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has not been described. OBJECTIVE: We sought to characterize TLR activation across multiple immune cell subsets and subjects, with the goal of establishing a reference framework against which to compare pathologic processes. METHODS: Peripheral whole-blood samples were stimulated with TLR ligands and analyzed by means of mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied 17 healthy volunteer donors and 8 patients with newly diagnosed and untreated SLE. RESULTS: Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of natural killer cells and T cells selectively induced nuclear factor kappa light chain enhancer of activated B cells in response to TLR2 ligands. CD14(hi) monocytes exhibited the most polyfunctional cytokine expression patterns, with more than 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared among a group of healthy donors, with minimal intraindividual and interindividual variability. Furthermore, autoimmune disease altered baseline cytokine production; newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity. CONCLUSION: Mass cytometry defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in patients with inflammatory diseases, such as SLE. PMID- 26037559 TI - [In Process Citation]. PMID- 26037558 TI - [In Process Citation]. PMID- 26037560 TI - [In Process Citation]. PMID- 26037561 TI - [In Process Citation]. PMID- 26037562 TI - [In Process Citation]. PMID- 26037563 TI - [In Process Citation]. PMID- 26037564 TI - [In Process Citation]. PMID- 26037565 TI - [In Process Citation]. PMID- 26037566 TI - [In Process Citation]. PMID- 26037567 TI - [In Process Citation]. 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PMID- 26037591 TI - The Exchange Relationship between Work-Family Enrichment and Affective Commitment: the Moderating Role of Gender. AB - Workers' perception that their job experience enriches their family life has been considered a mechanism that explains their positive attitudes toward the organization where they work. However, because women and men live their work and family differently, gender may condition this relationship between the work family enrichment and workers' attitudes. With a sample of 1885 workers from one Portuguese bank, with 802 women, the current study investigated the relationship between work-family enrichment and organizational affective commitment as well as the role of sex as a moderator of this relationship. The hypotheses were tested by using regression analysis. The results indicated that the perception held by workers that their work enriches their family is positively correlated with their affective commitment toward the organization. Furthermore, the data revealed that this relationship is stronger for women than for men. Study results have implications for management, particularly for human resource management, enhancing their knowledge about the relationship of work-family enrichment and workers' affective commitment toward organization. PMID- 26037592 TI - Neuromuscular ultrasound imaging in low back pain patients with radiculopathy. AB - BACKGROUND: Patients suffering from chronic low back pain with associated radiculopathy (LBP-R), or sciatica, experience neuromuscular symptoms in the lower back and leg; however, research to date has focussed solely on the lower back. OBJECTIVES: To expand neuromuscular research of LBP-R patients into the lower limb, using ultrasound imaging. DESIGN: Case control study comparing LBP-R patients to matched healthy controls. METHODS: LBP-R patients with disc bulge or herniation (L3/L4 to L5/S1) resulting in unilateral radiculopathy (n = 17) and healthy matched controls (n = 17) were recruited. High-resolution ultrasound imaging was used to investigate sciatic nerve structure, as well as the quality (relative magnitude of fat/fibrosis infiltration) and contraction (muscle thickening) of associated musculature in the lower back (paraspinals) and lower limb (biceps femoris, gastrocnemius, soleus). RESULTS: LBP-R patients had swollen sciatic nerves (increased cross sectional area), but this was not associated with evidence of reduced lower limb muscle quality. As compared to controls, LBP-R patients demonstrated less soleus muscle thickening during submaximal contraction; however, there were no impairments in the hamstring or lower back musculature. CONCLUSIONS: Ultrasound imaging was an effective method to detect sciatic nerve swelling in mild to moderately affected LBP-R patients. Nerve swelling was not associated with poorer muscle quality, nor consistently impaired muscle contraction. PMID- 26037593 TI - Controlling the Spatial Organization of Liquid Crystalline Nanoparticles by Composition of the Organic Grafting Layer. AB - Understanding how the spatial ordering of liquid crystalline nanoparticles can be controlled by different factors is of great importance in the further development of their photonic applications. In this paper, we report a new key parameter to control the mesogenic behavior of gold nanoparticles modified by rodlike thiols. An efficient method to control the spatial arrangement of hybrid nanoparticles in a condensed state is developed by changing the composition of the mesogenic grafting layer on the surface of the nanoparticles. The composition can be tuned by different conditions of the ligand exchange reaction. The thermal and optical behavior of the mesogenic and promesogenic ligands were investigated by using differential scanning calorimetry (DSC) and hot-stage polarized optical microscopy. The chemical structure of the synthesized hybrid nanoparticles was characterized by (1) H NMR spectroscopy, thermogravimetric analysis (TGA), XPS, and elemental analysis, whereas the superstructures were examined by small-angle X-ray diffraction (SAXSRD) analysis. Structural studies showed that the organic sublayer made of mesogenic ligands is denser with an increasing the average ligand number, thereby separating the nanoparticles in the liquid crystalline phases, which changes the parameters of these phases. PMID- 26037594 TI - Asymmetric conformational maturation of HIV-1 reverse transcriptase. AB - HIV-1 reverse transcriptase utilizes a metamorphic polymerase domain that is able to adopt two alternate structures that fulfill catalytic and structural roles, thereby minimizing its coding requirements. This ambiguity introduces folding challenges that are met by a complex maturation process. We have investigated this conformational maturation using NMR studies of methyl-labeled RT for the slower processes in combination with molecular dynamics simulations for rapid processes. Starting from an inactive conformation, the p66 precursor undergoes a unimolecular isomerization to a structure similar to its active form, exposing a large hydrophobic surface that facilitates initial homodimer formation. The resulting p66/p66' homodimer exists as a conformational heterodimer, after which a series of conformational adjustments on different time scales can be observed. Formation of the inter-subunit RH:thumb' interface occurs at an early stage, while maturation of the connection' and unfolding of the RH' domains are linked and occur on a much slower time scale. PMID- 26037595 TI - Stability of implants placed in fresh sockets versus healed alveolar sites: Early findings. AB - OBJECTIVES: The present study measured implant stability quotient (ISQ) values at three different time points after surgical procedures to compare whether the stability values differed between implants placed in fresh extraction sockets versus healed alveolar sites. MATERIALS AND METHODS: To measure implant stability, resonance frequency analysis (RFA) was performed in 77 patients (53 women, 24 men) with a total of 120 dental implants. These implants were divided into two groups: Group 1 included 60 implants in healed alveolar sites (22 in the maxilla, 38 in the mandible), and Group 2 included 60 implants in fresh sockets (41 in the maxilla, 19 in the mandible). Implant stability was measured immediately at implant placement (baseline), 90, and 150 days later. Statistical analysis was made using a multivariate regression linear model at implant level (alpha = 0.05). RESULTS: Overall, the means and standard deviations of the ISQ values were 62.7 +/- 7.14 (95% confidence interval [CI], 39-88) at baseline, 70.0 +/- 6.22 (95% CI, 46-88) at 90 days, and 73.4 +/- 5.84 (95% CI, 58-88) at 150 days. In Group 1, the ISQs ranged between 64.3 +/- 6.20 and 75.0 +/- 5.69, while in Group 2, presented lower values that ranged between 61.2 +/- 8.09 and 71.9 +/- 5.99 (P = 0.002). Anatomic location and times periods were the only identified variables with an influence on ISQ values at implant level (P < 0.0001). CONCLUSIONS: The stabilities of the implants placed in the fresh sockets and in healed sites exhibited similar evolutions in ISQ values and thus osseointegration; however, the implants in the healed alveolar sites exhibited superior values at all time points. PMID- 26037597 TI - Electric polarization of magnetic domain walls in magnetoelectrics. AB - Two prominent magnetoelectrics MnWO4 and CuO possess low-temperature commensurate paraelectric magnetically ordered phase. Here using Monte Carlo simulations we show that the walls between the domains of this phase are ferroelectric with the same electric polarization direction and value as those in the magnetoelectric phases of these compounds. We also suggest that experimental observation of electric polarization of domain walls in MnWO4 should help to determine the macroscopic interactions responsible for its magnetoelectric properties. PMID- 26037596 TI - Heparin treatment increases thioredoxin interacting protein expression in hepatocellular carcinoma cells. AB - Heparins play an important role in cell growth, differentiation, migration and invasion. However, the molecular mechanisms of heparin mediated cellular behaviors are not well defined. To determine the effect of heparin on gene expression, we performed a cDNA microarray in a hepatocellular carcinoma cell line and found that heparin regulates transcription of genes involved in glucose metabolism. In this study, we showed a new role of heparin in the regulation of thioredoxin interacting protein, which is a major regulator of glucose metabolism, in hepatocellular carcinoma cell lines. We determined the importance of a unique carbohydrate response element located on its promoter for the heparin induced activation of thioredoxin-interacting protein and the modulatory role of heparin on nuclear accumulation of carbohydrate response element associated proteins. We showed the importance of heparin mediated histone modifications and down-regulation of Enhancer of zeste 2 polycomb repressive complex 2 expression for heparin mediated overexpression of thioredoxin-interacting protein. When we tested biological significance of these data; we observed that cells overexpressing thioredoxin-interacting protein are less adhesive and proliferative, however they have a higher migration and invasion ability. Interestingly, heparin treatment increased thioredoxin-interacting protein expression in liver of diabetic rats. In conclusion, our results show that heparin activates thioredoxin-interacting protein expression in liver and hepatocellular carcinoma cells and provide the first evidences of regulatory roles of heparin on carbohydrate response element associated factors. This study will contribute future understanding of the effect of heparin on glucose metabolism and glucose independent overexpression of thioredoxin-interacting protein during hepatocarcinogenesis. PMID- 26037598 TI - Psychometric properties of the Dutch version of the Orofacial Esthetic Scale (OES NL) in dental patients with and without self-reported tooth wear. AB - The aim of this study was to test the psychometric properties of the Dutch version of the Orofacial Esthetic Scale (OES) in dental patients with and without self-reported tooth wear. The English version of the OES was translated into Dutch, following established guidelines for cross-cultural adaptation of health related quality of life measures. The reliability of the resulting OES-NL was tested in a test-retest study on 343 subjects; its validity was tested with the use of convergent validity on 582 subjects. The test-retest reliability of the OES-NL showed intra-class correlation coefficients (ICC) that ranged from 0.76 to 0.82, which can be qualified as excellent. The Cronbach's alpha revealed that the overall internal consistency of the scale was good (alpha = 0.89). Convergent validity was confirmed by the association between the OES-NL summary scores and three questions of the Dutch version of the Oral Health Impact Profile (OHIP-NL). The calculated Spearman's rank correlation coefficients ranged from -0.43 to 0.54 and were all significant (P < 0.001). The Dutch version of the Orofacial Esthetic Scale (OES-NL) showed good psychometric properties, making it suitable for the assessment of self-perceived aesthetics in Dutch dental patients with and without self-reported tooth wear. PMID- 26037599 TI - Impact of incomplete revascularization of coronary artery disease on long-term cardiac outcomes. Retrospective comparison of angiographic and myocardial perfusion imaging criteria for completeness. AB - BACKGROUND: Coronary revascularization in patients with coronary artery disease may be guided by coronary angiography (CA) or alternatively by ischemia on stress myocardial perfusion imaging (MPI). Which strategy leads to optimal cardiac outcomes is uncertain. METHODS: We performed a retrospective analysis of 170 patients with MPI ischemia and percutaneous coronary intervention. The primary endpoint was all-cause mortality at a mean follow-up of 47 +/- 21 months; the secondary end point was the composite of deaths, nonfatal myocardial infarction, and repeat coronary revascularization (MACE). The coronary revascularization was defined as complete (CCR) or incomplete (ICR) as judged by CA criteria and by MPI ischemia matched with CA criteria. RESULTS: Nighty-two patients (54%) had ICR by CA criteria (ICR-CA) and 84 (49%) had ICR by MPI criteria (ICR-MPI). Mortality and MACE were lower in patients with CCR-MPI than with ICR-MPI (P = .048, and P = .025). Survival of patients with CCR-CA and ICR-CA was not different (P = .081). Patients with both ICR-MPI and ICR-CA had the worst survival, whereas patients with CCR-MPI and CCR-CA had the best survival (P = .047). By multivariate analysis, ICR-MPI + ICR-CA was an independent predictor of death (P = .025). CONCLUSION: Patients with ICR by MPI were at higher risk than those with CCR. Patients with both ICR by MPI and CA were at the highest risk, while patients with CCR by both MPI and CA had the best long-term event-free survival. PMID- 26037601 TI - Aortic composite tube valve graft infection due to Streptococcus pneumoniae. PMID- 26037600 TI - Outcome of patients with high-risk Duke treadmill score and normal myocardial perfusion imaging on spect. AB - BACKGROUND: Annual mortality rate can range from <1% for patients with normal myocardial perfusion by SPECT to >5% based on a high-risk Duke treadmill score (DTS). Information on the prognosis of patients with the combination of HRDTS and normal SPECT is limited and is the purpose of this study. METHODS: Data from a large nuclear cardiology registry (n = 17,972 patients) were reviewed. A total of 340 had HRDTS (score <= -11) while undergoing SPECT. Combined cardiovascular mortality and non-fatal myocardial infarction (MI) and cardiovascular mortality alone were available in 310 patients at a mean follow-up of 4.01 +/- 1.5 years. RESULTS: The majority of the patients had abnormal SPECT (n = 270, 71%). The abnormal SPECT patients compared to the normal were older (65.6 vs 62.8 years of age; P = .025), more likely to have abnormal left ventricular ejection fraction (26.1% vs 0%; P < .0001), known coronary artery disease (CAD, 35.9% vs 7.8%; P < .0001) and lower DTS (-14.5 vs -13.2; P = .0006), Kaplan-Meier survival analysis demonstrated a significantly lower cardiovascular mortality (5.4% vs 0%, P = .02) and combined outcome of MI and cardiovascular mortality (15% vs 4.4%, P = .009) in patients with normal versus abnormal SPECT. CONCLUSIONS: High-risk DTS is associated with abnormal perfusion SPECT in most patients, but nearly one-third of the patients had normal perfusion. Patients with a normal SPECT had a lower cardiovascular event rates. PMID- 26037602 TI - Ultimate osmosis engineered by the pore geometry and functionalization of carbon nanostructures. AB - Osmosis is the key process in establishing versatile functions of cellular systems and enabling clean-water harvesting technologies. Membranes with single atom thickness not only hold great promises in approaching the ultimate limit of these functions, but also offer an ideal test-bed to explore the underlying physical mechanisms. In this work, we explore diffusive and osmotic transport of water and ions through carbon nanotube and porous graphene based membranes by performing molecular dynamics simulations. Our comparative study shows that the cylindrical confinement in carbon nanotubes offers much higher salt rejection at similar permeability in osmosis compared to porous graphene. Moreover, chemical functionalization of the pores modulates the membrane performance by its steric and electrostatic nature, especially at small-size pores due to the fact that the optimal transport is achieved by ordered water transport near pore edges. These findings lay the ground for the ultimate design of forward osmosis membranes with optimized performance trade-off, given the capability of nano-engineering nanostructures by their geometry and chemistry. PMID- 26037604 TI - Longitudinal association between habitual physical activity and depressive symptoms in older people. AB - AIMS: Prevention of depressive symptoms is an essential issue with regard to the promotion of healthy lifestyles in older people. To date, few studies have examined the relation between fluctuations in physical activity and depression among older individuals. We thus conducted a longitudinal survey of older adults to examine the effect of long-term fluctuating physical activity on the incidence of depressive symptoms. METHODS: A 3-year prospective cohort study was performed in a community-based environment. A total of 680 individuals (291 men and 389 women) aged 65 years and over at the baseline assessment participated. The 15 item Geriatric Depression Scale was used to assess depressive symptoms, with scores of >=6 indicative of depression. Participants were categorized into the following four groups based on change in physical activity status between 2002 and 2003: sedentary, cessation, initiation, and maintenance. RESULTS: The incidence of depressive symptoms was 16.9% (16.8% in men and 17.0% in women) at the 3-year follow up (in 2006). Multiple logistic regression analyses showed that physical activity maintenance (odds ratio, 0.50; 95% confidence interval, 0.30 0.83) only reduced the incidence of depressive symptoms at the 3-year follow up after adjusting for confounding variables. CONCLUSIONS: Continuous physical activity may be a valuable and simple way to prevent depressive symptoms in community-dwelling older people. Therefore, it is necessary to implement interventions that teach older adults how to integrate physical activity into their daily lives. PMID- 26037605 TI - Skin Diseases in Horses. AB - Skin disease in horses is a common and potentially challenging clinical problem. Information pertaining to skin disease is lacking in horses when compared with that in other companion animal species. Certainly, both horse-specific and location-specific patterns are present, but these can often be confounded by other factors. There are many possible ways in which to organize skin disease; in this article, they are organized based loosely on their most common clinical feature. Space limits the number of conditions that can be described here, and those chosen were seen relatively frequently in a multiinstitutional study of equine biopsies. PMID- 26037606 TI - Toxicology for the Equine Practitioner. AB - A wide variety of toxins cause diseases in the horse and are investigated routinely by veterinarians and veterinary pathologists to identify the cause of illness and death. A complete investigation involves performing a thorough necropsy and requires macroscopic and microscopic examination of lesions and a variety of laboratory testing to obtain an accurate diagnosis. The identification of gross lesions by equine practitioners is often the first step in formulating a diagnostic plan. This article provides a description of selected common toxins producing detectable gross lesions in horses in North America. The article is useful to equine practitioners and veterinary pathologists investigating a toxicology-related death. PMID- 26037603 TI - Early-life influences on obesity: from preconception to adolescence. AB - The double burden of under- and overnutrition profoundly affects human health globally. According to the World Health Organization, obesity and diabetes rates have almost doubled worldwide since 1980, and, in 2011, more than 40 million children under 5 years of age were overweight. Ecologic factors, parental genetics and fitness, and the intrauterine environment significantly influence the likelihood of offspring developing the dysmetabolic diathesis of obesity. This report examines the effects of these factors, including preconception, intrauterine and postnatal energy balance affecting programming of transgenerational transmission, and development of chronic diseases later in life in particular, diabesity and its comorbidities. PMID- 26037607 TI - Musculoskeletal Pathology. AB - The current understanding of pathology as it relates to common diseases of the equine musculoskeletal system is reviewed. Conditions are organized under the fundamental categories of developmental, exercise-induced, infectious, and miscellaneous pathology. The overview of developmental pathology incorporates the new classification system of juvenile osteochondral conditions. Discussion of exercise-induced pathology emphasizes increased understanding of the contribution of cumulative microdamage caused by repetitive cyclic loading. Miscellaneous musculoskeletal pathology focuses on laminitis, which current knowledge indicates should be regarded as a clinical syndrome with a variety of possible distinct mechanisms of structural failure that are outlined in this overview. PMID- 26037608 TI - Respiratory Disease: Diagnostic Approaches in the Horse. AB - Evaluation of the upper and lower respiratory tract of horses requires strategic selection of possible diagnostic tests based on location of suspected pathologic lesions and purpose of testing and must also include consideration of patient status. This article discusses the various diagnostic modalities that may be applied to the respiratory system of horses under field conditions, indications for use, and aspects of sample collection, handling, and laboratory processing that can impact test results and ultimately a successful diagnosis in cases of respiratory disease. PMID- 26037609 TI - A novel molecularly imprinted method with computational simulation for the affinity isolation and knockout of baicalein from Scutellaria baicalensis. AB - A novel molecularly imprinted polymer (MIP) was synthesized by precipitation polymerization with baicalein (BAI) as the template and used as solid-phase extraction (SPE) adsorbent, aiming at the affinity isolation and selective knockout of BAI from Scutellaria baicalensis Georgi (SB). We used computational simulation to predict the optimal functional monomer, polymerization solvent and molar ratio of template to functional monomer. Characterization and performance tests revealed that MIP exhibited uniform spherical morphology, rapid binding kinetics, and higher adsorption capacity for BAI compared with nonimprinted polymer (NIP). The application of MIP in SPE coupled with high-performance liquid chromatography to extract BAI from SB showed excellent recovery (94.3%) and purity (97.0%). Not only the single BAI compound, but also the BAI-removed SB extract was obtained by one-step process. This new method is useful for isolation and knockout of key bioactive compounds from herbal medicines. PMID- 26037610 TI - Discovery and structural analyses of S-adenosyl-L-homocysteine hydrolase inhibitors based on non-adenosine analogs. AB - Optimization of a new series of S-adenosyl-L-homocysteine hydrolase (AdoHcyase) inhibitors based on non-adenosine analogs led to very potent compounds 14n, 18a, and 18b with IC50 values of 13 +/- 3, 5.0 +/- 2.0, and 8.5 +/- 3.1 nM, respectively. An X-ray crystal structure of AdoHcyase with NAD(+) and 18a showed a novel open form co-crystal structure. 18a in the co-crystals formed intramolecular eight membered ring hydrogen bond formations. A single crystal X ray structure of 14n also showed an intramolecular eight-membered ring hydrogen bond interaction. PMID- 26037611 TI - Synthesis and biological activity of novel deoxycholic acid derivatives. AB - We report the synthesis and biological activity of new semi-synthetic derivatives of naturally occurring deoxycholic acid (DCA) bearing 2-cyano-3-oxo-1-ene, 3-oxo 1(2)-ene or 3-oxo-4(5)-ene moieties in ring A and 12-oxo or 12-oxo-9(11)-ene moieties in ring C. Bioassays using murine macrophage-like cells and tumour cells show that the presence of the 9(11)-double bond associated with the increased polarity of ring A or with isoxazole ring joined to ring A, improves the ability of the compounds to inhibit cancer cell growth. PMID- 26037613 TI - N-mustard analogs of S-adenosyl-L-methionine as biochemical probes of protein arginine methylation. AB - Nucleosomes, the fundamental building blocks of eukaryotic chromatin, undergo post-synthetic modifications and play a major role in the regulation of transcriptional processes. Combinations of these modifications, including methylation, regulate chromatin structure, determining its different functional states and playing a central role in differentiation. The biological significance of cellular methylation, particularly on chromatin, is widely recognized, yet we know little about the mechanisms that link biological methylation events. To characterize and fully understand protein methylation, we describe here novel N mustard analogs of S-adenosyl-l-methionine (SAM) as biochemical tools to better understand protein arginine methylation events using protein arginine methyltransferase 1 (PRMT1). Specifically, azide- and alkyne-functionalized N mustard analogs serve as cofactor mimics of SAM and are enzymatically transferred to a model peptide substrate in a PRMT1-dependent fashion. Once incorporated, the resulting alkynes and azides can be modified through chemoselective ligations, including click chemistry and the Staudinger ligation. These results readily demonstrate the feasibility of utilizing N-mustard analogs as biochemical tools to site-specifically label substrates of PRMT1 and serve as an alternative approach to study protein methylation events. PMID- 26037612 TI - Exploiting translational stalling peptides in an effort to extend azithromycin interaction within the prokaryotic ribosome nascent peptide exit tunnel. AB - The ribosome is the primary protein synthesis machine in the cell and is a target for treatment of a variety of diseases including bacterial infection and cancer. The ribosomal peptide exit tunnel, the route of egress for the nascent peptide, is an inviting site for drug design. Toward a rational engagement of the nascent peptide components for the design of small molecule inhibitors of ribosome function, we designed and disclosed herein a set of N-10 indole functionalized azithromycin analogs. The indole moiety of these compounds is designed to mimic the translation stalling interaction of SecM W155 side-chain with the prokaryotic (Escherichia coli) ribosome A751 residue. Many of these N-10 functionalized compounds have enhanced translation inhibition activities against E. coli ribosome relative to azithromycin while a subset inhibited the growth of representative susceptible bacteria strains to about the same extent as azithromycin. Moreover, the inclusion of bovine serum in the bacterial growth media enhanced the anti-bacterial potency of the N-10 functionalized azithromycin analogs by as high as 10-fold. PMID- 26037614 TI - Statins can improve proteinuria and glomerular filtration rate loss in chronic kidney disease patients, further reducing cardiovascular risk. Fact or fiction? AB - INTRODUCTION: The prevalence of chronic kidney disease (CKD), a risk factor for cardiovascular disease (CVD), is increasing worldwide. Statin treatment, the cornerstone of prevention or treatment of CVD, might have beneficial effects on urine protein excretion and renal function as determined by the glomerular filtration rate, whereas it might protect from acute kidney injury (AKI), mainly due to contrast-induced AKI. These beneficial effects on CKD may not be drug class effects; specific statins at specific doses may help prevent CKD deterioration and reduce CVD risk. We analysed all statin studies that had renal and CVD endpoints as main outcome measures. MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were searched up to February 2015. AREAS COVERED: We consider the effects of statins on microalbuminuria, proteinuria, glomerular filtration rate, AKI associated with angiography or percutaneous coronary intervention and on CVD event rates in patients with CKD. EXPERT OPINION: Current evidence points towards the need to prescribe high-potency statins in patients with CKD, before a major decline in kidney function occurs. This may reduce CVD risk and delay the progress of CKD. Administration of either atorvastatin or rosuvastatin can prevent contrast-induced AKI before angiography or percutaneous coronary intervention. The combination of simvastatin + ezetimibe may decrease vascular events in patients with advanced CKD. PMID- 26037615 TI - The N-terminal degenerated metal-binding domain is involved in the heavy metal transport activity of TaHMA2. AB - KEY MESSAGE: We identified key residues of TaHMA2, and the N- and C-terminal regions of the protein have different roles in its transport function when heterologously expressed in yeast. TaHMA2, a P1B-type ATPase from wheat (Triticum aestivum L.), plays an important role in heavy metal homeostasis in plants. A previous study showed that overexpressing TaHMA2 in rice (Oryza sativa L.), Arabidopsis thaliana, or tobacco (Nicotiana tabacum L.) resulted in various responses to heavy metals. Here, we report the heterologous expression of TaHMA2 in the yeast Saccharomyces cerevisiae. TaHMA2 expression increased the yeast's sensitivity to Cd, but not to Zn, Pb or Co, and increased Cd accumulation was concurrently observed. The eGFP-TaHMA2 fusion protein was localized to the plasma membrane and showed a discontinuous pattern. Mutagenesis of the cysteine and glutamate residues in the N-terminal metal-binding domain (N-MBD) impaired the function of TaHMA2. Deletion of most of the C terminus (TaHMA2DeltaC, 712-1003) partially abolished the protein's function, whereas deletion of the N terminus (TaHMA2DeltaN, 2-699) completely abolished Cd sensitivity. These data suggest that cysteine and glutamate residues are important for the metal binding/translocation function of TaHMA2. Additional studies are needed to further understand the selectivity of TaHMA2 in planta. PMID- 26037617 TI - Motivational interviewing for improving recovery after stroke. AB - BACKGROUND: Psychological problems are common complications following stroke that can cause stroke survivors to lack the motivation to take part in activities of daily living. Motivational interviewing provides a specific way for enhancing intrinsic motivation, which may help to improve activities of daily living for stroke survivors. OBJECTIVES: To investigate the effect of motivational interviewing for improving activities of daily living after stroke. SEARCH METHODS: We searched the Cochrane Stroke Group's Trials Register (November 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1), MEDLINE (1948 to March 2015), EMBASE (1980 to March 2015), CINAHL (1982 to March 2015), AMED (1985 to March 2015), PsycINFO (1806 to March 2015), PsycBITE (March 2015) and four Chinese databases. In an effort to identify further published, unpublished and ongoing trials, we searched ongoing trials registers and conference proceedings, checked reference lists, and contacted authors of relevant studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing motivational interviewing with no intervention, sham motivational interviewing or other psychological therapy for people with stroke were eligible. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted eligible data and assessed risk of bias. Outcome measures included activities of daily living, mood and death. MAIN RESULTS: One study involving a total of 411 participants, which compared motivational interviewing with usual care, met our inclusion criteria. The results of this review did not show significant differences between groups receiving motivational interviewing or usual stroke care for participants who were not dependent on others for activities of daily living, nor on the death rate after three-month and 12-month follow-up, but participants receiving motivational interviewing were more likely to have a normal mood than those who received usual care at three months and 12-months follow-up. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the use of motivational interviewing for improving activities of daily living after stroke. Further well designed RCTs are needed. PMID- 26037621 TI - Work Domain Analysis for understanding medication safety in care homes in England: an exploratory study. AB - Medication safety and errors are a major concern in care homes. In addition to the identification of incidents, there is a need for a comprehensive system description to avoid the danger of introducing interventions that have unintended consequences and are therefore unsustainable. The aim of this study was to explore the impact and uniqueness of Work Domain Analysis (WDA) to facilitate an in-depth understanding of medication safety problems within the care home system and identify the potential benefits of WDA to design safety interventions to improve medication safety. A comprehensive, systematic and contextual overview of the care home medication system was developed for the first time. The novel use of the abstraction hierarchy (AH) to analyse medication errors revealed the value of the AH to guide a comprehensive analysis of errors and generate system improvement recommendations that took into account the contextual information of the wider system. PRACTITIONER SUMMARY: It is widely acknowledged that a systems approach is necessary to improve medication safety. This study used a cognitive engineering method, Work Domain Analysis, to map the care home medication system and analyse medication errors. A macro-level view of the system was developed and this has provided a knowledge base for future interventions. PMID- 26037620 TI - Late-Stage Peptide Diversification by Bioorthogonal Catalytic C-H Arylation at 23 degrees C in H2 O. AB - The step-economical late-stage diversification of tryptophan-containing peptides was accomplished through chemo- and site-selective palladium-catalyzed C-H arylation under exceedingly mild reaction conditions. Thus, the C-H functionalization occurred efficiently at 23 degrees C with a catalyst loading as low as 0.5 mol %, and/or in H2 O. PMID- 26037616 TI - Adverse Pregnancy Conditions, Infertility, and Future Cardiovascular Risk: Implications for Mother and Child. AB - Adverse pregnancy conditions in women are common and have been associated with adverse cardiovascular and metabolic outcomes such as myocardial infarction and stroke. As risk stratification in women is often suboptimal, recognition of non traditional risk factors such as hypertensive disorders of pregnancy and premature delivery has become increasingly important. Additionally, such conditions may also increase the risk of cardiovascular disease in the children of afflicted women. In this review, we aim to highlight these conditions, along with infertility, and the association between such conditions and various cardiovascular outcomes and related maternal risk along with potential translation of risk to offspring. We will also discuss proposed mechanisms driving these associations as well as potential opportunities for screening and risk modification. PMID- 26037619 TI - Structural insights into the translational infidelity mechanism. AB - The decoding of mRNA on the ribosome is the least accurate process during genetic information transfer. Here we propose a unified decoding mechanism based on 11 high-resolution X-ray structures of the 70S ribosome that explains the occurrence of missense errors during translation. We determined ribosome structures in rare states where incorrect tRNAs were incorporated into the peptidyl-tRNA-binding site. These structures show that in the codon-anticodon duplex, a G.U mismatch adopts the Watson-Crick geometry, indicating a shift in the tautomeric equilibrium or ionization of the nucleobase. Additional structures with mismatches in the 70S decoding centre show that the binding of any tRNA induces identical rearrangements in the centre, which favours either isosteric or close to the Watson-Crick geometry codon-anticodon pairs. Overall, the results suggest that a mismatch escapes discrimination by preserving the shape of a Watson-Crick pair and indicate that geometric selection via tautomerism or ionization dominates the translational infidelity mechanism. PMID- 26037622 TI - Successful living-related renal transplantation in a patient with factor H antibody-associated atypical hemolytic uremic syndrome. AB - CFH-Ab-associated aHUS requires different diagnostic and therapeutic approaches and then the genetically defined aHUS forms. The risk of post-transplant recurrence with graft dysfunction in CFH-Ab aHUS is not well documented. It is suggested that recurrence can be expected if a significant CFH-Ab load persists at the time of transplantation. A pretransplant procedure to reduce CFH-Ab titer seems reasonable, but accurate recommendations are lacking. Whether further prophylactic interventions after transplantation are necessary has to be decided on an individual basis. We report the case of a late diagnosed CFH-Ab HUS with initial ESRD and a successful living-related renal transplantation over a post transplant period of four and a half years on the basis of a prophylactic pretransplant IVIG admission. PMID- 26037623 TI - Decellularized Versus Fresh-Frozen Allografts in Anterior Cruciate Ligament Reconstruction: An In Vitro Study in a Rabbit Model. AB - BACKGROUND: The common fresh-frozen allografts that are used for anterior cruciate ligament (ACL) reconstructions behave slower during the remodeling process and produce weaker tendon-bone integrations than do autografts. Decellularization of allogenic tendons results in a clean and porous collagen scaffold with low antigenicity and high compatibility, which may be more suitable for ACL reconstructions. HYPOTHESIS: Allograft decellularization will result in a tissue structure with suitable mechanical characteristics for ACL reconstruction, thereby promoting graft remodeling and enhancing tendon-bone healing. STUDY DESIGN: Controlled laboratory study. METHODS: Decellularized allograft tissues were prepared with a pH-modified decellularization process and evaluated for their biocompatibility and biomechanical character in vitro. Eighty New Zealand White rabbits were divided into 2 groups, with 40 in each group, to receive ACL reconstruction with either fresh-frozen (common) allografts or decellularized allografts on both knees. At 2, 4, 8, and 12 weeks postoperatively, the rabbits were euthanized for biomechanical testing, micro-computed tomography analysis, and histologic analysis. RESULTS: The pH-modified decellularized allograft tissues kept excellent biocompatibility and biomechanical character during the in vitro study. Biomechanical testing indicated that the decellularized allograft had significantly higher ultimate load (P = .02) and stiffness (P = .01) levels than the common allograft at 12 weeks, and there was no significant difference between the 2 groups at any other time point. The micro-CT evaluation determined significantly higher bone mineral density (P < .01) in the decellularized allograft group than that in the common allograft group at 12 weeks, but no difference between the 2 groups was observed at any other time point. Regarding bone volume/total volume, there was no difference between the 2 groups at any time point. Fibroblast ingrowths, vascular formation, and connective tissue formation in the tendon-bone interface were better in the decellularized group within 8 weeks. New bone formation was more common in the decellularized allograft group. The collagen birefringence was restored more quickly in the decellularized allograft group than in the common allograft group at all time points. CONCLUSION: The use of pH-modified decellularized allografts compared with the common allografts resulted in better cellularity, vascularity, collagen matrix remolding, new bone formation around the graft, enhanced tendon-bone healing, and higher ultimate failure load and stiffness of the graft after ACL reconstruction in the rabbit model. CLINICAL RELEVANCE: The pH-modified decellularized allograft may be a better graft option than the common fresh frozen allograft for knee ligament reconstructions. PMID- 26037624 TI - Client-identified needs and agency-provided services at a harm reduction community based organization in the District of Columbia. AB - BACKGROUND: Harm reduction case management relies on client-identified goals to drive the provision of care in order to "meet clients where they are at". This research measured the level of agreement between client-identified needs and agency-provided services at a community based organization (CBO) in Washington DC by examining: (1) the services clients most often identified, (2) the services most often given to clients by the CBO, and (3) the level of alignment between client-identified needs and services provided. METHODS: Case file reviews were completed for 151 clients who received case management services at the CBO between January 2010 and February 2011. Client-identified needs and agency provided services were extracted from case files and divided into 9 matching need and service categories: pharmaceutical assistance (e.g., prescription renewal), medical or dental care, housing, mental health services, substance use services, support services (e.g., support group meetings), legal assistance, and employment/job training. Client-identified needs and services provided were analyzed using McNemar's Chi-square to assess for significant differences in discordant pairs. RESULTS: Clients were mostly Black (90.7 %), heterosexual (63.6 %), HIV positive (93.4 %), and over 40 years old at the time of intake (76.2 %). On average, clients identified 2.44 needs and received 3.29 services. The most common client-identified needs were housing (63.7 %), support services (34.3 %), and medical/dental care (29.5 %). The most common agency-provided services were housing (58.2 %), support services (51.4 %), and medical/dental care (45.2 %). In 6 of the 9 service categories, there were statistically significant (p < .01) differences between those who received services not asked for and those who did not receive asked for services in the categories of pharmaceutical assistance, medical/dental care, substance abuse services, support services, legal assistance, and food access. In each of these matched service categories, the percentage of clients who received services not asked for was significantly higher than those who did not. CONCLUSION: This research shows that, while there is general alignment between the services that clients most often want and the services most often provided, there are still instances where services are requested but are not being provided. PMID- 26037625 TI - Cardiovascular risk in chronic kidney disease patients: intima-media thickness predicts the incidence and severity of histologically assessed medial calcification in radial arteries. AB - BACKGROUND: The objective of the study was to determine the relationship between common carotid artery intima-media thickness (CCA-IMT) and histologically assessed calcification of radial artery in relation to clinical features and laboratory markers of bone and mineral metabolism, inflammation, and oxidative stress in patients with stage 5 chronic kidney disease (CKD). METHODS: The study comprised 59 patients (36 hemodialyzed, 23 predialysis). CCA-IMT was measured by ultrasonography; the biochemical parameters examined were assessed using routine laboratory methods, ELISA micro-plate immunoassays and spectrophotometry. Fragments of radial artery obtained during creation of hemodialysis access were cryosectioned and stained for calcifications using von Kossa method and alizarin red. RESULTS: Glucose, osteoprotegerin, pentraxin 3 and Framingham risk score significantly correlated with CCA-IMT. In multiple regression analysis, OPG positively predicted CCA-IMT. Radial artery calcifications were found in 34 patients who showed higher CCA-IMT (0.98 +/- 0.13 vs 0.86 +/- 0.14 mm; P = 0.006). Higher CCA-IMT values were also associated with more advanced calcifications. CCA-IMT and the presence of plaques in common carotid artery were positive predictors of radial artery calcifications, independent of dialysis status, Framingham risk score, CRP and Ca x Pi [OR for calcifications 2.19 (1.08 4.45) per 0.1 mm increase in CCA-IMT]. The presence of radial artery calcifications was a significant predictor of mortality, independent of dialysis status and Framingham risk score [HR 3.16 (1.03-9.64)]. CONCLUSIONS: In CKD patients, CCA-IMT examination can be used as a surrogate measure to assess the incidence and severity of arterial medial calcification which is associated with poor clinical outcome in these patients. PMID- 26037626 TI - Electro-acupuncture for treatment of knee pain from osteoarthritis and the possible endocrinology changes: a study protocol for a randomized controlled trial. AB - BACKGROUND: Osteoarthritis of the knee is a major cause of disability among adults. Electro-acupuncture is considered a potentially useful treatment for osteoarthritis. The purpose of this study is to assess the efficacy of electro acupuncture on pain control, pain perception, plasma cortisol and beta-endorphin levels, patient-perceived quality of life, and pain medication use in patients with chronic knee pain. METHODS/DESIGN: This study is a placebo-controlled, randomized, double-blind, parallel design trial. One hundred sixty out-patients who are more than 50 years old and who have osteoarthritis of the knee will be recruited from the island of Mallorca, Spain. Each participant will be randomly placed into one of two groups: (sham) electro-acupuncture non-insertion technique and real electro-acupuncture. Acupuncture treatments will be the Traditional Chinese Medicine type. The patients will be evaluated after a period of 1 month (with two weekly sessions), 3 months (with one monthly session), 6 months (with one session every 45 days), and 1 year later with follow-up sessions at the end of the study (with one session every 2 months). The primary outcomes will be based on the observed changes from the baseline of the visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for pain measured at 12 weeks after the end of treatment. Also to be included in the study are the possible changes in the secondary efficacy variables from baseline as assessed by the Short Form 36 version 2 health survey (patient-perceived quality of life), patient plasma cortisol and beta-endorphin levels at the different treatment stages, the Goldberg Anxiety and Depression Scale, pain medication use, functional capacity and stiffness (WOMAC subscales), and a VAS. These variables will be assessed at 1 month, 3 months, 6 months, and 1 year after study commencement. DISCUSSION: The findings from this study will help to determine whether electro-acupuncture is effective for chronic knee pain management in older people and whether electro-acupuncture can deliver results for the improvement of pain relief, stiffness, and disability. The study will therefore be a major step toward understanding the roles of the hypothalamic pituitary-adrenal axis and the endogenous opioid system in the effectiveness of electro-acupuncture for chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02299713 (11 Nov. 2014). PMID- 26037628 TI - Perioperative Pain Correlates and Prolonged Postoperative Pain Predictors: Demographic and Psychometric Questionnaires. AB - INTRODUCTION: Perioperatively, patients are near-guaranteed to experience acute pain by virtue of the surgical tissue insult. The transition of acute pain to pathological chronic pain is a complex and poorly understood process. To study this, the prevalence of pain was examined preoperatively, and at 6 weeks and 3 months postoperatively. METHODS: Fifty-four patients undergoing moderate-major gynaecological surgery at Christchurch Women's Hospital (Christchurch, New Zealand) were recruited over a period of 11 weeks. Follow-up by telephone was conducted at 6 weeks and 3 months following surgery. Demographic information including age, gender, ethnicity, work, and education status were collected, as well as aspects of medical history. Participants were subjected to psychometric questionnaires at each time-point. RESULTS: Of the participants, 15.7% experienced significant pain at 6 weeks postoperatively; 8.2% of participants experienced significant pain at 3 months postoperatively. The psychometric questionnaires used found differences between those experiencing pain and those not experiencing pain at given observation points. Only the Brief Illness Perception Questionnaire (BIPQ) appeared predictive of developing prolonged postoperative pain. The mean difference (7.4 on a 0-50) scale should assist in clinical decision-making regarding analgesia. CONCLUSION: Only the BIPQ was predictive of developing prolonged postoperative pain. While none of the demographic factors observed significantly predicted the development of 'prolonged pain', the not significant data followed expected trends. Several relationships were detected in this study that should further efforts in developing preoperative predictors to promote the secondary prevention of postoperative pain states. PMID- 26037627 TI - T regulatory markers expression in unexplained recurrent spontaneous abortion. AB - OBJECTIVE: To evaluate expression of glucocorticoid-induced tumor necrosis factor receptor (GITR), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and IL-10 in peripheral blood mononuclear cells (PBMCs) of 20 women with unexplained recurrent spontaneous abortion (URSA) compared to 20 normal non-pregnant women (NNP) during luteal phase in the window of implantation. METHODS: Quantitative real-time PCR (qRT-PCR) was performed using the Taqman method for expression of GITR and SYBR Green method for expression of CTLA-4 and IL-10. RESULTS: Expression of CTLA-4 in the NNPs (median; interquartile range; 3; 1.8-10) was significantly higher than the URSAs (0.72; 0.26-3.81, p = 0.015). Expression of GITR in the NNPs (53; 10-139) was significantly higher than the URSAs (6; 3-27, p = 0.005). However, IL-10 expression in the URSAs was significantly higher than the NNPs, did not meet a significant value. A significant correlation was found between CTLA-4 and GITR expression in the study population (p = 0.0001). CONCLUSIONS: Expression of CTLA-4 and GITR were significantly down-regulated in the URSAs compared to NNPs at the window of implantation, which shows the essential role of Treg cells in creating an immunological privileged site for fetus as an allograft at the maternal-fetal interface by high expression levels of CTLA-4 and GITR during a normal pregnancy. PMID- 26037629 TI - Dual protection of hydroxytyrosol, an olive oil polyphenol, against oxidative damage in PC12 cells. AB - Hydroxytyrosol (3,4-dihydroxyphenylethanol, HT), a major polyphenol in olive oils, has received increasing attention due to its multiple pharmacological activities. However, it is not well understood how HT works on the neuronal system. We report herein that HT efficiently scavenges free radicals in vitro and displays cytoprotection against oxidative stress-induced damage in PC12 cells. HT completely protects the cells from hydrogen peroxide-induced death and rescues the cells from 6-hydroxydopamine-induced damage. Mechanistic studies reveal that Nrf2 is a prerequisite for the neuroprotection of HT as knocking down Nrf2 eliminated this action. HT, via activation of the Keap1-Nrf2 pathway, elevates a panel of cytoprotective enzymes, including glutamate-cysteine ligase, HO-1, NQO1 and thioredoxin reductase. Our study reveals that HT provides dual neuroprotection and cellular antioxidant defense as both a free radical scavenger and Nrf2 activator, suggesting the potential pharmaceutical usage of HT for the treatment of neurodegenerative disorders. PMID- 26037630 TI - China's overuse of inpatient treatment and routine preoperative testing. PMID- 26037632 TI - Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation. AB - Nitrate derived from vegetables is consumed as part of a normal diet and is reduced endogenously via nitrite to nitric oxide. It has been shown to improve endothelial function, reduce blood pressure and the oxygen cost of sub-maximal exercise, and increase regional perfusion in the brain. The current study assessed the effects of dietary nitrate on cognitive performance and prefrontal cortex cerebral blood-flow (CBF) parameters in healthy adults. In this randomised, double-blind, placebo-controlled, parallel-groups study, 40 healthy adults received either placebo or 450 ml beetroot juice (~5.5 mmol nitrate). Following a 90 minute drink/absorption period, participants performed a selection of cognitive tasks that activate the frontal cortex for 54 min. Near-Infrared Spectroscopy (NIRS) was used to monitor CBF and hemodynamics, as indexed by concentration changes in oxygenated and deoxygenated-haemoglobin, in the frontal cortex throughout. The bioconversion of nitrate to nitrite was confirmed in plasma by ozone-based chemi-luminescence. Dietary nitrate modulated the hemodynamic response to task performance, with an initial increase in CBF at the start of the task period, followed by consistent reductions during the least demanding of the three tasks utilised. Cognitive performance was improved on the serial 3s subtraction task. These results show that single doses of dietary nitrate can modulate the CBF response to task performance and potentially improve cognitive performance, and suggest one possible mechanism by which vegetable consumption may have beneficial effects on brain function. PMID- 26037631 TI - Microstructural analysis of rat ethanol and water drinking patterns using a modified operant self-administration model. AB - BACKGROUND: Ethanol drinking pattern has emerged as an important factor in the development, maintenance, and health consequences of alcohol use disorders in humans. The goal of these studies was to further our understanding of this important factor through refinement of an operant rodent model of ethanol consumption capable of drinking pattern microstructural analysis. We evaluated measures of total consumption, appetitive behavior, and drinking microstructure for ethanol and water at baseline and assessed alterations induced by two treatments previously shown to significantly alter gross ethanol appetitive and consummatory behaviors in opposing directions. METHODS: Male Long-Evans rats were trained on an FR1 operant paradigm which allowed for continuous liquid access until an 8 second pause in consumption resulted in termination of liquid access. Total appetitive and consummatory behaviors were assessed in addition to microstructural drinking pattern for both ethanol and water during a five day baseline drinking period, after chronic intermittent ethanol vapor exposure, and following administration of a cannabinoid receptor antagonist SR141716a. RESULTS: As in previous operant studies, ethanol vapor exposure resulted in increases in ethanol-directed responding, total consumption, and rate of intake. Further, striking differential alterations to ethanol and water bout size, duration, and lick pattern occurred consistent with alterations in hedonic evaluation. Vapor additionally specifically reduced the number of ethanol-directed lever presses which did not result in subsequent consumption. SR141716a administration reversed many of these effects. CONCLUSIONS: The addition of microstructural analysis to operant self-administration by rodents provides a powerful and translational tool for the detection of specific alterations in ethanol drinking pattern which may enable insights into neural mechanisms underlying specific components of drug consumption. PMID- 26037633 TI - The biology of appetite control: Do resting metabolic rate and fat-free mass drive energy intake? AB - The prevailing model of homeostatic appetite control envisages two major inputs; signals from adipose tissue and from peptide hormones in the gastrointestinal tract. This model is based on the presumed major influence of adipose tissue on food intake. However, recent studies have indicated that in obese people fat-free mass (FFM) is strongly positively associated with daily energy intake and with meal size. This effect has been replicated in several independent groups varying in cultural and ethnic backgrounds, and appears to be a robust phenomenon. In contrast fat mass (FM) is weakly, or mildly negatively associated with food intake in obese people. In addition resting metabolic rate (RMR), a major component of total daily energy expenditure, is also associated with food intake. This effect has been replicated in different groups and is robust. This action is consistent with the proposal that energy requirements - reflected in RMR (and other aspects of energy expenditure) constitute a biological drive to eat. Consistent with its storage function, FM has a strong inhibitory effect on food intake in lean subjects, but this effect appears to weaken dramatically as adipose tissue increases. This formulation can account for several features of the development and maintenance of obesity and provides an alternative, and transparent, approach to the biology of appetite control. PMID- 26037635 TI - Building trust: Heart rate synchrony and arousal during joint action increased by public goods game. AB - The physiological processes underlying trust are subject of intense interest in the behavioral sciences. However, very little is known about how trust modulates the affective link between individuals. We show here that trust has an effect on heart rate arousal and synchrony, a result consistent with research on joint action and experimental economics. We engaged participants in a series of joint action tasks which, for one group of participants, was interleaved with a PGG, and measured their heart synchrony and arousal. We found that the introduction of the economic game shifted participants' attention to the dynamics of the interaction. This was followed by increased arousal and synchrony of heart rate profiles. Also, the degree of heart rate synchrony was predictive of participants' expectations regarding their partners in the economic game. We conclude that the above changes in physiology and behavior are shaped by the valuation of other people's social behavior, and ultimately indicate trust building process. PMID- 26037634 TI - Multiple estrogen receptor subtypes influence ingestive behavior in female rodents. AB - Postmenopausal women are at an increased risk of obesity and cardiovascular related diseases. This is attributable, at least in part, to loss of the ovarian hormone estradiol, which inhibits food and fluid intake in humans and laboratory animal models. Although the hypophagic and anti-dipsogenic effects of estradiol have been well documented for decades, the precise mechanisms underlying these effects are not fully understood. An obvious step toward addressing this open question is identifying which estrogen receptor subtypes are involved and what intracellular processes are involved. This question, however, is complicated not only by the variety of estrogen receptor subtypes that exist, but also because many subtypes have multiple locations of action (i.e. in the nucleus or in the plasma membrane). This review will highlight our current understanding of the roles that specific estrogen receptor subtypes play in mediating estradiol's anorexigenic and anti-dipsogenic effects along with highlighting the many open questions that remain. This review will also describe recent work being performed by our laboratory aimed at answering these open questions. PMID- 26037636 TI - Identification of an NPHP1 deletion causing adult form of nephronophthisis. AB - AIMS: Nephronophthisis (NPHP) is an autosomal recessive cystic disease of the kidney with main characteristic features of polyuria/polydipsia, mild or absent proteinuria, interstitial fibrosis, and tubular cysts. NPHP is responsible for 5 10 % of inheritable end-stage renal disease (ESRD) cases. We investigated the clinical features and genetic cause of NPHP in a Persian family with three siblings affected by tubulointerstitial nephropathy reaching ESRD in adulthood. METHODS: Uromodulin (UMOD), known to be involved in adult medullary cystic kidney disease, and nephronophthisis 1 (NPHP1) were investigated in the genomic DNA of the probands using DNA sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis and molecular karyotyping. RESULTS: No mutation was detected in UMOD. Copy number variation analysis of the NPHP1 gene using the commercially available MLPA kit identified a recurrent large homozygous deletion encompassing all NPHP1 exons. The parents were heterozygous for this deletion. Whole genome array-CGH analysis confirmed a homozygous deletion on chromosome 2q13, NPHP1 site, and revealed that the size of the copy number loss was approximately 102 Kbp. CONCLUSION: This is the first report of determination of an NPHP1 deletion size using routine diagnostic methods. The results of this study expand the knowledge about the genotype-phenotype correlations in NPHP1, and have implications for genetic counseling and family planning advice for other affected families. This is the first molecular analysis of NPHP1 in an Iranian kindred. PMID- 26037637 TI - Should we call the neurologist? The value and cost of a growing neurology consultation service. AB - BACKGROUND: St Vincent's University Hospital has an established neurology consultation service. Referral volumes have been growing. The Department regularly reviews its service to monitor changes and seek improvements. AIMS: We sought to determine the impact of the growing service on patient care, on the department itself in delivering the service, and on inpatient admission trends. METHODS: We reviewed the electronic referral forms of all consults seen over a 9 week period in 2014 (n = 213). We recorded the source of each consult, demographic information, clinical presentation, time from referral to consult, and outcome. We compared the consult list to inpatient admissions list to determine the proportion admitted from consults. We compared our results to previous reviews by this and other neurology departments in Ireland. RESULTS: Three quarters of neurology consults relate to acute admissions. Patients are all seen within one working day of referral. A significant change in management (83.6 %) resulted from the majority of consults. Consultants see an average of 4.8 (range 0-10) consults per day, needing up to 7.5 h per day to deliver the service. One-third of the department's inpatients come from consults. CONCLUSIONS: The service significantly benefits patient care. The increasing number of consults will require increased resources and/or service reorganisation to maintain the current level of service. PMID- 26037638 TI - Goldindec: A Novel Algorithm for Raman Spectrum Baseline Correction. AB - Raman spectra have been widely used in biology, physics, and chemistry and have become an essential tool for the studies of macromolecules. Nevertheless, the raw Raman signal is often obscured by a broad background curve (or baseline) due to the intrinsic fluorescence of the organic molecules, which leads to unpredictable negative effects in quantitative analysis of Raman spectra. Therefore, it is essential to correct this baseline before analyzing raw Raman spectra. Polynomial fitting has proven to be the most convenient and simplest method and has high accuracy. In polynomial fitting, the cost function used and its parameters are crucial. This article proposes a novel iterative algorithm named Goldindec, freely available for noncommercial use as noted in text, with a new cost function that not only conquers the influence of great peaks but also solves the problem of low correction accuracy when there is a high peak number. Goldindec automatically generates parameters from the raw data rather than by empirical choice, as in previous methods. Comparisons with other algorithms on the benchmark data show that Goldindec has a higher accuracy and computational efficiency, and is hardly affected by great peaks, peak number, and wavenumber. PMID- 26037639 TI - Medical Aid, Repression, and International Relations: The East German Hospital at Metema. AB - Between 1984 and 1988, the German Democratic Republic (GDR) built a hospital in a remote part of Ethiopia, close to the Sudanese border. The project evolved in a complex combination of contexts, including the general foreign policy goals of the GDR, its specific alliance with Ethiopia, the famine of 1984-85, civil war in Ethiopia, and a controversial resettlement program by the government of Mengistu Haile Mariam. Though almost unknown today, it was a high-profile project at the time, which received the personal support both by Erich Honecker in the GDR and Mengistu Haile Mariam in Ethiopia. However, their interest was directed more at the political goals the project was expected to serve than at the hospital itself. Both the preparation and the implementation of the project were extremely difficult and almost failed due to problems of transportation, of red tape, and of security. The operation of the hospital was also not ideal, involving frustrated personnel and less than complete acceptance by the local population. Ironically, for all its practical difficulties, the hospital has outlived both governments and their political goals, surviving as a medical institution. PMID- 26037640 TI - Does History Matter? Commentary on "Making the Case for History in Medical Education". PMID- 26037641 TI - Evaluation of different methods for immobilization of Candida antarctica lipase B (CalB lipase) in polyurethane foam and its application in the production of geranyl propionate. AB - With the aim of studying the best method for the interaction of polyurethane (PU) foam and Candida antarctica lipase B, different methods of CalB immobilization were studied: adsorption (PU-ADS), bond (using polyethyleneimine) (PU-PEI), ionic adsorption by PEI with cross-linking with glutaraldehyde (PU-PEI-GA) and entrapment (PU). The characterization of immobilized enzyme derivatives was performed by apparent density and Fourier transform infrared spectroscopy. The free enzyme and enzyme preparations were evaluated at different pH values and temperatures. The highest enzyme activity was obtained using the PU method (5.52 U/g). The methods that stood out to compare the stabilities and kinetic parameters were the PU and PU-ADS. Conversions of 83.5 and 95.9 % for PU and PU ADS derivatives were obtained, in 24 h reaction, using citronella oil and propionic acid as substrates. PMID- 26037642 TI - The diagnosis and management of hypercalcaemia. PMID- 26037643 TI - Total laparoscopic intestinal vaginoplasty as neovaginal reconstruction in an HIV positive transgender woman. AB - A 46-year-old, HIV-positive transgender woman of South American ethnicity consulted our outpatient clinic to discuss the possibilities of a surgical, secondary neovaginal reconstruction because of complete stenosis of her inverted penile skin-lined neovagina. She was taking abacavir/lamivudine and nevirapine as antiretroviral therapy. We successfully performed a total laparoscopic sigmoid vaginoplasty without any complications. There was no short-term morbidity and no complications were reported after 15 months of follow-up. To our knowledge, this is the first report of laparoscopic sigmoid vaginoplasty as vaginal reconstruction in a HIV-positive transgender woman. Worldwide, transgender women have a high burden of HIV infection. This report shows that intestinal vaginoplasty is a feasible surgical option for HIV-positive transgender women in need of vaginal reconstruction. Because patients are again able to engage in penetrative sexual intercourse, we emphasise the importance of practicing safe sex and early initiation of adequate antiretroviral therapy in this patient population. PMID- 26037645 TI - Identification and quantitation of major phenolic compounds from Penthorum chinense Pursh. by HPLC with tandem mass spectrometry and HPLC with diode array detection. AB - Penthorum chinense Pursh. is a traditional Chinese herbal medicine used for the treatment of various ailments specially related to liver. Gansu Granule, the medicine made from the extract of P. chinense, has been widely used in the clinical setting. But the information about its active ingredients is lacking. In this paper, the extract of P. chinense was analyzed by high performance liquid chromatography with electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry. Among the 27 compounds that were identified based on their mass spectrometry data, ten were reported for the first time from P. chinense. Chromatographic fingerprints generated by high-performance liquid chromatography by analyzing 21 batches of P. chinense, displayed six common peaks. Finally, four major compounds were identified namely; gallic acid, brevifolin carboxylic acid, 2,6-dihydroxyacetophenone-4-O-beta-D-glucoside, and pinocembrin-7-O-beta-D-glucoside. The average content of each compound was 24.58, 109.6, 15.52, and 18.81 mg/g, respectively. In addition, this study also suggests that the qualitative liquid chromatography with mass spectrometry and the quantitative high-performance liquid chromatography analytical methods using monolithic columns are simple, rapid, accurate, and reproducible and have the potential to be used for the comprehensive quality control of P. chinense. PMID- 26037646 TI - Exploring mechanisms of resistance to dimethachlone in Sclerotinia sclerotiorum. AB - BACKGROUND: The dicarboximide fungicide dimethachlone has been widely used in China for more than 12 years to control the Sclerotinia stem rot caused by Sclerotinia sclerotiorum disease. First signs of resistance in the field are reported at low frequency. In this study, four resistant isolate/mutants were used to explore still unknown mechanisms leading to dimethachlone resistance. RESULTS: The resistant isolate/mutants had significantly higher EC50 values compared with the sensitive control isolates. Cross-resistance was confirmed between dimethachlone and procymidone, iprodione and fludioxonil. The resistant isolate/mutants revealed a decreased mycelial growth rate, were less pathogenic on leaves of oilseed rape, were more sensitive to osmotic pressure and oxidative stress and released more electrolytes compared with the sensitive isolates. Only in one lab mutant did we find a point mutation (V238A) in the SsOs1 gene of the high-osmolarity glycerol (HOG) signalling pathway. The expression of this gene was lost in the field resistant isolate HN456-1-JBJ and decreased in mycelium that was subjected to either high osmotic pressure or dimethachlone; however, another key gene in the HOG pathway, SsHog1, could be induced in the resistant isolate and mutants with NaCl treatment. CONCLUSION: This study demonstrates that resistance to dicarboximide fungicide dimethachlone in S. sclerotiorum is emerging in China. Several fitness parameters, including mycelial growth rate, sclerotia formed in vitro, aggressiveness on leaves and osmotic and H2 O2 sensitivity, indicate that the resistant strains may not effectively compete with sensitive isolates in the field in the absence of selection pressure. Lost expression or the V238A point mutation in the SsOs1 gene may confer resistance to dicarboximide fungicide dimethachlone in S. sclerotiorum, but this study illustrates that other, yet unknown mechanisms also exist. PMID- 26037647 TI - Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations. AB - KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared with other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution of the active site induced by the G13D mutation as shown by X-ray crystallography. High-resolution X ray structures are also provided for the GDP-bound forms of KRAS G12V, G12R, and Q61L and reveal additional insight. Overall, the structural data and measurements, obtained herein, indicate that measurable biochemical properties provide clues for identifying KRAS-driven tumors that preferentially signal through RAF. IMPLICATIONS: Biochemical profiling and subclassification of KRAS driven cancers will enable the rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors. PMID- 26037648 TI - The 'super digit' revisited. PMID- 26037649 TI - Assessing the ages of delayed unions and non-unions of the scaphoid on plain radiographs: apparently unreliable. PMID- 26037650 TI - Surgical treatment of acute distal radioulnar joint instability associated with distal radius fractures. AB - This study investigates the question of whether open repair of acute distal radioulnar joint instability at the time of volar plating of distal radius fractures would enable early mobilization of the wrist without the risk of distal radioulnar joint instability. We evaluated 29 patients of mean age 53 years with a distal radius fracture and acute distal radioulnar joint instability who underwent volar plating of the radius combined with surgical repair of the triangular fibrocartilage complex or an ulnar styloid base fracture, followed by active motion exercise of the wrist at 1 week after surgery. At 1 year after treatment, all patients had a stable distal radioulnar joint and grip strength averaged 90% of the normal side. This study demonstrates that surgical repair of the triangular fibrocartilage complex or ulnar styloid fracture followed by early mobilization did not result in distal radioulnar joint instability, and suggests that the surgical treatment of distal radioulnar joint instability may permit early mobilization of the wrist in patients who are considered suitable for rapid rehabilitation after surgery. Type of study: Therapeutic Level IV. PMID- 26037651 TI - Comment on Fabrizi et al.: Treatment of hepatitis C after kidney transplant: A pooled analysis of observational studies. PMID- 26037652 TI - Reply to the letter by Pan Yanna et al. 'treatment of hepatitis C after kidney transplant: A pooled analysis of observational studies'. PMID- 26037653 TI - Isolation by environment in White-breasted Nuthatches (Sitta carolinensis) of the Madrean Archipelago sky islands: a landscape genomics approach. AB - Understanding landscape processes driving patterns of population genetic differentiation and diversity has been a long-standing focus of ecology and evolutionary biology. Gene flow may be reduced by historical, ecological or geographic factors, resulting in patterns of isolation by distance (IBD) or isolation by environment (IBE). Although IBE has been found in many natural systems, most studies investigating patterns of IBD and IBE in nature have used anonymous neutral genetic markers, precluding inference of selection mechanisms or identification of genes potentially under selection. Using landscape genomics, the simultaneous study of genomic and ecological landscapes, we investigated the processes driving population genetic patterns of White-breasted Nuthatches (Sitta carolinensis) in sky islands (montane forest habitat islands) of the Madrean Archipelago. Using more than 4000 single nucleotide polymorphisms and multiple tests to investigate the relationship between genetic differentiation and geographic or ecological distance, we identified IBE, and a lack of IBD, among sky island populations of S. carolinensis. Using three tests to identify selection, we found 79 loci putatively under selection; of these, seven matched CDS regions in the Zebra Finch. The loci under selection were highly associated with climate extremes (maximum temperature of warmest month and minimum precipitation of driest month). These results provide evidence for IBE - disentangled from IBD - in sky island vertebrates and identify potential adaptive genetic variation. PMID- 26037655 TI - Association of Antibodies to Interferon-Inducible Protein-16 With Markers of More Severe Disease in Primary Sjogren's Syndrome. AB - OBJECTIVE: Interferon-inducible protein-16 (IFI16) is an intracellular DNA receptor involved in innate immunity. We evaluated the frequency, phenotypic characteristics, and clinical associations of anti-IFI16 antibodies in patients with primary Sjogren's syndrome (SS), and quantitated expression levels of IFI16 in SS and control salivary gland lysates. METHODS: Anti-IFI16 antibodies were assayed by enzyme-linked immunosorbent assay using sera from patients with primary SS (n = 133) and from healthy controls (n = 47). Sera from systemic lupus erythematosus (SLE) patients (n = 132) were included as disease controls. Immunoprecipitation of in vitro transcription-translated IFI16 was used to determine which portion of IFI16 the antibodies recognized. Expression of IFI16 in salivary gland lysates was quantitated by immunoblotting. RESULTS: Anti-IFI16 antibodies were present in the sera of 38 of 133 SS patients (29%) compared to 1 of 47 healthy controls (2.1%) (SS versus controls; P < 0.0002) and in 31 of 132 SLE controls (24%). In SS, anti-IFI16 antibodies were associated with an abnormal Schirmer's test (P = 0.003), hyperglobulinemia (P = 0.02), antinuclear antibody >=1:320 (P = 0.01), germinal center-like structures in labial salivary gland lymphoid infiltrates (P = 0.01), and higher focus scores (3.4 versus 2.4; P = 0.005). High-titer IFI16 antibodies were directed against an epitope outside the N-terminus in 9 of 13 SS patients (69%). IFI16 was expressed in 4 of 5 (80%) of SS and 1 of 6 (17%) of control labial salivary glands. CONCLUSION: Anti-IFI16 antibodies are a prominent specificity in primary SS and are associated with markers of severe disease. IFI16 is expressed at higher levels in SS salivary glands compared to controls. These high levels in disease target tissue may contribute to the ongoing anti-IFI16 immune response. PMID- 26037656 TI - Tracking Cancer Metastasis In Vivo by Using an Iridium-Based Hypoxia-Activated Optical Oxygen Nanosensor. AB - We have developed a nanosensor for tracking cancer metastasis by noninvasive real time whole-body optical imaging. The nanosensor is prepared by the formation of co-micelles from a poly(N-vinylpyrrolidone)-conjugated iridium(III) complex (Ir PVP) and poly(epsilon-caprolactone)-b-poly(N-vinylpyrrolidone) (PCL-PVP). The near-infrared phosphorescence emission of the nanosensor could be selectively activated in the hypoxic microenvironment induced by cancer cells. The detection ability of the nanosensor was examined in cells and different animal models. After intravenous injection, the nanosensor can be effectively delivered to the lung and lymph node, and cancer cell metastasis through bloodstream or lymphatics can be quickly detected with high signal-to-background ratio by whole-body imaging and organ imaging. Moreover, the nanosensor exhibits good biocompatibility both in vitro and in vivo. The nanosensor is believed to be a powerful tool for the diagnosis of cancer metastasis. PMID- 26037654 TI - Identifying learning patterns of children at risk for Specific Reading Disability. AB - Differences in learning patterns of vocabulary acquisition in children at risk (+SRD) and not at risk (-SRD) for Specific Reading Disability (SRD) were examined using a microdevelopmental paradigm applied to the multi-trial Foreign Language Learning Task (FLLT; Baddeley et al., 1995). The FLLT was administered to 905 children from rural Chitonga-speaking Zambia. A multi-group Latent Growth Curve Model (LGCM) was implemented to study interindividual differences in intraindividual change across trials. Results showed that the +SRD group recalled fewer words correctly in the first trial, learned at a slower rate during the subsequent trials, and demonstrated a more linear learning pattern compared to the -SRD group. This study illustrates the promise of LGCM applied to multi-trial learning tasks, by isolating three components of the learning process (initial recall, rate of learning, and functional pattern of learning). Implications of this microdevelopmental approach to SRD research in low-to-middle income countries are discussed. PMID- 26037659 TI - Radiation exposure in interventional pain management: we still have much to learn. PMID- 26037660 TI - Impact of Processing Conditions on Inter-tablet Coating Thickness Variations Measured by Terahertz In-Line Sensing. AB - A novel in-line technique utilising pulsed terahertz radiation for direct measurement of the film coating thickness of individual tablets during the coating process was previously developed and demonstrated on a production-scale coater. Here, we use this technique to monitor the evolution of tablet film coating thickness and its inter-tablet variability during the coating process under a number of different process conditions that have been purposefully induced in the production-scale coating process. The changes that were introduced to the coating process include removing the baffles from the coater, adding uncoated tablets to the running process, halting the drum, blockage of spray guns and changes to the spray rate. The terahertz sensor was able to pick up the resulting changes in average coating thickness in the coating drum and we report the impact of these process changes on the resulting coating quality. PMID- 26037661 TI - Low-level laser therapy improves bone formation: stereology findings for osteoporosis in rat model. AB - Low-level laser therapy (LLLT) benefits bone metabolism, but its use needs to be standardized. We evaluated the effects of LLLT on bone defects in calvaria of ovariectomized rats. Stereology was used to calculate tissue repair volume (V tr ), density of trabecular bone volume (Vv t ), total volume of newly formed trabecular bone (Vtot), and the area occupied by collagen fibers (A C ). Fifty four Wistar rats were submitted to bilateral ovariectomy, and bone defects were created in calvaria after 150 days. The animals were divided into nine groups (n = 6), and 24 h after defects, the treatment started with a 780-nm low-intensity GaAlAs laser: G1, G2, and G3 received 3 sessions of 0, 20, and 30 J/cm(2) respectively; G4, G5, and G6 received 6 sessions of 0, 20, and 30 J/cm(2), respectively; and G7, G8, and G9 received 12 sessions of 0, 20, and 30 J/cm(2), respectively. A normal distribution was found for all of the data. The test used to verify the normality was the Kolmogorov-Smirnov (KS, p > 0.05). The one-way ANOVA followed by Tukey's post hoc test was used for data processing. A difference of p < 0.05 was considered statistically significant. Groups G2 and G1 showed significance for V tr , Vv t , Vtot, and (A C ). Results were significant for (Vv t ) and (Vtot) between G3 and G1. There were no significant results between G5 and G4 as well as between G8 and G7. Groups G6 and G4 results showed statistical difference for V tr , Vv t , Vtot, and (A C ). Groups G9 and G7 showed significance for V tr , Vv t , Vtot, and (A C ). In conclusion, there was new bone formation in the groups that received 20 and 30 J/cm(2) when compared to control groups, but over time, the dose of 30 J/cm(2) showed better stereological parameters when compared to 20 J/cm(2). PMID- 26037662 TI - High genetic diversity in the endangered and narrowly distributed amphibian species Leptobrachium leishanense. AB - Threatened species typically have a small or declining population size, which make them highly susceptible to loss of genetic diversity through genetic drift and inbreeding. Genetic diversity determines the evolutionary potential of a species; therefore, maintaining the genetic diversity of threatened species is essential for their conservation. In this study, we assessed the genetic diversity of the adaptive major histocompatibility complex (MHC) genes in an endangered and narrowly distributed amphibian species, Leptobrachium leishanense in Southwest China. We compared the genetic variation of MHC class I genes with that observed in neutral markers (5 microsatellite loci and cytochrome b gene) to elucidate the relative roles of genetic drift and natural selection in shaping the current MHC polymorphism in this species. We found a high level of genetic diversity in this population at both MHC and neutral markers compared with other threatened amphibian species. Historical positive selection was evident in the MHC class I genes. The higher allelic richness in MHC markers compared with that of microsatellite loci suggests that selection rather than genetic drift plays a prominent role in shaping the MHC variation pattern, as drift can affect all the genome in a similar way but selection directly targets MHC genes. Although demographic analysis revealed no recent bottleneck events in L. leishanense, additional population decline will accelerate the dangerous status for this species. We suggest that the conservation management of L. leishanense should concentrate on maximizing the retention of genetic diversity through preventing their continuous population decline. Protecting their living habitats and forbidding illegal hunting are the most important measures for conservation of L. leishanense. PMID- 26037665 TI - In vitro generation and characterization of chicken long-term germ cells from different embryonic origins. AB - Primordial germ cells (PGCs) are the precursors of differentiated germ cells. Located in the epiblast of a stage X (EG&K) embryo, the PGCs translocate anteriorly to the germinal crescent and migrate, within 48 to 56 hours of development, through the blood vascular system to the germinal ridges where they become the gonadal germ cells (GGCs). We aim to generate, compare, and determine the basic characters of the in vitro long-term cultured PGCs derived from (1) the chicken blastodermal cells (at stages IX-XII); (2) the chicken blood of a 2-day old embryo (stages 14-17 Hamburger Hamilton [HH]); and (3) the long-term cultured gonocytes taken from male gonads of a 5- to 6-day-old embryo (stages 29-30 HH). In presence of fibroblast growth factor, chicken blastodermal cells are able to long-term proliferate and generate small, round, alkaline phosphatase-positive cell clusters. Molecular characterization shows that these selected and amplified clusters show a PGC-like cell profile, as they express cPOUV (a pluripotent associated marker), NR6A1/GCNF and DDX4/CVH (germ cell-specific genes). Both chicken PGCs and GGCs, obtained from embryonic blood and gonads, at 14 to 17 HH and 29 to 30 HH, respectively, generate long-term germ cell cultures and positively react in vitro to periodic acid-Schiff. Immunochemical analyses reveal that these cell lines are specifically recognized by anti-SSEA-1, anti-EMA-1, anti-CVH, anti-beta1-integrin, and anti-CEACAM antibodies. The presence of surrounding cells may suggest a stronger dependency toward the niche process for the GGCs. The reactivity of chicken embryonic germ cells obtained from the two different sources to the specific markers used in this study was not altered through the culture. In conclusion, the morphologic analysis specific for chicken PGCs and GGCs will further contribute to quick and reliable characterization of long-term cultured in vitro chicken germ cells. PMID- 26037666 TI - In vivo and in vitro study of the function of the left and right bovine ovaries. AB - Inequality in function of the left and right bovine ovaries and uterine horns was evaluated in two separate experiments. In the first experiment (in vivo), the relationship between the left and right ovarian activities and reproductive indices was evaluated. Therefore, the total number of 1284 randomly chosen lactating dairy cows were examined from Day 50 to 60 postpartum, and according to the presence of an active CL on the ovaries, they were divided into 502 LCL3-cows and 782 RCL3-cows (cows with an active CL on the left [L] or right [R] ovary, respectively). To induce estrus synchronization and investigate the effects of PGF2alpha administration on the incidence of estrus in both LCL3-cows and RCL3 cows, the cows were treated with one luteolytic dose of PGF2alpha and were inseminated after observed estrus (via visual observation lasting at least 30 minutes three times a day). To investigate the effects of side of ovulation at the time of PGF2alpha administration on reproductive parameters, pregnancy diagnosis was performed 28 days after insemination (using ultrasound) and 42 days after insemination (using transrectal palpation). The results showed that the percentage of the RCL3-cows was greater than the LCL3-cows (60.9% vs. 39.1%, respectively). Furthermore, ovulations switching from the left to right ovary in two successive ovulations were greater than those that switched from the right to left ovary. On the other hand, the sex ratio (male percentage) in the right uterine horn was greater than that of the left one. In the second experiment (in vitro), the developmental potential of bovine oocytes derived from the left (L oocytes) and right (R-oocytes) ovaries after in vitro embryo production and heterogeneity in the developmental competence of L-oocytes and R-oocytes using the brilliant cresyl blue staining test as a selection criterion were evaluated. Results of the in vitro experiment showed that the percentage of cleavage and blastocyst rate of R-oocytes were greater (P < 0.001) than those of L-oocytes. Moreover, it appears that the side of ovaries had greater effects on the developmental competence of oocytes than other factors associated with heterogeneity in the developmental competence of oocytes, which can be detected by the brilliant cresyl blue test. In conclusion, the results of the in vivo study confirmed the observations in previous studies in which the right ovarian response (distribution of ovulation) was superior to that of the left ones. Interestingly, the in vitro experiments for the first time clearly showed that more ovulation on the right side is not the only reason for this unequal activity. In fact, in cattle, the greater developmental potential of oocytes originating from right ovaries may cause superior activity of the right side, and the effect is even higher than the differences in ovulation response between the left and right ovaries. PMID- 26037668 TI - Region-specific up-regulation of oxytocin receptor binding in the brain of mice following chronic nicotine administration. AB - Nicotine addiction is considered to be the main preventable cause of death worldwide. While growing evidence indicates that the neurohypophysial peptide oxytocin can modulate the addictive properties of several abused drugs, the regulation of the oxytocinergic system following nicotine administration has so far received little attention. Here, we examined the effects of long-term nicotine or saline administration on the central oxytocinergic system using [(125)I]OVTA autoradiographic binding in mouse brain. Male, 7-week old C57BL6J mice were treated with either nicotine (7.8 mg/kg daily; rate of 0.5 MUl per hour) or saline for a period of 14-days via osmotic minipumps. Chronic nicotine administration induced a marked region-specific upregulation of the oxytocin receptor binding in the amygdala, a brain region involved in stress and emotional regulation. These results provide direct evidence for nicotine-induced neuroadaptations in the oxytocinergic system, which may be involved in the modulation of nicotine-seeking as well as emotional consequence of chronic drug use. PMID- 26037664 TI - Fusing Functional MRI and Diffusion Tensor Imaging Measures of Brain Function and Structure to Predict Working Memory and Processing Speed Performance among Inter episode Bipolar Patients. AB - Evidence for abnormal brain function as measured with diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) and cognitive dysfunction have been observed in inter-episode bipolar disorder (BD) patients. We aimed to create a joint statistical model of white matter integrity and functional response measures in explaining differences in working memory and processing speed among BD patients. Medicated inter-episode BD (n=26; age=45.2+/-10.1 years) and healthy comparison (HC; n=36; age=46.3+/-11.5 years) participants completed 51-direction DTI and fMRI while performing a working memory task. Participants also completed a processing speed test. Tract-based spatial statistics identified common white matter tracts where fractional anisotropy was calculated from atlas defined regions of interest. Brain responses within regions of interest activation clusters were also calculated. Least angle regression was used to fuse fMRI and DTI data to select the best joint neuroimaging predictors of cognitive performance for each group. While there was overlap between groups in which regions were most related to cognitive performance, some relationships differed between groups. For working memory accuracy, BD-specific predictors included bilateral dorsolateral prefrontal cortex from fMRI, splenium of the corpus callosum, left uncinate fasciculus, and bilateral superior longitudinal fasciculi from DTI. For processing speed, the genu and splenium of the corpus callosum and right superior longitudinal fasciculus from DTI were significant predictors of cognitive performance selectively for BD patients. BD patients demonstrated unique brain-cognition relationships compared to HC. These findings are a first step in discovering how interactions of structural and functional brain abnormalities contribute to cognitive impairments in BD. PMID- 26037670 TI - The NFKB Inducing Kinase Modulates Hematopoiesis During Stress. AB - The genetic programs that maintain hematopoiesis during steady state in physiologic conditions are different from those activated during stress. Here, we show that hematopoietic stem cells (HSCs) with deficiencies in components of the alternative NFkappaB pathway (the NFkappaB inducing kinase, NIK, and the downstream molecule NFkappaB2) had a defect in response to stressors such as supraphysiological doses of cytokines, chemotherapy, and hematopoietic transplantation. NIK-deficient mice had peripheral blood and bone marrow leukocyte numbers within normal ranges (except for the already reported defects in B-cell maturation); however, HSCs showed significantly slower expansion capacity in in vitro cultures compared to wild-type HSCs. This was due to a delayed cell cycle and increased apoptosis. In vivo experiments showed that NIK deficient HSCs did not recover at the same pace as controls when challenged with myeloablative chemotherapy. Finally, NIK-deficient HSCs showed a significantly decreased competitive repopulation capacity in vivo. Using HSCs from mice deficient in one of two downstream targets of NIK, that is, either NFkappaB2 or c Rel, only NFkappaB2 deficiency recapitulated the defects detected with NIK deficient HSCs. Our results underscore the role of NIK and the alternative NFkappaB pathway for the recovery of normal levels of hematopoiesis after stress. PMID- 26037669 TI - Executive Functioning in Children and Adolescents Prenatally Exposed to Alcohol: A Meta-Analytic Review. AB - Prenatal alcohol exposure is associated with a constellation of adverse physical, neurocognitive and behavior outcomes, which comprise a continuum of disorders labeled Fetal Alcohol Spectrum Disorders (FASD). Extant research has consistently identified executive functions (EF) as a central impairment associated with FASD. Despite this, heterogeneity exists regarding the strength of the association between FASD and different EF, and this association has not yet been quantitatively synthesized. The current meta-analysis reviews 46 studies that compare children and adolescents with FASD to participants without FASD, on a variety of EF measures. In accordance with Miyake et al. Cognitive Psychology, 41, 49-100 (2000) three-factor model of EF, findings for the primary EF domains of working memory, inhibition, and set shifting are reviewed. Results indicate that children and adolescents with FASD demonstrate significant deficits across these EF, although the magnitude of effects diverged between EF, with working memory and inhibition yielding medium effects and set shifting yielding large effects. These results were moderated by sample characteristics, type of FASD diagnosis, and EF methodology. This quantitative synthesis offers novel future research directions. PMID- 26037672 TI - [Significance of Procalcitonin Measurement in Cases with Febrile Condition during Chemotherapy for Urological Cancer]. AB - We examined the usefulness of measurement of procalcitonin (PCT) for patients, who developed febrile neutropenia during cancer chemotherapy for urological cancer. Of the Patients who underwent cancer chemotherapy for bladder, renal pelvic or ureteral, and testicular cancer in our department from 2010 to 2013, 51 had febrile events. Their clinical courses and PCT values were retrospectively reviewed and analyzed. PCT was positive in 12 patients and negative in 39. The duration with febrile status was significantly longer in the PCT-positive group than in the PCT-negative group. There was no significant difference between the blood count values in each group, but C-reactive protein (CRP) was significantly higher in the PCT-positive group than in the PCT-negative group. There were no significant differences between the 2 groups in other tests with blood. There were 12 patients with febrile neutropenia (FN) but all were classified into low risk by the MASCC scoring system. Four of these 12 patients were positive for PCT. Our results suggested that, in patients with a fever of 37.5 degrees C or more during the course of cancer chemotherapy for urologic cancer, bacteremia possibly existed if the patient was positive for PCT. In addition, the duration of fever tended to be longer and the condition was more severe. When the patients with urological cancer undergo cancer chemotherapy manifest high-grade fever, PCT is promising and valuable as an indicator of the severity of infection. PMID- 26037671 TI - [Prognostic factors and efficacy of molecular targeted therapy for metastatic clear cell renal cell carcinoma]. AB - We retrospectively reviewed the medical records of patients with metastatic clear cell renal cell carcinoma who received molecular targeted therapy between 2005 and 2011. Cancer-specific survival was analyzed using the Kaplan-Meier method. Predictors of cancer-specific survival were analyzed using the Cox regression hazards model. A total of 89 patients, consisting of 50 first line patients and 39 patients receiving prior cytokine were included in the analysis. The two-year cancer-specific survival rate of the firstlinegroup was 60.2% and that of theprior cytokinethe rapy group was 62.1%. In univariateanalysis, Karnofsky performance status (KPS)<80%, time from diagnosis to treatment less than one year, bone metastasis and C-reactive protein (CRP)>1.3 mg/dl in were statistically significant prognostic factors (p<0.05). In multivariate analysis, time from diagnosis to treatment less than one year (HR 2.46, 95%CI 1.11-5.82, p=0.025) and CRP (HR 4.92, 95%CI 2.23-11.3, p<0.001) were independent prognostic factors. Time from diagnosis to treatment less than one year and CRP were independent prognostic factors in patients who received molecular targeted therapy. PMID- 26037673 TI - [Outcomes of high-risk prostate cancer patients at Hakodate Goryoukaku Hospital]. AB - We assessed the outcomes of high-risk prostate cancer patients who received radical prostatectomy (RP), external beamradiation therapy (EBRT) or androgen deprivation therapy (ADT). Two hundred nineteen patients who were diagnosed with pathologically confirmed high-risk prostate cancer as defined by D'Amico between 2005 and 2011 were included in this study. Of them, 74 patients underwent RP. The 5-year cancer-specific survival (5yCSS) and 5-year PSA recurrence-free survival (5yPRFS) rates were 100 and 67.2%, respectively. A positive surgical margin and Gleason score?8 were risk factors for PSA recurrence. The 5yPRFSs were 100, 74.4% and 'unmeasurable' for patients with 0, 1 and 2 risk factors, respectively. Ninety patients underwent EBRT. The 5yCSS and 5yPRFS rates were 95.2 and 74.2%, respectively. Fifty-five patients underwent ADT alone. Their 5yCSS and 5yPRFS rates were 93. 3 and 64. 3%, respectively. There was no significant difference in 5yCSS and 5yPRFS rates among the treatment groups. These results show that RP can be a treatment option for high-risk prostate cancer patients. PMID- 26037674 TI - [Pazopanib for three patients with recurrence of retroperitoneal liposarcoma : initial clinical experience]. AB - Pazopanib, a novel tyrosine kinase inhibitor, is an effective therapeutic agent for patients with advanced soft tissue sarcoma. Here we report three patients with recurrent retroperitoneal liposarcoma who were treated with pazopanib. Case 1: A 54-year-old male received three courses of combined chemotherapy consisting of doxorubicin and ifosfamide for recurrent left retroperitoneal dedifferentiated liposarcoma and liver metastasis following tumor excision. Because of the lack of response to chemotherapy, 400 mg/day of pazopanib was subsequently administered for two weeks. The patient died 3 weeks after the initiation of pazopznib therapy. Case 2: A 78-year-old male with right retroperitoneal dedifferentiated liposarcoma underwent irradiation for a recurrent tumor 16 months after the initial tumor excision. Pazopanib (600 mg/day) was partially effective for 2 months. Pazopanib was administered for 7 months, but the patient died 8 months after the initiation of pazopanib therapy. Case 3 : An 80-year-old male with locally recurrent right retroperitoneal myxoid liposacroma was treated with 600 mg/day of pazopanib from 5 months after tumor excision. He remains alive and has had stable disease for 17 months to date. In conclusion, pazopanib may be effective in a subset of patients with recurrent retroperitoneal liposarcoma. PMID- 26037675 TI - [A case of chronic expanding hematoma with xanthogranuloma in retroperitoneal space]. AB - Chronic expanding hematoma (CEH), which is defined as persistent hematoma manifesting as enlarging space-occupying mass, rarely occurs in the retroperitoneal space. Here, we report a case of retroperitoneal CEH with xanthogranulama. A 72-year-old man with a history of genuine polycythemia was admitted for idiopathic renal subcapsular hematoma 3 years ago. Regular follow-up imaging revealed that the hematoma was gradually expanding in the left retroperitoneal space with the capsules invading psoas muscles. Given the possibility that the mass was a neoplastic intratumoral hemorrhage, we resected the mass. Complete removal of the capsule was impossible due to severe adhesion and its extension in his psoas muscles. Moreover, postoperative bleeding from psoas muscles occurred and emergency exploration to control the bleeding was required. Microscopic findings showed that the hematoma capsule consisted of collagenous tissue with chronic inflammatory infiltrate and foreign-body granuloma with foam cells and giant cells. The final diagnosis was CEH with xanthogranuloma. Our case suggests that early resection for retroperitoneal CEH may be desirable to avoid severe adhesion and invasion around the capsule. PMID- 26037676 TI - [A case of growing teratoma syndrome; long-term control accomplished by systemic interferon therapy with adequate local therapies]. AB - A 31-year-old man came to our hospital with chest pain and was diagnosed to have a left testicular tumor with metastasis to the lung, and cervical, mediastinal, and retroperitoneal lymph nodes. Left orchiectomy was performed, and histological diagnosis was seminoma. Serum tumor markers were normalized after 3rd-line chemotherapy, but lymph node metastases were still enlarged. Then the cervical lymph node was excised, and histologically diagnosed as mature teratoma. Based on these results, we diagnosed this case as growing teratoma syndrome. Since the whole metastasis was too large to be completely excised, we started systemic interferon alfa-2b (IntronR A) administration. The metastasis initially responded to the therapy by 20% reduction in size and remained stable thereafter. However, the mediastinal lesion caused obstructive pneumonia, which was bronchoscopically resected. At the time of 12 years after the initial presentation, the tumors are well controlled with stable disease or only modest increase. PMID- 26037677 TI - [Adenocarcinoma of an augmented bladder 49 years after enterocystoplasty : a case report]. AB - A 69-year-old man visited our hospital presenting with bladder tamponade. The patient had undergone bladder augmentation using the ileocecum and the ascending colon for an atrophy bladder due to tuberculosis 49 years previously. Cystoscopy revealed an invasive bladder tumor in the anastomotic region of the bladder and the intestine. He underwent cystourethrectomy and ileal conduit (utilizing the previous ureteroileal anastomosis). A deliberate procedure of urinary tract diversion was required because of the severe postoperative adhesion by the augmentation. The pathological diagnosis showed adenocarcinoma. The tumor spread over the intestinal tract side and the deepest part reached the adventitia of the intestinal tract. The patient is receiving additional therapy of combined modality including chemotherapy. PMID- 26037678 TI - [A case of metachronal testicular tumor eight years after medical treatment of extragonadal germ cell tumor]. AB - A 22-year-old man was admitted to our hospital complaining of a left cervical mass. Computed tomography (CT) showed multiple enlarged lymph nodes at the left cervical vein and para-aortic areas. Histological examination of a biopsy indicated an embryonal carcinoma. The levels of human beta-chorionic gonadotropin (beta-HCG) and lactic dehydrogenase (LDH) were both elevated. Ultrasonography revealed testicular calcification, but there were no findings on magnetic resonance imaging (MRI). The patient was diagnosed as having an extragonadal germ cell tumor. After four courses of chemotherapy with BEP protocol (bleomycin, etoposide and cisplatin), retroperineal lymph node dissection (RPLND) was performed and there was no involvement of the viable cells in the resected lymph nodes. Eight years after chemotherapy, he noticed an enlargement of his left scrotum without pain. beta-HCG was again elevated. A unilateral high orchiectomy was performed, and histology revealed a seminoma. He was staged as pT1N0M0S0. Six months later he remains disease-free. PMID- 26037679 TI - [A case of strangulation of the penis with difficult release]. AB - We report a case of penile strangulation by a metal ring. An 81-year-old man visited our hospital with a complaint of penile swelling and urinary retention caused by a ring placed around the penile root to control the patient's sexual desire; the ring had been placed some days prior to presentation. We could not release the penile strangulation by hand or with a ring cutter in the emergency room. We decided to cut the thick metal ring in the operating room under local anesthesia and sedation with a surgical tool used in the orthopedic department. It took approximately 2 hours to cut the ring. The patient had made a satisfactory recovery 7 days postoperatively, and no complications were observed during the postoperative period. PMID- 26037680 TI - Are patient-nurse relationships in breast cancer linked to adult attachment style? AB - AIMS: The aim of this study was to ascertain if patients with breast cancer who have positive attachment models of 'self' and 'other' perceive higher levels of support from nurses than do patients with negative attachment models. BACKGROUND: Attachment models of 'self' and 'other' develop in childhood and affect relationships throughout life. People with negative attachment models tend to perceive themselves as unworthy of receiving support and to perceive others as incapable or unwilling to offer support. Attachment processes are activated when individuals feel threatened and seek support from those close to them. Breast cancer may represent such a threat and relationships between patients with breast cancer and nurses may therefore be influenced by patients' attachment models. DESIGN: A between-subjects cross-sectional design was used. Explanatory variables were indicators of patients' attachment models. Response variables were patient ratings of nurse support. Covariates were patient age and patient distress levels. METHOD: One hundred and fifty-three patients with breast cancer, diagnosed 1-3 years previously, were recruited when attending follow-up oncology appointments over 51 weeks in 2010-2011. Participants completed questionnaires assessing attachment models, distress and perceived support, from the nurse who was available to support them through their cancer. The hypotheses were tested by logistic regression analysis. RESULTS: Patients with more positive models of 'self' perceived more support from nurses. CONCLUSIONS: Patients' perceptions of nurses when being treated for breast cancer are influenced by patients' own models of attachment. Knowledge of this would help nurses further to individualize the emotional support they give patients. PMID- 26037681 TI - Cyclodextrin nanoassemblies: a promising tool for drug delivery. AB - Among the biodegradable and nontoxic compounds that can form nanoparticles for drug delivery, amphiphilic cyclodextrins are very promising. Apart from ionic cyclodextrins, which have been extensively studied and reviewed because of their application in gene delivery, our purpose is to provide a clear description of the supramolecular assemblies of nonionic amphiphilic cyclodextrins, which can form nanoassemblies for controlled drug release. Moreover, we focus on the relationship between their structure and physicochemical characteristics, which is crucial for self assembly and drug delivery. We also highlight the importance of the nanoparticle technology preparation for the stability and application of this nanodevice. PMID- 26037682 TI - Biography. Professor Ronald John Roberts. PMID- 26037683 TI - [Atypical metastatic breast localization in lung cancer]. AB - INTRODUCTION: In the context of bronchial cancers, the most frequent sites for metastases to occur are the lung, bone, brain, liver and adrenal glands. However, metastasis to other sites does additionally occur and this might be influenced by the biological characteristics of the tumour. OBSERVATION: We report the case of a 54-year-old woman with a primary bronchial adenocarcinoma with an EML4-ALK translocation. During her treatment with crizotinib, the patient developed a lesion in her right breast. The initial pathological diagnosis was of an invasive ductal adenocarcinoma of the breast. However, an additional immuno-histochemical analysis revealed it to be a metastasis from her bronchial tumour. CONCLUSION: This case is an illustration that, in the context of a lung cancer with ALK rearrangement, synchronous or secondary lesions must be interpreted with caution. Specific biological analysis - ALK immunohistochemistry or FISH - must be performed to confirm a primary or metastatic origin for these lesions. PMID- 26037684 TI - Acute pontine infarction after percutaneous coronary intervention: a very rare but devastating complication. AB - A 64-year-old man suffering from an acute posterior wall myocardial infarction underwent primary percutaneous coronary intervention. After several aspiration attempts, tirofiban infusion and pre- and post-dilatation, a bare-metal stent was successfully implanted in the culprit right coronary artery. While the patient did not show any neurological symptoms before or during the procedure, he exhibited hemiplegia and loss of spontaneous speech. Additional magnetic resonance imaging showed an extensive brain stem infarction. This is the first report of a brain stem infarction as a complication of percutaneous coronary intervention. PMID- 26037685 TI - Practical pharmacotherapy for acute schizophrenia patients. AB - Well-organized clinical guidelines of pharmacotherapy for schizophrenia are not necessarily applicable to emergency and acute-phase situations. Thus, practical pharmacotherapy for acute schizophrenia patients should be based on data from real clinical practice and be independent of pharmaceutical companies. This study investigated the current guidelines being used to determine the initially preferred antipsychotics, durations required before an antipsychotic is viewed as being ineffective, and the strategies utilized for early non-responders that include switching, high dose, and augmentation. In patients who develop side effects to the preferred antipsychotic drug, continued use may depend on the specific characteristics of the side-effects. For acute-phase patients, antipsychotics with high efficacy and effectiveness may be chosen based on meta analysis findings for not only double-blinded but also rater-blinded randomized controlled trials. Many previous studies have reported being able to make an early prediction at 2 weeks regarding the later response. These predictions were supported by the findings of a recent meta-analysis of 34 studies that examined 9975 participants. In early non-responders to the initial antipsychotic, the effectiveness of the switching strategy appears to depend on the initial antipsychotic administered and the antipsychotic the patient is subsequently switched to. Furthermore, the effectiveness of the strategy between switching and augmentation might also depend on the initial antipsychotic administered. The current findings might serve as the basis for the use of dosing above the licensed range versus continuing the use of conventional dosing in non responders, provided there is close monitoring of the side-effects. Further research is required before any modifications of routine practices are undertaken regarding the direction of new potential treatments. PMID- 26037687 TI - Synthetic vectors for gene delivery: An overview of their evolution depending on routes of administration. AB - Nucleic acid delivery constitutes an emerging therapeutic strategy to cure various human pathologies. This therapy consists of introducing genetic material into the whole body or isolated cells to correct a cellular abnormality or disfunction. As with any drug, the main objective of nucleic acid delivery is to establish optimal balance between efficacy and tolerance. The methods of administration and the vectors used are selected depending on whether the goal of treatment is the production of an active protein; the replacement of a missing or inactive gene; or the combat of acquired diseases, such as cancer or AIDS. In that sense, synthetic vectors represent a valuable solution because they are well characterized, their structure can be fine tuned, and their potential toxicity can be reduced, since toxicity depends on the composition of the formulations. Here we review various synthetic vectors for gene delivery and address the question of their biodistribution as a function of the route of administration. We highlight the modifications to vectors structure and formulations necessary to overcome the major hurdles limiting the effectiveness of nucleic acid therapies. PMID- 26037688 TI - A quantification of regenerated bone tissue in human sinus biopsies: influences of anatomical region, age and sex. AB - OBJECTIVES: Sinus augmentation is a standard procedure to increase vertical bone supply for dental implants in the atrophic posterior maxilla. Despite the longstanding application of this method, information about some basic factors that could potentially influence bone regeneration after sinus augmentation is rare. The objective of this study was therefore to quantify the impact of the maxillary region (premolar/molar) and patients' age and sex on bone regeneration after sinus grafting. MATERIAL AND METHODS: Sinus augmentation procedures were performed in 107 patients (66 female: 52.8 +/- 11.0 years, 41 male: 50.6 +/- 11.3 years). After 6 +/- 1 months, 201 sinus biopsies were harvested and histomorphometrically analysed. Height (oldHt) and bone volume fraction of pristine bone (oldBV/TV), as well as the amount of new bone (newBV/TV) and bone to-bone substitute contact (BBSC) in the augmentation area, were assessed. RESULTS: In women, newBV/TV in the augmented sinus decreased significantly by 0.22 +/- 0.08% per year. In men, no similar trend was observed. There were strong influences of the maxillary region and the dimensions of the host bone. In the premolar region, newBV/TV was 23.1 +/- 7.9% and 25.1 +/- 10.1%; in the molar region, newBV/TV averaged 20.4 +/- 9.4% and 17.8 +/- 8.8% for women and men, respectively. The greater the thickness of the wall of the sinus floor (mainly in the former premolar region), the greater was the amount of new bone tissue formed in the spaces in-between bone substitute particles. CONCLUSIONS: These empirical results derived from a large human sample, link factors that influence the quality of biomaterial integration to the known clinical risks for the success of dental implants. PMID- 26037689 TI - Agranulocytosis with ceftaroline high-dose monotherapy or combination therapy with clindamycin. AB - INTRODUCTION: The only clinically available cephalosporin with in vivo and in vitro activity against methicillin-resistant Staphylococcus aureus is ceftaroline, which is approved for the treatment of soft tissue infection and community-acquired pneumonia in doses of 600 mg intravenously every 12 hours for 2 weeks or less. However, many clinicians use ceftaroline to treat more serious infections and dose more frequently (every 8 hours) for longer periods of time. METHODS: A retrospective medication safety assessment was performed at two centers where agranulocytosis was observed in four patients (two at each center) who were treated with ceftaroline. The cases were reviewed by the treating physicians for common features, and the frequency of agranulocytosis was calculated based on the total number of treated patients. RESULTS: We report four cases of agranulocytosis associated with ceftaroline use, highlighted by prolonged use (more than 14 days) and 8-hour dosing intervals or 12-hour dosing intervals with concomitant clindamycin therapy. When ceftaroline (600 mg every 12 hours) and clindamycin (900 mg every 8 hours) were coadministered for more than 2 weeks, the frequency of agranulocytosis was 18% (2 of 18 patients treated). When ceftaroline alone was administered for more than 2 weeks at 600 mg every 8 hours, agranulocytosis occurred in 5.4% (2 of 37 treated patients). No cases of ceftaroline-related agranulocytosis were seen that did not have these features. In these patients, granulocyte-colony stimulating factor therapy usually resulted in rapid myeloid recovery. CONCLUSIONS: Clinicians should have a heightened awareness of agranulocytosis when using ceftaroline in such settings and monitor complete blood counts at least once/week. PMID- 26037692 TI - Special Issue: the 2014 Banff Conference: Troubling Practice. PMID- 26037690 TI - First experiences with a two-step method for discussing goals with community dwelling frail older people. AB - BACKGROUND: Although frail older people can be more reluctant to become involved in clinical decision making, they do want professionals to take their concerns and wishes into account. Discussing goals can help professionals to achieve this. OBJECTIVE: To describe the development of a two-step method for discussing goals with frail older people in primary care and professionals' first experiences with it. METHODS: The method consisted of (i) an open-ended question: If there is one thing we can do for you to improve your situation, what would you like? if necessary, followed by (ii) a bubble diagram with goal subject categories. We reviewed the goals elaborated with the method and surveyed professionals' (primary care nurses and social workers) experiences, using questions concerning time investment, reasons for not formulating goals, and perceived value of the method. RESULTS: One hundred and thirty-seven community-dwelling frail older people described 173 goals. These most frequently concerned mobility (n = 43; 24.9%), well-being (n = 52; 30.1%) and social context (n = 57; 32.9%). Professionals (n = 18) were generally positive about the method, as it improved their knowledge about what the frail older person valued. Not all frail older people formulated goals; reasons for this included being perfectly comfortable, not being used to discussing goals or cognitive problems limiting their ability to formulate goals. CONCLUSIONS: This two-step method for discussing goals can assist professionals in gaining insight into what a frail older person values. This can guide professionals and frail older people in choosing the most appropriate treatment option, thus increasing frail older people's involvement in decision making. PMID- 26037691 TI - Technology platforms for remote monitoring of vital signs in the new era of telemedicine. AB - Driven by healthcare cost and home healthcare need, the development of remote monitoring technologies is poised to improve and revolutionize healthcare delivery and accessibility. This paper reviews the recent progress in the field of remote monitoring technologies that may have the potential to become the basic platforms for telemedicine. In particular, key techniques and devices for monitoring cardiorespiratory activity, blood pressure and blood glucose concentration are summarized and discussed. In addition, the US FDA approved remote vital signs monitoring devices currently available on the market are presented. PMID- 26037693 TI - Salt sensitivity in chickpea: Growth, photosynthesis, seed yield components and tissue ion regulation in contrasting genotypes. AB - Chickpea is a relatively salt sensitive species but shows genotypic variation for salt tolerance, measured as grain yield per plant in mild-to-moderately saline soil. This experiment was designed to evaluate some physiological responses to salinity in three contrasting genotypes. One tolerant (Genesis836), one moderately tolerant (JG11) and one sensitive (Rupali) genotype were grown for 108d in non-saline nutrient solution (controls) and two levels of salinity treatment (30 and 60mM NaCl). No plants survived to maturity in the 60mM NaCl treatment; however, Genesis836 survived longer (87d) than JG11 (67d) while Rupali died after 27d; only Genesis836 flowered, but no pods were filled. At 30mM NaCl, Genesis836 produced a few filled pods, whereas JG11 and Rupali did not. Genotypic differences in plant dry mass at the vegetative stage were evident only at 60mM NaCl, while at maturity differences were evident at 30mM NaCl. Photosynthesis was maintained to different degrees by the three genotypes (e.g. at 30mM NaCl, 35-81% of controls; highest in Genesis836); photosynthesis was restricted predominately due to non-stomatal limitations as the intercellular CO2 concentration was only modestly affected (94-99% of controls). Photosystem II damage was evident in the less tolerant genotypes (e.g. at 30mM NaCl, actual quantum efficiency of photosystem II values were 63-96% of controls). Across treatments, shoot dry mass was negatively correlated with both Na(+) and Cl(-) shoot concentrations. However, the sensitive genotype (Rupali) had equal or lower concentrations of these ions in green leaves, stems or roots compared to tolerant genotypes (JG11 and Genesis836); ion 'exclusion' does not explain variation for salt tolerance among these three chickpea genotypes. The large difference between Rupali (sensitive) and Genesis836 (tolerant) in the salt-induced reduction in net photosynthesis via non-stomatal limitations and the assessed damage to photosystem II, but with similar leaf ion concentrations, provides evidence that variation in 'tissue tolerance' of Na(+) and/or Cl(-) in leaves contributes to the differential salt tolerance of these chickpea genotypes. PMID- 26037694 TI - Exogenous application of methyl jasmonate induces a defense response and resistance against Sclerotinia sclerotiorum in dry bean plants. AB - Sclerotinia sclerotiorum (Lib.) de Bary is a necrotrophic fungal pathogen that causes a disease known as white mold, which is a major problem for dry bean (Phaseolus vulgaris L.) and other crops in many growing areas in Brazil. To investigate the role of methyl jasmonate (MeJA) in defending dry bean plants against S. sclerotiorum, we used suppression subtractive hybridization (SSH) of cDNA and identified genes that are differentially expressed during plant-pathogen interactions after treatment. Exogenous MeJA application enhanced resistance to the pathogen, and SSH analyses led to the identification of 94 unigenes, presumably involved in a variety of functions, which were classified into several functional categories, including metabolism, signal transduction, protein biogenesis and degradation, and cell defense and rescue. Using RT-qPCR, some unigenes were found to be differentially expressed in a time-dependent manner in dry bean plants during the interaction with S. sclerotiorum after MeJA treatment, including the pathogenesis-related protein PR3 (chitinase), PvCallose (callose synthase), PvNBS-LRR (NBS-LRR resistance-like protein), PvF-box (F-box family protein-like), and a polygalacturonase inhibitor protein (PGIP). Based on these expression data, the putative roles of differentially expressed genes were discussed in relation to the disease and MeJA resistance induction. Changes in the activity of the pathogenesis-related proteins beta-1,3-glucanase, chitinase, phenylalanine ammonia-lyase, and peroxidase in plants after MeJA treatment and following inoculation of the pathogen were also investigated as molecular markers of induced resistance. Foliar application of MeJA induced partial resistance against S. sclerotiorum in plants as well as a consistent increase in pathogenesis-related protein activities. Our findings provide new insights into the physiological and molecular mechanisms of resistance induced by MeJA in the P. vulgaris-S. sclerotiorum pathosystem. PMID- 26037695 TI - Brassinosteroid insensitive 1-associated kinase 1 (OsI-BAK1) is associated with grain filling and leaf development in rice. AB - Brassinosteroid Insensitive 1 (BRI1)-Associated Kinase I (BAK1) has been reported to interact with BRI1 for brassinosteroid (BR) perception and signal transduction that regulate plant growth and development. The aim of this study is to investigate the functions of a rice OsBAK1 homologue, designated as OsI-BAK1, which is highly expressed after heading. Silencing of OsI-BAK1 in rice plants produced a high number of undeveloped green and unfilled grains compared to the untransformed plants. Histological analyses demonstrated that embryos were either absent or retarded in their development in these unfilled rice grains of OsI-BAK1 RNAi plants. Down regulation of OsI-BAK1 caused a reduction in cell number and enlargement in leaf bulliform cells. Furthermore, transgenic rice plants overexpressing OsI-BAK1 were demonstrated to have corrugated and twisted leaves probably due to increased cell number that caused abnormal bulliform cell structure which were enlarged and plugged deep into leaf epidermis. The current findings suggest that OsI-BAK1 may play an important role in the developmental processes of rice grain filling and leaf cell including the bulliform cells. PMID- 26037696 TI - Sonodynamic antimicrobial chemotherapy: First steps towards a sound approach for microbe inactivation. AB - Sonodynamic therapy (SDT) relies on the ability of ultrasound to activate sonosensitisers and trigger the generation of reactive oxygen species (ROS) to achieve cell death. SDT was explored as an anticancer approach until 6 years ago, when its potential application as an antimicrobial strategy was pointed out and the term "sonoantimicrobial chemotherapy" (SACT) was coined. The excellent penetration of ultrasound in liquid media make SACT a particularly promising approach for the non-invasive treatment of deep-seated infections, and for the reduction of bacterial load in turbid water. In this review we provide an account of the brief history of SACT, from its molecular bases to the current state of the art and perspective applications. PMID- 26037697 TI - Morphological and Phylogenetic Characterization of New Gephyrocapsa Isolates Suggests Introgressive Hybridization in the Emiliania/Gephyrocapsa Complex (Haptophyta). AB - The coccolithophore genus Gephyrocapsa contains a cosmopolitan assemblage of pelagic species, including the bloom-forming Gephyrocapsa oceanica, and is closely related to the emblematic coccolithophore Emiliania huxleyi within the Noelaerhabdaceae. These two species have been extensively studied and are well represented in culture collections, whereas cultures of other species of this family are lacking. We report on three new strains of Gephyrocapsa isolated into culture from samples from the Chilean coastal upwelling zone using a novel flow cytometric single-cell sorting technique. The strains were characterized by morphological analysis using scanning electron microscopy and phylogenetic analysis of 6 genes (nuclear 18S and 28S rDNA, plastidial 16S and tufA, and mitochondrial cox1 and cox3 genes). Morphometric features of the coccoliths indicate that these isolates are distinct from G. oceanica and best correspond to G. muellerae. Surprisingly, both plastidial and mitochondrial gene phylogenies placed these strains within the E. huxleyi clade and well separated from G. oceanica isolates, making Emiliania appear polyphyletic. The only nuclear sequence difference, 1bp in the 28S rDNA region, also grouped E. huxleyi with the new Gephyrocapsa isolates and apart from G. oceanica. Specifically, the G. muellerae morphotype strains clustered with the mitochondrial beta clade of E. huxleyi, which, like G. muellerae, has been associated with cold (temperate and sub-polar) waters. Among putative evolutionary scenarios that could explain these results we discuss the possibility that E. huxleyi is not a valid taxonomic unit, or, alternatively the possibility of past hybridization and introgression between each E. huxleyi clade and older Gephyrocapsa clades. In either case, the results support the transfer of Emiliania to Gephyrocapsa. These results have important implications for relating morphological species concepts to ecological and evolutionary units of diversity. PMID- 26037698 TI - Comparative studies on exenatide-loaded poly (D,L-lactic-co-glycolic acid) microparticles prepared by a novel ultra-fine particle processing system and spray drying. AB - The purpose of this study was to compare the properties of exenatide-loaded poly (D,L-lactic-co-glycolic acid) microparticles (Ex-PLGA-MPs) prepared by a novel ultra-fine particle processing system (UPPS) and spray drying. UPPS is a proprietary technology developed by our group based on the disk rotation principle. Characteristics of the MPs including morphology, particle size distribution, drug content, encapsulation efficiency and in vitro release were comparatively studied. Cytotoxicity of the MPs was examined on A549 cells and the pharmacodynamics was investigated in vivo in type 2 diabetes Sprague-Dawley (SD) rats. Ex-PLGA-MPs prepared by UPPS showed larger particle size, denser surface, greater encapsulation efficiency, less initial burst release, and stable sustained release for more than one month in vitro as compared with the spray drying MPs. Meanwhile, the UPPS MPs effectively controlled the body growth rate and blood glucose in diabetes rats for at least three weeks after a single injection, while the spray drying MPs showed effective control period of about two weeks. UPPS technology was demonstrated to manufacture Ex-PLGA-MPs as a potential sustained release protein/polypeptide delivery system, which is an alternative method for the most commonly used spray drying. This comparative research provides a new guidance for microparticle preparation technology. PMID- 26037699 TI - Variation in bacterial ATP concentration during rapid changes in extracellular pH and implications for the activity of attached bacteria. AB - In this study we investigated the relationship between a rapid change in extracellular pH and the alteration of bacterial ATP concentration. This relationship is a key component of a hypothesis indicating that bacterial bioenergetics - the creation of ATP from ADP via a proton gradient across the cytoplasmic membrane - can be altered by the physiochemical charge-regulation effect, which results in a pH shift at the bacteria's surface upon adhesion to another surface. The bacterial ATP concentration was measured during a rapid change in extracellular pH from a baseline pH of 7.2 to pH values between 3.5 and 10.5. Experiments were conducted with four neutrophilic bacterial strains, including the Gram-negative Escherichia coli and Pseudomonas putida and the Gram positive Bacillus subtilis and Staphylococcus epidermidis. A change in bulk pH produced an immediate response in bacterial ATP, demonstrating a direct link between changes in extracellular pH and cellular bioenergetics. In general, the shifts in ATP were similar across the four bacterial strains, with results following an exponential relationship between the extracellular pH and cellular ATP concentration. One exception occurred with S. epidermidis, where there was no variation in cellular ATP at acidic pH values, and this finding is consistent with this species' ability to thrive under acidic conditions. These results provide insight into obtaining a desired bioenergetic response in bacteria through (i) the application of chemical treatments to vary the local pH and (ii) the selection and design of surfaces resulting in local pH modification of attached bacteria via the charge-regulation effect. PMID- 26037700 TI - Understanding the biocide action of poly(hexamethylene biguanide) using Langmuir monolayers of dipalmitoyl phosphatidylglycerol. AB - The disinfectant activity of poly(hexamethylene biguanide) (PHMB) has been explored in industrial applications, in agriculture and in food manipulation, but this biocide action is not completely understood. It is believed to arise from electrostatic interactions between the polyhexanide group and phosphatidylglycerol, which is the main phospholipid on the bacterial membrane. In this study, we investigated the molecular-level interactions between PHMB and dipalmitoyl phosphatidylglycerol (DPPG) in Langmuir monolayers that served as cell membrane models. PHMB at a concentration of 2*10(-4) g L(-1) in a Theorell Stenhagen at pH 3.0 and in a phosphate at pH 7.4 was used as a subphase to prepare the DPPG monolayers. Surface pressure-area isotherms showed that PHMB adsorbs and penetrates into the DPPG monolayers, expanding them and increasing their elasticity under both conditions examined. Results from polarization modulated infrared reflection absorption spectroscopy (PM-IRRAS) indicated that PHMB induces disorder in the DPPG chains and dehydrates their C=O groups, especially for the physiological medium. Overall, these findings point to hydrophobic interactions and dehydration being as relevant as electrostatic interactions to explain changes in membrane fluidity and permeability, believed to be responsible for the biocide action of PHMB. PMID- 26037701 TI - One-pot, green synthesis of gold nanoparticles by gelatin and investigation of their biological effects on Osteoblast cells. AB - It is useful to find new methods to synthesize and, more importantly, to control the size and shape of gold nanoparticles (AuNPs) without using relatively toxic reducing agents and surfactants. In this work, we present a one-pot, green synthesis of AuNPs taking the advantage of gelatin biopolymer to operate as unique reducing, growth controlling and stabilizing agent in aqueous solution of tetrachloroauric acid (HAuCl4) at temperatures above its melting point (~35 degrees C). The shape and size of AuNPs were found to be strongly influenced by the gelatin concentration (0.5-5%), while the growth rate of AuNPs is controlled by temperature of synthesis (40-80 degrees C) and viscosity of the biopolymer. A specific class of gelatin-coated AuNPs was selected to investigate its stability in simulated physiological conditions and cellular media and subsequently to evaluate the in vitro biocompatibility and capacity to sustain proliferation and differentiation of Osteoblast cells. Dark-field microscopy and Rayleigh scattering spectra prove a more efficient internalization of gelatin-coated AuNPs as compared with citrate-coated AuNPs, while methylthiazoltetrazolium bromide (MTT) assay demonstrates enhanced cell proliferation. Interestingly, in the presence of gelatin-coated AuNPs, we find out a first sign of Osteoblast cells differentiation with bone nodules formation, as confirmed by alkaline phosphatase (ALP) activity assay. PMID- 26037702 TI - Synthesis of poly(sulfobetaine methacrylate)-grafted chitosan under gamma-ray irradiation for alamethicin assembly. AB - Interaction between peptide and lipid membrane plays a major role in biological activity of membrane-active peptide. We describe here a new biocompatible polymeric assembly to support membrane peptide. Specifically, chitosan-graft poly(sulfobetaine methacrylate) (CS-g-PSBMA) was synthesized for alamethicin assembly by controlled polymerization under gamma-ray irradiation. The graft copolymer could self-assemble into micelles in distilled water for supporting alamethicin. The assembly of alamethicin with CS-g-PSBMA micelles in aqueous solutions was related with the ratio of alamethicin/CS-g-PSBMA: the more alamethicin, the smaller sizes of the hybrid complex. Moreover, alamethicin penetrated into the hydrophobic cores of CS-g-PSBMA micelles while displayed secondary helical conformation in the complex. The results indicate that CS-g PSBMA assemblies can be used to support membrane peptide. PMID- 26037703 TI - Parenterally administrable nano-micelles of 3,4-difluorobenzylidene curcumin for treating pancreatic cancer. AB - Pancreatic cancer remains one of the most devastating diseases in terms of patient mortality rates for which current treatment options are very limited. 3,4 Difluorobenzylidene curcumin (CDF) is a nontoxic analog of curcumin (CMN) developed in our laboratory, which exhibits extended circulation half-life, while maintaining high anticancer activity and improved pancreas specific accumulation in vivo, compared with CMN. CDF however has poor aqueous solubility and its dose escalation for systemic administration remains challenging. We have engineered self-assembling nano-micelles of amphiphilic styrene-maleic acid copolymer (SMA) with CDF by non-covalent hydrophobic interactions. The SMA-CDF nano-micelles were characterized for size, charge, drug loading, release, serum stability, and in vitro anticancer activity. The SMA-CDF nano-micelles exhibited tunable CDF loading from 5 to 15% with excellent aqueous solubility, stability, favorable hemocompatibility and sustained drug release characteristics. The outcome of cytotoxicity testing of SMA-CDF nano-micelles on MiaPaCa-2 and AsPC-1 pancreatic cancer cell lines revealed pronounced antitumor response due to efficient intracellular trafficking of the drug loaded nano-micelles. Additionally, the nano-micelles are administrable via the systemic route for future in vivo studies and clinical translation. The currently developed SMA based nano-micelles thus portend to be a versatile carrier for dose escalation and targeted delivery of CDF, with enhanced therapeutic margin and safety. PMID- 26037704 TI - Natural polysaccharides promote chondrocyte adhesion and proliferation on magnetic nanoparticle/PVA composite hydrogels. AB - This paper aims to investigate the synergistic effects of natural polysaccharides and inorganic nanoparticles on cell adhesion and growth on intrinsically cell non adhesive polyvinyl alcohol (PVA) hydrogels. Previously, we have demonstrated that Fe2O3 and hydroxyapatite (nHAP) nanoparticles are effective in increasing osteoblast growth on PVA hydrogels. Herein, we blended hyaluronic acid (HA) and chondroitin sulfate (CS), two important components of cartilage extracellular matrix (ECM), with Fe2O3/nHAP/PVA hydrogels. The presence of these natural polyelectrolytes dramatically increased the pore size and the equilibrium swelling ratio (ESR) while maintaining excellent compressive strength of hydrogels. Chondrocytes were seeded and cultured on composite PVA hydrogels containing Fe2O3, nHAP and Fe2O3/nHAP hybrids and Fe2O3/nHAP with HA or CS. Confocal laser scanning microscopy (CLSM) and cell counting kit-8 (CCK-8) assay consistently confirmed that the addition of HA or CS promotes chondrocyte adhesion and growth on PVA and composite hydrogels. Particularly, the combination of HA and CS exhibited further promotion to cell adhesion and proliferation compared with any single polysaccharide. The results demonstrated that the magnetic composite nanoparticles and polysaccharides provided synergistic promotion to cell adhesion and growth. Such polysaccharide-augmented composite hydrogels may have potentials in biomedical applications. PMID- 26037705 TI - Dual stimuli-sensitive dendrimers: Photothermogenic gold nanoparticle-loaded thermo-responsive elastin-mimetic dendrimers. AB - Dendrimers are synthetic macromolecules with unique structures that can work as nanoplatforms for both photothermogenic gold nanoparticles (AuNPs) and thermosensitive elastin-like peptides (ELPs) with valine-proline-glycine-valine glycine (VPGVG) repeats. In this study, photothermogenic AuNPs were loaded into thermo-responsive elastin-mimetic dendrimers (dendrimers conjugating ELPs at their periphery) to produce dual stimuli-sensitive nanoparticles. Polyamidoamine G4 dendrimers were modified with acetylated VPGVG and (VPGVG)2, and the resulting materials were named ELP1-den and ELP2-den, respectively. The AuNPs were prepared by the reduction of Au ions using a dendrimer-nanotemplated method. The AuNP loaded elastin-mimetic dendrimers exhibited photothermal properties. ELP1-den and ELP2-den showed similar temperature-dependent changes in their conformations. Phase transitions were observed at around 55 degrees C and 35 degrees C for the AuNP-loaded ELP1-den and AuNP-loaded ELP2-den, respectively, but not for the corresponding PEGylated dendrimer. In contrast to the AuNP-loaded PEGylated dendrimer, AuNP-loaded ELP2-den readily associated with cells and induced efficient photocytotoxicity at 37 degrees C. The cell association and the photocytotoxicity properties of AuNP-loaded ELP2-den could be controlled by temperature. These results therefore suggest that dual stimuli-sensitive dendrimer nanoparticles of this type could be used for photothermal therapy. PMID- 26037706 TI - Polymeric micelles based on poly(ethylene oxide) and alpha-carbon substituted poly(E-caprolactone): An in vitro study on the effect of core forming block on polymeric micellar stability, biocompatibility, and immunogenicity. AB - A series of block copolymers based on methoxy poly(ethylene oxide)-block-poly(E caprolactone) (PEO-b-PCL), PEO-b-PCL bearing side groups of benzyl carboxylate (PEO-b-PBCL), or free carboxyl (PEO-b-PCCL) on the PCL backbone with increasing degrees of polymerization of the PCL backbone were synthesized. Prepared block copolymers assembled to polymeric micelles by co-solvent evaporation. The physical stability of prepared micelles was assessed by measuring their tendency toward aggregation over time using dynamic light scattering (DLS). The resistance of micelles against dissociation in the presence of a micelle destabilizing agent, i.e., sodium dodecyl sulfate (SDS), was also investigated using DLS. The rate of micellar core degradation was determined using (1)H NMR for polymer molecular weight measurement upon incubation of micelles in PBS (pH=7.4) at 37 degrees C followed by dialysis of the remaining polymer at different time intervals. The effect of pendent group chemistry in the micellar core on the adsorption of serum proteins to micellar structure was then evaluated using Bradford Protein assay kit. Finally, the effect of micellar core structure on the induction of bone marrow derived dendritic cell (BMDC) maturation and secretion of IL-12 was studied as a measure of micellar immunogenicity. The results showed micelle structures from polymers with higher degree of polymerization in the hydrophobic block and/or those with more hydrophobic substituents on the core forming block, to be more stable. This was reflected by a decreased tendency for micellar aggregation, reduced dissociation of micelles in the presence of SDS, and diminished core degradation. All micelles were shown to have insignificant adsorption of serum protein suggesting that the hydrophilic PEO shell provided sufficient protection of the core. However, the protein adsorption increased with increase in the hydrophobicity and molecular weight of the core-forming block. Irrespective of the micellar core structure, all tested micelles were found to be non-immunogenic in BMDCs. PMID- 26037707 TI - Long, Multicenter Bonding--A New Concept for Supramolecular Materials. AB - A new concept for constructing supramolecular architectures is discussed. In addition to van der Waals and hydrogen-bonding intermolecular interactions that primarily account for supramolecular structures for all materials lacking extended 3D network structures, directional, long, multicenter bonding that can occur for anionic, cationic, neutral, and zwitterionic radicals and can direct intermolecular recognition through pi interactions and form extended network supramolecular structural motifs. PMID- 26037709 TI - Supramolecular pentapeptide-based fullerene nanofibers: effect of molecular chirality. AB - The supramolecular organization of new fullerene derivatives endowed with peptides as biomolecular templates affords ordered nanofibers of several micrometres length based on hydrogen bonds and pi-pi interactions. PMID- 26037708 TI - Genome-wide assessment of recurrent genomic imbalances in canine leukemia identifies evolutionarily conserved regions for subtype differentiation. AB - Leukemia in dogs is a heterogeneous disease with survival ranging from days to years, depending on the subtype. Strides have been made in both human and canine leukemia to improve classification and understanding of pathogenesis through immunophenotyping, yet classification and choosing appropriate therapy remains challenging. In this study, we assessed 123 cases of canine leukemia (28 ALLs, 24 AMLs, 25 B-CLLs, and 46 T-CLLs) using high-resolution oligonucleotide array comparative genomic hybridization (oaCGH) to detect DNA copy number alterations (CNAs). For the first time, such data were used to identify recurrent CNAs and inclusive genes that may be potential drivers of subtype-specific pathogenesis. We performed predictive modeling to identify CNAs that could reliably differentiate acute subtypes (ALL vs. AML) and chronic subtypes (B-CLL vs. T-CLL) and used this model to differentiate cases with up to 83.3 and 95.8 % precision, respectively, based on CNAs at only one to three genomic regions. In addition, CGH datasets for canine and human leukemia were compared to reveal evolutionarily conserved copy number changes between species, including the shared gain of HSA 21q in ALL and ~25 Mb of shared gain of HSA 12 and loss of HSA 13q14 in CLL. These findings support the use of canine leukemia as a relevant in vivo model for human leukemia and justify the need to further explore the conserved genomic regions of interest for their clinical impact. PMID- 26037710 TI - National risk factors and estimated costs for redo ureteroneocystostomy after pediatric renal transplant. AB - Approximately 800 pediatric renal transplants are performed annually in the United States. VUR or obstruction may cause graft failure requiring redo ureteroneocystostomy. We examined possible risk factors and cost using the PHIS national database. We examined the PHIS for 8.5 yr to determine the association between redo ureteroneocystostomy following pediatric renal transplant to demographics, comorbidities, GU conditions, insurance status, and hospital characteristics, and looked at relative costs using descriptive and comparative statistics. A total of 2390 pediatric renal transplants were identified, of which 69 (2.3%) underwent redo ureteroneocystostomy (median 11.6 months post transplant). Risk factors for redo ureteroneocystostomy are younger age (p = 0.048), PUVs (p < 0.001), female gender (p = 0.005), race (p = 0.014), insurance type (p < 0.027), region (p = 0.045), and transplant surgery volume (p = 0.048). Redo ureteroneocystostomy after transplant does not significantly increase the overall cost of transplant (p = 0.175). We confirmed previous findings that younger age and PUVs increase the risk of post-transplant redo ureteroneocystostomy, with a five-yr plateau. We found an association with gender, race, insurance status, and hospital characteristics. Redo ureteroneocystostomy, which increases costs, does not statistically significantly increase overall cost of individual treatment in this database, although costs may be underreported. PMID- 26037711 TI - Light-field-characterization in a continuous hydrogen-producing photobioreactor by optical simulation and computational fluid dynamics. AB - Externally illuminated photobioreactors (PBRs) are widely used in studies on the use of phototrophic microorganisms as sources of bioenergy and other photobiotechnology research. In this work, straightforward simulation techniques were used to describe effects of varying fluid flow conditions in a continuous hydrogen-producing PBR on the rate of photofermentative hydrogen production (rH2 ) by Rhodobacter sphaeroides DSM 158. A ZEMAX optical ray tracing simulation was performed to quantify the illumination intensity reaching the interior of the cylindrical PBR vessel. 24.2% of the emitted energy was lost through optical effects, or did not reach the PBR surface. In a dense culture of continuously producing bacteria during chemostatic cultivation, the illumination intensity became completely attenuated within the first centimeter of the PBR radius as described by an empirical three-parametric model implemented in Mathcad. The bacterial movement in chemostatic steady-state conditions was influenced by varying the fluid Reynolds number. The "Computational Fluid Dynamics" and "Particle Tracing" tools of COMSOL Multiphysics were used to visualize the fluid flow pattern and cellular trajectories through well-illuminated zones near the PBR periphery and dark zones in the center of the PBR. A moderate turbulence (Reynolds number = 12,600) and fluctuating illumination of 1.5 Hz were found to yield the highest continuous rH2 by R. sphaeroides DSM 158 (170.5 mL L(-1) h(-1) ) in this study. PMID- 26037712 TI - The use of lower resolution viewing devices for mammographic interpretation: implications for education and training. AB - AIMS: To establish whether lower resolution, lower cost viewing devices have the potential to deliver mammographic interpretation training. METHODS: On three occasions over eight months, fourteen consultant radiologists and reporting radiographers read forty challenging digital mammography screening cases on three different displays: a digital mammography workstation, a standard LCD monitor, and a smartphone. Standard image manipulation software was available for use on all three devices. Receiver operating characteristic (ROC) analysis and ANOVA (Analysis of Variance) were used to determine the significance of differences in performance between the viewing devices with/without the application of image manipulation software. The effect of reader's experience was also assessed. RESULTS: Performance was significantly higher (p < .05) on the mammography workstation compared to the other two viewing devices. When image manipulation software was applied to images viewed on the standard LCD monitor, performance improved to mirror levels seen on the mammography workstation with no significant difference between the two. Image interpretation on the smartphone was uniformly poor. Film reader experience had no significant effect on performance across all three viewing devices. CONCLUSION: Lower resolution standard LCD monitors combined with appropriate image manipulation software are capable of displaying mammographic pathology, and are potentially suitable for delivering mammographic interpretation training. KEY POINTS: * This study investigates potential devices for training in mammography interpretation. * Lower resolution standard LCD monitors are potentially suitable for mammographic interpretation training. * The effect of image manipulation tools on mammography workstation viewing is insignificant. * Reader experience had no significant effect on performance in all viewing devices. * Smart phones are not suitable for displaying mammograms. PMID- 26037713 TI - Usefulness of combining gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging and contrast-enhanced ultrasound for diagnosing the macroscopic classification of small hepatocellular carcinoma. AB - OBJECTIVE: Non-simple nodules in hepatocellular carcinoma (HCC) correlate with poor prognosis. Therefore, we examined the diagnostic ability of gadolinium ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) and contrast-enhanced ultrasound (CEUS) for diagnosing the macroscopic classification of small HCCs. METHODS: A total of 85 surgically resected nodules (<=30 mm) were analyzed. HCCs were pathologically classified as simple nodular (SN) and non-SN. By evaluating hepatobiliary phase (HBP) of EOB MRI and Kupffer phase of CEUS, the diagnostic abilities of both modalities to correctly distinguish between SN and non-SN were compared. RESULTS: Forty-six nodules were diagnosed as SN and the remaining 39 nodules as non-SN. The area under the ROC curve (AUROCs, 95% confidence interval) for the diagnosis of non-SN were EOB-MRI, 0.786 (0.682-0.890): CEUS, 0.784 (0.679-0.889), in combination, 0.876 (0.792-0.959). The sensitivity, specificity, and accuracy were 64.1%, 95.7%, and 81.2% in EOB-MRI, 56.4%, 97.8%, and 78.8% in CEUS, and 84.6%, 95.7%, and 90.6% in combination, respectively. High diagnostic ability was obtained when diagnosed in both modalities combined. The sensitivity was especially statistically significant compared to CEUS. CONCLUSION: Combined diagnosis by EOB MRI and CEUS can provide high-quality imaging assessment for determining non-SN in small HCCs. KEY POINTS: * Non-SN has a higher frequency of MVI and intrahepatic metastasis than SN. * Macroscopic classification is useful to choose the treatment strategy for small HCCs. * Diagnostic ability for macroscopic findings of EOB-MRI and CEUS were statistically equal. * The diagnosis of macroscopic findings by individual modality has limitations. * Combined diagnosis of EOB-MRI and CEUS provides high diagnostic ability. PMID- 26037714 TI - Paediatric CT dose: a multicentre audit of subspecialty practice in Australia and New Zealand. AB - OBJECTIVES: To evaluate paediatric CT dosimetry in Australia and New Zealand and calculate size-specific dose estimates (SSDEs) for chest and abdominal examinations. METHODS: Eight hospitals provided data from 12 CT systems for 1462 CTs in children aged 0-15. Imaging data were recorded for eight examinations: head (trauma, shunt), temporal bone, paranasal sinuses, chest (mass) and chest HRCT (high-resolution CT), and abdomen/pelvis (mass/inflammation). Dose data for cranial examinations were categorised by age and SSDEs by lateral dimension. Diagnostic reference ranges (DRRs) were defined by the 25th and 75th percentiles. Centralised image quality assessment was not undertaken. RESULTS: DRRs for 201 abdominopelvic SSDEs were: 2.8-4.7, 3.6-11.5, 8.5-15.0, 7.6-15, and 10.6-16.2 for the <15 cm, 15-19 cm, 20-24 cm, 25-29 cm and >30 cm groups, respectively. For 147 chest examinations using these body width categories, SSDE DRRs were 2.0-4.4, 3.3 7.9, 4.0-9.4, 4.5-12, and 6.5-12. Kilovoltage peak (kVp), but not AEC or IR, was associated with SSDE (parameter estimate [standard error]: 0.12 (0.03); p < 0.0001). CONCLUSIONS: Australian and New Zealand paediatric CT DRRs and abdominal SSDEs are comparable to international data. SSDEs for chest examinations are proposed. Dose variations could be reduced by adjusting kVp. KEY POINTS: * SSDEs can be calculated for all patients, CT systems, and practices * Kilovoltage peak (kVp) has the greatest association with dose in similar-sized patients * Paediatric DRRs for CT are now available for use internationally. PMID- 26037715 TI - T2 mapping of CT remodelling patterns in interstitial lung disease. AB - OBJECTIVES: To evaluate lung T2 mapping for quantitative characterization and differentiation of ground-glass opacity (GGO), reticulation (RE) and honeycombing (HC) in usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). METHODS: Twelve patients with stable UIP or NSIP underwent thin section multislice CT and 1.5-T MRI of the lung. A total of 188 regions were classified at CT into normal (n = 29) and pathological areas, including GGO (n = 48), RE (n = 60) and HC (n = 51) predominant lesions. Entire lung T2 maps based on multi-echo single shot TSE sequence (TE: 20, 40, 79, 140, 179 ms) were generated from each subject with breath-holds at end-expiration and ECG triggering. RESULTS: The median T2 relaxation of GGO was 67 ms (range 60-72 ms). RE predominant lesions had a median relaxation of 74 ms (range 69-79 ms), while for HC pattern this was 79 ms (range 74-89 ms). The median T2 relaxation for normal lung areas was 41 ms (ranged 38-49 ms), and showed significant difference to pathological areas (p < 0.001). A statistical difference was found between the T2 relaxation of GGO, RE and HC (p < 0.05). CONCLUSIONS: The proposed method provides quantitative information for pattern differentiation, potentially allowing for monitoring of progression and response to treatment, in interstitial lung disease. KEY POINTS: * Multi-echo single shot TSE sequence allows for entire lung T2 mapping. * Lung remodelling patterns in ILD show different T2 relaxation. * Quantitative T2 mapping may provide information for monitoring of ILD. PMID- 26037716 TI - Free DICOM de-identification tools in clinical research: functioning and safety of patient privacy. AB - PURPOSE: To compare non-commercial DICOM toolkits for their de-identification ability in removing a patient's personal health information (PHI) from a DICOM header. MATERIALS AND METHODS: Ten DICOM toolkits were selected for de identification tests. Tests were performed by using the system's default de identification profile and, subsequently, the tools' best adjusted settings. We aimed to eliminate fifty elements considered to contain identifying patient information. The tools were also examined for their respective methods of customization. RESULTS: Only one tool was able to de-identify all required elements with the default setting. Not all of the toolkits provide a customizable de-identification profile. Six tools allowed changes by selecting the provided profiles, giving input through a graphical user interface (GUI) or configuration text file, or providing the appropriate command-line arguments. Using adjusted settings, four of those six toolkits were able to perform full de-identification. CONCLUSION: Only five tools could properly de-identify the defined DICOM elements, and in four cases, only after careful customization. Therefore, free DICOM toolkits should be used with extreme care to prevent the risk of disclosing PHI, especially when using the default configuration. In case optimal security is required, one of the five toolkits is proposed. KEY POINTS: * Free DICOM toolkits should be carefully used to prevent patient identity disclosure. * Each DICOM tool produces its own specific outcomes from the de-identification process. * In case optimal security is required, using one DICOM toolkit is proposed. PMID- 26037717 TI - Is bronchial wall imaging affected by temporal resolution? comparative evaluation at 140 and 75 ms in 90 patients. AB - PURPOSE: To evaluate the influence of temporal resolution (TR) on cardiogenic artefacts at the level of bronchial walls. MATERIAL AND METHODS: Ninety patients underwent a dual-source, single-energy chest CT examination enabling reconstruction of images with a TR of 75 ms (i.e., optimized TR) (Group 1) and 140 ms (i.e., standard TR) (Group 2). Cardiogenic artefacts were analyzed at the level of eight target bronchi, i.e., right (R) and left (L) B1, B5, B7, and B10 (total number of bronchi examined: n = 720). RESULTS: Cardiogenic artefacts were significantly less frequent and less severe in Group 1 than in Group 2 (p < 0.0001) with the highest scores of discordant ratings for bronchi in close contact with cardiac cavities: RB5 (61/90; 68%); LB5 (66/90; 73%); LB7 (63/90; 70%). In Group 1, 78% (560/720) of bronchi showed no cardiac motion artefacts, whereas 22% of bronchi (160/720) showed artefacts rated as mild (152/160; 95%), moderate (7/160; 4%), and severe (1/160; 1%). In Group 2, 70% of bronchi (503/720) showed artefacts rated as mild (410/503; 82%), moderate (82/503; 16%), and severe (11/503; 2%). CONCLUSION: At 75 ms, most bronchi can be depicted without cardiogenic artefacts. KEY POINTS: * Quantitative CT helps analyze morphologic changes in COPD patients * Cardiogenic artefacts may hamper precise analysis of bronchial dimensions * Temporal resolution of CT acquisitions is an important parameter for bronchial imaging. PMID- 26037718 TI - Optimizing radiation dose by using advanced modelled iterative reconstruction in high-pitch coronary CT angiography. AB - PURPOSE: To evaluate the potential of advanced modeled iterative reconstruction (ADMIRE) for optimizing radiation dose of high-pitch coronary CT angiography (CCTA). METHODS: High-pitch 192-slice dual-source CCTA was performed in 25 patients (group 1) according to standard settings (ref. 100 kVp, ref. 270 mAs/rot). Images were reconstructed with filtered back projection (FBP) and ADMIRE (strength levels 1-5). In another 25 patients (group 2), high-pitch CCTA protocol parameters were adapted according to results from group 1 (ref. 160 mAs/rot), and images were reconstructed with ADMIRE level 4. In ten patients of group 1, vessel sharpness using full width at half maximum (FWHM) analysis was determined. Image quality was assessed by two independent, blinded readers. RESULTS: Interobserver agreements for attenuation and noise were excellent (r = 0.88/0.85, p < 0.01). In group 1, ADMIRE level 4 images were most often selected (84%, 21/25) as preferred data set; at this level noise reduction was 40% compared to FBP. Vessel borders showed increasing sharpness (FWHM) at increasing ADMIRE levels (p < 0.05). Image quality in group 2 was similar to that of group 1 at ADMIRE levels 2-3. Radiation dose in group 2 (0.3 +/- 0.1 mSv) was significantly lower than in group 1 (0.5 +/- 0.3 mSv; p < 0.05). CONCLUSIONS: In a selected population, ADMIRE can be used for optimizing high-pitch CCTA to an effective dose of 0.3 mSv. KEY POINTS: * Advanced modeled IR (ADMIRE) reduces image noise up to 50% as compared to FBP. * Coronary artery vessel borders show an increasing sharpness at higher ADMIRE levels. * High-pitch CCTA with ADMIRE is possible at a radiation dose of 0.3 mSv. PMID- 26037719 TI - Tailoring Building Blocks and Their Boundary Interaction for the Creation of New, Potentially Superhard, Carbon Materials. AB - A strategy for preparing hybrid carbon structures with amorphous carbon clusters as hard building blocks by compressing a series of predesigned two-component fullerides is presented. In such constructed structures the building blocks and their boundaries can be tuned by changing the starting components, providing a way for the creation of new hard/superhard materials with desirable properties. PMID- 26037720 TI - Development of the web-based Spanish and Catalan versions of the Euroqol 5D-Y (EQ 5D-Y) and comparison of results with the paper version. AB - BACKGROUND: The objectives of the study were to develop web-based Spanish and Catalan versions of the EQ-5D-Y, and to compare scores and psychometric properties with the paper version. METHODS: Web-based and paper versions of EQ-5D Y were included in a cross-sectional study in Palafolls (Barcelona), Spain and administered to students (n = 923) aged 8 to 18 years from 2 primary and 1 secondary school and their parents. All students completed both the web-based and paper versions during school time with an interval of at least 2 h between administrations. The order of administration was randomized. Participants completed EQ-5D-Y, a measure of mental health status (the Strengths and Difficulties Questionnaire), and sociodemographic variables using a self administered questionnaire. Parents questionnaire included parental level of education and presence of chronic conditions in children. Missing values, and floor and ceiling effects were compared between versions. Mean score differences were computed for the visual analogue scale (VAS). Percentage of agreement, kappa index (k) and intraclass correlation coefficient (ICC) were computed to analyze the level of agreement between web-based and paper versions on EQ-5D-Y dimensions and VAS. Known groups validity was analyzed and compared between the two formats. RESULTS: Participation rate was 77 % (n = 715). Both formats of EQ-5D-Y showed low percentages of missing values (n = 2, and 4 to 9 for web and paper versions respectively), and a high ceiling effect by dimension (range from 79 % to 96 %). Percent agreement for EQ-5D-Y dimensions on the web and paper versions was acceptable (range 89 % to 97 %), and k ranged from 0.55 (0.48-0.61, usual activities dimension) to 0.75 (0.68-0.82, mobility dimension). Mean score difference on the VAS was 0.07, and the ICC for VAS scores on the two formats was 0.84 (0.82-0.86). Both formats showed acceptable ability to discriminate according to self-perceived health, reporting chronic conditions, and mental health status. CONCLUSIONS: The digital EQ-5D-Y showed almost identical VAS scores and acceptable levels of agreement on dimensions. Both formats demonstrated acceptable levels of construct validity. Availability of the Spanish and Catalan web-version will facilitate its use in HRQOL assessment and in economic evaluation. PMID- 26037721 TI - Principles of miRNA-mRNA interactions: beyond sequence complementarity. AB - MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression by altering the translation efficiency and/or stability of targeted mRNAs. In vertebrates, more than 50% of all protein-coding RNAs are assumed to be subject to miRNA-mediated control, but current high-throughput methods that reliably measure miRNA-mRNA interactions either require prior knowledge of target mRNAs or elaborate preparation procedures. Consequently, experimentally validated interactions are relatively rare. Furthermore, in silico prediction based on sequence complementarity of miRNAs and their corresponding target sites suffers from extremely high false positive rates. Apparently, sequence complementarity alone is often insufficient to reflect the complex post transcriptional regulation of mRNAs by miRNAs, which is especially true for animals. Therefore, combined analysis of small non-coding and protein-coding RNAs is indispensable to better understand and predict the complex dynamics of miRNA regulated gene expression. Single-nucleotide polymorphisms (SNPs) and alternative polyadenylation (APA) can affect miRNA binding of a given transcript from different individuals and tissues, and especially APA is currently emerging as a major factor that contributes to variations in miRNA-mRNA interplay in animals. In this review, we focus on the influence of APA and SNPs on miRNA-mediated gene regulation and discuss the computational approaches that take these mechanisms into account. PMID- 26037723 TI - Is there a difference in the maternal and neonatal outcomes between patients discharged after 24 h versus 72 h following cesarean section? A prospective randomized observational study on 2998 patients. AB - OBJECTIVE: To compare the incidence of postpartum maternal and neonatal complications and hospital readmission in patients discharged 24 versus 72 h after cesarean section. METHODS: Using randomization, 1495 patients were discharged after 24 h and 1503 patients were discharged after 72 h. All patients fulfilled the discharge criteria. Patients were assessed 6 weeks after delivery, any maternal or neonatal problems or hospital readmissions during this time interval were reported. RESULTS: There was no difference in maternal hospital readmission between the two groups, but there was a significantly higher neonatal readmission rate in the 24-h group mainly due to neonatal jaundice. As for the complications reported after 6 weeks, the only two significant outcomes were initiating breast feeding, being significantly higher in the 72-h group [OR and 95% CI 0.77 (0.66-0.89)] and the mood swings being significantly lower in the 72 h group [OR and 95% CI 2.28 (1.94-2.68)]. CONCLUSION: Our recommendation is still in favor of late discharge, after cesarean delivery. Bearing in mind, that an early 24-h discharge, after cesarean delivery is feasible, but with special care of the neonate, with early visit to the pediatrician and early establishment of effective lactation. PMID- 26037722 TI - ADF/cofilin: a crucial regulator of synapse physiology and behavior. AB - Actin filaments (F-actin) are the major structural component of excitatory synapses, being present in presynaptic terminals and in postsynaptic dendritic spines. In the last decade, it has been appreciated that actin dynamics, the assembly and disassembly of F-actin, is crucial not only for the structure of excitatory synapses, but also for pre- and postsynaptic physiology. Hence, regulators of actin dynamics take a central role in mediating neurotransmitter release, synaptic plasticity, and ultimately behavior. Actin depolymerizing proteins of the ADF/cofilin family are essential regulators of actin dynamics, and a number of recent studies highlighted their crucial functions in excitatory synapses. In dendritic spines, ADF/cofilin activity is required for spine enlargement during initial long-term potentiation (LTP), but needs to be switched off during spine stabilization and LTP consolidation. Conversely, active ADF/cofilin is needed for spine pruning during long-term depression (LTD). Moreover, ADF/cofilin controls activity-induced synaptic availability of glutamate receptors, and exocytosis of synaptic vesicles. These data show that the activity of ADF/cofilin in synapses needs to be spatially and temporally tightly controlled through several upstream regulatory pathways, which have been identified recently. Hence, ADF/cofilin-controlled actin dynamics emerged as a critical and central regulator of synapse physiology. In this review, I will summarize and discuss our current knowledge on the roles of ADF/cofilin in synapse physiology and behavior, by focusing on excitatory synapses of the mammalian central nervous system. PMID- 26037724 TI - Prevalence of antenatal depressive symptoms among women in Sabah, Malaysia. AB - OBJECTIVE: To investigate the prevalence of antenatal depression and to assess whether the common risk factors identified in previous studies were applicable to women in Sabah, Malaysia. METHODS: A prospective cohort study of 2072 women was conducted in Sabah during 2009-2010. Participants were recruited at 36-38 weeks of gestation to complete a self-administered questionnaire regarding their demographic, socioeconomic and health characteristics. The presence of depression was assessed using the validated Malay version of the Edinburgh Postnatal Depression Scale. RESULTS: The prevalence of antenatal depression was 13.8% [95% confidence interval (CI) 12.3%, 15.3%]. Women who were happy with the pregnancy [odds ratio (OR) 0.43, 95% CI 0.21, 0.89] and those with a planned pregnancy (OR 0.45, 95% CI 0.33, 0.60) were less likely to suffer from antenatal depression. Pregnant mothers who were taking oral contraceptives before pregnancy (OR 1.63, 95% CI 1.20, 2.22) and women who experienced antenatal anxiety (OR 3.17, 95% CI 2.35, 4.26) appeared to have an increased risk of antenatal depression. CONCLUSION: A substantial proportion of women suffered from antenatal depression in Sabah, Malaysia. Screening and culturally tailored intervention programs targeting vulnerable subgroups of women in the early stage of pregnancy are recommended to deal with the problem. PMID- 26037725 TI - A case series of neonatal arrhythmias. AB - OBJECTIVE: Neonatal arrhythmias (NAs) are defined as abnormal heart rates in the neonatal period. They may occur as a result of various cardiovascular, systemic and metabolic problems. METHODS: A retrospective chart review was performed on newborns who were diagnosed with NA during hospitalization in a neonatal intensive care unit (NICU), or who were admitted to the NICU because of an arrhythmia diagnosis in two NICUs in Turkey from May 2011 to June 2013. RESULTS: Seventeen neonates with arrhythmias were identified. The incidence of NA was 0.4% and 0.3% in the two NICUs, and was 0.37% in the study population as a whole. Mean gestational age was 37 (29-40) weeks. Nine of the infants (53%) were diagnosed with fetal arrhythmia (FA) during the last week of gestation. The distribution of NA types was as follows: six (35%) supraventricular tachycardia (SVT), six (35%) premature atrial contractions (PACs), two (11%) premature ventricular contractions (PVCs), two (11%) multiple arrhythmias such as SVT + PAC and AV block + PVC, and one (5%) AV block. Wolff-Parkinson-White syndrome was present in one patient. An association of NA with congenital heart malformations was identified in five cases. CONCLUSIONS: Cardiac arrhythmias are important causes of infant morbidity, and an occasional cause of infant mortality if undiagnosed and untreated. It is important for the physician to be aware of the etiology, development and natural history of arrhythmias in the fetal and neonatal period. PMID- 26037726 TI - Utility of intrapartum transperineal ultrasound to predict cases of failure in vacuum extraction attempt and need of cesarean section to complete delivery. AB - OBJECTIVES: We aim to evaluate the predictive capacity of intrapartum transperineal ultrasound (ITU) to predict cases of failure in fetal extraction in operative deliveries with vacuum. Prospective, observational study performed on 61 nulliparous women, >= 37 weeks, singleton pregnancies at full dilatation who underwent transperineal ultrasound before placement of vacuum to complete fetal extraction. Working on the transperineal longitudinal plane, we evaluated the following: Angle of Progression (AoP), Progression Distance (PD) and head direction. In the transverse plane, midline angle (MLA) and head-perineum distance were assessed. Vacuum extractions were classified as easy (EG) (three or less vacuum pulls), difficult (DG) (more than three vacuum pulls) or impossible (IG) (delivery completed by cesarean section). Occipito-posterior presentations were not evaluated. RESULTS: Fifty-two patients were studied (26-EG, 19-DG and 7 IG). No differences in obstetric, intrapartum or neonatal characteristics were observed between study groups, with the following exceptions: weight at birth (3147 g-EG, 3523 g-DG and 3588 g-IG) and number of vacuum pulls (1.4-EG, 4.4-DG and 4.1-IG; p < 0.0005). The AoP pushing was 133.1 degrees +/- 13.6-EG, 112.8 degrees +/- 12.8-DG and 99.1 degrees +/- 8.9-IG (p < 0.0005); "head-up" direction was identified in 84.6% of EG, 36.8% of DG and 28.6% of IG (p < 0.001); PD were 37.0 +/- 10.4 mm, 33.3 +/- 23.3 mm and 20.8 +/- 9.5 mm (p < 0.0005); MLA were 35.0 degrees +/- 19.6, 55.3 degrees +/- 24.4 and 76.0 degrees +/- 23.2 (p = 0.003); and head-perineum distances were 41.8 +/- 6.6 mm, 49.2 +/- 9.8 mm and 48.0 +/- 3.4 mm (p = 0.072), respectively. CONCLUSION: We have observed that the presence of an AoP with pushing <105 degrees , a PD <25 mm, a "head-down" direction and a >45 degrees MLA are very unfavorable ITU parameters which can be used to identify cases of high risk of fetal extraction failure in vacuum assisted deliveries. PMID- 26037727 TI - Intrapartum sonography: two sings to detect asynclitism degree. PMID- 26037728 TI - Lactoferrin versus ferrous sulphate for the treatment of iron deficiency anemia during pregnancy: a randomized clinical trial. AB - OBJECTIVE: This study was conducted to evaluate the efficacy and safety of lactoferrin in comparison to ferrous sulphate for the treatment of iron deficiency anemia (IDA) during pregnancy. MATERIALS AND METHODS: This prospective, randomized, parallel-group, single-center study was conducted in the Department of Obstetrics and Gynecology at Menoufia University Hospital, Egypt and included a total of 200 pregnant women in the second trimester with IDA who were enrolled and randomly assigned either to receive 150 mg of dried ferrous sulphate capsules or lactoferrin 250 mg capsules once daily for eight consecutive weeks. The primary efficacy parameter was the amount of increase in hemoglobin concentration by 4 and 8 weeks, the adverse effects related to iron therapy and the patient compliance to the treatment. RESULTS: Total increase in Hb after 2 months with lactoferrin was higher (2.26 +/- 0.51 g/dL) compared to ferrous sulfate (1.11 +/- 0.22 g/dL) (p < 0.001). Gastrointestinal adverse events occurred more frequently with ferrous sulphate than the lactoferrin group (p < 0.001). The number of women requesting change the drug was higher in the ferrous sulphate group (p < 0.001). CONCLUSION: Lactoferrin was more effective than ferrous sulfate over a two-month period in pregnant women with IDA, with fewer gastrointestinal adverse events and better treatment acceptability. PMID- 26037729 TI - Neonatal morbidity after cesarean section before labor at 34(+0) to 38(+6) weeks: a cohort study. AB - OBJECTIVE: To describe morbidity in neonates born by cesarean section (CS) before labor between 34(+0) and 38(+6) weeks, stratified by gestational age. METHODS: Cohort study from five Italian tertiary care hospitals. Consecutive singleton pregnancies delivered by CS before labor between 34(+0) and 38(+6) weeks of gestation from January 2010 to August 2011 were included. Women in labor, with premature rupture of membranes, or with previous administration of steroids were excluded. The incidence of neonatal complication by gestational week was calculated. RESULTS: A total of 1135 cases were analyzed. Composite adverse neonatal outcomes, respiratory distress syndrome, transient tachypnea and use of continuous airway positive pressure decreased from 50%, 28%, 5% and 22% at 34 weeks of gestation, to 4.7%, 1.0%, 0.9% and 0.3% at 38 weeks of gestation. Multivariate analysis showed that the only variable independently associated with composite adverse neonatal outcome was gestational age at delivery (adjusted odds ratio 0.49; 95% confidence interval 0.39-0.61). CONCLUSIONS: The prevalence of neonatal complications in newborns delivered by CS before labor halves at each week of gestation from 34 to 38 weeks. Nonetheless complications, and mainly respiratory problems, are still present at early term gestation. PMID- 26037730 TI - Acupuncture for the sequelae of Bell's palsy: a randomized controlled trial. AB - BACKGROUND: Incomplete recovery from facial palsy results in social and physical disabilities, and the medical options for the sequelae of Bell's palsy are limited. Acupuncture is widely used for Bell's palsy patients in East Asia, but its efficacy is unclear. METHODS: We performed a randomized controlled trial including participants with the sequelae of Bell's palsy with the following two parallel arms: an acupuncture group (n = 26) and a waiting list group (n = 13). The acupuncture group received acupuncture treatments for 8 weeks, whereas the waiting list group did not receive acupuncture treatments during the 8-week period after randomization. The primary outcome measure was change in the Facial Disability Index (FDI) social and well-being subscale at week 8. We also analyzed changes in the FDI physical function subscale, the House-Brackmann score, the Sunnybrook Facial Nerve Grading system, lip mobility and stiffness at 5 and 8 weeks after randomization. An intention-to-treat analysis was applied. RESULTS: The acupuncture group exhibited greater improvements in the FDI social score (mean difference, 23.54; 95% confidence interval, 12.99 to 34.08) and better results on the FDI physical function subscale (mean difference, 21.54; 95% confidence interval, 7.62 to 35.46), Sunnybrook Facial Nerve Grading score (mean difference, 14.77; 95% confidence interval, 5.05 to 24.49), and stiffness scale (mean difference, -1.58; 95% confidence interval,-2.26 to -0.89) compared with the waiting list group after 8 weeks. No severe adverse event occurred in either group. CONCLUSION: Compared with the waiting list group, acupuncture had better therapeutic effects on the social and physical aspects of sequelae of Bell's palsy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43104115. PMID- 26037731 TI - The Impact of Inpatient Versus Outpatient Initiation on Early Warfarin Dosing. AB - BACKGROUND AND OBJECTIVES: Dosing algorithms for warfarin incorporate clinical and genetic factors but may not account for the numerous comorbidities affecting patients who start warfarin while hospitalized. We aimed to determine whether these algorithms perform differently when warfarin is initiated for inpatients compared with outpatients. PATIENTS AND METHODS: We analyzed a prospective cohort of 1015 participants from the Clarification of Optimal Anticoagulation through Genetics (COAG) trial who were randomized to either pharmacogenetically or clinically guided warfarin dosing algorithms. Clinicians and participants were blinded to dose during the first 28 days. We compared groups, based on location at the time of the first warfarin dose request, in relation to the following outcomes: percentage of time in the therapeutic international normalized ratio (INR) range (PTTR) during the first 4 weeks, time to first therapeutic INR, time to maintenance dose, and the difference between predicted and observed maintenance doses. RESULTS: A total of 527 participants started warfarin as inpatients and 488 as outpatients. There was no difference in PTTR based on location: 43.2 % for inpatient versus 47.4 % for outpatient initiation [mean adjusted difference -2.2 %; 95 % confidence interval (CI) -5.9 to 1.6]. Similarly, there were no differences in time to first therapeutic INR [hazard ratio (HR) 1.06; 95 % CI 0.91-1.24] or to maintenance dose (HR 0.96; 95 % CI 0.81 1.14). There was no evidence of interaction between study intervention (pharmacogenetically vs. clinically guided therapy) and location of initiation for these main outcomes. The difference between predicted and observed maintenance doses was similar for both locations. CONCLUSION: The warfarin dosing algorithms performed similarly for subjects who initiated warfarin as inpatients and outpatients, regardless of whether dosing was pharmacogenetically or clinically guided. PMID- 26037732 TI - Mid-Aortic Syndrome in a Preterm Infant: A Rare Cause of Hypertension. PMID- 26037734 TI - New knowledge on the antiglycoxidative mechanism of chlorogenic acid. AB - The role of chlorogenic acid (CGA) in the formation of advanced glycation end products (AGEs) (glycoxidation reaction) was studied. Model systems composed of bovine serum albumin (BSA) (1 mg mL(-1)) and methylglyoxal (5 mM) under mimicked physiological conditions (pH 7.4, 37 degrees C) were used to evaluate the antiglycoxidative effect of CGA (10 mM). The stability of CGA under reaction conditions was assayed by HPLC and MALDI-TOF MS. The glycoxidation reaction was estimated by analysis of free amino groups by the OPA assay, spectral analysis of fluorescent AGEs and total AGEs by ELISA, and colour formation by absorbance at 420 nm. Structural changes in protein were evaluated by analysis of phenol bound to the protein backbone using the Folin reaction, UV-Vis spectral analysis and MALDI-TOF-MS, while changes in protein function were measured by determining the antioxidant capacity using the ABTS radical cation decolourisation assay. CGA was isomerised and oxidised under our experimental conditions. Evidence of binding between BSA and multiple CGA and/or its derivative molecules (isomers and oxidation products) was found. CGA inhibited (p < 0.05) the formation of fluorescent and total AGEs at 72 h of reaction by 91.2 and 69.7%, respectively. The binding of phenols to BSA significantly increased (p < 0.001) its antioxidant capacity. Correlations between free amino group content, phenol bound to protein and antioxidant capacity were found. Results indicate that CGA simultaneously inhibits the formation of potentially harmful compounds (AGEs) and promotes the generation of neoantioxidant structures. PMID- 26037733 TI - Assisting Australians with mental health problems and financial difficulties: a Delphi study to develop guidelines for financial counsellors, financial institution staff, mental health professionals and carers. AB - BACKGROUND: There is a strong association between mental health problems and financial difficulties. Therefore, people who work with those who have financial difficulties (financial counsellors and financial institution staff) need to have knowledge and helping skills relevant to mental health problems. Conversely, people who support those with mental health problems (mental health professionals and carers) may need to have knowledge and helping skills relevant to financial difficulties. The Delphi expert consensus method was used to develop guidelines for people who work with or support those with mental health problems and financial difficulties. METHODS: A systematic review of websites, books and journal articles was conducted to develop a questionnaire containing items about the knowledge, skills and actions relevant to working with or supporting someone with mental health problems and financial difficulties. These items were rated over three rounds by five Australian expert panels comprising of financial counsellors (n = 33), financial institution staff (n = 54), mental health professionals (n = 31), consumers (n = 20) and carers (n = 24). RESULTS: A total of 897 items were rated, with 462 items endorsed by at least 80 % of members of each of the expert panels. These endorsed statements were used to develop a set of guidelines for financial counsellors, financial institution staff, mental health professionals and carers about how to assist someone with mental health problems and financial difficulties. CONCLUSIONS: A diverse group of expert panel members were able to reach substantial consensus on the knowledge, skills and actions needed to work with and support people with mental health problems and financial difficulties. These guidelines can be used to inform policy and practice in the financial and mental health sectors. PMID- 26037735 TI - Efficient saccade planning requires time and clear choices. AB - We use eye movements constantly to gather information. Saccades are efficient when they maximize the information required for the task, however there is controversy regarding the efficiency of eye movement planning. For example, saccades are efficient when searching for a single target (Nature, 434 (2005) 387 391), but are inefficient when searching for an unknown number of targets in noise, particularly under time pressure (Vision Research 74 (2012), 61-71). In this study, we used a multiple-target search paradigm and explored whether altering the noise level or increasing saccadic latency improved efficiency. Experiments used stimuli with two levels of discriminability such that saccades to the less discriminable stimuli provided more information. When these two noise levels corresponded to low and moderate visibility, most observers did not preferentially select informative locations, but looked at uncertain and probable target locations equally often. We then examined whether eye movements could be made more efficient by increasing the discriminability of the two stimulus levels and by delaying the first saccade so that there was more time for decision processes to influence the saccade choices. Some observers did indeed increase the proportion of their saccades to informative locations under these conditions. Others, however, made as many saccades as they could during the limited time and were unselective about the saccade goal. A clear trend that emerges across all experiments is that conditions with a greater proportion of efficient saccades are associated with a longer latency to initiate saccades, suggesting that the choice of informative locations requires deliberate planning. PMID- 26037736 TI - Research project will use cervical cells to predict risk of cancers. PMID- 26037737 TI - Treatment of sleep-related eating disorder. AB - OPINION STATEMENT: Sleep-related eating disorder (SRED) is classified as an NREM related parasomnia characterized by recurrent episodes of dysfunctional eating that occur after an arousal from the main sleep period with partial or complete amnesia for the event, resulting in weight gain from eating high calorie foods and causing various injuries due to consumption of inedible or toxic items. SRED can be idiopathic or commonly associated with other primary sleep disorders such as sleepwalking, restless legs syndrome (RLS), obstructive sleep apnea syndrome (OSAS), other clinical conditions, or use of sedative-hypnotic medications. First line treatment of idiopathic SRED includes selective serotonin reuptake inhibitors (SSRIs) at mean dosages of 20 to 30 mg/day. Topiramate at 100-300 mg/day and clonazepam at 0.5-2.0 mg/day can be valid alternative options. SRED related to other parasomnias or sleep disturbances that cause sleep fragmentation benefit most from treatment of the associated sleep disorder. In particular, RLS related SRED is best treated with dopamine agonists such as pramipexole, while sleepwalking-related SRED benefits from low-dose benzodiazepines such as clonazepam. Different kinds of drug associations have been proposed in a limited number of cases, especially in the past. We strongly recommend that all patients suffering from SRED should undergo consistent and regular follow-up about 2-3 times per year or otherwise according to the physician's judgment, in order to assess the evolution of symptom severity and frequency and re-evaluate treatment efficacy and any side effects that may arise. PMID- 26037738 TI - Outcome of post-infectious renal scarring. AB - In this issue of Pediatric Nephrology, Geback et al. from Gothenburg, Sweden, show that after a mean follow-up after childhood urinary tract infection of 41 years, kidney function decreases from a mean of 93 ml/min/1.73m(2) to 81 ml/min/1.73m(2). This was found in women with severe bilateral renal scarring. They had experienced their UTI during childhood in the 1950s and 1960s and had been drawn from a population-based cohort of more than 1,000 children. A previous paper on this same group of women had shown a higher systolic blood pressure of 3 mmHg during the day and 5 mmHg during the night compared with a control group. This contrasted with a follow-up study published earlier by the same group on two different cohorts in which no impairment of kidney function or increase in hypertension could be found. The present follow-up time was 13 years longer than that of any previous studies. Data on the long-term outcome of children who have had one or several urine infections is very important, as the fear of long-term complications has been driving the extensive investigations to which these children have traditionally been subjected. Further population-based follow-up data can help us to outline modern guidance on imaging after UTI. PMID- 26037739 TI - Validated questionnaires on intimacy in patients who have had cancer. AB - Problems with intimacy in patients with cancer of the head and neck may not be recognised. Our aim was to review published papers on patient-reported outcomes that record concerns about intimacy, sex, and function, to help develop a tool for use in head and neck cancer. We specifically looked for instruments with evidence of validation in patients with cancer, which could be used to identify problems with intimacy and sexuality. After evaluating 2563 papers, we identified 20 that satisfied our inclusion criteria, and these have been presented in a tabulated form. This review has shown the need to develop a questionnaire on intimacy that is specific to patients with cancer of the head and neck. It is an important issue that must be addressed by clinical and research teams, and will be done most effectively if it is linked to specific interventions. PMID- 26037741 TI - Call for a systematic approach to teaching trauma in medical schools. PMID- 26037740 TI - Does intra-articular fracture change the lubricant content of synovial fluid? AB - BACKGROUND: Lubrication function is impaired and the lubricant content of synovial fluid (SF) changes immediately after plateau tibia fractures. Here, we aimed to analyze the lubricant content of SF at chronic term following plateau tibia fracture. METHODS: Forty-eight surgically treated patients without joint incongruency (<2 mm displacement) were included in the study. Joint aspiration had been possible in 16 of the participants. However, sampling could be made from healthy knees in only ten of these patients. Twenty-six SF samples (16 injured knees, 10 healthy knees) were analyzed for concentrations of hyaluronic acid (HA), proteoglycan-4 (PRG4), TNF-alpha, IL-1beta, and IL-6. RESULTS: The group of experimental samples were obtained at a mean of 31 (12-66) months after injury from patients with a mean age of 45.1 (32-57) years. There were no relationships detected between biochemical analysis results and patient ages, sexes, postoperative time, and fracture type. After excluding six patients for whom we could not sample from their healthy knee, ten patients' values were compared with paired Wilcoxon signed rank test and no significant differences detected between the healthy and injured knee in terms of the SF concentrations of HA and PRG4 (p = 0.225 and 0.893, respectively). Similarly, there were no statistically significant differences in SF sample concentrations of TNF-alpha, IL-1beta, and IL-6 between healthy and injured knees. CONCLUSIONS: Despite acute changes, the long-term concentrations of HA and PRG4 were similar after plateau tibial fracture. We could not detect any concentration level differences between healthy knees and injured knees regarding HA and PRG4 in the long-term follow-up. PMID- 26037742 TI - Investigating Canadian medical school attrition metrics to inform socially accountable admissions planning. AB - OBJECTIVE: Attrition from Canadian medical degree programs was never described despite differences in admissions requirements at the 17 faculties of medicine. Knowledge on attrition metrics could help the faculties evaluate new avenues for addressing the Association of Faculties of Medicine's (AFMC) Future of Medical Education in Canada (FMEC MD) recommendation to enhance admissions practices with the goal to improve social accountability and student diversity. METHOD: AFMC databases were used to track medical degree completion of all Canadian M.D. students who enrolled between 2003 and 2007. Students were followed and assigned an M.D. completion status as of by July 1, 2013. Bivariate statistics were used to evaluate if demographic, admission and degree progression variables were associated with medical school attrition. RESULTS: Of 11,454 students enrolled in Canadian M.D. programs from 2003 to 2007, only 197 (1.7%) did not complete. Quebec had significantly higher attrition than other jurisdictions with age, educational attainment at time of enrolment, MCAT completion and struggling academically associated with attrition. CONCLUSION: Attrition from Canadian MD programs is rare and associated with differences in admission requirements and possibly suggests an optimum life stage for medical studies. Improved knowledge of attrition-related factors may offer an additional level of evidence for improving the alignment between admissions policies and the social accountability objectives of medical schools. PMID- 26037743 TI - Assistantship improves medical students' perception of their preparedness for starting work. AB - BACKGROUND: The GMC has recommended introducing student assistantships during which final year students, under supervision, undertake most of the responsibilities of a FY1 doctor. The Medical School at Queen's University Belfast in 2011/12 introduced an assistantship programme. We have evaluated the impact of the assistantship on students' perception of their preparedness for starting work. METHODS: Students were asked to complete a questionnaire at the beginning of the assistantship. It assessed the students' perception of their preparedness in five areas: clinical and practical skills, communications skills, teaching and learning, understanding the work environment and team working. After the assistantship they again completed the questionnaire. Comparison of the results allowed an assessment of the impact of the assistantship. RESULTS: There was a statistically significant improvement in the students' perception of their preparation for 49 of 56 tasks contained within the questionnaire. After the assistantship 81.2% of students felt well prepared for starting work compared with 38.9% before the assistantship. 93.9% agreed that the assistantship had improved their preparedness for starting work. CONCLUSIONS: The assistantship at Queen's University improves medical students' perception of their preparedness for starting work. The majority of medical students feel well prepared for starting work after completing the assistantship. PMID- 26037744 TI - How we tackled the problem of assessing humanities, social and behavioural sciences in medical education. AB - BACKGROUND: Assessment serves as an important motivation for learning. However, multiple choice and short answer question formats are often considered unsatisfactory for assessment of medical humanities, and the social and behavioural sciences. Little consensus exists as to what might constitute 'best' assessment practice. What we did: We designed an assessment format closely aligned to the curricular approach of problem-based learning which allows for greater assessment of students' understanding, depth of knowledge and interpretation, rather than recall of rote learning. CONCLUSION: The educational impact of scenario-based assessment has been profound. Students reported changing their approach to PBL, independent learning and exam preparation by taking a less reductionist, more interpretative approach to the topics studied. PMID- 26037745 TI - How doctors do not wish to die. PMID- 26037746 TI - [Re: The core journal as a work tool?]. PMID- 26037747 TI - [J. Haffner replies]. PMID- 26037748 TI - [Re: Femoral fracture and temporomandibular joint destruction following the use of bisphosphonates]. PMID- 26037750 TI - [Different guidelines for treatment of prostate cancer]. PMID- 26037751 TI - [Time is brain--also when the posterior circulation is affected]. PMID- 26037752 TI - [The Disneyland epidemic--could the same happen in Norway?]. PMID- 26037755 TI - Health in adolescence and subsequent receipt of social insurance benefits - The HUNT Study. AB - BACKGROUND: Long-term illness and work incapacity in young adulthood has consequences for both the individual and for society. The purpose of the study was to investigate the association between adolescent health and receipt of long term sickness and disability benefits for young adults in their twenties. MATERIAL AND METHOD: An adolescent population of 8949 school students (aged 13-21 years) assessed their own health in the Young-HUNT1 Study (1995-1997). Health was measured by means of a questionnaire enquiring about chronic somatic illnesses, somatic symptoms, symptoms of anxiety and depression, sleep disturbance, poor concentration, self-reported health and smoking, and by measuring height and weight. Information about receipt of long-term benefits was retrieved from the FD Trygd registry for the period 1998-2008 and defined as receipt of sickness benefit (>180 days/year), medical/vocational rehabilitation benefit and disability pension in the age group 20-29 years. We investigated the relationship between adolescent health and long-term social insurance benefits with logistic regression, adjusted for sex, age, follow-up time, mother's education and family composition. Siblings with different exposure and outcome were investigated to adjust for all familial factors shared by siblings. RESULTS: Each of the health measures was associated with an increased risk of long-term benefit. For example, adolescents who reported one or more somatic illnesses or poor concentration had a 5.4 and 3.4 percentage point higher risk, respectively, of receiving long-term benefits at the age of 20-29 years than adolescents who did not report somatic illness or poor concentration. Moreover the risk increased with an increase in the number of health problems. Sibling analyses supported these associations. INTERPRETATION: Health in adolescence is an indicator of increased vulnerability in the transition to the labour market. Preventing health selection during this transition should be a priority for welfare policy. PMID- 26037756 TI - [Posterior cortical atrophy]. AB - BACKGROUND: Posterior cortical atrophy is a neurodegenerative condition with atrophy of posterior parts of the cerebral cortex, including the visual cortex and parts of the parietal and temporal cortices. It presents early, in the 50s or 60s, with nonspecific visual disturbances that are often misinterpreted as ophthalmological, which can delay the diagnosis. The purpose of this article is to present current knowledge about symptoms, diagnostics and treatment of this condition. METHOD: The review is based on a selection of relevant articles in PubMed and on the authors' own experience with the patient group. RESULTS: Posterior cortical atrophy causes gradually increasing impairment in reading, distance judgement, and the ability to perceive complex images. Examination of higher visual functions, neuropsychological testing, and neuroimaging contribute to diagnosis. In the early stages, patients do not have problems with memory or insight, but cognitive impairment and dementia can develop. It is unclear whether the condition is a variant of Alzheimer's disease, or whether it is a separate disease entity. There is no established treatment, but practical measures such as the aid of social care workers, telephones with large keypads, computers with voice recognition software and audiobooks can be useful. INTERPRETATION: Currently available treatment has very limited effect on the disease itself. Nevertheless it is important to identify and diagnose the condition in its early stages in order to be able to offer patients practical assistance in their daily lives. PMID- 26037757 TI - [Button battery in the oesophagus]. PMID- 26037758 TI - Woman with high central venous oxygen saturation. PMID- 26037759 TI - [E-cigarettes--harmful or beneficial?]. PMID- 26037760 TI - [Biosimilar medicines]. PMID- 26037768 TI - Considerations before undertaking concerted action. PMID- 26037773 TI - Selective and Quantitative Detection of Trace Amounts of Mercury(II) Ion (Hg2+) and Copper(II) Ion (Cu2+) Using Surface-Enhanced Raman Scattering (SERS). AB - We report the development of a surface-enhanced Raman scattering (SERS)-based heavy metal ion sensor targeting the detection of mercury(II) ion (Hg(2+)) and copper(II) ion (Cu(2+)) with high sensitivity and selectivity. To achieve the detection of vibrational-spectroscopically silent heavy metal ions, the SERS substrate composed of gold nanorod (AuNR)-polycaprolactone (PCL) nanocomposite fibers was first functionalized using metal ion-binding ligands. Specifically, 2,5-dimercapto-1,3,4-thiadiazole dimer (di-DMT) and trimercaptotriazine (TMT) were attached to the SERS substrates serving as bridging molecules to capture Hg(2+) and Cu(2+), respectively, from solution. Upon heavy metal ion coordination, changes in the vibrational spectra of the bridging molecules, including variations in the peak-intensity ratios and peak shifts were observed and taken as indicators of the capture of the target ions. With rigorous spectral analysis, the coordination mechanism between the heavy metal ion and the corresponding bridging molecule was investigated. Mercury(II) ion primarily interacts with di-DMT through the cleavage of the disulfide bond, whereas Cu(2+) preferentially interacts with the heterocyclic N atoms in TMT. The specificity of the coordination chemistry provided both di-DMT and TMT with excellent selectivity for the detection of Hg(2+) and Cu(2+) in the presence of other interfering metal ion species. In addition, quantitative analysis of the concentration of the heavy metal ions was achieved through the construction of internal calibration curves using the peak-intensity ratios of 287/387 cm(-1) for Hg(2+) and 1234/973 cm(-1) for Cu(2+). PMID- 26037774 TI - Ten ways to be secretary of state for health. PMID- 26037775 TI - Detection, genotyping and quantitation of multiple hpv infections in south African women with cervical squamous cell carcinoma. AB - In Africa, data is limited on quantitation of human papillomavirus (HPV) types in women with multiple infections. This study applied a real time PCR (qPCR) assay for detection, genotyping and quantitation of multiple HPV infections in 90 tissue blocks of South African women with cervical squamous cell carcinoma. One sample with multiple HPV types was subjected to laser micro-dissection and qPCR. Four samples were negative for beta-globin and these were excluded from the analysis. The HPV DNA positivity rate was 93.0% (80/86). All 80 positives showed the presence of HR HPV types; HPV 68 was the only type negative in all the samples. Overall, HPV 16 was positive in most of the samples (88.8%), followed by HPV 56 (28.7%), HPV 18 (20.0%) and HPV 39 (18.7%). More than half of the samples (65.0%) had multiple infections. HPV 16 was present in majority of single (85.7%) and multiple infections (90.4%). HPV 16 showed higher viral loads in 70.3% of the HPV 16 co-infected samples. In one multiple infected sample laser micro dissection and qPCR identified HPV 18 with higher viral load as the most likely cause of the invasive lesion. There is large number of multiple HPV infections in South African women with cervical squamous cell carcinoma. HPV 16 is the most frequently detected type and often presents with higher viral load, suggesting it could be responsible for pathogenesis of the lesions in the majority of cases. PMID- 26037776 TI - Impact of centralization of pancreatoduodenectomy on reported radical resections rates in a nationwide pathology database. AB - BACKGROUND: Centralization of a pancreatoduodenectomy (PD) leads to a lower post operative mortality, but is unclear whether it also leads to improved radical (R0) or overall resection rates. METHODS: Between 2004 and 2009, pathology reports of 1736 PDs for pancreatic and peri-ampullary neoplasms from a nationwide pathology database were analysed. Pre-malignant lesions were excluded. High volume hospitals were defined as performing >= 20 PDs annually. The relationship between R0 resections, PD-volume trends, quality of pathology reports and hospital volume was analysed. RESULTS: During the study period, the number of hospitals performing PDs decreased from 39 to 23. High-volume hospitals reported more R0 resections in the pancreatic head and distal bile duct tumours than low volume hospitals (60% versus 54%, P = 0.035) although they operated on more advanced (T3/T4) tumours (72% versus 58%, P < 0.001). The number of PDs increased from 258 in 2004 to 394 in 2009 which was partly explained by increased overall resection rates of pancreatic head and distal bile duct tumours (11.2% in 2004 versus 17.5% in 2009, P < 0.001). The overall reported R0 resection rate of pancreatic head and distal bile duct tumours increased (6% in 2004 versus 11% in 2009, P < 0.001). Pathology reports of low-volume hospitals lacked more data including tumour stage (25% versus 15%, P < 0.001). CONCLUSIONS: Centralization of PD was associated with both higher resection rates and more reported R0 resections. The impact of this finding on overall survival should be further assessed. PMID- 26037777 TI - Evaluation of the Disease Activity Score in Twenty-Eight Joints-Based Flare Definitions in Rheumatoid Arthritis: Data From a Three-Year Clinical Trial. AB - OBJECTIVE: To assess the flare rate using published criteria (Disease Activity Score in 28 joints [DAS28-2] increase between visits of >1.2 or >0.6 if current DAS28 >=3.2) in patients receiving constant treatment, and to compare published flare criteria to criteria used by study investigators after biologic treatment discontinuation in the ACT-RAY study. METHODS: Patients with rheumatoid arthritis (n = 553) were randomized to add tocilizumab to ongoing methotrexate, or switch to tocilizumab plus placebo. If DAS28 <=3.2 occurred at week 24, treatment remained constant until week 52; here we assessed the DAS28-2 flare rate. Between weeks 52 and 104, patients in sustained remission (DAS28 <2.6 at 2 consecutive visits 12 weeks apart) discontinued tocilizumab and were assessed every 4 weeks. Per protocol, flare was defined as a worsening of disease activity that required treatment beyond the permitted therapy based on investigator opinions (investigator flare) and was compared with the DAS28-2 definition. RESULTS: After tocilizumab discontinuation, DAS28-2 was sensitive (88-100%), but not specific (57-65%), for detecting investigator flare. Under constant treatment, DAS28-2 criteria were met in 136 cases per 100 patient-years despite stable disease activity. Sustained flares were infrequent. Other DAS28-based criteria led to similar conclusions. CONCLUSION: DAS28-based flare occurred more often than investigator-defined flares after biologic agent discontinuation. More stringent criteria may be more appropriate for clinical practice. PMID- 26037778 TI - Synthesis and characterization of reduced graphite oxide-polymer composites and their application in adsorption of lead. AB - Herein, we report the in situ polymerization of 1,5-diaminonaphthalene (15DAN) and 1,4-diaminoanthraquinone (14DAA) on the surface of reduced graphite oxide (RGO). Synthesized RGO-P15DAN and RGO-P14DAA were characterized by FTIR, Raman, SEM, TGA and XRD. The adsorption capacity and adsorptivity of the synthesized composites were investigated by Atomic Absorption Spectroscopy (AAS) using 100 ppm aqueous solution of Pb(2+) ions. Further, we compared the results of the composites with those of poly 1,5-(diaminonaphthalene) (P15DAN), poly 1,4 (diaminoanthraquinone) (P14DAA), RGO, graphite oxide (GO) and graphite. Among the tested adsorbents, RGO-P15DAN demonstrated the high adsorptivity. PMID- 26037779 TI - Structural and optical properties of Purpurin for dye-sensitized solar cells. AB - In this work, we reported a combined experimental and theoretical study on molecular structure, vibrational spectra and Homo-Lumo analysis of Purpurin and TiO2/Purpurin. The geometries, electronic structures, molecular orbital analysis of natural dye sensitizer Purpurin were studied based on density functional theory (DFT) using the hybrid functional B3LYP. Fourier transform infrared (FT IR) and FT-Raman spectra have been recorded and extensive spectroscopic investigations have been carried out on Purpurin. The optimized geometries, wave number and intensity of the vibrational bands of Purpurin have been calculated using density functional level of theory (DFT/B3LYP) employing 6-311G (d,p) basis set. Based on the comparison between calculated and experimental results, assignments of the fundamental vibrational modes are examined. Features of the electronic absorption spectrum in the visible and near-UV regions were assigned based on TD-DFT calculations. The calculated results suggest that the three excited states with the lowest excited energies in 1,2,4, trihydroxy 9-10 anthraquinone was due to photo-induced electron transfer processes. Frontier molecular orbitals (FMO), LUMO, HOMO, and energy gap, of these dyes have been analyzed to show their effect on the process of electron injection and dye regeneration. Interaction between HOMO and LUMO of Purpurin are investigated to understand the recombination process and charge transfer process involving these dyes. We also performed analysis of I-V characteristics to investigate the role of charge transfer and the stability of the dye molecule. PMID- 26037780 TI - Transition-Metal-Mediated Cleavage of a Si=Si Double Bond. AB - Reaction of carbene-stabilized disilicon (1) with Fe(CO)5 gives the 1:1 adduct L:Si=Si[Fe(CO)4 ]:L (L:=C{N(2,6-Pr(i) 2 C6 H3 )CH}2 ) (2) at room temperature. At raised temperature, however, 2 may react with another equivalent of Fe(CO)5 to give L:Si[MU-Fe2 (CO)6 ](MU-CO)Si:L (3) through insertion of both CO and Fe2 (CO)6 into the Si2 core, which represents the first experimental realization of transition metal-carbonyl-mediated cleavage of a Si=Si double bond. The structures and bonding of both 2 and 3 have been investigated by spectroscopic, crystallographic, and computational methods. PMID- 26037781 TI - Histone Deacetylase Inhibitor Entinostat Inhibits Tumor-Initiating Cells in Triple-Negative Breast Cancer Cells. AB - Mortality following breast cancer diagnosis is mainly due to the development of distant metastasis. To escape from the primary site, tumor cells undergo the epithelial-to-mesenchymal transition (EMT), which helps them acquire a more motile and invasive phenotype. In our previous study, we showed that class I selective HDAC inhibitor entinostat reverses the EMT phenotype through reversal of epigenetic repression of E-cadherin. Recent evidence suggests that a subset of cells within a breast tumor may drive the metastatic outgrowth following escape from the primary site. These cells, termed tumor-initiating cells (TIC), represent a great threat to overall prognosis. They are critical in terms of drug resistance and tumor initiation at metastatic sites. Acquisition of EMT traits has also been shown to impart TIC phenotype to the cells, making EMT a "dual threat" for prognosis. In the current study, we show that entinostat treatment can reduce the percentage of TIC cells from triple-negative breast cancer (TNBC) cells. Entinostat treatment was able to reduce the CD44(high)/CD24(low) cell population, ALDH-1 activity, as well as protein and mRNA expression of known TIC markers such as Bmi-1, Nanog, and Oct-4. Next, we inoculated MDA-MB-231 cells transfected with firefly luciferase (231/Luc) in mammary fat pad of NSG mice. The mice were then treated with entinostat (2.5 mg/kg/d), and tumor development and formation of metastasis were assessed by bioluminescence imaging. Treatment with entinostat significantly reduced tumor formation at the primary site as well as lung metastasis. As such, entinostat may help prevent development of distant metastasis. PMID- 26037782 TI - Tissue-Engineered Tracheal Replacement in a Child: A 4-Year Follow-Up Study. AB - In 2010, a tissue-engineered trachea was transplanted into a 10-year-old child using a decellularized deceased donor trachea repopulated with the recipient's respiratory epithelium and mesenchymal stromal cells. We report the child's clinical progress, tracheal epithelialization and costs over the 4 years. A chronology of events was derived from clinical notes and costs determined using reference costs per procedure. Serial tracheoscopy images, lung function tests and anti-HLA blood samples were compared. Epithelial morphology and T cell, Ki67 and cleaved caspase 3 activity were examined. Computational fluid dynamic simulations determined flow, velocity and airway pressure drops. After the first year following transplantation, the number of interventions fell and the child is currently clinically well and continues in education. Endoscopy demonstrated a complete mucosal lining at 15 months, despite retention of a stent. Histocytology indicates a differentiated respiratory layer and no abnormal immune activity. Computational fluid dynamic analysis demonstrated increased velocity and pressure drops around a distal tracheal narrowing. Cross-sectional area analysis showed restriction of growth within an area of in-stent stenosis. This report demonstrates the long-term viability of a decellularized tissue-engineered trachea within a child. Further research is needed to develop bioengineered pediatric tracheal replacements with lower morbidity, better biomechanics and lower costs. PMID- 26037785 TI - Global parasite and Rattus rodent invasions: The consequences for rodent-borne diseases. AB - We summarize the current knowledge on parasitism-related invasion processes of the globally invasive Rattus lineages, originating from Asia, and how these invasions have impacted the local epidemiology of rodent-borne diseases. Parasites play an important role in the invasion processes and successes of their hosts through multiple biological mechanisms such as "parasite release," "immunocompetence advantage," "biotic resistance" and "novel weapon." Parasites may also greatly increase the impact of invasions by spillover of parasites and other pathogens, introduced with invasive hosts, into new hosts, potentially leading to novel emerging diseases. Another potential impact is the ability of the invader to amplify local parasites by spillback. In both cases, local fauna and humans may be exposed to new health risks, which may decrease biodiversity and potentially cause increases in human morbidity and mortality. Here we review the current knowledge on these processes and propose some research priorities. PMID- 26037784 TI - Plasma Protein Binding of Challenging Compounds. AB - Accurately determining fraction unbound (fu ) with currently available methods has been challenging for certain compounds. Inaccurate fu values can lead to the misinterpretation of important attributes of a drug candidate. Our analysis of over 2000 Pfizer drug discovery compounds showed no systematic bias in low or high fu precision using the equilibrium dialysis method. However, the accuracy of the plasma protein binding (PPB) estimate for highly bound compounds may be poor, should equilibrium not be fully achieved in the equilibrium dialysis assay. Here, a dilution method and a presaturation method were applied to accelerate equilibration for a set of challenging compounds. These improved methods demonstrate the ability to provide an accurate measurement of PPB for highly bound compounds with fu values much less than 1%. Therefore, we recommend that the actual experimental fu value be used for the prediction of drug-drug interaction potential and for the characterization of important drug candidate properties. Our recommendation calls into question the need for current regulatory guidelines that restrict the reporting of fu values below 1%. PMID- 26037783 TI - Phase II trial of an alternating regimen consisting of first-line mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab for patients with metastatic colorectal cancer: FIREFOX plus bevacizumab trial (KSCC0801). AB - OBJECTIVES: The purpose of this phase II study was to explore the efficacy and safety of an alternating regimen consisting of folinic acid, 5-fluorouracil (5 FU) and oxaliplatin (mFOLFOX6) plus bevacizumab, and folinic acid, 5-FU and irinotecan (FOLFIRI) plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer. METHODS: Fifty-two patients with metastatic colorectal cancer received an alternating regimen consisting of four cycles of mFOLFOX6 plus bevacizumab followed by four cycles of FOLFIRI plus bevacizumab until disease progression. The primary endpoint was progression-free survival. RESULTS: The median age was 60 years (range 37-75 years). Median progression-free survival was 14.2 months (95 % confidence interval [CI] 10.6-16.3) and median overall survival was 28.4 months (95 % CI 22.6-39.1). The overall response rate was 60.0 % (95 % CI 45.2-73.6). Regarding toxicity, the commonest grade 3-4 hematological adverse events were neutropenia (34.6 %) and leukopenia (7.7 %), and the commonest grade 3-4 non-hematological adverse events were anorexia (13.5 %), fatigue (9.6 %), nausea (9.6 %), and vomiting (9.6 %). Bevacizumab-related grade 3-4 adverse events included hypertension (1.9 %) and thrombosis (1.9 %). CONCLUSIONS: An alternating regimen consisting of mFOLFOX6 plus bevacizumab and FOLFIRI plus bevacizumab is an effective and well-tolerated first-line chemotherapy combination for patients with metastatic colorectal cancer. PMID- 26037786 TI - Sesamin enhances nitric oxide bioactivity in aortas of spontaneously hypertensive rats. AB - BACKGROUND: The blood pressure lowering effect of sesamin has been demonstrated to be associated with the increase in vascular nitric oxide (NO) biological activity by our previous studies and others. The present study was designed to explore the underlying mechanisms involved in the effect of sesamin on aortic NO bioactivity in spontaneously hypertensive rats (SHRs). METHODS: Sesamin was orally administered for 8 consecutive weeks in SHRs. Systolic blood pressure (SBP) was measured using the tail-cuff method. The aortas were isolated and in vitro vascular reactivity studies were performed. Superoxide anion production in carotid arteries was assessed by dihydroethidium fluorescence staining. The protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (P-eNOS), dihydrofolate reductase (DHFR), nicotinamide adenine dinucleotide phosphate oxidase subunit p47phox, and copper, zinc superoxide dismutase (Cu/Zn SOD) in aortas was detected by Western blotting. The dimeric form of eNOS in aortas was determined by low-temperature sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Aortic level of nitrotyrosine and activities of antioxidant enzymes, namely, total SOD (T-SOD), glutathione peroxidase (GPx) and catalase were also detected. RESULTS: In SHRs, sesamin treatment reduced SBP, improved vascular relaxation induced by acetylcholine and enhanced aortic NO bioactivity. Sesamin treatment enhanced NO biosynthesis in SHR aortas was due to upregulated P-eNOS and suppressed eNOS uncoupling, and the latter effect might be attributed to decreased nitrotyrosine and upregulated DHFR. Sesamin also reduced the NO oxidative inactivation and decreased the superoxide anion production through downregulation of p47(phox) and amelioration of eNOS uncoupling. In addition, sesamin treatment did not alter the levels of GPx and catalase activity but obviously reduced the compensatory elevated T-SOD activity and Cu/Zn-SOD protein expression. CONCLUSION: Chronic treatment with sesamin could reduce hypertension and improve endothelial dysfunction through enhancement of NO bioactivity in SHR aortas. PMID- 26037787 TI - Ten year experience of using a novel metabolic protocol in 'off pump' coronary artery bypass revascularization. AB - PURPOSE: Assessment of both short- and long-term outcomes in patients undergoing off-pump coronary artery bypass using a perioperative metabolic protocol. METHODS: A total of 975 of 995 adult patients underwent coronary artery bypass 'off-pump' from 1997 through 2006. Patients presenting in cardiogenic shock were excluded from this assessment. A perioperative metabolic protocol, which included the implementation of allopurinol, insulin supplementation, magnesium sulfate, supplemental corticosteroids, milrinone, norepinephrine (prn), aspirin, clopidogrel, statins and beta-blockers, was used in these patients. RESULTS: The mean age at the time of surgery was 70.5 years and the average number of bypass grafts was 4 per procedure; 18% (n = 176) of the cases had a preoperative intra aortic balloon pump inserted for hemodynamic instability, tight left main coronary artery stenosis or angina. The 30-day mortality was 1.8% versus a Society of Thoracic Surgeons (STS) predicted mortality of 4.8%. Left main coronary artery disease was present in 38% (n = 371) of the patients. No strokes occurred intra-operatively and the postoperative incidence of stroke was 0.9% (n = 9). Incidence of renal failure requiring dialysis was 0.8% (n = 8). There was a single sternal infection. Mean follow up was 65 months with a survival rate of 90% (n = 955). Re-intervention, which commonly involved PTCA +/- stent placement or re-do coronary artery bypass grafting (CABG), was 4% at 1 year and 11.6% (n = 113) during the 65-month follow-up period. CONCLUSIONS: Off-pump coronary artery bypass coupled with this novel metabolic protocol was associated with a low operative mortality and acceptable perioperative morbidities, including patients with left main coronary artery disease. These benefits are apparent at both short and medium-term follow up. PMID- 26037789 TI - Characterization of residual stresses in zirconia veneered bilayers assessed via sharp and blunt indentation. AB - OBJECTIVES: The present study evaluated the effect of the coefficient of thermal expansion (CTE) mismatch and the cooling protocol on the distribution of residual stresses and crack propagation in veneered zirconia bilayers. METHODS: Ceramic discs with two different CTEs (Vita VM9 and Lava Ceram) were fired onto zirconia plates and cooled following a slow (0.5 degrees C/s) or a fast (45 degrees C/s) cooling protocol. The residual stress distribution throughout the veneer thickness was assessed by means of depth-wise Vickers indentation after sequentially sectioning the bilayers parallel compared to normal to the interface. A mathematical solution for the residual stress distribution was used as reference. Additionally, Hertzian cone crack propagation in the veneers was induced by cyclic contact loading and measured at different number of cycles to estimate the crack growth rate. RESULTS: The higher CTE mismatch of the VM9 group generated an important stress gradient with high compressive residual stresses near the interface, hindering the crack propagation. The low CTE mismatch group (Lava Ceram) developed only a slight stress gradient and higher cone crack growth rates. No differences were observed between the two cooling protocols applied regarding stress magnitude and crack propagation behavior. SIGNIFICANCE: The CTE mismatch has a predominant role in the generation of residual stress gradients within the veneer, which directly influences contact-induced crack propagation. Based on the results, the cooling protocol had no significant effect on the residual stress distribution in zirconia-veneer bilayers. PMID- 26037788 TI - Stability and change in fruit and vegetable intake of Brazilian adolescents over a 3-year period: 1993 Pelotas Birth Cohort. AB - OBJECTIVE: To assess the stability and changes in fruit and vegetable (FV) consumption over a 3-year period during adolescence in a population-based birth cohort. DESIGN: Longitudinal descriptive study. FV consumption was collected in 2008 and 2011/12 using an FFQ. We conducted descriptive analyses of medians to assess the trends in FV intake over time. Stability of FV intake was assessed by percentage of agreement and kappa coefficients. SETTING: Pelotas, Rio Grande do Sul, Brazil. SUBJECTS: Adolescents from 15 to 18 years of age (n 3915). RESULTS: We observed an overall slight decrease in FV consumption during adolescence and also a moderate stability, especially in those with higher socio-economic status (proportion of agreement 38.6% and 40.5% for boys and girls, respectively). About a half of those consuming low levels of FV at 15 years of age still consumed low levels 3 years later. CONCLUSIONS: Our results showed that FV consumption presented a moderate stability across a 3-year period during adolescence, especially in those with higher socio-economic status. Given the great proportions of non-communicable diseases such as CVD, diabetes and obesity, knowledge about the patterns of FV consumption during adolescence has implications for health promotion interventions. PMID- 26037790 TI - Effect of pretreatment with collagen crosslinkers on dentin protease activity. AB - OBJECTIVES: This study evaluated the effect of dentin pretreatment with collagen crosslinkers on matrix metalloproteinase (MMP) and cathepsin K mediated collagen degradation. METHODS: Dentin beams (1mm*2mm*6mm) were demineralized in 10% H3PO4 for 24h. After baseline measurements of dry mass, beams were divided into 11 groups (n=10/group) and, were pretreated for 5min with 1% glutaraldehyde (GA); 5% GA; 1% grape-seed extract (GS); 5% GS; 10% sumac (S); 20MUM curcumin (CR); 200MUM CR; 0.l% riboflavin/UV (R); 0.5% R; 0.1% riboflavin-5-phosphate/UV (RP); and control (no pretreatment). After pretreatment, the beams were blot-dried and incubated in 1mL calcium and zinc-containing medium (CM, pH 7.2) at 37 degrees C for 3, 7 or 14 days. After incubation, dry mass was reassessed and aliquots of the incubation media were analyzed for collagen C-telopeptides, ICTP and CTX using specific ELISA kits. Data were analyzed by repeated-measures ANOVA. RESULTS: The rate of dry mass loss was significantly different among test groups (p<0.05). The lowest 14 day mean dry mass loss was 6.98%+/-1.99 in the 200MUM curcumin group compared to control loss of dry mass at 32.59%+/-5.62, p<0.05, at 14 days. The ICTP release over the incubation period (ng/mg dry dentin) ranged between 1.8+/-0.51 and 31.8+/-1.8. CTX release from demineralized beams pretreated with crosslinkers was significantly lower than CM (5.7+/-0.2ng/mg dry dentin). SIGNIFICANCE: The results of this study indicate that collagen crosslinkers tested in this study are good inhibitors of cathepsin K activity in dentin. However, their inhibitory effect on MMP activity was highly variable. PMID- 26037791 TI - Bone turnover markers in Paget's disease of the bone: A Systematic review and meta-analysis. AB - The aim of this systematic review and meta-analysis is to study the utility of the commonly used bone turnover markers in evaluating disease activity in patients with Paget's disease of bone before and after treatment with bisphosphonates. We found good correlation between the bone turnover marker concentrations and disease activity assessed by bone scintigraphy. INTRODUCTION: Paget's disease of bone is a common skeletal disorder of the elderly. Bone turnover marker concentrations are used for diagnosis and follow-up. We aimed to compare the available bone turnover markers and determine their utility in assessing disease activity when compared to quantitative bone scintigraphy. METHODS: We conducted a systematic review and meta-analysis searching MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus. We evaluated total alkaline phosphatase (total ALP), bone-specific alkaline phosphatase (bone ALP), procollagen type 1 amino terminal propeptide (P1NP), serum, and urine C-terminal telopeptide (uCTx and sCTx, respectively), and urine N-terminal telopeptide (uNTx). The main outcome of interest was the correlation of disease activity with concentrations of bone turnover markers in Paget's disease patients before and after treatment with bisphosphonates. Correlation coefficients were pooled across studies using the random effects model. RESULTS: We included 17 observational studies and one trial reporting on 953 patients. Prior to treatment, all studied bone turnover markers had moderate to strong correlation with scintigraphic indices (correlation coefficients ranging from 0.58 to 0.80) with no statistically significant difference between the bone turnover markers overall (p = 0.08). P1NP, uNTx, and bone ALP tend to have higher correlation with scintigraphy. After starting treatment with bisphosphonate, there was moderate to strong correlation with disease activity with all markers except bone ALP (correlation coefficients ranging from 0.43 to 0.70). CONCLUSION: The findings of this meta-analysis suggest the Paget's disease activity is best monitored by following P1NP levels. However, total ALP, bone ALP, and uNTx are good alternatives as markers of disease activity in untreated patients. Total ALP and uNTx can be useful in following patients with Paget's disease after treatment if P1NP is not available. Clinicians, however, should take availability, cost, and the presence of liver disease into consideration when deciding which bone turnover marker is most appropriate when evaluating patients with Paget's disease. PMID- 26037793 TI - Reply to "Thoracolumbar fascia injury associated with residual back pain after percutaneous vertebroplasty: a compelling study". PMID- 26037792 TI - Intraoperative detection of viable bone with fluorescence imaging using Visually Enhanced Lesion Scope in patients with bisphosphonate-related osteonecrosis of the jaw: clinical and pathological evaluation. AB - There is no standard surgical protocol of bisphosphonate-related osteonecrosis of the jaws (BRONJ), because of the impossibility to visualize this feature intraoperatively. The aim of this study was to introduce how to provide preoperative labeling of the viable bone with minocycline bone fluorescence technique (MBFT) by using VELscope(r) and investigate histopathologically. INTRODUCTION: The American Association of Oral and Maxillofacial Surgeons (AAOMS) and the Japanese Society of Oral and Maxillofacial Surgeons (JSOMS) now recommend a more conservative treatment strategy. There is no standard surgical protocol of bisphosphonate-related osteonecrosis of the jaws (BRONJ) because of the impossibility to visualize this feature intraoperatively. The aim of this study was to introduce a mechanism providing preoperative labeling of a viable bone using minocycline bone fluorescence technique (MBFT) with VELscope(r) and to histopathologically investigate. METHODS: This report describes a surgical technique used in six patients with BRONJ who underwent jawbone resection under minocycline bone fluorescence imaging using VELscope(r). Subsequently, we investigated and compared the clinical findings using VELscope(r) and histopathological findings. RESULTS: Histopathological examinations showed that the non-fluorescent moiety was consistent with the BRONJ lesions. CONCLUSIONS: The surgical treatments that were exactly performed using MBFT with VELscope(r) offered successful management of BRONJ. This bone fluorescence helped to define the margins of resection, thus improving surgical therapy for extended osteonecrosis. PMID- 26037796 TI - The new therapeutical scenario of Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) remains one of the most curable human cancers, as modern combination chemotherapy and radiation therapy cure ~ 80% of patients. Over the last two decades, the major efforts were focused on the development of more intensive front-line regimens for patients with advanced stage HL, decreasing the number of chemotherapy cycles and radiation therapy field and doses for patients with early-stage HL and incorporating positron emission tomography imaging in diagnostic, prognostic, and treatment planning. More recently, the improved knowledge of the molecular biology of the disease led to the development of highly active new agents, including the antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors. Accordingly, the current efforts are focusing on incorporating these new agents into standard of care regimens, aiming at further improving cure rates, while reducing treatment-related toxicity. In this review, we will focus on the current status of HL therapy and how the development of new agents is re-shaping standard of care regimens. PMID- 26037794 TI - Improve the prevention of sudden cardiac arrest in emerging countries: the Improve SCA clinical study design. AB - AIMS: This study aims to demonstrate that primary prevention (PP) patients with one or more additional risk factors are at a similar risk of life-threatening ventricular arrhythmias when compared with secondary prevention (SP) patients, and would receive similar benefit from an implantable cardioverter defibrillator (ICD), or cardiac resynchronization therapy-defibrillator (CRT-D) implant. The study evaluates the benefits of therapy for high-risk patients in countries where defibrillation therapy for PP of SCA is underutilized. METHODS: Enrolment will consist of 4800 ICD-eligible patients from Asia, Latin America, Eastern Europe, the Middle East, and Africa. Upon enrolment, patients will be categorized as SP or PP. Primary prevention patients will be assessed for additional risk factors: syncope/pre-syncope, non-sustained ventricular tachycardia, frequent premature ventricular contractions, and low left ventricular ejection fraction. Those PP patients with one or more risk factors will be categorized as '1.5' patients. Implant of an ICD/CRT-D will be left to the patient and/or physician's discretion. The primary endpoint will compare the appropriate ICD therapy rate between SP and 1.5 patients. The secondary endpoint compares mortality between 1.5 implanted and non-implanted patients. CONCLUSION: The Improve SCA study will investigate a subset of PP patients, believed to be at similar risk of life threatening ventricular arrhythmias as SP patients. Results may help clinicians identify and refer the highest risk PP patients for ICDs, help local societies expand guidelines to include PP of SCA utilizing ICDs, and provide additional geographical-relevant evidence to allow patients to make an informed decision whether to receive an ICD. TRIAL REGISTRATION: NCT02099721. PMID- 26037795 TI - The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600. AB - BACKGROUND: BRAF inhibitors (BRAFi) improve survival in metastatic melanoma patients (MMP) but the duration of clinical benefit is limited by development of drug resistance. Here, we investigated whether the expression of programmed death ligand 1 (PD-L1) and the density of tumor-infiltrating mononuclear cells (TIMC) predict the occurrence of resistance, hence affecting the clinical outcome in BRAFi-treated MMP. METHODS: PD-L1 expression (cutoff 5%) was analyzed by immunohistochemistry with two different antibodies in BRAF(V600)-mutated formalin fixed and paraffin-embedded samples from 80 consecutive MMP treated with BRAFi at a single institution. TIMC were evaluated by conventional hematoxylin and eosin staining. RESULTS: Forty-six and 34 patients received vemurafenib and dabrafenib, respectively. Membranous expression of PD-L1 was detected in 28/80 (35%) of patients. At multivariate analysis, absence of tumoral PD-L1 staining [odd ratio (OR) 10.8, 95% confidence interval (CI) 2.7-43.3, P < 0.001] and the presence of TIMC (OR 6.5, 95% CI 1.7-24.3, P < 0.005) were associated with a better response to treatment. Median progression-free survival (PFS) and overall survival were 10 and 15 months, respectively. By multivariate assessment, PD-L1 expression [hazard ratio (HR) 4.3, 95% CI 2.1-8.7, P < 0.0001] and absence of TIMC (HR 2.5, 95% CI 1.4-4.7, P < 0.002) correlated with shorter PFS. PD-L1 overexpression (HR 6.2, 95% CI 2.8-14.2, P < 0.0001) and absence of TIMC (HR 3.1, 95% CI 1.5-6.5, P < 0.002) were independent prognostic factors for melanoma-specific survival. CONCLUSION: Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAF(V600)-mutated MMP treated with BRAFi. PMID- 26037797 TI - Treatment outcome and patterns of relapse following adjuvant carboplatin for stage I testicular seminomatous germ-cell tumour: results from a 17-year UK experience. AB - BACKGROUND: Following inguinal orchidectomy, management options for patients with stage I seminoma include initial surveillance or treatment with adjuvant radiotherapy or chemotherapy. The anticipated relapse rate for patients followed by surveillance alone is ~15%, with adjuvant treatment this risk is reduced to ~4%-5% at 5 years. After carboplatin treatment, follow-up strategies vary and there are no validated, predictive markers of relapse. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients presenting with stage I seminoma who received a single cycle of adjuvant carboplatin in South Central England between 1996 and 2013. We report on outcome and the results of univariate and multivariate analysis evaluating possible risk factors for post carboplatin relapse. RESULTS: A total of 517 eligible patients were identified. All underwent nuclear medicine estimation of glomerular filtration rate before treatment with carboplatin (dosed at area under the curve * 7). With a median follow-up of 47.2 months (range 0.4-214 months), 21/517 patients have relapsed resulting in a 5 year estimated relapse-free survival of 95.0% (95% confidence interval 92.8% to 97.3%). Median time to relapse was 22.7 months (range 12.5-109.5 months). Relapse beyond 3 years was rare (4/517; 0.8%). Twenty of 21 (95%) relapsed patients had retroperitoneal lymph node metastases. The majority (16/21; 76%) of patients had elevated tumour markers at relapse. Twenty of 517 (3.9%) patients developed a new contralateral testicular germ-cell cancer. There were no seminoma-related deaths. Tumour size was the only variable significantly associated with an increased risk of relapse. CONCLUSIONS: Overall results for this large cohort of patients confirm an excellent prognosis for these patients with outcomes equivalent to those seen in prospective clinical trials. Increasing tumour size alone appears to be associated with an increased risk of post chemotherapy relapse. PMID- 26037798 TI - Derived neutrophil lymphocyte ratio may predict benefit from cisplatin in the advanced biliary cancer: the ABC-02 and BT-22 studies. AB - BACKGROUND: The superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone in patients with advanced biliary tract cancer (ABC) has been demonstrated in two randomised trials; ABC02 and the Biliary Tract (BT) 22 study. We used a combined dataset from these two trials to investigate the derived neutrophil-to-lymphocyte ratio (dNLR), which is thought to be a prognostic factor associated with clinical outcomes in several solid tumours, including ABC. METHODS: White blood cell (WBC) and absolute neutrophil count (ANC) were available for 379 of 410 patients from ABC-02 and all 83 patients in BT-22. The dNLR was calculated as ANC/(WBC-ANC), as previously specified. We examined the association between dNLR and overall survival (OS) and progression free survival (PFS), as well as comparing the treatment effect in two patient groups defined by their dNLR level. A high dNLR was defined as >=3.0, which was approximately the upper tertile value. RESULTS: A total of 462 individual patient records were analysed, 328 with baseline dNLR <3 and 134 with dNLR >=3. There were 443 deaths in the cohort, and all surviving patients had a dNLR <3. There was strong evidence that dNLR was closely associated with both OS [hazard ratio (HR), 1.62; 95% confidence interval (CI) 1.32-2.01] and PFS (HR, 1.40; 95% CI 1.13-1.72). There was limited evidence (P = 0.10) of a differential effect of CisGem on OS between the two dNLR groups, but this was clearest in the ABC-02 dataset (P = 0.06). There was good evidence (P = 0.008) of an association between low baseline dNLR and long-term survival on a CisGem regimen. There was also good evidence of an association between ECOG performance status (split at 0 and 1 versus 2) on both OS (P < 0.001) and PFS (P = 0.01), but no evidence of a differential treatment effect, with both groups receiving benefit from the addition of cisplatin. CONCLUSIONS: These data confirm that high dNLR is associated with worse OS and PFS, and suggests it may also be predictive of benefit for the addition of cisplatin to gemcitabine in European patients with ABC. Incorporating dNLR into the clinical context may better inform prognosis and chemotherapy decisions in ABC patients. PMID- 26037799 TI - Transcranial magnetic stimulation reveals complex cognitive control representations in the rostral frontal cortex. AB - Convergent evidence suggests that the lateral frontal cortex is at the heart of a brain network subserving cognitive control. Recent theories assume a functional segregation along the rostro-caudal axis of the lateral frontal cortex based on differences in the degree of complexity of cognitive control. However, the functional contribution of specific rostral and caudal sub-regions remains elusive. Here we investigate the impact of disrupting rostral and caudal target regions on cognitive control processes, using Transcranial Magnetic Stimulation (TMS). Participants performed three different task-switching conditions that assessed differences in the degree of complexity of cognitive control processes, after temporally disrupting rostral, or caudal target regions, or a control region. Disrupting the rostral lateral frontal region specifically impaired behavioral performance of the most complex task-switching condition, in comparison to the caudal target region and the control region. These novel findings shed light on the neuroanatomical architecture supporting control over goal-directed behavior. PMID- 26037800 TI - An endocannabinoid system is present in the mouse olfactory epithelium but does not modulate olfaction. AB - Endocannabinoids modulate a diverse array of functions including progenitor cell proliferation in the central nervous system, and odorant detection and food intake in the mammalian central olfactory system and larval Xenopus laevis peripheral olfactory system. However, the presence and role of endocannabinoids in the peripheral olfactory epithelium have not been examined in mammals. We found the presence of cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) receptor protein and mRNA in the olfactory epithelium. Using either immunohistochemistry or calcium imaging we localized CB1 receptors on neurons, glia-like sustentacular cells, microvillous cells and progenitor-like basal cells. To examine the role of endocannabinoids, CB1- and CB2- receptor-deficient (CB1(-/-)/CB2(-/-)) mice were used. The endocannabinoid 2-arachidonylglycerol (2 AG) was present at high levels in both C57BL/6 wildtype and CB1(-/-)/CB2(-/-) mice. 2-AG synthetic and degradative enzymes are expressed in wildtype mice. A small but significant decrease in basal cell and olfactory sensory neuron numbers was observed in CB1(-/-)/CB2(-/-) mice compared to wildtype mice. The decrease in olfactory sensory neurons did not translate to impairment in olfactory-mediated behaviors assessed by the buried food test and habituation/dishabituation test. Collectively, these data indicate the presence of an endocannabinoid system in the mouse olfactory epithelium. However, unlike in tadpoles, endocannabinoids do not modulate olfaction. Further investigation on the role of endocannabinoids in progenitor cell function in the olfactory epithelium is warranted. PMID- 26037802 TI - Absence epileptic activity changing effects of non-adenosine nucleoside inosine, guanosine and uridine in Wistar Albino Glaxo Rijswijk rats. AB - Adenosine (Ado) and non-adenosine (non-Ado) nucleosides such as inosine (Ino), guanosine (Guo) and uridine (Urd) may have regionally different roles in the regulation of physiological and pathophysiological processes in the central nervous system (CNS) such as epilepsy. It was demonstrated previously that Ino and Guo decreased quinolinic acid (QA)-induced seizures and Urd reduced penicillin-, bicuculline- and pentylenetetrazole (PTZ)-induced seizures. It has also been demonstrated that Ino and Urd may exert their effects through GABAergic system by altering the function of GABA(A) type of gamma-aminobutyric acid receptors (GABAA receptors) whereas Guo decreases glutamate-induced excitability through glutamatergic system, which systems (GABAergic and glutamatergic) are involved in pathomechanisms of absence epilepsy. Thus, we hypothesized that Ino and Guo, similarly to the previously described effect of Urd, might also decrease absence epileptic activity. We investigated in the present study whether intraperitoneal (i.p.) application of Ino (500 and 1000mg/kg), Guo (20 and 50mg/kg), Urd (500 and 1000mg/kg), GABA(A) receptor agonist muscimol (1 and 3mg/kg), GABA(A) receptor antagonist bicuculline (2 and 4mg/kg), non-selective Ado receptor antagonist theophylline (5 and 10mg/kg) and non-competitive N-methyl d-aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo (a,d) cyclohepten-5,10-imine maleate (MK-801, 0.0625 and 0.1250mg/kg) alone and in combination have modulatory effects on absence epileptic activity in Wistar Albino Glaxo Rijswijk (WAG/Rij) rats. We found that Guo decreased the number of spike-wave discharges (SWDs) whereas Ino increased it dose-dependently. We strengthened that Urd can decrease absence epileptic activity. Our results suggest that Guo, Urd and their analogs could be potentially effective drugs for treatment of human absence epilepsy. PMID- 26037804 TI - Increased cross-education of muscle strength and reduced corticospinal inhibition following eccentric strength training. AB - AIM: Strength training of one limb results in a substantial increase in the strength of the untrained limb, however, it remains unknown what the corticospinal responses are following either eccentric or concentric strength training and how this relates to the cross-education of strength. The aim of this study was to determine if eccentric or concentric unilateral strength training differentially modulates corticospinal excitability, inhibition and the cross transfer of strength. METHODS: Changes in contralateral (left limb) concentric strength, eccentric strength, motor-evoked potentials, short-interval intracortical inhibition and silent period durations were analyzed in groups of young adults who exercised the right wrist flexors with either eccentric (N=9) or concentric (N=9) contractions for 12 sessions over 4weeks. Control subjects (N=9) did not train. RESULTS: Following training, both groups exhibited a significant strength gain in the trained limb (concentric group increased concentric strength by 64% and eccentric group increased eccentric strength by 62%) and the extent of the cross-transfer of strength was 28% and 47% for the concentric and eccentric group, respectively, which was different between groups (P=0.031). Transcranial magnetic stimulation revealed that eccentric training reduced intracortical inhibition (37%), silent period duration (15-27%) and increased corticospinal excitability (51%) compared to concentric training for the untrained limb (P=0.033). There was no change in the control group. CONCLUSION: The results show that eccentric training uniquely modulates corticospinal excitability and inhibition of the untrained limb to a greater extent than concentric training. These findings suggest that unilateral eccentric contractions provide a greater stimulus in cross-education paradigms and should be an integral part of the rehabilitative process following unilateral injury to maximize the response. PMID- 26037801 TI - Using human brain imaging studies as a guide toward animal models of schizophrenia. AB - Schizophrenia is a heterogeneous and poorly understood mental disorder that is presently defined solely by its behavioral symptoms. Advances in genetic, epidemiological and brain imaging techniques in the past half century, however, have significantly advanced our understanding of the underlying biology of the disorder. In spite of these advances clinical research remains limited in its power to establish the causal relationships that link etiology with pathophysiology and symptoms. In this context, animal models provide an important tool for causally testing hypotheses about biological processes postulated to be disrupted in the disorder. While animal models can exploit a variety of entry points toward the study of schizophrenia, here we describe an approach that seeks to closely approximate functional alterations observed with brain imaging techniques in patients. By modeling these intermediate pathophysiological alterations in animals, this approach offers an opportunity to (1) tightly link a single functional brain abnormality with its behavioral consequences, and (2) to determine whether a single pathophysiology can causally produce alterations in other brain areas that have been described in patients. In this review we first summarize a selection of well-replicated biological abnormalities described in the schizophrenia literature. We then provide examples of animal models that were studied in the context of patient imaging findings describing enhanced striatal dopamine D2 receptor function, alterations in thalamo-prefrontal circuit function, and metabolic hyperfunction of the hippocampus. Lastly, we discuss the implications of findings from these animal models for our present understanding of schizophrenia, and consider key unanswered questions for future research in animal models and human patients. PMID- 26037803 TI - Astrocytes regulate alpha-secretase-cleaved soluble amyloid precursor protein secretion in neuronal cells: Involvement of group IIA secretory phospholipase A2. AB - Astrocytes are major supportive cells in brains with important functions including providing nutrients and regulating neuronal activities. In this study, we demonstrated that astrocytes regulate amyloid precursor protein (APP) processing in neuronal cells through secretion of group IIA secretory phospholipase A2 (sPLA2-IIA). When astrocytic cells (DITNC) were mildly stimulated with the pro-inflammatory cytokines, such as TNF alpha and IL-1beta, sPLA2-IIA was secreted into the medium. When conditioned medium containing sPLA2 IIA was applied to human neuroblastoma (SH-SY5Y) cells, there was an increase in both cell membrane fluidity and secretion of alpha-secretase-cleaved soluble amyloid precursor protein (sAPPalpha). These changes were abrogated by KH064, a selective inhibitor of sPLA2-IIA. In addition, exposing SH-SY5Y cells to recombinant human sPLA2-IIA also increased membrane fluidity, accumulation of APP at the cell surface, and secretion of sAPPalpha, but without altering total expressions of APP, alpha-secretases and beta-site APP cleaving enzyme (BACE1). Taken together, our results provide novel information regarding a functional role of sPLA2-IIA in astrocytes for regulating APP processing in neuronal cells. PMID- 26037805 TI - Theta frequency prefrontal-hippocampal driving relationship during free exploration in mice. AB - Inter-connected brain areas coordinate to process information and synchronized neural activities engage in learning and memory processes. Recent electrophysiological studies in rodents have implicated hippocampal-prefrontal connectivity in anxiety, spatial learning and memory-related tasks. In human patients with schizophrenia and autism, robust reduced connectivity between the hippocampus (HPC) and prefrontal cortex (PFC) has been reported. However little is known about the directionality of these oscillations and their roles during active behaviors remain unclear. Here the directional information processing in mice was measured by Granger causality, a mathematical tool that has been used in neuroscience to quantify the oscillatory driving relationship between the ventral HPC (vHPC) and the PFC in two anxiety tests and between the dorsal HPC (dHPC) and the PFC in social interaction test. In the open field test, stronger vHPC driving to the PFC was found in the center compartment than in the wall area. In the light-dark box test, PFC to vHPC causality was higher than vHPC to PFC causality although no difference was found between the light and dark areas for the causality in both directions. In the social interaction test using Cx3cr1 knockout mice which model for deficient microglia-dependent synaptic pruning, higher PFC driving to the dHPC was found than driving from the dHPC to the PFC in both knockout mice and wild-type mice. Cx3cr1 knockout mice showed reduced baseline PFC driving to the dHPC compared to their wild-type littermates. PFC to dHPC causality could predict the actual time spent interacting with the social stimuli. The current findings indicate that directed oscillatory activities between the PFC and the HPC have task-dependent roles during exploration in the anxiety test and in the social interaction test. PMID- 26037808 TI - Design, synthesis and biological evaluation of novel condensed pyrrolo[1,2 c]pyrimidines featuring morpholine moiety as PI3Kalpha inhibitors. AB - Four series of condensed pyrrolo[1,2-c]pyrimidines 6a-d, 8a-d, 10a,b and 12a-e designed as PI3Kalpha inhibitors were synthesized and evaluated for inhibitory activity and selectivity toward different PI3K isoforms. The tested compounds displayed PI3Kalpha kinase inhibitory activity at either low micromolar or nanomolar level. In particular, the morpholino-pyrimidopyrrolopyrimidinones 8a-d and morpholino-pyridopyrrolopyrimidine-2-carbonitriles 12a-e proved to be highly potent and selective PI3Kalpha inhibitors (IC50 = 0.1-7.7 nM). Moreover, the target compounds exhibited considerable cytotoxic activity against cervical cancer cell line HeLa that over-expresses p110alpha (0.21-1.99 MUM). Molecular modeling simulation revealed that, the designed compounds docked well into p110alpha active site and their complexes are stabilized by a key H-bonding with the backbone amide of Val851 as well as other favorable hydrophobic and H-bond interactions with different amino acids within the enzyme active site. PMID- 26037809 TI - Identifying the key predictors for retention in critical care nurses. AB - AIMS: The aim of this study was to explore the key predictors of retention in nurses working in critical care areas. BACKGROUND: The shortage of critical care nurses is reaching crisis proportions in Canada and throughout the industrialized world. Identifying the key influencing (i.e. person and organizational) factors and intermediary factors (i.e. job satisfaction, engagement, professional quality of life and caring) that affect intent to leave is central to developing optimal retention strategies for critical care nurses. DESIGN: As part of a larger mixed methods study, we used a quantitative, cross-sectional research design. A novel framework: the Conceptual Framework for Predicting Nurse Retention was used to guide this study. METHODS: On-line survey data were collected from on a convenience sample of 188 registered nurses working in critical care areas of hospitals in the province of Manitoba, CANADA in 2011. RESULTS: Twenty-four per cent of the respondents reported that they would probably/definitely leave critical care in the next year. Based on bivariate and regression analyses, the key influencing factors that were significantly related to the intermediary factors and intent to leave critical care and nursing included: professional practice, management, physician/nurse collaboration, nurse competence, control/responsibility and autonomy. Of the intermediary factors, all but compassion satisfaction were related to intent to leave both critical care and nursing. CONCLUSION: This study highlights the importance of exploring multiple organizational and intermediary factors to determine strategies to retain critical care nurses. The findings also support the Conceptual Framework for Predicting Nurse Retention as a theoretical basis for further research. PMID- 26037810 TI - Adipose Stromal Cell Contact with Endothelial Cells Results in Loss of Complementary Vasculogenic Activity Mediated by Induction of Activin A. AB - Adipose stem/stromal cells (ASCs) after isolation produce numerous angiogenic growth factors. This justifies their use to promote angiogenesis per transplantation. In parallel, local coimplantation of ASC with endothelial cells (ECs) leading to formation of functional vessels by the donor cells suggests the existence of a mechanism responsible for fine-tuning ASC paracrine activity essential for vasculogenesis. As expected, conditioned media (CM) from ASC promoted ECs survival, proliferation, migration, and vasculogenesis. In contrast, media from EC-ASC cocultures had neutral effects upon EC responses. Media from cocultures exhibited lower levels of vascular endothelial growth factor (VEGF), hepatic growth factor, angiopoietin-1, and stromal cell-derived factor-1 compared with those in ASC CM. Activin A was induced in ASC in response to EC exposure and was responsible for overall antivasculogenic activity of EC-ASC CM. Except for VEGF, activin A diminished secretion of all tested factors by ASC. Activin A mediated induction of VEGF expression in ASC, but also upregulated expression of VEGF scavenger receptor FLT-1 in EC in EC-ASC cocultures. Blocking the FLT-1 expression in EC led to an increase in VEGF concentration in CM. In vitro pre exposure of ASC to low number of EC before subcutaneous coimplantation with EC resulted in decrease in vessel density in the implants. In vitro tests suggested that activin A was partially responsible for this diminished ASC activity. This study shows that neovessel formation is associated with induction of activin A expression in ASC; this factor, by affecting the bioactivity of both ASC and EC, directs the crosstalk between these complementary cell types to establish stable vessels. PMID- 26037807 TI - Astrocytes and lysosomal storage diseases. AB - Lysosomal storage diseases (LSDs) encompass a wide range of disorders characterized by inborn errors of lysosomal function. The majority of LSDs result from genetic defects in lysosomal enzymes, although some arise from mutations in lysosomal proteins that lack known enzymatic activity. Neuropathological abnormalities are a feature of several LSDs and when severe, represent an important determinant in disease outcome. Glial dysfunction, particularly in astrocytes, is also observed in numerous LSDs and has been suggested to impact neurodegeneration. This review will discuss the potential role of astrocytes in LSDs and highlight the possibility of targeting glia as a beneficial strategy to counteract the neuropathology associated with LSDs. PMID- 26037811 TI - Prevalence and Correlates of Aggression and Hostility in Hospitalized Schizophrenic Patients. AB - This study is aimed at identifying the incidence as well as clinical and socio demographic correlates of aggression in hospitalized schizophrenic patients. We prospectively recruited participants with Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.) diagnosis of schizophrenia presenting to the Clinic for Psychiatry during a 2-year period. We used the Modified Overt Aggression Scale to assess the aggression and Positive and Negative Syndrome Scale (PANSS) to assess the clinical characteristics of participants. One out of three patients with schizophrenia (31%) was aggressive and hostile at the time of presentation. Socio-demographic variables (such as gender, age, duration of illness, and number of hospitalizations) were poor predictors of aggression for schizophrenic patients. The level of aggression was not associated with the clinical characteristics in aggressive and hostile hospitalized schizophrenic patients. However, there was a weak negative association between the level of aggression and the PANSS Negative Scale ( p < .01). In conclusion, socio demographic variables and clinical characteristics seem to be not such good predictors of aggressive behavior in hospitalized schizophrenic patients. Nevertheless, the results of our study contribute to the understanding of the prediction and treatment of aggression in a well-defined cohort of schizophrenic patients. PMID- 26037812 TI - Witnessing Partner Violence: Exploring the Role of Partner Preferences on Dating Violence. AB - Research has shown that witnessing partner violence (WPV) increases the likelihood of experiencing or perpetrating violence in later romantic relationships, but little is known about the mechanisms underlying this process. This study examines the relationships between preference for unsuitable partners and teen dating violence (TDV) among adolescents who have witnessed parental violence or not. Attachment was also considered. Participants were 356 adolescents, both witnesses and non-witnesses of partner violence. Results showed no difference in preferences (for good, risky, or loving partners) between the two groups. However, preference for unsuitable partners did significantly predict TDV perpetration and victimization, but only among witnesses. Also, loving partner preference moderates the relationship between WPV and TDV perpetration among highly avoidant witnesses. Findings indicate a new avenue for prevention through targeting partner preferences. PMID- 26037813 TI - Entrapment of Victims of Spousal Abuse in Ghana: A Discursive Analysis of Family Identity and Agency of Battered Women. AB - Drawing on discursive psychology and positioning theory, this study explores the influence of cultural and familial value orientations on battered women's identity, agency, and decision to leave or stay in abusive conjugal relationship in Ghana. Two semi-structured focus group discussions and four in-depth personal interviews were conducted with 16 victims of husband-to-wife abuse from rural and urban Ghana. The findings indicate that entrapment of victims of spousal abuse in Ghana reflects their social embeddedness and that battered women's identities and agency are expressed in the context of familial and cultural value orientations. The primacy of family identity and victims' apparent implicit moral obligation to preserve the social image of their extended family influence their entrapment. Participants' discursive accounts further suggest that stay or leave decisions of battered women in Ghana reflect a joint product of negotiated agency between victims and their extended family. It is thus argued that the agency of battered women in Ghana is not constituted by individual psychological states or motives, but instead, viewed as a property of victims who exercise it in a given relational context, and partly constituted by familial relationships and identities. The study suggests that intervention initiatives in Ghana should focus on the phenomenon of conjugal violence beyond immediate victims to include families and the larger communities in which victims are embedded. PMID- 26037814 TI - The Impact of the Bystander's Relationship With the Victim and the Perpetrator on Intent to Help in Situations Involving Sexual Violence. AB - A large body of research has explored the individual and situational factors that influence bystander intervention for sexual violence. However, little research has explored the how the bystander's relationship to the victim and the perpetrator impacts helping. To explore this gap in the literature, the present study used vignettes to experimentally manipulate the bystander's relationship to the victim, and the bystander's relationship to the perpetrator to examine how these factors impact intent to help in low (i.e., unwanted contact) and high (i.e., situation at high risk of rape) severity situations of sexual violence. The gender of the bystander was also examined by recruiting a sample of women and men. Results suggested that bystanders were more likely to intervene when the situation was more severe and when the bystander was female. Results were mixed regarding intent to help when the bystander knew the victim or the perpetrator. Moreover, these factors interacted in complicated ways such that, for example, women are equally likely to intend to help a victim whether they know the perpetrator or not while men are more likely to help a victim if the perpetrator is someone they do not know. The results of this study suggest that bystander intervention for situations involving sexual violence are complex and future research should further tease out the moderating effects. Prevention programs using a bystander framework may need some segments of training that are more gender specific and that directly address the relationship between the bystander and the victim and perpetrator. PMID- 26037806 TI - Pathogenesis of depression: Insights from human and rodent studies. AB - Major depressive disorder (MDD) will affect one out of every five people in their lifetime and is the leading cause of disability worldwide. Nevertheless, mechanisms associated with the pathogenesis of MDD have yet to be completely understood and current treatments remain ineffective in a large subset of patients. In this review, we summarize the most recent discoveries and insights for which parallel findings have been obtained in human depressed subjects and rodent models of mood disorders in order to examine the potential etiology of depression. These mechanisms range from synaptic plasticity mechanisms to epigenetics and the immune system where there is strong evidence to support a functional role in the development of specific depression symptomology. Ultimately we conclude by discussing how novel therapeutic strategies targeting central and peripheral processes might ultimately aid in the development of effective new treatments for MDD and related stress disorders. PMID- 26037815 TI - Impact of short-term training camp on arterial stiffness in endurance runners. AB - Lack of elasticity in the central artery causes an increase in left ventricular (LV) afterload. Although regular moderate-intensity endurance exercise improves cardiovascular function, including arterial destiffening, little is known about the effect of short-term vigorous exercise on cardiovascular function (i.e., the interaction between cardiac and arterial functions). We measured arterial stiffness [via pulse wave velocity from the heart to ankle (haPWV)] and LV contractility (via systolic interval time) before and after a 1-week training camp in a total of 33 regularly highly-trained collegiate endurance runners. They participated in three training sessions per day which mainly consisted of long distance running and sprint training. The averaged running distance was ~ 44% longer during the camp than the regular training program. After the camp, heart rate at rest and haPWV were significantly increased, whereas blood pressure remained unchanged. Although a ratio of pre-ejection period and LV ejection time (PEP/LVET, an index of blunted LV contractility) was unaltered, presumably due to the large variability of individual response, there was a significant correlation between changes in haPWV and PEP/LVET (r = 0.54, P < 0.01). These results suggest that, in regularly highly-trained endurance athletes, arterial stiffness increases after a training camp characterized by greater training volume (vs. regular training), and that the individual response in arterial stiffness correlates with the corresponding changes in myocardial contractility. PMID- 26037816 TI - Microbial community composition of a household sand filter used for arsenic, iron, and manganese removal from groundwater in Vietnam. AB - Household sand filters are used in rural areas of Vietnam to remove As, Fe, and Mn from groundwater for drinking water purposes. Currently, it is unknown what role microbial processes play in mineral oxide formation and As removal during water filtration. We performed most probable number counts to quantify the abundance of physiological groups of microorganisms capable of catalyzing Fe- and Mn-redox transformation processes in a household sand filter. We found up to 10(4) cells g(-1) dry sand of nitrate-reducing Fe(II)-oxidizing bacteria and Fe(III)-reducing bacteria, and no microaerophilic Fe(II)-oxidizing bacteria, but up to 10(6) cells g(-1) dry sand Mn-oxidizing bacteria. 16S rRNA gene amplicon sequencing confirmed MPN counts insofar as only low abundances of known taxa capable of performing Fe- and Mn-redox transformations were detected. Instead the microbial community on the sand filter was dominated by nitrifying microorganisms, e.g. Nitrospira, Nitrosomonadales, and an archaeal OTU affiliated to Candidatus Nitrososphaera. Quantitative PCR for Nitrospira and ammonia monooxygenase genes agreed with DNA sequencing results underlining the numerical importance of nitrifiers in the sand filter. Based on our analysis of the microbial community composition and previous studies on the solid phase chemistry of sand filters we conclude that abiotic Fe(II) oxidation processes prevail over biotic Fe(II) oxidation on the filter. Yet, Mn-oxidizing bacteria play an important role for Mn(II) oxidation and Mn(III/IV) oxide precipitation in a distinct layer of the sand filter. The formation of Mn(III/IV) oxides contributes to abiotic As(III) oxidation and immobilization of As(V) by sorption to Fe(III) (oxyhydr)oxides. PMID- 26037818 TI - Carbon mineralization and nutrient availability in calcareous sandy soils amended with woody waste biochar. AB - Many studies have reported the positive effect of biochar on soil carbon sequestration and soil fertility improvement in acidic soils. However, biochar may have different impacts on calcareous sandy soils. A 90-day incubation experiment was conducted to quantify the effects of woody waste biochar (10 g kg( 1)) on CO2-C emissions, K2SO4-extractable C and macro-(N, P and K) and micro-(Fe, Mn, Zn and Cu) nutrient availability in the presence or absence of poultry manure (5 g kg(-1) soil). The following six treatments were applied: (1) conocarpus (Conocarpus erectus L.) waste (CW), (2) conocarpus biochar (BC), (3) poultry manure (PM), (4) PM+CW, (5) PM+BC and (6) untreated soil (CK). Poultry manure increased CO2-C emissions and K2SO4-extractable C, and the highest increases in CO2-C emission rate and cumulative CO2-C and K2SO4-extractable C were observed for the PM+CW treatment. On the contrary, treatments with BC halted the CO2-C emission rate, indicating that the contribution of BC to CO2-C emissions is negligible compared with the soils amended with CW and PM. Furthermore, the combined addition of PM+BC increased available N, P and K compared with the PM or BC treatments. Overall, the incorporation of biochar into calcareous soils might have benefits in carbon sequestration and soil fertility improvement. PMID- 26037817 TI - Perfluoroalkyl sulfonates and carboxylic acids in liver, muscle and adipose tissues of black-footed albatross (Phoebastria nigripes) from Midway Island, North Pacific Ocean. AB - The Great Pacific Garbage Patch (GPGP) is a gyre of marine plastic debris in the North Pacific Ocean, and nearby is Midway Atoll which is a focal point for ecological damage. This study investigated 13 C4-C16 perfluorinated carboxylic acids (PFCAs), four (C4, C6, C8 and C10) perfluorinated sulfonates and perfluoro 4-ethylcyclohexane sulfonate [collectively perfluoroalkyl acids (PFAAs)] in black footed albatross tissues (collected in 2011) from Midway Atoll. Of the 18 PFCAs and PFSAs monitored, most were detectable in the liver, muscle and adipose tissues. The concentrations of PFCAs and PFSAs were higher than those in most seabirds from the arctic environment, but lower than those in most of fish-eating water birds collected in the U.S. mainland. The concentrations of the PFAAs in the albatross livers were 7-fold higher than those in Laysan albatross liver samples from the same location reported in 1994. The concentration ranges of PFOS were 22.91-70.48, 3.01-6.59 and 0.53-8.35 ng g(-1) wet weight (ww), respectively, in the liver, muscle and adipose. In the liver samples PFOS was dominant, followed by longer chain PFUdA (8.04-18.70 ng g(-1) ww), PFTrDA, and then PFNA, PFDA and PFDoA. Short chain PFBA, PFPeA, PFBS and PFODA were below limit of quantification. C8-C13 PFCAs showed much higher composition compared to those found in other wildlife where PFOS typically predominated. The concentrations of PFUdA in all 8 individual albatross muscle samples were even higher than those of PFOS. This phenomenon may be attributable to GPGP as a pollution source as well as PFAA physicochemical properties. PMID- 26037819 TI - Isotope evidence of hexavalent chromium stability in ground water samples. AB - Chromium stable isotopes are of interest in many geochemical studies as a tool to identify Cr(VI) reduction and/or dilution in groundwater aquifers. For such studies the short term stability of Cr(VI) in water samples is required before the laboratory analyses can be carried out. Here the short term stability of Cr(VI) in groundwater samples was studied using an isotope approach. Based on commonly available methods for Cr(VI) stabilization, water samples were filtered and the pH value was adjusted to be equal to or greater than 8 before Cr isotope analysis. Based on our Cr isotope data (expressed as delta(53)CrNIST979), Cr(VI) was found to be unstable over short time periods in anthropogenically contaminated groundwater samples regardless of water treatment (e.g., pH adjustment, different storage temperatures). Based on our laboratory experiments, delta(53)CrNIST979 of the Cr(VI) pool was found to be unstable in the presence of dissolved Fe(II), Mn(IV) and/or SO2. Threshold concentrations of Fe(II) causing Cr(VI) reduction range between 10 mg L(-1) and 100 mg L(-1)and less than 1 mg L( 1) for Mn. Hence our isotope data show that water samples containing Cr(VI) should be processed on-site through anion column chemistry to avoid any isotope shifts. PMID- 26037820 TI - Perfluorinated carboxylic acids discharged from the Yodo River Basin, Japan. AB - We investigated perfluorinated carboxylic acids (PFCAs) with 7-14 carbon atoms (C7-C14) in the Yodo River system in 2013. C7-C11 were detected at most sampling sites. The range and median of total PFCAs (SigmaPFCAs) concentrations were 1.0 89.7 and 11.2 ng L(-1), respectively. The dominant component was C8 (average for all samples=53.3+/-8.8%), followed by C7 (19.2+/-6.7%) and C9 (17.6+/-7.1%). The levels of C8 were confirmed to decrease greatly over the last 10 years. We assessed the fluxes in C7-C11 discharged from the basin based on the concentrations in river water and river flow rate. The flux of discharged SigmaPFCAs was 237.0 g d(-1) at the most downriver point of the assessment areas. Considering the variability in flow rate due to precipitation, the annual SigmaPFCAs flux was estimated to be 86.5-173.4 kg y(-1). Identification and quantification of PFCAs sources is difficult because the strength of the sources changes with time, and available information is quite limited. Further monitoring and investigation are necessary to understand sources of PFCAs, as well as their potential for human exposure. PMID- 26037821 TI - Management of drug interaction between posaconazole and sirolimus in patients who undergo hematopoietic stem cell transplant. AB - STUDY OBJECTIVE: To determine an appropriate empiric oral sirolimus dose adjustment when given concurrently with posaconazole oral suspension in patients who undergo hematopoietic stem cell transplant (HSCT). DESIGN: Retrospective cohort study. SETTING: Comprehensive cancer center in the United States. SUBJECTS: Seventy five allogeneic HSCT patients who received posaconazole oral suspension and oral sirolimus concurrently between 2009 and 2011. MEASUREMENTS AND MAIN RESULTS: Sirolimus concentrations were recorded at baseline and for up to 28 days after posaconazole initiation. The sirolimus concentration/dose (C/D) ratio was determined for each sirolimus concentration obtained. Following analysis of patient data and based on the initial empiric sirolimus dose reduction, patients were stratified into two groups: >=50% sirolimus dose reduction (Group 1) and <50% sirolimus dose reduction (Group 2). The mean sirolimus C/D ratio was 2.29 ng/mL/mg prior to posaconzole initiation. Coadministration of posaconazole and sirolimus resulted in an increase in the steady state sirolimus C/D ratio to 6.24 ng/mL/mg, which occurred approximately 17-20 days after initiation of posaconazole. The mean maximum sirolimus concentration was significantly higher in Group 2 compared to Group 1 (12.64 ng/mL vs. 9.24 ng/mL, p=0.001). Significantly more patients in Group 2 than Group 1 experienced at least one sirolimus concentration >15 ng/mL (27% vs. 2.6%, p=0.003). CONCLUSION: Coadministration of posaconazole oral suspension with oral sirolimus increases the sirolimus C/D ratio by approximately 2.7-fold in HSCT patients. An initial empiric oral sirolimus dose reduction between 50% and 65% may be recommended for most clinically stable patients with close sirolimus concentration monitoring for at least 3 weeks following posaconazole initiation. PMID- 26037822 TI - Sleep-Disordered Breathing and Cardiac Arrhythmias. AB - Over the past few years sleep-disordered breathing has been identified as an important factor in arrhythmogenesis and a potential target of therapy to prevent cardiac arrhythmias in selected patients. In this review we highlight the role of obstructive sleep apnea and Cheyne-Stokes respiration in the pathophysiology of arrhythmias, address their clinical effect in supraventricular and ventricular tachyarrhythmias, and in conduction disturbances, and address the role of current treatment options for sleep-disordered breathing in the primary and secondary prevention of arrhythmic events. PMID- 26037823 TI - Epidemiology of Sleep Disturbances and Cardiovascular Consequences. AB - It is increasingly recognized that disruption of sleep and reduced amounts of sleep can have significant adverse cardiovascular consequences. For example, obstructive sleep apnea (OSA) is a common underdiagnosed disorder characterized by recurrent nocturnal asphyxia resulting from repetitive collapse of the upper airway; this leads to repetitive episodes of nocturnal hypoxemia and arousal from sleep. Risk factors for disease include obesity, increased age, male sex, and family history. In epidemiologic studies, OSA appears to be an independent risk factor for cardiovascular disease (CVD), and treatment is associated with better outcomes. Habitual short sleep duration is common in today's society. In epidemiologic studies, short sleep duration is associated with a number of adverse health effects, including all-cause mortality, weight gain, and incident CVD. Given the links between sleep disorders and adverse health outcomes, obtaining adequate quality and amounts of sleep should be considered a component of a healthy lifestyle, similar to good diet and exercise. PMID- 26037824 TI - The role of community pharmacies in counseling of personal medical devices and drug-delivery products in Estonia. AB - OBJECTIVES: To evaluate the current situation on medical technology at community pharmacies in Estonia, looking into the availability, dispensing and counseling of personal medical devices/drug-delivery products (PMDs/DDPs) and related professional knowledge of community pharmacists. METHODS: A descriptive cross sectional questionnaire-based study using an internet-based eFormular study platform. RESULTS: In total, 137 community pharmacies responded to the study. Of the pharmacies, 51.8% dispensed and 32.1% counseled PMDs/DDPs several times a day. 55.4% of the respondents assessed their professional knowledge on PMDs/DDPs as good to medium and 44.6% as satisfactory to poor. Of the respondents, 79.6% reported a need for systematic education about named devices. CONCLUSION: Community pharmacies are a frequent source for the dispensing and counseling of PMDs/DDPs in Estonia. However, community pharmacists admitted a strong need for continuing education about general and practical aspects related to the use of PMDs/DDPs for the provision of more professional services in the future. PMID- 26037825 TI - Magma Ocean Depth and Oxygen Fugacity in the Early Earth--Implications for Biochemistry. AB - A large class of elements, referred to as the siderophile (iron-loving) elements, in the Earth's mantle can be explained by an early deep magma ocean on the early Earth in which the mantle equilibrated with metallic liquid (core liquid). This stage would have affected the distribution of some of the classic volatile elements that are also essential ingredients for life and biochemistry - H, C, S, and N. Estimates are made of the H, C, S, and N contents of Earth's early mantle after core formation, considering the effects of variable temperature, pressure, oxygen fugacity, and composition on their partitioning. Assessment is made of whether additional, exogenous, sources are required to explain the observed mantle concentrations, and areas are identified where additional data and experimentation would lead to an improved understanding of this phase of Earth's history. PMID- 26037826 TI - The enigma of effective path length for (18) O enrichment in leaf water of conifers. AB - The Peclet correction is often used to predict leaf evaporative enrichment and requires an estimate of effective path length (L). Studies to estimate L in conifer needles have produced unexpected patterns based on Peclet theory and leaf anatomy. We exposed seedlings of six conifer species to different vapour pressure deficits (VPD) in controlled climate chambers to produce steady-state leaf water enrichment (in (18) O). We measured leaf gas exchange, stable oxygen isotopic composition (delta(18) O) of input and plant waters as well as leaf anatomical characteristics. Variation in bulk needle water delta(18) O was strongly related to VPD. Conifer needles had large amounts of water within the vascular strand that was potentially unenriched (up to 40%). Both standard Craig-Gordon and Peclet models failed to accurately predict conifer leaf water delta(18) O without taking into consideration the unenriched water in the vascular strand and variable L. Although L was linearly related to mesophyll thickness, large within species variation prevented the development of generalizations that could allow a broader use of the Peclet effect in predictive models. Our results point to the importance of within needle water pools and isolating mechanisms that need further investigation in order to integrate Peclet corrections with 'two compartment' leaf water concepts. PMID- 26037827 TI - Contribution of donor factors to post-reperfusion severe hyperglycemia in patients undergoing living donor liver transplantation. AB - BACKGROUND: Blood glucose levels increase abruptly after graft reperfusion during living donor liver transplantation (LDLT), but studies on perioperative factors contributing to this phenomenon are rare. We developed a predictive model for post-reperfusion severe hyperglycemia (PRSH) based on donor-related factors. MATERIAL AND METHODS: Preoperative and intraoperative recipient data, as well as donor data, on 279 LDLT cases were reviewed. The mean blood glucose levels at each LDLT surgical phase were calculated, and patients were divided into PRSH and non-PRSH groups using a cutoff of 230 mg/dL mean blood glucose level during the neo-hepatic phase. Perioperative variables were compared between the 2 groups, and selected variables were subjected to multivariate logistic regression to establish a predictive model for PRSH. RESULTS: There were 128 patients (45.9%) who developed PRSH, which was associated with preoperative diabetes mellitus but not with model for end-stage liver disease or Child-Pugh-Turcotte score. Intraoperatively, the PRSH group required more blood transfusions and experienced more circulatory insufficiency than did the non-PRSH group. PRSH patients received grafts with higher-level fatty changes and greater graft-to-recipient ratios (GRWRs) (both p<0.05). The multivariate predictive model included GRWR, graft fatty change >=10% (OR 3.53), post-reperfusion syndrome >=5 min in duration (OR 5.68), and recipient diabetes mellitus (OR 2.92) as independent risk factors. The risk of PRSH was proportional to the rise in GRWR. CONCLUSIONS: PRSH development was heavily influenced by donor-related factors. Graft size, extent of fatty change, and post-reperfusion syndrome were identified as independent donor-associated predictors of PRSH. PMID- 26037828 TI - Hermeneutics and pragmatism offer a way of exploring the consequences of advanced assessment. AB - Linking specific nursing actions to outcomes in the healthcare setting is challenging. Patient outcomes are varied and influenced by a myriad of factors, and always involve a wider team than any one nurse. It is difficult to control for a single action or set of actions of a particular nurse. Furthermore, practice is seldom about any 'one' action, for one thing leads to another, all within a complex interplay of influencing factors. In this article, we outline a research method which combined Dewey's pragmatism with Gadamer's hermeneutics to explore the consequences of the nurse's use of advanced assessment skills in the acute care setting of medical and surgical wards. This pragmatic hermeneutic methodological approach allowed the complex interplay of influences to be revealed in the unfolding story. Reflection of the nurse brought insights that may otherwise have been passed over. The philosophical notions of Dewey drew attention to the play of 'means' and 'ends'. A hermeneutic approach that calls for 'thinking' extends understanding and raises insights that can inform education and practice. PMID- 26037829 TI - Defective functionality of small, dense HDL3 subpopulations in ST segment elevation myocardial infarction: Relevance of enrichment in lysophosphatidylcholine, phosphatidic acid and serum amyloid A. AB - BACKGROUND: Low plasma levels of high-density lipoprotein-cholesterol (HDL-C) are typical of acute myocardial infarction (MI) and predict risk of recurrent cardiovascular events. The potential relationships between modifications in the molecular composition and the functionality of HDL subpopulations in acute MI however remain indeterminate. METHODS AND RESULTS: ST segment elevation MI (STEMI) patients were recruited within 24h after diagnosis (n=16) and featured low HDL-C (-31%, p<0.05) and acute-phase inflammation (determined as marked elevations in C-reactive protein, serum amyloid A (SAA) and interleukin-6) as compared to age- and sex-matched controls (n=10). STEMI plasma HDL and its subpopulations (HDL2b, 2a, 3a, 3b, 3c) displayed attenuated cholesterol efflux capacity from THP-1 cells (up to -32%, p<0.01, on a unit phospholipid mass basis) vs. CONTROLS: Plasma HDL and small, dense HDL3b and 3c subpopulations from STEMI patients exhibited reduced anti-oxidative activity (up to -68%, p<0.05, on a unit HDL mass basis). HDL subpopulations in STEMI were enriched in two proinflammatory bioactive lipids, lysophosphatidylcholine (up to 3.0-fold, p<0.05) and phosphatidic acid (up to 8.4-fold, p<0.05), depleted in apolipoprotein A-I (up to -23%, p<0.05) and enriched in SAA (up to +10.2-fold, p<0.05); such changes were most marked in the HDL3b subfraction. In vitro HDL enrichment in both lysophosphatidylcholine and phosphatidic acid exerted deleterious effects on HDL functionality. CONCLUSIONS: In the early phase of STEMI, HDL particle subpopulations display marked, concomitant alterations in both lipidome and proteome which are implicated in impaired HDL functionality. Such modifications may act synergistically to confer novel deleterious biological activities to STEMI HDL. SIGNIFICANCE: Our present data highlight complex changes in the molecular composition and functionality of HDL particle subpopulations in the acute phase of STEMI, and for the first time, reveal that concomitant modifications in both the lipidome and proteome contribute to functional deficiencies in cholesterol efflux and antioxidative activities of HDL particles. These findings may provide new biomarkers and new insights in therapeutic strategy to reduce cardiovascular risk in this clinical setting where such net deficiency in HDL function, multiplied by low circulating HDL concentrations, can be expected to contribute to accelerated atherogenesis. PMID- 26037830 TI - Idiopathic interstitial pneumonias in 2015: A new era. PMID- 26037832 TI - Regulated and unregulated emissions from modern 2010 emissions-compliant heavy duty on-highway diesel engines. AB - The U.S. Environmental Protection Agency (EPA) established strict regulations for highway diesel engine exhaust emissions of particulate matter (PM) and nitrogen oxides (NOx) to aid in meeting the National Ambient Air Quality Standards. The emission standards were phased in with stringent standards for 2007 model year (MY) heavy-duty engines (HDEs), and even more stringent NOX standards for 2010 and later model years. The Health Effects Institute, in cooperation with the Coordinating Research Council, funded by government and the private sector, designed and conducted a research program, the Advanced Collaborative Emission Study (ACES), with multiple objectives, including detailed characterization of the emissions from both 2007- and 2010-compliant engines. The results from emission testing of 2007-compliant engines have already been reported in a previous publication. This paper reports the emissions testing results for three heavy-duty 2010-compliant engines intended for on-highway use. These engines were equipped with an exhaust diesel oxidation catalyst (DOC), high-efficiency catalyzed diesel particle filter (DPF), urea-based selective catalytic reduction catalyst (SCR), and ammonia slip catalyst (AMOX), and were fueled with ultra-low sulfur diesel fuel (~6.5 ppm sulfur). Average regulated and unregulated emissions of more than 780 chemical species were characterized in engine exhaust under transient engine operation using the Federal Test Procedure cycle and a 16-hr duty cycle representing a wide dynamic range of real-world engine operation. The 2010 engines' regulated emissions of PM, NOX, nonmethane hydrocarbons, and carbon monoxide were all well below the EPA 2010 emission standards. Moreover, the unregulated emissions of polycyclic aromatic hydrocarbons (PAHs), nitroPAHs, hopanes and steranes, alcohols and organic acids, alkanes, carbonyls, dioxins and furans, inorganic ions, metals and elements, elemental carbon, and particle number were substantially (90 to >99%) lower than pre-2007-technology engine emissions, and also substantially (46 to >99%) lower than the 2007-technology engine emissions characterized in the previous study. PMID- 26037833 TI - Single photons for all. PMID- 26037834 TI - Notes on a retraction. Correcting the scientific literature with the help of the research community. PMID- 26037835 TI - Learning from the past. PMID- 26037837 TI - Nanomechanics: Rocking at the nanoscale. PMID- 26037838 TI - Addendum: A nanophotonic solar thermophotovoltaic device. PMID- 26037839 TI - Retraction: DNA sequencing using electrical conductance measurements of a DNA polymerase. PMID- 26037840 TI - Inspired by competition. PMID- 26037841 TI - Cardiac and vascular toxicities of angiogenesis inhibitors: The other side of the coin. AB - Angiogenesis is one of the best-described tumor hallmarks. Targeting angiogenesis is becoming a successful strategy to suppress cancer growth. Vascular endothelial growth factor (VEGF), the fulcrum of angiogenesis, contributes to vascular and cardiac homeostasis. Angiogenesis inhibitors classically associated with vascular side effects are increasingly recognized for cardiac adverse effects as reflected by several meta-analyses. A global approach to these findings is a pressing need, and future strategies involving collaboration among different medical specialties are highly encouraged. PMID- 26037842 TI - Haptic characterization of human skin in vivo in response to shower gels using a magnetic levitation device. AB - BACKGROUND/PURPOSE: Skin products such as shower gels have a direct impact on skin health and wellness. Although qualitative haptic characterization through explicit, verbal measures in consumer studies are often sufficient for general comparison on consumer perceived skin feel, a quantitative approach is desired to characterize minute changes in skin condition in response to various skin products. Prior research has sought to characterize the haptic properties of human skin in vitro and in vivo, but very few studies have compared the haptic effects of commercial skin products having relatively similar formulations. In addition, related studies have typically utilized simple, low-precision devices and fixtures. The purpose of this study was to use a precision magnetic levitation haptic device to characterize the frictional properties of human skin in vivo before, during, and after treatment with commercially available shower gels, to capture the entire cycle of consumer experience on skin feel. METHODS: A hybrid force-position control algorithm was used to control a precision magnetic levitation haptic device with silicone tactor to stroke the human skin (on the volar forearm) in vivo. Position and force data were collected from 32 human subjects using eight different commercially available shower gels, while stroking the skin before, during, and after treatment. The data were analyzed to produce coefficients of friction and viscous damping constant, which were used as metrics for comparing the effects of each shower gel type. Other factors investigated include skin test location, order, and subject age and gender. RESULTS: Results showed significant differences between the effects of eight various shower gels, especially after accounting for variance between subjects. Most notably, Shower Gel four with high level of petrolatum, along with Shower Gels five and six with low levels of castoryl maleate (a skin lipid analog), as well as Shower Gel two with high levels of vegetable oils yielded higher skin coefficients of friction 20 min after treatment, indicating higher levels of skin hydration than other shower gels without either high levels of skin beneficial agents or low levels of castoryl maleate. Conversely, Shower Gel eight treatment yielded the lowest skin coefficient of friction both immediately after rinsing and 20 min after treatment. In addition, when applied to the skin as un-lathered gels, Shower Gels six and seven with acrylate polymers yielded viscous damping constants twice that of other gels, while Shower Gel three yielded the lowest. When lathered into foam on skin, Shower Gel eight yielded the highest viscous damping constant, while Shower Gel three, along with Shower Gels one and five yielded lower values than others. CONCLUSION: The results of this study show that different shower gels do have significant measurable differences in their effects on skin properties, and that using a high-precision haptic device can be a useful tool for quantifying the haptic properties of skin in vivo. PMID- 26037843 TI - Effect of GLT-1 modulator and P2X7 antagonists alone and in combination in the kindling model of epilepsy in rats. AB - INTRODUCTION: Multiple lines of investigation have explored the role of glutamatergic and purinergic systems in epilepsy, related cognitive impairment, and oxidative stress. Glutamate transporters, particularly GLT-1 expression, were found to be decreased, and purinergic receptor, P2X7 expression, was found to be increased in brain tissue associated with epilepsy. The present study was carried out to investigate the effect of ceftriaxone (GLT-1 upregulator) and Brilliant Blue G (P2X7 antagonist) against PTZ-induced kindling in rats. The study was further extended to elucidate the cross-link between glutamatergic and purinergic pathways in epilepsy. MATERIAL AND METHODS: Systemic administration of subconvulsant dose of PTZ (30 mg/kg) every other day for 27days (14 injections) significantly increased the mean kindling, and developed generalized tonic-clonic seizures, and reduced motor co-ordination, cognitive skills, oxidative defense (increases lipid peroxidation, nitrite levels and decreases GSH level) and acetylcholinesterase enzyme activities in the cortex and subcortical region. Treatments with CEF (100 and 200mg/kg) and BBG (15 and 30 mg/kg) alone and in combination (CEF 100mg/kg and BBG 15 mg/kg) significantly decreased the mean kindling score and restored behavioral and oxidative defense activities compared with treatment with PTZ. CONCLUSIONS: The combination of both the drugs was shown to have better effect in preventing kindled seizures and a significantly synergistic effect compared with their effect alone in PTZ-kindled rats. The present study elucidated the mechanistic role of GLT-1 modulator and selective P2X7 antagonist and their combination against PTZ-induced kindling. The study for the first time demonstrated the cross-link between glutamatergic and purinergic pathways in epilepsy treatment. PMID- 26037844 TI - Can emotional stress trigger the onset of epilepsy? AB - OBJECTIVE: The aim of this study was to investigate the potential role of an acute adverse stress as "trigger" for the onset of epilepsy. METHODS: Among 4618 consecutive patients, twenty-two reported a major life event within three months before the onset of epilepsy. RESULTS: All patients had focal epilepsy except one with idiopathic generalized epilepsy. The temporal lobe was involved in 90% of patients with focal epilepsy. More precisely, 13 patients (62% of patients with focal epilepsy) had medial temporal lobe epilepsy (MTLE), two had lateral temporal lobe epilepsy, four had temporoparietooccipital junction epilepsy, and two patients had central lobe epilepsy. The mean age and the median age at onset of epilepsy for patients with MTLE were both 38 years (range: 9.5-65 years). Ten patients had right and three had left MTLE. Among patients with focal epilepsy, MRI was abnormal in 7 (33%) with hippocampal sclerosis in four, periventricular nodular heterotopia in two, and complex cortical dysgenesis in one. The mean age at onset of epilepsy for patients with brain lesions was 26 years (range: 9.5 49). Twelve patients (54%) reported a death as a triggering factor for the onset of their epilepsy. Seven patients (32%) reported that a relationship of trust had been broken. Three patients (14%) had been subjects of violence. No patient reported sexual abuse as a triggering factor. CONCLUSION: This study provides evidence that some patients (5/1000 patients) began their seizures in the wake of significant life events. The average age at onset of epilepsy is quite late, around age 30, even in the presence of brain lesions. These patients are emotionally and affectively more prone to have consequences of a stressful life event. The recognition and management of such situations may bring significant relief with improvement of the control of epilepsy. PMID- 26037846 TI - Therapeutic misconception correlates with willingness to participate in clinical drug trials among patients with epilepsy; need for better counseling. AB - OBJECTIVES: To ensure the development of new effective treatments in medicine, clinical trials (CTs) need to be conducted. The study was aimed at assessing knowledge of and attitudes toward clinical drug trials among patients with epilepsy, along with factors that motivate them to participate in CTs. Use of this information could improve recruitment for future trials and enhance their quality. METHODS: A 45-item questionnaire on the views of patients with epilepsy about CTs was developed. It included statements that the respondents assessed on a Likert scale from 1 ('strongly disagree') to 5 ('strongly agree'). The questionnaire was mailed to a random sample (n=1875) of members of the Finnish Epilepsy Association aged at least 18 years. In all, 342 questionnaires were returned, and 325 were accepted after exclusion. RESULTS: The analysis indicates that the general attitudes of patients with epilepsy toward CTs are positive. Most of the patients with epilepsy saw participation in clinical trials as indispensable to new treatments becoming available. Retired respondents and persons who had developed epilepsy when young had inadequate knowledge of general issues related to CTs. Level of education and number of antiepileptic medications (AEDs) were significant predictors for failure to understand the nature and purpose of clinical research - i.e., for therapeutic misconception (TM). Additionally, strong correlation was found between TM and respondents' willingness to participate in clinical trials. CONCLUSIONS: The new treatments are often studied in patients with a high risk of TM and impaired comprehension of general procedures associated with CTs. Clinically, it may be worthwhile for the investigators to be able to recognize vulnerable individuals and pay special attention to the information provided on the purposes and methods of the trial, to contribute to high-quality AED studies. PMID- 26037845 TI - Cortical feature analysis and machine learning improves detection of "MRI negative" focal cortical dysplasia. AB - Focal cortical dysplasia (FCD) is the most common cause of pediatric epilepsy and the third most common lesion in adults with treatment-resistant epilepsy. Advances in MRI have revolutionized the diagnosis of FCD, resulting in higher success rates for resective epilepsy surgery. However, many patients with histologically confirmed FCD have normal presurgical MRI studies ('MRI negative'), making presurgical diagnosis difficult. The purpose of this study was to test whether a novel MRI postprocessing method successfully detects histopathologically verified FCD in a sample of patients without visually appreciable lesions. We applied an automated quantitative morphometry approach which computed five surface-based MRI features and combined them in a machine learning model to classify lesional and nonlesional vertices. Accuracy was defined by classifying contiguous vertices as "lesional" when they fell within the surgical resection region. Our multivariate method correctly detected the lesion in 6 of 7 MRI-positive patients, which is comparable with the detection rates that have been reported in univariate vertex-based morphometry studies. More significantly, in patients that were MRI-negative, machine learning correctly identified 14 out of 24 FCD lesions (58%). This was achieved after separating abnormal thickness and thinness into distinct classifiers, as well as separating sulcal and gyral regions. Results demonstrate that MRI-negative images contain sufficient information to aid in the in vivo detection of visually elusive FCD lesions. PMID- 26037849 TI - Succession planning for AJA. PMID- 26037848 TI - Sustained improvement of attitudes about epilepsy following a reduction in media coverage of car accidents involving persons with epilepsy. AB - To evaluate changes in the attitudes of nonmedical students about epilepsy, the present study compared the results of a questionnaire that was completed in three different time periods: before media coverage of car accidents associated with epilepsy, during a period of abundant media coverage about epilepsy-related accidents, and after media coverage of epilepsy-related accidents. The nonmedical students who completed the questionnaire were divided into three groups: Years 08 10 (preaccident era), Years 11-12 (media coverage era), and Years 13-14 (postmedia coverage era). The rates of students who had read or heard about epilepsy and of students who did not think that epilepsy was a mental disorder increased annually throughout the study period. There was an improvement in attitudes about epilepsy after the media coverage era, and this change was not altered even after a decrease in the media coverage of epilepsy-related car accidents. Additionally, the rate of positive answers did not differ between Years 11-12 and Years 13-14. These findings demonstrate that the familiarity with and improved attitudes about epilepsy were sustained even after the media coverage of car accidents involving persons with epilepsy had decreased. PMID- 26037847 TI - The effect of acute aripiprazole treatment on chemically and electrically induced seizures in mice: The role of nitric oxide. AB - Aripiprazole is an antipsychotic drug which acts through dopamine and serotonin receptors. Aripiprazole was noted to have antiseizure effects in a study on mice, while it induced seizures in a few human case reports. Dopaminergic and serotonergic systems relate to nitric oxide, and aripiprazole also has effects on dopamine and serotonin receptors. This study investigated the effects of aripiprazole on seizures and the potential role of nitric oxide in the process. The following three models were examined to explore the role of aripiprazole on seizures in mice: 1 - pentylenetetrazole administered intravenously, 2 - pentylenetetrazole administered intraperitoneally, and 3 - electroshock. Aripiprazole administration delayed clonic seizure in intravenous and intraperitoneal pentylenetetrazole models. In the electroshock-induced seizure model, tonic seizure and mortality protection percent were increased after aripiprazole administration. In intraperitoneal administration of pentylenetetrazole, aripiprazole effects on clonic seizure latency were significantly decreased when l-NAME - a nonselective nitric oxide synthase (NOS) inhibitor, 7-nitroindazole - a selective neuronal NOS (nNOS) inhibitor, or aminoguanidine - a selective inducible NOS (iNOS) inhibitor was injected before aripiprazole administration. In the intravenous pentylenetetrazole method, administration of l-NAME or aminoguanidine inhibited aripiprazole effects on clonic seizure threshold. Aminoguanidine or l-NAME administration decreased aripiprazole-induced protection against tonic seizures and death in the electroshock model. In both intravenous and intraperitoneal seizure models, aripiprazole and l-arginine coadministration delayed the onset of clonic seizures. Moreover, it increased protection against tonic seizures and death in intraperitoneal pentylenetetrazole and electroshock models. In conclusion, the release of nitric oxide via iNOS or nNOS may be involved in anticonvulsant properties of aripiprazole. PMID- 26037850 TI - [Not Available]. PMID- 26037851 TI - [Improvement of stroke management: The most important might still have to come]. PMID- 26037852 TI - Optimization of a miniaturized fluid array device for cell-free protein synthesis. AB - Cell-free protein synthesis (CFPS), which entails synthesizing proteins outside of intact cells, is conducted in several formats with the continuous-exchange cell-free (CECF) format generally having the greatest protein expression yields. With this format, continuous chemical exchange occurs through a dialysis membrane separating a reaction solution from a feeding solution containing supplemental nutrient/energy molecules. Here, we describe the optimization of the miniaturized fluid array device (uFAD) by studying the effects of structural and experimental parameters responsible for the heightened chemical exchange across the dialysis membranes and enhanced protein expression capabilities of the high-throughput device. The interface area and number between the reaction and feeding solutions have a direct impact on protein expression, with a 1.6% enhancement in protein expression yield with each square millimeter increase in area and a 20% decrease with each additional interface. For nutrient/energy availability, an increasing solution volume ratio and height difference increase protein expression yield until the expression yield plateaus at a volume ratio of 20 to 1 (feeding to reaction solution) and a solution height difference of 2 mm. This yield can be further increased by 7% every 30 min with feeding solution replacement. Of the studied experimental factors (feeding solution stirring, device shaking, and temperature increase), feeding solution stirring has a significant effect on protein expression in this device. In the optimized system, green fluorescent protein (GFP), beta-glucuronidase (GUS), beta-galactosidase (LacZ), luciferase, and tissue plasminogen activator (tPA) expression increased 77.8-, 212-, 3.66-, 463-, and 5.43-fold, respectively, compared to the conventional batch format in a standard microplate. These results highlight the significance of structural/experimental conditions on the productive expression of proteins in the CECF format. PMID- 26037853 TI - Pharmacological management of persistent hostility and aggression in persons with schizophrenia spectrum disorders: a systematic review. AB - The incidence of aggressive behaviors is higher among persons with schizophrenia spectrum disorders (SSDs) than among persons without such disorders. This phenomenon represents a risk to the well-being of patients, their families, and society. The authors undertook a systematic review of the English language literature to determine the efficacy of neuropharmacological agents for the management of hostility and aggression among persons with SSDs. The search combined findings from the Medline, EMBASE, and PsycINFO databases. Ninety-two full text articles were identified that reported relevant findings. The American Academy of Neurology criteria were used to determine levels of evidence. Paliperidone-extended release is probably effective for the management of hostility among inpatients with SSDs who have not been preselected for aggression (Level B). Clozapine is possibly more effective than haloperidol for the management of overt aggression and possibly more effective than chlorpromazine for the management of hostility among inpatients with SSDs who have not been preselected for aggression (Level C). Clozapine is also possibly more effective than olanzapine or haloperidol for reducing aggression among selected physically assaultive inpatients (Level C). Adjunctive propranolol, valproic acid, and famotidine are possibly effective for reducing some aspects of hostility or aggression among inpatients with SSDs (Level C). Paliperidone-extended release currently appears to be the agent for the management of hostility among inpatients with SSDs for which there is the strongest evidence of efficacy. PMID- 26037854 TI - Behavioral health symptoms associated with chronic traumatic encephalopathy: a critical review of the literature and recommendations for treatment and research. AB - Chronic traumatic encephalopathy (CTE) is a neurodegenerative syndrome that has been linked to serious psychiatric symptoms, including depression, aggression, and suicidal behavior. This review critically examines the extant research on the behavioral manifestations of CTE and concludes that the paucity of longitudinal prospective studies on CTE, combined with a lack of research-accepted diagnostic criteria for identifying individuals who are considered at risk for CTE, makes it difficult to reliably establish a causal relationship between CTE and the onset of behavioral health problems. Selection and reporting bias and inconsistency in data collection methods are other concerns. To advance the field, there is a critical need for more empirical research on the behavioral manifestations of CTE. Recommendations and intervention models are also discussed. PMID- 26037855 TI - Conventional SPECT Versus 3D Thresholded SPECT Imaging in the Diagnosis of ADHD: A Retrospective Study. AB - Brain single photon emission CT (SPECT) scans indirectly show functional activity via measurement of regional cerebral blood flow. In conventional SPECT scans, the typical tomographic slices are produced. In three-dimensional thresholded SPECT scans, pixels representing activity below a certain threshold are discarded. A retrospective analysis of 427 patients shows that three-dimensional thresholded SPECT scans yield a sensitivity for predicting clinical attention deficit hyperactivity disorder of 54% [95% confidence interval (CI), 46%-61%; specificity, 76%; 95% CI, 71%-81%] compared with 4% sensitivity [95% CI, 2%-8%; specificity, 97%; 95% CI, 94%-98%] for conventional SPECT scans. For 170 of the patients originating from a general psychiatry practice, conventional SPECT showed 10% sensitivity (95% CI, 4%-23%) and 98% specificity (95% CI, 93%-99%), whereas three-dimensional thresholded SPECT showed 83% sensitivity (95% CI, 68% 91%) and 77% specificity (95% CI, 69%-83%). These findings indicate that a much stronger signal is obtained when the three-dimensional thresholded SPECT scan is performed rather than the conventional SPECT scan in detecting attention deficit hyperactivity disorder and suggest similar results may be obtained for other psychiatric disorders. PMID- 26037856 TI - The Association of BDNF Val66Met Polymorphism With Trait Anxiety in Panic Disorder. AB - Recent studies indicate that early-onset panic disorder (PD) may show distinct clinical characteristics. The authors compared patients with early-onset PD, patients with late-onset PD, and healthy control subjects in terms of brain derived neurotrophic factor (BDNF), the Val66Met polymorphism, State-Trait Anxiety Inventory (STAI) scores, and the Revised NEO Personality Inventory. In patients with early-onset PD, the STAI-T score was high in the Met/Met group, whereas the STAI-T score of the Val/Val group tended to be higher for healthy control subjects. The conflicting effect of the BDNF genotype between patients with early-onset PD and healthy control subjects suggests that the BDNF Met/Met genotype may increase trait anxiety in early-onset PD. PMID- 26037857 TI - Diagnostic Utility of the International HIV Dementia Scale for HIV-Associated Neurocognitive Impairment and Disorder in South Africa. AB - Studies in sub-Saharan Africa indicate that most HIV seropositive persons have HIV-associated neurocognitive disorder (HAND). HAND diagnosis is facilitated by specific screening. Seventy participants were recruited from an HIV voluntary counseling and testing clinic in Durban, South Africa. The diagnostic utility of the International HIV Dementia Scale (IHDS) was analyzed using a receiver operating characteristic (ROC) model. The ROC analysis comparing any HAND diagnosis (based on two neuropsychological tests) versus no diagnosis was statistically significant, with an optimal cut-off score of 10.5, sensitivity of 69%, and specificity of 74%. Sensitivity of the IHDS was highest for HIV associated dementia. PMID- 26037858 TI - Longitudinal evaluation of the psychomotor syndrome in schizophrenia. AB - Little is known about the longitudinal course of psychomotor signs and symptoms after illness onset in schizophrenia. Therefore, a 1-year follow-up study was conducted in which patients with schizophrenia were assessed three times with an extensive battery of psychomotor rating scales and tests. The syndromic structure of psychomotor symptoms was also studied. In accordance with a neurodevelopmental view on schizophrenia, psychomotor functioning was found to remain stable or improve slightly. Prospective studies with longer follow-up periods are needed to rule out the possibility of neurodegeneration in subgroups of patients and to evaluate possible covariation in the course of psychomotor symptoms. PMID- 26037859 TI - Erratum. PMID- 26037860 TI - Erratum. PMID- 26037861 TI - Decreased dopamine concentrations in the frontal cortex after ablative surgeries in patients exhibiting self-injurious behavior: a microdialysis study. AB - The authors examined brain neurochemistry in four patients with mental retardation with self-injurious behaviors after ablative surgeries. The authors found that surgeries in the human limbic system can alter dopamine levels in the frontal cortex over a 36-hour period. PMID- 26037862 TI - Erratum. PMID- 26037863 TI - The effect of transient ischemic attack clinical pathway. AB - BACKGROUND: Clinical pathway (CP) of transient ischemic attack (TIA) is an interdisciplinary, comprehensive, standardized management model for medical care of TIA. It aims to standardize the procedure, reduce the cost, and improve the quality of medical care. However, its effect is still unclear. OBJECTIVE: To evaluate the effect of TIA CP and provide evidence for control of medical care cost, optimize the structure of hospital cost, and make best use of medical resource. METHODS: 112 patients in the CP group and 179 patients in the nonclinical pathway (NCP) group were included in this nonconcurrent cohort study. RESULTS: The average length of stay was 9.55 +/- 3.89 days in the NCP group, and it was 7.26 +/- 2.09 days in the CP group. The average length of stay was significantly shortened by 2.29 days. Hospital cost in the CP group significantly increased by 7.9% (868 yuan) compared with that in the NCP group. The proportion of medication cost significantly decreased by 5%, while the proportion of examination cost significantly increased by 8%. As for the clinical outcomes of patients with TIA, 98.21% of the patients in the CP group were discharged in a good condition, while the proportion was 97.77% in the NCP group, and no significant difference was found between the improvement rate of the two groups. Eight patients (4%) in the NCP group were admitted to the hospital because of a 30-day recurrent TIA or cerebral infarction; four of them had cerebral infarction, whereas no recurrent TIA or cerebral infarction was found in the CP group at the 30-day follow-up. CONCLUSIONS: Implementation of TIA CP could reduce the length of stay, the proportion of medication cost, and optimize the structure of hospital expense, thus making best use of medical resources and improve the quality of TIA medical care. PMID- 26037864 TI - The science of neuropsychiatry: past, present, and future. AB - The field of neuropsychiatry aims to overcome the separation of neurology and psychiatry, which is reflected in a gap between the neurologist, searching for the underlying neuroanatomical basis of a disorder, and the psychiatrist, dipping into its phenomenology and underlying genetics. This gap becomes slighter in our day, as recent research in clinical neurosciences enables us to better investigate the neural basis of neuropsychiatric disorders. This article reviews the history and development of neuropsychiatry in the occidental world, suggesting that the science of neuropsychiatry could optimize for the diagnosis, monitoring, and treatment of behavioral, cognitive, and so-called mental disorders. PMID- 26037865 TI - Do patients with Tourette syndrome jump to conclusions? AB - Tourette syndrome can be associated with impulsive and compulsive symptoms and changes in reasoning. This controlled study revealed that patients with Tourette syndrome exhibit a tendency toward jumping to conclusions on a probabilistic reasoning task, with implications for social cognition. PMID- 26037867 TI - A Case of Hashimoto's Encephalopathy Presenting With Acute Psychosis. PMID- 26037868 TI - A Case of Anti-NMDA Receptor Encephalitis With the Highest Reported CSF White Cells to Date. PMID- 26037869 TI - Fluoxetine-induced pulmonary hypertension in a patient with schizophrenia. PMID- 26037870 TI - Analysis spectrum of normal and ataxia Purkinje cell output and classification using artificial neural network. PMID- 26037871 TI - Refractory schizo-obsessive disorder responsive to electroconvulsive therapy. PMID- 26037872 TI - A Rare Association of Fahr's Disease With an Autoimmune Triad. PMID- 26037873 TI - Severe hyponatremia and seizures secondary to psychogenic polydipsia in a case of frontotemporal dementia. PMID- 26037874 TI - Pathological crying associated with fragile X-associated tremor/ataxia syndrome. PMID- 26037875 TI - Capgras syndrome with left hemisphere neurological damage. PMID- 26037876 TI - Nonketotic hyperglycemia presenting as choreoathetosis in a female schizophrenia patient. PMID- 26037877 TI - Chronic Manic Episode Associated With Hypothyroidism due to Hashimoto's Disease: A Case Report. PMID- 26037878 TI - Bulimia Nervosa Treated With an Adapted Version of Carroll's Cognitive-Behavioral Approach for Treatment of Cocaine Addiction. PMID- 26037880 TI - Avoiding stimulants may not prevent manic switch: a case report with atomoxetine. PMID- 26037879 TI - Hyponatremia masquerading as panic symptoms in bipolar affective disorder. PMID- 26037881 TI - Aripiprazole monotherapy can relieve ruminations in a case with nonpsychotic depression. PMID- 26037882 TI - Cerebral Cryptococcoma in an HIV-Negative Patient: Experience Learned From a Case. PMID- 26037883 TI - Neuroleptic malignant syndrome probably induced by asenapine. PMID- 26037884 TI - Hippocampal volume increased after cognitive behavioral therapy in a patient with social anxiety disorder: a case report. PMID- 26037885 TI - Marked exacerbation of ADHD after onset of inhalant use: a case report. PMID- 26037886 TI - Punding behavior in bipolar disorder type 1: case report. PMID- 26037887 TI - Insular cortex: structural and functional neuroanatomy. PMID- 26037888 TI - Speech acquisition predicts regions of enhanced cortical response to auditory stimulation in autism spectrum individuals. AB - A continuum of phenotypes makes up the autism spectrum (AS). In particular, individuals show large differences in language acquisition, ranging from precocious speech to severe speech onset delay. However, the neurological origin of this heterogeneity remains unknown. Here, we sought to determine whether AS individuals differing in speech acquisition show different cortical responses to auditory stimulation and morphometric brain differences. Whole-brain activity following exposure to non-social sounds was investigated. Individuals in the AS were classified according to the presence or absence of Speech Onset Delay (AS SOD and AS-NoSOD, respectively) and were compared with IQ-matched typically developing individuals (TYP). AS-NoSOD participants displayed greater task related activity than TYP in the inferior frontal gyrus and peri-auditory middle and superior temporal gyri, which are associated with language processing. Conversely, the AS-SOD group only showed enhanced activity in the vicinity of the auditory cortex. We detected no differences in brain structure between groups. This is the first study to demonstrate the existence of differences in functional brain activity between AS individuals divided according to their pattern of speech development. These findings support the Trigger-threshold-target model and indicate that the occurrence of speech onset delay in AS individuals depends on the location of cortical functional reallocation, which favors perception in AS SOD and language in AS-NoSOD. PMID- 26037890 TI - N-Fused BDOPV: a tetralactam derivative as a building block for polymer field effect transistors. AB - An N-fused BDOPV derivative, NBDOPV, was designed and synthesized. The photophysical and electrochemical properties of NBDOPV were systematically investigated. The NBDOPV-based conjugated polymer PITET shows a large hole mobility of 1.92 cm(2) V(-1) s(-1). PMID- 26037889 TI - Childhood maltreatment, 9/11 exposure, and latent dimensions of psychopathology: A test of stress sensitization. AB - On September 11, 2001, a terrorist attack occurred in the U.S. (9/11). Research on 9/11 and psychiatric outcomes has focused on individual disorders rather than the broader internalizing (INT) and externalizing (EXT) domains of psychopathology, leaving unknown whether direct and indirect 9/11 exposure differentially impacted these domains rather than individual disorders. Further, whether such effects were exacerbated by earlier childhood maltreatment (i.e. stress sensitization) is unknown. 18,713 participants from a U.S. national sample with no history of psychiatric disorders prior to 9/11 were assessed using a structured in-person interview. Structural equation modeling conducted in a sample who endorsed no psychiatric history prior to 9/11, indicated that indirect exposure to 9/11 (i.e. media, friends/family) was related to both EXT (alcohol, nicotine, and cannabis dependence, and antisocial personality disorder) and INT (major depression, generalized anxiety, and post-traumatic stress disorder (PTSD)) dimensions of psychopathology (EXT: beta = 0.10, p < 0.001; INT: beta = 0.11, p < 0.001) whereas direct exposure was associated with the INT dimension only (beta = 0.11, p < 0.001). For individuals who had experienced childhood maltreatment, the risk for EXT and INT dimensions associated with 9/11 was exacerbated (Interactions: beta = 0.06, p < 0.01; beta = 0.07, p < 0.001, respectively). These findings indicate that 9/11 impacted latent liability to broad domains of psychopathology in the US general population rather than specific disorders with the exception of PTSD, which had independent effects beyond INT (as indicated by a significant (p < 0.05) improvement in modification indices). Findings also indicated that childhood maltreatment increases the risk associated with adult trauma exposure, providing further evidence for the concept of stress sensitization. PMID- 26037893 TI - Hospital Utilization and Universal Health Insurance Coverage: Evidence from the Massachusetts Health Care Reform Act. AB - OBJECTIVE: The Affordable Care Act is currently in the roll-out phase. To gauge the likely implications of the national policy we analyze how the Massachusetts Health Care Reform Act impacted various hospitalization outcomes in each of the 25 major diagnostic categories (MDC). METHODS: We utilize a difference-in difference approach to identify the impact of the Massachusetts reform on insurance coverage and patient outcomes. This identification is achieved using six years of data from the Nationwide Inpatient Sample from the Healthcare Cost and Utilization Project. We report MDC-specific estimates of the impact of the reform on insurance coverage and type as well as length of stay, number of diagnoses, and number of procedures. RESULTS: The requirement of universal insurance coverage increased the probability of being covered by insurance. This increase was in part a result of an increase in the probability of being covered by Medicaid. The percentage of admissions covered by private insurance fell. The number of diagnoses rose as a result of the law in the vast majority of diagnostic categories. Our results related to length of stay suggest that looking at aggregate results hides a wealth of information. The most disparate outcomes were pregnancy related. The length of stay for new-born babies and neonates rose dramatically. In aggregate, this increase serves to mute decreases across other diagnoses. Also, the number of procedures fell within the MDCs for pregnancy and child birth and that for new-born babies and neonates. CONCLUSIONS: The Massachusetts Health Care Reform appears to have been effective at increasing insurance take-up rates. These increases may have come at the cost of lower private insurance coverage. The number of diagnoses per admission was increased by the policy across nearly all MDCs. Understanding the changes in length of stay as a result of the Massachusetts reform, and perhaps the Affordable Care Act, requires MDC-specific analysis. It appears that the most important distinction to make is to differentiate care related to new-born babies and neonates from that related to other diagnostic categories. PMID- 26037891 TI - Role of active surveillance and focal therapy in low- and intermediate-risk prostate cancers. AB - PURPOSE: Low-risk prostate cancer is found in about half of newly diagnosed men subjected to PSA screening. METHODS: To define the role of active surveillance and focal therapy in low- and intermediate-risk prostate cancers, an invited international panel of practicing physicians in the field of localized prostate cancer discussed the available literature in three consecutive meetings to come to a broad interpretation of the available data. RESULTS: The panel ("new prostate cancer management group," npm) agreed on the following observations. In most men with a low-volume Gleason 6 tumor, initial conservative management is appropriate. In men with a larger unifocal Gleason score 6 or 3 + 4 lesion, focal therapy, although still considered an investigational approach, appears to be a suitable option in early non-randomized comparison studies. Furthermore, in patients with multifocal small satellite Gleason 6 lesions in the presence of a larger index lesion, focal therapy of the index lesion is an option. For patients with high-grade, large-volume disease, or in young men with evidence of high volume multifocal low-grade prostate cancer, whole-gland treatment should be considered. CONCLUSION: Active surveillance is a preferred and safe option for low-risk prostate cancer. Focal therapy is still under investigation, but the available phase II data are promising. Clinical benefits must be shown in prospective trials. With improved imaging, focal therapy may be an option for patients not choosing active surveillance with low-risk disease, progression upon active surveillance or intermediate-risk cancers with a localizable lesion. PMID- 26037894 TI - Carbon-Atom Extrusion from Halobenzenes and Its Coupling with a Methylene Ligand to Form Acetylene. AB - Mechanistic aspects of an unusual gas-phase reaction of [LaCH2](+) with halobenzenes have been investigated using Fourier-transform ion cyclotron resonance (FTICR) mass spectrometry combined with density functional theory (DFT) calculations. In this thermal process a carbon-atom from the benzene ring, most likely the ipso-position, and the carbene ligand are coupled to form C2H2. PMID- 26037892 TI - Alpha-enolase is a potential prognostic marker in clear cell renal cell carcinoma. AB - Clear cell renal cell carcinoma (ccRCC) is an aggressive disease with unpredictable behaviour. Clinical parameters are not always accurate for prognosis prediction. The integration of molecular markers to prognostic models can significantly improve prognostic assessment and consequently patient management. We assessed the expression of alpha-enolase (ENO1) protein by immunohistochemistry in 360 patients with primary ccRCC and correlated its expression with multiple clinicopathological parameters including stage, grade, tumor size, disease-free and overall survival. Cox proportional hazard regression models adjusted for clinicopathological factors were used to test for a link between ENO1 expression and both disease-free and overall survival. We correlated ENO1 mRNA expression with overall survival in an independent set of 428 ccRCC cases from The Cancer Genome Atlas. ENO1 showed cytoplasmic, membranous and nuclear staining patterns. There is a statistically significant negative correlation between ENO1 expression, tumor stage, and grade. ENO1 expression also shows a statistically significant direct correlation with disease-free survival (p = 0.011) and overall survival (p = 0.030) in ccRCC. Patients with higher ENO1 expression had lower hazard ratio of recurrence, although this was not statistically significant (HR = 0.330, p = 0.060). These findings were validated at the mRNA level in an independent set of 428 ccRCC cases which also showed that low ENO1 expression is associated with significantly shorter overall survival. Down-regulation of ENO1 can be a predictor of poor prognosis in ccRCC, and it can be a potential prognostic marker. PMID- 26037895 TI - Nanofluidic Transport through Isolated Carbon Nanotube Channels: Advances, Controversies, and Challenges. AB - Owing to their simple chemistry and structure, controllable geometry, and a plethora of unusual yet exciting transport properties, carbon nanotubes (CNTs) have emerged as exceptional channels for fundamental nanofluidic studies, as well as building blocks for future fluidic devices that can outperform current technology in many applications. Leveraging the unique fluidic properties of CNTs in advanced systems requires a full understanding of their physical origin. Recent advancements in nanofabrication technology enable nanofluidic devices to be built with a single, nanometer-wide CNT as a fluidic pathway. These novel platforms with isolated CNT nanochannels offer distinct advantages for establishing quantitative structure-transport correlations in comparison with membranes containing many CNT pores. In addition, they are promising components for single-molecule sensors as well as for building nanotube-based circuits wherein fluidics and electronics can be coupled. With such advanced device architecture, molecular and ionic transport can be manipulated with vastly enhanced control for applications in sensing, separation, detection, and therapeutic delivery. Recent achievements in fabricating isolated-CNT nanofluidic platforms are highlighted, along with the most-significant findings each platform enables for water, ion, and molecular transport. The implications of these findings and remaining open questions on the exceptional fluidic properties of CNTs are also discussed. PMID- 26037896 TI - Clinical Trial Application in Europe: What Will Change with the New Regulation? AB - The European framework surrounding clinical trials on medicinal products for human use is going to change as demonstrated by the large debate at European institutional level. One of the major challenges is to overcome the lack of harmonisation of clinical trial procedures among countries. This aspect is gaining more and more importance, considering the increasing number of multicentre and multinational studies. In this work, the actual European rules governing the Clinical Trial Application have been analysed throughout the different steps including the registration of the trial in the European database; the preparation of documents to be submitted and their contents; the preparation of documents related to the information and consent process; the submission to competent bodies. Specific issues related to paediatric research and trials involving non EU/EEA countries have been addressed as well. Results reveal that the European legislation offers a well defined set of European rules covering different aspects of a Clinical Trial Application. However, these are not suitable to meet the challenges from multicentre and multinational clinical studies. A stronger set of rules, such as is available in a composite European Regulation has been adopted and is expected to harmonise practices and enable sponsors to carry out well conducted trials. But will the new regulation overcome the existing criticisms of Directive 2001/20/EC? PMID- 26037897 TI - Microfluidic droplet handling by bulk acoustic wave (BAW) acoustophoresis. AB - Droplet microfluidics has emerged as a prospering field for lab-on-a-chip devices, where droplets serve as liquid vessels e.g. for biochemical reagents. Key to the fluid processing in droplet format are the controlled droplet handling and movement on the microscale. Hence this paper proposes droplet handling by combining droplet microfluidics with bulk acoustic wave (BAW) acoustophoresis. BAW acoustophoresis has formerly focused on cell and particle handling, whereas here we determine the various abilities of this method for the field of droplet microfluidics. In silicon microdevices, water-in-oil droplets of 200 MUm size were generated for a set of unit operations including droplet fusion, focusing, sorting and medium exchange around 0.5-1 MHz acoustic frequency. Compared to existing droplet handling methods, the shown method is simple in fabrication, robust in operation and versatile to meet the needs of various droplet processing microfluidic devices. PMID- 26037898 TI - Evaluation of in vitro chemoresponse profiles in women with Type I and Type II epithelial ovarian cancers: An observational study ancillary analysis. AB - OBJECTIVE: Type I epithelial ovarian cancers (EOCs) are reported to be relatively chemoresistant. This study sought to compare pretreatment chemoresponse assays in Type I vs. Type II EOCs. STUDY DESIGN: 383 women with stage III-IV EOC enrolled in an observational study, with known chemoresponse assay results for 7 common therapeutic agents, were included. Type I EOCs were defined as grade 1 serous/endometrioid cancers and all clear cell/mucinous cancers. Type II EOCs were classified as grade 2-3 serous/endometrioid cancers and undifferentiated cancers. Chemotherapy assay responses were classified as sensitive (S), intermediately sensitive (I), or resistant (R). All patients were treated with platinum/taxane therapy following cytoreductive surgery. RESULTS: Thirty (7.8%) tumors were classified as Type I EOC, and 353 (92.2%) as Type II EOC. Type I patients were younger at the time of diagnosis (median age: 57 vs. 62 years, p=0.018) and had longer survival compared to Type II patients (mPFS: 25.8 vs. 16.4 months, HR=1.71, p=0.042). Eighty-six percent of Type I EOC specimens demonstrated a sensitive chemoresponse assay result to at least 1 agent; 35.7% were pan-S to all 7 agents. After adjusting for stage, debulking status, and type of EOC, multi-drug resistance was twice as likely in women with Type I EOC compared to Type II EOC (pan-R, 14.3% vs. 6.8% (p=0.268); pan-S, 35.7% vs. 51.2% (p=0.183)), but did not attain statistical significance. CONCLUSION(S): The majority of women with Type I EOC displayed assay sensitivity to at least one agent. Given the small sample size these findings need to be evaluated further. PMID- 26037899 TI - Investigating the disparities in cervical cancer screening among Namibian women. AB - OBJECTIVES: We examined the influence of knowledge and information, health care access and different socio-economic variables on women's decision to screen for cervical cancer using a nationally representative dataset. METHODS: We use hierarchical binary logit regression models to explore the determinants of screening for cervical cancer among women who reported hearing about cervical cancer. This enabled us to include the effect of unobserved heterogeneity at the cluster level that may affect screening behaviors. RESULTS: Among women who have heard about cervical cancer (N=6542), only 39% of them did undergo screening with a mean age of 33 years. The univariate results reveal that women who are educated, insured, can afford money needed for treatment and reported distance not a barrier to accessing healthcare were more likely to screen. Our multivariate results indicate that insured women (OR=1.89, p=0.001) and women who had access to information through education and contact with a health worker (OR=1.41, p=0.001) were more likely to undertake screening compared to uninsured women and those with no contact with a health personnel, after controlling for relevant variables. CONCLUSIONS: The adoption of a universal health insurance scheme that ensures equity in access to health care and extension of public health information targeting women in rural communities especially within the Caprivi region may be needed for a large scale increase in cervical cancer screening in Namibia. PMID- 26037900 TI - Predictive value of the Age-Adjusted Charlson Comorbidity Index on perioperative complications and survival in patients undergoing primary debulking surgery for advanced epithelial ovarian cancer. AB - OBJECTIVE: To assess the ability of the Age-Adjusted Charlson Comorbidity Index (ACCI) to predict perioperative complications and survival in patients undergoing primary debulking for advanced epithelial ovarian cancer (EOC). METHODS: Data were analyzed for all patients with stage IIIB-IV EOC who underwent primary cytoreduction from 1/2001-1/2010 at our institution. Patients were divided into 3 groups based on an ACCI of 0-1, 2-3, and >=4. Clinical and survival outcomes were assessed and compared. RESULTS: We identified 567 patients; 199 (35%) had an ACCI of 0-1, 271 (48%) had an ACCI of 2-3, and 97 (17%) had an ACCI of >=4. The ACCI was significantly associated with the rate of complete gross resection (0-1=44%, 2-3=32%, and >=4=32%; p=0.02), but was not associated with the rate of minor (47% vs 47% vs 43%, p=0.84) or major (18% vs 19% vs 16%, p=0.8) complications. The ACCI was also significantly associated with progression-free (PFS) and overall survival (OS). Median PFS for patients with an ACCI of 0-1, 2-3, and >=4 was 20.3, 16, and 15.4 months, respectively (p=0.02). Median OS for patients with an ACCI of 0-1, 2-3, and >=4 was 65.3, 49.9, and 42.3 months, respectively (p<0.001). On multivariate analysis, the ACCI remained a significant prognostic factor for both PFS (p=0.02) and OS (p<0.001). CONCLUSIONS: The ACCI was not associated with perioperative complications in patients undergoing primary cytoreduction for advanced EOC, but was a significant predictor of PFS and OS. Prospective clinical trials in ovarian cancer should consider stratifying for an age-comorbidity covariate. PMID- 26037901 TI - Impact of obesity on secondary cytoreductive surgery and overall survival in women with recurrent ovarian cancer. AB - OBJECTIVES: Obesity may negatively influence tumor biology in women with epithelial ovarian cancers. To date, only body mass indices (BMI) determined at the time of diagnosis have correlated with clinical outcome. We hypothesized that obesity negatively affects survival throughout the disease course, and sought to determine the prognostic role of BMI at the time of secondary cytoreductive surgery (SCS) for recurrent ovarian cancer. METHODS: We performed a review of patients undergoing SCS for recurrent epithelial ovarian or peritoneal cancer between 1997 and 2012. We retrospectively reviewed data which were analyzed using Fisher's exact test, Kaplan-Meier survival, and Cox regression analysis. BMI was defined according to the National Institutes of Health's categorizations. RESULTS: We identified 104 patients; 2 were underweight, 46 were of ideal body weight, 32 were overweight, and 24 were obese. Overall, 90 patients underwent optimal resection and BMI did not correlate with ability to perform optimal SCS (p=0.25). When examining BMI strata (underweight, ideal, overweight, and obese), we observed a statistical trend between increasing BMI and poor outcome; median survival was undetermined (greater than 50 months), 46 months, 38 months, and 34 months, respectively (p=0.04). In a multivariate analysis, BMI was an independent predictor of survival (p=0.02). CONCLUSIONS: In this cohort of women undergoing SCS for recurrent ovarian cancer, BMI significantly and independently correlated with overall survival. This observation suggests an effect of excess weight on tumor biology and/or response to treatment that is prevalent throughout the disease course. PMID- 26037902 TI - The diagnostic process of cervical cancer; areas of good practice, and windows of opportunity. AB - OBJECTIVE: Despite an extensive screening programme in The Netherlands, some cases of cervical cancer are still diagnosed in late stages of disease. The aim of the present study was to investigate which elements in the diagnostic process of cervical cancer may be improved. METHODS: This is a retrospective study of 120 patients with cervical cancer diagnosed between January 1st 2008 and June 1st 2010 at the University Medical Center Utrecht. Patient charts, referral information, and pathology results were analyzed. RESULTS: 39.1% of cancer cases were screen or interval detected; the other 60.9% of patients had not been screened, either due to non-attendance or because they fell outside the age range for screening. The final diagnosis of cervical cancer was established by biopsy in 77 (64.2%) and by excision of the cervical transformation zone in 35 (29.2%) of the patients. Fifteen (43%) of these excisions could have been avoided if biopsies would have been taken at the first examination, and had shown invasive cancer. CONCLUSIONS: Cervical cancer screening aims at early detection of precursor lesions to decrease the incidence of cancer. This in-depth analysis suggests that improvement of quality of care is to be expected from correct recognition of cervical cancer by physicians and adjustments of the screening programme to reach younger women and non-responders. PMID- 26037904 TI - [Clinical examination of the hip joint in adults]. AB - Complaints in the region of the hips and pelvis are often difficult to classify. This is due to the fact that pain projection and overlapping can occur; therefore, the complete region of the lumbar spine, pelvis and hips must be considered as a single entity in which alterations can result in radiation throughout the whole region. There are many different anatomical structures within the pelvic region so that the function of various muscle components can be impaired and cause pathological alterations to positional relationships of bony structures or even alterations to other soft tissues, such as ligaments, tendons and labra. In terms of differential diagnostics the groin must be seen as the weak point of the peritoneum and vascular system and taken into consideration. Therefore, a detailed and targeted medical history, functional testing and specific examinations and tests are necessary to narrow down the pathology in question and reach a definitive diagnosis. Orthopedic surgeons must know which conspicuous features can lead to which problems and which anatomical structures are likely to be affected by irritation. The results of the clinical examination are the basis for targeted imaging diagnostics and subsequent therapy. PMID- 26037903 TI - Tea, but not coffee consumption, is associated with components of arterial pressure. The Observation of Cardiovascular Risk Factors study in Luxembourg. AB - There is uncertainty regarding the impact of tea and coffee consumption on arterial blood pressure. The present study aimed to examine the association between blood pressure (BP) components, namely, systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure (PP), and tea or coffee consumption, taking into account simultaneous consumption. The study population was derived from a national cross-sectional stratified sample of 1352 individuals aged 18 to 69 years, recruited between November 2007 and January 2009 to participate in the Observation of Cardiovascular Risk Factors in Luxembourg study. We hypothesized that greater tea consumption would be independently associated with lower BP. Tea and coffee consumptions in deciliters per day were obtained from a semiquantitative food frequency questionnaire. Participants were classified into 3 groups: nonconsumers, <=3-dL/d consumers, and >3-dL/d consumers of each beverage separately. After exclusion of subjects taking antihypertensive medications, several general linear models were performed to investigate the independent relationship between tea/coffee consumption and BP components. Tea consumers (36.3%) were more likely to be younger women, nonsmokers, with better cardiometabolic profiles, and less frequent chronic pathologies, whereas the reverse was true for coffee consumers (88%). Greater tea consumption was associated with lower SBP and PP values, after adjustment for age, sex, education, lifestyle, and dietary confounding factors, including coffee drinking. No association between BP components and coffee consumption was observed. Daily consumption of 1 dL of tea was associated with a significant reduction of SBP by 0.6 mm Hg and PP by 0.5 mm Hg. Given the widespread consumption of tea and coffee throughout the world, together with the major cardiovascular disease risk, our findings have important implications for human health. PMID- 26037905 TI - Contact-dependent transfer of TiO2 nanoparticles between mammalian cells. AB - Cellular organelles have been shown to shuttle between cells in co-culture. We hereby show that titanium dioxide (TiO2) nanoparticles (NPs) can be transferred in such a manner, between cells in direct contact, along with endosomes and lysosomes. A co-culture system was employed for this purpose and the NP transfer was observed in mammalian cells including normal rat kidney (NRK) and HeLa cells. We found that the small GTPase Arf6 facilitates the intercellular transfer of smaller NPs and agglomerates. Spherical, anatase nano-TiO2 with sizes of 5 (Ti5) and 40 nm (Ti40) were used in this study. Humans are increasingly exposed to TiO2 NPs from external sources such as constituents of foods, cosmetics, and pharmaceuticals, or from internal sources represented by Ti-based implants, which release NPs upon abrasion. Exposure to 5 mg/l of Ti5 and Ti40 for 24 h did not affect cellular viability but modified their ability to communicate with surrounding cells. Altogether, our results have important implications for the design of nanomedicines, drug delivery and toxicity. PMID- 26037906 TI - Factors influencing the use of magnesium sulphate in pre-eclampsia/eclampsia management in health facilities in Northern Nigeria: a mixed methods study. AB - BACKGROUND: Eclampsia remains a major cause of perinatal and maternal morbidity and mortality worldwide. We examined facilitators and barriers to the use of magnesium sulphate (MgSO4) in the management of pre-eclampsia/eclampsia (PE/E) in health facilities in Bauchi and Sokoto States in Nigeria. METHODS: Data were collected from 80 health facilities using a cross-sectional, mixed method (quantitative and qualitative) design. We assessed health facility readiness to manage PE/E and use MgSO4 as the drug of choice, through provider interviews, in depth interviews with facility managers and an inventory of equipment and supply in facilities. Bivariate and qualitative data analyses were performed to isolate the principal enabling factors and barriers to the management of PE/E and use of MgSO4. RESULTS: The majority of health facility providers correctly mentioned MgSO4 as the drug of choice for the prevention and termination of convulsions in severe PE/E (65 %). Sixty-four percent of the health facilities had service registers available. About 45 % of providers had been trained on the use of MgSO4 for the management of PE/E. Regarding providers' practices, 45 % of respondents indicated that MgSO4 was used to prevent and treat convulsions in severe PE/E in their facilities. Barriers to management of PE/E included inadequate numbers of skilled providers, frequent shortages of MgSO4, lack of essential equipment and supplies, irregular supply of electricity and water, and non-availability of guidelines and clinical protocols at the health facilities. Technical support to providers was inadequate. CONCLUSION: The study revealed that a constellation of factors adversely affect the management of PE/E and especially the use of MgSO4 by service providers. Efforts to improve the management of PE/E in facilities should include integrated programs that substantially improve provider and facility readiness to manage PE/E for better maternal and newborn health outcomes in Northern Nigeria. PMID- 26037907 TI - Titanium versus absorbable tacks comparative study (TACS): a multicenter, non inferiority prospective evaluation during laparoscopic repair of ventral and incisional hernia: study protocol for randomized controlled trial. AB - BACKGROUND: Laparoscopic repair of ventral and incisional hernias has gained popularity since many studies have reported encouraging results in terms of outcomee and recurrence. Choice of mesh and fixation methods are considered crucial issues in preventing recurrences and complications. Lightweight meshes are considered the first choice due to their biomechanical properties and the ability to integrate into the abdominal wall. Titanium helicoidal tacks still represent the "gold standard" for mesh fixation, even if they have been suggested to be involved in the genesis of post-operative pain and complications. Recently, absorbable tacks have been introduced, under the hypothesis that there will be no need to maintain a permanent fixation device after mesh integration. Nevertheless, there is no evidence that absorbable tacks may guarantee the same results as titanium tacks in terms of strength of fixation and recurrence rates. The primary end point of the present trial is to test the hypothesis that absorbable tacks are non-inferior to titanium tacks in laparoscopic incisional and ventral hernia repair (LIVHR) by lightweight polypropylene mesh, in terms of recurrence rates at 3-year follow-up. Surgical complications, post-operative stay, comfort and pain are secondary end points to be assessed. METHODS/DESIGN: Two hundred and twenty patients with ventral hernia will be randomized into 2 groups: Group A (110) patients will be submitted to LIVHR by lightweight polypropylene mesh fixed by titanium tacks; Group B (110) patients will be submitted to LIVHR by lightweight polypropylene mesh fixed by absorbable tacks. DISCUSSION: A few retrospective studies have reported similar results when comparing absorbable versus non-absorbable tacks in terms of intraoperative and early post-operative outcomes. These studies have the pitfalls to be retrospective evaluation of small series of patients, and the reported results still need to be validated by larger series and prospective studies. The aim of the present trial is to investigate and test the non-inferiority of absorbable versus non-absorbable tacks in terms of hernia recurrence rates, in order to assess whether the use of absorbable tacks may achieve the same results as non absorbable tacks in mid-term and long-term settings. TRIAL REGISTRATION NUMBER: NCT02076984: 5 June 2014 (ClinicalTrials.gov). PMID- 26037908 TI - The mzqLibrary--An open source Java library supporting the HUPO-PSI quantitative proteomics standard. AB - The mzQuantML standard has been developed by the Proteomics Standards Initiative for capturing, archiving and exchanging quantitative proteomic data, derived from mass spectrometry. It is a rich XML-based format, capable of representing data about two-dimensional features from LC-MS data, and peptides, proteins or groups of proteins that have been quantified from multiple samples. In this article we report the development of an open source Java-based library of routines for mzQuantML, called the mzqLibrary, and associated software for visualising data called the mzqViewer. The mzqLibrary contains routines for mapping (peptide) identifications on quantified features, inference of protein (group)-level quantification values from peptide-level values, normalisation and basic statistics for differential expression. These routines can be accessed via the command line, via a Java programming interface access or a basic graphical user interface. The mzqLibrary also contains several file format converters, including import converters (to mzQuantML) from OpenMS, Progenesis LC-MS and MaxQuant, and exporters (from mzQuantML) to other standards or useful formats (mzTab, HTML, csv). The mzqViewer contains in-built routines for viewing the tables of data (about features, peptides or proteins), and connects to the R statistical library for more advanced plotting options. The mzqLibrary and mzqViewer packages are available from https://code.google.com/p/mzq-lib/. PMID- 26037909 TI - Neonatal outcome of singleton term breech deliveries in Norway from 1991 to 2011. AB - INTRODUCTION: The objective of this study was to examine the association between planned mode of delivery and neonatal outcomes in breech deliveries. MATERIAL AND METHODS: In this retrospective cohort study we studied singleton term breech deliveries in Norway from 1991 to 2011 (n = 30 861) using the Medical Birth Registry of Norway. We compared planned vaginal delivery with planned cesarean delivery across two time periods: from 1 January 1991 to 31 October 2000 (first period) and from 1 November 2000 to 31 December 2011 (second period). Intrapartum and neonatal deaths were validated against source data in medical records, autopsy reports, and other relevant documents. The main outcome measures were intrapartum and neonatal mortality within the first 28 days of life, 5-min Apgar scores <7 and <4, neonatal intensive care unit stays >=4 days, respiratory morbidity, and intracranial bleeding disorders. RESULTS: Rate of planned cesarean delivery increased from 34.4 to 51.3% over the period. Simultaneously, early neonatal mortality rate (0-6 days) declined (from 0.10% to 0.04%, p = 0.04). During the second period, 30.7% of term breech presentations were delivered vaginally. Eight deaths in the planned vaginal vs. four in the planned cesarean groups were observed (OR 2.11 95% CI 0.64-7.01). Neonatal morbidity outcomes were significantly worse in planned vaginal deliveries compared with planned cesarean deliveries in both periods. CONCLUSION: Overall intrapartum and neonatal mortality decreased during the entire period. Higher mortality in planned vaginal delivery relative to planned cesarean delivery in the second period was not statistically significant. However, neonatal morbidity was significantly higher in planned vaginal than planned cesarean deliveries in both periods. This warrants continuous surveillance of breech deliveries. PMID- 26037910 TI - Learning From Animal Models of Obsessive-Compulsive Disorder. AB - Obsessive-compulsive disorder (OCD) affects 2%-3% of the population worldwide and can cause significant distress and disability. Substantial challenges remain in the field of OCD research and therapeutics. Approved interventions alleviate symptoms only partially, with 30%-40% of patients being resistant to treatment. Although the etiology of OCD is still unknown, research evidence points toward the involvement of cortico-striato-thalamocortical circuitry. This review focuses on the most recent behavioral, genetics, and neurophysiologic findings from animal models of OCD. Based on evidence from these models and parallels with human studies, we discuss the circuit hyperactivity hypothesis for OCD, a potential circuitry dysfunction of action termination, and the involvement of candidate genes. Adding a more biologically valid framework to OCD will help researchers define and test new hypotheses and facilitate the development of targeted therapies based on disease-specific mechanisms. PMID- 26037914 TI - Sym004: Truly a New Level of Anti-EGFR Treatment? AB - Sym004 is a new antibody mixture to target EGFR in metastatic colorectal cancer. Preclinical data suggest efficacy in anti-EGFR-resistant tumors, but it remains unclear whether a higher toxicity is outweighed by those advantages. PMID- 26037911 TI - Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior. AB - BACKGROUND: Stress exposure is one of the greatest risk factors for psychiatric illnesses like major depressive disorder and posttraumatic stress disorder. However, not all individuals exposed to stress develop affective disorders. Stress resilience, the ability to experience stress without developing persistent psychopathology, varies from individual to individual. Enhancing stress resilience in at-risk populations could potentially protect against stress induced psychiatric disorders. Despite this fact, no resilience-enhancing pharmaceuticals have been identified. METHODS: Using a chronic social defeat (SD) stress model, learned helplessness (LH), and a chronic corticosterone (CORT) model in mice, we tested if ketamine could protect against depressive-like behavior. Mice were administered a single dose of saline or ketamine and then 1 week later were subjected to 2 weeks of SD, LH training, or 3 weeks of CORT. RESULTS: SD robustly and reliably induced depressive-like behavior in control mice. Mice treated with prophylactic ketamine were protected against the deleterious effects of SD in the forced swim test and in the dominant interaction test. We confirmed these effects in LH and the CORT model. In the LH model, latency to escape was increased following training, and this effect was prevented by ketamine. In the CORT model, a single dose of ketamine blocked stress-induced behavior in the forced swim test, novelty suppressed feeding paradigm, and the sucrose splash test. CONCLUSIONS: These data show that ketamine can induce persistent stress resilience and, therefore, may be useful in protecting against stress-induced disorders. PMID- 26037915 TI - Two Faces of SIVA. AB - In non-small cell lung cancer cells that contain a mutated KRAS gene, SIVA, a p53 target gene that is critical for apoptosis, is overexpressed in a p53-independent manner and promotes tumorigenesis through the stimulation of mTOR signaling. The ablation of Siva in conditional knockout mice results in an inhibition of tumor development that makes SIVA an interesting new candidate therapeutic target for the treatment of a carcinoma with few therapeutic options. PMID- 26037916 TI - Through a Clear Cell, Darkly: HIF2alpha/PLIN2-Maintained Fat Droplets Protect ccRCCs from ER Stress. AB - Qiu and colleagues describe how a structural component of lipid droplets is markedly induced in pseudohypoxic renal tumors, where it maintains endoplasmic reticulum (ER) homeostasis. This adaptation is indispensable in tumor cells-where growth demands and a fluctuating blood supply place unnatural stresses on ER function-and is therefore an attractive therapeutic target. PMID- 26037917 TI - Variable Temperature Infrared Spectroscopy Investigation of Benzoic Acid Interactions with Montmorillonite Clay Interlayer Water. AB - Molecular interactions between benzoic acid and cations and water contained in montmorillonite clay interlayer spaces are characterized by using variable temperature diffuse reflection infrared Fourier transform spectroscopy (VT DRIFTS). Using sample perturbation and difference spectroscopy, infrared spectral changes resulting from removal of interlayer water and associated changes in local benzoic acid environments are identified. Difference spectra features can be correlated with changes in specific molecular vibrations that are characteristic of benzoic acid molecular orientation. Results suggest that the carboxylic acid functionality of benzoic acid interacts with interlayer cations through a bridging water molecule and that this interaction is affected by the nature of the cation present in the clay interlayer space. PMID- 26037918 TI - Once a month, or the secret to raising the status of medical ethics. PMID- 26037919 TI - Gender differences in chronic HBsAg carriers in Italy: Evidence for the independent role of male sex in severity of liver disease. AB - It has been shown that sexual hormones have an opposite effect on hepatic fibrosis progression and hepatocellular carcinoma development. Sex differences among 2,762 chronic HBsAg carriers consecutively referring Italian hospitals in 2001 and in 2007 have been evaluated, particularly focusing on the role of gender on severity of liver disease. The overall sex ratio (males/females) was 2.6. Females were more likely born abroad and new diagnosis cases; but less likely HIV coinfected. No sex difference was observed regarding coinfection with other hepatitis viruses. The sex ratio linearly increased with increasing severity of liver disease, being 1.3 in normal ALT, 2.8 in chronic hepatitis, 3.6 in liver cirrhosis, and 6.8 in hepatocellular carcinoma. Adjustment by multiple logistic regression analysis for the confounding effect of age, alcohol intake, HDV infection, HCV infection, and BMI shows that male gender is an independent predictor of the likelihood of more severe liver disease (O.R. 1.7; C.I. 95% = 1.3-2.1). HBV-DNA levels resulted not associated with the outcome of chronic HBV infection. Despite some potential risk factors associated with liver disease, such as HBV genotype or mutations, not having been controlled for due to lack of availability, the observed sex disparity in the outcome of chronic HBV infection may support biological observation that HBV infection could be considered a sex hormone-responsive virus. PMID- 26037920 TI - Graphene-Based Materials in Regenerative Medicine. AB - Graphene possesses many unique properties such as two-dimensional planar structure, super conductivity, chemical and mechanical stability, large surface area, and good biocompatibility. In the past few years, graphene-based materials have risen as a shining star on the path of researchers seeking new materials for future regenerative medicine. Herein, the recent research advances made in graphene-based materials mostly utilizing the mechanical and electrical properties of graphene are described. The most exciting findings addressing the impact of graphene-based materials on regenerative medicine are highlighted, with particular emphasis on their applications including nerve, bone, cartilage, skeletal muscle, cardiac, skin, adipose tissue regeneration, and their effects on the induced pluripotent stem cells. Future perspectives and emerging challenges are also addressed in this Review article. PMID- 26037921 TI - A personalised mobile-based home monitoring system for heart failure: The SUPPORT HF Study. AB - BACKGROUND: Despite their potential for improving health outcomes, mobile-based home monitoring systems for heart failure have not yet been taken up widely by the patients and providers. OBJECTIVES: To design and iteratively move towards a personalised mobile health monitoring system for patients living with heart failure, according to their health care and usability needs. METHODS: We present an iterative approach to refining a remote health monitoring system that is based on interactions between different actors (patients, clinicians, social scientists and engineers) and supports the collection of quantitative and qualitative information about user experience and engagement. Patients were provided with tablet computers and commercially available sensing devices (a blood pressure monitor, a set of weighing scales, and a pulse oximeter) in order to complete physiological measurements at home, answer symptom-specific questionnaires, review their personal readings, view educational material on heart failure self management, and communicate with their health professionals. The system supported unobtrusive remote software upgrades via an application distribution channel and the activation or deactivation of functional components by health professionals during run-time operation. We report early findings from the application of this approach in a cohort of 26 heart failure patients (mean age 72+/-15 years), their caregivers and healthcare professionals who participated in the SUPPORT-HF (Seamless User-centred Proactive Provision Of Risk-stratified Treatment for Heart Failure) study over a one-year study period (mean patient follow-up duration=270+/-62 days). RESULTS: The approach employed in this study led to several system upgrades dealing in particular with patient requirements for better communication with the development team and personalised self-monitoring interfaces. Engagement with the system was constantly high throughout the study and during the last week of the evaluation, 23 patients (88%) used the system at least once and 16 patients (62%) at least three times. CONCLUSIONS: Designers of future mobile-based home monitoring systems for heart failure and other chronic conditions could leverage the described approach as a means of meeting patients' needs during system use within the home environment and facilitating successful uptake. PMID- 26037922 TI - The Werner Protein Acts as a Coactivator of Nuclear Factor kappaB (NF-kappaB) on HIV-1 and Interleukin-8 (IL-8) Promoters. AB - The Werner syndrome helicase (WRN) plays a role in maintaining genomic stability. The lack of WRN results in Werner syndrome, a rare autosomal recessive genetic disorder, which causes premature aging accompanied by many complications such as rare forms of cancer and type 2 diabetes. However, the underlying mechanisms of these complications, arising due to the loss of WRN, are poorly understood. In this study, we demonstrated the function of WRN in transcriptional regulation of NF-kappaB targets. WRN physically interacts via its RecQ C-terminal (RQC) domain with the Rel homology domain of both the RelA (p65) and the p50 subunits of NF kappaB. In the steady state, WRN is recruited to HIV-1 long terminal repeat (LTR), a typical NF-kappaB-responsive promoter, as well as the p50/p50 homodimer, in an NF-kappaB site-dependent manner. The amount of WRN on LTR increased along with the transactivating RelA/p50 heterodimer in response to TNF-alpha stimulation. Further, a knockdown of WRN reduced the transactivation of LTR in exogenous RelA/p50-introduced or TNF-alpha-stimulated cells. Additionally, knockdown of WRN reduced TNF-alpha stimulation-induced activation of the endogenous promoter of IL-8, an NF-kappaB-responsive gene, and WRN increased its association with the IL-8 promoter region together with RelA/p50 after TNF-alpha stimulation. In conjunction with studies that have shown NF-kappaB to be a key regulator of aging and inflammation, our results indicate a novel role of WRN in transcriptional regulation. Along with NF-kappaB, the loss of WRN is expected to result in incorrect regulation of downstream targets and leads to immune abnormalities and homeostatic disruption. PMID- 26037923 TI - Oxidation of Monolignols by Members of the Berberine Bridge Enzyme Family Suggests a Role in Plant Cell Wall Metabolism. AB - Plant genomes contain a large number of genes encoding for berberine bridge enzyme (BBE)-like enzymes. Despite the widespread occurrence and abundance of this protein family in the plant kingdom, the biochemical function remains largely unexplored. In this study, we have expressed two members of the BBE-like enzyme family from Arabidopsis thaliana in the host organism Komagataella pastoris. The two proteins, termed AtBBE-like 13 and AtBBE-like 15, were purified, and their catalytic properties were determined. In addition, AtBBE-like 15 was crystallized and structurally characterized by x-ray crystallography. Here, we show that the enzymes catalyze the oxidation of aromatic allylic alcohols, such as coumaryl, sinapyl, and coniferyl alcohol, to the corresponding aldehydes and that AtBBE-like 15 adopts the same fold as vanillyl alcohol oxidase as reported previously for berberine bridge enzyme and other FAD-dependent oxidoreductases. Further analysis of the substrate range identified coniferin, the glycosylated storage form of coniferyl alcohol, as a substrate of the enzymes, whereas other glycosylated monolignols were rather poor substrates. A detailed analysis of the motifs present in the active sites of the BBE-like enzymes in A. thaliana suggested that 14 out of 28 members of the family might catalyze similar reactions. Based on these findings, we propose a novel role of BBE-like enzymes in monolignol metabolism that was previously not recognized for this enzyme family. PMID- 26037924 TI - The Non-canonical Tetratricopeptide Repeat (TPR) Domain of Fluorescent (FLU) Mediates Complex Formation with Glutamyl-tRNA Reductase. AB - The tetratricopeptide repeat (TPR)-containing protein FLU is a negative regulator of chlorophyll biosynthesis in plants. It directly interacts through its TPR domain with glutamyl-tRNA reductase (GluTR), the rate-limiting enzyme in the formation of delta-aminolevulinic acid (ALA). Delineation of how FLU binds to GluTR is important for understanding the molecular basis for FLU-mediated repression of synthesis of ALA, the universal tetrapyrrole precursor. Here, we characterize the FLU-GluTR interaction by solving the crystal structures of the uncomplexed TPR domain of FLU (FLU(TPR)) at 1.45-A resolution and the complex of the dimeric domain of GluTR bound to FLU(TPR) at 2.4-A resolution. Three non canonical TPR motifs of each FLU(TPR) form a concave surface and clamp the helix bundle in the C-terminal dimeric domain of GluTR. We demonstrate that a 2:2 FLU(TPR)-GluTR complex is the functional unit for FLU-mediated GluTR regulation and suggest that the formation of the FLU-GluTR complex prevents glutamyl-tRNA, the GluTR substrate, from binding with this enzyme. These results also provide insights into the spatial regulation of ALA synthesis by the membrane-located FLU protein. PMID- 26037926 TI - Functional Interaction between the Scaffold Protein Kidins220/ARMS and Neuronal Voltage-Gated Na+ Channels. AB - Kidins220 (kinase D-interacting substrate of 220 kDa)/ankyrin repeat-rich membrane spanning (ARMS) acts as a signaling platform at the plasma membrane and is implicated in a multitude of neuronal functions, including the control of neuronal activity. Here, we used the Kidins220(-/-) mouse model to study the effects of Kidins220 ablation on neuronal excitability. Multielectrode array recordings showed reduced evoked spiking activity in Kidins220(-/-) hippocampal networks, which was compatible with the increased excitability of GABAergic neurons determined by current-clamp recordings. Spike waveform analysis further indicated an increased sodium conductance in this neuronal subpopulation. Kidins220 association with brain voltage-gated sodium channels was shown by co immunoprecipitation experiments and Na(+) current recordings in transfected HEK293 cells, which revealed dramatic alterations of kinetics and voltage dependence. Finally, an in silico interneuronal model incorporating the Kidins220 induced Na(+) current alterations reproduced the firing phenotype observed in Kidins220(-/-) neurons. These results identify Kidins220 as a novel modulator of Nav channel activity, broadening our understanding of the molecular mechanisms regulating network excitability. PMID- 26037925 TI - Biological Relevance and Therapeutic Potential of the Hypusine Modification System. AB - Hypusine modification of the eukaryotic initiation factor 5A (eIF-5A) is emerging as a crucial regulator in cancer, infections, and inflammation. Although its contribution in translational regulation of proline repeat-rich proteins has been sufficiently demonstrated, its biological role in higher eukaryotes remains poorly understood. To establish the hypusine modification system as a novel platform for therapeutic strategies, we aimed to investigate its functional relevance in mammals by generating and using a range of new knock-out mouse models for the hypusine-modifying enzymes deoxyhypusine synthase and deoxyhypusine hydroxylase as well as for the cancer-related isoform eIF-5A2. We discovered that homozygous depletion of deoxyhypusine synthase and/or deoxyhypusine hydroxylase causes lethality in adult mice with different penetrance compared with haploinsufficiency. Network-based bioinformatic analysis of proline repeat-rich proteins, which are putative eIF-5A targets, revealed that these proteins are organized in highly connected protein-protein interaction networks. Hypusine-dependent translational control of essential proteins (hubs) and protein complexes inside these networks might explain the lethal phenotype observed after deletion of hypusine-modifying enzymes. Remarkably, our results also demonstrate that the cancer-associated isoform eIF-5A2 is dispensable for normal development and viability. Together, our results provide the first genetic evidence that the hypusine modification in eIF-5A is crucial for homeostasis in mammals. Moreover, these findings highlight functional diversity of the hypusine system compared with lower eukaryotes and indicate eIF-5A2 as a valuable and safe target for therapeutic intervention in cancer. PMID- 26037929 TI - Reductive Catenation of Phosphine Antimony Complexes. AB - Reactions of triarylphosphines with fluoroantimony(III) triflates give phosphine antimony(III) complexes, which undergo spontaneous reductive elimination of fluorophosphonium cations. The resulting phosphine antimony(I) complexes catenate to give the first examples of cationic antimony bicyclic compounds, [(R3P)4Sb6](4+), featuring a bicyclo[3.1.0]hexastibine framework stabilized by four phosphine ligands. The unprecedented 14-electron redox process illustrates the generality of the reductive catenation method. PMID- 26037928 TI - Lipopolysaccharide Primes the NALP3 Inflammasome by Inhibiting Its Ubiquitination and Degradation Mediated by the SCFFBXL2 E3 Ligase. AB - The inflammasome is a multiprotein complex that augments the proinflammatory response by increasing the generation and cellular release of key cytokines. Specifically, the NALP3 inflammasome requires two-step signaling, priming and activation, to be functional to release the proinflammatory cytokines IL-1beta and IL-18. The priming process, through unknown mechanisms, increases the protein levels of NALP3 and pro-IL-1beta in cells. Here we show that LPS increases the NALP3 protein lifespan without significantly altering steady-state mRNA in human cells. LPS exposure reduces the ubiquitin-mediated proteasomal processing of NALP3 by inducing levels of an E3 ligase component, FBXO3, which targets FBXL2. The latter is an endogenous mediator of NALP3 degradation. FBXL2 recognizes Trp 73 within NALP3 for interaction and targets Lys-689 within NALP3 for ubiquitin ligation and degradation. A unique small molecule inhibitor of FBXO3 restores FBXL2 levels, resulting in decreased NALP3 protein levels in cells and, thereby, reducing the release of IL-1beta and IL-18 in human inflammatory cells after NALP3 activation. Our findings uncover NALP3 as a molecular target for FBXL2 and suggest that therapeutic targeting of the inflammasome may serve as a platform for preclinical intervention. PMID- 26037930 TI - Solitary lesion on the glans penis. PMID- 26037927 TI - Inhibition of Caspase-1 Activation in Endothelial Cells Improves Angiogenesis: A NOVEL THERAPEUTIC POTENTIAL FOR ISCHEMIA. AB - Deficient angiogenesis may contribute to worsen the prognosis of myocardial ischemia, peripheral arterial disease, ischemic stroke, etc. Dyslipidemic and inflammatory environments attenuate endothelial cell (EC) proliferation and angiogenesis, worsening the prognosis of ischemia. Under these dyslipidemic and inflammatory environments, EC-caspase-1 becomes activated and induces inflammatory cell death that is defined as pyroptosis. However, the underlying mechanism that correlates caspase-1 activation with angiogenic impairment and the prognosis of ischemia remains poorly defined. By using flow cytometric analysis, enzyme and receptor inhibitors, and hind limb ischemia model in caspase-1 knock out (KO) mice, we examined our novel hypothesis, i.e. inhibition of caspase-1 in ECs under dyslipidemic and inflammatory environments attenuates EC pyroptosis, improves EC survival mediated by vascular endothelial growth factor receptor 2 (VEGFR-2), angiogenesis, and the prognosis of ischemia. We have made the following findings. Proatherogenic lipids induce higher caspase-1 activation in larger sizes of human aortic endothelial cells (HAECs) than in smaller sizes of HAECs. Proatherogenic lipids increase pyroptosis significantly more in smaller sizes of HAECs than in larger sizes of the cells. VEGFR-2 inhibition increases caspase-1 activation in HAECs induced by lysophosphatidylcholine treatment. Caspase-1 activation inhibits VEGFR-2 expression. Caspase-1 inhibition improves the tube formation of lysophosphatidylcholine-treated HAECs. Finally, caspase-1 depletion improves angiogenesis and blood flow in mouse hind limb ischemic tissues. Our results have demonstrated for the first time that inhibition of proatherogenic caspase-1 activation in ECs improves angiogenesis and the prognosis of ischemia. PMID- 26037931 TI - Is end-stage lateral osteoarthritic knee always valgus? Mechanical alignment analysis and radiographic severity assessment. AB - BACKGROUND: We hypothesized that not all persons with end-stage lateral osteoarthritis (OA) have valgus malalignment and that full extension radiographs may underreport radiographic disease severity. The purpose of this study was to examine the demographic and radiographic features of end-stage lateral compartment knee OA. MATERIALS AND METHODS: We retrospectively studied 133 knees in 113 patients who had undergone total knee arthroplasty between June 2008 and August 2010. All patients had predominantly lateral idiopathic compartment OA according to the compartment-specific Kellgren-Lawrence grade (KLG). The mechanical axis angle (MAA), compartment-specific KLG and joint space narrowing (JSN) of the tibiofemoral joint at extension and 30 degrees of knee flexion, tibia vara angle, tibial slope angle, body mass index, age, and sex were surveyed. RESULTS: End-stage lateral compartment knee OA has varus (37.6 %), neutral (22.6 %), and valgus (39.8 %) MAA on both-leg standing hip-knee-ankle radiographs. KLGs at 30 degrees of knee flexion (fKLG) were grades 3 and 4 in all patients. However, for KLGs at full extension (eKLG), 54 % of all patients had grades 3 and 4. The others (46 %) showed grades 1 and 2. We observed significant differences in lateral compartment eKLG/eJSN (2.3/2.3 mm in varus, 2.5/1.9 mm in neutral, 2.9/1.6 mm in valgus, p = 0.01 and 0.03, respectively), tibia vara angle (4.9 degrees in varus, 4.1 degrees in neutral, 3.0 degrees in valgus, p < 0.01), and medial compartment eKLG/eJSN (2.1/3.1 mm in varus, 2.0/3.4 mm in neutral, 1.8/4.3 mm in valgus, p < 0.01 and 0.01, respectively) between MAA groups, except for the tibial slope angle (9.7 degrees in varus, 10.1 degrees in neutral, 9.8 degrees in valgus, p = 0.31). CONCLUSION: Varus alignment was paradoxically shown in approximately one-third of those with end-stage lateral knee OA on both-leg standing hip-knee-ankle radiographs. Films taken in full extension underreported the degree of OA radiographic severity. LEVEL OF EVIDENCE: Level IV, observational study. PMID- 26037932 TI - Zanamivir Amidoxime- and N-Hydroxyguanidine-Based Prodrug Approaches to Tackle Poor Oral Bioavailability. AB - The neuraminidase (NA) inhibitor zanamivir (1) is potently active against a broad panel of influenza A and B strains, including mutant viruses, but suffers from pharmacokinetic (PK) shortcomings. Here, distinct prodrug approaches are described that aimed at overcoming zanamivir's lack of oral bioavailability. Lowering the high basicity of the 4-guanidino group in zanamivir and of a bioisosteric 4-acetamidine analog (5) by N-hydroxylation was deemed to be a plausible tactic. The carboxylic acid and glycerol side chain were also masked with different ester groups. The bioisosteric amidine 5 turned out to be potently active against a panel of H1N1 (IC50 = 2-10 nM) and H3N2 (IC50 = 5-10 nM) influenza A viruses (NA inhibition assay). In vitro PK studies showed that all prodrugs were highly soluble, exhibited low protein binding, and were bioactivated by N-reduction to the respective guanidines and amidines. The most promising prodrug candidates, amidoxime ester 7 and N-hydroxyguanidine ester 8, were subjected to in vivo bioavailability studies. Unfortunately, both prodrugs were not orally bioavailable to a convincing degree (F <= 3.7%, rats). This finding questions the general feasibility of improving the oral bioavailability of 1 by lipophilicity-increasing prodrug strategies, and suggests that intrinsic structural features represent key hurdles. PMID- 26037933 TI - Foreword: SI printing pharmaceuticals. PMID- 26037934 TI - Combined use of bile acids and aminoacids to improve permeation properties of acyclovir. AB - The aim of this work was to develop a topical formulation with improved permeation properties of acyclovir. Ursodeoxycholic (UDC) and dehydrocholic (DHC) acids were tested as potential enhancers, alone or in combination with different aminoacids. Equimolar binary and ternary systems of acyclovir with cholic acids and basic, hydrophilic or hydrophobic aminoacids were prepared by co-grinding in a high vibrational micromill. Differential scanning calorimetry (DSC) was used to characterize the solid state of these systems, while their permeation properties were evaluated in vitro through a lipophilic artificial membrane. UDC was more than 2 times more effective than DHC in improving drug AUC and permeation rate. As for the ternary systems drug-UDC-aminoacid, only the combined use of l-lysine with UDC acid produced an evident synergistic effect in enhancing drug permeation properties, enabling an almost 3 and 8 times AUC increase compared to the binary UDC system or the pure drug, respectively. The best systems were selected for the development of topical cream formulations, adequately characterized and tested for in vitro drug permeation properties and stability on storage. The better performance revealed by acyclovir-UDC-l-lysine was mainly attributed to the formation of a more permeable activated system induced by the multicomponent co grinding process. PMID- 26037935 TI - Detection of chromosomal translocations in formalin-fixed paraffin-embedded (FFPE) leukemic specimens by digital expression profiling. AB - INTRODUCTION: Detection of chromosomal translocations in formalin-fixed paraffin embedded (FFPE) leukemic samples is important for confirmation of histopathological findings, classification, prognostication, and therapeutic decisions. Herein, we aim to determine whether digital expression profiling could detect chromosomal translocations in FFPE leukemic samples identified by RT-PCR, FISH, and/or karyotyping. METHODS: RNA was extracted from 28 FFPE bone marrow specimens from 19 patients diagnosed with leukemia. Eight patients were translocation t(9;22) positive, three inv(16)/t(16/16) positive, five translocation t(15;17) positive, and one translocation t(8;21) positive. Two patients (four specimens) were normal. The extracted RNA was hybridized to DNA reporter probes overnight at 65 degrees C, followed by purification of the labeled translocations. Six hundred fields of view were counted to enumerate the number of translocations. RESULTS: Digital expression profiling had 100% concordance with RT-PCR, FISH, or karyotyping analysis in the two normal individuals, eight translocation t(9;22) samples, five translocation t(15;17) samples, and one translocation t(8;21) sample. None of the inv(16) positive samples were detected. Digital expression profiling detected translocations with 0.014 p190 allelic burden. CONCLUSION: Digital expression profiling can be used to measure translocation t(9;22), t(15;17), and t(8;21) in FFPE samples and is useful when a confirmatory test from a FFPE sample is necessary. PMID- 26037936 TI - Endovascular coiling vs. surgical clipping for unruptured intracranial aneurysm: A meta-analysis. AB - BACKGROUND: With increasing use of high-resolution imaging of brain, unruptured aneurysms are more and more frequently detected. With the advances in treatment techniques, an increasing number of aneurysms are now occluded using endovascular coiling instead of conventional surgical clipping. However, the better modality for unruptured intracranial aneurysm has been poorly understood. OBJECTIVE: The objective of this meta-analysis was to compare the outcomes between endovascular coiling and surgical clipping among patients with unruptured intracranial aneurysms. METHODS: PubMed, Embase, Web of Science, CENTRAL, and SIGLE were electronically searched from January 1, 1990 to March 13, 2012 with no language restriction for randomized or nonrandomized clinical controlled trials. Article screening and data extraction were conducted in duplicate. Results were statistically pooled through Review Manager 5 and StatsDirect 2.7.9. RESULTS: Seven studies met our inclusion criteria. The pooled risk ratios (coiling vs. clipping) were 0.59 (95% CI = 0.23-1.54) for death; 0.37 (95% CI = 0.10-1.41) for bleeding; 0.78 (95% CI = 0.38-1.58) for cerebral ischemia; 0.87 (95% CI = 0.70 1.08) for occlusion of aneurysm; 0.53 (95% CI = 0.18-1.52) for independence in daily activities. The pooled rates of death, bleeding, ischemia, occlusion of aneurysm, and mRS no less than 3 were 1% (95% CI = 0-2%), 2% (95% CI = 0-5%), 8% (95% CI = 4-13%), 82% (95% CI = 64-95%), and 5% (95% CI = 1-10%) for endovascular coiling, respectively, and 1% (95% CI = 0-2%), 6% (95% CI = 3-10%), 9% (95% CI = 5-15%), 95% (95% CI = 90-98%), and 8% (95% CI = 3-14%) for surgical clipping, respectively. We failed to evaluate quality of life and cognitive outcome due to insufficient data. Both meta-regression and sensitivity analysis showed consistent results. Furthermore, Begg's test and Egger's test failed to detect publication bias. CONCLUSION: We suggest that endovascular coiling and surgical clipping bear similar risk ratios of death, bleeding, cerebral ischemia, occlusion of aneurysm, and independence in daily activities and encourage further studies on quality of life and cognitive outcome. However, albeit the results in this meta-analysis are robust, due to great clinical heterogeneity and low quality of studies, the results in this meta-analysis should be interpreted with caution. PMID- 26037937 TI - Correlation between pedicle size and the rate of pedicle screw misplacement in the treatment of thoracic fractures: Can we predict how difficult the task will be? AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To correlate the incidence of pedicle-screw (PS) misplacement with the dimensions of the pedicles in the treatment of thoracic spine fractures. SUMMARY OF BACKGROUND DATA: The technical challenge of internal fixation with PS in the thoracic spine has been well documented in the literature. However, there are no publications that document the correlation between the pedicle dimensions of the thoracic vertebrae in the preoperative computed tomography scans (CT) and the rate of PS misplacement. METHODS: All patients who had PSs inserted between the T1 and T12 vertebrae during a 24-month period were included in this study. PS position was assessed on high quality CT scans by two independent observers and classified in 2 categories: correct or misplaced. The transverse diameter, craniocaudal diameter and cross-sectional area of the pedicles from T1 to T12 were measured in the pre operative CT. RESULTS: During the period of this study 36 patients underwent internal fixation with 218 PS. Of the 218 screws, 184 (84.5%) were correct and 34 (15.5%) were misplaced. Misplacement rate was 33% for pedicles with a transverse diameter less than 5 mm, 10.7% for those with a transverse diameter between 5 and 7 mm and 0% for those with a transverse diameter larger than 7 mm. There was a statistically significant difference in the rate of PS misplacement in pedicles with transverse diameter smaller than 5 mm compared with the others. Also, those with transverse diameter between 5.1 and 7 mm compared with those bigger than 7 mm in diameter. The rate of PS misplacement was higher between T3 and T9 (p < 0.05), which in turn correlated with pedicle transverse diameter. CONCLUSION: The rate of PS misplacement in the mid thoracic spine (T4-T9) is high and correlates with pedicle transverse diameter. PMID- 26037938 TI - Recurrent, symptomatic, late-onset, contralateral subdural effusion following decompressive craniectomy treated by cranial strapping. AB - Subdural effusions following decompressive craniotomy for trauma are usually benign, ipsilateral to the craniotomy and resolve spontaneously. Far less common and more dangerous are contralateral subdural effusions causing external cerebral herniation. We report a case of recurrent contralateral effusion and highlight the management dilemmas. Arachnoid tear is probably the cause of these collections. Contralateral subdural effusions should be suspected in patients who have delayed neurological deterioration after an initial improvement particularly in the setting of increased "flap bulge" though they may also be found in patients who remain moribund after initial surgery. There are no clear-cut guidelines on their management due to their rarity. A variety of options like subduro-peritoneal shunt and drainage with simultaneous cranioplasty may be tried. In situations where resources or patient compliance is an issue, tapping the effusion followed by cranial strapping may be tried as was done in our case. PMID- 26037939 TI - Transitory spinal accessory nerve injury following post-fossa surgery for Chiari malformation. AB - We report the case of a young patient with a transient transitory spinal accessory injury after foramen magnum decompression for Chiari malformation. The pathophysiology and the possible mechanisms of injury are highlighted and discussed. Some tips to avoid this potentially severe iatrogenic complication are provided. PMID- 26037940 TI - New oral anticoagulant and antiplatelet agents for neurosurgeons. AB - Until recently, warfarin, clopidogrel and aspirin have provided the mainstay for prevention of thrombotic disease in cardiac patients. However, new classes of drugs have recently emerged that promise better clinical outcomes and lower risks. Use of such agents has increased, but increased risk and severity of intra cranial haemorrhage (ICH) still remain. These cases of intra-cranial bleeds present as emergencies to neurosurgical units. It is of paramount importance that neurosurgical practitioners are aware of those new drugs, useful monitoring tests and available emergency reversal options in case the patient needs emergency intervention. In this review we survey newly available agents in the U.K. at the time of publication. We look at the data provided by the manufacturers, related publications and international guidelines for their use and reversal. New anticoagulants offer a lower incidence of ICH compared with warfarin. Advanced and accurate monitoring tests are emerging, as are prospective data on reversal of anticoagulation in bleeding. Some standard coagulation tests may be of use, whilst reversal agents are available and being evaluated. The trial data shows that new antiplatelet agents have similar or increased incidence and severity of intra-cranial ICH compared with clopidogrel. There is currently limited data on monitoring or reversal. We suggest they may be managed similarly to clopidogrel by using platelet reactivity assays, optimising platelet count and using platelet transfusion with adjunctive agents. PMID- 26037942 TI - Inhibition of BRAF and MEK in BRAF-mutant melanoma. PMID- 26037941 TI - Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. AB - BACKGROUND: Previously, a study of ours showed that the combination of dabrafenib and trametinib improves progression-free survival compared with dabrafenib and placebo in patients with BRAF Val600Lys/Glu mutation-positive metastatic melanoma. The study was continued to assess the secondary endpoint of overall survival, which we report in this Article. METHODS: We did this double-blind phase 3 study at 113 sites in 14 countries. We enrolled previously untreated patients with BRAF Val600Glu or Val600Lys mutation-positive unresectable stage IIIC or stage IV melanoma. Participants were computer-randomised (1:1) to receive a combination of dabrafenib (150 mg orally twice daily) and trametinib (2 mg orally once daily), or dabrafenib and placebo. The primary endpoint was progression-free survival and overall survival was a secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT01584648. FINDINGS: Between May 4, 2012, and Nov 30, 2012, we screened 947 patients for eligibility, of whom 423 were randomly assigned to receive dabrafenib and trametinib (n=211) or dabrafenib only (n=212). The final data cutoff was Jan 12, 2015, at which time 222 patients had died. Median overall survival was 25.1 months (95% CI 19.2-not reached) in the dabrafenib and trametinib group versus 18.7 months (15.2-23.7) in the dabrafenib only group (hazard ratio [HR] 0.71, 95% CI 0.55-0.92; p=0.0107). Overall survival was 74% at 1 year and 51% at 2 years in the dabrafenib and trametinib group versus 68% and 42%, respectively, in the dabrafenib only group. Based on 301 events, median progression-free survival was 11.0 months (95% CI 8.0 13.9) in the dabrafenib and trametinib group and 8.8 months (5.9-9.3) in the dabrafenib only group (HR 0.67, 95% CI 0.53-0.84; p=0.0004; unadjusted for multiple testing). Treatment-related adverse events occurred in 181 (87%) of 209 patients in the dabrafenib and trametinib group and 189 (90%) of 211 patients in the dabrafenib only group; the most common was pyrexia (108 patients, 52%) in the dabrafenib and trametinib group, and hyperkeratosis (70 patients, 33%) in the dabrafenib only group. Grade 3 or 4 adverse events occurred in 67 (32%) patients in the dabrafenib and trametinib group and 66 (31%) patients in the dabrafenib only group. INTERPRETATION: The improvement in overall survival establishes the combination of dabrafenib and trametinib as the standard targeted treatment for BRAF Val600 mutation-positive melanoma. Studies assessing dabrafenib and trametinib in combination with immunotherapies are ongoing. FUNDING: GlaxoSmithKline. PMID- 26037943 TI - D-amphetamine improves attention performance in adolescent Wistar, but not in SHR rats, in a two-choice visual discrimination task. AB - The validity of spontaneous hypertensive rat (SHR) as a model of attention deficit hyperactivity disorder (ADHD) has been explored by comparing SHR with Wistar rats in a test of attention, the two-choice visual discrimination task (2 CVDT). Animals were 4-5 weeks old during the training phase of the experiment and 6-7 weeks old during the testing phase in which they were tested with D amphetamine, a stimulant drug used for the treatment of ADHD. As compared to Wistar, SHR showed a slightly better attention performance, a slightly lower impulsivity level, and a lower general activity during the training phase, but these differences disappeared or lessened thereafter, during the testing phase. D amphetamine (0.5, 1 mg/kg) improved attention performance in Wistar, but not in SHR, and did not modify impulsivity and activity in the two strains. In conclusion, the present study did not demonstrate that SHR represents a valid model of ADHD, since it did not show face validity regarding the behavioral symptoms of ADHD and predictive validity regarding the effect of a compound used for the treatment of ADHD. On the other hand, this study showed that the 2-CVDT may represent a suitable tool for evaluating in adolescent Wistar rats the effect on attention of compounds intended for the treatment of ADHD. PMID- 26037944 TI - Is there a role for immune-to-brain communication in schizophrenia? AB - Schizophrenia is characterised by hallucinations, delusions, depression-like so called negative symptoms, cognitive dysfunction, impaired neurodevelopment and neurodegeneration. Epidemiological and genetic studies strongly indicate a role of inflammation and immunity in the pathogenesis of symptoms of schizophrenia. Evidence accrued over the last two decades has demonstrated that there are a number of pathways through which systemic inflammation can exert profound influence on the brain leading to changes in mood, cognition and behaviour. The peripheral immune system-to-brain communication pathways have been studied extensively in the context of depression where inflammatory cytokines are thought to play a key role. In this review, we highlight novel evidence suggesting an important role of peripheral immune-to-brain communication pathways in schizophrenia. We discuss recent population-based longitudinal studies that report an association between elevated levels of circulating inflammatory cytokines and subsequent risk of psychosis. We discuss emerging evidence indicating potentially important role of blood-brain barrier endothelial cells in peripheral immune-to-brain communication, which may be also relevant for schizophrenia. Drawing on clinical and preclinical studies, we discuss whether immune-mediated mechanisms could help to explain some of the clinical and pathophysiological features of schizophrenia. We discuss implication of these findings for approaches to diagnosis, treatment and research in future. Finally, pointing towards links with early-life adversity, we consider whether persistent low-grade activation of the innate immune response, as a result of impaired foetal or childhood development, could be a common mechanism underlying the high comorbidity between certain neuropsychiatric and physical illnesses, such as schizophrenia, depression, heart disease and type-two diabetes. PMID- 26037946 TI - Anti-hyperalgesic effects of imidazoline I2 receptor ligands in a rat model of inflammatory pain: interactions with oxycodone. AB - RATIONALE: Emerging preclinical evidence suggests that imidazoline I2 receptor ligands may be effective analgesics. Quantitative analysis of the combined I2 receptor ligands and opioids is needed for the justification of combination therapy. OBJECTIVE: This study systematically examined the anti-hyperalgesic and response rate-suppressing effects of selective I2 receptor ligands (2-BFI and phenyzoline) alone and in combination with oxycodone in rats. METHODS: Von Frey filament test was used to examine the anti-hyperalgesic effects of drugs in a rat model of complete Freund's adjuvant (CFA)-induced inflammatory pain. Schedule controlled responding was used to assess the rate-altering effects of study drugs. Duration of actions of individual drugs (2-BFI, phenyzoline, and oxycodone) alone or in combination was studied. Dose-addition analysis was employed to assess the anti-hyperalgesic interactions between drugs. RESULTS: Oxycodone (0.1-3.2 mg/kg, i.p.), 2-BFI (1-17.8 mg/kg, i.p.), and phenyzoline (17.8-56 mg/kg, i.p.) all dose-dependently produced significant antinociceptive effects. When studied as combinations, 2-BFI and oxycodone produced additive interactions while phenyzoline and oxycodone produced supra-additive interactions under all fixed ratios. The same drug combinations did not alter or significantly reduced the operant responding depending on the ratios of the drug combinations. CONCLUSIONS: Quantitative analysis of the anti-hyperalgesic effects of I2 receptor ligands strongly supports the therapeutic potential of I2 receptor ligands against inflammatory pain. In addition, the data reveal that phenyzoline is superior to the prototypic I2 receptor ligand 2-BFI for the management of pain and warrants further consideration as a novel analgesic. PMID- 26037947 TI - Movement asymmetry in working polo horses. AB - REASONS FOR PERFORMING STUDY: The high, repetitive demands imposed on polo horses in training and competition may predispose them to musculoskeletal injuries and lameness. OBJECTIVES: To quantify movement symmetry and lameness in a population of polo horses, and to investigate the existence of a relationship with age. STUDY DESIGN: Convenience sampled cross-sectional study. METHODS: Sixty polo horses were equipped with inertial measurement units (IMUs) attached to the poll, and between the tubera sacrale. Six movement symmetry measures were calculated for vertical head and pelvic displacement during in-hand trot and compared with values for perfect symmetry, compared between left and right limb lame horses, and compared with published thresholds for lameness. Regression lines were calculated as a function of age of horse. RESULTS: Based on 2 different sets of published asymmetry thresholds 52-53% of the horses were quantified with head movement asymmetry and 27-50% with pelvic movement asymmetry resulting in 60-67% of horses being classified with movement asymmetry outside published guideline values for either the forelimbs, hindlimbs or both. Neither forelimb nor hindlimb asymmetries were preferentially left or right sided, with directional asymmetry values across all horses not different from perfect symmetry and absolute values not different between left and right lame horses (P values >0.6 for all forelimb symmetry measures and >0.2 for all hindlimb symmetry measures). None of the symmetry parameters increased or decreased significantly with age. CONCLUSIONS: A large proportion of polo horses show gait asymmetries consistent with previously defined thresholds for lameness. These do not appear to be lateralised or associated with age. PMID- 26037945 TI - Behavioral impairments and serotonin reductions in rats after chronic L-dopa. AB - RATIONALE: L-dopa, the main therapeutic for Parkinson's disease (PD), has been shown to increase brain dopamine concentrations that are necessary for proper motor control; however, PD patients experience non-motor symptoms that are not improved or could be exacerbated by L-dopa. OBJECTIVES: The purpose of this study is to determine the effects of L-dopa treatment on cognitive and affective behavioral responses of rats, as well as their corresponding monoamine brain concentrations. METHODS: Rats were treated with L-dopa (6 mg/kg; twice daily) for 10 consecutive days. Sodium ascorbate (400 mg/kg) was co-administered with L-dopa to investigate the effects of antioxidant co-treatment on behavior and monoamine concentrations. Rats underwent cognitive and affective behavioral testing. Monoamine concentrations of several brain regions were analyzed. RESULTS: L-dopa treatment resulted in significant impairment in the performance in the Barnes maze and improvement in conditioned fear stress paradigms. Specifically, L-dopa caused an increase in latency to find the goal box during Barnes maze testing and increased freezing behavior in context-induced conditioned fear testing. Furthermore, the rats in the conditioned fear stress experiments showed corresponding depletions in serotonin (5-HT) and its metabolite, 5-HIAA, in the dorsal raphe nucleus (DRN) and the mPFC. The behavioral impairments as well as monoamine depletions were blocked by ascorbate co-treatment. CONCLUSIONS: Chronic L-dopa may contribute to non-motor symptoms related to spatial memory and fear. These effects may be attributable to a dysregulation of brain 5-HT caused by L dopa treatment. The results presented here provide further rationale for investigating adjunctive therapeutics to L-dopa for PD, such as antioxidants. PMID- 26037949 TI - The role of the small airways in the pathophysiology of asthma and chronic obstructive pulmonary disease. AB - Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD), represent a major social and economic burden for worldwide health systems. During recent years, increasing attention has been directed to the role of small airways in respiratory diseases, and their exact contribution to the pathophysiology of asthma and COPD continues to be clarified. Indeed, it has been suggested that small airways play a distinct role in specific disease phenotypes. Besides providing information on small airways structure and diagnostic procedures, this review therefore aims to present updated and evidence-based findings on the role of small airways in the pathophysiology of asthma and COPD. Most of the available information derives from either pathological studies or review articles and there are few data on the natural history of small airways disease in the onset or progression of asthma and COPD. Comparisons between studies on the role of small airways are hard to draw because both asthma and COPD are highly heterogeneous conditions. Most studies have been performed in small population samples, and different techniques to characterize aspects of small airways function have been employed in order to assess inflammation and remodelling. Most methods of assessing small airways dysfunction have been largely confined to research purposes, but some data are encouraging, supporting the utilization of certain techniques into daily clinical practice, particularly for early-stage diseases, when subjects are often asymptomatic and routine pulmonary function tests may be within normal ranges. In this context further clinical trials and real-life feedback on large populations are desirable. PMID- 26037948 TI - Optimization of bioprocess conditions improves production of a CHO cell-derived, bioengineered heparin. AB - Heparin is the most widely used anticoagulant drug in the world today. Heparin is currently produced from animal tissues, primarily porcine intestines. A recent contamination crisis motivated development of a non-animal-derived source of this critical drug. We hypothesized that Chinese hamster ovary (CHO) cells could be metabolically engineered to produce a bioengineered heparin, equivalent to current pharmaceutical heparin. We previously engineered CHO-S cells to overexpress two exogenous enzymes from the heparin/heparan sulfate biosynthetic pathway, increasing the anticoagulant activity ~100-fold and the heparin/heparan sulfate yield ~10-fold. Here, we explored the effects of bioprocess parameters on the yield and anticoagulant activity of the bioengineered GAGs. Fed-batch shaker flask studies using a proprietary, chemically-defined feed, resulted in ~two-fold increase in integrated viable cell density and a 70% increase in specific productivity, resulting in nearly three-fold increase in product titer. Transferring the process to a stirred-tank bioreactor increased the productivity further, yielding a final product concentration of ~90 MUg/mL. Unfortunately, the product composition still differs from pharmaceutical heparin, suggesting that additional metabolic engineering will be required. However, these studies clearly demonstrate bioprocess optimization, in parallel with metabolic engineering refinements, will play a substantial role in developing a bioengineered heparin to replace the current animal-derived drug. PMID- 26037950 TI - Varenicline and risk of psychiatric conditions, suicidal behaviour, criminal offending, and transport accidents and offences: population based cohort study. AB - OBJECTIVE: To examine associations between varenicline and the incidence of a range of adverse outcomes. DESIGN: Population based cohort study using within person analyses to control for confounding by indication. SETTING: Whole population of Sweden. PARTICIPANTS: 7,917,436 people aged 15 and over, of whom 69,757 were treated with varenicline between 2006 and 2009. MAIN OUTCOME MEASURES: Incidence of new psychiatric conditions, suicidal behaviour, suspected and convicted criminal offending, transport accidents, and suspected and convicted traffic offences. RESULTS: In the whole population, 337,393 new psychiatric conditions were diagnosed during follow-up. In addition, 507,823 suspected and 338,608 convicted crimes, 40,595 suicidal events, 124,445 transport accidents, and 99,895 suspected and 57,068 convicted traffic crimes were recorded. Within person analyses showed that varenicline was not associated with significant hazards of suicidal behaviour, criminal offending, transport accidents, traffic offences, or psychoses. However, varenicline was associated with a small increase in the risk of anxiety conditions (hazard ratio 1.23, 95% confidence interval 1.01 to 1.51) and mood conditions (1.31, 1.06 to 1.63), which was only seen in people with pre-existing psychiatric disorders. CONCLUSIONS: Concerns that varenicline is associated with an increased risk of many adverse outcomes, including suicidality and accidents, are not supported in this observational study. The small increase in risk of two psychiatric conditions in people with pre-existing psychiatric disorders needs to be confirmed using other research designs. PMID- 26037952 TI - Adolescent bullying linked to depression in early adulthood. PMID- 26037951 TI - Peer victimisation during adolescence and its impact on depression in early adulthood: prospective cohort study in the United Kingdom. AB - OBJECTIVE: To investigate the strength of the association between victimisation by peers at age 13 years and depression at 18 years. DESIGN: Longitudinal observational study. SETTING: Avon Longitudinal Study of Parents and Children, a UK community based birth cohort. PARTICIPANTS: 6719 participants who reported on peer victimisation at age 13 years. MAIN OUTCOME MEASURES: Depression defined according to international classification of diseases, 10th revision (ICD-10) criteria, assessed using the clinical interview schedule-revised during clinic assessments with participants when they were aged 18 years. 3898 participants had data on both victimisation by peers at age 13 years and depression at age 18 years. RESULTS: Of the 683 participants who reported frequent victimisation at age 13 years, 101 (14.8%) were depressed according to ICD-10 criteria at 18 years; of the 1446 participants reporting some victimisation at age 13 years, 103 (7.1%) were depressed at age 18 years; and of the 1769 participants reporting no victimisation at age 13 years, 98 (5.5%) were depressed at age 18 years. Compared with children who were not victimised those who were frequently victimised by peers had over a twofold increase in odds of depression (odds ratio 2.96, 95% confidence interval 2.21 to 3.97, P<0.001). This association was slightly reduced when adjusting for confounders (2.32, 1.49 to 3.63, P<0.001). The population attributable fraction suggested that 29.2% (95% confidence interval 10.9% to 43.7%) of depression at age 18 years could be explained by peer victimisation if this were a causal relation. CONCLUSION: When using observational data it is impossible to be certain that associations are causal. However, our results are consistent with the hypothesis that victimisation by peers in adolescence is associated with an increase in the risk of developing depression as an adult. PMID- 26037953 TI - Interleukin-17A-Induced Human Mesenchymal Stem Cells Are Superior Modulators of Immunological Function. AB - Interferon-gamma (IFN-gamma)-preactivated mesenchymal stem cells (MSC-gamma) are highly immunosuppressive but immunogenic in vivo due to their inherent expression of major histocompatibility (MHC) molecules. Here, we present an improved approach where we modified human bone marrow-derived MSC with interleukin-17A (MSC-17) to enhance T cell immunosuppression but not their immunogenicity. MSC 17, unlike MSC-gamma, showed no induction or upregulation of MHC class I, MHC class II, and T cell costimulatory molecule CD40, but maintained normal MSC morphology and phenotypic marker expression. When cocultured with phytohemagglutinin (PHA)-activated human T cells, MSCs-17 were potent suppressors of T cell proliferation. Furthermore, MSC-17 inhibited surface CD25 expression and suppressed the elaboration of Th1 cytokines, IFN-gamma, tumor necrosis factor alpha (TNF-alpha), and IL-2 when compared with untreated MSCs (UT-MSCs). T cell suppression by MSC-17 correlated with increased IL-6 but not with indoleamine 2,3 dioxygenase 1, cyclooxygenase 1, and transforming growth factor beta-1. MSC-17 but not MSC-gamma consistently induced CD4(+) CD25(high) CD127(low) FoxP3(+) regulatory T cells (iTregs) from PHA-activated CD4(+) CD25(-) T cells. MSC induced iTregs expressed CD39, CD73, CD69, OX40, cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), and glucocorticoid-induced TNFR-related protein (GITR). These suppressive MSCs-17 can engender Tregs to potently suppress T cell activation with minimal immunogenicity and thus represent a superior T cell immunomodulator for clinical application. PMID- 26037955 TI - Use of a nerve stimulator to assist cricothyroid membrane puncture during difficult airway topicalization. PMID- 26037954 TI - Intergenerational transmission of parenting: findings from a UK longitudinal study. AB - BACKGROUND: The quality of parenting is associated with a wide range of child and adult outcomes, and there is evidence to suggest that some aspects of parenting show patterns of intergenerational transmission. This study aimed to determine whether such intergenerational transmission occurs in mothers and fathers in a UK birth cohort. METHODS: The study sample consisted of 146 mothers and 146 fathers who were recruited from maternity wards in England and followed up for 24 months ['Generation 2' (G2)]. Perceptions of their own parenting [by 'Generation1' (G1)] were assessed from G2 parents at 12 months using the Parental Bonding Instrument (PBI). G2 parents were filmed interacting with their 'Generation 3' (G3) children at 24 months. RESULTS: We found that G1 mothers' 'affection' was associated with positive parenting behaviour in the G2 fathers ('positive responsiveness' beta = 0.19, P = 0.04 and 'cognitive stimulation' beta = 0.26, P < 0.01). G1 mothers' 'control' was associated with negative parenting behaviour in G2 mothers (decreased 'engagement' beta = -0.19, P = 0.04), and negative parenting behaviour in G2 fathers (increased 'control' beta = 0.18, P = 0.05). None of the G1 fathers' parenting variables were significantly associated with G2 parenting. CONCLUSIONS: There is evidence of intergenerational transmission of parenting behaviour in this highly educated UK cohort, with reported parenting of grandmothers associated with observed parenting in both mothers and fathers. No association was seen with reported parenting of grandfathers. This raises the possibility that parenting interventions may have benefits that are realised across generations. PMID- 26037956 TI - Measured and predicted affinities of binding and relative potencies to activate the AhR of PAHs and their alkylated analogues. AB - Polycyclic aromatic hydrocarbons (PAHs) and their alkylated forms are important components of crude oil. Both groups of PAHs have been reported to cause dioxin like responses, mediated by aryl hydrocarbon receptor (AhR). Thus, characterization of binding affinity to the AhR of unsubstituted or alkylated PAHs is important to understand the toxicological consequences of oil contamination on ecosystems. We investigated the potencies of major PAHs of crude oil, e.g., chrysene, phenanthrene and dibenzothiophene, and their alkylated forms (n=17) to upregulate expression of AhR-mediated processes by use of the H4IIE-luc transactivation bioassay. In addition, molecular descriptors of different AhR activation potencies among PAHs were investigated by use of computational molecular docking models. Based on responses of the H4IIE-luc in vitro assay, it was shown that potencies of PAHs were determined by alkylation in addition to the number and conformation of rings. Potencies of AhR-mediated processes were generally greater when a chrysene group was substituted, especially in 1-methyl chrysene. Significant negative correlations were observed between the in vitro dioxin-like potency measured in H4IIE-luc cells and the binding distance estimated from the in silico modeling. The difference in relative potency for AhR activation observed among PAHs and their alkylated forms could be explained by differences among binding distances in the ligand binding domain of the AhR caused by alkylation. The docking model developed in the present study may have utility in predicting risks of environmental contaminants of which toxicities are mediated by AhR binding. PMID- 26037957 TI - A century of oil and gas exploration in Albania: assessment of Naturally Occurring Radioactive Materials (NORMs). AB - The Naturally Occurring Radioactive Materials (NORMs) that are potentially generated from oil and gas extractions in Albania have been disposed of without regulations for many decades, and therefore, an extensive survey in one of the most productive regions (Vlora-Elbasan) was performed. A total of 52 gamma ray spectrometry measurements of soil, oil-sand, sludge, produced water and crude oil samples were performed. We discovered that relatively low activity concentrations of (226)Ra, (228)Ra, (228)Th and (40)K, with concentrations of 23+/-2Bq/kg, 23+/ 2Bq/kg, 24+/-3Bq/kg and 549+/-12Bq/kg, respectively, came from the oil-sands produced by the hydrocarbon extraction of the molasses formations. The mineralogical characterizations and the (228)Ra/(40)K and (226)Ra/(40)K ratios of these Neogene deposits confirmed the predictions of the geological and geodynamic models of a dismantling of the Mesozoic source rocks. The average activity concentrations (+/-standard deviations) of the radium isotopes ((226)Ra and (228)Ra) and of the (228)Th and (40)K radionuclides in soil samples were 20+/ 5Bq/kg, 25+/-10Bq/kg, 25+/-9Bq/kg and 326+/-83Bq/kg, respectively. Based on the measurements in this study, the future radiological assessments of other fields in the region should be strategically planned to focus on the oil-sands from the molasses sediments. Disequilibrium in the (228)Ra decay segment was not observed in the soil, sludge or oil-sand samples within the standard uncertainties. After a detailed radiological characterization of the four primary oil fields, we concluded that the outdoor absorbed dose rate never exceeded the worldwide population weighted average absorbed dose rate in outdoor air from terrestrial gamma radiation. PMID- 26037958 TI - The toxicity of a new disinfection by-product, 2,2-dichloroacetamide (DCAcAm), on adult zebrafish (Danio rerio) and its occurrence in the chlorinated drinking water. AB - The detection method of 2,2-dichloroacetamide (DCAcAm), a new disinfection by product (DBP) in chlorinated drinking water, was established using a gas chromatograph coupled with a micro-electron capture detector. The chlorinated water samples were taken from ten drinking water treatment plants around Yangtze River or Taihu Lake in China. The concentration of DCAcAm was detected ranging from 0.5 to 1.8MUg/L in the waterworks around Yangtze River, and 1.5-2.6MUg/L around Taihu Lake. The toxicity of DCAcAm on adult zebrafish was assessed by investigating the metabolism damage with multiple metabolic biomarkers and the accumulation capability with bio-concentration factor. The results showed that DCAcAm could cause the acute metabolism damage and was easily accumulated in zebrafish, and should be extremely cautioned. PMID- 26037959 TI - Dynamic probability control limits for risk-adjusted Bernoulli CUSUM charts. AB - The risk-adjusted Bernoulli cumulative sum (CUSUM) chart developed by Steiner et al. (2000) is an increasingly popular tool for monitoring clinical and surgical performance. In practice, however, the use of a fixed control limit for the chart leads to a quite variable in-control average run length performance for patient populations with different risk score distributions. To overcome this problem, we determine simulation-based dynamic probability control limits (DPCLs) patient-by patient for the risk-adjusted Bernoulli CUSUM charts. By maintaining the probability of a false alarm at a constant level conditional on no false alarm for previous observations, our risk-adjusted CUSUM charts with DPCLs have consistent in-control performance at the desired level with approximately geometrically distributed run lengths. Our simulation results demonstrate that our method does not rely on any information or assumptions about the patients' risk distributions. The use of DPCLs for risk-adjusted Bernoulli CUSUM charts allows each chart to be designed for the corresponding particular sequence of patients for a surgeon or hospital. PMID- 26037960 TI - In the Dark: Challenges of Caring for Sons with Klinefelter Syndrome. AB - The purpose of this mixed method study was to describe family management challenges for parents who have sons with Klinefelter Syndrome (KS). Standardized survey results showed that stress, quality of life and family management struggles varied by parent age. When interviewed, parents described feeling uninformed and without support to make decisions about managing their sons' KS. Parents reported that a lack of guidance and case coordination created barriers in caring for their sons throughout childhood. Given the prevalence of KS, health care providers need to be prepared to provide comprehensive evaluation and anticipatory guidance for KS boys and families. PMID- 26037961 TI - Apomorphine hydrochloride for the treatment of Parkinson's disease. AB - Apomorphine (APO) is a potent D1 and D2 dopamine agonist. Plasma maximal concentration is reached in 8-16 min with a plasma half-life of 34-70 min. Bioavailability is close to 100%. It has a rapid antiparkinsonian action after subcutaneous (s.c.) administration with a size effect comparable with that of levodopa. Trials of s.c., oral, sublingual, intravenous, rectal, intranasal and iontophoretic transdermal administration of APO have been attempted in Parkinson's disease (PD), each of these routes have shown some potential for clinical effectiveness but the majority of studies indicate that APO intermittent s.c. administration, on which this review is mainly focused, is an effective therapy for the management of motor symptoms in PD, particularly in advanced phases mainly characterized by motor fluctuations, such as wearing OFF and unpredictable "off". Data on the effect of APO on non-motor symptoms in PD patients are limited but there is strong suggestion of a beneficial effect that warrants further investigation. PMID- 26037962 TI - Controls of the quantum yield and saturation light of isoprene emission in different-aged aspen leaves. AB - Leaf age alters the balance between the use of end-product of plastidic isoprenoid synthesis pathway, dimethylallyl diphosphate (DMADP), in prenyltransferase reactions leading to synthesis of pigments of photosynthetic machinery and in isoprene synthesis, but the implications of such changes on environmental responses of isoprene emission have not been studied. Because under light-limited conditions, isoprene emission rate is controlled by DMADP pool size (SDMADP ), shifts in the share of different processes are expected to particularly strongly alter the light dependency of isoprene emission. We examined light responses of isoprene emission in young fully expanded, mature and old non-senescent leaves of hybrid aspen (Populus tremula x P. tremuloides) and estimated in vivo SDMADP and isoprene synthase activity from post-illumination isoprene release. Isoprene emission capacity was 1.5-fold larger in mature than in young and old leaves. The initial quantum yield of isoprene emission (alphaI ) increased by 2.5-fold with increasing leaf age primarily as the result of increasing SDMADP . The saturating light intensity (QI90 ) decreased by 2.3-fold with increasing leaf age, and this mainly reflected limited light-dependent increase of SDMADP possibly due to feedback inhibition by DMADP. These major age dependent changes in the shape of the light response need consideration in modelling canopy isoprene emission. PMID- 26037963 TI - Outcomes of Bilateral Uterine Artery Chemoembolization in Combination with Surgical Evacuation or Systemic Methotrexate for Cervical Pregnancy. AB - STUDY OBJECTIVE: To evaluate the use of bilateral uterine artery chemoembolization in combination with surgical evacuation or systemic methotrexate (MTX) in the conservative treatment of cervical pregnancy (CP). DESIGN: Clinical case series (Canadian Task Force classification II-3). SETTING: Tertiary university hospital. PATIENTS: Women with a CP who were treated at West China Second University Hospital of Sichuan University between January 2006 and January 2013. INTERVENTION: Bilateral uterine artery chemoembolization in combination with surgical evacuation or systemic MTX. MEASUREMENTS AND MAIN RESULTS: beta-Human chorionic gonadotropin (beta-hCG), cervical mass, blood transfusion, length of hospital stay, future menstruation, and fertility were assessed. Thirty-nine patients were successfully treated by chemoembolization in combination with surgical evacuation or systemic MTX. All massive bleeding was controlled after chemoembolization, and the 35 subsequent evacuation surgeries were uneventful. Nine patients received blood transfusions. The time for serum beta-hCG normalization was 28.7 +/- 9.8 days (range, 7-60). The time for CP mass disappearance by ultrasonography was 27.0 +/- 6.9 days (range, 11-48) days. The length of hospital stay was 7.7 +/- 4.9 days (range, 3-33). Complications were mainly fever and pain, which were alleviated with symptomatic treatment. Thiry eight patients had recovered their normal menstruation, and 7 patients had future pregnancies at follow-up. CONCLUSION: Bilateral uterine artery chemoembolization is effective in controlling and preventing massive hemorrhage associated with CP. It is proved to treat CP with optimal recovery time, few outpatient follow-ups, and efficient fertility preservation when combined with surgical evacuation or systemic MTX. PMID- 26037964 TI - Rhabdomyomatous mesenchymal hamartoma of the face causing trigeminal neuralgia. AB - BACKGROUND: Rhabdomyomatous mesenchymal hamartoma (RMH) is a benign, potentially pigmented lesion that occurs in the head and neck region. It generally consists of haphazardly arranged skeletal muscle with adipose tissue, blood vessels, collagen and nerve fibers and is largely asymptomatic. Trigeminal neuralgia is pain due to compression of the trigeminal nerve. TN may be idiopathic or associated with lesion-mediated compression. CASE REPORT: We describe the case of a 14-year-old female presenting with trigeminal neuralgia (TN) associated with RMH. On initial consultation, the patient presented with a history of right-sided lower facial swelling, numbness, and pain. Evaluation by various specialists confirmed TN. Surgical resection of the lesion resolved the condition and pathology confirmed RMH. CONCLUSIONS: This is the first case report demonstrating RMH-mediated TN. Surgical resection of the RMH is a safe management approach for this diagnosis. PMID- 26037965 TI - Just how wide should 'wide reading' be? AB - Educationalists introduce students to literature search strategies that, with rare exceptions, focus chiefly on the location of primary research reports and systematic reviews of those reports. These sources are, however, unlikely to adequately address the normative and/or metaphysical questions that nurses frequently and legitimately interest themselves in. To meet these interests, non research texts exploring normative and/or metaphysical topics might and perhaps should, in some situations, be deemed suitable search targets. This seems plausible and, moreover, students are encouraged to 'read widely'. Yet accepting this proposition creates significant difficulties. Specifically, if non-research scholarly sources and artistic or literary (humanities) products dealing with normative/metaphysical issues were included in what are, at present, scientifically orientated searches, it is difficult to draw boundaries around what--if anything--is to be excluded. Engaging with this issue highlights problems with qualitative scholarship's designation as 'evidence'. Thus, absurdly, if qualitative scholarship's findings are labelled evidence because they generate practice-relevant understanding/insight, then any literary or artistic artefact (e.g. a throwaway lifestyle magazine) that generates kindred understandings/insights is presumably also evidence? This conclusion is rejected and it is instead proposed that while artistic, literary, and qualitative inquiries can provide practitioners with powerful and stimulating non-evidential understanding, these sources are not evidence as commonly conceived. PMID- 26037966 TI - From the authors. PMID- 26037967 TI - Distribution of Hg, As and Se in material and flue gas streams from preheater precalciner cement kilns and vertical shaft cement kilns in China. AB - The aim of this study was to evaluate the behavior of Hg, As, and Se in cement production. Two types of cement plants were studied, including the vertical shaft kiln (VSK) and preheater-precalciner kiln (PPK) processes. Determination of Hg, As, and Se in the main material and gas streams were performed. It was found that recycling of particulate matter captured by an air pollution control device caused a significant enrichment of Hg and As inside both processes. The total quantity of Hg entering the process and the quantity emitted to the atmosphere were found to be 10-109 and 6.3-38 mg, respectively, per ton of clinker produced. The average Hg emission was calculated to be around 41% of the total mercury input. The emissions found complied with the European Union (EU) limit and exceeded partly the U.S. limit. Furthermore, it was found that oxidized mercury was the dominant species in the PPK process, whereas the reduced form was dominant in the VSK process, due to the oxidizing and reducing gas conditions, respectively. Regarding the distribution of As and Se, the major amounts were bound to the solid materials, that is, cement clinker and particulate matter. Based on cement production data in China in 2013, the annual emissions of Hg and As were estimated to be in the range of 8.6-52 and 4.1-9.5 tons, respectively. PMID- 26037968 TI - New insights into the resolution of inflammation. AB - The goal of treating chronic inflammatory diseases must be to inhibit persistent inflammation and restore tissue function. To achieve this we need to improve our understanding of the pathways that drive inflammation as well as those that bring about its resolution. In particular, resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of injury or infection and restore homeostasis. Indeed, it may be argued that dysfunctional resolution may underpin the aetiology of some chronic inflammatory disease and that a novel goal in treating such diseases is to develop drugs based on the mode of endogenous pro-resolution factors in order to drive on-going inflammation down a pro-resolution pathway. And while we are improving our understanding of the resolution of acute and chronic inflammation, much remains to be discovered. Here we will discuss the key endogenous checkpoints necessary for mounting an effective yet limited inflammatory response and the crucial biochemical pathways necessary to prevent its persistence and trigger its resolution. In doing so, we will provide an update on what is known about resolution of acute inflammation, in particular its link with adaptive immunity. PMID- 26037969 TI - In which direction does skin move during joint movement? AB - BACKGROUND/ PURPOSE: A skin movement artifact is a major problem in three dimensional motion analysis. Furthermore, skin tension lines are important in plastic surgery. Skin tension depends upon the body area and the direction of resistance. From the perspective of skin continuity and clinical observation, we hypothesized that the contralateral side of the skin of the extremities moves in the opposite direction. This study aimed to examine kinematics of thigh skin including movement direction during pelvic sway. METHODS: Fifteen healthy men participated in this study. Kinematic data were obtained using a three dimensional motion analysis system. To detect opposite skin movement, 42 markers were attached to the front, back, lateral, and medial sides of the thigh and pelvis. Front and back markers in the sagittal plane and lateral and medial markers in the frontal plane were arranged in a line connecting the hip and ankle joint centers, respectively. Subjects performed maximal pelvic movements in the anterior-posterior and rightward-leftward directions. RESULTS: The results showed that the front skin of the thigh was transferred upward and that the back skin was transferred downward during pelvic anterior sway. Opposite skin movements were observed during posterior pelvic sway. We also found that the lateral skin was transferred upward and that the medial skin was transferred downward during hip adduction and vice-versa during hip abduction. CONCLUSION: These findings suggest that the skin moves according to certain physiological rules. PMID- 26037970 TI - New medical diagnoses and length of stay of acutely unwell older patients: Implications for funding models. AB - AIM: To examine the relationship between newly made medical diagnoses and length of stay (LOS) of acutely unwell older patients. METHODS: Consecutive patients admitted under the care of four geriatricians were randomly allocated to a model development sample (n = 937) or a model validation sample (n = 855). Cox regression was used to model LOS. Variables considered for inclusion in the development model were established risk factors for LOS and univariate predictors from our dataset. Variables selected in the development sample were tested in the validation sample. RESULTS: A median of five new medical diagnoses were made during a median LOS of 10 days. New diagnoses predicted an increased LOS (hazard ratio 0.90, 95% confidence interval 0.88-0.92). Other significant predictors of increased LOS in both samples were malnutrition and frailty. CONCLUSIONS: Identification of new medical diagnoses may have implications for Diagnosis Related Groups-based funding models and may improve the care of older people. PMID- 26037971 TI - Hijacked then lost in translation: the plight of the recombinant host cell in membrane protein structural biology projects. AB - Membrane protein structural biology is critically dependent upon the supply of high-quality protein. Over the last few years, the value of crystallising biochemically characterised, recombinant targets that incorporate stabilising mutations has been established. Nonetheless, obtaining sufficient yields of many recombinant membrane proteins is still a major challenge. Solutions are now emerging based on an improved understanding of recombinant host cells; as a 'cell factory' each cell is tasked with managing limited resources to simultaneously balance its own growth demands with those imposed by an expression plasmid. This review examines emerging insights into the role of translation and protein folding in defining high-yielding recombinant membrane protein production in a range of host cells. PMID- 26037973 TI - The incidence of deep vein thrombosis and pulmonary embolism following cast immobilisation and early functional bracing of Tendo Achilles rupture without thromboprophylaxis. AB - PURPOSE: The routine use of thromboprophylaxis during cast immobilisation for lower leg trauma is controversial. The concern involves the perceived increased risk of deep vein thrombosis (DVT) and its sequelae following leg immobilisation. However, immobilisation is used for a spectrum of trauma and for varying duration. This heterogenicity in management is reflected in the current evidence and coupled with the risks of thromboprophylaxis; no clear consensus has been made. METHODS: In this retrospective study, we report the incidence of DVT and pulmonary embolism (PE) observed following cast immobilisation and early functional management of patients with Tendo Achilles rupture. Over 12 years, 945 consecutive patients (949 tendons) were treated without additional thromboprophylaxis. RESULTS: The incidence of DVT was 1.05 % and PE was 0.32 %. Females were significantly more likely to develop a DVT but not a PE. When compared to the incidence of DVT and PE observed in the general population, DVT rate was statistically significantly higher than that observed in the general population. There was no significant difference in PE rates. The number needed to treat to reduce the DVT incidence is 106. The number needed to treat to reduce the PE incidence is 475. CONCLUSIONS: Although we can conclude that conservative treatment for Tendo Achilles does increase the incidence of symptomatic DVT from the general population, we feel that large randomised control trials are required to evaluate the efficacy, compliance and cost effectiveness of routine DVT thromboprophylaxis in the outpatient setting. PMID- 26037972 TI - The pathophysiology, diagnosis and treatment of the acute coagulopathy of trauma and shock: a literature review. AB - BACKGROUND: The acute coagulopathy of trauma and shock is associated with significant mortality and, currently, there are no validated laboratory tests which allow for a rapid recognition and treatment of this condition. Therefore, early detection of any clot abnormality in trauma could improve the diagnosis of trauma-associated coagulopathy and subsequent interventions. METHODS: Review of the literature. RESULTS: The standard laboratory tests, including prothrombin time and activated partial thromboplastin time, are unreliable and describe only an isolated fragment of the complex coagulation pathways. Additionally, thromboelastography and thromboelastometry operate in a non-linear regime which implies that clot formation is the product of both the clotting process and the effect of the measurement. The assessment of the clot microstructure using a scanning electron microscope has resulted in a subjective analysis of a clot structure, showing also poor correlation between the coagulation pathways and clot development. The fractal dimension provides information on the structure and quality of the initial clot, which subsequently acts as a template for how the mature clot will behave. However, these data require further verification in an in vivo setting. At present, the treatment of the coagulopathy is delivered by empirically administered massive transfusion protocols, which lack a specific target for replacement therapy. CONCLUSIONS: There is enough evidence to demonstrate that we urgently need a robust test, which would determine and quantify both the rate and the extent of coagulation abnormalities. This could help to tailor the treatment of coagulopathy according to the patient's needs. PMID- 26037974 TI - Utility of complete trauma series radiographs in alert pediatric patients presenting to Emergency Department of a Tertiary Care Hospital. AB - PURPOSE: To assess the utility of trauma series radiographs in the management of alert pediatric patients with traumatic injury and to ascertain whether it is necessary to acquire the entire trauma series in these children. METHODS: A total of 176 consecutive children below the age of 15 years and having Glasgow Coma Scale score greater than 12, who presented to the emergency department of a tertiary care hospital with a history of recent trauma, were retrospectively reviewed. All the children had undergone a thorough clinical examination followed by complete trauma series radiographs, according to the American College of Surgery guidelines. RESULTS: A total of 558 radiographs were reviewed by a consultant pediatric radiologist including 528 trauma series radiographs and 30 additional radiographs. Among the trauma series radiographs, 35 (6.63 %) had evidence of injury; 24 (4.54 %) and 11 (2.08 %) involving the chest and pelvic regions, respectively. All children with normal physical examination had normal cervical spine and chest radiographs. Among the 11 positive pelvic X-rays, only two had radiological signs of injury in the absence of localizing physical signs, and all these children were less than 3 years of age. In all the remaining cases, children had localizing signs on physical examination. Out of the 30 additional X rays, 27 (90 %) had radiological evidence of injury. CONCLUSIONS: The routine use of entire radiological trauma series in alert pediatric patients with a normal physical examination has a very low yield. In these children, the localizing signs and symptoms can help us in determining the specific radiological examination to be utilized. PMID- 26037975 TI - Gender, age and ethnicity influence on pain levels and analgesic use in the acute whiplash injury. AB - PURPOSE: Initial pain level in the acute whiplash injury is the most consistent predictor of transformation to a chronic pain syndrome. The risk factors for those early pain levels were, to our knowledge, scarcely evaluate to this date. We set to evaluate whether gender, age or ethnicity comprise a risk factor for those initial pain levels. Further, gender, age and ethnicity have been shown to be bias factors in pain management. We investigated if gender, age or ethnicity are bias factor in pain management in the face of a standardized pain treatment protocol in the acute whiplash injury. METHODS: We reviewed 2,538 patients with acute whiplash injury that were treated at our emergency department (ED). Gender, age and ethnicity were investigated as risk factors for elevated visual analog scale (VAS) scores. Those factors were also investigated as bias in pain medication administration in the face of a standardized analgesic protocol. RESULTS: Women had significantly higher VAS scores (p = 0.009). Age and ethnicity did not influence pain levels. There was no influence of gender or age on pain medication administration. The Jewish patients (the majority in Israel) were administered fewer pain medication (p < 0.0001). CONCLUSION: Women have higher initial pain levels in the acute whiplash injury. Age and ethnicity have less impact on those pain levels. A pain management protocol might reduce bias in pain management in the acute whiplash injury in the ED. The Jewish population tends to be less receptive to pain medication administration. PMID- 26037976 TI - Medial plantar flap to repair defects of palm volar skin. AB - PURPOSE: The methods of repairing defects in fingers, volar skin of the palm and soft tissue were investigated. METHODS: From 2010 to the present, we examined 12 cases in which medial plantar skin flaps were used to repair defects in the fingers and palm. According to skin and soft tissue defects in the fingers and palm, a flap was designed using the medial plantar artery as the vessel pedicle. The flap was dissected and isolated between the abductor hallucis and flexor digitorum brevis, and transplanted to the hand. We then observed the skin colour, skin texture and tactile sensitivity of the hand, as well as the shape and function of the foot. RESULTS: Follow-up for 3-28 months showed that the flaps survived in all 12 cases, with soft skin, healthy appearance, colour consistent with the palm skin and no pigmentation. The two-point discrimination was 5-7 mm. The donor foot functioned well, and the scar at the donor site was slight and had an aesthetic appearance. CONCLUSION: The free medial plantar flap is an ideal flap for repairing soft tissue defects in the palm. PMID- 26037977 TI - Young adults with mild traumatic brain injury--the influence of alcohol consumption--a retrospective analysis. AB - PURPOSE: Alcohol abuse has been associated with aggressive behavior and interpersonal violence. Aim of the study was to investigate the role of alcohol consumption in a population of young adults with mild traumatic brain injuries and the attendant epidemiological circumstances of the trauma. SUBJECTS AND METHODS: All cases of mild traumatic brain injury among young adults under 30 with an injury severity score <16 who were treated as inpatients between 2009 and 2012 at our trauma center were analyzed with regard to the influence of alcohol consumption by multiple regression analysis. RESULTS: 793 patients, 560 men, and 233 women were included. The age median was 23 (range 14-30). Alcohol consumption was present in 302 cases. Most common trauma mechanism was interpersonal violence followed by simple falls on even ground. Alcohol consumption was present more often in men, unemployed men, patients who had interpersonal violence as a trauma mechanism, and in patients who were admitted to the hospital at weekends or during night time. It also increased the odds ratio to suffer concomitant injuries, open wounds, or fractures independently from the trauma mechanism. Length of hospital stay or incapacity to work did not increase with alcohol consumption. CONCLUSIONS: Among young adults men and unemployed men have a higher statistical probability to have consumed alcohol prior to suffering mild traumatic brain injury. The most common trauma mechanism in this age group is interpersonal violence and occurs more often in patients who have consumed alcohol. Alcohol consumption and interpersonal violence increase the odds ratio for concomitant injuries, open wounds, and fractures independently from another. PMID- 26037978 TI - Risk associated with traumatic intracranial bleed and outcome in patients following a fall from a standing position. AB - BACKGROUND: A fall from a standing position (FFS) is a low impact injury; however, in certain patient populations it can result in serious, complex injuries associated with significant morbidity and mortality. OBJECTIVES: The purpose of the study was to identify the patient population, risk factors and outcomes of intracranial bleed (ICB) after a fall from a standing position. METHODS: Data of all patients from the trauma database at State designated Trauma Center were analyzed who FFS. Patient's demography, clinical information was obtained. An ICB seen on computed tomography (CT) scan was considered positive. RESULTS: From January 2001 through December 2008, 163 patients admitted to the trauma center after FFS. Ninety-one out of 163 patients (56 %) had positive CT scan. There was no significant difference between the groups with a positive or negative CT regarding age (P = 0.07), gender (P = 0.58), race (P = 0.15), Glasgow Coma Scale (P = 0.27), aspirin use (P = 0.06), Plavix (P = 0.92), combination of aspirin and Plavix (P = 0.86) or use of Coumadin (P = 0.82). Patients with ICB had significantly higher injury severity score (ISS) than patients without ICB (P < 0.0001). However, the overall mortality between the groups was not significant (P = 0.66). From a multiple logistic regression model, age >=70 years was the only predictor for the ICB. CONCLUSION: A high proportion of our patients had positive ICB due to falls from a standing position. No significant differences were seen between the groups in terms of mortality. Age >=70 years was the only factor for positive ICB. LEVEL OF EVIDENCE: Prognostic study investigating the effect of a patient characteristic on the outcome of the disease, level III. PMID- 26037979 TI - Biomechanical properties of different external fixator frame configurations. AB - PURPOSE: External fixators are easy to apply and maximize soft tissue preservation. However, frames need providing an adequate stiffness in order to avoid excessive interfragmentary movement during the healing period. We characterized the stiffness of four different configurations of the newly developed Hoffmann 3 external fixation system. METHODS: A synthetic fracture gap model was stabilized using four different frame configurations: a double-? 11 mm rod configuration (group DR), a hybrid double-? 8 mm rod configuration (group H), a single ? 11 mm rod direct link configuration (group DL) and a single ? 11 mm rod side arm configuration (group SA). The stiffness of each configuration was measured under anterior-posterior bending, medial-lateral bending and axial torsion loading directions and the results statistically compared. RESULTS: The basic frame construct (group DR) showed the highest bending and torsional stiffness properties while the single rod side arm configuration (group SA) the lowest. CONCLUSIONS: The diameter and the amount of used connecting rods as well as the adequate placement of these rods towards the main loading directions determine the construct stiffness. These results could help the surgeons estimating how different frames can potentially affect the interfragmentary motion. This information might help in choosing specific configuration when treating different fracture types on given patients. PMID- 26037980 TI - Assessment of traumatic deaths in a level one trauma center in Ankara, Turkey. AB - Trauma management shows significant progress in last decades. Determining the time and place of deaths indicate where to focus to improve our knowledge about trauma. We conducted this retrospective study from data of trauma victims who were brought to a major tertiary hospital which is a level one trauma center in Ankara, Turkey, and died even if during transport or in the hospital between 1 March 2010 and 1 March 2013. The patients' demographic characteristics, trauma mechanisms, time frames and causes of deaths determined by physicians were recorded. Traumas were grouped as "high energy trauma" (HET) and "low energy trauma" (LET). Falls from ground level were defined as LET. 209 traumatic deaths due to trauma or trauma-related conditions were found in the study period. 161 of 209 (78 %) patients suffered from HET. Motor vehicle collisions (MVC) (56 %) were the most common mechanism of trauma followed by burns (16 %), falls (11 %), gunshots (9 %) and stabs (6 %) in this group and traumatic brain injuries (TBI) (41 %) were the most common cause of death followed by circulatory collapse (22 %) and multi-organ failure (20 %). 36 % of deaths occurred before arrival at hospital, 25 % in the first 24 h of admission, 18 % between 2nd and 7th day and 21 % after first week. Trimodal distribution of traumatic deaths was not valid for all types of injuries and the most important factor to decrease traumatic deaths is still prevention. Also we have to keep on searching to improve our knowledge about trauma management. PMID- 26037981 TI - Erratum to: the incidence of deep vein thrombosis and pulmonary embolism following cast immobilisation and early functional bracing of Tendo Achilles rupture without thromboprophylaxis. PMID- 26037982 TI - Use of local pro-coagulant haemostatic agents for intra-cavity control of haemorrhage after trauma. AB - INTRODUCTION: Uncontrolled haemorrhage as a result of trauma remains a significant surgical challenge, accounting for approximately 25-40% of trauma related mortality. A wide range of local internal haemostatic agents have been developed to help achieve intra-cavity control of bleeding, with choice of agent influenced by the circumstances and nature of the haemorrhage. Trauma patients are frequently coagulopathic, so products that incorporate pro-coagulant technology and thereby act independently of the clotting cascade may be more effective in these settings. A range of products that utilise thrombin and fibrinogen to promote local haemostasis at intra-cavity bleeding points are available or in development, including fibrin glues (e.g. Tisseel(r)/Tissucol(r) and Evicel(r)/Crosseal(r)/Quixil(r)), fibrin sealant patches (e.g. TachoSil(r)) and products based on a gelatin-thrombin haemostatic matrix (e.g. FloSeal(r)). MATERIALS AND METHODS: This systematic review was performed to assess all peer reviewed evidence of product efficacy. RESULTS: Fibrin sealant patches have shown haemostatic efficacy in a variety of surgical procedures and appear to offer practical advantages over liquid fibrin glues. Existing evidence suggests that patch products enable delivery of pro-coagulants to defined areas with less chance of dilution and/or displacement by blood flow, but they require a pressure buttress for a suitable amount of time to achieve good results after trauma. CONCLUSIONS: Our experience, supported by other reports in the literature, suggests the use of such fibrin patches may provide an effective option in helping to control haemorrhage after trauma. However, there is a general paucity of clinical data for intra-cavity haemostatic agent use, with the majority of data being based on animal models and case reports. Further clinical evidence, ideally including comparative studies between different agents, would be beneficial in helping guide surgeon choice to the most appropriate products to use in trauma settings. PMID- 26037983 TI - Loop versus end colostomy reversal: has anything changed? AB - PURPOSE: Though primary repair of colon injuries is preferred, certain injury patterns require colostomy creation. Colostomy reversal is associated with significant morbidity and healthcare cost. Complication rates may be influenced by technique of diversion (loop vs. end colostomy), though this remains ill defined. We hypothesized that reversal of loop colostomies is associated with fewer complications than end colostomies. METHODS: This is a retrospective, multi institutional study (four, level-1 trauma centers) of patients undergoing colostomy takedown for trauma during the time period 1/2006-12/2012. Data were collected from index trauma admission and subsequent admission for reversal and included demographics and complications of reversal. Student's t test was used to compare continuous variables against loop versus end colostomy. Discrete variables were compared against both groups using Chi-squared tests. RESULTS: Over the 6-year study period, 218 patients underwent colostomy takedown after trauma with a mean age of 30; 190 (87%) were male, 162 (74%) had penetrating injury as their indication for colostomy, and 98 (45%) experienced at least one complication. Patients in the end colostomy group (n = 160) were more likely to require midline laparotomy (145 vs. 18, p < 0.001), had greater intra-operative blood loss (260.7 vs. 99.4 mL, p < 0.001), had greater hospital length of stay (8.4 vs. 5.5 days, p < 0.001), and had more overall complications (81 vs. 17, p = 0.005) than patients managed with loop colostomy (n = 58). CONCLUSIONS: Local takedown of a loop colostomy is safe and leads to shorter hospital stays, less intra-operative blood loss, and fewer complications when compared to end colostomy. PMID- 26037984 TI - Penetrating trauma; experience from Southwest Finland between 1997 and 2011, a retrospective descriptive study. AB - BACKGROUND: (1) There is lack of epidemiological data on penetrating trauma in European countries. (2) In Finland most acts of violence are performed under the influence of alcohol. The aim of this study was to determine the incidence and types of injury, treatment and survival of patients with penetrating injuries to the thorax and abdomen. METHODS: This study includes two trauma centers with combined catchment area of approximately 720,000 patients. Patients were identified from patient records using ICD-10 codes. RESULTS: Patients were predominantly young males and they were stab victims. The average yearly incidence for penetrating trauma was 0.9/100,000 inhabitants. Thirteen percent of patients admitted gave a negative toxicology screen or breathalyzer test for alcohol. Twenty two percent of wounds were self-inflicted. Fifty five percent of patients received a chest tube and 30 patients (23%) underwent emergent thoracotomy after sustaining critical injury to the thorax. A considerable proportion (12%) of the study group also later died due to alcohol and/or violence, highlighting the psychosocial co-morbidity among penetrating trauma victims. DISCUSSION: Chest tube insertion is a skill to be mastered by any on call physician. This simple procedure can be potentially life-saving. There is also a call for assessment of psychosocial well-being among penetrating trauma victims. PMID- 26037985 TI - Assessment of elevated compartment pressures by pressure-related ultrasound: a cadaveric model. AB - PURPOSE: There is a risk of misinterpreting the clinical signs of acute compartment syndrome of the lower limb resulting in delayed fasciotomy. Up to date, the diagnosis of compartment syndrome is based on clinical assessment and of invasive needle pressure measurement in uncertain cases. Close monitoring is necessary for early recognition of raising compartment pressures. Clinical assessment of muscle firmness by the physician's palpation alone is unreliable. Thus, a device objectifying this assessment would be beneficial. The purpose of this study was to determine the feasibility of muscle compartment elasticity measurements by a novel and non-invasive device using pressure-related ultrasound. METHODS: In a cadaveric model, the anterior tibial compartment was prepared to simulate raising intra-compartmental pressures (0-80 mmHg) by saline infusion. Standard invasive pressure monitoring was compared with a novel method to determine tissue elasticity. Changing cross-sectional view in B-mode ultrasound was exerted to measure the compartment depth before and after physician's probe compression of 100 mmHg. Compartment displacement (?d) was measured and related to the corresponding compartmental pressure (Spearman correlation coefficient). Delta (mm) of the control group at 10 mmHg compartment pressure was compared with measured data at rising compartmental pressures of 30, 50, and 70 mmHg using the Wilcoxon rank-sum test. The intra-observer reliability (kappa) was additionally calculated. RESULTS: Fresh and never frozen lower human limbs (n = 6) were used. The average displacement measured in the anterior tibial compartment was 2.7 mm (0.3-6.7 mm). A concordant consistent correlation between the compartmental displacement and the intra-compartmental pressure occurred. The Spearman coefficient (r s = 0.979) showed a significant correlation between the rising pressure and the decreasing tissue displacement visualized by ultrasound. The intra-observer value kappa showed reliable values (kappa 10 = 0.73, kappa 30 = 0.80, and kappa 70 = 0.79). CONCLUSIONS: We introduce a new method of ultrasound imaging enhanced with probe pressure measurement to determine changes of the visco-elastic behavior of isolated muscle compartments. Pressure-related ultrasound could be a reliable tool to determine the correlation between the measured compartmental displacement and the increasing intra-compartmental pressure. Its accuracy revealed promising results. This technique may help the physician to objectify the clinical assessment of compartment elasticity, mainly indicated in cases of unconscious patients and imminent pathology. Further clinical studies and improvements of this technique are required to prove its accuracy and reliability in cases of compartment syndrome. PMID- 26037986 TI - 30-Day and 1-year mortality in emergency general surgery laparotomies: an area of concern and need for improvement? AB - AIMS: Emergency surgery is associated with poorer outcomes and higher mortality with recent studies suggesting the 30-day mortality to be 14-15%. The aim of this study was to analyse the 30-day mortality, age-related 30-day mortality and 1 year mortality following emergency laparotomy. We hope this will encourage prospective data collection, improvement of care and initiate strategies to establish best practice in this area. METHODS: This was a retrospective study of patients who underwent emergency laparotomy from June 2010 to May 2012. The primary end point of the study was 30-day mortality, age-related 30-day mortality and 1-year all-cause mortality. RESULTS: 477 laparotomies were performed in 446 patients. 57% were aged <70 and 43% aged >70 years. 30-day mortality was 12, 4% in those aged <70 years and 22% in those >70 years (p < 0.001). 1-year mortality was 25, 15% in those aged under 70 years and 38% in those aged >70 years (p < 0.001). CONCLUSIONS: Emergency laparotomy carries a high rate of mortality, especially in those over the age of 70 years, and more needs to be done to improve outcomes, particularly in this group. This could involve increasing acute surgical care manpower, early recognition of patients requiring emergency surgery, development of clear management protocols for such patients or perhaps even considering centralisation of emergency surgical services to specialist centres with multidisciplinary teams involving emergency surgeons and care of the elderly physicians in hospital and related community outreach services for post discharge care. PMID- 26037987 TI - Haemorrhage in fragility fractures of the pelvis. AB - INTRODUCTION: Fragility fractures of the pelvis (FFP) are one of the most visible and debilitating consequences of osteoporosis. In contrast to pelvic ring fractures of the young, fragility fractures are caused by falls from a standing height or even by repetitive physiological loads. Even though haemorrhage is rarely found in fragility fractures of the pelvis, one must be aware of the potential risk. MATERIALS AND METHODS: In a computer literature search, we identified eight papers about patients with haemorrhage and/or haemodynamic instability as a complication of a low-velocity pelvic ring fracture, all of which were case reports. CONCLUSION: In our review, an overview of the case reports is provided, risk factors identified and a recommendation for the treatment and clinical observation given. PMID- 26037988 TI - Scoring system for traumatic liver injury (SSTLI) in polytraumatic patients: a predictor of mortality. AB - PURPOSE: The aim of this study was to examine prognostic factors in polytraumatic patients with liver injury and to develop a scoring system for traumatic liver injury (SSTLI) to predict mortality. METHODS: The medical records of 175 patients treated for traumatic liver injury from July 2009 to April 2013 were reviewed. The primary outcome variable was hospital mortality. All risk factors were analyzed by multivariate logistic regression analysis. The SSTLI was created based on the predictive power of each factor. RESULTS: Age, injury severity score (ISS), trauma and injury severity score, the shock index, and the volume of packed red blood cells transfused were strong predictors of mortality. We hypothesized that the SSTLI would use five clinical measures (total bilirubin, prothrombin time, serum creatinine, age, and ISS). Each measure was scored 0-1 (age and ISS) or 0-3 (total bilirubin, prothrombin time, and creatinine), with 3 indicating the most severe derangement. The receiver-operating characteristic curve of the SSTLI was significant at post-traumatic days 0, 1, 3, and 5 [area under the curve (AUC), 0.830; AUC, 0.912; AUC, 0.941; and AUC, 0.930, respectively]. A value of 5 points was the threshold for reliability dividing low risk (<5) from high-risk (>=5) patients. CONCLUSIONS: The SSTLI may be available to predict mortality in polytraumatic patients with liver injury, although external validation is needed before widespread implementation. PMID- 26037989 TI - Infrastructure and clinical practice for the detection and management of trauma associated haemorrhage and coagulopathy. AB - PURPOSE: Early detection and management of post-traumatic haemorrhage and coagulopathy have been associated with improved outcomes, but local infrastructures, logistics and clinical strategies may differ. METHODS: To assess local differences in infrastructure, logistics and clinical management of trauma associated haemorrhage and coagulopathy, we have conducted a web-based survey amongst the delegates to the 15th European Congress of Trauma and Emergency Surgery (ECTES) and the 2nd World Trauma (WT) Congress held in Frankfurt, Germany, 25-27 May 2014. RESULTS: 446/1,540 delegates completed the questionnaire yielding a response rate of 29%. The majority specified to work as consultants/senior physicians (47.3%) in general (36.1%) or trauma/orthopaedic surgery (44.5%) of level I (70%) or level II (19%) trauma centres. Clinical assessment (>80%) and standard coagulation assays (74.6%) are the most frequently used strategies for early detection and monitoring of bleeding trauma patients with coagulopathy. Only 30% of the respondents declared to use extended coagulation assays to better characterise the bleeding and coagulopathy prompted by more individualised treatment concepts. Most trauma centres (69%) have implemented local protocols based on international and national guidelines using conventional blood products, e.g. packed red blood cell concentrates (93.3%), fresh frozen plasma concentrates (93.3%) and platelet concentrates (83%), and antifibrinolytics (100%). 89% considered the continuous intake of anticoagulants including "new oral anticoagulants" and platelet inhibitors as an increasing threat to bleeding trauma patients. CONCLUSIONS: This study confirms differences in infrastructure, logistics and clinical practice for the detection and management of trauma-haemorrhage and trauma-associated coagulopathy amongst international centres. Ongoing work will focus on geographical differences. PMID- 26037990 TI - Functional outcome of unstable pelvic ring injuries after iliosacral screw fixation: single versus two screw fixation. AB - INTRODUCTION: A clinical series of patients was studied to compare the functional score after the use of a single versus two percutaneous iliosacral screws for unstable posterior pelvic ring fractures with or without anterior fixation with the aim to explore if the addition of a second screw would provide better results regarding the functional outcome score. MATERIALS AND METHODS: This case series includes 77 patients with an average of 32.6 years who suffered unstable posterior pelvic ring fractures. Forty-six were Tile type C and 31 were Tile type B. Patients underwent closed reduction and were fixed using percutaneous fluoroscopic-guided iliosacral screws in the supine position with 1 screw in 50 fractures, 2 screws in 37 fractures, 2 fractures were fixed with plates after ORIF, and in 6 cases (out of the bilateral cases) the undisplaced side was unfixed. Postoperatively three patients were lost to follow up and 74 patients (84 posterior fractures fixed with screws) were followed up for a mean of 37.4 months (range 6-151 months) and were evaluated using the Majeed score (1989). RESULTS: Clinical union occurred in all the patients, although in two cases posterior fixation failed and was revised. Radiologically excellent reduction was achieved in 55 patients (71.4%), good in 16 (20.8%), fair in 6 (7.8%) and none had poor reduction. Statistically; among 62 cases that completed the Majeed score evaluation at the last follow-up session, there was no significant difference p value 0.051 between two groups. We also compared Majeed score in Tile B and C fractures fixed with one versus two screws. CONCLUSION: The addition of a second screw for posterior fixation did not show any statistically significant difference regarding functional outcome. LEVEL OF EVIDENCE: Level IV clinical trial. PMID- 26037991 TI - Radiographic fracture features predicting failure of internal fixation of displaced femoral neck fractures. AB - INTRODUCTION: Fixation-related complications of displaced femoral neck fractures treated by internal fixation are accompanied by high mortality and morbidity. The aim of this study is to investigate the pre- and postoperative radiographic fracture characteristics in relation to patient age and the occurrence of reoperation caused by fixation failure. METHODS: The preoperative radiographs of all patients presenting with a proximal femur fracture between January 2004 and December 2012 were retrospectively assessed for fracture type and dislocation (AP and lateral view). Patients with a displaced femoral neck fracture treated by closed reduction and internal fixation were included. The postoperative radiographs were assessed on adequate fracture reduction and correct position of the implant. Patient characteristics and outcome in terms of occurrence of fixation failure (implant breakout, non-union) and reoperation rate were recorded. RESULTS: Hundred and-forty-nine patients were admitted with a displaced femoral neck fracture and treated by internal fixation. Fixation failure was seen in 34 (23%) patients; 9 patients suffered from osteonecrosis. In total, 37 (25%) patients underwent reoperation caused by fixation-related complications. Taking the different age categories into account, 44% of the patients >75 years suffered fixation failure compared with 17% of the patients <65 years. Postoperative incorrect reduction, with persisting dorsoventral dislocation and/or lack of medial support resulted in reoperation in 37% of the patients, compared to 19% reoperations in patients with adequate reduction. CONCLUSION: The results of this study show that patient age and fracture reduction are important predictors for reoperation. In the preoperative treatment plan, patient age should be taken into account and surgeons should strive for anatomical reduction. Patients over 75 should always undergo arthroplasty. In patients aged 65-75, conversion to arthroplasty should be strongly considered if anatomical reduction is impossible. PMID- 26037992 TI - Non-iatrogenic civilian vascular trauma in a well-defined geographical region in Finland. AB - PURPOSE: The purpose of this study was to assess the incidence, treatment and outcome of vascular trauma in a well-defined geographical region in Finland. METHODS: A retrospective analysis was conducted of patients admitted to Tampere University Hospital (TAUH), Pirkanmaa, Finland, due to vascular trauma between January 2006 and December 2010. Data regarding trauma mechanism, anatomical location, treatment, and short-term outcome were collected from patients' files and vascular register. RESULTS: Altogether, 143 non-iatrogenic vascular traumas occurred during the study period resulting in an annual trauma incidence of 5.8/100,000/year in the TAUH region. The majority of the injuries were located in the upper extremities (N = 83, 58%). Penetrating injuries comprised 58% (83 patients) of all vascular trauma admissions and were significantly more common among men compared to women (83 and 17%, respectively). The majority (N = 93, 65%) of the injuries were treated surgically, while in 15 (11%) patients the trauma was resolved by endovascular means. The remaining 35 (24%) patients were successfully managed conservatively, i.e., by observation or wound exploration only without the need for later (30-day) vascular repair. Two out of 17 patients (12%) with lower extremity vascular trauma required major amputation. Procedure related complications occurred in five patients. In-hospital and 30-day mortality was zero. CONCLUSIONS: This paper demonstrates that the incidence of non iatrogenic civilian vascular trauma in the Pirkanmaa region is low and mainly caused by penetrating injury. Further, the majority of vascular traumas are still treated surgically. In general, the short-term survival of patients who survive the initial trauma is good. PMID- 26037993 TI - Nonunions and malunions of the pelvis. AB - INTRODUCTION: Neglected pelvic fractures manifesting as pelvic nonunion or malunion are usually due to inadequate initial fixation or negligence of the injury because of increased attention towards other associated life-threatening conditions. The management of such injuries is complex. A systematic review was conducted to spot the clinical manifestations, evaluation, management and outcome of pelvic nonunion and malunion. MATERIALS AND METHODS: Two databases ("Pubmed" and "Google scholar") were searched to look for relevant literature on pelvic non union and malunion. The search was limited to 'English language' and 'Human being'. RESULTS: A total of 500 articles found, of which 10 articles were only reviewed which met the inclusion criteria. These articles discussed the clinical management and treatment of pelvic malunion and non-union following trauma without associated acetabular injury. CONCLUSION: The usual presentations of pelvic non-union and malunion are pain, deformity, gait abnormality or instability. A detailed preoperative evaluation is essential as a majority of them have associated hip and spine injury which may be the cause of symptoms. Radiographs and 3D CT scans have helped surgeons in deciding the best way of management. The surgeries are usually complex and may need multiple-staged procedures. Soft tissue release, multiple osteotomies to achieve anatomical or near-anatomical reduction, augmentation of healing process using bone graft and stabilizing the nonunion/ osteotomy site using plates/screws/rods is the basic principle of surgery. Per-operative use of somato-sensory evoked potential evaluation helps the surgeon in preventing iatrogenic nerve injury. Despite these precautions and surgeries, most of the patients do not regain their preinjury functional activity. PMID- 26037994 TI - Management of neglected acetabular fractures. AB - Management of neglected acetabular fractures is a difficult task. Osteosynthesis in such cases may not be an ideal solution because of the femoral head damage due to pressure by the fractured acetabular edge, avascular necrosis, difficulty in mobilizing the fragments due to callus formation, difficulty in indirect reduction of the fracture fragments and macerated acetabular fragments all contributing to inadequate fracture reduction. Majority of such fractures are now treated with total hip replacement. While treating such fractures with THR, problems associated with neglected acetabular fractures such as fracture non union, hip dislocation, protrusio, cavitary bone defect or peripheral bone defect must be considered. 3D computed tomography scan provides a clear view about the acetabular and periacetabular bony anatomy. Impaction grafting and antiprotrusio cage or ring with a cemented acetabular cup can address most of the hip protrusio and cavitary bone defects. Segmental bone defect needs cortical strut-bone graft fixation and subsequent implantation of a cemented or uncemented acetabular cup implantation. Fracture non-union needs approximate reduction and fixation with plates followed by bone grafting and implantation of an acetabular cup. Despite these efforts, the outcome of THR in neglected acetabular fracture is considerable worse than after conventional hip replacement. PMID- 26037995 TI - Proximal femoral nail antirotation against dynamic hip screw for unstable trochanteric fractures; a prospective randomized comparison. AB - AIM: We sought to determine whether intramedullary fixation with proximal femoral nail antirotation produces comparable outcomes to dynamic hip screw in the treatment of unstable trochanteric fractures. MATERIALS AND METHODS: Patients were randomly allocated to receive proximal femoral nail antirotation (Group 1, n = 96, mean age; 77.22 +/- 6.82 years) or dynamic hip screw (Group 2, n = 102, mean age; 76.86 +/- 6.74 years). Outcome measures were time of operation and fluoroscopy, amount of blood loss and occurrence of surgery-related complications. Tip-apex distance and femoral neck shortening were also evaluated. Patients were evaluated at the sixth month to assess the recovery of walking ability. Survival information was obtained from a civil registry. RESULTS: Operative and fluoroscopy times were significantly shorter and blood loss was significantly lower in Group 1 than those in Group 2. Complication rates, mean tip-apex indices and recovery of walking ability were similar between groups, whereas independent walking was more common in Group 1 than in Group 2. Until the sixth month, screw cutout occurred in eight (7.8%) and seven (7.3%) patients in Group 1 and Group 2, respectively (p = 0.88). Three-year survival rate was 61.6 +/- 9.4 vs 57.3 +/- 9.7 % in Group 1 and Group 2, respectively (p = 0.50). CONCLUSION: Proximal femoral nail antirotation technique offers better recovery than dynamic hip screw, whereas both techniques possess the same risk of postoperative complications. PMID- 26037996 TI - Modern sonology and the bedside practitioner: evolution of ultrasound from curious novelty to essential clinical tool. PMID- 26037998 TI - Open pneumothorax: the spectrum and outcome of management based on Advanced Trauma Life Support recommendations. AB - INTRODUCTION: The current management of open pneumothorax (OPTX) is based on Advanced Trauma Life Support (ATLS) recommendations and consists of the application of a three-way occlusive dressing, followed by intercostal chest drain insertion. Very little is known regarding the spectrum and outcome of this approach, especially in the civilian setting. MATERIALS AND METHODS: We conducted a retrospective review of 58 consecutive patients with OPTX over a four-year period managed in a high volume metropolitan trauma service in South Africa. RESULTS: Of the 58 patients included, 95% (55/58) were male, and the mean age for all patients was 21 years. Ninety-seven percent of all injuries were inflicted by knives and the remaining 3% (2/58) of injuries were inflicted by unknown weapons. 59% of injuries were left sided. In six patients (10%) a protocol violation was present in their management. Five of the six patients (83%) in whom protocol violation occurred developed a life-threatening event (tension PTX) compared to none amongst those where the protocol was followed (p < 0.001). There was no mortality as a direct result of management of OPTX following ATLS recommendations. CONCLUSIONS: ATLS recommendations for OPTX are safe and effective. Any deviation from this standard practice is associated with avoidable morbidity and potential mortality. PMID- 26037997 TI - An update on the evaluation and treatment of syndesmotic injuries. AB - INTRODUCTION: Injuries to the distal tibiofibular syndesmosis are frequent and continue to generate controversy. METHODS: The majority of purely ligamentous injuries ("high ankle sprains") is not sassociated with a latent or frank tibiofibular diastasis and may be treated with an extended protocol of physical therapy. Relevant instability of the syndesmosis with diastasis results from rupture of two or more ligaments that require surgical stabilization. Syndesmosis disruptions are commonly associated with bony avulsions or malleolar fractures. Treatment consists in anatomic reduction of the distal fibula into the corresponding incisura of the distal tibia and stable fixation. Proposed means of fixation are refixation of bony syndesmotic avulsions, one or two tibiofibular screws and suture button. There is no consensus on how long to maintain fixation. Both syndesmotic screws and suture buttons need to be removed if symptomatic. RESULTS/COMPLICATIONS: The most frequent complication is syndesmotic malreduction and may be minimized with open reduction and intraoperative 3D scanning. Other complications include hardware failure, heterotopic ossification, tibiofibular synostosis, chronic instability and posttraumatic arthritis. CONCLUSION: The single most important prognostic factor is anatomic reduction of the distal fibula into the tibial incisura. PMID- 26037999 TI - Trauma registry comparison: six-year results in trauma care in Southern Finland and Germany. AB - PURPOSE: To compare the treatment and survival of trauma patients in Germany and Southern Finland. METHODS: Data from Helsinki University Hospital trauma registry (TR-THEL) and TraumaRegister DGU((r)) (TR-DGU) were compared in a period from 2006 until 2011. From TR-DGU level-one trauma centers treating annually >50 injury severity score (ISS) >15 patients were included. The inclusion criterion was ISS >15. Patients under 16 years with penetrating trauma without head injury and transferred in with isolated head injury were excluded. The compared parameters were age, sex, pre-injury ASA, injury scoring, injury pattern, mechanism of injury, injury distribution, pre-hospital timings, transportation method, pre-hospital intubation, treatment at hospital, discharge destination, and 30-day hospital mortality. Expected mortality was defined with the Revised Injury Severity Classification score (RISC). RESULTS: Eighty-five German level one trauma centers were included. A total of 15,306 and 1,274 patients were included in the outcome analysis from TR-DGU and TR-THEL, respectively. The difference between the observed and expected mortality of all patients was -4.1% (standardized mortality ratio [SMR] 0.82) at German hospitals and -4.0% (SMR 0.79) in Helsinki. Differences in the pre- and in-hospital treatment between the two countries were noted (transportation method, intubation rate, intensive care unit treatment, ventilation time, length of stay). CONCLUSION: The overall outcome results of the Helsinki University Hospital trauma unit were similar to those of the German level-one trauma centers. Registry comparison is a feasible method of quality control in a trauma centre. PMID- 26038000 TI - Helmet use in bicycle trauma patients: a population-based study. AB - INTRODUCTION: In recent years, the increasing number of bicyclists has evoked the debate on use of bicycle helmet. The aim of this study was to investigate the association between helmet use and injury pattern in bicycle trauma patients. PATIENTS AND METHODS: We performed a retrospective population-based study of 186 patients treated for bicycle-related injuries at a Level 1 Trauma Centre in Sweden during a 3-year period. Data were collected from case records. Unconditional logistic regression was used to calculate odds ratios (ORs), and 95% confidence intervals (CIs). RESULTS: 43.5% of the 186 patients used a bicycle helmet at the time of the crash. Helmet users were less likely to get head and facial injuries in collisions than non-helmet users (OR, 0.3; 95% CI, 0.07-0.8, and OR, 0.07; 95% CI, 0.02-0.3), whereas no difference was seen in single-vehicle accidents. The risk of limb injuries was higher among helmet users. CONCLUSIONS: Non-helmet use is associated with an increased risk of injury to head and face in collisions, whereas helmet use is associated with an increased risk of limb injuries in all types of crashes. PMID- 26038001 TI - Bone healing of critical size defects of the rat femur after the application of bone marrow aspirate and two different rh-BMP7 concentrations. AB - BACKGROUND: It is known that the application of growth factors can enhance fracture healing in defect fractures. The role of bone marrow aspirate (BMA) in combination with BMP-7 and the dosage of rh BMP-7 are still under discussion. Our hypothesis was that the combination of rh-BMP-7 with BMA can heal bone defects more effectively than rh-BMP-7 alone. METHODS: Twenty-eight rats obtained a 5 mm critical size defect in the diaphysis of the right femur which was stabilized by a plate. Rh-BMP-7 was applied at 10 and 200 ug either with collagen or together with collagen and BMA. Collagen only and collagen with BMA served as control groups. Blood flow was assessed by laser Doppler flowmetry in regular time intervals until euthanasia. Callus formation and bone density were measured by micro-computed tomography and biomechanical stability was evaluated by torsional testing at 4 weeks, postoperatively. RESULTS: Blood flow increased at the operated side after surgery until the second postoperative week independent of treatment. Animals treated with high dose BMP-7 showed significantly (p = 0.001) increased mechanical stiffness independent of BMA treatment. Failure loads were lowest for the two control groups (p = 0.001). The reduction of the BMP-7 dose led to less callus tissue and lower biomechanical stability. BMA did not show significant influence on bone healing. CONCLUSION: The combination of an rhBMP-7 dose that would be equivalent to a dose used clinically in humans with bone marrow aspirate does not heal a critical bone defect more effectively than the same rhBMP-7 dose alone. PMID- 26038002 TI - Does lesser trochanter implication affect hip flexion strength in proximal femur fracture? AB - PURPOSE: In pertrochanteric and intertrochanteric femoral fractures, the avulsion of the lesser trochanter by the pull of the iliopsoas muscle is not uncommon. This fragment is not commonly fixed because the avulsion of the lesser is tough to not influence the clinical outcome but up to date there is no evidence to support this statement. The aim of this study is to evaluate if lesser trochanter implication affects psoas muscle strength in proximal femur fracture. MATERIALS AND METHODS: Patients with a consolidated intertrochanteric or pertrochanteric fracture associated or not with lesser trochanter fracture were enrolled, respectively, in group A and group B. Criteria of inclusion were the achievement of an anatomic reduction with gamma nail and a complete consolidation of the fracture. Criteria of exclusion were a follow-up shorter than 6 months and age over 65 years old at surgery. Patients were retrospectively reviewed for the purpose of this study. Range of motion, modified Harris Hip Score (mHHS), flexion strength with hip in neutral position, at 90 degrees of flexion and in "figure four" position were evaluated on injured and healthy side. On the pre-operative X rays, the vertical displacement of the lesser trochanter was calculated. RESULTS: Groups A and B showed no significant difference in age and follow-up. No statistical difference between the two groups was found in range of motion, mean mHHS, hip flexion strength at 90 degrees of hip flexion. Lesser trochanter fracture group showed a significantly reduced strength in flexion with hip in neutral flexion (mean difference between two groups was 18.5 kgf). Lesser trochanter displacement showed a significant correlation with strength at 90 degrees of flexion. CONCLUSIONS: Our results showed that lesser trochanter implication may result in decreased hip flexion strength. Lesser trochanter displacement is directly correlated with flexion strength. Further studies will be necessary to understand if lesser trochanter fixation may be a good solution for those patients. PMID- 26038003 TI - Abdominal injuries involving bicycle handlebars in 219 children: results of 8 year follow-up. AB - OBJECTIVES: Handlebar injuries are one of the most common causes of abdominal injuries in children. We aim to investigate the epidemiology of bicycle handlebar injuries and to emphasize the severity of the injuries. METHODS: A retrospective analysis of children admitted to our hospital with abdominal injury related to bicycle handlebars was performed. RESULTS: A total of 219 children (187 males and 32 females) younger than 17 years were hospitalized for abdominal handlebar injuries between 2005 and 2013. The age range of the patients was 4-17 (mean 10.93 +/- 3.68) years. Most patients had an imprint of the handlebar edge on their abdomen. The most common abdominal organ injury was liver laceration. 33 patients had pancreas injury and 13 patients had hollow organ injury. Most patients were treated conservatively. Surgery was performed in 24 patients. Hospital stay was 4-60 (mean 9.63 +/- 13.37) days. CONCLUSIONS: Trend of bicycle handlebar trauma over this time period was related to the local floating population and economy. The most common abdominal organ injury was liver. Hollow organ injury required emergency exploratory laparotomy and the Roux-y anastomosis applied well in cases whose gastrointestinal tract damaged seriously. Pancreatic injury usually led to secondary pseudocyst. The percutaneous ultrasound-guided drainage of pancreatic pseudocyst was really an effective way. The trend in the amylase and lipase levels could reflect the pancreatic injury condition and predict prognosis. Early diagnosis and optimal care without delay may help to reduce the morbidity of injuries to the internal organs. Children with abdominal handlebar injuries should be treated with great care. PMID- 26038004 TI - Comparison of recombinant human thrombomodulin and gabexate mesylate for treatment of disseminated intravascular coagulation (DIC) with sepsis following emergent gastrointestinal surgery: a retrospective study. AB - PURPOSE: Recombinant thrombomodulin (rTM) has been available in Japan since 2008, but there is concern about its association with postoperative hemorrhage. The efficacy and safety of rTM were examined in patients with disseminated intravascular coagulation (DIC) caused by a septic condition after gastrointestinal surgery. METHODS: Forty-two patients were emergently admitted to the intensive care unit after emergent gastrointestinal surgery in Kyushu University Hospital from May 2008 to April 2013. Of these patients, 22 had DIC (defined as an acute DIC score >= 4). All but three patients received treatment with gabexate mesylate (GM) (n = 9) or rTM (n = 10). The causes of sepsis were peritonitis with colorectal perforation, anastomotic leakage, and intestinal necrosis. Acute DIC score, sepsis-related organ failure assessment score, platelet count, and a variety of biochemical parameters were compared between rTM and GM recipients after treatment administration. RESULTS: There were no significant differences between the groups for any parameter except C-reactive protein levels. The CRP level tended to be lower in the rTM group than in the GM group. Acute DIC score in the rTM group resolved significantly earlier than that in the GM group. No patient stopped the administration of rTM because of postoperative bleeding. CONCLUSION: rTM may be an effective therapeutic drug for the treatment of septic patients with DIC following emergent gastrointestinal surgery. PMID- 26038005 TI - Use of propofol as an induction agent in the acutely injured patient. AB - PURPOSE: Etomidate is a commonly used agent for rapid sequence induction (RSI) in trauma due to its limited hemodynamic effects. Given a recent nationwide shortage of etomidate, alternative induction agents may be required. Propofol is a frequent substitute; however, concern exists regarding its potential hypotensive effects. The study attempts to determine the hemodynamic effects of propofol and etomidate following RSI in trauma bay. METHODS: A retrospective study was performed on 76 consecutive trauma patients requiring RSI at a single academic medical center. Patients were stratified by age, gender, mechanism of injury, Injury Severity Score (ISS), and Glasgow Coma Scale (GCS). Pre-induction and post induction hemodynamic parameters were evaluated, and a multivariate regression analysis was performed. RESULTS: The mean age was 42, ISS was 13, and GCS was 9.8. The mean dose of propofol was 127 +/- 5 mg and the mean dose of etomidate was 21 +/- 6 mg. Patients who received propofol were younger and had a lower ISS. The etomidate group had significantly increased post-induction systolic blood pressure but no difference in mean arterial pressure or heart rate when compared to pre-induction parameters. The propofol group had no significant changes in any post-induction parameter compared to pre-induction parameter. CONCLUSION: RSI with propofol did not result in hypotension in our patient population, suggesting that a reduced dose of propofol may represent a reasonable alternative to etomidate in hemodynamically stable trauma patient. Further research is warranted to assess the safety of propofol in the acutely injured patient. PMID- 26038006 TI - When do anterior external or internal fixators provide additional stability in an unstable (Tile C) pelvic fracture? A biomechanical study. AB - PURPOSE: This study aimed at evaluating the additional stability that is provided by anterior external and internal fixators in an unstable pelvic fracture model (OTA 61-C). METHODS: An unstable pelvic fracture (OTA 61-C) was created in 27 synthetic pelves by making a 5-mm gap through the sacral foramina (posterior injury) and an ipsilateral pubic rami fracture (anterior injury). The posterior injury was fixed with either a single iliosacral (IS) screw, a single trans iliac, trans-sacral (TS) screw, or two iliosacral screws (S1S2). Two anterior fixation techniques were utilized: external fixation (Ex-Fix) and supra acetabular external fixation and internal fixation (In-Fix); supra-acetabular pedicle screws connected with a single subcutaneous spinal rod. The specimens were tested using a nondestructive single-leg stance model. Peak-to-peak (P2P) displacement and rotation and conditioning displacement (CD) were calculated. RESULTS: The Ex-Fix group failed in 83.3 % of specimens with concomitant single level posterior fixation (Total: 15/18-7 of 9 IS fixation, 8 of 9 TS fixation), and 0 % (0/9) of specimens with concomitant two-level (S1S2) posterior fixation. All specimens with the In-Fix survived testing except for two specimens treated with In-Fix combined with IS fixation. Trans-sacral fixation had higher pubic rotation and greater sacral and pubic displacement than S1S2 (p < 0.05). Rotation of the pubis and sacrum was not different between In-Fix constructs combined with single-level IS and TS fixation. CONCLUSION: In this model of an unstable pelvic fracture (OTA 61-C), anterior fixation with an In-Fix was biomechanically superior to an anterior Ex-Fix in the setting of single-level posterior fixation. There was no biomechanical difference between the In-Fix and Ex-Fix when each was combined with two levels of posterior sacral fixation. PMID- 26038007 TI - Closed reduction and immobilization of displaced distal radial fractures. Method of choice for the treatment of children? AB - PURPOSE: The therapy of distal radial fractures in children is expected to be as non-invasive as possible but also needs to deliver the definite care for gaining optimal reduction and stabilizing the fracture. Therefore, closed reduction and immobilization is competing with routine Kirschner wire fixation. The aim of our study was to investigate if closed reduction and immobilization without osteosynthesis can ensure stabilization of the fracture. METHODS: We chose a retrospective study design and analyzed 393 displaced distal radial fractures in children from 1 to 18 years with open epiphyseal plates studying medical files and X-rays. The Pearson's chi (2) test was applied. Statistical analysis was performed using IBM SPSS Statistics 20.0. Statistical significance was set at an alpha level of P = 0.05. RESULTS: Of these studied fractures 263 cases were treated with closed reduction and immobilization. Only 38 of these needed secondary interventions, 28 of these underwent reduction after redisplacement and ten patients received secondary Kirschner wire fixation. The last follow-up examination after 4-6 weeks revealed that 96.4% of fractures initially treated with closed reduction and immobilization were measured within the limits of remodeling. 104 of the studied fractures were treated with cast immobilization alone when displacement was expected to correct due to remodeling. Here 22.1% of patients needed secondary reduction. Furthermore, primary Kirschner wire fixation was performed in only 25 children with unstable fractures and only one received further treatment. Interestingly, operative reports of primary closed reduction revealed that repeated maneuvers of reduction as well as residual displacement are risk factors for redisplacement. CONCLUSION: For the treatment of displaced distal radial fractures in children closed reduction and immobilization can be considered the method of choice. However, for cases with repeated reduction maneuvers or residual displacement we recommend primary Kirschner wire fixation to avoid redisplacement. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 26038008 TI - The accuracy of physical examination in identifying significant pathologies in penetrating thoracic trauma. AB - INTRODUCTION: Accurate physical examination (PE) remains a key component in the assessment of penetrating thoracic trauma (PTT), despite the increasing availability of advanced radiological imaging. Evidence regarding the accuracy of PE in identifying significant pathology following PTT is limited. MATERIALS AND METHODS: A retrospective review of 405 patients was undertaken over a twelve month period to determine the accuracy of PE in identifying significant pathology (SP) subsequently confirmed on chest radiographs (CXRs) in patients who sustained stab injuries to the thorax. RESULTS: Ninety-seven per cent (372/405) of patients were males, and the mean age was 24 years. The weapons involved were knives in 98 % (398/405), screwdrivers in 1 % (3/405) and unknown in the remaining 1 %. Fifty nine per cent (238/405) of all injuries were on the left side. There were 306 (76 %) SPs identified on CXR. Ninety-nine (24 %) CXRs were entirely normal. Based on PE alone, 223 (55 %) patients were thought to have SPs present, 182 (45 %) patients were thought to have no SPs. The overall sensitivity of PE in identifying SPs was 68 % (63-73, 95 % CI), with a specificity of 86 % (77-92, 95 % CI). The PPV of PE was 94 % (90-97, 95 % CI) and the NPV was 47 % (39-54, 95 % CI). The sensitivity of PE for identifying a pneumothorax was 59 % (51-66, 95 % CI), with a specificity of 96 % (89-99, 95 % CI) and the sensitivity of PE for identifying a haemothorax was 79 % (72-86, 95 % CI), with a specificity of 96 % (89-99, 95 % CI). CONCLUSIONS: PE is inaccurate in identifying SPs in PTT. The increased reliance on advanced radiological imaging and the subsequent reduced emphasis on PE may have contributed to rapid deskilling amongst surgical residents. The importance of PE must be repeatedly re-emphasised. PMID- 26038009 TI - Decreased muscle strength is associated with impaired long-term functional outcome after intramedullary nailing of femoral shaft fracture. AB - PURPOSE: To examine the long-term outcome after intramedullary nailing of femoral diaphysial fractures measured as disease-specific patient reported function, walking ability, muscle strength, pain and quality of life (QOL). METHODS: Cross sectional study. Retrospective review and follow-up with clinical examination of 48 patients treated with intramedullary nailing after femoral shaft fracture between 2007 and 2010. The patients underwent a clinical examination and assessment of walking ability, maximal muscle strength during knee flexion and extension and hip abduction. Hip disability and Osteoarthritis Outcome Score (HOOS) and questionnaire evaluating QOL (Eq5D-5L) were completed by patients. RESULTS: Fourty-eight patients agreed to participate. Mean time for follow-up was 4.7 years. The mean HOOS scores were 84.9 (Pain), 86.6 (ADL), 85.0 (Symptoms), 72.6 (QOL), and 69.1 (Sport). The mean muscle strength of knee flexion with the injured leg (226.0 N) was significantly lower then knee flexion with the non injured leg (259.5 N, P < 0.0001). Likewise for knee extension (335.2 vs 406.4 N, P < 0.001) and hip abduction (129.2 vs 156.0 N, P < 0.001). Significant association between HOOS and an increase in the difference in muscle strength were observed as well as between worse HOOS outcome and increasing body mass index. CONCLUSION: This study showed that decreased muscle strength for knee flexion, knee extension and hip abduction was associated with worse long-term functional outcome measured with a disease-specific questionnaire (HOOS) after intramedullary nailing of femoral shaft fracture. PMID- 26038010 TI - 5-HT2a receptor antagonism reduces burn-induced macromolecular efflux in rats. AB - BACKGROUND: Major thermal injuries lead to a systemic inflammatory response with systemic capillary leakage and multiple organ dysfunction. This systemic inflammatory response is induced by a variety of immunmodulative molecules including TNFalpha and serotonin. Unspecific serotonin antagonism leads to reduced macromolecular efflux in rat mesenteries after burn plasma transfer. The aim of the present study was to evaluate the effect of specific 5-HT2a antagonism on early burn edema. METHODS: Donor rats (DR) underwent thermal injury (100 degrees C water, 30% BSA, 12 s) for positive controls. For negative controls, DR underwent sham burn (37 degrees C water, 30% BSA, 12 s). DR plasma (harvested 4 h post-trauma) was transferred to healthy individuals for positive controls. Study rats received burn plasma (BP) and a Bolus injection of Ketanserin (Ket) (1 mg kg(-1) body weight). Negative controls underwent sham burn plasma infusion. Intravital microscopy was performed in mesenteric venules (0/60/120 min). Edema was assessed by FITC-albumin extravasation. Additionally, leukocyte rolling and sticking (cells mm(-2)) as well as microhemodynamic parameters were assessed. RESULTS: Significant systemic capillary leakage was observed after BP transfer at 120 min and additional administration of Ket attenuated the postburn edema to sham burn levels. Ket also leads to significantly decreased leukocyte-endothelial interactions when compared to positive controls. CONCLUSION: 5-HT2a antagonism reduces plasma extravasation after burn plasma transfer in healthy individuals. The influence of leukocyte-endothelial interactions on postburn edema remains unclear. PMID- 26038011 TI - The impact of body mass index on severity, patterns and outcomes after traumatic brain injuries caused by low level falls. AB - PURPOSE: Low level falls are a common cause of traumatic brain injuries (TBI) and are associated with significant mortality and disability. The aim of this study was to analyse whether BMI, height and weight of patients were related to severity, patterns and outcomes of TBI caused by low level falls. METHODS: Data on patients with TBI where cause of injury was a low level fall (fall < 3 m) with known body mass index (BMI) (N = 683) were analysed. Patients were categorized into underweight, normal, pre-obese and obese based on BMI and demographic characteristics, injury severity, patterns and outcomes were compared. In addition, physiological status, comorbidities and length of hospitalization were analysed in a subset of patients where this information was available. RESULTS: The median BMI was 25.6. About 1/10 of patients were obese. The mean age and proportion of male sex of patients was increasing with increasing BMI. The patients in all BMI groups were of similar injury severity and neurological status. There was also no difference in mortality and functional outcome based on patient's BMI. Obese and pre-obese patients required longer stay at ICU and in hospital. CONCLUSION: We found no associations between BMI and severity or outcome of TBI caused by low level falls. More detailed data and further studies are needed to fully elucidate these complex relationships. PMID- 26038012 TI - Penetrating torso injuries in older adults: increased mortality likely due to "failure to rescue". AB - PURPOSE: Approximately 8 % of injuries in the elderly are from penetrating mechanisms. The natural history of potentially survivable penetrating torso wounds in the elderly is not well studied. Older adults with penetrating injuries to the torso may have worse outcomes than matched, younger patients due to a failure to rescue after complications. METHODS: A retrospective chart review of all patients >=55 (older) with a penetrating injury (GSW or SW) to the torso over 20 years was performed. All patients with a maximum AIS chest or abdomen >1 and <6 were included. A matched cohort (mechanism, AIS chest and abdomen, ISS and sex) of patients between the ages of 20-40 years (young) was created (3 young, 1 older). Differences in hemodynamics, complications, length of stay and mortality were analyzed. RESULTS: 105 older met inclusion criteria were compared to 315 young patients. Hemodynamic status was similar between the groups. Older patients required ICU care more often than younger patients, p < 0.05. Older patients required longer ICU stays, p < 0.001 and longer hospitalizations, p = 0.0012. More older patients (41.0 %) suffered post-injury complications compared to the young (26.4 %), p = 0.005. Older patients who suffered a complication had a higher mortality (30.2 %) than the young after a complication (10.8 %), p = 0.007. CONCLUSIONS: While uncommon, penetrating injuries to older adults are associated with higher rates of post-injury complications and increased mortality. This may represent a "failure to rescue" and represent an opportunity for improved post-injury care in older adults who suffer potentially survivable penetrating torso injuries. PMID- 26038013 TI - Clinician-performed ultrasound in hemodynamic and cardiac assessment: a synopsis of current indications and limitations. AB - Accurate hemodynamic and intravascular volume status assessment is essential in the diagnostic and therapeutic management of critically ill patients. Over the last two decades, a number of technological advances were translated into a variety of minimally invasive or non-invasive hemodynamic monitoring modalities. Despite the promise of less invasive technologies, the quality, reliability, reproducibility, and generalizability of resultant hemodynamic and intravascular volume status data have been lacking. Since its formal introduction, ultrasound technology has provided the medical community with a more standardized, higher quality, broadly applicable, and reproducible method of accomplishing the above mentioned objectives. With the advent of portable, hand-carried devices, the importance of sonography in hemodynamic and volume status assessment became clear. From basic venous collapsibility and global cardiac assessment to more complex tasks such as the assessment of cardiac flow and tissue Doppler signals, the number of real-life indications for sonology continues to increase. This review will provide an outline of the essential ultrasound applications in hemodynamic and volume status assessment, focusing on evidence-based uses and indications. PMID- 26038014 TI - Child drowning deaths in Aydin province, western Turkey, 2002-2012. AB - INTRODUCTION: Drowning, a major public health problem worldwide, occurs as an accident, suicide, or homicide. Deaths with an accidental origin are common in childhood in the 0-18 age group. In our study, pediatric drowning cases for whom a postmortem examination and an autopsy were conducted by Adnan Menderes University Department of Forensic Medicine were evaluated. The characteristics were determined and compared with domestic and foreign studies. MATERIALS AND METHODS: A total of 39 cases in the 0-18 age group in Aydin between 2002 and 2012 were analyzed regarding age, gender, cause of death, origin, the accident scene, and the month in which the death occurred. RESULTS: Of the drowning cases, 33 (84.6 %) were male, and 6 (15.4 %) were female. The average age was 9.08 years, and drowning is most common in the 0-4 age group (33.3 %). The scene of the accident was an irrigation channel in 43.5 % of the cases, a river in 15.3 %, a sea in 12.8 %, a pool in 10.2 %, and a lake or pond in 7.69 %. CONCLUSION: Drowning deaths are a serious and preventable public health problem worldwide. There are strong correlations among lack of adult supervision, lack of precautions, and neglect. PMID- 26038016 TI - Electrical burn injuries secondary to copper theft. PMID- 26038015 TI - Out of hospital point of care ultrasound: current use models and future directions. AB - INTRODUCTION: Ultrasound has evolved from a modality that was once exclusively reserved to certain specialities of its current state, in which its portability and durability lend to its broadly increasing applications. OBJECTIVES: This review describes portable ultrasound in the hospital setting and its comparison to gold standard imaging modalities. Also, this review summarizes current literature describing portable ultrasound use in prehospital, austere and remote environments, highlighting successes and barriers to use in these environments. DISCUSSION: Prehospital ultrasound has the ability to increase diagnostic ability and allow for therapeutic intervention in the field. In austere environments, ultrasound may be the only available imaging modality and thus can guide diagnosis, therapeutics and determine which patients may need emergent transfer to a healthcare facility. The most cutting edge applications of portable ultrasound employ telemedicine to obtain and transmit ultrasound images. This technology and ability to transmit images via satellite and cellular transmission can allow for even novice users to obtain interpretable images in austere environments. Portable ultrasound uses have steadily grown and will continue to do so with the introduction of more portable and durable technologies. As applications continue to grow, certain technologic considerations and future directions are explored. PMID- 26038017 TI - Sepsis in fatal pelvic trauma patients: report from a level-1 Indian Trauma Centre. PMID- 26038018 TI - The outcome after lateral tibial plateau fracture treated with percutaneus screw fixation show a tendency towards worse functional outcome compared with a reference population. AB - PURPOSE: The objective of this study was to evaluate the functional and radiological outcome after lateral tibial plateau fractures (Muller AO classification (AO) 41-B1, B2 and B3) treated with minimal invasive bone tamp reduction and percutaneous screw fixation. METHODS: Retrospective, cross sectional study. Review and clinical examination of 37 patients treated between 2005 and 2010. The patients completed a clinical examination, Knee Injury and Osteoarthritis Outcome Score (KOOS) and questionnaire evaluating QOL (Eq5D-5L). RESULTS: Thirty-seven patients agreed to participate (76 %). Mean time of follow up was 5.2 years. At final follow-up, maintained anatomical joint reduction was achieved in 34 patients. The mean KOOS score was pain = 84.4, ADL = 88.4, symptoms = 80.7, QOL = 70.3, sport = 59.6. Compared with the established KOOS reference population patients, the current study reports a tendency towards worse KOOS scores but is only significant for KOOS sport. The mean Eq5D-5L index was 0.815 and shows a tendency towards worse outcome compared with the reference population. Mean knee flexion: 125.7 degrees (95-135). A reduced number of sit to-stands in the mean 30-s chair stand test showed a significant negative association with KOOS. The study showed a significant association between younger age at surgery and worse KOOS outcome. CONCLUSION: At 5.2-year follow-up, the patients reported a tendency towards worse KOOS and Eq5D-5L scores compared with established reference populations. This study shows a significant association between a decrease in muscle strength and worse KOOS outcome. Furthermore, a significant association between younger age at the time of surgery and worse KOOS outcome score was observed. PMID- 26038020 TI - 13-Year experience in external fixation of the pelvis: complications, reduction and removal. AB - PURPOSE: To evaluate the complications associated with anterior pelvic external fixation and the success of this device in maintaining reduction when used in conjunction with sacroiliac screws. METHODS: Through a retrospective clinical study at an academic Level I Trauma Center, 129 patients fit the criteria for inclusion with a mean duration of anterior pelvic external fixation of 62 days and mean follow-up of 360 days. Charts were reviewed for complications postoperatively. The symphysis diastasis, vertical displacement and posterior displacement of each hemipelvis were quantified from pelvic radiographs. RESULTS: Of the 129 patients receiving anterior pelvic external fixation, 14 (10.9 %) presented to an emergency department for problems with their anterior pelvic external fixation. Of these 14 patients, 7 (5.4 %) required readmission, all for infectious concerns necessitating IV antibiotics. 6 (4.7 %) required formal operative debridement and device removal. 13 patients (10.1 %) had superficial pin site infections successfully treated with oral antibiotics. Reduction was maintained (rated as fair, good or excellent) in all patients with radiographic follow-up (n = 74, average radiographic follow-up of 216 days) following removal of their anterior pelvic external fixation. 38 patients (30.4 %) had their anterior pelvic external fixation removed in clinic, while 87 (69.6 %) had formal removal in the operating room. CONCLUSION: While previous data suggest high complication rates in definitive anterior pelvic external fixation, we present the largest cohort of patients receiving anterior pelvic external fixation and sacroiliac screws, demonstrating a low complication rate while maintaining reduction of the pelvic ring. In addition, we found that these devices could be reliably removed in a clinic setting. PMID- 26038021 TI - The orthopaedic experience of Kasr Al Ainy Hospitals in the Egyptian revolution. AB - BACKGROUND: 25 January 2011 marks the onset of the Egyptian revolution. Causalities were estimated to be at least 846 moralities and 6000 injuries. The purpose of this study is to document the orthopaedic injuries coming to the tertiary center of Cairo University Hospitals (Kasr Al Ainy) during the climax of the Egyptian revolution and the lessons learnt. MATERIAL AND METHODS: We retrospectively reviewed all hospital admissions in the period of 28 January 2011 till 4th February 2011 due to injuries related to the revolution. Total number of patients examined by the orthopaedic residents and staff members in the emergency room during that period was 553 patients. A total of 110 patients were admitted to the orthopaedic department. RESULTS: Various injuries were encountered. The most common were gun shot injuries (45 cases), followed by falls (28 cases), road traffic accidents (26) and trauma by blunt objects (11 cases). Overall 121 operative procedures were conducted in the operative theater by our residents and staff members. Fractures of the femur were the most common fractures (27 cases) followed by forearm fractures (13 cases). Limitations were the availability of a limited variety of orthopaedic implants. CONCLUSION: We believe that tertiary centers should be prepared for mass causalities. A variety of orthopaedic implants should be within reach and that personnel should be trained to work under stressful environments with a well laid disaster management plan. PMID- 26038019 TI - Portable ultrasound in disaster triage: a focused review. AB - Ultrasound technology has become ubiquitous in modern medicine. Its applications span the assessment of life-threatening trauma or hemodynamic conditions, to elective procedures such as image-guided peripheral nerve blocks. Sonographers have utilized ultrasound techniques in the pre-hospital setting, emergency departments, operating rooms, intensive care units, outpatient clinics, as well as during mass casualty and disaster management. Currently available ultrasound devices are more affordable, portable, and feature user-friendly interfaces, making them well suited for use in the demanding situation of a mass casualty incident (MCI) or disaster triage. We have reviewed the existing literature regarding the application of sonology in MCI and disaster scenarios, focusing on the most promising and practical ultrasound-based paradigms applicable in these settings. PMID- 26038022 TI - Traumatic tension pneumothorax: experience from 115 consecutive patients in a trauma service in South Africa. AB - INTRODUCTION: Traumatic tension pneumothorax (TPTX) is a life threatening condition, but literature describing this condition specifically in developing countries is scarce. MATERIALS AND METHODS: We conducted a retrospective review of 115 patients with a TPTX, managed over a 4-year period in a high volume trauma service in South Africa. RESULTS: A total of 118 TPTXs were identified in 115 patients. Eighty-nine percent (102/115) were males, and the mean age was 26 years (SD +/- 6 years). Seventy-four percent (87/118) of all TPTXs occurred on the left side. The mechanisms of injury were penetrating in 71 % (82/115) [82 stab injuries], and blunt in 29 % (33/115) [31 road traffic accidents and 2 assaults]. Ninety-seven percent (111/115) of patients presented directly to our unit, while 3 % (4/115) were referrals from other hospitals. Fifteen percent (17/115) of needle decompressions were performed in the pre-hospital setting while the remaining 85 % (98/115) were performed on arrival (73 were recognised clinically and 25 were not). Of the 25 TPTXs that were not recognised clinically on initial assessment, 12 were discovered on CXR, 8 on CT scans and 5 in the operating room (OR). The overall mortality was 9 % (10/115) [7 in CXR, 2 in CT, 1 in OR]. None of the patients who had the TPTXs identified on initial clinical assessment died (0/73), compared with those who were missed on initial clinical assessment, in which the mortality was significantly higher at 40 % (10/25), (p < 0.001). CONCLUSIONS: Penetrating injuries accounted for the majority of TPTXs seen in our setting. Clinical recognition of the entity may be challenging and delayed recognition is associated with significant mortality. PMID- 26038023 TI - Increase in urinary sodium excretion in spinal cord injury patients in the emergency department. AB - OBJECTIVE: Spinal cord injury (SCI) is a pathological condition known to produce hyponatremia. The aim of this study was to elucidate the dynamics of urinary sodium excretion in patients with spinal cord injury. METHODS: SCI patients undergoing intensive care management were enrolled in this study. These patients were divided into two groups: those with Frankel Grade A spinal cord injury manifesting complete, severe motor disorders (FA group) and those with incomplete spinal cord injury (non-FA group). The occurrence of episode of hyponatremia (serum sodium <135 mmol/L), hypotension, and bradycardia during the first 14 hospital days was counted and fractional excretion of sodium (FENa) was calculated on the 1st, 7th, and 14th hospital days. RESULTS: Thirty-four patients (FA group, n = 9; non-FA group, n = 25) were included. Eight patients (88.9 %) in the FA group and three patients (12 %) in the non-FA group experienced at least one episode of hyponatremia during the first 14 hospital days. In the FA group, the FENa was significantly increased on the 7th and 14th hospital days compared to the 1st hospital day. FENa on the 14th hospital day was a significant independent predictor of hyponatremic episodes. Hypotension and bradycardia as the symptoms of sympathetic blockade differed significantly as independent predictors of increased FENa on the 14th hospital day. CONCLUSION: Urinary sodium excretion calculated by FENa increased in patients with severe spinal cord injury. Sympathetic blockade due to SCI may increase urine sodium excretion and lead to hyponatremia. PMID- 26038024 TI - Impact of haemorrhagic shock intensity on the dynamic of alarmins release in porcine poly-trauma animal model. AB - PURPOSE: Traumatic insults result in an altered inflammatory response, in which alarmins release has a central role. The impact of haemorrhagic shock intensity on the long-term kinetics of alarmins is not yet fully elucidated. We investigated these aspects in a combined trauma (chest, abdominal, and extremities injury) porcine model with different severities and durations of haemorrhagic shock. METHODS: After induction of combined trauma (tibia fracture, lung contusion, and liver laceration), haemorrhagic shock was induced at different intensities: moderate haemorrhage (MH; n = 15): mean arterial pressure (MAP) <30 +/- 5 mmHg [maximum loss of total blood volume (TBVmax): 45 %] for 90 min, and severe haemorrhage (SH; n = 10): MAP <25 +/- 5 mmHg (TBVmax 50 %) for 120 min. Resuscitation was performed using a standardized crystalloid infusion protocol. Animals were mechanically ventilated and underwent ICU-monitoring for 48 h (MH) and 48.5 h (SH). Blood samples were collected over the clinical time course, and systemic levels of serum alarmins [High-Mobility Group Protein B-1 (HMGB-1) and Heat Shock Protein 70 (HSP70)] were measured using an ELISA kit. RESULTS: Heart rate, systemic blood pressure, lactate, and base excess were significantly altered as a function of haemorrhagic shock in both trauma groups (MH and SH). Systemic HMGB-1 levels were significantly elevated in both trauma groups when compared to the sham group. Haemorrhagic shock severity and duration were positively correlated with HMGB-1 levels and compared to baseline values, concentrations remained significantly increased in SH when compared to MH. On the other hand, we observed a significant decrease in the systemic HSP70 levels of trauma groups (MH, and SH) when compared to the sham group, which was significantly decreased compared to baseline values in SH over the entire time course. CONCLUSION: Our data show that haemorrhagic shock duration and severity affect the systemic levels of HMGB-1 and HSP70. This early alarmins release after trauma can be used to guide the treatment strategies (e.g. surgical procedures) of polytrauma patients. PMID- 26038025 TI - Comparison of the topical haemostatic efficacy of nano-micro particles of clinoptilolite and kaolin in a rat model of haemorrhagic injury. AB - PURPOSE: This study was designed to investigate if the potential haemostatic efficacy of gauze-impregnated clinoptilolite created with nano-technology is as strong as the widely used kaolin to control pulsatile arterial bleeding due to major vascular injury. METHODS: 42 rats were separated into three groups of kaolin, clinoptilolite and control groups. The femoral artery was isolated and active arterial haemorrhage was performed. After 30 s of free arterial haemorrhage, compression was applied with a standard 100 g scale and haemostasis was assessed at the 1st, 3rd and 5th minutes. All groups were observed throughout 60 min for survival without any fluid resuscitation and the mean arterial pressure, pulse, body/surface temperature and arterial blood gas values were measured. RESULTS: In the control group, haemostasis did not develop in any of the 12 rats and the survival rate was 5/12 (41.66 %). In the kaolin group, haemostasis developed in seven rats and of these, bleeding reoccurred in four. The survival rate was 10/13 (76.92 %). In the clinoptilolite group, haemostasis developed in eight rats and bleeding recurred in only one. The survival rate was 100 %. In terms of survival, the clinoptilolite and kaolin groups showed superiority to the control group (p = 0.002, p = 0.082). In the evaluation of recurrent haemorrhaging in the rats with haemostasis, clinoptilolite was observed to provide better coagulation than kaolin. CONCLUSION: A statistically significant difference was determined in clinoptilolite and kaolin group, when they are separately compared with the control group in respect of the effect on MAP, HCO3 (-), lactate, base excess, haemostasis duration and survival rates. The effect of clinoptilolite on haemostasis and survival time was observed to be at least as good as that of kaolin; therefore, clinoptilolite can be used as an active ingredient in a topical haemostat. PMID- 26038026 TI - Open reduction and internal fixation versus percutaneous transverse Kirschner wire fixation for single, closed second to fifth metacarpal shaft fractures: a systematic review. AB - PURPOSE: Open reduction and internal fixation (ORIF) of single, closed metacarpal shaft fractures is increasingly preferred over closed reduction and percutaneous fixation (K-wire). The aim of this systematic review is to determine whether the preference for ORIF can be substantiated based on the available literature regarding the functional outcome and complications after surgery. METHODS: A systematic review was performed using a computer-based search on MedLine and Embase, following the preferred reporting items for systematic and meta-analyses guidelines. RESULTS: Five non-comparative studies were found. Two studies reported on 36 ORIF-treated patients. Three studies reported on 65 K-wire-treated patients. Complications were reported in 8 ORIF-treated patients (22 %) and in 23 K-wire-treated patients (35 %). Functional outcome was generally reported as good for both techniques. Nonetheless functional impairment requiring reoperation was reported in 6 ORIF-treated patients (17 %) and in none of the K-wire-treated patients. CONCLUSIONS: Although for both techniques good functional outcomes were reported, the significance of the functional impairment after ORIF requiring reoperation suggests ORIF to be a less favorable technique for single, closed metacarpal shaft fractures. PMID- 26038027 TI - Clinician-performed abdominal sonography. AB - INTRODUCTION: Point-of-care ultrasonography is increasingly utilized across a wide variety of physician specialties. This imaging modality can be used to evaluate patients rapidly and accurately for a wide variety of pathologic conditions. METHODS: A literature search was performed for articles focused on clinician-performed ultrasonography for the diagnosis of appendicitis, gallbladder disease, small bowel obstruction, intussusception, and several types of renal pathology. The findings of this search were summarized including the imaging techniques utilized in these studies. CONCLUSION: Clinician performed point-of-care sonography is particularly well suited to abdominal applications. Future investigations may further confirm and extend its utility at the bedside. PMID- 26038028 TI - Treatment of traumatically cutaneous necrosis of buttocks using vacuum sealing drainage combined with ileostomy. AB - PURPOSE: The purpose of this study is to evaluate the surgical technique and review the therapeutic effect of vacuum sealing drainage combined with ileostomy treating patients of traumatically buttock skin necrosis. METHODS: 26 patients with buttock wounds were dressed and 6-12 days later, buttock skin necrosis boundaries were clear and debridement was performed. General surgeons were invited to perform the ileostomy. Thorough debridement was conducted and vacuum sealing drainage (VSD) devices were used to cover buttock wounds. Debridement and VSD were operated every 5-7 days until the granulation tissue of buttock wound was fresh. Then epidermal skin graft from thigh was performed to cover the granulation wound. About 3 months later after skin graft survival completely, the ileum was reversed by general surgeons and the patients recovered defecation using anus. RESULTS: The granulation tissues of all patients were fresh after debridement and VSD 2-3 times. In 20 cases, transplanted epidermal skin grew well. In six cases, necrosis was observed at the margins of the flap and further debridement and skin graft were conducted. During the follow-up period of approximate 6 months, the flaps grew well and the patients defecated normally from anus. CONCLUSIONS: Treating traumatically cutaneous necrosis of buttocks with vacuum sealing drainage and ileostomy can gain good therapeutic effect. PMID- 26038029 TI - Management of blunt pancreatic trauma: what's new? AB - Pancreatic injuries are relatively uncommon but present a major challenge to the surgeon in terms of both diagnosis and management. Pancreatic injuries are associated with significant mortality, primarily due to associated injuries, and pancreas-specific morbidity, especially in cases of delayed diagnosis. Early diagnosis of pancreatic trauma is a key for optimal management, but remains a challenge even with more advanced imaging modalities. For both penetrating and blunt pancreatic injuries, the presence of main pancreatic ductal injury is the major determinant of morbidity and the major factor guiding management decisions. For main pancreatic ductal injury, surgery remains the preferred approach with distal pancreatectomy for most injuries and more conservative surgical management for proximal ductal injuries involving the head of the pancreas. More recently, nonoperative management has been utilized, especially in the pediatric population, with the potential for increased rates of pseudocyst and pancreatic fistulae and the potential for the need for further intervention and increased hospital stay. This review presents recent data focusing on the diagnosis, management, and outcomes of blunt pancreatic injury. PMID- 26038030 TI - Nine-year change of mortality and discharge against medical advice among major trauma patients in a Chinese Intensive Care Unit. AB - BACKGROUND: The mortality/morbidity of patients can be used to evaluate the quality of a trauma care, which can be influenced by incidence of discharge against medical advice (DAMA). OBJECTIVE: This study was to investigate annual changes of mortality/morbidity and DAMA of trauma patients in one Chinese Intensive Care Unit (ICU) in 9 years. METHODS: A retrospective analysis of data [age, Injury Severity Score (ISS), Acute Physiology and Chronic Health Evaluation II (APACHE II), Glasgow Coma Scale (GCS), mortality rate, and DAMA] was performed with trauma patients admitted in the emergency ICU of the Second Affiliated Hospital of Zhejiang University from 2003 to 2011. RESULTS: The rate of total mortality (in-hospital death and dying at discharge) was 6.9 % and the rate of DAMA (deterioration at discharge and improvement at discharge) was 6.6 %. The mortality rate was significantly decreased from 11.1 to 4.6 %, and the rate of deterioration at discharge was increased from 2.8 to 6.4 %. Among the three periods (2003-2005, 2006-2008, and 2009-2011), the age and APACHE II score of patients in total death, deterioration at discharge, and death plus deterioration at discharge groups were highest in the period 2009-2011, whereas the GCS was statistically lower in all groups except in the deterioration at discharge group. CONCLUSION: The medical quality of trauma care has been improved through gradual improvement of instruments and trained medical staffs. The rate of deterioration at discharge was increased, especially in elder patient group. The DAMA had a significant impact on the accurate assessment of trauma care, which should be paid more attention on its potential roles in the future. PMID- 26038031 TI - From FAST to E-FAST: an overview of the evolution of ultrasound-based traumatic injury assessment. AB - Ultrasound is a ubiquitous and versatile diagnostic tool. In the setting of acute injury, ultrasound enhances the basic trauma evaluation, influences bedside decision-making, and helps determine whether or not an unstable patient requires emergent procedural intervention. Consequently, continued education of surgeons and other acute care practitioners in performing focused emergency ultrasound is of great importance. This article provides a synopsis of focused assessment with sonography for trauma (FAST) and the extended FAST (E-FAST) that incorporates basic thoracic injury assessment. The authors also review key pitfalls, limitations, controversies, and advances related to FAST, E-FAST, and ultrasound education. PMID- 26038032 TI - Blunt abdominal trauma and mesenteric avulsion: a systematic review. AB - PURPOSE: The aim of this study is to establish the biomechanics, presentation and diagnosis of mesenteric avulsions following blunt abdominal trauma and reach a consensus on their overall management. MATERIALS AND METHODS: A systematic review of literature in MedLine, Embase, Scopus and CINHAL in English language from 1951 to November 2014 was performed. A total of 20 reported cases were identified. Variables including patient's demographics, signs and symptoms, mechanism of injury, investigative modality, management, length of stay, follow-up and outcomes were reviewed and analyzed. RESULTS: The median age of the cohort was 28.5 years (range 10-58 years), with a male-to-female ratio of 3:1. The commonest mechanism of injury was road traffic accident due to seat belt restraint (n = 12, 60 %). The commonest presentation was diffuse abdominal tenderness (n = 10, 45 %) followed by ecchymosis/bruising (n = 9, 40 %). Computed tomography (CT) remained the investigative modality of choice (n = 9, 45 %). All cases had an emergency exploratory laparotomy (n = 18, 90 %) within the initial 24 h and the median length of stay was 19 days (range 4-90 days). The overall mortality was 15 % (n = 3). CONCLUSION: Mesenteric avulsion is rare and has a complex and vague presentation. Due to its potential mortality and morbidity, emergency physicians should keep a high index of suspicion in individuals with blunt abdominal trauma from any mechanism of injury. PMID- 26038034 TI - "Management of blunt renal injury: what is new?". AB - The diagnosis, workup and management of blunt renal injury have evolved greatly over the past decades. Evaluation and management of blunt renal injury echoes the increasing success of nonoperative management in other blunt abdominal solid organ injury, such as liver and spleen. Decision-making difficulties still remain regarding the optimal imaging, grading and degree of interventional or operative exploration used. Increasingly, initial nonoperative management has gained acceptance and appears to be applicable even high-grade injuries. Emerging techniques in highly sensitive imaging as well as interventional angiography have allowed safe nonoperative management in the appropriate patient. This review will focus on the contemporary workup and management of blunt renal injury while focusing on some of the emerging literatures in regard to refined imaging and grading of injuries as well as techniques to increase the success of nonoperative management. PMID- 26038036 TI - Focus on pelvis and acetabulum. PMID- 26038035 TI - The outcomes of the elderly in acute care general surgery. AB - INTRODUCTION: Elderly patients form a growing subset of the acute care surgery (ACS) population. Older age may be associated with poorer outcomes for some elective procedures, but there are few studies focusing on outcomes for the elderly ACS population. Our objective is to characterize differences in mortality and morbidity for acute care surgery patients >80 years old. METHODS: A retrospective review of all ACS admissions at a large teaching hospital over 1 year was conducted. Patients were classified into non-elderly (<80 years old) and elderly (>=80 years old). In addition to demographic differences, outcomes including care efficiency, mortality, postoperative complications, and length of stay were studied. Data analysis was completed with the Student's t test for continuous variables and Fisher's exact test for categorical variables using STATA 12 (College Station, TX, USA). RESULTS: We identified 467 non-elderly and 60 elderly patients with a mean age-adjusted Charlson score of 3.2 and 7.2, respectively (p < 0.001) and a mortality risk of 1.9 and 11.7 %, respectively (p < 0.001). The elderly were at risk of longer duration (>4 days) hospital stay (p = 0.05), increased postoperative complications (p = 0.002), admission to the ICU (p = 0.002), and were more likely to receive a non-operative procedure (p = 0.003). No difference was found (p = NS) for patient flow factors such as time to consult general surgery, time to see consult by general surgery, and time to operative management and disposition. CONCLUSIONS: Compared to younger patients admitted to an acute care surgery service, patients over 80 years old have a higher risk of complications, are more likely to require ICU admission, and stay longer in the hospital. PMID- 26038037 TI - Open distal tibial shaft fractures: a retrospective comparison of medial plate versus nail fixation. AB - PURPOSE: Studies comparing open reduction internal fixation (ORIF) vs. intramedullary nailing (IMN) for distal tibia shaft fractures focus upon closed injuries containing small patient series with open fractures. As such, complication rates for open fractures are unknown. To characterize complications associated with ORIF vs. IMN, we compared complications based on surgical approach in a large patient series of open distal tibia shaft fractures. METHODS: Through retrospective analysis at an urban level I trauma center, 180 IMN and 36 ORIF patients with open distal tibia fractures from 2002 to 2012 were evaluated. Patient charts were reviewed to identify patient demographics, fracture grade (G), patient comorbidities, and postoperative complications including nonunion, malunion, infection, hardware-related pain, and wound dehiscence. Fisher's exact tests compared complications between ORIF and IMN groups. Multivariate regression identified risk factors with statistical significance for the development of a postoperative complication. RESULTS: One hundred and eighty IMN (G1 22, G2 79, and G3 79) and 36 ORIF (G1 10, G2 16, and G3 10) patients were included for analysis. ORIF patients had a higher rate of nonunion (25.0 %, n = 9) compared with IMN patients (10.6 %, n = 20, p = 0.03). No additional complication had a significant statistical difference between groups. Multivariable analysis shows only surgical method influenced the development of complications: ORIF patients had 2.52 greater odds of developing complications compared with IMN patients (95 % CI 1.05-6.02; p = 0.04). CONCLUSIONS: ORIF leads to higher rates of nonunion and significantly increases the odds of developing a complication compared with IMN for open distal tibia fractures. This is the first study investigating complication rates based on surgical approach in a large cohort of patients with exclusively open distal tibia fractures. PMID- 26038038 TI - Nonoperative management of blunt splenic injury: what is new? AB - The majority of splenic injuries are currently managed nonoperatively. The primary indication for operative management of blunt splenic injury is hemodynamic instability. Findings which correlate with failure of nonoperative management include grade IV or V splenic injury, high Injury Severity Scores, or active extravasation. The role of angiograph/embolization is becoming better defined, appropriate in the patient with pseudoaneurysm or active extravasation or the stable patient with grade IV or V splenic injury. PMID- 26038039 TI - Management of blunt liver injury: what is new? AB - Nonoperative management has become the surgical treatment of choice in the hemodynamically stable patient with blunt hepatic trauma. The increased use and success of nonoperative management have been facilitated by the development of increasingly higher resolution computed tomography imaging, improved management of physiology and resuscitation (damage control), and routine availability of interventional procedures such as angiography and embolization, image-guided percutaneous drainage, and endoscopy. On the other hand, recognition of the patient who should proceed to immediate laparotomy is of utmost importance. A systematic and logical approach to the control of hemorrhage is required in the operating room. Thorough knowledge of the anatomy and surgical techniques, such as perihepatic packing, effective Pringle maneuver, hepatic mobilization, infrahepatic and suprahepatic control of the IVC, and stapled hepatectomy, is essential. PMID- 26038040 TI - Thorough debridement and immediate primary wound closure for animal bite injuries of the upper limbs. AB - PURPOSE: Animal bite injuries are often encountered in daily practice. In particular, these injuries of the upper limbs can result in severe functional impairment. We have performed early debridement of contaminated tissue and primary closure for these injuries. METHODS: The subjects consisted of 15 patients (6 males and 9 females) aged 1-91 years (mean 53.6 years) who visited our hospital due to animal bite injuries (dog in 9 patients, cat in 6). The bite site was the forearm in 5 patients and the hand in 10. In the operating room, contaminated tissue was removed, and primary wound closure was performed after irrigation. RESULTS: The bite penetrated to the muscle layer in 6 patients, tendon sheath in 5, joint in 1, bone in 1, and involved only the subcutaneous tissue in 3 patients. The mean period until the completion of wound treatment was 19.8 +/- 8.4 days. As complications, numbness of finger, metaphalangeal joint contracture and superficial radial nerve injury were observed in each one case. In a patient with bite injury of the palmar and dorsal sides of the thumb reaching the bone, additional debridement was necessary. At the final observation, the visual analog scale was 1.2 +/- 1.4, and the Quick Disabilities of the Arm, Shoulder, and Hand score was 9.7 +/- 12.2. CONCLUSIONS: Debridement to achieve wound closure is indispensable in patients with animal bite injuries of the upper limbs. The results of our study suggest that thorough debridement allows primary closure, even for animal bite injuries. PMID- 26038041 TI - The role of computed tomography in determining delayed intervention for gunshot wounds through the liver. AB - INTRODUCTION: Gunshot wounds through the liver are highly lethal and are prone to delayed morbidity due to late complications. METHODS: A retrospective study was performed to determine the incidence, morbidity, and need for late interventions in patients shot through the liver, and the role of post-injury CT in making those determinations. RESULTS: 83 patients were shot through the liver. Injury grades were: Grade V-12 (14 %), Grade IV-41 (49 %), Grade III-12 (14 %), Grade II 8 (10 %), Grade I-1 (1 %), and nine were ungraded. Ten (12 %) died in the ED, three (4 %) died in the OR, and two (2 %) died postoperatively. Of the 68 survivors, 52 (76 %) had follow-up CT scans performed a median of 7 days (95 % CI 2-13 days) after injury. Seventeen (33 %) had 25 complications related to the bullet tract: 12 (48 %) abscesses, 6 (24 %) infected hematomas, 3 (12 %) bilomas, 3 (12 %) unclassified fluid collections, and 1 (4 %) hepatic necrosis. Treatment included CT-guided drainage in 15 (60 %), ultrasound-guided drainage in 3 (12 %), surgical drainage and debridement in 2 (8 %), and observation in 5 (20 %). Overall morbidity rate including hepatic and non-hepatic complications was 74 % (50/68). Patients having their CT scan-determined intervention (for all complications) within 7 days of injury (n = 24), compared to those having their CT scan-determined intervention on day 8 or later (n = 28), had a significantly decreased rate of overall complications and morbidity (p = 0.03). This difference was due to early detection and intervention for abscesses, anastomotic breakdown, and missed injuries. Those having a CT scan within 7 days of injury also had a significantly reduced length of stay compared to those scanned on day 8 or later (median 14 days, 95 % CI 4-24 days versus 18 days, 95 % CI 6-30 days, p = 0.05). CONCLUSIONS: Gunshot wounds to the liver have a high morbidity and mortality rate. Survivors should have a follow-up CT scan performed within 7 days to allow detection and intervention for complications, as this dramatically decreases the overall morbidity rate and length of stay. PMID- 26038042 TI - Secondary abdominal compartment syndrome after complicated traumatic lower extremity vascular injuries. AB - INTRODUCTION: Secondary abdominal compartment syndrome (ACS) can occur in trauma patients without abdominal injuries. Surgical management of patients presenting with secondary ACS after isolated traumatic lower extremity vascular injury (LEVI) continues to evolve, and associated outcomes remain unknown. METHODS: From January 2006 to September 2011, 191 adult trauma patients presented to the Ryder Trauma Center, an urban level I trauma center in Miami, Florida with traumatic LEVIs. Among them 10 (5.2 %) patients were diagnosed with secondary ACS. Variables collected included age, gender, mechanism of injury, and clinical status at presentation. Surgical data included vessel injury, technical aspects of repair, associated complications, and outcomes. RESULTS: Mean age was 37.4 +/- 18.0 years (range 16-66 years), and the majority of patients were males (8 patients, 80 %). There were 7 (70 %) penetrating injuries (5 gunshot wounds and 2 stab wounds), and 3 blunt injuries with mean Injury Severity Score (ISS) 21.9 +/- 14.3 (range 9-50). Surgical management of LEVIs included ligation (4 patients, 40 %), primary repair (1 patient, 10 %), reverse saphenous vein graft (2 patients, 20 %), and PTFE interposition grafting (3 patients, 30 %). The overall mortality rate in this series was 60 %. CONCLUSIONS: The association between secondary ACS and lower extremity vascular injuries carries high morbidity and mortality rates. Further research efforts should focus at identifying parameters to accurately determine resuscitation goals, and therefore, prevent such a devastating condition. PMID- 26038043 TI - Damage control laparotomy and delayed pancreatoduodenectomy for complex combined pancreatoduodenal and venous injuries. AB - BACKGROUND: This single-centre study evaluated the efficacy of damage control surgery and delayed pancreatoduodenectomy and reconstruction in patients who had combined severe pancreatic head and visceral venous injuries. METHODS: Prospectively recorded data of patients who underwent an initial damage control laparotomy and a subsequent pancreatoduodenectomy for severe pancreatic injuries were evaluated to assess optimal operative sequencing. RESULTS: During the 20 year study period, 312 patients were treated for pancreatic injuries of whom 14 underwent a pancreatoduodenectomy. Six (five men, one woman, median age 20, range 16-39 years) of the 14 patients were in extremis with exsanguinating venous bleeding and non-reconstructable AAST grade 5 pancreatoduodenal injuries and underwent a damage control laparotomy followed by delayed pancreatoduodenectomy and reconstruction when stable. During the initial DCS, the blood loss compared to the subsequent laparotomy and definitive procedure was 5456 ml, range 2318 7665 vs 1250 ml, range 850-3600 ml (p < 0.01). The mean total fluid administered in the operating room was 11,150 ml, range 8450-13,320 vs 6850 ml, range 3350 9020 ml (p < 0.01). The mean operating room time was 113 min, range 90-140 vs 335 min, range 260-395 min (p < 0.01). During the second laparotomy five patients had a pylorus-preserving pancreatoduodenectomy and one a standard Whipple resection. Four of the six patients survived. Two patients died in hospital, one of MOF and coagulopathy and the other of intra-abdominal sepsis and multi-organ failure. Median duration of intensive care was 6 days, (range 1-20 days) and median duration of hospital stay was 29 days, (range 1-94 days). CONCLUSION: Damage control laparotomy and delayed secondary pancreatoduodenectomy is a live-saving procedure in the small cohort of patients who have dire pancreatic and vascular injuries. When used appropriately, the staged resection and reconstruction allows survival in a previously unsalvageable group of patients who have severe physiological derangement. PMID- 26038044 TI - Factors affecting morbidity and mortality in pancreatic injuries. AB - PURPOSE: Difficulties in the detection of pancreatic damage result in morbidity and mortality in cases of pancreatic trauma. This study was performed to determine factors affecting morbidity and mortality in pancreatic trauma. METHODS: The records of 33 patients who underwent surgery for pancreatic trauma between January 2004 and December 2013 were analyzed retrospectively. RESULTS: The types of injury were penetrating injury and blunt abdominal trauma in 75.8 and 24.2 % of all cases, respectively. Injuries were classified as stage 1 in 6 cases (18.2 %), stage 2 in 18 cases (54.5 %), stage 3 in 5 cases (15.2 %), and stage 4 in 4 cases (12.1 %). The average injury severity scale (ISS) value was 25.70 +/- 9:33. Six patients (18.2 %) had isolated pancreatic injury, 27 (81.2 %) had additional intraabdominal organ injuries and 10 patients (30.3 %) had extraabdominal organ injuries. The mean length of hospital stay was 13.24 +/- 9 days. Various complications were observed in eight patients (24.2 %) and mortality occurred in three (9.1 %). Complications were more frequent in patients with high pancreatic damage scores (p = 0.024), additional organ injuries (p = 0.05), and blunt trauma (p = 0.026). Pancreatic injury score was associated with morbidity, while the presence of major vascular injury was associated with mortality. CONCLUSIONS: Complications were significantly more common in injuries with higher pancreatic damage scores, additional organ injuries, and blunt abdominal trauma. Pancreatic injury score was associated with morbidity, while the presence of major vascular injury was associated with mortality. PMID- 26038045 TI - A multicentre cross-sectional study to examine physicians' ability to rule out a distal radius fracture based on clinical findings. AB - PURPOSE: To study current use of radiography in patients with wrist trauma and examine physicians' ability to rule out a distal radius fracture based on their physical findings. METHODS: We performed a multicentre cross-sectional observational study in five Emergency Departments (ED) between November 2010 and June 2014 and included all consecutive adult patients with wrist trauma. Physicians were asked to perform a standardized examination of the wrist and to subsequently indicate the probability of a distal radius fracture. RESULTS: The majority of the 924 included patients were referred for radiography (99.6 %). Of the 920 patients that were imaged, 402 (44 %) had sustained a distal radius fracture, 82 (9 %) an isolated carpal fracture and 12 (1 %) an isolated ulna fracture. Overall, physicians were able to accurately discriminate between patients with and without a distal radius fracture (area under the receiver operating characteristics curve: 0.87, 95 % CI 0.85-0.89). Physicians were absolutely certain of their clinical diagnosis in 180 patients (19 %), for whom they indicated either a 0 % or a 100 % probability. In these patients, physicians showed a 99 % sensitivity (95 % CI 98-100) and 67 % specificity (95 % CI 53-80) for predicting a distal radius fracture. CONCLUSIONS: Although physicians in the ED are able to accurately discriminate between patients with and without a distal radius fracture based on their physical findings, they were only completely certain of their diagnosis in 19 % of the patients. A validated clinical decision rule could reinforce physician's clinical judgment and support them in their decision not to routinely request radiography. PMID- 26038046 TI - Clinical results of treatment of garden type 1 and 2 femoral neck fractures in patients over 70-year old. AB - INTRODUCTION: We retrospectively analyzed the clinical results of treatment of impacted or undisplaced femoral neck fractures (Garden types 1 and 2) by osteosynthesis in elderly patients >70-year old. MATERIALS AND METHODS: We retrospectively reviewed the radiological results of 52 patients who were followed up for at least 6 months from April 2002 to December 2008. The average age of the patients was 77.6 years (range 70-97 years), and 38 patients were females. The mean follow-up period was 11.7 months (range 6-19 months). Thirteen cases were Garden type 1 fractures, and 39 were Garden type 2 fractures. We assessed the relationships between the occurrence of complications and age, sex, Garden stage, bone mineral density (BMD), history of contralateral hip fracture, and any additional hip injury. RESULTS: Major complications occurred in 18 cases (34.6 %), including nonunion (8 cases), osteonecrosis (6 cases), stress fracture of the subtrochanter (2 cases), excessive pull-out of a screw (1 case), and deep infection (1 case). The development of complications was associated with Garden stage 2, BMD, and additional hip injury. However, other factors were not associated with complications. Reoperations were performed in 16 cases (30.1 %), and 2 of the patients died during follow-up. CONCLUSION: A relatively high rate of complications or reoperations developed after treatment of Garden 2 femoral neck fractures in senile patients >70 years of age with osteoporosis. Although internal fixation has been recommended in the literature for undisplaced femoral neck fractures, primary arthroplasty may be a better option for treatment of Garden type 2 fractures in elderly patients. PMID- 26038047 TI - Symphyseal internal rod fixation versus standard plate fixation for open book pelvic ring injuries: a biomechanical study. AB - PURPOSE: This study investigates the biomechanical stability of a novel technique for symphyseal internal rod fixation (SYMFIX) using a multiaxial spinal screw-rod implant that allows for direct reduction and can be performed percutaneously and compares it to standard internal plate fixation of the symphysis. METHODS: Standard plate fixation (PLATE, n = 6) and the SYMFIX (n = 6) were tested on pelvic composite models with a simulated open book injury using a universal testing machine. On a previously described testing setup, 500 consecutive cyclic loadings were applied with sinusoidal resulting forces of 200 N. Displacement under loading was measured using an optoelectronic camera system and construct rigidity was calculated as a function of load and displacement. RESULTS: The rigidity of the PLATE construct was 122.8 N/mm (95 % CI: 110.7-134.8), rigidity of the SYMFIX construct 119.3 N/mm (95 % CI: 105.8-132.7). Displacement in the symphyseal area was mean 0.007 mm (95 % CI: 0.003-0.012) in the PLATE group and 0.021 mm (95 % CI: 0.011-0.031) in the SYMFIX group. Displacement in the sacroiliac joint area was mean 0.156 mm (95 % CI: 0.051-0.261) in the PLATE group and 0.120 mm (95 % CI: 0.039-0.201) in the SYMFIX group. CONCLUSIONS: In comparison to standard internal plate fixation for the stabilization of open book pelvic ring injuries, symphyseal internal rod fixation using a multiaxial spinal screw-rod implant in vitro shows a similar rigidity and comparable low degrees of displacement. PMID- 26038049 TI - Focus on blunt abdominal trauma. PMID- 26038048 TI - Fragility fractures of the sacrum: how to identify and when to treat surgically? AB - The increasing prevalence of fragility fractures of the sacrum (FFS) occurring predominantly in osteoporotic individuals poses a diagnostic and therapeutic challenge. The clinical presentation varies from longstanding low back pain without the patient remembering a traumatic event to immobilized patients after suffering a low-energy trauma. FFS are often combined with a fracture of the anterior pelvic ring; hence they are classified as a part of fragility fractures of the pelvis (FFP). If not displaced, the patients are treated with weight bearing as tolerated and analgesics; however, we advocate to treat displaced fractures surgically according to the fracture personality and the patient's comorbidities. Surgical options include minimal invasive sacro-iliac screws, trans-sacral bar osteosynthesis, open reduction and internal fixation, or spinopelvic stabilization. In the light of the high complication rate associated with immobilized patients, an operative approach often is indicated to accelerate the patient's mobility. PMID- 26038050 TI - Segway(r) related injuries in Vienna: report from the Lorenz Bohler Trauma Centre. AB - INTRODUCTION: The Segway(r) vehicle facilitates a new way of eco-friendly mobility and is currently used all over the world. In the last years, the use of the Segway(r) transporters for sightseeing tours in Vienna has increased distinctly, resulting in a growing number of Segway(r) related injuries and subsequent admissions of these patients to the Lorenz Bohler Trauma Centre in Vienna, Austria. METHODS: A retrospective analysis of clinical records in the electronic data system of the LBTC in Vienna, Austria, was performed to identify Segway(r) transporter related injuries between January 2010 and December 2012. RESULTS: Eighty-six patients represented the study cohort. The median age was 38 years (range 14-80 years) with a majority of male patients. Most common injuries were contusions (24, 6 %, n = 44) and fractures (23, 5 %, n = 42). The most frequent injury was a fracture of the radial head in 15, 1 % of all patients. 13 (15, 1 %) of 86 patients required admission and seven (8, 1 %) of these 13 patients had surgical treatment. CONCLUSION: This case series presents severe injuries related to the use of a Segway(r) transporter. As a consequence, it has to be ensured that public tour operators need to provide sufficient safety instructions and equipment for people who are unfamiliar with riding a Segway(r) . PMID- 26038051 TI - Outcome of penetrating chest injuries in an urban level I trauma center in the Netherlands. AB - INTRODUCTION: Most patients with penetrating chest injuries benefit from early treatment with chest tube drainage or surgery. Although penetrating chest injury is not uncommon, few descriptive studies are published, especially in Europe. The aim of this study was to review our experience and further improve our management of penetrating chest injuries in a level I trauma center in the Netherlands. METHODS: All patients with penetrating chest injury between August 2004 and December 2012 were included. Demographics, mechanism of injury, physiological parameters, Injury Severity Scores (ISS), surgical and non-surgical treatment, length of intensive care unit (ICU) stay, length of hospital stay (LOS), complications and rate of mortality were collected. RESULTS: A total of 159 patients were analyzed. Patients included 116 (73 %) stab wounds and 34 (21 %) gunshot wounds. In 27 patients (17 %), cardiac injury was seen. The mean ISS was 12. Almost half of all patients (49 %) were treated with only chest tube drainage. Alternatively, surgical treatment was performed in 24 % of all cases. Anterolateral incision was most frequently used to gain access to the thoracic cavity. The mean LOS was 9 days. Among all patients, 17 % were admitted to the ICU with a mean stay of 3 days. In 18 (11 %) patients, one or more complications occurred. The 30-day mortality was 7.5 %. CONCLUSION: Patients presenting with penetrating chest injury are not uncommon in the Netherlands and can mostly be treated conservatively. In one-fourth of the patients, surgical treatment is performed. A structural and vigorous approach is needed for good clinical outcome. PMID- 26038052 TI - Is augmentation plating an effective treatment for non-union of femoral shaft fractures with nail in situ? AB - PURPOSE: There are few reports of non-union femur shaft fractures treated with plate fixation with the nail in situ. This study reports our results in 40 cases. METHODS: Retrospective series of non-union and delayed union of femoral shaft after intramedullary nailing treated with plate fixation. Patients were serially followed-up till 12 months. Fracture union, time to union, knee range of motion, deformity, shortening and complications were recorded. Descriptive statistics were performed as applicable. RESULTS: There were 40 patients with mean age of 35 years (18-65). There were 14 cases of hypertrophic non-union, 24 cases of atrophic non-union and 2 cases of delayed union. The average time of surgery was 1 1/2 h and average blood loss was 300 ml. Exchange nailing was done in 9 cases. Union was achieved in 39 patients. The mean time to fracture union was 4 months. Post-operative knee range of motion was >120 degrees in 35 patients. One patient developed deep infection which was treated with removal of implants and exchange nailing with a vancomycin coated nail and union was achieved. CONCLUSION: Plating is an effective treatment for non-union of diaphyseal femur fractures after intramedullary fixation with the nail in situ. PMID- 26038053 TI - Ultrasound in medical education: listening to the echoes of the past to shape a vision for the future. AB - PURPOSE: Ultrasound in medical education has seen a tremendous growth over the last 10-20 years but ultrasound technology has been around for hundreds of years and sound has an even longer scientific history. The development of using sound and ultrasound to understand our body and our surroundings has been a rich part of human history. From the development of materials to produce piezoelectric conductors, ultrasound has been used and improved in many industries and medical specialties. METHODS: As diagnostic medical ultrasound has improved its resolution and become more portable, various specialties from radiology, cardiology, obstetrics and more recently emergency, critical care and proceduralists have found the added benefits of using ultrasound to safely help patients. The past advancements in technology have established the scaffold for the possibilities of diagnostic ultrasound's use in the present and future. RESULTS: A few medical educators have integrated ultrasound into medical school while a wealth of content exists online for learning ultrasound. Twenty-first century learners prefer blended learning where material can be reviewed online and personalize the education on their own time frame. This material combined with hands-on experience and mentorship can be used to develop learners' aptitude in ultrasound. CONCLUSIONS: As educators embrace this ultrasound technology and integrate it throughout the medical education journey, collaboration across specialties will synthesize a clear path forward when needs and resources are paired with vision and a strategic plan. PMID- 26038055 TI - Grade IV renal trauma management. A revision of the AAST renal injury grading scale is mandatory. AB - INTRODUCTION: The AAST renal injury grading scale is currently the most important variable predicting the need for kidney repair or removal, morbidity and mortality after blunt or penetrating kidney injuries. The 2011 revised version included renal pelvis, uretero-pelvic junction and segmental vascular injuries as grade IV, limiting grade V to severe hilar injuries. However, patients requiring surgery cannot be properly identified because of hemodynamic instability due to grade IV renal injuries. This study proposes an add-on for the AAST grade IV renal injury scale to improve the management of these patients. METHOD: We searched the Medline and Scopus databases up to September 2014. Searches were not restricted by date, language or publication status. Pediatric studies were excluded. RESULTS: 71 articles were found, 57 were pertinent, including 6 directly related to the topic. 3 risk factors were identified to be associated with surgery for hemodynamic instability: perirenal hematoma >3.5 cm, intravascular contrast extravasation and medial renal laceration. Presence of two or more of these criteria has been validated in two other studies to predict the need for intervention. Patients with >25 % devascularized fragments also have poor prognosis and should be treated more aggressively. CONCLUSION: These elements should be included in future classification reassessment to efficiently determine the time for surgery in grade IV renal traumas, generally leading to nephrectomy. PMID- 26038056 TI - Infectious complications and mortality in an American acute care surgical service. AB - BACKGROUND: Acute care surgery (ACS) services have evolved in an effort to provide 24-h surgical services for a wide array of general surgical emergencies. The formation of ACS services has been shown to improve outcomes and lead to more expeditious care. Despite the advances of ACS, the etiology and timing of patient mortality has yet to be described. We hypothesized that infectious complications occur more frequently in ACS patients that die during their hospitalization. METHODS: A retrospective review of a local ACS service (non-trauma) registry was conducted. Demographic variables, admission and discharge data, and ICD-9 codes were collected. ICD-9 codes were used to identify patients with sepsis, shock, GI perforation, peritonitis, and other hospital acquired infections (urinary tract, bloodstream, and ventilator-associated pneumonias). Univariate and multivariate logistic regression analysis was performed to model the outcome of death. RESULTS: 1,329 patients were analyzed. 53 % were male with the mean age of 52 years and an average length of stay of 13 days. 106 (8 %) died while in the hospital. Of the patients who died, 34 (32 %) died within 7 days of admission. The majority of mortalities (56 %) occurred after hospital day 14. In ACS patients that died, there were significantly higher rates of sepsis, shock, peritonitis, urinary tract infections, and VAP. After adjustment; age, sepsis on admission, and shock on admission were associated with greater odds of death. CONCLUSION: ACS patients with sepsis and shock have higher mortality rate than those patients without. The majority of ACS patient deaths occurred after hospital day 14. Further investigation and continued focus on preventing and rapidly treating infectious complications as they arise is warranted. PMID- 26038058 TI - Duty. PMID- 26038057 TI - Hyperbilirubinaemia in appendicitis: the diagnostic value for prediction of appendicitis and appendiceal perforation. AB - AIM: The aim of this study is to evaluate the diagnostic value of pre-operative bilirubin levels in the diagnosis of acute appendicitis and appendiceal perforation. METHOD: A retrospective analysis of 557 patients undergoing emergency appendicectomy over a 24-month period at a large teaching hospital. Hyperbilirubinaemia was defined as >25 umol/L. Data were analysed using descriptive statistics. RESULTS: 484 of the 557 (86.9 %) operated cases were found histologically to be appendicitis. 116 cases of the 484 were perforated (24 %). Bilirubin levels were significantly higher in the group with appendicitis versus the group found to have a normal appendix at histology, [median (IQR) 12.0 umol/L (9.00) vs. 8.0 umol/L (7.00) respectively, p < 0.001], despite being within normal serum bilirubin range. Sensitivity of hyperbilirubinaemia for acute appendicitis was only 8 %, however specificity was 94 %. PPV was 85 % and NPV was 26 %. Whilst bilirubin was higher in patients with a perforated appendix versus acute appendicitis [median (IQR) 13.0 umol/L (9.00) vs. 11.0 umol/L (9.00), respectively], statistically, there was no significant difference in pre operative bilirubin levels between the perforated appendicitis cases and the non perforated appendicitis cases (p = 0.326). However, the specificity of hyperbilirubinaemia for perforated appendicitis was 93 %, sensitivity 9.4 %, PPV 24 % and NPV 82 %. CONCLUSION: Bilirubin levels may be high, but remain within normal range, in cases of appendicitis. Therefore, bilirubin levels may be a useful measurement when investigating a patient with suspected appendicitis. Hyperbilirubinaemia is highly specific with regards to perforation, a finding supported by other studies. However, possibly because of the few perforated cases in this study, we cannot recommend that hyperbilirubinaemia be used to predict perforation. PMID- 26038059 TI - Motive, motivation, and the 100-year anniversary. PMID- 26038060 TI - Comprehensive treatment for an adult with bilateral cleft lip and palate. PMID- 26038061 TI - Authors' response. PMID- 26038062 TI - Author's response. PMID- 26038063 TI - Treatment effects evaluated with cone-beam computed tomography. PMID- 26038064 TI - Molar uprighting by a nickel-titanium spring. PMID- 26038065 TI - Authors' response. PMID- 26038067 TI - Robert Edison Moyers: War hero, motivator, collaborator. PMID- 26038068 TI - A difference of opinion. PMID- 26038069 TI - Evolution of treatment mechanics and contemporary appliance design in orthodontics: A 40-year perspective. AB - Until the early 1970s, successful treatment with the Begg technique and the Tweed edgewise technique required tedious wire bending. The introduction of Andrews' straight wire appliance changed that, and it was one of the most significant contributions in the history of orthodontics. The straight wire appliance significantly reduced the amount of wire bending and also brought along other options in treatment mechanics. Retraction of the canines with elastic chains and ligature wires became more common. Sliding mechanics in place of closing loops became the method of space closure for a significant number of clinicians. Edgewise force levels were initially used to close spaces; however, it was soon observed that lighter forces were more effective with sliding mechanics. Along with these changes, it became apparent that compensation in the appliance was needed, depending on the type of malocclusion and particularly with varying extraction sequences. Various appliance designs were developed to accommodate changes in mechanics and force levels. These modifications improved tooth positions at the end of treatment as long as the brackets were properly placed. These major changes in appliances, force levels, and treatment mechanics can be traced back to the work of Dr Lawrence Andrews and the straight wire appliances. PMID- 26038070 TI - The CONSORT Statement: Application within and adaptations for orthodontic trials. AB - High-quality randomized controlled trials (RCTs) are an integral part of evidence based medicine. RCTs are the bricks and mortar of high-quality systematic reviews, which are important determinants of health care policy and clinical practice. For published research to be used most effectively, investigators and authors should follow the guidelines for accurate and transparent reporting of RCTs. The consolidated standards of reporting trials (CONSORT) statement and its extensions are among the most widely used reporting guidelines in biomedical research. CONSORT was adopted by the American Journal of Orthodontics and Dentofacial Orthopedics in 2004. Since 2011, this Journal has been actively implementing compliance with the CONSORT reporting guidelines. The objective of this explanatory article is to highlight the relevance and implications of the various CONSORT items to help authors to achieve CONSORT compliance in their research submissions of RCTs to this and other orthodontic journals. PMID- 26038071 TI - Characteristics and fate of orthodontic articles submitted for publication: An exploratory study of the American Journal of Orthodontics and Dentofacial Orthopedics. AB - INTRODUCTION: In this study, we aimed to give insight into the article review process by investigating the characteristics and the fate of manuscripts submitted to the American Journal of Orthodontics and Dentofacial Orthopedics (AJO-DO). METHODS: The following information was obtained for original articles submitted to the AJO-DO in 2008: (1) for rejected articles: the reasons for rejection and the journal of subsequent publication when applicable; (2) for accepted articles: the number of revisions and the time elapsed to publication; and (3) for all articles: study topic, study design, area of origin, and statistically significant findings. Findings were reported using descriptive statistics, the chi-square test for equality of proportions, and multiple regression where appropriate. Post-hoc pair-wise tests were checked against the Bonferroni correction to account for multiple testing. RESULTS: Of the 440 original articles submitted to AJO-DO in 2008, 116 (26%) were accepted and published an average of 21 months (SD, 5 months) after acceptance. Rejected articles totaled 324 (74%), with 137 (42%) finding subsequent publication an average of 22 months (SD, 11 months) after rejection by the AJO-DO. The top 3 reasons for rejection by the AJO-DO were (1) poor study design (59% of rejected articles), (2) outdated or unoriginal topic (42%), and (3) inappropriate for the AJO-DO's audience (27%). Manuscripts rejected for poor study design had the least success for subsequent publication, whereas those rejected as inappropriate for the AJO-DO had the highest rate of publication elsewhere. Area of origin was significantly associated with acceptance by the AJO-DO, with articles from United States and Canada most likely to be accepted (P < 0.01). Articles from countries with the lowest publication rate in the AJO-DO had the highest publication rate elsewhere. The presence of statistically significant findings was shown to be significantly associated with acceptance by the AJO-DO (P = 0.013) but not with publication elsewhere (P = 0.77). CONCLUSIONS: Rejection by the AJO-DO does not preclude publication elsewhere, although articles rejected for poor study design were least likely to be eventually published. Many publishable articles are rejected by the AJO-DO as inappropriate for its readership, and these were the most likely to find publication elsewhere. Articles with the highest chance of acceptance by the AJO-DO were those from the United States and Canada and those reporting statistically significant results. PMID- 26038072 TI - Mandibular canine intrusion with the segmented arch technique: A finite element method study. AB - INTRODUCTION: Mandibular canines are anatomically extruded in approximately half of the patients with a deepbite. Although simultaneous orthodontic intrusion of the 6 mandibular anterior teeth is not recommended, a few studies have evaluated individual canine intrusion. Our objectives were to use the finite element method to simulate the segmented intrusion of mandibular canines with a cantilever and to evaluate the effects of different compensatory buccolingual activations. METHODS: A finite element study of the right quadrant of the mandibular dental arch together with periodontal structures was modeled using SolidWorks software (Dassault Systemes Americas, Waltham, Mass). After all bony, dental, and periodontal ligament structures from the second molar to the canine were graphically represented, brackets and molar tubes were modeled. Subsequently, a 0.021 * 0.025-in base wire was modeled with stainless steel properties and inserted into the brackets and tubes of the 4 posterior teeth to simulate an anchorage unit. Finally, a 0.017 * 0.025-in cantilever was modeled with titanium molybdenum alloy properties and inserted into the first molar auxiliary tube. Discretization and boundary conditions of all anatomic structures tested were determined with HyperMesh software (Altair Engineering, Milwaukee, Wis), and compensatory toe-ins of 0 degrees , 4 degrees , 6 degrees , and 8 degrees were simulated with Abaqus software (Dassault Systemes Americas). RESULTS: The 6 degrees toe-in produced pure intrusion of the canine. The highest amounts of periodontal ligament stress in the anchor segment were observed around the first molar roots. This tooth showed a slight tendency for extrusion and distal crown tipping. Moreover, the different compensatory toe-ins tested did not significantly affect the other posterior teeth. CONCLUSIONS: The segmented mechanics simulated in this study may achieve pure mandibular canine intrusion when an adequate amount of compensatory toe-in (6 degrees ) is incorporated into the cantilever to prevent buccal and lingual crown tipping. The effects on the posterior anchorage segment were small and initially concentrated on the first molar. PMID- 26038073 TI - Expectations of treatment and satisfaction with dentofacial appearance in patients applying for orthodontic treatment. AB - INTRODUCTION: Satisfaction with dentofacial appearance and expectations of orthodontic treatment have been analyzed in many studies. In 2002, in a study in The Netherlands, significant correlations were found between dental satisfaction and orthodontic treatment expectations. Satisfaction significantly decreased with increasing age. The aim of this study was to compare the satisfaction and expectations of current patients with the results of a study 10 years ago. METHODS: A questionnaire about dentofacial satisfaction and a questionnaire about the expectations of orthodontic treatment were completed by 146 subjects. The mean scores in the present study were compared with the mean scores 10 years ago. RESULTS: The subjects in the present study were more satisfied with their dental appearance. Differences in expectations were found on the subscales of general well-being and self-image. As in the study in 2002, no significant correlations were found between sex, satisfaction, and expectations of orthodontic treatment. Dentofacial satisfaction predicts expectations about orthodontic treatment, especially in the group of subjects aged 17 years and above. CONCLUSIONS: The subjects in this study had greater expectations of orthodontic treatment about general well-being and were more satisfied with their dental appearance than were the subjects studied 10 years ago. PMID- 26038074 TI - What factors predict the uptake of orthodontic treatment among adults? AB - INTRODUCTION: Our aim was to evaluate the factors that predict orthodontic treatment uptake among adults attending a specialist practice. METHODS: A cross sectional controlled design was adopted in a private practice setting. The test group included 62 adults seeking fixed orthodontic treatment. The controls were 52 parents of children undergoing orthodontics but who had not undergone treatment themselves. All subjects completed a set of validated questionnaires: the Rosenberg Self-Esteem Scale, the shortened version of the Oral Health Impact Profile, and the demographic and socioeconomic position characteristics. The Dental Health Component and the Aesthetic Component of the Index of Orthodontic Treatment Need were used to assess the severity of the malocclusions. RESULTS: A 100% response rate was achieved. Subjects without a partner (P <0.001), with a high oral health impact (P <0.001), or with a need for orthodontic treatment (as assessed by the clinician or the subject using the Aesthetic Component of the Index of Orthodontic Treatment Need; P = 0.003 and P = 0.031, respectively) were more likely to have orthodontic treatment than were their counterparts with a partner (odds ratio [OR] = 20.8; 95% confidence interval [CI] = 4.63-93.25), with a low oral health impact (OR = 5.3; 95% CI = 2.36-11.88), or with no treatment need (OR = 3.6 and 4.4; 95% CI = 1.57-8.99 and 1.15-16.77, respectively). Self esteem and demographic and socioeconomic position characteristics were not significantly associated with orthodontic treatment uptake (P >0.05). CONCLUSIONS: The significance of age, marital status, and the shortened version of the Oral Health Impact Profile in predicting the uptake of orthodontic treatment among adults was demonstrated. PMID- 26038075 TI - Craniodentofacial characteristics, dental esthetics-related quality of life, and self-esteem. AB - INTRODUCTION: Self-esteem is a psychological trait that may develop in interaction with craniodentofacial esthetics. The aim of this study was to explore the relationship among craniodentofacial characteristics, dental esthetics-related quality of life, and self-esteem in adolescents and young adults. METHODS: The study was cross-sectional; the sample included 200 pupils and university students (58% female) aged 13 to 33 years. The Rosenberg Self Esteem Scale and the Psychosocial Impact of Dental Aesthetics Questionnaire were used. Craniodentofacial features were estimated by the method of Martin and Saller, the Index of Orthodontic Treatment Need, and the Index of Complexity, Outcome and Need. RESULTS: When malocclusion severity increases, dental esthetics related quality of life decreases. The multiple linear regression showed that with the control of all other predictors in the model, the social impact of dental esthetics, borderline dental self-confidence, and facial type contribute the most to explain the variability of self-esteem, accounting for 3.2%, 1.3%, and 1.4%, respectively, of the variability values. The whole model accounts for 24.2% of the variability of self-esteem. CONCLUSIONS: In adolescents and young adults, self-esteem appears to be more influenced by the self-perceived psychosocial impacts of dental esthetics than the normative level of malocclusion, craniofacial typology, sex, or age. PMID- 26038076 TI - Effect of mobile phone use on metal ion release from fixed orthodontic appliances. AB - INTRODUCTION: The aim of this study was to evaluate the effect of exposure to radiofrequency electromagnetic fields emitted by mobile phones on the level of nickel in saliva. METHODS: Fifty healthy patients with fixed orthodontic appliances were asked not to use their cell phones for a week, and their saliva samples were taken at the end of the week (control group). The patients recorded their time of mobile phone usage during the next week and returned for a second saliva collection (experimental group). Samples at both times were taken between 8:00 and 10:00 pm, and the nickel levels were measured. Two-tailed paired-samples t test, linear regression, independent t test, and 1-way analysis of variance were used for data analysis. RESULTS: The 2-tailed paired-samples t test showed significant differences between the levels of nickel in the control and experimental groups (t [49] = 9.967; P <0.001). The linear regression test showed a significant relationship between mobile phone usage time and the nickel release (F [1, 48] = 60.263; P <0.001; R(2) = 0.577). CONCLUSIONS: Mobile phone usage has a time-dependent influence on the concentration of nickel in the saliva of patients with orthodontic appliances. PMID- 26038077 TI - Quantitative evaluation of maxillary interradicular bone with cone-beam computed tomography for bicortical placement of orthodontic mini-implants. AB - INTRODUCTION: The purpose of this study was to propose a protocol for safe bicortical placement of mini-implants by measuring the interradicular spaces of the maxillary teeth and the bone quality. METHODS: Cone-beam computed tomography data were obtained from 50 adults. Three-dimensional reconstructions and measurements were made with SimplantPro software (Materialise, Leuven, Belgium). For each interradicular site, the bone thicknesses and interradicular distances at the planes 1.5, 3, 6, and 9 mm above the cementoenamel junction were measured. Standard bone units were defined to evaluate the influences of bone density and the different placement patterns on the stability of the mini-implants. RESULTS: The safe interradicular sites in the maxilla for bicortical placement of 1.5-mm diameter mini-implants were in all planes between the first and second premolars, and between the second premolar and the first molar. The safe palatal sites were between the first and second molars, and the safe labial sites of the 9-mm plane were between the central incisors, and between the lateral incisor and the canine. The safe buccal sites of the 6- and 9-mm planes were between the first and second molars, and the safe buccal sites of the 3-, 6-, and 9-mm planes were between the canine and the first premolar. Most bone thicknesses were from 8 to 12 mm. The optimal placement angle between the second premolar and the first molar was 58 degrees . Bicortical placement could have more standard bone units than unicortical placement in the maxilla. CONCLUSIONS: Bicortical placement would be more stable in the maxilla. For the site between the molars, special care should be taken at a plane higher than 6 mm to prevent maxillary sinus penetration. The most favorable interradicular area in the maxilla was between the second premolar and the first molar. PMID- 26038078 TI - Physical properties of root cementum: Part 25. Extent of root resorption after the application of light and heavy buccopalatal jiggling forces for 12 weeks: A microcomputed tomography study. AB - INTRODUCTION: The aims of this study were to evaluate with microcomputed tomography the orthodontically induced inflammatory root resorption in premolars caused by buccopalatal jiggling movement with light and heavy forces and to compare it with the resorption caused by equivalent but continuous buccal forces. METHODS: The sample consisted of 60 maxillary first premolars collected from 30 patients (15 girls, 15 boys; ages, 13-18 years) who required orthodontic treatment with extractions. They were divided into 3 groups of 10 patients. Light (25 g) or heavy (225 g) buccal tipping orthodontic forces were randomly assigned on the maxillary right or left quadrant with either continuous buccal (positive controls) or buccopalatal jiggling forces for 12 weeks. At the end of the experimental period, the teeth were carefully extracted and processed for 3 dimensional imaging and volumetric evaluations of resorption craters. Data were analyzed with Wilcoxon signed rank tests. RESULTS: There was no statistically significant difference between positive control light (P = 0.0173) and heavy (P = 0.0173) continuous forces and jiggling forces for both force magnitudes. However, statistically significant differences were observed between heavy and light jiggling forces (P = 0.038), with heavy jiggling forces causing greater total root resorption than light jiggling forces. CONCLUSIONS: Light and heavy jiggling forces in the buccopalatal direction did not cause significantly different amounts of root resorption when compared with continuous forces of the same magnitude. On the other hand, light jiggling forces resulted in less root resorption than heavy jiggling forces. PMID- 26038079 TI - Changes in natural head position after orthognathic surgery in skeletal Class III patients. AB - INTRODUCTION: The purpose of this study was to evaluate the change in natural head position (NHP) after orthognathic surgery in skeletal Class III patients. METHODS: We used pretreatment (T1) and posttreatment (T2) cephalometric radiographs and T1 and T2 lateral facial photographs of 20 skeletal Class III patients (mean age, 21.6 years), with 20 skeletal Class I patients (mean age, 22.2 years) as the controls. The Class III patients had undergone mandibular setback surgery, and the patients in the control group had received conventional orthodontic treatment. All lateral facial photographs were recorded in NHP. The true vertical line (TVL) was transferred from the photograph to the cephalometric radiograph, and then the angle between the TVL and the Frankfort horizontal plane (TVL/FH) was measured. A t test and a paired t test were used to verify the differences between the 2 groups, and between the T1 and T2 measurements in each group. RESULTS: The mean TVL/FH at T1 was significantly greater in the Class III group than in the Class I group; this indicated that the Class III group showed head flexion. However, the mean TVL/FH of the Class III group decreased by -3.1 degrees at T2; this indicated head extension, and it did not significantly differ from that of the Class I group. Nineteen of the 20 Class I patients showed minimal or no change in their TVL/FH (-1.5 degrees to 1.5 degrees ) at T2. On the other hand, 6 of the 20 Class III patients showed more than a 4.5 degrees decrease in their TVL/FH at T2. CONCLUSIONS: Most of the Class I patients showed minimal or no change in their NHP at T2, but some Class III patients had changes in their NHP that tended toward head extension after mandibular setback surgery. Thus, soft tissue analysis using the TVL in NHP may not be reliable for some skeletal Class III patients who undergo mandibular setback surgery. PMID- 26038080 TI - Replacement of a first molar and 3 second molars by the mesial inclination of 4 impacted third molars in an adult with a Class II Division 1 malocclusion. AB - This case report presents the successful replacement of 1 first molar and 3 second molars by the mesial inclination of 4 impacted third molars. A woman, 23 years 6 months old, had a chief complaint of crowding of her anterior teeth and linguoclination of a second molar on the left side. The panoramic radiographic images showed that the maxillary and mandibular third molars on both sides were impacted. Root resorption on the distal surfaces of the maxillary second molars was suspected. The patient was given a diagnosis of Angle Class II Division 1 malocclusion with severe crowding of the anterior teeth and 4 impacted third molars. After we extracted the treated maxillary second premolars and the second molars on both sides, the treated mandibular second premolar and the second molar on the left side, and the root canal-filled mandibular first molar on the right side, the 4 impacted third molars were uprighted and formed part of the posterior functional occlusion. The total active treatment period was 39 months. The maxillary and mandibular third molars on both sides successfully replaced the first and second molars. The replacement of a damaged molar by an impacted third molar is a useful treatment option for using sound teeth. PMID- 26038081 TI - Interdisciplinary orthodontic treatment for a patient with generalized aggressive periodontitis: Assessment of IgG antibodies to identify type of periodontitis and correct timing of treatment. AB - Aggressive periodontitis is a great challenge to clinicians when providing orthodontic treatment because of the potential for progression of periodontal disease. In this article, we report the successful comprehensive orthodontic treatment of bimaxillary protrusion and severe crowding in an adult with generalized aggressive periodontitis. A woman, aged 22 years 7 months, with a chief complaint of incisal crowding was diagnosed with a skeletal Class I malocclusion associated with severe anterior crowding, possibly worsened by generalized aggressive periodontitis. In addition to a periodontal examination, a blood IgG antibody titer analysis and microbiologic examination for periodontal pathogens were used to diagnose the type of periodontal disease and determine the proper timing to initiate orthodontic treatment. The total active treatment period was 28 months, followed by periodontal prostheses and regeneration therapy. Consequently, satisfactory facial profile, occlusion, and periodontal health were maintained for at least 36 months. These results indicate that efficient screening is important for providing successful orthodontic treatment in patients with advanced periodontal disease. This report also demonstrates the diagnostic importance of blood IgG antibody titer assays and microbiologic examinations to detect periodontal pathogens. PMID- 26038082 TI - Modified method of recording and reproducing natural head position with a multicamera system and a laser level. AB - INTRODUCTION: As computer-assisted surgical design becomes increasingly popular in maxillofacial surgery, recording patients' natural head position (NHP) and reproducing it in the virtual environment are vital for preoperative design and postoperative evaluation. Our objective was to test the repeatability and accuracy of recording NHP using a multicamera system and a laser level. METHODS: A laser level was used to project a horizontal reference line on a physical model, and a 3-dimensional image was obtained using a multicamera system. In surgical simulation software, the recorded NHP was reproduced in the virtual head position by registering the coordinate axes with the horizontal reference on both the frontal and lateral views. The repeatability and accuracy of the method were assessed using a gyroscopic procedure as the gold standard. RESULTS: The interclass correlation coefficients for pitch and roll were 0.982 (0.966, 0.991) and 0.995 (0.992, 0.998), respectively, indicating a high degree of repeatability. Regarding accuracy, the lack of agreement in orientation between the new method and the gold standard was within the ranges for pitch (-0.69 degrees , 1.71 degrees ) and for roll (-0.92 degrees , 1.20 degrees ); these have no clinical significance. CONCLUSIONS: This method of recording and reproducing NHP with a multicamera system and a laser level is repeatable, accurate, and clinically feasible. PMID- 26038083 TI - Litigation and Legislation. Transfer tragedies. PMID- 26038084 TI - Inference from a sample mean--Part 1. PMID- 26038085 TI - Analytical solution of Luedeking-Piret equation for a batch fermentation obeying Monod growth kinetics. AB - Not so many fermentation mathematical models allow analytical solutions of batch process dynamics. The most widely used is the combination of the logistic microbial growth kinetics with Luedeking-Piret bioproduct synthesis relation. However, the logistic equation is principally based on formalistic similarities and only fits a limited range of fermentation types. In this article, we have developed an analytical solution for the combination of Monod growth kinetics with Luedeking-Piret relation, which can be identified by linear regression and used to simulate batch fermentation evolution. Two classical examples are used to show the quality of fit and the simplicity of the method proposed. A solution for the combination of Haldane substrate-limited growth model combined with Luedeking Piret relation is also provided. These models could prove useful for the analysis of fermentation data in industry as well as academia. PMID- 26038086 TI - Augmentation index as an indicator of central arterial stiffness and indicators of carotid atherosclerosis by ultrasonography in relation to life stress. PMID- 26038087 TI - Life satisfaction post stroke: The role of illness cognitions. AB - OBJECTIVE: To describe illness cognitions two months and two years post stroke and to investigate changes in illness cognitions over time. We also examined the associations between illness cognitions and life satisfaction at two months and two years post stroke and investigated if changes in illness cognitions predicted life satisfaction two years post stroke, taking demographic and stroke-related factors and emotional symptoms into account. METHODS: Prospective cohort study in which 287 patients were assessed at two months and two years post stroke. The illness cognitions helplessness (maladaptive), acceptance (adaptive) and perceiving benefits (adaptive) were measured with the Illness Cognition Questionnaire. Life satisfaction was assessed with two life satisfaction questions. Correlational and regression analyses were performed. RESULTS: Patients experienced both maladaptive and adaptive illness cognitions two months and two years post stroke. Only acceptance increased significantly from two months to two years post stroke (p<=0.01). Helplessness, acceptance and perceiving benefits were significantly associated with life satisfaction at two months (R2=0.42) and two years (R2=0.57) post stroke. Furthermore, illness cognitions two months post stroke and changes in illness cognitions predicted life satisfaction two years post stroke (R2=0.57). CONCLUSION: Illness cognitions and changes in illness cognitions were independently associated with life satisfaction two years post stroke. It is therefore important during rehabilitation to focus on reducing maladaptive behavior and feelings to promote life satisfaction, and on promoting adaptive illness cognitions. PMID- 26038088 TI - Advances in engineered microorganisms for improving metabolic conversion via microgravity effects. AB - As an extreme and unique environment, microgravity has significant effects on microbial cellular processes, such as cell growth, gene expression, natural pathways and biotechnological products. Application of microgravity effects to identify the regulatory elements in reengineering microbial hosts will draw much more attention in further research. In this commentary, we discuss the microgravity effects in engineered microorganisms for improving metabolic conversion, including cell growth kinetics, antimicrobial susceptibility, resistance to stresses, secondary metabolites production, recombinant protein production and enzyme activity, as well as gene expression changes. Application of microgravity effects in engineered microorganisms could provide valuable platform for innovative approaches in bioprocessing technology to largely improve the metabolic conversion efficacy of biopharmaceutical products. PMID- 26038089 TI - [Excitement over the color of a dress: Blue-black or white-gold or else?]. AB - BACKGROUND: The overexposed photograph of a dress caused a worldwide media hype in February 2015. The picture of the dress was posted on a social site with the question of which colour it was. Markedly different views on the color were voiced and strongly defended. OBJECTIVE: The phenomenon is presented in this article, the actual color of the dress is clarified and a discussion on why such conflicting views were held is presented. CONCLUSION: It becomes clear that in the perception of colors we unconsciously but appropriately take the lighting situation into consideration. Because we additionally name colors categorically, small differences in hue and illumination can lead to an assignment to very different categories. PMID- 26038090 TI - DNA methylation analysis of the temporal artery microenvironment in giant cell arteritis. AB - OBJECTIVE: To investigate the inflammatory response in giant cell arteritis (GCA) by characterising the DNA methylation pattern within the temporal artery microenvironment. METHODS: Twelve patients with non-equivocal histological evidence for GCA and 12 age-matched, sex-matched and ethnicity-matched controls with normal biopsies were studied. DNA was extracted from the affected portions of temporal artery tissue in patients with GCA and from histologically confirmed normal arteries in controls. Genome-wide DNA methylation status was evaluated using the Illumina Infinium HumanMethylation450 BeadChip Array. Differentially methylated loci between affected and unaffected arterial tissues were identified, and subsequent bioinformatic analysis performed. Immunohistochemistry was used to examine tissue expression patterns in temporal artery biopsies. RESULTS: We identified 1555 hypomethylated CG sites (853 genes) in affected temporal artery tissue from patients with GCA compared with normal controls. Gene ontology enrichment analysis of hypomethylated genes revealed significant representation in T cell activation and differentiation pathways, including both TH1 and TH17 signatures. Our DNA methylation data suggest a role for increased activity of the calcineurin/nuclear factor of activated T cells (NFAT) signalling pathway in GCA, confirmed by immunohistochemistry showing increased expression and nuclear localisation of NFAT1. NFAT signalling downstream targets such as interleukin (IL)-21/IL-21R and CD40L were overexpressed in GCA-affected arteries. Further, proinflammatory genes including TNF, LTA, LTB, CCR7, RUNX3, CD6, CD40LG, IL2, IL6, NLRP1, IL1B, IL18, IL21, IL23R and IFNG were hypomethylated in the cellular milieu of GCA arteries. CONCLUSIONS: We characterised the inflammatory response in GCA-affected arteries using 'epigenetic immunophenotyping' and identified molecules and pathways relevant to disease pathogenesis in GCA. PMID- 26038092 TI - Target protein induced cleavage of a specific peptide for prostate-specific antigen detection with positively charged gold nanoparticles as signal enhancer. AB - In this work, a new "signal-on" electrochemical biosensor for sensitive detection of prostate-specific antigen (PSA) was developed on the basis of target protein induced cleavage of a specific peptide with positively charged gold nanoparticles (AuNPs) as signal enhancer. PMID- 26038091 TI - A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon alpha) in patients with systemic lupus erythematosus (ROSE). AB - OBJECTIVES: To examine the safety and efficacy of rontalizumab, a humanised IgG1 anti-interferon alpha (anti-IFN-alpha) monoclonal antibody, in patients with moderate-to-severe systemic lupus erythematosus (SLE). METHODS: Patients with active SLE were randomised (2:1) to 750 mg intravenous rontalizumab every 4 weeks or placebo (Part 1), and 300 mg subcutaneous rontalizumab every 2 weeks or placebo (Part 2). BACKGROUND: Hydroxychloroquine and corticosteroids were allowed. Patients taking immunosuppressants at baseline were required per protocol to discontinue. Efficacy end points included reduction in disease activity by British Isles Lupus Disease Activity Group (BILAG)-2004 (primary), and SLE response index (SRI, secondary) at Week 24. Efficacy was also examined by an exploratory measure of IFN-regulated gene expression (interferon signature metric, ISM). RESULTS: Patients (n=238) received rontalizumab (n=159) or placebo (n=79). At baseline, the mean Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI) score in all cohorts was ~10, and 75.6% of patients had a high ISM (ISM-High). Efficacy response rates by BILAG and SRI were similar between rontalizumab and placebo groups. However, in the exploratory subgroup of ISM-Low patients, SRI response was higher and steroid use was lower in the rontalizumab-treated patients. There was also a reduction in SELENA-SLEDAI flare index rates (HR 0.61, 0.46 to 0.81, p=0.004) in this subgroup. Adverse events were similar between placebo and rontalizumab groups. CONCLUSIONS: The primary and secondary end points of this trial were not met in all patients or in patients with high ISM scores. In an exploratory analysis, rontalizumab treatment was associated with improvements in disease activity, reduced flares and decreased steroid use in patients with SLE with low ISM scores. TRIAL REGISTRATION NUMBER: NCT00962832. PMID- 26038093 TI - Two-Year Outcomes After Exclusive Enteral Nutrition Induction Are Superior to Corticosteroids in Pediatric Crohn's Disease Treated Early with Thiopurines. AB - BACKGROUND: Impact of first-line induction therapy on medium-term outcomes in the setting of early thiopurine (TP) use in children with Crohn's disease has not been evaluated, in particular whether choice of exclusive enteral nutrition (EEN) over corticosteroids (CS) for induction impacts clinical outcomes at 12 and 24 months. AIMS AND METHODS: In this retrospective study, 89 children from our database with new diagnosis CD and follow-up of at least 2 years following induction with exclusive course of CS or EEN and early, dose-optimized TP (within 6 months from diagnosis) were evaluated. We compared steroid dependency (relapse <3 months of tapering first course CS or inability to wean <10 mg prednisolone), need for IFX, linear growth, and surgical resections over the first 2 years. RESULTS: Choice of EEN over CS induction was associated with reduced linear growth failure (7 vs. 26%, p = 0.02), CS dependency (7 vs. 43%, p = 0.002), and improved primary sustained response to IFX (86 vs. 68%, p = 0.02). Combined CS/IFX-free remission and surgical resection rates were similar. CONCLUSION: In the setting of early TP commencement, EEN induction is superior to CS induction for reducing growth failure, CS dependency, and loss of response to IFX over the first 2 years. PMID- 26038094 TI - Analysis of Endoscopic Radiofrequency Ablation of Biliary Malignant Strictures in Pancreatic Cancer Suggests Potential Survival Benefit. AB - BACKGROUND: Pancreatic carcinoma is often inoperable, carries a poor prognosis, and is commonly complicated by malignant biliary obstruction. Phase I/II studies have demonstrated good safety and early stent patency using endoscopic biliary radiofrequency ablation (RFA) as an adjunct to self-expanding metal stent (SEMS) insertion for biliary decompression. AIM: To analyze the clinical efficacy of endobiliary RFA. METHODS: Retrospective case-control analysis was carried out for 23 patients with surgically unresectable pancreatic carcinoma and malignant biliary obstruction undergoing endoscopic RFA and SEMS insertion and 46 controls (SEMS insertion alone) in a single tertiary care center. Controls were stringently matched for age, sex, metastases, ASA/comorbidities. Survival, morbidity, and stent patency rates were assessed. RESULTS: RFA and control groups were closely matched-ASA 2.35 +/- 0.65 versus 2.54 +/- 0.50, p = 0.086; metastases 9/23 (39.1%) versus 18/46 (39.1%), p = 0.800; chemotherapy 16/23 (69.6%) versus 24/46 (52.2%), p = 0.203. Median survival in RFA group was 226 days (IQR 140-526 days) versus 123.5 days (IQR 44-328 days) in controls (p = 0.010). RFA was independently predictive of survival at 90 days (OR 21.07, 95% CI 1.45-306.64, p = 0.026) and 180 days (OR 4.48, 95% CI 1.04-19.30, p = 0.044) in multivariate analysis. SEMS patency rates were equivalent in both groups. RFA was well tolerated with minimal side effects. CONCLUSIONS: Endoscopic RFA is a safe and efficacious adjunctive treatment in patients with advanced pancreatic malignancy and biliary obstruction and may confer early survival benefit. Randomized prospective clinical trials of this new modality are mandated. PMID- 26038095 TI - Differences in binding behavior of (-)-epigallocatechin gallate to beta lactoglobulin heterodimers (AB) compared to homodimers (A) and (B). AB - The lipocalin beta-lactoglobulin (beta-LG) exists in different natural genetic variants--of which beta-LG A and B are predominant in bovine milk. At physiological conditions the protein dimerizes--building homodimers of beta-LG A and beta-LG B and heterodimers of beta-LG AB. Although beta-LG is one of the most intensely characterized lipocalins, the interaction behavior of ligands with hetero- and homodimers of beta-LG is largely unknown. The present findings revealed significant differences for hetero- and homodimers regarding ligand binding capacity as tested with a model ligand (i.e. surface binding (-) epigallocatechin gallate (EGCG)). These findings were confirmed using FT-IR, where the addition of EGCG influenced the beta-sheet backbone of homodimer A and B with significantly higher intensity compared to heterodimer AB. Further, shape analysis by SAXS revealed oligomerization of both types of dimers upon addition of EGCG; however, homodimer A and B produced significantly larger aggregates compared to the heterodimer AB. In summary, the present study revealed that EGCG showed significantly different interaction reactivity (binding sites, aggregation size and conformational changes) to the hetero and homodimers of beta-LG in the order beta-LG A > B > AB. The results suggest that conformational differences between homodimers and heterodimers strongly influence the EGCG binding ability. This may also occur with other polyphenols and ligands of beta-LG and gives not only important information for beta-LG binding studies, but may also apply for polymorphisms of other self-aggregating lipocalins. PMID- 26038097 TI - Corrigendum. PMID- 26038096 TI - Clinical Pharmacokinetics of Once-Daily Tacrolimus in Solid-Organ Transplant Patients. AB - Tacrolimus is a pivotal immunosuppressant agent used in solid-organ transplantation. It was originally formulated for oral administration as Prograf((r)), a twice-daily immediate-release capsule. In an attempt to improve patient adherence, retain manufacturer market share and/or reduce health care costs, newer once-daily prolonged-release formulations of tacrolimus (Advagraf((r)) and Envarsus((r)) XR) and various generic versions of Prograf((r)) are becoming available. Tacrolimus has a narrow therapeutic index. Small variations in drug exposure due to formulation differences can have a significant impact on patient outcomes. The aim of this review is to critically analyse the published data on the clinical pharmacokinetics of once-daily tacrolimus in solid organ transplant patients. Forty-three traditional (non-compartmental) and five population pharmacokinetic studies were identified and evaluated. On the basis of the stricter criteria for narrow-therapeutic-index drugs, Prograf((r)), Advagraf((r)) and Envarsus((r)) XR are not bioequivalent [in terms of the area under the concentration-time curve from 0 to 24 h (AUC0-24) or the minimum concentration (C min)]. Patients may require a daily dosage increase if converted from Prograf((r)) to Advagraf((r)), while a daily dosage reduction appears necessary for conversion from Prograf((r)) to Envarsus((r)) XR. Prograf((r)) itself, or generic immediate-release tacrolimus, can be administered in a once daily regimen with a lower than double daily dose being reported to give 24-h exposure equivalent to that of a twice-daily regimen. Intense clinical and concentration monitoring is prudent in the first few months after any conversion to once-daily tacrolimus dosing; however, there is no guarantee that therapeutic drug monitoring strategies applicable to one formulation (or twice-daily dosing) will be equally applicable to another. The correlation between the tacrolimus AUC0-24 and C min is variable and not strong for all three formulations, indicating that trough measurements may not always give a good indication of overall drug exposure. Further investigation is required into whether the prolonged-release formulations have reduced within-subject pharmacokinetic variability, which would be a distinct advantage. Whether the effects of factors that influence tacrolimus absorption and pre-systemic metabolism (patient genotype status; gastrointestinal disease and disorders) and drug interactions differ across the formulations needs to be further elucidated. Most pharmacokinetic comparison studies to date have involved relatively stable patients, and many have been sponsored by the pharmaceutical companies manufacturing the new formulations. Larger randomized, controlled trials are needed in different transplant populations to determine whether there are differences in efficacy and toxicity across the formulations and whether formulation conversion is worthwhile in the longer term. While it has been suggested that once-daily administration of tacrolimus may improve patient compliance, further studies are required to demonstrate this. Mistakenly interchanging different tacrolimus formulations can lead to serious patient harm. Once-daily tacrolimus is now available as an alternative to twice-daily tacrolimus and can be used de novo in solid-organ transplant recipients or as a different formulation for existing patients, with appropriate dosage modifications. Clinicians need to be fully aware of pharmacokinetic and possible outcome differences across the different formulations of tacrolimus. PMID- 26038099 TI - Efficient CH3 NH3 PbI3 Perovskite Solar Cells Employing Nanostructured p-Type NiO Electrode Formed by a Pulsed Laser Deposition. AB - Highly transparent and nanostructured nickel oxide (NiO) films through pulsed laser deposition are introduced for efficient CH3 NH3 PbI3 perovskite solar cells. The (111)-oriented nanostructured NiO film plays a key role in extracting holes and preventing electron leakage as hole transporting material. The champion device exhibits a power conversion efficiency of 17.3% with a very high fill factor of 0.813. PMID- 26038098 TI - A Multi-institutional Analysis of Perioperative Outcomes in 106 Men Who Underwent Radical Prostatectomy for Distant Metastatic Prostate Cancer at Presentation. AB - BACKGROUND: Current trials are investigating radical intervention in men with metastatic prostate cancer. However, there is a lack of safety data for radical prostatectomy as therapy in this setting. OBJECTIVE: To examine perioperative outcomes and short-term complications after radical prostatectomy for locally resectable, distant metastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case series from 2007 to 2014 comprising 106 patients with newly diagnosed metastatic (M1) prostate cancer from the USA, Germany, Italy, and Sweden. INTERVENTION: Radical prostatectomy and extended pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics were used to present margin status, continence, and readmission, reoperation, and overall complication rates at 90 d, as well as for 21 specific complications. Kaplan-Meier plots were used to estimate survival function. Intercenter variability and M1a/ M1b subgroups were examined. RESULTS AND LIMITATIONS: Some 79.2% of patients did not suffer any complications; positive-margin (53.8%), lymphocele (8.5%), and wound infection (4.7%) rates were higher in our cohort than in a meta-analysis of open radical prostatectomy performed for standard indications. At a median follow-up of 22.8 mo, 94/106 (88.7%) men were still alive. The study is limited by its retrospective design, differing selection criteria, and short follow-up. CONCLUSIONS: Radical prostatectomy for men with locally resectable, distant metastatic prostate cancer appears safe in expert hands for meticulously selected patients. Overall and specific complication rates related to the surgical extirpation are not more frequent than when radical prostatectomy is performed for standard indications, and the use of extended pelvic lymphadenectomy in all of this cohort compared to its selective use in localized/locally advanced prostate cancer accounts for any extra morbidity. PATIENT SUMMARY: Men presenting with advanced prostate cancer that has spread beyond the prostate are increasingly being considered for treatments directed at the prostate itself. On the basis of results for our international series of 106 men, surgery appears reasonably safe in this setting for certain patients. PMID- 26038101 TI - Liquids on-chip: direct storage and release employing micro-perforated vapor barrier films. AB - Liquids on-chip describes a reagent storage concept for disposable pressure driven Lab-on-Chip (LoC) devices, which enables liquid storage in reservoirs without additional packaging. On-chip storage of liquids can be considered as one of the major challenges for the commercial break through of polymer-based LoC devices. Especially the ability for long-term storage and reagent release on demand are the most important aspects for a fully developed technology. On-chip storage not only replaces manual pipetting, it creates numerous advantages: fully automated processing, ease of use, reduction of contamination and transportation risks. Previous concepts for on-chip storage are based on liquid packaging solutions (e.g. stick packs, blisters, glass ampoules), which implicate manufacturing complexity and additional pick and place processes. That is why we prefer on-chip storage of liquids directly in reservoirs. The liquids are collected in reservoirs, which are made of high barrier polymers or coated by selected barrier layers. Therefore, commonly used polymers for LoC applications as cyclic olefin polymer (COP) and polycarbonate (PC) were investigated in the context of novel polymer composites. To ensure long-term stability the reservoirs are sealed with a commercially available barrier film by hot embossing. The barrier film is structured by pulsed laser ablation, which installs rated break points without affecting the barrier properties. A flexible membrane is actuated through pneumatic pressure for reagent release on demand. The membrane deflection breaks the barrier film and leads to efficient cleaning of the reservoirs in order to provide the liquids for further processing. PMID- 26038100 TI - Opportunities to improve postpartum care for mothers and infants: design of context-specific packages of postpartum interventions in rural districts in four sub-Saharan African countries. AB - BACKGROUND: Postpartum maternal and infant mortality is high in sub-Saharan Africa and improving postpartum care as a strategy to enhance maternal and infant health has been neglected. We describe the design and selection of suitable, context-specific interventions that have the potential to improve postpartum care. METHODS: The study is implemented in rural districts in Burkina Faso, Kenya, Malawi and Mozambique. We used the four steps 'systems thinking' approach to design and select interventions: 1) we conducted a stakeholder analysis to identify and convene stakeholders; 2) we organised stakeholders causal analysis workshops in which the local postpartum situation and challenges and possible interventions were discussed; 3) based on comprehensive needs assessment findings, inputs from the stakeholders and existing knowledge regarding good postpartum care, a list of potential interventions was designed, and; 4) the stakeholders selected and agreed upon final context-specific intervention packages to be implemented to improve postpartum care. RESULTS: Needs assessment findings showed that in all study countries maternal, newborn and child health is a national priority but specific policies for postpartum care are weak and there is very little evidence of effective postpartum care implementation. In the study districts few women received postpartum care during the first week after childbirth (25 % in Burkina Faso, 33 % in Kenya, 41 % in Malawi, 40 % in Mozambique). Based on these findings the interventions selected by stakeholders mainly focused on increasing the availability and provision of postpartum services and improving the quality of postpartum care through strengthening postpartum services and care at facility and community level. This includes the introduction of postpartum home visits, strengthening postpartum outreach services, integration of postpartum services for the mother in child immunisation clinics, distribution of postpartum care guidelines among health workers and upgrading postpartum care knowledge and skills through training. CONCLUSION: There are extensive gaps in availability and provision of postpartum care for mothers and infants. Acknowledging these gaps and involving relevant stakeholders are important to design and select sustainable, context-specific packages of interventions to improve postpartum care. PMID- 26038102 TI - Immobilization of carbonic anhydrase on carboxyl-functionalized ferroferric oxide for CO2 capture. AB - New materials of Fe3O4 magnetic microspheres were functionalized with carboxyl and prepared for carbonic anhydrase (CA) immobilization to capture CO2. The optimum conditions for immobilization, such as carrier dose, enzyme dose, pH, shaking speed, temperature and contact time, were determined. The pH and thermal stability of the free and the immobilized CA were compared. The results presented that the immobilized CA had a better enzyme activity, a higher pH and thermal stability than that of the free CA. Meanwhile, CO2 capture was respectively enhanced by the free and the immobilized CA in tris(hydroxymethyl) aminomethane (Tris) buffer solution. Moreover, the immobilized CA maintained 58.5% of its initial catalytic ability even after ten recovery cycles due to the protest of the magnetic microspheres. All the results confirmed the potential use of the carboxyl-functionalized Fe3O4 magnetic microspheres immobilized CA to remove CO2 from air or flue gas. PMID- 26038103 TI - Production and optimization of xylooligosaccharides from corncob by Bacillus aerophilus KGJ2 xylanase and its antioxidant potential. AB - The aim of the present study is to produce xylooligosaccharides (XOS) from corncob xylan. The xylan was extracted from corncob using methods like dilute acid, dilute alkali and sodium hypochlorite treatment. Corncob xylan extracted using alkali was characterized by FT-IR and TG-DSC. The extracted xylan was subjected to enzymatic hydrolysis using Bacillus aerophilus KGJ2 xylanase for XOS production. To increase the yield of XOS, the effects of various process parameters like substrate concentration, reaction time, and enzyme concentration on XOS production were investigated. XOS prepared was characterized by HPTLC. Anti oxidant potential of produced XOS was evaluated and the DPPH assay showed that XOS possessed concentration dependent free radical scavenging activity. PMID- 26038104 TI - Anesthetic 2,2,2-trifluoroethanol induces amyloidogenesis and cytotoxicity in human serum albumin. AB - Trifluoroethanol (TFE) mimics the membrane environments as it simulates the hydrophobic environment and better stabilizes the secondary structures in peptides owing to its hydrophobicity and hydrogen bond-forming properties. Its dielectric constant approximates that of the interior of proteins and is one third of that of water. Human serum albumin (HSA) is a biological transporter. The effect of TFE on HSA gives the clue about the conformational changes taking place in HSA on transport of ligands across the biological membranes. At 25% (v/v) and 60% (v/v) TFE, HSA exhibits non-native beta-sheet, altered tryptophan fluorescence, exposed hydrophobic clusters, increased thioflavin T fluorescence and prominent red shifted Congo red absorbance, and large hydrodynamic radii suggesting the aggregate formation. Isothermal titration calorimetric results indicate weak binding of TFE and HSA. This suggests that solvent-mediated effects dominate the interaction of TFE and HSA. TEM confirmed prefibrillar at 25% (v/v) and fibrillar aggregates at 60% (v/v) TFE. Comet assay of prefibrillar aggregates showed DNA damage causing cell necrosis hence confirming cytotoxic nature. On increasing concentration of TFE to 80% (v/v), HSA showed retention of native-like secondary structure, increased Trp and ANS fluorescence, a transition from beta sheet to alpha-helix. Thus, TFE at high concentration possess anti- aggregating potency. PMID- 26038105 TI - Mimicking enzymatic effects of cytochrome P450 by an efficient biosensor for in vitro detection of DNA damage. AB - A novel biosensor for detecting DNA damage induced by benzo(a)pyrene (BP) and its metabolite was presented in this work. The nafion-solubilized single wall carbon nanotubes-ionic liquid (SWCNTs-NA-IL) composite film was prepared and then horseradish peroxidase (HRP) and double-stranded DNA were alternately assembled on the composite film by the layer-by-layer method. The biosensor was characterized by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), differential pulse voltammetry (DPV), scanning electron microscopy (SEM) and computational methods. UV-vis spectrophotometry was also used to investigate DNA damage induced by BP and its metabolites in solution. The DNA biosensor was treated separately in BP, hydrogen peroxide (H2O2) and in their mixture, respectively. The EIS analysis showed a decrease in the charge transfer resistance at the DNA/HRP/SWCNTs-NA-IL/GCE incubated in a mixture of HRP and H2O2, because HRP in the presence of H2O2 could mimic enzymatic effects of cytochrome P450 (CYP450) to metabolize BP which could cause significant DNA damage and the exposed DNA bases reduced the electrostatic repulsion of the negatively charged redox probe and leads to Faradaic impedance changes. Finally, a novel biosensor for BP determination was developed and this method provided an indirect, and quantitative estimation of DNA damage in vitro. PMID- 26038106 TI - Crosslinking effect of dialdehyde starch (DAS) on decellularized porcine aortas for tissue engineering. AB - Biological tissue-derived biomaterials must be chemically modified to avoid immediate degradation and immune response before being implanted in human body to replace malfunctioning organs. DAS with active aldehyde groups was employed to replace glutaraldehyde (GA), a most common synthetic crosslinking reagent in clinical practice, to fix bioprostheses for lower cytotoxicity. The aim of this research was to evaluate fixation effect of DAS. The tensile strength, crosslinking stability, cytotoxicity especially the anti-calcification capability of DAS-fixed tissues were investigated. The tensile strength and resistance to enzymatic degradation of samples were increased after DAS fixation, the values maintained stably in D-Hanks solution for several days. Meanwhile, ultrastructure of samples preserved well and the anti-calcification capability of samples were improved, the amount of positive staining points in the whole visual field of 15% DAS-fixed samples was only 0.576 times to GA-fixed ones. Moreover, both unreacted DAS and its hydrolytic products were nontoxic in cytotoxicity study. The results demonstrated DAS might be an effective crosslinking reagent to fix biological tissue-derived biomaterials in tissue engineering. PMID- 26038107 TI - Nano-encapsulation of isolated lactoferrin from camel milk by calcium alginate and evaluation of its release. AB - Lactoferrin is a glycoprotein, playing several biological roles. The main goal of our work was to nanoencapsulate the isolated lactoferrin from camel milk through alginate nanocapsuls. We studied the influence of alginate concentration (0.2 and 0.5 w/w%) and encapsulation method (thermal vs. non-thermal treatment) on the encapsulation efficiency, zeta potential, particle size and release of lactoferrin from nanocapsuls. Our results revealed in 0.8 and 0.9 M NaCl fractions, lactoperoxidase was present. So these fractions were not passed to further experiments. On average, we measured the lactoferrin content to be 0.5 g/l within the original camel milk. In general, higher alginate concentration resulted in higher encapsulation efficiency and nanocapsuls prepared with thermal treatment had a higher efficiency (almost 100%) along with smaller particle sizes (mostly<100 nm). By evaluating the release of lactoferrin from nanocapsuls, it was revealed that there was no release at the first 30 min in both pH values (2 and 7). This could be particularly useful since lactoferrin would be maintained intact within stomach conditions and it can reach lower gastrointestinal tract to be delivered safely into the body. PMID- 26038109 TI - Efficacy of drug treatment for acute mania differs across geographic regions: An individual patient data meta-analysis of placebo-controlled studies. AB - Given globalization trends in the conduct of clinical trials, the external validity of trial results across geographic regions is questioned. The objective of this study was to examine the efficacy of treatment in acute mania in bipolar disorder across regions and to explain potential differences by differences in patient characteristics. We performed a meta-analysis of individual patient data from 12 registration studies for the indication acute manic episode of bipolar disorder. Patients (n = 3207) were classified into one of three geographic regions: Europe (n = 981), USA (n = 1270), and other regions (n = 956). Primary outcome measures were mean symptom change score on the Young Mania Rating Scale (YMRS) from baseline to endpoint and responder status (50% improvement form baseline). Effect sizes were significantly smaller in the USA (g = 0.203, 95% confidence interval (CI) 0.062-0.344; odds ratio (OR) 1.406, 95% CI 0.998-1.980) than in Europe (g = 0.476, 95% CI 0.200-0.672; OR 2.380, 95% CI 1.682-3.368) or other regions (g = 0.533, 95% CI 0.399-0.667; OR 2.300, 95% CI 1.800-2.941). Regional differences in age, gender, initial severity, body mass index, placebo response, discontinuation rate, and type of compound could not explain the geographic differences in effect. Less severe symptoms at baseline in the US patients did explain some of the difference in responder status between patients in Europe and the USA. These findings suggest that the results of studies involving patients with acute mania cannot be extrapolated across geographic regions. Similar findings have been identified in schizophrenia, contraceptive, and in cardiovascular trials. Therefore, this finding may indicate a more general problem regarding the generalizability of pharmacological trials over geographic regions. PMID- 26038110 TI - Immunodetection and subcellular distribution of imidazoline receptor proteins with three antibodies in mouse and human brains: Effects of treatments with I1- and I2-imidazoline drugs. AB - Various imidazoline receptor (IR) proteins have been proposed to mediate the effects of selective I1- and I2-IR drugs. However, the association of these IR binding proteins with classic I1- and I2-radioligand binding sites remains somewhat controversial. In this study, three IR antibodies (anti-NISCH and anti nischarin for I1-IRs; and anti-IRBP for I1/I2-IRs) were used to immunodetect, characterize and compare IR protein patterns in brain (mouse and human; total homogenate, subcellular fractionation, grey and white matter) and some cell systems (neurones, astrocytes, human platelets). Various immunoreactive IRs (specific molecular weight bands coincidently detected with the different antibodies) were related to I1-IR (167 kDa, 105/115 kDa and 85 kDa proteins) or I2-IR (66 kDa, 45 kDa and 30 kDa proteins) types. The biochemical characterization of cortical 167 kDa protein, localized in the membrane/cytosol but not in the nucleus, indicated that this I1-IR also forms part of higher order nischarin-related complexes. The contents of I1-IR (167 kDa, 105/115 kDa, and 85 kDa) proteins in mouse brain cortex were upregulated by treatment with I1-drugs (moxonidine, efaroxan) but not with I2-drugs (BU-224, LSL 61122). Conversely, the contents of I2-IR (66 kDa, 45 kDa and 30 kDa) proteins in mouse brain cortex were modulated by treatment with I2-drugs (decreases after BU-224 and LSL 61122, and increases after idazoxan) but not with I1-drugs (with the exception of moxonidine). These findings further indicate that brain immunoreactive IR proteins exist in multiple forms that can be grouped in the already known I1- and I2-IR types, which are expressed both in neurones and astrocytes. PMID- 26038111 TI - Auditory event-related potentials in methadone substituted opiate users. AB - The effects of methadone maintenance treatment (MMT) on neurophysiological function are unclear. Using an auditory oddball paradigm, event-related potential (ERP) amplitudes and latencies were measured in 32 patients undertaking MMT, 17 opiate users who were addicted but not receiving substitution treatment and 25 healthy control subjects. Compared with healthy control subjects, the MMT and opiate user groups showed an increased P200 amplitude in response to target stimuli. The opiate user group also exhibited a decreased amplitude and an increased latency of N200, and a greater number of task-related errors than either healthy control subjects or patients undertaking MMT. There were no significant group differences in the P300 amplitude. However, it is noteworthy that the frontal P300 amplitude of the MMT group was greater than that of opiate users or healthy controls. Our findings suggest that altered sensory information processing associated with a history of opiate use remains in patients undertaking MMT. However, there are less marked ERP abnormalities in those receiving MMT than in active opiate users. The deficits in information processing associated with illicit opiate use are likely to be reduced during MMT. PMID- 26038108 TI - Single-residue posttranslational modification sites at the N-terminus, C-terminus or in-between: To be or not to be exposed for enzyme access. AB - Many protein posttranslational modifications (PTMs) are the result of an enzymatic reaction. The modifying enzyme has to recognize the substrate protein's sequence motif containing the residue(s) to be modified; thus, the enzyme's catalytic cleft engulfs these residue(s) and the respective sequence environment. This residue accessibility condition principally limits the range where enzymatic PTMs can occur in the protein sequence. Non-globular, flexible, intrinsically disordered segments or large loops/accessible long side chains should be preferred whereas residues buried in the core of structures should be void of what we call canonical, enzyme-generated PTMs. We investigate whether PTM sites annotated in UniProtKB (with MOD_RES/LIPID keys) are situated within sequence ranges that can be mapped to known 3D structures. We find that N- or C-termini harbor essentially exclusively canonical PTMs. We also find that the overwhelming majority of all other PTMs are also canonical though, later in the protein's life cycle, the PTM sites can become buried due to complex formation. Among the remaining cases, some can be explained (i) with autocatalysis, (ii) with modification before folding or after temporary unfolding, or (iii) as products of interaction with small, diffusible reactants. Others require further research how these PTMs are mechanistically generated in vivo. PMID- 26038112 TI - Experiments on Hemoglobin in Single Crystals and Silica Gels Distinguish among Allosteric Models. AB - Trapping quaternary structures of hemoglobin in single crystals or by encapsulation in silica gels has provided a demanding set of data to test statistical mechanical models of allostery. In this work, we compare the results of those experiments with predictions of the four major allosteric models for hemoglobin: the quaternary two-state model of Monod, Wyman, and Changeux; the tertiary two-state model of Henry et al., which is the simplest extension of the Monod-Wyman-Changeux model to include pre-equilibria of tertiary as well as quaternary conformations; the structure-based model of Szabo and Karplus; and the modification of the latter model by Lee and Karplus. We show that only the tertiary two-state model can provide a near quantitative explanation of the single-crystal and gel experimental results. PMID- 26038113 TI - Mesh use in surgery for pelvic organ prolapse. PMID- 26038115 TI - Alpha, beta and gamma electrocorticographic rhythms in somatosensory, motor, premotor and prefrontal cortical areas differ in movement execution and observation in humans. AB - OBJECTIVE: In the present study, we tested the hypothesis that both movement execution and observation induce parallel modulations of alpha, beta, and gamma electrocorticographic (ECoG) rhythms in primary somatosensory (Brodmann area 1-2, BA1-2), primary motor (BA4), ventral premotor (BA6), and prefrontal (BA44 and BA45, part of putative human mirror neuron system underlying the understanding of actions of other people) areas. METHODS: ECoG activity was recorded in drug resistant epileptic patients during the execution of actions to reach and grasp common objects according to their affordances, as well as during the observation of the same actions performed by an experimenter. RESULTS: Both action execution and observation induced a desynchronization of alpha and beta rhythms in BA1-2, BA4, BA6, BA44 and BA45, which was generally higher in amplitude during the former than the latter condition. Action execution also induced a major synchronization of gamma rhythms in BA4 and BA6, again more during the execution of an action than during its observation. CONCLUSION: Human primary sensorimotor, premotor, and prefrontal areas do generate alpha, beta, and gamma rhythms and differently modulate them during action execution and observation. Gamma rhythms of motor areas are especially involved in action execution. SIGNIFICANCE: Oscillatory activity of neural populations in sensorimotor, premotor and prefrontal (part of human mirror neuron system) areas represents and distinguishes own actions from those of other people. This methodological approach might be used for a neurophysiological diagnostic imaging of social cognition in epileptic patients. PMID- 26038114 TI - Systems-wide analysis of BCR signalosomes and downstream phosphorylation and ubiquitylation. AB - B-cell receptor (BCR) signaling is essential for the development and function of B cells; however, the spectrum of proteins involved in BCR signaling is not fully known. Here we used quantitative mass spectrometry-based proteomics to monitor the dynamics of BCR signaling complexes (signalosomes) and to investigate the dynamics of downstream phosphorylation and ubiquitylation signaling. We identify most of the previously known components of BCR signaling, as well as many proteins that have not yet been implicated in this system. BCR activation leads to rapid tyrosine phosphorylation and ubiquitylation of the receptor-proximal signaling components, many of which are co-regulated by both the modifications. We illustrate the power of multilayered proteomic analyses for discovering novel BCR signaling components by demonstrating that BCR-induced phosphorylation of RAB7A at S72 prevents its association with effector proteins and with endo lysosomal compartments. In addition, we show that BCL10 is modified by LUBAC mediated linear ubiquitylation, and demonstrate an important function of LUBAC in BCR-induced NF-kappaB signaling. Our results offer a global and integrated view of BCR signaling, and the provided datasets can serve as a valuable resource for further understanding BCR signaling networks. PMID- 26038116 TI - Estrogen Protects against Obesity-Induced Mammary Gland Inflammation in Mice. AB - Obesity is a risk factor for the development of hormone receptor (HR)-positive breast cancer in postmenopausal women. Obesity causes subclinical inflammation in white adipose tissue (WAT), characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase. Previously, we demonstrated CLS and elevated levels of proinflammatory mediators and aromatase in the mammary glands of obese mice and breast tissue of obese women. Here, we tested the hypothesis that supplemental estrogen could prevent or reverse WAT inflammation (WATi) and related molecular changes in the mammary gland. C57BL/6J mice were ovariectomized (OVX) to simulate the postmenopausal state. Supplementation with 17beta-estradiol (E2) protected against high fat diet (HFD)-induced weight gain and mammary glands WATi. Expression of proinflammatory mediators (Cox-2, TNFalpha, IL1beta) and aromatase were also reduced in the mammary glands of mice that received supplemental E2. Next, to determine whether E2 supplementation can reverse WATi, obese OVX mice were treated with E2 or placebo and then continued on HFD. E2 supplementation induced weight loss, reversed mammary gland inflammation, and downregulated expression of proinflammatory mediators and aromatase. Finally, we determined whether the protective effects of E2 were mediated by estrogen receptor-alpha (ERalpha). Knocking out ERalpha in ovary intact mice fed a HFD led to weight gain, WATi and elevated levels of proinflammatory mediators and aromatase mimicking the effects of OVX. Taken together, our findings indicate that estrogen via ERalpha protects against weight gain, WATi and associated increases in proinflammatory mediators and aromatase in the mammary gland. PMID- 26038117 TI - Activation of the Mitochondrial Apoptotic Pathway Produces Reactive Oxygen Species and Oxidative Damage in Hepatocytes That Contribute to Liver Tumorigenesis. AB - Chronic hepatitis, including viral hepatitis and steatihepatitis, is a well-known high-risk condition for hepatocellular carcinoma. We previously reported that continuous hepatocyte apoptosis drives liver tumors in hepatocyte-specific Bcl-xL or Mcl-1 knockout mice. In this study, we further examine the underlying cellular mechanisms of generating tumors in apoptosis-prone liver. In cultured hepatocytes, the administration of ABT-737, a Bcl-xL/-2/-w inhibitor, led to production of reactive oxygen species (ROS) as well as activation of caspases. Mitochondria isolated from murine liver, upon administration of truncated-Bid, a proapoptotic Bcl-2 family protein, released cytochrome c and produced ROS, which was dependent on mitochondrial respiration. Hepatic apoptosis, regeneration, accumulation of oxidative damages, and tumorigenesis observed in hepatocyte specific Mcl-1 knockout mice were substantially attenuated by further deficiency of Bax or Bid, suggesting that a balance of mitochondrial Bcl-2 family proteins governs generation of oxidative stress and other pathologies. Whole-exome sequencing clarified that C>A/G>T transversion, which is often caused by oxidative DNA damage in proliferating cells, was a frequently observed mutation pattern in liver tumors of Mcl-1 knockout mice. The administration of antioxidant L-N-acetylcysteine did not affect apoptosis, compensatory regeneration, or fibrotic responses but significantly reduced oxidative DNA damage and incidence and multiplicity of live tumors in Mcl-1 knockout mice. In conclusion, activation of the mitochondrial apoptotic pathway in hepatocytes accumulates intracellular oxidative damages, leading to liver tumorigenesis, independently of liver regeneration or fibrosis. This study supports a concept that antioxidant therapy may be useful for suppressing liver carcinogenesis in patients with chronic liver disease. PMID- 26038118 TI - Trends in maternal obesity in a large university hospital 2009-2013. AB - INTRODUCTION: Maternal obesity has been identified as an important clinical priority in contemporary obstetrics. This study aimed to determine the incidence of maternal obesity in early pregnancy and track recent trends in body mass index (BMI) categories over 5 years 2009-2013. MATERIAL AND METHODS: This prospective observational study included all women who delivered an infant weighing >=500 g during the 5 years 2009-2013 in a large university teaching hospital in Ireland. Body mass index was calculated using early pregnancy weight and height measured at first antenatal visits. Sociodemographic and clinical data were gathered prospectively. Trends in maternal obesity were tracked over 5 years and epidemiological associations with obesity were examined using logistic regression, adjusted for confounding variables. RESULTS: Of 42 362 women, 99.0% (n = 41 927) were eligible for analysis with a mean BMI of 25.5 kg/m(2) , mean age of 30.7 years and 40.7% (n = 17054) primigravidas. The absolute number of cases of severe obesity (BMI >=40.0 kg/m(2) ) increased by 48.5% from 2009 to 2013 (p < 0.001). After multivariate logistic regression analyses, obesity incidence increased with increasing parity, advancing age and socioeconomic disadvantage. The maternal obesity rate among women born in the 13 European Union Accession countries was 8.6%, nearly half that of those born in existing European Union countries (p < 0.001). CONCLUSION: It is concerning that while the overall obesity rate remained stable, the number of cases of severe obesity increased over 5 years. We recommend renewed public health efforts addressing obesity rates before pregnancy and reinforcing attempts to optimize a woman's weight after delivery. PMID- 26038119 TI - Guidance is published on sharing data from publicly funded trials. PMID- 26038120 TI - Phase I trial of low-dose oral Clofarabine in myelodysplastic syndromes patients who have failed frontline therapy. AB - We investigated protracted low-dose oral Clofarabine for the treatment of myelodysplastic syndromes (MDS). Adults with an International Prognostic Scoring System (IPSS) score of INT-1 or higher who had failed first line therapy were eligible. INT-1 patients had to be transfusion-dependent. We started with oral Clofarabine at 5mg (fixed dose) daily for 10 consecutive days on a 28-day cycle. Toxicity prompted a modification to 1mg PO daily for 10 days and then 1mg PO daily for 7 days. Patients received treatment indefinitely until loss of response or unacceptable toxicity. Nine patients (5 women) were enrolled and evaluable (median age 65 years; range 55-81). A 10-day regimen of oral Clofarabine at 5mg/day induced Grade IV pancytopenia. A dose of 1 mg/day for 7/28 days was very well tolerated without significant toxicity. Three patients had responses (2 with responses lasting up to 21 and 51 cycles) defined as stable disease in spite of no significant change on bone marrow evaluation. Low-dose oral Clofarabine (1mg daily for 7/28 days) proved both effective and safe for patients with MDS who had failed prior therapy. This patient population is particularly sensitive to more protracted Clofarabine treatment schedules. PMID- 26038121 TI - Surrogate molecular markers for IGHV mutational status in chronic lymphocytic leukemia for predicting time to first treatment. AB - ZAP-70 is a marker of clinical outcome in chronic lymphocytic leukemia (CLL), however its assessment suffers from a lack of standardization consensus. To identify novel markers able to surrogate IGHV mutational status, CD19(+)CD5(+)-B lymphocytes from 216 patients enrolled in a prospective study (ClinicalTrial.gov Identifier:NCT00917540), underwent gene expression profiling. Samples were split into CLL-Training (n=102) and CLL-Validation (n=114) sets, and an independent supervised analysis for IGHV mutational status was performed considering all genes with gene expression equal or above that of ZAP-70. Thirty-one genes (23 up and 8 down-regulated) and 23 genes (18 up- and 5 down-regulated) satisfied these criteria in the CLL-Training and CLL-Validation sets, respectively, and 20 common genes (15 up and 5 down) were found to be differentially regulated in both sets. Two (SNORA70F, NRIP1) of the down-regulated and 6 (SEPT10, ZNF667, TGFBR3, MBOAT1, LPL, CRY1) of the up-regulated genes were significantly associated with a reduced risk of disease progression in both sets. Forcing the afore-mentioned genes in a Cox multivariate model together with IGHV mutational status, only CRY1 (HR=2.3, 95% CI: 1.1-4.9, P=.027) and MBOAT1 (HR=2.1, 95% CI: 1.1-3.7, P=.018) retained their independent prognostic impact, supporting the hypothesis that these genes may potentially act as surrogates for predicting IGHV mutational status. PMID- 26038122 TI - The value of a new image classification system for planning treatment and prognosis of spontaneous isolated superior mesenteric artery dissection. AB - OBJECTIVE: To aid diagnosis of spontaneous isolated superior mesenteric artery dissection and planning management, we investigated the role of classification of features as observed on computed tomography angiography images. METHODS: A retrospective study was conducted, comprising computed tomography angiography images and clinical data of 28 consecutive patients with spontaneous isolated superior mesenteric artery dissection. Based on the computed tomography angiography images, a new classification for spontaneous isolated superior mesenteric artery dissection was proposed. Patients with intestinal ischemia not relieved or worsened after 10 days of conservative treatment underwent surgery or stenting. All patients were followed up with computed tomography angiography. RESULTS: Spontaneous isolated superior mesenteric artery dissection was categorized into five types (I-V). Type III was further divided into subtypes IIIa-IIIc. Spontaneous isolated superior mesenteric artery dissection IIIa and IV typified nine (32.1%) and seven (25%) patients, respectively. Six (21.4%) patients had aortic or branch artery abnormalities and 21 (78%) showed prior intestinal ischemia. Four (14.3%) patients had intestinal ischemia and underwent surgery or stenting. CONCLUSIONS: Spontaneous isolated superior mesenteric artery dissection type IIIa is more likely to occur than other types. Long-term computed tomography angiography follow-up is valuable for determining treatment strategy for spontaneous isolated superior mesenteric artery dissection. Conservative therapy with anticoagulants is recommended for five days, and surgery or stenting should be considered if symptoms of intestinal ischemia are not relieved. Stent implantation provides relatively satisfactory mid-term outcome for true lumen construction of the superior mesenteric artery. PMID- 26038123 TI - Competitive assessments of pulmonary embolism: Noninvasiveness versus the golden standard. AB - Diagnosis of suspected pulmonary embolism (PE) is crucial as undiagnosed and over diagnosis can both lead to serious consequences. Contemporary diagnostic approach of PE is a sequential combination assessment beginning with clinical assessment, validated with D-dimer measurement and confirmed with pulmonary angiography or imaging. Since the invasive pulmonary angiography is risky and costly, imaging is a warranted tool in the diagnosis procedure. CT pulmonary angiography is a less invasive method with general availability, studies provide favorable evidences for CT pulmonary angiography as a stand-alone test for excluding PE, and it has become the first choice of tests in emergency department for suspected PE in most centers. Ventilation/perfusion single-photon emission CT signifies a new era in nuclear medicine. It has excellent sensitivity and specificity, fast procedure, low radiation exposure, few complications and contradictions. Besides, MR angiography is another possible and promising approach for diagnosis of suspected PE with much safer contrast agents than CT and no ionizing radiation. With wide availability and less invasive effects, imaging becomes a firsthand tool to obtain optimal accuracy in the diagnosis work up in clinic nowadays. This review summarizes the current methods in diagnosing PE and the update of imaging assessments of the disease. PMID- 26038126 TI - Plant community associations of two invasive thistles. AB - In order to combat the growing problems associated with biological invasions, many researchers have focused on identifying which communities are most vulnerable to invasion by exotic species. However, once established, invasive species can significantly change the composition of the communities that they invade. The first step to disentangling the direction of causality is to discern whether a relationship with other vegetation exists at all. Carduus nutans and C. acanthoides are similar invasive thistles, which have caused substantial economic damage worldwide. We assessed the associations between the thistles and the standing flora in four sites in central Pennsylvania in which they co-occur. After sampling nearly 2000 plots of 1 m(2), we used partial Mantel tests to assess the differences in vegetation between thistle and non-thistle plots after accounting for location, and non-metric multidimensional scaling to visualize differences among plots and sites. We found significant differences in community composition in plots with and without Carduus thistles. The non-native species Sisymbrium officinale and Coronilla varia were consistently associated with the presence of Carduus thistles. Several species were associated with areas that were free of Carduus thistles, including an important non-native pasture species (Trifolium repens). We found no evidence for differences in composition between plots with C. nutans versus C. acanthoides, suggesting that they have similar associations with the vegetation community. We conclude that even at the within field scale, areas invaded by Carduus thistles have different vegetation associations than uninvaded areas, allowing us to target future research about the role of vegetation structure in resisting and responding to invasion. PMID- 26038124 TI - Generation and characterization of a trackable plant-made influenza H5 virus-like particle (VLP) containing enhanced green fluorescent protein (eGFP). AB - Medicago, Inc. has developed an efficient virus-like particle (VLP) vaccine production platform using the Nicotiana benthamiana expression system, and currently has influenza-based products targeting seasonal/pandemic hemagglutinin (HA) proteins in advanced clinical trials. We wished to generate a trackable HA based VLP that would allow us to study both particle assembly in plants and VLP interactions within the mammalian immune system. To this end, a fusion protein was designed, composed of H5 (from influenza A/Indonesia/05/2005 [H5N1]) with enhanced green fluorescent protein (eGFP). Expression of H5-eGFP in N. benthamiana produced brightly fluorescent ~160 nm particles resembling H5-VLPs. H5-eGFP-VLPs elicited anti-H5 serologic responses in mice comparable to those elicited by H5-VLPs in almost all assays tested (hemagglutination inhibition/IgG(total)/IgG1/IgG2b/IgG2a:IgG1 ratio), as well as a superior anti GFP IgG response (mean optical density = 2.52 +/- 0.16 sem) to that elicited by soluble GFP (mean optical density = 0.12 +/- 0.06 sem). Confocal imaging of N. benthamiana cells expressing H5-eGFP displayed large fluorescent accumulations at the cell periphery, and draining lymph nodes from mice given H5-eGFP-VLPs via footpad injection demonstrated bright fluorescence shortly after administration (10 min), providing proof of concept that the H5-eGFP-protein/VLPs could be used to monitor both VLP assembly and immune trafficking. Given these findings, this novel fluorescent reagent will be a powerful tool to gain further fundamental insight into the biology of influenza VLP vaccines. PMID- 26038125 TI - Crosstalk between bone marrow-derived mesenchymal stem cells and regulatory T cells through a glucocorticoid-induced leucine zipper/developmental endothelial locus-1-dependent mechanism. AB - Bone marrow is a reservoir for regulatory T (T(reg)) cells, but how T(reg) cells are regulated in that environment remains poorly understood. We show that expression of glucocorticoid (GC)-induced leucine zipper (GILZ) in bone marrow mesenchymal lineage cells or bone marrow-derived mesenchymal stem cells (BMSCs) increases the production of T(reg) cells via a mechanism involving the up regulation of developmental endothelial locus-1 (Del-1), an endogenous leukocyte endothelial adhesion inhibitor. We found that the expression of Del-1 is increased ~4-fold in the bone tissues of GILZ transgenic (Tg) mice, and this increase is coupled with a significant increase in the production of IL-10 (2.80 vs. 0.83) and decrease in the production of IL-6 (0.80 vs. 2.33) and IL-12 (0.25 vs. 1.67). We also show that GILZ-expressing BMSCs present antigen in a way that favors T(reg) cells. These results indicate that GILZ plays a critical role mediating the crosstalk between BMSCs and T(reg) in the bone marrow microenvironment. These data, together with our previous findings that overexpression of GILZ in BMSCs antagonizes TNF-alpha-elicited inflammatory responses, suggest that GILZ plays important roles in bone-immune cell communication and BMSC immune suppressive functions. PMID- 26038127 TI - Exposure of FVIII in the Presence of Phosphatidyl Serine Reduces Generation of Memory B-Cells and Induces Regulatory T-Cell-Mediated Hyporesponsiveness in Hemophilia A Mice. AB - A major complication of replacement therapy with Factor VIII (FVIII) for hemophilia A (HA) is the development of unwanted immune responses. Previous studies showed that administration of FVIII in the presence of phosphatidyl serine (PS) reduced the development of anti-FVIII antibodies in HA mice. However, the impact of PS-mediated effects on immunological memory, such as generation of memory B-cells, is not clear. The effect of PS on memory B-cells was therefore investigated using adoptive transfer approach in FVIII(-/-) HA mice. Adoptive transfer of memory B-cells from a PS-FVIII-treated group to naive mice followed by challenge of the recipient mice with FVIII showed a significantly reduced anti FVIII antibody response in the recipient mice, compared with animals that received memory B-cells from free FVIII and FVIII-charge matched phosphatidyl glycerol (PG) group. The decrease in memory B-cell response is accompanied by an increase in FoxP3 expressing regulatory T-cells (Tregs). Flow cytometry studies showed that the generation of Tregs is higher in PS-treated animals as compared with FVIII and FVIII-PG treated animals. The PS-mediated hyporesponsiveness was found to be antigen-specific. The PS-FVIII immunization showed hyporesponsiveness toward FVIII rechallenge but not against ovalbumin (OVA) rechallenge, an unrelated antigen. This demonstrates that PS reduces immunologic memory of FVIII and induces antigen-specific peripheral tolerance in HA mice. PMID- 26038128 TI - [Radiological study on rat lumbar vertebral semidislocation model]. AB - OBJECTIVE: To investigate the impact of fixation in part lumbar segment on rat model with radiography. METHODS: One hundred and twenty SPF male SD rats (350~450g) were randomly divided into simple fixation group (SF group), rotary fixation group (RF group) and sham-operation group (Sham group). The external link fixation system was implanted into the L4-L6 of SF group and RF group rats. In RF group, L5 spinous process of rats was rotated to the right side, making the L4, L6 and L5 spinous process not in a straight line. In SF group, the external link fixation system was implanted simply and not rotated. The anterior and posterior diameter in the intervertebral space and the distance between spinous processes were examined 1, 4, 8 and 12 weeks after fixation. RESULTS: The anterior diameter in the intervertebral space between L3-L4, L4-L5, L5-L6, and L6 S1 of SF groups 4 weeks after fixation were 28.11 +/- 3.94, 25.73 +/- 4.70, 29.51 +/- 6.34 and 34.97 +/- 4.65 pixels; the posterior diameter were 7.39 +/- 1.63, 6.65 +/- 1.76, 7.02+/-1.52 and 9.62 +/- 2.50 pixels; the distance between spinous process were 39.33 +/- 11.74, 14.11 +/- 5.75, 21.32 +/- 6.84 and 77.43 +/- 13.69 pixels, the values were less than those in Sham groups (P<0.05). The anterior and posterior diameter in the intervertebral space and the distance between spinous process of SF groups 8 and 12 weeks after fixation continuously decreased compared with Sham group rats (P<0.05). The results of RF groups were consistent with the measurement of SF groups, the anterior and posterior diameter in the intervertebral space and the distance between spinous process of RF group rats were less than those in Sham groups 4, 8 and 12 weeks after fixation (P<0.05). Osteophyte formation was observed in SF and RF groups 8 weeks after fixation. CONCLUSION: The fixation in part lumbar segment can result in the decrease of intervertebral space and the formation of osteophytes. PMID- 26038129 TI - [Effect of spinal manipulation on brain functional activity in patients with lumbar disc herniation]. AB - OBJECTIVE: To investigate the effects of spinal manipulation (SM) on brain functional activity in patients with lumbar disc herniation (LDH). METHODS: Eleven patients with LDH were recruited in the study. All patients received 6 times of lumbar SM treatment and then clinical efficacy was evaluated. All patients received brain functional magnetic resonance imaging (fMRI) scans before and after SM treatment. RESULTS: Three subjects dropped out and 8 subjects completed the study, among whom 4 cases were effective and 4 ineffective after SM treatment. The required pressure value producing the same level (VAS 50) pain was (7.43 +/- 1.47) kg and (10.53 +/- 0.55) kg before and after SM treatment in effective patients(P<0.05); however, there was no significant difference in ineffective patients (P>0.05). Compared to pre-treatment level, the brain functional activity in effective patients was mainly inhibited, the inhibited areas were located in the right side of prefrontal cortex and cerebellum; while the brain functional activity was generally enhanced in ineffective patients. CONCLUSION: SM can affect the brain functional activity of patients with LDH, the inhibited areas is mainly located in prefrontal cortex and cerebellum when SM treatment is effective. PMID- 26038130 TI - [Construction of a human cervical spine with bilateral vertebral artery fluid solid coupling model]. AB - OBJECTIVE: To construct a human cervical spine with bilateral vertebral artery fluid-solid coupling model. METHODS: Helical CT images under the principle of reverse engineering and meshed in finite element model(FEM) related software were used to establish a human cervical spine with bilateral vertebral artery fluid solid coupling model. In the process of modeling of vertebral body, vertebral artery, ligament, intervertebral disc, cartilage and endplate large anatomic data and cadaver experiments results were referenced. From the morphology and function the simulation of model with real physiological status was tested. RESULTS: The study showed that the stress concentration on the surface of vertebral body and the blood wall of the bilateral vertebral artery, and the result of the volume flow rate-time curve of bilateral vertebral artery of the model were consistent with the published literatures. This model was well consistent with the clinical phenomenon. CONCLUSION: The three-dimensional FEM of the human cervical spine established by the introduced method has been effectively verified. The modeling method would provide a new tool for research on the cervical spine biomechanics. PMID- 26038131 TI - [Development of Chinese version vertigo symptom scale (VSS): reliability and validity]. AB - OBJECTIVE: To develop a Chinese version of Vertigo Symptom Scale (VSS-C) and to examine its reliability and validity. METHODS: The VSS was translated into Chinese and developed a Chinese version VSS (VSS-C) with the consent of the author. The VSS-C scale was tested in 52 subjects with cervical spondylosis of vertebral artery type (CSA group) and 21 healthy subjects (control group). In CSA group VSS-C scale and SF-36 scale investigation was performed for 2 times with 1 week interval, after receiving 1-week orthopedic rehabilitation the patients were evaluated with the VSS-C and SF-36 scale; while subjects in control group received the investigation twice in two weeks. The reliability of the scale was evaluated with Cronbach's alpha method and the correlation between SF-36 scale and the VSS-C were also evaluated for the validity. RESULTS: The internal consistency of VSS-C was good with Cronbach's alpha of 0.886. Test-retest reliability was also very good with an intraclass correlation coefficient (ICC) between two time points, being 0.970 for VSS-C, 0.965 for VSS-AA and 0.992 for the VSS-VER. Regarding concurrent validity, significant low correlation was found between the VSS-AA and VSS-VER (r=0.379, P<0.05). Significant expected correlation was detected between the VSS-C and SF-36 (r>0.5, P<0.05) . The independent-samples t test results (t=6.261, P<0.01) of the CSA group and the control group showed that the VSS-C was able to distinguish healthy people from CSA patients. The paired-samples t test results (t=5.513, P<0.01) showed that VSS C reflected the improvement of patients after treatment of Chinese massage manipulation. CONCLUSION: The Chinese version of VSS has a high comprehensibility, internal consistency and validity, and it can be a useful instrument for evaluation of patients with cervical spondylosis of vertebral artery type in China. PMID- 26038132 TI - [Screening of active compounds with myocardial protective effects from Tongmai Yangxin pill]. AB - OBJECTIVE: Based on cell model and HPLC-MS technology, to screen myocardial protection active compounds from traditional patent medicine Tongmai Yangxin pill (TMYXP). METHODS: Fractions of TMYXP were prepared by high performance liquid preparation technology. The cardioprotective effects of prepared fractions were tested on H2O2 oxidation-damaged H9c2 myocardiocytes. The active components were analyzed by high performance liquid chromatography (HPLC) coupled with high resolution mass spectrometry. The possible active compounds were putatively identified by comparison of their MS ions and molecular weight with literatures. RESULTS: Ten TMYXP components presented significant myocardial protective activities, 5 of which were investigated and presented good dose-effect relationships. Their median effective concentrations (EC50) were respectively 11.66, 17.44, 13.10, 7.332, 15.15 MUg/mL. Totally, 11 potential active compounds were analyzed and identified, including Glycyrrhizic acid, Glycycoumarin, Licoisoflavone, Ophiopogonin D', Licoricon, Gancaonin L, Neoglycyrol, Emodin, Angeloylgomisin H, Angeloylgomisin Q and Glyasperin A. CONCLUSION: The myocardial protection active compounds of TMYXP were screened successfully. PMID- 26038133 TI - [Th17 and Treg cell levels in patients with sarcoidosis and their relation to disease activation]. AB - OBJECTIVE: To investigate the Th17 cell and Treg cell levels in patients with sarcoidosis, and their relation to disease activation and glucocorticoids treatment. METHODS: Twenty-three sarcoidosis patients admitted in Yinzhou People's Hospital from January 2009 to December 2013 and 25 healthy subjects (controls) were included in this study. The blood samples and bronchoalveolar lavage fluid (BALF) samples were collected in all patients before and after glucocorticoids treatment. The serum angiotensin converting enzyme (SACE) levels were detected. The percentages of Th17 cells and Treg cells in peripheral blood and BALF were determined by flow cytometry, the concentrations of cytokines in serum and supernatants of BALF were measured by enzyme-linked immunosorbent assay (ELISA). The levels of ROR-gammat and Foxp3 mRNA transcripts in peripheral blood mononuclear cells (PBMC) were determined by real-time quantitative PCR. The potential correlation between the percentages of Th17 or Treg cells and SACE levels was evaluated. RESULTS: Compared with healthy controls, significantly higher frequencies of Th17 cells (4.34%+/-0.89% vs 1.60% +/- 0.42%), lower frequencies of Treg cells (1.28% +/- 0.37% vs 3.39% +/- 0.50%) in peripheral blood were observed. Higher level of ROR-gammat mRNA (21.31 +/- 3.55 vs 3.63 +/- 1.00) and lower level of Foxp3 mRNA (1.60 +/- 0.24 vs 3.12 +/- 0.76) in peripheral blood were detected in sarcoidosis patients in active stage (before glucocorticoids treatment) (all P<0.01). After the treatment of glucocorticoids, these index in peripheral blood were significantly improved (Th17 cells 2.16% +/- 0.68%,Treg cells 2.21% +/- 0.42%, ROR-gammat mRNA 10.15 +/- 1.93, Foxp3 mRNA 2.44 +/- 0.38) ( all P<0.05). The changing trends of Th17 and Treg cell cytokines levels in serum were consistent with two type cells. Meanwhile, the changing trends of above index in BALF of patients treated by glucocorticoids were consistent with those in sarcoidosis patients in active stage. The increased ratios of Th17 cells to Treg cells were positively correlated with the level of serum SACE (r= 0.781). CONCLUSION: The imbalance of Th17 cells and Treg cells in peripheral blood and airway may be involved in the pathogenesis of sarcoidosis, which was associated with the activity of disease, and the treatment of glucocorticoids may achieve a therapeutic effect by correcting the immune imbalance. PMID- 26038134 TI - [Effect of irradiated human lung fibroblasts on activation of canonical Wnt/beta catenin signaling pathway in mesenchymal stem cells]. AB - OBJECTIVE: To investigate the effect of irradiated human lung fibroblasts (HLFs) on the canonical Wnt/beta-catenin signaling pathway in human umbilical cord mesenchymal stem cells (HUMSCs). METHODS: HUMSCs were cultured alone (single group) or co-cultured with HLFs exposed to 5Gy X-rays (co-culture group). The protein levels of GSK-3beta, p-GSK-3beta, FRAT1 and beta-catenin in HUMSCs were examined by Western blotting 3 days after culture or co-culture. WISP-1 protein levels in conditioned medium were examined by ELISA. RESULTS: The levels of p GSK3beta/GSK3beta (0.15 +/- 0.05), FRAT1 (0.48 +/- 0.07) and beta-catenin (0.50 +/- 0.07) in co-cultured HUMSCs significantly decreased compared to those in single group (0.55 +/- 0.05, 1.16 +/- 0.13 and 2.39 +/- 0.15, all P<0.05). The supernatant level of WISP-1 in co-culture group was significantly decreased [(602.23 +/- 161.47) ng/mL], compared to the single group [(977.77 +/- 110.56) ng/mL, P<0.05]. CONCLUSION: Irradiated HLFs attenuate the activation of canonical Wnt/beta-catenin signaling pathway in HUMSCs in vitro. PMID- 26038135 TI - [Preretinal hemorrhage and prognosis following vitrectomy and silicone oil tamponade for severe proliferative diabetic retinopathy]. AB - OBJECTIVE: To examine the prognosis of preretinal hemorrhage following vitrectomy and silicone oil tamponade for severe proliferative diabetic retinopathy. METHODS: Clinical data of 76 cases of proliferative diabetic retinopathy treated with vitrectomy and silicone oil infusion tamponade in Sir Run Run Shaw Hospital from October 2006 to September 2013 were retrospectively reviewed. Intraoperative bleeding,postoperative preretinal bleeding,blood reabsorption time, and preretinal fibrosis were assessed. RESULTS: All preretinal hemorrhage developed within 1 week after surgery, blood was distributed in thin and scattered patterns (32 cases), thick and localized patterns (25 cases) or thick and scattered patterns (19 cases). The preretinal hemorrhage was ceased in 1 day after operation in 35 cases, in 2 days after operation in 18 cases, in two weeks after operation in 23 case. Recurrent hemorrhage occurred within 1 week after operation in 15 cases. Thin blood was largely reabsorbed in about two weeks, and thick blood was largely reabsorbed in about five weeks. Fibrosis tissue was resulted in 15 cases(34.1%) with thick blood. CONCLUSION: Most of preretinal hemorrhage occurs within 1 week after surgery and is reabsorpted with 5 weeks in patients with proliferative diabetic retinopathy undergoing vitrectomy and silicone oil tamponade. The major complication of preretinal bleeding is the formation of preretinal fibrosis. PMID- 26038136 TI - [Apoptosis of acute myeloid leukemia HL-60 cells induced by CDK inhibitor SNS-032 and its molecular mechanisms]. AB - OBJECTIVE: To investigate the effects of cycle-dependent kinase (CDK) inhibitor SNS-032 on apoptosis in human acute myeloid leukemia (AML) HL-60 cells and its molecular mechanisms. METHODS: Cultured AML HL-60 cells were treated with various concentrations of SNS-032. Cell apoptosis was determined with flow cytometry;cell viability was measured by MTT assay; the profiles of microRNA expression of HL-60 cells were analyzed by microRNA microarray;the protein expressions of JAK2/STAT3 pathway were detected by Western blotting. RESULTS: Apoptosis of AML HL-60 cells was induced by SNS-032; the rate of apoptosis was (5.9+/-1.7)%, (12.1+/-3.1)% and (59.4+/-3.6)% when HL-60 cells were treated with 0,100 and 200 nmol/L SNS-032. MicroRNA microarray analysis revealed that the levels of miR-30a, miR-183, miR 20b, miR-26b, miR-20a, miR-589, miR-107, miR-181a, miR-106a, miR-17 and miR-378c were down-regulated by SNS-032,whereas the levels of miR-320a and miR-H7* were up regulated. Western blotting showed that SNS-032 strongly inhibited phosphorylation of STAT3 and protein expression of JAK2,C-MYC and MCL-1. CONCLUSION: CDK inhibitor SNS-032 can induce apoptosis of AML HL-60 cells, which is associated with the inhibition of MCL-1,C-MYC and JAK2/STAT3, and down regulation of miR-17-92 family. PMID- 26038137 TI - [Imatinib mesylate for chronic myeloid leukemia: in patients with initial treatment versus those with Recombinant Human IFN-alpha2b treatment failure]. AB - OBJECTIVE: To evaluate the efficacy of imatinib mesylate (IM) for patients with newly diagnosed chronic myeloid leukemia (CML) and patients after failure of Recombinant Human interferon-alpha2b (IFN-alpha2b) therapy. METHODS: A total of 86 patients with CML in chronic-phase, including 61 newly diagnosed cases and 25 cases of IFN-alpha2b failure, who received IM at 400 mg daily were retrospectively analyzed. Conventional cytogenetic analysis of R-banding was used to detect chromosome abnormalities and real-time PCR was used to detect BCR-ABL fusion gene. RESULTS: 81.9% of newly diagnosed patients and 36.0% of IFN-alpha2b failure patients achieved partial cytogenetic response (PCyR) by 6 months. In addition, 86.9% of newly diagnosed patients and 68.0% of IFN-alpha2b failure patients achieved complete cytogenetic response (CCyR) in 24 months. There was significant difference between two groups (P<0.001). The median time achieved CCyR in newly diagnosed group and IFN-alpha2b failure group were 6 months and 15 months, respectively. Compared with newly diagnosed group, IFN-alpha2b failure group showed lower rate of complete molecular remission (CMR) (70.4% vs 40.0%, P=0.033). There are 14 patients (22.9%) in newly diagnosed patients with cytogenetic resistance, among whom 4 with primary cytogenetic resistance; while there were 14 patients (56.0%) in IFN-alpha2b failure group with cytogenetic resistance, all of whom with primary resistance. CONCLUSION: Compared with newly diagnosed patients, CML patients after failure of IFN-alpha2b therapy have a high rate of primary cytogenetic resistance and low response rate to IM. PMID- 26038138 TI - [Expression of neuron-specific enolase and synaptophysin in esophageal development of human embryos]. AB - OBJECTIVE: To investigate the expression of neuron-specific enolase (NSE) and synaptophysin(SYN) proteins in different developmental stages of human embryonic esophagus. METHODS: Immunohistochemistry was used to detect the expressions of NSE and SYN proteins in embryonic esophagus tissues of fetuses of 2, 3 and 4 month gestational age (n=16). One-way ANOVA and LSD-t test were employed to compare the staining intensity and number of positive expression cells in embryonic esophageal tissues of different gestational age. RESULTS: In fetuses with 2, 3 and 4 months of gestation, the number of NSE-positive nerve cells in the myenteric nerve plexus and submucosa of human embryonic esophageal tissues were 18.38 +/- 8.37, 25.00 +/- 11.54 and 38.00 +/- 15.09, respectively; the staining intensity of NSE-positive nerve cells and nerve fibers in myenteric nerve plexus and submucosa of embryonic esophageal tissues were 74.38 +/- 14.93, 62.25 +/- 18.59 and 56.44 +/- 14.70, respectively. NSE-positive cells were detected in the esophageal epithelium only at the third month. In the fetuses at 2, 3 and 4 months of gestation, SYN in all layers of esophageal tissue were positively or strong positively expressed, especially in the myenteric plexus and submucosal plexus. The staining intensity of SYN-positive cells in embryonic esophagus tissues of 2, 3 and 4 month gestation were 54.69 +/- 9.34, 51.84 +/- 6.10 and 46.41 +/- 6.44, respectively. CONCLUSION: SYN and NSE may be involved in the regulation of nerve system of esophageal tissues during the human embryonic development. PMID- 26038139 TI - [Body mass index and all-cause mortality in Asian adults: a meta-analysis]. AB - OBJECTIVE: To perform a systematic review between all-cause mortality and body mass index (BMI) in Asian adults. METHOD: Relevant prospective studies that reported the relative risks (RRs) of all-cause mortality for community-based adults in Asia were identified by a literature search.PubMed and CNKI electronic databases were searched from inception through September 30, 2014, with language restrictions of English and Chinese. Data were extracted by 1 reviewer and then reviewed by 3 independent reviewers. The overall effect of varied levels of BMI and all-cause mortality were then pooled and analyzed.Potential sources of heterogeneity were detected by stratification analyses and sensitivity analyses. Publication bias was detected by funnel plot, Egger's test and Begg's test. RESULTS: Seventeen studies met the inclusion criteria; these studies included 1 769 369 individuals with 104 888 deaths. Random-effects summary all-cause mortality RRs was calculated. With the use of a BMI (in kg/m2) of 18.5~22.9 as the reference, the summary RRs were 1.39(95% CI: 1.31~1.47) for BMI less than 18.5 kg/m2 , 0.88 (95% CI: 0.85~0.92) for BMI of 23.0~29.9 kg/m2 and 1.14 (95% CI: 1.05~1.23) for BMI more than 30.0 kg/m2. The RRs tended to be higher when weight and height were self-reported rather than measured. The RRs were higher when papers were published before the year 2005 rather than after the year 2006. Also, the RRs were higher when the quality scores were higher. Potential sources of heterogeneity were gender, the method of obtaining weight and height, geography, publication year and quality scores. There was no publication bias (P>0.05) in this meta-analysis. CONCLUSION: There was an increased risk of all cause mortality for those both at the lower and higher level of BMI in Asian adults. PMID- 26038140 TI - [Effects of DNMT3A gene mutations on prognosis of patients with acute myeloid leukemia: a meta-analysis]. AB - OBJECTIVE: To evaluate the effects of DNMT3A gene mutation on prognosis of patients with acute myeloid leukemia (AML) by a meta-analysis. METHODS: Methods of Cochrane systematic review was followed by 7 databases,including PubMed, Embase, Ovid, CNKI, CBM, WanFang Data and VIP, were searched for peer-reviewed articles related to DNMT3A gene mutations and prognosis of patients with AML.Then manual retrieval was applied into literature references. After the evaluation of quality and extract of clinical trialliterature data, Stata 11.0 was employed to perform meta-analysis. RESULTS: Seven randomized controlled trials involving 1493 cases were included in the meta-analysis. The prognosis of patients with DNMT3A mutations and without DNMT3A mutations was compared. There was no statistically significant difference in complete remission(CR) rate (OR=1.034, 95%CI: 0.596~1.796, P=0.905 between two groups, but the overall survival (OS(HR=1.990, 95%CI: 1.463~2.510, P=0.000 and disease free survival (DFS) (HR= 2.840, 95%CI: 1.063~4.613, P=0.002) of patients without DNMT3A mutations were longer than those with DNMT3A mutation. CONCLUSION: DNMT3A gene mutation is an independent risk factor of poor prognosis of patients with acute myeloid leukemia. PMID- 26038141 TI - [Progress on association between autophagy and cancer]. AB - Autophagy is an evolutionarily well conserved cellular catabolic process.Cellular proteins and organelles are engulfed to autophagosomes and eventually delivered to lysosomes for degradation. Autophagy is closely associated with a variety of human diseases especially cancer. At present, it has been widely accepted that autophagy is a "double-edged sword" in cancer: it blocks tumorigenesis at the early stage, while it facilitates tumor development at the promotion and progression stage. Moreover, autophagy can be induced by chemotherapy and radiotherapy, which is generally play a pro-survival function. Thus, autophagy is an important target for cancer therapy, and suppression of autophagy to enhance the efficacy of cancer therapeutic agents is a novel strategy in cancer therapy under active clinical trials. PMID- 26038142 TI - [Research progress on epithelial-mesenchymal transition in cancer recurrence and metastasis]. AB - Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells lose their morphology and function and gradually transformed into mesenchymal like cells. It is considered that EMT is the main cause for tumor recurrence and metastasis. Many factors are involved in the regulation of EMT, such as E cadherin, transforming growth factor-beta, Wnt signaling pathway, microRNA and EMT-related transcription factors. This article reviews the research progress on EMT and the involved mechanisms, and thus to provide a new perspective on cancer therapy in the future. PMID- 26038143 TI - [Research advances on ubiquitin C-terminal hydrolase in oncogenesis and progression]. AB - By regulating the ubiquitination and deubiquitination of key proteins, ubiquitin proteasome system mediates a variety of cellular activities. Ubiquitin C-terminal hydrolase (UCH) is a deubiquitinating enzyme which can remove ubiquitin chains at the end of ubiquited proteins. The abnormal expression of UCH has been found in a variety of tumor tissues, indicating that it participates in the process of tumor development. Here we review the characteristics of UCH members and current understanding about the role of UCH in tumor development, and the potential target for cancer treatment. PMID- 26038144 TI - [Progress on interleukin-27 in tumor immunity]. AB - As a member of IL-6/IL-12 cytokine family, IL-27 is a heterodimeric cytokine composed of the p28 and EBI3. Functioning as a linkage between innate and adaptive immunity, IL-27 is mainly produced by activated antigen-presenting cells and has a variety of responder cells including T cells, NK cells, macrophages and dendritic cells. IL-27 plays an antitumor role through promoting the production of cytotoxic T cells, regulating the differentiation of T cell subsets, enhancing the function of NK cells and inhibiting the angiogenesis. On the other hand, IL 27 may also have a positive effect on tumor progress and metastasis. IL-27 can be used as a reference marker for tumor diagnosis, due to its relation to the occurrence and development of tumors. This article reviews the research progress on the roles of IL-27 in tumor biological regulation. PMID- 26038145 TI - [Carotid artery dissection with Horner syndrome as main manifestation: a case report]. AB - A 44-year old male patient was admitted to the First Affiliated Hospital, Zhejiang University School of Medicine with left ptosis and pain on the left head and neck for 20 days.Brain MRI showed subacute cerebral infarction on left parietal lobe and intramural hematoma on left internal carotid artery. CT angiography showed stenosis line on the C1 segment of left internal carotid artery. Digital subtraction angiography showed dissection on the C1 segment of left internal carotid artery.The condition of patients was improved after anticoagulant therapy. PMID- 26038146 TI - [Pure spinal epidural cavernous hemangioma: report of one case]. AB - A 55-year-old man presented with progressive numbness and weakness of both lower limbs is reported. MRI demonstrated a pure epidural lesion at T3-6 space appearing as isointense on T1-weighted images with enhancement by contrast medium and hyperintense on T2-weighted images. The lesion was totally removed microsurgically. Histological examination revealed cavernous hemangioma. The patient made a good recovery after surgery. PMID- 26038147 TI - Difficult transition from a new oral anticoagulant to parenteral anticoagulant in an overweight female. PMID- 26038148 TI - An extension of Bayesian predictive sample size selection designs for monitoring efficacy and safety. AB - Most exploratory clinical trials in cancer are designed as single-arm trials using a binary efficacy outcome with or without interim monitoring. In this context, we have proposed a Bayesian adaptive design denoted as predictive sample size selection design (PSSD), which considered a binary efficacy outcome associated with early futility stopping (Statistics in Medicine 2012; 31: 4243 4254). As a matter of course, it would be more ethical and informative to evaluate safety as well as efficacy during the course of a trial. However, in most of the trials, only major adverse events are taken into account for early termination of the trial, and safety itself is used as a secondary endpoint. In this paper, we propose an extension of the PSSD to monitor efficacy, take into consideration the sample size adaptation during the trial and add continuous monitoring of safety to the trial design. This method is developed in the Bayesian framework, in which a decision to stop for reasons of safety can be made based on the posterior probability or predictive probability, not necessarily at the time of pre-specified monitoring for efficacy. We investigate the operating characteristics of the proposed method through simulation studies and show that the posterior probability-based method with less informative prior to monitor safety has more reasonable performance. PMID- 26038149 TI - 'Everything works': the need to address confirmation bias in evaluations of drug misuse prevention interventions for adolescents. PMID- 26038150 TI - How common is frailty in older Australians? AB - AIM: To determine the prevalence of frailty in a cohort of older Australians. METHODS: Frailty status of the 2087 participants of the Australian Longitudinal Study of Ageing was assessed based on the questionnaire responses at the baseline interview. Frailty status and prevalence were assessed using four measures: two unidimensional measures (the Frailty Phenotype and Simplified Frailty Phenotype) and two multidimensional measures (Frailty Index and Prognostic Frailty Score). Agreement between the four measures was determined. RESULTS: The multidimensional measures identified more people as frail (17.5 and 49.4%) than did the unidimensional (2 and 8.8%). There was little agreement between the measures; only 0.5% of the participants were identified as frail by all four measures. CONCLUSIONS: The apparent prevalence of frailty varied when different measures were used. It is important for clinicians and researchers to be aware that different frailty measures may identify different groups of older people as frail. PMID- 26038151 TI - Anticancer effects of traditional Chinese herbs with phlegm-eliminating properties - An overview. AB - ETHONOPHARMACOLOGICAL RELEVANCE: Cancer is considered to be the second leading cause of human death. It is unsatisfactory that in the past decades, the treatment for cancer has not progressed as fast as it was expected, as only 50% of newly diagnosed patients could be cured even today. The development of cancer is a multifactorial process, involving tumor cells themselves, the interactions between tumor cells and their microenvironments, as well as the interactions between tumor cells and the host's immunity. Focusing on any single goal may bring limited benefits. AIM AND METHODS OF THE STUDY: Phlegm-eliminating herbs, which can reduce phlegm and eliminate pathological metabolites, are commonly used to treat cancer in China. However, the underlying molecular targets and efficacy of herbal medicines in cancer treatment still remain unclear. In this study, we reviewed the potential anticancer mechanisms of some phlegm-eliminating herbs and their active ingredients from the articles through such scientific databases as MEDLINE, PubMed, and Google Scholar. RESULTS: We found that the anticancer mechanisms of phlegm-eliminating herbs and ingredients include inducing apoptosis, anti-proliferation, preventing tumor invasion and metastasis, and reducing resistance to chemotherapy. In addition, some phlegm-eliminating herbs and their ingredients have anti-inflammatory and anti-metabolic syndrome effects. CONCLUSIONS: We suggest that the phlegm-eliminating herbs and ingredients are potential candidates for anticancer treatment and cancer prevention by playing a comprehensive role. PMID- 26038152 TI - Facile Protocol for Catalytic Frustrated Lewis Pair Hydrogenation and Reductive Deoxygenation of Ketones and Aldehydes. AB - A series of ketones and aldehydes are reduced in toluene under H2 in the presence of 5 mol % B(C6F5)3 and either cyclodextrin or molecular sieves affording a facile metal-free protocol for reduction to alcohols. Similar treatment of aryl ketones resulted in metal-free deoxygenation yielding aromatic hydrocarbons. PMID- 26038154 TI - Age-related differences in tissue dielectric constant values of female forearm skin measured noninvasively at 300 MHz. AB - BACKGROUND/PURPOSE: We hypothesized that reported age-related shifts in skin water from less-to-more mobile states would result in increased skin tissue dielectric constant (TDC) values as TDC values depend strongly on water content and state. One aim was to test this hypothesis. Further, as skin-to-fat TDC values are used as a tool for edema and lymphedema assessment, a second aim was to establish reference values suitable for young and older women. METHODS: TDC was measured bilaterally on volar forearm skin in young (20-40 years) and older (>=60 years) women. There were four groups with 50, 50, 100, and 50 subjects per age group measured to depths of 0.5, 1.5, 2.5, and 5.0 mm, respectively. RESULTS: For each age group, TDC values decreased with increasing depth (P < 0.001). TDC values at 0.5 and 1.5 mm were greater for older women (P < 0.001). At 2.5 mm, there was no age-group difference (P = 0.108). At 5.0 mm the direction of the difference reversed with older TDC values less than the younger (P < 0.001). CONCLUSION: Results are consistent with age-related shifts in water state from less-to-more mobile and explain depth-dependence differences between age groups. Data also give age-related TDC reference values for assessing local edematous or lymphedematous states. PMID- 26038155 TI - Patient and family perceptions of physical therapy in the medical intensive care unit. AB - PURPOSE: Patient and family member perceptions of physical therapy (PT) in the intensive care unit and the factors that influence their degree of satisfaction have not been described. METHODS: A panel of experts developed a questionnaire that assessed patient and family perceptions of PT. Critically ill patients and their family members were asked to complete the survey. Patient and family member scores were compared and stratified by age, sex, and mechanical ventilation for greater than 14 days compared to 14 days or less. RESULTS: A total of 55 patients and 49 family members completed the survey. Patients and family members reported that PT was necessary and beneficial to recovery, despite associating PT with difficulty, exertion, and discomfort. Patient perceptions were similar regardless of age or sex. Family members underestimated a patient's enjoyment of PT (P = .03). For individuals who required prolonged mechanical ventilation (>14 days), patients reported that PT was more difficult (P = .03) and less enjoyable (P = .049), and family members reported PT as causing greater discomfort (P = .005). In addition, family members of patients who required prolonged mechanical ventilation felt that PT was less beneficial (P = .01). CONCLUSIONS: Physical therapy is perceived as necessary and beneficial to recovery by critically ill patients and family members. PMID- 26038153 TI - Protein-DNA binding in high-resolution. AB - Recent advances in experimental and computational methodologies are enabling ultra-high resolution genome-wide profiles of protein-DNA binding events. For example, the ChIP-exo protocol precisely characterizes protein-DNA cross-linking patterns by combining chromatin immunoprecipitation (ChIP) with 5' -> 3' exonuclease digestion. Similarly, deeply sequenced chromatin accessibility assays (e.g. DNase-seq and ATAC-seq) enable the detection of protected footprints at protein-DNA binding sites. With these techniques and others, we have the potential to characterize the individual nucleotides that interact with transcription factors, nucleosomes, RNA polymerases and other regulatory proteins in a particular cellular context. In this review, we explain the experimental assays and computational analysis methods that enable high-resolution profiling of protein-DNA binding events. We discuss the challenges and opportunities associated with such approaches. PMID- 26038156 TI - Limitations of current in vitro test protocols for investigation of instrumented adjacent segment biomechanics: critical analysis of the literature. AB - PURPOSE: Accelerated degenerative changes at intervertebral levels adjacent to a spinal fusion, the so-called adjacent segment degeneration (ASD), have been reported in many clinical studies. Even though the pathogenesis of ASD is still widely unknown, biomechanical in vitro approaches have often been used to investigate the impact of spinal instrumentation on the adjacent segments. The goal of this review is (1) to summarize the results of these studies with respect to the applied protocol and loads and (2) to discuss if the assumptions made for the different protocols match the patients' postoperative situation. METHODS: A systematic MEDLINE search was performed using the keywords "adjacent", "in vitro" and "spine" in combination. This revealed a total of 247 articles of which 33 met the inclusion criteria. In addition, a mechanical model was developed to evaluate the effects of the current in vitro biomechanical test protocols on the changes in the adjacent segments resulting from different stiffnesses of the "treated" segment. RESULTS: The surgical treatments reported in biomechanical in vitro studies investigating ASD can be categorized into fusion procedures, total disc replacement (TDR), and dynamic implants. Three different test protocols (i.e. flexibility, stiffness, hybrid) with different loading scenarios (e.g. pure moment or eccentric load) are used in current biomechanical in vitro studies investigating ASD. According to the findings with the mechanical model, we found that the results for fusion procedures highly depend on the test protocol and method of load application, whereas for TDR and dynamic implants, most studies did not find significant changes in the adjacent segments, independent of which test protocol was used. CONCLUSIONS: The three test protocols mainly differ in the assumption on the postoperative motion behavior of the patients, which is the main reason for the conflicting findings. However, the protocols have never been validated using in vivo kinematic data. In a parallel review on in vivo kinematics by Malakoutian et al., it was found that the assumption that the patients move exactly the same after fusion implemented with the stiffness- and hybrid protocol does not match the patients' behavior. They showed that the motion of the whole lumbar spine rather tends to decrease in most studies, which could be predicted by the flexibility protocol. However, when the flexibility protocol is used with the "gold standard" pure moment, the difference in the kinematic changes between the cranial and caudal adjacent segment cannot be reproduced, putting the validity of current in vitro protocols into question. PMID- 26038157 TI - Does lumbar spinal stenosis increase the risk of spondylotic cervical spinal cord compression? AB - PURPOSE: The aim of this prospective cross-sectional observational comparative study was to determine the prevalence of spondylotic cervical cord compression (SCCC) and symptomatic cervical spondylotic myelopathy (CSM) in patients with symptomatic lumbar spinal stenosis (LSS) in comparison with a general population sample and to seek to identify predictors for the development of CSM. METHODS: A group of 78 patients with LSS (48 men, median age 66 years) was compared with a randomly selected age- and sex-matched group of 78 volunteers (38 men, median age 66 years). We evaluated magnetic resonance imaging findings from the cervical spine and neurological examination. RESULTS: The presence of SCCC was demonstrated in 84.6% of patients with LSS, but also in 57.7% of a sample of volunteers randomly recruited from the general population. Clinically symptomatic CSM was found in 16.7% of LSS patients in comparison with 1.3% of volunteers (p = 0.001). Multivariable logistic regression proposed the Oswestry Disability Index of 43% or more as the only independent predictor of symptomatic CSM in LSS patients (OR 9.41, p = 0.008). CONCLUSIONS: The presence of symptomatic LSS increases the risk of SCCC; the prevalence of SCCC is higher in patients with symptomatic LSS in comparison with the general population, with an evident predominance of more serious types of MRI-detected compression and a clinically symptomatic form (CSM). Symptomatic CSM is more likely in LSS patients with higher disability as assessed by the Oswestry Disability Index. PMID- 26038158 TI - Modeling Causal Relationship Between Brain Regions Within the Drug-Cue Processing Network in Chronic Cocaine Smokers. AB - The cues associated with drugs of abuse have an essential role in perpetuating problematic use, yet effective connectivity or the causal interaction between brain regions mediating the processing of drug cues has not been defined. The aim of this fMRI study was to model the causal interaction between brain regions within the drug-cue processing network in chronic cocaine smokers and matched control participants during a cocaine-cue exposure task. Specifically, cocaine smoking (15M; 5F) and healthy control (13M; 4F) participants viewed cocaine and neutral cues while in the scanner (a Siemens 3 T magnet). We examined whole brain activation, including activation related to drug-cue processing. Time series data extracted from ROIs determined through our General Linear Model (GLM) analysis and prior publications were used as input to IMaGES, a computationally powerful Bayesian search algorithm. During cocaine-cue exposure, cocaine users showed a particular feed-forward effective connectivity pattern between the ROIs of the drug-cue processing network (amygdala -> hippocampus -> dorsal striatum -> insula -> medial frontal cortex, dorsolateral prefrontal cortex, anterior cingulate cortex) that was not present when the controls viewed the cocaine cues. Cocaine craving ratings positively correlated with the strength of the causal influence of the insula on the dorsolateral prefrontal cortex in cocaine users. This study is the first demonstration of a causal interaction between ROIs within the drug cue processing network in cocaine users. This study provides insight into the mechanism underlying continued substance use and has implications for monitoring treatment response. PMID- 26038160 TI - Editorial. PMID- 26038161 TI - Ganga hospital open injury score in management of open injuries. AB - INTRODUCTION: Open injuries of the limbs offer challenges in management as there are still many grey zones in decision making regarding salvage, timing and type of reconstruction. As a result, there is still an unacceptable rate of secondary amputations which lead to tremendous waste of resources and psychological devastation of the patient and his family. Gustilo Anderson's classification was a major milestone in grading the severity of injury but however suffers from the disadvantages of imprecise definition, a poor interobserver correlation, inability to address the issue of salvage and inclusion of a wide spectrum of injuries in Type IIIb category. Numerous scores such as Mangled Extremity Severity Score, the Predictive Salvage Index, the Limb Salvage Index, Hannover Fracture Scale-97 etc have been proposed but all have the disadvantage of retrospective evaluation, inadequate sample sizes and poor sensitivity and specificity to amputation, especially in IIIb injuries. METHODS: The Ganga Hospital Open Injury Score (GHOIS) was proposed in 2004 and is designed to specifically address the outcome in IIIb injuries of the tibia without vascular deficit. It evaluates the severity of injury to the three components of the limb- the skin, the bone and the musculotendinous structures separately on a grade from 0 to 5. Seven comorbid factors which influence the treatment and the outcome are included in the score with two marks each. The application of the total score and the individual tissue scores in management of IIIB injuries is discussed. RESULTS: The total score was shown to predict salvage when the value was 14 or less; amputation when the score was 17 and more. A grey zone of 15 and 16 is provided where the decision making had to be made on a case to case basis. The additional value of GHOIS was its ability to guide the timing and type of reconstruction. A skin score of more than 3 always required a flap and hence it indicated the need for an orthoplastic approach from the index procedure. Bone score of 4 and 5 will require complex reconstruction procedures like bone transport, extensive bone grafting or free fibular graft. Regarding the timing of reconstruction, injuries with a score of 9 or less indicated a low violence trauma and were amenable for early soft tissue reconstruction whereas injuries with a score of 10 or more indicated high violence injuries where a staged reconstruction policy must be followed. CONCLUSIONS: Ganga Hospital Open Injury Score was found to be highly useful in decision making regarding salvage in IIIB injuries. The individual tissue scores were also useful to provide guidance regarding the timing and type of bone and soft tissue reconstruction. PMID- 26038159 TI - Low Doses of Ethanol Enhance LTD-like Plasticity in Human Motor Cortex. AB - Humans liberally use ethanol for its facilitating effects on social interactions but its effects on central nervous system function remain underexplored. We have recently described that very low doses of ethanol abolish long-term potentiation (LTP)-like plasticity in human cortex, most likely through enhancement of tonic inhibition [Lucke et al, 2014, Neuropsychopharmacology 39:1508-18]. Here, we studied the effects of low-dose ethanol on long-term depression (LTD)-like plasticity. LTD-like plasticity was induced in human motor cortex by paired associative transcranial magnetic stimulation (PASLTD), and measured as decreases of motor evoked potential input-output curve (IO-curve). In addition, sedation was measured by decreases in saccade peak velocity (SPV). Ethanol in two low doses (EtOH<10mM, EtOH<20mM) was compared to single oral doses of alprazolam (APZ, 1mg) a classical benzodiazepine, and zolpidem (ZLP, 10 mg), a non benzodiazepine hypnotic, in a double-blinded randomized placebo-controlled crossover design in ten healthy human subjects. EtOH<10mM and EtOH<20mM but not APZ or ZLP enhanced the PASLTD-induced LTD-like plasticity, while APZ and ZLP but not EtOH<10mM or EtOH<20mM decreased SPV. Non-sedating low doses of ethanol, easily reached during social drinking, enhance LTD-like plasticity in human cortex. This effect is most likely explained by the activation of extrasynaptic alpha4-subunit containing gamma-aminobutyric type A receptors by low-dose EtOH, resulting in increased tonic inhibition. Findings may stimulate cellular research on the role of tonic inhibition in regulating excitability and plasticity of cortical neuronal networks. PMID- 26038162 TI - Reconstruction of post-traumatic long segment bone defects of the lower end of the femur by free vascularized fibula combined with allograft (modified Capanna's technique). AB - PURPOSE: Salvage of long segment bone loss in the limbs particularly near the joints continues to be a challenge to the trauma surgeon. None of the techniques available are universally successful and all share the disadvantages of multi staged procedures. A reliable single-stage technique would be ideal to reduce the treatment time and the cost of care. We are presenting here our experience of successfully using the modified Capanna technique of combining allograft and free vascularized fibular graft in treating large bone defects in the distal third of the femur. METHODS: Between April 2012 and October 2013, six patients with post traumatic long segment bone loss in the distal femur had reconstruction of the bone defect by the Capanna technique. The average age was 33 years (range of 18 49 years). The bone defect ranged from 10 to 20 cm (average 15 cm). Five patients had primary reconstruction while one was done after allograft failure. Bone union time and occurrence of any complications were noted. Follow-up ranged from 7 to 24 months (average 15 months). RESULTS: All grafts went onto union. No patient required secondary procedure to achieve union. Average time to union was 6 months. One patient had deep infection and delayed union of distal end of the fibula graft. CONCLUSION: Free vascularized fibular graft combined with allograft increases initial stability, allows early weight bearing, has higher chances of union and is a good single-stage technique of reconstruction of distal third femur defects. PMID- 26038163 TI - Intramedullary nailing after external fixation of the femur and tibia: a review of advantages and limits. AB - PURPOSE AND METHODS: External fixation is a safe option for stabilisation of extremity lesions in the polytraumatised patient as well as in fractures with severe soft tissue damage. Nevertheless, long-term-complications are to be expected when external fixation is chosen as a definitive treatment. The purpose of this review article is twofold: primarily, to define the rationale of a procedural change from an external fixator to an intramedullary nail; secondarily, to assess the possible advantages and pitfalls of a single- or two staged procedure. RESULTS AND CONCLUSIONS: External fixation of the femur is recommended in multiply injured patients who are critically ill to avoid an additional inflammatory response caused by the surgical trauma of primary nailing. The conversion towards nailing must be done as soon as the clinical condition of the patient has been stabilised. Stable polytraumatised patients do not benefit from initial stabilisation with an external fixator and should immediately be treated with a definitive osteosynthesis. In tibial fractures, external fixation followed by intramedullary nailing is recommendable in fractures with severe soft tissue injuries. Conversion should be done as soon as the soft tissues allow before pin-tract infections occur and performed in a one staged procedure. PMID- 26038164 TI - The role of intramedullary nailing in treatment of open fractures. AB - The management of open fractures remains one of the greatest challenges to orthopedic trauma surgeons. Damage to the soft tissue envelope together with periosteal stripping are the most important factors making open fractures prone to complications such as nonunion and infection. Urgent and thorough soft tissue debridement, proper surgical fracture stabilization as well as the administration of intravenous and local antibiotics as adjunctive therapy are mandatory to reduce the risk of infection. Intramedullary nail osteosynthesis has become an accepted treatment method of open long bone fractures. Especially at sites of sparse soft tissue coverage like the proximal and distal tibia, early intramedullary stabilization proved advantageous for its superior biomechanical stability, the chance of early soft tissue reconstruction, shorter healing times, and quicker rehabilitation. However, due to a potential risk of deep infection, especially when a reamed technique is applied, nailing of open fractures remains contentious. In this review, we focus on the current evidence of nail osteosynthesis in open fractures and delineate its value with respect to other possible treatment options. PMID- 26038165 TI - Viscoelastic hemostatic fibrinogen assays detect fibrinolysis early. AB - PURPOSE: Viscoelastic hemostatic assays are emerging as the standard-of-care in the early detection of post-injury coagulopathy. TEG and ROTEM are most commonly used. Although similar in technique, each uses different reagents, which may affect their sensitivity to detect fibrinolysis. Therefore, the purpose of this study is to determine the ability of each device to detect fibrinolysis. METHODS: TEG (Rapid, Kaolin, Functional Fibrinogen) and ROTEM (EXTEM, INTEM, FIBTEM) were run simultaneously on normal blood as well as blood containing tPA from healthy volunteers (n = 10). A two-tailed, paired t-test and ANOVA were used to determine the significance between parameters obtained from normal blood and blood with tPA, and individual TEG and ROTEM assays, respectively. RESULTS: TEG detected significant changes in clot strength and 30-min lysis after the addition of tPA (p < 0.0001). All ROTEM assays detected changes in the 30-min lysis (p < 0.0001), but only INTEM detected changes in clot strength (p < 0.05). Kaolin and Rapid TEG assays detected greater changes in clot strength and lysis, but INTEM and EXTEM had decreased lysis onset times compared to TEG (p < 0.001). Functional Fibrinogen and FIBTEM assays detected lysis sooner than other TEG/ROTEM assays, and were comparable. CONCLUSIONS: TEG assays detect greater changes in clot strength compared to ROTEM. Despite this, Functional Fibrinogen and FIBTEM assays detect fibrinolysis sooner than their corresponding intrinsic and extrinsic assays. Therefore, fibrinogen assays should be employed in actively bleeding trauma patients in order to provide timely antifibrinolytic therapy. PMID- 26038167 TI - Profile of fatal patients admitted to a neuro trauma critical care unit. PMID- 26038166 TI - Dynamic detection of N-terminal pro-B-type natriuretic peptide helps to predict the outcome of patients with major trauma. AB - INTRODUCTION: NT-proBNP and BNP have been demonstrated to be prognostic markers in cardiac disease and sepsis. However, the prognostic value and the dynamic changes of BNP or NT-proBNP in trauma patients remain unclear. The present study was conducted to investigate the dynamic changes of NT-proBNP in patients with major trauma (injury severity score >=16), determine whether NT-proBNP could be used as a simple index to predict mortality in major trauma patients. METHODS: This prospective observational study included 60 patients with major trauma. Serum NT-proBNP levels were measured on the 1st, 3rd and 7th day after injury The NT-proBNP levels in survivors were compared with those in non-survivors. The efficacy of NT-proBNP to predict survival was analyzed using receiver operating characteristic curves. An analysis of correlations between NT-proBNP and various factors, including injury severity score, Glasgow coma score, acute physiology and chronic health evaluation II, central venous pressure, creatine kinase-MB, cardiac troponin I and procalcitonin (PCT) was performed. NT-proBNP levels in patients with traumatic brain injury were compared with those in patients without traumatic brain injury. A comparison of NT-proBNP levels between patients with and without sepsis was also performed at each time point. RESULTS: NT-proBNP levels in non-survivors were significantly higher than those in survivors at all the indicated time points. In the group of non-survivors, NT-proBNP levels on the 7th day were markedly higher than those on the 1st day. In contrast, NT-proBNP levels in survivors showed a reduction over time. The efficacy of NT-proBNP to predict survival was analyzed using ROC curves, and there was no difference in the area under the ROC between NT-proBNP and APACHE II/ISS at the three time points. A significant correlation was found between NT-proBNP and ISS on the 1st day, NT-proBNP and CK-MB, Tn-I and APACHE II on the 3rd day, NT-proBNP and PCT on the 7th day. There were no significant differences in NT-proBNP levels between patients with or without brain trauma at all the indicated time points. NT-proBNP levels in patients with sepsis were significantly higher than those in patients without sepsis at all the indicated time points. CONCLUSION: These findings suggest that dynamic detection of serum NT-proBNP might help to predict death in patients with major trauma. A high level of NT-proBNP at admission or maintained for several days after trauma indicates poor survival. PMID- 26038168 TI - Efficacy of computed tomography for abdominal stab wounds: a single institutional analysis. AB - PURPOSE: There are several diagnostic tools to support the decision for abdominal stab wounds. The aim of this study is to evaluate the ability of computed tomography (CT) to facilitate decisions on the initial management in patients with anterior abdominal stab wounds. METHODS: The medical records of all 118 patients who sustained abdominal stab wounds from March 2004 to January 2012 were reviewed retrospectively. RESULTS: The average age of patients was 41 years, and 84 (71%) patients were male. Ten patients underwent an immediate laparotomy due to hemodynamic instability, peritonitis, or definite evisceration. The other 108 patients underwent CT scans, and 91 patients had positive CT findings, leading to performance of laparotomy in 82 patients. One patient underwent a non-therapeutic laparotomy. Seventeen patients had negative CT results; however, seven patients underwent early laparotomy according to the attending surgeon's decision using serial physical examination or other diagnostic tools. The sensitivity of the CT scan was 94.2%, and the positive-predictive value was 98.8%. CONCLUSIONS: CT can be used efficiently along with physical examination as an initial diagnostic tool in patients with abdominal stab wounds. However, there can be missed injuries, then surgeon should consider other diagnostic methods. PMID- 26038169 TI - The selective conservative management of small traumatic pneumothoraces following stab injuries is safe: experience from a high-volume trauma service in South Africa. AB - OBJECTIVE: The selective conservative management of small pneumothoraces (PTXs) following stab injuries is controversial. We reviewed a cohort of patients managed conservatively in a high volume trauma service in South Africa. MATERIALS AND METHODS: A retrospective review over a 2-year period identified 125 asymptomatic patients with small PTXs measuring <2 cm on chest radiograph who were managed conservatively. RESULTS: Of the 125 patients included in the study, 92% were male (115/125), and the median age for all patients was 21 years (19 24). Ninety-seven per cent (121/125) of the weapons involved were knives, and 3% (4/125) were screwdrivers. Sixty-one per cent of all injuries were on the left side. Eighty-two per cent (102/125) sustained a single stab, and 18% (23/125) had multiple stabs. Thirty-nine per cent (49/125) had a PTX <0.5 cm (Group A), 26% (32/125) were >= 0.5 to <1 cm (Group B), 19% (24/125) were >= 1 to <1.5 cm (Group C) and 15% (20/125) were >= 1.5 to <2 cm (Group D). Three per cent of all patients (4/125) eventually required ICDs (one in Group C, three in Group D). All four patients had ICDs in situ for 24 h. The remaining 97% (121/125) were all managed successfully by active clinical observation alone. There were no subsequent readmissions, morbidity or mortality as a direct result of our conservative approach. CONCLUSIONS: The selective conservative management of asymptomatic small PTXs from stab injuries is safe if undertaken in the appropriate setting. PMID- 26038170 TI - Non-operative management of blunt hepatic trauma: Does angioembolization have a major impact? AB - PURPOSE: A paradigm shift toward non-operative management (NOM) of blunt hepatic trauma has occurred. With advances in percutaneous interventions, even severe liver injuries are being managed non-operatively. However, although overall mortality is decreased with NOM, liver-related morbidity remains high. This study was undertaken to explore the morbidity and mortality of blunt hepatic trauma in the era of angioembolization (AE). METHODS: A retrospective cohort of trauma patients with blunt hepatic injury who were assessed at our centre between 1999 and 2011 were identified. Logistic regression was undertaken to identify factors increasing the likelihood of operative management (OM) and mortality. RESULTS: We identified 396 patients with a mean ISS of 33 (+/- 14). Sixty-two (18%) patients had severe liver injuries (>= AAST grade IV). OM occurred in 109 (27%) patients. Logistic regression revealed high ISS (OR 1.07; 95% CI 1.05-1.10), and lower systolic blood pressure on arrival (OR 0.98; 95% CI 0.97-0.99) to be associated with OM. The overall mortality was 17%. Older patients (OR 1.05; 95% CI 1.03 1.07), those with high ISS (OR 1.11; 95% CI 1.08-1.14) and those requiring OM (OR 2.89; 95% CI 1.47-5.69) were more likely to die. Liver-related morbidities occurred in equal frequency in the OM (23%) and AE (29%) groups (p = 0.32). Only 3% of those with NOM experienced morbidity. CONCLUSIONS: The majority of patients with blunt hepatic trauma can be successfully managed non-operatively. Morbidity associated with NOM was low. Patients requiring AE had morbidity similar to OM. PMID- 26038171 TI - Is laparoscopic appendectomy going to be standard procedure for acute appendicitis; a 5-year single center experience with 1,788 patients. AB - PURPOSE: To evaluate whether laparoscopic appendectomy can be the gold standard for acute appendicitis regarding the applicability and cost effectivity. MATERIALS AND METHODS: The study included patients who were operated by laparoscopically for acute appendicitis between January 2008 and September 2012. Patients' sex, ages, hospitalization time, the type for closure of the appendiceal stump, complication rate, surgery time and other parameters were recorded. RESULTS: 1,788 patients with acute appendicitis on laparoscopic evaluation constituted the study population. Average age of the patient group was 30.1 +/- 2.3 years old. Average hospitalization time was 1.2 +/- 1.1 days. Metal clips were used in 1,100 (61.5%) patients, intracorporeal knotting was performed in the remaining. Total complication rate was 3.8%. CONCLUSION: By the using of metal clips and increased experience; laparoscopy may be gold standard for acute appendicitis. PMID- 26038173 TI - Glove perforation, blunt needles and surgeons' safety. PMID- 26038172 TI - Early versus delayed enteral feeding in patients with abdominal trauma: a retrospective cohort study. AB - PURPOSE: Early enteral feeding within 24-48 h of intensive care unit admission is recommended for critically ill patients. This study aimed to determine if early enteral feeding could be safely implemented with purported benefits in patients with abdominal trauma. METHODS: A retrospective cohort study was performed that included 88 adult patients with abdominal trauma. Patients receiving enteral feeding within 72 h of surgical intensive care unit (SICU) admission (early initiation group, n = 28) were compared to those receiving enteral feeding later (delayed-initiation group, n = 60). RESULTS: The two groups were comparable in demographic characteristics and injury severity. There were no differences in feeding intolerance (53.6 vs. 43.3%, p = 0.37) and mortality at 28 days (0 vs. 5%, p = 0.55) between the early-initiation group and the delayed-initiation group. However, patients in the early-initiation group had fewer infectious complications (17.9 vs. 40 %, p = 0.04) and shorter length of stay in SICU and hospital (p < 0.01) than patients in the delayed-initiation group. CONCLUSIONS: Early enteral feeding administered within 72 h of SICU admission was associated with improved clinical outcomes without risk of increasing feeding intolerance in patients with abdominal trauma. Our results support the implementation of early enteral feeding in abdominal trauma management. PMID- 26038174 TI - ESTES News 1.2015. PMID- 26038175 TI - Characterization of the Pall Celeris system as a point-of-care device for therapeutic angiogenesis. AB - BACKGROUND AIMS: The Pall Celeris system is a filtration-based point-of-care device designed to obtain a high concentrate of peripheral blood total nucleated cells (PB-TNCs). We have characterized the Pall Celeris-derived TNCs for their in vitro and in vivo angiogenic potency. METHODS: PB-TNCs isolated from healthy donors were characterized through the use of flow cytometry and functional assays, aiming to assess migratory capacity, ability to form capillary-like structures, endothelial trans-differentiation and paracrine factor secretion. In a hind limb ischemia mouse model, we evaluated perfusion immediately and 7 days after surgery, along with capillary, arteriole and regenerative fiber density and local bio-distribution. RESULTS: Human PB-TNCs isolated by use of the Pall Celeris filtration system were shown to secrete a panel of angiogenic factors and migrate in response to vascular endothelial growth factor and stromal-derived factor-1 stimuli. Moreover, after injection in a mouse model of hind limb ischemia, PB-TNCs induced neovascularization by increasing capillary, arteriole and regenerative fiber numbers, with human cells detected in murine tissue up to 7 days after ischemia. CONCLUSIONS: The Pall Celeris system may represent a novel, effective and reliable point-of-care device to obtain a PB-derived cell product with adequate potency for therapeutic angiogenesis. PMID- 26038176 TI - Contraction dynamics and function of the muscle-tendon complex depend on the muscle fibre-tendon length ratio: a simulation study. AB - Experimental studies show different muscle-tendon complex (MTC) functions (e.g. motor or spring) depending on the muscle fibre-tendon length ratio. Comparing different MTC of different animals examined experimentally, the extracted MTC functions are biased by, for example, MTC-specific pennation angle and fibre-type distribution or divergent experimental protocols (e.g. influence of temperature or stimulation on MTC force). Thus, a thorough understanding of variation of these inner muscle fibre-tendon length ratios on MTC function is difficult. In this study, we used a hill-type muscle model to simulate MTC. The model consists of a contractile element (CE) simulating muscle fibres, a serial element (SE) as a model for tendon, and a parallel elastic element (PEE) modelling tissue in parallel to the muscle fibres. The simulation examines the impact of length variations of these components on contraction dynamics and MTC function. Ensuring a constant overall length of the MTC by L(MTC) = L(SE) + L(CE), the SE rest length was varied over a broad physiological range from 0.1 to 0.9 MTC length. Five different MTC functions were investigated by simulating typical physiological experiments: the stabilising function with isometric contractions, the motor function with contractions against a weight, the capability of acceleration with contractions against a small inertial mass, the braking function by decelerating a mass, and the spring function with stretch-shortening cycles. The ratio of SE and CE mainly determines the MTC function. MTC with comparably short tendon generates high force and maximal shortening velocity and is able to produce maximal work and power. MTC with long tendon is suitable to store and release a maximum amount of energy. Variation of muscle fibre-tendon ratio yielded two peaks for MTC's force response for short and long SE lengths. Further, maximum work storage capacity of the SE is at long relL(SE,0). Impact of fibre-tendon length ratio on MTC functions will be discussed. Considering a constant set of MTC parameters, quantitative changes in MTC performance (work, stiffness, force, energy storage, dissipation) depending on varying muscle fibre tendon length ratio were provided, which enables classification and grading of different MTC designs. PMID- 26038180 TI - Improving the quality of genome, protein sequence, and taxonomy databases: a prerequisite for microbiome meta-omics 2.0. AB - High-throughput shotgun metaproteomic approaches on environmental or medical microbiomes are producing huge amounts of tandem mass spectrometry data. These can be interpreted either with a general protein sequence database comprising tens of thousands of sequenced genomes or with a more customized database such as those obtained after metagenome sequencing of the DNA extracted from the same sample. However, not all entries in a nucleotide or protein sequence database are of equal quality and this can critically impact metaproteomic data interpretation. In this viewpoint article, we exemplify several key issues. First, either genome or transcriptome data interpretation due to inaccurate contig assembly and gene prediction may be erroneous, for its mitigation the metaproteogenomic strategies could have an interesting perspective. Errors in sample handling and taxonomical characterization may also be problematic. Cross contamination of genome sequences is also underestimated while frequent. As a consequence of these structural errors regarding protein sequences and additional problems due to homology-based functional annotation of proteins, specific efforts for better interpretation of metaproteomic data are required. We propose the development of new bioinformatic pipelines devoted to detection and correction of errors and contaminations to improve the overall quality of sequence and taxonomy databases for metaproteomics. PMID- 26038179 TI - Subdural Continuous Theta Burst Stimulation of the Motor Cortex in Essential Tremor. PMID- 26038181 TI - N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials. AB - In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided to investigate the effect of replacing the cinnamoyl moiety with other acyl groups. Thus, a series of N-acylated analogues were synthesized, and their activities against blood- and liver-stage Plasmodium spp. were assessed along with their in vitro cytotoxicities. Although the new N-acylated analogues were found to be somewhat less active and more cytotoxic than their N cinnamoylated counterparts, they equally displayed nanomolar activities in vitro against blood-stage drug-sensitive and drug-resistant P. falciparum, and significant in vitro liver-stage activity against P. berghei. Therefore, it is demonstrated that simple N-acylated surrogates of classical antimalarial drugs are promising dual-stage antimalarial leads. PMID- 26038182 TI - Formation of Uniform Fe3 O4 Hollow Spheres Organized by Ultrathin Nanosheets and Their Excellent Lithium Storage Properties. AB - Hierarchical Fe3 O4 hollow spheres constructed by nanosheets are obtained from solvothermally synthesized Fe-glycerate hollow spheres. With the unique structural features, these hierarchical Fe3 O4 hollow spheres exhibit excellent electrochemical lithium-storage performance. PMID- 26038184 TI - Characterization of the Lactobacillus plantarum plasmid pCD033 and generation of the plasmid free strain L. plantarum 3NSH. AB - Lactobacillus plantarum CD033, a strain isolated from grass silage in Austria, harbors a 7.9 kb plasmid designated pCD033. Sequence analysis identified 14 open reading frames and 8 of these were supposed to be putative coding sequences. Gene annotation revealed no putative essential genes being plasmid encoded, but a plasmid addiction system based on a PemI/PemK-like toxin-antitoxin system, able to stabilize plasmid maintenance. Absence of a replication initiation protein, a double strand origin as well as a single strand origin on plasmid pCD033 suggests replication via a new type of theta mechanism, whereby plasmid replication is potentially initiated and regulated by non-coding RNA. Detailed examination of segregational stability of plasmid vectors consisting of pCD033-fragments, combined with a selection marker, resulted in definition of a stably maintained minimal replicon. A gene encoding a RepB/OrfX-like protein was found to be not essential for plasmid replication. Alignment of the amino acid sequence of this protein with related proteins unveiled a highly conserved amino acid motif (LLDQQQ). L. plantarum CD033 was cured of pCD033 resulting in the novel plasmid free strain L. plantarum 3NSH. Plasmid curing demonstrated that no essential features are provided by pCD033 under laboratory conditions. PMID- 26038185 TI - A novel suicide plasmid for efficient gene mutation in Listeria monocytogenes. AB - Although several plasmids have been used in Listeria monocytogenes for generating mutants by allelic exchange, construction of L. monocytogenes mutants has been inefficient due to lack of effective selection markers for first and second recombination events. To address this problem, we have developed a new suicide plasmid, pHoss1, by using the pMAD plasmid backbone and anhydrotetracycline selection marker (secY antisense RNA) driven by an inducible Pxyl/tetO promoter. Expression of the secY antisense RNA eliminates merodiploids and selects for the loss of plasmid via a second allelic exchange, which enriches the number of mutants with deleted genes. To assess the effectiveness of pHoss1 for the generation of stable in-frame deletion mutations, we deleted the ispG and ispH genes of L. monocytogenes serotype 4b strain F2365. Results showed that identification of the second allelic exchange mutants was very efficient with 80 100% of the colonies yielding desired deletion mutants. L. monocytogenes' intestinal cell attachment was not altered when ispG and ispH genes were deleted. We expect that this new plasmid will be very useful for construction of marker free deletion mutants in L. monocytogenes and in other Gram-positive bacteria, including Staphylococcus aureus and Bacillus cereus. PMID- 26038186 TI - Melanoma, sentinel node, and full-thickness skin graft: modification of Junod's procedure. PMID- 26038187 TI - Seroprevalence, risk factors and genetic characterization of Toxoplasma gondii in free-range white yaks (Bos grunniens) in China. AB - The objective of this study was to determine the seroprevalence, risk factors and genotypes of Toxoplasma gondii in white yaks (Bos grunniens) in China. A total of 974 serum samples were collected from white yaks in Tianzhu Tibetan Autonomous County (TTAC), Gansu province, northwest China for detecting T. gondii antibodies by the modified agglutination test (MAT), and 414 tissues belonging to 138 white yaks were collected for detecting T. gondii DNA by amplification of B1 gene with a semi-nested PCR. A total of 155 serum samples (15.91%) were seropositive for T. gondii antibodies at a 1:100 cut-off, and 10 DNA samples (7.25%) were positive for the T. gondii B1 gene, which were genetically characterized using multilocus PCR-RFLP. Only one genotype (ToxoDB#9) was identified from two samples with complete genotyping results. Statistically significant differences were not observed between T. gondii seroprevalence and gender, season or pregnancy in the logistic regression analysis (P>0.05). Ages of white yaks was considered as a main risk factor associated with T. gondii infection. Our results indicated a widespread exposure to T. gondii among white yaks, and revealed the genotype ToxoDB#9 of T. gondii in white yaks for the first time in China. PMID- 26038189 TI - Characterization of botulinum neurotoxin type A subtypes by immunocapture enrichment and liquid chromatography-tandem mass spectrometry. AB - Botulinum neurotoxins (BoNT) are divided into seven toxinotypes based on their immunological properties and each toxinotype contains several subtypes according to their amino acid sequences. Here, we designed a mass spectrometry method able to identify BoNT/A subtypes in complex matrices including crude culture supernatants, food, and environmental samples. Peptides from BoNT light chain (L) specific to the subtypes BoNT/A1 to A3 and BoNT/A5 to A8 were identified. The method consists of an immunocapture step with antibodies specific to BoNT/A L chains followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) on a triple quadrupole mass spectrometer (QqQ) in multiple reaction monitoring (MRM) mode. BoNT/A subtypes were correctly identified in culture supernatants and in tap water or orange juice samples with a limit of detection of 20 to 150 mouse lethal doses (MLD) and with a lower sensitivity in serum samples. PMID- 26038188 TI - Association between Interleukin-1beta Gene -511C>T/+3954C>T Polymorphisms and Aggressive Periodontitis Susceptibility: Evidence from a Meta-Analysis. AB - BACKGROUND: Interleukin-1beta (IL-1beta) is an important inflammatory cytokine. The associations between IL-1beta gene -511C>T/+3954C>T polymorphisms and aggressive periodontitis (AgP) susceptibility have been conflicting. We therefore conducted a meta-analysis to investigate the association of IL-1beta genetic polymorphisms with susceptibility to AgP. MATERIAL AND METHODS: PubMed and Embase electronic databases were searched for relevant studies. Odds ratios (ORs) with 95% confidence interval (CIs) were used to assess the association between IL 1beta polymorphisms and AgP risk. Heterogeneity, publication bias, and sensitivity analysis were performed to guarantee the statistical power. RESULTS: Twenty published studies involving 965 patients and 1234 control subjects were included. No significant association between IL-1beta polymorphisms and AgP was found. For -511C>T (T vs. C: OR=0.966, 95%CI=0.696-1.341, P=0.869; CT vs. CC: OR=0.936, 95%CI=0.761-1.151; TT vs. CC: OR=0.892, 95%CI=0.464-1.715, P=0.719; CT+TT vs. CC: OR=1.026, 95%CI=0.795-1.323; TT vs. CC+CT: OR=0.864, 95%CI=0.436 1.713). For +3954C>T (T vs. C: OR=1.069, 95%CI=0.901-1.268; CT vs. CC: OR=0.921, 95%CI=0.699-1.212; TT vs. CC: OR=1.064, 95%CI=0.747-1.515; CT+TT vs. CC: OR=0.990, 95%CI=0.764-1.283; TT vs. CC+CT: OR=1.229, 95%CI=0.919-1.643). Subgroup analyses were conducted with HWE, ethnicity, and study design, and no significant association was detected. CONCLUSIONS: These results demonstrate that IL-1beta 511C>T and +3954C>T polymorphisms are not the risk factors for developing AgP. PMID- 26038190 TI - Certification of a new certified reference material of honokiol. AB - Honokiol is the most important active pharmaceutical ingredient in Magnolia officinalis, which is a famous traditional Chinese medicine and commonly used in clinical practice. In order to control the quality of honokiol and related pharmaceuticals, a new certified reference material (CRM) of honokiol was developed. The studies of sample preparation, homogeneity, stability, value assignment, and uncertainty evaluation were accomplished in this paper. Three different methods, including differential scanning calorimetry (DSC), mass balance method (MB), and coulometric titration (CT), were employed to determine the purity of honokiol. Specifically, the DSC and CT methods for purity determination of honokiol were established for the first time. The purity of honokiol CRM, after validation and evaluation, was found to be 99.3%, with an expanded uncertainty of 0.5% (k = 2). PMID- 26038191 TI - Development pathways from abusive parenting to delinquency: the mediating role of depression and aggression. AB - This study investigated the long-term relationship between abusive parenting and adolescent mental health, and the path to delinquent behavior. Longitudinal data from 5th through 7th graders from the Korean Children and Youth Panel Survey (KCYPS) were analyzed to examine if abusive parenting was a predictor of early adolescent delinquency behavior, via aggression and depression as mediating factors. The results were as follows. First, parental abuse (both emotional and physical) was found to have significant effects on children's psychosocial factors (aggression and depression), while parental neglect (both emotional and physical) had significant effects on depression alone and not on aggression. Second, aggression exerted significant effects on both violent and non-violent delinquent behaviors, while depression had a significant effect on only non violent delinquent behaviors. Third, children's psychosocial factors (aggression and depression) played significant mediating roles between earlier abusive parenting and delinquent behaviors. Fourth, for children living in a family with their grandparents, paths from abusive parenting, psychosocial adaptation, and later delinquent behaviors were not significant, implying that living with grandparents played a protective factor in these relationships. PMID- 26038192 TI - Body weight, BMI and insulin resistance as influential factors on heart rate variability. PMID- 26038193 TI - Both tumor depth and diameter are predictive of sentinel lymph node status and survival in Merkel cell carcinoma. AB - BACKGROUND: The purposes of this study were 1) to determine the impact of primary tumor-related factors on the prediction of the sentinel lymph node (SLN) status and 2) to identify clinical and pathologic factors associated with survival in Merkel cell carcinoma (MCC). METHODS: An institutional review board-approved, retrospective review of patients with MCC treated between 1988 and 2011 at a single center was performed. Patients were categorized into 5 groups: 1) negative SLN, 2) positive SLN, 3) clinically node-negative but SLN biopsy not performed, 4) regional nodal disease without a known primary tumor, and 5) primary MCC with synchronous clinically evident regional nodal disease. Factors predictive of the SLN status were analyzed with logistic regressions, and overall survival (OS) and disease-specific survival (DSS) were analyzed with Cox models and competing risk models assuming proportional hazards, respectively. RESULTS: Three hundred seventy-five patients were analyzed, and 70% were male; the median age was 75 years. The median tumor diameter was 1.5 cm (range, 0.2-12.5 cm), and the median tumor depth was 4.8 mm (range, 0.3-45.0 mm). One hundred ninety-one patients underwent SLN biopsy, and 59 (31%) were SLN-positive. Increasing primary tumor diameter and increasing tumor depth were associated with SLN positivity (P = .007 and P = .017, respectively). Age and sex were not associated with the SLN status. Immunosuppression, increasing tumor diameter, and increasing tumor depth were associated with worse OS (P = .007, P = .003, and P = .025, respectively). DSS differed significantly by group and was best for patients with a negative SLN and worst for those with primary MCC and synchronous clinically evident nodal disease (P = .018). CONCLUSION: For patients with MCC, increasing primary tumor diameter and increasing tumor depth are independently predictive of a positive SLN, worse OS, and worse DSS. Tumor depth should be routinely reported when primary MCC specimens are being evaluated histopathologically. PMID- 26038194 TI - Mast Cell Serotonin Immunoregulatory Effects Impacting on Neuronal Function: Implications for Neurodegenerative and Psychiatric Disorders. AB - Mast cells (MCs) are derived from hemopoietic precursor cells, undergo their maturation in peripheral tissues, and play a significant role in both the innate and adaptive immune response. Cross-linking of the FcepsilonRI on MCs initiates activation of several cytoplasmic protein tyrosine kinases which rapidly lead to phosphorylation and recruitment of adaptor molecules. These effects trigger the release of preformed mediators stored in the cytoplasmic granules, including histamine, serotonin and tryptase, as well as newly synthesized mediators, such as cytokines/chemokines, prostaglandins, leukotrienes, and growth factors. Serotonin (5-HT) is a bioactive monoamine, which has seven specific cell surface membrane bound receptors which are coupled to G-proteins, plays an important role in the central and peripheral nervous system, and is one of the key mediators in signaling between nervous and immune systems. Serotonin is not stored in all MC types but is implicated in MC adhesion, chemotaxis, tumorigenesis, and tissue regeneration through smooth muscle differentiation of stromal cells. Recent evidence indicates that serotonin has immunoregulatory actions that may be important in neuropsychiatric conditions. Chemokines, RANTES/CCL5, MCP-1/CCL2, and related molecules, constitute the C-C class of chemokine supergene family, play a role in regulating T helper-cell cytokine production and MC trafficking, and are involved in histamine and serotonin generation and MC functions. Pro inflammatory cytokines such as interleukin-1-beta and tumor necrosis factor which mediate MC response, are capable of activating p38 MAPK, and might increase serotonin generation through p38 MAPK activation. Here, we review the relationship between MCs and serotonin and its role in inflammatory diseases and neuroimmune interactions. PMID- 26038196 TI - Maize maintains growth in response to decreased nitrate supply through a highly dynamic and developmental stage-specific transcriptional response. AB - Elucidation of the gene networks underlying the response to N supply and demand will facilitate the improvement of the N uptake efficiency of plants. We undertook a transcriptomic analysis of maize to identify genes responding to both a non-growth-limiting decrease in NO3- provision and to development-based N demand changes at seven representative points across the life cycle. Gene co expression networks were derived by cluster analysis of the transcript profiles. The majority of NO3--responsive transcription occurred at 11 (D11), 18 (D18) and 29 (D29) days after emergence, with differential expression predominating in the root at D11 and D29 and in the leaf at D18. A cluster of 98 probe sets was identified, the expression pattern of which is similar to that of the high affinity NO3- transporter (NRT2) genes across the life cycle. The cluster is enriched with genes encoding enzymes and proteins of lipid metabolism and transport, respectively. These are candidate genes for the response of maize to N supply and demand. Only a few patterns of differential gene expression were observed over the entire life cycle; however, the composition of the classes of the genes differentially regulated at individual time points was unique, suggesting tightly controlled regulation of NO3--responsive gene expression. PMID- 26038195 TI - Effects of Antidepressants on DSP4/CPT-Induced DNA Damage Response in Neuroblastoma SH-SY5Y Cells. AB - DNA damage is a form of cell stress and injury. Increased systemic DNA damage is related to the pathogenic development of neurodegenerative diseases. Depression occurs in a relatively high percentage of patients suffering from degenerative diseases, for whom antidepressants are often used to relieve depressive symptoms. However, few studies have attempted to elucidate why different groups of antidepressants have similar effects on relieving symptoms of depression. Previously, we demonstrated that neurotoxins N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4)- and camptothecin (CPT) induced the DNA damage response in SH-SY5Y cells, and DSP4 caused cell cycle arrest which was predominately in the S-phase. The present study shows that CPT treatment also resulted in similar cell cycle arrest. Some classic antidepressants could reduce the DNA damage response induced by DSP4 or CPT in SH-SY5Y cells. Cell viability examination demonstrated that both DSP4 and CPT caused cell death, which was prevented by spontaneous administration of some tested antidepressants. Flow cytometric analysis demonstrated that a majority of the tested antidepressants protect cells from being arrested in S-phase. These results suggest that blocking the DNA damage response may be an important pharmacologic characteristic of antidepressants. Exploring the underlying mechanisms may allow for advances in the effort to improve therapeutic strategies for depression appearing in degenerative and psychiatric diseases. PMID- 26038197 TI - Cholinergic Enhancement of Cell Proliferation in the Postnatal Neurogenic Niche of the Mammalian Spinal Cord. AB - The region surrounding the central canal (CC) of the spinal cord is a highly plastic area, defined as a postnatal neurogenic niche. Within this region are ependymal cells that can proliferate and differentiate to form new astrocytes and oligodendrocytes following injury and cerebrospinal fluid contacting cells (CSFcCs). The specific environmental conditions, including the modulation by neurotransmitters that influence these cells and their ability to proliferate, are unknown. Here, we show that acetylcholine promotes the proliferation of ependymal cells in mice under both in vitro and in vivo conditions. Using whole cell patch clamp in acute spinal cord slices, acetylcholine directly depolarized ependymal cells and CSFcCs. Antagonism by specific nicotinic acetylcholine receptor (nAChR) antagonists or potentiation by the alpha7 containing nAChR (alpha7*nAChR) modulator PNU 120596 revealed that both alpha7*nAChRs and non alpha7*nAChRs mediated the cholinergic responses. Using the nucleoside analogue EdU (5-ethynyl-2'-deoxyuridine) as a marker of cell proliferation, application of alpha7*nAChR modulators in spinal cord cultures or in vivo induced proliferation in the CC region, producing Sox-2 expressing ependymal cells. Proliferation also increased in the white and grey matter. PNU 120596 administration also increased the proportion of cells coexpressing oligodendrocyte markers. Thus, variation in the availability of acetylcholine can modulate the rate of proliferation of cells in the ependymal cell layer and white and grey matter through alpha7*nAChRs. This study highlights the need for further investigation into how neurotransmitters regulate the response of the spinal cord to injury or during aging. PMID- 26038198 TI - Phase II Study of a Platinum-Based Adapted Chemotherapy Regimen Combined with Radiotherapy in Patients 75 Years and Older with Esophageal Cancer. AB - BACKGROUND AND OBJECTIVE: The management of elderly patients with cancer is a therapeutic challenge and a public health problem. The aim of this phase II single-arm study was to evaluate the acute toxicities and efficacy of chemoradiotherapy (CRT) comprising a single platinum-based agent combined with radiotherapy in elderly patients with esophageal cancer. METHODS: Between March 2000 and October 2011, patients aged 75 years and older were prospectively treated with external beam radiotherapy combined with cisplatin or oxaliplatin. Other selection criteria included Eastern Cooperative Oncology Group status 0-2, disease stage II-III, squamous cell carcinoma or adenocarcinoma, and an adequate biological profile. The radiotherapy dose was 50 Gy administered over 5 weeks to the primary tumor and involved lymph nodes. Cisplatin was planned at a dose of 75 mg/m(2) on days 1 and 21 and oxaliplatin at 85 mg/m(2) on days 1, 15, and 29. Treatment was delivered an outpatient setting. RESULTS: Thirty patients with a mean age of 85.2 (range 79.4-92.0) years were included; 28 completed the treatment. Dysphagia was the only grade 4 toxicity to occur during the study; no grade 5 toxicities were observed. Six weeks after the completion of treatment, 16 patients (53.3%) were in complete response. Two patients in complete response died from pneumonitis 5 and 7 months after CRT. With a 36-month median follow-up, 18 patients died from cancer (nine from local failure, nine from metastasis). Seven patients died from other causes and two patients were alive 40.3 and 56 months after the end of their treatment. Three-year overall survival was 22.2%. CONCLUSIONS: Selected elderly patients with esophageal cancer and adequate functional status should not be excluded from CRT and may be able to tolerate the treatment with acceptable acute toxicities. However, mid-term efficacy is mediocre. Our data also suggest that the therapeutic ratio or locoregional control might be improved by increasing the radiotherapy dose or by testing new radiosensitizer agents since half of the failures were within the treated volume. TRIAL REGISTRATION: EudraCT no. 2009-010113-76. PMID- 26038199 TI - Porous decellularized tissue engineered hypertrophic cartilage as a scaffold for large bone defect healing. AB - Clinical translation of tissue engineered therapeutics is hampered by the significant logistical and regulatory challenges associated with such products, prompting increased interest in the use of decellularized extracellular matrix (ECM) to enhance endogenous regeneration. Most bones develop and heal by endochondral ossification, the replacement of a hypertrophic cartilaginous intermediary with bone. The hypothesis of this study is that a porous scaffold derived from decellularized tissue engineered hypertrophic cartilage will retain the necessary signals to instruct host cells to accelerate endogenous bone regeneration. Cartilage tissue (CT) and hypertrophic cartilage tissue (HT) were engineered using human bone marrow derived mesenchymal stem cells, decellularized and the remaining ECM was freeze-dried to generate porous scaffolds. When implanted subcutaneously in nude mice, only the decellularized HT-derived scaffolds were found to induce vascularization and de novo mineral accumulation. Furthermore, when implanted into critically-sized femoral defects, full bridging was observed in half of the defects treated with HT scaffolds, while no evidence of such bridging was found in empty controls. Host cells which had migrated throughout the scaffold were capable of producing new bone tissue, in contrast to fibrous tissue formation within empty controls. These results demonstrate the capacity of decellularized engineered tissues as 'off-the-shelf' implants to promote tissue regeneration. PMID- 26038202 TI - Animal models of adrenocortical tumorigenesis. AB - This comparative review highlights animal models of adrenocortical neoplasia useful either for mechanistic studies or translational research. Three model species-mouse, ferret, and dog-are detailed. The relevance of each of these models to spontaneous and inherited adrenocortical tumors in humans is discussed. PMID- 26038203 TI - The genetics of adrenocortical tumors. AB - Advances in genomics accelerated greatly progress in the study of the genetics adrenocortical tumors. Bilateral nodular hyperplasias causing Cushing's syndrome are frequently caused by germline alterations leading to cAMP/PKA pathway activation (micronodular) and ARMC5 inactivation (macronodular). Somatic mutations of beta-catenin and PRKACA are observed in non secreting or cortisol producing adenomas, respectively. Alterations of the beta-catenin (CTNN1B, ZNFR3) or TP53 pathways are found in carcinomas. Mutations in cancers are more common in aggressive tumors and correlate with transcriptome or methylation profiles. Identification of these alterations helps to refine the molecular classification of these tumors and to develop molecular diagnostic tools. PMID- 26038201 TI - Adrenal steroidogenesis and congenital adrenal hyperplasia. AB - Adrenal steroidogenesis is a dynamic process, reliant on de novo synthesis from cholesterol, under the stimulation of ACTH and other regulators. The syntheses of mineralocorticoids (primarily aldosterone), glucocorticoids (primarily cortisol), and adrenal androgens (primarily dehydroepiandrosterone and its sulfate) occur in separate adrenal cortical zones, each expressing specific enzymes. Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal-recessive enzymatic defects in cortisol biosynthesis. 21-Hydroxylase (21OHD) deficiency accounts for more than 90% of CAH cases and, when milder or nonclassic forms are included, 21OHD is one of the most common genetic diseases. PMID- 26038204 TI - Adrenal incidentalomas: a disease of modern technology offering opportunities for improved patient care. AB - Adrenal incidentalomas (AIs) are found in approximately 4% of patients undergoing abdominal imaging, with peak prevalence in the sixth and seventh decades of life. Detection of AI warrants clinical, biochemical, and radiological evaluation to establish its secretory status and risk of malignancy. Careful review of the lipid content, size, and imaging phenotype of an adrenal mass is needed to evaluate the risk for malignancy. Identification of an AI may be an opportunity to identify an underlying secretory tumor that may have been otherwise unrecognized. A practical approach to investigation and follow-up of AIs is presented in this article. PMID- 26038200 TI - Development of adrenal cortex zonation. AB - The human adult adrenal cortex is composed of the zona glomerulosa (zG), zona fasciculata (zF), and zona reticularis (zR), which are responsible for production of mineralocorticoids, glucocorticoids, and adrenal androgens, respectively. The final completion of cortical zonation in humans does not occur until puberty with the establishment of the zR and its production of adrenal androgens; a process called adrenarche. The maintenance of the adrenal cortex involves the centripetal displacement and differentiation of peripheral Sonic hedgehog-positive progenitors cells into zG cells that later transition to zF cells and subsequently zR cells. PMID- 26038205 TI - Primary aldosteronism: challenges in diagnosis and management. AB - Primary aldosteronism (PA) is the main cause of endocrine hypertension, present in approximately 10% of hypertensive patients; about one-third is secondary to aldosterone-producing adenomas. Cardiovascular and renal morbidity are out of proportion to the degree of hypertension. Physicians have compelling rationale to correctly identify and treat PA. Physicians are challenged with patient selection for screening with the aldosterone/renin ratio (ARR), interpretation of ARR, and selecting a confirmatory test. Adrenal vein sampling is performed for subtype differentiation. The treatment depends on the disease subtype and results in control of hypertension and reversal of associated excess morbidity. PMID- 26038206 TI - Adrenal mild hypercortisolism. AB - Adrenal incidentalomas have become detected more often as the use of abdominal imaging has increased. Up to one-third of these may be secreting low levels of cortisol, known as mild hypercortisolism or subclinical Cushing syndrome. These low levels of cortisol have been found to be associated with an increased in the metabolic syndrome, osteoporosis, cardiovascular events, and mortality. This article discusses in detail the epidemiology, diagnosis, clinical associations, and treatment options of mild hypercortisolism. PMID- 26038207 TI - Management of adrenal tumors in pregnancy. AB - Adrenal diseases, including Cushing syndrome (CS), primary aldosteronism (PA), pheochromocytoma, and adrenocortical carcinoma, are uncommon in pregnancy; a high degree of clinical suspicion must exist. Physiologic changes to the hypothalamus pituitary-adrenal axis in a normal pregnancy result in increased cortisol, renin, and aldosterone levels, making the diagnosis of CS and PA in pregnancy challenging. However, catecholamines are not altered in pregnancy and allow a laboratory diagnosis of pheochromocytoma that is similar to that of the nonpregnant state. Although adrenal tumors in pregnancy result in significant maternal and fetal morbidity, and sometimes mortality, early diagnosis and appropriate treatment often improve outcomes. PMID- 26038208 TI - Adrenocortical carcinoma: review of the pathologic features, production of adrenal steroids, and molecular pathogenesis. AB - Adrenocortical carcinoma (ACC) is a malignant neoplasm often associated with an aggressive biological behavior. The histologic differentiation between ACC and adrenocortical adenoma (ACA) is largely determined by employing the Weiss criteria, although this classification may not apply to all the cases. Additionally, various genomic features of ACC could be an auxiliary mode to establish the diagnosis of ACC. Most ACC cases are hormonally functional, and immunohistochemical analysis of steroidogenic enzymes has provided pivotal information as to the analysis of intratumoral production of corticosteroids. This article summarizes the current status of the histopathological diagnosis, molecular pathogenesis, and hormonal features of ACC. PMID- 26038210 TI - Surgical management of adrenocortical carcinoma. AB - Adrenocortical carcinoma (ACC) is rare but one of the most malignant endocrine tumors. This article reviews and summarizes the current knowledge about the treatment of ACC. The epidemiology and molecular events involved in the pathogenesis of ACC are briefly outlined. The different diagnostic tools to distinguish benign from malignant adrenocortical tumors, including biochemical analysis and imaging, are discussed. The surgical treatment of ACC has evolved in the last 2 decades. The different surgical alternatives for the treatment of ACC in the context of primary, recurrent, or metastatic disease are reviewed, and the remaining challenges and controversies are discussed. PMID- 26038211 TI - Adrenal cortical neoplasia. PMID- 26038209 TI - Adrenocortical carcinoma. AB - Recent developments in the treatment of adrenocortical carcinoma (ACC) include diagnostic and prognostic risk stratification algorithms, increasing evidence of the impact of historical therapies on overall survival, and emerging targets from integrated epigenomic and genomic analyses. Advances include proper clinical and molecular characterization of all patients with ACC, standardization of proliferative index analyses, referral of these patients to large cancer referral centers at the time of first surgery, and development of new trials in patients with well-characterized ACC. Networking and progress in the molecular characterization of ACC constitute the basis for significant future therapeutic breakthroughs. PMID- 26038212 TI - Genetics and the clinical approach to adrenal cortical neoplasia: connecting the dots. PMID- 26038213 TI - Reliability and construct validity of PROMIS(r) measures for patients with heart failure who undergo heart transplant. AB - PURPOSE: To evaluate the reliability and construct validity of measures from the Patient-Reported Outcomes Measurement Information System((r)) (PROMIS((r))) for patients with heart failure before and after heart transplantation. METHODS: We assessed reliability of the PROMIS short forms using Cronbach's alpha and the average marginal reliability. To assess the construct validity of PROMIS computerized adaptive tests and short-form measures, we calculated Pearson product moment correlations between PROMIS measures of physical function, fatigue, depression, and social function and existing PRO measures of similar domains (i.e., convergent validity) as well as different domains (i.e., discriminate validity) in patients with heart failure awaiting heart transplant. We evaluated the responsiveness of these measures to change after heart transplant using effect sizes. RESULTS: Forty-eight patients were included in the analyses. Across the many domains examined, correlations between conceptually similar domains were larger than correlations between different domains of health, demonstrating construct validity. Health status improved substantially after heart transplant (standardized effect sizes, 0.63-1.24), demonstrating the responsiveness of the PROMIS measures. Scores from the computerized adaptive tests and the short forms were similar. CONCLUSIONS: This study provides evidence for the reliability and construct validity (including responsiveness to change) of four PROMIS domains in patients with heart failure before and after heart transplant. PROMIS measures are a reasonable choice in this context and will facilitate comparisons across studies and health conditions. PMID- 26038214 TI - Factor structure and construct validity of the Adult Social Care Outcomes Toolkit for Carers (ASCOT-Carer). AB - BACKGROUND: The ASCOT-Carer is a self-report instrument designed to measure social care-related quality of life (SCRQoL). This article presents the psychometric testing and validation of the ASCOT-Carer four response-level interview (INT4) in a sample of unpaid carers of adults who receive publicly funded social care services in England. METHODS: Unpaid carers were identified through a survey of users of publicly funded social care services in England. Three hundred and eighty-seven carers completed a face-to-face or telephone interview. Data on variables hypothesised to be related to SCRQoL (e.g. characteristics of the carer, cared-for person and care situation) and measures of carer experience, strain, health-related quality of life and overall QoL were collected. Relationships between these variables and overall SCRQoL score were evaluated through correlation, ANOVA and regression analysis to test the construct validity of the scale. Internal reliability was assessed using Cronbach's alpha and feasibility by the number of missing responses. RESULTS: The construct validity was supported by statistically significant relationships between SCRQoL and scores on instruments of related constructs, as well as with characteristics of the carer and care recipient in univariate and multivariate analyses. A Cronbach's alpha of 0.87 (seven items) indicates that the internal reliability of the instrument is satisfactory and a low number of missing responses (<1 %) indicates a high level of acceptance. CONCLUSION: The results provide evidence to support the construct validity, factor structure, internal reliability and feasibility of the ASCOT-Carer INT4 as an instrument for measuring social care-related quality of life of unpaid carers who care for adults with a variety of long-term conditions, disability or problems related to old age. PMID- 26038215 TI - Evaluation of the stages of completion and scoring of the Patient Generated Index (PGI) in patients with rheumatic diseases. AB - PURPOSE: To evaluate the stages of completion and approaches to scoring the PGI for reliability, validity and responsiveness. METHODS: Participants of inpatient rehabilitation or self-management programmes completed the closed PGI with the same areas at 1 year as baseline. Test-retest reliability, validity and responsiveness were assessed for area scores (stage one), points (stage two) and methods of scoring the PGI. RESULTS: One hundred and forty-five patients participated, and 118 (81 %) completed the PGI correctly. Test-retest intraclass correlations were over 0.90 for area scores (stage two) and were 0.87 and 0.86 for final PGI scores with and without the sixth "rest of life" box. Individual area scores had the highest correlations with those for instruments assessing similar constructs; those for the area "rest of life" were lower. Compared to scores based on the sum of the stage two areas, PGI scores had higher correlations of a moderate level with those for patient-reported instruments widely used within rheumatology. Correlations were of a similar level with and without the sixth "rest of life" area, and those based on baseline points at follow-up were highest. The PGI had higher SRMs than the other instruments at 1 year, the highest being for PGI scores based on baseline points. CONCLUSIONS: The fully closed version of the PGI, which uses baseline areas and baseline stage three points at follow-up, is most appropriate for assessing outcomes within healthcare evaluation. The sixth "rest of life" area has poorer measurement properties, and its removal does not adversely affect the measurement properties of the PGI. PMID- 26038216 TI - Child and adolescent perceptions of oral health over the life course. AB - PURPOSE: To elicit perceptions of oral health in children and adolescents as an initial step in the development of oral health item banks for the Patient Reported Oral Health Outcomes Measurement Information System project. METHODS: We conducted focus groups with ethnically, socioeconomically, and geographically diverse youth (8-12, 13-17 years) to identify perceptions of oral health status. We performed content analysis, including a thematic and narrative analysis, to identify important themes. RESULTS: We identified three unique themes that the youth associated with their oral health status: (1) understanding the value of maintaining good oral health over the life course, with respect to longevity and quality of life in the adult years; (2) positive association between maintaining good oral health and interpersonal relationships at school, and dating, for older youth; and (3) knowledge of the benefits of orthodontic treatment to appearance and positive self-image, while holding a strong view as to the discomfort associated with braces. CONCLUSIONS: The results provide valuable information about core domains for the oral health item banks to be developed and generated content for new items to be developed and evaluated with cognitive interviews and in a field test. PMID- 26038217 TI - Health-related quality of life after stroke: reliability and validity of the Duke Health Profile for use in Vietnam. AB - INTRODUCTION: Health-related quality of life (HRQoL) is commonly used to assess outcomes after stroke. The Duke Health Profile (DHP) has been translated and culturally adapted for use in Vietnam, but its reliability and validity for use with stroke patients in Vietnam or elsewhere have not been assessed. METHODS: First-ever stroke patients (n = 108) who were admitted to 115 People's Hospital between February and September 2012 and survived for 3 months after stroke had HRQoL assessed using the DHP and a comparison instrument (EQ-5D). Caregivers of 94 patients completed these questionnaires as a proxy. After 1 week, these questionnaires were re-administered to patients and proxies. RESULTS: The mean differences between test and retest assessments of HRQoL by patients were small and not clinically meaningful and were not consistently associated with sex, age, type of stroke or severity of impairment or disability. Direct assessments by the patient were on average greater than those obtained from the proxy. The ICCs ranged from 0.60 to 0.86 (patient test-retest) and from 0.55 to 0.98 (patient proxy agreement). The ICCs were greatest for physical functioning components (patient test-retest 0.63-0.86, patient-proxy 0.69-0.98). The correlations between the DHP dimensions and EQ-5D were generally stronger when they measured similar constructs (r = 0.53-0.66) and were lower for less related constructs (r = 0.11-0.43). CONCLUSION: The DHP has moderate reliability and validity for use with stroke patients in Vietnam even when information is obtained from proxy respondents. PMID- 26038218 TI - A new perspective on proxy report: Investigating implicit processes of understanding through patient-proxy congruence. AB - BACKGROUND: Utilizing proxy report is a common solution to gathering quality-of life information from people who are not capable of reliably answering questionnaires, such as people with dementia. Proxy report could, however, also provide information about patients' implicit processes of understanding, which we define as automatic, schema-driven cognitive processes that allow one to have a better understanding of oneself and of one's body, make oneself known and knowable to members of the social network, and allow one to react proactively in response to cues. We investigated whether implicit processes of understanding explain some of the association between reserve and healthy lifestyle behaviors. METHODS: We operationalized three implicit processes of understanding: (a) psychosocial understanding; (b) insight into physical disability; and (c) somatic awareness. This secondary analysis involved a cohort of multiple sclerosis patients and their caregiver informants (n = 118 pairs). Measures included a neurologist-administered Expanded Disability Status Scale, patient- and informant completed survey measures, and a heartbeat perception test (interoception). Patient-other congruence assessed implicit processes of understanding: psychosocial understanding (neurocognitive and personality); physical-disability insight; and somatic awareness (interoception). RESULTS: Effect sizes (ES) for the inter-correlations between the three implicit processes were small. Psychosocial understanding was associated with higher past reserve-building activities (small ES). Psychosocial understanding explained variance in healthy lifestyle behaviors over and above the variance explained by current reserve building activities (?R (2) = 0.04; model R Adjusted (2) = 0.18). CONCLUSIONS: Proxy versus patient report can provide information about underlying interpretational processes related to insight. These processes are distinct from reserve, predict health outcomes, and can inform lifestyle-changing interventions. PMID- 26038219 TI - Do individuals with and without depression value depression differently? And if so, why? AB - PURPOSE: Health state valuations, used to evaluate the effectiveness of healthcare interventions, can be obtained either by the patients or by the general population. The general population seems to value somatic conditions more negatively than patients, but little is known about valuations of psychological conditions. This study examined whether individuals with and without depression differ in their valuations of depression and whether perceptions regarding depression (empathy, perceived susceptibility, stigma, illness perceptions) and individual characteristics (mastery, self-compassion, dysfunctional attitudes) bias valuations of either individuals with or without depression. METHODS: In an online study, a general population sample used a time-trade-off task to value 30 vignettes describing depression states (four per participant) and completed questionnaires on perceptions regarding depression and individual characteristics. Participants were assigned to depression groups (with or without depression), based on the PHQ-9. A generalized linear mixed model was used to assess discrepancies in valuations and identify their determinants. RESULTS: The sample (N = 1268) was representative of the Dutch population on age, gender, education and residence. We found that for mild depression states, individuals with depression (N = 200) valued depression more negatively than individuals without depression (N = 1068) (p = .007). Variables related to perceptions of depression and individual characteristics were not found to affect valuations of either individuals with or individuals without depression. CONCLUSION: Since the general population values depression less negatively, using their perspective might result in less effectiveness for interventions for mild depression. Perceptions of depression or to individual characteristics did not seem to differentially affect valuations made by either individuals with or without depression. PMID- 26038220 TI - Subjective perceptions of cognitive deficits and their influences on quality of life among patients with schizophrenia. AB - PURPOSE: Functional outcomes in schizophrenia may be more closely related to social cognition than to neurocognition; however, the extent to which social cognition influences quality of life (QoL) remains unclear. We conducted a cross sectional survey study of the impact of patients' and clinicians' subjective perceptions of neurocognitive and social cognitive deficits on quality of life. METHODS: The study included 253 patients with schizophrenia and their clinicians from public mental health clinics in Bolivia, Chile, and Peru. We utilized the GEOPTE Scale of Social Cognition for Psychosis, the Schizophrenia Quality of Life Questionnaire, and the Positive and Negative Syndrome Scale for schizophrenia. RESULTS: Patients' subjective perceptions of their neurocognitive deficits (B = 1.13; CI -1.56 to -0.70) were significantly associated with QoL, whereas there was no independent association between the clinicians' ratings of the patients' neurocognitive deficits and QoL (B = -0.33; CI -0.98 to 0.31). However, patients' subjective perceptions of their neurocognitive deficits were no longer associated with QoL (B = -0.23; CI -0.71 to 0.24) once their perceptions of social cognitive impairments were accounted for (B = -1.03; CI -1.39 to -0.68). CONCLUSION: Patients' perceptions of their social cognitive function (but not neurocognitive functioning) have a significant impact on their QoL. Clinicians' ratings of patients' cognitive deficits were only weakly correlated with patients' subjective perceptions of their own neurocognitive, suggesting a mismatch between clinician and patient assessments of such deficits. Closer attention should therefore be paid toward patients' perception of their own deficits by clinicians in order to improve QoL. PMID- 26038221 TI - Assessment of the Swedish EQ-5D experience-based value sets in a total hip replacement population. AB - BACKGROUND: All patients undergoing elective total hip replacement (THR) in Sweden are asked to complete a survey, including the EQ-5D. Thus far, EQ-5D values have been presented using the UK TTO value set based on hypothetical values. Shift to the use of the recently introduced Swedish experience-based value set, derived from a representative Swedish population, is an appealing alternative. PURPOSE: To investigate how accurate the Swedish experience-based VAS value set predicts observed EQ VAS values and to compare correlations between Swedish and UK value sets including two provisional value sets derived from the THR population. METHODS: Pre- and one-year postoperative data from 56,062 THR patients from the Swedish Hip Arthroplasty Register were used. Agreement between the observed and the predicted EQ VAS values was assessed with correlation. Based on pre- and postoperative data, we constructed two provisional VAS value sets. RESULTS: Correlations between observed and calculated values using the Swedish VAS value set were moderate (r = 0.46) in preoperative data and high (r = 0.72) in postoperative data. Correlations between UK and register-based value sets were constantly lower compared to Swedish value sets. Register-based values and Swedish values were highly correlated. CONCLUSIONS: The Swedish value sets are more accurate in terms of representation of the Swedish THR patients than the currently used UK TTO value set. We find it feasible to use the experience-based Swedish value sets for further presentation of EQ-5D values in the Swedish THR population. PMID- 26038222 TI - Relationship of type of work with health-related quality of life. AB - PURPOSE: To examine the relation of work type with health-related quality of life (HRQoL) in healthy workers. METHODS: We cross-sectionally examined 4427 (3605 men and 822 women) healthy workers in Japan, aged 19-69 years. We assessed HRQoL based on scores for five scales of the SF-36. Multiple regression was applied to examine the relation of work type (nighttime, shift, day to night, and daytime) with the five HRQoL norm-based scores, lower scores of which indicate poorer health status, adjusted for confounding factors, including sleeping duration. RESULTS: Shiftwork was inversely related to role physical [regression estimate (beta) = -2.12, 95 % confidence intervals (CI) -2.94, -1.30, P < 0.001], general health (beta = -1.37, 95 % CI -2.01, -0.72, P < 0.001), role emotional (beta = 1.24, 95% CI -1.98, -0.50, P < 0.001), and mental health (beta = -1.31, 95% CI 2.01, -0.63, P < 0.001) independent of confounding factors, but not to vitality. Day-to-nighttime work was inversely related to all the five HRQoL subscales (Ps 0.012 to <0.001). CONCLUSION: Shiftwork was significantly inversely related to four out of the five HRQoL, except for vitality, and day-to-nighttime work was significantly inversely related to all five HRQoL, independent of demographic and lifestyle factors. PMID- 26038223 TI - Long-term health and quality of life experiences of Vietnam veterans with combat related limb loss. AB - PURPOSE: This paper describes the long-term health and quality of life (QOL) outcomes of Vietnam veterans with combat-related limb loss. METHODS: This mixed method, cross-sectional study analyzes survey data of 247 Vietnam veterans with combat-related limb loss measuring several comorbidities [measured as ever diagnosed], PTSD using the PTSD Checklist Military (PCL-M), depression using the Patient Health Questionnaire (PHQ-8), and QOL using the SF-12. In-depth interviews with 20 such veterans about their health and QOL experiences were conducted. RESULTS: Of 247 Vietnam veterans, most report good to excellent health (79.7 %) and several comorbidities: arthritis (61.1 %), cardiovascular disease (18.2 %), diabetes (22.7 %), obesity (17.4 %), phantom-limb pain (76.1 %), back pain (76.5 %), PTSD (15.8 %), and depression (17.8 %). Those with depression fared worse on the SF-12 physical component summary score (PCS), whereas those with arthritis, depression, and PTSD fared worse on the SF-12 mental component summary score. Interview data describe these comorbidities and QOL from the veterans' perspective and illustrate how such comorbidities may be directly related to the veterans' combat and/or limb loss experiences. CONCLUSION: The prevalence of these health issues and the adverse effects of some of these on QOL underscore the importance of effective rehabilitation over the life course, especially including better mental health care and pain management. PMID- 26038224 TI - Quality of life and metastatic breast cancer: the role of body image, disease site, and time since diagnosis. AB - PURPOSE: Too little is understood about the quality of life (QoL) concerns of patients diagnosed with advanced disease. While body image has been found to be consistently important for women with early-stage breast cancer, the impact of body image on women with metastatic breast cancer (MBC) is less frequently studied. This cross-sectional study aimed to identify factors affecting QoL in a sample of patients diagnosed with MBC, with particular attention to body image, disease site, and time since diagnosis. METHODS: In total, 113 women diagnosed with MBC completed two QoL scales (EORTC QLQ30; EORTC BR23) as part of a larger study. Clinical characteristics were obtained via medical record review. Demographics, disease characteristics, and clinical factors were examined. RESULTS: Time since diagnosis and location of metastases were found to affect patients' QoL, and most strikingly, this effect often differed for those with higher and lower body image. Body image appears to remain highly influential even for those living with a shortened life expectancy. CONCLUSIONS: These findings indicate that the development of QoL support should more carefully consider patients diagnosed with MBC and the unique sets of body concerns that affect this population. PMID- 26038225 TI - The added effect of comorbidity on health-related quality of life in patients with asthma. AB - PURPOSE: To examine the effect of comorbidities on health-related quality of life (HRQoL) and their interaction with asthma control. METHODS: In a random sample of adults with asthma, we measured generic (EQ5D) and disease-specific (AQ5D) utility scores. Asthma symptom control was determined using the 2014 Global Initiative for Asthma Management Strategy. Comorbidity scores were calculated using a validated questionnaire. We used two-part regression models to measure the adjusted difference in utility across levels of symptom control and comorbidity scores and to examine the relative role of symptom control and comorbidity in explaining the variation in HRQoL. RESULTS: A total of 2,299 observations from 460 adult patients (mean age 52 years, 67 % women) were included. Compared to controlled asthma, uncontrolled asthma was associated with 0.018 reduction (95 % CI -0.028, -0.009) in EQ5D and -0.076 reduction (95 % CI 0.115, -0.052) in AQ5D utilities. An increase by one standard deviation in comorbidity score relative to the mean was associated with a change of -0.029 (95 % CI -0.043, -0.016) in EQ5D and -0.010 (95 % CI -0.020, -0.004) in AQLQ utilities. The impact of comorbidity was greater than asthma symptom control in explaining EQ5D variance (12 vs. 1 %) but smaller in explaining AQ5D variance (3 vs. 12 %). CONCLUSIONS: Generic and disease-specific HRQoL instruments differentially capture the impact of symptom control and comorbidity in asthma. The selection of HRQoL instruments for asthma studies should depend on the prevalence of comorbidity in the target population and the impact of interventions on asthma control and comorbidity. PMID- 26038226 TI - Orebro Questionnaire: short and long forms of the Brazilian-Portuguese version. AB - PURPOSE: To translate, cross-culturally adapt and test the measurement properties of the Orebro Musculoskeletal Pain Screening Questionnaire (OMPSQ) short and long versions in Brazilian-Portuguese. METHODS: The OMPSQ versions were translated, cross-culturally adapted and pretested in 30 patients with acute and subacute non specific low back pain. Internal consistency, reproducibility (reliability and agreement), construct validity, and ceiling and floor effects were tested in 100 patients. Construct validity was assessed using the Roland-Morris Disability Questionnaire (RMDQ), the Tampa Scale for Kinesiophobia (TSK), and the Pain Numerical Rating Scale. RESULTS: Internal consistency was adequate (OMPSQ: Cronbach's alpha = 0.83; OMPSQ-short: Cronbach's alpha = 0.72). Reliability was substantial (OMPSQ: ICC2,1 0.76; OMPSQ-short: 0.78). Standard error of measurement was very good for the OMPSQ (5 %) and good for the OMPSQ-short (6.7 %); limits of agreement were 13.07 for the OMPSQ and 1.37 for the OMPSQ-short; and the minimum detectable change was 25.12 for the OMPSQ and 15.51 for the OMPSQ short. The OMPSQ total score showed a good correlation with the RMDQ (r = 0.73) and the TSK (r = 0.64) and a moderate correlation with pain intensity (current pain: r = 0.36; last 2 weeks: r = 0.37; last episode: r = 0.46). Moreover, OMPSQ short showed a good correlation with RMDQ (r = 0.69) and a moderate correlation with TSK (r = 0.57) and pain (current pain: r = 0.34; last 2 weeks: r = 0.36; last episode: r = 0.54). No ceiling or floor effects were detected in both versions. CONCLUSION: The Brazilian-Portuguese OMPSQ and OMPSQ-short showed acceptable measurement properties and provide evidence that the Brazilian Portuguese versions of OMPSQ and OMPSQ-short are similar to the original versions. PMID- 26038228 TI - Estimating diversity via frequency ratios. AB - We wish to estimate the total number of classes in a population based on sample counts, especially in the presence of high latent diversity. Drawing on probability theory that characterizes distributions on the integers by ratios of consecutive probabilities, we construct a nonlinear regression model for the ratios of consecutive frequency counts. This allows us to predict the unobserved count and hence estimate the total diversity. We believe that this is the first approach to depart from the classical mixed Poisson model in this problem. Our method is geometrically intuitive and yields good fits to data with reasonable standard errors. It is especially well-suited to analyzing high diversity datasets derived from next-generation sequencing in microbial ecology. We demonstrate the method's performance in this context and via simulation, and we present a dataset for which our method outperforms all competitors. PMID- 26038227 TI - Recent advances in engineering microbial rhodopsins for optogenetics. AB - Protein engineering of microbial rhodopsins has been successful in generating variants with improved properties for applications in optogenetics. Members of this membrane protein family can act as both actuators and sensors of neuronal activity. Chimeragenesis, structure-guided mutagenesis, and directed evolution have proven effective strategies for tuning absorption wavelength, altering ion specificity and increasing fluorescence. These approaches facilitate the development of useful optogenetic tools and, in some cases, have yielded insights into rhodopsin structure-function relationships. PMID- 26038229 TI - Staff burnout threatens plans for NHS, says think tank. PMID- 26038230 TI - ETHYLENE RESPONSE FACTOR 96 positively regulates Arabidopsis resistance to necrotrophic pathogens by direct binding to GCC elements of jasmonate - and ethylene-responsive defence genes. AB - The ERF (ethylene responsive factor) family is composed of transcription factors (TFs) that are critical for appropriate Arabidopsis thaliana responses to biotic and abiotic stresses. Here we identified and characterized a member of the ERF TF group IX, namely ERF96, that when overexpressed enhances Arabidopsis resistance to necrotrophic pathogens such as the fungus Botrytis cinerea and the bacterium Pectobacterium carotovorum. ERF96 is jasmonate (JA) and ethylene (ET) responsive and ERF96 transcripts accumulation was abolished in JA-insensitive coi1-16 and in ET-insensitive ein2-1 mutants. Protoplast transactivation and electrophoresis mobility shift analyses revealed that ERF96 is an activator of transcription that binds to GCC elements. In addition, ERF96 mainly localized to the nucleus. Microarray analysis coupled to chromatin immunoprecipitation-PCR of Arabidopsis overexpressing ERF96 revealed that ERF96 enhances the expression of the JA/ET defence genes PDF1.2a, PR-3 and PR-4 as well as the TF ORA59 by direct binding to GCC elements present in their promoters. While ERF96-RNAi plants demonstrated wild-type resistance to necrotrophic pathogens, basal PDF1.2 expression levels were reduced in ERF96-silenced plants. This work revealed ERF96 as a key player of the ERF network that positively regulates the Arabidopsis resistance response to necrotrophic pathogens. PMID- 26038231 TI - Tumors Escape CD4+ T-cell-Mediated Immunosurveillance by Impairing the Ability of Infiltrating Macrophages to Indirectly Present Tumor Antigens. AB - Tumors cells can escape cytotoxic CD8+ T cells by preventing MHC I display of tumor antigens. It is unknown how tumors evade CD4+ T-cell responses, but because many tumor cells lack MHC II expression, novel mechanisms would be required. We have investigated this issue in a model in which MHC II(NEG) myeloma cells secrete a monoclonal Ig containing a V region L chain (VL) epitope recognized by CD4+ T cells. Infiltrating macrophages process and present the secreted tumor antigen to Th1 cells, resulting in induction of macrophage cytotoxicity and apparent rejection of the tumor. Despite long-term tumor protection in VL specific T-cell receptor transgenic mice, we here describe that some myeloma cells persisted in a dormant state and, eventually, formed expanding tumors. Escape tumor cells maintained their secretion of complete (H+L) monoclonal Ig with unchanged sequence, while secretion of surplus free L chain was severely diminished. Although free L chains were efficiently processed and presented by tumor-infiltrating macrophages to CD4+ T cells, complete (H+L) monoclonal Ig was not. Forced overexpression of free L chain secretion reinstated tumor rejection. These results show that tumors can escape CD4+ T-cell-mediated rejection by impairing indirect presentation of tumor antigen by infiltrating macrophages. This occurs through a novel mechanism of immunoediting, in which modulation of the quaternary structure of the secreted tumor-specific antigen reduces its immunogenicity. PMID- 26038232 TI - Sequential myosin phosphorylation activates tarantula thick filament via a disorder-order transition. AB - Phosphorylation of myosin regulatory light chain (RLC) N-terminal extension (NTE) activates myosin in thick filaments. RLC phosphorylation plays a primary regulatory role in smooth muscles and a secondary (modulatory) role in striated muscles, which is regulated by Ca(2+)via TnC/TM on the thin filament. Tarantula striated muscle exhibits both regulatory systems: one switches on/off contraction through thin filament regulation, and another through PKC constitutively Ser35 phosphorylated swaying free heads in the thick filaments that produces quick force on twitches regulated from 0 to 50% and modulation is accomplished recruiting additional force-potentiating free and blocked heads via Ca(2+)4-CaM MLCK Ser45 phosphorylation. We have used microsecond molecular dynamics (MD) simulations of tarantula RLC NTE to understand the structural basis for phosphorylation-based regulation in tarantula thick filament activation. Trajectory analysis revealed that an inter-domain salt bridge network (R39/E58,E61) facilitates the formation of a stable helix-coil-helix (HCH) motif formed by helices P and A in the unphosphorylated NTE of both myosin heads. Phosphorylation of the blocked head on Ser45 does not induce any substantial structural changes. However, phosphorylation of the free head on Ser35 disrupts this salt bridge network and induces a partial extension of helix P along RLC helix A. While not directly participating in the HCH folding, phosphorylation of Ser35 unlocks a compact structure and allows the NTE to spontaneously undergo coil-helix transitions. The modest structural change induced by the subsequent Ser45 diphosphorylation monophosphorylated Ser35 free head facilitates full helix P extension into a single structurally stable alpha-helix through a network of intra-domain salt bridges (pS35/R38,R39,R42). We conclude that tarantula thick filament activation is controlled by sequential Ser35-Ser45 phosphorylation via a conserved disorder-to-order transition. PMID- 26038233 TI - Novel porous soy protein-based blend structures for biomedical applications: Microstructure, mechanical, and physical properties. AB - Use of naturally derived materials for biomedical applications is steadily increasing. Soy protein has advantages over various types of natural proteins employed for biomedical applications due to its low price, nonanimal origin, and relatively long storage time and stability. In the current study, blends of soy protein with other polymers (gelatin, alginate, pectin, polyvinyl alcohol, and polyethylene glycol) were developed and studied. The mechanical tensile properties of dense films were studied in order to select the best secondary polymer for porous three-dimensional structures. The porous soy-gelatin and soy alginate structures were then studied for physical properties, degradation behavior, and microstructure. The results show that these blends can be assembled into porous three-dimensional structures by combining chemical crosslinking with freeze-drying. The soy-alginate blends are advantageous over soy-gelatin blends, demonstrated better stability, and degradation time along with controlled swelling behavior due to more effective crosslinking and higher water uptake than soy-gelatin blends. Water vapor transmission rate experiments showed that all porous blend structures were in the desired range for burn treatment [2000-2500 g/(m(2) d)] and can be controlled by the crosslinking process. We conclude that these novel porous three-dimensional structures have a high potential for use as scaffolds for tissue engineering, especially for skin regeneration applications. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1109-1120, 2016. PMID- 26038234 TI - Recommendations in debate on psychiatric drugs are insufficiently justified. PMID- 26038235 TI - Analysis of alpha-amylase inhibitor from corni fructus by coupling magnetic cross linked enzyme aggregates of alpha-amylase with HPLC-MS. AB - As a carrier-free immobilization strategy, magnetic cross-linked enzyme aggregates (MCLEAs) showed improved enzyme activity, stability and magnetic response. In this study, MCLEAs of alpha-amylase (MCLEAs-amylase) was prepared under optimized conditions and characterized with scanning electron microscope and vibrating sample magnetometer. The prepared MCLEAs-amylase showed an amorphous structure and the saturation magnetization was 33.5emu/g, which was sufficient for magnetic separation. Then MCLEAs-amylase coupled with high performance liquid chromatography-mass spectrometry (HPLC-MS) was utilized to screen and identify alpha-amylase inhibitors from ethyl acetate extract of corni fructus. The experiment conditions were optimized. At the optimum conditions (incubation time: 10min, pH: 7.0 and temperature: 20 degrees C), querciturone was successfully screened and identified with weak non-specific binding. The screening result was verified by inhibition assays and the IC50 value of querciturone was 22.5MUg/mL. This method provided a rapid way to screen active compounds from natural products. PMID- 26038236 TI - Analysis of caffeine and paraxanthine in human saliva with ultra-high-performance liquid chromatography for CYP1A2 phenotyping. AB - Cytochrome P450 1A2 (CYP1A2) plays an important role in drug metabolism. Caffeine (CAF) is converted into paraxanthine (PX) by this enzyme and is used as a xenobiotic substrate to determine the CYP1A2 phenotype in humans. A method for the quantification of CAF and PX in saliva was developed using liquid-liquid extraction with ethyl acetate and analysis with ultra-high-performance liquid chromatography. Peaks from CAF, PX and internal standard were resolved within 6min. The method was validated from 0.05 to 5MUgmL(-1) CAF and 0.025-2.5MUgmL(-1) PX. Inter- and intra-day accuracies ranged from 91.2 to 107.2% with precisions <13.5%. The limits of detection were 0.16 and 0.63 ngmL(-1) for PX and CAF, respectively. PX/CAF concentration ratios from volunteers were 0.26-1.09 with mean ratios of 0.78+/-0.26 and 0.38+/-0.10 for regular and light/non-coffee drinkers, respectively. PMID- 26038237 TI - Tentative identification of new metabolites of cnidilin by liquid chromatography mass spectrometry. AB - Cnidilin is one of the major bioactive constituents of Radix Angelicae dahuricae. The present study was designed to characterize and interpret the structures of metabolites in rats after oral administration of cnidilin at a dose of 48mg/kg body weight. Metabolite identification was accomplished using a predictive multiple reaction monitoring-information-dependent acquisition-enhanced product ion (pMRM-IDA-EPI) scan and precursor ion scan-information-dependent acquisition enhanced product ion (PREC-IDA-EPI) scan in positive ion mode. Comparing the changes in protonated molecular masses, MS/MS spectra and retention times with the parent drug, 18 metabolites were identified. The result shows that the metabolic pathways contain deisopentenyl, combination with glucose, hydroxylation, oxidation, demethylation and addition reaction. The study identified 18 metabolites, analyzed and summarized the fragmentation regularities of mass spectra of 8-methoxy-5-hydroxy psoralen. The study provides a new pathway to discovery new compounds, new fragmentation regularities and the mode of metabolites. PMID- 26038238 TI - An Improved Detection Method for Hyperspectral Imagery Based on White Gaussian Noise. AB - To solve the low detection efficiency of the present hyperspectral detection method based on adaptive coherence estimator (ACE), an improved detection method based on white Gaussian noise (WGN) is proposed in this paper. Primarily the method uses the spectral angle mapping (SAM) method to adaptively set an optimal signal-to-noise (SNR) parameter based on the hyperspectral image. Then, a corresponding white Gaussian noise is generated according to this SNR parameter and is added to the original image to get a new image data. Finally, based on the new image data, a better target detection result can be obtained by using the ACE detection algorithm. The image data, added to the white Gaussian noise, are more consistent with the theoretical hypotheses of the ACE algorithm. Therefore the detection performance of the algorithm can be efficiently improved. Meanwhile, the adaptivity of setting the optimum SNR parameter in various images can make the method more universal. Experimental results of real world hyperspectral data show that the proposed ACE-WGN method can effectively improve detection performance. PMID- 26038239 TI - Transformation of tetracycline by TetX and its subsequent degradation in a heterologous host. AB - TetX is a flavin-dependent monooxygenase. It has been reported to inactivate all tested tetracyclines. In this study, Escherichia coli overexpressing TetX was added to soil bacterial enrichment cultures along with varying levels of tetracycline and was found to affect community-wide tetracycline resistance levels. Soil microbial communities developed lower levels of tetracycline resistance upon exposure to 25 MUg/mL of tetracycline when an E. coli expressing TetX was present (6% of cultivable bacteria were resistant to 40 MUg/mL tetracycline). In contrast, in the absence of TetX activity, a similar tetracycline exposure selected for greater levels of resistant bacteria in the soil microbial community (90% of cultivable bacteria were resistant to 40 MUg/mL tetracycline). We also describe new metabolites formed after tetracycline transformation by TetX and report the transient generation of redox-active metabolite(s). The results presented here are particularly pertinent in the light of the recent emergence of tet(X) in different bacterial species, including clinical isolates. PMID- 26038240 TI - Abiotic autumnal organic matter deposition and grazing disturbance effects on epilithic biofilm succession. AB - Stream epilithic biofilm community assembly is influenced in part by environmental factors. Autumn leaf deposition is an annual resource subsidy to streams, but the physical effects of leaves settling on epilithic biofilms has not been investigated.We hypothesized that bacterial and microeukaryotic community assembly would follow a successional sequence that was mediated by abiotic effects that were simulating leaf deposition (reduced light and flow) and by biotic (snail grazing)disturbance. This hypothesis was tested using an in situ experimental manipulation. Ambient biofilms had greater algal biomass and distinct ARISA community profiles compared to biofilms developed under manipulated conditions. There were no significant differences in biofilm characteristics associated with grazing, suggesting that results were driven by reduced light/flow rather than invertebrate disturbance; however, grazing appeared to increase bacterial taxon richness.Interestingly at day 38, all treatments grouped together in ordination space and had similar algal/total biomass ratios. We suggest that algal priming promoted a shift in ambient biofilms but that this effect is dependent upon successional timing of algal establishment. These data demonstrate that abiotic effects were more influential than local grazing disturbance and imply that leaf litter deposition may have bottom-up effects on the stream ecosystem through altered epilithic biofilms. PMID- 26038241 TI - Connecting cyto-nano-architectural attributes and epithelial molecular expression in oral submucous fibrosis progression to cancer. AB - OBJECTIVE: Problems in pre-cancer diagnosis complicate cancer theragnosis as well as life expectancy. There is uncertainty regarding malignant transformation of oral submucous fibrosis (OSF), an oral pre-cancer with dysplastic (OSFWD) and non dysplastic (OSFWT) subtypes. Understanding the structural, molecular and physical aspects of epithelial homeostasis may be useful. MATERIALS AND METHODS: Histopathological grading of biopsy sections was performed using H&E staining. Alterations in epithelial surface architecture in different groups was evaluated using scanning electron microscopy (SEM). The expression of crucial epithelial genes (p63, CK-5/6, CK-10, E-cadherin and beta-catenin) was studied by immunohistochemistry, Western blot and RT-PCR analysis. RESULTS: SEM observations revealed that the surface epithelial ridge pattern became thick and dense, and pit pattern gradually decreased in OSFWD and oral squamous cell carcinoma (OSCC). p63, DeltaNp63 and CK-5/6 were up-regulated in OSFWD and OSCC but down-regulated in OSFWT. CK-10 was down-regulated in OSFWD compared to OSFWT. Cytoplasmic expression of E-cadherin and beta-catenin was elevated in dysplastic and cancerous conditions. Moreover, statistical correlation between SEM features (ridges and pits) and molecular attributes demonstrated a significant positive relationship between the ridge-to-pit ratio and p63 population density (r=0.85) and the ridge-to-pit ratio and CK-5/6 intensity (r=0.63). CONCLUSIONS: Molecular changes related to epithelial progressive maturation and cellular proliferation are correlated with concomitant alteration of epithelial surface architecture which helps to predict the malignant potentiality of OSF. PMID- 26038242 TI - Enhanced regulation of cell cycle and suppression of osteoblast differentiation molecular signatures by prostate cancer stem-like holoclones. AB - AIMS: Targeting the stem cell properties of tumor-initiating cells is an avenue through which cancer treatment may be improved. Before this can be achieved, so called 'cancer stem cell' (CSC) models must be developed and characterized in specific malignancies. METHODS: In this study, holoclone formation assays were used to characterise stem-like molecular signatures in prostate cancer (PCa) cells. RESULTS: LNCaP and PC3 parent cells were capable of responding to stem cell differentiation morphogen retinoic acid (RA), suggesting the presence of inherent stem-like properties. LNCaP cells, which represent early, androgen responsive disease, formed holoclones after twenty six days. PC3 cells, which represent advanced, metastatic, castration-resistant disease, formed holoclones after only six days. Holoclones displayed decreased expression of RA-genes, suggesting a more immature, less differentiated phenotype. Gene and microRNA arrays demonstrated that holoclones downregulated a number of stem cell differentiation regulators while displaying enhanced regulation of G2 to M transition and the mitotic spindle checkpoint components of the cell cycle. PC3 holoclones displayed pronounced downregulation of known regulators of osteoblast differentiation from mesenchymal stem cells and Epithelial Mesenchymal Transition. CONCLUSIONS: Our results suggest that some PCa cells retain the ability to transition to a more immature state in which differentiation and metastatic mechanisms are suppressed. The highlighting of osteoblast differentiation regulators in this mechanism is particularly notable, considering the propensity of PCa to metastasise to bone. PMID- 26038243 TI - Improved Organizational Outcomes Associated With Incorporation of Early Clinical Experiences for Second-Year Student Pharmacists at an Academic Medical Center. AB - PURPOSE: To assess the feasibility of engaging second professional year student pharmacists in the medication reconciliation process on hospital and health system pharmacy practice outcomes. METHODS: Student pharmacists in their second professional year in the Doctor of Pharmacy degree program at our institution were randomly selected from volunteers to participate. Each participant completed training prior to completing three 5-hour evening shifts. Organizational metrics, student pharmacist perception regarding quality of interactions with health care professionals, and pharmacist perceptions were collected. RESULTS: A total of 83 medication histories were performed on complex medical patients (57.0 +/- 19.2 years, 51% female, 65% Caucasian, 12 +/- 6 medications); of those, 93% were completed within 24 hours of hospital admission. Second professional student pharmacists completed on average 1.9 +/- 0.6 medication histories per shift (range 1-3). Student pharmacists identified 0.9 medication-related problems per patient in collaboration with a pharmacist preceptor. Student pharmacists believed the quality of their interactions with health care professionals in the Student Medication and Reconciliation Team (SMART) program was good or excellent. The program has been well received by clinical pharmacists involved in its design and implementation. CONCLUSION: This study provides evidence that second professional year student pharmacists can assist pharmacy departments in the care of medically complex patients upon hospital admission. PMID- 26038244 TI - Genetic Variation in CYP2R1 and GC Genes Associated With Vitamin D Deficiency Status. AB - This cross-sectional study enrolled 180 patients at a private family practice in Virginia. Total serum vitamin D concentrations were obtained weekly from January 30, 2013, through March 30, 2013, in consecutive patients regularly scheduled for laboratory work at the practice. Patients were categorized into 2 groups and analyzed for variant alleles in vitamin D receptor ( VDR; rs2228570), cytochrome P450 2R1 ( CYP2R1; rs10741657), 7-dehydrocholesterol reductase ( DHCR7; rs12785878), and group-specific component ( GC; rs2282679) to determine whether variants of those alleles influenced total serum 25(OH)D concentrations. One hundred and eighty patients were enrolled, with 40 (22%) being sufficient, 25 hydroxy vitamin D level 25(OH)D >= 30 ng/mL, and 140 (78%) being insufficient, 25(OH)D < 30 ng/mL. Of the 4 genes, 2 genes, CYP2R1 (rs10741657) and GC (rs2282679), demonstrated a significant association related to vitamin D status. Subjects with 1 or more variant alleles at rs10741657 were almost 3.7 (odds ratio [OR] 3.67; 95% confidence interval [CI]: 1.35-9.99) times more likely be insufficient in vitamin D and subjects with 1 or more variant alleles at rs2282679 were about half (OR 0.42; 95% CI: 0.18-0.93) as likely to be insufficient in vitamin D. Allelic variations in CYP2R1 (rs10741657) and GC (rs2282679) affect vitamin D levels, but variant alleles on VDR (rs2228570) and DHCR7 (rs12785878) were not correlated with vitamin D deficiency, 25(OH)D < 30 ng/mL. PMID- 26038245 TI - Allergic Reactions in Hospitalized Patients With a Self-Reported Penicillin Allergy Who Receive a Cephalosporin or Meropenem. AB - BACKGROUND: Cefepime and meropenem are used frequently in hospitalized patients for broad-spectrum empiric coverage, however, practitioners are often reluctant to prescribe these antibiotics for patients with a self-reported nonsevere, nontype I allergic reaction to penicillin. METHODS: Retrospective review of electronic medical records of adults with a self-reported allergy to penicillin who received at least 1 dose of cefepime, ceftriaxone, cefoxitin, cephalexin, or meropenem to assess incidence and type of allergic reactions. RESULTS: Of 175 patients included, 10 (6%) patients experienced an allergic reaction. The incidence for individual study drugs were cefepime 6% (6 of 96), meropenem 5% (3 of 56), cefoxitin 8% (1 of 13), ceftriaxone 0% (0 of 69), and cephalexin 0% (0 of 8). The majority of patients experienced a rash with or without pruritus and fever. Patients with a concomitant "sulfa" allergy (odds ratio [OR] 5.4, 95% confidence interval [CI] 1.4-21, P = .02) or >=3 other drug allergies (OR 6.4, 95% CI 1.3-32, P = .025) were more likely to have an allergic reaction. CONCLUSIONS: In one of the largest retrospective reviews of hospitalized patients who received full dose therapy with cefepime, ceftriaxone, and meropenem, the incidence of allergic reactions was low and reactions were mild. Cefepime, ceftriaxone, and meropenem can be considered for use in patients with a self reported nontype I penicillin allergy. PMID- 26038246 TI - Do trauma center levels matter in older isolated hip fracture patients? AB - BACKGROUND: Younger, multi-trauma patients have improved survival when treated at a trauma center. Many regions now propose that older patients be triaged to a higher level trauma centers (HLTCs-level I or II) versus lower level trauma centers (LLTCs-level III or nondesignated TC), even for isolated injury, despite the absence of an established benefit in this elderly cohort. We therefore sought to determine if older isolated hip fracture patients have improved survival outcomes based on trauma center level. METHODS: A retrospective cohort of 1.07 million patients in The Nationwide Emergency Department Sample from 2006-2010 was used to identify 239,288 isolated hip fracture patients aged >=65 y. Multivariable logistic regression was performed controlling for patient- and hospital-level variables. The main outcome measures were inhospital mortality and discharge disposition. RESULTS: Unadjusted logistic regression analyses revealed 8% higher odds of mortality (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.00-1.16) and 10% lower odds of being discharged home (OR, 0.90; 95% CI, 0.80 1.00) among patients admitted to an HLTC versus LLTC. After controlling for patient- and hospital-level factors, neither the odds of mortality (OR, 1.06; 95% CI, 0.97-1.15) nor the odds of discharge to home (OR, 0.98; 95% CI, 0.85-1.12) differed significantly between patients treated at an HLTC versus LLTC. CONCLUSIONS: Among patients with isolated hip fractures admitted to HLTCs, mortality and discharge disposition do not differ from similar patients admitted to LLTCs. These findings have important implications for trauma systems and triage protocols. PMID- 26038247 TI - C-reactive protein has a better discriminative power than white cell count in the diagnosis of acute cholecystitis. AB - BACKGROUND: The diagnosis of acute cholecystitis (AC) is challenging and may result in a delay in surgery, hospital discharge, and increased mortality. To improve its diagnosis, C-reactive protein (CRP) has been proposed as a benchmark. The aim of this study was to evaluate discriminative power of CRP against white cell count (WCC) in AC. METHODS: This was a retrospective cohort study. Over a 5 y period, 1959 patients were identified from the audit of cholecystectomies. The exclusion criteria were coexisting acute surgical conditions, absence of blood tests within 3 d before hospital admission for elective surgery, and private patients. RESULTS: The eligibility criteria were met by 1843 patients. Comparison of the area under receiver operating characteristic (AUC) curve of CRP and WCC in acute on chronic, edematous, necrotic, suppurative, and gangrenous AC showed a better discriminative power of CRP. Both tests performed equally well in patients with pericholecystic abscess and gallbladder perforation. CRP was superior than WCC in mild AC, AUC = 0.93 (95% confidence interval [CI], 0.9-0.95) and 0.79 (95% CI, 0.74-0.84), P < 0.00005, in moderate and severe AC, AUC = 0.99 (95% CI, 0.97 1.0) and 0.92 (95% CI, 0.88-0.97), P = 0.009, and in all forms of AC combined, AUC = 0.94; (95% CI, 0.92-0.97) and 0.83 (95% CI, 0.79-0.87), respectively, P < 0.00005. CONCLUSIONS: CRP has a better discriminative power than WCC in most forms of AC and is a useful diagnostic marker of AC. PMID- 26038248 TI - Cholecalciferol (vitamin D3) prevents postoperative adhesion formation by inactivating the nuclear factor kappa B pathway: a randomized experimental study. AB - BACKGROUND: Postoperative peritoneal adhesions are major complications of abdomino-pelvic surgeries. We aim to investigate the preventive and therapeutic effects of cholecalciferol (vitamin D3) supplementation on postoperative peritoneal adhesion (PPA) in a rat model. MATERIALS AND METHODS: This randomized, controlled, single blinded animal study was performed in university laboratory. Thirty-two female Wistar albino rats were randomly separated into four equal groups as, group 1: (21-d vitamin-D treatment group), group 2: (21-d corn oil group), group 3: (14-d vitamin-D treatment group), and group 4: (control group). Uterine horns were traumatized with bipolar cautery for adhesion formation process. On postoperative day 14, all the animals were sacrificed and evaluated for adhesions. Adhesion extent, severity, degree, and total adhesion scores were evaluated macroscopically. Histopathologically, adhesions were evaluated for inflammation, fibrosis, and NFkappaB (nuclear factor kappa b) staining. RESULTS: On postoperative day 14, we found lesser peritoneal adhesion severity, degree, extent, and total adhesion scores with vitamin-D administration compared with control and corn oil-treated groups; the difference was statistically significant (P < 0.001). Histopathologic adhesion scores of inflammation and fibrosis were statistically different among the four groups (P < 0.001). NFkappaB staining was markedly increased in control and vehicle groups. The NFkappaB staining scores were statistically different between the groups (P < 0.001). The intensity of NFkappaB staining was lower in both vitamin 14 and 21-d vitamin-D groups. CONCLUSIONS: Vitamin D as a supplement and as a therapeutic medicine decreases the formation of PPA in an animal model. In future studies, the association of vitamin D deficiency and PPA should be studied. In addition, vitamin D should be investigated in future clinical studies for the prevention of PPAs. PMID- 26038250 TI - Corruption impairs discussion on long term use of psychiatric drugs. PMID- 26038249 TI - Synthesis and In Vitro Evaluation of Thiolated Carrageenan. AB - The aim of this study was to generate and characterize a thiolated carrageenan. Thiolated carrageenan (carrageenan-SH) was synthesized from kappa (kappa)- and iota (iota)-carrageenan by bromine replacement of the hydroxyl moieties followed by substitution to thiol groups using thiourea. Thiolated kappa- and iota carrageenan exhibited 176.57 +/- 20.11 and 109.51 +/- 18.26 MUmol thiol groups per gram polymer, respectively. The resazurin test in Caco-2 cells revealed no toxic effect of both thiolated carrageenans at a concentration below 0.1% (w/v). Regarding efflux pump inhibitory effect, cellular accumulation of multidrug resistance protein 2 substrate, sulforhodamine 101, was 1.38- and 1.35-fold increased in cells treated with thiolated kappa- and iota-carrageenan, respectively. Modification of kappa- and iota-carrageenan led to 3.9- and 2.0 fold increase in dynamic viscosity of mucus-thiolated carrageenan mixture within 4 h. Furthermore, residence time of kappa- and iota-carrageenan-SH on porcine intestinal mucosa was 6.4- and 1.8-fold prolonged, respectively, as demonstrated by rotating cylinder method, indicating improved mucoadhesive properties. Hence, thiolation of carrageenans led to novel pharmaceutical excipients for various applications. PMID- 26038251 TI - An efficient genetic manipulation protocol for Ustilago esculenta. AB - Ustilago esculenta grows within the flowering stem of the aquatic grass Zizania latifolia, resembling a fungal endophyte. The fungus colonizes Z. latifolia and induces swelling which results in the formation of galls near the base of the plant. Due to their unique flavor and textures these galls are considered as a delicacy in southern China. Efficient genetic manipulation is required to determine the relationship between U. esculenta and Z. latifolia. In this study, we report a protoplast-based transformation system for this unique fungal species. We have explored various factors (enzyme digesting conditions, osmotic pressure stabilizers, vectors and selection agents) that might impact protoplast yield and high frequencies of transformation. A haploid strain (UeT55) of U. esculenta was found to produce higher yields of protoplasts when treating with 15 mg mL(-1) lywallzyme in a sucrose-containing solution at 30 degrees C for 3 h. The transformation frequencies were higher when fungal strain was transformed with a linear plasmid harboring hygromycin or carboxin resistance gene and regenerated on a sucrose-containing medium. A UeICL gene (coding isocitrate lyase) was disrupted and an EGFP (coding enhanced green fluorescent protein) gene was overexpressed successfully in the UeT55 strain using the developed conditions. The genetic manipulation system reported in this study will open up new opportunities for forward and reverse genetics in U. esculenta. PMID- 26038252 TI - Tackling risky alcohol consumption in sport: a cluster randomised controlled trial of an alcohol management intervention with community football clubs. AB - BACKGROUND: An increased prevalence of risky alcohol consumption and alcohol related harm has been reported for members of sporting groups and at sporting venues compared with non-sporting populations. While sports clubs and venues represent opportune settings to implement strategies to reduce such risks, no controlled trials have been reported. The purpose of the study was to examine the effectiveness of an alcohol management intervention in reducing risky alcohol consumption and the risk of alcohol-related harm among community football club members. METHOD: A cluster randomised controlled trial of an alcohol management intervention was undertaken with non-elite, community football clubs and their members in New South Wales, Australia. Risky alcohol consumption (5+ drinks) at the club and risk of alcohol-related harm using the Alcohol Use Disorders Identification Test (AUDIT) were measured at baseline and postintervention. RESULTS: Eighty-eight clubs participated in the trial (n=43, INTERVENTION; n=45, CONTROL) and separate cross-sectional samples of club members completed the baseline (N=1411) and postintervention (N=1143) surveys. Postintervention, a significantly lower proportion of intervention club members reported: risky alcohol consumption at the club ( INTERVENTION: 19%; CONTROL: 24%; OR: 0.63 (95% CI 0.40 to 1.00); p=0.05); risk of alcohol-related harm ( INTERVENTION: 38%; CONTROL: 45%; OR: 0.58 (95% CI 0.38 to 0.87); p<0.01); alcohol consumption risk ( INTERVENTION: 47%; CONTROL: 55%; OR: 0.60 (95% CI 0.41 to 0.87); p<0.01) and possible alcohol dependence ( INTERVENTION: 1%; CONTROL: 4%; OR: 0.20 (95% CI 0.06 to 0.65); p<0.01). CONCLUSIONS: With large numbers of people worldwide playing, watching and sports officiating, enhancing club-based alcohol management interventions could make a substantial contribution to reducing the burden of alcohol misuse in communities. TRIAL REGISTRATION NUMBER: ACTRN12609000224224. PMID- 26038253 TI - Synthesis and Molecular Recognition of Water-Soluble S6 Corona[3]arene[3]pyridazines. AB - We report the efficient and scalable synthesis and molecular-recognition properties of novel and water-soluble S6-corona[3]arene[3]pyridazines. The synthesis comprises a one-pot nucleophilic aromatic substitution reaction between diesters of 2,5-dimercaptoterephthalate and 3,6-dichlorotetrazine followed by the inverse electron-demand Diels-Alder reaction of the tetrazine moieties with an enamine and exhaustive saponification of esters. The resulting S6 corona[3]arene[3]pyridazines, which adopt a 1,3,5-alternate conformation in the crystalline state, are able to selectively form stable 1:1 complexes with dicationic guest species in water with association constants ranging from (1.10+/ 0.06)*10(3) M(-1) to (1.18+/-0.06)*10(5) M(-1). The easy availability, large cavity size, strong and selective binding power render the water-soluble S6 corona[3]arene[3]pyridazines useful macrocyclic hosts in various disciplines of supramolecular chemistry. PMID- 26038254 TI - Introduction to the 7th focus-on issue devoted to disaster- and military surgery. PMID- 26038256 TI - Contemporary wars and their contributions to vascular injury management. AB - INTRODUCTION: Man's inhumanity for man still knows no boundaries, as we continue as a species as a whole to engage in war. According to Kohn's Dictionary of Wars [1], of over 3,700 years of recorded history, there have been a total of 3,010 wars. One is hard pressed to actually find a period of time in which here has not been an active conflict in the globe. The world has experienced two world wars: WWI (1914-1918) and WWII (1939-1945). The total number of military casualties in WWI was over 37 million, while WWII so far, has been the deadliest military conflict in history with over 60 million people killed accounting for slightly over 2.5% of the world's population. MATERIAL AND METHODS: The purpose of this study is to review contemporary wars and their contributions to vascular injury management. It is precisely wartime contributions that have led to the more precise identification and management of these injuries resulting in countless lives and extremities saved. However, surgeons dealing with vascular injuries have faced a tough and arduous road. Their journey was initiated by surgical mavericks which undaunted, pressed on against all odds guided by William Stewart Halsted's classic statement in 1912: "One of the chief fascinations in surgery is the management of wounded vessels." CONCLUSION: Contemporary wars of the XX-XXI centuries gave birth, defined and advanced the field of vascular injury management. PMID- 26038255 TI - The ebb and flow of fluid (as in resuscitation). AB - Since the early 1960's "resuscitation" following major trauma involved use of replacement crystalloid fluid/estimated blood loss in volumes of 3/1, in the ambulance, emergency room, operating room and surgical intensive care unit. During the past 20 years, MAJOR paradigm shifts have occurred in this concept. As a result hypotensive resuscitation with a view towards restriction of crystalloid, and prevention of complications has occurred. Improved results in both civilian and military environments have been reported. As a result there is new focus on trauma surgical involvement in all aspects of trauma patient management, focus on early aggressive surgical approaches (which may or may not involve an operation), and movement from crystalloid to blood, plasma, and platelet replacement therapy. PMID- 26038257 TI - Surgical management of Syria's war casualties: experience from a French surgical team deployed in the Zaatari refugee camp (Jordan). AB - PURPOSE: In August 2012, the Zaatari refugee camp was opened in Jordan under the auspices of the United Nations High Commissioner for Refugees. France deployed there a surgical facility to treat victims of war trauma. METHODS: After a phase of intensive care and resuscitation, surgical management meeting the current standards of war surgery was conducted. Then, patients were transferred to a Jordanian civilian hospital or stayed in the Zaatari camp. A retrospective analysis of patient data was performed. RESULTS: From January to March 2013, 95 patients were managed: 85% of patients were male with a median age of 27 years (4 65); 5% of patients were <18 years of age. All patients were Syrian, civilian or members of the "Free Syrian Army." Penetrating trauma accounted for 95% of lesions. A total of 105 surgeries were performed, including: 33 external fixators, 8 laparotomies, 8 nerve repairs, 6 cover flaps, 4 direct arterial repairs, 2 reversed saphenous vein bypass grafts, and 1 amputation. The median length of stay on the wards was 3.71 days; 43% of patients were transferred to Jordanian civilian hospitals. CONCLUSIONS: The presence at the Zaatari camp of a surgical facility, which is experienced and specialized in war surgery, is essential, as long as battles are ongoing. Many victims will later require long term surgical care for the management of the sequelae associated with these traumas. PMID- 26038258 TI - Role 2 military hospitals: results of a new trauma care concept on 170 casualties. AB - INTRODUCTION: In recent military conflicts, military surgeons encounter more high energy injuries associated with explosives. Advances in the field care and shorter evacuation time increased survival. However, casualties still incur severe injuries especially to the extremities. We present wound patterns, anatomical distribution and severity of injuries in a Role 2 hospital. MATERIALS AND METHODS: Two years data have been retrospectively reviewed. Only explosives and firearms injuries were included in the study. Patient profile, admission details, mechanism of injury, AIS anatomical locations, ISS, surgical and medical treatments have been analyzed. RESULTS: Data revealed 170 male casualties. IEDs and GSW accounted for 133 (78%) and 37 (22%) casualties, respectively. An average of 1.8 IED and 1.2 GSW anatomical locations were exposed to injuries. Regardless of the mechanism, injuries were most commonly located in the extremities. IEDs caused significantly higher soft tissue injuries. DISCUSSION: Explosives do not necessarily cause more severe injuries than firearms. However, fragments create multiple, complicated soft tissue injuries which constitute more than half of the injuries. Timely wound debridement and excision of contaminated tissue are crucial to manage extremity soft tissue injuries. CONCLUSION: Casualty care should be assessed within the context of the capabilities present at a hospital and the cause, type and severity of the wounds. The NATO description of Role 2 care only requires an integrated surgical team for damage control surgery with limited diagnostic and infrastructural capabilities. PMID- 26038259 TI - Penetrating shrapnel injuries of the posterior fossa. AB - BACKGROUND: Gunshot injuries of the posterior fossa are rare and may follow a fatal course. In posterior fossa gunshot injuries, cerebellar hematoma, contusion, obstruction of cerebrospinal fluid (CSF) circulation by the shrapnel, and intracranial hypertension caused by autoregulation loss lead to mortality in the early stage. METHODS: In this study, four cases of patients who underwent surgical intervention after penetrating shrapnel injuries of the pure posterior fossa were evaluated. RESULTS: All of the patients were male; their mean age was 26.5 +/- 5 years. The lowest and highest Glasgow Coma Scale scores were 4 and 12, respectively. Neural injury was detected by computed tomography performed after systemic and neurological examination following admission to the emergency service. The shrapnel was found in the cerebellar tissue in three cases and in the fourth ventricle in one case. Following preoperative procedures, surgery was performed with the patient in the prone position. Postoperative monitoring revealed no CSF fistula, meningitis, or hydrocephalus. None of the patients required revision surgery. There were no postoperative mortalities. CONCLUSION: Due to the small volume of the posterior fossa, acute pathologies may lead to rapid neurological deterioration and death. Early surgical intervention and close postoperative follow-up after penetrating shrapnel injuries of the posterior fossa play a significant role in reducing mortality and morbidity. PMID- 26038260 TI - Retained weapon injuries: experience from a civilian metropolitan trauma service in South Africa. AB - INTRODUCTION: Retained weapon (RW) injuries are uncommon, but there is no current consensus on the best management approach. METHODS: We reviewed our experience of 102 consecutive patients with non-missile RWs in a high-volume metropolitan trauma service managed over a 10-year period. RESULTS: Of the 102 patients, 95 were males (93%), 7 were females (7%), and median age was 24 (21-28) years. Weapons: 73% (74/102) knives, 17% (17/102) screwdrivers, 5% spears, 6% (6/102) others [axe (1), glass fragment (1), stick (1), sickle blade (1), wire (1) and stone (1)]. LOCATION: 8% (8/102) head, 20% (20/102) in the face, 9% (9/102) neck, 14% (14/102) thorax, 25% (26/102) abdomen, 23% (23/102) upper limb, 2% (2/102) lower limb. Four per cent (4/102) were haemodynamically unstable and proceed immediately to the operating theatre for operative exploration and weapon extraction. Imagining: 88 (86%) plain radiographs, 65 (64%) non-contrast CT scans, 41 (40%) contrast CT angiography, 4 (4%) formal angiography. Seventy-two underwent simple extraction, and 29 underwent extract plus open operation. One patient absconded. Specialist surgeons involved in extraction: trauma surgeons (74), neurosurgeons (10), ophthalmic surgeons (11) and ENT surgeons (4). Overall, 92% (94/102) survived to discharge. CONCLUSIONS: The vast majority of patients with RWs will be admitted in a stable condition and haemodynamic instability was almost exclusively seen in the anterior thorax. The most common site was the posterior abdomen. Detailed imagining should be used liberally in stable patients and unplanned extraction in an uncontrolled environment should be strongly discouraged. PMID- 26038261 TI - Indoor fire in a nursing home: evaluation of the medical response to a mass casualty incident based on a standardized protocol. AB - PURPOSE: This retrospective study reports the outcome of a mass casualty incident (MCI) caused by a fire in a nursing home. METHODS: Data from the medical charts and registration system of the Major Incident Hospital (MIH) and ambulance service were analyzed. The evaluation reports from the MIH and an independent research institute were used. The protocol for reports from major accidents and disaster was used to standardize the reporting [Lennquist, in Int J Disaster Med 1(1):79-86, 2003]. RESULTS: The emergency services were quickly at the scene. The different levels of pre-hospital management performed a tight coordination. However, miscommunication led to confusion in the registration and tracking of patients. In total, 49 persons needed medical treatment, 46 were treated in the MIH. Because of (possible) inhalation injury nine patients needed mechanical ventilation and nine patients were hospitalized to exclude delayed onset of pulmonary symptoms. No incident related deaths occurred. The intensive care unit of the MIH was initially understaffed despite the efforts of the automated calling system and switchboard operators. The handwritten registration of incoming staff was incomplete and should be performed digitally. Some staff members were unfamiliar with the MIH procedures. The medical chart appeared too extensive. Miscommunication between chain partners resulted in the delayed sharing of (semi) medical information. CONCLUSION: The different levels of incident managers performed a tight coordination. The MIH demonstrated its potency to provide emergency care for 46 patients and 9 intubated patients. No deaths or persistent disabilities occurred. Areas of improvement were recognized both in the pre-hospital as the hospital phase. PMID- 26038262 TI - Wounds of war in the civilian sector: principles of treatment and pitfalls to avoid (Eur J Trauma Emerg Surg (2014) 40:461-468). PMID- 26038263 TI - Pulmonary pseudocyst secondary to blunt or penetrating chest trauma: clinical course and diagnostic issues. AB - PURPOSE: Traumatic pulmonary pseudocysts (TPPs) are rare complications of chest trauma. The aim of this retrospective study was to report the clinical presentations, diagnosis, complications and treatment for a series of TPPs at a hospital in Turkey. METHODS: The charts of 996 patients who were admitted for thoracic trauma between 1999 and 2012 were retrospectively reviewed. Fifty-two patients had TPPs, and the data collected for these individuals were sex, age, and type of trauma (blunt and/or penetrating). Univariate analysis of categorical data was performed using Pearson's Chi square test. Results for continuous variables were statistically compared using the Mann-Whitney U test. RESULTS: The patients were 42 males and 10 females aged 12-72 years (mean age 33.1 years). Forty-one had blunt trauma and 11 had penetrating trauma. There was no significant difference between the proportion of blunt trauma patients who developed TPP (41/761, 5.3%) and the proportion of penetrating trauma patients who developed TPP (11/235, 4.6%) (p > 0.05). All 42 patients had pulmonary contusion. Only 10 patients (19.2%) had TPP identified on their chest X-ray, and thoracic computed tomography revealed TPP clearly in all these cases. Forty-two patients (80.7%) were diagnosed with TPP on day 1 post-trauma. The hospital stays ranged from 2 to 35 days for the patients with blunt-trauma, and from 4 to 15 days for those with penetrating trauma (means 8.8 and 8.0 days, respectively; p > 0.05). Only one patient required thoracotomy for a pseudocyst that did not resolve and became progressively enlarged. This TPP was resected at 6 months post trauma. One patient died on day 9 post-trauma due to multiple organ failure. The other 40 pseudocysts resolved spontaneously within 1-5 months. CONCLUSIONS: Traumatic pulmonary pseudocysts are pulmonary lesions that occur after either blunt or penetrating trauma and tend to be overlooked. Most of these lesions are self-limiting, benign lesion. PMID- 26038264 TI - One-stage posterior procedure in treating active thoracic spinal tuberculosis: a retrospective study. AB - PURPOSE: To investigate the clinical efficacy and feasibility of surgical treatment for thoracic spinal tuberculosis with neurological deficit by one-stage posterior instrumentation, proper transpedicular debridement, without anterior instrumentation and without anterior or posterior bone graft. METHODS: A total of 19 cases with thoracic tuberculosis, neurological deficit and bone destruction (without severe kyphosis) admitted to the hospital from May 2005 to January 2010 were treated by internal fixation, transpedicular debridement without bone graft via the isolated posterior approach. Operating time, blood loss, complications, neurological function, deformity correction, pain relief, and inter-body fusion were investigated. RESULTS: The average mean operating time was 168.9 +/- 21.1 min. The average blood loss during operation was 655.8 +/- 82.8 ml. All patients were followed for 28-46 months post-operation (average, 36.8 +/- 5.8 months). All patients had significant postoperative improvement in ASIA classification scores and VAS scores. The thoracic kyphotic angle was significantly decreased to 11.6 degrees -20.2 degrees after operation (average, 15.6 degrees +/- 2.2 degrees ), and the angle was 12.3 degrees -21.6 degrees (average, 16.4 degrees +/- 2.2 degrees ) at final follow-up. No severe complications or spinal cord injury occurred. The erythrocyte sedimentation rate and C-reactive protein recovered to normal within 3 months after operation in all patients. All patients have got spontaneous bony fusion within 6-9 months after surgery. CONCLUSIONS: One-stage posterior instrumentation, transpedicular debridement without bone graft can be an effective and feasible treatment method for selected thoracic spinal tuberculosis. PMID- 26038265 TI - A technique for visual confirmation of intrathoracic placement of tube thoracostomy using a fiberoptic laryngoscope in a cadaver. AB - PURPOSE: Safe intrathoracic placement of chest tubes is a continual challenge. Current techniques for determining the intrathoracic location of the thoracostomy site include blunt dissection and digital exploration, with subsequent tube placement. Using current techniques, complication rates for this procedure approach 30%. We present a novel technique using available endotracheal intubation technology for determining intrathoracic placement of tube thoracostomy. METHODS: One cadaver was used for placement of tube thoracostomy. Both sides of the thorax were prepared in the standard fashion for tube thoracostomy placement, and tube thoracostomy was performed on each hemithorax at interspaces 3 through 7. The right side of the thorax was used for standard thoracostomy placement, and the left side was used for fiberoptic visualization of thoracostomy placement using a video laryngoscope. Thoracic wall thickness was measured at all thoracostomy sites. Proper placement and any injuries were documented for each site. RESULTS: Chest wall thickness ranged from 2.4 to 3.8 cm on the right and 2.8 to 4.0 cm on the left. With use of fiberoptic thoracostomy, no injuries were generated. During the standard thoracostomy placement in the sixth intercostal space, a pulmonary laceration was caused using blunt dissection. CONCLUSIONS: Use of a fiberoptic laryngoscope offers a novel technique for direct visualization the thoracic space during tube thoracostomy. Further studies are needed to determine the safety of this technique in patients. PMID- 26038268 TI - Computational design of an Iridium based catalyst for releasing H2 from hydrogenated BN nanotubes. AB - Through carefully calibrated density functional studies we predict that Ir pincer complexes, previously known to effectuate simultaneous proton and hydride transfer from ammonia-borane under ambient conditions, are equally efficient catalysts for the concerted dehydrogenation and subsequent release of H2 from hydrogenated boron nitride nanotubes overcoming free energy of activation accessible at room temperature. PMID- 26038266 TI - Initial venous lactate levels in patients with isolated penetrating extremity trauma: a retrospective cohort study. AB - INTRODUCTION: Elevated initial lactate levels have been shown to be associated with severe injury in trauma patients, but some patients who do not appear to be in shock also presented with elevated lactate levels. We hypothesized that in hemodynamically stable patients with isolated penetrating extremity trauma, initial lactate level does not predict clinically significant bleeding. METHODS: A 5-year institutional database review was performed. Hemodynamically stable patients (HR < 101, SBP > 90) with isolated penetrating extremity trauma with an initial lactate sent were included. The exposure of interest was captured as a dichotomous variable by initial lactate level normal (N <= 2.2 mEq/L), elevated (E > 2.2 mEq/L). The primary outcome measurement was clinically significant bleeding, defined by need for intervention (operation, angioembolization, or transfusion) or laboratory evidence of bleeding (presenting Hg < 7 g/dL, or Hg decrease by >2 g/dL/24 h). Chi-squared and Mann-Whitney tests were used to compare variables. RESULTS: A total of 132 patients were identified. There were no differences in demographics or mechanism of injury between the N (n = 43, 7%) and E (n = 89, 14%) groups. Median lactate levels were 1.6 (IQR 1.2-1.9) mEq/dL vs. 3.8 (IQR 2.8-5.2) in the N and E groups, p < 0.001. Lactate was elevated in 89 (67%) patients but was not associated with clinically significant bleeding (37% elevated vs. 39 % not elevated p = 0.82). CONCLUSIONS: In hemodynamically stable patients with isolated penetrating trauma to the extremity, elevated initial venous lactate levels (>2.2 mEq/L) are not associated with bleeding or need for interventions. Clinical judgment remains the gold standard for evaluation and management of these patients. PMID- 26038269 TI - Excitatory connections of nonspiking interneurones in the terminal abdominal ganglion of the crayfish. AB - The output effects of the nonspiking interneurones in the crayfish terminal abdominal ganglion upon the uropod motor neurones were characterized using simultaneous intracellular recordings. Inhibitory interactions from nonspiking interneurones to the uropod motor neurones were one-way and chemically mediated. The depolarization of the motor neurones with current injection increased the amplitude of the nonspiking interneurone-mediated hyperpolarization, while hyperpolarization of the motor neurone decreased it. By contrast, excitatory interactions from the nonspiking interneurones to the motor neurones were not mediated via chemical synaptic transmissions. These excitatory connections with the slow motor neurones were one-way while connections with fast motor neurones were bidirectional. Nonspiking interneurone-mediated membrane depolarization of the motor neurones was not affected by the passage of hyperpolarizing current. Each motor neurone spike elicited a time-locked EPSP in the nonspiking interneurones with very short delay (0.2 ms) that suggested electrical coupling between nonspiking interneurones and motor neurones. Nonspiking interneurones directly control the organization of slow motor neurone activity, while they appear to regulate the background activity of the fast motor neurones. A single nonspiking interneurone is possible to inhibit some inter and/or motor neurones via direct chemical synapses and simultaneously excite other neurones via electrical synapses. PMID- 26038270 TI - Isolation of differentially expressed sex genes in garden asparagus using suppression subtractive hybridization. AB - Garden asparagus (Asparagus officinalis L.) is a dioecious species whose male and female flowers are found in separate unisexual individuals. A region called the M locus, located on a pair of homomorphic sex chromosomes, controls sexual dimorphism in asparagus. To date, no sex determining gene has been isolated from asparagus. To identify more genes involved in flower development in asparagus, subtractive hybridization library of male flowers in asparagus was constructed by suppression subtraction hybridization. A total of 107 expressed sequence tags (ESTs) were identified. BLASTX analysis showed that the library contained several genes that could be related to flower development. The expression patterns of seven selected genes believed to be involved in the development of asparagus male flower were further analyzed by semi-quantitative or real-time reverse transcription polymerase chain reaction (RT-PCR). Results showed that AOEST4-5, AOEST12-40, and AOEST13-38 were strongly expressed in the male flower stage, whereas no transcript level of AOEST13-38 was detected in the female flower stage. The expression levels of AOEST13-87, AOEST13-92, AOEST13-40, and AOEST18 87 in the male flower stage were also higher than those in the female flower stage, although these transcripts were also expressed in other tissues. The identified genes can provide a strong starting point for further studies on the underlying molecular differences between the male and female flowers of asparagus. PMID- 26038271 TI - Rapid response of leaf photosynthesis in two fern species Pteridium aquilinum and Thelypteris dentata to changes in CO2 measured by tunable diode laser absorption spectroscopy. AB - We investigated stomatal conductance (g(s)) and mesophyll conductance (g(m)) in response to atmospheric CO2 concentration [CO2] in two primitive land plants, the fern species Pteridium aquilinum and Thelypteris dentata, using the concurrent measurement of leaf gas exchange and carbon isotope discrimination. [CO2] was initially decreased from 400 to 200 MUmol mol(-1), and then increased from 200 to 700 MUmol mol(-1), and finally decreased from 700 to 400 MUmol mol(-1). Analysis by tunable diode laser absorption spectroscopy (TDLAS) revealed a rapid and continuous response in g m within a few minutes. In most cases, both ferns showed rapid and significant responses of g m to changes in [CO2]. The largest changes (quote % decrease) were obtained when [CO2] was decreased from 400 to 200 MUmol mol(-1). This is in contrast to angiosperms where an increase in g(m) is commonly observed at low [CO2]. Similarly, fern species observed little or no response of g(s) to changes in [CO2] whereas, a concomitant decline of g(m) and g(s) with [CO2] is often reported in angiosperms. Together, these results suggest that regulation of g(m) to [CO2] may differ between angiosperms and ferns. PMID- 26038274 TI - Circadian rhythms: Translating the clock. PMID- 26038273 TI - Locoregional Therapy for Hepatocellular Carcinoma with and without Extrahepatic Spread. AB - PURPOSE: To evaluate the use of locoregional therapy in patients with hepatocellular carcinoma (HCC) with and without extrahepatic disease (EHD). MATERIALS AND METHODS: Patients who underwent locoregional therapy for HCC were identified from institutional databases. Clinicopathologic and treatment characteristics were compared between patients with and without EHD. Survival and progression were assessed using the Kaplan-Meier method, and multivariate analysis was completed. RESULTS: Of 224 patients, 39 (17%) had radiologic evidence of EHD. Patients without EHD were older than patients with EHD (68.8 y +/- 10.1 vs 65.0 y +/- 11.7, P = .04); underlying liver disease/function and tumor characteristics were not different. Type of locoregional therapy (hepatic artery embolization vs drug-eluting bead transarterial chemoembolization, P = .12; radiofrequency ablation + embolization, P = .07) was similar. Progression occurred in 75% (169/224) of patients. Progression-free survival (PFS) did not differ between the 2 groups (13 [10.3-15.7] mo EHD vs18 [14.6-21.4] mo no EHD, P = .13). Overall survival (OS) was 13 (4.1-21.9) months and 25 (20.4-29.6) months in the EHD and no EHD groups, respectively (P = .02). On multivariate analysis, systemic therapy after locoregional treatment was the only variable independently associated with PFS (hazard ratio [HR] 0.70 [0.49-1.00], P = .04); EHD (HR 1.60 [1.02-2.50], P = .04) and tumor size (HR 1.77 [1.21-2.58], P = .003) were independently associated with worse OS. CONCLUSIONS: Patients with HCC and limited EHD treated with locoregional therapy had worse OS than patients without EHD; PFS was not different. Use of systemic therapy after locoregional therapy was independently associated with improved PFS in this cohort. Further prospective studies of locoregional, systemic, and combination therapies are necessary to improve outcome in these high-risk patients. PMID- 26038275 TI - Impact of oligodendroglial component in glioblastoma (GBM-O): Is the outcome favourable than glioblastoma? AB - BACKGROUND: Prognosis of patients with glioblastoma with oligodendroglial component (GBM-O) is not well defined. We report our experience of patients of GBM-O treated at our center. METHODS: Between January 2007 and August 2013, out of 817 consecutive patients with glioblastoma (GBM), 74 patients with GBM-O were identified in our prospectively maintained database. An experienced neuropathologist revaluated the histopathology of all these 74 patients and the diagnosis of GBM-O was eventually confirmed in 57 patients. Patients were uniformly treated with maximal safe resection followed by focal radiotherapy with concurrent and adjuvant temozolamide (TMZ). RESULTS: At a median follow up of 16 months, median overall survival (OS) and progression free survival (PFS) of the entire cohort was 23 months and 13 months respectively. Near total excision was performed in 30/57 (52.6%). On univariate analysis, age < 50 years was a significant favourable prognostic factor for OS (p = 0.009) and PFS (p = 0.017), while patients with near total resection had a significantly better PFS (p = 0.017), patients who completed a minimum of 6 cycles of adjuvant TMZ had significantly better OS (p = 0.000) and PFS (p = 0.003). On multivariate analysis, none of the above factors were significant except for patient who had completed a minimum of 6 cycles of TMZ (OS; p = 0.000 & PFS; p = 0.015). A comparative analysis of GBM-O patients with a similarly treated cohort of 105 GBM patients during the same period revealed significantly better median OS in favour of GBM-O (p = 0.01). CONCLUSIONS: Our experience suggests patients with GBM-O have a more favourable clinical outcome as compared to GBM. PMID- 26038276 TI - Giant cell arteritis presenting as spinal cord infarction. PMID- 26038277 TI - Movable intraoperative magnetic resonance imaging incorporating a seismic system. AB - INTRODUCTION: A high-field ceiling-mounted and movable intraoperative MR imaging (iMRI) can minimize additional risks for MRI and enhance safety by not moving the patient. In this system, hanging the heavy magnet from the ceiling requires structural stability; this stability was confirmed in earlier studies, but not proved during a seismic event. OBJECTIVE: We have installed a 1.5 T movable iMRI system with an incorporated seismic system in our hospital in Japan, a seismic event-prone region. This arrangement is the first in the world, to our knowledge. The objective of this study was to describe the mechanism of this seismic system and the first clinical experience using this system. METHODS: The seismic system consists of a stabilizer pad that is mounted directly under the magnet, in addition to the structural stability. The seismic system was tested with using a shaker table testing at a test laboratory. RESULTS: Ninety-one patients underwent neurosurgical intervention using this iMRI and seismic system at our hospital. In all patients, intra-, pre, and/or postoperative MR images were successfully obtained, and image quality was excellent. The workflow of moving the magnet and scanning were smooth and unproblematic. We had 169 seismic events in our city during this time period, but had no incidental or accidental events related to the seismic events. CONCLUSION: With the use of the seismic system, a ceiling mounted, movable iMRI system can be more safely used. This seismic system may contribute to the spread of movable iMRI systems in countries where seismic events occur. PMID- 26038278 TI - Deep anterior cerebellar stimulation reduces symptoms of secondary dystonia in patients with cerebral palsy treated due to spasticity. AB - INTRODUCTION: Deep anterior cerebellar stimulation (DACS) is a neuromodulation therapy of spasticity. Bilateral DACS is applied in young patients with cerebral palsy (CP). In these patients symptoms of spasticity coexist with symptoms of focal or segmental dystonia, which can cause chronic pain. We performed the study to investigate the therapeutic effects of DACS in spasticity, secondary dystonia and pain. METHODS: We examined 10 from 13 patients with CP treated with DACS due to spasticity in years 2006-2012. We compared Ashworth scores of spasticity, VAS scale of pain and UDRS (Unified Dystonia Rating Scale) score before DACS and after it in follow-up lasting from 2 to 11 years it in these patients basing on clinical examination and evaluating forms given by the patients or parents. RESULTS: We received statistically significant reduction of spasticity in upper extremities (median: from 3 to 1,5 in Ashworth scale) in 8 patients (p = 0,01), in lower extremities in 7 patients (median: from 3 to 1,75) (p = 0,02). Symptoms of focal dystonia were reduced. Total score for the UDRS (median = 18,0 before surgery) after DACS decreased significantly (median = 10,3) (p = 0,043). Change in consecutive parts of UDRS before (median = 1,6) and after (median = 1,0) surgery in 7 patients had statistical significance (p = 0,0179). There were not significant changes in intensity of pain before and after surgery (p = 0,108). DISCUSSION: Chronic bilateral DACS aimed for spasticity treatment not only decreases muscular tone in quadriplegic or paraplegic patients with CP but also is associated with reduction of symptoms of focal or segmental, secondary dystonia. PMID- 26038279 TI - Predicting success: What medical student measures predict resident performance in neurology? AB - OBJECTIVE: Many medical school metrics are used by residency programs to differentiate residency applicants. The importance of each metric in the field of neurology is unclear. MATERIALS AND METHODS: This is a single-site retrospective evaluation of characteristics that predict resident quality. Several measures from all 57 adult neurology residents over 8 years were obtained including Step I scores, college and medical school rankings, in-service training examination scores, advanced degrees, and number of publications during residency. Two program directors, blinded to these data and each other's ratings, rated the quality of all residents at the end of the residency. The data were then anonymized for all analyses. RESULTS: There was no significant relationship between Step I scores and resident quality, though Step I scores correlated significantly with in-service training examination scores. Medical students with PhDs did not perform differently in terms of resident quality, number of publications in residency, or in-service training examination scores. Resident quality was correlated with the ranking of each applicant's undergraduate college, but not the ranking of their medical school. CONCLUSIONS: While Step I is used by many residency programs in ranking potential residents, it does not correlate with overall resident quality, although Step I scores may predict success on future standardized medical examinations. Students with PhDs do not differ from other residents across several metrics. Applicants from highly selective colleges, though not highly selective medical schools, had significantly higher quality ratings. Further research is needed to determine characteristics of medical students that predict performance during neurology residency. PMID- 26038280 TI - Delayed thromboembolic events more than 30 days after self expandable intracranial stent-assisted embolization of unruptured intracranial aneurysms. AB - OBJECTIVE: The Enterprise stent is used for endovascular treatment of complex intracranial aneurysms. The purpose of this study was to evaluate delayed thromboembolic events (DTEs) that developed more than 30 days after Enterprise stent-assisted embolization (SAC) and its associated risk factors. METHODS: There were 125 consecutive patients (90 women and 35 men; mean age, 56.1 years) who received endovascular treatment for 126 complex intracranial aneurysms using the Enterprise stent during December 2008 to May 2011. A DTE was defined as a symptomatic or asymptomatic ischemic stroke with positive findings on brain magnetic resonance imaging in the territory of the treated aneurysm and transient ischemic attack. Asymptomatic in-stent stenosis and occlusion were excluded. RESULTS: During a mean follow-up of 32.4 months, DTEs occurred in 10 patients (7.93%). DTEs occurred on antiplatelet therapy (dual medication, n = 2, 2 months after embolization; single medication, n = 6, 10-20 months after SAC) or after discontinuation of antiplatelet therapy (n = 2, 14 months after embolization). Multivariate analysis showed that current smoking (p = 0.005) and maximum parent artery diameter >4.5mm (p = 0.003) were associated with DTE. CONCLUSIONS: SAC with the Enterprise stent poses a considerable risk of DTE. Our results suggest that a longer duration of antiplatelet therapy and clinical follow-up may be warranted for cases with suggested risk factors. The protocol for antiplatelet therapy after SAC should be determined in a large prospective trial. PMID- 26038281 TI - Personalised approach to treating early Hodgkin's lymphoma. PMID- 26038282 TI - Frontiers in Medicinal Chemistry 2015: Meet the Experts of MedChem near the Cradle of Medicinal and Pharmaceutical Chemistry. AB - Pioneering inspiration: Right next to the former laboratories of Johannes Hartmann, the first so-called "Professor of Chymiatrie", the 2015 Frontiers in Medicinal Chemistry meeting was held last March at Philipps University in Marburg, Germany. Herein we give readers an idea of what it was like to attend the conference, which was organized jointly by the DPhG, GDCh, and SCS. Along with the lectures, we also describe the poster sessions, social program, and awards. PMID- 26038283 TI - An epidemological study of obsessive compulsive disorder in adolescents from India. AB - OBJECTIVES: There is scarce data on the prevalence of OCD among adolescents in India. This study reports point prevalence of OCD among school students (age 12 18years) in the Kerala state of India and examines its association with ADHD, psychological distress, tobacco/alcohol abuse, suicide risk and history of sexual abuse. METHOD: 7560 students of 73 schools were self-administered the OCD subsection of Clinical Interview Schedule-Revised, the Composite International Diagnostic Interview (CIDI) for obsessive compulsive symptoms and other relevant instruments to identify OCD and related clinical measures. A diagnosis of ICD-10 OCD was derived through the CIS-R algorithm which required duration of at least 2weeks and at least a thought/behavior to be resisted along with a cut-off score for severity and impairment. RESULTS: In the sample, 50.3% were males with a mean age of 15.2years (range of 12-18years). The response rate was 97.3% (7380 valid responses). 0.8% (n=61) fulfilled criteria for OCD with a male predominance (1.1 vs. 0.5%, p=0.005). Prevalence was higher among Muslims and increased with age. Taboo thoughts (62.3%) and mental rituals (45.9%) were the commonest symptoms. Those with OCD had significantly higher suicidal thoughts (59 vs. 16.3%, p<0.01) suicide attempts (24.6 vs. 3.8%, p<0.01), ADHD (28 vs. 4%, p<0.001), sexual abuse (24.6 vs. 4.2%, p<0.01), and tobacco use (23 vs. 6.8%, p=0.01). They also reported greater psychological distress and poorer academic performance. CONCLUSIONS: OCD is common among adolescents in India. Its associations with ADHD, sexual abuse, psychological distress, poorer academic performance and suicidal behavior are additional reasons for it to be recognized and treated early. PMID- 26038284 TI - Bronchiectasis and gastro-oesophageal reflux; some progress but still a long way to go. PMID- 26038285 TI - Current structural biology of the heparin interactome. AB - Heparin is the best known therapeutically active carbohydrate. It can bind and regulate multiple functional proteins such as coagulation cofactors, chemokines, and growth factors. This versatility has led to the recently developed concept of the heparin interactome--a group of proteins that, as the name implies, interact with heparin. The heparin interactome is structurally and functionally diverse. Though natural ligands of this class of proteins may be any of the glycosaminoglycans however, their structural biology is generally studied using heparin as a model compound. NMR spectroscopy contributes significantly to structural investigations of the resultant complexes in solution. This review aims therefore at discussing the current status in structural biology of the molecular complexes formed between heparin and its protein partners through the current concept of the heparin interactome. PMID- 26038286 TI - Hydrogen peroxide mediated the neurotoxicity of an antibody against plasmalemmal neuronspecific enolase in primary cortical neurons. AB - Neuron-specific enolase (NSE) is not only a glycolytic enzyme in the cytosol, but also localized in the synaptic plasma membrane. The plasmalemmal NSE is one of autoantigen targets in post-streptococcal autoimmune central nervous system disease. Although anti-neuronal antibodies in patients bind to a restricted group of NSE in cerebral cortex, it has not yet been clarified how the anti-NSE antibody have negative impacts on cortical neurons. Here, we found that NSE was also localized at neuronal cell bodies and neuritis on the neuronal cell surface in the primary culture of rat cortical neurons. The anti-NSE antibody induced neuronal cell death in a concentration-dependent manner. The neuronal cell death required a lag time and was not accompanied with caspase-3 activation and chromatin condensation. The anti-NSE antibody elevated a level of intracellular H2O2 prior to neuronal cell death. Catalase protected neurons from the anti-NSE antibody-induced H2O2 generation and cell death. The post-treatment of neurons with catalase after the application of the anti-NSE antibody exhibited neuroprotective effects as well as the co-treatment. The cascade of mitogen activated protein kinase (MAPK) is one of signal transductions of H2O2. Among MAPK, a c-Jun N-terminal kinase partially contributed to the neurotoxicity of anti-NSE antibody. Thus, the anti-NSE antibody acted at the plasmalemmal NSE, produced H2O2, and caused neuronal cell death via non-apoptotic pathway in the cortical neurons. PMID- 26038287 TI - Prognostic factors and immunobiologic insights into Merkel cell carcinoma. PMID- 26038288 TI - Myocyte enhancer factor 2D regulates ectoderm specification and adhesion properties of animal cap cells in the early Xenopus embryo. AB - In Xenopus, animal cap (AC) cells give rise to ectoderm and its derivatives: epidermis and the central nervous system. Ectoderm has long been considered a default pathway of embryonic development, with cells that are not under the influence of vegetal Nodal signaling adopting an ectodermal program of gene expression. In the present study, we describe the involvement of the animally localized maternal transcription factor myocyte enhancer factor (Mef) 2D in regulating the identity of AC cells. We find that Mef2D is required for the formation of both ectodermal lineages: neural and epidermis. Gain and loss of function experiments indicate that Mef2D regulates early gastrula expression of key ectodermal/epidermal genes in the animal region. Mef2D controls the activity of zygotic bone morphogenetic protein (BMP) signaling known to dictate the epidermal differentiation program. Exogenous expression of Mef2D in vegetal blastomeres was sufficient to induce ectopic expression of ectoderm/epidermal genes in the vegetal half of the embryo, when Nodal signaling was inhibited. Depletion of Mef2D caused a loss of AC cell adhesion that was rescued by the expression of E-cadherin or bone morphogenetic protein 4. In addition, expression of Mef2D in the prospective endoderm caused unusual aggregation of vegetal cells with animal cells in vitro and inappropriate segregation to other germ layers in vivo. Mef2D cooperates with another animally-expressed transcription factor, FoxI1e. Together, they regulate the expression of genes encoding signaling proteins and the transcription factors that control the regional identity of animal cells. Therefore, we describe a new role for the animally-localized Mef2D protein in early ectoderm specification, which is similar to that of the vegetally-localized VegT in endoderm and mesoderm formation. PMID- 26038289 TI - Latent tuberculosis infection--Revisiting and revising concepts. AB - Host- and pathogen-specific factors interplay with the environment in a complex fashion to determine the outcome of infection with Mycobacterium tuberculosis (Mtb), resulting in one of three possible outcomes: cure, latency or active disease. Although much remains unknown about its pathophysiology, latent tuberculosis infection (LTBI) defined by immunologic evidence of Mtb infection is a continuum between self-cure and asymptomatic, yet active tuberculosis (TB) disease. Strain virulence, intensity of exposure to the index case, size of the bacterial inoculum, and host factors such as age and co-morbidities, each contribute to where one settles on the continuum. Currently, the diagnosis of LTBI is based on reactive tuberculin skin testing (TST) and/or a positive interferon-gamma release assay (IGRA). Neither diagnostic test reflects the activity of the infectious focus or the risk of progression to active TB. This is a critical shortcoming, as accurate and efficient detection of those with LTBI at higher risk of progression to TB disease would allow for provision of targeted preventive therapy to those most likely to benefit. Host biomarkers may prove of value in stratifying risk of development of TB. New guidelines are required for interpretation of discordance between TST and IGRA, which may be due in part to a lack of stability (that is reproducibility) of IGRA or TST results or to a delay in conversion of IGRA to positivity compared to TST. In this review, the authors elaborate on the definition, diagnosis, pathophysiology and natural history of LTBI, as well as promising methods for better stratifying risk of progression to TB. The review is centered on the human host and the clinical and epidemiologic features of LTBI that are relevant to the development of new and improved diagnostic tools. PMID- 26038290 TI - The antimicrobial effect of colistin methanesulfonate on Mycobacterium tuberculosis in vitro. AB - Polymyxins have previously been described to have activity against Mycobacterium tuberculosis (MTB), but further research was abandoned due to systemic toxicity concerns to achieve the required MIC. Colistin methanesulfonate (CMS), a polymyxin, is well tolerated when inhaled directly into the lungs, resulting in high local concentrations. We report here for the first time, MIC and MBC data for CMS determined by the microtiter Alamar Blue assay (MABA). We also determined how the MIC would be affected by the presence of pulmonary surfactant (PS) and if any synergy with isoniazid (INH) and rifampicin (RIF) exists. The effect of CMS on the ultrastructure of MTB was also determined. The MIC for CMS was 16 mg/L, while the MBC was 256 mg/L. MIC for CMS in PS was antagonised by eight fold. For synergy, indifference was determined while time-kill assays revealed a greater killing effect when CMS was used together with INH. Ultrastructure analysis suggests that the disruption of the outer polysaccharide layer of MTB by CMS may lead to enhanced uptake of INH. Our findings may provide insight for further investigations of CMS against MTB. PMID- 26038291 TI - Transport of lipopolysaccharide to the Gram-negative bacterial cell surface. AB - Lipopolysaccharides (LPS) are major lipidic components of the outer membrane of most Gram-negative bacteria. They form a permeability barrier that protects these bacteria from harmful compounds in the environment. In addition, they are important signaling molecules for the innate immune system. The mechanism of transport of these molecules to the bacterial cell surface has remained enigmatic for a long time. However, intense research during the last decade, particularly in Escherichia coli and Neisseria meningitidis, has led to the identification of the machinery that mediates LPS transport. In this review, we summarize the current knowledge of the LPS transport machinery and provide an overview of the distribution of the components of this machinery among diverse bacteria, even organisms that don't produce LPS. We also discuss the current insights in the regulation of LPS biosynthesis. PMID- 26038292 TI - Erratum to: Comparison of salivary and calculated free cortisol levels during low and standard dose of ACTH stimulation tests in healthy volunteers. PMID- 26038293 TI - Is laparoscopic treatment of incisional and recurrent hernias associated with an increased risk for complications? AB - INTRODUCTION: Hernias of the ventral abdominal wall can be treated with an intraperitoneal onlay mesh (IPOM). The aim of this cohort study was to analyze the complications and recurrence rates after laparoscopic ventral hernia repair focusing especially on incisional and recurrent hernias. METHODS: The study population comprised 149 patients with a hernia of the abdominal wall, which was treated with an IPOM between January 2006 and January 2011. RESULTS: Fifty-one patients had a primary hernia (group I) and 98 patients had preceding abdominal surgery (group II). In group II 64 patients had an incisional hernia and 34 patients had a recurrent hernia. The median body mass index was 30.3 kg/m(2) (14.8-69.1) without any significance in sub-group comparison. The mean duration of surgery and the length of stay were significantly longer in group II (p < 0.05). The overall rate of minor complications was 18.1%. There were significantly more minor complications in group II (7.8% vs. 23.5%, p = 0.02). Notably, there were also significantly more major complications in group II (14.3% vs. 2.0%; p = 0.02). The recurrence rate was significantly higher in group II (group I: 3.9% vs. group II: 16.3%, p < 0.05). There were no early recurrences in group I, but 5 early recurrences in group II. CONCLUSION: Laparoscopic treatment of complex hernias as incisional hernias, recurrent hernias and hernias with interenteric and enteroperitoneal adhesions is associated with high rates of minor and major complications. A high level of expertise of the surgeon and the camera-guiding assistant is therefore needed. PMID- 26038294 TI - Genetics and ethics: a possible and necessary dialogue. AB - Genetics and ethics have had numerous convergences and divergences over time. From Darwin through the Asilomar Conference and the Universal Declaration on the Human Genome and Human Rights, much has been achieved, but much still remains to be done. The use of biological materials that are already being stored and the adequacy of new technologies, such as clustered regularly interspaced short palindromic repeats (CRISPR), are some of the current challenges of this possible and necessary interaction. This paper will discuss some ethical aspects involved in current genetics. PMID- 26038295 TI - The Interaction of Voluntary Running Exercise and Food Restriction Induces Low Bone Strength and Low Bone Mineral Density in Young Female Rats. AB - There is a concern that the combination of exercise with food intake reduction has a risk of reducing bone strength and bone mass in young female athletes. We examined the influence of the interaction of voluntary running exercise and food restriction on bone in young female rats. Seven-week-old female Sprague-Dawley rats were divided into four groups: the sedentary and ad libitum feeding group (SED), voluntary running exercise and ad libitum feeding group (EX), sedentary and 30 % food restriction group (SED-FR), and voluntary running exercise and 30 % food restriction group (EX-FR). The experiment lasted 12 weeks. Statistical analysis was carried out by two-way analysis of variance with exercise and restriction as the between-subjects factors. As a result, there were significant interactions of running and restriction on energy availability, breaking force, breaking energy, and bone mineral density (BMD). Breaking force and energy in the EX group were significantly higher than in the SED group; breaking force and energy were significantly lower in the EX-FR group than in the EX group, and breaking force in the EX-FR group was significantly lower than that in the SED-FR group. BMD in the EX-FR group was significantly lower than in the EX and SED-FR groups. These results suggest that food restriction induced low bone strength in young female rats engaging in voluntary running exercise. Also, through the interaction of exercise and food restriction, voluntary running exercise combined food restriction, unlike ad libitum feeding conditions, induced low bone strength, and low BMD in young female rats. PMID- 26038296 TI - Policy Makers' Views of Obesity-Related Challenges Around the World : An interview between Pierre Cremieux (of Analysis Group, Inc., and Guest Editor of this Special Issue) and policy makers from Brazil (Patricia Constante Jaime), Canada (Kimberly Elmslie), China (Bin Wang), France (Francois Cremieux), and the USA (Mark McClellan). PMID- 26038298 TI - Evidence analysis library review of best practices for performing indirect calorimetry in healthy and non-critically ill individuals. AB - When measurement of resting metabolic rate (RMR) by indirect calorimetry is necessary, following evidence-based protocols will ensure the individual has achieved a resting state. The purpose of this project was to update the best practices for measuring RMR by indirect calorimetry in healthy and non-critically ill adults and children found the Evidence Analysis Library of the Academy of Nutrition and Dietetics. The Evidence Analysis process described by the Academy of Nutrition and Dietetics was followed. The Ovid database was searched for papers published between 2003 and 2012 using key words identified by the work group and research consultants, studies used in the previous project were also considered (1980 to 2003), and references were hand searched. The work group worked in pairs to assign papers to specific questions; however, the work group developed evidence summaries, conclusion statements, and recommendations as a group. Only 43 papers were included to answer 21 questions about the best practices to ensure an individual is at rest when measuring RMR in the non critically ill population. In summary, subjects should be fasted for at least 7 hours and rest for 30 minutes in a thermoneutral, quiet, and dimly lit room in the supine position before the test, without doing any activities, including fidgeting, reading, or listening to music. RMR can be measured at any time of the day as long as resting conditions are met. The duration of the effects of nicotine and caffeine and other stimulants is unknown, but lasts longer than 140 minutes and 240 minutes, respectively. The duration of the effects of various types of exercise on RMR is unknown. Recommendations for achieving steady state, preferred gas-collection devices, and use of respiratory quotient to detect measurement errors are also given. Of the 21 conclusions statements developed in this systemic review, only 5 received a grade I or II. One limitation is the low number of studies available to address the questions and most of the included studies had small sample sizes and were conducted in healthy adults. More research on how to conduct an indirect calorimetry measurement in healthy adults and children and in sick, but not critically ill, individuals is needed. PMID- 26038297 TI - Bone Mineral Density and Protein-Derived Food Clusters from the Framingham Offspring Study. AB - BACKGROUND: Dietary protein is beneficial to bone health; however, dietary patterns of protein intake and their relationship with bone mineral density (BMD) have not been evaluated. OBJECTIVE: To examine the relationship of dietary protein food clusters with BMD at the femoral neck, trochanter, total femur, and lumbar spine among middle-aged and older men and women. DESIGN: Cross-sectional study. PARTICIPANTS AND SETTING: Two thousand seven hundred fifty-eight community dwelling individuals from the Framingham Offspring Study. METHODS: BMD was measured by Lunar DPX-L (Lunar Radiation Corporation) in 1996-2001. Dietary intakes were estimated using the Willett food frequency questionnaire in either 1995-1998 or 1998-2001, and the exam closest to a participant's BMD measurement was used. Cluster analysis (FASTCLUS procedure, k-means method) was used to classify participants into groups, determined by major sources of protein. Generalized linear regression was used to compare adjusted least-squares mean BMD across protein food clusters for all pairwise comparisons. RESULTS: From 2,758 participants (44% men; mean age 61+/-9 years, range=29 to 86 years), five protein food clusters were identified (chicken, fish, processed foods, red meat, and low fat milk). Three of these food clusters showed associations with BMD. The red meat protein food cluster presented with significantly lower femoral neck BMD compared with the low-fat milk cluster (red meat 0.898+/-0.005 g/cm(2) vs low-fat milk 0.919+/-0.007 g/cm(2); P=0.04). Further, the processed foods protein cluster presented with significantly lower femoral neck BMD compared with the low-fat milk cluster (processed foods 0.897+/-0.004 g/cm(2) vs low-fat milk 0.919+/-0.007 g/cm(2); P=0.02). A similar, yet nonsignificant, trend was observed for other BMD sites examined. CONCLUSIONS: Diets with the greatest proportion of protein intake from red meat and processed foods may not be as beneficial to the skeleton compared with dietary patterns where the highest proportion of protein is derived from low-fat milk. PMID- 26038299 TI - SRT1720 counteracts glucosamine-induced endoplasmic reticulum stress and endothelial dysfunction. AB - AIMS: We hypothesized that a disproportionate activation of the glucosamine (GlcN) pathway, caused by a prolonged exposure to hyperglycaemia, could impair endothelial integrity promoting endoplasmic reticulum (ER) stress. We also tested the possibility that SRT1720 may be able to counteract GlcN-induced ER stress. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs), human cardiac microvascular endothelial cells, and human retinal endothelial cells were treated with GlcN in the presence or absence of the chemical chaperone phenyl butyric acid (PBA) or SRT1720. Expression of ER stress markers, activation of apoptosis, and pro-inflammatory/pro-thrombotic pathways were evaluated by western blot, real-time RT-PCR, and ELISA assays. GlcN treatment resulted in a significantly increased expression of the major ER stress mediators. ER stress activation was paralleled by increased levels of apoptotic markers and by pro inflammatory/pro-coagulant pathway activation. In HUVECs, ER stress inhibition by PBA alleviated a GlcN-induced pro-apoptotic and pro-inflammatory/pro-thrombotic state, suggesting a crucial role of ER stress in endothelial dysfunction caused by GlcN. Furthermore, SRT1720 treatment abolished GlcN-induced ER stress and reversed its effects on apoptosis and pro-inflammatory/pro-coagulant pathways. This SRT1720 action was mediated by its ability to modulate Raptor acetylation, thus inhibiting mammalian target of Rapamycin complex 1 (mTORC1)-dependent protein synthesis and alleviating ER overload. CONCLUSIONS: Our data show that GlcN promotes a pro-apoptotic and pro-inflammatory/pro-thrombotic phenotype in endothelial cells by activating ER stress. The observation that SRT1720, inhibiting ER stress, was able to counteract GlcN effects lays the basis for future studies aimed to exploit this drug and cognate compounds in the treatment of endothelial dysfunction and atherosclerosis. PMID- 26038300 TI - Classical pathway deficiencies - A short analytical review. AB - Deficiencies in the classical pathway of complement activation have some common features but show also great differences. Deficiencies of each of the components (C1q, C1s, C1r, C4 and C2) imply increased susceptibility to bacterial infections. They are also associated with increased risk to develop systemic lupus erythematosus where deficiency of C1q is strongly associated to the disease while C4 less and C2 much less. Deficiency of C1q affects only activation of the classical pathway while deficiency of C4 and C2 also prevent activation of the lectin pathway. Bypass mechanisms may result in complement activation also in absence of C2 but not in absence of C1q or C4. The genes for C2 and C4 isotypes are closely located within the MHC class III region on chromosome 6p and the genes for the 3 C1q chains are on chromosome 1p. Deficiencies of C1q and of C4 show genetic heterogeneity while deficiency of C2 in the great majority of cases is caused by a specific deletion. The production of C4 and C2 is mainly by the hepatocytes in the liver while C1q is produced by monocytic bone marrow derived cells. This has implications for the possibility to treat the deficiency and hematopoietic stem cell transplantation has been tried in C1q deficiency. PMID- 26038301 TI - S100A9-induced release of interleukin (IL)-6 and IL-8 through toll-like receptor 4 (TLR4) in human periodontal ligament cells. AB - S100A8, S100A9, and calprotectin (the S100A8/S100A9 complex) are calcium-binding proteins that promote extracellular pro-inflammatory functions and may play an important role in periodontal disease. Both toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-products (RAGE) are thought to be important receptors for S100A8, S100A9, and calprotectin, but the specific pathways in periodontal ligament (PDL) cells are not yet clear. Our study was designed to identify the specific receptors for S100A9 in human PDL cells. Additionally, we investigated the specific pathways that activate the secretion of pro inflammatory cytokines interleukins (IL)-6 and IL-8 in PDL cells. The role of nuclear factor (NF)-kappaB, mitogen-activated protein kinase (MAPK) and reactive oxygen species (ROS) in S100A9-induced pro-inflammatory cytokines were investigated through western blot analysis, dichlorodihydrofluorescein diacetate (H2DCFDA) probe and the application of specific pathway inhibitors. Our results suggest that the S100A9-induced release of IL-6 and IL-8 from human PDL cells is dependent on TLR4, but not RAGE. We provide evidence that S100A9 promotes the secretion of IL-6 and IL-8 through different pathways. Specifically, S100A9 up regulates the secretion of IL-6 from human PDL cells through NF-kappaB and p38 pathways and up-regulates the release of IL-8 from human PDL cells through the NF kappaB, extracellular-regulated kinase (ERK) 1/2, c-Jun amino-terminal kinase (JNK) 1/2, and p38 signaling pathways. In addition, the release of both cytokines depends on ROS production. The release of both cytokines depends on ROS production. These results suggest that S100A9 promotes pro-inflammatory responses in PDL cells through the TLR4-mediated NF-kappaB and MAPK signaling pathways. PMID- 26038302 TI - Tarantula myosin free head regulatory light chain phosphorylation stiffens N terminal extension, releasing it and blocking its docking back. AB - Molecular dynamics simulations of smooth and striated muscle myosin regulatory light chain (RLC) N-terminal extension (NTE) showed that diphosphorylation induces a disorder-to-order transition. Our goal here was to further explore the effects of mono- and diphosphorylation on the straightening and rigidification of the tarantula myosin RLC NTE. For that we used MD simulations followed by persistence length analysis to explore the consequences of secondary and tertiary structure changes occurring on RLC NTE following phosphorylation. Static and dynamic persistence length analysis of tarantula RLC NTE peptides suggest that diphosphorylation produces an important 24-fold straightening and a 16-fold rigidification of the RLC NTE, while monophosphorylation has a less profound effect. This new information on myosin structural mechanics, not fully revealed by previous EM and MD studies, add support to a cooperative phosphorylation dependent activation mechanism as proposed for the tarantula thick filament. Our results suggest that the RLC NTE straightening and rigidification after Ser45 phosphorylation leads to a release of the constitutively Ser35 monophosphorylated free head swaying away from the thick filament shaft. This is so because the stiffened diphosphorylated RLC NTE would hinder the docking back of the free head after swaying away, becoming released and mobile and unable to recover its original interacting position on activation. PMID- 26038303 TI - Chemical ecology of fungi. AB - Fungi are widespread in nature and have conquered nearly every ecological niche. Fungi occur not only in terrestrial but also in freshwater and marine environments. Moreover, fungi are known as a rich source of secondary metabolites. Despite these facts, the ecological role of many of these metabolites is still unknown and the chemical ecology of fungi has not been investigated systematically so far. This review intends to present examples of the various chemical interactions of fungi with other fungi, plants, bacteria and animals and to give an overview of the current knowledge of fungal chemical ecology. PMID- 26038305 TI - Ruptured carotid aneurysm revealing a Behcet's disease. AB - We report the case of a 20-year-old male who was operated for a large ruptured aneurysm of the right common carotid artery, revealing a Behcet's disease. The aneurysm was excised and the right common carotid artery was repaired with a polytetrafluoroethylene prosthesis. None of the criteria of the International Study Group for Behcet's disease was present at the time of the diagnosis. PMID- 26038306 TI - Comprehensive transcript profiling of two grapevine rootstock genotypes contrasting in drought susceptibility links the phenylpropanoid pathway to enhanced tolerance. AB - In light of ongoing climate changes in wine-growing regions, the selection of drought-tolerant rootstocks is becoming a crucial factor for developing a sustainable viticulture. In this study, M4, a new rootstock genotype that shows tolerance to drought, was compared from a genomic and transcriptomic point of view with the less drought-tolerant genotype 101.14. The root and leaf transcriptome of both 101.14 and the M4 rootstock genotype was analysed, following exposure to progressive drought conditions. Multifactorial analyses indicated that stress treatment represents the main factor driving differential gene expression in roots, whereas in leaves the genotype is the prominent factor. Upon stress, M4 roots and leaves showed a higher induction of resveratrol and flavonoid biosynthetic genes, respectively. The higher expression of VvSTS genes in M4, confirmed by the accumulation of higher levels of resveratrol in M4 roots compared with 101.14, was coupled to an up-regulation of several VvWRKY transcription factors. Interestingly, VvSTS promoter analyses performed on both the resequenced genomes highlighted a significantly higher number of W-BOX elements in the tolerant genotype. It is proposed that the elevated synthesis of resveratrol in M4 roots upon water stress could enhance the plant's ability to cope with the oxidative stress usually associated with water deficit. PMID- 26038304 TI - Physiological mechanisms and therapeutic potential of bone mechanosensing. AB - Skeletal loading is an important physiological regulator of bone mass. Theoretically, mechanical forces or administration of drugs that activate bone mechanosensors would be a novel treatment for osteoporotic disorders, particularly age-related osteoporosis and other bone loss caused by skeletal unloading. Uncertainty regarding the identity of the molecular targets that sense and transduce mechanical forces in bone, however, has limited the therapeutic exploitation of mechanosesning pathways to control bone mass. Recently, two evolutionally conserved mechanosensing pathways have been shown to function as "physical environment" sensors in cells of the osteoblasts lineage. Indeed, polycystin-1 (Pkd1, or PC1) and polycystin-2 (Pkd2, or PC2' or TRPP2), which form a flow sensing receptor channel complex, and TAZ (transcriptional coactivator with PDZ-binding motif, or WWTR1), which responds to the extracellular matrix microenvironment act in concert to reciprocally regulate osteoblastogenesis and adipogenesis through co-activating Runx2 and a co-repressing PPARgamma activities. Interactions of polycystins and TAZ with other putative mechanosensing mechanism, such as primary cilia, integrins and hemichannels, may create multifaceted mechanosensing networks in bone. Moreover, modulation of polycystins and TAZ interactions identify novel molecular targets to develop small molecules that mimic the effects of mechanical loading on bone. PMID- 26038308 TI - Gestational age and adolescent mental health: evidence from Hong Kong's 'Children of 1997' birth cohort. AB - BACKGROUND: Preterm, and more recently early term, birth has been identified as a risk factor for poor health. Whether the sequelae of late preterm or early term birth extends to poor mental health and well-being in adolescence is unclear and has not been systematically assessed. METHOD: Linear regression was used to assess the adjusted associations of gestational age (very/moderate preterm (<34 weeks, n=85), late preterm (34-36 weeks, n=305), early term (37-38 weeks, n=2228), full term (39-40 weeks, n=4018), late term (41 weeks, n=809), post-term (>=42 weeks, n=213)) with self-reported self-esteem at ~11 years (n=6935), parent reported Rutter score assessing the common emotional and behavioural problems at ~7 years (n=6292) and ~11 years (n=5596) and self-reported depressive symptoms at ~13 years (n=5795) in a population-representative Hong Kong Chinese birth cohort 'Children of 1997' where gestational age has little social patterning. RESULTS: Very/moderate preterm birth was associated with higher Rutter subscore for hyperactivity (beta coefficients 0.5, 95% CI 0.01 to 1.00) at ~7 years but not at ~11 years, adjusted for sex, age, socio-economic position, parents' age at birth, birth order and secondhand smoke exposure. Similarly adjusted, late preterm, early term, late term and post-term birth were not associated with self-esteem or depressive symptoms. CONCLUSIONS: In a population-representative birth cohort from a non-Western-developed setting, gestational age had few associations with mental health and well-being in adolescence, whereas very preterm birth was specifically associated with hyperactivity in childhood. Inconsistencies with studies from Western settings suggest setting specific unmeasured confounding may underlie any observed associations. PMID- 26038307 TI - Nitrogen deficiency in barley (Hordeum vulgare) seedlings induces molecular and metabolic adjustments that trigger aphid resistance. AB - Agricultural nitrous oxide (N2O) pollution resulting from the use of synthetic fertilizers represents a significant contribution to anthropogenic greenhouse gas emissions, providing a rationale for reduced use of nitrogen (N) fertilizers. Nitrogen limitation results in extensive systems rebalancing that remodels metabolism and defence processes. To analyse the regulation underpinning these responses, barley (Horedeum vulgare) seedlings were grown for 7 d under N deficient conditions until net photosynthesis was 50% lower than in N-replete controls. Although shoot growth was decreased there was no evidence for the induction of oxidative stress despite lower total concentrations of N-containing antioxidants. Nitrogen-deficient barley leaves were rich in amino acids, sugars and tricarboxylic acid cycle intermediates. In contrast to N-replete leaves one day-old nymphs of the green peach aphid (Myzus persicae) failed to reach adulthood when transferred to N-deficient barley leaves. Transcripts encoding cell, sugar and nutrient signalling, protein degradation and secondary metabolism were over-represented in N-deficient leaves while those associated with hormone metabolism were similar under both nutrient regimes with the exception of mRNAs encoding proteins involved in auxin metabolism and responses. Significant similarities were observed between the N-limited barley leaf transcriptome and that of aphid-infested Arabidopsis leaves. These findings not only highlight significant similarities between biotic and abiotic stress signalling cascades but also identify potential targets for increasing aphid resistance with implications for the development of sustainable agriculture. PMID- 26038310 TI - Do antibiotics cause obesity? PMID- 26038309 TI - Influence of adiposity on health-related quality of life in the Gateshead Millennium Study cohort: longitudinal study at 12 years. AB - OBJECTIVE: To examine whether adiposity is associated with an impaired quality of life (an individual's perception of their life) in general population samples in early adolescence. DESIGN AND METHODS: Relationships between a direct measure of adiposity (fat mass index from bioimpedance) and a proxy measure (waist circumference), and a generic (KIDSCREEN-27) and a weight-specific measure of health-related quality of life (HRQoL, Impact of Weight on Quality of Life-Kids (IWQOL-Kids)) were examined in a longitudinal population-based cohort of young adolescents aged 12 years (n=519). The effects of change in adiposity over time (from 7 years and 9 years) were also examined (n=331-445 in longitudinal analyses). RESULTS: Impairment in HRQoL was associated with current adiposity but it was not predicted by earlier adiposity. At 12 years, higher adiposity was associated with lower Physical Well-Being on KIDSCREEN-27, and with lower Total Scores on the weight-specific IWQOL-Kids instrument, the latter particularly in girls. CONCLUSIONS: Health and education professionals need to be aware in their clinical practice that higher adiposity impairs HRQoL in general populations of young adolescents. Further research would be useful to determine whether or not children of primary school age self-reporting lower HRQoL are more likely to develop higher adiposity later in adolescence or early adulthood. PMID- 26038311 TI - Synthesis of oxazoles by silver catalysed oxidative decarboxylation-cyclization of alpha-oxocarboxylates and isocyanides. AB - A silver catalysed synthesis of oxazoles by the oxidative decarboxylation cyclization of alpha-oxocarboxylates and isocyanides was developed. This method provided a novel strategy to construct oxazole rings compared to traditional methods. Mechanistic investigations such as operando IR, EPR and radical inhibition experiments were carefully done and confirmed the acyl cation and Ag(II) as the intermediates in this transformation, and the involvement of a radical decarboxylative process. PMID- 26038312 TI - Bacteriophage Xp10 anti-termination factor p7 induces forward translocation by host RNA polymerase. AB - Regulation of transcription elongation is based on response of RNA polymerase (RNAP) to various pause signals and is modulated by various accessory factors. Here we report that a 7 kDa protein p7 encoded by bacteriophage Xp10 acts as an elongation processivity factor of RNAP of host bacterium Xanthomonas oryzae, a major rice pathogen. Our data suggest that p7 stabilizes the upstream DNA duplex of the elongation complex thus disfavouring backtracking and promoting forward translocated states of the elongation complex. The p7-induced 'pushing' of RNAP and modification of RNAP contacts with the upstream edge of the transcription bubble lead to read-through of various types of pauses and termination signals and generally increase transcription processivity and elongation rate, contributing for transcription of an extremely long late genes operon of Xp10. Forward translocation was observed earlier upon the binding of unrelated bacterial elongation factor NusG, suggesting that this may be a general pathway of regulation of transcription elongation. PMID- 26038313 TI - RNautophagy/DNautophagy possesses selectivity for RNA/DNA substrates. AB - Lysosomes can degrade various biological macromolecules, including nucleic acids, proteins and lipids. Recently, we identified novel nucleic acid-degradation systems termed RNautophagy/DNautophagy (abbreviated as RDA), in which RNA and DNA are directly taken up by lysosomes in an ATP-dependent manner and degraded. We also found that a lysosomal membrane protein, LAMP2C, the cytoplasmic region of which binds to RNA and DNA, functions, at least in part, as an RNA/DNA receptor in the process of RDA. However, it has been unclear whether RDA possesses selectivity for RNA/DNA substrates and the RNA/DNA sequences that are recognized by LAMP2C have not been determined. In the present study, we found that the cytosolic region of LAMP2C binds to poly-G/dG, but not to poly-A/dA, poly-C/dC, poly-dT or poly-U. Consistent with this binding activity, poly-G/dG was transported into isolated lysosomes via RDA, while poly-A/dA, poly-C/dC, poly-dT and poly-U were not. GGGGGG or d(GGGG) sequences are essential for the interaction between poly-G/dG and LAMP2C. In addition to poly-G/dG, G/dG-rich sequences, such as a repeated GGGGCC sequence, interacted with the cytosolic region of LAMP2C. Our findings indicate that RDA does possess selectivity for RNA/DNA substrates and that at least some consecutive G/dG sequence(s) can mediate RDA. PMID- 26038314 TI - TBP-like protein (TLP) interferes with Taspase1-mediated processing of TFIIA and represses TATA box gene expression. AB - TBP-TFIIA interaction is involved in the potentiation of TATA box-driven promoters. TFIIA activates transcription through stabilization of TATA box-bound TBP. The precursor of TFIIA is subjected to Taspase1-directed processing to generate alpha and beta subunits. Although this processing has been assumed to be required for the promoter activation function of TFIIA, little is known about how the processing is regulated. In this study, we found that TBP-like protein (TLP), which has the highest affinity to TFIIA among known proteins, affects Taspase1 driven processing of TFIIA. TLP interfered with TFIIA processing in vivo and in vitro, and direct binding of TLP to TFIIA was essential for inhibition of the processing. We also showed that TATA box promoters are specifically potentiated by processed TFIIA. Processed TFIIA, but not unprocessed TFIIA, associated with the TATA box. In a TLP-knocked-down condition, not only the amounts of TATA box bound TFIIA but also those of chromatin-bound TBP were significantly increased, resulting in the stimulation of TATA box-mediated gene expression. Consequently, we suggest that TLP works as a negative regulator of the TFIIA processing and represses TFIIA-governed and TATA-dependent gene expression through preventing TFIIA maturation. PMID- 26038316 TI - Lack of correlation between Legionella colonization and microbial population quantification using heterotrophic plate count and adenosine triphosphate bioluminescence measurement. AB - This investigation compared biological quantification of potable and non-potable (cooling) water samples using pour plate heterotrophic plate count (HPC) methods and adenosine triphosphate (ATP) concentration measurement using bioluminescence. The relationship between these measurements and the presence of Legionella spp. was also examined. HPC for potable and non-potable water were cultured on R2A and PCA, respectively. Results indicated a strong correlation between HPC and ATP measurements in potable water (R = 0.90, p < 0.001). In the make-up water and two cooling towers, the correlations between ATP and HPC were much weaker but statistically significant (make-up water: R = 0.37, p = 0.005; cooling tower 1: R = 0.52, p < 0.001; cooling tower 2: R = 0.54, p < 0.001). For potable and non potable samples, HPC exhibited higher measurement variability than ATP. However, ATP measurements showed higher microbial concentrations than HPC measurements. Following chlorination of the cooling towers, ATP measurements indicated very low bacterial concentrations (<10 colony-forming units (CFU)/mL) despite high HPC concentrations (>1000 CFU/mL) which consisted primarily of non-tuberculous mycobacteria. HPC concentrations have been suggested to be predictive of Legionella presence, although this has not been proven. Our evaluation showed that HPC or ATP demonstrated a fair predictive capacity for Legionella positivity in potable water (HPC: receiver operating characteristic (ROC) = 0.70; ATP: ROC = 0.78; p = 0.003). However, HPC or ATP correctly classified sites as positive only 64 and 62% of the time, respectively. No correlation between HPC or ATP and Legionella colonization in non-potable water samples was found (HPC: ROC = 0.28; ATP: ROC = 0.44; p = 0.193). PMID- 26038315 TI - PRC2 regulates RNA polymerase III transcribed non-translated RNA gene transcription through EZH2 and SUZ12 interaction with TFIIIC complex. AB - Polycomb repression complex 2 (PRC2) component EZH2 tri-methylates H3K27 and exerts epigenetic repression on target gene expression. EZH2-mediated epigenetic control of RNA polymerase II (Pol II) transcribed coding gene transcription has been well established. However, little is known about EZH2-mediated epigenetic regulation of RNA polymerase III (Pol III) transcription. Here we present a paradigm that EZH2 is involved in the repression of Pol III transcription via interaction with transcriptional factor complex IIIC (TFIIIC). EZH2 and H3K27me3 co-occupy the promoter of tRNA(Tyr), 5S rRNA and 7SL RNA genes. Depletion of EZH2 or inhibition of EZH2 methyltransferase activity led to upregulation of Pol III target gene transcription. EZH2-mediated repression of Pol III transcribed gene expression requires presence of SUZ12. SUZ12 was able to interact with TFIIIC complex and knockdown of SUZ12 decreased occupancy of EZH2 and H3K27me3 at the promoter of Pol III target genes. Our findings pointed out a previously unidentified role of PRC2 complex in suppressing transcription of Pol III transcribed non-translated RNA genes, putting Pol III on a new layer of epigenetic regulation. PMID- 26038317 TI - Dissipation patterns of the fungicide difenoconazole (25% EC) in apples grown in Kashmir, India. AB - Dissipation patterns were studied following two applications of difenoconazole (score 25% EC) at 300 and 600 g ai ha(-1) as single and double dose respectively on Golden Delicious and Starkrimson cultivars of apple. Samples were collected at 0, 3, 6, 9, 12 and 30 days (harvest) post treatment. Limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.004 and 0.008 MUg g(-1), respectively. Half-life periods for Golden Delicious were found to be 6.09 and 6.70 days, and for Starkrimson, these values were observed to be 5.34 and 5.80 days, at single and double doses, respectively. Difenoconazole residues dissipated below its LOQ of 0.008 MUg g(-1) after 30 day post treatment at a single dose in both the cultivars. Waiting periods of 13.06 and 10.72 days are suggested for Golden Delicious and Starkrimson cultivars at a recommended dose of 300 g ai ha(-1), respectively. PMID- 26038318 TI - Health risk assessment of heavy metals and metalloid in drinking water from communities near gold mines in Tarkwa, Ghana. AB - Concentrations of heavy metals and metalloid in borehole drinking water from 18 communities in Tarkwa, Ghana, were measured to assess the health risk associated with its consumption. Mean concentrations of heavy metals (MUg/L) exceeded recommended values in some communities. If we take into consideration the additive effect of heavy metals and metalloid, then oral hazard index (HI) results raise concerns about the noncarcinogenic adverse health effects of drinking groundwater in Huniso. According to the US Environmental Protection Agency's (USEPA) guidelines, HI values indicating noncarcinogenic health risk for adults and children in Huniso were 0.781 (low risk) and 1.08 (medium risk), respectively. The cancer risk due to cadmium (Cd) exposure in adults and children in the sampled communities was very low. However, the average risk values of arsenic (As) for adults and children through drinking borehole water in the communities indicated medium cancer risk, but high cancer risk in some communities such as Samahu and Mile 7. Based on the USEPA assessment, the average cancer risk values of As for adults (3.65E-05) and children (5.08E-05) indicated three (adults) and five (children) cases of neoplasm in a hundred thousand inhabitants. The results of this study showed that residents in Tarkwa who use and drink water from boreholes could be at serious risk from exposure to these heavy metals and metalloid. PMID- 26038319 TI - Comparison of sampling strategies for monitoring water quality in mesoscale Canadian Prairie watersheds. AB - The Canadian Prairies are subject to cold winter dynamics, spring snowmelt runoff, and summer storms; a process variability that makes it difficult to identify an adequate sampling strategy for capturing representative water quality data. Hence, our research objective was to compare multiple water quality sampling strategies for Prairie watersheds and rank them based on operational and statistical criteria. The focus was on the Catfish Creek Watershed (Manitoba, Canada), which drains into the hypereutrophic Lake Winnipeg. Water samples were collected every 7 h during the 2013 open-water season and notably analyzed for nitrate and orthophosphate. The original high-frequency dataset (7 h) was then deconstructed into lower-frequency datasets to mimic strategies involving sample collection on a daily, weekly, bi-weekly, monthly, and seasonal basis. A comparison and decision matrix was also built to assess the ability of the lower frequency datasets to retain the statistical properties of the original (7 h) dataset. Results indicate that nutrient concentrations vary significantly over short timescales and are affected by both sampling time (day versus night) and water level fluctuations. The decision matrix revealed that seasonal sampling is sufficient when the goal is only to capture mean water quality conditions; however, sub-daily to daily sampling is required for accurate process signal representation. While we acknowledge that sampling programs designed by researchers and public agencies are often driven by different goals, we found daily sampling to be the most parsimonious strategy for the study watershed and suggest that it would help to better quantify nutrient loads to Lake Winnipeg. PMID- 26038320 TI - Preparation of malathion MIP-SPE and its application in environmental analysis. AB - Malathion is an organophosphorous insecticide for controlling insects on fruits and vegetables, miscellaneous household insects, and animal parasites. It is important to develop highly efficient and selective pre-treatment method for analyzing malathion residues in environment and samples from agricultural products based on the molecularly imprinted polymers (MIPs). In this study, we developed a tailor-made MIP method with highly specific recognization to the template. The MIPs were prepared using malathion as a template, methacrylic acid (MAA) as a functional monomer, ethylene glycol dimethacrylate (EGDMA) as a crosslinker, azodiisobutyronitrile (AIBN) as an initiator, and the acetonitrile chloroform (1:1, v/v) as a porogen. The molecular recognization mechanism of malathion and MAA was evaluated by molecular simulation, ultraviolet spectrometry (UV), and (1)H-nuclear magnetic resonance ((1)H-NMR). MAA interacted specifically with malathion by hydrogen bond with a ratio of 2:1. The MIPs exhibit a high affinity, recognition specificity, and efficient adsorption performance for malathion. The Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), surface area and porosimeter analyzer, thermogravimetric/differential thermal analyzer (TG/DTA) were used to characterize the properties of MIP. The malathion residues in soil, tap water, and cabbage were cleaned up by MIP-SPE, detected quantitatively using GC-FPD, and confirmed by GC-MS/MS. The limits of tap water, soil, and cabbage were confined to 0.001 mg L(-1), 0.004 and 0.004 mg kg(-1), respectively. The spiked recoveries of malathion were 96.06-111.49% (with RSD being 5.7-9.2%), 98.13-103.83% (RSD, 3.5-8.7%), and 84.94-93.69% (RSD, 4.7-5.8%) for tap water, soil, and cabbage samples, respectively. Thus, the method developed here can be used effectively in assessing malathion residues in multiple environmental samples. The aim of the study was to provide an efficient, selective, and accurate method for analyzing malathion at trace levels in multiple media. PMID- 26038321 TI - An application of MC-SDSS for water supply management during a drought crisis. AB - Climate change influences many countries' rainfall patterns and temperatures. In Iran, population growth has increased water demands. Tabriz is the capital of East Azerbaijan province, in northwestern Iran. A large proportion of the water required for this city is supplied from dams; thus, it is important to find alternatives to supply water for this city, which is the largest industrial city in northwestern Iran. In this paper, the groundwater quality was assessed using 70 wells in Tabriz Township. This work seeks to define the spatial distribution of groundwater quality parameters such as chloride, electrical conductivity (EC), pH, hardness, and sulfate using Geographic Information Systems (GIS) and geostatistics; map groundwater quality for drinking purposes employing multiple criteria decision-making (MCDM), such as the Analytical Hierarchy Process (AHP) and fuzzy logic, in the study area; and develop an Spatial Decision Support System (SDSS) for managing a water crisis in the region. The map produced by the AHP is more accurate than the map produced using fuzzy logic because in the AHP, priorities were assigned to each parameter based on the weights given by water quality experts. The final map indicates that the groundwater quality increases from the north to the south and from the west to the east within the study area. During critical conditions, the groundwater quality maps and the presented SDSS core can be utilized by East Azerbaijan Regional Water Company to develop an SDSS to drill new wells or to select existing wells to supply drinking water to Tabriz City. PMID- 26038322 TI - Greenhouse gas emissions and production cost of ethanol produced from biosyngas fermentation process. AB - Life cycle (LC) of ethanol has been evaluated to determine the environmental and economical viability of ethanol that was derived from biosyngas fermentation process (gasification-biosynthesis). Four scenarios [S1: untreated (raw), S2: treated (torrefied); S3: untreated-chemical looping gasification (CLG), S4: treated-CLG] were considered. The simulated biosyngas composition was used in this evaluation process. The GHG emissions and production cost varied from 1.19 to 1.32 kg-CO2 e/L and 0.78 to 0.90$/L, respectively, which were found to be dependent on the scenarios. The environmental and economical viability was found be improved when untreated feedstock was used instead of treated feedstock. Although the GHG emissions slightly reduced in the case of CLG process, production cost was nominally increased because of the cost incurred by the use of CaO. This study revealed that miscanthus is a promising feedstock for the ethanol industry, even if it is grown on marginal land, which can help abate GHG emissions. PMID- 26038323 TI - Impact of hazardous events on the removal of nutrients and trace organic contaminants by an anoxic-aerobic membrane bioreactor receiving real wastewater. AB - The impacts of four simulated hazardous events, namely, aeration failure, power loss, and chemical shocks (ammonia or bleach) on the performance of an anoxic aerobic membrane bioreactor (MBR) receiving real wastewater were investigated. Hazardous events could alter pH and/or oxidation reduction potential of the mixed liquor and inhibit biomass growth, thus affecting the removal of bulk organics, nutrients and trace organic contaminants (TrOC). Chemical shocks generally exerted greater impact on MBR performance than aeration/power failure events, with ammonia shock exerting the greatest impact. Compared to total organic carbon, nutrient removal was more severely affected. Removal of the hydrophilic TrOCs that are resistant and/or occur at high concentrations in wastewater was notably affected. The MBR effectively reduced estrogenicity and toxicity from wastewater, but chemical shocks could temporarily increase the endocrine activity of the effluent. Depending on the chemical shock-dose and the membrane flux, hazardous events can exacerbate membrane fouling. PMID- 26038324 TI - Comprehensive monitoring and management of a long-term thermophilic CSTR treating coffee grounds, coffee liquid, milk waste, and municipal sludge. AB - The CSTR process has previously not been successfully applied to treat coffee residues under thermophilic temperature and long term operation. In this experiment, the CSTR was fed with mixture substrate (TS ~ 70 g/L) of coffee grounds, coffee wastewater, milk waste and municipal sludge and it was operated under 55 degrees C for 225 days. A steady state was achieved under HRT 30 days and OLR 4.0 kg-COD/m(3)/d. However, there was an 35 days inhibition with VFA accumulation (propionic acid 700-1900 mg/L) when doubling the OLR by shortening HRT to 15 days. But, an addition of microelements and sulfate (0.5 g/L) in feedstock increased reactor resilience and stability under high loading rate and propionic acid stress. Continuous monitoring of hydrogen in biogas indicated the imbalance of acetogenesis. The effectiveness of comprehensive parameters (total VFA, propionic acid, IA/PA, IA/TA and CH4 content) was proved to manage the thermophilic system. PMID- 26038325 TI - Extraction and characterization of lignin from oil palm biomass via ionic liquid dissolution and non-toxic aluminium potassium sulfate dodecahydrate precipitation processes. AB - The objective of this study is to extract and characterize lignin from oil palm biomass (OPB) by dissolution in 1-butyl-3-methylimidazolium chloride ([bmim][Cl]), followed by the lignin extraction through the CO2 gas purging prior to addition of aluminum potassium sulfate dodecahydrate (AlK(SO4)2 . 12H2O). The lignin yield, Y(L) (%wt.) was found to be dependent of the types of OPB observed for all precipitation methods used. The lignin recovery, RL (%wt.) obtained from CO2-AlK(SO4)2 . 12H2O precipitation was, however dependent on the types of OPB, which contradicted to that of the acidified H2SO4 and HCl solutions of pH 0.7 and 2 precipitations. Only about 54% of lignin was recovered from the OPB. The FTIR results indicate that the monodispersed lignin was successfully extracted from the OPT, OPF and OPEFB having a molecular weight (MW) of 1331, 1263 and 1473 g/mol, and degradation temperature of 215, 207.5 and 272 degrees C, respectively. PMID- 26038326 TI - Treatment of oil sands process-affected water using moving bed biofilm reactors: With and without ozone pretreatment. AB - Two moving bed biofilm reactors (MBBRs) were operated to treat raw (untreated) and 30 mg/L ozone-treated oil sands process-affected water (OSPW). After 210 days, the MBBR process showed 18.3% of acid-extractable fraction (AEF) and 34.8% of naphthenic acids (NAs) removal, while the ozonation combined MBBR process showed higher removal of AEF (41.0%) and NAs (78.8%). Biodegradation of raw and ozone treated OSPW showed similar performance. UPLC/HRMS analysis showed a highest NAs removal efficiency with a carbon number of 14 and a -Z number of 4. Confocal laser scanning microscopy (CLSM) showed thicker biofilms in the raw OSPW MBBR (97 +/- 5 MUm) than in the ozonated OSPW MBBR (71 +/- 12 MUm). Quantitative polymerase chain reaction (q-PCR) results showed higher abundance of gene copies of total bacteria and nitrogen removal relevant bacteria in the ozonated OSPW MBBR, but no significant difference was found. MiSeq sequencing showed Proteobacteria, Nitrospirae, and Acidobacteria were dominant. PMID- 26038327 TI - Ethanol production from sugars obtained during enzymatic hydrolysis of elephant grass (Pennisetum purpureum, Schum.) pretreated by steam explosion. AB - In this work, steam explosion was used a pretreatment method to improve the conversion of elephant grass (Pennisetum purpureum) to cellulosic ethanol. This way, enzymatic hydrolysis of vaccum-drained and water-washed steam-treated substrates was carried out with Penicillium echinulatum enzymes while Saccharomyces cerevisiae CAT-1 was used for fermentation. After 48 h of hydrolysis, the highest yield of reducing sugars was obtained from vaccum-drained steam-treated substrates that were produced after 10 min at 200 degrees C (863.42 +/- 62.52 mg/g). However, the highest glucose yield was derived from water-washed steam-treated substrates that were produced after 10 min at 190 degrees C (248.34 +/- 6.27 mg/g) and 200 degrees C (246.00 +/- 9.60 mg/g). Nevertheless, the highest ethanol production was obtained from water-washed steam treated substrates that were produced after 6 min at 200 degrees C. These data revealed that water washing is a critical step for ethanol production from steam treated elephant grass and that pretreatment generates a great deal of water soluble inhibitory compounds for hydrolysis and fermentation, which were partly characterized as part of this study. PMID- 26038328 TI - Self-sustained reduction of multiple metals in a microbial fuel cell-microbial electrolysis cell hybrid system. AB - A self-sustained hybrid bioelectrochemical system consisting of microbial fuel cell (MFC) and microbial electrolysis cell (MEC) was developed to reduce multiple metals simultaneously by utilizing different reaction potentials. Three heavy metals representing spontaneous reaction (chromium, Cr) and unspontaneous reaction (lead, Pb and nickel, Ni) were selected in this batch-mode study. The maximum power density of the MFC achieved 189.4 mW m(-2), and the energy recovery relative to the energy storage circuit (ESC) was ~ 450%. At the initial concentration of 100 mg L(-1), the average reduction rate of Cr(VI) was 30.0 mg L(-1) d(-1), Pb(II) 32.7 mg L(-1) d(-1), and Ni(II) 8.9 mg L(-1) d(-1). An electrochemical model was developed to predict the change of metal concentration over time. The power output of the MFC was sufficient to meet the requirement of the ESC and MEC, and the "self-sustained metal reduction" was achieved in this hybrid system. PMID- 26038329 TI - Calcium-catalyzed pyrolysis of lignocellulosic biomass components. AB - The present study examines the effect of calcium pretreatment on pyrolysis of individual lignocellulosic compounds. Previous work has demonstrated that the incorporation of calcium compounds with the feedstock prior to pyrolysis has a significant effect on the oxygen content and stability of the resulting oil. The aim of this work was to further explore the chemistry of calcium-catalyzed pyrolysis. Bench-scale pyrolysis of biomass constituents, including lignin, cellulose and xylan is performed and compared to the oils produced from pyrolysis of the same components after calcium pretreatment. The resulting oils were analyzed by quantitative GC-MS and SEC. These analyses, together with data collected from previous work provide evidence which was used to develop proposed reaction pathways for pyrolysis of calcium-pretreatment biomass. PMID- 26038330 TI - Efficient production of glucose by microwave-assisted acid hydrolysis of cellulose hydrogel. AB - To improve the production of glucose from cellulose, a simple and effective route was developed. This process uses a combination of a step of cellulose dissolution in aqueous NaOH/urea solution and then regeneration with water, followed by an acid hydrolysis step under microwave irradiation. The method is effective to obtain glucose from alpha-cellulose, microcrystalline cellulose, filter paper, ramie fiber and absorbent cotton. Increased with the acid concentration the glucose yield from hydrogel hydrolysis increased from 0.42% to 44.6% at 160 degrees C for 10 min. Moreover, the ozone treatment of cellulose in NaOH/urea solution before regeneration significantly enhanced the hydrolysis efficiency with a glucose yield of 59.1%. It is believed that the chains in cellulose hydrogel are relatively free approached, making that the acids easily access the beta-glycosidic bonds. PMID- 26038331 TI - Anaerobic digestion of antibiotic residue in combination with hydrothermal pretreatment for biogas. AB - Antibiotic residues are difficult to be treated or utilized because of their high water content and residual antibiotics. This article is devoted to investigating the possibility of biogas production from cephalosporin C residue (CPCAR), one typical type of antibiotic residues, via anaerobic digestion in combination with hydrothermal pretreatment (HTPT). The results from the bench-scale experiments showed that the combination of HTPT and anaerobic digestion can provide a viable way to convert CPCAR into biogas, and the biogas and methane yields reached 290 and 200 ml(g TS)(-1), respectively. This article further evaluated the proposed technology in terms of energy balance and technical feasibility based on theoretical calculation using the data from a pilot HTPT test. It was shown that the process is totally self-sufficient in energy and its main challenging problem of ammonia inhibition can be solved via ammonia stripping. PMID- 26038332 TI - Investigation of effect of particle size and rumen fluid addition on specific methane yields of high lignocellulose grass silage. AB - This work examines the digestion of advanced growth stage grass silage. Two variables were investigated: particle size (greater than 3 cm and less than 1cm) and rumen fluid addition. Batch studies indicated particle size and rumen fluid addition had little effect on specific methane yields (SMYs). In continuous digestion of 3 cm silage the SMY was 342 and 343 L CH4 kg(-1)VS, respectively, with and without rumen fluid addition. However, digester operation was significantly affected through silage floating on the liquor surface and its entanglement in the mixing system. Digestion of 1cm silage with no rumen fluid addition struggled; volatile fatty acid concentrations rose and SMYs dropped. The best case was 1cm silage with rumen fluid addition, offering higher SMYs of 371 L CH4 kg(-1)VS and stable operation throughout. Thus, physical and biological treatments benefited continuous digestion of high fibre grass silage. PMID- 26038333 TI - Biochar accelerates organic matter degradation and enhances N mineralisation during composting of poultry manure without a relevant impact on gas emissions. AB - A composting study was performed to assess the impact of biochar addition to a mixture of poultry manure and barley straw. Two treatments: control (78% poultry manure + 22% barley straw, dry weight) and the same mixture amended with biochar (3% dry weight), were composted in duplicated windrows during 19 weeks. Typical monitoring parameters and gaseous emissions (CO2, CO, CH4, N2O and H2S) were evaluated during the process as well as the agronomical quality of the end products. Biochar accelerated organic matter degradation and ammonium formation during the thermophilic phase and enhanced nitrification during the maturation phase. Our results suggest that biochar, as composting additive, improved the physical properties of the mixture by preventing the formation of clumps larger than 70 mm. It favoured microbiological activity without a relevant impact on N losses and gaseous emissions. It was estimated that biochar addition at 3% could reduce the composting time by 20%. PMID- 26038334 TI - Internal Pulse Generators in Deep Brain Stimulation: Rechargeable or Not? AB - OBJECTIVE: Deep brain stimulation (DBS) is a cost-effective strategy for the treatment of different neurologic disorders. However, DBS procedures are associated with high costs of implantation and replacement of the internal pulse generator (IPG). Different manufacturers propose the use of rechargeable IPGs. The objective of this study is to compare the implantation costs of nonrechargeable IPGs versus the estimated costs of rechargeable IPGs in different categories of patients to evaluate if an economic advantage for the health care system could be derived. METHODS: The study looked at 149 patients who underwent a surgical procedure for IPG replacement. In a hypothetical scenario, rechargeable IPGs were implanted instead of nonrechargeable IPGs at the time of DBS system implantation. Another scenario was outlined in a perspective period of time, corresponding to the patients' life expectancy. Costs were calculated, and inferential analysis was performed. RESULTS: A savings of ?234,194, including the cost of management of complications, was calculated during a follow-up period of 7.9 years. In a comprehensive life expectancy period of 47 years, a savings of ?5,918,188 would be obtained (P < 0.05). Long-term group data point out that a relevant savings would be expected from implantation of rechargeable IPGs in dystonic patients (P < 0.05) and patients with Parkinson disease (P < 0.05), and a savings is projected to occur in other categories of patients (P < 0.05). CONCLUSIONS: Implantation of rechargeable IPGs presents clinical advantages compared with nonrechargeable devices. A huge economic savings can be realized with the implantation of rechargeable IPGs in categories of patients implanted with IPGs for DBS. PMID- 26038335 TI - Sex-Related Prognostic Predictors for Parkinson Disease Undergoing Subthalamic Stimulation. AB - BACKGROUND: A few reports have addressed the sex-related efficacy of deep brain stimulation (DBS) in the subthalamic nucleus (STN) to treat advanced Parkinson disease (PD). The present study evaluates the sex-related prognostic factors for STN-DBS outcomes. METHODS: Seventy-two consecutive patients (48 men and 24 women) were reviewed retrospectively. Changes in the Unified PD Rating Scale scores were compared between men and women in the 6-month drug-off/DBS-on state relative to the preoperative drug-off baseline. A multivariate linear regression model was used to identify the preoperative factors predictive of motor improvements after surgery. RESULTS: Before surgery, the male and female patient groups were comparable in clinical severity, except the women were associated with slightly inferior cognition (P < 0.05) and a relatively better response to levodopa (LD) (P < 0.05) than the men. Both sexes showed similar clinical improvements after STN-DBS therapy. In men, preoperative lower LD requirement and higher motor dysfunction, particularly tremor (adjusted R(2) = 0.613, P < 0.001), as well as greater improvement in tremor and rigidity after LD therapy (adjusted R(2) = 0.232, P = 0.001) were favorable predictors of surgical outcomes. Women achieved a significant improvement if they performed well in activities of daily living even with higher baseline motor scores (adjusted R(2) = 0.620, P < 0.001), or exhibited improvements in akinesia disability after preoperative LD therapy (adjusted R(2) = 0.305, P = 0.003). CONCLUSIONS: STN-DBS therapy is equally beneficial for both sexes. Sex-related differences exist with regard to favorable prognostic predictors for early surgical outcomes. PMID- 26038336 TI - Treatment Response and Prognosis After Recurrence of Atypical Meningiomas. AB - OBJECTIVE: Intracranial atypical meningiomas have a greater rate of recurrence than benign meningiomas. Scant literature, however, is available regarding the treatment and prognosis of these tumors after recurrence. The objective of this study was to analyze the treatment outcomes and prognostic factors of atypical meningiomas after recurrence of disease. METHODS: Forty-one cases with clinical characteristics and follow-up data were available in our department from 2000 to 2013. Certain factors, such as sex, age, preoperative Karnofsky Performance Status Scale score, location, prerecurrence tumor precursor, interval time, Simpson grade, histologic grade after recurrence, and radiotherapy, were selected to study the relationship with the prognosis of the tumors. RESULTS: The mean progression-free survival (PFS) and overall survival (OS) in our cases were 40.5 +/- 4.7 and 57.1 +/- 5.8 months, respectively. The 1-, 3-, and 5-year PFS rates were 79.8%, 44.1%, and 39.2%, respectively, and the corresponding OS rates were 92.4%, 66.1%, and 48.8%, respectively. The precursors of recurrent tumors were transformed meningiomas, an interval time less than 24 months, and a postrecurrence histologic diagnosis of anaplastic meningioma might predict an unfavorable outcome. Surgery Simpson I and II can improve the PFS and OS of tumors. Because of the limited number of cases, we could not identify a relationship between radiotherapy and prognosis. CONCLUSIONS: Recurrent atypical meningiomas are intractable tumors with a high rate of recurrence and death. Total resection of the tumors under relatively safe conditions remains the most suitable treatment strategy. PMID- 26038337 TI - Effects of PEGylated paclitaxel nanocrystals on breast cancer and its lung metastasis. AB - As an attractive strategy developed rapidly in recent years, nanocrystals are used to deliver insoluble drugs. PEGylation may further prolong the circulation time of nanoparticles and improve the therapeutic outcome of drugs. In this study, paclitaxel (PTX) nanocrystals (PTX-NCs) and PEGylated PTX nanocrystals (PEG-PTX-NCs) were prepared using antisolvent precipitation augmented by probe sonication. The characteristics and antitumor efficacy of nanocrystals were investigated. The results indicated that the nanocrystals showed rod-like morphology, and the average particle size was 240 nm and 330 nm for PTX-NCs and PEG-PTX-NCs, respectively. The PEG molecules covered the surface of nanocrystals with an 11.54 nm fixed aqueous layer thickness (FALT), much higher than that of PTX-NCs (0.2 nm). PEG-PTX-NCs showed higher stability than PTX-NCs under both storage and physiological conditions. In breast cancer xenografted mice, PEG-PTX NCs showed significantly better tumor inhibition compared to saline (p < 0.001) and PTX-NC groups (p < 0.05) after intravenous administration. In a model of lung tumor metastasis quantified by the luciferase activity, the PEG-PTX-NCs group showed higher anticancer efficacy not only than saline and PTX-NCs groups, but also than Taxol(r), achieving an 82% reduction at the end of the experiment. These studies suggested the potential advantages of PEGylated PTX nanocrystals as alternative drug delivery systems for anticancer therapy. PMID- 26038338 TI - Vitreomacular Interface after Anti-Vascular Endothelial Growth Factor Injections in Neovascular Age-Related Macular Degeneration. AB - PURPOSE: To evaluate the incidence of posterior vitreous detachment (PVD) induced by intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents in cases of neovascular age-related macular degeneration (AMD). DESIGN: Cohort study conducted at a single tertiary referral vitreoretinal practice. PARTICIPANTS: A total of 396 eyes of 295 patients were diagnosed with neovascular AMD between 2009 and 2014. A total of 125 eyes of 112 patients met the inclusion criteria and were evaluated in this study. METHODS: This study included patients with neovascular AMD who presented vitreomacular adhesion (VMA) detected by spectral-domain optical coherence tomography (OCT) at baseline. Eyes with VMA were classified according to the diameter of vitreous attachment to the macular surface measured by OCT, with attachment of <=1500 MUm defined as focal and attachment of >1500 MUm defined as broad. All patients received at least 3 monthly intravitreal injections of anti-VEGF agents. Follow-up visits were performed 1 month after each intravitreal injection and included OCT analysis to evaluate the incidence of PVD. MAIN OUTCOME MEASURES: Posterior vitreous detachment induced by anti-VEGF injections. RESULTS: The mean follow-up period was 21.3 months (range, 3-59 months). The mean number of intravitreal injections was 8.3 (range, 3-29 injections). Intravitreal drugs used in the study were ranibizumab (51.5%), bevacizumab (33.5%), and aflibercept (15.0%). Seven eyes (5.6%) developed PVD after intravitreal drug injection (3 eyes after the first intravitreal injection: bevacizumab in 1 and ranibizumab in 2; 2 eyes after the second injection: ranibizumab in 1 and bevacizumab in 1; 1 eye after the fourth injection: ranibizumab; and 1 eye after the sixth injection: aflibercept). A total of 118 eyes remained with persistent VMA. All 7 eyes that developed PVD were classified as having focal VMA, with the diameter of vitreous attachment ranging from 210 to 1146 MUm (mean, 600 MUm). CONCLUSIONS: Intravitreal injections of commonly used anti-VEGF intravitreal drugs rarely induce PVD in patients with neovascular AMD. Eyes with focal VMA have a greater chance to develop PVD than eyes with a broad area of VMA. PMID- 26038339 TI - Safety and Efficacy of Lacrimal Drainage System Plugs for Dry Eye Syndrome: A Report by the American Academy of Ophthalmology. AB - OBJECTIVE: To review the published literature assessing the efficacy and safety of lacrimal drainage system plug insertion for dry eye in adults. METHODS: Literature searches of the PubMed and Cochrane Library databases were last conducted on March 9, 2015, without date restrictions and were limited to English language abstracts. The searches retrieved 309 unique citations. The primary authors reviewed the titles and abstracts. Inclusion criteria specified reports that provided original data on plugs for the treatment of dry eyes in at least 25 patients. Fifty-three studies of potential relevance were assigned to full-text review. The 27 studies that met the inclusion criteria underwent data abstraction by the panels. Abstracted data included study characteristics, patient characteristics, plug type, insertion technique, treatment response, and safety information. All studies were observational and rated by a methodologist as level II or III evidence. RESULTS: The plugs included punctal, intracanalicular, and dissolving types. Fifteen studies reported metrics of improvement in dry eye symptoms, ocular-surface status, artificial tear use, contact lens comfort, and tear break-up time. Twenty-five studies included safety data. Plug placement resulted in >=50% improvement of symptoms, improvement in ocular-surface health, reduction in artificial tear use, and improved contact lens comfort in patients with dry eye. Serious complications from plugs were infrequent. Plug loss was the most commonly reported problem with punctal plugs, occurring on average in 40% of patients. Overall, among all plug types, approximately 9% of patients experienced epiphora and 10% required removal because of irritation from the plugs. Canaliculitis was the most commonly reported problem for intracanalicular plugs and occurred in approximately 8% of patients. Other complications were reported in less than 4% of patients on average and included tearing, discomfort, pyogenic granuloma, and dacryocystitis. CONCLUSIONS: On the basis of level II and III evidence in these studies, plugs improve the signs and symptoms of moderate dry eye that are not improved with topical lubrication, and they are well tolerated. There are no level I studies that describe the efficacy or safety of lacrimal drainage system plugs. PMID- 26038340 TI - A novel peptide-based recognition probe for the sensitive detection of CD44 on breast cancer stem cells. AB - Metastasis and recurrence of breast cancer remain significant clinical problems. The expression level of CD44 protein is higher in breast cancer-initiating cancer stem cells; therefore, the early detection of CD44 using a sensitive diagnostic probe is important for breast cancer diagnosis and therapeutic purposes. In this study, we fabricated a polyvalent directed peptide polymer (PDPP) that specifically recognized the CD44 biomarker, as confirmed by immunocytochemistry tests and fluorescence-activated cell sorting assessment. Our results indicate that PDPP is useful as a novel tool for the sensitive detection of breast cancer stem cells. PMID- 26038341 TI - Yeast genes required for conversion of grape precursors to varietal thiols in wine. AB - Three varietal thiols are important for the tropical fruit aromas of Sauvignon blanc: 4-mercapto-4-methylpentan-2-one (4MMP), 3-mercaptohexanol (3MH) and its acetylated derivative 3-mercaptohexyl acetate (3MHA). These thiols are produced by yeast during fermentation from precursors in grape juice. Here we identify genes in Saccharomyces cerevisiae that are required for the transport and cleavage of two thiol precursors: cysteine-4MMP and glutathione-3MH. A full length copy of IRC7 is absolutely required for the cleavage of both precursors in the tested strains; the deleted form of the enzyme found in most yeast strains is incapable of converting these compounds into detectable thiols. By using strains that overexpress full-length IRC7, we further show that the glutathione transporter OPT1 and the transpeptidase CIS2 are also required for conversion of glut-3MH to its varietal thiol. No transporter for cys-4MMP was identified: a strain deleted for all nine known cysteine transport genes was still capable of converting cys-4MMP to its varietal thiol, and was also able to take up cysteine at high concentrations. Based on these results, we conclude that cysteine and glutathione precursors make a relatively minor contribution to 3MH production from most grape juices. PMID- 26038343 TI - Lupus cystitis in Korean patients with systemic lupus erythematosus: risk factors and clinical outcomes. AB - This study was performed to investigate the clinical characteristics of lupus cystitis and determine the risk factors and clinical outcomes of lupus cystitis in patients with systemic lupus erythematosus (SLE). We retrospectively reviewed 1064 patients at Seoul St. Mary's Hospital in Seoul, Korea, from 1998 to 2013. Twenty-four patients had lupus cystitis. Lupus cystitis was defined as unexplained ureteritis and/or cystitis as detected by imaging studies, cystoscopy, or bladder histopathology without urinary microorganisms or stones. Three-fourths of patients with lupus cystitis had concurrent lupus mesenteric vasculitis (LMV). The initial symptoms were gastrointestinal in nature for most patients (79.2%). High-dose methylprednisolone was initially administered to most patients (91.7%) with lupus cystitis. Two patients (8.3%) died of urinary tract infections. Sixty-five age- and sex-matched patients with SLE who were admitted with other manifestations were included as the control group. Patients with lupus cystitis showed a lower C3 level (p = 0.031), higher SLE Disease Activity Index score (p = 0.006), and higher ESR (p = 0.05) upon admission; more frequently had a history of LMV prior to admission (p < 0.001); and less frequently had a history of neuropsychiatric lupus (p = 0.031) than did patients with SLE but without lupus cystitis. The occurrence of lupus cystitis was associated with a history of LMV (OR, 21.794; 95% CI, 4.061-116.963). The median follow-up period was 3.4 years, and the cumulative one-year mortality rate was 20%. Complications developed in 33.3% of patients with lupus cystitis and were related to survival (log-rank p = 0.021). Our results suggest that the possibility of lupus cystitis should be considered when a patient with SLE and history of LMV presents with gastrointestinal symptoms or lower urinary tract symptoms. Development of complications in patients with lupus cystitis can be fatal. Thus, intensive treatment and follow-up are needed, especially in the presence of complications. PMID- 26038344 TI - Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS). AB - OBJECTIVE: In recent years, there have been a number of studies suggesting that POTS may have an autoimmune etiology. This study examined whether the prevalence of antinuclear antibodies (ANA), other markers of autoimmunity and co-morbid autoimmune disorders is higher in patients with POTS than in the general population. METHODS AND RESULTS: Medical records of 100 consecutive patients with POTS evaluated at our clinic were reviewed. In this cohort (90% females, mean age 32, range 13-54 years), 25% had positive ANA, 7% had at least one positive aPL antibody and 31% had markers of autoimmunity. When compared to the general population, patients with POTS had a higher prevalence of ANA (25% vs. 16%, OR 1.8, CI 1.1-2.8, p < 0.05), aPL antibody (7% vs. 1%, OR 7.5, CI 3.4-16.1, p < 0.001) and co-morbid autoimmune disorders (20% vs. highest estimated 9.4%, OR 2.4, CI 1.5-3.9, p < 0.001). The most prevalent autoimmune disorder was Hashimoto's thyroiditis (11% vs. up to 2%, OR 6.1, CI 3.2-11.3, p < 0.001), followed by RA (4% vs. up to 1%, OR 4.1, CI 1.5-11.2, p < 0.01) and SLE (2% vs. up to 0.12%, OR 17, CI 4.1-69.7, p < 0.001). The prevalence of CVID was very high (2% vs. 0.004%, OR 510.2, CI 92.4-2817.8, p < 0.001), while celiac disease showed a nonsignificant trend toward increased prevalence. CONCLUSION: Patients with POTS have a higher prevalence of autoimmune markers and co-morbid autoimmune disorders than the general population. One in four patients have positive ANA, almost one in three have some type of autoimmune marker, one in five have a co morbid autoimmune disorder, and one in nine have Hashimoto's thyroiditis. PMID- 26038342 TI - Imaging of cardiovascular complications in patients with systemic lupus erythematosus. AB - In the long-term survival of patients with systemic lupus erythematosus (SLE), cardiovascular disease (CVD) is a leading cause of death. Recently, multimodality cardiovascular imaging methods have been adopted for the evaluation of cardiovascular risk, which has shown to be associated with both traditional cardiovascular risk factors and SLE-specific conditions. Quantitative imaging biomarkers, which can describe both morphological and functional abnormalities in the heart, are expected to provide new insights to stratify cardiovascular risks and to guide SLE management by assessing individual responses to therapies either protecting the cardiovascular system or suppressing the autoimmune reactions. In this review, we will discuss cutting-edge cardiovascular imaging techniques and potential clinical applications and limitations of those techniques for the evaluation of major SLE-related heart disorders. PMID- 26038345 TI - Psychometric validation of the Brief Pain Inventory-Short Form in patients with systemic lupus erythematosus in the United States. AB - This study evaluated the Brief Pain Inventory-Short Form (BPI-SF) in patients with moderate-to-severe systemic lupus erythematosus (SLE). Patients >=18 years old who self-reported a physician diagnosis of SLE (confirmed by medical record review) and active SLE (Systemic Lupus Activity Questionnaire (SLAQ) score of >=11) were included. The BPI-SF and Short Form Health Survey version 2 (SF-36v2) were administered electronically at baseline, week 2 and week 12. Psychometric properties of the BPI-SF were evaluated. Cronbach alphas were >0.9 for all BPI-SF items, domains and total score. Test-retest reliability correlations for responses between baseline and week 2 of the BPI-SF had intraclass correlation coefficients (ICCs) >=0.5. The BPI-SF domains and total score were moderately positively correlated to the SLAQ score (r >= 0.4), but negatively correlated to the SF-36v2 bodily pain domain (r <= -0.6). The BPI-SF domains and total score were moderately negatively correlated to the SF-36v2 physical functioning domain and physical component summary (r <= -0.4), with low correlations between the BPI SF severity domain and SF-36v2 mental component summary (r = -0.16). Assessment of pain, as measured by the BPI-SF, demonstrated validity and reliability in a sample of patients with moderate-to-severe SLE. PMID- 26038346 TI - Association of the interleukin-6 polymorphisms with systemic lupus erythematosus: a meta-analysis. AB - BACKGROUND: Interleukin (IL)-6, an important proinflammatory cytokine, plays a potential pathological role in systemic lupus erythematosus (SLE). Studies on the relationship of IL-6 gene polymorphisms with SLE are inconclusive. The aim of this study was to estimate the relationship more precisely. METHODS: The databases of PubMed and Web of Science updated to 30 August 2014 were retrieved. Meta-analysis was conducted using allelic contrast, dominant, recessive and homozygote contrast models. Fifteen studies were included in this study and ethnicity-specific meta-analysis was performed on European, Iranian and Asian populations. RESULTS: Analysis for the IL-6-174 G/C polymorphism under all models except the homozygote contrast model indicated an association in the overall population (allelic contrast model: odds ratio (OR) 1.428, 95% confidence interval (CI) 1.124-1.812, dominant model: OR 1.382, 95% CI 1.037-1.842, recessive model: OR 1.610, 95% CI 1.158-2.240, homozygote contrast model: OR 1.759, 95% CI 0.989-3.127), as well as in European individuals under all four genetic models (allelic contrast model: OR 1.557, 95% CI 1.155-2.098, dominant model: OR 1.699, 95% CI 1.203-2.400, recessive model: OR 1.506, 95% CI 1.176 1.930, homozygote contrast model: OR 2.118, 95% CI 1.103-4.065). Analysis for the IL-6-572 G/C polymorphism indicated significant association in overall ethnicities under the recessive model (OR 1.491, 95% CI 1.104-2.014), but not under other models or in Asian individuals. In addition, significant association between the IL-6-174 G/C polymorphism and discoid skin lesions and antinuclear antibodies (ANAs) were found under the allelic contrast model and recessive model, respectively (discoid skin lesions: OR 2.271, 95% CI 1.053-4.895; ANAs: OR 2.244, 95% CI 1.141-4.416). CONCLUSION: This meta-analysis provides evidence of the association between the IL-6 polymorphism and the risk of SLE, hinting that the IL-6-174 G/C and IL-6-572 G/C polymorphisms may play a role in SLE susceptibility. PMID- 26038347 TI - Pulse oximetry as a screening tool for detecting major congenital heart defects in Indian newborns. AB - OBJECTIVE: To evaluate the use of pulse oximetry as a screening tool for detecting major congenital heart defects (CHDs) in Indian newborns. DESIGN: Cross sectional observational study. PATIENTS: In a community hospital of north India, babies born during a specific 8 h period of the day were recruited over a period of 3 years. Newborns with incomplete documentation were excluded. INTERVENTION: Routine clinical examination, pulse oximetry and bedside echocardiography. OUTCOME MEASURES: Any abnormalities in clinical examination and pulse oximetry were recorded. CHDs were diagnosed using bedside echocardiography. Accuracy of pulse oximetry, clinical examination and their combination for detecting major CHDs was calculated. RESULTS: Among the 19 009 newborns screened, 70 had major CHDs at birth (44 serious, 26 critical). Pulse oximetry detected 39 major (sensitivity 55.7%, 95% CI 44.1% to 66.8%; specificity 68.3%, 67.6% to 68.9%) and 22 critical CHDs (sensitivity 84.6%, 66.5% to 93.9%; specificity 68.3%, 67.6% to 68.9%). Addition of pulse oximetry to clinical examination significantly improved sensitivity for major CHDs (35.7% (25.5% to 47.4%) to 75.7% (64.5% to 85.3%), p<0.01) and critical CHDs (11.5% (4.0% to 29.0%) to 84.6% (66.5% to 93.9%), p<0.01). CONCLUSIONS: Pulse oximetry is a sensitive screening tool for detecting major CHDs in Indian newborns. It adds significant value to the current practice of using clinical examination as a sole screening tool for detecting major CHDs. However, specificity of pulse oximetry was much lower in our study. Possible reasons for low specificity could be non-repetition of pulse oximetry in newborns with initial lower saturations, high prevalence of infections and respiratory issues in our cohort and use of non-motion tolerant oximeter. PMID- 26038348 TI - Catch Me if You Can: Adaptation from Standing Genetic Variation to a Moving Phenotypic Optimum. AB - Adaptation lies at the heart of Darwinian evolution. Accordingly, numerous studies have tried to provide a formal framework for the description of the adaptive process. Of these, two complementary modeling approaches have emerged: While so-called adaptive-walk models consider adaptation from the successive fixation of de novo mutations only, quantitative genetic models assume that adaptation proceeds exclusively from preexisting standing genetic variation. The latter approach, however, has focused on short-term evolution of population means and variances rather than on the statistical properties of adaptive substitutions. Our aim is to combine these two approaches by describing the ecological and genetic factors that determine the genetic basis of adaptation from standing genetic variation in terms of the effect-size distribution of individual alleles. Specifically, we consider the evolution of a quantitative trait to a gradually changing environment. By means of analytical approximations, we derive the distribution of adaptive substitutions from standing genetic variation, that is, the distribution of the phenotypic effects of those alleles from the standing variation that become fixed during adaptation. Our results are checked against individual-based simulations. We find that, compared to adaptation from de novo mutations, (i) adaptation from standing variation proceeds by the fixation of more alleles of small effect and (ii) populations that adapt from standing genetic variation can traverse larger distances in phenotype space and, thus, have a higher potential for adaptation if the rate of environmental change is fast rather than slow. PMID- 26038349 TI - An Early Assessment of Accountable Care Organizations' Efforts to Engage Patients and Their Families. AB - Accountable care organizations (ACOs) have incentives to meet quality and cost targets to share in any resulting savings. Achieving these goals will require ACOs to engage more actively with patients and their families. The extent to which ACOs do so is currently unknown. Using mixed methods, including a national survey, phone interviews, and site-visits, we examine the extent to which ACOs actively engage patients and their families, explore challenges involved, and consider approaches for dealing with those challenges. Results indicate that greater ACO use of patient activation and engagement (PAE) activities at the point-of-care may be related to positive perceptions among ACO leaders of the impact of PAE investments on ACO costs, quality, and outcomes of care. We identify a number of important practices associated with greater PAE, including high-level leadership commitment, goal-setting supported by adequate resources, extensive provider training, use of interdisciplinary care teams, and frequent monitoring and reporting on progress. PMID- 26038350 TI - Relocation of remote dwellers living with hemodialysis: a time trade-off survey. AB - BACKGROUND: There has been little research exploring the experience of dialysis therapy for people living in remote communities. Remote residence location has previously been associated with excess mortality in hemodialysis (HD) patients, suggesting that relocation to a referral center might improve outcomes. It is unknown whether patients view this approach as acceptable. METHODS: We studied 121 remote-dwelling chronic HD patients using the time trade-off method applied to hypothetical scenarios. RESULTS: Participants indicated that they would trade a median of 6 years of life in their current location (including current social supports) (95% CI 2.25-7) for 10 years of life in a referral center without any of their existing social supports (meaning they would be willing to forgo 4 years of life to remain in their current residence location). When current social supports were assumed to continue in both locations, people were only willing to forego a median of 2 years of life (95% CI 1-4) to remain in their current location. Older participants were much less willing to accept relocation than younger participants; the median time trade-off associated with relocation and without social supports was 2 years for participants aged <50 years, 3 years for those aged 50-69.9 years and 9 years for those aged >=70 years. CONCLUSIONS: Hemodialysis patients currently living remotely were willing to forgo much of their remaining life expectancy rather than relocate-especially among older participants. These findings suggest that decisions about relocation should be accompanied by discussion of anticipated changes in quality of life and life expectancy. PMID- 26038351 TI - Incremental haemodialysis. AB - Thrice-weekly haemodialysis schedules have become the standard default haemodialysis prescription worldwide. Whereas the measurement of residual renal function is accepted practice for peritoneal dialysis patients and the importance of residual renal function in determining technique success is well established, few centres routinely assess residual renal function in haemodialysis patients. Although intradialytic hypotension and episodes of acute kidney injury may predispose to an earlier loss of residual renal function, a significant proportion of haemodialysis patients maintain some residual function long after dialysis initiation. As such, an incremental approach to the initiation of dialysis with careful monitoring of residual renal function may potentially provide some haemodialysis patients with an improved quality of life and greater preservation of residual renal function whilst fewer dialysis sessions may reduce health care costs. Prospective trials are required to determine the optimum approach to the initiation of haemodialysis for the oliguric patient. Once residual renal function has been lost, then dialysis prescriptions should be re examined to consider the use of longer or more frequent treatment sessions and switching from low-flux to high-flux dialysis or haemodiafiltration to offset retention of middle sized molecules and protein-bound azotaemic solutes. PMID- 26038352 TI - The Medical Innovation Bill and the logic of scientific discovery. PMID- 26038353 TI - What is mental health? Evidence towards a new definition from a mixed methods multidisciplinary international survey. AB - OBJECTIVE: Lack of consensus on the definition of mental health has implications for research, policy and practice. This study aims to start an international, interdisciplinary and inclusive dialogue to answer the question: What are the core concepts of mental health? DESIGN AND PARTICIPANTS: 50 people with expertise in the field of mental health from 8 countries completed an online survey. They identified the extent to which 4 current definitions were adequate and what the core concepts of mental health were. A qualitative thematic analysis was conducted of their responses. The results were validated at a consensus meeting of 58 clinicians, researchers and people with lived experience. RESULTS: 46% of respondents rated the Public Health Agency of Canada (PHAC, 2006) definition as the most preferred, 30% stated that none of the 4 definitions were satisfactory and only 20% said the WHO (2001) definition was their preferred choice. The least preferred definition of mental health was the general definition of health adapted from Huber et al (2011). The core concepts of mental health were highly varied and reflected different processes people used to answer the question. These processes included the overarching perspective or point of reference of respondents (positionality), the frameworks used to describe the core concepts (paradigms, theories and models), and the way social and environmental factors were considered to act. The core concepts of mental health identified were mainly individual and functional, in that they related to the ability or capacity of a person to effectively deal with or change his/her environment. A preliminary model for the processes used to conceptualise mental health is presented. CONCLUSIONS: Answers to the question, 'What are the core concepts of mental health?' are highly dependent on the empirical frame used. Understanding these empirical frames is key to developing a useful consensus definition for diverse populations. PMID- 26038354 TI - Variations in Health-Related Quality of Life (HRQoL) and survival 1 year after stroke: five European population-based registers. AB - OBJECTIVE: There were two main objectives: to describe and compare clinical outcomes and Patient-Reported Outcome Measures (PROMs) collected using standardised procedures across the European Registers of Stroke (EROS) at 3 and 12 months after stroke; and to examine the relationship between patients' Health Related Quality of Life (HRQoL) at 3 months after stroke and survival up to 1 year across the 5 populations. DESIGN: Analysis of data from population-based stroke registers. SETTING: European populations in Dijon (France); Kaunas (Lithuania); London (UK); Warsaw (Poland) and Sesto Fiorentino (Italy). PARTICIPANTS: Patients with ischaemic or intracerebral haemorrhage (ICH) stroke, registered between 2004 and 2006. OUTCOME MEASURES: (1) HRQoL, assessed by the physical component summary (PCS) and mental component summary (MCS) of the Short Form Health Survey (SF-12), mapped into the EQ-5D to estimate responses on 5 dimensions (mobility, activity, pain, anxiety and depression, and self-care) and utility scores. (2) Mortality within 3 months and within 1 year of stroke. RESULTS: Of 1848 patients, 325 were lost to follow-up and 500 died within a year of stroke. Significant differences in mortality, HRQoL and utility scores were found, and remained after adjustments. Kaunas had an increased risk of death; OR 2.34, 95% CI (1.32 to 4.14) at 3 months after stroke in Kaunas, compared with London. Sesto Fiorentino had the highest adjusted PCS: 43.54 (SD=0.96), and Dijon had the lowest adjusted MCS: 38.67 (SD=0.67). There are strong associations between levels of the EQ-5D at 3 months and survival within the year. The trend across levels suggests a dose-response relationship. CONCLUSIONS: The study demonstrated significant variations in survival, HRQoL and utilities across populations that could not be explained by stroke severity and sociodemographic factors. Strong associations between HRQoL at 3 months and survival to 1 year after stroke were identified. PMID- 26038355 TI - Transitions in Parkinson's disease in primary care: protocol of a longitudinal mixed methods study. AB - INTRODUCTION: Parkinson's disease affects many aspects of the lives of patients and their relatives. Patients must adapt continuously to disabilities that necessitate changes in (medical) support, such as domestic adjustments, involvement of (non)professional caregivers or admission to hospital. Such changes mark a transition: a transfer of a patient between levels or locations of care. Transitions are likely to be multifold and complex, given that Parkinson's disease care extends across all echelons of healthcare. Patients and relatives are vulnerable during a transition, which imposes risks for their safety and quality of life. Guidance by the general practitioner, who knows the preferences of the patient, can help to overcome challenges associated with a transition. However, patient-centred primary care requires insight into the transitions patients with Parkinson's disease encounter. We aim to examine these transitions and the way patients, relatives and general practitioners experience them and cope with them. Moreover, we will study the patients' expectations of their general practitioner during a transition and the general practitioners' views on their role. METHODS AND ANALYSIS: A longitudinal mixed methods study will be conducted, using qualitative research methods combined with quantitative data as a validated questionnaire on quality of life. Patients will be asked to make a video diary every 2 weeks for a period of 1 year. Once they encounter a transition, patients and their general practitioners will be interviewed to identify causes and consequences of the transition. The verbatim transcripts of the videos and interviews will be analysed according to the principles of constant comparative analysis. ETHICS AND DISSEMINATION: Ethical approval was not needed according to Dutch legislation. Informed consent of patients, relatives and general practitioners will be obtained. We will disseminate the results in peer-reviewed journals, at research conferences and on the website of the Dutch Parkinson's Disease Association. PMID- 26038357 TI - Perinatal risk factors for premature ischaemic heart disease in a Swedish national cohort. AB - OBJECTIVE: Several studies have reported associations between restricted fetal development, as shown by birth weight or birth length, and later ischaemic heart disease (IHD). However, few studies have examined the importance of these perinatal factors when taking into account gestational age at birth, hereditary factors, sociodemographic factors and comorbidities. This study investigated the importance of perinatal risk factors for premature IHD and myocardial infarction (MI) in a large Swedish cohort. SETTING AND PARTICIPANTS: National cohort study of 1,970,869 individuals who were live-born in Sweden in 1973 through 1992, and followed up to 2010 (ages 18-38 years). PRIMARY AND SECONDARY OUTCOME MEASURES: The main outcome was IHD, and the secondary outcome was MI. RESULTS: A total of 668 individuals were diagnosed with IHD in 18.8 million person-years of follow up. After adjusting for gestational age at birth, sociodemographic factors, comorbidities and family history of IHD, low fetal growth was associated with increased risk of IHD (HR for <-2 vs -1 to <1 SD, 1.54; 95% CI 1.15 to 2.07; p=0.004) and increased risk of MI (HR for <-2 vs -1 to <1 SD, 2.48; 95% CI 1.66 to 3.71; p<0.001) in young adulthood. In contrast, gestational age at birth was not associated with the risk of IHD or MI. CONCLUSIONS: In this large national cohort, low fetal growth was strongly associated with IHD and MI in young adulthood, independently of gestational age at birth, sociodemographic factors, comorbidities and family history of IHD. PMID- 26038356 TI - Ibandronate to treat skeletal-related events and bone pain in metastatic bone disease or multiple myeloma: a meta-analysis of randomised clinical trials. AB - OBJECTIVE: Randomised controlled trials (RCTs) have given contradictory results about the efficacy and safety of ibandronate in treating metastatic bone disease (MBD) or multiple myeloma. This review meta-analysed the literature to gain a more comprehensive picture. DESIGN: Systematic review and meta-analysis of ibandronate compared with placebo or zoledronate. DATA SOURCES: PubMed, EMBASE and the Cochrane Library databases were systematically searched to identify RCTs published up to March 2015 evaluating ibandronate to treat MBD or multiple myeloma. REVIEW METHOD: 10 RCTs involving 3474 patients were included. Six RCTs were placebo-controlled and four compared ibandronate with zoledronate. The studies included in this review were mainly from European countries. RESULTS: Intravenous ibandronate (6 mg) or oral drug (50 mg) decreased the risk of skeletal-related events compared to placebo (risk ratio (RR) 0.80, 95% CI 0.71 to 0.90, p=0.002). It also reduced the bone pain score below baseline significantly more than did placebo at 96 weeks (weighted mean difference -0.41, 95% CI -0.56 to -0.27, p<0.001). The incidence of diarrhoea, nausea and adverse renal events was similar between the ibandronate and placebo groups, but ibandronate was associated with greater risk of abdominal pain. Ibandronate was associated with similar risk of skeletal-related events as another bisphosphonate drug, zoledronate (RR 1.02, 95% CI 0.82 to 1.26, p=0.87). The incidence of nausea, jaw osteonecrosis and fatigue was similar for the two drugs, but the incidence of adverse renal events was significantly lower in the ibandronate group. CONCLUSIONS: Ibandronate significantly reduces the incidence of skeletal-related events and bone pain in patients with MBD or multiple myeloma relative to placebo. It is associated with a similar incidence of skeletal-related events as zoledronate. PMID- 26038358 TI - Selected maternal morbidities in women with a prior caesarean delivery planning vaginal birth or elective repeat caesarean section: a retrospective cohort analysis using data from the UK Obstetric Surveillance System. AB - OBJECTIVE: To conduct a secondary analysis of data from the UK Obstetric Surveillance System (UKOSS) to estimate the rates of specific maternal risks associated with planned vaginal birth after caesarean (VBAC) and elective repeat caesarean section (ERCS). DESIGN: A retrospective cohort analysis using UKOSS data from 4 studies conducted between 2005 and 2012. SETTING: All hospitals with consultant-led maternity units in the UK. POPULATION: Pregnant women who had a previous caesarean section. METHOD: Women who had undergone a previous caesarean section were divided into 2 exposure groups: planned VBAC and ERCS. We calculated the incidence of each of the 4 outcomes of interest with 95% CIs for the 2 exposure groups using proxy denominators (total estimated VBAC and ERCS maternities in a given year). Incidences were compared between groups using chi(2) test or Fisher's exact test and risk ratios with 95% CI. MAIN OUTCOME MEASURES: Severe maternal morbidities: peripartum hysterectomy, severe sepsis, peripartum haemorrhage and failed tracheal intubation. RESULTS: The risks of all complications examined in both groups were low. The rates of peripartum hysterectomy, severe sepsis, peripartum haemorrhage and failed tracheal intubation were not significantly different between the 2 groups in absolute or relative terms. CONCLUSIONS: While the risk of uterine rupture in the VBAC and ERCS groups is well understood, this national study did not demonstrate any other clear differences in the outcomes we examined. The absolute and relative risks of maternal complications were small in both groups. Large epidemiological studies could further help to assess whether the incidence of these rare outcomes would significantly differ between the VBAC and ERCS groups if a larger number of cases were to be examined. In the interim, this study provides important information to help pregnant women in their decision-making process. PMID- 26038359 TI - Trends in dietary cholesterol intake among Chinese adults: a longitudinal study from the China Health and Nutrition Survey, 1991-2011. AB - OBJECTIVES: Dietary cholesterol is the leading risk factor for cardiovascular disease and other chronic diseases. Changes in dietary patterns in China recently might have an impact on the trends of diet-related risk factors of chronic diseases. This study aims to monitor the changes in daily cholesterol intake and its food sources in Chinese adults. DESIGN: A longitudinal study using demographic and dietary data of adults younger than 60 years from eight waves (1991-2011) of the China Health and Nutrition Surveys was conducted. Mixed-effect models were used in this study. SETTING: The data were derived from urban and rural communities in nine provinces (autonomous regions) in China. PARTICIPANTS: There were 21,273 participants (10,091 males and 11,182 females) in this study. OUTCOMES: The major outcome is daily cholesterol intake amount, which was calculated by using the Chinese Food Composition Table, based on dietary data. RESULTS: The mean daily cholesterol intake in Chinese adults increased from 165.8 mg/day in 1991 to 266.3 mg/day in 2011. Cholesterol consumed by participants in different age (18-39 and 40-59 years), sex and urbanisation groups steadily elevated over time (p<0.0001), as did the proportions of participants with greater than 300 mg/day cholesterol consumption. In each subgroup, cholesterol originating from most of the food groups showed increasing trends over time (p<0.0001), except for animal fat and organ meats. Eggs, pork, fish and shellfish in that order remained the top three sources in 1991, 2000 and 2011, whereas milks were a negligible contributor. Cholesterol from animal fat declined and was insignificant in 2011 in most of the subgroups, while cholesterol being of poultry origin increased and became considerable in 2011. CONCLUSIONS: Adults in China consumed increasingly high cholesterol and deviated from the recommended intake level over the past two decades. Adults need to pay more attention to intakes of eggs, pork, fish and shellfish. PMID- 26038360 TI - The ETTAA study protocol: a UK-wide observational study of 'Effective Treatments for Thoracic Aortic Aneurysm'. AB - INTRODUCTION: Chronic thoracic aortic aneurysm (CTAA) affecting the arch or descending aorta is an indolent but life-threatening condition with a rising prevalence as the UK population ages. Treatment may be in the form of open surgical repair (OSR) surgery, endovascular stent grafting (ESG) or best medical therapy (BMT). Currently, there is no consensus on the best management strategy, and no UK-specific economic studies that assess outcomes beyond the chosen procedure, but this is required in the context of greater demand for treatment and limited National Health Service (NHS) resources. METHODS AND ANALYSIS: This is a prospective, multicentre observational study with statistical and economic modelling of patients with CTAA affecting the arch or descending aorta. We aim to gain an understanding of how treatments are currently chosen, and to determine the clinical effectiveness and cost-effectiveness of the three available treatment strategies (BMT, ESG and OSR). This will be achieved by: (1) following consecutive patients who are referred to the teams collaborating in this proposal and collecting data regarding quality of life (QoL), medical events and hospital stays over a maximum of 5 years; (2) statistical analysis of the comparative effectiveness of the three treatments; and (3) economic modelling of the comparative cost-effectiveness of the three treatments. Primary study outcomes are: aneurysm growth, QoL, freedom from reintervention, freedom from death or permanent neurological injury, incremental cost per quality-adjusted life year gained. ETHICS AND DISSEMINATION: The study will generate an evidence base to guide patients and clinicians to determine the indications and timing of treatment, as well as informing healthcare decision-makers about which treatments the NHS should provide. The study has achieved ethical approval and will be disseminated primarily in the form of a Health Technology Assessment monograph at its completion. TRIAL REGISTRATION NUMBER: ISRCTN04044627. PMID- 26038361 TI - Insulin treatment of maternal diabetes mellitus and respiratory outcome in late preterm and term singletons. AB - OBJECTIVES: While the incidence of diabetes mellitus (DM) during pregnancy has been steadily increasing in recent years, the link between gestational DM and respiratory outcome in neonates has not been definitely established. We asked the question whether DM status and its treatment during pregnancy could influence the risk of neonatal respiratory distress. DESIGN: We studied in a large retrospective cohort the relationship between maternal DM status (non-DM, insulin treated DM (IT-DM) and non-insulin-treated DM (NIT-DM)), and respiratory distress in term and near-term inborn singletons. RESULTS: Among 18,095 singletons delivered at 34 weeks of gestation or later, 412 (2.3%) were admitted to the neonatal intensive care unit (NICU) for respiratory distress within the first hours of life. The incidence of NICU admission due to respiratory distress groups was 2.2%, 5.7% and 2.1% in the non-DM, IT-DM and NIT-DM groups, respectively. Insulin treatment of DM, together with several other perinatal factors, was associated with a significant increased risk for respiratory distress. Several markers of the severity of respiratory illness, including durations of mechanical ventilation and supplemental oxygen, and hypertrophic cardiomyopathy were also found increased following IT-DM as compared with NIT-DM. In a multivariate model, we found that IT-DM, but not NIT-DM, was significantly associated with respiratory distress independent of gestational age and caesarean section, with an incidence rate ratio of 1.44 (1.00-2.08). CONCLUSIONS: This study shows that the treatment of maternal DM with insulin during pregnancy is an independent risk factor for respiratory distress in term and near-term newborns. PMID- 26038363 TI - Extreme mentoring in cardiothoracic surgery. PMID- 26038362 TI - The Association of Pain With Smoking and Quit Attempts in an Electronic Diary Study of Cancer Patients Trying to Quit. AB - INTRODUCTION: The purpose of this electronic daily diary study was to examine the relation of pain to smoking and quit attempts among 34 cancer patients with pain enrolled in a smoking cessation program. METHODS: Electronic daily diary assessments of pain and smoking were collected at the end of each day for a 2 week period during smoking cessation treatment. Pain experienced throughout the day was measured on a scale from 1 to 5, from "no pain" to "pain as bad as you can imagine." Smoking was defined as the number of cigarettes smoked per day. RESULTS: Linear multilevel modeling was used in examining associations between pain and smoking. A within-person pain and smoking association was found, such that greater daily pain was linked to greater daily smoking within individuals, controlling for baseline symptoms, nicotine dependence, smoking urge, age, and gender. No between-person pain and smoking association was observed. Additionally, cancer patients with higher average pain across the 2-week assessment period were less likely to make a quit attempt (defined as a day on which participants smoked no cigarettes) during the study period. CONCLUSIONS: The findings of this study add to a nascent literature on pain and smoking by providing initial evidence that pain may be a barrier to quitting among cancer patients who smoke and have pain. Future research examining the effectiveness of integrated pain and smoking cessation treatment in this population may be warranted. PMID- 26038364 TI - Shared Genomic Regions Between Derivatives of a Large Segregating Population of Maize Identified Using Bulked Segregant Analysis Sequencing and Traditional Linkage Analysis. AB - Delayed transition from the vegetative stage to the reproductive stage of development and increased plant height have been shown to increase biomass productivity in grasses. The goal of this project was to detect quantitative trait loci using extremes from a large synthetic population, as well as a related recombinant inbred line mapping population for these two traits. Ten thousand individuals from a B73 * Mo17 noninbred population intermated for 14 generations (IBM Syn14) were grown at a density of approximately 16,500 plants ha(-1). Flowering time and plant height were measured within this population. DNA was pooled from the 46 most extreme individuals from each distributional tail for each of the traits measured and used in bulk segregant analysis (BSA) sequencing. Allelic divergence at each of the ~1.1 million SNP loci was estimated as the difference in allele frequencies between the selected extremes. Additionally, 224 intermated B73 * Mo17 recombinant inbred lines were concomitantly grown at a similar density adjacent to the large synthetic population and were assessed for flowering time and plant height. Using the BSA sequencing method, 14 and 13 genomic regions were identified for flowering time and plant height, respectively. Linkage mapping with the RIL population identified eight and three regions for flowering time and plant height, respectively. Of the regions identified, three colocalized between the two populations for flowering time and two colocalized for plant height. This study demonstrates the utility of using BSA sequencing for the dissection of complex quantitative traits important for production of lignocellulosic ethanol. PMID- 26038365 TI - Nested Levels of Adaptive Divergence: The Genetic Basis of Craniofacial Divergence and Ecological Sexual Dimorphism. AB - Exemplary systems for adaptive divergence are often characterized by their large degrees of phenotypic variation. This variation represents the outcome of generations of diversifying selection. However, adaptive radiations can also contain a hierarchy of differentiation nested within them where species display only subtle phenotypic differences that still have substantial effects on ecology, function, and ultimately fitness. Sexual dimorphisms are also common in species displaying adaptive divergence and can be the result of differential selection between sexes that produce ecological differences between sexes. Understanding the genetic basis of subtle variation (between certain species or sexes) is therefore important for understanding the process of adaptive divergence. Using cichlids from the dramatic adaptive radiation of Lake Malawi, we focus on understanding the genetic basis of two aspects of relatively subtle phenotypic variation. This included a morphometric comparison of the patterns of craniofacial divergence between two ecologically similar species in relation to the larger adaptive radiation of Malawi, and male-female morphological divergence between their F2 hybrids. We then genetically map craniofacial traits within the context of sex and locate several regions of the genome that contribute to variation in craniofacial shape that is relevant to sexual dimorphism within species and subtle divergence between closely related species, and possibly to craniofacial divergence in the Malawi radiation as a whole. To enhance our search for candidate genes we take advantage of population genomic data and a genetic map that is anchored to the cichlid genome to determine which genes within our QTL regions are associated with SNPs that are alternatively fixed between species. This study provides a holistic understanding of the genetic underpinnings of adaptive divergence in craniofacial shape. PMID- 26038367 TI - The Safety and Efficacy of Cryolipolysis: A Systematic Review of Available Literature. AB - BACKGROUND: In the past decade, the practice of body contouring using cryolipolysis has increased tremendously. While numerous anecdotal reports extol the efficacy of this product, the majority of these studies are small, retrospective case-series that lack control groups. OBJECTIVE: The authors aim to systematically review available literature to better illustrate the efficacy and safety of this new procedure. METHODS: A systematic literature review performed using MEDLINE, Embase, PubMed, and Cochrane databases identified all published studies evaluating cryolipolysis for body contouring. RESULTS: A total of 34 articles up to February 2015 were identified. Nineteen articles matched the selection criteria and were included in the analysis. Sixteen were evaluated in the final analysis. A total of 1445 patients had reportable data for analysis of the safety profile. Twelve patients (0.82%) reported complications with the most common being diminished sensation lasting greater than 4 weeks. An aggregate total of 295 patients had objective data for evaluation of tissue reduction. The mean time from procedure to objective outcome evaluation was 3.83 months. The mean reduction of subcutaneous tissue was 19.55% with respect to a designated control site. CONCLUSIONS: Selective cryolipolysis appears, at short-term follow up, to reliably decrease subcutaneous tissue deposits. Reported complications are uncommon and appear to resolve without intervention. Future studies should aim to optimize patient selection and treatment characteristics while obtaining long term follow-up data. PMID- 26038366 TI - A Mutation in Caenorhabditis elegans NDUF-7 Activates the Mitochondrial Stress Response and Prolongs Lifespan via ROS and CED-4. AB - The mevalonate pathway is responsible for the synthesis of cholesterol, coenzyme Q, and prenyl groups essential for small GTPase modification and function, and for the production of dolichols important for protein glycosylation. Statins, i.e., cholesterol-lowering drugs that inhibit the rate-limiting enzyme in the mevalonate pathway, HMG-CoA reductase, are lethal to Caenorhabditis elegans even though this animal lacks the branch of the mevalonate pathway that leads to cholesterol synthesis. To better understand the effects of statins that are not related to cholesterol, we have adopted the strategy of isolating statin resistant C. elegans mutants. Previously, we showed that such mutants often have gain-of-function mutations in ATFS-1, a protein that activates the mitochondrial unfolded protein response. Here, we describe the isolation of a statin-resistant mutant allele of the NDUF-7 protein, which is a component of complex I in the mitochondrial electron transport chain. The novel nduf-7(et19) mutant also exhibits constitutive and ATFS-1-dependent activation of the mitochondrial unfolded protein response (UPR(mt)) and prolonged life span, both of which are mediated through production of ROS. Additionally, lifespan extension, but not activation, of the mitochondrial unfolded protein response was dependent on the pro-apoptotic gene ced-4. We conclude that the nduf-7(et19) mutant allele causes an increase in reactive oxygen species that activate ATFS-1, hence UPR(mt) mediated statin resistance, and extends life span via CED-4. PMID- 26038368 TI - Commentary on: The Development of Assessment Tools for Plastic Surgery Competencies. PMID- 26038369 TI - The Role of Microfat Grafting in Facial Contouring. AB - BACKGROUND: Congenital hypoplasia of facial bones has traditionally been treated by orthognathic surgery. However, the inherent invasiveness of orthognathic surgery often leads to a high complication rate. Facial fat grafting could be a less invasive method to correct facial deformities. OBJECTIVES: The aim of this study was to evaluate the results of microfat grafting for facial contouring. METHODS: This retrospective chart review evaluated 166 patients who were treated with microfat grafting for maxillary and/or mandibular hypoplasia. Pretreatment and posttreatment photographs were compared regarding improvement of facial contour, and complications were recorded. RESULTS: The follow-up period ranged from 4 months to 10 years (mean, 2 years 7 months). Thirty-eight percent of the patients had a refill procedure 6 or more months after the first procedure. A majority of the evaluated patients stated that they benefited from the microfat grafting, with ratings of excellent (50%), sufficient (48%), and poor (2%). Complications included visible fat lobules under the lower eyelid skin (7%), which was seen during the first 4 years and was resolved by changing the injection cannulae and technique, and fat resorption, which was seen in all patients, with a clinical range from +/-15% in the immobile malar area and chin region to +/-50% in the mobile lip area. CONCLUSIONS: Facial microfat grafting is a valuable alternative to more complicated advancement osetotomies being performed in patients solely for aesthetic reasons. The low morbidity and rapid recovery make facial microfat grafting a welcome tool in the armamentarium of the modern facial aesthetic surgeon. PMID- 26038370 TI - Motivations for seeking minimally invasive cosmetic procedures in an academic outpatient setting. AB - BACKGROUND: The demand for minimally invasive cosmetic procedures has continued to rise, yet few studies have examined this patient population. OBJECTIVES: This study sought to define the demographics, social characteristics, and motivations of patients seeking minimally invasive facial cosmetic procedures. METHODS: A prospective, single-institution cohort study of 72 patients was conducted from 2011 through 2014 at an urban academic medical center. Patients were aged 25 through 70 years; presented for botulinum toxin or soft tissue filler injections; and completed demographic, informational, and psychometric questionnaires before treatment. Descriptive statistics were conducted using Stata statistical software. RESULTS: The average patient was 47.8 years old, was married, had children, was employed, possessed a college or advanced degree, and reported an above-average income. Most patients felt that the first signs of aging occurred around their eyes (74.6%), and a similar percentage expressed this area was the site most desired for rejuvenation. Almost one-third of patients experienced a "major life event" within the preceding year, nearly half had sought prior counseling from a mental health specialist, and 23.6% were being actively prescribed psychiatric medication at the time of treatment. CONCLUSIONS: Patients undergoing injectable aesthetic treatments in an urban outpatient academic center were mostly employed, highly educated, affluent women who believed that their procedure would positively impact their appearance. A significant minority experienced a major life event within the past year, which an astute clinician should address during the initial patient consultation. This study helps to better understand the psychosocial factors characterizing this patient population. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26038371 TI - Preoperative Saline Implant Deflation in Revisional Aesthetic Breast Surgery. AB - BACKGROUND: Preoperative saline deflation is a clinically useful intervention in revisional breast surgery. It allows suspensory ligament recovery, reveals true glandular volume, and simplifies mastopexy markings. Presently unknown are the volumetric changes that occur after deflation. OBJECTIVES: The authors report the three-dimensional (3D) changes that occur with preoperative deflation prior to revisional breast surgery. METHODS: We reviewed available charts of revisional breast surgery patients who underwent preliminary saline implant deflation. Our protocol is deflation 4 weeks prior to revision. Three weeks following deflation, the patient is evaluated to finalize the operative plan, including the need for implants, mastopexy, and adjunctive procedures. A subset underwent 3D imaging to quantify the volumetric changes over the 3-week deflation period. RESULTS: Between 2002 and 2014, 55 patients underwent saline implant deflation prior to 57 revisional surgeries. Seventeen were revised without implants and 40 with implants. The 3D subset of 10 patients showed a mean 15.2% volume increase and 0.18 cm notch-to-nipple distance decrease over the 3 weeks following deflation and prior to definitive surgical correction. CONCLUSIONS: Breast volume increases and the notch-to-nipple distance decreases during the 3-week interval prior to reoperation. This "elastic breast recoil" occurs after the mass effect of the implant is removed, resulting in recovery of stretched suspensory ligaments and gland reexpansion. We believe 4 weeks is optimal for gland normalization. Ideal candidates include patients requiring secondary mastopexy without implants, implant downsizing in the same pocket, and secondary augmentation mastopexy. Preoperative saline deflation and 3D analyses are useful for preoperative planning in reoperative breast surgery. PMID- 26038372 TI - The rise of predatory journals: what difference does it make? PMID- 26038373 TI - Central Lip Lift as Aesthetic and Physiognomic Plastic Surgery: The Effect on Lower Facial Profile. AB - BACKGROUND: A central lip lift was introduced to Westerners in 1980s. However, no studies have been conducted on the facial aesthetic and physiognomic perspectives of a central lip lift in the Asian population. OBJECTIVES: The authors presented the central lip lift as aesthetic and physiognomic treatment in Asians and explained its effect on lower facial profile. METHODS: A retrospective chart review was performed in 202 cases of asians. The authors analyzed patient age, cause of long philtrum, purpose of the treatment, and postoperative satisfaction. The authors then performed an anthropometric assessment and a photographic analysis. RESULTS: The vertical disproportion of the lower face was improved after the treatment, and there was significant shortening of the philtrum length (P < .001) and an increase in a visible upper vermilion (P < .001). In Westerners, a long philtrum was mainly caused by the aging process. Aging patients (range, 40-59 years) underwent the central lip lift for upper lip rejuvenation. In contrast, in Asia, a long philtrum was primarily caused by bone retraction after an orthognathic surgery or orthodontic procedure. Young patients (range, 20-39 years old) underwent the central lip lift to correct a relatively lengthened philtrum after 2-jaw surgery. Furthermore, about half of the patients (52.0%) underwent the central lip lift for facial physiognomic improvement. CONCLUSIONS: In today's multiracial society, plastic surgeons planning a central lip lift in Asian patients should consider both aesthetic and physiognomic perspectives. Regardless of the aesthetic outcome, the surgeon should strive to maximize patient satisfaction. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26038374 TI - Commentary on: The Safety and Efficacy of Cryolipolysis: A Systematic Review of Available Literature. PMID- 26038375 TI - Nurses' knowledge and performance of the patients' bill of rights. AB - BACKGROUND: Observance of the patients' bill of rights is one of the main features of moral codes in hospitals. In this regard, nurses bear great responsibility because they spend a long time with patients. Therefore, the continuous evaluation of the nurses' performance and assessing their knowledge about the patients' bill of rights are a need. OBJECTIVES: We aimed to determine the nurses' awareness of the patients' rights and measure their performance in this regard. Research design and participants: This cross-sectional study was carried out in 2013. To measure the nurses' knowledge and performance, 250 nurses and 300 patients were surveyed. The participants were selected randomly from five teaching hospitals in Tehran, Iran. Two questionnaires, one for nurses (17 questions) and the other for patients (11 questions), were applied. The data were analyzed in SPSS software using descriptive and inferential statistics. Ethical consideration: The research protocol was submitted and approved by the research and ethics committees of the participating hospitals. Additionally, the consent of all of the participants was obtained before the study. FINDINGS: The mean score of the nurses' knowledge regarding the patients' rights was acceptable (69.85 +/- 11.7 of 85). Furthermore, the mean score of nurses' performance in observing the patients' rights was relatively acceptable (11.2 +/- 4.6 of 22). More experienced and educated nurses had higher knowledge regarding the patients' rights, and patients with higher education level or experience of being hospitalized were less satisfied with the nurses' performance. CONCLUSION: Nurses' knowledge of the patients' bill of rights was acceptable; however, observance of the patients' rights was not. It seems that notification of the patients' bill of rights has increased the nurses' awareness of the patients' rights, although improvement of the nurses' performance needs more extensive measures. PMID- 26038376 TI - Solving work-related ethical problems. AB - BACKGROUND: Nurse managers are responsible for solving work-related ethical problems to promote a positive ethical culture in healthcare organizations. OBJECTIVES: The aim of this study was to describe the activities that nurse managers use to solve work-related ethical problems. The ultimate aim was to enhance the ethical awareness of all nurse managers. RESEARCH DESIGN: The data for this descriptive cross-sectional survey were analyzed through inductive content analysis and quantification. Participants and research context: The data were collected in 2011 using a questionnaire that included an open-ended question and background factors. Participants were nurse managers working in Finnish healthcare organizations (n = 122). Ethical considerations: Permission for the study was given by the Finnish Association of Academic Managers and Experts of Health Sciences. FINDINGS: Nurse managers identified a variety of activities they use to solve work-related ethical problems: discussion (30%), cooperation (25%), work organization (17%), intervention (10%), personal values (9%), operational models (4%), statistics and feedback (4%), and personal examples (1%). However, these activities did not follow any common or systematic model. DISCUSSION AND CONCLUSION: In the future, nurse managers need a more systematic approach to solve ethical problems. It is important to establish new kinds of ethics structures in organizations, such as a common, systematic ethical decision-making model and an ethics club for nurse manager problems, to support nurse managers in solving work-related ethical problems. PMID- 26038377 TI - What ethics for case managers? Literature review and discussion. AB - BACKGROUND: Little is known about case managers' ethical issues and professional values. OBJECTIVES: This article presents an overview of ethical issues in case managers' current practice. Findings are examined in the light of nursing ethics, social work ethics and principle-based biomedical ethics. RESEARCH DESIGN: A systematic literature review was performed to identify and analyse empirical studies concerning ethical issues in case management programmes. It was completed by systematic content analysis of case managers' national codes of ethics. FINDINGS: Only nine empirical studies were identified, eight of them from North America. The main dilemmas were how to balance system goals against the client's interest and client protection against autonomy. Professional codes of ethics shared important similarities, but offered different responses to these two dilemmas. DISCUSSION: We discuss the respective roles of professional and organizational ethics. Further lines of research are suggested. PMID- 26038378 TI - Professional values of nurse lecturers at three universities in Colombia. AB - OBJECTIVE: To describe the professional values of the nurse lectures according to 241 nursing students, who participated voluntarily, in three different universities of Bogota. METHODOLOGY: This is a quantitative, descriptive cross sectional study that applied the Nurses Professional Values Scale-permission secured-Spanish; three dimensions of values were applied: ethics, commitment, and professional knowledge. Ethical consideration: Project had ethical review and approval from an ethics committee and participants were given information sheets to read before they agreed to participate in the project. FINDINGS: It was concluded that nursing students, in general, do perceive these values in their professors, and they give priority to the dimension of ethics, followed by the knowledge dimension, and finally, commitment. DISCUSSION: It is evident that professional values are transmitted by professors and students place importance to such values. Values related to the other's care are paramount in nursing training in Colombia as well as in other countries. CONCLUSION: It was found that participating students observed professors directly in relation to values focused on direct patient care, respect for privacy, respect for life, while matters related to professional improvement, participation in unions were not actually analyzed may be due to poor promotion activities and unions during undergraduate studies. The results obtained are primary approach to the study of values related to nursing, a topic which needs to be researched, something vital to all the country offering nursing training programs. PMID- 26038379 TI - Success of a sustained pharmaceutical care service with electronic adherence monitoring in patient with diabetes over 12 months. AB - We report on the first polypharmacy adherence monitoring over 371 days, integrated into a pharmaceutical care service (counselling, electronic multidrug punch cards, feedback on recent electronic records) for a 65-year-old man with diabetes after hospital discharge. The initial daily regimen of four times per day with 15 pills daily changed after 79 days into a daily regimen of two times per day with 9 pills daily for the next 292 days. The patient removed all medication from the multidrug punch cards (taking adherence 100%) and had 96.9% correct dosing intervals (timing adherence). The 57 evening doses showed the least variation in intake times at 17 h 45 min+/-8 min. Over the observation year, the patient was clinically stable. He was very satisfied with the multidrug punch card and the feedback on electronic records. In conclusion, long-term monitoring of polypharmacy was associated with the benefit of successful disease management. PMID- 26038380 TI - Targeted epidural patch with n-butyl cyanoacrylate (n-BCA) through a single catheter access site for treatment of a cerebral spinal fluid leak causing spontaneous intracranial hypotension. AB - Spontaneous intracranial hypotension (SIH) usually occurs in the setting of a spontaneous cerebral spinal fluid (CSF) leak. We report the first description of a case of SIH caused by a CSF leak which improved after a targeted epidural patch with n-butyl cyanoacrylate (n-BCA) at the right T1-T2 level. An 81-year-old woman presented with an orthostatic headache for 6 days. MRI of the brain with contrast demonstrated low lying cerebellar tonsils, an engorged transverse sinus flow void, bifrontal small subdural fluid collections, and diffuse dural enhancement. CT myelography showed extravasation of intrathecal contrast at the right T1-T2 level. A targeted epidural patch was performed by injection of n-BCA through a catheter at the right T1-T2 level. After treatment, the patient's symptoms immediately improved and she was without a headache at 1-year follow-up. PMID- 26038381 TI - First report of Nocardia fusca isolated in humans. AB - Nocardia fusca was first described in 1983; however, to date, no report of human infection has been done. In this work, we report the first case of N. fusca isolation during an episode of acute exacerbation in a patient with chronic obstructive pulmonary disease. The extent of the role of N. fusca as human pathogen still has to be determined. PMID- 26038382 TI - Primary herpes simplex virus infection mimicking cervical cancer. AB - We report the case of an 18-year-old woman presenting with ulceration of the cervix caused by primary type 2 herpes simplex infection in the absence of skin lesions. The differential diagnosis included cervical cancer and we referred the patient for urgent colposcopy. However, laboratory tests proved the viral aetiology of the cervical ulceration and the cervix had healed completely 3 weeks later. The case highlights the need to consider herpes simplex infection in the differential diagnosis of ulceration of the cervix even when there are no cutaneous signs of herpes. PMID- 26038383 TI - Mild encephalopathy with reversible splenial lesion in a patient with influenza A infection--first report in an adult patient in the USA. AB - We present a case of a 51-year-old man with panhypopituarism who developed clinically mild encephalopathy with a lesion in the splenium of the corpus callosum, in the setting of acute influenza A infection. The patient's initial presentation included hypernatraemia due to pre-existing iatrogenic central diabetes insipidus. Despite adequate treatment of hypernatraemia, his course was complicated by otherwise unexplained mild encephalopathy. Brain MRI revealed a diffusion restricted lesion in the splenium of the corpus callosum. This presentation was consistent with mild encephalopathy with reversible splenial lesion (MERS). The patient subsequently tested positive for influenza A. This is the first reported case of MERS syndrome due to influenza A infection in an adult patient in the USA. Mild encephalopathy associated with influenza A infection and a reversible splenial lesion of the corpus callosum has a favourable prognosis and resolves spontaneously. PMID- 26038384 TI - Clonidine withdrawal induced sympathetic surge. AB - A 30-year-old man with a history of epilepsy and substance misuse presented to the hospital with status epilepticus. Difficult seizure control necessitated anaesthetising the patient followed by intubation and ventilation. A clonidine infusion was started as the patient developed withdrawal syndrome and was difficult to wean off mechanical ventilation. Once the withdrawal syndrome was controlled, the clonidine was abruptly stopped. Two hours after stopping the infusion, the patient developed high-grade fever, severe hypertension, tachycardia, profound sweating and lacrimation. The patient then developed respiratory distress syndrome secondary to acute pulmonary oedema. Clonidine withdrawal as a cause of such response was proposed. Reversal of symptoms and successful reweaning was achieved by restarting a low-dose clonidine infusion followed by slow downward titration and use of oral clonidine as a step-down measure. The patient was subsequently discharged from the intensive care unit. PMID- 26038385 TI - Acute cervical artery dissection after a dental procedure due to a second inferior molar infection. AB - Periodontal infections might represent one of the causative factors for cervical artery dissection. We present a case of a 49-year-old woman admitted due to headache. The patient had been suffering from a right second inferior molar infection with a cervical phlegmon for 1 week prior to admission. On 2 October 2014, the patient went to the dentist and a molar extraction was performed in the morning. In the afternoon, the patient began to experience right hemifacial pain that progressed towards an intense and bilateral headache. Neurological status at the time of admission revealed right miosis, ptosis and conjuntival hyperaemia. A CT angiography showed a right internal carotid artery dissection provoking a high degree stenosis. The relationship between periodontal infection and vascular disease has been previously presented. Microbial agents may directly, and inflammatory and immunological host response indirectly, influence inflammatory changes in cervical arteries favouring dissections with minor traumas. PMID- 26038386 TI - Oscillococcinum leading to angioedema, a rare adverse event. AB - Oscillococcinum is an alternative medicine prepared by serial dilution of wild duck heart and liver extracts. This preparation has been labelled as a 'non drowsy, homoeopathic medicine' that 'reduces the duration and severity of flu and flu-like symptoms'. Clinical evidence exists to support this claim and the product has not previously been reported to cause any serious adverse drug reactions. We bring to light, however, a case of angioedema in our patient who was using oscillococcinum for flu-like symptoms. Consumers must therefore exercise caution at the outset of allergy symptoms. PMID- 26038387 TI - Eye injuries in the extreme environment ultra-marathon runner. AB - We present the case of an ultra-marathon runner who developed a painful irritated eye due to prolonged exposure to high wind speed and sub-zero temperatures causing transient freezing and subsequent abrasion of the cornea. We recommend that all ultra-marathon runners racing in windy or exposed conditions should wear wrap-around eye protection or goggles. If runners present to checkpoints or after the race to primary care or the emergency department with ocular pain, corneal freezing and abrasions should be considered. Management should include ocular examination and withdrawing the runner from harmful conditions. PMID- 26038389 TI - Fetal growth and subsequent maternal risk of colorectal cancer. AB - BACKGROUND: High birth weight has been associated with subsequent increased risk of breast cancer in the infant's mother, possibly related to maternal estrogen and growth factor pathways. However, its association with maternal risk of colorectal cancer, the third most common cancer among women, is unknown. METHODS: We conducted a national cohort study of 1,838,509 mothers who delivered 3,590,523 babies in Sweden in 1973-2008, followed up for colorectal cancer incidence through 2009. RESULTS: There were 7,318 mothers diagnosed with colorectal cancer in 36.8 million person-years of follow-up. After adjusting for maternal age, body mass index, diabetes, and other potential confounders, high fetal growth was associated with a subsequent increased risk of colorectal cancer in the mother [incidence rate ratio (IRR) per additional 1 SD relative to mean birth weight for gestational age and sex, 1.05; 95% confidence intervals (CI), 1.03-1.07; P < 0.0001]. Each 1,000 g increase in the infant's birth weight was associated with a 12% increase in the mother's subsequent risk of colorectal cancer (IRR, 1.12; 95% CI, 1.07-1.17; P < 0.0001). Multiple gestation was also independently associated with increased maternal risk of colorectal cancer (IRR for twin or higher order vs. singleton, 1.22; 95% CI, 1.04-1.44; P = 0.02). CONCLUSION: In this large cohort study, high fetal growth and multiple gestation were independently associated with subsequent higher maternal risk of colorectal cancer. These findings warrant further investigation of maternal growth factor and estrogen pathways in the etiology of colorectal cancer. IMPACT: If confirmed, our findings may help identify subgroups of women at high risk of colorectal cancer. PMID- 26038392 TI - Carotid Artery Sacrifice and Reconstruction in the Setting of Advanced Head and Neck Cancer. AB - OBJECTIVE: To determine oncological and neuromorbidity outcomes in patients with advanced head and neck cancer (stage IVB) requiring sacrifice and reconstruction of the carotid artery. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care referral center. SUBJECTS AND METHODS: Overall, 51 patients underwent carotid artery sacrifice during surgical treatment of the neck, in both the primary and salvage setting. All patients underwent autogenous in-line carotid artery bypass grafting with either saphenous vein or the deep femoral vein in conjunction with vascular surgery. In all, the study included 39 males and 12 female subjects, with age ranging from 39 to 82 (mean, 62.7). RESULTS: Two patients (3.9%) had a cerebral vascular accident in the immediate postoperative period. The remaining 49 patients (96%) had no neurologic sequela. Serial ultrasonic evaluation revealed 4 patients with intra-luminal thrombus within the site of reconstruction. Perioperative mortality occurred in a single patient. Disease-related mortality occurred in 9.8% (5) of patients, with an overall 2 year survival of 82%. CONCLUSIONS: We presently report the largest series of surgical treatment for advanced head and neck cancer with carotid artery involvement. We document an overall 2-year survival of 82% in the setting of low perioperative neuromorbidity and mortality rates. We therefore consider carotid artery sacrifice and autogenous vein graft reconstruction in the absence of distant metastatic disease as a viable treatment option for what was once thought to be a palliative procedure. PMID- 26038390 TI - Association between body mass index and mortality for colorectal cancer survivors: overall and by tumor molecular phenotype. AB - BACKGROUND: Microsatellite instability (MSI) and BRAF mutation status are associated with colorectal cancer survival, whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF mutation, sex, and other factors. METHODS: This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Prediagnosis BMI was derived from self-reported weight approximately one year before diagnosis and height. Tumor MSI and BRAF mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CI) were estimated from delayed-entry Cox proportional hazards models. RESULTS: In multivariable models, high prediagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5 kg/m(2); HR, 1.10; 95% CI, 1.06-1.15), with similar associations stratified by sex (Pinteraction: 0.41), colon versus rectum (Pinteraction: 0.86), MSI status (Pinteraction: 0.84), and BRAF mutation status (Pinteraction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR, 1.32; P value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR, 0.86; P value: 0.29), and approximately the same for MSI-high and obese BMI (HR, 1.00; P value: 0.98). CONCLUSIONS: High prediagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype. IMPACT: High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors. PMID- 26038391 TI - Fibrosis, gene expression and orbital inflammatory disease. AB - BACKGROUND/AIMS: To clarify the pathogenesis of fibrosis in inflammatory orbital diseases, we analysed the gene expression in orbital biopsies and compared our results with those reported for idiopathic pulmonary fibrosis. METHODS: We collected 140 biopsies from 138 patients (58 lacrimal glands; 82 orbital fat). Diagnoses included healthy controls (n=27), non-specific orbital inflammation (NSOI) (n=61), thyroid eye disease (TED) (n=29), sarcoidosis (n=14) and granulomatosis with polyangiitis (GPA) (n=7). Fibrosis was scored on a 0-3 scale by two experts, ophthalmic pathologists. Gene expression was quantified using Affymetrix U133 plus 2.0 microarray. RESULTS: Within orbital fat, fibrosis was greatest among subjects with GPA (2.75+/-0.46) and significantly increased in tissue from subjects with GPA, NSOI or sarcoidosis (p<0.01), but not for TED, compared with healthy controls (1.13+/-0.69). For lacrimal gland, the average score among controls (1.36+/-0.48) did not differ statistically from any of the four disease groups. Seventy-three probe sets identified transcripts correlating with fibrosis in orbital fat (false discovery rate <0.05) after accounting for batch effects, disease type, age and sex. Transcripts with increased expression included fibronectin, lumican, thrombospondin and collagen types I and VIII, each of which has been reported upregulated in pulmonary fibrosis. CONCLUSIONS: A pathologist's recognition of fibrosis in orbital tissue correlates well with increased expression of transcripts that are considered essential in fibrosis. Many transcripts implicated in orbital fibrosis have been previously implicated in pulmonary fibrosis. TED differs from other causes of orbital fat inflammation because fibrosis is not a major component. Marked fibrosis is less common in the lacrimal gland compared with orbital adipose tissue. PMID- 26038393 TI - The Minimal Clinically Important Difference in Vestibular Schwannoma Quality-of Life Assessment: An Important Step beyond P < .05. AB - OBJECTIVE: Several studies have demonstrated small but statistically significant differences in quality-of-life (QOL) scores among vestibular schwannoma (VS) treatment modalities. However, does a several-point difference on a 100-point scale really matter? The minimal clinically important difference (MCID)-defined as the smallest difference in scores that patients perceive as important and that could lead to a change in management-was developed to answer this important question. While the MCID has been determined for QOL measures used in other diseases, it remains undefined in the VS literature. STUDY DESIGN: Distribution- and anchor-based techniques were utilized to define the MCID for the Penn Acoustic Neuroma Quality of Life (PANQOL) and 36-Item Short Form Health Survey (SF-36). SETTING: Two academic referral centers. PATIENTS: Patients with VS (N = 538). INTERVENTION: Cross-sectional postal survey. MAIN OUTCOME MEASURES: MCID for PANQOL domains and total score and SF-36 Physical and Mental Health Component Summary scores. RESULTS: The MCID (median, interquartile range) for the PANQOL total score was 11 points (10-12); the MCIDs for individual domains were as follows: hearing, 6 (5-8); balance, 16 (14-19); facial, 10 (no interquartile range); pain, 11 (10-13); energy, 13 (10-17); anxiety, 11 (5-22); and general, 15 (11-19). The MCID was 7 points (6-11) for the SF-36 Mental Health Component Summary score and 8 points (6-10) for the Physical Health Component Summary score. CONCLUSIONS: The MCIDs determined in the current study generally exceed differences reported in previous prospective studies, in which conclusions about QOL benefit (or harm) among VS treatment modalities were based on statistical significance alone. Moving forward, these MCIDs should be considered when interpreting results of VS QOL studies. PMID- 26038395 TI - The mitochondrial side of epigenetics. AB - The bidirectional cross talk between nuclear and mitochondrial DNA is essential for cellular homeostasis and proper functioning. Mitochondria depend on nuclear contribution for much of their functionality, but their activities have been recently recognized to control nuclear gene expression as well as cell function in many different ways. Epigenetic mechanisms, which tune gene expression in response to environmental stimuli, are key regulatory events at the interplay between mitochondrial and nuclear interactions. Emerging findings indicate that epigenetic factors can be targets or instruments of mitochondrial-nuclear cross talk. Additionally, the growing interest into mtDNA epigenetic modifications opens new avenues into the interaction mechanisms between mitochondria and nucleus. In this review we summarize the points of mitochondrial and nuclear reciprocal control involving epigenetic factors, focusing on the role of mitochondrial genome and metabolism in shaping epigenetic modulation of gene expression. The relevance of the new findings on the methylation of mtDNA is also highlighted as a new frontier in the complex scenario of mitochondrial-nuclear communication. PMID- 26038394 TI - Muscle transcriptome response to ACTH administration in a free-ranging marine mammal. AB - While much of our understanding of stress physiology is derived from biomedical studies, little is known about the downstream molecular consequences of adaptive stress responses in free-living animals. We examined molecular effectors of the stress hormones cortisol and aldosterone in the northern elephant seal, a free ranging study system in which extreme physiological challenges and cortisol fluctuations are a routine part of life history. We stimulated the neuroendocrine stress axis by administering exogenous adrenocorticotropic hormone (ACTH) and examined the resultant effects by measuring corticosteroid hormones, metabolites, and gene expression before, during, and following administration. ACTH induced an elevation in cortisol, aldosterone, glucose, and fatty acids within 2 h, with complete recovery observed within 24 h of administration. The global transcriptional response of elephant seal muscle tissue to ACTH was evaluated by transcriptomics and involved upregulation of a highly coordinated network of conserved glucocorticoid (GC) target genes predicted to promote metabolic substrate availability without causing deleterious effects seen in laboratory animals. Transcriptional recovery from ACTH was characterized by downregulation of GC target genes and restoration of cell proliferation, metabolism, and tissue maintenance pathways within 24 h. Differentially expressed genes included several adipokines not previously described in muscle, reflecting unique metabolic physiology in fasting-adapted animals. This study represents one of the first transcriptome analyses of cellular responses to hypothalamic-pituitary-adrenal axis stimulation in a free-living marine mammal and suggests that compensatory, tissue-sparing mechanisms may enable marine mammals to maintain cortisol and aldosterone sensitivity while avoiding deleterious long-term consequences of stress. PMID- 26038396 TI - Transport of Ebolavirus Nucleocapsids Is Dependent on Actin Polymerization: Live Cell Imaging Analysis of Ebolavirus-Infected Cells. AB - BACKGROUND: Transport of ebolavirus (EBOV) nucleocapsids from perinuclear viral inclusions, where they are formed, to the site of budding at the plasma membrane represents an obligatory step of virus assembly. Until now, no live-cell studies on EBOV nucleocapsid transport have been performed, and participation of host cellular factors in this process, as well as the trajectories and speed of nucleocapsid transport, remain unknown. METHODS: Live-cell imaging of EBOV infected cells treated with different inhibitors of cellular cytoskeleton was used for the identification of cellular proteins involved in the nucleocapsid transport. EBOV nucleocapsids were visualized by expression of green fluorescent protein (GFP)-labeled nucleocapsid viral protein 30 (VP30) in EBOV-infected cells. RESULTS: Incorporation of the fusion protein VP30-GFP into EBOV nucleocapsids was confirmed by Western blot and indirect immunofluorescence analyses. Importantly, VP30-GFP fluorescence was readily detectable in the densely packed nucleocapsids inside perinuclear viral inclusions and in the dispersed rod-like nucleocapsids located outside of viral inclusions. Live-cell imaging of EBOV-infected cells revealed exit of single nucleocapsids from the viral inclusions and their intricate transport within the cytoplasm before budding at the plasma membrane. Nucleocapsid transport was arrested upon depolymerization of actin filaments (F-actin) and inhibition of the actin nucleating Arp2/3 complex, and it was not altered upon depolymerization of microtubules or inhibition of N-WASP. Actin comet tails were often detected at the rear end of nucleocapsids. Marginally located nucleocapsids entered filopodia, moved inside, and budded from the tip of these thin cellular protrusions. CONCLUSIONS: Live-cell imaging of EBOV-infected cells revealed actin dependent long-distance transport of EBOV nucleocapsids before budding at the cell surface. These findings provide useful insights into EBOV assembly and have potential application in the development of antivirals. PMID- 26038397 TI - Modeling the Disease Course of Zaire ebolavirus Infection in the Outbred Guinea Pig. AB - BACKGROUND: Rodent models that accurately reflect human filovirus infection are needed as early screens for medical countermeasures. Prior work in rodents with the Zaire species of Ebola virus (ZEBOV) primarily used inbred mice and guinea pigs to model disease. However, these inbred species do not show some of the important features of primate ZEBOV infection, most notably, coagulation abnormalities. METHODS: Thirty-six outbred guinea pigs were infected with guinea pig-adapted ZEBOV and examined sequentially over an 8-day period to investigate the pathologic events that lead to death. RESULTS: Features of disease in ZEBOV infected outbred guinea pigs were largely consistent with disease in humans and nonhuman primates and included early infection of macrophages and dendritiform cells, apoptosis of bystander lymphocytes, and increases in levels of proinflammatory cytokines. Most importantly, dysregulation of circulating levels of fibrinogen, protein C activity, and antifibrinolytic proteins and deposition of fibrin in tissues demonstrated both biochemical and microscopic evidence of disseminated intravascular coagulation. CONCLUSIONS: These findings suggest that the outbred guinea pig model recapitulates ZEBOV infection of primates better than inbred rodent models, is useful for dissecting key events in the pathogenesis of ZEBOV, and is useful for evaluating candidate interventions prior to assessment in primates. PMID- 26038398 TI - Optimization of Prime-Boost Vaccination Strategies Against Mouse-Adapted Ebolavirus in a Short-Term Protection Study. AB - In nonhuman primates, complete protection against an Ebola virus (EBOV) challenge has previously been achieved after a single injection with several vaccine platforms. However, long-term protection against EBOV after a single immunization has not been demonstrated to this date. Interestingly, prime-boost regimens have demonstrated longer protection against EBOV challenge, compared with single immunizations. Since prime-boost regimens have the potential to achieve long-term protection, determining optimal vector combinations is crucial. However, testing prime-boost efficiency in long-term protection studies is time consuming and resource demanding. Here, we investigated the optimal prime-boost combination, using DNA, porcine-derived adeno-associated virus serotype 6 (AAV-po6), and human adenovirus serotype 5 (Ad5) vector, in a short-term protection study in the mouse model of EBOV infection. In addition, we also investigated which immune parameters were indicative of a strong boost. Each vaccine platform was titrated in mice to identify which dose (single immunization) induced approximately 20% protection after challenge with a mouse-adapted EBOV. These doses were then used to determine the protection efficacy of various prime-boost combinations, using the same mouse model. In addition, humoral and cellular immune responses against EBOV glycoprotein were analyzed by an enzyme-linked immunosorbent assay, a neutralizing antibody assay, and an interferon gamma-specific enzyme-linked immunospot assay. When DNA was used as a prime, Ad5 boost induced the best protection, which correlated with a higher cellular response. In contrast, when AAV-po6 or Ad5 were injected first, better protection was achieved after DNA boost, and this correlated with a higher total glycoprotein-specific immunoglobulin G titer. Prime-boost regimens using independent vaccine platforms may provide a useful strategy to induce long-term immune protection against filoviruses. PMID- 26038399 TI - The Role of Conserved N-Linked Glycans on Ebola Virus Glycoprotein 2. AB - BACKGROUND: N-linked glycosylation is a common posttranslational modification found on viral glycoproteins (GPs) and involved in promoting expression, cellular attachment, protection from proteases, and antibody evasion. The GP subunit GP2 of filoviruses contains 2 completely conserved N-linked glycosylation sites (NGSs) at N563 and N618, suggesting that they have been maintained through selective pressures. METHODS: We assessed mutants lacking these glycans for expression and function to understand the role of these sites during Ebola virus entry. RESULTS: Elimination of either GP2 glycan individually had a modest effect on GP expression and no impact on antibody neutralization of vesicular stomatitis virus pseudotyped with Ebola virus GP. However, loss of the N563 glycan enhanced entry by 2-fold and eliminated GP detection by a well-characterized monoclonal antibody KZ52. Loss of both sites dramatically decreased GP expression and abolished entry. Surprisingly, a GP that retained a single NGS at N563, eliminating the remaining 16 NGSs from GP1 and GP2, had detectable expression, a modest increase in entry, and pronounced sensitivity to antibody neutralization. CONCLUSIONS: Our findings support the importance of the GP2 glycans in GP expression/structure, transduction efficiency, and antibody neutralization, particularly when N-linked glycans are also removed from GP1. PMID- 26038401 TI - PulseNet China. PMID- 26038400 TI - Zoster Vaccine and the Risk of Postherpetic Neuralgia in Patients Who Developed Herpes Zoster Despite Having Received the Zoster Vaccine. AB - BACKGROUND: Although it is evident that zoster vaccination reduces postherpetic neuralgia (PHN) risk by reducing herpes zoster (HZ) occurrence, it is less clear whether the vaccine protects against PHN among patients who develop HZ despite previous vaccination. METHODS: This cohort study included immunocompetent patients with HZ. The vaccinated cohort included 1155 individuals who were vaccinated against HZ at age >=60 years and had an HZ episode after vaccination. Vaccinated patients were matched 1:1 by sex and age with unvaccinated patients. Trained medical residents reviewed the full medical record to determine the presence of HZ-related pain at 1, 2, 3, and 6 months after HZ diagnosis. The incidence of PHN was compared between vaccinated and unvaccinated -patients. RESULTS: Thirty vaccinated women (4.2%) experienced PHN, compared with 75 unvaccinated women (10.4%), with an adjusted relative risk of 0.41 (95% confidence interval, .26-.64). PHN occurred in 26 vaccinated men (6.0%) versus 25 unvaccinated men (5.8%), with an adjusted relative risk of 1.06 (.58-1.94). These associations did not differ significantly by age. CONCLUSIONS: Among persons experiencing HZ, prior HZ vaccination is associated with a lower risk of PHN in women but not in men. This sex-related difference may reflect differences in healthcare-seeking patterns and deserve further investigation. PMID- 26038402 TI - Naturally acquired Mycobacterium tuberculosis complex in laboratory pig-tailed macaques. AB - Here we present a case series from a primate research facility. The index case, a 4-year-old pig-tailed macaque (Macaca nemestrina) experimentally infected with chimeric simian-human immunodeficiency virus (SHIVSF162 P4), developed weight loss and was euthanized. Based on necropsy results the animal was diagnosed with opportunistic atypical mycobacteriosis associated with simian AIDS (SAIDS). Subsequently, tissues from the index animal, as well as tissues and oral mucosal swabs from six SHIV-infected contacts, were analyzed using molecular methods and found to contain nucleic acid sequences characteristic of Mycobacterium tuberculosis complex (MTBC). These data suggest that existing protocols fail to reliably detect MTBC infection in laboratory primates used as experimental models. PMID- 26038403 TI - In memory of Patrick Manson, founding father of tropical medicine and the discovery of vector-borne infections. AB - Patrick Manson, a clinician-scientist serving in China (1866-1889), discovered that many tropical infectious diseases require a vector peculiar to warm climate for person to person transmission. He demonstrated the nocturnal periodicity of microfilariae in the blood of patients with elephantiasis. These microfilariae undergo metamorphosis when ingested by the mosquito acting as the vector for the completion of their life cycle. Furthermore, he demonstrated the linkage between the lung fluke and endemic haemoptysis by finding operculated eggs in patients' sputa. He predicted that the miracidium from hatched eggs uses crustaceans, such as fresh-water snails found at tropical conditions, as the intermediate hosts in the life cycle of many trematodes. His vector hypothesis leads to vector control which is now the cornerstone for the World Health Organization's programme for the elimination/control of lymphatic filariasis, dracunculiasis and malaria. Before leaving China, he established the Alice Memorial Hospital, the Hong Kong College of Medicine for Chinese (the forerunner of the University of Hong Kong), and the Hong Kong Medical Society for medical service and education. He also incepted the Hong Kong Dairy Farm for supplying hygienic milk affordable by pregnant women, children and patients. PMID- 26038404 TI - Molecular evidence for interspecies transmission of H3N2pM/H3N2v influenza A viruses at an Ohio agricultural fair, July 2012. AB - Evidence accumulating in 2011-2012 indicates that there is significant intra- and inter-species transmission of influenza A viruses at agricultural fairs, which has renewed interest in this unique human/swine interface. Six human cases of influenza A (H3N2) variant (H3N2v) virus infections were epidemiologically linked to swine exposure at fairs in the United States in 2011. In 2012, the number of H3N2v cases in the Midwest had exceeded 300 from early July to September, 2012. Prospective influenza A virus surveillance among pigs at Ohio fairs resulted in the detection of H3N2pM (H3N2 influenza A viruses containing the matrix (M) gene from the influenza A (H1N1) pdm09 virus). These H3N2pM viruses were temporally and spatially linked to several human H3N2v cases. Complete genomic analyses of these H3N2pM isolates demonstrated >99% nucleotide similarity to the H3N2v isolates recovered from human cases. Actions to mitigate the bidirectional interspecies transmission of influenza A virus between people and animals at agricultural fairs may be warranted. PMID- 26038405 TI - Genetic relatedness of the novel human group C betacoronavirus to Tylonycteris bat coronavirus HKU4 and Pipistrellus bat coronavirus HKU5. AB - The recent outbreak of severe respiratory infections associated with a novel group C betacoronavirus (HCoV-EMC) from Saudi Arabia has drawn global attention to another highly probable "SARS-like" animal-to-human interspecies jumping event in coronavirus (CoV). The genome of HCoV-EMC is most closely related to Tylonycteris bat coronavirus HKU4 (Ty-BatCoV HKU4) and Pipistrellus bat coronavirus HKU5 (Pi-BatCoV HKU5) we discovered in 2006. Phylogenetically, HCoV EMC is clustered with Ty-BatCoV HKU4/Pi-BatCoV HKU5 with high bootstrap supports, indicating that HCoV-EMC is a group C betaCoV. The major difference between HCoV EMC and Ty-BatCoV HKU4/Pi-BatCoV HKU5 is in the region between S and E, where HCoV-EMC possesses five ORFs (NS3a-NS3e) instead of four, with low (31%-62%) amino acid identities to Ty-BatCoV HKU4/Pi-BatCoV HKU5. Comparison of the seven conserved replicase domains for species demarcation shows that HCoV-EMC is a novel CoV species. More intensive surveillance studies in bats and other animals may reveal the natural host of HCoV-EMC. PMID- 26038406 TI - Plague vaccines: current developments and future perspectives. AB - Despite many decades of intensive studies of Yersinia pestis, the causative agent of plague, there is no safe and efficient vaccine against this devastating disease. A recently developed F1/V subunit vaccine candidate, which relies mainly on humoral immunity, showed promising results in animal studies; however, its efficacy in humans still has to be carefully evaluated. In addition, those developing next-generation plague vaccines need to pay particular attention to the importance of eliciting cell-mediated immunity. In this review, we analyzed the current progress in developing subunit, DNA and live carrier platforms of delivery by bacterial and viral vectors, as well as approaches for controlled attenuation of virulent strains of Y. pestis. PMID- 26038407 TI - An insight into future antibacterial therapy. PMID- 26038408 TI - Identification and characterization of a novel incompatibility group X3 plasmid carrying bla NDM-1 in Enterobacteriaceae isolates with epidemiological links to multiple geographical areas in China. AB - The New Delhi metallo-beta-lactamase (NDM-1) is one of the most important resistance traits in Enterobacteriaceae. We characterized nine bla NDM-1 producing Enterobacteriaceae recovered from seven patients who have recently travelled or been treated in India (n=1) or mainland China (n=6) during December 2010-May 2012. All the China-linked patients had no links to the Indian subcontinent. The bla NDM-1 carrying plasmids belonged to the novel IncX3 (~50 kb, in seven isolates including two Escherichia coli, two Klebsiella pneumoniae, one Citrobacter freundii, one Enterobacter aerogenes and one E. cloacae), IncA/C2 (~140 kb, in one E. coli) or FII-F1B groups (~110 kb, in one E. coli). Restriction fragment length polymorphism analysis of the seven IncX3 plasmids revealed identical pattern in six and two bands difference in the remaining one. The IncX3 plasmids carrying bla NDM-1 were epidemiologically linked to Guangzhou (n=1), Hunan (n=4), Haifeng (n=1) and Dongguan (n=1) in mainland China. Complete sequencing of the IncX3 plasmid pNDM-HN380 revealed that it was 54 035 bp long and encoded 52 open reading frames. The bla NDM-1 gene was found in a transposon like structure flanked by ISAba125 and IS26, inserted into the plasmid genetic load region. The sequences of the bla NDM-1 containing module within the two IS elements were identical to those previously described for bla NDM-1-positive Tn125 in the plasmids or chromosome of Acinetobacter isolates. In summary, this is the first description of IncX3 plasmids carrying bla NDM-1. The findings indicate the worrisome involvement of an epidemic plasmid in the dissemination of NDM-1 in China. PMID- 26038409 TI - Compounding drugs contaminated with fungi: a recipe for disaster. PMID- 26038411 TI - Biosecurity and biosafety in research on emerging pathogens. PMID- 26038410 TI - Adaptive mutation in influenza A virus non-structural gene is linked to host switching and induces a novel protein by alternative splicing. AB - Little is known about the processes that enable influenza A viruses to jump into new host species. Here we show that the non-structural protein1 nucleotide substitution, A374G, encoding the D125G(GAT->GGT) mutation, which evolved during the adaptation of a human virus within a mouse host, activates a novel donor splice site in the non-structural gene, hence producing a novel influenza A viral protein, NS3. Using synonymous 125G mutations that do not activate the novel donor splice site, NS3 was shown to provide replicative gain-of-function. The protein sequence of NS3 is similar to NS1 protein but with an internal deletion of a motif comprised of three antiparallel beta-strands spanning codons 126 to 168 in NS1. The NS1-125G(GGT) codon was also found in 33 natural influenza A viruses that were strongly associated with switching from avian to mammalian hosts, including human, swine and canine populations. In addition to the experimental human to mouse switch, the NS1-125G(GGT) codon was selected on avian to human transmission of the 1997 H5N1 and 1999 H9N2 lineages, as well as the avian to swine jump of 1979 H1N1 Eurasian swine influenza viruses, linking the NS1 125G(GGT) codon with host adaptation and switching among multiple species. PMID- 26038412 TI - Pearls and pitfalls of genomics-based microbiome analysis. PMID- 26038414 TI - Detection of Plasmodium vivax in a child returning from India by use of broad range PCR and electrospray ionization mass spectrometry. AB - Plasmodium vivax is a common cause of imported malaria in the USA, second only to P. falciparum. We present a case of P. vivax malaria in a child returning from India. P. vivax was initially diagnosed by standard methodology and detected retrospectively by use of broad-range PCR and electrospray ionization mass spectrometry using a panel of primers designed to detect vector-borne pathogens. This is the first reported case of P. vivax detection using PCR and electrospray ionization mass spectrometry. PMID- 26038413 TI - Emerging virus diseases: can we ever expect the unexpected? AB - Emerging virus diseases are a major threat to human and veterinary public health. With new examples occurring approximately one each year, the majority are viruses originating from an animal host. Of the many factors responsible, changes to local ecosystems that perturb the balance between pathogen and principal host species is one of the major drivers, together with increasing urbanization of mankind and changes in human behavior. Many emerging viruses have RNA genomes and as such are capable of rapid mutation and selection of new variants in the face of environmental changes in host numbers and available target species. This review summarizes recent work on aspects of virus emergence and the current understanding of the molecular and immunological basis whereby viruses may cross between species and become established in new ecological niches. Emergence is hard to predict, although mathematical modeling and spatial epidemiology have done much to improve the prediction of where emergence may occur. However, much needs to be done to ensure adequate surveillance is maintained of animal species known to present the greatest risk thus increasing general alertness among physicians, veterinarians and those responsible for formulating public health policy. PMID- 26038415 TI - Welcome from the Editors-in-Chief. PMID- 26038417 TI - Future vaccines for a globalized world. PMID- 26038416 TI - Streptococcus pyogenes and re-emergence of scarlet fever as a public health problem. AB - Explosive outbreaks of infectious diseases occasionally occur without immediately obvious epidemiological or microbiological explanations. Plague, cholera and Streptococcus pyogenes infection are some of the epidemic-prone bacterial infections. Besides epidemiological and conventional microbiological methods, the next-generation gene sequencing technology permits prompt detection of genomic and transcriptomic profiles associated with invasive phenotypes. Horizontal gene transfer due to mobile genetic elements carrying virulence factors and antimicrobial resistance, or mutations associated with the two component CovRS operon are important bacterial factors conferring survival advantage or invasiveness. The high incidence of scarlet fever in children less than 10 years old suggests that the lack of protective immunity is an important host factor. A high population density, overcrowded living environment and a low yearly rainfall are environmental factors contributing to outbreak development. Inappropriate antibiotic use is not only ineffective for treatment, but may actually drive an epidemic caused by drug-resistant strains and worsen patient outcomes by increasing the bacterial density at the site of infection and inducing toxin production. Surveillance of severe S. pyogenes infection is important because it can complicate concurrent chickenpox and influenza. Concomitant outbreaks of these two latter infections with a highly virulent and drug-resistant S. pyogenes strain can be disastrous. PMID- 26038418 TI - 'Z(S)-MDR-TB' versus 'Z(R)-MDR-TB': improving treatment of MDR-TB by identifying pyrazinamide susceptibility. AB - Indispensable for shortening treatment of drug-susceptible tuberculosis (TB), pyrazinamide (PZA, Z) is also essential in the treatment of multidrug-resistant (MDR)-TB. While resistance to PZA in MDR-TB is associated with poor treatment outcome, bacillary susceptibility to PZA along with the use of fluoroquinolone (FQ) and second-line injectable drugs (SLIDs) may predict improved treatment success in MDR-TB. Despite a high prevalence of PZA resistance among MDR-TB patients (10%-85%), PZA susceptibility testing is seldom performed because of technical challenges. To improve treatment of MDR-TB, we propose to: (i) classify MDR-TB into PZA-susceptible MDR-TB (Z(S)-MDR-TB) and PZA-resistant MDR-TB (Z(R) MDR-TB); (ii) use molecular tests such as DNA sequencing (pncA, gyrA, rrs, etc.) to rapidly identify Z(S)-MDR-TB versus Z(R)-MDR-TB and susceptibility profile for FQ and SLID; (iii) refrain from using PZA in Z(R)-MDR-TB; and (iv) explore the feasibility of shortening the treatment duration of Z(S)-MDR-TB with a regimen comprising PZA plus at least two bactericidal agents especially new agents like TMC207 or PA-824 or delamanid which the bacilli are susceptible to, with one or two other agents. These measures may potentially shorten therapy, save costs, and reduce side effects of MDR-TB treatment. PMID- 26038419 TI - Tuberculosis vaccine research in China. AB - It is now privately acknowledged that there may be little if any perceptible impact of the national Bacille Calmette-Guerin (BCG) vaccination program on disease prevalence, despite the extensive coverage of the newborn infant population and likely benefit in the early years of life. A better preventive vaccine than BCG is now being sought by Chinese researchers. Urgency has been added to the control problem by the emergence of multidrug-resistant tuberculosis (TB). Furthermore, expensive second-line drugs seem unlikely to be made available by the government to treat drug-resistant cases, so attention in addition has turned to the potential of immunotherapy as an adjunct to chemotherapy. Research trends are summarized here. PMID- 26038420 TI - The role of biomedical research in global tuberculosis control: gaps and challenges: A perspective from the US National Institute of Allergy and Infectious Diseases, National Institutes of Health. AB - Tuberculosis (TB) has been a persistent public health concern for hundreds of years. Despite advances in medicine and science, eliminating this disease has been beyond our reach. Several organizations, including the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), have expressed their commitment to advancing biomedical research in TB in order to increase our understanding of the causative pathogen and the disease. This basic knowledge is a critical first step in the development and implementation of new therapeutics, vaccines and diagnostics. Collaboration between researchers is a key component to accomplishing this goal; product development can no longer be limited to separate programs. Rather, the interconnectedness and possible combination of interventions must be investigated. This review will discuss ongoing TB research including NIAID's role, as well as future research that is needed to improve TB control. Emphasizing the importance of coordination among researchers, funders and advocacy groups, we aim to illustrate the fact that biomedical research, and particularly basic research, is a vital part of a complementary approach to eliminating TB across the globe. PMID- 26038421 TI - Energy-Dense Formulae May Slow Gastric Emptying in the Critically Ill. AB - BACKGROUND: Enteral feed intolerance occurs frequently in critically ill patients and can be associated with adverse outcomes. "Energy-dense formulae" (ie, >1 kcal/mL) are often prescribed to critically ill patients to reduce administered volume and are presumed to maintain or increase calorie delivery. The aim of this study was to compare gastric emptying of standard and energy-dense formulae in critically ill patients. METHODS: In a retrospective comparison of 2 studies, data were analyzed from 2 groups of patients that received a radiolabeled 100-mL "meal" containing either standard calories (1 kcal/mL) or concentrated calories (energy-dense formulae; 2 kcal/mL). Gastric emptying was measured using a scintigraphic technique. Radioisotope data were collected for 4 hours and gastric emptying quantified. Data are presented as mean +/- SE or median [interquartile range] as appropriate. RESULTS: Forty patients were studied (n = 18, energy-dense formulae; n = 22, standard). Groups were well matched in terms of demographics. However, patients in the energy-dense formula group were studied earlier in their intensive care unit admission (P = .02) and had a greater proportion requiring inotropes (P = .002). A similar amount of calories emptied out of the stomach per unit time (P = .57), but in patients receiving energy-dense formulae, a greater volume of meal was retained in the stomach (P = .045), consistent with slower gastric emptying. CONCLUSIONS: In critically ill patients, the administration of the same volume of a concentrated enteral nutrition formula may not result in the delivery of more calories to the small intestine over time because gastric emptying is slowed. PMID- 26038422 TI - Two disciplines, one priority: the seamless integration of human and veterinary microbiology is urgent. PMID- 26038423 TI - The use of antibodies in the prophylaxis and treatment of infections. AB - The use of antibodies to provide passive immunity to infections has a long history. Although the coming of antibiotics greatly reduced its use for bacterial infections, it is still widely used for a variety of purposes which are reviewed here. The use of animal antisera gave way to the use of human convalescent serum as a source of antibodies and more recently human and monoclonal antibodies have become widely used, not just providing passive immunity but as therapeutic agents. The current uses of antibody therapy are discussed as are the problems of antibody-mediated immunopathology and how this can be avoided. More recent developments include the making of monoclonal antibodies that react with cross reacting determinants on flu viruses. Such antibodies are not usually made following infection and they provide a very promising approach to providing passive immunity that will be effective against a variety of different strains of the flu virus. It is also pointed out that passive immunotherapy can act as a surrogate vaccine providing that the subject gets infected while protected by the passive antibodies. Finally, there is a section on the possible use of oral antibodies given as food to prevent diseases such as infantile gastroenteritis. PMID- 26038424 TI - Receptor-binding domains of spike proteins of emerging or re-emerging viruses as targets for development of antiviral vaccines. AB - A number of emerging and re-emerging viruses have caused epidemics or pandemics of infectious diseases leading to major devastations throughout human history. Therefore, developing effective and safe vaccines against these viruses is clearly important for the protection of at-risk populations. Our previous studies have shown that the receptor-binding domain (RBD) in the spike protein of severe acute respiratory syndrome (SARS)-associated coronavirus (SARS-CoV) is a key target for the development of SARS vaccines. In this review, we highlight some key advances in the development of antiviral vaccines targeting the RBDs of spike proteins of emerging and re-emerging viruses, using SARS-CoV, influenza virus, Hendra virus (HeV) and Nipah virus (NiV) as examples. PMID- 26038425 TI - A significant number of reported Absidia corymbifera (Lichtheimia corymbifera) infections are caused by Lichtheimia ramosa (syn. Lichtheimia hongkongensis): an emerging cause of mucormycosis. AB - Recently, we and others reported the discovery of Lichtheimia ramosa (syn. Lichtheimia hongkongensis). We also hypothesized that a proportion of 'Absidia corymbifera (Lichtheimia corymbifera)' reported in the literature could be L. ramosa. In this study, we characterized 13 strains that had been reported as 'A. corymbifera (L. corymbifera)' in the literature over an 11-year period. Microscopic examination of agar block smear preparations of all 13 strains showed abundant circinate side branches and pleomorphic giant cells with finger-like projections of L. ramosa. ITS1-5.8S-ITS2 rRNA gene cluster (internal transcribed spacer (ITS)) and partial elongation factor-1alpha (EF1alpha) gene sequencing showed that all 13 strains were clustered with L. ramosa; partial beta-actin gene sequencing showed that most of the 13 strains were clustered with L. ramosa; and partial 28S rRNA gene sequencing showed that all 13 strains were clustered with L. ramosa, but one strain of L. corymbifera (HKU25) was also clustered with other strains of L. ramosa. A significant number of reported A. corymbifera (L. corymbifera) infections are L. ramosa infections which are of global distribution. In clinical microbiology laboratories, L. ramosa should be suspected if an Absidia-like mold that possesses abundant circinate side branches on the sporangiophores and pleomorphic giant cells with finger-like projections is observed. ITS and partial EF1alpha gene sequencing are more reliable than partial beta-actin and 28S rRNA gene sequencing for identification of the Lichtheimia species. PMID- 26038426 TI - Molecular biology and replication of hepatitis E virus. AB - Hepatitis E virus (HEV), a single-stranded, positive-sense RNA virus, is responsible for acute hepatitis E epidemics in many developing countries, and the virus is also endemic in some industrialized countries. Hepatitis E is a recognized zoonotic disease, and several animal species, including pigs, are potential reservoirs for HEV. The genome of HEV contains three open reading frames (ORFs). ORF1 encodes the nonstructural proteins, ORF2 encodes the capsid protein, and ORF3 encodes a small multifunctional protein. The ORF2 and ORF3 proteins are translated from a single, bicistronic mRNA. The coding sequences for these two ORFs overlap each other, but neither overlaps with ORF1. Whereas the mechanisms underlying HEV replication are poorly understood, the construction of infectious viral clones, the identification of cell lines that support HEV replication, and the development of small animal models have allowed for more detailed study of the virus. As result of these advances, recently, our understanding of viral entry, genomic replication and viral egress has improved. Furthermore, the determination of the T=1 and T=3 structure of HEV virus-like particles has furthered our understanding of the replication of HEV. This article reviews the latest developments in the molecular biology of HEV with an emphasis on the genomic organization, the expression and function of genes, and the structure and replication of HEV. PMID- 26038428 TI - Identification of a divergent O-acetyltransferase gene oac 1b from Shigella flexneri serotype 1b strains. AB - Shigella flexneri is a leading cause of bacterial dysentery in developing countries. Among the 15 known serotypes, four (1b, 3a, 3b and 4b) contain a group 6 epitope due to an acetyl group connected to the O-2 position of rhamnose III on the tetrasaccharide structure of the lipopolysaccharide. O-acetyltransferase encoded by a bacteriophage, Sf6, mediates the acetylation reaction. We found that the oac gene in serotype 1b strains was very different from that in serotypes 3a, 3b and 4b strains and is herein after referred to as oac 1b which shares with oac 88%-89% identity at the DNA level and 85% identity at the protein level. Considering that S. flexneri strains of serotypes 1-5 share a recent common ancestry, the divergent oac 1b is more likely to have been obtained from outside S. flexneri than to have undergone rapid divergence from the oac gene in the other serotypes (3a, 3b and 4b) within S. flexneri. The cloned oac 1b gene was found to perform the same acetylation function as oac. Analysis of the genomic regions flanking oac 1b showed that it was present in a prophage on the chromosome and the organizational structure is different from that of phage Sf6. Additionally, phage conversion assay showed that serotype 1b cannot be generated by infecting serotype 1a strains with Sf6. We conclude that oac 1b was carried by a non-Sf6 phage and is uniquely present in serotype 1b. PMID- 26038427 TI - Past, present and future molecular diagnosis and characterization of human immunodeficiency virus infections. AB - Substantive and significant advances have been made in the last two decades in the characterization of human immunodeficiency virus (HIV) infections using molecular techniques. These advances include the use of real-time measurements, isothermal amplification, the inclusion of internal quality assurance protocols, device miniaturization and the automation of specimen processing. The result has been a significant increase in the availability of results to a high level of accuracy and quality. Molecular assays are currently widely used for diagnostics, antiretroviral monitoring and drug resistance characterization in developed countries. Simple and cost-effective point-of-care versions are also being vigorously developed with the eventual goal of providing timely healthcare services to patients residing in remote areas and those in resource-constrained countries. In this review, we discuss the evolution of these molecular technologies, not only in the context of the virus, but also in the context of tests focused on human genomics and transcriptomics. PMID- 26038429 TI - Understanding the T cell immune response in SARS coronavirus infection. AB - The severe acute respiratory syndrome (SARS) epidemic started in late 2002 and swiftly spread across 5 continents with a mortality rate of around 10%. Although the epidemic was eventually controlled through the implementation of strict quarantine measures, there continues a need to investigate the SARS coronavirus (SARS-CoV) and develop interventions should it re-emerge. Numerous studies have shown that neutralizing antibodies against the virus can be found in patients infected with SARS-CoV within days upon the onset of illness and lasting up to several months. In contrast, there is little data on the kinetics of T cell responses during SARS-CoV infection and little is known about their role in the recovery process. However, recent studies in mice suggest the importance of T cells in viral clearance during SARS-CoV infection. Moreover, a growing number of studies have investigated the memory T cell responses in recovered SARS patients. This review covers the available literature on the emerging importance of T cell responses in SARS-CoV infection, particularly on the mapping of cytotoxic T lymphocyte (CTL) epitopes, longevity, polyfunctionality and human leukocyte antigen (HLA) association as well as their potential implications on treatment and vaccine development. PMID- 26038431 TI - Emerging hepatitis B virus infection in vaccinated populations: a rising concern? AB - Hepatitis B infection, especially by perinatal transmission, is endemic in Asian countries. After the first successful universal hepatitis B virus (HBV) vaccination programme for newborns in Taiwan, it became feasible to prevent HBV transmission and the resultant hepatocellular carcinoma in endemic countries. However, a small subset of vaccinated people have a suboptimal immunological response to vaccination, and the immunity of some young adults who were vaccinated as infants seems to have waned over time. Despite this loss, recent studies suggest that anamnestic anti-HBs antibody responses rapidly resume and eliminate acute HBV infection acquired through sexual contact or blood transfusion, even though the anti-HBs antibody titre has decreased below a protective level. These observations indicate prolonged protection by the HBV vaccine. Therefore, for people with a low infection risk, a universal booster vaccination is not currently recommended, but it should be considered for high risk groups. However, we still advocate close monitoring of acute hepatitis B among patients who lack a protective level of anti-HBs antibody and suggest a wait-and-see policy to determine the necessity for booster vaccines. PMID- 26038432 TI - Characterization of right ventricular remodeling in pulmonary hypertension associated with patient outcomes by 3-dimensional wall motion tracking echocardiography. AB - BACKGROUND: Adverse right ventricular (RV) remodeling has significant prognostic and therapeutic implications to patients with pulmonary hypertension (PH). However, differentiating RV adaption from adverse remodeling associated with poor outcomes is difficult. We hypothesized that novel 3-dimensional (3D) wall motion tracking echocardiography can differentiate morphological features of RV adaption from adverse remodeling heralding an unfavorable short-term prognosis in patients with PH. METHODS AND RESULTS: We studied 112 subjects: 92 patients with PH and 20 normal controls with 3D wall motion tracking for RV end-systolic volume index (ESVi), RV ejection fraction (EF), and RV global area strain. Patients with PH also had invasive hemodynamic measurements. Pressure-volume relations classified patients with PH into 3 groups, such as RV adapted, RV adapted-remodeled, and RV adverse-remodeled. The predefined combined end point was PH-related hospitalization, death, or lung surgery (lung transplantation or pulmonary endarterectomy) during 6 months. The 92 patients with PH had significantly larger RV volumes, lower RVEF and global area strain than normal controls as expected. Patients with PH classified as RV adapted (ESVi, <=72 mL/m(2)) had a more favorable clinical outcome than those classified as RV adapted-remodeled (ESVi, 73-113 mL/m(2)) or RV adverse-remodeled (ESVi, >=114 mL/m(2)): hazard ratio, 0.15; 95% confidence intervals, 0.07 to 0.39; P<0.0001. RV adverse-remodeled patients (ESVi, >=114 mL/m(2)) had worse short-term outcome than the RV adapted remodeled patients: hazard ratio, 2.2; 95% confidence interval, 0.91 to 5.39; P=0.04. CONCLUSIONS: Quantitative 3D echocardiography in patients with PH demonstrated morphological subsets of RV adaption and remodeling associated with clinical outcomes. PMID- 26038433 TI - Right ventricle in pulmonary hypertension: echocardiography strikes back? PMID- 26038430 TI - Avian influenza A H5N1 virus: a continuous threat to humans. AB - We report the first case of severe pneumonia due to co-infection with the emerging avian influenza A (H5N1) virus subclade 2.3.2.1 and Mycoplasma pneumoniae. The patient was a returning traveller who had visited a poultry market in South China. We then review the epidemiology, virology, interspecies barrier limiting poultry-to-human transmission, clinical manifestation, laboratory diagnosis, treatment and control measures of H5N1 clades that can be transmitted to humans. The recent controversy regarding the experiments involving aerosol transmission of recombinant H5N1 virus between ferrets is discussed. We also review the relative contribution of the poor response to antiviral treatment and the virus-induced hyperinflammatory damage to the pathogenesis and the high mortality of this infection. The factors related to the host, virus or medical intervention leading to the difference in disease mortality of different countries remain unknown. Because most developing countries have difficulty in instituting effective biosecurity measures, poultry vaccination becomes an important control measure. The rapid evolution of the virus would adversely affect the efficacy of poultry vaccination unless a correctly matched vaccine was chosen, manufactured and administered in a timely manner. Vigilant surveillance must continue to allow better preparedness for another poultry or human pandemic due to new viral mutants. PMID- 26038434 TI - Perinatal chronic hypoxia induces cortical inflammation, hypomyelination, and peripheral myelin-specific T cell autoreactivity. AB - pCH is an important risk factor for brain injury and long-term morbidity in children, occurring during the developmental stages of neurogenesis, neuronal migration, and myelination. We show that a rodent model of pCH results in an early decrease in mature myelin. Although pCH does increase progenitor oligodendrocytes in the developing brain, BrdU labeling revealed a loss in dividing progenitor oligodendrocytes, indicating a defect in mature cell replacement and myelinogenesis. Mice continued to exhibited hypomyelination, concomitant with long-term impairment of motor function, weeks after cessation of pCH. The implication of a novel neuroimmunologic interplay, pCH also induced a significant egress of infiltrating CD4 T cells into the developing brain. This pCH-mediated neuroinflammation included oligodendrocyte-directed autoimmunity, with an increase in peripheral myelin-specific CD4 T cells. Thus, both the loss of available, mature, myelin-producing glial cells and an active increase in autoreactive, myelin-specific CD4 T cell infiltration into pCH brains may contribute to early pCH-induced hypomyelination in the developing CNS. The elucidation of potential mechanisms of hypoxia-driven autoimmunity will expand our understanding of the neuroimmune axis during perinatal CNS disease states that may contribute to long-term functional disability. PMID- 26038435 TI - A highly pathogenic new bunyavirus emerged in China. AB - Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that was discovered in China in 2010. The causative agent has been identified as a new member of the Phlebovirus genus in the family Bunyaviridae and has been designated severe fever with thrombocytopenia virus (SFTSV). SFTSV infection can be transmitted person-to-person, and the average case fatality rate is approximately 10% in humans. There is a high seroprevalence of SFTSV infection in a wide range of domesticated animals, including sheep, goats, cattle, pigs, dogs and chickens. Ticks are suspected to be the vector that transmits the virus to humans. Currently, the SFTS endemic area is expanding. Therefore, SFTSV infection is an increasingly important public health threat. PMID- 26038436 TI - Prevalence of phocine distemper virus specific antibodies: bracing for the next seal epizootic in north-western Europe. AB - In 1988 and 2002, two major phocine distemper virus (PDV) outbreaks occurred in harbour seals (Phoca vitulina) in north-western European coastal waters, causing the death of tens of thousands seals. Here we investigated whether PDV is still circulating among seals of the Dutch coastal waters and whether seals have protective serum-antibodies against PDV. Therefore seal serum samples, collected from 2002 to 2012, were tested for the presence of PDV-neutralizing antibodies. Antibodies were detected in most seals in 2002 and 2003 while after 2003 antibodies were detected only in seals less than two month-old and adult seals that probably had survived the 2002 PDV-epizootic. We estimated the current proportion of seals with antibodies against PDV at 11%. These findings suggest that at present the vast majority of seals are not immune to PDV infection. PDV re-introduction in this area may cause a major epizootic with infection of >80% and mass-mortality of >50% of the population. PMID- 26038438 TI - Beyond buzzing: mosquito watching stimulates malaria bednet use-a household-based cluster-randomized controlled assessor blind educational trial. AB - Malaria remains a severe health problem in Sub-Saharan Africa, with approximately one million deaths and 365 million cases each year. In terms of malaria control, insecticide-treated bednets are an effective tool, and many organizations have distributed free or highly subsidized bednets in malaria endemic areas. Nevertheless, some recipients do not use bednets because of social, environmental or cultural factors. Making vulnerable populations aware of the presence of mosquitoes may improve bednet use among people owning but not using a bednet. We hypothesized that showing freshly collected mosquitoes from the vicinity could improve bednet use in households owning but not using bednets. To test this hypothesis, we applied a household-based cluster-randomized controlled assessor blind educational trial. Indirect observation of mosquitoes, via educational leaflets, produced no change in bednet use, while showing freshly captured mosquitoes led to a 13-fold increase in bednet use. Our results suggest that direct observation of freshly captured mosquitoes can encourage bednet use and may potentially improve effective bednet coverage for malaria control and elimination. PMID- 26038437 TI - The fibronectin-binding motif within FlpA facilitates Campylobacter jejuni adherence to host cell and activation of host cell signaling. AB - Campylobacter jejuni is a gram-negative, curved and rod-shaped bacterium that causes human gastroenteritis. Acute disease is associated with C. jejuni invasion of the intestinal epithelium. Epithelial cells infected with C. jejuni strains containing mutations in the FlpA and CadF fibronectin (Fn)-binding proteins exhibit reduced invasion of host cells and a C. jejuni CadF FlpA double mutant is impaired in the activation of epidermal growth factor receptor (EGFR) and Rho GTPase Rac1. Although these observations establish a role for Fn-binding proteins during C. jejuni invasion, their mechanistic contributions to invasion-associated signaling are unclear. We examined FlpA, a C. jejuni Fn-binding protein composed of three FNIII-like repeats D1, D2 and D3, to identify the interactions required for cellular adherence on pathogen-induced host cell signaling. We report that FlpA binds the Fn gelatin-binding domain via a motif within the D2 repeat. Epithelial cells infected with a flpA mutant exhibited decreased Rac1 activation and reduced membrane ruffling that coincided with impaired delivery of the secreted Cia proteins and reduced cell association. Phosphorylation of the Erk1/2 kinase, a downstream effector of EGFR signaling, was specifically associated with FlpA-mediated activation of beta1-integrin and EGFR signaling. In vivo experiments revealed that FlpA is necessary for C. jejuni disease based on bacterial dissemination to the spleen of IL-10(-/-) germ-free mice. Thus, a novel Fn-binding motif within FlpA potentiates activation of Erk1/2 signaling via beta1 integrin during C. jejuni infection. PMID- 26038439 TI - Incidence of methicillin-resistant Staphylococcus aureus infection in a children's hospital in the Washington metropolitan area of the United States, 2003 - 2010. AB - Methicillin-resistant Staphylococcus aureus (MRSA) has emerged as a major public health threat. In this retrospective cohort study, we included patients with laboratory-confirmed MRSA infections treated at Children's National Medical Center in Washington, District of Columbia between July 2003 and December 2010. The secular trends in the incidence rates of skin/soft tissue and invasive MRSA infections were assessed. Molecular analyses were performed on a subset of patients with invasive infections whose MRSA isolates were available for genotyping. The study identified 3750 patients with MRSA infections. The incidence of MRSA infections peaked in 2007 (incidence rate: 5.34 per 1000 patient-visits) and subsequently declined at a rate of 5% per year. By December 2010, the MRSA incidence rate reached 3.77 per 1000 patient-visits. Seventeen (14.7%) patients with invasive MRSA infections died, and the mortality risk significantly increased if the MRSA infections were healthcare-associated (HA) or if an isolate was resistant to clindamycin and/or trimethoprim/sulfamethoxazole. In conclusion, this study described a descending trend in MRSA infections in children since 2007. Although invasive MRSA infections only accounted for a small portion of the total MRSA infections, they were associated with a high mortality risk. The prevention and control of the spread of MRSA remains a crucial and challenging task. PMID- 26038440 TI - The expanding spectrum of human infections caused by Kocuria species: a case report and literature review. AB - Although not previously known to cause human infections, Kocuria species have now emerged as human pathogens, mostly in compromised hosts with severe underlying disease. Recently, there has been an increasing incidence of different types of Kocuria infections reported, most likely due to the adoption of better identification methods. Here, we report a case of peritonitis caused by Kocuria rosea in a diabetic nephropathy patient who was on continuous ambulatory peritoneal dialysis. Sepsis and peritonitis caused by K. rosea in our case yielded two identical Kocuria isolates from the peritoneal dialysate fluid within a period of three days. The infection was subsequently resolved by antibiotic treatment and catheter removal. In addition to reporting this case, we herein review the literature concerning the emergence of Kocuria as a significant human pathogen. The majority of cases were device-related, acquired in the hospital or endogenous, and different Kocuria species appear to share a common etiology of peritonitis. The overall disease burden associated with Kocuria appears to be high, and the treatment guidelines for diseases associated with Kocuria have not yet been clearly defined. PMID- 26038441 TI - Children of rural-to-urban migrant workers in China are at a higher risk of contracting severe hand, foot and mouth disease and EV71 infection: a hospital based study. AB - The incidence and severity of hand, foot and mouth disease have increased in mainland China since 2008. Therapies and vaccines are currently at different stages of development. This study aimed to determine the social factors associated with the outbreaks and severity of the disease in Chinese children. A multicentre, prospective, case-controlled study was conducted in Shanghai, Chongqing, Guangzhou and Shantou to identify the sociodemographic and behavioural risk factors for hand, foot and mouth disease. Children hospitalized for hand, foot and mouth disease were randomly enrolled from April to November 2011. Stool samples were collected to test for the presence of enterovirus 71 (EV71). A total of 443 children between 1.6 and 68 months of age were enrolled; 304 were uncomplicated cases and 139 were severe cases with central nervous system involvement. The overall detection rate of EV71 was 54.2%, and the positivity rate of EV71 was significantly higher in the severe group than in the uncomplicated group (82.0% versus 40.9%, odds ratio (OR): 8.35, P=0.000). The children of migrant workers (OR: 3.014, P=0.000) and children attending kindergarten (OR: 2.133, P=0.002) were significantly associated with a severe outcome of the disease (OR: 1.765, P=0.026). Our findings indicate that kindergarten attendance and migrant worker parents are the major risk factors associated with severe hand, foot and mouth disease in children <5 years of age. Future public health intervention vaccination campaigns should consider the particular difficulties of achieving high compliance with multiple-dose vaccination regimens in the children of migrant workers. PMID- 26038442 TI - Dolphin Morbillivirus: a lethal but valuable infection model. AB - Dolphin Morbillivirus (DMV), which has caused at least four epidemics in the Western Mediterranean during the last 20-25 years, may dramatically impact the health and conservation of striped dolphins (Stenella coeruleoalba) living in this area. The viral and host factors driving the host-DMV interaction, along with those related to the climate change that underlie the occurrence of DMV epidemics, warrant further investigation. PMID- 26038443 TI - Assessing the fitness of distinct clades of influenza A (H9N2) viruses. AB - Influenza A (H9N2) viruses are a genetically diverse population that infects wild and domestic avian species and mammals and contributed the internal gene segments to the A/H5N1 and A/H7N9 viruses associated with lethal human infections. Here we comprehensively assess the potential risk to mammals of a diverse panel of A/H9N2 viruses, representing the major H9N2 clades, using a combination of in vitro assays (e.g., antiviral susceptibility and virus growth in primary differentiated human airway cells) and in vivo assays (e.g., replication, transmission and/or pathogenicity of viruses in ducks, pigs, mice and ferrets). We observed that viruses isolated from humans, A/Hong Kong/1073/1999 and A/Hong Kong/33982/2009, had the highest risk potential. However, the A/swine/Hong Kong/9A-1/1998 and A/chicken/Hong Kong/G9/1997 viruses also displayed several features suggesting a fitness profile adapted to human infection and transmission. The North American avian H9N2 clade virus had the lowest risk profile, and the other viruses tested displayed various levels of fitness across individual assays. In many cases, the known genotypic polymorphisms alone were not sufficient to accurately predict the virus' phenotype. Therefore, we conclude that comprehensive risk analyses based on surveillance of circulating influenza virus strains are necessary to assess the potential for human infection by emerging influenza A viruses. PMID- 26038444 TI - Imino sugar glucosidase inhibitors as broadly active anti-filovirus agents. AB - Ebola virus and Marburg virus are members of the family of Filoviridae and are etiological agents of a deadly hemorrhagic fever disease. The clinical symptoms of Ebola and Marburg hemorrhagic fevers are difficult to distinguish and there are currently no specific antiviral therapies against either of the viruses. Therefore, a drug that is safe and effective against both would be an enormous breakthrough. We and others have shown that the folding of the glycoproteins of many enveloped viruses, including the filoviruses, is far more dependent upon the calnexin pathway of protein folding than are most host glycoproteins. Drugs that inhibit this pathway would be expected to be selectively antiviral. Indeed, as we summarize in this review, imino sugars that are competitive inhibitors of the host endoplasmic reticular alpha-glucosidases I and II, which are enzymes that process N-glycan on nascent glycoproteins and thereby inhibit calnexin binding to the nascent glycoproteins, have been shown to have antiviral activity against a number of enveloped viruses including filoviruses. In this review, we describe the state of development of imino sugars for use against the filoviruses, and provide an explanation for the basis of their antiviral activity as well as limitations. PMID- 26038445 TI - Progress towards a hepatitis C virus vaccine. AB - New drugs to treat hepatitis C are expected to be approved over the next few years which promise to cure nearly all patients. However, due to issues of expected drug resistance, suboptimal activity against diverse hepatitis C virus (HCV) genotypes and especially because of their extremely high cost, it is unlikely that these HCV drugs will substantially reduce the world's HCV carrier population of around 170 million in the near future or the estimated global incidence of millions of new HCV infections. For these reasons, there is an urgent need to develop a prophylactic HCV vaccine and also to determine if therapeutic vaccines can aid in the treatment of chronically infected patients. After much early pessimism on the prospects for an effective prophylactic HCV vaccine, our recent knowledge of immune correlates of protection combined with the demonstrated immunogenicity and protective animal efficacies of various HCV vaccine candidates now allows for realistic optimism. This review summarizes the current rationale and status of clinical and experimental HCV vaccine candidates based on the elicitation of cross-neutralizing antibodies and broad cellular immune responses to this highly diverse virus. PMID- 26038446 TI - The risk of Rift Valley fever virus introduction and establishment in the United States and European Union. AB - Rift Valley fever virus (RVFV) is an arthropod-borne disease resulting in severe morbidity and mortality in both human and ruminant populations. First identified in Kenya in 1930, the geographical range of RVFV has been largely constrained to the African continent, yet has recently spread to new regions, and is identified as a priority disease with potential for geographic emergence. We present a systematic literature review assessing the potential for RVFV introduction and establishment in the United States (US) and European Union (EU). Viable pathways for the introduction of RVFV include: transport of virus-carrying vectors, importation of viremic hosts and intentional entry of RVFV as a biological weapon. It is generally assumed that the risk of RVFV introduction into the US or EU is low. We argue that the risk of sporadic introduction is likely high, though currently an insufficient proportion of such introductions coincide with optimal environmental conditions. Future global trends may increase the likelihood of risk factors for RVFV spread. PMID- 26038447 TI - Slow immunological progression in HIV-1 CRF07_BC-infected injecting drug users. AB - Human immunodeficiency virus type 1 (HIV-1) circulating recombinant form (CRF) 07_BC has caused serious HIV-1 epidemics among injecting drug users (IDUs) in East Asia. Little is known about the characteristics of the virus and its impact on disease progression among the infected individuals. In this study, we compared immunological progression between 423 IDUs infected with CRF07_BC and 194 men who have sex with men (MSM) with primary subtype B infection, and a representative full-length CRF07_BC molecular clone, pCRF07_BC, was constructed to characterize the virus. We found that IDUs infected with CRF07_BC had significantly slower immunological progression in the Cox proportional hazards model (hazard ratio: 0.30; 95% confidence interval: 0.13-0.69; P=0.004). The constructed recombinant CRF07_BC viruses had a reduced processing of the Gag/Gag-Pol polyproteins, a decreased incorporation of Vpr in the virus particle, tethering of virus particles on the plasma membrane and decreased virus growth kinetics. These phenotypes are related to the unique 7-amino acid deletion in the p6 of CRF07_BC, since complementation of the 7-amino acid in pCRF07_BC could improve the defective phenotypes. In summary, compared with MSM infected with HIV-1 subtype B, IDUs infected with CRF07_BC had slower immunological progression, which is likely correlated with interference of virus particle maturation by the 7-amino acid deletion in p6. PMID- 26038449 TI - A threshold analysis of dengue transmission in terms of weather variables and imported dengue cases in Australia. AB - Dengue virus (DENV) transmission in Australia is driven by weather factors and imported dengue fever (DF) cases. However, uncertainty remains regarding the threshold effects of high-order interactions among weather factors and imported DF cases and the impact of these factors on autochthonous DF. A time-series regression tree model was used to assess the threshold effects of natural temporal variations of weekly weather factors and weekly imported DF cases in relation to incidence of weekly autochthonous DF from 1 January 2000 to 31 December 2009 in Townsville and Cairns, Australia. In Cairns, mean weekly autochthonous DF incidence increased 16.3-fold when the 3-week lagged moving average maximum temperature was <32 degrees C, the 4-week lagged moving average minimum temperature was >=24 degrees C and the sum of imported DF cases in the previous 2 weeks was >0. When the 3-week lagged moving average maximum temperature was >=32 degrees C and the other two conditions mentioned above remained the same, mean weekly autochthonous DF incidence only increased 4.6 fold. In Townsville, the mean weekly incidence of autochthonous DF increased 10 fold when 3-week lagged moving average rainfall was >=27 mm, but it only increased 1.8-fold when rainfall was <27 mm during January to June. Thus, we found different responses of autochthonous DF incidence to weather factors and imported DF cases in Townsville and Cairns. Imported DF cases may also trigger and enhance local outbreaks under favorable climate conditions. PMID- 26038448 TI - Receptor binding and transmission studies of H5N1 influenza virus in mammals. AB - The H5N1 influenza A virus that is currently circulating in Asia, Africa and Europe has resulted in persistent outbreaks in poultry with sporadic transmission to humans. Thus far, it is believed that H5N1 does not possess sufficient ability for human-to-human transmission and subsequent pandemic infection. Both receptor binding specificity and virus infectivity are key factors in determining whether influenza A virus becomes pandemic. The use of human viral isolates in various studies has helped to illustrate the changes in receptor binding specificity and virulence as a result of adaptation in humans. In this review, we highlight the important amino acids and domains of viral proteins related to receptor binding specificity that have been reported for humans and avians using mammalian models. Thus, this review will consolidate findings from studies that have shed light on the receptor binding and transmission characteristics of the H5N1 influenza virus, with the goal of improving our ability to predict the transmission efficiency or pandemic potential of new viral strains. PMID- 26038450 TI - Silent geographical spread of the H7N9 virus by online knowledge analysis of the live bird trade with a distributed focused crawler. AB - Unlike those infected by H5N1, birds infected by the newly discovered H7N9 virus have no observable clinical symptoms. Public health workers in China do not know where the public health threat lies. In this study, we used a distributed focused crawler to analyze online knowledge of the live bird trade in first-wave provinces, namely, Jiangsu, Zhejiang, Anhui, and Shanghai, to track the new H7N9 virus and predict its spread. Of the 18 provinces proposed to be at high risk of infection, 10 reported human infections and one had poultry specimens that tested positive. Five provinces (Xinjiang, Yunnan, Guizhou, Shaanxi, and Tibet) as well as Hong Kong, Macao, and Taiwan were proposed to have no risk of H7N9 virus infection from the live bird trade. These data can help health authorities and the public to respond rapidly to reduce damage related to the spread of the virus. PMID- 26038451 TI - Epidemiology, geographical distribution, and economic consequences of swine zoonoses: a narrative review. AB - We sought to review the epidemiology, international geographical distribution, and economic consequences of selected swine zoonoses. We performed literature searches in two stages. First, we identified the zoonotic pathogens associated with swine. Second, we identified specific swine-associated zoonotic pathogen reports for those pathogens from January 1980 to October 2012. Swine-associated emerging diseases were more prevalent in the countries of North America, South America, and Europe. Multiple factors were associated with the increase of swine zoonoses in humans including: the density of pigs, poor water sources and environmental conditions for swine husbandry, the transmissibility of the pathogen, occupational exposure to pigs, poor human sanitation, and personal hygiene. Swine zoonoses often lead to severe economic consequences related to the threat of novel pathogens to humans, drop in public demand for pork, forced culling of swine herds, and international trade sanctions. Due to the complexity of swine-associated pathogen ecology, designing effective interventions for early detection of disease, their prevention, and mitigation requires an interdisciplinary collaborative "One Health" approach from veterinarians, environmental and public health professionals, and the swine industry. PMID- 26038452 TI - Pathogen-host-environment interplay and disease emergence. AB - Gaining insight in likely disease emergence scenarios is critical to preventing such events from happening. Recent focus has been on emerging zoonoses and on identifying common patterns and drivers of emerging diseases. However, no overarching framework exists to integrate knowledge on all emerging infectious disease events. Here, we propose such a conceptual framework based on changes in the interplay of pathogens, hosts and environment that lead to the formation of novel disease patterns and pathogen genetic adjustment. We categorize infectious disease emergence events into three groups: (i) pathogens showing up in a novel host, ranging from spill-over, including zoonoses, to complete species jumps; (ii) mutant pathogens displaying novel traits in the same host, including an increase in virulence, antimicrobial resistance and host immune escape; and (iii) disease complexes emerging in a new geographic area, either through range expansion or through long distance jumps. Each of these categories is characterized by a typical set of drivers of emergence, matching pathogen trait profiles, disease ecology and transmission dynamics. Our framework may assist in disentangling and structuring the rapidly growing amount of available information on infectious diseases. Moreover, it may contribute to a better understanding of how human action changes disease landscapes globally. PMID- 26038453 TI - Protease activation mutants elicit protective immunity against highly pathogenic avian influenza viruses of subtype H7 in chickens and mice. AB - Protease activation mutants of the highly pathogenic avian influenza virus A/FPV/Rostock/34 (H7N1) have been generated that are fully dependent on the presence of trypsin for growth in cell culture. Unlike wild-type virus, the mutants do not induce systemic infection in chicken embryos and show low pathogenicity in both chicken embryos and adult chickens. Inactivated vaccines prepared from the mutants protected chickens and mice very efficiently against infection with highly pathogenic wild-type virus in a cross-reactive manner. The potential of these mutants to be used as veterinary and prepandemic vaccines will be discussed. PMID- 26038455 TI - Integrated whole-genome sequencing and temporospatial analysis of a continuing Group A Streptococcus epidemic. AB - Analysis of microbial epidemics has been revolutionized by whole-genome sequencing. We recently sequenced the genomes of 601 type emm59 Group A Streptococcus (GAS) organisms responsible for an ongoing epidemic of invasive infections in Canada and some of the United States. The epidemic has been caused by the emergence of a genetically distinct, hypervirulent clone that has genetically diversified. The ease of obtaining genomic data contrasts with the relatively difficult task of translating them into insightful epidemiological information. Here, we sequenced the genomes of 90 additional invasive Canadian emm59 GAS organisms, including 80 isolated recently in 2010-2011. We used an improved bioinformatics pipeline designed to rapidly process and analyze whole genome data and integrate strain metadata. We discovered that emm59 GAS organisms are undergoing continued multiclonal evolutionary expansion. Previously identified geographic patterns of strain dissemination are being diluted as mixing of subclones over time and space occurs. Our integrated data analysis strategy permits prompt and accurate mapping of the dissemination of bacterial organisms in an epidemic wave, permitting rapid generation of hypotheses that inform public health and virulence studies. PMID- 26038454 TI - Hepatitis B virus genetic variants: biological properties and clinical implications. AB - Hepatitis B virus (HBV) causes a chronic infection in 350 million people worldwide and greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. The majority of chronic HBV carriers live in Asia. HBV can be divided into eight genotypes with unique geographic distributions. Mutations accumulate during chronic infection or in response to external pressure. Because HBV is an RNA-DNA virus the emergence of drug resistance and vaccine escape mutants has become an important clinical and public health concern. Here, we provide an overview of the molecular biology of the HBV life cycle and an evaluation of the changing role of hepatitis B e antigen (HBeAg) at different stages of infection. The impact of viral genotypes and mutations/deletions in the precore, core promoter, preS, and S gene on the establishment of chronic infection, development of fulminant hepatitis and liver cancer is discussed. Because HBV is prone to mutations, the biological properties of drug-resistant and vaccine escape mutants are also explored. PMID- 26038457 TI - Pathobiology of hepatitis E: lessons learned from primate models. AB - Like the other hepatitis viruses, hepatitis E virus (HEV) has been difficult to study because of limitations in cell culture systems and small animal models. Much of what we know has come from epidemiological studies in developing countries and, more recently, in industrialized countries. However, the epidemiology is very different in these two settings: hepatitis E in developing countries is epidemic as well as sporadic, principally water-borne, most likely to cause disease in older children and young adults and relatively severe, especially in pregnant women; in industrialized countries the disease is sporadic, principally food-borne, most common in the elderly and probably associated with mostly inapparent infections. These differences are believed to be genotypically determined. To examine the biological parameters of hepatitis E, we have studied HEV infections in nonhuman primates, which are surrogates of man. Infections with HEV genotypes 1-3 were compared in rhesus and cynomolgus macaques and chimpanzees. In general, the biological characteristics of the different HEV genotypes mirrored their epidemiological characteristics. PMID- 26038456 TI - T-cell responses in hepatitis B and C virus infection: similarities and differences. AB - Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are global health problems affecting 600 million people worldwide. Indeed, HBV and HCV are hepatotropic viruses that can cause acute and chronic liver disease progressing to liver cirrhosis and even hepatocellular carcinoma. Furthermore, co-infections of HBV and HCV with HIV are emerging worldwide. These co-infections are even more likely to develop persistent infection and are difficult to treat. There is growing evidence that virus-specific CD4(+) and CD8(+) T-cell responses play a central role in the outcome and pathogenesis of HBV and HCV infection. While virus-specific T-cell responses are able to successfully clear the virus in a subpopulation of patients, failure of these T-cell responses is associated with the development of viral persistence. In this review article, we will discuss similarities and differences in HBV- and HCV-specific T-cell responses that are central in determining viral clearance, persistence and liver disease. PMID- 26038458 TI - Rare Elizabethkingia meningosepticum meningitis case in an immunocompetent adult. AB - Though Elizabethkingia meningosepticum typically causes meningitis in neonates, its occurrence in adult is rare, with sixteen cases described worldwide. We report a case of E. meningosepticum meningitis in an immunocompetent adult. Bacterial identification was made a day earlier than conventional method by using matrix assisted laser desorption ionization time-of-flight (MALDI-TOF) Vitek mass spectrometry RUO (VMS), which resulted in successful treatment with rifampin, trimethoprim-sulfamethoxazole, levofloxacin and minocycline. PMID- 26038459 TI - H7N9 avian influenza virus - search and re-search. PMID- 26038460 TI - A fatal case caused by novel H7N9 avian influenza A virus in China. PMID- 26038461 TI - Prevalence and characterization of influenza viruses in diverse species in Los Llanos, Colombia. AB - While much is known about the prevalence of influenza viruses in North America and Eurasia, their prevalence in birds and mammals in South America is largely unknown. To fill this knowledge gap and provide a baseline for future ecology and epidemiology studies, we conducted 2 years of influenza surveillance in the eastern plains (Los Llanos) region of Colombia. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) identified influenza viruses in wild birds, domestic poultry, swine and horses. Prevalence ranged from 2.6% to 13.4% across species. Swine showed the highest prevalence and were infected primarily with 2009 pandemic H1N1 (pH1N1) viruses genetically related to those in humans. In addition, we isolated H5N2 viruses from two resident species of whistling ducks (genus Dendrocygna) that differed completely from previous South American isolates, instead genetically resembling North American wild bird viruses. Both strains caused low pathogenicity in chickens and mammals. The prevalence and subtype diversity of influenza viruses isolated from diverse species within a small area of Colombia highlights the need for enhanced surveillance throughout South America, including monitoring of the potential transmissibility of low pathogenic H5N2 viruses from wild birds to domestic poultry and the emergence of reassortant viruses in domestic swine. PMID- 26038462 TI - Emerging human respiratory syncytial virus genotype ON1 found in infants with pneumonia in Beijing, China. PMID- 26038463 TI - Clinical presentation and sequence analyses of HA and NA antigens of the novel H7N9 viruses. AB - Recently, a novel H7N9 avian influenza A virus has led to a human influenza outbreak in China. Here we report a 64-year old man with possible history of chronic bronchitis died from the H7N9 infection in Huzhou City, Zhejiang Province in Eastern China. The patient had been exposed to poultry before disease onset. Phylogenetic analyses of hemagglutinin and neuraminidase genes showed a close genetic relationship between viruses from the patient and from poultry booths where he had visited, indicating that the patient may have been exposed from the infected poultry. Two poultry venders and close contacts of the patient were negative for H7N9, suggesting that there are some unknown mechanisms to prevent them from being infected by the novel H7N9 virus. Furthermore, we found five novel H7N9 virus-specific sequence variations in receptor-binding site of hemagglutinin, which may be associated with the acquisition of the ability to infect humans. PMID- 26038464 TI - Poor responses to oseltamivir treatment in a patient with influenza A (H7N9) virus infection. AB - In March 2013, the cases of human infection with influenza A of H7N9 subtype were first reported. Preliminary data suggested that the H7N9 isolates are sensitive to neuraminidase inhibitors, such as oseltamivir, which is the recommended choice of treatment. On April 2(nd), a 56-year-old male patient was presented with fever and cough to our hospital. He had previous history of close contact with another H7N9 patient. After caring for his wife (a confirmed H7N9 infection case died on April 3(rd)), this patient showed flu like symptoms on April 2(nd). On the same day, oseltamivir (75 mg bid) treatment was started. Throat swab specimens were screened for H7N9 virus by real-time reverse transcriptase-polymerase chain reaction. The patient was hospitalized on April 4(th). Initial specimens on April 4(th) and April 5(th) were negative for H7N9. But the specimen collected on April 10(th) was tested positive for H7N9. The result was confirmed by Shanghai Municipal Center of Disease Control and Prevention. By April 25(th) when we submitted this report, swab specimens of this patient were still positive for H7N9. This case calls for increased awareness of potential resistance of H7N9 to oseltamivir. PMID- 26038466 TI - Virus ecology: a gap between detection and prediction. PMID- 26038465 TI - Population dynamics of rhesus macaques and associated foamy virus in Bangladesh. AB - Foamy viruses are complex retroviruses that have been shown to be transmitted from nonhuman primates to humans. In Bangladesh, infection with simian foamy virus (SFV) is ubiquitous among rhesus macaques, which come into contact with humans in diverse locations and contexts throughout the country. We analyzed microsatellite DNA from 126 macaques at six sites in Bangladesh in order to characterize geographic patterns of macaque population structure. We also included in this study 38 macaques owned by nomadic people who train them to perform for audiences. PCR was used to analyze a portion of the proviral gag gene from all SFV-positive macaques, and multiple clones were sequenced. Phylogenetic analysis was used to infer long-term patterns of viral transmission. Analyses of SFV gag gene sequences indicated that macaque populations from different areas harbor genetically distinct strains of SFV, suggesting that geographic features such as forest cover play a role in determining the dispersal of macaques and SFV. We also found evidence suggesting that humans traveling the region with performing macaques likely play a role in the translocation of macaques and SFV. Our studies found that individual animals can harbor more than one strain of SFV and that presence of more than one SFV strain is more common among older animals. Some macaques are infected with SFV that appears to be recombinant. These findings paint a more detailed picture of how geographic and sociocultural factors influence the spectrum of simian-borne retroviruses. PMID- 26038467 TI - Salmonella type III effector SopB modulates host cell exocytosis. AB - Salmonella enterica pathogenesis is dependent on its ability to enter and replicate inside host cells. Replication occurs inside the Salmonella-containing vacuole (SCV), a vacuolar compartment that is modified by bacterial effectors secreted through the two type III secretion systems (T3SS-1 and T3SS-2). Type III effectors interact with the host cell endocytic pathway to aid replication. We investigated whether Salmonella effector proteins may also interact with the host's exocytic pathway. A secreted alkaline phosphatase (SEAP) assay indicated three Salmonella effectors inhibited the secretory pathway, although only Salmonella outer protein B (SopB) was confirmed to block exocytosis using a vesicular stomatitis virus glycoprotein-green fluorescent protein (VSVG-GFP) transport assay. The 4-phosphatase activity of SopB was crucial to its effect on exocytosis. The interaction with the secretory pathway could potentially be important for providing replicating Salmonella with nutrients, contributing membrane material necessary for SCV biogenesis, altering antibacterial peptide/protein secretion or manipulating cell surface proteins important in the host response to infection. PMID- 26038468 TI - Insulin-resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue. AB - Reduced vessel density in adipose tissue and skeletal muscle is associated with obesity and may result in decreased perfusion, decreased oxygen consumption, and insulin resistance. In the presence of VEGFA, Angiopoietin-2 (Angpt2) and Angiopoietin-1 (Angpt1) are central determinants of angiogenesis, with greater Angpt2:Angpt1 ratios promoting angiogenesis. In skeletal muscle, exercise training stimulates angiogenesis and modulates transcription of VEGFA, Angpt1, and Angpt2. However, it remains unknown whether exercise training stimulates vessel growth in human adipose tissue, and it remains unknown whether adipose angiogenesis is mediated by angiopoietin signaling. We sought to determine whether insulin-resistant subjects would display an impaired angiogenic response to aerobic exercise training. Insulin-sensitive (IS, N = 12) and insulin resistant (IR, N = 14) subjects had subcutaneous adipose and muscle (vastus lateralis) biopsies before and after 12 weeks of cycle ergometer training. In both tissues, we measured vessels and expression of pro-angiogenic genes. Exercise training did not increase insulin sensitivity in IR Subjects. In skeletal muscle, training resulted in increased vessels/muscle fiber and increased Angpt2:Angpt1 ratio in both IR and IS subjects. However, in adipose, exercise training only induced angiogenesis in IS subjects, likely due to chronic suppression of VEGFA expression in IR subjects. These results indicate that skeletal muscle of IR subjects exhibits a normal angiogenic response to exercise training. However, the same training regimen is insufficient to induce angiogenesis in adipose tissue of IR subjects, which may help to explain why we did not observe improved insulin sensitivity following aerobic training. PMID- 26038469 TI - Irisin evokes bradycardia by activating cardiac-projecting neurons of nucleus ambiguus. AB - Irisin is a newly identified hormone induced in muscle and adipose tissues by physical activity. This protein and its encoding gene have been identified in the brain; in addition, the precursor for irisin, FNDC5, can cross the blood-brain barrier. The fact that irisin is secreted during exercise together with the lower resting heart rate in athletes prompted us to investigate the effect of irisin on cardiac-projecting vagal neurons of nucleus ambiguus, a key regulatory site of heart rate. In vitro experiments in cultured nucleus ambiguus neurons indicate that irisin activates these neurons, inducing an increase in cytosolic Ca(2+) concentration and neuronal depolarization. In vivo microinjection of irisin into the nucleus ambiguus promotes bradycardia in conscious rats. Our study is the first to report the effects of irisin on the neurons controlling the cardiac vagal tone and to link a myokine to a cardioprotective role, by modulating central cardiovascular regulation. PMID- 26038470 TI - Exercise intensity modulates brachial artery retrograde blood flow and shear rate during leg cycling in hypoxia. AB - The purpose of this study was to elucidate the effect of exercise intensity on retrograde blood flow and shear rate (SR) in an inactive limb during exercise under normoxic and hypoxic conditions. The subjects performed two maximal exercise tests on a semi-recumbent cycle ergometer to estimate peak oxygen uptake (VO2peak) while breathing normoxic (inspired oxygen fraction [FIO2 = 0.21]) and hypoxic (FIO2 = 0.12 or 0.13) gas mixtures. Subjects then performed four exercise bouts at the same relative intensities (30 and 60% VO2peak) for 30 min under normoxic or hypoxic conditions. Brachial artery diameter and blood velocity were simultaneously recorded, using Doppler ultrasonography. Retrograde SR was enhanced with increasing exercise intensity under both conditions at 10 min of exercise. Thereafter, retrograde blood flow and SR in normoxia returned to pre exercise levels, with no significant differences between the two exercise intensities. In contrast, retrograde blood flow and SR in hypoxia remained significantly elevated above baseline and was significantly greater at 60% than at 30% VO2peak. We conclude that differences in exercise intensity affect brachial artery retrograde blood flow and SR during prolonged exercise under hypoxic conditions. PMID- 26038471 TI - Mutations in panD encoding aspartate decarboxylase are associated with pyrazinamide resistance in Mycobacterium tuberculosis. AB - Pyrazinamide (PZA) is a frontline anti-tuberculosis drug that plays a crucial role in the treatment of both drug susceptible and multidrug-resistant tuberculosis (MDR-TB). Resistance to PZA is most commonly associated with mutations in the pncA gene encoding nicotinamidase/pyrazinamidase which converts the prodrug PZA to the active form pyrazinoic acid (POA). RpsA (ribosomal protein S1) involved in trans-translation was recently shown to be a target of PZA and mutations in RpsA are found in some PZA-resistant TB strains. However, some other PZA-resistant strains lack mutations in either pncA or rpsA. To identify potential new mechanisms of PZA resistance, we isolated 174 in vitro mutants of M. tuberculosis H37Rv resistant to PZA to search for resistant isolates that do not have pncA or rpsA mutations. DNA sequencing revealed that 169 of the 174 (97.1%) PZA-resistant mutants had pncA mutations but 5 mutants lacked pncA or rpsA mutations. Whole genome sequencing analyses revealed that the 5 PZA resistant mutants had different mutations all occurring in the same gene panD encoding aspartate decarboxylase, which is involved in synthesis of beta-alanine that is a precursor for pantothenate and co-enzyme A biosynthesis. panD mutations were identified in naturally PZA-resistant Mycobacterium canetti strain and a PZA resistant MDR-TB clinical isolate. Future studies are needed to address the role of panD mutations in PZA resistance and confirm PanD as a new target of PZA. PMID- 26038472 TI - Severe fever with thrombocytopenia syndrome virus expands its borders. PMID- 26038473 TI - Perspectives of public health laboratories in emerging infectious diseases. AB - The world has experienced an increased incidence and transboundary spread of emerging infectious diseases over the last four decades. We divided emerging infectious diseases into four categories, with subcategories in categories 1 and 4. The categorization was based on the nature and characteristics of pathogens or infectious agents causing the emerging infections, which are directly related to the mechanisms and patterns of infectious disease emergence. The factors or combinations of factors contributing to the emergence of these pathogens vary within each category. We also classified public health laboratories into three types based on function, namely, research, reference and analytical diagnostic laboratories, with the last category being subclassified into primary (community based) public health and clinical (medical) analytical diagnostic laboratories. The frontline/leading and/or supportive roles to be adopted by each type of public health laboratory for optimal performance to establish the correct etiological agents causing the diseases or outbreaks vary with respect to each category of emerging infectious diseases. We emphasize the need, especially for an outbreak investigation, to establish a harmonized and coordinated national public health laboratory system that integrates different categories of public health laboratories within a country and that is closely linked to the national public health delivery system and regional and international high-end laboratories. PMID- 26038474 TI - Influenza A(H1N1)pdm09 virus infection in marine mammals in California. PMID- 26038475 TI - Mild infection of a novel H7N9 avian influenza virus in children in Shanghai. PMID- 26038476 TI - Recruitment of HIV-1 target cells at topical mucosal sites: a sensitive and early marker for determining the safety of microbicide candidates. AB - To explore early biomarkers for establishing more sensitive safety evaluation assays in preclinical settings that determine the potential risks during the application of microbicide candidates, three representative microbicide candidates (cellulose sulphate, nonoxynol-9 and tenofovir), whose safety profiles have been well established in clinical trials, were included to gauge the sensitivities of different assays. Both mouse models and cell lines were employed to determine the sensitivities. The recruitment of immune cells at topical mucosal sites and the upregulation of HIV receptor/coreceptors in vitro were identified as highly sensitive biomarkers of the impact of microbicide candidates. Our data suggest that different evaluations/assays have their inherent sensitivities, and at least one assay from each sensitivity level should be included in the safety evaluation algorithm. PMID- 26038477 TI - EV71-infected CD14(+) cells modulate the immune activity of T lymphocytes in rhesus monkeys. AB - Preliminary studies of the major pathogen enterovirus 71 (EV71), a member of the Picornaviridae family, have suggested that EV71 may be a major cause of fatal hand, foot and mouth disease cases. Currently, the role of the pathological changes induced by EV71 infection in the immunopathogenic response remains unclear. Our study focused on the interaction between this virus and immunocytes and indicated that this virus has the ability to replicate in CD14(+) cells. Furthermore, these EV71-infected CD14(+) cells have the capacity to stimulate the proliferation of T cells and to enhance the release of certain functional cytokines. An adaptive immune response induced by the back-transfusion of EV71 infected CD14(+) cells was observed in donor neonatal rhesus monkeys. Based on these observations, the proposed hypothesis is that CD14(+) cells infected by the EV71 virus might modulate the anti-EV71 adaptive immune response by inducing simultaneous T-cell activation. PMID- 26038478 TI - New features of the HIV epidemic among men who have sex with men in China. AB - Men who have sex with men (MSM) have accounted for an alarmingly increasing proportion of nationally reported human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) cases recently. While the latest HIV epidemic among this population was not well understood, the underlying reasons for the rapid increase of the HIV epidemic were even more rarely evaluated. This study reviewed all published articles and national surveillance data in recent years to analyze the new HIV epidemic among MSM in China, and this study finally concluded that a culture of risky sexual behaviors, low adoption of HIV testing and a high prevalence of syphilis infection were the major risk factors that predominantly facilitate homosexual HIV transmission. Both HIV infection and homosexuality remain highly stigmatized in China, which further exacerbates attempts at HIV prevention and control. A great deal of work still needs to be done for the national policy makers, programming, research and clinical sectors to help curb the HIV epidemic among Chinese MSM. PMID- 26038479 TI - Development of a loop-mediated isothermal amplification targeting a gene within the pyruvate dehydrogenase complex, the pdhA gene, for rapid detection of Mycoplasma gallisepticum. AB - Mycoplasma gallisepticum infections impose a significant economic burden on the poultry industry. In the current study, a loop-mediated isothermal amplification (LAMP) assay was developed and optimized to detect M. gallisepticum based on a gene within the pyruvate dehydrogenase complex, the pdhA gene, which codes for the major subunit (E1alpha) in the complex. The reaction conditions were optimized, and the specificity was confirmed by successful amplification of several M. gallisepticum strains, while no amplification was detected with 20 other major bacterial and viral pathogens of poultry. Additionally, the LAMP assay achieved 10-fold higher sensitivity than an existing polymerase chain reaction (PCR) method. The LAMP assay was applied to swab samples collected from poultry farms and compared with PCR. The positive detection rate was 20.2% (37/183) by LAMP and 13.1% (24/183) by PCR. The LAMP assay could provide a cost effective, quick, and sensitive method for the detection of M. gallisepticum. PMID- 26038481 TI - PRNP variants in goats reduce sensitivity of detection of PrP(Sc) by immunoassay. AB - Diagnostic analyses often employ single antibody systems but are potentially limited by epitope sequence variation. United States regulatory testing for scrapie primarily uses antibody F99/97.6.1 for immunohistochemistry (IHC) of the prion protein associated with scrapie (PrP(Sc)). Whereas the epitope bound by F99/97.6.1 is highly conserved in sheep, a polymorphism in caprine PRNP results in a glutamine to lysine change at codon 222 and affects PrP detection. This study evaluated the performance of immunoassays (Western blot and IHC) in the presence of PRNP polymorphisms observed in U.S. goat populations. Effects of naturally occurring caprine prion protein alterations at codons 142, 143, 146, 154, or 222 were first evaluated using bacterially expressed recombinant normal cellular prion protein (rec-PrP(C)) and commercially available antibodies (F99/97.6.1, F89/160.1.5, L42, and SAF84). Detection of rec-PrP(C) using F89/160.1.5 was reduced by alterations at 142 and 143; this was also observed in brain PrP(C) from goats expressing these PRNP variants. Effect of allelic variation at 222 was confirmed by Western blot with F99/97.6.1. No differences were observed with L42 or SAF84. IHC of brain demonstrated reduced signal with F89/160.1.5 in animals heterozygous at 143. Decreasing F89/160.1.5 titers were used to demonstrate the impact of PrP(Sc) immunolabeling in preclinical goats and as a surrogate for F99/97.6.1 detection in 222 variants. In the absence of epitope-relevant knowledge of individual goat PRNP, a multi-antibody approach or an antibody that binds an invariant site may provide a more robust immunoassay of PrP(Sc) in classical scrapie, thus reducing the likelihood of false-negative results due to allelic variation. PMID- 26038480 TI - The degree of acceptability of swine blood values at increasing levels of hemolysis evaluated through visual inspection versus automated quantification. AB - The pronounced fragility that characterizes swine erythrocytes is likely to produce a variable degree of hemolysis during blood sampling, and the free hemoglobin may then unpredictably bias the quantification of several analytes. The aim of this study was to evaluate the degree of acceptability of values obtained for several biochemical parameters at different levels of hemolysis. Progressively increased degrees of physical hemolysis were induced in 3 aliquots of 30 nonhemolytic sera, and the relative effects on the test results were assessed. To define the level of hemolysis, we used both visual estimation (on a scale of 0 to 3+) and analytical assessment (hemolytic index) and identified the best analytical cutoff values for discriminating the visual levels of hemolysis. Hemolysis led to a variable and dose-dependent effect on the test results that was specific for each analyte tested. In mildly hemolyzed specimens, C-reactive protein, haptoglobin, beta1-globulin, beta2-globulin, alpha1-globulin, gamma globulin, sodium, calcium, and alkaline phosphatase were not significantly biased, whereas alpha2-globulin, albumin, urea, creatinine, glucose, total cholesterol, aspartate aminotransferase, alanine aminotransferase, gamma-glutamyl transferase, nonesterified fatty acids, bilirubin, phosphorus, magnesium, iron, zinc, copper, lipase, triglycerides, lactate dehydrogenase, unbound iron-binding capacity, and uric acid were significantly biased. Chloride and total protein were unbiased even in markedly hemolyzed samples. Analytical interference was hypothesized to be the main source of this bias, leading to a nonlinear trend that confirmed the difficulty in establishing reliable coefficients of correction for adjusting the test results. PMID- 26038482 TI - Time-trend analyses of bleeding and mortality after primary percutaneous coronary intervention during out of working hours versus in-working hours: an observational study of 11 466 patients. AB - BACKGROUND: Primary percutaneous coronary intervention (PPCI) is the treatment of choice for ST-segment-elevation myocardial infarction. Resources are limited during out of working hours (OWH). Whether PPCI outside working hours is associated with worse outcomes and whether outcomes have improved over time are unknown. METHODS AND RESULTS: We analyzed 11 466 patients undergoing PPCI between 2004 and 2011 at all 8 tertiary cardiac centers in London, United Kingdom. We defined working hours as 9 am to 5 pm (Monday to Friday). We analyzed in-hospital bleeding and all-cause mortality <=3 years, comparing OWH versus in-working hours. A total of 7494 patients (65.3%) were treated during OWH. Multivariable analyses demonstrated that PPCI during OWH was not a predictor for bleeding (odds ratio, 1.47; 95% confidence interval [CI], 0.97-2.24; P=0.071) or 3-year mortality (hazard ratio, 1.11; 95% CI, 0.94-1.32; P=0.20). This was confirmed in propensity-matched analyses. Time-stratified analyses demonstrated that PPCI during OWH was a predictor for bleeding (odds ratio, 2.00; 95% CI, 1.06-3.80; P=0.034) and 3-year mortality during 2005 to 2008 (hazard ratio, 1.23; 95% CI, 1.00-1.50; P=0.050), but this association was lost during 2009 to 2011. During 2005 to 2008, transradial access was predominantly used during in-working hours and PPCI during OWH was predictive of reduced transradial access use (odds ratio, 0.83; 95% CI, 0.71-0.98; P=0.033), but this association was lost during 2009 to 2011. CONCLUSIONS: In this study of unselected patients with ST-segment-elevation myocardial infarction, PPCI during OWH versus in-working hours had comparable bleeding and mortality. Time-stratified analyses demonstrated a reduction in adjusted bleeding and mortality during OWH over time. This may reflect the improved service provision, but the increased adoption of transradial access during OWH may also be contributory. PMID- 26038483 TI - Pulmonary hypertension in patients undergoing transcatheter aortic valve replacement: discussion of the current evidence. PMID- 26038485 TI - Infection of inbred BALB/c and C57BL/6 and outbred Institute of Cancer Research mice with the emerging H7N9 avian influenza virus. AB - A new avian-origin influenza virus A (H7N9) recently crossed the species barrier and infected humans; therefore, there is an urgent need to establish mammalian animal models for studying the pathogenic mechanism of this strain and the immunological response. In this study, we attempted to develop mouse models of H7N9 infection because mice are traditionally the most convenient models for studying influenza viruses. We showed that the novel A (H7N9) virus isolated from a patient could infect inbred BALB/c and C57BL/6 mice as well as outbred Institute of Cancer Research (ICR) mice. The amount of bodyweight lost showed differences at 7 days post infection (d.p.i.) (BALB/c mice 30%, C57BL/6 and ICR mice approximately 20%), and the lung indexes were increased both at 3 d.p.i. and at 7 d.p.i.. Immunohistochemistry demonstrated the existence of the H7N9 viruses in the lungs of the infected mice, and these findings were verified by quantitative real-time polymerase chain reaction (RT-PCR) and 50% tissue culture infectious dose (TCID50) detection at 3 d.p.i. and 7 d.p.i.. Histopathological changes occurred in the infected lungs, including pulmonary interstitial inflammatory lesions, pulmonary oedema and haemorrhages. Furthermore, because the most clinically severe cases were in elderly patients, we analysed the H7N9 infections in both young and old ICR mice. The old ICR mice showed more severe infections with more bodyweight lost and a higher lung index than the young ICR mice. Compared with the young ICR mice, the old mice showed a delayed clearance of the H7N9 virus and higher inflammation in the lungs. Thus, old ICR mice could partially mimic the more severe illness in elderly patients. PMID- 26038484 TI - Human H7N9 avian influenza virus infection: a review and pandemic risk assessment. AB - China is undergoing a recent outbreak of a novel H7N9 avian influenza virus (nH7N9) infection that has thus far involved 132 human patients, including 37 deaths. The nH7N9 virus is a reassortant virus originating from the H7N3, H7N9 and H9N2 avian influenza viruses. nH7N9 isolated from humans contains features related to adaptation to humans, including a Q226L mutation in the hemagglutinin cleavage site and E627K and D701N mutations in the PB2 protein. Live poultry markets provide an environment for the emergence, spread and maintenance of nH7N9 as well as for the selection of mutants that facilitate nH7N9 binding to and replication in the human upper respiratory tract. Innate immune suppression conferred by the internal genes of H9N2 may contribute to the virulence of nH7N9. The quail may serve as the intermediate host during the adaptation of avian influenza viruses from domestic waterfowl to gallinaceous poultry, such as chickens and related terrestrial-based species, due to the selection of viral mutants with a short neuraminidase stalk. Infections in chickens, common quails, red-legged partridges and turkeys may select for mutants with human receptor specificity. Infection in Ratitae species may lead to the selection of PB2-E627K and PB2-D701N mutants and the conversion of nH7N9 to a highly pathogenic avian influenza virus. PMID- 26038486 TI - Rapidly produced SAM((r)) vaccine against H7N9 influenza is immunogenic in mice. AB - The timing of vaccine availability is essential for an effective response to pandemic influenza. In 2009, vaccine became available after the disease peak, and this has motivated the development of next generation vaccine technologies for more rapid responses. The SAM((r)) vaccine platform, now in pre-clinical development, is based on a synthetic, self-amplifying mRNA, delivered by a synthetic lipid nanoparticle (LNP). When used to express seasonal influenza hemagglutinin (HA), a SAM vaccine elicited potent immune responses, comparable to those elicited by a licensed influenza subunit vaccine preparation. When the sequences coding for the HA and neuraminidase (NA) genes from the H7N9 influenza outbreak in China were posted on a web-based data sharing system, the combination of rapid and accurate cell-free gene synthesis and SAM vaccine technology allowed the generation of a vaccine candidate in 8 days. Two weeks after the first immunization, mice had measurable hemagglutinin inhibition (HI) and neutralizing antibody titers against the new virus. Two weeks after the second immunization, all mice had HI titers considered protective. If the SAM vaccine platform proves safe, potent, well tolerated and effective in humans, fully synthetic vaccine technologies could provide unparalleled speed of response to stem the initial wave of influenza outbreaks, allowing first availability of a vaccine candidate days after the discovery of a new virus. PMID- 26038487 TI - Reduction of influenza virus-induced lung inflammation and mortality in animals treated with a phosophodisestrase-4 inhibitor and a selective serotonin reuptake inhibitor. AB - Inflammatory responses contribute to the morbidity and mortality of severe influenza. Current antiviral therapy offers limited success in treating severe influenza infection with both H1N1 and H5N1 viruses. We evaluated the effect of a neuraminidase inhibitor in combination with immunomodulatory drugs in vitro and in a mouse model of influenza A H1N1 infection by determining survival rate, lung inflammation markers and histopathology. Sertraline and rolipram significantly improved survival in mice infected with a lethal dose of influenza A H1N1 virus. Prophylactic treatment resulted in survival rates of 40% (rolipram), 30% (oseltamivir), 0% (sertraline), 100% (rolipram/oseltamivir) and 70% (sertraline/oseltamivir). Treatment in a therapeutic setting (24 h post infection) resulted in 80% (rolipram/oseltamivir) and 40% (sertraline/oseltamivir) survival. Sertraline and rolipram had no effect on virus replication in vitro and in vivo, but significantly reduced lung inflammation. A significant reduction in cellular infiltration (10-fold) along with inflammatory cytokines monocyte chemotactic protein-1 (10-fold), interleukin-6 (5-fold) and regulated on activation normal T cell expressed and secreted (5-fold) was observed in the animals treated with the combination compared to oseltamivir alone. Lung histopathology of mice treated with combinations revealed significantly reduced consolidation, infiltration and alveolitis compared to oseltamivir alone. Rolipram and sertraline reduced H1N1 virus-induced lung inflammation and mortality. These data support further development of immunomodulatory agents for severe influenza. PMID- 26038489 TI - Zoonotic simian foamy virus in Bangladesh reflects diverse patterns of transmission and co-infection. AB - Simian foamy viruses (SFVs) are ubiquitous in non-human primates (NHPs). As in all retroviruses, reverse transcription of SFV leads to recombination and mutation. Because more humans have been shown to be infected with SFV than with any other simian borne virus, SFV is a potentially powerful model for studying the virology and epidemiology of viruses at the human/NHP interface. In Asia, SFV is likely transmitted to humans through macaque bites and scratches that occur in the context of everyday life. We analyzed multiple proviral sequences from the SFV gag gene from both humans and macaques in order to characterize retroviral transmission at the human/NHP interface in Bangladesh. Here we report evidence that humans can be concurrently infected with multiple SFV strains, with some individuals infected by both an autochthonous SFV strain as well as a strain similar to SFV found in macaques from another geographic area. These data, combined with previous results, suggest that both human-facilitated movement of macaques leading to the introduction of non-resident strains of SFV and retroviral recombination in macaques contribute to SFV diversity among humans in Bangladesh. PMID- 26038488 TI - Hepatitis B virus reverse transcriptase: diverse functions as classical and emerging targets for antiviral intervention. AB - Hepatitis B virus (HBV) infection remains a global health problem with over 350 million chronically infected, causing an increased risk of cirrhosis and hepatocellular carcinoma. Current antiviral chemotherapy for HBV infection include five nucleos(t)ide analog reverse transcriptase inhibitors (NRTIs) that all target one enzymatic activity, DNA strand elongation, of the HBV polymerase (HP), a specialized reverse transcriptase (RT). NRTIs are not curative and long term treatment is associated with toxicity and the emergence of drug resistant viral mutations, which can also result in vaccine escape. Recent studies on the multiple functions of HP have provided important mechanistic insights into its diverse roles during different stages of viral replication, including interactions with viral pregenomic RNA, RNA packaging into nucleocapsids, protein priming, minus- and plus-strand viral DNA synthesis, RNase H-mediated degradation of viral RNA, as well as critical host interactions that regulate the multiple HP functions. These diverse functions provide ample opportunities to develop novel HP-targeted antiviral treatments that should contribute to curing chronic HBV infection. PMID- 26038490 TI - IL-17 cytokines in immunity and inflammation. AB - Interleukin 17 (IL-17) and its closest relative, IL-17F, have recently drawn much attention in the field of immunology. IL-17 and IL-17F are expressed by a distinct type of T cells, T helper 17 cells and certain other lymphocytes. These cytokines play key regulatory roles in host defense and inflammatory diseases. In this review, we summarize the recent findings in IL-17 biology and the progress towards understanding the regulatory mechanisms of IL-17 expression and signaling mechanisms. This knowledge will benefit the development of novel immune modulators that enhance immunity to various infections and reduce inflammatory damage in infected patients. PMID- 26038491 TI - Clostridium difficile infection in the twenty-first century. AB - Clostridium difficile is a spore-forming gram-positive bacillus, and the leading cause of antibiotic-associated nosocomial diarrhea and colitis in the industrialized world. With the emergence of a hypervirulent strain of C. difficile (BI/NAP1/027), the epidemiology of C. difficile infection has rapidly changed in the last decade. C. difficile infection, once thought to be an easy to treat bacterial infection, has evolved into an epidemic that is associated with a high rate of mortality, causing disease in patients thought to be low-risk. In this review, we discuss the changing face of C .difficile infection and the novel treatment and prevention strategies needed to halt this ever growing epidemic. PMID- 26038492 TI - CsgD regulatory network in a bacterial trait-altering biofilm formation. AB - In response to the limited nutrients and stressful conditions of their habitats, many microorganisms including Salmonella form a biofilm by secreting a polymeric matrix to interweave individual cells and to build structural communities on an abiotic or living surface. The biofilm formation in Salmonella is tightly regulated by a regulatory network that involves multiple transcriptional regulators. As a master transcriptional regulator in biofilm formation, curli subunit gene D (csgD) functions by activating the biosynthesis of the extracellular polymeric matrix composed of exopolysaccharide cellulose, curli and biofilm-associated proteins (Baps), assisting bacterial cells in transitioning from the planktonic stage to the multicellular state. The expression of CsgD itself is affected by cell growth stage and environmental stimuli through the action of other transcriptional factors, bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), regulatory small RNAs (sRNAs) and other elements. The formation of biofilm confers new physiological characteristics on the bacteria within, especially resistance against unfavorable environmental conditions. Herein, we summarize the CsgD regulatory network of Salmonella biofilm formation and the new traits acquired by Salmonella when within biofilm. PMID- 26038494 TI - Exploration of risk factors contributing to the presence of influenza A virus in swine at agricultural fairs. AB - Influenza A virus infections occurring in exhibition swine populations at agricultural fairs during 2012 served as a source of H3N2 variant influenza A viruses transmitted to humans resulting in more than 300 documented cases. Prior to the outbreak, this investigation was initiated to identify fair-level risk factors contributing to influenza A virus infections in pigs at agricultural fairs. As part of an ongoing active surveillance program, nasal swabs and associated fair-level metadata were collected from pigs at 40 junior fair market swine shows held in Ohio during the 2012 fair season. Analyses of the data show that the adjusted odds of having influenza A virus-infected pigs at a fair were 1.27 (95% confidential interval (CI): 1.04-1.66) higher for every 20 pig increase in the size of the swine show. Additionally, four of the five fairs that hosted breeding swine shows in addition to their junior fair market swine shows had pigs test positive for influenza A virus. While the current study was limited to 40 fairs within one state, the findings provided insight for veterinary and public health officials developing mitigation strategies to decrease the intra- and inter-species transmission of influenza A virus at fairs. PMID- 26038493 TI - Persisters, persistent infections and the Yin-Yang model. AB - Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics or stresses but can regrow under appropriate conditions. Persisters underlie persistent and latent infections and post-treatment relapse, posing significant challenges for the treatment of many bacterial infections. The current definition of persisters has drawbacks, and a Yin-Yang model is proposed to describe the heterogeneous nature of persisters that have to be defined in highly specific conditions. Despite their discovery more than 70 years ago, the mechanisms of persisters are poorly understood. Recent studies have identified a number of genes and pathways that shed light on the mechanisms of persister formation or survival. These include toxin-antitoxin modules, stringent response, DNA repair or protection, phosphate metabolism, alternative energy production, efflux, anti-oxidative defense and macromolecule degradation. More sensitive single-cell techniques are required for a better understanding of persister mechanisms. Studies of bacterial persisters have parallels in other microbes (fungi, parasites, viruses) and cancer stem cells in terms of mechanisms and treatment approaches. New drugs and vaccines targeting persisters are critical for improved treatment of persistent infections and perhaps cancers. Novel treatment strategies for persisters and persistent infections are discussed. PMID- 26038495 TI - A gorilla reservoir for human T-lymphotropic virus type 4. AB - Of the seven known species of human retroviruses only one, human T-cell lymphotropic virus type 4 (HTLV-4), lacks a known animal reservoir. We report the largest screening for simian T-cell lymphotropic virus (STLV-4) to date in a wide range of captive and wild non-human primate (NHP) species from Cameroon. Among the 681 wild and 426 captive NHPs examined, we detected STLV-4 infection only among gorillas by using HTLV-4-specific quantitative polymerase chain reaction. The large number of samples analyzed, the diversity of NHP species examined, the geographic distribution of infected animals relative to the known HTLV-4 case, as well as detailed phylogenetic analyses on partial and full genomes, indicate that STLV-4 is endemic to gorillas, and that rather than being an ancient virus among humans, HTLV-4 emerged from a gorilla reservoir, likely through the hunting and butchering of wild gorillas. Our findings shed further light on the importance of gorillas as keystone reservoirs for the evolution and emergence of human infectious diseases and provide a clear course for preventing HTLV-4 emergence through management of human contact with wild gorillas, the development of improved assays for HTLV-4/STLV-4 detection and the ongoing monitoring of STLV-4 among gorillas and for HTLV-4 zoonosis among individuals exposed to gorilla populations. PMID- 26038496 TI - Burkholderia pseudomallei in soil samples from an oceanarium in Hong Kong detected using a sensitive PCR assay. AB - Melioidosis, caused by Burkholderia pseudomallei, is an emerging infectious disease with an expanding geographical distribution. Although assessment of the environmental load of B. pseudomallei is important for risk assessment in humans or animals in endemic areas, traditional methods of bacterial culture for isolation have low sensitivities and are labor-intensive. Using a specific polymerase chain reaction (PCR) assay targeting a Tat domain protein in comparison with a bacterial culture method, we examined the prevalence of B. pseudomallei in soil samples from an oceanarium in Hong Kong where captive marine mammals and birds have contracted melioidosis. Among 1420 soil samples collected from various sites in the oceanarium over a 15-month period, B. pseudomallei was detected in nine (0.6%) soil samples using bacterial culture, whereas it was detected in 96 (6.8%) soil samples using the specific PCR assay confirmed by sequencing. The PCR-positive samples were detected during various months, with higher detection rates observed during summer months. Positive PCR detection was significantly correlated with ambient temperature (P<0.0001) and relative humidity (P=0.011) but not with daily rainfall (P=0.241) or a recent typhoon (P=0.787). PCR-positive samples were obtained from all sampling locations, with the highest detection rate in the valley. Our results suggest that B. pseudomallei is prevalent and endemic in the oceanarium. The present PCR assay is more sensitive than the bacterial culture method, and it may be used to help better assess the transmission of melioidosis and to design infection control measures for captive animals in this unique and understudied environment. PMID- 26038497 TI - The Rift Valley fever accessory proteins NSm and P78/NSm-GN are distinct determinants of virus propagation in vertebrate and invertebrate hosts. AB - Rift Valley fever virus (RVFV) is an enzootic virus circulating in Africa that is transmitted to its vertebrate host by a mosquito vector and causes severe clinical manifestations in humans and ruminants. RVFV has a tripartite genome of negative or ambisense polarity. The M segment contains five in-frame AUG codons that are alternatively used for the synthesis of two major structural glycoproteins, GN and GC, and at least two accessory proteins, NSm, a 14-kDa cytosolic protein, and P78/NSm-GN, a 78-kDa glycoprotein. To determine the relative contribution of P78 and NSm to RVFV infectivity, AUG codons were knocked out to generate mutant viruses expressing various sets of the M-encoded proteins. We found that, in the absence of the second AUG codon used to express NSm, a 13 kDa protein corresponding to an N-terminally truncated form of NSm, named NSm', was synthesized from AUG 3. None of the individual accessory proteins had any significant impact on RVFV virulence in mice. However, a mutant virus lacking both NSm and NSm' was strongly attenuated in mice and grew to reduced titers in murine macrophages, a major target cell type of RVFV. In contrast, P78 was not associated with reduced viral virulence in mice, yet it appeared as a major determinant of virus dissemination in mosquitoes. This study demonstrates how related accessory proteins differentially contribute to RVFV propagation in mammalian and arthropod hosts. PMID- 26038498 TI - An adult zebrafish model for Laribacter hongkongensis infection: Koch's postulates fulfilled. AB - Laribacter hongkongensis is a gram-negative emerging bacterium associated with invasive bacteremic infections in patients with liver disease and fish-borne community-acquired gastroenteritis and traveler's diarrhea. Although the complete genome of L. hongkongensis has been sequenced, no animal model is available for further study of its pathogenicity mechanisms. In this study, we showed that adult zebrafish infected with L. hongkongensis by immersion following dermal abrasion or intraperitoneal injection suffered mortality in a dose-dependent manner, with lethal dose 50 (LD50) of 2.1*10(4) and 1.9*10(4) colony-forming units (CFU)/mL, respectively. All mortalities occurred in the first four days post-infection. Zebrafish that died showed characteristic clinicopathological features: swimming near water surface, marked lethargy and sidestroke; abdominal hemorrhage, ulcers and marked swelling with ascites; and hydropic degeneration and necrosis of hepatocytes around central vein and inflammatory cells infiltration. L. hongkongensis was recovered from the ascitic fluid and tissues of zebrafish that died. Of the 30 zebrafish infected with 2.1*10(4) CFU/mL (LD50) L. hongkongensis isolated from dead zebrafish using the immersion following dermal abrasion method, 18 (60%) died. All zebrafish that died also showed the characteristic clinical and pathological features. Histopathological studies also showed dilation of hepatic central vein and hydropic degeneration. L. hongkongensis was isolated from the zebrafish that died. The Koch's postulates for L. hongkongensis as an infectious agent have been fulfilled. This highly reproducible and effective zebrafish model is of crucial importance for future studies on virulence factors for L. hongkongensis infection. PMID- 26038499 TI - Pathobiological features of a novel, highly pathogenic avian influenza A(H5N8) virus. AB - The endemicity of highly pathogenic avian influenza (HPAI) A(H5N1) viruses in Asia has led to the generation of reassortant H5 strains with novel gene constellations. A newly emerged HPAI A(H5N8) virus caused poultry outbreaks in the Republic of Korea in 2014. Because newly emerging high-pathogenicity H5 viruses continue to pose public health risks, it is imperative that their pathobiological properties be examined. Here, we characterized A/mallard duck/Korea/W452/2014 (MDk/W452(H5N8)), a representative virus, and evaluated its pathogenic and pandemic potential in various animal models. We found that MDk/W452(H5N8), which originated from the reassortment of wild bird viruses harbored by migratory waterfowl in eastern China, replicated systemically and was lethal in chickens, but appeared to be attenuated, albeit efficiently transmitted, in ducks. Despite predominant attachment to avian-like virus receptors, MDk/W452(H5N8) also exhibited detectable human virus-like receptor binding and replicated in human respiratory tract tissues. In mice, MDk/W452(H5N8) was moderately pathogenic and had limited tissue tropism relative to previous HPAI A(H5N1) viruses. It also induced moderate nasal wash titers in inoculated ferrets; additionally, it was recovered in extrapulmonary tissues and one of three direct-contact ferrets seroconverted without shedding. Moreover, domesticated cats appeared to be more susceptible than dogs to virus infection. With their potential to become established in ducks, continued circulation of A(H5N8) viruses could alter the genetic evolution of pre-existing avian poultry strains. Overall, detailed virological investigation remains a necessity given the capacity of H5 viruses to evolve to cause human illness with few changes in the viral genome. PMID- 26038500 TI - The quest for effective Ebola treatment: Ebola VP35 is an evidence-based target for dsRNA drugs. PMID- 26038502 TI - Using convalescent whole blood or plasma as passive immune therapy for the global war against Ebola. AB - The number of Ebola infections from the current outbreak continues to grow with imported cases now being reported outside West Africa. There is an urgent need to develop immediate and effective countermeasures. Convalescent whole blood or plasma from patients who have recovered from Ebola virus diseases (EVD) is a unique resource that should be used on a larger scale through well-developed formal programs following the WHO interim guidance. This type of treatment has been proven effective in the past and it can contribute significantly to the control of the current Ebola outbreak. PMID- 26038501 TI - Drug susceptibility profile and pathogenicity of H7N9 influenza virus (Anhui1 lineage) with R292K substitution. AB - Neuraminidase inhibitors (NAIs) are the only available licensed therapeutics against human H7N9 influenza virus infections. The emergence of NAI-resistant variants of H7N9viruses with an NA R292K mutation poses a therapeutic challenge. A comprehensive understanding of the susceptibility of these viruses to clinically available NAIs, non-NAIs and their combinations is crucial for effective treatment. In this study, by using limited serial passage and plaque purification, an R292K variant of the Anhui1 lineage was isolated from a patient with clinical evidence of resistance to oseltamivir. In vitro and cell-based assays confirmed a high level of resistance conferred by the R292K mutation to oseltamivir carboxylate and a moderate level of resistance to zanamivir and peramivir. Non-NAI antivirals, such as T-705, ribavirin and NT-300, efficiently inhibited both the variant and the wild-type in cell-based assays. A combination of NAIs and non-NAIs did not exhibit a marked synergistic effect against the R292K variant. However, the combination of two non-NAIs (T-705 and ribavirin) exhibited significant synergism against the mutant virus. In experimentally infected mice, the variant showed delayed onset of symptoms, a reduced viral load and attenuated lethality compared with the wild-type. Our study suggested non NAIs should be tested clinically for H7N9 patients with a sustained high viral load. Possible drug combination regimens, such as T-705 plus ribavirin, should be further tested in animal models. The pathogenicity and transmissibility of the R292K H7N9 variant should be further assessed with genetically well-characterized pairs of viruses and, most-desirably, with competitive fitness experiments. PMID- 26038503 TI - Traditional passive immune therapy for emerging Ebola infection. PMID- 26038504 TI - Potential impact on kidney infection: a whole-genome analysis of Leptospira santarosai serovar Shermani. AB - Leptospira santarosai serovar Shermani is the most frequently encountered serovar, and it causes leptospirosis and tubulointerstitial nephritis in Taiwan. This study aims to complete the genome sequence of L. santarosai serovar Shermani and analyze the transcriptional responses of L. santarosai serovar Shermani to renal tubular cells. To assemble this highly repetitive genome, we combined reads that were generated from four next-generation sequencing platforms by using hybrid assembly approaches to finish two-chromosome contiguous sequences without gaps by validating the data with optical restriction maps and Sanger sequencing. Whole-genome comparison studies revealed a 28-kb region containing genes that encode transposases and hypothetical proteins in L. santarosai serovar Shermani, but this region is absent in other pathogenic Leptospira spp. We found that lipoprotein gene expression in both L. santarosai serovar Shermani and L. interrogans serovar Copenhageni were upregulated upon interaction with renal tubular cells, and LSS19962, a L. santarosai serovar Shermani-specific gene within a 28-kb region that encodes hypothetical proteins, was upregulated in L. santarosai serovar Shermani-infected renal tubular cells. Lipoprotein expression during leptospiral infection might facilitate the interactions of leptospires within kidneys. The availability of the whole-genome sequence of L. santarosai serovar Shermani would make it the first completed sequence of this species, and its comparison with that of other Leptospira spp. may provide invaluable information for further studies in leptospiral pathogenesis. PMID- 26038505 TI - Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs. AB - In light of the current outbreak of Ebola virus disease, there is an urgent need to develop effective therapeutics to treat Ebola infection, and drug repurposing screening is a potentially rapid approach for identifying such therapeutics. We developed a biosafety level 2 (BSL-2) 1536-well plate assay to screen for entry inhibitors of Ebola virus-like particles (VLPs) containing the glycoprotein (GP) and the matrix VP40 protein fused to a beta-lactamase reporter protein and applied this assay for a rapid drug repurposing screen of Food and Drug Administration (FDA)-approved drugs. We report here the identification of 53 drugs with activity of blocking Ebola VLP entry into cells. These 53 active compounds can be divided into categories including microtubule inhibitors, estrogen receptor modulators, antihistamines, antipsychotics, pump/channel antagonists, and anticancer/antibiotics. Several of these compounds, including microtubule inhibitors and estrogen receptor modulators, had previously been reported to be active in BSL-4 infectious Ebola virus replication assays and in animal model studies. Our assay represents a robust, effective and rapid high throughput screen for the identification of lead compounds in drug development for the treatment of Ebola virus infection. PMID- 26038506 TI - Russian vaccines against especially dangerous bacterial pathogens. AB - In response to the epidemiological situation, live attenuated or killed vaccines against anthrax, brucellosis, cholera, glanders, plague and tularemia were developed and used for immunization of at-risk populations in the Former Soviet Union. Certain of these vaccines have been updated and currently they are used on a selective basis, mainly for high risk occupations, in the Russian Federation. Except for anthrax and cholera these vaccines currently are the only licensed products available for protection against the most dangerous bacterial pathogens. Development of improved formulations and new products is ongoing. PMID- 26038507 TI - Genesis of avian influenza H9N2 in Bangladesh. AB - Avian influenza subtype H9N2 is endemic in many bird species in Asia and the Middle East and has contributed to the genesis of H5N1, H7N9 and H10N8, which are potential pandemic threats. H9N2 viruses that have spread to Bangladesh have acquired multiple gene segments from highly pathogenic (HP) H7N3 viruses that are presumably in Pakistan and currently cocirculate with HP H5N1. However, the source and geographic origin of these H9N2 viruses are not clear. We characterized the complete genetic sequences of 37 Bangladeshi H9N2 viruses isolated in 2011-2013 and investigated their inter- and intrasubtypic genetic diversities by tracing their genesis in relationship to other H9N2 viruses isolated from neighboring countries. H9N2 viruses in Bangladesh are homogenous with several mammalian host-specific markers and are a new H9N2 sublineage wherein the hemagglutinin (HA) gene is derived from an Iranian H9N2 lineage (Mideast_B Iran), the neuraminidase (NA) and polymerase basic 2 (PB2) genes are from Dubai H9N2 (Mideast_C Dubai), and the non-structural protein (NS), nucleoprotein (NP), matrix protein (MP), polymerase acidic (PA) and polymerase basic 1 (PB1) genes are from HP H7N3 originating from Pakistan. Different H9N2 genotypes that were replaced in 2006 and 2009 by other reassortants have been detected in Bangladesh. Phylogenetic and molecular analyses suggest that the current genotype descended from the prototypical H9N2 lineage (G1), which circulated in poultry in China during the late 1990s and came to Bangladesh via the poultry trade within the Middle East, and that this genotype subsequently reassorted with H7N3 and H9N2 lineages from Pakistan and spread throughout India. Thus, continual surveillance of Bangladeshi HP H5N1, H7N3 and H9N2 is warranted to identify further evolution and adaptation to humans. PMID- 26038508 TI - Multiple introductions of highly pathogenic avian influenza H5N1 viruses into Bangladesh. AB - Highly pathogenic H5N1 and low pathogenic H9N2 influenza viruses are endemic to poultry markets in Bangladesh and have cocirculated since 2008. H9N2 influenza viruses circulated constantly in the poultry markets, whereas highly pathogenic H5N1 viruses occurred sporadically, with peaks of activity in cooler months. Thirty highly pathogenic H5N1 influenza viruses isolated from poultry were characterized by antigenic, molecular, and phylogenetic analyses. Highly pathogenic H5N1 influenza viruses from clades 2.2.2 and 2.3.2.1 were isolated from live bird markets only. Phylogenetic analysis of the 30 H5N1 isolates revealed multiple introductions of H5N1 influenza viruses in Bangladesh. There was no reassortment between the local H9N2 influenza viruses and H5N1 genotype, despite their prolonged cocirculation. However, we detected two reassortant H5N1 viruses, carrying the M gene from the Chinese H9N2 lineage, which briefly circulated in the Bangladesh poultry markets and then disappeared. On the other hand, interclade reassortment occurred within H5N1 lineages and played a role in the genesis of the currently dominant H5N1 viruses in Bangladesh. Few 'human like' mutations in H5N1 may account for the limited number of human cases. Antigenically, clade 2.3.2.1 H5N1 viruses in Bangladesh have evolved since their introduction and are currently mainly homogenous, and show evidence of recent antigenic drift. Although reassortants containing H9N2 genes were detected in live poultry markets in Bangladesh, these reassortants failed to supplant the dominant H5N1 lineage. PMID- 26038509 TI - Three decades of USAID investments in immunization through the child survival revolution. AB - The US Agency for International Development (USAID) launched a significant effort to improve global immunization coverage in the mid-1980s, beginning a long history of investments in various approaches to supporting the improvement of national vaccination programs in developing countries. As Primary Health Care evolved, USAID's approach to immunization also evolved, heavily influenced by the child survival revolution, a period when the global community struggled to define an approach that incorporated the essence of the Alma-Ata Conference with the selective primary health-care approach. Eventually, what became known as the 'twin engines' approach, a focus on two high impact interventions-immunization and oral rehydration therapy-would characterize USAID's child survival program. As coverage fell during the less favorable international economic climate of the 1990s, USAID re-evaluated its approach and moved toward a more system strengthening concept. At the turn of the century, with the pressure of measurable impact, the Agency moved toward more easily measured inputs and away from the longer-term system strengthening activities of the previous two decades. This approach emphasized simple, proven technologies, more public/private partnerships and greater investment in vertical disease programs with short-term impact. Investments such as polio eradication and vaccine purchase through the GAVI Alliance (formerly the Global Alliance for Vaccines and Immunization) became funding priorities for the Agency. Today, USAID faces a challenge of how it will support developing country vaccination programs. Will it provide assistance through vertical disease efforts and material inputs or will it shift back to a more system strengthening approach? The answer has not yet been provided. PMID- 26038510 TI - Saffold virus is able to productively infect primate and rodent cell lines and induces apoptosis in these cells. AB - Saffold virus (SAFV), a newly discovered human cardiovirus of the Picornaviridae family, causes widespread infection among children, as shown by previous seroprevalence studies. To determine the host cell range of SAFV and its cytopathogenicity, eight mammalian cell lines that were available in the laboratory were screened for productive SAFV infection by a laboratory-adapted SAFV of genotype 3. Five of the cell lines (Neuro2A, CHO-K1, NIH/3T3, Vero and HEp-2) were found to be permissible. The time required for SAFV to induce complete lysis as a cytopathic effect (CPE) in these permissibly infected cells and the resultant end point virus titer differed for each cell type. HEp-2 exhibited the shortest time frame to reach full CPE compared to the others. All infected cell lines produced a high virus titer at 72 h post-infection. In addition to causing lytic cell death, SAFV also induced apoptotic cell death in host cells through both extrinsic and intrinsic pathways, although the apoptotic events in HEp-2 cells appeared to have been blocked between the early and late stages. In conclusion, laboratory-adapted SAFV is able to productively infect a number of mammalian cell lines and induce apoptosis in the infected host cells. However, apoptosis in HEp-2 cells is blocked before the end stage. PMID- 26038511 TI - Host adaptation and transmission of influenza A viruses in mammals. AB - A wide range of influenza A viruses of pigs and birds have infected humans in the last decade, sometimes with severe clinical consequences. Each of these so-called zoonotic infections provides an opportunity for virus adaptation to the new host. Fortunately, most of these human infections do not yield viruses with the ability of sustained human-to-human transmission. However, animal influenza viruses have acquired the ability of sustained transmission between humans to cause pandemics on rare occasions in the past, and therefore, influenza virus zoonoses continue to represent threats to public health. Numerous recent studies have shed new light on the mechanisms of adaptation and transmission of avian and swine influenza A viruses in mammals. In particular, several studies provided insights into the genetic and phenotypic traits of influenza A viruses that may determine airborne transmission. Here, we summarize recent studies on molecular determinants of virulence and adaptation of animal influenza A virus and discuss the phenotypic traits associated with airborne transmission of newly emerging influenza A viruses. Increased understanding of the determinants and mechanisms of virulence and transmission may aid in assessing the risks posed by animal influenza viruses to human health, and preparedness for such risks. PMID- 26038513 TI - Association of gyrA/B mutations and resistance levels to fluoroquinolones in clinical isolates of Mycobacterium tuberculosis. AB - To evaluate the association between mutations in the genes gyrA/B and resistance levels to fluoroquinolones in clinical isolates of Mycobacterium tuberculosis, a total of 80 ofloxacin-resistant isolates collected in 2009 by the Shanghai Municipal Centers for Disease Control and Prevention were studied. The minimum inhibitory concentration (MIC) of ofloxacin, moxifloxacin and gatifloxacin for each isolate was determined using the microscopic observation drug susceptibility assay. Sequencing was used to identify mutations in the quinolone resistance determining region (QRDR) of the gyrA and gyrB genes. In total, 68 isolates had mutations in gyrA, three isolates had mutations in gyrB, six isolates had mutations in both gyrA and gyrB, and three isolates had no mutations. Two common mutations in gyrA, the D94G and D94N mutations, were associated with higher-level resistance to all three fluoroquinolones than two other common mutations (A90V and D94A). Understanding the relationship between MICs and mutations in ofloxacin resistant isolates will facilitate the optimization of the use of new-generation fluoroquinolones to treat patients with ofloxacin-resistant tuberculosis (TB). PMID- 26038512 TI - The impact of drug resistance on Mycobacterium tuberculosis physiology: what can we learn from rifampicin? AB - The emergence of drug-resistant pathogens poses a major threat to public health. Although influenced by multiple factors, high-level resistance is often associated with mutations in target-encoding or related genes. The fitness cost of these mutations is, in turn, a key determinant of the spread of drug-resistant strains. Rifampicin (RIF) is a frontline anti-tuberculosis agent that targets the rpoB-encoded beta subunit of the DNA-dependent RNA polymerase (RNAP). In Mycobacterium tuberculosis (Mtb), RIF resistance (RIF(R)) maps to mutations in rpoB that are likely to impact RNAP function and, therefore, the ability of the organism to cause disease. However, while numerous studies have assessed the impact of RIF(R) on key Mtb fitness indicators in vitro, the consequences of rpoB mutations for pathogenesis remain poorly understood. Here, we examine evidence from diverse bacterial systems indicating very specific effects of rpoB polymorphisms on cellular physiology, and consider these observations in the context of Mtb. In addition, we discuss the implications of these findings for the propagation of clinically relevant RIF(R) mutations. While our focus is on RIF, we also highlight results which suggest that drug-independent effects might apply to a broad range of resistance-associated mutations, especially in an obligate pathogen increasingly linked with multidrug resistance. PMID- 26038514 TI - Natural reservoirs for homologs of hepatitis C virus. AB - Hepatitis C virus is considered a major public health problem, infecting 2%-3% of the human population. Hepatitis C virus infection causes acute and chronic liver disease, including chronic hepatitis, cirrhosis and hepatocellular carcinoma. In fact, hepatitis C virus infection is the most frequent indication for liver transplantation and a vaccine is not available. Hepatitis C virus displays a narrow host species tropism, naturally infecting only humans, although chimpanzees are also susceptible to experimental infection. To date, there is no evidence for an animal reservoir of viruses closely related to hepatitis C virus which may have crossed the species barrier to cause disease in humans and resulted in the current pandemic. In fact, due to this restricted host range, a robust immunocompetent small animal model is still lacking, hampering mechanistic analysis of virus pathogenesis, immune control and prophylactic vaccine development. Recently, several studies discovered new viruses related to hepatitis C virus, belonging to the hepaci- and pegivirus genera, in small wild mammals (rodents and bats) and domesticated animals which live in close contact with humans (dogs and horses). Genetic and biological characterization of these newly discovered hepatitis C virus-like viruses infecting different mammals will contribute to our understanding of the origins of hepatitis C virus in humans and enhance our ability to study pathogenesis and immune responses using tractable animal models. In this review article, we start with an introduction on the genetic diversity of hepatitis C virus and then focus on the newly discovered viruses closely related to hepatitis C virus. Finally, we discuss possible theories about the origin of this important viral human pathogen. PMID- 26038517 TI - Co-infection of visceral leishmaniasis and HIV-1: a surviving case in China and review of treatment strategies. AB - Co-infection of visceral leishmaniasis (VL) and human immunodeficiency virus type 1 (HIV-1) is known to have higher rates of initial treatment failure, relapse and mortality than in those without HIV-1 infection. Co-infection of VL and HIV-1 usually results in death by the end of treatment in previously reported cases in China. Here we report on a patient with VL and HIV-1 co-infection who received a high dose and an extended course of sodium stibogluconate treatment in addition to antiretroviral therapy (ART). This treatment regimen resulted in good control of VL and HIV-1 infection, while the conventional protocol of sodium stibogluconate treatment was not able to prevent multiple VL relapses. To the best of our knowledge, this is the first surviving case of VL and HIV-1 co infection with this particular treatment regimen in China. PMID- 26038516 TI - The saga of XMRV: a virus that infects human cells but is not a human virus. AB - Xenotropic murine leukemia virus-related virus (XMRV) was discovered in 2006 in a search for a viral etiology of human prostate cancer (PC). Substantial interest in XMRV as a potentially new pathogenic human retrovirus was driven by reports that XMRV could be detected in a significant percentage of PC samples, and also in tissues from patients with chronic fatigue syndrome (CFS). After considerable controversy, etiologic links between XMRV and these two diseases were disproven. XMRV was determined to have arisen during passage of a human PC tumor in immunocompromised nude mice, by activation and recombination between two endogenous murine leukemia viruses from cells of the mouse. The resulting XMRV had a xentropic host range, which allowed it replicate in the human tumor cells in the xenograft. This review describes the discovery of XMRV, and the molecular and virological events leading to its formation, XMRV infection in animal models and biological effects on infected cells. Lessons from XMRV for other searches of viral etiologies of cancer are discussed, as well as cautions for researchers working on human tumors or cell lines that have been passed through nude mice, includingpotential biohazards associated with XMRV or other similar xenotropic murine leukemia viruses (MLVs). PMID- 26038518 TI - When climate change couples social neglect: malaria dynamics in Panama. AB - A major challenge of infectious disease elimination is the need to interrupt pathogen transmission across all vulnerable populations. Ethnic minorities are among the key vulnerable groups deserving special attention in disease elimination initiatives, especially because their lifestyle might be intrinsically linked to locations with high transmission risk. There has been a renewed interest in malaria elimination, which has ignited a quest to understand factors necessary for sustainable malaria elimination, highlighting the need for diverse approaches to address epidemiological heterogeneity across malaria transmission settings. An analysis of malaria incidence among the Guna Amerindians of Panama over the last 34 years showed that this ethnic minority was highly vulnerable to changes that were assumed to not impact malaria transmission. Epidemic outbreaks were linked with El Nino Southern Oscillations and were sensitive to political instability and policy changes that did not ensure adequate attention to the malaria control needs of the Gunas. Our results illustrate how the neglect of minorities poses a threat to the sustainable control and eventual elimination of malaria in Central America and other areas where ethnic minorities do not share the benefits of malaria control strategies intended for dominant ethnic groups. PMID- 26038519 TI - EV71 vaccines: a milestone in the history of global vaccine development. PMID- 26038515 TI - Molecular basis of host specificity in human pathogenic bacteria. AB - Pathogenic bacteria display various levels of host specificity or tropism. While many bacteria can infect a wide range of hosts, certain bacteria have strict host selectivity for humans as obligate human pathogens. Understanding the genetic and molecular basis of host specificity in pathogenic bacteria is important for understanding pathogenic mechanisms, developing better animal models and designing new strategies and therapeutics for the control of microbial diseases. The molecular mechanisms of bacterial host specificity are much less understood than those of viral pathogens, in part due to the complexity of the molecular composition and cellular structure of bacterial cells. However, important progress has been made in identifying and characterizing molecular determinants of bacterial host specificity in the last two decades. It is now clear that the host specificity of bacterial pathogens is determined by multiple molecular interactions between the pathogens and their hosts. Furthermore, certain basic principles regarding the host specificity of bacterial pathogens have emerged from the existing literature. This review focuses on selected human pathogenic bacteria and our current understanding of their host specificity. PMID- 26038520 TI - Marked Regional Variation in Acute Stroke Treatment Among Medicare Beneficiaries. AB - BACKGROUND AND PURPOSE: Little is known about how regions vary in their use of thrombolysis (intravenous tissue-type plasminogen activator and intra-arterial treatment) for acute stroke. We sought to determine regional variation in thrombolysis treatment and investigate the extent to which regional variation is accounted for by patient demographics, regional factors, and elements of stroke systems of care. METHODS: Retrospective cross-sectional study of all fee-for service Medicare patients with ischemic stroke admitted via the Emergency Department from 2007 to 2010 who were assigned to 1 of 3436 hospital service areas. Multilevel logistic regression was used to estimate regional thrombolysis rates, determine the variation in thrombolysis treatment attributable to the region and estimate thrombolysis treatment rates and disability prevented under varied improvement scenarios. RESULTS: There were 844 241 ischemic stroke admissions of which 3.7% received intravenous tissue-type plasminogen activator and 0.5% received intra-arterial stroke treatment without or without intravenous tissue-type plasminogen activator over the 4-year period. The unadjusted proportion of patients with ischemic stroke who received thrombolysis varied from 9.3% in the highest treatment quintile compared with 0% in the lowest treatment quintile. Measured demographic and stroke system factors were weakly associated with treatment rates. Region accounted for 7% to 8% of the variation in receipt of thrombolysis treatment. If all regions performed at the level of 75th percentile region, ~7000 additional patients with ischemic stroke would be treated with thrombolysis. CONCLUSIONS: There is substantial regional variation in thrombolysis treatment. Future studies to determine features of high performing thrombolysis treatment regions may identify opportunities to improve thrombolysis rates. PMID- 26038521 TI - Family History in Young Patients With Stroke. AB - BACKGROUND AND PURPOSE: Family history of stroke is an established risk factor for stroke. We evaluated whether family history of stroke predisposed to certain stroke subtypes and whether it differed by sex in young patients with stroke. METHODS: We used data from the Stroke in Fabry Patients study, a large prospective, hospital-based, screening study for Fabry disease in young patients (aged <55 years) with stroke in whom cardiovascular risk factors and family history of stroke were obtained and detailed stroke subtyping was performed. RESULTS: A family history of stroke was present in 1578 of 4232 transient ischemic attack and ischemic stroke patients (37.3%). Female patients more often had a history of stroke in the maternal lineage (P=0.027) than in the paternal lineage. There was no association with stroke subtype according to Trial of Org 10172 in Acute Stroke Treatment nor with the presence of white matter disease on brain imaging. Patients with dissection less frequently reported a family history of stroke (30.4% versus 36.3%; P=0.018). Patients with a parental history of stroke more commonly had siblings with stroke (3.6% versus 2.6%; P=0.047). CONCLUSIONS: Although present in about a third of patients, a family history of stroke is not specifically related to stroke pathogenic subtypes in patients with young stroke. Young women with stroke more often report stroke in the maternal lineage. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583. PMID- 26038522 TI - Homocysteine, Ischemic Stroke, and Coronary Heart Disease in Hypertensive Patients: A Population-Based, Prospective Cohort Study. AB - BACKGROUND AND PURPOSE: Total homocysteine level (tHcy) is a risk factor of ischemic stroke (IS) and coronary heart disease. However, the results are conflicting and mainly focused on healthy individuals in developed countries. METHODS: A prospective, population-based cohort study was conducted among 5935 participants from 60 communities in the city of Shenzhen, China. A Cox regression analysis was applied to evaluate the contribution of tHcy to the risk of IS and coronary heart disease. The effect of folic acid supplementation on tHcy levels was also evaluated among 501 patients with essential hypertension, who received an average of 2.5 years of folic acid supplementation. RESULTS: After adjustment for confounding factors, the hazard ratios (95% confidence intervals) of IS caused by hyperhomocysteinemia were 2.18 (1.65-2.89), 2.40 (1.56-3.67), and 2.73 (1.83-4.08) in the total, male, and female participants, respectively. Compared with normal levels of tHcy (<15 MUmol/L), the hazard ratios (95% confidence intervals) for IS in the highest tHcy category (>=30 MUmol/L) were 4.96 (3.03 8.12), 6.11 (3.44-10.85), and 1.84 (0.52-6.46) in the total, males, and females participants, respectively. However, we did not observe a significant relationship between tHcy and the risk of coronary heart disease. The 2.5 years of folic acid supplementation reduced tHcy levels by 6.7 MUmol/L (27.92%) in patients with essential hypertension. CONCLUSIONS: Hyperhomocysteinemia in Chinese hypertensive patients is significantly associated with IS risk but not coronary heart disease susceptibility, and folic acid supplementation can efficiently reduce tHcy levels. PMID- 26038523 TI - Building the Case for Clopidogrel as a World Health Organization Essential Medicine. PMID- 26038524 TI - Early Medication Nonadherence After Acute Myocardial Infarction: Insights into Actionable Opportunities From the TReatment with ADP receptor iNhibitorS: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) Study. AB - BACKGROUND: Nonadherence to prescribed evidence-based medications after acute myocardial infarction (MI) can contribute to worse outcomes and higher costs. We sought to better understand the modifiable factors contributing to early nonadherence of evidence-based medications after acute MI. METHODS AND RESULTS: We assessed 7425 acute MI patients treated with percutaneous coronary intervention at 216 US hospitals participating in TReatment with ADP receptor iNhibitorS: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) between April 2010 and May 2012. Using the validated Morisky instrument to assess cardiovascular medication adherence at 6 weeks post MI, we stratified patients into self-reported high (score, 8), moderate (score, 6-7), and low (score, <6) adherence groups. Moderate and low adherence was reported in 25% and 4% of patients, respectively. One third of low adherence patients described missing doses of antiplatelet therapy at least twice a week after percutaneous coronary intervention. Signs of depression and patient reported financial hardship because of medication expenses were independently associated with a higher likelihood of medication nonadherence. Patients were more likely to be adherent at 6 weeks if they had follow-up appointments made before discharge and had a provider explain potential side effects of their medications. Lower medication adherence may be associated with a higher risk of 3 month death/readmission (adjusted hazard ratio, 1.35; 95% confidence interval, 0.98-1.87) although this did not reach statistical significance. CONCLUSIONS: Even early after MI, a substantial proportion of patients report suboptimal adherence to prescribed medications. Tailored patient education and pre discharge planning may represent actionable opportunities to optimize patient adherence and clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01088503. PMID- 26038525 TI - Implantable Cardioverter-Defibrillator Use in Older Adults: Proceedings of a Hartford Change AGEnts Symposium. PMID- 26038526 TI - Glomerular Aging and Focal Global Glomerulosclerosis: A Podometric Perspective. AB - Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density >300 per 10(6) um(3)), but by 70-80 years of age, average podocyte nuclear density decreased to, <100 per 10(6) um(3), with corresponding podocyte hypertrophy. In older age podocyte detachment rate (urine podocin mRNA-to-creatinine ratio) was higher than at younger ages and podocytes were stressed (increased urine podocin-to-nephrin mRNA ratio). Moreover, in older kidneys, proteinaceous material accumulated in the Bowman space of glomeruli with low podocyte density. In a subset of these glomeruli, mass podocyte detachment events occurred in association with podocytes becoming binucleate (mitotic podocyte catastrophe) and subsequent wrinkling of glomerular capillaries, tuft collapse, and periglomerular fibrosis. In kidneys of young patients with underlying glomerular diseases similar pathologic events were identified in association with focal global glomerulosclerosis. Podocyte density reduction with age may therefore directly lead to focal global glomerulosclerosis, and all progressive glomerular diseases can be considered superimposed accelerators of this underlying process. PMID- 26038527 TI - Glomerular Effects of Age and APOL1. PMID- 26038528 TI - ADAMTS13 Endopeptidase Protects against Vascular Endothelial Growth Factor Inhibitor-Induced Thrombotic Microangiopathy. AB - Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor-related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor-related TMA. ADAMTS13(-/-) mice overexpressing sFlt 1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor-related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13(-/-) mice overexpressing sFlt 1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition. PMID- 26038529 TI - APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults: An Autopsy Study. AB - APOL1 genetic variants contribute to kidney disease in African Americans. We assessed correlations between APOL1 profiles and renal histological features in subjects without renal disease. Glomerular number (N glom) and mean glomerular volume (V glom) were measured by the dissector/fractionator method in kidneys of African-American and non-African-American adults without renal disease, undergoing autopsies in Jackson, Mississippi. APOL1 risk alleles were genotyped and the kidney findings were evaluated in the context of those profiles. The proportions of African Americans with none, one, and two APOL1 risk alleles were 38%, 43%, and 19%, respectively; 38% of African Americans had G1 allele variants and 31% of African Americans had G2 allele variants. Only APOL1-positive African Americans had significant reductions in N glom and increases in V glom with increasing age. Regression analysis predicted an annual average loss of 8834 (P=0.03, sex adjusted) glomeruli per single kidney over the first 38 years of adult life in African Americans with two risk alleles. Body mass index above the group medians, but below the obesity definition of >= 30 kg/m(2), enhanced the expression of age-related changes in N glom in African Americans with either one or two APOL1 risk alleles. These findings indicate that APOL1 risk alleles are associated with exaggerated age-related nephron loss, probably decaying from a larger pool of smaller glomeruli in early adult life, along with enlargement of the remaining glomeruli. These phenomena might mark mechanisms of accentuated susceptibility to kidney disease in APOL1-positive African Americans. PMID- 26038530 TI - Vascular Endothelial Growth Factor C for Polycystic Kidney Diseases. AB - Polycystic kidney diseases (PKD) are genetic disorders characterized by progressive epithelial cyst growth leading to destruction of normally functioning renal tissue. Current therapies have focused on the cyst epithelium, and little is known about how the blood and lymphatic microvasculature modulates cystogenesis. Hypomorphic Pkd1(nl/nl) mice were examined, showing that cystogenesis was associated with a disorganized pericystic network of vessels expressing platelet/endothelial cell adhesion molecule 1 and vascular endothelial growth factor receptor 3 (VEGFR3). The major ligand for VEGFR3 is VEGFC, and there were lower levels of Vegfc mRNA within the kidneys during the early stages of cystogenesis in 7-day-old Pkd1(nl/nl) mice. Seven-day-old mice were treated with exogenous VEGFC for 2 weeks on the premise that this would remodel both the VEGFR3(+) pericystic vascular network and larger renal lymphatics that may also affect the severity of PKD. Treatment with VEGFC enhanced VEGFR3 phosphorylation in the kidney, normalized the pattern of the pericystic network of vessels, and widened the large lymphatics in Pkd1(nl/nl) mice. These effects were associated with significant reductions in cystic disease, BUN and serum creatinine levels. Furthermore, VEGFC administration reduced M2 macrophage pericystic infiltrate, which has been implicated in the progression of PKD. VEGFC administration also improved cystic disease in Cys1(cpk/cpk) mice, a model of autosomal recessive PKD, leading to a modest but significant increase in lifespan. Overall, this study highlights VEGFC as a potential new treatment for some aspects of PKD, with the possibility for synergy with current epithelially targeted approaches. PMID- 26038531 TI - Vascular Endothelial Growth Factor Therapy for the Kidney: Are We There Yet? PMID- 26038532 TI - Endothelial Dysfunction: The Secret Agent Driving Kidney Disease. PMID- 26038533 TI - Microfibrillar-associated protein 4 modulates airway smooth muscle cell phenotype in experimental asthma. AB - BACKGROUND: Recently, several proteins of the extracellular matrix have been characterised as active contributors to allergic airway disease. Microfibrillar associated protein 4 (MFAP4) is an extracellular matrix protein abundant in the lung, whose biological functions remain poorly understood. In the current study we investigated the role of MFAP4 in experimental allergic asthma. METHODS: MFAP4 deficient mice were subjected to alum/ovalbumin and house dust mite induced models of allergic airway disease. In addition, human healthy and asthmatic primary bronchial smooth muscle cell cultures were used to evaluate MFAP4 dependent airway smooth muscle responses. RESULTS: MFAP4 deficiency attenuated classical hallmarks of asthma, such as eosinophilic inflammation, eotaxin production, airway remodelling and hyperresponsiveness. In wild-type mice, serum MFAP4 was increased after disease development and correlated with local eotaxin levels. MFAP4 was expressed in human bronchial smooth muscle cells and its expression was upregulated in asthmatic cells. Regarding the underlying mechanism, we showed that MFAP4 interacted with integrin alphavbeta5 and promoted asthmatic bronchial smooth muscle cell proliferation and CCL11 release dependent on phosphatidyloinositol-3-kinase but not extracellular signal-regulated kinase pathway. CONCLUSIONS: MFAP4 promoted the development of asthmatic airway disease in vivo and pro-asthmatic functions of bronchial smooth muscle cells in vitro. Collectively, our results identify MFAP4 as a novel contributor to experimental asthma, acting through modulation of airway smooth muscle cells. PMID- 26038534 TI - Association of incident obstructive sleep apnoea with outcomes in a large cohort of US veterans. AB - RATIONALE: There is a paucity of large cohort studies examining the association of obstructive sleep apnoea (OSA) with clinical outcomes including all-cause mortality, coronary heart disease (CHD), strokes and chronic kidney disease (CKD). OBJECTIVES: We hypothesised that a diagnosis of incident OSA is associated with higher risks of these adverse clinical outcomes. METHODS, MEASUREMENTS: In a nationally representative cohort of over 3 million (n=3 079 514) US veterans (93% male) with baseline estimated glomerular filtration rate (eGFR)>=60 mL/min/1.73 m(2), we examined the association between the diagnosis of incident OSA, treated and untreated with CPAP, and: (1) all-cause mortality, (2) incident CHD, (3) incident strokes, (4)incident CKD defined as eGFR<60 mL/min/1.73 m(2), and (5) slopes of eGFR. MAIN RESULTS: Compared with OSA-negative patients, untreated and treated OSA was associated with 86% higher mortality risk, (adjusted HR and 95% CI 1.86 (1.81 to 1.91) and 35% (1.35 (1.21 to 1.51)), respectively. Similarly, untreated and treated OSA was associated with 3.5 times (3.54 (3.40 to 3.69)) and 3 times (3.06 (2.62 to 3.56)) higher risk of incident CHD; 3.5 times higher risk of incident strokes (3.48 (3.28 to 3.64) and 3.50 (2.92 to 4.19)) for untreated and treated OSA, respectively. The risk of incident CKD was also significantly higher in untreated (2.27 (2.19 to 2.36)) and treated (2.79 (2.48 to 3.13)) patients with OSA. The median (IQR) of the eGFR slope was -0.41 (-2.01 to 0.99), 0.61 (-2.69 to 0.93) and -0.87 (-3.00 to 0.70) mL/min/1.73 m(2) in OSA-negative patients, untreated OSA-positive patients and treated OSA-positive patients, respectively. CONCLUSIONS: In this large and contemporary cohort of more than 3 million US veterans, a diagnosis of incident OSA was associated with higher mortality, incident CHD, stroke and CKD and with faster kidney function decline. PMID- 26038535 TI - Risk of Heart Failure and Death After Prolonged Smoking Cessation: Role of Amount and Duration of Prior Smoking. AB - BACKGROUND: According to the 2004 Surgeon General's Report on Health Consequences of Smoking, after >15 years of abstinence, the cardiovascular risk of former smokers becomes similar to that of never-smokers. Whether this health benefit of smoking cessation varies by amount and duration of prior smoking remains unclear. METHODS AND RESULTS: Of the 4482 adults >=65 years without prevalent heart failure (HF) in the Cardiovascular Health Study, 2556 were never-smokers, 629 current smokers, and 1297 former smokers with >15 years of cessation, of whom 312 were heavy smokers (highest quartile; >=32 pack-years). Age-sex-race-adjusted hazard ratios (aHR) and 95% confidence intervals (CI) for centrally adjudicated incident HF and mortality during 13 years of follow-up were estimated using Cox regression models. Compared with never-smokers, former smokers as a group had similar risk for incident HF (aHR, 0.99; 95% CI, 0.85-1.16) and all-cause mortality (aHR, 1.08; 95% CI, 0.96-1.20), but former heavy smokers had higher risk for both HF (aHR, 1.45; 95% CI, 1.15-1.83) and mortality (aHR, 1.38; 95% CI, 1.17-1.64). However, when compared with current smokers, former heavy smokers had lower risk of death (aHR, 0.64; 95% CI, 0.53-0.77), but not of HF (aHR, 0.97; 95% CI, 0.74-1.28). CONCLUSIONS: After >15 years of smoking cessation, the risk of HF and death for most former smokers becomes similar to that of never-smokers. Although this benefit of smoking cessation is not extended to those with >=32 pack-years of prior smoking, they have lower risk of death relative to current smokers. PMID- 26038536 TI - Wnt/beta-Catenin Signaling Contributes to Skeletal Myopathy in Heart Failure via Direct Interaction With Forkhead Box O. AB - BACKGROUND: There are changes in the skeletal muscle of patients with chronic heart failure (CHF), such as volume reduction and fiber type shift toward fatigable type IIb fiber. Forkhead box O (FoxO) signaling plays a critical role in the development of skeletal myopathy in CHF, and functional interaction between FoxO and the Wnt signal mediator beta-catenin was previously demonstrated. We have recently reported that serum of CHF model mice activates Wnt signaling more potently than serum of control mice and that complement C1q mediates this activation. We, therefore, hypothesized that C1q-induced activation of Wnt signaling plays a critical role in skeletal myopathy via the interaction with FoxO. METHODS AND RESULTS: Fiber type shift toward fatigable fiber was observed in the skeletal muscle of dilated cardiomyopathy model mice, which was associated with activation of both Wnt and FoxO signaling. Wnt3a protein activated FoxO signaling and induced fiber type shift toward fatigable fiber in C2C12 cells. Wnt3a-induced fiber type shift was inhibited by suppression of FoxO1 activity, whereas Wnt3a-independent fiber type shift was observed by overexpression of constitutively active FoxO1. Serum of dilated cardiomyopathy mice activated both Wnt and FoxO signaling and induced fiber type shift toward fatigable fiber in C2C12 cells. Wnt inhibitor and C1-inhibitor attenuated FoxO activation and fiber type shift both in C2C12 cells and in the skeletal muscle of dilated cardiomyopathy mice. CONCLUSIONS: C1q-induced activation of Wnt signaling contributes to fiber type shift toward fatigable fiber in CHF. Wnt signaling may be a novel therapeutic target to prevent skeletal myopathy in CHF. PMID- 26038537 TI - Long-Term Outcomes With Cardiac Resynchronization Therapy in Patients With Mild Heart Failure With Moderate Renal Dysfunction. AB - BACKGROUND: We aimed to determine the impact of renal function on long-term outcomes with cardiac resynchronization therapy with defibrillator among patients with mild heart failure (HF). METHODS AND RESULTS: We stratified 1820 Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy patients by QRS morphology into those with and without left bundle-branch block. Subgroups within each QRS morphology category were created based on glomerular filtration rate (GFR): GFR <60 and >=60 mL/min per 1.73 m(2). Primary end point was death; secondary end points were HF/death and HF events alone during long term follow-up. Among 1274 left bundle-branch block patients, 413 (32%) presented with GFR <60 (mean, 48.1+/-8.3) mL/min per 1.73 m(2). Relative to the 861 (68%) patients with GFR >=60 (mean, 79.6+/-16.0) mL/min per 1.73 m(2), low-GFR patients experienced higher risk of death (hazard ratio [HR], 2.09; 95% confidence interval [CI], 1.53-2.86; P<0.01) and HF/death (HR, 1.46; 95% CI, 1.17-1.82; P<0.01). In both GFR groups, cardiac resynchronization therapy with defibrillator was associated with reduction in death (GFR <60: HR, 0.66; 95% CI, 0.44-1.00; P=0.05 and GFR >=60: HR, 0.68; 95% CI, 0.44-1.05; P=0.08) and HF/death (GFR <60: HR, 0.49; 95% CI, 0.36-0.67; P<0.01 and GFR >=60: HR, 0.50; 95% CI, 0.38-0.66; P<0.01). In the low-GFR group, there was greater absolute reduction in risk of death (GFR <60: 14% and GFR >=60: 6%) and HF/death (GFR <60: 25 and GFR >=60: 15%). Among non-left bundle-branch block patients, low GFR predicted outcomes; however, no benefit from cardiac resynchronization therapy with defibrillator was observed. CONCLUSIONS: In patients with mild HF, moderate renal dysfunction is associated with higher risk of death and HF during long-term follow-up. Patients with left bundle-branch block, regardless of baseline renal function, derive long term benefit from cardiac resynchronization therapy with defibrillator, with greater absolute risk reduction in death and HF among those with moderate renal dysfunction. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00180271, NCT01294449, and NCT02060110. PMID- 26038538 TI - News Feature: Building benchtop human models. PMID- 26038539 TI - Scene perception in early vision: Figure-ground organization in the lateral geniculate nucleus. PMID- 26038541 TI - Laser printing hierarchical structures with the aid of controlled capillary driven self-assembly. AB - Capillary force is often regarded as detrimental because it may cause undesired distortion or even destruction to micro/nanostructures during a fabrication process, and thus many efforts have been made to eliminate its negative effects. From a different perspective, capillary force can be artfully used to construct specific complex architectures. Here, we propose a laser printing capillary assisted self-assembly strategy for fabricating regular periodic structures. Microscale pillars are first produced by localized femtosecond laser polymerization and are subsequently assembled into periodic hierarchical architectures with the assistance of controlled capillary forces in an evaporating liquid. Spatial arrangements, pillar heights, and evaporation processes are readily tuned to achieve designable ordered assemblies with various geometries. Reversibility of the assembly is also revealed by breaking the balance between the intermolecular force and the elastic standing force. We further demonstrate the functionality of the hierarchical structures as a nontrivial tool for the selective trapping and releasing of microparticles, opening up a potential for the development of in situ transportation systems for microobjects. PMID- 26038542 TI - Efficient and selective molecular catalyst for the CO2-to-CO electrochemical conversion in water. AB - Substitution of the four paraphenyl hydrogens of iron tetraphenylporphyrin by trimethylammonio groups provides a water-soluble molecule able to catalyze the electrochemical conversion of carbon dioxide into carbon monoxide. The reaction, performed in pH-neutral water, forms quasi-exclusively carbon monoxide with very little production of hydrogen, despite partial equilibration of CO2 with carbonic acid-a low pKa acid. This selective molecular catalyst is endowed with a good stability and a high turnover frequency. On this basis, prescribed composition of CO-H2 mixtures can be obtained by adjusting the pH of the solution, optionally adding an electroinactive buffer. The development of these strategies will be greatly facilitated by the fact that one operates in water. The same applies for the association of the cathode compartment with a proton-producing anode by means of a suitable separator. PMID- 26038543 TI - Paleoarchean trace fossils in altered volcanic glass. AB - Microbial corrosion textures in volcanic glass from Cenozoic seafloor basalts and the corresponding titanite replacement microtextures in metamorphosed Paleoarchean pillow lavas have been interpreted as evidence for a deep biosphere dating back in time through the earliest periods of preserved life on earth. This interpretation has been recently challenged for Paleoarchean titanite replacement textures based on textural and geochronological data from pillow lavas in the Hooggenoeg Complex of the Barberton Greenstone Belt in South Africa. We use this controversy to explore the strengths and weaknesses of arguments made in support or rejection of the biogenicity interpretation of bioalteration trace fossils in Cenozoic basalt glasses and their putative equivalents in Paleoarchean greenstones. Our analysis suggests that biogenicity cannot be taken for granted for all titanite-based textures in metamorphosed basalt glass, but a cautious and critical evaluation of evidence suggests that biogenicity remains the most likely interpretation for previously described titanite microtextures in Paleoarchean pillow lavas. PMID- 26038544 TI - Predictive information in a sensory population. AB - Guiding behavior requires the brain to make predictions about the future values of sensory inputs. Here, we show that efficient predictive computation starts at the earliest stages of the visual system. We compute how much information groups of retinal ganglion cells carry about the future state of their visual inputs and show that nearly every cell in the retina participates in a group of cells for which this predictive information is close to the physical limit set by the statistical structure of the inputs themselves. Groups of cells in the retina carry information about the future state of their own activity, and we show that this information can be compressed further and encoded by downstream predictor neurons that exhibit feature selectivity that would support predictive computations. Efficient representation of predictive information is a candidate principle that can be applied at each stage of neural computation. PMID- 26038545 TI - Assessing the role of static length scales behind glassy dynamics in polydisperse hard disks. AB - The possible role of growing static order in the dynamical slowing down toward the glass transition has recently attracted considerable attention. On the basis of random first-order transition theory, a new method to measure the static correlation length of amorphous order, called "point-to-set" (PTS) length, has been proposed and used to show that the dynamic length grows much faster than the static length. Here, we study the nature of the PTS length, using a polydisperse hard-disk system, which is a model that is known to exhibit a growing hexatic order upon densification. We show that the PTS correlation length is decoupled from the steeper increase of the correlation length of hexatic order and dynamic heterogeneity, while closely mirroring the decay length of two-body density correlations. Our results thus provide a clear example that other forms of order can play an important role in the slowing down of the dynamics, casting a serious doubt on the order-agnostic nature of the PTS length and its relevance to slow dynamics, provided that a polydisperse hard-disk system is a typical glass former. PMID- 26038546 TI - Selfish third parties act as peacemakers by transforming conflicts and promoting cooperation. AB - The tremendous costs of conflict have made humans resourceful not only at warfare but also at peacemaking. Although third parties have acted as peacemakers since the dawn of history, little is known about voluntary, informal third-party intervention in conflict. Here we introduce the Peacemaker Game, a novel experimental paradigm, to model and study the interdependence between disputants and third parties in conflict. In the game, two disputants choose whether to cooperate or compete and a third party chooses whether or not to intervene in the conflict. Intervention introduces side payments that transform the game disputants are playing; it also introduces risk for the third party by making it vulnerable to disputants' choices. Six experiments revealed three robust effects: (i) The mere possibility of third-party intervention significantly increases cooperation in interpersonal and intergroup conflicts; (ii) reducing the risk to third parties dramatically increases intervention rates, to everyone's benefit; and (iii) disputants' cooperation rates are consistently higher than third parties' intervention rates. These findings explain why, how, and when self interested third parties facilitate peaceful conflict resolution. PMID- 26038547 TI - Evaluating taboo trade-offs in ecosystems services and human well-being. AB - Managing ecosystems for multiple ecosystem services and balancing the well-being of diverse stakeholders involves different kinds of trade-offs. Often trade-offs involve noneconomic and difficult-to-evaluate values, such as cultural identity, employment, the well-being of poor people, or particular species or ecosystem structures. Although trade-offs need to be considered for successful environmental management, they are often overlooked in favor of win-wins. Management and policy decisions demand approaches that can explicitly acknowledge and evaluate diverse trade-offs. We identified a diversity of apparent trade-offs in a small-scale tropical fishery when ecological simulations were integrated with participatory assessments of social-ecological system structure and stakeholders' well-being. Despite an apparent win-win between conservation and profitability at the aggregate scale, food production, employment, and well-being of marginalized stakeholders were differentially influenced by management decisions leading to trade-offs. Some of these trade-offs were suggested to be "taboo" trade-offs between morally incommensurable values, such as between profits and the well-being of marginalized women. These were not previously recognized as management issues. Stakeholders explored and deliberated over trade offs supported by an interactive "toy model" representing key system trade-offs, alongside qualitative narrative scenarios of the future. The concept of taboo trade-offs suggests that psychological bias and social sensitivity may exclude key issues from decision making, which can result in policies that are difficult to implement. Our participatory modeling and scenarios approach has the potential to increase awareness of such trade-offs, promote discussion of what is acceptable, and potentially identify and reduce obstacles to management compliance. PMID- 26038548 TI - Exploring the potential impact of an expanded genetic code on protein function. AB - With few exceptions, all living organisms encode the same 20 canonical amino acids; however, it remains an open question whether organisms with additional amino acids beyond the common 20 might have an evolutionary advantage. Here, we begin to test that notion by making a large library of mutant enzymes in which 10 structurally distinct noncanonical amino acids were substituted at single sites randomly throughout TEM-1 beta-lactamase. A screen for growth on the beta-lactam antibiotic cephalexin afforded a unique p-acrylamido-phenylalanine (AcrF) mutation at Val-216 that leads to an increase in catalytic efficiency by increasing kcat, but not significantly affecting KM. To understand the structural basis for this enhanced activity, we solved the X-ray crystal structures of the ligand-free mutant enzyme and of the deacylation-defective wild-type and mutant cephalexin acyl-enzyme intermediates. These structures show that the Val-216-AcrF mutation leads to conformational changes in key active site residues-both in the free enzyme and upon formation of the acyl-enzyme intermediate-that lower the free energy of activation of the substrate transacylation reaction. The functional changes induced by this mutation could not be reproduced by substitution of any of the 20 canonical amino acids for Val-216, indicating that an expanded genetic code may offer novel solutions to proteins as they evolve new activities. PMID- 26038549 TI - The messenger RNA decapping and recapping pathway in Trypanosoma. AB - The 5' terminus of trypanosome mRNA is protected by a hypermethylated cap 4 derived from spliced leader (SL) RNA. Trypanosoma brucei nuclear capping enzyme with cap guanylyltransferase and methyltransferase activities (TbCgm1) modifies the 5'-diphosphate RNA (ppRNA) end to generate an m7G SL RNA cap. Here we show that T. brucei cytoplasmic capping enzyme (TbCe1) is a bifunctional 5'-RNA kinase and guanylyltransferase that transfers a gamma-phosphate from ATP to pRNA to form ppRNA, which is then capped by transfer of GMP from GTP to the RNA beta phosphate. A Walker A-box motif in the N-terminal domain is essential for the RNA kinase activity and is targeted preferentially to a SL RNA sequence with a 5' terminal methylated nucleoside. Silencing of TbCe1 leads to accumulation of uncapped mRNAs, consistent with selective capping of mRNA that has undergone trans-splicing and decapping. We identify T. brucei mRNA decapping enzyme (TbDcp2) that cleaves m7GDP from capped RNA to generate pRNA, a substrate for TbCe1. TbDcp2 can also remove GDP from unmethylated capped RNA but is less active at a mature cap 4 end and thus may function in RNA cap quality surveillance. Our results establish the enzymology and relevant protein catalysts of a cytoplasmic recapping pathway that has broad implications for the functional reactivation of processed mRNA ends. PMID- 26038550 TI - Uncoupling protein 1 binds one nucleotide per monomer and is stabilized by tightly bound cardiolipin. AB - Uncoupling protein 1 (UCP1) catalyzes fatty acid-activated, purine nucleotide sensitive proton leak across the mitochondrial inner membrane of brown adipose tissue to produce heat, and could help combat obesity and metabolic disease in humans. Studies over the last 30 years conclude that the protein is a dimer, binding one nucleotide molecule per two proteins, and unlike the related mitochondrial ADP/ATP carrier, does not bind cardiolipin. Here, we have developed novel methods to purify milligram amounts of UCP1 from native sources by using covalent chromatography that, unlike past methods, allows the protein to be prepared in defined conditions, free of excess detergent and lipid. Assessment of purified preparations by TLC reveal that UCP1 retains tightly bound cardiolipin, with a lipid phosphorus content equating to three molecules per protein, like the ADP/ATP carrier. Cardiolipin stabilizes UCP1, as demonstrated by reconstitution experiments and thermostability assays, indicating that the lipid has an integral role in the functioning of the protein, similar to other mitochondrial carriers. Furthermore, we find that UCP1 is not dimeric but monomeric, as indicated by size exclusion analysis, and has a ligand titration profile in isothermal calorimetric measurements that clearly shows that one nucleotide binds per monomer. These findings reveal the fundamental composition of UCP1, which is essential for understanding the mechanism of the protein. Our assessment of the properties of UCP1 indicate that it is not unique among mitochondrial carriers and so is likely to use a common exchange mechanism in its primary function in brown adipose tissue mitochondria. PMID- 26038551 TI - Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening. AB - Fragment-based screening methods can be used to discover novel active site or allosteric inhibitors for therapeutic intervention. Using saturation transfer difference (STD) NMR and in vitro activity assays, we have identified fragment sized inhibitors of HIV-1 reverse transcriptase (RT) with distinct chemical scaffolds and mechanisms compared to nonnucleoside RT inhibitors (NNRTIs) and nucleoside/nucleotide RT inhibitors (NRTIs). Three compounds were found to inhibit RNA- and DNA-dependent DNA polymerase activity of HIV-1 RT in the micromolar range while retaining potency against RT variants carrying one of three major NNRTI resistance mutations: K103N, Y181C, or G190A. These compounds also inhibit Moloney murine leukemia virus RT but not the Klenow fragment of Escherichia coli DNA polymerase I. Steady-state kinetic analyses demonstrate that one of these fragments is a competitive inhibitor of HIV-1 RT with respect to deoxyribonucleoside triphosphate (dNTP) substrate, whereas a second compound is a competitive inhibitor of RT polymerase activity with respect to the DNA template/primer (T/P), and consequently also inhibits RNase H activity. The dNTP competing RT inhibitor retains activity against the NRTI-resistant mutants K65R and M184V, demonstrating a drug resistance profile distinct from the nucleotide competing RT inhibitors indolopyridone-1 (INDOPY-1) and 4-dimethylamino-6 vinylpyrimidine-1 (DAVP-1). In antiviral assays, the T/P competing compound inhibits HIV-1 replication at a step consistent with an RT inhibitor. Screening of additional structurally related compounds to the three fragments led to the discovery of molecules with improved potency against HIV-1 RT. These fragment inhibitors represent previously unidentified scaffolds for development of novel drugs for HIV-1 prevention or treatment. PMID- 26038552 TI - Determining protein structures by combining semireliable data with atomistic physical models by Bayesian inference. AB - More than 100,000 protein structures are now known at atomic detail. However, far more are not yet known, particularly among large or complex proteins. Often, experimental information is only semireliable because it is uncertain, limited, or confusing in important ways. Some experiments give sparse information, some give ambiguous or nonspecific information, and others give uncertain information where some is right, some is wrong, but we don't know which. We describe a method called Modeling Employing Limited Data (MELD) that can harness such problematic information in a physics-based, Bayesian framework for improved structure determination. We apply MELD to eight proteins of known structure for which such problematic structural data are available, including a sparse NMR dataset, two ambiguous EPR datasets, and four uncertain datasets taken from sequence evolution data. MELD gives excellent structures, indicating its promise for experimental biomolecule structure determination where only semireliable data are available. PMID- 26038553 TI - Mechanical force effect on the two-state equilibrium of the hyaluronan-binding domain of CD44 in cell rolling. AB - CD44 is the receptor for hyaluronan (HA) and mediates cell rolling under fluid shear stress. The HA-binding domain (HABD) of CD44 interconverts between a low affinity, ordered (O) state and a high-affinity, partially disordered (PD) state, by the conformational change of the C-terminal region, which is connected to the plasma membrane. To examine the role of tensile force on CD44-mediated rolling, we used a cell-free rolling system, in which recombinant HABDs were attached to beads through a C-terminal or N-terminal tag. We found that the rolling behavior was stabilized only at high shear stress, when the HABD was attached through the C-terminal tag. In contrast, no difference was observed for the beads coated with HABD mutants that constitutively adopt either the O state or the PD state. Steered molecular dynamics simulations suggested that the force from the C terminus disrupts the interaction between the C-terminal region and the core of the domain, thus providing structural insights into how the mechanical force triggers the allosteric O-to-PD transition. Based on these results, we propose that the force applied from the C terminus enhances the HABD-HA interactions by inducing the conformational change to the high-affinity PD transition more rapidly, thereby enabling CD44 to mediate lymphocyte trafficking and hematopoietic progenitor cell homing under high-shear conditions. PMID- 26038554 TI - Two-tiered coupling between flowing actin and immobilized N-cadherin/catenin complexes in neuronal growth cones. AB - Neuronal growth cones move forward by dynamically connecting actin-based motility to substrate adhesion, but the mechanisms at the individual molecular level remain unclear. We cultured primary neurons on N-cadherin-coated micropatterned substrates, and imaged adhesion and cytoskeletal proteins at the ventral surface of growth cones using single particle tracking combined to photoactivated localization microscopy (sptPALM). We demonstrate transient interactions in the second time scale between flowing actin filaments and immobilized N cadherin/catenin complexes, translating into a local reduction of the actin retrograde flow. Normal actin flow on micropatterns was rescued by expression of a dominant negative N-cadherin construct competing for the coupling between actin and endogenous N-cadherin. Fluorescence recovery after photobleaching (FRAP) experiments confirmed the differential kinetics of actin and N-cadherin, and further revealed a 20% actin population confined at N-cadherin micropatterns, contributing to local actin accumulation. Computer simulations with relevant kinetic parameters modeled N-cadherin and actin turnover well, validating this mechanism. Such a combination of short- and long-lived interactions between the motile actin network and spatially restricted adhesive complexes represents a two tiered clutch mechanism likely to sustain dynamic environment sensing and provide the force necessary for growth cone migration. PMID- 26038555 TI - Using homology relations within a database markedly boosts protein sequence similarity search. AB - Inference of homology from protein sequences provides an essential tool for analyzing protein structure, function, and evolution. Current sequence-based homology search methods are still unable to detect many similarities evident from protein spatial structures. In computer science a search engine can be improved by considering networks of known relationships within the search database. Here, we apply this idea to protein-sequence-based homology search and show that it dramatically enhances the search accuracy. Our new method, COMPADRE (COmparison of Multiple Protein sequence Alignments using Database RElationships) assesses the relationship between the query sequence and a hit in the database by considering the similarity between the query and hit's known homologs. This approach increases detection quality, boosting the precision rate from 18% to 83% at half-coverage of all database homologs. The increased precision rate allows detection of a large fraction of protein structural relationships, thus providing structure and function predictions for previously uncharacterized proteins. Our results suggest that this general approach is applicable to a wide variety of methods for detection of biological similarities. The web server is available at prodata.swmed.edu/compadre. PMID- 26038556 TI - GABARAPs regulate PI4P-dependent autophagosome:lysosome fusion. AB - The Atg8 autophagy proteins are essential for autophagosome biogenesis and maturation. The gamma-aminobutyric acid receptor-associated protein (GABARAP) Atg8 family is much less understood than the LC3 Atg8 family, and the relationship between the GABARAPs' previously identified roles as modulators of transmembrane protein trafficking and autophagy is not known. Here we report that GABARAPs recruit palmitoylated PI4KIIalpha, a lipid kinase that generates phosphatidylinositol 4-phosphate (PI4P) and binds GABARAPs, from the perinuclear Golgi region to autophagosomes to generate PI4P in situ. Depletion of either GABARAP or PI4KIIalpha, or overexpression of a dominant-negative kinase-dead PI4KIIalpha mutant, decreases autophagy flux by blocking autophagsome:lysosome fusion, resulting in the accumulation of abnormally large autophagosomes. The autophagosome defects are rescued by overexpressing PI4KIIalpha or by restoring intracellular PI4P through "PI4P shuttling." Importantly, PI4KIIalpha's role in autophagy is distinct from that of PI4KIIIbeta and is independent of subsequent phosphatidylinositol 4,5 biphosphate (PIP2) generation. Thus, GABARAPs recruit PI4KIIalpha to autophagosomes, and PI4P generation on autophagosomes is critically important for fusion with lysosomes. Our results establish that PI4KIIalpha and PI4P are essential effectors of the GABARAP interactome's fusion machinery. PMID- 26038557 TI - Biotic interactions mediate soil microbial feedbacks to climate change. AB - Decomposition of organic material by soil microbes generates an annual global release of 50-75 Pg carbon to the atmosphere, ~7.5-9 times that of anthropogenic emissions worldwide. This process is sensitive to global change factors, which can drive carbon cycle-climate feedbacks with the potential to enhance atmospheric warming. Although the effects of interacting global change factors on soil microbial activity have been a widespread ecological focus, the regulatory effects of interspecific interactions are rarely considered in climate feedback studies. We explore the potential of soil animals to mediate microbial responses to warming and nitrogen enrichment within a long-term, field-based global change study. The combination of global change factors alleviated the bottom-up limitations on fungal growth, stimulating enzyme production and decomposition rates in the absence of soil animals. However, increased fungal biomass also stimulated consumption rates by soil invertebrates, restoring microbial process rates to levels observed under ambient conditions. Our results support the contemporary theory that top-down control in soil food webs is apparent only in the absence of bottom-up limitation. As such, when global change factors alleviate the bottom-up limitations on microbial activity, top-down control becomes an increasingly important regulatory force with the capacity to dampen the strength of positive carbon cycle-climate feedbacks. PMID- 26038558 TI - Rodent reservoirs of future zoonotic diseases. AB - The increasing frequency of zoonotic disease events underscores a need to develop forecasting tools toward a more preemptive approach to outbreak investigation. We apply machine learning to data describing the traits and zoonotic pathogen diversity of the most speciose group of mammals, the rodents, which also comprise a disproportionate number of zoonotic disease reservoirs. Our models predict reservoir status in this group with over 90% accuracy, identifying species with high probabilities of harboring undiscovered zoonotic pathogens based on trait profiles that may serve as rules of thumb to distinguish reservoirs from nonreservoir species. Key predictors of zoonotic reservoirs include biogeographical properties, such as range size, as well as intrinsic host traits associated with lifetime reproductive output. Predicted hotspots of novel rodent reservoir diversity occur in the Middle East and Central Asia and the Midwestern United States. PMID- 26038559 TI - Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis. AB - Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such that some progeny of Th17 cell precursors retain a predominantly IL-17A(+) phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-gamma, giving rise to "Th1-like" cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-gamma deficient Th17 cells retained an IL-17A(+) phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-gamma receptors. Moreover, Th17 cells could provide "help" for the development of pathogenic Th1 cells from naive precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells. PMID- 26038560 TI - Identification of an epithelial cell receptor responsible for Clostridium difficile TcdB-induced cytotoxicity. AB - Clostridium difficile is the leading cause of hospital-acquired diarrhea in the United States. The two main virulence factors of C. difficile are the large toxins, TcdA and TcdB, which enter colonic epithelial cells and cause fluid secretion, inflammation, and cell death. Using a gene-trap insertional mutagenesis screen, we identified poliovirus receptor-like 3 (PVRL3) as a cellular factor necessary for TcdB-mediated cytotoxicity. Disruption of PVRL3 expression by gene-trap mutagenesis, shRNA, or CRISPR/Cas9 mutagenesis resulted in resistance of cells to TcdB. Complementation of the gene-trap or CRISPR mutants with PVRL3 resulted in restoration of TcdB-mediated cell death. Purified PVRL3 ectodomain bound to TcdB by pull-down. Pretreatment of cells with a monoclonal antibody against PVRL3 or prebinding TcdB to PVRL3 ectodomain also inhibited cytotoxicity in cell culture. The receptor is highly expressed on the surface epithelium of the human colon and was observed to colocalize with TcdB in both an explant model and in tissue from a patient with pseudomembranous colitis. These data suggest PVRL3 is a physiologically relevant binding partner that can serve as a target for the prevention of TcdB-induced cytotoxicity in C. difficile infection. PMID- 26038561 TI - Subcortical barrelette-like and barreloid-like structures in the prosimian galago (Otolemur garnetti). AB - Galagos are prosimian primates that resemble ancestral primates more than most other extant primates. As in many other mammals, the facial vibrissae of galagos are distributed across the upper and lower jaws and above the eye. In rats and mice, the mystacial macrovibrissae are represented throughout the ascending trigeminal pathways as arrays of cytoarchitecturally distinct modules, with each module having a nearly one-to-one relationship with a specific facial whisker. The macrovibrissal representations are termed barrelettes in the trigeminal somatosensory brainstem, barreloids in the ventroposterior medial subnucleus of the thalamus, and barrels in primary somatosensory cortex. Despite the presence of facial whiskers in all nonhuman primates, barrel-like structures have not been reported in primates. By staining for cytochrome oxidase, Nissl, and vesicular glutamate transporter proteins, we show a distinct array of barrelette-like and barreloid-like modules in the principal sensory nucleus, the spinal trigeminal nucleus, and the ventroposterior medial subnucleus of the galago, Otolemur garnetti. Labeled terminals of primary sensory neurons in the brainstem and cell bodies of thalamocortically projecting neurons demonstrate that barrelette-like and barreloid-like modules are located in areas of these somatosensory nuclei that are topographically consistent with their role in facial touch. Serendipitously, the plane of section that best displays the barreloid-like modules reveals a remarkably distinct homunculus-like patterning which, we believe, is one of the clearest somatotopic maps of an entire body surface yet found. PMID- 26038562 TI - Kinetically coupled folding of a single HIV-1 glycoprotein 41 complex in viral membrane fusion and inhibition. AB - HIV-1 glycoprotein 41 (gp41) mediates viral entry into host cells by coupling its folding energy to membrane fusion. Gp41 folding is blocked by fusion inhibitors, including the commercial drug T20, to treat HIV/AIDS. However, gp41 folding intermediates, energy, and kinetics are poorly understood. Here, we identified the folding intermediates of a single gp41 trimer-of-hairpins and measured their associated energy and kinetics using high-resolution optical tweezers. We found that folding of gp41 hairpins was energetically independent but kinetically coupled: Each hairpin contributed a folding energy of ~-23 kBT, but folding of one hairpin successively accelerated the folding rate of the next one by ~20 fold. Membrane-mimicking micelles slowed down gp41 folding and reduced the stability of the six-helix bundle. However, the stability was restored by cooperative folding of the membrane-proximal external region. Surprisingly, T20 strongly inhibited gp41 folding by actively displacing the C-terminal hairpin strand in a force-dependent manner. The inhibition was abolished by a T20 resistant gp41 mutation. The energetics and kinetics of gp41 folding established by us provides a basis to understand viral membrane fusion, infection, and therapeutic intervention. PMID- 26038563 TI - Substrate-binding domain conformational dynamics mediate Hsp70 allostery. AB - Binding of ATP to the N-terminal nucleotide-binding domain (NBD) of heat shock protein 70 (Hsp70) molecular chaperones reduces the affinity of their C-terminal substrate-binding domain (SBD) for unfolded protein substrates. ATP binding to the NBD leads to docking between NBD and betaSBD and releasing of the alpha helical lid that covers the substrate-binding cleft in the SBD. However, these structural changes alone do not fully account for the allosteric mechanism of modulation of substrate affinity and binding kinetics. Through a multipronged study of the Escherichia coli Hsp70 DnaK, we found that changes in conformational dynamics within the betaSBD play a central role in interdomain allosteric communication in the Hsp70 DnaK. ATP-mediated NBD conformational changes favor formation of NBD contacts with lynchpin sites on the betaSBD and force disengagement of SBD strand beta8 from strand beta7, which leads to repacking of a betaSBD hydrophobic cluster and disruption of the hydrophobic arch over the substrate-binding cleft. In turn, these structural rearrangements drastically enhance conformational dynamics throughout the entire betaSBD and particularly around the substrate-binding site. This negative, entropically driven allostery between two functional sites of the betaSBD-the NBD binding interface and the substrate-binding site-confers upon the SBD the plasticity needed to bind to a wide range of chaperone clients without compromising precise control of thermodynamics and kinetics of chaperone-client interactions. PMID- 26038564 TI - Imperfect drug penetration leads to spatial monotherapy and rapid evolution of multidrug resistance. AB - Infections with rapidly evolving pathogens are often treated using combinations of drugs with different mechanisms of action. One of the major goal of combination therapy is to reduce the risk of drug resistance emerging during a patient's treatment. Although this strategy generally has significant benefits over monotherapy, it may also select for multidrug-resistant strains, particularly during long-term treatment for chronic infections. Infections with these strains present an important clinical and public health problem. Complicating this issue, for many antimicrobial treatment regimes, individual drugs have imperfect penetration throughout the body, so there may be regions where only one drug reaches an effective concentration. Here we propose that mismatched drug coverage can greatly speed up the evolution of multidrug resistance by allowing mutations to accumulate in a stepwise fashion. We develop a mathematical model of within-host pathogen evolution under spatially heterogeneous drug coverage and demonstrate that even very small single-drug compartments lead to dramatically higher resistance risk. We find that it is often better to use drug combinations with matched penetration profiles, although there may be a trade-off between preventing eventual treatment failure due to resistance in this way and temporarily reducing pathogen levels systemically. Our results show that drugs with the most extensive distribution are likely to be the most vulnerable to resistance. We conclude that optimal combination treatments should be designed to prevent this spatial effective monotherapy. These results are widely applicable to diverse microbial infections including viruses, bacteria, and parasites. PMID- 26038565 TI - AMCase is a crucial regulator of type 2 immune responses to inhaled house dust mites. AB - Chitinases are enzymes that cleave chitin, a component of the exoskeleton of many organisms including the house dust mite (HDM). Here we show that knockin mice expressing an enzymatically inactive acidic mammalian chitinase (AMCase), the dominant true chitinase in mouse lung, showed enhanced type 2 immune responses to inhaled HDM. We found that uncleaved chitin promoted the release of IL-33, whereas cleaved chitin could be phagocytosed and could induce the activation of caspase-1 and subsequent activation of caspase-7; this results in the resolution of type 2 immune responses, probably by promoting the inactivation of IL-33. These data suggest that AMCase is a crucial regulator of type 2 immune responses to inhaled chitin-containing aeroallergens. PMID- 26038566 TI - Reversal of mitochondrial defects with CSB-dependent serine protease inhibitors in patient cells of the progeroid Cockayne syndrome. AB - UV-sensitive syndrome (UV(S)S) and Cockayne syndrome (CS) are human disorders caused by CSA or CSB gene mutations; both conditions cause defective transcription-coupled repair and photosensitivity. Patients with CS also display neurological and developmental abnormalities and dramatic premature aging, and their cells are hypersensitive to oxidative stress. We report CSA/CSB-dependent depletion of the mitochondrial DNA polymerase-gamma catalytic subunit (POLG1), due to HTRA3 serine protease accumulation in CS, but not in UV(s)S or control fibroblasts. Inhibition of serine proteases restored physiological POLG1 levels in either CS fibroblasts and in CSB-silenced cells. Moreover, patient-derived CS cells displayed greater nitroso-redox imbalance than UV(S)S cells. Scavengers of reactive oxygen species and peroxynitrite normalized HTRA3 and POLG1 levels in CS cells, and notably, increased mitochondrial oxidative phosphorylation, which was altered in CS cells. These data reveal critical deregulation of proteases potentially linked to progeroid phenotypes in CS, and our results suggest rescue strategies as a therapeutic option. PMID- 26038568 TI - Cell rejuvenation and social behaviors promoted by LPS exchange in myxobacteria. AB - Bacterial cells in their native environments must cope with factors that compromise the integrity of the cell. The mechanisms of coping with damage in a social or multicellular context are poorly understood. Here we investigated how a model social bacterium, Myxococcus xanthus, approaches this problem. We focused on the social behavior of outer membrane exchange (OME), in which cells transiently fuse and exchange their outer membrane (OM) contents. This behavior requires TraA, a homophilic cell surface receptor that identifies kin based on similarities in a polymorphic region, and the TraB cohort protein. As observed by electron microscopy, TraAB overexpression catalyzed a prefusion OM junction between cells. We then showed that damage sustained by the OM of one population was repaired by OME with a healthy population. Specifically, LPS mutants that were defective in motility and sporulation were rescued by OME with healthy donors. In addition, a mutant with a conditional lethal mutation in lpxC, an essential gene required for lipid A biosynthesis, was rescued by Tra-dependent interactions with a healthy population. Furthermore, lpxC cells with damaged OMs, which were more susceptible to antibiotics, had resistance conferred to them by OME with healthy donors. We also show that OME has beneficial fitness consequences to all cells. Here, in merged populations of damaged and healthy cells, OME catalyzed a dilution of OM damage, increasing developmental sporulation outcomes of the combined population by allowing it to reach a threshold density. We propose that OME is a mechanism that myxobacteria use to overcome cell damage and to transition to a multicellular organism. PMID- 26038567 TI - Virus-induced translational arrest through 4EBP1/2-dependent decay of 5'-TOP mRNAs restricts viral infection. AB - The mosquito-transmitted bunyavirus, Rift Valley fever virus (RVFV), is a highly successful pathogen for which there are no vaccines or therapeutics. Translational arrest is a common antiviral strategy used by hosts. In response, RVFV inhibits two well-known antiviral pathways that attenuate translation during infection, PKR and type I IFN signaling. Despite this, translational arrest occurs during RVFV infection by unknown mechanisms. Here, we find that RVFV infection triggers the decay of core translation machinery mRNAs that possess a 5'-terminal oligopyrimidine (5'-TOP) motif in their 5'-UTR, including mRNAs encoding ribosomal proteins, which leads to a decrease in overall ribosomal protein levels. We find that the RNA decapping enzyme NUDT16 selectively degrades 5'-TOP mRNAs during RVFV infection and this decay is triggered in response to mTOR attenuation via the translational repressor 4EBP1/2 axis. Translational arrest of 5'-TOPs via 4EBP1/2 restricts RVFV replication, and this increased RNA decay results in the loss of visible RNA granules, including P bodies and stress granules. Because RVFV cap-snatches in RNA granules, the increased level of 5' TOP mRNAs in this compartment leads to snatching of these targets, which are translationally suppressed during infection. Therefore, translation of RVFV mRNAs is compromised by multiple mechanisms during infection. Together, these data present a previously unknown mechanism for translational shutdown in response to viral infection and identify mTOR attenuation as a potential therapeutic avenue against bunyaviral infection. PMID- 26038569 TI - Retinal waves regulate afferent terminal targeting in the early visual pathway. AB - Current models of retinogeniculate development have proposed that connectivity between the retina and the dorsal lateral geniculate nucleus (dLGN) is established by gradients of axon guidance molecules, to allow initial coarse connections, and by competitive Hebbian-like processes, to drive eye-specific segregation and refine retinotopy. Here we show that when intereye competition is eliminated by monocular enucleation, blocking cholinergic stage II retinal waves disrupts the intraeye competition-mediated expansion of the retinogeniculate projection and results in the permanent disorganization of its laminae. This disruption of stage II retinal waves also causes long-term impacts on receptive field size and fine-scale retinotopy in the dLGN. Our results reveal a novel role for stage II retinal waves in regulating retinogeniculate afferent terminal targeting by way of intraeye competition, allowing for correct laminar patterning and the even allocation of synaptic territory. These findings should contribute to answering questions regarding the role of neural activity in guiding the establishment of neural circuits. PMID- 26038570 TI - MicroRNA-103/107 Regulate Programmed Necrosis and Myocardial Ischemia/Reperfusion Injury Through Targeting FADD. AB - RATIONALE: Necrosis is one of the main forms of cardiomyocyte death in heart disease. Recent studies have demonstrated that certain types of necrosis are regulated and programmed dependent on the activation of receptor-interacting serine/threonine-protein kinase (RIPK) 1 and 3 which may be negatively regulated by Fas-associated protein with death domain (FADD). In addition, microRNAs and long noncoding RNAs have been shown to play important roles in various biological processes recently. OBJECTIVE: The purpose of this study was to test the hypothesis that microRNA-103/107 and H19 can participate in the regulation of RIPK1- and RIPK3-dependent necrosis in fetal cardiomyocyte-derived H9c2 cells and myocardial infarction through targeting FADD. METHODS AND RESULTS: Our results show that FADD participates in H2O2-induced necrosis by influencing the formation of RIPK1 and RIPK3 complexes in H9c2 cells. We further demonstrate that miR 103/107 target FADD directly. Knockdown of miR-103/107 antagonizes necrosis in the cellular model and also myocardial infarction in a mouse ischemia/reperfusion model. The miR-103/107-FADD pathway does not participate in tumor necrosis factor alpha-induced necrosis. In exploring the molecular mechanism by which miR-103/107 are regulated, we show that long noncoding RNA H19 directly binds to miR-103/107 and regulates FADD expression and necrosis. CONCLUSIONS: Our results reveal a novel myocardial necrosis regulation model, which is composed of H19, miR 103/107, and FADD. Modulation of their levels may provide a new approach for preventing myocardial necrosis. PMID- 26038571 TI - Interdependence of Parkin-Mediated Mitophagy and Mitochondrial Fission in Adult Mouse Hearts. AB - RATIONALE: The role of Parkin in hearts is unclear. Germ-line Parkin knockout mice have normal hearts, but Parkin is protective in cardiac ischemia. Parkin mediated mitophagy is reportedly either irrelevant, or a major factor, in the lethal cardiomyopathy evoked by cardiac myocyte-specific interruption of dynamin related protein 1 (Drp1)-mediated mitochondrial fission. OBJECTIVE: To understand the role of Parkin-mediated mitophagy in normal and mitochondrial fission defective adult mouse hearts. METHODS AND RESULTS: Parkin mRNA and protein were present at low levels in normal mouse hearts, but were upregulated after cardiac myocyte-directed Drp1 gene deletion in adult mice. Alone, forced cardiac myocyte Parkin overexpression activated mitophagy without adverse effects. Likewise, cardiac myocyte-specific Parkin deletion evoked no adult cardiac phenotype, revealing no essential function for, and tolerance of, Parkin-mediated mitophagy in normal hearts. Concomitant conditional Parkin deletion with Drp1 ablation in adult mouse hearts prevented Parkin upregulation in mitochondria of fission defective hearts, also increasing 6-week survival, improving ventricular ejection performance, mitigating adverse cardiac remodeling, and decreasing cardiac myocyte necrosis and replacement fibrosis. Underlying the Parkin knockout rescue was suppression of Drp1-induced hyper-mitophagy, assessed as ubiquitination of mitochondrial proteins and mitochondrial association of autophagosomal p62/sequestosome 1 (SQSTM1) and processed microtubule-associated protein 1 light chain 3 (LC3-II). Consequently, mitochondrial content of Drp1-deficient hearts was preserved. Parkin deletion did not alter characteristic mitochondrial enlargement of Drp1-deficient cardiac myocytes. CONCLUSIONS: Parkin is rare in normal hearts and dispensable for constitutive mitophagic quality control. Ablating Drp1 in adult mouse cardiac myocytes not only interrupts mitochondrial fission, but also markedly upregulates Parkin, thus provoking mitophagic mitochondrial depletion that contributes to the lethal cardiomyopathy. PMID- 26038572 TI - Epidemiology of adenovirus respiratory infections among hospitalized children in Seremban, Malaysia. AB - BACKGROUND: There is scarcity of data regarding epidemiology and clinical aspects of human adenovirus acute respiratory infection (ARI) among children in developing countries. METHODS: Retrospective data on demographics, clinical presentation, outcomes and laboratory findings of 116 children admitted into Tuanku Jaafar Hospital in Seremban, Malaysia from 2012 to 2013 with documented diagnosis of community-acquired adenovirus ARI were collected and analyzed. RESULTS: Male to female ratio was 1.70. Median age was 14 (1-107) months. The commonest symptoms were fever (94.8%; 110/116), cough (82.8%, 96), rhinorrhea (63.8%; 74), interrupted feeding (66.4%; 77), diarrhea (33.6%; 39) and conjunctivitis (21.6%; 25). Mean temperature on admission was 38.4 degrees C+/ 0.9 degrees C. Among all 116 subjects, 20.7% (24) needed oxygen supplementation, 57.8% (67) required intravenous hydration, 11.2% (13) were admitted into the pediatric intensive care unit and 6.9% (8) required mechanical ventilation. Only 1% (1/87) had positive blood culture (Streptococcus pneumoniae) among 87 who received antibiotic treatment. Case fatality rate was 2.6% (3/116) and 1.7% (2/116) developed bronchiolitis obliterans. Median length of hospital stay was 4 (1-50) days. CONCLUSION: Adenovirus ARI caused significant morbidity and substantial resource utilization among hospitalized Malaysian children. It should be considered in the differential diagnosis of infants below two years presenting with ARI associated with high fever. Antibiotics should not be prescribed as secondary bacterial infections are uncommon. PMID- 26038573 TI - Serum miR-21, miR-29a, and miR-125b Are Promising Biomarkers for the Early Detection of Colorectal Neoplasia. AB - PURPOSE: Circulating microRNAs (miRNA) are emerging as promising diagnostic biomarkers for colorectal cancer, but their usefulness for detecting early colorectal neoplasms remains unclear. This study aimed to identify serum miRNA biomarkers for the identification of patients with early colorectal neoplasms. EXPERIMENTAL DESIGN: A cohort of 237 serum samples from 160 patients with early colorectal neoplasms (148 precancerous lesions and 12 cancers) and 77 healthy subjects was analyzed in a three-step approach that included a comprehensive literature review for published biomarkers, a screening phase, and a validation phase. RNA was extracted from sera, and levels of miRNAs were examined by real time RT-PCR. RESULTS: Nine miRNAs (miR-18a, miR-19a, miR-19b, miR-20a, miR-21, miR-24, miR-29a, miR-92, and miR-125b) were selected as candidate biomarkers for initial analysis. In the screening phase, serum levels of miR-21, miR-29a, and miR-125b were significantly higher in patients with early colorectal neoplasm than in healthy controls. Elevated levels of miR-21, miR-29a, and miR-125b were confirmed in the validation phase using an independent set of subjects. Area under the curve (AUC) values for serum miR-21, miR-29a, miR-125b, and their combined score in discriminating patients with early colorectal neoplasm from healthy controls were 0.706, 0.741, 0.806, and 0.827, respectively. Serum levels of miR-29a and miR-125b were significantly higher in patients who had only small colorectal neoplasms (<=5 mm) than in healthy subjects. CONCLUSIONS: Because serum levels of miR-21, miR-29a, and miR-125b discriminated patients with early colorectal neoplasm from healthy controls, our data highlight the potential clinical use of these molecular signatures for noninvasive screening of patients with colorectal neoplasia. PMID- 26038574 TI - Measuring ruggedness in fitness landscapes. PMID- 26038575 TI - Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy. AB - Circular dichroism (CD) spectroscopy is a widely used technique for the study of protein structure. Numerous algorithms have been developed for the estimation of the secondary structure composition from the CD spectra. These methods often fail to provide acceptable results on alpha/beta-mixed or beta-structure-rich proteins. The problem arises from the spectral diversity of beta-structures, which has hitherto been considered as an intrinsic limitation of the technique. The predictions are less reliable for proteins of unusual beta-structures such as membrane proteins, protein aggregates, and amyloid fibrils. Here, we show that the parallel/antiparallel orientation and the twisting of the beta-sheets account for the observed spectral diversity. We have developed a method called beta structure selection (BeStSel) for the secondary structure estimation that takes into account the twist of beta-structures. This method can reliably distinguish parallel and antiparallel beta-sheets and accurately estimates the secondary structure for a broad range of proteins. Moreover, the secondary structure components applied by the method are characteristic to the protein fold, and thus the fold can be predicted to the level of topology in the CATH classification from a single CD spectrum. By constructing a web server, we offer a general tool for a quick and reliable structure analysis using conventional CD or synchrotron radiation CD (SRCD) spectroscopy for the protein science research community. The method is especially useful when X-ray or NMR techniques fail. Using BeStSel on data collected by SRCD spectroscopy, we investigated the structure of amyloid fibrils of various disease-related proteins and peptides. PMID- 26038576 TI - Evolutionary and phenotypic analysis of live virus isolates suggests arthropod origin of a pathogenic RNA virus family. AB - The evolutionary origins of arboviruses are unknown because their typical dual host tropism is paraphyletic within viral families. Here we studied one of the most diversified and medically relevant RNA virus families, the Bunyaviridae, in which four of five established genera are transmitted by arthropods. We define two cardinally novel bunyavirus groups based on live isolation of 26 viral strains from mosquitoes (Jonchet virus [JONV], eight strains; Ferak virus [FERV], 18 strains). Both viruses were incapable of replicating at vertebrate-typical temperatures but replicated efficiently in insect cells. Replication involved formation of virion-sense RNA (vRNA) and mRNA, including cap-snatching activity. SDS/PAGE, mass spectrometry, and Edman degradation identified translation products corresponding to virion-associated RNA-dependent RNA polymerase protein (RdRp), glycoprotein precursor protein, glycoproteins Gn and Gc, as well as putative nonstructural proteins NSs and NSm. Distinct virion morphologies suggested ancient evolutionary divergence, with bunyavirus-typical morphology for FERV (spheres of 60-120 nm) as opposed to an unusual bimorphology for JONV (tubular virions of 60 * 600 nm and spheres of 80 nm). Both viruses were genetically equidistant from all other bunyaviruses, showing <15% amino acid identity in the RdRp palm domain. Both had different and unique conserved genome termini, as in separate bunyavirus genera. JONV and FERV define two novel sister taxons to the superclade of orthobunyaviruses, tospoviruses, and hantaviruses. Phylogenetic ancestral state reconstruction with probabilistic hypothesis testing suggested ancestral associations with arthropods at deep nodes throughout the bunyavirus tree. Our findings suggest an arthropod origin of bunyaviruses. PMID- 26038578 TI - DAPK2 Downregulation Associates With Attenuated Adipocyte Autophagic Clearance in Human Obesity. AB - Adipose tissue dysfunction in obesity has been linked to low-grade inflammation causing insulin resistance. Transcriptomic studies have identified death associated protein kinase 2 (DAPK2) among the most strongly downregulated adipose tissue genes in human obesity, but the role of this kinase is unknown. We show that mature adipocytes rather than the stromal vascular cells in adipose tissue mainly expressed DAPK2 and that DAPK2 mRNA in obese patients gradually recovered after bariatric surgery-induced weight loss. DAPK2 mRNA is also downregulated in high-fat diet-induced obese mice. Adenoviral-mediated DAPK2 overexpression in 3T3 L1 adipocytes did not affect lipid droplet size or cell viability but did increase autophagic clearance in nutrient-rich conditions, dependent on protein kinase activity. Conversely, DAPK2 inhibition in human preadipocytes by small interfering RNA decreased LC3-II accumulation rates with lysosome inhibitors. This led us to assess autophagic clearance in adipocytes freshly isolated from subcutaneous adipose tissue of obese patients. Severe reduction in autophagic flux was observed in obese adipocytes compared with control adipocytes, inversely correlated to fat cell lipids. After bariatric surgery, adipocyte autophagic clearance partially recovered proportional to the extent of fat cell size reduction. This study links adipocyte expression of an autophagy-regulating kinase, lysosome-mediated clearance and fat cell lipid accumulation; it demonstrates obesity-related attenuated autophagy in adipocytes, and identifies DAPK2 dependence in this regulation. PMID- 26038577 TI - Extrachromosomal circular DNA is common in yeast. AB - Examples of extrachromosomal circular DNAs (eccDNAs) are found in many organisms, but their impact on genetic variation at the genome scale has not been investigated. We mapped 1,756 eccDNAs in the Saccharomyces cerevisiae genome using Circle-Seq, a highly sensitive eccDNA purification method. Yeast eccDNAs ranged from an arbitrary lower limit of 1 kb up to 38 kb and covered 23% of the genome, representing thousands of genes. EccDNA arose both from genomic regions with repetitive sequences >= 15 bases long and from regions with short or no repetitive sequences. Some eccDNAs were identified in several yeast populations. These eccDNAs contained ribosomal genes, transposon remnants, and tandemly repeated genes (HXT6/7, ENA1/2/5, and CUP1-1/-2) that were generally enriched on eccDNAs. EccDNAs seemed to be replicated and 80% contained consensus sequences for autonomous replication origins that could explain their maintenance. Our data suggest that eccDNAs are common in S. cerevisiae, where they might contribute substantially to genetic variation and evolution. PMID- 26038579 TI - Fasting-Induced Lipolysis and Hypothalamic Insulin Signaling Are Regulated by Neuronal Glucosylceramide Synthase. AB - Central nervous regulation of body weight and adipose tissue function is mainly conducted by hypothalamic neurons. Neuronal function depends on the integrity of the membrane lipid microenvironment. Lipid microdomains contain large quantities of cholesterol and glycosphingolipids, including glucosylceramide synthase (GCS) (gene Ugcg)-derived gangliosides. The current study demonstrates that Ugcgf/f//CamKCreERT2 mice with genetic GCS deletion in forebrain neurons, dominantly targeting mediobasal hypothalamus (MBH), display impaired fasting induced lipolysis accompanied by a decreased norepinephrine content in white adipose tissue (WAT). MBH insulin receptor (IR) levels and signaling are increased in Ugcgf/f//CamKCreERT2 mice. These results are in concordance with reports stating that MBH insulin signaling restrains sympathetic nervous outflow to WAT in fasted mice. In line with the in vivo data, pharmacological GCS inhibition by Genz123346 also increases IR levels as well as IR phosphorylation in insulin-stimulated hypothalamic cells. In addition to studies suggesting that simple gangliosides like GM3 regulate peripheral IR signaling, this work suggests that complex neuronal gangliosides also modulate hypothalamic IR signaling and protein levels. For example, the complex ganglioside GD1a interacts dynamically with the IRs on adult hypothalamic neurons. In summary, our results suggest that neuronal GCS expression modulates MBH insulin signaling and WAT function in fasted mice. PMID- 26038581 TI - Atypical lymphocytes and leukocytes in the peripheral circulation of caged hens. AB - Lymphocytes comprise a family of cells descended from bursa and thymus progenitors whose differentiation is not possible by standard hematology. However, if they are small with a nuclear/cytoplasmic ratio near 1, they are "resting" at least in the microscopic sense. Activation, increases their size, and decreases the nuclear:cytoplasmic (N:C) ratio. Reactive cells are infrequent in healthy animal blood. Their presence indicates an immune response in progress, inflammation, stress, or other pathology. Here the purpose is to describe unusual leukocytes and lymphocytes found in the periphery of commercial hens. Samples of Wright stained blood films obtained from commercial hens housed in modern cages are the data source. Photomicroscopy used an Olympus CX41 light microscope equipped with an Infinity-2 1.4 megapixel charge-coupled device (CCD) Universal Serial Bus (USB) 2.0 camera, at 100* (oil) magnification. Collectively these cells illustrate a continuum between mildly "reactive" to grossly "atypical" states. The description begins with normal resting cells, proceeds to mildly atypical, and concludes with grossly abnormal cells. Bone marrow cells, a source of plasmacytes, are included for comparison. Examples of circulating plasmacytes, large plasmacytoid lymphocytes (LPL), foam cells, and cells expressing properties of more than one lineage are included. The importance of these observations lies in their contribution to cytology, hematology, and immunology. Last, because of the wide use of heterophil:lymphocyte ratios (H:L) as a stress measure they bear directly the welfare issues of caged animals. When cells similar to the types described here are in blood, they indicate stress independent of H:L or other standard measures. PMID- 26038580 TI - Inactivation of NF-kappaB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway. AB - The transcription factor nuclear factor-kappaB (NF-kappaB) mediates inflammation and stress signals in cells. To test NF-kappaB in the control of hepatic insulin sensitivity, we inactivated NF-kappaB in the livers of C57BL/6 mice through deletion of the p65 gene, which was achieved by crossing floxed-p65 and Alb-cre mice to generate L-p65-knockout (KO) mice. KO mice did not exhibit any alterations in growth, reproduction, and body weight while on a chow diet. However, the mice on a high-fat diet (HFD) exhibited an improvement in systemic insulin sensitivity. Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate tolerance, Akt phosphorylation, and decreased gene expression in hepatic gluconeogenesis. In the liver, a decrease in intracellular cAMP was observed with decreased CREB phosphorylation. Cyclic nucleotide phosphodiesterase 3B (PDE3B), a cAMP-degrading enzyme, was increased in mRNA and protein as a result of the absence of NF-kappaB activity. NF-kappaB was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-alpha. Body composition, food intake, energy expenditure, and systemic and hepatic inflammation were not significantly altered in KO mice on HFD. These data suggest that NF-kappaB inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription. PMID- 26038582 TI - Effect of Type 2 Diabetes on Recurrent Major Cardiovascular Events for Patients With Symptomatic Vascular Disease at Different Locations. AB - OBJECTIVE: Our aim is to compare the effect of type 2 diabetes on recurrent major cardiovascular events (MCVE) for patients with symptomatic vascular disease at different locations. RESEARCH DESIGN AND METHODS: A total of 6,841 patients from the single-center, prospective Second Manifestations of ARTerial disease (SMART) cohort study from Utrecht, the Netherlands, with clinically manifest vascular disease with (n = 1,155) and without (n = 5,686) type 2 diabetes were monitored between 1996 and 2013. The effect of type 2 diabetes on recurrent MCVE was analyzed with Cox proportional hazards models, stratified for disease location (cerebrovascular disease, peripheral artery disease, abdominal aortic aneurysm, coronary artery disease, or polyvascular disease, defined as >=2 vascular locations). RESULTS: Five-year risks for recurrent MCVE were 9% in cerebrovascular disease, 9% in peripheral artery disease, 20% in those with an abdominal aortic aneurysm, 7% in coronary artery disease, and 21% in polyvascular disease. Type 2 diabetes increased the risk of recurrent MCVE in coronary artery disease (hazard ratio [HR] 1.67; 95% CI 1.25-2.21) and seemed to increase the risk in cerebrovascular disease (HR 1.36; 95% CI 0.90-2.07), while being no risk factor in polyvascular disease (HR 1.12; 95% CI 0.83-1.50). Results for patients with peripheral artery disease (HR 1.42; 95% CI 0.79-2.56) or an abdominal aortic aneurysm (HR 0.93; 95% CI 0.23-3.68) were inconclusive. CONCLUSIONS: Type 2 diabetes increased the risk of recurrent MCVE in patients with coronary artery disease, but there is no convincing evidence that it is a major risk factor for subsequent MCVE in all patients with symptomatic vascular disease. PMID- 26038583 TI - A longitudinally extensive myelopathy in a patient with AIDS. PMID- 26038584 TI - Brain injury and deprivation of liberty on neurosciences wards: 'a gilded cage is still a cage'. AB - In March 2014, a UK Supreme Court case, known as Cheshire West, reached a judgement that greatly expanded the group of people in England and Wales who could be considered deprived of their liberty when under the care of the state. This now includes anyone meeting what is known as the 'acid test': whether the person is under 'continuous supervision and control' and 'not free to leave'. The case concerned three people with learning disability, living in community residential placements; all were judged to have been deprived of their liberty, despite being apparently content, and having 'relative normality' for people in their situation. Many people consider the case to apply to hospital settings. Clearly, many neurosciences inpatients are under 'continuous supervision and control'. This might include being told when to eat or sleep, what medication to take or being under close nursing observation. Many also are not free to leave because of safety concerns. Inpatients may also be eligible for detention under Mental Health Act--if they have a mental disorder sufficient to warrant this- such as a risk to that person's health or safety, or the safety of others. Thus, we have a confusing combination of two laws that might apply. This article aims to demystify the legal background and apply it to clinical practice in England and Wales and elsewhere. PMID- 26038585 TI - Intradural extramedullary spinal candida infection. PMID- 26038586 TI - The Quadruple Aim: care, health, cost and meaning in work. PMID- 26038587 TI - A unit-based intervention aimed at improving patient adherence to pharmacological thromboprophylaxis. AB - BACKGROUND: Pharmacological thromboprophylaxis is necessary among many hospitalised patients to prevent venous thromboembolism (VTE). However, a significant number of clinician-ordered doses are not administered with many doses refused by patients. We aimed to assess the impact and sustainability of a multifaceted intervention to improve medication adherence to pharmacological thromboprophylaxis. The intervention included a standardised nursing response to patient refusal, daily assessment of VTE prophylaxis usage and regular feedback on refusal rates. METHODS: We conducted a quasi-experimental study of patients admitted between January 2010 and November 2012 to one of six hospital intervention units (three medical and three oncology units) or five control units. The primary outcome was the proportion of VTE prophylaxis doses missed for any reason. RESULTS: A total of 20,208 admissions occurred at the six hospital units during the study period. In the pre-post analysis, the rate of missed and refused doses decreased significantly after the intervention (24.7% to 14.7% and 18.3% to 9.4%, respectively; p value <0.01 for both comparisons). In multiple regression models with interrupted time series analysis, the intervention was associated with an immediate and sustained decrease in missed (adjusted OR 0.64; 95% CI 0.55 to 0.74 and 0.98; 95%CI 0.97 to 0.99) and refused doses (adjusted OR per month 0.58; 95% CI 0.48 to 0.71 and 0.97; 95%CI 0.96 to 0.98). No immediate or sustained reduction in missed or refused doses was observed in the control units. CONCLUSIONS: Implementation of a multifaceted intervention resulted in an immediate and sustained decrease in the proportion of missed and refused doses of pharmacological thromboprophylaxis. Efforts aimed at increasing patient adherence are a promising approach to improve rates of VTE thromboprophylaxis administration. PMID- 26038589 TI - Ischaemic stroke and ST-segment elevation myocardial infarction: fast-track single-stop approach. AB - Current management of patients with AIS relies primarily on conservative approach. Suggested streamlined fast-track single-stop approach should expedite the workflow and improve clinical outcomes. Given the broadly available interventional cardiology expertise cardiologist should play an active and sensible role in the development of new interventional concepts of care of patients with acute ischaemic stroke. PMID- 26038590 TI - Exercise-induced right ventricular dysfunction is associated with ventricular arrhythmias in endurance athletes. AB - AIMS: Intense exercise places disproportionate strain on the right ventricle (RV) which may promote pro-arrhythmic remodelling in some athletes. RV exercise imaging may enable early identification of athletes at risk of arrhythmias. METHODS AND RESULTS: Exercise imaging was performed in 17 athletes with RV ventricular arrhythmias (EA-VAs), of which eight (47%) had an implantable cardiac defibrillator (ICD), 10 healthy endurance athletes (EAs), and seven non-athletes (NAs). Echocardiographic measures included the RV end-systolic pressure-area ratio (ESPAR), RV fractional area change (RVFAC), and systolic tricuspid annular velocity (RV S'). Cardiac magnetic resonance (CMR) measures combined with invasive measurements of pulmonary and systemic artery pressures provided left ventricular (LV) and RV end-systolic pressure-volume ratios (SP/ESV), biventricular volumes, and ejection fraction (EF) at rest and during intense exercise. Resting measures of cardiac function were similar in all groups, as was LV function during exercise. In contrast, exercise-induced increases in RVFAC, RV S', and RVESPAR were attenuated in EA-VAs during exercise when compared with EAs and NAs (P < 0.0001 for interaction group * workload). During exercise-CMR, decreases in RVESV and augmentation of both RVEF and RV SP/ESV were significantly less in EA-VAs relative to EAs and NAs (P < 0.01 for the respective interactions). Receiver-operator characteristic curves demonstrated that RV exercise measures could accurately differentiate EA-VAs from subjects without arrhythmias [AUC for DeltaRVESPAR = 0.96 (0.89-1.00), P < 0.0001]. CONCLUSION: Among athletes with normal cardiac function at rest, exercise testing reveals RV contractile dysfunction among athletes with RV arrhythmias. RV stress testing shows promise as a non-invasive means of risk-stratifying athletes. PMID- 26038591 TI - Arrhythmogenic right ventricular remodelling in endurance athletes: Pandora's box or Achilles' heel? PMID- 26038588 TI - Fractional flow reserve-guided management in stable coronary disease and acute myocardial infarction: recent developments. AB - Coronary artery disease (CAD) is a leading global cause of morbidity and mortality, and improvements in the diagnosis and treatment of CAD can reduce the health and economic burden of this condition. Fractional flow reserve (FFR) is an evidence-based diagnostic test of the physiological significance of a coronary artery stenosis. Fractional flow reserve is a pressure-derived index of the maximal achievable myocardial blood flow in the presence of an epicardial coronary stenosis as a ratio to maximum achievable flow if that artery were normal. When compared with standard angiography-guided management, FFR disclosure is impactful on the decision for revascularization and clinical outcomes. In this article, we review recent developments with FFR in patients with stable CAD and recent myocardial infarction. Specifically, we review novel developments in our understanding of CAD pathophysiology, diagnostic applications, prognostic studies, clinical trials, and clinical guidelines. PMID- 26038592 TI - What is nuclear medicine? PMID- 26038593 TI - A focus on quality, credentialing, and standards. PMID- 26038594 TI - Year in Review 2014: Patient Safety. AB - The topic of patient safety has received much attention in recent years. There are a number of areas in which the subject of patient safety impacts respiratory care practice. This paper focuses on articles published in 2014 related to pressure injury, handoffs, protocols and multidisciplinary teams, perioperative obstructive sleep apnea, and readmissions. PMID- 26038595 TI - Year in Review 2014: COPD. AB - Clinicians responsible for treating pulmonary disease often encounter challenges in the management of patients with COPD. This is due in part to the number of drugs now available to ameliorate COPD symptoms and the complexity of adhering to good disease management programs. Each aspect of treatment is a critical component in improving outcomes for these patients. The purpose of this article is to review some of the most significant findings regarding the treatment of COPD, with emphasis on disease management and pharmacotherapy. PMID- 26038596 TI - Year in Review 2014: Aerosol Delivery Devices. AB - After centuries of discoveries and technological growth, aerosol therapy remains a cornerstone of care in the management of both acute and chronic respiratory conditions. Aerosol therapy embraces the concept that medicine is both an art and a science, where an explicit understanding of the science of aerosol therapy, the nuances of the different delivery devices, and the ability to provide accurate and reliable education to patients become increasingly important. The purpose of this article is to review recent literature regarding aerosol delivery devices in a style that readers of Respiratory Care may use as a key topic resource. PMID- 26038597 TI - Cardiac arrhythmias during or after epileptic seizures. AB - Seizure-related cardiac arrhythmias are frequently reported and have been implicated as potential pathomechanisms of Sudden Unexpected Death in Epilepsy (SUDEP). We attempted to identify clinical profiles associated with various (post)ictal cardiac arrhythmias. We conducted a systematic search from the first date available to July 2013 on the combination of two terms: 'cardiac arrhythmias' and 'epilepsy'. The databases searched were PubMed, Embase (OVID version), Web of Science and COCHRANE Library. We attempted to identify all case reports and case series. We identified seven distinct patterns of (post)ictal cardiac arrhythmias: ictal asystole (103 cases), postictal asystole (13 cases), ictal bradycardia (25 cases), ictal atrioventricular (AV)-conduction block (11 cases), postictal AV-conduction block (2 cases), (post)ictal atrial flutter/atrial fibrillation (14 cases) and postictal ventricular fibrillation (3 cases). Ictal asystole had a mean prevalence of 0.318% (95% CI 0.316% to 0.320%) in people with refractory epilepsy who underwent video-EEG monitoring. Ictal asystole, bradycardia and AV-conduction block were self-limiting in all but one of the cases and seen during focal dyscognitive seizures. Seizure onset was mostly temporal (91%) without consistent lateralisation. Postictal arrhythmias were mostly found following convulsive seizures and often associated with (near) SUDEP. The contrasting clinical profiles of ictal and postictal arrhythmias suggest different pathomechanisms. Postictal rather than ictal arrhythmias seem of greater importance to the pathophysiology of SUDEP. PMID- 26038598 TI - Combining three antibodies nullifies feedback-mediated resistance to erlotinib in lung cancer. AB - Despite initial responses to targeted kinase inhibitors, lung cancer patients presenting with primary epidermal growth factor receptor (EGFR) mutations acquire resistance, often due to a second-site mutation (T790M). However, clinical trials found no survival benefits in patients treated with a monoclonal antibody (mAb) to EGFR that should block activation of the mutated receptor and thus bypass resistance to molecules that target the catalytic or ATP-binding site. Using cell lines with the T790M mutation, we discovered that prolonged exposure to mAbs against only the EGFR triggered network rewiring by (i) stimulating the extracellular signal-regulated kinase (ERK) pathway; (ii) inducing the transcription of HER2 (human epidermal growth factor receptor 2) and HER3, which encode other members of the EGFR family, and the gene encoding HGF, which is the ligand for the receptor tyrosine kinase MET; and (iii) stimulating the interaction between MET and HER3, which promoted MET activity. Supplementing the EGFR-specific mAb with those targeting HER2 and HER3 suppressed these compensatory feedback loops in cultured lung cancer cells. The triple mAb combination targeting all three receptors prevented the activation of ERK, accelerated the degradation of the receptors, inhibited the proliferation of tumor cells but not of normal cells, and markedly reduced the growth of tumors in mice xenografted with cells that were resistant to combined treatment with erlotinib and the single function-blocking EGFR mAb. These findings uncovered feedback loops that enable resistance to treatment paradigms that use a single antibody and indicate a new strategy for the treatment of lung cancer patients. PMID- 26038599 TI - The scaffold protein RACK1 mediates the RANKL-dependent activation of p38 MAPK in osteoclast precursors. AB - The E3 ubiquitin ligase TRAF6 [tumor necrosis factor (TNF) receptor (TNFR) associated factor 6] and the associated kinase TAK1 [transforming growth factor beta (TGF-beta)-activated kinase 1] are key components of the signaling pathways that activate nuclear factor kappaB (NF-kappaB) and mitogen-activated protein kinases (MAPKs) in response to various stimuli. The cytokine RANKL (receptor activator of NF-kappaB ligand) is essential for the differentiation of bone marrow cells into bone-resorbing osteoclasts through the activation of NF-kappaB and MAPK. We found that the scaffold protein RACK1 (receptor for activated C kinase 1) selectively mediated the RANKL-dependent activation of p38 MAPK through the TRAF6-TAK1 axis by interacting with the MAPK kinase MKK6 (MAPK kinase kinase 6), which is upstream of p38 MAPK. RACK1 was necessary for the differentiation of bone marrow cells into osteoclasts through the stimulation of p38 MAPK activation. Osteoclast precursors exposed to RANKL exhibited an interaction among RACK1, RANK, TRAF6, TAK1, and the kinase MKK6, thereby leading to the activation of the MKK6-p38 MAPK pathway. Experiments in which RACK1 or TAK1 was knocked down in osteoclast precursors indicated that RACK1 acted as a bridge, bringing MKK6 to the TRAF6-TAK1 complex. Furthermore, local administration of RACK1-specific small interfering RNA (siRNA) into mice calvariae reduced the RANKL-induced bone loss by reducing the numbers of osteoclasts. These findings suggest that RACK1 specifies the RANKL-stimulated activation of p38 MAPK by facilitating the association of MKK6 with TAK1 and may provide a molecular target for a new therapeutic strategy to treat bone diseases. PMID- 26038601 TI - Posterior dislocation of clavicle with potential for great vessel injury. PMID- 26038600 TI - The role of ciliary trafficking in Hedgehog receptor signaling. AB - Defects in the biogenesis of or transport through primary cilia affect Hedgehog protein signaling, and many Hedgehog pathway components traffic through or accumulate in cilia. The Hedgehog receptor Patched negatively regulates the activity and ciliary accumulation of Smoothened, a seven-transmembrane protein that is essential for transducing the Hedgehog signal. We found that this negative regulation of Smoothened required the ciliary localization of Patched, as specified either by its own cytoplasmic tail or by provision of heterologous ciliary localization signals. Surprisingly, given that Hedgehog binding promotes the exit of Patched from the cilium, we observed that an altered form of Patched that is retained in the cilium nevertheless responded to Hedgehog, resulting in Smoothened activation. Our results indicate that whereas ciliary localization of Patched is essential for suppression of Smoothened activation, the primary event enabling Smoothened activation is binding of Hedgehog to Patched, and Patched ciliary removal is secondary. PMID- 26038602 TI - Opsoclonus-myoclonus syndrome associated with non-small cell lung cancer. AB - A 68-year-old man developed progressive vertigo, saccadic eye movements, and tremors. Computed tomography showed multiple lung nodules. Surgery was performed and the pathological diagnosis was large cell neuroendocrine carcinoma in the left upper lobe with ipsilobar metastases, and adenocarcinoma in the left lower lobe. The neurological symptoms resolved dramatically after complete resection of the tumors. Opsoclonus-myoclonus syndrome associated with non-small-cell lung carcinoma is extremely rare. Surgery should not be delayed if a complete resection is expected. PMID- 26038603 TI - Pleural fat-forming variant of solitary fibrous tumor. AB - The fat-forming variant of solitary fibrous tumor is rare. It occurs predominantly in the deep soft tissues of the retroperitoneum and thigh. We describe a case of fat-forming solitary fibrous tumor arising from the pleura, which was successfully treated using a video-assisted thoracoscopic approach. The patient remained free of recurrence 2 years after surgery and continues to be under long-term follow-up. PMID- 26038604 TI - Management of partial anomalous pulmonary venous connection in single ventricle. AB - We herein report a case of a hypoplastic left heart syndrome variant complicated with partial anomalous pulmonary venous connection to the left innominate vein. We left the vertical vein at the time of the bidirectional Glenn procedure, and ligated the vertical vein at the time of the total cavopulmonary connection procedure, without reconnecting the vertical vein to the left atrium. Because of the development of an interlobar vein draining from the left upper lung into the lower lung after the bidirectional Glenn procedure, the circulation of the left upper lung was preserved after the total cavopulmonary connection procedure. PMID- 26038605 TI - Primary Burkitt lymphoma in the posterior mediastinum. AB - A 13-year-old boy was admitted to our hospital with complaints of posterior chest pain and dyspnea. Computed tomography and magnetic resonance imaging of the chest revealed a mass in the posterior mediastinum, extending from T8 to T11 with intraspinal involvement. A percutaneous core needle biopsy confirmed the diagnosis of Burkitt lymphoma. He was treated according to the Lymphoma Malignancy B protocol 2001 arm C3, but he presented with liver and brain relapses and died 7.5 months after admission. Although lymphoma is rarely localized in the posterior mediastinum, it should be considered in the differential diagnosis of posterior mediastinal masses in children. PMID- 26038606 TI - Cerebrospinal fluid lactate: measurement of an adult reference interval. AB - BACKGROUND: Differentiating bacterial meningitis from viral meningitis is a diagnostic challenge. Cerebrospinal fluid lactate has been proposed as a valuable test to differentiate disease states; however, its use in adults is limited by a lack of robust reference interval data. METHODS: Cerebrospinal fluid samples with no cells or organisms detected, no culture growth after 48 h, and no increase in cerebrospinal fluid bilirubin were used to derive reference interval data for cerebrospinal fluid lactate in adults (n = 120). RESULTS: A cerebrospinal fluid lactate reference interval of 1.0 (90% CI 0.9-1.1) - 2.2 mmol/L (90% CI 2.0-2.6) was defined. CONCLUSIONS: Cerebrospinal fluid lactate results are rapidly available to the clinician. When interpreted against the adult reference interval derived in this study, results can help to triage patients presenting with symptoms of meningitis. PMID- 26038607 TI - Raised circulating Neurokinin A predicts prognosis in metastatic small bowel neuroendocrine tumours. Lowering Neurokinin A indicates improved prognosis. AB - BACKGROUND: Assessing prognosis is important in patients with neuroendocrine tumours of the small bowel as disease progression and survival is variable. We previously identified raised Neurokinin A as an independent indicator of poor prognosis and have shown that prognosis worsens when circulating Neurokinin A rises >=50 ng/L. In the present study we have examined survival in relation to Neurokinin A concentrations. METHODS: Patients in whom Neurokinin A rose >=50 ng/L between January 1989 and December 2010 were identified. All circulating Neurokinin A concentrations were recorded and survival was followed up to 31 December 2014 or to death. RESULTS: Median survival, from the date when Neurokinin A was first >=50 ng/L was 11.1 (2.0-117.8) months if Neurokinin A remained >=50 ng/L and 72.4 (4.8-152.6) months when Neurokinin A was reduced below 50 ng/L and controlled below that concentration for >=3 months (P < 0.001). Survival was significantly better for patients attending the neuroendocrine tumour specialist clinic than for those not attending (P = 0.009). Comparing patients identified during 1989-2000, and those during 2001-2010, Neurokinin A was successfully reduced in the earlier period in 30.3% patients with median survival 23.2 (2.0-152.6) months and this improved in 58.1% with median survival of 43.3 (2.0-141.1) months in the later period (P = 0.019). Significance was greater between the earlier and later periods when only patients attending the neuroendocrine tumour clinic were compared (P = 0.016). CONCLUSIONS: Circulating Neurokinin A >= 50 ng/L is a strong indicator of poor prognosis when Neurokinin A remains above this concentration. Lowering Neurokinin A below 50 ng/L indicates a significant improvement in prognosis (P < 0.001). This prognostic indicator reflects improved treatment and survival in more recent years. PMID- 26038608 TI - Decision Analysis for Metric Selection on a Clinical Quality Scorecard. AB - Clinical quality scorecards are used by health care institutions to monitor clinical performance and drive quality improvement. Because of the rapid proliferation of quality metrics in health care, BJC HealthCare found it increasingly difficult to select the most impactful scorecard metrics while still monitoring metrics for regulatory purposes. A 7-step measure selection process was implemented incorporating Kepner-Tregoe Decision Analysis, which is a systematic process that considers key criteria that must be satisfied in order to make the best decision. The decision analysis process evaluates what metrics will most appropriately fulfill these criteria, as well as identifies potential risks associated with a particular metric in order to identify threats to its implementation. Using this process, a list of 750 potential metrics was narrowed to 25 that were selected for scorecard inclusion. This decision analysis process created a more transparent, reproducible approach for selecting quality metrics for clinical quality scorecards. PMID- 26038610 TI - Visual cues combined with treadmill training to improve gait performance in Parkinson's disease: a pilot randomized controlled trial. AB - OBJECTIVE: To evaluate the effects of visual cues combined with treadmill training on gait performance in patients with Parkinson's disease and to compare the strategy with pure treadmill training. DESIGN: Pilot, exploratory, non blinded, randomized controlled trial. SETTING: University Hospital of Munich, Germany. SUBJECTS: Twenty-three outpatients with Parkinson's disease (Hoehn and Yahr stage II-IV). INTERVENTIONS: Patients received 12 training sessions within five weeks of either visual cues combined with treadmill training (n = 12) or pure treadmill training (n = 11). MAIN MEASURES: Outcome measures were gait speed, stride length and cadence recorded on the treadmill. Functional tests included the Timed Up and Go Test, the Unified Parkinson's Disease Rating Scale and the Freezing of gait-questionnaire. Assessments were conducted at baseline, after the training period and at two months follow-up. RESULTS: After the training period (n = 20), gait speed and stride length had increased in both groups (p ? 0.05). Patients receiving the combined training scored better in the Timed Up and Go Test compared with the patients receiving pure treadmill training (p ? 0.05). At two months follow-up (n = 13), patients who underwent the combined training sustained better results in gait speed and stride length (p ? 0.05) and sustained the improvement in the Timed Up and Go Test (p ? 0.05). CONCLUSIONS: This pilot study suggests that visual cues combined with treadmill training have more beneficial effects on gait than pure treadmill training in patients with a moderate stage of Parkinson's disease. A large-scale study with longer follow-up is required. PMID- 26038611 TI - Effects of whole body vibration on pulmonary function, functional exercise capacity and quality of life in people with chronic obstructive pulmonary disease: a systematic review. AB - OBJECTIVE: To examine the effect of whole-body vibration in enhancing pulmonary function, functional exercise capacity and quality of life in people with chronic obstructive pulmonary disease and examine its safety. METHOD: Randomized controlled trials examining the effects of whole body vibration among people with chronic obstructive pulmonary disease were identified by two independent researchers. Articles were excluded if they were studies on people with other primary diagnosis, abstracts published in the conferences or books. PEDro scale was used to assess the methodological quality of the selected studies. We evaluated the level of evidence by using the GRADE approach. The results were extracted by two researchers and confirmed by the third researcher if disagreement existed. DATA SOURCE: Sources included Cochrane Central Register of Controlled Trials, PubMed, CINAHL, EMBASE, PEDro, AMED, PsycINFO, ClinicalTrials.gov, Current Controlled Trials and reference lists of all relevant articles. RESULT: Four studies involving 206 participants were included in this systematic review. Methodological quality was rated as good for two studies. No great benefits on pulmonary function were found in whole body vibration treatment group. Two studies showed that quality of life was improved in people with chronic obstructive pulmonary disease. Whole body vibration led to significant improvements in functional exercise capacity measured with six minutes walking test. Nearly no adverse events were observed. CONCLUSION: Whole body vibration may improve functional exercise capacity and quality of life in people with chronic obstructive pulmonary disease. There was insufficient evidence to prove the effects of whole body vibration on pulmonary function. PMID- 26038612 TI - Spaces for Citizen Involvement in Healthcare: An Ethnographic Study. AB - This ethnographic study examines how participatory spaces and citizenship are co constituted in participatory healthcare improvement efforts. We propose a theoretical framework for participatory citizenship in which acts of citizenship in healthcare are understood in terms of the spaces they are in. Participatory spaces consist of material, temporal and social dimensions that constrain citizens' actions. Participants draw on external resources to try to make participatory spaces more productive and collaborative, to connect and expand them. We identify three classes of tactics they use to do this: 'plotting', 'transient combination' and 'interconnecting'. All tactics help participants assemble to a greater or lesser extent a less fragmented participatory landscape with more potential for positive impact on healthcare. Participants' acts of citizenship both shape and are shaped by participatory spaces. To understand participatory citizenship, we should take spatiality into account, and track the ongoing spatial negotiations and productions through which people can improve healthcare. PMID- 26038614 TI - A moment for reflection. PMID- 26038613 TI - Successful phonological awareness instruction with preschool children: Lessons from the classroom. PMID- 26038615 TI - Management of dysfunctional catheters and tubes inserted by interventional radiology. AB - Minimally invasive percutaneous interventions are often used for enteral nutrition, biliary and urinary diversion, intra-abdominal fluid collection drainage, and central venous access. In most cases, radiologic and endoscopic placement of catheters and tubes has replaced the comparable surgical alternative. As experience with catheters and tubes grows, it becomes increasingly evident that the interventional radiologist needs to be an expert not only on device placement but also on device management. Tube dysfunction represents the most common complication requiring repeat intervention, which can be distressing for patients and other health care professionals. This manuscript addresses the etiologies and solutions to leaking and obstructed feeding tubes, percutaneous biliary drains, percutaneous catheter nephrostomies, and drainage catheters, including abscess drains. In addition, we will address the obstructed central venous catheter. PMID- 26038616 TI - Prevention and management of infectious complications of percutaneous interventions. AB - Infectious complications following interventional radiology (IR) procedures can cause significant patient morbidity and, potentially, mortality. As the number and breadth of IR procedures grow, it becomes increasingly evident that interventional radiologists must possess a thorough understanding of these potential infectious complications. Furthermore, given the increasing incidence of antibiotic-resistant bacteria, emphasis on cost containment, and attention to quality of care, it is critical to have infection control strategies to maximize patient safety. This article reviews infectious complications associated with percutaneous ablation of liver tumors, transarterial embolization of liver tumors, uterine fibroid embolization, percutaneous nephrostomy, percutaneous biliary interventions, central venous catheters, and intravascular stents. Emphasis is placed on incidence, risk factors, prevention, and management. With the use of these strategies, IR procedures can be performed with reduced risk of infectious complications. PMID- 26038617 TI - Diagnosis and management of hemorrhagic complications of interventional radiology procedures. AB - Image-guided interventions have allowed for minimally invasive treatment of many common diseases, obviating the need for open surgery. While percutaneous interventions usually represent a safer approach than traditional surgical alternatives, complications do arise nonetheless. Inadvertent injury to blood vessels represents one of the most common types of complications, and its affect can range from inconsequential to catastrophic. The interventional radiologist must be prepared to manage hemorrhagic risks from percutaneous interventions. This manuscript discusses this type of iatrogenic injury, as well as preventative measures and treatments for postintervention bleeding. PMID- 26038618 TI - Clinical Presentation, Imaging, and Management of Complications due to Neurointerventional Procedures. AB - Neurointervention is a rapidly evolving and complex field practiced by clinicians with backgrounds ranging from neurosurgery to radiology, neurology, cardiology, and vascular surgery. New devices, techniques, and clinical applications create exciting opportunities for impacting patient care, but also carry the potential for new iatrogenic injuries. Every step of every neurointerventional procedure carries risk, and a thorough appreciation of potential complications is fundamental to maximizing safety. This article presents the most frequent and dangerous iatrogenic injuries, their presentation, identification, prevention, and management. PMID- 26038619 TI - Iatrogenic percutaneous vascular injuries: clinical presentation, imaging, and management. AB - Vascular interventional radiology procedures are relatively safe compared with analogous surgical procedures, with overall major complication rates of less than 1%. However, major vascular injuries resulting from these procedures may lead to significant morbidity and mortality. This review will discuss the etiology, clinical presentation, diagnosis, and management of vascular complications related to percutaneous vascular interventions. Early recognition of these complications and familiarity with treatment options are essential skills for the interventional radiologist. PMID- 26038620 TI - Transjugular intrahepatic portosystemic shunt complications: prevention and management. AB - Transjugular intrahepatic portosystemic shunt (TIPS) insertion has been well established as an effective treatment in the management of sequelae of portal hypertension. There are a wide variety of complications that can be encountered, such as hemorrhage, encephalopathy, TIPS dysfunction, and liver failure. This review article summarizes various approaches to preventing and managing these complications. PMID- 26038622 TI - Radiation-related injuries and their management: an update. AB - Ionizing radiation (in the form of X-rays) is used for the majority of procedures in interventional radiology. This review article aimed at promoting safer use of this tool through a better understanding of radiation dose and radiation effects, and by providing guidance for setting up a quality assurance program. To this end, the authors describe different radiation descriptive quantities and their individual strengths and challenges, as well as the biologic effects of ionizing radiation, including patient-related effects such as tissue reactions (previously known as deterministic effects) and stochastic effects. In this article, the clinical presentation, immediate management, and clinical follow-up of these injuries are also discussed. Tissue reactions are important primarily from the patients' perspective, whereas stochastic effects are most relevant for pediatric patients and from an occupational viewpoint. The factors affecting the likelihood of skin reaction (the most common tissue reaction) are described, and how this condition should be managed is discussed. Setting up a robust quality assurance program around radiation dose is imperative for effective monitoring and reduction of radiation exposure to patients and operators. Recommendations for the pre-, peri-, and postprocedure periods are given, including recommendations for follow-up of high-dose cases. Special conditions such as pregnancy and radiation recall are also discussed. PMID- 26038621 TI - Iatrogenic-related transplant injuries: the role of the interventional radiologist. AB - As advances in surgical techniques and postoperative care continue to improve outcomes, the use of solid organ transplants as a treatment for end-stage organ disease is increasing. With the growing population of transplant patients, there is an increasing need for radiologic diagnosis and minimally invasive procedures for the management of posttransplant complications. Typical complications may be vascular or nonvascular. Vascular complications include arterial stenosis, graft thrombosis, and development of fistulae. Common nonvascular complications consist of leaks, abscess formation, and stricture development. The use of interventional radiology in the management of these problems has led to better graft survival and lower patient morbidity and mortality. An understanding of surgical techniques, postoperative anatomy, radiologic findings, and management options for complications is critical for proficient management of complex transplant cases. This article reviews these factors for kidney, liver, pancreas, islet cell, lung, and small bowel transplants. PMID- 26038623 TI - Complications in musculoskeletal intervention: important considerations. AB - Musculoskeletal (MSK) intervention has proliferated in recent years among various subspecialties in medicine. Despite advancements in image guidance and percutaneous technique, the risk of complication has not been fully eliminated. Overall, complications in MSK interventions are rare, with bleeding and infection the most common encountered. Other complications are even rarer. This article reviews various complications unique to musculoskeletal interventions, assists the reader in understanding where pitfalls lie, and highlights ways to avoid them. PMID- 26038624 TI - Common complications of nonvascular percutaneous thoracic interventions: diagnosis and management. AB - Percutaneous thoracic interventions are among the most common procedures in today's medical practice. From the simple placement of a pleural drain to the ablation of lung tumors, the advent of image guidance has revolutionized minimally invasive procedures and has allowed for the introduction of new techniques and widened the range of indications. It is therefore imperative to understand the complications associated with these interventions and their management. This article illustrates the common complications associated with these interventions and highlights the relative safety of these interventions. PMID- 26038625 TI - Iatrogenic hepatopancreaticobiliary injuries: a review. AB - Iatrogenic hepatopancreaticobiliary injuries occur after various types of surgical and nonsurgical procedures. Symptomatically, these injuries may lead to a variety of clinical presentations, including tachycardia and hypotension from hemobilia or hemorrhage. Iatrogenic injuries may be identified during the intervention, immediately afterwards, or have a delayed presentation. These injuries are categorized into nonvascular and vascular injuries. Nonvascular injuries include biliary injuries such as biliary leak or stricture, pancreatic injury, and the development of fluid collections such as abscesses. Vascular injuries include pseudoaneurysms, arteriovenous fistulas, dissection, and perforation. Imaging studies such as ultrasound, computed tomography, magnetic resonance imaging, and digital subtraction angiography are critical for proper diagnosis of these conditions. In this article, we describe the clinical and imaging presentations of these iatrogenic injuries and the armamentarium of minimally invasive procedures (percutaneous drainage catheter placement, balloon dilatation, stenting, and coil embolization) that are useful in their management. PMID- 26038626 TI - Iatrogenic urinary tract injuries: etiology, diagnosis, and management. AB - Iatrogenic injury to the urinary tract, including the kidneys, ureters, bladder, and urethra, is a potential complication of surgical procedures performed in or around the retroperitoneal abdominal space or pelvis. While both diagnostic and interventional radiologists often play a central and decisive role in the identification and initial management of a variety of iatrogenic injuries, discussions of these injuries are often directed toward specialists such as urologists, obstetricians, gynecologists, and general surgeons whose procedures are most often implicated in iatrogenic urinary tract injuries. Interventional radiologic procedures can also be a source of an iatrogenic urinary tract injury. This review describes the clinical presentation, risk factors, imaging findings, and management of iatrogenic renal vascular and urinary tract injuries, as well as the radiologist's role in the diagnosis, treatment, and cause of these injuries. PMID- 26038627 TI - Medical management of tumor lysis syndrome, postprocedural pain, and venous thromboembolism following interventional radiology procedures. AB - The rapid expansion of minimally invasive image-guided procedures has led to their extensive use in the interdisciplinary management of patients with vascular, hepatobiliary, genitourinary, and oncologic diseases. Given the increased availability and breadth of these procedures, it is important for physicians to be aware of common complications and their management. In this article, the authors describe management of select common complications from interventional radiology procedures including tumor lysis syndrome, acute on chronic postprocedural pain, and venous thromboembolism. These complications are discussed in detail and their medical management is outlined according to generally accepted practice and evidence from the literature. PMID- 26038628 TI - A practical review of the use of stents for the maintenance of hemodialysis access. PMID- 26038629 TI - Hepatoma Rupture following Drug-Eluting Bead Chemoembolization. PMID- 26038630 TI - A focused review of the pathogenesis, diagnosis, and management of tumor lysis syndrome for the interventional radiologist. PMID- 26038631 TI - Developmental and Individual Differences in Chinese Writing. AB - The goal of the present study was to examine the generalizability of a model of the underlying dimensions of written composition across writing systems (Chinese Mandarin vs. English) and level of writing skill. A five-factor model of writing originally developed from analyses of 1st and 4th grade English writing samples was applied to Chinese writing samples obtained from 4th and 7th grade students. Confirmatory factor analysis was used to compare the fits of alternative models of written composition. The results suggest that the five-factor model of written composition generalizes to Chinese writing samples and applies to both less skilled (Grade 4) and more skilled (Grade 7) writing, with differences in factor means between grades that vary in magnitude across factors. PMID- 26038632 TI - Translating evidence into impact: The case of 'supermagnet' desk toys. PMID- 26038633 TI - Why don't families initiate treatment? A qualitative multicentre study investigating parents' reasons for declining paediatric weight management. AB - BACKGROUND: Many families referred to specialized health services for managing paediatric obesity do not initiate treatment; however, reasons for noninitiation are poorly understood. OBJECTIVE: To understand parents' reasons for declining tertiary-level health services for paediatric weight management. METHOD: Interviews were conducted with 18 parents of children (10 to 17 years of age; body mass index >=85th percentile) who were referred for weight management, but did not initiate treatment at one of three Canadian multidisciplinary weight management clinics. A semi-structured interview guide was used to elicit parents' responses about reasons for noninitiation. Interviews were audio-recorded and transcribed verbatim. Data were managed using NVivo 9 (QSR International, Australia) and analyzed thematically. RESULTS: Most parents (mean age 44.1 years; range 34 to 55 years) were female (n=16 [89%]), obese (n=12 [66%]) and had a university degree (n=13 [71%]). Parents' reasons for not initiating health services were grouped into five themes: no perceived need for paediatric weight management (eg, perceived children did not have a weight or health problem); no perceived need for further actions (eg, perceived children already had a healthy lifestyle); no intention to initiate recommended care (eg, perceived clinical program was not efficacious); participation barriers (eg, children's lack of motivation); and situational factors (eg, weather). CONCLUSION: Physicians should not only discuss the need for and value of specialized care for managing paediatric obesity, but also explore parents' intention to initiate treatment and address reasons for noninitiation that are within their control. PMID- 26038634 TI - Use of growth charts in Canada: A National Canadian Paediatric Surveillance Program survey. AB - BACKGROUND: In 2010, the WHO Growth Charts for Canada were recommended for use in Canada, while the US Centers for Disease Control and Prevention (Georgia, USA) charts remained in active use. OBJECTIVE: To assess the availability, utilization of and satisfaction with growth charts in clinical practice in Canada. METHODS: In October 2012, a one-time survey was sent through the Canadian Paediatric Surveillance Program (CPSP) to 2544 paediatricians and 280 family physicians with a stated interest in paediatrics. RESULTS: The response rate was 24% (63% general paediatricians, 36% subspecialists, 1% family physicians). Of these respondents, 68% preferred the WHO charts for infants and 49% for children and youth. Regarding the WHO charts, 49.7% of respondents reported concerns with their inability to assess weight for children >10 years of age, and many believed that there were too few percentile lines between the third and 97th percentiles for infant (24%) and for child and youth measures (19%). The addition of extreme percentiles (0.1 and 99.9), shading on charts and lack of availability with electronic medical record providers were other concerns mentioned by 10% to 13% of respondents. CONCLUSION: There is support for the use of the WHO data for monitoring the growth of Canadian children. Concerns regarding the design of the charts were raised. These survey results lend support to the redesign of the WHO Growth Charts for Canada, as was recently completed in 2014. PMID- 26038636 TI - Psychological interventions for needle-related procedural pain and distress in children and adolescents. PMID- 26038635 TI - Health-related quality of life in long-term survivors of paediatric liver transplantation. AB - BACKGROUND: Long-term survival after paediatric liver transplantation is now the rule rather than the exception. Improving long-term outcomes after transplantation must consider not only the quantity but also the quality of life years restored. OBJECTIVES: To characterize health-related quality of life (HRQOL) of LT recipients >=15 years after paediatric LT. METHODS: Recipients of a paediatric LT performed before December 1996 in a single institution with continuous follow-up at either the paediatric or adult partner centre were identified. Patients with severe developmental or neurological impairment were excluded. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0, the Medical Outcomes Study Short Form-36 version 2 and the Pediatric Liver Transplant Quality of Life Tool. RESULTS: A total of 27 (67% male) subjects (mean age 24.3+/-6.7 years [median 23.2 years; range 16.6 to 40.3 years]) participated. The median age at transplant was 1.7 years (range 0.5 to 17.0 years). Seven (26%) participants underwent retransplantation. Seventeen (63%) participants were engaged in full-time work/study. Mean Short Form-36 version 2 scores included physical (49.6+/-11.1) and mental (45.3+/-12.5) subscale scores. The mean score for the disease-specific quality of life tool for paediatric liver transplant recipients (the Pediatric Liver Transplant Quality of Life Tool) was 64.70+/ 15.2. The physical health of the young adults strongly correlated with level of involvement in work/study (r=0.803; P<0.05). CONCLUSIONS: The self-reported HRQOL of participants <18 years of age was comparable with a standardized healthy population. In contrast, participants between 18 and 25 years of age had HRQOL scores that were more similar to a group with chronic illness. Participants engaged in full-time work/study experienced enhanced physical health. PMID- 26038637 TI - Case 1: A six-year-old boy with finger contractures. PMID- 26038638 TI - Case 2: An 12-year-old girl with recurrent sleep attacks. PMID- 26038639 TI - Misdiagnosis of attention deficit hyperactivity disorder: 'Normal behaviour' and relative maturity. AB - Attention deficit hyperactivity disorder (ADHD) is one of the most frequently diagnosed disorders in children, yet it remains poorly understood. Substantial controversy exists regarding correct diagnosis of ADHD, and areas of subjectivity in diagnosis have been identified. Concerns for appropriate diagnosis are critical in terms of children's educational outcomes, as well as health concerns associated with the use and potential overuse of stimulant medications. There exists a relative-age effect in which children who are relatively younger than their peers and born closest to the school start age cut-off are more frequently diagnosed and treated for ADHD. Additionally, substantial variation exists in ADHD diagnosis between boys and girls, with boys often presenting with more stereotypical symptoms. Both the relative-age effect and variation in sex diagnosis, as well as the challenges of early preschool diagnosis, emphasize the importance of considering relative maturity in ADHD diagnosis of children. Implications and knowledge translation strategies for practitioners, parents and the education system are presented. PMID- 26038640 TI - Child poverty. Ways forward for the paediatrician: A comprehensive overview of poverty reduction strategies requiring paediatric support. AB - The harmful effects of child poverty are well documented. Despite this, progress in poverty reduction in Canada has been slow. A significant gap exists between what is known about eradicating poverty and its implementation. Paediatricians can play an important role in bridging this gap by understanding and advancing child poverty reduction. Establishment of a comprehensive national poverty reduction plan is essential to improving progress. The present review identifies the key components of an effective poverty reduction strategy. These elements include effective poverty screening, promoting healthy child development and readiness to learn, ensuring food and housing security, providing extended health care coverage for the uninsured and using place-based solutions and team-level interventions. Specific economic interventions are also reviewed. Addressing the social determinants of health in these ways is crucial to narrowing disparities in wealth and health so that all children in Canada reach their full potential. PMID- 26038641 TI - Ankyloglossia and breastfeeding. AB - Ankyloglossia ('tongue-tie') is a relatively common congenital anomaly characterized by an abnormally short lingual frenulum, which may restrict tongue tip mobility. There is considerable controversy regarding its diagnosis, clinical significance and management, and there is wide variation in practice in this regard. Most infants with ankyloglossia are asymptomatic and do not exhibit feeding problems. Based on available evidence, frenotomy cannot be recommended for all infants with ankyloglossia. There may be an association between ankyloglossia and significant breastfeeding difficulties in some infants. This subset of infants may benefit from frenotomy (the surgical division of the lingual frenulum). When an association between significant tongue-tie and major breastfeeding problems is clearly identified and surgical intervention is deemed to be necessary, frenotomy should be performed by a clinician experienced with the procedure and using appropriate analgesia. More definitive recommendations regarding the management of tongue-tie in infants await clear diagnostic criteria and appropriately designed trials. PMID- 26038642 TI - 'Nosodes' are no substitute for vaccines. AB - A growing antivaccine movement in Canada and elsewhere is hearing more about an unproven homeopathic therapy, 'nosodes', as an alternative to routine vaccines. The present statement defines nosodes and describes limitations for their use in children. There is scant evidence in the medical literature for either the efficacy or safety of nosodes, which have not been well studied for the prevention of any infectious disease in humans. Recommendations to change the labelling on these products to reflect such limitations are made. PMID- 26038643 TI - The use of mechanical ventilation protocols in Canadian neonatal intensive care units. AB - OBJECTIVES: To identify the proportion of Canadian neonatal intensive care units with existing mechanical ventilation protocols and to determine the characteristics and respiratory care practices of units that have adopted such protocols. METHODS: A structured survey including 36 questions about mechanical ventilation protocols and respiratory care practices was mailed to the medical directors of all tertiary care neonatal units in Canada and circulated between December 2012 and March 2013. RESULTS: Twenty-four of 32 units responded to the survey (75%). Of the respondents, 91% were medical directors and 71% worked in university hospitals. Nine units (38%) had at least one type of mechanical ventilation protocol, most commonly for the acute and weaning phases. Units with pre-existing protocols were more commonly university-affiliated and had higher ratios of ventilated patients to physicians or respiratory therapists, although this did not reach statistical significance. The presence of a mechanical ventilation protocol was highly correlated with the coexistence of a protocol for noninvasive ventilation (P<0.001, OR 4.5 [95% CI 1.3 to 15.3]). There were overall wide variations in ventilation practices across units. However, units with mechanical ventilation protocols were significantly more likely to extubate neonates from the assist control mode (P=0.039, OR 8.25 [95% CI 1.2 to 59]). CONCLUSION: Despite the lack of compelling evidence to support their use in neonates, a considerable number of Canadian neonatal intensive care units have adopted mechanical ventilation protocols. More research is needed to better understand their role in reducing unnecessary variations in practice and improving short- and long-term outcomes. PMID- 26038644 TI - Tooth discoloration induced by calcium-silicate-based pulp-capping materials. AB - OBJECTIVES: The aim of this study was to evaluate tooth discoloration induced by contact with various calcium silicate-based pulp capping materials in the presence or absence of blood in vitro. MATERIALS AND METHODS: Eighty bovine samples were divided into six experimental groups and two control groups according to the type of material used (ProRoot [PR], Endocem [EC], or EndocemZr [ECZ]) and the presence or absence of contamination with blood. A spectrophotometer was used to calculate the color difference (DeltaE) between the baseline measurement (after placement of materials) and measurements taken 1, 2, 4, and 8 weeks. The results were analyzed with repeated measures analysis of variance, Tukey's post-hoc tests and independent t-tests (P = 0.05). RESULTS: The PR group and EC group showed significantly higher mean values of DeltaE than the negative control group after 2 weeks (P < 0.05), whereas ECZ did not. There were larger DeltaE values when there was contact with blood, especially in PR and EC group (P < 0.05). CONCLUSIONS: ECZ which contains zirconium oxide as a radiopacifier showed less discoloration irrespective of blood contamination compared to PR and EC. PMID- 26038645 TI - Evaluation of silent period on masticatory cycles of different muscles in dentate oral contraceptives users and nonusers. AB - OBJECTIVE: The aim of this study was to evaluate the influence of oral contraceptive use on the silent period (SP) of anterior temporal and masseter muscles during the menstrual cycle. MATERIALS AND METHODS: Totally, 28 women on reproductive age were selected including 15 nonusers of any hormone and 13 contraceptive users. All patients were dentate without muscular temporomandibular disorders. Electromyography (SP test) of the anterior temporal and masseter muscles was conducted every week during three consecutive menstrual cycles at 1(st) day of menstruation (P1), 7(th) day (P2), 14(th) day (P3) and 21(st) day (P4). RESULTS: The SP values in the anterior temporal and masseter muscles were measured at both sides. The SP values of the right side (13.49 ms) at P2 were significantly different compared to the left side (12.28 ms). However, there was no significant difference on the interactions among the three factors. CONCLUSION: It can be concluded that the SP values in healthy women in reproductive age may not be influenced by the menstrual cycle with similar results for both muscles. PMID- 26038646 TI - Bonding of contemporary glass ionomer cements to different tooth substrates; microshear bond strength and scanning electron microscope study. AB - OBJECTIVE: This study was conducted to evaluate the microshear bond strength (MUSBS) and ultramorphological characterization of glass ionomer (GI) cements; conventional GI cement (Fuji IX, CGI), resin modified GI (Fuji II LC, RMGI) and nano-ionomer (Ketac N100, NI) to enamel, dentin and cementum substrates. MATERIALS AND METHODS: Forty-five lower molars were sectioned above the cemento enamel junction. The occlusal surfaces were ground flat to obtain enamel and dentin substrates, meanwhile the cervical one-third of the root portion were utilized to evaluate the bonding efficacy to cementum substrate. Each substrate received microcylinders from the three tested materials; which were applied according to manufacturer instructions. MUSBS was assessed using a universal testing machine. The data were analyzed using two-way analysis of variance (ANOVA) and Tukey's post-hoc test. Modes of failure were examined using stereomicroscope at *25 magnification. Interfacial analysis of the bonded specimens was carried out using environmental field emission scanning electron microscope. RESULTS: Two-way ANOVA revealed that materials, substrates and their interaction had a statistically significant effect on the mean MUSBS values at P values; ?0.0001, 0.0108 and 0.0037 respectively. RMGI showed statistically significant the highest MUSBS values to all examined tooth substrates. CGI and RMGI show substrate independent bonding efficiency, meanwhile; NI showed higher MUSBS values to dentin and cementum compared to enamel. CONCLUSION: Despite technological development of GI materials, mainly the nano-particles use, better results have not been achieved for both investigations, when compared to RMGI, independent of tooth substrate. PMID- 26038647 TI - A study of dentists' preferences for the restoration of shortened dental arches with partial dentures. AB - OBJECTIVE: This study aimed to use a utility method in order to assess dentists' preferences for the restoration of shortened dental arches (SDAs) with partial dentures. Also, the impact of patient age and length of the SDA on dentists' preferences for the partial dentures was investigated. MATERIALS AND METHODS: Totally, 104 subjects holding a basic degree in dentistry and working as staff members in a private dental college in Saudi Arabia were interviewed and presented with 12 scenarios for patients of different ages and mandibular SDAs of varying length. Participants were asked to indicate on a standardized visual analog scale how they would value the health of the patient's mouth if the mandibular SDAs were restored with cobalt-chromium removable partial dentures (RPDs). RESULTS: With a utility value of 0.0 representing the worst possible health state for a mouth and 1.0 representing the best, dentists' average utility value of the RPD for the SDAs was 0.49 (sd= 0.15). Mean utility scores of the RPDs across the 12 SDA scenarios ranged between 0.35 and 0.61. RPDs that restored the extremely SDAs attracted the highest utility values and dentists' utility of the RPD significantly increased with the increase in the number of missing posterior teeth. No significant differences in dentists' mean utility values for the RPD were identified among SDA scenarios for patients of different ages. CONCLUSION: Restoration of the mandibular SDAs by RPDs is not a highly preferred treatment option among the surveyed group of dentists. Length of the SDA affects dentists' preferences for the RPD, but patient age does not. PMID- 26038648 TI - Fracture strength of roots instrumented with three different single file systems in curved root canals. AB - OBJECTIVE: The aim of this study was to compare the fracture strength of roots instrumented with three different single file rotary systems in curved mesial root canals of maxillary molars. MATERIALS AND METHODS: Curvatures of 25 degrees 35 degrees on mesial roots of 60 maxillary molar teeth were sectioned below the cementoenamel junction to obtain roots 11 mm in length. The roots were balanced with respect to buccolingual and mesiodistal diameter and weight. They were distributed into three experimental groups and one control group (no instrumentation) (n = 15): Reciproc rotary file (R25, VDW, Munich, Germany), WaveOne Primary rotary file (Dentsply Tulsa Dental Specialties, Tulsa, UK) and OneShape (Micro-Mega, Besancon, France) rotary file. Vertical load was applied until fracture occurred. Data were statistically analyzed using one-way analysis of variance test (P < 0.05). RESULTS: The mean fracture load was 412 +/- 72 Newton (N) for the control group, 395 +/- 69 N for the Reciproc group, 373 +/- 63 N for the WaveOne group and 332 +/- 68 N for the OneShape group. The fracture load differences among three experimental groups were not statistically significant (P > 0.05.) Whereas, the fracture loads of control and OneShape groups were significantly different (P = 0.012). CONCLUSIONS: Fracture resistance of the roots instrumented with WaveOne and Reciproc file systems were similar to the control group whereas it was observed that OneShape rotary file systems enhance the fracture strength of standardized curved roots when compared with the control group. PMID- 26038649 TI - Comparison of temperature rise in pulp chamber during polymerization of materials used for direct fabrication of provisional restorations: An in-vitro study. AB - OBJECTIVE: The purpose is to compare temperature rise in the pulp chamber during fabrication of provisional crowns using different materials and on different types of teeth using direct technique. MATERIALS AND METHODS: An extracted, sound, caries free maxillary central incisor and a mandibular molar were selected for the study and crown preparations of all ceramic and all metal were done on central incisor and mandibular molar, respectively. Materials tested were DPI tooth molding self-curing material and protemp-4. Addition silicone putty was used as a matrix and 80 provisional crowns were fabricated, of which 40 were on central incisor and 40 on mandibular molar. Depending on the type of material used, they were further divided into two subgroups: Each comprising 20 provisional crowns. Temperature readings were recorded using K type of thermocouple with 0.1 degrees C precision digital thermometer. STATISTICAL ANALYSIS USED: Analysis of variance, Tukey honest significant difference and Kruskall-Wallis H-test. RESULTS: Statistically significant difference exists between two materials tested on the basis of peak temperature achieved and time taken by a particular material to reach peak temperature. Peak temperature achieved was highest for provisional crowns with DPI tooth molding self-curing material on maxillary central incisor (40.39 + 0.46), followed by DPI tooth molding self-curing material on mandibular molar (40.03 + 0.32), protemp-4 on maxillary central incisor (39.46 + 0.26) and least with protemp-4 on mandibular molar (39.09 + 0.33). The time taken to reach peak temperature was almost double in DPI tooth molding self-curing material (5 min) than in protemp-4. CONCLUSION: Polymethyl methacrylate resin produced higher intra-pulpal rise when compared to newer generation bis-acrylic composite. PMID- 26038650 TI - Comparison of speed of action and injection discomfort of 4% articaine and 2% mepivacaine for pulpal anesthesia in mandibular teeth: A randomized, double-blind cross-over trial. AB - OBJECTIVE: To compare the injection pain and speed of local anesthetic effect induced by tissue infiltration of mepivacaine 2% with epinephrine 1:100,000 versus articaine 4% with epinephrine 1:100,000 in securing mandibular first molar pulp anesthesia. MATERIALS AND METHODS: Totally, 25 patients were recruited in a crossover, randomized, double-blind study. Each subject received injections of mepivacaine 2% with epinephrine 1:100,000 as inferior alveolar nerve block (IANB) supplemented with either articaine 4% with epinephrine 1:100,000 (septocaine) or mepivacaine 2% buccal infiltration (BI) injection on two visits. The time of first numbness to associated lip, tongue and tooth was recorded by asking the participant directly and using electrical pulp tester. Anesthetic success was considered when two consecutive maximal stimulation on pulp testing readings without sensation. The patients rated the pain of infiltration using a 100 mm visual analog scale immediately after receiving each injection. The pain scores were compared using the paired t-test. RESULTS: There were significant differences in the meantime of first numbness to associated lip and tooth of volunteers between mepivacaine and articaine BI groups P = 0.03 and 0.002. Volunteers in articaine group recorded earlier lip and teeth numbness than those in mepivacaine group. There were significant differences between the mean pain scores for volunteers in the post IANB and postbuccal injection groups (t-test: P <0.001). Mepivacaine IANB injection was significantly more painful than articaine/mepivacaine buccal injection. CONCLUSIONS: About 4% articaine was faster than 2% mepivacaine (both with 1:100,000 adrenaline) in anesthetizing the pulps of lower molar teeth after BIs. Earlier lip and teeth numbness were recorded in articaine group. Articaine and mepivacaine BIs were more comfortable than mepivacaine IANB injections. PMID- 26038651 TI - Effect of silver nanoparticles incorporation on viscoelastic properties of acrylic resin denture base material. AB - OBJECTIVE: The objective was to investigate the effect of silver nanoparticles (AgNPs) incorporation on viscoelastic properties of acrylic resin denture base material. MATERIALS AND METHODS: A total of 20 specimens (60 * 10 * 2 mm) of heat cured acrylic resin were constructed and divided into four groups (five for each), according to the concentration of AgNPs (1%, 2%, and 5% vol.) which incorporated into the liquid of acrylic resin material and one group without additives (control group). The dynamic viscoelastic test for the test specimens was performed using the computerized material testing system. The resulting deflection curves were analyzed by material testing software NEXYGEN MT. RESULTS: The 5% nanoparticles of silver (NAg) had significantly highest mean storage modulus E' and loss tangent Tan delta values followed by 2% NAg (P < 0.05). For 1% nanosilver incorporation (group B), there were no statistically significant differences in storage modulus E', lost modulus E" or loss tangent Tan delta with other groups (P > 0.05). CONCLUSION: The AgNPs incorporation within the acrylic denture base material can improve its viscoelastic properties. PMID- 26038652 TI - Identifying the tooth shade in group of patients using Vita Easyshade. AB - OBJECTIVE: The aim of the present investigation is to identify tooth shade among a group of Sudanese patients. MATERIALS AND METHODS: Total number of patients was 227. Participant's age ranged from 15 to 72 years, which, was divided into four groups. The tooth included in the study was either right or left sounds maxillary central incisor. Vita Easyshade was used to select the tooth shade. Investigation of the differences of Commission International de l'Eclairage (CIELab) coordinates among gender and state of origin was conducted together with an examination of the relationship between CIELab coordinates and age. One-way analysis of variance was used to test the differences in L*, a* and b* according to state of origin. RESULTS: Results showed that A3 was the most common classical tooth shade respectively. There was highly significant difference in L* between males and females (P = 0.002). There was a significant relation between tooth shade and age (P = 0.026). There was a high significant association between classical tooth shade and Sudan regions (P = 0.00). CONCLUSION: In conclusion, most common classical shade was A3, women's teeth were lighter than men's. There was a relation between ethnic background and tooth shade. PMID- 26038653 TI - Effects of pulp capping materials on fracture resistance of Class II composite restorations. AB - OBJECTIVE: The aim of this study was to investigate the effect of cavity design and the type of pulp capping materials on the fracture resistance of Class II composite restorations. MATERIALS AND METHODS: Sixty freshly extracted, sound molar teeth were selected for the study. A dovetail cavity on the mesio-occlusal and a slot cavity on disto-occlusal surfaces of each tooth were prepared, and the teeth were divided 4 groups which one of them as a control group. The pulp capping materials (TheraCal LC, Calcimol LC, Dycal) applied on pulpo-axial wall of each cavity, and the restoration was completed with composite resin. The teeth were subjected to a compressive load in a universal mechanical testing machine. The surfaces of the tooth and restoration were examined under a stereomicroscope. The data were analyzed using factorial analysis of variance and Tukey's test. RESULTS: For pulp capping materials, the highest fracture load (931.15 +/- 203.81 N) and the lowest fracture load (832.28 +/- 245.75 N) were calculated for Control and Dycal group, respectively. However, there were no statistically significant differences among all groups (P > 0.05). The fracture load of the dovetail groups was significantly higher than those of the slot cavity groups (P < 0.05). CONCLUSION: Dovetail cavity design shows better fracture resistance in Class II composite restorations, independent of used or not used pulp capping materials. PMID- 26038654 TI - Microshear bond strength evaluation of surface pretreated zirconia ceramics bonded to dentin. AB - OBJECTIVES: To comparatively assess the micro shear bond strength (MSBS) of dentin bonded surface pre-treated zirconia ceramics. MATERIALS AND METHODS: Zirconia blocks were sectioned into 50 cubical blocks. The blocks were further categorized into five groups (n = 10 each). Group I: No treatment was performed on zirconia samples; Group II: The zirconia samples were sand-blasted; Group III: Group II + etched with 9.8% of hydrofluoric (HF) acid for 60 s; Group IV: The sandblasted zirconia samples were selectively infiltrated with low fusing porcelain; and Group V: Group IV + etched using 9.8% HF acid gel. The zirconia specimens were then bonded to dentin samples, and the samples were tested for MSBS evaluation using universal testing machine. RESULTS: The MSBS of all the four experimental groups shows greater value than group I. Among the experimental groups, group V and group IV do not show any statistical significant difference, whereas the mean MSBS of groups IV and V were statistically greater than group III and group II. However, groups I, II, and III do not show any statistical significant difference in mean MSBS values between them. CONCLUSION: Selective infiltration etching of zirconia ceramics provides the highest bond strength with resin cement. PMID- 26038655 TI - The minimum residual root thickness after using ProTaper, RaCe and Gates-Glidden drills: A cone beam computerized tomography study. AB - OBJECTIVE: The aim of this study was to evaluate the minimum residual root thickness (MRRT) of the danger zone after preflaring of the mesio-buccal (MB) canal of mandibular first molars using ProTaper, RaCe and Gates-Glidden (GG) drills as coronal shapers by cone beam computerized tomography (CBCT). MATERIALS AND METHODS: In this experimental study, the initial CBCT scans of 75 MB canals of mandibular first molars were provided within 1, 2, 3 and 4 mm of the furcation level. The samples were divided into three groups. The samples of ProTaper and RaCe groups were prepared up to F2 and #25.04 as the master apical file (MAF), respectively. The coronal preparation of the samples in the GG group was done using GG drills #2, #3 and #4 and canals were prepared till MAF # 25. After obtaining the postinstrumentation images, the MRRT and the amount of removed dentin were analyzed by t-test and ANOVA statistical analyses. RESULTS: The GG drills removed significantly more dentin than RaCe at all the sections (P < 0.05) and more than ProTaper at 3 mm from the furcation. Statistically there was no significant difference between ProTaper and RaCe groups (P > 0.05). There was no significant difference in MRRT between the groups (P > 0.05). The mean MRRT was not < 0.75 mm at all sections. CONCLUSION: Based on the results of this study, when an appropriate root thickness is initially present, all of the instruments that were investigated may safely be used as coronal shapers in MB canals of mandibular first molars. PMID- 26038656 TI - Root canal retreatment using reciprocating and continuous rotary nickel-titanium instruments. AB - OBJECTIVE: The complete filling material removal during endodontic retreatment is a clinical procedure difficult to achieve. The aim of this study was to evaluate the efficacy of reciprocating and continuous rotary nickel-titanium instruments used in root canal retreatment. MATERIALS AND METHODS: Forty freshly extracted human premolars were cleaned and shaped by the crown-down technique, followed by filling by the lateral compaction technique. The teeth were randomly separated into two groups (n = 20), according to the system used for filling material removal: G1 - Reciproc and G2 - ProTaper Universal Retreatment System. The teeth were photographed under operating microscope at *8 magnification; and the total area of the root canal and remaining filling material were quantified. RESULTS: No statistically significant difference (P > 0.05) in residual filling material was observed between groups; however, the time required for filling removal was significantly shorter for Reciproc system (P < 0.05). CONCLUSIONS: It was observed remaining filling material in all teeth, irrespective of the system used; however, root canal retreatment was faster when reciprocating motion was used. PMID- 26038657 TI - An assessment of antibacterial activity of three pulp capping materials on Enterococcus faecalis by a direct contact test: An in vitro study. AB - OBJECTIVE: The aim of this in vitro study was to evaluate antimicrobial activities of three different pulp capping materials; Biodentine, mineral trioxide aggregate (MTA) Angelus, and Dycal against Enterococcus faecalis and their durability with time. MATERIALS AND METHODS: Direct contact test was used for the assessment. Three sets of sealers were mixed and placed on microtiter plate wells: One set was used within 20 min of recommended setting time while others were used after 24-h and 1-week. E. faecalis suspension was placed directly on the materials for 1 h and then transferred to another plate with fresh media. Nine wells of bacteria without the tested cements served as the positive control. One well of the tested cements without bacteria served as the negative control. Bacterial growth was evaluated by a temperature-controlled microplate spectrophotometer for 1-h intervals among 24 h. Data were analyzed using Kruskal-Wallis test. RESULTS: All tested materials showed less bacterial density than the control group. MTA, Biodentine, and Dycal showed significantly higher bacterial density than the control group in freshly mixed samples (P < 0.05). And MTA showed significantly higher antibacterial activity than Dycal (P < 0.05). In 24 h, materials did not show any differences (P > 0.05). MTA and Biodentine samples showed significant differences than Dycal; MTA also showed higher antibacterial activity than control in 1-week samples (P < 0.05). CONCLUSION: While freshly mixed MTA showed the best antibacterial activity over time, Biodentine had shown similar antibacterial activity to MTA. PMID- 26038658 TI - Effect of peroxide bleaching on the biaxial flexural strength and modulus of bovine dentin. AB - OBJECTIVE: This study evaluated the effects of carbamide peroxide and hydrogen peroxide on the biaxial flexural strength and flexural modulus of bovine dentin. MATERIALS AND METHODS: Thirty coronal dentin disks (0.5 mm thick * 6.0 mm diameter) were prepared from bovine teeth. The disks were randomly divided into three groups (n=10): A control group (unbleached), a group bleached with 10% carbamide peroxide (8 h at 37 degrees C), and a group bleached with 38% hydrogen peroxide (three 10 min applications at 37 degrees C). The specimens were tested in a biaxial flexural apparatus held in a universal testing machine at 1.27 mm/min until failure occurred, and the biaxial mechanical properties were calculated. For each test parameter, the data were statistically analyzed by Fisher's PLSD test (predetermined alpha = 0.05). RESULTS: The group bleached with 38% hydrogen peroxide demonstrated significantly lower flexural strength than the unbleached control group. Hydrogen peroxide treatment resulted in a significantly lower flexural modulus compared with the control group and with carbamide peroxide bleaching. CONCLUSION: Exposure of dentin to hydrogen peroxide significantly reduced both the flexural strength and the flexural modulus compared with the no-treatment control, whereas exposure to carbamide peroxide did not significantly affect either parameter. PMID- 26038659 TI - The reliability of the Greulich and Pyle atlas when applied to a Southern Turkish population. AB - OBJECTIVE: The aim of this study was to evaluate the applicability of Greulich and Pyle (GP) method for Southern Turkish population. MATERIALS AND METHODS: Hand and wrist radiographs of 535 patients (276 females, 259 males aged from 10 to 18 years) selected retrospectively from the archive. Skeletal age (SA) estimation was performed according to GP atlas. The chronological age (CA) and SA were compared using the Paired t-test. RESULTS: The mean difference between the CA and SA ranged from 0.07 to 1.11 years. These differences between the CA and estimated SA were statistically significant in group I (10-10.90 years) (P < 0.001), group II (11-11.90 years) (P < 0.050), group III (12-12.90 years) (P < 0.001), group IV (13-13.90 years) (P < 0.010), and group V (14-14.90 years) (P < 0.001) for females. The mean difference between the CA and SA ranged from -0.41 to -1.79 years for females. These differences between the CA and estimated SA were statistically significant in all age groups. CONCLUSIONS: Statistically significant differences were found in the CA and SA assessed by GP method for the Southern Turkish sample. SA was significantly over-predicted in the 10-15 year ages in males and for 10-18 year ages for females. It is appropriate to use GP method in Southern Turkish children; however, a revision is needed for better results and to minimize the mistakes. PMID- 26038660 TI - A three-dimension finite element analysis to evaluate the stress distribution in tooth supported 5-unit intermediate abutment prosthesis with rigid and nonrigid connector. AB - OBJECTIVE: The aim of the study is to evaluate the stress distribution in tooth supported 5-unit fixed partial denture (FPD) having tooth as pier abutment using rigid and nonrigid connectors respectively, under simultaneous and progressive loading. MATERIAL AND METHODS: The three-dimensional (3D) finite element program (ANSYS software) was used to construct the mathematical model. Two 5-unit FPD'S were simulated, one with rigid connector and another one with nonrigid connector. For analysis, each of these models were subjected to axial and oblique forces under progressive loading (180, 180, 120, 120, 80 N force on first and second molars, premolars and canine respectively) and simultaneous loading (100, 100, 100, 100, 100 N force on first and second molars, premolars and canine respectively). RESULTS: The rigid and nonrigid connector design have effect on stress distribution in 5-unit FPDs with pier abutments. CONCLUSION: Oblique forces produce more stresses than vertical forces. Nonrigid connector resulted in decrease in stress at the level of prosthesis and increase in stress at the level of alveolar crest. PMID- 26038661 TI - Effect of storage solutions on microhardness of crown enamel and dentin. AB - OBJECTIVE: The aim of this study was to determine alterations in microhardness of crown dentin and enamel, after 2 and 12-month storage in de-ionized water, 0.2% glutaraldehyde, Hanks' Balanced Salt Solution (HBSS), 0.1% sodium hypochlorite (NaOCl) or 0.1% thymol. MATERIALS AND METHODS: Freshly extracted, nonsterile 60 intact human premolars were distributed to five groups. Six teeth from each group were evaluated after two, and other six teeth were evaluated after 12 months storage. After grinding and polishing of teeth, Vickers hardness was evaluated with making indentations on enamel and dentin, using a pyramid diamond indenter tip exerting 100 g load for 15 s. RESULTS: After 2 months storage in solutions, range of the hardness values (HV) of enamel and dentin were in between 315-357 and 64-67, respectively. However, 12 months storage of the teeth resulted in a statistically significant decrease in microhardness when compared to microhardness of teeth stored for 2 months (P = 0.001). Although the differences were not significant regarding solutions, all solutions decreased the microhardness both in enamel and dentin (P > 0.05). However, decrease in microhardness was relatively less in de-ionized water and thymol solutions while glutaraldehyde decreased microhardness the most: 63% for enamel and 53% for dentin. CONCLUSIONS: Microhardness of enamel and dentin was in an acceptable range when teeth were stored for 2 months in de-ionized water, glutaraldehyde, HBSS, NaOCl or in thymol; thus, teeth kept up to 2 months in these solutions can be used for mechanical in vitro tests. However, 12 months storage significantly decreased the microhardness of enamel and dentin. PMID- 26038662 TI - Hypodontia prevalence and distribution pattern in a group of Qatari orthodontic and pediatric patients: A retrospective study. AB - OBJECTIVES: The aim of this study was to investigate the prevalence and distribution of hypodontia in the permanent teeth among a group of the Qatari sample and to compare the present results with findings from other populations. MATERIALS AND METHODS: Records of 1269 Qatari patients (674 females; mean age 11.8 +/- 2.3 and 595 males; mean age 11.4 +/- 2.2) which included panoramic radiographs were examined to identify hypodontia. All permanent teeth were investigated except third molars. RESULTS: The prevalence of hypodontia was 6.2% (females 8% and males 4.2%; P < 0.05). The majority of patients had one or two missing teeth. There were no significant differences between right and left sides for any particular tooth. The most frequently missing teeth were maxillary lateral incisors (36.2%), followed by mandibular second premolar (32.6%) and maxillary second premolar (20.2%). Hypodontia was more commonly found unilaterally than bilaterally (63.2% and 44.3%; respectively). CONCLUSIONS: The prevalence of hypodontia in a group of the Qatari population was within the average value of the majority of published studies in the literature. Hypodontia was significantly more prevalent in females. Although less prevalent, considerable cases of bilateral missing were found in the present study, which necessitates the urgent need for intervention and multi-disciplinary team approach for management. PMID- 26038663 TI - The comparative effect of propolis in two different vehicles; mouthwash and chewing-gum on plaque accumulation and gingival inflammation. AB - OBJECTIVE: In general, chemical plaque agents have been used in mouthwashes, gels, and dentifrices. In some situations, application of mouthwashes and dentifrices can be difficult. Therefore, different approaches for oral health care have been needed. The aim of this study was to evaluate the effect of propolis chewing-gum compared to propolis-containing mouthwash on gingival inflammation and plaque accumulation on patients that refrained from daily oral hygiene procedures for 5 days. MATERIALS AND METHODS: 10 college students with systemically healthy and very good oral hygiene and gingival health were included in this randomized, single-blind, crossover 5-day plaque regrowth with a 3-day washout period clinical study. After plaque scores were reduced to zero, participants were asked to refrain from oral hygiene procedures and allocated to either propolis mouthwash or chewing-gum group. Chewing-gum was performed after meals 3 times a day for 20 min mouthwash group was instructed to rinse mouthwash 2 times a day for 1 min. On day 5, the clinical periodontal measurements containing plaque and gingival indexes were taken from the participants. RESULTS: The both plaque and gingival indexes of propolis mouthwash group were significantly lower than that of the propolis chewing-gum group (P = 0.005). CONCLUSION: It was demonstrated that the propolis mouthwash was more effective than the propolis chewing gum on the plaque inhibition and the gingival inflammation. PMID- 26038664 TI - Surgical and prosthetic management of maxillary odontogenic myxoma. AB - Odontogenic myxomas are uncommon tumors of comprising of 3% of all the tumors of odontogenic origin. They usually occur during the second and third decades of life and are more commonly seen in females. The current case report sheds light upon the surgical treatment of a myxoma of odontogenic origin in posterior maxilla of a young female patient. Prosthodontic rehabilitation stages are also briefly described following complete healing of the lesion after surgery. PMID- 26038665 TI - The use of Erbium: Yttrium-aluminum-garnet laser in cavity preparation and surface treatment: 3-year follow-up. AB - From the currently available choices, esthetic restorative materials for posterior teeth are limited to composite and ceramic restoration. Ceramic inlays/onlays are reliable solutions for both of these treatments. For successful treatment planning, usable ceramic and adhesive systems should be chosen by the dentist. Since the Federal Drug Administration approval of the erbium: Yttrium aluminum-garnet (Er:YAG) laser-for caries removal, cavity preparation and the conditioning of tooth substance-in 1997, there have been many reports on the use of this technique in combination with composite resins. In addition, cavity pretreatment with the Er:YAG laser (laser etching) has been proposed as an alternative to acid etching of enamel and dentin. This case report presents the use of the Er:YAG in cavity preparation for composite resin restoration and surface treatment for ceramic onlay restoration of adjacent permanent molars. PMID- 26038666 TI - Periodontal treatment in a generalized severe chronic periodontitis patient: A case report with 7-year follow-up. AB - The aim of the periodontal treatment is to provide healthy and functional dentition all through a lifetime. In this report, periodontal treatment of a 42 year-old male patient with generalized severe chronic periodontitis is presented. He received initial periodontal treatment together with adjunctive antimicrobials. The devital teeth were endodontically treated, and free gingival grafts were placed at the inadequate keratinized tissue zones before regenerative surgery. Following the surgical treatment using enamel matrix derivatives and xenogenic bone graft combination, the patient was put on a strict recall program. After 12 months, favorable clinical and radiographical improvements were obtained. The 7-year maintenance of the present case with several initially hopeless teeth has been shown and discussed in this report. It can be concluded that optimum oral hygiene level as well as the positive cooperation of the patient enhanced the success of periodontal treatment results even in extremely severe periodontal destruction. PMID- 26038668 TI - Does atraumatic restorative treatment reduce dental anxiety in children? A systematic review and meta-analysis. AB - Dental anxiety is one of the major problems affecting children, which impairs the rendering of dental care, leading to impaired quality of life. It often leads to occupational stress in dental personnel and conflict between parents/caregivers. The objective of this study was to conduct a systematic review and meta-analysis of randomized controlled trials done in children, to synthesize evidence of the effectiveness of atraumatic restorative treatment (ART) in reducing dental anxiety in children compared to conventional restorative treatments. The databases searched included PubMed, Google Scholar and The Cochrane Oral Health Group's Trials Register. Eligible studies reporting dental anxiety by a variety of psychometric scales were tabulated. The review was conducted and reported in accordance with the guidelines provided by the Cochrane Collaboration. Among 416 studies retrieved through literature search, six studies matched the inclusion criteria. Due to lack of data, only three studies were included for meta-analysis using RevMan software (Review Manager, Version 5.3;The Cochrane Collaboration, Copenhagen, 2014). The pooled meta-analysis data, (standardized mean difference - 2.12 [95% confidence interval: -4.52, 0.27]) failed to show any difference between ART group and the conventional treatment group. In conclusion, ART was not more beneficial in reducing dental anxiety among pediatric dental patients. The findings are relevant in the field of clinical practice in dentistry in the management of the anxious pediatric dental patient. PMID- 26038667 TI - Cracked tooth diagnosis and treatment: An alternative paradigm. AB - This article reviews the diagnosis and treatment of cracked teeth, and explores common clinical examples of cracked teeth, such as cusp fractures, fractures into tooth furcations, and root fractures. This article provides alternative definitions of terms such as cracked teeth, complete and incomplete fractures and crack lines, and explores the scientific rationale for dental terminology commonly used to describe cracked teeth, such as cracked tooth syndrome, structural versus nonstructural cracks, and vertical, horizontal, and oblique fractures. The article explains the advantages of high magnification loupes (*6-8 or greater), or the surgical operating microscope, combined with co-axial or head mounted illumination, when observing teeth for microscopic crack lines or enamel craze lines. The article explores what biomechanical factors help to facilitate the development of cracks in teeth, and under what circumstances a full coverage crown may be indicated for preventing further propagation of a fracture plane. Articles on cracked tooth phenomena were located via a PubMed search using a variety of keywords, and via selective hand-searching of citations contained within located articles. PMID- 26038669 TI - Antagonism at combined effects of chemical fertilizers and carbamate insecticides on the rice-field N2-fixing cyanobacterium Cylindrospermum sp. in vitro. AB - Effects of chemical fertilizers (urea, super phosphate and potash) on toxicities of two carbamate insecticides, carbaryl and carbofuran, individually to the N2 fixing cyanobacterium, Cylindrospermum sp. were studied in vitro at partially lethal levels (below highest permissive concentrations) of each insecticide. The average number of vegetative cells between two polar heterocysts was 16.3 in control cultures, while the mean value of filament length increased in the presence of chemical fertilizers, individually. Urea at the 10 ppm level was growth stimulatory and at the 50 ppm level it was growth inhibitory in control cultures, while at 100 ppm it was antagonistic, i.e. toxicity-enhancing along with carbaryl, individually to the cyanobacterium, antagonism was recorded. Urea at 50 ppm had toxicity reducing effect with carbaryl or carbofuran. At 100 and 250 ppm carbofuran levels, 50 ppm urea only had a progressive growth enhancing effect, which was marked well at 250 ppm carbofuran level, a situation of synergism. Super phosphate at the 10 ppm level only was growth promoting in control cultures, but it was antagonistic at its higher levels (50 and 100 ppm) along with both insecticides, individually. Potash (100, 200, 300 and 400 ppm) reduced toxicity due to carbaryl 20 and carbofuran 250 ppm levels, but potash was antagonistic at the other insecticide levels. The data clearly showed that the chemical fertilizers used were antagonistic with both the insecticides during toxicity to Cylindrospermum sp. PMID- 26038670 TI - Comparative study of the fungicide Benomyl toxicity on some plant growth promoting bacteria and some fungi in pure cultures. AB - Six laboratory experiments were carried out to investigate the effect of the fungicide Benomyl on pure cultures of some plant growth promoting bacteria (PGPB) and some fungi. The highest LD50 was recorded for Bacillus circulans and proved to be the most resistant to the fungicide, followed by Azospirillum braziliense, while Penicillium sp. was the most affected microorganism. LD50 values for the affected microorganisms were in 21-240 orders of magnitude lower in comparison with the LD50 value for Azospirillum braziliense. The results indicate a strong selectivity for Benomyl against Rhizobium meliloti and Penicillium sp. when compared to other microorganisms tested. The highest safety coefficient was recorded for Bacillus circulans followed by Azospirillum braziliense, while Rhizobium meliloti, showed the lowest safety coefficient value compared to other bacteria. The lowest toxicity index was recorded for Bacillus circulans and Azospirillum braziliense. The slope of the curves for Bacillus sp. and Rhizobium meliloti was steeper than that of the other curves, suggesting that even a slight increase of the dose of the fungicide can cause a very strong negative effect. In conclusion, Benomyl could be applied without restriction when using inocula based on growth promoting bacteria such as symbiotic nitrogen fixers (Rhizobium meliloti), non-symbiotic nitrogen fixers (Azospirillum braziliense) or potassium solibilizers (Bacillus circulans), given that the fungicide is applied within the range of the recommended field dose. PMID- 26038671 TI - Exposure-dependent variation in cryolite induced lethality in the non-target insect, Drosophila melanogaster. AB - The starting point of toxicity testing of any chemical in an organism is the determination of its Lethal Concentration 50 (LC50). In the present study, LC50 of a fluorinated insecticide cryolite is determined in a non-target insect model, Drosophila melanogaster. Interestingly, the result shows that acute LC50 of cryolite was much greater in comparison to the chronic one in case of Drosophila larvae. Larvae which were exposed to 65,000 to 70,000 ug/ml cryolite through food showed 50% mortality after 18 hours of acute exposure, whereas only 150 to 160 ug/ml cryolite was sufficient to cause 50% mortality in case of chronic exposure. Thus cryolite in a small amount when applied once cannot produce noticeable changes in Drosophila, whereas the same amount when used continuously can be fatal. The non-feeding pupal stage was also seen to be affected by chemical treatment. This suggests that the test chemical affects the developmental fate and results in failure of adult emergence. Absence of chemical-induced mortality in adults assumes that the toxicity of cryolite might be restricted to the preimaginal stages of the organism. Reduction in body size of larvae after ingestion of cryolite (with food) in acute treatment schedule is another interesting finding of this study. Some individuals consuming cryolite containing food cannot survive whereas the few survivors manifest a significant growth retardation which might be due to a tendency of refusal in feeding. Hence the present findings provide a scope of assessment of risk of other similar non target groups. PMID- 26038672 TI - Long-term (30 days) toxicity of NiO nanoparticles for adult zebrafish Danio rerio. AB - Nickel oxide in the form of nanoparticles (NiO NPs) is extensively used in different industrial branches. In a test on adult zebrafish, the acute toxicity of NiO NPs was shown to be low, however longlasting contact with this compound can lead to its accumulation in the tissues and to increased toxicity. In this work we determined the 30-day toxicity of NiO NPs using a static test for zebrafish Danio rerio. We found the 30-day LC50 value to be 45.0 mg/L, LC100 (minimum concentration causing 100% mortality) was 100.0 mg/L, and LC0 (maximum concentration causing no mortality) was 6.25 mg/L for adult individuals of zebrafish. Considering a broad use of Ni in the industry, NiO NPs chronic toxicity may have a negative impact on the population of aquatic organisms and on food web dynamics in aquatic systems. PMID- 26038673 TI - Antioxidant action of SMe1EC2, the low-basicity derivative of the pyridoindole stobadine, in cell free chemical models and at cellular level. AB - The aim of the study was to evaluate the antioxidant action of SMe1EC2, the structural analogue of the hexahydropyridoindole antioxidant stobadine. The antiradical activity of SMe1EC2 was found to be higher when compared to stobadine, as determined both in cell-free model systems of AAPH-induced oxidation of dihydrorhodamine 123 and 2',7'-dichloro-dihydrofluorescein diacetate, and in the cellular system of stimulated macrophages RAW264.7. Analysis of proliferation of HUVEC and HUVEC-ST cells revealed absence of cytotoxic effect of SMe1EC2 at concentrations below 100 uM. The antioxidant activity of SMe1EC2, superior to the parent drug stobadine, is accounted for by both the higher intrinsic free radical scavenging action and by the better bioavailability of the low-basicity SMe1EC2 relative to the high-basicity stobadine. PMID- 26038674 TI - Peripheral blood and bone marrow responses under stress of cypermethrin in albino rats. AB - Pyrethroids, commercially available pesticides, are greatly in use these days, and thus they carry considerable chances of contaminating various ecosystems. Haematotoxicity of cypermethrin, a broadly used type II pyrethroid, has been assessed in the present study. Selected parameters included determination of total RBC count, haemoglobin concentration (Hb conc.), packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), erythrocyte sedimentation rate (ESR), total leukocyte count (TLC), differential leukocyte count (DLC), along with qualitative analysis of blood and bone marrow. Of these parameters, those showing significant decline following cypermethrin intoxication included total RBC count, Hb conc., PCV, MCV, MCH, whereas non-significant decrease was observed in the case of MCHC. ESR, TLC and DLC, on the other hand, increased significantly following cypermethrin intoxication. Qualitative changes included altered red cell morphology such as microcystosis, appearance of stomatocytes, poikilocytosis, giant platelet formation, etc. in peripheral blood and increased erythroid precursors in bone marrow of treated rats. These parameters were however normalised following twenty-two days of recovery phase. PMID- 26038675 TI - Melatonin protects uterus and oviduct exposed to nicotine in mice. AB - Smoking is associated with higher infertility risk. The aim of this study was to evaluate protective effects of melatonin on the uterus and oviduct in mice exposed to nicotine. Adult female mice (n=32) were divided into four groups. Group A: control animals received normal saline, Group B: injected with nicotine 40ug/kg, Group C: injected with melatonin 10 ug, Group D: injected with nicotine 40ug/kg and melatonin 10 ug. All animals were treated over 15 days intraperitoneally. On the 16th day, animals in the estrus phase were dissected and their uterus and oviducts were removed. Immunohistochemistry was recruited for studying apoptosis and for detection of estrogen receptor (ER) alpha in luminal epithelium of the uterus and oviduct. Enzyme-linked immunosorbent assay was used for serum estradiol level determination. Nicotine in group B decreased estradiol level and ERalpha numbers both in the uterus and oviduct (p<0.05). Co administration of melatonin-nicotine in Group D ameliorated the histology of the uterus and oviduct, increased ERalpha numbers and reduced apoptosis in the uterus and oviduct compared with the nicotine Group B (p<0.05). This study indicates that nicotine impairs the histology of the uterus and oviduct and co administration of melatonin-nicotine ameliorates these findings, partly through alteration in ERalpha numbers and reduction of apoptosis. PMID- 26038676 TI - Serum tryptase detected during acute coronary syndrome is significantly related to the development of major adverse cardiovascular events after 2 years. AB - BACKGROUND: One of the greatest challenges in cardiovascular medicine is to define the best tools for performing an accurate risk stratification for the recurrence of ischemic events in acute coronary syndrome (ACS) patients. METHODS: We followed 65 ACS patients enrolled in a previous pilot study for 2 years after being discharged, focusing on the occurrence of major adverse cardiovascular events (MACE). The relationship between serum tryptase levels on admission, SYNergy between percutaneous coronary intervention with the TAXUS drug-eluting stent and the cardiac surgery score (SX-score), cardiovascular complexity and MACE at 2 years follow-up were analyzed. RESULTS: The ACS population was divided in two groups: patients with MACE (n = 23) and patients without MACE (n = 42). The tryptase measurement at admission (T0) and at discharge (T3) and SX-score were higher in patients who experienced MACE than in those without (p = 0.0001, p < 0.0001 and p = 0.006, respectively). Conversely, we found no significant association between MACE and C-reactive protein (CRP), and between MACE and maximum level of high-sensitivity troponin (hs-Tn) values. Among all patients with MACE, 96% belonged to the group that presented with cardiovascular complexity at the beginning of ACS index admission (p < 0.0001). The predictive accuracy of serum tryptase for MACE at follow up set at the cut-off point of 4.95 ng/ml at T0 and of 5.2 ng/ml at T3. Interestingly, patients with both the above cut-off tryptase values at T0 and at T3 presented a 1320% increase in the odds of developing MACE (p < 0.0001). CONCLUSION: In ACS patients, serum tryptase measured during index admission is significantly correlated to the development of MACE up to 2 years, demonstrating a possible long-term prognostic role of this biomarker. PMID- 26038677 TI - Sera from patients with active systemic lupus erythematosus patients enhance the toll-like receptor 4 response in monocyte subsets. AB - BACKGROUND: Systemic Lupus Erythematosus (SLE) is an auto-immune disease whose complex pathogenesis remains unraveled. Here we aim to explore the inflammatory ability of SLE patients' sera upon peripheral blood (PB) monocyte subsets and myeloid dendritic cells (mDCs) obtained from healthy donors. METHODS: In this study we included 11 SLE patients with active disease (ASLE), 11 with inactive disease (ISLE) and 10 healthy controls (HC). PB from healthy donors was stimulated with patients' sera, toll-like receptor (TLR) 4 ligand - lipopolysaccharide or both. The intracellular production of TNF-alpha was evaluated in classical, non-classical monocytes and mDCs, using flow cytometry. TNF-alpha mRNA expression was assessed in all these purified cells, after sera treatment. RESULTS: We found that sera of SLE patients did not change spontaneous TNF-alpha production by monocytes or dendritic cells. However, upon stimulation of TLR4, the presence of sera from ASLE patients, but not ISLE, significantly increased the intracellular expression of TNF-alpha in classical and non classical monocytes. This ability was related to titers anti-double stranded DNA antibodies in the serum. High levels of anti-TNF-alpha in the patients' sera were associated with increased TNF-alpha expression by co-cultured mDCs. No relationship was found with the levels of a wide variety of other pro inflammatory cytokines. A slight increase of TNF-alpha mRNA expression was observed in these purified cells when they were cultured only in the presence of SLE serum. CONCLUSIONS: Our data suggest that SLE sera induce an abnormal in vitro TLR4 response in classical and non-classical monocytes, reflected by a higher TNF-alpha intracellular expression. These effects may be operative in the pathogenesis of SLE. PMID- 26038678 TI - The plasma proteomic signature as a strategic tool for early diagnosis of acute coronary syndrome. AB - BACKGROUND: Acute coronary syndrome is the major cause of death in developed countries. Despite its high prevalence, there is still a strong need for new biomarkers which permit faster and more accurate diagnostics and new therapeutic drugs. The basis for this challenge lay in improving our understanding of the whole atherosclerotic process from atherogenesis to atherothrombosis. In this study, we conducted two different proteomic analyses of peripheral blood plasma from non-ST elevation acute coronary syndrome and ST elevation acute coronary syndrome patients vs healthy controls. RESULTS: Two-dimensional Fluorescence Difference in Gel Electrophoresis and mass spectrometry permitted the identification of 31 proteins with statistical differences (p < 0.05) between experimental groups. Additionally, validation by Western blot and Selected Reaction Monitoring permitted us to confirm the identification of a different and characteristic plasma proteomic signature for NSTEACS and STEACS patients. CONCLUSIONS: We purpose the severity of hypoxia as the cornerstone for explaining the differences observed between both groups. PMID- 26038679 TI - Hydration status and fluid intake of urban, underprivileged South African male adolescent soccer players during training. AB - BACKGROUND: Poor hydration compromises performance and heightens the risk of heat stress which adolescents are particularly susceptible to as they produce comparatively larger amount of metabolic heat during exercise. This study determined the hydration status and fluid intake of socio-economically disadvantaged, male adolescent soccer players during training. METHODS: A pilot study was conducted among 79 soccer players (mean age 15.9 +/- 0.8 years; mean BMI 20.2 +/- 2.1 kg/m(2)). Hydration status was determined before and after two training sessions, using both urine specific gravity and percent loss of body weight. The type and amount of fluid consumed was assessed during training. A self-administered questionnaire was used to determine the players' knowledge regarding fluid and carbohydrate requirements for soccer training. RESULTS: Players were at risk of developing heat illness during six of the 14 training sessions (60 - 90 minutes in length). Although on average players were slightly dehydrated (1.023 +/- 0.006 g/ml) before and after (1.024 +/- 0.007 g/ml) training, some were extremely dehydrated before (24%) and after (27%) training. Conversely some were extremely hyperhydrated before (3%) and after training (6%). The mean percent loss of body weight was 0.7 +/- 0.7%. The majority did not consume fluid during the first (57.0%) and second (70.9%) training sessions. An average of 216.0 +/- 140.0 ml of fluid was consumed during both training sessions. The majority (41.8%) consumed water, while a few (5.1%) consumed pure fruit juice. More than 90% stated that water was the most appropriate fluid to consume before, during and after training. Very few (5.0%) correctly stated that carbohydrate should be consumed before, during and after training. CONCLUSIONS: Approximately a quarter were severely dehydrated. Many did not drink or drank insufficient amounts. The players' beliefs regarding the importance of fluid and carbohydrate consumption did not correspond with their practices. A nutrition education programme is needed to educate players on the importance of fluid and carbohydrate to prevent dehydration and ensure appropriate carbohydrate intake. PMID- 26038680 TI - The evaluation of swallowing in patients with spinocerebellar ataxia and oropharyngeal dysphagia: A comparison study of videofluoroscopic and sonar doppler. AB - INTRODUCTION: Spinocerebellar ataxia (SCA) is a degenerative disease that can cause loss of coordination of voluntary muscle movement such as that required for swallowing. AIMS: The purposes of this cross-sectional and comparative case study were: (1) to assess the severity of dysphagia through a videofluoroscopic swallow study, and (2) to compare differences in frequency, intensity, and duration of sound waves produced during swallowing in normal and SCA patients by using sonar Doppler. METHOD: During swallow evaluation using videofluoroscopy, a sonar Doppler transducer was placed on the right side of the neck, at the lateral edge of the trachea, just below the cricoid cartilage to capture the sounds of swallowing in 30 SCA patients and 30 controls. RESULT: The prevalence in the dynamic evaluation of swallowing videofluoroscopy was by changes in the oral phase of swallowing. The analysis of variance of the averages found in each variable - frequency, intensity and duration of swallowing - shows there was a significant correlation when compared to the healthy individual curve. CONCLUSION: The study demonstrates the prevalence of oral dysphagia observed in dynamic videofluoroscopic swallow evaluation. In patients with SCA, the mean initial frequency (IF), initial intensity (II), and final intensity (FI) were higher and the time (T) and peak frequency (PF) were lower, demonstrating a pattern of cricopharyngeal opening very close to that found in normal populations. PMID- 26038681 TI - Annual Conference of the GMA, Hamburg, Germany, 2014. PMID- 26038682 TI - State of Digital Education Options in the areas of Medical Terminology and the History, Theory and Ethics of Medicine. AB - BACKGROUND: Institutes of the history of medicine, the theory of medicine, and medical ethics at German institutions of higher learning have created various e learning options that are based on different learning platforms and tailored to the specific curricular needs of individual teaching. Up to now no valid data has been available about the types of such e-learning options as well as possibilities of future developments thanks to coordinated cooperation among the different institutes. METHODS: Of 31 German institutes of the history and theory of medicine and medical ethics that were asked to fill out a questionnaire, 30 answered, which equals a return rate of 97 per cent. The questionnaire was completed between July and August 2012 using a telephone survey. RESULTS: Available to students online, digitally interactive teaching tools have boomed in the course of the last few years at German institutes of the history of medicine, the theory of medicine, and medical ethics. This trend is also reflected in a willingness of more than half of the respective departments (67 per cent) to expand their e-learning options on the basis of previous experience. The offered e-learning systems are accepted very well by the students. 57 per cent of the institutes stated, that 90-100 per cent of the students use the offered systems regularly. E-learning courses for terminology are offered particularly often, this is also reflected in the intended extension of these courses by the majority of institutes which plan to expand their e-learning systems. CONCLUSIONS: This article discusses the results of a comprehensive empirical survey about e learning. It illustrates ways in which individual German institutes plan to expand their e-learning options in the future. Finally, specific proposals for cooperation among institutions (not just online) are introduced, the purpose of which is to produce synergy in e-learning. PMID- 26038683 TI - Audience-response systems for evaluation of pediatric lectures--comparison with a classic end-of-term online-based evaluation. AB - AIM: Course evaluations are often conducted and analyzed well after the course has taken place. By using a digital audience response system (ARS), it is possible to collect, view and discuss feedback during or directly following a course or lecture session. This paper analyzes a student evaluation of a lecture course with ARS to determine if significant differences exist between the results of the ARS lecture evaluation and those of the online evaluation at the end of the semester. In terms of the overall evaluation, consideration is given to the level of students' prior knowledge, the presentation of the lecture material by the lecturers and the relevance of the lecture topic for students. METHOD: During the 2011-12 winter semester, the lecture on Pediatrics at the Freiburg Center for Pediatric and Adolescent Medicine (Zentrum fur Kinder- und Jugendmedizin (ZKJ) Freiburg) was evaluated using ARS. Thirty-four lectures were evaluated by an average of 22 (range 8-44) students, who responded to four questions each time an evaluation took place. RESULTS: On a 6-point Likert scale (1=very good to 6=deficient), the students rated their level of preparedness with a mean of 3.18, the presentation of the lecture with 2.44, and the relevance of the lecture topic with 2.19. The overall evaluation of the lecture course by means of ARS resulted in 2.31. The online evaluation conducted at the end of the semester yielded a score of 2.45. Highly significant correlations were seen between the results of the ARS for the overall evaluation, assessment of prior knowledge, lecture presentation, and the estimated relevance of the lecture topic. CONCLUSION: The use of ARS is suitable for immediate evaluation of lectures, in particular regarding timely feedback for the individual lecturer/lecturers. In comparison with an end-of-term evaluation, ARS yielded a better assessment. PMID- 26038684 TI - The Teamwork Assessment Scale: A Novel Instrument to Assess Quality of Undergraduate Medical Students' Teamwork Using the Example of Simulation-based Ward-Rounds. AB - BACKGROUND: Simulation-based teamwork trainings are considered a powerful training method to advance teamwork, which becomes more relevant in medical education. The measurement of teamwork is of high importance and several instruments have been developed for various medical domains to meet this need. To our knowledge, no theoretically-based and easy-to-use measurement instrument has been published nor developed specifically for simulation-based teamwork trainings of medical students. Internist ward-rounds function as an important example of teamwork in medicine. PURPOSES: The purpose of this study was to provide a validated, theoretically-based instrument that is easy-to-use. Furthermore, this study aimed to identify if and when rater scores relate to performance. METHODS: Based on a theoretical framework for teamwork behaviour, items regarding four teamwork components (Team Coordination, Team Cooperation, Information Exchange, Team Adjustment Behaviours) were developed. In study one, three ward-round scenarios, simulated by 69 students, were videotaped and rated independently by four trained raters. The instrument was tested for the embedded psychometric properties and factorial structure. In study two, the instrument was tested for construct validity with an external criterion with a second set of 100 students and four raters. RESULTS: In study one, the factorial structure matched the theoretical components but was unable to separate Information Exchange and Team Cooperation. The preliminary version showed adequate psychometric properties (Cronbach's alpha=.75). In study two, the instrument showed physician rater scores were more reliable in measurement than those of student raters. Furthermore, a close correlation between the scale and clinical performance as an external criteria was shown (r=.64) and the sufficient psychometric properties were replicated (Cronbach's alpha=.78). CONCLUSIONS: The validation allows for use of the simulated teamwork assessment scale in undergraduate medical ward round trainings to reliably measure teamwork by physicians. Further studies are needed to verify the applicability of the instrument. PMID- 26038685 TI - Quality management of eLearning for medical education: current situation and outlook. AB - INTRODUCTION: In 2008, the German Council of Science had advised universities to establish a quality management system (QMS) that conforms to international standards. The system was to be implemented within 5 years, i.e., until 2014 at the latest. The aim of the present study was to determine whether a QMS suitable for electronic learning (eLearning) domain of medical education to be used across Germany has meanwhile been identified. METHODS: We approached all medical universities in Germany (n=35), using an anonymous questionnaire (8 domains, 50 items). RESULTS: Our results (response rate 46.3%) indicated very reluctant application of QMS in eLearning and a major information deficit at the various institutions. CONCLUSIONS: Authors conclude that under the limitations of this study there seems to be a considerable need to improve the current knowledge on QMS for eLearning, and that clear guidelines and standards for their implementation should be further defined. PMID- 26038686 TI - Assessing family medicine trainees--what can we learn from the European neighbours? AB - BACKGROUND: Although demands on family physicians (FP) are to a large extent similar in the European Union, uniform assessment standards for family medicine (FM) specialty training and assessment do not exist. Aim of this pilot study was to elicit and compare the different modalities and assessment methods of FM specialty training in five European countries. METHODS: A semi structured survey was undertaken based on a convenient sample in five European countries (Denmark, Germany, Poland, the Netherlands and the United Kingdom). The respondents were asked to respond to ten items about aspects of FM specialty training and assessment methods in their respective countries. If available, this data was completed with information from official websites of the countries involved. RESULTS: FM specialty training is performed heterogeneously in the surveyed countries. Training time periods range from three to five years, in some countries requiring a foundation program of up to two years. Most countries perform longitudinal assessment during FM specialty training using a combination of competence-based approach with additional formative and summative assessment. There is some evidence on the assessments methods used, however the assessment method used and costs of assessment differs remarkably between the participating countries. CONCLUSIONS: Longitudinal and competence-based assessment is the presently preferred approach for FM specialty training. Countries which use less multifaceted methods for assessment could learn from best practice. Potential changes have significant cost implications. PMID- 26038687 TI - Position statement GMA Committee--"Interprofessional Education for the Health Care Professions". PMID- 26038688 TI - Core Competencies for Medical Teachers (KLM)--A Position Paper of the GMA Committee on Personal and Organizational Development in Teaching. AB - Recent developments in medical education have created increasing challenges for medical teachers which is why the majority of German medical schools already offer educational and instructional skills trainings for their teaching staff. However, to date no framework for educational core competencies for medical teachers exists that might serve as guidance for the qualification of the teaching faculty. Against the background of the discussion about competency based medical education and based upon the international literature, the GMA Committee for Faculty and Organizational Development in Teaching developed a model of core teaching competencies for medical teachers. This framework is designed not only to provide guidance with regard to individual qualification profiles but also to support further advancement of the content, training formats and evaluation of faculty development initiatives and thus, to establish uniform quality criteria for such initiatives in German-speaking medical schools. The model comprises a framework of six competency fields, subdivided into competency components and learning objectives. Additional examples of their use in medical teaching scenarios illustrate and clarify each specific teaching competency. The model has been designed for routine application in medical schools and is thought to be complemented consecutively by additional competencies for teachers with special duties and responsibilities in a future step. PMID- 26038690 TI - UnoViS: the MedIT public unobtrusive vital signs database. AB - While PhysioNet is a large database for standard clinical vital signs measurements, such a database does not exist for unobtrusively measured signals. This inhibits progress in the vital area of signal processing for unobtrusive medical monitoring as not everybody owns the specific measurement systems to acquire signals. Furthermore, if no common database exists, a comparison between different signal processing approaches is not possible. This gap will be closed by our UnoViS database. It contains different recordings in various scenarios ranging from a clinical study to measurements obtained while driving a car. Currently, 145 records with a total of 16.2 h of measurement data is available, which are provided as MATLAB files or in the PhysioNet WFDB file format. In its initial state, only (multichannel) capacitive ECG and unobtrusive PPG signals are, together with a reference ECG, included. All ECG signals contain annotations by a peak detector and by a medical expert. A dataset from a clinical study contains further clinical annotations. Additionally, supplementary functions are provided, which simplify the usage of the database and thus the development and evaluation of new algorithms. The development of urgently needed methods for very robust parameter extraction or robust signal fusion in view of frequent severe motion artifacts in unobtrusive monitoring is now possible with the database. PMID- 26038691 TI - Risk factors for Enterobius vermicularis infection in children in Gaozhou, Guangdong, China. AB - BACKGROUND: Enterobius vermicularis infection is a prevalent intestinal parasitic disease in children. In this study, we explored the epidemiological status and risk factors for E. vermicularis infection in children in southern China. METHODS: A cross-sectional survey was carried out in Gaozhou city, Guangdong province, China, in December 2011. Children aged 2-12 years from five schools participated in the study. The adhesive cellophane-tape perianal swab method was applied to detect E. vermicularis infection, while a questionnaire was sent to each child's guardian(s) to collect demographic and socioeconomic data, as well as hygiene behaviors, pertaining to each child. Univariate and multivariate logistic regression analyses were performed to capture the potential risk factors. RESULTS: Out of the 802 children surveyed, 440 were infected with E. vermicularis, with an average prevalence of 54.86 %, and a range from 45.96 to 68.13 %. The age variable was found to be statistically significant, whereas the sex variable was not. It was found that a mother's education level (low) and not washing hands before dinner were major risk factors in all children (802). After stratification by age, a father's education level (primary or below) and biting pencils (or toys) were significant risk factors in the younger children (508), while not washing hands before dinner and playing on the ground were important risk factors in the older children (294). CONCLUSION: This study demonstrates the prevalence of E. vermicularis infection in children in Gaozhou and reveals underlying risk factors. Most importantly, it reveals that risk factors differ among the different age groups, which indicates that different control measures targeted at particular age groups should be implemented. PMID- 26038692 TI - Pituitary injury and persistent hypofunction resulting from a peripartum non hemorrhagic, vaso-occlusive event. AB - Cerebral vascular accidents are caused by vasospasm when induced by preeclampsia or by dopamine agonists. However, six arteries nourish the pituitary and prevent against vasospasm-induced damage, which up until now has not been thought to occur. Bromocriptine was used to arrest lactation in a 31-year-old with secondary amenorrhea following preeclampsia and fetal demise at 28 weeks gestation. Tests and history revealed panhypopituitarism not associated with hemorrhage or mass infarction but instead caused by vasospasm. The present study is the first report of pituitary damage from a non-hemorrhagic, vaso-occlusive event in the literature. In keeping with Sheehan's and Simon's syndromes, we have named pituitary damage resulting from vaso-occlusion as Dahan's syndrome, and a literature review suggests that it may be a common and previously overlooked disorder. LEARNING POINTS: Vasospasm can cause damage to the pituitary gland, although it was not previously believed to do so.Preeclampsia and the use of a dopamine agonist, particularly in the peripartum state, may trigger vasospasm.Vasospasm resulting from dopamine agonists may be a common cause of injury to the pituitary gland, and it may have been overlooked in the past. PMID- 26038693 TI - Renal responses produced by microinjection of the kappa opioid receptor agonist, U50-488H, into sites within the rat lamina terminalis. AB - Activation of central kappa opioid receptors (KOR) has been demonstrated to produce marked free water diuresis with a concurrent increase in renal sympathetic nerve activity (RSNA). This study investigated the cardiovascular (CV) and renal effects evoked by central activation of KOR in two lamina terminalis sites, the median preoptic area (MPA) and anterolateral division of the bed nuclei of the stria terminalis (BST). Rats anesthetized with urethane alpha-chloralose were instrumented to record mean arterial pressure, heart rate, RSNA, and urine output (V). Rats were infused with isotonic saline (25 MUL/min) and urine samples were collected during two 10-min control periods and six consecutive 10-min experimental periods following microinjection of vehicle, U50 448H (U50, KOR agonist) alone or norbinaltorphimine (nor-BNI, KOR antagonist) plus U50. Microinjection of U50 into the BST increased V (peak at 30 min, 84.8 +/ 12.9 MUL/min) as compared to its respective control, vehicle, or nor-BNI plus U50. This diuretic effect occurred without any significant changes in CV parameters, RSNA, or urinary sodium excretion. In contrast, U50 injection into the MPA significantly increased RSNA (peak at 20 mins: 129 +/- 9.9) without increasing the other parameters. This study demonstrated novel sites through which activation of KOR selectively increases V and RSNA. The ability of U50 to increase V without affecting sodium excretion and RSNA raises the possibility that LT neurons could be an important substrate through which drugs targeting KOR could selectively facilitate water excretion in sodium-retaining diseases such as congestive heart failure. PMID- 26038695 TI - Pharmacological effects of recombinant human tissue kallikrein on bradykinin B2 receptors. AB - Tissue kallikrein (KLK-1), a serine protease, initiates the release of bradykinin (BK)-related peptides from low-molecular weight kininogen. KLK-1 and the BK B2 receptor (B2R) mediate beneficial effects on the progression of type 2 diabetes and renal disease, but the precise role of KLK-1 independent of its kinin-forming activity remains unclear. We used DM199, a recombinant form of human KLK-1, along with the isolated human umbilical vein, a robust bioassay of the B2R, to address the previous claims that KLK-1 directly binds to and activates the human B2R, with possible receptor cleavage. DM199 (1-10 nmol/L) contracted the isolated vein via the B2R, but in a tachyphylactic, kinin-dependent manner, without desensitization of the tissue to exogenously added BK. In binding experiments with recombinant N-terminally tagged myc-B2Rs expressed in HEK 293a cells, DM199 displaced [(3)H]BK binding from the rabbit myc-B2R, but not from the human or rat myc-B2Rs. No evidence of myc-B2R degradation by immunoblot analysis was apparent following treatment of these 3 myc-B2R constructs with DM199 (30 min, <=10 nmol/L). In HEK 293 cells stably expressing rabbit B2R-GFP, DM199 (11-108 pmol/L) elicited signaling-dependent endocytosis and reexpression, while a higher concentration (1.1 nmol/L) induced a partially irreversible endocytosis of the construct (microscopy), paralleled by the appearance of free GFP in cells (immunoblotting, indicative of incomplete receptor down-regulation). The pharmacology of DM199 at relevant concentrations (<10 nmol/L) is essentially based on the activity of locally generated kinins. Binding to and mild down regulation of the B2R is possibly a species-dependent idiosyncratic response to DM199. PMID- 26038694 TI - Natural compound methyl protodioscin protects against intestinal inflammation through modulation of intestinal immune responses. AB - Dioscoreaceae, a kind of yam plant, has been recommended for treatment of chronic inflammatory conditions. However, the mechanisms are poorly defined. Methyl protodioscin (MPD) is one of the main bioactive components in Dioscoreaceae. Here, we aim to determine the mechanisms by which MPD ameliorates intestinal inflammation. Surgical intestinal specimens were collected from inflammatory bowel diseases (IBD) patients to perform organ culture. Experimental colitis was induced in mice by dextran sulfate sodium (DSS) or Citrobacter rodentium, and was then treated with MPD. NF-kappaB activation, expression of mucosal pro inflammatory cytokines, disease severity, and epithelial proliferation/apoptosis were determined. Mouse crypts and Caco-2 monolayers were cultured to observe the effect of MPD upon intestinal epithelial differentiation and barrier function. We found that MPD increased the percentage of survival from high-dose DSS-(4%) treated mice, and accelerated mucosal healing and epithelial proliferation in low dose DSS-(2.5%) treated mice characterized by marked reduction in NF-kappaB activation, pro-inflammatory cytokines expression and bacterial translocation. Consistently, MPD protected colonic mucosa from C. rodentium-induced colonic inflammation and bacterial colonization. In vitro studies showed that MPD significantly increased crypt formation and restored intestinal barrier dysfunction induced by pro-inflammatory cytokines. In conclusion, MPD ameliorates the intestinal mucosal inflammation by modulating the intestinal immunity to enhance intestinal barrier differentiation. MPD could be an alternative for treating chronic intestinal inflammatory diseases. PMID- 26038696 TI - Human hepatic metabolism of the anti-osteoporosis drug eldecalcitol involves sterol C4-methyl oxidase. AB - The metabolism of eldecalcitol (ED-71), a 2beta-hydroxypropoxylated analog of the active form of vitamin D3 was investigated by using in vitro systems. ED-71 was metabolized to 1alpha,2beta,25-trihydroxyvitamin D3 (1alpha,2beta,25(OH)3D3) in human small intestine and liver microsomes. To identify the enzymes involved in this metabolism, we examined NADPH-dependent metabolism by recombinant P450 isoforms belonging to the CYP1, 2, and 3 families, and revealed that CYP3A4 had the activity. However, the CYP3A4 -specific inhibitor, ketoconazole, decreased the activity in human liver microsomes by only 36%, suggesting that other enzymes could be involved in ED-71 metabolism. Because metabolism was dramatically inhibited by cyanide, we assumed that sterol C4-methyl oxidase like gene product (SC4MOL) might contribute to the metabolism of ED-71. It is noted that SC4MOL is physiologically essential for cholesterol synthesis. Recombinant human SC4MOL expressed in COS7, Saccharomyces cerevisiae, or Escherichia coli cells converted ED-71 to 1alpha,2beta,25(OH)3D3. Furthermore, we evaluated the metabolism of ED 71 by recombinant CYP24A1, which plays an important role in the metabolism of the active form of vitamin D3 (1alpha,25(OH)2D3) and its analogs. The k cat/K m value for 24- or 23-hydroxylation of ED-71 was only 3% of that for 1alpha,25(OH)2D3, indicating that ED-71 was resistant to CYP24A1-dependent catabolism. Among the three enzymes catalyzing ED-71, SC4MOL appears to be most important in the metabolism of ED-71. To the best of our knowledge, this is the first study showing that SC4MOL can function as a drug-metabolizing enzyme. The yeast and E. coli expression systems for SC4MOL could be useful for structure-function analyses of SC4MOL. PMID- 26038697 TI - Inhibition of adenosine deaminase (ADA)-mediated metabolism of cordycepin by natural substances. AB - Cordycepin, which is an analogue of a nucleoside adenosine, exhibits a wide variety of pharmacological activities including anticancer effects. In this study, ADA1- and ADA2-expressing HEK293 cells were established to determine the major ADA isoform responsible for the deamination of cordycepin. While the metabolic rate of cordycepin deamination was similar between ADA2-expressing and Mock cells, extensive metabolism of cordycepin was observed in the ADA1 expressing cells with K m and V max values of 54.9 MUmol/L and 45.8 nmole/min/mg protein. Among five natural substances tested in this study (kaempferol, quercetin, myricetin, naringenin, and naringin), naringin strongly inhibited the deamination of cordycepin with K i values of 58.8 MUmol/L in mouse erythrocytes and 168.3 MUmol/L in human erythrocytes. A treatment of Jurkat cells with a combination of cordycepin and naringin showed significant cytotoxicity. Our in silico study suggests that not only small molecules such as adenosine derivatives but also bulky molecules like naringin can be a potent ADA1 inhibitor for the clinical usage. PMID- 26038698 TI - Analysis of differential secondary effects of novel rexinoids: select rexinoid X receptor ligands demonstrate differentiated side effect profiles. AB - In order to determine the feasibility of utilizing novel rexinoids for chemotherapeutics and as potential treatments for neurological conditions, we undertook an assessment of the side effect profile of select rexinoid X receptor (RXR) analogs that we reported previously. We assessed pharmacokinetic profiles, lipid and thyroid-stimulating hormone (TSH) levels in rats, and cell culture activity of rexinoids in sterol regulatory element-binding protein (SREBP) induction and thyroid hormone inhibition assays. We also performed RNA sequencing of the brain tissues of rats that had been dosed with the compounds. We show here for the first time that potent rexinoid activity can be uncoupled from drastic lipid changes and thyroid axis variations, and we propose that rexinoids can be developed with improved side effect profiles than the parent compound, bexarotene (1). PMID- 26038699 TI - ATP-induced cellular stress and mitochondrial toxicity in cells expressing purinergic P2X7 receptor. AB - Under pathological conditions, the purinergic P2X7 receptor is activated by elevated concentrations of extracellular ATP. Thereby, the receptor forms a slowly dilating pore, allowing cations and, upon prolonged stimulation, large molecules to enter the cell. This process has a strong impact on cell signaling, metabolism, and viability. This study aimed to establish a link between gradual P2X7 activation and pharmacological endpoints including oxidative stress, hydrogen peroxide generation, and cytotoxicity. Mechanisms of cellular stress and cytotoxicity were studied in P2X7-transfected HEK293 cells. We performed real time monitoring of metabolic and respiratory activity of cells expressing the P2X7-receptor protein using a cytosensor system. Agonistic effects were monitored using exogenously applied ATP or the stable analogue BzATP. Oxidative stress induced by ATP or BzATP in target cells was monitored by hydrogen peroxide release in human mononuclear blood cells. P2X7-receptor activation was studied by patch-clamp experiments using a primary mouse microglia cell line. Stimulation of the P2X7 receptor leads to ion influx, metabolic activation of target cells, and ultimately cytotoxicity. Conversion of the P2X7 receptor from a small cation channel to a large pore occurring under prolonged stimulation can be monitored in real time covering a time frame of milliseconds to hours. Selectivity of the effects can be demonstrated using the selective P2X7-receptor antagonist AZD9056. Our findings established a direct link between P2X7-receptor activation by extracellular ATP or BzATP and cellular events culminating in cytotoxicity. Mechanisms of toxicity include metabolic and oxidative stress, increase in intracellular calcium concentration and disturbance of mitochondrial membrane potential. Mitochondrial toxicity is suggested to be a key event leading to cell death. PMID- 26038700 TI - Eslicarbazepine acetate for the treatment of focal epilepsy: an update on its proposed mechanisms of action. AB - Eslicarbazepine acetate (ESL) is a once daily antiepileptic drug (AED) approved by the European Medicines Agency (EMA), the Food and Drug Administration (FDA) and Health Canada as an adjunctive therapy in adults with partial-onset seizures (POS). In humans and in relevant animal laboratory species, ESL undergoes extensive first pass hydrolysis to its major active metabolite eslicarbazepine that represents ~95% of circulating active moieties. ESL and eslicarbazepine showed anticonvulsant activity in animal models. ESL may not only suppress seizure activity but may also inhibit the generation of a hyperexcitable network. Data reviewed here suggest that ESL and eslicarbazepine demonstrated the following in animal models: (1) the selectivity of interaction with the inactive state of the voltage-gated sodium channel (VGSC), (2) reduction in VGSC availability through enhancement of slow inactivation, instead of alteration of fast inactivation of VGSC, (3) the failure to cause a paradoxical upregulation of persistent Na(+) current (I NaP), and (4) the reduction in firing frequencies of excitatory neurons in dissociated hippocampal cells from patients with epilepsy who were pharmacoresistant to carbamazepine (CBZ). In addition, eslicarbazepine effectively inhibited high- and low-affinity hCaV3.2 inward currents with greater affinity than CBZ. These preclinical findings may suggest the potential for antiepileptogenic effects; furthermore, the lack of effect upon KV7.2 outward currents may translate into a reduced potential for eslicarbazepine to facilitate repetitive firing. PMID- 26038701 TI - Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis. AB - The majority of chronic liver diseases are accompanied by oxidative stress, which induces apoptosis in hepatocytes and liver injury. Recent studies suggest that oxidative stress and insulin resistance are important in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the pathophysiology of diabetes complications. Metformin has been shown to be hepatoprotective in the insulin resistant and leptin-deficient ob/ob mouse model of NAFLD. However, the mechanism involved in the protective effects of metformin has not been elucidated yet. Therefore, we investigated the protective effect of metformin against oxidative stress-induced apoptosis. Primary rat hepatocytes were exposed to the oxidative stress-generating compound menadione in the presence and absence of metformin. Apoptosis was determined by measuring caspase activity and poly(ADP-ribose) polymerase (PARP)-cleavage, and necrosis was measured by Sytox Green nuclear staining. We demonstrate that (1) Metformin inhibits menadione-induced caspase-9, 6,-3 activation and PARP-cleavage in a concentration-dependent manner. (2) Metformin increases menadione-induced heme oxygenase-1 (HO-1) expression and inhibits c-Jun N-terminal kinase (JNK)-phosphorylation. (3) Metformin does not induce necrosis in primary hepatocytes. Metformin protects hepatocytes against oxidative stress-induced caspase activation, PARP-cleavage and apoptosis. The anti-apoptotic effect of metformin is in part dependent on HO-1 and bcl-xl induction and inhibition of JNK activation and independent of insulin signaling. Our results elucidate novel protective mechanisms of metformin and indicate that metformin could be investigated as a novel therapeutic agent for the treatment of oxidative stress-related liver diseases. PMID- 26038702 TI - A neuroligin-1-derived peptide stimulates phosphorylation of the NMDA receptor NR1 subunit and rescues MK-801-induced decrease in long-term potentiation and memory impairment. AB - Neuroligins (NLs) are postsynaptic adhesion molecules, interacting with presynaptic neurexins (NXs), which determine the differential formation of excitatory (glutamatergic, NL1) and inhibitory (GABAergic, NL2) synapses. We have previously demonstrated that treatment with a NL2-derived peptide, neurolide-2, reduces sociability and increase animal aggression. We hypothesized that interfering with NL1 function at the excitatory synapses might regulate synaptic plasticity and learning, and counteract memory deficits induced by N-methyl-d aspartate (NMDA) receptor inhibition. First, neuronal NMDA receptor phosphorylation after treatment with NL1 or a mimetic peptide, neurolide-1, was quantified by immunoblotting. Subsequently, we investigated effects of neurolide 1 on long-term potentiation (LTP) induction in hippocampal slices compromised by NMDA receptor inhibitor MK-801. Finally, we investigated neurolide-1 effects on short- and long-term social and spatial memory in social recognition, Morris water-maze, and Y-maze tests. We found that subcutaneous neurolide-1 administration, restored hippocampal LTP compromised by NMDA receptor inhibitor MK-801. It counteracted MK-801-induced memory deficit in the water-maze and Y maze tests after long-term treatment (24 h and 1-2 h before the test), but not after short-term exposure (1-2 h). Long-term exposure to neurolide-1 also facilitated social recognition memory. In addition, neurolide-1-induced phosphorylation of the NMDA receptor NR1 subunit on a site important for synaptic trafficking, potentially favoring synaptic receptor retention. Our findings emphasize the role of NL1-NMDA receptor interaction in cognition, and identify neurolide-1, as a valuable pharmacological tool to examine the in vivo role of postsynaptic NL1 in cognitive behavior in physiological and pathological conditions. PMID- 26038703 TI - Inhibition of the compound action potentials of frog sciatic nerves by aroma oil compounds having various chemical structures. AB - Plant-derived chemicals including aroma oil compounds have an ability to inhibit nerve conduction and modulate transient receptor potential (TRP) channels. Although applying aroma oils to the skin produces a local anesthetic effect, this has not been yet examined throughly. The aim of the present study was to know how nerve conduction inhibitions by aroma oil compounds are related to their chemical structures and whether these activities are mediated by TRP activation. Compound action potentials (CAPs) were recorded from the frog sciatic nerve by using the air-gap method. Citral (aldehyde), which activates various types of TRP channels, attenuated the peak amplitude of CAP with the half-maximal inhibitory concentration (IC50) value of 0.46 mmol/L. Another aldehyde (citronellal), alcohol (citronellol, geraniol, (+/-)-linalool, (-)-linalool, (+)-borneol, (-) borneol, alpha-terpineol), ester (geranyl acetate, linalyl acetate, bornyl acetate), and oxide (rose oxide) compounds also reduced CAP peak amplitudes (IC50: 0.50, 0.35, 0.53, 1.7, 2.0, 1.5, 2.3, 2.7, 0.51, 0.71, 0.44, and 2.6 mmol/L, respectively). On the other hand, the amplitudes were reduced by a small extent by hydrocarbons (myrcene and p-cymene) and ketone (camphor) at high concentrations (2-5 mmol/L). The activities of citral and other TRP agonists ((+) borneol and camphor) were resistant to TRP antagonist ruthenium red. An efficacy sequence for the CAP inhibitions was generally aldehydes >= esters >= alcohols > oxides >> hydrocarbons. The CAP inhibition by the aroma oil compound was not related to its octanol-water partition coefficient. It is suggested that aroma oil compounds inhibit nerve conduction in a manner specific to their chemical structures without TRP activation. PMID- 26038704 TI - A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa. AB - Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (I sc). Subsequent I sc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. I sc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation. PMID- 26038705 TI - LP-925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2. AB - Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti diabetic agents that improve glycemic control by inhibiting SGLT2-mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP-925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild-type (WT) mice. We first tested LP-925219 inhibition of glucose transport by HEK293 cells expressing SGLT1 or SGLT2, and then characterized LP-925219 pharmacokinetics. We found that LP-925219 was a potent inhibitor of mouse SGLT1 (IC50 = 22.6 nmol/L) and SGLT2 (IC50 = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half life (7 h). We next delivered LP-925219 by oral gavage to WT, SGLT1 knockout (KO), SGLT2 KO, and SGLT1/SGLT2 double KO (DKO) mice and measured their 24-h UGE. We found that, in vehicle-treated mice, DKO UGE was maximal and SGLT2 KO, SGLT1 KO, and WT UGEs were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP-925219 dosed at 60 mg/kg twice daily increased UGE of SGLT1 KO, SGLT2 KO, and WT mice to DKO UGE levels. These findings show that orally available dual SGLT1/SGLT2 inhibitors can maximize 24-h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT2 inhibitors. PMID- 26038706 TI - Incorporation of concentration data below the limit of quantification in population pharmacokinetic analyses. AB - Handling of data below the lower limit of quantification (LLOQ), below the limit of quantification (BLOQ) in population pharmacokinetic (PopPK) analyses is important for reducing bias and imprecision in parameter estimation. We aimed to evaluate whether using the concentration data below the LLOQ has superior performance over several established methods. The performance of this approach ("All data") was evaluated and compared to other methods: "Discard," "LLOQ/2," and "LIKE" (likelihood-based). An analytical and residual error model was constructed on the basis of in-house analytical method validations and analyses from literature, with additional included variability to account for model misspecification. Simulation analyses were performed for various levels of BLOQ, several structural PopPK models, and additional influences. Performance was evaluated by relative root mean squared error (RMSE), and run success for the various BLOQ approaches. Performance was also evaluated for a real PopPK data set. For all PopPK models and levels of censoring, RMSE values were lowest using "All data." Performance of the "LIKE" method was better than the "LLOQ/2" or "Discard" method. Differences between all methods were small at the lowest level of BLOQ censoring. "LIKE" method resulted in low successful minimization (<50%) and covariance step success (<30%), although estimates were obtained in most runs (~90%). For the real PK data set (7.4% BLOQ), similar parameter estimates were obtained using all methods. Incorporation of BLOQ concentrations showed superior performance in terms of bias and precision over established BLOQ methods, and shown to be feasible in a real PopPK analysis. PMID- 26038707 TI - A novel 2-decenoic acid thioester ameliorates corticosterone-induced depression- and anxiety-like behaviors and normalizes reduced hippocampal signal transduction in treated mice. AB - We characterized mice administered corticosterone (CORT) at a dose of 20 mg/kg for 3 weeks to determine their suitability as a model of mood disorders and found that the time immobilized in the tail suspension test was longer and the time spent in the open arms of the elevated plus-maze test was shorter than those of the vehicle-treated group, findings demonstrating that chronic CORT induced both depression-like and anxiety-like behaviors. Furthermore, the levels of phosphorylated extracellular signal-regulated kinase (pERK) 1/2 in the hippocampus and cerebral cortex were reduced in the CORT-treated group. Using this model, we investigated the protective effect of the ester, thioester, and amide compounds of 2-decenoic acid derivatives (termed compounds A, B, and C, respectively). The potency of the protective activity against the CORT-induced depression-like or anxiety-like behaviors and the reduction in pERK1/2 level were found to be in the following order: compound B > compound C > compound A. Therefore, we further investigated the therapeutic activity of only compound B, and its effect on depression-like behavior was observed after oral administration for 1 or 2 weeks, and its effect on anxiety-like behavior was observed after oral administration for 3 weeks. The ratios of phosphorylated ERK1/2, Akt, and cAMP response element-binding protein to their respective nonphosphorylated forms were smaller in the CORT-treated group than in the vehicle-treated group; however, subsequent treatment with compound B at either 0.3 or 1.5 mg/kg significantly ameliorated this reduction. Compound B appeared to elicit intracellular signaling, similar to that elicited by brain-derived neurotrophic factor, and its mode of action was shown to be novel and different from that of fluvoxamine, a currently prescribed drug for mood disorders. PMID- 26038708 TI - Sporting programs for inactive population groups: factors influencing implementation in the organized sports setting. AB - BACKGROUND: The organized sports sector has received increased attention as a setting to promote health-enhancing physical activity (HEPA) to the general population. For significant public health impact, it is important that successful HEPA programs are widely adopted, implemented and continued as ongoing practice. The importance of evaluating the context in which programs are implemented has been identified as critical. However, little research has focused on understanding the organized sports implementation context, including factors facilitating and impeding implementation. In this study, the main factors influencing implementation of HEPA programs in the organized sports setting were studied. METHODS: Fourteen sporting programs in the Netherlands aimed at increasing participation in sports by inactive population groups and funded within the National Action Plan for Sport and Exercise (NAPSE) were investigated. The programs were developed by ten Dutch National Sports Federations (NSFs) and implemented by different sports clubs in the Netherlands over a 3-year implementation period (June 2008-June 2011). The qualitative research component involved yearly face-to-face interviews (i.e. fourteen interviews each year, n = 12 program coordinators) and a group meeting with the program coordinators of the NSFs (n = 8). Cross-case comparisons and thematic analyses were performed to identify and categorize important facilitating and impeding factors respectively. The quantitative research component, used to identify the most important facilitating and impeding factors across all sporting programs, consisted of ranking of factors according to importance by the program coordinators (n = 12). RESULTS: Different factors act during six identified (implementation) phases. When comparing factors across phases, several key learnings were evident. Successful implementation relied, for example, on program design and enthusiastic individuals within sporting organizations. On the other hand, inactive people were hard to reach and participation of sports clubs was not self-evident. The findings were discussed in a broader context. CONCLUSIONS: This study adds to the knowledge base concerning the implementation of sporting programs, aimed at inactive people, in the organized sports setting. The main factors facilitating and impeding implementation were identified. The results of this study can be used by sports practitioners and policy makers when developing and implementing HEPA programs in this setting. PMID- 26038709 TI - Cardiac biomarkers and health-related quality of life in new hemodialysis patients without symptomatic cardiac disease. AB - BACKGROUND: Health Related Quality of Life (HRQOL) is impaired in hemodialysis patients and cardiac biomarkers are elevated, but their relationship is uncertain. OBJECTIVES: To determine whether the cardiac biomarkers, troponin T and N terminal pro-B type natriuretic peptide (NT-proBNP), predict deterioration in the physical domains of HRQOL. DESIGN: A prospective cohort study of patients in a randomized controlled clinical trial of correction of anemia with erythropoietin. SETTING: Multiple hemodialysis centers located throughout Canada and Europe. PARTICIPANTS: Patients who started maintenance hemodialysis within the previous 3-18 months, with no clinical evidence or prior history of symptomatic cardiac failure or ischemic heart disease, and left ventricular volume < 100 ml/m(2). MEASUREMENTS: PREDICTOR: Baseline concentrations of Troponin T and NT-proBNP. OUTCOMES: Physical function and vitality scores using the SF-36 questionnaire and fatigue scores using the FACIT questionnaire at baseline and after 24, 48, and 96 weeks follow-up. METHODS: Univariate analysis of the association between baseline variables and baseline HRQOL scores and change in scores over time was undertaken using linear regression. Multivariate models were created using multiple linear regression, and it was pre-specified that these include the variables which were associated with the outcome at a p < 0.05 in the univariate regression. RESULTS: Baseline median (interquartile range) physical function score was 70 (50-85), vitality 55 (40-75), and fatigue 73 (58 86). The 75th percentile for Troponin T was 0.05 ng/mL and for NT-proBNP 652 ng/mL. High Troponin T levels were significantly associated with deterioration in the 3 physical domains, independent of other risk factors, whereas high NT-proBNP were not associated. In multivariate models baseline Troponin T > 0.05 ng/mL were significantly associated with the change from baseline to 96 weeks follow-up for SF-36 vitality and FACIT-fatigue scores, and approached statistical significance for SF-36 physical function (0.056). LIMITATIONS: Not possible to confirm whether Troponin T associations were independent of subsequent cardiac events. CONCLUSIONS: In hemodialysis patients without prior symptomatic cardiac disease and without a dilated left ventricle at baseline, elevated baseline Troponin T levels, but not NT-pro BNP, were independently associated with deterioration in the physical domains of HRQOL. PMID- 26038710 TI - Patient and stone characteristics associated with surgical intervention in pediatrics. AB - BACKGROUND: The incidence of kidney stones in children is increasing. While guidelines exist for acute surgical intervention, there is limited data to inform the decision as to when to intervene non-urgently. OBJECTIVES: To identify patient and stone characteristics predicting stone surgery in children. DESIGN: Retrospective chart review. SETTING: Stollery Children's Hospital, Edmonton, Alberta, Canada from 1990 to 2013. PATIENTS: Sixty-three children aged 0-18 years old who presented with a total of 142 stones. MEASUREMENTS: Patient's surgical history, demographics, metabolic measures, and stone number, type, and location. METHODS: Univariate and multivariate analysis, controlling for presentation number and individual-level variation by repeated measures analysis were conducted to assess for patient and stone characteristics associated with surgical intervention. RESULTS: Sixty-five percent (41/63) required surgery during a mean follow-up of 19 months. Stone characteristics associated with surgical intervention by multivariate analysis included larger stone size (>6 mm), and stone composition of calcium oxalate. LIMITATIONS: Single center study with a limited sample size and duration of follow up, thereby limiting predictive power. There were some missing data (i,e. stone type was not always available). Despite this, stone type remained significant in multivariate modeling. CONCLUSION: Stone size > 6mm and composition with calcium oxalate but not patient age or symptoms associated with presentation predicted surgical intervention. These observations can be used to inform decisions as to whether urolithiasis should be surgically managed electively or observed. PMID- 26038711 TI - Increased systemic inflammation is associated with cardiac and vascular dysfunction over the first 12 weeks of antiretroviral therapy among undernourished, HIV-infected adults in Southern Africa. AB - INTRODUCTION: Persistent systemic inflammation is associated with mortality among undernourished, HIV-infected adults starting antiretroviral therapy (ART) in sub Saharan Africa, but the etiology of these deaths is not well understood. We hypothesized that greater systemic inflammation is accompanied by cardiovascular dysfunction over the first 12 weeks of ART. METHODS: In a prospective cohort of 33 undernourished (body mass index <18.5 kg/m2) Zambian adults starting ART, we measured C-reactive protein (CRP), tumor necrosis factor-alpha receptor 1 (TNF alpha R1), and soluble CD163 and CD14 at baseline and 12 weeks. An EndoPAT device measured the reactive hyperemia index (LnRHI; a measure of endothelial responsiveness), peripheral augmentation index (AI; a measure of arterial stiffness), and heart rate variability (HRV; a general marker of autonomic tone and cardiovascular health) at the same time points. We assessed paired changes in inflammation and cardiovascular parameters, and relationships independent of time point (adjusted for age, sex, and CD4+ T-cell count) using linear mixed models. RESULTS: Serum CRP decreased (median change -3.5 mg/l, p=0.02), as did TNF-alpha R1 (-0.31 ng/ml, p<0.01), over the first 12 weeks of ART. A reduction in TNF alpha R1 over 12 weeks was associated with an increase in LnRHI (p=0.03), and a similar inverse relationship was observed for CRP and LnRHI (p=0.07). AI increased in the cohort as a whole over 12 weeks, and a reduction in sCD163 was associated with a rise in the AI score (p=0.04). In the pooled analysis of baseline and 12 week data, high CRP was associated with lower HRV parameters (RMSSD, p=0.01; triangular index, p<0.01), and higher TNF- alpha R1 accompanied lower HRV (RMSSD, p=0.07; triangular index, p=0.06). CONCLUSIONS: Persistent inflammation was associated with impaired cardiovascular health over the first 12 weeks of HIV treatment among undernourished adults in Africa, suggesting cardiac events may contribute to high mortality in this population. PMID- 26038712 TI - Copepods enhance nutritional status, growth and development in Atlantic cod (Gadus morhua L.) larvae - can we identify the underlying factors? AB - The current commercial production protocols for Atlantic cod depend on enriched rotifers and Artemia during first-feeding, but development and growth remain inferior to fish fed natural zooplankton. Two experiments were conducted in order to identify the underlying factors for this phenomenon. In the first experiment (Exp-1), groups of cod larvae were fed either (a) natural zooplankton, mainly copepods, increasing the size of prey as the larvae grew or (b) enriched rotifers followed by Artemia (the intensive group). In the second experiment (Exp-2), two groups of larvae were fed as in Exp-1, while a third group was fed copepod nauplii (approximately the size of rotifers) throughout the larval stage. In both experiments, growth was not significantly different between the groups during the first three weeks after hatching, but from the last part of the rotifer feeding period and onwards, the growth of the larvae fed copepods was higher than that of the intensive group. In Exp-2, the growth was similar between the two copepod groups during the expeimental period, indicating that nutrient composition, not prey size caused the better growth on copepods. Analyses of the prey showed that total fatty acid composition and the ratio of phospholipids to total lipids was slightly different in the prey organisms, and that protein, taurine, astaxanthin and zinc were lower on a dry weight basis in rotifers than in copepods. Other measured nutrients as DHA, all analysed vitamins, manganese, copper and selenium were similar or higher in the rotifers. When compared to the present knowledge on nutrient requirements, protein and taurine appeared to be the most likely limiting nutrients for growth in cod larvae fed rotifers and Artemia. Larvae fed rotifers/Artemia had a higher whole body lipid content than larvae fed copepods at the end of the experiment (stage 5) after the fish had been fed the same formulated diet for approximately 2 weeks. PMID- 26038713 TI - Genes affecting novel seed constituents in Limnanthes alba Benth: transcriptome analysis of developing embryos and a new genetic map of meadowfoam. AB - The seed oil of meadowfoam, a new crop in the Limnanthaceae family, is highly enriched in very long chain fatty acids that are desaturated at the Delta5 position. The unusual oil is desirable for cosmetics and innovative industrial applications and the seed meal remaining after oil extraction contains glucolimnanthin, a methoxylated benzylglucosinolate whose degradation products are herbicidal and anti-microbial. Here we describe EST analysis of the developing seed transcriptome that identified major genes involved in biosynthesis and assembly of the seed oil and in glucosinolate metabolic pathways. mRNAs encoding acyl-CoA Delta5 desaturase were notably abundant. The library was searched for simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs). Fifty-four new SSR markers and eight candidate gene markers were developed and combined with previously developed SSRs to construct a new genetic map for Limnanthes alba. Mapped genes in the lipid biosynthetic pathway encode 3-ketoacyl-CoA synthase (KCS), Delta5 desaturase (Delta5DS), lysophosphatidylacyl-acyl transferase (LPAT), and acyl-CoA diacylglycerol acyl transferase (DGAT). Mapped genes in glucosinolate biosynthetic and degradation pathways encode CYP79A, myrosinase (TGG), and epithiospecifier modifier protein (ESM). The resources developed in this study will further the domestication and improvement of meadowfoam as an oilseed crop. PMID- 26038715 TI - Morphometric comparisons of Diaphorina citri (Hemiptera: Liviidae) populations from Iran, USA and Pakistan. AB - The Asian citrus psyllid (ACP), Diaphorina citri Kuwayama (Hemiptera: Liviidae), vector of citrus greening disease pathogen, Huanglongbing (HLB), is considered the most serious pest of citrus in the world. Prior molecular based studies have hypothesized a link between the D. citri in Iran and the USA (Florida). The purpose of this study was to collect morphometric data from D. citri populations from Iran (mtCOI haplotype-1), Florida (mtCOI haplotype-1), and Pakistan (mtCOI haplotype-6), to determine whether different mtCOI haplotypes have a relationship to a specific morphometric variation. 240 samples from 6 ACP populations (Iran Jiroft, Chabahar; Florida-Ft. Pierce, Palm Beach Gardens, Port St. Lucie; and Pakistan-Punjab) were collected for comparison. Measurements of 20 morphological characters were selected, measured and analysed using ANOVA and MANOVA. The results indicate differences among the 6 ACP populations (Wilks' lambda = 0.0376, F = 7.29, P < 0.0001). The body length (BL), circumanal ring length (CL), antenna length (AL), forewing length (WL) and Rs vein length of forewing (RL) were the most important characters separating the populations. The cluster analysis showed that the Iran and Florida populations are distinct from each other but separate from the Pakistan population. Thus, three subgroups can be morphologically discriminated within D. citri species in this study, (1) Iran, (2) USA (Florida) and (3) Pakistan population. Morphometric comparisons provided further resolution to the mtCOI haplotypes and distinguished the Florida and Iranian populations. PMID- 26038714 TI - Longitudinal relations among inattention, working memory, and academic achievement: testing mediation and the moderating role of gender. AB - Introduction. Behavioral inattention, working memory (WM), and academic achievement share significant variance, but the direction of relationships across development is unknown. The aim of the present study was to determine whether WM mediates the pathway between inattentive behaviour and subsequent academic outcomes. Methods. 204 students from grades 1-4 (49.5% female) were recruited from elementary schools. Participants received assessments of WM and achievement at baseline and one year later. WM measures included a visual-spatial storage task and auditory-verbal storage and manipulation tasks. Teachers completed the SWAN behaviour rating scale both years. Mediation analysis with PROCESS (Hayes, 2013) was used to determine mediation pathways. Results. Teacher-rated inattention indirectly influenced math addition fluency, subtraction fluency and calculation scores through its effect on visual-spatial WM, only for boys. There was a direct relationship between inattention and math outcomes one year later for girls and boys. Children who displayed better attention had higher WM scores, and children with higher WM scores had stronger scores on math outcomes. Bias corrected bootstrap confidence intervals for the indirect effects were entirely below zero for boys, for the three math outcomes. WM did not mediate the direct relationship between inattention and reading scores. Discussion. Findings identify inattention and WM as longitudinal predictors for math addition and subtraction fluency and math calculation outcomes one year later, with visual spatial WM as a significant mediator for boys. Results highlight the close relationship between inattention and WM and their importance in the development of math skills. PMID- 26038716 TI - Can parasites halt the invader? Mermithid nematodes parasitizing the yellow legged Asian hornet in France. AB - Since its introduction in France 10 years ago, the yellow-legged Asian bee hawking hornet Vespa velutina has rapidly spread to neighboring countries (Spain, Portugal, Belgium, Italy, and Germany), becoming a new threat to beekeeping activities. While introduced species often leave behind natural enemies from their original home, which benefits them in their new environment, they can also suffer local recruitment of natural enemies. Three mermithid parasitic subadults were obtained from V. velutina adults in 2012, from two French localities. However, these were the only parasitic nematodes reported up to now in Europe, in spite of the huge numbers of nests destroyed each year and the recent examination of 33,000 adult hornets. This suggests that the infection of V. velutina by these nematodes is exceptional. Morphological criteria assigned the specimens to the genus Pheromermis and molecular data (18S sequences) to the Mermithidae, due to the lack of Pheromermis spp. sequences in GenBank. The species is probably Pheromermis vesparum, a parasite of social wasps in Europe. This nematode is the second native enemy of Vespa velutina recorded in France, after a conopid fly whose larvae develop as internal parasitoids of adult wasps and bumblebees. In this paper, we provide arguments for the local origin of the nematode parasite and its limited impact on hornet colony survival. We also clarify why these parasites (mermithids and conopids) most likely could not hamper the hornet invasion nor be used in biological control programs against this invasive species. PMID- 26038717 TI - A white-box model of S-shaped and double S-shaped single-species population growth. AB - Complex systems may be mechanistically modelled by white-box modeling with using logical deterministic individual-based cellular automata. Mathematical models of complex systems are of three types: black-box (phenomenological), white-box (mechanistic, based on the first principles) and grey-box (mixtures of phenomenological and mechanistic models). Most basic ecological models are of black-box type, including Malthusian, Verhulst, Lotka-Volterra models. In black box models, the individual-based (mechanistic) mechanisms of population dynamics remain hidden. Here we mechanistically model the S-shaped and double S-shaped population growth of vegetatively propagated rhizomatous lawn grasses. Using purely logical deterministic individual-based cellular automata we create a white box model. From a general physical standpoint, the vegetative propagation of plants is an analogue of excitation propagation in excitable media. Using the Monte Carlo method, we investigate a role of different initial positioning of an individual in the habitat. We have investigated mechanisms of the single-species population growth limited by habitat size, intraspecific competition, regeneration time and fecundity of individuals in two types of boundary conditions and at two types of fecundity. Besides that, we have compared the S shaped and J-shaped population growth. We consider this white-box modeling approach as a method of artificial intelligence which works as automatic hyper logical inference from the first principles of the studied subject. This approach is perspective for direct mechanistic insights into nature of any complex systems. PMID- 26038718 TI - Accuracy of the interferon-gamma release assay for the diagnosis of tuberculous pleurisy: an updated meta-analysis. AB - Background and Objectives. The best method for diagnosing tuberculous pleurisy (TP) remains controversial. Since a growing number of publications focus on the interferon-gamma release assay (IGRA), we meta-analyzed the available evidence on the overall diagnostic performance of IGRA applied to pleural fluid and peripheral blood. Materials and Methods. PubMed and Embase were searched for relevant English papers up to October 31, 2014. Statistical analyses were performed using Stata and Meta-DiSc. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), positive predictive value (PPV), negative predictive value (NPV) and diagnostic odds ratio (DOR) were count. Summary receiver operating characteristic curves and area under the curve (AUC) were used to summarize the overall diagnostic performance. Results. Fifteen publications met our inclusion criteria and were included in the meta analysis. The following pooled estimates for diagnostic parameters of pleural IGRA were obtained: sensitivity, 0.82 (95% CI [0.79-0.85]); specificity, 0.87 (95% CI [0.84 0.90]); PLR, 4.94 (95% CI [2.60-9.39]); NLR, 0.22 (95% CI [0.13-0.38]); PPV, 0.91 (95% CI [0.85-0.96]); NPV, 0.79 (95% CI [0.71-0.85]); DOR, 28.37 (95% CI [10.53 76.40]); and AUC, 0.91. The corresponding estimates for blood IGRA were as follows: sensitivity, 0.80 (95% CI [0.76-0.83]); specificity, 0.70 (95% CI [0.65 0.75]); PLR, 2.48 (95% CI [1.95-3.17]); NLR, 0.30 (95% CI [0.24-0.37]); PPV, 0.79 (95% CI [0.60-0.87]); NPV, 0.75 (95% CI [0.62-0.83]); DOR, 9.96 (95% CI [6.02 16.48]); and AUC, 0.89. Conclusions. This meta analysis suggested that pleural IGRA has potential for serving as a complementary method for diagnosing TP; however, its cost, high turn around time, and sub-optimal performance make it unsuitable as a stand-alone diagnostic tool. Better tests for the diagnosis of TP are required. PMID- 26038719 TI - Vorinostat enhances chemosensitivity to arsenic trioxide in K562 cell line. AB - Objective. This study aimed to investigate the chemosensitive augmentation effect and mechanism of HDAC inhibitor Vorinostat (SAHA) in combination with arsenic trioxide (ATO) on proliferation and apoptosis of K562 cells. Methods. The CCK-8 assay was used to compare proliferation of the cells. Annexin-V and PI staining by flow cytometry and acridine orange/ethidium bromide stains were used to detect and quantify apoptosis. Western blot was used to detect expression of p21, Akt, pAkt, p210, Acetyl-Histone H3, and Acetyl-Histone H4 proteins. Results. SAHA and ATO inhibited proliferation of K562 cells in an additive and time- and dose dependent manner. SAHA in combination with ATO showed significant apoptosis of K562 cells in comparison to the single drugs alone (p < 0.01). Both SAHA and ATO alone and in combination showed lower levels of p210 expression. SAHA and SAHA and ATO combined treatment showed increased levels of Acetyl-Histone H3 and Acetyl-Histone H4 protein expression. SAHA alone showed increased expression of p21, while ATO alone and in combination with SAHA showed no significant change. SAHA and ATO combined therapy showed lower levels of Akt and pAkt protein expression than SAHA or ATO alone. Conclusion. SAHA and ATO combined treatment inhibited proliferation, induced apoptosis, and showed a chemosensitive augmentation effect on K562 cells. The mechanism might be associated with increasing histone acetylation levels as well as regulating the Akt signaling pathway. PMID- 26038720 TI - Using 3D printed eggs to examine the egg-rejection behaviour of wild birds. AB - The coevolutionary relationships between brood parasites and their hosts are often studied by examining the egg rejection behaviour of host species using artificial eggs. However, the traditional methods for producing artificial eggs out of plasticine, plastic, wood, or plaster-of-Paris are laborious, imprecise, and prone to human error. As an alternative, 3D printing may reduce human error, enable more precise manipulation of egg size and shape, and provide a more accurate and replicable protocol for generating artificial stimuli than traditional methods. However, the usefulness of 3D printing technology for egg rejection research remains to be tested. Here, we applied 3D printing technology to the extensively studied egg rejection behaviour of American robins, Turdus migratorius. Eggs of the robin's brood parasites, brown-headed cowbirds, Molothrus ater, vary greatly in size and shape, but it is unknown whether host egg rejection decisions differ across this gradient of natural variation. We printed artificial eggs that encompass the natural range of shapes and sizes of cowbird eggs, painted them to resemble either robin or cowbird egg colour, and used them to artificially parasitize nests of breeding wild robins. In line with previous studies, we show that robins accept mimetically coloured and reject non mimetically coloured artificial eggs. Although we found no evidence that subtle differences in parasitic egg size or shape affect robins' rejection decisions, 3D printing will provide an opportunity for more extensive experimentation on the potential biological or evolutionary significance of size and shape variation of foreign eggs in rejection decisions. We provide a detailed protocol for generating 3D printed eggs using either personal 3D printers or commercial printing services, and highlight additional potential future applications for this technology in the study of egg rejection. PMID- 26038721 TI - Caveolar disruption causes contraction of rat femoral arteries via reduced basal NO release and subsequent closure of BKCa channels. AB - Background and Purpose. Caveolae act as signalling hubs in endothelial and smooth muscle cells. Caveolar disruption by the membrane cholesterol depleting agent methyl-beta-cyclodextrin (M-beta-CD) has various functional effects on arteries including (i) impairment of endothelium-dependent relaxation, and (ii) alteration of smooth muscle cell (SMC) contraction independently of the endothelium. The aim of this study was to explore the effects of M-beta-CD on rat femoral arteries. Methods. Isometric force was measured in rat femoral arteries stimulated to contract with a solution containing 20 mM K(+) and 200 nM Bay K 8644 (20 K/Bay K) or with one containing 80 mM K(+)(80 K). Results. Incubation of arteries with M beta-CD (5 mM, 60 min) increased force in response to 20 K/Bay K but not that induced by 80 K. Application of cholesterol saturated M-beta-CD (Ch-MCD, 5 mM, 50 min) reversed the effects of M-beta-CD. After mechanical removal of endothelial cells M-beta-CD caused only a small enhancement of contractions to 20 K/Bay K. This result suggests M-beta-CD acts via altering release of an endothelial derived vasodilator or vasoconstrictor. When nitric oxide synthase was blocked by pre-incubation of arteries with L-NAME (250 uM) the contraction of arteries to 20 K/Bay K was enhanced, and this effect was abolished by pre-treatment with M-beta CD. This suggests M-beta-CD is inhibiting endothelial NO release. Inhibition of large conductance voltage- and Ca(2+)-activated (BKCa) channels with 2 mM TEA(+) or 100 nM Iberiotoxin (IbTX) enhanced 20 K/Bay K contractions. L-NAME attenuated the contractile effect of IbTX, as did endothelial removal. Conclusions. Our results suggest caveolar disruption results in decreased release of endothelial derived nitric oxide in rat femoral artery, resulting in a reduced contribution of BKCa channels to the smooth muscle cell membrane potential, causing depolarisation and contraction. PMID- 26038722 TI - Astym treatment vs. eccentric exercise for lateral elbow tendinopathy: a randomized controlled clinical trial. AB - Introduction. Patients with chronic lateral elbow (LE) tendinopathy, commonly known as tennis elbow, often experience prolonged symptoms and frequent relapses. Astym treatment, evidenced in animal studies to promote the healing and regeneration of soft tissues, is hypothesized to improve outcomes in LE tendinopathy patients. This study had two objectives: (1) to compare the efficacy of Astym treatment to an evidence-based eccentric exercise program (EE) for patients with chronic LE tendinopathy, and (2) to quantify outcomes of subjects non-responsive to EE who were subsequently treated with Astym treatment. Study Design. Prospective, two group, parallel, randomized controlled trial completed at a large orthopedic center in Indiana. INCLUSION CRITERIA: age range of 18-65 years old, with clinical indications of LE tendinopathy greater than 12 weeks, with no recent corticosteriod injection or disease altering comorbidities. Methods. Subjects with chronic LE tendinopathy (107 subjects with 113 affected elbows) were randomly assigned using computer-generated random number tables to 4 weeks of Astym treatment (57 elbows) or EE treatment (56 elbows). Data collected at baseline, 4, 8, 12 weeks, 6 and 12 months. PRIMARY OUTCOME MEASURE: DASH; secondary outcome measures: pain with activity, maximum grip strength and function. The treating physicians and the rater were blinded; subjects and treating clinicians could not be blinded due to the nature of the treatments. Results. Resolution response rates were 78.3% for the Astym group and 40.9% for the EE group. Astym subjects showed greater gains in DASH scores (p = 0.047) and in maximum grip strength (p = 0.008) than EE subjects. Astym therapy also resolved 20/21 (95.7%) of the EE non-responders, who showed improvements in DASH scores (p < 0.005), pain with activity (p = 0.002), and function (p = 0.004) following Astym treatment. Gains continued at 6 and 12 months. No adverse effects were reported. Conclusion. This study suggests Astym therapy is an effective treatment option for patients with LE tendinopathy, as an initial treatment, and after an eccentric exercise program has failed. Registration/Funding. Ball Memorial Hospital provided limited funding. Trial registration was not required by FDAAA 801. Known about the Subject. Under the new paradigm of degenerative tendinopathy, eccentric exercise (EE) is emerging as a first line conservative treatment for LE tendinopathy. EE and Astym treatment are among the few treatment options aiming to improve the degenerative pathophysiology of the tendon. In this trial, Astym therapy, which has shown success in the treatment of tendinopathy, is compared to EE, which has also shown success in the treatment of tendinopathy. Clinical Relevance. There is a need for more effective, conservative treatment options. Based on the current efficacy study, Astym therapy appears to be a promising, non-invasive treatment option. PMID- 26038723 TI - Back from the dead; the curious tale of the predatory cyanobacterium Vampirovibrio chlorellavorus. AB - An uncultured non-photosynthetic basal lineage of the Cyanobacteria, the Melainabacteria, was recently characterised by metagenomic analyses of aphotic environmental samples. However, a predatory bacterium, Vampirovibrio chlorellavorus, originally described in 1972 appears to be the first cultured representative of the Melainabacteria based on a 16S rRNA sequence recovered from a lyophilised co-culture of the organism. Here, we sequenced the genome of V. chlorellavorus directly from 36 year-old lyophilised material that could not be resuscitated confirming its identity as a member of the Melainabacteria. We identified attributes in the genome that likely allow V. chlorellavorus to function as an obligate predator of the microalga Chlorella vulgaris, and predict that it is the first described predator to use an Agrobacterium tumefaciens-like conjugative type IV secretion system to invade its host. V. chlorellavorus is the first cyanobacterium recognised to have a predatory lifestyle and further supports the assertion that Melainabacteria are non-photosynthetic. PMID- 26038724 TI - Rapid cessation of acute diarrhea using a novel solution of bioactive polyphenols: a randomized trial in Nicaraguan children. AB - Goal. We assessed the effectiveness of bioactive polyphenols contained in solution (LX) to restore normal bowel function in pediatric patients with acute diarrhea. Background. While providing oral rehydration solution (ORS) is standard treatment for diarrhea in developing countries, plant-derived products have been shown to positively affect intestinal function. If a supplement to ORS resolves diarrhea more rapidly than ORS alone, it is an improvement to current care. Study. In a randomized, double-blind, placebo-controlled cross-over study, 61 pediatric patients with uncontrolled diarrhea were randomized to receive either ORS + LX on day 1 and then ORS + water on day 2 (study arm) or ORS + water on day 1 and then ORS + LX on day 2 (control arm). Time to resolution and number of bowel movements were recorded. Results. On day 1, the mean time to diarrhea resolution was 3.1 h (study arm) versus 9.2 h (control arm) (p = 0.002). In the study arm, 60% of patients had normal stool at their first bowel movement after consumption of the phenolic redoxigen solution (LX). On day 2, patients in the study arm continued to have normal stool while patients in the control arm achieved normal stool within 24 h after consuming the test solution. Patients in the control arm experienced a reduction in the mean number of bowel movements from day 1 to day 2 after consuming the test solution (p = 0.0001). No adverse events were observed. Conclusions. Significant decreases in bowel movement frequency and rapid normalization of stool consistency were observed with consumption of this novel solution. PMID- 26038725 TI - PANDA: pathway and annotation explorer for visualizing and interpreting gene centric data. AB - Objective. Bringing together genomics, transcriptomics, proteomics, and other omics technologies is an important step towards developing highly personalized medicine. However, instrumentation has advances far beyond expectations and now we are able to generate data faster than it can be interpreted. Materials and Methods. We have developed PANDA (Pathway AND Annotation) Explorer, a visualization tool that integrates gene-level annotation in the context of biological pathways to help interpret complex data from disparate sources. PANDA is a web-based application that displays data in the context of well-studied pathways like KEGG, BioCarta, and PharmGKB. PANDA represents data/annotations as icons in the graph while maintaining the other data elements (i.e., other columns for the table of annotations). Custom pathways from underrepresented diseases can be imported when existing data sources are inadequate. PANDA also allows sharing annotations among collaborators. Results. In our first use case, we show how easy it is to view supplemental data from a manuscript in the context of a user's own data. Another use-case is provided describing how PANDA was leveraged to design a treatment strategy from the somatic variants found in the tumor of a patient with metastatic sarcomatoid renal cell carcinoma. Conclusion. PANDA facilitates the interpretation of gene-centric annotations by visually integrating this information with context of biological pathways. The application can be downloaded or used directly from our website: http://bioinformaticstools.mayo.edu/research/panda-viewer/. PMID- 26038727 TI - For 481 biomedical open access journals, articles are not searchable in the Directory of Open Access Journals nor in conventional biomedical databases. AB - Background. Open access (OA) journals allows access to research papers free of charge to the reader. Traditionally, biomedical researchers use databases like MEDLINE and EMBASE to discover new advances. However, biomedical OA journals might not fulfill such databases' criteria, hindering dissemination. The Directory of Open Access Journals (DOAJ) is a database exclusively listing OA journals. The aim of this study was to investigate DOAJ's coverage of biomedical OA journals compared with the conventional biomedical databases. Methods. Information on all journals listed in four conventional biomedical databases (MEDLINE, PubMed Central, EMBASE and SCOPUS) and DOAJ were gathered. Journals were included if they were (1) actively publishing, (2) full OA, (3) prospectively indexed in one or more database, and (4) of biomedical subject. Impact factor and journal language were also collected. DOAJ was compared with conventional databases regarding the proportion of journals covered, along with their impact factor and publishing language. The proportion of journals with articles indexed by DOAJ was determined. Results. In total, 3,236 biomedical OA journals were included in the study. Of the included journals, 86.7% were listed in DOAJ. Combined, the conventional biomedical databases listed 75.0% of the journals; 18.7% in MEDLINE; 36.5% in PubMed Central; 51.5% in SCOPUS and 50.6% in EMBASE. Of the journals in DOAJ, 88.7% published in English and 20.6% had received impact factor for 2012 compared with 93.5% and 26.0%, respectively, for journals in the conventional biomedical databases. A subset of 51.1% and 48.5% of the journals in DOAJ had articles indexed from 2012 and 2013, respectively. Of journals exclusively listed in DOAJ, one journal had received an impact factor for 2012, and 59.6% of the journals had no content from 2013 indexed in DOAJ. Conclusions. DOAJ is the most complete registry of biomedical OA journals compared with five conventional biomedical databases. However, DOAJ only indexes articles for half of the biomedical journals listed, making it an incomplete source for biomedical research papers in general. PMID- 26038726 TI - Identification of miR-194-5p as a potential biomarker for postmenopausal osteoporosis. AB - The incidence of osteoporosis is high in postmenopausal women due to altered estrogen levels and continuous calcium loss that occurs with aging. Recent studies have shown that microRNAs (miRNAs) are involved in the development of osteoporosis. These miRNAs may be used as potential biomarkers to identify women at a high risk for developing the disease. In this study, whole blood samples were collected from 48 postmenopausal Chinese women with osteopenia or osteoporosis and pooled into six groups according to individual T-scores. A miRNA microarray analysis was performed on pooled blood samples to identify potential miRNA biomarkers for postmenopausal osteoporosis. Five miRNAs (miR-130b-3p, -151a 3p, -151b, -194-5p, and -590-5p) were identified in the microarray analysis. These dysregulated miRNAs were subjected to a pathway analysis investigating whether they were involved in regulating osteoporosis-related pathways. Among them, only miR-194-5p was enriched in multiple osteoporosis-related pathways. Enhanced miR-194-5p expression in women with osteoporosis was confirmed by quantitative reverse transcription-polymerase chain reaction analysis. For external validation, a significant correlation between the expression of miR-194 5p and T-scores was found in an independent patient collection comprised of 24 postmenopausal women with normal bone mineral density, 30 postmenopausal women with osteopenia, and 32 postmenopausal women with osteoporosis (p < 0.05). Taken together, the present findings suggest that miR-194-5p may be a viable miRNA biomarker for postmenopausal osteoporosis. PMID- 26038728 TI - Bird biodiversity assessments in temperate forest: the value of point count versus acoustic monitoring protocols. AB - Effective monitoring programs for biodiversity are needed to assess trends in biodiversity and evaluate the consequences of management. This is particularly true for birds and faunas that occupy interior forest and other areas of low human population density, as these are frequently under-sampled compared to other habitats. For birds, Autonomous Recording Units (ARUs) have been proposed as a supplement or alternative to point counts made by human observers to enhance monitoring efforts. We employed two strategies (i.e., simultaneous-collection and same-season) to compare point count and ARU methods for quantifying species richness and composition of birds in temperate interior forests. The simultaneous collection strategy compares surveys by ARUs and point counts, with methods matched in time, location, and survey duration such that the person and machine simultaneously collect data. The same-season strategy compares surveys from ARUs and point counts conducted at the same locations throughout the breeding season, but methods differ in the number, duration, and frequency of surveys. This second strategy more closely follows the ways in which monitoring programs are likely to be implemented. Site-specific estimates of richness (but not species composition) differed between methods; however, the nature of the relationship was dependent on the assessment strategy. Estimates of richness from point counts were greater than estimates from ARUs in the simultaneous-collection strategy. Woodpeckers in particular, were less frequently identified from ARUs than point counts with this strategy. Conversely, estimates of richness were lower from point counts than ARUs in the same-season strategy. Moreover, in the same-season strategy, ARUs detected the occurrence of passerines at a higher frequency than did point counts. Differences between ARU and point count methods were only detected in site-level comparisons. Importantly, both methods provide similar estimates of species richness and composition for the region. Consequently, if single visits to sites or short-term monitoring are the goal, point counts will likely perform better than ARUs, especially if species are rare or vocalize infrequently. However, if seasonal or annual monitoring of sites is the goal, ARUs offer a viable alternative to standard point-count methods, especially in the context of large-scale or long-term monitoring of temperate forest birds. PMID- 26038729 TI - Sex differences in human gregariousness. AB - Research on human sociality rarely includes kinship, social structure, sex, and familiarity, even though these variables influence sociality in non-human primates. However, cross-cultural ethnographic and observational studies with humans indicate that, beginning after age 5 years, males and females form differing social structures with unrelated individuals in a community. Specifically, compared with females, human males exhibit greater tolerance for and form larger, interconnected groups of peers which we term "gregariousness." To examine sex differences in gregariousness early in life when children first interact with peers without adult supervision, 3- to 6-year-old children were given the choice to enter one of three play areas: an empty one, one with an adult, or one with a familiar, same-sex peer. More males than females initially chose the play area with the same-sex peer, especially after age 5 years. Sex differences in gregariousness with same-sex peers likely constitute one facet of human sociality. PMID- 26038730 TI - Causes of mortality across different immigrant groups in Northeastern Italy. AB - Background. Despite massive immigration towards Southern Europe in the last two decades, data on mortality by cause among immigrants in Italy are scarce. The aim of this study was to investigate mortality from all and from specific causes of death among immigrants residing in the Veneto Region (Northeastern Italy). Methods. Mortality records for the period 2008-2013 were extracted from the regional archive of causes of death, whereas population data were obtained from the 2011 Italian census. Immigrants were grouped by area of provenience based on the information on country of citizenship available both in mortality and census data. Standardized Mortality Ratios (SMR) with 95% Confidence Intervals (CI) were computed for the period 2008-2013 in subjects aged 20-59 years, with rates of Italian citizens as a reference. Results. Overall mortality was reduced both in male (SMR 0.86, CI [0.80-0.92]) and female immigrants (SMR 0.72, CI [0.65-0.78]), although an increased risk was observed for subjects from Sub-Saharan Africa. Significantly raised SMR for circulatory diseases were found among Sub-Saharan Africans and Southern Asians in both genders. Sub-Saharan Africans experienced a higher risk of death, especially from cerebrovascular diseases: SMR 4.78 (CI [2.67-7.89]) and SMR 6.09 (CI [1.96-14.2]) in males and females, respectively. Among Southern Asians, the increase in mortality from ischemic heart diseases reached statistical significance in males (SMR 2.53, CI [1.42-4.18]). In spite of a lower risk of death for all neoplasms combined, mortality from cancer of cervix uteri was increased among immigrants (SMR 2.61, CI [1.35-4.56]), as well as for other cancer sites in selected immigrant groups. A raised mortality was found for infectious diseases in Sub-Saharan Africans (both genders), and for transport accidents among females from Eastern Europe. Conclusion. Our study showed great variations in mortality by cause and area of provenience among immigrants resident in the Veneto Region and highlighted specific health issues that should be addressed through tailored efforts in chronic diseases prevention. PMID- 26038732 TI - Evolution of heritable behavioural differences in a model of social division of labour. AB - The spectacular diversity of personality and behaviour of animals and humans has evoked many hypotheses intended to explain its developmental and evolutionary background. Although the list of the possible contributing mechanisms seems long, we propose that an underemphasised explanation is the division of labour creating negative frequency dependent selection. We use analytical and numerical models of social division of labour to show how selection can create consistent and heritable behavioural differences in a population, where randomly sampled individuals solve a collective task together. We assume that the collective task needs collaboration of individuals performing one of the two possible subtasks. The total benefit of the group is highest when the ratio of different subtasks is closest to 1. The probability of choosing one of the two costly subtasks and the costs assigned to them are under selection. By using adaptive dynamics we show that if a trade-off between the costs of the subtasks is strong enough, then evolution leads to coexistence of specialized individuals performing one of the subtasks with high probability and low cost. Our analytical results were verified and extended by numerical simulations. PMID- 26038731 TI - Trans-species polymorphism at antimicrobial innate immunity cathelicidin genes of Atlantic cod and related species. AB - Natural selection, the most important force in evolution, comes in three forms. Negative purifying selection removes deleterious variation and maintains adaptations. Positive directional selection fixes beneficial variants, producing new adaptations. Balancing selection maintains variation in a population. Important mechanisms of balancing selection include heterozygote advantage, frequency-dependent advantage of rarity, and local and fluctuating episodic selection. A rare pathogen gains an advantage because host defenses are predominantly effective against prevalent types. Similarly, a rare immune variant gives its host an advantage because the prevalent pathogens cannot escape the host's apostatic defense. Due to the stochastic nature of evolution, neutral variation may accumulate on genealogical branches, but trans-species polymorphisms are rare under neutrality and are strong evidence for balancing selection. Balanced polymorphism maintains diversity at the major histocompatibility complex (MHC) in vertebrates. The Atlantic cod is missing genes for both MHC-II and CD4, vital parts of the adaptive immune system. Nevertheless, cod are healthy in their ecological niche, maintaining large populations that support major commercial fisheries. Innate immunity is of interest from an evolutionary perspective, particularly in taxa lacking adaptive immunity. Here, we analyze extensive amino acid and nucleotide polymorphisms of the cathelicidin gene family in Atlantic cod and closely related taxa. There are three major clusters, Cath1, Cath2, and Cath3, that we consider to be paralogous genes. There is extensive nucleotide and amino acid allelic variation between and within clusters. The major feature of the results is that the variation clusters by alleles and not by species in phylogenetic trees and discriminant analysis of principal components. Variation within the three groups shows trans-species polymorphism that is older than speciation and that is suggestive of balancing selection maintaining the variation. Using Bayesian and likelihood methods positive and negative selection is evident at sites in the conserved part of the genes and, to a larger extent, in the active part which also shows episodic diversifying selection, further supporting the argument for balancing selection. PMID- 26038733 TI - Earthworm assemblages in different intensity of agricultural uses and their relation to edaphic variables. AB - The objective of this study was to relate earthworm assemblage structure with three different soil use intensities, and to indentify the physical, chemical, and microbiological soil variables that are associated to the observed differences. Three soil uses were evaluated: 1-Fifty year old naturalized grasslands, low use intensity; 2-Recent agricultural fields, intermediate use intensity, and 3-Fifty year old intensive agricultural fields, high use intensity. Three different sites for each soil use were evaluated from winter 2008 through summer 2011. Nine earthworm species were identified across all sampling sites. The sites shared five species: the native Microscolex dubius, and the introduced Aporrectodea caliginosa, A. rosea, Octalasion cyaneum, and O. lacteum, but they differed in relative abundance by soil use. The results show that the earthworm community structure is linked to and modulated by soil properties. Both species abundance and diversity showed significant differences depending on soil use intensity. A principal component analysis showed that species composition is closely related to the environmental variability. The ratio of native to exotic species was significantly lower in the intensive agricultural system when compared to the other two, lower disturbance systems. Microscolex dubius abundance was related to naturalized grasslands along with soil Ca, pH, mechanical resistance, and microbial respiration. Aporrectodea caliginosa abundance was related to high K levels, low enzymatic activity, slightly low pH, low Ca, and appeared related to the highly disturbed environment. Eukerria stagnalis and Aporrectodea rosea, commonly found in the recent agricultural system, were related to high soil moisture condition, low pH, low Ca and low enzymatic activity. These results show that earthworm assemblages can be good indicators of soil use intensities. In particular, Microscolex dubius, Aporrectodea caliginosa, and Aporrectodea rosea, showed different temporal patterns and species associations, due to the changes in soil properties attributable to soil use intensity, defined as the amount and type of agricultural operations. PMID- 26038735 TI - Have the "mega-journals" reached the limits to growth? AB - A "mega-journal" is a new type of scientific journal that publishes freely accessible articles, which have been peer reviewed for scientific trustworthiness, but leaves it to the readers to decide which articles are of interest and importance to them. In the wake of the phenomenal success of PLOS ONE, several other publishers have recently started mega-journals. This article presents the evolution of mega-journals since 2010 in terms of article publication rates. The fastest growth seems to have ebbed out at around 35,000 annual articles for the 14 journals combined. Acceptance rates are in the range of 50-70%, and speed of publication is around 3-5 months. Common features in mega journals are alternative impact metrics, easy reusability of figures and data, post-publication discussions and portable reviews from other journals. PMID- 26038734 TI - ACE and UCP2 gene polymorphisms and their association with baseline and exercise related changes in the functional performance of older adults. AB - Maintaining high levels of physical function is an important aspect of successful ageing. While muscle mass and strength contribute to functional performance in older adults, little is known about the possible genetic basis for the heterogeneity of physical function in older adults and in how older adults respond to exercise. Two genes that have possible roles in determining levels of muscle mass, strength and function in young and older adults are angiotensin converting enzyme (ACE) and mitochondrial uncoupling protein 2 (UCP2). This study examined whether polymorphisms in these two individual genes were associated with baseline functional performance levels and/or the training-related changes following exercise in previously untrained older adults. Five-eight Caucasian older adults (mean age 69.8 years) with no recent history of resistance training enrolled in a 12 week program of resistance, balance and cardiovascular exercises aimed at improving functional performance. Performance in 6 functional tasks was recorded at baseline and after 12 weeks. Genomic DNA was assayed for the ACE intron 16 insertion/deletion (I/D) and the UCP2 G-866A polymorphism. Baseline differences among genotype groups were tested using analysis of variance. Genotype differences in absolute and relative changes in physical function among the exercisers were tested using a general linear model, adjusting for age and gender. The genotype frequencies for each of the studied polymorphisms conformed to the Hardy-Weinberg equilibrium. The ACE I/D genotype was significantly associated with mean baseline measures of handgrip strength (II 30.9 +/- 3.01 v. ID 31.7 +/- 1.48 v. DD 29.3 +/- 2.18 kg, p < 0.001), 8ft Up and Go time (II 6.45 +/- 0.48 v. ID/DD 4.41 +/- 0.19 s, p < 0.001) and 6 min walk distance (II 458 +/- 28.7 v. ID/DD 546 +/- 12.1m, p = 0.008). The UCP2 G-866A genotype was also associated with baseline 8ft Up and Go time (GG 5.45 +/- 0.35 v. GA 4.47 +/- 0.26 v. AA 3.89 +/- 0.71 s, p = 0.045). After 12 weeks of training, a significant difference between UCP2 G-886A genotype groups for change in 8ft Up and Go time was detected (GG -0.68 +/- 0.17 v. GA -0.10 +/- 0.14 v. AA +0.05 +/- 0.31 s, p = 0.023). While several interesting and possibly consistent associations with older adults' baseline functional performance were found for the ACE and UCP2 polymorphisms, we found no strong evidence of genetic associations with exercise responses in this study. The relative equivalence of some of these training response findings to the literature may have reflected the current study's focus on physical function rather than just strength, the relatively high levels of baseline function for some genotype groups as well as the greater statistical power for detecting baseline differences than the training-related changes. PMID- 26038736 TI - Genetic approaches to the conservation of migratory bats: a study of the eastern red bat (Lasiurus borealis). AB - Documented fatalities of bats at wind turbines have raised serious concerns about the future impacts of increased wind power development on populations of migratory bat species. However, for most bat species we have no knowledge of the size of populations and their demographic trends, the degree of structuring into discrete subpopulations, and whether different subpopulations use spatially segregated migratory routes. Here, we utilize genetic data from eastern red bats (Lasiurus borealis), one of the species most highly affected by wind power development in North America, to (1) evaluate patterns of population structure across the landscape, (2) estimate effective population size (Ne ), and (3) assess signals of growth or decline in population size. Using data on both nuclear and mitochondrial DNA variation, we demonstrate that this species forms a single, panmictic population across their range with no evidence for the historical use of divergent migratory pathways by any portion of the population. Further, using coalescent estimates we estimate that the effective size of this population is in the hundreds of thousands to millions of individuals. The high levels of gene flow and connectivity across the population of eastern red bats indicate that monitoring and management of eastern red bats must integrate information across the range of this species. PMID- 26038737 TI - VirSorter: mining viral signal from microbial genomic data. AB - Viruses of microbes impact all ecosystems where microbes drive key energy and substrate transformations including the oceans, humans and industrial fermenters. However, despite this recognized importance, our understanding of viral diversity and impacts remains limited by too few model systems and reference genomes. One way to fill these gaps in our knowledge of viral diversity is through the detection of viral signal in microbial genomic data. While multiple approaches have been developed and applied for the detection of prophages (viral genomes integrated in a microbial genome), new types of microbial genomic data are emerging that are more fragmented and larger scale, such as Single-cell Amplified Genomes (SAGs) of uncultivated organisms or genomic fragments assembled from metagenomic sequencing. Here, we present VirSorter, a tool designed to detect viral signal in these different types of microbial sequence data in both a reference-dependent and reference-independent manner, leveraging probabilistic models and extensive virome data to maximize detection of novel viruses. Performance testing shows that VirSorter's prophage prediction capability compares to that of available prophage predictors for complete genomes, but is superior in predicting viral sequences outside of a host genome (i.e., from extrachromosomal prophages, lytic infections, or partially assembled prophages). Furthermore, VirSorter outperforms existing tools for fragmented genomic and metagenomic datasets, and can identify viral signal in assembled sequence (contigs) as short as 3kb, while providing near-perfect identification (>95% Recall and 100% Precision) on contigs of at least 10kb. Because VirSorter scales to large datasets, it can also be used in "reverse" to more confidently identify viral sequence in viral metagenomes by sorting away cellular DNA whether derived from gene transfer agents, generalized transduction or contamination. Finally, VirSorter is made available through the iPlant Cyberinfrastructure that provides a web-based user interface interconnected with the required computing resources. VirSorter thus complements existing prophage prediction softwares to better leverage fragmented, SAG and metagenomic datasets in a way that will scale to modern sequencing. Given these features, VirSorter should enable the discovery of new viruses in microbial datasets, and further our understanding of uncultivated viral communities across diverse ecosystems. PMID- 26038738 TI - Neutralizing antibody responses to enterovirus and adenovirus in healthy adults in China. AB - Hand, foot and mouth disease (HFMD) is an important public health problem that has emerged over the past several years. HFMD predominantly infects children under seven years old and occasionally causes severe disease in adults. Among the enteroviruses, enterovirus 71 (EV71) and coxsackievirus 16 (CA16) are the major causative agents of HFMD. In addition, adenovirus cocirculates with enterovirus and has become a possible additional pathogenic factor for HFMD in some cases. Here, we have investigated the neutralizing antibody responses to both enterovirus and adenovirus in adults, with the aim of exploring the prevalence trends of these viruses and the nature of protective immunity in humans to these viral infections. Sera from 391 healthy adults from 21 provinces and cities in China were tested for the presence of antibodies against EV71, CA16, adenovirus human serotype 5 (AdHu5) and chimpanzee adenovirus pan7 (AdC7) using neutralization tests. High seroprevalence rates of EV71, CA16 and AdHu5 were found in the population (85.7%, 58.8% and 74.2%, respectively). The coseropositivity rate of these three viruses was 39.4% (154 of 391), with median neutralizing antibody titers of 80, 40 and 640, respectively, and the neutralizing antibody titer for EV71 was found to be correlated with those of CA16 and AdHu5. AdC7 was found to be a rare adenovirus serotype in the human population, with a seropositivity rate of 11.8%, suggesting that it could be a good choice for a vaccine carrier that could be used in vaccine development. PMID- 26038739 TI - Emerging sporotrichosis is driven by clonal and recombinant Sporothrix species. AB - Sporotrichosis, caused by agents of the fungal genus Sporothrix, occurs worldwide, but the infectious species are not evenly distributed. Sporothrix propagules usually gain entry into the warm-blooded host through minor trauma to the skin from contaminated plant debris or through scratches or bites from felines carrying the disease, generally in the form of outbreaks. Over the last decade, sporotrichosis has changed from a relatively obscure endemic infection to an epidemic zoonotic health problem. We evaluated the impact of the feline host on the epidemiology, spatial distribution, prevalence and genetic diversity of human sporotrichosis. Nuclear and mitochondrial markers revealed large structural genetic differences between S. brasiliensis and S. schenckii populations, suggesting that the interplay of host, pathogen and environment has a structuring effect on the diversity, frequency and distribution of Sporothrix species. Phylogenetic data support a recent habitat shift within S. brasiliensis from plant to cat that seems to have occurred in southeastern Brazil and is responsible for its emergence. A clonal structure was found in the early expansionary phase of the cat-human epidemic. However, the prevalent recombination structure in the plant-associated pathogen S. schenckii generates a diversity of genotypes that did not show any significant increase in frequency as etiological agents of human infection over time. These results suggest that closely related pathogens can follow different strategies in epidemics. Thus, species-specific types of transmission may require distinct public health strategies for disease control. PMID- 26038740 TI - Detection of Rickettsia amblyommii in ticks collected from Missouri, USA. PMID- 26038741 TI - A neonatal gnotobiotic pig model of human enterovirus 71 infection and associated immune responses. AB - Vaccine development and pathogenesis studies for human enterovirus 71 are limited by a lack of suitable animal models. Here, we report the development of a novel neonatal gnotobiotic pig model using the non-pig-adapted neurovirulent human enterovirus 71 strain BJ110, which has a C4 genotype. Porcine small intestinal epithelial cells, peripheral blood mononuclear cells and neural cells were infected in vitro. Oral and combined oral-nasal infection of 5-day-old neonatal gnotobiotic pigs with 5*10(8) fluorescence forming units (FFU) resulted in shedding up to 18 days post-infection, with viral titers in rectal swab samples peaking at 2.22*10(8) viral RNA copies/mL. Viral capsid proteins were detected in enterocytes within the small intestines on post-infection days (PIDs) 7 and 14. Additionally, viral RNA was detected in intestinal and extra-intestinal tissues, including the central nervous system, the lung and cardiac muscle. The infected neonatal gnotobiotic pigs developed fever, forelimb weakness, rapid breathing and some hand, foot and mouth disease symptoms. Flow cytometry analysis revealed increased frequencies of both CD4(+) and CD8(+) IFN-gamma-producing T cells in the brain and the blood on PID 14, but reduced frequencies were observed in the lung. Furthermore, high titers of serum virus-neutralizing antibodies were generated in both orally and combined oral-nasally infected pigs on PIDs 7, 14, 21 and 28. Together, these results demonstrate that neonatal gnotobiotic pigs represent a novel animal model for evaluating vaccines for human enterovirus 71 and for understanding the pathogenesis of this virus and the associated immune responses. PMID- 26038742 TI - Genetic diversity of Streptococcus pneumoniae causing meningitis and sepsis in Singapore during the first year of PCV7 implementation. AB - Streptococcus pneumoniae is a major cause of sepsis, meningitis and respiratory disease worldwide. Pneumococcal conjugate vaccines (PCVs) have now been implemented in many countries worldwide, including Singapore. To evaluate the effectiveness of these vaccines, pneumococcal surveillance studies are required. Detailed and unified pneumococcal epidemiology data are currently scarce in South East Asia. Thus, we present data on invasive pneumococcal (IPD) isolates from Singapore that could assist in evaluating the effectiveness of pneumococcal vaccine in Singapore. One hundred and fifty-nine invasive pneumococcal disease isolates were received by the National Public Health Laboratory in Singapore between June 2009 and August 2010. Isolates were characterized using serotyping and multilocus sequence typing. Twenty-four different serotypes were found, the most common of which were 19A, 3, 7F, 23F, 6B, 14, 8 and 19F (in rank order). One hundred and two sequence types were observed, of which 38 were novel due to new alleles or new combinations of already existing alleles. Based on the Simpson's Index of Diversity, serotypes 3, 6B and 19A were the most genetically diverse. Novel sequence types were more prevalent among conjugate vaccine serotypes 3, 19F and 23F and non-conjugate vaccine serotype 8, serogroup 15 and in non-typable isolates. We have demonstrated considerable genetic diversity among invasive pneumococci before and during the widespread use of conjugate vaccines in Singapore. Approximately half of all novel IPD clones identified in this study were non-conjugate vaccine serotypes. Although PCVs would target the most common serotypes, the high genetic diversity in non-vaccine serotypes would require further surveillance studies. PMID- 26038743 TI - A novel MLST sequence type discovered in the first fatal case of Laribacter hongkongensis bacteremia clusters with the sequence types of other human isolates. AB - Laribacter hongkongensis is a gram-negative, facultative anaerobic, motile, S shaped, asaccharolytic, urease-positive bacillus in the Neisseriaceae family of beta-proteobacteria. To date, all patients with L. hongkongensis infection have survived, including the two patients with L. hongkongensis bacteremia and patients with L. hongkongensis gastroenteritis. In this study, we describe the clinical, microbiological and molecular characterization of the first fatal case associated with L. hongkongensis bacteremia in a patient with colonic carcinoma that metastasized to the liver. The identity of the isolate was confirmed via phenotypic tests and 16S rRNA gene sequencing. Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), using the Bruker database extended with L. hongkongensis reference strains, also identified the isolate as L. hongkongensis, with a top match score of 2.473. Multilocus sequence typing revealed a new sequence type (ST), and phylogenetic analysis and eBURST demonstrated unambiguously that the ST of the isolate was clustered with two other STs found exclusively in human patients, consistent with the theory that some clones of L. hongkongensis could be more virulent than others. Underlying liver diseases and ascites potentially represent distinct risk factors for invasive L. hongkongensis infection. More widespread use of MALDI-TOF MS for identification and improvements of selective media should facilitate the identification of more cases of L. hongkongensis infection. PMID- 26038744 TI - Assessing control bundles for Clostridium difficile: a review and mathematical model. AB - Clostridium difficile is the leading cause of infectious diarrhea in hospitalized patients. Integrating several infection control and prevention methods is a burgeoning strategy for reducing disease incidence in healthcare settings. We present an up-to-date review of the literature on 'control bundles' used to mitigate the transmission of this pathogen. All clinical studies of control bundles reported substantial reductions in disease rates, in the order of 33% 61%. Using a biologically realistic mathematical model we then simulated the efficacy of different combinations of the most prominent control methods: stricter antimicrobial stewardship; the administering of probiotics/intestinal microbiota transplantation; and improved hygiene and sanitation. We also assessed the health gains that can be expected from reducing the average length of stay of inpatients. In terms of reducing the rates of colonization, all combinations had the potential to give rise to marked improvements. For example, halving the number of inpatients on broad-spectrum antimicrobials combined with prescribing probiotics or intestinal microbiota transplantation could cut pathogen carriage by two-thirds. However, in terms of symptomatic disease incidence reduction, antimicrobials, probiotics and intestinal microbiota transplantation proved substantially less effective. Eliminating within-ward transmission by improving sanitation and reducing average length of stay (from six to three days) yielded the most potent symptomatic infection control combination, cutting rates down from three to less than one per 1000 hospital bed days. Both the empirical and theoretical exploration of C. difficile control combinations presented in the current study highlights the potential gains that can be achieved through strategically integrated infection control. PMID- 26038746 TI - Characterization of a G1P[8] rotavirus causing an outbreak of gastroenteritis in the Northern Territory, Australia, in the vaccine era. AB - In 2010, a large outbreak of rotavirus gastroenteritis occurred in the Alice Springs region of the Northern Territory, Australia. The outbreak occurred 43 months after the introduction of the G1P[8] rotavirus vaccine Rotarix((r)). Forty three infants were hospitalized during the outbreak and analysis of fecal samples from each infant revealed a G1P[8] rotavirus strain. The outbreak strain was adapted to cell culture and neutralization assays were performed using VP7 and VP4 neutralizing monoclonal antibodies. The outbreak strain exhibited a distinct neutralization resistance pattern compared to the Rotarix((r)) vaccine strain. Whole genome sequencing of the 2010 outbreak virus strain demonstrated numerous amino acid differences compared to the Rotarix((r)) vaccine strain in the characterized neutralization epitopes of the VP7 and VP4 proteins. Phylogenetic analysis of the outbreak strain revealed a close genetic relationship to global strains, in particular RVA/Human-wt/BEL/BE0098/2009/G1P[8] and RVA/Human wt/BEL/BE00038/2008/G1P[8] for numerous genes. The 2010 outbreak strain was likely introduced from a globally circulating population of strains rather than evolving from an endemic Australian strain. The outbreak strain possessed antigenic differences in the VP7 and VP4 proteins compared to the Rotarix((r)) vaccine strain. The outbreak was associated with moderate vaccine coverage and possibly low vaccine take in the population. PMID- 26038747 TI - Identification of novel activity against Borrelia burgdorferi persisters using an FDA approved drug library. AB - Although antibiotic treatment for Lyme disease is effective in the majority of cases, especially during the early phase of the disease, a minority of patients suffer from post-treatment Lyme disease syndrome (PTLDS). It is unclear what mechanisms drive this problem, and although slow or ineffective killing of Borrelia burgdorferi has been suggested as an explanation, there is a lack of evidence that viable organisms are present in PTLDS. Although not a clinical surrogate, insight may be gained by examining stationary-phase in vitro Borrelia burgdorferi persisters that survive treatment with the antibiotics doxycycline and amoxicillin. To identify drug candidates that can eliminate B. burgdorferi persisters more effectively, we screened an Food and Drug Administration (FDA) approved drug library consisting of 1524 compounds against stationary-phase B. burgdorferi by using a newly developed high throughput SYBR Green I/propidium iodide (PI) assay. We identified 165 agents approved for use in other disease conditions that had more activity than doxycycline and amoxicillin against B. burgdorferi persisters. The top 27 drug candidates from the 165 hits were confirmed to have higher anti-persister activity than the current frontline antibiotics. Among the top 27 confirmed drug candidates from the 165 hits, daptomycin, clofazimine, carbomycin, sulfa drugs (e.g., sulfamethoxazole), and certain cephalosporins (e.g. cefoperazone) had the highest anti-persister activity. In addition, some drug candidates, such as daptomycin and clofazimine (which had the highest activity against non-growing persisters), had relatively poor activity or a high minimal inhibitory concentration (MIC) against growing B. burgdorferi. Our findings may have implications for the development of a more effective treatment for Lyme disease and for the relief of long-term symptoms that afflict some Lyme disease patients. PMID- 26038745 TI - Streptococcus suis, an important pig pathogen and emerging zoonotic agent-an update on the worldwide distribution based on serotyping and sequence typing. AB - Streptococcus suis is an important pathogen causing economic problems in the pig industry. Moreover, it is a zoonotic agent causing severe infections to people in close contact with infected pigs or pork-derived products. Although considered sporadic in the past, human S. suis infections have been reported during the last 45 years, with two large outbreaks recorded in China. In fact, the number of reported human cases has significantly increased in recent years. In this review, we present the worldwide distribution of serotypes and sequence types (STs), as determined by multilocus sequence typing, for pigs (between 2002 and 2013) and humans (between 1968 and 2013). The methods employed for S. suis identification and typing, the current epidemiological knowledge regarding serotypes and STs and the zoonotic potential of S. suis are discussed. Increased awareness of S. suis in both human and veterinary diagnostic laboratories and further establishment of typing methods will contribute to our knowledge of this pathogen, especially in regions where complete and/or recent data is lacking. More research is required to understand differences in virulence that occur among S. suis strains and if these differences can be associated with specific serotypes or STs. PMID- 26038749 TI - Receptors for enterovirus 71. AB - Enterovirus 71 (EV71) is one of the major causative agents of hand, foot and mouth disease (HFMD). Occasionally, EV71 infection is associated with severe neurological diseases, such as acute encephalitis, acute flaccid paralysis and cardiopulmonary failure. Several molecules act as cell surface receptors that stimulate EV71 infection, including scavenger receptor B2 (SCARB2), P-selectin glycoprotein ligand-1 (PSGL-1), sialylated glycan, heparan sulfate and annexin II (Anx2). SCARB2 plays critical roles in attachment, viral entry and uncoating, and it can facilitate efficient EV71 infection. The three-dimensional structures of the mature EV71 virion, procapsid and empty capsid, as well as the exofacial domain of SCARB2, have been elucidated. This structural information has greatly increased our understanding of the early steps of EV71 infection. Furthermore, SCARB2 plays essential roles in the development of EV71 neurological disease in vivo. Adult mice are not susceptible to infection by EV71, but transgenic mice that express human SCARB2 become susceptible to EV71 infection and develop similar neurological diseases to those found in humans. This mouse model facilitates the in vivo investigation of many issues related to EV71. PSGL-1, sialylated glycan, heparan sulfate and Anx2 are attachment receptors, which enhance viral infection by retaining the virus on the cell surface. These molecules also contribute to viral infection in vitro either by interacting with SCARB2 or independently of SCARB2. However, the cooperative effects of these receptors, and their contribution to EV71 pathogenicity in vivo, remain to be elucidated. PMID- 26038750 TI - Emergence of human babesiosis along the border of China with Myanmar: detection by PCR and confirmation by sequencing. AB - Babesiosis is a tick-borne, zoonotic disease caused by Babesia spp. Two cases of babesiosis were detected by nested polymerase chain reaction (PCR) in Yunnan province, China, and further confirmed by molecular assay. The blood smears showed intraerythrocytic ring form and tetrads typical of small B. microti. In both cases, the rapid diagnostic test (RDT) ruled out the possibility of co infections with malaria. Neither case was initially diagnosed because of the low Babesia parasitemia. These two cases of babesiosis in areas along the Myanmar China border pose the question of the emergence of this under recognized infection in countries or areas where malaria is endemic. PMID- 26038748 TI - The impact of the interferon-lambda family on the innate and adaptive immune response to viral infections. AB - Type-III interferons (IFN-lambda, IFNL) are the most recently described family of IFNs. This family of innate cytokines are increasingly being ascribed pivotal roles in host-pathogen interactions. Herein, we will review the accumulating evidence detailing the immune biology of IFNL during viral infection, and the implications of this novel information on means to advance the development of therapies and vaccines against existing and emerging pathogens. IFNLs exert antiviral effects via induction of IFN-stimulated genes. Common single nucleotide polymorphisms (SNPs) in the IFNL3, IFNL4 and the IFNL receptor alpha-subunit genes have been strongly associated with IFN-alpha-based treatment of chronic hepatitis C virus infection. The clinical impact of these SNPs may be dependent on the status of viral infection (acute or chronic) and the potential to develop viral resistance. Another important function of IFNLs is macrophage and dendritic cell polarization, which prime helper T-cell activation and proliferation. It has been demonstrated that IFNL increase Th1- and reduce Th2-cytokines. Therefore, can such SNPs affect the IFNL signaling and thereby modulate the Th1/Th2 balance during infection? In turn, this may influence the subsequent priming of cytotoxic T cells versus antibody-secreting B cells, with implications for the breadth and durability of the host response. PMID- 26038751 TI - Complex temporal climate signals drive the emergence of human water-borne disease. AB - Predominantly occurring in developing parts of the world, Buruli ulcer is a severely disabling mycobacterium infection which often leads to extensive necrosis of the skin. While the exact route of transmission remains uncertain, like many tropical diseases, associations with climate have been previously observed and could help identify the causative agent's ecological niche. In this paper, links between changes in rainfall and outbreaks of Buruli ulcer in French Guiana, an ultraperipheral European territory in the northeast of South America, were identified using a combination of statistical tests based on singular spectrum analysis, empirical mode decomposition and cross-wavelet coherence analysis. From this, it was possible to postulate for the first time that outbreaks of Buruli ulcer can be triggered by combinations of rainfall patterns occurring on a long (i.e., several years) and short (i.e., seasonal) temporal scale, in addition to stochastic events driven by the El Nino-Southern Oscillation that may disrupt or interact with these patterns. Long-term forecasting of rainfall trends further suggests the possibility of an upcoming outbreak of Buruli ulcer in French Guiana. PMID- 26038752 TI - The vaccine potential of Bordetella pertussis biofilm-derived membrane proteins. AB - Pertussis is an infectious respiratory disease of humans caused by the gram negative pathogen Bordetella pertussis. The use of acellular pertussis vaccines (aPs) which induce immunity of relative short duration and the emergence of vaccine-adapted strains are thought to have contributed to the recent resurgence of pertussis in industrialized countries despite high vaccination coverage. Current pertussis vaccines consist of antigens derived from planktonic bacterial cultures. However, recent studies have shown that biofilm formation represents an important aspect of B. pertussis infection, and antigens expressed during this stage may therefore be potential targets for vaccination. Here we provide evidence that vaccination of mice with B. pertussis biofilm-derived membrane proteins protects against infection. Subsequent proteomic analysis of the protein content of biofilm and planktonic cultures yielded 11 proteins which were >=three fold more abundant in biofilms, of which Bordetella intermediate protein A (BipA) was the most abundant, surface-exposed protein. As proof of concept, mice were vaccinated with recombinantly produced BipA. Immunization significantly reduced colonization of the lungs and antibodies to BipA were found to efficiently opsonize bacteria. Finally, we confirmed that bipA is expressed during respiratory tract infection of mice, and that anti-BipA antibodies are present in the serum of convalescent whooping cough patients. Together, these data suggest that biofilm proteins and in particular BipA may be of interest for inclusion into future pertussis vaccines. PMID- 26038754 TI - Lessons to be learned from the ebolavirus outbreak in West Africa. PMID- 26038753 TI - Aspartate decarboxylase (PanD) as a new target of pyrazinamide in Mycobacterium tuberculosis. AB - Pyrazinamide (PZA) is a frontline anti-tuberculosis drug that plays a crucial role in the treatment of both drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). PZA is a prodrug that is converted to its active form, pyrazinoic acid (POA), by a nicotinamidase/pyrazinamidase encoded by the pncA gene, the mutation of which is the major cause of PZA resistance. Although RpsA (ribosomal protein S1, involved in trans-translation) has recently been shown to be a target of POA/PZA, whole-genome sequencing has identified mutations in the panD gene encoding aspartate decarboxylase in PZA-resistant strains lacking pncA and rpsA mutations. To gain more insight into a possible new target of PZA, we isolated 30 POA-resistant mutants lacking mutations in pncA and rpsA from M. tuberculosis in vitro, and whole-genome sequencing of 3 mutants identified various mutations in the panD gene. Additionally, sequencing analysis revealed that the remaining 27 POA-resistant mutants all harbored panD mutations affecting the C-terminus of the PanD protein, with PanD M117I being the most frequent mutation (24/30, 80%). Conditional overexpression of panD from M. tuberculosis, M. smegmatis or E. coli, or of M. tuberculosis mutant PanD M117I, all conferred resistance to POA and PZA in M. tuberculosis. beta-alanine and pantothenate, which are downstream products of PanD, were found to antagonize the antituberculosis activity of POA. In addition, the activity of the M. tuberculosis PanD enzyme was inhibited by POA at therapeutically relevant concentrations in a concentration-dependent manner but was not inhibited by the prodrug PZA or the control compound nicotinamide. These findings suggest that PanD represents a new target of PZA/POA. These results have implications for a better understanding of this peculiar persister drug and for the design of new drugs targeting M. tuberculosis persisters for improved treatment. PMID- 26038755 TI - The approved pediatric drug suramin identified as a clinical candidate for the treatment of EV71 infection-suramin inhibits EV71 infection in vitro and in vivo. AB - Enterovirus 71 (EV71) causes severe central nervous system infections, leading to cardiopulmonary complications and death in young children. There is an urgent unmet medical need for new pharmaceutical agents to control EV71 infections. Using a multidisciplinary approach, we found that the approved pediatric antiparasitic drug suramin blocked EV71 infectivity by a novel mechanism of action that involves binding of the naphtalentrisulonic acid group of suramin to the viral capsid. Moreover, we demonstrate that when suramin is used in vivo at doses equivalent to or lower than the highest dose already used in humans, it significantly decreased mortality in mice challenged with a lethal dose of EV71 and peak viral load in adult rhesus monkeys. Thus, suramin inhibits EV71 infection by neutralizing virus particles prior to cell attachment. Consequently, these findings identify suramin as a clinical candidate for further development as a therapeutic or prophylactic treatment for severe EV71 infection. PMID- 26038758 TI - Regulatory science accelerates the development of biotechnology drugs and vaccines by NIFDC. AB - The Chinese National Institutes for Food and Drug Control (NIFDC) is the national laboratory responsible for the quality control of pharmaceutical products. In recent years, to ensure the quality of biological products and improve the research and development (R&D) of new biological drugs and vaccines, NIFDC conducted a series of regulatory science studies on key technologies for quality control and evaluation, and established a quality control and evaluation platform for biological drugs and vaccines. These studies accelerated the R&D of the biological drugs and vaccines in China and assured their safety and efficacy. In this paper, NIFDC's duties and achievements in the biological drug and vaccine field are summarized. PMID- 26038757 TI - Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance. AB - Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV). Extensive research over the past decades has unveiled the important role of cccDNA in the natural history and antiviral treatment of chronic HBV infection. cccDNA can persist in patients recovering from acute HBV infection for decades. This explains why HBV reactivation occasionally occurs in patients with resolved hepatitis B receiving intensive immunosuppressive agents. In addition, although advances in antiviral treatment dramatically improve the adverse outcomes of chronic hepatitis B (CHB), accumulating evidence demonstrates that current antiviral treatments alone, be they nucleos(t)ide analogs (NAs) or interferon (IFN), fail to cure most CHB patients because of the persistent cccDNA. NA suppresses HBV replication by directly inhibiting viral polymerase, while IFN enhances host immunity against HBV infection. Viral rebound often occurs after discontinuation of antiviral treatment. The loss of cccDNA can be induced by non-cytolytic destruction of cccDNA or immune-mediated killing of infected hepatocytes. It is known that NA has no direct effect on viral transcription or cccDNA stability. Therefore, the long half-life of hepatocytes leads to a very slow decline in cccDNA in patients under antiviral therapy. Novel antiviral agents targeting cccDNA or cccDNA-containing hepatocytes are thus required for curing chronic HBV infection. PMID- 26038756 TI - Oncogenes and RNA splicing of human tumor viruses. AB - Approximately 10.8% of human cancers are associated with infection by an oncogenic virus. These viruses include human papillomavirus (HPV), Epstein-Barr virus (EBV), Merkel cell polyomavirus (MCV), human T-cell leukemia virus 1 (HTLV 1), Kaposi's sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV) and hepatitis B virus (HBV). These oncogenic viruses, with the exception of HCV, require the host RNA splicing machinery in order to exercise their oncogenic activities, a strategy that allows the viruses to efficiently export and stabilize viral RNA and to produce spliced RNA isoforms from a bicistronic or polycistronic RNA transcript for efficient protein translation. Infection with a tumor virus affects the expression of host genes, including host RNA splicing factors, which play a key role in regulating viral RNA splicing of oncogene transcripts. A current prospective focus is to explore how alternative RNA splicing and the expression of viral oncogenes take place in a cell- or tissue specific manner in virus-induced human carcinogenesis. PMID- 26038759 TI - Antibacterial and anti-biofilm activities of thiazolidione derivatives against clinical staphylococcus strains. AB - Both Staphylococcus aureus and Staphylococcus epidermidis can form biofilms on natural surfaces or abiotic surfaces, such as medical implants, resulting in biofilm-associated diseases that are refractory to antibiotic treatment. We previously reported a promising antibacterial compound (Compound 2) and its derivatives with bactericidal and anti-biofilm activities against both S. epidermidis and S. aureus. We have further evaluated the antibacterial activities of four Compound 2 derivatives (H2-38, H2-39, H2-74 and H2-81) against 163 clinical strains of S. epidermidis and S. aureus, including methicillin susceptible and methicillin-resistant strains, as well as biofilm-forming and non biofilm-forming strains. The four derivatives inhibited the planktonic growth of all of the clinical staphylococcal isolates, including methicillin-resistant S. aureus and methicillin-resistant S. epidermidis and displayed bactericidal activities against both immature (6 h) and mature (24 h) biofilms formed by the strong biofilm-forming strains. The derivatives, which all target YycG, will help us to develop new antimicrobial agents against multidrug-resistant staphylococci infections and biofilm-associated diseases. PMID- 26038760 TI - Dengue fever in China: an emerging problem demands attention. PMID- 26038761 TI - 'Supermutators' found amongst highly levofloxacin-resistant E. coli isolates: a rapid protocol for the detection of mutation sites. AB - Fluoroquinolone resistance is gradually acquired through several mechanisms. In particular, chromosomal mutations in the genes encoding topoisomerases II and IV and increased expression of the multidrug efflux pump AcrAB-TolC are the most common mechanisms. In this study, multiplex polymerase chain reaction (PCR) protocols were designed for high-throughput sequencing of the quinolone resistance determining regions of topoisomerases genes (gyrA, parC and parE) and/or the expression regulation systems of multidrug efflux pump AcrAB (acrRAB, marRAB and soxSR). These protocols were applied to sequence samples from five subpopulations of 103 clinical Escherichia coli isolates. These subpopulations were classified according to their levofloxacin susceptibility pattern as follows: highly resistant (HR), resistant (R), intermediate (I), reduced susceptibility (RS) and susceptible (S). All HR isolates had mutations in the six genes surveyed, with two 'supermutator' isolates harboring 13 mutations in these six genes. Strong associations were observed between mutations in acrR and HR isolates, parE and R/HR isolates and parC and I/R/HR isolates, whereas surprisingly, gyrA mutations were common in RS/I/R/HR isolates. Further investigation revealed that strong associations were limited to the triple mutations gyrA-S83L/D87N/R237H and HR isolates and the double mutations S83L/D87N and I/R/HR isolates, whereas the single mutation S83L was common in RS/I/R/HR isolates. Interestingly, two novel mutations (gyrA-R237H and acrR-V29G) were located and found to strongly associate with HR isolates. To the best of our knowledge, the gyrA-R237H and acrR-V29G mutations have never been reported and require further investigation to determine their exact role in resistance or 'fitness' as defined by their ability to compensate for the organismal cost of gaining resistance. PMID- 26038762 TI - Identification of specific metabolites in culture supernatant of Mycobacterium tuberculosis using metabolomics: exploration of potential biomarkers. AB - Although previous studies have reported the use of metabolomics for Mycobacterium species differentiation, little is known about the potential of extracellular metabolites of Mycobacterium tuberculosis (MTB) as specific biomarkers. Using an optimized ultrahigh performance liquid chromatography-electrospray ionization quadruple time of flight-mass spectrometry (UHPLC-ESI-Q-TOF-MS) platform, we characterized the extracellular metabolomes of culture supernatant of nine MTB strains and nine non-tuberculous Mycobacterium (NTM) strains (four M. avium complex, one M. bovis Bacillus Calmette-Guerin (BCG), one M. chelonae, one M. fortuitum and two M. kansasii). Principal component analysis readily distinguished the metabolomes between MTB and NTM. Using multivariate and univariate analysis, 24 metabolites with significantly higher levels in MTB were identified. While seven metabolites were identified by tandem mass spectrometry (MS/MS), the other 17 metabolites were unidentified by MS/MS against database matching, suggesting that they may be potentially novel compounds. One metabolite was identified as dexpanthenol, the alcohol analog of pantothenic acid (vitamin B5), which was not known to be produced by bacteria previously. Four metabolites were identified as 1-tuberculosinyladenosine (1-TbAd), a product of the virulence associated enzyme Rv3378c, and three previously undescribed derivatives of 1 TbAd. Two derivatives differ from 1-TbAd by the ribose group of the nucleoside while the other likely differs by the base. The remaining two metabolites were identified as a tetrapeptide, Val-His-Glu-His, and a monoacylglycerophosphoglycerol, phosphatidylglycerol (PG) (16?0/0?0), respectively. Further studies on the chemical structure and biosynthetic pathway of these MTB-specific metabolites would help understand their biological functions. Studies on clinical samples from tuberculosis patients are required to explore for their potential role as diagnostic biomarkers. PMID- 26038763 TI - High frequency of the 23S rRNA A2058G mutation of Treponema pallidum in Shanghai is associated with a current strategy for the treatment of syphilis. AB - The preferred drugs for the treatment of syphilis, benzathine and procaine penicillin, have not been available in Shanghai for many years, and currently, the incidence of syphilis is increasing. Alternative antibiotics for patients with syphilis during the benzathine and procaine penicillin shortage include macrolides. The failure of macrolide treatment in syphilis patients has been reported in Shanghai, but the reason for this treatment failure remains unclear. We used polymerase chain reaction technology to detect a 23S rRNA A2058G mutation in Treponema pallidum in 109 specimens from syphilis patients. The use of azithromycin/erythromycin in the syphilis patients and the physicians' prescription habits were also assessed based on two questionnaires regarding the use of macrolides. A total of 104 specimens (95.4%) were positive for the A2058G mutation in both copies of the 23S rRNA gene, indicating macrolide resistance. A questionnaire provided to 122 dermatologists showed that during the penicillin shortage, they prescribed erythromycin and azithromycin for 8.24+/-13.95% and 3.21+/-6.37% of their patients, respectively, and in the case of penicillin allergy, erythromycin and azithromycin were prescribed 15.24+/-22.89% and 7.23+/ 16.60% of the time, respectively. A second questionnaire provided to the syphilis patients showed that 150 (33.7%), 106 (23.8%) and 34 (7.6%) individuals had used azithromycin, erythromycin or both, respectively, although the majority did not use the drugs for syphilis treatment. Our findings suggest that macrolide resistance in Treponema pallidum is widespread in Shanghai. More than half of the syphilis patients had a history of macrolide use for other treatment purposes, which may have led to the high prevalence of macrolide resistance. Physicians in China are advised to not use azithromycin for early syphilis. PMID- 26038764 TI - Phylogenetic analysis of the major causative agents of hand, foot and mouth disease in Suzhou City, Jiangsu province, China, in 2012-2013. AB - Hand, foot and mouth disease (HFMD) is a serious public health problem that has emerged over the past several decades. Pathogen detection by the Chinese national HFMD surveillance system has focused mainly on enterovirus 71 (EV71) and coxsackievirus A16 (CA16). Therefore, epidemiological information regarding the other causative enteroviruses is limited. To identify the pandemic enterovirus in Suzhou, Jiangsu province, China, clinical samples from patients with HFMD were collected from 2012 to 2013 and analyzed. The results revealed that CA16 was the most dominant HFMD pathogen in 2012, whereas CA6 and CA10 were the dominant pathogens in 2013. Phylogenetic analysis revealed that the C4a sub-genogroup of EV71 and the B1a and B1b sub-genogroups of CA16 continued to evolve and circulate in Suzhou. The CA6 strains were assigned to six genotypes (A-F) and the CA10 strains were assigned to seven genotypes (A-G), with clear geographical and temporal distributions. All of the CA6 strains in Suzhou belonged to genogroup F, and there were several lineages circulating in Suzhou. All of the CA10 strains in Suzhou belonged to genogroup G, and they had the same genetic origin. Co infections of EV71/CA16 and CA6/CA10 were found in the samples, and bootscan analysis of 5'-untranslated regions (UTRs) revealed that some CA16 strains in Suzhou had genetic recombination with EV71. This property might allow CA16 to alter its evolvability and circulating ability. This study underscores the need for surveillance of CA6 and CA10 in the Yangtze River Delta and East China. PMID- 26038765 TI - The diversity of avian influenza virus subtypes in live poultry markets before and during the second wave of A(H7N9) infections in Hangzhou, China. PMID- 26038766 TI - Strategic measures for the control of surging antimicrobial resistance in Hong Kong and mainland of China. AB - Antimicrobial-resistant bacteria are either highly prevalent or increasing rapidly in Hong Kong and China. Treatment options for these bacteria are generally limited, less effective and more expensive. The emergence and dynamics of antimicrobial resistance genes in bacteria circulating between animals, the environment and humans are not entirely known. Nonetheless, selective pressure by antibiotics on the microbiomes of animal and human, and their associated environments (especially farms and healthcare institutions), sewage systems and soil are likely to confer survival advantages upon bacteria with antimicrobial resistance genes, which may be further disseminated through plasmids or transposons with integrons. Therefore, antibiotic use must be tightly regulated to eliminate such selective pressure, including the illegalization of antibiotics as growth promoters in animal feed and regulation of antibiotic use in veterinary practice and human medicine. Heightened awareness of infection control measures to reduce the risk of acquiring resistant bacteria is essential, especially during antimicrobial use or institutionalization in healthcare facilities. The transmission cycle must be interrupted by proper hand hygiene, environmental cleaning, avoidance of undercooked or raw food and compliance with infection control measures by healthcare workers, visitors and patients, especially during treatment with antibiotics. In addition to these routine measures, proactive microbiological screening of hospitalized patients with risk factors for carrying resistant bacteria, including history of travel to endemic countries, transfer from other hospitals, and prolonged hospitalization; directly observed hand hygiene before oral intake of drugs, food and drinks; and targeted disinfection of high-touch or mutual-touch items, such as bed rails and bed curtains, are important. Transparency of surveillance data from each institute for public scrutiny provides an incentive for controlling antimicrobial resistance in healthcare settings at an administrative level. PMID- 26038767 TI - T-cell reprogramming through targeted CD4-coreceptor and T-cell receptor expression on maturing thymocytes by latent Circoviridae family member porcine circovirus type 2 cell infections in the thymus. AB - Although porcine circovirus type 2 (PCV2)-associated diseases have been evaluated for known immune evasion strategies, the pathogenicity of these viruses remained concealed for decades. Surprisingly, the same viruses that cause panzootics in livestock are widespread in young, unaffected animals. Recently, evidence has emerged that circovirus-like viruses are also linked to complex diseases in humans, including children. We detected PCV2 genome-carrying cells in fetal pig thymi. To elucidate virus pathogenicity, we developed a new pig infection model by in vivo transfection of recombinant PCV2 and the immunosuppressant cofactor cyclosporine A. Using flow cytometry, immunofluorescence and fluorescence in situ hybridization, we found evidence that PCV2 dictates positive and negative selection of maturing T cells in the thymus. We show for the first time that PCV2 infected cells reside at the corticomedullary junction of the thymus. In diseased animals, we found polyclonal deletion of single positive cells (SPs) that may result from a loss of major histocompatibility complex class-II expression at the corticomedullary junction. The percentage of PCV2 antigen-presenting cells correlated with the degree of viremia and, in turn, the severity of the defect in thymocyte maturation. Moreover, the reversed T-cell receptor/CD4-coreceptor expression dichotomy on thymocytes at the CD4(+)CD8(interm) and CD4SP cell stage is viremia-dependent, resulting in a specific hypo-responsiveness of T-helper cells. We compare our results with the only other better-studied member of Circoviridae, chicken anemia virus. Our data show that PCV2 infection leads to thymocyte selection dysregulation, adding a valuable dimension to our understanding of virus pathogenicity. PMID- 26038768 TI - Factors responsible for the emergence of arboviruses; strategies, challenges and limitations for their control. AB - Slave trading of Africans to the Americas, during the 16th to the 19th century was responsible for the first recorded emergence in the New World of two arthropod-borne viruses (arboviruses), yellow fever virus and dengue virus. Many other arboviruses have since emerged from their sylvatic reservoirs and dispersed globally due to evolving factors that include anthropological behaviour, commercial transportation and land-remediation. Here, we outline some characteristics of these highly divergent arboviruses, including the variety of life cycles they have developed and the mechanisms by which they have adapted to evolving changes in habitat and host availability. We cite recent examples of virus emergence that exemplify how arboviruses have exploited the consequences of the modern human lifestyle. Using our current understanding of these viruses, we also attempt to demonstrate some of the limitations encountered in developing control strategies to reduce the impact of future emerging arbovirus diseases. Finally, we present recommendations for development by an international panel of experts reporting directly to World Health Organization, with the intention of providing internationally acceptable guidelines for improving emerging arbovirus disease control strategies. Success in these aims should alleviate the suffering and costs encountered during recent decades when arboviruses have emerged from their sylvatic environment. PMID- 26038771 TI - Preliminary Design and Evaluation of a B-Scan OCT-Guided Needle. AB - Real-time intraoperative B-scan optical coherence tomography (OCT) visualization of intraocular tissues is a desired ophthalmic feature during retinal procedures. A novel intraocular 25-gauge B-mode forward-imaging OCT probe was combined with a 36-gauge needle into a prototype instrument. Imaging of the needle tip itself and the effects of saline injection into a gelatin phantom were performed. A combined B-scan forward-imaging OCT-needle prototype was capable of real-time-imaging of saline injection into a gelatin phantom. Additional future miniaturization may permit this instrument to be an adjunctive realtime imaging and procedure tool for vitreoretinal surgery. PMID- 26038772 TI - Unusual breast mass: lymphoma with crystal-storing histiocytosis. PMID- 26038770 TI - An H5N1-based matrix protein 2 ectodomain tetrameric peptide vaccine provides cross-protection against lethal infection with H7N9 influenza virus. AB - In March 2013, a patient infected with a novel avian influenza A H7N9 virus was reported in China. Since then, there have been 458 confirmed infection cases and 177 deaths. The virus contains several human-adapted markers, indicating that H7N9 has pandemic potential. The outbreak of this new influenza virus highlighted the need for the development of universal influenza vaccines. Previously, we demonstrated that a tetrameric peptide vaccine based on the matrix protein 2 ectodomain (M2e) of the H5N1 virus (H5N1-M2e) could protect mice from lethal infection with different clades of H5N1 and 2009 pandemic H1N1 influenza viruses. In this study, we investigated the cross-protection of H5N1-M2e against lethal infection with the new H7N9 virus. Although five amino acid differences existed at positions 13, 14, 18, 20, and 21 between M2e of H5N1 and H7N9, H5N1-M2e vaccination with either Freund's adjuvant or the Sigma adjuvant system (SAS) induced a high level of anti-M2e antibody, which cross-reacted with H7N9-M2e peptide. A mouse-adapted H7N9 strain, A/Anhui/01/2013m, was used for lethal challenge in animal experiments. H5N1-M2e vaccination provided potent cross protection against lethal challenge of the H7N9 virus. Reduced viral replication and histopathological damage of mouse lungs were also observed in the vaccinated mice. Our results suggest that the tetrameric H5N1-M2e peptide vaccine could protect against different subtypes of influenza virus infections. Therefore, this vaccine may be an ideal candidate for developing a universal vaccine to prevent the reemergence of avian influenza A H7N9 virus and the emergence of potential novel reassortants of influenza virus. PMID- 26038773 TI - Metaphors and representations of systemic lupus erythematosus: comment on the article by Sutanto et a. PMID- 26038769 TI - Understanding the interplay between host immunity and Epstein-Barr virus in NPC patients. AB - Epstein-Barr virus (EBV) has been used as a paradigm for studying host-virus interactions, not only because of its importance as a human oncogenic virus associated with several malignancies including nasopharyngeal carcinoma (NPC) but also owing to its sophisticated strategies to subvert the host antiviral responses. An understanding of the interplay between EBV and NPC is critical for the development of EBV-targeted immunotherapy. Here, we summarize the current knowledge regarding the host immune responses and EBV immune evasion mechanisms in the context of NPC. PMID- 26038774 TI - [LAMA / LABA fixed combination 2 times daily]. PMID- 26038775 TI - [Nintedanib receives EMA-approval]. PMID- 26038776 TI - [For the monotherapy a LAMA is the first choice]. PMID- 26038777 TI - [The challenge of early diagnosis and the doctor-patient communication]. PMID- 26038778 TI - [Early combination therapy may delay progression]. PMID- 26038779 TI - [Therapy with new LAMA / LABA combination]. PMID- 26038780 TI - [Therapeutic option after failure of first-line chemotherapy]. PMID- 26038781 TI - [Expanded approval for 13-valent pneumococcal conjugate vaccine]. PMID- 26038782 TI - Reply to letter by Bassareo regarding the article of Tauzin et al. 'Increased systemic blood pressure and arterial stiffness in young adults born prematurely'. PMID- 26038783 TI - Response: advanced heart failure care: Aequanimitas and compassion are both essential. PMID- 26038785 TI - Disaster turns into blessings. PMID- 26038786 TI - ED-based interventions to break cycle among patients presenting with violence related injuries. AB - Studies have shown that patients who present to the ED with violence-related injuries are at high risk of being involved in future violent incidents. Consequently, investigators say the ED is an ideal setting to intervene with these individuals with the kind of care and support that will lead them toward a safer path. Helping Hurt People (HHP), a hospital-based trauma support program developed at Drexel University in Philadelphia, PA, has been fulfilling this function at Hahnemann University Hospital and St. Christopher's Hospital for Children in Philadelphia since 2007, and now the program is being expanded to three other trauma centers, along with a research program aimed at documenting HHP's effectiveness. When a patient presents with injuries from an assault or other form of violence, ED personnel are encouraged to contact the HHP social worker who then follows up with the patient. Interventions offered through HHP include a range of social and mental health services such as behavioral health counseling, job placement assistance, help with housing, and educational guidance. Program administrators say HHP interventions have reduced symptoms of PTSD, depression, and anxiety, and that it has successfully linked many patients with health insurance and primary care. With expansion of the program to three new trauma centers, more comprehensive research is planned to document the program's effectiveness. PMID- 26038787 TI - Study: emergency providers often lack consensus on what patients intend when end of-life forms come into play. AB - A new study suggests there is a lack of consensus or understanding about what patients intend when they fill out Physicians Orders for Life Sustaining Treatment (POLST) forms, and that this likely leads to patients either receiving or not receiving treatment contrary to their wishes. Investigators suggest more training on these issues is needed, and recommend that clinicians take the time to clarify choices during periods of critical illness. A new study found that when presented with a range of clinical scenarios coupled with POLST forms reflecting patient wishes, emergency providers did not often reach a consensus on what actions they would take. Researchers say that "do not resuscitate" orders are commonly misinterpreted to mean do not treat, and there are also practice and regional variations in how end-of-life-care documents are interpreted. While a national organization establishes POLST recommendations and sample policies, the documents themselves are established and regulated at the state level, along with training procedures. Experts recommend that hospitals establish quality control procedures to ensure that end-of-life-care documents are prepared and interpreted accurately. PMID- 26038784 TI - The role of endoscopy in the bariatric surgery patient. PMID- 26038788 TI - Clean up coding practices to maximize revenue, minimize compliance issues, and be optimally prepared for ICD-10. PMID- 26038789 TI - TJC: HCOs need to be on alert for HIT problems related to sociotechnical factors, take steps to improve safety culture, process, and leadership. AB - Noting that too many errors related to health information technology (HIT) are resulting in adverse consequences, The Joint Commission (TJC) has issued a Sentinel Event Alert, urging health care providers to take steps to improve their safety culture, approach to process improvement, and leadership in this area. In this latest alert, the accrediting agency is taking particular aim at risks posed by sociotechnical factors--or the ways in which HIT is implemented and used. Experts say that many of these risks are, in fact, exemplified at a higher level in the emergency setting, where providers are under constant pressure to see more patients and move them though the system faster. In an analysis of 3,375 sentinel events that resulted in permanent patient harm or death between January 1, 2010, and June 20, 2013, The Joint Commission (TJC) found that 120 events included HIT related contributing factors. Many of the problems cited by TJC relate to orders or medicines being prescribed for the wrong patients. These can result from toggling errors or pop-up screens where providers are asked to click on the appropriate patient or medicine, and they mistakenly click on the wrong selection. In the ED, experts recommend the creation of a multidisciplinary performance improvement group to continuously monitor the ED information system (EDIS), recognize problems, and work with the vendor to resolve them. Also important is a quick and easy way for providers to report HIT-related problems. Experts add that emergency providers need to be fully engaged in the process of selecting HIT that they will be using, and that health care organizations should arrange for usability assessments before purchasing HIT. PMID- 26038790 TI - Most types of cancer not due to 'bad luck' IARC responds to scientific article claiming that environmental and lifestyle factors account for less than one third of cancers. PMID- 26038791 TI - Liver disease in children: from neonatal jaundice to living donor liver transplantation. PMID- 26038792 TI - Paediatric liver transplantation in Johannesburg revisited: 59 transplants and challenges met. AB - BACKGROUND: A paediatric liver transplant programme was started at the Wits Donald Gordon Medical Centre, Johannesburg, South Africa (SA), in November 2005. We reported on the first 29 patients in 2012. Since then we have performed a further 30 transplants in 28 patients, having met the major challenge of donor shortage by introducing a living related donor programme and increasing the use of split liver grafts. OBJECTIVE: To review the Wits Donald Gordon Medical Centre paediatric liver transplant programme to date. We describe how the programme has evolved and specifically compare the outcomes of the first cohort with the most recent 28 patients. METHODS: Case notes of all paediatric liver transplants performed between 14 November 2005 and 30 June 2014 were retrospectively reviewed. Data were analysed for age and weight at transplantation, indication and type of graft. Morbidity and mortality were documented, specifically biliary and vascular complications. Comparison was made between Era 1 (November 2005 - October 2012) and Era 2 (November 2012 - June 2014). RESULTS: A total of 59 transplants were performed in 57 patients. Age at transplantation ranged from 9 months to 213 months (mean 82.39 months) and weight ranged from 5 kg to 62 kg (mean 21 kg). A total of 23 whole livers, 10 reduced-size grafts, 14 split liver grafts and 12 living donor liver transplants (LDLTs) were performed. Eight patients were referred with fulminant hepatic failure (FHF), all in Era 2. Of these, three patients were successfully transplanted. Of the 57 patients, 45 are alive and well with actuarial 1-year patient and graft survival of 85% and 84% and 5-year patient and graft survival of 78% and 74%, respectively. Sixteen (25.42%) biliary complications occurred in 15 of our 59 transplants. Seven patients developed significant vascular complications. Comparing Era 1 with Era 2, mean age at transplant decreased from 100.86 months to 64.73 months, mean weight from 25.2 kg to 16.9 kg, and type of graft utilised changed with a trend away from the use of whole livers and reduced-sized grafts to split livers and segment 2,3 LDLT grafts. CONCLUSION: Initially limited by a shortage of donor organs, we aggressively explored optimal utilisation, splitting liver grafts from deceased donors as often as possible and establishing an LDLT programme. This increased access to donor livers allowed us to include patients with FHF and to perform retransplantation in recipients with early graft failure. It remains to offer liver transplantation to the entire paediatric community in SA, in conjunction with the only other established paediatric liver transplant unit, at Red Cross War Memorial Children's Hospital in Cape Town. PMID- 26038793 TI - Paediatric pancreatic trauma: a review of the literature and results of a multicentre survey on patient management. AB - BACKGROUND: It is generally accepted that paediatric solid organ injury should be treated conservatively, unless there is haemodynamic instability unresponsive to resuscitation. When it comes to pancreatic trauma, there is much debate about appropriate management. OBJECTIVES: To review the literature and determine how pancreatic trauma is managed in South African (SA) tertiary institutions and compares with international standards. METHOD: A survey was emailed to 45 paediatric surgical consultants working in various paediatric surgical units in SA, Italy, England and Australia. The questionnaire comprised two scenarios of isolated pancreatic trauma (grade III), the main difference between them being the time interval between initial injury and presentation. In the first scenario, the patient presented 6 hours post injury whereas in the second scenario, the patient presented 6 days post initial injury. The survey enquired about diagnosis and subsequent work-up (including preferred imaging techniques), supportive management (including nutrition), the various options of definitive intervention and follow-up procedure. RESULTS: There were 21 responders from four different countries. In the first scenario, 10 surgeons would operate, 8 would treat conservatively and 3 would perform an endoscopic retrograde cholangiopancreatogram (ERCP) and stent. In. the second scenario, 4 surgeons would operate, 13 would treat conservatively and 4 would undertake ERCP with stent. There was no difference in management between the SA surgeons and their international counterparts. CONCLUSION: Management of blunt pancreatic trauma in SA is consistent with that reported in the literature. There is still controversy regarding the optimal management of pancreatic injury involving ducts. No absolute algorithm can be used to treat these patients. All patients should be treated individually and managed with an approach and techniques that are feasible. PMID- 26038794 TI - Acute liver failure and transplantation in children. AB - Acute liver failure (ALF) was relatively easy to recognise in the days before liver transplantation became available as rescue therapy, because the diagnosis was based on end-stage disease manifestations such as profound coagulopathy, jaundice, encephalopathy and cerebral oedema (in a patient with no history of chronic liver disease). These criteria no longer help us in an era in which we struggle to define which patients are going to progress to this end-stage picture in the time necessary for evaluation and listing for life-saving transplantation. Ideally, identifying which patients will recover spontaneously or with appropriate treatment would relieve the justifiable concern that some patients receive a transplant when, given time, they would have recovered. Currently, the data to guide us in avoiding death without transplantation and unnecessary transplantation remain elusive. PMID- 26038795 TI - Liver tumours in children: current surgical management and role of transplantation. AB - This article reviews the current surgical management of liver tumours in children in the light of improved chemotherapy, surgical techniques and outcomes from transplantation. It is a principle of management that complete removal of a tumour must be achieved for cure. Neoadjuvant chemotherapy may downstage advanced local disease to enable safe curative tumour resection. When this is not achievable, transplant is indicated. Conventional indications for transplant are unresectable stages 3 and 4 tumours confined to the liver. With the realisation that lifelong immunosuppressive therapy has considerable adverse consequences, there has been a recent trend towards extreme and 'acrobatic' liver resection to avoid transplantation, but still obtain a cure. The current literature is reviewed in the light of these trends and our own experience. PMID- 26038796 TI - Controversies in choledochal malformation. AB - Choledochal malformations (some of which are choledochal cysts) may be characterised as an abnormal dilatation of the biliary tract in the absence of acute obstruction. Most appear to be of congenital origin, probably related to distal bile duct stenosis, and almost 15% can now be detected antenatally. Excision and biliary reconstruction using a Roux loop as an open operation is still the standard to compare against, although laparoscopic reconstruction is increasingly reported. This article discusses recent advances in the understanding of choledochal malformation aetiology and classification, together with the role of newer modalites of surgical treatment such as laparoscopic excision and biliary reconstruction. Although these are definitely feasible, care should be taken before dispensing with standard open techniques that have minimal complications and proven long-term benefit. PMID- 26038797 TI - Role of laparoscopy during surgery at the porta hepatis. AB - Minimally invasive surgery in children has evolved to the extent that complex procedures can be performed with safety, with comparable outcomes to open surgery and with the advantages of minimal scarring and less pain. In this article, we describe the latest laparoscopic techniques used at Juntendo University Hospital in Japan, for treating conditions affecting the porta hepatis, focusing on biliary atresia and choledochal cysts. We also summarise our postoperative management protocols and discuss preliminary outcomes. PMID- 26038798 TI - The role of interventional radiology in complications after paediatric liver transplantation. AB - Liver transplantation has become an established treatment in both adults and children for end-stage liver disease, acute hepatic failure and certain liver tumours. There is a significant risk of complications after all forms of liver transplantation. The interventional radiologist plays a critical role in the diagnosis and treatment of these complications. The use of image-guided, minimally invasive procedures reduces the need for surgical revision or retransplantation and improves graft and patient survival rate. This article reviews some of the most common vascular and non-vascular complications after paediatric liver transplantation, and the interventional radiology techniques used to diagnose and treat them. PMID- 26038799 TI - Paediatric liver transplantation for children treated at public health facilities in South Africa: time for change. AB - Paediatric liver transplantation (PLT) is the only therapeutic option for many children with end-stage chronic liver disease or irreversible fulminant hepatic failure, and is routinely considered as a therapy by paediatric gastroenterologists and surgeons working in developed countries. In South Africa (SA), a PLT programme has been available at Red Cross War Memorial Children's Hospital in Cape Town since November 1991, and another has rapidly developed at the Wits Donald Gordon Medical Centre in Johannesburg over the past decade. However, for most children with progressive chronic liver disease who are reliant on the services provided at state facilities in SA, PLT is not an option because of a lack of resources in a mismanaged public health system. This article briefly outlines the services offered at Chris Hani Baragwanath Academic Hospital--which is typical of state facilities in SA--and proposes that resources be allocated to establish an innovative, nationally funded centre that would enable greater numbers of children access to a PLT programme. PMID- 26038800 TI - Improving arachidonic acid fermentation by Mortierella alpina through multistage temperature and aeration rate control in bioreactor. AB - Effective production of arachidonic acid (ARA) using Mortierella alpina was conducted in a 30-L airlift bioreactor. Varying the aeration rate and temperature significantly influenced cell morphology, cell growth, and ARA production, while the optimal aeration rate and temperature for cell growth and product formation were quite different. As a result, a two-stage aeration rate control strategy was constructed based on monitoring of cell morphology and ARA production under various aeration rate control levels (0.6-1.8 vvm). Using this strategy, ARA yield reached 4.7 g/L, an increase of 38.2% compared with the control (constant aeration rate control at 1.0 vvm). Dynamic temperature-control strategy was implemented based on the fermentation performance at various temperatures (13-28 degrees C), with ARA level in total cellular lipid increased by 37.1% comparing to a constant-temperature control (25 degrees C). On that basis, the combinatorial fermentation strategy of two-stage aeration rate control and dynamic temperature control was applied and ARA production achieved the highest level of 5.8 g/L. PMID- 26038802 TI - Layer-by-Layer Surface Molecular Imprinting on Polyacrylonitrile Nanofiber Mats. AB - Surface molecular imprinting in layer-by-layer (SMI-LbL) film is known as a facile and effective strategy to build imprinting sites that are more accessible to template molecules compared with molecular imprinting in polymers. Herein, we accomplished the formation of SMI-LbL film on electrospun nanofibers for the first time. The SMI-LbL nanofibers were prepared by a template-induced LbL process on the polyacrylonitrile (PAN) nanofiber substrates, followed by postinfiltrating and photo-cross-linking of photosensitive agent 4,4' diazostilbene-2,2'-disulfonic acid disodium salt (DAS). The obtained nanofiber mat maintained the nanofibrous structure and showed rapid absorption and extraction of template molecules of meso-tetra(4-carboxyphenyl)-porphine (Por). The binding capacity of Por reached 2.1 mg/g when 3.5 bilayers were deposited on the nanofibers. After six cycles of extraction and reabsorption, the binding capacity of Por remained at 83%. Moreover, the absorption results of the targeted templated molecule of Por and the control molecule of Fast Green, which had a very similar chemical structure and charge status to Por, indicated the specific absorption for template molecule of Por. Thus, a surface molecular imprinted nanofiber mat with high selectivity of the templated molecule has been demonstrated. PMID- 26038801 TI - Low-Concentration PM2.5 and Mortality: Estimating Acute and Chronic Effects in a Population-Based Study. AB - BACKGROUND: Both short- and long-term exposures to fine particulate matter (<= 2.5 MUm; PM2.5) are associated with mortality. However, whether the associations exist at levels below the new U.S. Environmental Protection Agency (EPA) standards (12 MUg/m3 of annual average PM2.5, 35 MUg/m3 daily) is unclear. In addition, it is not clear whether results from previous time series studies (fit in larger cities) and cohort studies (fit in convenience samples) are generalizable. OBJECTIVES: We estimated the effects of low-concentration PM2.5 on mortality. METHODS: High resolution (1 km * 1 km) daily PM2.5 predictions, derived from satellite aerosol optical depth retrievals, were used. Poisson regressions were applied to a Medicare population (>= 65 years of age) in New England to simultaneously estimate the acute and chronic effects of exposure to PM2.5, with mutual adjustment for short- and long-term exposure, as well as for area-based confounders. Models were also restricted to annual concentrations < 10 MUg/m3 or daily concentrations < 30 MUg/m3. RESULTS: PM2.5 was associated with increased mortality. In the study cohort, 2.14% (95% CI: 1.38, 2.89%) and 7.52% (95% CI: 1.95, 13.40%) increases were estimated for each 10-MUg/m3 increase in short- (2 day) and long-term (1 year) exposure, respectively. The associations held for analyses restricted to low-concentration PM2.5 exposure, and the corresponding estimates were 2.14% (95% CI: 1.34, 2.95%) and 9.28% (95% CI: 0.76, 18.52%). Penalized spline models of long-term exposure indicated a larger effect for mortality in association with exposures >= 6 MUg/m3 versus those < 6 MUg/m3. In contrast, the association between short-term exposure and mortality appeared to be linear across the entire exposure distribution. CONCLUSIONS: Using a mutually adjusted model, we estimated significant acute and chronic effects of PM2.5 exposure below the current U.S. EPA standards. These findings suggest that improving air quality with even lower PM2.5 than currently allowed by U.S. EPA standards may benefit public health. CITATION: Shi L, Zanobetti A, Kloog I, Coull BA, Koutrakis P, Melly SJ, Schwartz JD. 2016. Low-concentration PM2.5 and mortality: estimating acute and chronic effects in a population-based study. Environ Health Perspect 124:46-52; http://dx.doi.org/10.1289/ehp.1409111. PMID- 26038803 TI - Carbon Nanotubes Enhanced Fluorinated Polyurethane Macroporous Membranes for Waterproof and Breathable Application. AB - Waterproof and breathable macroporous membranes that are both completely resistant to liquid water penetration and easily allowable to vapor transmission would have significant implication for numerous applications; however, fabrication of such materials has proven to be tremendously challenging. Herein, we reported novel electrospun composite fibrous membranes with high waterproof and breathable performance, which consisted of polyurethane (PU), terminal fluorinated polyurethane (FPU), and carbon nanotubes (CNTs). Benefiting from the utilization of FPU and CNTs, the fibrous membranes were endowed with superhydrophobic surface, optimized pores size and porosity, along with enhanced fibers, which resulted in excellent waterproof, breathable and mechanical properties. Significantly, the relationship among waterproofness, pore structure and surface wettability has been confirmed finely accordance with Young-Laplace equation. Ultimately, the resultant membranes presented high waterproofness with hydrostatic pressure up to 108 kPa, good breathability with water vapor transmission rate over 9.2 kg m(-2) d(-1), as well as robust mechanical properties with bursting strength of 47.6 kPa and tensile strength of 12.5 MPa, suggesting them as promising alternatives for a number of potential applications, such as protective clothing. PMID- 26038804 TI - Benchmarking Data Sets for the Evaluation of Virtual Ligand Screening Methods: Review and Perspectives. AB - Virtual screening methods are commonly used nowadays in drug discovery processes. However, to ensure their reliability, they have to be carefully evaluated. The evaluation of these methods is often realized in a retrospective way, notably by studying the enrichment of benchmarking data sets. To this purpose, numerous benchmarking data sets were developed over the years, and the resulting improvements led to the availability of high quality benchmarking data sets. However, some points still have to be considered in the selection of the active compounds, decoys, and protein structures to obtain optimal benchmarking data sets. PMID- 26038805 TI - Strong protection against ricin challenge induced by a novel modified ricin A chain protein in mouse model. AB - Ricin toxin (RT) is an extremely potent toxin derived from the castor bean plant. As a possible bioterrorist weapon, it was categorized as a level B agent in international society. With the growing awareness and concerns of the "white powder incident" in recent years, it is indispensable to develop an effective countermeasure against RT intoxication. In this study we used site-directed mutagenesis and polymerase chain reaction (PCR) techniques to modify the gene of ricin A-chain (RTA). As a result, we have generated a mutated and truncated ricin A-chain (mtRTA) vaccine antigen by E.coli strain. The cytotoxicity assay was used to evaluate the safety of the as-prepared mtRTA antigen, and the results showed that there was no residual toxicity observed when compared to the recombinant RTA (rRTA) or native RT. Furthermore, BALB/c mice were subcutaneously (s.c.) vaccinated with mtRTA 3 times at an interval of 2 weeks, and then the survivals were evaluated after intraperitoneal (i.p.) or intratracheal challenge of RT. The vaccinated mice developed a strong protective immune response that was wholly protective against 40 * LD50 of RT i.p. injection or 20 * LD50 of RT intratracheal spraying. The mtRTA antigen has great potential to be a vaccine candidate for future application in humans. PMID- 26038807 TI - Extremely Elastic Wearable Carbon Nanotube Fiber Strain Sensor for Monitoring of Human Motion. AB - The increasing demand for wearable electronic devices has made the development of highly elastic strain sensors that can monitor various physical parameters an essential factor for realizing next generation electronics. Here, we report an ultrahigh stretchable and wearable device fabricated from dry-spun carbon nanotube (CNT) fibers. Stretching the highly oriented CNT fibers grown on a flexible substrate (Ecoflex) induces a constant decrease in the conductive pathways and contact areas between nanotubes depending on the stretching distance; this enables CNT fibers to behave as highly sensitive strain sensors. Owing to its unique structure and mechanism, this device can be stretched by over 900% while retaining high sensitivity, responsiveness, and durability. Furthermore, the device with biaxially oriented CNT fiber arrays shows independent cross-sensitivity, which facilitates simultaneous measurement of strains along multiple axes. We demonstrated potential applications of the proposed device, such as strain gauge, single and multiaxial detecting motion sensors. These devices can be incorporated into various motion detecting systems where their applications are limited to their strain. PMID- 26038806 TI - Understanding the Short- and Long-Term Respiratory Outcomes of Prematurity and Bronchopulmonary Dysplasia. AB - Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease associated with premature birth that primarily affects infants born at less than 28 weeks' gestational age. BPD is the most common serious complication experienced by premature infants, with more than 8,000 newly diagnosed infants annually in the United States alone. In light of the increasing numbers of preterm survivors with BPD, improving the current state of knowledge of long-term respiratory morbidity for infants with BPD is a priority. We undertook a comprehensive review of the published literature to analyze and consolidate current knowledge of the effects of BPD that are recognized at specific stages of life, including infancy, childhood, and adulthood. In this review, we discuss both the short-term and long term respiratory outcomes of individuals diagnosed as infants with the disease and highlight the gaps in knowledge needed to improve early and lifelong management of these patients. PMID- 26038808 TI - [Medicine/sciences (m/s), brief history of a brilliant success]. PMID- 26038809 TI - [30 years before, and tomorrow?]. PMID- 26038810 TI - [The 1980 years]. PMID- 26038811 TI - [The 1990 years]. PMID- 26038812 TI - [The 2000 years]. PMID- 26038813 TI - [The 2010 years]. PMID- 26038815 TI - Formation of Giant Unilamellar Proteo-Liposomes by Osmotic Shock. AB - Giant unilamellar vesicles (GUVs), composed of a phospholipid bilayer, are often used as a model system for cell membranes. However, the study of proteo-membrane interactions in this system is limited as the incorporation of integral and lipid anchored proteins into GUVs remains challenging. Here, we present a simple generic method to incorporate proteins into GUVs. The basic principle is to break proteo-liposomes with an osmotic shock. They subsequently reseal into larger vesicles which, if necessary, can endure the same to obtain even larger proteo GUVs. This process does not require specific lipids or reagents, works under physiological conditions with high concentrations of protein, the proteins remains functional after incorporation. The resulting proteo-GUVs can be micromanipulated. Moreover, our protocol is valid for a wide range of protein substrates. We have successfully reconstituted three structurally different proteins, two trans-membrane proteins (TolC and the neuronal t-SNARE), and one lipid-anchored peripheral protein (GABARAP-Like 1 (GL1)). In each case, we verified that the protein remains active after incorporation and in its correctly folded state. We also measured their mobility by performing diffusion measurements via fluorescence recovery after photobleaching (FRAP) experiments on micromanipulated single GUVs. The diffusion coefficients are in agreement with previous data. PMID- 26038816 TI - The G1 phase E3 ubiquitin ligase TRUSS that gets deregulated in human cancers is a novel substrate of the S-phase E3 ubiquitin ligase Skp2. AB - E3 ubiquitin ligases have been implicated in the ubiquitination and proteasome mediated degradation of several key regulators of cell cycle. Owing to their pleotropic behavior, E3 ubiquitin ligases are tightly regulated both at transcriptional and post-translational levels. The E3 ubiquitin ligase TRUSS (tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein) which negatively regulates c-Myc, are found down-regulated in most human cancer cell lines. However, the mechanism of regulation of intracellular levels of TRUSS remains elusive. Here we show that TRUSS is expressed majorly during the G1 phase of cell cycle and its level starts to decline with the expression of S phase specific E3 ligase Skp2. Enforced expression of Skp2 led to a marked increase in the ubiquitination of TRUSS after its phosphorylation by GSK3beta and followed by rapid proteolytic degradation. Our co-immunoprecipitation studies suggested a direct interaction between Skp2 and TRUSS through the LRR motif of Skp2. Interestingly, the human tumor samples that exhibited elevated expression of Skp2, showed relatively poor expression of TRUSS. Further, enforced expression of HBx, the oncoprotein of Hepatitis B virus which is known to stabilize c-Myc and enhance its oncogenic potential, led to the intracellular accumulation of TRUSS as well as c-Myc. Apparently, HBx also interacted with TRUSS which negatively impacted the TRUSS-c-Myc and TRUSS-Skp2 interactions leading to stabilization of TRUSS. Thus, the present study suggests that TRUSS is a novel substrate of E3 ligase Skp2 and that disruption of TRUSS-Skp2 interaction by viral oncoproteins could lead to pathophysiological sequelae. PMID- 26038818 TI - Combined Training (Aerobic Plus Strength) Potentiates a Reduction in Body Fat but Demonstrates No Difference on the Lipid Profile in Postmenopausal Women When Compared With Aerobic Training With a Similar Training Load. AB - The aim of this study was to verify the effects of aerobic and combined training on the body composition and lipid profile of obese postmenopausal women and to analyze which of these models is more effective after equalizing the training load. Sixty-five postmenopausal women (age = 61.0 +/- 6.3 years) were divided into 3 groups: aerobic training (AT, n = 15), combined training (CT [strength + aerobic], n = 32), and control group (CG, n = 18). Their body composition upper body fat (TF), fat mass (FM), percentage of FM, and fat-free mass (FFM) were estimated by dual-energy x-ray absorptiometry. The lipid profile, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein cholesterol were assessed. There was a statistically significant difference in the TF (AT = -4.4%, CT = -4.4%, and CG = 1.0%, p = 0.001) and FFM (AT = 1.7%, CT = 2.6%, and CG = -1.4%, p = 0.0001) between the experimental and the control groups. Regarding the percentage of body fat, there was a statistically significant difference only between the CT and CG groups (AT = 2.8%, CT = -3.9%, and CG = 0.31%; p = 0.004). When training loads were equalized, the aerobic and combined training decreased core fat and increased FFM, but only the combined training potentiated a reduction in percentage of body fat in obese postmenopausal women after the training program. High-density lipoprotein-c levels increased in the combined group, and the chol/HDL ratio (atherogenic index) decreased in the aerobic group; however, there were no significant differences between the intervention programs. Taken together, both the exercise training programs were effective for improving body composition and inducing an antiatherogenic status. PMID- 26038817 TI - Childhood neglect predicts disorganization in schizophrenia through grey matter decrease in dorsolateral prefrontal cortex. AB - OBJECTIVE: Psychosocial trauma during childhood is associated with schizophrenia vulnerability. The pattern of grey matter decrease is similar to brain alterations seen in schizophrenia. Our objective was to explore the links between childhood trauma, brain morphology and schizophrenia symptoms. METHOD: Twenty-one patients with schizophrenia stabilized with atypical antipsychotic monotherapy and 30 healthy control subjects completed the study. Anatomical MRI images were analysed using optimized voxel-based morphometry (VBM). Childhood trauma was assessed with the Childhood Trauma Questionnaire, and symptoms were rated on the Scale for the Assessment of Negative Symptoms (SANS) and Scale for the Assessment of Positive Symptoms (SAPS) (disorganization, positive and negative symptoms). In the schizophrenia group, we used structural equation modelling in a path analysis. RESULTS: Total grey matter volume was negatively associated with emotional neglect (EN) in patients with schizophrenia. Whole-brain VBM analyses of grey matter in the schizophrenia group revealed a specific inversed association between EN and the right dorsolateral prefrontal cortex (DLPFC). Path analyses identified a well-fitted model in which EN predicted grey matter density in DLPFC, which in turn predicted the disorganization score. CONCLUSION: Our findings suggest that EN during childhood could have an impact on psychopathology in schizophrenia, which would be mediated by developmental effects on brain regions such as the DLPFC. PMID- 26038819 TI - Splenocytes seed bone marrow of myeloablated mice: implication for atherosclerosis. AB - Extramedullary hematopoiesis has been shown to contribute to the pathogenesis of a variety of diseases including cardiovascular diseases. In this process, the spleen is seeded with mobilized bone marrow cells that augment its hematopoietic ability. It is unclear whether these immigrant cells that are produced/reprogrammed in spleen are similar or different from those found in the bone marrow. To begin to understand this, we investigated the relative potency of adult splenocytes per se to repopulate bone marrow of lethally-irradiated mice and its functional consequences in atherosclerosis. The splenocytes were harvested from GFP donor mice and transplanted into myeloablated wild type recipient mice without the inclusion of any bone marrow helper cells. We found that adult splenocytes repopulated bone marrow of myeloablated mice and the transplanted cells differentiated into a full repertoire of myeloid cell lineages. The level of monocytes/macrophages in the bone marrow of recipient mice was dependent on the cell origin, i.e., the donor splenocytes gave rise to significantly more monocytes/macrophages than the donor bone marrow cells. This occurred despite a significantly lower number of hematopoietic stem cells being present in the donor splenocytes when compared with donor bone marrow cells. Atherosclerosis studies revealed that donor splenocytes displayed a similar level of atherogenic and atheroprotective activities to those of donor bone marrow cells. Cell culture studies showed that the phenotype of macrophages derived from spleen is different from those of bone marrow. Together, these results demonstrate that splenocytes can seed bone marrow of myeloablated mice and modulate atherosclerosis. In addition, our study shows the potential of splenocytes for therapeutic interventions in inflammatory disease. PMID- 26038820 TI - Robust muscle activity onset detection using an unsupervised electromyogram learning framework. AB - Accurate muscle activity onset detection is an essential prerequisite for many applications of surface electromyogram (EMG). This study presents an unsupervised EMG learning framework based on a sequential Gaussian mixture model (GMM) to detect muscle activity onsets. The distribution of the logarithmic power of EMG signal was characterized by a two-component GMM in each frequency band, in which the two components respectively correspond to the posterior distribution of EMG burst and non-burst logarithmic powers. The parameter set of the GMM was sequentially estimated based on maximum likelihood, subject to constraints derived from the relationship between EMG burst and non-burst distributions. An optimal threshold for EMG burst/non-burst classification was determined using the GMM at each frequency band, and the final decision was obtained by a voting procedure. The proposed novel framework was applied to simulated and experimental surface EMG signals for muscle activity onset detection. Compared with conventional approaches, it demonstrated robust performance for low and changing signal to noise ratios in a dynamic environment. The framework is applicable for real-time implementation, and does not require the assumption of non EMG burst in the initial stage. Such features facilitate its practical application. PMID- 26038821 TI - Bacterial Ventures into Multicellularity: Collectivism through Individuality. AB - Multicellular eukaryotes can perform functions that exceed the possibilities of an individual cell. These functions emerge through interactions between differentiated cells that are precisely arranged in space. Bacteria also form multicellular collectives that consist of differentiated but genetically identical cells. How does the functionality of these collectives depend on the spatial arrangement of the differentiated bacteria? In a previous issue of PLOS Biology, van Gestel and colleagues reported an elegant example of how the spatial arrangement of differentiated cells gives rise to collective behavior in Bacillus subtilus colonies, further demonstrating the similarity of bacterial collectives to higher multicellular organisms. PMID- 26038822 TI - Somatic Embryogenesis: Identified Factors that Lead to Embryogenic Repression. A Case of Species of the Same Genus. AB - Somatic embryogenesis is a powerful biotechnological tool for the mass production of economically important cultivars. Due to the cellular totipotency of plants, somatic cells under appropriate conditions are able to develop a complete functional embryo. During the induction of somatic embryogenesis, there are different factors involved in the success or failure of the somatic embryogenesis response. Among these factors, the origin of the explant, the culture medium and the in vitro environmental conditions have been the most studied. However, the secretion of molecules into the media has not been fully addressed. We found that the somatic embryogenesis of Coffea canephora, a highly direct embryogenic species, is disrupted by the metabolites secreted from C. arabica, a poorly direct embryogenic species. These metabolites also affect DNA methylation. Our results show that the abundance of two major phenolic compounds, caffeine and chlorogenic acid, are responsible for inhibiting somatic embryogenesis in C. canephora. PMID- 26038823 TI - Neuronal Cx3cr1 Deficiency Protects against Amyloid beta-Induced Neurotoxicity. AB - Cx3cr1, the receptor for the chemokine Cx3cl1 (fractalkine), has been implicated in the progression and severity of Alzheimer's disease-like pathology in mice, but the underlying mechanisms remain unclear. A complicating factor is that Cx3cr1 has been demonstrated in both neurons and microglia. Here, we have dissected the differences between neuronal and microglial Cx3cr1, specifically by comparing direct amyloid-beta-induced toxicity in cultured, mature, microglia depleted hippocampal neurons from wild-type and Cx3cr1-/- mice. Wild-type neurons expressed both Cx3cl1 and Cx3cr1 and released Cx3cl1 in response to amyloid-beta. Knockout of neuronal Cx3cr1 abated amyloid-beta-induced lactate dehydrogenase release. Furthermore, amyloid-beta differentially induced depression of pre- and postsynaptic components of miniature excitatory postsynaptic currents, in a peptide conformation-dependent manner. Knockout of neuronal Cx3cr1 abated effects of both amyloid-beta conformational states, which were differentiable by aggregation kinetics and peptide morphology. We obtained similar results after both acute and chronic treatment of cultured neurons with the Cx3cr1 antagonist F1. Thus, neuronal Cx3cr1 may impact Alzheimer's disease-like pathology by modulating conformational state-dependent amyloid-beta-induced synaptotoxicity. PMID- 26038824 TI - Association between Mindfulness and Weight Status in a General Population from the NutriNet-Sante Study. AB - BACKGROUND: Mindfulness is defined as non-judgmental awareness of the present moment. There is some evidence of the efficacy of mindfulness-based interventions in weight loss. However, this psychological concept has only been rarely explored in observational studies, and no study to date has examined the association between dispositional mindfulness and weight status in a large population-based sample. OBJECTIVE: We aimed to examine the relationship between mindfulness scores and weight status in a large sample of the adult general population in France. DESIGN AND METHODS: A total of 14,400 men and 49,228 women aged >=18 y participating in the NutriNet-Sante study were included in this cross-sectional analysis. We collected mindfulness data using the Five Facet Mindfulness Questionnaire as well as self-reported weight and height. The association between weight status and dispositional mindfulness, as well as its subscales (observing, describing, acting with awareness, non-judging and non-reactivity), was assessed using multinomial logistic regression models adjusted for socio-demographic and lifestyle factors. RESULTS: Women with higher dispositional mindfulness scores were less likely to be overweight (excluding obesity) (OR quartile 4 vs. 1 = 0.84, 95% CI: 0.79-0.90) and obese (OR quartile 4 vs. 1 = 0.71, 95% CI: 0.65 0.78). In addition, overall, in this group, all subscales were inversely associated with weight status, with the strongest association found for the "observing" subscale. In men, higher mindfulness was associated only with lower odds of obesity (OR quartile 4 vs. 1 = 0.81 (0.69, 0.96)), and only the "observing" and "non-reactivity" subscales were significantly inversely associated with weight status. CONCLUSION: Results support the interest of a shift in perspective that takes into account positive psychological and cognitive factors such as dispositional mindfulness in the investigation of obesity and its associated factors. PMID- 26038825 TI - Alterations of Gray and White Matter Networks in Patients with Obsessive Compulsive Disorder: A Multimodal Fusion Analysis of Structural MRI and DTI Using mCCA+jICA. AB - Many of previous neuroimaging studies on neuronal structures in patients with obsessive-compulsive disorder (OCD) used univariate statistical tests on unimodal imaging measurements. Although the univariate methods revealed important aberrance of local morphometry in OCD patients, the covariance structure of the anatomical alterations remains unclear. Motivated by recent developments of multivariate techniques in the neuroimaging field, we applied a fusion method called "mCCA+jICA" on multimodal structural data of T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) of 30 unmedicated patients with OCD and 34 healthy controls. Amongst six highly correlated multimodal networks (p < 0.0001), we found significant alterations of the interrelated gray and white matter networks over occipital and parietal cortices, frontal interhemispheric connections and cerebella (False Discovery Rate q <= 0.05). In addition, we found white matter networks around basal ganglia that correlated with a subdimension of OC symptoms, namely 'harm/checking' (q <= 0.05). The present study not only agrees with the previous unimodal findings of OCD, but also quantifies the association of the altered networks across imaging modalities. PMID- 26038826 TI - Perchlorate in Lake Water from an Operating Diamond Mine. AB - Mining-related perchlorate [ClO4(-)] in the receiving environment was investigated at the operating open-pit and underground Diavik diamond mine, Northwest Territories, Canada. Samples were collected over four years and ClO4(-) was measured in various mine waters, the 560 km(2) ultraoligotrophic receiving lake, background lake water and snow distal from the mine. Groundwaters from the underground mine had variable ClO4(-) concentrations, up to 157 MUg L(-1), and were typically an order of magnitude higher than concentrations in combined mine waters prior to treatment and discharge to the lake. Snow core samples had a mean ClO4(-) concentration of 0.021 MUg L(-1) (n=16). Snow and lake water Cl(-)/ClO4( ) ratios suggest evapoconcentration was not an important process affecting lake ClO4(-) concentrations. The multiyear mean ClO4(-) concentrations in the lake were 0.30 MUg L(-1) (n = 114) in open water and 0.24 MUg L(-1) (n = 107) under ice, much below the Canadian drinking water guideline of 6 MUg L(-1). Receiving lake concentrations of ClO4(-) generally decreased year over year and ClO4(-) was not likely [biogeo]chemically attenuated within the receiving lake. The discharge of treated mine water was shown to contribute mining-related ClO4(-) to the lake and the low concentrations after 12 years of mining were attributed to the large volume of the receiving lake. PMID- 26038827 TI - Correlation between the Uptake of 18F-Fluorodeoxyglucose (18F-FDG) and the Expression of Proliferation-Associated Antigen Ki-67 in Cancer Patients: A Meta Analysis. AB - OBJECTIVE: To study the correlation between 18F-FDG uptake and cell proliferation in cancer patients by meta-analysis of published articles. METHODS: We searched PubMed (MEDLINE included), EMBASE, and Cochrane Database of Systematic Review, and selected research articles on the relationship between 18F-FDG uptake and Ki 67 expression (published between August 1, 1994-August 1, 2014), according to the literature inclusion and exclusion criteria. The publishing language was limited to English. The quality of included articles was evaluated according to the Quality Assessment of Diagnosis Accuracy Studies-2 (QUADAS-2). The correlation coefficient (r) was extracted from the included articles and processed by Fisher's r-to-z transformation. The combined correlation coefficient (r) and the 95% confidence interval (CI) were calculated with STATA 11.0 software under a random-effects model. Begg's test was used to analyze the existence of publication bias and draw funnel plot, and the sources of heterogeneity were explored by sensitivity and subgroup analyses. RESULTS: According to the inclusion and exclusion criteria, 79 articles were finally included, including 81 studies involving a total of 3242 patients. All the studies had a combined r of 0.44 (95% CI, 0.41-0.46), but with a significant heterogeneity (I2 = 80.9%, P<0.01). Subgroup analysis for different tumor types indicated that most subgroups showed a reduced heterogeneity. Malignant melanoma (n = 1) had the minimum correlation coefficient (-0.22) between 18F-FDG uptake and Ki-67 expression, while the thymic epithelial tumors (TETs; n = 2) showed the maximum correlation coefficient of 0.81. The analytical results confirmed that correlation between 18F-FDG uptake and Ki-67 expression was extremely significant in TETs, significant in gastrointestinal stromal tumors (GISTs), moderate in patients with lung, breast, bone and soft tissue, pancreatic, oral, thoracic, and uterine and ovarian cancers, average in brain, esophageal and colorectal cancers, and poor in head and neck, thyroid, gastric and malignant melanoma tumors. Subgroup analysis indicated that positron emission tomography (PET) or PET/CT imaging technology or Ki-67 and standardized uptake value (SUV) measurement technology did not significantly affect the results of r values, and Begg's test showed no significant publication bias. CONCLUSION: In cancer patients, 18F-FDG uptake showed a moderate positive correlation with tumor cell proliferation. Different tumor types exhibited varied degree of correlation, and the correlation was significant in TETs and GSTs. However, our results need further validation by clinical trials with a large sample of different tumor types. PMID- 26038829 TI - Mitochondrial Targeting of Doxorubicin Eliminates Nuclear Effects Associated with Cardiotoxicity. AB - The highly effective anticancer agent doxorubicin (Dox) is a frontline drug used to treat a number of cancers. While Dox has a high level of activity against cancer cells, its clinical use is often complicated by dose-limiting cardiotoxicity. While this side effect has been linked to the drug's direct activity in the mitochondria of cardiac cells, recent studies have shown that these result primarily from downstream effects of nuclear DNA damage. Our lab has developed a mitochondrially targeted derivative of Dox that enables the selective study of toxicity generated by the presence of Dox in the mitochondria of human cells. We demonstrate that mitochondria-targeted doxorubicin (mtDox) lacks any direct nuclear effects in H9c2 rat cardiomyocytes, and that these cells are able to undergo mitochondrial biogenesis. This recovery response compensates for the mitotoxic effects of Dox and prevents cell death in cardiomyocytes. Furthermore, cardiac toxicity was only observed in Dox but not mtDox treated mice. This study supports the hypothesis that mitochondrial damage is not the main source of the cardiotoxic effects of Dox. PMID- 26038828 TI - Expression and new exon mutations of the human Beta defensins and their association on colon cancer development. AB - The development of cancer involves genetic predisposition and a variety of environmental exposures. Genome-wide linkage analyses provide evidence for the significant linkage of many diseases to susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Human beta-defensins (hBDs) are important molecules of innate immunity. This study was designed to analyze the expression and genetic variations in hBDs (hBD-1, hBD-2, hBD-3 and hBD-4) and their putative association with colon cancer. hBD gene expression and relative protein expression were evaluated by Real-Time polymerase chain reaction (qPCR) and immunohistochemistry, respectively, from 40 normal patients and 40 age matched patients with colon cancer in Saudi Arabia. In addition, hBD polymorphisms were genotyped by exon sequencing and by promoter methylation. hBD 1, hBD-2, hBD-3 and hBD-4 basal messenger RNA expression was significantly lower in tumor tissues compared with normal tissues. Several insertion mutations were detected in different exons of the analyzed hBDs. However, no methylation in any hBDs promoters was detected because of the limited number of CpG islands in these regions. We demonstrated for the first time a link between hBD expression and colon cancer. This suggests that there is a significant link between innate immunity deregulation through disruption of cationic peptides (hBDs) and the potential development of colon cancer. PMID- 26038831 TI - Correction: increasing trends of herpes zoster in Australia. PMID- 26038830 TI - Altered Markers of Cortical gamma-Aminobutyric Acid Neuronal Activity in Schizophrenia: Role of the NARP Gene. AB - IMPORTANCE: In schizophrenia, working memory deficits appear to reflect abnormalities in the generation of gamma oscillations in the dorsolateral prefrontal cortex. The generation of gamma oscillations requires the phasic excitation of inhibitory parvalbumin-containing interneurons. Thus, gamma oscillations depend, in part, on the number of synaptic glutamate receptors on parvalbumin interneurons. However, little is known about the molecular factors that regulate glutamate receptor-mediated excitation of parvalbumin interneurons in schizophrenia. OBJECTIVE: To quantify in individuals with schizophrenia the expression of immediate early genes (NARP, ARC, and SGK1) regulating glutamate synaptic neurotransmission. DESIGN, SETTING, AND PARTICIPANTS: Postmortem brain specimens (n = 206) were obtained from individuals with schizophrenia, bipolar disorder, or major depressive disorder and from well-matched healthy persons (controls). For a study of brain tissue, quantitative polymerase chain reaction, in situ hybridization, or microarray analyses were used to measure transcript levels in the dorsolateral prefrontal cortex at gray matter, laminar, and cellular levels of resolutions. This study was conducted between January 1, 2013, and November 30, 2014. MAIN OUTCOMES AND MEASURES: Expression levels for NARP, ARC, and SGK1 messenger RNA (mRNA) were compared between specimens from individuals with schizophrenia and controls. Diagnostic specificity was assessed by quantifying NARP mRNA levels in specimens from individuals with mood disorders. RESULTS: By quantitative polymerase chain reaction, levels of NARP mRNA were significantly lower by 25.6% in specimens from individuals with schizophrenia compared with the controls (mean [SD], 0.036 [0.018] vs 0.049 [0.015]; F1,114 = 21.0; P < .001). Levels of ARC (F1,112 = 0.93; P = .34) and SGK1 (F1,110 = 2.52; P = .12) were not significant. These findings were supported by in situ hybridization (NARP; individuals with schizophrenia vs controls: 40.1% lower [P = .003]) and microarray analyses (NARP; individuals with schizophrenia vs controls: 12.2% lower in layer 3 [P = .11] and 14.6% lower in layer 5 pyramidal cells [P = .001]). In schizophrenia specimens, NARP mRNA levels were positively correlated with GAD67 mRNA (r = 0.55; P < .001); the expression of GAD67 mRNA in parvalbumin interneurons is activity dependent. The NARP mRNA levels were also lower than healthy controls in bipolar disorder (-18.2%; F1,60 = 11.39; P = .001) and major depressive disorder (-21.7%; F1,30 = 5.36; P = .03) specimens, especially those from individuals with psychosis. In all 3 diagnostic groups, NARP mRNA levels were positively correlated (all r >= 0.53; all P <= .02) with somatostatin mRNA, the expression of which is activity dependent. CONCLUSIONS AND RELEVANCE: Given the role of NARP in the formation of excitatory inputs to parvalbumin (and perhaps somatostatin) interneurons, our findings suggest that lower NARP mRNA expression contributes to lower excitatory drive onto parvalbumin interneurons in schizophrenia. This reduced excitatory drive may lead to lower synthesis of gamma-aminobutyric acid in these interneurons, contributing to a reduced capacity to generate the gamma oscillations required for working memory. PMID- 26038832 TI - Blockade of Salusin-beta in Hypothalamic Paraventricular Nucleus Attenuates Hypertension and Cardiac Hypertrophy in Salt-induced Hypertensive Rats. AB - Salusin-beta, a multifunctional bioactive peptide, is considered as a promising candidate biomarker for predicting cardiovascular diseases. This study was designed to determine whether inhibition of salusin-beta in the hypothalamic paraventricular nucleus (PVN) delays the progression of hypertension and attenuates cardiac hypertrophy by restoring neurotransmitters and cytokines. Male Sprague Dawley rats were fed with a normal salt diet (NS, 0.3%) or a high salt diet (HS, 8%) for 8 weeks to induce hypertension. Then, these rats received bilateral PVN infusion of a specific salusin-beta blocker, antisalusin-beta IgG (SIgG), or control IgG (CIgG) for 2 weeks. HS rats exhibited higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/bodyweight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and messenger RNA levels of cardiac atrial natriuretic peptide (ANP), and beta-myosin heavy chain. Compared with NS rats, HS rats had higher levels of glutamate, norepinephrine, tyrosine hydroxylase, proinflammatory cytokines, and lower levels of gamma-aminobutyric acid, interleukin 10, and the 67-kDa isoform of glutamate decarboxylase (GAD67) in the PVN, and higher plasma levels of proinflammatory cytokines. Chronic PVN infusion of SIgG attenuated all these changes in HS rats. Our findings suggest that HS rats have an imbalance between excitatory and inhibitory neurotransmitters, as well as an imbalance between proinflammatory and anti-inflammatory cytokines in the PVN; and chronic inhibition of salusin-beta in the PVN restores neurotransmitters and cytokines in the PVN, thereby attenuating hypertensive responses and cardiac hypertrophy. PMID- 26038833 TI - Novel handheld magnetometer probe based on magnetic tunnelling junction sensors for intraoperative sentinel lymph node identification. AB - Using magnetic tunnelling junction sensors, a novel magnetometer probe for the identification of the sentinel lymph node using magnetic tracers was developed. Probe performance was characterised in vitro and validated in a preclinical swine model. Compared to conventional gamma probes, the magnetometer probe showed excellent spatial resolution of 4.0 mm, and the potential to detect as few as 5 MUg of magnetic tracer. Due to the high sensitivity of the magnetometer, all first-tier nodes were identified in the preclinical experiments, and there were no instances of false positive or false negative detection. Furthermore, these preliminary data encourage the application of the magnetometer probe for use in more complex lymphatic environments, such as in gastrointestinal cancers, where the sentinel node is often in close proximity to other non-sentinel nodes, and high spatial resolution detection is required. PMID- 26038834 TI - Lewis Acid Catalyzed Condensation-Cyclization Cascade: Direct Synthesis of Di/Trifluoromethyl-1,2,3,4-tetrahydroquinazolines. AB - Condensed heterocycles such as quinazolines constitute the framework of many promising drugs. The great impact of the dramatic fluorine effect in pharmaceuticals prompted a great surge in the quest for fluorinated drug design resulting in over 20 % fluorine-containing drugs in the market today. Therefore, finding an efficient and cost-effective method for the direct synthesis of fluorine-tagged quinazoline systems is of great significance in the pharmaceutical arena. For the first time, a one-pot sequential condensation cyclization reaction to form selectively the difluoro/trifluoromethylated tetrahydroquinazolines from simple components difluoro/trifluoroacetaldehyde hemiacetal and aromatic amines is reported. Our recent studies using difluoro/trifluoroacetaldehyde hemiacetal as simple and elegant difluoro/trifluoromethyl synthons and metal triflates such as gallium triflate as safe and stable Lewis acid catalysts led us to this direct synthesis protocol for the expedient and convenient synthesis of fluorinated quinazolines. DFT calculations at PCM/B3LYP/6-31++G** were carried out for evaluating a possible reaction mechanism for this cyclization. According to the DFT calculations, product stereochemistry is thermodynamically driven, favoring the cis isomer as the major product, which is also confirmed experimentally. PMID- 26038835 TI - Astrocyte-conditioned medium attenuates glutamate-induced apoptotic cell death in primary cultured spinal cord neurons of rats. AB - OBJECTIVES: To better understand the neuroprotective role of astrocytes in spinal cord injury (SCI), we investigated whether astrocyte-conditioned medium (ACM) can attenuate glutamate-induced apoptotic cell death in primary cultured spinal cord neurons. METHODS: Spinal cord neurons were pretreated with ACM for 24 hours. Subsequently, they were exposed to glutamate (125 MUM) for 1 hour. The neurons were then incubated for 24 hours. Following that, measurements assessing cell viability and lactate dehydrogenase (LDH) release were performed. Apoptosis was confirmed through cell morphology using Hoechst 33342 staining and terminal deoxynucleotidyl transferase dUTP-mediated nicked end labeling (TUNEL) assay. Assessment for expression of apoptotic enzymes, including Caspase-3, Bcl-2 and Bax, was performed using Western Blot Analysis. RESULTS: Astrocyte-conditioned medium pretreatment of neurons showed both an increase in spinal cord neuron viability and a decrease in LDH release in a dose-dependent pattern. Moreover, pretreatment seems to attenuate glutamate-induced apoptotic cell death, antagonise glutamate-induced up-regulation of Caspase-3 expression and downregulate Bcl-2/Bax protein expression ratio. CONCLUSIONS: By attenuating glutamate-induced apoptotic cell death in primary cultured spinal cord neurons of rats, ACM seems to provide a neuroprotective effect by regulating apoptosis related protein expression. Our results provide an experimental basis for clinical applications and potential therapeutic use of ACM in SCI. PMID- 26038836 TI - Basketball shot types and shot success in different levels of competitive basketball. AB - The purpose of our research was to investigate the relative frequencies of different types of basketball shots (above head, hook shot, layup, dunk, tip-in), some details about their technical execution (one-legged, two-legged, drive, cut, ...), and shot success in different levels of basketball competitions. We analysed video footage and categorized 5024 basketball shots from 40 basketball games and 5 different levels of competitive basketball (National Basketball Association (NBA), Euroleague, Slovenian 1st Division, and two Youth basketball competitions). Statistical analysis with hierarchical multinomial logistic regression models reveals that there are substantial differences between competitions. However, most differences decrease or disappear entirely after we adjust for differences in situations that arise in different competitions (shot location, player type, and attacks in transition). Differences after adjustment are mostly between the Senior and Youth competitions: more shots executed jumping or standing on one leg, more uncategorised shot types, and more dribbling or cutting to the basket in the Youth competitions, which can all be attributed to lesser technical and physical ability of developing basketball players. The two discernible differences within the Senior competitions are that, in the NBA, dunks are more frequent and hook shots are less frequent compared to European basketball, which can be attributed to better athleticism of NBA players. The effect situational variables have on shot types and shot success are found to be very similar for all competitions. PMID- 26038838 TI - Correction: nicotinamide impairs entry into and exit from meiosis I in mouse oocytes. PMID- 26038837 TI - A Multifaceted Study of Scedosporium boydii Cell Wall Changes during Germination and Identification of GPI-Anchored Proteins. AB - Scedosporium boydii is a pathogenic filamentous fungus that causes a wide range of human infections, notably respiratory infections in patients with cystic fibrosis. The development of new therapeutic strategies targeting S. boydii necessitates a better understanding of the physiology of this fungus and the identification of new molecular targets. In this work, we studied the conidium-to germ tube transition using a variety of techniques including scanning and transmission electron microscopy, atomic force microscopy, two-phase partitioning, microelectrophoresis and cationized ferritin labeling, chemical force spectroscopy, lectin labeling, and nanoLC-MS/MS for cell wall GPI-anchored protein analysis. We demonstrated that the cell wall undergoes structural changes with germination accompanied with a lower hydrophobicity, electrostatic charge and binding capacity to cationized ferritin. Changes during germination also included a higher accessibility of some cell wall polysaccharides to lectins and less CH3/CH3 interactions (hydrophobic adhesion forces mainly due to glycoproteins). We also extracted and identified 20 GPI-anchored proteins from the cell wall of S. boydii, among which one was detected only in the conidial wall extract and 12 only in the mycelial wall extract. The identified sequences belonged to protein families involved in virulence in other fungi like Gelp/Gasp, Crhp, Bglp/Bgtp families and a superoxide dismutase. These results highlighted the cell wall remodeling during germination in S. boydii with the identification of a substantial number of cell wall GPI-anchored conidial or hyphal specific proteins, which provides a basis to investigate the role of these molecules in the host-pathogen interaction and fungal virulence. PMID- 26038839 TI - CD38-mediated Ca(2+) signaling contributes to glucagon-induced hepatic gluconeogenesis. AB - CD38 is a multifunctional enzyme for the synthesis of Ca(2+) second messengers. Glucagon promotes hepatic glucose production through Ca(2+) signaling in the fasting condition. In this study, we investigated the role of CD38 in the glucagon signaling of hepatocytes. Here, we show that glucagon induces cyclic ADP ribose (cADPR) production and sustained Ca(2+) increases via CD38 in hepatocytes. 8-Br-cADPR, an antagonistic cADPR analog, completely blocked glucagon-induced Ca(2+) increases and phosphorylation of cAMP response element-binding protein (CREB). Moreover, glucagon-induced sustained Ca(2+) signals and translocation of CREB-regulated transcription coactivator 2 to the nucleus were absent and glucagon-induced glucose production and expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (Pck1) are remarkably reduced in hepatocytes from CD38(-/-) mice. Furthermore, in the fasting condition, CD38(-/-) mice have decreased blood glucose and hepatic expression of G6Pase and Pck1 compared to wild type mice. Our data suggest that CD38/cADPR-mediated Ca(2+) signals play a key role in glucagon-induced gluconeogenesis in hepatocytes, and that the signal pathway has significant clinical implications in metabolic diseases, including type 2 diabetes. PMID- 26038841 TI - Prevalence and clinical significance of abnormal serum kappa/lambda light chain ratio in patients with chronic kidney disease. AB - INTRODUCTION: A range of malignant diseases (both solid organ tumors and hematogenous malignancies) may manifest as proteinuria/nephrotic syndrome. Multiple myeloma (MM) typically involves the kidneys and proteinuria, and chronic kidney disease (CKD) may also be the first manifestation of MM. OBJECTIVES: The aim of the study was to evaluate the prevalence and clinical significance of abnormal serum free kappa/lambda light chain ratio in patients referred to a renal center for a diagnostic workup for proteinuria or CKD of an unknown origin (or both). PATIENTS AND METHODS: Free light chain tests were performed in 92 consecutive patients (mean age, 63 +/-13.9 years; women, 38%; men, 62%) using FreeLite kits. In addition, serum creatinine, calcium, and albumin levels as well as estimated glomerular filtration rate (eGFR) were measured and blood count and proteinuria were assessed. In 39 patients, kidney biopsy was also performed. Nephrotic syndrome was found in 38% of the patients; nonnephrotic proteinuria, in 39.1%; and isolated reduction of eGFR (without proteinuria), in 22.9%. RESULTS: MM was confirmed in 5 patients (5.43%; all patients had a highly abnormal kappa/lambda ratio). After the exclusion of the subjects with MM, the abnormal kappa/lambda ratio was found in 37 patients (42.5%); MM was excluded in all patients after careful hematological evaluation, including bone marrow biopsy in 12 cases. The percentage of the abnormal kappa/lambda ratio was high regardless of the proteinuria level, eGFR, or the type of glomerulopathy diagnosed by kidney biopsy. The kappa/ lambda ratio did not correlate with age, proteinuria, or eGFR. CONCLUSIONS: Our results suggest that an abnormal kappa/lambda ratio (in most cases higher than normal) is a common and, most likely, nonspecific finding in patients with proteinuria or CKD of an unknown origin (or both). PMID- 26038843 TI - [Living conditions, nutritional status and morbidity in children in prisons and detention centers in Burkina Faso]. AB - In Burkina Faso, although children are sometimes separated from adults in prisons, they still live in the same conditions of overcrowding, which can reach 180% of the capacity. The aim of our study was to describe living conditions, nutritional status, and morbidity of children in detention centers of Burkina Faso. The objective of this cross-sectional descriptive study is to describe the social and health conditions of children held in 20 detention centers in Burkina Faso. During the study period, 109 children, with a mean age of 16.3 years, were examined in 20 correction centers. The main reason for incarceration was theft (66% cases, n = 72). Detention exceeded more than one month for 76 children (70%), and 59% (N = 46) had had fewer than one visit per month since their incarceration. Of these 20 facilities, 6 had no separate quarters for children. The main symptoms and diseases encountered in these children were fever in 19% of the cases (N = 16), macroscopic hematuria in 13% (N = 11), urinary tract infection in 12% (N = 10) and diarrhea in 12% (N = 10). These results show that there is a need to take preventive measures to protect these children's health, especially by improving the quality of living conditions in detention center. PMID- 26038842 TI - Mapping of Replication Origins in the X Inactivation Center of Vole Microtus levis Reveals Extended Replication Initiation Zone. AB - DNA replication initiates at specific positions termed replication origins. Genome-wide studies of human replication origins have shown that origins are organized into replication initiation zones. However, only few replication initiation zones have been described so far. Moreover, few origins were mapped in other mammalian species besides human and mouse. Here we analyzed pattern of short nascent strands in the X inactivation center (XIC) of vole Microtus levis in fibroblasts, trophoblast stem cells, and extraembryonic endoderm stem cells and confirmed origins locations by ChIP approach. We found that replication could be initiated in a significant part of XIC. We also analyzed state of XIC chromatin in these cell types. We compared origin localization in the mouse and vole XIC. Interestingly, origins associated with gene promoters are conserved in these species. The data obtained allow us to suggest that the X inactivation center of M. levis is one extended replication initiation zone. PMID- 26038844 TI - [Improving the provision of major obstetric interventions by task delegation in Africa: An example from the Bogodogo health district hospital in Ouagadougou, Burkina Faso]. AB - OBJECTIVE: To describe the role of task delegation in the practice of major obstetric procedures in the Bogodogo health district hospital. MATERIALS AND METHODS: This descriptive and analytic prospective study took place in the hospital's department of obstetrics and gynecology from February through October 2013. It included all women undergoing a major obstetric surgical intervention, performed by either by a gynecologist-obstetrician or by a nurse specializing in surgery. Data were collected from individual records and analyzed by SPSS and Epidata software. RESULTS: There were 601 major obstetric interventions during the study period. The women's mean age was 26.7 years. Cesarean deliveries accounted for 90% of these procedures, followed by laparotomy (7.7%). The Misgav Ladach technique was used for cesareans by 86.5% of the obstetricians and 95.3% of the nurses specialized in surgery. The primary complications were anemia and postpartum hemorrhage. Maternal mortality did not differ significantly between the groups of operators, nor did maternal, fetal, and neonatal outcomes. CONCLUSION: Task delegation in obstetric surgery at the Bogodogo district hospital is effective. Its extension to the national level would make it possible to overcome the lack of highly qualified human resources to enable adequate availability of major obstetric interventions in rural hospitals. PMID- 26038845 TI - The Impact of Jumping during Recovery on Repeated Sprint Ability in Young Soccer Players. AB - This study compared the effect of counter-movement-jump (CMJ)-based recovery on repeated-sprint-ability (RSA). Eighteen male footballers (16 +/- 0 years, 65 +/- 10 kg, 1.74 +/- 0.10 m) performed three RSA-tests. RSA-1/-3 were performed according to standard procedures, while three CMJs (over 10") - as a potential fatigue-determinant and/or running mechanics interference--were administered during RSA-2 recoveries. RSA performance, exercise effort (fatigue index [FI], rating of perceived exertion [RPE], blood lactate concentration [BLa]), simple kinematics (steps number), vertical-jump characteristics (stretch-shortening cycle-efficiency [SSCE] assessed before/after RSA) were investigated. ANOVA showed no differences between RSA-1,-3. During RSA-2, performance was lower than RSA-1/-3, while steps number did not change. During RSA-2, FI, BLa, RPE were higher than RSA-1/-3 (FI +21.10/+20.43%, P<0.05; BLa +16.25/+13.34%, P<0.05; RPE +12.50/+9.57%, P<0.05). During RSA-2, SSCE, as the CMJ/squat-jump-height-ratio, was not significantly different from RSA-1/-3. Passive recovery RSA allows better performance. Yet, RSA CMJ-based recovery is effective in increasing training load (FI, BLa, RPE) without perturbing running mechanics (simple kinematics, SSCE). PMID- 26038846 TI - Cephalic and limb anatomy of a new Isoxyid from the Burgess Shale and the role of "stem bivalved arthropods" in the disparity of the frontalmost appendage. AB - We herein describe Surusicaris elegans gen. et sp. nov. (in Isoxyidae, amended), a middle (Series 3, Stage 5) Cambrian bivalved arthropod from the new Burgess Shale deposit of Marble Canyon (Kootenay National Park, British Columbia). Surusicaris exhibits 12 simple, partly undivided biramous trunk limbs with long tripartite caeca, which may illustrate a plesiomorphic "fused" condition of exopod and endopod. We construe also that the head is made of five somites (= four segments), including two eyes, one pair of anomalocaridid-like frontalmost appendages, and three pairs of poorly sclerotized uniramous limbs. This fossil may therefore be a candidate for illustrating the origin of the plesiomorphic head condition in euarthropods, and questions the significance of the "two segmented head" in, e.g., fuxianhuiids. The frontalmost appendage in isoxyids is intriguingly disparate, bearing similarities with both dinocaridids and euarthropods. In order to evaluate the relative importance of bivalved arthropods, such as Surusicaris, in the hypothetical structuro-functional transition between the dinocaridid frontal appendage and the pre-oral-arguably deutocerebral-appendage of euarthropods, we chose a phenetic approach and computed morphospace occupancy for the frontalmost appendages of 36 stem and crown taxa. Results show different levels of evolutionary decoupling between frontalmost appendage disparity and body plans. Variance is greatest in dinocaridids and "stem bivalved" arthropods, but these groups do not occupy the morphospace homogeneously. Rather, the diversity of frontalmost appendages in "stem bivalved" arthropods, distinct in its absence of clear clustering, is found to link the morphologies of "short great appendages," chelicerae and antennules. This find fits the hypothesis of an increase in disparity of the deutocerebral appendage prior to its diversification in euarthropods, and possibly corresponds to its original time of development. The analysis of this pattern, however, is sensitive to the-still unclear-extent of polyphyly of the "stem bivalved" taxa. PMID- 26038847 TI - Rupatadine 20 mg and 40 mg are Effective in Reducing the Symptoms of Chronic Cold Urticaria. AB - Chronic cold urticaria (ColdU) is a rare disease characterized by mast cell mediated wheals and angioedema following cold exposure. Second-generation H1 antihistamines, such as rupatadine, are the recommended first-line therapy. As of yet, the effects of rupatadine up-dosing on development of ColdU symptom have only been partially characterized. Two-centre, randomized, double-blind, 3-way crossover, placebo-controlled study in patients with a confirmed ColdU was designed to assess the effects of up-dosing of rupatadine. A total of 23 patients were randomized to receive placebo, rupatadine 20 mg/day, and rupatadine 40 mg/day for 1 week. The primary outcome was change in critical temperature thresholds and critical stimulation time thresholds after treatment. Secondary endpoints included assessment of safety and tolerability of rupatadine. Both 20 and 40 mg rupatadine were highly effective in reducing critical temperature thresholds (p < 0.001) and critical stimulation time thresholds (p < 0.001). In conclusion, rupatadine 20 and 40 mg significantly reduced the development of chronic cold urticaria symptom without an increase in adverse effects. PMID- 26038848 TI - Roads traveled. PMID- 26038849 TI - Horizons and challenges. PMID- 26038850 TI - "Sick and unable to march:" life and death in the army of the Dutch West India Company in the Northeast of Brazil, 1630-1654. AB - Of the many evils that were inflicted upon the army of the West India Company in its years of activity in Brazil, few could be compared to diseases. However, there is little quantitative data in the field of historiography regarding the impact of disease on these troops. Apart from the limited amount of information about the diseases that affected many soldiers, little is known about the medical treatments that were available, the main diseases that affected the troops, and what were the causes. This article provides information to understand aspects that have been little studied in quantitative and systematic terms in the field of historiography, and demonstrates how the diseases afflicted the Company and affected its actions in the territory. PMID- 26038851 TI - Control, containment and health education in the smallpox-vaccination campaigns in Mexico in the 1940s. AB - This article examines some of the changes that the Mexican vaccination programs underwent starting in 1943, the year when the National Smallpox Campaign (Campana Nacional contra la Viruela) was established. It analyzes why a uniform and coordinated vaccination method was adopted to counter the outbreaks of this endemic disease, especially in central Mexico; the actions of its numerous and heterogeneous staff; and the reasons why smallpox vaccination was considered critical to establish a culture of prevention. In summary, the article examines why selective vaccination was chosen and the expansion of the health-education programs, topics that have been seldom addressed in historical research. PMID- 26038852 TI - Between the examination of children's bodies and the shaping of racial norms: aspects of the activities of the Sao Paulo State School Medical Inspection Service. AB - This article analyzes aspects of the activities of the School Medical Inspection Service, an agency created in 1911 under the Sao Paulo State Sanitary Service and transferred in 1916 to the Secretary of Public Instruction. It focuses, more specifically, on the practice of the individual examination of students with the purpose of understanding the motivations behind these practices, the role they played in establishing standards of normality and abnormality, as well as their underlying racial tenor. To this end, its sources are articles published in the periodical Imprensa Medica, works written by the agency's head physician, Balthazar Vieira de Mello, and the Anuarios do ensino, the official publication of the General Board for Public Instruction. PMID- 26038853 TI - [Prevention rather than cure: the emergence and first stage of the Centros de Higiene Infantil in Mexico City, 1922-1932]. AB - This article deals with the main features of the emergence and first ten years of the Centros de Higiene Infantil, facilities run by the Departamento de Salubridad Publica from 1922 on in Mexico City with the goal of providing care for mothers from pregnancy onwards and children from birth to two years of age. It reviews the actions that gave rise to this project and how it became established. It analyzes the structure of these centers, the characteristics of the mothers and children seen there and the functions performed by doctors and nurses, stressing the notion of preventing childhood illnesses, and ends with a first assessment of the effects and limitations of these centers. PMID- 26038854 TI - [Health in school: an examination of the reference documents for the forty years of compulsory health programs, 1971-2011]. AB - Health is a traditional subject in Brazilian school curriculums, and is evident in teaching materials since the end of the nineteenth century. Taking as its starting point the establishment of compulsory development of health programs in 1971, this article aims to examine certain official documents which sought to set out guidelines for health education in schools, as regards the actual conception of health, the objectives to be achieved, and the role of health studies in the general education of pupils. The analysis highlights an important lack of reference points for regulating health education in schools, and points out ideas which have remained unaltered, despite the social changes and theoretical advances that have occurred during the period. PMID- 26038855 TI - [Health education as a transversal proposal: an analysis of the national curriculum guidelines and certain teaching conceptions]. AB - Starting from the assumption that transversality is conceived as a proposal for change in education, the article outlines certain inferences on the subject. The analysis is founded on the transversal subject of "health" in the national curriculum guidelines (PCN), on semi-structured interviews and on reports resulting from conversations with teachers. It reveals that, in Brazil, the notion of transversality gained importance during the 1990s, when the PCN were established, which listed "transversal themes." In the view of the teachers interviewed, health education appears as something apart, on the margins of the curriculum. The authors believe that this is the case owing to the consolidation of the subject fields at school and the curricular structure in teacher training courses. PMID- 26038856 TI - [Variations on the "scientific culture" in four Brazilian authors]. AB - The concept of "scientific culture" varies historically, and the examination of its continuities and transformations can help us understand the relationship between the scientific community and society. The views on the role of science in society go far beyond the advancement of a particular form of knowledge and its possible or promising fruit. They involve values, postures and practices to be disseminated and reveal expectations of social and cultural advancement. This article discusses four expressive visions of different moments in Brazilian history. The formulations of four influential authors in scientific and educational policies of the country at different times are presented and analyzed: Miguel Ozorio de Almeida, Anisio Teixeira, Mauricio Rocha e Silva and Carlos Vogt. PMID- 26038857 TI - [Beyond the transparent body: a consideration of the methods and strategies for examining the homosexual subject]. AB - The aims of the study are to look at methods and strategies used for analyzing people and classifying them as homosexual and to discuss how certain mechanisms which have been established have made it possible to look at their bodies and arrive at conclusions with regard to such persons. We analyze articles from Science Direct, using a Foucaultian approach. We observe the operation of two technologies: medical body imaging techniques and examinations. These techniques transform the individuals into parts of a strategic device which can be used to build up knowledge, produce files and data, and classify the subjects. The development of this research makes it possible for us to identify certain relationships between homosexuality, the production of scientific knowledge, prejudice, politics and health. PMID- 26038858 TI - [Infinite metamorphosis: witches, spirits and apuntes in Havana]. AB - This article offers an alternative reading of Hampa afro-cubana: los negros brujos, by the Cuban Fernando Ortiz y Fernandes, and discusses the need to make the different ideas expounded by the author more complex. For this reason, it disputes the interpretations of some commentators influenced by his work. The article suggests some clues with regard to what Ortiz y Fernandes understood as forces capable of acting and manifesting themselves in the "bodies" of persons affected by the activities of those accused of being involved with magical practices and objects. It examines the creation of witches - as described by Ortiz y Fernandes - as an epistemic phenomenon and discusses the arguments and the practices and knowledge required for this purpose. PMID- 26038859 TI - [City-laboratory: Campinas and yellow fever at the dawn of the Republican era]. AB - In the late nineteenth century, there were yellow fever epidemics in Campinas. Considered a seaside disease, the fever startled lay people and physicians. The scientific debate about the etiology of the disease left the domain of magazines and medical correspondence to orient political and sanitary actions. In order to combat the disease, the city began to resemble a laboratory and experienced its "era of sanitation and demolition," with victories over the ailment and inconvenience to the public. The State Sanitary Commission led by Emilio Ribas, aware of Finlay's Culicidae theory, rehearsed in Campinas what would happen with Oswaldo Cruz and Pereira Passos in Rio de Janeiro. The novelty of combating mosquitoes coexisted with age-old practices dear to miasmatic theory, such as disinfection. PMID- 26038860 TI - [Santa Casa de Misericordia and hygienist policies in Belem do Para in the late nineteenth century]. AB - The article analyzes the relationship between hygienist policies in effect in Belem in the late nineteenth century and the expansion of activities of the Santa Casa de Misericordia do Para. Considered one of the first hospital institutions in the former Grao-Para Province, in addition to its own hospital, the Brotherhood administered several other health facilities in the capital, and the study of its physical displacement made it possible to "map" three health centers in Belem: Pioneer, Expansion and the Santa Casa, which reinforce the growth vectors of the city. The expansion of its activities is configured as the expansion of the Santa Casa de Misericordia to serve the underprivileged and sick, preceding the establishment of a public health system in Para. PMID- 26038861 TI - [Discussions regarding the reconstruction of the significance of leprosy in the post-sulfone period, Minas Gerais, in the 1950s]. AB - From a historical viewpoint, all the elements surrounding a disease, from its name to the weight of meaning attached to it, are the result of "negotiations" in which many sections of society are participants. In the case of leprosy, the discovery of sulfones in 1941 made a significant contribution towards transforming our understanding of this disease, leading to questions being raised as to the measures adopted for its prevention and control, particularly the compulsory isolation of sufferers. On the basis of these assumptions, this article examines the debate which took place regarding the process whereby the old prophylactic procedures for the control of leprosy were replaced, in an important national journal, Arquivos Mineiros de Leprologia, in the 1950s. PMID- 26038862 TI - [Early decentralization of health services in Argentina: the construction of the health system in Cordoba, 1930-1955]. AB - This paper analyzes the process of construction of the Argentine public health system, highlighting the limitations that occurred in the proposed nationalization of health policy in the postwar period and the central role played by subnational jurisdictions, making the provision of services rendered on a provincial basis. More precisely, in this respect it is seen how the expansion of health services in some provinces shows us how, in the second quarter of the twentieth century, it was primarily the result of the action of local rather than national departments. In order to better elucidate this process, the trajectory of public healthcare facilities in the province of Cordoba between 1930 and 1955 was studied. PMID- 26038863 TI - [Constructing images and territories: thinking on the visuality and materiality of remote sensing]. AB - This article offers a reflection on the question of the image in science, thinking about how visual practices contribute towards the construction of knowledge and territories. The growing centrality of the visual in current scientific practices shows the need for reflection that goes beyond the image. The object of discussion will be the scientific images used in the monitoring and visualization of territory. The article looks into the relations between visuality and a number of other factors: the researchers that construct it; the infrastructure involved in the construction; and the institutions and policies that monitor the territory. It is argued that such image-relations do not just visualize but help to construct the territory based on specific forms. Exploring this process makes it possible to develop a more complex understanding of the forms through which sciences and technology help to construct realities. PMID- 26038864 TI - [The body and the medical knowledge in the eighteenth century: an interview with Jean Abreu]. AB - The history of science is a growing and well-recognized area in Brazil, however, medicine during the colonial period is not well covered by research. Aiming to address this subject, this interview was carried out with Professor Jean Luiz Neves Abreu, an important researcher of the history of medicine during the Luso Brazilian Empire of the eighteenth century. By speaking of his personal career, his academic experience and his involvement with the subject, Professor Abreu clarifies theoretical and methodological aspects related to the history of health sciences. He highlights the potential of medical texts and manuals as a source and discusses means of accessibility and different sources that can allow new themes and objects to be reconsidered in this area of research. PMID- 26038865 TI - [The art of uniting time and space: Fernand Braudel, geohistory and the long run]. AB - This article presents the concept of geohistory, as developed by the French historian Fernand Braudel in his text "Geohistoire: la societe, l'espace et le temps", written while he was imprisoned during the Second World War. The concept expresses his criticism of the boundaries of academic disciplines, and the importance of geography in the construction of his long-term history. Inspired both by the study of relations between society and environment based on the work of French geographers, and by the triangular link of space-economy-society of German geographers, Braudel's geohistory presents an approach more consistent and more complex than Lucien Febvre's theses found in The earth and human evolution: e geographical introduction to history. PMID- 26038867 TI - [Biblioteca Fundamentos de la Construccion de Chile: building the nation by means of science]. PMID- 26038866 TI - [Forensic medical examinations and teaching: disagreements and discussions within the Brazilian Society of Neurology, Psychiatry, and Forensic Medicine]. AB - In order to observe the influence wielded by forensic medicine in the development of the field of psychiatry in Brazil, this research note analyzes the debates that took place from May to July 1918 within the Brazilian Society of Neurology, Psychiatry, and Forensic Medicine over the use of forensic medical examinations as course material in the study of Public Medicine at the Rio de Janeiro School of Medicine. The focus is on how the controversy unfolded within the Society and how this scientific organization influenced the institution of the theoretical and practical training of medical experts. PMID- 26038868 TI - [Homeopathy and allopathy in dispute at the beginning of the twentieth century]. PMID- 26038869 TI - [Multiply to grow]. PMID- 26038870 TI - [New insights on madness and the early years of psychiatry in Spain]. PMID- 26038871 TI - Robustness of plasmon phased array nanoantennas to disorder. AB - We present cathodoluminescence experiments that quantify the response of plasmonic Yagi-Uda antennas fabricated on one-dimensional silicon nitride waveguides as function of electron beam excitation position and emission wavelength. At the near-infrared antenna design wavelength cathodoluminescence signal robustly is strongest when exciting the antenna at the reflector element. Yet at just slightly shorter wavelengths the signal is highly variable from antenna to antenna and wavelength to wavelength. Hypothesizing that fabrication randomness is at play, we analyze the resilience of plasmon Yagi-Uda antennas to variations in element size of just 5 nm. While in our calculations the appearance of directivity is robust, both the obtained highest directivity and the wavelength at which it occurs vary markedly between realizations. The calculated local density of states is invariably high at the reflector for the design wavelength, but varies dramatically in spatial distribution for shorter wavelengths, consistent with the cathodoluminescence experiments. PMID- 26038872 TI - Donor-specific HLA Antibodies Are Associated With Late Allograft Dysfunction After Pediatric Liver Transplantation. AB - BACKGROUND: The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes. METHODS: Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA. RESULTS: DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively. CONCLUSIONS: Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection. PMID- 26038874 TI - Knowledge, Attitudes, and Willingness Toward Organ Donation Among Health Professionals in China. AB - BACKGROUND: The purposes of this study were to assess the knowledge, attitudes, and willingness toward organ donation among the health professionals in China. METHODS: Questionnaires were delivered to 400 health professionals from 7 hospitals in Dalian and 1 hospital in Chaozhou of China between October 2013 and January 2014. RESULTS: In all, 400 health professionals were approached, 373 valid responses were returned. Over 90% of the participants knew about organ donation, but only 17.4% had taken part in some training courses or lectures about organ donation. Health professionals (64.9%) knew the shortage status of organ, and doctors knew more than nurses and nonclinical staffs (P < 0.01). Health professionals (97.3%) knew brain death, and 68.9% professionals thought brain death was the reasonable criteria to judge death. Doctors showed a higher knowledge level about brain death than nurses and nonclinical staffs (P < 0.01). Altogether, 60.1% approved deceased donation; however, only 48.5% approved living donation. Doctors' attitudes were more positive than nurses and nonclinical both in deceased donation (P < 0.01) and in living donation (P < 0.05). In all, 49.3% were willing to donate their own organs postmortem, and doctors had higher willingness to donation postmortem compared with nurses and nonclinical staffs (P < 0.01). The most (49.2%) commonly cited reason for refraining from donation was: "afraid that organs would be picked up inhumanely and body would be disfigured". CONCLUSIONS: Health professionals showed lower favorable attitudes and willingness toward organ donation than Chinese general public. A proportion of Chinese health professionals' knowledge about organ donation was limited. PMID- 26038875 TI - Donor-specific Antibody in Pediatric Liver Transplantation-Identifying a Tree by Its Fruit. PMID- 26038873 TI - Rational Basis for Optimizing Short and Long-term Hepatitis B Virus Prophylaxis Post Liver Transplantation: Role of Hepatitis B Immune Globulin. AB - Antiviral therapy using newer nucleos(t)ide analogues with lower resistance rates, such as entecavir or tenofovir, suppress hepatitis B virus (HBV) replication, improve liver function in patients with compensated or decompensated cirrhosis, and delay or obviate the need for liver transplantation in some patients. After liver transplantation, the combination of long-term antiviral and low-dose hepatitis B Immune globulin (HBIG) can effectively prevent HBV recurrence in greater than 90% of transplant recipients. Some forms of HBV prophylaxis need to be continued indefinitely after transplantation but, in patients with a low-risk of HBV recurrence (i.e., HBV DNA levels undetectable before transplantation), it is possible to discontinue HBIG and maintain only long-term nucleos(t)ide analogue(s) therapy. A more cautious approach is necessary for those patients with high pretransplant HBV DNA levels, those with limited antiviral options if HBV recurrence occurs (i.e., HIV or hepatitis D virus coinfection, preexisting drug resistance), those with a high risk of hepatocellular carcinoma recurrence, and those at risk of noncompliance with antiviral therapy. In this group, HBIG-free prophylaxis cannot be recommended. PMID- 26038876 TI - Organ Transplantation in China. PMID- 26038877 TI - Increased Circulating Anti-inflammatory Cells in Marathon-trained Runners. AB - Exercise training can alter immune function. Marathon training has been associated with an increased susceptibility to infectious diseases and an increased activity of inflammatory-based diseases, but the precise mechanisms are unknown. The purpose of this study was to compare levels of circulating CD4+ T cell subsets in the periphery of marathon-trained runners and matched non marathon controls. 19 recreational marathoners that were 4 weeks from running a marathon and 19 demographically-matched healthy control subjects had the percentage of CD4+ T cell subpopulations (T helper 1, T helper 2, T helper 1/T helper 2 ratio, regulatory T cells, CD4+ IL10+, and CD4+ TGFbeta+ (Transforming Growth Factor-beta) measured by flow cytometry. Marathon-trained runners had significantly less T helper 1 and regulatory T cells and significantly more T helper 2, CD4+ IL10+, and TGFbeta+ cells than the control subjects. The alterations in the percentage of T helper 1 and T helper 2 cells led to a significantly lower T helper 1/T helper 2 ratio in the marathon-trained runners. These data suggest that endurance-based training can increase the number of anti inflammatory cells. This may be a potential mechanism for the increased incidence of both infectious and inflammatory diseases observed in endurance athletes. PMID- 26038878 TI - The Effects of Vibrations Experienced during Road vs. Off-road Cycling. AB - The purpose of this investigation was to compare the effects of vibrations experienced during off-road and road cycling. It was hypothesised that additional damping will be expressed through a greater work demand and increased physiological markers when travelling at the same speed over an identical terrain profile. Participants ascended a tar-sealed road climb and a single-track off road climb at a predetermined speed. Time, speed, power, cadence, heart rate and V O2 were sampled and logged every second while tri-axial accelerometers recorded accelerations (128 Hz) to quantify vibrations experienced. Statistical analysis indicated accelerations to be greater during the off-road condition (p<0.0001) with post-hoc analysis exposing differences (p<0.001) for handlebar, arm, leg and seat post but not the lower back or head. The increased accelerations during off road riding are associated with the increased vibrations and rolling resistance experienced. This led to increases in the work done (road: 280+/-69 vs. off-road: 312+/-74 W, p=0.0003) and, consequentially, a significant increase in the physiological markers V O2 (road: 48.5+/-7.5 off-road 51.4+/-7.3 ml.kg(-1).min( 1), p=0.0033) and heart rate (road: 161+/-10 off-road 170+/-10 bpm, p=0.0001) during the off-road condition. Such physiological differences and their causes are important to understand in order to provide suitable training recommendations or technological interventions for improving competitive performance or recreational enjoyment. PMID- 26038879 TI - Intermittent Palm Cooling's Impact on Resistive Exercise Performance. AB - To examine palm cooling's (15 degrees C) impact, subjects performed 3 four-set leg press workouts in a randomized sequence. Per workout they received 1 of 3 treatments: no palm cooling, palm cooling between sets, or palm cooling between sets and post-exercise. Dependent variables were examined with three-way ANOVAs; average power underwent a three-way ANCOVA with body fat percentage as the covariate. Simple effects analysis was our post hoc and alpha=0.05. Left hand skin temperatures produced a two-way interaction (no palm cooling, palm cooling between sets>palm cooling between sets and post-exercise at several time points). A "high responder" subset had their data analyzed with an additional three-way ANOVA that again produced a two-way interaction (palm cooling between sets>no palm cooling>palm cooling between sets and post-exercise at multiple time points). Blood lactate results included a two-way interaction (no palm cooling>palm cooling between sets, palm cooling between sets and post-exercise at 0 min post-exercise). Average power yielded a two-way interaction (palm cooling between sets, palm cooling between sets>no palm cooling for the fourth set). Intermittent palm cooling hastened heat removal and blood lactate clearance, as well as delayed average power decrements. PMID- 26038880 TI - Utility of a Non-Exercise VO2max Prediction Model for Designing Ramp Test Protocols. AB - This study investigated the validity of determining the final work rates of cycling and walking ramp-incremented maximal cardiopulmonary exercise tests (CPETs) using a non-exercise model to predict maximal oxygen uptake VO2max and the American College of Sports Medicine ACSM's metabolic equations. The validity of using this methodology to elicit the recommended test duration of between 8 and 12 min was then evaluated. First, 83 subjects visited the laboratory once to perform a cycling (n=49) or walking (n=34) CPET to investigate the validity of the methodology. Second, 25 subjects (cycling group: n=13; walking group: n=12) performed a CPET on 2 separate days to test the reliability of CPET outcomes. Observed VO2max was 1.0 ml.kg(-1).min(-1) lower than predicted in the cycling CPET (P=0.001) and 1.4 ml.kg(-1).min(-1) lower in the walking CPET (P=0.001). Only one of the 133 conducted CPETs was outside the test duration range of 8-12 min. Test-retest reliability was high for all CPET outcomes, with intraclass correlation coefficients of 0.90 to 0.99. In conclusion, the non-exercise model is a valid and reliable method for establishing the final work rate of cycling and walking CPETs for eliciting test durations of between 8 and 12 min. PMID- 26038881 TI - Reliability of a 3-min all-out Arm Crank Ergometer Exercise Test. AB - The 3-min all-out test is a well-established exercise test developed for cycling ergometry. However, no such test exists in arm cranking. Thus the aim of this study was to investigate the test-retest reliability of a 3-min all-out exercise test on an arm crank ergometer. 21 healthy participants (9 male and 12 female, age 34+/-11 years, body mass 69.6+/-11.1 kg and height 175.5+/-6.9 cm) twice performed a 3-min all-out exercise test on an arm crank ergometer separated by 7 days. Peak power (PP), mean power (MP), fatigue index (FI), time to peak (TTP) and total work (TW) were assessed to detect test-retest reliability. PP, MP, FI and TW showed an excellent intra-class correlation coefficient (ICC) ranging from 0.940 to 0.984. Only TTP showed very low reliability with an ICC of 0.379. The results from this test-retest analysis showed that all parameters except the TTP were highly reliable in a 3-min all-out exercise test on an arm crank ergometer in able-bodied participants. PMID- 26038882 TI - All-out Test in Tethered Canoe System can Determine Anaerobic Parameters of Elite Kayakers. AB - The aims of this study were to use a specific all-out 30-sec tethered test to determine the anaerobic parameters in elite kayakers and verify the relationship between these results and sports performance. Twelve elite slalom kayakers were evaluated. The tethered canoe system was created and used for the all-out 30-sec test application. Measurements of peak force, mean force, minimum force, fatigue index and impulse were performed. Performance evaluation was determined by measuring the time of race in a simulated race containing 24 gates on a white water course. Blood was collected (25-ul) for analysis of lactate concentration at rest and at 2, 4, 6, 8 and 10-min intervals after both the all-out test and the simulated race. The Pearson product moment correlation shows a inverse and significant relationship of peak force, mean force and impulse with time of race. Blood lactate concentrations after the all-out test and the simulated race peak at same time (4 min). Additionally, no interaction was visualized between time and all-out test/simulated race for blood lactate concentrations (P <0.365). These results suggest a relationship between the parameters of the all-out test and performance. Thus, the tethered canoe system is a useful tool for determining parameters that could be used in training control of slalom kayakers. PMID- 26038883 TI - Self-Assembly Process of Dodecanuclear Pt(II)-Linked Cyclic Hexagon. AB - The self-assembly process of a Pt(II)-linked hexagonal macrocycle consisting of six linear dinuclear Pt(II) units and six organic ditopic bent ligands was investigated. The process was monitored by (1)H NMR, and the intermediates in the self-assembly were analyzed by the n-k analysis. It was found that a 1:2 complex of a dinuclear Pt(II) unit and an organic ditopic ligand was exclusively observed as an intermediate with a certain lifetime and that the reaction of the 1:2 complex is the rate-determining step in the supramolecular macrocycle formation. The key 1:2 complex was unambiguously characterized by (1)H and DOSY NMR and ESI TOF mass measurement. PMID- 26038885 TI - Crystal structure of caspase recruiting domain (CARD) of apoptosis repressor with CARD (ARC) and its implication in inhibition of apoptosis. AB - Apoptosis repressor with caspase recruiting domain (ARC) is a multifunctional inhibitor of apoptosis that is unusually over-expressed or activated in various cancers and in the state of the pulmonary hypertension. Therefore, ARC might be an optimal target for therapeutic intervention. Human ARC is composed of two distinct domains, N-terminal caspase recruiting domain (CARD) and C-terminal P/E (proline and glutamic acid) rich domain. ARC inhibits the extrinsic apoptosis pathway by interfering with DISC formation. ARC CARD directly interacts with the death domains (DDs) of Fas and FADD, as well as with the death effector domains (DEDs) of procaspase-8. Here, we report the first crystal structure of the CARD domain of ARC at a resolution of 2.4 A. Our structure was a dimer with novel homo dimerization interfaces that might be critical to its inhibitory function. Interestingly, ARC did not exhibit a typical death domain fold. The sixth helix (H6), which was detected at the typical death domain fold, was not detected in the structure of ARC, indicating that H6 may be dispensable for the function of the death domain superfamily. PMID- 26038886 TI - Acoustic asymmetric transmission based on time-dependent dynamical scattering. AB - An acoustic asymmetric transmission device exhibiting unidirectional transmission property for acoustic waves is extremely desirable in many practical scenarios. Such a unique property may be realized in various configurations utilizing acoustic Zeeman effects in moving media as well as frequency-conversion in passive nonlinear acoustic systems and in active acoustic systems. Here we demonstrate a new acoustic frequency conversion process in a time-varying system, consisting of a rotating blade and the surrounding air. The scattered acoustic waves from this time-varying system experience frequency shifts, which are linearly dependent on the blade's rotating frequency. Such scattering mechanism can be well described theoretically by an acoustic linear time-varying perturbation theory. Combining such time-varying scattering effects with highly efficient acoustic filtering, we successfully develop a tunable acoustic unidirectional device with 20 dB power transmission contrast ratio between two counter propagation directions at audible frequencies. PMID- 26038888 TI - A family of uranyl-aromatic dicarboxylate (pht-, ipa-, tpa-) framework hybrid materials: photoluminescence, surface photovoltage and dye adsorption. AB - Four uranyl complexes [(UO2)(pht)H2O].H2O (pht = phthalic acid) (1), (UO2)2(Hipa)4(H2O)2 (Hipa = isophthalic acid) (2), (UO2)(tpa)(DMF)2 (tpa = terephthalic acid) (3) and (UO2)(box)2 (box = benzoic acid) (4) were synthesized by the reaction of UO2(CH3COO)2.2H2O as the metal source and phthalic acid, isophthalic acid, terephthalic acid or benzoic acid as the ligand. They were characterized by elemental analyses, IR, UV-Vis, XRD, single crystal X-ray diffraction analysis and thermal gravimetric analysis. The structural analysis reveals that complex 1 exhibits a one-dimensional chain structure constructed by the building unit [(UO2)2(pht)4(H2O)2] and further extends the chain into a 2D supramolecular architecture by hydrogen bonding interactions. Complex 2 is a discrete [(UO2)2(Hipa)4(H2O)2] structure, and by the hydrogen bonding interaction, forms a 3D supramolecular structure. In complexes 3 and 4, adjacent uranyl polyhedra form a 1D chain through bridging terephthalic acid and benzoic acid, respectively. In order to extend their functional properties, their photoluminescence, surface photovoltage and dye adsorption properties have been studied. PMID- 26038887 TI - Association Between Specific Mutations in KRAS Codon 12 and Colorectal Liver Metastasis. AB - IMPORTANCE: Currently, one of the most commonly available biomarkers in the treatment of patients with colorectal liver metastases (CRLM) is the Kirsten rat sarcoma viral oncogene homolog (KRAS); however, the prognostic implications of specific mutations of the KRAS gene are still not well defined. OBJECTIVE: To investigate the prognostic impact of specific KRAS mutations on patients undergoing liver resection for CRLM. DESIGN, SETTING, AND PARTICIPANTS: This retrospective single-center study was conducted from January 1, 2003, to December 31, 2013. Data about specific KRAS mutations for 331 patients who underwent hepatic resection for CRLM at Johns Hopkins Hospital between 2003 and 2013 were analyzed. Clinicopathological characteristics, perioperative details, and outcomes were stratified by specific KRAS mutation at codons 12 and 13. INTERVENTION: Resection of CRLM. MAIN OUTCOMES AND MEASURES: Overall survival (OS) and recurrence-free survival. RESULTS: A mutated KRAS (mtKRAS) was identified in 91 patients (27.5%). At a median follow-up of 27.4 months, recurrence was observed in 48 patients (52.7%) with mtKRAS and 130 patients (54.2%) with wild-type KRAS (wtKRAS) (P = .82). Median and 5-year survival among patients with mtKRAS was 32.4 months and 32.7%, respectively, vs 58.5 months and 46.9%, respectively, for patients with wtKRAS (P = .02). Patients with KRAS codon 12 mutations had worse OS (hazard ratio [HR], 1.54; 95% CI, 1.05-2.27; P = .03) vs those with wtKRAS, whereas a KRAS codon 13 mutation was not associated with prognosis (HR, 1.47; 95% CI, 0.83-2.62; P = .19). Among the 6 most common mutations in codons 12 and 13, only G12V (HR, 1.78; 95% CI, 1.00-3.17; P = .05) and G12S (HR, 3.33; 95% CI, 1.22-9.10; P = .02) were associated with worse OS compared with patients with wtKRAS (both P < .05). Among patients who recurred, G12V (HR, 2.96; 95% CI, 1.32-6.61; P = .01), G12C (HR, 6.74; 95% CI, 2.05-22.2; P = .002), and G12S mutations (HR, 4.91; 95% CI, 1.52-15.8; P = .01) were associated with worse OS (both P < .05). CONCLUSIONS AND RELEVANCE: G12V and G12S mutations of codon 12 were independent prognostic factors of worse OS. Among patients who recurred after resection of CRLM, G12V, G12C, and G12S mutations were associated with worse OS. Information on specific KRAS mutations may help individualize therapeutic and surveillance strategies for patients with resected CRLM. PMID- 26038890 TI - Correction: Wood Chemical Composition in Species of Cactaceae: The Relationship between Lignification and Stem Morphology. PMID- 26038894 TI - State estimates for the annual cost of foodborne illness. AB - An understanding of the costs associated with foodborne illnesses is important to policy makers for prioritizing resources and assessing whether proposed interventions improve social welfare. At the national level, measured costs have been used by federal food safety regulatory agencies in regulatory impact analyses. However, when costs differ across states, use of national cost-of illness values for state-based interventions will lead to biased estimates of intervention effectiveness. In this study, the costs of foodborne illness at the state level were estimated. Using a more conservative economic model, the average cost per case ranged from $888 (90% credible interval [CI], $537 to $1,419) in West Virginia to $1,766 (90% CI, $1,231 to $2,588) in the District of Columbia. A less conservative model generated average costs per case of $1,505 (90% CI, $557 to $2,836) in Kentucky to $2,591 (90% CI, $857 to $5,134) in Maryland. Aggregated across the states, the average national cost of foodborne illness was estimated as $55.5 billion (90% CI, $33.9 to $83.3 billion) using the conservative model and $93.2 billion (90% CI, $33.0 to $176.3 billion) using the enhanced model. PMID- 26038895 TI - Comparing the microbiological status of pre- and postharvest produce from small organic production. AB - Consumption of locally, organically grown produce is increasing in popularity. Organic farms typically produce on a small scale, have limited resources, and adopt low technology harvest and postharvest handling practices. Data on the food safety risk associated with hand harvesting, field packing, and packing-house handling with minimal treatment, at this production scale, are lacking. We followed produce from small organic farms from the field through postharvest handling and packing. Pre- and postharvest produce (177 samples) and water (29 samples) were collected and analyzed quantitatively for Escherichia coli, total coliforms (TC), aerobic bacteria (APC), yeasts, molds (M), and enteric pathogens. No pathogens were recovered. E. coli was detected in 3 (3.6%) of 83 preharvest produce samples, 2 (6.3%) of 32 unwashed and 0 of 42 washed postharvest produce samples, and 10 (34.5%) of 29 water samples. No correlation was found between bacterial levels in irrigation water and those on produce. Postharvest handling without washing was a factor for APC and M counts on tomatoes, with lower frequencies postharvest. Postharvest handling with washing was a factor for leafy greens for TC counts, with higher frequencies postharvest. APC (P = 0.03) and yeast (P = 0.05) counts were higher in preharvest than in unwashed postharvest tomatoes. Washed postharvest leafy greens had higher M counts (P = 0.03) and other washed produce had higher TC counts (P = 0.01) than did their preharvest counterparts. Barriers were found to the use of sanitizer in wash water for leafy greens among small farms using organic practices. Hand harvesting and dry handling did not appear to be associated with a significant food safety risk, but washed leafy greens carried higher levels of some microbial indicators, possibly because of the lack of sanitizer in the wash water. The development of resources and materials customized for this sector of growers could enhance dissemination of information on best practices for handling of leafy greens. PMID- 26038891 TI - Arsenic trioxide sensitizes glioblastoma to a myc inhibitor. AB - Glioblastoma multiforme (GBM) is associated with high mortality due to infiltrative growth and recurrence. Median survival of the patients is less than 15 months, increasing requirements for new therapies. We found that both arsenic trioxide and 10058F4, an inhibitor of Myc, induced differentiation of cancer stem like cells (CSC) of GBM and that arsenic trioxide drastically enhanced the anti proliferative effect of 10058F4 but not apoptotic effects. EGFR-driven genetically engineered GBM mouse model showed that this cooperative effect is higher in EGFRvIII-expressing INK4a/Arf-/- neural stem cells (NSCs) than in control wild type NSCs. In addition, treatment of GBM CSC xenografts with arsenic trioxide and 10058F4 resulted in significant decrease in tumor growth and increased differentiation with concomitant decrease of proneural and mesenchymal GBM CSCs in vivo. Our study was the first to evaluate arsenic trioxide and 10058F4 interaction in GBM CSC differentiation and to assess new opportunities for arsenic trioxide and 10058F4 combination as a promising approach for future differentiation therapy of GBM. PMID- 26038896 TI - Assessing the status of food safety management systems for fresh produce production in East Africa: evidence from certified green bean farms in Kenya and noncertified hot pepper farms in Uganda. AB - The farms of fresh produce farmers are major sources of food contamination by microbiological organisms and chemical pesticides. In view of their choice for farming practices, producers are influenced by food safety requirements. This study analyzes the role of food safety standard certification toward the maturity of food safety management systems (FSMS) in the primary production of fresh produce. Kenya and Uganda are two East African countries that export green beans and hot peppers, respectively, to the European Union but have contrasting features in terms of agricultural practices and certification status. In the fresh produce chain, a diagnostic instrument for primary production was used to assess context factors, core control and assurance activities, and system output to measure the performance of FSMS for certified green bean farms in Kenya and noncertified hot pepper farms in Uganda. Overall, our findings show that in Uganda, noncertified hot pepper farms revealed only a "basic level of control and assurance" activities in their FSMS, which was not satisfactory, because no insight into potential pesticide microbial contamination was presented by these farmers. On the other hand, certified green bean farms in Kenya had an "average level of control and assurance," providing insight into the delivered food safety and quality by the farmers. Farm size did not impact the maturity level of FSMS. This study confirms the role played by food safety standard certification toward the maturity of FSMS implemented in developing countries and demonstrates the possibility of Ugandan farms to upgrade agricultural practices in the fresh produce sector. PMID- 26038897 TI - Effects of Plant-Derived Extracts, Other Antimicrobials, and Their Combinations against Escherichia coli O157:H7 in Beef Systems. AB - The antimicrobial effects of thyme oil (TO), grapefruit seed extract (GSE), and basil essential oil, alone or in combination with cetylpyridinium chloride (CPC), sodium diacetate, or lactic acid, were evaluated against Escherichia coli O157:H7 in a moisture-enhanced beef model system. The model system was composed of a nonsterile beef homogenate to which NaCl (0.5%) and sodium tripolyphosphate (0.25%) were added, together with the tested antimicrobial ingredients. Beef homogenate treatments were inoculated (ca. 3 log CFU/ml) with rifampin-resistant E. coli O157:H7 (eight-strain mixture) and incubated at 15 degrees C (48 h). The most effective individual treatments were TO (0.25 or 0.5%) and GSE (0.5 or 1.0%), which immediately reduced (P < 0.05) pathogen levels by >= 3.4 log CFU/ml. Additionally, CPC (0.04%) reduced initial E. coli O157:H7 counts by 2.7 log CFU/ml. Most combinations of the tested plant-derived extracts with CPC (0.02 or 0.04%) and sodium diacetate (0.25%) had an additive effect with respect to antibacterial activity. In a second study, antimicrobial interventions were evaluated for their efficacy in reducing surface contamination of E. coli O157:H7 on beef cuts and to determine the effect of these surface treatments on subsequent internalization of the pathogen during blade tenderization. Beef cuts (10 by 8 by 3.5 cm) were inoculated (ca. 4 log CFU/g) on one side with the rifampin-resistant E. coli O157:H7 strain mixture and were then spray treated (20 lb/in(2), 10 s) with water, GSE (5 and 10%), lactic acid (5%), or CPC (5%). Untreated (control) and spray-treated surfaces were then subjected to double-pass blade tenderization. Surface contamination (4.4 log CFU/g) of E. coli O157:H7 was reduced (P < 0.05) to 3.4 (5% CPC) to 4.1 (water or 5% GSE) log CFU/g following spray treatment. The highest and lowest transfer rates of pathogen cells from the surface to deeper tissues of blade-tenderized sections were obtained in the untreated control and CPC-treated samples, respectively. PMID- 26038899 TI - Development of a Dry Inoculation Method for Thermal Challenge Studies in Low Moisture Foods by Using Talc as a Carrier for Salmonella and a Surrogate (Enterococcus faecium). AB - The objective of this study was to obtain dry inocula of Salmonella Tennessee and Enterococcus faecium, a surrogate for thermal inactivation of Salmonella in low moisture foods, and to compare their thermal resistance and stability over time in terms of survival. Two methods of cell growth were compared: cells harvested from a lawn on tryptic soy agar (TSA-cells) and from tryptic soy broth (TSB cells). Concentrated cultures of each organism were inoculated onto talc powder, incubated at 35 degrees C for 24 h, and dried for additional 24 h at room temperature (23 +/- 2 degrees C) to achieve a final water activity of <= 0.55 before sieving. Cell reductions of Salmonella and E. faecium during the drying process were between 0.14 and 0.96 log CFU/g, depending on growth method used. There was no difference between microbial counts at days 1 and 30. Heat resistance of the dry inoculum on talc inoculated into a model peanut paste (50 % fat and 0.6 water activity) was determined after 1 and 30 days of preparation, using thermal death time tests conducted at 85 degrees C. For Salmonella, there was no significant difference between the thermal resistance (D(85 degrees C)) for the TSB-cells and TSA-cells (e.g. day 1 cells D(85 degrees C) = 1.05 and 1.07 min, respectively), and there was no significant difference in D(85 degrees C) between dry inocula on talc used either 1 or 30 days after preparation (P > 0.05). However, the use the dry inocula of E. faecium yielded different results: the TSB-grown cells had a significantly (P < 0.05) greater heat resistance than TSA-grown cells (e.g. D(85 degrees C) for TSB-cells = 3.42 min versus 2.60 min for TSA-cells). E. faecium had significantly (P < 0.05) greater heat resistance than Salmonella Tennessee regardless what cell type was used for dry inoculum preparation; therefore, it proved to be a conservative but appropriate surrogate for thermal inactivation of Salmonella in low-moisture food matrices under the tested conditions. PMID- 26038898 TI - Inactivation of Escherichia coli O157:H7 on Orange Fruit Surfaces and in Juice Using Photocatalysis and High Hydrostatic Pressure. AB - Nonpasteurized orange juice is manufactured by squeezing juice from fruit without peel removal. Fruit surfaces may carry pathogenic microorganisms that can contaminate squeezed juice. Titanium dioxide-UVC photocatalysis (TUVP), a nonthermal technique capable of microbial inactivation via generation of hydroxyl radicals, was used to decontaminate orange surfaces. Levels of spot-inoculated Escherichia coli O157:H7 (initial level of 7.0 log CFU/cm(2)) on oranges (12 cm(2)) were reduced by 4.3 log CFU/ml when treated with TUVP (17.2 mW/cm(2)). Reductions of 1.5, 3.9, and 3.6 log CFU/ml were achieved using tap water, chlorine (200 ppm), and UVC alone (23.7 mW/cm(2)), respectively. E. coli O157:H7 in juice from TUVP (17.2 mW/cm(2))-treated oranges was reduced by 1.7 log CFU/ml. After orange juice was treated with high hydrostatic pressure (HHP) at 400 MPa for 1 min without any prior fruit surface disinfection, the level of E. coli O157:H7 was reduced by 2.4 log CFU/ml. However, the E. coli O157:H7 level in juice was reduced by 4.7 log CFU/ml (to lower than the detection limit) when TUVP treatment of oranges was followed by HHP treatment of juice, indicating a synergistic inactivation effect. The inactivation kinetics of E. coli O157:H7 on orange surfaces followed a biphasic model. HHP treatment did not affect the pH, degrees Brix, or color of juice. However, the ascorbic acid concentration and pectinmethylesterase activity were reduced by 35.1 and 34.7%, respectively. PMID- 26038900 TI - Analysis of Vibrio vulnificus Infection Risk When Consuming Depurated Raw Oysters. AB - A beta Poisson dose-response model for Vibrio vulnificus food poisoning cases leading to septicemia was used to evaluate the effect of depuration at 15 degrees C on the estimated health risk associated with raw oyster consumption. Statistical variability sources included V. vulnificus level at harvest, time and temperature during harvest and transportation to processing plants, decimal reductions (SV) observed during experimental circulation depuration treatments, refrigerated storage time before consumption, oyster size, and number of oysters per consumption event. Although reaching nondetectable V. vulnificus levels (<30 most probable number per gram) throughout the year and a 3.52 SV were estimated not possible at the 95% confidence level, depuration for 1, 2, 3, and 4 days would reduce the warm season (June through September) risk from 2,669 cases to 558, 93, 38, and 47 cases per 100 million consumption events, respectively. At the 95% confidence level, 47 and 16 h of depuration would reduce the warm and transition season (April through May and October through November) risk, respectively, to 100 cases per 100 million consumption events, which is assumed to be an acceptable risk; 1 case per 100 million events would be the risk when consuming untreated raw oysters in the cold season (December through March). PMID- 26038901 TI - Interlaboratory Validation for a Real-Time PCR Salmonella Detection Method Using the ABI 7500 FAST Real-Time PCR System. AB - Sixteen FERN (Food Emergency Response Network) member laboratories collaborated in this study to verify extension of the real-time PCR Salmonella detection method originally designed for the single-tube Cepheid SmartCycler II and validated against the Salmonella method of the U. S. Food and Drug Administration Bacteriological Analytical Manual to the Applied Biosystems (ABI) 7500 FAST Real Time PCR system multiwell plate platform. Four foods were selected for this study: chili powder, soft cheese, fish, and tomatoes; these foods represent products that are commonly analyzed for the presence of Salmonella for regulatory purposes. Each food consisted of six uninoculated control samples, six samples inoculated with low Salmonella levels (target 1 to 5 CFU/25 g), and six samples inoculated with high levels (target 10 to 50 CFU/25 g). All samples were tested for Salmonella using the 24-h quantitative PCR (qPCR) method for detecting Salmonella, which utilizes modified buffered peptone water as the sole enrichment medium and an internal control for the qPCR. Each of these 18 samples was individually analyzed for Salmonella by the collaborating laboratories using both the ABI 7500 FAST system (alternative method) and the SmartCycler II system (reference method). Statistical analysis of the data revealed no significant difference (P >= 0.05) between these two qPCR platforms except for the chili powder samples. The differences noted with chili powder (P = 0.0455) were attributed to the enhanced sensitivity of the ABI 7500 FAST system compared with the SmartCycler II system. The detection limit of both qPCR methods was 0.02 to 0.15 CFU/g. These results provide a solid basis for extending the 24-h qPCR Salmonella method to the ABI 7500 FAST system for high-throughput detection of Salmonella in foods. PMID- 26038902 TI - Growth of Salmonella enterica and Listeria monocytogenes on Fresh-Cut Cantaloupe under Different Temperature Abuse Scenarios. AB - Effective cold chain management is a critical component of food safety practice. In this study, we examined the impact of commonly encountered temperature abuse scenarios on the proliferation of Salmonella enterica and Listeria monocytogenes on fresh-cut cantaloupe. Inoculated fresh-cut cantaloupe cubes were subjected to various temperature abuse conditions, and the growth of S. enterica and L. monocytogenes was determined. During 1 week of storage, Salmonella cell counts on fresh-cut cantaloupe increased by -0.26, 1.39, and 2.23 log units at 4 degrees C (control), 8 degrees C, and 12 degrees C (chronic temperature abuse), respectively, whereas that of L. monocytogenes increased by 0.75, 2.86, and 4.17 log units. Under intermittent temperature abuse conditions, where storage temperature fluctuated twice daily to room temperature for 30 min, Salmonella cell count increased by 2.18 log units, whereas that of L. monocytogenes increased by 1.86 log units. In contrast, terminal acute temperature abuses for 2 to 4 h resulted in upwards to 0.6 log unit for Salmonella, whereas the effect on L. monocytogenes was less significant compared with L. monocytogenes on cut cantaloupe stored at 4 degrees C. Significant deterioration of produce visual quality and tissue integrity, as reflected by electrolyte leakage, was also observed under various temperature abuse conditions. PMID- 26038903 TI - Irrigation Is Significantly Associated with an Increased Prevalence of Listeria monocytogenes in Produce Production Environments in New York State. AB - Environmental (i.e., meteorological and landscape) factors and management practices can affect the prevalence of foodborne pathogens in produce production environments. This study was conducted to determine the prevalence of Listeria monocytogenes, Listeria species (including L. monocytogenes), Salmonella, and Shiga toxin-producing Escherichia coli (STEC) in produce production environments and to identify environmental factors and management practices associated with their isolation. Ten produce farms in New York State were sampled during a 6-week period in 2010, and 124 georeferenced samples (80 terrestrial, 33 water, and 11 fecal) were collected. L. monocytogenes, Listeria spp., Salmonella, and STEC were detected in 16, 44, 4, and 5% of terrestrial samples, 30, 58, 12, and 3% of water samples, and 45, 45, 27, and 9% of fecal samples, respectively. Environmental factors and management practices were evaluated for their association with terrestrial samples positive for L. monocytogenes or other Listeria species by univariate logistic regression; analysis was not conducted for Salmonella or STEC because the number of samples positive for these pathogens was low. Although univariate analysis identified associations between isolation of L. monocytogenes or Listeria spp. from terrestrial samples and various water-related factors (e.g., proximity to wetlands and precipitation), multivariate analysis revealed that only irrigation within 3 days of sample collection was significantly associated with isolation of L. monocytogenes (odds ratio = 39) and Listeria spp. (odds ratio = 5) from terrestrial samples. These findings suggest that intervention at the irrigation level may reduce the risk of produce contamination. PMID- 26038904 TI - Methicillin-Resistant Staphylococcus aureus in Raw Milk: Prevalence, SCCmec Typing, Enterotoxin Characterization, and Antimicrobial Resistance Patterns. AB - Staphylococcus aureus is a known major cause of foodborne illnesses, and raw milk and dairy products are often contaminated by enterotoxigenic and antimicrobial resistant S. aureus strains. In the present study, 35 S. aureus strains were isolated from 383 raw milk samples collected from various dairy herds in the province of Milan (northern Italy). The isolates were characterized based on their antimicrobial susceptibility patterns and the presence of genes encoding staphylococcal enterotoxins (sea, seb, sec, sed, and see). About half (45.7%) of the strains were enterotoxigenic, and 37.1% were resistant to at least one of the antimicrobial drugs tested. Seven (20%) of 35 isolates were identified as methicillin-resistant S. aureus (MRSA), and SCCmec typing performed with a multiplex PCR assay revealed the presence of gene cassettes IV and V, typical of community-acquired MRSA, and I and II, characteristic of health care-associated MRSA. The MRSA strains were evaluated for the presence of the Panton-Valentine leukocidin gene, but this gene was not found. The results of the present study revealed the presence of toxin-producing S. aureus and MRSA strains in raw milk. MRSA and enterotoxigenic S. aureus in dairy farms are an important risk factor for the spread of staphylococcal infections; therefore, further studies are needed to find strategies for monitoring and controlling the presence of S. aureus, especially MRSA, in dairy products. PMID- 26038905 TI - Comparative Study on the Efficacy of Bacteriophages, Sanitizers, and UV Light Treatments To Control Listeria monocytogenes on Sliced Mushrooms (Agaricus bisporus). AB - The following reports on a comparative study on the efficacy of different decontamination technologies to decrease Listeria monocytogenes inoculated onto white sliced mushrooms and assesses the fate of residual levels during posttreatment storage under aerobic conditions at 8 degrees C. The treatments were chemical (hydrogen peroxide, peroxyacetic acid, ozonated water, electrolyzed water, chitosan, lactic acid), biological (Listeria bacteriophages), and physical (UV-C, UV-hydrogen peroxide). None of the treatments achieved >1.2 log CFU reduction in L. monocytogenes levels; bacteriophages at a multiplicity of infection of 100 and 3% (vol/vol) hydrogen peroxide were the most effective of the treatments tested. However, growth of residual L. monocytogenes during posttreatment storage attained levels equal to or greater than levels in the nontreated controls. The growth of L. monocytogenes was inhibited on mushrooms treated with chitosan, electrolyzed water, peroxyacetic acid, or UV. Yet, L. monocytogenes inoculated onto mushrooms and treated with UV-hydrogen peroxide decreased during posttreatment storage, through a combination of sublethal injury and dehydration of the mushroom surface. Although mushrooms treated with UV hydrogen peroxide became darker during storage, the samples were visually acceptable relative to controls. In conclusion, of the treatments evaluated, UV hydrogen peroxide holds promise to control L. monocytogenes on mushroom surfaces. PMID- 26038906 TI - Effect of Acidified Sorbate Solutions on the Lag-Phase Durations and Growth Rates of Listeria monocytogenes on Meat Surfaces. AB - The surfaces of ready-to-eat meats are susceptible to postprocessing contamination by Listeria monocytogenes. This study quantified the lag-phase durations (LPD) and growth rates (GR) of L. monocytogenes on the surfaces of cooked ham as affected by sorbate solutions of different concentrations and pH levels. Slices of cooked ham inoculated with a four-strain mixture of L. monocytogenes (ca. 10(3) CFU/g) were surface treated with sorbate solutions of 0 to 4% (wt/vol) at pH 4.0 to 6.5, vacuum packaged, and stored at 4 to 12 degrees C for up to 45 days. The LPD and GR of L. monocytogenes were used to develop response surface models. The models estimated that the LPD of L. monocytogenes in samples treated with solutions of pH 4.0 to 5.5 (no sorbate) were 0 to 11 days and the GR were 0.25 to 0.36 log CFU/day, respectively, at 4 degrees C. With the treatments of 2 and 4% (wt/vol) sorbate solutions, the LPD were estimated to be extended to 2 to 26 days and 34 to >45 days, and the GR were reduced to 0.15 to 0.30 and 0 to 0.19 log CFU/day, respectively. At 4 degrees C, increasing sorbate concentrations by 1% (wt/vol) to 2, 3, and 4% (wt/vol) at pH 5.5 to 4.0 led to an extension of LPD by 2 to 11, 10 to 19, and 18 to 27 days, whereas the GR were reduced by 0.037 to 0.055, 0.048 to 0.066, and 0.060 to 0.078 log CFU/day, respectively. Sorbate also extended the LPD and reduced the GR of L. monocytogenes at 8 and 12 degrees C. Results indicated that sorbate concentration and pH level were significant factors affecting the LPD and GR of L. monocytogenes and that the combination of sorbate and low pH has potential for use as a surface treatment to control L. monocytogenes on meat surfaces. PMID- 26038907 TI - Toxoplasmosis-Related Knowledge and Preventive Practices among Undergraduate Female Students in Jordan. AB - Foodborne toxoplasmosis is a leading cause of foodborne deaths and hospitalization worldwide. The level of exposure to Toxoplasma gondii is influenced by culture and eating habits. There is a scarcity of data about women's knowledge and perception of this disease. The aim of this study was to determine toxoplasmosis knowledge and preventive practices of young childbearing age women in Jordan. A descriptive cross-sectional study recruited a random sample of 1,390 undergraduate university female students and was stratified based on place of residency. About half of students (51.1%) reported having "ever" heard or read about toxoplasmosis, and almost all students (98.6%) had never been tested for toxoplasmosis. Overall, there was a lack of awareness about toxoplasmosis, its risk factors, symptoms, and timing of infection, and preventive practices. High percentages of females reported a high level of hygienic practices related to hand washing after gardening, changing cat litter, and handling raw meat. However, 16.7% of students reported eating raw meat, 26.5% usually eat traditional herbs, and 17.2% drink untreated spring water. This study establishes a baseline for the awareness levels about toxoplasmosis among young women in Jordan. These findings highlight the urgent need for toxoplasmosis awareness and preventive education for childbearing females. An effective education and outreach program should cover important topics concerning risk factors, high-risk foods, and preventive measures against toxoplasmosis. PMID- 26038908 TI - Detection and Quantification of Gluten during the Brewing and Fermentation of Beer Using Antibody-Based Technologies. AB - In 2013 the U.S. Food and Drug Administration (FDA) defined the term ''gluten free'' and identified a gap in the analytical methodology for detection and quantification of gluten in foods subjected to fermentation and hydrolysis. To ascertain the ability of current enzyme-linked immunosorbent assays (ELISAs) to detect and quantify gluten in fermented and hydrolyzed products, sorghum beer was spiked in the initial phases of production with 0, 20, and 200 MUg/ml wheat gluten, and samples were collected throughout the beer production process. The samples were analyzed using five sandwich ELISAs and two competitive ELISAs and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with Western analysis employing four antibodies (MIoBS, R5, G12, and Skerritt). The sensitivity of the MIoBS ELISA (0.25 ppm) enabled the reliable detection of gluten throughout the manufacturing process, including fermentation, when the initial concentration of 20 MUg/ml dropped to 2 MUg/ml. The R5 antibody-based and G12 antibody-based sandwich ELISAs were unable to reliably detect gluten, initially at 20 MUg/ml, after the onset of production. The Skerritt antibody based sandwich ELISA overestimated the gluten concentration in all samples. The R5 antibody-based and G12 antibody-based competitive ELISAs were less sensitive than the sandwich ELISAs and did not provide accurate results for quantifying gluten concentration. The Western analyses were able to detect gluten at less than 5 MUg/ml in the samples and confirmed the results of the ELISAs. Although further research is necessary before all problems associated with detection and quantification of hydrolyzed and fermented gluten are resolved, the analytical methods recommended by the FDA for regulatory samples can detect >= 20 MUg/ml gluten that has undergone brewing and fermentation processes associated with the manufacture of beer. PMID- 26038909 TI - Assessment of the Prevalence of Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae in Ready-to-Eat Salads, Fresh-Cut Fruit, and Sprouts from the Swiss Market. AB - Ready-to-eat (RTE) prepacked salads and fruit have been successfully marketed for the last decade in Switzerland and are increasingly important as a component of everyday diets. To determine whether extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae are present in RTE salads, fresh-cut fruit, and sprouts on the Swiss market, samples of 238 mixed and unmixed RTE produce from a large production plant and 23 sprout samples from two sprout farms were analyzed. Further, four samples from the production plant's recycled wash water, which is used for crop irrigation, were analyzed. Twelve (5%) of the 238 RTE products and one of the recycled wash water samples yielded ESBL-producing Enterobacteriaceae. Strain identification and PCR analysis of the blaESBL genes revealed Kluyvera ascorbata isolated from a tomato sample harboring a blaCTX-M-2-like gene; multidrug-resistant (MDR) Enterobacter cloacae detected in a chives sample imported from Spain harboring the clinically important bla(CTX-M-15) gene; and 10 Serratia spp. isolated from mixed salads (bla(FONA-2) and bla(FONA-2)-like genes were found in 6 [60%] and bla(FONA-4)-like and bla(FONA-5)-like genes were each found in 2 [20%] of the isolates). The recycled wash water sample tested positive for one extraintestinal pathogenic MDR Escherichia coli B2:ST131 harboring bla(CTX-M-27) and for one MDR E. coli A:ST88 containing bla(CTX-M-3). None of the sprout samples tested positive for ESBL-producing Enterobacteriaceae. Overall, the majority of the Enterobacteriaceae detected in Swiss RTE produce were environmental strains producing minor ESBLs. The detection of an isolate producing a clinically important ESBL in a single sample and of an international circulating pathogenic strain (B2:ST131) in recycled wash water highlights the importance of surveillance of fresh produce and of recycled wash water that will be reused for irrigation purposes. PMID- 26038910 TI - Improvements to a PCR-Based Serogrouping Scheme for Salmonella enterica from Dairy Farm Samples. AB - Molecular serotyping through the use of PCR is a simple and useful technique for characterizing isolates of Salmonella enterica subsp. enterica belonging to serogroups B, C1, C2, D1, and E1, which are the majority of the isolates associated with human disease outbreaks. However, many of the Salmonella strains currently isolated from dairy farms in the northeastern United States are serovar Cerro, a group K strain not detected by this assay. Primers from a well-known PCR assay for the identification of Salmonella were added to a commonly used serotyping assay so that strains, such as Salmonella Cerro, that do not produce bands in the original assay can be confirmed as belonging to S. enterica subsp. enterica. The modified assay frequently misidentified the serogroup of Salmonella Mbandaka isolates because of failure to amplify the wzxC1 amplicon. Therefore, the reverse primer for the wzxC1 target was modified based on in silico analysis to provide consistent classification of Salmonella Mbandaka as belonging to serogroup C1. These two modifications to the serogrouping PCR method enhance the utility of the method for characterizing Salmonella isolates. PMID- 26038911 TI - Adhesion of Asaia bogorensis to Glass and Polystyrene in the Presence of Cranberry Juice. AB - The aim of the study was to evaluate the adhesion abilities of the acetic acid bacterium Asaia bogorensis to glass and polystyrene in the presence of American cranberry (Vaccinium macrocarpon) juice. The strain of A. bogorensis used was isolated from spoiled commercial fruit-flavored drinking water. The cranberry juice was analyzed for polyphenols, organic acids, and carbohydrates using high performance liquid chromatography and liquid chromatography-mass spectrometry techniques. The adhesive abilities of bacterial cells in culture medium supplemented with cranberry juice were determined using luminometry and microscopy. The viability of adhered and planktonic bacterial cells was determined by the plate count method, and the relative adhesion coefficient was calculated. This strain of A. bogorensis was characterized by strong adhesion properties that were dependent upon the type of surface. The highest level of cell adhesion was found on the polystyrene. However, in the presence of 10% cranberry juice, attachment of bacterial cells was three times lower. Chemical analysis of juice revealed the presence of sugars, organic acids, and anthocyanins, which were identified as galactosides, glucosides, and arabinosides of cyanidin and peonidin. A-type proanthocyanidins responsible for the antiadhesion properties of V. macrocarpon also were detected. PMID- 26038912 TI - Reevaluation of a Suspected Cronobacter sakazakii Outbreak in Mexico. AB - In 2010, two infants became ill at a hospital in Mexico. Subsequently, a range of clinical, environmental, and powdered and rehydrated infant formula isolates were identified by using a combination of phenotyping and PCR probes. The strains were clustered according to pulsed-field gel electrophoresis. The causative agent was reported as Cronobacter sakazakii, with powdered infant formula (PIF) identified as the likely source of the infections. This new study further characterized the isolates from this outbreak by using multilocus sequence typing and whole genome sequencing of selected strains. Though four PIF isolates and one hospital environmental isolate were identified as C. sakazakii sequence type 297 by multilocus sequence typing, they were isolated 6 months prior to the outbreak. Genotypic analyses of patient isolates identified them as Enterobacter hormaechei and Enterobacter spp. The pulsed-field gel electrophoresis profile of the Enterobacter spp. isolates matched those of isolates from previously unopened tins of PIF. E. hormaechei was only isolated from the two infants and not PIF. The reevaluation of this outbreak highlights the need for accurate detection and identification assays, particularly during outbreak investigations in which incorrect identifications may mislead the investigation and attribution of the source. Though the species responsible for the symptoms could not be determined, this outbreak demonstrated the possible transmission of Enterobacter spp. from PIF to infants. These are possibly the first reported cases of Enterobacter spp. infection of infants from bacterial-contaminated PIF. PMID- 26038913 TI - Investigation into Formation of Lipid Hydroperoxides from Membrane Lipids in Escherichia coli O157:H7 following Exposure to Hot Water. AB - Although studies have shown antimicrobial treatments consisting of hot water sprays alone or paired with lactic acid rinses are effective for reducing Escherichia coli O157:H7 loads on beef carcass surfaces, the mechanisms by which these interventions inactivate bacterial pathogens are still poorly understood. It was hypothesized that E. coli O157:H7 exposure to hot water in vitro at rising temperatures for longer time periods would result in increasing deterioration of bacterial outer membrane lipids, sensitizing the pathogen to subsequent lactic acid application. Cocktails of E. coli O157:H7 strains were subjected to hot water at 25 (control) 65, 75, or 85 degrees C incrementally up to 60 s, after which surviving cells were enumerated by plating. Formation of lipid hydroperoxides from bacterial membranes and cytoplasmic accumulation of L-lactic acid was quantified spectrophotometrically. Inactivation of E. coli O157:H7 proceeded in a hot water exposure duration- and temperature-dependent manner, with populations being reduced to nondetectable numbers following heating of cells in 85 degrees C water for 30 and 60 s (P < 0.05). Lipid hydroperoxide formation was not observed to be dependent upon increasing water temperature or exposure period. The data suggest that hot water application prior to organic acid application may function to increase the sensitivity of E. coli O157:H7 cells by degrading membrane lipids. PMID- 26038914 TI - Evaluation of commercial kit based on loop-mediated isothermal amplification for rapid detection of low levels of uninjured and injured Salmonella on duck meat, bean sprouts, and fishballs in Singapore. AB - The objective of this study was to evaluate performance of the commercial kit based on loop-mediated isothermal amplification (LAMP) in comparison with the International Organization for Standardization method for detecting uninjured and sublethally injured Salmonella cells artificially inoculated at levels of 10(0) and 10(1) CFU/25 g on raw duck wing, raw mung bean sprouts, and processed fishballs. Injured cells were prepared by a heat treatment for duck wings and fishball samples and a chlorine treatment for bean sprout samples. Additionally, a validation study was performed on naturally contaminated food samples sold in Singapore. A total of 110 samples of each commodity were analyzed in this study. Regardless of inoculum levels, the detection by the commercial LAMP kit showed 100% sensitivity and specificity for both inoculated and uninoculated samples compared with the International Organization for Standardization method, with the exception of bean sprout samples. Only 20% of bean sprout samples inoculated with 10(0) CFU/25 g injured Salmonella cells were positive by using the commercial LAMP-based kit. However, all negative samples became positive following a secondary enrichment in Rappaport-Vassiliadis medium with soy broth or after concentration by centrifugation. These results suggest that secondary enrichment or centrifugation should be considered as an additional step to increase the sensitivity of the commercial LAMP-based kit with low numbers of injured target cells in samples with high background microflora (such as mung bean sprouts). The validation study also showed that the commercial LAMP-based kit provided 91% sensitivity and 95% specificity for naturally contaminated samples. Thus, this study demonstrates that the commercial LAMP-based kit might be a cost-effective method, as this system could provide rapid, accurate detection of both uninjured and injured Salmonella cells on raw duck wings, raw mung bean sprouts, and processed fishballs in less than 26 h. PMID- 26038915 TI - Comparative Effects of Ohmic and Conventional Heating for Inactivation of Escherichia coli O157:H7, Salmonella enterica Serovar Typhimurium, and Listeria monocytogenes in Skim Milk and Cream. AB - Ohmic heating has proven advantages over conventional thermal processing and novel thermal alternative technologies. In this study, the effect of ohmic and conventional heating for pasteurizing skim milk and cream was examined. All treatment conditions for ohmic and conventional heating were identical except for composition of the heating chamber. In most cases, the reduction of three pathogens did not differ significantly between ohmic heating and conventional heating at fixed treatment temperatures and times. However, temperature can be increased more rapidly with ohmic than with conventional heating treatment, both in skim milk and in cream. Therefore, E. coli O157:H7, Salmonella Typhimurium, and L. monocytogenes were inactivated more effectively by ohmic heating treatment for the same treatment time intervals. Also, the time required for pathogen populations to decrease to below the detection limit was less for ohmic heating than conventional heating. Quality aspects (viscosity, pH, and color) of skim milk and cream suffered less degradation by ohmic than by conventional heating. Although there was little evidence of a nonthermal effect of ohmic heating, the results demonstrate significant advantages in the use of ohmic heating over conventional methods for pasteurizing skim milk and cream. PMID- 26038916 TI - Validating the Inhibition of Staphylococcus aureus in Shelf-Stable, Ready-to-Eat Snack Sausages with Varying Combinations of pH and Water Activity. AB - Shelf-stable, ready-to-eat meat and poultry products represent a large sector of the meat snack category in the meat and poultry industry. Determining the physiochemical conditions that prevent the growth of foodborne pathogens, namely, Staphylococcus aureus postprocessing, is not entirely clear. Until recently, pH and water activity (a(w)) criteria for shelf stability has been supported from the U.S. Department of Agriculture training materials. However, concern about the source and scientific validity of these critical parameters has brought their use into question. Therefore, the objective of this study was to evaluate different combinations of pH and aw that could be used for establishing scientifically supported shelf stability criteria defined as preventing S. aureus growth postprocessing. Snack sausages were manufactured with varying pH (5.6, 5.1, and 4.7) and a(w) (0.96, 0.92, and 0.88) to achieve a total of nine treatments. The treatments were inoculated with a three-strain mixture of S. aureus, with populations measured at days 0, 7, 14, and 28 during 21 degrees C storage. Results revealed treatments with a pH <= 5.1 and a(w) <= 0.96 did not support the growth of S. aureus and thus could be considered shelf stable for this pathogen. The results provide validated shelf stability parameters to inhibit growth of S. aureus in meat and poultry products. PMID- 26038917 TI - Sporicidal Activities of Various Surfactant Components against Bacillus subtilis Spores. AB - The sporicidal activities against Bacillus subtilis spores of surfactant components with hydrophilic and hydrophobic properties that can lead to the denaturation of various proteins comprising the spore structure were investigated. The reduction in spore numbers by each of the surfactant components bornyl acetate, geranyl acetate, pinene, p-cymene, camphene, citral, 2,3 dihydrobenzofuran, polylysine, and thiamine dilaurylsulfate at 1% was estimated at 1 to 2 log CFU/ml. The average hydrophilelipophile balance value of surfactants with sporicidal activity causing a reduction of 1 to 2 log CFU/ml was 9.3, with a range from 6.7 to 15.8, which is similar to the values of various chemical surfactants of 9.6 to 16.7. The results also showed that the surfactants that were hydrophobic were more effective than those that were hydrophilic in killing B. subtilis spores. Furthermore, the sporicidal effect of surfactants like geranyl acetate and gamma-terpinene was significantly enhanced in the presence of a germinant, because L-alanine and synergistic cofactors (e.g., K(+) ions) trigger cortex hydrolysis in spores. PMID- 26038918 TI - Simple high-performance liquid chromatography method for the simultaneous analysis of aflatoxins, ochratoxin A, and zearalenone in dried and ground red pepper. AB - Aflatoxins B1, B2, G1, G2 (AFB1, AFB2, AFG1, AFG2), ochratoxin A (OTA), and zearalenone (ZEA) in dried and ground red pepper (Capsicum annuum) were simultaneously analyzed with high-performance liquid chromatography coupled to fluorescence detection after post-column derivatization. The analytical method was validated for specificity, selectivity, linearity, limits of detection and quantification, recovery, precision, and measurement of uncertainty. The limits of detection and quantification were 0.10 and 0.25 MUg/kg for AFB1, 0.04 and 0.06 MUg/kg for AFB2, 0.14 and 0.50 MUg/kg for AFG1, 0.05 and 0.10 MUg/kg for AFG2, 0.12 and 0.45 MUg/kg for OTA, and 4.00 and 13.25 MUg/kg for ZEA, respectively. The average recoveries ranged from 80.4 to 98.5% for different concentrations of AFB1, AFB2, AFG1, AFG2, OTA, and ZEA in spiked samples. The measurement uncertainties were 0.64 to 1.62 MUg/kg for AFB1, 0.24 to 0.45 MUg/kg for AFB2, 0.79 to 2.19 MUg/kg for AFG1, 0.32 to 0.61 MUg/kg for AFG2, 0.81 to 2.31 MUg/kg for OTA, and 8.48 to 26.25 MUg/kg for ZEA. This method was successfully applied for the simultaneous determination of mycotoxins for 78 red peppers collected from Korean and Indian markets. Aflatoxins (sum of AFB1, AFB2, AFG1, and AFG2) were detected in 2% of nonpacked samples (n = 23) and 43% of packed samples (n = 55), at levels of 0.04 to 38.03 MUg/kg. OTA was detected in 4% of nonpacked samples and 48% of packed samples, at levels of 0.15 to 56.30 MUg/kg. ZEA was not detected in any samples. These findings indicate that the analytical method described here is suitable for the routine determination of the amounts of AFs, OTA, and ZEA in dried and ground red pepper. PMID- 26038919 TI - Inaccuracy of Labeling and Visual Inspection for Microsporidian Parasites in Anglerfish Lophius litulon (Jordan, 1902) Collected from Chinese Retail Markets in Sardinia, Italy. AB - The aim of the present study was to evaluate the accuracy of labeling and the efficacy of visual inspection to detect the lesions by visible parasites in anglerfish Lophius litulon. One hundred samples were collected over a 2-year period (2011 to 2012) from Chinese retail markets in Sardinia, Italy. To assess the conformity of the items with the trade name, a preliminary visual inspection of the samples by a simple morphological analysis was performed. According to the Council Regulations (EC) 104/2000, 1224/2009, and 2074/2005, the Italian labels were examined to verify the appropriate indication of relevant information on traceability (trade name, scientific name, geographical area, and production method), and the samples of L. litulon were subjected to visual inspection to detect "visible parasites." Altogether, a high percentage of mismatching (70%) between the scientific name and trade name was pointed out. Moreover, 60% of the samples were visibly infected by Spraguea lophii, a microsporidian parasite of the nervous tissue that forms typical lesions (xenomas) in the fish flesh near the vertebral column. Although S. lophii is not pathogenic to humans, the presence of xenomas can decompose the fish flesh and render it unfit for human consumption. The high percentage of mislabeling, together with the inaccuracy in the visual inspection by Chinese food business operators highlighted the need to improve the European Union control system of fishery products imported from China and marketed in Europe. PMID- 26038920 TI - Survey of tea for the presence of gluten. AB - In 2013, the U.S. Food and Drug Administration conducted a survey of green and white teas marketed in the northeastern United States for the presence of undeclared wheat. Based on the requirement for concurrence between the RIDASCREEN gliadin (R5) enzyme-linked immunosorbent assay (ELISA) and the Morinaga Institutes of Biological Science (MIoBS) wheat protein ELISA, none of the 20 products included in the survey tested positive for wheat, rye, barley, or gluten. However, eight of the teas generated responses indicative of the presence of gluten with the RIDASCREEN gliadin (R5), AgraQuant gluten G12, and Aller-Tek (Skerritt) sandwich ELISAs. Five of the eight teas generated responses indicative of >20 ppm of gluten using the RIDASCREEN and AgraQuant ELISA test kits, and all eight had >= 20 ppm based on the Aller-Tek ELISA. Extracts prepared using the RIDASCREEN validated protocol and the MIoBS validated sodium dodecyl sulfate plus beta-mercaptoethanol (overnight) protocol were analyzed using both test kits. The extracts prepared using the RIDASCREEN protocol tested positive for gluten with both test kits. Western blot analyses of the two sets of extracts using the R5 and MIoBS antibodies to visualize the bands revealed the presence of antigenic proteins in both sets of extracts, although the profiles and band intensities were different and inconsistent with the ELISA results. These results raise questions regarding the screening procedures used to detect gluten and how the observation of a homologous antigenic element is defined. PMID- 26038921 TI - Intracranial electrographic analysis of preictal spiking and ictal onset in uni and bitemporal epilepsy. AB - AIM: Ictal onset patterns in bilateral mesial temporal lobe epilepsy have not been comprehensively studied. A retrospective review of intracranial electrographic data was undertaken to establish whether it is possible to distinguish between unilateral and bilateral mesial temporal lobe epilepsy based on ictal onset patterns, including periodic preictal spiking. METHODS: A total of 470 ictal onset patterns were analyzed by bitemporal extraoperative electrocorticography in 13 patients with medically intractable mesial temporal lobe epilepsy. Ictal onset patterns were categorized, by frequency, as type A (<12 Hz), type B (12-40 Hz) and type C (>40 Hz). Preictal rhythmic spiking, of at least five seconds duration, and time to contralateral propagation were also measured with each ictal event. We determined if the proportion of "ictal onset pattern frequencies" or "incidence of preictal spiking" differed between unilateral and bilateral mesial temporal lobe epilepsy. RESULTS: Seven patients with unilateral mesial temporal lobe epilepsy received surgery and achieved Engel class I outcomes, while the remaining six did not undergo resective surgery, due to the bilateral ictal onsets in extraoperative electrocorticography. The proportion of patients experiencing any preictal spikes was higher in unitemporal than in bitemporal cases (100% vs 50%;p=0.069). Ofthe470 ictal onset patterns analyzed (174 unitemporal and 296 bitemporal), a significant greater percentage of preictal spikes was found in unilateral cases (78% unitemporal vs 14% bitemporal; p=0.002). Low-frequency patterns were more evident in bitemporal cases (45%) than in unitemporal (10%), although the difference was not statistically significant (p=0.129). No differences were detected between the unitemporal and bitemporal groups regarding age at onset or at presentation. CONCLUSION: A greater proportion of pre ictal spiking, based on extraoperative electrocorticography, was present in unilateral, compared to bilateral, mesial temporal lobe epilepsy. Further studies are warranted to determine the causal significance of preictal spiking in mesial temporal lobe epilepsy. PMID- 26038922 TI - Distribution and characteristic of PAHs in sediments from the southwest Caspian Sea, Guilan Province, Iran. AB - Contamination by polycyclic aromatic hydrocarbons (PAHs) in the southwest Caspian Sea was assessed by examination of 45 sediment samples, collected from the coasts of the Guilan Province in 2012 and analyzed for 29 PAHs. The concentrations of PAHs were in the range of 232.1-1,014 ng g(-1) dry weight (mean 520+/-246.4 ng g( 1)). The predominance of alkyl-substituted naphthalenes and phenanthrenes and the higher contributions of petrogenic compounds (NPD=35.4-74.4%) compared to pyrogenic PAH compounds (COM=18.1-47.4%) reveal a petrogenic source for PAHs with ubiquitous distribution in the study area. Offshore increase of total PAH concentrations was found to be correlated with increase of organic matter content of sediments, but no correlations with particle size fractions were found. The evaluation of ecotoxicological risk by sediment quality guidelines indicated that total PAH concentrations at all sites were below the effects range-low (ERL), but some individual petrogenic PAHs at some stations were significantly above their ERL and likely to adversely affect benthic biota. According to the diagnostic ratios used, most stations revealed the major source of the PAHs to be petrogenic, but some stations suggested a mixed petrogenic-pyrogenic source. PMID- 26038923 TI - Effects of Chlorella sp. on nutrient treatment in cultures with different carbon to nitrogen ratios. AB - Chlorella sp. is often used in the treatment of wastewater to produce lipids, a practice which could go beyond wastewater treatment and be used to generate green energy. Our objectives here are to explore how the ratio of carbon to nitrogen (C/N) affects the removal of carbon and nitrogen in a wastewater treatment system, while simultaneously generating biomass and lipids. In this study, the C/N ratio is adjusted to 0.002, 6, 8, 10, 12 and 32. The results indicate that a C/N of 10 is sufficient to ensure the consumption of carbon and nitrogen, achieving the lowest concentration in the shortest culturing time (32 h). When nitrogen is lacking in the culture, there will be a slight decrease in the rate of carbon consumption which leads to a limitation of nitrogen and an increase in the lipid/cell density even at 96 h of culture time. The highest lipid content (0.57 g/L) and lipid increase rate (0.4 g/L) occurs with a C/N of 32. The greatest amount of biomass, 1.42 g/L is achieved when the C/N is 32. The carbon concentration is the main factor affecting the nitrogen consumption and the increase in the biomass and lipid content. PMID- 26038924 TI - Anaerobic biological treatment of methylparaben in an expanded granular sludge bed (EGSB). AB - This study evaluated the behavior of an anaerobic expanded granular sludge bed system using different methylparaben (MPB) concentrations. The assay was conducted for 268 days and was divided into seven stages of operation, which included the starting stage and subsequent stages where the MPB concentration was increased. The inoculum that was used was a mixture of anaerobic granular sludge with flocculent active sludge that contained 21.7 g/L of total suspended solids and 17.4 g/L of volatile suspended solids, resulting in an organic content of approximately 80%. The MPB removals after applying concentrations of 300 mg/L, 500 mg/L and 1,000 mg/L during the different stages and adding glucose to the influent were 94+/-2.4%, 84+/-5.8% and 88+/-7.4%, respectively. For phases without glucose, the results were 97.4+/-0.4%, 96+/-1.6% and 98.2+/-0.3%, respectively. The results showed a high pollutant removal and good progress in terms of the physical and biological characteristics of the granular biomass, which showed no change in the presence of the compound or a concentration increase. PMID- 26038925 TI - Alkaline deoxygenated graphene oxide as adsorbent for cadmium ions removal from aqueous solutions. AB - Alkaline deoxygenated graphene oxide (aGO) was prepared through alkaline hydrothermal treatment and used as adsorbent to remove Cd(II) ions from aqueous solutions for the first time. The characterization results of transmission electron microscopy, X-ray diffraction, Raman spectroscopy, and Fourier transform infrared (FT-IR) spectra indicate that aGO was successfully synthesized. The batch adsorption experiments showed that the adsorption kinetics could be described by the pseudo-second-order kinetic model, and the isotherms equilibrium data were well fitted with the Langmuir model. The maximum adsorption capacity of Cd(II) on aGO was 156 mg/g at pH 5 and T=293 K. The adsorption thermodynamic parameters indicated that the adsorption process was a spontaneous and endothermic reaction. The mainly adsorption mechanism speculated from FT-IR results may be attributed to the electrostatic attraction between Cd2+ and negatively charged groups (-CO-) of aGO and cation-pi interaction between Cd2+ and the graphene planes. The findings of this study demonstrate the potential utility of the nanomaterial aGO as an effective adsorbent for Cd(II) removal from aqueous solutions. PMID- 26038926 TI - Inhibitory effect of erythromycin, tetracycline and sulfamethoxazole antibiotics on anaerobic treatment of a pharmaceutical wastewater. AB - Pharmaceuticals enter ecosystems, which causes changes to microbial community structure and development of resistant genes. Anaerobic treatments can be an alternative application for treatment of pharmaceutical wastewaters, which has high organic content. This study aims to develop an understanding of the effects of sulfamethoxazole-erythromycin-tetracycline (ETS), sulfamethoxazole tetracycline (ST), erythromycin-sulfamethoxazole (ES) and erythromycin tetracycline (ET) combinations on the anaerobic treatment of pharmaceutical industry wastewater. The results of this investigation revealed that bacteria have a competitive advantage over archaea under all antibiotic combinations. The ET reactor showed a better performance compared to other reactors; this could be due to antagonistic effects of sulfamethoxazole. Acute inhibition in the microbial community was also strongly affected by antibiotics concentrations. This indicated that the composition of the microbial community changed in association with anaerobic sequencing batch reactor performances. The results of this research support the idea that an acute test could be used to control and improve the anaerobic treatment system. PMID- 26038927 TI - Perchlorate adsorption onto orange peel modified by cross-linking amine groups from aqueous solutions. AB - Orange peel was made into a highly efficient bio-sorbent by modification with cross-linking amine groups for perchlorate removal. Bench-scale experiments were performed to explore the factors affecting the perchlorate adsorption onto the modified orange peel (MOP). Perchlorate could be removed effectively at a wide range of pH (from 1.5 to 11). The maximum adsorption capacity of MOP for perchlorate was calculated as 154.1 mg/g within 15 min. The Redlich-Peterson model was fitted to the adsorption isotherm very well (R2>0.99). The adsorption process was spontaneous and exothermic, which was proved by thermodynamic parameters (Gibbs energy and enthalpy). The pseudo-second-order kinetic model could provide satisfactory fitting of the experimental data (R2>0.99). The scanning electron microscopy and energy-dispersive X-ray analysis indicated that the surface of MOP became smooth and the contents of N and Cl in MOP were increased during the modification process. Elemental analysis results showed that the nitrogen content in MOP was increased to 5.5%, while it was 1.06% in orange peel. The adsorption mechanism was also explored using zeta potential and Fourier transform infrared spectroscopy analysis. Ion exchange was the primary mechanism responsible for uptake of perchlorate onto MOP. PMID- 26038928 TI - Manufacturing ceramic bricks with polyaluminum chloride (PAC) sludge from a water treatment plant. AB - The objective of this research work is to assess the viability of manufacturing ceramic bricks with sludge from a water treatment plant (WTP) for use in real world applications. Sludge was collected from settling tanks at the Bolonha WTP, which is located in Belem, capital of the state of Para, Brazil. After dewatering in drainage beds, sludge was added to the clay at a local brickworks at different mass percentages (7.6, 9.0, 11.7, 13.9 and 23.5%). Laboratory tests were performed on the bricks to assess their resistance to compression, water absorption, dimensions and visual aspects. Percentages of 7.6, 9.0, 11.7 and 13.9% (w/w) of WTP sludge presented good results in terms of resistance, which indicates that technically, ceramic bricks can be produced by incorporating up to 13.9% of WTP sludge. PMID- 26038929 TI - Kinetics analysis of zinc sorption in fixed bed column using a strongly basic anionic exchange resin. AB - The aim of this study was to examine the capacity of anionic resins to remove zinc as zinc chloride complexes in fixed bed. The applicability of the kinetics models and the characteristics of the bed (sorption capacity, breakthrough curve, depth of the adsorption zone) were taken into account. The influence of the process parameters, such as resin quantity (bed height) and zinc initial concentration, on the removal process was also considered. The obtained results (Amberlite IRA410) were analyzed using sorption kinetic models such as Thomas, Adam-Bohart, and Clark, by linear regression analysis. Similarly, the concept of the mass transfer zone was applied in order to properly design the fixed bed adsorption process. By comparing various resins, the following series was depicted based on sorption capacities: Amberlite IRA410>Purolite A103S>Purolite NRW700>Purolite A400MBOH. The experimental data were in good agreement with the Clark model, while for the other models, lower correlation coefficients were obtained under the same experimental conditions. The MTZ height and rate of movement increased with increasing initial concentration. PMID- 26038930 TI - Submerged anaerobic membrane bioreactor for wastewater treatment and energy generation. AB - Compared with conventional wastewater treatment processes, membrane bioreactors (MBRs) offer several advantages including high biodegradation efficiency, excellent effluent quality and smaller footprint. However, it has some limitations on account of its energy intensive operation. In recent years, there has been growing interest in use of anaerobic membrane bioreactors (AnMBRs) due to their potential advantages over aerobic systems, which include low sludge production and energy generation in terms of biogas. The aim of this study was to evaluate the performance of a submerged AnMBR for the treatment of synthetic wastewater having 4,759 mg/l chemical oxygen demand (COD). The COD removal efficiency was over 95% during the performance evaluation study. Treated effluent with COD concentration of 231 mg/l was obtained for 25.5 hours hydraulic retention time. The obtained total organic carbon concentrations in feed and permeate were 1,812 mg/l and 89 mg/l, respectively. An average biogas generation and yield were 25.77 l/d and 0.36 m3/kg COD, respectively. Evolution of trans membrane pressure (TMP) as a function of time was studied and an average TMP of 15 kPa was found suitable to achieve membrane flux of 12.17 l/(m2h). Almost weekly back-flow chemical cleaning of the membrane was found necessary to control TMP within the permissible limit of 20 kPa. PMID- 26038931 TI - Model-based control structure design of a full-scale WWTP under the retrofitting process. AB - The anoxic-oxic (A/O) municipal wastewater treatment plant (WWTP) of Manresa (Catalonia, Spain) was studied for a possible conversion to an anaerobic/anoxic/oxic (A2/O) configuration to promote enhanced biological phosphorus removal. The control structure had to be redesigned to satisfy the new necessity to control phosphorus concentration, besides ammonium and nitrate concentrations (main pollutant concentrations). Thereby, decentralized control structures with proportional-integral-derivative (PID) controllers and centralized control structures with model-predictive controllers (MPC) were designed and tested. All the designed control structures had their performance systematically tested regarding effluent quality and operating costs. The centralized control structure, A2/O-3-MPC, achieved the lowest operating costs with the best effluent quality using the A2/O plant configuration for the Manresa WWTP. The controlled variables used in this control structure were ammonium in the effluent, nitrate at the end of the anoxic zone and phosphate at the end of the anaerobic zone, while the manipulated variables were the internal and external recycle flow rates and the dissolved oxygen setpoint in the aerobic reactors. PMID- 26038932 TI - Biological regeneration of ferric (Fe3+) solution during desulphurisation of gaseous streams: effect of nutrients and support material. AB - This paper evaluates the biological regeneration of ferric Fe3+ solution during desulphurisation of gaseous streams. Hydrogen sulphide (H2S) is absorbed into aqueous ferric sulphate solution and oxidised to elemental sulphur, while ferric ions Fe3+ are reduced to ferrous ions Fe2+. During the industrial regeneration of Fe3+, nutrients and trace minerals usually provided in a laboratory setup are not present and this depletion of nutrients may have a negative impact on the bacteria responsible for ferrous iron oxidation and may probably affect the oxidation rate. In this study, the effect of nutrients and trace minerals on ferrous iron oxidation have been investigated and the results showed that the presence of nutrients and trace minerals affects the efficiency of bacterial Fe2+oxidation. The scanning electron microscopy analysis of the geotextile support material was also conducted and the results showed that the iron precipitate deposits appear to play a direct role on the bacterial biofilm formation. PMID- 26038933 TI - Aniline chlorination by in situ formed Ag-Cl complexes under simulated solar light irradiation. AB - Ag speciation in a chloride medium was dependent upon the Cl/Ag ratio after releasing into surface water. In this study, the photoreaction of in situ formed Ag-Cl species and their effects on aniline photochlorination were systematically investigated. Our results suggested that formation of chloroaniline was strongly relevant to the Cl/Ag ratio and could be interpreted using the thermodynamically expected speciation of Ag in the presence of Cl-. AgCl was the main species responsible for the photochlorination of aniline. Both photoinduced hole and *OH drove the oxidation of Cl- to radical *Cl, which promoted the chlorination of aniline. Ag0 formation was observed from the surface plasmon resonance absorption during AgCl photoreaction. This study revealed that Ag+ released into Cl- containing water may result in the formation of chlorinated intermediates of organic compounds under solar light irradiation. PMID- 26038934 TI - Rheological behavior of sewage sludge with high solid content. AB - Sludge rheological properties play a fundamental role in determining its performance in pipes, tanks or reactors. However, the relative information on high-solids sludge is very rare. In this study, the rheological properties of high-solids sludge were investigated systematically and a new rheological model was built. The results showed that the low-solids sludge with total solids content (TS) 2-15% was pseudoplastic fluid, and the high-solids sludge with TS 7 15% exhibited thixotropic property. Sludge viscosity increased exponentially with the increasing TS, and decreased in function of power along with the increasing shear rate. The new complex model combining the exponential model and the power model can perfectly describe the relation between TS, shear rate and viscosity of the high-solids sludge. Both sludge organic content and temperature have influence on sludge viscosity, but the influence was not significant for the low solids sludge. For the high-solids sludge with TS 6%, 8%, 10% and 12%, their viscosities increased by 5.0, 9.1, 25.7 and 24.9 times, respectively, when sludge organic content increased from 28% to 53%, and decreased by 36.5%, 49.5%, 54.0% and 65.4%, respectively, when sludge temperature rose from 9 to 55 degrees C. PMID- 26038935 TI - Characteristics and kinetics of hexavalent chromium reduction by gallic acid in aqueous solutions. AB - Gallic acid (GA) is a naturally occurring plant polyphenol compound. Experiments were conducted to study the kinetics and effects of pH, temperature, irradiation, and initial hexavalent chromium (Cr(VI)) concentration on Cr(VI) reduction by GA. Results indicated that Cr(VI) could be reduced to chromium oxide (Cr(III)) with GA in a wide range of pH values from 2.0 to 8.5. The reaction followed a pseudo first-order kinetic model with respect to Cr(VI) and GA in acid conditions (pH 2.0-5.0). However, the reaction did not follow the pseudo-first-order kinetic model at pH 6.5 and 8.5. Removal efficiencies and reaction rate constants of Cr(VI) significantly increased with decreasing pH value and increasing temperature. The effect of irradiation on Cr(VI) reduction increased with increasing pH, and irradiation improved the removal efficiency of Cr(VI) by 11.29% at pH 6.5. At pH 2.0, nearly all molar ratios of GA required for the reduction of Cr(VI) were 1:2 (+/-0.1) under different initial Cr(VI) concentrations; however, the molar ratios of GA required for the reduction of Cr(VI) were 1:1.29, 1:1.43, and 1:1.69, respectively, when the initial Cr(VI) concentrations were 10, 25, and 50 mg/L at pH 5.5. PMID- 26038936 TI - Influence of operating parameters on the fate and removal of three estrogens in a laboratory-scale AAO system. AB - A laboratory-scale anaerobic-anoxic-oxic (AAO) process was constructed to investigate the influence of hydraulic residence time (HRT) and sludge retention time (SRT) on the removal and fate of estrone (E1), 17beta-estradiol (E2) and 17alpha-ethinylestradiol (EE2), and their removal mechanisms in a biological treatment system. In an HRT range of 5-15 h, the highest removal efficiencies for E1, E2 and EE2 were obtained at an HRT of 8 h, with values of 91.2, 94.6 and 81.5%, respectively. When the SRT was increased from 10 to 20 d, all three estrogen removal efficiencies stayed above 80%, while the optimal SRT for each estrogen was different. The contribution of each tank for removal of the three estrogens was in the order of aerobic tank>anoxic tank>anaerobic tank. The optimal HRT and SRT for the removal of both the three estrogens and nutrients were 8 h and 15d, respectively. At this condition, respectively, about 50.7, 70.1 and 11.3% of E1, E2 and EE2 were biodegraded, 28.8, 17.2 and 50% were accumulated in the system, 8.3, 5.4 and 17.3% were discharged in the effluent, and 12.2, 7.3 and 20.34% were transported into excess sludge. It indicated that biodegradation by sludge microorganisms was the main removal mechanism of E1 and E2, while adsorption onto sludge was the main mechanism for EE2 removal. PMID- 26038937 TI - Spatial-temporal characteristics of phosphorus in non-point source pollution with grid-based export coefficient model and geographical information system. AB - In this paper, the spatial changes and trends in non-point source (NPS) total phosphorus (TP) pollution were analyzed by land and non-land uses in the Songliao River Basin from 1986 to 2000 (14 years). A grid-based export coefficient model was used in the process of analysis based on to a geographic information system. The Songliao Basin is divided in four regions: Liaoning province, Jilin province (JL), Heilongjiang province and the eastern part of the Inner Mongolia (IM) Autonomous Region. Results indicated that the NPS phosphorus load caused by land use and non-land use increased steadily from 3.11*10(4) tons in 1986 to 3.49*10(4) tons in 2000. The southeastern region of the Songliao Plain was the most important NPS pollution contributor of all the districts. Although the TP load caused by land use decreased during the studied period in the Songliao River Basin, the contribution of land use to the TP load was dominant compared to non land uses. The NPS pollution caused by non-land use steadily increased over the studied period. The IM Autonomous Region and JL province had the largest mean annual rate of change among all districts (more than 30%). In this area, livestock and poultry breeding had become one of the most important NPS pollution sources. These areas will need close attention in the future. PMID- 26038938 TI - The effects of salinity on coupled nitrification and aerobic denitrification in an estuarine system. AB - Salinity has significant effects on nitrification and denitrification processes, particularly in estuarine systems. A dissolved oxygen-enriched river and its estuary in northern China were selected to investigate the impact of salinity gradients (0.6, 4, 7.6, 11.4 and 14.70/00) obtained from the mixing of river samples and estuarine samples with different proportions on coupled nitrification and aerobic denitrification via incubation experiments (35 and 10 degrees C). Results indicated that: (a) nitrification and coupled nitrification-aerobic denitrification occurred for all treatments, which resulted in NO3- being either accumulated or removed at the end of the incubation; (b) a suitable range of salinity is 4.0-11.40/00 for nitrification and 4.0-7.60/00 for coupled nitrification-aerobic denitrification; and (c) the relatively higher temperature (35 degrees C) can effectively stimulate N transformation processes compared to the lover temperature (10 degrees C) in the incubation experiment. PMID- 26038939 TI - Highly effective biosorption of Sr(II) from low level radioactive wastewater. AB - Bacillus subtilis was first used to remove Sr(II) from low-level radioactive wastewater. Influence parameters, biosorption kinetics and biosorption equilibrium were investigated. The results showed that the maximum adsorption capacity of Sr(II) at over 2,000 mg g(-1) by Bacillus subtilis was higher than for other biosorbents. At pH 6.3, Sr(II) concentration of 15 mg L(-1), biomass dosage of 0.3 g L(-1) and temperature of 20 degrees C, the maximum removal efficiency was as high as 96.3% at 1,440 minutes. The biosorption kinetics and the equilibrium isotherm data can be described by the pseudo-second-order equation and Freundlich isotherm equation, respectively. The negative values of DeltaG and the positive values of DeltaH implied that Sr(II) biosorption on Bacillus subtilis was a spontaneous and endothermic process. Fourier transform infrared spectroscopy indicated that the functional groups, hydroxyl, carboxylate and amide groups, might participate in the interaction between Sr(II) and Bacillus subtilis. PMID- 26038940 TI - High Pb concentration stress on Typha latifolia growth and Pb removal in microcosm wetlands. AB - When constructed wetlands are used to treat high-Pb wastewater, Pb may become a stress to wetland plants, which subsequently reduces treatment performance and the other ecosystem services. To facilitate the design and operation of constructed wetlands for treatment of Pb-rich wastewater, we investigated the irreversible inhibitory level of Pb for Typha latifolia through experiments in microcosm wetlands. Seven horizontal subsurface flow constructed wetlands were built with rectangular plastic tanks and packed with marble chips and sand. All wetlands were transplanted with nine stems of Typha latifolia each. The wetlands were batch operated in a greenhouse with artificial wastewater (10 L each) for 12 days. Influent to the seven wetlands had different concentrations of Pb: 0 mg/L, 10 mg/L, 25 mg/L, 50 mg/L, 100 mg/L, 200 mg/L, and 500 mg/L, respectively. The results suggested that leaf chlorophyll relative content, relative growth rate, photosynthetic characteristics, activities of superoxide dismutase, peroxidase, and content of malondialdehyde were not affected when initial Pb concentration was at 100 mg/L and below. But when initial Pb concentration was above 100 mg/L, all of them were seriously affected. We conclude that high Pb concentrations wastewater could inhibit the growth of Typha latifolia and decrease the removal rate of wetlands. PMID- 26038941 TI - Statistical evaluation of bioretention system for hydrologic performance. AB - Long-term retention performance is a common performance indicator for low-impact development practices, such as rain barrels, rain gardens, and green roofs. This paper introduces a numerical approach for the estimation of annual retention ratios of stormwater by bioretention. The annual retention ratio is taken as the ratio of the annual accumulated volume of stormwater retained by bioretention over the total volume of runoff draining into the system. The hydrologic model Storm Water Management Model (SWMM) is used to simulate the relevant flows of a bioretention system with parametric variations of the watershed area ratio and hydraulic conductivity of the soil media. Under these two dominant performance governing parameters, retention ratios are calculated using the 10-year (2004 2013) rainfall record in Hong Kong at 1-min intervals. This indicator can be readily applied to estimate the long-term retention performance of a bioretention using particular values of watershed area ratio and hydraulic conductivity of soil media under the climate of Hong Kong. The study also analyzes the influence of variation of annual precipitation on the estimated retention performance. Flow data monitored on a pilot-scale physical model of bioretention during a number of rainfall events are used to validate the numerical simulation. PMID- 26038942 TI - Structural evidence for Scc4-dependent localization of cohesin loading. AB - The cohesin ring holds newly replicated sister chromatids together until their separation at anaphase. Initiation of sister chromatid cohesion depends on a separate complex, Scc2(NIPBL)/Scc4(Mau2) (Scc2/4), which loads cohesin onto DNA and determines its localization across the genome. Proper cohesin loading is essential for cell division, and partial defects cause chromosome missegregation and aberrant transcriptional regulation, leading to severe developmental defects in multicellular organisms. We present here a crystal structure showing the interaction between Scc2 and Scc4. Scc4 is a TPR array that envelops an extended Scc2 peptide. Using budding yeast, we demonstrate that a conserved patch on the surface of Scc4 is required to recruit Scc2/4 to centromeres and to build pericentromeric cohesion. These findings reveal the role of Scc4 in determining the localization of cohesin loading and establish a molecular basis for Scc2/4 recruitment to centromeres. PMID- 26038944 TI - Plasma biomarkers as predictors of recurrence of atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation (AF) is the most common arrhythmia in the general population. There are numerous factors associated with the incidence and relapse of AF. It seems that some of them, such as neurohumoral changes, may affect AF-related atrial structural remodeling and lead to recurrence of AF. OBJECTIVES: The study aimed to assess the predictive value of plasma brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), aldosterone (ALD), and endothelin 1 (ET-1) concentrations before and after electrical cardioversion (CV). PATIENTS AND METHODS: The study included 60 patients with a dual-chamber pacemaker, persistent AF, and preserved left ventricular function who underwent successful CV. Blood samples were collected before and 24 hours and 7 days after CV. Recurrence of AF was identified by pacemaker logs lasting 30 minutes or longer. RESULTS: During a 12-month follow-up, only 5 patients (8%) had no recurrence of AF. Before cardioversion, ANP, ALD, and ET-1 levels were the same as those observed in the control group. BNP levels were significantly elevated and the level of 1237 fmol/ml or higher differentiated between patients with and without the recurrence of AF (sensitivity, 68%; specificity, 67%). Sinus rhythm restoration resulted in a significant decrease only in the BNP level. The BNP level of 700 fmol/ml or higher on day 7 after cardioversion was the most predictive for AF recurrence (sensitivity, 78%; specificity, 71%). In a multivariate analysis, only BNP levels of 700 fmol/ml or higher on day 7 after cardioversion (P = 0.04) and lack of amiodarone (P = 0.03) were independent predictors of AF recurrence. CONCLUSIONS: A BNP level of 700 fmol/ml or higher 7 days after cardioversion is an independent predictor of AF recurrence during 12 months after cardioversion. ANP, ALD, and ET-1 levels at baseline or 7 days after cardioversion are not predictive of AF recurrence. PMID- 26038943 TI - DICER Inactivation Identifies Pancreatic beta-Cell "Disallowed" Genes Targeted by MicroRNAs. AB - Pancreatic beta-cells are the body's sole source of circulating insulin and essential for the maintenance of blood glucose homeostasis. Levels of up to 66 "disallowed" genes, which are strongly expressed and play housekeeping roles in most other mammalian tissues, are unusually low in beta-cells. The molecular mechanisms involved in repressing these genes are largely unknown. Here, we explore the role in gene disallowance of microRNAs (miRNAs), a type of small noncoding RNAs that silence gene expression at the posttranscriptional level and are essential for beta-cell development and function. To selectively deplete miRNAs from adult beta-cells, the miRNA-processing enzyme DICER was inactivated by deletion of the RNase III domain with a tamoxifen-inducible Pdx1CreER transgene. In this model, beta-cell dysfunction was apparent 2 weeks after recombination and preceded a decrease in insulin content and loss of beta-cell mass. Of the 14 disallowed genes studied, quantitative RT-quantitative real-time PCR revealed that 6 genes (Fcgrt, Igfbp4, Maf, Oat, Pdgfra, and Slc16a1) were up regulated (1.4- to 2.1-fold, P < .05) at this early stage. Expression of luciferase constructs bearing the 3'-untranslated regions of the corresponding mRNAs in wild-type or DICER-null beta-cells demonstrated that Fcgrt, Oat, and Pdgfra are miRNA direct targets. We thus reveal a role for miRNAs in the regulation of disallowed genes in beta-cells and provide evidence for a novel means through which noncoding RNAs control the functional identity of these cells independently of actions on beta-cell mass. PMID- 26038945 TI - [More than 50 years' experience in the treatment of patients with congenital heart disease at a Hungarian university hospital]. AB - Improvements in surgical techniques and technical advancements have made possible for several patients with congenital heart disease to grow up to adulthood. It has been decided to create a registry for their more precise treatment. This registry now includes 2770 patients with data on 3043 operations, with almost 30 different diagnoses. The purpose of this paper is to review the facts and the basics leading to the establishment of this registry. PMID- 26038946 TI - [The role of mobile communication devices in the spread of infections]. AB - Mobile communication devices have an invaluable feature of communication within hospital, and they may support certain aspects of clinical diagnosis and education. However, there may be a risk for contamination of these devices with various pathogens. The aim of the authors was to perform a systematic review on the potential role of mobile communication devices in the dissemination of pathogens and to identify effective prevention measures. A detailed literature search was conducted using PubMed and ScienceDirect databases for papers published in English between January, 2004 and August, 2014. With the use of specific search term combinations 30 of the 216 articles met the inclusion criteria. It was found that only 8% of healthcare workers routinely cleaned their mobile communication devices resulting in a high rate of contamination (40-100%). Coagulase-negative Staphylococci and Staphylococcus aureus were the most commonly identified bacteria and most of them were methicillin resistant (10-95.3%). This systematic review identified effective interventions to reduce bacterial contamination risks including staff education, hand hygiene and regular decontamination of mobile communication devices. PMID- 26038947 TI - [Assistance medicine, a novel discipline of emergency medicine]. AB - The number of international travels has been continuously increasing since World War II. Though the travelers' demand for safer ways of travelling appeared, only a handful of them sought pretravel advices. This is the reason why 50% of the travelers have to face some kind of medical problem during their journey. If they have travel insurance, the company's assistance team organizes, monitors and covers their abroad treatment. A doctor of the assistance team has to find her/his ways in various fields: not only a multidisciplinary medical knowledge is a must for a professional like this, but she/he needs to have a good grasp of the basic idea behind the insurance policy, too. Also, she/he should be familiar with the public health care systems of different countries and some legal knowledge is also needed. If the patients are unable to continue their trip, they must be repatriated. Making a decision about the repatriation's timing and modality requires interdisciplinary medical experience and the approach of a critical care/emergency doctor. Among further tasks for the assistance team's doctor one can find medical escort and on-spot medical visit for foreign patients. Both of these two aforementioned medical activities are highly different from - for example - a general practitioner's routine. That is the reason why an assistance doctor has to be familiar with the critical and emergency care. Organizing and monitoring medical treatment for a traveler abroad, providing medical escort, making decisions about repatriation and providing medical help for a foreign patient all fall within the competence of a new medical discipline, the assistance medicine. Creating a body of knowledge, collecting appropriate protocols and establishing postgraduate courses for assistance medicine diplomas are the tasks of the critical care and emergency medicine professionals. PMID- 26038948 TI - [Anxiety, depression, health-related control beliefs, and their association with health behavior in patients with ischemic heart disease]. AB - INTRODUCTION: Psychological and lifestyle factors affect the development and outcome of heart disease considerably. AIM: The aims of the authors were to examine health control, level of anxiety and depression and to analyse their relationship with health behaviour in patients with ischemic heart disease. METHOD: The present cross-sectional study involved 116 patients who took part in residential cardiac rehabilitation (56.9% men, mean age: 57.65+/-8.22 years). RESULTS: 30.9% of the patients reported elevated anxiety and 21.9% increased depressive symptomatology. Social-external control belief was the strongest among respondents. Further, anxiety and depression were negatively associated with healthy diet and the frequency of exercise. Patients with stronger social external control beliefs were more likely to seek medical attention if they suspected a disease. CONCLUSIONS: It is important to assess psychological risk factors linked to cardiovascular diseases in cardiac rehabilitation departments and to initiate psychological interventions if indicated. PMID- 26038949 TI - [Follower of Semmelweis, forerunner to Fodor: Janos Ambro (1827-1890)]. PMID- 26038952 TI - Critical review on the physical and mechanical factors involved in tissue engineering of cartilage. AB - Articular cartilage defects often progress to osteoarthritis, which negatively impacts quality of life for millions of people worldwide and leads to high healthcare expenditures. Tissue engineering approaches to osteoarthritis have concentrated on proliferation and differentiation of stem cells by activation and suppression of signaling pathways, and by using a variety of scaffolding techniques. Recent studies indicate a key role of environmental factors in the differentiation of mesenchymal stem cells to mature cartilage-producing chondrocytes. Therapeutic approaches that consider environmental regulation could optimize chondrogenesis protocols for regeneration of articular cartilage. This review focuses on the effect of scaffold structure and composition, mechanical stress and hypoxia in modulating mesenchymal stem cell fate and the current use of these environmental factors in tissue engineering research. PMID- 26038951 TI - Cdk1 plays matchmaker for the Polo-like kinase and its activator SPAT-1/Bora. AB - Mitosis is orchestrated by several protein kinases including Cdks, Plks and Aurora kinases. Despite considerable progress toward understanding the individual function of these protein kinases, how their activity is coordinated in space and time during mitosis is less well understood. In a recent article published in the Journal of Cell Biology, we show that CDK-1 regulates PLK-1 activity during mitosis in C. elegans embryos through multisite phosphorylation of the PLK-1 activator SPAT-1 (Aurora Borealis, Bora in human). SPAT-1 variants mutated on CDK 1 phosphorylation sites results in severe delays in mitotic entry, mimicking embryos lacking spat-1 or plk-1 function. We further show that SPAT-1 phosphorylation by CDK-1 promotes its binding to PLK-1 and stimulates PLK-1 phosphorylation on its activator T-loop by Aurora A kinase in vitro. Likewise, we find that phosphorylation of Bora by Cdk1 promotes phosphorylation of human Plk1 by Aurora A suggesting that this mechanism is conserved in humans. These results indicate that Cdk1 regulates Plk1 by boosting its kinase activity. Here we discuss these recent findings and open questions regarding the regulation of Plk1/PLK-1 by Cdk1/CDK-1 and Bora/SPAT-1. PMID- 26038953 TI - HIV and coronary artery calcium score: comparison of the Hawaii Aging with HIV Cardiovascular Study and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts. AB - OBJECTIVES: To determine the association of HIV, immunologic, and inflammatory factors on coronary artery calcium (CAC), a marker of subclinical atherosclerosis. METHODS: Cross-sectional study comparing baseline data of males from Hawaii Aging with HIV - Cardiovascular Study (HAHCS) with the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The cohorts were pooled to determine effects of HIV on CAC and explore immunologic and inflammatory factors that may explain development of CAC in HIV. Multivariable regression models compared CAC prevalence in HAHCS with MESA adjusting for coronary heart disease (CHD) risk profiles. RESULTS: We studied 100 men from HAHCS and 2733 men from MESA. Positive CAC was seen in 58% HAHCS participants and 57% MESA participants. Mean CAC was 260.8 in HAHCS and 306.5 in MESA. Using relative risk (RR) regression, HAHCS participants had a greater risk (RR = 1.20, P < 0.05) of having positive CAC than MESA when adjusting for age, smoking status, diabetes, antihypertensive therapy, BMI, systolic blood pressure, total cholesterol, and HDL cholesterol. Among participants with positive CAC, HIV infection was not associated with larger amounts of CAC. Among HAHCS participants, current HIV viral load, CD4, length of HIV, interleukin 6 (IL-6), fibrinogen, C-reactive protein (CRP), and D-dimer were not associated with the presence or amount of CAC. DISCUSSION: HIV was independently associated with a positive CAC in men with increased likelihood occurring between 45 and 50 years of age. Current HIV viral load, CD4 count, length of HIV, and inflammatory markers were unrelated to either presence or amount of CAC. PMID- 26038954 TI - Simple quantitative measurement based on DWI to objectively judge DWI-FLAIR mismatch in a canine stroke model. AB - PURPOSE: Diffusion-weighted imaging (DWI) - fluid attenuated inversion recovery (FLAIR) mismatch was proven useful to time the onset of wake-up stroke; however, identifying the status of FLAIR imaging has been mostly subjective. We aimed to evaluate the value of relative DWI signal intensity (rDWI), and relative apparent diffusion coefficient (rADC) in identifying the FLAIR status in the acute period. METHODS: Autologous clot was used to embolize left middle cerebral artery in 20 dogs. Magnetic resonance imaging was performed 3-6 hours and 24 hours after embolization. DWI-FLAIR mismatch was defined as hyperintense signal detected on DWI, but not on FLAIR. The mean values of rDWI or rADC of FLAIR- and FLAIR+ lesions were compared and the critical cutoff values of rDWI and rADC for identifying the FLAIR status were determined. RESULTS: Stroke models were successfully established in all animals. DWI+ lesions were found in all 20 dogs from three hours, while FLAIR+ lesions were found in three, 11, 16, 19, and 20 dogs at five time points after embolization, respectively. The mean rDWI values were significantly different between FLAIR- and FLAIR+ lesions (P < 0.001), but rADC values were not (P = 0.73). Using rDWI=1.90 as the threshold value, excellent diagnostic efficacy was achieved (AUC, 0.88; sensitivity, 0.77; specificity, 0.88). However, rADC appeared not useful (AUC, 0.48; sensitivity, 0.52; specificity, 0.58) in identifying the FLAIR status. CONCLUSION: In our embolic canine stroke model, rDWI was useful to identify FLAIR imaging status in the acute period, while rADC was not. PMID- 26038955 TI - [Prevalence of hypertension and assessment of its impact on self-rated health in rural populations: a cross-sectional study in northern Senegal]. AB - INTRODUCTION: High blood pressure (hypertension) is a growing public health problem, and its impact on the overall health of patients in Africa is not well known. The objective of this study was to determine its prevalence and its influence on self-rated health among people living in rural areas of Senegal. POPULATION AND METHODS: This cross-sectional study was conducted over a two-week period in the rural communities of Labgar and Lougre Thiolly, located in the central northern region of Senegal, in an agricultural area. Randomly recruited volunteers were questioned during direct individual interviews about socio demographic (age, sex, marital status, education, occupation) and lifestyle data (smoking or alcohol, physical activity). Clinical data (medical history, weight, height, blood pressure, course of treatment) were also collected. Self-rated health (SRH) was assessed by asking if they felt their health was bad or good. RESULTS: We included 627 patients with a mean age of 40.93 +/- 17.2 years (range: 15-100 years), 59.9% of them women. Illiteracy and overweight were more common among women than among men, and smoking and alcohol consumption more frequent in men. The overall prevalence of hypertension was 23.4% and did not differ significantly between men (24.9%) and women (22.4%)(P = 0.50). Self-rated health was similar in men and women (with respectively 66.9% and 72.9% reporting good health, P = 0.10). On univariate analysis, the factors associated with perceived health status were age (OR = 1.34, P = 0.04), smoking (OR = 2.16, P = 0.03), educational level (OR = 1.21, P = 0.04), and the presence of hypertension (OR = 0.63, P = 0.05). The multivariate regression analysis showed that among women, advanced age (>=50 years) and hypertension (>=140/90 mmHg) were associated with poorer perceived health, whereas for men, only smoking was significantly correlated with poor health status (OR = 0.41, P = 0.01). CONCLUSION: This study shows that hypertension is common in this rural area of Senegal and is significantly associated with a lower self-rated health in women but not men. In the absence of longitudinal studies in these populations and given the predictive value of SRH, this correlation suggests higher morbidity and mortality in women with hypertension. PMID- 26038956 TI - Theoretical Strategy To Design Novel n-Type Copolymers Based on Anthracene Diimide and Pyrido[2,3-g]quinoline Diimide for Organic Solar Cells. AB - The design and synthesis of efficient electron-transporting materials have been an active area of research in the area of organic solar cells (OSCs), organic field-effect transistors (OFETs), and organic light-emitting diodes (OLEDs). This paper is focused on designing novel n-type donor-acceptor (D-A) copolymers as electron-transporting materials for replacing the widely used fullerene acceptor materials in OSC applications. We first present a strategy which can remarkably improve the photovoltaic performances of D-A copolymer acceptors by means of adjusting the molecular planarity and intensifying the electron-withdrawing ability of electron-deficient units. Then we further analyze the role played by the D-A copolymer acceptor in the light-absorbing performance of the active layer. On the basis of two reported two D-A copolymer acceptors (PNDIT and P(NDI2OD-T2)) which are composed of an electron-deficient naphthalene diimide (NDI) unit and different electron-rich units of thiophene or bithiophene, replacement of the NDI unit with an anthracene diimide (ADI) unit and a pyrido[2,3-g]quinoline diimide (PQD) unit can produce two types of copolymer acceptors (P2, P3 and P2a, P3a). From the calculated results, the introduction of ADI and PQD units to replace the NDI unit can significantly improve the optoelectronic properties, light-absorbing efficiencies, and intermolecular electron transport abilities of the copolymers as well as exciton separation efficiencies at donor/acceptor interface. Finally, this study would give us a theoretical guidance to design efficient D-A copolymer acceptors for replacing fullerene acceptors in organic solar cells. PMID- 26038957 TI - Nivolumab in renal cell carcinoma. AB - INTRODUCTION: Immune-based therapies (e.g., IL-2, IFN) have been used for some time in advanced clear cell renal cell carcinoma (RCC) with overall modest success. Recent advances have demonstrated that tumor cells evade immune-mediated destruction by inducing inhibitory signals that result in effector T-cell exhaustion. One mechanism involves interaction between the T-cell programmed death-1 (PD-1) receptor and its ligand, PD ligand-1, expressed on tumor and inflammatory cells. Nivolumab , an anti-PD-1 antibody, blocks this pathway, thereby reversing T-cell suppression and activating antitumor responses. AREAS COVERED: In this review, the authors summarize selected aspects of PD-1 signaling, the development of immune checkpoint therapeutic agents, and clinical data regarding the safety and efficacy of nivolumab in RCC from Phase I and II clinical trials. EXPERT OPINION: Objective responses and safety profiles of single-agent nivolumab are favorable in patients with previously treated and treatment-naive metastatic RCC. Combination therapies involving nivolumab are ongoing and have generated encouraging results. The use of nivolumab will have substantial impact on the management of patients with RCC. PMID- 26038958 TI - Optimisation of a quantitative polymerase chain reaction-based strategy for the detection and quantification of human herpesvirus 6 DNA in patients undergoing allogeneic haematopoietic stem cell transplantation. AB - Human herpesvirus 6 (HHV-6) may cause severe complications after haematopoietic stem cell transplantation (HSCT). Monitoring this virus and providing precise, rapid and early diagnosis of related clinical diseases, constitute essential measures to improve outcomes. A prospective survey on the incidence and clinical features of HHV-6 infections after HSCT has not yet been conducted in Brazilian patients and the impact of this infection on HSCT outcome remains unclear. A rapid test based on real-time quantitative polymerase chain reaction (qPCR) has been optimised to screen and quantify clinical samples for HHV-6. The detection step was based on reaction with TaqMan(r) hydrolysis probes. A set of previously described primers and probes have been tested to evaluate efficiency, sensitivity and reproducibility. The target efficiency range was 91.4% with linearity ranging from 10-106 copies/reaction and a limit of detection of five copies/reaction or 250 copies/mL of plasma. The qPCR assay developed in the present study was simple, rapid and sensitive, allowing the detection of a wide range of HHV-6 loads. In conclusion, this test may be useful as a practical tool to help elucidate the clinical relevance of HHV-6 infection and reactivation in different scenarios and to determine the need for surveillance. PMID- 26038959 TI - Interleukin-10 rs2227307 and CXCR2 rs1126579 polymorphisms modulate the predisposition to septic shock. AB - Despite major improvements in its treatment and diagnosis, sepsis is still a leading cause of death and admittance to the intensive care unit (ICU). Failure to identify patients at high risk of developing septic shock contributes to an increase in the sepsis burden and rapid molecular tests are currently the most promising avenue to aid in patient risk determination and therapeutic anticipation. The primary goal of this study was to evaluate the genetic susceptibility that affects sepsis outcome in 72 sepsis patients admitted to the ICU. Seven polymorphisms were genotyped in key inflammatory response genes in sepsis, including tumour necrosis factor-alpha, interlelukin (IL)-1beta, IL-10, IL-8, Toll-like receptor 4, CXCR1 and CXCR2. The primary finding showed that patients who were homozygous for the major A allele in IL-10 rs1800896 had almost five times higher chance to develop septic shock compared to heterozygotes. Similarly, selected clinical features and CXCR2 rs1126579 single nucleotide polymorphisms modulated septic shock susceptibility without affecting survival. These data support the hypothesis that molecular testing has clinical usefulness to improve sepsis prognostic models. Therefore, enrichment of the ICU portfolio by including these biomarkers will aid in the early identification of sepsis patients who may develop septic shock. PMID- 26038960 TI - Using a single tablet daily to treat latent tuberculosis infection in Brazil: bioequivalence of two different isoniazid formulations (300 mg and 100 mg) demonstrated by a sensitive and rapid high-performance liquid chromatography tandem mass spectrometry method in a randomised, crossover study. AB - The recommended treatment for latent tuberculosis (TB) infection in adults is a daily dose of isoniazid (INH) 300 mg for six months. In Brazil, INH was formulated as 100 mg tablets. The treatment duration and the high pill burden compromised patient adherence to the treatment. The Brazilian National Programme for Tuberculosis requested a new 300 mg INH formulation. The aim of our study was to compare the bioavailability of the new INH 300 mg formulation and three 100 mg tablets of the reference formulation. We conducted a randomised, single dose, open label, two-phase crossover bioequivalence study in 28 healthy human volunteers. The 90% confidence interval for the INH maximum concentration of drug observed in plasma and area under the plasma concentration vs. time curve from time zero to the last measurable concentration "time t" was 89.61-115.92 and 94.82-119.44, respectively. The main limitation of our study was that neither adherence nor the safety profile of multiple doses was evaluated. To determine the level of INH in human plasma, we developed and validated a sensitive, simple and rapid high-performance liquid chromatography-tandem mass spectrometry method. Our results showed that the new formulation was bioequivalent to the 100 mg reference product. This finding supports the use of a single 300 mg tablet daily strategy to treat latent TB. This new formulation may increase patients' adherence to the treatment and quality of life. PMID- 26038962 TI - Coincidence of Tracheobronchomegaly (Mounier-Kuhn Syndrome) and Juvenile Idiopathic Arthritis. AB - Mounier-Kuhn syndrome (MKS) or tracheobronchomegaly includes clinical and radiographic findings of tracheobronchial dilatation and recurrent respiratory infections. MKS is a very rare pathology, especially in the paediatric age group which makes it a diagnostic challenge. A 4-year-old girl suffered from dyspnea, recurrent respiratory infections and joint pain. Chest radiography detected peribronchial reinforcement and CT-scan revealed extended tracheal dilatation and bronchiectasis. In addition to MKS our patient was diagnosed with juvenile idiopathic arthritis (JIA) and scleroderma. MKS can be caused by congenital disorder or acquired aetiology. Several connective tissue diseases have been associated with MKS but no cases of JIA or scleroderma are described previously. Our case illustrates that patients who suffer from recurrent respiratory infections with unsatisfactory evolution and unspecific chest X-ray alteration, MKS always has to be considered in the differential diagnosis particularly in patients who suffer from connective tissue diseases. PMID- 26038961 TI - Influence of the Paracoccidioides brasiliensis 14-3-3 and gp43 proteins on the induction of apoptosis in A549 epithelial cells. AB - The fungal strain Paracoccidioides brasiliensis remains viable inside of epithelial cells and can induce apoptosis in this population. However, until now, the molecules that participate in this process remained unknown. Thus, this study evaluated the contribution of two P. brasiliensis molecules, the 14-3-3 and glycoprotein of 43 kDa proteins, which had been previously described as extracellular matrix adhesins and apoptosis inductors in human pneumocytes. Accordingly, epithelial cells were treated with these molecules for different periods of time and the expression of the apoptosis regulating-proteins Bak, Bax, Bcl-2, p53 and caspases were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labelling, flow cytometry and real-time polymerase chain reaction analysis. Our results demonstrated that treatment with these molecules induces apoptosis signalling in pulmonary epithelial cells, showing the same pattern of programmed cell-death as that observed during infection with P. brasiliensis. Thus, we could conclude that P. brasiliensis uses these molecules as virulence factors that participate not only in the fungal adhesion process to host cells, but also in other important cellular mechanisms such as apoptosis. PMID- 26038963 TI - [Phosphate Intoxication after Application of Enema--a Life-threatening Iatrogenic Complication]. AB - INTRODUCTION: Enemas are used in pediatric patients with constipation. Retention of phosphate containing enemas with prolonged resorption or reduced renal elimination of phosphate can result in life-threatening hyperphosphatemia with subsequent lethal hypocalcemia and acidosis. CASE PRESENTATION: We report the case of a 6-month-old child who received phosphate-containing enema to treat acute aggravation of constipation. The used enema here was not licensed for this age group. Phosphate intoxication resulted (phosphate 19.87 mmol/l) and presented like a sepsis. Hyperphosphatemia was treated by hemodialysis. A non-diagnosed Hirschsprung disease had led to prolonged resorption of phosphate containing enema and to an ileus and toxic megacolon that had to be operated. CONCLUSION: Insufficient elimination of phosphate containing enema can result in lethal or life threatening hyperphosphatemia, hypocalcemia and metabolic acidosis. These can be treated efficaciously by hemodialysis. Because of the high risk of intoxication in using enemas containing phosphate in infants or in patients with gastrointestinal or renal comorbidities, physicians treating constipation should choose enemas without phosphate but with ingredients with lower risk like glycerol or sorbitol in this age group. PMID- 26038964 TI - Long-term Surveillance of Children with Congenital Hypothyroidism: Data from the German Registry for Congenital Hypothyroidism (AQUAPE "Hypo Dok"). AB - BACKGROUND: The German study group for quality assurance in pediatric endocrinology and the University of Ulm have established a software ("Hypo Dok") for the documentation of longitudinal data of patients with congenital primary hypothyroidism (CH). Aim of this study was to analyse the long-term follow-up of patients with CH and to compare treatment with current guidelines. METHODS/PATIENTS: Anonymised data of 1,080 patients from 46 centres were statistically analysed. RESULTS: Newborn screening result was available at a mean age of 7.3 days. Confirmation of the diagnosis was established at 8.4 days and therapy was started at 11 days. The average screening TSH was 180.0 mIU/L. During the first 3 months mean levothyroxine (LT4) dose was 10.7 ug/kg/day or 186.0 ug/m2/day. Weight-, BMI- and height-SDS did not differ significantly from the normal population. Only 25% of the patients (n=262) underwent formal EQ/IQ testing. Their average IQ was 98.8 +/- 13.2 points. DISCUSSION: In Germany screening, confirmation and start of treatment of CH are within the recommended time frame of 14 days. Initial LT4-doses are adequate. The auxological longterm outcome of young CH patients is normal. The implementation of standardized IQ testing has to be improved in routine patient care. CONCLUSION: Longitudinal data of patients with CH was analysed and compared to current guidelines. Confirmation and start of treatment are according to the recommendations. However standardised IQ testing requires improvement. PMID- 26038965 TI - Mental and Motor Development of Children with Preterm Birth and Children with Fetal Alcohol Syndrome. AB - OBJECTIVE: Children with preterm birth (PTB), particularly if medical complications after birth are recorded, are at risk of developmental handicaps. More than half of the children with fetal alcohol syndrome (FAS) are born preterm. METHODS: Using the Bayley Scales of Infant Development - Second Edition, we assessed the mental (MDI) and psychomotor development (PDI) of children with PTB and children with FAS. PTB children without (PTB_c-, N=31) and with (PTB_c+, N=17) medical complications as well as children with FAS (N=30; N=10 preterm, N=14 in term; N=6 not known) were tested at the age of 2 years (PTB: M=25 months, SD=3 months; FAS: M=27 months, SD=6 months). RESULTS: PTBc+ (MDI=85; PDI=80) as well as FAS (MDI=79; PDI=80) children show a poorer mental and motor development than PTBc- (MDI=99; PDI=92) children. FAS children with PTB show a significantly higher mental development (MDI=84) than FAS children born in term (MDI=75), while there are no differences concerning their motor development (PDI=79 in both groups). DISCUSSION: The results demonstrate that children with FAS are as developmental delayed as PTBc+children. PTB itself, although frequently occurring in FAS, seems not to exacerbate the mental or motor development deficits in children with FAS. Quite the contrary, developmental delay in FAS children seems to be positively moderated by PTB, as being born preterm is cutting short the noxious intrauterine alcohol exposition of the child. PMID- 26038966 TI - Less Oxygen, Later Intubation and Reduced Respiratory Pressures for ELBW Infants from 1997 to 2011. AB - INTRODUCTION: Evidence concerning delivery room management in extremely low birth weight infants (ELBW) has grown substantially within the last 20 years, leading to several guidelines and recommendations. However, it is unknown in which extent local treatment strategies have changed and if they reflect current recommendations. METHODS: A detailed questionnaire about treatment strategies for ELBW infants was sent to all German neonatal intensive care units (NICUs) treating ELBW infants in 1997. A follow-up survey was conducted in 2011 and sent to all NICUs in Germany, Austria and Switzerland. RESULTS on delivery room management were compared to the first survey. RESULTS: In 1997 and 2011, 63.6 and 66.2% of the approached hospitals responded. In 2011 similar results were observed between university and non-university hospitals as well as NICUs of different size. Differences between Germany, Austria and Switzerland were minimal. Changes over time were a lower initially applied fraction of inspired oxygen (FiO2) and peak inspiratory pressure (PiP) in 2011 compared to 1997. A longer time of apnea was tolerated before tracheal intubation is performed; the time of apnea was less frequently a sole criterion for intubation and surfactant was applied at lower FiO2 in 2011. The time of no thorax excursions and transport of the infant were considered an indication for intubation in 30.2 and 22.5%, and did not change in the observation period. CONCLUSION: Treatment strategies for delivery room management in ELBW infants changed significantly between 1997 and 2011 and largely reflect current recommendations. PMID- 26038967 TI - [Is the Intrahepatic Sound Speed an Indicator of the Fat Content of the Liver in Children?]. AB - PURPOSE: Can the sonographically estimated intrahepatic sound speed give hints on the hepatic fat content in children? MATERIALS AND METHODS: In 75 children and adolescents the intrahepatic sound speed was estimated during routine sonography of the liver as a result of an image reconstruction algorithm. It was correlated with weight, age, size, and body mass index (BMI) oft he children, respectively. RESULTS: The average hepatic sound speed in children of normal weight was 1 566 m/s (standard deviation (STD) 29 m/s, in overweight or obese children it was 1 501 m/s (STD 22 m/s), and in obese children it was 1 497 ms (STD 24 m/s). The strongest correlation was found between sound speed and BMI of the children, respectively. The difference of sound speed in normal weighing subjects and overweight/obese children was statistically significant. CONCLUSION: There is a good correlation between the estimated intrahepatic sound speed and the fat content of the liver. Further examinations are encouraged. PMID- 26038968 TI - [Language Delay: What is the Prognosis of Late Bloomers?]. AB - BACKGROUND: 30-50% of late talkers catch-up their language delay during the third year of life. So far it is unclear whether this is a permanent or an illusionary recovery. The aim of the study was to examine the further language development of late bloomers. METHOD: Language skills of 83 three-year-old children (16 late bloomers [LB], 29 late talkers [LT] with persistent language problems, 38 Non-LT) were assessed with a standardized language test. Before school entry formal language skills, expressive and receptive vocabulary and precursors of written language (verbal memory, phonological awareness, verbal information-processing speed) were assessed. RESULTS: At follow-up before school entry LB scored below Non-LT on phonological memory test. 31% of the LB in contrast to 3% of the Non-LT had slight language problems. 38% had received speech-language therapy. Nevertheless, no LB met the criteria of developmental language disorder. The language skills of LT with persistent language problems remained significantly below the level of LB and Non-LT. Every fourth of these children was language impaired. CONCLUSION: LB as a group are not at risk for later clinically relevant language disorders. However, their language abilities are often within the lower range of normal variation. Therefore, it is recommended to facilitate their language acquisition either by kindergarten training programs or by parent directed intervention programs to provide a more stimulating environment. PMID- 26038969 TI - Acute "Tumour-like" Tongue Haematoma: The Challenge to Diagnose Haemophilia A. PMID- 26038970 TI - Anemia and B Symptoms as Leading Symptoms for a Hepatic Inflammatory Pseudotumor- 2 Case Reports. PMID- 26038971 TI - Self-healing Nanofiber-Reinforced Polymer Composites. 2. Delamination/Debonding and Adhesive and Cohesive Properties. AB - The capacity for core-shell nanofiber mats containing healing agents (resin monomer and cure) in their cores to adhere to a substrate was studied using blister testing. After extended periodic bending, the adhesion energy was measured, and the effect of self-healing on the composite's delamination from the substrate was considered. In addition, the cohesion of two layers of the self healing nanofibers was examined using blister testing and compared to that of ordinary nanofiber mats. The damage inflicted by prolonged periodic bending to the interface of the two nanofiber mats was demonstrated to have self-healed, and the cohesion energy was measured. PMID- 26038972 TI - Nucleophilic Substitution in Reactions between Partially Hydrated Superoxide Anions and Alkyl Halides. AB - The effect of solvation by water molecules on the nucleophilicity of the superoxide anion, O2(*-), has been investigated in detail by mass spectrometric experiments and quantum chemical calculations, including direct dynamics trajectory calculations. Specifically, the SN2 reactions of O2(*-)(H2O)n clusters (n = 0-5) with CH3Cl and CH3Br were studied. It was found that the reaction rate decreases when the number of water molecules in the cluster increases; furthermore, reaction with CH3Br is in general faster than reaction with CH3Cl for clusters of the same size. In addition, key transition-state geometries were identified and probed by Born-Oppenheimer molecular dynamics, showing how a water molecule may be transferred from the nucleophile to the leaving group during the reaction. The computational models are in good agreement with the experimental observations. PMID- 26038973 TI - Effective adsorption of phosphate from wastewaters by big composite pellets made of reduced steel slag and iron ore concentrate. AB - In order to remove phosphate from wastewater, a large plastic adsorption column filled with big phosphate-adsorbing pellets with diameters of 10 mm, heated by electromagnetic induction coils, was conceived. It was found that the prepared big pellets, which were made of reduced steel slag and iron ore concentrate, contain magnetic Fe and Fe3O4. The thermodynamics and kinetics of adsorption of phosphate from synthetic wastewaters on the pellets were studied in this work. The phosphate adsorption on the pellets followed three models of Freundlich, Langmuir and Dubinin-Kaganer-Radushkevick. The maximum phosphate adsorption capacity Qmax of the pellets were 2.46, 2.74 and 2.77 mg/g for the three temperatures of 20 degrees C, 30 degrees C and 40 degrees C, respectively, based on the Langmuir model. The apparent adsorption energies were -12.9 kJ/mol for the three temperatures. It implied that ion exchange was the main mechanism involved in the adsorption processes. The adsorbed phosphate existed on the pellet surface mainly in the form of Fe3(PO4)2. A reduction pre-treatment of the pellet precursor with H2 greatly enhanced pellet adsorption for phosphate. The adsorption kinetics is better represented by a pseudo-first-order model. The adsorbed phosphate amounts were similar for both real and synthetic wastewaters under similar adsorption conditions. The percentage of adsorbed phosphate for a real wastewater increased with increasing pellet concentration and reached 99.2% at a pellet concentration of 64 (g/L). Some specific phosphate adsorption mechanisms for the pellets were revealed and the pellets showed the potential to efficiently adsorb phosphate from a huge amount of real wastewaters in an industrial scale. PMID- 26038975 TI - Reservoirs of Selenium in Coal Waste Rock: Elk Valley, British Columbia, Canada. AB - Selenium (Se) reservoirs in coal waste rock from the Elk Valley, southeastern British Columbia, the location of Canada's major steelmaking coal mines, were characterized and quantified by analyzing samples collected from the parent rock, freshly blasted waste rock (less than 10 days old), and aged waste rock (deposited between 1982 and 2012). Se is present throughout the waste rock dumps at a mean digestible (SeD) concentration of 3.12 mg/kg. Microprobe analyses show that Se is associated with the primary minerals sphalerite, pyrite, barite, and chalcopyrite and secondary Fe oxyhydroxides. Selenium K-edge X-ray absorption near-edge spectroscopy analyses indicate that, on average, 21% of Se is present as selenide (Se(2-)) in pyrite and sphalerite, 19% of Se is present as selenite (Se(4+)) in barite, 21% of Se is present as exchangeable Fe oxyhydroxide and clay adsorbed Se(4+), and 39% of Se is present as organoselenium associated with coaly matter. The dominant source minerals for aqueous-phase Se are pyrite and sphalerite. Secondary Fe oxyhydroxide sequesters, on average, 37% of Se released by pyrite oxidation. Measured long-term Se fluxes from a rock drain at the base of a waste dump suggest that at least 20% of Se(2-)-bearing sulfides were oxidized and released from that dump over the past 30 year period; however, the Se mass lost was not evident in SeD analyses. PMID- 26038976 TI - Cushing's Syndrome in a 6-month-old Boy: A Rare Side-effect due to Inadequate use of Topical Corticosteroids. PMID- 26038974 TI - Pulmonary Nontuberculous Mycobacterial Infection. A Multisystem, Multigenic Disease. AB - RATIONALE: The clinical features of patients infected with pulmonary nontuberculous mycobacteria (PNTM) are well described, but the genetic components of infection susceptibility are not. OBJECTIVES: To examine genetic variants in patients with PNTM, their unaffected family members, and a control group. METHODS: Whole-exome sequencing was done on 69 white patients with PNTM and 18 of their white unaffected family members. We performed a candidate gene analysis using immune, cystic fibrosis transmembrance conductance regulator (CFTR), cilia, and connective tissue gene sets. The numbers of patients, family members, and control subjects with variants in each category were compared, as was the average number of variants per person. MEASUREMENTS AND MAIN RESULTS: A significantly higher number of patients with PNTM than the other subjects had low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue categories (35, 26, 90, and 90%, respectively). Patients with PNTM also had significantly more cilia and connective tissue variants per person than did control subjects (2.47 and 2.55 compared with 1.38 and 1.40, respectively; P = 1.4 * 10(-6) and P = 2.7 * 10(-8), respectively). Patients with PNTM had an average of 5.26 variants across all categories (1.98 in control subjects; P = 2.8 * 10(-17)), and they were more likely than control subjects to have variants in multiple categories. We observed similar results for family members without PNTM infection, with the exception of the immune category. CONCLUSIONS: Patients with PNTM have more low-frequency, protein-affecting variants in immune, CFTR, cilia, and connective tissue genes than their unaffected family members and control subjects. We propose that PNTM infection is a multigenic disease in which combinations of variants across gene categories, plus environmental exposures, increase susceptibility to the infection. PMID- 26038977 TI - Electrocatalytic Oxygen Reduction Performance of Silver Nanoparticle Decorated Electrochemically Exfoliated Graphene. AB - We have developed a potentiostatic double-pulse technique for silver nanoparticle (Ag NP) deposition on graphene (GRn) with superior electronic and ionic conductivity. This approach yielded a two-dimensional electrocatalyst with a homogeneous Ag NP spatial distribution having remarkable performance in the oxygen reduction reaction (ORR). GRn sheets were reproducibly prepared by the electrochemical exfoliation of graphite (GRp) at high yield and purity with a low degree of oxidation. Polystyrenesulfonate added during exfoliation enhanced the stability of the GRn solution by preventing the restacking of the graphene sheets and increased its ionic conductivity. The potentiostatic double-pulse technique is generally used to electrodeposit Pt nanoparticles and remains challenging for silver metal that exhibits nucleation and growth potentials relatively close to each other. We judiciously exploited this narrow margin of potential, and for the first time we report Ag NP electrodeposited onto graphene with the subsequent ability to control both the density and the size of metallic nanoparticles. Considering the high activity along with the lower cost of Ag compared to Pt, these findings are highly relevant to the successful commercialization of fuel cells and other electrochemical energy devices. PMID- 26038978 TI - Comparing the Influence of Simulated Experimental Errors on 12 Machine Learning Algorithms in Bioactivity Modeling Using 12 Diverse Data Sets. AB - To date, no systematic study has assessed the effect of random experimental errors on the predictive power of QSAR models. To address this shortage, we have benchmarked the noise sensitivity of 12 learning algorithms on 12 data sets (15,840 models in total), namely the following: Support Vector Machines (SVM) with radial and polynomial (Poly) kernels, Gaussian Process (GP) with radial and polynomial kernels, Relevant Vector Machines (radial kernel), Random Forest (RF), Gradient Boosting Machines (GBM), Bagged Regression Trees, Partial Least Squares, and k-Nearest Neighbors. Model performance on the test set was used as a proxy to monitor the relative noise sensitivity of these algorithms as a function of the level of simulated noise added to the bioactivities from the training set. The noise was simulated by sampling from Gaussian distributions with increasingly larger variances, which ranged from zero to the range of pIC50 values comprised in a given data set. General trends were identified by designing a full-factorial experiment, which was analyzed with a normal linear model. Overall, GBM displayed low noise tolerance, although its performance was comparable to RF, SVM Radial, SVM Poly, GP Poly, and GP Radial at low noise levels. Of practical relevance, we show that the bag fraction parameter has a marked influence on the noise sensitivity of GBM, suggesting that low values (e.g., 0.1-0.2) for this parameter should be set when modeling noisy data. The remaining 11 algorithms display a comparable noise tolerance, as a smooth and linear degradation of model performance is observed with the level of noise. However, SVM Poly and GP Poly display significant noise sensitivity at high noise levels in some cases. Overall, these results provide a practical guide to make informed decisions about which algorithm and parameter values to use according to the noise level present in the data. PMID- 26038979 TI - Non-Faradaic Energy Storage by Room Temperature Ionic Liquids in Nanoporous Electrodes. AB - The enhancement of non-Faradaic charge and energy density stored by ionic electrolytes in nanostructured electrodes is an intriguing issue of great practical importance for energy storage in electric double layer capacitors. On the basis of extensive molecular dynamics simulations of various carbon-based nanoporous electrodes and room temperature ionic liquid (RTIL) electrolytes, we identify atomistic mechanisms and correlations between electrode/electrolyte structures that lead to capacitance enhancement. In the symmetric electrode setup with nanopores having atomically smooth walls, most RTILs showed up to 50% capacitance increase compared to infinitely wide pore. Extensive simulations using asymmetric electrodes and pores with atomically rough surfaces demonstrated that tuning of electrode nanostructure could lead to further substantial capacitance enhancement. Therefore, the capacitance in nanoporous electrodes can be increased due to a combination of two effects: (i) the screening of ionic interactions by nanopore walls upon electrolyte nanoconfinement, and (ii) the optimization of nanopore structure (volume, surface roughness) to take into account the asymmetry between cation and anion chemical structures. PMID- 26038980 TI - Bevacizumab plus chemotherapy versus chemotherapy alone for preventing brain metastasis derived from advanced lung cancer. AB - This retrospective analysis evaluated the mechanism of bevacizumab plus chemotherapy (BV+CT) for preventing brain metastasis derived from lung cancer. From the total of 159 patients with advanced non-small cell lung cancer (NSCLC), 110 received BV+CT and 49 received CT. After medication, both groups had 15 patients with brain metastases (14 vs 31%, P < 0.05). With BV+CT treatment, 40 patients (33.89%) survived, whereas only 11 patients (18.64%) survived with CT treatment. The outcome for the BV+CT group was significantly better than that for the CT group only for vascular endothelial growth factor (VEGF)-positive patients. A post-treatment with BV+CT was significantly reduced than with CT only for patients with high carbonic anhydrase-9 (CA9) expression. This retrospective analysis provides supportive evidence that BV+CT can significantly reduce the incidence of brain metastasis in patients with advanced NSCLC compared with CT alone. Vascular endothelial growth factor -positive patients may benefit more from BV treatment and the outcomes with BV may be related to CA9 expression. PMID- 26038981 TI - Profiling Nonribosomal Peptide Synthetase Activities Using Chemical Proteomic Probes for Adenylation Domains. AB - Nonribosomal peptide synthetases (NRPSs) and polyketide synthases are large diverse families of biosynthetic enzymes that catalyze the synthesis of natural products that display biologically important activities. Genetic investigations have greatly contributed to our understanding of these biosynthetic enzymes; however, proteomic studies are limited. Here we describe the application of active site-directed proteomic probes for adenylation (A) domains to profile the activity of NRPSs directly in native proteomic environments. Derivatization of a 5'-O-N-(aminoacyl)sulfamoyladenosine appended clickable benzophenone functionality enabled activity-based protein profiling of the A-domains in NRPSs in proteomic extracts. These probes were used to identify natural product producing microorganisms, optimize culture conditions, and profile the activity dynamics of NRPSs. Our proteomic approach offers a simple and versatile method to monitor NRPS expression at the protein level and will facilitate the identification of orphan enzymatic pathways involved in secondary metabolite production. PMID- 26038982 TI - High-yield production of a human monoclonal IgG by rhizosecretion in hydroponic tobacco cultures. AB - Rhizosecretion of recombinant pharmaceuticals from in vitro hydroponic transgenic plant cultures is a simple, low cost, reproducible and controllable production method. Here, we demonstrate the application and adaptation of this manufacturing platform to a human antivitronectin IgG1 monoclonal antibody (mAb) called M12. The rationale for specific growth medium additives was established by phenotypic analysis of root structure and by LC-ESI-MS/MS profiling of the total protein content profile of the hydroponic medium. Through a combination of optimization approaches, mAb yields in hydroponic medium reached 46 MUg/mL in 1 week, the highest figure reported for a recombinant mAb in a plant secretion-based system to date. The rhizosecretome was determined to contain 104 proteins, with the mAb heavy and light chains the most abundant. This enabled evaluation of a simple, scalable extraction and purification protocol and demonstration that only minimal processing was necessary prior to protein A affinity chromatography. MALDI-TOF MS revealed that purified mAb contained predominantly complex-type plant N-glycans, in three major glycoforms. The binding of M12 purified from hydroponic medium to vitronectin was comparable to its Chinese hamster ovary (CHO)-derived counterpart. This study demonstrates that in vitro hydroponic cultivation coupled with recombinant protein rhizosecretion can be a practical, low-cost production platform for monoclonal antibodies. PMID- 26038983 TI - W8, a new Sup35 prion strain, transmits distinctive information with a conserved assembly scheme. AB - Prion strains are different self-propagating conformers of the same infectious protein. Three strains of the [PSI] prion, infectious forms of the yeast Sup35 protein, have been previously characterized in our laboratory. Here we report the discovery of a new [PSI] strain, named W8. We demonstrate its robust cellular propagation as well as the protein-only transmission. To reveal strain-specific sequence requirement, mutations that interfered with the propagation of W8 were identified by consecutive substitution of residues 5-55 of Sup35 by proline and insertion of glycine at alternate sites in this segment. Interestingly, propagating W8 with single mutations at residues 5-7 and around residue 43 caused the strain to transmute. In contrast to the assertion that [PSI] existed as a dynamic cloud of sub-structures, no random drift in transmission characteristics was detected in mitotically propagated W8 populations. Electron diffraction and mass-per-length measurements indicate that, similar to the 3 previously characterized strains, W8 fibers are composed of about 1 prion molecule per 4.7-A cross-beta repeat period. Thus differently folded single Sup35 molecules, not dimeric and trimeric assemblies, form the basic repeating units to build the 4 [PSI] strains. PMID- 26038985 TI - Comparative efficacy of antibiotics for the treatment of acute bacterial skin and skin structure infections (ABSSSI): a systematic review and network meta analysis. AB - OBJECTIVE: The objective was to conduct a systematic review and network meta analysis (NMA) of existing treatments for ABSSSI focusing on the novel lipoglycopeptide oritavancin. METHODS: EMBASE, MEDLINE, MEDLINE in Process, CENTRAL (Cochrane), and select conferences were searched for randomized controlled trials investigating antimicrobial agents for the treatment of ABSSSI. NMA was used to estimate the odds ratios of the Test-Of-Cure (TOC) and Early Clinical Response (ECR) outcomes for treatments relative to vancomycin in the ITT populations. Sub-group analyses in MRSA and MSSA populations were conducted for TOC; sensitivity analyses investigated the use of the clinically evaluable (CE) populations and the restriction to trials following the recent FDA guidelines for clinical trials. RESULTS: The systematic review identified 52 trials. The most commonly investigated treatments were vancomycin and linezolid; most trials reported TOC, but not ECR. The posterior mean and 95% credible intervals for odds ratios of TOC for antimicrobial agents relative to vancomycin were: linezolid (1.55; 0.91-2.57), daptomycin (2.18; 0.90-5.42), and oritavancin 1200 mg (1.06; 0.80-1.43). The odds ratio of ECR for oritavancin 1200 mg was 1.02 (0.23-4.33). In the MRSA sub-group the odds ratios relative to vancomycin for TOC were: linezolid (1.55; 0.96-2.46), daptomycin (0.74; 0.13-3.66), and oritavancin 1200 mg (0.94; 0.44-2.02). In the MSSA sub-group they were linezolid (1.36; 0.15 13.34) and oritavancin 1200 mg (0.82; 0.08-7.83). These results were robust to the sensitivity analyses. CONCLUSIONS: This NMA provides a unified framework for the comparison of all available antimicrobial agents used in the treatment of ABSSSI and is the first to assess the ECR end-point. The results suggest equivalence of clinical efficacy between vancomycin, daptomycin, linezolid, and novel antimicrobial agents including oritavancin for the treatment of ABSSSI at TOC. The wide uncertainty margins indicate the heterogeneity of the available evidence and the need for further research. PMID- 26038986 TI - [Child and Ebola disease. A day of study and discussion, Dakar, October 1st 2014]. PMID- 26038984 TI - A Compact Structure of Cytochrome c Trapped in a Lysine-Ligated State: Loop Refolding and Functional Implications of a Conformational Switch. AB - It has been suggested that the alkaline form of cytochrome c (cyt c) regulates function of this protein as an electron carrier in oxidative phosphorylation and as a peroxidase that reacts with cardiolipin (CL) during apoptosis. In this form, Met80, the native ligand to the heme iron, is replaced by a Lys. While it has become clear that the structure of cyt c changes, the extent and sequence of conformational rearrangements associated with this ligand replacement remain a subject of debate. Herein we report a high-resolution crystal structure of a Lys73-ligated cyt c conformation that reveals intricate change in the heme environment upon this switch in the heme iron ligation. The structure is surprisingly compact, and the heme coordination loop refolds into a beta-hairpin with a turn formed by the highly conserved residues Pro76 and Gly77. Repositioning of residue 78 modifies the intraprotein hydrogen-bonding network and, together with adjustments of residues 52 and 74, increases the volume of the heme pocket to allow for insertion of one of the CL acyl moieties next to Asn52. Derivatization of Cys78 with maleimide creates a solution mimic of the Lys ligated cyt c that has enhanced peroxidase activity, adding support for a role of the Lys-ligated cyt c in the apoptotic mechanism. Experiments with the heme peptide microperoxidase-8 and engineered model proteins provide a thermodynamic rationale for the switch to Lys ligation upon perturbations in the protein scaffold. PMID- 26038987 TI - Relationship Between Serum IL-12 and p40 Subunit Concentrations and Lipid Parameters in Overweight and Obese Women. AB - BACKGROUND: Obesity is a chronic low-grade inflammatory state associated with the development of insulin resistance, type 2 diabetes mellitus, and atherosclerosis. Interleukin-12 (IL-12) is a proinflammatory cytokine composed of a 40-kD (p40) subunit and a 35-kD (p35) subunit. p40 might have an independent role in initiating the immune response. Recent findings indicate that IL-12 could be involved in the development of obesity-associated co-morbidities, especially atherosclerosis. It is unclear if there are alternations in circulating concentrations of total IL-12 and its subunit p40 in young subjects with increased adiposity without overt metabolic disturbances. The aim of the present study was to estimate serum total IL-12 together with its p40 subunit in young overweight and obese women and to investigate the associations of these parameters with insulin sensitivity and serum lipids. METHODS: We studied 77 healthy women (37 lean and 40 obese or overweight). Anthropometric measurements, blood biochemical analyses, determination of serum IL-12, IL-12p40 concentrations, and euglycemic-hyperinsulinemic clamp were performed. RESULTS: We demonstrated an increase in serum p40 in obese subjects (P=0.029). We found positive correlations between p40 and fat mass (r=0.24, P=0.04) and significant negative associations with high-density lipoprotein cholesterol (HDL-C) (r=-0.27, P=0.002). Detectable concentrations of serum IL-12 were observed in 55% of subjects. Individuals with detectable serum concentrations of IL-12 had significantly higher levels of serum triglycerides (P=0.049). A significant association between IL-12 and serum total cholesterol (r=0.32, P=0.042) was observed in this subgroup. No association between p40 or IL-12 and insulin sensitivity was found. CONCLUSIONS: Our data indicate that the IL-12/IL-12p40 system may be associated with lipid abnormalities in obese subjects. PMID- 26038988 TI - Reading Groundwater in the 21st Century. PMID- 26038989 TI - [Editorial commentary: Hepatitis C]. PMID- 26038990 TI - [The pathology of hepatitis C]. AB - The hepatitis C virus is an RNA virus, which belongs to the genus Hepaciviruses of the family Flaviviridae. Chronic hepatitis, cirrhosis, and ultimately even liver cancer may develop in over 80% of infected cases. The histological features of hepatitis C and hepatitis caused by other hepatotropic viruses show many similarities, however, certain specific histological characteristics are observable. Accordingly, intense lymphocytic infiltration around the periportal areas, steatosis and biliary alterations are frequent findings. Further characteristics of hepatitis C include liver cell destruction (apoptosis, necrosis), periportal inflammation and fibrosis, the degrees of which can be determined by means of the histology activity index. Our knowledge on the hepatitis C virus genome and the mechanism of replication of the virus have established the use of modern, direct-acting antivirals in the treatment of chronic hepatitis C. PMID- 26038991 TI - [New era in the treatment of chronic hepatitis C - novel direct acting antivirals]. AB - Chronic hepatitis C, without treatment, can cause liver cirrhosis, liver failure and liver cancer. The availability of new oral direct acting antivirals, such as the protease inhibitors simeprevir, asunaprevir and paritaprevir, the NS5A inhibitors daclatasvir, ledipasvir, and ombitasvir, the polymerase inhibitors Sofosbuvir and dasabuvir have resulted an enormous progress in the treatment of chronic hepatitis C, leading to >90% sustained viral response rates. Even the hard-to-treat or previously treatment ineligible patients can be cured with the combination of these drugs. Furthermore the treatment duration is much shorter, and the side effects are minimal. Today, treatment of all hepatitis C virus infected patients is recommended, and the best choices are the interferon-free options. Eradication of hepatitis C virus has become realistic, however, appropriate screening programs are mandatory to achieve this goal. PMID- 26038992 TI - [Significance of hepatitis C virus baseline polymorphism during the antiviral therapy]. AB - The treatment of chronic hepatitis C has developed significantly during the last 25 years. In patients with genotype 1 infection 40-50% sustained virologic response could be achieved using pegylated interferon and ribavirin dual combination, which could be increased significantly with the introduction of direct acting antivirals. Three major groups of direct acting antivirals are known, which directly inhibit different phases of viral life cycle, by inhibiting the function of several non-structural proteins (NS3/4A protease, NS5A protein and NS5B polymerase). Due to the rapid replication rate of hepatitis C virus and the error-prone NS5B polymerase activity, mutant virions are generated, which might have reduced susceptibility to direct acting antiviral therapy. Since these resistance associated variants might exist before the antiviral therapy, they are still able to replicate during the direct acting antiviral treatment. Due to this selection pressure, the resistant virus will replace the wild type. This was especially detected during monotherapy, therefore, the first generation of direct acting antivirals have been combined with pegylated interferon and ribavirin, while recently interferon-free combinations are being developed including 2 or 3 direct acting antivirals. Using the first generation protease inhibitors boceprevir and telaprevir, it could have been seen, that the rate of resistance associated variants is higher and the therapeutic outcome is worse in patients with hepatitis C virus genotype 1a, than in 1b. Similar phenomenon was seen with the second generation of NS3/4A protease inhibitors as well as with NS5A or NS5B polymerase. This is due to the lower genetic barrier to resistance, ie. usually fewer mutations are enough for the emergence of resistance in genotype 1a. The selection of resistance associated variants is one of the most important challenges during the interferon-free therapy. PMID- 26038993 TI - [Non-invasive diagnostic methods of fibrosis in chronic hepatitis C virus infection: their role in treatment indication, follow-up and assessment of prognosis]. AB - Chronic hepatitis C virus infection associated with necroinflammation predisposes to liver fibrosis and cirrhosis, which lead to severe end-stage complications. Staging of fibrosis is of basic importance for the indication of antiviral treatment, for monitoring the response and predicting the prognosis of patients with hepatitis C virus related liver disease. Since liver biopsy, the "gold standard" diagnosis of fibrosis is invasive and it has some other limitations, non-invasive methods have been developed and widely used in the clinical practice. Serum biomarkers and physical approaches measuring liver stiffness by elastography as well as combination algorithms have been gradually been integrated into guidelines resulting in a reduction of the need for liver biopsy. The authors review these non-invasive fibrosis markers and discuss their role in the indication of treatment, follow-up, and assessment of prognosis of patients with chronic hepatitis C virus infection. PMID- 26038994 TI - [Financial burden of hepatitis C infection and its treatment]. AB - The worldwide prevalence of hepatitis C infection is 2-3%. In addition to its individual consequences, it generates huge financial impact on national level. In particular, lack of recognition or late diagnosis of the disease is associated with high rate of liver cirrhosis related complications (hepatic encephalopathy, ascites, variceal bleeding, hepatocellular carcinoma) and/or demands liver transplantation. Loss of quality assisted life years and/or those spent in employment, reduced work productivity, as well as costs of antiviral therapy also contribute to the financial burden. The costs of new interferon-free therapies may exceed the prices of previous pegylated interferon based therapies with or without protease inhibitors; however, shorter treatment durations and extremely low rates of severe side-effects with much less related expenses can reduce total costs of these treatments. In addition to the moral obligations, published cost effectiveness analyses conclude that early diagnosis and treatment of this primarily iatrogenic infection through organized screening programs and wide access to effective therapies may lead to long term financial benefit. PMID- 26038995 TI - [Clinical Implications of Inflammation and Immunity in Acute and Chronic Liver Disease: Advances in Diagnosis, Treatment and Clinical Practice. AASLD Liver Meeting, Boston, November 7-11, 2014]. PMID- 26038997 TI - Importance of malnutrition in patients with cirrhosis. AB - Malnutrition is common in patients with chronic liver disease and is associated with poor outcomes. Inadequate intake, poor quality diet, maldigestion, malabsorption, altered macronutrient metabolism, and hypermetabolism all contribute to the development of malnutrition in this patient population. Although it is generally easy to detect, clinicians often overlook malnutrition and its measurement is complicated by the lack of a simple, standardized diagnostic method. Early detection of malnutrition and multidisciplinary treatment approaches greatly increase the probability for successful outcomes. PMID- 26038998 TI - The nutritional status of hospitalized children: Has this subject been overlooked? AB - BACKGROUND/AIMS: To determine the nutritional status of hospitalized children at the time of admission and to investigate the relationship between diagnosis and nutritional status. MATERIALS AND METHODS: Body weight, height, triceps skinfold thickness, and mid-arm circumference were measured on admission and percentages of weight-for-age, weight-for-height, body mass index, mid-arm circumference, and triceps skinfold thickness were calculated. The nutritional status was evaluated using the Waterlow, Gomez, and other anthropometric assessments. RESULTS: A total of 511 patients were included in the study with a mean age of 5.8+/-4.9 years. Malnutrition was determined in 52.7% of patients according to the Waterlow classification. Mild malnutrition was determined in 39%, moderate in 12%, and severe in 1.7%, with the characteristics of acute malnutrition in 23.9%, acute chronic in 7.3%, and chronic in 21.5%. The highest rate of malnutrition was in the 0-2 years age group (62.3%). According to the Gomez classification, malnutrition rate was determined as 46.8%. The rates of malnutrition in malignant, gastrointestinal, and infectious diseases were 60%, 59.8%, and 54.5%, respectively. CONCLUSION: The prevalence of malnutrition in hospitalized children was noticeably high. The nutritional evaluation of all patients and an early start to nutritional support could provide a significant positive contribution. PMID- 26038996 TI - Two-way communication between the metabolic and cell cycle machineries: the molecular basis. AB - The relationship between cellular metabolism and the cell cycle machinery is by no means unidirectional. The ability of a cell to enter the cell cycle critically depends on the availability of metabolites. Conversely, the cell cycle machinery commits to regulating metabolic networks in order to support cell survival and proliferation. In this review, we will give an account of how the cell cycle machinery and metabolism are interconnected. Acquiring information on how communication takes place among metabolic signaling networks and the cell cycle controllers is crucial to increase our understanding of the deregulation thereof in disease, including cancer. PMID- 26038999 TI - Tenofovir-best hope for treatment of chronic hepatitis B infection? AB - BACKGROUND/AIMS: To evaluate the effectiveness of tenofovir in patients with chronic hepatitis B infection in a real life setting. MATERIALS AND METHODS: We performed a retrospective analysis of data from 164 patients with chronic hepatitis B who were treated with Tenofovir. Eighty-six patients (52.4%) were naive. Seventy-seven (46.9%) patients were previously treated with anti-viral drugs, including standard interferon (n=4), pegylated (PEG) interferon (n=14), standard interferon together with lamivudine (n=13), lamivudine alone (n=41), adefovir (n=2), lamivudine together with adefovir (n=1), and entecavir (n=2). Six patients (3.7%) had liver cirrhosis before treatment of tenofovir. RESULTS: The patients who have hepatitis B viral DNA>104 copy/mL with chronic hepatitis B infection were included in the treatment of Tenofovir. Average follow up time was 30.31+/-14.33 months. HBV DNA negativity and alanine aminotransferase (ALT) normalization were 86.5% and 71.3%, respectively, at the last visit. Hepatitis B e-Antigen (HBeAg) seroconversion occurred in 11 (19.6%) out of 164 patients. During the follow-up period, 4 (2.4%) patients developed liver cirrhosis and in 5 (3%) patients hepatocellular carcinoma (HCC) occurred out of 164 patients. HBsAg seroconversion occurred in one patient (0.6%). CONCLUSION: Tenofovir can be used safely and successfully in those patients that were naive, experienced with immune modulators and/or antivirals, HBeAg-positive, and HBeAg-negative patients. PMID- 26039000 TI - Validity and reliability of the patient assessment of constipation quality of life questionnaire for the Turkish population. AB - BACKGROUND/AIMS: There are few specific evaluation forms for evaluating the quality of life among patients with chronic constipation. Our study aimed to determine the validity and reliability of the translated Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaire for the Turkish population because evidence of its reliability and validity is required to justify its use in other studies and clinical practice. MATERIALS AND METHODS: This study included 154 patients with constipation who were treated at the Department of Gastroenterology, Dokuz Eylul University Hospital between January and June 2012. The translated PAC-QOL questionnaire was completed by patients at the clinic and also at a 2-week follow-up to test its reliability. RESULTS: Cronbach's alpha coefficient (internal consistency) was 0.91 (good) for the translated PAC-QOL questionnaire. Time validity was evaluated using the intraclass correlation coefficient (ICC) method, and the ICC value for all questions was confirmed as 0.68 at the 2-week follow-up. The validity of the tool in the study group was evaluated using factor analysis, and the results were highly significant (Kaiser Meyer-Olkin value: 0.857; Bartlett's test: p=0.001). Questions were categorized according to six factors based on the factor analysis, and these factors explained 65.1% of the total variation. For hypothesis verification of the tool, the correlation coefficient for PAC-QOL and PAC Symptoms (PAC-SYM) was r=0.577 (p<0.001), whereas the correlation coefficient for PAC-QOL and constipation severity score was r=0.457 (p<0.001). CONCLUSION: The PAC-QOL questionnaire was reliable, although not valid because of the limited sample group. PMID- 26039001 TI - The rate of mucosal healing by azathioprine therapy and prediction by artificial systems. AB - BACKGROUND/AIMS: We aimed to assess the effect of azathioprine on mucosal healing in patients with inflammatory bowel diseases (IBD). Artificial neural networks were applied to IBD data for predicting mucosal remission. MATERIALS AND METHODS: Two thousand seven hundred patients with IBD were evaluated. According to the computer-based study, data of 129 patients with IBD were used. Artificial neural networks were performed and tested. RESULTS: Endoscopic mucosal healing was found in 37% patients with IBD. Male gender group showed a negative impact on the efficacy of azathioprine (p<0.05). Responder patients with IBD were older than the nonresponder (p<0.05) patients. According to this study, the cascade-forward neural network study provides 79.1% correct results. In addition to a 0.16033 training error, mean square error (MSE) was taken at the 16th epoch from the feed forward back-propagation neural network. This neural structure, used for predicting mucosal remission with azathioprine, was also validated. CONCLUSION: Analyzing all parameters within each other to azathioprine therapy were shown that which parameters gave better healing were determined by statistical, and for the most weighted six input parameters, artificial neural network structures were constructed. In this study, feed-forward back-propagation and cascade-forward artificial neural network models were used. PMID- 26039002 TI - The cytokine response in THP-1 (monocyte) and HL-60 (neutrophil-differentiated) cells infected with different genotypes of Helicobacter pylori strains. AB - BACKGROUND/AIMS: Helicobacter pylori (H. pylori) is a microaerophilic bacterium related with peptic ulcer and gastric cancer. Its virulence factors include cytotoxin-associated gene A (CagA) and vacuolating cytotoxin gene A (VacA) proteins. Cytokine release inducted by H. pylori colonization has an important role in pathogenesis of H. pylori. The severity of gastric pathologies depends on the H. pylori genotypes found in different geographical regions. We aimed to determine the relationship between different H. pylori genotypes and their effects on the cytokine release levels. MATERIALS AND METHODS: ureC, cagA, vacAs1/s2, vacAm1/m2, and blood group antigen-binding adhesion protein A2 (babA2) virulence related genes were investigated in 21 H. pylori strains. Genotyping of 21 strains were made due to the presence of cagA, vacAs1/s2, vacAm1/m2, and babA2 genes. The H. pylori strains were cultured together with THP-1 and neutrophil differentiated Human promyelocytic leukemia cells (HL-60) cells. The levels of cytokines interleukin (IL)-1beta, IL-6, IL-8, IL-12, tumor necrosis factor-alpha (TNF-alpha), and IL-10 in these cells were measured after co-culturing with H. pylori strains. RESULTS: The following five different genotypes were detected: Genotype1: cagA and vacAs1m2; Genotype2: cagA and vacAs1m1; Genotype3: cagA, vacAs1m2, and babA2; Genotype4: vacAs2m2; and Genotype5: cagA and vacAs2m2. All these genotypes significantly induced the levels of IL-1beta, IL-6, IL-8, IL 10, and TNF-alpha in THP-1 cells. Genotype 5 caused higher amounts of IL-1beta, IL-6, TNF-alpha, and IL-10, whereas genotype 1 induced the highest levels of IL-8. In neutrophil-differentiated HL-60 cells, genotype 4 increased IL-6 levels and genotype 3 and 4 elevated IL-8 levels significantly. CONCLUSION: These results suggested that cytokine response of the host varies depending on the specific immune response of the host against different H. pylori strains. PMID- 26039003 TI - Additional BCAA-enriched nutrient mixture improves the nutritional condition in cirrhotic patients with hypoalbuminemia despite treatment with regular BCAA granules: A pilot study. AB - BACKGROUND/AIMS: To elucidate the effect of adding branched-chain amino acid (BCAA)-enriched nutrient mixtures in cirrhotic patients with hypoalbuminemia despite the use of BCAA granules. MATERIALS AND METHODS: A BCAA-enriched nutrient mixture containing 5.6 g of BCAA and 210 kcal was additionally administered in 40 cirrhotic patients with hypoalbuminemia despite their treatment with BCAA granules containing 12 g of BCAA. Laboratory data were assessed at 6 months before beginning additional therapy, at baseline, and at 6 months after baseline. RESULTS: Serum albumin levels significantly decreased from 6 months before baseline (3.14+/-0.47 g/dL) to baseline (2.83+/-0.46 g/dL), despite the treatment with BCAA granules (p<0.001), and tended to increase from baseline to 6 months after baseline (2.95+/-0.42 g/dL) (p=0.084). In the subset of 23 patients without hepatocellular carcinoma treatments, upper gastrointestinal tract bleeding, or albumin infusion, serum albumin levels significantly increased from baseline (2.93+/-0.38 g/dL) to 6 months after baseline (3.15+/-0.34 g/dL) (p=0.014). CONCLUSION: Additional therapy with BCAA-enriched nutrient mixtures increased serum albumin levels of the cirrhotic patients with hypoalbuminemia despite the treatment with BCAA granules and without hepatocellular carcinoma treatment, upper gastrointestinal tract bleeding, or albumin infusion. PMID- 26039004 TI - A vegetarian diet does not protect against nonalcoholic fatty liver disease (NAFLD): A cross-sectional study between Buddhist priests and the general population. AB - BACKGROUND/AIMS: There is limited data that supports a role for a vegetarian diet in nonalcoholic fatty liver disease (NAFLD). The aim of this study is to evaluate the relationship between vegetarian diets and NAFLD, considering metabolic syndrome and obesity. MATERIALS AND METHODS: This is a cross-sectional, retrospective study comparing the prevalence of NAFLD of 615 Buddhist priests and age-, sex-, Body mass index (BMI)-and presence/absence of metabolic syndrome matched controls who underwent routine health checkups in a health promotion center. Diagnosis and severity of NAFLD was determined based on ultrasonographic findings. RESULTS: The prevalence of NAFLD was not statistically significantly different between the Buddhist priests and the general population (29.9% vs. 25.05%, p=0.055). The Buddhist priest group had higher serum albumin, serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and serum triglyceride levels and lower serum total bilirubin, serum fasting glucose, and serum high density lipoprotein (HDL) levels than the general population group. In univariate analysis and multivariate analysis, NAFLD was associated with old age, male gender, increased BMI, increased waist circumference, metabolic syndrome, high albumin, high glucose, high AST, high ALT, high gamma glutamyl transpeptidase (GGT), high triglycerides, low HDL, high low density lipoprotein (LDL), and high total cholesterol. CONCLUSION: The vegetarian diet does not protect against NAFLD. PMID- 26039005 TI - 18F-FDG PET CT as a prognostic factor in hepatocellular carcinoma. AB - BACKGROUND/AIMS: To elucidate the role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging as an independent prognostic factor in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 104 patients with newly diagnosed HCC who underwent 18F-FDG PET/CT imaging from 2009 to 2014 were reviewed retrospectively. The ratio of the maximal tumor standardized uptake value (SUV) to the mean mediastinum SUV (TSUVmax/MSUVmean) was evaluated as the predictive factor. RESULTS: A high TSUVmax/MSUVmean ratio (>=3.1) was significantly associated with tumor burden indices, including alpha-fetoprotein (p<0.001), amino transaminase (AST) (p=0.007), tumor size (p=0.043), Tumor, Node, and Metastasis (TNM) stage (p<0.001), and Barcelona Clinic Liver Cancer (BCLC) staging (p<0.001). The mortality rate was higher (48.1% vs. 23.1%, p<0.001) in patients with a high TSUVmax/MSUVmean ratio (>=3.1). Among the 47 patients who underwent transarterial chemoembolization (TACE), patients with a high TSUVmax/MSUVmean ratio (>=3.1) were more likely to have recurrence following TACE (18/19 vs. 18/28, p=0.016). CONCLUSION: A high TSUVmax/MSUVmean ratio on 18F-FDG-PET/CT imaging can serve as an independent prognostic factor in HCC and may predict tumor recurrence after TACE. PMID- 26039007 TI - Blood hemoglobin values are a strong predictor of serum adiponectin levels. PMID- 26039006 TI - The relationship of recurrent aphthous stomatitis and Helicobacter pylori, cytokine gene polymorphism and cobalamin. AB - BACKGROUND/AIMS: The aim of the present study was to investigate whether Helicobacter pylori causes or triggers recurrent aphthous stomatitis (RAS) through cytokine gene polymorphism and/or cobalamin deficiency. MATERIALS AND METHODS: Thirty-six patients with RAS and 130 patients without RAS were genotyped for IL-1beta (-511C/T) and IL-6 (-174G/C) and evaluated for H. pylori infection and serum cobalamin level. RESULTS: The patient groups according to RAS had similar rates of H. pylori gastritis and interleukin genotypes/alleles, and there was a non-significant difference between serum cobalamin levels (p>0.05). RAS patients with H. pylori gastritis showed a higher frequency (51.9%) of GC IL-6 genotype than RAS patients without H. pylori gastritis (11.1%) (p=0.036). Non-GG genotype and C allele were increased in patients without RAS and with H. pylori gastritis (p<0.05). Patients with H. pylori gastritis showed a lower value of serum cobalamin without statistical significance, although this difference was more prominent in RAS patients (p=0.07). CONCLUSION: The carriage of the C allele of IL-6 may lead a susceptibility to chronic gastric inflammation after contamination with H. pylori. If H. pylori infection is justified as a predisposing factor for RAS and its severity by further studies, we can speculate that subjects with genetic susceptibility to this infection may benefit from H. pylori eradication treatment with respect to RAS. PMID- 26039008 TI - Importance of serum hepatitis B surface antigen and hepatitis e antigen quantification among patients with chronic hepatitis B. PMID- 26039009 TI - A rare solid tumor of the retroperitoneum with venous extension and lung metastasis: Extra-gastrointestinal stromal tumor. PMID- 26039010 TI - Importance of ascites adenosine deaminase in diagnosing abdominal tuberculosis with ascites. PMID- 26039011 TI - Co-occurrence of inflammatory fibroid polyp in Crohn's disease: A MR enterography study. PMID- 26039012 TI - Pulmonary Large-Cell Neuroendocrine Carcinoma: From Epidemiology to Therapy. AB - Lung neuroendocrine tumors are a heterogeneous subtype of pulmonary cancers representing approximately 20% of all lung cancers, including small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). The frequency appears to be approximately 3% for LCNEC. Diagnosis of LCNEC requires attention to neuroendocrine features by light microscopy and confirmation by immunohistochemical staining for neuroendocrine markers. Both SCLC and pulmonary LCNEC are high-grade and poor-prognosis tumors, with higher incidence in males and smokers and peripheral localization. LCNEC is very rare, and the precise diagnosis on small specimens is very difficult, so we have still too few data to define a standard of treatment for pulmonary LCNECs. Data of literature, most based on retrospective analysis, indicated a poor 5-year overall survival, with a high incidence of recurrence after surgery, even in stage I disease. Primary surgery should be the first option in all operable patients because there is no validate therapeutic approach for LCNEC due to lack of clinical trials in this setting. Neoadjuvant platinum-based regimens remain only an option for potentially resectable tumors. In advanced stages, SCLC-like chemotherapy seems the best option of treatment, with a good response rate but a poor overall survival (from 8 to 16 months in different case series). New agents are under clinical investigation to improve LCNEC patients' outcome. We reviewed all data on treatment options feasible for pulmonary LCNEC, both for localized and extensive disease. PMID- 26039014 TI - Bigger Is Better: Increasing Cortical Auditory Response Amplitude Via Stimulus Spectral Complexity. AB - OBJECTIVE: To determine the influence of auditory stimuli spectral characteristics on cortical auditory evoked potentials (CAEPs). DESIGN: CAEPs were obtained from 15 normal-hearing adults in response to six multitone (MT), four pure-tone (PT), and two narrowband noise stimuli. The sounds were presented at 10, 20, and 40 dB above threshold, which were estimated behaviorally beforehand. The root mean square amplitude of the CAEP and the detectability of the response were calculated and analyzed. RESULTS: Amplitudes of the CAEPs to the MT were significantly larger compared with PT for stimuli with frequencies centered around 1, 2, and 4 kHz, whereas no significant difference was found for 0.5 kHz. The objective detection score for the MT was significantly higher compared with the PT. For the 1- and 2-kHz stimuli, the CAEP amplitudes to narrowband noise were not significantly different than those evoked by PT. CONCLUSION: The study supports the notion that spectral complexity, not just bandwidth, has an impact on the CAEP amplitude for stimuli with center frequency above 0.5 kHz. The implication of these findings is that the clinical test time required to estimate thresholds can potentially be decreased by using complex band-limited MT rather than conventional PT stimuli. PMID- 26039013 TI - Goal-Directed Resilience in Training (GRIT): A Biopsychosocial Model of Self Regulation, Executive Functions, and Personal Growth (Eudaimonia) in Evocative Contexts of PTSD, Obesity, and Chronic Pain. AB - This paper presents a biopsychosocial model of self-regulation, executive functions, and personal growth that we have applied to Goal-Directed Resilience in Training (GRIT) interventions for posttraumatic stress disorder (PTSD), obesity, and chronic pain. Implications of the training for the prevention of maladaptation, including psychological distress and health declines, and for promoting healthy development are addressed. Existing models of attention, cognition, and physiology were sourced in combination with qualitative study findings in developing this resilience skills intervention. We used qualitative methods to uncover life skills that are most salient in cases of extreme adversity, finding that goal-directed actions that reflected an individual's values and common humanity with others created a context-independent domain that could compensate for the effects of adversity. The efficacy of the resilience skills intervention for promoting positive emotion, enhancing neurocognitive capacities, and reducing symptoms was investigated in a randomized controlled trial with a veteran population diagnosed with PTSD. The intervention had low attrition (8%) and demonstrated improvement on symptom and wellbeing outcomes, indicating that the intervention may be efficacious for PTSD and that it taps into those mechanisms which the intervention was designed to address. Feasibility studies for groups with comorbid diagnoses, such as chronic pain and PTSD, also showed positive results, leading to the application of the GRIT intervention to other evocative contexts such as obesity and chronic pain. PMID- 26039015 TI - Gabapentin Treatment in Bruxism Associated With Fluoxetine. PMID- 26039016 TI - [Mental disorders in digestive system diseases - internist's and psychiatrist's insight]. AB - Mental disorders accompanying digestive system diseases constitute interdisciplinary yet scarcely acknowledged both diagnostic and therapeutic problem. One of the mostly recognized examples is coeliac disease where patients endure the large spectrum of psychopathological symptoms, starting with attention deficit all the way down to the intellectual disability in extreme cases. It has not been fully explained how the pathomechanism of digestive system diseases affects patient's mental health, however one of the hypothesis suggests that it is due to serotonergic or opioid neurotransmission imbalance caused by gluten and gluten metabolites effect on central nervous system. Behavioral changes can also be invoked by liver or pancreatic diseases, which causes life-threatening abnormalities within a brain. It occurs that these abnormalities reflexively exacerbate the symptoms of primary somatic disease and aggravate its course, which worsens prognosis. The dominant mental disease mentioned in this article is depression which because of its effect on a hypothalamuspituitary- adrenal axis and on an autonomic nervous system, not only aggravates the symptoms of inflammatory bowel diseases but may accelerate their onset in genetically predisposed patients. Depression is known to negatively affects patients' ability to function in a society and a quality of their lives. Moreover, as far as children are concerned, the occurrence of digestive system diseases accompanied by mental disorders, may adversely affect their further physical and psychological development, which merely results in worse school performance. All those aspects of mental disorders indicate the desirability of the psychological care for patients with recognized digestive system disease. The psychological assistance should be provided immediately after diagnosis of a primary disease and be continued throughout the whole course of treatment. PMID- 26039017 TI - CD34+ progenitor cells in pulmonary sarcoidosis. AB - Sarcoidosis is a disease of unclear etiology, immunopathogenesis complex and diverse clinical course. AIM: The aim of study was to evaluate the usefulness of CD34+ cells, CD4 and CD8 lymphocytes in peripheral blood for the diagnosis and better understanding of the sarcoidosis pathogenesis. MATERIALS AND METHODS: The study included 40 patients (16 women and 24 men) aged 29-71 years (mean 45 years) with newly diagnosed pulmonary sarcoidosis. The control group consisted of 30 healthy subjects (18 women and 12 men) aged 24-65 years (mean 47 years). Tests were performed in peripheral blood, and lymphocytes CD4 and CD8 and progenitor CD34+ cells surface antigens were determined by flow cytometry. RESULTS: It has been shown that number of CD34+ progenitor cells in peripheral blood was significantly higher in patients with newly diagnosed pulmonary sarcoidosis and showed a positive correlation with CD4/ CD8 rate. CONCLUSIONS: CD34+ progenitor cells may be important in the pathogenesis of sarcoidosis. It is necessary to conduct further studies that identify heterogenous population of CD34+ cells with particular focus on fibrocytes. PMID- 26039018 TI - [The effectiveness of comprehensive rehabilitation after a first episode of ischemic stroke]. AB - Ischemic stroke is the most common cause of hospitalization in the Department of Neurological Rehabilitation. Comprehensive rehabilitation is essential for regaining lost functional efficiency. AIM: The aim of study was to evaluate the effectiveness of specific disorder rehabilitation program in 57 patients with first-ever ischemic stroke. MATERIALS AND METHODS: The study included 57 patients (27 women, 30 men) aged from 47 to 89. Patients were admitted for comprehensive rehabilitation, lasted an average of 25 days. The treatment program consisted of exercises aimed at reeducation of posture and gait. In addition, physical treatments were used. Evaluation of the effectiveness of rehabilitation was measured using the Activity Daily Living scale, Modified Rankin Scale, Rivermead Measure Assessment (RMA1-global movements, RMA2-lower limb and trunk, RMA3-upper limb) and the psychological tests - Geriatric Depression Scale (GDS) and Beck Depression Inventory (BDI). RESULTS: As a result of comprehensive rehabilitation treatment, functional status and mental health improvement was observed in relation to the ADL scale by 32% (woman 36%, man 30%), Rankin scale by 22% (woman 22%, man 21%). In the RMA, improvement was observed with the statistical significance of p=0.001 in all of the subscales. The highest rate of improvement affected upper limb function: RMA/3 (41%). In other subscales women have achieved statistically more significant improvement than men (RMA/1-43% versus 25%; RMA/2 41% versus 30%). The results related to the psychological assessment showed statistically significant GDS improvement p<0.001 (<60 years old) and BDI (> 60 years old) in test men (p=0.038). Spearman correlation coefficient showed no relation between mental state and functional improvement (GDS versus ADL; BDI versus ADL). CONCLUSIONS: The 25 days comprehensive rehabilitation program during the subacute stroke phase affects mainly the improvement of upper limb function. Women have achieved better functional improvement in all of the parameters. In addition, it was observed that symptoms of depression were presented in all study group, and the improvement of mental focused primarily on patients after 60 years old. PMID- 26039019 TI - [Physical activity in patients with symptoms of metabolic syndrome reduces the concentration of plasma antioxidant vitamins - protective effect of vitamin C]. AB - Patients with cardiovascular diseases, including those with the symptoms of metabolic syndrome (MS), are recommended regular exercise but many studies indicate its role in the production of reactive oxygen species. Vitamin C supplementation may enhance the antioxidant barrier in MS patients. AIM: The aim of the study was to assess the impact of regular physical activity (PA)and vitamin C supplementation on plasma vitamin A, C and E levels in patients with MS. MATERIALS AND METHODS: The study included 62 patients with MS according to International Diabetes Federation criteria, 32 men and 30 women, aged 38-57 years (mean age 51,24 +/- 5,29 years). The patients were divided in two groups: group I (MS+PA) - 31 patients with recommended regular physical activity; group II ( MS+PA+C) - 31 patients with recommended regular physical activity and vitamin C supplementation per os. The control group consisted of 23 healthy individuals without MS, 17 men and 6 women, aged 49-56 years (mean age 53,21 +/- 3,6 years), who were not recommended any vitamin supplementation nor physical activity. Plasma vitamin A, C and E levels were estimated in MS patients with spectrophotometry using T60V spectrophotometer (PG Instruments) before and after regular exercise with and without vitamin C supplementation. In the control group plasma levels of antioxidant vitamins were assessed only once. RESULTS: The plasma vitamin A, C and E levels were significantly lower (p<0,05) in MS patients than in the control group. After 6 weeks of regular physical activity a significant fall in plasma levels of antioxidant vitamins was observed in MS patients. In the group of patients with regular physical activity and vitamin C supplementation there was detected a significant rise in the level of all the tested vitamins close to the levels in control group. CONCLUSIONS: Regular physical activity enhances the decrease in plasma antioxidant vitamin level in patients with MS. Vitamin C supplementation conducted in parallel with regular physical activity normalize plasma vitamin A, C and E levels in these patients. PMID- 26039020 TI - [Long-term outcomes after "anatomic" reconstruction of anterior cruciate ligament using central third of patellar tendon]. AB - Reconstruction of the anterior cruciate ligament (ACL) is one of the most commonly performed procedures in orthopedics. AIM: The aim of the study was to evaluate long-term results of anterior cruciate ligament reconstruction using middle third patellar tendon grafts. MATERIALS AND METHODS: The study included 29 patients with an average 8 years follow - up. All patients underwent arthroscopic reconstruction of ACL using the central third of the patellar tendon ligament. The grafts attachment points were determined by using the Howell pointer. The average patient age was 36 years (range from 16 to 48 years). Postoperative assessment was based on the modified Lysholm score, intensity of the degenerative changes in the Lawrence-Kellgren scale and stabilometric measurments of the knee by Rolimeter and Telos Stress Device. RESULTS: According to the Lyscholm score 21 of 29 patients achieved good and very good result, 7 sufficient, and one case was reported as a bad result. Most of the unsatisfactory results were related with coexisting intraarticular injuries: meniscus and articular cartilage lesions. Outcomes of stabilometric measurments was strongly correlated with subjective results of survey. CONCLUSIONS: In spite evolution of techniques and the introduction of new methods of ACL reconstruction, treatments performed several years ago using the BPTB transtibial technique was possible to obtain good results of treatment. PMID- 26039021 TI - [Emotional and language prosody and working memory in patients with depression]. AB - AIM: The aim of the study was to verify the hypothesis about the relationship between the efficiency of executive functions and emotional prosody and linguistic prosody among patients with recurrent depressive disorder (rDD). MATERIALS AND METHODS: The study comprised 80 subjects, patients with rDD. Assessment of cognitive function was based on performance of the Trail Making Test (TMT), the Stroop Test, the Verbal Fluency Test (VFT), the Auditory Verbal Learning Test (AVLT), Ruff Figural Fluency Test (RFFT) and emotional prosody and linguistic prosody. RESULTS: Efficiency of emotional prosody is linked to the execution of one part of the test VFT. Efficiency in the language prosody goes hand in hand with the speed of execution of both parts of the TMT, correctness of the implementation of VFT and RFFT. A negative impact of depressive symptoms only for language prosody was observed. CONCLUSIONS: Deficits in the recognition of emotional stimuli in depression are not necessarily limited to visual information, but may also apply to non-verbal auditory stimuli (prosody). The severity of symptoms of depression impairs efficiency of linguistic prosody. The efficiency of frontal functions (both visual-spatial and verbal-auditory) is related to the ability of patients to use non-verbal communication of emotional information. PMID- 26039022 TI - [Multiple right ventricular thrombi in arrhythmogenic right ventricular cardiomyopathy - a case report]. AB - Typical complications of arrhythmogenic right ventricular cardiomyopathy (ARVC) are heart failure and ventricular arrhythmias which may lead to sudden cardiac death. Intracardiac thrombosis is diagnosed only in 2-4% of patients. The authors present a case of a 50-year-old male admitted to hospital due to symptomatic ventricular tachycardia. Echocardiography and cardiac magnetic resonance showed advanced ARVC with multiple right ventricular thrombi. The biggest one was localized in the inflow tract below the tricuspid valve, whereas the smallest one beneath it, on the inferior wall; the remaining two - in the apex. Chest computed tomography did not confirm pulmonary embolism. Disappearance of thrombi was observed after 4 weeks of anticoagulation. Detection and appropriate treatment of intracardiac thrombi in ARVC may have relevance in prevention of sudden death, not related to arrhythmia, and is of special importance before cardioverterdefibrillator implantation. PMID- 26039023 TI - Electric cardioversion of atrial fibrillation resulting in pulmonary oedema in patient with apical hypertrophic cardiomyopathy. AB - The direct-current electric shock is considered to be safe treatment of arrhythmias and rarely leads to serious hemodynamic complications. A 62-year-old patient was admitted to the hospital due to a first symptomatic episode of atrial fibrillation. Patient was diagnosed with apical hypertrophic cardiomyopathy 20 years ago. Transoesophageal echocardiography was performed to exclude an atrial thrombus followed by electrical cardioversion with restoration of sinus rhythm. After 6 hours symptoms of pulmonary oedema developed. The patient's condition improved after furosemide administration. As the possible cause of the oedema, inotropic effect of administered propafenone and atrial stunning were considered. The atria seem to be responsible for important part of forward cardiac output even during AF, especially in cardiomyopathies. Contractility deterioration of the left atrium (stunning) along with earlier resumption of the right atrium contractile function could be associated with hemodynamic instability causing pulmonary oedema in subjects with hypertrophied myocardium. It is necessary to take into consideration the atrial function while administrating antiarrhythmic drugs, especially those with negative inotropic effect. PMID- 26039024 TI - [Ten years progression-free survival obtained in a patient with mantle cell lymphoma]. AB - Mantle cell lymphoma is a rare aggressive lymphoma derived from B cells, characterized by rapid progression and subsequent recurrence. It is considered to be an incurable disease, with exception of a certain group of patients treated with an autogenic stem cell transplantation. The mean survival time is three years, after applying the conventional regimen based on COP (cyclophosphamide, vincristine, prednisone) or CHOP chemotherapy (COP + doxorubicin). An addition of rituximab to CHOP regimen significantly prolongs progression-free survival. The present case reports ten years progression-free survival in a female patient with mantle cell lymphoma with baseline clinical stage IVB (MIPI 5), treated with nine courses of CHOP chemotherapy. Rituximab was added from 3 to 8 course. The complete clinical, radiological and histopathological response has been obtained. PMID- 26039025 TI - [Symptoms and treatment of radiation-induced reactions]. AB - Radiotherapy is one of the main methods of cancer treatment alone or in combination with chemotherapy. It is applied in about 60% of oncological patients. However, in spite of its clinical usefulness, radiotherapy is associated with a high risk of radiation-induced side effects, including dermatitis, enteritis, cystitis, pericarditis, pneumonia or depression, sexual function disorders, cardiomiopathy, coronary heart disease, anomalies of heart valves and development of second malignant tumor. The early diagnosis and proper treatment of radiation-induced side effects have a major impact on patients' quality of life and future prognosis. Radiation reactions can be categorized as acute or late, occurring before and after six months after radiotherapy. Among the most common acute reactions there were observed: skin rash, mucositis, nausea, vomiting, fever and radiation pneumonitis. Within reference to the late complications, we distinguish for instance fibrosis of organs, a radiation necrosis of bone, ulcers, fistulas, sexual dysfunction and the development of second malignant carcinomas. PMID- 26039026 TI - [Endocrine abnormalities in patients with chronic renal failure - part I]. AB - The kidney plays an important role in synthesis, metabolism and elimination of a plethora of hormones. In subjects with chronic renal failure, particularly at its later stages, these adaptive responses are impaired and some of these alterations are of clinical relevance. Endocrine disturbances which are the most characteristic for chronic renal failure include: secondary and tertiary hyperparathyroidism, hypothalamic-pituitary-thyroid axis dysfunction and impaired growth. The pathogenesis of these complications is complex and multifactorial. This review discusses the most important changes in the function of the parathyroid glands, thyroid and the growth hormone-insulin-like growth factor 1 axis in the light of recent developments in this field. This article also tries to give insights into diagnosis and putative therapeutic strategies. PMID- 26039027 TI - [Endocrine abnormalities in patients with chronic renal failure - part II]. AB - The kidneys play a crucial role in maintaining homeostasis of fluids and electrolytes, acid-base balance, and volume regulation. In subjects with chronic renal failure, particularly at its later stages, these adaptive responses are impaired and some of these alterations are of clinical relevance. The ways in which chronic renal failure affects function of endocrine organs include impaired secretion of kidney-derived hormones, altered peripheral hormone metabolism, disturbed binding to carrier proteins, accumulation of hormone inhibitors, as well as abnormal target organ responsiveness. Apart from secondary hyperparathyroidism, thyroid dysfunction and impaired growth, reviewed in our previous study, endocrine disturbances that most frequently affect this group of patients include: abnormal functioning of the hypothalamic-pituitary-adrenal and hypothalamicpituitary- gonadal axes, bone loss and gynecomastia. The clinical picture and laboratory findings of these endocrine disturbances depend on the treatment strategy. PMID- 26039028 TI - [Amygdalin - structure and clinical significance]. AB - In this publication we described amygdalin. It was isolated for the first time in the 19th century. Amygdalin is called interchangeably vitamin B17 or laetrile. Since more than a hundred years, there has been reports about its unique anticancer properties. We tried to introduce the present knowledge about therapeutic efficacy of laetrile. Most of these studies has been made in the in vitro environment. The lack of appropriate studies forced scientists to examine the positive influence of amygdalin on many diseases like: bladder cancer, prostate cancer, cervical cancer, colon cancer, promyelocytic leukemia, chronic kidney disease, psoriasis and other. PMID- 26039029 TI - [Medical particularities during prolonged demanding activity in a tropical forest. Experience of the tropical forest training center (French Guyana)]. AB - A tropical forest is a hostile environment for humans. The military physician supporting these immersion activities must cope with varied clinical situations with limited resources to reduce operational unavailability. This article reports a prospective cross-sectional epidemiologic study conducted from January to May 2012, observing the daily activity at sick call during the rainy season at the tropical forest training center (CEFE) advanced jungle commando training, located in French Guyana. The aim was to observe the distribution of traumatic injuries and specific diseases in this tropical environment. In all, 9,221 army staff members participated in the training (mean age: 30.8 years) during the 120-day study period. There were 486 medical visits, for a mean daily incidence of 5.3% (trainees: 83.8%, trainers: 16.5%). Skin lesions were most frequent (39%), principally irritative dermatitis and skin maceration (moisture/dressing associated dermatitis). A third (34%) of these conditions were due to trauma, mainly limb contusions and ligament injuries. Tropical diseases accounted for 3% of the reasons for consultation, with rare problems related to equatorial fauna or flora. The remaining conditions (24%) were not specific to the environment or activity. Operational attrition averaged five days. Removal from the training course was necessary in 13.8% of the cases. In an isolated area with a demanding environment , edical practice in a tropical forest requires health prevention actions and close medical follow-up. The permanent presence of a physician provides both care and expertise and is an important asset for both trainees and trainers. PMID- 26039030 TI - Aromatization Energy and Strain Energy of Buckminsterfullerene from Homodesmotic Reactions. AB - The amount of aromatic stabilization of C60 fullerene (E(aroma)) and the amount of its destabilizing strain effect (E(strain)) are unknown quantities because both are intimately connected and difficult to separate. Based on experimentally known transformation of C60H30 to C60 and conversion of a polycyclic aromatic hydrocarbon C60H20 to the nonaromatic linear conjugated C60H62, new homodesmotic reaction schemes have been proposed to evaluate E(aroma) and E(strain). The E(aroma) values obtained at M06L/6-311G(d,p), M062X/6-311G(d,p), and B3LYP-D3/6 311G(d,p) levels of density functional theory are 122.3, 169.8, and 152.4 kcal/mol, respectively, whereas E(strain) values at these levels are 327.3, 382.0, and 381.4 kcal/mol, respectively. These data suggest that a CC bond of C60 is destabilized by ~2.28-2.54 kcal/mol compared to that of benzene, and this minor energetic effect explains the existence of C60 as a stable molecule. PMID- 26039031 TI - Axitinib: from preclinical development to future clinical perspectives in renal cell carcinoma. AB - INTRODUCTION: Based on extensive preclinical data and abundant evidence for clinical activity, vascular endothelial growth factor receptor (VEGFR) inhibitors are currently standard of care for metastatic renal cell carcinoma (mRCC). Axitinib is one of the most selective molecules in the class of anti-angiogenic agents, which confers an optimal profile between its safety and anti-cancer activity spectrum. AREA COVERED: In this review, the authors discuss the different stages that lead to the approval of axitinib in the clinic as well as the current perspectives for its clinical use with other promising therapies in mRCC such as immune checkpoint inhibitors and vaccines. EXPERT OPINION: In 2015, axitinib has emerged as one of the major agents used in mRCC. Based on robust preclinical data, this highly specific VEGFR inhibitor continues to be evaluated in different indications, including the adjuvant setting but also sequential administration with other molecularly targeted agents or combinations with immune therapies. PMID- 26039032 TI - Broad-Spectrum Antimicrobial/Antifouling Soft Material Coatings Using Poly(ethylenimine) as a Tailorable Scaffold. AB - Microbial colonization and biofilm formation is the leading cause of contact lens related keratitis. Treatment of the condition remains a challenge because of the need for prolonged therapeutic course and high doses of antimicrobial agents especially for biofilm eradication. The development of strategies to prepare nonfouling contact lens surfaces is a more practical way to ensure users' safety and relieve the excessive public healthcare burden. In this study, we report a series of polymers that were modified to introduce functionality designed to facilitate coating adhesion, antimicrobial and antifouling properties. Cyclic carbonate monomers having different functional groups including adhesive catechol, antifouling poly(ethylene glycol) (PEG), and hydrophobic urea/ethyl were conjugated onto branched poly(ethylenimine) (bPEI, 25 kDa) at various degrees in a facile and well-controlled manner using a simple one step, atom economical approach. Immersion of contact lenses into an aqueous solution of the catechol-functionalized polymers at room temperature resulted in robust and stable coating on the lens surfaces, which survived the harsh condition of autoclaving and remained on the surface for a typical device application lifetime (7 days). The deposition of the polymer was unambiguously confirmed by static contact angle measurement and X-ray photoelectron spectroscopy (XPS). Polymer coating did not change light transmission significantly. Combinatorial optimization demonstrated that lenses coated with bPEI functionalized with catechol, PEG (5 kDa) and urea groups at 1:12:3:23 molar ratio for 18 h provided the highest antifouling effect against four types of keratitis-causing pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Fusarium solani, after 7 days of incubation. The polymer coating also inhibited protein adsorption onto the contact lens surfaces after exposure to bovine serum albumin solution for up to 24 h, owing to the flexible and large PEG constituent. Notably, all the polymer coatings used in this study were biocompatible, achieving >=90% cell viability following direct contact with human corneal epithelial cells for 24 h. Hence, these polymer coatings are envisaged to be promising for the prevention of contact lens-related keratitis. PMID- 26039033 TI - Relationships among the Y balance test, Berg Balance Scale, and lower limb strength in middle-aged and older females. AB - BACKGROUND: Older females have less dynamic postural control and muscle strength than do middle-aged females. Aging-related strength losses may limit balancing performance. OBJECTIVE: The purpose of this study was to investigate the ability of the Y Balance Test (YBT) and lower limb strength to discriminate between females in 2 age groups, the relationship between YBT distance and the Berg Balance Scale (BBS), and the degree to which performance on YBT distance is related to lower limb strength in middle-aged and older females. METHOD: The 40 healthy, independently active females were divided into 2 groups: older and middle-aged. The participants underwent measurements of YBT distance using the YBT, maximal muscular strength of the lower limbs using a handheld dynamometer, and the BBS. RESULTS: The YBT distance in 3 directions and lower limb muscle strength for both lower limbs were significantly lower in the older adults than in the middle-aged group. A moderate correlation but insignificant correlation was found between the YBT composite distance and the BBS score. In the older females, YBT distance was significantly positively correlated with strength of the knee flexor and hip abductor. In the middle-aged group, YBT distance was significantly positively correlated with strength of the knee flexor and hip extensor. CONCLUSIONS: Performance on the YBT was influenced by the strength of lower limb. We suggested that YBT can be used to alternative as a measurement of dynamic balance. Proper training programs for older people could include not only strengthening exercises but also YBT performance to improve balance. PMID- 26039034 TI - Effectiveness of hip muscle strengthening in patellofemoral pain syndrome patients: a systematic review. AB - INTRODUCTION: Patellofemoral pain syndrome (PFPS) is characterized by anterior knee pain, which may limit the performance of functional activities. The influence of hip joint motion on the development of this syndrome has already been documented in the literature. In this regard, studies have investigated the effectiveness of hip muscle strengthening in patients with PFPS. OBJECTIVES: The aims of this systematic review were (1) to summarize the literature related to the effects of hip muscle strengthening on pain intensity, muscle strength, and function in individuals with PFPS and (2) to evaluate the methodological quality of the selected studies. METHOD: A search for randomized controlled clinical trials was conducted using the following databases: Google Scholar, MEDLINE, PEDro, LILACS, and SciELO. The selected studies had to distinguish the effects of hip muscle strengthening in a group of patients with PFPS, as compared to non intervention or other kinds of intervention, and had to investigate the following outcomes: pain, muscle strength, and function. The methodological quality of the selected studies was analyzed by means of the PEDro scale. RESULTS: Seven studies were selected. These studies demonstrated that hip muscle strengthening was effective in reducing pain. However, the studies disagreed regarding the treatments' ability to improve muscle strength. Improvement in functional capabilities after hip muscle strengthening was found in five studies. CONCLUSION: Hip muscle strengthening is effective in reducing the intensity of pain and improving functional capabilities in patients with PFPS, despite the lack of evidence for its ability to increase muscle strength. PMID- 26039035 TI - Association among measures of mobility-related disability and self-perceived fatigue among older people: a population-based study. AB - OBJECTIVE: To investigate the relationship between self-perceived fatigue with different physical functioning tests and functional performance scales used for evaluating mobility-related disability among community-dwelling older persons. METHOD: This is a cross-sectional, population-based study. The sample was composed of older persons with 65 years of age or more living in Cuiaba, MT, and Barueri, SP, Brazil. The data for this study is from the FIBRA Network Study. The presence of self-perceived fatigue was assessed using self-reports based on the Center for Epidemiologic Studies-Depression Scale. The Lawton instrumental activities of daily living scale (IADL) and the advanced activities of daily living scale (AADL) were used to assess performance and participation restriction. The following physical functioning tests were used: five-step test (FST), the Short Physical Performance Battery (SPPB), and usual gait speed (UGS). Three models of logistic regression analysis were conducted, and a significance level of alpha<0.05 was adopted. RESULTS: The sample was composed of 776 older adults with a mean age (SD) of 71.9 (5.9) years, of whom the majority were women (74%). The prevalence of self-perceived fatigue within the participants was 20%. After adjusting for covariates, SPPB, UGS, IADL, and AADL remained associated with self-perceived fatigue in the final multivariate regression model. CONCLUSION: Our results suggest that there is an association between self perceived fatigue and lower extremity function, usual gait speed and activity limitation and participation restriction in older adults. Further cohort studies are needed to investigate which physical performance measure may be able to predict the negative impact of fatigue in older adults. PMID- 26039036 TI - Reproducibility of the six-minute walk test and Glittre ADL-test in patients hospitalized for acute and exacerbated chronic lung disease. AB - BACKGROUND: The 6-minute walk test (6MWT) and the Glittre ADL-test (GT) are used to assess functional capacity and exercise tolerance; however, the reproducibility of these tests needs further study in patients with acute lung diseases. OBJECTIVES: The aim of this study was to investigate the reproducibility of the 6MWT and GT performed in patients hospitalized for acute and exacerbated chronic lung diseases. METHOD: 48 h after hospitalization, 81 patients (50 males, age: 52 +/- 18 years, FEV1: 58 +/- 20% of the predicted value) performed two 6MWTs and two GTs in random order on different days. RESULTS: There was no difference between the first and second 6MWT (median 349 m [284-419] and 363 m [288-432], respectively) (ICC: 0.97; P < 0.0001). A difference between the first and second tests was found in GT (median 286 s [220 378] and 244 s [197-323] respectively; P < 0.001) (ICC: 0.91; P < 0.0001). CONCLUSION: Although both the 6MWT and GT were reproducible, the best results occurred in the second test, demonstrating a learning effect. These results indicate that at least two tests are necessary to obtain reliable assessments. PMID- 26039038 TI - [Circulating tumor cells in head and neck cancer]. AB - Circulating tumor cells are defined as tumor cells which are circulating in the peripheral blood of the cancer patient. While several large studies have investigated the role of circulating tumor cells in other solid tumors, the importance of these tumor cells in patients with head and neck cancer was turned into the focus not until the recent years. In other solid tumor the presence of circulating tumor cells often seems to be a negative prognostic marker and seems to be a marker for therapy response. The present article wants to give an overview about the knowledge on circulating tumor cells and their clinical relevance in head and neck cancer. The methodology to detect circulating tumor cells will be critically reflected. The future potential of the detection of circulating tumor cells in head and neck cancer patients will be discussed. PMID- 26039039 TI - [Chronic rhinosinusitis]. AB - Chronic Rhinosinusitis (CRS) is a common disease with a major impact on quality of life. Its etiology is multifactorial and the causal pathology is an inflammation and not an infection. The affected region is the nasal mucosa as well as the mucosa of the sinuses. The symptoms are nasal obstruction, nasal discharge (anterior/post nasal drip), facial pain or pressure and/or olfactory disorder for more than 12 weeks. Beside association to hereditary or systemic diseases, CRS can be divided in chronic local findings (e.g. dental origin, muco- or pyocele, local mycosis, choanal polyp) and general CRS. The latter appears as CRS with nasal polyps or without nasal polyps. According to this, nasal endoscopy combined with investigation for the above mentioned symptoms is essential to diagnose CRS. In order to indicate and plan surgical treatment, CT-scans are necessary. Furthermore, diagnostic tools such as allergy tests, olfactory assessment, laboratory and microbiologic examination, biopsies and tests for aspirin hypersensitivity complete the diagnostic pathway of CRS. The therapeutic approach is local and if necessary oral application of steroids, nasal saline douche and oral long term antibiotics. If this conservative therapy leads to no effect, surgical treatment in terms of functional endoscopic sinus surgery (FESS) has to be considered. PMID- 26039040 TI - [Physician expert - consulting physician - private physician - attending physician clarification of the jungle of terminology]. PMID- 26039041 TI - [Recommendations]. PMID- 26039042 TI - KCN Chemical Etch for Interface Engineering in Cu2ZnSnSe4 Solar Cells. AB - The removal of secondary phases from the surface of the kesterite crystals is one of the major challenges to improve the performances of Cu2ZnSn(S,Se)4 (CZTSSe) thin film solar cells. In this contribution, the KCN/KOH chemical etching approach, originally developed for the removal of CuxSe phases in Cu(In,Ga)(S,Se)2 thin films, is applied to CZTSe absorbers exhibiting various chemical compositions. Two distinct electrical behaviors were observed on CZTSe/CdS solar cells after treatment: (i) the improvement of the fill factor (FF) after 30 s of etching for the CZTSe absorbers showing initially a distortion of the electrical characteristic; (ii) the progressive degradation of the FF after long treatment time for all Cu-poor CZTSe solar cell samples. The first effect can be attributed to the action of KCN on the absorber, that is found to clean the absorber free surface from most of the secondary phases surrounding the kesterite grains (e.g., Se0, CuxSe, SnSex, SnO2, Cu2SnSe3 phases, excepting the ZnSe-based phases). The second observation was identified as a consequence of the preferential etching of Se, Sn, and Zn from the CZTSe surface by the KOH solution, combined with the modification of the alkali content of the absorber. The formation of a Cu-rich shell at the absorber/buffer layer interface, leading to the increase of the recombination rate at the interface, and the increase in the doping of the absorber layer after etching are found to be at the origin of the deterioration of the FF of the solar cells. PMID- 26039043 TI - Effects of the CYP3A4*1B Genetic Polymorphism on the Pharmacokinetics of Tacrolimus in Adult Renal Transplant Recipients: A Meta-Analysis. AB - BACKGROUND AND OBJECTIVE: The association between the CYP3A4*1B single nucleotide polymorphism (SNP) and tacrolimus pharmacokinetics in different studies is controversial. Therefore, a meta-analysis was employed to evaluate the correlation between the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics at different post-transplantation times in adult renal transplant recipients. METHODS: Studies evaluating the CYP3A4*1B genetic polymorphism and tacrolimus pharmacokinetics were retrieved through a systematical search of Embase, PubMed, the Cochrane Library, ClinicalTrials.gov and three Chinese literature databases (up to Sept. 2014). The pharmacokinetic parameters (weight-adjusted tacrolimus daily dose and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio) were extracted, and the meta-analysis was performed using Stata 12.1. RESULTS: Seven studies (involving 1182 adult renal transplant recipients) were included in this meta analysis. For the weight-adjusted tacrolimus daily dose, in all included renal transplant recipients (European & Indian populations), CYP3A4*1/*1 recipients required a significantly lower weight-adjusted tacrolimus daily dose than did CYP3A4*1B carriers at 7 days (WMD -0.048; 95% CI -0.083 ~ -0.014), 6 months (WMD 0.058; 95% CI -0.081 ~ -0.036) and 12 months (WMD - 0.061; 95% CI -0.096 ~ 0.027) post-transplantation. In light of the heterogeneity, the analysis was repeated after removing the only study in an Indian population, and CYP3A4*1/*1 European recipients (mostly Caucasian) required a lower weight-adjusted tacrolimus daily dose within the first year post-transplantation. The tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio (C0/Dose ratio) was significantly higher in CYP3A4*1/*1 recipients than in CYP3A4*1B carriers at 6 months (WMD 52.588; 95% CI 22.387 ~ 82.789) and 12 months (WMD 62.219; 95% CI 14.218 ~ 110.221) post-transplantation. When the only study in an Indian population was removed to examine European recipients (mostly Caucasian), the significant difference persisted at 1 month, 6 months and 12 months post transplantation. CONCLUSION: Based on our meta-analysis, the CYP3A4*1B genetic polymorphism affects tacrolimus dose requirements and tacrolimus trough concentration/weight-adjusted tacrolimus daily dose ratio within the first year post-transplantation in adult renal transplant recipients, especially in European recipients (mostly Caucasian). PMID- 26039044 TI - Population-Specific Covariation between Immune Function and Color of Nesting Male Threespine Stickleback. AB - Multiple biological processes can generate sexual selection on male visual signals such as color. For example, females may prefer colorful males because those males are more readily detected (perceptual bias), or because male color conveys information about male quality and associated direct or indirect benefits to females. For example, male threespine stickleback often exhibit red throat coloration, which females prefer both because red is more visible in certain environments, and red color is correlated with male immune function and parasite load. However, not all light environments favor red nuptial coloration: more tannin-stained water tends to favor the evolution of a melanic male phenotype. Do such population differences in stickleback male color, driven by divergent light environments, lead to changes in the relationship between color and immunity? Here, we show that, within stickleback populations, multiple components of male color (brightness and hue of four body parts) are correlated with multiple immune variables (ROS production, phagocytosis rates, and lymphocyte:leukocyte ratios). Some of these color-immune associations persist across stickleback populations with very different male color patterns, whereas other color-immune associations are population-specific. Overall, lakes with red males exhibit stronger color immune covariance while melanic male populations exhibit weak if any color-immune associations. Our finding that color-immunity relationships are labile implies that any evolution of male color traits (e.g., due to female perceptual bias in a given light environment), can alter the utility of color as an indicator of male quality. PMID- 26039045 TI - Correction: eps8 regulates axonal filopodia in hippocampal neurons in response to brain-derived neurotrophic factor (BDNF). PMID- 26039046 TI - Circulating B-vitamins and smoking habits are associated with serum polyunsaturated Fatty acids in patients with suspected coronary heart disease: a cross-sectional study. AB - The long-chain polyunsaturated fatty acids are considered to be of major health importance, and recent studies indicate that their endogenous metabolism is influenced by B-vitamin status and smoking habits. We investigated the associations of circulating B-vitamins and smoking habits with serum polyunsaturated fatty acids among 1,366 patients who underwent coronary angiography due to suspected coronary heart disease at Haukeland University Hospital, Norway. Of these, 52% provided information on dietary habits by a food frequency questionnaire. Associations were assessed using partial correlation (Spearman's rho). In the total population, the concentrations of most circulating B-vitamins were positively associated with serum n-3 polyunsaturated fatty acids, but negatively with serum n-6 polyunsaturated fatty acids. However, the associations between B-vitamins and polyunsaturated fatty acids tended to be weaker in smokers. This could not be solely explained by differences in dietary intake. Furthermore, plasma cotinine, a marker of recent nicotine exposure, showed a negative relationship with serum n-3 polyunsaturated fatty acids, but a positive relationship with serum n-6 polyunsaturated fatty acids. In conclusion, circulating B-vitamins are, in contrast to plasma cotinine, generally positively associated with serum n-3 polyunsaturated fatty acids and negatively with serum n 6 polyunsaturated fatty acids in patients with suspected coronary heart disease. Further studies should investigate whether B-vitamin status and smoking habits may modify the clinical effects of polyunsaturated fatty acid intake. PMID- 26039047 TI - Pin1 Inhibitor Juglone Exerts Anti-Oncogenic Effects on LNCaP and DU145 Cells despite the Patterns of Gene Regulation by Pin1 Differing between These Cell Lines. AB - BACKGROUND: Prostate cancer initially develops in an androgen-dependent manner but, during its progression, transitions to being androgen-independent in the advanced stage. Pin1, one of the peptidyl-prolyl cis/trans isomerases, is reportedly overexpressed in prostate cancers and is considered to contribute to accelerated cell growth, which may be one of the major factors contributing to their androgen-independent growth. Thus, we investigated how Pin1 modulates the gene expressions in both androgen-dependent and androgen-independent prostate cancer cell lines using microarray analysis. In addition, the effects of Juglone, a commercially available Pin1 inhibitor were also examined. METHODS: Two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen-independent), were treated with Pin1 siRNA and its effects on gene expressions were analyzed by microarray. Individual gene regulations induced by Pin1 siRNA or the Pin1 inhibitor Juglone were examined using RT-PCR. In addition, the effects of Juglone on the growth of LNCaP and DU145 transplanted into mice were investigated. RESULTS: Microarray analysis revealed that transcriptional factors regulated by Pin1 differed markedly between LNCaP and DU145 cells, the only exception being that Nrf was regulated in the same way by Pin1 siRNA in both cell lines. Despite this marked difference in gene regulations, Pin1 siRNA and Juglone exert a strong inhibitory effect on both the LNCaP and the DU145 cell line, suppressing in vitro cell proliferation as well as tumor enlargement when transplanted into mice. CONCLUSIONS: Despite Pin1-regulated gene expressions differing between these two prostate cancer cell-lines, LNCaP (androgen-dependent) and DU145 (androgen independent), Pin1 inhibition suppresses proliferation of both cell-lines. These findings suggest the potential effectiveness of Pin1 inhibitors as therapeutic agents for prostate cancers, regardless of their androgen sensitivity. PMID- 26039048 TI - MEK and TGF-beta Inhibition Promotes Reprogramming without the Use of Transcription Factor. AB - The possibility of replacing the originally discovered and widely used DNA reprogramming transcription factors is stimulating enormous effort to identify more effective compounds that would not alter the genetic information. Here, we describe the generation of induced pluripotent stem cells (iPSc) from head derived primary culture of mouse embryonic cells using small chemical inhibitors of the MEK and TGF-beta pathways without delivery of exogenous transcription factors. These iPSc express standard pluripotency markers and retain their potential to differentiate into cells of all germ layers. Our data indicate that head-derived embryonic neural cells might have the reprogramming potential while neither the same primary cells cultivated over five passages in vitro nor a cell population derived from adult brain possesses this capacity. Our results reveal the potential for small molecules to functionally replace routinely used transcription factors and lift the veil on molecular regulation controlling pluripotency. The conditions described here could provide a platform upon which other genome non integrative and safer reprogramming processes could be developed. This work also shows novel potential for developing embryonic neural cells. PMID- 26039049 TI - Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ: A Population-Based Cohort Study. AB - IMPORTANCE: While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear. OBJECTIVE: To investigate the survival benefit of breast surgery for low-grade DCIS. DESIGN, SETTING, AND PARTICIPANTS: A retrospective longitudinal cohort study using the Surveillance, Epidemiology, and End Results (SEER) database from October 9, 2014, to January 15, 2015, at the Dana Farber/Brigham Women's Cancer Center. Between 1988 and 2011, 57,222 eligible cases of DCIS with known nuclear grade and surgery status were identified. EXPOSURES: Patients were divided into surgery and nonsurgery groups. MAIN OUTCOMES AND MEASURES: Propensity score weighting was used to balance patient backgrounds between groups. A log-rank test and multivariable Cox proportional hazards model was used to assess factors related to overall and breast cancer specific survival. RESULTS: Of 57,222 cases of DCIS identified in this study, 1169 cases (2.0%) were managed without surgery and 56,053 cases (98.0%) were managed with surgery. With a median follow-up of 72 months from diagnosis, there were 576 breast cancer-specific deaths (1.0%). The weighted 10-year breast cancer specific survival was 93.4% for the nonsurgery group and 98.5% for the surgery group (log-rank test, P < .001). The degree of survival benefit among those managed surgically differed according to nuclear grade (P = .003). For low-grade DCIS, the weighted 10-year breast cancer-specific survival of the nonsurgery group was 98.8% and that of the surgery group was 98.6% (P = .95). Multivariable analysis showed there was no significant difference in the weighted hazard ratios of breast cancer-specific survival between the surgery and nonsurgery groups for low-grade DCIS. The weighted hazard ratios of intermediate- and high-grade DCIS were significantly different (low grade: hazard ratio, 0.85; 95% CI, 0.21-3.52; intermediate grade: hazard ratio, 0.23; 95% CI, 0.14-0.42; and high grade: hazard ratio, 0.15; 95% CI, 0.11-0.23) and similar results were seen for overall survival. CONCLUSIONS AND RELEVANCE: The survival benefit of performing breast surgery for low-grade DCIS was lower than that for intermediate- or high-grade DCIS. A prospective clinical trial is warranted to investigate the feasibility of active surveillance for the management of low-grade DCIS. PMID- 26039050 TI - Correction: ex situ conservation priorities for the wild relatives of potato (solanum L. Section petota). PMID- 26039051 TI - Perinatal outcomes and unconventional natural gas operations in Southwest Pennsylvania. AB - Unconventional gas drilling (UGD) has enabled extraordinarily rapid growth in the extraction of natural gas. Despite frequently expressed public concern, human health studies have not kept pace. We investigated the association of proximity to UGD in the Marcellus Shale formation and perinatal outcomes in a retrospective cohort study of 15,451 live births in Southwest Pennsylvania from 2007-2010. Mothers were categorized into exposure quartiles based on inverse distance weighted (IDW) well count; least exposed mothers (first quartile) had an IDW well count less than 0.87 wells per mile, while the most exposed (fourth quartile) had 6.00 wells or greater per mile. Multivariate linear (birth weight) or logistical (small for gestational age (SGA) and prematurity) regression analyses, accounting for differences in maternal and child risk factors, were performed. There was no significant association of proximity and density of UGD with prematurity. Comparison of the most to least exposed, however, revealed lower birth weight (3323 +/- 558 vs 3344 +/- 544 g) and a higher incidence of SGA (6.5 vs 4.8%, respectively; odds ratio: 1.34; 95% confidence interval: 1.10-1.63). While the clinical significance of the differences in birth weight among the exposure groups is unclear, the present findings further emphasize the need for larger studies, in regio-specific fashion, with more precise characterization of exposure over an extended period of time to evaluate the potential public health significance of UGD. PMID- 26039052 TI - Correction: chronic traumatic encephalopathy in contact sports: a systematic review of all reported pathological cases. PMID- 26039053 TI - Perceptions and attitudes of health professionals in kenya on national health care resource allocation mechanisms: a structural equation modeling. AB - BACKGROUND: Health care resource allocation is key towards attaining equity in the health system. However, health professionals' perceived impact and attitude towards health care resource allocation in Sub-Saharan Africa is unknown; furthermore, they occupy a position which makes them notice the impact of different policies in their health system. This study explored perceptions and attitudes of health professionals in Kenya on health care resource allocation mechanism. METHOD: We conducted a survey of a representative sample of 341 health professionals in Moi Teaching and Referral Hospital from February to April 2012, consisting of over 3000 employees. We assessed health professionals' perceived impact and attitudes on health care resource allocation mechanism in Kenya. We used structural equation modeling and applied a Confirmatory Factor Analysis using Robust Maximum Likelihood estimation procedure to test the hypothesized model. RESULTS: We found that the allocation mechanism was negatively associated with their perceived positive impact (-1.04, p < .001), health professionals' satisfaction (-0.24, p < .01), and professionals' attitudes (-1.55, p < .001) while it was positively associated with perceived negative impact (1.14, p < .001). Perceived positive impact of the allocation mechanism was negatively associated with their overall satisfaction (-0.08) and attitude (-0.98) at p < .001, respectively. Furthermore, overall satisfaction was negatively associated with attitude (-1.10, p <.001). On the other hand, perceived negative impact of the allocation was positively associated with overall satisfaction (0.29, p <.001) but was not associated with attitude. CONCLUSION: The result suggests that health care resource allocation mechanism has a negative effect towards perceptions, attitudes and overall satisfaction of health professionals who are at the frontline in health care. These findings can serve as a crucial reference for policymakers as the Kenyan health system move towards devolving the system of governance. PMID- 26039054 TI - Correction: Refugia Persistence of Qinghai-Tibetan Plateau by the Cold-Tolerant Bird Tetraogallus tibetanus (Galliformes: Phasianidae). PMID- 26039055 TI - RNA Interference-Guided Targeting of Hepatitis C Virus Replication with Antisense Locked Nucleic Acid-Based Oligonucleotides Containing 8-oxo-dG Modifications. AB - The inhibitory potency of an antisense oligonucleotide depends critically on its design and the accessibility of its target site. Here, we used an RNA interference-guided approach to select antisense oligonucleotide target sites in the coding region of the highly structured hepatitis C virus (HCV) RNA genome. We modified the conventional design of an antisense oligonucleotide containing locked nucleic acid (LNA) residues at its termini (LNA/DNA gapmer) by inserting 8 oxo-2'-deoxyguanosine (8-oxo-dG) residues into the central DNA region. Obtained compounds, designed with the aim to analyze the effects of 8-oxo-dG modifications on the antisense oligonucleotides, displayed a unique set of properties. Compared to conventional LNA/DNA gapmers, the melting temperatures of the duplexes formed by modified LNA/DNA gapmers and DNA or RNA targets were reduced by approximately 1.6-3.3 degrees C per modification. Comparative transfection studies showed that small interfering RNA was the most potent HCV RNA replication inhibitor (effective concentration 50 (EC50): 0.13 nM), whereas isosequential standard and modified LNA/DNA gapmers were approximately 50-fold less efficient (EC50: 5.5 and 7.1 nM, respectively). However, the presence of 8-oxo-dG residues led to a more complete suppression of HCV replication in transfected cells. These modifications did not affect the efficiency of RNase H cleavage of antisense oligonucleotide:RNA duplexes but did alter specificity, triggering the appearance of multiple cleavage products. Moreover, the incorporation of 8-oxo-dG residues increased the stability of antisense oligonucleotides of different configurations in human serum. PMID- 26039056 TI - Genomic Comparison of the Closely-Related Salmonella enterica Serovars Enteritidis, Dublin and Gallinarum. AB - The Salmonella enterica serovars Enteritidis, Dublin, and Gallinarum are closely related but differ in virulence and host range. To identify the genetic elements responsible for these differences and to better understand how these serovars are evolving, we sequenced the genomes of Enteritidis strain LK5 and Dublin strain SARB12 and compared these genomes to the publicly available Enteritidis P125109, Dublin CT 02021853 and Dublin SD3246 genome sequences. We also compared the publicly available Gallinarum genome sequences from biotype Gallinarum 287/91 and Pullorum RKS5078. Using bioinformatic approaches, we identified single nucleotide polymorphisms, insertions, deletions, and differences in prophage and pseudogene content between strains belonging to the same serovar. Through our analysis we also identified several prophage cargo genes and pseudogenes that affect virulence and may contribute to a host-specific, systemic lifestyle. These results strongly argue that the Enteritidis, Dublin and Gallinarum serovars of Salmonella enterica evolve by acquiring new genes through horizontal gene transfer, followed by the formation of pseudogenes. The loss of genes necessary for a gastrointestinal lifestyle ultimately leads to a systemic lifestyle and niche exclusion in the host-specific serovars. PMID- 26039057 TI - Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease. AB - To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal), intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios) at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL) and maximally tolerated doses (MTD) in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited >=40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg/kg. The predicted MTD in human female is 0.37mg/kg. In male rats the NOAEL and MTD were less than those determined for female. Outcomes of these PK/PD studies predict a safe and efficacious dose range for initial clinical trials of allopregnanolone for Alzheimer's disease. These findings have translational relevance to multiple neurodegenerative conditions. PMID- 26039058 TI - MtgA Deletion-Triggered Cell Enlargement of Escherichia coli for Enhanced Intracellular Polyester Accumulation. AB - Bacterial polyester polyhydroxyalkanoates (PHAs) have been produced in engineered Escherichia coli, which turned into an efficient and versatile platform by applying metabolic and enzyme engineering approaches. The present study aimed at drawing out the latent potential of this organism using genome-wide mutagenesis. To meet this goal, a transposon-based mutagenesis was carried out on E. coli, which was transformed to produce poly(lactate-co-3-hydroxybutyrate) from glucose. A high-throughput screening of polymer-accumulating cells on Nile red-containing plates isolated one mutant that produced 1.8-fold higher quantity of polymer without severe disadvantages in the cell growth and monomer composition of the polymer. The transposon was inserted into the locus within the gene encoding MtgA that takes part, as a non-lethal component, in the formation of the peptidoglycan backbone. Accordingly, the mtgA-deleted strain E. coli JW3175, which was a derivate of superior PHA-producing strain BW25113, was examined for polymer production, and exhibited an enhanced accumulation of the polymer (7.0 g/l) compared to the control (5.2 g/l). Interestingly, an enlargement in cell width associated with polymer accumulation was observed in this strain, resulting in a 1.6-fold greater polymer accumulation per cell compared to the control. This result suggests that the increase in volumetric capacity for accumulating intracellular material contributed to the enhanced polymer production. The mtgA deletion should be combined with conventional engineering approaches, and thus, is a promising strategy for improved production of intracellularly accumulated biopolymers. PMID- 26039061 TI - Correction: Finite Element Analysis of the Cingulata Jaw: An Ecomorphological Approach to Armadillo's Diets. PMID- 26039059 TI - Circadian Dependence of Infarct Size and Acute Heart Failure in ST Elevation Myocardial Infarction. AB - OBJECTIVES: There are conflicting data on the relationship between the time of symptom onset during the 24-hour cycle (circadian dependence) and infarct size in ST-elevation myocardial infarction (STEMI). Moreover, the impact of this circadian pattern of infarct size on clinical outcomes is unknown. We sought to study the circadian dependence of infarct size and its impact on clinical outcomes in STEMI. METHODS: We studied 6,710 consecutive patients hospitalized for STEMI from 2006 to 2009 in a tropical climate with non-varying day-night cycles. We categorized the time of symptom onset into four 6-hour intervals: midnight-6:00 A.M., 6:00 A.M.-noon, noon-6:00 P.M. and 6:00 P.M.-midnight. We used peak creatine kinase as a surrogate marker of infarct size. RESULTS: Midnight-6:00 A.M patients had the highest prevalence of diabetes mellitus (P = 0.03), more commonly presented with anterior MI (P = 0.03) and received percutaneous coronary intervention less frequently, as compared with other time intervals (P = 0.03). Adjusted mean peak creatine kinase was highest among midnight-6:00 A.M. patients and lowest among 6:00 A.M.-noon patients (2,590.8+/ 2,839.1 IU/L and 2,336.3+/-2,386.6 IU/L, respectively, P = 0.04). Midnight-6:00 A.M patients were at greatest risk of acute heart failure (P<0.001), 30-day mortality (P = 0.03) and 1-year mortality (P = 0.03), while the converse was observed in 6:00 A.M.-noon patients. After adjusting for diabetes, infarct location and performance of percutaneous coronary intervention, circadian variations in acute heart failure incidence remained strongly significant (P = 0.001). CONCLUSION: We observed a circadian peak and nadir in infarct size during STEMI onset from midnight-6:00A.M and 6:00A.M.-noon respectively. The peak and nadir incidence of acute heart failure paralleled this circadian pattern. Differences in diabetes prevalence, infarct location and mechanical reperfusion may account partly for the observed circadian pattern of infarct size and acute heart failure. PMID- 26039060 TI - Reliable Screening of Dye Phototoxicity by Using a Caenorhabditis elegans Fast Bioassay. AB - Phototoxicity consists in the capability of certain innocuous molecules to become toxic when subjected to suitable illumination. In order to discover new photoactive drugs or characterize phototoxic pollutants, it would be advantageous to use simple biological tests of phototoxicy. In this work, we present a pilot screening of 37 dyes to test for phototoxic effects in the roundworm Caenorhabditis elegans. Populations of this nematode were treated with different dyes, and subsequently exposed to 30 min of white light. Behavioral outcomes were quantified by recording the global motility using an infrared tracking device (WMicrotracker). Of the tested compounds, 17 dyes were classified as photoactive, being phloxine B, primuline, eosin Y, acridine orange and rose Bengal the most phototoxic. To assess photoactivity after uptake, compounds were retested after washing them out of the medium before light irradiation. Dye uptake into the worms was also analyzed by staining or fluorescence. All the positive drugs were incorporated by animals and produced phototoxic effects after washing. We also tested the stress response being triggered by the treatments through reporter strains. Endoplasmic reticulum stress response (hsp-4::GFP strain) was activated by 22% of phototoxic dyes, and mitochondrial stress response (hsp-6::GFP strain) was induced by 16% of phototoxic dyes. These results point to a phototoxic perturbation of the protein functionality and an oxidative stress similar to that reported in cell cultures. Our work shows for the first time the feasibility of C. elegans for running phototoxic screenings and underscores its application on photoactive drugs and environmental pollutants assessment. PMID- 26039062 TI - Incidence of Parental Support and Pressure on Their Children's Motivational Processes towards Sport Practice Regarding Gender. AB - Grounded in Self-Determination Theory, structural equation modeling (SEM) with the aim of examining how parental support/pressure could influence their children's motivational processes in sport was conducted, as well as the models' differences in operability regarding gender. The sample size was 321 children ranging in age from 10 to 16 years old who were athletes from Extremadura, and 321 parents (included only the father or mother more involved with the sport of his or her child). 175 participants were male and 146 were female from individual (n = 130), and team sports (n=191). A questionnaire was conducted to assess parental perception of support/pressure and another questionnaire was conducted to measure satisfaction of basic psychological needs, type of motivation and enjoyment/boredom showed by their children towards sport practice. Results revealed that parental pressure negatively predicted satisfaction of the basic psychological needs. It also emerged as a strong positive predictor of intrinsic motivation and negative predictor of amotivation. Moreover, intrinsic motivation emerged as positive predictor of enjoyment and a negative predictor of boredom, whereas amotivation positively predicted boredom and negatively predicted enjoyment. Furthermore, results showed there were mean differences by gender: male athletes perceived greater parental pressure. Hence, it is necessary to decrease parental pressure towards their children in sport, with the aim of making them more motivated and enjoy, promoting positive consequences. PMID- 26039063 TI - In vitro model for studying esophageal epithelial differentiation and allergic inflammatory responses identifies keratin involvement in eosinophilic esophagitis. AB - Epithelial differentiation is an essential physiological process that imparts mechanical strength and barrier function to squamous epithelia. Perturbation of this process can give rise to numerous human diseases, such as atopic dermatitis, in which antigenic stimuli can penetrate the weakened epithelial barrier to initiate the allergic inflammatory cascade. We recently described a simplified air-liquid interface (ALI) culture system that facilitates the study of differentiated squamous epithelia in vitro. Herein, we use RNA sequencing to define the genome-wide transcriptional changes that occur within the ALI system during epithelial differentiation and in response to allergic inflammation. We identified 2,191 and 781 genes that were significantly altered upon epithelial differentiation or dysregulated in the presence of interleukin 13 (IL-13), respectively. Notably, 286 genes that were modified by IL-13 in the ALI system overlapped with the gene signature present within the inflamed esophageal tissue from patients with eosinophilic esophagitis (EoE), an allergic inflammatory disorder of the esophagus that is characterized by elevated IL-13 levels, altered epithelial differentiation, and pro-inflammatory gene expression. Pathway analysis of these overlapping genes indicated enrichment in keratin genes; for example, the gene encoding keratin 78, an uncharacterized type II keratin, was upregulated during epithelial differentiation (45-fold) yet downregulated in response to IL-13 and in inflamed esophageal tissue from patients. Thus, our findings delineate an in vitro experimental system that models epithelial differentiation that is dynamically regulated by IL-13. Using this system and analyses of patient tissues, we identify an altered expression profile of novel keratin differentiation markers in response to IL-13 and disease activity, substantiating the potential of this combined approach to identify relevant molecular processes that contribute to human allergic inflammatory disease. PMID- 26039064 TI - New small molecules targeting apoptosis and cell viability in osteosarcoma. AB - Despite the option of multimodal therapy in the treatment strategies of osteosarcoma (OS), the most common primary malignant bone tumor, the standard therapy has not changed over the last decades and still involves multidrug chemotherapy and radical surgery. Although successfully applied in many patients a large number of patients eventually develop recurrent or metastatic disease in which current therapeutic regimens often lack efficacy. Thus, new therapeutic strategies are urgently needed. In this study, we performed a phenotypic high throughput screening campaign using a 25,000 small-molecule diversity library to identify new small molecules selectively targeting osteosarcoma cells. We could identify two new small molecules that specifically reduced cell viability in OS cell lines U2OS and HOS, but affected neither hepatocellular carcinoma cell line (HepG2) nor primary human osteoblasts (hOB). In addition, the two compounds induced caspase 3 and 7 activity in the U2OS cell line. Compared to conventional drugs generally used in OS treatment such as doxorubicin, we indeed observed a greater sensitivity of OS cell viability to the newly identified compounds compared to doxorubicin and staurosporine. The p53-negative OS cell line Saos-2 almost completely lacked sensitivity to compound treatment that could indicate a role of p53 in the drug response. Taken together, our data show potential implications for designing more efficient therapies in OS. PMID- 26039066 TI - A gigantic shark from the lower cretaceous duck creek formation of Texas. AB - Three large lamniform shark vertebrae are described from the Lower Cretaceous of Texas. We interpret these fossils as belonging to a single individual with a calculated total body length of 6.3 m. This large individual compares favorably to another shark specimen from the roughly contemporaneous Kiowa Shale of Kansas. Neither specimen was recovered with associated teeth, making confident identification of the species impossible. However, both formations share a similar shark fauna, with Leptostyrax macrorhiza being the largest of the common lamniform sharks. Regardless of its actual identification, this new specimen provides further evidence that large-bodied lamniform sharks had evolved prior to the Late Cretaceous. PMID- 26039065 TI - Temporal expression profiling identifies pathways mediating effect of causal variant on phenotype. AB - Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants' effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1 pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression. PMID- 26039068 TI - An Iterative Leave-One-Out Approach to Outlier Detection in RNA-Seq Data. AB - The discrete data structure and large sequencing depth of RNA sequencing (RNA seq) experiments can often generate outlier read counts in one or more RNA samples within a homogeneous group. Thus, how to identify and manage outlier observations in RNA-seq data is an emerging topic of interest. One of the main objectives in these research efforts is to develop statistical methodology that effectively balances the impact of outlier observations and achieves maximal power for statistical testing. To reach that goal, strengthening the accuracy of outlier detection is an important precursor. Current outlier detection algorithms for RNA-seq data are executed within a testing framework and may be sensitive to sparse data and heavy-tailed distributions. Therefore, we propose a univariate algorithm that utilizes a probabilistic approach to measure the deviation between an observation and the distribution generating the remaining data and implement it within in an iterative leave-one-out design strategy. Analyses of real and simulated RNA-seq data show that the proposed methodology has higher outlier detection rates for both non-normalized and normalized negative binomial distributed data. PMID- 26039067 TI - Functional coupling of duplex translocation to DNA cleavage in a type I restriction enzyme. AB - Type I restriction-modification enzymes are multifunctional heteromeric complexes with DNA cleavage and ATP-dependent DNA translocation activities located on motor subunit HsdR. Functional coupling of DNA cleavage and translocation is a hallmark of the Type I restriction systems that is consistent with their proposed role in horizontal gene transfer. DNA cleavage occurs at nonspecific sites distant from the cognate recognition sequence, apparently triggered by stalled translocation. The X-ray crystal structure of the complete HsdR subunit from E. coli plasmid R124 suggested that the triggering mechanism involves interdomain contacts mediated by ATP. In the present work, in vivo and in vitro activity assays and crystal structures of three mutants of EcoR124I HsdR designed to probe this mechanism are reported. The results indicate that interdomain engagement via ATP is indeed responsible for signal transmission between the endonuclease and helicase domains of the motor subunit. A previously identified sequence motif that is shared by the RecB nucleases and some Type I endonucleases is implicated in signaling. PMID- 26039069 TI - Inhibitory properties of cysteine protease pro-peptides from barley confer resistance to spider mite feeding. AB - C1A plant cysteine proteases are synthesized as pre-pro-enzymes that need to be processed to become active by the pro-peptide claves off from its cognate enzyme. These pro-sequences play multifunctional roles including the capacity to specifically inhibit their own as well as other C1A protease activities from diverse origin. In this study, it is analysed the potential role of C1A pro regions from barley as regulators of cysteine proteases in target phytophagous arthropods (coleopteran and acari). The in vitro inhibitory action of these pro sequences, purified as recombinant proteins, is demonstrated. Moreover, transgenic Arabidopsis plants expressing different fragments of HvPap-1 barley gene containing the pro-peptide sequence were generated and the acaricide function was confirmed by bioassays conducted with the two-spotted spider mite Tetranychus urticae. Feeding trials resulted in a significant reduction of leaf damage in the transgenic lines expressing the pro-peptide in comparison to non transformed control and strongly correlated with an increase in mite mortality. Additionally, the analysis of the expression levels of a selection of potential mite targets (proteases and protease inhibitors) revealed a mite strategy to counteract the inhibitory activity produced by the C1A barley pro-prodomain. These findings demonstrate that pro-peptides can control mite pests and could be applied as defence proteins in biotechnological systems. PMID- 26039071 TI - Correction: genetic variants associated with increased risk of malignant pleural mesothelioma: a genome-wide association study. PMID- 26039072 TI - Topology analysis of social networks extracted from literature. AB - In a world where complex networks are an increasingly important part of science, it is interesting to question how the new reading of social realities they provide applies to our cultural background and in particular, popular culture. Are authors of successful novels able to reproduce social networks faithful to the ones found in reality? Is there any common trend connecting an author's oeuvre, or a genre of fiction? Such an analysis could provide new insight on how we, as a culture, perceive human interactions and consume media. The purpose of the work presented in this paper is to define the signature of a novel's story based on the topological analysis of its social network of characters. For this purpose, an automated tool was built that analyses the dialogs in novels, identifies characters and computes their relationships in a time-dependent manner in order to assess the network's evolution over the course of the story. PMID- 26039070 TI - Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions III. AB - IMPORTANCE: National epidemiologic information from recently collected data on the new DSM-5 classification of alcohol use disorder (AUD) using a reliable, valid, and uniform data source is needed. OBJECTIVE: To present nationally representative findings on the prevalence, correlates, psychiatric comorbidity, associated disability, and treatment of DSM-5 AUD diagnoses overall and according to severity level (mild, moderate, or severe). DESIGN, SETTING, AND PARTICIPANTS: We conducted face-to-face interviews with a representative US noninstitutionalized civilian adult (>=18 years) sample (N = 36 309) as the 2012 2013 National Epidemiologic Survey on Alcohol and Related Conditions III (NESARC III). Data were collected from April 2012 through June 2013 and analyzed in October 2014. MAIN OUTCOMES AND MEASURES: Twelve-month and lifetime prevalences of AUD. RESULTS: Twelve-month and lifetime prevalences of AUD were 13.9% and 29.1%, respectively. Prevalence was generally highest for men (17.6% and 36.0%, respectively), white (14.0% and 32.6%, respectively) and Native American (19.2% and 43.4%, respectively), respondents, and younger (26.7% and 37.0%, respectively) and previously married (11.4% and 27.1%, respectively) or never married (25.0% and 35.5%, respectively) adults. Prevalence of 12-month and lifetime severe AUD was greatest among respondents with the lowest income level (1.8% and 1.5%, respectively). Significant disability was associated with 12 month and lifetime AUD and increased with the severity of AUD. Only 19.8% of respondents with lifetime AUD were ever treated. Significant associations were found between 12-month and lifetime AUD and other substance use disorders, major depressive and bipolar I disorders, and antisocial and borderline personality disorders across all levels of AUD severity, with odds ratios ranging from 1.2 (95% CI, 1.08-1.36) to 6.4 (95% CI, 5.76-7.22). Associations between AUD and panic disorder, specific phobia, and generalized anxiety disorder were modest (odds ratios ranged from 1.2 (95% CI, 1.01-1.43) to 1.4 (95% CI, 1.13-1.67) across most levels of AUD severity. CONCLUSIONS AND RELEVANCE: Alcohol use disorder defined by DSM-5 criteria is a highly prevalent, highly comorbid, disabling disorder that often goes untreated in the United States. The NESARC-III data indicate an urgent need to educate the public and policy makers about AUD and its treatment alternatives, to destigmatize the disorder, and to encourage those who cannot reduce their alcohol consumption on their own, despite substantial harm to themselves and others, to seek treatment. PMID- 26039073 TI - Effects of climate change on plant population growth rate and community composition change. AB - The impacts of climate change on forest community composition are still not well known. Although directional trends in climate change and community composition change were reported in recent years, further quantitative analyses are urgently needed. Previous studies focused on measuring population growth rates in a single time period, neglecting the development of the populations. Here we aimed to compose a method for calculating the community composition change, and to testify the impacts of climate change on community composition change within a relatively short period (several decades) based on long-term monitoring data from two plots Dinghushan Biosphere Reserve, China (DBR) and Barro Colorado Island, Panama (BCI) that are located in tropical and subtropical regions. We proposed a relatively more concise index, Slnlambda, which refers to an overall population growth rate based on the dominant species in a community. The results indicated that the population growth rate of a majority of populations has decreased over the past few decades. This decrease was mainly caused by population development. The increasing temperature had a positive effect on population growth rates and community change rates. Our results promote understanding and explaining variations in population growth rates and community composition rates, and are helpful to predict population dynamics and population responses to climate change. PMID- 26039074 TI - In Silico Analysis of the Metabolic Potential and Niche Specialization of Candidate Phylum "Latescibacteria" (WS3). AB - The "Latescibacteria" (formerly WS3), member of the Fibrobacteres-Chlorobi Bacteroidetes (FCB) superphylum, represents a ubiquitous candidate phylum found in terrestrial, aquatic, and marine ecosystems. Recently, single-cell amplified genomes (SAGs) representing the "Latescibacteria" were obtained from the anoxic monimolimnion layers of Sakinaw Lake (British Columbia, Canada), and anoxic sediments of a coastal lagoon (Etoliko lagoon, Western Greece). Here, we present a detailed in-silico analysis of the four SAGs to gain some insights on their metabolic potential and apparent ecological roles. Metabolic reconstruction suggests an anaerobic fermentative mode of metabolism, as well as the capability to degrade multiple polysaccharides and glycoproteins that represent integral components of green (Charophyta and Chlorophyta) and brown (Phaeophycaea) algae cell walls (pectin, alginate, ulvan, fucan, hydroxyproline-rich glycoproteins), storage molecules (starch and trehalose), and extracellular polymeric substances (EPSs). The analyzed SAGs also encode dedicated transporters for the uptake of produced sugars and amino acids/oligopeptides, as well as an extensive machinery for the catabolism of all transported sugars, including the production of a bacterial microcompartment (BMC) to sequester propionaldehyde, a toxic intermediate produced during fucose and rhamnose metabolism. Finally, genes for the formation of gas vesicles, flagella, type IV pili, and oxidative stress response were found, features that could aid in cellular association with algal detritus. Collectively, these results indicate that the analyzed "Latescibacteria" mediate the turnover of multiple complex organic polymers of algal origin that reach deeper anoxic/microoxic habitats in lakes and lagoons. The implications of such process on our understanding of niche specialization in microbial communities mediating organic carbon turnover in stratified water bodies are discussed. PMID- 26039075 TI - Evaluating the Impact of Test-and-Treat on the HIV Epidemic among MSM in China Using a Mathematical Model. AB - BACKGROUND: Various studies have modeled the impact of test-and-treat policies on the HIV epidemics worldwide. However, few modeling studies have taken into account China's context. To understand the potential effect of test-and-treat on the HIV epidemic among men who have sex with men (MSM) in China, we developed a mathematical model to evaluate the impact of the strategy. METHOD: Based on the natural history of the CD4 count of people living with HIV and AIDS (PLWHA), we constructed a dynamic compartmental model of HIV transmission among Chinese MSM to project the number of HIV new infections and prevalence over 10 years. We predicted the annual number of HIV new infections and the total number of MSM living with HIV and AIDS (based on Beijing data) between 2010 and 2022 under the following conditions: (1) current practice (testing rate of 50% and ART coverage of 39%); (2) both testing rate and ART coverage increasing to 70% in 2013; (3) both testing rate and ART coverage increasing to 90% in 2013; and (4) both testing rate and ART coverage increasing gradually every year until 90% since 2013. RESULTS: Based on our model, if the HIV test-and-treat policy was implemented among Chinese MSM, the total number of HIV new infections over 10 years (2013-2022) would be reduced by 50.6-70.9% compared with the current policy. When ART coverage for PLWHA increased to 58% since 2013, the 'turning point' would occur on the curve of HIV new infections by 2015. A 25% reduction in annual number of HIV new infections by 2015 might be achieved if the testing rate increased from 50% to 70% and treatment coverage for PLWHA increased to 55% since 2013. CONCLUSION: Implementation of the test-and-treat strategy may significantly reduce HIV new infections among MSM in China. Great efforts need to be made to scale up HIV testing rate and ART coverage among Chinese MSM. PMID- 26039076 TI - A Novel Innate Response of Human Corneal Epithelium to Heat-killed Candida albicans by Producing Peptidoglycan Recognition Proteins. AB - Fungal infections of the cornea can be sight-threatening and have a worse prognosis than other types of microbial corneal infections. Peptidoglycan recognition proteins (PGLYRP), which are expressed on the ocular surface, play an important role in the immune response against bacterial corneal infections by activating toll-like receptors (TLRs) or increasing phagocytosis. However, the role of PGLYRPs in innate immune response to fungal pathogens has not been investigated. In this study, we observed a significant induction of three PGLYRPs 2-4 in primary human corneal epithelial cells (HCECs) exposed to live or heat killed Candida albicans (HKCA). The C-type lectin receptor dectin-1 plays a critical role in controlling Candida albicans infections by promoting phagocytic activity and cytokine production in macrophages and dendritic cells. Here, we demonstrate that dectin-1 is expressed by normal human corneal tissue and primary HCECs. HKCA exposure increased expression of dectin-1 on HCECs at mRNA and protein levels. Interestingly, dectin-1 neutralizing antibody, IkappaB-alpha inhibitor BAY11-7082, and NF-kappaB activation inhibitor quinazoline blocked NF kappaB p65 nuclear translocation, as well as the induction of the PGLYRPs by HKCA in HCECs. Furthermore, rhPGLYRP-2 was found to suppress colony-forming units of Candida albicans in vitro. In conclusion, these findings demonstrate that dectin 1 is expressed by human corneal epithelial cells, and dectin-1/NF-kappaB signaling pathway plays an important role in regulating Candida albicans/HKCA induced PGLYRP secretion by HCECs. PMID- 26039077 TI - Minimum incidence of adult invasive pneumococcal disease in Blantyre, Malawi an urban african setting: a hospital based prospective cohort study. AB - Invasive pneumococcal disease causes substantial morbidity and mortality in Africa. Evaluating population level indirect impact on adult disease of pneumococcal conjugate vaccine (PCV) programmes in infants requires baseline population incidence rates but these are often lacking in areas with limited disease surveillance. We used hospital based blood culture and cerebrospinal fluid surveillance to calculate minimal incidence of invasive pneumococcal disease in the adult (>=15 years old) population of Blantyre, a rapidly growing urban centre in southern Malawi, in the period preceding vaccine introduction. Invasive pneumococcal disease incidence in Blantyre district was high, mean 58.1 (95% confidence interval (CI): 53.7, 62.7) per 100,000 person years and peaking among 35 to 40 year olds at 108.8 (95%CI: 89.0, 131.7) mirroring the population age prevalence of HIV infection. For pneumococcal bacteraemia in urban Blantyre, mean incidence was 60.6 (95% CI: 55.2, 66.5) per 100,000 person years, peaking among 35 to 40 year olds at 114.8 (95%CI: 90.3, 143.9). We suspected that our surveillance may under-ascertain the true burden of disease, so we used location data from bacteraemic subjects and projected population estimates to calculate local sub-district incidence, then examined the impact of community level socio demographic covariates as possible predictors of local sub-district incidence of pneumococcal and non-pneumococcal pathogenic bacteraemia. Geographic heterogeneity in incidence was marked with localised hotspots but ward level covariates apart from prison were not associated with pneumococcal bacteraemia incidence. Modelling suggests that the current sentinel surveillance system under ascertains the true burden of disease. We outline a number of challenges to surveillance for pneumococcal disease in our low-resource setting. Subsequent surveillance in the vaccine era will have to account for geographic heterogeneity when evaluating population level indirect impact of PCV13 introduction to the childhood immunisation program. PMID- 26039078 TI - The rs2237892 Polymorphism in KCNQ1 Influences Gestational Diabetes Mellitus and Glucose Levels: A Case-Control Study and Meta-Analysis. AB - OBJECTIVE: Recent genetic studies have shown that potassium voltage-gated channel, KQT-like subfamily, member1 (KCNQ1) gene is related to gestational diabetes mellitus (GDM). However, studies for the rs2237892 polymorphism in KCNQ1 and GDM remain conflicting in Asians. Furthermore, associations of this polymorphism with glucose levels during oral glucose tolerance test (OGTT) have not been described in Chinese pregnant women. The present study aimed to provide evidence for the associations of rs2237892 in KCNQ1 with GDM and glucose levels, and to systematically evaluate the effect of rs2237892 on GDM in Asians. METHODS: A case-control study on 562 women with GDM and 453 controls was conducted in Beijing, China. The association of rs2237892 with risk of GDM was analyzed using logistic regression. The associations with quantitative glucose levels were assessed using linear regression models. A meta-analysis including the present case-control study and four previously published reports in Asians was conducted. RESULTS: The rs2237892 polymorphism in KCNQ1 was associated with GDM (OR (95%CI) =1.99(1.26-3.15)). Additionally, the polymorphism was associated with levels of 1h and 2h glucose during OGTT. The pre-pregnancy BMI, age and genotypes of KCNQ1 polymorphism were independent risk factors of GDM. Subsequently, we performed a meta-analysis in Asians. In total, C-allele carriers of rs2237892 polymorphism had a 50% higher risk for GDM (OR (95%CI) =1.50(1.15-1.78)). CONCLUSION: The study demonstrated for the first time that the KCNQ1 rs2237892 polymorphism was associated with GDM and glucose levels in Chinese women. The study provides systematic evidence for the association between this polymorphism and GDM in Asians. PMID- 26039079 TI - A Single-Nucleotide Polymorphism in an Endo-1,4-beta-Glucanase Gene Controls Seed Coat Permeability in Soybean. AB - Physical dormancy, a structural feature of the seed coat known as hard seededness, is an important characteristic for adaptation of plants against unstable and unpredictable environments. To dissect the molecular basis of qHS1, a quantitative trait locus for hard seededness in soybean (Glycine max (L) Merr.), we developed a near-isogenic line (NIL) of a permeable (soft-seeded) cultivar, Tachinagaha, containing a hard-seed allele from wild soybean (G. soja) introduced by successive backcrossings. The hard-seed allele made the seed coat of Tachinagaha more rigid by increasing the amount of beta-1,4-glucans in the outer layer of palisade cells of the seed coat on the dorsal side of seeds, known to be a point of entrance of water. Fine-mapping and subsequent expression and sequencing analyses revealed that qHS1 encodes an endo-1,4-beta-glucanase. A single-nucleotide polymorphism (SNP) introduced an amino acid substitution in a substrate-binding cleft of the enzyme, possibly reducing or eliminating its affinity for substrates in permeable cultivars. Introduction of the genomic region of qHS1 from the impermeable (hard-seeded) NIL into the permeable cultivar Kariyutaka resulted in accumulation of beta-1,4-glucan in the outer layer of palisade cells and production of hard seeds. The SNP allele found in the NIL was further associated with the occurrence of hard seeds in soybean cultivars of various origins. The findings of this and previous studies may indicate that qHS1 is involved in the accumulation of beta-1,4-glucan derivatives such as xyloglucan and/or beta-(1,3)(1,4)-glucan that reinforce the impermeability of seed coats in soybean. PMID- 26039081 TI - Mental health problems in adolescence and the interpretation of unambiguous threat. AB - Aberrant threat perception has been linked to paranoia, anxiety and other mental health problems, and is widely considered to be a core, transdiagnostic feature of psychopathology. However, to date there has been only limited investigation of whether mental health problems are associated with a biased interpretation of stimuli that have explicit (as opposed to ambiguous) connotations of threat. In the present study, 41 adolescents diagnosed with a mental illness and 45 demographically matched controls were asked to provide danger ratings of stimuli normatively rated as being either low or high in potential threat. All participants were also asked to complete background measures of cognitive function, mental health and wellbeing. The results indicated that the two groups did not differ in their capacity to discriminate between low and high threat stimuli, nor did they differ in the absolute level of threat that they attributed to these stimuli. However, for the control group, the overall level of threat perceived in facial stimuli was correlated with two important indices of mental health (depression and anxiety). No associations emerged in the clinical group. These data are discussed in relation to their potential implications for the role of aberrant threat perception in transdiagnostic models of mental health. PMID- 26039082 TI - Small steps and giant leaps. AB - A study of kinesin-1 has shed new light on how motor proteins are able to move along microtubules inside cells. PMID- 26039080 TI - Roux-en-Y Gastric Bypass Alters Brain Activity in Regions that Underlie Reward and Taste Perception. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is a very effective bariatric procedure to achieve significant and sustained weight loss, yet little is known about the procedure's impact on the brain. This study examined the effects of RYGB on the brain's response to the anticipation of highly palatable versus regular food. METHODS: High fat diet-induced obese rats underwent RYGB or sham operation and were then tested for conditioned place preference (CPP) for the bacon-paired chamber, relative to the chow-paired chamber. After CPP, animals were placed in either chamber without the food stimulus, and brain-glucose metabolism (BGluM) was measured using positron emission tomography (MUPET). RESULTS: Bacon CPP was only observed in RYGB rats that had stable weight loss following surgery. BGluM assessment revealed that RYGB selectively activated regions of the right and midline cerebellum (Lob 8) involved in subjective processes related to reward or expectation. Also, bacon anticipation led to significant activation in the medial parabrachial nuclei (important in gustatory processing) and dorsomedial tegmental area (key to reward, motivation, cognition and addiction) in RYGB rats; and activation in the retrosplenial cortex (default mode network), and the primary visual cortex in control rats. CONCLUSIONS: RYGB alters brain activity in areas involved in reward expectation and sensory (taste) processing when anticipating a palatable fatty food. Thus, RYGB may lead to changes in brain activity in regions that process reward and taste-related behaviors. Specific cerebellar regions with altered metabolism following RYGB may help identify novel therapeutic targets for treatment of obesity. PMID- 26039083 TI - Cytoplasmic and Nuclear Localizations Are Important for the Hypersensitive Response Conferred by Maize Autoactive Rp1-D21 Protein. AB - Disease resistance (R) genes have been isolated from many plant species. Most encode nucleotide binding leucine-rich repeat (NLR) proteins that trigger a rapid localized programmed cell death called the hypersensitive response (HR) upon pathogen recognition. Despite their structural similarities, different NLR are distributed in a range of subcellular locations, and analogous domains play diverse functional roles. The autoactive maize NLR gene Rp1-D21 derives from an intragenic recombination between two NLR genes, Rp1-D and Rp1-dp2, and confers a HR independent of the presence of a pathogen. Rp1-D21 and its N-terminal coiled coil (CC) domain (CCD21) confer autoactive HR when transiently expressed in Nicotiana benthamiana. Rp1-D21 was predominantly localized in cytoplasm with a small amount in the nucleus, while CCD21 was localized in both nucleus and cytoplasm. Targeting of Rp1-D21 or CCD21 predominantly to either the nucleus or the cytoplasm abolished HR-inducing activity. Coexpression of Rp1-D21 or CCD21 constructs confined, respectively, to the nucleus and cytoplasm did not rescue full activity, suggesting nucleocytoplasmic movement was important for HR induction. This work emphasizes the diverse structural and subcellular localization requirements for activity found among plant NLR R genes. PMID- 26039084 TI - Secondary Analysis of the NCI-60 Whole Exome Sequencing Data Indicates Significant Presence of Propionibacterium acnes Genomic Material in Leukemia (RPMI-8226) and Central Nervous System (SF-295, SF-539, and SNB-19) Cell Lines. AB - The NCI-60 human tumor cell line panel has been used in a broad range of cancer research over the last two decades. A landmark 2013 whole exome sequencing study of this panel added an exceptional new resource for cancer biologists. The complementary analysis of the sequencing data produced by this study suggests the presence of Propionibacterium acnes genomic sequences in almost half of the datasets, with the highest abundance in the leukemia (RPMI-8226) and central nervous system (SF-295, SF-539, and SNB-19) cell lines. While the origin of these contaminating bacterial sequences remains to be determined, observed results suggest that computational control for the presence of microbial genomic material is a necessary step in the analysis of the high throughput sequencing (HTS) data. PMID- 26039086 TI - Correction: study and characterization of an ancient European flint white maize rich in anthocyanins: Millo Corvo from Galicia. PMID- 26039085 TI - Suppressing of slow magnetic relaxation in tetracoordinate Co(II) field-induced single-molecule magnet in hybrid material with ferromagnetic barium ferrite. AB - The novel field-induced single-molecule magnet based on a tetracoordinate mononuclear heteroleptic Co(II) complex involving two heterocyclic benzimidazole (bzi) and two thiocyanido ligands, [Co(bzi)2(NSC)2], (CoL4), was prepared and thoroughly characterized. The analysis of AC susceptibility data resulted in the spin reversal energy barrier U = 14.7 cm(-1), which is in good agreement with theoretical prediction, U(theor). = 20.2 cm(-1), based on axial zero-field splitting parameter D = -10.1 cm(-1) fitted from DC magnetic data. Furthermore, mutual interactions between CoL4 and ferromagnetic barium ferrite BaFe12O19 (BaFeO) in hybrid materials resulted in suppressing of slow relaxation of magnetization in CoL4 for 1:2, 1:1 and 2:1 mass ratios of CoL4 and BaFeO despite the lack of strong magnetic interactions between two magnetic phases. PMID- 26039087 TI - Climate change and the macroeconomic structure in pre-industrial europe: new evidence from wavelet analysis. AB - The relationship between climate change and the macroeconomy in pre-industrial Europe has attracted considerable attention in recent years. This study follows the combined paradigms of evolutionary economics and ecological economics, in which wavelet analysis (spectrum analysis and coherence analysis) is applied as the first attempt to examine the relationship between climate change and the macroeconomic structure in pre-industrial Europe in the frequency domain. Aside from confirming previous results, this study aims to further substantiate the association between climate change and macroeconomy by presenting new evidence obtained from the wavelet analysis. Our spectrum analysis shows a consistent and continuous frequency band of 60-80 years in the temperature, grain yield ratio, grain price, consumer price index, and real wage throughout the study period. Besides, coherence analysis shows that the macroeconomic structure is shaped more by climate change than population change. In addition, temperature is proven as a key climatic factor that influences the macroeconomic structure. The analysis reveals a unique frequency band of about 20 years (15-35 years) in the temperature in AD1600-1700, which could have contributed to the widespread economic crisis in pre-industrial Europe. Our findings may have indications in re examining the Malthusian theory. PMID- 26039088 TI - Widespread albedo decreasing and induced melting of Himalayan snow and ice in the early 21st century. AB - BACKGROUND: The widely distributed glaciers in the greater Himalayan region have generally experienced rapid shrinkage since the 1850s. As invaluable sources of water and because of their scarcity, these glaciers are extremely important. Beginning in the twenty-first century, new methods have been applied to measure the mass budget of these glaciers. Investigations have shown that the albedo is an important parameter that affects the melting of Himalayan glaciers. METHODOLOGY/PRINCIPAL FINDINGS: The surface albedo based on the Moderate Resolution Imaging Spectroradiometer (MODIS) data over the Hindu Kush, Karakoram and Himalaya (HKH) glaciers is surveyed in this study for the period 2000-2011. The general albedo trend shows that the glaciers have been darkening since 2000. The most rapid decrease in the surface albedo has occurred in the glacial area above 6000 m, which implies that melting will likely extend to snow accumulation areas. The mass-loss equivalent (MLE) of the HKH glacial area caused by surface shortwave radiation absorption is estimated to be 10.4 Gt yr-1, which may contribute to 1.2% of the global sea level rise on annual average (2003-2009). CONCLUSIONS/SIGNIFICANCE: This work probably presents a first scene depicting the albedo variations over the whole HKH glacial area during the period 2000-2011. Most rapidly decreasing in albedo has been detected in the highest area, which deserves to be especially concerned. PMID- 26039090 TI - Parameter identification of robot manipulators: a heuristic particle swarm search approach. AB - Parameter identification of robot manipulators is an indispensable pivotal process of achieving accurate dynamic robot models. Since these kinetic models are highly nonlinear, it is not easy to tackle the matter of identifying their parameters. To solve the difficulty effectively, we herewith present an intelligent approach, namely, a heuristic particle swarm optimization (PSO) algorithm, which we call the elitist learning strategy (ELS) and proportional integral derivative (PID) controller hybridized PSO approach (ELPIDSO). A specified PID controller is designed to improve particles' local and global positions information together with ELS. Parameter identification of robot manipulators is conducted for performance evaluation of our proposed approach. Experimental results clearly indicate the following findings: Compared with standard PSO (SPSO) algorithm, ELPIDSO has improved a lot. It not only enhances the diversity of the swarm, but also features better search effectiveness and efficiency in solving practical optimization problems. Accordingly, ELPIDSO is superior to least squares (LS) method, genetic algorithm (GA), and SPSO algorithm in estimating the parameters of the kinetic models of robot manipulators. PMID- 26039089 TI - Transcriptional and Post-Transcriptional Modulation of SPI1 and SPI2 Expression by ppGpp, RpoS and DksA in Salmonella enterica sv Typhimurium. AB - The expression of genes within Salmonella Pathogenicity Islands 1 and 2 (SPI1, SPI2) is required to facilitate invasion and intracellular replication respectively of S. Typhimurium in host cell lines. Control of their expression is complex and occurs via a variety of factors operating at transcriptional and post transcriptional levels in response to the environmental stimuli found within the host. Several of the factors that modulate SPI1 and SPI2 expression are involved in the redistribution or modification of RNA polymerase (RNAP) specificity. These factors include the bacterial alarmone, ppGpp, the alternative sigma factor, RpoS, and the RNAP accessory protein, DksA. In this report we show not only how these three factors modulate SPI1 and SPI2 expression but also how they contribute to the 'phased' expression of SPI1 and SPI2 during progress through late-log and stationary phase in aerobic rich broth culture conditions. In addition, we demonstrate that the expression of at least one SPI1-encoded protein, SipC is subject to DksA-dependent post-transcriptional control. PMID- 26039091 TI - Differences in the metabolic rates of exploited and unexploited fish populations: a signature of recreational fisheries induced evolution? AB - Non-random mortality associated with commercial and recreational fisheries have the potential to cause evolutionary changes in fish populations. Inland recreational fisheries offer unique opportunities for the study of fisheries induced evolution due to the ability to replicate study systems, limited gene flow among populations, and the existence of unexploited reference populations. Experimental research has demonstrated that angling vulnerability is heritable in Largemouth Bass Micropterus salmoides, and is correlated with elevated resting metabolic rates (RMR) and higher fitness. However, whether such differences are present in wild populations is unclear. This study sought to quantify differences in RMR among replicated exploited and unexploited populations of Largemouth Bass. We collected age-0 Largemouth Bass from two Connecticut drinking water reservoirs unexploited by anglers for almost a century, and two exploited lakes, then transported and reared them in the same pond. Field RMR of individuals from each population was quantified using intermittent-flow respirometry. Individuals from unexploited reservoirs had a significantly higher mean RMR (6%) than individuals from exploited populations. These findings are consistent with expectations derived from artificial selection by angling on Largemouth Bass, suggesting that recreational angling may act as an evolutionary force influencing the metabolic rates of fishes in the wild. Reduced RMR as a result of fisheries induced evolution may have ecosystem level effects on energy demand, and be common in exploited recreational populations globally. PMID- 26039093 TI - Pt Diffusion Dynamics for the Formation Cr-Pt Core-Shell Nanoparticles. AB - Layered core-shell bimetallic Cr-Pt nanoparticles were prepared by the formation and later reduction of an intermediate Pt-ion-containing supramolecular complex onto preformed Cr nanoparticles. The resultant nanoparticles were characterized by X-ray diffraction analysis, transmission electron microscopy, X-ray photoelectron spectroscopy, and aberration-corrected scanning transmission electron microscopy. The results are consistent with the presence of Pt diffusion during or after bimetallic nanoparticle formation, which has resulted in a Pt/Cr alloyed core and shell. We postulate that such Pt diffusion occurs by an electric field-assisted process according to Cabrera-Mott theory and that it originates from the low work function of the preformed oxygen-defective Cr nanoparticles and the rather large electron affinity of Pt. PMID- 26039092 TI - Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential. AB - Mitochondria play a vital role in embryo development. They are the principal site of energy production and have various other critical cellular functions. Despite the importance of this organelle, little is known about the extent of variation in mitochondrial DNA (mtDNA) between individual human embryos prior to implantation. This study investigated the biological and clinical relevance of the quantity of mtDNA in 379 embryos. These were examined via a combination of microarray comparative genomic hybridisation (aCGH), quantitative PCR and next generation sequencing (NGS), providing information on chromosomal status, amount of mtDNA, and presence of mutations in the mitochondrial genome. The quantity of mtDNA was significantly higher in embryos from older women (P=0.003). Additionally, mtDNA levels were elevated in aneuploid embryos, independent of age (P=0.025). Assessment of clinical outcomes after transfer of euploid embryos to the uterus revealed that blastocysts that successfully implanted tended to contain lower mtDNA quantities than those failing to implant (P=0.007). Importantly, an mtDNA quantity threshold was established, above which implantation was never observed. Subsequently, the predictive value of this threshold was confirmed in an independent blinded prospective study, indicating that abnormal mtDNA levels are present in 30% of non-implanting euploid embryos, but are not seen in embryos forming a viable pregnancy. NGS did not reveal any increase in mutation in blastocysts with elevated mtDNA levels. The results of this study suggest that increased mtDNA may be related to elevated metabolism and are associated with reduced viability, a possibility consistent with the 'quiet embryo' hypothesis. Importantly, the findings suggest a potential role for mitochondria in female reproductive aging and the genesis of aneuploidy. Of clinical significance, we propose that mtDNA content represents a novel biomarker with potential value for in vitro fertilisation (IVF) treatment, revealing chromosomally normal blastocysts incapable of producing a viable pregnancy. PMID- 26039095 TI - Correction: vitamin d metabolic pathway genes and pancreatic cancer risk. PMID- 26039096 TI - Monodisperse aqueous microspheres encapsulating high concentration of l-ascorbic acid: insights of preparation and stability evaluation from straight-through microchannel emulsification. AB - Stabilization of l-ascorbic acid (l-AA) is a challenging task for food and pharmaceutical industries. The study was conducted to prepare monodisperse aqueous microspheres containing enhanced concentrations of l-AA by using microchannel emulsification (MCE). The asymmetric straight-through microchannel (MC) array used here constitutes 11 * 104 MUm microslots connected to a 10 MUm circular microholes. 5-30% (w/w) l-AA was added to a Milli-Q water solution containing 2% (w/w) sodium alginate and 1% (w/w) magnesium sulfate, while the continuous phase constitutes 5% (w/w) tetraglycerol condensed ricinoleate in water-saturated decane. Monodisperse aqueous microspheres with average diameters (dav) of 18.7-20.7 MUm and coefficients of variation (CVs) below 6% were successfully prepared via MCE regardless of the l-AA concentrations applied. The collected microspheres were physically stable in terms of their dav and CV for >10 days of storage at 40 degrees C. The aqueous microspheres exhibited l-AA encapsulation efficiency exceeding 70% during the storage. PMID- 26039097 TI - Comparing Medical Costs and Use After Laparoscopic Adjustable Gastric Banding and Roux-en-Y Gastric Bypass. AB - IMPORTANCE: There is conflicting evidence about how different bariatric procedures impact health care use. OBJECTIVE: To compare the impact of laparoscopic adjustable gastric banding (AGB) and laparoscopic Roux-en-Y gastric bypass (RYGB) on health care use and costs. DESIGN, SETTING, AND PARTICIPANTS: Retrospective interrupted time series with comparison series study using a national claims data set. The data analysis was initiated in September 2011 and completed in January 2015. We identified bariatric surgery patients aged 18 to 64 years who underwent a first AGB or RYGB between 2005 and 2011. We propensity score matched 4935 AGB to 4935 RYGB patients according to baseline age group, sex, race/ethnicity, socioeconomic variables, comorbidities, year of procedure and baseline costs, emergency department (ED) visits, and hospital days. Median postoperative follow-up time was 2.5 years. MAIN OUTCOMES AND MEASURES: Quarterly and yearly total health care costs, ED visits, hospital days, and prescription drug costs. We used segmented regression to compare pre-to-post changes in level and trend of these measures in the AGB vs the RYGB groups and difference-in differences analysis to estimate the magnitude of difference by year. RESULTS: Both AGB and RYGB were associated with downward trends in costs; however, by year 3, AGB patients had total annual costs that were 16% higher than RYGB patients (P < .001; absolute change: $818; 95% CI, $278 to $1357). In postoperative years 1 and 2, AGB was associated with 27% to 29% fewer ED visits than RYGB (P < .001; absolute changes: -0.6; 95% CI, -0.9 to -0.4 and -0.4; 95% CI, -0.6 to -0.1 visits/person, respectively); however, by year 3, there were no detectable differences. Postoperative annual hospital days were not significantly different between the groups. Although both procedures lowered prescription costs, annual postoperative prescription costs were 17% to 32% higher for AGB patients than RYGB patients (P < .001). CONCLUSIONS AND RELEVANCE: Both laparoscopic AGB and RYGB were associated with flattened total health care cost trajectories but RYGB patients experienced lower total and prescription costs by 3 years postsurgery. On the other hand, RYGB was associated with increased ED visits in the 2 years after surgery. Clinicians and policymakers should weigh such differences in use and costs when making recommendations or shaping regulatory guidance about these procedures. PMID- 26039098 TI - Antineuropathic profile of N-palmitoylethanolamine in a rat model of oxaliplatin induced neurotoxicity. AB - Neurotoxicity is a main side effect of the anticancer drug oxaliplatin. The development of a neuropathic syndrome impairs quality of life and potentially results in chemotherapy dose reductions and/or early discontinuation. In the complex pattern of molecular and morphological alterations induced by oxaliplatin in the nervous system, an important activation of glia has been preclinically evidenced. N-Palmitoylethanolamine (PEA) modulates glial cells and exerts antinociceptive effects in several animal models. In order to improve the therapeutic chances for chemotherapy-dependent neuropathy management, the role of PEA was investigated in a rat model of oxaliplatin-induced neuropathy (2.4 mg kg 1 daily, intraperitoneally). On day 21, a single administration of PEA (30 mg kg 1 i.p.) was able to reduce oxaliplatin-dependent pain induced by mechanical and thermal stimuli. The repeated treatment with PEA (30 mg kg-1 daily i.p. for 21 days, from the first oxaliplatin injection) prevented lowering of pain threshold as well as increased pain on suprathreshold stimulation. Ex vivo histological and molecular analysis of dorsal root ganglia, peripheral nerves and spinal cord highlighted neuroprotective effects and glia-activation prevention induced by PEA repeated administration. The protective effect of PEA resulted in the normalization of the electrophysiological activity of the spinal nociceptive neurons. Finally, PEA did not alter the oxaliplatin-induced mortality of the human colon cancer cell line HT-29. The efficacy of PEA in neuropathic pain control and in preventing nervous tissue alteration candidates this endogenous compound as disease modifying agent. These characteristics, joined to the safety profile, suggest the usefulness of PEA in chemotherapy-induced neuropathy. PMID- 26039100 TI - Three-way analysis of spectrospatial electromyography data: classification and interpretation. AB - Classifying multivariate electromyography (EMG) data is an important problem in prosthesis control as well as in neurophysiological studies and diagnosis. With modern high-density EMG sensor technology, it is possible to capture the rich spectrospatial structure of the myoelectric activity. We hypothesize that multi way machine learning methods can efficiently utilize this structure in classification as well as reveal interesting patterns in it. To this end, we investigate the suitability of existing three-way classification methods to EMG based hand movement classification in spectrospatial domain, as well as extend these methods by sparsification and regularization. We propose to use Fourier domain independent component analysis as preprocessing to improve classification and interpretability of the results. In high-density EMG experiments on hand movements across 10 subjects, three-way classification yielded higher average performance compared with state-of-the art classification based on temporal features, suggesting that the three-way analysis approach can efficiently utilize detailed spectrospatial information of high-density EMG. Phase and amplitude patterns of features selected by the classifier in finger-movement data were found to be consistent with known physiology. Thus, our approach can accurately resolve hand and finger movements on the basis of detailed spectrospatial information, and at the same time allows for physiological interpretation of the results. PMID- 26039099 TI - Changes in cannabinoid receptors, aquaporin 4 and vimentin expression after traumatic brain injury in adolescent male mice. Association with edema and neurological deficit. AB - Traumatic brain injury (TBI) incidence rises during adolescence because during this critical neurodevelopmental period some risky behaviors increase. The purpose of this study was to assess the contribution of cannabinoid receptors (CB1 and CB2), blood brain barrier proteins (AQP4) and astrogliosis markers (vimentin) to neurological deficit and brain edema formation in a TBI weight drop model in adolescent male mice. These molecules were selected since they are known to change shortly after lesion. Here we extended their study in three different timepoints after TBI, including short (24h), early mid-term (72h) and late mid term (two weeks). Our results showed that TBI induced an increase in brain edema up to 72 h after lesion that was directly associated with neurological deficit. Neurological deficit appeared 24 h after TBI and was completely recovered two weeks after trauma. CB1 receptor expression decreased after TBI and was negatively correlated with edema formation and behavioral impairments. CB2 receptor increased after injury and was associated with high neurological deficit whereas no correlation with edema was found. AQP4 increased after TBI and was positively correlated with edema and neurological impairments as occurred with vimentin expression in the same manner. The results suggest that CB1 and CB2 differ in the mechanisms to resolve TBI and also that some of their neuroprotective effects related to the control of reactive astrogliosis may be due to the regulation of AQP4 expression on the end-feet of astrocytes. PMID- 26039101 TI - Field Flight Dynamics of Hummingbirds during Territory Encroachment and Defense. AB - Hummingbirds are known to defend food resources such as nectar sources from encroachment by competitors (including conspecifics). These competitive intraspecific interactions provide an opportunity to quantify the biomechanics of hummingbird flight performance during ecologically relevant natural behavior. We recorded the three-dimensional flight trajectories of Ruby-throated Hummingbirds defending, being chased from and freely departing from a feeder. These trajectories allowed us to compare natural flight performance to earlier laboratory measurements of maximum flight speed, aerodynamic force generation and power estimates. During field observation, hummingbirds rarely approached the maximal flight speeds previously reported from wind tunnel tests and never did so during level flight. However, the accelerations and rates of change in kinetic and potential energy we recorded indicate that these hummingbirds likely operated near the maximum of their flight force and metabolic power capabilities during these competitive interactions. Furthermore, although birds departing from the feeder while chased did so faster than freely-departing birds, these speed gains were accomplished by modulating kinetic and potential energy gains (or losses) rather than increasing overall power output, essentially trading altitude for speed during their evasive maneuver. Finally, the trajectories of defending birds were directed toward the position of the encroaching bird rather than the feeder. PMID- 26039102 TI - Alkylation of Amines with Alcohols and Amines by a Single Catalyst under Mild Conditions. AB - An efficient catalytic system for the alkylation of amines with either alcohols or amines under mild conditions has been developed, using cyclometallated iridium complexes as catalysts. The method has broad substrate scope, allowing for the synthesis of a diverse range of secondary and tertiary amines with good to excellent yields. By controlling the ratio of substrates, both mono- and bis alkylated amines can be obtained with high selectivity. In particular, methanol can be used as the alkylating reagent, affording N-methylated products selectively. A strong solvent effect is observed for the reaction. PMID- 26039103 TI - Th2 cytokines inhibit lymphangiogenesis. AB - Lymphangiogenesis is the process by which new lymphatic vessels grow in response to pathologic stimuli such as wound healing, inflammation, and tumor metastasis. It is well-recognized that growth factors and cytokines regulate lymphangiogenesis by promoting or inhibiting lymphatic endothelial cell (LEC) proliferation, migration and differentiation. Our group has shown that the expression of T-helper 2 (Th2) cytokines is markedly increased in lymphedema, and that these cytokines inhibit lymphatic function by increasing fibrosis and promoting changes in the extracellular matrix. However, while the evidence supporting a role for T cells and Th2 cytokines as negative regulators of lymphatic function is clear, the direct effects of Th2 cytokines on isolated LECs remains poorly understood. Using in vitro and in vivo studies, we show that physiologic doses of interleukin-4 (IL-4) and interleukin-13 (IL-13) have profound anti-lymphangiogenic effects and potently impair LEC survival, proliferation, migration, and tubule formation. Inhibition of these cytokines with targeted monoclonal antibodies in the cornea suture model specifically increases inflammatory lymphangiogenesis without concomitant changes in angiogenesis. These findings suggest that manipulation of anti-lymphangiogenic pathways may represent a novel and potent means of improving lymphangiogenesis. PMID- 26039104 TI - FK506-Binding Protein 10, a Potential Novel Drug Target for Idiopathic Pulmonary Fibrosis. AB - RATIONALE: Increased abundance and stiffness of the extracellular matrix, in particular collagens, is a hallmark of idiopathic pulmonary fibrosis (IPF). FK506 binding protein 10 (FKBP10) is a collagen chaperone, mutations of which have been indicated in the reduction of extracellular matrix stiffness (e.g., in osteogenesis imperfecta). OBJECTIVES: To assess the expression and function of FKBP10 in IPF. METHODS: We assessed FKBP10 expression in bleomycin-induced lung fibrosis (using quantitative reverse transcriptase-polymerase chain reaction, Western blot, and immunofluorescence), analyzed microarray data from 99 patients with IPF and 43 control subjects from a U.S. cohort, and performed Western blot analysis from 6 patients with IPF and 5 control subjects from a German cohort. Subcellular localization of FKBP10 was assessed by immunofluorescent stainings. The expression and function of FKBP10, as well as its regulation by endoplasmic reticulum stress or transforming growth factor-beta1, was analyzed by small interfering RNA-mediated loss-of-function experiments, quantitative reverse transcriptase-polymerase chain reaction, Western blot, and quantification of secreted collagens in the lung and in primary human lung fibroblasts (phLF). Effects on collagen secretion were compared with those of the drugs nintedanib and pirfenidone, recently approved for IPF. MEASUREMENTS AND MAIN RESULTS: FKBP10 expression was up-regulated in bleomycin-induced lung fibrosis and IPF. Immunofluorescent stainings demonstrated localization to interstitial (myo)fibroblasts and CD68(+) macrophages. Transforming growth factor-beta1, but not endoplasmic reticulum stress, induced FKBP10 expression in phLF. The small interfering RNA-mediated knockdown of FKBP10 attenuated expression of profibrotic mediators and effectors, including collagens I and V and alpha-smooth muscle actin, on the transcript and protein level. Importantly, loss of FKBP10 expression significantly suppressed collagen secretion by phLF. CONCLUSIONS: FKBP10 might be a novel drug target for IPF. PMID- 26039105 TI - Combination of Electromembrane Extraction and Liquid-Phase Microextraction in a Single Step: Simultaneous Group Separation of Acidic and Basic Drugs. AB - Electromembrane extraction (EME) and liquid-phase microextraction (LPME) were combined in a single step for the first time to realize simultaneous and clear group separation of basic and acidic drugs. Using 2-nitrophenyl octyl ether as the supported liquid membrane (SLM) for EME and dihexyl ether as the SLM for LPME, basic and acidic drugs were extracted and separated simultaneously from a low pH sample by EME and LPME, respectively. After 15 min of extraction, basic drugs (citalopram and sertraline) were exhaustively extracted, whereas the recoveries for acidic drugs (ketoprofen and ibuprofen) were in the range of 76% 86%. Longer extraction time provided higher recoveries for the acidic drugs, but this somewhat deteriorated the group separation. Matrices effects from the coexisting acidic drugs/basic drugs were tested, and we observed that simultaneous EME/LPME was not affected by coexisting drugs at high concentration. This approach was further investigated from human plasma. Extraction recoveries were strongly dependent on dilution of plasma with buffer and on extraction time. Finally, this simultaneous EME/LPME approach was evaluated in combination with liquid chromatography (LC)-MS. The linearity ranges for the basic and acidic drugs were 10-600 ng/mL and 1-60 MUg/mL, respectively, with R(2) > 0.997 for all analytes. The repeatability at three different levels for all analytes was less than 15%. The limits of quantification (LOQ, S/N = 10) were found to be 4.0-6.3 ng/mL and 0.6-0.9 MUg/mL for basic and acidic drugs, respectively. Simultaneous EME/LPME enabled efficient group separation of basic and acidic analytes under optimum experimental conditions for both EME and LPME. PMID- 26039107 TI - F-18-FDG PET-CT in children and young adults with Ewing sarcoma diagnosed in Norway during 2005-2012: a national population-based study. AB - BACKGROUND: To examine national imaging strategies regarding the use of F-18-FDG PET-CT in patients with Ewing sarcoma and study factors that might influence the use of PET-CT, such as tumour biology (Picci grade of operation specimen), clinical disease stage and age. METHODS: We examined the medical records including pathology and imaging of all patients below 30 years diagnosed with Ewing sarcoma in Norway in 2005-2012. RESULTS: Of 61 patients treated at one of the two national sarcoma treatment service centres (Oslo: 35, Bergen: 26), 29 patients had localized disease, 8 had tumour extending to organs nearby and 24 had metastases. Among 35 operated patients with neoadjuvant chemotherapy, 15 had Picci grades II and III (good responders) and 20 grade I (poor responders). We found a significant difference in the use of PET-CT (Oslo/Bergen 0.9 versus 2.0 scans per patient, P = 0.010) and in the use of MRI (Oslo/Bergen: eight versus 13, P = 0.006). No differences were proven for ultrasound, radiography, CT or skeletal scintigraphy. The number of PET-CTs was associated with clinical disease stage at diagnosis (P = 0.041) but not with Picci grade or age. The number of PET studies was not correlated to the number of MR studies. CONCLUSIONS: The use of PET-CT in children and young adults diagnosed with Ewing sarcoma in Norway during 2005-2012 at the two national sarcoma treatment service centres differed significantly. The use of PET-CT imaging was related to the clinical disease stage at diagnosis but unrelated to patient age and tumour biology (Picci grade). PMID- 26039108 TI - Van der Waals Epitaxy of Two-Dimensional MoS2-Graphene Heterostructures in Ultrahigh Vacuum. AB - In this work, we demonstrate direct van der Waals epitaxy of MoS2-graphene heterostructures on a semiconducting silicon carbide (SiC) substrate under ultrahigh vacuum conditions. Angle-resolved photoemission spectroscopy (ARPES) measurements show that the electronic structure of free-standing single-layer (SL) MoS2 is retained in these heterostructures due to the weak van der Waals interaction between adjacent materials. The MoS2 synthesis is based on a reactive physical vapor deposition technique involving Mo evaporation and sulfurization in a H2S atmosphere on a template consisting of epitaxially grown graphene on SiC. Using scanning tunneling microscopy, we study the seeding of Mo on this substrate and the evolution from nanoscale MoS2 islands to SL and bilayer (BL) MoS2 sheets during H2S exposure. Our ARPES measurements of SL and BL MoS2 on graphene reveal the coexistence of the Dirac states of graphene and the expected valence band of MoS2 with the band maximum shifted to the corner of the Brillouin zone at K in the SL limit. We confirm the 2D character of these electronic states via a lack of dispersion with photon energy. The growth of epitaxial MoS2-graphene heterostructures on SiC opens new opportunities for further in situ studies of the fundamental properties of these complex materials, as well as perspectives for implementing them in various device schemes to exploit their many promising electronic and optical properties. PMID- 26039109 TI - Correction: bees for development: brazilian survey reveals how to optimize stingless beekeeping. PMID- 26039110 TI - Molecular and structural analysis of Legionella DotI gives insights into an inner membrane complex essential for type IV secretion. AB - The human pathogen Legionella pneumophila delivers a large array of the effector proteins into host cells using the Dot/Icm type IVB secretion system. Among the proteins composing the Dot/Icm system, an inner membrane protein DotI is known to be crucial for the secretion function but its structure and role in type IV secretion had not been elucidated. We report here the crystal structures of the periplasmic domains of DotI and its ortholog in the conjugation system of plasmid R64, TraM. These structures reveal a striking similarity to VirB8, a component of type IVA secretion systems, suggesting that DotI/TraM is the type IVB counterpart of VirB8. We further show that DotI and its partial paralog DotJ form a stable heterocomplex. R64 TraM, encoded by the conjugative plasmid lacking DotJ ortholog, forms a homo-hexamer. The DotI-DotJ complex is distinct from the core complex, which spans both inner and outer membranes to form a substrate conduit, and seems not to stably associate with the core complex. These results give insight into VirB8-family inner membrane proteins essential for type IV secretion and aid towards understanding the molecular basis of secretion systems essential for bacterial pathogenesis. PMID- 26039112 TI - Eyes on new product development. PMID- 26039111 TI - Is Ambient Light during the High Arctic Polar Night Sufficient to Act as a Visual Cue for Zooplankton? AB - The light regime is an ecologically important factor in pelagic habitats, influencing a range of biological processes. However, the availability and importance of light to these processes in high Arctic zooplankton communities during periods of 'complete' darkness (polar night) are poorly studied. Here we characterized the ambient light regime throughout the diel cycle during the high Arctic polar night, and ask whether visual systems of Arctic zooplankton can detect the low levels of irradiance available at this time. To this end, light measurements with a purpose-built irradiance sensor and coupled all-sky digital photographs were used to characterize diel skylight irradiance patterns over 24 hours at 79 degrees N in January 2014 and 2015. Subsequent skylight spectral irradiance and in-water optical property measurements were used to model the underwater light field as a function of depth, which was then weighted by the electrophysiologically determined visual spectral sensitivity of a dominant high Arctic zooplankter, Thysanoessa inermis. Irradiance in air ranged between 1-1.5 x 10-5 MUmol photons m-2 s-1 (400-700 nm) in clear weather conditions at noon and with the moon below the horizon, hence values reflect only solar illumination. Radiative transfer modelling generated underwater light fields with peak transmission at blue-green wavelengths, with a 465 nm transmission maximum in shallow water shifting to 485 nm with depth. To the eye of a zooplankter, light from the surface to 75 m exhibits a maximum at 485 nm, with longer wavelengths (>600 nm) being of little visual significance. Our data are the first quantitative characterisation, including absolute intensities, spectral composition and photoperiod of biologically relevant solar ambient light in the high Arctic during the polar night, and indicate that some species of Arctic zooplankton are able to detect and utilize ambient light down to 20-30m depth during the Arctic polar night. PMID- 26039113 TI - Pharmacological substances in vitro in limiting growth and development of fungi Colletotrichum genera. AB - PURPOSE: The aim of the study was to determine the antimycotic effect of selected substances, povidone iodine at various concentrations and fluconazole, on the growth and development of Colletotrichum spp., which is one of the ocular pathogens. METHODS: The materials used for the study consisted of 1-spore cultures of 4 fungal species of the genus Colletotrichum: C. dematium, C. gloeosporioides, C. acutatum, and C. coccodes. The method of poisoning culture media and the method of stippling the substance onto fungal colonies were used in the study. Different concentrations of fluconazole (1%) and povidone iodine (1%, 2% and 5%) were evaluated. RESULTS: The growth of the studied fungal species was inhibited in 100% on the medium containing povidone iodine at the concentration of 1%, 2%, and 5%. After 24 h from the application of povidone iodine, a local disappearance of aerial mycelium was observed. In the case of C. coccodes, the colonies were not damaged. After 24 h from the application of fluconazole on C. dematium, C. gloeosporioides and C. acutatum colonies, slight disappearance of aerial mycelium was observed at these points. Despite dispensing the substance during the next few days, the inhibitory effect did not increase. After the application fluconazole on the C. coccodes colonies, the inhibitory effect of the preparation was not observed. CONCLUSIONS: The method of stippling of a preparation onto fungal colonies is a quick and reliable method to test many pharmacological substances. One percent, 2%, and 5% povidone iodine in culture medium is fungicidal for Colletotrichum spp. One percent fluconazole in culture medium is fungistatic for Colletotrichum spp. C. coccodes reveals the highest degree of insusceptibility to antimycotic treatment. PMID- 26039114 TI - Erratum: H7N9 avian influenza virus - search and re-search. AB - [This corrects the article DOI: 10.1038/emi.2013.18.]. PMID- 26039115 TI - Cost-effectiveness of robotic surgery for rectal cancer focusing on short-term outcomes: a propensity score-matching analysis. AB - Although the total cost of robotic surgery (RS) is known to be higher than that of laparoscopic surgery (LS), the cost-effectiveness of RS has not yet been verified. The aim of the study is to clarify the cost-effectiveness of RS compared with LS for rectal cancer.From January 2007 through December 2011, 311 and 560 patients underwent totally RS and conventional LS for rectal cancer, respectively. A propensity score-matching analysis was performed with a ratio of 1:1 to reduce the possibility of selection bias. Costs and perioperative short term outcomes in both the groups were compared. Additional costs due to readmission were also analyzed.The characteristics of the patients were not different between the 2 groups. Most perioperative outcomes were not different between the groups except for the operation time. Complications within 30 days of surgery were not significantly different. Total hospital charges and patients' bill were higher in RS than in LS. The total hospital charges for patients who recovered with or without complications were higher in RS than in LS, although their short-term outcomes were similar. In patients with complications, the postoperative course after RS appeared to be milder than that of LS. Total hospital charges for patients who were readmitted due to complications were similar between the groups.RS showed similar short-term outcomes with higher costs than LS. Therefore, cost-effectiveness focusing on short-term perioperative outcomes of RS was not demonstrated. PMID- 26039116 TI - Dermatopathic Lymphadenopathy With Increased IgG4-Positive Plasma Cells. AB - Both dermatopathic lymphadenopathy (DL) and immunoglobulin G4-related disease (IgG4-RD) are frequently complicated with allergic diseases. However, the relationship between DL and IgG4-RD is not well known. To clarify this relationship on the basis of clinical and pathological findings, including IgG4 positive (IgG4+) plasma cell infiltration in lymph nodes (LNs) of DL patients, we analyzed LNs of 11 DL patients using immunostaining of IgG, IgG4, forkhead box P3 (FOXP3), transforming growth factor (TGF)-beta, interferon (IFN)-gamma, and matrix metalloproteinase (MMP)-1, MMP-8, and MMP-13. Toluidine blue staining was also performed to identify mast cells. Of 3 patients with a high ratio of IgG4+/IgG+ cells (>40%) and elevated serum IgG4 levels, 2 developed IgG4-RD, whereas the other patient did not. Of 8 patients with a low ratio of IgG4+/IgG+ cells (<40%) or no infiltration of IgG4+ cells, 5 who could be followed did not develop IgG4-RD. The numbers of mast cells were similar to those of TGF-beta positive cells, and serial sections showed that mast cells possibly produce TGF beta. LNs of DL patients with a high ratio of IgG4+/IgG+ cells had significantly more mast cells and TGF-beta-positive cells than those of patients with a low ratio of IgG4+/IgG+ cells or no infiltration of IgG4+ cells. However, no fibrosis was observed in LNs of both groups. IFN-gamma was positive in interdigitating dendritic cells, Langerhans cells, and macrophages. MMP-1, MMP-8, or MMP-13 was expressed in macrophages. The lack of fibrosis in LNs may have been due to the production of IFN-gamma, MMP-1, MMP-8, or MMP-13. Thus, DL with increased IgG4+ cells seems to be a phenotype of IgG4-RD in LNs. PMID- 26039117 TI - Renin-Angiotensin system blockers may prolong survival of metastatic non-small cell lung cancer patients receiving erlotinib. AB - The aim of this study is to determine whether renin-angiotensin system blockers (RASBs), which include angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-2 receptor 1 blockers (ARBs), improve the overall survival (OS) of patients with metastatic non-small cell lung cancer (NSCLC).The medical charts of 117 patients with metastatic NSCLC were retrospectively assessed. Thirty-seven patients (RASB group) using RASBs during systemic treatment were compared with 80 controls (control group) who did not use RASBs following the diagnosis of NSCLC. The histological tumor subtype, performance status, age, sex, smoking status, comorbidities, other medications, chemotherapeutics (CT), and erlotinib that were received in any line of treatment were recorded. We compared the OS of the patients in the RASB and control groups.The median (+/-SD) age of the patients was 61 (+/-1) years and all patients were administered systemic treatment (CT or erlotinib). The patients in RASB group were more likely to be smokers, have hypertension and ischemic heart disease, and use erlotinib, thiazides, beta blockers, and calcium-channel blockers (P < 0.05 for all) compared with the control group. The median follow-up time was 18.9 months (range 1-102 months) for the entire group. The median follow-up period was longer for RASB group than control group (17 vs 11 months, P = 0.033). The most commonly prescribed RASB agent was valsartan (n = 12/37). At the time of the analysis, 98 (83.7%) of all patients had died. In the univariate analysis, the median OS was longer in the RASB group compared with the control group (17 [+/-4.1] vs 12 [+/-1.4] months, P = 0.016). Interestingly, further analyses revealed that RASBs significantly improved OS only if used with erlotinib concurrently (34 [+/-13.8] vs 25 [+/-5] months, P = 0.002) and the OS benefit was more attributable to ARBs because only 4 patients received ACEI and erlotinib concurrently. However, the benefit of ARBs on OS disappeared in the multivariate analysis.The use of ARBs during erlotinib treatment may prolong OS of patients with metastatic NSCLC. PMID- 26039118 TI - MDCT Evaluation of Costal Bone Lesions: Comparison of Axial, Multiplanar, and 3D Volume-Rendered Images: A Retrospective Study. AB - The aim of this retrospective study was to compare accuracies of axial, multiplanar, and volume-rendered 3-dimensional (3D) images in the diagnosis of costal bone lesions.Forty-one patients, aged from 10 to 72-years old, with costal bone lesions underwent multidetector CT (MDCT). Axial, multiplanar, and 3D-volume rendered images were reviewed by 3 reviewers for the property of the lesions (fracture, tumor, and tumor-like lesions or inflammation). In case of fracture, the diagnosis was demonstrated with the location of the fracture and the amounts of the costal bone involved. In case of a tumor or tumor-like lesions, the diagnosis was demonstrated pathological property. Final diagnosis was determined by biopsy or surgery. Diagnostic accuracy and interreviewers agreement were evaluated.For the diagnosis of fractures, average accuracy was 77%, 100%, and 100% for axial, multiplanar, and 3D-volume-rendered images, respectively. For the diagnosis of tumor and tumor-like lesions, average accuracy was 90% for axial, 96% for multiplanar, and 99% for 3D-volume-rendered images. For the diagnosis of inflammation lesions, average accuracy was 100% for all the 3 image formats. Interobserver agreement independence of imaging formats was high.Multiplanar and 3D-volume-rendered images were superior to axial images in diagnosis of fracture, tumor, and tumor-like lesions; however, for the evaluation of inflammation lesions, there were no difference by 3 image formats. PMID- 26039119 TI - Complete recovery of visual disorder following surgical resection of adenoid cystic carcinoma arising in the pterygopalatine fossa: case report and review of the literature. AB - Adenoid cystic carcinoma (ACC) arising in the pterygopalatine fossa was rare, only 3 cases have been reported. In previous literature, few authors reported whether the visual deficit could be resolved following the resection of the tumor. One patient with visual dysfunction induced by ACC arising in the pterygopalatine fossa was reported. Complete visual recovery was achieved following the operation. And the patient was satisfied with the appearance and the functional results in the follow-up. Visual loss contributed by the tumor in the pterygopalatine fossa could recover in selected patients. PMID- 26039120 TI - Deceptive muscle invasive bladder cancer recurrence with benign biopsy foci after bladder sparing treatment. AB - Most of recurrent bladder carcinoma after partial cystectomy did not cause diagnostic difficulties for urologists, because of the appearance of typical papillary in ultrasonography or cystoscopy, and could be easily confirmed by tumor biopsy. Three patients, ages from 35 to 62 years, had undergone bladder sparing treatment for muscle invasive bladder cancer, all of them had biopsy revealed benign bladder lesion at surveillance cystoscopy. However, transurethral resection of bladder tumor showed high-grade muscle invasive urothelial bladder carcinoma for these patients. Two patients were thus delayed for timely cystectomy and consequently resulted in local or distal metastasis.As a result, we recommended that timely pelvic enhanced computed tomography and transurethral resection of bladder tumor were necessary when bladder lesion occurred after partial cystectomy, avoiding the possibility of missing muscle invasive urothelial bladder carcinoma recurrence and delaying timely cystectomy. PMID- 26039121 TI - High 18F-Fluorodeoxyglucose Uptake in Adrenal Angiomyolipoma: Case Report and Review of Literature. AB - Adrenal angiomyolipoma is an extremely rare tumor, although computed tomography (CT) or magnetic resonance imaging findings of adrenal angiomyolipoma have been reported, there are no reports regarding integrated fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography ((18)F FDG PET/CT) imaging. We report a case of adrenal angiomyolipoma showing a significantly high uptake of (18)F-fluorodeoxyglucose on PET/CT study. The maximal standardized uptake value (SUV) of the lesion was 18.8. Adrenal angiomyolipoma can show an intense uptake in FDG-PET/CT, and this can easily be confused with a malignant disease. Adrenal angiomyolipoma should be considered as one of the differential diagnoses in cases of adrenal incidentaloma with intense FDG uptake. PMID- 26039122 TI - Adjuvant Chemotherapy for the Completely Resected Stage IB Nonsmall Cell Lung Cancer: A Systematic Review and Meta-Analysis. AB - Adjuvant chemotherapy is recommended for postoperative stage II-IIIB nonsmall cell lung cancer patients. However, its effect remains controversial in stage IB patients. We, therefore, performed a meta-analysis to compare the efficacy of adjuvant chemotherapy versus surgery alone in stage IB patients. Six electronic databases were searched for relevant articles. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS). The time-to-event outcomes were compared by hazard ratio using log-rank test. Sixteen eligible trials were identified. A total of 4656 patients were included and divided into 2 groups: 2338 in the chemotherapy group and 2318 in the control group (surgery only). Patients received platinum-based therapy, uracil-tegafur, or a combination of them. Our results demonstrated that patients can benefit from the adjuvant chemotherapy in terms of OS (HR 0.74 95% CI 0.63-0.88) and DFS (HR 0.64 95% CI 0.46-0.89). Patients who received 6-cycle platinum-based therapy (HR 0.45 95% CI 0.29-0.69), uracil-tegafur (HR 0.71 95% CI 0.56-0.90), or a combination of them (HR 0.51 95% CI 0.36-0.74) had better OS, but patients who received 4 or fewer cycles platinum-based therapy (HR 0.97 95% CI 0.85-1.11) did not. Moreover, 6 cycle platinum-based therapy (HR 0.29 95% CI 0.13-0.63) alone or in combination with uracil-tegafur (HR 0.44 95% CI 0.30-0.66) had advantages in DFS. However, 4 or fewer cycles of platinum-based therapy (HR 0.89 95% CI 0.76-1.04) or uracil tegafur alone (HR 1.19 95% CI 0.79-1.80) were not beneficial. Six-cycle platinum based chemotherapy can improve OS and DFS in stage IB NSCLC patients. Uracil tegafur alone or in combination with platinum-based therapy is beneficial to the patients in terms of OS, but uracil-tegafur seems to have no advantage in prolonging DFS, unless it is administered with platinum-based therapy. PMID- 26039123 TI - Malignant perivascular epithelioid cell neoplasm of the mediastinum and the lung: one case report. AB - A perivascular epithelioid cell neoplasm (PEComa) in the chest is rare, let alone in the mediastinum and lung. A 63-year-old man was admitted to our hospital with chest pain for more than 2 months and was found to have an opacity in his mediastinum and lung for 3 weeks. Enhanced chest computed tomography (CT) revealed a mass in both the left upper lobe and central anterior mediastinum. To identify the disease, a CT-guided percutaneous transthoracic needle biopsy of the upper left lung lesions was performed. The pathology result was consistent with epithelioid angiomyolipoma/PEComa. After a standard preparation for surgery, the neoplasms in the mediastinum and left lung were resected. The operative findings revealed extensive mediastinal tumor invasion in parts adjacent to the pericardium, including the mediastinal pleura, left pulmonary artery and vein, and phrenic nerve. The left lung tumor had invaded the lung membranes. The final pathologic diagnosis was malignant epithelioid angioleiomyoma in the left upper lung and mediastinum. Later, the mediastinal tumor recurred. The radiography of this case resembles left upper lobe lung cancer with mediastinal lymph node metastasis. Because this tumor lacks fat, the enhanced CT indicated that it was malignant but failed to identify it as a perivascular epithelioid cell neoplasm.This case reminds clinicians that, although most PEComa are benign, some can be malignant. As the radiology indicated, chest PEComas lack fat, which makes their preoperative diagnosis difficult. Therefore, needle biopsy is valuable for a definitive diagnosis. PMID- 26039124 TI - A coin-like peripheral small cell lung carcinoma associated with acute paraneoplastic axonal Guillain-Barre-like syndrome. AB - A 65-year-old previously healthy male heavy smoker was hospitalized with a 2-week history of progressive muscle weakness in the lower and upper extremities. After 10 days of hospitalization, urinary sphincter incompetence and fecal incontinence were added and tetraparesis was established. The computer-tomography scan examination revealed a massive right hydrothorax and multifocal solid acinar structures with peripheral localization in the left lung, which suggested pulmonary cancer. Bone marrow metastases were also suspected. Based on the examination results, the final diagnosis was acute paraneoplastic axonal Guillain Barre-like syndrome. The patient died 3 weeks after hospitalization. At autopsy, bronchopneumonia and a right hydrothorax were confirmed. Several 4 to 5-mm-sized round peripherally located white nodules were identified in the left lung, without any central tumor mass. Under microscope, a coin-shaped peripheral/subpleural small cell carcinoma was diagnosed, with generalized bone metastases. A huge thrombus in the abdominal aorta and acute pancreatitis was also seen at autopsy. This case highlights the difficulty of diagnosis of lung carcinomas and the necessity of a complex differential diagnosis of severe progressive ascending neuropathies. This is the 6th reported case of small cell lung cancer-associated acute Guillain-Barre-like syndrome and the first report about an association with a coin-like peripheral pattern. PMID- 26039125 TI - Low intensive lifestyle modification in young adults with metabolic syndrome a community-based interventional study in Taiwan. AB - The study aims to find whether a low intensity lifestyle modification (LILM) program was effective to achieve weight reduction and improves metabolic syndrome in young adults. Our study prospectively enrolled young adults aged 30 to 45 years with metabolic syndrome in northeastern Taiwan from June 1, 2008 to December 31, 2009. The participants in the intervention group attended a LILM program for 6 months, which included 4 interactive group discussion sessions and weekly phone contact with volunteer counselors. Participants in the comparison group, however, attended only 1 noninteractive session on diet and physical activity. The main outcomes measured the weight reduction and prevalence of metabolic syndrome in intervention and comparison groups. Generalized estimating equation modeling was used to analyze the effects at baseline, during the study, and postcompletion of the program. Compared with comparison group, the intervention group showed significantly greater reductions in body weight (-2.95 +/- 3.52 vs -0.76 +/- 2.76 kg, P < 0.0001) and body mass index (-1.03 +/- 1.25 vs -0.30 +/- 1.16 kg/m(2), P < 0.0001). After adjustment for potential confounders, a modest decrease in body weight resulted in a statistically significant 43.32% resolution in the prevalence of metabolic syndrome in the intervention group compared with 33.64% in the comparison group (P < 0.01).The 6 month LILM program is not only effective in weight reduction but also an efficient intervention tool of metabolic syndrome in a community setting. The program with restricted manpower and limited medical resources can be practically transferred into primary care in rural area. PMID- 26039126 TI - The prognostic effects of ventricular heart rate among patients with permanent atrial fibrillation with and without coronary artery disease: a multicenter prospective observational study. AB - Heart rate control is important among patients with either atrial fibrillation (AF) or coronary artery disease (CAD). However, the relationship between the ventricular heart rate and adverse outcomes among patients with AF and CAD remains unclear. This study aimed to assess the prognostic effects of ventricular heart rate in patients with permanent AF (permAF) and CAD. We performed a multicenter, prospective, observational study of patients with AF in China. Patients>=18 years old with permAF were included and divided into a CAD group and a non-CAD group. All patients underwent 1 year of follow-up. The primary outcome was total mortality. Cox proportional hazard models were used to evaluate the relationship between risk factors and the survival rate in the study population.A total of 852 patients (69.1+/-12.7 years old, 43.3% male, 44.7% with CAD) were included in the analysis. Patients with CAD were older, were more likely to be male and exhibited higher prevalences of hypertension, diabetes mellitus, LV dysfunction, chronic obstructive pulmonary disease (COPD) and stroke compared with patients without CAD. During the follow-up period, a higher total mortality rate was noted in the CAD group than in the non-CAD group (21.5% vs 15.5%, P = 0.023). In the patients without CAD, the lowest quartile (<=76 beats/min) exhibited the best 1-year survival rate; however, in the patients with CAD, the highest quartile (>110 beats/min) exhibited the worst survival rate. Multivariate adjusted Cox analysis indicated that age (HR 1.039, 95% CI 1.025 1.055, P < 0.001) and heart rate (P = 0.004) were each independently associated with total mortality. Patients with CAD have more risk factors, and comorbidities and higher mortality rates than patients without CAD. In the patients with permAF without CAD, a ventricular rate of <=76 beats/minute was associated with the best survival rate; however, among the patients with CAD, no increased mortality was observed unless the heart rate was >110 beats/min. PMID- 26039127 TI - An investigation into the vancomycin concentration in the cerebrospinal fluid due to vancomycin intraventricular administration in newborns: a study of 13 cases. AB - Treatment against shunt infection by transvenous antimicrobial treatment is difficult, with a high risk of relapse. Consequently, to maintain a sufficient cerebrospinal fluid (CSF) concentration, intraventricular administration is utilized in combination with the transvenous administration of vancomycin (VCM). Few studies have so far investigated the optimum administration dose for newborns and the concentration in the CSF. Therefore, we chronologically measured the VCM concentration in the CSF after VCM intraventricular administration in newborns and attempted to elucidate the optimum administration method.The participants consisted of newborns admitted to Juntendo University Neonatal intensive care unit from March 2007 to June 2011 who underwent interventricular shunting placement. VCM was intraventricularly administered to 10 patients for a total of 13 cases. The CSF concentration of VCM was chronologically measured at 12 to 120 hours following the intraventricular administration of VCM.The intraventricular administration groups with VCM of 20 (n = 6) and 10 mg (n = 2) had a high concentration in the CSF at 24 hours following administration (95-168 mg/L), with the concentration remaining high at 72 hours (13.2-72 mg/L). At the same time, in the 5 mg group (n = 5), the concentration in the CSF 24 hours following VCM administration was sufficiently maintained (33.2-62.9 mg/L), with a sufficient trough concentration still maintained at 72 hours (11.7-16.5 mg/L).The concentration in the CSF is prolonged in newborns, thus allowing a sufficient therapeutic range to be maintained even at an intraventricular administration of 5 mg. It is therefore believed that the monitoring of the CSF is very important regarding the administration interval because the VCM concentration in the CSF differs depending on the case. PMID- 26039128 TI - Impact of V-ets Erythroblastosis Virus E26 Oncogene Homolog 1 Gene Polymorphisms Upon Susceptibility to Autoimmune Diseases: A Meta-Analysis. AB - V-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1) is recognized as a gene of risk to autoimmune diseases (ADs). Two single nucleotide polymorphisms (SNPs) in ETS1 (rs1128334 G>A and rs10893872 T>C) were considered associated with ADs risk. However, the results remain conflicting.We performed a meta-analysis to evaluate more precise estimations of any relationship. We searched PubMed, OvidSP, and Chinese National Knowledge Infrastructure databases (papers published prior to September 12, 2014) and extracted data from eligible studies. Meta analysis was performed using the STATA 12.0 software. Random effect model or fixed effect model were chosen according to the study heterogeneities.A total of 11 studies including 7359 cases (9660 controls) for rs1128334 and 8 studies including 5419 cases (7122 controls) for rs10893872 were involved in this meta analysis. Overall, our results showed that there were significant associations for rs1128334 with AD risk in 5 genetic models, both in pooled analysis and in systemic lupus erythematous (SLE) subgroup, and in 3 genetic models of the uveitis subgroup. Although for rs10893872, the results showed that there were significant associations in allele model both in pooled analysis and in SLE subgroup. As a conclusion, this meta-analysis demonstrated that these 2 SNPs (rs1128334 and rs10893872) in ETS1 were associated with ADs risk. PMID- 26039129 TI - Exome-Wide Association Study Identifies New Low-Frequency and Rare UGT1A1 Coding Variants and UGT1A6 Coding Variants Influencing Serum Bilirubin in Elderly Subjects: A Strobe Compliant Article. AB - Genome-wide association studies (GWASs) have identified loci contributing to total serum bilirubin level. However, no exome-wide approaches have been performed to address this question. Using exome-wide approach, we assessed the influence of protein-coding variants on unconjugated, conjugated, and total serum bilirubin levels in a well-characterized cohort of 773 ambulatory elderly subjects from Italy. Coding variants were replicated in 227 elderly subjects from the same area. We identified 4 missense rare (minor allele frequency, MAF < 0.5%) and low-frequency (MAF, 0.5%-5%) coding variants located in the first exon of the UGT1A1 gene, which encodes for the substrate-binding domain (rs4148323 [MAF = 0.06%; p.Gly71Arg], rs144398951 [MAF = 0.06%; p.Ile215Val], rs35003977 [MAF = 0.78%; p.Val225Gly], and rs57307513 [MAF = 0.06%; p.Ser250Pro]). These variants were in strong linkage disequilibrium with 3 intronic UGT1A1 variants (rs887829, rs4148325, rs6742078), which were significantly associated with total bilirubin level (P = 2.34 * 10(-34), P = 7.02 * 10(-34), and P = 8.27 * 10(-34)), as well as unconjugated, and conjugated bilirubin levels. We also identified UGT1A6 variants in association with total (rs6759892, p.Ser7Ala, P = 1.98 * 10(-26); rs2070959, p.Thr181Ala, P = 2.87 * 10(-27); and rs1105879, p.Arg184Ser, P = 3.27 * 10(-29)), unconjugated, and conjugated bilirubin levels. All UGT1A1 intronic variants (rs887829, rs6742078, and rs4148325) and UGT1A6 coding variants (rs6759892, rs2070959, and rs1105879) were significantly associated with gallstone-related cholecystectomy risk. The UGT1A6 variant rs2070959 (p.Thr181Ala) was associated with the highest risk of gallstone-related cholecystectomy (OR, 4.58; 95% CI, 1.58-13.28; P = 3.21 * 10(-3)). Using an exome wide approach we identified coding variants on UGT1A1 and UGT1A6 genes in association with serum bilirubin level and hyperbilirubinemia risk in elderly subjects. UGT1A1 intronic single-nucleotide polymorphisms (SNPs) (rs6742078, rs887829, rs4148324) serve as proxy markers for the low-frequency and rare UGT1A1 variants, thereby providing mechanistic explanation to the relationship between UGT1A1 intronic SNPs and the UGT1A1 enzyme activity. UGT1A1 and UGT1A6 variants might be potentially associated with gallstone-related cholecystectomy risk. PMID- 26039130 TI - 99Tcm-MDP Imaging of Osteopetrosis: Case Report. AB - Osteopetrosis, also known as marble bone disease, is a clinically rare genetic disease, which represents a heterogeneous group of rare, inherited bone dysplasias that share the hallmark of abnormally increased bone density caused by osteoclast dysfunction. Hereby, the authors describe a case of osteopetrosis that showed increased diffuse radioactive uptake on whole body bone (99)Tc(m) methylene diphosphonate imaging in a 56-year-old man, which increased universal radioactive uptake on craniofacial bone imaging, and enlargement of the limb long bone near the joints with evenly symmetrical enriched distribution of radioactivity. Osteopetrosis was made which based on these features and characteristics shown on (99)Tc(m)-MDP imaging.Skeletal scintigraphy with Tc methylene diphosphonate imaging is helpful to the diagnosis of osteopetrosis. There is a characteristic of osteopetrosis different from other bone metabolic diseases. PMID- 26039131 TI - The effectiveness and safety of acupuncture for patients with Alzheimer disease: a systematic review and meta-analysis of randomized controlled trials. AB - The use of acupuncture for treating Alzheimer disease (AD) has been increasing in frequency over recent years. As more studies are conducted on the use of acupuncture for treating AD, it is necessary to re-assess the effectiveness and safety of this practice. The objective of this study was to assess the effectiveness and safety of acupuncture for treating AD. Central Register of Controlled Trials (CENTRAL), PubMed, MEDLINE, Embase, PsycINFO, Chinese Biomedicine Literature (CBM), Chinese Medical Current Content (CMCC) and China National Knowledge Infrastructure (CNKI) were searched from their inception to June 2014. Randomized controlled trials (RCTs) with AD treated by acupuncture or by acupuncture combined with 1 kind of drugs were included. Two authors extracted data independently. The continuous data were expressed as mean differences (MD) with 95% confidence intervals (CIs). Weighted MD (WMD) was used instead of standardized MD (SMD) when the same scales were used. Adverse reactions related to acupuncture were also investigated.Ten randomized controlled trials with a total of 585 participants were included in the meta-analysis. The combined results of 6 trials showed that acupuncture was better than drugs at improving scores on the Mini Mental State Examination (MMSE) scale (MD 1.05, 95% CI 0.16 1.93). Evidence from the pooled results of 3 trials showed that acupuncture plus donepezil was more effective than donepezil alone at improving the MMSE scale score (MD 2.37, 95% CI 1.53-3.21). Out of 141 clinical trials, 2 trials reported the incidence of adverse reactions related to acupuncture. Seven out of 3416 patients had adverse reactions related to acupuncture during or after treatment; the reactions were described as tolerable and not severe.Acupuncture may be more effective than drugs and may enhance the effect of drugs for treating AD in terms of improving cognitive function. Acupuncture may also be more effective than drugs at improving AD patients' ability to carry out their daily lives. Moreover, acupuncture is safe for treating people with AD. PROTOCOL REGISTRATION: PROSPERO CRD42014009619. Protocol published in BMJ-open. PMID- 26039132 TI - Rare Variants of ATG5 Are Likely to Be Associated With Chinese Patients With Systemic Lupus Erythematosus. AB - Recently, common variants within or near ATG5, which is a key autophagy gene required for the formation of autophagosomes, have been identified as a candidate gene of systemic lupus erythematosus (SLE) by several genome-wide association studies. Moreover, elevated ATG5 expression was observed in SLE as well as other autoimmune diseases. However, no significant associations between variants within ATG5 and SLE were identified in several Chinese populations. The present study was conducted to further check the genetic role of ATG5 by associating both common and rare variants of ATG5 in Chinese patients with lupus nephritis (LN), a major phenotype with poor prognosis in SLE.To detect the association of common variants of ATG5 with LN, 7 tagging single nucleotide polymorphisms (SNPs) designed in immunochip and 4 SNPs reported to be associated with SLE were genotyped in 500 LN patients and 500 healthy controls. Furthermore, direct sequencing of exons and their flanking regions in 90 LN patients, 30 SLE patients, and 60 healthy controls were performed. Functional genomic annotation was performed by using public databases.None of the 11 tagging SNPs was observed to be associated with LN. By sequencing, 13 variants were identified, including 5 common SNPs, 7 not previously described, and 1 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genome project. None of the 5 common SNPs showed significant association between patients and controls, whereas increased frequencies of rare or novel variants were observed in patients compared with healthy controls, with 6/90 in LN patients, 2/30 in SLE patients, and 1/163 in healthy controls. Although these rare variants were observed to be located in the flanking regions of exons instead of missense mutations, patients carrying them tended to have severe clinical phenotype, and in silicon analysis suggested their regulatory effects.Increased frequencies of rare variants of ATG5 were identified in patients with LN and SLE compared with healthy controls, highlighting a likely important role of rare ATG5 variants in Chinese SLE patients. PMID- 26039133 TI - Evaluation of factors associated with response to hepatitis B vaccination in patients with inflammatory bowel disease. AB - It is recommended to investigate the serology of hepatitis B virus (HBV) and vaccinate seronegative patients at the time of diagnosis in inflammatory bowel diseases (IBD). This study aimed to investigate the efficacy of HBV vaccine and factors affecting the response.In this retrospective, observational study, HBV seronegative IBD patients were administered 3 doses (at months 0, 1, and 6) recombinant 20 MUg HbsAg. Patients' demographics, IBD attributes, and treatment methods were investigated as the factors with potential impacts on vaccination outcomes.One hundred twenty-five patients with IBD were evaluated. The number of patients with Anti-HBs >10 IU/L was 71 (56.8%), and the number of patients with anti-HBs >100 IU/L was 50 (40%). Age, disease activity, Crohn disease subtype, and immunosuppressive treatment (IST) were found to have significant effects on immune response (P = 0.011, P < 0.001, P = 0.003, and P < 0.001, respectively). With multivariate analysis, age < 45 years (OR 3.1, 95% CI 1.2-8.3, P = 0.020), vaccination during remission (OR 5.6, 95% CI 2.3-14, P < 0.001), and non-IST (OR 11.1, 95% CI 2.9-43.2, P = 0.001) had favorable effects on the occurrence of adequate vaccine response.The likelihood of achieving adequate immune response with standard HBV vaccination protocol in IBD is low. Selecting vaccination protocols with more potent immunogenicity is a better approach to achieve effective vaccine response in patients with multiple unfavorable factors. PMID- 26039134 TI - Management of an ingested fish bone in the lung using video-assist thoracic surgery: a case report. AB - We report a case of lung abscess caused by an ingested fish bone that was successfully treated by minimally invasive surgery. Although cases of ingested foreign body abscess are well reported, lung abscess caused by ingested fish bone is extremely rare. To date, less than 10 similar cases have been reported in the literature. To the best of our knowledge, the case presented in this case report is the first report of this kind that was successfully treated by video-assist thoracic surgery (VATS). A 47-year-old man was admitted to department of thoracic surgery with the complaint of continues dry cough and fever. The patient accidentally swallowed a long sharp-blade-shaped fish bone 20 days before, which perforated the upper thoracic esophagus on the right and embedded in the right upper lobe.The diagnosis was verified by computed tomography scan and a video assist thoracic surgery procedure was successfully performed to treat the patient. The patient survived the esophageal perforation fortunately without involvement of great vessel injury and probable mediastinitis. This report may provide additional experience on lung abscess caused by ingested fish bones. However, it is also important to educate the public of the risks of trying to force an ingested object down into the stomach. PMID- 26039135 TI - Risk of spontaneous bacterial peritonitis associated with gastric Acid suppression. AB - The primary objective of this study was to determine the association between the use of gastric acid suppressants (GAS) and the risk of developing spontaneous bacterial peritonitis (SBP) in patients with advanced liver cirrhosis (LC). A case-control study nested within a cohort of 480,000 representatives of Taiwan National Health Insurance beneficiaries was carried out. A case was matched with 100 controls on age, gender, and index date of SBP diagnosis. GAS use was identified from the 1-year period before the index date. Conditional logistic regression analysis was used to adjust for various unbalanced covariates between users and nonusers of GAS. A total of 947 cases of SBP were identified among the 86,418 patients with advanced LC. A significant increased risk of developing SBP was found to be associated with current (within 30 days), and recent (within 30 90 day) use of 2 different classes of GAS: proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs). The confounder adjusted rate ratio (aRR) for the current use of PPIs was 2.77 (95% CI: 1.90-4.04) and H2RAs was 2.62 (95% CI: 2.00-3.42). The risk of SBP attenuated for the recent use of PPIs (aRR: 2.20, 95%CI: 1.60-3.02) or H2RAs (aRR: 1.72, 95% CI: 1.25-2.37). In addition, sensitivity analysis using hospitalized SBP as the primary outcome showed a similar risk for the current use of PPIs (aRR, 3.24; 95% CI: 2.08-5.05) and H2RAs (aRR 2.43; 95% CI 1.71-3.46). Furthermore, higher cumulative days of gastric acid suppression were associated with a higher risk of SBP (trend P < 0.0001). To conclude, exposure to GAS was associated with an increased risk of SBP in patients with advanced LC. The association was more pronounced in current PPI users compared with nonusers. PMID- 26039137 TI - A Scholarly Pathway in Quality Improvement and Patient Safety. AB - PROBLEM: There are several challenges to teaching quality improvement (QI) and patient safety material to medical students, as successful programs should combine didactic and experiential teaching methods, integrate the material into the preclinical and clinical years, and tailor the material to the schools' existing curriculum. APPROACH: The authors describe the development, implementation, and assessment of the Quality Improvement and Patient Safety (QuIPS) Scholarly Pathway-a faculty-mentored, three-year experience for students interested in gaining exposure to QI and patient safety concepts at the Medical College of Wisconsin (MCW). The QuIPS pathway capitalized on the existing structure of scholarly pathways for MCW medical students, allowing QI and patient safety to be incorporated into the existing curriculum using didactic and experiential instruction and spanning preclinical and clinical education. OUTCOMES: Student reaction to the QuIPS pathway has been favorable. Preliminary data demonstrate that student knowledge as measured by the Quality Improvement Knowledge Assessment Tool significantly increased after the first year of implementation. NEXT STEPS: A novel curriculum such as the QuIPS pathway provides an important opportunity to develop and test new assessment tools for curricula in systems-based practice and practice-based learning and improvement. The authors also hope that by bringing together local QI and patient safety experts and stakeholders during the curricular development process, they have laid the groundwork for the creation of a more pervasive curriculum that will reach all MCW students in the future. The model may be generalizable to other U.S. medical schools with scholarly pathways as well. PMID- 26039136 TI - Prevalence and Incidence of Hypertension in the General Adult Population: Results of the CARLA-Cohort Study. AB - Hypertension is a leading cause of cardiovascular disease. There are very few studies dealing with the incidence of hypertension and changes in blood pressure (BP) over time. We aimed to evaluate the prevalence and incidence of hypertension within an adult population-based cohort.The sample included 967 men and 812 women aged 45 to 83 years at baseline, 1436 subjects completed follow-up1 after 4 years and 1079 completed follow-up2 after 9 years. BP was measured according to a standardized protocol with oscillometric devices and hypertension was defined as mean systolic BP (SBP) >=140 mmHg and/or diastolic BP (DBP) >=90 mmHg and/or use of antihypertensive medication if hypertension was known. We examined prevalence and incidence of hypertension, by age and sex.The age-standardized prevalence of hypertension at baseline was 74.3% for men and 70.2% for women. The age-standardized annual incidence rate of hypertension for men was 8.6 (95% confidence interval [95% CI] 4.3-12.9) for follow-up period1 and 5.4 (95% CI 2.8 10.6) for follow-up period2 and for women 8.2 (95% CI 3.6-12.8) for follow-up1 and 5.6 (95%CI 2.7-11.4) for follow-up2. A clear decrease in SBP and DBP between baseline and follow-up1 and follow-up2 was seen, accompanied by an increase in anti-hypertensive medication consumption and a higher awareness of the condition.Hypertension prevalence and incidence in the CARLA Study appear to be elevated compared with other studies. The decrease of BP over time seems to be caused by improved hypertension control due to interventional effects of our observational study and improved health care. PMID- 26039138 TI - Bridging the Gap: A Framework and Strategies for Integrating the Quality and Safety Mission of Teaching Hospitals and Graduate Medical Education. AB - Integrating the quality and safety mission of teaching hospitals and graduate medical education (GME) is a necessary step to provide the next generation of physicians with the knowledge, skills, and attitudes they need to participate in health system improvement. Although many teaching hospital and health system leaders have made substantial efforts to improve the quality of patient care, few have fully included residents and fellows, who deliver a large portion of that care, in their efforts. Despite expectations related to the engagement of these trainees in health care quality improvement and patient safety outlined by the Accreditation Council for Graduate Medical Education in the Clinical Learning Environment Review program, a structure for approaching this integration has not been described.In this article, the authors present a framework that they hope will assist teaching hospitals in integrating residents and fellows into their quality and safety efforts and in fostering a positive clinical learning environment for education and patient care. The authors define the six essential elements of this framework-organizational culture, teaching hospital-GME alignment, infrastructure, curricular resources, faculty development, and interprofessional collaboration. They then describe the organizational characteristics required for each element and offer concrete strategies to achieve integration. This framework is meant to be a starting point for the development of robust national models of infrastructure, alignment, and collaboration between GME and health care quality and safety leaders at teaching hospitals. PMID- 26039139 TI - The Educational Model of Private Colleges of Osteopathic Medicine: Revisited for 2003-2013. AB - Trends in the development of new private colleges of osteopathic medicine (COMs) described by the author in 2003 have accelerated in the ensuing decade. During 2003 to 2013, 10 new COMs as well as 2 remote teaching sites and 4 new branch campuses at private institutions were accredited, leading to a 98% increase in the number of students enrolled in private COMs. The key features of the private COM educational model during this period were a reliance on student tuition, the establishment of health professions education programs around the medical school, the expansion of class size, the creation of branch campuses and remote teaching sites, an environment that emphasizes teaching over research, and limited involvement in facilities providing clinical services to patients. There is institutional ownership of preclinical instruction, but clinical instruction occurs in affiliated hospitals and medical institutions where students are typically taught by volunteer and/or adjunct faculty.Between 2003 and 2013, this model attracted smaller universities and organizations, which implemented the strategies of established private COMs in initiating new private COMs, branch campuses, and remote teaching sites. The new COMs have introduced changes to the osteopathic profession and private COM model by expanding to new parts of the country and establishing the first for-profit medical school accredited in the United States in modern times. They have also increased pressure on the system of osteopathic graduate medical education, as the number of funded GME positions available to their graduates is less than the need. PMID- 26039140 TI - Training health care professionals for 21st-century practice: a systematic review of educational interventions on chronic care. AB - PURPOSE: To systematically review the evidence for high-quality and effective educational strategies to train health care professionals across the education continuum on chronic disease care. METHOD: A search of English-language publications and conference proceedings was performed in November 2013 and updated in April 2014. Studies that evaluated a newly developed curriculum targeting chronic disease care with learner outcomes were included. Two primary reviewers and one adjudicating reviewer evaluated the studies and assessed their quality using the validated Medical Education Research Study Quality Instrument (MERSQI). Studies were also mapped onto elements of Wagner's chronic care model (CCM) to evaluate their use of established evidence-based models for chronic care delivery. Miller's classification of clinical competence was used to assess the quality of learner achievements for each educational intervention. RESULTS: A total of 672 articles were found for this review. Twenty-two met criteria for data extraction. The majority of studies were of moderate quality according to MERSQI scoring. Only three studies reported both learner and patient outcomes. The highest-quality studies incorporated more elements of Wagner's CCM and showed high-level learner competence according to Miller's classification. Successful interventions redesigned health care delivery systems to include team-based care, emphasized training of health care professionals on patient self-management, and included learner-based quality improvement initiatives. CONCLUSIONS: The growing number of children and adults with chronic disease necessitates improved educational interventions for health care professionals that involve evidence based models for restructuring chronic care delivery, aim for high-level learner behavioral outcomes, and evolve through quality improvement initiatives. PMID- 26039141 TI - Positioning Medical Assistants for a Greater Role in the Era of Health Reform. AB - Medical assistants (MAs) are one of the fastest-growing occupations in the United States. As of 2014 there were about 585,000 MAs in the United States, and the Bureau of Labor Statistics projected the MA workforce to grow by 29% from 2012 to 2022. The MA population is primarily female, ethnically and racially diverse, and paid about $15.01 per hour. MAs are primarily educated in private schools, many at for-profit institutions. The MA curriculum and length of training can be quite varied and can lead to uneven preparation for practice. Traditionally, the MA role has involved a limited clinical role and little involvement with team care, particularly in larger practices or clinics. Medical groups, clinics, and health systems are now taking a new look at MAs and how they can play a greater role in reforming health care delivery models. Expanded roles for MAs might include health coach, referral coordinator, disease registry manager, and health screener using protocols. In expanding MA roles, education and regulatory issues need to be addressed by the provider community including current inconsistent regulation and certification requirements and the lack of preparation for expanded roles in traditional MA training programs. MAs are well positioned to help address challenges in the health care delivery system including improving access to care while reducing overall cost. Successful model practices using MAs in expanded roles need further formal evaluation and replication across practice settings. PMID- 26039143 TI - Nanotechnologies in protein microarrays. AB - Protein microarray technology became an important research tool for study and detection of proteins, protein-protein interactions and a number of other applications. The utilization of nanoparticle-based materials and nanotechnology based techniques for immobilization allows us not only to extend the surface for biomolecule immobilization resulting in enhanced substrate binding properties, decreased background signals and enhanced reporter systems for more sensitive assays. Generally in contemporarily developed microarray systems, multiple nanotechnology-based techniques are combined. In this review, applications of nanoparticles and nanotechnologies in creating protein microarrays, proteins immobilization and detection are summarized. We anticipate that advanced nanotechnologies can be exploited to expand promising fields of proteins identification, monitoring of protein-protein or drug-protein interactions, or proteins structures. PMID- 26039142 TI - Blood-borne biomarkers of mortality risk: systematic review of cohort studies. AB - BACKGROUND: Lifespan and the proportion of older people in the population are increasing, with far reaching consequences for the social, political and economic landscape. Unless accompanied by an increase in health span, increases in age related diseases will increase the burden on health care resources. Intervention studies to enhance healthy ageing need appropriate outcome measures, such as blood-borne biomarkers, which are easily obtainable, cost-effective, and widely accepted. To date there have been no systematic reviews of blood-borne biomarkers of mortality. AIM: To conduct a systematic review to identify available blood borne biomarkers of mortality that can be used to predict healthy ageing post retirement. METHODS: Four databases (Medline, Embase, Scopus, Web of Science) were searched. We included prospective cohort studies with a minimum of two years follow up and data available for participants with a mean age of 50 to 75 years at baseline. RESULTS: From a total of 11,555 studies identified in initial searches, 23 fulfilled the inclusion criteria. Fifty-one blood borne biomarkers potentially predictive of mortality risk were identified. In total, 20 biomarkers were associated with mortality risk. Meta-analyses of mortality risk showed significant associations with C-reactive protein (Hazard ratios for all-cause mortality 1.42, p<0.001; Cancer-mortality 1.62, p<0.009; CVD-mortality 1.31, p = 0.033), N Terminal-pro brain natriuretic peptide (Hazard ratios for all-cause mortality 1.43, p<0.001; CHD-mortality 1.58, p<0.001; CVD-mortality 1.67, p<0.001) and white blood cell count (Hazard ratios for all-cause mortality 1.36, p = 0.001). There was also evidence that brain natriuretic peptide, cholesterol fractions, erythrocyte sedimentation rate, fibrinogen, granulocytes, homocysteine, intercellular adhesion molecule-1, neutrophils, osteoprotegerin, procollagen type III aminoterminal peptide, serum uric acid, soluble urokinase plasminogen activator receptor, tissue inhibitor of metalloproteinases 1 and tumour necrosis factor receptor II may predict mortality risk. There was equivocal evidence for the utility of 14 biomarkers and no association with mortality risk for CD40 ligand, cortisol, dehydroepiandrosterone, ferritin, haemoglobin, interleukin-12, monocyte chemoattractant protein 1, matrix metalloproteinase 9, myelopereoxidase, P-selectin, receptor activator of nuclear factor KappaB ligand, sex hormone binding globulin, testosterone, transferrin, and thyroid stimulating hormone and thyroxine. CONCLUSIONS: Twenty biomarkers should be prioritised as potential predictors of mortality in future studies. More studies using standardised protocols and reporting methods, and which focus on mortality rather than risk of disease or health status as an outcome, are needed. PMID- 26039144 TI - Alkaline Phosphatase-Mimicking Peptide Nanofibers for Osteogenic Differentiation. AB - Recognition of molecules and regulation of extracellular matrix synthesis are some of the functions of enzymes in addition to their catalytic activity. While a diverse array of enzyme-like materials have been developed, these efforts have largely been confined to the imitation of the chemical structure and catalytic activity of the enzymes, and it is unclear whether enzyme-mimetic molecules can also be used to replicate the matrix-regulatory roles ordinarily performed by natural enzymes. Self-assembled peptide nanofibers can provide multifunctional enzyme-mimetic properties, as the active sequences of the target enzymes can be directly incorporated into the peptides. Here, we report enhanced bone regeneration efficiency through peptide nanofibers carrying both catalytic and matrix-regulatory functions of alkaline phosphatase, a versatile enzyme that plays a critical role in bone formation by regulating phosphate homeostasis and calcifiable bone matrix formation. Histidine presenting peptide nanostructures were developed to function as phosphatases. These molecules are able to catalyze phosphate hydrolysis and serve as bone-like nodule inducing scaffolds. Alkaline phosphatase-like peptide nanofibers enabled osteogenesis for both osteoblast-like and mesenchymal cell lines. PMID- 26039145 TI - Diiodobodipy-styrylbodipy Dyads: Preparation and Study of the Intersystem Crossing and Fluorescence Resonance Energy Transfer. AB - 2,6-Diiodobodipy-styrylbodipy dyads were prepared to study the competing intersystem crossing (ISC) and the fluorescence-resonance-energy-transfer (FRET), and its effect on the photophysical property of the dyads. In the dyads, 2,6 diiodobodipy moiety was used as singlet energy donor and the spin converter for triplet state formation, whereas the styrylbodipy was used as singlet and triplet energy acceptors, thus the competition between the ISC and FRET processes is established. The photophysical properties were studied with steady-state UV-vis absorption and fluorescence spectroscopy, electrochemical characterization, and femto/nanosecond time-resolved transient absorption spectroscopies. FRET was confirmed with steady state fluorescence quenching and fluorescence excitation spectra and ultrafast transient absorption spectroscopy (kFRET = 5.0 * 10(10) s( 1)). The singlet oxygen quantum yield (PhiDelta = 0.19) of the dyad was reduced as compared with that of the reference spin converter (2,6-diiodobodipy, PhiDelta = 0.85), thus the ISC was substantially inhibited by FRET. Photoinduced intramolecular electron transfer (ET) was studied by electrochemical data and fluorescence quenching. Intermolecular triplet energy transfer was studied with nanosecond transient absorption spectroscopy as an efficient (PhiTTET = 92%) and fast process (kTTET = 5.2 * 10(4) s(-1)). These results are useful for designing organic triplet photosensitizers and for the study of the photophysical properties. PMID- 26039146 TI - Heterogeneity of ovarian theca and interstitial gland cells in mice. AB - It has been established that two developmentally and functionally distinct cell types emerge within the mammalian testis and adrenal gland throughout life. Fetal and adult types of steroidogenic cells (i.e., testicular Leydig cells and adrenocortical cells) develop in the prenatal and postnatal period, respectively. Although the ovary synthesizes steroids postnatally, the presence of fetal-type steroidogenic cells has not been described. We had previously established transgenic mouse lines in which fetal Leydig cells were labeled with an EGFP reporter gene by the FLE (fetal Leydig enhancer) of the Ad4BP/SF-1 (Nr5a1) gene. In the present study, we examined the reporter gene expression in females and found that the reporter gene is turned on in postnatal ovaries. A comparison of the expressions of the EGFP and marker genes revealed that EGFP is expressed in not all but rather a proportion of steroidogenic theca and in interstitial gland cells in the ovary. This finding was further supported by experiments using BAC transgenic mice in which reporter gene expression recapitulated endogenous Ad4BP/SF-1 gene expression. In conclusion, our observations from this study strongly suggest that ovarian theca and interstitial gland cells in mice consist of at least two cell types. PMID- 26039147 TI - A Chemical Approach for the Detection of Protein Sulfinylation. AB - Protein sulfinic acids are formed by the reaction of reactive oxygen species with protein thiols. Sulfinic acid formation has long been considered an irreversible state of oxidation and is associated with high cellular oxidative stress. Increasing evidence, however, indicates that cysteine is oxidized to sulfinic acid in cells to a greater extent, and is more controlled, than first thought. The discovery of sulfiredoxin has demonstrated that cysteine sulfinic acid can be reversed, pointing to a vast array of potential implications for redox biology. Identification of the site of protein sulfinylation is crucial in clarifying the physiological and pathological effects of post-translational modifications. Currently, the only methods for detection of sulfinic acids involve mass spectroscopy and the use of specific antibodies. However, these methodologies are not suitable for proteomic studies. Herein, we report the first probe for detection of protein sulfinylation, NO-Bio, which combines a C-nitroso warhead for rapid labeling of sulfinic acid with a biotin handle. Based on this new tool, we developed a selective two-step approach. In the first, a sulfhydryl-reactive compound is introduced to selectively block free cysteine residues. Thereafter, the sample is treated with NO-Bio to label sulfinic acids. This new technology represents a rapid, selective, and general technology for sulfinic acid detection in biological samples. As proof of our concept, we also evaluated protein sulfinylation levels in various human lung tumor tissue lysates. Our preliminary results suggest that cancer tissues generally have higher levels of sulfinylation in comparison to matched normal tissues. A new ability to monitor protein sulfinylation directly should greatly expand the impact of sulfinic acid as a post-translational modification. PMID- 26039148 TI - Tree Rings Show Recent High Summer-Autumn Precipitation in Northwest Australia Is Unprecedented within the Last Two Centuries. AB - An understanding of past hydroclimatic variability is critical to resolving the significance of recent recorded trends in Australian precipitation and informing climate models. Our aim was to reconstruct past hydroclimatic variability in semi arid northwest Australia to provide a longer context within which to examine a recent period of unusually high summer-autumn precipitation. We developed a 210 year ring-width chronology from Callitris columellaris, which was highly correlated with summer-autumn (Dec-May) precipitation (r = 0.81; 1910-2011; p < 0.0001) and autumn (Mar-May) self-calibrating Palmer drought severity index (scPDSI, r = 0.73; 1910-2011; p < 0.0001) across semi-arid northwest Australia. A linear regression model was used to reconstruct precipitation and explained 66% of the variance in observed summer-autumn precipitation. Our reconstruction reveals inter-annual to multi-decadal scale variation in hydroclimate of the region during the last 210 years, typically showing periods of below average precipitation extending from one to three decades and periods of above average precipitation, which were often less than a decade. Our results demonstrate that the last two decades (1995-2012) have been unusually wet (average summer-autumn precipitation of 310 mm) compared to the previous two centuries (average summer autumn precipitation of 229 mm), coinciding with both an anomalously high frequency and intensity of tropical cyclones in northwest Australia and the dominance of the positive phase of the Southern Annular Mode. PMID- 26039149 TI - Altered pain sensitivity in elderly women with chronic neck pain. AB - BACKGROUND: Age-related changes occur in both the peripheral and central nervous system, yet little is known about the influence of chronic pain on pain sensitivity in older persons. The aim of this study was to investigate pain sensitivity in elders with chronic neck pain compared to healthy elders. METHODS: Thirty elderly women with chronic neck pain and 30 controls were recruited. Measures of pain sensitivity included pressure pain thresholds, heat/cold pain thresholds and suprathreshold heat pain responses. The pain measures were assessed over the cervical spine and at a remote site, the tibialis anterior muscle. RESULTS: Elders with chronic neck pain had lower pressure pain threshold over the articular pillar of C5-C6 and decreased cold pain thresholds over the cervical spine and tibialis anterior muscle when compared with controls (p < 0.05). There were no between group differences in heat pain thresholds and suprathreshold heat pain responses (p > 0.05). CONCLUSION: The presence of pain hypersensitivity in elderly women with chronic neck pain appears to be dependent on types of painful stimuli. This may reflect changes in the peripheral and central nervous system with age. PMID- 26039150 TI - Coupled Geochemical Impacts of Leaking CO2 and Contaminants from Subsurface Storage Reservoirs on Groundwater Quality. AB - The leakage of CO2 and the concomitant brine from deep storage reservoirs to overlying groundwater aquifers is considered one of the major potential risks associated with geologic CO2 sequestration (GCS). In this work both batch and column experiments were conducted to determine the fate of trace metals in groundwater in the scenarios of CO2 and metal-contaminated brine leakage. The sediments for this study were from an unconsolidated sand and gravel aquifer in Kansas, containing 0-4 wt % carbonates. Cd (114 MUg/L) and As (40 MUg/L) were spiked into the reaction system to represent potential contaminants from the reservoir brine. Through this research we demonstrated that Cd and As were adsorbed on the sediments, in spite of the lowered pH due to CO2 dissolution in the groundwater. Cd concentrations in the effluent were below the Cd MCL, even for sediments without detectable carbonate to buffer the pH. Arsenic concentrations in the effluent were also significantly lower than the influent concentration, suggesting that the sediments tested have the capacity to mitigate the coupled adverse effects of CO2 leakage and brine intrusion. The mitigation capacity of sediment is a function of its geochemical properties (e.g., the presence of carbonate minerals, adsorbed As, and phosphate). PMID- 26039151 TI - Assortative mating and the reversal of gender inequality in education in europe: an agent-based model. AB - While men have always received more education than women in the past, this gender imbalance in education has turned around in large parts of the world. In many countries, women now excel men in terms of participation and success in higher education. This implies that, for the first time in history, there are more highly educated women than men reaching the reproductive ages and looking for a partner. We develop an agent-based computational model that explicates the mechanisms that may have linked the reversal of gender inequality in education with observed changes in educational assortative mating. Our model builds on the notion that individuals search for spouses in a marriage market and evaluate potential candidates based on preferences. Based on insights from earlier research, we assume that men and women prefer partners with similar educational attainment and high earnings prospects, that women tend to prefer men who are somewhat older than themselves, and that men prefer women who are in their mid twenties. We also incorporate the insight that the educational system structures meeting opportunities on the marriage market. We assess the explanatory power of our model with systematic computational experiments, in which we simulate marriage market dynamics in 12 European countries among individuals born between 1921 and 2012. In these experiments, we make use of realistic agent populations in terms of educational attainment and earnings prospects and validate model outcomes with data from the European Social Survey. We demonstrate that the observed changes in educational assortative mating can be explained without any change in male or female preferences. We argue that our model provides a useful computational laboratory to explore and quantify the implications of scenarios for the future. PMID- 26039152 TI - [Fighting viral hepatitis B and C in Africa. Focus on Benin]. AB - Despite the existence of effective means of fighting viral hepatitis B and C, they remain one of the leading causes of death in sub-Saharan Africa. The failure to take these diseases into account in national health policies in most African countries has resulted in a scarcity of information campaigns and actions for prevention, the unavailability of epidemiological indicators and data for action, and a lack both of policies to screen patients and refer them for follow-up or treatment and of training programs for health professionals in managing hepatitis. Awareness by countries and the international community is absolutely necessary to make the fight against hepatitis a public health priority. Beyond a noticeable decrease in the prevalence of hepatitis B and C and primary liver cancer, the final target is the eradication of hepatitis B, the leading cause of liver cancer worldwide, through universal vaccination of newborns within 24 hours of birth. PMID- 26039154 TI - Effect of Sex Differences on Brain Mitochondrial Function and Its Suppression by Ovariectomy and in Aged Mice. AB - Sex steroids regulate brain function in both normal and pathological states. Mitochondria are an essential target of steroids, as demonstrated by the experimental administration of 17beta-estradiol or progesterone (PROG) to ovariectomized female rodents, but the influence of endogenous sex steroids remains understudied. To address this issue, mitochondrial oxidative stress, the oxidative phosphorylation system, and brain steroid levels were analyzed under 3 different experimental sets of endocrine conditions. The first set was designed to study steroid-mediated sex differences in young male and female mice, intact and after gonadectomy. The second set concerned young female mice at 3 time points of the estrous cycle in order to analyze the influence of transient variations in steroid levels. The third set involved the evaluation of the effects of a permanent decrease in gonadal steroids in aged male and female mice. Our results show that young adult females have lower oxidative stress and a higher reduced nicotinamide adenine dinucleotide (NADH)-linked respiration rate, which is related to a higher pyruvate dehydrogenase complex activity as compared with young adult males. This sex difference did not depend on phases of the estrous cycle, was suppressed by ovariectomy but not by orchidectomy, and no longer existed in aged mice. Concomitant analysis of brain steroids showed that pregnenolone and PROG brain levels were higher in females during the reproductive period than in males and decreased with aging in females. These findings suggest that the major male/female differences in brain pregnenolone and PROG levels may contribute to the sex differences observed in brain mitochondrial function. PMID- 26039156 TI - Extension of a Highly Discriminating Topological Index. AB - A highly discriminating topological index, EAID, is generated in our laboratory. A systematic search for degeneracy was performed on a total of over 14 million structures, and no duplicate occurred. These structures are as follows: over 3.8 million alkane trees with 1-22 carbon atoms; over 0.38 million structures containing heteroatoms; over 4 million benzenoids with 1-13 benzene rings; and over 5.9 million compounds from three reality databases. However, in a search of over 20 million alkane trees with 23 and 24 carbon atoms, five and 13 duplicates occurred, respectively, and for over 20 million compounds from the ZINC database, 10 duplicates occurred. To increase the discriminating power of the index, EAID has been extended, and the resulting index is termed 2-EAID. All of the over 55 million structures mentioned above were uniquely identified by 2-EAID except for two duplicates that occurred for the ZINC database. EAID and 2-EAID are the most highly discriminating indices examined to date. Thus, the two indices possess not only theoretical significance but also potential applications. For example, they could possibly be used as a supplementary reference for CAS Registry Numbers for structure documentation. PMID- 26039155 TI - Maternal Dexamethasone Treatment Alters Tissue and Circulating Components of the Renin-Angiotensin System in the Pregnant Ewe and Fetus. AB - Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnant ewe and fetus. From 125 days of gestation (term, 145 +/- 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10-11 pm, with dexamethasone (2 * 12 mg, n = 5) or saline (n = 5) at 24-hour intervals. At 10 hours after the second injection, maternal dexamethasone treatment increased angiotensin-converting enzyme (ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment. PMID- 26039157 TI - The First Step of Amyloidogenic Aggregation. AB - The structural and dynamic characterization of the on-pathway intermediates involved in the mechanism of amyloid fibril formation is one of the major remaining biomedical challenges of our time. In addition to mature fibrils, various oligomeric structures are implicated in both the rate-limiting step of the nucleation process and the neuronal toxicity of amyloid deposition. Single molecule fluorescence spectroscopy (SMFS) is an excellent tool for extracting most of the relevant information on these molecular systems, especially advanced multiparameter approaches, such as pulsed interleaved excitation (PIE). In our investigations of an amyloidogenic SH3 domain of alpha-spectrin, we have found dynamic oligomerization, even prior to incubation. Our single-molecule PIE experiments revealed that these species are small, mostly dimeric, and exhibit a loose and dynamic molecular organization. Furthermore, these experiments have allowed us to obtain quantitative information regarding the oligomer stability. These pre-amyloidogenic oligomers may potentially serve as the first target for fibrillization-prevention strategies. PMID- 26039158 TI - Closed and Semiclosed Interhelical Structures in Membrane vs Closed and Open Structures in Detergent for the Influenza Virus Hemagglutinin Fusion Peptide and Correlation of Hydrophobic Surface Area with Fusion Catalysis. AB - The ~25 N-terminal "HAfp" residues of the HA2 subunit of the influenza virus hemagglutinin protein are critical for fusion between the viral and endosomal membranes at low pH. Earlier studies of HAfp in detergent support (1) N helix/turn/C-helix structure at pH 5 with open interhelical geometry and N helix/turn/C-coil structure at pH 7; or (2) N-helix/turn/C-helix at both pHs with closed interhelical geometry. These different structures led to very different models of HAfp membrane location and different models of catalysis of membrane fusion by HAfp. In this study, the interhelical geometry of membrane-associated HAfp is probed by solid-state NMR. The data are well-fitted to a population mixture of closed and semiclosed structures. The two structures have similar interhelical geometries and are planar with hydrophobic and hydrophilic faces. The different structures of HAfp in detergent vs membrane could be due to the differences in interaction with the curved micelle vs flat membrane with better geometric matching between the closed and semiclosed structures and the membrane. The higher fusogenicity of longer sequences and low pH is correlated with hydrophobic surface area and consequent increased membrane perturbation. PMID- 26039159 TI - Amyloids or prions? That is the question. AB - Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation. PMID- 26039160 TI - Lactate rescues neuronal sodium homeostasis during impaired energy metabolism. AB - Recently, we established that recurrent activity evokes network sodium oscillations in neurons and astrocytes in hippocampal tissue slices. Interestingly, metabolic integrity of astrocytes was essential for the neurons' capacity to maintain low sodium and to recover from sodium loads, indicating an intimate metabolic coupling between the 2 cell types. Here, we studied if lactate can support neuronal sodium homeostasis during impaired energy metabolism by analyzing whether glucose removal, pharmacological inhibition of glycolysis and/or addition of lactate affect cellular sodium regulation. Furthermore, we studied the effect of lactate on sodium regulation during recurrent network activity and upon inhibition of the glial Krebs cycle by sodium-fluoroacetate. Our results indicate that lactate is preferentially used by neurons. They demonstrate that lactate supports neuronal sodium homeostasis and rescues the effects of glial poisoning by sodium-fluoroacetate. Altogether, they are in line with the proposed transfer of lactate from astrocytes to neurons, the so-called astrocyte-neuron-lactate shuttle. PMID- 26039161 TI - Collective matrix remodeling by isolated cells: unionizing home improvement do-it yourselfers. PMID- 26039162 TI - Exploring the dynamics of cell processes through simulations of fluorescence microscopy experiments. AB - Fluorescence correlation spectroscopy (FCS) methods are powerful tools for unveiling the dynamical organization of cells. For simple cases, such as molecules passively moving in a homogeneous media, FCS analysis yields analytical functions that can be fitted to the experimental data to recover the phenomenological rate parameters. Unfortunately, many dynamical processes in cells do not follow these simple models, and in many instances it is not possible to obtain an analytical function through a theoretical analysis of a more complex model. In such cases, experimental analysis can be combined with Monte Carlo simulations to aid in interpretation of the data. In response to this need, we developed a method called FERNET (Fluorescence Emission Recipes and Numerical routines Toolkit) based on Monte Carlo simulations and the MCell-Blender platform, which was designed to treat the reaction-diffusion problem under realistic scenarios. This method enables us to set complex geometries of the simulation space, distribute molecules among different compartments, and define interspecies reactions with selected kinetic constants, diffusion coefficients, and species brightness. We apply this method to simulate single- and multiple point FCS, photon-counting histogram analysis, raster image correlation spectroscopy, and two-color fluorescence cross-correlation spectroscopy. We believe that this new program could be very useful for predicting and understanding the output of fluorescence microscopy experiments. PMID- 26039163 TI - GUVs melt like LUVs: the large heat capacity of MLVs is not due to large size or small curvature. AB - The excess heat capacity functions (DeltaCp) associated with the main phase transition of large unilamellar vesicles (LUVs) and multilamellar vesicles (MLVs) are very different. Two explanations are possible. First, the difference in vesicle size (curvature) results in different gel-fluid interactions in the membrane; those interactions have a large effect on the cooperativity of the phase transition. Second, there is communication between the bilayers in an MLV when they undergo the gel-fluid transition; this communication results in thermodynamic coupling of the phase transitions of the bilayers in the MLV and, consequently, in an apparent increase in the cooperativity of the transition. To test these hypotheses, differential scanning calorimetry was performed on giant unilamellar vesicles (GUVs) of pure dipalmitoylphosphatidylcholine. The DeltaCp curve of GUVs was found to resemble that of the much smaller LUVs. The transition in GUVs and LUVs is much broader (half-width ~1.5 degrees C) than in MLVs (~0.1 degrees C). This similarity in GUVs and LUVs indicates that their size has little effect on gel-fluid interactions in the phase transition. The result suggests that coupling between the transitions in the bilayers of an MLV is responsible for their apparent higher cooperativity in melting. PMID- 26039164 TI - Microfluidic study of enhanced deposition of sickle cells at acute corners. AB - Sickle cell anemia is a blood disorder, known to affect the microcirculation and is characterized by painful vaso-occlusive crises in deep tissues. During the last three decades, many scenarios based on the enhanced adhesive properties of the membrane of sickle red blood cells have been proposed, all related to a final decrease in vessels lumen by cells accumulation on the vascular walls. Up to now, none of these scenarios considered the possible role played by the geometry of the flow on deposition. The question of the exact locations of occlusive events at the microcirculatory scale remains open. Here, using microfluidic devices where both geometry and oxygen levels can be controlled, we show that the flow of a suspension of sickle red blood cells around an acute corner of a triangular pillar or of a bifurcation, leads to the enhanced deposition and aggregation of cells. Thanks to our devices, we follow the growth of these aggregates in time and show that their length does not depend on oxygenation levels; instead, we find that their morphology changes dramatically to filamentous structures when using autologous plasma as a suspending fluid. We finally discuss the possible role played by such aggregates in vaso-occlusive events. PMID- 26039165 TI - Underestimated sensitivity of mammalian cochlear hair cells due to splay between stereociliary columns. AB - Current-displacement (I-X) and the force-displacement (F-X) relationships characterize hair-cell mechano-transduction in the inner ear. A common technique for measuring these relationships is to deliver mechanical stimulations to individual hair bundles with microprobes and measure whole cell transduction currents through patch pipette electrodes at the basolateral membrane. The sensitivity of hair-cell mechano-transduction is determined by two fundamental biophysical properties of the mechano-transduction channel, the stiffness of the putative gating spring and the gating swing, which are derived from the I-X and F X relationships. Although the hair-cell stereocilia in vivo deflect <100 nm even at high sound pressure levels, often it takes >500 nm of stereocilia displacement to saturate hair-cell mechano-transduction in experiments with individual hair cells in vitro. Despite such discrepancy between in vivo and in vitro data, key biophysical properties of hair-cell mechano-transduction to define the transduction sensitivity have been estimated from in vitro experiments. Using three-dimensional finite-element methods, we modeled an inner hair-cell and an outer hair-cell stereocilia bundle and simulated the effect of probe stimulation. Unlike the natural situation where the tectorial membrane stimulates hair-cell stereocilia evenly, probes deflect stereocilia unevenly. Because of uneven stimulation, 1) the operating range (the 10-90% width of the I-X relationship) increases by a factor of 2-8 depending on probe shapes, 2) the I-X relationship changes from a symmetric to an asymmetric function, and 3) the bundle stiffness is underestimated. Our results indicate that the generally accepted assumption of parallel stimulation leads to an overestimation of the gating swing and underestimation of the gating spring stiffness by an order of magnitude. PMID- 26039166 TI - In situ quantification of protein binding to the plasma membrane. AB - This study presents a fluorescence-based assay that allows for direct measurement of protein binding to the plasma membrane inside living cells. An axial scan through the cell generates a fluorescence intensity profile that is analyzed to determine the membrane-bound and cytoplasmic concentrations of a peripheral membrane protein labeled by the enhanced green fluorescent protein (EGFP). The membrane binding curve is constructed by mapping those concentrations for a population of cells with a wide range of protein expression levels, and a fit of the binding curve determines the number of binding sites and the dissociation coefficient. We experimentally verified the technique, using myosin-1C-EGFP as a model system and fit its binding curve. Furthermore, we studied the protein-lipid interactions of the membrane binding domains from lactadherin and phospholipase C delta1 to evaluate the feasibility of using competition binding experiments to identify specific lipid-protein interactions in living cells. Finally, we applied the technique to determine the lipid specificity, the number of binding sites, and the dissociation coefficient of membrane binding for the Gag matrix domain of human T-lymphotropic virus type 1, which provides insight into early assembly steps of the retrovirus. PMID- 26039167 TI - Different KChIPs compete for heteromultimeric assembly with pore-forming Kv4 subunits. AB - Auxiliary Kv channel-interacting proteins 1-4 (KChIPs1-4) coassemble with pore forming Kv4 alpha-subunits to form channel complexes underlying somatodendritic subthreshold A-type current that regulates neuronal excitability. It has been hypothesized that different KChIPs can competitively bind to Kv4 alpha-subunit to form variable channel complexes that can exhibit distinct biophysical properties for modulation of neural function. In this study, we use single-molecule subunit counting by total internal reflection fluorescence microscopy in combinations with electrophysiology and biochemistry to investigate whether different isoforms of auxiliary KChIPs, KChIP4a, and KChIP4bl, can compete for binding of Kv4.3 to coassemble heteromultimeric channel complexes for modulation of channel function. To count the number of photobleaching steps solely from cell membrane, we take advantage of a membrane tethered k-ras-CAAX peptide that anchors cytosolic KChIP4 proteins to the surface for reduction of background noise. Single-molecule subunit counting reveals that the number of KChIP4 isoforms in Kv4.3-KChIP4 complexes can vary depending on the KChIP4 expression level. Increasing the amount of KChIP4bl gradually reduces bleaching steps of KChIP4a isoform proteins, and vice versa. Further analysis of channel gating kinetics from different Kv4 KChIP4 subunit compositions confirms that both KChIP4a and KChIP4bl can modulate the channel complex function upon coassembly. Taken together, our findings show that auxiliary KChIPs can heteroassemble with Kv4 in a competitive manner to form heteromultimeric Kv4-KChIP4 channel complexes that are biophysically distinct and regulated under physiological or pathological conditions. PMID- 26039168 TI - Skin lipids: localization of ceramide and fatty acid in the unit cell of the long periodicity phase. AB - The lipid matrix of the skin's stratum corneum plays a key role in the barrier function, which protects the body from desiccation. The lipids that make up this matrix consist of ceramides, cholesterol, and free fatty acids, and can form two coexisting crystalline lamellar phases: the long periodicity phase (LPP) and the short periodicity phase (SPP). To fully understand the skin barrier function, information on the molecular arrangement of the lipids in the unit cell of these lamellar phases is very desirable. To determine this arrangement in previous studies, we examined the molecular arrangement of the SPP. In this study, neutron diffraction studies were performed to obtain information on the molecular arrangement of the LPP. The diffraction pattern reveals nine diffraction orders attributed to the LPP with a repeating unit of 129.4 +/- 0.5 A. Using D2O/H2O contrast variation, the scattering length density profiles were calculated for protiated samples and samples that included either the perdeuterated acyl chain of the most abundant ceramide or the most abundant perdeuterated fatty acid. Both perdeuterated chains are predominantly located in the central part of the unit cell with substantial interdigitation of the acyl chains in the unit cell center. However, a fraction of the perdeuterated chains is also located near the border of the unit cell with their acyl chains directing toward the center. This arrangement of lipids in the LPP unit cell corresponds with the location of their lipid headgroups at the border and also inside of the unit cell at a well-defined position (+/-21 A from the unit cell center), indicative of a three-layer lipid arrangement within the 129.4 +/- 0.5 A repeating unit. PMID- 26039169 TI - Crystal structures of the L1, L2, N, and O states of pharaonis halorhodopsin. AB - Halorhodopsin from Natronomonas pharaonis (pHR) functions as a light-driven halide ion pump. In the presence of halide ions, the photochemical reaction of pHR is described by the scheme: K-> L1 -> L2 -> N -> O -> pHR' -> pHR. Here, we report light-induced structural changes of the pHR-bromide complex observed in the C2 crystal. In the L1-to-L2 transition, the bromide ion that initially exists in the extracellular vicinity of retinal moves across the retinal Schiff base. Upon the formation of the N state with a bromide ion bound to the cytoplasmic vicinity of the retinal Schiff base, the cytoplasmic half of helix F moves outward to create a water channel in the cytoplasmic interhelical space, whereas the extracellular half of helix C moves inward. During the transition from N to an N-like reaction state with retinal assuming the 13-cis/15-syn configuration, the translocated bromide ion is released into the cytoplasmic medium. Subsequently, helix F relaxes into its original conformation, generating the O state. Anion uptake from the extracellular side occurs when helix C relaxes into its original conformation. These structural data provide insight into the structural basis of unidirectional anion transport. PMID- 26039170 TI - Retrograde NGF axonal transport--motor coordination in the unidirectional motility regime. AB - We present a detailed motion analysis of retrograde nerve growth factor (NGF) endosomes in axons to show that mechanical tugs-of-war and intracellular motor regulation are complimentary features of the near-unidirectional endosome directionality. We used quantum dots to fluorescently label NGF and acquired trajectories of retrograde quantum-dot-NGF-endosomes with <20-nm accuracy at 32 Hz in microfluidic neuron cultures. Using a combination of transient motion analysis and Bayesian parsing, we partitioned the trajectories into sustained periods of retrograde (dynein-driven) motion, constrained pauses, and brief anterograde (kinesin-driven) reversals. The data shows many aspects of mechanical tugs-of-war and multiple-motor mechanics in NGF-endosome transport. However, we found that stochastic mechanical models based on in vitro parameters cannot simulate the experimental data, unless the microtubule-binding affinity of kinesins on the endosome is tuned down by 10 times. Specifically, the simulations suggest that the NGF-endosomes are driven on average by 5-6 active dyneins and 1 2 downregulated kinesins. This is also supported by the dynamics of endosomes detaching under load in axons, showcasing the cooperativity of multiple dyneins and the subdued activity of kinesins. We discuss the possible motor coordination mechanism consistent with motor regulation and tugs-of-war for future investigations. PMID- 26039172 TI - Conformational switching in a light-harvesting protein as followed by single molecule spectroscopy. AB - Among the ultimate goals of protein physics, the complete, experimental description of the energy paths leading to protein conformational changes remains a challenge. Single protein fluorescence spectroscopy constitutes an approach of choice for addressing protein dynamics, and, among naturally fluorescing proteins, light-harvesting (LH) proteins from purple bacteria constitute an ideal object for such a study. LHs bind bacteriochlorophyll a molecules, which confer on them a high intrinsic fluorescence yield. Moreover, the electronic properties of these pigment-proteins result from the strong excitonic coupling between their bound bacteriochlorophyll a molecules in combination with the large energetic disorder due to slow fluctuations in their structure. As a result, the position and probability of their fluorescence transition delicately depends on the precise realization of the disorder of the set of bound pigments, which is governed by the LH protein dynamics. Analysis of these parameters using time resolved single-molecule fluorescence spectroscopy thus yields direct access to the protein dynamics. Applying this technique to the LH2 protein from Rhodovulum (Rdv.) sulfidophilum, the structure-and consequently the fluorescence properties of which depends on pH, allowed us to follow a single protein, pH-induced, reversible, conformational transition. Hence, for the first time, to our knowledge, a protein transition can be visualized through changes in the electronic structure of the intrinsic cofactors, at a level of a single LH protein, which opens a new, to our knowledge, route for understanding the changes in energy landscape that underlie protein function and adaptation to the needs of living organisms. PMID- 26039171 TI - Molecular dynamics analysis of antibody recognition and escape by human H1N1 influenza hemagglutinin. AB - The antibody immunoglobulin (Ig) 2D1 is effective against the 1918 hemagglutinin (HA) and also known to cross-neutralize the 2009 pandemic H1N1 influenza HA through a similar epitope. However, the detailed mechanism of neutralization remains unclear. We conducted molecular dynamics (MD) simulations to study the interactions between Ig-2D1 and the HAs from the 1918 pandemic flu (A/South Carolina/1/1918, 18HA), the 2009 pandemic flu (A/California/04/2009, 09HA), a 2009 pandemic flu mutant (A/California/04/2009, 09HA_mut), and the 2006 seasonal flu (A/Solomon Islands/3/2006, 06HA). MM-PBSA analyses suggest the approximate free energy of binding (DeltaG) between Ig-2D1 and 18HA is -74.4 kcal/mol. In comparison with 18HA, 09HA and 06HA bind Ig-2D1 ~6 kcal/mol (DeltaDeltaG) weaker, and the 09HA_mut bind Ig-2D1 only half as strong. We also analyzed the contributions of individual epitope residues using the free-energy decomposition method. Two important salt bridges are found between the HAs and Ig-2D1. In 09HA, a serine-to-asparagine mutation coincided with a salt bridge destabilization, hydrogen bond losses, and a water pocket formation between 09HA and Ig-2D1. In 09HA_mut, a lysine-to-glutamic-acid mutation leads to the loss of both salt bridges and destabilizes interactions with Ig-2D1. Even though 06HA has a similar DeltaG to 09HA, it is not recognized by Ig-2D1 in vivo. Because 06HA contains two potential glycosylation sites that could mask the epitope, our results suggest that Ig-2D1 may be active against 06HA only in the absence of glycosylation. Overall, our simulation results are in good agreement with observations from biological experiments and offer novel mechanistic insights, to our knowledge, into the immune escape of the influenza virus. PMID- 26039174 TI - Distinct functional roles of cardiac mitochondrial subpopulations revealed by a 3D simulation model. AB - Experimental characterization of two cardiac mitochondrial subpopulations, namely, subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), has been hampered by technical difficulties, and an alternative approach is eagerly awaited. We previously developed a three-dimensional computational cardiomyocyte model that integrates electrophysiology, metabolism, and mechanics with subcellular structure. In this study, we further developed our model to include intracellular oxygen diffusion, and determined whether mitochondrial localization or intrinsic properties cause functional variations. For this purpose, we created two models: one with equal SSM and IFM properties and one with IFM having higher activity levels. Using these two models to compare the SSM and IFM responses of [Ca(2+)], tricarboxylic acid cycle activity, [NADH], and mitochondrial inner membrane potential to abrupt changes in pacing frequency (0.25-2 Hz), we found that the reported functional differences between these subpopulations appear to be mostly related to local [Ca(2+)] heterogeneity, and variations in intrinsic properties only serve to augment these differences. We also examined the effect of hypoxia on mitochondrial function. Under normoxic conditions, intracellular oxygen is much higher throughout the cell than the half saturation concentration for oxidative phosphorylation. However, under limited oxygen supply, oxygen is mostly exhausted in SSM, leaving the core region in an anoxic condition. Reflecting this heterogeneous oxygen environment, the inner membrane potential continues to decrease in IFM, whereas it is maintained to nearly normal levels in SSM, thereby ensuring ATP supply to this region. Our simulation results provide clues to understanding the origin of functional variations in two cardiac mitochondrial subpopulations and their differential roles in maintaining cardiomyocyte function as a whole. PMID- 26039173 TI - Quantitative interpretation of FRET experiments via molecular simulation: force field and validation. AB - Molecular simulation is a valuable and complementary tool that may assist with the interpretation of single-molecule Forster resonance energy transfer (FRET) experiments, if the energy function is of sufficiently high quality. Here we present force-field parameters for one of the most common pairs of chromophores used in experiments, AlexaFluor 488 and 594. From microsecond molecular-dynamics simulations, we are able to recover both experimentally determined equilibrium constants and association/dissociation rates of the chromophores with free tryptophan, as well as the decay of fluorescence anisotropy of a labeled protein. We find that it is particularly important to obtain a correct balance of solute water interactions in the simulations in order to faithfully capture the experimental anisotropy decays, which provide a sensitive benchmark for fluorophore mobility. Lastly, by a combination of experiment and simulation, we address a potential complication in the interpretation of experiments on polyproline, used as a molecular ruler for FRET experiments, namely the potential association of one of the chromophores with the polyproline helix. Under conditions where simulations accurately capture the fluorescence anisotropy decay, we find at most a modest, transient population of conformations in which the chromophores associate with the polyproline. Explicit calculation of FRET transfer efficiencies for short polyprolines yields results in good agreement with experiment. These results illustrate the potential power of a combination of molecular simulation and experiment in quantifying biomolecular dynamics. PMID- 26039177 TI - Cardiovascular protection by natural products. PMID- 26039175 TI - Patterns of intersecting fiber arrays revealed in whole muscle with generalized Q space imaging. AB - The multiscale attributes of mammalian muscle confer significant challenges for structural imaging in vivo. To achieve this, we employed a magnetic resonance method, termed "generalized Q-space imaging", that considers the effect of spatially distributed diffusion-weighted magnetic field gradients and diffusion sensitivities on the morphology of Q-space. This approach results in a subvoxel scaled probability distribution function whose shape correlates with local fiber orientation. The principal fiber populations identified within these probability distribution functions can then be associated by streamline methods to create multivoxel tractlike constructs that depict the macroscale orientation of myofiber arrays. We performed a simulation of Q-space input parameters, including magnetic field gradient strength and direction, diffusion sensitivity, and diffusional sampling to determine the optimal achievable fiber angle separation in the minimum scan time. We applied this approach to resolve intravoxel crossing myofiber arrays in the setting of the human tongue, an organ with anatomic complexity based on the presence of hierarchical arrays of intersecting myocytes. Using parameters defined by simulation, we imaged at 3T the fanlike configuration of the human genioglossus and the laterally positioned merging fibers of the styloglossus, inferior longitudinalis, chondroglossus, and verticalis. Comparative scans of the excised mouse tongue at 7T demonstrated similar midline and lateral crossing fiber patterns, whereas histological analysis confirmed the presence and distribution of these myofiber arrays at the microscopic scale. Our results demonstrate a magnetic resonance method for acquiring and displaying diffusional data that defines highly ordered myofiber patterns in architecturally complex tissue. Such patterns suggest inherent multiscale fiber organization and provide a basis for structure-function analyses in vivo and in model tissues. PMID- 26039178 TI - Synthesis of (+)-Antroquinonol: An Antihyperglycemic Agent. AB - The total synthesis of antroquinonol has been accomplished through Suzuki-Miyaura cross-coupling and Barton-McCombie reaction, and the alpha,beta-unsaturation was achieved through selenylation and oxidation protocols. In vitro and in vivo studies on the glucose-lowering properties of antroquinonol indicate that it is a potential antidiabetic agent. PMID- 26039179 TI - Loteprednol etabonate in the treatment of allergic conjunctivitis: a meta analysis. AB - OBJECTIVE: This meta-analysis was designed to assess the efficacy, as well as the safety of loteprednol etabonate (LE) ophthalmic suspension compared with placebo and other commonly used eye drops for treatment of allergic conjunctivitis. METHODS: Comprehensive searches of randomized controlled trials were carried out in a database of Medline, Embase, and the Cochrane Library. Eight qualified studies were included. This study assessed the reduction from baseline in scores of cardinal signs and symptoms, proportion of patients with improvement of allergic signs and symptoms, and incidence of clinically significant intraocular pressure (IOP) elevation (IOP elevation >=10 mmHg). RESULTS: The results showed that topical LE was significantly superior to placebo in reduction from baseline in signs scores (standardized mean difference [SMD] = -0.48; 95% confidence interval [CI] = -0.65 to -0.32) and symptoms scores (weighted mean difference [WMD] = -0.51; 95% CI = -0.64 to -0.38) of allergic conjunctivitis, and as effective as olopatadine and fluorometholone acetate. Topical LE was associated with a higher improvement rate of signs (risk ratio [RR] = 1.53; 95% CI = 1.26 1.86; I (2 )= 57%) and symptoms (RR = 1.29; 95% CI = 1.15-1.46; I (2 )= 54%) than placebo and the positive control treatment. Clinically significant IOP elevation was more frequent in the group of LE than the group of control treatment (pooled odds ratio = 3.03; 95% CI = 1.04-8.80), which was affected by the response to corticosteroid of the individual patient and the wearing of contact lenses. CONCLUSIONS: Topical LE is effective in treating allergic conjunctivitis. However, it should be used with caution due to the higher incidence of IOP elevation compared with placebo and olopatadine. A large-scale trial would be required to confirm the effect of different concentrations of LE on IOP. PMID- 26039180 TI - Effect of ursodeoxycholic acid on atherosclerosis. PMID- 26039182 TI - Epidermolysis Bullosa Pruriginosa Excoriee: A Deceptive Pruritic Variant in Two Female Patients. PMID- 26039183 TI - [Investigation and analysis of an outbreak of cutaneous leishmaniasis in Ksar Ouled Dabbab, Tataouine (Tunisia), 2012-2013]. AB - Zoonotic cutaneous leishmaniasis (ZCL), due to Leishmania major, and chronic CL, due to L. tropica, are endemic in the governorate (administrative subdivision) of Tataouine (southeast Tunisia). This study aims to analyze epidemiologic, clinical, parasitologic, and entomologic data collected during the 2012-2013 epidemic in Ksar Ouled Dabbab (KOD). METHODS: The KOD health care center diagnosed 164 CL cases from July 2012 to March 2013, identifying 21 Leishmania isolates and local sandflies. RESULTS: The incidence rate of CL in KOD was around 27.5/1000 inhabitants. The age groups most strongly affected were children younger than 10 years (19.9%) and those aged 10-20 years (23.1%). The number of patients with multiple lesions (67.9%) and their location on limbs (71.3%) indicated ZCL. This hypothesis is supported by the high proportions of L. major (81%) and Phlebotomus papatasi found. CONCLUSION: The epidemiologic and clinical profiles of the cases and the predominance of L. major and P. papatasi confirm that the recent outbreak in KOD was related to ZCL. It probably followed recent environmental changes and transmission spread from adjacent neighboring foci. PMID- 26039184 TI - Trans-generational responses to low pH depend on parental gender in a calcifying tubeworm. AB - The uptake of anthropogenic CO2 emissions by oceans has started decreasing pH and carbonate ion concentrations of seawater, a process called ocean acidification (OA). Occurring over centuries and many generations, evolutionary adaptation and epigenetic transfer will change species responses to OA over time. Trans generational responses, via genetic selection or trans-generational phenotypic plasticity, differ depending on species and exposure time as well as differences between individuals such as gender. Males and females differ in reproductive investment and egg producing females may have less energy available for OA stress responses. By crossing eggs and sperm from the calcareous tubeworm Hydroides elegans (Haswell, 1883) raised in ambient (8.1) and low (7.8) pH environments, we observed that paternal and maternal low pH experience had opposite and additive effects on offspring. For example, when compared to offspring with both parents from ambient pH, growth rates of offspring of fathers or mothers raised in low pH were higher or lower respectively, but there was no difference when both parents were from low pH. Gender differences may result in different selection pressures for each gender. This may result in overestimates of species tolerance and missed opportunities of potentially insightful comparisons between individuals of the same species. PMID- 26039186 TI - Relative contribution of maize and external manure amendment to soil carbon sequestration in a long-term intensive maize cropping system. AB - We aimed to quantify the relative contributions of plant residue and organic manure to soil carbon sequestration. Using a 27-year-long inorganic fertilizer and manure amendment experiment in a maize (Zea mays L.) double-cropping system, we quantified changes in harvestable maize biomass and soil organic carbon stocks (0-20 cm depth) between 1986-2012. By employing natural (13)C tracing techniques, we derived the proportional contributions of below-ground crop biomass return (maize-derived carbon) and external manure amendment (manure-derived carbon) to the total soil organic carbon stock. The average retention of maize-derived carbon plus manure-derived carbon during the early period of the trial (up to 11 years) was relatively high (10%) compared to the later period (22 to 27 years, 5.1-6.3%). About 11% of maize-derived carbon was converted to soil organic carbon, which was double the retention of manure-derived carbon (4.4-5.1%). This result emphasized that organic amendments were necessary to a win-win strategy for both SOC sequestration and maize production. PMID- 26039187 TI - High-Quality Solution-Processed Silicon Oxide Gate Dielectric Applied on Indium Oxide Based Thin-Film Transistors. AB - A silicon oxide gate dielectric was synthesized by a facile sol-gel reaction and applied to solution-processed indium oxide based thin-film transistors (TFTs). The SiOx sol-gel was spin-coated on highly doped silicon substrates and converted to a dense dielectric film with a smooth surface at a maximum processing temperature of T = 350 degrees C. The synthesis was systematically improved, so that the solution-processed silicon oxide finally achieved comparable break downfield strength (7 MV/cm) and leakage current densities (<10 nA/cm(2) at 1 MV/cm) to thermally grown silicon dioxide (SiO2). The good quality of the dielectric layer was successfully proven in bottom-gate, bottom-contact metal oxide TFTs and compared to reference TFTs with thermally grown SiO2. Both transistor types have field-effect mobility values as high as 28 cm(2)/(Vs) with an on/off current ratio of 10(8), subthreshold swings of 0.30 and 0.37 V/dec, respectively, and a threshold voltage close to zero. The good device performance could be attributed to the smooth dielectric/semiconductor interface and low interface trap density. Thus, the sol-gel-derived SiO2 is a promising candidate for a high-quality dielectric layer on many substrates and high-performance large area applications. PMID- 26039188 TI - Correct folding of an alpha-helix and a beta-hairpin using a polarized 2D torsional potential. AB - A new modification to the AMBER force field that incorporates the coupled two dimensional main chain torsion energy has been evaluated for the balanced representation of secondary structures. In this modified AMBER force field (AMBER03(2D)), the main chain torsion energy is represented by 2-dimensional Fourier expansions with parameters fitted to the potential energy surface generated by high-level quantum mechanical calculations of small peptides in solution. Molecular dynamics simulations are performed to study the folding of two model peptides adopting either alpha-helix or beta-hairpin structures. Both peptides are successfully folded into their native structures using an AMBER03(2D) force field with the implementation of a polarization scheme (AMBER03(2D)p). For comparison, simulations using a standard AMBER03 force field with and without polarization, as well as AMBER03(2D) without polarization, fail to fold both peptides successfully. The correction to secondary structure propensity in the AMBER03 force field and the polarization effect are critical to folding Trpzip2; without these factors, a helical structure is obtained. This study strongly suggests that this new force field is capable of providing a more balanced preference for helical and extended conformations. The electrostatic polarization effect is shown to be indispensable to the growth of secondary structures. PMID- 26039189 TI - Childhood abuse increases the risk of depressive and anxiety symptoms and history of suicidal behavior in Mexican pregnant women. AB - OBJECTIVE: To explore the relationship between individual and co-occurring childhood sexual, physical, and verbal abuse, prenatal depressive (PDS) and anxiety symptoms (PAS), and history of suicidal behavior (HSB) among Mexican pregnant women at risk of depression. METHODS: A sample of 357 women screened for PDS was interviewed using the Childhood Experience of Care and Abuse Questionnaire (CECA-Q), the Beck Depression Inventory (BDI-II), the anxiety subscale of the Hopkins Symptoms Checklist (SCL-90), and specific questions on verbal abuse and HSB. RESULTS: Logistic regression analyses showed that women who had experienced childhood sexual abuse (CSA) were 2.60 times more likely to develop PDS, 2.58 times more likely to develop PAS, and 3.71 times more likely to have HSB. Childhood physical abuse (CPA) increased the risk of PAS (odds ratio [OR] = 2.51) and HSB (OR = 2.62), while childhood verbal abuse (CVA) increased PDS (OR = 1.92). Experiencing multiple abuses increased the risk of PDS (OR = 3.01), PAS (OR = 3.73), and HSB (OR = 13.73). CONCLUSIONS: Childhood sexual, physical, and verbal abuse, especially when they co-occur, have an impact on PDS and PAS and lifetime HSB. These findings suggest that pregnant women at risk for depression should also be screened for trauma as a risk factor for perinatal psychopathology. PMID- 26039190 TI - Neural Oscillations and Synchrony in Brain Dysfunction and Neuropsychiatric Disorders: It's About Time. AB - Neural oscillations are rhythmic fluctuations over time in the activity or excitability of single neurons, local neuronal populations or "assemblies," and/or multiple regionally distributed neuronal assemblies. Synchronized oscillations among large numbers of neurons are evident in electrocorticographic, electroencephalographic, magnetoencephalographic, and local field potential recordings and are generally understood to depend on inhibition that paces assemblies of excitatory neurons to produce alternating temporal windows of reduced and increased excitability. Synchronization of neural oscillations is supported by the extensive networks of local and long-range feedforward and feedback bidirectional connections between neurons. Here, we review some of the major methods and measures used to characterize neural oscillations, with a focus on gamma oscillations. Distinctions are drawn between stimulus-independent oscillations recorded during resting states or intervals between task events, stimulus-induced oscillations that are time locked but not phase locked to stimuli, and stimulus-evoked oscillations that are both time and phase locked to stimuli. Synchrony of oscillations between recording sites, and between the amplitudes and phases of oscillations of different frequencies (cross-frequency coupling), is described and illustrated. Molecular mechanisms underlying gamma oscillations are also reviewed. Ultimately, understanding the temporal organization of neuronal network activity, including interactions between neural oscillations, is critical for elucidating brain dysfunction in neuropsychiatric disorders. PMID- 26039192 TI - The role of pragmatics in mediating the relationship between social disadvantage and adolescent behavior. AB - OBJECTIVE: The relationship between social disadvantage, behavior, and communication in childhood is well established. Less is known about how these 3 interact across childhood and specifically whether pragmatic language skills act as a mediator between early social disadvantage and adolescent behavior. METHOD: The sample was the Avon Longitudinal Study of Parents and Children, a representative birth cohort initially recruited in England in 1991/1992 and followed through to adolescence and beyond. Of the original 13,992 live births, data were available for 2926 children at 13 years. Univariable analysis was first used to identify sociodemographic and other predictors of the Strengths and Difficulties Questionnaire (SDQ) at 13 years. The mediational role of the pragmatics scale of the Children's Communication Checklist (CCC) at 9 years was then tested, controlling for age, gender, and IQ. RESULTS: There was evidence of both a direct effect from social disadvantage (path C') to SDQ Total Behavior Score at 13 years (-.205; p < .001) and an indirect effect from social disadvantage to SDQ Total (-.225; p < .001) after adjusting for the CCC pragmatics scale as a mediator. The latter represents a reduction in the magnitude of the unadjusted effect or "total effect" (-.430), demonstrating that the pragmatics scale partially mediates the relationship of early social disadvantage and adolescent behavior (even after controlling for other covariates). The same relationship held for all but the pro-social subscale of the SDQ. CONCLUSION: The results provide evidence to suggest that there maybe a causal relationship between these variables, suggesting that interventions targeting pragmatic skills have the potential to reduce adolescent behavioral symptoms. PMID- 26039191 TI - Depression, anxiety, and perinatal-specific posttraumatic distress in mothers of very low birth weight infants in the neonatal intensive care unit. AB - OBJECTIVE: To compare the trajectories and determine the predictors of maternal distress defined as a continuous spectrum of symptomatology and elevated symptomatology, of depression, anxiety, and perinatal-specific posttraumatic stress (PPTS), in mothers of very low birth weight (VLBW) infants throughout the neonatal intensive care unit (NICU) hospitalization. METHOD: Sixty-nine mothers completed psychological questionnaires within the first month of their infant's NICU hospitalization and again 2 weeks before NICU discharge. Multiple regression models determined maternal psychological, reproductive, sociodemographic, and infant medical predictors of maternal distress. RESULTS: Perinatal-specific posttraumatic stress remained stable throughout the NICU hospitalization, whereas other aspects of distress declined. Previous psychological history and infant medical variables predicted higher PPTS but no other aspects of distress. Reproductive variables predicted anxiety and PPTS; history of fetal loss initially predicted lower PPTS but throughout hospitalization primipara status emerged as a predictor of higher anxiety and PPTS. Sociodemographic variables predicated initial, but not later, depressive distress. CONCLUSIONS: Psychological screening is important in the NICU. The PPTS profile suggests it may require distinct treatment. Primiparas should be targeted for intervention. PMID- 26039194 TI - Whole Genome Sequencing Investigation of a Tuberculosis Outbreak in Port-au Prince, Haiti Caused by a Strain with a "Low-Level" rpoB Mutation L511P - Insights into a Mechanism of Resistance Escalation. AB - The World Health Organization recommends diagnosing Multidrug-Resistant Tuberculosis (MDR-TB) in high burden countries by detection of mutations in Rifampin (RIF) Resistance Determining Region of Mycobacterium tuberculosis rpoB gene with rapid molecular tests GeneXpert MTB/RIF and Hain MTBDRplus. Such mutations are found in >95% of Mycobacterium tuberculosis strains resistant to RIF by conventional culture-based drug susceptibility testing (DST). However routine diagnostic screening with molecular tests uncovered specific "low level" rpoB mutations conferring resistance to RIF below the critical concentration of 1 MUg/ml in some phenotypically susceptible strains. Cases with discrepant phenotypic (susceptible) and genotypic (resistant) results for resistance to RIF account for at least 10% of resistant diagnoses by molecular tests and urgently require new guidelines to inform therapeutic decision making. Eight strains with a "low level" rpoB mutation L511P were isolated by GHESKIO laboratory between 2008 and 2012 from 6 HIV-negative and 2 HIV-positive patients during routine molecular testing. Five isolates with a single L511P mutation and two isolates with double mutation L511P&M515T had MICs for RIF between 0.125 and 0.5 MUg/ml and tested susceptible in culture-based DST. The eighth isolate carried a double mutation L511P&D516C and was phenotypically resistant to RIF. All eight strains shared the same spoligotype SIT 53 commonly found in Haiti but classic epidemiological investigation failed to uncover direct contacts between the patients. Whole Genome Sequencing (WGS) revealed that L511P cluster isolates resulted from a clonal expansion of an ancestral strain resistant to Isoniazid and to a very low level of RIF. Under the selective pressure of RIF-based therapy the strain acquired mutation in the M306 codon of embB followed by secondary mutations in rpoB and escalation of resistance level. This scenario highlights the importance of subcritical resistance to RIF for both clinical management of patients and public health and provides support for introducing rpoB mutations as proxy for MICs into laboratory diagnosis of RIF resistance. This study illustrates that WGS is a promising multi-purpose genotyping tool for high-burden settings as it provides both "gold standard" sequencing results for prediction of drug susceptibility and a high-resolution data for epidemiological investigation in a single assay. PMID- 26039196 TI - Association Between Weekend Discharge and Hospital Readmission Rates Following Major Surgery. AB - IMPORTANCE: Although evidence suggests worse outcomes for patients admitted to the hospital on a weekend, to our knowledge, no previous studies have investigated the effects of weekend discharge. OBJECTIVE: To determine whether weekend discharge would be associated with an increased rate of 30- and 90-day hospital readmission. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of discharge abstracts from the California Office of State Health Planning and Development from 2012 identifying all patients who underwent abdominal aortic aneurysm (AAA) repair, colectomy, total hip arthroplasty, and pancreatectomy. This study was conducted from January to December 2012. MAIN OUTCOMES AND MEASURES: Thirty- and 90-day readmission rates were compared between patients discharged on a weekend vs weekday. RESULTS: Of 128 057 patients, 5225 patients (4.1%) underwent AAA repair; 29 388 (22.9%), colectomy; 91 168 (71.2%), hip replacement; and 2276 (1.8%), pancreatectomy. Overall, 29 883 (23.3%) were discharged on a weekend. Although there were no significant differences with respect to sex, age, race/ethnicity, insurance status, or type of admission, patients discharged on a weekend had shorter length of stays and were less often discharged to a skilled nursing facility. Overall, the 30-day readmission rate was 9.4% after AAA repair, 13.6% after colectomy, 7.5% after hip replacement, and 16.3% after pancreatectomy. Hospital readmission rates were similar for those discharged on a weekend vs weekday after AAA repair (8.8% vs 9.3%; P = .55) and pancreatectomy (17.5% vs 15.9%; P = .40). However, weekend discharge was associated with a lower 30-day readmission rate for patients undergoing colectomy (12.1% vs 14.1%; P < .001) and hip replacement (6.9% vs 7.7%; P < .001). On multivariable analysis, weekend discharge was inversely associated with readmission after colectomy (odds ratio [OR], 0.86; 95% CI, 0.79-0.93) but not AAA repair (OR, 0.93; 95% CI, 0.73-1.19), hip replacement (OR, 0.97; 95% CI, 0.91 1.03), or pancreatectomy (OR, 1.02; 95% CI, 0.76-1.36). Finally, a substantial percentage of 30-day readmissions occurred at a different hospital (AAA repair: 40.5%; colectomy: 25.8%; hip replacement: 32.5%; and pancreatectomy: 19.7%) compared with the index hospitalization. Similar results were seen for 90-day readmissions. CONCLUSIONS AND RELEVANCE: Weekend discharge after major surgery is not associated with higher 30- or 90-day readmission rates. PMID- 26039195 TI - Prolyl Oligopeptidase from the Blood Fluke Schistosoma mansoni: From Functional Analysis to Anti-schistosomal Inhibitors. AB - BACKGROUND: Blood flukes of the genus Schistosoma cause schistosomiasis, a parasitic disease that infects over 240 million people worldwide, and for which there is a need to identify new targets for chemotherapeutic interventions. Our research is focused on Schistosoma mansoni prolyl oligopeptidase (SmPOP) from the serine peptidase family S9, which has not been investigated in detail in trematodes. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate that SmPOP is expressed in adult worms and schistosomula in an enzymatically active form. By immunofluorescence microscopy, SmPOP is localized in the tegument and parenchyma of both developmental stages. Recombinant SmPOP was produced in Escherichia coli and its active site specificity investigated using synthetic substrate and inhibitor libraries, and by homology modeling. SmPOP is a true oligopeptidase that hydrolyzes peptide (but not protein) substrates with a strict specificity for Pro at P1. The inhibition profile is analogous to those for mammalian POPs. Both the recombinant enzyme and live worms cleave host vasoregulatory, proline containing hormones such as angiotensin I and bradykinin. Finally, we designed nanomolar inhibitors of SmPOP that induce deleterious phenotypes in cultured schistosomes. CONCLUSIONS/SIGNIFICANCE: We provide the first localization and functional analysis of SmPOP together with chemical tools for measuring its activity. We briefly discuss the notion that SmPOP, operating at the host parasite interface to cleave host bioactive peptides, may contribute to the survival of the parasite. If substantiated, SmPOP could be a new target for the development of anti-schistosomal drugs. PMID- 26039197 TI - Correction: baseline omega-3 index correlates with aggressive and attention deficit disorder behaviours in adult prisoners. PMID- 26039198 TI - Evaluating Variations of Bladder Volume Using an Ultrasound Scanner in Rectal Cancer Patients during Chemoradiation: Is Protocol-Based Full Bladder Maintenance Using a Bladder Scanner Useful to Maintain the Bladder Volume? AB - PURPOSE: The maintenance of full bladder is important to reduce radiation-induced toxicities and maintain the therapeutic consistency in locally advanced rectal cancer patients who underwent radiotherapy (RT). So, the aim of this study was to evaluate the effectiveness of protocol-based full bladder maintenance by assessing bladder volume variation using an ultrasound bladder scanner to maintain bladder volume. MATERIALS AND METHODS: From March 2011 to May 2011, twenty consecutive rectal cancer patients receiving external beam RT participated in this prospective study. Protocol-based full bladder maintenance consisted of education, training and continuous biofeedback by measuring bladder volume. Bladder volume was measured by bladder scan immediately before simulation CT scan and before each treatment three times weekly during the RT period. The relative bladder volume change was calculated. Intra-patient bladder volume variations were quantified using interquartile range (IQR) of relative bladder volume change in each patient. We compared intra-patient bladder volume variations obtained (n=20) with data from our previous study patients (n=20) performing self controlled maintenance without protocol. RESULTS: Bladder volumes measured by bladder scan highly correlated with those on simulation CT scan (R=0.87, p<0.001). Patients from this study showed lower median IQR of relative bladder volume change compared to patients of self-controlled maintenance from our previous study, although it was not statistically significant (median 32.56% vs. 42.19%, p=0.058). Upon logistic regression, the IQR of relative bladder volume change was significantly related to protocol-based maintenance [relative risk 1.045, 95% confidence intervals (CI) 1.004-1.087, p=0.033]. Protocol-based maintenance included significantly more patients with an IQR of relative bladder volume change less than 37% than self-controlled maintenance (p=0.025). CONCLUSION: Our findings show that bladder volume could be maintained more consistently during RT by protocol-based management using a bladder scan. PMID- 26039199 TI - Haploidentical hematopoietic stem cell transplantation: state of art. AB - For patients with hematologic malignancies at high risk of relapse who do not have matched donors, a suitable alternative stem cell source is the HLA haploidentical 2- or 3-loci mismatched family donor who is readily available for nearly all patients. Transplantation across the major HLA barrier is associated with strong T-cell alloreactions, which were originally manifested as a high incidence of severe GVHD and graft rejection. The present overview of the 7th symposium on haplidentical transplantation that took place at the Weizmann Institute on February 2014, shows how these obstacles to successful transplantation can now be overcome. The review also discusses the advantages and drawbacks of current options for full haplotype-mismatched transplantation and highlights innovative approaches for rebuilding immunity, reducing leukemia relapse and improving survival after transplantation. In addition, new modalities for immune tolerance induction following nonmyeloablative conditioning are discussed, showing new options for treatment of elderly patients who cannot tolerate myeloablative conditioning protocols, as well as novel strategies for immune tolerance and chimerism induction as a platform for cell therapy and organ transplantation. PMID- 26039200 TI - T-cell depletion: from positive selection to negative depletion in adult patients. AB - Clinical trials have shown that a strategy for haploidentical transplantation based on the infusion of high numbers of T-cell-depleted hematopoietic progenitor cells and no post-transplant immunosuppression controls graft rejection and GvHD in patients with acute leukemia. Overall, event-free survival compares favorably with reports of transplants using sources of stem cells other than the matched sibling. Current studies are focussing on rebuilding post-transplant immunity to improve clinical outcomes separating GvHD from favourable donor immune responses. PMID- 26039202 TI - Improving the clinical outcome of unmanipulated haploidentical blood and marrow transplantation. AB - Unmanipulated haploidentical blood and marrow transplantation (HBMT) has been one of the most applied haploidentical transplant protocol, which offers rapid immune recovery, desirable health-related quality of life and comparable survival rate with those who received HLA-identical sibling transplantation or HLA-matched unrelated donor transplantation. Compared with HLA-identical sibling recipients, HBMT recipients experienced a lower risk of late effects. The HBMT protocol also shows superior in treating pediatric hematological malignancies compared with umbilical cord blood transplantation and could be successfully used as a post remission treatment algorithm for adults acute myeloid leukemia with unfavorable cytogenetics. Several approaches, including optimal dose investigation of anti thymocyte globulin, selecting the best donor, and modified donor lymphocyte infusion, have been designed to improve transplant outcomes. PMID- 26039201 TI - The role of donor-derived veto cells in nonmyeloablative haploidentical HSCT. AB - Allogeneic HSCT offers a route for achieving immune tolerance via mixed chimerism and remains the sole curative option for many nonmalignant, autoimmune and metabolic diseases. Present-day improvements of nonmyeloablative protocols are increasing the safety of HSCT, thereby widening the target population and resurrecting the interest of HSCT application as a platform for tolerance induction in organ transplantation. Using high cell doses of T-cell-depleted (TCD) grafts has been shown to circumvent graft-vs-host disease, leaving graft rejection as the main hindrance due to the robust host immunity that remains after mild conditioning. In this review we highlight the advantages of utilizing unique non-alloreactive 'veto' cells, such as anti-third party central memory CD8 T cells (Tcm), to enable induction of mixed chimerism after megadose HSCT under nonmyeloablative conditioning. Co-administration of HSCT with veto Tcm allows for induction of mixed chimerism that was successfully translated into immune tolerance, as demonstrated by engraftment of donor-type skin grafts. These veto Tcm cells have been shown to specifically eradicate anti-donor host T cells, through lymph-node sequestration and deletion, thus sparing host immunity and circumventing the need for life-long immunosuppression. Hence, data indicate that this treatment modality of combined TCD HSCT and adoptive transfer of Tcm veto cells under nonmyeloablative conditions may serve as a valuable tool for treatment of patients with a wide array of disorders such as hemoglobinopathies, autoimmune diseases and as a prelude for organ tolerance. PMID- 26039203 TI - Haploidentical, G-CSF-primed, unmanipulated bone marrow transplantation for patients with high-risk hematological malignancies: an update. AB - Ninety-seven patients affected by high-risk hematological malignancies underwent G-CSF primed, unmanipulated bone marrow (BM) transplantation from a related, haploidentical donor. All patients were prepared with an identical conditioning regimen including Thiotepa, Busilvex, Fludarabine (TBF) and antithymocyte globulin given at myeloablative (MAC = 68) or reduced (reduced intensity conditioning (RIC) = 29) dose intensity and received the same GvHD prophylaxis consisting of the combination of methotrexate, cyclosporine, mycofenolate-mofetil and basiliximab. Patients were transplanted in 1st or 2nd CR (early phase: n = 60) or in > 2nd CR or active disease (advanced phase: n = 37). With a median time of 21 days (range 12-38 days), the cumulative incidence (CI) of neutrophil engraftment was 94 +/- 3%. The 100-day CI of III-IV grade acute GvHD and the 2 year CI of extensive chronic GvHD were 9 +/- 3% and 12 +/- 4%, respectively. Overall, at a median follow-up of 2.2 years (range 0.3-5.6), 44 out of 97 (45%) patients are alive in CR. The 5-year probability of overall survival (OS) and disease-free survival (DFS) for patients in early and advanced phase was 53 +/- 7 vs 24 +/- 8% (P = 0.006) and 48 +/- 7 vs 22 +/- 8% (P = 0.01), respectively. By comparing MAC with RIC patient groups, the transplant-related mortality was equivalent (36 +/- 6 vs 28 +/- 9%) while the relapse risk was lower for the MAC patients (22 +/- 6 vs 45 +/- 11%), who showed higher OS (48 +/- 7 vs 29 +/- 10%) and DFS (43 +/- 7 vs 26 +/- 10%). However, all these differences did not reach a statistical significance. In multivariate analysis, diagnosis and recipient age were significant factors for OS and DFS. In conclusion, this analysis confirms, on a longer follow-up and higher number of patients, our previous encouraging results obtained by using MAC and RIC TBF regimen as conditioning for G-CSF primed, unmanipulated BM transplantation from related, haploidentical donor in patients with high-risk hematological malignancies, lacking an HLA-identical sibling or unrelated donor and in need to be urgently transplanted. PMID- 26039204 TI - HLA-haploidentical blood or marrow transplantation with high-dose, post transplantation cyclophosphamide. AB - In the past, partially HLA-mismatched related donor, or HLA-haploidentical, blood or marrow transplantation (haploBMT), for hematologic malignancies has been complicated by unacceptably high incidences of graft rejection or GvHD resulting from intense bi-directional alloreactivity. Administration of high doses of cyclophosphamide early after haploBMT selectively kills proliferating, alloreactive T cells while sparing non-alloreactive T cells responsible for immune reconstitution and resistance to infection. In the clinic, haploBMT with high-dose, post-transplantation cyclophosphamide is associated with acceptably low incidences of fatal graft rejection, GvHD and non-relapse mortality, and provides an acceptable treatment option for hematologic malignancies patients lacking suitably HLA-matched donors. HaploBMT with PTCy is now being investigated as a treatment of hemoglobinopathy and as a method for inducing tolerance to solid organs transplanted from the same donor. Ongoing and future clinical trials will establish the hierarchy of donor preference for hematologic malignancy patients lacking an HLA-matched sibling. PMID- 26039205 TI - Unmanipulated haploidentical bone marrow transplantation and post-transplant cyclophosphamide for hematologic malignanices following a myeloablative conditioning: an update. AB - This is a report of 148 patients with hematologic malignancies who received an unmanipulated haploidentical bone marrow transplant (BMT), followed by post transplant high-dose cyclophosphamide (PT-CY). All patients received a myeloablative conditioning consisting of thiotepa, busulfan, fludarabine (n=92) or TBI, fludarabine (n=56). The median age was 47 years (17-74); 47 patients were in first remission (CR1), 37 in second remission (CR2) and 64 had an active disease; all patients were first grafts. The diagnosis was acute leukemia (n=75), myelodisplastic syndrome (n=24), myelofibrosis (n=16), high-grade lymphoma (n=15) and others (n=18). GVHD prophylaxis consisted in PT-CY on days +3 and +5, cyclosporine (from day 0), and mycophenolate (from day +1). The median day for neutrophil engraftment was day +18 (13-32). The cumulative incidence of grades II IV acute GVHD was 24%, and of grades III-IV GVHD 10%. The incidence of moderate severe chronic GVHD was 12%. With a median follow-up for the surviving patients of 313 days (100-1162), the cumulative incidence of transplant-related mortality (TRM) is 13%, and the relapse-related death is 23%. The actuarial 22 months overall survival is 77% for CR1 patients, 49% for CR2 patients and 38% for patients grafted in relapse (P<0.001). Major causes of death were relapse (22%), GVHD (2%) and infections (6%). We confirm our initial results, suggesting that a myeloablative conditioning regimen followed by unmanipulated haploidentical BMT with PT-CY, results in a low risk of acute and chronic GVHD and encouraging rates of TRM and overall survival, also for patients with active disease at the time of transplant. PMID- 26039206 TI - Who is the best alternative allotransplant donor? AB - Assuming that most physicians will chose an HLA-identical sibling as the best allotransplant donor, the question arises who is the best alternative donor when an HLA-identical sibling is unavailable? The most commonly used alternative donors are HLA-identical or -mismatched unrelated donors, HLA-matched or mismatched umbilical cord blood donor or a related, HLA-haplotype-matched related donors. Each alternative donor option has advantages and disadvantages. We discuss selected aspects of these issues based on data from randomized clinical trials and observational databases. However, because there are limited data to address specific clinical settings, quantification of expert opinion is sometimes needed. PMID- 26039207 TI - T-cell depleted allogeneic hematopoietic cell transplants as a platform for adoptive therapy with leukemia selective or virus-specific T-cells. AB - Allogeneic hematopoietic cell transplants adequately depleted of T-cells can reduce or prevent acute and chronic GVHD in both HLA-matched and haplotype disparate hosts, without post-transplant prophylaxis with immunosuppressive drugs. Recent trials indicate that high doses of CD34+ progenitors from G-CSF mobilized peripheral blood leukocytes isolated and T-cell depleted by immunoadsorption to paramagnetic beads, when administered after myeloablative conditioning with TBI and chemotherapy or chemotherapy alone can secure consistent engraftment and abrogate GVHD in patients with acute leukemia without incurring an increased risk of a recurrent leukemia. Early clinical trials also indicate that high doses of in vitro generated leukemia-reactive donor T-cells can be adoptively transferred and can induce remissions of leukemia relapse without GVHD. Similarly, virus-specific T-cells generated from the transplant donor or an HLA partially matched third party, have induced remissions of Rituxan refractory EBV lymphomas and can clear CMV disease or viremia persisting despite antiviral therapy in a high proportion of cases. Analyses of treatment responses and failures illustrate both the advantages and limitations of donor or banked, third party-derived T-cells, but underscore the potential of adoptive T-cell therapy in the absence of ongoing immunosuppression. PMID- 26039208 TI - Immunotherapy for viral and fungal infections. AB - Allogenic stem cell transplantation (allo-SCT) represents the only curative option for several hematological malignancies. Due to a delayed and dysfunctional immunological recovery infectious complications and residual tumor cells following allo-SCT are still major causes of failure of this procedure. Here we discuss the most common infectious complications of allo-SCT and describe current and future strategies to prophylaxe or treat these complications using novel immunotherapeutic strategies. PMID- 26039210 TI - Improved immune recovery after transplantation of TCRalphabeta/CD19-depleted allografts from haploidentical donors in pediatric patients. AB - Immune recovery was retrospectively analyzed in a cohort of 41 patients with acute leukemia, myelodysplastic syndrome and nonmalignant diseases, who received alphabeta T- and B-cell-depleted allografts from haploidentical family donors. Conditioning regimens consisted of fludarabine or clofarabine, thiotepa, melphalan and serotherapy with OKT3 or ATG-Fresenius. Graft manipulation was carried out with anti-TCRalphabeta and anti-CD19 Abs and immunomagnetic microbeads. The gammadelta T cells and natural killer cells remained in the grafts. Primary engraftment occurred in 88%, acute GvHD (aGvHD) grades II and III IV occurred in 10% and 15%, respectively. Immune recovery data were available in 26 patients and comparable after OKT3 (n=7) or ATG-F (n=19). Median time to reach >100 CD3+ cells/MUL, >200 CD19+ cells/MUL and >200 CD56+ cells/MUL for the whole group was 13, 127 and 12.5 days, respectively. Compared with a historical control group of patients with CD34+ selected grafts, significantly higher cell numbers were found for CD3+ at days +30 and +90 (267 vs 27 and 397 vs 163 cells/MUL), for CD3+4+ at day +30 (58 vs 11 cells/MUL) and for CD56+ at day +14 (622 vs 27 cells/MUL). The clinical impact of this accelerated immune recovery will be evaluated in an ongoing prospective multicenter trial. PMID- 26039209 TI - Umbilical cord blood graft engineering: challenges and opportunities. AB - We are entering a very exciting era in umbilical cord blood transplantation (UCBT), where many of the associated formidable challenges may become treatable by ex vivo graft manipulation and/or adoptive immunotherapy utilizing specific cellular products. We envisage the use of double UCBT rather than single UCBT for most patients; this allows for greater ability to treat larger patients as well as to manipulate the graft. Ex vivo expansion and/or fucosylation of one cord will achieve more rapid engraftment, minimize the period of neutropenia and also give certainty that the other cord will provide long-term engraftment/immune reconstitution. The non-expanded (and future dominant) cord could be chosen for characteristics such as better HLA matching to minimize GvHD, or larger cell counts to enable part of the unit to be utilized for the development of specific cellular therapies such as the production of virus-specific T-cells or chimeric antigen receptor T-cells which are reviewed in this study. PMID- 26039211 TI - Next generation HLA-haploidentical HSCT. AB - Relapse is still the major cause of failure of allogeneic stem cell transplantation in high-risk acute leukemia patients. Indeed, whoever the donor and whatever the transplantation strategy, post-transplant relapse rates are ~30%, which is hardly satisfactory. The present phase 2 study analyzed the impact of adoptive immunotherapy with naturally occurring FoxP3+ T-regulatory cells (2 * 10(6) per kg) and conventional T lymphocytes (1 * 10(6) per kg) on prevention of GvHD and leukemia relapse in 43 high-risk adults undergoing full-haplotype mismatched transplantation without any post-transplant immunosuppression. Ninety five percent of patients achieved full-donor type engraftment. Only 6/41 patients (15%) developed ? grade II acute GvHD. Specific CD4(+) and CD8(+) for opportunistic pathogens emerged significantly earlier than after standard T-cell depleted haplo-transplantation. The probability of disease-free survival was 0.56. At a median follow-up of 46 months (range 18-65 months), only 2/41 evaluable patients have relapsed. The cumulative incidence of relapse was significantly lower than in historical controls (0.05 vs 0.21; P = 0.03). These results demonstrate that the immunosuppressive potential of Tregs can be used to suppress GvHD without loss of the benefits of GvL activity. Humanized murine models provided insights into the mechanisms underlying separation of GvL from GvHD. PMID- 26039212 TI - Haploidentical HSCT: a 15-year experience at San Raffaele. AB - Hematopoietic SCT (HSCT) from HLA haploidentical family donors is a promising therapy for high-risk hematological malignancies. In the past 15 years at San Raffaele Scientific Institute, we investigated several transplant platforms and post transplant cellular-based interventions. We showed that T cell-depleted haploidentical transplantation followed by the infusion of genetically modified donor T cells (TK007 study, Eudract-2005-003587-34) promotes fast and wide immune reconstitution and GvHD control. This approach is currently tested in a phase III multicenter randomized trial (TK008 study, NCT00914628). We targeted patients with advanced leukemia with a sirolimus-based, calcineurin inhibitor-free prophylaxis of GvHD to allow the safe infusion of unmanipulated PBSCs from haploidentical family donors (TrRaMM study, Eudract 2007-5477-54). Results of these approaches are summarized and discussed. PMID- 26039214 TI - Sex steroid ablation: an immunoregenerative strategy for immunocompromised patients. AB - Age-related decline in thymic function is a well-described process that results in reduced T-cell development and thymic output of new naive T cells. Thymic involution leads to reduced response to vaccines and new pathogens in otherwise healthy individuals; however, reduced thymic function is particularly detrimental in clinical scenarios where the immune system is profoundly depleted such as after chemotherapy, radiotherapy, infection and shock. Poor thymic function and restoration of immune competence has been correlated with an increased risk of opportunistic infections, tumor relapse and autoimmunity. Apart from their primary role in sex dimorphism, sex steroid levels profoundly affect the immune system in general and, in fact, age-related thymic involution has been at least partially attributed to the increase in sex steroids at puberty. Subsequently it has been demonstrated that the removal of sex steroids, or sex steroid ablation (SSA), triggers physiologic changes that ultimately lead to thymic re-growth and improved T-cell reconstitution in settings of hematopoietic stem cell transplant (HSCT). Although the cellular and molecular process underlying these regenerative effects are still poorly understood, SSA clearly represents an attractive therapeutic approach to enhance thymic function and restore immune competence in immunodeficient individuals. PMID- 26039213 TI - Favorable NK cell activity after haploidentical hematopoietic stem cell transplantation in stage IV relapsed Ewing's sarcoma patients. AB - Natural killer (NK) cell activity has been shown to have potential activity against Ewing's sarcoma (EWS) especially in tumors with low HLA I expression and high NKG2D expression. Two patients with metastatic relapsed and primary metastatic stage IV EWS who had received two courses of high dose chemotherapy with autologous stem cell rescue were transplanted from a haploidentical parental stem cell donor. Patients are alive in ongoing CR for 10.2 and 3.4 years now. Post transplant local second and first relapses were treated successfully in both patients. In vivo IL-2 stimulation not only increased the number and activity of effector cells in one patient but was also associated with severe GvHD. In vitro studies demonstrated high NK cell activity against K562 and relevant activity against EWS cell line A673 post transplant. NK activity was enhanced by cytokine prestimulation as well as by EWS targeting anti-GD2 Ab. Haploidentical hematopoietic stem cell transplantation (HSCT) might contribute to long-term survival by NK cell-mediated effect exerted by donor-derived NK cells. Local tumor recurrence was manageable in both high-risk patients indicating systemic immune control preventing subsequent metastasizing. The efficacy of haploidentical HSCT, cytokine application and tumor targeting antibodies for the use of Ab-dependent cellular cytotoxicity needs evaluation in clinical trials. PMID- 26039215 TI - Immune tolerance in recipients of combined haploidentical bone marrow and kidney transplantation. AB - The success of allogeneic hematopoietic cell transplantation (HCT) has been limited by transplant-associated toxicities related to the conditioning regimens used and to graft-vs-host disease (GVHD). The frequency and severity of GVHD observed when extensive HLA barriers are transgressed has greatly impeded the routine use of extensively HLA-mismatched HCT. Allogeneic HCT also has potential as an approach to organ allograft tolerance induction, but this potential has not been previously realized because of the toxicity associated with traditional conditioning. This paper reviews an approach to HCT involving reduced intensity conditioning that demonstrated sufficient safety in patients with hematologic malignancies, even in the HLA-mismatched transplant setting, to be applied for the induction of kidney allograft tolerance in humans with no other indication for HCT. These studies provided the first successful example of intentional organ allograft tolerance induction across HLA barriers in humans. Current data and hypotheses on the mechanisms of tolerance in these patients are reviewed. PMID- 26039216 TI - High definition infrared spectroscopic imaging for lymph node histopathology. AB - Chemical imaging is a rapidly emerging field in which molecular information within samples can be used to predict biological function and recognize disease without the use of stains or manual identification. In Fourier transform infrared (FT-IR) spectroscopic imaging, molecular absorption contrast provides a large signal relative to noise. Due to the long mid-IR wavelengths and sub-optimal instrument design, however, pixel sizes have historically been much larger than cells. This limits both the accuracy of the technique in identifying small regions, as well as the ability to visualize single cells. Here we obtain data with micron-sized sampling using a tabletop FT-IR instrument, and demonstrate that the high-definition (HD) data lead to accurate identification of multiple cells in lymph nodes that was not previously possible. Highly accurate recognition of eight distinct classes - naive and memory B cells, T cells, erythrocytes, connective tissue, fibrovascular network, smooth muscle, and light and dark zone activated B cells was achieved in healthy, reactive, and malignant lymph node biopsies using a random forest classifier. The results demonstrate that cells currently identifiable only through immunohistochemical stains and cumbersome manual recognition of optical microscopy images can now be distinguished to a similar level through a single IR spectroscopic image from a lymph node biopsy. PMID- 26039218 TI - Effects of airgun sounds on bowhead whale calling rates: evidence for two behavioral thresholds. AB - In proximity to seismic operations, bowhead whales (Balaena mysticetus) decrease their calling rates. Here, we investigate the transition from normal calling behavior to decreased calling and identify two threshold levels of received sound from airgun pulses at which calling behavior changes. Data were collected in August-October 2007-2010, during the westward autumn migration in the Alaskan Beaufort Sea. Up to 40 directional acoustic recorders (DASARs) were deployed at five sites offshore of the Alaskan North Slope. Using triangulation, whale calls localized within 2 km of each DASAR were identified and tallied every 10 minutes each season, so that the detected call rate could be interpreted as the actual call production rate. Moreover, airgun pulses were identified on each DASAR, analyzed, and a cumulative sound exposure level was computed for each 10-min period each season (CSEL10-min). A Poisson regression model was used to examine the relationship between the received CSEL10-min from airguns and the number of detected bowhead calls. Calling rates increased as soon as airgun pulses were detectable, compared to calling rates in the absence of airgun pulses. After the initial increase, calling rates leveled off at a received CSEL10-min of ~94 dB re 1 MUPa2-s (the lower threshold). In contrast, once CSEL10-min exceeded ~127 dB re 1 MUPa2-s (the upper threshold), whale calling rates began decreasing, and when CSEL10-min values were above ~160 dB re 1 MUPa2-s, the whales were virtually silent. PMID- 26039217 TI - Activation of Transient Receptor Potential Ankyrin-1 by Insoluble Particulate Material and Association with Asthma. AB - Inhaled irritants activate transient receptor potential ankyrin-1 (TRPA1), resulting in cough, bronchoconstriction, and inflammation/edema. TRPA1 is also implicated in the pathogenesis of asthma. Our hypothesis was that particulate materials activate TRPA1 via a mechanism distinct from chemical agonists and that, in a cohort of children with asthma living in a location prone to high levels of air pollution, expression of uniquely sensitive forms of TRPA1 may correlate with reduced asthma control. Variant forms of TRPA1 were constructed by mutating residues in known functional elements and corresponding to single nucleotide polymorphisms in functional domains. TRPA1 activity was studied in transfected HEK-293 cells using allyl-isothiocynate, a model soluble electrophilic agonist; 3,5-ditert butylphenol, a soluble nonelectrophilic agonist and a component of diesel exhaust particles; and insoluble coal fly ash (CFA) particles. The N-terminal variants R3C and R58T exhibited greater, but not additive, activity with all three agonists. The ankyrin repeat domain-4 single nucleotide polymorphisms E179K and K186N exhibited decreased response to CFA. The predicted N-linked glycosylation site residues N747A and N753A exhibited decreased responses to CFA, which were not attributable to differences in cellular localization. The pore-loop residue R919Q was comparable to wild-type, whereas N954T was inactive to soluble agonists but not CFA. These data identify roles for ankyrin domain-4, cell surface N-linked glycans, and selected pore-loop domain residues in the activation of TRPA1 by insoluble particles. Furthermore, the R3C and R58T polymorphisms correlated with reduced asthma control for some children, which suggest that TRPA1 activity may modulate asthma, particularly among individuals living in locations prone to high levels of air pollution. PMID- 26039221 TI - Impact of Contact on the Operation and Performance of Back-Gated Monolayer MoS2 Field-Effect-Transistors. AB - Metal contacts to atomically thin two-dimensional (2D) crystal based FETs play a decisive role in determining their operation and performance. However, the effects of contacts on the switching behavior, field-effect mobility, and current saturation of monolayer MoS2 FETs have not been well explored and, hence, is the focus of this work. The dependence of contact resistance on the drain current is revealed by four-terminal-measurements. Without high-kappa dielectric boosting, an electron mobility of 44 cm(2)/(V.s) has been achieved in a monolayer MoS2 FET on SiO2 substrate at room temperature. Velocity saturation is identified as the main mechanism responsible for the current saturation in back-gated monolayer MoS2 FETs at relatively higher carrier densities. Furthermore, for the first time, electron saturation velocity of monolayer MoS2 is extracted at high-field condition. PMID- 26039220 TI - Hbr1 Activates and Represses Hyphal Growth in Candida albicans and Regulates Fungal Morphogenesis under Embedded Conditions. AB - Transitions between yeast and hyphae are essential for Candida albicans pathogenesis. The genetic programs that regulate its hyphal development can be distinguished by embedded versus aerobic surface agar invasion. Hbr1, a regulator of white-opaque switching, is also a positive and negative regulator of hyphal invasion. During embedded growth at 24 degrees C, an HBR1/hbr1 strain formed constitutively filamentous colonies throughout the matrix, resembling EFG1 null colonies, and a subset of long unbranched hyphal aggregates enclosed in a spindle shaped capsule. Inhibition of adenylate cyclase with farnesol perturbed the filamentation of HBR1/hbr1 cells producing cytokinesis-defective hyphae whereas farnesol treated EFG1 null cells produced abundant opaque-like cells. Point mutations in the Hbr1 ATP-binding domain caused distinct filamentation phenotypes including uniform radial hyphae, hyphal sprouts, and massive yeast cell production. Conversely, aerobic surface colonies of the HBR1 heterozygote on Spider and GlcNAc media lacked filamentation that could be rescued by growth under low (5%) O2. Consistent with these morphogenesis defects, the HBR1 heterozygote exhibited attenuated virulence in a mouse candidemia model. These data define Hbr1 as an ATP-dependent positive and negative regulator of hyphal development that is sensitive to hypoxia. PMID- 26039222 TI - Nodal bilayer-splitting controlled by spin-orbit interactions in underdoped high Tc cuprates. AB - The highest superconducting transition temperatures in the cuprates are achieved in bilayer and trilayer systems, highlighting the importance of interlayer interactions for high Tc. It has been argued that interlayer hybridization vanishes along the nodal directions by way of a specific pattern of orbital overlap. Recent quantum oscillation measurements in bilayer cuprates have provided evidence for a residual bilayer-splitting at the nodes that is sufficiently small to enable magnetic breakdown tunneling at the nodes. Here we show that several key features of the experimental data can be understood in terms of weak spin-orbit interactions naturally present in bilayer systems, whose primary effect is to cause the magnetic breakdown to be accompanied by a spin flip. These features can now be understood to include the equidistant set of three quantum oscillation frequencies, the asymmetry of the quantum oscillation amplitudes in c-axis transport compared to ab-plane transport, and the anomalous magnetic field angle dependence of the amplitude of the side frequencies suggestive of small effective g-factors. We suggest that spin-orbit interactions in bilayer systems can further affect the structure of the nodal quasiparticle spectrum in the superconducting phase. PACS numbers: 71.45.Lr, 71.20.Ps, 71.18.+y. PMID- 26039223 TI - Effects of Therapeutic Physical Agents on Achilles Tendon Microcirculation. AB - STUDY DESIGN: Controlled laboratory study. OBJECTIVES: To measure Achilles tendon microcirculation (total hemoglobin [THb] and oxygen saturation [StO2]) before and after the application of a physical agent in asymptomatic participants, and to compare differences between application location and physical agent dosage. BACKGROUND: Tendon microcirculation can be altered by superficial heating or cryotherapy. METHODS: Fifty-one healthy adults (median age, 22 years; range, 20 34 years) were recruited and randomly assigned into 1 of 4 groups. Participants in each group received an intervention consisting of 1 of the following 4 physical agents: ultrasound (n = 12), interferential current (n = 14), low-level laser (n = 11), or vibration massage (n = 14). In each group, the selected intervention was applied at 2 different doses (ultrasound, 0.8 or 1.2 W/cm(2); laser, 5.4 or 18 J) or target locations (vibration and electrostimulation, calf muscle or Achilles tendon). For each participant, each dose or target location was randomly applied to 1 randomly selected lower leg (each leg receiving only 1 of the 2 options). RESULTS: The StO2 values significantly increased after ultrasound at both doses (P<.008), and the THb value significantly increased for the higher dose only (P<.008). Both THb and StO2 values also significantly increased in response to vibration massage targeting the Achilles tendon (P<.008), and these values were greater than those resulting from the vibration massage applied to the calf muscle (P = .003 and .002, respectively). No significant THb and StO2 differences were found after the application of interferential current or low-level laser. CONCLUSION: Tendon microcirculation increases after ultrasound and vibration massage intervention concentrated on the Achilles tendon. These modalities may be considered for the purpose of temporarily increasing microcirculation in the tendon. PMID- 26039224 TI - National Trends and In-hospital Complication Rates in More Than 1600 Hemispherectomies From 1988 to 2010: A Nationwide Inpatient Sample Study. AB - BACKGROUND: Anatomic and functional hemispherectomies are relatively infrequent and technically challenging. The literature is limited by small samples and single institution data. OBJECTIVE: We used the Nationwide Inpatient Sample (NIS) database to report on a large population of hemispherectomy patients and their in hospital complication rates over a 23-year period. METHODS: Between 1988 and 2010, we identified 304 pediatric hospitalizations in the NIS database where hemispherectomy was performed. Using the NIS weighting scheme, this inferred an estimated 1611 hospitalizations nationwide during this time period. Descriptive statistics were calculated on this inferred sample for patient and hospital characteristics and stratified by the presence of in-hospital complications. The adjusted odds of in-hospital complications and nonroutine discharge were estimated using multivariable models. RESULTS: The mean age of the patients was 5.9 years; 46% were female, and 54% were white. In the inferred series, 909 hospitalizations (56%) encountered at least 1 in-hospital complication; 42% were surgery related, and 25% were related to the hospitalization itself. For every 1 year increase in age, there was a corresponding 8% increase in the odds of a nonroutine discharge, adjusting for other potential confounders (95% confidence interval: 1.01-1.16). The most common in-hospital complication was the need for a blood transfusion (30%), followed by meningitis (10%), hydrocephalus (8%), postoperative hematoma/stroke (8%), and adverse pulmonary event (8%). Thirty three mortalities (2%) were inferred from this series. CONCLUSION: This is the largest study to date examining hemispherectomy and associated in-hospital complication rates. This study supports early surgery in patients with medically intractable epilepsy and severe hemispheric disease. PMID- 26039225 TI - Efficacy of Whole-Lung Lavage in Treatment of Pulmonary Alveolar Proteinosis. AB - The aim of the study was to investigate the therapeutic effect of whole-lung lavage (WLL) for pulmonary alveolar proteinosis (PAP). The cohort studies that investigated the therapeutic effect of WLL for PAP were selected strictly on the basis of the inclusion and exclusion criteria. The statistical analysis was performed using STATA statistical software (version 12.0; Stata Corporation, College Station, TX). Twelve studies were included in this meta-analysis. Totally, 206 PAP patients who received WLL were recruited in the 12 studies. We compared the differences in blood gas analysis and lung function before and after the treatment in this meta-analysis. The results indicated that there were statistical differences in the levels of diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen after the treatment of WLL for patients with PAP, whereas there were no evident differences in the levels of arterial partial pressure of carbon dioxide and arterial oxygen saturation. In conclusion, WLL can evidently improve the diffusing capacity for carbon monoxide, forced expiratory volume in 1 second, forced vital capacity, and arterial partial pressure of oxygen of patients with PAP, thus WLL may be an important treatment of PAP. PMID- 26039226 TI - Erratum: A fatal case caused by novel H7N9 avian influenza A virus in China. AB - [This corrects the article DOI: 10.1038/emi.2013.22.]. PMID- 26039227 TI - Using transference-focused psychotherapy principles in the pharmacotherapy of patients with severe personality disorders. AB - Transference-focused psychotherapy (TFP) is an evidence-based, manualized treatment for severe personality disorders. TFP provides clinicians with a comprehensive diagnostic approach, overarching theoretical orientation, and specific clinical techniques. While TFP was developed as a long-term psychodynamic psychotherapy for patients with personality disorders, the approach, orientation, and techniques used in psychotherapy treatment may be of use in pharmacotherapy with the same patients. Patients with borderline personality disorder, in particular, are high utilizers of all subtypes of psychotropic medication despite limited evidence for their effectiveness, creating multiple challenges for the prescribing clinician. The author suggests specific ways the TFP model can assist prescribers, including those who do not practice TFP psychotherapy. PMID- 26039228 TI - Transference-focused psychotherapy training during residency: an aide to learning psychodynamic psychotherapy. AB - Competency in psychodynamic psychotherapy is a requirement for residency training in psychiatry. However, for a variety of reasons, learning psychodynamic psychotherapy is difficult for residents. In this article, we share our experience in an elective in Transference-Focused Psychotherapy (TFP), a manualized treatment for severe personality disorders. Originally, this elective was conceptualized as an advanced component of training, offering specialized training in treating a subgroup of patients with severe personality disorders with a specific type of psychodynamic psychotherapy. However, contrary to the expectations of the residents and the training director, the elective in TFP strengthened understanding of core components of basic psychodynamic psychotherapy with all patients, not just those with severe personality disorders. We discuss various challenges in learning psychodynamic psychotherapy and how TFP served to address them. Two case vignettes illustrate several key points. PMID- 26039229 TI - Discussion of transference-focused psychotherapy training during residency: an aide to learning psychodynamic psychotherapy. PMID- 26039230 TI - "My sister tried to kill me": enactment and foreclosure in a mixed-race dyad. AB - How is treatment complicated when both patient and therapist bring into the room multiracial identities that stand in contrast to their visible race or ethnicity? Using relational psychoanalysis's concepts of dissociation, enactment, and relational trauma, this article examines the way multiple racial realities, beyond the more familiar black/white binary, can coexist in the consulting room. The implications and potential pitfalls of a cross-cultural dyad, in which each participant carries a mixed-race identity, are considered through a clinical vignette. PMID- 26039231 TI - Further evidence of self-medication: personality factors influencing drug choice in substance use disorders. AB - According to Khantzian's (2003) self-medication hypothesis (SMH), substance dependence is a compensatory means to modulate affects and self-soothe in response to distressing psychological states. Khantzian asserts: (1) Drugs become addicting because they have the power to alleviate, remove, or change human psychological suffering, and (2) There is a considerable degree of specificity in a person's choice of drugs because of unique psychological and physiological effects. The SMH has received criticism for its variable empirical support, particularly in terms of the drug-specificity aspect of Khantzian's hypothesis. We posit that previous empirical examinations of the SMH have been compromised by methodological limitations. Also, more recent findings supporting the SMH have yet to be replicated. Addressing previous limitations to the research, this project tested this theory in a treatment sample of treatment-seeking individuals with substance dependence (N = 304), using more heterogeneous, personality-driven measures that are theory-congruent. Using an algorithm based on medical records, individuals were reliably classified as being addicted to a depressant, stimulant, or opiate by two independent raters. Theory-based a priori predictions were that the three groups would exhibit differences in personality characteristics and emotional-regulation strategies. Specifically, our hypotheses entailed that when compared against each other: (1) Individuals with a central nervous system (CNS) depressant as drug of choice (DOC) will exhibit defenses of repression, over-controlling anger, and emotional inhibition to avoid acknowledging their depression; (2) Individuals with an opiate as DOC will exhibit higher levels of aggression, hostility, depression, and trauma, greater deficits in ego functioning, and externalizing/antisocial behavior connected to their use; and (3) Individuals with a stimulant as DOC will experience anhedonia, paranoia, have a propensity to mania, and display lower levels of emotional inhibition. MANOVAs were used to test three hypotheses regarding drug group differences on the personality variables that were in keeping with the SMH. The MANOVAs for Hypothesis I (Depressant group) and Hypothesis II (Opiate group) were statistically significant. Findings partially support the SMH, particularly in its characterization of personality functioning in those addicted to depressants and opiates. PMID- 26039232 TI - Multimodal psychoanalytic and dialectical behavioral approaches: a case study. AB - Psychoanalysis and dialectical behavior therapy (DBT) benefit populations that overlap in many ways. Patients who seek both treatments often have significant problems with affect regulation, relationships, and workplace functioning. This article's case report describes a patient receiving both treatments concurrently, and demonstrates that these interventions may be synergistic and can be effective when used together. PMID- 26039233 TI - Invited review of Becoming Freud: the Making of a Psychoanalyst, by Adam Phillips. PMID- 26039235 TI - Altered Phenotypes in Saccharomyces cerevisiae by Heterologous Expression of Basidiomycete Moniliophthora perniciosa SOD2 Gene. AB - Heterologous expression of a putative manganese superoxide dismutase gene (SOD2) of the basidiomycete Moniliophthora perniciosa complemented the phenotypes of a Saccharomyces cerevisiae sod2Delta mutant. Sequence analysis of the cloned M. perniciosa cDNA revealed an open reading frame (ORF) coding for a 176 amino acid polypeptide with the typical metal-binding motifs of a SOD2 gene, named MpSOD2. Phylogenetic comparison with known manganese superoxide dismutases (MnSODs) located the protein of M. perniciosa (MpSod2p) in a clade with the basidiomycete fungi Coprinopsis cinerea and Laccaria bicolor. Haploid wild-type yeast transformants containing a single copy of MpSOD2 showed increased resistance phenotypes against oxidative stress-inducing hydrogen peroxide and paraquat, but had unaltered phenotype against ultraviolet-C (UVC) radiation. The same transformants exhibited high sensitivity against treatment with the pro-mutagen diethylnitrosamine (DEN) that requires oxidation to become an active mutagen/carcinogen. Absence of MpSOD2 in the yeast sod2Delta mutant led to DEN hyper-resistance while introduction of a single copy of this gene restored the yeast wild-type phenotype. The haploid yeast wild-type transformant containing two SOD2 gene copies, one from M. perniciosa and one from its own, exhibited DEN super-sensitivity. This transformant also showed enhanced growth at 37 degrees C on the non-fermentable carbon source lactate, indicating functional expression of MpSod2p. The pro-mutagen dihydroethidium (DHE)-based fluorescence assay monitored basal level of yeast cell oxidative stress. Compared to the wild type, the yeast sod2Delta mutant had a much higher level of intrinsic oxidative stress, which was reduced to wild type (WT) level by introduction of one copy of the MpSOD2 gene. Taken together our data indicates functional expression of MpSod2 protein in the yeast S. cerevisiae. PMID- 26039236 TI - Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs) results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1(+/-)) mice. Nf1(+/-) MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT) MSPCs. Additionally, Nf1(+/-) MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1(+/-) MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K) and mitogen activated protein kinase (MAPK) signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs. PMID- 26039237 TI - Nuclear and Cytoplasmic Soluble Proteins Extraction from a Small Quantity of Drosophila's Whole Larvae and Tissues. AB - The identification and study of protein's function in several model organisms is carried out using both nuclear and cytoplasmic extracts. For a long time, Drosophila's embryos have represented the main source for protein extractions, although in the last year, the importance of collecting proteins extracts also from larval tissues has also been understood. Here we report a very simple protocol, improved by a previously developed method, to produce in a single extraction both highly stable nuclear and cytoplasmic protein extracts from a small quantity of whole Drosophila's larvae or tissues, suitable for biochemical analyses like co-immunoprecipitation. PMID- 26039238 TI - Polymorphisms of the CD24 Gene Are Associated with Risk of Multiple Sclerosis: A Meta-Analysis. AB - CD24 is a cell-surface protein mainly expressed in cells of the immune and central nervous system (CNS), cells that play a critical role in the development of multiple sclerosis (MS). In the current study, we investigated four polymorphisms of the CD24 gene regarding their associations with MS. To this end, univariate and multivariate meta-analysis were applied along with modifications to include data from family-trios so as to increase the robustness of the meta analysis. We found that the polymorphism 226 C>T (Ala57Val) of the CD24 gene is associated with MS according to the recessive mode of inheritance (odds ratio = 1.75; 95% CI: 1.09, 2.81). Moreover, the 1527-1528 TG>del polymorphism is inversely associated with MS according to the dominant mode of inheritance (odds ratio = 0.57; 95% CI 0.39, 0.83). Conversely, the 1056 A>G and 1626 A>G polymorphisms were not found to be associated with MS. We conclude that the CD24 226 C>T polymorphism increases the risk of MS, while the 1527-1528 TG>del polymorphism seems to have a protective role against MS, suggesting that these two polymorphisms can be used as predictive biomarkers for MS development. PMID- 26039240 TI - Correction: The Gene YALI0E20207g from Yarrowia lipolytica Encodes an N Acetylglucosamine Kinase Implicated in the Regulated Expression of the Genes from the N-Acetylglucosamine Assimilatory Pathway. PMID- 26039239 TI - Hemipteran mitochondrial genomes: features, structures and implications for phylogeny. AB - The study of Hemipteran mitochondrial genomes (mitogenomes) began with the Chagas disease vector, Triatoma dimidiata, in 2001. At present, 90 complete Hemipteran mitogenomes have been sequenced and annotated. This review examines the history of Hemipteran mitogenomes research and summarizes the main features of them including genome organization, nucleotide composition, protein-coding genes, tRNAs and rRNAs, and non-coding regions. Special attention is given to the comparative analysis of repeat regions. Gene rearrangements are an additional data type for a few families, and most mitogenomes are arranged in the same order to the proposed ancestral insect. We also discuss and provide insights on the phylogenetic analyses of a variety of taxonomic levels. This review is expected to further expand our understanding of research in this field and serve as a valuable reference resource. PMID- 26039242 TI - Central upwind scheme for a compressible two-phase flow model. AB - In this article, a compressible two-phase reduced five-equation flow model is numerically investigated. The model is non-conservative and the governing equations consist of two equations describing the conservation of mass, one for overall momentum and one for total energy. The fifth equation is the energy equation for one of the two phases and it includes source term on the right-hand side which represents the energy exchange between two fluids in the form of mechanical and thermodynamical work. For the numerical approximation of the model a high resolution central upwind scheme is implemented. This is a non-oscillatory upwind biased finite volume scheme which does not require a Riemann solver at each time step. Few numerical case studies of two-phase flows are presented. For validation and comparison, the same model is also solved by using kinetic flux vector splitting (KFVS) and staggered central schemes. It was found that central upwind scheme produces comparable results to the KFVS scheme. PMID- 26039241 TI - Mapping Microbial Response Metabolomes for Induced Natural Product Discovery. AB - Intergeneric microbial interactions may originate a significant fraction of secondary metabolic gene regulation in nature. Herein, we expose a genomically characterized Nocardiopsis strain, with untapped polyketide biosynthetic potential, to intergeneric interactions via coculture with low inoculum exposure to Escherichia, Bacillus, Tsukamurella, and Rhodococcus. The challenge-induced responses of extracted metabolites were characterized via multivariate statistical and self-organizing map (SOM) analyses, revealing the magnitude and selectivity engendered by the limiting case of low inoculum exposure. The collected inventory of cocultures revealed substantial metabolomic expansion in comparison to monocultures with nearly 14% of metabolomic features in cocultures undetectable in monoculture conditions and many features unique to coculture genera. One set of SOM-identified responding features was isolated, structurally characterized by multidimensional NMR, and revealed to comprise previously unreported polyketides containing an unusual pyrrolidinol substructure and moderate and selective cytotoxicity. Designated ciromicin A and B, they are detected across mixed cultures with intergeneric preferences under coculture conditions. The structural novelty of ciromicin A is highlighted by its ability to undergo a diastereoselective photochemical 12-pi electron rearrangement to ciromicin B at visible wavelengths. This study shows how organizing trends in metabolomic responses under coculture conditions can be harnessed to characterize multipartite cultures and identify previously silent secondary metabolism. PMID- 26039243 TI - Bone marrow mesenchymal cells improve muscle function in a skeletal muscle re injury model. AB - Skeletal muscle injury is the most common problem in orthopedic and sports medicine, and severe injury leads to fibrosis and muscle dysfunction. Conventional treatment for successive muscle injury is currently controversial, although new therapies, like cell therapy, seem to be promise. We developed a model of successive injuries in rat to evaluate the therapeutic potential of bone marrow mesenchymal cells (BMMC) injected directly into the injured muscle. Functional and histological assays were performed 14 and 28 days after the injury protocol by isometric tension recording and picrosirius/Hematoxilin & Eosin staining, respectively. We also evaluated the presence and the fate of BMMC on treated muscles; and muscle fiber regeneration. BMMC treatment increased maximal skeletal muscle contraction 14 and 28 days after muscle injury compared to non treated group (4.5 +/- 1.7 vs 2.5 +/- 0.98 N/cm2, p<0.05 and 8.4 +/- 2.3 vs. 5.7 +/- 1.3 N/cm2, p<0.05 respectively). Furthermore, BMMC treatment increased muscle fiber cross-sectional area and the presence of mature muscle fiber 28 days after muscle injury. However, there was no difference in collagen deposition between groups. Immunoassays for cytoskeleton markers of skeletal and smooth muscle cells revealed an apparent integration of the BMMC within the muscle. These data suggest that BMMC transplantation accelerates and improves muscle function recovery in our extensive muscle re-injury model. PMID- 26039244 TI - Microbial Transport, Retention, and Inactivation in Streams: A Combined Experimental and Stochastic Modeling Approach. AB - Long-term survival of pathogenic microorganisms in streams enables long-distance disease transmission. In order to manage water-borne diseases more effectively we need to better predict how microbes behave in freshwater systems, particularly how they are transported downstream in rivers. Microbes continuously immobilize and resuspend during downstream transport owing to a variety of processes including gravitational settling, attachment to in-stream structures such as submerged macrophytes, and hyporheic exchange and filtration within underlying sediments. We developed a stochastic model to describe these microbial transport and retention processes in rivers that also accounts for microbial inactivation. We used the model to assess the transport, retention, and inactivation of Escherichia coli in a small stream and the underlying streambed sediments as measured from multitracer injection experiments. The results demonstrate that the combination of laboratory experiments on sediment cores, stream reach-scale tracer experiments, and multiscale stochastic modeling improves assessment of microbial transport in streams. This study (1) demonstrates new observations of microbial dynamics in streams with improved data quality than prior studies, (2) advances a stochastic modeling framework to include microbial inactivation processes that we observed to be important in these streams, and (3) synthesizes new and existing data to evaluate seasonal dynamics. PMID- 26039246 TI - [Panton-Valentine leukocidin-positive osteoarticular infections]. AB - OBJECTIVES: The aim of our study was to evaluate the frequency of osteoarticular infections with Panton-Valentine leukocidin-positive (PVL) Staphylococcus aureus (PVL-SA) among patients admitted to the orthopedic ward at the Sahloul University Hospital (Sousse, Tunisia) and to study the characteristics of these strains and patients. MATERIALS AND METHODS: We conducted a retrospective descriptive study over a 5-year period. Bacterial identification, antibiotic susceptibility, and molecular study (PCR to detect of the luk-PV gene that encodes PVL) were performed for 44 S. aureus isolates. RESULTS: Panton-Valentine toxin was found in 41% of S. aureus cases, mainly males, and 39% of the PVL(+) cases were methicillin-sensitive (MSSA). These strains constitute a reservoir of PVL genes that can lead to the emergence and spread of PVL-SA clones resistant to methicillin (MRSA). In our series, PVL-MRSA accounted for 9% of all S. aureus isolates. Their profile and antibiotic resistance is that of clone ST80, frequently isolated in Europe and also reported in Algeria and Tunisia. CONCLUSION: It is desirable to test for PVL routinely in the laboratory to implement appropriate treatment and to monitor the epidemiology of these PVL-SA strains actively. Further measures should be undertaken to prevent and fight infections by these strains. PMID- 26039245 TI - Androgen Receptor (AR), E-Cadherin, and Ki-67 as Emerging Targets and Novel Prognostic Markers in Triple-Negative Breast Cancer (TNBC) Patients. AB - BACKGROUND: TNBC is an aggressive subset of breast cancer (BC) without specific target therapy. METHODS: This observational, retrospective study included 45 cases of TNBC. The aim of this study was to evaluate the expression of the AR, E cadherin and Ki-67 in relation to histological type, time to relapse and overall survival (OS). Immunohistochemistry (IHC) was carried out on formalin-fixed paraffin-embedded tumor samples obtained from patients defined TNBC. RESULTS: The AR was positive (IHC >10%) in 26.6%. E-cadherin (CDH1) expression was considered positive if the score was >= 2. This expression was negative in 53.3% cases. The Ki-67 index was >= 20% in 37.7%. Univariate analyses showed that AR, CDH1 and Ki 67 are significantly associated with OS. Multivariate analysis showed that AR and Ki-67 expression are independent variables associated with OS. The statistical analysis showed that patients with AR negative and Ki-67 positive expression have a significant correlation with poor outcome. CONCLUSIONS: Our data suggest that the combination of AR and E-cadherin expression as well as Ki-67 status might be useful prognostic markers in TNBC. Hence, these molecular determinants could play an interesting role to classify subgroups of TNBC. PMID- 26039248 TI - Chromosome X genomic and epigenomic aberrations and clinical implications in breast cancer by base resolution profiling. AB - AIM: Abnormal inactivation or loss of inactivated X chromosome (Xi) is implicated in women's cancer. However, the underlying mechanisms and clinical relevance are little known. MATERIALS & METHODS: High-throughput sequencing was conducted on breast cancer cell lines for copy number, RNA expression and 5'-methylcytosine in ChrX. The results were examined in primary breast tumors. RESULTS & CONCLUSION: Breast cancer cells demonstrated reduced or total loss of hemimethylation. Most cell lines lost part or one of X chromosomes. Cell lines without ChrX loss were more active in gene expression. DNA methylation was corroborated with Xi control lincRNA XIST. Similar transcriptome and DNA methylation changes were observed in primary breast cancer datasets with clinical phenotype associations. Dramatic genomic and epigenomic changes in ChrX may be used for potential diagnostic or prognostic markers in breast cancer. PMID- 26039249 TI - A new approach to reduce toxicities and to improve bioavailabilities of platinum containing anti-cancer nanodrugs. AB - Platinum (Pt) drugs are the most potent and commonly used anti-cancer chemotherapeutics. Nanoformulation of Pt drugs has the potential to improve the delivery to tumors and reduce toxic side effects. A major challenge for translating nanodrugs to clinical settings is their rapid clearance by the reticuloendothelial system (RES), hence increasing toxicities on off-target organs and reducing efficacy. We are reporting that an FDA approved parenteral nutrition source, Intralipid 20%, can help this problem. A dichloro (1, 2 diaminocyclohexane) platinum (II)-loaded and hyaluronic acid polymer-coated nanoparticle (DACHPt/HANP) is used in this study. A single dose of Intralipid (2 g/kg, clinical dosage) is administrated [intravenously (i. v.), clinical route] one hour before i.v. injection of DACHPt/HANP. This treatment can significantly reduce the toxicities of DACHPt/HANP in liver, spleen, and, interestingly, kidney. Intralipid can decrease Pt accumulation in the liver, spleen, and kidney by 20.4%, 42.5%, and 31.2% at 24-hr post nanodrug administration, respectively. The bioavailability of DACHPt/HANP increases by 18.7% and 9.4% during the first 5 and 24 hr, respectively. PMID- 26039250 TI - Otopathogens Detected in Middle Ear Fluid Obtained during Tympanostomy Tube Insertion: Contrasting Purulent and Non-Purulent Effusions. AB - Otitis media is a prominent disease among children. Previous literature indicates that otitis media is a polymicrobial disease, with Haemophilus influenzae, Streptococcus pneumoniae, Alloiococcus otitidis and Moraxella catarrhalis being the most commonly associated bacterial pathogens. Recent literature suggests that introduction of pneumococcal conjugate vaccines has had an effect on the etiology of otitis media. Using a multiplex PCR procedure, we sought to investigate the presence of the aforementioned bacterial pathogens in middle ear fluid collected from children undergoing routine tympanostomy tube placement at Wake Forest Baptist Medical Center during the period between January 2011 and March 2014. In purulent effusions, one or more bacterial organisms were detected in ~90% of samples. Most often the presence of H. influenzae alone was detected in purulent effusions (32%; 10 of 31). In non-purulent effusions, the most prevalent organism detected was A. otitidis (26%; 63 of 245). Half of the non-purulent effusions had none of these otopathogens detected. In purulent and non-purulent effusions, the overall presence of S. pneumoniae was lower (19%; 6 of 31, and 4%; 9 of 245, respectively) than that of the other pathogens being identified. The ratio of the percentage of each otopathogen identified in purulent vs. non-purulent effusions was >1 for the classic otopathogens but not for A. otitidis. PMID- 26039253 TI - Diiron bridged-thiolate complexes that bind N2 at the Fe(II)Fe(II), Fe(II)Fe(I), and Fe(I)Fe(I) redox states. AB - All known nitrogenase cofactors are rich in both sulfur and iron and are presumed capable of binding and reducing N2. Nonetheless, synthetic examples of transition metal model complexes that bind N2 and also feature sulfur donor ligands remain scarce. We report herein an unusual series of low-valent diiron complexes featuring thiolate and dinitrogen ligands. A new binucleating ligand scaffold is introduced that supports an Fe(MU-SAr)Fe diiron subunit that coordinates dinitrogen (N2-Fe(MU-SAr)Fe-N2) across at least three oxidation states (Fe(II)Fe(II), Fe(II)Fe(I), and Fe(I)Fe(I)). The (N2-Fe(MU-SAr)Fe-N2) system undergoes reduction of the bound N2 to produce NH3 (~50% yield) and can efficiently catalyze the disproportionation of N2H4 to NH3 and N2. The present scaffold also supports dinitrogen binding concomitant with hydride as a co ligand. Synthetic model complexes of these types are desirable to ultimately constrain hypotheses regarding Fe-mediated nitrogen fixation in synthetic and biological systems. PMID- 26039251 TI - Particulate matter from both heavy fuel oil and diesel fuel shipping emissions show strong biological effects on human lung cells at realistic and comparable in vitro exposure conditions. AB - BACKGROUND: Ship engine emissions are important with regard to lung and cardiovascular diseases especially in coastal regions worldwide. Known cellular responses to combustion particles include oxidative stress and inflammatory signalling. OBJECTIVES: To provide a molecular link between the chemical and physical characteristics of ship emission particles and the cellular responses they elicit and to identify potentially harmful fractions in shipping emission aerosols. METHODS: Through an air-liquid interface exposure system, we exposed human lung cells under realistic in vitro conditions to exhaust fumes from a ship engine running on either common heavy fuel oil (HFO) or cleaner-burning diesel fuel (DF). Advanced chemical analyses of the exhaust aerosols were combined with transcriptional, proteomic and metabolomic profiling including isotope labelling methods to characterise the lung cell responses. RESULTS: The HFO emissions contained high concentrations of toxic compounds such as metals and polycyclic aromatic hydrocarbon, and were higher in particle mass. These compounds were lower in DF emissions, which in turn had higher concentrations of elemental carbon ("soot"). Common cellular reactions included cellular stress responses and endocytosis. Reactions to HFO emissions were dominated by oxidative stress and inflammatory responses, whereas DF emissions induced generally a broader biological response than HFO emissions and affected essential cellular pathways such as energy metabolism, protein synthesis, and chromatin modification. CONCLUSIONS: Despite a lower content of known toxic compounds, combustion particles from the clean shipping fuel DF influenced several essential pathways of lung cell metabolism more strongly than particles from the unrefined fuel HFO. This might be attributable to a higher soot content in DF. Thus the role of diesel soot, which is a known carcinogen in acute air pollution-induced health effects should be further investigated. For the use of HFO and DF we recommend a reduction of carbonaceous soot in the ship emissions by implementation of filtration devices. PMID- 26039252 TI - Plasma biomarkers discriminate clinical forms of multiple sclerosis. AB - Multiple sclerosis, the most common cause of neurological disability in young population after trauma, represents a significant public health burden. Current challenges associated with management of multiple sclerosis (MS) patients stem from the lack of biomarkers that might enable stratification of the different clinical forms of MS and thus prompt treatment for those patients with progressive MS, for whom there is currently no therapy available. In the present work we analyzed a set of thirty different plasma cytokines, chemokines and growth factors present in circulation of 129 MS patients with different clinical forms (relapsing remitting, secondary progressive and primary progressive MS) and 53 healthy controls, across two independent cohorts. The set of plasma analytes was quantified with Luminex xMAP technology and their predictive power regarding clinical outcome was evaluated both individually using ROC curves and in combination using logistic regression analysis. Our results from two independent cohorts of MS patients demonstrate that the divergent clinical and histology based MS forms are associated with distinct profiles of circulating plasma protein biomarkers, with distinct signatures being composed of chemokines and growth/angiogenic factors. With this work, we propose that an evaluation of a set of 4 circulating biomarkers (HGF, Eotaxin/CCL11, EGF and MIP-1beta/CCL4) in MS patients might serve as an effective tool in the diagnosis and more personalized therapeutic targeting of MS patients. PMID- 26039254 TI - Activity and specificity of TRV-mediated gene editing in plants. AB - Plant trait engineering requires efficient targeted genome-editing technologies. Clustered regularly interspaced palindromic repeats (CRISPRs)/ CRISPR associated (Cas) type II system is used for targeted genome-editing applications across eukaryotic species including plants. Delivery of genome engineering reagents and recovery of mutants remain challenging tasks for in planta applications. Recently, we reported the development of Tobacco rattle virus (TRV)-mediated genome editing in Nicotiana benthamiana. TRV infects the growing points and possesses small genome size; which facilitate cloning, multiplexing, and agroinfections. Here, we report on the persistent activity and specificity of the TRV-mediated CRISPR/Cas9 system for targeted modification of the Nicotiana benthamiana genome. Our data reveal the persistence of the TRV- mediated Cas9 activity for up to 30 d post-agroinefection. Further, our data indicate that TRV mediated genome editing exhibited no off-target activities at potential off targets indicating the precision of the system for plant genome engineering. Taken together, our data establish the feasibility and exciting possibilities of using virus-mediated CRISPR/Cas9 for targeted engineering of plant genomes. PMID- 26039255 TI - Probing Lewis Acid-Base Interactions with Born-Oppenheimer Molecular Dynamics: The Electronic Absorption Spectrum of p-Nitroaniline in Supercritical CO2. AB - The structure and dynamics of p-nitroaniline (PNA) in supercritical CO2 (scCO2) at T = 315 K and rho = 0.81 g cm(-3) are investigated by carrying out Born Oppenheimer molecular dynamics, and the electronic absorption spectrum in scCO2 is determined by time dependent density functional theory. The structure of the PNA-scCO2 solution illustrates the role played by Lewis acid-base (LA-LB) interactions. In comparison with isolated PNA, the nu(N-O) symmetric and asymmetric stretching modes of PNA in scCO2 are red-shifted by -17 and -29 cm( 1), respectively. The maximum of the charge transfer (CT) absorption band of PNA in scSCO2 is at 3.9 eV, and the predicted red-shift of the pi -> pi* electronic transition relative to the isolated gas-phase PNA molecule reproduces the experimental value of -0.35 eV. An analysis of the relationship between geometry distortions and excitation energies of PNA in scCO2 shows that the pi -> pi* CT transition is very sensitive to changes of the N-O bond distance, strongly indicating a correlation between vibrational and electronic solvatochromism driven by LA-LB interactions. Despite the importance of LA-LB interactions to explain the solvation of PNA in scCO2, the red-shift of the CT band is mainly determined by electrostatic interactions. PMID- 26039256 TI - Fluctuations of hi-hat timing and dynamics in a virtuoso drum track of a popular music recording. AB - Long-range correlated temporal fluctuations in the beats of musical rhythms are an inevitable consequence of human action. According to recent studies, such fluctuations also lead to a favored listening experience. The scaling laws of amplitude variations in rhythms, however, are widely unknown. Here we use highly sensitive onset detection and time series analysis to study the amplitude and temporal fluctuations of Jeff Porcaro's one-handed hi-hat pattern in "I Keep Forgettin'"-one of the most renowned 16th note patterns in modern drumming. We show that fluctuations of hi-hat amplitudes and interbeat intervals (times between hits) have clear long-range correlations and short-range anticorrelations separated by a characteristic time scale. In addition, we detect subtle features in Porcaro's drumming such as small drifts in the 16th note pulse and non-trivial periodic two-bar patterns in both hi-hat amplitudes and intervals. Through this investigation we introduce a step towards statistical studies of the 20th and 21st century music recordings in the framework of complex systems. Our analysis has direct applications to the development of drum machines and to drumming pedagogy. PMID- 26039258 TI - Large-Area Nanosphere Self-Assembly by a Micro-Propulsive Injection Method for High Throughput Periodic Surface Nanotexturing. AB - A high throughput surface texturing process for optical and optoelectric devices based on a large-area self-assembly of nanospheres via a low-cost micropropulsive injection (MPI) method is presented. The novel MPI process enables the formation of a well-organized monolayer of hexagonally arranged nanosphere arrays (NAs) with tunable periodicity directly on the water surface, which is then transferred onto the preset substrates. This process can readily reach a throughput of 3000 wafers/h, which is compatible with the high volume photovoltaic manufacturing, thereby presenting a highly versatile platform for the fabrication of periodic nanotexturing on device surfaces. Specifically, a double-sided grating texturing with top-sided nanopencils and bottom-sided inverted-nanopyramids is realized in a thin film of crystalline silicon (28 MUm in thickness) using chemical etching on the mask of NAs to significantly enhance antireflection and light trapping, resulting in absorptions nearly approaching the Lambertian limit over a broad wavelength range of 375-1000 nm and even surpassing this limit beyond 1000 nm. In addition, it is demonstrated that the NAs can serve as templates for replicas of three-dimensional conformal amorphous silicon films with significantly enhanced light harvesting. The MPI induced self-assembly process may provide a universal and cost-effective solution for boosting light utilization, a problem of crucial importance for ultrathin solar cells. PMID- 26039257 TI - L-type calcium channels as drug targets in CNS disorders. AB - L-type calcium channels are present in most electrically excitable cells and are needed for proper brain, muscle, endocrine and sensory function. There is accumulating evidence for their involvement in brain diseases such as Parkinson disease, febrile seizures and neuropsychiatric disorders. Pharmacological inhibition of brain L-type channel isoforms, Cav1.2 and Cav1.3, may therefore be of therapeutic value. Organic calcium channels blockers are clinically used since decades for the treatment of hypertension, cardiac ischemia, and arrhythmias with a well-known and excellent safety profile. This pharmacological benefit is mainly mediated by the inhibition of Cav1.2 channels in the cardiovascular system. Despite their different biophysical properties and physiological functions, both brain channel isoforms are similarly inhibited by existing calcium channel blockers. In this review we will discuss evidence for altered L-type channel activity in human brain pathologies, new therapeutic implications of existing blockers and the rationale and current efforts to develop Cav1.3-selective compounds. PMID- 26039261 TI - Studies on Unprocessed and Acid-Treated Arabinogalactan from Larch as an Inhibitor of Glycan Binding of a Plant Toxin and Biomedically Relevant Human Lectins. AB - The increasing evidence for the physiological significance of glycan-protein (lectin) interactions prompts considerations for respective bioactivity of plant polysaccharides. Arabinogalactan from larch, a polysaccharide with a beta1,3 linked galactose core and branches at the 6'-hydroxyl, was thus tested, together with two processed forms treated either with oxalic or trifluoroacetic acid. Hydrolysis by acid reduced the arabinose contents without backbone degradation. The three preparations were tested as an inhibitor of lectin binding in solid phase and cell-based assays, using the toxin from Viscum album and a panel of seven human lectins (six galectins and a C-type lectin). Increasing potency correlating with the molecular contents of galactose was seen for the plant toxin. In general, relatively weak or no inhibitory capacity was detected for the three preparations, when binding of the human galectins and avian orthologues used as controls was measured. Acid-treated polysaccharides also weakly interfered with binding of the galactose-specific C-type lectin of human macrophages. Larch arabinogalactan, tested as a model, will thus most likely not impair (ga)lectin functionality physiologically. PMID- 26039259 TI - FOXP3+ T Cells Recruited to Sites of Sterile Skeletal Muscle Injury Regulate the Fate of Satellite Cells and Guide Effective Tissue Regeneration. AB - Muscle injury induces a classical inflammatory response in which cells of the innate immune system rapidly invade the tissue. Macrophages are prominently involved in this response and required for proper healing, as they are known to be important for clearing cellular debris and supporting satellite cell differentiation. Here, we sought to assess the role of the adaptive immune system in muscle regeneration after acute damage. We show that T lymphocytes are transiently recruited into the muscle after damage and appear to exert a pro myogenic effect on muscle repair. We observed a decrease in the cross-sectional area of regenerating myofibers after injury in Rag2-/- gamma-chain-/- mice, as compared to WT controls, suggesting that T cell recruitment promotes muscle regeneration. Skeletal muscle infiltrating T lymphocytes were enriched in CD4+CD25+FOXP3+ cells. Direct exposure of muscle satellite cells to in vitro induced Treg cells effectively enhanced their expansion, and concurrently inhibited their myogenic differentiation. In vivo, the recruitment of Tregs to acutely injured muscle was limited to the time period of satellite expansion, with possibly important implications for situations in which inflammatory conditions persist, such as muscular dystrophies and inflammatory myopathies. We conclude that the adaptive immune system, in particular T regulatory cells, is critically involved in effective skeletal muscle regeneration. Thus, in addition to their well-established role as regulators of the immune/inflammatory response, T regulatory cells also regulate the activity of skeletal muscle precursor cells, and are instrumental for the proper regeneration of this tissue. PMID- 26039262 TI - In Silico and In Vitro Investigation of the Piperine's Male Contraceptive Effect: Docking and Molecular Dynamics Simulation Studies in Androgen-Binding Protein and Androgen Receptor. AB - Understanding the molecular mechanism of action of traditional medicines is an important step towards developing marketable drugs from them. Piperine, an active constituent present in the Piper species, is used extensively in Ayurvedic medicines (practiced on the Indian subcontinent). Among others, piperine is known to possess a male contraceptive effect; however, the molecular mechanism of action for this effect is not very clear. In this regard, detailed docking and molecular dynamics simulation studies of piperine with the androgen-binding protein and androgen receptors were carried out. Androgen receptors control male sexual behavior and fertility, while the androgen-binding protein binds testosterone and maintains its concentration at optimal levels to stimulate spermatogenesis in the testis. It was found that piperine docks to the androgen binding protein, similar to dihydrotestosterone, and to androgen receptors, similar to cyproterone acetate (antagonist). Also, the piperine-androgen-binding protein and piperine-androgen receptors interactions were found to be stable throughout 30 ns of molecular dynamics simulation. Further, two independent simulations for 10 ns each also confirmed the stability of these interactions. Detailed analysis of the piperine-androgen-binding protein interactions shows that piperine interacts with Ser42 of the androgen-binding protein and could block the binding with its natural ligands dihydrotestosterone/testosterone. Moreover, piperine interacts with Thr577 of the androgen receptors in a manner similar to the antagonist cyproterone acetate. Based on the in silico results, piperine was tested in the MDA-kb2 cell line using the luciferase reporter gene assay and was found to antagonize the effect of dihydrotestosterone at nanomolar concentrations. Further detailed biochemical experiments could help to develop piperine as an effective male contraceptive agent in the future. PMID- 26039263 TI - In Vitro Evidence for the Use of Astragali Radix Extracts as Adjuvant against Oxaliplatin-Induced Neurotoxicity. AB - The repeated exposure to the anticancer drug oxaliplatin induces a disabling, painful neuropathy. The current pharmacological treatments are unsatisfactory and unable to modify the complex nervous damage induced by the platin derivative. Recently, we described a system of cellular measures of oxidative stress as a method for studying features of oxaliplatin neurotoxicity and screening new compounds able to reduce oxaliplatin-induced neuropathy. Based on this experimental design, the protective properties of Astragali radix were studied comparing aqueous and two hydroalcoholic root extracts. Aqueous and the 20 % hydroalcoholic (20 % water) extract were prepared from plant material, while the 50 % hydroalcoholic (50 % water) extract was a commercial one. All of the extracts were characterized in terms of drug extract ratio and content of typical isoflavonoids, Astragaloside IV, and related saponins. Furthermore, the molecular weight of the polysaccharide fraction was evaluated by light scattering analysis. Oxaliplatin increased the superoxide anion production both in the neuronal derived cell line SH-SY5Y and in primary cultures of rat cortical astrocytes. Aqueous and the 50 % hydroalcoholic extract (50 ug/mL) showed significant antioxidant effects. In astrocytes, aqueous and the 50 % hydroalcoholic extract showed protective effects against oxaliplatin-induced lipid peroxidation (malonyl dialdehyde levels), protein (carbonylated proteins), and DNA oxidation (8-OH-2-dG levels). The 50 % hydroalcoholic extract was the most active in preventing the activation of the apoptotic enzyme caspase-3 and it was the only able to stimulate astrocyte viability. None of the tested extracts interfered with the toxicity elicited by oxaliplatin in the human colon adenocarcinoma cell line HT 29. The pharmacological profile of Astragali radix extracts, in particular, the aqueous and 50 % hydroalcoholic extracts, makes these natural products candidates as therapeutic adjuvant agents against oxaliplatin neurotoxicity. PMID- 26039264 TI - Diketopiperazines and Sesquilignans from the Branches and Leaves of Claoxylon polot. AB - Six new diketopiperazines (1-6), two new sesquilignans (7-8), and ten known compounds (9-18) were isolated from the branches and leaves of Claoxylon polot. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of 1-3 were assigned by computational methods. Compounds 1 and 2 exhibited antiviral activity against Coxsackie B3 virus with IC50 values of 14.6 and 25.9 uM, respectively. PMID- 26039266 TI - Cytotoxic Amides from Fruits of Kawakawa, Macropiper excelsum. AB - Cytotoxic amides have been isolated from the fruits of the endemic New Zealand medicinal plant kawakawa, Macropiper excelsum (Piperaceae). The main amide was piperchabamide A and this is the first report of this rare compound outside the genus Piper. Eleven other amides were purified including two new compounds with the unusual 3,4-dihydro-1(2H)-pyridinyl group. The new compounds were fully characterized by 2D NMR spectroscopy, which showed a slow exchange between two rotamers about the amide bond, and they were chemically synthesized. In view of the antitumor activity of the related piperlongumine, all of these amides plus four synthetic analogs were tested for cytotoxicity. The most active was the piperine homolog piperdardine, with an IC50 of 14 uM against HT 29 colon cancer cells. PMID- 26039265 TI - Inhibition of Collagenase by Mycosporine-like Amino Acids from Marine Sources. AB - Matrix metalloproteinases play an important role in extracellular matrix remodeling. Excessive activity of these enzymes can be induced by UV light and leads to skin damage, a process known as photoaging. In this study, we investigated the collagenase inhibition potential of mycosporine-like amino acids, compounds that have been isolated from marine organisms and are known photoprotectants against UV-A and UV-B. For this purpose, the commonly used collagenase assay was optimized and for the first time validated in terms of relationships between enzyme-substrate concentrations, temperature, incubation time, and enzyme stability. Three compounds were isolated from the marine red algae Porphyra sp. and Palmaria palmata, and evaluated for their inhibitory properties against Chlostridium histolyticum collagenase. A dose-dependent, but very moderate, inhibition was observed for all substances and IC50 values of 104.0 uM for shinorine, 105.9 uM for porphyra, and 158.9 uM for palythine were determined. Additionally, computer-aided docking models suggested that the mycosporine-like amino acids binding to the active site of the enzyme is a competitive inhibition. PMID- 26039267 TI - Antioxidative Activity of Flavonoids from Abrus cantoniensis against Ethanol Induced Gastric Ulcer in Mice. AB - The present study investigated the flavonoids from Abrus cantoniensis against ethanol-induced gastric ulcers in mice. The flavonoids from A. cantoniensis were extracted with ethanol and purified by macroporous resin and polyamide. The 2,2 diphenyl-1-picrylhydrazyl assay was used to measure the antioxidative activities in vitro. The ethanol-induced ulcer mouse model was used to evaluate the gastroprotective activities of the flavonoids from A. cantoniensis. In addition, a method was established to ensure accuracy for animal ulcer evaluation. The flavonoids from A. cantoniensis showed a strong free radical scavenging capacity with an IC50 of 43.83 ug/mL in the 2,2-diphenyl-1-picrylhydrazyl assay. At doses between 28.16-112.67 mg/kg, the flavonoids conspicuously reduced the ulcer index in ethanol-induced mice (p<0.001). Significant differences were found in the levels of superoxide dismutase, catalase, glutathione, and myeloperoxidase in the stomach tissues between the flavonoids from the A. cantoniensis groups and the ethanol control group. The gastroprotective effect of the flavonoids from A. cantoniensis could be due to its antioxidative activity of the defensive mechanism. The data revealed that the flavonoids from A. cantoniensis could be a potential therapeutic agent for gastric ulcer prevention and treatment. PMID- 26039268 TI - Effect of Processing on the Traditional Chinese Herbal Medicine Flos Lonicerae: An NMR-based Chemometric Approach. AB - The processing of medicinal materials, known as Pao Zhi in traditional Chinese medicine, is a unique part of traditional Chinese medicine and has been widely used for the preparation of Chinese materia medica. It is believed that processing can alter the properties and functions of remedies, increase medical potency, and reduce toxicity and side effects. Both processed and unprocessed Flos Lonicerae (flowers of Lonicera japonica) are important drug ingredients in traditional Chinese medicine. To gain insights on the effect of processing factors (heating temperature and duration) on the change of chemical composition, nuclear magnetic resonance combined with chemometric analysis was applied to investigate the processing of F. Lonicerae. Nuclear magnetic resonance spectral data were analyzed by means of a heat map and principal components analysis. The results indicated that the composition changed significantly, particularly when processing at the higher temperature (210 degrees C). Five chemical components, viz. 3,4-dicaffeoylquinic acid, 4,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid, chlorogenic acid, and myo-inositol, whose concentration changed significantly during the processing, were isolated and identified. The patterns for the concentration change observed from nuclear magnetic resonance analysis during the processing were confirmed and quantitatively determined by ultrahigh performance liquid chromatography analysis. The study demonstrated that a nuclear magnetic resonance-based chemometric approach could be a promising tool for investigation of the processing of herbal medicines in traditional Chinese medicine. PMID- 26039269 TI - Regioisomeric and Substituent Effects upon the Outcome of the Reaction of 1 Borodienes with Nitrosoarene Compounds. AB - A study of the reactivity of 1-borodienes with nitrosoarene compounds has been carried out showing an outcome that differs according to the hybridization state of the boron moiety. Using an sp(2) boron substituent, a one-pot hetero-Diels Alder/ring contraction cascade occurred to afford N-arylpyrroles with low to good yields depending on the electronic properties of the substituents on the borodiene, whereas an sp(3) boron substituent led to the formation of stable boro oxazines with high regioselectivity in most of the cases, in moderate to good yields. (1)H and (11)B NMR studies on two boro-oxazine regioisomers showed that selective deprotection can be performed. Formation of either the pyrrole or the furan derivative is pH- and regioisomer-structure-dependent. The results obtained, together with previous B3LYP calculations, support mechanistic proposals which suggest that pyrrole, or furan, formation proceeds via oxazine formation, followed by a boryl rearrangement and an intramolecular addition elimination sequence. PMID- 26039271 TI - Cutaneous Cryptococcosis Mimicking Pyoderma Gangrenosum: A Report of Four Cases. PMID- 26039273 TI - Assessing exposure to outdoor lighting and health risks. PMID- 26039272 TI - Leukocyte telomere length and mortality in the National Health and Nutrition Examination Survey, 1999-2002. AB - BACKGROUND: This study examined the association between leukocyte telomere length -a marker of cell aging--and mortality in a nationally representative sample of US adults ages 50-84 years. We also examined moderating effects of age, sex, race/ethnicity, and education. METHODS: Data were from the National Health and Nutrition Examination Survey, 1999-2002 (n = 3,091). Cox proportional hazards regression was used to estimate the risk of all-cause and cause- specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions. RESULTS: Eight hundred and seventy deaths occurred over an average of 9.5 years of follow-up. In the full sample, a decrease of 1 kilobase pair in telomere length at baseline was marginally associated with a 10% increased hazard of all-cause mortality (hazard ratio [HR]: 1.1, 95% confidence interval [CI]: 0.9, 1.4) and a 30% increased hazard of death due to diseases other than cardiovascular disease or cancer (HR: 1.3, 95% CI: 0.9, 1.9). Among African-American but not white or Mexican-American respondents, a decrease of 1 kilobase pair in telomere length at baseline was associated with a two-fold increased hazard of cardiovascular mortality (HR: 2.0, 95% CI: 1.3, 3.1). There was no association between telomere length and cancer mortality. CONCLUSIONS: The association between leukocyte telomere length and mortality differs by race/ethnicity and cause of death. PMID- 26039274 TI - The authors respond. PMID- 26039275 TI - [Mycobacterium simiae pneumonia: a case report]. AB - We report a case of Mycobacterium simiae pneumonia in an immunocompetent women aged 55 years, after a stay in Thailand. The diagnosis was based on culture isolation of non-tuberculous mycobacteria from bronchoalveolar lavage. The culture isolate was identified as M. simiae by biochemical and molecular methods. The patient was treated. Her condition remained stable for 5 years. During the sixth years, a relapse occurred, and a new treatment was prescribed. This is a rare case in view of the absence of any predisposing factor. M. simiae should be considered a possible causative agent of pulmonary disease, even in immunocompetent patients. PMID- 26039276 TI - KA1-targeted regulatory domain mutations activate Chk1 in the absence of DNA damage. AB - The Chk1 protein kinase is activated in response to DNA damage through ATR mediated phosphorylation at multiple serine-glutamine (SQ) residues within the C terminal regulatory domain, however the molecular mechanism is not understood. Modelling indicates a high probability that this region of Chk1 contains a kinase associated 1 (KA1) domain, a small, compact protein fold found in multiple protein kinases including SOS2, AMPK and MARK3. We introduced mutations into Chk1 designed to disrupt specific structural elements of the predicted KA1 domain. Remarkably, six of seven Chk1 KA1 mutants exhibit constitutive biological activity (Chk1-CA) in the absence of DNA damage, profoundly arresting cells in G2 phase of the cell cycle. Cell cycle arrest induced by selected Chk1-CA mutants depends on kinase catalytic activity, which is increased several-fold compared to wild-type, however phosphorylation of the key ATR regulatory site serine 345 (S345) is not required. Thus, mutations targeting the putative Chk1 KA1 domain confer constitutive biological activity by circumventing the need for ATR mediated positive regulatory phosphorylation. PMID- 26039278 TI - In silico identification of AMPylating enzymes and study of their divergent evolution. AB - AMPylation is a novel post-translational modification (PTM) involving covalent attachment of an AMP moiety to threonine/tyrosine side chains of a protein. AMPylating enzymes belonging to three different families, namely Fic/Doc, GS ATase and DrrA have been experimentally characterized. Involvement of these novel enzymes in a myriad of biological processes makes them interesting candidates for genome-wide search. We have used SVM and HMM to develop a computational protocol for identification of AMPylation domains and their classification into various functional subfamilies catalyzing AMPylation, deAMPylation, phosphorylation and phosphocholine transfer. Our analysis has not only identified novel PTM catalyzing enzymes among unannotated proteins, but has also revealed how this novel enzyme family has evolved to generate functional diversity by subtle changes in sequence/structures of the proteins. Phylogenetic analysis of Fic/Doc has revealed three new isofunctional subfamilies, thus adding to their functional divergence. Also, frequent occurrence of Fic/Doc proteins on highly mobile and unstable genomic islands indicated their evolution via extensive horizontal gene transfers. On the other hand phylogenetic analyses indicate lateral evolution of GS-ATase family and an early duplication event responsible for AMPylation and deAMPylation activity of GS-ATase. Our analysis also reveals molecular basis of substrate specificity of DrrA proteins. PMID- 26039279 TI - Revealing Invisible Photonic Inscriptions: Images from Strain. AB - Photonic structural materials have received intensive interest and have been strongly developed over the past few years for image displays, sensing, and anticounterfeit materials. Their "smartness" arises from their color responsivity to changes of environment, strain, or external fields. Here, we introduce a novel invisible photonic system that reveals encrypted images or characters by simply stretching, or immersing in solvents. This type of intriguing photonic material is composed of regularly arranged core-shell particles that are selectively cross linked by UV irradiation, giving different strain response compared to un-cross linked regions. The images reversibly appear and disappear when cycling the strain and releasing it. The unique advantages of this soft polymer opal system compared with other types of photonic gels are that it can be produced in roll to roll quantities, can be vigorously deformed to achieve strong color changes, and has no solvent evaporation issues because it is a photonic rubber system. We demonstrate potential applications together with a fabrication procedure which is straightforward and scalable, vital for user take-up. Our work deepens understanding of this rubbery photonic system based on core-shell nanospheres. PMID- 26039280 TI - High-Throughput and Rapid Screening of Low-Mass Hazardous Compounds in Complex Samples. AB - Rapid screening and identification of hazardous chemicals in complex samples is of extreme importance for public safety and environmental health studies. In this work, we report a new method for high-throughput, sensitive, and rapid screening of low-mass hazardous compounds in complex media without complicated sample preparation procedures. This method is achieved based on size-selective enrichment on ordered mesoporous carbon followed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry analysis with graphene as a matrix. The ordered mesoporous carbon CMK-8 can exclude interferences from large molecules in complex samples (e.g., human serum, urine, and environmental water samples) and efficiently enrich a wide variety of low-mass hazardous compounds. The method can work at very low concentrations down to part per trillion (ppt) levels, and it is much faster and more facile than conventional methods. It was successfully applied to rapidly screen and identify unknown toxic substances such as perfluorochemicals in human serum samples from athletes and workers. Therefore, this method not only can sensitively detect target compounds but also can identify unknown hazardous compounds in complex media. PMID- 26039281 TI - Bone formation in mono cortical mandibular critical size defects after augmentation with two synthetic nanostructured and one xenogenous hydroxyapatite bone substitute - in vivo animal study. AB - OBJECTIVES: Healing characteristics as well as level of tissue integration and degradation of two different nanostructured hydroxyapatite bone substitute materials (BSM) in comparison with a deproteinized hydroxyapatite bovine BSM were evaluated in an in vivo animal experiment. MATERIAL AND METHODS: In the posterior mandible of 18 minipigs, bilateral mono cortical critical size bone defects were created. Randomized augmentation procedures with NanoBone((r)) (NHA1), Ostim((r)) (NHA2) or Bio-Oss((r)) (DBBM) were conducted (each material n = 12). Samples were analyzed after five (each material n = 6) and 8 months (each material n = 6). Defect healing, formation of soft tissue and bone as well as the amount of remaining respective BSM were quantified both macro- and microscopically. RESULTS: For NHA2, the residual bone defect after 5 weeks was significantly less compared to NHA1 or DBBM. There was no difference in residual BSM between NHA1 and DBBM, but the amount in NHA2 was significantly lower. NHA2 also showed the least amount of soft tissue and the highest amount of new bone after 5 weeks. Eight months after implantation, no significant differences in the amount of residual bone defects, in soft tissue or in bone formation were detected between the groups. Again, NHA2 showed significant less residual material than NHA1 and DBBM. DISCUSSION: We observed non-significant differences in the biological hard tissue response of NHA1 and DBBM. The water-soluble NHA2 initially induced an increased amount of new bone but was highly compressed which may have a negative effect in less stable augmentations of the jaw. PMID- 26039283 TI - Novel Programs and Discoveries Aim to Combat Antibiotic Resistance. PMID- 26039282 TI - A cross comparison of technologies for the detection of microRNAs in clinical FFPE samples of hepatoblastoma patients. AB - Although formalin fixed paraffin embedded (FFPE) tissue is a major biological source in cancer research, it is challenging to work with due to macromolecular fragmentation and nucleic acid crosslinking. Therefore, it is important to characterise the quality of data that can be obtained from FFPE samples. We have compared three independent platforms (next generation sequencing, microarray and NanoString) for profiling microRNAs (miRNAs) using clinical FFPE samples from hepatoblastoma (HB) patients. The number of detected miRNAs ranged from 228 to 345 (median = 294) using the next generation sequencing platform, whereas 79 to 125 (median = 112) miRNAs were identified using microarrays in three HB samples, including technical replicates. NanoString identified 299 to 372 miRNAs in two samples. Between the platforms, we observed high reproducibility and significant levels of shared detection. However, for commonly detected miRNAs, a strong correlation between platforms was not observed. Analysis of 10 additional HB samples with NanoString identified significantly overlapping miRNA expression profiles, and an alternative pattern was identified in a poorly differentiated HB with an aggressive phenotype. This investigation serves as a roadmap for future studies investigating miRNA expression in clinical FFPE samples, and as a guideline for the selection of an appropriate platform. PMID- 26039286 TI - For a comprehensive health system. PMID- 26039287 TI - Quality of life of men with AIDS and the model of social determinants of health. AB - OBJECTIVE: to analyze the quality of life (QoL) of men with AIDS from the perspective of the model of social determinants of health (MSDH). METHOD: cross sectional study conducted in an outpatient infectious diseases clinic from a Brazilian university hospital over the course of one year with a sample of 138 patients. A form based on the MSDH was used to collect sociodemographic data addressing individual, proximal, intermediate determinants and the influence of social networks together with an instrument used to assess the QoL of people with HIV/AIDS. The project was approved by the Institutional Review Board (Protocol No. 040.06.12). RESULTS: according to MSDH, most men with AIDS were between 30 and 49 years old (68.1%), mixed race (59.4%), heterosexual (46.4%), single (64.5%), Catholic (68.8%), had a bachelor's degree (39.2%), had no children (61.6%), and had a formal job (71.0%). The perception of QoL in the physical, level of independence, environment, and spirituality domains was intermediate, while QoL was perceived to be superior in the domains of psychological and social relationship. A perception of lower QoL was presented by homosexual (p=0.037) and married men (p=0.077), and those with income below one times the minimum wage (p=0.042). A perception of greater QoL was presented by those without a religion (p=0.005), living with a partner (p=0.049), and those who had a formal job (p=0.045). CONCLUSION: social determinants influence the QoL of men with AIDS. PMID- 26039288 TI - Quality of life, socioeconomic profile, knowledge and attitude toward sexuality from the perspectives of individuals living with Human Immunodeficiency Virus. AB - OBJECTIVES: to analyze the quality of life of "patients" with Human Immunodeficiency Virus and relate it to their socioeconomic profile, knowledge and attitudes toward sexuality. METHOD: crosssectional and analytical study with 201 individuals who are 50 years old or older. The Targeted Quality of Life and Aging Sexual Knowledge and Attitudes Scales were applied during interviews. Multiple Linear Regression was used in data analysis. RESULTS: dimensions of quality of life more strongly compromised were disclosure worries (39.0), sexual function (45.9), and financial worries (55.6). Scores concerning knowledge and attitudes toward sexuality were 31.7 and 14.8, respectively. There was significant correlation between attitudes and the domains of overall function, health worries, medication worries, and HIV mastery. CONCLUSION: guidance concerning how the disease is transmitted, treated and how it progresses, in addition to providing social and psychological support, could minimize the negative effects of the disease on the quality of life of patients living with the Human Immunodeficiency Virus. PMID- 26039289 TI - Effectiveness of individual and group interventions for people with type 2 diabetes. AB - OBJECTIVE: to compare the effectiveness of two educational interventions used by a healthcare provider in the monitoring of individuals with type 2 diabetes mellitus (T2DM), regarding knowledge of the disease, impact on quality of life and adoption of self-care actions. METHODS: comparative, longitudinal, prospective study performed with 150 subjects with type 2 diabetes, analyzed according to the type of participation in the program (individual and/or group). Participants of the individual intervention (II) received nursing consultations every six months and those of the group intervention (GI) took part in weekly meetings for three months. Data were collected through four questionnaires: Identification questionnaire, Problem Areas in Diabetes Questionnaire (PAID), Summary of Diabetes Self-Care Activities Questionnaire (SDSCA) and the Diabetes Knowledge Scale (DKN-A). Data were analyzed using the Friedman and Mann Whitney tests, considering a statistical significance of p <= 0.05. RESULTS: there was an increase in knowledge about the disease in the II (p<0.003) and GI (p<0.007), with reduction of the impact on the quality of life in the II (p<0.007) and improvement in self-care actions in the GI (p<0.001). CONCLUSION: in both intervention models improvements were observed in the indicators, over the six month monitoring period. PMID- 26039290 TI - Somatic and cognitive-affective depressive symptoms among patients with heart disease: differences by sex and age. AB - OBJECTIVE: this study investigated the association of somatic and cognitive affective symptoms with sex and age, among patients hospitalized with heart disease. METHOD: this study was a secondary analysis of two previous observational studies totaling 531 patients with heart disease, hospitalized from 2005 to 2011 in two public hospitals in Ribeirao Preto, state of Sao Paulo, Brazil. Somatic and cognitive-affective symptoms were assessed using the subscales of the Beck Depression Inventory - I (BDI-I). RESULTS: of 531 participants, 62.7% were male, with a mean age 57.3 years (SD= 13.0) for males and 56.2 years (SD= 12.1) for females. Analyses of variance showed an effect of sex (p<0.001 for somatic and p=0.005 for cognitive-affective symptoms), but no effect of age. Women presented with higher mean values than men in both BDI-I subscales: 7.1 (4.5) vs. 5.4 (4.3) for somatic, and 8.3 (7.9) vs. 6.7 (7.2) for cognitive-affective symptoms. There were no differences by age for somatic (p=0.84) or cognitive-affective symptoms (p=0.84). CONCLUSION: women hospitalized with heart disease had more somatic and cognitive-affective symptoms than men. We found no association of somatic and cognitive-affective symptoms with age. Future research for these patients could reveal whether these differences according to sex continue throughout the rehabilitation process. PMID- 26039291 TI - Clinical factors predicting risk for aspiration and respiratory aspiration among patients with Stroke. AB - OBJECTIVE: to investigate the association of risk factors with the Risk for aspiration nursing diagnosis and respiratory aspiration. METHOD: cross-sectional study assessing 105 patients with stroke. The instrument used to collect data addressing sociodemographic information, clinical variables and risk factors for Risk for aspiration. The clinical judgments of three expert RNs were used to establish the diagnosis. The relationship between variables and strength of association using Odds Ratio (OR) was verified both in regard to Risk for aspiration and respiratory aspiration. RESULTS: risk for aspiration was present in 34.3% of the patients and aspiration in 30.5%. The following stood out among the risk factors: Dysphagia, Impaired or absent gag reflex, Neurological disorders, and Impaired physical mobility, all of which were statistically associated with Risk for aspiration. Note that patients who develop such a diagnosis were seven times more likely to develop respiratory aspiration. CONCLUSION: dysphagia, Impaired or absent gag reflex were the best predictors both for Risk for aspiration and respiratory aspiration. PMID- 26039292 TI - Coordinated hospital-home care for kidney patients on hemodialysis from the perspective of nursing personnel. AB - OBJECTIVE: To examine, from the nursing perspective, the needs and challenges of coordinated hospital-home care for renal patients on hemodialysis. METHODS: A qualitative analysis was conducted with an ethnographic approach in a hemodialysis unit in San Luis Potosi, Mexico. Semistructured interviews were conducted with nine nurses, selected by purposeful sampling. Structured content analysis was used. RESULTS: Nurses recounted the needs and challenges involved in caring for renal patients. They also identified barriers that limit coordinated patient care in the hospital and the home, mainly the work overload at the hemodialysis unit and the lack of a systematic strategy for education and lifelong guidance to patients, their families and caregivers. CONCLUSIONS: This study shows the importance and necessity of establishing a strategy that goes beyond conventional guidance provided to caregivers of renal patients, integrating them into the multidisciplinary group of health professionals that provide care for these patients in the hospital to establish coordinated hospital home care that increases therapeutic adherence, treatment substitution effectiveness and patient quality of life. PMID- 26039293 TI - Assessment of nursing care using indicators generated by software. AB - OBJECTIVE: to analyze the efficacy of the Nursing Process in an Intensive Care Unit using indicators generated by software. METHOD: cross-sectional study using data collected for four months. RNs and students daily registered patients, took history (at admission), performed physical assessments, and established nursing diagnoses, nursing plans/prescriptions, and assessed care delivered to 17 patients using software. Indicators concerning the incidence and prevalence of nursing diagnoses, rate of effectiveness, risk diagnoses, and rate of effective prevention of complications were computed. RESULTS: the Risk for imbalanced body temperature was the most frequent diagnosis (23.53%), while the least frequent was Risk for constipation (0%). The Risk for Impaired skin integrity was prevalent in 100% of the patients, while Risk for acute confusion was the least prevalent (11.76%). Risk for constipation and Risk for impaired skin integrity obtained a rate of risk diagnostic effectiveness of 100%. The rate of effective prevention of acute confusion and falls was 100%. CONCLUSION: the efficacy of the Nursing Process using indicators was analyzed because these indicators reveal how nurses have identified patients' risks and conditions, and planned care in a systematized manner. PMID- 26039294 TI - Evaluation of the functional performance and technical quality of an Electronic Documentation System of the Nursing Process. AB - OBJECTIVE: To evaluate the functional performance and the technical quality of the Electronic Documentation System of the Nursing Process of the Teaching Hospital of the University of Sao Paulo. METHOD: exploratory-descriptive study. The Quality Model of regulatory standard 25010 and the Evaluation Process defined under regulatory standard 25040, both of the International Organization for Standardization/International Electrotechnical Commission. The quality characteristics evaluated were: functional suitability, reliability, usability, performance efficiency, compatibility, security, maintainability and portability. The sample was made up of 37 evaluators. RESULTS: in the evaluation of the specialists in information technology, only the characteristic of usability obtained a rate of positive responses of less than 70%. For the nurse lecturers, all the quality characteristics obtained a rate of positive responses of over 70%. The staff nurses of the medical and surgical clinics with experience in using the system) and staff nurses from other units of the hospital and from other health institutions (without experience in using the system) obtained rates of positive responses of more than 70% referent to the functional suitability, usability, and security. However, performance efficiency, reliability and compatibility all obtained rates below the parameter established. CONCLUSION: the software achieved rates of positive responses of over 70% for the majority of the quality characteristics evaluated. PMID- 26039295 TI - Association between overweight and characteristics of young adult students: support for nursing care. AB - OBJECTIVE: to verify associations between overweight and the characteristics of young adult students to support nursing care. METHOD: case-control study conducted with young adults from public schools. The sample was composed of 441 participants (147 cases and 294 controls, with and without excess weight, respectively). Sociodemographic and clinical characteristics were collected together with exposure factors and anthropometrics. Multiple logistic regression was used. The study received Institutional Review Board approval. RESULTS: statistically significant association with overweight: non-Caucasian, having a partner; weight gain during adolescence, mother's excess weight, the use of obesogenic medication, augmented diastolic blood pressure, of abdominal circumference and waist/hip ratio. In addition to these, schooling and weight gain during childhood were also included in the multivariate analysis. After adjustment, the final model included: having a partner, weight gain during adolescence, augmented diastolic blood pressure and abdominal circumference. CONCLUSION: the analysis of predictor variables for excess weight among young adult students supports nurses in planning and developing educational practices aimed to prevent this clinical condition, which is a risk factor for other chronic comorbidities, such as cardiovascular diseases. PMID- 26039296 TI - Combined therapy of Ulmo honey (Eucryphia cordifolia) and ascorbic acid to treat venous ulcers. AB - OBJECTIVE: to assess the clinical effect of topical treatment using Ulmo honey associated with oral ascorbic acid in patients with venous ulcers. METHOD: longitudinal and descriptive quantitative study. During one year, 18 patients were assessed who were clinically diagnosed with venous ulcer in different stages, male and female, adult, with a mean injury time of 13 months. Ulmo honey was topically applied daily. The dressing was applied in accordance with the technical standard for advanced dressings, combined with the daily oral consumptions of 500 mg of ascorbic acid. The monitoring instrument is the assessment table of venous ulcers. RESULTS: full healing was achieved in 100% of the venous ulcers. No signs of complications were observed, such as allergies or infection. CONCLUSION: the proposed treatment showed excellent clinical results for the healing of venous ulcers. The honey demonstrated debriding and non adherent properties, was easy to apply and remove and was well accepted by the users. The described results generated a research line on chronic wound treatment. PMID- 26039297 TI - Cancer patients with oral mucositis: challenges for nursing care. AB - OBJECTIVE: to analyze nursing care provided to cancer patients with oral mucositis based on the Nursing Process (NP). METHOD: this exploratory, descriptive, cross-sectional and quantitative study was conducted with 213 patients undergoing chemotherapy and/or radiotherapy in two cancer facilities: one philanthropic and one private service. RESULTS: the participants were mainly female, aged 45.8 years old on average, with up to 11 years of schooling and income of up to one times the minimum wage. Severe mucositis was related to chemotherapy associated with radiotherapy. Only 25.3% of the patients reported having received guidance from nurses during their treatment concerning self-care. The perceptions of patients regarding quality of care did not significantly differ between the private and public facilities. The basic human needs mainly affected were comfort, eating, and hygiene. Based on this finding, one NP was established listing the diagnoses, interventions and expected results to establish an ideal, though individualized, standard of nursing care to be provided to these patients. CONCLUSION: to understand oral mucositis is crucial to establish nursing care that includes prevention based on the implementation of an oral care plan. PMID- 26039298 TI - The causes of bullying: results from the National Survey of School Health (PeNSE). AB - OBJECTIVE: to identify the characteristics and reasons reported by Brazilian students for school bullying. METHOD: this cross-sectional study uses data from an epidemiological survey (National Survey of School Health) conducted in 2012. A total of 109,104 9th grade students from private and public schools participated. Data were collected through a self-applied questionnaire and the analysis was performed using SPSS, version 20, Complex Samples Module. RESULTS: the prevalence of bullying was 7.2%, most frequently affecting Afro-descendant or indigenous younger boys, whose mothers were characterized by low levels of education. In regard to the reasons/causes of bullying, 51.2% did not specify; the second highest frequency of victimization was related to body appearance (18.6%); followed by facial appearance (16.2%); race/color (6.8%); sexual orientation 2.9%; religion 2.5%; and region of origin 1.7%. The results are similar to those found in other sociocultural contexts. CONCLUSION: the problem belongs to the health field because it gathers aspects that determine the students' health disease-care continuum. PMID- 26039299 TI - Exclusive breastfeeding practices reported by mothers and the introduction of additional liquids. AB - AIM: To assess the concept of exclusive breastfeeding held by nursing women by comparing the period they consider that they perform it and the infants' age at the introduction of additional liquids. METHOD: Cross-sectional descriptive study conducted with 309 women who delivered babies at a university hospital in the interior of Sao Paulo, Brazil. The data were subjected to descriptive analysis; the variables of interest were crossed using the non-parametric Kruskal-Wallis test, the chi-square test and Fisher's exact test. RESULTS: Approximately 30% of the women reported having introduced additional liquids before the infants reached aged six months old, while asserting that they were performing exclusive breastfeeding. The following variables were associated with early introduction of liquids: lack of employment (p = 0.0386), younger maternal age (p = 0.0159) and first pregnancy (p = 0.003). CONCLUSION: The concept of exclusive breastfeeding might not be fully clear to women, as they seem to believe that it means not to feed the children other types of milk but that giving other liquids is allowed. These results show that promotion of breastfeeding should take beliefs and values into consideration to achieve effective dialogue and understanding with mothers. PMID- 26039300 TI - Care for technology dependent children and their relationship with the health care systems. AB - OBJECTIVE: to understand the experience of care delivery to technology dependent children based on the mothers' experience. METHOD: exploratory study with qualitative approach, based on the theoretical framework of medical anthropology and the narrative method. Twelve mothers participated and, as the technique to obtain the narratives, open interviews were held at the participants' homes. RESULTS: the narratives were organized into three thematic categories: the family system, identifying the care forms, the association between popular and scientific knowledge and the participation of the social network; the professional system, which discusses the relations between professionals and family, the hegemony of the biomedical model and the role of nursing; and the popular system, presenting popular care practices like spirituality and religiosity. CONCLUSION: the study provided support for a health care project that takes into account the families' moral and symbolic values and beliefs in view of the illness of a technology-dependent child. The results found can contribute towards changes in the health work process, so that its foundation is guided not only by the biomedical model, allowing the integration of the sociocultural dimensions into the health care movement. PMID- 26039301 TI - Health needs: the interface between the discourse of health professionals and victimized women. AB - OBJECTIVE: to understand the limits and the evaluative possibilities of the Family Health Strategy regarding the recognition of the health needs of women who experience violence. METHOD: a study with a qualitative approach, grounded in the perspective of gender, and which adopted health needs as the analytical category. The data were collected through interviews with health professionals and women who made use of a health service, and were analyzed using the method of discourse analysis. RESULTS: the meeting between the discourses of women who use the services and the professionals of the health service revealed, as the interface, human needs, as in the example of autonomy and of bonds. The understanding regarding the needs was limited to the recognition of health problems of physical and psychological natures, just as the predominance of the recognition of needs for maintaining life in the light of essentially human needs was revealed in the professionals' discourses as an important limitation of the practices. CONCLUSION: emphasis is placed on the perspective of gender as a tool which must be aggregated to the routine of the professional practices in health so as to confirm or deny the transformative character of the care in place regarding the recognition and confronting of the women's health needs. PMID- 26039302 TI - Leisure activities and attitude of institutionalized elderly people: a basis for nursing practice. AB - AIM: to identify the leisure activities performed in Long-Stay Institutions for the Elderly (LSIEs), registered in the city of Maringa-PR, Brazil, and to analyze the attitude of the elderly people toward leisure promoted by the institutions. METHOD: this was a descriptive and transversal study with a quantitative approach, carried out with 97 elderly people, through the establishment of the socio-demographic profile and the application of the Leisure Attitude Scale. The data was subjected to descriptive statistical analysis, association tests (chi square or Fisher's) and Spearman's correlation. RESULTS: males, aged 80 or over, widowed, with one to eight years of study, who had a monthly income were predominant. Age group and income were significantly associated with the performance of leisure activities. The results reflected the positive attitude of the elderly people in relation to leisure activities, except in the behavioral component. CONCLUSION: the findings of this study indicate the need for further investigation into the difficulties linked to the attitude toward leisure in the behavioral component, considering aspects such as individual concepts of leisure and the health status of the elderly people. PMID- 26039303 TI - Psychosocial factors and mental work load: a reality perceived by nurses in intensive care units. AB - OBJECTIVE: To analyse the perception of psychosocial factors and mental workload of nurses who work in intensive care units. It is hypothesised that nurses in these units could perceive psychosocial risks, manifesting in a high mental work load. The psychosocial dimension related to the position's cognitive demands is hypothesised to mostly explain mental work load. METHOD: Quantitative study, with a descriptive, cross-sectional, and comparative design. A total of 91% of the intensive care unit populations of three Chilean hospitals was surveyed, corresponding to 111 nurses. The instruments utilised included (A) a biosociodemographic history questionnaire; (b) the SUSESO-ISTAS 21 questionnaire; and (c) the Mental Work Load Subjective Scale (ESCAM, in Spanish). RESULTS: In total, 64% and 57% of participants perceived high levels of exposure to the psychosocial risks Psychosocial demands and Double shift, respectively. In addition, a medium-high level of overall mental load was observed. Positive and significant correlations between some of the SUSESO-ISTAS 21 and ESCAM dimensions were obtained. Using a regression analysis, it was determined that three dimensions of the psychosocial risk questionnaire helped to explain 38% of the overall mental load. CONCLUSION: Intensive care unit nurses felt that inadequate psychosocial factors and mental work overload existed in several of the tested dimensions. PMID- 26039304 TI - A comparison of the level of fear of death among students and nursing professionals in Mexico. AB - OBJECTIVE: to compare the level of fear of death in nursing students and professionals. METHOD: this was a comparative-transversal study examining 643 nursing students and professionals from a third-level institution. A random sampling method was employed, and the sample size was calculated by power analysis. The study was developed during three stages: the first stage consisted of the application of a pilot test, the second stage involved the recruitment of the participants, and the third stage measured the participants' responses on the Collett-Lester Fear of Death Scale. RESULTS: the average fear of death was moderate-high (-X=3.19+/-0.55), and the highest score was observed for the fear of the death of others (-X=3.52+/-0.20). Significant differences in the perceptions of fear of death were observed among the students of the first three years (p<.05). However, no significant differences were observed among the first- and fourth-year students and professionals (p>.05). CONCLUSIONS: it is possible that first-year students exhibit a reduced fear of death because they have not had the experience of hospital practice. Students in their second and third year may have a greater fear of death because they have cared for terminal patients. However, it appears that greater confidence is acquired over time, and thus fourth-year students and professionals exhibit less fear of death than second- and third-year students (p<.05). PMID- 26039305 TI - Social determinants of health, inequality and social inclusion among people with disabilities. AB - OBJECTIVE: to analyze the socio-familial and community inclusion and social participation of people with disabilities, as well as their inclusion in occupations in daily life. METHOD: qualitative study with data collected through open interviews concerning the participants' life histories and systematic observation. The sample was composed of ten individuals with acquired or congenital disabilities living in the region covered by a Family Health Center. The social conception of disability was the theoretical framework used. Data were analyzed according to an interpretative reconstructive approach based on Habermas' Theory of Communicative Action. RESULTS: the results show that the socio-familial and community inclusion of the study participants is conditioned to the social determinants of health and present high levels of social inequality expressed by difficult access to PHC and rehabilitation services, work and income, education, culture, transportation and social participation. CONCLUSION: there is a need to develop community-centered care programs in cooperation with PHC services aiming to cope with poverty and improve social inclusion. PMID- 26039306 TI - Frequent users of emergency services: associated factors and reasons for seeking care. AB - AIM: to identify the profile of frequent users of emergency services, to verify the associated factors and to analyze the reasons for the frequent use of the services. METHOD: An explanatory sequential type mixed method was adopted. Quantitative data were collected from the electronic medical records, with a sample of 385 users attended four or more times in an emergency service, during the year 2011. Qualitative data were collected through semi-structured interviews with 18 users, intentionally selected from the results of the quantitative stage. Quantitative data were analyzed using descriptive and inferential statistics and qualitative data using thematic analysis. RESULTS: It was found that 42.9% were elderly, 84.9% had chronic diseases, 63.5% were classified as urgent, 42.1% stayed for more than 24 hours in the service and 46.5% were discharged. Scheduled follow-up appointment, risk classification, length of stay and outcome were factors associated with frequent use. The reasons for seeking the services were mainly related to the exacerbation of chronic diseases, to easier access and concentration of technology, to the bond, and to the scheduled appointments. CONCLUSIONS: The results contribute to comprehending the repeated use of emergency services and provide additional data to plan alternatives to reduce frequent use. PMID- 26039307 TI - Validation of the Portuguese version of the Evidence-Based Practice Questionnaire. AB - OBJECTIVES: to describe the process of translation and linguistic and cultural validation of the Evidence Based Practice Questionnaire for the Portuguese context: Questionario de Eficacia Clinica e Pratica Baseada em Evidencias (QECPBE). METHOD: a methodological and cross-sectional study was developed. The translation and back translation was performed according to traditional standards. Principal Components Analysis with orthogonal rotation according to the Varimax method was used to verify the QECPBE's psychometric characteristics, followed by confirmatory factor analysis. Internal consistency was determined by Cronbach's alpha. Data were collected between December 2013 and February 2014. RESULTS: 358 nurses delivering care in a hospital facility in North of Portugal participated in the study. QECPBE contains 20 items and three subscales: Practice (alpha=0.74); Attitudes (alpha=0.75); Knowledge/Skills and Competencies (alpha=0.95), presenting an overall internal consistency of alpha=0.74. The tested model explained 55.86% of the variance and presented good fit: chi2(167)=520.009; p = 0.0001; chi2df=3.114; CFI=0.908; GFI=0.865; PCFI=0.798; PGFI=0.678; RMSEA=0.077 (CI90%=0.07-0.08). CONCLUSION: confirmatory factor analysis revealed the questionnaire is valid and appropriate to be used in the studied context. PMID- 26039308 TI - Family care of people with severe mental disorders: an integrative review. AB - OBJECTIVE: to analyze the scientific literature on home-based family care of people with severe mental illness. METHOD: integrative review of 14 databases (CINALH, Cochrane Plus, Cuidatge, CUIDEN, Eric, IBECS, EMI, ISOC, JBI COnNECT, LILACS, PsycINFO, PubMed, SciELO, and Scopus) searched with the key words "family caregivers", "severe mental illness", and "home" between 2003 and 2013. RESULTS: of 787 articles retrieved, only 85 met the inclusion criteria. The articles appeared in 61 journals from different areas and disciplines, mainly from nursing (36%). The countries producing the most scientific literature on nursing were Brazil, the UK, and the US, and authorship predominantly belonged to university centers. A total of 54.12% of the studies presented quantitative designs, with descriptive ones standing out. Work overload, subjective perspectives, and resources were the main topics of these papers. CONCLUSIONS: the international scientific literature on home-based, informal family care of people with severe mental disorder is limited. Nursing research stands out in this field. The prevalent topics coincide with the evolution of the mental health system. The expansion of the scientific approach to family care is promoted to create evidence-based guidelines for family caregivers and for the clinical practice of professional caregivers. PMID- 26039309 TI - The American Board of Surgery Maintenance of Certification Program: Building on Past Successes. PMID- 26039310 TI - A supervised approach to quantifying sentence similarity: with application to evidence based medicine. AB - Following the Evidence Based Medicine (EBM) practice, practitioners make use of the existing evidence to make therapeutic decisions. This evidence, in the form of scientific statements, is usually found in scholarly publications such as randomised control trials and systematic reviews. However, finding such information in the overwhelming amount of published material is particularly challenging. Approaches have been proposed to automatically extract scientific artefacts in EBM using standardised schemas. Our work takes this stream a step forward and looks into consolidating extracted artefacts-i.e., quantifying their degree of similarity based on the assumption that they carry the same rhetorical role. By semantically connecting key statements in the literature of EBM, practitioners are not only able to find available evidence more easily, but also can track the effects of different treatments/outcomes in a number of related studies. We devise a regression model based on a varied set of features and evaluate it both on a general English corpus (the SICK corpus), as well as on an EBM corpus (the NICTA-PIBOSO corpus). Experimental results show that our approach performs on par with the state of the art on the general English and achieves encouraging results on the biomedical text when compared against human judgement. PMID- 26039312 TI - Correction: polyglutamine- and temperature-dependent conformational rigidity in mutant huntingtin revealed by immunoassays and circular dichroism spectroscopy. PMID- 26039311 TI - Human-Mediated Marine Dispersal Influences the Population Structure of Aedes aegypti in the Philippine Archipelago. AB - BACKGROUND: Dengue virus (DENV) is an extraordinary health burden on global scale, but still lacks effective vaccine. The Philippines is endemic for dengue fever, but massive employment of insecticides favored the development of resistance mutations in its major vector, Aedes aegypti. Alternative vector control strategies consist in releasing artificially modified mosquitos in the wild, but knowledge on their dispersal ability is necessary for a successful implementation. Despite being documented that Ae. aegypti can be passively transported for long distances, no study to date has been aimed at understanding whether human marine transportation can substantially shape the migration patterns of this mosquito. With thousands of islands connected by a dense network of ships, the Philippines is an ideal environment to fill this knowledge gap. METHODOLOGY/PRINCIPAL FINDINGS: Larvae of Ae. aegypti from 15 seaports in seven major islands of central-western Philippines were collected and genotyped at seven microsatellite loci. Low genetic structure and considerable gene flow was found in the area. Univariate and multivariate regression analyses suggested that anthropic factors (specifically the amount of processed cargo and human population density) can explain the observed population structure, while geographical distance was not correlated. Interestingly, cargo shipments seem to be more efficient than passenger ships in transporting Ae. aegypti. Bayesian clustering confirmed that Ae. aegypti from busy ports are more genetically similar, while populations from idle ports are relatively structured, regardless of the geographical distance that separates them. CONCLUSIONS/SIGNIFICANCE: The results confirmed the pivotal role of marine human-mediated long-range dispersal in determining the population structure of Ae. aegypti. Hopefully corroborated by further research, the present findings could assist the design of more effective vector control strategies. PMID- 26039313 TI - Phylogenetic Analysis of Bacterial Communities in Different Regions of the Gastrointestinal Tract of Agkistrodon piscivorus, the Cottonmouth Snake. AB - Vertebrates are metagenomic organisms in that they are composed not only of their own genes but also those of their associated microbial cells. The majority of these associated microorganisms are found in the gastrointestinal tract (GIT) and presumably assist in processes such as energy and nutrient acquisition. Few studies have investigated the associated gut bacterial communities of non mammalian vertebrates, and most rely on captive animals and/or fecal samples only. Here we investigate the gut bacterial community composition of a squamate reptile, the cottonmouth snake, Agkistrodon piscivorus through pyrosequencing of the bacterial 16S rRNA gene. We characterize the bacterial communities present in the small intestine, large intestine and cloaca. Many bacterial lineages present have been reported by other vertebrate gut community studies, but we also recovered unexpected bacteria that may be unique to squamate gut communities. Bacterial communities were not phylogenetically clustered according to GIT region, but there were statistically significant differences in community composition between regions. Additionally we demonstrate the utility of using cloacal swabs as a method for sampling snake gut bacterial communities. PMID- 26039314 TI - Body composition during growth in children: limitations and perspectives of bioelectrical impedance analysis. AB - There are a number of differences between the body composition of children and adults. Body composition measurements in children are inherently challenging, because of the rapid growth-related changes in height, weight, fat-free mass (FFM) and fat mass (FM), but they are fundamental for the quality of the clinical follow-up. All body composition measurements for clinical use are 'indirect' methods based on assumptions that do not hold true in all situations or subjects. The clinician must primarily rely on two-compartment models (that is, FM and FFM) for routine determination of body composition of children. Bioelectrical impedance analysis (BIA) is promising as a bedside method, because of its low cost and ease of use. This paper gives an overview of the differences in body composition between adults and children in order to understand and appreciate the difference in body composition during growth. It further discusses the use and limitations of BIA/bioelectrical spectroscopy (BIA/BIS) in children. Single frequency and multi-frequency BIA equations must be refined to better reflect the body composition of children of specific ethnicities and ages but will require development and cross-validation. In conclusion, recent studies suggest that BIA derived body composition and phase angle measurements are valuable to assess nutritional status and growth in children, and may be useful to determine baseline measurements at hospital admission, and to monitor progress of nutrition treatment or change in nutritional status during hospitalization. PMID- 26039315 TI - Clustering of lifestyle behaviours and relation to body composition in European children. The IDEFICS study. AB - BACKGROUND: Dietary patterns, physical activity (PA) and sedentary behaviours are some of the main behavioural determinants of obesity; their combined influence in children has been addressed in a limited number of studies. SUBJECTS/METHODS: Children (16,228) aged 2-9 years old from eight European countries participated in the baseline survey of the IDEFICS study. A subsample of 11,674 children (50.8% males) were included in the present study. Children's food and beverage consumption (fruit and vegetables (F&V) and sugar-sweetened beverages (SSBs)), PA and sedentary behaviours were assessed via parental questionnaires. Sex-specific cluster analysis was applied to identify behavioural clusters. Analysis of covariance and logistic regression were applied to examine the association between behavioural clusters and body composition indicators (BCIs). RESULTS: Six behavioural clusters were identified (C1-C6) both in boys and girls. In both sexes, clusters characterised by high level of PA (C1 and C3) included a large proportion of older children, whereas clusters characterised by low SSB consumption (C5 and C6) included a large proportion of younger children. Significant associations between derived clusters and BCI were observed only in boys; those boys in the cluster with the highest time spent in sedentary activities and low PA had increased odds of having a body mass index z-score (odds ratio (OR)=1.33; 95% confidence interval (CI)=(1.01, 1.74)) and a waist circumference z-score (OR=1.41; 95%CI=(1.06, 1.86)) greater than one. CONCLUSION: Clusters characterised by high sedentary behaviour, low F&V and SSB consumption and low PA turned out to be the most obesogenic factors in this sample of European children. PMID- 26039317 TI - Aspects of protected mealtimes are associated with improved mealtime energy and protein intakes in hospitalized adult patients on medical and surgical wards over 2 years. AB - BACKGROUND/OBJECTIVES: Protected mealtimes programs aim to improve inpatient intakes. Yet its efficacy has not yet been established. We aimed to determine which patient-related factors and aspects of protected mealtimes, for example, mealtime assistance and meal within reach, were associated with energy and protein intakes of adult inpatients on medical and surgical wards. SUBJECTS/METHODS: Patient characteristics and dietary intake data were collected at main meals over 2 years. Proportions of individual foods and drinks consumed were visually estimated and converted to nutrients using averaged ready reckoner data. Mealtime factors associated with energy and protein intakes were determined using multivariate linear hierarchical regression analyses. RESULTS: Over 2 years, mealtime nutrient intakes of 798 inpatients were calculated ((63 +/- 19) years, 52% male). Average intakes at main meals were 1419 +/- 614 kJ and 15 +/- 7 g protein. Inpatient intakes were significantly associated with gender, age, season, stopping or refusing a meal, time until discharge and eating at dinner (B = -829-222 kJ, B = -8.8 to 2.2 g protein, P = 0.000-0.032). Protected mealtimes program implementation was not associated with inpatient intake (P=0.094-0.157). However, aspects of protected mealtimes were associated with intake. This included requiring and documenting the need for mealtime assistance, introduction of mealtime volunteers, time to eat and appropriate positioning during mealtimes (B = 177-296 kJ, B = 0.07-3.9 g protein, P=0.000-0.014, R(2) = 0.148-0.154). In those specifically requiring mealtime assistance, inpatient protein intake was associated with mealtime volunteers and appropriate positioning (B = 4.1-4.4 g protein, P = 0.013-0.026, R(2) = 0.197). CONCLUSIONS: Aspects of protected mealtimes were associated with improved intake. Identifying these achievable aspects during planning and ensuring successful implementation of protected mealtimes may be critical for optimizing acute inpatient intake. PMID- 26039316 TI - Association of oxidative stress biomarkers with adiposity and clinical staging in women with breast cancer. AB - BACKGROUND/OBJECTIVES: Breast cancer is a disease characterised by both oxidative reactions and inflammation. However, few studies have focused on the oxidative and inflammatory biomarkers. The aim of the present study was to evaluate the association between oxidative stress markers and adiposity and clinical staging, as well as the association between the oxidative and the antioxidant biomarkers of women with breast cancer. SUBJECTS/METHODS: A total of 135 cases of breast cancer occurring in 2011 and 2012 were assessed. After exclusions, 101 pre- and post-menopausal women with clinical staging I to IV were eligible to participate in the study. The anthropometric evaluation was performed by collecting data on waist circumference, body mass index and body composition. The socioeconomic and clinical profiles were determined using a standard questionnaire. For the oxidative biomarkers, thiobarbituric acid reactive substances (TBARS), oxidative DNA damage (8-hydroxy-2-deoxyguanosine (8-OHdG)), low-density lipoprotein(-) (LDL(-)), autoantibody anti-LDL(-) and liposoluble antioxidants (alpha tocopherol, retinol and beta-carotene) were analysed. The data were analysed using differences in the mean values, correlation tests and multiple linear regression. RESULTS: The antioxidant levels were higher in postmenopausal women with clinical staging I and II and negative lymph nodes. The TBARS level was associated with clinical staging. Adiposity was associated with levels of retinol and 8-OHdG, whereas LDL(-), 8-OHdG and TBARS were correlated with liposoluble antioxidants after adjusting for the confounders. CONCLUSIONS: The adiposity and clinical staging of patients were associated with oxidative stress. The oxidative and antioxidant biomarkers showed a negative correlation in patients with breast cancer. PMID- 26039318 TI - Changes in muscle and fat mass with haemodialysis detected by multi-frequency bioelectrical impedance analysis. AB - BACKGROUND/OBJECTIVES: Multi-frequency bioelectrical impedance analysis (MFBIA) is becoming more widely used to assess hydration status and body composition in haemodialysis patients. Most centres only measure MFBIA pre dialysis when patients are overhydrated. We wished to determine whether body composition assessments change post dialysis following fluid removal. SUBJECTS/METHODS: Lean body and fat mass were measured by MFBIA pre and post haemodialysis in 676 stable outpatients. RESULTS: Weight fell post dialysis from 72.9 +/- 17.8 to 70.9 +/- 19.9 kg, P<0.001, soft lean mass from 48.2 +/- 12.1 to 45.4 +/- 11.0 kg and fat free mass from 51.8 +/- 19.2 to 48.1 +/- 11.8 kg, P<0.001, whereas percentage body fat (PBF) increased from 28.8 +/- 11.9 to 30.8 +/- 12.1% post dialysis, P<0.001, with a mean increase post dialysis of 2.0% (95% confidence limits 1.55 to 2.45). There were correlations between the fall in total body water and extracellular water and skeletal muscle mass (r=0.826, P<0.001 and r=0.711, P<0.001, respectively), and negative correlation between the fall in total body water and ICW and the increase in PBF (r=-0.72, P<0.001, and -0.72, P<0.001, respectively). The relative changes were greater for the arms compared with the legs. CONCLUSIONS: Although more convenient for both patients and staff to undertake bioimpedance measurements pre dialysis, overhydration over estimates muscle mass and under estimates fat. For more reliable and reproducible assessments of nutritional status, we suggest that bioimpedance measurements of body composition should be made when patients are closer to their target weight than when overhydrated. PMID- 26039319 TI - Vitamin B6 intoxication after inappropriate supplementation with micronutrients following bariatric surgery. AB - A 50-year-old Caucasian woman was admitted to our hospital with intermittent diarrhoea, emesis and increasingly brown-coloured skin, mainly the in light exposed areas, after biliopancreatic diversion for obesity treatment. Differential diagnoses such as adrenal insufficiency were ruled out, but biochemical analysis demonstrated unusual high pyridoxine serum levels (vitamin B6). History revealed the intake of 300 mg of vitamin B6 per day over 6 months as described by her general practitioner. All symptoms disappeared after the discontinuation of vitamin B6 supplementation. Importantly, in contrast to many other vitamins and supplements, there is no evidence in the literature of the occurrence of vitamin B6 deficiency after bariatric surgery. Therefore, supplementation of vitamins and supplements in bariatric patients has to be carefully considered according to the existing clinical guidelines, as uncritical oversupplementation of micronutrients might result in intoxication and serious illness as presented here. PMID- 26039322 TI - Effects of grazing and precipitation on herbage biomass, herbage nutritive value, and yak performance in an alpine meadow on the Qinghai-Tibetan Plateau. AB - The Qinghai-Tibetan Plateau is a very large land unit and an important terrestrial ecosystem within the Eurasian continent. Because of the harsh climate associated with the high altitude, alpine meadows on the plateau are susceptible to degradation from overgrazing. For this region, and for other alpine meadow pastures internationally, there is a need to define the sustainable stocking rate, to develop sound policy pertaining to future land use. Here we report biomass and liveweight gain per animal and per ha for pastures grazed by yaks at high, medium, or low stocking rates over 4 growing seasons from 2010 to 2013. Measures of herbage nutritive value are reported. The influence of inter-year variation in precipitation on standing herbage biomass was also evaluated. Higher precipitation increased standing herbage biomass and herbage nutritive value, indicating that vegetation suffered summer water deficit even in this environment. The sustainable stocking rate in this environment was determined to be approximately 1 yak ha-1 (grown from 80 kg to 120 kg liveweight in 90 d). At this stocking rate, yak weight gain per ha was 88% of that achieved at higher stocking rates typically used by farmers, but with little or no evidence of land degradation. PMID- 26039320 TI - Lipoxin Signaling in Murine Lung Host Responses to Cryptococcus neoformans Infection. AB - Lipoxins (LX) are proresolving mediators that augment host defense against bacterial infection. Here, we investigated roles for LX in lung clearance of the fungal pathogen Cryptococcus neoformans (Cne). After intranasal inoculation of 5,000 CFU Cne, C57BL/6 and C.B-17 mice exhibited strain-dependent differences in Cne clearance, immunologic responses, and lipoxin A4 (LXA4) formation and receptor (ALX/FPR2) expression. Compared with C.B-17 mice, C57BL/6 lungs had increased and persistent Cne infection 14 days after inoculation, increased eosinophils, and distinct profiles of inflammatory cytokines. Relative to C.B-17 mice, bronchoalveolar lavage fluid levels of LXA4 were increased before and after infection in C57BL/6. The kinetics for 15-epi-LXA4 production were similar in both strains. Lung basal expression of the LX biosynthetic enzyme Alox12/15 (12/15-lipoxygenase) was increased in C57BL/6 mice and further increased after Cne infection. In contrast, lung basal expression of the LXA4 receptor Alx/Fpr2 was higher in C.B-17 relative to C57BL/6 mice, and after Cne infection, Alx/Fpr2 expression was significantly increased in only C.B-17 mice. Heat-killed Cne initiated lung cell generation of IFN-gamma and IL-17 and was further increased in C.B-17 mice by 15-epi-LXA4. A trend toward reduced Cne clearance and IFN-gamma production was observed upon in vivo administration of an ALX/FPR2 antagonist. Together, these findings provide the first evidence that alterations in cellular immunity against Cne are associated with differences in LXA4 production and receptor expression, suggesting an important role for ALX/FPR2 signaling in the regulation of pathogen-mediated inflammation and antifungal lung host defense. PMID- 26039323 TI - Piezo-phototronic Effect Enhanced UV/Visible Photodetector Based on Fully Wide Band Gap Type-II ZnO/ZnS Core/Shell Nanowire Array. AB - A high-performance broad band UV/visible photodetector has been successfully fabricated on a fully wide bandgap ZnO/ZnS type-II heterojunction core/shell nanowire array. The device can detect photons with energies significantly smaller (2.2 eV) than the band gap of ZnO (3.2 eV) and ZnS (3.7 eV), which is mainly attributed to spatially indirect type-II transition facilitated by the abrupt interface between the ZnO core and ZnS shell. The performance of the device was further enhanced through the piezo-phototronic effect induced lowering of the barrier height to allow charge carrier transport across the ZnO/ZnS interface, resulting in three orders of relative responsivity change measured at three different excitation wavelengths (385, 465, and 520 nm). This work demonstrates a prototype UV/visible photodetector based on the truly wide band gap semiconducting 3D core/shell nanowire array with enhanced performance through the piezo-phototronic effect. PMID- 26039324 TI - Solid-state Reaction of Azolium Hydrohalogen Salts with Silver Dicyanamide- Unexpected Formation of Cyanoguanidine-azoles, Reaction Mechanism and Their Hypergolic Properties. AB - Cyanoguanidines as well as azoles are important bioactive groups, which play an important role in the medical application; meanwhile, the high nitrogen content makes them excellent backbones for energetic materials. A Novel and simple method that combined these two fragments into one molecular compound was developed through the transformation of dicyanamide ionic salts. In return, compounds 4-11 were synthesized, and fully characterized by IR, MS, NMR and elemental analysis. Meanwhile, the structures of compounds 4, 8 and 11 were confirmed by X-ray crystal diffraction. Detailed reaction mechanisms were studied through accurate calculations on the reaction energy profiles of the azolium cations and DCA anion, which revealed the essence of the transformation proceeding. Meanwhile, compound 8 exhibits excellent hypergolic property, which could be potentially novel molecular hypergolic fuel. PMID- 26039326 TI - Neglect in human communication: quantifying the cost of cell-phone interruptions in face to face dialogs. AB - There is a prevailing belief that interruptions using cellular phones during face to face interactions may affect severely how people relate and perceive each other. We set out to determine this cost quantitatively through an experiment performed in dyads, in a large audience in a TEDx event. One of the two participants (the speaker) narrates a story vividly. The listener is asked to deliberately ignore the speaker during part of the story (for instance, attending to their cell-phone). The speaker is not aware of this treatment. We show that total amount of attention is the major factor driving subjective beliefs about the story and the conversational partner. The effects are mostly independent on how attention is distributed in time. All social parameters of human communication are affected by attention time with a sole exception: the perceived emotion of the story. Interruptions during day-to-day communication between peers are extremely frequent. Our data should provide a note of caution, by indicating that they have a major effect on the perception people have about what they say (whether it is interesting or not . . .) and about the virtues of the people around them. PMID- 26039327 TI - Infantile Hemangioma in the Airway. PMID- 26039325 TI - Endothelial cell and podocyte autophagy synergistically protect from diabetes induced glomerulosclerosis. AB - The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of Atg5 specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelial-specific deletion of Atg5 also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN. PMID- 26039328 TI - Biological Impact of Transpulmonary Driving Pressure in Experimental Acute Respiratory Distress Syndrome. AB - BACKGROUND: Ventilator-induced lung injury has been attributed to the interaction of several factors: tidal volume (VT), positive end-expiratory pressure (PEEP), transpulmonary driving pressure (difference between transpulmonary pressure at end-inspiration and end-expiration, DeltaP,L), and respiratory system plateau pressure (Pplat,rs). METHODS: Forty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, animals were randomized into combinations of VT and PEEP, yielding three different DeltaP,L levels: DeltaP,LLOW (VT = 6 ml/kg, PEEP = 3 cm H2O); DeltaP,LMEAN (VT = 13 ml/kg, PEEP = 3 cm H2O or VT = 6 ml/kg, PEEP = 9.5 cm H2O); and DeltaP,LHIGH (VT = 22 ml/kg, PEEP = 3 cm H2O or VT = 6 ml/kg, PEEP = 11 cm H2O). In other groups, at low VT, PEEP was adjusted to obtain a Pplat,rs similar to that achieved with DeltaP,LMEAN and DeltaP,LHIGH at high VT. RESULTS: At DeltaP,LLOW, expressions of interleukin (IL)-6, receptor for advanced glycation end products (RAGE), and amphiregulin were reduced, despite morphometric evidence of alveolar collapse. At DeltaP,LHIGH (VT = 6 ml/kg and PEEP = 11 cm H2O), lungs were fully open and IL-6 and RAGE were reduced compared with DeltaP,LMEAN (27.4 +/- 12.9 vs. 41.6 +/- 14.1 and 0.6 +/- 0.2 vs. 1.4 +/- 0.3, respectively), despite increased hyperinflation and amphiregulin expression. At DeltaP,LMEAN (VT = 6 ml/kg and PEEP = 9.5 cm H2O), when PEEP was not high enough to keep lungs open, IL-6, RAGE, and amphiregulin expression increased compared with DeltaP,LLOW (41.6 +/- 14.1 vs. 9.0 +/- 9.8, 1.4 +/- 0.3 vs. 0.6 +/- 0.2, and 6.7 +/- 0.8 vs. 2.2 +/- 1.0, respectively). At Pplat,rs similar to that achieved with DeltaP,LMEAN and DeltaP,LHIGH, higher VT and lower PEEP reduced IL-6 and RAGE expression. CONCLUSION: In the acute respiratory distress syndrome model used in this experiment, two strategies minimized ventilator-induced lung injury: (1) low VT and PEEP, yielding low DeltaP,L and Pplat,rs; and (2) low VT associated with a PEEP level sufficient to keep the lungs open. PMID- 26039329 TI - Miller's Textbook: A Review for Undergraduates. PMID- 26039330 TI - Harlequin Syndrome Associated with Thoracic Epidural Analgesia. PMID- 26039331 TI - Radiological Comparison of the Lacrimal Sac Fossa Anatomy Between Black Africans and Caucasians. AB - PURPOSE: To compare, in black Africans and Caucasians, the radiological anatomy of the intranasal structures and lacrimal sac fossa as relevant to dacryocystorhinostomy. METHODS: 0.75 mm section cranio-orbital computed tomography scans from 72 patients (42 black Africans and 30 Caucasian) were included in this retrospective observational case series. Only one orbit from each scan was utilized. The main outcome measures were: the thickness and proportions of the lacrimal bone and frontal process of the maxilla evaluated at 3 axial planes (upper, middle, lower) in the lacrimal sac fossa; 2 measurements of maxillary thickness were obtained at each plane-namely, the "midpoint thickness" and the "maximum thickness." The anterior extent of the nasal mucosa was also evaluated. RESULTS: The frontal process of the maxilla was thickest inferiorly (p < 0.001) and the maximum maxillary thickness was significantly thicker in black Africans as compared with Caucasians (p < 0.001) at all planes. At midfossa level, the proportion of maxillary bone forming the lacrimal fossa wall was significantly greater in black Africans (p < 0.01). In contrast, the length of nasal mucosa available for creation of an anastomosis, as estimated from the greatest mucosal height, was significantly greater in Caucasians (p < 0.01). CONCLUSIONS: Black Africans have a lacrimal sac fossa bounded by thicker maxillary bone, this bone constituting a higher proportion of the fossa wall at its midpoint, and also have significantly less nasal mucosa available for soft tissue anastomosis during lacrimal drainage surgery. The anterior lacrimal crest, comprising the frontal process of the maxilla, was thickest at the lowest plane in both black Africans and Caucasians. PMID- 26039332 TI - Multidrug-resistant Trichosporon: an unusual fungal sepsis in preterm neonates. AB - We report a cluster of three extremely-low birth weight (ELBW), preterm neonates who developed late-onset sepsis (LOS) by Trichosporon asahii within a span of 1 week period. Two of these cases had the initial diagnosis of respiratory distress syndrome and the third one was admitted for low birth weight and prematurity. Initial sepsis screen was negative and blood culture was sterile in all. Late onset sepsis was developed after the first week of life and the presenting features were lethargy, feeding intolerance, bleeding manifestations, positive sepsis screen and severe thrombocytopaenia. The isolates were sensitive to voriconazole but resistant to both amphotericin-B and fluconazole on all occasions. All the infants were treated with liposomal amphotericin-B before the availability of culture reports but the clinical deterioration was rapid and all three neonates succumbed to death before we could procure voriconazole. The source of the outbreak could not be identified from multiple surface cultures from the unit and screening of the health care staffs. We emphasise the need for high index of suspicion for unusual fungal pathogens, resistant to conventional antifungal drugs while treating preterm neonates with LOS. PMID- 26039333 TI - Synthesis and biological evaluation of 2-picolylamide-based diselenides with non bonded interactions. AB - In this paper, we report the synthesis and biological evaluation of picolylamide based diselenides with the aim of developing a new series of diselenides with O...Se non-bonded interactions. The synthesis of diselenides was performed by a simple and efficient synthetic route. All the products were obtained in good yields and their structures were determined by 1H-NMR, 13C-NMR and HRMS. All these new compounds showed promising activities when tested in different antioxidant assays. These amides exhibited strong thiol peroxidase-like (TPx) activity. In fact one of the compounds showed 4.66 times higher potential than the classical standard i.e., diphenyl diselenide. The same compound significantly inhibited iron (Fe)-induced thiobarbituric acid reactive species (TBARS) production in rat's brain homogenate. In addition, the X-ray structure of the most active compound showed non-bonded interaction between the selenium and the oxygen atom that are in close proximity and may be responsible for the increased antioxidant activity. The present study provides evidence about the possible biochemical influence of nonbonding interactions on organochalcogens potency. PMID- 26039334 TI - Application of the Cre/loxP Site-Specific Recombination System for Gene Transformation in Aurantiochytrium limacinum. AB - The Cre/loxP site-specific recombination system was applied to Aurantiochytrium limacinum to obtain a transformant without the antibiotic resistance marker gene. First, the enhanced green fluorescent protein gene (egfp) and chloramphenicol resistance gene (Cmr), along with the two loxP loci, were integrated into the genome of A. limacinum OUC88 using 18S rDNA sequences as the homologous recombination sites. Then plasmid pSH65, containing a zeocin resistance gene (Bler) was transferred into A. limacinum OUC_CG. After induction with galactose, repeated passage in culture and PCR-based assessment, the pSH65 plasmid was lost and A. limacinum OUC_EG host was shown to no longer have resistance to 100 mg chloramphenicol/L or 5 mg zeocin/L. Through southern blotting and fluorescence detection, egfp was found to be integrated into the genome of A. limacinum OUC_EG, and EGFP was successfully expressed in the cells. The successful application of the Cre/loxP system demonstrates an experimental basis for genetic modification of A. limacinum so as to obtain transformed strains with no antibiotic resistance marker genes. PMID- 26039335 TI - Chlorination of (Phebox)Ir(mesityl)(OAc) by Thionyl Chloride. AB - Pincer (Phebox)Ir(mesityl)(OAc) (2) (Phebox = 3,5-dimethylphenyl-2,6 bis(oxazolinyl)) complex, formed by benzylic C-H activation of mesitylene (1,3,5 trimethylbenzene) using (Phebox)Ir(OAc)2OH2 (1), was treated with thionyl chloride to rapidly form 1-(chloromethyl)-3,5-dimethylbenzene in 50% yield at 23 degrees C. A green species was obtained at the end of reaction, which decomposed during flash column chromatography to form (Phebox)IrCl2OH2 in 87% yield. PMID- 26039336 TI - An Alternative Method for Generating Arynes from ortho-Silylaryl Triflates: Activation by Cesium Carbonate in the Presence of a Crown Ether. AB - An alternative method for generating arynes from ortho-silylaryl triflates using cesium carbonate and 18-crown-6 is reported. The method was efficiently applied to a variety of reactions between several arynes and arynophiles. We also demonstrated that the efficiency of aryne generation is significantly affected by the alkali metal countercation of the carbonate. PMID- 26039337 TI - Isolation of an Angiotensin I-Converting Enzyme Inhibitory Protein with Antihypertensive Effect in Spontaneously Hypertensive Rats from the Edible Wild Mushroom Leucopaxillus tricolor. AB - An 86-kDa homodimeric angiotensin I-converting enzyme (ACE) inhibitory protein designated as LTP was isolated from fruit bodies of the mushroom Leucopaxillus tricolor. The isolation procedure involved ultrafiltration through a membrane with a molecular weight cutoff of 10-kDa, ion exchange chromatography on Q Sepharose, and finally fast protein liquid chromatography-gel filtration on Superdex 75. LTP exhibited an IC50 value of 1.64 mg?mL-1 for its ACE inhibitory activity. The unique N-terminal amino acid sequence of LTP was disclosed by Edman degradation to be DGPTMHRQAVADFKQ. In addition, seven internal sequences of LTP were elucidated by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Results of the Lineweaver-Burk plot suggested that LTP competitively inhibited ACE. Both LTP and the water extract of L. tricolor exhibited a clear antihypertensive effect on spontaneously hypertensive rats. PMID- 26039339 TI - Erratum: Salmonella type III effector SopB modulates host cell exocytosis. AB - [This corrects the article DOI: 10.1038/emi.2013.31.]. PMID- 26039338 TI - No evidence for ape Plasmodium infections in humans in Gabon. AB - African great apes are naturally infected by a multitude of Plasmodium species most of them recently discovered, among which several are closely related to human malaria agents. However, it is still unknown whether these animals can serve as source of infections for humans living in their vicinity. To evaluate this possibility, we analysed the nature of Plasmodium infections from a bank of 4281 human blood samples collected in 210 villages of Gabon, Central Africa. Among them, 2255 were detected positive to Plasmodium using molecular methods (Plasmodium Cytochrome b amplification). A high throughput sequencing technology (454 GS-FLX Titanium technology, Roche) was then used to identify the Plasmodium species present within each positive sample. Overall, we identified with confidence only three species infecting humans in Gabon: P. falciparum, P. malariae and P. ovale. None of the species known to infect non-human primates in Central Africa was found. Our study shows that ape Plasmodium parasites of the subgenus Laverania do not constitute a frequent source of infection for humans. It also suggests that some strong host genetic barriers must exist to prevent the cross species transmission of ape Plasmodium in a context of ever increasing contacts between humans and wildlife. PMID- 26039342 TI - Correction: epstein-barr virus genetic variation in lymphoblastoid cell lines derived from Kenyan pediatric population. PMID- 26039340 TI - Identification of novel gene targets and putative regulators of arsenic associated DNA methylation in human urothelial cells and bladder cancer. AB - There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic-induced carcinogenesis. Genome wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total arsenic and arsenic species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 arsenic-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the arsenic- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer. PMID- 26039341 TI - Design of Protease Activated Optical Contrast Agents That Exploit a Latent Lysosomotropic Effect for Use in Fluorescence-Guided Surgery. AB - There is a need for new molecular-guided contrast agents to enhance surgical procedures such as tumor resection that require a high degree of precision. Cysteine cathepsins are highly up-regulated in a wide variety of cancers, both in tumor cells and in the tumor-supporting cells of the surrounding stroma. Therefore, tools that can be used to dynamically monitor their activity in vivo could be used as imaging contrast agents for intraoperative fluorescence image guided surgery (FGS). Although multiple classes of cathepsin-targeted substrate probes have been reported, most suffer from overall fast clearance from sites of protease activation, leading to reduced signal intensity and duration in vivo. Here we describe the design and synthesis of a series of near-infrared fluorogenic probes that exploit a latent cationic lysosomotropic effect (LLE) to promote cellular retention upon protease activation. These probes show tumor specific retention, fast activation kinetics, and rapid systemic distribution. We demonstrate that they are suitable for detection of diverse cancer types including breast, colon and lung tumors. Most importantly, the agents are compatible with the existing, FDA approved, da Vinci surgical system for fluorescence guided tumor resection. Therefore, our data suggest that the probes reported here can be used with existing clinical instrumentation to detect tumors and potentially other types of inflammatory lesions to guide surgical decision making in real time. PMID- 26039343 TI - DOSY NMR, X-ray Structural and Ion-Mobility Mass Spectrometric Studies on Electron-Deficient and Electron-Rich M6L4 Coordination Cages. AB - A novel modular approach to electron-deficient and electron-rich M6L4 cages is presented. From the same starting compound, via a minor modulation of the synthesis route, two C3-symmetric ligands L1 and L2 with different electronic properties are obtained in good yield. The trifluoro-triethynylbenzene-based ligand L1 is more electron-deficient than the well-known 2,4,6-tri(4-pyridyl) 1,3,5-triazine, while the trimethoxy-triethynylbenzene-based ligand L2 is more electron-rich than the corresponding benzene analogue. Complexation of the ligands with cis-protected square-planar [(dppp)Pt(OTf)2] or [(dppp)Pd(OTf)2] corner-complexes yields two electron-deficient (1a and 1b) and two electron-rich (2a and 2b) M6L4 cages. The single crystal X-ray diffraction study of 1a and 2a confirms the expected octahedral shape with a ca. 2000 A(3) cavity and ca. 11 A wide apertures. The crystallographically determined diameters of 1a and 2a are 3.7 and 3.6 nm, respectively. The hydrodynamic diameters obtained from the DOSY NMR in CDCl3:CD3OD (4:1), and diameters calculated from collision cross sections (CCS) acquired by ion-mobility mass spectrometry (IM-MS) were for all four cages similar. In solution, the cage structures have diameters between 3.3 to 3.6 nm, while in the gas phase the corresponding diameters varied between 3.4 to 3.6 nm. In addition to the structural information the relative stabilities of the Pt6L4 and Pd6L4 cages were studied in the gas phase by collision-induced dissociation (CID) experiments, and the photophysical properties of the ligands L1 and L2 and cages 1a, 1b, 2a, and 2b were studied by UV-vis and fluorescence spectroscopy. PMID- 26039344 TI - Movement and specificity in a modular DNA binding protein. AB - The single-stranded DNA (ssDNA) binding protein RPA binds to and protects ssDNA while simultaneously recruiting numerous replication and repair proteins essential for genome integrity. In this issue of Structure, Brosey et al. (2015) show that the flexibility and interactions of the modular domains of RPA are altered by ssDNA binding and suggest that these changes in configurational freedom are important for the many functions of RPA. PMID- 26039345 TI - Kinase Regulation in Mycobacterium tuberculosis: Variations on a Theme. AB - In this issue of Structure, Lisa et al. (2015) examine how the PknG protein kinase of M. tuberculosis efficiently binds and phosphorylates substrates. The work highlights interesting parallels between PknG and eukaryotic protein kinases. PMID- 26039346 TI - Ribosome subunit joining frozen in time. AB - In this issue of Structure, Chen et al. (2015) report the use of a mixing spraying method of time-resolved cryogenic electron microscopy, which allowed the progression of ribosomal subunit association to be visualized on the millisecond timescale. PMID- 26039347 TI - From shellfish poisoning to neuroscience. AB - In this issue of Structure, Bourne et al. (2015) report X-ray structures of acetylcholine binding protein with two fast-acting phycotoxins from the pinnatoxin family. The results may pave the way for development of new CNS penetrant and subtype-selective nAChR antagonists. PMID- 26039348 TI - Computational Refinement and Validation Protocol for Proteins with Large Variable Regions Applied to Model HIV Env Spike in CD4 and 17b Bound State. AB - Envelope glycoprotein gp120 of HIV-1 possesses several variable regions; their precise structure has been difficult to establish. We report a new model of gp120, in complex with antibodies CD4 and 17b, complete with its variable regions. The model was produced by a computational protocol that uses cryo electron microscopy (EM) maps, atomic-resolution structures of the core, and information on binding interactions. Our model has excellent fit with EMD: 5020, is stereochemically and energetically favorable, and has the expected binding interfaces. Comparison of the ternary arrangement of the loops in this model with those bound to PGT122 and PGV04 suggested a possible motion of the V1V2 away from the CCR5 binding site and toward CD4. Our study also revealed that the CD4-bound state of the V1V2 loop is not optimal for gp120 bound with several neutralizing antibodies. PMID- 26039349 TI - Patterns of Mass Mortality among Rocky Shore Invertebrates across 100 km of Northeastern Pacific Coastline. AB - Mass mortalities in natural populations, particularly those that leave few survivors over large spatial areas, may cause long-term ecological perturbations. Yet mass mortalities may remain undocumented or poorly described due to challenges in responding rapidly to unforeseen events, scarcity of baseline data, and difficulties in quantifying rare or patchily distributed species, especially in remote or marine systems. Better chronicling the geographic pattern and intensity of mass mortalities is especially critical in the face of global changes predicted to alter regional disturbance regimes. Here, we couple replicated post-mortality surveys with preceding long-term surveys and historical data to describe a rapid and severe mass mortality of rocky shore invertebrates along the north-central California coast of the northeastern Pacific Ocean. In late August 2011, formerly abundant intertidal populations of the purple sea urchin (Strongylocentrotus purpuratus, a well-known ecosystem engineer), and the predatory six-armed sea star (Leptasterias sp.) were functionally extirpated from ~100 km of coastline. Other invertebrates, including the gumboot chiton (Cryptochiton stelleri) the ochre sea star (Pisaster ochraceus), and subtidal populations of purple sea urchins also exhibited elevated mortality. The pattern and extent of mortality suggest the potential for long-term population, community, and ecosystem consequences, recovery from which may depend on the different dispersal abilities of the affected species. PMID- 26039352 TI - [Severe leg trauma in a resource-poor environment: indications for amputation in emergencies]. AB - Although the development of multitissue limb reconstruction has reduced the role of post-traumatic primary amputation of the leg, some patients should nonetheless undergo emergency amputations. In developing countries, the socioeconomic context associated with the limited health care supply compromises still further the prognosis of preservation efforts. The decision criteria for surgery are thus different in these settings. The choice of emergency leg amputation or attempted preservation in developing countries depends on the epidemiology of severe leg trauma, the local and general prognosis, and the practice conditions. Three factors must be combined before limb preservation can be attempted: adequate local and general adequate wound elements, an available, experienced surgeon with a competent care structure, and a favorable social context. PMID- 26039353 TI - Realization of high-luminous-efficiency InGaN light-emitting diodes in the "green gap" range. AB - Light-emitting diodes (LEDs) in the wavelength region of 535-570 nm are still inefficient, which is known as the "green gap" problem. Light in this range causes maximum luminous sensation in the human eye and is therefore advantageous for many potential uses. Here, we demonstrate a high-brightness InGaN LED with a normal voltage in the "green gap" range based on hybrid multi-quantum wells (MQWs). A yellow-green LED device is successfully fabricated and has a dominant wavelength, light output power, luminous efficiency and forward voltage of 560 nm, 2.14 mW, 19.58 lm/W and 3.39 V, respectively. To investigate the light emitting mechanism, a comparative analysis of the hybrid MQW LED and a conventional LED is conducted. The results show a 2.4-fold enhancement of the 540 nm light output power at a 20-mA injection current by the new structure due to the stronger localization effect, and such enhancement becomes larger at longer wavelengths. Our experimental data suggest that the hybrid MQW structure can effectively push the efficient InGaN LED emission toward longer wavelengths, connecting to the lower limit of the AlGaInP LEDs' spectral range, thus enabling completion of the LED product line covering the entire visible spectrum with sufficient luminous efficacy. PMID- 26039354 TI - Transcranial Near-Infrared Laser Transmission (NILT) Profiles (800 nm): Systematic Comparison in Four Common Research Species. AB - BACKGROUND AND PURPOSE: Transcranial near-infrared laser therapy (TLT) is a promising and novel method to promote neuroprotection and clinical improvement in both acute and chronic neurodegenerative diseases such as acute ischemic stroke (AIS), traumatic brain injury (TBI), and Alzheimer's disease (AD) patients based upon efficacy in translational animal models. However, there is limited information in the peer-reviewed literature pertaining to transcranial near infrared laser transmission (NILT) profiles in various species. Thus, in the present study we systematically evaluated NILT characteristics through the skull of 4 different species: mouse, rat, rabbit and human. RESULTS: Using dehydrated skulls from 3 animal species, using a wavelength of 800nm and a surface power density of 700 mW/cm2, NILT decreased from 40.10% (mouse) to 21.24% (rat) to 11.36% (rabbit) as skull thickness measured at bregma increased from 0.44 mm in mouse to 0.83 mm in rat and then 2.11 mm in rabbit. NILT also significantly increased (p<0.05) when animal skulls were hydrated (i.e. compared to dehydrated); but there was no measurable change in thickness due to hydration. In human calvaria, where mean thickness ranged from 7.19 mm at bregma to 5.91 mm in the parietal skull, only 4.18% and 4.24% of applied near-infrared light was transmitted through the skull. There was a slight (9.2-13.4%), but insignificant effect of hydration state on NILT transmission of human skulls, but there was a significant positive correlation between NILT and thickness at bregma and parietal skull, in both hydrated and dehydrated states. CONCLUSION: This is the first systematic study to demonstrate differential NILT through the skulls of 4 different species; with an inverse relationship between NILT and skull thickness. With animal skulls, transmission profiles are dependent upon the hydration state of the skull, with significantly greater penetration through hydrated skulls compared to dehydrated skulls. Using human skulls, we demonstrate a significant correlation between thickness and penetration, but there was no correlation with skull density. The results suggest that TLT should be optimized in animals using novel approaches incorporating human skull characteristics, because of significant variance of NILT profiles directly related to skull thickness. PMID- 26039355 TI - Treatment Satisfaction and Well-Being in Patients with Myopic Choroidal Neovascularization Treated with Ranibizumab in the REPAIR Study. AB - The Ranibizumab for the Treatment of Choroidal Neovascularisation (CNV) Secondary to Pathological Myopia (PM): an Individualized Regimen (REPAIR) trial was a prospective study exploring the efficacy and safety of intravitreal ranibizumab 0.5 mg using an individualized treatment regimen over 12 months. The current study investigated the impact of treatment with ranibizumab as needed (pro re nata [PRN]) on individuals with myopic choroidal neovascularization (mCNV) in the REPAIR study, using patient-reported outcome measures (PROMs) for treatment satisfaction and well-being. This study included 65 adults with mCNV and a best corrected visual acuity (BCVA) letter score of 24-78 in the study eye. Patients completed the Macular Disease Treatment Satisfaction Questionnaire (MacTSQ) at months 1, 6 and 12, and the 12-item Well-Being Questionnaire (W-BQ12) at baseline and months 1, 6 and 12. Subgroup analyses investigated the relationship between PROM scores and treatment in the better- or worse-seeing eye (BSE/WSE), number of injections received, baseline BCVA, BCVA improvement and age. Pearson correlations between change in BCVA, MacTSQ scores and W-BQ12 scores were calculated. The main outcome measures were treatment satisfaction measured with the MacTSQ (score 0-72) and well-being measured with the W-BQ12 (score 0-36). Treatment satisfaction significantly increased over the study period (p = 0.0001). Mean MacTSQ scores increased by 9.7 and 10.0 in patients treated in their WSE and BSE, respectively. Treatment satisfaction was highest in individuals receiving only one injection at month 1; however, by month 12, scores were similar across injection subgroups. Patients aged 68 years or older had the highest MacTSQ scores. Well-being scores also significantly increased over the study period (p = 0.03). Mean W-BQ12 scores increased by 1.7 in patients treated in their WSE and by 2.1 in patients treated in their BSE. Individuals aged 40 years or younger had the greatest increases in general well-being. Patients who experienced stable or improved BCVA at month 12 had greater increases in W-BQ12 scores than those who experienced a decrease. Correlations between BCVA, MacTSQ scores and W-BQ12 scores were largely non-significant. In conclusion, treatment satisfaction and well-being increased during treatment with ranibizumab PRN. Although directly comparable data are limited for the MacTSQ and W-BQ12 in mCNV, these results complement PROM outcomes reported in related studies. PMID- 26039356 TI - Oral Selective Estrogen Receptor Downregulators (SERDs), a Breakthrough Endocrine Therapy for Breast Cancer. AB - Drugs that inhibit estrogen receptor alpha (ERalpha) or that block the production of estrogens remain frontline interventions in the treatment and management of breast cancer at all stages. However, resistance to endocrine therapies, especially in the setting of advanced disease, remains an impediment to durable clinical responses. Although the mechanisms underlying resistance to existing agents are complex, preclinical studies suggest that selective estrogen receptor downregulators (SERDs), molecules which eliminate ERalpha expression, may have particular utility in the treatment of breast cancers that have progressed on tamoxifen and/or aromatase inhibitors. The discovery and development of orally bioavailable SERDs provide the opportunity to evaluate the utility of eliminating ERalpha expression in advanced metastatic breast cancers. PMID- 26039358 TI - The Similarity Relations Set on the Basis of Symmetrization of the Liquid-Vapor Phase Diagram. AB - An approach to symmetrize the liquid-vapor phase coexistence curve is proposed. It is based on the introduction of the lattice-like density x = rho1/(rho1 + rho2), where rho1 and rho2 are the densities along the liquid-gas binodal. The global symmetrical phase diagram is created using experimental and simulation data for the real substances and models (noble gases, polyatomic molecules, organic substances and two metals, van der Waals system, Lennard-Jones system). The pressure and the temperature along the binodal are shown to satisfy some new similarity relations. PMID- 26039357 TI - The Arabidopsis thaliana TCP transcription factors: A broadening horizon beyond development. AB - The TCP family of transcription factors is named after the first 4 characterized members, namely TEOSINTE BRANCHED1 (TB1) from maize (Zea mays), CYCLOIDEA (CYC) from snapdragon (Antirrhinum majus), as well as PROLIFERATING CELL NUCLEAR ANTIGEN FACTOR1 (PCF1) and PCF2 from rice (Oryza sativa). Phylogenic analysis of this plant-specific protein family unveils a conserved bHLH-containing DNA binding motif known as the TCP domain. In accordance with the structure of this shared domain, TCP proteins are grouped into class I (TCP-P) and class II (TCP C), which are suggested to antagonistically modulate plant growth and development via competitively binding similar cis-regulatory modules called site II elements. Over the last decades, TCPs across the plant kingdom have been demonstrated to control a plethora of plant processes. Notably, TCPs also regulate plant development and defense responses via stimulating the biosynthetic pathways of bioactive metabolites, such as brassinosteroid (BR), jasmonic acid (JA) and flavonoids. Besides, mutagenesis analysis coupled with biochemical experiments identifies several crucial amino acids located within the TCP domain, which confer the redox sensitivity of class I TCPs and determine the distinct DNA binding properties of TCPs. In this review, developmental functions of TCPs in various biological pathways are briefly described with an emphasis on their involvement in the synthesis of bioactive substances. Furthermore, novel biochemical aspects of TCPs with respect to redox regulation and DNA-binding preferences are elaborated. In addition, the unexpected participation of TCPs in effector-triggered immunity (ETI) and defense against insects indicates that the widely recognized developmental regulators are capable of fine-tuning defense signaling and thereby enable plants to evade deleterious developmental phenotypes. Altogether, these recent impressive breakthroughs remarkably advance our understanding as to how TCPs integrate internal developmental cues with external environmental stimuli to orchestrate plant development. PMID- 26039360 TI - Kv3.4 channel function and dysfunction in nociceptors. AB - Recently, we reported the isolation of the Kv3.4 current in dorsal root ganglion (DRG) neurons and described dysregulation of this current in a spinal cord injury (SCI) model of chronic pain. These studies strongly suggest that rat Kv3.4 channels are major regulators of excitability in DRG neurons from pups and adult females, where they help determine action potential (AP) repolarization and spiking properties. Here, we characterized the Kv3.4 current in rat DRG neurons from adult males and show that it transfers 40-70% of the total repolarizing charge during the AP across all ages and sexes. Following SCI, we also found remodeling of the repolarizing currents during the AP. In the light of these studies, homomeric Kv3.4 channels expressed in DRG nociceptors are emerging novel targets that may help develop new approaches to treat neuropathic pain. PMID- 26039361 TI - Dynamical Evolution of Anisotropic Response in Black Phosphorus under Ultrafast Photoexcitation. AB - Black phosphorus has recently emerged as a promising material for high performance electronic and optoelectronic device for its high mobility, tunable mid-infrared bandgap, and anisotropic electronic properties. Dynamical evolution of photoexcited carriers and the induced transient change of electronic properties are critical for materials' high-field performance but remain to be explored for black phosphorus. In this work, we perform angle-resolved transient reflection spectroscopy to study the dynamical evolution of anisotropic properties of black phosphorus under photoexcitation. We find that the anisotropy of reflectivity is enhanced in the pump-induced quasi-equilibrium state, suggesting an extraordinary enhancement of the anisotropy in dynamical conductivity in hot carrier dominated regime. These results raise attractive possibilities of creating high-field, angle-sensitive electronic, optoelectronic, and remote sensing devices exploiting the dynamical electronic anisotropy with black phosphorus. PMID- 26039359 TI - MiRNA-Related SNPs and Risk of Esophageal Adenocarcinoma and Barrett's Esophagus: Post Genome-Wide Association Analysis in the BEACON Consortium. AB - Incidence of esophageal adenocarcinoma (EA) has increased substantially in recent decades. Multiple risk factors have been identified for EA and its precursor, Barrett's esophagus (BE), such as reflux, European ancestry, male sex, obesity, and tobacco smoking, and several germline genetic variants were recently associated with disease risk. Using data from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls, we examined single nucleotide polymorphisms (SNPs) that potentially affect the biogenesis or biological activity of microRNAs (miRNAs), small non-coding RNAs implicated in post transcriptional gene regulation, and deregulated in many cancers, including EA. Polymorphisms in three classes of genes were examined for association with risk of EA or BE: miRNA biogenesis genes (157 SNPs, 21 genes); miRNA gene loci (234 SNPs, 210 genes); and miRNA-targeted mRNAs (177 SNPs, 158 genes). Nominal associations (P<0.05) of 29 SNPs with EA risk, and 25 SNPs with BE risk, were observed. None remained significant after correction for multiple comparisons (FDR q>0.50), and we did not find evidence for interactions between variants analyzed and two risk factors for EA/BE (smoking and obesity). This analysis provides the most extensive assessment to date of miRNA-related SNPs in relation to risk of EA and BE. While common genetic variants within components of the miRNA biogenesis core pathway appear unlikely to modulate susceptibility to EA or BE, further studies may be warranted to examine potential associations between unassessed variants in miRNA genes and targets with disease risk. PMID- 26039364 TI - Synthesis of N-Vinyl Nitrones via 1,4-Conjugate Elimination. AB - A number of structurally and electronically diverse N-vinyl nitrones have been synthesized by a two-step method. The sequence consists of condensation of an alpha-chloroaldehyde or an alpha-phenoxy- or alpha-acetoxy ketone with a substituted benzyl hydroxylamine to provide the corresponding nitrone. Treatment of these species with a base induces a 1,4-elimination to provide the desired N vinyl nitrone in good to excellent yields. PMID- 26039362 TI - Evolution of the Selfing Syndrome in Arabis alpina (Brassicaceae). AB - INTRODUCTION: The transition from cross-fertilisation (outcrossing) to self fertilisation (selfing) frequently coincides with changes towards a floral morphology that optimises self-pollination, the selfing syndrome. Population genetic studies have reported the existence of both outcrossing and selfing populations in Arabis alpina (Brassicaceae), which is an emerging model species for studying the molecular basis of perenniality and local adaptation. It is unknown whether its selfing populations have evolved a selfing syndrome. METHODS: Using macro-photography, microscopy and automated cell counting, we compared floral syndromes (size, herkogamy, pollen and ovule numbers) between three outcrossing populations from the Apuan Alps and three selfing populations from the Western and Central Alps (Maritime Alps and Dolomites). In addition, we genotyped the plants for 12 microsatellite loci to confirm previous measures of diversity and inbreeding coefficients based on allozymes, and performed Bayesian clustering. RESULTS AND DISCUSSION: Plants from the three selfing populations had markedly smaller flowers, less herkogamy and lower pollen production than plants from the three outcrossing populations, whereas pistil length and ovule number have remained constant. Compared to allozymes, microsatellite variation was higher, but revealed similar patterns of low diversity and high Fis in selfing populations. Bayesian clustering revealed two clusters. The first cluster contained the three outcrossing populations from the Apuan Alps, the second contained the three selfing populations from the Maritime Alps and Dolomites. CONCLUSION: We conclude that in comparison to three outcrossing populations, three populations with high selfing rates are characterised by a flower morphology that is closer to the selfing syndrome. The presence of outcrossing and selfing floral syndromes within a single species will facilitate unravelling the genetic basis of the selfing syndrome, and addressing which selective forces drive its evolution. PMID- 26039365 TI - IL-10 genetic polymorphisms were associated with valvular calcification in Han, Uygur and Kazak populations in Xinjiang, China. AB - OBJECTIVE: Valvular calcification occurs via ongoing endothelial injury associated with inflammation. IL-10 is an anti-inflammatory cytokine and 75% of the variation in IL-10 production is genetically determined. However, the relationship between genetic polymorphisms of IL-10 and valvular calcification has not been studied. The objective of this study was to investigate the association between valvular calcification and IL-10 genetic polymorphisms in the Han, Uygur and Kazak populations in China. PATIENTS AND METHODS: All of the participants were selected from subjects participating in the Cardiovascular Risk Survey (CRS) study. The single nucleotide polymorphisms (SNPs) rs1800871 and rs1800872 of the IL-10 gene were genotyped using the polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. Three independent case-control studies involving the Han population, the Uygur population and the Kazak population were used in the analysis. RESULTS: For the Han and Kazak populations, rs1800871 was found to be associated with valvular calcification in the recessive model, and the difference remained statistically significant following multivariate adjustment (p<0.001, p=0.031, respectively). For the Han, Uygur and Kazak populations, rs1800872 was found to be associated with valvular calcification in the dominant model, and the difference remained statistically significant following multivariate adjustment (p<0.001, p=0.009, and p=0.023,respectively). CONCLUSION: Both rs1800871 and rs1800872 of the IL-10 gene are associated with valvular calcification in the Han and Kazak populations in China. Rs1800872 is also associated with valvular calcification in the Uygur population. PMID- 26039366 TI - [Family Focused Grief Therapy - A Suitable Model for the Palliative Care of Cancer Patients and their Families?]. AB - Loss is a universal human experience. Within the context of cancer and especially in the palliative care of oncological patients, anticipated and real losses and their management play a crucial role. A high proportion of patients and family members develop a treatment requiring psychiatric comorbidity (for both groups between 20 and 30%, mainly adjustment and anxiety disorders and depression). Approximately 15% of the bereaved persons suffer from complicated grief after the death of their relative. Within the early palliative care, the implementation of the Family Focused Grief Therapy (FFGT) has the potential to reduce psychological distress incl. mental comorbidities in patients and their relatives. Simultaneously, the incidence of the prolonged grief disorder in bereaved persons could be diminished (after the death of their relative). Thus, the FFGT can make a substantial contribution in order to improve the palliative care of cancer patients and their bereaved persons. PMID- 26039367 TI - [Psychometric Properties of the Sibling Relationship Questionnaire in the German Version (SRQ-deu)]. AB - The present study examines the psychometric properties of the German version of the Sibling Relationship Questionnaire (SRQ-deu, self-rating) in 961 children and adolescents aged 8-18 years. Internal consistency was satisfactory to high. Associations with other clinical instruments point in the expected direction and support the external validity of the SRQ-deu. A confirmatory factor analysis largely supported the 4-factor structure generated by the German version of the SRQ (SRQ-deu). PMID- 26039368 TI - [Diuretic-Abuse in Chronic Bulimia Nervosa--Case Report and Clinical Management]. AB - We give account of a patient, who works in health care, with bulimia nervosa (BN) and a long term abuse of Furosemide. Due to patients' tendency to conceal addictive behavior and symptoms of BN, the prevalence of purging behavior caused by the intake of diuretics is difficult to quantify 10% of BN patients exhibit a long-term harmful abuse. Discontinuation of diuretics causes the development of edema, attributable to pathophysiological changes with hyperaldosteronism. These can lead to renewed escalation of purging behaviour, provoked either by phobia of weight gain or by unbearable feelings of tension in the facial area or in the legs. For an adequate clinical management, it is vital to have thorough knowledge of the pathophysiological context which consists of psychoeducation, provision of information, treatment of water-electrolyte imbalance and, in individual cases, the administration of aldosterone antagonists. PMID- 26039369 TI - [Psychometric Properties of a New Questionnaire for the Assessment of Partner Oriented Fascination (FfP)]. AB - BACKGROUND: Research on partner-related has been neglected in the past. According to the attribution theory of fascination, partner appreciation is an integral part for a successful relationship. So far, however, no available validated instruments exist or the assessment of partner-related fascination. Hence, the aim of the present study was the development and validation of a new instrument to assess partner-related fascination (FfP). METHODS: The questionnaire was validated in an online study including 265 individuals (aged 18-63). The psychometric properties and the dimensional structure of the questionnaire were investigated using internal consistencies, as well as exploratory and confirmatory factor analyses. RESULTS: The factorial validation resulted in 2 subscales. The internal consistency was unsatisfactory for the first factor (alpha=0.58) but acceptable for the second factor (alpha=0.86). The results tentatively indicate that only the second subscale of the FfP should be used. This 8-item subscale, however, shows good psychometric properties and can therefore be applied as an adequate research instrument for the assessment of long-term partner fascination. PMID- 26039370 TI - [The Current State of Intercultural Opening in Psychosocial Services--The Results of an Assessment in an Inner-City District of Berlin]. AB - The need for intercultural opening of supply facilities for improving access and treatment of people with migration background is acknowledged in Germany. The purpose of the survey was to determine the current state of intercultural opening of psychosocial services in one Berlin district. 127 representatives of institutions were interviewed using a semi-structured assessment tool. The response rate was very high. The cross-cultural opening was implemented on a small scale. Staff as well as users with migration background were underrepresented. Varying and missing standardized documentation as well as problems in assessing users with migration background might be responsible for their low utilization rates. The use of professional interpreters was often not implemented. To judge the low level of implementation of cross-cultural opening in the psychosocial supply system in general, a review of responsible causes is required. PMID- 26039371 TI - Propionic Acid Produced by Propionibacterium acnes Strains Contri-butes to Their Pathogenicity. AB - Propionibacterium acnes is an important member of the skin microbiome. The bacterium can initiate signalling events and changes in cellular properties in keratinocytes. The aim of this study was to analyse the effect of the bacterium on an immortalized human keratinocyte cell line. The results show that various P. acnes strains affect the cell-growth properties of these cells differentially, inducing cytotoxicity in a strain-specific and dose-dependent manner. We propose that bacterially secreted propionic acid may contribute to the cytotoxic effect. This acid has a role in maintaining skin pH and exhibits antimicrobial properties, but may also have deleterious effects when the local concentration rises due to excessive bacterial growth and metabolism. These results, together with available data from the literature, may provide insight into the dual role of P. acnes in healthy skin and during pathogenic conditions, as well as the key molecules involved in these functions. PMID- 26039373 TI - Biased random walk model for the prioritization of drug resistance associated proteins. AB - Multi-drug resistance is the main cause of treatment failure in cancer patients. How to identify molecules underlying drug resistance from multi-omics data remains a great challenge. Here, we introduce a data biased strategy, ProteinRank, to prioritize drug-resistance associated proteins in cancer cells. First, we identified differentially expressed proteins in Adriamycin and Vincristine resistant gastric cancer cells compared to their parental cells using iTRAQ combined with LC-MS/MS experiments, and then mapped them to human protein protein interaction network; second, we applied ProteinRank to analyze the whole network and rank proteins similar to known drug resistance related proteins. Cross validations demonstrated a better performance of ProteinRank compared to the method without usage of MS data. Further validations confirmed the altered expressions or activities of several top ranked proteins. Functional study showed PIM3 or CAV1 silencing was sufficient to reverse the drug resistance phenotype. These results indicated ProteinRank could prioritize key proteins related to drug resistance in gastric cancer and provided important clues for cancer research. PMID- 26039374 TI - [Panorama of digestives violations related to HIV in CHU Campus in Lome (Togo)]. AB - OBJECTIVE: To describe the different gastrointestinal manifestations encountered in adult patients with HIV infection in a gastroenterology department in Togo. PATIENTS AND METHODS: This one-year (2011) prospective, descriptive study included all adult HIV-positive patients admitted to our department. Patients not known to be HIV-positive before admission were tested after informed consent. RESULTS: 82 (8.4% of departmental admissions) HIV-positive patients participated in the study. Their mean age was 38.78 years +/- 9 years, and they were mainly women (sex-ratio = 0.82). The reasons for consultation were mainly asthenia (39%), weight loss (35.4%), and vomiting (34.1%). Their histories included tuberculosis (4%), jaundice (4%), and herpes zoster (2%). Nearly all (91%) had CD4 counts below 350 cells/L, and most (80%) were treated with antiretroviral agents (ARV) before admission. Most patients were also chronic alcoholics (72%) and took traditional herbal treatments (55%). General symptoms included deterioration of the general condition (77%) and conjunctival pallor (48%). Physical signs included ascites (32%) and hepatomegaly (29%). All patients were positive for HIV-1; 30% were co-infected with HBV and 1.2% with HCV. The main diagnoses were hepatobiliary diseases (46%), including cirrhosis (24.4%), acute toxic hepatitis (12%), and hepatocellular carcinoma (6.1%). Of the latter, one also had lung metastases. Esophageal diseases included candidal esophagitis (24%), and the gastric diseases, two gastric ulcers (2%) and one case of gastric cancer. The primary disease of the colon and small bowel was acute gastroenteritis (38%). Peritoneal conditions were all tuberculosis (7%), and pancreatic involvement was acute pancreatitis (2%). PMID- 26039375 TI - New Insight for the Genetic Evaluation of Resistance to Ostreid Herpesvirus Infection, a Worldwide Disease, in Crassostrea gigas. AB - The Pacific oyster, Crassostrea gigas, is the most important commercial oyster species cultivated in the world. Meanwhile, the ostreid herpesvirus 1 (OsHV-1) is one of the major pathogens affecting the Pacific oyster, and numerous mortality outbreaks related to this pathogen are now reported worldwide. To assess the genetic basis of resistance to OsHV-1 infection in spat C. gigas and to facilitate breeding programs for such a trait, if any exist, we compared the mortality of half- and full-sib families using three field methods and a controlled challenge by OsHV-1 in the laboratory. In the field, three methods were tested: (A) one family per bag; (B) one family per small soft mesh bag and all families inside one bag; (C) same as the previous methods but the oysters were individually labelled and then mixed. The mean mortality ranged from 80 to 82% and was related to OsHV-1 based on viral DNA detection. The narrow-sense heritability for mortality, and thus OsHV-1 resistance, ranged from 0.49 to 0.60. The high positive genetic correlations across the field methods suggested no genotype by environment interaction. Ideally, selective breeding could use method B, which is less time- and space-consuming. The narrow sense heritability for mortality under OsHV-1 challenge was 0.61, and genetic correlation between the field and the laboratory was ranged from 0.68 to 0.75, suggesting a weak genotype by environment interaction. Thus, most of families showing the highest survival performed well in field and laboratory conditions, and a similar trend was also observed for families with the lowest survival. In conclusion, this is the first study demonstrating a large additive genetic variation for resistance to OsHV-1 infection in C. gigas, regardless of the methods used, which should help in selective breeding to improve resistance to viral infection in C. gigas. PMID- 26039377 TI - Enhanced Performance of Polymeric Bulk Heterojunction Solar Cells via Molecular Doping with TFSA. AB - Organic solar cells based on bis(trifluoromethanesulfonyl)amide (TFSA, [CF3SO2]2NH) bulk doped poly[N-9''-hepta-decanyl-2,7-carbazole-alt-5,5-(4',7'-di 2-thienyl-2',1',3'-benzothiadiazole) (PCDTBT):C71-butyric acid methyl ester (PC71BM) were fabricated to study the effect of molecular doping. By adding TFSA (0.2-0.8 wt %, TFSA to PCDTBT) in the conventional PCDTBT:PC71BM blends, we found that the hole mobility was increased with the reduced series resistance in photovoltaic devices. The p-doping effect of TFSA was confirmed by photoemission spectroscopy that the Fermi level of doped PCDTBT shifts downward to the HOMO level and it results in a larger internal electrical field at the donor/acceptor interface for more efficient charge transfer. Moreover, the doping effect was also confirmed by charge modulated electroabsorption spectroscopy (CMEAS), showing that there are additional polaron signals in the sub-bandgap region in the doped thin films. With decreased series resistance, the open-circuit voltage (Voc) was increased from 0.85 to 0.91 V and the fill factor (FF) was improved from 60.7% to 67.3%, resulting in a largely enhanced power conversion efficiency (PCE) from 5.39% to 6.46%. Our finding suggests the molecular doping by TFSA can be a facile approach to improve the electrical properties of organic materials for future development of organic photovoltaic devices (OPVs). PMID- 26039376 TI - Whole genome methylation array reveals the down-regulation of IGFBP6 and SATB2 by HIV-1. AB - Nowadays, the knowledge in DNA methylation-mediated gene regulation has shed light on the understanding of virus-host interplay in the context of genome alteration. It has also been shown that HIV is able to change the DNA methylation pattern by DNA methyltransferases and such changes can be correlated with the progression of AIDS. In this study, we have investigated the relationship between genome-wide DNA methylation pattern and HIV infection using the methylated DNA immunoprecipitation--microarray method. A pair of monozygotic twins was recruited: one of the twins was infected with HIV while the other was not. Based on data from the microarray experiment, 4679 differentially methylated regions in the HIV positive subject with the significant peak values were identified. Selected genes were then validated in human T lymphocyte CEM*174 cell line and HIV/AIDS patients by comparing with normal subjects. We found that IGFBP6 and SATB2 were significantly down-regulated in HIV-infected CEM*174 cells and 3 different cohorts of HIV/AIDS patients while their promoters were predominantly hyper-methylated compared with normal controls. This study also provides a resource for the identification of HIV-induced methylation and contributes to better understanding of the development of HIV/AIDS. PMID- 26039378 TI - The Design of Simple Bacterial Microarrays: Development towards Immobilizing Single Living Bacteria on Predefined Micro-Sized Spots on Patterned Surfaces. AB - In this paper we demonstrate a procedure for preparing bacterial arrays that is fast, easy, and applicable in a standard molecular biology laboratory. Microcontact printing is used to deposit chemicals promoting bacterial adherence in predefined positions on glass surfaces coated with polymers known for their resistance to bacterial adhesion. Highly ordered arrays of immobilized bacteria were obtained using microcontact printed islands of polydopamine (PD) on glass surfaces coated with the antiadhesive polymer polyethylene glycol (PEG). On such PEG-coated glass surfaces, bacteria were attached to 97 to 100% of the PD islands, 21 to 62% of which were occupied by a single bacterium. A viability test revealed that 99% of the bacteria were alive following immobilization onto patterned surfaces. Time series imaging of bacteria on such arrays revealed that the attached bacteria both divided and expressed green fluorescent protein, both of which indicates that this method of patterning of bacteria is a suitable method for single-cell analysis. PMID- 26039379 TI - Reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray: A case report. AB - BACKGROUND: This is a case report describing a reversal of fentanyl overdose with naloxone nasal spray. The patient was not aware that he overdosed on fentanyl being sold as heroin. METHODS: The Veterans Health Administration (VHA) has implemented an initiative to provide education for veterans, their families, friends and significant others about opioid overdose and use of naloxone reversal kits. The Atlanta VA Medical Center adopted this program to reduce the risk of opioid overdose in high risk patients. RESULTS: Over the past year, we provided educational sessions for 63 veterans and their families. We also prescribed 41 naloxone kits. We have received three reports of opioid overdose reversal with use of naloxone kits prescribed by the Atlanta VA Medical Center. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The authors recommend that public health administrators and policy makers advocate for the implementation of these programs to reduce the rising number of overdose death in the United States and worldwide. PMID- 26039380 TI - Pre-yield non-affine fluctuations and a hidden critical point in strained crystals. AB - A crystalline solid exhibits thermally induced localised non-affine droplets in the absence of external stress. Here we show that upon an imposed shear, the size of these droplets grow until they percolate at a critical strain, well below the value at which the solid begins to yield. This critical point does not manifest in most thermodynamic or mechanical properties, but is hidden and reveals itself in the onset of inhomogeneities in elastic moduli, marked changes in the appearance and local properties of non-affine droplets and a sudden enhancement in defect pair concentration. Slow relaxation of stress and an-elasticity appear as observable dynamical consequences of this hidden criticality. Our results may be directly verified in colloidal crystals with video microscopy techniques but are expected to have more general validity. PMID- 26039382 TI - Optical-fiber-based laser-induced breakdown spectroscopy for detection of early caries. AB - A laser-induced breakdown spectroscopy (LIBS) system targeting for the in vivo analysis of tooth enamel is described. The system is planned to enable real-time analysis of teeth during laser dental treatment by utilizing a hollow optical fiber that transmits both Q-switched Nd:YAG laser light for LIBS and infrared Er:YAG laser light for tooth ablation. The sensitivity of caries detection was substantially improved by expanding the spectral region under analysis to ultraviolet (UV) light and by focusing on emission peaks of Zn in the UV region. Subsequently, early caries were distinguished from healthy teeth with accuracy rates above 80% in vitro. PMID- 26039381 TI - Screening of patients with bronchopulmonary diseases using methods of infrared laser photoacoustic spectroscopy and principal component analysis. AB - A human exhaled air analysis by means of infrared (IR) laser photoacoustic spectroscopy is presented. Eleven healthy nonsmoking volunteers (control group) and seven patients with chronic obstructive pulmonary disease (COPD, target group) were involved in the study. The principal component analysis method was used to select the most informative ranges of the absorption spectra of patients' exhaled air in terms of the separation of the studied groups. It is shown that the data of the profiles of exhaled air absorption spectrum in the informative ranges allow identifying COPD patients in comparison to the control group. PMID- 26039383 TI - Study on the validity of 3 * 3 Mueller matrix decomposition. AB - Using Monte Carlo simulations based on previously developed scattering models consisting of spherical and cylindrical scatterers imbedded in birefringent interstitial medium, we compare the polarization parameters extracted from the 3*3 and 4*4 Mueller matrix decomposition methods in forward and backward scattering directions. The results show that the parameters derived from the 3*3 Mueller matrix decomposition are usually not the same as those from the 4*4 Mueller matrix decomposition but display similar qualitative relations to changes in the microstructure of the sample, such as the density, size, and orientation distributions of the scatterers, and birefringence of the interstitial medium. The simulations are backed up by experiments when suitable samples are available. PMID- 26039384 TI - The use of ocular hypotensive drugs for glaucoma treatment: changing trend in Taiwan from 1997 to 2007. AB - PURPOSE: Treatment of glaucoma has increasingly favored better intraocular pressure (IOP) lowering efficacy and safety of topical medications. The introduction of newer ocular hypotensive drugs (OHDs) has led changes in the prescribing patterns and treatment approaches. This study aimed to investigate the prescribing patterns, trends, and corresponding expenditures of OHDs in Taiwan over an 11-year period from 1997 to 2007. PATIENTS AND METHODS: A nationally representative sample of 1 million ambulatory visits from the National Health Research Institute data sets was used. Patients with glaucoma who aged >=18 years were identified with ICD-9-CM and A230 codes. Six categories of OHDs were used to describe the rates, patterns, expenditures, and changes of annual prescriptions for glaucoma patients. RESULTS: The number of OHD prescriptions has tripled during the 11 years. Although the prescribing trend was being away from monotherapy with beta-blockers, this class remained the most commonly used OHD up to 2007. Prostaglandin analogs were the second most frequently prescribed OHDs since 2000. Changing prescribing patterns and increased patients were the main contributors to the rise in OHD expenditures. Part of increased expenditure was likely offset by reduced needs for laser and surgical interventions. CONCLUSIONS: The prescriptions of OHDs are shifting to newer categories and combination therapy. These findings provided insights into recent trends in management of glaucoma patients in Taiwan and implied a similar trend toward recent clinical reports and practices recommendations in the guidelines. PMID- 26039385 TI - Effect of age and disc size on rim order rules by Heidelberg Retina Tomograph. AB - PURPOSE: The ISNT rule for nonglaucomatous eyes suggests that the neuroretinal rim is thickest at the inferior quadrant (I), followed by the superior (S), nasal (N), and temporal (T) quadrants. This study aimed to use Heidelberg Retina Tomograph (HRT III) measurements to assess (a) fulfillment of the ISNT rule and its derivatives in a large normative database and (b) effect of disc size and age on rule fulfillment. PATIENTS AND METHODS: A multicenter, prospective, cross sectional study of a Caucasian normative database consisting of 280 subjects with normal comprehensive biomicroscopic examination, intraocular pressure <21 mm Hg, and normal automated visual field testing was conducted. Right eye neuroretinal rim and disc area, measured by HRT III, for each of the 4 quadrants were analyzed. Compliance of the rim area to the ISNT rule (I>=S>=N>=T) and its derivates was determined. Effect of age and disc area on rule compliance was further determined. RESULTS: Only 18% of normal eyes had rim areas that complied with the ISNT rule; however, a majority complied to IS (77%) and IST (73%) rules. The temporal quadrant had the smallest rim area [(I,S,N)>T] in 91% of patients. The likelihood of ISNT rule violation was increased in larger discs (chi2, P=0.003) but was not affected by age. CONCLUSIONS: The ISNT rule does not apply to neuroretinal rim area as measured by HRT, as only 18% of the eyes complied with the ISNT rule in this normative database. Although the ISNT rule may be more applicable to normal eyes with a smaller disc area, the IS and IST rules seem to better represent the normative database. PMID- 26039386 TI - Erratum. PMID- 26039387 TI - Trends in the use of antidepressants among older adults: Bambui Project. AB - OBJECTIVE To analyze the trends and factors associated with the antidepressant use among older adults. METHODS This population-based study evaluated older adults in 1997 (n = 351, baseline) and the survivors at the 15th follow-up year (n = 462, in 2012) among the aging cohort of Bambui. The prevalence of antidepressant use was estimated, and the most commonly used antidepressants each year were identified. Prevalence ratios with 95% confidence intervals were estimated using Poisson regression with robust variance to investigate differences in the prevalence of use between 1997 and 2012. RESULTS The overall consumption of antidepressants (PR = 2.87, 95%CI 1.94;4.25) and of selective serotonin reuptake inhibitors (PR = 7.50, 95%CI 3.74;15.02) was significantly higher in 2012. However, no significant difference was observed in the use of tricyclic antidepressants between the two cohorts (PR = 0.89, 95%CI 0.49;1.62). In the 2012 cohort, antidepressant use was associated with females, increased age, increased income (>= 4 minimum wages), self-assessment of health as reasonable, and attending >= 5 medical consultations in the last 12 months. CONCLUSIONS The increased consumption of antidepressants in the period due to increased use of selective serotonin reuptake inhibitors was consistent with results observed in international studies of different population groups and contexts. The positive correlation observed between antidepressant use and family income may be a warning of possible inequalities in access to mental health services. PMID- 26039388 TI - Chronic use of benzodiazepines among older adults. AB - OBJECTIVE To analyze the perception of and motivation for the chronic use of benzodiazepine among older adults. METHODS A qualitative study was conducted on 22 older adults living in Bambui, MG, Southeastern Brazil, who were taking benzodiazepines and had the clinical and cognitive ability to respond to interview questions. The collected data were analyzed on the basis of the "signs, meanings, and actions" model. RESULTS The main reasons pointed out for the use of benzodiazepines were "nervousness", "sleep problems", and "worry" due to family and financial problems, everyday problems, and existential difficulties. None of the interviewees said that they used benzodiazepines in a dose higher than that recommended or had been warned by health professionals about any risks of their continuous use. Different strategies were used to obtain the prescription for the medication, and any physician would prescribe it, indicating that a bond was established with the drug and not with the health professional or healthcare service. Obtaining and consuming the medication turned into a crucial issue because benzodiazepine assumes the status of an essential food, which leads users to not think but sleep. It causes a feeling of relief from their problems such as awareness of human finitude and fragility, existential difficulties, and family problems. CONCLUSIONS Benzodiazepine assumes the characteristics of polyvalence among older adults, which extrapolate specific clinical indications, and of essentiality to deal with life's problems in old age. Although it relieves the "nerves", the chronic use of benzodiazepines buffers suffering and prevents older adults from going through the suffering. This shows important difficulties in the organization and planning of strategies that are necessary for minimizing the chronic use in this population. PMID- 26039389 TI - Prescription, dispensation and marketing patterns of methylphenidate. AB - OBJECTIVE To analyze the patterns and legal requirements of methylphenidate consumption. METHODS We conducted a cross-sectional study of the data from prescription notification forms and balance lists of drugs sales - psychoactive and others - subject to special control in the fifth largest city of Brazil, in 2006. We determined the defined and prescribed daily doses, the average prescription and dispensation periods, and the regional sales distribution in the municipality. In addition, we estimated the costs of drug acquisition and analyzed the individual drug consumption profile using the Lorenz curve. RESULTS The balance lists data covered all notified sales of the drug while data from prescription notification forms covered 50.6% of the pharmacies that sold it, including those with the highest sales volumes. Total methylphenidate consumption was 0.37 DDD/1,000 inhabitants/day. Sales were concentrated in more developed areas, and regular-release tablets were the most commonly prescribed pharmaceutical formulation. In some regions of the city, approximately 20.0% of the prescriptions and dispensation exceeded 30 mg/day and 30 days of treatment. CONCLUSIONS Methylphenidate was widely consumed in the municipality and mainly in the most developed areas. Of note, the consumption of formulations with the higher abuse risk was the most predominant. Both its prescription and dispensation contrasted with current pharmacotherapeutic recommendations and legal requirements. Therefore, the commercialization of methylphenidate should be monitored more closely, and its use in the treatment of behavioral changes of psychological disorders needs to be discussed in detail, in line with the concepts of the quality use of medicines. PMID- 26039390 TI - Isolated and synergistic effects of PM10 and average temperature on cardiovascular and respiratory mortality. AB - OBJECTIVE To analyze the effect of air pollution and temperature on mortality due to cardiovascular and respiratory diseases. METHODS We evaluated the isolated and synergistic effects of temperature and particulate matter with aerodynamic diameter < 10 um (PM10) on the mortality of individuals > 40 years old due to cardiovascular disease and that of individuals > 60 years old due to respiratory diseases in Sao Paulo, SP, Southeastern Brazil, between 1998 and 2008. Three methodologies were used to evaluate the isolated association: time-series analysis using Poisson regression model, bidirectional case-crossover analysis matched by period, and case-crossover analysis matched by the confounding factor, i.e., average temperature or pollutant concentration. The graphical representation of the response surface, generated by the interaction term between these factors added to the Poisson regression model, was interpreted to evaluate the synergistic effect of the risk factors. RESULTS No differences were observed between the results of the case-crossover and time-series analyses. The percentage change in the relative risk of cardiovascular and respiratory mortality was 0.85% (0.45;1.25) and 1.60% (0.74;2.46), respectively, due to an increase of 10 MUg/m3 in the PM10 concentration. The pattern of correlation of the temperature with cardiovascular mortality was U-shaped and that with respiratory mortality was J-shaped, indicating an increased relative risk at high temperatures. The values for the interaction term indicated a higher relative risk for cardiovascular and respiratory mortalities at low temperatures and high temperatures, respectively, when the pollution levels reached approximately 60 MUg/m3. CONCLUSIONS The positive association standardized in the Poisson regression model for pollutant concentration is not confounded by temperature, and the effect of temperature is not confounded by the pollutant levels in the time-series analysis. The simultaneous exposure to different levels of environmental factors can create synergistic effects that are as disturbing as those caused by extreme concentrations. PMID- 26039391 TI - Association between food assistance program participation and overweight. AB - OBJECTIVE The objective of this study was to investigate the association between food assistance program participation and overweight/obesity according to poverty level. METHODS A cross-sectional analysis of data from 46,217 non-pregnant and non-lactating women in Lima, Peru was conducted; these data were obtained from nationally representative surveys from the years 2003, 2004, 2006, and 2008-2010. The dependent variable was overweight/obesity, and the independent variable was food assistance program participation. Poisson regression was used to stratify the data by family socioeconomic level, area of residence (Lima versus the rest of the country; urban versus rural), and survey year (2003-2006 versus 2008 2010). The models were adjusted for age, education level, urbanization, and survey year. RESULTS Food assistance program participation was associated with an increased risk of overweight/obesity in women living in homes without poverty indicators [prevalence ratio (PR) = 1.29; 95% confidence interval (CI) 1.06;1.57]. When stratified by area of residence, similar associations were observed for women living in Lima and urban areas; no associations were found between food assistance program participation and overweight/obesity among women living outside of Lima or in rural areas, regardless of the poverty status. CONCLUSIONS Food assistance program participation was associated with overweight/obesity in non-poor women. Additional studies are required in countries facing both aspects of malnutrition. PMID- 26039392 TI - Evaluation of dengue fever reports during an epidemic, Colombia. AB - OBJECTIVE To assess the validity of dengue fever reports and how they relate to the definition of case and severity. METHODS Diagnostic test assessment was conducted using cross-sectional sampling from a universe of 13,873 patients treated during the fifth epidemiological period in health institutions from 11 Colombian departments in 2013. The test under analyses was the reporting to the National Public Health Surveillance System, and the reference standard was the review of histories identified by active institutional search. We reviewed all histories of patients diagnosed with dengue fever, as well as a random sample of patients with febrile syndromes. The specificity and sensitivity of reports were estimated for this purpose, considering the inverse of the probability of being selected for weighting. The concordance between reporting and the findings of the active institutional search was calculated using Kappa statistics. RESULTS We included 4,359 febrile patients, and 31.7% were classified as compatible with dengue fever (17 with severe dengue fever; 461 with dengue fever and warning signs; 904 with dengue fever and no warning signs). The global sensitivity of reports was 13.2% (95%CI 10.9;15.4) and specificity was 98.4% (95%CI 97.9;98.9). Sensitivity varied according to severity: 12.1% (95%CI 9.3;14.8) for patients presenting dengue fever with no warning signs; 14.5% (95%CI 10.6;18.4) for those presenting dengue fever with warning signs, and 40.0% (95%CI 9.6;70.4) for those with severe dengue fever. Concordance between reporting and the findings of the active institutional search resulted in a Kappa of 10.1%. CONCLUSIONS Low concordance was observed between reporting and the review of clinical histories, which was associated with the low reporting of dengue fever compatible cases, especially milder cases. PMID- 26039394 TI - Spatial distribution of specialized cardiac care units in the state of Santa Catarina. AB - OBJECTIVE To analyze the methodology used for assessing the spatial distribution of specialized cardiac care units. METHODS A modeling and simulation method was adopted for the practical application of cardiac care service in the state of Santa Catarina, Southern Brazil, using the p-median model. As the state is divided into 21 health care regions, a methodology which suggests an arrangement of eight intermediate cardiac care units was analyzed, comparing the results obtained using data from 1996 and 2012. RESULTS Results obtained using data from 2012 indicated significant changes in the state, particularly in relation to the increased population density in the coastal regions. The current study provided a satisfactory response, indicated by the homogeneity of the results regarding the location of the intermediate cardiac care units and their respective regional administrations, thereby decreasing the average distance traveled by users to health care units, located in higher population density areas. The validity of the model was corroborated through the analysis of the allocation of the median vertices proposed in 1996 and 2012. CONCLUSIONS The current spatial distribution of specialized cardiac care units is more homogeneous and reflects the demographic changes that have occurred in the state over the last 17 years. The comparison between the two simulations and the current configuration showed the validity of the proposed model as an aid in decision making for system expansion. PMID- 26039393 TI - Factors associated with vaccination coverage in children < 5 years in Angola. AB - OBJECTIVE To analyze vaccination coverage and factors associated with a complete immunization scheme in children < 5 years old. METHODS This cross-sectional household census survey evaluated 1,209 children < 5 years old living in Bom Jesus, Angola, in 2010. Data were obtained from interviews, questionnaires, child immunization histories, and maternal health histories. The statistical analysis used generalized linear models, in which the dependent variable followed a binary distribution (vaccinated, unvaccinated) and the association function was logarithmic and had the children's individual, familial, and socioeconomic factors as independent variables. RESULTS Vaccination coverage was 37.0%, higher in children < 1 year (55.0%) and heterogeneous across neighborhoods; 52.0% of children of both sexes had no immunization records. The prevalence rate of vaccination significantly varied according to child age, mother's level of education, family size, ownership of household appliances, and destination of domestic waste. CONCLUSIONS Vulnerable groups with vaccination coverage below recommended levels continue to be present. Some factors indicate inequalities that represent barriers to full immunization, indicating the need to implement more equitable policies. The knowledge of these factors contributes to planning immunization promotion measures that focus on the most vulnerable groups. PMID- 26039395 TI - Tracking of physical activity during adolescence: the 1993 Pelotas Birth Cohort, Brazil. AB - OBJECTIVE To analyze physical activity during adolescence in participants of the 1993 Pelotas Birth Cohort Study, Brazil. METHODS Data on leisure time physical activity at 11, 15, and 18 years of age were analyzed. At each visit, a cut-off point of 300 min/week was used to classify adolescents as active or inactive. A total of 3,736 participants provided data on physical activity at each of the three age points. RESULTS A significant decline in the proportion of active adolescents was observed from 11 to 18 years of age, particularly among girls (from 32.9% to 21.7%). The proportions of girls and boys who were active at all three age points were 28.0% and 55.1%, respectively. After adjustment for sex, economic status, and skin color, participants who were active at 11 and 15 years of age were 58.0% more likely to be active at 18 years of age compared with those who were inactive at 11 and 15 years of age. CONCLUSIONS Physical activity declined during adolescence and inactivity tended to track over time. Our findings reinforce the need to promote physical activity at early stages of life, because active behavior established early tends to be maintained over time. PMID- 26039396 TI - Mammography in asymptomatic women aged 40-49 years. AB - OBJECTIVE To assess findings of mammography of and interventions resulting from breast cancer screening in women aged 40-49 years with no increased risk (typical risk) of breast cancer. METHODS This cross-sectional study evaluated women aged 40-49 years who underwent mammography screening in a mastology reference center in Recife, PE, Northeastern Brazil, between January 2010 and October 2011. Women with breast-related complaints, positive findings in the physical examination, or high risk of breast cancer were excluded. RESULTS The 1,000 mammograms performed were classified into the following Breast Imaging-Reporting and Data System (BI RADS) categories BI-RADS 0, 232; BI-RADS 1, 294; BI-RADS 2, 294; BI-RADS 3, 16; BI-RADS 4A, 2; BI-RADS 5, 1. There was one case of grade II invasive ductal carcinoma and various interventions, including 469 ultrasound scans, 53 referrals to mastologists, 11 cytological examinations, and 8 biopsies. CONCLUSIONS Mammography screening in women aged 40-49 years with typical risk of breast cancer led to the performance of other interventions. However, it also resulted in increased costs without demonstrable efficacy in decreasing mortality. PMID- 26039397 TI - Public school ?? teachers' perceptions about mental health. AB - OBJECTIVE To examine public school teachers' perceptions about general health and mental health, and the way in which they obtained this information. METHODS Qualitative research was conducted with 31 primary and secondary school teachers at a state school in the municipality of Sao Paulo, SP, Southeastern Brazil, in 2010. The teachers responded to a questionnaire containing open-ended questions about mental health and general health. The following aspects were evaluated: Teachers' understanding of the terms "health and "mental health," the relevance of the need for information on the subject, the method preferred for obtaining information, their experience with different media regarding such matters, and perceptions about the extent to which this available information is sufficient to support their practice. The data were processed using the Qualiquantisoft software and analyzed according to the Discourse of the Collective Subject technique. RESULTS From the teachers' perspective, general health is defined as the proper physiological functioning of the body and mental health is related to the balance between mind and body, as a requirement for happiness. Most of the teachers (80.6%) showed great interest in acquiring knowledge about mental health and receiving educational materials on the subject. For these teachers, the lack of information creates insecurity and complicates the management of everyday situations involving mental disorders. For 61.3% of the teachers, television is the medium that provides the most information on the topic. CONCLUSIONS The data indicate that there is little information available on mental health for teachers, showing that strategies need to be developed to promote mental health in schools. PMID- 26039398 TI - Lifestyle factors, direct and indirect costs for a Brazilian airline company. AB - OBJECTIVE To analyze lifestyle risk factors related to direct healthcare costs and the indirect costs due to sick leave among workers of an airline company in Brazil. METHODS In this longitudinal 12-month study of 2,201 employees of a Brazilian airline company, the costs of sick leave and healthcare were the primary outcomes of interest. Information on the independent variables, such as gender, age, educational level, type of work, stress, and lifestyle-related factors (body mass index, physical activity, and smoking), was collected using a questionnaire on enrolment in the study. Data on sick leave days were available from the company register, and data on healthcare costs were obtained from insurance records. Multivariate linear regression analysis was used to investigate the association between direct and indirect healthcare costs with sociodemographic, work, and lifestyle-related factors. RESULTS Over the 12-month study period, the average direct healthcare expenditure per worker was US$505.00 and the average indirect cost because of sick leave was US$249.00 per worker. Direct costs were more than twice the indirect costs and both were higher in women. Body mass index was a determinant of direct costs and smoking was a determinant of indirect costs. CONCLUSIONS Obesity and smoking among workers in a Brazilian airline company were associated with increased health costs. Therefore, promoting a healthy diet, physical activity, and anti-tobacco campaigns are important targets for health promotion in this study population. PMID- 26039399 TI - Hospitalizations for ambulatory care-sensitive conditions, Minas Gerais, Southeastern Brazil, 2000 and 2010. AB - OBJECTIVE To analyze hospitalization rates and the proportion of deaths due to ambulatory care-sensitive hospitalizations and to characterize them according to coverage by the Family Health Strategy, a primary health care guidance program. METHODS An ecological study comprising 853 municipalities in the state of Minas Gerais, under the purview of 28 regional health care units, was conducted. We used data from the Hospital Information System of the Brazilian Unified Health System. Ambulatory care-sensitive hospitalizations in 2000 and 2010 were compared. Population data were obtained from the demographic censuses. RESULTS The number of ambulatory care-sensitive hospitalizations declined from 20.75/1,000 inhabitants [standard deviation (SD) = 10.42) in 2000 to 14.92/thousand inhabitants (SD = 10.04) in 2010 Heart failure was the most frequent cause in both years. Hospitalizations rates for hypertension, asthma, and diabetes mellitus, decreased, whereas those for angina pectoris, prenatal and birth disorders, kidney and urinary tract infections, and other acute infections increased. Hospitalization durations and the proportion of deaths due to ambulatory care-sensitive hospitalizations increased significantly. CONCLUSIONS Mean hospitalization rates for sensitive conditions were significantly lower in 2010 than in 2000, but no correlation was found with regard to the expansion of the population coverage of the Family Health Strategy. Hospitalization rates and proportion of deaths were different between the various health care regions in the years evaluated, indicating a need to prioritize the primary health care with high efficiency and quality. PMID- 26039400 TI - Socioeconomic inequalities in the access to and quality of health care services. AB - OBJECTIVE To assess the inequalities in access, utilization, and quality of health care services according to the socioeconomic status. METHODS This population-based cross-sectional study evaluated 2,927 individuals aged >= 20 years living in Pelotas, RS, Southern Brazil, in 2012. The associations between socioeconomic indicators and the following outcomes were evaluated: lack of access to health services, utilization of services, waiting period (in days) for assistance, and waiting time (in hours) in lines. We used Poisson regression for the crude and adjusted analyses. RESULTS The lack of access to health services was reported by 6.5% of the individuals who sought health care. The prevalence of use of health care services in the 30 days prior to the interview was 29.3%. Of these, 26.4% waited five days or more to receive care and 32.1% waited at least an hour in lines. Approximately 50.0% of the health care services were funded through the Unified Health System. The use of health care services was similar across socioeconomic groups. The lack of access to health care services and waiting time in lines were higher among individuals of lower economic status, even after adjusting for health care needs. The waiting period to receive care was higher among those with higher socioeconomic status. CONCLUSIONS Although no differences were observed in the use of health care services across socioeconomic groups, inequalities were evident in the access to and quality of these services. PMID- 26039401 TI - Factors associated with lack of prenatal care in a large municipality. AB - OBJECTIVE To analyze the factors associated with a lack of prenatal care in a large municipality in southern Brazil. METHODS In this case-control age-matched study, 716 women were evaluated; of these, 179 did not receive prenatal care and 537 received prenatal care (controls). These women were identified using the Sistema Nacional de Informacao sobre Nascidos Vivos (Live Birth Information System) of Pelotas, RS, Southern Brazil, between 2009 and 2010. Multivariate analysis was performed using conditional logistic regression to estimate the odds ratios (OR). RESULTS In the final model, the variables associated with a lack of prenatal care were the level of education, particularly when it was lesser than four years [OR 4.46; 95% confidence interval (CI) 1.92;10.36], being single (OR 3.61; 95%CI 1.85;7.04), and multiparity (OR 2.89; 95%CI 1.72;4.85). The prevalence of a lack of prenatal care among administrative regions varied between 0.7% and 3.9%. CONCLUSIONS The risk factors identified must be considered when planning actions for the inclusion of women in prenatal care by both the central management and healthcare teams. These indicated the municipal areas with greater deficits in prenatal care. The reorganization of the actions to identify women with risk factors in the community can be considered to be a starting point of this process. In addition, the integration of the activities of local programs that target the mother and child is essential to constantly identify pregnant women without prenatal care. PMID- 26039402 TI - Determinants of the exclusive breastfeeding abandonment: psychosocial factors. AB - OBJECTIVE To assess the determinants of exclusive breastfeeding abandonment. METHODS Longitudinal study based on a birth cohort in Vicosa, MG, Southeastern Brazil. In 2011/2012, 168 new mothers accessing the public health network were followed. Three interviews, at 30, 60, and 120 days postpartum, with the new mothers were conducted. Exclusive breastfeeding abandonment was analyzed in the first, second, and fourth months after childbirth. The Edinburgh Postnatal Depression Scale was applied to identify depressive symptoms in the first and second meetings, with a score of >= 12 considered as the cutoff point. Socioeconomic, demographic, and obstetric variables were investigated, along with emotional conditions and the new mothers' social network during pregnancy and the postpartum period. RESULTS The prevalence of exclusive breastfeeding abandonment at 30, 60, and 120 days postpartum was 53.6% (n = 90), 47.6% (n = 80), and 69.6% (n = 117), respectively, and its incidence in the fourth month compared with the first was 48.7%. Depressive symptoms and traumatic delivery were associated with exclusive breastfeeding abandonment in the second month after childbirth. In the fourth month, the following variables were significant: lower maternal education levels, lack of homeownership, returning to work, not receiving guidance on breastfeeding in the postpartum period, mother's negative reaction to the news of pregnancy, and not receiving assistance from their partners for infant care. CONCLUSIONS Psychosocial and sociodemographic factors were strong predictors of early exclusive breastfeeding abandonment. Therefore, it is necessary to identify and provide early treatment to nursing mothers with depressive symptoms, decreasing the associated morbidity and promoting greater duration of exclusive breastfeeding. Support from health professionals, as well as that received at home and at work, can assist in this process. PMID- 26039403 TI - Healthcare-associated infections: challenges to public health in Brazil. AB - This study presents a critical evaluation of the scientific literature related to this subject, aiming to assess the policies and administrative issues regarding the prevention and magnitude of healthcare-associated infections and discuss the challenges for their prevention in Brazil. The topics discussed included historical and administrative issues, challenges imposed by the characteristics of the healthcare system and the territorial dimension, laboratorial support limitations, costs, institutional culture, professional qualification, and patient engagement. It is urgent to hold a nationwide discussion among government representatives, institutions, and healthcare workers and users to overcome these challenges. PMID- 26039404 TI - The American Board of Internal Medicine Maintenance of Certification Program: Cocreating the Future. PMID- 26039405 TI - Molecular CsF5 and CsF2+. AB - D5h star-like CsF5 , formally isoelectronic with known XeF5 (-) ion, is computed to be a local minimum on the potential energy surface of CsF5 , surrounded by reasonably large activation energies for its exothermic decomposition to CsF+2 F2 , or to CsF3 (three isomeric forms)+F2 , or for rearrangement to a significantly more stable isomer, a classical Cs(+) complex of F5 (-) . Similarly the CsF2 (+) ion is computed to be metastable in two isomeric forms. In the more symmetrical structures of these molecules there is definite involvement in bonding of the formally core 5p levels of Cs. PMID- 26039406 TI - Correction: Potential Role of Masting by Introduced Bamboos in Deer Mice (Peromyscus maniculatus) Population Irruptions Holds Public Health Consequences. PMID- 26039407 TI - Natural shorelines promote the stability of fish communities in an urbanized coastal system. AB - Habitat loss and fragmentation are leading causes of species extinctions in terrestrial, aquatic and marine systems. Along coastlines, natural habitats support high biodiversity and valuable ecosystem services but are often replaced with engineered structures for coastal protection or erosion control. We coupled high-resolution shoreline condition data with an eleven-year time series of fish community structure to examine how coastal protection structures impact community stability. Our analyses revealed that the most stable fish communities were nearest natural shorelines. Structurally complex engineered shorelines appeared to promote greater stability than simpler alternatives as communities nearest vertical walls, which are among the most prevalent structures, were most dissimilar from natural shorelines and had the lowest stability. We conclude that conserving and restoring natural habitats is essential for promoting ecological stability. However, in scenarios when natural habitats are not viable, engineered landscapes designed to mimic the complexity of natural habitats may provide similar ecological functions. PMID- 26039408 TI - Ancient DNA microsatellite analyses of the extinct New Zealand giant moa (Dinornis robustus) identify relatives within a single fossil site. AB - By analysing ancient DNA (aDNA) from 74 (14)C-dated individuals of the extinct South Island giant moa (Dinornis robustus) of New Zealand, we identified four dyads of closely related adult females. Although our total sample included bones from four fossil deposits located within a 10 km radius, these eight individuals had all been excavated from the same locality. Indications of kinship were based on high pairwise genetic relatedness (rXY) in six microsatellite markers genotyped from aDNA, coupled with overlapping radiocarbon ages. The observed rXY values in the four dyads exceeded a conservative cutoff value for potential relatives obtained from simulated data. In three of the four dyads, the kinship was further supported by observing shared and rare mitochondrial haplotypes. Simulations demonstrated that the proportion of observed dyads above the cutoff value was at least 20 times higher than expected in a randomly mating population with temporal sampling, also when introducing population structure in the simulations. We conclude that the results must reflect social structure in the moa population and we discuss the implications for future aDNA research. PMID- 26039409 TI - Life history as a constraint on plasticity: developmental timing is correlated with phenotypic variation in birds. AB - Understanding why organisms vary in developmental plasticity has implications for predicting population responses to changing environments and the maintenance of intraspecific variation. The epiphenotype hypothesis posits that the timing of development can constrain plasticity-the earlier alternate phenotypes begin to develop, the greater the difference that can result amongst the final traits. This research extends this idea by considering how life history timing shapes the opportunity for the environment to influence trait development. We test the prediction that the earlier an individual begins to actively interact with and explore their environment, the greater the opportunity for plasticity and thus variation in foraging traits. This research focuses on life history variation across four groups of birds using museum specimens and measurements from the literature. We reasoned that greater phenotypic plasticity, through either environmental effects or genotype-by-environment interactions in development, would be manifest in larger trait ranges (bills and tarsi) within species. Among shorebirds and ducks, we found that species with relatively shorter incubation times tended to show greater phenotypic variation. Across warblers and sparrows, we found little support linking timing of flight and trait variation. Overall, our results also suggest a pattern between body size and trait variation, consistent with constraints on egg size that might result in larger species having more environmental influences on development. Taken together, our results provide some support for the hypothesis that variation in life histories affects how the environment shapes development, through either the expression of plasticity or the release of cryptic genetic variation. PMID- 26039410 TI - Correction: morphology, molecules, and monogenean parasites: an example of an integrative approach to cichlid biodiversity. PMID- 26039411 TI - Pancreatic cancer patient survival correlates with DNA methylation of pancreas development genes. AB - DNA methylation is an epigenetic mark associated with regulation of transcription and genome structure. These markers have been investigated in a variety of cancer settings for their utility in differentiating normal tissue from tumor tissue. Here, we examine the direct correlation between DNA methylation and patient survival. We find that changes in the DNA methylation of key pancreatic developmental genes are strongly associated with patient survival. PMID- 26039413 TI - [In Process Citation]. AB - Approximately 70,000 people are infected with hepatitis C virus in Hungary, and more than half of them are not aware of their infection. From the point of infected individuals early recognition and effective treatment of related liver injury may prevent consequent advanced liver diseases and complications (liver cirrhosis, liver failure and liver cancer) and can increase work productivity and life expectancy. From a socioeconomic aspect, this could also prevent further spread of the virus as well as reduce substantially long term financial burden of related morbidity. Pegylated interferon + ribavirin dual therapy, which is available in Hungary since 2003, can clear the virus in 40-45% of previously not treated (naive), and in 5-21% of previous treatment-failure patients. Addition of a direct acting first generation protease inhibitor drug (boceprevir or telaprevir) to the dual therapy increases the chance of sustained viral response to 63-75% and 59-66%, respectively. These two protease inhibitors are available and financed for a segment of Hungarian patients since May 2013. Between 2013 and February 2015, other direct acting antiviral interferon-free combination therapies have been registered for the treatment of chronic hepatitis C, with a potential efficacy over 90% and typical short duration of 8-12 weeks. Indication of therapy includes exclusion of contraindications to the drugs and demonstration of viral replication with consequent liver injury, i.e., inflammation and / or fibrosis in the liver. Non-invasive methods (elastography and biochemical methods) are accepted and preferred for staging liver damage (fibrosis). For initiation of treatment as well as for on-treatment decisions, accurate and timely molecular biology tests are mandatory. Eligibility for treatment is a subject of individual central medical review. Due to budget limitations therapy is covered only for a proportion of patients by the National Health Insurance Fund. Priority is given to those with urgent need based on a Hungarian Priority Index system reflecting primarily the stage of liver disease, and considering also additional factors, i.e., activity and progression of liver disease, predictive factors of treatment and other special issues. Approved treatments are restricted to the most cost-effective combinations based on the cost per sustained viral response value in different patient categories with consensus between professional organizations, National Health Insurance Fund and patient organizations. More expensive therapies might be available upon co-financing by the patient or a third party. Interferon-free treatments and shorter therapy durations preferred as much as financially feasible. A separate budget is allocated to cover interferon-free treatments for the most-in-need interferon ineligible/intolerant patients, and for those who have no more interferon-based therapy option. Orv. Hetil., 2015, 156(Suppl. 1), 3-23. PMID- 26039412 TI - Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival Rates. AB - RATIONALE: Chronic obstructive pulmonary disease is associated with a worse overall survival in non-small cell lung cancer. Lung emphysema is one component of chronic obstructive pulmonary disease. We hypothesized that emphysema of the tumor region may result in larger tumors and a poorer overall survival. METHODS: We evaluated 304 cases of non-small cell lung cancer from a prospectively enrolled cohort. The lung was divided into equal volumetric thirds (upper, middle, or lower region). Emphysema was defined as percentage of low-attenuation areas less than -950 Hounsfield units (%LAA-950) and measured for each region. Whole-lung %LAA-950 was defined as the emphysema score of the entire lung parenchyma, whereas regional %LAA-950 was the score within that particular region (upper, middle, or lower). The emphysema score of the region in which the tumor occurred was defined as the tumor %LAA-950. Tumor diameter was measured while blinded to characteristics of the lung parenchyma. A proportional hazards model was used to control for multiple factors associated with survival. MEASUREMENTS AND MAIN RESULTS: Increasing tumor %LAA-950 was associated with larger tumors (P = 0.024). Survival, stratified by stage, was significantly worse in those with tumor %LAA-950 greater than or equal to the 50th percentile versus less than the 50th percentile (P = 0.046). Whole-lung %LAA-950 and regional %LAA-950 (e.g., regional emphysema without tumor occurring in the region) were not significantly associated with survival. There were no differences in presenting symptoms or locations of mediastinal or distant metastasis by emphysema score. Increasing tumor %LAA-950 was associated with an increased risk of death (adjusted hazard ratio, 1.36; confidence interval, 1.09-1.68; P = 0.006) after adjustment for age, sex, smoking status, histology, stage, performance status, chemotherapy, radiation, and surgery. Sensitivity analyses revealed no significant difference in the effect size or test of significance for each of the following conditions: (1) exclusion of cases with central tumor location, (2) exclusion of cases where surgery was performed, (3) exclusion of cases where radiation therapy was performed, (4) exclusion of cases where epidermal growth factor receptor tyrosine kinase inhibitors were administered, and (5) inclusion of only stage IV disease. CONCLUSIONS: Increasing emphysema of the region in which a non-small cell lung cancer tumor occurs is associated with increasing tumor size and worse overall survival. PMID- 26039414 TI - [In Process Citation]. AB - Diagnosis and treatment of hepatitis B and D virus infections mean that the patient is able to maintain working capacity, increase quality of life, prevent cancer, and prolong life expectancy, while the society benefits from eliminating the chances of further transmission of the viruses, and decreasing the overall costs of serious complications. The guideline delineates the treatment algorithms for 2015, which is agreed on a consensus meeting of specialists involved in the treatment of the above diseases. The prevalence of hepatitis B virus infection in the Hungarian general population is 0.5-0.7%. The indications of treatment is based upon viral examinations (including viral nucleic acid determination), determinations of disease activity and stage (including biochemical, pathologic, and/or non-invasive methods), and excluding contraindications. To avoid unnecessary side effects and for cost-effective approach the guideline emphasizes the importance of quick and detailed virologic evaluations, the applicability of transient elastography as an acceptable alternative of liver biopsy in this regard, as well as the relevance of appropriate consistent follow up schedule for viral response during therapy. The first choice of therapy in chronic hepatitis B infection can be pegylated interferon for 48 weeks or continuous entecavir or tenofovir therapy. The latter two must be continued for at least 12 months after hepatitis B surface antigen seroconversion. Adefovir dipivoxil is recommended mainly in combination therapy. Lamivudine is no longer a first choice; patients currently taking lamivudine must switch if response is inadequate. Appropriate treatment of patients taking immunosuppressive medications is highly recommended. Pegylated interferon based therapy is recommended for the treatment of concomitant hepatitis D infection. Orv. Hetil., 2015, 156(Suppl. 1), 25-35. PMID- 26039415 TI - Self-Structured Conductive Filament Nanoheater for Chalcogenide Phase Transition. AB - Ge2Sb2Te5-based phase-change memories (PCMs), which undergo fast and reversible switching between amorphous and crystalline structural transformation, are being utilized for nonvolatile data storage. However, a critical obstacle is the high programming current of the PCM cell, resulting from the limited pattern size of the optical lithography-based heater. Here, we suggest a facile and scalable strategy of utilizing self-structured conductive filament (CF) nanoheaters for Joule heating of chalcogenide materials. This CF nanoheater can replace the lithographical-patterned conventional resistor-type heater. The sub-10 nm contact area between the CF and the phase-change material achieves significant reduction of the reset current. In particular, the PCM cell with a single Ni filament nanoheater can be operated at an ultralow writing current of 20 MUA. Finally, phase-transition behaviors through filament-type nanoheaters were directly observed by using transmission electron microscopy. PMID- 26039417 TI - FEN1-mediated alpha-segment error editing during Okazaki fragment maturation. PMID- 26039416 TI - Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. AB - Sepsis is the predominant cause of mortality in ICUs, and opioids are the preferred analgesic in this setting. However, the role of opioids in sepsis progression has not been well characterized. The present study demonstrated that morphine alone altered the gut microbiome and selectively induced the translocation of Gram-positive gut bacteria in mice. Using a murine model of poly microbial sepsis, we further demonstrated that morphine treatment led to predominantly Gram-positive bacterial dissemination. Activation of TLR2 by disseminated Gram-positive bacteria induced sustained up-regulation of IL-17A and IL-6. We subsequently showed that overexpression of IL-17A compromised intestinal epithelial barrier function, sustained bacterial dissemination and elevated systemic inflammation. IL-17A neutralization protected barrier integrity and improved survival in morphine-treated animals. We further demonstrated that TLR2 expressed on both dendritic cells and T cells play essential roles in IL-17A production. Additionally, intestinal sections from sepsis patients on opioids exhibit similar disruption in gut epithelial integrity, thus establishing the clinical relevance of this study. This is the first study to provide a mechanistic insight into the opioid exacerbation of sepsis and show that neutralization of IL-17A might be an effective therapeutic strategy to manage Gram-positive sepsis in patients on an opioid regimen. PMID- 26039418 TI - The effects of intraplantar and intrathecal botulinum toxin type B on tactile allodynia in mono and polyneuropathy in the mouse. AB - BACKGROUND: Mononeuropathies (MNs: nerve ligation) and polyneuropathies (PNs: cisplatin) produce unilateral and bilateral tactile allodynia, respectively. We examined the effects of intraplantar (IPLT) and intrathecal (IT) botulinum toxin B (BoNT-B) on this allodynia. METHODS: Mice (male c57Bl/6) were prepared with an L5 nerve ligation. Others received cisplatin (IP 2.3 mg/kg/d, every other day for 6 injections). Saline and BoNT-B were administered through the IPLT or IT route. We examined mechanical allodynia (von Frey hairs) before and at intervals after BoNT. As a control, we injected IPLT BoNT-B treated with dithiothreitol to cleave heavy chain from light chain. We measured motor function using acute thermal escape and sensorimotor tests. RESULTS: MN and PN mice showed a persistent ipsilateral and bilateral allodynia, respectively. IPLT BoNT-B resulted in an ipsilateral dorsal horn reduction in the synaptic protein target of BoNT-B (vesicle-associated membrane protein) and a long-lasting (up to approximately 17 days) reversal of allodynia in PN and MN models. The predominant effect after IPLT delivery was ipsilateral to IPLT BoNT. The effects of IPLT BoNT-B in MN mice were blocked by prior reduction of BoNT-B with dithiothreitol. IT BoNT-B in mice with PN resulted in a bilateral reversal of allodynia. With these dosing parameters, hind paw placing and stepping reflexes were unaltered, and there were no changes in thermal escape latencies. After cisplatin, dorsal root ganglions displayed increases in activation transcription factor 3, which were reduced by IT, but not IPLT BoNT-B. CONCLUSIONS: BoNT-B given IPLT and IT yields a long lasting attenuation of the allodynia in mice displaying MN and PN allodynia. PMID- 26039419 TI - Tracking Changes in Cardiac Output: Statistical Considerations on the 4-Quadrant Plot and the Polar Plot Methodology. AB - When comparing 2 technologies for measuring hemodynamic parameters with regard to their ability to track changes, 2 graphical tools are omnipresent in the literature: the 4-quadrant plot and the polar plot recently proposed by Critchley et al. The polar plot is thought to be the more advanced statistical tool, but care should be taken when it comes to its interpretation. The polar plot excludes possibly important measurements from the data. The polar plot transforms the data nonlinearily, which may prevent it from being seen clearly. In this article, we compare the 4-quadrant and the polar plot in detail and thoroughly describe advantages and limitations of each. We also discuss pitfalls concerning the methods to prepare the researcher for the sound use of both methods. Finally, we briefly revisit the Bland-Altman plot for the use in this context. PMID- 26039420 TI - A rapid method to achieve aero-engine blade form detection. AB - This paper proposes a rapid method to detect aero-engine blade form, according to the characteristics of an aero-engine blade surface. This method first deduces an inclination error model in free-form surface measurements based on the non contact laser triangulation principle. Then a four-coordinate measuring system was independently developed, a special fixture was designed according to the blade shape features, and a fast measurement of the blade features path was planned. Finally, by using the inclination error model for correction of acquired data, the measurement error that was caused by tilt form is compensated. As a result the measurement accuracy of the Laser Displacement Sensor was less than 10 MUm. After the experimental verification, this method makes full use of optical non-contact measurement fast speed, high precision and wide measuring range of features. Using a standard gauge block as a measurement reference, the coordinate system conversion data is simple and practical. It not only improves the measurement accuracy of the blade surface, but also its measurement efficiency. Therefore, this method increases the value of the measurement of complex surfaces. PMID- 26039422 TI - Tightly-coupled stereo visual-inertial navigation using point and line features. AB - This paper presents a novel approach for estimating the ego-motion of a vehicle in dynamic and unknown environments using tightly-coupled inertial and visual sensors. To improve the accuracy and robustness, we exploit the combination of point and line features to aid navigation. The mathematical framework is based on trifocal geometry among image triplets, which is simple and unified for point and line features. For the fusion algorithm design, we employ the Extended Kalman Filter (EKF) for error state prediction and covariance propagation, and the Sigma Point Kalman Filter (SPKF) for robust measurement updating in the presence of high nonlinearities. The outdoor and indoor experiments show that the combination of point and line features improves the estimation accuracy and robustness compared to the algorithm using point features alone. PMID- 26039421 TI - Design and evaluation of potentiometric principles for bladder volume monitoring: a preliminary study. AB - Recent advances in microelectronics and wireless transmission technology have led to the development of various implantable sensors for real-time monitoring of bladder conditions. Although various sensing approaches for monitoring bladder conditions were reported, most such sensors have remained at the laboratory stage due to the existence of vital drawbacks. In the present study, we explored a new concept for monitoring the bladder capacity on the basis of potentiometric principles. A prototype of a potentiometer module was designed and fabricated and integrated with a commercial wireless transmission module and power unit. A series of in vitro pig bladder experiments was conducted to determine the best design parameters for implementing the prototype potentiometric device and to prove its feasibility. We successfully implemented the potentiometric module in a pig bladder model in vitro, and the error of the accuracy of bladder volume detection was <+/-3%. Although the proposed potentiometric device was built using a commercial wireless module, the design principles and animal experience gathered from this research can serve as a basis for developing new implantable bladder sensors in the future. PMID- 26039423 TI - Supplemental blue LED lighting array to improve the signal quality in hyperspectral imaging of plants. AB - Hyperspectral imaging systems used in plant science or agriculture often have suboptimal signal-to-noise ratio in the blue region (400-500 nm) of the electromagnetic spectrum. Typically there are two principal reasons for this effect, the low sensitivity of the imaging sensor and the low amount of light available from the illuminating source. In plant science, the blue region contains relevant information about the physiology and the health status of a plant. We report on the improvement in sensitivity of a hyperspectral imaging system in the blue region of the spectrum by using supplemental illumination provided by an array of high brightness light emitting diodes (LEDs) with an emission peak at 470 nm. PMID- 26039425 TI - Evidence-based practice guidelines in pediatric critical care: laying the foundation for moving forward. PMID- 26039424 TI - Impact of alcohol dehydrogenase gene 4 polymorphisms on esophageal squamous cell carcinoma risk in a Chinese population. AB - BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is very common in China and is also one of the most common cancers worldwide. The purpose of this study was to examine the associations between genetic variants of various cancer-related genes and the risk of ESCC. METHODS: In this study, we first examined the association between 18 potentially disruptive genetic variants of 17 genes, including alcohol dehydrogenase 4 (ADH4) and checkpoint kinase 2 (CHEK2), and ESCC risk in a Hangzhou population of 617 patients matched with 534 controls. Among the 18 single nucleotide polymorphisms (SNPs), two were validated in a Jinan population of 540 patients matched with 550 controls. RESULTS: Sixteen SNPs in 15 genes, including CHEK2, did not have significantly different allele frequency distributions between ESCC patients and control subjects. A significantly increased risk of developing ESCC was revealed in subjects with the AA genotype of rs3805322 (ADH4) compared with those with the AG or GG genotype by unconditional univariate logistic regression analysis. Using a dominant model, the CC genotype of rs4822983 (CHEK2) had a marginally significant protective effect compared to the CT and TT genotypes. The association of ESCC risk with these two SNPs (rs3805322 and rs4822983) was further validated in a Jinan case control set. Individuals with the ADH4 rs3805322 AA or AG genotype had ORs of 1.10 (95% CI = 0.81-1.49, P < 0.001) or 1.86 (95% CI = 1.33-2.59, P = 0.559), respectively, for developing ESCC compared with individuals with the GG genotype. CHEK2 rs4822983 CC carriers showed a marginally significantly decreased ESCC risk compared with those carrying the CT and TT genotypes in the validation set (95% CI = 0.61-1.01, P = 0.064). However, no evidence of interaction existed between the two SNPs and smoking or drinking in the Jinan case-control set. CONCLUSIONS: In conclusion, this current study provides substantial evidence that genetic polymorphisms of rs3805322 in the ADH4 gene may be associated with an increased risk of developing ESCC in two Chinese Han populations. Future studies to address the biological function of this polymorphism in the development of ESCC are warranted. PMID- 26039426 TI - Pediatric sepsis from start to finish. PMID- 26039427 TI - Noninvasive ventilation in pediatric intensive care: from a promising to an established therapy, but for whom, when, why, and how? PMID- 26039428 TI - Pediatric acute respiratory distress syndrome: much more than little acute respiratory distress syndrome. PMID- 26039429 TI - Improving outcomes following neonatal cardiac surgery: weight can be taken none too lightly! PMID- 26039430 TI - Seizure Detection in the PICU: Can We "See" Seizures Better in Color? PMID- 26039431 TI - To Err One's Dirty Laundry. PMID- 26039432 TI - Another step in understanding glucocorticoid resistance in critical illness. PMID- 26039433 TI - Neonatal tracheal intubation: unsolved issue. PMID- 26039434 TI - The authors reply. PMID- 26039435 TI - Noninvasive ventilation: more useful than it seems? PMID- 26039436 TI - The authors reply. PMID- 26039437 TI - Extubation during pediatric extracorporeal membrane oxygenation: is it always safe? PMID- 26039438 TI - The authors reply. PMID- 26039439 TI - Erratum: Human H7N9 avian influenza virus infection: a review and pandemic risk assessment. AB - [This corrects the article DOI: 10.1038/emi.2013.48.]. PMID- 26039440 TI - Examining the Predictive Validity of NIH Peer Review Scores. AB - The predictive validity of peer review at the National Institutes of Health (NIH) has not yet been demonstrated empirically. It might be assumed that the most efficient and expedient test of the predictive validity of NIH peer review would be an examination of the correlation between percentile scores from peer review and bibliometric indices of the publications produced from funded projects. The present study used a large dataset to examine the rationale for such a study, to determine if it would satisfy the requirements for a test of predictive validity. The results show significant restriction of range in the applications selected for funding. Furthermore, those few applications that are funded with slightly worse peer review scores are not selected at random or representative of other applications in the same range. The funding institutes also negotiate with applicants to address issues identified during peer review. Therefore, the peer review scores assigned to the submitted applications, especially for those few funded applications with slightly worse peer review scores, do not reflect the changed and improved projects that are eventually funded. In addition, citation metrics by themselves are not valid or appropriate measures of scientific impact. The use of bibliometric indices on their own to measure scientific impact would likely increase the inefficiencies and problems with replicability already largely attributed to the current over-emphasis on bibliometric indices. Therefore, retrospective analyses of the correlation between percentile scores from peer review and bibliometric indices of the publications resulting from funded grant applications are not valid tests of the predictive validity of peer review at the NIH. PMID- 26039441 TI - Alkaline Earth Metal Ion/Dihydroxy-Terephthalate MOFs: Structural Diversity and Unusual Luminescent Properties. AB - Alkaline earth (group 2) metal ion organic frameworks (AEMOFs) represent an important subcategory of MOFs with interesting structures and physical properties. Five MOFs, namely, [Mg2(H2dhtp)2(MU-H2O)(NMP)4] (AEMOF-2), [Mg2(H2dhtp)1.5(DMAc)4]Cl.DMAc (AEMOF-3), [Ca(H2dhtp)(DMAc)2] (AEMOF-4), [Sr3(H2dhtp)3(DMAc)6].H2O (AEMOF-5), and [Ba(H2dhtp)(DMAc)] (AEMOF-6) (H4dhtp = 2,5-dihydroxy-terepthalic acid; DMAc = N,N-dimethylacetamide; NMP = N methylpyrrolidone), are presented herein. The reported MOFs display structural variety with diverse topologies and new structural features. Interestingly, AEMOF 6 is the first example of a Ba(2+)-H2dhtp(2-) MOF, and AEMOF-5 is only the second known Sr(2+)-H2dhtp(2-) MOF. Detailed photoluminescence studies revealed alkaline earth metal ion-dependent fluorescence properties of the materials, with the heavier alkaline earth metal ions exhibiting red-shifted emission with respect to the lighter ions at room temperature. A bathochromic shift of the emission was observed for the MOFs (mostly for AEMOF-3 and AEMOF-4) at 77 K as a result of excited state proton transfer (ESIPT), which involves an intramolecular proton transfer from a hydroxyl to an adjacent carboxylic group of the H2dhtp(2-) ligand. Remarkably, AEMOF-6 displays rare yellow fluorescence at room temperature, which is attractive for solid state lighting applications. To probe whether the alkaline earth metal ions are responsible for the unusual luminescence properties of the reported MOFs, the potential energy surfaces (PESs) of the ground, S0, and lowest energy excited singlet, S1, states of model complexes along the intramolecular proton transfer coordinate were calculated by DFT and TD-DFT methods. PMID- 26039442 TI - Leptin keeps working, even in obesity. AB - The concept of leptin resistance posits that elevated endogenous leptin fails to decrease food intake in obese animals due to diminished leptin signaling. In this issue, Ottaway et al. (2015) use leptin antagonists to reveal persistence (or even elevation) of endogenous leptin signaling and physiologic action in diet induced obesity. PMID- 26039443 TI - Innate immune recognition of mtDNA--an undercover signal? AB - In addition to their roles in cellular metabolism and apoptosis, mitochondria function as signaling platforms in the innate immune response. In Nature, West et al. (2015) demonstrate that mitochondrial stress triggers a type I interferon response and confers viral resistance via release of mtDNA and activation of the cGAS-STING pathway. PMID- 26039444 TI - The sum of all browning in FGF21 therapeutics. AB - FGF21 mimetics are a promising therapeutic tool, believed to exert their anti obesity effect partly through browning of white fat. Veniant et al. (2015) and Samms et al. (2015) present evidence arguing against fat browning as the primary mechanism causal to weight loss following FGF21-based treatment in mice. PMID- 26039445 TI - The reparative function of cardiomyocytes in the infarcted myocardium. AB - Effective repair of the infarcted heart requires spatial containment of the inflammatory reaction within the infarcted area. A recently published study demonstrates that in the pro-inflammatory environment of the infarct border zone, surviving cardiomyocytes restrain inflammation by activating a Reg3beta-dependent cascade that recruits reparative macrophages and promotes neutrophil clearance. PMID- 26039446 TI - Beyond energy homeostasis: the expanding role of AMP-activated protein kinase in regulating metabolism. AB - The recent exciting advances in our understanding of the regulation of the energy sensor AMP-activated protein kinase (AMPK), together with renewed appreciation of its importance in maintaining cellular function, brought together leading scientists at a recent FASEB-sponsored meeting in September 2014. Here, we report some of the highlights of this conference. PMID- 26039447 TI - Acetyl coenzyme A: a central metabolite and second messenger. AB - Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger. PMID- 26039448 TI - The OPA1-dependent mitochondrial cristae remodeling pathway controls atrophic, apoptotic, and ischemic tissue damage. AB - Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1) dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo. PMID- 26039450 TI - ATP citrate lyase improves mitochondrial function in skeletal muscle. AB - Mitochondrial dysfunction is associated with skeletal muscle pathology, including cachexia, sarcopenia, and the muscular dystrophies. ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes mitochondria-derived citrate into oxaloacetate and acetyl-CoA. Here we report that activation of ACL in skeletal muscle results in improved mitochondrial function. IGF1 induces activation of ACL in an AKT dependent fashion. This results in an increase in cardiolipin, thus increasing critical mitochondrial complexes and supercomplex activity, and a resultant increase in oxygen consumption and cellular ATP levels. Conversely, knockdown of ACL in myotubes not only reduces mitochondrial complex I, IV, and V activity but also blocks IGF1-induced increases in oxygen consumption. In vivo, ACL activity is associated with increased ATP. Activation of this IGF1/ACL/cardiolipin pathway combines anabolic signaling with induction of mechanisms needed to provide required ATP. PMID- 26039449 TI - Opa1 overexpression ameliorates the phenotype of two mitochondrial disease mouse models. AB - Increased levels of the mitochondria-shaping protein Opa1 improve respiratory chain efficiency and protect from tissue damage, suggesting that it could be an attractive target to counteract mitochondrial dysfunction. Here we show that Opa1 overexpression ameliorates two mouse models of defective mitochondrial bioenergetics. The offspring from crosses of a constitutive knockout for the structural complex I component Ndufs4 (Ndufs4(-/-)), and of a muscle-specific conditional knockout for the complex IV assembly factor Cox15 (Cox15(sm/sm)), with Opa1 transgenic (Opa1(tg)) mice showed improved motor skills and respiratory chain activities compared to the naive, non-Opa1-overexpressing, models. While the amelioration was modest in Ndufs4(-/-)::Opa1(tg) mice, correction of cristae ultrastructure and mitochondrial respiration, improvement of motor performance and prolongation of lifespan were remarkable in Cox15(sm/sm)::Opa1(tg) mice. Mechanistically, respiratory chain supercomplexes were increased in Cox15(sm/sm)::Opa1(tg) mice, and residual monomeric complex IV was stabilized. In conclusion, cristae shape amelioration by controlled Opa1 overexpression improves two mouse models of mitochondrial disease. PMID- 26039451 TI - AMPK activation of muscle autophagy prevents fasting-induced hypoglycemia and myopathy during aging. AB - The AMP-activated protein kinase (AMPK) activates autophagy, but its role in aging and fasting-induced muscle function has not been defined. Here we report that fasting mice lacking skeletal muscle AMPK (AMPK-MKO) results in hypoglycemia and hyperketosis. This is not due to defective fatty acid oxidation, but instead is related to a block in muscle proteolysis that leads to reduced circulating levels of alanine, an essential amino acid required for gluconeogenesis. Markers of muscle autophagy including phosphorylation of Ulk1 Ser555 and Ser757 and aggregation of RFP-LC3 puncta are impaired. Consistent with impaired autophagy, aged AMPK-MKO mice possess a significant myopathy characterized by reduced muscle function, mitochondrial disease, and accumulation of the autophagy/mitophagy proteins p62 and Parkin. These findings establish an essential requirement for skeletal muscle AMPK-mediated autophagy in preserving blood glucose levels during prolonged fasting as well as maintaining muscle integrity and mitochondrial function during aging. PMID- 26039452 TI - Detection of FGF15 in plasma by stable isotope standards and capture by anti peptide antibodies and targeted mass spectrometry. AB - Fibroblast growth factor 15 (FGF15) has been proposed as a postprandial hormone that signals from intestine to liver to regulate bile acid and carbohydrate homeostasis. However, detecting FGF15 in blood using conventional techniques has proven difficult. Here, we describe a stable isotope standards and capture by anti-peptide antibodies (SISCAPA) assay that combines immuno-enrichment with selected reaction monitoring (SRM) mass spectrometry to overcome this issue. Using this assay, we show that FGF15 circulates in plasma in an FXR and circadian rhythm-dependent manner at concentrations that activate its receptor. Consistent with the proposed endocrine role for FGF15 in liver, mice lacking hepatocyte expression of the obligate FGF15 co-receptor, beta-Klotho, have increased bile acid synthesis and reduced glycogen storage despite having supraphysiological plasma FGF15 concentrations. Collectively, these data demonstrate that FGF15 functions as a hormone and highlight the utility of SISCAPA-SRM as a sensitive assay for detecting low-abundance proteins in plasma. PMID- 26039453 TI - Epigenome-wide association of liver methylation patterns and complex metabolic traits in mice. AB - Heritable epigenetic factors can contribute to complex disease etiology. Here we examine the contribution of DNA methylation to complex traits that are precursors to heart disease, diabetes, and osteoporosis. We profiled DNA methylation in the liver using bisulfite sequencing in 90 mouse inbred strains, genome-wide expression levels, proteomics, metabolomics, and 68 clinical traits and performed epigenome-wide association studies (EWAS). We found associations with numerous clinical traits including bone density, insulin resistance, expression, and protein and metabolite levels. A large proportion of associations were unique to EWAS and were not identified using GWAS. Methylation levels were regulated by genetics largely in cis, but we also found evidence of trans regulation, and we demonstrate that genetic variation in the methionine synthase reductase gene Mtrr affects methylation of hundreds of CpGs throughout the genome. Our results indicate that natural variation in methylation levels contributes to the etiology of complex clinical traits. PMID- 26039455 TI - Correction: Oscillatory brain activity reveals linguistic prints in the quantity code. PMID- 26039454 TI - Differential response of pig masseter to botulinum neurotoxin serotypes a and b. AB - INTRODUCTION: Pigs respond to direct administration of botulinum neurotoxins (BoNTs), although they are resistant to botulism. The human masseter is frequently targeted for BoNT therapy. We aimed to understand how BoNT affects chewing by injecting porcine masseters. METHODS: One masseter of minipigs was injected with BoNT serotype A or B at doses comparable to those used in humans. Masticatory function was evaluated electromyographically. Muscle force was measured during tetany. Four weeks after injection, strain gauges affixed to the mandible assessed bone strain during chewing. Masseter mass and fiber diameter were measured after euthanasia. RESULTS: BoNT-A had no measurable effect. In contrast, BoNT-B reduced electrical activity and muscle force, producing substantial asymmetry between injected and uninjected muscles. CONCLUSIONS: The pig masseter is highly resistant to direct injection of BoNT-A, but it is affected by BoNT-B. PMID- 26039456 TI - Electrochemical Activity of Dendrimer-Stabilized Tin Nanoparticles for Lithium Alloying Reactions. AB - The synthesis and characterization of Sn nanoparticles in organic solvents using sixth-generation dendrimers modified on their periphery with hydrophobic groups as stabilizers are reported. Sn(2+):dendrimer ratios of 147 and 225 were employed for the synthesis, corresponding to formation of Sn147 and Sn225 dendrimer stabilized nanoparticles (DSNs). Transmission electron microscopy analysis indicated the presence of ultrasmall Sn nanoparticles having an average size of 3.0-5.0 nm. X-ray absorption spectroscopy suggested the presence of Sn nanoparticles with only partially oxidized surfaces. Cyclic voltammetry studies of the Sn DSNs for Li alloying/dealloying reactions demonstrated good reversibility. Control experiments carried out in the absence of DSNs clearly indicated that these ultrasmall Sn DSNs react directly with Li to form SnLi alloys. PMID- 26039457 TI - Advances in the treatment of chronic wounds: a patent review. AB - INTRODUCTION: About 2% of the Western world population suffer from chronic wounds, resulting from underlying disorders (e.g., diabetes, excessive pressure, vascular insufficiencies and vasculitis), with a significant adverse effect on Quality of Life. Despite high incidence and economic burden, management of chronic wounds is still far from effective and novel therapies are in urgent need. Wound healing is a dynamic process of transient expression, function and clearance of mediators, enzymes and cell types. Failure to initiate, terminate or regulate leads to pathologic wound healing. AREAS COVERED: The present review discusses patents of the seven most promising classes of biological agents, mostly published in 2009 - 2014 (CYP11B1 inhibitors, peptide growth factors, prolyl-4-hydroxylase and matrix metalloproteinase inhibitors, bone marrow-derived mesenchymal stem cells, elastase and connexin43 inhibitors). Relevant information from peer-reviewed journals is also presented. EXPERT OPINION: The aforementioned biological agents have different mechanisms of action, and considering the multifactorial pathogenesis of chronic wounds, they hold promise in treating chronic wounds. However, as administration of a certain biological agent may be beneficial in an early phase, it may slow down wound healing in a later phase. Basic and clinical research on chronic wound healing should therefore investigate the efficacy of these agents, alone and in concert, during the consecutive phases of wound healing. PMID- 26039459 TI - [A bulky lateral cervical mass]. AB - Branchial cysts are rare, benign cervical lesions that can mimic thyroid goiters, in particular in areas where goiters are endemic. This case describes an Ivorian patient who presented with what appeared to be a voluminous thyroid goiter. At surgery, it proved to be a cyst of the second pharyngeal arch. PMID- 26039461 TI - A rapid, efficient, and facile solution for dental hypersensitivity: The tannin iron complex. AB - Dental hypersensitivity due to exposure of dentinal tubules under the enamel layer to saliva is a very popular and highly elusive technology priority in dentistry. Blocking water flow within exposed dentinal tubules is a key principle for curing dental hypersensitivity. Some salts used in "at home" solutions remineralize the tubules inside by concentrating saliva ingredients. An "in office" option of applying dense resin sealants on the tubule entrance has only localized effects on well-defined sore spots. We report a self-assembled film that was formed by facile, rapid (4 min), and efficient (approximately 0.5 g/L concentration) dip-coating of teeth in an aqueous solution containing a tannic acid-iron(III) complex. It quickly and effectively occluded the dentinal tubules of human teeth. It withstood intense tooth brushing and induced hydroxyapatite remineralisation within the dentinal tubules. This strategy holds great promise for future applications as an effective and user-friendly desensitizer for managing dental hypersensitivity. PMID- 26039463 TI - Synthesis, Characterization, and Antifungal Activities of Amphiphilic Derivatives of Diethylaminoethyl Chitosan against Aspergillus flavus. AB - Amphiphilic derivatives of diethylaminoethyl chitosan (DEAE-CH) were synthesized using a two-step process involving initial substitution with diethylaminoethyl (DEAE) groups followed by reductive amination with dodecylaldehyde. The synthesized derivatives were characterized by (1)H NMR, gel permeation, and FTIR. The associative behaviors of these compounds in aqueous solution were studied using fluorescence spectroscopy, whereas their antifungal activities against Aspergillus flavus were evaluated in terms of mycelial growth. The effects of deacetylated chitosans and their derivatives on the mycelial growth of A. flavus were evaluated at several polymer concentrations (0.05-1.0 g/L), and the results were compared. The inhibition indices of the deacetylated chitosans increased with increasing Mw (16.9 kDa < 176 kDa < 517.7 kDa); however, derivatives with a combination of either a high molecular weight (Mw) and low hydrophobicity or a low Mw and high hydrophobicity were the most effective in inhibiting the in vitro radial growth of A. flavus. PMID- 26039462 TI - Disruption of parenting behaviors in california mice, a monogamous rodent species, by endocrine disrupting chemicals. AB - The nature and extent of care received by an infant can affect social, emotional and cognitive development, features that endure into adulthood. Here we employed the monogamous, California mouse (Peromyscus californicus), a species, like the human, where both parents invest in offspring care, to determine whether early exposure to endocrine disrupting chemicals (EDC: bisphenol A, BPA; ethinyl estradiol, EE) of one or both parents altered their behaviors towards their pups. Females exposed to either compound spent less time nursing, grooming and being associated with their pups than controls, although there was little consequence on their weight gain. Care of pups by males was less affected by exposure to BPA and EE, but control, non-exposed females appeared able to "sense" a male partner previously exposed to either compound and, as a consequence, reduced their own parental investment in offspring from such pairings. The data emphasize the potential vulnerability of pups born to parents that had been exposed during their own early development to EDC, and that effects on the male, although subtle, also have consequences on overall parental care due to lack of full acceptance of the male by the female partner. PMID- 26039464 TI - Next-generation sequencing as a tool to quickly identify causative EMS-generated mutations. AB - The advent of next generation sequencing has influenced every aspect of biological research. Many labs are now using whole genome sequencing in Arabidopsis thaliana as a means to quickly identify EMS-generated mutations present in isolated mutants. Following identification of these mutations, examination of T-DNA insertional alleles defective in candidate genes or complementation of the mutant phenotype with a wild type copy of candidate genes can be used to verify which mutation is causative for the phenotype of interest. Here, we discuss the benefits and pitfalls of using this method to identify mutations underlying phenotypes. PMID- 26039465 TI - Overexpressing components of the nuclear transport apparatus causes severe growth symptoms in tobacco leaves. AB - Regulating nucleo-cytoplasmic transport of RNA and protein is a key cellular control point. Perturbing the function of plant nuclear transport components can cause significant developmental defects and in this report we add an important line to this evidence. Overexpression of AtRAN1 or AtNUP62 in Nicotiana benthamiana causes significant damage to leaf tissue. This demonstrates that the precise control of nuclear transport is an important aspect of maintaining tissue integrity. PMID- 26039466 TI - Overexpressing CAPRICE and GLABRA3 did not change the anthocyanin content of tomato (Solanum lycopersicum) fruit peel. AB - In Arabidopsis thaliana, the R3-type MYB transcription factor CAPRICE (CPC) and bHLH transcription factor GLABRA3 (GL3) cooperatively regulate epidermal cell differentiation. CPC and GL3 are involved in root-hair differentiation, trichome initiation and anthocyanin biosynthesis in Arabidopsis epidermal cells. Previously, we showed that CPC and GL3 also influence anthocyanin accumulation in tomato. Introduction of 35S::CPC into tomato significantly inhibits anthocyanin accumulation in cotyledons, leaves and stems. In contrast, introduction of GL3::GL3 strongly enhances anthocyanin accumulation in cotyledons, leaves and stems of tomato. In this study, we investigated the effect of CPC and GL3 on anthocyanin accumulation in the epidermis of tomato fruit. Unlike the results with vegetative tissues, overexpression of CPC and GL3 did not influence anthocyanin biosynthesis in tomato fruit peel. PMID- 26039467 TI - Shoot HAR1 mediates nitrate inhibition of nodulation in Lotus japonicus. AB - Nitrate is a major environmental factor in the inhibition of nodulation. In a model legume Lotus japonicus, a CLV1-like receptor kinase, HAR1, mediates nitrate inhibition and autoregulation of nodulation. Autoregulation of nodulation involves root-to-shoot-to-root long-distance communication, and HAR1 functions in shoots. However, it remains elusive where HAR1 functions in the nitrate inhibition of nodulation. We performed grafting experiments with the har1 mutant under various nitrate conditions, and found that shoot HAR1 is critical for the inhibition of nodulation at 10 mM nitrate. Combined with our recent finding that the nitrate-induced CLE-RS2 glycopeptide binds directly to the HAR1 receptor, this result suggests that CLE-RS2/HAR1 long-distance signaling plays an important role in the both nitrate inhibition and the autoregulation of nodulation. PMID- 26039468 TI - New insight in the Gibberellin biosynthesis and signal transduction. AB - Gibberellin (GA) plays important roles through plant growth and development. However, where GA is synthesized inside a cell and how it regulates sex determination is obscure. We analyzed the classic dwarf1 (d1) mutant in maize and revealed that D1 encodes GA 3-oxidase converting inactive GA intermediates to bioactive GA. As such, the D1 protein marks the sites where GA is potentially synthesized. Interestingly, the D1 protein was found to localize in the cytosol and nucleus, a dual-localization coinciding with the GA receptor. The same result was found for GA 20-oxidase catalyzing the upstream reaction. These results suggest that GA can be synthesized in the cytosol and nucleus. The D1 protein was highly and specifically expressed in the stamen primordia in the ear florets, but low in the whole tassel. Hence it is possible that low level of GA in the tassel is insufficient to suppress stamen development. As jasmonic acid (JA) plays antagonistic role to GA in the tassel florets, here we propose a model to explain this antagonism effect on the regulation of the stamen and pistil organ development in the tassel florets in maize. PMID- 26039469 TI - The regulation of UV-B responses by the circadian clock. AB - The circadian clock modulates plant responses to environmental stimuli. In a recent study we showed that light and the circadian clock regulate daily changes in sensitivity to short treatments of high UV-B. Here we demonstrate that these time dependent changes in UV-B stress sensitivity are not mediated by the UV-B receptor UV resistantce locus 8. We also discuss the potential mechanisms involved in this process and the role of the circadian clock in the acclimation to UV-B. PMID- 26039470 TI - In situ analysis of epigenetic modifications in the chromatin of Brachypodium distachyon embryos. AB - Epigenetic modifications of the chromatin structure are crucial for many biological processes and act on genes during the development and germination of seeds. The spatial distribution of 3 epigenetic markers, i.e. H4K5ac, H3K4me2 and H3K4me1 was investigated in 'matured,' 'dry,' 'imbibed" and 'germinating' embryos of a model grass, Brachypodium. Our results indicate that the patterns of epigenetic modification differ in the various types of tissues of embryos that were analyzed. Such a tissue-specific manner of these modifications may be linked to the switch of the gene expression profiles in various organs of the developing embryo. PMID- 26039471 TI - Cortex proliferation in the root is a protective mechanism against abiotic stress. AB - Although as an organ the root plays a pivotal role in nutrient and water uptake as well anchorage, individual cell types function distinctly. Cortex is regarded as the least differentiated cell type in the root, but little is known about its role in plant growth and physiology. In recent studies, we found that cortex proliferation can be induced by oxidative stress. Since all types of abiotic stress lead to oxidative stress, this finding suggests a role for cortex in coping with abiotic stress. This hypothesis was tested in this study using the spy mutant, which has an extra layer of cortex in the root. Interestingly, the spy mutant was shown to be hypersensitive to salt and oxidizing reagent applied to the leaves, but it was as tolerant as the wild type to these compounds in the soil. This result lends support to the notion that cortex has a protective role against abiotic stress arising from the soil. PMID- 26039472 TI - Chloroplast-generated ROS dominate NaCl(-) induced K(+) efflux in wheat leaf mesophyll. AB - Mesophyll K(+) retention ability has been recently reported as an important component of salinity stress tolerance in wheat. In order to investigate the role of ROS in regulating NaCl(-)induced K(+) efflux in wheat leaf mesophyll, a series of pharmacological experiments was conducted using MV (methyl viologen, superoxide radical inducer), DPI (an inhibitor of NADPH oxidase), H2O2 (to mimic apoplastic ROS), and EGCG ((-)-Epigallocatechin gallate, ROS scavenger). Mesophyll pre-treatment with 10 MUM MV resulted in a significantly higher NaCl( )induced K(+) efflux in leaf mesophyll, while 50 MUM EGCG pre-treatment alleviated K(+) leakage under salt stress. No significant change in NaCl( )induced K(+) efflux in leaf mesophyll was found in specimens pre-treated by H2O2 and DPI, compared with the control. The highest NaCl(-)induced H(+) efflux in leaf mesophyll was also found in samples pre-treated with MV, suggesting a futile cycle between increased H(+)-ATPase activity and ROS-induced K(+) leak. Overall, it is suggested that, under saline stress, K(+) efflux from wheat mesophyll is mediated predominantly by non-selective cation channels (NSCC) regulated by ROS produced in chloroplasts, at least in bread wheat. PMID- 26039473 TI - Reduced activity of Arabidopsis chromosome-cohesion regulator gene CTF7/ECO1 alters cytosine methylation status and retrotransposon expression. AB - Multicellular organisms such as higher plants require timely regulation of DNA replication and cell division to grow and develop. Recent work in Arabidopsis has shown that chromosome segregation during meiosis and mitosis depends on the activity of several genes that in yeast are involved in the establishment of chromosomal cohesion. In this process, proteins of the structural maintenance of chromosomes (SMC) family tether chromosomes and establish inter- and intrachromosomal connections. In Arabidopsis, recruitment of SMC proteins and establishment of cohesion during key stages of the cell cycle depend on the activity of chromosome transmission fidelity 7/establishment of cohesion 1 (CTF7/ECO1). Here we show that loss of CTF7/ECO1 activity alters the status of cytosine methylation in both intergenic regions and transposon loci. An increase in expression was also observed for transposon copia28, which suggests a link between CTF7/ECO1 activity, DNA methylation and gene silencing. More work is needed to determine the mechanistic relationships that intervene in this process. PMID- 26039474 TI - Photoperiodic control of sugar release during the floral transition: What is the role of sugars in the florigenic signal? AB - Florigen is a mobile signal released by the leaves that reaching the shoot apical meristem (SAM), changes its developmental program from vegetative to reproductive. The protein FLOWERING LOCUS T (FT) constitutes an important element of the florigen, but other components such as sugars, have been also proposed to be part of this signal. (1-5) We have studied the accumulation and composition of starch during the floral transition in Arabidopsis thaliana in order to understand the role of carbon mobilization in this process. In A. thaliana and Antirrhinum majus the gene coding for the Granule-Bound Starch Synthase (GBSS) is regulated by the circadian clock (6,7) while in the green alga Chlamydomonas reinhardtii the homolog gene CrGBSS is controlled by photoperiod and circadian signals. (8,9) In a recent paper(10) we described the role of the central photoperiodic factor CONSTANS (CO) in the regulation of GBSS expression in Arabidopsis. This regulation is in the basis of the change in the balance between starch and free sugars observed during the floral transition. We propose that this regulation may contribute to the florigenic signal and to the increase in sugar transport required during the flowering process. PMID- 26039475 TI - The Arabidopsis EIN2 restricts organ growth by retarding cell expansion. AB - The growth of plant organ to its characteristic size is a fundamental developmental process, but the mechanism is still poorly understood. Plant hormones play a great role in organ size control by modulating cell division and/or cell expansion. Ethylene insensitve 2 (EIN2) was first identified by a genetic screen for ethylene insensitivity and is regarded as a central component of ethylene signaling, but its role in cell growth has not been reported. Here we demonstrate that changed expression of EIN2 led to abnormity of cell expansion by morphological and cytological analyses of EIN2 loss-of-function mutants and the overexpressing transgenic plant. Our findings suggest that EIN2 controls final organ size by restricting cell expansion. PMID- 26039476 TI - Bundle-sheath aquaporins play a role in controlling Arabidopsis leaf hydraulic conductivity. AB - The role of molecular mechanisms in the regulation of leaf hydraulics (K(leaf)) is still not well understood. We hypothesized that aquaporins (AQPs) in the bundle sheath may regulate K(leaf). To examine this hypothesis, AQP genes were constitutively silenced using artificial microRNAs and recovery was achieved by targeting the expression of the tobacco AQP (NtAQP1) to bundle-sheath cells in the silenced plants. Constitutively silenced PIP1 plants exhibited decreased PIP1 transcript levels and decreased K(leaf). However, once the plants were recovered with NtAQP1, their K(leaf) values were almost the same as those of WT plants. We also demonstrate the important role of ABA, acting via AQP, in that recovery and K(leaf) regulation. These results support our previously raised hypothesis concerning the role of bundle-sheath AQPs in the regulation of leaf hydraulics. PMID- 26039477 TI - Discordance between protein and transcript levels detected by selected reaction monitoring. AB - Expression levels between transcript and protein are not always correlated. In the present study, the abundance of protein PDR9/ABCG37 in 3 Arabidopsis pdr9/abcg37 mutant alleles was evaluated using selected reaction monitoring analysis. The results showed that protein and mRNA expression levels were similar in 2 mutant alleles. The mRNA expression levels in another mutant, determined by both semi-quantitative and quantitative RT-PCR, were similar to the wild-type, although the abundance of protein was about half the abundance of the wild-type. These results suggested that using only mRNA expression levels to infer protein abundance, compare mutants or responses to various stimuli may lead to incorrect interpretation and conclusions. PMID- 26039478 TI - Stress defense mechanisms of NADPH-dependent thioredoxin reductases (NTRs) in plants. AB - Plants establish highly and systemically organized stress defense mechanisms against unfavorable living conditions. To interpret these environmental stimuli, plants possess communication tools, referred as secondary messengers, such as Ca(2+) signature and reactive oxygen species (ROS) wave. Maintenance of ROS is an important event for whole lifespan of plants, however, in special cases, toxic ROS molecules are largely accumulated under excess stresses and diverse enzymes played as ROS scavengers. Arabidopsis and rice contain 3 NADPH-dependent thioredoxin reductases (NTRs) which transfer reducing power to Thioredoxin/Peroxiredoxin (Trx/Prx) system for scavenging ROS. However, due to functional redundancy between cytosolic and mitochondrial NTRs (NTRA and NTRB, respectively), their functional involvements under stress conditions have not been well characterized. Recently, we reported that cytosolic NTRA confers the stress tolerance against oxidative and drought stresses via regulation of ROS amounts using NTRA-overexpressing plants. With these findings, mitochondrial NTRB needs to be further elucidated. PMID- 26039479 TI - Circadian rhythms synchronise intracellular calcium dynamics and ATP production for facilitating Arabidopsis pollen tube growth. AB - Experimental evidences support that the circadian rhythm regulates the transcription levels of genes encoding the enzymes involved in plant metabolism. However, there is no paper to refer the correlation of the circadian rhythms and the metabolic processes for facilitating pollen tube growth. In this study, we found that many central components of the circadian clock were highly enriched and specifically present in the in vivo grown Arabidopsis pollen tubes. Our analysis also identified the significant differentially expressed genes encoding co-expressed enzymes in the consecutive steps of fatty acid beta-oxidation II, pentose phosphate pathway (oxidative branch) and phosphatidic acid biosynthesis pathway in the in vivo grown Arabidopsis pollen tubes during pollination. Thus, it is implicated that the circadian rhythms of pollen tube may be adjusted and have a greater probability of the direct or indirect functional relationship with enhanced intracellular Ca(2+) dynamics and ATP production for facilitating pollen tube growth in vivo. PMID- 26039480 TI - The calcium-dependent protein kinase CPK28 negatively regulates the BIK1-mediated PAMP-induced calcium burst. AB - Plants are protected from microbial infection by a robust immune system. Two of the earliest responses mediated by surface-localized immune receptors include an increase in cytosolic calcium (Ca(2+)) and a burst of apoplastic reactive oxygen species (ROS). The Arabidopsis plasma membrane-associated cytoplasmic kinase BIK1 is an immediate convergent substrate of multiple surface-localized immune receptors that is genetically required for the PAMP-induced Ca(2+) burst and directly regulates ROS production catalyzed by the NADPH oxidase RBOHD. We recently demonstrated that Arabidopsis plants maintain an optimal level of BIK1 through a process of continuous degradation regulated by the Ca(2+)-dependent protein kinase CPK28. cpk28 mutants accumulate more BIK1 protein and display enhanced immune signaling, while plants over-expressing CPK28 accumulate less BIK1 protein and display impaired immune signaling. Here, we show that CPK28 additionally contributes to the PAMP-induced Ca(2+) burst, supporting its role as a negative regulator of BIK1. PMID- 26039481 TI - CHS silencing suggests a negative cross-talk between wax and flavonoid pathways in tomato fruit cuticle. AB - Tomato fruits (Solanum lycopersicum L.) accumulate flavonoids in their cuticle and epidermal cells during ripening. These flavonoids come from de novo biosynthesis due to a significant increase in chalcone synthase (CHS) activity during ripening. Virus-induced gene silencing (VIGS) of tomato fruits have been used to down-regulate SlCHS expression during ripening and analyze the effects at the epidermal and cuticle level. Besides the expected change in fruit color due to a lack of flavonoids incorporated to the cuticle, several other modifications such as a decrease in the amount of cutin and polysaccharides were observed. These indicate a role for either flavonoids or CHS in the alteration of the expression levels of some genes involved in cuticle biosynthesis. Moreover, a negative interaction between the 2 cuticle components, flavonoids and waxes, suggests a relationship between these 2 metabolic pathways. PMID- 26039482 TI - Importance of phosphoinositide-dependent signaling pathways in the control of gene expression in resting cells and in response to phytohormones. AB - "Phosphoinositide" refers to phosphorylated forms of phosphatidylinositol, including phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5 bisphosphate. Both of these molecules could be in vivo substrates of plant phospholipase C. These phosphoinositides can also be biologically active "per se," by directly binding to proteins and thus altering their location and/or activity. The use of pharmacological agents in Arabidopsis suspension cells allowed us to identify genes whose expression was positively or negatively controlled, in the basal state, by products of phosphoinositide-dependent phospholipase C. In this basal state, it seems that no genes exhibit a phosphoinositide-dependent expression "per se." However, many genes whose expression is altered in the presence of phospholipase C inhibitors appeared to be responsive to salicylic acid. This allowed us to show that salicylic acid acts both by increasing the phosphoinositide pool and by inhibiting the phospholipase C. In response to salicylic acid it is possible to identify genes whose expression is controlled by products of PI-PLC, but also genes whose expression is controlled by phosphoinositides "per se." Our data highlight the importance of phosphoinositide-dependent pathways in gene expression in resting cells and in response to phytohormones. PMID- 26039483 TI - Yield enhancement strategies for the production of picroliv from hairy root culture of Picrorhiza kurroa Royle ex Benth. AB - Fast-growing hairy root cultures of Picrorhiza kurroa induced by Agrobacterium rhizogenes offers a potential production system for iridoid glycosides. In present study we have investigated the effects of various nutrient medium formulations viz B5, MS, WP and NN, and sucrose concentrations (1-8%) on the biomass and glycoside production of selected clone (14-P) of P. kurroa hairy root. Full strength B5 medium was found to be most suitable for maximum biomass yield on the 40th day of culture (GI = 32.72 +/- 0.44) followed by the NN medium of the same strength (GI = 22.9 +/- 0.43). Secondary metabolite production was 1.1 and 1.3 times higher in half strength B5 medium respectively in comparison to MS medium. Maximum biomass accumulation along with the maximum picroliv content was achieved with 4% sucrose concentration in basal medium. RT vitamin and Thiamine-HCl effected the growth and secondary metabolite production of hairy roots growing on MS medium but did not show any effect on other media. The pH of the medium played significant role in growth and secondary metabolite production and was found to be highest at pH 6.0 while lowest at pH 3.0 and pH 8.0. To enhance the production of biomass and Picroliv 5 liter working capacity bioreactor was used, 27-fold (324 g FW) higher growth was observed in bioreactor than shake flask and secondary metabolite production was similarly enhanced. PMID- 26039484 TI - Quantitative analysis of microtubule orientation in interdigitated leaf pavement cells. AB - Leaf pavement cells are shaped like a jigsaw puzzle in most dicotyledon species. Molecular genetic studies have identified several genes required for pavement cells morphogenesis and proposed that microtubules play crucial roles in the interdigitation of pavement cells. In this study, we performed quantitative analysis of cortical microtubule orientation in leaf pavement cells in Arabidopsis thaliana. We captured confocal images of cortical microtubules in cotyledon leaf epidermis expressing GFP-tubulinbeta and quantitatively evaluated the microtubule orientations relative to the pavement cell growth axis using original image processing techniques. Our results showed that microtubules kept parallel orientations to the growth axis during pavement cell growth. In addition, we showed that immersion treatment of seed cotyledons in solutions containing tubulin polymerization and depolymerization inhibitors decreased pavement cell complexity. Treatment with oryzalin and colchicine inhibited the symmetric division of guard mother cells. PMID- 26039485 TI - Arabidopsis thaliana KORRIGAN1 protein: N-glycan modification, localization, and function in cellulose biosynthesis and osmotic stress responses. AB - Plant cellulose biosynthesis is a complex process involving cellulose-synthase complexes (CSCs) and various auxiliary factors essential for proper orientation and crystallinity of cellulose microfibrils in the apoplast. Among them is KORRIGAN1 (KOR1), a type-II membrane protein with multiple N-glycans within its C terminal cellulase domain. N-glycosylation of the cellulase domain was important for KOR1 targeting to and retention within the trans-Golgi network (TGN), and prevented accumulation of KOR1 at tonoplasts. The degree of successful TGN localization of KOR1 agreed well with in vivo-complementation efficacy of the rsw2-1 mutant, suggesting non-catalytic functions in the TGN. A dynamic interaction network involving microtubules, CSCs, KOR1, and currently unidentified glycoprotein component(s) likely determines stress-triggered re organization of cellulose biosynthesis and resumption of cell-wall growth under stress. PMID- 26039486 TI - Protein phosphatase 2A regulatory subunits affecting plant innate immunity, energy metabolism, and flowering time--joint functions among B'eta subfamily members. AB - Protein phosphatase 2A (PP2A) is a heterotrimeric complex comprising a catalytic, scaffolding, and regulatory subunit. The regulatory subunits are essential for substrate specificity and localization of the complex and are classified into B/B55, B', and B" non-related families in higher plants. In Arabidopsis thaliana, the close paralogs B'eta, B'theta, B'gamma, and B'zeta were further classified into a subfamily of B' called B'eta. Here we present results that consolidate the evidence for a role of the B'eta subfamily in regulation of innate immunity, energy metabolism and flowering time. Proliferation of the virulent Pseudomonas syringae in B'theta knockout mutant decreased in comparison with wild type plants. Additionally, B'theta knockout plants were delayed in flowering, and this phenotype was supported by high expression of FLC (FLOWERING LOCUS C). B'zeta knockout seedlings showed growth retardation on sucrose-free medium, indicating a role for B'zeta in energy metabolism. This work provides insight into functions of the B'eta subfamily members, highlighting their regulation of shared physiological traits while localizing to distinct cellular compartments. PMID- 26039487 TI - ZEITLUPE positively regulates hypocotyl elongation at warm temperature under light in Arabidopsis thaliana. AB - Hypocotyl cell elongation has been studied as a model to understand how cellular expansion contributes to plant organ growth. Hypocotyl elongation is affected by multiple environmental factors, including light quantity and light quality. Red light inhibits hypocotyl growth via the phytochrome signaling pathways. Proteins of the flavin-binding KELCH repeat F-box 1 / LOV KELCH protein 2 / ZEITLUPE family are positive regulators of hypocotyl elongation under red light in Arabidopsis. These proteins were suggested to reduce phytochrome-mediated inhibition of hypocotyl elongation. Here, we show that ZEITLUPE also functions as a positive regulator in warmth-induced hypocotyl elongation under light in Arabidopsis. PMID- 26039488 TI - PINOID functions in root phototropism as a negative regulator. AB - The PINOID (PID) family, which belongs to AGCVIII kinases, is known to be involved in the regulation of auxin efflux transporter PIN-formed (PIN) proteins through changes in the phosphorylation status. Recently, we demonstrated that the PID family is necessary for phytochrome-mediated phototropic enhancement in Arabidopsis hypocotyls and that the downregulation of PID expression by red-light pretreatment results in the promotion of the PIN-mediated auxin gradient during phototropic responses. However, whether PID participates in root phototropism in Arabidopsis seedlings has not been well studied. Here, we demonstrated that negative root phototropic responses are enhanced in the pid quadruple mutant and are severely impaired in transgenic plants expressing PID constitutively. The results indicate that the PID family functions in a negative root phototropism as a negative regulator. On the other hand, analysis with PID fused to a yellow fluorescent protein, VENUS, showed that unilateral blue-light irradiation causes a lower accumulation of PID proteins on the shaded side than on the irradiated side. This result suggests that the blue-light-mediated asymmetrical distribution of PID proteins may be one of the critical responses in phototropin-mediated signals during a negative root phototropism. Alternatively, such a transverse gradient of PID proteins may result from gravitropic stimulation produced by phototropic bending. PMID- 26039489 TI - Inbreeding compromises host plant defense gene expression and improves herbivore survival. AB - Inbreeding commonly occurs in flowering plants and often results in a decline in the plant's defense response. Insects prefer to feed and oviposit on inbred plants more than outbred plants--suggesting that selecting inbred host plants offers them fitness benefits. Until recently, no studies have examined the effects of host plant inbreeding on insect fitness traits such as growth and dispersal ability. In a recent article, we documented that tobacco hornworm (Manduca sexta L.) larvae that fed on inbred horsenettle (Solanum carolinense L.) plants exhibited accelerated larval growth and increased adult flight capacity compared to larvae that fed on outbred plants. Here we report that M. sexta mortality decreased by 38.2% when larvae were reared on inbred horsenettle plants compared to larvae reared on outbreds. Additionally, inbred plants showed a notable reduction in the average relative expression levels of lipoxygenease-D (LoxD) and 12-oxophytodienoate reductase-3 (OPR3), two genes in the jasmonic acid signaling pathway that are upregulated in response to herbivore damage. Our study presents evidence that furthers our understanding of the biochemical mechanism responsible for differences in insect performance on inbred vs. outbred host plants. PMID- 26039490 TI - Catalytic Cycle of Multicopper Oxidases Studied by Combined Quantum- and Molecular-Mechanical Free-Energy Perturbation Methods. AB - We have used combined quantum mechanical and molecular mechanical free-energy perturbation methods in combination with explicit solvent simulations to study the reaction mechanism of the multicopper oxidases, in particular, the regeneration of the reduced state from the native intermediate. For 52 putative states of the trinuclear copper cluster, differing in the oxidation states of the copper ions and the protonation states of water- and O2-derived ligands, we have studied redox potentials, acidity constants, isomerization reactions, as well as water- and O2 binding reactions. Thereby, we can propose a full reaction mechanism of the multicopper oxidases with atomic detail. We also show that the two copper sites in the protein communicate so that redox potentials and acidity constants of one site are affected by up to 0.2 V or 3 pKa units by a change in the oxidation state of the other site. PMID- 26039491 TI - Modulation of nociceptive ion channels and receptors via protein-protein interactions: implications for pain relief. AB - In the last 2 decades biomedical research has provided great insights into the molecular signatures underlying painful conditions. However, chronic pain still imposes substantial challenges to researchers, clinicians and patients alike. Under pathological conditions, pain therapeutics often lack efficacy and exhibit only minimal safety profiles, which can be largely attributed to the targeting of molecules with key physiological functions throughout the body. In light of these difficulties, the identification of molecules and associated protein complexes specifically involved in chronic pain states is of paramount importance for designing selective interventions. Ion channels and receptors represent primary targets, as they critically shape nociceptive signaling from the periphery to the brain. Moreover, their function requires tight control, which is usually implemented by protein-protein interactions (PPIs). Indeed, manipulation of such PPIs entails the modulation of ion channel activity with widespread implications for influencing nociceptive signaling in a more specific way. In this review, we highlight recent advances in modulating ion channels and receptors via their PPI networks in the pursuit of relieving chronic pain. Moreover, we critically discuss the potential of targeting PPIs for developing novel pain therapies exhibiting higher efficacy and improved safety profiles. PMID- 26039492 TI - Reversible Aptamer-Au Plasmon Rulers for Secreted Single Molecules. AB - Plasmon rulers, consisting of pairs of gold nanoparticles, allow single-molecule analysis without photobleaching or blinking; however, current plasmon rulers are irreversible, restricting detection to only single events. Here, we present a reversible plasmon ruler, comprised of coupled gold nanoparticles linked by a single aptamer, capable of binding individual secreted molecules with high specificity. We show that the binding of target secreted molecules to the reversible plasmon ruler is characterized by single-molecule sensitivity, high specificity, and reversibility. Such reversible plasmon rulers should enable dynamic and adaptive live-cell measurement of secreted single molecules in their local microenvironment. PMID- 26039493 TI - Generating Electricity during Walking with a Lower Limb-Driven Energy Harvester: Targeting a Minimum User Effort. AB - BACKGROUND: Much research in the field of energy harvesting has sought to develop devices capable of generating electricity during daily activities with minimum user effort. No previous study has considered the metabolic cost of carrying the harvester when determining the energetic effects it has on the user. When considering device carrying costs, no energy harvester to date has demonstrated the ability to generate a substantial amount of electricity (> 5W) while maintaining a user effort at the same level or lower than conventional power generation methods (e.g. hand crank generator). METHODOLOGY/PRINCIPAL FINDINGS: We developed a lower limb-driven energy harvester that is able to generate approximately 9W of electricity. To quantify the performance of the harvester, we introduced a new performance measure, total cost of harvesting (TCOH), which evaluates a harvester's overall efficiency in generating electricity including the device carrying cost. The new harvester captured the motion from both lower limbs and operated in the generative braking mode to assist the knee flexor muscles in slowing the lower limbs. From a testing on 10 participants under different walking conditions, the harvester achieved an average TCOH of 6.1, which is comparable to the estimated TCOH for a conventional power generation method of 6.2. When generating 5.2W of electricity, the TCOH of the lower limb driven energy harvester (4.0) is lower than that of conventional power generation methods. CONCLUSIONS/SIGNIFICANCE: These results demonstrated that the lower limb driven energy harvester is an energetically effective option for generating electricity during daily activities. PMID- 26039494 TI - Post-operative benefits of animal-assisted therapy in pediatric surgery: a randomised study. AB - BACKGROUND: Interest in animal-assisted therapy has been fuelled by studies supporting the many health benefits. The purpose of this study was to better understand the impact of an animal-assisted therapy program on children response to stress and pain in the immediate post-surgical period. PATIENTS AND METHODS: Forty children (3-17 years) were enrolled in the randomised open-label, controlled, pilot study. Patients were randomly assigned to the animal-assisted therapy-group (n = 20, who underwent a 20 min session with an animal-assisted therapy dog, after surgery) or the standard-group (n = 20, standard postoperative care). The study variables were determined in each patient, independently of the assigned group, by a researcher unblinded to the patient's group. The outcomes of the study were to define the neurological, cardiovascular and endocrinological impact of animal-assisted therapy in response to stress and pain. Electroencephalogram activity, heart rate, blood pressure, oxygen saturation, cerebral prefrontal oxygenation, salivary cortisol levels and the faces pain scale were considered as outcome measures. RESULTS: After entrance of the dog faster electroencephalogram diffuse beta-activity (> 14 Hz) was reported in all children of the animal-assisted therapy group; in the standard-group no beta activity was recorded (100% vs 0%, p<0.001). During observation, some differences in the time profile between groups were observed for heart rate (test for interaction p = 0.018), oxygen saturation (test for interaction p = 0.06) and cerebral oxygenation (test for interaction p = 0.09). Systolic and diastolic blood pressure were influenced by animal-assisted therapy, though a higher variability in diastolic pressure was observed. Salivary cortisol levels did not show different behaviours over time between groups (p=0.70). Lower pain perception was noted in the animal-assisted group in comparison with the standard group (p = 0.01). CONCLUSION: Animal-assisted therapy facilitated rapid recovery in vigilance and activity after anaesthesia, modified pain perception and induced emotional prefrontal responses. An adaptative cardiovascular response was also present. TRIAL REGISTRATION: ClinicalTrials.gov NCT02284100. PMID- 26039497 TI - Background Knowledge and Attitude of Pregnant Women towards Ultrasound Screening at 20-23 Weeks Gestation. AB - BACKGROUND: Prenatal ultrasound screening in the second trimester is widely used in maternal health care. Prenatal diagnosis and prenatal screening is often exposed to several accusation, such as inducing unnecessary anxiety, carrying out a selection and forcing pregnant women into attending ultrasound screening. The aim of this study was to investigate the knowledge and the intention of pregnant women attending the second trimester ultrasound screening. PATIENTS AND METHODS: This was a prospective study. Women attending the 20 weeks anomaly scan were given an anonymous questionnaire to evaluate the background knowledge about the anomaly scan and their opinion about prenatal screening. RESULTS: 600 (96.7%) of 620 recruited women filled in the questionnaire completely. To the majority (>80%) of women it is important to exclude severe fetal anomalies and to secure normal fetal growth. The background knowledge of the women was good, but a clear supply of information and a detail counselling would improve the understanding, especially in the group of lower education. The majority of the women stated that the 20 weeks anomaly scan should be offered to every woman. CONCLUSION: Prenatal ultrasound examination is not only essential from a medical point of view for example for important information regarding the status of the fetus, but also has a major impact as a positive psychological factor for pregnant women. PMID- 26039498 TI - [Methods in neonatal abstinence syndrome (NAS): results of a nationwide survey in Austria]. AB - BACKGROUND: Neonatal abstinence syndrome (NAS) occurs in neonates whose mothers have taken addictive drugs or were under substitution therapy during pregnancy. Incidence numbers of NAS are on the rise globally, even in Austria NAS is not rare anymore. The aim of our survey was to reveal the status quo of dealing with NAS in Austria. METHODS: A questionnaire was sent to 20 neonatology departments all over Austria, items included questions on scoring, therapy, breast-feeding and follow-up procedures. RESULTS: The response rate was 95%, of which 94.7% had written guidelines concerning NAS. The median number of children being treated per year for NAS was 4. Finnegan scoring system is used in 100% of the responding departments. Morphine is being used most often, in opiate abuse (100%) as well as in multiple substance abuse (44.4%). The most frequent forms of morphine preparation are morphine and diluted tincture of opium. Frequency as well as dosage of medication vary broadly. 61.1% of the departments supported breast feeding, regulations concerned participation in a substitution programme and general contraindications (HIV, HCV, HBV). Our results revealed that there is a big west-east gradient in patients being treated per year. CONCLUSION: NAS is not a rare entity anymore in Austria (up to 50 cases per year in Vienna). Our survey showed that most neonatology departments in Austria treat their patients following written guidelines. Although all of them base these guidelines on international recommendations there is no national consensus. PMID- 26039496 TI - Detecting minimal hepatic encephalopathy in an endemic country for hepatitis B: the role of psychometrics and serum IL-6. AB - BACKGROUND & AIMS: It remains unknown what the prevalence of minimal hepatic encephalopathy is in Taiwan, a highly endemic country for chronic viral hepatitis infection. It is also unclear whether abnormal serum cytokine levels can be indicative of the presence of minimal hepatic encephalopathy. We aimed to standardize the tests of psychometric hepatic encephalopathy score and predictive value of proinflammatory cytokines in minimal hepatic encephalopathy in Taiwan. METHODS: 180 healthy subjects and 94 cirrhotic patients without a history of overt hepatic encephalopathy from a tertiary center were invited to participate in this cross-sectional study. Blood sampling for determination of serum levels of interleukin 6 and 18 and tumor necrosis factor-alpha was performed. Based on the normogram of psychometric hepatic encephalopathy score from healthy volunteers, patients with minimal hepatic encephalopathy were identified from the cirrhotic patients using the criterion of a psychometric hepatic encephalopathy score less than -4. RESULTS: In the healthy subjects, age and education were predictors of subtests of psychometric hepatic encephalopathy score. Minimal hepatic encephalopathy was identified in 27 (29%) cirrhotic patients. Serum interleukin 6 level (OR = 6.50, 95% CI = 1.64-25.76, P = 0.008) was predictive of the presence of minimal hepatic encephalopathy after multivariate analysis. CONCLUSIONS: The psychometric hepatic encephalopathy score can be a useful tool for detecting patients with minimal hepatic encephalopathy in Taiwan and around one third of cirrhotic outpatients fulfill this diagnosis. A high serum interleukin 6 level is predictive of the presence of minimal hepatic encephalopathy. PMID- 26039499 TI - [Resident Gynaecologists' Attitudes towards the Inclusion of the Screening for Gestational Diabetes into the Maternity Directive: A Qualitative Study]. AB - BACKGROUND: In March 2012, the screening for gestational diabetes was included as a 2-step screening into the German maternity directive. However, up to now it is unclear what resident gynaecologists, who are affected directly by this change in the maternity directive, think about the inclusion of the screening and the kind of screening introduced. METHODS: In order to approach this topic from a scientific point of view, gynaecologists in the German cities Mannheim, Ludwigshafen, and Heidelberg were interviewed face-to-face using a semi structured interview guide with open-ended questions (mean interview length: 33:12 min). The interviews were audiotaped, transcribed verbatim (191 pages), coded by 2 independent reviewers, and analysed using qualitative content analysis. RESULTS: The majority of the gynaecologists supported the introduction of the screening into the maternity directives. However, some gynaecologists felt that this amendment is not strong enough criticising the GCT with 50 g glucose. Many gynaecologists would prefer an oral glucose tolerance test (OGTT, 75 g glucose). But there were also some gynaecologists who thought that the OGTT would strain pregnant women too much and thus deemed it unsuitable for a screening. Additionally, the gynaecologists named difficulties concerning the implementation of the test such as, for example, the non-availability of a ready-made glucose syrup for the GCT and the delayed introduction of billing codes. DISCUSSION: In the framework of this qualitative study, resident gynaecologists--the main actors in the conduct of the screening--had the possibility to offer their opinion on this current topic. The results provide a first insight into the conduct of the screening and may serve as a basis for larger, quantitative studies. PMID- 26039500 TI - [Parental Information and Consent in Neonatology]. AB - Careful analysis of current adjudication reveals increasing demand of adequate record-keeping as well as meticulously documented informed consent forms regarding all aspects of medicine. Although standardized informed consent forms or explicit guidelines for obtaining procedural consent already exist in surgical disciplines there is strong evidence that, however, in neonatology (and paediatric intensive care) these processes are still incomplete and qualitatively insufficiently implemented. Therefore the author discussed all existing information prescriptions with the legal department and quality management of a large German clinic group especially in terms of relevant legislation, recent case law and specialist literature in order to obtain potential for improvement. Based on the results of this audit of expert opinions improved recommendations could be implemented in the daily practise of a department of neonatology and paediatric intensive care on a tertiary level. PMID- 26039501 TI - [The experiences of chronically ill women in the time of pregnancy, birth and postnatal period - a review of qualitative studies]. AB - BACKGROUND: Chronic diseases are an increasing problem worldwide, especially in the industrialized countries. In pregnancy, during birth and in the post natal period the affected women are confronted with interventions and medical treatment in addition to the general physical and psychological challenges. However, there is only little knowledge about coping strategies and the experiences of women with chronic diseases during the childbirth period. METHOD: An international literature search was conducted from 11/2013 till 03/2014. Relevant papers were identified from databases including Cinahl, Cochrane Library and Pubmed. Key search terms were related to the topics of experiences regarding the medical system and the professional caregivers, the role of the partners and families and the effects on the mother-child relationship. RESULTS: 11 studies were eligible for inclusion. In the childbearing period women with chronic diseases often feel under pressure because their general condition can cause medical complications. This leads to inner conflicts due to the necessity to derive to varying decisions concerning possible risks for the baby and their own body. Additionally the given information and main medical concepts do often not fit to their special needs and problems. The women feel excluded from the main professional concepts for childbearing women. CONCLUSION: RESULTS of international studies demonstrate differences in available settings, supportive persons and concepts and impede that the right conclusions can be drawn for the German context. National Research is needed to evaluate the experiences and situation of childbearing women with chronic diseases and to implement adjusted concepts of professional care for this group of woman. PMID- 26039502 TI - [Pregnancy and cystic fibrosis - an overview]. AB - Life expectancy and quality of life of cystic fibrosis (CF) patients have been steadily increasing for many decades, due to intensified therapy and research. Correspondingly, the number of pregnancies in women with CF rises. Often it is not possible for the patients to assess the consequences of pregnancy in terms of their disease and the impact of their disease on the growing child. A pre existing poor lung function, low body mass index, CF-related diabetes, chronic microbial colonisation, and transplanted lungs are the main risk factors for complications during pregnancy in CF. Generally, the best outcome for mother and child can be reached under exact planning and meshed multidisciplinary care. The purpose of this summary is to give a practical review of the risks and options associated with pregnancy in CF patients. PMID- 26039504 TI - Clinical and muscle imaging findings in 14 mainland chinese patients with oculopharyngodistal myopathy. AB - Oculopharyngodistal myopathy (OPDM) is an extremely rare, adult-onset hereditary muscular disease characterized by progressive external ocular, pharyngeal, and distal muscle weakness and myopathological rimmed vacuole changes. The causative gene is currently unknown; therefore, diagnosis of OPDM is based on clinical and histopathological features and genetic exclusion of similar conditions. Moreover, variable manifestations of this disorder are reported in terms of muscle involvement and severity. We present the clinical profile and magnetic resonance imaging (MRI) changes of lower limb muscles in 14 mainland Chinese patients with OPDM, emphasizing the role of muscle MRI in disease identification and differential diagnosis. The patients came from 10 unrelated families and presented with progressive external ocular, laryngopharyngeal, facial, distal limb muscle weakness that had been present since early adulthood. Serum creatine kinase was mildly to moderately elevated. Electromyography revealed myogenic changes with inconsistent myotonic discharge. The respiratory function test revealed subclinical respiratory muscle involvement. Myopathological findings showed rimmed vacuoles with varying degrees of muscular dystrophic changes. All known genes responsible for distal and myofibrillar myopathies, vacuolar myopathies, and muscular dystrophies were excluded by PCR or targeted next generation sequencing. Muscle MRI revealed that the distal lower legs had more severe fatty replacement than the thigh muscles. Serious involvement of the soleus and long head of the biceps femoris was observed in all patients, whereas the popliteus, gracilis and short head of biceps femoris were almost completely spared, even in advanced stages. Not only does our study widen the spectrum of OPDM in China, but it also demonstrates that OPDM has a specific pattern of muscle involvement that may provide valuable information for its differential diagnosis and show further evidence supporting the conclusion that OPDM is a unique disease phenotype. PMID- 26039505 TI - A Case of Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-cell Lymphoma Misdiagnosed as Febrile Ulceronecrotic Mucha-Habermann Disease. PMID- 26039506 TI - Experiment and Optimization for Simultaneous Carbonation of Ca(2+) and Mg(2+) in A Two-phase System of Insoluble Diisobutylamine and Aqueous Solution. AB - An optimized approach of CO2 fixation in Ca(2+)/Mg(2+)-rich aqueous solutions using insoluble amine as an enhancing medium was reported. Apparent basicity was verified to be an effective indicator for the selection and optimization of organic amine systems and finally the diisobutylamine + n-octanol system was selected to enhance the carbonation reactions of CO2 in an artificial Ca(2+)/Mg(2+)-rich solution. In our experiments, when the volume ratio of insoluble organic phase to aqueous one was 2:1 and the reaction temperature was 28 degrees C, 92% of Ca(2+) and 80% of Mg(2+) could be converted to calcium and magnesium carbonate precipitates within 5 min of reaction with the bubbling-in of CO2. The organic amine system could be regenerated by using carbide slag as the regeneration agent and could still show attractive enhancement performances after 7 rounds of carbonation-regeneration experiments. In this way, the CO2 capture and sequestration was realized within one single process, with value-added Ca/Mg carbonates being the byproducts. In view of the vast availability of Ca(2+)/Mg(2+)-rich aqueous solutions and the feasible technical coordination with desalination industry, this novel process may have a good application potential in the future. PMID- 26039508 TI - [Management of Snakebites in Sub-Saharan Africa]. AB - Although common in sub-Saharan Africa, snakebites remain a neglected topic. The paper reviews some diagnostic and therapeutic rules for this medical and surgical emergency that occurs mainly in remote health centers. Intravenous administration of polyvalent antivenom is the preferred treatment in any proven envenomation. Antivenom should be associated with symptomatic treatment. Patient surveillance is well codified and the management of complications is specified. PMID- 26039509 TI - R(2)OBBIE-3D, a Fast Robotic High-Resolution System for Quantitative Phenotyping of Surface Geometry and Colour-Texture. AB - While recent imaging techniques provide insights into biological processes from the molecular to the cellular scale, phenotypes at larger scales remain poorly amenable to quantitative analyses. For example, investigations of the biophysical mechanisms generating skin morphological complexity and diversity would greatly benefit from 3D geometry and colour-texture reconstructions. Here, we report on R(2)OBBIE-3D, an integrated system that combines a robotic arm, a high-resolution digital colour camera, an illumination basket of high-intensity light-emitting diodes and state-of-the-art 3D-reconstruction approaches. We demonstrate that R(2)OBBIE generates accurate 3D models of biological objects between 1 and 100 cm, makes multiview photometric stereo scanning possible in practical processing times, and enables the capture of colour-texture and geometric resolutions better than 15 MUm without the use of magnifying lenses. R(2)OBBIE has the potential to greatly improve quantitative analyses of phenotypes in addition to providing multiple new applications in, e.g., biomedical science. PMID- 26039510 TI - Insecticide resistance in the bed bug comes with a cost. AB - Adaptation to new environmental stress is often associated with an alteration of one or more life history parameters. Insecticide resistant populations of insects often have reduced fitness relative to susceptible populations in insecticide free environments. Our previous work showed that three populations of bed bugs, Cimex lectularius L., evolved significantly increased levels of resistance to one product containing both beta-cyfluthrin and imidacloprid insecticides with only one generation of selection, which gave us an opportunity to explore potential tradeoffs between life history parameters and resistance using susceptible and resistant strains of the same populations. Life history tables were compiled by collecting weekly data on mortality and fecundity of bugs from each strain and treatment throughout their lives. Selection led to a male-biased sex ratio, shortened oviposition period, and decreased life-time reproductive rate. Generation time was shortened by selection, a change that represents a benefit rather than a cost. Using these life history characteristics we calculated that there would be a 90% return to pre-selection levels of susceptibility within 2- 6.5 generations depending on strain. The significant fitness costs associated with resistance suggest that insecticide rotation or utilization of non insecticidal control tactics could be part of an effective resistance management strategy. PMID- 26039511 TI - Knowledge, Indications and Willingness to Take Pre-Exposure Prophylaxis among Transwomen in San Francisco, 2013. AB - Safe and effective HIV prevention strategies are needed for transwomen. Transwomen in the US have a 34 times greater odds of being infected with HIV than all adults age 15-49, and in San Francisco, California 42.4% of transwomen are estimated to be infected with HIV. Pre-exposure prophylaxis (PrEP) is the first biomedical intervention with promise for reducing HIV acquisition in transwomen. However, little is known about whether transwomen know about PrEP, are taking PrEP and would be good candidates for PrEP based on their risk profile and behaviors. A population-based dataset was analyzed to determine how many transwomen in San Francisco knew about PrEP by the end of 2013 - more than a year after iPrex results demonstrated efficacy of PrEP in preventing HIV. We found that of 233 transwomen, only 13.7% had heard of PrEP. Transwomen who were living with HIV compared to those who were HIV-negative, and those who recently injected drugs compared to non-injection drug users were more likely to have heard of PrEP. Based on CDC guidelines for PrEP among MSM and IDU, 45 (30.2%) transwomen of the 149 HIV-negative transwomen in the sample were candidates for PrEP. This estimate based on CDC criteria is arguably low. Given that almost half of transwomen in San Francisco are living with HIV, this findings points to a need for further consideration of PrEP criteria that are specific and tailored to the risks for HIV faced by transwomen that are different from MSM and injection drug users. Research to scale up access and test the effectiveness of PrEP for transwomen is also urgently needed. PMID- 26039512 TI - Surface Passivation of MoO3 Nanorods by Atomic Layer Deposition toward High Rate Durable Li Ion Battery Anodes. AB - We demonstrate an effective strategy to overcome the degradation of MoO3 nanorod anodes in lithium (Li) ion batteries at high-rate cycling. This is achieved by conformal nanoscale surface passivation of the MoO3 nanorods by HfO2 using atomic layer deposition (ALD). At high current density such as 1500 mA/g, the specific capacity of HfO2-coated MoO3 electrodes is 68% higher than that of bare MoO3 electrodes after 50 charge/discharge cycles. After 50 charge/discharge cycles, HfO2-coated MoO3 electrodes exhibited specific capacity of 657 mAh/g; on the other hand, bare MoO3 showed only 460 mAh/g. Furthermore, we observed that HfO2 coated MoO3 electrodes tend to stabilize faster than bare MoO3 electrodes because nanoscale HfO2 layer prevents structural degradation of MoO3 nanorods. Additionally, the growth temperature of MoO3 nanorods and the effect of HfO2 layer thickness was studied and found to be important parameters for optimum battery performance. The growth temperature defines the microstructural features and HfO2 layer thickness defines the diffusion coefficient of Li-ions through the passivation layer to the active material. Furthermore, ex situ high resolution transmission electron microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and X-ray diffraction were carried out to explain the capacity retention mechanism after HfO2 coating. PMID- 26039513 TI - Correction: Imaging mass spectrometry of a mouse brain by tapping-mode scanning probe electrospray ionization. AB - Correction for 'Imaging mass spectrometry of a mouse brain by tapping-mode scanning probe electrospray ionization' by Yoichi Otsuka et al., Analyst, 2014, 139, 2336-2341. PMID- 26039514 TI - Delay discounting and self-reported impulsivity in adolescent smokers and nonsmokers living in rural Appalachia. AB - Background and Objectives This study evaluated whether impulsivity (delay discounting and BIS-11-A) is associated with adolescent smoking status in a region with strong environmental risk factors for smoking. Methods Forty-two adolescent smokers and nonsmokers from rural Appalachia completed discounting and self-reported impulsivity assessments. Results The BIS-11-A, but not the measure of discounting, was associated with smoking status; however, neither assessment predicted smoking status once parent/best-friend smoking variables were statistically accounted for. Discussion and Conclusions In regions with strong environmental risk factors for smoking, delay discounting may play a more limited role in risk of initiation. Scientific Significance Helps to better define impulsivity as risk factors for smoking in relation to familial and broader cultural variables. PMID- 26039515 TI - Single-Molecule Imaging Reveals Dynamics of CREB Transcription Factor Bound to Its Target Sequence. AB - Proper spatiotemporal gene expression is achieved by selective DNA binding of transcription factors in the genome. The most intriguing question is how dynamic interactions between transcription factors and their target sites contribute to gene regulation by recruiting the basal transcriptional machinery. Here we demonstrate individual binding and dissociation events of the transcription factor cAMP response element-binding protein (CREB), both in vitro and in living cells, using single-molecule imaging. Fluorescent-tagged CREB bound to its target sequence cAMP-response element (CRE) for a remarkably longer period (dissociation rate constant: 0.21 s(-1)) than to an unrelated sequence (2.74 s(-1)). Moreover, CREB resided at restricted positions in the living cell nucleus for a comparable period. These results suggest that CREB stimulates transcription by binding transiently to CRE in the time range of several seconds. PMID- 26039516 TI - Nicotinic Acetylcholine Receptor (nAChR) Dependent Chorda Tympani Taste Nerve Responses to Nicotine, Ethanol and Acetylcholine. AB - Nicotine elicits bitter taste by activating TRPM5-dependent and TRPM5-independent but neuronal nAChR-dependent pathways. The nAChRs represent common targets at which acetylcholine, nicotine and ethanol functionally interact in the central nervous system. Here, we investigated if the nAChRs also represent a common pathway through which the bitter taste of nicotine, ethanol and acetylcholine is transduced. To this end, chorda tympani (CT) taste nerve responses were monitored in rats, wild-type mice and TRPM5 knockout (KO) mice following lingual stimulation with nicotine free base, ethanol, and acetylcholine, in the absence and presence of nAChR agonists and antagonists. The nAChR modulators: mecamylamine, dihydro-beta-erythroidine, and CP-601932 (a partial agonist of the alpha3beta4* nAChR), inhibited CT responses to nicotine, ethanol, and acetylcholine. CT responses to nicotine and ethanol were also inhibited by topical lingual application of 8-chlorophenylthio (CPT)-cAMP and loading taste cells with [Ca2+]i by topical lingual application of ionomycin + CaCl2. In contrast, CT responses to nicotine were enhanced when TRC [Ca2+]i was reduced by topical lingual application of BAPTA-AM. In patch-clamp experiments, only a subset of isolated rat fungiform taste cells exposed to nicotine responded with an increase in mecamylamine-sensitive inward currents. We conclude that nAChRs expressed in a subset of taste cells serve as common receptors for the detection of the TRPM5-independent bitter taste of nicotine, acetylcholine and ethanol. PMID- 26039519 TI - Capacitive Deionization using Biomass-based Microporous Salt-Templated Heteroatom Doped Carbons. AB - Invited for this month's cover are the groups of Tim-Patrick Fellinger (MPI Potsdam) and Volker Presser (INM Saarbrucken and Saarland University). The image shows the dynamic process of ion electrosorption: anions are attracted and cations repelled from electrically charged electrodes based on carbons with heteroatoms. This process of capacitive deionization is particularly attractive for facile low-energy water treatment applications. PMID- 26039520 TI - Proof That Lower Is Better--LDL Cholesterol and IMPROVE-IT. PMID- 26039522 TI - The 21st Century Cures Act--Will It Take Us Back in Time? PMID- 26039524 TI - Brave New Genome. PMID- 26039523 TI - Breast-cancer screening--viewpoint of the IARC Working Group. PMID- 26039525 TI - From blood pressure measurement to antihypertensive treatment. PMID- 26039526 TI - Effects of blood pressure-lowering on outcome incidence in hypertension: 5. Head to-head comparisons of various classes of antihypertensive drugs - overview and meta-analyses. AB - BACKGROUND AND OBJECTIVES: We have recently published an overview and meta analysis of the effects of the five major classes of blood pressure-lowering drugs on cardiovascular outcomes when compared with placebo. However, possible differences in effectiveness of the various classes can correctly be estimated only by head-to-head comparisons of different classes of agents. This has been the objective of a new survey and meta-analysis. METHODS: A database search between 1966 and August 2014 ide ntified 50 eligible randomized controlled trials for 58 two-drug comparisons (247 006 patients for 1 029 768 patient-years). Risk ratios and their 95% confidence intervals of seven outcomes were estimated by a random-effects model. RESULTS: The effects of all drug classes are not significantly different on most outcomes when their blood pressure effect is equivalent. However, there are also significant differences involving almost all classes of drugs. When compared to all other classes together, diuretics are superior in preventing heart failure; beta-blockers less effective in preventing stroke; calcium antagonists superior in preventing stroke and all-cause death, but inferior in preventing heart failure; angiotensin-converting enzyme inhibitors more effective in preventing coronary heart disease and less in preventing stroke; angiotensin receptor blockers inferior in preventing coronary heart disease; and renin-angiotensin system blockers more effective in preventing heart failure. When stratifying randomized controlled trials according to total cardiovascular risk, no drug class was found to change in effectiveness with the level of risk. CONCLUSIONS: The results of all available evidence from head-to head drug class comparisons do not allow the formulation of a fixed paradigm of drug choice valuable for all hypertensive patients, but the differences found may suggest specific choices in specific conditions, or preferable combinations of drugs. PMID- 26039527 TI - Arterial hypertension in Turner syndrome: a review of the literature and a practical approach for diagnosis and treatment. AB - Turner syndrome is a rare chromosomal disorder with complete or partial absence of one X chromosome that only occurs in women. Clinical presentation is variable, but congenital and acquired cardiovascular diseases are frequently associated diseases that add significantly to the increased morbidity and mortality in Turner syndrome patients. Arterial hypertension is reported in 13-58% of adult Turner syndrome patients and confers an increased risk for stroke and aortic dissection. Hypertension can be present from childhood on and is reported in one quarter of the paediatric Turner syndrome patients. This article reviews the prevalence and cause of arterial hypertension in Turner syndrome and describes the relationship between blood pressure, aortic dilation and increased cardiovascular risk. We compare current treatment strategies and also propose an integrated practical approach for the diagnosis and treatment of hypertension in Turner syndrome applicable in daily practice. PMID- 26039528 TI - Screening for hypertension in children and adolescents: the controversy, the research questions and a plan for action. PMID- 26039529 TI - Assessing blood pressure response to exercise: methodological issues and clinical relevance. PMID- 26039530 TI - Urinary angiotensinogen and salt sensitivity of blood pressure: the challenge of finding biomarkers of salt-sensitivity. PMID- 26039531 TI - Safety of digoxin use in patients with hypertensive heart disease and atrial fibrillation. PMID- 26039532 TI - Abnormal central control underlies impaired baroreflex control of heart rate and sympathetic nerve activity in female Lewis polycystic kidney rats. AB - OBJECTIVE: Why baroreflex dysfunction occurs in females with chronic kidney disease is unknown. We therefore aimed to examine whether temporal changes in baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) occur in female Lewis polycystic kidney (LPK) rats and whether this is associated with any changes in afferent, central or efferent processing of the reflex pathway. METHOD: Using urethane-anaesthetized juvenile and adult LPK and Lewis control rats (n = 40), baroreflex-mediated changes in HR, RSNA and aortic depressor nerve activity (ADNA) were examined. Reflex changes to aortic depressor and vagal efferent nerve stimulation were also determined. RESULTS: In the juvenile LPK rats, except for a slight reduction in the gain of the normalized HR and RSNA baroreflex function curves, no difference in baroreflex control of HR, RSNA or ADNA was observed. Responses to aortic depressor and vagal efferent nerve stimulation were also comparable. In the adult hypertensive LPK rats, the range of both HR (35 +/- 8 vs. 78 +/- 9 bpm, P <= 0.05 LPK vs. Lewis) and RSNA (60 +/- 7 vs. 80 +/- 3%, P <= 0.05 LPK vs. Lewis) was also reduced. This was not associated with any change in the ADNA baroreflex function curves or reflex HR responses to vagal efferent nerve stimulation, but was associated with a reduction in the reflex bradycardic (-21 +/- 4 vs. -34 +/- 8 bpm, P < 0.01 LPK vs. Lewis) and sympathoinhibitory (-30 +/- 8 vs. -54 +/- 12%, P < 0.001 LPK vs. Lewis) responses to aortic depressor nerve stimulation. CONCLUSION: In female LPK rats, baroreflex dysfunction results from impaired central processing of the reflex. PMID- 26039533 TI - The impact of age and risk factors on carotid and carotid-femoral pulse wave velocity. AB - OBJECTIVE: Segmental carotid-femoral pulse-wave velocity (PWV) is a gold standard method for arterial stiffness assessment; recently, a local carotid PWV measurement by ultrasound has been developed. The present study compared the impact of age and established risk factors on carotid and carotid-femoral PWV. METHODS: Three hundred and seven volunteers (167 men; age from 15 to 78 years) free of cardiovascular disease, diabetes, antihypertensive and lipid-lowering treatment underwent sequential measurement of carotid and carotid-femoral PWV. RESULTS: In the entire study population, both carotid and carotid-femoral PWV were independently associated mainly with age and blood pressure. In individuals more than 50 years old (N = 132, 80 men), carotid-femoral PWV, but not carotid PWV, was also associated with high-density lipoprotein (HDL)-cholesterol and fasting glucose. The annual increase in carotid and carotid-femoral PWV was similar (0.087 +/- 0.004 and 0.090 +/- 0.005 m/s, respectively; P = 0.69). Carotid PWV increased with age more rapidly in women than in men (0.099 +/- 0.005 vs. 0.076 +/- 0.005 m/s per year, P < 0.005), whereas carotid-femoral PWV showed a steeper increase in individuals more than 50 years old than individuals aged 50 years or less (0.150 +/- 0.019 vs. 0.088 +/- 0.007 m/s per year, P = 0.001). CONCLUSION: In apparently healthy population, both carotid and carotid-femoral PWV were influenced above all by age and blood pressure. Other established cardiovascular risk factors had a limited impact only on carotid-femoral PWV of older individuals. The age-related increase in carotid and carotid-femoral PWV seemed to follow different patterns; increase in carotid PWV showed age-sex interaction, being steeper in women, whereas increase in carotid-femoral PWV was more prominent in older individuals. PMID- 26039535 TI - Differences between clinic and home blood pressure measurements during pregnancy. PMID- 26039534 TI - Effects of candesartan in acute stroke on activities of daily living and level of care at 6 months. AB - OBJECTIVE: The Scandinavian Candesartan Acute Stroke Trial (SCAST) indicated that blood pressure-lowering treatment with candesartan in the acute phase of stroke has a negative effect on functional outcome at 6 months, measured by the modified Rankin scale. We wanted to see if similar effects can be observed on activities of daily living and level of care. METHODS: SCAST was an international multicentre, randomized and placebo-controlled trial of candesartan in 2029 patients recruited within 30 h of acute ischaemic or haemorrhagic stroke. Treatment lowered blood pressure by 5/2 mmHg from day 2 onwards, and was administered for 7 days. At 6 months, activities of daily living were assessed by the Barthel index, and categorized as 'dependency' (<=55 points), 'assisted dependency' (60-90), or 'independency' (>=95). Level of care was categorized as 'living at own home without public help', 'living at home with public help, or in institution for rehabilitation', or 'living in institution for long or permanent stay'. We used ordinal and binary logistic regression for statistical analysis, and adjusted for predefined key variables. RESULTS: Data were available in 1825 patients, of which 1559 (85%) patients had ischaemic and 247 (13%) had haemorrhagic stroke. There were no statistically significant effects of candesartan on the Barthel index or on level of care (adjusted common odds ratio for poor outcome 1.09, 95% confidence interval 0.88-1.35, P = 0.44; and odds ratio 1.05, 95% confidence interval 0.82-1.34, P = 0.69, respectively). In the individual Barthel index domains, there were also no statistically significant differences. CONCLUSION: Blood pressure-lowering treatment with candesartan had no beneficial effect on activities of daily living and level of care at 6 months. This result is compatible with the results of the main analysis of the modified Rankin scale, and supports the conclusion that there is no indication for routine blood pressure treatment with candesartan in the acute phase of stroke. PMID- 26039536 TI - Healthcare resource utilization and costs of outpatient follow-up after liver transplantation in a university hospital in Sao Paulo, Brazil: cost description study. AB - CONTEXT AND OBJECTIVE: Data on the costs of outpatient follow-up after liver transplantation are scarce in Brazil. The purpose of the present study was to estimate the direct medical costs of the outpatient follow-up after liver transplantation, from the first outpatient visit after transplantation to five years after transplantation. DESIGN AND SETTING: Cost description study conducted in a university hospital in Sao Paulo, Brazil. METHODS: Cost data were available for 20 adults who underwent liver transplantation due to acute liver failure (ALF) from 2005 to 2009. The data were retrospectively retrieved from medical records and the hospital accounting information system from December 2010 to January 2011. RESULTS: Mean cost per patient/year was R$ 13,569 (US$ 5,824). The first year of follow-up was the most expensive (R$ 32,546 or US$ 13,968), and medication was the main driver of total costs, accounting for 85% of the total costs over the five-year period and 71.9% of the first-year total costs. In the second year after transplantation, the mean total costs were about half of the amount of the first-year costs (R$ 15,165 or US$ 6,509). Medication was the largest contributor to the costs followed by hospitalization, over the five-year period. In the fourth year, the costs of diagnostic tests exceeded the hospitalization costs. CONCLUSION: This analysis provides significant insight into the costs of outpatient follow-up after liver transplantation due to ALF and the participation of each cost component in the Brazilian setting. PMID- 26039537 TI - Semiquantitative fecal calprotectin test in postinfectious and non-postinfectious irritable bowel syndrome: cross-sectional study. AB - CONTEXT AND OBJECTIVE: The presence of a certain degree of inflammation in the gut wall is now accepted in irritable bowel syndrome (IBS). Fecal calprotectin is considered to be a reliable test for detecting intestinal inflammation. Our aim was to assess the presence of inflammation in postinfectious IBS (PI-IBS), compared with non-postinfectious IBS (NPI-IBS). A secondary objective was to determine the usefulness of a rapid fecal calprotectin test in inflammatory bowel diseases (IBD). DESIGN AND SETTING: This was a cross-sectional study. Patients with IBS and IBD at a single tertiary gastroenterology center were prospectively included in this study. METHODS: 116 patients with Rome III IBS score (76 females; 48 +/- 12 years) were investigated; 24 patients (15 females) had PI-IBS. Intestinal inflammation was assessed using the semiquantitative fecal calprotectin test. The results were expressed as T1, T2 or T3 according to the severity of inflammation (< 15 MUg/g; 15-60 MUg/g; > 60 MUg/g). Using the same test, we evaluated 20 patients with IBD (12 males; 47 +/- 13 years). RESULTS: None of the patients with IBS had a T2 or T3 positive test. Among PI-IBS patients, 33% had a T1 positive test. Among NPI-IBS patients, 9.8% had a T1 positive test, which was significantly different to PI-IBS. The calprotectin test was positive in all IBD patients: 80% with T3, 10% with T2 and 10% with T1. CONCLUSIONS: Using a semiquantitative test for fecal calprotectin, positive tests were more frequent in PI-IBS patients than in NPI-IBS patients. PMID- 26039539 TI - Treatment of Scarring Alopecia in Discoid Variant of Chronic Cutaneous Lupus Erythematosus With Tacrolimus Lotion, 0.3. AB - IMPORTANCE: Discoid lupus erythematosus (DLE) is a chronic variant of cutaneous lupus erythematosus, an autoimmune inflammatory disorder of the skin. Lesions are often localized to the scalp and can result in permanent scarring, disfiguration, and irreversible alopecia. Although DLE usually responds to topical or intralesional corticosteroids and/or oral antimalarials, some DLE is resistant to these treatments or adverse effects limit their effectiveness. OBSERVATIONS: Three patients with treatment-refractory, biopsy-proved DLE were prescribed a novel, off-label preparation of tacrolimus lotion, 0.3%, in an alcohol base as an adjunct to oral antimalarial therapy. All 3 patients demonstrated improvement in lesion severity and hair regrowth with the use of this regimen after 3 months and continued improvement thereafter. We report a retrospective analysis of these 3 cases. CONCLUSIONS AND RELEVANCE: This report is, to our knowledge, the first mention of tacrolimus being used in a lotion formulation to treat DLE lesions, resulting in hair regrowth. Topical tacrolimus lotion, 0.3%, in an alcohol base may be a potential therapeutic option for patients with DLE that is refractory to first-line therapies and who risk late-stage disease with permanent scarring alopecia. PMID- 26039538 TI - A systematic review of studies comparing diagnostic clinical prediction rules with clinical judgment. AB - BACKGROUND: Diagnostic clinical prediction rules (CPRs) are developed to improve diagnosis or decrease diagnostic testing. Whether, and in what situations diagnostic CPRs improve upon clinical judgment is unclear. METHODS AND FINDINGS: We searched MEDLINE, Embase and CINAHL, with supplementary citation and reference checking for studies comparing CPRs and clinical judgment against a current objective reference standard. We report 1) the proportion of study participants classified as not having disease who hence may avoid further testing and or treatment and 2) the proportion, among those classified as not having disease, who do (missed diagnoses) by both approaches. 31 studies of 13 medical conditions were included, with 46 comparisons between CPRs and clinical judgment. In 2 comparisons (4%), CPRs reduced the proportion of missed diagnoses, but this was offset by classifying a larger proportion of study participants as having disease (more false positives). In 36 comparisons (78%) the proportion of diagnoses missed by CPRs and clinical judgment was similar, and in 9 of these, the CPRs classified a larger proportion of participants as not having disease (fewer false positives). In 8 comparisons (17%) the proportion of diagnoses missed by the CPRs was greater. This was offset by classifying a smaller proportion of participants as having the disease (fewer false positives) in 2 comparisons. There were no comparisons where the CPR missed a smaller proportion of diagnoses than clinical judgment and classified more participants as not having the disease. The design of the included studies allows evaluation of CPRs when their results are applied independently of clinical judgment. The performance of CPRs, when implemented by clinicians as a support to their judgment may be different. CONCLUSIONS: In the limited studies to date, CPRs are rarely superior to clinical judgment and there is generally a trade-off between the proportion classified as not having disease and the proportion of missed diagnoses. Differences between the two methods of judgment are likely the result of different diagnostic thresholds for positivity. Which is the preferred judgment method for a particular clinical condition depends on the relative benefits and harms of true positive and false positive diagnoses. PMID- 26039540 TI - Fluorine-Rich Fluorides: New Insights into the Chemistry of Polyfluoride Anions. AB - Polyfluoride anions have been investigated by matrix-isolation spectroscopy and quantum-chemical methods. For the first time the higher polyfluoride anion [F5 ]( ) has been observed under cryogenic conditions in neon matrices at 850 cm(-1) . In addition, a new band for the Cs(+) [F3 ](-) complex in neon is reported. PMID- 26039541 TI - Cell Surface CD74-MIF Interactions Drive Melanoma Survival in Response to Interferon-gamma. AB - Melanoma is believed to be a highly immunogenic tumor and recent developments in immunotherapies are promising. IFN-gamma produced by immune cells has a crucial role in tumor immune surveillance; however, it has also been reported to be pro tumorigenic. In the current study, we found that IFN-gamma enhances the expression of CD74, which interacts with its ligand, macrophage migration inhibitory factor (MIF), and thereby activates the PI3K/AKT pathway in melanoma, promoting tumor survival. IFN-gamma increased phosphorylation of AKT Ser473 and upregulated total cell surface expression of CD74 in human melanoma cell lines tested. CD74 was highly expressed in melanoma tissues. Moreover, the expression of CD74 on tumor cells correlated with plasma IFN-gamma levels in melanoma patient samples. In our analysis of melanoma cell lines, all produced MIF constitutively. Blockade of CD74-MIF interaction reduced AKT phosphorylation and expression of pro-tumorigenic molecules, including IL-6, IL-8, and BCL-2. Inhibition of CD74-MIF interaction significantly suppressed tumor growth in the presence of IFN-gamma in our xenograft mouse model. Thus, we conclude that IFN gamma promotes melanoma cell survival by regulating CD74-MIF signaling, suggesting that targeting the CD74-MIF interaction under IFN-gamma-stimulatory conditions would be an effective therapeutic approach for melanoma. PMID- 26039543 TI - Creatine loading elevates the intracellular phosphorylation potential and alters adaptive responses of rat fast-twitch muscle to chronic low-frequency stimulation. AB - This study tested the hypothesis that elevating the intracellular phosphorylation potential (IPP = [ATP]/[ADP]free) within rat fast-twitch tibialis anterior muscles by creatine (Cr) loading would prevent fast-to-slow fibre transitions induced by chronic low-frequency electrical stimulation (CLFS, 10 Hz, 12 h/day). Creatine-control and creatine-CLFS groups drank a solution of 1% Cr + 5% dextrose, ad libitum, for 10 days before and during 10 days of CLFS; dextrose control and dextrose-CLFS groups drank 5% dextrose. Cr loading increased total Cr (P < 0.025), phosphocreatine (PCr) (P < 0.003), and the IPP (P < 0.0008) by 34%, 45%, and 64%, respectively. PCr and IPP were 46% (P < 0.002) and 76% (P < 0.02) greater in creatine-CLFS than in dextrose-CLFS. Higher IPP was confirmed by a 58% reduction in phospho-AMP-activated protein kinase alpha (Thr172) (P < 0.006). In dextrose-CLFS, myosin heavy chain (MyHC) I and IIa transcripts increased 32- and 38-fold (P < 0.006), respectively, whereas MyHC-IIb mRNA decreased by 75% (P < 0.03); the corresponding MyHC-I and MyHC-IIa protein contents increased by 2.0- (P < 0.03) and 2.7-fold (P < 0.05), respectively, and MyHC-IIb decreased by 30% (P < 0.03). In contrast, within creatine-CLFS, MyHC-I and MyHC-IIa mRNA were unchanged and MyHC-IIb mRNA decreased by 75% (P < 0.003); the corresponding MyHC isoform contents were not altered. Oxidative reference enzymes were similarly elevated (P < 0.01) in dextrose-CLFS and creatine-CLFS, but reciprocal reductions in glycolytic reference enzymes occurred only in dextrose-CLFS (P < 0.02). Preservation of the glycolytic potential and greater SERCA2 and parvalbumin contents in creatine-CLFS coincided with prolonged time to peak tension and half rise time (P < 0.01). These results highlight the IPP as an important physiological regulator of muscle fibre plasticity and demonstrate that training induced changes typically associated with improvements in muscular endurance or increased power output are not mutually exclusive in Cr-loaded muscles. PMID- 26039542 TI - XL888 Limits Vemurafenib-Induced Proliferative Skin Events by Suppressing Paradoxical MAPK Activation. PMID- 26039545 TI - Precision medicine and health disparities: advancing the science of individualizing patient care. PMID- 26039544 TI - Hepatic fibrinogen storage disease: identification of two novel mutations (p.Asp316Asn, fibrinogen Pisa and p.Gly366Ser, fibrinogen Beograd) impacting on the fibrinogen gamma-module. AB - BACKGROUND: Quantitative fibrinogen deficiencies (hypofibrinogenemia and afibrinogenemia) are rare congenital disorders characterized by low/unmeasurable plasma fibrinogen antigen levels. Their genetic basis is invariably represented by mutations within the fibrinogen genes (FGA, FGB and FGG coding for the Aalpha, Bbeta and gamma chains). Currently, only four mutations (p.Gly284Arg, p.Arg375Trp, delGVYYQ 346-350, p.Thr314Pro), all affecting the fibrinogen gamma chain, have been reported to cause fibrinogen storage disease (FSD), a disorder characterized by protein aggregation, endoplasmic reticulum retention and hypofibrinogenemia. OBJECTIVES: To investigate the genetic basis of FSD in two hypofibrinogenemic patients. METHODS: The mutational screening of the fibrinogen genes was performed by direct DNA sequencing. The impact of identified mutations on fibrinogen structure was investigated by in-silico molecular modeling. Liver histology was evaluated by light microscopy, electron microscopy and immunocytochemistry. RESULTS: Here, we describe two hypofibrinogenemic children with persistent abnormal liver function parameters. Direct sequencing of the coding portion of fibrinogen genes disclosed two novel FGG missense variants (p.Asp316Asn, fibrinogen Pisa; p.Gly366Ser, fibrinogen Beograd), both present in the heterozygous state and affecting residues located in the fibrinogen C terminal gamma-module. Liver sections derived from biopsies of the two patients were examined by immunocytochemical analyses, revealing hepatocyte cytoplasmic inclusions immunoreactive to anti-fibrinogen antibodies. CONCLUSIONS: Our work strongly confirms the clustering of mutations causing FSD in the fibrinogen gamma chain between residues 284 and 375. Based on an in-depth structural analysis of all FSD-causing mutations and on their resemblance to mutations leading to serpinopathies, we also comment on a possible mechanism explaining fibrinogen polymerization within hepatocytes. PMID- 26039546 TI - Embarking on a science vision for health disparities research. PMID- 26039547 TI - Neural correlates of post-conventional moral reasoning: a voxel-based morphometry study. AB - Going back to Kohlberg, moral development research affirms that people progress through different stages of moral reasoning as cognitive abilities mature. Individuals at a lower level of moral reasoning judge moral issues mainly based on self-interest (personal interests schema) or based on adherence to laws and rules (maintaining norms schema), whereas individuals at the post-conventional level judge moral issues based on deeper principles and shared ideals. However, the extent to which moral development is reflected in structural brain architecture remains unknown. To investigate this question, we used voxel-based morphometry and examined the brain structure in a sample of 67 Master of Business Administration (MBA) students. Subjects completed the Defining Issues Test (DIT 2) which measures moral development in terms of cognitive schema preference. Results demonstrate that subjects at the post-conventional level of moral reasoning were characterized by increased gray matter volume in the ventromedial prefrontal cortex and subgenual anterior cingulate cortex, compared with subjects at a lower level of moral reasoning. Our findings support an important role for both cognitive and emotional processes in moral reasoning and provide first evidence for individual differences in brain structure according to the stages of moral reasoning first proposed by Kohlberg decades ago. PMID- 26039548 TI - Correction: essential amino acids in the gluten-free diet and serum in relation to depression in patients with celiac disease. PMID- 26039549 TI - Correction: new insights into samango monkey speciation in South Africa. PMID- 26039550 TI - Evaluation of two highly-multiplexed custom panels for massively parallel semiconductor sequencing on paraffin DNA. AB - BACKGROUND: AIM: Massively parallel sequencing (MPS) holds promise for expanding cancer translational research and diagnostics. As yet, it has been applied on paraffin DNA (FFPE) with commercially available highly multiplexed gene panels (100s of DNA targets), while custom panels of low multiplexing are used for re sequencing. Here, we evaluated the performance of two highly multiplexed custom panels on FFPE DNA. METHODS: Two custom multiplex amplification panels (B, 373 amplicons; T, 286 amplicons) were coupled with semiconductor sequencing on DNA samples from FFPE breast tumors and matched peripheral blood samples (n samples: 316; n libraries: 332). The two panels shared 37% DNA targets (common or shifted amplicons). Panel performance was evaluated in paired sample groups and quartets of libraries, where possible. RESULTS: Amplicon read ratios yielded similar patterns per gene with the same panel in FFPE and blood samples; however, performance of common amplicons differed between panels (p<0.001). FFPE genotypes were compared for 1267 coding and non-coding variant replicates, 999 out of which (78.8%) were concordant in different paired sample combinations. Variant frequency was highly reproducible (Spearman's rho 0.959). Repeatedly discordant variants were of high coverage / low frequency (p<0.001). Genotype concordance was (a) high, for intra-run duplicates with the same panel (mean+/-SD: 97.2+/ 4.7, 95%CI: 94.8-99.7, p<0.001); (b) modest, when the same DNA was analyzed with different panels (mean+/-SD: 81.1+/-20.3, 95%CI: 66.1-95.1, p = 0.004); and (c) low, when different DNA samples from the same tumor were compared with the same panel (mean+/-SD: 59.9+/-24.0; 95%CI: 43.3-76.5; p = 0.282). Low coverage / low frequency variants were validated with Sanger sequencing even in samples with unfavourable DNA quality. CONCLUSIONS: Custom MPS may yield novel information on genomic alterations, provided that data evaluation is adjusted to tumor tissue FFPE DNA. To this scope, eligibility of all amplicons along with variant coverage and frequency need to be assessed. PMID- 26039551 TI - Robust Excitons and Trions in Monolayer MoTe2. AB - Molybdenum telluride (MoTe2) has emerged as a special member in the family of two dimensional transition metal dichalcogenide semiconductors, owing to the strong spin-orbit coupling and relatively small energy gap, which offers new applications in valleytronic and excitonic devices. Here we successfully demonstrated the electrical modulation of negatively charged (X(-)), neutral (X(0)), and positively charged (X(+)) excitons in monolayer MoTe2 via photoluminescence spectroscopy. The binding energies of X(+) and X(-) were measured to be ~24 and ~27 meV, respectively.The exciton binding energy of monolayer MoTe2 was measured to be 0.58 +/- 0.08 eV via photoluminescence excitation spectroscopy, which matches well with our calculated value of 0.64 eV. PMID- 26039553 TI - Presence control of DNA repair controllers. PMID- 26039552 TI - Plant tolerance to excess light energy and photooxidative damage relies on plastoquinone biosynthesis. AB - Plastoquinone-9 is known as a photosynthetic electron carrier to which has also been attributed a role in the regulation of gene expression and enzyme activities via its redox state. Here, we show that it acts also as an antioxidant in plant leaves, playing a central photoprotective role. When Arabidopsis plants were suddenly exposed to excess light energy, a rapid consumption of plastoquinone-9 occurred, followed by a progressive increase in concentration during the acclimation phase. By overexpressing the plastoquinone-9 biosynthesis gene SPS1 (solanesyl diphosphate synthase 1) in Arabidopsis, we succeeded in generating plants that specifically accumulate plastoquinone-9 and its derivative plastochromanol-8. The SPS1-overexpressing lines were much more resistant to photooxidative stress than the wild type, showing marked decreases in leaf bleaching, lipid peroxidation and PSII photoinhibition under excess light. Comparison of the SPS1 overexpressors with other prenyl quinone mutants indicated that the enhanced phototolerance of the former plants is directly related to their increased capacities for plastoquinone-9 biosynthesis. PMID- 26039554 TI - Respiratory Failure in a Pediatric Patient with Biventricular Assist Devices: Identification and Novel Management of Inflow Cannula Obstruction. AB - Respiratory failure after ventricular assist device (VAD) placement may threaten transplant candidacy and can be lethal. Refractory respiratory failure may require addition of extracorporeal membrane oxygenation (ECMO) support. Providing ECMO in a VAD-supported patient is uniquely challenging, particularly in the case of LVAD inflow cannula obstruction in a pediatric patient who may be more prone to cannula obstruction. Surgical intervention to alleviate obstruction may not be feasible. Here, we present a novel nonsurgical strategy for conversion to ECMO in a VAD-supported pediatric patient with respiratory failure because of LVAD inflow cannula obstruction. PMID- 26039555 TI - Omacetaxine (Synribo) for CML. PMID- 26039556 TI - Afatinib (Gilotrif) for advanced non-small cell lung cancer. PMID- 26039557 TI - Erratum: The expanding spectrum of human infections caused by Kocuria species: a case report and literature review. AB - [This corrects the article DOI: 10.1038/emi.2013.71.]. PMID- 26039558 TI - Nature of the Surface-Exposed Cytochrome-Electrode Interactions in Electroactive Biofilms of Desulfuromonas acetoxidans. AB - Metal-respiring bacteria are microorganisms capable of oxidizing organic pollutants present in wastewater and transferring the liberated electrons to an electrode. This ability has led to their application as catalysts in bioelectrochemical systems (BESs), a sustainable technology coupling bioremediation to electricity production. Crucial for the functioning of these BESs is a complex protein architecture consisting of several surface-exposed multiheme proteins, called outer membrane cytochromes, wiring the cell metabolism to the electrode. Although the role of these proteins has been increasingly understood, little is known about the protein-electrode interactions and their impact on the performance of BESs. In this study, we used surface-enhanced resonance Raman spectroscopy in combination with electrochemical techniques to unravel the nature of the protein-electrode interaction for the outer membrane cytochrome OmcB from Desulfuromonas acetoxidans (Dace). Comparing the spectroelectrochemical properties of OmcB bound directly to the electrode surface with those of the same protein embedded inside an electroactive biofilm, we have shown that the surface-exposed cytochromes of Dace biofilms are in direct contact with the electrode surface. Even if direct binding causes protein denaturation, the biofilm possesses the ability to minimize the extent of the damage maximizing the amount of cells in direct electrical communication with the electrode. PMID- 26039559 TI - Cation Exchange in Small ZnS and CdS Molecular Analogues. AB - The simplest means of altering the chemistry and electronic structure of any material, from molecular clusters to single crystals, is by the introduction of chemical impurities. We present a systematic study of the cation exchange reaction involving Co(2+) ions with metal benzenethiolate clusters, [M4(SPh)10](2 ) (M = Zn, Cd), yielding diluted magnetic clusters having the general formula [(M1-xCox)4(SPh)10](2-). This method allows high concentrations of doping at the molecular level without forming concentrated magnetic clusters such as [Co4(SPh)10](2-). Changes in the electronic structure of the molecular species containing on average <1 Co(2+) per cluster were observed and characterized by a variety of analytical (high-resolution electrospray mass spectrometry) and spectroscopic techniques (electronic absorption including stopped-flow kinetics, luminescence, and paramagnetic (1)H NMR). The mass spectrometry results strongly suggest that the cation exchange reaction with Co(2+) is thermodynamically favored for the [Zn4(SPh)10](2-) cluster compared to the [Cd4(SPh)10](2-) clusters at room temperature. The rate of the cation exchange is orders of magnitude faster for the [Cd4(SPh)10](2-) cluster than for [Zn4(SPh)10](2-) and is governed by ligand interconversion processes. This simple room temperature cation exchange into molecular clusters is a model reaction that provides important structural information regarding the effect of Co(2+) doping on the cluster stability. PMID- 26039560 TI - Modular advanced oxidation process enabled by cathodic hydrogen peroxide production. AB - Hydrogen peroxide (H2O2) is frequently used in combination with ultraviolet (UV) light to treat trace organic contaminants in advanced oxidation processes (AOPs). In small-scale applications, such as wellhead and point-of-entry water treatment systems, the need to maintain a stock solution of concentrated H2O2 increases the operational cost and complicates the operation of AOPs. To avoid the need for replenishing a stock solution of H2O2, a gas diffusion electrode was used to generate low concentrations of H2O2 directly in the water prior to its exposure to UV light. Following the AOP, the solution was passed through an anodic chamber to lower the solution pH and remove the residual H2O2. The effectiveness of the technology was evaluated using a suite of trace contaminants that spanned a range of reactivity with UV light and hydroxyl radical (HO(*)) in three different types of source waters (i.e., simulated groundwater, simulated surface water, and municipal wastewater effluent) as well as a sodium chloride solution. Irrespective of the source water, the system produced enough H2O2 to treat up to 120 L water d(-1). The extent of transformation of trace organic contaminants was affected by the current density and the concentrations of HO(*) scavengers in the source water. The electrical energy per order (EEO) ranged from 1 to 3 kWh m(-3), with the UV lamp accounting for most of the energy consumption. The gas diffusion electrode exhibited high efficiency for H2O2 production over extended periods and did not show a diminution in performance in any of the matrices. PMID- 26039562 TI - Three-Dimensional in Vitro Model to Study Osteobiology and Osteopathology. AB - The bone is an amazing organ that grows and remodels itself over a lifetime. It is generally accepted that bone sculpting in response to stress and force is carried out by groups of cells contained within bone multicellular units that are coordinated to degrade existing bone and form new bone. Because of the nature of bone and the extensiveness of the skeleton, it is difficult to study bone remodeling in vivo. On the other hand, because the bone contains a complex environment of many cell types, is it possible to study bone remodeling in vitro? We propose that one can at minimum study the interaction between osteoblasts (bone formation) and osteoclasts (bone degradation) in a three dimensional (3D) "bioreactor". Furthermore, one can add bone degrading metastatic cancer cells, and study how they contribute to and take part in the bone degradation process. We have primarily cultured and differentiated MC3T3-E1 osteoblasts for long periods (2-10 months) before addition of bone marrow osteoclasts and/or metastatic (MDA-MB-231), metastasis suppressed (MDA-MB-231BRMS1) or non metastatic (MCF-7) breast cancer cells. In the co-culture of osteoblasts and osteoclasts there was clear evidence of matrix degradation. Loss of matrix was also evident after co-culture with metastatic breast cancer cells. Tri-culture permitted an evaluation of the interaction of the three cell types. The 3D system holds promise for further studies of cancer dormancy, hormone, and cytokine effects and matrix manipulation. PMID- 26039563 TI - Coalescence, Growth, and Stability of Surface-Attached Nanobubbles. AB - Surface-attached nanobubbles once formed and kept under constant conditions show remarkable stability against dissolution. When observing a large population of nanobubbles using total internal reflection fluorescence (TIRF) microscopy, we find rare events of coalescence, i.e., the merging of two neighboring bubbles. The new bubble covers the convex hull of their "footprint", with most of the three-phase contact line remaining pinned. Interestingly, the newly formed bubble is not shape-stable but grows in height within several 100 ms. This growth dynamic can be described with the classical diffusion theory using contact line pinning and Henry's law. This theory also shows that surface nanobubbles can attain a stable shape with a contact angle larger than 90 degrees in supersaturated liquid. PMID- 26039561 TI - Design and evaluation of antimalarial peptides derived from prediction of short linear motifs in proteins related to erythrocyte invasion. AB - The purpose of this study was to investigate the blood stage of the malaria causing parasite, Plasmodium falciparum, to predict potential protein interactions between the parasite merozoite and the host erythrocyte and design peptides that could interrupt these predicted interactions. We screened the P. falciparum and human proteomes for computationally predicted short linear motifs (SLiMs) in cytoplasmic portions of transmembrane proteins that could play roles in the invasion of the erythrocyte by the merozoite, an essential step in malarial pathogenesis. We tested thirteen peptides predicted to contain SLiMs, twelve of them palmitoylated to enhance membrane targeting, and found three that blocked parasite growth in culture by inhibiting the initiation of new infections in erythrocytes. Scrambled peptides for two of the most promising peptides suggested that their activity may be reflective of amino acid properties, in particular, positive charge. However, one peptide showed effects which were stronger than those of scrambled peptides. This was derived from human red blood cell glycophorin-B. We concluded that proteome-wide computational screening of the intracellular regions of both host and pathogen adhesion proteins provides potential lead peptides for the development of anti-malarial compounds. PMID- 26039564 TI - Immunotherapy for non-small-cell lung cancer: the past 10 years. AB - ABSTRACT In the past decade, the approach to patients with metastatic non-small cell lung cancer has relied on chemotherapy and on targeted agents for molecularly selected subgroups of patients. Recent work has introduced immunotherapy as another area of progress, and likely as a new treatment paradigm in the near future. While the large Phase III studies with cancer vaccination with the current technologies remain at present disappointing, the immunomodulation strategies with immune checkpoint inhibitors have delivered remarkable results in expanded Phase I studies and are now intensively studied in large Phase III studies. This review summarizes the past decade of immunotherapy for non-small-cell lung cancer, gives an updated overview of trials in this field, and the context of future development in this exciting field. PMID- 26039565 TI - Correction: a robust in vivo-like persistent firing supported by a hybrid of intracellular and synaptic mechanisms. PMID- 26039566 TI - [Cultural meanings and relations to the world in psychopathological disorders during pregnancy and the puerperium in the Cameroonian context]. AB - Pregnancy, delivery, and the postpartum period are significant moments that raise questions about women's relation to the world. Globally, the puerperium (the first 42 days after delivery) remains a time when several psychopathological disorders, related to the sexual sphere, may be manifested. This article considers some standard psychopathological knowledge that sheds light on this, while stressing the impact of culture on the woman's individuality and her psychosexual life experiences. It underlines the sensitizing role of psychological experience, affected by beliefs and various taboos, that can cause her to relive traumas from her psychosexual life experience; the women is often unaware of these experiences, but they make it possible to interpret and prevent disorders during the puerperium. PMID- 26039569 TI - Correction: MEDI-573, Alone or in Combination with Mammalian Target of Rapamycin Inhibitors, Targets the Insulin-like Growth Factor Pathway in Sarcomas. PMID- 26039570 TI - Design, Synthesis, and Structure-Activity Relationships of Pyridine-Based Rho Kinase (ROCK) Inhibitors. AB - The Rho kinases (ROCK1 and ROCK2) are highly homologous serine/threonine kinases that act on substrates associated with cellular motility, morphology, and contraction and are of therapeutic interest in diseases associated with cellular migration and contraction, such as hypertension, glaucoma, and erectile dysfunction. Beginning with compound 4, an inhibitor of ROCK1 identified through high-throughput screening, systematic exploration of SAR, and application of structure-based design, led to potent and selective ROCK inhibitors. Compound 37 represents significant improvements in inhibition potency, kinase selectivity, and CYP inhibition and possesses pharmacokinetics suitable for in vivo experimentation. PMID- 26039571 TI - Gene Perturbation Atlas (GPA): a single-gene perturbation repository for characterizing functional mechanisms of coding and non-coding genes. AB - Genome-wide transcriptome profiling after gene perturbation is a powerful means of elucidating gene functional mechanisms in diverse contexts. The comprehensive collection and analysis of the resulting transcriptome profiles would help to systematically characterize context-dependent gene functional mechanisms and conduct experiments in biomedical research. To this end, we collected and curated over 3000 transcriptome profiles in human and mouse from diverse gene perturbation experiments, which involved 1585 different perturbed genes (microRNAs, lncRNAs and protein-coding genes) across 1170 different cell lines/tissues. For each profile, we identified differential genes and their associated functions and pathways, constructed perturbation networks, predicted transcription regulation and cancer/drug associations, and assessed cooperative perturbed genes. Based on these transcriptome analyses, the Gene Perturbation Atlas (GPA) can be used to detect (i) novel or cell-specific functions and pathways affected by perturbed genes, (ii) protein interactions and regulatory cascades affected by perturbed genes, and (iii) perturbed gene-mediated cooperative effects. The GPA is a user-friendly database to support the rapid searching and exploration of gene perturbations. Particularly, we visualized functional effects of perturbed genes from multiple perspectives. In summary, the GPA is a valuable resource for characterizing gene functions and regulatory mechanisms after single-gene perturbations. The GPA is freely accessible at http://biocc.hrbmu.edu.cn/GPA/. PMID- 26039572 TI - Impact of Hydrophobicity on Antioxidant Efficacy in Low-Moisture Food. AB - The polarity and partitioning of antioxidants (AOX) in lipid dispersions and bulk oils have a large impact on efficacy, but this has not yet been studied in low moisture foods. Using a homologous series of rosmarinic esters as AOX in crackers, we determined that efficacy increases with increasing hydrophobicity based on lipid hydroperoxide and hexanal generation. Confocal microscopy was used to determine the location of both lipids and AOX. Hydrophobic rosmarinic esters partitioned more closely with the lipid than rosmarinic acid, presumably placing the hydrophobic AOX at the site of oxidation reactions. Partitioning and efficacy of the intermediate polarity ester were affected by mode of incorporation (e.g., added to the water or to the lipid prior to dough formation). The synthetic AOXs propyl gallate, butylhydroxytoluene, and tert-butylhydroquinone gave similar results with the more hydrophobic BHT and TBHQ being more effective at reducing lipid hydroperoxide and hexanal generation than the more hydrophilic propyl gallate. These results provide important information on which AOX would be most effective in low-moisture foods. PMID- 26039574 TI - Sodium Deoxycholate Hydrogels: Effects of Modifications on Gelation, Drug Release, and Nanotemplating. AB - In the present study, sodium deoxycholate (NaDC) was used to produce gelation of tris(hydroxymethyl)amino-methane (TRIS) solutions above, below, and near the pKa of NaDC, respectively, which yielded a neutral gelator, a charged gelator, and a mixture of each. Impacts of ionic interactions on gel formation were studied in detail and showed that pH can be used to modify many hydrogel properties including sol-gel temperature, crystallinity, and mechanical strength. Several formulations yielded a unique rheological finding of two stable regions of elastic modulus. The release of a small molecule has been investigated under different hydrogel conditions and at variable shear rate, suggesting utility as a drug-delivery vehicle. It was also observed that pH modification of the hydrogels affected nanoparticle formation. Nanoparticles derived from a Group of Uniform Materials Based on Organic Salts (nanoGUMBOS), specifically cyanine-based NIR dyes, were templated within the hydrogel network for potential applications in tissue imaging. These nanoGUMBOS were found to be size-tunable, although material dependent. Further understanding of NaDC/TRIS gelation has broadened the tunability and multidimensional applications of these tailored hydrogel systems. PMID- 26039573 TI - Virulence genes and cytokine profile in systemic murine Campylobacter coli infection. AB - Campylobacter coli are one of the most common bacteria in bacterial gastroenteritis and acute enterocolitis in humans. However, relatively little is known regarding the mechanisms of pathogenesis and host response to C. coli infections. To investigate the influence of genetic changes, we first used PCR to demonstrate the presence of the known virulence genes cadF, virB11, cdtB, cdtC and ceuE in the clinical isolate C. coli 26536, which was isolated from the liver of infected BALB/c mice. Sequence analyses of the cadF, virB11, cdtB and ceuE genes in C. coli 26536 confirmed the stability in these virulence genes during their transmission through the host. We further investigated C. coli infection for the bacterial clearance from the liver and spleen of infected mice, and for their immune response. C. coli persisted well in both organs, with better survival in the liver. We also determined the levels of several pro-inflammatory cytokines (i.e., interleukin [IL]-6, IL-12, interferon-gamma, tumor necrosis factor-alpha) and the anti-inflammatory cytokine IL-10 in plasma and in liver homogenates from the infected mice, using enzyme-linked immunosorbent assays. The lowest levels among these cytokines were for tumor necrosis factor-alpha in the plasma and IL-6 in the liver on days 1, 3 and 8 post-infection. The most pronounced production was for IL-10, in both plasma (days 1 and 8 post-infection) and liver (day 8 post-infection), which suggests that it has a role in healing of the organ inflammation. Our findings showed dynamic relationships between pro- and anti-inflammatory cytokines and thus contribute toward clarification of the healing processes involved in the resolution of C. coli infections. PMID- 26039575 TI - Periodic Charging of Individual Molecules Coupled to the Motion of an Atomic Force Microscopy Tip. AB - Individual molecules at the edges of self-assembled islands grown on Ag(111) can be deliberately switched in their charge state with the electric field from a scanning-probe tip. Close to the threshold voltage for a charge state transition, periodic switching of the charge is directly driven by the cantilever motion in frequency-modulated atomic force microscopy (AFM), as can be deduced from the signature in the measured frequency shift. In this regime, the integrated frequency shift yields the tip-sample force that is due to a single additional electron. Further, the signature of the dynamic charging response provides information on the electronic coupling of the molecule to the substrate. In analogy to previous experiments on quantum dots, this may also be used in the future to access excited state properties of single molecules from AFM experiments. PMID- 26039576 TI - DNA methylation levels and long-term trihalomethane exposure in drinking water: an epigenome-wide association study. AB - Trihalomethanes (THM) are undesired disinfection byproducts (DBPs) formed during water treatment. Mice exposed to DBPs showed global DNA hypomethylation and c-myc and c-jun gene-specific hypomethylation, while evidence of epigenetic effects in humans is scarce. We explored the association between lifetime THM exposure and DNA methylation through an epigenome-wide association study. We selected 138 population-based controls from a case-control study of colorectal cancer conducted in Barcelona, Spain, exposed to average lifetime THM levels <=85 MUg/L vs. >85 MUg/L (N = 68 and N = 70, respectively). Mean age of participants was 70 years, and 54% were male. Average lifetime THM level in the exposure groups was 64 and 130 ug/L, respectively. DNA was extracted from whole blood and was bisulphite converted to measure DNA methylation levels using the Illumina HumanMethylation450 BeadChip. Data preprocessing was performed using RnBeads. Methylation was compared between exposure groups using empirical Bayes moderated linear regression for CpG sites and Gaussian kernel for CpG regions. ConsensusPathDB was used for gene set enrichment. Statistically significant differences in methylation between exposure groups was found in 140 CpG sites and 30 gene-related regions, after false discovery rate <0.05 and adjustment for age, sex, methylation first principal component, and blood cell proportion. The annotated genes were localized to several cancer pathways. Among them, 29 CpGs had methylation levels associated with THM levels (|Deltabeta|>=0.05) located in 11 genes associated with cancer in other studies. Our results suggest that THM exposure may affect DNA methylation in genes related to tumors, including colorectal and bladder cancers. Future confirmation studies are required. PMID- 26039581 TI - Identification of a Circulating MicroRNA Profile as a Biomarker of Metastatic Cutaneous Melanoma. AB - No specific biomarkers for prognostication or evaluation of tumour load in melanoma have been reported to our knowledge. MicroRNAs (miRNAs) are strongly implicated in oncogenesis and tumour progression, and their circulating forms have been studied as potential biomarkers in oncology. The aim of this prospective study was to identify a melanoma-specific profile of plasma miRNAs. A screening phase, using RNA microarray, was conducted on plasma from 14 patients with metastatic melanoma and 5 healthy subjects. Selected miRNAs were analysed by RTqPCR in 2 independent training and validation cohorts including, respectively, 29 and 31 patients and 16 and 43 control subjects. A profile of 2 miRNAs (miR 1246 and miR-185) significantly associated with metastatic melanoma with a sensitivity of 90.5% and a specificity of 89.1% was identified. This plasma miRNA profile may become an accurate non-invasive biomarker for melanoma. PMID- 26039580 TI - Navigation using sensory substitution in real and virtual mazes. AB - Under certain specific conditions people who are blind have a perception of space that is equivalent to that of sighted individuals. However, in most cases their spatial perception is impaired. Is this simply due to their current lack of access to visual information or does the lack of visual information throughout development prevent the proper integration of the neural systems underlying spatial cognition? Sensory Substitution devices (SSDs) can transfer visual information via other senses and provide a unique tool to examine this question. We hypothesize that the use of our SSD (The EyeCane: a device that translates distance information into sounds and vibrations) can enable blind people to attain a similar performance level as the sighted in a spatial navigation task. We gave fifty-six participants training with the EyeCane. They navigated in real life-size mazes using the EyeCane SSD and in virtual renditions of the same mazes using a virtual-EyeCane. The participants were divided into four groups according to visual experience: congenitally blind, low vision & late blind, blindfolded sighted and sighted visual controls. We found that with the EyeCane participants made fewer errors in the maze, had fewer collisions, and completed the maze in less time on the last session compared to the first. By the third session, participants improved to the point where individual trials were no longer significantly different from the initial performance of the sighted visual group in terms of errors, time and collision. PMID- 26039582 TI - First-principles study of the influence of different interfaces and core types on the properties of CdSe/CdS core-shell nanocrystals. AB - With the expanding field of nanoengineering and the production of nanocrystals (NCs) with higher quality and tunable size, having reliable theoretical calculations to complement the experimental results is very important. Here we present such a study of CdSe/CdS core-shell NCs using density functional theory, where we focus on dependence of the properties of these NCs on core types and interfaces between the core and the shell, as well as on the core/shell ratio. We show that the density of states and the absorption indices depend rather weakly on the type of interface and core type. We demonstrate that the HOMO wavefunction is mainly localised in the core of the nanocrystal, depending primarily on the core/shell ratio. On the other hand the LUMO wavefunction spreads more into the shell of the nanocrystal, where its confinement in the core is almost the same in each of the studied structural models. Furthermore, we show that the radiative lifetimes decrease with increasing core sizes due to changes in the dipolar overlap integral of the HOMO and LUMO wavefunctions. In addition, the electron hole Coulomb interaction energies follow a similar pattern as the localisation of the wavefunctions, with the smaller NCs having higher Coulomb interaction energies. PMID- 26039583 TI - [Epidemiology and outcome of Congolese children who had surgery for heart defects]. AB - AIMS: to determine the principal heart defects for which children underwent surgery and to determine the survival rate. PATIENT AND METHODS: this retrospective cohort study involves Congolese babies treated surgically from September 1989 to September 2010 in France for congenital heart defects (through "Mecenat chirurgie cardiaque" and "Chaine de l'espoir"). It includes only 110 of the 182 recorded patients during the study period. RESULTS: The sex ratio for the 110 subjects included in the analysis was 1. Their mean age at surgery was 77.4 +/- 57.6 months old (range: 8 to 204 months). The main congenital heart defects for which surgery was performed were ventricular septal defect (21.9%), tetralogy of Fallot either isolated (22.8%) or associated with patent foramen ovale (1.8%) or coronary anomalies (1.8%), atrial septal defect associated with other malformations (8.2%), pulmonary atresia with ventricular septal defect (5.5%), aortic stenosis (3.7%), atrioventricular septal defect (0.9%), and Laubry-Pezzi syndrome (0.9%). The median length of follow-up was 42.4 +/- 35.6 months (range, 3-240 months). Patients' mean age at the study's end was 121.1 +/- 86.3 months (range 20-372 months). The 5-year survival rate was 90% and the 20-year survival, 83.3%. CONCLUSION: Heart surgery for congenital heart defects has improved survival. PMID- 26039586 TI - Rapid and Easy Histological Evaluation of Alveolar Human Bone Quality at Dental Implant Sites Using a Nondecalcified Frozen Cryofilm Section Technique: A Technical Report. AB - INTRODUCTION: The evaluation of bone quality at the site of the alveolar bone for a dental implant is very important. This study presents an easy technique for direct evaluation of alveolar bone quality using nondecalcified cryofilm frozen sections on human alveolar bone core samples. MATERIALS AND METHODS: Core samples harvested from alveolar bone were immediately frozen in cooled hexanen and slowly cut using a disposable tungsten carbide blade; the sliced sections were collected with adhesive cryofilms. Staining was performed using von toluidine blue and von Kossa for microscopic observations. RESULTS: All core samples clearly showed bone structure components of cortical bone, trabecular bone, bone marrow, blood vessels, and bone-related cells. CONCLUSION: These results suggest the efficacy of a nondecalcified cryofilm frozen section technique for histological observation of surgical implant sites. PMID- 26039584 TI - Identification of an Antimicrobial Agent Effective against Methicillin-Resistant Staphylococcus aureus Persisters Using a Fluorescence-Based Screening Strategy. AB - Persisters are a subpopulation of normal bacterial cells that show tolerance to conventional antibiotics. Persister cells are responsible for recalcitrant chronic infections and new antibiotics effective against persisters would be a major development in the treatment of these infections. Using the reporter dye SYTOX Green that only stains cells with permeabilized membranes, we developed a fluorescence-based screening assay in a 384-well format for identifying compounds that can kill methicillin-resistant Staphylococcus aureus (MRSA) persisters. The assay proved robust and suitable for high throughput screening (Z'-factor: >0.7). In screening a library of hits from a previous screen, which identified compounds that had the ability to block killing of the nematode Caenorhabditis by MRSA, we discovered that the low molecular weight compound NH125, a bacterial histidine kinase inhibitor, kills MRSA persisters by causing cell membrane permeabilization, and that 5 MUg/mL of the compound can kill all cells to the limit of detection in a 108 CFU/mL culture of MRSA persisters within 3h. Furthermore, NH125 disrupts 50% of established MRSA biofilms at 20 MUg/mL and completely eradicates biofilms at 160 MUg/mL. Our results suggest that the SYTOX Green screening assay is suitable for large-scale projects to identify small molecules effective against MRSA persisters and should be easily adaptable to a broad range of pathogens that form persisters. Since NH125 has strong bactericidal properties against MRSA persisters and high selectivity to bacteria, we believe NH125 is a good anti-MRSA candidate drug that should be further evaluated. PMID- 26039587 TI - The Anatomy and Phylogenetic Relationships of "Pelorosaurus" becklesii (Neosauropoda, Macronaria) from the Early Cretaceous of England. AB - The sauropod dinosaur "Pelorosaurus" becklesii was named in 1852 on the basis of an associated left humerus, ulna, radius and skin impression from the Early Cretaceous (Berriasian-Valanginian) Hastings Beds Group, near Hastings, East Sussex, southeast England, United Kingdom. The taxonomy and nomenclature of this specimen have a complex history, but most recent workers have agreed that "P." becklesii represents a distinct somphospondylan (or at least a titanosauriform) and is potentially the earliest titanosaur body fossil from Europe or even globally. The Hastings specimen is distinct from the approximately contemporaneous Pelorosaurus conybeari from Tilgate Forest, West Sussex. "P." becklesii can be diagnosed on the basis of five autapomorphies, such as: a prominent anteriorly directed process projecting from the anteromedial corner of the distal humerus; the proximal end of the radius is widest anteroposteriorly along its lateral margin; and the unique combination of a robust ulna and slender radius. The new generic name Haestasaurus is therefore erected for "P." becklesii. Three revised and six new fore limb characters (e.g. the presence/absence of condyle-like projections on the posterodistal margin of the radius) are discussed and added to three cladistic data sets for Sauropoda. Phylogenetic analysis confirms that Haestasaurus becklesii is a macronarian, but different data sets place this species either as a non-titanosauriform macronarian, or within a derived clade of titanosaurs that includes Malawisaurus and Saltasauridae. This uncertainty is probably caused by several factors, including the incompleteness of the Haestasaurus holotype and rampant homoplasy in fore limb characters. Haestasaurus most probably represents a basal macronarian that independently acquired the robust ulna, enlarged olecranon, and other states that have previously been regarded as synapomorphies of clades within Titanosauria. There is growing evidence that basal macronarian taxa survived into the Early Cretaceous of Europe and North America. PMID- 26039588 TI - Illumina Synthetic Long Read Sequencing Allows Recovery of Missing Sequences even in the "Finished" C. elegans Genome. AB - Most next-generation sequencing platforms permit acquisition of high-throughput DNA sequences, but the relatively short read length limits their use in genome assembly or finishing. Illumina has recently released a technology called Synthetic Long-Read Sequencing that can produce reads of unusual length, i.e., predominately around 10 Kb. However, a systematic assessment of their use in genome finishing and assembly is still lacking. We evaluate the promise and deficiency of the long reads in these aspects using isogenic C. elegans genome with no gap. First, the reads are highly accurate and capable of recovering most types of repetitive sequences. However, the presence of tandem repetitive sequences prevents pre-assembly of long reads in the relevant genomic region. Second, the reads are able to reliably detect missing but not extra sequences in the C. elegans genome. Third, the reads of smaller size are more capable of recovering repetitive sequences than those of bigger size. Fourth, at least 40 Kbp missing genomic sequences are recovered in the C. elegans genome using the long reads. Finally, an N50 contig size of at least 86 Kbp can be achieved with 24 * reads but with substantial mis-assembly errors, highlighting a need for novel assembly algorithm for the long reads. PMID- 26039589 TI - The Current Collapse in AlGaN/GaN High-Electron Mobility Transistors Can Originate from the Energy Relaxation of Channel Electrons? AB - Influence of the energy relaxation of the channel electrons on the performance of AlGaN/GaN high-electron mobility transistors (HEMTs) has been investigated using self-consistent solution to the coupled Schrodinger equation and Poisson equation. The first quantized energy level in the inversion layer rises and the average channel electron density decreases when the channel electric field increases from 20 kV/cm to 120 kV/cm. This research also demonstrates that the energy relaxation of the channel electrons can lead to current collapse and suggests that the energy relaxation should be considered in modeling the performance of AlGaN/GaN HEMTs such as, the gate leakage current, threshold voltage, source-drain current, capacitance-voltage curve, etc. PMID- 26039590 TI - Evaluation of fiber reinforced cement using digital image correlation. AB - The effect of short fiber reinforcements on the mechanical properties of cement has been examined using a splitting tensile - digital image correlation (DIC) measurement method. Three short fiber reinforcement materials have been used in this study: fiberglass, nylon, and polypropylene. The method outlined provides a simple experimental setup that can be used to evaluate the ultimate tensile strength of brittle materials as well as measure the full field strain across the surface of the splitting tensile test cylindrical specimen. Since the DIC measurement technique is a contact free measurement this method can be used to assess sample failure. PMID- 26039591 TI - Enhanced Field Emission Performance of Hierarchical ZnO/Si Nanotrees with Spatially Branched Heteroassemblies. AB - Silicon nanorods (SiNRs) with a large interspace and regularly aligned structure were fabricated by combining silver-catalyzed etching with a polysterene (PS) sphere template, then a hydrothermal reaction was utilized to synthesize large scale ZnO nanowires (NWs) on Si nanorods. Compared with the as-prepared SiNRs and ZnO NWs, the high-density ZnO NWs on SiNRs have exhibited predominant field emission (FE) characteristics with a low turn-on field of 2.18 V/MUm and a high field enhancement factor of ~8100. The FE enhancement was attributed to highly crystallized ZnO NWs densely distributed on the surface of SiNRs, which can effectively increase emission site density, diminish screening effect, favor electron transfer due to band bending, and quickly transmit heat from the nanotrees to substrate. Our results indicate that ZnO/Si hierarchical structures might be an effective candidate for field emission cathode. PMID- 26039592 TI - UV Light Reveals the Diversity of Jurassic Shell Colour Patterns: Examples from the Cordebugle Lagerstatte (Calvados, France). AB - Viewed under UV light the diverse and exceptionally well-preserved molluscs from the Late Jurassic Cordebugle Konservat Lagerstatte (Calvados, Normandy, France) reveal fluorescent fossil shell colour patterns predating the oldest previously known instance of such patterns by 100 Myr. Evidently, residual colour patterns are observable in Mesozoic molluscs by application of this non-destructive method, provided the shells are not decalcified or recrystallized. Among 46 species which are assigned to twelve gastropod families and eight bivalve families, no less than 25 species yielded positive results. Out of nine colour pattern morphologies that have been distinguished six occur in gastropods and three in bivalves. The presence of these variant morphologies clearly indicates a significant pre-Cenozoic diversification of colour patterns, especially in gastropods. In addition, the occurrence of two distinct types of fluorescence highlights a major difference in the chemical composition of the pigments involved in colour pattern formation in gastropods. This discovery enables us to discriminate members of higher clades, i.e. the Vetigastropoda emitting red fluorescence from the Caenogastropoda and Heterobranchia emitting whitish-beige to yellow fluorescence. Consequently, fluorescent colour patterns may help to allocate part of the numerous enigmatic Mesozoic gastropod taxa to their correct systematic position. PMID- 26039594 TI - What factors influence older adults to discuss falls with their health-care providers? AB - OBJECTIVE: To identify from the older adults' perspective, the factors associated with discussion about falls with their general practitioners and other health professionals and the factors associated with initiation of these discussions. We explored the content of and barriers to discussion about falls. METHODS: A prospective cohort study where a baseline cross-sectional survey was followed by a survey 1 year later. Survey domains were drawn from constructs of behavioural change models. Data from 245 older community dwellers in Victoria, Australia, in the follow-up survey were used for this study. Survey format consisted of yes and no responses, Likert scale and open/closed-ended responses. RESULTS: Few older adults talked with and initiated a talk with their health-care providers about falls in the follow-up period. Multiple regression showed anxiety or depression [OR = 2.78, 95% CI (1.21-6.41)], chronic medical conditions such as diabetes [OR = 2.71, 95% CI (1.19-6.17)] and having a self-reported fall in the last 12 months [OR = 4.26, 95% CI (2.16-8.41)] were associated with discussion of falls with general practitioners. Higher perception of risk of sustaining a serious injury from falling [OR = 1.49 (1.03-2.13)] was associated with discussion about falls with other health professionals. Participants discussed various topics of falls with their health-care providers. Different barriers to discussion about falls were identified. CONCLUSION: Health-care providers should routinely discuss falls prevention with older adults. Dissemination of evidence-based advice and followed up with referral during consultations, particularly in general practitioners could advance falls prevention practice. The results could help to develop a conceptual framework to predict the likelihood of falls discussion. PMID- 26039595 TI - Inherent noise appears as a Levy walk in fish schools. AB - Recent experimental and observational data have revealed that the internal structures of collective animal groups are not fixed in time. Rather, individuals can produce noise continuously within their group. These individuals' movements on the inside of the group, which appear to collapse the global order and information transfer, can enable interactions with various neighbors. In this study, we show that noise generated inherently in a school of ayus (Plecoglossus altivelis) is characterized by various power-law behaviors. First, we show that individual fish move faster than Brownian walkers with respect to the center of the mass of the school as a super-diffusive behavior, as seen in starling flocks. Second, we assess neighbor shuffling by measuring the duration of pair-wise contact and find that this distribution obeys the power law. Finally, we show that an individual's movement in the center of a mass reference frame displays a Levy walk pattern. Our findings suggest that inherent noise (i.e., movements and changes in the relations between neighbors in a directed group) is dynamically self-organized in both time and space. In particular, Levy walk in schools can be regarded as a well-balanced movement to facilitate dynamic collective motion and information transfer throughout the group. PMID- 26039593 TI - Contribution of Fdh3 and Glr1 to Glutathione Redox State, Stress Adaptation and Virulence in Candida albicans. AB - The major fungal pathogen of humans, Candida albicans, is exposed to reactive nitrogen and oxygen species following phagocytosis by host immune cells. In response to these toxins, this fungus activates potent anti-stress responses that include scavenging of reactive nitrosative and oxidative species via the glutathione system. Here we examine the differential roles of two glutathione recycling enzymes in redox homeostasis, stress adaptation and virulence in C. albicans: glutathione reductase (Glr1) and the S-nitrosoglutathione reductase (GSNOR), Fdh3. We show that the NADPH-dependent Glr1 recycles GSSG to GSH, is induced in response to oxidative stress and is required for resistance to macrophage killing. GLR1 deletion increases the sensitivity of C. albicans cells to H2O2, but not to formaldehyde or NO. In contrast, Fdh3 detoxifies GSNO to GSSG and NH3, and FDH3 inactivation delays NO adaptation and increases NO sensitivity. C. albicans fdh3? cells are also sensitive to formaldehyde, suggesting that Fdh3 also contributes to formaldehyde detoxification. FDH3 is induced in response to nitrosative, oxidative and formaldehyde stress, and fdh3Delta cells are more sensitive to killing by macrophages. Both Glr1 and Fdh3 contribute to virulence in the Galleria mellonella and mouse models of systemic infection. We conclude that Glr1 and Fdh3 play differential roles during the adaptation of C. albicans cells to oxidative, nitrosative and formaldehyde stress, and hence during the colonisation of the host. Our findings emphasise the importance of the glutathione system and the maintenance of intracellular redox homeostasis in this major pathogen. PMID- 26039596 TI - A new transition. PMID- 26039598 TI - Brazil's family health strategy--delivering community-based primary care in a universal health system. PMID- 26039597 TI - Mutation burden of rare variants in schizophrenia candidate genes. AB - BACKGROUND: Schizophrenia (SCZ) is a very heterogeneous disease that affects approximately 1% of the general population. Recently, the genetic complexity thought to underlie this condition was further supported by three independent studies that identified an increased number of damaging de novo mutations DNM in different SCZ probands. While these three reports support the implication of DNM in the pathogenesis of SCZ, the absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion that has been supported by the moderate success of Genome-Wide Association Studies (GWAS). METHODS: To further examine the genetic heterogeneity of this disease, we resequenced 62 genes that were found to have a DNM in SCZ patients, and 40 genes that encode for proteins known to interact with the products of the genes with DNM, in a cohort of 235 SCZ cases and 233 controls. RESULTS: We found an enrichment of private nonsense mutations amongst schizophrenia patients. Using a kernel association method, we were able to assess for association for different sets. Although our power of detection was limited, we observed an increased mutation burden in the genes that have DNM. PMID- 26039599 TI - A NICE delivery--the cross-Atlantic divide over treatment intensity in childbirth. PMID- 26039601 TI - Vasopressin antagonists. PMID- 26039602 TI - Images in clinical medicine. Measles. PMID- 26039603 TI - Clinical problem-solving. In sight and out of mind. PMID- 26039604 TI - Long-term efficacy of a hepatitis E vaccine. PMID- 26039605 TI - Long-term efficacy of a hepatitis E vaccine. PMID- 26039606 TI - Outcomes of pregnancy after bariatric surgery. PMID- 26039607 TI - Outcomes of pregnancy after bariatric surgery. PMID- 26039608 TI - Outcomes of pregnancy after bariatric surgery. PMID- 26039600 TI - Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. AB - BACKGROUND: The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering, as compared with standard therapy, did not significantly reduce the rate of major cardiovascular events among 1791 military veterans (median follow-up, 5.6 years). We report the extended follow-up of the study participants. METHODS: After the conclusion of the clinical trial, we followed participants, using central databases to identify procedures, hospitalizations, and deaths (complete cohort, with follow-up data for 92.4% of participants). Most participants agreed to additional data collection by means of annual surveys and periodic chart reviews (survey cohort, with 77.7% follow-up). The primary outcome was the time to the first major cardiovascular event (heart attack, stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, or cardiovascular-related death). Secondary outcomes were cardiovascular mortality and all-cause mortality. RESULTS: The difference in glycated hemoglobin levels between the intensive-therapy group and the standard-therapy group averaged 1.5 percentage points during the trial (median level, 6.9% vs. 8.4%) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a median follow-up of 9.8 years, the intensive-therapy group had a significantly lower risk of the primary outcome than did the standard-therapy group (hazard ratio, 0.83; 95% confidence interval [CI], 0.70 to 0.99; P=0.04), with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years, but did not have reduced cardiovascular mortality (hazard ratio, 0.88; 95% CI, 0.64 to 1.20; P=0.42). No reduction in total mortality was evident (hazard ratio in the intensive-therapy group, 1.05; 95% CI, 0.89 to 1.25; P=0.54; median follow up, 11.8 years). CONCLUSIONS: After nearly 10 years of follow-up, patients with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to standard therapy, but no improvement was seen in the rate of overall survival. (Funded by the VA Cooperative Studies Program and others; VADT ClinicalTrials.gov number, NCT00032487.). PMID- 26039610 TI - Ovarian protection during adjuvant chemotherapy. PMID- 26039609 TI - Ovarian protection during adjuvant chemotherapy. PMID- 26039611 TI - Ovarian protection during adjuvant chemotherapy. PMID- 26039612 TI - Bortezomib-based therapy for mantle-cell lymphoma. PMID- 26039613 TI - Bortezomib-based therapy for mantle-cell lymphoma. PMID- 26039614 TI - Bortezomib-based therapy for mantle-cell lymphoma. PMID- 26039615 TI - Management of potential bioterrorism-related conditions. PMID- 26039616 TI - Management of potential bioterrorism-related conditions. PMID- 26039618 TI - Acute appendicitis--appendectomy or the "antibiotics first" strategy. PMID- 26039617 TI - Management of potential bioterrorism-related conditions. PMID- 26039619 TI - Liberal or restrictive transfusion after cardiac surgery. PMID- 26039620 TI - Case 10-2015: A 15-year-old girl with Graves' disease and psychotic symptoms. PMID- 26039621 TI - Videos in clinical medicine. Noninvasive positive-pressure ventilation. PMID- 26039622 TI - Images in clinical medicine. Enlarged pinna. PMID- 26039623 TI - Daily potassium intake and sodium-to-potassium ratio in the reduction of blood pressure: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: To evaluate the efficacy of daily potassium intake on decreasing blood pressure in non-medicated normotensive or hypertensive patients, and to determine the relationship between potassium intake, sodium-to-potassium ratio and reduction in blood pressure. DESIGN: Mixed-effect meta-analyses and meta regression models. DATA SOURCES: Medline and the references of previous meta analyses. STUDIES ELIGIBILITY CRITERIA: Randomized controlled trials with potassium supplementation, with blood pressure as the primary outcome, in non medicated patients. RESULTS: Fifteen randomized controlled trials of potassium supplementation in patients without antihypertensive medication were selected for the meta-analyses (917 patients). Potassium supplementation resulted in reduction of SBP by 4.7 mmHg [95% confidence interval (CI) 2.4-7.0] and DBP by 3.5 mmHg (95% CI 1.3-5.7) in all patients. The effect was found to be greater in hypertensive patients, with a reduction of SBP by 6.8 mmHg (95% CI 4.3-9.3) and DBP by 4.6 mmHg (95% CI 1.8-7.5). Meta-regression analysis showed that both increased daily potassium excretion and decreased sodium-to-potassium ratio were associated with blood pressure reduction (P < 0.05). Increased total daily potassium urinary excretion from 60 to 100 mmol/day and decrease of sodium-to potassium ratio were shown to be necessary to explain the estimated effect. CONCLUSION: Potassium supplementation is associated with reduction of blood pressure in patients who are not on antihypertensive medication, and the effect is significant in hypertensive patients. The reduction in blood pressure significantly correlates with decreased daily urinary sodium-to-potassium ratio and increased urinary potassium. Patients with elevated blood pressure may benefit from increased potassium intake along with controlled or decreased sodium intake. PMID- 26039624 TI - No Surgery for Low-Grade Ductal Carcinoma In Situ? PMID- 26039626 TI - Indoor Tanning Devices in Student Apartment Complexes: A Study of 2 Texas University Communities. PMID- 26039627 TI - E2F1-Mediated Induction of NFYB Attenuates Apoptosis via Joint Regulation of a Pro-Survival Transcriptional Program. AB - The E2F1 transcription factor regulates cell proliferation and apoptosis through the control of a considerable variety of target genes. Previous work has detailed the role of other transcription factors in mediating the specificity of E2F function. Here we identify the NF-YB transcription factor as a novel direct E2F1 target. Genome-wide expression analysis of the effects of NFYB knockdown on E2F1 mediated transcription identified a large group of genes that are co-regulated by E2F1 and NFYB. We also provide evidence that knockdown of NFYB enhances E2F1 induced apoptosis, suggesting a pro-survival function of the NFYB/E2F1 joint transcriptional program. Bioinformatic analysis suggests that deregulation of these NFY-dependent E2F1 target genes might play a role in sarcomagenesis as well as drug resistance. PMID- 26039628 TI - Combination of Autoantibody Signature with PSA Level Enables a Highly Accurate Blood-Based Differentiation of Prostate Cancer Patients from Patients with Benign Prostatic Hyperplasia. AB - Although an increased level of the prostate-specific antigen can be an indication for prostate cancer, other reasons often lead to a high rate of false positive results. Therefore, an additional serological screening of autoantibodies in patients' sera could improve the detection of prostate cancer. We performed protein macroarray screening with sera from 49 prostate cancer patients, 70 patients with benign prostatic hyperplasia and 28 healthy controls and compared the autoimmune response in those groups. We were able to distinguish prostate cancer patients from normal controls with an accuracy of 83.2%, patients with benign prostatic hyperplasia from normal controls with an accuracy of 86.0% and prostate cancer patients from patients with benign prostatic hyperplasia with an accuracy of 70.3%. Combining seroreactivity pattern with a PSA level of higher than 4.0 ng/ml this classification could be improved to an accuracy of 84.1%. For selected proteins we were able to confirm the differential expression by using luminex on 84 samples. We provide a minimally invasive serological method to reduce false positive results in detection of prostate cancer and according to PSA screening to distinguish men with prostate cancer from men with benign prostatic hyperplasia. PMID- 26039629 TI - Novel mutations in the inverted formin 2 gene of Chinese families contribute to focal segmental glomerulosclerosis. AB - Here, we report a genetic study of an extended family of Chinese ancestry with focal segmental glomerulosclerosis (FSGS), with one of the affected members also concurrently diagnosed with IgA nephropathy (IgAN). By genome-wide linkage analysis and subsequent sequencing, we identified an S85W mutation in the inverted formin 2 (INF2) gene that perfectly cosegregated with the kidney disease phenotype. The entire INF2 coding region was sequenced in 200 healthy controls, 55 families with FSGS, and 34 families with IgAN. This analysis identified a novel insertion, S129_Q130insVRQLS, in another FSGS pedigree. In vitro studies found that alpha-actinin 4 expression was decreased and INF2 showed perinuclear localization in S85W-transfected podocytes. Phosphorylation of serum response factor, and that its nuclear translation was decreased in S85W podocytes, indicated decreased activation in mutants. Abnormal actin organization was also found in S85W podocytes, while no change of microtubule structure was observed. Co-immunoprecipitation and immunofluorescence found decreased interaction between INF2 and Cdc42 in S85W podocytes. However, all these changes were not found in S129_Q130insVRQLS podocytes. The overall frequency of INF2 mutations was ~3.6% among Chinese familial FSGS, which was considerably lower than that from studies of European FSGS families. Thus, S85W but not the S129_Q130insVRQLS variant leads to podocyte cytoskeletal abnormalities, probably by impaired serum response factor phosphorylation. PMID- 26039630 TI - The SAM domain of ANKS6 has different interacting partners and mutations can induce different cystic phenotypes. AB - The ankyrin repeat and sterile alpha motif (SAM) domain-containing six gene (Anks6) is a candidate for polycystic kidney disease (PKD). Originally identified in the PKD/Mhm(cy/+) rat model of PKD, the disease is caused by a mutation (R823W) in the SAM domain of the encoded protein. Recent studies support the etiological role of the ANKS6 SAM domain in human cystic diseases, but its function in kidney remains unknown. To investigate the role of ANKS6 in cyst formation, we screened an archive of N-ethyl-N-nitrosourea-treated mice and derived a strain carrying a missense mutation (I747N) within the SAM domain of ANKS6. This mutation is only six amino acids away from the PKD-causing mutation (R823W) in cy/+ rats. Evidence of renal cysts in these mice confirmed the crucial role of the SAM domain of ANKS6 in kidney function. Comparative phenotype analysis in cy/+ rats and our Anks6(I747N) mice further showed that the two models display noticeably different PKD phenotypes and that there is a defective interaction between ANKS6 with ANKS3 in the rat and between ANKS6 and BICC1 (bicaudal C homolog 1) in the mouse. Thus, our data demonstrate the importance of ANKS6 for kidney structure integrity and the essential mediating role of its SAM domain in the formation of protein complexes. PMID- 26039632 TI - IL-17A and the Promotion of Neutrophilia in Acute Exacerbation of Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Nontypeable Haemophilus influenzae (NTHi) causes acute exacerbation of chronic obstructive pulmonary disease (AECOPD). IL-17A is central for neutrophilic inflammation and has been linked to COPD pathogenesis. OBJECTIVES: We investigated whether IL-17A is elevated in NTHi-associated AECOPD and required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke. METHODS: Experimental studies with cigarette smoke and NTHi infection were pursued in gene targeted mice and using antibody intervention. IL-17A was measured in sputum collected from patients with COPD at baseline, during, and after AECOPD. MEASUREMENTS AND MAIN RESULTS: Exacerbated airway neutrophilia in cigarette smoke exposed mice infected with NTHi was associated with an induction of IL-17A. In agreement, elevated IL-17A was observed in sputum collected during NTHi associated AECOPD, compared with samples collected before or after the event. NTHi-exacerbated neutrophilia and induction of neutrophil chemoattractants over the background of cigarette smoke, as observed in wild-type mice, was absent in Il17a(-/-) mice and in mice treated with a neutralizing anti-IL-17A antibody. Further studies revealed that IL-1 receptor (R)1 signaling was required for IL 17A-dependent neutrophilia. Moreover, deficiency or therapeutic neutralization of IL-17A did not increase bacterial burden or delay bacterial clearance. CONCLUSIONS: IL-17A is induced during NTHi-associated AECOPD. Functionally, IL 1R1-dependent IL-17A is required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke. Targeting IL-17A in AECOPD may thus be beneficial to reduce neutrophil recruitment to the airways. PMID- 26039633 TI - Nanomedicine for Cancer Immunotherapy: Tracking Cancer-Specific T-Cells in Vivo with Gold Nanoparticles and CT Imaging. AB - Application of immune cell-based therapy in routine clinical practice is challenging due to the poorly understood mechanisms underlying success or failure of treatment. Development of accurate and quantitative imaging techniques for noninvasive cell tracking can provide essential knowledge for elucidating these mechanisms. We designed a novel method for longitudinal and quantitative in vivo cell tracking, based on the superior visualization abilities of classical X-ray computed tomography (CT), combined with state-of-the-art nanotechnology. Herein, T-cells were transduced to express a melanoma-specific T-cell receptor and then labeled with gold nanoparticles (GNPs) as a CT contrast agent. The GNP-labeled T cells were injected intravenously to mice bearing human melanoma xenografts, and whole-body CT imaging allowed examination of the distribution, migration, and kinetics of T-cells. Using CT, we found that transduced T-cells accumulated at the tumor site, as opposed to nontransduced cells. Labeling with gold nanoparticles did not affect T-cell function, as demonstrated both in vitro, by cytokine release and proliferation assays, and in vivo, as tumor regression was observed. Moreover, to validate the accuracy and reliability of the proposed cell tracking technique, T-cells were labeled both with green fluorescent protein for fluorescence imaging, and with GNPs for CT imaging. A remarkable correlation in signal intensity at the tumor site was observed between the two imaging modalities, at all time points examined, providing evidence for the accuracy of our CT cell tracking abilities. This new method for cell tracking with CT offers a valuable tool for research, and more importantly for clinical applications, to study the fate of immune cells in cancer immunotherapy. PMID- 26039631 TI - Circulating primers enhance platelet function and induce resistance to antiplatelet therapy. AB - BACKGROUND: Aspirin and P2Y12 antagonists are antiplatelet compounds that are used clinically in patients with thrombosis. However, some patients are 'resistant' to antiplatelet therapy, which increases their risk of developing acute coronary syndromes. These patients often present with an underlying condition that is associated with altered levels of circulating platelet primers and platelet hyperactivity. Platelet primers cannot stimulate platelet activation, but, in combination with physiologic stimuli, significantly enhance platelet function. OBJECTIVES: To explore the role of platelet primers in resistance to antiplatelet therapy, and to evaluate whether phosphoinositide 3 kinase (PI3K) contributes to this process. METHODS AND RESULTS: We used platelet aggregation, thromboxane A2 production and ex vivo thrombus formation as functional readouts of platelet activity. Platelets were treated with the potent P2Y12 inhibitor AR-C66096, aspirin, or a combination of both, in the presence or absence of the platelet primers insulin-like growth factor-1 (IGF-1) and thrombopoietin (TPO), or the Gz-coupled receptor ligand epinephrine. We found that platelet primers largely overcame the inhibitory effects of antiplatelet compounds on platelet functional responses. IGF-1-mediated and TPO-mediated, but not epinephrine-mediated, enhancements in the presence of antiplatelet drugs were blocked by the PI3K inhibitors wortmannin and LY294002. CONCLUSIONS: These results demonstrate that platelet primers can contribute to antiplatelet resistance. Furthermore, our data demonstrate that there are PI3K-dependent and PI3K-independent mechanisms driving primer-mediated resistance to antiplatelet therapy. PMID- 26039634 TI - The Anterior Insula Tracks Behavioral Entropy during an Interpersonal Competitive Game. AB - In competitive situations, individuals need to adjust their behavioral strategy dynamically in response to their opponent's behavior. In the present study, we investigated the neural basis of how individuals adjust their strategy during a simple, competitive game of matching pennies. We used entropy as a behavioral index of randomness in decision-making, because maximizing randomness is thought to be an optimal strategy in the game, according to game theory. While undergoing functional magnetic resonance imaging (fMRI), subjects played matching pennies with either a human or computer opponent in each block, although in reality they played the game with the same computer algorithm under both conditions. The winning rate of each block was also manipulated. Both the opponent (human or computer), and the winning rate, independently affected subjects' block-wise entropy during the game. The fMRI results revealed that activity in the bilateral anterior insula was positively correlated with subjects' (not opponent's) behavioral entropy during the game, which indicates that during an interpersonal competitive game, the anterior insula tracked how uncertain subjects' behavior was, rather than how uncertain subjects felt their opponent's behavior was. Our results suggest that intuitive or automatic processes based on somatic markers may be a key to optimally adjusting behavioral strategies in competitive situations. PMID- 26039635 TI - Neighborhood deprivation is strongly associated with participation in a population-based health check. AB - BACKGROUND: We sought to examine whether neighborhood deprivation is associated with participation in a large population-based health check. Such analyses will help answer the question whether health checks, which are designed to meet the needs of residents in deprived neighborhoods, may increase participation and prove to be more effective in preventing disease. In Europe, no study has previously looked at the association between neighborhood deprivation and participation in a population-based health check. METHODS: The study population comprised 12,768 persons invited for a health check including screening for ischemic heart disease and lifestyle counseling. The study population was randomly drawn from a population of 179,097 persons living in 73 neighborhoods in Denmark. Data on neighborhood deprivation (percentage with basic education, with low income and not in work) and individual socioeconomic position were retrieved from national administrative registers. Multilevel regression analyses with log links and binary distributions were conducted to obtain relative risks, intraclass correlation coefficients and proportional change in variance. RESULTS: Large differences between neighborhoods existed in both deprivation levels and neighborhood health check participation rate (mean 53%; range 35-84%). In multilevel analyses adjusted for age and sex, higher levels of all three indicators of neighborhood deprivation and a deprivation score were associated with lower participation in a dose-response fashion. Persons living in the most deprived neighborhoods had up to 37% decreased probability of participating compared to those living in the least deprived neighborhoods. Inclusion of individual socioeconomic position in the model attenuated the neighborhood deprivation coefficients, but all except for income deprivation remained statistically significant. CONCLUSION: Neighborhood deprivation was associated with participation in a population-based health check in a dose-response manner, in which increasing neighborhood deprivation was associated with decreasing participation. This suggests the need to develop preventive health checks tailored to deprived neighborhoods. PMID- 26039637 TI - Stem cell, CRISPR and HIV. PMID- 26039636 TI - Three-dimensional patterns from the thin-film drying of amino acid solutions. AB - Experimental atomic force microscopy (AFM) images show the dried-in patterns from amino acid solutions which can be in the form of dots or networks. The three dimensional lattice-gas Kinetic Monte Carlo (KMC) model is applied to simulate the formation of dot-like and network-like particle structures from the evaporating thin films of solutions. A sigmoidal jump in the chemical potential value is implemented to obtain dual-scale structures with the grain size distribution peaking at two distinctive values. The simulated and experimental results are qualitatively comparable. PMID- 26039638 TI - Correction: Modelling Terrestrial and Marine Foraging Habitats in Breeding Audouin's Gulls Larus audouinii: Timing Matters. PMID- 26039639 TI - Strategies for RUN1 Deployment Using RUN2 and REN2 to Manage Grapevine Powdery Mildew Informed by Studies of Race Specificity. AB - The Toll/interleukin-1 receptor nucleotide-binding site leucine-rich repeat gene, "resistance to Uncinula necator 1" (RUN1), from Vitis rotundifolia was recently identified and confirmed to confer resistance to the grapevine powdery mildew fungus Erysiphe necator (syn. U. necator) in transgenic V. vinifera cultivars. However, sporulating powdery mildew colonies and cleistothecia of the heterothallic pathogen have been found on introgression lines containing the RUN1 locus growing in New York (NY). Two E. necator isolates collected from RUN1 vines were designated NY1-131 and NY1-137 and were used in this study to inform a strategy for durable RUN1 deployment. In order to achieve this, fitness parameters of NY1-131 and NY1-137 were quantified relative to powdery mildew isolates collected from V. rotundifolia and V. vinifera on vines containing alleles of the powdery mildew resistance genes RUN1, RUN2, or REN2. The results clearly demonstrate the race specificity of RUN1, RUN2, and REN2 resistance alleles, all of which exhibit programmed cell death (PCD)-mediated resistance. The NY1 isolates investigated were found to have an intermediate virulence on RUN1 vines, although this may be allele specific, while the Musc4 isolate collected from V. rotundifolia was virulent on all RUN1 vines. Another powdery mildew resistance locus, RUN2, was previously mapped in different V. rotundifolia genotypes, and two alleles (RUN2.1 and RUN2.2) were identified. The RUN2.1 allele was found to provide PCD-mediated resistance to both an NY1 isolate and Musc4. Importantly, REN2 vines were resistant to the NY1 isolates and RUN1REN2 vines combining both genes displayed additional resistance. Based on these results, RUN1-mediated resistance in grapevine may be enhanced by pyramiding with RUN2.1 or REN2; however, naturally occurring isolates in North America display some virulence on vines with these resistance genes. The characterization of additional resistance sources is needed to identify resistance gene combinations that will further enhance durability. For the resistance gene combinations currently available, we recommend using complementary management strategies, including fungicide application, to reduce populations of virulent isolates. PMID- 26039521 TI - Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. AB - BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (>=30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.). PMID- 26039640 TI - Vitis rupestris B38 Confers Isolate-Specific Quantitative Resistance to Penetration by Erysiphe necator. AB - Vitis rupestris B38 is a North American grapevine resistant to the major pathogen of cultivated grapevines, Erysiphe necator. Sources of powdery mildew resistance, like V. rotundifolia, are widely used in grape breeding but are already threatened, even before commercialization, by isolates that can reproduce on Run1 and other rotundifolia-derived breeding lines. Thus, complementary sources of resistance are needed to improve resistance durability. The segregation of foliar powdery mildew severity in an F1 family, derived from a cross of V. rupestris B38*V. vinifera 'Chardonnay', was observed in the field over three growing seasons and in potted vines following single-isolate inoculation. A pattern of continuous variation was observed in every instance. Mechanisms of resistance were analyzed on the resistant and susceptible parent by using microscopy to quantify the ability of the pathogen to penetrate and to form a colony on detached leaves. While 'Chardonnay' was susceptible in all tested conditions, V. rupestris B38 resistance was characterized by a reduction in pathogen penetration, with an effect of leaf position and significant differences among powdery mildew isolates. Segregation of the ability of the pathogen to penetrate and form a colony in F1 individuals showed a pattern of quantitative penetration resistance with no delay or restriction on colony formation once penetration has been achieved. Moreover, V. rupestris B38 showed an enhanced penetration resistance to a powdery mildew isolate with the ability to overcome the Run1 gene, making it an interesting resistance source to prolong the durability of this gene. PMID- 26039644 TI - Applying the Beers and STOPP Criteria to Care of the Critically Ill Older Adult. AB - Potentially inappropriate medications impact pharmacotherapy for the older adult in critical care settings. Critical care teams must be aware of the Beers and Screening Tool of Older Person's Prescriptions criteria as resources to identify medications that may cause adverse drug events in the elderly. Although criteria should not replace clinical judgment, awareness of these guidelines may direct critical care teams to minimize dosing and duration of potentially inappropriate medications to improve outcomes in the intensive care unit. PMID- 26039645 TI - Pain assessment and management in critically ill older adults. AB - Older adults comprise approximately 50% of patients admitted to critical care units in the United States. This population is particularly susceptible to multiple morbidities that can be exacerbated by confounding factors like age related safety risks, polypharmacy, poor nutrition, and social isolation. The elderly are particularly vulnerable to health conditions (heart disease, stroke, and diabetes) that put them at greater risk of morbidity and mortality. When an older adult presents to the emergency department with 1 or more of these life altering diagnoses, an admission to the intensive care unit is often inevitable. Pain is one of the most pervasive manifestations exhibited by intensive care unit patients. There are myriad challenges for critical care nurses in caring for patients experiencing pain-inadequate communication (cognitively impaired or intubated patients), addressing the concerns of family members, or gaps in patients' knowledge. The purpose of this article was to discuss the multidimensional nature of pain and identify concepts innate to pain homeostenosis for elderly patients in the critical care setting. Evidence-based strategies, including an interprofessional team approach and best practice recommendations regarding pharmacological and nonpharmacological pain management, are presented. PMID- 26039643 TI - NICHE Recommended Care of the Critically Ill Older Adult. AB - Nurses Improving Care for Healthsystem Elders provides evidence-based best practices for the care of the hospitalized older adult. Older adults are a vulnerable population at greater risk of functional decline during and after hospitalization, safety concerns related to polypharmacy, ineffective pain management, and population-specific physiological responses to medications. Family members of hospitalized older adults are also vulnerable and may experience postintensive care syndrome. This manuscript explores the application of Nurses Improving Care for Healthsystem Elders standards through a case study approach to optimize patient/family-centered care of the critically ill older adult. PMID- 26039642 TI - Elder Issues in the Intensive Care Unit. PMID- 26039646 TI - Stuck Inside a Cloud: Optimizing Sedation to Reduce ICU-Associated Delirium in Geriatric Patients. AB - Elderly population account for more than 50% of all intensive care admissions, and during their stay, up to 87% of them suffer from delirium. There is a large body of evidence demonstrating increased mortality and worse cognitive function for elderly patients who become delirious during their intensive care unit stay. Although the cause of delirium is multifactorial, inappropriate and outdated sedation methods are preventable causes. We review the current best evidences and provide what we believe are the best sedation strategies that are in line with the Society of Critical Care Medicine's Pain, Agitation and Delirium best practice guideline to reduce the incidence of intensive care unit-associated delirium. PMID- 26039647 TI - Enteral nutritional support of the critically ill older adult. AB - Nutrition continues to be a concern for the older adult in the intensive care setting despite widespread knowledge of the benefits of adequate nutrition and existing evidence-based protocols. The incidence of malnutrition in hospitalized patients ranges between 22% and 43% with the highest probability of occurrence, 50% or more, in the intensive care unit patient. The deleterious effects of malnutrition for the critically ill older adult are described with suggested and accepted screening tools for existing or acquired malnutrition. A discussion of early oral and enteral feeding interventions and strategies for overcoming barriers is explored. Enteral feeding complications are delineated, and perceived barriers or risks are disputed. This paper concludes with suggestions for future research and a definitive role for advanced nursing nutrition champions. PMID- 26039648 TI - Severe sepsis in older adults. AB - Severe sepsis may be underrecognized in older adults. Therefore, the purpose of this article is to review special considerations related to early detection of severe sepsis in older adults. Normal organ changes attributed to aging may delay early detection of sepsis at the time when interventions have the greatest potential to improve patient outcomes. Systems are reviewed for changes. For example, the cardiovascular system may have a limited or absent compensatory response to inflammation after an infectious insult, and the febrile response and recruitment of white blood cells may be blunted because of immunosenescence in aging. Three of the 4 hallmark responses (temperature, heart rate, and white blood cell count) to systemic inflammation may be diminished in older adults as compared with younger adults. It is important to consider that older adults may not always manifest the typical systemic inflammatory response syndrome. Atypical signs such as confusion, decreased appetite, and unsteady gait may occur before sepsis related organ failure. Systemic inflammatory response syndrome criteria and a comparison of organ failure criteria were reviewed. Mortality rates in sepsis and severe sepsis remain high and are often complicated by multiple organ failures. As the numbers of older adults increase, early identification and prompt treatment is crucial in improving patient outcomes. PMID- 26039649 TI - The perfect storm: older adults and acute kidney injury. AB - Older adults have a high risk for acute kidney injury (AKI), often necessitating critical care admission. The majority of older adults live with 1 or more chronic conditions requiring multiple medications, and when faced with acute illness increased vulnerability can lead to poor health outcomes. When combined with circumstances that exacerbate chronic conditions, clinicians may witness the perfect storm. Some factors that contribute to AKI risk include the aging kidney, sepsis, polypharmacy, and nephrotoxic medications and contrast media. This paper discusses specific risks and approaches to care for older adults with AKI who are in critical care. PMID- 26039641 TI - Characterization of a Large Panel of Rabbit Monoclonal Antibodies against HIV-1 gp120 and Isolation of Novel Neutralizing Antibodies against the V3 Loop. AB - We recently reported the induction of potent, cross-clade neutralizing antibodies (nAbs) against Human Immunodeficiency Virus type-1 (HIV-1) in rabbits using gp120 based on an M-group consensus sequence. To better characterize these antibodies, 93 hybridomas were generated, which represent the largest panel of monoclonal antibodies (mAbs) ever generated from a vaccinated rabbit. The single most frequently recognized epitope of the isolated mAbs was at the very C-terminal end of the protein (APTKAKRRVVEREKR), followed by the V3 loop. A total of seven anti V3 loop mAbs were isolated, two of which (10A3 and 10A37) exhibited neutralizing activity. In contrast to 10A3 and most other anti-V3 loop nAbs, 10A37 was atypical with its epitope positioned more towards the C-terminal half of the loop. To our knowledge, 10A37 is the most potent and broadly neutralizing anti-V3 loop mAb induced by vaccination. Interestingly, all seven anti-V3 loop mAbs competed with PGT121, suggesting a possibility that early induction of potent anti-V3 loop antibodies could prevent induction of more broadly neutralizing PGT121-like antibodies that target the conserved base of the V3 loop stem. PMID- 26039650 TI - Catheter-Related Bloodstream Infections (CR-BSI) in Geriatric Patients in Intensive Care Units. AB - Catheter-related bloodstream infections (CR-BSIs) are bloodstream infections that, through specific laboratory testing, identify the intravascular catheter as the source of the bloodstream infection. By 2015, the rate of elderly patients 80 years of age and older admitted to the intensive care unit (ICU) will represent 1 in 4 admissions. Approximately 80 000 CR-BSIs occur in ICUs annually, potentially resulting in as many as 56 000 CR-BSIs occurring in the geriatric ICU patient, with 20% of these cases resulting in death. To minimize the occurrence of CR-BSIs in these patients, specific knowledge about the geriatric patient will have to be factored into the ICU health care professional's practice, including the development of a vascular access plan, which includes selection of the correct device and proper insertion of that device along with an evidence-based care and maintenance program. Intensive care unit health care professionals may be at a loss when it comes to navigating the vast array of vascular access medical devices available today. The Healthcare and Technology Synergy framework can assist the ICU health care professional to logically review each vascular access device and select those devices that best meet patient needs. PMID- 26039651 TI - Indicators of abuse in the elderly ICU patient. AB - Elder abuse is a growing problem in the United States. Incidents of physical and sexual abuse, as well as neglect, continue to rise as the population ages. Maltreatment of the elderly is associated with increased morbidity and mortality rate, as well as increased health care costs. Fear, shame, and lack of knowledge contribute to underreporting of elder abuse and put the safety of elders at risk. This paper describes indicators of physical and sexual abuse and neglect in the elderly intensive care unit patient and presents how abuse can be identified in the critical care setting. PMID- 26039652 TI - Elderly trauma. AB - Across the world, the population is aging. Adults 65 years and older make up one of the fastest growing segments of the US population. Trauma is a disease process that affects all age groups. The mortality and morbidity that result from an injury can be influenced by many factors including age, physical condition, and comorbidities. The management of the elderly trauma patient can present some unique challenges. This paper addresses the differences that occur in the management of elderly patient who has been injured. This paper also includes a discussion of how to prevent injury in the elderly. PMID- 26039653 TI - After rescue: the importance of Beers Criteria for medication assessment in older adults. AB - Critical care units serve the vital function of patient rescue through life saving and life-preserving treatments. When an older patient's life hangs in the balance, preserving life takes priority over potential serious adverse drug events. There may be a tendency to consider transfer out of the unit as a less serious event; therefore, less attention is given to medication assessment. Often thought of by nurses as an almost clerical level task, the professional nurse plays a key role in identifying potentially harmful medications or medication combinations. If older patients remain on medications considered to be potentially dangerous, then patients are at risk for adverse drug events. Once the emergent nature of critical care interventions has passed, it is important to judiciously appraise patient status and conduct a medication assessment to discontinue or change the medication regimen to safer alternatives for older adults. Nurses can be instrumental in further research, education, and awareness for practitioners, patients, and families regarding the role of medications for older adults. Beers Criteria are not intended to be a clinical mandate, rather a designated as a clinical guideline with a clinical recommendation to support a provider's clinical judgment. PMID- 26039654 TI - The 3 Ds, and newly acquired cognitive impairment: issues for the ICU nurse. AB - As the United States population ages, patients in intensive care units (ICUs) bring with them the challenges of an aging population. One challenge is the different types of confusions seen in the geriatric patient. Intensive care unit nurses must be knowledgeable about the different types of confusions, be able to differentiate among them, and know the appropriate prevention and management strategies for each type. Failure to do so results in consequences that impact the patient long after the ICU stay had ended. The purpose of this article was to differentiate between the 3 most common confusions among older adults--delirium, dementia, and depression. In addition, this article discusses confusion seen postoperatively and post-ICU stay. PMID- 26039655 TI - Water-Soluble Iron(IV)-Oxo Complexes Supported by Pentapyridine Ligands: Axial Ligand Effects on Hydrogen Atom and Oxygen Atom Transfer Reactivity. AB - We report the photochemical generation and study of a family of water-soluble iron(IV)-oxo complexes supported by pentapyridine PY5Me2-X ligands (PY5Me2 = 2,6 bis(1,1-bis(2-pyridyl)ethyl)pyridine; X = CF3, H, Me, or NMe2), in which the oxidative reactivity of these ferryl species correlates with the electronic properties of the axial pyridine ligand. Synthesis of a systematic series of [Fe(II)(L)(PY5Me2-X)](2+) complexes, where L = CH3CN or H2O, and characterizations by several methods, including X-ray crystallography, cyclic voltammetry, and Mossbauer spectroscopy, show that increasing the electron donating ability of the axial pyridine ligand tracks with less positive Fe(III)/Fe(II) reduction potentials and quadrupole splitting parameters. The Fe(II) precursors are readily oxidized to their Fe(IV)-oxo counterparts using either chemical outer-sphere oxidants such as CAN (ceric ammonium nitrate) or flash-quench photochemical oxidation with [Ru(bpy)3](2+) as a photosensitizer and K2S2O8 as a quencher. The Fe(IV)-oxo complexes are capable of oxidizing the C-H bonds of alkane (4-ethylbenzenesulfonate) and alcohol (benzyl alcohol) substrates via hydrogen atom transfer (HAT) and an olefin (4-styrenesulfonate) substrate by oxygen atom transfer (OAT). The [Fe(IV)(O)(PY5Me2-X)](2+) derivatives with electron-poor axial ligands show faster rates of HAT and OAT compared to their counterparts supported by electron-rich axial donors, but the magnitudes of these differences are relatively modest. PMID- 26039656 TI - Erratum: The saga of XMRV: a virus that infects human cells but is not a human virus. AB - [This corrects the article DOI: 10.1038/emi.2014.25.]. PMID- 26039657 TI - Application of passive sampling for measuring dissolved concentrations of organic contaminants in the water column at three marine superfund sites. AB - Currently, there is an effort under way to encourage remedial project managers at contaminated sites to use passive sampling to collect freely dissolved concentrations (Cfree ) of hydrophobic organic contaminants to improve site assessments. The objective of the present study was to evaluate the use of passive sampling for measuring water column Cfree for several hydrophobic organic contaminants at 3 US Environmental Protection Agency Superfund sites. Sites investigated included New Bedford Harbor (New Bedford, MA, USA), Palos Verdes Shelf (Los Angeles, CA, USA), and Naval Station Newport (Newport, RI, USA); and the passive samplers evaluated were polyethylene, polydimethylsiloxane-coated solid-phase microextraction fibers, semipermeable membrane devices, and polyoxymethylene. In general, the different passive samplers demonstrated good agreement, with Cfree values varying by a factor of 2 to 3. Further, at New Bedford Harbor, where conventional water sample concentrations were also measured (i.e., grab samples), passive sampler-based Cfree values agreed within a factor of 2. These findings suggest that all of the samplers were experiencing and measuring similar Cfree during their respective deployments. Also, at New Bedford Harbor, a strong log-linear, correlative, and predictive relationship was found between polyethylene passive sampler accumulation and lipid-normalized blue mussel bioaccumulation of polychlorinated biphenyls (r(2) = 0.92, p < 0.05). The present study demonstrates the utility of passive sampling for generating scientifically accurate water column Cfree values, which is critical for making informed environmental management decisions at contaminated sediment sites. PMID- 26039658 TI - Adsorption of Polyether Block Copolymers at Silica-Water and Silica-Ethylammonium Nitrate Interfaces. AB - Atomic force microscope (AFM) force curves and images are used to characterize the adsorbed layer structure formed by a series of diblock copolymers with solvophilic poly(ethylene oxide) (PEO) and solvophobic poly(ethyl glycidyl ether) (PEGE) blocks at silica-water and silica-ethylammoniun nitrate (EAN, a room temperature ionic liquid (IL)) interfaces. The diblock polyethers examined are EGE109EO54, EGE113EO115, and EGE104EO178. These experiments reveal how adsorbed layer structure varies as the length of the EO block varies while the EGE block length is kept approximately constant; water is a better solvent for PEO than EAN, so higher curvature structures are found at the interface of silica with water than with EAN. At silica-water interfaces, EGE109EO54 forms a bilayer and EGE113EO115 forms elongated aggregates, while a well-ordered array of spheres is present for EGE104EO178. EGE109EO54 does not adsorb at the silica-EAN interface because the EO chain is too short to compete with the ethylammonium cation for surface adsorption sites. However, EGE113EO115 and EGE104EO178 do adsorb and form a bilayer and elongated aggregates, respectively. PMID- 26039659 TI - Heart failure with preserved left ventricular ejection fraction in patients with acute myocardial infarction. AB - BACKGROUND: The prevalence and clinical outcomes of heart failure with preserved left ventricular ejection fraction after acute myocardial infarction have not been well elucidated. OBJECTIVE: To analyze the prevalence of heart failure with preserved left ventricular ejection fraction in acute myocardial infarction and its association with mortality. METHODS: Patients with acute myocardial infarction (n = 1,474) were prospectively included. Patients without heart failure (Killip score = 1), with heart failure with preserved left ventricular ejection fraction (Killip score > 1 and left ventricle ejection fraction >= 50%), and with systolic dysfunction (Killip score > 1 and left ventricle ejection fraction < 50%) on admission were compared. The association between systolic dysfunction with preserved left ventricular ejection fraction and in-hospital mortality was tested in adjusted models. RESULTS: Among the patients included, 1,256 (85.2%) were admitted without heart failure (72% men, 67 +/- 15 years), 78 (5.3%) with heart failure with preserved left ventricular ejection fraction (59% men, 76 +/- 14 years), and 140 (9.5%) with systolic dysfunction (69% men, 76 +/- 14 years), with mortality rates of 4.3%, 17.9%, and 27.1%, respectively (p < 0.001). Logistic regression (adjusted for sex, age, troponin, diabetes, and body mass index) demonstrated that heart failure with preserved left ventricular ejection fraction (OR 2.91; 95% CI 1.35-6.27; p = 0.006) and systolic dysfunction (OR 5.38; 95% CI 3.10 to 9.32; p < 0.001) were associated with in-hospital mortality. CONCLUSION: One-third of patients with acute myocardial infarction admitted with heart failure had preserved left ventricular ejection fraction. Although this subgroup exhibited more favorable outcomes than those with systolic dysfunction, this condition presented a three-fold higher risk of death than the group without heart failure. Patients with acute myocardial infarction and heart failure with preserved left ventricular ejection fraction encounter elevated short-term risk and require special attention and monitoring during hospitalization. PMID- 26039660 TI - p.Q192R SNP of PON1 seems not to be Associated with Carotid Atherosclerosis Risk Factors in an Asymptomatic and Normolipidemic Brazilian Population Sample. AB - BACKGROUND: Evidences suggest that paraoxonase 1 (PON1) confers important antioxidant and anti-inflammatory properties when associated with high-density lipoprotein (HDL). OBJECTIVE: To investigate the relationships between p.Q192R SNP of PON1, biochemical parameters and carotid atherosclerosis in an asymptomatic, normolipidemic Brazilian population sample. METHODS: We studied 584 volunteers (females n = 326, males n = 258; 19-75 years of age). Total genomic DNA was extracted and SNP was detected in the TaqMan(r) SNP OpenArray(r) genotyping platform (Applied Biosystems, Foster City, CA). Plasma lipoproteins and apolipoproteins were determined and PON1 activity was measured using paraoxon as a substrate. High-resolution beta-mode ultrasonography was used to measure cIMT and the presence of carotid atherosclerotic plaques in a subgroup of individuals (n = 317). RESULTS: The presence of p.192Q was associated with a significant increase in PON1 activity (RR = 12.30 (11.38); RQ = 46.96 (22.35); QQ = 85.35 (24.83) MUmol/min; p < 0.0001), HDL-C (RR= 45 (37); RQ = 62 (39); QQ = 69 (29) mg/dL; p < 0.001) and apo A-I (RR = 140.76 +/- 36.39; RQ = 147.62 +/- 36.92; QQ = 147.49 +/- 36.65 mg/dL; p = 0.019). Stepwise regression analysis revealed that heterozygous and p.192Q carriers influenced by 58% PON1 activity towards paraoxon. The univariate linear regression analysis demonstrated that p.Q192R SNP was not associated with mean cIMT; as a result, in the multiple regression analysis, no variables were selected with 5% significance. In logistic regression analysis, the studied parameters were not associated with the presence of carotid plaques. CONCLUSION: In low-risk individuals, the presence of the p.192Q variant of PON1 is associated with a beneficial plasma lipid profile but not with carotid atherosclerosis. PMID- 26039661 TI - New exercise-dipyridamole combined test for nuclear cardiology in insufficient effort: appropriate diagnostic sensitivity keeping exercise prognosis. AB - BACKGROUND: Myocardial perfusion scintigraphy (MPS) in patients not reaching 85% of the maximum predicted heart rate (MPHR) has reduced sensitivity. OBJECTIVES: In an attempt to maintain diagnostic sensitivity without losing functional exercise data, a new exercise and dipyridamole combined protocol (EDCP) was developed. Our aim was to evaluate the feasibility and safety of this protocol and to compare its diagnostic sensitivity against standard exercise and dipyridamole protocols. METHODS: In patients not reaching a sufficient exercise (SE) test and with no contraindications, 0.56 mg/kg of dipyridamole were IV administered over 1 minute simultaneously with exercise, followed by 99mTc-MIBI injection. RESULTS: Of 155 patients, 41 had MPS with EDCP, 47 had a SE test (>= 85% MPHR) and 67 underwent the dipyridamole alone test (DIP). They all underwent coronary angiography within 3 months. The three stress methods for diagnosis of coronary lesions had their sensitivity compared. For stenosis >= 70%, EDCP yielded 97% sensitivity, SE 90% and DIP 95% (p = 0.43). For lesions >= 50%, the sensitivities were 94%, 88% and 95%, respectively (p = 0.35). Side effects of EDCP were present in only 12% of the patients, significantly less than with DIP (p < 0.001). CONCLUSIONS: The proposed combined protocol is a valid and safe method that yields adequate diagnostic sensitivity, keeping exercise prognostic information in patients unable to reach target heart rate, with fewer side effects than the DIP. PMID- 26039662 TI - Role of MMP-2 and MMP-9 in resistance to drug therapy in patients with resistant hypertension. AB - BACKGROUND: Despite the increased evidence of the important role of matrix metalloproteinases (MMP-9 and MMP-2) in the pathophysiology of hypertension, the profile of these molecules in resistant hypertension (RHTN) remains unknown. OBJECTIVES: To compare the plasma levels of MMP-9 and MMP-2 and of their tissue inhibitors (TIMP-1 and TIMP-2, respectively), as well as their MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios, between patients with controlled RHTN (CRHTN, n=41) and uncontrolled RHTN (UCRHTN, n=35). In addition, the association of those parameters with clinical characteristics, office blood pressure (BP) and arterial stiffness (determined by pulse wave velocity) was evaluate in those subgroups. METHODS: This study included 76 individuals diagnosed with RHTN and submitted to physical examination, electrocardiogram, and laboratory tests to assess biochemical parameters. RESULTS: Similar values of MMP-9, MMP-2, TIMP-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios were found in the UCRHTN and CRHTN subgroups (P>0.05). A significant correlation was found between diastolic BP (DBP) and MMP-9/TIMP-1 ratio (r=0.37; P=0.02) and DPB and MMP-2 (r=-0.40; P=0.02) in the UCRHTN subgroup. On the other hand, no correlation was observed in the CRHTN subgroup. Logistic regression models demonstrated that MMP-9, MMP-2, TIMP 1, TIMP-2 and their ratios were not associated with the lack of BP control. CONCLUSION: These findings suggest that neither MMP-2 nor MMP-9 affect BP control in RHTN subjects. PMID- 26039663 TI - Tramadol alleviates myocardial injury induced by acute hindlimb ischemia reperfusion in rats. AB - BACKGROUND: Organ injury occurs not only during periods of ischemia but also during reperfusion. It is known that ischemia reperfusion (IR) causes both remote organ and local injuries. OBJECTIVE: This study evaluated the effects of tramadol on the heart as a remote organ after acute hindlimb IR. METHODS: Thirty healthy mature male Wistar rats were allocated randomly into three groups: Group I (sham), Group II (IR), and Group III (IR + tramadol). Ischemia was induced in anesthetized rats by left femoral artery clamping for 3 h, followed by 3 h of reperfusion. Tramadol (20 mg/kg, intravenous) was administered immediately prior to reperfusion. At the end of the reperfusion, animals were euthanized, and hearts were harvested for histological and biochemical examination. RESULTS: The levels of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were higher in Groups I and III than those in Group II (p < 0.05). In comparison with other groups, tissue malondialdehyde (MDA) levels in Group II were significantly increased (p < 0.05), and this increase was prevented by tramadol. Histopathological changes, including microscopic bleeding, edema, neutrophil infiltration, and necrosis, were scored. The total injuryscore in Group III was significantly decreased (p < 0.05) compared with Group II. CONCLUSION: From the histological and biochemical perspectives, treatment with tramadol alleviated the myocardial injuries induced by skeletal muscle IR in this experimental model. PMID- 26039664 TI - Comparison of ACUITY and CRUSADE Scores in Predicting Major Bleeding during Acute Coronary Syndrome. AB - BACKGROUND: The ACUITY and CRUSADE scores are validated models for prediction of major bleeding events in acute coronary syndrome (ACS). However, the comparative performances of these scores are not known. OBJECTIVE: To compare the accuracy of ACUITY and CRUSADE in predicting major bleeding events during ACS. METHODS: This study included 519 patients consecutively admitted for unstable angina, non-ST elevation or ST-elevation myocardial infarction. The scores were calculated based on admission data. We considered major bleeding events during hospitalization and not related to cardiac surgery, according to the Bleeding Academic Research Consortium (BARC) criteria (type 3 or 5: hemodynamic instability, need for transfusion, drop in hemoglobin >= 3 g, and intracranial, intraocular or fatal bleeding). RESULTS: Major bleeding was observed in 31 patients (23 caused by femoral puncture, 5 digestive, 3 in other sites), an incidence of 6%. While both scores were associated with bleeding, ACUITY demonstrated better C-statistics (0.73, 95% CI = 0.63 - 0.82) as compared with CRUSADE (0.62, 95% CI = 0.53 - 0.71; p = 0.04). The best performance of ACUITY was also reflected by a net reclassification improvement of + 0.19 (p = 0.02) over CRUSADE's definition of low or high risk. Exploratory analysis suggested that the presence of the variables 'age' and 'type of ACS' in ACUITY was the main reason for its superiority. CONCLUSION: The ACUITY Score is a better predictor of major bleeding when compared with the CRUSADE Score in patients hospitalized for ACS. PMID- 26039665 TI - Rationale for targeting the ErbB family of receptors in patients with advanced squamous cell carcinoma of the lung. AB - Squamous cell carcinoma (SCC) of the lung represents around 30% of all non-small cell lung cancers. Treatment options for nonsquamous histology have increased in recent years following the development of pemetrexed chemotherapy and the identification of activating EGFR mutations and ALK rearrangements as targets for effective noncytotoxic agents. By contrast, until recently the development of new therapies for SCC has lagged behind. However, the identification of important genetic events driving SCC, including a greater understanding of the role of the ErbB receptor family in SCC pathogenesis, as well as recent immunotherapy advances, have led to new treatment options for SCC. PMID- 26039666 TI - 'Are We Not Human?' Stories of Stigma, Disability and HIV from Lusaka, Zambia and Their Implications for Access to Health Services. AB - BACKGROUND: The advent of anti-retroviral therapy (ART) in Southern Africa holds the promise of shifting the experience of HIV toward that of a manageable chronic condition. However, this potential can only be realized when persons living with HIV are able to access services without barriers, which can include stigma. Our qualitative study explored experiences of persons living with disabilities (PWD) in Lusaka, Zambia who became HIV-positive (PWD/HIV+). METHODS AND FINDINGS: We conducted interviews with 32 participants (21 PWD/HIV+ and 11 key informants working in the fields of HIV and/or disability). Inductive thematic analysis of interview transcripts was informed by narrative theory. Participants' accounts highlighted the central role of stigma experienced by PWD/HIV+, with stigmatizing attitudes closely linked to prevailing societal assumptions that PWD are asexual. Seeking diagnostic and treatment services for HIV was perceived as evidence of PWD being sexually active. Participants recounted that for PWD/HIV+, stigma was enacted in a variety of settings, including the queue for health services, their interactions with healthcare providers, and within their communities. Stigmatizing accounts told about PWD/HIV+ were described as having important consequences. Not only did participants recount stories of internalized stigma (with its damaging effects on self-perception), but also that negative experiences resulted in some PWD preferring to "die quietly at home" rather than being subjected to the stigmatizing gaze of others when attempting to access life preserving ART. Participants recounted how experiences of stigma also affected their willingness to continue ART, their willingness to disclose their HIV status to others, as well as their social relations. However, participants also offered counter-stories, actively resisting stigmatizing accounts and portraying themselves as resilient and resourceful social actors. CONCLUSIONS: The study highlights a significant barrier to healthcare experienced by PWD/HIV+, with important implications for the future design and equitable delivery of HIV services in Zambia. Stigma importantly affects the abilities of PWD/HIV+ to manage their health conditions. PMID- 26039667 TI - [Ten years of destructive eyeball surgery in Lome]. AB - INTRODUCTION: Destructive surgery of the eyeball comprises radical procedures - evisceration, enucleation, and exenteration - with various indications. The purpose of this study was to determine the features of these procedures in Lome. PATIENTS AND METHODS: We conducted a retrospective study reviewing records for all patients undergoing these procedures in 3 ophthalmic centers in Lome in the decade from 2002 through 2011. RESULTS: Of 6240 eye operations, 76 involved one of these three procedures, for a frequency of 1.2%. Patients' mean age was 40.1 +/- 26.9 years (range: 1 day to 91 years). The sex ratio (of men to women) was 1.2. The principal indications were staphyloma (38%), ocular and orbital tumors (30%), and phthisis bulbi (24%). Retinoblastoma was the leading type of ocular/orbital tumor (52%). Local anesthesia was performed in 64% of cases, and general anesthesia in 36%. Evisceration was practiced in 67% of cases, enucleation in 24%, and exenteration in 9%. An ocular prosthesis was placed in 46%. CONCLUSION: Staphyloma was the leading indication for destructive surgery. Given the damage of this type of procedure, primary prevention is important, including early and adequate management of ocular conditions. PMID- 26039669 TI - Surface Mn(II) oxidation actuated by a multicopper oxidase in a soil bacterium leads to the formation of manganese oxide minerals. AB - In this manuscript, we report that a bacterial multicopper oxidase (MCO266) catalyzes Mn(II) oxidation on the cell surface, resulting in the surface deposition of Mn(III) and Mn(IV) oxides and the gradual formation of bulky oxide aggregates. These aggregates serve as nucleation centers for the formation of Mn oxide micronodules and Mn-rich sediments. A soil-borne Escherichia coli with high Mn(II)-oxidizing activity formed Mn(III)/Mn(IV) oxide deposit layers and aggregates under laboratory culture conditions. We engineered MCO266 onto the cell surfaces of both an activity-negative recipient and wild-type strains. The results confirmed that MCO266 governs Mn(II) oxidation and initiates the formation of deposits and aggregates. By contrast, a cell-free substrate, heat killed strains, and intracellularly expressed or purified MCO266 failed to catalyze Mn(II) oxidation. However, purified MCO266 exhibited Mn(II)-oxidizing activity when combined with cell outer membrane component (COMC) fractions in vitro. We demonstrated that Mn(II) oxidation and aggregate formation occurred through an oxygen-dependent biotic transformation process that requires a certain minimum Mn(II) concentration. We propose an approximate electron transfer pathway in which MCO266 transfers only one electron to convert Mn(II) to Mn(III) and then cooperates with other COMC electron transporters to transfer the other electron required to oxidize Mn(III) to Mn(IV). PMID- 26039671 TI - Discovery of Multitarget Antivirals Acting on Both the Dengue Virus NS5-NS3 Interaction and the Host Src/Fyn Kinases. AB - This study describes the discovery of novel dengue virus inhibitors targeting both a crucial viral protein-protein interaction and an essential host cell factor as a strategy to reduce the emergence of drug resistance. Starting from known c-Src inhibitors, a virtual screening was performed to identify molecules able to interact with a recently discovered allosteric pocket on the dengue virus NS5 polymerase. The selection of cheap-to-produce scaffolds and the exploration of the biologically relevant chemical space around them suggested promising candidates for chemical synthesis. A series of purines emerged as the most interesting candidates able to inhibit virus replication at low micromolar concentrations with no significant toxicity to the host cell. Among the identified antivirals, compound 16i proved to be 10 times more potent than ribavirin, showed a better selectivity index and represents the first-in-class DENV-NS5 allosteric inhibitor able to target both the virus NS5-NS3 interaction and the host kinases c-Src/Fyn. PMID- 26039672 TI - Simple, Rapid, and Selective Isolation of 2S Albumins from Allergenic Seeds and Nuts. AB - The 2S albumins belong to the group of seed storage proteins present in different seeds and nuts. Due to their pronounced allergenic potential, which is often associated with severe allergic reactions, this protein family is of special interest in the field of allergen research. Here we present a simple, rapid, and selective method for the purification of 2S albumins directly from allergenic seeds and nuts. We systematically optimized the parameters "buffer system", "extraction temperature", "buffer molarity", and "pH " and were able to achieve 2S albumin purities of about 99% without further purification and demonstrate transferability of this method to nine different allergenic food matrices. Compared to conventional isolation routines, significant reduction of hands-on time and required laboratory equipment is achieved, but nonetheless higher protein yields are obtained. The presented method allows for the rapid purification of different 2S albumins including the corresponding isoforms from natural material. PMID- 26039673 TI - Correction: tRNAGlu Increases the Affinity of Glutamyl-tRNA Synthetase for Its Inhibitor Glutamyl-Sulfamoyl-Adenosine, an Analogue of the Aminoacylation Reaction Intermediate Glutamyl-AMP: Mechanistic and Evolutionary Implications. PMID- 26039675 TI - Trends in global approvals of biotech crops (1992-2014). AB - With the increasing number of genetically modified (GM) events, traits, and crops that are developed to benefit the global population, approval of these technologies for food, feed, cultivation and import in each country may vary depending on needs, demand and trade interest. ISAAA established a GMO Approval Database to document global approvals of biotech crops. GM event name, crops, traits, developer, year of approval for cultivation, food/feed, import, and relevant dossiers were sourced from credible government regulatory websites and biosafety clearinghouses. This paper investigates the trends in GM approvals for food, feed and cultivation based on the number of approving countries, GM crops, events, and traits in the last 23 y (1992-2014), rationale for approval, factors influencing approvals, and their implications in GM crop adoption. Results show that in 2014, there was an accumulative increase in the number of countries granting approvals at 29 (79% developing countries) for commercial cultivation and 31 (70% developing countries) for food and 19 (80% developing developing) for feed; 2012 had the highest number of approving countries and cultivation approvals; 2011 had the highest number of country approvals for feed, and 2014 for food approvals. Herbicide tolerance trait had the highest events approved, followed by insect tolerance traits. Approvals for food product quality increased in the second decade. Maize had the highest number of events approved (single and stacked traits), and stacked traits product gradually increased which is already 30% of the total trait approvals. These results may indicate understanding and acceptance of countries to enhance regulatory capability to be able to benefit from GM crop commercialization. Hence, the paper provided information on the trends on the growth of the GM crop industry in the last 23 y which may be vital in predicting future GM crops and traits. PMID- 26039676 TI - Structural Order of Water Molecules around Hydrophobic Solutes: Length-Scale Dependence and Solute-Solvent Coupling. AB - It has been suggested that the structure and thermodynamics of the water molecules in the hydration layer of simple hydrophobic solutes undergo an order disorder transition around a nanometer length-scale of the solute size. Using extensive atomistic molecular dynamics (MD) and replica exchange molecular dynamics (REMD) simulation studies, we have probed this order-disorder transition around model hydrophobic solutes of varying size and shape (spherical, planar, and linear), as well as flexible hydrophobic homopolymer chains (n-alkanes), where the conformational fluctuations are likely to create both spatial and temporal heterogeneity on the solvent accessible surface. We have explored the structural response of the water molecules in the hydration shell due to the local variations of the length-scale (or curvature) upon hydrophobic collapse and/or local conformational changes of these polymers. We have shown that the tetrahedral order of the water molecules in the hydration shell is practically independent of the polymer size in the extended state of the polymer due to the availability of a subnanometer cross-sectional length-scale, allowing the water molecules to form hydrogen bonds around the polymer chain. Beyond a certain length of the polymer chains, the collapsed states (associated with larger solute length-scale) start to induce disorder in the surface water molecules. We demonstrate that the local structure (both local number density and tetrahedral order) of the hydration layer is dynamically coupled to the local topology of the polymer. Thus, we envisage that in a flexible (bio)polymer, the hydration shell properties will be sensitive to the local conformational state of the molecule (both spatially and temporally), and the overall observed water structure and dynamics will be dependent on the topological/chemical heterogeneity, and the time-scale of fluctuations in the local curvature (length-scale) of the solvent accessible surface. Moreover, we have demonstrated the direct coupling between the local density fluctuations of water and the local hydrophobic collapse of the polymer. For the extended state of the polymer, the local solvent density fluctuation is practically independent of the solute coordinate (length-scale), and the hydrophobic collapse of the polymer is prompted by a "local dewetting" process induced by these fluctuations. PMID- 26039674 TI - Comparative genomic analysis of Brucella abortus vaccine strain 104M reveals a set of candidate genes associated with its virulence attenuation. AB - The Brucella abortus strain 104M, a spontaneously attenuated strain, has been used as a vaccine strain in humans against brucellosis for 6 decades in China. Despite many studies, the molecular mechanisms that cause the attenuation are still unclear. Here, we determined the whole-genome sequence of 104M and conducted a comprehensive comparative analysis against the whole genome sequences of the virulent strain, A13334, and other reference strains. This analysis revealed a highly similar genome structure between 104M and A13334. The further comparative genomic analysis between 104M and A13334 revealed a set of genes missing in 104M. Some of these genes were identified to be directly or indirectly associated with virulence. Similarly, a set of mutations in the virulence-related genes was also identified, which may be related to virulence alteration. This study provides a set of candidate genes associated with virulence attenuation in B.abortus vaccine strain 104M. PMID- 26039677 TI - Tetrahydro-1,3-oxazepines via Intramolecular Amination of Cyclopropylmethyl Cation. AB - An efficient synthesis of tetrahydro-1,3-oxazepines was developed involving the regioselective intramolecular amination of cyclopropylmethyl cation. The cation was generated by the abstraction of one imidate group in bis-imidate bearing a carbocation-stabilizing substituent. Using 1,1,2,3-tetrasubstituted cyclopropane substrates, highly diastereoselective intramolecular amination to trans tetrahydro-1,3-oxazepines was achieved. The resulting tetrahydro-1,3-oxazepines were transformed to the homoallylamine derivatives in high yields. PMID- 26039678 TI - Budesonide for induction of remission in Crohn's disease. AB - BACKGROUND: Corticosteroids are commonly used for the induction of remission in Crohn's disease. However, traditional corticosteroids can cause significant adverse events. Budesonide is an alternative glucocorticoid with limited systemic bioavailability. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of oral budesonide for the induction of remission in Crohn's disease. SEARCH METHODS: The following electronic databases were searched up to June 2014: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane IBD/FBD Group Specialised Trial Register, and ClinicalTrials.gov. Reference lists of articles, as well as conference proceedings were manually searched. SELECTION CRITERIA: Randomised controlled trials comparing budesonide to a placebo or active comparator were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two independent investigators reviewed studies for eligibility, extracted the data and assessed study quality. Methodological quality was assessed using the Cochrane risk of bias tool The overall quality of the evidence supporting the outcomes was evaluated using the GRADE criteria. Meta-analysis was performed using RevMan 5.3.5 software. The primary outcome was induction of remission (defined by a Crohn's disease activity index (CDAI) < 150) by week 8 to 16 of treatment. Secondary outcomes included: time to remission, mean change in CDAI, clinical, histological or endoscopic improvement, improvement in quality of life, adverse events and early withdrawal. We calculated the relative risk (RR) and corresponding 95% confidence intervals (CIs) for each dichotomous outcome and the mean difference and corresponding 95% CI for each continuous outcome. Data were analyzed on an intention-to-treat basis. A random-effects model was used for the pooled analyses. The overall quality of the evidence supporting the primary outcomes and selected secondary outcomes was evaluated using the GRADE criteria. MAIN RESULTS: Fourteen studies (1805 patients) were included: Nine (779 patients) compared budesonide to conventional corticosteroids, three (535 patients) were placebo-controlled, and two (491 patients) compared budesonide to mesalamine. Ten studies were judged to be at low risk of bias. Three studies were judged to be at high risk of bias due to open label design. One study was judged to be at high risk of bias due to selective reporting. After eight weeks of treatment, 9 mg budesonide was significantly more effective than placebo for induction of clinical remission. Forty-seven per cent (115/246) of budesonide patients achieved remission at 8 weeks compared to 22% (29/133) of placebo patients (RR 1.93, 95% CI 1.37 to 2.73; 3 studies, 379 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to sparse data (144 events). Budesonide was significantly less effective than conventional steroids for induction of remission at eight weeks. Fifty-two per cent of budesonide patients achieved remission at week 8 compared to 61% of patients who received conventional steroids (RR 0.85, 95% CI 0.75 to 0.97; 8 studies, 750 patients). A GRADE analysis indicated that the overall quality of the evidence for this outcome was moderate due to risk of bias. Budesonide was significantly less effective than conventional steroids among patients with severe disease (CDAI > 300) (RR 0.52, 95% CI 0.28 to 0.95). Studies comparing budesonide to mesalamine were not pooled due to heterogeneity (I(2) = 81%). One study (n = 182) found budesonide to be superior to mesalamine for induction of remission at 8 weeks. Sixty-eight per cent (63/93) of budesonide patients were in remission at 8 weeks compared to 42% (37/89) of mesalamine patients (RR 1.63, 95% CI 1.23 to 2.16). The other study found no statistically significant difference in remission rates at eight weeks. Sixty-nine per cent (107/154) of budesonide patients were in remission at 8 weeks compared to 62% (132/242) of mesalamine patients (RR 1.12, 95% CI 0.95 to 1.32). Fewer adverse events occurred in those treated with budesonide compared to conventional steroids (RR 0.64, 95% CI 0.54 to 0.76) and budesonide was better than conventional steroids in preserving adrenal function (RR for abnormal ACTH test 0.65, 95% CI 0.55 to 0.78). AUTHORS' CONCLUSIONS: Budesonide is more effective than placebo for induction of remission in Crohn's disease. Although short-term efficacy with budesonide is less than with conventional steroids, particularly in those with severe disease or more extensive colonic involvement, the likelihood of adverse events and adrenal suppression with budesonide is lower. The current evidence does not allow for a firm conclusion on the relative efficacy of budesonide compared to 5-ASA products. PMID- 26039679 TI - Essential and toxic elements in honeys from a region of central Italy. AB - Levels of iron (Fe), manganese (Mn), chromium (Cr), copper (Cu), zinc (Zn), mercury (Hg), cadmium (Cd), and lead (Pb) in several types of honey produced in a region of Central Italy were determined by atomic absorption spectroscopy (AAS). The degree of humidity, sugar content, pH, free acidity, combined acidity (lactones), and total acidity were also measured. These elements were found to be present in honey in various proportions depending upon (1) the area foraged by bees, (2) flower type visited for collection of nectar, and (3) quality of water in the vicinity of the hive. Strong positive correlations occurred between Pb and Hg, Pb and Cd, Pb and Fe, Pb and Cr, Hg and Cd, and Hg and Fe. The honey products synthesized in Central Italy were of good quality, but not completely free of heavy metal contamination. Compared with established recommended daily intakes, heavy metals or trace element intoxication following honey consumption in Italy was found not to be a concern for human health. PMID- 26039680 TI - NFE2L2 Gene Variants and Arsenic Susceptibility: A Lymphoblastoid Model. AB - Arsenic (As) exposure is a major risk for several types of cancer and metabolic diseases such as diabetes. The transcription factor nuclear factor erythroid 2 related factor (Nrf2) is a key mediator in the cellular defense against As induced adverse effects. The -653G/A and -617C/A gene variants modulate expression levels of the Nrf2 coding gene (NFE2L2) and are postulated to be associated with several illnesses. In this study the functional effect of these polymorphisms was investigated in the cellular sensitivity to As-mediated effects. Using quantitative real-time polymerase chain reaction (qRT-PCR) the basal levels of NFE2L2 mRNA and the induced levels of NFE2L2 and its target gene NQO1 were measured in lymphoblastoid cells carrying different genotypes for 653G/A and -617C/A polymorphisms following As exposure. The effects of different NFE2L2 gene genotypes on cell proliferation were also explored after chronic metal exposure. A tendency toward reduction in basal levels of NFE2L2 mRNA was noted in the heterozygous (GA/CA) and risk homozygous (AA/AA) genotypes of both polymorphisms in immortalized lymphoblastoid cells. Although the expression of NFE2L2 and NQO1 after acute acute iAs exposure was not markedly influenced by 653G/A and -617C/A genotype, it was found that these single-nucleotide polymorphisms (SNPs) were correlated with a differential sensitivity to chronic exposure to the metalloid. Further studies are needed to completely understand the role of -653G/A and -617C/A SNPs in regulation of the NFE2L2 gene. PMID- 26039682 TI - Comparing acute toxicity of gunshot particles, from firing conventional and lead free ammunition, in pulmonary epithelial cell cultures. AB - Numerous studies demonstrated that the use of lead (Pb)-containing ammunition is associated with mainly chronic health problems and also is a burden on the environment and wildlife. Recently, a number of reports showed evidence of undesirable acute health effects related to the use of newly developed Pb-free small-caliber ammunition. In this study, particles from leaded and Pb-free ammunition were collected in liquid collection medium, in a highly controlled chamber, while firing a pistol (9 mm) or a rifle (7.62 * 51 mm). The emitted particles were typically smaller than 4 MUm, with the great majority in even smaller size ranges, as shown by gravimetrical analysis and a multistage impactor. Chemical analysis revealed significant differences in content and concentration of several metals in the particles. After administration of the liquids to alveolar and bronchial in vitro cell systems, particles were taken up by the cells; the Pb-free particles displayed higher cytotoxicity (EC50 = 2 MUg/cm(2)) than particles from Pb ammunition. High correlation factors (>0.9) were found between cell death and content of copper and zinc. Particles from both Pb-containing and Pb-free ammunition were able to induce oxidative stress and the proinflammatory marker interleukin (IL)-8 in both in vitro systems. These results support previous findings that indicate an association between gunshot emissions and metal fume fever. This study demonstrates the usefulness of combining chemical data with biological in vitro responses in assessing acute toxicological effects from emissions from firing both Pb and Pb-free ammunition. PMID- 26039681 TI - Prenatal exposure to the phytoestrogen daidzein resulted in persistent changes in ovarian surface epithelial cell height, folliculogenesis, and estrus phase length in adult Sprague-Dawley rat offspring. AB - Daidzein (DZ), an isoflavone with the potential to interfere with estrogen signaling, is found in soy products, which have gained popularity due to purported beneficial effects on the cardiovascular and skeletal systems and potential antineoplastic properties. However, the ingestion of phytoestrogens has been associated with impaired reproductive function in many species. The aim of this study was to determine the long-term effects on the ovaries of rat offspring exposed to DZ or ethinyl estradiol (EE) during prenatal development. Gravid rats were administered either vehicle or 5 or 60 mg DZ/kg body weight/d or 0.002 mg 17 alpha EE /kg body weight/d on gestational days 6-21. Ovarian-related endpoints were investigated during adulthood in female offspring. The mean cell height of the ovarian surface epithelium was significantly reduced in all treated groups. Alterations in folliculogenesis included increased follicular atresia, a reduction in secondary and tertiary follicle numbers, and cyst formation. An elevated prevalence of a slightly prolonged estrus phase was also observed. The morphological changes to the ovarian surface epithelium are consistent with an antiproliferative effect, while ovarian folliculogenesis was adversely affected. The effects of the high dose DZ were similar to those observed with 17-alpha EE. PMID- 26039683 TI - Corticosteroid Phobia Among Pharmacists Regarding Atopic Dermatitis in Children: A National French Survey. AB - Fear of corticosteroid use among patients and parents of children with atopic dermatitis (AD) may be increased by professional caregiver's mistrust to corticosteroids and a lack of consistency in information provision. This study used a French national survey to assess mistrust among pharmacists of the use of topical steroids for treatment of AD in children. From all pharmacies in France, a random sample of 500 (approximately 2%) was selected to receive a postal survey comprising a standardized questionnaire of 50 items exploring trust, knowledge, beliefs and practices related to the use of topical steroids for children with AD. The main outcome was self-assessment of pharmacists' confidence in topical steroids on a 0-10 visual analogue scale. The mean confidence was 4.46 (95% confidence interval 4.11-4.82). This study highlights that pharmacists have only moderate confidence in topical steroids. This lack of trust may have a high impact on maintaining fear of corticosteroids in parents and patients. PMID- 26039685 TI - [Tuberculosis of the female genital tract discovered during work-ups for infertility: the first two cases at the Fianarantsoa Teaching Hospital in Madagascar]. AB - The rarity of genital tuberculosis and the non-specificity of its manifestations lead to delayed diagnosis and the need to treat this disease at an advanced stage. We report two cases observed and treated at the Fianarantsoa Teaching Hospital: two young women (aged 22 and 33 years) discovered during work-ups for primary infertility and secondary amenorrhea. The diagnosis was established by histological examination of granulomatous tissue with caseous necrosis, pathognomonic for tuberculous. Isolation of mycobacterium by inoculation on Lowenstein-Jensen medium and culture are not available in Fianarantsoa. Chemotherapy against tuberculosis is most often effective for the disease, but fertility is definitely compromised, even though in vitro fertilization is possible in some cases. PMID- 26039684 TI - A repeat unit of Vibrio diarrheal T3S effector subverts cytoskeletal actin homeostasis via binding to interstrand region of actin filaments. AB - A novel bacterial type III secretion effector, VopV, from the enteric pathogen Vibrio parahaemolyticus has been identified as a key factor in pathogenicity due to its interaction with cytoskeletal actin. One of the repeat units in the long repetitive region of VopV, named VopV(rep1), functions as an actin-binding module. Despite its importance in pathogenesis, the manner in which the effector binds to actin and the subsequent effects on actin dynamics remain unclear. Here, we report the molecular basis of the VopV(rep1)/actin interaction. VopV(rep1) exists as an unstructured protein in solution but potently and specifically binds filamentous actin (F-actin) and not globular actin (G-actin). The F actin/VopV(rep1) complex was directly visualized at 9.6-A resolution using electron cryomicroscopy (cryoEM) and helical image reconstitution. The density map revealed the binding site of VopV(rep1) at the interface between two actin strands, which is close to the binding site of the bicyclic heptapeptide toxin phalloidin. Consistent with this observation, VopV(rep1) alone prevented the depolymerization of F-actin. Overall, VopVr(ep1) demonstrated unique characteristics in comparison to known actin-binding proteins, but was relatively similar to phalloidin. The phalloidin-like behavior, targeting the interstrand region of actin filaments to stabilize the filament structure, likely contributes to the pathogenicity of V. parahaemolyticus. PMID- 26039686 TI - Electrical impedance tomography of electrolysis. AB - The primary goal of this study is to explore the hypothesis that changes in pH during electrolysis can be detected with Electrical Impedance Tomography (EIT). The study has relevance to real time control of minimally invasive surgery with electrolytic ablation. To investigate the hypothesis, we compare EIT reconstructed images to optical images acquired using pH-sensitive dyes embedded in a physiological saline agar gel phantom treated with electrolysis. We further demonstrate the biological relevance of our work using a bacterial E.Coli model, grown on the phantom. The results demonstrate the ability of EIT to image pH changes in a physiological saline phantom and show that these changes correlate with cell death in the E.coli model. The results are promising, and invite further experimental explorations. PMID- 26039687 TI - Six Month In Situ High-Resolution Carbonate Chemistry and Temperature Study on a Coral Reef Flat Reveals Asynchronous pH and Temperature Anomalies. AB - Understanding the temporal dynamics of present thermal and pH exposure on coral reefs is crucial for elucidating reef response to future global change. Diel ranges in temperature and carbonate chemistry parameters coupled with seasonal changes in the mean conditions define periods during the year when a reef habitat is exposed to anomalous thermal and/or pH exposure. Anomalous conditions are defined as values that exceed an empirically estimated threshold for each variable. We present a 200-day time series from June through December 2010 of carbonate chemistry and environmental parameters measured on the Heron Island reef flat. These data reveal that aragonite saturation state, pH, and pCO2 were primarily modulated by biologically-driven changes in dissolved organic carbon (DIC) and total alkalinity (TA), rather than salinity and temperature. The largest diel temperature ranges occurred in austral spring, in October (1.5 - 6.6 degrees C) and lowest diel ranges (0.9 - 3.2 degrees C) were observed in July, at the peak of winter. We observed large diel total pH variability, with a maximum range of 7.7 - 8.5 total pH units, with minimum diel average pH values occurring during spring and maximum during fall. As with many other reefs, the nighttime pH minima on the reef flat were far lower than pH values predicted for the open ocean by 2100. DIC and TA both increased from June (end of Fall) to December (end of Spring). Using this high-resolution dataset, we developed exposure metrics of pH and temperature individually for intensity, duration, and severity of low pH and high temperature events, as well as a combined metric. Periods of anomalous temperature and pH exposure were asynchronous on the Heron Island reef flat, which underlines the importance of understanding the dynamics of co-occurrence of multiple stressors on coastal ecosystems. PMID- 26039688 TI - Sexual dysfunction during treatment of major depressive disorder with vilazodone, citalopram, or placebo: results from a phase IV clinical trial. AB - Sexual dysfunction commonly occurs with major depressive disorder (MDD). Vilazodone, a selective serotonin reuptake inhibitor and 5-HT1A receptor partial agonist antidepressant approved for the treatment of MDD in adults, was evaluated to determine its effects on sexual function. The primary study was a double blind, randomized, controlled trial comparing vilazodone 20 and 40 mg/day with placebo; citalopram 40 mg/day was an active control (NCT01473381; http://www.clinicaltrials.gov). Post-hoc analyses evaluated change from baseline to week 10 on the Changes in Sexual Functioning Questionnaire (CSFQ); no inferential statistics were performed. CSFQ scores increased for women [1.2 (citalopram) to 3.0 (vilazodone 40 mg)] and men [1.2 (vilazodone 40 mg) to 3.5 (placebo)] in all treatment groups. Greater changes in CSFQ scores were seen in responders [women: 2.33 (citalopram) to 5.06 (vilazodone 40 mg); men: 2.26 (vilazodone 40 mg) to 4.35 (placebo)] versus nonresponders. CSFQ change from baseline was small for patients with normal baseline sexual function; in patients with baseline sexual dysfunction, CSFQ scores improved across groups [women: 2.35 (citalopram) to 4.52 (vilazodone 40 mg); men 2.83 (vilazodone 40 mg) to 6.43 (placebo)]. Across treatment groups, baseline sexual function improved in women and men, MDD responders, and patients with baseline sexual dysfunction. PMID- 26039689 TI - Trends in Transmission of Drug Resistance and Prevalence of Non-B Subtypes in Patients with Acute or Recent HIV-1 Infection in Barcelona in the Last 16 Years (1997-2012). AB - OBJECTIVES: To evaluate the prevalence of transmitted drug resistance (TDR) and non-B subtypes in patients with acute/recent HIV-1 infection in Barcelona during the period 1997-2012. METHODS: Patients from the "Hospital Clinic Primary HIV-1 Infection Cohort" with a genotyping test performed within 180 days of infection were included. The 2009 WHO List of Mutations for Surveillance of Transmitted HIV 1 Drug Resistance was used for estimating the prevalence of TDR and phylogenetic analysis for subtype determination. RESULTS: 189 patients with acute/recent HIV-1 infection were analyzed in 4 time periods (1997-2000, n=28; 2001-4, n=42; 2005-8, n=55 and 2009-12, n=64). The proportion of patients with acute/recent HIV-1 infection with respect to the total of newly HIV-diagnosed patients in our center increased over the time and was 2.18%, 3.82%, 4.15% and 4.55% for the 4 periods, respectively (p=0.005). The global prevalence of TDR was 9%, or 17.9%, 9.5%, 3.6% and 9.4% by study period (p=0.2). The increase in the last period was driven by protease-inhibitor and nucleoside-reverse-transcriptase-inhibitor resistance mutations while non-nucleoside-reverse-transcriptase inhibitor TDR and TDR of more than one family decreased. The overall prevalence of non-B subtypes was 11.1%, or 0%, 4.8%, 9.1% and 20.3 by study period (p=0.01). B/F recombinants, B/G recombinants and subtype F emerged in the last period. We also noticed an increase in the number of immigrant patients (p=0.052). The proportion of men-who have-sex-with-men (MSM) among patients with acute/recent HIV-1 infection increased over the time (p=0.04). CONCLUSIONS: The overall prevalence of TDR in patients with acute/recent HIV-1 infection in Barcelona was 9%, and it has stayed relatively stable in recent years. Non-B subtypes and immigrants proportions progressively increased. PMID- 26039690 TI - Association of mtDNA M/N haplogroups with systemic lupus erythematosus: a case control study of Han Chinese women. AB - To investigate whether mitochondrial DNA haplogroups M or N are related to occurrence or manifestations of systemic lupus erythematosus (SLE), we collected M/N haplogrouping and clinical characteristics from 868 Han Chinese women with SLE, as well as for 870 age-matched healthy Han Chinese control women. M/N haplogroups were determined in all subjects using allele-specific amplification. The frequency of M haplogroup in all patients was 429 (49.4%) and the frequency of N haplogroup, 439 (50.6%). The corresponding frequencies in controls were 456 (52.4%) and 414 (47.6%) (P = 0.213). Among women older than 50 years at onset age, the N haplogroup was significantly higher in patients than in healthy controls (59.6% vs 41.7%, P = 0.042). The N haplogroup was associated with significantly higher risk for certain SLE characteristics: hematological system damage (OR 2.128, 95%CI 1.610 to 2.813), skin impairment (OR 1.873, 95%CI 1.428 to 2.457), neurological disturbance (OR 3.956, 95%CI 1.874 to 8.352) and alopecia (OR 1.322, 95%CI 1.007 to 1.737). Our results suggest that in Han Chinese women, the mtDNA N haplogroup is associated with higher risk of late-onset SLE, skin impairment, neurological disturbance, hematological system damage and alopecia. PMID- 26039691 TI - Gamma activity coupled to alpha phase as a mechanism for top-down controlled gating. AB - Coupling between neural oscillations in different frequency bands has been proposed to coordinate neural processing. In particular, gamma power coupled to alpha phase is proposed to reflect gating of information in the visual system but the existence of such a mechanism remains untested. Here, we recorded ongoing brain activity using magnetoencephalography in subjects who performed a modified Sternberg working memory task in which distractors were presented in the retention interval. During the anticipatory pre-distractor period, we show that the phase of alpha oscillations was coupled with the power of high (80-120Hz) gamma band activity, i.e. gamma power consistently was lower at the trough than at the peak of the alpha cycle (9-12Hz). We further show that high alpha power was associated with weaker gamma power at the trough of the alpha cycle. This result is in line with alpha activity in sensory region implementing a mechanism of pulsed inhibition silencing neuronal firing every ~100 ms. PMID- 26039693 TI - A new species of pengornithidae (aves: enantiornithes) from the lower cretaceous of China suggests a specialized scansorial habitat previously unknown in early birds. AB - We describe a new enantiornithine bird, Parapengornis eurycaudatus gen. et sp. nov. from the Lower Cretaceous Jiufotang Formation of Liaoning, China. Although morphologically similar to previously described pengornithids Pengornis houi, Pengornis IVPP V18632, and Eopengornis martini, morphological differences indicate it represents a new taxon of the Pengornithidae. Based on new information from this specimen we reassign IVPP V18632 to Parapengornis sp. The well preserved pygostyle of the new specimen elucidates the morphology of this element for the clade, which is unique in pengornithids among Mesozoic birds. Similarities with modern scansores such as woodpeckers may indicate a specialized vertical climbing and clinging behavior that has not previously been inferred for early birds. The new specimen preserves a pair of fully pennaceous rachis dominated feathers like those in the holotype of Eopengornis martini; together with the unique morphology of the pygostyle, this discovery lends evidence to early hypotheses that rachis-dominated feathers may have had a functional significance. This discovery adds to the diversity of ecological niches occupied by enantiornithines and if correct reveals are remarkable amount of locomotive differentiation among Enantiornithes. PMID- 26039692 TI - ZnO Nanoparticles Affect Bacillus subtilis Cell Growth and Biofilm Formation. AB - Zinc oxide nanoparticles (ZnO NPs) are an important antimicrobial additive in many industrial applications. However, mass-produced ZnO NPs are ultimately disposed of in the environment, which can threaten soil-dwelling microorganisms that play important roles in biodegradation, nutrient recycling, plant protection, and ecological balance. This study sought to understand how ZnO NPs affect Bacillus subtilis, a plant-beneficial bacterium ubiquitously found in soil. The impact of ZnO NPs on B. subtilis growth, FtsZ ring formation, cytosolic protein activity, and biofilm formation were assessed, and our results show that B. subtilis growth is inhibited by high concentrations of ZnO NPs (>= 50 ppm), with cells exhibiting a prolonged lag phase and delayed medial FtsZ ring formation. RedoxSensor and Phag-GFP fluorescence data further show that at ZnO-NP concentrations above 50 ppm, B. subtilis reductase activity, membrane stability, and protein expression all decrease. SDS-PAGE Stains-All staining results and FT IR data further demonstrate that ZnO NPs negatively affect exopolysaccharide production. Moreover, it was found that B. subtilis biofilm surface structures became smooth under ZnO-NP concentrations of only 5-10 ppm, with concentrations <= 25 ppm significantly reducing biofilm formation activity. XANES and EXAFS spectra analysis further confirmed the presence of ZnO in co-cultured B. subtilis cells, which suggests penetration of cell membranes by either ZnO NPs or toxic Zn+ ions from ionized ZnO NPs, the latter of which may be deionized to ZnO within bacterial cells. Together, these results demonstrate that ZnO NPs can affect B. subtilis viability through the inhibition of cell growth, cytosolic protein expression, and biofilm formation, and suggest that future ZnO-NP waste management strategies would do well to mitigate the potential environmental impact engendered by the disposal of these nanoparticles. PMID- 26039694 TI - Colorectal Liver Metastasis Resection Outcomes Defined by Molecular Biology. PMID- 26039695 TI - Use of forecasted assessment of quality of life to validate time-trade-off utilities and a prostate cancer screening decision-analytic model. AB - PURPOSE: To determine whether the forecasted assessment of how someone would feel in a future health state can be predictive of utilities (e.g. as elicited by the time-trade-off method) and also predictive of optimal decisions as determined by a decision-analytic model. METHODS: We elicited time-trade-off utilities for prostate cancer treatment outcomes from 168 men. We also elicited forecasted assessments, that is, an informal, non-quantitative, descriptive evaluation, of impotence and incontinence from these men. We used multivariate regression analysis to explore the relationship between forecasted assessment and reluctance to trade length for improved quality of life, that is, the unwillingness to trade length of life for improved quality of life in the time-trade-off utility assessment and the relationship between the forecasted assessments and the optimal decision of whether to undergo screening for prostate cancer as determined from a previously published decision-analytic model. RESULTS: Importance of sexual function was strongly related to impotence utilities (P < 0.05). Based on the multivariate analysis, significant predictors for the utility of severe incontinence were family income, family history of prostate cancer, work status and attitude towards needing to wear an incontinence pad. However, no variables were statistically significant predictors for the utility of complete impotence. The importance of sexual functioning was a significant predictor of the optimal decision. CONCLUSION: Anticipated difficulty adjusting to adverse health effects were highly related to preferences and could be used as a proxy measure of utility. Similarly, the importance of sexual functioning, a future preference, was highly related to the optimal decision, which validates our previously published decision-analytic model. PMID- 26039696 TI - Three-Dimensional Crumpled Reduced Graphene Oxide/MoS2 Nanoflowers: A Stable Anode for Lithium-Ion Batteries. AB - Recently, layered transition-metal dichalcogenides (TMDs) have gained great attention for their analogous graphite structure and high theoretical capacity. However, it has suffered from rapid capacity fading. Herein, we present the crumpled reduced graphene oxide (RGO) decorated MoS2 nanoflowers on carbon fiber cloth. The three-dimensional framework of interconnected crumpled RGO and carbon fibers provides good electronic conductivity and facile strain release during electrochemical reaction, which is in favor of the cycling stability of MoS2. The crumpled RGO decorated MoS2 nanoflowers anode exhibits high specific capacity (1225 mAh/g) and excellent cycling performance (680 mAh/g after 250 cycles). Our results demonstrate that the three-dimensional crumpled RGO/MoS2 nanoflowers anode is one of the attractive anodes for lithium-ion batteries. PMID- 26039697 TI - The role of heparanase in pulmonary cell recruitment in response to an allergic but not non-allergic stimulus. AB - Heparanase is an endo-beta-glucuronidase that specifically cleaves heparan sulfate proteoglycans in the extracellular matrix. Expression of this enzyme is increased in several pathological conditions including inflammation. We have investigated the role of heparanase in pulmonary inflammation in the context of allergic and non-allergic pulmonary cell recruitment using heparanase knockout (Hpa-/-) mice as a model. Following local delivery of LPS or zymosan, no significant difference was found in the recruitment of neutrophils to the lung between Hpa-/- and wild type (WT) control. Similarly neutrophil recruitment was not inhibited in WT mice treated with a heparanase inhibitor. However, in allergic inflammatory models, Hpa-/- mice displayed a significantly reduced eosinophil (but not neutrophil) recruitment to the airways and this was also associated with a reduction in allergen-induced bronchial hyperresponsiveness, indicating that heparanase expression is associated with allergic reactions. This was further demonstrated by pharmacological treatment with a heparanase inhibitor in the WT allergic mice. Examination of lung specimens from patients with different severity of chronic obstructive pulmonary disease (COPD) found increased heparanase expression. Thus, it is established that heparanase contributes to allergen-induced eosinophil recruitment to the lung and could provide a novel therapeutic target for the development of anti-inflammatory drugs for the treatment of asthma and other allergic diseases. PMID- 26039698 TI - Antimicrobial Resistance of Shigella flexneri Serotype 1b Isolates in China. AB - Shigella flexneri serotype 1b is among the most prominent serotypes in developing countries, followed by serotype 2a. However, only limited data is available on the global phenotypic and genotypic characteristics of S. flexneri 1b. In the present study, 40 S. flexneri 1b isolates from different regions of China were confirmed by serotyping and biochemical characterization. Antimicrobial susceptibility testing showed that 85% of these isolates were multidrug-resistant strains and antibiotic susceptibility profiles varied between geographical locations. Strains from Yunnan were far more resistant than those from Xinjiang, while only one strain from Shanghai was resistant to ceftazidime and aztreonam. Fifteen cephalosporin resistant isolates were identified in this study. ESBL genes (blaSHV, blaTEM, blaOXA, and blaCTX-M) and ampC genes (blaMOX, blaFOX, blaMIR(ACT-1), blaDHA, blaCIT and blaACC) were subsequently detected among the 15 isolates. The results showed that these strains were positive only for blaTEM, blaOXA, blaCTX-M, intI1, and intI2. Furthermore, pulsed-field gel electrophoresis (PFGE) analysis showed that the 40 isolates formed different profiles, and the PFGE patterns of Xinjiang isolates were distinct from Yunnan and Shanghai isolates by one obvious, large, missing band. In summary, similarities in resistance patterns were observed in strains with the same PFGE pattern. Overall, the results supported the need for more prudent selection and use of antibiotics in China. We suggest that antibiotic susceptibility testing should be performed at the start of an outbreak, and antibiotic use should be restricted to severe Shigella cases, based on resistance pattern variations observed in different regions. The data obtained in the current study might help to develop a strategy for the treatment of infections caused by S. flexneri 1b in China. PMID- 26039699 TI - Disordering of the vortex lattice through successive destruction of positional and orientational order in a weakly pinned Co0.0075NbSe2 single crystal. AB - The vortex lattice in a Type II superconductor provides a versatile model system to investigate the order-disorder transition in a periodic medium in the presence of random pinning. Here, using scanning tunnelling spectroscopy in a weakly pinned Co(0.0075)NbSe(2) single crystal, we show that the vortex lattice in a 3 dimensional superconductor disorders through successive destruction of positional and orientational order, as the magnetic field is increased across the peak effect. At the onset of the peak effect, the equilibrium quasi-long range ordered state transforms into an orientational glass through the proliferation of dislocations. At a higher field, the dislocations dissociate into isolated disclination giving rise to an amorphous vortex glass. We also show the existence of a variety of additional non-equilibrium metastable states, which can be accessed through different thermomagnetic cycling. PMID- 26039700 TI - Health Behavior in Hypochondriasis. AB - The relationship between health behavior and hypochondriasis has not yet been sufficiently examined, as previous studies investigated only individual dimensions of health behavior. In the present study, we extend current literature by examining multiple dimensions of health behavior. One hundred twenty-six participants, consisting of 40 participants with a primary diagnosis of hypochondriasis, 41 participants with a primary diagnosis of anxiety disorder, and 45 healthy controls, completed a multidimensional questionnaire for the assessment of health behavior and other measures for the evaluation of general psychopathology, illness anxiety, depression, and general anxiety. Patients with hypochondriasis revealed a less active way of life (d = 0.89) and lower hygiene (d = 0.60) than healthy controls, but did not differ from healthy controls regarding their compliance to medical recommendations. No differences were found in substance avoidance, security orientation, and diet. Hypochondriasis-specific behavior should be monitored in the treatment of the disorder. PMID- 26039701 TI - Contusive spinal cord injury up regulates mu-opioid receptor (mor) gene expression in the brain and down regulates its expression in the spinal cord: possible implications in spinal cord injury research. AB - Traumatic spinal cord injury (SCI) is one of the dreaded neurological conditions and finding a cure for it has been a hot area of research. Naloxone - a mu-opiate receptor (mor) antagonist was considered for SCI treatment based on its positive effects under shock conditions. In contrary to animal studies based reports about the potential benefits of naloxone in treating SCI, a large scale clinical trial [National Acute Spinal Cord Injury Study II (NASCIS II)] conducted in USA failed to witness any effectiveness. The inconsistency noticed was intriguing. Therefore, the objective of the present study was to re-examine the role of naloxone in treating SCI using a highly standardised Multicenter Animal Spinal Cord Injury Study (MASCIS) animal model of contusive SCI. Results indicated that naloxone produced negligible and insignificant neuroprotection. In an attempt to understand the cause for the failure, it was found that mu-opioid receptor (mor) gene expression was upregulated in the brain but was down regulated in the spinal cord after contusive SCI. Given that the beneficial effects of naloxone are through its action on the mor, the results indicate that unlike the brain, spinal cord might not be bracing to utilise the opiate system in the repair process. This could possibly explain the failure of naloxone treatment in NASCIS II. To conclude, opiate antagonists like naloxone may be neuroprotective for treating traumatic brain injuries, but not for traumatic/contusive spinal cord injuries. PMID- 26039702 TI - Interstitial Granulomatous Dermatitis as the Initial Manifestation of Myeloma. PMID- 26039704 TI - Early depression screening is feasible in hospitalized stroke patients. AB - BACKGROUND AND PURPOSE: Post-stroke depression (PSD) is common but is not routinely assessed for in hospitalized patients. As a Comprehensive Stroke Center, we screen all stroke inpatients for depression, though the feasibility of early screening has not been established. We assessed the hypothesis that early depression screening in stroke patients is feasible. We also explored patient level factors associated with being screened for PSD and the presence of early PSD. METHODS: The medical records of all patients admitted with ischemic stroke (IS) or intracerebral hemorrhage (ICH) between 01/02/13 and 15/04/13 were reviewed. A depression screen, modified from the Patient Health Questionnaire-9, was administered (maximum score 27, higher scores indicating worse depression). Patients were eligible if they did not have a medical condition precluding screening. Feasibility was defined as screening 75% of all eligible patients. RESULTS: Of 303 IS and ICH inpatients, 70% (211) were eligible for screening, and 75% (158) of all eligible patients were screened. More than one-third of all patients screened positive for depression (score > 4). Women (OR 2.06, 95% CI 1.06-4.01) and younger patients (OR 0.97, 95% CI 0.96-0.99) were more likely to screen positive. Screening positive was not associated with poor discharge/day 7 outcome (mRS > 3; OR 1.45, 95% CI 0.74-2.83). CONCLUSIONS: Screening stroke inpatients for depression is feasible and early depression after stroke is common. Women and younger patients are more likely to experience early PSD. Our results provide preliminary evidence supporting continued screening for depression in hospitalized stroke patients. PMID- 26039703 TI - A model for aryl hydrocarbon receptor-activated gene expression shows potency and efficacy changes and predicts squelching due to competition for transcription co activators. AB - A stochastic model of nuclear receptor-mediated transcription was developed based on activation of the aryl hydrocarbon receptor (AHR) by 2,3,7,8 tetrachlorodibenzodioxin (TCDD) and subsequent binding the activated AHR to xenobiotic response elements (XREs) on DNA. The model was based on effects observed in cells lines commonly used as in vitro experimental systems. Following ligand binding, the AHR moves into the cell nucleus and forms a heterodimer with the aryl hydrocarbon nuclear translocator (ARNT). In the model, a requirement for binding to DNA is that a generic coregulatory protein is subsequently bound to the AHR-ARNT dimer. Varying the amount of coregulator available within the nucleus altered both the potency and efficacy of TCDD for inducing for transcription of CYP1A1 mRNA, a commonly used marker for activation of the AHR. Lowering the amount of available cofactor slightly increased the EC50 for the transcriptional response without changing the efficacy or maximal response. Further reduction in the amount of cofactor reduced the efficacy and produced non monotonic dose-response curves (NMDRCs) at higher ligand concentrations. The shapes of these NMDRCs were reminiscent of the phenomenon of squelching. Resource limitations for transcriptional machinery are becoming apparent in eukaryotic cells. Within single cells, nuclear receptor-mediated gene expression appears to be a stochastic process; however, intercellular communication and other aspects of tissue coordination may represent a compensatory process to maintain an organism's ability to respond on a phenotypic level to various stimuli within an inconstant environment. PMID- 26039705 TI - Standard setting. PMID- 26039706 TI - Role of Nerve Growth Factor in Development and Persistence of Experimental Pulmonary Hypertension. AB - RATIONALE: Pulmonary hypertension (PH) is characterized by a progressive elevation in mean pulmonary arterial pressure, often leading to right ventricular failure and death. Growth factors play significant roles in the pathogenesis of PH, and their targeting may therefore offer novel therapeutic strategies in this disease. OBJECTIVES: To evaluate the nerve growth factor (NGF) as a potential new target in PH. METHODS: Expression and/or activation of NGF and its receptors were evaluated in rat experimental PH induced by chronic hypoxia or monocrotaline and in human PH (idiopathic or associated with chronic obstructive pulmonary disease). Effects of exogenous NGF were evaluated ex vivo on pulmonary arterial inflammation and contraction, and in vitro on pulmonary vascular cell proliferation, migration, and cytokine secretion. Effects of NGF inhibition were evaluated in vivo with anti-NGF blocking antibodies administered both in rat chronic hypoxia- and monocrotaline-induced PH. MEASUREMENTS AND MAIN RESULTS: Our results show increased expression of NGF and/or increased expression/activation of its receptors in experimental and human PH. Ex vivo/in vitro, we found out that NGF promotes pulmonary vascular cell proliferation and migration, pulmonary arterial hyperreactivity, and secretion of proinflammatory cytokines. In vivo, we demonstrated that anti-NGF blocking antibodies prevent and reverse PH in rats through significant reduction of pulmonary arterial inflammation, hyperreactivity, and remodeling. CONCLUSIONS: This study highlights the critical role of NGF in PH. Because of the recent development of anti-NGF blocking antibodies as a possible new pain treatment, such a therapeutic strategy of NGF inhibition may be of interest in PH. PMID- 26039707 TI - Nasal endoscopic evaluation and its impact on survival in patients with stage I/II extranodal natural killer/T-cell lymphoma, nasal type. AB - BACKGROUND: Endoscopic findings of extranodal natural killer/T-cell lymphoma (ENKTL), nasal type, are heterogeneous, but not fully understood. The objective of this study was to evaluate the role of nasal endoscopic examination and its implications for treatment of stage I/II ENKTL. METHODS: This retrospective study included 60 consecutive patients diagnosed with stage I/II ENKTL, nasal type, from 2000 to 2011. RESULTS: The endoscopic findings were classified into early (45%) and advanced (55%) lesions. Furthermore, the primary tumor extent assessed by endoscopy was significantly correlated with the radiologic imaging (p < 0.001). The results of univariate analysis showed that the patients with advanced lesions had worse overall survival (p = 0.004) and disease-free survival (p = 0.001) than those with early lesions. In multivariate analysis, advanced lesions on nasal endoscopy was an independent prognostic factor (p = 0.024; hazard ratio 5.29; 95% confidence interval, 1.25-22.39). CONCLUSION: We found that nasal endoscopic findings were important prognostic factors in stage I/II ENKTL, nasal type, suggesting that comprehensive endoscopic evaluation of primary tumor should be performed in this setting. PMID- 26039708 TI - Somatic Copy Number Abnormalities and Mutations in PI3K/AKT/mTOR Pathway Have Prognostic Significance for Overall Survival in Platinum Treated Locally Advanced or Metastatic Urothelial Tumors. AB - BACKGROUND: An integrative analysis was conducted to identify genomic alterations at a pathway level that could predict overall survival (OS) in patients with advanced urothelial carcinoma (UC) treated with platinum-based chemotherapy. PATIENTS AND METHODS: DNA and RNA were extracted from 103 formalin-fixed paraffin embedded (FFPE) invasive high-grade UC samples and were screened for mutations, copy number variation (CNV) and gene expression analysis. Clinical data were available from 85 cases. Mutations were analyzed by mass-spectrometry based on genotyping platform (Oncomap 3) and genomic imbalances were detected by comparative genomic hybridization (CGH) analysis. Regions with threshold of log2 ratio >=0.4, or <=0.6 were defined as either having copy number gain or loss and significantly recurrent CNV across the set of samples were determined using a GISTIC analysis. Expression analysis on selected relevant UC genes was conducted using Nanostring. To define the co-occurrence pattern of mutations and CNV, we grouped genomic events into 5 core signal transduction pathways: 1) TP53 pathway, 2) RTK/RAS/RAF pathway, 3) PI3K/AKT/mTOR pathway, 4) WNT/CTNNB1, 5) RB1 pathway. Cox regression was used to assess pathways abnormalities with survival outcomes. RESULTS: 35 samples (41%) harbored mutations on at least one gene: TP53 (16%), PIK3CA (9%), FGFR3 (2%), HRAS/KRAS (5%), and CTNNB1 (1%). 66% of patients had some sort of CNV. PIK3CA/AKT/mTOR pathway alteration (mutations+CNV) had the greatest impact on OS (p=0.055). At a gene level, overexpression of CTNNB1 (p=0.0008) and PIK3CA (p=0.02) were associated with shorter OS. Mutational status on PIK3CA was not associated with survival. Among other individually found genomic alterations, TP53 mutations (p=0.07), mTOR gain (p=0.07) and PTEN overexpression (p=0.08) have a marginally significant negative impact on OS. CONCLUSIONS: Our study suggests that targeted therapies focusing on the PIK3CA/AKT/mTOR pathway genomic alterations can generate the greatest impact in the overall patient population of high-grade advanced UC. PMID- 26039709 TI - A comparision of nalbuphine with morphine for analgesic effects and safety : meta analysis of randomized controlled trials. AB - Although morphine is the standard opioid analgesic for pain control and has been widely used, certain drug-induced adverse effects have been reported as intolerable and need to be addressed. Nalbuphine may have a few advantages over morphine in this respect. We aimed to describe the effect of nalbuphine as well as its safety compared to morphine by analyzing published randomized controlled trials (RCTs) with meta-analysis approach. We analysed 15 trials (820 patients). Overall, there was no evidence to show that the effect of pain relief had any difference between nalbuphine and morphine (pooled relative risks [RRs], 1.01; 95% CI, 0.91 to 1.11; P = 0.90). On the other hand, the incidences of pruritus, nausea, vomiting, respiratory depression were significantly lower in nalbuphine group compared with morphine group, and the pooled RRs were 0.78(95%CI, 0.602 0.997; P = 0.048) for nausea, 0.65(95%CI, 0.50-0.85; P = 0.001) for vomiting, 0.17(95%CI, 0.09-0.34; P < 0.0001) for pruritus, and 0.27(95%CI, 0.12-0.57; P = 0.0007) for respiratory depression. The analgesic efficacy of nalbuphine is comparable to morphine, but nalbuphine provides a better safety profile than morphine in the aspect of certain side-effects, especially related to pruritus and respiratory depression. PMID- 26039710 TI - Biased recognition of facial affect in patients with major depressive disorder reflects clinical state. AB - Cognitive theories of depression posit that perception is negatively biased in depressive disorder. Previous studies have provided empirical evidence for this notion, but left open the question whether the negative perceptual bias reflects a stable trait or the current depressive state. Here we investigated the stability of negatively biased perception over time. Emotion perception was examined in patients with major depressive disorder (MDD) and healthy control participants in two experiments. In the first experiment subjective biases in the recognition of facial emotional expressions were assessed. Participants were presented with faces that were morphed between sad and neutral and happy expressions and had to decide whether the face was sad or happy. The second experiment assessed automatic emotion processing by measuring the potency of emotional faces to gain access to awareness using interocular suppression. A follow-up investigation using the same tests was performed three months later. In the emotion recognition task, patients with major depression showed a shift in the criterion for the differentiation between sad and happy faces: In comparison to healthy controls, patients with MDD required a greater intensity of the happy expression to recognize a face as happy. After three months, this negative perceptual bias was reduced in comparison to the control group. The reduction in negative perceptual bias correlated with the reduction of depressive symptoms. In contrast to previous work, we found no evidence for preferential access to awareness of sad vs. happy faces. Taken together, our results indicate that MDD related perceptual biases in emotion recognition reflect the current clinical state rather than a stable depressive trait. PMID- 26039712 TI - Correction: age-related variation in health status after age 60. PMID- 26039711 TI - Identifying the Functional Flexion-extension Axis of the Knee: An In-Vivo Kinematics Study. AB - PURPOSE: This study aimed to calculate the flexion-extension axis (FEA) of the knee through in-vivo knee kinematics data, and then compare it with two major anatomical axes of the femoral condyles: the transepicondylar axis (TEA) defined by connecting the medial sulcus and lateral prominence, and the cylinder axis (CA) defined by connecting the centers of posterior condyles. METHODS: The knee kinematics data of 20 healthy subjects were acquired under weight-bearing condition using bi-planar x-ray imaging and 3D-2D registration techniques. By tracking the vertical coordinate change of all points on the surface of femur during knee flexion, the FEA was determined as the line connecting the points with the least vertical shift in the medial and lateral condyles respectively. Angular deviation and distance among the TEA, CA and FEA were measured. RESULTS: The TEA-FEA angular deviation was significantly larger than that of the CA-FEA in 3D and transverse plane (3.45 degrees vs. 1.98 degrees , p < 0.001; 2.72 degrees vs. 1.19 degrees , p = 0.002), but not in the coronal plane (1.61 degrees vs. 0.83 degrees , p = 0.076). The TEA-FEA distance was significantly greater than that of the CA-FEA in the medial side (6.7 mm vs. 1.9 mm, p < 0.001), but not in the lateral side (3.2 mm vs. 2.0 mm, p = 0.16). CONCLUSION: The CA is closer to the FEA compared with the TEA; it can better serve as an anatomical surrogate for the functional knee axis. PMID- 26039713 TI - CpG-ODN Class C Mediated Immunostimulation in Rabbit Model of Trypanosoma evansi Infection. AB - CpG oligodeoxynucleotides (CpG-ODN) stimulate immune cells from a wide spectrum of mammalian species. Class C CpG-ODN is relatively stable and has the combined immune effects of both A and B classes of CpG-ODN. Trypanosoma evansi produces the state of immuno-suppression in the infected hosts. The current chemotherapeutic agents against this parasite are limited in number and usually associated with severe side effects. The present work aimed to determine the immunostimulatory effects of CpG-ODN class C in T. evansi infected rabbits. Rabbits inoculated with CpG C and challenged with T. evansi resulted in delayed onset of clinical signs with reduced severity in comparison to that of T. evansi infected rabbits. The treatment also enhanced humoral immune responses. Histopathological findings in liver and spleen revealed enhancement of mononuclear cell infiltration and secondary B cell follicles. These results demonstrate that CpG-ODN class C, has immunostimulatory properties in rabbit model of trypanosomosis. The use of booster doses or sustained delivery of CpG ODN will further elucidate the prolonged CpG-ODN generated immune responses. PMID- 26039715 TI - [Rabies in children: an often unknown risk among populations at risk]. AB - INTRODUCTION: Rabies is a public health problem in many African countries including Burkina Faso. Although animal bites, including dog bites, are relatively common, the persistence of public ignorance about their risk means that children who are bitten may receive no prophylaxis and are thus at serious risk. We report two cases of early childhood rabies in the past 2 years; both children were bitten by infected dogs. The clinical manifestations were those of encephalitis, with agitation and hydrophobia. In the absence of a reference laboratory for human rabies testing, confirmation of this diagnosis was not possible. Neither child received prophylaxis after being bitten. These cases are a reminder that rabies remains a problems today, a disease to which humans and animals of all ages are subject. Access to prevention messages about post exposure prophylaxis against this disease is essential, for it is always fatal once its symptoms appear. Awareness and education about rabies should be intensified in view of the widespread ignorance of this risk. PMID- 26039716 TI - [Telemedicine guideline in Patient Care with Acute Coronary Syndrome and Other heart Diseases]. PMID- 26039717 TI - Correction: measurement and analysis of the tracheobronchial tree in chinese population using computed tomography. PMID- 26039714 TI - Administration of progranulin (PGRN) triggers ER stress and impairs insulin sensitivity via PERK-eIF2alpha-dependent manner. AB - Progranulin (PGRN) has recently emerged as an important regulator for glucose metabolism and insulin sensitivity. However, the direct effects of PGRN in vivo and the underlying mechanisms between PGRN and impaired insulin sensitivity are not fully understood. In this study, mice treated with PGRN for 21 d exhibited the impaired glucose tolerance and insulin sensitivity, remarkable ER stress as well as attenuated insulin signaling in liver and adipose tissue but not in skeletal muscle. Furthermore, treatment of mice with phenyl butyric acid (PBA), a chemical chaperone alleviating ER stress, resulted in a significant restoration of systemic insulin sensitivity and recovery of insulin signaling induced by PGRN. Consistent with these findings in vivo, we also observed that PGRN treatment induced ER stress, impaired insulin signaling in cultured hepatocytes and adipocytes, with such effects being partially nullified by blockade of PERK. Whereas PGRN-deficient hepatocytes and adipocytes were more refractory to palmitate-induced insulin resistance, indicating the causative role of the PERK eIF2alpha axis of the ER stress response in action of PGRN. Collectively, our findings supported the notion that PGRN is a key regulator of insulin resistance and that PGRN may mediate its effects, at least in part, by inducing ER stress via the PERK-eIF2alpha dependent pathway. PMID- 26039718 TI - Gene-environment interactions in inflammatory bowel disease pathogenesis. AB - PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) has long been known to have genetic risk factors because of increased prevalence in the relatives of affected individuals. However, genome-wide association studies have only explained limited heritability in IBD. The observed globally rising incidence of IBD has implicated the role of environmental factors. The hidden unexplained heritability remains to be explored. RECENT FINDINGS: Recent aggregate evidence has highlighted the extent and nature of host genome-microbiome associations, a key next step in understanding the mechanisms of pathogenesis in IBD. An individual's gut microbiota is shaped not only by genetic but also by environmental factors like diet. Minimizing exposure of the intestinal lumen to selected food items has shown to prolong the remission state of IBD. Among a genetically susceptible host, the shift of gut microbiota (or 'dysbiosis') can lead to increasing the susceptibility to IBD. With the advances in high-throughput large-scale 'omics' technologies in combination with creative data mining and system biology-based network analyses, the complexity of biological functional networks behind the cause of IBD has become more approachable. Therefore, the hidden heritability in IBD has become more explainable, and can be attributable to the changing environmental factors, epigenetic modifications, and gene-host microbial ('in vironmental') or gene-extrinsic environmental interactions. SUMMARY: This review discusses the perspectives of relevance to clinical translation with emphasis on gene-environment interactions. No doubt, the use of system-based approaches will lead to the development of alternative, and hopefully better, diagnostic, prognostic, and monitoring tools in the management of IBD. PMID- 26039719 TI - When it is not inflammatory bowel disease: differential diagnosis. AB - PURPOSE OF REVIEW: Inflammatory bowel diseases (IBDs) represent a heterogeneous entity whose diagnosis is sometimes difficult to ascertain. Many pathological processes may mimic IBD phenotypes. Among the classical differential diagnoses are enteric infections and infestations as well as drug toxicity. However, recently, more specific differential diagnoses have been included, including monogenic causes of gastrointestinal tract inflammation, particularly in young children. The purpose of the present review is to describe the differential diagnosis of IBD, putting it in a specific clinical and demographic context. This differential diagnosis will be discussed specifically for young children, elderly patients, and immunosuppressed patients. RECENT FINDINGS: We will focus on the most recent findings and concepts, including monogenic diseases in young children, diverticular disease-associated colitis in elderly patients, and toxic colitis in patients receiving immunosuppressants such as mycophenolate mofetil or biologics such as ipilimumab. SUMMARY: The aim of this review is to alert the clinician dealing with IBD, concerning a series of specific diagnoses that should be recognized because they may require specific treatment, different from the ones of classical idiopathic IBD. PMID- 26039720 TI - Biosimilars in inflammatory bowel disease: ready for prime time? AB - PURPOSE OF REVIEW: The goal is to review the most recent literature about biosimilars in inflammatory bowel disease (IBD), with emphasis on controversial regulatory issues. RECENT FINDINGS: Although biosimilars have been in use in Europe since 2005, the recent approval of CT-P13 (Remsima, Inflectra), a biosimilar of the reference infliximab (Remicade), by the European Medicines Agency (EMA) and several regulatory agencies has become a widely discussed topic in IBD, rheumatology, and other areas. Biologics are the main drivers of cost in current IBD units, and biosimilars can reduce prices thus increasing the availability of this type of treatment. The guidelines for evaluation of biosimilars are considerably different from those of the reference biologics, regulatory agencies relying on detailed in-vitro studies for defining 'high similarity', and requiring many fewer clinical data. 'High similarity' is considered sufficient for clinical trials, as the new molecule is demonstrated so structurally similar to the reference one that no significant difference in efficacy or safety is expected. Two trials in ankylosing spondylitis and rheumatoid arthritis gave no evidence of real difference and provided the required pharmacokinetic and PD data. The main controversy remains in the 'extrapolation' of indications, accepted by EMA but not by Health Canada. Position statements from several scientific societies and some expert's reviews have expressed concerns to the concept of extrapolation without direct IBD clinical evidence, whereas EMA experts have published detailed reviews supporting extrapolation. SUMMARY: Biosimilars in IBD are here to stay. New data are awaited to settle the controversy of extrapolation, but only the complex behavior of markets will show whether biosimilars fuel competition and extend access to biologics with significant cuts in drug costs. PMID- 26039721 TI - Complications of biologics in inflammatory bowel disease. AB - PURPOSE OF REVIEW: The treatment of inflammatory bowel disease (IBD) in the modern area has improved with more biological agents available. Although the efficacy of these drugs has been demonstrated, concerns about their safety profile have been raised, and new data have emerged in the past year. RECENT FINDINGS: New data regarding the safety profile of anti-TNF were published over the last year, with a better identification of patients at risk of infection, and specific recommendations for the prevention of infections. There is a mild increase in malignancy in patients receiving anti-TNF, mainly lymphoma and skin cancer, which seems mainly attributable to combination with thiopurines. Specific recommendations for management of pregnancy were published. SUMMARY: Biological treatments are effective and safe in the treatment of IBD, provided that the recommendations for their use and monitoring are followed. PMID- 26039723 TI - Long-term durability of radiofrequency ablation for Barrett's-related neoplasia. AB - PURPOSE OF REVIEW: Here, we examine data on the long-term durability of endoscopic therapy in patients with mucosal neoplasia in Barrett's esophagus. RECENT FINDINGS: Short-term success is seen in most patients undergoing endoscopic therapy for Barrett's esophagus neoplasia, but long-term outcomes are only just becoming available. SUMMARY: The incidence of esophageal adenocarcinoma (EAC) continues to rise with poor survival seen in the majority of patients. The only known precursor to EAC is Barrett's esophagus. Although the risk of progression from metaplastic Barrett's esophagus to neoplasia is low, surveillance is advocated as patients who progress to mucosal neoplasia carry a significantly higher risk of progressing to invasive EAC. Minimally invasive endoscopic therapy with endoscopic resection and radiofrequency ablation are now the gold standard treatments for patients with intramucosal neoplasia in Barrett's esophagus. After successful treatment, follow-up is still required as long-term durability is not 100% and recurrences are not rare. This review highlights the need for vigilant follow-up, but emphasizes the consensus that most patients have durable disease reversal. PMID- 26039722 TI - Proton pump inhibitor-responsive oesophageal eosinophilia and eosinophilic oesophagitis: more similarities than differences. AB - PURPOSE OF REVIEW: The purpose of this study is to discuss the clinical, endoscopic and histologic features, pathogenesis and disease mechanisms of proton pump inhibitor (PPI)-responsive oesophageal eosinophilia (PPI-REE), and to highlight similarities and differences with eosinophilic oesophagitis (EoE). RECENT FINDINGS: PPI-REE is a condition in which patients have clinical and histologic findings similar to EoE, but achieve complete remission with PPI treatment. More than one-third of patients who have oesophageal symptoms associated with oesophageal eosinophilia respond to PPI treatment. Emerging data elucidating the pathogenesis of PPI-REE have shown that Th2-related inflammatory factors such as interleukin (IL)-13, IL-5, eotaxin-3 and major basic protein (MBP) are elevated in PPI-REE, similar to EoE. PPI-REE also shares a genetic expression signature with EoE that reverses with PPI treatment. Mechanisms proposed to explain the PPI response include an acid-independent, anti inflammatory action of PPIs and PPI-induced restoration of oesophageal barrier function. SUMMARY: Multiple features of PPI-REE overlap extensively with EoE. This raises the question of whether PPI-REE is merely a subtype of EoE rather than an independent condition. This similarity may have future implications for algorithms informing evaluation and treatment of oesophageal eosinophilia. PMID- 26039724 TI - Molecular pathogenesis of eosinophilic esophagitis. AB - PURPOSE OF REVIEW: Eosinophilic esophagitis (EoE) is an esophageal disease characterized by an accumulation of eosinophils in the esophagus, which is normally devoid of eosinophils. The interest of the scientific community in EoE has grown considerably over the past two decades, and understanding of the molecular mechanisms involved in this disease has increased greatly in the last 2 years. RECENT FINDINGS: Important new insights into the pathogenesis of EoE recently have been achieved. Recent evaluations considering genetic and the environmental risk factors have led to the concept that some still-unknown environmental factors influence the risk of developing EoE more than the genetic predisposition. New molecules (in addition to interleukin-13, eotaxin-3, transforming growth factor-beta1, thymic stromal lymphopoietin, filaggrin, or interleukin-5) also have been shown to be involved in the disease pathogenesis. SUMMARY: The present review describes recent advances in the understanding of the molecular mechanisms underlying EoE, and how these new findings have enhanced understanding of the pathogenesis of this new esophageal disorder. PMID- 26039725 TI - Distal esophageal spasm. AB - PURPOSE OF REVIEW: Distal esophageal spasm (DES) is a rare esophageal motility disorder associated with dysphagia and chest pain. In 2011, the diagnosis of DES was refined based on the occurrence of premature (rather than rapid) contractions by high-resolution manometry. New therapeutic options have also been recently proposed. Thus, a review on DES incorporating publications since 2012 is timely because of these revisions in definition and management. RECENT FINDINGS: DES remains a heterogeneous clinical disorder. Its pathophysiology is still debated and DES might be related to achalasia. Alternatively, it might be secondary to medications, especially opiates. Endoscopic ultrasound might be informative diagnostically by demonstrating muscularis propria hypertrophy and thickening. Botulinum toxin injection in the esophageal body has been shown superior to placebo to relieve symptoms associated with DES. Finally, per oral endoscopic myotomy is a promising therapeutic approach, but may be less effective in DES than in achalasia. SUMMARY: The diagnosis of DES should lead to a systematic search for medication that might promote the occurrence of esophageal dysmotility. Endoscopic treatment of DES (botulinum toxin injection or per oral endoscopic myotomy) should be further evaluated in controlled studies using current diagnostic criteria by high-resolution manometry. PMID- 26039726 TI - Evaluation of the LINX antireflux procedure. AB - PURPOSE OF REVIEW: To evaluate the current data on the safety, efficacy, and indications for magnetic sphincter augmentation (MSA) using the LINX device to treat gastroesophageal reflux disease (GERD). RECENT FINDINGS: The LINX device has demonstrated excellent safety and GERD efficacy in several recent nonblinded, single arm studies with strict inclusion criteria and up to 3 years follow-up. Dysphagia has been the most common adverse effect occurring after LINX. Other gastrointestinal side-effects seen after laparoscopic fundoplication (bloating, gas, and inability to belch) may be less common after LINX. SUMMARY: The LINX device is a safe, well tolerated, and effective therapy for GERD in the short term. MSA should be considered for selected GERD patients without significant anatomic or motility defects. However, the long-term safety and efficacy of LINX both alone and in comparison to current GERD therapies - remains to be determined. PMID- 26039728 TI - Design of Light-Triggered Lyotropic Liquid Crystal Mesophases and Their Application as Molecular Switches in "On Demand" Release. AB - Here, we present the design and assembly of a new light-responsive functional lyotropic liquid crystal system using host-guest lipidic mesophases (LMPs). Light as an external stimulus has many advantages in comparison to other stimuli: it is milder than acids or bases, and variation of intensity and duration can provide a high level of pharmacological control. The LMPs are composed of monoolein (MO) and oleic acid (OA) as host lipids and a small amount of a judiciously synthesized lipid bearing an azobenzene photoactive unit as a guest. While preserving the structure and stability of the host lipidic aggregates, the guest lipids render them specific functionalities. Single-step and sequential light triggered release and retention of the embedded dye molecules are demonstrated, thereby achieving exquisite temporal, spatial, and dosage control of the release, opening up the possibility of using such lipidic biomaterials as effective matrices in therapy, when a continuous release of active drugs might be toxic. PMID- 26039729 TI - The effect of gastrointestinal nematode infection level on grazing distance from dung. AB - Avoiding grazing near feces is an efficient strategy to prevent parasitic infection and contamination; therefore, in the evolution of herbivorous species, this behavior may have developed as a mechanism to protect the host against infection by gastrointestinal nematodes. The aim of this study was to assess whether grazing distance from dung is related to the level of parasitic infection in cattle. Based on Fecal Egg Count (FEC) means, 18 castrated male steers, aged 18 months, were divided into three groups: High (FEC >= 315); Medium (FEC = 130 160); and Low (FEC = 40-70). To analyze the response to a new natural infection by gastrointestinal nematodes and to standardize infection levels, all animals received anthelmintic treatment at twenty days prior to field observation. Three observers simultaneously collected data on grazing behavior for 2.5 hours/week for 12 weeks. Observers recorded the distance when grazing occurred at less than one meter from dung. Every two weeks, fecal samples were collected for FEC, as well as serum samples to measure immunoglobulin G (IgG) levels against larvae and adult antigens of the parasitic species Haemonchus placei. All groups grazed farther from the dung on days of greater insolation (r = 0.62; P = 0.03). Animals with high levels of parasitism grazed farther from the dung (P < 0.05) but had lower levels (P < 0.0001) of IgG serum levels compared to those with medium and low levels of infection. FEC values varied over the experiment, remaining below 200 for the low and medium group and reaching 1000 (P < 0.01) for the animals with the highest rates of parasitism. Our results indicate that cattle showing high levels of parasitism are more likely to avoid contaminated areas than animals with lower infection levels, and the immune system seems to be involved in such behavior. PMID- 26039730 TI - A long-term experimental case study of the ecological effectiveness and cost effectiveness of invasive plant management in achieving conservation goals: bitou bush control in booderee national park in eastern australia. AB - Invasive plant management is often justified in terms of conservation goals, yet progress is rarely assessed against these broader goals, instead focussing on short-term reductions of the invader as a measure of success. Key questions commonly remain unanswered including whether invader removal reverses invader impacts and whether management itself has negative ecosystem impacts. We addressed these knowledge gaps using a seven year experimental investigation of Bitou Bush, Chrysanthemoides monilifera subsp. rotundata. Our case study took advantage of the realities of applied management interventions for Bitou Bush to assess whether it is a driver or passenger of environmental change, and quantified conservation benefits relative to management costs of different treatment regimes. Among treatments examined, spraying with herbicide followed by burning and subsequent re-spraying (spray-fire-spray) proved the most effective for reducing the number of individuals and cover of Bitou Bush. Other treatment regimes (e.g. fire followed by spraying, or two fires in succession) were less effective or even exacerbated Bitou Bush invasion. The spray-fire-spray regime did not increase susceptibility of treated areas to re-invasion by Bitou Bush or other exotic species. This regime significantly reduced plant species richness and cover, but these effects were short-lived. The spray-fire-spray regime was the most cost-effective approach to controlling a highly invasive species and facilitating restoration of native plant species richness to levels characteristic of uninvaded sites. We provide a decision tree to guide management, where recommended actions depend on the outcome of post-treatment monitoring and performance against objectives. Critical to success is avoiding partial treatments and treatment sequences that may exacerbate invasive species impacts. We also show the value of taking advantage of unplanned events, such as wildfires, to achieve management objectives at reduced cost. PMID- 26039732 TI - 2-Naphthylmethoxymethyl as a Mildly Introducible and Oxidatively Removable Benzyloxymethyl-Type Protecting Group. AB - 2-Naphthylmethoxymethyl (NAPOM) was developed for the protection of various hydroxy (including phenolic hydroxy and carboxy) and mercapto groups. The NAPOM group can be introduced in extremely mild conditions (naphthylmethoxymethyl chloride, 2,6-lutidine, room temperature) without concomitant acyl migration in a 1,2-diol system. Furthermore, selective removal of NAPOM in the presence of naphthylmethyl (NAP) and p-methoxybenzyl (PMB) groups and, conversely, that of PMB in the presence of NAPOM were realized. These results, as well as its easy handling and compatibility with various solvents, show that NAPOM is a novel and useful choice as a protecting group. PMID- 26039731 TI - Intravenous Mycobacterium Bovis Bacillus Calmette-Guerin Ameliorates Nonalcoholic Fatty Liver Disease in Obese, Diabetic ob/ob Mice. AB - Inflammation and immune response profoundly influence metabolic syndrome and fatty acid metabolism. To analyze influence of systemic inflammatory response to metabolic syndrome, we inoculated an attenuated vaccine strain of Mycobacterium bovis Bacillus Calmette-Guerin (BCG) into leptin-deficient ob/ob mice. BCG administration significantly decreased epididymal white adipose tissue weight, serum insulin levels, and a homeostasis model assessment of insulin resistance. Serum high molecular weight (HMW) adiponectin level and HMW/total adiponectin ratio of the BCG treated mice were significantly higher than those of control mice. Hepatic triglyceride accumulation and macrovesicular steatosis were markedly alleviated, and the enzymatic activities and mRNA levels of lipogenic related genes in liver were significantly decreased in the BCG injected mice. We also exposed human hepatocellular carcinoma HepG2 cells to high levels of palmitate, which enhanced endoplasmic reticulum stress-related gene expression and impaired insulin-stimulated Akt phosphorylation (Ser473). BCG treatment ameliorated both of these detrimental events. The present study therefore suggested that BCG administration suppressed development of nonalcoholic fatty liver disease, at least partly, by alleviating fatty acid-induced insulin resistance in the liver. PMID- 26039734 TI - Transmission vs. Diffuse Transmission in Circular Dichroism: What to Choose for Probing Solid-State Samples? AB - Recent advances in equipment enabled the collection of solid-state electronic circular dichroism (ECD) spectra using the commercially available integrating sphere attachment for a regular ECD spectrometer. This accessory was designed to reduce negative factors occurring in solid-state ECD measurements, and is, thereby, very useful for recording diffuse transmittance CD (DTCD) spectra using the pellet technique. In the present article, the operating principle of the integrating sphere and utility of the DTCD method in recording solid-state ECD spectra is demonstrated. Based on illustrative examples, i.e., 10-camphorsulfonic acid ammonium, cholest-4-en-3-one, (3R,4R,5S)-oseltamivir, and (S)-linezolid, ECD solid-state measurements were performed by means of both transmission and diffusion methods and later compared. Selection of these compounds as models for comparative studies was made in view of their different chromophoric systems and the profound importance in the pharmaceutical industry. During the course of this work the benefits and limitations of the use of integrating sphere are presented. The final conclusion is that more relevant solid-state spectra can be obtained by means of the DTCD method. PMID- 26039733 TI - Factors That Affect Quality of Life among People Living with HIV Attending an Urban Clinic in Uganda: A Cohort Study. AB - INTRODUCTION: With the availability of antiretroviral therapy (ART) and primary general care for people living with HIV (PLHIV) in resource limited settings, PLHIV are living longer, and HIV has been transformed into a chronic illness. People are diagnosed and started on treatment when they are relatively well. Although ART results in clinical improvement, the ultimate goal of treatment is full physical functioning and general well-being, with a focus on quality of life rather than clinical outcomes. However, there has been little research on the relationship of specific factors to quality of life in PLHIV. The objective of this study was to investigate factors associated with quality of life among PLHIV in Uganda receiving basic care and those on ART. METHODS: We enrolled 1274 patients attending an HIV outpatient clinic into a prospective cohort study. Of these, 640 received ART. All were followed up at 3 and 6 months. Health related quality of life was assessed with the MOS-HIV Health Survey and the Global Person Generated Index (GPGI). Multivariate linear regression and logistic regression with generalized estimating equations were used to examine the relationship of social behavioral and disease factors with Physical Health Summary (PHS) score, Mental Health Summary (MHS) score, and GPGI. RESULTS: Among PLHIV receiving basic care, PHS was associated with: sex (p=0.045) - females had lower PHS; age in years at enrollment (p=0.0001) - older patients had lower PHS; and depression (p<0.001) - depressed patients had lower PHS. MHS was only associated with opportunistic infection (p=0.01) - presence of an opportunistic infection was associated with lower MHS. For the GPG the associated variables were age (p=0.03) - older patients had lower GPGI; education (p=0.01) - higher education associated with higher GPGI; and depression - patients with depression had a lower GPGI (p<0.001). Among patients on ART, PHS was associated with: study visit (p=0.01), with increase in time there was better PHS, and this also improved with increase in education level (p=0.002). Patients with WHO disease stage 3&4 had a lower PHS compared to patients at stage 1&2 (p=0.006), and depressed patients had lower PHS (p<0.001). MHS improved from baseline to six month study visit (p<0.001), and females had lower MHS compared to males (p=0.01). GPGI was associated with higher income (p=0.04), alcohol use was associated with lower GPGI (p=0.004), and depressed patients had a lower GPGI (p<0.001). CONCLUSION: Quality of life improved over time for PLHIV on ART. Regardless of treatment status, PLHIV with depression or low education level and female gender were at risk of having a poor quality of life. Clinicians and policy makers should be aware of these findings, and address them to improve quality of life for PLHIV. PMID- 26039735 TI - Active Chiral Plasmonics. AB - Active control over the handedness of a chiral metamaterial has the potential to serve as key element for highly integrated polarization engineering approaches, polarization sensitive imaging devices, and stereo display technologies. However, this is hard to achieve as it seemingly involves the reconfiguration of the metamolecule from a left-handed into a right-handed enantiomer and vice versa. This type of mechanical actuation is intricate and usually neither monolithically realizable nor viable for high-speed applications. Here, enabled by the phase change material Ge3Sb2Te6 (GST-326), we demonstrate a tunable and switchable mid infrared plasmonic chiral metamaterial in a proof-of-concept experiment. A large tunability range of the circular dichroism response from lambda = 4.15 to 4.90 MUm is achieved, and we experimentally demonstrate that the combination of a passive bias-type chiral layer with the active chiral metamaterial allows for switchable chirality, that is, the reversal of the circular dichroism sign, in a fully planar, layered design without the need for geometrical reconfiguration. Because phase change materials can be electrically and optically switched, our designs may open up a path for highly integrated mid-IR polarization engineering devices that can be modulated on ultrafast time scales. PMID- 26039736 TI - Bisthiodiketopiperazines and Acorane Sesquiterpenes Produced by the Marine Derived Fungus Penicillium adametzioides AS-53 on Different Culture Media. AB - Chemical investigation of the marine-sponge-derived fungus Penicillium adametzioides AS-53 resulted in the identification of two new bisthiodiketopiperazine derivatives, adametizines A (1) and B (2), from cultivation in a liquid potato-dextrose broth (PDB) culture medium, whereas two new acorane sesquiterpenes, adametacorenols A (3) and B (4), were isolated from a rice solid culture medium. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The absolute configuration of compound 1 was determined by X-ray crystallographic analysis, and that of 3 was determined by modified Mosher's method. Compound 1 exhibited lethality against brine shrimp (Artemia salina) with an LD50 value of 4.8 MUM and inhibitory activities against Staphyloccocus aureus, Aeromonas hydrophilia, Vibrio spp. V. harveyi and V. parahaemolyticus, and Gaeumannomyces graminis with minimum inhibitory concentration values of 8, 8, 32, 8, and 16 MUg/mL, respectively. Chlorination at C-7 significantly increased the brine shrimp lethality and antimicrobial activity of the bisthiodiketopiperazines. PMID- 26039737 TI - Aptamer-based Sandwich Assay and its Clinical Outlooks for Detecting Lipocalin-2 in Hepatocellular Carcinoma (HCC). AB - We validated a single-stranded, DNA aptamer-based, diagnostic method capable of detecting Lipocalin-2 (LCN2), a biomarker from clinically relevant hepatocellular carcinoma (HCC) patient serum, in the sandwich assay format. Nine aptamers (LCN2_apta1 to LCN2_apta9) for LCN2 were screened with SELEX processes, and a sandwich pair (LCN2_apta2 and LCN2_apta4) was finally chosen using surface plasmon resonance (SPR) and dot blotting analysis. The result of the proposed aptamer sandwich construction shows that LCN2 was sensitively detected in the concentration range of 2.5-500 ng mL(-1) with a limit of detection of 0.6 ng mL( 1). Quantitative measurement tests in HCC patients were run on straight serum and were compared with the performance of the conventional antibody-based ELISA kit. The aptamer sandwich assay demonstrated an excellent dynamic range for LCN2 at clinically relevant serum levels, covering sub-nanogram per mL concentrations. The new approach offers a simple and robust method for detecting serum biomarkers that have low and moderate abundance. It consists of functionalization, hybridization and signal read-out, and no dilution is required. The results of the study demonstrate the capability of the aptamer sandwich assay platform for diagnosing HCC and its potential applicability to the point-of-care testing (POCT) system. PMID- 26039739 TI - Factors associated with higher sitting time in general, chronic disease, and psychologically-distressed, adult populations: findings from the 45 & up study. AB - This study examined factors associated with higher sitting time in general, chronic disease, and psychologically-distressed, adult populations (aged >=45 years). A series of logistic regression models examined potential socio demographic and health factors associated with higher sitting (>=6hrs/day) in adults from the 45 and Up Study (n = 227,187), including four separate subsamples for analysis comprising those who had ever had heart disease (n = 26,599), cancer (n = 36,381), diabetes (n = 19,550) or psychological distress (n = 48,334). Odds of higher sitting were significantly (p<.01) associated with a number of factors across these groups, with an effect size of ORs>=1.5 observed for the high-income >=$70,000AUD, employed full-time and severe physical limitations demographics. Identification of key factors associated with higher sitting time in this population-based sample will assist development of broad-based, public health and targeted strategies to reduce sitting-time. In particular, those categorized as being high-income earners, full-time workers, as well as those with severe physical limitations need to be of priority, as higher sitting appears to be substantial across these groups. PMID- 26039740 TI - Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion. AB - BACKGROUND: Sleep deprivation (SD) plays a complex role in central nervous system (CNS) diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR). METHODS: One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU) and neuron-specific enolase (NSE), respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d. RESULTS: The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects. CONCLUSIONS: Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG) of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process. PMID- 26039742 TI - US FDA oncology drug approvals in 2014. AB - Cancer is a close second to heart disease for cause of death in the USA, and could soon surpass heart disease as the population ages and the incidence of cancer continues to increase. While heart disease can be addressed through behavior modification and education (e.g., smoking cessation, dietary changes, exercises that promote cardiovascular fitness), pharmacology and improved surgical devices and methods, cancer ultimately requires improved and novel drug treatments to bring mortality rates down. In 2014, the US FDA approved 17 drugs and/or drug combinations in 12 disease sites for a total of 19 indications in melanoma, hematologic malignancies, gastrointestinal carcinoma, non-small-cell lung cancer, gynecologic malignancies and lymphoma/lymphoproliferative disorders. PMID- 26039743 TI - Bioaccumulation of Heavy Metals and Microelements in Silver Bream (Brama brama L.), Northern Pike (Esox lucius L.), Sterlet (Acipenser ruthenus L.), and Common Carp (Cyprinus carpio L.) From Tisza River, Serbia. AB - The aim of this study was to determine the concentrations of Al, As, B, Cd, Co, Cr, Cu, Fe, Hg, Mn, Ni, Pb, Se, Sr, and Zn in liver, gills, gonads, and brain of four ecologically different fish species in Serbia: piscivorous northern pike, benthivorous sterlet and silver bream, and omnivorous common carp. Fish were caught at four sites along the stretch of the River Tisza in the Pannonian part of Serbia during October 2010. Results revealed that heavy metals and microelements with the highest values in fish samples were Fe, Al, and Zn. The highest concentration of heavy metals and microelements was recorded in omnivorous common carp, and organs that most intensively accumulated the greatest number of metals were liver and gills, whereas the locality did not exert a marked impact on level of bioaccumulation. PMID- 26039741 TI - Anthropogenic and ecological drivers of amphibian disease (ranavirosis). AB - Ranaviruses are causing mass amphibian die-offs in North America, Europe and Asia, and have been implicated in the decline of common frog (Rana temporaria) populations in the UK. Despite this, we have very little understanding of the environmental drivers of disease occurrence and prevalence. Using a long term (1992-2000) dataset of public reports of amphibian mortalities, we assess a set of potential predictors of the occurrence and prevalence of Ranavirus-consistent common frog mortality events in Britain. We reveal the influence of biotic and abiotic drivers of this disease, with many of these abiotic characteristics being anthropogenic. Whilst controlling for the geographic distribution of mortality events, disease prevalence increases with increasing frog population density, presence of fish and wild newts, increasing pond depth and the use of garden chemicals. The presence of an alternative host reduces prevalence, potentially indicating a dilution effect. Ranavirosis occurrence is associated with the presence of toads, an urban setting and the use of fish care products, providing insight into the causes of emergence of disease. Links between occurrence, prevalence, pond characteristics and garden management practices provides useful management implications for reducing the impacts of Ranavirus in the wild. PMID- 26039744 TI - Increased Levels of 8-Isoprostane in EBC of NO2-Exposed Rats. AB - Several epidemiological studies have shown the impact on respiratory health of pollution of nitrogen dioxide (NO2), particulate matter (PM10), and ozone (O3) as an environmental mixture. However, the influence of individual components of airborne pollutants is less well known. Our study examined the cumulative effects of a single pollutant, NO2, on sensitized rats by measurement of isoprostane release in exhaled breath condensate (EBC). Three groups of six rats were used: (1) controls (only exposed to air), (2) sensitized and challenged by ovalbumin and exposed to air, and (3) sensitized, challenged by ovalbumin, and exposed to NO(2). There was no marked change in 8-isoprostane levels in EBC of sensitized rats, whereas a significant increase of 8-isoprostane was found in rats sensitized and exposed to NO2. Data indicate effect of exposure to NO2 is evident as increased 8-isoprostane levels in EBC, a relevant marker for assessment of pulmonary inflammation or oxidant stress and conventionally found in EBC of asthmatic subjects. PMID- 26039745 TI - In vivo effects of naproxen, salicylic acid, and valproic acid on the pharmacokinetics of trichloroethylene and metabolites in rats. AB - It was recently demonstrated that some drugs modulate in vitro metabolism of trichloroethylene (TCE) in humans and rats. The objective was to assess in vivo interactions between TCE and three drugs: naproxen (NA), valproic acid (VA), and salicylic acid (SA). Animals were exposed to TCE by inhalation (50 ppm for 6 h) and administered a bolus dose of drug by gavage, equivalent to 10-fold greater than the recommended daily dose. Samples of blood, urine, and collected tissues were analyzed by headspace gas chromatography coupled to an electron capture detector for TCE and metabolites (trichloroethanol [TCOH] and trichloroacetate [TCA]) levels. Coexposure to NA and TCE significantly increased (up to 50%) total and free TCOH (TCOHtotal and TCOHfree, respectively) in blood. This modulation may be explained by an inhibition of glucuronidation. VA significantly elevated TCE levels in blood (up to 50%) with a marked effect on TCOHtotal excretion in urine but not in blood. In contrast, SA produced an increase in TCOHtotal levels in blood at 30, 60, and 90 min and urine after coexposure. Data confirm in vitro observations that NA, VA, and SA affect in vivo TCE kinetics. Future efforts need to be directed to evaluate whether populations chronically medicated with the considered drugs display greater health risks related to TCE exposure. PMID- 26039746 TI - Airborne microorganisms associated with packaging glass sorting facilities. AB - In recent years, efforts have been undertaken to reduce the volume of residual waste through sorting and recycling. The waste management and recycling sector is thriving and the number of workers there is increasing. In this context, prior knowledge of the risks to which workers may be exposed is of crucial importance, and preventive measures need to be put in place to accurately identify and quantify those risks. This study aimed to assess occupational risk of exposure to biological agents (viable bacteria and fungi) in a Portuguese waste packaging glass sorting plant. Air samples were collected from selected locations in waste sorting cabins (critical area, CA), administrative services (noncritical area, NCA) and outdoors (control point, CP). Duplicate air samples were collected through an impaction method. The investigation was carried out over an 8-mo period with two collection periods, autumn/winter (AW) and spring/summer (SS), in order to access the influence of any seasonal variation. In the 36 air samples collected, 319 bacterial and 196 mold identifications were performed. Air samples revealed existence of high environmental contamination by bacteria (1.6 * 10(4) colony forming units [cfu]/m(3)) and fungi (1.5 * 10(4) cfu/m(3)). The predominant bacterial genus was Staphylococcus (coagulase negative) with values ranging from 29.6 to 60% of the total count of bacteria. Genera Bacillus, Micrococcus, and Staphylococcus (coagulase negative) were also present at all sampling sites, regardless of the season. However, the counts of these genera, in the CA, were higher in warmer seasons. The genus Penicillium was the most frequent genus present with an approximate value of 95% of total fungal count in the CA. Seasonal variation was a significant factor for total bacteria and fungi, except for NCA versus CP. Overall, the highest levels of bacterial and fungal species (10(4) cfu/m(3)) were found in the waste sorting cabin (CA). These results highlight the importance of proper design and risk evaluation when planning a new waste facility, such that working conditions minimize proliferation of biological agents in the workplace. PMID- 26039747 TI - Mitochondrial-mediated apoptosis pathway in alveolar epithelial cells exposed to the metals in combustion-generated particulate matter. AB - Previously a significant mitochondrial impairment was identified in alveolar epithelial cells exposed to metals adsorbed to combustion-generated particulate matter (PM). Due to the critical role of mitochondria in apoptosis, the aim of this study was to investigate the pro-apoptotic potential of metals present in oil fly ash (OFA). A549 cells were exposed to water-soluble components of an OFA sample, containing vanadium [V(IV)], iron [Fe(III)], and nickel [Ni(II)] (68.8, 110.4, and 18 MUM, respectively). Experiments were also performed using individual metal solutions. Apoptosis was detected and the mitochondrial role was assessed by a caspase-9 inhibitor (Z-LEHD-FMK). To determine whether the presence of impaired mitochondria in unexposed daughter cells increased apoptosis, an in vitro model was developed that allowed determination of effects until the third cell generation. To specifically examine the toxicity of vanadium (V), that characterize the airborne pollutant examined in this study, p53involvement and metabolic impairment through changes in HIF-1alpha and Glut-1 expression were determined. OFA and individual metal solutions produced significant apoptosis in the progeny of exposed cells, triggering the intrinsic apoptosis pathway. In apoptosis induced by poorly genotoxic metal V, p53 did not play a significant role. However, V exposure increased nuclear translocation of HIF-1alpha and expression of the Glut-1 receptor, indicating metabolic impairment due to metal induced mitochondrial dysfunction. Overall, these results improve our knowledge of the pathogenic role that airborne metals and in particular V exerted in respiratory epithelium. PMID- 26039749 TI - Erratum: When climate change couples social neglect: malaria dynamics in Panama. AB - [This corrects the article DOI: 10.1038/emi.2014.27.]. PMID- 26039748 TI - A Network Meta-Analysis of Efficacy and Evaluation of Safety of Subcutaneous Pegylated Interferon Beta-1a versus Other Injectable Therapies for the Treatment of Relapsing-Remitting Multiple Sclerosis. AB - Subcutaneous pegylated interferon beta-1a (peginterferon beta-1a [PEG-IFN]) 125 MUg every two or four weeks has been studied in relapsing-remitting multiple sclerosis (RRMS) patients in the pivotal Phase 3 ADVANCE trial. In the absence of direct comparative evidence, a network meta-analysis (NMA) was conducted to provide an indirect assessment of the relative efficacy, safety, and tolerability of PEG-IFN versus other injectable RRMS therapies. Systematic searches were conducted in MEDLINE, Embase, and the Cochrane Library, and conference proceedings from relevant annual symposia were hand-searched. Included studies were randomized controlled trials evaluating >=1 first-line treatments including interferon beta-1a 30, 44, and 22 MUg, interferon beta-1b, and glatiramer acetate in patients with RRMS. Studies were included based on a pre-specified protocol and extracted by a team of independent reviewers and information scientists, utilizing criteria from NICE and IQWiG. In line with ADVANCE findings, NMA results support that PEG-IFN every 2 weeks significantly reduced annualized relapse rate, and 3- and 6-month confirmed disability progression (CDP) versus placebo. There was numerical trend favoring PEG-IFN every 2 weeks versus other IFNs assessed for annualized relapse rate, and versus all other injectables for 3 and 6-month CDP (6-month CDP was significantly reduced versus IFN beta-1a 30 MUg). The safety and tolerability profile of PEG-IFN beta-1a 125 MUg every 2 weeks was consistent with that of other evaluated treatments. Study limitations for the NMA include variant definitions of relapse and other systematic differences across trials, assumptions that populations were sufficiently similar, and inability to perform NMA of adverse events. With similar efficacy compared to other RRMS treatments in terms of annualized relapse rate and 3- and 6-month CDP, a promising safety profile, and up to 93% reduction in number of injections (which may improve adherence), PEG-IFN every 2 weeks offers a valuable alternative treatment option for patients with RRMS. PMID- 26039750 TI - Influence of Nano-HA Coated Bone Collagen to Acrylic (Polymethylmethacrylate) Bone Cement on Mechanical Properties and Bioactivity. AB - OBJECTIVE: This research investigated the mechanical properties and bioactivity of polymethylmethacrylate (PMMA) bone cement after addition of the nano hydroxyapatite(HA) coated bone collagen (mineralized collagen, MC). MATERIALS & METHODS: The MC in different proportions were added to the PMMA bone cement to detect the compressive strength, compression modulus, coagulation properties and biosafety. The MC-PMMA was embedded into rabbits and co-cultured with MG 63 cells to exam bone tissue compatibility and gene expression of osteogenesis. RESULTS: 15.0%(wt) impregnated MC-PMMA significantly lowered compressive modulus while little affected compressive strength and solidification. MC-PMMA bone cement was biologically safe and indicated excellent bone tissue compatibility. The bone cement interface crosslinking was significantly higher in MC-PMMA than control after 6 months implantation in the femur of rabbits. The genes of osteogenesis exhibited significantly higher expression level in MC-PMMA. CONCLUSIONS: MC-PMMA presented perfect mechanical properties, good biosafety and excellent biocompatibility with bone tissues, which has profoundly clinical values. PMID- 26039752 TI - Highly Selective Relaxation of the OH Stretching Overtones in Isolated HDO Molecules Observed by Infrared Pump-Repump-Probe Spectroscopy. AB - A quantitative investigation of the relaxation dynamics of higher-lying vibrational states is afforded by a novel method of infrared pump-repump-probe spectroscopy. The technique is used to study the dynamics of OH stretching overtones in NaClO4.HDO monohydrate. We observe a continuous decrease of the energy separation for the first four states, i.e. v01 = 3575 cm(-1), v12 = 3370 cm(-1), and v23 = 3170 cm(-1), respectively. The population lifetime of the first excited state is 7.2 ps, while the one of the second excited state is largely reduced to 1.4 ps. The relaxation of the v = 2 state proceeds nearly quantitatively to the v = 1 state. The new information on the OH stretching overtones demands improved theoretical potentials and modeling of the H bond interactions. This work shows the potential of the new technique for the precise study of complex vibrational relaxation pathways. PMID- 26039751 TI - Protection of Candida parapsilosis from neutrophil killing through internalization by human endothelial cells. AB - Candida parapsilosis is a fungal pathogen that is associated with hematogenously disseminated disease in premature neonates, acutely ill or immunocompromised patients. In cell culture, C. parapsilosis cells are actively and avidly endocytosed by endothelial cells via actin polymerization mediated by N-WASP. Here we present evidence that C. parapsilosis that were internalized by endothelial cells remained alive, and avoided being acidified or otherwise damaged via the host cell. Internalized fungal cells reproduced intracellularly and eventually burst out of the host endothelial cell. When neutrophils were added to endothelium and C. parapsilosis, they patrolled the endothelial surface and efficiently killed most adherent fungal cells prior to endocytosis. But after endocytosis by endothelial cells, internalized fungal cells evaded neutrophil killing. Silencing endothelial N-WASP blocked endocytosis of C. parapsilosis and left fungal cells stranded on the cell surface, where they were susceptible to neutrophil killing. These observations suggest that for C. parapsilosis to escape from the bloodstream, fungi may adhere to and be internalized by endothelial cells before being confronted and phagocytosed by a patrolling leukocyte. Once internalized by endothelial cells, C. parapsilosis may safely replicate to cause further rounds of infection. Immunosurveillance of the intravascular lumen by leukocytes crawling on the endothelial surface and rapid killing of adherent yeast may play a major role in controlling C. parapsilosis dissemination and infected endothelial cells may be a significant reservoir for fungal persistence. PMID- 26039754 TI - Evaluating heterogeneous conservation effects of forest protection in Indonesia. AB - Establishing legal protection for forest areas is the most common policy used to limit forest loss. This article evaluates the effectiveness of seven Indonesian forest protected areas introduced between 1999 and 2012. Specifically, we explore how the effectiveness of these parks varies over space. Protected areas have mixed success in preserving forest, and it is important for conservationists to understand where they work and where they do not. Observed differences in the estimated treatment effect of protection may be driven by several factors. Indonesia is particularly diverse, with the landscape, forest and forest threats varying greatly from region to region, and this diversity may drive differences in the effectiveness of protected areas in conserving forest. However, the observed variation may also be spurious and arise from differing degrees of bias in the estimated treatment effect over space. In this paper, we use a difference in-differences approach comparing treated observations and matched controls to estimate the effect of each protected area. We then distinguish the true variation in protected area effectiveness from spurious variation driven by several sources of estimation bias. Based on our most flexible method that allows the data generating process to vary across space, we find that the national average effect of protection preserves an additional 1.1% of forest cover; however the effect of individual parks range from a decrease of 3.4% to an increase of 5.3% and the effect of most parks differ from the national average. Potential biases may affect estimates in two parks, but results consistently show Sebangau National Park is more effective while two parks are substantially less able to protect forest cover than the national average. PMID- 26039753 TI - Shiga toxin 2a and Enteroaggregative Escherichia coli--a deadly combination. AB - In 2011, a Shiga toxin (Stx) type 2a-producing enteroaggregative E. coli (EAEC) strain of serotype O104:H4 caused a large lethal outbreak in Northern Europe. Until recently, the pathogenic mechanisms explaining the high virulence of the strain have remained unclear. Our laboratories have shown that EAEC genes encoded on the pAA virulence plasmid, particularly the AggR-regulated AAF/I fimbriae, enhance inflammation and enable the outbreak strain to both adhere to epithelial cells and translocate Stx2a across the intestinal epithelium, possibly explaining the high incidence of the life threatening post-diarrheal sequelae of hemolytic uremic syndrome. Epidemiologic evidence supports a model of EAEC pathogenesis comprising the concerted action of multiple virulence factors along with induction of inflammation. Here, we suggest a model for the pathogenesis of the O104:H4 outbreak strain that includes contributions from EAEC alone, but incorporating additional injury induced by Stx2a. PMID- 26039756 TI - Correction: Associations between Neuroticism and Depression in Relation to Catastrophizing and Pain-Related Anxiety in Chronic Pain Patients. PMID- 26039755 TI - Melanophilin Stimulates Myosin-5a Motor Function by Allosterically Inhibiting the Interaction between the Head and Tail of Myosin-5a. AB - The tail-inhibition model is generally accepted for the regulation of myosin-5a motor function. Inhibited myosin-5a is in a folded conformation in which its globular tail domain (GTD) interacts with its head and inhibits its motor function, and high Ca(2+) or cargo binding may reduce the interaction between the GTD and the head of myosin-5a, thus activating motor activity. Although it is well established that myosin-5a motor function is regulated by Ca(2+), little is known about the effects of cargo binding. We previously reported that melanophilin (Mlph), a myosin-5a cargo-binding protein, is capable of activating myosin-5a motor function. Here, we report that Mlph-GTBDP, a 26 amino-acid-long peptide of Mlph, is sufficient for activating myosin-5a motor function. We demonstrate that Mlph-GTBDP abolishes the interaction between the head and GTD of myosin-5a, thereby inducing a folded-to-extended conformation transition for myosin-5a and activating its motor function. Mutagenesis of the GTD shows that the GTD uses two distinct, non-overlapping regions to interact with Mlph-GTBDP and the head of myosin-5a. We propose that the GTD is an allosteric protein and that Mlph allosterically inhibits the interaction between the GTD and head of myosin-5a, thereby activating myosin-5a motor function. PMID- 26039758 TI - The socially responsible medical school. PMID- 26039759 TI - The social mission in medical school mission statements: associations with graduate outcomes. AB - BACKGROUND AND OBJECTIVES: Mission statements of medical schools vary considerably. These statements reflect institutional values and may also be reflected in the outputs of their institutions. The authors explored the relationship between US medical school mission statement content and outcomes in terms of graduate location and specialty choices. METHODS: A panel of stakeholders (medical school deans, faculty, medical students, and administrators) completed a Web-based instrument to create a linear scale of social mission content (SMC scale), scoring the degree to which medical school mission statements reflect the social mission of medical education to address inequities. The SMC scale and targeted medical school outputs were analyzed via OLS regression, controlling for allopathic/osteopathic and public/private school designation. The medical school outputs of interest included percent physician output in primary care specialties (family medicine, pediatrics, and general internal medicine), as well as percent physician output in designated Health Professional Shortage Areas (HPSA) and Medically Underserved Areas/Populations (MUA/P). RESULTS: SMC scale was a statistically significant, positive predictor of the percent of physician graduates entering primary care (?=2.526, P=.001). When examining the specialties within primary care, the SMC scale only significantly predicted percent of graduating physicians entering family medicine (?=1.936, P=.003). SMC scale was also a statistically significant predictor of several measures of physician output to work in underserved areas and populations, the strongest of which was the percent of graduating physicians working in MUA/Ps (?=4.256, P?.01). CONCLUSIONS: Mission statements that are diligently utilized by leaders in medical education may produce a higher degree of alignment between institutional structure, ideology, and workforce outcomes. PMID- 26039757 TI - Molecular Epidemiology of HIV-1 Infection among Men who Have Sex with Men in Taiwan in 2012. AB - The number of men who have sex with men (MSM) infected with HIV-1 in Taiwan has increased rapidly in the past few years. The goal of this study was to conduct a molecular epidemiological study of HIV-1 infection among MSM in Taiwan to identify risk factors for intervention. Voluntary counseling program and anonymous testing were provided to patrons at 1 gay bar, 7 night clubs and 3 gay saunas in Taipei and New Taipei Cities in 2012. HIV-1 subtypes were determined using gag subtype-specific PCR and phylogenetic analysis by env sequences. Recent HIV-1 infection was determined using LAg-Avidity EIA. In-depth interviews and questionnaires were used to identify risk factors. The prevalence and incidence of HIV-1 among MSM in Taiwan were 4.38% (53/1,208) and 3.29 per 100 person-years, respectively. Of 49 cases genotyped, 48 (97.9%) were infected with subtype B and 1 with CRF01_AE (2%). Phylogenetic analysis of 46 HIV-1 strains showed that 25 (54.4%) subtype B strains formed 9 clusters with each other or with other local strains. The CRF01_AE case clustered with a reference strain from a Thai blood donor with bootstrap value of 99. Multivariate logistic regression analysis showed that risk factors associated with HIV-1 infection included use of oil based solution as lubricant (vs. saliva or water-based lubricants, OR= 4.23; p <0.001); exclusively receptive role (vs. insertive role, OR= 9.69; p <0.001); versatile role (vs. insertive role, OR= 6.45; p= 0.003); oral sex (vs. insertive role, OR= 11.93; p= 0.044); times of sexual contact per week (2-3 vs. zero per week, OR= 3.41; p= 0.021); illegal drug use (OR= 4.12; p <0.001); and history of sexually transmitted diseases (OR= 3.65; p= 0.002). In conclusion, there was no new HIV-1 subtype or circulating recombinant form responsible for the increase of HIV-1 among MSM in Taiwan in 2012. Misuse of oil-based solution as lubricant is a new risk factor identified among MSM in Taiwan. The Taiwan's Centers for Disease Control has created a video (www.youtube.com/watch?v=BinExvvOTMM&feature=iv&src_vid=BW81 PfmY3E&annotation_id=annotation_2436493705) to correct such misconception in its AIDS prevention campaign. PMID- 26039760 TI - Perceptions of interprofessional education in the Australian Advanced Life Support in Obstetrics (ALSO) course. AB - BACKGROUND AND OBJECTIVES: Interprofessional education (IPE) was investigated in the context of an evaluation of the Advanced Life Support in Obstetrics (ALSO) course in Australia. Our objectives were to examine doctors' and midwives' perceptions regarding interprofessional learning and measure changes in self reported confidence in specific interprofessional clinical situations. METHODS: A prospective, mixed methods design was used to survey 165 ALSO course participants before the course and 6 weeks after the course (n=101). Quantitative data were analysed using the Wilcoxon signed rank test, and all P levels lower than .05 were considered significant. Qualitative data were analyzed using content analysis. RESULTS: There were significant increases in midwives' confidence in all four aspects of interprofessional interaction measured 6 weeks following the course. However, the doctors only reported a significant increase in one aspect, the confidence that their clinical decisions were respected by the midwives with whom they worked. The qualitative data demonstrated an appreciation of different professional approaches to clinical situations and the importance of teamwork, communication, respect, and understanding. While most participants were positive about the advantages of IPE, just under half also believed there were some disadvantages, particularly due to the variable learning needs of individual professionals. CONCLUSIONS: Both doctors and midwives reported various benefits from IPE, and many believed that IPE assisted maternity team collaboration and communication in the workplace. However, educators need to skillfully manage IPE sessions to ensure a similar distribution of learning and that opportunities for discussion are equivalent for all individuals and professional groups. PMID- 26039761 TI - Teaching residents electronic fetal monitoring: a national needs assessment. AB - BACKGROUND AND OBJECTIVES: Competence and standardization in Electronic Fetal Monitoring (EFM) interpretation are important elements for improving intrapartum fetal outcomes. Computer-based learning modules constitute a tool that can facilitate access and standardize education of EFM interpretation in family medicine residencies. The goals of this study were to determine current practices related to EFM education strategies in family medicine residency programs as well as evaluate the perceptions of residents' EFM competency and need for computer based EFM learning. METHODS: We surveyed obstetrics curriculum directors at 423 family medicine residency programs using a 10-question, web-based survey. RESULTS: A total of 208 programs participated (49% response rate); 74% (151/204) of obstetrics curriculum directors reported a need for a new computer-based EFM tutorial. This need was reported while 33% (68/204) of programs reported already using a computer-based EFM resource, and 91% (178/196) reported having resident trainees with competent EFM interpretation skills. CONCLUSIONS: This national study of family medicine obstetrics curriculum directors identified a perceived need for computer-based EFM learning to enhance family medicine obstetrics training. PMID- 26039762 TI - Resident-as-teacher in family medicine: a CERA survey. AB - BACKGROUND AND OBJECTIVES: Teaching has been increasingly recognized as a primary responsibility of residents. Residents enjoy teaching, and their majority report interest in the continuation of teaching activities after graduation. Resident-as teacher programs have emerged nationally as a means of enhancing teaching skills. This study examined the current use of residents-as-teachers programs in family medicine residencies through a national survey of family medicine residency program directors. METHODS: This survey project was part of the Council of Academic Family Medicine Education Research Alliance (CERA) 2014 survey to family medicine program directors that was conducted between February 2014 and May 2014. RESULTS: The response rate of the survey was 49.6% (224/451). The majority (85.8%) of residency programs offer residents formal instruction in teaching skills. The vast majority (95.6%) of programs mandated the training. The average total hours of teaching instruction residents receive while in residency training was 7.72. The residents are asked to formally evaluate the teaching instruction in 68.1% of the programs. Less than a quarter (22.6%) of residency programs offer the teaching instruction in collaboration with other programs. "Retreat, workshop, and seminars" were identified as the main form of instruction by 33.7% of programs. In 83.3% of programs not offering instruction, lack of resources was identified as the primary barrier. CONCLUSIONS: The majority of family medicine residency programs provide resident-as-teacher instructions, which reflects increasing recognition of importance of the teaching role of residents. Further research is needed to assess the effectiveness of such instruction on residents' teaching skills and their attitudes toward teaching. PMID- 26039764 TI - Family medicine residents remain unaware of hospital charges for diagnostic testing. AB - BACKGROUND AND OBJECTIVES: The Accreditation Council for Graduate Medical Education (ACGME) has mandated that resident training programs incorporate instruction on the economic reality of health care. Studies over the past 15 years have demonstrated that resident physicians, as well as physicians in practice, are unaware of the charges associated with commonly ordered diagnostic tests. The last study to document family medicine residents' knowledge of the hospital charges associated with diagnostic studies was published over 10 years ago. With increasing emphasis on cost containment in the past decade, we attempted to determine if any change over time had occurred in family medicine residents' knowledge of the charges associated with commonly ordered diagnostic studies. METHODS: Sixteen common laboratory and radiology tests were surveyed and distributed to 30 resident physicians at a community-based, family medicine residency program. Estimates within 25% of the actual charges were considered correct. These results were then compared to prior similar research. Correlation between years of completed training and percentage of correct estimates was also assessed. RESULTS: A total of 26 of 30 surveys (87%) were completed and compared to actual charges. Only 81 (19%) of 416 estimates were within 25% of actual charges. No improvement was noted with advanced years of training. Compared to previous work, this study does not show gains in cost awareness among family medicine residents. CONCLUSIONS: Family medicine residents remain largely unaware of the hospital charges associated with diagnostic studies despite increasing emphasis on cost containment. These results will hopefully expose the persistent lack of awareness of the costs associated with ordered radiology and laboratory studies. PMID- 26039763 TI - Teaching maternity care in family medicine residencies: what factors predict graduate continuation of obstetrics? A 2013 CERA program directors study. AB - BACKGROUND AND OBJECTIVES: Maternity care is an essential component of family medicine, yet the number of residency graduates providing this care continues to decline. Residency programs have struggled to identify strategies to increase continuation of obstetric practice among graduates. Leaders in family medicine obstetrics previously proposed a tiered model of training to ensure adequate volume for those desiring to continue maternity care upon graduation. However, whether this approach will be successful is unknown. This study aimed to identify program characteristics and teaching methods that may influence residents to continue obstetrics practice upon graduation. METHODS: A nationwide survey of family medicine residency program directors (PDs) was conducted as part of the 2013 CERA survey to characterize teaching in maternity care and identify program level predictors of graduate continuation of obstetrics (OB). RESULTS: Family medicine programs, which were community-based, university-affiliated programs in the Midwest and West, contributed more trainees who continued to provide OB care upon graduation. Trainees at these programs received greater supervision by family medicine faculty preceptors on labor and delivery, reported at least 80 deliveries by graduates during residency, and experienced greater autonomy in decision-making during OB rotations. CONCLUSIONS: This study supports a targeted approach to teaching maternity care in family medicine residency programs. Prioritizing continuity delivery experiences and fostering resident independence are strategies toward promoting increased provision of obstetric care by family medicine graduates. Further research is needed to evaluate the impact of tiered or track systems in practice. PMID- 26039765 TI - Free pregnancy testing increases maternity care volume in family medicine residencies. AB - BACKGROUND AND OBJECTIVES: Increased prenatal volume in family medicine residencies is associated with a higher proportion of graduates including maternity care in their post-residency practices. However, family medicine residencies struggle just to meet the Residency Review Committee's minimum requirements for maternity care volume. Our objective was to evaluate the effectiveness of free pregnancy testing on increasing maternity care volume in our residency. METHODS: In this before-after intervention study, free pregnancy testing was offered at the residency's Family Health Center (FHC) from May 2011 through November 2012 to established patients and non-patients. Participants with positive tests were provided information on maternity care and an opportunity to schedule an initial prenatal visit. The primary outcome was the percentage of self-referred patients who established prenatal care at FHC. RESULTS: Over 19 months, 241 tests were performed on 224 women with a mean age of 26.2+/-6.3. Over half were minorities (130 [58%]). Most were under-insured or uninsured (193 [86.1%]). Ninety-nine women (41.1%) had positive tests; 74 of these 99 women (74.7%) established prenatal care at FHC, and 57 of these 74 women (77%) were new patients. The number of obstetric patients increased 13% from 405 to 456 patients. The percentage of self-referred patients increased from 31.9% to 40.8% (P<.001). The total cost of 241 pregnancy tests was $256.24, and maternity care revenue for just one patient was $1,553. CONCLUSIONS: The program's return on investment is favorable. Offering free pregnancy testing is a simple and inexpensive way to increase maternity care volume in a family medicine residency. PMID- 26039766 TI - IUD knowledge and experience among family medicine residents. AB - BACKGROUND AND OBJECTIVES: The intrauterine device (IUD) is a highly effective contraceptive method with few contraindications; however, clinician lack of training in insertion and misconceptions about IUD risks are barriers to utilization. Previous research has shown gaps in IUD training in family medicine residency programs. METHODS: An online survey addressing experience with IUD insertion, knowledge of patient eligibility and IUD risks, and intent to insert IUDs in practice was circulated to residents at 15 US family medicine residency programs. Programs were eligible to participate if they were receiving funding to enhance training in family planning and abortion care and interested in additional support to enhance IUD training. RESULTS: The overall response rate for the surveys was 76.1% (332/436). Experience with the levonorgestrel intrauterine system was more common than with the copper IUD. Residents performed well on knowledge questions, but many would not insert in common patient scenarios in which insertion was not contraindicated, including a history of sexually transmitted infection in the past 6 months (48.2% would not insert), a history of ectopic pregnancy (37.0%), no pap smear in the past year (30.7%), or if the patient was not in a monogamous relationship (29.2%). The vast majority of residents (88.7%) reported that they were likely or very likely to provide IUDs in their future family medicine practice. CONCLUSIONS: Although residents overwhelmingly expressed interest in providing IUDs after residency, our results suggest that additional clinical and didactic training is needed, particularly interventions targeted at dispelling misconceptions about patient eligibility for IUDs. PMID- 26039769 TI - Family medicine leadership: the time is now. PMID- 26039770 TI - Self-treatment and informal treatment for depression among resident physicians. PMID- 26039771 TI - Reply to "self-treatment and informal treatment for depression among resident physicians". PMID- 26039772 TI - Patient comfort during positron emission tomography/magnetic resonance and positron emission tomography/computed tomography examinations: subjective assessments with visual analog scales. AB - OBJECTIVES: The aims of this study were to investigate subjective perceptions and sensory side effects during whole-body positron emission tomography (PET)/magnetic resonance (MR) examinations and to evaluate differences between PET/MR and standard PET/computed tomography (CT) examinations. MATERIAL AND METHODS: During prospective clinical trials using a PET/MR hybrid system after a standard PET/CT examination, 266 patients (including 19 juveniles) were asked to complete questionnaires on causes of discomfort and side effects after both examinations (self-assessment). In case of complaints regarding causes of discomfort, physicians were also asked to complete the questionnaires to provide an external assessment. Visual analog scales were used for the ratings. RESULTS: Seventy-four percent (183/247) of all adult patients and 68% (13/19) of all teenage patients completed the questionnaires. In most of the cases, patient compliance was good and allowed for the acquisition of diagnostic images. Most patients did not report side effects or discomfort at all. Only 11 of 247 PET/MR scans of adult patients (4.4%) and 4 of 19 scans of juvenile patients (21%) were aborted prematurely by the patients' requests; however, this did not influence the final PET/MR diagnoses in most cases (12/15). In terms of noise levels and examination times, patients rated the PET/MR significantly lower than the PET/CT. With the exception of male patients not tolerating the examination time as well as female patients, no significant influences of sex, age, body mass index, and real scan times were observed. The attending physicians tended to underestimate their patient's discomfort, particularly when the discomfort was because of time (in the case of children) or noise exposure (all patients). CONCLUSIONS: Patient comfort should drive the design and development of optimized scanner types, workflow processes, and scan protocols. For PET/MR, the most important aim should be to shorten the scan time. However, patient-centered management may be the best instrument to improve patient compliance. PMID- 26039773 TI - Fifty Years of Technological Innovation: Potential and Limitations of Current Technologies in Abdominal Magnetic Resonance Imaging and Computed Tomography. AB - Magnetic resonance imaging (MRI) has become an important modality for the diagnosis of intra-abdominal pathology. Hardware and pulse sequence developments have made it possible to derive not only morphologic but also functional information related to organ perfusion (dynamic contrast-enhanced MRI), oxygen saturation (blood oxygen level dependent), tissue cellularity (diffusion-weighted imaging), and tissue composition (spectroscopy). These techniques enable a more specific assessment of pathologic lesions and organ functionality. Magnetic resonance imaging has thus transitioned from a purely morphologic examination to a modality from which image-based disease biomarkers can be derived. This fits well with several emerging trends in radiology, such as the need to accurately assess response to costly treatment strategies and the need to improve lesion characterization to potentially avoid biopsy. Meanwhile, the cost-effectiveness, availability, and robustness of computed tomography (CT) ensure its place as the current workhorse for clinical imaging. Although the lower soft tissue contrast of CT relative to MRI is a long-standing limitation, other disadvantages such as ionizing radiation exposure have become a matter of public concern. Nevertheless, recent technical developments such as dual-energy CT or dynamic volume perfusion CT also provide more functional imaging beyond morphology.The aim of this article was to review and discuss the most important recent technical developments in abdominal MRI and state-of-the-art CT, with an eye toward the future, providing examples of their clinical utility for the evaluation of hepatic and renal pathologies. PMID- 26039774 TI - Correlation of quantitative dual-energy computed tomography iodine maps and abdominal computed tomography perfusion measurements: are single-acquisition dual energy computed tomography iodine maps more than a reduced-dose surrogate of conventional computed tomography perfusion? AB - OBJECTIVES: Study objectives were the quantitative evaluation of whether conventional abdominal computed tomography (CT) perfusion measurements mathematically correlate with quantitative single-acquisition dual-energy CT (DECT) iodine concentration maps, the determination of the optimum time of acquisition for achieving maximum correlation, and the estimation of the potential for radiation exposure reduction when replacing conventional CT perfusion by single-acquisition DECT iodine concentration maps. MATERIALS AND METHODS: Dual-energy CT perfusion sequences were dynamically acquired over 51 seconds (34 acquisitions every 1.5 seconds) in 24 patients with histologically verified pancreatic carcinoma using dual-source DECT at tube potentials of 80 kVp and 140 kVp. Using software developed in-house, perfusion maps were calculated from 80-kVp image series using the maximum slope model after deformable motion correction. In addition, quantitative iodine maps were calculated for each of the 34 DECT acquisitions per patient. Within a manual segmentation of the pancreas, voxel-by-voxel correlation between the perfusion map and each of the iodine maps was calculated for each patient to determine the optimum time of acquisition topt defined as the acquisition time of the iodine map with the highest correlation coefficient. Subsequently, regions of interest were placed inside the tumor and inside healthy pancreatic tissue, and correlation between mean perfusion values and mean iodine concentrations within these regions of interest at topt was calculated for the patient sample. RESULTS: The mean (SD) topt was 31.7 (5.4) seconds after the start of contrast agent injection. The mean (SD) perfusion values for healthy pancreatic and tumor tissues were 67.8 (26.7) mL per 100 mL/min and 43.7 (32.2) mL per 100 mL/min, respectively. At topt, the mean (SD) iodine concentrations were 2.07 (0.71) mg/mL in healthy pancreatic and 1.69 (0.98) mg/mL in tumor tissue, respectively. Overall, the correlation between perfusion values and iodine concentrations was high (0.77), with correlation of 0.89 in tumor and of 0.56 in healthy pancreatic tissue at topt. Comparing radiation exposure associated with a single DECT acquisition at topt (0.18 mSv) to that of an 80 kVp CT perfusion sequence (2.96 mSv) indicates that an average reduction of Deff by 94% could be achieved by replacing conventional CT perfusion with a single-acquisition DECT iodine concentration map. CONCLUSIONS: Quantitative iodine concentration maps obtained with DECT correlate well with conventional abdominal CT perfusion measurements, suggesting that quantitative iodine maps calculated from a single DECT acquisition at an organ-specific and patient-specific optimum time of acquisition might be able to replace conventional abdominal CT perfusion measurements if the time of acquisition is carefully calibrated. This could lead to large reductions of radiation exposure to the patients while offering quantitative perfusion data for diagnosis. PMID- 26039777 TI - Wayne Katon, MD. PMID- 26039778 TI - Suicide risk: sunshine or temperature increase? PMID- 26039779 TI - Missing byline author. PMID- 26039780 TI - Medusa's Head and Ancient Aristotelian Biology. PMID- 26039787 TI - [Management of sigmoid volvulus in the tropical area of Thies (Senegal)]. AB - The aim of this study is to report our experience in the management of sigmoid volvulus in a tropical environment. This retrospective study covers the period from June 1, 2010, to December 31, 2013, in the department of emergency surgery at the regional hospital of Thies: 40 patients were admitted with sigmoid volvulus: 36 men and 4 women, with a mean age of 45 years (20-89 years). Twelve had chronic constipation. All four signs of occlusion were present in 72.5% of cases. Abdominal radiography confirmed the diagnosis in all cases. The volvulus resolved spontaneously in one patient, while the other 39 required laparotomy: 25 had a one-stage colectomy, and 11 patients a sigmoidectomy with a temporary colostomy. Two patients underwent a sigmoidopexy, one with a simple closure of a perforated duodenal ulcer. The morbidity rate was 7.5%, due mainly to complications of infection. The mortality rate was 10%. After a mean follow-up of 2.77 months (range: 15 days-12 months), no recurrences were observed. Sigmoid volvulus is a common condition in Africa especially in younger patients. The diagnosis is easy, based on clinical and abdominal radiography findings. Several procedures have been described but the one-stage colectomy remains the method of choice, especially in tropical areas where socioeconomic conditions are difficult. PMID- 26039788 TI - Sun Protection and Skin Examination Practices in a Setting of High Ambient Solar Radiation: A Population-Based Cohort Study. AB - IMPORTANCE: Primary prevention and early detection are integral strategies to reduce the burden of skin cancer. OBJECTIVES: To describe the prevalence of sun protection and skin examination practices in a population exposed to high levels of ambient solar radiation and to identify associated factors. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses of baseline data from a prospective cohort of 40,172 adults aged 40 through 69 years from Queensland, Australia, recruited in 2011. We obtained data on all melanoma diagnoses through 2009 via record linkage with the Queensland Cancer Registry (notifications have been mandatory since 1982). MAIN OUTCOMES AND MEASURES: We calculated prevalence proportion ratios to compare prevalence of sun protection and skin examination practices in 3 separate groups: those with a history of melanoma (group 1), those with a self-reported history of treated actinic lesions (group 2), and those without either (group 3). We used multivariate generalized linear models to identify factors associated with each practice. RESULTS: Participants with a previously confirmed melanoma (group 1; n = 1433) and/or treated actinic lesions (group 2; n = 24,006) were more likely than those without (group 3; n = 14,733) to report sun protection practices, including regular use of sunscreen (53.3%, 45.1%, and 38.1%, respectively) and wearing hats (74.7%, 68.2%, and 58.2%, respectively). They were also more likely to have had a whole-body skin examination by a physician in the past 3 years (93.7%, 83.4%, and 52.1%, respectively). Within all 3 groups, the strongest association with sun protection practices was with sun-sensitive skin type. Within group 3 (no history of treated skin lesions), the strongest factor associated with clinical skin examinations was self-reported nevus density at 21 years of age, whereas a family history of melanoma was a significant factor in groups 2 and 3. CONCLUSIONS AND RELEVANCE: In this large sample exposed to high levels of ambient solar radiation, sun protection and skin examination practices were most frequent among those with a history of treated skin lesions or sun-sensitive skin types. PMID- 26039789 TI - Mechanisms linking metabolism of Helicobacter pylori to (18)O and (13)C-isotopes of human breath CO2. AB - The gastric pathogen Helicobacter pylori utilize glucose during metabolism, but the underlying mechanisms linking to oxygen-18 ((18)O) and carbon-13 ((13)C) isotopic fractionations of breath CO2 during glucose metabolism are poorly understood. Using the excretion dynamics of (18)O/(16)O and (13)C/(12)C-isotope ratios of breath CO2, we found that individuals with Helicobacter pylori infections exhibited significantly higher isotopic enrichments of (18)O in breath CO2 during the 2h-glucose metabolism regardless of the isotopic nature of the substrate, while no significant enrichments of (18)O in breath CO2 were manifested in individuals without the infections. In contrast, the (13)C-isotopic enrichments of breath CO2 were significantly higher in individuals with Helicobacter pylori compared to individuals without infections in response to (13)C-enriched glucose uptake, whereas a distinguishable change of breath (13)C/(12)C-isotope ratios was also evident when Helicobacter pylori utilize natural glucose. Moreover, monitoring the (18)O and (13)C-isotopic exchange in breath CO2 successfully diagnosed the eradications of Helicobacter pylori infections following a standard therapy. Our findings suggest that breath (12)C(18)O(16)O and (13)C(16)O(16)O can be used as potential molecular biomarkers to distinctively track the pathogenesis of Helicobacter pylori and also for eradication purposes and thus may open new perspectives into the pathogen's physiology along with isotope-specific non-invasive diagnosis of the infection. PMID- 26039790 TI - Weekday or Weekend Discharge-Does It Make a Difference? PMID- 26039791 TI - Correction: construction of multi-scale consistent brain networks: methods and applications. PMID- 26039792 TI - Ultrathin Bronchoscopy with Multimodal Devices for Peripheral Pulmonary Lesions. A Randomized Trial. AB - RATIONALE: The combination of an ultrathin bronchoscope, navigational technology, and endobronchial ultrasound (EBUS) seems to combine the best of mutual abilities for evaluating peripheral pulmonary lesions, but ultrathin bronchoscopes that allow the use of EBUS have not been developed so far. OBJECTIVES: To compare the diagnostic yield of transbronchial biopsy under EBUS, fluoroscopy, and virtual bronchoscopic navigation guidance using a novel ultrathin bronchoscope with that using a thin bronchoscope with a guide sheath for peripheral pulmonary lesions. METHODS: In four centers, patients with suspected peripheral pulmonary lesions less than or equal to 30 mm in the longest diameter were included and randomized to undergo transbronchial biopsy with EBUS, fluoroscopy, and virtual bronchoscopic navigation guidance using a 3.0-mm ultrathin bronchoscope (UTB group) or a 4.0-mm thin bronchoscope with a guide sheath (TB-GS group). MEASUREMENTS AND MAIN RESULTS: A total of 310 patients were enrolled and randomized, among whom 305 patients (150, UTB group; 155, TB-GS group) were analyzed. The ultrathin bronchoscope could reach more distal bronchi than the thin bronchoscope (median fifth- vs. fourth-generation bronchi; P < 0.001). Diagnostic histologic specimens were obtained in 74% (42% for benign and 81% for malignant lesions) of the UTB group and 59% (36% for benign and 70% for malignant lesions) of the TB-GS group (P = 0.044, Mantel-Haenszel test). Complications including pneumothorax, bleeding, chest pain, and pneumonia occurred in 3% and 5% in the respective groups. CONCLUSIONS: The diagnostic yield of the UTB method is higher than that of the TB-GS method. Clinical trial registered with www.umin.ac.jp/ctr/ (UMIN 000003177). PMID- 26039794 TI - Synthesis of a New Bimetallic Re(I)-NCS-Pt(II) Complex as Chemodosimetric Ensemble for the Selective Detection of Mercapto-Containing Pesticides. AB - Detection of mercapto-containing pesticides plays a crucial role in food and water safety. A new Re(I)-NCS-Pt(II) complex, [Re(4,4'-di-tert-butyl-2,2' bipyridine)(CO)3(NCS)]-[Pt(DMSO)(Cl)2] (1), was synthesized and characterized. The synthetic procedure, characterization results, and photophysical data for 1 are reported in this paper. Solvated complex 1 demonstrated luminescent chemodosimetric selectivity for phorate, demeton, and aldicarb (three common mercapto-containing pesticides) with method detection limits (MDLs) of 1.00, 2.87, and 2.08 ppm, respectively. The binding constants (log K) of 1 toward them were in the 3.24-3.44 range. The analyte selectivity of the complex was found to be dependent on the bridging linkage (C=N and N?C?S) between the Re(I) and Pt(II) centers. The solid-supported dosimetric device 1 was fabricated by blending complex 1 with Al2O3 and poly(vinyl chloride) (PVC) powder. The MDLs of the device toward the mercapto-containing pesticides were 0.48-0.60 ppm. The device was applicable to pesticides in real water bodies such as taps, rivers, lakes, and underground water bodies with excellent recoveries and relative standard deviations of 76.2-108.0% and 2.9-6.7%, respectively. Its spectrofluorimetric changes could be analyzed by naked eye within 20 min with a linear luminometric response toward increases in the phorate concentration (0-8.0 ppm) with R = 0.999. PMID- 26039793 TI - Characterizations of individual mouse red blood cells parasitized by Babesia microti using 3-D holographic microscopy. AB - Babesia microti causes "emergency" human babesiosis. However, little is known about the alterations in B. microti invaded red blood cells (Bm-RBCs) at the individual cell level. Through quantitative phase imaging techniques based on laser interferometry, we present the simultaneous measurements of structural, chemical, and mechanical modifications in individual mouse Bm-RBCs. 3-D refractive index maps of individual RBCs and in situ parasite vacuoles are imaged, from which total contents and concentration of dry mass are also precisely quantified. In addition, we examine the dynamic membrane fluctuation of Bm-RBCs, which provide information on cell membrane deformability. PMID- 26039795 TI - Extraction of pore-morphology and capillary pressure curves of porous media from synchrotron-based tomography data. AB - The elevated level of atmospheric carbon dioxide (CO2) has caused serious concern of the progression of global warming. Geological sequestration is considered as one of the most promising techniques for mitigating the damaging effect of global climate change. Investigations over wide range of length-scales are important for systematic evaluation of the underground formations from prospective CO2 reservoir. Understanding the relationship between the micro morphology and the observed macro phenomena is even more crucial. Here we show Synchrotron based X ray micro tomographic study of the morphological buildup of Sandstones. We present a numerical method to extract the pore sizes distribution of the porous structure directly, without approximation or complex calculation. We have also demonstrated its capability in predicting the capillary pressure curve in a mercury intrusion porosimetry (MIP) measurement. The method presented in this work can be directly applied to the morphological studies of heterogeneous systems in various research fields, ranging from Carbon Capture and Storage, and Enhanced Oil Recovery to environmental remediation in the vadose zone. PMID- 26039799 TI - Total laparoscopic pancreaticoduodenectomy may benefit patients with severe impaired pulmonary function. PMID- 26039798 TI - Sbi00515, a Protein of Unknown Function from Streptomyces bingchenggensis, Highlights the Functional Versatility of the Acetoacetate Decarboxylase Scaffold. AB - The acetoacetate decarboxylase-like superfamily (ADCSF) is a group of ~4000 enzymes that, until recently, was thought to be homogeneous in terms of the reaction catalyzed. Bioinformatic analysis shows that the ADCSF consists of up to seven families that differ primarily in their active site architectures. The soil dwelling bacterium Streptomyces bingchenggensis BCW-1 produces an ADCSF enzyme of unknown function that shares a low level of sequence identity (~20%) with known acetoacetate decarboxylases (ADCs). This enzyme, Sbi00515, belongs to the MppR like family of the ADCSF because of its similarity to the mannopeptimycin biosynthetic protein MppR from Streptomyces hygroscopicus. Herein, we present steady state kinetic data that show Sbi00515 does not catalyze the decarboxylation of any alpha- or beta-keto acid tested. Rather, we show that Sbi00515 catalyzes the condensation of pyruvate with a number of aldehydes, followed by dehydration of the presumed aldol intermediate. Thus, Sbi00515 is a pyruvate aldolase-dehydratase and not an acetoacetate decarboxylase. We have also determined the X-ray crystal structures of Sbi00515 in complexes with formate and pyruvate. The structures show that the overall fold of Sbi00515 is nearly identical to those of both ADC and MppR. The pyruvate complex is trapped as the Schiff base, providing evidence that the Schiff base chemistry that drives the acetoacetate decarboxylases has been co-opted to perform a new function, and that this core chemistry may be conserved across the superfamily. The structures also suggest possible catalytic roles for several active site residues. PMID- 26039796 TI - Will the introduction of non-invasive prenatal testing for Down's syndrome undermine informed choice? AB - OBJECTIVE: To investigate whether the introduction of non-invasive pre-natal testing for Down's syndrome (DS) has the potential to undermine informed choice. PARTICIPANTS: Three hundred and ninety-three health professionals; 523 pregnant women. METHODS: A cross-sectional questionnaire study across nine maternity units and three conferences in the UK designed to assess opinions regarding test delivery and how information should be communicated to women when offered Down's syndrome screening (DSS) or diagnosis using invasive (IDT) or non-invasive testing (NIPT). RESULTS: Both pregnant women and health professionals in the NIPT and DSS groups were less likely than the IDT group to consider that testing should take place at a return visit or that obtaining written consent was necessary, and more likely to think testing should be carried out routinely. Compared to health professionals, pregnant women expressed a stronger preference for testing to occur on the same day as pre-test counselling (P = 0.000) and for invasive testing to be offered routinely (P = 0.000). They were also more likely to indicate written consent as necessary for DSS (P = 0.000) and NIPT (P < 0.05). CONCLUSIONS: Health professionals and pregnant women view the consenting process differently across antenatal test types. These differences suggest that informed choice may be undermined with the introduction of NIPT for DS into clinical practice. To maintain high standards of care, effective professional training programmes and practice guidelines are needed which prioritize informed consent and take into account the views and needs of service users. PMID- 26039800 TI - Securing the surgical field in laparoscopic pancreatectomy using a Penrose drain and Endo Close. AB - INTRODUCTION: We adopted the use of Penrose drains and Endo Close to secure a good surgical field during laparoscopic pancreatectomy. METHODS: We used a Penrose drain with threads ligated on both ends to suspend the stomach. We then pulled the threads out of the body from the side of the trocar or from besides the xiphisternum by using Endo Close. In most cases, 2 Penrose drains were used to retract the stomach. When the greater omentum on the left side of the cardia still blocks the surgical field, we sewed the posterior wall of the stomach onto the dome of the diaphragm. RESULTS: The use of 2 Penrose drains and Endo Close were effective to retract the stomach in most cases. However, in 3 cases, we needed to additionally sew the stomach onto the diaphragm to fully open up the field. CONCLUSION: This is a simple and effective method to ensure a good surgical field. PMID- 26039801 TI - Computational Study of Uniaxial Deformations in Silica Aerogel Using a Coarse Grained Model. AB - Simulations of a flexible coarse-grained model are used to study silica aerogels. This model, introduced in a previous study (J. Phys. Chem. C 2007, 111, 15792), consists of spherical particles which interact through weak nonbonded forces and strong interparticle bonds that may form and break during the simulations. Small deformation simulations are used to determine the elastic moduli of a wide range of material models, and large-deformation simulations are used to probe structural evolution and plastic deformation. Uniaxial deformation at constant transverse pressure is simulated using two methods: a hybrid Monte Carlo approach combining molecular dynamics for the motion of individual particles and stochastic moves for transverse stress equilibration, and isothermal molecular dynamics simulations at fixed Poisson ratio. Reasonable agreement on elastic moduli is obtained except at very low densities. The model aerogels exhibit Poisson ratios between 0.17 and 0.24, with higher-density gels clustered around 0.20, and Young's moduli that vary with aerogel density according to a power-law dependence with an exponent near 3.0. These results are in agreement with reported experimental values. The models are shown to satisfy the expected homogeneous isotropic linear-elastic relationship between bulk and Young's moduli at higher densities, but there are systematic deviations at the lowest densities. Simulations of large compressive and tensile strains indicate that these materials display a ductile-to-brittle transition as the density is increased, and that the tensile strength varies with density according to a power law, with an exponent in reasonable agreement with experiment. Auxetic behavior is observed at large tensile strains in some models. Finally, at maximum tensile stress very few broken bonds are found in the materials, in accord with the theory that only a small fraction of the material structure is actually load-bearing. PMID- 26039802 TI - MOF-Derived Porous Co/C Nanocomposites with Excellent Electromagnetic Wave Absorption Properties. AB - Composites incorporating ferromagnetic metal nanopartices into a highly porous carbon matrix are promising as electromagnetic wave absorption materials. Such special composite nanomaterials are potentially prepared by the thermal decomposition of metal-organic framework (MOF) materials under controlled atmospheres. In this study, using Co-based MOFs (Co-MOF, ZIF-67) as an example, the feasibility of this synthetic strategy was demonstrated by the successful fabrication of porous Co/C composite nanomaterials. The atmosphere and temperature for the thermal decomposition of MOF precursors were crucial factors for the formation of the ferromagnetic metal nanopartices and carbon matrix in the porous Co/C composites. Among the three Co/C composites obtained at different temperatures, Co/C-500 obtained at 500 degrees C exhibited the best performance for electromagnetic wave absorption. In particular, the maximum reflection loss (RL) of Co/C-500 reached -35.3 dB, and the effective absorption bandwidth (RL <= 10 dB) was 5.80 GHz (8.40 GHz-14.20 GHz) corresponding to an absorber thickness of 2.5 mm. Such excellent electromagnetic wave absorption properties are ascribed to the synergetic effects between the highly porous structure and multiple components, which significantly improved impedance matching. PMID- 26039803 TI - Microspray and microflow LC-MS/MS: the perfect fit for bioanalysis. PMID- 26039804 TI - Replication in bioanalytical studies with HDX MS: aim as high as possible. PMID- 26039805 TI - Collagenase as an effective tool for drug quantitation in tissues. AB - BACKGROUND: In early drug-discovery research, traditional techniques to analyze drug concentrations in tissues for bioanalytical needs include bead beaters and probe homogenization devices, but are not as effective for tough fibrous tissues. To prepare these tissues, the enzyme collagenase was used to digest the collagen fibers present in epithelial and connective tissue. RESULTS: The benefits of tissue homogenization using a bead beater following collagenase treatment of samples, as opposed to using bead beating alone, was investigated. Matrix effect, recovery factor and stability with and without collagenase were assessed. CONCLUSION: Little to no effects on the quality and reliability of collagenase treated samples were observed. This enzymatic approach is a feasible and effective tool for tissue homogenization and subsequent analysis by LC-MS/MS. PMID- 26039806 TI - Simple and rapid determination of unsaturated fatty acids in 1 ul of rat plasma by LC-MS/MS. AB - BACKGROUND: Deficiency or imbalance of unsaturated fatty acids will promote the pathogenesis of many diseases. In order to monitor the exposure of unsaturated fatty acids, the method based on LC-MS/MS was developed. RESULTS: Standard calibration curves for alpha-linolenic acid, linoleic acid, palmitoleic acid and oleic acid were linear (r >=0.99). The intra-and interbatch accuracy (RE%) ranged from -4.5 to 8.6%, while the intra- and interbatch precisions (RSD%) were <=8.7%. The extraction recovery varied from 85.4 to 99.6%, and no obvious matrix effect was observed. CONCLUSION: The method offers a simple approach for measuring 4 unsaturated fatty acids in 1 MUl rat plasma within 3.95 min. PMID- 26039807 TI - Anti-PEG antibody bioanalysis: a clinical case study with PEG-IFN-lambda-1a and PEG-IFN-alpha2a in naive patients. AB - BACKGROUND: Extensive use of polyethylene glycol (PEG) in consumer products necessitates the assessment of anti-PEG antibodies (APAb). METHODS: In clinical trials comparing PEG-IFN-lambda to PEG-IFN-alpha, conventional bridge and direct assays were assessed. RESULTS & CONCLUSION: The bridge assay detected IgM and IgG APAb reactive with common PEG sizes and derivatives at sufficient sensitivity, 15 500 ng/ml. Of subjects evaluated, 6% of PEG-IFN-lambda and 9% of PEG-IFN-alpha subjects had persistent APAb while 60% of PEG-IFN-lambda and 33% of PEG-IFN-alpha subjects had persistent anti-interferon antibodies (AIAb). Pre-existing APAb and AIAb prevalence was comparable (approximately 10% of subjects). APAb were earlier onset, less frequent, less persistent and lower titer than AIAb. No associated hypersensitivity events were reported. PMID- 26039808 TI - A dispersive liquid-liquid microextraction and chiral separation of carvedilol in human plasma using capillary electrophoresis. AB - BACKGROUND: Development of simple, rapid and precise analysis of chiral drugs in biological samples is an important issue. Dispersive liquid-liquid microextraction in combination with CE using field amplified sample injection has been of interest because of its capability to analyze trace amount of drugs. METHODS: Dispersive liquid-liquid microextraction-CE-field amplified sample injection was employed for chiral separation of carvedilol in human plasma using UV-DAD detector and the developed method has been validated according to US FDA method validation guideline for bioanalysis. RESULTS: The method was linear over a concentration range of 12.5-100 ng/ml for each carvedilol enantiomer (R(2) = 0.998) and the mean recoveries ranged from 91 to 107%. CONCLUSION: The method was adapted for sensitive, selective and rapid determination of carvedilol enantiomers in human plasma samples. PMID- 26039809 TI - Detection and quantification of 56 new psychoactive substances in whole blood and urine by LC-MS/MS. AB - BACKGROUND: New psychoactive substances (NPS) have become increasingly prevalent and are sold in internet shops as 'bath salts' or 'research chemicals' and comprehensive bioanalytical methods are needed for their detection. METHODOLOGY: We developed and validated a method using LC and MS/MS to quantify 56 NPS in blood and urine, including amphetamine derivatives, 2C compounds, aminoindanes, cathinones, piperazines, tryptamines, dissociatives and others. Instrumentation included a Synergi Polar-RP column (Phenomenex) and a 3200 QTrap mass spectrometer (AB Sciex). Run time was 20 min. CONCLUSION: A novel method is presented for the unambiguous identification and quantification of 56 NPS in blood and urine samples in clinical and forensic cases, e.g., intoxications or driving under the influence of drugs. PMID- 26039810 TI - Simultaneous determination of trimethoprim and sulfamethoxazole in dried plasma and urine spots. AB - BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is an antimicrobial drug combination commonly prescribed in children and adults. The study objectives were to validate and apply an HPLC-MS/MS method to quantify TMP-SMX in dried plasma spots (DPS) and dried urine spots (DUS), and perform a comparability analysis with liquid matrices. RESULTS: For TMP the validated range was 100-50,000 ng/ml for DPS and 500-250,000 ng/ml for DUS; for SMX, the validated range was 1000 500,000 ng/ml for both DPS and DUS. Good agreement was noted between DPS/DUS and liquid plasma and urine samples for TMP, while only modest agreement was observed for SMX in both matrices. CONCLUSION: A precise, accurate and reproducible method was developed to quantify TMP-SMX in DPS and DUS samples. PMID- 26039811 TI - Japanese bioanalytical method validation guideline: the world's first regulatory guideline dedicated to ligand-binding assays. PMID- 26039814 TI - Corrigendum. PMID- 26039813 TI - Bioanalytical methods for food allergy diagnosis, allergen detection and new allergen discovery. AB - For effective monitoring and prevention of the food allergy, one of the emerging health problems nowadays, existing diagnostic procedures and allergen detection techniques are constantly improved. Meanwhile, new methods are also developed, and more and more putative allergens are discovered. This review describes traditional methods and summarizes recent advances in the fast evolving field of the in vitro food allergy diagnosis, allergen detection in food products and discovery of the new allergenic molecules. A special attention is paid to the new diagnostic methods under laboratory development like various immuno- and aptamer based assays, including immunoaffinity capillary electrophoresis. The latter technique shows the importance of MS application not only for the allergen detection but also for the allergy diagnosis. PMID- 26039812 TI - Bioanalytical techniques for detecting biomarkers of response to human asbestos exposure. AB - Asbestos exposure is known to cause lung cancer and mesothelioma and its health and economic impacts have been well documented. The exceptionally long latency periods of most asbestos-related diseases have hampered preventative and precautionary steps thus far. We aimed to summarize the state of knowledge on biomarkers of response to asbestos exposure. Asbestos is not present in human biological fluids; rather it is inhaled and trapped in lung tissue. Biomarkers of response, which reflect a change in biologic function in response to asbestos exposure, are analyzed. Several classes of molecules have been studied and evaluated for their potential utility as biomarkers of asbestos exposure. These studies range from small molecule oxidative stress biomarkers to proteins involved in immune responses. PMID- 26039815 TI - Pyridoxine (vitamin B6) supplementation during pregnancy or labour for maternal and neonatal outcomes. AB - BACKGROUND: Vitamin B6 plays vital roles in numerous metabolic processes in the human body, such as nervous system development and functioning. It has been associated with some benefits in non-randomised studies, such as higher Apgar scores, higher birthweights, and reduced incidence of pre-eclampsia and preterm birth. Recent studies also suggest a protection against certain congenital malformations. OBJECTIVES: To evaluate the clinical effects of vitamin B6 supplementation during pregnancy and/or labour. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (31 March 2015) and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials comparing vitamin B6 administration in pregnancy and/or labour with: placebos, no supplementations, or supplements not containing vitamin B6. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. For this update, we assessed methodological quality of the included trials using risk of bias and the GRADE approach. MAIN RESULTS: Four trials (1646 women) were included. The method of randomisation was unclear in all four trials and allocation concealment was reported in only one trial. Two trials used blinding of participants and outcomes. Vitamin B6 as oral capsules or lozenges resulted in decreased risk of dental decay in pregnant women (capsules: risk ratio (RR) 0.84; 95% confidence interval (CI) 0.71 to 0.98; one trial, n = 371, low quality of evidence; lozenges: RR 0.68; 95% CI 0.56 to 0.83; one trial, n = 342, low quality of evidence). A small trial showed reduced mean birthweights with vitamin B6 supplementation (mean difference -0.23 kg; 95% CI -0.42 to -0.04; n = 33; one trial). We did not find any statistically significant differences in the risk of eclampsia (capsules: n = 1242; three trials; lozenges: n = 944; one trial), pre eclampsia (capsules n = 1197; two trials, low quality of evidence; lozenges: n = 944; one trial, low-quality evidence) or low Apgar scores at one minute (oral pyridoxine: n = 45; one trial), between supplemented and non-supplemented groups. No differences were found in Apgar scores at five minutes, or breastmilk production between controls and women receiving oral (n = 24; one trial) or intramuscular (n = 24; one trial) loading doses of pyridoxine at labour. Overall, the risk of bias was judged as unclear. The quality of the evidence using GRADE was low for both pre-eclampsia and dental decay. The other primary outcomes, preterm birth before 37 weeks and low birthweight, were not reported in the included trials. AUTHORS' CONCLUSIONS: There were few trials, reporting few clinical outcomes and mostly with unclear trial methodology and inadequate follow up. There is not enough evidence to detect clinical benefits of vitamin B6 supplementation in pregnancy and/or labour other than one trial suggesting protection against dental decay. Future trials assessing this and other outcomes such as orofacial clefts, cardiovascular malformations, neurological development, preterm birth, pre-eclampsia and adverse events are required. PMID- 26039816 TI - Association study between C-reactive protein polymorphisms and ischaemic stroke. AB - OBJECTIVE: C-reactive protein (CRP), a marker of inflammation, is strongly related to cardiovascular disease. Elevated CRP levels are considered to be a predictor of ischaemic stroke in elderly individuals. Recently, some single nucleotide polymorphisms (SNPs) within the CRP gene have been associated with serum CRP levels. However, associations between these SNPs and ischaemic stroke remain controversial. In this study, we accessed the association between two CRP SNPs and ischaemic stroke in Chinese Han population. METHODS: A population-based case-control study was conducted in 158 patients with ischaemic stroke and 290 control subjects. Two CRP SNPs, rs1130864 and rs3093059 were genotyped from patients using the PCR-restriction fragment length polymorphism (PCR-RFLP)-based analysis. The haplotype-based association study was assessed with a permutation test. RESULTS: rs1130864 and rs3093059 were in Hardy-Weinberg equilibrium in control subjects. The genotype distributions of both genotypes were not statistically different between patients and controls. Because rs1130864 and rs3093059 presented strong linkage disequilibrium, three major haplotypes were identified as C-T, T-T, C-C. None of these haplotypes was associated with ischaemic stroke or its subtype before and after adjustment for traditional risk factors. CONCLUSIONS: There is no association between rs1130864 or rs3093059 and ischaemic stroke in Chinese Han population. PMID- 26039817 TI - Sustaining teaching-fellow networks. PMID- 26039819 TI - Eye movements reflect and shape strategies in fraction comparison. AB - The comparison of fractions is a difficult task that can often be facilitated by separately comparing components (numerators and denominators) of the fractions- that is, by applying so-called component-based strategies. The usefulness of such strategies depends on the type of fraction pair to be compared. We investigated the temporal organization and the flexibility of strategy deployment in fraction comparison by evaluating sequences of eye movements in 20 young adults. We found that component-based strategies could account for the response times and the overall number of fixations observed for the different fraction pairs. The analysis of eye movement sequences showed that the initial eye movements in a trial were characterized by stereotypical scanning patterns indicative of an exploratory phase that served to establish the kind of fraction pair presented. Eye movements that followed this phase adapted to the particular type of fraction pair and indicated the deployment of specific comparison strategies. These results demonstrate that participants employ eye movements systematically to support strategy use in fraction comparison. Participants showed a remarkable flexibility to adapt to the most efficient strategy on a trial-by-trial basis. Our results confirm the value of eye movement measurements in the exploration of strategic adaptation in complex tasks. PMID- 26039818 TI - Enantioselective small molecule synthesis by carbon dioxide fixation using a dual Bronsted acid/base organocatalyst. AB - Carbon dioxide exhibits many of the qualities of an ideal reagent: it is nontoxic, plentiful, and inexpensive. Unlike other gaseous reagents, however, it has found limited use in enantioselective synthesis. Moreover, unprecedented is a tool that merges one of the simplest biological approaches to catalysis-Bronsted acid/base activation-with this abundant reagent. We describe a metal-free small molecule catalyst that achieves the three component reaction between a homoallylic alcohol, carbon dioxide, and an electrophilic source of iodine. Cyclic carbonates are formed enantioselectively. PMID- 26039821 TI - Microtiter plate tests for segregation of bioluminescent bacteria. AB - It has been recently shown that bioluminescence imaging can be usefully applied to provide new insights into bacterial self-organization. In this work we employ bioluminescence imaging to record images of nutrient rich liquid cultures of the lux-gene reporter Escherichia coli in microtiter plate wells. The images show that patterns of inhomogenous bioluminescence form along the three-phase contact lines. The paper analyzes the dependencies of the average number of luminous aggregates (clouds) on various environmental factors. In particular, our results show that optimal (neutral) pH and high aeration rates determine the highest mean number of clouds, and that spatiotemporal patterns do not form in the pH buffered suspensions. In addition, a sigmoidal (switch-like) dependence of the number of aggregates on the rate of aeration was observed. The obtained bioluminescence imaging data was interpreted by employing the Keller-Segel-Fisher (KSF) model of chemotaxis and logistic growth, adapted to systems of metabolically flexible (two state) bacteria. The modified KSF model successfully simulated the observed switch-like responses. The results of the microtiter plate tests and their simulations indicate that the segregation of bacteria with different activities proceeds in the three-phase contact line region. PMID- 26039822 TI - The departure of a Brazilian master of gastroenterology. PMID- 26039820 TI - Cellular adaptation to nutrient deprivation: crosstalk between the mTORC1 and eIF2alpha signaling pathways and implications for autophagy. AB - The hostile tumor microenvironment results in the generation of intracellular stresses including hypoxia and nutrient deprivation. In order to adapt to such conditions, the cell utilizes several stress-response mechanisms, including the attenuation of protein synthesis, the inhibition of cellular proliferation, and induction of autophagy. Autophagy leads to the degradation of cellular contents, including damaged organelles and mutant proteins, which the cell can then use as an alternate energy source. Two integral changes to the signaling milieu to promote such a response include inhibition of the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of eIF2alpha. This review will describe how conditions found in the tumor microenvironment regulate mTORC1 as well as eIF2alpha, the downstream impact of these modifications, and the implications in tumorigenesis. We will then discuss the remarkable similarities and overlapping function of these 2 signaling pathways, focusing on the response to amino acid deprivation, and present a new model involving crosstalk between them based on our recent work. PMID- 26039823 TI - ANTIBIOTIC PROPHYLAXIS IN BARIATRIC SURGERY: a continuous infusion of cefazolin versus ampicillin/sulbactam and ertapenem. AB - BACKGROUND: The incidence of surgical site infection in bariatric patients is significant and the current recommendations for antibiotic prophylaxis are sometimes inadequate. Objective: The aim of this study was to analyze the effect of three prophylactic antibiotic regimens on the incidence of surgical site infection. METHODS: A prospective, cross-sectional study was conducted between January 2009 and January 2013 in which 896 Roux-en-Y gastric bypasses were performed to treat obesity. The study compared three groups of patients according to the perioperative antibiotic prophylaxis administered intravenously and beginning at anesthesia induction: Group I consisting of 194 patients treated with two 3-g doses of ampicillin/sulbactam; Group II with 303 patients treated with a single 1-g dose of ertapenem; and Group III with 399 patients treated with a 2-g dose of cefazolin at anesthesia induction followed by a continuous infusion of cefazolin 1g throughout the surgical procedure. The rate of surgical site infection was analyzed, as well as its association with age, sex, preoperative weight, body mass index and comorbidities. RESULTS: The rates of surgical site infection were 4.16% in the group treated prophylactically with ampicillin/sulbactam, 1.98% in the ertapenem group and 1.55% in the continuous cefazolin group. CONCLUSION: The prophylactic use of continuous cefazolin in surgeries for morbid obesity shows very promising results. These findings suggest that some prophylactic regimens need to be reconsidered and even substituted by more effective therapies for the prevention of surgical site infections in bariatric patients. PMID- 26039824 TI - Nutritional, metabolic and cardiovascular correlations of morning cortisol in health care workers in a gastroenterology service. AB - BACKGROUND: Workplace stress has been associated with obesity. Diminished body weight has also been anticipated in some contexts. OBJECTIVE: In a cohort of healthcare personnel, morning cortisol was compared to nutritional and metabolic variables, aiming to identify the correlates of such marker. METHODS: Population n=185, 33.8 +/- 9.8 years, 88.1% females, body mass index (BMI) 25.6 +/- 4.4 kg/m2, included nurses and other nosocomial professionals, the majority with high social-economic status (75.2%). Participants were stratified according to BMI, fasting blood glucose (FBG) and metabolic syndrome (MS). Fasting plasma cortisol and the Framingham Coronary Risk Score was calculated. RESULTS: Mean cortisol was acceptable (19.4 +/- 7.9 ug/dL) although with elevation in 21.6%. No correlation with FBG or MS occurred, and nonobese persons (BMI <25) exhibited the highest values (P=0.049). Comparison of the lowest and highest cortisol quartiles confirmed reduced BMI and waist circumference in the former, with unchanged Framingham Coronary Risk Score. CONCLUSION: Cortisol correlated with reduced BMI. Despite low BMI and waist circumference, Framingham Coronary Risk Score was not benefitted, suggesting that exposure to cardiovascular risk continues, besides psychological strain. Initiatives to enhance organizational and staff health are advisable in the hospital environment. PMID- 26039825 TI - Copper and magnesium deficiencies in patients with short bowel syndrome receiving parenteral nutrition or oral feeding. AB - BACKGROUND: Patients with short bowel syndrome have significant fluid and electrolytes loss. OBJECTIVE: Evaluate the mineral and electrolyte status in short bowel syndrome patients receiving intermittent parenteral nutrition or oral feeding. METHODS: Twenty two adults with short bowel syndrome, of whom 11 were parenteral nutrition dependent (PN group), and the 11 remaining had been weaned off parenteral nutrition for at least 1 year and received all nutrients by oral feeding (OF group). The study also included 14 healthy volunteers paired by age and gender (control group). Food ingestion, anthropometry, serum or plasma levels of sodium, potassium, phosphorus, magnesium, calcium, zinc, iron and copper were evaluated. PN group subjects were evaluated before starting a new parenteral nutrition cycle. RESULTS: The levels of sodium, potassium, phosphorus, calcium and zinc were similar between the groups. The magnesium value was lower in the PN group (1.0 +/- 0.4 mEq /L) than other groups. Furthermore, this electrolyte was lower in the OF group (1.4 +/- 0.3 mEq /L) when compared to the Control group (1.8 +/- 0.1 mEq/L). Lower values of copper (69+/-24 vs 73+/-26 vs 109+/-16 ug/dL) were documented, respectively, for the PN and OF groups when compared to the control group. CONCLUSION: Hypomagnesemia and hypocupremia are electrolyte disturbances commonly observed in short bowel syndrome. Patients with massive intestinal resection require monitoring and supplementation in order to prevent magnesium and copper deficiencies. PMID- 26039826 TI - Health-related quality of life of pregnant women with heartburn and regurgitation. AB - BACKGROUND: Heartburn and regurgitation frequently occur in the third trimester of pregnancy, but their impact on quality of life has not been thoroughly investigated. OBJECTIVE: To measure health-related quality of life of third trimester pregnant women with heartburn and regurgitation. Methods Data on obstetric history, heartburn and regurgitation frequency and intensity, history of heartburn and regurgitation and health-related quality of life were collected of 82 third-trimester pregnant women. RESULTS: Sixty-two (76%) women had heartburn, and 58 (71%), regurgitation; 20 were asymptomatic. Mean gestational age was 33.8+/-3.7 weeks; 35 (43%) women had a family history of heartburn and/or regurgitation, and 57 (70%) were asymptomatic before pregnancy. The following quality of life concepts were significantly reduced: physical problems and social functioning for heartburn; physical problems and emotional functioning for regurgitation. There was agreement between heartburn in present and previous pregnancies. CONCLUSION: Heartburn and/or regurgitation affected health-related quality of life of third trimester pregnant women. PMID- 26039827 TI - Oral mucosa lesions and oral symptoms in inflammatory bowel disease patients. AB - BACKGROUND: Inflammatory Bowel Disease is known for its extra intestinal manifestations, the oral cavity is no exception. OBJECTIVES: The aim of this study was to evaluate the association between Inflammatory Bowel Disease and oral mucosa lesions and symptoms, and complementary to evaluate their possible relation with oral hygiene, smoking habits, drug therapy, duration and activity of the disease. METHODS: Patients were selected from the Gastroenterology Clinic of a Portuguese tertiary referral hospital. This sample consisted of 113 patients previously diagnosed with ulcerative colitis or Crohn's disease along with a control group of 58 healthy individuals that were accompanying the study group patients to their appointments. Clinical interviews and clinical examinations were performed for data collection. RESULTS: The patients in the study group were more affected by oral symptoms (P=0.011), and showed a trend towards a higher incidence of oral mucosal lesions, even though statistical significance was not reached (8.8% versus 3.4% in the control group; P=0.159). Patients in active phase were the most affected. No differences were detected between Crohn's disease and ulcerative colitis, or concerning smoking habits. The corticosteroid and immunosuppressant therapy seemed to increase the incidence of oral symptoms (P=0.052). The oral mucosa lesions increased and the oral symptoms decreased over the course of the disease, however without statistical significance. CONCLUSION: Oral mucosa's lesions and oral symptoms were positively associated with Inflammatory Bowel Disease, mainly during disease activity periods and conceivably, associated with corticosteroid and immunosuppressant therapy. PMID- 26039828 TI - Nonalcoholic fatty liver disease in patients with coronary disease from a Brazil northeast area. AB - Background Nonalcoholic fatty liver disease (NAFLD) is the most frequent chronic liver injury around the world. It is associated with metabolic syndrome and cardiovascular diseases. Objective To evaluate the frequency and relevance of NAFLD in patients with coronary artery disease (CAD). Methods Patients from a Brazil Northeast area, who underwent elective coronary angiography (CAG) from 2009 to 2010 were included. All of them had suspicion of CAD. Criteria to CAD: presence of obstructive lesions in the epicardial coronary arteries, or in their major branches. NAFLD criteria: presence of hepatic steatosis on ultrasound; exclusion of other liver diseases; ethanol intake <= 20g/day. Statistics analysis included Independent t-test, Mann-Whitney and Pearson's chi-squared test. Multivariate regression analysis measured the relationship between the risk factors and the concomitant presence of CAD and NAFLD. Results A total of 244 patients were evaluated: 63.5% had CAD and 42.2% had NAFLD. NAFLD was observed in 43.9% of the CAD patients. The regression analysis showed that the relationship between CAD and NAFLD was positively correlated with HOMA-IR >=3.0 or insulin resistance and overweight/obesity. Conclusion NAFLD was frequent among CAD patients; insulin resistance and overweight/obesity were the most relevant risk factors related to the association NAFLD and CAD. The results suggest that patients with CAD should be evaluated for NAFLD. PMID- 26039829 TI - Prevalence of non-alcoholic fatty liver disease in women with polycystic ovary syndrome and its correlation with metabolic syndrome. AB - BACKGROUND: The polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women at childbearing age. Metabolic syndrome is present from 28% to 46% of patients with PCOS. Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic expression of metabolic syndrome. There are few published studies that correlate PCOS and NAFLD. OBJECTIVE: To determine the prevalence of NAFLD and metabolic syndrome in patients with PCOS, and to verify if there is a correlation between NAFLD and metabolic syndrome in this population. METHODS: Study developed at Gynecology Department of Clinical Hospital of Federal University of Parana (UFPR). The sessions were conducted from April 2008 to January 2009. One hundred and thirty-one patients joined the analysis; 101 were diagnosed with PCOS and 30 formed the control group. We subdivided the PCOS patients into two subgroups: PCOS+NAFLD and PCOS. All the patients were submitted to hepatic sonography. For hepatoestheatosis screening, hepatic ecotexture was compared do spleen's. For diagnosis of metabolic syndrome, we adopted the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) criteria, as well as the criteria proposed by International Diabetes Federation. Statistical analysis were performed with t of student and U of Mann-Whitney test for means and chi square for proportions. RESULTS: At PCOS group, NAFLD was present in 23.8% of the population. At control group, it represented 3.3%, with statistical significance (P=0.01). Metabolic syndrome, by NCEP/ATP III criteria, was diagnosed in 32.7% of the women with PCOS and in 26.6% of the women at control group (no statistical difference, P=0.5). At PCOS+DHGNA subgroup, age, weight, BMI, abdominal circumference and glucose tolerance test results were higher when compared to PCOS group (P<0.01). Metabolic syndrome by NCEP/ATPIII criteria was present in 75% and by International Diabetes Federation criteria in 95.8% of women with PCOS+NAFLD with P<0.01. Insulin levels at SOP+DHGNA were higher than at PCOS group with P<0.01. CONCLUSION: Almost 25% of the patients with PCOS were diagnosed for NAFLD. Metabolic syndrome was present between 32.7% and 44.6% of patients with PCOS. At subgroup PCOS+NAFLD, metabolic syndrome is highly prevalent. These patients are more obese, with higher BMI and higher glucose levels. PMID- 26039830 TI - The influence of end-stage liver disease and liver transplantation on thyroid hormones. AB - BACKGROUND: Thyroid dysfunction has been reported in most chronic illnesses including severe liver disease. These defects in thyroid hormone metabolism result in the sick euthyroid syndrome, also known as low T3 syndrome. OBJECTIVES: Our objective was to evaluate the thyroid function in patients with end stage liver disease prior and after deceased donor liver transplantation and to correlate thyroid hormonal changes with the MELD score (Model for End stage Liver Disease). METHODS: In a prospective study, serum levels of thyrotropin (thyroid stimulating hormone TSH), total thyroxine (tT4), free thyroxine (fT4) and triiodothyronine (T3) from 30 male adult patients with end stage liver disease were measured two to four hours before and 6 months after liver transplantation (LT). MELD was determined on the day of transplant. For this analysis, extra points were not added for patients with hepatocellular carcinoma. RESULTS: The patients had normal TSH and fT4 levels before LT and there was no change after the procedure. Total thyroxine and triiodothyronine were within the normal range before LT, except for four patients (13.3%) whose values were lower. Both hormones increased to normal values in all four patients after LT (P=0.02 and P<0.001, respectively). When the patients were divided into two groups (MELD <18 and MELD >18), it was observed that there was no change in the TSH, freeT4, and total T4 levels in both groups after LT. Although there was no significant variation in the level of T3 in MELD <18 group (P=0.055), there was an increase in the MELD >18 group after LT (P=0.003). CONCLUSION: Patients with end stage liver disease subjected to liver transplantation had normal TSH and fT4 levels before and after LT. In a few patients with lower tT4 and T3 levels before LT, the level of these hormones increased to normal after LT. PMID- 26039831 TI - COELIAC DISEASE IN CENTRAL AND SOUTH AMERICA: time for a concerted approach to its epidemiology. AB - Central and South America offer an opportunity to resolve some of the current controversies that surround the epidemiology of celiac disease. Through a concerted action which brings together clinicians, researchers and patients there is an opportunity to establish robust data sets which will allow detailed analysis of environmental and genetic factors. In this review available data from the continent together with data from Spain and Italy are drawn together to give a current picture in the hope that it will stimulate further research. PMID- 26039832 TI - Peripheral neuropathy electrophysiological screening in children with celiac disease. AB - BACKGROUND: The involvement of the peripheral nervous system in children with celiac disease is particularly rare. OBJECTIVE: The aim of this study was to assess the need for neurophysiological testing in celiac disease patients without neurological symptoms in order to detect early subclinical neuropathy and its possible correlations with clinical and demographic characteristics. METHODS: Two hundred and twenty consecutive children with celiac disease were screened for neurological symptoms and signs, and those without symptoms or signs were included. Also, patients with comorbidities associated with peripheral neuropathy or a history of neurological disease were excluded. The remaining 167 asymptomatic patients as well as 100 control cases were tested electro physiologically for peripheral nervous system diseases. Motor nerve conduction studies, including F-waves, were performed for the median, ulnar, peroneal, and tibial nerves, and sensory nerve conduction studies were performed for the median, ulnar, and sural nerves with H reflex of the soleus muscle unilaterally. All studies were carried out using surface recording electrodes. Normative values established in our laboratory were used. RESULTS: Evidence for subclinical neuropathy was not determined with electrophysiological studies in any of the participants. CONCLUSION: In this highly selective celiac disease group without any signs, symptoms as well as the predisposing factors for polyneuropathy, we did not determine any cases with neuropathy. With these results we can conclude that in asymptomatic cases with celiac disease electrophysiological studies are not necessary. However, larger studies with the electrophysiological studies performed at different stages of disease at follow-ups are warranted. PMID- 26039833 TI - HELICOBACTER PYLORI PREVALENCE IN PATIENTS WITH CELIAC DISEASE: results from a cross-sectional study. AB - BACKGROUND: Some previously published studies have suggested an inverse relationship between celiac disease and Helicobacter pylori, raising the possibility of the protective role Helicobacter pylori could have against celiac disease development. Nevertheless, this association is inconclusive. OBJECTIVES: To determine the prevalence of Helicobacter pylori infection in celiac subjects. METHODS: Between January 2013 and June 2014, patients over 18 years old undergoing upper endoscopy who required both gastric and duodenal biopsies were included for analysis. Enrolled subjects were divided in two groups: those with a diagnosis of celiac disease and those without a celiac disease diagnosis. Helicobacter pylori infection prevalence was compared between groups. Among celiac patients, endoscopic markers of villous atrophy as well as histological damage severity were compared between those with and without Helicobacter pylori infection. RESULTS: Overall, 312 patients were enrolled. Seventy two of them had a diagnosis of celiac disease. Helicobacter pylori infection prevalence among celiac disease patients was 12.5%, compared to 30% in non-celiac patients [OR=0.33 (0.15-0.71)]. There was not a significant difference in terms of the severity of villous atrophy in patients with Helicobacter pylori infection compared to those without it. There was a slight increase in the prevalence of endoscopic markers in those Helicobacter pylori-negative celiac subjects. CONCLUSION: Helicobacter pylori infection seems to be less frequent in celiac patients; among those celiac subjects with concomitant Helicobacter pylori infection, histological damage degree and presence of endoscopic markers suggesting villous atrophy seem to be similar to those without Helicobacter pylori infection. PMID- 26039834 TI - Simplifying celiac disease predisposing HLA-DQ alleles determination by the real time PCR method. AB - BACKGROUND: Celiac disease is an autoimmune enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Genetic susceptibility is associated with two sets of alleles, DQA1*05 - DQB1*02 and DQA1*03 - DQB1*03:02, which code for class II MHC DQ2 and DQ8 molecules, respectively. Approximately 90%-95% of celiac patients are HLA-DQ2 positive, and half of the remaining patients are HLA-DQ8 positive. In fact, during a celiac disease diagnostic workup, the absence of these specific DQA and DQB alleles has a near perfect negative predictive value. OBJECTIVE: Improve the detection of celiac disease predisposing alleles by combining the simplicity and sensitivity of real-time PCR (qPCR) and melting curve analysis with the specificity of sequence-specific primers (SSP). METHODS: Amplifications of sequence-specific primers for DQA1*05 (DQ2), DQB1*02 (DQ2), and DQA1*03 (DQ8) were performed by the real time PCR method to determine the presence of each allele in independent reactions. Primers for Human Growth Hormone were used as an internal control. A parallel PCR-SSP protocol was used as a reference method to validate our results. RESULTS: Both techniques yielded equal results. From a total of 329 samples the presence of HLA predisposing alleles was determined in 187 (56.8%). One hundred fourteen samples (61%) were positive for a single allele, 68 (36.3%) for two alleles, and only 5 (2.7%) for three alleles. CONCLUSION: Results obtained by qPCR technique were highly reliable with no discordant results when compared with those obtained using PCR-SSP. PMID- 26039835 TI - FLUCTUATING JAUNDICE IN THE ADENOCARCINOMA OF THE AMPULLA OF VATER: a classic sign or an exception? AB - BACKGROUND: Some authors consider the fluctuating jaundice as a classic sign of the adenocarcinoma of the ampulla of Vater. OBJECTIVE: Assessing the frequency of fluctuating jaundice in their forms of its depiction in the patients with adenocarcinoma of the ampulla of Vater. METHODS: Observational and retrospective study, conducted through analyses of medical records from patients subjected to pancreatic cephalic resections between February 2008 and July 2013. The pathological examination of the surgical specimen was positive to adenocarcinoma of the ampulla of Vater. Concepts and differences on clinical and laboratory fluctuating jaundice were standardized. It was subdivided into type A and type B laboratory fluctuating jaundice. RESULTS: Twenty patients were selected. One of them always remained anicteric, 11 patients developed progressive jaundice, 2 of them developed clinical and laboratory fluctuating jaundice, 5 presented only laboratory fluctuating jaundice and one did not present significant variations on total serum bilirubin levels. Among the seven patients with fluctuating jaundice, two were classified as type A, one as type B and four were not classified due to lack information. Finally, progressive jaundice was the prevailing presentation form in these patients (11 cases). CONCLUSION: This series of cases suggested that clinical fluctuating jaundice is a uncommon signal in adenocarcinoma of the ampulla of Vater. PMID- 26039836 TI - Immunohistochemical expression of HER2 in adenocarcinoma of the stomach. AB - BACKGROUND: Worldwide, gastric cancer is the fourth cancer in incidence and the second most common cause of cancer death. Gastric cancer is asymptomatic in the early stages and very often diagnosed at advanced stages, determining a dismal prognosis. Expression of the HER2 gene has been identified in about 20% of gastric cancer cases, and its hyper-expression is associated with poor prognosis. OBJECTIVE: To investigate HER2 immunohistochemical expression in gastric adenocarcinoma and its relationship to the histological type and anatomic location. METHODS: A cross-sectional retrospective study analyzed the immunohistochemical expression of HER2 in a sample of 48 specimens of gastric cancer. Immunohistochemical analysis were performed using avidin-biotin peroxidase method with C-erb B2 (clone EP1045Y), as a primary antibody (Biocare Medical, USA). Standardized gastric adenocarcinoma's HER2 expression criteria has been used in the analysis of samples. RESULTS: There were seven cases with reactivity for HER2. Five were of intestinal-type while two cases were of mixed type in which the expression occurred in the intestinal component. It was identified a significant association of HER2 expression in the intestinal subtype of gastric adenocarcinoma (P=0.003). Regarding the anatomical site, HER2 was positive in only one (16.6%) of the six proximal cases and six (14.28%) of the 42 distal cases (P=0.88). CONCLUSION: HER2 immunoexpression was identified in 14.6% of the samples, and the expression was significantly associated to Lauren's intestinal subtype. PMID- 26039837 TI - The ontogeny of saliva secretion in infants and esophagoprotection. AB - BACKGROUND: Several studies have reported that severe reflux esophagitis is rare in infants despite the well known high occurrence of regurgitation in early infancy. There is evidence of the importance of saliva for the pre-epithelial protection of the esophageal mucosa. RESULTS: A longitudinal study conducted on healthy infants indicated that the stimulated capacity of saliva secretion (saliva output per kg of body weight) was significantly higher during their first year of age compared to older children and adults. In addition, this secretion pattern was also observed in low weight newborns during the first weeks of life and persisted in infants with severe protein-calorie malnutrition (marasmus). CONCLUSION: The greater ability to secrete saliva is an important physiological condition that may protect the infant from acid/pepsin aggression to the esophagus during early stages of development. PMID- 26039842 TI - Preface. Totally psyched. PMID- 26039838 TI - A PHASE II TRIAL EXPLORING THE EXTENSIVE INTRA-OPERATIVE PERITONEAL LAVAGE (EIPL) AS A PROPHYLACTIC STRATEGY FOR PERITONEAL RECURRENCE IN LOCALLY ADVANCED GASTRIC CANCER: reporting postoperative morbidity and mortality after early closure. AB - BACKGROUND: The Extensive Intraoperative Peritoneal Lavage (EIPL) has been proposed as a practical prophylactic strategy to decrease the risk of peritoneal metastasis in gastric cancer. OBJECTIVE: To explore the safety and efficacy of the EIPL in our locally advanced gastric cancer patients. METHODS: This study is an open-label, double-center, single-arm phase II clinical trial developed at two tertiary hospitals from Recife (Pernambuco, Brazil). RESULTS: The study protocol was prematurely closed due to slow accrual after only 16 patients had been recruited to participate. Eight of them were excluded of the protocol study during the laparotomy, whereas four cases were also excluded from the per protocol analysis. Two patients had died in hospital before 30 days and six were alive with no evidence of cancer relapses after a follow-up ranging from five to 14,2 months (median of 10.6 months). In the intention-to-treat analysis, three of eight patients suffered of gastrointestinal leakages and two of them had died. On a per-protocol basis, two of four patients presented this type of postoperative complication and one of them had died. All deaths occurred as a somewhat consequence of gastrointestinal leakages. CONCLUSION: We could not make any conclusion about the safety and efficacy of the EIPL, but the possibility of this approach might increase the rate of gastrointestinal leakage is highlighted. PMID- 26039843 TI - Neurobehavioral assessment. AB - PURPOSE OF REVIEW: This article presents a multidimensional, integrative approach to clinical assessment and management of neurobehavioral disorders. RECENT FINDINGS: Behavioral neurology and neuropsychiatry has grown as a subspecialty along with increased recognition of two common brain disorders: dementia and traumatic brain injury. Alzheimer disease is a highly prevalent dementia and a prototypical memory disorder, which has led to a primary focus on cognitive screening and assessment. By contrast, recent attention concerning possible long term sequelae of repetitive traumatic brain injury has emphasized aberrant behavior (eg, depression, impulsivity, aggression). Clinical phenotyping across cognitive and behavioral dimensions, in conjunction with advancements in structural and functional neuroimaging, brain electrophysiologic techniques, and molecular genetics, is essential to improve diagnostic precision and therapeutic targeting along the spectrum of CNS disorders. SUMMARY: All neurologists benefit from honing their clinical skills in neurobehavioral assessment. A systematic approach to cognitive and behavioral assessment increases differential diagnostic specificity, helps focus appropriate therapeutic interventions, and improves the quality of life for patients and their families. This article highlights practical approaches to neurobehavioral assessment in support of differential diagnosis and therapeutic monitoring in general neurology practice. PMID- 26039844 TI - Memory dysfunction. AB - PURPOSE OF REVIEW: This article highlights the dissociable human memory systems of episodic, semantic, and procedural memory in the context of neurologic illnesses known to adversely affect specific neuroanatomic structures relevant to each memory system. RECENT FINDINGS: Advances in functional neuroimaging and refinement of neuropsychological and bedside assessment tools continue to support a model of multiple memory systems that are distinct yet complementary and to support the potential for one system to be engaged as a compensatory strategy when a counterpart system fails. SUMMARY: Episodic memory, the ability to recall personal episodes, is the subtype of memory most often perceived as dysfunctional by patients and informants. Medial temporal lobe structures, especially the hippocampal formation and associated cortical and subcortical structures, are most often associated with episodic memory loss. Episodic memory dysfunction may present acutely, as in concussion; transiently, as in transient global amnesia (TGA); subacutely, as in thiamine deficiency; or chronically, as in Alzheimer disease. Semantic memory refers to acquired knowledge about the world. Anterior and inferior temporal lobe structures are most often associated with semantic memory loss. The semantic variant of primary progressive aphasia (svPPA) is the paradigmatic disorder resulting in predominant semantic memory dysfunction. Working memory, associated with frontal lobe function, is the active maintenance of information in the mind that can be potentially manipulated to complete goal directed tasks. Procedural memory, the ability to learn skills that become automatic, involves the basal ganglia, cerebellum, and supplementary motor cortex. Parkinson disease and related disorders result in procedural memory deficits. Most memory concerns warrant bedside cognitive or neuropsychological evaluation and neuroimaging to assess for specific neuropathologies and guide treatment. PMID- 26039845 TI - Language dysfunction. AB - PURPOSE OF REVIEW: Language is a complex brain function requiring a number of cognitive processes and is commonly affected by both focal brain lesions and neurodegenerative disorders. This article reviews the neuroanatomic basis of language, assessment techniques of language function, and disorders affecting language. RECENT FINDINGS: Recent functional imaging studies of language suggest that the classic connectionist models of language function may be incomplete. These studies and those analyzing how the primary progressive aphasias (PPAs) affect language function suggest that language processing is completed through large-scale distributed networks. The use of structured, standardized techniques allows for the diagnosis of focal brain lesions affecting language function as well as neurodegenerative and psychogenic causes of language dysfunction. SUMMARY: By employing an accurate, neuroanatomically grounded language assessment technique, the neurologist can reach the correct diagnosis and implement the optimal management plan for patients with language disorders. Neurologists should also be aware of new information regarding the neural basis of language function as our understanding of the complex cognitive process of language continues to evolve. PMID- 26039847 TI - Dysfunction of social cognition and behavior. AB - PURPOSE OF REVIEW: Neurologists have generally paid relatively little attention to social behavior and its disorders. As a result, many individuals with suspected brain disorders primarily involving changes in social behavior have sought evaluations by psychiatrists or psychologists. This review summarizes recent findings from the growing field of social neuroscience and illustrates the relevance of this knowledge for the neurologist by reviewing contemporary research on frontotemporal dementia and its differential diagnosis. RECENT FINDINGS: An explosion of research over the past 10 to 15 years has illuminated specific psychological processes involved in core facets of social behavior and their neural bases. In parallel, knowledge of the genetics, neurobiology, neuroimaging features, and clinical phenomenology of frontotemporal dementia has grown dramatically. SUMMARY: As the understanding of specific component processes involved in social behavior and their neural underpinnings deepen, neurologists may lead the way in using this knowledge to provide sophisticated evaluation and monitoring for patients with disorders of social behavior and ultimately may develop new therapeutic options to treat these brain disorders. PMID- 26039846 TI - Executive dysfunction. AB - PURPOSE OF REVIEW: Executive functions represent a constellation of cognitive abilities that drive goal-oriented behavior and are critical to the ability to adapt to an ever-changing world. This article provides a clinically oriented approach to classifying, localizing, diagnosing, and treating disorders of executive function, which are pervasive in clinical practice. RECENT FINDINGS: Executive functions can be split into four distinct components: working memory, inhibition, set shifting, and fluency. These components may be differentially affected in individual patients and act together to guide higher-order cognitive constructs such as planning and organization. Specific bedside and neuropsychological tests can be applied to evaluate components of executive function. While dysexecutive syndromes were first described in patients with frontal lesions, intact executive functioning relies on distributed neural networks that include not only the prefrontal cortex, but also the parietal cortex, basal ganglia, thalamus, and cerebellum. Executive dysfunction arises from injury to any of these regions, their white matter connections, or neurotransmitter systems. Dysexecutive symptoms therefore occur in most neurodegenerative diseases and in many other neurologic, psychiatric, and systemic illnesses. Management approaches are patient specific and should focus on treatment of the underlying cause in parallel with maximizing patient function and safety via occupational therapy and rehabilitation. SUMMARY: Executive dysfunction is extremely common in patients with neurologic disorders. Diagnosis and treatment hinge on familiarity with the clinical components and neuroanatomic correlates of these complex, high-order cognitive processes. PMID- 26039848 TI - Perceptual-motor dysfunction. AB - PURPOSE OF REVIEW: This article highlights the importance of integrated perceptual information (motor planning, sequencing, and representation) and discusses the integration of these cognitive domains by means of feedforward and feedback loops in the successful acquisition and execution of voluntary behaviors. The article also discusses the dysfunction in the perceptual-motor process that can occur with neurologic injury, resulting in apraxias, agnosia, hemineglect, and Balint syndrome. RECENT FINDINGS: A combination of functional imaging and lesional studies continues to refine our understanding of the role of the posterior parietal region in the integration of perception with motor action. Different disorders provide contrasting views into the nature of perceptual-motor function and its disruption. Novel rehabilitation techniques may provide improved function in the future. SUMMARY: Studies continue to demonstrate the importance of unimodal and heteromodal association cortices, as well as the extrapyramidal system (especially the basal ganglia) in perceptual-motor functions across a wide range of activities and disease states. The nondominant hemisphere dictates where attention and intention are to be directed in space, and the dominant hemisphere provides information on how to accomplish skilled complex actions. While the role of perceptual-motor dysfunction in developmental disorders has been long considered, the role of perceptual-motor dysfunction in neurodegenerative diseases, from Parkinson disease to corticobasal syndrome to posterior cortical atrophy, is becoming more apparent. A clear need exists for more robust rehabilitation strategies in these neurodegenerative diseases. PMID- 26039849 TI - Neurodevelopmental behavioral and cognitive disorders. AB - PURPOSE OF REVIEW: Neurodevelopmental disorders are a group of heterogeneous conditions characterized by a delay or disturbance in the acquisition of skills in a variety of developmental domains, including motor, social, language, and cognition. This article reviews the most commonly diagnosed neurodevelopmental disorders, which include attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, global developmental delay, and intellectual disability and also provides updates on diagnosis, neurobiology, treatment, and issues surrounding the transition to adulthood. RECENT FINDINGS: Although symptoms emerge at discrete points in childhood, these disorders result from abnormal brain maturation that likely precedes clinical impairment. As a result, research has focused on the identification of predictive biological and behavioral markers, with the ultimate goal of initiating treatments that may either alter developmental trajectories or lessen clinical severity. Advances in the methods used to identify genetic variants, from chromosomal microarray analysis to whole exome sequencing, have facilitated the characterization of many genetic mutations and syndromes that share common pathways to abnormal circuit formation and brain development. Not only do genetic discoveries enrich our understanding of mechanisms underlying atypical development, but they also allow us to identify more homogeneous subgroups within this spectrum of conditions. Impairments do continue into adulthood, with challenges in the transition to adulthood including the management of comorbidities and the provision of educational and vocational supports. SUMMARY: Advances in our understanding of the neurobiology and developmental trajectories of these disorders will pave the way for tremendous advances in treatment. Mechanism-based therapies for genetic syndromes are being studied with the goal of expanding targeted treatments to nonsyndromic forms of neurodevelopmental disorders. PMID- 26039850 TI - Psychosis. AB - PURPOSE OF REVIEW: Psychosis is a common and functionally disruptive symptom of many psychiatric, neurodevelopmental, neurologic, and medical conditions and an important target of evaluation and treatment in neurologic and psychiatric practice. The purpose of this review is to define psychosis, communicate recent changes to the classification of and criteria for primary psychotic disorders described in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), and summarize current evidence-based approaches to the evaluation and management of primary and secondary psychoses. RECENT FINDINGS: The DSM-5 classification of and criteria for primary psychotic disorders emphasize that these conditions occur along a spectrum, with schizoid (personality) disorder and schizophrenia defining its mild and severe ends, respectively. Psychosis is also identified as only one of several dimensions of neuropsychiatric disturbance in these disorders, with others encompassing abnormal psychomotor behaviors, negative symptoms, cognitive impairments, and emotional disturbances. This dimensional approach regards hallucinations and delusions as arising from neural systems subserving perception and information processing, thereby aligning the neurobiological framework used to describe and study such symptoms in primary psychotic disorders with those used to study psychosis associated with other neurologic conditions. SUMMARY: This article provides practicing neurologists with updates on current approaches to the diagnosis, evaluation, and treatment of primary and secondary psychoses. PMID- 26039851 TI - Mania. AB - PURPOSE OF REVIEW: Primary mania and hypomania in full or subsyndromal forms are the defining features of bipolar disorder and are common in neurologic patients, as are manic syndromes precipitated by medications used to treat neurologic disorders. This article addresses the diagnosis, pathophysiology, treatment, and course of bipolar disorder after a manic episode as well as mania as a manifestation of neurologic disease. RECENT FINDINGS: Mania can be a primary psychiatric disorder but can also be a symptom of a neurologic disorder, especially right-sided cerebrovascular disease. Treatments (such as corticosteroids and dopaminergic agents) for neurologic illnesses regularly induce mania. The neurobiology of primary mania and bipolar disorder involves alterations in intracellular signaling, changes in gene expression, neural network interactions, and apoptosis. Except when induced by time-limited treatment with a provoking agent, mania tends to be highly recurrent and to alternate or be exhibited alongside depression. Symptoms of mania become more complex and treatment refractory with time, although effective treatment improves the long-term outcome. SUMMARY: Behavioral manifestations of mania may be more obvious than affective symptoms, especially in patients with aprosodia. Atypical antipsychotic drugs are often first-line acute treatments, but the evidence supporting their long-term prophylactic efficacy is questionable. In addition to being an established mood stabilizer, lithium has putative neuroprotective properties, although a side effect can be impaired memory. PMID- 26039852 TI - Depression. AB - PURPOSE OF REVIEW: Depression is a presenting symptom of common psychiatric disorders such as major depressive disorder, bipolar disorder, and schizophrenia. Depression can also be the presenting symptom of several neurodegenerative disorders, including Alzheimer disease, dementia with Lewy bodies, frontotemporal dementia, and Parkinson disease. Depression can also cause cognitive impairment and is a risk factor for dementia. As a result of the intimate relationship between depression and dementia, differentiating between a psychiatric and a neurologic cause of depression and dementia can sometimes be very difficult. The purpose of this review is to discuss the diagnosis and treatment of depression and to demonstrate how new diagnostic tools are helping to identify the differential diagnosis of depression. RECENT FINDINGS: It is a time of great advancement in the management of depression. Innovative new medications, psychotherapeutic modalities, and new and investigational somatic treatments (eg, transcranial magnetic stimulation, deep brain stimulation) are making it possible to ameliorate and manage symptoms more effectively in more patients. SUMMARY: With our greater ability to improve the lives of patients with depression, it is important for neurologists to recognize depression and work with our psychiatric colleagues to help patients access the newest and best treatments. PMID- 26039853 TI - Anxiety. AB - PURPOSE OF REVIEW: This article provides an overview of anxiety disorders including the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnostic criteria with practical key features. The article discusses neurologic and other medical comorbidities as well as treatment strategies, keeping in mind the co-occurrence of anxiety disorders with depression. RECENT FINDINGS: Several studies have emphasized the high prevalence of comorbid mental and medical conditions including, but not limited to, cardiovascular and neurologic illnesses, making the overall management of these patients more costly and complex, ultimately leading to decreased length and quality of life. However, several research studies have suggested that appropriate and effective comanagement of anxiety and depression improves overall outcomes of those individuals with chronic medical conditions. SUMMARY: Anxiety and depression are common psychiatric conditions that not only co-occur, but also co-occur with other neurologic illnesses. Early recognition and treatment of these comorbidities are imperative in order to achieve better health outcomes for patients. PMID- 26039854 TI - Obsessive-compulsive disorder. AB - PURPOSE OF REVIEW: This article discusses the neurobiology, clinical features, and treatment of obsessive-compulsive disorder (OCD), as well as its association with psychiatric and neurologic disease. RECENT FINDINGS: OCD can be associated with various neurologic disorders. Recent studies have better elucidated the neurobiology of OCD, and this new knowledge promises to have a significant impact on future treatments. SUMMARY: OCD is a syndrome characterized by obsessions and compulsions, as well as other neuropsychiatric features, and is often associated with primary psychiatric disorders and various neurologic conditions. If severe, OCD can seriously interfere with the patient's quality of life. The mainstay of treatment is psychotherapy, especially cognitive-behavioral therapy, and pharmacologic interventions, especially with selective serotonin reuptake inhibitors (SSRIs). Unfortunately, a significant proportion of patients are refractory to these treatment modalities. New understanding about the neurobiology of OCD has led to novel investigational treatments, especially neuromodulation techniques. PMID- 26039855 TI - Posttraumatic stress disorder. AB - PURPOSE OF REVIEW: The objectives of this article are to update the reader on the current definition and diagnostic assessment of posttraumatic stress disorder (PTSD) and to describe its clinical characteristics, discuss its epidemiology and pathophysiologic aspects, as well as to summarize the current therapeutic options for PTSD. RECENT FINDINGS: The new nomenclature of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) includes 20 PTSD symptoms clustered into four symptomatic domains: intrusive symptoms, active avoidance, disturbed emotional states, and alterations of arousal and reactivity. Diagnostic structured interviews and severity scales have been updated in order to address this recent revision. It is also recognized that the neural circuits whose disruption might explain the genesis of PTSD symptoms, although overlapping, may be different between these four domains, a fact that may inform new biologically based phenotypes with prognostic and therapeutic implications.During the past years, there has been active research into the different factors influencing vulnerability and resilience to stress, including the effect of genetic and epigenetic variations. The neural circuits involved in the processing of threatening stimuli have been studied in patients with PTSD through paradigms inspired in animal research. These studies suggest that patients with PTSD have difficulty discriminating danger from safety cues and have problems suppressing fear in the presence of safety cues. Functional MRI (fMRI) studies suggest that the increased amygdala activation observed in these patients results from abnormal modulatory input from the ventromedial prefrontal cortex. Structural brain abnormalities, on the other hand, have been more consistently identified in the hippocampus.Prolonged exposure therapy and cognitive reprocessing are the interventions that have the more extensive validation of their psychotherapeutic efficacy. Medications are modestly more effective than placebo to treat PTSD symptoms, and selective serotonin reuptake inhibitors (SSRIs) are considered a safe initial choice. Use of combined strategies including pharmacologic modulation of fear processing is an area of active research. SUMMARY: PTSD is a frequent psychopathologic condition with a lifetime prevalence that is close to 10%. In the past few years, there have been significant advances in the definition of the disorder, in elucidating the neurobiology of vulnerability and resilience, and in developing new treatment alternatives. PMID- 26039856 TI - Personality disorders. AB - PURPOSE OF REVIEW: This article reviews the current information about the diagnostic criteria, pathophysiology, and treatment of personality disorders. These disorders are common in the general population and even more common in medical settings. Rigid thinking and inflexible behavior patterns are characteristic of all personality disorders. The related impairment in social adaptation and associated morbidity and mortality are described. RECENT FINDINGS: Recent advances have led to a change in the way these disorders are classified. Personality disorders are now understood to be heritable and biologically based. Neurobiological, metabolic, and brain structural differences exist in individuals with these disorders. Historically, personality disorders, or Axis II disorders, have been seen as distinct from the more biological Axis I disorders. This multiaxial diagnostic structure has now been abandoned, eliminating the artificial partitioning off of personality disorders. SUMMARY: In this article, the epidemiology, etiology, classification, and treatment of the various personality disorders are reviewed. Emphasis is placed on the need for compassion when working with patients with personality disorders and an understanding that the nature of these disorders engenders interpersonal conflict. Although the bulk of available research focuses on borderline personality disorder, significant findings related to a variety of personality disorders are presented. PMID- 26039857 TI - Functional neurologic disorders. AB - PURPOSE OF REVIEW: Functional neurologic disorders, also called psychogenic, nonorganic, conversion, and dissociative disorders, are among the most common problems in neurologic practice. This article presents a practical guide to clinical assessment and treatment, incorporating emerging research evidence. This article places an emphasis on encouraging neurologists to use the assessment as treatment, take an active role in educating and treating the patient, and work in a multidisciplinary way with psychiatry, psychology, and physical therapy. RECENT FINDINGS: Classification of functional neurologic disorders now emphasizes the importance of positive diagnosis based on physical signs, not psychological features. Studies of mechanism have produced new clinical and neurobiological ways of thinking about these disorders. Evidence has emerged to support the use of physical therapy for functional movement disorders and psychotherapy for dissociative (nonepileptic) attacks. SUMMARY: The diagnosis and management of functional neurologic disorders has entered a new evidence-based era and deserves a standard place in the neurologic curriculum. PMID- 26039858 TI - Managing outpatients with suicidal or homicidal ideation. AB - Regardless of their specialty, physicians encounter various potential clinical emergencies in their outpatients that may require referring patients for the appropriate level and urgency of care. One such situation is the outpatient who presents with suicidal or homicidal ideation. In this circumstance, the physician is faced with performing a rapid evaluation of the symptoms, determining the acuity of the situation, and safely referring the patient to an appropriate level of care. Using case vignettes, this article reviews some of the immediate critical factors to consider in evaluating and managing the outpatient who expresses thoughts of suicide or homicide. PMID- 26039859 TI - Coding in behavioral neurology and neuropsychiatry. PMID- 26039864 TI - Patient management problem. PMID- 26039867 TI - Formation of Light Absorbing Soluble Secondary Organics and Insoluble Polymeric Particles from the Dark Reaction of Catechol and Guaiacol with Fe(III). AB - Transition metals such as iron are reactive components of environmentally relevant surfaces. Here, dark reaction of Fe(III) with catechol and guaiacol was investigated in an aqueous solution at pH 3 under experimental conditions that mimic reactions in the adsorbed phase of water. Using UV-vis spectroscopy, liquid chromatography, mass spectrometry, elemental analysis, dynamic light scattering, and electron microscopy techniques, we characterized the reactants, intermediates, and products as a function of reaction time. The reactions of Fe(III) with catechol and guaiacol produced significant changes in the optical spectra of the solutions due to the formation of light absorbing secondary organics and colloidal organic particles. The primary steps in the reaction mechanism were shown to include oxidation of catechol and guaiacol to hydroxy- and methoxy-quinones. The particles formed within a few minutes of reaction and grew to micron-size aggregates after half an hour reaction. The mass-normalized absorption coefficients of the particles were comparable to those of strongly absorbing brown carbon compounds produced by biomass burning. These results could account for new pathways that lead to atmospheric secondary organic aerosol formation and abiotic polymer formation on environmental surfaces mediated by transition metals. PMID- 26039868 TI - Aggregation of Colloidal Particles in the Presence of Multivalent Co-Ions: The Inverse Schulze-Hardy Rule. AB - Shifts of the critical coagulation concentration (CCC) in particle suspensions in salt solutions containing multivalent co-ions and monovalent counterions are rationalized. One observes that the CCC is inversely proportional to the valence, and this behavior is referred to as the inverse Schulze-Hardy rule. This dependence is established by means of measurements of the stability ratio for positively and negatively charged latex particles with time-resolved light scattering. The same dependence is equally suggested by calculations of the CCC with the Derjaguin, Landau, Verwey, and Overbeek (DLVO) theory, whereby the full Poisson-Boltzmann equation for the asymmetric electrolytes has to be used. The latter aspect is essential, since in the case of multivalent co-ions the surface charge is principally neutralized by monovalent counterions. This rule complements the classical Schulze-Hardy rule, which applies in the case of multivalent counterions, and states that the CCC is inversely proportional to the sixth power of the valence. PMID- 26039871 TI - Synthesis and Enantioseparation Ability of Xylan Bisphenylcarbamate Derivatives as Chiral Stationary Phases in HPLC. AB - Ten novel xylan bisphenylcarbamate derivatives bearing meta- and para substituents on their phenyl groups were synthesized and their chiral recognition abilities were evaluated as the chiral stationary phases (CSPs) for high performance liquid chromatography (HPLC) after coating them on macroporous silica. The chiral recognition abilities of these CSPs depended on the nature, position, and number of the substituents on the phenyl moieties. The introduction of an electron-donating group was more attractive than an electron-withdrawing group to improve the chiral recognition ability of the xylan phenylcarbamate derivatives. Among the CSPs discussed in this study, xylan bis(3,5 dimethylphenylcarbamate)-based CSP seems to possess the highest resolving power for many racemates, and the meta-substituted CSPs showed relatively better chiral recognition than the para-substituted ones. For some racemates, the xylan bis(3,5 dimethylphenylcarbamate) derivative exhibited higher enantioselectivity than the CSP based on cellulose tris(3,5-dimethylphenylcarbamate). PMID- 26039872 TI - Structure and Absolute Configuration of Diterpenoids from Hymenaea stigonocarpa. AB - Chemical investigations of the ethanolic extracts from the flowers and leaves of Hymenaea stigonocarpa Mart. ex Hayne afforded one new ent-halimane diterpenoid, 18-hydroxy-ent-halima-1(10),13-(E)-dien-15-oic acid (1), together with five known compounds (2-6). The structural elucidation was performed by means of NMR (COSY, HSQC, HMBC, and NOESY) and MS analyses. Complete (1)H and (13)C NMR data assignments are also reported for labd-13-en-8beta-ol-15-oic (2) and labd-7,13 dien-15-oic (3) acids. The absolute configurations of 1 and 2 were established by comparison of experimental and calculated Raman optical activity spectra. PMID- 26039869 TI - Non-coding RNAs: Epigenetic regulators of bone development and homeostasis. AB - Non-coding RNAs (ncRNAs) have evolved in eukaryotes as epigenetic regulators of gene expression. The most abundant regulatory ncRNAs are the 20-24 nt small microRNAs (miRNAs) and long non-coding RNAs (lncRNAs, <200 nt). Each class of ncRNAs operates through distinct mechanisms, but their pathways to regulating gene expression are interrelated in ways that are just being recognized. While the importance of lncRNAs in epigenetic control of transcription, developmental processes and human traits is emerging, the identity of lncRNAs in skeletal biology is scarcely known. However, since the first profiling studies of miRNA at stages during osteoblast and osteoclast differentiation, over 1100 publications related to bone biology and pathologies can be found, as well as many recent comprehensive reviews summarizing miRNA in skeletal cells. Delineating the activities and targets of specific miRNAs regulating differentiation of osteogenic and resorptive bone cells, coupled with in vivo gain- and loss-of function studies, discovered unique mechanisms that support bone development and bone homeostasis in adults. We present here "guiding principles" for addressing biological control of bone tissue formation by ncRNAs. This review emphasizes recent advances in understanding regulation of the process of miRNA biogenesis that impact on osteogenic lineage commitment, transcription factors and signaling pathways. Also discussed are the approaches to be pursued for an understanding of the role of lncRNAs in bone and the challenges in addressing their multiple and complex functions. Based on new knowledge of epigenetic control of gene expression to be gained for ncRNA regulation of the skeleton, new directions for translating the miRNAs and lncRNAs into therapeutic targets for skeletal disorders are possible. This article is part of a Special Issue entitled Epigenetics and Bone. PMID- 26039875 TI - Correction: Rapidly improved determination of metabolites from biological data sets using the high-efficient TransOmics tool. AB - Correction for 'Rapidly improved determination of metabolites from biological data sets using the high-efficient TransOmics tool' by Aihua Zhang et al., Mol. BioSyst., 2014, 10, 2160-2165. PMID- 26039874 TI - Extracellular Matrix can Recover the Downregulation of Adhesion Molecules after Cell Detachment and Enhance Endothelial Cell Engraftment. AB - The low cell engraftment after transplantation limits the successful application of stem cell therapy and the exact pathway leading to acute donor cell death following transplantation is still unknown. Here we investigated if processes involved in cell preparation could initiate downregulation of adhesion-related survival signals, and further affect cell engraftment after transplantation. Human embryonic stem cell-derived endothelial cells (hESC-ECs) were suspended in PBS or Matrigel and kept at 4 degrees C. Quantitative RT-PCR analysis was used to test the adhesion and apoptosis genes' expression of hESC-ECs. We demonstrated that cell detachment can cause downregulation of cell adhesion and extracellular matrix (ECM) molecules, but no obvious cell anoikis, a form of apoptosis after cell detachment, was observed. The downregulation of adhesion and ECM molecules could be regained in the presence of Matrigel. Finally, we transplanted hESC-ECs into a mouse myocardial ischemia model. When transplanted with Matrigel, the long term engraftment of hESC-ECs was increased through promoting angiogenesis and inhibiting apoptosis, and this was confirmed by bioluminescence imaging. In conclusion, ECM could rescue the functional genes expression after cell detached from culture dish, and this finding highlights the importance of increasing stem cell engraftment by mimicking stem cell niches through ECM application. PMID- 26039876 TI - Gene expression profiling of shoot-derived calli from adult radiata pine and zygotic embryo-derived embryonal masses. AB - BACKGROUND: Although somatic embryogenesis has an unprecedented potential for large-scale clonal propagation of conifers, the ability to efficiently induce the embryonal cultures required for somatic embryo production has long been a challenge. Furthermore, because early stage zygotic embryos remain the only responsive explants for pines, it is not possible to clone individual trees from vegetative explants at a commercial scale. This is of particular interest for adult trees because many elite characteristics only become apparent following sexual maturation. FINDINGS: Shoot explants collected from adult radiata pine trees were cultured on four induction media differing in plant growth regulator composition, either directly after collection or from in vitro-generated axillary shoots. Six callus lines were selected for microscopic examination, which failed to reveal any embryonal masses (EM). qPCR expression profiling of five of these lines indicated that explant type influenced the absolute level of gene expression, but not the type of genes that were expressed. The analysis, which also included three EM lines induced from immature zygotic embryos, encompassed five categories of genes reflective of metabolic, mitotic and meristematic activity, along with putative markers of embryogenicity. Culture medium was found to have no significant impact on gene expression, although differences specific to the explant's origin were apparent. Expression of transcriptional factors associated with vegetative meristems further suggested that all of the callus lines possessed a substantive vegetative character. Most notable, however, was that they all also expressed a putative embryogenic marker (LEC1). CONCLUSIONS: While limited in scope, these results illustrate the utility of expression profiling for characterizing tissues in culture. For example, although the biological significance of LEC1 expression is unclear, it does present the possibility that these callus lines possess some level of embryogenic character. Additionally, expression of vegetative meristem markers is consistent with their vegetative origin, as are differences in expression patterns as compared with EM. PMID- 26039877 TI - Human fertility, molecular genetics, and natural selection in modern societies. AB - Research on genetic influences on human fertility outcomes such as number of children ever born (NEB) or the age at first childbirth (AFB) has been solely based on twin and family-designs that suffer from problematic assumptions and practical limitations. The current study exploits recent advances in the field of molecular genetics by applying the genomic-relationship-matrix based restricted maximum likelihood (GREML) methods to quantify for the first time the extent to which common genetic variants influence the NEB and the AFB of women. Using data from the UK and the Netherlands (N = 6,758), results show significant additive genetic effects on both traits explaining 10% (SE = 5) of the variance in the NEB and 15% (SE = 4) in the AFB. We further find a significant negative genetic correlation between AFB and NEB in the pooled sample of -0.62 (SE = 0.27, p-value = 0.02). This finding implies that individuals with genetic predispositions for an earlier AFB had a reproductive advantage and that natural selection operated not only in historical, but also in contemporary populations. The observed postponement in the AFB across the past century in Europe contrasts with these findings, suggesting an evolutionary override by environmental effects and underscoring that evolutionary predictions in modern human societies are not straight forward. It emphasizes the necessity for an integrative research design from the fields of genetics and social sciences in order to understand and predict fertility outcomes. Finally, our results suggest that we may be able to find genetic variants associated with human fertility when conducting GWAS-meta analyses with sufficient sample size. PMID- 26039880 TI - Canonical Potentials and Spectra within the Born-Oppenheimer Approximation. AB - A generalized formulation of canonical transformations and spectra are used to investigate the concept of a canonical potential strictly within the Born Oppenheimer approximation. Data for the most accurate available ground electronic state pairwise intermolecular potentials in H2, HD, D2, HeH(+), and LiH are used to rigorously evaluate such transformations. The corresponding potentials are generated explicitly using parameters calculated with algebraic functions from that of the single canonical potential of the simplest molecule, H2(+). The efficacy of this approach is further tested by direct comparison of the predicted eigenvalues of all vibrational states in the selected molecular systems considered with the corresponding most accurately known Born-Oppenheimer eigenvalues currently available. Deviations are demonstrated to be less than 2 cm(-1) for all vibrational states in H2, HD, D2, HeH(+), and LiH, with an average standard deviation of 0.27 cm(-1) for the 87 states considered. The implications of these results for molecular quantum chemistry are discussed. PMID- 26039878 TI - Use of autoantigen-loaded phosphatidylserine-liposomes to arrest autoimmunity in type 1 diabetes. AB - INTRODUCTION: The development of new therapies to induce self-tolerance has been an important medical health challenge in type 1 diabetes. An ideal immunotherapy should inhibit the autoimmune attack, avoid systemic side effects and allow beta cell regeneration. Based on the immunomodulatory effects of apoptosis, we hypothesized that apoptotic mimicry can help to restore tolerance lost in autoimmune diabetes. OBJECTIVE: To generate a synthetic antigen-specific immunotherapy based on apoptosis features to specifically reestablish tolerance to beta-cells in type 1 diabetes. METHODS: A central event on the surface of apoptotic cells is the exposure of phosphatidylserine, which provides the main signal for efferocytosis. Therefore, phosphatidylserine-liposomes loaded with insulin peptides were generated to simulate apoptotic cells recognition by antigen presenting cells. The effect of antigen-specific phosphatidylserine liposomes in the reestablishment of peripheral tolerance was assessed in NOD mice, the spontaneous model of autoimmune diabetes. MHC class II-peptide tetramers were used to analyze the T cell specific response after treatment with phosphatidylserine-liposomes loaded with peptides. RESULTS: We have shown that phosphatidylserine-liposomes loaded with insulin peptides induce tolerogenic dendritic cells and impair autoreactive T cell proliferation. When administered to NOD mice, liposome signal was detected in the pancreas and draining lymph nodes. This immunotherapy arrests the autoimmune aggression, reduces the severity of insulitis and prevents type 1 diabetes by apoptotic mimicry. MHC class II tetramer analysis showed that peptide-loaded phosphatidylserine-liposomes expand antigen-specific CD4+ T cells in vivo. The administration of phosphatidylserine free liposomes emphasizes the importance of phosphatidylserine in the modulation of antigen-specific CD4+ T cell expansion. CONCLUSIONS: We conclude that this innovative immunotherapy based on the use of liposomes constitutes a promising strategy for autoimmune diseases. PMID- 26039879 TI - Contribution of nuclease to the pathogenesis of Aeromonas hydrophila. AB - Aeromonas hydrophila is a gram-negative bacterium that is widely distributed in aquatic environments and can cause septicemia in both fish and humans. However, the underlying mechanisms leading to severe infection are not well understood. In this study, an A. hydrophila nuclease (ahn) deletion mutant was constructed to investigate its contribution to pathogenesis. This mutant did not differ from the wild-type strain in terms of its growth or hemolytic phenotype. However, the ahn deficient mutant was more susceptible to being killed by fish macrophages and mouse blood in vitro. Furthermore, evidence obtained using both fish and murine infection models strongly indicated that the inactivation of Ahn impaired the ability of A. hydrophila to evade innate immune clearance in vivo. More importantly, the virulence of the mutant was attenuated in both fish and mice, with reductions in dissemination capacities and mortality rates. These findings implicate Ahn in A. hydrophila virulence, with important functions in evading innate immune defenses. PMID- 26039881 TI - Erratum: Antibacterial and anti-biofilm activities of thiazolidione derivatives against clinical staphylococcus strains. AB - [This corrects the article DOI: 10.1038/emi.2015.1.]. PMID- 26039882 TI - Relationships of sagittal skeletal discrepancy, natural head position, and craniocervical posture in young Chinese children. AB - OBJECTIVE: The aim of this study was to investigate the relationships of sagittal skeletal discrepancy, natural head position (NHP), and craniocervical posture in young Chinese children with average vertical facial pattern. METHODS: Ninety patients with average Frankfort mandibular plane angle (FH/ML) were classified into skeletal class I, II, and III relationships according to their ANB angle. Cephalometric radiographs in NHP were taken. Variables representing sagittal and vertical craniofacial morphology, head posture, and craniocervical posture were measured and compared. RESULTS: Subjects in the skeletal class II group showed the largest craniovertical angles and craniocervical angles, while subjects in the skeletal class III group exhibited the smallest craniovertical angles and craniocervical angles, though not all the measurements showed significant differences. The angle formed by the nasion-sella line and the tangent to the posterior border of the mandibular ramus (NSL/RL) was largest in the skeletal class II group and smallest in the skeletal class III group (p = 0.05). DISCUSSION: Significant differences exist in NHP and craniocervical posture among skeletal class I, II, and III relationships in young Chinese children. Subjects with skeletal class II relationship tended to exhibit more extended head, and children with skeletal class III relationship often exhibited flexed head. PMID- 26039884 TI - Chemical compartmentalisation by membranes: from biological mechanism to biomimetic applications. PMID- 26039883 TI - Addition of CpG ODN and Poly (I:C) to a standard maturation cocktail generates monocyte-derived dendritic cells and induces a potent Th1 polarization with migratory capacity. AB - Monocyte-derived dendritic cells (DCs) are used as immunoadjuvant cells in cancer vaccines and have made great progress. However, an optimal DCs subset is vital for this treatment effect, the current 'gold standard' cytokine cocktail DCs have a shortcoming in their cytokines secretion, especially IL-12p70, mainly because of the existence of PGE2. Therefore, it is necessary to find an appropriate DCs based immunotherapeutic protocol. In this study, we compared a novel 'improved' maturation cytokine cocktail with the current 'gold standard' maturation cytokine cocktail used for generating standard DCs. The 'improved' maturation cytokine cocktail DCs showed a higher levels surface markers expression (CD80, CD83, CD86 and HLA-DR), the chemokine receptors CXCR4 and CCR7 and chemokine CCL19, CCL21 and CXCL21, whereas CCR5 expression was reduced. Most importantly, in contrast to 'gold standard' DCs, which secrete little IL-12p70 and as a result induce mainly Th2 immunity, 'improved' cytokine cocktail DCs secreted higher levels IL-12p70 and also secreted similar concentration IL-10. To removal of PGE2 from the 'improved' DCs did increase the IL-12p70 production. In conclusion, we here present the 'improved' DCs, as an optimal maturation cocktail protocol, can induce high migratory potential, generate immunostimulatory DCs, produce higher levels IL-12p70 with superior capacity to induce Th1 immunity, when compared with the 'gold standard' DCs. PMID- 26039885 TI - Explore the Functional Connectivity between Brain Regions during a Chemistry Working Memory Task. AB - Previous studies have rarely examined how temporal dynamic patterns, event related coherence, and phase-locking are related to each other. This study assessed reaction-time-sorted spectral perturbation and event-related spectral perturbation in order to examine the temporal dynamic patterns in the frontal midline (F), central parietal (CP), and occipital (O) regions during a chemistry working memory task at theta, alpha, and beta frequencies. Furthermore, the functional connectivity between F-CP, CP-O, and F-O were assessed by component event-related coherence (ERCoh) and component phase-locking (PL) at different frequency bands. In addition, this study examined whether the temporal dynamic patterns are consistent with the functional connectivity patterns across different frequencies and time courses. Component ERCoh/PL measured the interactions between different independent components decomposed from the scalp EEG, mixtures of time courses of activities arising from different brain, and artifactual sources. The results indicate that the O and CP regions' temporal dynamic patterns are similar to each other. Furthermore, pronounced component ERCoh/PL patterns were found to exist between the O and CP regions across each stimulus and probe presentation, in both theta and alpha frequencies. The consistent theta component ERCoh/PL between the F and O regions was found at the first stimulus and after probe presentation. These findings demonstrate that temporal dynamic patterns at different regions are in accordance with the functional connectivity patterns. Such coordinated and robust EEG temporal dynamics and component ERCoh/PL patterns suggest that these brain regions' neurons work together both to induce similar event-related spectral perturbation and to synchronize or desynchronize simultaneously in order to swiftly accomplish a particular goal. The possible mechanisms for such distinct component phase locking and coherence patterns were also further discussed. PMID- 26039886 TI - Pupal melanization is associated with higher fitness in Spodoptera exigua. AB - Melanism has long been thought to be a habitat adaptation with a fitness cost. Here we reported a homozygous melanic strain (SEM) of Spodoptera exigua (Hubner) (Insecta: Lepidoptera: Noctuidae) established with black pupae spontaneously occurring within a typical laboratory population (SEW). The melanization is expressed globally, and only in the pupal stage. After pupation, the melanic SEM pupae gradually accumulate melanin to become completely black within 6 hours, whereas the wild-type SEW pupae gradually turn yellow-brown. The melanic SEM strain exhibits faster development in all life stages, heavier pupa weight, more mating time, higher fecundity, and accordingly, higher net reproductive rate and population trend index. While no reproductive isolation was observed between the SEM and SEW strains, the mating times per female of the reciprocal crosses and the SEM intracrosses were significantly higher than those of the SEW intracrosses. This represents a rare case of melanization that has fitness gains, rather than costs. Analysis of the life-history traits of this case and 14 previously reported cases of insect melanism indicate that none of melanization origin, stage, space and variation type determining whether melanism will cause fitness gain or cost. PMID- 26039887 TI - Trends in Basal Cell Carcinoma Incidence and Identification of High-Risk Subgroups, 1998-2012. AB - IMPORTANCE: The incidence of basal cell carcinomas (BCCs) is increasing globally, but incidence rates in the United States are difficult to quantify because BCCs are not reportable tumors. OBJECTIVE: To estimate annual BCC incidence rates by age, sex, and race/ethnicity to identify demographically distinct high-risk subgroups and to assess changes in rates over time. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study (January 1, 1998, through December 31, 2012), we studied 147 093 patients with BCC from Kaiser Permanente Northern California, a large, integrated health care provision system, identified using a previously validated BCC registry. MAIN OUTCOMES AND MEASURES: We estimated annual BCC incidence rates by age, sex, and race/ethnicity and assessed changes in rates over time. The BCC incidence rates were standardized to the age, sex, and race/ethnicity distribution of the 2010 US Census population. RESULTS: In models adjusting for age, sex, and race, male patients had higher rates than female patients (incidence rate ratio [IRR], 1.65; 95% CI, 1.60-1.70). Persons 65 through 79 years of age and those 80 years and older had higher rates than persons 40 through 64 years of age (IRR, 2.96; 95% CI, 2.86-3.06; and IRR, 5.14; 95% CI, 4.94-5.35, respectively). Whites had higher rates than multiracial persons (IRR, 1.96; 95% CI, 1.80-2.13), Hispanics (IRR, 8.56; 95% CI, 7.79-9.41), Asians (IRR, 33.13; 95% CI, 27.84-39.42), and blacks (IRR, 72.98; 95% CI, 49.21 108.22). CONCLUSIONS AND RELEVANCE: We estimate that BCCs occur in approximately 2 million Americans annually. Our findings provide an updated estimate of the incidence of BCCs, highlight the changing epidemiologic findings, and better identify demographically distinct high-risk subgroups. PMID- 26039888 TI - [Cryoglobulinemia in a Tunisian internal medicine department]. AB - AIM: Cryoglobulinemia is characterized by multiple organ involvement, mainly including the skin, liver, kidneys, and peripheral nerves. Our aim was to investigate the demographic, clinical, and serologic features, as well as survival in a group of 16 Tunisian patients with cryoglobulinemia. RESULTS: The study included 12 women and 4 men, and their mean age was 41 years. In all but two, the cryoglobulinemia was associated with another disease. These included lupus for 9, Sjogren syndrome for 2, and polyarteritis nodosa for one. They also included infectious diseases: 3 patients with hepatitis B virus infection, one with hepatitis C virus infection, one with parvovirus B19, and another with lymph node tuberculosis. Only one case of lymphoproliferative disease was noted. General symptoms were present in 81% of the patients, cutaneous vasculitis in 43%, peripheral vascular-Raynaud phenomenon in 37%, joint polyarthralgia or arthritis in 62%, renal involvement in 68%, neuropathy in 25%, lung involvement in 56%, gastrointestinal involvement in 37%, and finally cardiac involvement in 31%. In some cases it was difficult to determine if the clinical signs were attributable to cryoglobulinemia or the underlying pathology. The course was favorable under treatment for 5 patients, while 7 patients became sicker and 5 finally died. CONCLUSION: Cryoglobulinemia is underdiagnosed. Treatment depends on the severity of the lesions and the underlying disease. PMID- 26039889 TI - Does Bariatric Surgery Reduce Health Care Costs?: Weighing the Evidence. PMID- 26039890 TI - Fetuses of Mothers with Thyroid Disease May Be at Higher Risk of Developing Supraventricular Tachycardia. AB - OBJECTIVE: Fetal tachyarrhythmias complicate 0.5% of pregnancies, with high morbidity and mortality. We hypothesized that maternal factors may predispose to fetal supraventricular tachycardia (SVT). STUDY DESIGN: We reviewed medical records of all 124 mothers who presented to the Vanderbilt Fetal Cardiology Clinic from 2004 to 2010 for fetal arrhythmias, excluding heart block. Maternal factors were compared between 28 fetuses with SVT and a control group of 112 fetuses screened for noncardiac conditions. The proportions were analyzed using chi-square or Fisher exact test for categorical variables and Wilcoxon rank sum test for continuous variables. RESULTS: Of maternal factors, thyroid disease was statistically significant compared with controls. Among mothers whose fetuses had SVT, 21% had thyroid disease (83% hypothyroidism) compared with 3% of controls (p < 0.001). CONCLUSION: In this cohort, the maternal thyroid disease was more common in fetuses with SVT compared with controls (odds ratio = 9.8, 95% confidence interval 2.3-42.3), suggesting closer screening for fetal arrhythmias and SVT in mothers with thyroid disease. Also, routine screening of thyroid functions and thyroid autoantibodies may be warranted in mothers of fetuses with SVT. PMID- 26039891 TI - Seasonal Variation in Solar Ultra Violet Radiation and Early Mortality in Extremely Preterm Infants. AB - BACKGROUND: Vitamin D production during pregnancy promotes fetal lung development, a major determinant of infant survival after preterm birth. Because vitamin D synthesis in humans is regulated by solar ultraviolet B (UVB) radiation, we hypothesized that seasonal variation in solar UVB doses during fetal development would be associated with variation in neonatal mortality rates. METHODS: This cohort study included infants born alive with gestational age (GA) between 23 and 28 weeks gestation admitted to a neonatal unit between 1996 and 2010. Three infant cohort groups were defined according to increasing intensities of solar UVB doses at 17 and 22 weeks gestation. The primary outcome was death during the first 28 days after birth. RESULTS: Outcome data of 2,319 infants were analyzed. Mean birth weight was 830 +/- 230 g and median gestational age was 26 weeks. Mortality rates were significantly different across groups (p = 0.04). High-intensity solar UVB doses were associated with lower mortality when compared with normal intensity solar UVB doses (hazard ratio: 0.70; 95% confidence interval: 0.54-0.91; p = 0.01). CONCLUSION: High-intensity solar UVB doses during fetal development seem to be associated with risk reduction of early mortality in preterm infants. Prospective studies are needed to validate these preliminary findings. PMID- 26039893 TI - Strong Acoustic Phonon Localization in Copolymer-Wrapped Carbon Nanotubes. AB - Understanding and controlling exciton-phonon interactions in carbon nanotubes has important implications for producing efficient nanophotonic devices. Here we show that laser vaporization-grown carbon nanotubes display ultranarrow luminescence line widths (120 MUeV) and well-resolved acoustic phonon sidebands at low temperatures when dispersed with a polyfluorene copolymer. Remarkably, we do not observe a correlation of the zero-phonon line width with (13)C atomic concentration, as would be expected for pure dephasing of excitons with acoustic phonons. We demonstrate that the ultranarrow and phonon sideband-resolved emission spectra can be fully described by a model assuming extrinsic acoustic phonon localization at the nanoscale, which holds down to 6-fold narrower spectral line width compared to previous work. Interestingly, both exciton and acoustic phonon wave functions are strongly spatially localized within 5 nm, possibly mediated by the copolymer backbone, opening future opportunities to engineer dephasing and optical bandwidth for applications in quantum photonics and cavity optomechanics. PMID- 26039892 TI - Microfluidic Generation of Monodisperse, Structurally Homogeneous Alginate Microgels for Cell Encapsulation and 3D Cell Culture. AB - Monodisperse alginate microgels (10-50 MUm) are created via droplet-based microfluidics by a novel crosslinking procedure. Ionic crosslinking of alginate is induced by release of chelated calcium ions. The process separates droplet formation and gelation reaction enabling excellent control over size and homogeneity under mild reaction conditions. Living mesenchymal stem cells are encapsulated and cultured in the generated 3D microenvironments. PMID- 26039895 TI - Mesoscopic patterns of neural activity support songbird cortical sequences. AB - Time-locked sequences of neural activity can be found throughout the vertebrate forebrain in various species and behavioral contexts. From "time cells" in the hippocampus of rodents to cortical activity controlling movement, temporal sequence generation is integral to many forms of learned behavior. However, the mechanisms underlying sequence generation are not well known. Here, we describe a spatial and temporal organization of the songbird premotor cortical microcircuit that supports sparse sequences of neural activity. Multi-channel electrophysiology and calcium imaging reveal that neural activity in premotor cortex is correlated with a length scale of 100 um. Within this length scale, basal-ganglia-projecting excitatory neurons, on average, fire at a specific phase of a local 30 Hz network rhythm. These results show that premotor cortical activity is inhomogeneous in time and space, and that a mesoscopic dynamical pattern underlies the generation of the neural sequences controlling song. PMID- 26039894 TI - A new mib allele with a chromosomal deletion covering foxc1a exhibits anterior somite specification defect. AB - mib(nn2002), found from an allele screen, showed early segmentation defect and severe cell death phenotypes, which are different from previously known mib mutants. Despite distinct morphological phenotypes, the typical mib molecular phenotypes: her4 down-regulation, neurogenic phenotype and cold sensitive dlc expression pattern, still remained. The linkage analysis also indicated that mib(nn2002) is a new mib allele. Failure of specification in anterior 7-10 somites is likely due to lack of foxc1a expression in mib(nn2002) homozygotes. Somites and somite markers gradually appeared after 7-10 somite stage, suggesting that foxc1a is only essential for the formation of anterior 7-10 somites. Apoptosis began around 16-somite stage with p53 up-regulation. To find the possible links of mib, foxc1a and apoptosis, transcriptome analysis was employed. About 140 genes, including wnt3a, foxc1a and mib, were not detected in the homozygotes. Overexpression of foxc1a mRNA in mib(nn2002) homozygotes partially rescued the anterior somite specification. In the process of characterizing mib(nn2002) mutation, we integrated the scaffolds containing mib locus into chromosome 2 (or linkage group 2, LG2) based on synteny comparison and transcriptome results. Genomic PCR analysis further supported the conclusion and showed that mib(nn2002) has a chromosomal deletion with the size of about 9.6 Mbp. PMID- 26039897 TI - Crystallographic and Computational Analyses of AUUCU Repeating RNA That Causes Spinocerebellar Ataxia Type 10 (SCA10). AB - Spinocerebellar ataxia type 10 (SCA10) is caused by a pentanucleotide repeat expansion of r(AUUCU) within intron 9 of the ATXN10 pre-mRNA. The RNA causes disease by a gain-of-function mechanism in which it inactivates proteins involved in RNA biogenesis. Spectroscopic studies showed that r(AUUCU) repeats form a hairpin structure; however, there were no high-resolution structural models prior to this work. Herein, we report the first crystal structure of model r(AUUCU) repeats refined to 2.8 A and analysis of the structure via molecular dynamics simulations. The r(AUUCU) tracts adopt an overall A-form geometry in which 3 * 3 nucleotide (5')UCU(3')/(3')UCU(5') internal loops are closed by AU pairs. Helical parameters of the refined structure as well as the corresponding electron density map on the crystallographic model reflect dynamic features of the internal loop. The computational analyses captured dynamic motion of the loop closing pairs, which can form single-stranded conformations with relatively low energies. Overall, the results presented here suggest the possibility for r(AUUCU) repeats to form metastable A-from structures, which can rearrange into single-stranded conformations and attract proteins such as heterogeneous nuclear ribonucleoprotein K (hnRNP K). The information presented here may aid in the rational design of therapeutics targeting this RNA. PMID- 26039898 TI - CD56+ T cells are increased in kidney transplant patients following cytomegalovirus infection. AB - BACKGROUND: CD56+ T cells previously have been identified as potentially cytotoxic lymphocytes, and relative numbers are increased in some infectious diseases. PATIENTS AND METHODS: Relative proportions of CD56+ T cells were measured by flow cytometry in groups of renal transplant patients differing in cytomegalovirus (CMV) status of donor (D) and recipient (R). These measurements were related to episodes of CMV viremia. RESULTS: Patient groups in which recipients (R+) or donors (D+/R-) were CMV+ had significantly higher proportions of CD56+ T cells (5.11 +/- 0.69% and 5.42 +/- 1.01%, respectively) than the D-/R- group (1.9 +/- 0.35%; P = 0.0018 and 0.017, respectively). In the high-risk D+/R- group, it was found that patients who had post-transplant CMV viremia had higher levels than those who remained CMV negative (9.09 +/- 2.34% vs. 3.16 +/- 1.22%; P = 0.01). CD56+ T cells from R+ and D+/R- groups had higher proportions of both CD4+ and CD8+ cells than the D-/R- group. When activation markers were examined, some CD56+ T cells from both CMV+ groups had a TEM phenotype, with significantly more expressing CD45RO and NKG2C, and less expressing CD28, CD62L, CD127, and CD161 compared to the D-/R- group. Some CD56+ T cells showed specificity for CMV antigens and similar proportions of CD8+ cells were positive for class I HLA-CMV tetramers containing immunodominant CMV peptides compared to the majority CD56- T cells. CONCLUSION: The results show significant increases in proportions of CD56+ T cells in relation to CMV infection in renal transplant patients and suggest that these cells have a cytotoxic function against CMV-infected cells. PMID- 26039900 TI - Effect of PTB7 Properties on the Performance of PTB7:PC71BM Solar Cells. AB - The effect of poly[[4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5-b']dithiophene-2,6 diyl][3-fluoro-2-[(2-ethylhexy)carbonyl]thieno[3,4-b]thiophenediyl]] (PTB7) properties on the optical properties, charge transport and photovoltaic performance of PTB7:[6,6]-phenyl C71 butyric acid methyl ester (PC71BM) blend films is investigated. We found that the variations in the molecular weight (Mw) and polydispersity index (PDI) of PTB7 mainly affect the phase separation and charge transport (hole mobility) in the blend films. The optical properties are also affected, but the increase in the extinction coefficient does not necessarily imply increased power conversion efficiency. The obtained power conversion efficiency for optimized thickness varied from 4.8% to 7.8% depending on the properties of PTB7. The wide range of obtained power conversion efficiencies illustrates the importance of optimizing the Mw and PDI to optimize bulk heterojunction morphology and achieve high performance solar cells. PMID- 26039899 TI - A Comparison of Methods To Enhance Protein Detection of Lipoproteins by Mass Spectrometry. AB - We sought to develop a new method to more efficiently analyze lipid-bound proteins by mass spectrometry using a combination of a lipid removal agent (LRA) that selectively targets lipid-bound proteins and a mass spectrometry compatible detergent, anionic acid labile surfactant (AALS), that is capable of eluting proteins off the LRA. This method was compared to established methods that use the lipid removal agent alone and straight proteomic analysis of human plasma after organic solvent delipidation (OSD). Plasma from healthy individuals was separated by gel filtration chromatography and prepared for mass spectrometry analysis by each of the described methods. The addition of AALS to LRA increased the overall number of proteins detected in both the high and low density lipoprotein size range, the number of peptide counts for each protein, and the overall sequence coverage. Organic solvent delipidation detected the most proteins, though with some decrease in overall protein detection and sequence coverage due to the presence of nonlipid-bound proteins. The use of LRA allows for selection and analysis of lipid-bound proteins. The addition of a mass spectrometry compatible detergent improved detection of lipid-bound proteins from human plasma using LRA. PMID- 26039901 TI - Can patients identify what triggers their back pain? Secondary analysis of a case crossover study. AB - The aim of this case-crossover study was to investigate the extent to which patients can accurately nominate what triggered their new episode of sudden-onset acute low back pain (LBP). We interviewed 999 primary care patients to record exposure to 12 standard triggers and also asked the patients to nominate what they believed triggered their LBP. Exposure to the patient-nominated trigger during the case window was compared with exposure in the control window. Conditional logistic regression models were constructed to quantify the risk of LBP onset associated with the patient-nominated trigger. Sensitivity analyses were conducted varying the duration and timing of case/control windows. We compared the extent to which patient-nominated triggers matched standard triggers. The odds ratios for exposure to patient-nominated triggers ranged from 8.60 to 30.00, suggesting that exposure increases the risk of LBP. Patients' understanding of triggers however seems incomplete, as we found evidence that while some of the standard triggers were well recognised (such as lifting heavy loads), others (such as being distracted during manual tasks) were under recognised as possible triggers of an episode of LBP. This study provides some evidence that patients can accurately nominate the activity that triggered their new episode of sudden-onset acute LBP. PMID- 26039902 TI - The Pain Course: a randomised controlled trial examining an internet-delivered pain management program when provided with different levels of clinician support. AB - The present study evaluated an internet-delivered pain management program, the Pain Course, when provided with different levels of clinician support. Participants (n = 490) were randomised to 1 of 4 groups: (1) Regular Contact (n = 143), (2) Optional Contact (n = 141), (3) No Contact (n = 131), and (4) a treatment-as-usual Waitlist Control Group (n = 75). The treatment program was based on the principles of cognitive behaviour therapy and comprised 5 internet delivered lessons provided over 8 weeks. The 3 Treatment Groups reported significant improvements (between-group Cohen's d; avg. reduction) in disability (ds >= 0.50; avg. reduction >= 18%), anxiety (ds >= 0.44; avg. reduction >= 32%), depression (ds >= 0.73; avg. reduction >= 36%), and average pain (ds >= 0.30; avg. reduction >= 12%) immediately posttreatment, which were sustained at or further improved to 3-month follow-up. High treatment completion rates and levels of satisfaction were reported, and no marked or consistent differences were observed between the Treatment Groups. The mean clinician time per participant was 67.69 minutes (SD = 33.50), 12.85 minutes (SD = 24.61), and 5.44 minutes (SD = 12.38) for those receiving regular contact, the option of contact, and no clinical contact, respectively. These results highlight the very significant public health potential of carefully designed and administered internet-delivered pain management programs and indicate that these programs can be successfully administered with several levels of clinical support. PMID- 26039903 TI - Effect of tannic and gallic acids alone or in combination with carbenicillin or tetracycline on Chromobacterium violaceum CV026 growth, motility, and biofilm formation. AB - Chromobacterium violaceum is an opportunistic pathogen that causes infections that are difficult to treat. The goal of this research was to evaluate the effect of selected tannins (tannic acid (TA) and gallic acid (GA)) on bacterial growth, motility, antibiotic (carbenicillin, tetracycline) susceptibility, and biofilm formation. Both tannins, particularly TA, impaired bacterial growth levels and swimming motilities at sub-minimum inhibitory concentrations (sub-MICs). In combination with tannins, antibiotics showed increased MICs, suggesting that tannins interfered with antibacterial activity. Sub-MICs of tetracycline or TA alone enhanced biofilm formation of C. violaceum; however, in combination, these compounds inhibited biofilm formation. In contrast, carbenicillin at sub-MICs was effective in inhibiting C. violaceum biofilm formation; however, in combination with lower concentrations of TA or GA, biofilms were enhanced. These results provide insights into the effects of tannins on C. violaceum growth and their varying interaction with antibiotics used to target C. violaceum infections. PMID- 26039904 TI - Tailor-made CRISPR/Cas system for highly efficient targeted gene replacement in the rice blast fungus. AB - CRISPR/Cas-derived RNA-guided nucleases (RGNs) that can generate DNA double strand breaks (DSBs) at a specific sequence are widely used for targeted genome editing by induction of DSB repair in many organisms. The CRISPR/Cas system consists of two components: a single Cas9 nuclease and a single-guide RNA (sgRNA). Therefore, the system for constructing RGNs is simple and efficient, but the utilization of RGNs in filamentous fungi has not been validated. In this study, we established the CRISPR/Cas system in the model filamentous fungus, Pyricularia oryzae, using Cas9 that was codon-optimized for filamentous fungi, and the endogenous RNA polymerase (RNAP) III U6 promoter and a RNAP II fungal promoter for the expression of the sgRNA. We further demonstrated that RGNs could recognize the desired sequences and edit endogenous genes through homologous recombination-mediated targeted gene replacement with high efficiency. Our system will open the way for the development of various CRISPR/Cas-based applications in filamentous fungi. PMID- 26039905 TI - A prospective study evaluating cochlear implant management skills: development and validation of the Cochlear Implant Management Skills survey. AB - OBJECTIVE: To investigate the ability of cochlear implant (CI) recipients to physically handle and care for their hearing implant device(s) and to identify factors that may influence skills. To assess device management skills, a clinical survey was developed and validated on a clinical cohort of CI recipients. DESIGN: Survey development and validation. A prospective convenience cohort design study. SETTING: Specialist hearing implant clinic. PARTICIPANTS: Forty-nine post lingually deafened, adult CI recipients, at least 12 months postoperative. MAIN OUTCOME MEASURES: Survey test-retest reliability, interobserver reliability and responsiveness. Correlations between management skills and participant demographic, audiometric, clinical outcomes and device factors. RESULTS: The Cochlear Implant Management Skills survey was developed, demonstrating high test retest reliability (0.878), interobserver reliability (0.972) and responsiveness to intervention (skills training) [t(20) = -3.913, P = 0.001]. Cochlear Implant Management Skills survey scores range from 54.69% to 100% (mean: 83.45%, sd: 12.47). No associations were found between handling skills and participant factors. CONCLUSIONS: This is the first study to demonstrate a range in cochlear implant device handling skills in CI recipients and offers clinicians and researchers a tool to systematically and objectively identify shortcomings in CI recipients' device handling skills. PMID- 26039907 TI - Efficacy of a triclosan formula in controlling early subgingival biofilm formation: a randomized trial. AB - The aim of this study was to determine the efficacy of rinses with slurries of a dentifrice containing triclosan (TCS), as compared with rinses with slurries from a control dentifrice, in controlling early subgingival biofilm formation. A double-blind, randomized and cross-over clinical trial was designed, and 26 dental students were included. In the first period, participants were randomized to rinse with a TCS slurry or a control slurry, in a 12 h interval, and to refrain from mechanical cleaning. A Plaque Free Zone Index was assessed at 24 h, 48 h, 72 h and 96 h. After a washout period of 10 days, the second experimental period was conducted, following the same protocol as the first period, except that the slurry groups were switched. Use of the TCS slurry resulted in a significantly higher percentage of plaque-free surfaces, both at 24 h and at 72 h (p < 0.01). In the of 48-72 h interval, the triclosan slurry showed a lower percentage of sites converted to a score of 2 (38.1% for the test versus 40% for the control product, p = 0.015). In conclusion, rinsing with slurries of dentifrice containing TCS retards the down growth of bacterial biofilms from the supra- to the subgingival environment. PMID- 26039906 TI - Low-cost glass ionomer cement as ART sealant in permanent molars: a randomized clinical trial. AB - Clinical trials are normally performed with well-known brands of glass ionomer cement (GIC), but the cost of these materials is high for public healthcare in less-affluent communities. Given the need to research cheaper materials, it seems pertinent to investigate the retention rate of a low-cost GIC applied as atraumatic restorative treatment (ART) sealants in two centers in Brazil. Four hundred and thirty-seven 6-to-8-year-old schoolchildren were selected in two cities in Brazil. The children were randomly divided into two groups, according to the tested GIC applied in the first permanent molars. The retention rate was evaluated after 3, 6 and 12 months. Kaplan-Meier survival analysis and the log rank test were performed. The variables were tested for association with sealant longevity, using logistic regression analyses (alpha = 5%). The retention rate of sealants after 12 months was 19.1%. The high-cost GIC brand presented a 2-fold more-likely-to-survive rate than the low-cost brand (p < 0.001). Significant difference was also found between the cities where the treatments were performed, in that Barueri presented a higher sealant survival rate than Recife (p < 0.001). The retention rate of a low-cost GIC sealant brand was markedly lower than that of a well-known GIC sealant brand. PMID- 26039908 TI - Impairment of resin cement application on the bond strength of indirect composite restorations. AB - The aims of this study were to evaluate the effect of immediate and delayed resin cement application on the microtensile bond strength of indirect composite resin restorations and, to evaluate adhesive strategies (for regular resin cement or humidity parameters for self-adhesive resin cement). Forty-five enamel/dentin discs (0.5 mm height and 10 mm of diameter) obtained from bovine teeth were divided into nine groups (n = 5). For regular cement, the variation factors were cementation technique at three levels (immediate cementation, 5 or 30 min after adhesive system application); and type of adhesive system at two levels (three- or two-step). For self-adhesive cement, the dentin moisture was the source of variation at three levels (normal, dry, or wet cementation). The specimens were submitted to microtensile bond strength (MUTBS) testing using a universal testing machine. Data were analyzed by ANOVA, Tukey's test, and linear regression. Regular cement and three-step etch-and-rinse adhesive system showed the highest values of bond strength (25.21 MPa-30 min of delay). Only for this condition, three-step adhesive showed higher bond strength than the two-step adhesive. Nevertheless, the linear regression showed that irrespective of the strategy, the use of the two-step approach when compared with three-step adhesive system decreased MUTBS (p < 0.001). The failure analysis showed predominant adhesive failures for all tested groups. All groups had comparable values of bond strength to bovine dentin when the same materials were used, even in suboptimal clinical conditions. PMID- 26039909 TI - Detection of horizontal root fracture using four different protocols of cone-beam computed tomography. AB - The purpose of this study was to analyze four different cone-beam computed tomography (CBCT) protocols to identify horizontal root fractures (HRF) in endodontically treated teeth, with or without the presence of a metallic post. Thirty extracted single-rooted human premolars were treated endodontically. Afterwards, an observer induced a horizontal fracture in 15 teeth. Each tooth was inserted in an empty mandibular socket and submitted to a computed tomography scan taken with and without the metallic post. The acquisition followed four different protocols, with different fields of view (FOV) and voxel sizes, as follows: FOV 6 X 16 cm/0.2 mm voxel; FOV 6 X 16 cm/0.25 mm voxel; FOV 8 X 8 cm/0.2 mm voxel; FOV 8 X 8 cm/0.25 mm voxel. Two observers checked all the acquisitions within a two-week interval, and the values of sensitivity, specificity, accuracy and kappa were calculated. The sensitivity, specificity and accuracy values were better for the 8 X 8 cm/0.2 mm and 16 X 6 cm/0.25 mm protocols, ranging from 0.60 to 0.86 and 0.53 to 0.80, respectively. The intra- and interobserver concordance ranged from 0.65 to 0.72. The protocols where FOV and voxel were proportional showed better results. The 8 x 8 cm/0.2 mm protocol had the least interference from the metallic artifact. All four protocols showed a decline in values in the presence of the metallic artifact. PMID- 26039910 TI - Temporomandibular disorder and anxiety, quality of sleep, and quality of life in nursing professionals. AB - To evaluate the association between temporomandibular disorder (TMD) and anxiety, quality of sleep, and quality of life in nursing professionals at the Hospital de Clinicas de Uberlandia of the Universidade Federal de Uberlandia--HCU-UFU (Medical University Hospital of the Federal University of Uberlandia), four questionnaires were given to nursing professionals. The questionnaires were completed by 160 of these professionals. The Fonseca's questionnaire was used to evaluate the presence and severity of TMD, the IDATE was used to evaluate anxiety, the SAQ was used to evaluate quality of sleep, and the SF-36 was used to evaluate quality of life. Forty-one nurses (25.6%) reported having no TMD (Fonseca's questionnaire score <= 15), 66 (41.3%) had mild TMD (Fonseca's questionnaire score 20-40), 39 (24.4%) had moderate TMD (Fonseca's questionnaire score 45-65), and 14 (8.8%) had severe TMD (Fonseca's questionnaire score >= 70). According to Fonseca's questionnaire, the presence of TMD was associated with trait anxiety, but the TMD severity was associated with state anxiety classification (mild, moderate, severe). The SAQ score differed significantly from Fonseca classification. The Fonseca's questionnaire score correlated negatively with the score of each dimension of the SF-36 (r = -0.419 to -0.183). We conclude that TMD is common among nursing professionals; its presence was associated with trait anxiety, and its severity was associated with state anxiety. Hence, the presence of TMD may reduce quality of sleep and quality of life. PMID- 26039911 TI - Supragingival biofilm control and systemic inflammation in patients with type 2 diabetes mellitus. AB - The objective of this study was to evaluate the effect of strict supragingival biofilm control on serum inflammatory markers and on periodontal clinical parameters in type 2 diabetes mellitus (T2DM) patients with chronic severe periodontitis. Twenty-four individuals with T2DM and periodontitis were randomly allocated to two treatment groups. The supragingival therapy group (ST, n = 12) received supragingival scaling, whereas the intensive therapy group (IT, n = 12) underwent supra- and subgingival scaling, as well as root planing. Patients from both groups received professional oral hygiene instructions every month. Data regarding visible plaque index (VPI), gingival bleeding index (GBI), bleeding on probing (BOP), probing pocket depth (PPD), clinical attachment level (CAL), serum levels of interleukin (IL)-6, IL-17A, IL-8, tumor necrosis factor alpha (TNF alpha), monocyte chemoattractant protein (MCP)-1 enzyme-linked immunosorbent assay (ELISA), and glycated hemoglobin (HbA1c) levels were obtained at baseline and at 6 months post-therapy. Both therapies resulted in the improvement of almost all clinical periodontal parameters (p < 0.05). There were no differences in TNF-alpha, IL-8, IL-17A and HbA1c levels in either group (p > 0.05), between the two periods. However, MCP-1 levels were significantly reduced in both the ST (p = 0.034) and the IT (p = 0.016) groups, whereas the serum IL-6 levels were significantly reduced only in the IT group (p = 0.001). Strict control of supragingival biofilm has a limited effect on systemic inflammatory markers, and a moderate effect on periodontal clinical parameters. PMID- 26039912 TI - T helper cell-related cytokine gene polymorphisms and vitamin D pathway gene polymorphisms as predictors of survival probability in patients on renal replacement therapy. AB - INTRODUCTION: Negative outcomes in patients on renal replacement therapy (RRT) may have a source in T helper (Th)-cell imbalance or vitamin D deficiency. OBJECTIVES: We examined the association of genes encoding cytokines related to Th1 and Th2 cells and vitamin D pathway genes with survival probability of patients on RRT. PATIENTS AND METHODS: The study included 1253 patients on hemodialysis. IL13, IL4R, IL18, IL12A, IL12B, IL28B, MCP1, GC, VDR, and RXRA gene polymorphisms were tested. The Kaplan-Meier method with the log-rank test was used to estimate significance of survival probabilities. RESULTS: Patients carrying the IL13 minor T allele had an increased risk of death compared with CC subjects (log-rank test, P = 0.005; hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.11-1.76; P = 0.005). IL28B rs8099 917 GG patients had higher mortality rates compared with IL28B GT+TT carriers (log-rank test, P = 0.04; HR, 1.82; 95% CI, 1.10-3.01; P =0.02). IL28B rs12979860 TT carriers had an increased risk of death compared with CC+CT carriers (log-rank test, P = 0.02; HR, 1.62; 95% CI, 1.09-2.42; P = 0.02) only when they were negative for hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. The prevalence of coronary artery disease differed significantly among patients with the IL28B rs12979860 TT genotype compared with CC+CT carriers (odds ratio, 1.87; 95% CI, 1.14-3.09; P = 0.01). There was no association between the GC, VDR, and RXRA nucleotide variants and survival. CONCLUSIONS: The IL13 rs20541 T allele and IL28B rs8099917 GG genotype are negative predictors of survival in patients on RRT, while the IL28B rs12979860 TT genotype increases the risk of death only in patients negative for HBV or HCV infection. PMID- 26039913 TI - Trapping of Sodium Dodecyl Sulfate at the Air-Water Interface of Oscillating Bubbles. AB - We report that at very low initial bulk concentrations, a couple of hundred times below the critical micellar concentration (CMC), anionic surfactant sodium dodecyl sulfate (SDS) adsorbed at the air-water interface of a gas bubble cannot be removed, on the time scale of the experiment (hours), when the surrounding solution is gently replaced by pure water. Extremely sensitive interferometric measurements of the resonance frequency of the bubble-forced oscillations give precise access to the concentration of the surfactant monolayer. The bulk interface dynamic exchange of SDS molecules is shown to be inhibited below a concentration which we believe refers to a kind of gas-liquid phase transition of the surface monolayer. Above this threshold we recover the expected concentration dependent desorption. The experimental observations are interpreted within simple energetic considerations supported by molecular dynamics (MD) calculations. PMID- 26039914 TI - [Old and new ways of personal and victim identification by dental methods. Review of the literature]. AB - The aim of this paper was to create a comprehensive literature review on forensic dental methods. This literature review is based on historical and the latest results of the forensic odontology. Thus, this comparative study deals with various methods including certain dental identification methods which are easy to use and do not require advanced technological background. Nowadays, the main reasons for the use of forensic odontology methods are natural disasters, however, their sensitivity depends on the availability of proper dental documentation of the subject/victim. Custom made prostheses offer the most accurate dental identification, which can allow an identification rate of 99.9%. Combination of different methods can also exhibit a high sensitivity (40-99.9%). It seems important that separation of old and novel methods is not recommended. Also, it is important to maintain and upgrade present methods which are capable of identifying one or more subjects/victims in practice. The authors propose several methods which could serve as a base of the new national policy in forensic dental identification and could be used by teams dealing with the identification of disaster victims. PMID- 26039915 TI - [Role of trimetazidine in the treatment of diabetic microangiopathy in ischaemic heart disease]. AB - Diabetes is one of the largest public health problems nowadays. We have to consider appearance of micro- and macroangiopathic complications as early as the time of diagnosis. In diabetes mellitus type 2, one of the main complications is ischemic heart disease caused by atherosclerosis of the coronary arteries manifested clinically as angina pectoris and myocardial infarction. However, microangiopathy and secondary injury of myocardial tissue are also not uncommon complications. In the treatment of ischemic heart disease coronary interventions, medications dilating coronaries and decreasing blood pressure and heart rate are frequently applied. The authors draw attention to a drug having no hemodynamic effects, which improves the quality of life of patients via its effect on the metabolism of the myocardium. PMID- 26039916 TI - [Occupational asthma in Hungary]. AB - Occupational asthma belongs to communicable diseases, which should be reported in Hungary. During a 24-year period between January 1990 and December 2013, 180 occupational asthma cases were reported in Hungary (52 cases between 1990 and 1995, 83 cases between 1996 and 2000, 40 cases between 2001 and 2006, and 5 cases between 2007 and 2013). These data are unusual, because according to the official report of the National Koranyi Pulmonology Institute in Budapest, at least 14,000 new adult asthma cases were reported in every year between 2000 and 2012 in Hungary. Also, international data indicate that at least 2% of adult patients with asthma have occupational asthma and at least 50 out of 1 million employees develop occupational asthma in each year. In 2003, 631 new occupational asthma patients were reported in the United Kingdom, but only 7 cases in Hungary. Because it is unlikely that the occupational environment in Hungary is much better than anywhere else in the world, it seems that not all new occupational asthma cases are reported in Hungary. Of the 180 reported cases in Hungary, 55 were bakers or other workers in flour mills. There were 11 metal-workers, 10 health care assistants, 9 workers dealing with textiles (tailors, dressmakers, workers in textile industry) and 9 employees worked upon leather and animal fur. According to international data, the most unsafe profession is the animal keeper in scientific laboratories, but only 4 of them were reported as having occupational asthma during the studied 24 years in Hungary. Interestingly, 3 museologists with newly-diagnosed occupational asthma were reported in 2003, but not such cases occurred before or after that year. In this paper the Hungarian literature of occupational asthma is summarized, followed by a review on the classification, pathomechanism, clinical presentation, predisposing factors, diagnostics and therapeutic aspects of the disease. Epidemiological data of adult asthma in Hungary and data from international studies on the occurrence of occupational asthma are also presented. Finally, the author draws attention to the low reporting activity of occupational asthma in Hungary and discusses the possible causes why this communicable disease is rarely reported. PMID- 26039917 TI - [Outbreak of vancomycin-resistant enterococci in a surgical intensive care unit]. AB - INTRODUCTION: Enterococci have increasing importance in intensive care units, and vancomycin-resistant strains express a new challenge. AIM: The aim of the authors was to present their findings obtained from the first vancomycin-resistant enterococci outbreak occurred in 2013 at the Intensive Care Unit of the 1st Department of Surgery, Semmelweis University. METHOD: This was a case-control study of patients who had Enterococci species isolated from their microbiological samples between January 1 and June 30, 2013. Changes of Enterococcal incidence and consequences of vancomycin-resistance in patient outcome were analyzed. Demographic data, hospital length of stay and mortality data were also collected. RESULTS: Enterococci were isolated from 114 patients and 14 of them had vancomycin-resistant strains. The incidence of Enterococcal strains was not different in the periods before and after the outbreak of the first vancomycin resistant Enterococci. Patients with vancomycin-resistant Enterococci had significantly higher mortality rate than those with vancomycin-sensitive Enterococcus (42.9% vs 30.0%, p = 0.005); however, length of stay was not significantly different. Co-morbidities and emergency surgery were significantly higher in patients who had vancomycin-resistant Enterococci. CONCLUSIONS: The higher mortality observed in patients with vancomycin-resistant Enterococcus infections highlights the importance of prevention and appropriate infection control, however, the direct relationship of vancomycin-resistance and increased mortality is questionable. PMID- 26039918 TI - [Frequency of T-cell mediated rejection in new-onset diabetes after kidney transplantation]. AB - INTRODUCTION: New-onset diabetes is one of the most common complications after kidney transplantation. AIM: The aims of the authors were to examine the frequency of new-onset diabetes mellitus in kidney transplanted patients receiving cyclosporine A (n = 95) and tacrolimus (n = 102) and to analyze the occurrence of T-cell mediated rejection in these two groups of patients. METHOD: Age, laboratory results, renal function and histological findings were evaluated one year after kidney transplantation. Histological evaluation was performed according to the 2007 modification of the Banff 1997 classification. RESULTS: New onset diabetes developed in 12% of patients receiving cyclosporine A-based immunosuppression and in 24% of patients taking tacrolimus (p = 0.002). Uric acid level (p = 0.002) and the age of the recipient (p = 0.003) were significantly different in the new-onset diabetic and non-diabetic groups, while renal function showed no significant difference. Evaluation of tissue samples revealed a significant difference in T-cell mediated rejection between the new-onset diabetic and non-diabetic groups (13 vs. 8 patients; 37% vs. 6%; p = 0.001). CONCLUSIONS: The results indicate an early development of the pathological effect of new-onset diabetes after kidney transplantation on the morphology of the renal allograft. PMID- 26039920 TI - Erratum. AB - The overall goal of this study is a short introduction into the Hungarian legal basis, and practical circumstances of informed consent trough the cases of the Data Protection Commissioner of Hungary, the Supreme Court of Hungary, and the Constitutional Court. The author begins by describing the basic law with an introduction to the dogmatic background of informed consent, as a common law category. PMID- 26039921 TI - Analysis of Physicochemical Properties for Drugs of Natural Origin. AB - The impact of time, therapy area, and route of administration on 13 physicochemical properties calculated for 664 drugs developed from a natural prototype was investigated. The mean values for the majority of properties sampled over five periods from pre-1900 to 2013 were found to change in a statistically significant manner. In contrast, lipophilicity and aromatic ring count remained relatively constant, suggesting that these parameters are the most important for successful prosecution of a natural product drug discovery program if the route of administration is not focused exclusively on oral availability. An examination by therapy area revealed that anti-infective agents had the most differences in physicochemical property profiles compared with other areas, particularly with respect to lipophilicity. However, when this group was removed, the variation between the mean values for lipophilicity and aromatic ring count across the remaining therapy areas was again found not to change in a meaningful manner, further highlighting the importance of these two parameters. The vast majority of drugs with a natural progenitor were formulated for either oral and/or injectable administration. Injectables were, on average, larger and more polar than drugs developed for oral, topical, and inhalation routes. PMID- 26039923 TI - Genetically assembled fluorescent biosensor for in situ detection of bio synthesized alkanes. AB - Construction of highly efficient microbial cell factories producing drop-in biofuel alkanes is severely limited due to the lack of a fast detection method against alkanes. Here we first developed a sensitive fluorescent biosensor for rapid and in situ monitoring of intracellular alkane synthesis. Using GFP as reporter, the biosensor could actively respond to the intracellular alkane products, especially for the mid- and long-chain alkanes synthesized in the recombinant Escherichia coli and give a concentration-dependent fluorescence response. Our results also suggested the feasibility of developing high throughput strategies basing on the alkane biosensor device in E. coli, and thus will greatly facilitate the application of directed evolution strategies to further improve the alkane-producing microbial cell factories. PMID- 26039926 TI - The Ganges-Brahmaputra-Meghna delta system: biophysical models to support analysis of ecosystem services and poverty alleviation. PMID- 26039925 TI - A Phytophthora sojae cytoplasmic effector mediates disease resistance and abiotic stress tolerance in Nicotiana benthamiana. AB - Each oomycete pathogen encodes a large number of effectors. Some effectors can be used in crop disease resistance breeding, such as to accelerate R gene cloning and utilisation. Since cytoplasmic effectors may cause acute physiological changes in host cells at very low concentrations, we assume that some of these effectors can serve as functional genes for transgenic plants. Here, we generated transgenic Nicotiana benthamiana plants that express a Phytophthora sojae CRN (crinkling and necrosis) effector, PsCRN115. We showed that its expression did not significantly affect the growth and development of N. benthamiana, but significantly improved disease resistance and tolerance to salt and drought stresses. Furthermore, we found that expression of heat-shock-protein and cytochrome-P450 encoding genes were unregulated in PsCRN115-transgenic N. benthamiana based on digital gene expression profiling analyses, suggesting the increased plant defence may be achieved by upregulation of these stress-related genes in transgenic plants. Thus, PsCRN115 may be used to improve plant tolerance to biotic and abiotic stresses. PMID- 26039927 TI - Zero Kinetic Energy Photoelectron Spectroscopy of Benzo[h]quinoline. AB - We report zero kinetic energy (ZEKE) photoelectron spectroscopy of benzo[h]quinoline (BhQ) via resonantly enhanced multiphoton ionization (REMPI) through the first electronically excited state S1. From the simulated REMPI spectra with and without Herzberg-Teller coupling, we conclude that vibronic coupling plays a minor but observable role in the electronic excitation to the S1 state. We further compare the S1 state of BhQ with the first two electronically excited states of phenanthrene, noticing a similarity of the S1 state of BhQ with the second electronically excited state S2 of phenanthrene. In the ZEKE spectra of BhQ, the vibrational frequencies of the cationic state D0 are consistently higher than those of the intermediate neutral state, indicating enhanced bonding upon ionization. The sparse ZEKE spectra, compared with the spectrum of phenanthrene containing rich vibronic activities, further imply that the nitrogen atom has attenuated the structural change between S1 and D0 states. We speculate that the nitrogen atom can withdraw an electron in the S1 state and donate an electron in the D0 state, thereby minimizing the structural change during ionization. The origin of the first electronically excited state is determined to be 29,410 +/- 5 cm(-1), and the adiabatic ionization potential is determined to be 65,064 +/- 7 cm(-1). PMID- 26039928 TI - Regulation of growth hormone secretion by (pro)renin receptor. AB - (Pro)renin receptor (PRR) has a single transmembrane domain that co-purifies with the vacuolar H(+)-ATPase (V-ATPase). In addition to its role in cellular acidification, V-ATPase has been implicated in membrane fusion and exocytosis via its Vo domain. Results from the present study show that PRR is expressed in pituitary adenoma cells and regulates growth hormone (GH) release via V-ATPase induced cellular acidification. Positive PRR immunoreactivity was detected more often in surgically resected, growth hormone-producing adenomas (GHomas) than in nonfunctional pituitary adenomas. GHomas strongly expressing PRR showed excess GH secretion, as evidenced by distinctly high plasma GH and insulin-like growth factor-1 levels, as well as an elevated nadir GH in response to the oral glucose tolerance test. Suppression of PRR expression in rat GHoma-derived GH3 cells using PRR siRNA resulted in reduced GH secretion and significantly enhanced intracellular GH accumulation. GH3 treatment with bafilomycin A1, a V-ATPase inhibitor, also blocked GH release, indicating mediation via impaired cellular acidification of V-ATPase. PRR knockdown decreased Atp6l, a subunit of the Vo domain that destabilizes V-ATPase assembly, increased intracellular GH, and decreased GH release. To our knowledge, this is the first report demonstrating a pivotal role for PRR in a pituitary hormone release mechanism. PMID- 26039929 TI - Impact of Patient-Selected Care Buddies on Adherence to HIV Care, Disease Progression, and Conduct of Daily Life Among Pre-antiretroviral HIV-Infected Patients in Rakai, Uganda: A Randomized Controlled Trial. AB - BACKGROUND: Data are limited on effects of household or community support persons ("care buddies") on enrollment into and adherence to pre-antiretroviral HIV care. We assessed the impact of care buddies on adherence to HIV clinic appointments, HIV progression, and conduct of daily life among pre-antiretroviral therapy (pre ART) HIV-infected individuals in Rakai, Uganda. METHODS: A total of 1209 HIV infected pre-ART patients aged >=15 years were randomized to standard of care (SOC) (n = 604) or patient-selected care buddy (PSCB) (n = 605) and followed at 6 and 12 months. Outcomes were adherence to clinic visits, HIV disease progression, and self-reported conduct of daily life. Incidence and prevalence rate ratios and 95% confidence intervals (CIs) were used to assess outcomes in the intent-to treat and as-treated analyses. RESULTS: Baseline characteristics were comparable. In the intent to treat analysis, both arms were comparable with respect to adherence to CD4 monitoring visits [adjusted prevalence risk ratio (adjPRR), 0.98; 95% CI: 0.93 to 1.04; P = 0.529], and ART eligibility (adjPRR, 1.00; 95% CI: 0.77 to 1.31; P = 0.946). Good conduct of daily life was significantly higher in the PSCB than the SOC arm (adjPRR, 1.08; 95% CI: 1.03 to 1.13; P = 0.001). More men (61%) compared with women (30%) selected spouses/partners as buddies (P < 0.0001). Twenty-two percent of PSCB arm participants discontinued use of buddies. CONCLUSIONS: In pre-ART persons, having care buddies improved the conduct of daily life of the HIV-infected patients but had no effect on HIV disease progression and only limited effect on clinic appointment adherence. PMID- 26039930 TI - Monoclonal Gammopathy in HIV-1-Infected Patients: Factors Associated With Disappearance Under Long-Term Antiretroviral Therapy. AB - OBJECTIVE: Monoclonal gammopathies (MGs) associated with HIV infection are frequent but their evolution and significance are uncertain in this population at high risk of lymphoproliferative disorder. Our aim was to describe the long-term evolution of MG in HIV-infected subjects under antiretroviral therapy. METHODS: Retrospective study of HIV-1-infected adults, with a monoclonal (M) protein detected by serum protein electrophoresis and confirmed by immunofixation. Logistic regression was used to analyze factors associated with peak disappearance. RESULTS: Between September 1997 and November 2012, 1219 serum protein electrophoreses were performed on our HIV cohort, and 137 (11.3%) MGs were detected. Seventy-seven subjects met the inclusion criteria: 68% male, median age 41 years, 47% AIDS stage, median CD4 count 237 per cubic millimeter, 81% uncontrolled HIV infection with HIV viral load over 400 copies per milliliter, 32% chronic hepatitis C, and 9% chronic hepatitis B. Eighteen subjects were not included because of previous or concomitant hemopathy. With a median follow-up of 6.8 years (interquartile range, 3.9-9.1), 66.2% of subjects showed a peak disappearance. In multivariate analysis, MG disappearance was associated with HIV virologic control (odds ratio, 5.98; 95% confidence interval: 1.63 to 21.87; P = 0.007) and the absence of hepatitis C virus replication at the end of follow-up (odds ratio, 10.16; 95% confidence interval: 2.36 to 43.69; P = 0.002). One subject developed a myeloma 3 years after the diagnosis of an IgA kappa MG. CONCLUSIONS: MG associated with HIV infection concerned a young population and had favorable evolution on antiretroviral therapy in most cases. M protein disappearance was associated with HIV virologic control and the absence of chronic hepatitis C virus. PMID- 26039932 TI - The Challenge of Retention Within Antiretroviral Treatment Programmes and the Need for Recent Data. PMID- 26039931 TI - Demographic and Health Services Characteristics Associated With Testing for Sexually Transmitted Infections Among a Commercially Insured Population of HIV Positive Patients. AB - BACKGROUND: Presence of a sexually transmitted infection (STI) can increase the likelihood of HIV transmission, and current treatment guidelines indicate that HIV-positive persons should be screened yearly for STIs. Therefore, we examined recent insurance claims data to determine whether private insurance beneficiaries who are HIV-positive were receiving recommended STI testing. METHODS: We used data from the 2011 and 2012 MarketScan data sets, a longitudinal population-based database that collects claims from commercially insured persons in private insurance and is conducted by Truven Health Analytics. Over a 13-month period, we calculated rates of testing for chlamydia, gonorrhea, and syphilis among an HIV positive population and determined the factors that contributed to differences in testing rates. RESULTS: Overall testing rates were 22.2% for chlamydia, 21.9% for gonorrhea, and 51.1% for syphilis. Significant predictors of STI testing were sex, age, type of health plan, engagement with the health care system, and geographic location. Most notably, persons receiving viral load testing were more likely to receive testing for chlamydia [odds ratio (OR): 1.72; 95% confidence interval (CI): 1.63 to 1.81], gonorrhea (OR: 1.72; 95% CI: 1.64 to 1.81), and syphilis (OR: 3.38; 95% CI: 3.25 to 3.53) compared with persons not receiving viral load testing. DISCUSSION: Not all commercially insured HIV-positive patients are receiving recommended testing for STIs. Presence of STIs could affect the transmission of HIV and has deleterious effects on health outcomes of the patients. Targeted efforts based on demographics, health plan type, and other quality-of-care measures could help identify populations for whom testing rates for STIs among HIV-positive persons could be improved. PMID- 26039934 TI - Interfacial Redox Catalysis on Gold Nanofilms at Soft Interfaces. AB - Soft or "liquid-liquid" interfaces were functionalized by roughly half a monolayer of mirror-like nanofilms of gold nanoparticles using a precise interfacial microinjection method. The surface coverage of the nanofilm was characterized by ion transfer voltammetry. These gold nanoparticle films represent an ideal model system for studying both the thermodynamic and kinetic aspects of interfacial redox catalysis. The electric polarization of these soft interfaces is easily controllable, and thus the Fermi level of the electrons in the interfacial gold nanoparticle film can be easily manipulated. Here, we study interfacial redox catalysis between two redox couples located in adjacent immiscible phases and highlight the catalytic properties of a gold nanoparticle film toward heterogeneous electron transfer reactions. PMID- 26039933 TI - Active Targeting of Sorafenib: Preparation, Characterization, and In Vitro Testing of Drug-Loaded Magnetic Solid Lipid Nanoparticles. AB - Sorafenib is an anticancer drug approved by the Food and Drug Administration for the treatment of hepatocellular and advanced renal carcinoma. The clinical application of sorafenib is promising, yet limited by its severe toxic side effects. The aim of this study is to develop sorafenib-loaded magnetic nanovectors able to enhance the drug delivery to the disease site with the help of a remote magnetic field, thus enabling cancer treatment while limiting negative effects on healthy tissues. Sorafenib and superparamagnetic iron oxide nanoparticles are encapsulated in solid lipid nanoparticles by a hot homogenization technique using cetyl palmitate as lipid matrix. The obtained nanoparticles (Sor-Mag-SLNs) have a sorafenib loading efficiency of about 90% and are found to be very stable in an aqueous environment. Plain Mag-SLNs exhibit good cytocompatibility, whereas an antiproliferative effect against tumor cells (human hepatocarcinoma HepG2) is observed for drug-loaded Sor-Mag-SLNs. The obtained results show that it is possible to prepare stable Sor-Mag-SLNs able to inhibit cancer cell proliferation through the sorafenib cytotoxic action, and to enhance/localize this effect in a desired area thanks to a magnetically driven accumulation of the drug. Moreover, the relaxivity properties observed in water suspensions hold promise for Sor-Mag-SLN tracking through clinical magnetic resonance imaging. PMID- 26039935 TI - Efficacy and Safety of Lixisenatide in Japanese Patients with Type 2 Diabetes Insufficiently Controlled with Basal Insulin+/-Sulfonylurea: A Subanalysis of the GetGoal-L-Asia Study. AB - The aim of the study was to evaluate the efficacy and safety of once-daily lixisenatide 20 MUg as add-on to basal insulin with or without sulfonylurea in Asian patients with type 2 diabetes mellitus. The study as a subanalysis of the 159 Japanese patients from the 24-week double-blind GetGoal-L-Asia study (NCT00866658) who received once-daily lixisenatide or placebo. The primary endpoint was change from baseline in HbA1c evaluated using analysis of covariance. Once-daily lixisenatide significantly reduced mean HbA1c [least squares mean difference vs. placebo - 1.1% (- 12 mmol/mol); p<0.0001]. Significantly more patients in the lixisenatide group reached HbA1c targets of < 7% (53 mmol/mol; 31.4 vs. 2.3% for placebo; p<0.0001) and <= 6.5% (48 mmol/mol; 12.9 vs. 1.2% for placebo; p=0.0028). Lixisenatide significantly reduced 2-h postprandial plasma glucose (least squares mean difference vs. placebo-8.64 mmol/l; p<0.0001), glucose excursion (least squares mean difference vs. placebo - 7.80 mmol/l; p<0.0001) and fasting plasma glucose (least squares mean difference vs. placebo - 0.96 mmol/l; p=0.0126). Body weight was reduced with lixisenatide but with no significant difference vs. placebo. Gastrointestinal adverse events were more frequent with lixisenatide (61.1 vs. 11.5% for placebo) but were generally transient and mild-to-moderate in intensity. The incidence of symptomatic hypoglycemia was 39.0 vs. 13.5% in patients receiving sulfonylureas and 32.3 vs. 22.9% in those not receiving sulfonylureas, for lixisenatide and placebo, respectively. In Japanese patients with type 2 diabetes mellitus, once daily lixisenatide was well tolerated and led to significant and clinically relevant improvement in glycemic control, with a pronounced effect on postprandial plasma glucose. PMID- 26039936 TI - Involvement of Human Herpesvirus 6 Infection in Renal Dysfunction Associated with DIHS/DRESS. PMID- 26039937 TI - CRISPR/Cas9-mediated reporter knock-in in mouse haploid embryonic stem cells. AB - Mouse parthenogenetic haploid embryonic stem cells (ESCs) are pluripotent cells generated from chemically activated oocytes. Haploid ESCs provide an opportunity to study the effect of genetic alterations because of their hemizygotic characteristics. However, their further application for the selection of unique phenotypes remains limited since ideal reporters to monitor biological processes such as cell differentiation are missing. Here, we report the application of CRISPR/Cas9-mediated knock-in of a reporter cassette, which does not disrupt endogenous target genes in mouse haploid ESCs. We first validated the system by inserting the P2A-Venus reporter cassette into the housekeeping gene locus. In addition to the conventional strategy using the Cas9 nuclease, we employed the Cas9 nickase and truncated sgRNAs to reduce off-target mutagenesis. These strategies induce targeted insertions with an efficiency that correlated with sgRNA guiding activity. We also engineered the neural marker gene Sox1 locus and verified the precise insertion of the P2A-Venus reporter cassette and its functionality by monitoring neural differentiation. Our data demonstrate the successful application of the CRISPR/Cas9-mediated knock-in system for establishing haploid knock-in ESC lines carrying gene specific reporters. Genetically modified haploid ESCs have potential for applications in forward genetic screening of developmental pathways. PMID- 26039939 TI - Probing the Redox States of Sodium Channel Cysteines at the Binding Site of MUOS Conotoxin GVIIJ. AB - MUOS-Conotoxin GVIIJ is a 35-amino acid peptide that readily blocks six of eight tested NaV1 subunit isoforms of voltage-gated sodium channels. MUOS-GVIIJ is unusual in having an S-cysteinylated cysteine (at residue 24). A proposed reaction scheme involves the peptide-channel complex stabilized by a disulfide bond formed via thiol-disulfide exchange between Cys24 of the peptide and a Cys residue at neurotoxin receptor site 8 in the pore module of the channel (specifically, Cys910 of rat NaV1.2). To examine this model, we synthesized seven derivatives of MUOS-GVIIJ in which Cys24 was disulfide-bonded to various thiols (or SR groups) and tested them on voltage-clamped Xenopus laevis oocytes expressing NaV1.2. In the proposed model, the SR moiety is a leaving group that is no longer present in the final peptide-channel complex; thus, the same koff value should be obtained regardless of the SR group. We observed that all seven derivatives, whose kon values varied over a 30-fold range, had the same koff value. Concordant results were observed with NaV1.6, for which the koff was 17 fold larger. Additionally, we tested two MUOS-GVIIJ derivatives (where SR was glutathione or a free thiol) on two NaV1.2 Cys replacement mutants (NaV1.2[C912A] and NaV1.2[C918A]) without and with reduction of channel disulfides by dithiothreitol. The results indicate that Cys910 in wild-type NaV1.2 has a free thiol and conversely suggest that in NaV1.2[C912A] and NaV1.2[C918A], Cys910 is disulfide-bonded to Cys918 and Cys912, respectively. Redox states of extracellular cysteines of sodium channels have hitherto received scant attention, and further experiments with GVIIJ may help fill this void. PMID- 26039940 TI - Laparoscopic rectopexy is feasible and safe in the emergency admission setting. AB - AIM: External rectal prolapse may require emergency admission in the elderly and comorbid population. We report the safety and efficacy of laparoscopic ventral rectopexy in patients having an emergency admission with external rectal prolapse. METHOD: A retrospective analysis was performed of a prospective database of all rectopexies performed from 2006. Outcome and follow-up data were assessed. RESULTS: Of 812 rectopexies performed, 28 were included for analysis. The mean length of hospital stay was 13.0 days. All operations were completed successfully and without intra-operative complications. Four patients developed a postoperative complication. Two patients developed a recurrence of prolapse. CONCLUSION: Laparoscopic correction of rectal prolapse following emergency admission is both feasible and safe. It can be considered for both recurring cases and cases with multiple comorbidities. PMID- 26039941 TI - Aortic Intima-Media Thickness as an Early Marker of Atherosclerosis in Children With Inflammatory Bowel Disease. AB - OBJECTIVES: The aims of this study were to determine the presence of endothelial dysfunction by measuring aortic intima-media thickness (aIMT) and carotid intima media thickness (cIMT) and to evaluate the role of traditional risk factors for premature atherosclerosis in children with inflammatory bowel disease (IBD). METHODS: Thirty-four children with IBD (25 Crohn disease [CD] and 9 ulcerative colitis [UC]; mean age 11.1 years) and 27 healthy subjects matched for sex and age were enrolled. In all of the patients, demographic characteristics and risk factors for atherosclerosis (age, sex, body mass index, blood pressure, dyslipidemia, active and passive smoking, and family history for cardiovascular diseases), CD and UC clinical activity scores, and inflammatory markers were evaluated. aIMT and cIMT were measured by high-resolution B-mode ultrasound. RESULTS: aIMT was significantly higher in patients than in controls (P < 0.0005). No significant differences were found for cIMT, although the carotid thickness was higher in patients with IBD than in healthy subjects. At a univariate analysis, inflammatory markers levels and tobacco smoking exposure were significantly related to higher aIMT values, whereas in a multivariate regression model, the inflammatory status was the only independent variable correlated with high aIMT. CONCLUSIONS: aIMT is an earlier marker of preclinical atherosclerosis than cIMT in young children with active IBD. The inflammatory status and the smoking exposure are significantly correlated with the premature endothelial dysfunction. These data emphasize the importance of controlling the chronic intestinal inflammation and endorsing smoke-free environments for children and adolescents with IBD. PMID- 26039942 TI - Characteristics and Prognosis of Allergic Proctocolitis in Infants. AB - OBJECTIVES: The dietary protein proctocolitis, also known as allergic proctocolitis (AP), is characterized by the presence of mucoid, frothy, and bloody stools in an otherwise healthy infant. The aim of this study was to describe a group of children with AP, diagnosed according to the criterion standard method, food challenge to provide clinicians with more information on typical presentation, and an overview on nutritional management strategies and prognosis. METHODS: We collected data on infants with AP in our allergy and gastroenterology outpatient clinics. Any other conditions that may cause bloody diarrhea were ruled out. Skin prick tests and atopy patch tests were performed for diagnosis, and patients were studied for resolution. To the patients whose rectal bleeding did not recover with oligoantigenic maternal diet in addition to amino acid-based formula, endoscopic evaluation was performed to confirm the diagnosis and to exclude other reasons of rectal bleeding. RESULTS: Sixty patients were diagnosed as having AP. The age of onset was 1.7 +/- 1.32 months. All of the patients were triggered by milk, 6.6% with milk and egg, 3.3% with milk and chicken, 1.7% with milk and wheat, 1.7% with milk and potato, and 3.3% had multiple food allergy. 53.3% (n = 32) acquired tolerance by age 1, 25.0% (n = 15) by 2 years, 5% (n = 3) by 3, and 1.7% (n = 1) by 4 years. CONCLUSIONS: Milk was a triggering factor for all of the patients. Resolution of AP is usually within 1 year but symptoms of some patients may continue even longer. An extension of the follow-up period is required according to our study. PMID- 26039943 TI - Song circuit in bird brain contains map of space and time. PMID- 26039944 TI - Investigation of surgically retrieved, vitamin E-stabilized, crosslinked UHMWPE implants after short-term in vivo service. AB - BACKGROUND: Antioxidant stabilized highly crosslinked ultra-high molecular weight polyethylene (UHMWPE) components have been in clinical use since 2008. In vitro testing has shown excellent oxidation resistance, wear resistance, mechanical properties, and fatigue strength. In this study, we analyzed surgically retrieved components to investigate in vivo behavior and changes in the material. METHODS: Fifteen surgically retrieved, vitamin E-stabilized, and radiation crosslinked UHMWPE components were analyzed to determine their oxidative stability, extent of lipid absorption in vivo, free radical content, hydroperoxide index, and extent of visible wear damage after in vivo service (0.1-36.6 months). RESULTS: Retrievals showed no significant carbonyls at the time of surgical removal, while free radical content was observed to decay with increasing in vivo duration. There was no increase in hydroperoxide index. Lipid penetration increased with time. Ex vivo oxidation was not observed after 18 months of aging in air at room temperature. CONCLUSIONS: The free-radical scavenging activity of the vitamin E appears to successfully prevent both in vivo and ex vivo oxidation for short durations, while reducing free radical content overall. Without an increase in hydroperoxides, the oxidation cascade initiated by radiation-induced and lipid derived free radicals appears to have been inhibited. Further investigation is required with longer duration implants. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1132-1140, 2016. PMID- 26039945 TI - Serum interleukin-17 levels are associated with nephritis in childhood-onset systemic lupus erythematosus. AB - OBJECTIVES: To determine the serum interleukin-17 (IL-17) levels in childhood onset systemic lupus erythematosus patients and to evaluate the association between IL-17 and clinical manifestations, disease activity, laboratory findings and treatment. METHODS: We included 67 consecutive childhood-onset systemic lupus erythematosus patients [61 women; median age 18 years (range 11-31)], 55 first degree relatives [50 women; median age 40 years (range 29-52)] and 47 age- and sex-matched healthy controls [42 women; median age 19 years (range 6-30)]. The childhood-onset systemic lupus erythematosus patients were assessed for clinical and laboratory systemic lupus erythematosus manifestations, disease activity [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index] and current drug use. Serum IL-17 levels were measured by an enzyme-linked immunosorbent assay using commercial kits. RESULTS: The median serum IL-17 level was 36.3 (range 17.36-105.92) pg/mL in childhood onset systemic lupus erythematosus patients and 29.47 (15.16-62.17) pg/mL in healthy controls (p=0.009). We observed an association between serum IL-17 levels and active nephritis (p=0.01) and migraines (p=0.03). Serum IL-17 levels were not associated with disease activity (p=0.32), cumulative damage (p=0.34), or medication use (p=0.63). CONCLUSION: IL-17 is increased in childhood-onset systemic lupus erythematosus and may play a role in the pathogenesis of neuropsychiatric and renal manifestations. Longitudinal studies are necessary to determine the role of IL-17 in childhood-onset systemic lupus erythematosus. PMID- 26039946 TI - Efficacy of levofloxacin, amoxicillin and a proton pump inhibitor in the eradication of Helicobacter pylori in Brazilian patients with peptic ulcers. AB - OBJECTIVES: The eradication of Helicobacter (H.) pylori allows peptic ulcers in patients infected with the bacteria to be cured. Treatment with the classic triple regimen (proton pump inhibitor, amoxicillin and clarithromycin) has shown decreased efficacy due to increased bacterial resistance to clarithromycin. In our country, the eradication rate by intention to treat with this regimen is 83%. In Brazil, a commercially available regimen for bacterial eradication that uses levofloxacin and amoxicillin with lansoprazole is available; however, its efficacy is not known. Considering that such a treatment may be an alternative to the classic regimen, we aimed to verify its efficacy in H. pylori eradication. METHODS: Patients with peptic ulcer disease infected with H. pylori who had not received prior treatment were treated with the following regimen: 30 mg lansoprazole bid, 1,000 mg amoxicillin bid and 500 mg levofloxacin, once a day for 7 days. RESULTS: A total of 66 patients were evaluated. The patients' mean age was 52 years, and women comprised 55% of the sample. Duodenal ulcers were present in 50% of cases, and gastric ulcers were present in 30%. The eradication rate was 74% per protocol and 73% by intention to treat. Adverse effects were reported by 49 patients (74%) and were mild to moderate, with a prevalence of diarrhea complaints. CONCLUSIONS: Triple therapy comprising lansoprazole, amoxicillin and levofloxacin for 7 days for the eradication of H. pylori in Brazilian peptic ulcer patients showed a lower efficacy than that of the classic triple regimen. PMID- 26039947 TI - Low educational level but not low income impairs the achievement of cytogenetic remission in chronic myeloid leukemia patients treated with imatinib in Brazil. AB - OBJECTIVES: In Brazil, imatinib mesylate is supplied as the first-line therapy for chronic myeloid leukemia in the chronic phase through the public universal healthcare program, Sistema Unico de Saude (SUS). We studied the socio demographic factors that influenced therapy success in a population in the northeast region of Brazil. METHODS: Patients with chronic myeloid leukemia from the state of Piaui were treated in only one reference center. Diagnosis was based on WHO 2008 criteria. Risk was assessed by Sokal, Hasford and EUTOS scores. Patients received 400 mg imatinib daily. We studied the influence of the following factors on the achievement of complete cytogenetic response within one year of treatment: age, clinical risk category, time interval between diagnosis and the start of imatinib treatment, geographic distance from the patient's home to the hospital, years of formal education and monthly income. RESULTS: Among 103 patients studied, the median age was 42 years; 65% of the patients had 2-9 years of formal education, and the median monthly income was approximately 100 US$. Imatinib was started in the first year after diagnosis (early chronic phase) in 69 patients. After 12 months of treatment, 68 patients had a complete cytogenetic response. The Hasford score, delay to start imatinib and years of formal education influenced the attainment of a complete cytogenetic response, whereas income and the distance from the home to the healthcare facility did not. CONCLUSION: Patients require additional healthcare information to better understand the importance of long-term oral anticancer treatment and to improve their compliance with the treatment. PMID- 26039948 TI - Vitamin D deficiency is independently associated with mortality among critically ill patients. AB - OBJECTIVE: Studies suggest an association between vitamin D deficiency and morbidity/mortality in critically ill patients. Several issues remain unexplained, including which vitamin D levels are related to morbidity and mortality and the relevance of vitamin D kinetics to clinical outcomes. We conducted this study to address the association of baseline vitamin D levels and vitamin D kinetics with morbidity and mortality in critically ill patients. METHOD: In 135 intensive care unit (ICU) patients, vitamin D was prospectively measured on admission and weekly until discharge from the ICU. The following outcomes of interest were analyzed: 28-day mortality, mechanical ventilation, length of stay, infection rate, and culture positivity. RESULTS: Mortality rates were higher among patients with vitamin D levels <12 ng/mL (versus vitamin D levels >12 ng/mL) (32.2% vs. 13.2%), with an adjusted relative risk of 2.2 (95% CI 1.07-4.54; p< 0.05). There were no differences in the length of stay, ventilation requirements, infection rate, or culture positivity. CONCLUSIONS: This study suggests that low vitamin D levels on ICU admission are an independent risk factor for mortality in critically ill patients. Low vitamin D levels at ICU admission may have a causal relationship with mortality and may serve as an indicator for vitamin D replacement among critically ill patients. PMID- 26039949 TI - Hemodynamic responses during and after multiple sets of stretching exercises performed with and without the Valsalva maneuver. AB - OBJECTIVE: This study investigated the acute hemodynamic responses to multiple sets of passive stretching exercises performed with and without the Valsalva maneuver. METHODS: Fifteen healthy men aged 21 to 29 years with poor flexibility performed stretching protocols comprising 10 sets of maximal passive unilateral hip flexion, sustained for 30 seconds with equal intervals between sets. Protocols without and with the Valsalva maneuver were applied in a random counterbalanced order, separated by 48-hour intervals. Hemodynamic responses were measured by photoplethysmography pre-exercise, during the stretching sets, and post-exercise. RESULTS: The effects of stretching sets on systolic and diastolic blood pressure were cumulative until the fourth set in protocols performed with and without the Valsalva maneuver. The heart rate and rate pressure product increased in both protocols, but no additive effect was observed due to the number of sets. Hemodynamic responses were always higher when stretching was performed with the Valsalva maneuver, causing an additional elevation in the rate pressure product. CONCLUSIONS: Multiple sets of unilateral hip flexion stretching significantly increased blood pressure, heart rate, and rate pressure product values. A cumulative effect of the number of sets occurred only for systolic and diastolic blood pressure, at least in the initial sets of the stretching protocols. The performance of the Valsalva maneuver intensified all hemodynamic responses, which resulted in significant increases in cardiac work during stretching exercises. PMID- 26039950 TI - Evaluation of oral-motor movements and facial mimic in patients with head and neck burns by a public service in Brazil. AB - OBJECTIVES: The purpose of this study was to analyze the characteristics of oral motor movements and facial mimic in patients with head and neck burns. METHODS: An observational descriptive cross-sectional study was conducted with patients who suffered burns to the head and neck and who were referred to the Division of Orofacial Myology of a public hospital for assessment and rehabilitation. Only patients presenting deep partial-thickness and full-thickness burns to areas of the face and neck were included in the study. Patients underwent clinical assessment that involved an oral-motor evaluation, mandibular range of movement assessment, and facial mimic assessment. Patients were divided into two groups: G1 - patients with deep partial-thickness burns; G2 - patients with full thickness burns. RESULTS: Our final study sample comprised 40 patients: G1 with 19 individuals and G2 with 21 individuals. The overall scores obtained in the clinical assessment of oral-motor organs indicated that patients with both second and third-degree burns presented deficits related to posture, position and mobility of the oral-motor organs. Considering facial mimic, groups significantly differed when performing voluntary facial movements. Patients also presented limited maximal incisor opening. Deficits were greater for individuals in G2 in all assessments. CONCLUSION: Patients with head and neck burns present significant deficits related to posture, position and mobility of the oral myofunctional structures, including facial movements. PMID- 26039951 TI - The reduction of serum aminotransferase levels is proportional to the decline of the glomerular filtration rate in patients with chronic kidney disease. AB - OBJECTIVE: This study sought to determine the serum aminotransferase levels of patients with predialysis chronic kidney disease and establish their relationships with serum creatinine levels and glomerular filtration rate. METHODS: Patients with chronic kidney disease were evaluated between September 2011 and May 2012. Aminotransferase and creatinine serum levels were measured using an automated kinetic method, and glomerular filtration rates were estimated using the Cockroft-Gault and Modification of Diet in Renal Disease formulas to classify patients into chronic kidney disease stages. RESULTS: Exactly 142 patients were evaluated (mean age: 64+/-16 years). The mean creatinine serum level and glomerular filtration rate were 3.3+/-1.2 mg/dL and 29.1+/-13 mL/min/1.73 m2, respectively. Patients were distributed according to their chronic kidney disease stages as follows: 3 (2.1%) patients were Stage 2; 54 (38%) were Stage 3; 70 (49.3%) were Stage 4; and 15 (10.5%) were Stage 5. The mean aspartate aminotransferase and alanine aminotransferase serum levels showed a reduction in proportion to the increase in creatinine levels (p=0.001 and p=0.05, respectively) and the decrease in glomerular filtration rate (p=0.007 and p=0.028, respectively). Alanine aminotransferase and aspartate aminotransferase serum levels tended to be higher among patients classified as stage 2 or 3 compared with those classified as stage 4 or 5 (p=0.08 and p=0.06, respectively). CONCLUSIONS: The aspartate aminotransferase and alanine aminotransferase serum levels of patients with predialysis chronic kidney disease decreased in proportion to the progression of the disease; they were negatively correlated with creatinine levels and directly correlated with glomerular filtration rate. PMID- 26039952 TI - Effectiveness of Limberg and Karydakis flap in recurrent pilonidal sinus disease. AB - OBJECTIVE: Sacrococcygeal pilonidal sinus is common in young men and may recur over time after surgery. We investigated whether a factor exists that can aid in the determination of the preferred technique between the early Limberg flap and Karydakis flap techniques for treating recurrent pilonidal sinus. MATERIALS AND METHODS: This prospective and randomized study enrolled 71 patients with recurrent pilonidal sinus in whom the Limberg flap or Karydakis flap techniques were applied for reconstruction after excision. Patients were divided into two groups as follows: 37 patients were treated with the Limberg flap technique and 34 patients were treated with the Karydakis flap technique. Fluid collection, wound infection, flap edema, hematoma, partial wound separation, return to daily activities, pain score, complete healing time, painless seating and patient satisfaction were compared between the groups. ClinicalTrial.gov: NCT02287935. RESULTS: The development rates of total fluid collection, wound infection, flap edema, hematoma, and partial wound separation were 9.8%, 16%, 7%, 15% and 4.2%, respectively; total flap necrosis was not observed in any patient (p<0.001). During the average follow-up of 28 months, no patients (0%) developed recurrent disease. The two groups differed with respect to early surgical complications (p<0.001). CONCLUSION: In this study, use of the Limberg flap was associated with lower complication rates, shorter length of hospital stay, early return to work, low pain score, high patient satisfaction and better complete healing duration. Therefore, we recommend the Limberg flap for treatment of recurrent pilonidal sinus. PMID- 26039953 TI - Unusual remodeling of the hyalinization band in vulval lichen sclerosus by type V collagen and ECM 1 protein. AB - OBJECTIVES: The vulva is the primary site affected in lichen sclerosus, a chronic dermatosis in women that is histologically characterized by a zone of collagen remodeling in the superior dermis. The normal physiological properties of the vulva depend on the assembly of collagen types I (COLI), III (COLIII) and V (COLV), which form heterotypic fibers, and extracellular matrix protein interactions. COLV regulates the heterotypic fiber diameter, and the preservation of its properties is important for maintaining normal tissue architecture and function. In the current work, we analyzed the expression of COLV and its relationship with COLI, COLIII, elastic fibers and extracellular matrix protein 1 in vulvar biopsies from patients with lichen sclerosus. METHODS: Skin biopsies from 21 patients with lichen sclerosus, classified according to Hewitt histological criteria, were studied and compared to clinically normal vulvar tissue (N=21). Morphology, immunohistochemistry, immunofluorescence, 3D reconstruction and morphometric analysis of COLI, COLIII, COLV deposition, elastic fibers and extracellular matrix 1 expression in a zone of collagen remodeling in the superior dermis were performed. RESULTS: A significant decrease of elastic fibers and extracellular matrix 1 protein was present in the hyalinization zone of lichen sclerosus compared to healthy controls. The non homogeneous distribution of collagen fibers visualized under immunofluorescence in the hyalinization zone of lichen sclerosus and control skin was confirmed by histomorphometry. Lichen sclerosus dermis shows a significant increase of COLI, COLIII and COLV expression compared to the healthy controls. Significant inverse associations were found between elastic fibers and COLV and between COLV and extracellular matrix 1 expression. A direct association was found between elastic fiber content and extracellular matrix 1 expression. Tridimensional reconstruction of the heterotypic fibers of the lichen sclerosus zone of collagen remodeling confirmed the presence of densely clustered COLV. CONCLUSIONS: Increased deposition of abnormal COLV and its correlation with extracellular matrix 1 and elastic fibers suggest that COLV may be a trigger in the pathogenesis of lichen sclerosus. PMID- 26039954 TI - Clinical outcomes and mortality in elderly peritoneal dialysis patients. AB - OBJECTIVES: To evaluate the clinical outcomes and identify the predictors of mortality in elderly patients undergoing peritoneal dialysis. METHODS: We conducted a retrospective study including all incident peritoneal dialysis cases in patients >=65 years of age treated from 2001 to 2014. Demographic and clinical data on the initiation of peritoneal dialysis and the clinical events during the study period were collected. Infectious complications were recorded. Overall and technique survival rates were analyzed. RESULTS: Fifty-eight patients who began peritoneal dialysis during the study period were considered for analysis, and 50 of these patients were included in the final analysis. Peritoneal dialysis exchanges were performed by another person for 65% of the patients, whereas 79.9% of patients preferred to perform the peritoneal dialysis themselves. Peritonitis and catheter exit site/tunnel infection incidences were 20.4+/-16.3 and 24.6+/ 17.4 patient-months, respectively. During the follow-up period, 40 patients were withdrawn from peritoneal dialysis. Causes of death included peritonitis and/or sepsis (50%) and cardiovascular events (30%). The mean patient survival time was 38.9+/-4.3 months, and the survival rates were 78.8%, 66.8%, 50.9% and 19.5% at 1, 2, 3 and 4 years after peritoneal dialysis initiation, respectively. Advanced age, the presence of additional diseases, increased episodes of peritonitis, the use of continuous ambulatory peritoneal dialysis, and low albumin levels and daily urine volumes (<100 ml) at the initiation of peritoneal dialysis were predictors of mortality. The mean technique survival duration was 61.7+/-5.2 months. The technique survival rates were 97.9%, 90.6%, 81.5% and 71% at 1, 2, 3 and 4 years, respectively. None of the factors analyzed were predictors of technique survival. CONCLUSIONS: Mortality was higher in elderly patients. Factors affecting mortality in elderly patients included advanced age, the presence of comorbid diseases, increased episodes of peritonitis, use of continuous ambulatory peritoneal dialysis, and low albumin levels and daily urine volumes (<100 ml) at the initiation of peritoneal dialysis. PMID- 26039955 TI - Accuracy of the Timed Up and Go test for predicting sarcopenia in elderly hospitalized patients. AB - OBJECTIVES: The ability of the Timed Up and Go test to predict sarcopenia has not been evaluated previously. The objective of this study was to evaluate the accuracy of the Timed Up and Go test for predicting sarcopenia in elderly hospitalized patients. METHODS: This cross-sectional study analyzed 68 elderly patients (>=60 years of age) in a private hospital in the city of Salvador-BA, Brazil, between the 1st and 5th day of hospitalization. The predictive variable was the Timed Up and Go test score, and the outcome of interest was the presence of sarcopenia (reduced muscle mass associated with a reduction in handgrip strength and/or weak physical performance in a 6-m gait-speed test). After the descriptive data analyses, the sensitivity, specificity and accuracy of a test using the predictive variable to predict the presence of sarcopenia were calculated. RESULTS: In total, 68 elderly individuals, with a mean age 70.4+/-7.7 years, were evaluated. The subjects had a Charlson Comorbidity Index score of 5.35+/-1.97. Most (64.7%) of the subjects had a clinical admission profile; the main reasons for hospitalization were cardiovascular disorders (22.1%), pneumonia (19.1%) and abdominal disorders (10.2%). The frequency of sarcopenia in the sample was 22.1%, and the mean length of time spent performing the Timed Up and Go test was 10.02+/-5.38 s. A time longer than or equal to a cutoff of 10.85 s on the Timed Up and Go test predicted sarcopenia with a sensitivity of 67% and a specificity of 88.7%. The accuracy of this cutoff for the Timed Up and Go test was good (0.80; IC=0.66-0.94; p=0.002). CONCLUSION: The Timed Up and Go test was shown to be a predictor of sarcopenia in elderly hospitalized patients. PMID- 26039956 TI - Immediate expression of c-fos and c-jun mRNA in a model of intestinal autotransplantation and ischemia-reperfusion in situ. AB - OBJECTIVE: Intestinal ischemia-reperfusion injury occurs in several clinical conditions and after intestinal transplantation. The aim of the present study was to investigate the phenomena of apoptosis and cell proliferation in a previously described intestinal ischemia-reperfusion injury autograft model using immunohistochemical markers. The molecular mechanisms involved in ischemia reperfusion injury repair were also investigated by measuring the expression of the early activation genes c-fos and c-jun, which induce apoptosis and cell proliferation. MATERIALS AND METHODS: Thirty adult male Wistar rats were subjected to surgery for a previously described ischemia-reperfusion model that preserved the small intestine, the cecum and the ascending colon. Following reperfusion, the cecum was harvested at different time points as a representative segment of the intestine. The rats were allocated to the following four subgroups according to the reperfusion time: subgroup 1: 5 min; subgroup 2: 15 min; subgroup 3: 30 min; and subgroup 4: 60 min. A control group of cecum samples was also collected. The expression of c-fos, c-jun and immunohistochemical markers of cell proliferation and apoptosis (Ki67 and TUNEL, respectively) was studied. RESULTS: The expression of both c-fos and c-jun in the cecum was increased beginning at 5 min after ischemia-reperfusion compared with the control. The expression of c-fos began to increase at 5 min, peaked at 30 min, and exhibited a declining tendency at 60 min after reperfusion. A progressive increase in c-jun expression was observed. Immunohistochemical analyses confirmed these observations. CONCLUSION: The early activation of the c-fos and c-jun genes occurred after intestinal ischemia-reperfusion injury, and these genes can act together to trigger cell proliferation and apoptosis. PMID- 26039958 TI - Iron/Bronsted Acid Catalyzed Asymmetric Hydrogenation: Mechanism and Selectivity Determining Interactions. AB - Hydrogenation catalysts involving abundant base metals such as cobalt or iron are promising alternatives to precious metal systems. Despite rapid progress in this field, base metal catalysts do not yet achieve the activity and selectivity levels of their precious metal counterparts. Rational improvement of base metal complexes is facilitated by detailed knowledge about their mechanisms and selectivity-determining factors. The mechanism for asymmetric imine hydrogenation with Knolker's iron complex in the presence of chiral phosphoric acids is here investigated computationally at the DFT-D level of theory, with models of up to 160 atoms. The resting state of the system is found to be an adduct between the iron complex and the deprotonated acid. Rate-limiting H2 splitting is followed by a stepwise hydrogenation mechanism, in which the phosphoric acid acts as the proton donor. C-H???O interactions between the phosphoric acid and the substrate are involved in the stereocontrol at the final hydride transfer step. Computed enantiomeric ratios show excellent agreement with experimental values, indicating that DFT-D is able to correctly capture the selectivity-determining interactions of this system. PMID- 26039957 TI - Lifespan extension and increased resistance to environmental stressors by N acetyl-L-cysteine in Caenorhabditis elegans. AB - OBJECTIVE: This study was performed to determine the effect of N-acetyl-L cysteine, a modified sulfur-containing amino acid that acts as a strong cellular antioxidant, on the response to environmental stressors and on aging in C. elegans. METHOD: The survival of worms under oxidative stress conditions induced by paraquat was evaluated with and without in vivo N-acetyl-L-cysteine treatment. The effect of N-acetyl-L-cysteine on the response to other environmental stressors, including heat stress and ultraviolet irradiation (UV), was also monitored. To investigate the effect on aging, we examined changes in lifespan, fertility, and expression of age-related biomarkers in C. elegans after N-acetyl L-cysteine treatment. RESULTS: Dietary N-acetyl-L-cysteine supplementation significantly increased resistance to oxidative stress, heat stress, and UV irradiation in C. elegans. In addition, N-acetyl-L-cysteine supplementation significantly extended both the mean and maximum lifespan of C. elegans. The mean lifespan was extended by up to 30.5% with 5 mM N-acetyl-L-cysteine treatment, and the maximum lifespan was increased by 8 days. N-acetyl-L-cysteine supplementation also increased the total number of progeny produced and extended the gravid period of C. elegans. The green fluorescent protein reporter assay revealed that expression of the stress-responsive genes, sod-3 and hsp-16.2, increased significantly following N-acetyl-L-cysteine treatment. CONCLUSION: N-acetyl-L cysteine supplementation confers a longevity phenotype in C. elegans, possibly through increased resistance to environmental stressors. PMID- 26039960 TI - Are We Ready to Assess Circadian Phase at Home? PMID- 26039959 TI - Blood Pressure Increases in OSA due to Maintained Neurovascular Sympathetic Transduction: Impact of CPAP. AB - STUDY OBJECTIVES: To test the hypothesis that greater resting sympathetic activity in obstructive sleep apnea (OSA) syndrome would not induce a lesser sympathetic neurovascular transduction. DESIGN: Case-controlled cohort study. PARTICIPANTS: 33 patients with newly diagnosed OSA without comorbidities and 14 healthy controls. INTERVENTIONS: 6 months of continuous positive airway pressure (CPAP) treatment for OSA patients and follow-up for 9 healthy controls. MEASUREMENTS AND RESULTS: We assessed resting sympathetic outflow and sympathetic neurovascular transduction. Sympathetic activity was directly measured (microneurography) at rest and in response to sustained isometric handgrip exercise. Neurovascular transduction was derived from the relationship of sympathetic activity and blood pressure to leg blood flow during exercise. Despite an elevated sympathetic activity of ~50% in OSA compared to controls, neurovascular transduction was not different (i.e., absence of tachyphylaxis). After six months of CPAP, there were significant declines in diastolic pressure, averaging ~4 mm Hg, and in sympathetic activity, averaging ~20% with no change in transduction. CONCLUSIONS: Greater sympathetic activity in obstructive sleep apnea does not appear to be associated with lesser neurovascular transduction. Hence, elevated sympathetic outflow without lesser transduction may underlie the prevalent development of hypertension in this population that is well controlled by continuous positive airway pressure treatment. PMID- 26039961 TI - How Can We Better Leverage the Nocturnal Polysomnogram in the Diagnosis of Childhood-Onset Narcolepsy? PMID- 26039962 TI - Stimulating Progress in the Upper Airway. PMID- 26039963 TI - Recommended Amount of Sleep for a Healthy Adult: A Joint Consensus Statement of the American Academy of Sleep Medicine and Sleep Research Society. AB - ABSTRACT: Sleep is essential for optimal health. The American Academy of Sleep Medicine (AASM) and Sleep Research Society (SRS) developed a consensus recommendation for the amount of sleep needed to promote optimal health in adults, using a modified RAND Appropriateness Method process. The recommendation is summarized here. A manuscript detailing the conference proceedings and evidence supporting the final recommendation statement will be published in SLEEP and the Journal of Clinical Sleep Medicine. PMID- 26039964 TI - Waking Up MRI-Visible Perivascular Spaces and Drainage Research. PMID- 26039966 TI - Prevalence and Clinical Correlates of a Short Onset REM Period (SOREMP) during Routine PSG. AB - STUDY OBJECTIVES: The objectives of this study were to quantify the (1) sensitivity and specificity of nocturnal PSG SOREMP (REM latency <= 15 min) for narcolepsy in those being evaluated for hypersomnolence and (2) prevalence and predictors of SOREMP during baseline PSG for patients being evaluated for various sleep disorders. DESIGN: This was a retrospective analysis of a large repository of de-identified PSG and MSLT test results from 2007 to 2013. SETTING AND PATIENTS: Patient records were retrieved from a repository of studies completed at a variety of sleep laboratories across the USA. Included in the analyses were 79,651 general sleep clinic patients (without an MSLT; 48% male; 72% Caucasian) and an additional 3,059 patients (31.3% male; 72% Caucasian) being evaluated for hypersomnolence (with a consecutive MSLT). INTERVENTIONS: NA. MEASUREMENTS AND RESULTS: For patients being evaluated for hypersomnolence, the prevalence of PSG SOREMP increased in a dose-response fashion with the number of REM onsets that occurred on a consecutive MSLT (0.5% for no MSLT SOREMPs to > 33.0% for those with 5 MSLT SOREMPs). Overall, having a PSG SOREMP was highly specific (99.5%; 95% CI: 99.1-99.7%) but not sensitive (6.7%; 95% CI: 4.7-9.2%) for narcolepsy. The prevalence of PSG SOREMP for patients in the general sleep clinic sample (i.e., not being evaluated by a consecutive MSLT) was 0.8% and was much higher in those that work night/swing shift. In adjusted models, African American race contributed to the most variance in PSG SOREMP. CONCLUSIONS: A short onset rapid eye movement (REM) latency occurs rarely in general sleep clinic samples (< 1.0%), but is highly specific for the diagnosis of narcolepsy. Although rare, the prevalence of the phenomenon is much higher than the estimated prevalence of narcolepsy and may provide a critical opportunity for practitioners to identify narcolepsy in sleep clinic patients. These data also suggest that the utility of polysomnography (PSG) short onset REM peroid (SOREMP) for the diagnosis of narcolepsy may be altered by a history of shift/night work and/ or other factors that may allow for a rebound of REM sleep (e.g., undergoing a positive airway pressure titration), supporting published guidelines that other sleep disorders and insufficient and/or poorly timed sleep should be ruled out and/or adequately controlled for prior to conducting sleep testing. Further research is needed to understand racial differences in PSG SOREMP and narcolepsy. This study was limited in that data on cataplexy (with exception to that in final diagnosis) and habitual sleep duration were not available. PMID- 26039965 TI - Chronic Stress is Prospectively Associated with Sleep in Midlife Women: The SWAN Sleep Study. AB - STUDY OBJECTIVES: Evaluate whether levels of upsetting life events measured over a 9-y period prospectively predict subjective and objective sleep outcomes in midlife women. DESIGN: Prospective cohort study. SETTING: Four sites across the United States. PARTICIPANTS: 330 women (46-57 y of age) enrolled in the Study of Women's Health Across the Nation (SWAN) Sleep Study. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Upsetting life events were assessed annually for up to 9 y. Trajectory analysis applied to life events data quantitatively identified three distinct chronic stress groups: low stress, moderate stress, and high stress. Sleep was assessed by self-report and in-home polysomnography (PSG) during the ninth year of the study. Multivariate analyses tested the prospective association between chronic stress group and sleep, adjusting for race, baseline sleep complaints, marital status, body mass index, symptoms of depression, and acute life events at the time of the Sleep Study. Women characterized by high chronic stress had lower subjective sleep quality, were more likely to report insomnia, and exhibited increased PSG-assessed wake after sleep onset (WASO) relative to women with low to moderate chronic stress profiles. The effect of chronic stress group on WASO persisted in the subsample of participants without baseline sleep complaints. CONCLUSIONS: Chronic stress is prospectively associated with sleep disturbance in midlife women, even after adjusting for acute stressors at the time of the sleep study and other factors known to disrupt sleep. These results are consistent with current models of stress that emphasize the cumulative effect of stressors on health over time. PMID- 26039967 TI - Mitochondrial DNA Copy Number in Sleep Duration Discordant Monozygotic Twins. AB - STUDY OBJECTIVES: Mitochondrial DNA (mtDNA) copy number is an important component of mitochondrial function and varies with age, disease, and environmental factors. We aimed to determine whether mtDNA copy number varies with habitual differences in sleep duration within pairs of monozygotic twins. SETTING: Academic clinical research center. PARTICIPANTS: 15 sleep duration discordant monozygotic twin pairs (30 twins, 80% female; mean age 42.1 years [SD 15.0]). DESIGN: Sleep duration was phenotyped with wrist actigraphy. Each twin pair included a "normal" (7-9 h/24) and "short" (< 7 h/24) sleeping twin. Fasting peripheral blood leukocyte DNA was assessed for mtDNA copy number via the n-fold difference between qPCR measured mtDNA and nuclear DNA creating an mtDNA measure without absolute units. We used generalized estimating equation linear regression models accounting for the correlated data structure to assess within-pair effects of sleep duration on mtDNA copy number. MEASUREMENTS AND RESULTS: Mean within pair sleep duration difference per 24 hours was 94.3 minutes (SD 62.6 min). We found reduced sleep duration (beta = 0.06; 95% CI 0.004, 0.12; P < 0.05) and sleep efficiency (beta = 0.51; 95% CI 0.06, 0.95; P < 0.05) were significantly associated with reduced mtDNA copy number within twin pairs. Thus every 1-minute decrease in actigraphy-defined sleep duration was associated with a decrease in mtDNA copy number of 0.06. Likewise, a 1% decrease in actigraphy-defined sleep efficiency was associated with a decrease in mtDNA copy number of 0.51. CONCLUSIONS: Reduced sleep duration and sleep efficiency were associated with reduced mitochondrial DNA copy number in sleep duration discordant monozygotic twins offering a potential mechanism whereby short sleep impairs health and longevity through mitochondrial stress. PMID- 26039968 TI - Study of a Novel APAP Algorithm for the Treatment of Obstructive Sleep Apnea in Women. AB - STUDY OBJECTIVES: To assess the efficacy of a novel female-specific autotitrating continuous positive airway pressure (CPAP) algorithm (AutoSet for her, AfH) in premenopausal women relative to a standard autotitrating algorithm (AutoSet, S9) (ResMed Ltd., Bella Vista, New South Wales, Australia). DESIGN: Prospective randomised crossover noninferiority trial. SETTING: Tertiary hospital sleep clinic and university research sleep laboratory. PARTICIPANTS: 20 female patients with obstructive sleep apnea (OSA) established on long-term CPAP treatment. INTERVENTIONS: Treatment with 1 night each of AfH and AutoSet while monitored with overnight laboratory-based polysomnography (PSG); order randomly allocated. MEASUREMENTS AND RESULTS: The primary outcome variables were the apnea-hypopnea index (AHI) and 3% oxygen desaturation index (ODI 3%) determined from PSG. Treatment efficacy on the AfH night was noninferior to the AutoSet night as assessed by median (IQR) AHI (1.2 [0.60-1.85]/h versus 1.15 [0.40-2.85]/h, respectively, P = 0.51) and 3% ODI (0.85 [0.25-1.5]/h versus 0.5 [0.25-2.55]/h, respectively, P = 0.83). Other PSG measures were similar, except for the percentage of the night spent in flow limitation, which was lower on the AfH (0.14%) than the AutoSet night (0.19%, P = 0.007). The device-downloaded 95th centile pressure on the AfH night was also lower than on the AutoSet night (10.6 +/- 1.7 versus 11.6 +/- 2.6 cmH2O, respectively; mean difference [95% confidence interval]: -1.1 [-2.13 to -0.01] cm H2O). CONCLUSION: Among premenopausal women a novel female-specific autotitrating algorithm (AfH) is as effective as the standard AutoSet algorithm in controlling obstructive sleep apnea (OSA). The new algorithm may reduce flow limitation more than the standard algorithm and achieve control of OSA at a lower (95th centile) pressure. PMID- 26039969 TI - On-the-Road Driving Performance the Morning after Bedtime Use of Suvorexant 20 and 40 mg: A Study in Non-Elderly Healthy Volunteers. AB - STUDY OBJECTIVE: To evaluate next-morning driving performance in adults younger than 65 years, after single and repeated doses of suvorexant 20 and 40 mg. DESIGN: Double-blind, placebo-controlled, 4-period crossover study. SETTING: Maastricht University, The Netherlands. PARTICIPANTS: 28 healthy volunteers (15 females), aged 23 to 64 years. INTERVENTIONS: Suvorexant (20 and 40 mg) for 8 consecutive nights; zopiclone 7.5 mg nightly on day 1 and 8; placebo. MEASUREMENTS: Performance on day 2 and 9 (9 h after dosing) using a one-hour standardized highway driving test in normal traffic, measuring standard deviation of lateral position (SDLP). Drug-placebo changes in SDLP > 2.4 cm were considered to reflect meaningful driving impairment. RESULTS: Mean drug-placebo changes in SDLP following suvorexant 20 and 40 mg were 1.01 and 1.66 cm on day 2, and 0.48 and 1.31 cm on Day 9, respectively. The 90% CIs of these changes were all below 2.4 cm. Symmetry analysis showed that more subjects had SDLP changes > 2.4 cm than < -2.4 cm following suvorexant 20 and 40 mg on day 2, and following suvorexant 40 mg on day 9. Four female subjects requested that a total of 5 driving tests--all following suvorexant--stop prematurely due to self-reported somnolence. CONCLUSIONS: As assessed by mean changes in standard deviation of lateral position (SDLP), there was no clinically meaningful residual effect of suvorexant in doses of 20 and 40 mg on next-morning driving (9 h after bedtime dosing) in healthy subjects < 65 years old. There may be some individuals who experience next-day effects, as suggested by individual changes in SDLP and prematurely stopped tests. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov NCT01311882. PMID- 26039971 TI - Inappropriate pattern of nutrient consumption and coexistent cardiometabolic disorders in elderly people from Poland. AB - INTRODUCTION: Nutritional recommendations are aimed at, among others, reducing morbidity and mortality from cardiovascular diseases and metabolic disorders, which are common in the aging population. Adherence to these recommendations allows not only to stop the progression of a disease but also to improve the overall health of elderly patients. OBJECTIVES: The aim of this study was to analyze differences in nutrition of elderly patients, with emphasis on the implementation of nutritional recommendations both for healthy people and for patients with cardiometabolic disorders. PATIENTS AND METHODS: Based on a 24-hour recall questionnaire of 239 volunteers (mean age, 72 +/-9.34 years) and using the Diet 5.0 software, we analyzed in detail the pattern of consumption of various nutrients. RESULTS: Compared with the recommendations of the World Health Organization and cardiology associations, more than 90% of the population did not cover the demand for calcium, potassium, vitamin D, folic acid, and alpha linolenic acid. The intake of polyunsaturated fatty acids, sodium, magnesium, fiber, water, and vitamin C was slightly higher. The appropriate intake was observed only in a diet of 15% to 40% of the subjects. The most significant differences were demonstrated for the coexisting diseases and the intake level of sodium, polyunsaturated fatty acids (particularly docosahexaenoic acid) vitamin C, iron, fiber, lauric acid, and sucrose. The diet of patients with hypercholesterolemia was the least deficient, while deficiencies were the most common in patients with a history of myocardial infarction, ischemic heart disease, and heart failure. CONCLUSIONS: Nutrition of geriatric patients is inadequate. Their diet is profoundly deficient in nutrients, and these deficiencies further deteriorate in the presence of cardiovascular or metabolic diseases. Our results indicate the need for education among elderly patients in terms of proper eating habits and, possibly, individual supplementation. PMID- 26039970 TI - The Circadian System Contributes to Apnea Lengthening across the Night in Obstructive Sleep Apnea. AB - STUDY OBJECTIVE: To test the hypothesis that respiratory event duration exhibits an endogenous circadian rhythm. DESIGN: Within-subject and between-subjects. SETTINGS: Inpatient intensive physiologic monitoring unit at the Brigham and Women's Hospital. PARTICIPANTS: Seven subjects with moderate/severe sleep apnea and four controls, age 48 (SD = 12) years, 7 males. INTERVENTIONS: Subjects completed a 5-day inpatient protocol in dim light. Polysomnography was recorded during an initial control 8-h night scheduled at the usual sleep time, then through 10 recurrent cycles of 2 h 40 min sleep and 2 h 40 min wake evenly distributed across all circadian phases, and finally during another 8-h control sleep period. MEASUREMENTS AND RESULTS: Event durations, desaturations, and apnea hypopnea index for each sleep opportunity were assessed according to circadian phase (derived from salivary melatonin), time into sleep, and sleep stage. Average respiratory event durations in NREM sleep significantly lengthened across both control nights (21.9 to 28.2 sec and 23.7 to 30.2 sec, respectively). During the circadian protocol, event duration in NREM increased across the circadian phases that corresponded to the usual sleep period, accounting for > 50% of the increase across normal 8-h control nights. AHI and desaturations were also rhythmic: AHI was highest in the biological day while desaturations were greatest in the biological night. CONCLUSIONS: The endogenous circadian system plays an important role in the prolongation of respiratory events across the night, and might provide a novel therapeutic target for modulating sleep apnea. PMID- 26039972 TI - Dual yolk-shell structure of carbon and silica-coated silicon for high performance lithium-ion batteries. AB - Silicon batteries have attracted much attention in recent years due to their high theoretical capacity, although a rapid capacity fade is normally observed, attributed mainly to volume expansion during lithiation. Here, we report for the first time successful synthesis of Si/void/SiO2/void/C nanostructures. The synthesis strategy only involves selective etching of SiO2 in Si/SiO2/C structures with hydrofluoric acid solution. Compared with reported results, such novel structures include a hard SiO2-coated layer, a conductive carbon-coated layer, and two internal void spaces. In the structures, the carbon can enhance conductivity, the SiO2 layer has mechanically strong qualities, and the two internal void spaces can confine and accommodate volume expansion of silicon during lithiation. Therefore, these specially designed dual yolk-shell structures exhibit a stable and high capacity of 956 mA h g(-1) after 430 cycles with capacity retention of 83%, while the capacity of Si/C core-shell structures rapidly decreases in the first ten cycles under the same experimental conditions. The novel dual yolk-shell structures developed for Si can also be extended to other battery materials that undergo large volume changes. PMID- 26039974 TI - The effect of curcumin on liver fibrosis in the rat model of microsurgical cholestasis. AB - We aimed to determine the effects of curcumin on liver fibrosis and to clarify the role of nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) in a model of microsurgical cholestasis in the early stage of extrahepatic biliary atresia. Twelve-week-old Wistar rats were divided into four groups (n = 8): sham-operated rats (received olive oil after laparotomy); a curcumin group (received curcumin, 200 mg kg(-1) per day, after laparotomy); a biliary duct ligated group (BDL, received olive oil after operation); and a biliary duct ligated/curcumin group (BDL curc, received curcumin, 200 mg kg(-1) per day, after operation). After 3 weeks of treatment, curcumin did not modify blood plasma markers as well as the expressions of iNOS and NF-kappaB (p65) in the livers of the sham group. Interestingly, there was a significant increase in the extent of both liver and kidney fibrosis. On the other hand, despite a decrease in the expression of iNOS and NF-kappaB (p65), treatment with curcumin did not affect fibrosis enlargement due to bile duct ligation in the liver. In the BDL group, treatment with curcumin decreased the level of blood plasma markers investigated. In conclusion, treatment with curcumin was able to improve the functional properties of hepatocytes and to inhibit the upregulations of both NF-kappaB and iNOS in the BDL group; however, no beneficial effect was observed on the liver fibrosis developed in this model of cholestasis. Thus, in the studied model of microsurgical cholestasis, other factors different from NF-kappaB and iNOS are responsible for fibrotic processes in the liver. PMID- 26039975 TI - Low-glucose enhances keratocyte-characteristic phenotype from corneal stromal cells in serum-free conditions. AB - The avascular cornea is a uniquely-isolated organ, with its stroma constituting a nutrient-poor environment. Consequently, the availability of metabolites such as glucose to corneal stromal cells is considerably reduced compared with other tissues, or indeed with media commonly used to culture these cells in vitro. However, the role of glucose in the behaviour of human corneal keratocytes has been overlooked. As such, we sought to investigate the effects of low-glucose formulations on the phenotype of human corneal stromal cells. Cells cultured in low-glucose were able to survive for extended periods when compared to high glucose, serum-free conditions. Furthermore, low-glucose enhanced their reversal to a keratocyte-characteristic phenotype. Specifically, cells within low-glucose medium assumed dendritic morphologies, with bean-shaped condensed nuclei, absence of alpha-smooth muscle actin or stress fibres, and a corresponding reduction in migratory and contractile activities when compared with high-glucose, serum-free conditions. Moreover, cells within low-glucose uniquely recovered the ability to express a robust keratocyte-characteristic marker, CD34, while still expressing elevated levels of other representative phenotypic markers such as keratocan, lumican, ALDH1A1, and ALDH3A1. These results indicate that low-glucose enhances keratocyte-characteristic phenotype above and beyond established media formulations and thus has important implications for corneal biology in health and disease. PMID- 26039977 TI - Cu mesh for flexible transparent conductive electrodes. AB - Copper electrodes with a micromesh/nanomesh structure were fabricated on a polyimide substrate using UV lithography and wet etching to produce flexible transparent conducting electrodes (TCEs). Well-defined mesh electrodes were realized through the use of high-quality Cu thin films. The films were fabricated using radio-frequency (RF) sputtering with a single-crystal Cu target--a simple but innovative approach that overcame the low oxidation resistance of ordinary Cu. Hybrid Cu mesh electrodes were fabricated by adding a capping layer of either ZnO or Al-doped ZnO. The sheet resistance and the transmittance of the electrode with an Al-doped ZnO capping layer were 6.197 ohm/sq and 90.657%, respectively, and the figure of merit was 60.502 * 10(-3)/ohm, which remained relatively unchanged after thermal annealing at 200 degrees C and 1,000 cycles of bending. This fabrication technique enables the mass production of large-area flexible TCEs, and the stability and high performance of Cu mesh hybrid electrodes in harsh environments suggests they have strong potential for application in smart displays and solar cells. PMID- 26039976 TI - Genome-Wide Association Studies of HIV-1 Host Control in Ethnically Diverse Chinese Populations. AB - Genome-wide association studies (GWASs) have revealed several genetic loci associated with HIV-1 outcome following infection (e.g., HLA-C at 6p21.33) in multi-ethnic populations with genetic heterogeneity and racial/ethnic differences among Caucasians, African-Americans, and Hispanics. To systematically investigate the inherited predisposition to modulate HIV-1 infection in Chinese populations, we performed GWASs in three ethnically diverse HIV-infected patients groups (i.e., HAN, YUN, and XIN, N = 538). The reported loci at 6p21.33 was validated in HAN (e.g., rs9264942, P = 0.0018). An independent association signal (rs2442719, P = 7.85 * 10(-7), HAN group) in the same region was observed. Imputation results suggest that haplotype HLA-B*13:02/C*06:02, which can partially account for the GWAS signal, is associated with lower viral load in Han Chinese. Moreover, several novel loci were identified using GWAS approach including the top association signals at 6q13 (KCNQ5, rs947612, P = 2.15 * 10(-6)), 6p24.1 (PHACTR1, rs202072, P = 3.8 * 10(-6)), and 11q12.3 (SCGB1D4, rs11231017, P = 7.39 * 10(-7)) in HAN, YUN, and XIN groups, respectively. Our findings imply shared or specific mechanisms for host control of HIV-1 in ethnically diverse Chinese populations, which may shed new light on individualized HIV/AIDS therapy in China. PMID- 26039980 TI - Efficacy comparison between cryoablation and radiofrequency ablation for patients with cavotricuspid valve isthmus dependent atrial flutter: a meta-analysis. AB - We perform this meta-analysis to compare the efficacy and safety of cryoablation versus radiofrequency ablation for patients with cavotricuspid valve isthmus dependent atrial flutter. By searching EMBASE, MEDLINE, PubMed and Cochrane electronic databases from March 1986 to September 2014, 7 randomized clinical trials were included. Acute (risk ratio[RR]: 0.93; P = 0.14) and long-term (RR: 0.94; P = 0.08) success rate were slightly lower in cryoablation group than in radiofrequency ablation group, but the difference was not statistically significant. Additionally, the fluoroscopy time was nonsignificantly reduced (weighted mean difference[WMD]: -2.83; P = 0.29), whereas procedure time was significantly longer (WMD: 25.95; P = 0.01) in cryoablation group compared with radiofrequency ablation group. Furthermore, Pain perception during the catheter ablation was substantially less in cryoablation group than in radiofrequency ablation group (standardized mean difference[SMD]: -2.36; P < 0.00001). Thus, our meta-analysis demonstrated that cryoablation and radiofrequency ablation produce comparable acute and long-term success rate for patients with cavotricuspid valve isthmus dependent atrial flutter. Meanwhile, cryoablation ablation tends to reduce the fluoroscopy time and significantly reduce pain perception in cost of significantly prolonged procedure time. PMID- 26039982 TI - Rethinking evolutionary individuality. AB - This paper considers whether multispecies biofilms are evolutionary individuals. Numerous multispecies biofilms have characteristics associated with individuality, such as internal integrity, division of labor, coordination among parts, and heritable adaptive traits. However, such multispecies biofilms often fail standard reproductive criteria for individuality: they lack reproductive bottlenecks, are comprised of multiple species, do not form unified reproductive lineages, and fail to have a significant division of reproductive labor among their parts. If such biofilms are good candidates for evolutionary individuals, then evolutionary individuality is achieved through other means than frequently cited reproductive processes. The case of multispecies biofilms suggests that standard reproductive requirements placed on individuality should be reconsidered. More generally, the case of multispecies biofilms indicates that accounts of individuality that focus on single-species eukaryotes are too restrictive and that a pluralistic and open-ended account of evolutionary individuality is needed. PMID- 26039983 TI - Synthesis of refractory organic matter in the ionized gas phase of the solar nebula. AB - In the nascent solar system, primitive organic matter was a major contributor of volatile elements to planetary bodies, and could have played a key role in the development of the biosphere. However, the origin of primitive organics is poorly understood. Most scenarios advocate cold synthesis in the interstellar medium or in the outer solar system. Here, we report the synthesis of solid organics under ionizing conditions in a plasma setup from gas mixtures (H2(O)-CO-N2-noble gases) reminiscent of the protosolar nebula composition. Ionization of the gas phase was achieved at temperatures up to 1,000 K. Synthesized solid compounds share chemical and structural features with chondritic organics, and noble gases trapped during the experiments reproduce the elemental and isotopic fractionations observed in primitive organics. These results strongly suggest that both the formation of chondritic refractory organics and the trapping of noble gases took place simultaneously in the ionized areas of the protoplanetary disk, via photon- and/or electron-driven reactions and processing. Thus, synthesis of primitive organics might not have required a cold environment and could have occurred anywhere the disk is ionized, including in its warm regions. This scenario also supports N2 photodissociation as the cause of the large nitrogen isotopic range in the solar system. PMID- 26039984 TI - Reconstructing folding energy landscapes from splitting probability analysis of single-molecule trajectories. AB - Structural self-assembly in biopolymers, such as proteins and nucleic acids, involves a diffusive search for the minimum-energy state in a conformational free energy landscape. The likelihood of folding proceeding to completion, as a function of the reaction coordinate used to monitor the transition, can be described by the splitting probability, p(fold)(x). P(fold) encodes information about the underlying energy landscape, and it is often used to judge the quality of the reaction coordinate. Here, we show how p(fold) can be used to reconstruct energy landscapes from single-molecule folding trajectories, using force spectroscopy measurements of single DNA hairpins. Calculating p(fold)(x) directly from trajectories of the molecular extension measured for hairpins fluctuating in equilibrium between folded and unfolded states, we inverted the result expected from diffusion over a 1D energy landscape to obtain the implied landscape profile. The results agreed well with the landscapes reconstructed by established methods, but, remarkably, without the need to deconvolve instrumental effects on the landscape, such as tether compliance. The same approach was also applied to hairpins with multistate folding pathways. The relative insensitivity of the method to the instrumental compliance was confirmed by simulations of folding measured with different tether stiffnesses. This work confirms that the molecular extension is a good reaction coordinate for these measurements, and validates a powerful yet simple method for reconstructing landscapes from single-molecule trajectories. PMID- 26039985 TI - Decreased water limitation under elevated CO2 amplifies potential for forest carbon sinks. AB - Increasing atmospheric CO2 concentrations and changing rainfall regimes are creating novel environments for plant communities around the world. The resulting changes in plant productivity and allocation among tissues will have significant impacts on forest carbon storage and the global carbon cycle, yet these effects may depend on mechanisms not included in global models. Here we focus on the role of individual-level competition for water and light in forest carbon allocation and storage across rainfall regimes. We find that the complexity of plant responses to rainfall regimes in experiments can be explained by individual-based competition for water and light within a continuously varying soil moisture environment. Further, we find that elevated CO2 leads to large amplifications of carbon storage when it alleviates competition for water by incentivizing competitive plants to divert carbon from short-lived fine roots to long-lived woody biomass. Overall, we find that plant dependence on rainfall regimes and plant responses to added CO2 are complex, but understandable. The insights developed here will serve as an important foundation as we work to predict the responses of plants to the full, multidimensional reality of climate change, which involves not only changes in rainfall and CO2 but also changes in temperature, nutrient availability, and disturbance rates, among others. PMID- 26039986 TI - Signatures of host/symbiont genome coevolution in insect nutritional endosymbioses. AB - The role of symbiosis in bacterial symbiont genome evolution is well understood, yet the ways that symbiosis shapes host genomes or more particularly, host/symbiont genome coevolution in the holobiont is only now being revealed. Here, we identify three coevolutionary signatures that characterize holobiont genomes. The first signature, host/symbiont collaboration, arises when completion of essential pathways requires host/endosymbiont genome complementarity. Metabolic collaboration has evolved numerous times in the pathways of amino acid and vitamin biosynthesis. Here, we highlight collaboration in branched-chain amino acid and pantothenate (vitamin B5) biosynthesis. The second coevolutionary signature is acquisition, referring to the observation that holobiont genomes acquire novel genetic material through various means, including gene duplication, lateral gene transfer from bacteria that are not their current obligate symbionts, and full or partial endosymbiont replacement. The third signature, constraint, introduces the idea that holobiont genome evolution is constrained by the processes governing symbiont genome evolution. In addition, we propose that collaboration is constrained by the expression profile of the cell lineage from which endosymbiont-containing host cells, called bacteriocytes, are derived. In particular, we propose that such differences in bacteriocyte cell lineage may explain differences in patterns of host/endosymbiont metabolic collaboration between the sap-feeding suborders Sternorrhyncha and Auchenorrhynca. Finally, we review recent studies at the frontier of symbiosis research that are applying functional genomic approaches to characterization of the developmental and cellular mechanisms of host/endosymbiont integration, work that heralds a new era in symbiosis research. PMID- 26039987 TI - Pheromone killing of multidrug-resistant Enterococcus faecalis V583 by native commensal strains. AB - Multidrug-resistant Enterococcus faecalis possess numerous mobile elements that encode virulence and antibiotic resistance traits as well as new metabolic pathways, often constituting over one-quarter of the genome. It was of interest to determine how this large accretion of mobile elements affects competitive growth in the gastrointestinal (GI) tract consortium. We unexpectedly observed that the prototype clinical isolate strain V583 was actively killed by GI tract flora, whereas commensal enterococci flourished. It was found that killing of V583 resulted from lethal cross-talk between accumulated mobile elements and that this cross-talk was induced by a heptapeptide pheromone produced by native E. faecalis present in the fecal consortium. These results highlight two important aspects of the evolution of multidrug-resistant enterococci: (i) the accretion of mobile elements in E. faecalis V583 renders it incompatible with commensal strains, and (ii) because of this incompatibility, multidrug-resistant strains sharing features found in V583 cannot coexist with commensal strains. The accumulation of mobile elements in hospital isolates of enterococci can include those that are inherently incompatible with native flora, highlighting the importance of maintaining commensal populations as means of preventing colonization and subsequent infection by multidrug-resistant strains. PMID- 26039988 TI - pH-Dependent recognition of apoptotic and necrotic cells by the human dendritic cell receptor DEC205. AB - Dendritic cells play important roles in regulating innate and adaptive immune responses. DEC205 (CD205) is one of the major endocytotic receptors on dendritic cells and has been widely used for vaccine generation against viruses and tumors. However, little is known about its structure and functional mechanism. Here we determine the structure of the human DEC205 ectodomain by cryoelectron microscopy. The structure shows that the 12 extracellular domains form a compact double ring-shaped conformation at acidic pH and become extended at basic pH. Biochemical data indicate that the pH-dependent conformational change of DEC205 is correlated with ligand binding and release. DEC205 only binds to apoptotic and necrotic cells at acidic pH, whereas live cells cannot be recognized by DEC205 at either acidic or basic conditions. These results suggest that DEC205 is an immune receptor that recognizes apoptotic and necrotic cells specifically through a pH dependent mechanism. PMID- 26039990 TI - Conditional steroidogenic cell-targeted deletion of TSPO unveils a crucial role in viability and hormone-dependent steroid formation. AB - Translocator protein (TSPO) is a key member of the mitochondrial cholesterol transport complex in steroidogenic tissues. To assess the function of TSPO, we generated two lines of Cre-mediated Tspo conditional knockout (cKO) mice. First, gonadal somatic cell-targeting Amhr2-Cre mice were crossed with Tspo-floxed mice to obtain F1 Tspo Amhr2 cKO mice (Tspo(fl/fl);Amhr2-Cre(/+)). The unexpected Mendelian ratio of 4.4% cKO mice was confirmed by genotyping of 12.5-day postcoitum (dpc) embryos. As Amhr2-Cre is expressed in gonads at 12.5 dpc, these findings suggest preimplantation selection of embryos. Analysis of expression databases revealed elevated levels of Amhr2 in two- and eight-cell zygotes, suggesting ectopic Tspo silencing before the morula stage and demonstrating elevated embryonic lethality and involvement of TSPO in embryonic development. To circumvent this issue, steroidogenic cell-targeting Nr5a1-Cre mice were crossed with Tspo-floxed mice. The resulting Tspo(fl/fl);Nr5a1-Cre(/+) mice were born at a normal Mendelian ratio. Nr5a1-driven Tspo cKO mice exhibited highly reduced Tspo levels in adrenal cortex and gonads. Treatment of mice with human chorionic gonadotropin (hCG) resulted in increased circulating testosterone levels despite extensive lipid droplet depletion. In contrast, Nr5a1-driven Tspo cKO mice lost their ability to form corticosterone in response to adrenocorticotropic hormone (ACTH). Important for ACTH-dependent steroidogenesis, Mc2r, Stard1, and Cypa11a1 levels were unaffected, whereas Scarb1 levels were increased and accumulation of lipid droplets was observed, indicative of a blockade of cholesterol utilization for steroidogenesis. TSPO expression in the adrenal medulla and increased epinephrine production were also observed. In conclusion, TSPO was found necessary for preimplantation embryo development and ACTH-stimulated steroid biosynthesis. PMID- 26039989 TI - Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy. AB - Serum biomarkers in Duchenne muscular dystrophy (DMD) may provide deeper insights into disease pathogenesis, suggest new therapeutic approaches, serve as acute read-outs of drug effects, and be useful as surrogate outcome measures to predict later clinical benefit. In this study a large-scale biomarker discovery was performed on serum samples from patients with DMD and age-matched healthy volunteers using a modified aptamer-based proteomics technology. Levels of 1,125 proteins were quantified in serum samples from two independent DMD cohorts: cohort 1 (The Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center), 42 patients with DMD and 28 age-matched normal volunteers; and cohort 2 (The Cooperative International Neuromuscular Research Group, Duchenne Natural History Study), 51 patients with DMD and 17 age-matched normal volunteers. Forty-four proteins showed significant differences that were consistent in both cohorts when comparing DMD patients and healthy volunteers at a 1% false-discovery rate, a large number of significant protein changes for such a small study. These biomarkers can be classified by known cellular processes and by age-dependent changes in protein concentration. Our findings demonstrate both the utility of this unbiased biomarker discovery approach and suggest potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, we hope, other rare and devastating diseases. PMID- 26039991 TI - hnRNP U protein is required for normal pre-mRNA splicing and postnatal heart development and function. AB - We report that mice lacking the heterogeneous nuclear ribonucleoprotein U (hnRNP U) in the heart develop lethal dilated cardiomyopathy and display numerous defects in cardiac pre-mRNA splicing. Mutant hearts have disorganized cardiomyocytes, impaired contractility, and abnormal excitation-contraction coupling activities. RNA-seq analyses of Hnrnpu mutant hearts revealed extensive defects in alternative splicing of pre-mRNAs encoding proteins known to be critical for normal heart development and function, including Titin and calcium/calmodulin-dependent protein kinase II delta (Camk2d). Loss of hnRNP U expression in cardiomyocytes also leads to aberrant splicing of the pre-mRNA encoding the excitation-contraction coupling component Junctin. We found that the protein product of an alternatively spliced Junctin isoform is N-glycosylated at a specific asparagine site that is required for interactions with specific protein partners. Our findings provide conclusive evidence for the essential role of hnRNP U in heart development and function and in the regulation of alternative splicing. PMID- 26039992 TI - High-resolution mapping of architectural DNA binding protein facilitation of a DNA repression loop in Escherichia coli. AB - Double-stranded DNA is a locally inflexible polymer that resists bending and twisting over hundreds of base pairs. Despite this, tight DNA bending is biologically important for DNA packaging in eukaryotic chromatin and tight DNA looping is important for gene repression in prokaryotes. We and others have previously shown that sequence nonspecific DNA kinking proteins, such as Escherichia coli heat unstable and Saccharomyces cerevisiae non-histone chromosomal protein 6A (Nhp6A), facilitate lac repressor (LacI) repression loops in E. coli. It has been unknown if this facilitation involves direct protein binding to the tightly bent DNA loop or an indirect effect promoting global negative supercoiling of DNA. Here we adapt two high-resolution in vivo protein mapping techniques to demonstrate direct binding of the heterologous Nhp6A protein at a LacI repression loop in living E. coli cells. PMID- 26039993 TI - On the question of whether lubricants fluidize in stick-slip friction. AB - Intermittent sliding (stick-slip motion) between solids is commonplace (e.g., squeaking hinges), even in the presence of lubricants, and is believed to occur by shear-induced fluidization of the lubricant film (slip), followed by its resolidification (stick). Using a surface force balance, we measure how the thickness of molecularly thin, model lubricant films (octamethylcyclotetrasiloxane) varies in stick-slip sliding between atomically smooth surfaces during the fleeting (ca. 20 ms) individual slip events. Shear fluidization of a film of five to six molecular layers during an individual slip event should result in film dilation of 0.4-0.5 nm, but our results show that, within our resolution of ca. 0.1 nm, slip of the surfaces is not correlated with any dilation of the intersurface gap. This reveals that, unlike what is commonly supposed, slip does not occur by such shear melting, and indicates that other mechanisms, such as intralayer slip within the lubricant film, or at its interface with the confining surfaces, may be the dominant dissipation modes. PMID- 26039994 TI - Human ortholog of Drosophila Melted impedes SMAD2 release from TGF-beta receptor I to inhibit TGF-beta signaling. AB - Drosophila melted encodes a pleckstrin homology (PH) domain-containing protein that enables normal tissue growth, metabolism, and photoreceptor differentiation by modulating Forkhead box O (FOXO), target of rapamycin, and Hippo signaling pathways. Ventricular zone expressed PH domain-containing 1 (VEPH1) is the mammalian ortholog of melted, and although it exhibits tissue-restricted expression during mouse development and is potentially amplified in several human cancers, little is known of its function. Here we explore the impact of VEPH1 expression in ovarian cancer cells by gene-expression profiling. In cells with elevated VEPH1 expression, transcriptional programs associated with metabolism and FOXO and Hippo signaling were affected, analogous to what has been reported for Melted. We also observed altered regulation of multiple transforming growth factor-beta (TGF-beta) target genes. Global profiling revealed that elevated VEPH1 expression suppressed TGF-beta-induced transcriptional responses. This inhibitory effect was verified on selected TGF-beta target genes and by reporter gene assays in multiple cell lines. We further demonstrated that VEPH1 interacts with TGF-beta receptor I (TbetaRI) and inhibits nuclear accumulation of activated Sma- and Mad-related protein 2 (SMAD2). We identified two TbetaRI-interacting regions (TIRs) with opposing effects on TGF-beta signaling. TIR1, located at the N terminus, inhibits canonical TGF-beta signaling and promotes SMAD2 retention at TbetaRI, similar to full-length VEPH1. In contrast, TIR2, located at the C terminal region encompassing the PH domain, decreases SMAD2 retention at TbetaRI and enhances TGF-beta signaling. Our studies indicate that VEPH1 inhibits TGF beta signaling by impeding the release of activated SMAD2 from TbetaRI and may modulate TGF-beta signaling during development and cancer initiation or progression. PMID- 26039996 TI - QnAs with Hopi Hoekstra. PMID- 26039995 TI - Sorafenib and its derivative SC-1 exhibit antifibrotic effects through signal transducer and activator of transcription 3 inhibition. AB - Signal transducer and activator of transcription 3 (STAT3) had been involved in liver fibrogenesis. We aimed to explore the antifibrotic activities of sorafenib and its derivative SC-1 (devoid of Raf kinase inhibition activity) both in vivo and in vitro with special focus on the STAT3 pathway in hepatic stellate cells (HSCs). The clinical role of STAT3 in chronic hepatitis B (CHB) was also investigated. Experimental fibrosis mouse models were established by thioacetamide injection and bile duct ligation in Balb/C mice and treated with sorafenib and SC-1. Rat and human HSCs were used for mechanistic investigations. Forty CHB patients were enrolled to quantify the hepatic phospho-STAT3 (p-STAT3) levels and correlated with liver fibrosis. Both sorafenib and SC-1 ameliorated liver fibrosis in vivo and promoted HSC apoptosis in vitro. p-STAT3 and downstream signals were down-regulated after sorafenib and SC-1 treatment in HSC. STAT3 overexpression in HSC enhanced cell proliferation and undermined the apoptotic effects of sorafenib and SC-1, whereas STAT3-specific inhibition promoted HSC apoptosis. Sorafenib and SC-1 activated Src-homology protein tyrosine phosphatase-1 (SHP-1) and STAT3 inhibition followed. Of particular interest, in CHB patients with advanced liver fibrosis, p-STAT3 in HSC was significantly overexpressed and positively correlated with the severity of liver fibrosis and plasma IL-6 levels. In conclusion, sorafenib and SC-1 ameliorate liver fibrosis through STAT3 inhibition in HSC and STAT3 may potentially serve as a promising fibrotic biomarker and target in liver fibrosis. SHP-1 phosphatase directed STAT3 inhibition may represent a previously unidentified strategy for antifibrotic drug discovery. PMID- 26039997 TI - Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy. AB - Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In PDR, retinal ischemia leads to the up-regulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR pathogenesis. Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Muller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Muller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from PDR patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease. PMID- 26039998 TI - In vitro model for lytic replication, latency, and transformation of an oncogenic alphaherpesvirus. AB - Marek's disease virus (MDV) is an alphaherpesvirus that causes deadly T-cell lymphomas in chickens and serves as a natural small animal model for virus induced tumor formation. In vivo, MDV lytically replicates in B cells that transfer the virus to T cells in which the virus establishes latency. MDV also malignantly transforms CD4+ T cells with a T(reg) signature, ultimately resulting in deadly lymphomas. No in vitro infection system for primary target cells of MDV has been available due to the short-lived nature of these cells in culture. Recently, we characterized cytokines and monoclonal antibodies that promote survival of cultured chicken B and T cells. We used these survival stimuli to establish a culture system that allows efficient infection of B and T cells with MDV. We were able to productively infect with MDV B cells isolated from spleen, bursa or blood cultured in the presence of soluble CD40L. Virus was readily transferred from infected B to T cells stimulated with an anti-TCRalphaVbeta1 antibody, thus recapitulating the in vivo situation in the culture dish. Infected T cells could then be maintained in culture for at least 90 d in the absence of TCR stimulation, which allowed the establishment of MDV-transformed lymphoblastoid cell lines (LCL). The immortalized cells had a signature comparable to MDV-transformed CD4+ alpha/beta T cells present in tumors. In summary, we have developed a novel in vitro system that precisely reflects the life cycle of an oncogenic herpesivrus in vivo and will allow us to investigate the interaction between virus and target cells in an easily accessible system. PMID- 26039999 TI - Netrin-1 exerts oncogenic activities through enhancing Yes-associated protein stability. AB - Yes-associated protein (YAP), a transcription coactivator, is the major downstream effector of the Hippo pathway, which plays a critical role in organ size control and cancer development. However, how YAP is regulated by extracellular stimuli in tumorigenesis remains incompletely understood. Netrin-1, a laminin-related secreted protein, displays proto-oncogenic activity in cancers. Nonetheless, the downstream signaling mediating its oncogenic effects is not well defined. Here we show that netrin-1 via its transmembrane receptors, deleted in colorectal cancer and uncoordinated-5 homolog, up-regulates YAP expression, escalating YAP levels in the nucleus and promoting cancer cell proliferation and migration. Inactivating netrin-1, deleted in colorectal cancer, or uncoordinated 5 homolog B (UNC5B) decreases YAP protein levels, abrogating cancer cell progression by netrin-1, whereas knockdown of mammalian STE20-like protein kinase 1/2 (MST1/2) or large tumor suppressor kinase 1/2 (Lats1/2), two sets of upstream core kinases of the Hippo pathway, has no effect in blocking netrin-1-induced up regulation of YAP. Netrin-1 stimulates phosphatase 1A to dephosphorylate YAP, which leads to decreased ubiquitination and degradation, enhancing YAP accumulation and signaling. Hence, our findings support that netrin-1 exerts oncogenic activity through YAP signaling, providing a mechanism coupling extracellular signals to the nuclear YAP oncogene. PMID- 26040000 TI - Metformin increases degradation of phospholamban via autophagy in cardiomyocytes. AB - Phospholamban (PLN) is an effective inhibitor of the sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA). Here, we examined PLN stability and degradation in primary cultured mouse neonatal cardiomyocytes (CMNCs) and mouse hearts using immunoblotting, molecular imaging, and [(35)S]methionine pulse-chase experiments, together with lysosome (chloroquine and bafilomycin A1) and autophagic (3 methyladenine and Atg5 siRNA) antagonists. Inhibiting lysosomal and autophagic activities promoted endogenous PLN accumulation, whereas accelerating autophagy with metformin enhanced PLN degradation in CMNCs. This reduction in PLN levels was functionally correlated with an increased rate of SERCA2a activity, accounting for an inotropic effect of metformin. Metabolic labeling reaffirmed that metformin promoted wild-type and R9C PLN degradation. Immunofluorescence showed that PLN and the autophagy marker, microtubule light chain 3, became increasingly colocalized in response to chloroquine and bafilomycin treatments. Mechanistically, pentameric PLN was polyubiquitinylated at the K3 residue and this modification was required for p62-mediated selective autophagy trafficking. Consistently, attenuated autophagic flux in HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1-null mouse hearts was associated with increased PLN levels determined by immunoblots and immunofluorescence. Our study identifies a biological mechanism that traffics PLN to the lysosomes for degradation in mouse hearts. PMID- 26040001 TI - Long-range electrostatic screening in ionic liquids. AB - Electrolyte solutions with high concentrations of ions are prevalent in biological systems and energy storage technologies. Nevertheless, the high interaction free energy and long-range nature of electrostatic interactions makes the development of a general conceptual picture of concentrated electrolytes a significant challenge. In this work, we study ionic liquids, single-component liquids composed solely of ions, in an attempt to provide a novel perspective on electrostatic screening in very high concentration (nonideal) electrolytes. We use temperature-dependent surface force measurements to demonstrate that the long range, exponentially decaying diffuse double-layer forces observed across ionic liquids exhibit a pronounced temperature dependence: Increasing the temperature decreases the measured exponential (Debye) decay length, implying an increase in the thermally driven effective free-ion concentration in the bulk ionic liquids. We use our quantitative results to propose a general model of long-range electrostatic screening in ionic liquids, where thermally activated charge fluctuations, either free ions or correlated domains (quasiparticles), take on the role of ions in traditional dilute electrolyte solutions. This picture represents a crucial step toward resolving several inconsistencies surrounding electrostatic screening and charge transport in ionic liquids that have impeded progress within the interdisciplinary ionic liquids community. More broadly, our work provides a previously unidentified way of envisioning highly concentrated electrolytes, with implications for diverse areas of inquiry, ranging from designing electrochemical devices to rationalizing electrostatic interactions in biological systems. PMID- 26040002 TI - Dissecting enzyme function with microfluidic-based deep mutational scanning. AB - Natural enzymes are incredibly proficient catalysts, but engineering them to have new or improved functions is challenging due to the complexity of how an enzyme's sequence relates to its biochemical properties. Here, we present an ultrahigh throughput method for mapping enzyme sequence-function relationships that combines droplet microfluidic screening with next-generation DNA sequencing. We apply our method to map the activity of millions of glycosidase sequence variants. Microfluidic-based deep mutational scanning provides a comprehensive and unbiased view of the enzyme function landscape. The mapping displays expected patterns of mutational tolerance and a strong correspondence to sequence variation within the enzyme family, but also reveals previously unreported sites that are crucial for glycosidase function. We modified the screening protocol to include a high-temperature incubation step, and the resulting thermotolerance landscape allowed the discovery of mutations that enhance enzyme thermostability. Droplet microfluidics provides a general platform for enzyme screening that, when combined with DNA-sequencing technologies, enables high-throughput mapping of enzyme sequence space. PMID- 26040004 TI - Adolescent health in Asia: insights from Thailand. AB - BACKGROUND: Adolescence in an age of opportunity in Thailand. The main health issues of this age group are related to pregnancy, injuries and poisoning, all which should be preventable. OBJECTIVE AND METHODS: This article presents the experiences of Thai physicians, who received adolescent medicine fellowship training in North America and brought their experience, knowledge, skills, and adolescent health care principles and practice back to Thailand. The anticipations and the facts faced in everyday practice, training, research, and collaboration in a place with their own culture and societal norms are described. RESULTS: Currently, there are six adolescent medicine specialists who work with experienced specialist in the subcommittee of adolescent health under the Royal College of Pediatricians of Thailand. There has been collaboration with both the public sector and health care sector, government and non-government organizations with regards to health care service and promotion. Many hospitals especially residency training institutes have increased the cut-off age of patients to be seen by pediatricians to 15 or 18 years of age. Since 2011, adolescent medicine was made one of the mandatory rotations in all pediatric resident training programs. CONCLUSION: There is still more work to be done - issues around policies for confidentiality and a lower age of consent, collaboration between other specialties to enable a large-scale youth-friendly one-stop services, and multicenter research opportunities are still awaiting. PMID- 26040003 TI - Structural, functional, and genetic analyses of the actinobacterial transcription factor RbpA. AB - Gene expression is highly regulated at the step of transcription initiation, and transcription activators play a critical role in this process. RbpA, an actinobacterial transcription activator that is essential in Mycobacterium tuberculosis (Mtb), binds selectively to group 1 and certain group 2 sigma factors. To delineate the molecular mechanism of RbpA, we show that the Mtb RbpA sigma-interacting domain (SID) and basic linker are sufficient for transcription activation. We also present the crystal structure of the Mtb RbpA-SID in complex with domain 2 of the housekeeping sigma-factor, sigma(A). The structure explains the basis of sigma-selectivity by RbpA, showing that RbpA interacts with conserved regions of sigma(A) as well as the nonconserved region (NCR), which is present only in housekeeping sigma-factors. Thus, the structure is the first, to our knowledge, to show a protein interacting with the NCR of a sigma-factor. We confirm the basis of selectivity and the observed interactions using mutagenesis and functional studies. In addition, the structure allows for a model of the RbpA SID in the context of a transcription initiation complex. Unexpectedly, the structural modeling suggests that RbpA contacts the promoter DNA, and we present in vivo and in vitro studies supporting this finding. Our combined data lead to a better understanding of the mechanism of RbpA function as a transcription activator. PMID- 26040005 TI - Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization. AB - In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a 'model' condition for autism spectrum disorders. PMID- 26040006 TI - Impact of food components during in vitro digestion of silver nanoparticles on cellular uptake and cytotoxicity in intestinal cells. AB - Because of the rising application of nanoparticles in food and food-related products, we investigated the influence of the digestion process on the toxicity and cellular uptake of silver nanoparticles for intestinal cells. The main food components--carbohydrates, proteins and fatty acids--were implemented in an in vitro digestion process to simulate realistic conditions. Digested and undigested silver nanoparticle suspensions were used for uptake studies in the well established Caco-2 model. Small-angle X-ray scattering was used to estimate particle core size, size distribution and stability in cell culture medium. Particles proved to be stable and showed radii from 3.6 to 16.0 nm. Undigested particles and particles digested in the presence of food components were comparably taken up by Caco-2 cells, whereas the uptake of particles digested without food components was decreased by 60%. Overall, these findings suggest that in vivo ingested poly (acrylic acid)-coated silver nanoparticles may reach the intestine in a nanoscaled form even if enclosed in a food matrix. While appropriate for studies on the uptake into intestinal cells, the Caco-2 model might be less suited for translocation studies. Moreover, we show that nanoparticle digestion protocols lacking food components may lead to misinterpretation of uptake studies and inconclusive results. PMID- 26040007 TI - Exogenous hydrogen sulfide exhibits anti-cancer effects though p38 MAPK signaling pathway in C6 glioma cells. AB - It has been documented that H2S, in some types of cancer, promotes tumor proliferation, whereas, in the other types, it inhibits the tumor cell growth. In the present study, we investigated the anti-cancer effects and relevant mechanisms of NaHS in C6 glioma cells. C6 cells were subjected to different concentrations of NaHS, then cell viability and morphological changes were examined by MTT assay and Hoechst staining. The protein expression of Caspase-3, Bcl-2, Bax, p38 MAPK (mitogen-activated protein kinase), and p53 was measured by Western blotting. This work demonstrated that NaHS could reduce cell number and induce apoptosis of C6 gliomas cells. The protein expression of Caspase-3 and Bax was up-regulated, while the protein expression of Bcl-2 was down-regulated. Additionally, p38 MAPK and p53 were activated in response to NaHS. Moreover, p38 MAPK inhibitor, SB203580, counteracted the inhibitory effect of NaHS on C6 glioma cells. These data suggest that NaHS can effectively reduce cell number of C6 cells by triggering the apoptosis via Caspase-dependent pathway. p38 MAPK and p53 play an important role in NaHS-induced apoptosis in C6 cells. These findings imply that administration of NaHS may represent a new strategy for the treatment of glioma. PMID- 26040008 TI - C-reactive protein and inflammation: conformational changes affect function. AB - The prototypic acute-phase reactant C-reactive protein (CRP) has long been recognized as a useful marker and gauge of inflammation. CRP also plays an important role in host defense against invading pathogens as well as in inflammation. CRP consists of five identical subunits arranged as a cyclic pentamer. CRP exists in at least two conformationally distinct forms, i.e. native pentameric CRP (pCRP) and modified/monomeric CRP (mCRP). These isoforms bind to distinct receptors and lipid rafts, and exhibit distinct functional properties. Dissociation of pCRP into its subunits occurs within the inflammatory microenvironment and newly formed mCRP may then contribute to localizing the inflammatory response. Accumulating evidence indicates that pCRP possesses both pro- and anti-inflammatory actions in a context-dependent manner, whereas mCRP exerts potent pro-inflammatory actions on endothelial cells, endothelial progenitor cells, leukocytes and platelets, and thus may amplify inflammation. Here, we review recent advances that may explain how conformational changes in CRP contribute to shaping the inflammatory response and discuss CRP isomers as potential therapeutic targets to dampen inflammation. PMID- 26040009 TI - A simple and highly sensitive method of measuring heme oxygenase activity. AB - Heme oxygenase (HO) is a rate-limiting step of heme degradation, which catalyzes the conversion of heme into biliverdin, iron, and CO. HO has been characterized in microorganisms, insects, plants, and mammals. Previously used assays of HO activity were complicated and had low sensitivity. We found that the use of an eel bilirubin-bound fluorescent protein, UnaG, can achieve a highly sensitive and simple assay of HO activity. Using several enzyme sources including human culture cells, homogenates of plant tissues, and recombinant yeast HO, data were successfully obtained. The present method can facilitate the examination of HO in various organisms. PMID- 26040010 TI - MicroRNA expression and its implications for diagnosis and therapy of gallbladder cancer. AB - Gallbladder cancer is the most common biliary tract malignancy with poor prognosis. MicroRNAs (miRNAs) are a class of small, endogenous, non-coding RNAs of 19-23 nucleotides in length, which regulate gene expression at post transcriptional and translational levels. Several studies have demonstrated aberrant expression of miRNAs in gallbladder cancer tissues. Recent evidences also demonstrated that specific miRNAs are functionally involved in gallbladder cancer development through modulating cell proliferation, apoptosis, migration, invasion and metastasis. In this review, we explore the possibilities of using miRNAs as prognostic, diagnostic markers and therapeutic targets in gallbladder cancer. PMID- 26040011 TI - Effect of HIV infection and menopause status on raltegravir pharmacokinetics in the blood and genital tract. AB - BACKGROUND: This study describes first dose and steady state pharmacokinetics of raltegravir (RAL) in cervicovaginal fluid (CVF) and blood plasma (BP). METHODS: Three cohorts of women were enrolled sequentially in a single-site, open-label pharmacokinetic study of oral raltegravir 400 mg twice daily: HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women. BP and CVF were collected over 12 h after a single observed dose and at steady state. RAL concentrations were measured by HPLC-MS methods. Data are expressed as median (IQR). The ANOVA rank-sum test was used to evaluate between-group differences in steady state raltegravir exposure (area under the concentration time curve over the 12-h dosing interval [AUC0-12 h]). RESULTS: First dose pharmacokinetics were obtained in HIV-negative premenopausal women and HIV infected post-menopausal women only. The median (IQR) BP AUC0-12 h was 3,099 (985 5,959) and 4,239 (2,781-13,695) ng*h/ml and the median (IQR) CVF AUC0-12 h was 1,720 (305-5,288) and 13,797 (11,066-19,563) ng*h/ml for HIV-negative premenopausal and HIV-infected post-menopausal women, respectively. All cohorts contributed to steady-state pharmacokinetic profiles. Median (IQR) BP AUC0-12 h did not differ between the groups: 8,436 (3,080-10,111), 5,761 (1,801-10,095) and 6,180 (5,295-8,282) ng*h/ml in HIV-negative premenopausal, HIV-infected premenopausal and HIV-infected post-menopausal women, respectively. There was a trend for lower CVF AUC0-12 h among HIV-negative women 3,164 (1,156-9,540) compared to 11,465 (9,725-17,138) and 9,568 (4,271-24,306) ng*h/ml HIV-infected premenopausal and HIV-infected post-menopausal women, respectively, but this was not statistically significant (P=0.08). HIV-negative premenopausal women had a median (IQR) CVF:BP AUC0-12 h ratio of 0.46 (0.2-1.1), whereas HIV-infected premenopausal and post-menopausal women had median (IQR) CVF:BP AUC0-12 h ratio of 3.9 (1.2-6.7) and 1.4 (0.7-4.3), respectively. CONCLUSIONS: This is the first study to investigate RAL exposure in BP and CVF in premenopausal HIV-negative and pre- and post-menopausal HIV-infected women. These data indicate HIV and menopausal status may influence antiretroviral distribution into the female genital tract. PMID- 26040012 TI - Hilbert-Huang transform based instrumental assessment of intention tremor in multiple sclerosis. AB - OBJECTIVE: This paper describes a method to extract upper limb intention tremor from gyroscope data, through the Hilbert-Huang transform (HHT), a technique suitable for the study of nonlinear and non-stationary processes. The aims of the study were to: (i) evaluate the method's ability to discriminate between healthy controls and MS subjects; (ii) validate the proposed procedure against clinical tremor scores assigned using Fahn's tremor rating scale (FTRS); and (iii) compare the performance of the HHT-based method with that of linear band-pass filters. APPROACH: HHT was applied on gyroscope data collected on 20 MS subjects and 13 healthy controls (CO) during finger-to-nose tests (FNTs) instrumented with an inertial sensor placed on the hand. The results were compared to those obtained after traditional linear filtering. The tremor amplitude was quantified with instrumental indexes (TIs) and clinical FTRS ratings. MAIN RESULTS: The TIs computed after HHT-based filtering discriminated between CO and MS subjects with clinically-detected intention tremor (MS_T). In particular, TIs were significantly higher in the final part of the movement (TI2) with respect to the first part (TI1), and, for all components (X, Y, Z), MS_T showed a TI2 significantly higher than in CO subjects. Moreover, the HHT detected subtle alterations not visible from clinical ratings, as TI2 (Z-component) was significantly increased in MS subjects without clinically-detected tremor (MS_NT). The method's validity was demonstrated by significant correlations between clinical FTRS scores and TI2 related to X (rs = 0.587, p = 0.006) and Y (rs = 0.682, p < 0.001) components. Contrarily, fewer differences among the groups and no correlation between instrumental and clinical indexes emerged after traditional filtering. SIGNIFICANCE: The present results supported the use of the HHT-based procedure for a fully-automated quantitative and objective measure of intention tremor in MS, which can overcome the limitations of clinical scales and provide supplementary information about this sign. PMID- 26040013 TI - Experimental and computational models of neurite extension at a choice point in response to controlled diffusive gradients. AB - OJECTIVE: Axons are guided toward desired targets through a series of choice points that they navigate by sensing cues in the cellular environment. A better understanding of how microenvironmental factors influence neurite growth during development can inform strategies to address nerve injury. Therefore, there is a need for biomimetic models to systematically investigate the influence of guidance cues at such choice points. APPROACH: We ran an adapted in silico biased turning axon growth model under the influence of nerve growth factor (NGF) and compared the results to corresponding in vitro experiments. We examined if growth simulations were predictive of neurite population behavior at a choice point. We used a biphasic micropatterned hydrogel system consisting of an outer cell restrictive mold that enclosed a bifurcated cell permissive region and placed a well near a bifurcating end to allow proteins to diffuse and form a gradient. Experimental diffusion profiles in these constructs were used to validate a diffusion computational model that utilized experimentally measured diffusion coefficients in hydrogels. The computational diffusion model was then used to establish defined soluble gradients within the permissive region of the hydrogels and maintain the profiles in physiological ranges for an extended period of time. Computational diffusion profiles informed the neurite growth model, which was compared with neurite growth experiments in the bifurcating hydrogel constructs. MAIN RESULTS: Results indicated that when applied to the constrained choice point geometry, the biased turning model predicted experimental behavior closely. Results for both simulated and in vitro neurite growth studies showed a significant chemoattractive response toward the bifurcated end containing an NGF gradient compared to the control, though some neurites were found in the end with no NGF gradient. SIGNIFICANCE: The integrated model of neurite growth we describe will allow comparison of experimental studies against growth cone guidance computational models applied to axon pathfinding at choice points. PMID- 26040014 TI - [Advances in molecular mechanisms of tenascin-C in promoting tumor metastasis]. AB - Tenascin-C (TNC) is an extracellular matrix glycoprotein, which is usually highly expressed in embryonic tissues and tumor tissues, but is not expressed or just lowly expressed in mature tissues. TNC is involved in various complex signaling pathways during tumor metastasis, especially through modulating FAK, RhoA, Wnt and Notch pathways by interacting with syndecan-4, integrin alpha5beta1, matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). As a result, TNC affects epithelial mesenchymal transition, tumor cell adhesion, proliferation and angiogenesis, which eventually enhances the invasion and metastasis ability of many tumors. Further studies have demonstrated that TNC could be used as prognosis or metastasis marker of patients with malignant tumor. PMID- 26040015 TI - [Combined middle meatus and expand prelacrimal recess-maxillary ainus approach for orbital fracture treatment]. AB - OBJECTIVE: To study surgical techniques and clinical applications of the intranasal endoscopic combined middle meatus and expand prelacrimal recess maxillary ainus approach for orbital fracture treatment. METHOD: A retrospective clinical analysis of 3 patients whose admitted for orbital floor fractures or medial wall fractures operated by the intranasal endoscopic middle meatus with expand prelacrimal recess-maxillary ainus approach surgical treatment was studied, and the treatment effects and the postoperative complications were analyzed. RESULT: All patients had been followed up for 6 to 12 months. All cases of diplopia symptom were disappeared, enophthalmos were totally corrected, no cases of complication were found. CONCLUSION: Endonasal endoscopic combined middle meatus and expand prelacrimal recess-maxillary ainus approach for orbital fracture treatment have great and clear view. This approach with less tissue damage and high therapeutic effect makes the cost lower than other methods and complications will be decreased as well, it has a great advantage in the orbital fracture treatment. PMID- 26040016 TI - [Expression of serum YKL-40 in anaphylactic rhinitis patients and association of serum YKL-40 with serum IL-4 and IFN-gamma]. AB - OBJECTIVE: This study intends to preliminarily discuss the expression and the clinical meaning of serum YKL-40 in anaphylactic rhinitis by comparing the different expressions of serum YKL-40 in types of anaphylactic rhinitis, and to preliminarily discuss possible mechanism of having anaphylactic rhinitis involved with serum YKL-40 by associating it with serum IL-4 and IFN-gamma in anaphylactic rhinitis. METHOD: Firstly, each select 20 people in our hospital who have anaphylactic rhinitis respectively according to different levels--mild intermittent, mild persistent, moderate-severe interminttent, moderate-severe persistent as the experimental groups, while 20 healthy people as the nomal control. Secondly, test the levels of serum YKL-40, IL-4 and IFN-gamma respectively in each group by the ELISA method. Thirdly, statistically analyze and discuss the collected data. RESULT: (1) There was a rise in the expression of serum YKL-40 between the experimental groups and the nomal control group, which contained a statistical significance (P < 0.05). There was a rise in the expression of serum YKL-40 between the mild persistent group and mild intermittent group, which contained a statistical significance (P < 0.05), as well as between the moderate-severe persistent group and the moderate-severe intermittent group (P < 0.05), while there was no significant difference in expression of serum YKL-40 between the mild intermittent group and the moderate severe intermittent group, as well as between the mild persistent group and the moderate-severe persistent group (P > 0.05). (2) There was a rise in the expression of serum IL-4 between the experimental groups and the nomal control group, which contained a statistical significance (P < 0.05), while there was no significant difference between each experimental group (P > 0.05). (3) There was a reduction in the expression of serum IL-4 be- tween the experimental groups and the nomal control group, which contained a statistical significance (P < 0.05), while there was no significant difference between each experimental group (P > 0.05). (4) The corelation between serum YKL-40 and IL-4 in anaphylactic rhinitis was positive, while the corelation between serum YKL-40 and IFN-gamma was negative. CONCLUSION: (1) Allergic rhinitis serum YKL-40 expression was increased. The corelation between serum YKL-40 and IL-4 in anaphylactic rhinitis was positive, while the corelation between serum YKL-40 and IFN-gamma was negative,suggesting that YKL-40 may regulate the differentiation of Th cells, Promote Th1 to Th2 immune shift, through this mechanism involved in the pathogenesis of allergic rhinitis. (2) Compared with patients with intermittent allergic rhinitis, persistent allergic rhinitis serum YKL-40 expression was increased, suggesting that YKL-40 may promote the continuous attacks of the symptoms of allergic rhinitis. PMID- 26040017 TI - [Application of soft tissue expansion combined with follicular unit extraction for burn cicatricial bald]. AB - OBJECTIVE: To investigate the therapeutic effect of soft tissue expansion combined with follicular unit extraction( FUE) for burn cicatricial bald. METHODS: 48 patients with burn cicatricial bald (> 25 cm2) were treated in three stages. The expanders were implanted on the first stage. After expansion for 8 weeks, the expanders were taken out and local flaps were transferred. One year later, follicular unit extraction( FUE) was applied on the bald area. RESULTS: 48 cases were followed up for 5 years with satisfactory cosmetic results. The VAS assessment of satisfaction on hair appearance after three-staged surgery was 8.2 +/- 2.1. CONCLUSIONS: Soft tissue expansion combined with FUE has a reliable effect for burn cicatricial bald. PMID- 26040018 TI - Mobile health and patient engagement in the safety net: a survey of community health centers and clinics. AB - Patient-centered technologies have emerged as a way to actively engage patients in care. The reach and potential of cell phones to engage diverse patient populations is great. Evidence of their effectiveness in improving health-related outcomes is limited. Researchers conducted an online survey of community health centers and clinics to assess if and how health care providers in the safety net use cell phones to support patient engagement. The findings indicate that the use of cell phones in patient care is at an early stage of deployment across the safety net. Organizations identify chronic disease management as an area where cell phones offer considerable potential to effectively engage patients. To promote widespread adoption and use, technical assistance to support the implementation and management of interventions, evidence-based or best practice models that highlight successful implementation strategies in care delivery, and the introduction of new payment or reimbursement policies will be essential. PMID- 26040019 TI - The Affordable Care Act's payment and delivery system reforms: a progress report at five years. AB - In addition to its expansion and reform of health insurance coverage, the Affordable Care Act (ACA) contains numerous provisions intended to resolve underlying problems in how health care is delivered and paid for in the United States. These provisions focus on three broad areas: testing new delivery models and spreading successful ones, encouraging the shift toward payment based on the value of care provided, and developing resources for systemwide improvement. This brief describes these reforms and, where possible, documents their initial impact at the ACA's five-year mark. While it is still far too early to offer any kind of definitive assessment of the law's transformation-seeking reforms, it is clear that the ACA has spurred activity in both the public and private sectors, and is contributing to momentum in states and localities across the U.S. to improve the value obtained for our health care dollars. PMID- 26040020 TI - [Abstracts from the 5th Hungarian Congress on Eating Disorders, September 19-20, 2014, Debrecen, Hungary]. PMID- 26040021 TI - Characterization and evaluation of apoptotic potential of double gene construct pVIVO.VP3.NS1. AB - Viral gene oncotherapy, targeted killing of cancer cells by viral genes, is an emerging non-infectious therapeutic cancer treatment modality. Chemo and radiotherapy in cancer treatment is limited due to their genotoxic side effects on healthy cells and need of functional p53, which is mutated in most of the cancers. VP3 (apoptin) of chicken infectious anaemia (CIA) and NS1 (Non structural protein 1) of Canine Parvovirus-2 (CPV-2) have been proven to have oncolytic potential in our laboratory. To evaluate oncolytic potential of VP3 and NS1 together these genes needed to be cloned in a bicistronic vector. In this study, both these genes were cloned and characterized for expression of their gene products and its apoptotic potential. The expression of VP3 and NS1 was studied by confocal microscopy and flowcytometry. Expression of VP3 and NS1 in pVIVO.VP3.NS1 transfected HeLa cells in comparison to mock transfected cells indicated that the double gene construct expresses both the products. This was further confirmed by flowcytometry where there was increase in cells expressing VP3 and NS1 in pVIVO.VP3.NS1 transfected group in comparison with the mock control group. The apoptotic inducing potential of this characterized pVIVO.VP3.NS1 was evaluated in human cervical cancer cell line (HeLa) by DNA fragmentation assay, TUNEL assay and Hoechst staning. This double construct was observed to induce apoptosis in HeLa cells. PMID- 26040022 TI - Enhanced chrysene degradation by a mixed culture Biorem-CGBD using response surface design. AB - Degradation of chrysene, a four ringed highly carcinogenic polycyclic aromatic hydrocarbon (PAH) has been demonstrated by bacterial mixed culture Biorem-CGBD comprising Achromobacter xylosoxidans, Pseudomonas sp. and Sphingomonas sp., isolated from crude oil polluted saline sites at Bhavnagar coast, Gujarat, India. A full factorial Central Composite Design (CCD) using Response Surface Methodology (RSM) was applied to construct response surfaces, predicting 41.93% of maximum chrysene degradation with an experimental validation of 66.45% chrysene degradation on 15th day, using a combination of 0.175, 0.175 and 0.385 mL of OD600 = 1 inoculum of A. xylosoxidans, Pseudomonas sp. and Sphingomonas sp., respectively and a regression coefficient (R2) of 0.9485 indicating reproducibility of the experiment. It was observed that chrysene degradation can be successfully enhanced using RSM, making mixed culture Biorem-CGBD a potential bioremediation target for PAH contaminated saline sites. PMID- 26040023 TI - Metabolic effects of high sucrose and saturated oil feeding on insulin resistance in Sprague-Dawley rats. AB - In this study, we explored the effects of long-term consumption of a high-sugar high-fat diet on glucose tolerance and insulin resistance in rats. Rats were fed with either standard rat chow diet (NC group) or high-sugar high-fat diet (HSHF group) for 16 weeks. The HSHF group showed significantly higher fasting insulin level than NC group. Following intraperitoneal glucose challenge, blood glucose and insulin levels in the NC and HSHF groups increased. However, the magnitude of the response in NC group was low compared to HSHF group. Insulin resistance was higher in HSHF group and insulin sensitivity decreased significantly (P < 0.05) in HSHF group in contrast to NC group. Low-density lipoprotein-cholesterol (LDL C) and triglyceride (TG)/high-density lipoprotein-cholesterol (HDL-C) levels showed significant increase in HSHF group, while triglyceride and total cholesterol levels did not show any difference. The study demonstrated that feeding high-sugar high-fat diet to the experimental Sprague-Dawley rats for 16 weeks increased possibility of insulin resistance in them but did not turn them hyperglycemic or diabetic. Thus, they prove to be a suitable animal model to explore various aspects of insulin resistance. PMID- 26040024 TI - Expression studies on NA+/K(+)-ATPase in gills of Penaeus monodon (Fabricius) acclimated to different salinities. AB - The decapod crustacean Penaeus monodon survives large fluctuations in salinity through osmoregulation in which Na+/K(+)-ATPase (NKA) activity in the gills plays a central role. Adult P. monodon specimens were gradually acclimatized to 5, 25 and 35 per thousand salinities and maintained for 20 days to observe long-term alterations in NKA expression. Specific NKA activity assayed in gill tissues was found to be 3 folds higher at 5 per thousand compared to 25 per thousand (isosmotic salinity) and 0.48 folds lower at 35 per thousand. The enzyme was immunolocalized in gills using mouse alpha-5 monoclonal antibody that cross reacts with P. monodon NKA alpha-subunit. At 5 per thousand the immunopositive cells were distributed on lamellar tips and basal lamellar epithelium of the secondary gill filaments and their number was visibly higher. At both 25 per thousand and 35 per thousand NKA positive cells were observed in the inter lamellar region but the expression was more pronounced at 25 per thousand. Gill architecture was normal at all salinities. However, the 1.5 fold increase in NKA alpha-subunit mRNA at 5 per thousand measured by quantitative RT-PCR (qRT-PCR) using EF1alpha as reference gene was not statistically significant. The study confirms the osmoregulating ability of P. monodon like other crustaceans at lower salinities. It is likely that significant increase in NKA transcript level happens at an earlier time point. At higher salinities all three methods record only marginal or no change from isosmotic controls confirming the hypothesis that the animal largely osmoconforms in hyperosmotic environment. PMID- 26040025 TI - Protective effect of Clerodendrum colebrookianum leaves against iron-induced oxidative stress and hepatotoxicity in Swiss albino mice. AB - Liver toxicity due to iron overload leads to oxidative damage of proteins, lipids and nucleic acids which in turn manifests several human diseases. Here, we evaluated the improving effect of Clerodendrum colebrookianum leaf on iron overload induced liver injury along with in vitro iron chelation and the protection of Fenton reaction induced DNA damage was conducted. Iron overload was induced by intraperitoneal administration of iron-dextran into mice. Post oral administration of different doses of the extract (50, 100 and 200 mg/kg body weight) showed significant decrease in different biochemical markers such as liver iron, serum ferritin and serum enzyme levels, along with decreased lipid peroxidation, protein oxidation and collagen content. In addition, the extract effectively enhanced the antioxidant enzyme levels and also exhibited the potential activity of the reductive release of ferritin iron. The protective effect of C. colebrookianum extract on injured liver was furthermore supported by the histopathological studies that showed improvement histologically. In conclusion, the present results demonstrated the hepatoprotective efficiency of C. colebrookianum leaf in iron overloaded mice, and hence, a potential iron chelating drug for iron overload diseases. PMID- 26040026 TI - Effect of ethanolic extract of Coriandrum sativum L. on tacrine induced orofacial dyskinesia. AB - The effect of ethanolic extract of Coriandrum sativum L. seeds (100, 200 mg/kg) was studied on tacrine induced orofacial dyskinesia. Tacrine (2.5 mg/kg, i.p.) treated animals were observed for vacuous chewing movements (VCM), tongue protrusions (TP) and orofacial bursts (OB) for 1 h followed by observations for locomotor changes and cognitive dysfunction. Sub-chronic administration of Coriandrum sativum L. seed extract (E-CS) (100, 200 mg/kg, p.o., for 15 days significantly (P < 0.05) decreased the tacrine induced VCM, TP and OB; and also significantly (P < 0.05), increased locomotion and cognition compared to the tacrine treated group. Biochemical analysis revealed that tacrine administration significantly (P < 0.05) decreased the levels of superoxide dismutase (SOD), Catalase (CAT), glutathione reductase (GSH) levels and also significantly (P < 0.05) increased lipid peroxidation (LPO) as an index of oxidative stress, whereas subchronic administration of E-CS significantly (P < 0.05) improved the antioxidant enzyme (i.e. SOD, CAT, and GSH) levels and also significantly (P < 0.05) decreased lipid peroxidation (LPO). The results have demonstrated the protective role of ethanolic extract of Coriandrum sativum. L against tacrine induced orofacial dyskinesia. PMID- 26040027 TI - Production of 4-ipomeanol, an anticancer agent from the root tubers and rhizogenic callus of Ipomoea batatas Lam.: a comparative study. AB - A comparative study was done on the production of 4-ipomeanol from root tubers of Ipomoea batatas and its rhizogenic callus. Best callusing response was obtained on MS medium supplemented with 11 MUM NAA (alpha-Naphthaleneacetic acid) and 1 MUM KIN (Kinetin). Effect of various elicitors (Fusarium solani, chitin and chitosan) on the production of 4-ipomeanol was studied. Methanol extract of the samples were purified by column chromatography and detected using TLC. Identification of 4-ipomeanol was confirmed using HPLC and quantified spectrophotometrically. A mass spectrum was recorded to confirm the presence of 4 ipomeanol. The calli grown under chitin produced highest (6.61mg g(-1)) amount of 4-ipomeanol. This is the first report on in vitro production of 4-ipomeanol from I. batatas. Since 4-ipomeanol is reported to be present only in I. batatas, this study would help in standardizing protocols for large scale production without affecting its natural flora. PMID- 26040028 TI - Conserved expression of ubiquitin carboxyl-terminal esterase L1 (UCHL1) in mammalian testes. AB - Spermatogonia, the adult germ cells that initiate spermatogenesis in mammalian testis, are capable of dividing both mitotically and meiotically. Isolation and preservation of spermatogonia helps in preserving genetic pool of endangered animals. In this context, identification of marker(s) that can distinguish spermatogonia from other cells in testis gains significance. Here, we examined the expression of ubiquitin carboxyl-terminal esterase L1 (UCHL1) gene and protein in the testes of several mammals, including highly endangered species. Semi-quantitative-reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed presence of UCHL1 amplicon of 442 bp in all the 18 mammals studied. Nucleotide sequence analysis of these amplicons and their predicted protein sequences revealed 88-99% and 95-100% homology with available human UCHL1 and UCHL1 sequences of other available species in the GenBank, respectively. Western blot analysis showed that UCHL1 protein size was unique in all wild mammals. Immunohistology results confirmed UCHL1 expression in the spermatogonia/gonocytes in testes of several mammals belonging to eight distinct families including highly endangered Felidae, Canidae and Cercopithecoidae. These findings suggest that UCHL1 expression is conserved in the mammalian testis, and could be used as a specific marker for gonocytes/spermatogonia for developing male germ-cell based conservation techniques. PMID- 26040029 TI - [Nanocerium restores the erythrocytes stability to acid hemolysis by inhibition of oxygen and nitrogen reactive species in old rats]. AB - In experiments in vivo the effect of nanocerium (cerium oxide nanoparticles) on the stability of red blood cells to acid hemolysis, levels of both ROS and RNS generation and H2S pools in plasma and erythrocytes of old rats were investigated. In red blood cells of old rats the proton penetration into the matrix of erythrocytes showed a significant raising and the fate of labile "aging" erythrocytes in old animals compared with adult were up- regulated. These phenomena paralleled with significant up-regulation of ROS and RNS generation. Introduction for 14 days per os to old rats 0.1 mg/kg of nanocerium fully restored resistance of erythrocytes to acid hemolysis by ROS and RNS in both plasma and erythrocytes reduction. Nanocerium decreased the erythrocytes and, conversely, significantly increased the plasma's pools of H2S. PMID- 26040030 TI - The expression of CCN2, IQSEC, RSPO1, DNAJC15, RIPK2, IL13RA2, IRS1, and IRS2 genes in blood of obese boys with insulin resistance. AB - The development of obesity and its metabolic complications is associated with dysregulation of various intrinsic mechanisms, which control basic metabolic processes via changes in the expression of numerous regulatory genes. We studied the expression of the subset of genes, which responsible for control of cell growth and glucose metabolism, in blood cells of obese boys with normal and impaired insulin sensitivity as well as in normal (control) individuals. It was shown that obesity with normal insulin sensitivity enhances the expression of IRS1, RIPK2, IL13RA2, RSPO1, IQSEC, and CCN2 genes but decreases the expression level IRS2 and DNAJC15 genes in the blood cells as compared to control group. Insulin resistance in obese boys leads to up-regulation of IRS2, RSPO1, and DNAJC15 gene expressions as wells to down-regulation of IRS1 and RIPK2 genes in the blood cells versus obese patients with normal insulin sensitivity. Results of this study provide evidence that obesity affects the expression of the subset of genes related to cell growth and glucose metabolism in blood cells and that insulin resistance in obesity is associated with changes in the expression level of IRS1, IRS2, RIPK2, RSPO1, and DNA JC15 genes, which contribute to the development of insulin resistance and glucose intolerance and possibly reflect some changes in fat tissue. PMID- 26040031 TI - [Association of allelic polymorphisms of genes matrix Gla-protein system with ischemic atherothrombotic stroke]. AB - There are results of the determination of 10 polymorphisms of matrix Gla-protein system (gene MGP-T(-138)-->C (rs1800802), G(-7)-->A (rs1800801), Thr83-->Ala (rs4236), gene VDR-FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236), gene GGCX-Arg325-->Gln (rs699664), gene VKORS1-T(2255)-->C (rs2359612), gene BMP-2-Ser37-->Ala (rs2273073)) into 170 patients with ischemic atherothrombotic stroke (IATS) and 124 healthy individual is (control group). It is established that there is a connection between the IATS and polymorphic variants of genes MGP (G(-7)-->A) and VKORC1 (T(2255)-->C). The risk of IATS in carriers of minor allele A/A (G(-7)-->A polymorphism) in 2.6 times higher than in carriers of the major allele (G/A + G/G), and C/C genotype (T(2255)-->C polymorphism) in 2.2 times higher than the homozygotes of major allele. The coincidence of patients T/C and G/G, C/C and G/A genotypes, and A/A genotype (G( 7)-->A polymorphism) with any genotype T(2255)-->C polymorphism are increases the risk of IATS. PMID- 26040032 TI - [Genotoxic stress and the pathways of thymus cell death and lymph nodes of mice in conditions of immunocomplex pathology]. AB - There were performed the studies of genotoxic stress and the ways of immunocompetent cells death (apoptosis and necrosis) in the modeling of immune system damage by immunization of CBA mice with the bovine serum albumin. Immunofluorescence studies of immunized mice were established the fixation of immune complexes in liver tissue, spleen, kidney and the aorta. Histological studies of these organs showed vascular system affection and, to a lesser extent, parenchyma. It has been shown that DNA comets index increases in 1,4 time in the lymph node cells and in 1,5 time in the thymus cells in the presence of BSA immunization. We also observed an increase in the number of cells with maximum damage DNA thymus preparations (3.4 fold) and lymph nodes (3.3-fold), respectively, indicating strong genotoxic stress. There were shown the reduce of live ICC number and their death increase, including the pro-inflammatory and immunogenic necrotic way. In that way, data which were obtained on the experimental model is evidenced that generalized immunecomplex pathologic process leads to DNA damage and ICC death both central and peripheral organs of the immune system. ICC genotoxic stress and their death amplification by the necrotic way may play a significant role in the immunecomplex deseases development. These factors of peripheral blood lymphocytes can serve as a prospective test system for assessing the severity of autoimmune and immune complex diseases and their treatment effectiveness. PMID- 26040033 TI - [Effects of mono-, poly- and composite probiotics on the ulceration caused by restraint stress]. AB - It was studied the effect of probiotic strains of Bifidobacterium animalis VKL, Bifidobacterium animalis VKB and Lactobacillus casei IMVB-7280, and their mixtures on erosive and ulcerative lesions of the gastric mucosa (GM) of rats. GM was induced by water-immersion restraint stress. It was found that investigated probiotics did not have gastroprotective properties under a single and seven-day prophylactic administration. However, multiprobiotics (polyprobiotic Bifidobacterium animalis VKL and Bifidobacterium animalis VKB and composite probiotic Bifidobacterium animalis VKL, Bifidobacterium animalis VKB and Lactobacillus casei IMVB-7280) reduced the erosive and ulcerative lesions and the intensity of bleeding in rat GM when given within 14 days. It was shown that one of the mechanisms of antiulcer preventive effect of the multistrain probiotics is the restoration of pro/antioxidant balance in the GM under the stress action. The obtained results show the effectiveness of poly- and composite probiotics in the gastric ulcer prevention. PMID- 26040035 TI - [Participation of parasympathetic part of nervous system in realization of bioflavonoids action on gastric secretion in rats]. AB - In this study we investigated the effects of corvitin--modified form of flavonoid quercetin on the stomach secretory function and physiological mechanisms involved in the maintenance of such effects in rat's pylorus-ligated model. In animals which corvitin was injected at a dose of 5 mg/kg, regardless of the route of administration--in the stomach or duodenum, did not observe any changes in the volume of gastric juice or general production of hydrochloric acid, compared with the control data. Dose of 40 mg/kg caused an increase in the volume of gastric juice and hydrochloric acid output as when administered in the stomach and in the duodenum. We also found that after the application of a large dose of corvitin (intragastrically) in the blood of experimental animals showed reduction in glucose levels, which was not detected when using the drug in a dose of 5 mg/kg. Nonspecific antagonist of M-cholinergic receptors--atropine almost completely blocked the enhancement of gastric secretion, which was caused by the introduction into the stomach of corvitin in large dose. From the present data, it is reasonable to conclude that intragastric administration of a large dose of corvitin to pylorus-ligated rats induces hypoglycemic reaction of blood, which may causes an increase in vagus nerve activity with subsequent stimulation of gastric secretion. The increase in gastric juice volume and gastric acid output induced by corvitin was completely inhibited by atropine. These results suggested that the increase in gastric secretion induced by intragastrically administered corvitin could be mediated by the parasympathetic nervous system. PMID- 26040034 TI - [Role of cyclooxygenase in modification of intestinal microflora under stress condition]. AB - Stress and nonsteroidal anti-inflammatory drugs, which act as nonselective inhibitors of cyclooxygenase, are the main factors of ulcerogenesis in digestive system. However, the peculiarities of their combined action upon the status of intestinal microflora and the parameters of NO-synthase system are still poorly understood. In experiments with rats we show that water-restrained stress was accompanied by a considerable increase of iNOS activity and intensity of lipoperoxidation processes. The increase of Escherichia coli content and the decrease in Enterococcus spp. concentration in the small intestine with their simultaneous rise in the large intestine were noticed under these conditions. Cyclooxygenese blockage with naproxen prior to induction of water-restrained stress was accompanied by the decease of iNOS in small and large intestines, with the synchronous rise of cNOS activity in the large intestine as compared with indexes in stress. The moderate increase in Enterococcus spp. content in duodenum with the rise of Escherichia coli concentration in the ileum was shown. The Escherichia coli content decreased in the proximal part of the large intestine and decreased in its distal part. Disbiosis, intensification of lipoperoxidation processes and changes in NO-synthase system parameters under condition of simultaneous action of stress and cyclooxygenase blockage can create preconditions for the development of destructive changes and enteropathias. PMID- 26040036 TI - [Effect of reduced oxygen concentrations and hydrogen sulfide on the amino acid metabolism and mesenchymal cells proliferation]. AB - We investigated the effect of hydrogen sulfide donor (10(-12) mol/l NaHS--I group) alone and together with the reduced oxygen concentrations (5% O2--II group, 3% O2--III group, 24 h) on the biological processes of human stem cells culture. It was shown that the cells proliferation by the third day of cultivation in I, II and III group decreased 1,7; 2,8 and 4,2 times. On the 4th day of culture proliferation inhibited in I, II and III group by 29; 33 and 54% compared to the control. Thus, adverse effects NaHS enhanced by reducing the oxygen concentration. It was established that in all experimental versions rapidly absorbed from the culture medium amino acids: cysteine and cystine, serine and aspartic acid, valine and tryptophan, proline and hydroxyproline, which are involved in the synthesis of proteins, in particular collagen. In the culture medium increased the concentration of free amino acids of the three factions: arginine, histidine and taurine; glycine and methionine; alanine and glutamine. We believe that in the applied concentration of hydrogen sulfide donor in conditions of low oxygen in a gaseous medium incubation inhibits the proliferation and alters the amino acid metabolism of human cells line 4BL. PMID- 26040037 TI - [Vascular endothelial growth factor during physical loads with different mechanism of energy's providing of muscular work]. AB - In the article the results of investigation of vascular endothelial growth factor's (VEGF) maintenance changes at the oxidative stress caused by physical activities and associated tissue hypoxia, for the representatives of types of sport with the different mechanisms of energy providing of muscular work are presented. The highest VEGF concentration of serum was marked in sports with representatives of aerobic energy supply mechanism of muscle activity--from 122.8+/-3.4 to 126.2+/-4.1 pg.ml(-1), intermediate values in VEGF marked in a mixed mechanism energy--102.4+/-4.91 pg.ml(-1). Anaerobic muscle activity observed providing the lowest of VEGF value (78.5+/-5.2 pg.ml(-1)). Initial VEGF concentration in athletes even before the current load is higher than in the healthy untrained people. A statistically significant positive correlation between the degree of antioxidant protection and the VEGF concentration has been found. It is concluded, that angiogenesis is one of the mechanisms of adaptation to tissue hypoxia during physical activities. Scientific Institute of the National University of Physical Education and Sport of Ukraine, Kiev. PMID- 26040038 TI - [The evoked activity of the dorsal root afferent fibres of the spinal cord of white rats in experimental diabetes mellitus]. AB - We analyzed the functional status of the dorsal root of spinal cord in experimental diabetes mellitus (DM), for instance the parameters of the action potential (AP): threshold, chronaxy and the dynamics of the dorsal root excitability. It was revealed the 1,5 times increase in threshold of excitation when compared to the control animals (P<0,001), the amplitude of AP decreased by 21,7% (P<0,05). It was also revealed a significant increase in response to the 2nd stimulus under applying the paired stimuli on the sciatic nerve in animals with experimental DM. Under applying the stimuli of increasing intensity there was found significant decrease in the amplitude of the AP in animals of the experimental group. It was concluded that hyperglycemia made changes to the processes of excitability and refractoriness in the afferent fibers of the spinal cord. PMID- 26040039 TI - [Radioprotective effect of food in the assimilation of carbohydrate substrates by two generations of posterity from the radiation-exposed male rats]. AB - The influence of food in the intestine of the radiation-exposed males predecessors on the functional activity of the small intestine of two generations of their posterity was investigated. It is shown that satiety of these animals during an irradiation determines a radioprotective effect on the systems of transport of carbohydrate substrates of different degree of polymerization only at their posterity of first generation. The second generation had the indexes of functional activity below than that observed in intact group, thus mainly due to a fermentative link. However, here they do not exceed the borders of active component of transport. Consequently, for protection of further generations from the radiation-exposed precursors the more powerful radioprotectors are needed, than simply food. PMID- 26040040 TI - [Modification of experimental rotenone model of Parkinson's disease]. AB - A modification of experimental model of Parkinson's disease is proposed presuming the stereotaxic infusion of rotenone solution using a special device into the cental part of substantia nigra (SN) pars compacta of adult Wistar rats. It was shown that 10 days after infusion of the neurotoxin the density of dopaminergic (DA) neurons in the infusion area drops nearly six-fold, to 20.2+/-3.2 neurons/mm2, with respect to the corresponding value in non-affected controlateral SN, 119.0+/-3.3 neurons/mm2. Electron microscopy has shown ultrastructural impairments in mitochondria of SN neurons in the infusion area displayed mainly as a cristae disarray. The absence of overall toxicity and selectivity of the brain tissue impairments provide an evidence that the proposed rotenone model modification is adequate and can be used to study the effects of DA neuronal degeneration typical of Parkinson's disease. PMID- 26040041 TI - [The role of uncoupling proteins in mechanisms of protection from oxidative stress]. AB - Uncoupling proteins, UCPs, are located in the inner mitochondrial membrane and catalize proton leak across the inner mitochondrial membrane. While UCP1 from brown adipose tissue (BAT) dissipates energy of proton gradient as heat mediating process of thermogenesis, the function of cardiac isoforms of UCPs is still debated. Since the content of UCPs in heart tissue is much lesser then in BAT mild uncoupling of respiratory chain by UCPs might regulate membrane potential of cardiac mitochondria, preventing excessive production of reactive oxygen species. The review is focused on own and literature evidences suggesting the protective role of UCPs activation from oxidative stress under ischemia-reperfusion conditions and aging. Participation of UCPs in endogenous mechanisms of cardioprotection induced by ischemic preconditioning is discussed. PMID- 26040042 TI - [Endothelial monocyte-activating polypeptide-II: properties, functions, and pathogenetic significance]. AB - Endothelial dysfunction is implicated in the pathogenesis of diabetes and atherosclerosis. Endothelial monocyte-activating polypeptide-II (EMAP-II) is a multifunctional polypeptide with proinflammatory and antiangiogenic activity. EMAP-II induces procoagulant activity on the surface of endothelial cells, increases expression of E- and P-selectins and tumor necrosis factor-1, directs migration of monocytes and neutrophils, induces apoptosis in endothelial cells. The mechanisms of effects on endothelial cells, inflammatory action, anti-tumor properties, pathogenic role in diseases of the central nervous system involved in the development of the lungs during embryogenesis and pathogenic role in diseases of the lungs, in the development of cardiovascular disease. PMID- 26040043 TI - Remembering Jewish physicians. PMID- 26040044 TI - Chronic health conditions in Jewish Holocaust survivors born during World War II. AB - BACKGROUND: Findings of studies addressing outcomes of war-related famine in non Jewish populations in Europe during the Second World War (WWII) confirmed an association between prenatal/early life exposure to hunger and adult obesity, diabetes, hypertension, cardiovascular disease and the metabolic syndrome. Fetal programming was suggested as the explanatory mechanism. OBJECTIVES: To study the association between being born during WWII in Europe and physical long-term outcomes in child Holocaust survivors. METHODS: We conducted a cross-sectional study on all Jewish Clalit Health Services (CHS) North District members born in 1940-1945 in Europe ('exposed', n = 653) or in Israel to Europe-born parents ('non-exposed', n = 433). Data on sociodemographic variables, medical diagnoses, medication procurement, laboratory tests and health services utilization were derived from the CHS computerized database and compared between the groups. RESULTS: The exposed were significantly more likely than the non-exposed to present with dyslipidemia (81% vs. 72%, respectively), hypertension (67% vs. 53%), diabetes mellitus (41% vs. 28%), vascular disease (18% vs. 9%) and the metabolic syndrome (17% vs. 9%). The exposed also made lower use of health services but used anti-depressive agents more often compared to the non-exposed. In multivariate analyses, being born during WWII remained an independent risk marker for hypertension (OR = 1.52), diabetes mellitus (OR = 1.60), vascular disease (OR = 1.99) and the metabolic syndrome (OR = 2.14). CONCLUSIONS: The results of this cross-sectional study based on highly validated data identify a high risk group for chronic morbidity. A question regarding potential trans generational effects that may impact the 'second generation' is also raised. PMID- 26040045 TI - Self-rated health is associated with elevated C-reactive protein even among apparently healthy individuals. AB - BACKGROUND: A single self-rated health (SRH) assessment is associated with clinical outcome and mortality, but the biological process linking SRH with immune status remains incompletely understood. OBJECTIVES: To examine the association between SRH and inflammation in apparently healthy individuals. METHODS: Our analysis included 13,773 apparently healthy individuals attending the Tel Aviv Sourasky Medical Center for periodic health examinations. Estimated marginal means of the inflammation-sensitive biomarkers [i.e., highly sensitive C reactive protein (hs-CRP) and fibrinogen] for the different SRH groups were calculated and adjusted for multiple potential confounders including risk factors, health behavior, socioeconomic status, and coexistent depression. RESULTS: The group with the lowest SRH had a significantly higher atherothrombotic profile and significantly higher conentrations of all inflammation-sensitive biomarkers in both genders. Hs-CRP was found to differ significantly between SRH groups in both genders even after gradual adjustments for all potential confounders. Fibrinogen differs significantly according to SRH in males only, with low absolute value differences. CONCLUSIONS: A valid association exists for apparently healthy individuals of both genders between inflammation-sensitive biomarker levels and SRH categories, especially when comparing levels of hs-CRP. Our findings underscore the importance of assessing SRH and treating it like other markers of poor health. PMID- 26040046 TI - Contour Transtar in true rectal prolapse. AB - BACKGROUND: A new device, the CCS-30 Contour Transtar, was recently launched for the treatment of obstructed defecation syndrome (ODS). OBJECTIVES: To evaluate the efficacy of the Contour Transtar in resection of true rectal prolapse in relation to age and concomitant urogynecologic procedures. METHODS: During a 50 (median) month period 15 women with rectal prolapse of >= 5 cm and complaints of obstructed defecation underwent perineal resection of rectal prolapse with the Contour Transtar. RESULTS: In 3 of the 15 patients (20%) rectal prolapse recurred. Amelioration of ODS symptoms and improved continence were noted in 82% and 75%, respectively, following surgery. CONCLUSIONS: The Contour Transtar procedure for full-thickness rectal prolapse is a safe and promising procedure and is likely suitable for elderly poor risk patients. PMID- 26040047 TI - Interferon-gamma-release assay prevents unnecessary tuberculosis therapy. AB - BACKGROUND: The mass influx of immigrants from tuberculosis-endemic countries into Israel was followed by a considerable increase in the incidence of tuberculosis (TB). All contacts of active TB patients are obliged to be screened by tuberculin skin tests (TST) and, if found positive, prophylactic treatment is considered. OBJECTIVES: To assess the utility of interferon-gamma (IFNgamma) release assay with a prolonged follow-up in preventing unnecessary anti-TB therapy in individuals with suspected false positive results. METHODS: Between 2008 and 2012 the QuantiFERON TB gold-in-tube test (QFT-G) was performed in 278 sequential individuals who were mostly TST-positive and/or were in contact with an active TB patient. In all, whole blood was examined by the IFNgamma-release assay. We correlated the TST diameter with the QFT-G assay and followed those patients with a negative assay. RESULTS: The QFT-G test was positive in only 72 (42%) of all 171 TST-positive individuals. There was no correlation between the diameter of TST and QFT-G positivity. Follow-up over 5 years was available in 128 (62%) of all QFT-G-negative individuals. All remained well and none developed active TB. CONCLUSIONS: A negative QFT-G test may obviate the need for anti-TB therapy in more than half of those with a positive TST. PMID- 26040048 TI - Non-surgical treatment of latrogenic postoperatively diagnosed ureteral injuries. AB - BACKGROUND: latrogenic ureteral injury may be seen following abdominopelvic surgeries. While ureteral injuries identified during surgery should be immediately and surgically repaired, those that are postoperatively diagnosed may be treated non-surgically by draining the ipsilateral kidney. Data regarding the outcome of this approach are still missing. OBJECTIVES: To evaluate the success rates of non-surgical management of ureteral injuries diagnosed following abdominopelvic surgeries. METHODS: We retrospectively reviewed the files of all patients treated for iatrogenic ureteral injuries diagnosed following abdominopelvic surgeries. Patients' ipsilateral kidney was percutaneously drained following diagnosis of injury by either nephrostomy tube (NT)/nephro-ureteral stent (NUS) or double-J stent (DJS) inserted retrogradely. The tube was left in place until a pyelogram confirmed healing or a conservative approach was abandoned due to failure. RESULTS: Twenty-nine patients were identified as having ureteral injury following abdominopelvic surgery. Median time from injury to renal drainage was 9 days, interquartile range (IQR) 4-17 days. Seven cases (24%) had surgical repair. Among the other 22 patients, in 2 oncology patients the conservative approach was maintained although renal drainage failed to resolve the injury. In the remaining 20, median drainage length was 60 days (IQR 43.5 85). Calculated overall success rates following renal drainage was 69% (18/29), and with NUS approached 78.5%. CONCLUSIONS: Ureteral injuries diagnosed following abdominopelvic surgeries can be treated conservatively. Ipsilateral renal drainage should be the first line of treatment before surgical repair, and NUS may be the preferred drainage to obtain spontaneous ureteral healing. PMID- 26040049 TI - Type I-II laryngeal cleft: clinical course and outcome. AB - BACKGROUND: Laryngeal cleft (LC) is a rare congenital anomaly manifesting in a variety of symptoms, including swallowing disorders and aspirations, dyspnea, stridor and hoarseness. The mild forms (types I-II) may be underdiagnosed, leading to protracted symptomatology and morbidity. OBJECTIVES: To evaluate the diagnostic process, clinical course, management and outcome in children with type I-II laryngeal clefts. METHODS: We conducted a retrospective case analysis for the years 2005-2012 in a tertiary referral center. RESULTS: Seven children were reviewed: five boys and two girls ranging in age from birth to 5 years. The most common presenting symptoms were cough, aspirations and pneumonia. Evaluation procedures included fiber-optic laryngoscopy (FOL), direct laryngoscopy (DL) and videofluoroscopy. Other pathologies were seen in three children. Six children underwent successful endoscopic surgery and one child was treated conservatively. The postoperative clinical course was uneventful in most of the cases. CONCLUSIONS: Types I-II LC should be considered in the differential diagnosis of children presenting with protracted cough and aspirations. DL is crucial for establishing the diagnosis. Endoscopic surgery is safe and should be applied promptly when conservative measures fail. PMID- 26040050 TI - Current solutions for obesity-related liver disorders: non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. PMID- 26040051 TI - The epidemiology of eosinophilic esophagitis: an ongoing enigma. PMID- 26040052 TI - The patient knows best. PMID- 26040053 TI - Autoimmune hepatitis and allergic reactions during anti-TNFalpha treatment. PMID- 26040054 TI - Helminths and autoimmunity: the good, the bad and the ugly. PMID- 26040055 TI - Intralesional cryosurgery for the treatment of severe stoma hypergranulation following percutaneous endoscopic gastrostomy. PMID- 26040056 TI - Fulminant HHV-8 associated Castleman's disease in a non-HIV, Kaposi sarcoma patient with borderline hemophagocytic syndrome. PMID- 26040057 TI - Autoimmune hepatitis triggered by adalimumab and allergic reactions after various anti-TNFalpha therapy agents in a patient with rheumatoid arthritis. PMID- 26040058 TI - Taenia solium in a patient with systemic lupus erythematosus: do parasites protect against autoimmune diseases. PMID- 26040059 TI - Stiff person syndrome: a tough and rigid case. PMID- 26040060 TI - Diffuse systemic sclerosis presenting as Meniere's disease-like symptoms as part of autoimmune inner ear disease. PMID- 26040061 TI - Development and validation of a questionnaire for evaluation of students' attitudes towards family medicine. AB - The development of the EURACT (European Academy of Teachers in General Practice) Educational Agenda helped many family medicine departments in development of clerkship and the aims and objectives of family medicine teaching. Our aims were to develop and validate a tool for assessment of students' attitudes towards family medicine and to evaluate the impact of the clerkship on students' attitudes regarding the competences of family doctor. In the pilot study, experienced family doctors were asked to describe their attitudes towards family medicine by using the Educational Agenda as a template for brainstorming. The statements were paraphrased and developed into a 164-items questionnaire, which was administered to 176 final-year students in academic year 2007/08. The third phase consisted of development of a final tool using statistical analysis, which resulted in the 60-items questionnaire in six domains which was used for the evaluation of students' attitudes. At the beginning of the clerkship, person centred care and holistic approach scored lower than the other competences. Students' attitudes regarding the competences at the end of 7 weeks clerkship in family medicine were more positive, with exception of the competence regarding primary care management. The students who named family medicine as his or her future career choice, found holistic approach as more important than the students who did not name it as their future career. With the decision tree, which included students' attitudes to the competences of family medicine, we can successfully predict the future career choice in family medicine in 93.5% of the students. This study reports on the first attempt to develop a valid and reliable tool for measuring attitudes towards family medicine based on EURACT Educational Agenda. The questionnaire could be used for evaluating changes of students' attitudes in undergraduate curricula and for prediction of students' preferences regarding their future professional career in family medicine. PMID- 26040062 TI - Development of SMOG-Cro readability formula for healthcare communication and patient education. AB - Effective communication shows a positive impact on patient satisfaction, compliance and medical outcomes, at the same time reducing the healthcare costs. Written information for patients needs to correspond to health literacy levels of the intended audiences. Readability formulas correlate well with the reading and comprehension tests but are considered an easier and quicker method to estimate a text difficulty. SMOG readability formula designed for English language needs to be modified if used for texts in other languages. The aim of this study was to develop a readability formula based on SMOG, that could be used to estimate text difficulty of written materials for patients in Croatian language. Contras- tive analysis of English and Croatian language covering a corpus of almost 100,000 running words showed clear linguis- tic differences in the number of polysyllabic words. The new formula, named SMOG-Cro, is presented as an equation: SMOG-Cro = 2 + ?4+ syllables, with the score showing the number of years of education a person needs to be able to understand a piece of writing. The presented methodology could help in the development of readability formulas for other languages. We hope the results of this study are soon put into practice for more effective healthcare communication and patient education, and for development of a health literacy assessment tool in Croatian language. PMID- 26040063 TI - Traditional Practices of Turkish infertile women: an example from a rural county. AB - Infertility is not only a health problem, but is also a central existential intrapersonal and relational conflict. Infertility treatments are invasive, expensive, time-consuming, emotionally draining. All over the world there are numerous traditional methods used in the treatment of infertility. This investigation was carried out to determine the traditional practices of infertile women in a rural county in Eastern Turkey. This is a descriptive study carried out in 105 primary infertile women. Data were collected between September 2007 and April 2008 by using a questionnaire. Data analysis included descriptive statistics. 55% of the women were in the 25-34 year age range. It was observed that only 17% of the women applied to a gynecologist without using any traditional applications while 83% of the women applied for traditional applications. The most prevalent traditional practices were consulting traditional healers, visiting mausoleums where religious leaders were buried, using traditional drugs, use of written fertility amulets. Various traditional practices against infertility are prevalent rural counties. Some of these practices may be potentially harmful for women. Health professionals should be aware that infertile women may sometimes follow questionable traditional practices and advices. PMID- 26040064 TI - Attention deficit hyperactivity disorder in children with intellectual disability in Bosnia and Herzegovina. AB - Attention deficit hyperactivity disorder (ADHD) is very frequent in children with intellectual disability. The aim of this study was to examine the occurrence of ADHD in children with intellectual disability in Bosnia and Herzegovina with regard to their sex, etiology and level of intellectual disability. The method for data collection was the examination of the children's medical records. The sample consisted of 167 children attending two special education facilities in Sarajevo. Overall occurrence of the disorder was found to be 20.4%, a finding which is in accordance with existing studies. The results in this study revealed different male to female ratio (1.5:1) of the disorder as compared to existing studies. A difference in the prevalence of ADHD was found in relation to the level of intellectual disability. There are many children with dual diagnosis of intellectual disability and ADHD. It is necessary that multidisciplinary team is involved in the creation of behavioral and educational programs for these children. PMID- 26040065 TI - Self-determined, goal orientations and motivational climate in physical education. AB - The aim of this study was to analyze the degree of prediction to which the goal orientation adopted by the student and the motivational climate created by the teacher as perceived by students in physical education classes, have on the students' self-determined behaviors. The sample included 846 high school students from the Murcia region (Spain) aged 12-19 years old. The Spanish versions of the Perception of Success Questionnaire, the Perceived Motivational Climate in Sport Questionnaire-2 and the Motivational Climate Scale were the instruments used to collect data. A descriptive, correlated and stepwise multiple regression analysis was carried out following the Self Determination Index. Results show that the majority of students were task oriented, they perceive a task climate and were intrinsically motivated. Moreover, the relevance of the role of the teacher in physical education classes was demonstrated, as the main predictor variable of self-determined behavior in students was the motivational climate. PMID- 26040066 TI - Ocular surface disease in pseudoexfoliation syndrome. AB - Aim of the study is to determine connection between pseudoexfoliation (PEX) syndrome and symptoms and signs of ocular surface disease. Tear film break-up time test, Schirmer II test and assessment of lid parallel conjunctival folds were performed in 40 PEX syndrome patients and 40 controls. All data was statistically analyzed. Results show statistically significant difference in every component between groups, most prominent in tear film break up time test. We have concluded that patients with PEX syndrome have higher predisposition of tear function disorders and that both components of dry eye syndrome are present in PEX syndrome. PMID- 26040067 TI - Ocular surface changes in glaucoma patients related to topical medications. AB - Topical glaucoma therapy is a long termed, usually lifelong. Antiglaucomatous drugs have toxic effects on ocular surface, due to preservative toxicitiy or the drug itself. Adding a lubricant eyedrops to antiglaucomatous therapy, especially if considering the preservative used, can have protective effect. The purpose of this study was to evaluate the stabilty of precorneal tear film in glaucoma patient prior and after administration of lubricant eye drops with different tipe of preservatives. The study showed the protective role of ocular surface lubrication especially when using drugs with less harmful preservatives. PMID- 26040068 TI - Ex-PRESS miniature glaucoma shunt in treatment of refractory glaucoma. AB - Refractory glaucoma in a complicated type of glaucoma of different ethyologies with one same characteristic--intraocular pressure of great resistance to therapy. There are different methods of treatment in such glaucomas, primary surgical options. Ex-PRESS miniature glaucoma shunt implantation was our treatment of choice. In our group of patients we achieved stabile intraocular pressure values in 4 month period of time with no serious or unexpected complications. PMID- 26040069 TI - Individually designed PALs vs. power optimized PALs adaptation comparison. AB - The practice shows that in everyday life we encounter ever-growing demand for better visual acuity at all viewing distances. The presbyopic population needs correction to far, near and intermediate distance with different dioptric powers. PAL lenses seem to be a comfortable solution. The object of the present study is the analysis of the factors determining adaptation to progressive addition lenses (PAL) of the first-time users. Only novice test persons were chosen in order to avoid the bias of previously worn particular lens design. For optimal results with this type of lens, several individual parameters must be considered: correct refraction, precise ocular and facial measures, and proper mounting of lenses into the frame. Nevertheless, first time wearers encounter various difficulties in the process of adapting to this type of glasses and adaptation time differs greatly between individual users. The question that arises is how much the individual parameters really affect the ease of adaptation and comfort when wearing progressive glasses. To clarify this, in the present study, the individual PAL lenses--Rodenstock's Impression FreeSign (with inclusion of all parameters related to the user's eye and spectacle frame: prescription, pupillary distance, fitting height, back vertex distance, pantoscopic angle and curvature of the frame) were compared to power optimized PAL--Rodenstock's Multigressiv MyView (respecting only prescription power and pupillary distance). Adaptation process was monitored over a period of four weeks. The collected results represent scores of user's subjective impressions, where the users themselves rated their adaptation to new progressive glasses and the degree of subjective visual impression. The results show that adaptation time to fully individually fit PAL is easier and quickly. The information obtained from users is valuable in everyday optometry practice because along with the manufacturer's specifications, the user's experience can give us a better insight in design and characteristics of progressive lenses. PMID- 26040070 TI - Corticosteroid therapy in patients with non-arteritic anterior ischemic optic neuropathy. AB - Non-arteritic anterior ischemic optic neuropathy is one of the most common conditions affecting the optic nerve in the elderly. It may lead to severe visual loss. Typical symptoms are painless impairment of visual function accompanied by relative afferent pupillary defect, edema of the optic disc and visual field defects. Aim is to present 38 patients with nonarteritic anterior ischemic optic neuropathy who were treated with corticosteroid therapy. This prospective study involved 38 patients, 20 men and 18 women aged 60-75 years who were treated with corticosteroid therapy. The study included patients with visual acuity in the affected eye from 0.1 to 0.8 according to Snellen. Every patient underwent clinical examination, the Octopus 900 perimetry in G program, laboratory testing, while the compressive optic neuropathy was rule out with MSCT of the brain and orbits. The most common forms of visual field defect are altitudinal defect and diffuse depression. Corticosteroid therapy led to recovery in 65% of patient, in 30% of patients did not change, while the deterioration occurred in 5% of patients. PMID- 26040071 TI - Treatment of advanced peripheral arterial insufficiency in the elderly. AB - Peripheral arterial insufficiency appears at all stages regardless of the patient age; however its appearance is most common in the elderly in which cases it mostly appears as stage described by Fontaine as stage III or IV The most com- mon cause of peripheral arterial insufficiency is atherosclerotic degeneration, and is remarkably often accompanied by the diabetes. In the years 2012 and 2013 department of vascular surgery, University Hospital Rijeka admitted 169 patients older than 70 with peripheral arterial insufficiency of type Fontaine III and IV That number represents 68.8% of total number of patients admitted for peripheral arterial insufficiency. The goal of this research is to identify to what extent and in what percentage can patients older than 70 with advanced peripheral arterial insufficiency be subjected to vascular treatment and if there exist and absolute indication for angiographic treatment of such patients. In majority of patients, 148 of them, three or more comorbidities were present. Diabetes was present at almost half of patients, to be exact 46.7%. Assessment of possibility for vascular treatment and the need for angiographic treatment was followed in patients in three age groups: 70-75 years of age, 76-80 years of age and over 80 years of age. Angiography was performed on 69 patients and the insight into angiographic finding resulted in only 33 patients being subjected to some type of vascular treatment. From the total number of patient's subjected to vascular treatment 20 had symptoms of Fontaine III while the remaining 13 had symptoms of Fontaine IV Amputation procedure was performed 119 times. The research shows that angiograph- ic treatment is not a routine treatment in mentioned patients and that the number of vascular procedures is significantly higher in the 70-75 years age group. PMID- 26040072 TI - Bone fragility fractures in hemodialysis patients: Croatian surveys. AB - Disturbances of bone mineral metabolism are common complications of chronic kidney disease with bone fractures as one of the most important consequences. The aim of this study was to estimate prevalence of bone fractures among Croatian hemodialysis patients and to determine the possible fracture risk. The study was carried out in 767 hemodialysis patients from nine Croatian hemodialysis centers. Demographic, laboratory and bone fracture data were collected from medical records as well as therapy with vitamin D analogs. Fragility fractures were defined according to the World Health Organization definition. In 31 patient a total of 36 fractures were recorded. The prevalence of patients with bone fractures was 4.0%. The mean age of patients with fractures was 68.6 years. There were 9 male and 22 female patients with frac- tures. The mean hemodialysis duration was 63.3 months. Among all fractures the most common were hip fractures (39%) followed by forearm fractures (22%). This is the first study regarding epidemiology of bone fractures in Croatian hemodialysis patients. The prevalence of patients with bone fractures in our group of hemodialysis patients is high. Fractures were more frequent among women and older patients, patients who have been longer on dialysis and in patients with higher concentration of PTH. PMID- 26040073 TI - Use of serum levels of proinflammatory cytokine IL-1alpha in chronic hepatitis C. AB - Immunoregulatory cytokines influence the persistence of hepatitis C virus chronic infection and the extent of liver damage. Interleukin-1 plays an important role in the inflammatory process. Some studies have demonstrated that IL-1 production was impaired in patients with chronic infections of hepatitis C virus, implying that IL-1 may play a role in viral clearance. In this study, along with routine laboratory tests, has been performed the analysis of serum levels of proinflammatory cytokine IL-1alpha in order of better understanding and monitoring of chronic hepatitis C. The aim of study was to analyze the usefulness of laboratory tests, which are routinely used in the assessment of liver disease with specified immunological parameters, in patients with chronic hepatitis C. Total of 60 subjects were divided into two groups: HCV-PCR positive and negative group. The control group of 30 healthy participans was included. Apart from standard laboratory tests, the analysis included serum levels of cytokine IL 1alpha. IL-1alpha had the highest mean concentration in group of viral hepatitis C, with PCR positive test (5.73 pg/mL), and then in of chronic viral hepatitis C, PCR negative test (5.39 pg/mL). ANOVA test proves that IL-1alpha in the healthy group was different from other groups as follows: in relation to HCV-RNA-PCR positive patients statistical significance level was p < 0.001 (F = 32,755); in relation to HCV-RNA-PCR negative was also statistically significant at p < 0.001 (F = 182,361); Cytokine IL-1 was statistically analyzed separately and compared by group 1 and 2 using Student t-test for independent samples. Statistical significance was observed at p = 0.026. IL-1alpha was positively correlated with the duration of the illness (p < 0.01) and with serum ALT activity (p < 0.01) and serum AST activity (p < 0.01). Using multivariate analysis model "Factor Analysis", was made significant stratification predic- tive parameters in relation to the cytokine IL-1alpha, stratified significance is indicated as follows: 1. Age, 2. history of receiv- ing transfusions, 3. ALT 4. AST, 5. MELD score (negative), 6. Child-Pugh score (negative). IL-1alpha was significantly ele vated in inflammatory conditions of pronounced activity (PCR positive hepatitis). IL-1alpha may have important role as marker of both inflammation and hepatic injury, particularly in the course of hepatitis C. Results suggest that inflammatory and immune parameters, analyzed together can significantly contribute to the understanding and predicting of chronic liver damage. PMID- 26040074 TI - HIV-related knowledge, attitudes and practice among health care workers in Montenegro. AB - The objective of the present study was to assess HIV-related knowledge, attitudes, and practice of health care workers (HCWs) in Montenegro. A cross sectional study was conducted in the University Clinical Centre of Montenegro in Podgorica. A self-administered anonymous questionnaire was used for data collecting. Out of 526 HCWs, 422 were included in the survey and response rate was 80%. An insufficient level of knowledge on HIV transmission and the risk after exposure was observed generally, although the knowledge was better in physicians compared to other HCWs categories. A rather high proportion of HCWs showed inappropriate attitude regarding the need of HIV testing of all hospitalized patients (64.7%) and obligation of HIV+ patient to report his/her HIV status (88.9%) in order to practice universal precaution. Additionally, 6.2% HCWs would refuse to treat an HIV+ patient. More than a half (55.7%) of study participants were educated in HIV/AIDS and 15.9% of them were HIV tested. Majority of HCWs (67.5%) always applied universal precautions during their daily work with patients. In spite of applying protective devices, number of accidents was great. A continuous education is necessary to increase the level of knowledge of HCWs about the risk of infection at the workplace. This would potentially influence the modification of their attitudes regarding HIV patients and improve prevention at the workplace. Continuous research regarding the professional risk would provide better health and safety among medical staff. PMID- 26040075 TI - Effects of different agility training programs among first-grade elementary school students. AB - The aim of the study was to determine which agility training program (low, moderate or high contextual interference) was more effective in first-grade primary school students to provide reliable information to physical education teachers for designing more effective agility programs. A total of 57 first-grade elementary school students participated in the present study. They were randomized into three groups to compare the effects of three different agility training programs based on contextual interference: low contextual interference (N = 19), moderate contextual interference (N = 19), and high contextual interference (N = 19). Contextual interference refers to the relative amount of interference created when integrating two or more tasks into a particular aspect of a training session. Significant improvements in agility were found in the low (p < 0.01, ES = 1.79) and moderate (p < 0.05, ES = 0.61) contextual interference groups after a 4-week training period. These improvements were higher in the low contextual interference group. The high contextual interference group showed no improvements (p > 0.05, ES = 0.28) after the intervention program. Our results suggested that the low contextual interference program is still more effective than the moderate contextual interference program in this group of primary school students. PMID- 26040076 TI - Macro-regional differences in motor abilities among the 5th grade primary school pupils in the Republic of Croatia. AB - The aim of this paper is to determine the differences in kinanthropological characteristics of elementary school pupils in relation to macro-regional characteristics of the Republic of Croatia. The research included 2358 subjects (1089 boys--average age 10.4 +/- 0.6; height 150.27 +/- 7.32; body mass 44.06 +/- 9.74; and 1269 girls--average age 10.6 +/- 0.5; height 152.02 +/- 7.74; body mass 45.12 +/- 10.39)--fifth grade elementary school pupils. Analyzed kinanthropological characteristics refer to statistically significant differences in the results based on the macro-region criterion (p < 0.05). It is possible to assume that climatic and temperature differences as well as gene frequency differences to a certain extent incite differences in the level of participating in physical activities, and with it the differences in kinanthropological characteristics of subjects. PMID- 26040077 TI - Nutritional knowledge and dietary habits survey in high school population. AB - During adolescence, young people are in a sensitive transition period when they gradually take over the responsibility for their own eating habits, health attitudes and behaviours and create lifelong habits so it is essential that they adopt healthy habits according to dietary recommendations. Knowledge is one of the factors necessary for the changes in dietary habits. The'objective of this study was to gain insight in nutritional knowledge and dietary habits of adolescents. The sample included 117 adolescents aged 17-19 years. Self administered, anonymous questionnaire, representing modified version of General Nutrition Knowledge Questionnaire was used to assess general characteristics, nutritional knowledge about nutrients, dietary recommendations, sources of nutrients, diet-disease relationship, and dietary habits. Less than one third of adolescents showed satisfactory knowledge, but boys, adolescents from rural environment and overweight adolescents showed significantly lower knowledge unlike others. Meal skipping was present habit, especially for breakfast consumption. Especially high consumption of meat and meat products was noted for boys, while fruit and vegetables for girls. Fad dieting was quite practiced habit, especially in girls and overweight adolescents. Among girls, high consumption of sweets was confirmed, while boys showed high consumption of soft drinks. Television presents the main source of infor- mation about nutrition for adolescents. Collected data shows similarity with other research in Europe and North America that confirm strong influence of globalization and fast spread of unhealthy habits. The results pointed out weak spots in nutritional knowledge and revealed unhealthy eating habits. This information is necessary for the development of new approaches to modulate their knowledge and consequently act on their behaviour. Behavioral changes would include higher number of meals per day, regular breakfast consumption, higher intake of fish, lower consumption of meat and meat products, sweetened foods and drinks etc. The final outcome would result in longterm positive impact on dietary habits. PMID- 26040078 TI - Morphological characteristics of adult male handball players considering five levels of performance and playing position. AB - This study aims 1--to describe and compare the anthropometric characteristics of male handball players from different levels of performance, and 2--to identify the morphological variables that allow differentiation of the level of performance for each individual playing position. A total of 212 male handball players (age, 23.6 +/- 5.2 years) were included in this study, and divided into five levels of performance for comparison. The playing position of each player was recorded. All participants were tested during the 2008-2009 Portuguese handball season. Twenty-eight anthropometric measures were taken by a group of anthropometrics accredited by International Society of the Advance of Kinanthropometry. Body composition, fat mass and muscle mass were calculated from the equations proposed by Faulkner26, Yuhase28, Durnin and Womersley25, Jackson and Pollock29, Matiegka33, Heymsfield, McManus, Smith, Stevens and Nixon34, Martin, Spenst, Drinkwater and Clarys21, Doupe, Martin, Searle, Kriellaars and Giesbrecht35 and Lee, Wang, Heo, Ross, Janssen and Heymsfield36. The research findings showed that the morphological optimization is important to have success in handball. PMID- 26040079 TI - Kinanthropometric comparison between young elite kayakers and canoeists. AB - The aims of this study were to describe and compare kinanthropometric characteristics of elite young kayakers and canoeists and to compare their proportionality with Olympic paddlers. One hundred and twenty young elite sprint paddlers (66 kayakers and 58 canoeists), aged 13- and 14-years-old, were assessed using a battery of 32 anthropometric dimensions. Somatotypes, Phantom Z-scores and corrected girths were calculated. Comparison between kayakers and canoeists showed that kayakers had greater height, body weight, sitting height, arm span and upper body lengths, breadths and girths than canoeists. Higher proportional humerus breadth and arm girths were also found in kayakers. However, canoeists had higher Z-scores in femur breadth. Olympic paddlers had higher proportional dimensions in upper body girths, and biacromial breadth in both disciplines. Mean somatotypes of kayakers were best described as balanced mesomorphs, while canoeists were ecto-mesomorphs. Differences between kayak and canoe paddlers may be explained by the continual need for physical development in kayakers, in order to remain competitive, compared to the young canoeists' need to place much greater emphasis on the development of their technical ability. The data provided in this study could be used as a guideline for talent identification in sprint canoeing and kayaking. PMID- 26040080 TI - Immunological status in patients with lower limb amputation due to peripheral arterial disease before and after comprehensive rehabilitation. AB - The immunological status before and after a comprehensive rehabilitation program was studied. Seven persons (4 males, 3 females, mean age 71.4 years) after lower limb amputation due to peripheral arterial disease (PAD) were subject to standard comprehensive rehabilitation program for amputees of four-week duration, which included training in activities of daily living, daily exercise of various types, training of crutch-assisted gait and use of leg prosthesis, and mild transcutaneous electrical stimulation. Before and after rehabilitation, peripherial blood was collected and the number and ratio of white blood cells were determined and analysed for the expression of cell surface antigens (CD3, CD4, CD8, CD19, CD25, CD69), cytokines (IFN-gamma, IL-4) and phagocytosis/oxidative killing functional tests. Due to strict patient selection criteria excluding serious accompanying disease, immunological parameters were within normal limits already before rehabilitation. After rehabilitation, an increase in oxidative burst was observed in monocytes and neutrophil granulocytes, but statistically significant only in monocytes. The expression of CD69 molecules by T cells and monocytes was significantly increased, as well as the expression of IL-4 by T cells. A significant decrease in the ratio of CD4 to CD8 cells was also found, but not a clinically critical one. It can therefore be concluded that the comprehensive rehabilitation treatment in patients with lower limb amputation due to PAD led to some--prevailingly positive--immunological changes, which were consistent with the patients' improved physical condition and clinical status. PMID- 26040081 TI - Differences in physical fitness among young tennis players in between 1992 and 2008. AB - The aim of this study was to find a trend of changes for selected anthropometric characteristics and motor abilities of young male and female tennis players of three different age groups. Trends were observed in the periods between 1992, 2000 and 2008. In addition, a comparison of results of tennis players and school pupils was included. The sample of subjects were selections of young tennis players and of primary and secondary schools pupils (boys and girls) divided into three age groups (12- to 13-year-olds, 14- to 15-year-olds, and 16- to 17-year olds). Fitness tests items (backwards obstacle course, forward bend on the bench, 20-second hand-tapping, 60-second sit-ups) and three anthropometric measurements (body height, body weight, BMI) were included in this study. The analysis of trends for different periods of measurement in male and female tennis players revealed an increase in some test items and a decrease in others. In the majority of observed fitness test items, young tennis players performed better than their school peers, indicating the positive effects of training and an appropriate selection process of tennis players. Male and female tennis players were taller than the school pupils, and body height values in both groups increased from 1992 to 2008. The body weight and BMI values for male and female tennis players, and male and female pupils in all three age groups have been constantly increasing. PMID- 26040082 TI - Analysis of Cesarean section delivery at Nova Bila Hospital according to the Robson classification. AB - An increase in Cesarean section birth rate is evident worldwide, especially in developed and developing countries. Since this trend is rapidly gaining epidemic status with unpredictable consequences regarding the reproductive and overall women's health, there is a need for systematic collection and analysis of Cesarean section occurrence data. At this moment, there is no standardized, internationally accepted classification that would be easy to understand and simple to apply. In 2001, Robson Cesarean section classification in ten groups, which might satisfy good classification criteria, was published. In this paper, we have retrospectively collected and sorted the data on Cesarean section births from the "Dr. Fra Mato Nikolic" Croatian Hospital in Nova Bila, according to Robson classification, for the period from January 1st, 1998 to December 31st, 2007. During this period, 6603 women have given birth. Of these, 1010 opted for Cesarean sec- tion (15.30%). The largest group of women giving birth belongs to group 3 (multiparous, single pregnancy, head down, 37 weeks gestation age or more, spontaneous labor), where 49.74% of all the analyzed births belong. The largest group for those with Cesarean sections is group 5 (previous Cesarean section) with 26.93% of all the Cesarean sections. Our results are similar to the results of studies done elsewhere in the world. Robson classification identifies the risk groups with high Cesarean section percentage and is appropriate for long term tracking and international comparison of the recognized increase of the Cesarean section trend. PMID- 26040083 TI - Temporomandibular disorders and orthodontic treatment need in orthodontically untreated children and adolescents. AB - The aim of this study was to explore the association between signs and symptoms of temporomandibular disorders (TMD) and orthodontic treatment need in orthodontically untreated children and adolescents. One thousand five hundred and ninety-seven subjects aged 11-19 years, without previous orthodontic history, from sixteen randomly selected public schools in Zagreb, Croatia, were examined. Malocclusion characteristics were assessed by using the criteria proposed by Bjork et al., the Dental Aesthetic Index, and the Aesthetic Component of Index of Orthodontic Treatment Need. Data on TMD signs/symptoms and parafunctional behaviour were obtained by means of questionnaire and clinical examination, respectively. Multiple logistic regression models were used for analysis. Twenty two percent of children and young adolescents had one or more signs of TMD, ranging from 17% in age of 11 years up to 24% in age of 19. There was poor correlation between presence of TMD and orthodontic treatment need. Multiple logistic regression models showed that Class III, crowding and spacing were related to mandibular deflection on opening. Ectopic eruption was related to TMJ clicking, and severely tipped teeth with reduced mouth opening. Headaches presented a positive relationship with reverse overjet and severe rotations, and tooth wear with crowding, spacing and lateral openbite. Age, female gender and parafunctional habits were related to several TMD signs. Although logistic regression models were statistically significant (p < 0.05) malocclusions, parafunctional behaviours, age and gender accounted for less than 20% of the variability in TMD signs/symptoms. TMD signs and symptoms seemed to be poorly related to malocclusions or treatment needs. PMID- 26040084 TI - Movements of temporomandibular condyles during swallowing. AB - There have been studies that investigated mandibular movements and positioning during swallowing, but the results were inconsistent, and still the exact position of the condyles during swallowing is unknown. The purpose of this investigation was to study the kinematics of the mandible and the condyles, and to determine the actual movement paths and position of mandible and condyles during the process of swallowing. The study was performed on a sample of 44 dental students. Measurements were done with an electronic axiograph. After non occlusing attachment was fixed in the mouth, every subject swallowed for five times from the rest position. The final swallowing position of the left and the right condyles was measured in the sagittal plane. The final swallowing position of the sagittal incisal point was measured in sagittal, frontal and horizontal plane, and data was statistically analyzed. The condyles showed average movement toward posterior (left 0.17 mm, SD 0.28, right 0.16 mm, SD 0.25) and superior (left 0.14 mm, SD 0.20, right 0.14 mm, SD 0.23). Anterior and/or inferior position had 20% of participants. The average sagittal incisal point movement during swallowing was toward anterior (0.30 mm, SD 0.53) and superior (0.81 mm, SD 0.84). The mean mandibular lateral movement was 0.1 mm (SD 0.1). The results of the study suggest that retrusion during swallowing is not the rule, although on average there is a slight tendency of condylar movement toward posterior. Swallowing can be used as auxiliary method for determining vertical dimension of occlusion. PMID- 26040085 TI - The lymph node roundness index in the evaluation of lymph nodes of the neck. AB - The study assessed the validity of the lymph node "roundness index" (RI) in the evaluation of enlarged lymph nodes of the neck. A total of 107 subjects were included in the prospective study, and 135 enlarged lymph nodes were examined. All the subjects were examined clinically and sonographically, the lymph node roundness index was determined, and soon after the nodes was surgically removed and pathohistologically diagnosed. On the basis of pathohistological diagnosis the study subjects were divided into two groups. The first group consisted of patients with benign lymph nodes, and the second one comprised patients with malignant nodes. The second group was further divided into two sub-groups: those with primary malignant nodes and those with secondary lymph nodes (metastases). The study showed that the lymph node RI statistically differs between the groups. In benign lymphadenopathy the RI was 1.66 +/- 0.26, in primary malignant lymphadenopathy it was 1.31 +/- 0.25 and in secondary malignant lymphadenopathy 1.13 +/- 0.11. The analysis demonstrated that 82.9% of subjects randomly chosen from the group with primary malignant lymphadenopathy and 94.6% from the group with the secondary malignant lymphadenopathy have a smaller RI compared to randomly chosen subjects from the group with benign lymphadenopathy. Sensitivity of the method for primary malignant lymphadenopathy was 66.7% and specificity was 92.9%. For secondary malignant lymphadenopathy the sensitivity was 95.5% and specificity 92.9%. Based on this result we can conclude that the lymph node RI is a valid, simple, cost-effective and non-aggressive method which may "increase the suspicion" for a benign or malignant lymphadenopathy. RI <= 1.5 is indicative of malignant lymphadenopathy and RI >= 1.5 of benign lymphadenopathy. PMID- 26040086 TI - A case of extensive inflammatory changes (osteomyelitis) in an infant's skeleton from the medieval burial ground (11th-12th c) in Wawrzenczyce (near Krakow). AB - The aim of this study was to diagnose and describe extensive inflammatory changes in a child's skeleton from Wawrzenczyce, (the medieval period). The aim of the analysis was to determine the nature of the inflammatory changes and their etiology by means of macroscopic techniques as well as X-ray analysis. The tests revealed that the individual suffered from a hematogenous multifocal osteitis. This condition might have been a result of an acute or sub-acute osteitis, and the untreated form of osteomyelitis might have contributed to the infection of the entire developing organism, leading to death. PMID- 26040087 TI - Modified cotton socks--possibility to protect from diabetic foot infection. AB - Diabetes has become a major public health problem and grows rapidly in the most developed countries of the world. Beside genetic and environmental factors, lifestyle habits play an important role in the development and progression of diabetes mellitus. According to the World Health Organization (WHO) about 15% of diabetic patients develop a foot ulcer in need of medical care. Infection is a serious complication and it is the major responsible cause of lower limb amputation. In this paper the possibility to protect from diabetic foot infection with modified cotton socks. Therefore, the socks made of modified cotton yarn by natural minerals and active carbon were investigated in vitro (fabric hand friction and adsorption) and in vivo (3 IDDM, 4NIDDM, 3 GDM to sweat and fabric hand) to accomplish highest possible level of comfort for diabetic patients. Antimicrobial protection to Gram positive, Gram negative and micro fungi was determined as well. For durability all the characteristics were investigated after 15 washing cycles. PMID- 26040088 TI - Ergonomic suitability of kitchen furniture regarding height accessibility. AB - It is possible to significantly ease kitchen chores with properly sized and appropriately arranged cupboards. In designing kitchen furniture and the optimal depth and the height of storage capacities, accessibility should be taken into consideration. It is known that the optimal storage zone is between 800 and 1100 mm and that there is reduced visibility and accessibility at the level between 1400 and 1700 mm, which is even more prominent for the elderly. This suggests that wall cabinets are not recommended for the elderly. The aim of this study was to determine to what extent kitchens manufactured by Slovenian furniture manufacturers are suitable for users of different age groups with regard to the accessibility of goods stored in the cupboards. Furthermore, based on the measurement analysis, recommendations are provided for designing kitchen furniture that would meet the needs of the elderly. The study, carried out using a computer simulation model, analyzed the products of three Slovenian kitchen manufacturers. The cross section of accessibility in the wall cabinets was determined for different age groups of men and women. The results show that the efficacy of the volume in wall cabinets higher than 600 mm, in comparison to places where objects are easily reachable, is 30% lower for women, thus indicating the inefficiency of storage space in wall cabinets. In terms of accessibility, existing kitchens are not optimal for the elderly, and a model with a deeper worktop and wall cabinets lowered onto the worktop is proposed. Accessibility in such wall cabinets is increased by up to 70% if the body is moved forward by 30 degrees . PMID- 26040089 TI - Metaphors about violence by preservice teachers. AB - Violence consists of a pattern of coercive behaviors used by a competent adult or adolescent to establish and maintain power and control over another competent adult or adolescent. These behaviors, which can occur alone or in combination, sporadically or continually, include physical violence, psychological abuse, talking, and nonconsensual sexual behavior. Research indicates that different types of violence are used as a means of enforcing discipline in the family and the school context. Children and adolescents who grow up in an environment where violence has a natural place tend to resort to violence at every stage of their lives without question. The aim of this research was therefore to preservice teachers' perception of the concept of violence through the use of metaphors. Accordingly, answers to the following questions were sought: What metaphors do the youth use to describe the concept of violence? Under which conceptual categories can these metaphors be grouped in terms of their common features? How do the conceptual categories vary in relation to the students' gender and the subjects they study at university? The study was conducted in 2009 with the help of 303 students at Mersin University and Eskisehir Osmangazi University (Faculty of Education). Incomplete statements such as "Violence is like..., because..." were used in an attempt to understand the students' perception of violence. The students were given questionnaire to complete the statements. Demographic questions were also asked on the students'age, gender and departments. The data were analyzed through qualitative analysis, and processes such as frequency distribution and quantitative correlation data were evaluated through SPSS data analysis. It emerged that the students used 74 metaphors of violence that could be divided into seven categories: (1) Violence as a way of controlling others; 2) Violence as part of social and affective life; (3) Violence as devastation; (4) Violence as learned helplessness; (5) Violence as a consequence of poor communication; (6) Violence as a phenomenon with psychological and physical effects; (7) Violence as a state of mind with long-term ongoing effects. The findings on these categories are presented and recommendations made. The analysis of the research results according to the students' departments indicated that the metaphors describing violence were grouped mainly under the theme (category) of "Violence as a way of controlling others". As the students in these fields of study received an education focused more on concrete and precise facts, they tended to perceive violence in a more conceptual way. PMID- 26040090 TI - Reply on: "Thermography is not a feasible method for breast cancer screening" by Brkljacic et al. PMID- 26040091 TI - Sudden death due to swimming in elderly women. AB - The aim was to analyze the rate of sudden death in elderly Croatian women in comparison to elderly Croatian men, who died suddenly due to swimming. In the period from 2002 to 2011 one elderly Croatian woman and five elderly men died suddenly during swimming. In the same time, the same number of elderly foreigners died due to swimming at the Croatian Adriatic coast. One Croatian woman aged 66, who suffered of arterial hypertension with left ventricular hyper- trophy of 15 mm, diabetes mellitus and alcoholic liver cirrhosis, drowned in the sea during swimming. She was intoxi- cated with alcohol and had alcohol level in urine of 3.03 per thousand. One foreign woman, aged 82, who suffered coronary heart disease with left ventricular scar after myocardial infarction, arterial hypertension with excessive left ventricular hypertrophy of 22 mm and nephroangiosclerosis, suddenly lost conscionsness during swimming. The death rate in elderly Croatian women due to swimming reached 0.25, and the death rate in men is eight times higher: 1.97 (p = 0.0701), but the difference is not significant probably because of a small observational number. PMID- 26040092 TI - Mastoid trepanation in a deceased from medieval Croatia: a case report. AB - We present a rare case of infratentorial mastoid trepanation, by drilling, from medieval Croatia. An artificial ante-mortal opening was found in a male skeleton from the 11th century cemetery Zvonimirovo. It was placed roughly at the intersection of the Frankfurt's plane and the midline of the right mastoid. The right posterior parietal of the deceased also exhibited a callus-like formation consistent with the linear cranial fracture. Our aim was to investigate by computed tomography (CT) a possible presence of otopathology--a chronic middle ear infection--MEI/mastoiditis or cholesteatoma. On the other hand, both standard radiography and CT were employed in a cranial fracture diagnostic agreement. The generated CT scans confirmed the presence of an artificial hole running into a well defined trepanne canal connected with the antrum. The presence of otopathology was not established. The radiography and CT substantiated the presence of a linear posterior parietal discontinuity--without displacement, in front of the right lambdoid suture. From the medical point of view, it would be unusual to perform infratentorial--mastoid trepanation for reasons of treating supratentorial trauma, i.e. possible posttraumatic acute subdural hematoma (PTASDH). However, since there was a lack of CT evidence of osteolysis in ME, there is a possibility of medieval trepanation procedure performed for reasons of posttraumatic treat- ment. To our best knowledge, usually, ancient trepanations described in Croatian bioarchaeology and all over the world are supratentorial and do not always reveal such sophisticated surgical techniques. PMID- 26040093 TI - Myxoma of the zygomatic bone--a case report. AB - Myxoma is a benign tumor composed of primitive connective tissue cells and mesenchymal mucousal stroma. Also referred to as, a gelationus or colloidal tumor. Although rare, it can be found in the atrium of the heart, and it is the most common heart tumor. It has also been described in other body sites, one of which is the bone. We report a case of a 57-year-old female patient, with recurrent headaches located in the area of the right half of the face. Radiological analysis (Multislice Computed Tomography of the paranasal sinuses and viscerocranium) was performed, and a formation of irregular contours, destroying the right zygomatic bone, was described, measuring 25 x 17 x 20 mm in its widest diameters. Its me- dial border was adjacent to the lateral wall of the right maxillary sinus and the cortical bone in this segment was thinned, but preserved. A probatory excision was performed in general anesthesia, and the histopathological finding showed, star-like tumor cells embedded in mucoid stroma and infiltrating the bone. After pathohistological confirmation of myxoma, the tumor was excised in total, using infraorbital surgical approach to the zygomatic bone. During the follow-up, the patient was symptom free, without headaches, and there were no signs of local tumor recurrence. Despite of the fact that myxoma behaves as a benign disease in its nature, it can cause destruction of the tissue in the vicinity of the tumor itself and thus major health issues for the patient. A timely proper diagnosis and the right choice of a surgical treatment can help avoid more extensive surgery procedures, as shown in our case report. PMID- 26040094 TI - A coincidence of HLA-B27 negative spondyloarthritis and paravertebral non Hodgkin's lymphoma--a lesson to be learnt from the past experience. AB - We reported a case of a 71-year-old woman with progressive low back pain and neurologic symptoms of lower extremities, who in the background had the coexistence of spondyloarthritis (SpA) and non Hodgkin's lymphoma of the paravertebral location. This example describes a situation where SpA with minimal sacroiliac joints affection has nevertheless led to the overt axial SpA. This situation included undifferentiated or reactive SpA, as well as unusual disease context, presented with late-life disease onset, older age, female gender and no obvious hereditary predisposition. This combination of comorbid factors could allow environmental and disease-specific factors to accumulate over time and to, by modifying the primary, low-penetrant genetic background, lead to the development of lymphoma. By achieving better understanding of disease pathophysiology dynamic, we will be able to improve our capabilities to navigate biologic therapy in the future, in order to prevent the development of both, overt SpA and lymphoproliferative disease. PMID- 26040095 TI - Morphological manifestations of the Dandy-Walker syndrom in female members of a family. AB - The Dandy-Walker syndrome (DWS) is a hereditary disorder, appearing somewhat more frequently in women. The most important characteristics of the DWS are the lack of the cerebellar vermis, varying from a partial lack to a complete agenesis, and enlargement of the cerebrospinal spaces, especially in the fourth ventricle. The above mentioned morphological changes clinically manifest in ataxia, increased intracranial pressure and hydrocephalus. Here is presented a family with DWS, where the disease is contracted only by female members, in two generations, whereas no signs of DWS have been noticed in male family members. DWS is clinically manifested from early childhood to middle age, with the morphological changes varying from hypoplastic cerebellar vermis to widening of the brain ventricles and hydrocephalus and arachnoid cyst in the occipital part. PMID- 26040096 TI - The level of improvement of visual acuity in high corneal astigmatism with rigid gas permeable contact lenses. AB - The aim of this study was to calculate the level of improvement of visual acuity comparing the best corrected visual acuity (VA) achieved with spectacles with the best corrected VA achieved with rigid gas permeable (RGP) contact lenses in patients with high, simple or compound corneal astigmatism (myopic, hypermetropic and mixed). The investigation of patients included auto-kerato-refractometry, manual keratometry, corneal topography and visual acuity with Snellen chart. The best corrected VA obtained with spectacles was compared with the best corrected VA obtained with RGP contact lenses in 72 patients (116 eyes). All patients showed a significant improvement in visual acuity with RGP lenses from one to seven lines compared to spectacles (p = 0.0001). Level of improvement in VA represented as the number of lines obtained was as follows: 74 percent of patients got two to four lines more in VA with RGP lenses compared to spectacles, and almost 10 percent of patients got five to seven lines. RGP contact lenses provide a significant improvement in VA compared to VA reached with spectacles in patients with high corneal astigmatism. The benefit in VA with RGP lenses is higher as the astigmatism is higher. PMID- 26040097 TI - Comparison of IOL--master and ultrasound biometry in preoperative intra ocular lens (IOL) power calculation. AB - Postoperative refractive outcome largely depends on the accuracy of calculating power of implanted IOL. Lens power calculation can be done by conventional ultrasound biometry and partial coherence laser interferometry (IOL Master). The aim was to compare the accuracy of IOL power calculations using conventional ultrasound biometry and partial coherence laser interferometry.40 eyes were included in this prospective randomized trial. Twenty eyes underwent IOL master and 20 eyes had aplanation ultrasound biometry. There were included only eyes with age-related cataract and postoperative natural visual acuity (VA) 0.7. Visual acuity was performed 6 weeks after cataract surgery. After 6 weeks best natural visual acuity were 0.9 (+/- 0.1) in IOL-Master group and 0.85 (+/- 0.15) in ultrasound biometry. The postoperative mean absolute refractive error was 0.75 (+/- 0.5) D for ultrasound biometry and 0.50 (+/- 0.50) D for IOL-Master. Optical biometry with the IOL-Master proved to be slightly more accurate than ultrasound biometry for IOL power calculation. PMID- 26040098 TI - Capsular tension ring in damaged zonules. AB - Capsular tension ring (CTR) is endocapsular support device important during cataract surgery in eyes with weak zonular apparatus. It was presented our experience, advantages and limitations of CTR in phacoemulsification cataract surgery with damaged zonules. Phacoemulsification surgery was performed by clear corneal technique using topical anesthesia. Capsular ring was implanted to stabilize the capsular bag before implantation of intraocular lens. CTR has become increasingly important in the management of zonular weakness during cataract extraction. It lowers the incidence of capsule contraction, stabilizes the capsular bag and enhances IOL centration. PMID- 26040099 TI - Combined procedure of phacoemulsification and implantation of Ex-PRESS miniature glaucoma shunt. AB - Glaucoma patients not responding to maximum medical therapy with coexistent cataract are candidates for combined cataract and glaucoma therapy. There are different therapy models. The choice of therapy depends on numerous patient and surgeon related factors. Ex-PRESS mini glaucoma shunt is a modified trabeculectomy and can be combined with cataract surgery when indicated. In this paper we presented our experience with this combined procedure. Our results showed good intraocular pressure control and visual acuity improvement, comparable to other therapy choices. PMID- 26040100 TI - The influence of retinal eye diseases on painting. AB - In this work the possible influences of some retinal eye problems on paintings of several famous artists are considered. The change of painting styles and artistic expression in different periods and ages in a group of world-wide well-known painters are described and correlated with known or suspected retinal diseases. Some of them largely became recognizable because of that. Contemplations are offered about the effects of retinal diseases in the works of Degas, Munch, Cezanne, O'Keeffe, Constable and Goya. Retinal eye diseases have a significant impact on the work of selected famous painters. PMID- 26040101 TI - Cluster analysis as a prediction tool for pregnancy outcomes. AB - Considering specific physiology changes during gestation and thinking of pregnancy as a "critical window", classification of pregnant women at early pregnancy can be considered as crucial. The paper demonstrates the use of a method based on an approach from intelligent data mining, cluster analysis. Cluster analysis method is a statistical method which makes possible to group individuals based on sets of identifying variables. The method was chosen in order to determine possibility for classification of pregnant women at early pregnancy to analyze unknown correlations between different variables so that the certain outcomes could be predicted. 222 pregnant women from two general obstetric offices' were recruited. The main orient was set on characteristics of these pregnant women: their age, pre-pregnancy body mass index (BMI) and haemoglobin value. Cluster analysis gained a 94.1% classification accuracy rate with three branch- es or groups of pregnant women showing statistically significant correlations with pregnancy outcomes. The results are showing that pregnant women both of older age and higher pre-pregnancy BMI have a significantly higher incidence of delivering baby of higher birth weight but they gain significantly less weight during pregnancy. Their babies are also longer, and these women have significantly higher probability for complications during pregnancy (gestosis) and higher probability of induced or caesarean delivery. We can conclude that the cluster analysis method can appropriately classify pregnant women at early pregnancy to predict certain outcomes. PMID- 26040102 TI - Working group for trichinellosis--a way of systematic prevention, control and eradication of trichinellosis in the Republic of Croatia. AB - At the end of the last century, human trichinellosis was an important public health problem in the eastern parts of Croatia. Moreover, the majority of clinically infected people were registered in Vukovar-Srijem County (up to 60% of all human cases registered in Croatia). Also, 95% of all Trichinella positive swine carcasses originated from Vukovar-Srijem County. Beside the health threat, trichinellosis implied not only notable economic expenses but also threatened to endanger traditional way of life and eating habits. In order to reduce all negative consequences of the disease, a multidisciplinary Working group for trichinellosis was founded. The group consisted of scientists and experts from different fields of work, who helped and significantly contributed to minimizing the threats of trichinellosis as well as to maintaining and preserving the method of traditional processing and consumption of swine meat. The members, the methods and the results of the Working group activities will be discussed in this paper. PMID- 26040103 TI - Genetic determination of motor neuron disease and neuropathy. AB - Following the completion of the Human Genome Project, a lot of progress has been made in understanding the genetic basis of motor neuron diseases (MNDs) and neuropathies. Spinal Muscular Atrophies (SMA) are caused by mutations in the SMN1 gene localized on Chromosome 5q11. Amyotrophic Lateral Sclerosis (ALS) has been found to have at least 18 different types, many of them associated to different genetic loci (e.g. SOD1, ALS2, SETX, FUS, VAPB, ANG, TARDBP and others), but many of the forms have still not been associated with a particular gene. Sensomotoric hereditary neuropathies (Charcot-Marie-Tooth) are a large heterogeneous group of various hereditary neuropathies, which have also been associated with a wide spectrum of genetic mutations, such as PMP22, LITAF, EGR2, P0 protein, KIF1B, MFN2, RAB7 and others. It is also apparent that more genes are being implicated, mutations discovered, and phenotypes recognised and broadened. Therefore, a lot of continuing, additional research effort will be required in the coming years to illuminate pathogenic mechanisms that underlie motor neuron diseases and neuropathies and that could lead to new and improved treatments. PMID- 26040104 TI - Recent diagnostic and therapeutic approaches to prenatally and perinatally diagnosed hydronephrosis and their implementation in the University Clinical Hospital Mostar. AB - A shift of the diagnostics of urological malformations towards the fetal age by means of ultrasound, especially hydronephrosis which, apart from reflux, is the most frequent developmental urological disorder, opened many dilemmas and debates. In the course of more than three decades the application of this diagnostic approach to the problem of hydrone- phrosis became a routine clinical practice in all modern clinics. In this paper we present the problems related to this diagnostic method and its delayed application in the Mostar University Clinical Hospital. Along with the exposition of a general approach to the problem of hydronephrosis we briefly present our modest collection of cases which points to the most recent trend of a vigorous medical development in this region, despite unfavorable overall conditions which prevailed so far. The observation included 56 children with prenatal, perinatal and early age determination of pyelon dilatation by means of ultrasonic exploration who were treated surgically. Of this number 32 (57.14%) were male, and 24 (42.86%) female children. Of the observed patients 56 had unilateral and 6 had bilateral pyelon dilatation so that 62 kidneys in all were observed and treated. The dilatation was determined prenatally in 24 (38.7%) out of 62 kidneys observed in all, in 7 (11.29%) the disorder was observed perinatally and in remaining 31 cases (49.9%) it manifested during early childhood, school age, even at the age of pre-puberty. Of the children with prenatally and perinatally determined dilatation, in 14 (45.16%) out of 31 (100.0%) observed kidneys the ap radius of the dilated pyelon was between 10-15 mm, and in 17 (54.84%) more than 15 mm. Along with other examinations (MAG3 and DMSA) the patients were followed-up by ultrasonic exploration of the observed kidney for 6 to 30 (average 18) months after postnatal diagnosis; the ultrasonic exploration was repeated in intervals of 6 months. Within 12 months of birth surgical intervention on the pyeloureteral junction was done on all 17 kidneys with an ap radius of the pyelon greater than 15 mm, as well as on 4 kidneys in which ap radius was between 10 and 15 mm. In other 10 kidneys with prenatally and perinatally determined ap radius of 10 to 15 mm the follow-up period was 25 to 30 months (average 275). As the examinations (ultrasound, MAG3 and DMSA) even after this period showed no signs of regression of the dilatation, nor an improvement in patency this provided an indication for surgical intervention with the aim of establishing a normal flow across the pyeloureteral junction. Antibiotic prophylaxis was not applied systematically, but in a targeted manner if the uroinfection was confirmed clinically and in the lab. Through the presentation of cases we demonstrate the relationship of earlier and more recent procedures in the treatment of hydronephrosis in the gravitational area of the Mostar University Clinical Hospital. The fact that some children were subjected to surgical treatment due to hydronephrosis at the time of pre-puberty reflects earlier views on this clinical entity. The successfulness of surgical treatment of hydronephrosis in the observed patients is complete and comparable to medically more developed environments, and our diagnostic capabilities are getting close to that level too. We specially wish to stress the recent introduction of ultrasonic examination of pregnant women and foetus in the third trimester with the aim of an early detection of anomalies and malformations of the urotract as an indicator of a marked medical devel- opment. On the global level there are still inconclusive and opposing opinions on this subject, as is seen in recent literature. The controversies relate to the diagnostics as well as to therapy. PMID- 26040105 TI - Some reflections on human needs, peace, transculturality and Igbo proverbs in the light of Emmanuel Edeh's African philosophy. AB - Within the framework of a transcultural, psychodynamic and holistic approach, Edeh's concept of Man as Mma-di (in Igbo language in Nigeria, mma-di = good that is, and mma-ndu = the beauty of Life) is presented as the nucleus of his philosophical articulation from an African metaphysical-anthropological perspective. In this context, some reflections are shown on the following topics: human creativity and peace... of mind, body and soul, as existential values and entity in bioethics; aspects of Edeh's philosophy and his work on the peace in the world; transculturality and Igbo proverbs shaped in form of Japanese Haiku poetry. These reflections emphasize the importance of induced aesthetic mental state in the subject, which derives from biological impulses but from archetypal and symbolic value of the object and continuously enter into a metaphysical experience as a form of life energy and human existential need. In this context, we discover also Edeh's philosophy as a new stimulus for further reflections and research on human life potentials, creativity, peace and Man's cosmic responsibility. PMID- 26040106 TI - Beta catenin is degraded by both caspase-3 and proteasomal activity during resveratrol-induced apoptosis in HeLa cells in a GSK3beta-independent manner. AB - Increased activity of beta-catenin, an important transcriptional activator for survival and proliferation-associated genes has been linked with many cancers. We examined whether beta-catenin is a target of resveratrol and whether its degradation contributes to the pro-apoptotic effects of resveratrol. HeLa cells were exposed to 60 MUM resveratrol for 48 h. Apoptosis was confirmed by measurement of annexin V externalization, caspase-3 activation and DNA fragmentation. Induction of apoptosis was observed as early as 12 h, when both caspase-3 activation and PARP (poly ADP ribose polymerase) cleavage occurred. Nuclear beta-catenin levels remained unchanged for 48 h during resveratrol exposure. However, extranuclear cell lysate beta-catenin underwent a decrease at a late stage of apoptosis namely at 36-48 h. Alterations in the phosphorylation status of Akt/GSK3beta were not observed during resveratrol-induced apoptosis. Furthermore, inhibition of GSK3beta activity which is. largely responsible for beta-catenin degradation failed to influence beta-catenin stability. However, inhibition of caspase-3 activity prevented the decline in beta-catenin levels at 36-48 h of resveratrol exposure. Lactacystin, a proteosomal inhibitor also prevented the degradation of beta-catenin by resveratrol. In conclusion, resveratrol induced apoptosis in HeLa cells in an Akt/GSK3beta-independent manner and down-regulated beta-catenin levels during apoptosis through action of caspase 3 and proteasomal degradation, independent of GSK3beta-mediated phosphorylation. PMID- 26040107 TI - Effect of different serine protease inhibitors in validating the 115 kDa Leishmania donovani secretory serine protease as chemotherapeutic target. AB - Proteases have been considered as an important group of targets for development of antiprotozoal drugs due to their essential roles in host-parasite interactions, parasite immune evasion, life cycle transition and pathogenesis of parasitic diseases. The development of potent and selective serine protease inhibitors targeting L. donovani secretory serine protease (pSP) could pave the way to the discovery of potential antileishmanial drugs. Here, we employed different classical serine protease inhibitors (SPIs), such as aprotinin, N-tosyl 1-phenylalanine chloromethyl ketone (TPCK), N-tosyl-lysine chloromethyl ketone (TLCK), benzamidine (Bza) and pSP-antibody to determine the role of the protease in parasitic survival, growth and infectivity. Among the different classical SPIs, aprotinin appeared to be more potent in arresting L. donovani promastigotes growth with significant morphological alterations. Furthermore, aprotinin and anti-pSP treated parasites significantly decreased the intracellular parasites and percentage of infected macrophages. These results suggest that SPIs may reduce the infectivity by targeting the serine protease activity and may prove useful to elucidate defined molecular mechanisms of pSP, as well as for the development of novel antileishmanial drugs in future. PMID- 26040108 TI - Analyzing resistance pattern of non-small cell lung cancer to crizotinib using molecular dynamic approaches. AB - Crizotinib is the potential anticancer drug used for the treatment of non-small cell lung cancer (NSCLC) approved by FDA in 2011. The main target for the crizotinib is anaplastic lymphoma kinase (ALK). Evidences available indicate that double mutant ALK (L1196M and G1269A) confers resistance to crizotinib. However, how mutation confers drug resistance is not well-understood. Hence, in the present study, molecular dynamic (MD) simulation approach was employed to study the impact of crizotinib binding efficacy with ALK structures at a molecular level. Docking results indicated that ALK double mutant (L1196M and G1269A) significantly affected the binding affinity for crizotinib. Furthermore, MD studies revealed that mutant ALK-crizotinib complex showed higher deviation, higher fluctuation and decreased number of intermolecular H-bonds, when compared to the native ALK-crizotinib complex. These results may be immense importance for the molecular level understanding of the crizotinib resistance pattern and also for designing potential drug molecule for the treatment of lung cancer. PMID- 26040109 TI - Serum neuron-specific enolase and S-100beta levels as prognostic follow-up markers for oxygen administered carbon monoxide intoxication cases. AB - Serum neuron-specific enolase (NSE) and S-100beta levels are considered novel biochemical markers of neuronal cell injury. In this study, the initial and post treatment levels of NSE and S-100beta were compared in carbon monoxide (CO) poisoning patients, who received normorbaric oxygen (NBO) or hyperbaric oxygen (HBO) therapy. Forty consecutive patients with acute CO poisoning were enrolled in this prospective, observational study. According to their clinical symptoms and observations, twenty patients were treated with NBO, and the other twenty with HBO. Serum S-100beta and NSE levels were measured both at time of admission and 6 h later (post-treatment). Serum NSE and S-100beta values decreased significantly in both of the therapeutic modalities. The initial and post treatment values of NSE and S-100beta in NBO or HBO patients were comparable. A clear negative correlation was observed between the decrease of NSE and S-100beta levels and initial blood carboxyhemoglobin levels. In conclusion, the present results suggested the use of serum S-100beta and NSE levels as indicators for brain injury. Due to the significant increase of their values with oxygen therapy, they may also be useful as prognostic follow-up markers. However, the current findings reflected no difference between the efficacy of NBO or HBO therapy. PMID- 26040110 TI - Computational prediction of MHC class I epitopes for most common viral diseases in cattle (Bos taurus). AB - Viral diseases like foot-and-mouth disease (FMD), calf scour (CS), bovine viral diarrhea (BVD), infectious bovine rhinotracheitis (IBR) etc. affect the growth and milk production of cattle (Bos taurus) causing severe economic loss. Epitope based vaccine designing have been evolved to provide a new strategy for therapeutic application of pathogen-specific immunity in animals. Therefore, identification of major histocompatibility complex (MHC) binding peptides as potential T-cell epitopes is widely applied in peptide vaccine designing and immunotherapy. In this study, MetaMHCI tool was used with seven different algorithms to predict the potential T-cell epitopes for FMD, BVD, IBR and CS in cattle. A total of 54 protein sequences were filtered out from a total set of 6351 sequences of the pathogens causing the said diseases using bioinformatics approaches. These selected protein sequences were used as the key inputs for MetaMHCI tool to predict the epitopes for the BoLA-All MHC class I allele of B. taurus. Further, the epitopes were ranked based on a proposed principal component analysis based epitope score (PbES). The best epitope for each disease based on its predictability through maximum number of predictors and low PbES was modeled in PEP-FOLD server and docked with the BoLA-A11 protein for understanding the MHC epitope interaction. Finally, a total of 78 epitopes were predicted, out of which 27 were for FMD, 25 for BVD, 12 for CS and 14 for IBR. These epitopes could be artificially synthesized and recommended to vaccinate the cattle for the considered diseases. Besides, the methodology adapted here could also be used to predict and analyze the epitopes for other microbial diseases of important animal species. PMID- 26040111 TI - Structural analysis and molecular docking of potential ligands with chorismate synthase of Listeria monocytogenes: a novel antibacterial drug target. AB - Listeriosis, in particular that caused by Listeria monocytogenes, is a major foodborne pathogen, and its control is becoming difficult because of widespread emergence of drug resistance strains. Chorismate synthase (CS), an essential enzyme of shikimate pathway present only in bacteria, fungi, plant and some apicomplexan parasites, is a validated potential antimicrobial drug target. Antimicrobial development through the elucidation of essential structural features of the CS of L. monocytogenes (LmCS), identification and prioritization of potential lead compounds targeted against LmCS were done. Structure-based virtual screening and docking studies were performed using Autodock tools to retrieve potential candidates with high affinity binding against LmCS model from several ligand repositories. The potency of binding was also checked with other structurally similar CS from Streptococcus pneumoniae (SpCS) and Mycobacterium tuberculosis (MtCS). The sequence and structural studies revealed LmCS was similar to be other CS structures (1Q1L, 1QXO, 1R52, 1R53, 1SQ1, 1UMO, 1UMF, 1ZTB, 2011, 2012, 4ECD and 2G85) with each monomer presenting beta-alpha-beta sandwich topology with a central helical core. Molecular docking studies and ADME/Tox results revealed that ZINC03803450 and ZINC20149031 were most potent molecules binding into the active site of LmCS. Other two ligands ZINC13387711 and ZINC16052528 showed a strong binding affinity score against all three structures (LmCS, SpCS and MtCS) and bind to LmCS with the predicted inhibition constant (K(i)) values of 22.94 nM and 35.84 nM, respectively. A reported benzofuran-3[2H]-one analog CHEMBL135212 with good ADME/Tox properties and experimental IC50 (nM) value of 7000 nM with SpCS could also be considered as a potential inhibitor of LmCS, as compared to previously reported 41 benzofuran 3[2H]-one analogs against SpCS. This information will assist in discovering those compounds that may act as potent CS inhibitors. Further experimental studies and evaluation of structure-activity relationship could help in the development of potential inhibitors against listeriosis, as well as antibacterial chemotherapy. PMID- 26040112 TI - Purification, characterization and synthetic application of a thermally stable laccase from Hexagonia tenuis MTCC-1119. AB - A thermally stable laccase was purified from the culture filtrate of Hexagonia tenuis MTCC-1119. The method involved concentration of the culture filtrate by ammonium sulphate precipitation and an anion-exchange chromatography on diethylaminoethyl (DEAE) cellulose. The sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and native polyacrylamide gel electrophoresis (native-PAGE) both gave single protein bands, indicating that the enzyme preparation was pure. The molecular mass of the enzyme determined from SDS-PAGE analysis was 100 kDa. The purification fold and percentage recovery of the enzyme activity were 12.75 and 30.12%, respectively. The pH and the temperature optima were 3.5 and 45 degrees C, respectively. The enzyme was most stable at pH 4.0 when exposed for 1 h. Using 2,6-dimethoxyphenol (DMP), 2,2 [azino-bis-(3 ethylbonzthiazoline-6-sulphonic acid) diammonium salt] (ABTS) and 3,5-dimethoxy-4 hydroxybenzaldehyde azine (syringaldazine) as the substrates, the K(m), k(cat) and k(cat)/K(m) values of the laccase were 80 MUM, 2.54 s(-1), 3.17 x 10(4) M( 1)s(-1), 36 MUM, 2.54 s(-1), 7.05 x 10(4) M(-1)s(-1) and 87 MUM, 2.54 s(-1), 2.92 x 10(4) M(-1)s(-1), respectively. The purified laccase was finally used for the selective biotransformation of aromatic methyl group to aldehyde group in presence of diammonium salt of ABTS as the mediator and products were characterized by HPLC, IR and 1H NMR. The percentage yields of these transformed products were > 91%. PMID- 26040113 TI - Expression and response surface optimization of the recovery and purification of recombinant D-galactose dehydrogenase from Pseudomonas fluorescens. AB - The enzyme D-galactose dehydrogenase (GalDH) has been used in diagnostic kits to screen blood serum of neonates for galactosemia. It is also a significant tool for the measurement of beta-D-galactose, alpha-D-galactose and lactose as well. In this study, response surface methodology (RSM) was used to identify the suitable conditions for recovery of recombinant GalDH from Pseudomonas fluorescens in aqueous two-phase systems (ATPS). The identified GalDH gene was amplified by PCR and confirmed by further cloning and sequencing. E. coli BL-21 (DE3) containing the GalDH gene on a plasmid (pET28aGDH) was used to express and purify the recombinant enzyme. The polyethylene glycol (PEG) and ammonium sulfate concentrations and pH value were selected as variables to analyze purification of GalDH. To build mathematical models, RSM with a central composite design was applied based on the conditions for the highest separation. The recombinant GalDH enzyme was expressed after induction with IPTG. It showed NAD'-dependent dehydrogenase activity towards D-Galactose. According to the RSM modeling, an optimal ATPS was composed of PEG-2000 14.0% (w/w) and ammonium sulfate 12.0% (w/w) at pH 7.5. Under these conditions, GalDH preferentially concentrated in the top PEG-rich phase. The enzyme activity, purification factor (PF) and recovery (R) were 1400 U/ml, 60.0% and 270.0%, respectively. The PEG and salt concentrations were found to have significant effect on the recovery of enzyme. Briefly, our data showed that RSM could be an appropriate tool to define the best ATPS for recombinant P. fluorescens GalDH recovery. PMID- 26040114 TI - Induced defence responses of contrasting bread wheat genotypes under differential salt stress imposition. AB - Plants, being sessile in nature, have developed mechanisms to cope with high salt concentrations in the soil. In this study, the effects of NaCl (50-200 mM) on expression of high-affinity potassium transporters (HKTs), antioxidant enzymes and their isozyme profiles were investigated in two contrasting bread wheat (Triticum aestivum L.) genotypes viz., HD2329 (salt-sensitive) and Kharchia65 (salt-tolerant). Kharchia65 can successfully grow in salt affected soils, while HD2329 cannot tolerate salt stress. Differential expression studies of two HKT genes (TaHKT2;1.1 and TaHKT2;3.1) revealed their up-regulated expression (-1.5 fold) in the salt-sensitive HD2329 and down-regulated (-5-fold) inducible expression in the salt-tolerant genotype (Kharchia65). Specific activity of antioxidant enzymes, viz. superoxide dismutase (SOD), peroxidase (POX), ascorbate peroxidase (APX), catalase (CAT) and glutathione reductase (GR) was found to be higher in the salt-tolerant genotype. Isozyme profile of two (POX and GR) antioxidant enzymes showed polymorphism between salt-tolerant and salt-sensitive genotypes. A new gene TaHKT2;3.1 was also identified and its expression profile and role in salt stress tolerance in wheat was also studied. Partial sequences of the TaHKT2;1.1 and TaHKT2;3.1 genes from bread wheat were submitted to the EMBL GenBank database. Our findings indicated that defence responses to salt stress were induced differentially in contrasting bread wheat genotypes which provide evidences for functional correlation between salt stress tolerance and differential biochemical and molecular expression patterns in bread wheat. PMID- 26040115 TI - Detection of DNA polymerase lambda activity during seed germination and enhancement after salinity stress and dehydration in the plumules of indica rice (Oryza sativa L. AB - DNA polymerase lambda (DNA pol lambda) is the only reported X-family DNA polymerases in plants and has been shown to play a significant role in dry quiescent seeds, growth, development and nuclear DNA repair. cDNA for DNA pol lambda has been reported in Arabidopsis and japonica rice cultivar and has been characterized from E. coli expressed protein, but very little is known about its activity at protein level in plants. The enzymatic activity of DNA pol lambda was studied in dry, imbibed and during different germination stages of indica rice IR 8 (salt sensitive) by in-gel activity assay to determine its physiological role in important stages of growth and development. The upstream sequence was also analyzed using plantCARE database and was found to contain several cis-acting elements, including light responsive elements, dehydration responsive elements, Myb binding sites, etc. Hence, 4-day-old germinating seedlings of IR29, a salt sensitive, but high yielding indica rice cultivar and Nonabokra, a salt-tolerant, but low yielding cultivar were treated with water (control) or 250 mM NaCl or 20% polyethyleneglycol-6000 for 4 and 8 h. The protein was analyzed by in vitro DNA pol lambda activity assay, in-gel activity assay and Western blot analysis. DNA pol lambda was not detected in dry seeds, but enhanced after imbibition and detectable from low level to high level during subsequent germination steps. Both salinity and dehydration stress led to the enhancement of the activity and protein level of DNA pol lambda, as compared to control tissues. This is the first evidence of the salinity or dehydration stress induced enhancement of DNA pol lambda activity in the plumules of rice (Oryza sativa L.) cultivars. PMID- 26040116 TI - In silico structural and functional analysis of protein encoded by wheat early salt-stress response gene (WESR3). AB - Salt stress is one of the major abiotic stresses limiting grain yield in wheat (Triticum aestivum L.). Wheat early salt-stress response gene (WESR3) is one of the major salt stress genes, which is affected in the first phase of salt stress. In this study, sequence and structural analysis of protein coded by WESR3 gene was carried out using various bioinformatics tools. Sequence analysis of WESR3 protein revealed the presence of highly conserved regions of Mlo gene family. Three-dimensional modeling was carried out to elucidate its structure and its active site. The sequence analysis revealed that WESR3 protein might be involved in fungal pathogen attack pathway. Thus, in addition to its involvement in abiotic stresses, it also seemed to play an important part in biotic stress pathways. Out of the three modeled protein structures obtained from I-TASSER, HHPred and QUARK, the I-TASSER protein model was the best model based on high confidence score and lesser number of bad contacts. The Ramchandran plot analysis also showed that all amino acid residues of I-TASSER model lie in the allowed region and thus indicating towards the overall good quality of the predicted model. Seventeen active sites were predicted in the protein bearing resemblance to the Mlo family conserved regions. In conclusion, a detailed analysis of WESR3 protein suggested an important role of WESR3 in biotic and abiotic stress. These results aid to the experimental data and help to build up a complete view of WESR3 proteins and their role in plant stress response. PMID- 26040117 TI - Evaluation of different protein extraction methods for banana (Musa spp.) root proteome analysis by two-dimensional electrophoresis. AB - Four protocols viz., the trichloroacetic acid-acetone (TCA), phenol-ammonium acetate (PAA), phenol/SDS-ammonium acetate (PSA) and trisbase-acetone (TBA) were evaluated with modifications for protein extraction from banana (Grand Naine) roots, considered as recalcitrant tissues for proteomic analysis. The two dimensional electrophoresis (2-DE) separated proteins were compared based on protein yield, number of resolved proteins, sum of spot quantity, average spot intensity and proteins resolved in 4-7 pI range. The PAA protocol yielded more proteins (0.89 mg/g of tissues) and protein spots (584) in 2-DE gel than TCA and other protocols. Also, the PAA protocol was superior in terms of sum of total spot quantity and average spot intensity than TCA and other protocols, suggesting phenol as extractant and ammonium acetate as precipitant of proteins were the most suitable for banana rooteomics analysis by 2-DE. In addition, 1:3 ratios of root tissue to extraction buffer and overnight protein precipitation were most efficient to obtain maximum protein yield. PMID- 26040118 TI - Rapid and simple method of photobleaching to reduce background autofluorescence in lung tissue sections. AB - Autofluorescence exhibited by tissues often interferes with immunofluorescence. Using imaging and spectral analysis, we observed remarkable reduction of autofluorescence of formalin fixed paraffin embedded tissues irradiated with light prior to incubation with immunofluorescent dyes. The technique of photobleaching offers significant improvement in the quality and specificity of immunofluorescence. This has the potential for better techniques for disease diagnosis. PMID- 26040119 TI - The dust is settling--let's focus on delivering. PMID- 26040120 TI - Gallipoli nurses should be equally recognized. PMID- 26040122 TI - Long service leave--the myths and what you need to know. PMID- 26040121 TI - Prophylactic application of negative pressure to high-risk surgical wounds. PMID- 26040123 TI - Issues for nurses highlighted at the inquest into infection deaths. PMID- 26040124 TI - R.E.S.P.E.C.T. PMID- 26040125 TI - [Searching for an identity]. PMID- 26040126 TI - [Improved transparency needed for nosocomial infections]. PMID- 26040128 TI - [Connecting nurses]. PMID- 26040127 TI - [Debate on the direct payment project]. PMID- 26040129 TI - [Creation of the National Commission of Paramedical Research Coordinators]. PMID- 26040130 TI - [Relevant legislation relating to the competence of surgical nurses]. PMID- 26040131 TI - [Recommendations to support nurses' aides]. PMID- 26040132 TI - [A new protocol in the management of chronic wounds: from theory to practice]. PMID- 26040133 TI - [Improving the assessment of pain in elderly people unable to communicate]. AB - An association grouping together the pain committees from several institutions carried out an assessment of professional practices in order to improve the screening and treatment of pain in elderly people unable to communicate. The study shows the benefit of a systematic assessment, with the aid of the Algoplus(r) scale, of all patients with communication disorders, and the need to improve the treatment of pain. PMID- 26040134 TI - [A Diabetes Collective to improve screening and prevention]. AB - Created in 2004, a Diabetes Collective in the south of France has organised almost 150 screening and information days. Made up of professionals and volunteers from associations, it includes the work of some 30 partners. It covers all territories and provides access to screening and prevention in rural areas. PMID- 26040135 TI - [The patients' journey in a medical-judicial unit]. AB - A medical-judicial unit is a care centre which receives and examines victims of violence as well as perpetrators of assault. At Marne-la-Vallee hospital, to ensure this unit is as operational as possible, separate areas have been organised and decorated to accommodate both of these two specific activities. PMID- 26040136 TI - [Myocardial infarction. Two key elements in prevention and research]. PMID- 26040137 TI - [Anatomy and physiology of the heart and coronary arteries]. AB - The myocardium assures the supply of oxygen to the body. The provision of oxygen to the myocardium by the coronary arteries is dependent on two key parameters: the coronary blood flow and the ability to extract oxygen from the arterial blood. Coronary artery disease is almost always the consequence of atherosclerosis and can lead to myocardial infarction. PMID- 26040138 TI - [Epidemiology of coronary disease and prevention of cardiovascular diseases]. AB - Cardiovascular diseases are the leading cause of death in most industrialised countries. In France, they are responsible for 142,000 deaths every year. Myocardial infarction and coronary deaths are also falling, but could rise for women in the future. There are different forms of prevention and lifestyles are important. PMID- 26040139 TI - [The latest treatments for myocardial infarction]. AB - Ischemic heart disease and its main complication, myocardial infarction, remain the leading cause of death after the age of forty in developed countries. Myocardial infarction is the consequence of a sudden obstruction of a coronary artery by a thrombus. Thrombolysis and coronary angioplasty are the two emergency coronary artery revascularisation techniques. A medication-based treatment and adapted lifestyle aim to prevent repeat infarction. PMID- 26040140 TI - [Pre-hospital management of acute coronary syndrome]. AB - The medical management of acute coronary syndrome (ACS) follows the recommendations of international medical societies. The call to the emergency services by the patient triggers a race against the clock in pre-hospital care. It is essential to reduce the duration of the inadequate perfusion of the heart in order to limit its consequences. An effective reperfusion strategy must be planned in advance taking into account the logistical constraints. It is crucial that the general public is educated to recognise the signs of ACS and to call the emergency services immediately (such as 15, 112 or 991). PMID- 26040141 TI - [Description of the two surgical myocardial revascularisation techniques]. AB - A coronary artery bypass involves taking blood vessels from another part of the patient's body to bypass one or several major coronary stenoses. Coronary artery bypass using cardiopulmonary bypass and off-pump coronary artery bypass are the two methods used to revascularise the heart after a myocardial infarction. PMID- 26040142 TI - [The care pathway of the coronary patient]. AB - After a myocardial infarction, the patient receiving pre-hospital care is transferred directly and as quickly as possible to the coronary angiography room. After reperfusion, they are admitted to a cardiac intensive care unit for pharmacological treatment and therapeutic education, in order to reduce the risk factors. Throughout their care pathway, the patient benefits from the skills of a multi-disciplinary team. PMID- 26040143 TI - [A multidisciplinary approach to cardiac rehabilitation]. AB - The rehabilitation of a coronary patient involves numerous professionals in a global care approach. The objective is to reintroduce physical activity and put in place lifestyle changes, in order to reduce the risk factors. Therapeutic education is an essential part of this support. PMID- 26040144 TI - [Managing infarctions in elderly people]. AB - Coronary disease is frequent and serious after the age of 80. The management of the elderly person's care depends on whether or not there is associated multiple pathology. After a global geriatric assessment, revascularisation techniques can also be used in this context. Caution must however be taken when introducing a pharmacological treatment. PMID- 26040145 TI - [Stem cells, hope for myocardial regeneration]. PMID- 26040146 TI - [The creation and authorization of a protocol of cooperation]. PMID- 26040147 TI - [Mexican Council of Orthopedics and Traumatology, A.C]. PMID- 26040148 TI - [Periprosthetic hip fractures]. AB - The incidence rate of periprosthetic fractures has increased in the past decade. Osteolysis, age and preoperative function are factors that influence morbidity. Treatment options include conservative and surgical treatment. OBJECTIVES: To conduct a study analyzing the functional results of the surgical treatment of periprosthetic hip fractures at the ABC Medical Center considering preoperative and postoperative variables. MATERIAL AND METHODS: Cross-sectional retrospective study of patients with a diagnosis of periprosthetic hip fracture between January 2000 and December 2011, classified using the Vancouver system. The Oxford Hip Score was used pre- and postoperatively as a functional measure. The variables to evaluate included age, sex, surgical technique, and the time elapsed between primary surgery and the periprosthetic fracture. RESULTS: Twenty-five patients were analyzed; frequency was 3.3 cases per year. 80% of periprosthetic fractures were postoperative; 72% were total hip arthroplasties. The time elapsed between primary surgery and the traumatic event was 2 to 4 years (68%), with a mean of 4.5 years for hemiarthroplasties and 3.9 years for total arthroplasties. Patients who according to the Oxford Hip Score had good function maintained their results; 75% of those with moderate function maintained their score. Patients with poor function improved. CONCLUSIONS: At the ABC Medical Center, the outcomes of the treatment of periprosthetic hip fractures are considered as good according to the Oxford Hip Score. PMID- 26040149 TI - [Relative clavicle shortening in pediatric fractures: its importance when selecting conservative treatment]. AB - BACKGROUND: Clavicle fractures represent 2-15% of pediatric fractures. The literature suggests operating on patients over 9 years of age with major shortening or severe comminution in the fracture line. However, no one establishes shortening or angulation parameters for conservative treatment in children. In pediatric patients it is important to take into account relative shortening, that is, the one caused by a fracture when compared with the length of the healthy clavicle. OBJECTIVE: To know the effect of relative clavicle shortening on movement in pediatric fractures treated conservatively. MATERIAL AND METHODS: Retrospective, longitudinal, observational study. We radiographically measured the relative shortening of the fractured clavicle comparing it with the healthy side at the time of the fracture and after fracture healing. Shortening was expressed in percentages. The following views were used: comparative anteroposterior view of the shoulders and panoramic view of both shoulders. Patients were divided into 2 groups: under 9 years and 9-15 years of age. RESULTS: We analyzed 94 fractures; 31 in females and 63 in males. No pseudoarthrosis or symptomatic malunion occurred. The prognosis was good regardless of the initial shortening percentage. Age and shortening are proportionally related with the rehabilitation period and the restoration of painless ranges of motion. The value ranges recorded for shortening were 9.5 to 28%. CONCLUSIONS: The surgical indications for shortening resulting from pediatric clavicle fractures should be revised. We have observed good results despite major shortening and total displacement. PMID- 26040150 TI - [Singler-segment degenerative lumbar spondylolisthesis treated with an interspinous spacer]. AB - BACKGROUND: The term degenerative spondylolisthesis, coined by Newman in 1963, refers to the forward slippage of an immediately inferior vertebra without isthmic lysis. It occurs predominantly in individuals over 40 years of age and affects mainly women, with a female:male ratio of 4:1. Prevalence is 7.5% in males and 28% in females among patients over 50 years of age with low back pain. MATERIAL AND METHODS: Assess the one-year results of the use of dynamic spacers for Meyerding grade 1 listhesis with the Oswestry disability scale. The patient's electronic and radiographic records from January 2008 to December 2010 were reviewed according to different criteria to conduct a retrospective, longitudinal and observational cohort study. RESULTS: The preoperative Oswestry score was 3.4% mild, 55.2% moderate, and 42.4% severe; the postoperative score was 79.3% mild and 20.7% moderate. The most common surgical procedure was exploration and release in 72.4% of patients; only 27.6% underwent diskectomy. Pain irradiating to the right pelvic limb occurred in 37.9% of patients, to the left pelvic limb in 44.8%, and to both pelvic limbs in 17.2%. Only 2.4% of patients experienced postoperative pain that irradiated to the pelvic limb, as 100% of cases had some type of irradiating pain. A DIAM spacer was used in 79.3% and a Wallis device in 20.7%. CONCLUSIONS: Treatment with an interspinous spacer results in a low reoperation rate and, at least one year later, it resulted in a significant improvement in the disability rate. PMID- 26040151 TI - [Quality of life of patients with acromioclavicular dislocation]. AB - OBJECTIVE: To compare quality of life in patients with Tossy type Ill acromioclavicular dislocation treated with the hook-plate ORIF technique, the Weaver & Dunn technique and the Bosworth technique. MATERIAL AND METHODS: A cross sectional analytical survey was conducted from January 2012 to April 2013 in patients with a diagnosis of Tossy type III acromioclavicular dislocation treated surgically with the hook-plate ORIF technique, the Weaver & Dunn technique, and the Bosworth technique. We included patients ages 18 to 70 years old, operated within three weeks after the diagnosis. Quality of life was assessed using the hetero-administered DASH questionnaire once the informed consent was obtained. RESULTS: Forty-seven patients were operated on. They were divided into 3 groups: hook-plate ORIF technique, with 26 patients: Weaver & Dunn technique, 11 patients; and Bosworth technique, 10 patients. Sex and age distribution were similar in all 3 groups, with p =0.137 and p = 0.252, respectively. Time elapsed after surgery was similar in all 3 groups, with p = 0.051. The hook-plate ORIF technique was the most frequently used one, in 26 surgeries. 96.4% of patients had mild disability and symptoms with the hook-plate ORIF technique, and 100% with the Bosworth and Weaver & Dunn techniques. CONCLUSIONS: Quality of life was similar with all 3 surgical techniques and involved mild disability and symptoms. The hook-plate ORIF technique was the most frequently used technique. PMID- 26040152 TI - [Individualized molds for alignment of primary knee arthroplasty]. AB - INTRODUCTION: Patient-specific cutting blocks (PSCB) have been proposed as an interesting option to achieve appropriate alignment in knee arthroplasty. However, there is no information as to which of the available planning methods is the right one. MATERIAL AND METHODS: A prospective study was designed to compare two, PSCB systems using different planning methods (Signature with CAT scan + teleradiography; Visionaire with MRI) with the standard alignment method. Radiographic and functional pre- and postoperative parameters were analyzed, together with hospital stay, blood transfusion needs, operative time and associated complications. RESULTS: A total of 10 patients per group were operated on. No statistically significant differences were observed between both of the patient-specific alignment systems and the standard system (p > 0.05). However, greater precision was achieved with the former systems and the Signature system was slightly more accurate. Operative time was shorter in patients in whom PSCBs were used, and it was still slightly shorter in those in whom the Visionaire system was used (p > 0.05). CONCLUSIONS: The new PSCB systems may be useful to improve alignment in knee arthroplasty and reduce the operative time. While larger case series confirming these data become available, the authors recommend using these systems in cases in which the standard systems do not work properly. PMID- 26040153 TI - [Assessment of bleeding and operative time in total knee arthroplasty with and without tourniquet. Comparative study]. AB - BACKGROUND: The use of the pneumatic tourniquet (PT) in total knee arthroplasty (TKA) has been controversial; its advantages, disadvantages and associated complications have been described. In order to assess its benefits we analyzed operative time; intraoperative, postoperative and total bleeding volume, as well as pre- and postoperative hemoglobin and hematocrit values in patients who had undergone primary TKA using the PT, and they were compared with a control group. MATERIAL AND METHODS: A retrospective analysis of the clinical records of cases who underwent TKA was conducted. Based on the inclusion criteria and the use or nonuse of PT, two groups were formed: a study group (n=19) and a control group (n=19). The following variables were compared: operative time, intra and postoperative bleeding and total bleeding; initial and final hemoglobin and hematocrit values. RESULTS: Significant differences in favor of the group with PT use were obtained in 7 out of the 8 variables studied. The most relevant ones were operative time (t = 2.08 p < 0.050); intraoperative bleeding (t = -6.44, p < 0.010); postoperative bleeding (t = -2.170 p < 0.050) and total bleeding (t = /7.52, p < 0.010). CONCLUSIONS: The results showed that patients in whom PT was used during TKA had a shorter operative time, and their total, intra- and postoperative bleeding and the estimated, blood loss were lower than in controls. Additional suppositions on the benefits of PT warrant the conduction'of more prospective research studies. PMID- 26040154 TI - [Postoperative treatment for lumbar disc herniation during rehabilitation. Systematic review]. AB - Various programs and interventions are available for the rehabilitation of patients who have undergone surgery for symptomatic lumbar disc herniation (LDH). Our aim is to determine the value of the different rehabilitation interventions included in the postoperative treatment of patients with symptomatic LDH. MATERIAL AND METHODS: Systematic review. Search in electronic data bases--from January 2000 to October 2012. Two independent reviewers certified in the use of the PEDro (Physiotherapy Evidence Data Base) scale assessed the clinical trials included in the final version; only those with high methodological quality were included. A third reviewer acted as arbitrator in case of discrepancy between reviewers. The reviewers were blinded to the authors, institutions and journals to increase the precision of their ratings and the inter-reviewer validity. RESULTS: Fifteen clinical trials were reviewed by the reviewers; 8 (53.3%) were considered as having a high methodological quality (average of 7.7/10). Were randomized 1099 participants to different treatment groups. It was not possible to conduct a meta-analysis with the clinical trial data due to the multiple interventions and outcome measures used. CONCLUSIONS: An immediate rehabilitation program is recommended in patients undergoing microiskectomy for the first time. Cognitive intervention with positive reinforcement together with exercise is an effective treatment. It is even considered as an alternative to vertebral fusion in patients who underwent LDH surgery with symptom recurrence after the first surgery. The results of early postoperative activity are usually excellent and involve no complications. The number and the methodological quality of the clinical trials on this topic need to be increased to justify the usefulness of these interventions in the daily clinical practice. PMID- 26040155 TI - [Tear of the posterior-inferior tibiofibular ligament in a child]. AB - Fracture-dislocations of the ankle are very frequent in adults. The injuries described by Salter and Harris in developing patients are also common. The authors present a case of tear of the posterior-inferior tibiofibular ligament of the left ankle in a 13 year-old patient. The initial diagnosis with plain X-rays was ankle sprain; however, an ankle CT scan confirmed the patient's injury and he was treated at Morelia's Children's Hospital. CT scan is an extremely useful aid in diagnosing inferior tibiofibular diastasis because the tear of the posterior distal tibiofibular ligament of the ankle mortise is missed in these patients, who initially are diagnosed as having an ankle sprain. PMID- 26040156 TI - [Unusual location of osteochondral lesions in adolescent's knees]. AB - Osteochondral knee lesions in adolescents are primarily located in loading areas at the level of the femoral condyles. Lesions located in the trochlea are exceptional and account for less than 1%. The etiology of juvenile osteochondritis dissecans (JOCD) is still unknown. Osteochondral lesions may be caused by direct frontal trauma of the femoral condyles and by direct trauma of the patella on the trochlea in dislocations of the latter. At this level both mechanisms may cause both chondral and osteochondral lesions. We present herein two cases with the same characteristics that include one patient with bilateral involvement of the trochlea. Arthroscopy was performed with removal of loose bodies, regularization of the bed and perforations, with appropriate long term results. Osteochondral lesions are rarely found in the trochlea; the literature contains very few bilateral cases described. The exact etiology of JOCD of the knee continues to be debated. In our cases the mechanism could be explained by a low-pressure high-speed impact of the patella on the trochlea. This type of lesions may be added to defects or abnormalities of ossification during childhood. The bilaterality of one of these cases would support this hypothesis. Treatment depends on lesion stability and patient age. Surgical treatment should be considered in patients with open physes with an un stable or detached lesion and in those in whom the physis is about to close but have not responded to conservative treatment, as well as in patients with an intraarticular loose body. Another point to consider is that insufficient fixation or fixation without a bone chip leads to mediocre results. PMID- 26040157 TI - [Calcaneus fractures as a complication of the percutaneous treatment of plantar fasciitis. Case report]. AB - Plantar fasciitis, a self-limiting pathologic entity, is a common cause of heel pain in adult patients. Surgical treatment is indicated when the patient does not improve after receiving conservative treatment for 4-6 months with proper surveillance. The complications of percutaneous techniques include: infection, persistent pain, and neurologic injuries, among others. We report the case of a patient with calcaneus fracture following percutaneous plantar fasciotomy and resection of a calcaneal spur. We conducted a review and discussion of the literature. PMID- 26040158 TI - [Evaluation and treatment of prosthetic hip dislocation]. AB - Hip dislocation is the second most common complication of total hip arthroplasty followed by aseptic loosening, is the second most common complication of THA presenting with an incidence of 2.4-3.9% in primary procedures and an incidence of up to 28% in revision surgeries. The hip dislocations can be classified into 3 groups: Early, middle and late. Generally early dislocations respond favorably to nonsurgical treatment and have low recurrence rate. In this case the need for revision surgery is much higher. The diagnosis of a dislocated hip is relatively easy to perform because the clinical picture is very typical. Having identified a dislocated hip the first step is to make an attempt to reduce a closed manner. Among the options are the following: Change of modular components, trochanteric progress, review of component orientation and ultimately the use of constrained components. One of the most common problems for which the patient presents early recurrent instability is inadequate orientation of the prosthetic components. The THA is one of the most useful and most successful surgeries the last 100 years, however requires a refined surgical technique, proper patient selection and planning to meet the expectations of it. It currently has a range of possible treatments for problem resolution, with the intent of restoring a stable and functional hip. PMID- 26040159 TI - ["To case report or not", the interest of studies n=1]. PMID- 26040160 TI - [Lung involvement in systemic sclerosis]. AB - Systemic sclerosis (SSc) is a protean disorder in which prognosis and treatment are tailored on the basis of organ involvement. Among SSc lung manifestations, interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) or the combination of both, are the first cause of SSc mortality and impact heavily on patient quality of life. ILD may begin early in disease and usually progresses slowly. However, approximately 10% of patients with ILD may reach terminal respiratory insufficiency. PAH may be an early or late complication of SSc in which increased blood pressure in pulmonary arteries leads to right heart failure. Current treatments provide some benefit, but both SSc-ILD and PAH still represent an enormous unmet need of more efficacious therapeutic strategies. PMID- 26040161 TI - [The anti-synthetases syndrome: diagnostic and treatments]. AB - The anti-synthetases syndrome is a rare disease with a specific constellation of clinical symptoms present in a subset of patients with inflammatory myopathy. Besides constitutional symptoms and myositis, it is associated with mechanic's hands, Raynaud phenomenon, and non-erosive arthritis. This syndrome is characterized by the presence of one of eight auto-antibodies to aminoacyl transfer ribonucleic acid synthetase enzymes in the serum. Interstitial lung disease is more frequent in this subpopulation of inflammatory myopathy and worsens the patient's prognosis. PMID- 26040162 TI - [IgG4-related disease: a possible cause of obstructive jaundice]. AB - Immunoglobulin G4 related disease (IgG4-RD) has been recognized since early 2000s as an entity comprising a set of inflammatory diseases with common histopathological features. The disease may affect almost all organs and tissues, and often occurs in a subacute fashion in males over 50 years as a mass or diffuse enlargement of affected organs. The histopathological appearance is characterized by a lymphoplasmacytic infiltration with predominantly IgG4 positive plasma cells and progressive fibrosis. Its clinical and radiological features can make the distinction with a malignancy difficult. The disease responds well to systemic glucocorticoids however with a high rate of recurrence after treatment discontinuation. PMID- 26040163 TI - [Myelodysplastic syndromes and autoimmunity]. AB - Myelodysplastic syndromes (MDS) are characterized by inefficient hematopoiesis and result in peripheral cytopenia. This heterogenous disease group arises from clonal disorders of hematopoietic stem cells. Several cohort studies and numerous case reports have highlighted a link between MDS and autoimmune disorders. Patients with MDS are more prone to develop particular systemic inflammatory diseases. On the other hand, patients suffering from autoimmune diseases are at higher risk to develop MDS. The scope of this article is to review the association between myelodysplasia and autoimmunity. It gives practical clues when to look for MDS in a patient suffering from autoimmunity and lists the main autoimmune diseases which may complicate the course of a MDS. PMID- 26040164 TI - [Allergies and adverse events associated with fluoroquinolones]. AB - The prescription ot fluoroquinolones has been constantly increasing over the past decade. consequently, an increasing number of hyper-sensitivity reactions and adverse events have been reported. The aim of the review is to discuss the incidence of hypersensitivity reactions either IgE (immediate) or T cells mediated (delayed). We will make an overview ofthe diagnostic tools available to detect such hypersensitivity reactions. Finally, the specific adverse events associated with fluoroquinolones, including tendinopathy, chondrotoxicity, peripheral neuropathy or retinal detachment will be discussed. PMID- 26040167 TI - [Under the paving stones, the paving stones]. PMID- 26040165 TI - [Subcutaneous immunoglobulin and support program: what level of interest of patients?]. AB - Two different routes of administration exist for the immunoglobulin therapy: intravenous (Ig IV - monthly administration in medical setting) and subcutaneous (Ig SC - weekly self-administration at home). According to the literature, efficacy and safety are similar,. but Ig SC could improve quality of life and treatment satisfaction. The Policlinique Medicale Universitaire of Lausanne has developed an interdisciplinary program for the long-term support of Ig SC patients. Moreover, it conducted an exploratory survey interviewing Ig IV patients about their interest for Ig SC: patients interested judged less favourably efficacy and/or tolerance of Ig IV and considered that Ig SC would improve their motivation for treatment and its impact on their private and professional life. PMID- 26040168 TI - [Empathy, practice of medicine and professional burnout]. PMID- 26040169 TI - [Brain, coma and dementia: the lights of Steven Laureys and Stanley Prusiner]. PMID- 26040170 TI - [Before treating COPD, do you have lung function consistent with this diagnosis?]. PMID- 26040171 TI - [Andreas Lubitz, forensic medicine, neuropsychiatry and linguistics]. PMID- 26040172 TI - [Crash of Germanwings: the medical secret in debate]. PMID- 26040173 TI - [DPI: the antis move up to the front]. PMID- 26040174 TI - [Can the patient's electronic record be communal?]. PMID- 26040175 TI - Oral health-related quality of life of edentulous patients after complete dentures relining. AB - BACKGROUND/AIM: Tooth loss affects oral health-related life quality. More than a third of edentulous patients are not fully satisfied with their complete dentures and mainly complain of insufficient stability, retention, and pain during mastication. Solving the problem may include relining by materials that are based on silicone or acrylic. The aim of this study was to determine the level of patients' satisfaction before and after relining upper dentures with soft and rigid liners. METHODS: The patients (n=24) were divided into two study groups. Maxillary denture relining of the first group of patients was performed with hard acrylic based resins while in the second group of patients complete denture was relined with a silicone-based soft liner. They were asked the questions from the specifically adapted the Oral Health Impact Profile Questionnaire for edentulous patients before and three months after relining dentures. RESULTS: After relining the patients showed a higher degree of satisfaction with their dentures in all the tested domains (masticatory function, psychological discomfort, social disability and retention and hygiene). The padents with soft denture relines were more satisfied. CONCLUSION: Refining of maxillary complete dentures significantly positively impacts the quality of life of patients in all the tested domains (masticatory function, psychological discomfort, social disability, pain and oral hygiene). Better results were achieved using a silicone-based soft liner, which recommends it as the material of choice for relining dentures. PMID- 26040176 TI - Clinicopathological characteristics, diagnosis and treatment of melanoma in Serbia--the Melanoma Focus Study. AB - BACKGROUND/AIM: Treatment options for metastatic melanoma in Serbia are limited due to the lack of newly approved biologic agents and the lack of clinical studies. Also, there is a paucity of data regarding the treatment approaches in different tertiary centers and efficacy of available chemotherapy protocols. The aim of this study was to obtain more detailed data about treatment protocols in Serbia based on structured survey in tertiary oncology centers. METHODS: Data about the melanoma patients treated in 2011 were analyzed from hospital databases in 6 referent oncology centers in Serbia, based on the structured survey, with the focus on metastatic melanoma patients (unresectable stage IIIC and IV). RESULTS: A total of 986 (79-315 in different centers) patients were treated, with 320 (32.45%) newly diagnosed patients. There were 317 patients in stage IIIC/IV, 77/317 aged < 50 years. At the time of diagnosis 47.3% of patients were < 60 years of age (24.2% < 40 years, 23% 50-59 years, 52.6% > 60 years). At initial diagnosis 12.5% of patients were in stage III and 4.5% in stage IV. The most common type was superficial spreading melanoma (50-660), followed by nodular melanoma (23.5-50%). Apart from the regional and distant lymph node metastases, the most frequent organs involved in stage IV disease were distant skin and soft tissues (12-55%), lungs (19-55.5%), liver (10-60%), and bones (3-10%). The first line therapy in stage IV metastatic melanoma was dacarbazine (DTIC) dimethyl triazenoimidozole-carboxamide in 61-93% of the patients, while the second line varied between the centers. Disease control (complete response + partial response + stable disease) was achieved in 25.7% of the patients treated with the first line chemotherapy and 23.1% of the patients treated with the second line therapy, but the duration of response was short, in first-line therapy 6.66 +/- 3.36 months (median 6.75 months). More than 90% of patients were treated outside the clinical trials. CONCLUSION: Based on this survey, there is a large unmet need for the new treatment options for metastatic melanoma in Serbia. The development of national guidelines, and greater involvement in international clinical studies could lead to widening of treatment options for this chemotherapy resistant disease. PMID- 26040177 TI - Significance of microvessel density in prostate cancer core biopsy. AB - BACKGROUND/AIM: In prostate tumors, angiogenesis, measured as microvessel density, is associated with tumor stage and Gleason score. The aim of this study was determine neovascularization of prostatic adenocarcinomas in core biopsies and corresponding prostatectomies. METHODS: The study population included 61 patients who underwent radical prostatectomy (RP) for localized prostate carcinoma patients and did not receive chemohormonal, or radiation therapy before surgery. Tumor blocks were immunostained using the endothelial-specific antibody CD31 and subsequently evaluated at x 400 magnification in both biopsies and corresponding prostatectomies. RESULTS: When comparing microvessel density in core biopsies and corresponding prostatectomies, no statistically significant difference was found (p > 0.1). A statistically significant positive correlation was found when determining correlation between microvessel density (as linear and categorical variable, i.e., with the cut-off value of 48) that was associated with the Gleason score (p < 0.05) and tumor stage (p < 0.0001). There was no correlation between microvessel density and preoperative values of serum prostate specific antigen (PSA) (p > 0.1). CONCLUSION: Microvessel density can be reliably applied to needle prostate biopsy specimens. Quantification of the microvascular density in biopsies is an accurate pre-operative predictor of tumor stage, discriminating between organ-confined and organ-extending neoplasms. PMID- 26040178 TI - Characteristics of norovirus infection in Serbia. AB - BACKGROUND/AIM: Norovirus (NoV), formerly Norwalk-like virus is the most common cause of acute gastroenteritis in humans of all ages. It is known that 90% of viral gastroenteritis and about 60-85% of all outbreaks of gastroenteritis, especially in the territory of United States of America, Europe and Japan are caused by this virus. For the countries of the northern hemisphere, individual cases and outbreaks of acute NoV gastroen teritis appear in seasonal pattern, mainly during the winter months. The aim of this study as to describe characteristics of acute gastroenteritis with the established NoV etiology in Serbia. METHODS: The study group included 88 patients with the symp toms of acute gastroenteritis, throughout the year 2010 and 2011. From all the patients, stool samples were taken less than three days from the onset of symptoms. Detection of NoV in stool samples was performed by commercial qualitative immunochromatography assay. Statistical analysis included application of x2 test, Mann-Whitney U-test, Kruskal-Wallis's test, Spearman's rank correlation test and logistic regression analysis. RESULTS: Outbreaks of acute gastroenteritis caused by NoV were recorded to be the most common in children with the incidence of infection of 50% in the age group 0-15 years. Analysis of individual symptoms in the NoV proven infection, showed that diarrhea was the most common symptom, followed by vomiting espe cially in small children, while abdominal pain was most common in elderly (> 65 years). The presence of frequent vomiting, more than 4 times/day, indicated NoV infection in the women, while for men the infection was always presented with diarrhea. CONCLUSION: The obtained results confirmed that small children and elderly are,the most susceptible to NoV infection and that outbreaks are more frequent in the winter months. Those who consumed food in restaurants and other public facilities were not at higher risk for NoV infection. PMID- 26040179 TI - End-of-life costs of medical care for advanced stage cancer patients. AB - BACKGROUND/AIM: Cancer, one of the leading causes of mortality in the world, imposes a substantial economic burden on each society, including Serbia. The aim of this study was to evaluate the major cancer cost drivers in Serbia. METHODS: A retrospective, in-depth, bottom-up analysis of two combined databases was performed in order to quantify relevant costs. End-of-life data were obtained from patients with cancer, who deceased within the first year of the established diagnose, including basic demographics, diagnosis, tumour histology, medical resource use and related costs, time and cause of death. All costs were allocated to one of the three categories of cancer health care services: primary care (included home care), hospital outpatient and hospital inpatient care. RESULTS: Exactly 114 patients were analyzed, out of whom a high percent (48.25%) had distant metastases at the moment of establishing the diagnosis. Malignant neoplasms of respiratory and intrathoracic organs were leading causes of morbidity. The average costs per patient were significantly different according to the diagnosis, with the highest (13,114.10 EUR) and the lowest (4.00 EUR) ones observed in the breast cancer and melanoma, respectively. The greatest impact on total costs was observed concerning pharmaceuticals, with 42% of share (monoclonal antibodies amounted to 34% of all medicines and 14% of total costs), followed by oncology medical care (21%), radiation therapy and interventional radiology (11%), surgery (90%), imaging diagnostics (9%) and laboratory costs (8%). CONCLUSION. Cancer treatment incurs high costs, especially for end-of-life pharmaceutical expenses, ensued from medical personnel tendency to improve such patients' quality of life in spite of nearing the end of life. Reimbursement policy on monoclonal antibodies, in particular at end-stage disease, should rely on cost-effectiveness evidence as well as documented clinical efficiency. PMID- 26040180 TI - Interferon alpha-induced reduction in the values of myeloid-derived suppressor cells in melanoma patients. AB - BACKGROUND/AIM: Interaction between tumor cells and host's immunoregulatory cells in creation of microenvironment that supports tumor progression is the focus of numerous investigations in recent years. Myeloid-derived suppressor cells (MIDSCs) are heterogeneous population of immature dendritic cells, macrophages and granulocytes. In cancer patients, these cells accumulate in tumor microenvironment, tumor-draining lymph nodes, peripheral blood and the liver and their numbers correlate with the stage of the disease and the metastatic disease. The aim of the study was to investigate the effect of interferon alpha on MDSCs percentage in peripheral blood of melanoma patients. METHODS: The interferon treated melanoma patients were given subcutaneously interferon alpha, in optimal dose, for a period of at least 6 months before the analysis. Blood samples were collected from the melanoma patients (n=91) and the age/sex matched healthy controls (n=8). The following anti-human monoclonal antibodies were used for immunostaining: anti-CD15-FITC, anti-CD33-PE, anti-CD45-ECD, anti-HLA-DR PE/Cy5, anti-CD14-FITC, anti-CD16-PE and anti-CD11b-PE. RESULTS: Comparison of myeloid- derived suppressor cells values in the stage 2 melanoma patients with and without interferon alpha therapy did not show a significant difference. When we compared the MDSCs values in the patients within stage 3 melanoma, we found a significant difference in granulocytic subset values between the interferon alpha-treated and the untreated group. Comparison of values of all suppressor cells populations between the interferon alpha-treated patients and healthy controls showed a significant increase in suppressor cells percentage in the melanoma patients. The granulocytic and total MDSCs values were significantly lower in the interferon alpha treated melanoma patients with progression in comparison with untreated patients with stable disease. CONCLUSION: We confirmed that interferon alpha effect in stage 3 melanoma patients was reduction in MDSCs percentage. We also found an unexpected bounce back of these suppressor cells levels, many months after the discontinuation of interferon alpha therapy. PMID- 26040181 TI - Levels of interleukin-6 in tears before and after excimer laser treatment. AB - BACKGROUND/AIM: Immune response and consequent inflammatory process which originate on ocular surface after a trauma are mediated by cytokines. Photoablation of corneal stroma performed by excimer laser causes surgically induced trauma. Interleukin-6 (IL-6) is mostly known as a proinflammatory cytokine. However, it also has regenerative and anti-inflammatory effects. It is supposed that this cytokine is likely to play a significant role in the process of corneal wound healing response after photoablation of stroma carried out by laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK) methods. The aim of this study was to determine and compare the levels of IL-6 in tears before and after treatment with LASIK and PRK methods. METHODS: The study included 68 shortsighted eyes up to -3.0 diopter sphere, i.e. 198 samples of tears (per three samples taken from each of the eyes), divided into two groups according to the kind of excimer laser intervention performed: the group 1--eyes treated by LASIK method (n=31), and the group 2--eyes treated by the PRK method (n=37). The samples of tears were taken from each eye at the following time points: before excimer laser treatment (0 h, the control group), 1 h after the treatment (1 h) and 24 h after the treatment (24 h). The patients did not use anti-inflammatory therapy 24 h after the intervention. Tear samples were collected using microsurgical sponge. Level of IL-6 in tear fluid was determined by the flow cytometry method, applying a commercial test kit which allowed cytokine detection from a small sample volume. Results. The values of IL-6 were detectable in 16% of samples before LASIK treatment and in 30% of samples before PRK treatment. One h after the treatment IL-6 was detectable in 29% of samples for the LASIK group and 43% of samples for the PRK group, and 24 h after the treatment it was detectable in 19% of samples for the LASIK group and in 57% of samples for the PRK group. When we analyzed the dynamics of IL76 production in particular groups, we noticed that both in the LASIK and PRK group the number of samples with increased values of IL-6 after 1 h, and after 24 h, was con- siderably larger than the number of samples with decreased values of IL-6 after the intervention. Analyzing the dynamics of IL-6 concentration changes in the 1 h samples vs. 24 h samples there was a statistically significant increase in the number of samples with IL-6 concentration decline in the LASIK group, while at the same time no considerable changes occurred in the PRK group. Comparing average IL-6 values between the two treatment groups in all tear samples at 0 h, 1 h and 24 h after intervention a significantly higher level in the PRK group 24 h after procedure (p = 0.0031) was detected. CONCLUSION: IL-6 level in tears increases 1 h and 24 h after LASIK and PRK treatments. This increment is significantly larger 24 h after the treatment with the PRK method than with the LASIK method. Changes of IL-6 production levels in tears after excimer laser treatment indicate that this cytokine takes part in the corneal recovery process after stromal photoablation. PMID- 26040182 TI - Analysis of the symmetric configuration of the circle of Willis in a series of autopsied corpses. AB - INTRODUCTION: The forming of the blood vessels network configuration at the base of the brain and interconnecting of blood vessels during the embryogenesis is directly related to the phylogenetic development of the brain and brain structures. A blood vessel configuration at the brain base, in the form of a ring or a hexagon, stands in direct relation to the perfusion needs of certain parts of the brain during its primary differentiation. The aim of this paper was to determine the incidence of certain blood vessel configurations at the base of the brain and understanding their symmetry or asymmetry. METHODS: Analysis of the blood vessels at the base of the brain was performed on the autopsied subjects. The object of observation was the anterior segment of the circle of Willis consisting of C1- a. carotis interna (ICA), above a. communicaus posterior (PcoA), the segment A1 a. cerebri anterior (ACA) from a. carotis interna bifurcation to the a. communicans anterior (AcoA) and a communicans anterior itself, as well as the posterior segment consisting of PcoA and the segment P1- a. cerebri posterior (PCA) from the a. basilaris bifurcation to the PcoA. For the purpose of grouping the findings, the four basic configuration types of the circle of Willis were identified based on its symmetry or asymmetry. Type-A (symmetric circle of Willis), type-B (asymmetric circle of Willis' due to the unilateral hypoplastic A1-ACA); type-C (symmetric circle of Willis with bilateral symmetric changes on PcoA) and type-D (asymmetric circle of Willis due to the asymmetric changes on PcoA). RESULTS: Autosy was performed on 56 corpses. A total of 41 (73.2%) subjects were recorded with a symmetric configuration of the circle of Willis', of which 27 (48.2%) subjects had type A and 14 (25%) type C. The asymmetric configuration was present in 15 (26.8%) subjects, of whom 9 (16%) had type B and 6 (10.8%) subjects, of whom 9 (16%) had type B and 6 (10.8%) type D. The symmetric Willis group (73.2%) did not have a homogeneous finding that would fit into the schematic presentation of the symmetric type A and type C. A total of 17 (30.4%) findings were classified in this group of the so-called conditionally symmetric configurations. In all the cases, type B (16%) had unilaterally reduced diameter A1 and hyperplastic AcoA. CONCLUSION: The presence of asymmetric Willis configuration in 26.8% of the cases, which makes up more than one fourth, indicates that the asymmetric configurations do not represent a pathological form of connecting the blood vessels at the base of the brain, but rather one aspect of its adaptation. The forming of the basic types of configurations of the circle of Willis is associated with a tendency toward certain types of hemodynamic disorders and more frequent pathological changes in places of reduced resistance. PMID- 26040183 TI - Administration of iron in renal anemia. PMID- 26040184 TI - Application of concentrated growth factors in reconstruction of bone defects after removal of large jaw cysts--the two cases report. AB - INTRODUCTION: Coagulation and blood clot formation in bone defects is sometimes followed by retraction of a blood clot and serum extrusion, thus producing peripheral serum-filled spaces between bony wall and coagulum. This can result in a higher incidence of postoperative complications. Stabilization of blood coagulum, which enables successful primary healing, may be accomplished by autotransplantation, allotransplantation, xenotransplantation, or application of autologous platelet concentrate and concentrated growth factors (CGF). Case report. Two patients with large cystic lesions in the upper and lower jaw were presented. In both patients postoperative bony defects were filled with autologous fibrin rich blocks containing CGF. Postoperative course passed uneventfully. CONCLUSION: Application of fibrin rich blocks containing CGF is one of the possible methods for reconstruction of bone defects. CGF can be applied alone or mixed with a bone graft. The method is relatively simple, without risk of transmissible and allergic diseases and economically feasible. PMID- 26040185 TI - Treatment of a large radicular cyst-enucleation or decompression? AB - INTRODUCTION: Radicular cysts treatment involves surgical approach, more or less aggressive. However, treatment of large cystic lesions, including radicular cysts, causes some of dilemmas concerning the choice of the surgical method, especially the degree of radicalism. CASE REPORT: We presented a 65-year-old male patient with large radicular cyst in the mandible. A large elliptical multilocular radiolucency, located in the left side of the mandible, being in close vicinity to the mandibular canal, was registered at the orthopantomographic radiography. There was a risk of pathological fracture of the mandible. However, the cyst was completely removed by enucleation without intraoperative and postoperative complications. CONCLUSION: The presented case support the opinion that careful enucleation of large mandibular cysts may be done without complications, such as damages of surrounding anatomical structures or mandibular fracture. The authors indicate reasons for strong support of the undertaken surgical approach of treating large radicular cysts in the mandible. PMID- 26040186 TI - Radiofrequency ablation of anteroseptal accessory pathway--a challenge to the electrophysiologist. AB - INTRODUCTION: Anteroseptal accessory pathways (APs) are located in the apex of the triangle of Koch's connecting the atrial and ventricular septum in the region of the His bundle. Ablation of anteroseptal pathway locations remains a challenge to the electrophysiologist due to a very high risk of transiet or permanent atrioventricular (AV) block. CASE REPORT: A male, 18-year-old, patient was hospitalized due to radiofrequency (RF) ablation of APs. He was an active football player with frequent palpitations during efforts accompanied by dyspnea and lightheadedness, but without syncope. Electrocardiography on admission showed intermittent preexcitations. Intracardiac mapping showed the earliest ventricular activation that preceded surface electrocardiographic delta wave in anteroseptal region very close to the AV node and His bundle. Using a long vascular sheath for stabilization of the catheter tip, RF energy was delivered at the target site starting at very low energy levels and because of the absence of either PR prolongation, as well as accelerated junctional rhythm during the first 15 sec, the power was gradually increased to 40 W, so after application RF energy preexcitation was not registered. CONCLUSION: Despite this proximity to the His bundle and very high risk of transiet or permanent AV block anteroseptal APs can still be ablated successfully. PMID- 26040187 TI - An experience with colistin applied in treatment of imunocompromised patients with peritonitis on peritoneal dialysis. AB - INTRODUCTION: Immunocompromised patients, such as those with multiple myeloma on peritoneal dialysis, are particularly susceptible to the occurrence of peritonitis. CASE REPORT: We presented a 56-year-old female patient with a 10 year history of multiple myeloma. The patient was on peritoneal dialysis since 2010. During 2012 the patient had the first episode of peritonitis that was successfully managed, but in 2013 the second episode of peritonitis occured. Analysis of dialysate culture and exit site swab revealed the presence of multiresistant Acinetobacter spp., which was susceptible only to colistin. Prompt colistin therapy was administered at the doses of 100,000 units/day during six days, which resulted in complete recovery of the patient, as well as improvement of local abdominal findings. Gram-negative bacteria (genus Acinetobacter) are common causative agents in hospital-acquired infections. Studies confirmed susceptibility of Acinetobacter to colistin, which was also the case with the presented patient. Intravenous administration of colistin resulted in a complete remission of this severe, life-threatening peritonitis. CONCLUSION: Patients with multiple myeloma and renal failure are highly prone to severe life-threatening infections. PMID- 26040188 TI - Management of myelofibrosis during pregnancy: a case report. AB - INTRODUCTION: Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm that occurs most commonly in the decade six of life and it is very rare in the young persons. CASE REPORT: We reported a 28-year-old female patient with primary myelofibrosis who had a normal pregnancy and delivery in the week 40 of pregnancy without any complications. Two years before the diagnosis of PMF she had normal pregnancy. The patient was treated with interferon-alpha and low dose aspirin during the whole pregnancy and with low-molecular-weight heparin a week before delivery and 6 weeks after. The patient had no complications during pregnancy. She delivered in term with healthy, normal baby weight. CONCLUSION: Decision about treatment strategy of pregnancy associated hematologic malignancies should be made for each patient individually. PMID- 26040190 TI - OHIP-TMDs: a patient-reported outcome measure for temporomandibular disorders. AB - OBJECTIVES: This research aims to assess the test-retest reliability, the face, content and known groups validity, and responsiveness to change, of OHIP-TMDs, a 22-item TMDs-specific version of the Oral Health Impact Profile (OHIP). METHODS: Test-retest reliability - A group of patients with TMDs (n = 20) was administered OHIP-TMDs twice before initial consultation with a 2-week interval. Face and content validity - Content validity index assessments were undertaken with professionals and patients. Known groups validity - Participants (n = 76) with confirmed Axis 1 RDC/TMD diagnoses completed OHIP-TMDs prior to TMDs treatment. Their responses were compared, using inferential statistics, with those of age- and gender-matched controls. Responsiveness to change - Using the same 76 participants, a comparison was made of OHIP-TMDs with OHIP-49 (order of administration randomized) both at baseline and 3 months after starting treatment. RESULTS: OHIP-TMDs showed good test-retest reliability ICC [2,1] 0.805 (95% CI: 0.565, 0.918); good face and content validity; significant differences (P < 0.001) between controls and participants demonstrating known groups validity. Its responsiveness to change was similar to OHIP-49. CONCLUSIONS: OHIP TMDs is an appropriate biopsychosocial, patient-centred, outcome measure for assessing QOL in patients with TMDs. It is less than half the length of OHIP-49 and contains proportionately more items relevant to TMDs. PMID- 26040191 TI - Low-grade serous carcinoma: molecular features and contemporary treatment strategies. AB - Epithelial ovarian carcinoma consists of several subtypes, including high-grade and low-grade serous carcinoma. In the recent past, women with all subtypes of epithelial ovarian carcinoma have been treated similarly and are included in the same clinical trials. However, a distinction has emerged between the type I, low grade tumors and the type 2, higher-grade epithelial malignancies. Low-grade serous carcinoma exhibits different molecular and clinical features from the other epithelial subtypes, as well as some degree of chemotherapy resistance. This review summarizes the genetic, molecular and clinical characteristics of low grade serous disease and provides an appraisal of the management strategies. PMID- 26040192 TI - Analysis of iron superoxide dismutase-encoding DNA vaccine on the evolution of the Leishmania amazonensis experimental infection. AB - The present work aimed to evaluate the immunogenicity of Leishmania amazonensis iron superoxide dismutase (SOD)-encoding DNA experimental vaccine and the protective properties of this DNA vaccine during infection. The SOD gene was subcloned into the pVAX1 plasmid, and it was used to immunize BALB/c mice. Twenty one days after the last immunization, mice were sacrificed (immunogenicity studies) or subcutaneously challenged with L. amazonensis (studies of protection), and alterations in cellular and humoral immune responses were evaluated, as well as the course of infection. Mice only immunized with pVAX1-SOD presented increased frequencies of CD4(+) IFN-gamma(+), CD8(+)IFN-gamma(+) and CD8(+)IL-4(+) lymphocytes; moreover, high levels of IgG2a were detected. After challenge, mice that were immunized with pVAX1-SOD had increased frequencies of the CD4(+)IL-4(+), CD8(+)IFN-gamma(+) and CD8(+)IL-4(+) T lymphocytes. In addition, the lymph node cells produced high amounts of IFN-gamma and IL-4 cytokines. Increased IgG2a was also detected. The pattern of immunity induced by pVAX1-SOD partially protected the BALB/c mice from a challenge with L. amazonensis, as the animals presented reduced parasitism and lesion size when compared to controls. Taken together, these results indicate that leishmanial SOD modulates the lymphocyte response, and that the elevation in IFN-gamma possibly accounted for the decreased skin parasitism observed in immunized animals. PMID- 26040193 TI - Public stigma in intellectual disability: do direct versus indirect questions make a difference? AB - BACKGROUND: Stigma may negatively impact individuals with intellectual disabilities (ID). However, most studies in the field have been based on the use of direct measurement methods for assessing stigma. This study examined public stigma towards individuals with ID within a representative sample of the Israeli public by comparing direct versus indirect questioning. METHODS: Vignette methodology was utilised with two questionnaire versions. In the direct questionnaire (n = 306), the participants were asked how they would think, feel and behave if a man with ID asked them a question in a public place. In the indirect questionnaire (n = 301), the participants were asked to report how a hypothetical 'other man' would think, feel and behave in the same situation. RESULTS: Higher levels of stigma were reported among participants that answered the indirect questionnaire version. Furthermore, among those participants that answered the indirect questionnaire version, subjective knowledge of ID was a less important correlate of stigma than for those participants that answered the direct questionnaire. CONCLUSION: Several explanations are suggested for the finding that indirect questioning elicits more negative stigmatic attitudes. Among others, indirect questioning may be a more appropriate methodology for eliciting immediate beliefs. Furthermore, the results call for implementing a comprehensive, multi-level programme to change stigma. PMID- 26040195 TI - The straight leg raise test for hamstring contractures: what is the contribution of sciatic nerve irritation? PMID- 26040194 TI - Intensive care practices in brain death diagnosis and organ donation. AB - We conducted a multicentre study of 1844 patients from 42 Spanish intensive care units, and analysed the clinical characteristics of brain death, the use of ancillary testing, and the clinical decisions taken after the diagnosis of brain death. The main cause of brain death was intracerebral haemorrhage (769/1844, 42%), followed by traumatic brain injury (343/1844, 19%) and subarachnoid haemorrhage (257/1844, 14%). The diagnosis of brain death was made rapidly (50% in the first 24 h). Of those patients who went on to die, the Glasgow Coma Scale on admission was <= 8/15 in 1146/1261 (91%) of patients with intracerebral haemorrhage, traumatic brain injury or anoxic encephalopathy; the Hunt and Hess Scale was 4-5 in 207/251 (83%) of patients following subarachnoid haemorrhage; and the National Institutes of Health Stroke Scale was >= 15 in 114/129 (89%) of patients with strokes. Brain death was diagnosed exclusively by clinical examination in 92/1844 (5%) of cases. Electroencephalography was the most frequently used ancillary test (1303/1752, 70.7%), followed by transcranial Doppler (652/1752, 37%). Organ donation took place in 70% of patients (1291/1844), with medical unsuitability (267/553, 48%) and family refusal (244/553, 13%) the main reasons for loss of potential donors. All life-sustaining measures were withdrawn in 413/553 of non-donors (75%). PMID- 26040197 TI - Size and polydispersity trends found in gold nanoparticles synthesized by laser ablation in liquids. AB - In this work, the effect of laser fluence on Au nanoparticles synthesized via laser ablation in liquids is studied for 1064 nm irradiation with 25 ps pulses. Particle size and polydispersity is found to display a negative trend with fluences up to ~14 J cm(-2). Erratic size tendencies are observed at low fluences, i.e. slightly above the ablation threshold. This overall behavior is reconciled with recent computational studies and to fluctuations in ablation due to surface morphology. The effectiveness of the commonly used surfactant sodium dodecyl sulfate (SDS) is shown to diminish at higher fluence due to pyrolysis. In addition, shadowgraph imaging of the cavitation bubble is shown as a useful technique for determining the ablation threshold. Our findings are in good agreement with threshold values determined by traditional methods and are comparable to computational values, when differences in pulse duration are taken into account. PMID- 26040198 TI - High-Throughput Generation of Emulsions and Microgels in Parallelized Microfluidic Drop-Makers Prepared by Rapid Prototyping. AB - We describe the preparation of rapid prototyped parallelized microfluidic drop maker devices. The manufacturing technique facilitates stacking of the drop makers vertically on top of each other allowing for a reduced footprint and minimized dead-volume through efficient design of the distribution channels. We showcase the potential of the additive manufacturing technique for microfluidics and the performance of the parallelized device by producing large amounts of microgels with a diameter of ca. 500 MUm, a size that is inaccessible using traditional synthetic approaches. PMID- 26040196 TI - A database for the taxonomic and phylogenetic identification of the genus Bradyrhizobium using multilocus sequence analysis. AB - BACKGROUND: Biological nitrogen fixation, with an emphasis on the legume-rhizobia symbiosis, is a key process for agriculture and the environment, allowing the replacement of nitrogen fertilizers, reducing water pollution by nitrate as well as emission of greenhouse gases. Soils contain numerous strains belonging to the bacterial genus Bradyrhizobium, which establish symbioses with a variety of legumes. However, due to the high conservation of Bradyrhizobium 16S rRNA genes - considered as the backbone of the taxonomy of prokaryotes - few species have been delineated. The multilocus sequence analysis (MLSA) methodology, which includes analysis of housekeeping genes, has been shown to be promising and powerful for defining bacterial species, and, in this study, it was applied to Bradyrhizobium, species, increasing our understanding of the diversity of nitrogen-fixing bacteria. DESCRIPTION: Classification of bacteria of agronomic importance is relevant to biodiversity, as well as to biotechnological manipulation to improve agricultural productivity. We propose the construction of an online database that will provide information and tools using MLSA to improve phylogenetic and taxonomic characterization of Bradyrhizobium, allowing the comparison of genomic sequences with those of type and representative strains of each species. CONCLUSION: A database for the taxonomic and phylogenetic identification of the Bradyrhizobium, genus, using MLSA, will facilitate the use of biological data available through an intuitive web interface. Sequences stored in the on-line database can be compared with multiple sequences of other strains with simplicity and agility through multiple alignment algorithms and computational routines integrated into the database. The proposed database and software tools are available at http://mlsa.cnpso.embrapa.br, and can be used, free of charge, by researchers worldwide to classify Bradyrhizobium, strains; the database and software can be applied to replicate the experiments presented in this study as well as to generate new experiments. The next step will be expansion of the database to include other rhizobial species. PMID- 26040199 TI - Composite SERS-based satellites navigated by optical tweezers for single cell analysis. AB - Herein, we have designed composite SERS-active micro-satellites, which exhibit a dual role: (i) effective probes for determining cellular composition and (ii) optically movable and easily detectable markers. The satellites were synthesized by the layer-by-layer assisted decoration of silica microparticles with metal (gold or silver) nanoparticles and astralen in order to ensure satellite SERS based microenvironment probing and satellite recognition, respectively. A combination of optical tweezers and Raman spectroscopy can be used to navigate the satellites to a certain cellular compartment and probe the intracellular composition following cellular uptake. In the future, this developed approach may serve as a tool for single cell analysis with nanometer precision due to the multilayer surface design, focusing on both extracellular and intracellular studies. PMID- 26040200 TI - The effects of radicular dentine treated with double antibiotic paste and ethylenediaminetetraacetic acid on the attachment and proliferation of dental pulp stem cells. AB - AIM: This study explored the effects of dentine treated with two concentrations of double antibiotic paste (DAP) and ethylenediaminetetraacetic acid (EDTA) on the attachment and proliferation of dental pulp stem cells (DPSCs). MATERIALS AND METHODS: Radicular dentine samples were prepared with identical dimensions and randomized into six groups (n = 4). Four groups were treated with double antibiotic paste (DAP) at concentrations of 500 mg ml(-1) or 1 mg ml(-1) with or without EDTA. The other two groups were treated with EDTA only or received no treatment. DPSCs were seeded on each dentine sample (10 000 cells per sample). Lactate dehydrogenase activity assays were used to calculate the attached DPSCs after 1 day of incubation. Water soluble tetrazolium assays were performed to investigate DPSCs proliferation on the treated dentine samples after three additional days of incubation. Two-way anova followed by Tukey-Kramer tests was used for statistical analyses (alpha = 0.05). RESULTS: Dentine treated with 1 or 500 mg ml(-1) of DAP followed by EDTA caused significant increases in DPSCs attachment compared to the dentine treated with the DAP alone. The 500 mg ml(-1) of DAP with or without EDTA caused significant reductions in DPSCs proliferation. However, the treatment of dentine with 1 mg ml(-1) of DAP did not have significant negative effects on DPSCs proliferation regardless of the use of EDTA. CONCLUSION: The use of 1 mg ml(-1) of DAP followed by 10 min of irrigation with EDTA in endodontic regeneration procedure may have no negative effects on the attachment and proliferation of DPSCs. PMID- 26040201 TI - Income, cumulative risk, and longitudinal profiles of hypothalamic-pituitary adrenal axis activity in preschool-age children. AB - Environmental risk predicts disrupted basal cortisol levels in preschool children. However, little is known about the stability or variability of diurnal cortisol morning levels or slope patterns over time in young children. This study used latent profile analysis to identify patterns of the hypothalamic-pituitary adrenal axis activity during the preschool period. Using a community sample (N = 306), this study measured income, cumulative risk, and children's diurnal cortisol (morning level and slope) four times across 2.5 years, starting when children were 36 months old. Latent profile analysis profiles indicated that there were predominantly stable patterns of diurnal cortisol level and slope over time and that these patterns were predicted by income and cumulative risk. In addition, there were curvilinear relations of income and cumulative risk to profiles of low morning cortisol level and flattened diurnal slope across time, suggesting that both lower and higher levels of income and cumulative risk were associated with a stress-sensitive physiological system. Overall, this study provides initial evidence for the role of environmental risk in predicting lower, flattened basal cortisol patterns that remain stable over time. PMID- 26040202 TI - Inability to perform because of pain/injury in elite adult Irish dance: A prospective investigation of contributing factors. AB - Previous research in Irish dancing (ID) has recorded high levels of pain/injury. Screening protocols in other genres have been developed to identify at-risk dancers. The aims of the study were to examine the factors that relate to absence from dancing because of musculo-skeletal pain/injury in ID, and to inform guidelines for the development of an evidence-based screening protocol. Baseline subjective data (n = 85) and physical data (n = 84) were gathered. Subjects completed a monthly online questionnaire for 1 year providing data on general physical and psychological health and rates of pain/injury. Subjects were allocated to a "More Time Absent (MTA)" or "Less Time Absent (LTA)" category depending on their duration of absence from performance over the year. Eighty four subjects completed the year-long follow-up (MTA: n = 32; LTA: n = 52). Two hundred seventy-eight complaints of pain/injury were recorded. Factors significantly associated with membership of the MTA group included greater anger hostility (P = 0.003), more subjective health complaints (P = 0.026), more severe previous pain/injury (P = 0.017), more general everyday pain (P = 0.020), more body parts affected by pain/injury (P = 0.028), always/often dancing in pain (P = 0.028), and insufficient sleep (P = 0.043). Several biopsychosocial factors appear to be associated with absence from ID because of pain/injury. Biopsychosocial screening protocols and prevention strategies may best identify at-risk dancers. PMID- 26040203 TI - ATTITUDES TOWARDS AND PRACTICE OF SEXUALITY AMONG UNIVERSITY STUDENTS IN LEBANON. AB - Sexuality is still a taboo in Middle Eastern countries, and Lebanon is no exception. This study's objective was to evaluate attitudes towards sexuality and its practice among university students in Lebanon and assess their respective correlates. The cross-sectional study was carried out among students selected from seventeen universities across Lebanon. The participants received a self administered standardized questionnaire that assessed their attitudes towards sexuality. It included questions on socio-demographic factors, risk-taking, risky behaviours and sexuality-related questions. Among 3384 students, 2700 (79.8%) answered the questions on sexuality. Around 15% had engaged in sexual activity, while 20% were regularly sexually active. Among males, 34.8% had never had sexual activity, 29.9% had tried it and 35.3% were regularly sexually active. Among females the results were respectively 85.1%, 5.3% and 9.6% (p<0.001). Only 36% regularly used condoms during their relationships. A liberal attitude towards sex, male sex, motives for risky behaviours, current cigarette smoking and problematic alcohol consumption were associated with sexual activity. Realizing that risky behaviours are dangerous, health concerns related to sexual relationships and a liberal attitude towards sex were associated with regular condom use. However, being bothered by condoms and female sex were inversely associated with condom use. Finally, participants who had motives for, and those who felt excited about risky behaviours, and those reporting current cigarette and waterpipe smoking and problematic alcohol consumption (beta=0.600; p=0.002) embraced a more liberal attitude towards sex. Conversely, females (beta=-7.58; p<0.001) and individuals who considered risky behaviours as dangerous reported an unfavourable attitude towards sexuality. A substantial proportion of Lebanese university students have regular sexual activity, but a low percentage use condoms for protection. Interventions are required among males in particular in view of these attitude and behavioural changes towards sexuality. PMID- 26040204 TI - Direct-write three-dimensional nanofabrication of nanopyramids and nanocones on Si by nanotumefaction using a helium ion microscope. AB - The recently commercialized helium ion microscope (HIM) has already demonstrated its outstanding imaging capabilities in terms of resolution, surface sensitivity, depth of field and ease of charge compensation. Here, we show its exceptional patterning capabilities by fabricating dense lines and three-dimensional (3D) nanostructures on a Si substrate. Small focusing spot size and confined ion-Si interaction volume of a high-energy helium ion beam account for the high resolution in HIM patterning. We demonstrate that a set of resolvable parallel lines with a half pitch as small as 3.5 nm can be achieved. During helium ion bombardment of the Si surface, implantation outperforms milling due to the small mass of the helium ions, which produces tumefaction instead of depression in the Si surface. The Si surface tumefaction is the result of different kinetic processes including diffusion, coalescence and nanobubble formation of the implanted ions, and is found to be very stable structurally at room temperature. Under appropriate conditions, a linear dependence of the surface swollen height on the ion doses can be observed. This relation has enabled us to fabricate nanopyramids and nanocones, thus demonstrating that HIM patterning provides a new 'bottom-up' approach to fabricate 3D nanostructures. This surface tumefaction method is direct, both positioning and height accurate, and free of resist, etch, mode and precursor, and it promises new applications in nanoimprint mold fabrication and photomask clear defect reparation. PMID- 26040205 TI - Biological Applications of Supramolecular Assemblies Designed for Excitation Energy Transfer. PMID- 26040206 TI - Morphological and attachment changes of Lamellodiscus theroni (Monogenea: Diplectanidae) during its post-larval development on fish. AB - Species of the genus Lamellodiscus Johnston et Tiegs, 1922 (Monogenea: Diplectanidae) are characterised by a complex haptor bearing many different attachment elements: two pairs of main hooks joined by medial bars, 14 peripheral marginal hooks and one or two lamellodiscs, formed by several overlapping sclerotised plates (lamellae). These haptoral structures appear gradually during parasite development and, therefore, attachment strategies vary with developmental stage. The main aim of this work was to study the developmental changes of Lamellodiscus theroni Amine, Euzet et Kechemir-Issad, 2007 under experimental conditions, with special attention to the gradual variations in attachment strategies and the pathological implications. Throughout the gradual development of the sclerotised structures, six developmental phases were distinguished in L. theroni: phase I, with only 14 peripheral marginal hooks; phase II, with main hooks (ventral and dorsal) formed; phase III, with ventral bar formed; phase IV, with dorsal bars formed; phase V, with dorsal and ventral lamellodiscs formed; and phase VI, adult stage with male copulatory organ formed. During development, parasites attach to different parts of the first and secondary gill lamellae and the mode of attachment changes from unspecific stage, i.e. based on piercing any flat gill tissue in the early stages, through an intermediate stage when ventral and dorsal main hooks are completely functional and parasites become restricted to the interlamellar space, and finally to the definitive adult attachment stage when lamellodiscs are fully developed. The timing of key events in the development of L. theroni was used to establish adequate intervals for anthelmintic drug administration. PMID- 26040207 TI - Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations. AB - Human leukocyte immunoglobulin-like receptors (LILR) are a family of 11 functional genes encoding five activating (LILRA1, 2, 4-6), five inhibitory (LILRB1-5) and one soluble (LILRA3) form. The number of LILR genes is conserved among individuals, except for LILRA3 and LILRA6, which exhibit copy-number variations. The LILR genes are rapidly evolving and showing large interspecies differences, making it difficult to analyze the functions of LILR using an animal model. LILRs are expressed on various cells such as lymphoid and myeloid cells and the expression patterns are different from gene to gene. The LILR gene expression and polymorphisms have been reported to be associated with autoimmune and infectious diseases such as rheumatoid arthritis and cytomegalovirus infection. Although human leukocyte antigen (HLA) class I is a well-characterized ligand for some LILRs, non-HLA ligands have been increasingly identified in recent years. LILRs have diverse functions, including the regulation of inflammation, immune tolerance, cell differentiation and nervous system plasticity. This review focuses on the genetic and functional diversity of the LILR family. PMID- 26040208 TI - Admixture mapping of genetic variants for uterine fibroids. AB - Uterine leiomyoma (UL) are benign neoplasms arising from the smooth muscle cells of the uterus. One of the established risk factors for UL is African American ethnicity. Studies have consistently shown that African Americans have two to three times higher risk compared with that of non-Hispanic Whites. However, there is still no adequate explanation for the higher risk among African Americans. To investigate the genetic contribution to the observed difference between the African American and European American populations, we conducted an admixture scan in 525 eligible African American women participants to the NIEHS uterine fibroid study (NIEHS-UFS). In models with no stratification, we found multiple genomic regions showing significant and suggestive evidence of association, with chromosomal band 2q32.2 at rs256552 showing the highest score (Z-score=7.86, Bonferroni adjusted P-value=5.5 * 10(-12)) consistent with the suggestive evidence reported for this genomic region in the Black Women's Health Study. However, in models stratified by the body mass index (BMI) covariate, chromosome 1q42.2 was the sole genomic region that consistently showed suggestive associations across the BMI categories tested (Z-scores ?-3.96, Bonferroni adjusted P-values ?0.107). In age-stratified models, a significant association was observed in the older category (age >40) reaching a Z-score of 6.44 (Bonferroni-adjusted P-value=1.64 * 10(-7)) at rs256552. The mean percentage of European ancestry among cases was lower than that among controls in the NIEHS-UFS study. However, our study did not show a significant association between mean percentage of European ancestry and UL. PMID- 26040209 TI - Awareness, attitudes and perspectives of direct-to-consumer genetic testing in Greece: a survey of potential consumers. AB - Direct-to-consumer genetic testing (DTCGT) is now offered by numerous companies. The present survey aimed to explore awareness, interest, reasons to take and refuse DTCGT, and understanding of results amongst 725 higher education students in Greece. A third of the responders were aware of DTCGT and interest was dependent on cost. More than 60% of the participants would undergo DTCGT to learn more about their health, to warn their children, so that their doctor can monitor their health and change their lifestyle. Nevertheless, they would prefer to consult their doctor first and expressed concerned about their personal data. After receiving results from a hypothetical DTC genetic test predicting higher risk for colon cancer, 59.5% of the responders thought that they could understand the results but 46.1% believed that the results have diagnostic value. In total, 83.6% of the participants would ask their doctor to explain the results and 70.4% would discuss results with their family. In conclusion, the majority of higher education students in Greece appreciate the benefits of genetic testing but with the involvement of their doctor. A physician's participation in the process and informing the public about the true value of genetic testing, are crucial to avoid misinterpretation of DTCGT results. PMID- 26040211 TI - Application of fuzzy control on the electrocoagulation process to treat textile wastewater. AB - Electrocoagulation (EC) is one of the effective ways of removing colour, turbidity and chemical oxygen demand from wastewater. In spite of the high-power consumption, EC has been gaining increasingly more attention due to its simplicity and effectiveness compared to the technical challenges and costs of conventional processes. Conductivity and pH are the main factors that affect the efficiency of wastewater treatment and its cost. Controlling the conductivity and pH of a wastewater treatment system is very important since it directly determines the amount of energy that must be used. We propose the use of fuzzy logic to control both conductivity and pH during the EC process, and we apply this approach in the treatment of textile wastewater. Removal efficiencies and operating costs of the EC process for dynamic and fuzzy-controlled cases are compared. PMID- 26040210 TI - Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature. AB - Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3'-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father-daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation. PMID- 26040212 TI - Expression and activity of V-H+ -ATPase in gill and kidney of marbled eel Anguilla marmorata in response to salinity challenge. AB - The full-length complementary (c)DNA of vacuolar-type-H(+) -ATPase B1 gene (vhab1) in marbled eel Anguilla marmorata with 1741 base pairs (bp) was identified. It contained a 1512 bp open reading frame encoding a polypeptide with 503 amino acids (55.9 kDa), an 83 bp 5'-untranslated region (UTR) and a 146 bp 3' UTR. The expression levels of A. marmorata vhab1 in gill and kidney of A. marmorata were evaluated at different intervals during the exposure to various salinities (0, 10 and 25). The results indicated that the expression levels of A. marmorata vhab1 messenger (m)RNA in gill and kidney had a significant increase and reached the highest level at 1 h in brackish water (BW, salinity 10) group and 6 h in seawater (SW, salinity 25) group. Therefore, salinity did affect the relative expression level of A. marmorata vhab1 mRNA in gills, which exhibited the enhancement by c. 44 times in SW group when compared with that in fresh water. No remarkable difference in the expression of A. marmorata vhab1 mRNA was observed after 15 days of SW exposure (P > 0.05). V-H(+) -ATPase activity exhibited an increase by two- to three-fold when compared with that in gill and kidney from the control group. The consequence primarily suggested that A. marmorata vhab1 gene product in elvers from A. marmorata plays an important role in adaptation response to SW. PMID- 26040213 TI - Loudness Context Effects in Normal-Hearing Listeners and Cochlear-Implant Users. AB - Context effects in loudness have been observed in normal auditory perception and may reflect a general gain control of the auditory system. However, little is known about such effects in cochlear-implant (CI) users. Discovering whether and how CI users experience loudness context effects should help us better understand the underlying mechanisms. In the present study, we examined the effects of a long-duration (1-s) intense precursor on the loudness relations between shorter duration (200-ms) target and comparison stimuli. The precursor and target were separated by a silent gap of 50 ms, and the target and comparison were separated by a silent gap of 2 s. For normal-hearing listeners, the stimuli were narrowband noises; for CI users, all stimuli were delivered as pulse trains directly to the implant. Significant changes in loudness were observed in normal-hearing listeners, in line with earlier studies. The CI users also experienced some loudness changes but, in contrast to the results from normal-hearing listeners, the effect did not increase with increasing level difference between precursor and target. A "dual-process" hypothesis, used to explain earlier data from normal hearing listeners, may provide an account of the present data by assuming that one of the two mechanisms, involving "induced loudness reduction," was absent or reduced in CI users. PMID- 26040214 TI - Elastic Properties of the Annular Ligament of the Human Stapes--AFM Measurement. AB - Elastic properties of the human stapes annular ligament were determined in the physiological range of the ligament deflection using atomic force microscopy and temporal bone specimens. The annular ligament stiffness was determined based on the experimental load-deflection curves. The elastic modulus (Young's modulus) for a simplified geometry was calculated using the Kirchhoff-Love theory for thin plates. The results obtained in this study showed that the annular ligament is a linear elastic material up to deflections of about 100 nm, with a stiffness of about 120 N/m and a calculated elastic modulus of about 1.1 MPa. These parameters can be used in numerical and physical models of the middle and/or inner ear. PMID- 26040216 TI - Global health governance - the next political revolution. AB - The recent Ebola crisis has re-opened the debate on global health governance and the role of the World Health Organization. In order to analyze what is at stake, we apply two conceptual approaches from the social sciences - the work on gridlock and the concept of cosmopolitan moments - to assess the ability of the multilateral governance system to reform. We find that gridlock can be broken open by a health crisis which in turn generates a political drive for change. We show that a set of cosmopolitan moments have led to the introduction of the imperative of health in a range of policy arenas and moved health into 'high politics' - this has been called a political revolution. We contend that this revolution has entered a second phase with increasing interest of heads of state in global health issues. Here lies the window of opportunity to reform global health governance. PMID- 26040215 TI - Current and emerging medications for overweight or obesity in people with comorbidities. AB - Recently, the recognition of obesity as a complex disease that requires chronic management has become more widespread. There has also been a movement away from a focus on body mass index alone, and toward the management of obesity-related comorbidities as well as excess weight. This article examines the current and emerging pharmacological options for weight management in people with overweight or obesity who have, or are at a high risk of, weight-related comorbidities. In the USA, the current options for pharmacological weight management are phentermine (indicated for short-term use only), orlistat, combined phentermine/topiramate extended release, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg. Currently, orlistat, naltrexone/bupropion and liraglutide 3.0 mg are approved in Europe. All of the above-mentioned medications have shown weight-loss efficacy versus placebo. Those approved for long-term weight management have also been associated with improvements in weight-related comorbidities, such as hypertension, prediabetes, diabetes or dyslipidaemia, or related biomarkers. As with all drugs, the safety and tolerability profiles of medications for weight management should be considered alongside their efficacy to ensure correct use. Additional medications for weight management that are in clinical development include bupropion/zonisamide and beloranib. The field of obesity treatment is advancing with a number of medications being recently approved, and with other pharmacological options emerging. PMID- 26040217 TI - Besifloxacin in the management of bacterial infections of the ocular surface. AB - Acute bacterial conjunctivitis is a common infection of the ocular surface. Increasing rates of bacterial resistance have prompted the development of new antibiotics with improved activity against the bacterial species most often found in this disease. Besifloxacin is the first topical chlorofluoroquinolone developed solely for ophthalmic use. Studies have attested to its in vitro potency against a broad range of bacteria, as well as its efficacy in clinical studies of bacterial conjunctivitis when dosed 2 or 3 times a day. This review provides an up-to-date summary of studies on causative pathogens in acute bacterial conjunctivitis; recent geographic trends in bacterial resistance among ocular pathogens, including that of methicillin-resistant Staphylococcus aureus; the efficacy of besifloxacin in preclinical and clinical studies; its safety; and the role of besifloxacin in combating resistant strains. Further, this review provides a brief update on bacterial keratitis, causative pathogens, the development of resistance among those pathogens, and the potential role of besifloxacin in the treatment of bacterial keratitis. PMID- 26040218 TI - Evaluation of primary open-angle glaucoma clinical practice guidelines. AB - OBJECTIVE: To evaluate the methodologic quality of 3 primary open-angle glaucoma (POAG) clinical practice guidelines (CPGs). DESIGN: The CPGs were assessed with the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. PARTICIPANTS: Four authors (A.M.W., C.M.W., B.K.Y., D.J.W.) performed independent assessments of POAG CPGs. METHODS: POAG CPGs published by the American Academy of Ophthalmology (AAO), Canadian Ophthalmological Society (COS), and National Institute for Health and Care Excellence (NICE) were appraised using the AGREE II instrument's 6 domains (Scope and Purpose, Stakeholder Involvement, Rigor of Development, Clarity of Presentation, Applicability, and Editorial Independence) and Overall Assessment score summarizing guideline quality across all domains. RESULTS: Scores ranged from 28% to 85% for the AAO CPG, 51% to 96% for the COS CPG, and 55% to 97% for the NICE CPG. Intraclass correlation coefficients for the reliability of mean scores for the AAO, COS, and NICE CPGs were 0.89, 0.86, and 0.74; 95% CIs were 0.80 to 0.95, 0.74 to 0.93, and 0.51 to 0.87, respectively. The strongest domains were Scope and Purpose (AAO, COS, NICE) and Clarity of Presentation (COS, NICE). The weakest domains were Stakeholder Involvement (AAO, COS) and Editorial Independence (AAO, COS, NICE). CONCLUSIONS: Future POAG CPGs can be improved by addressing potential conflicts of interest within the development group, ensuring transparency of guideline development methodology, and involving all relevant stakeholders in guideline development and review. PMID- 26040219 TI - Effect of endoscopic cyclophotocoagulation on refractive outcomes when combined with cataract surgery. AB - OBJECTIVE: To determine the difference between predicted and actual refractive outcomes after combined endoscopic cyclophotocoagulation and cataract surgery (phaco-ECP) in patients with open-angle glaucoma (OAG). DESIGN: Retrospective case-control study of patients with OAG who underwent phaco-ECP compared with cataract surgery alone. PARTICIPANTS: Eighty-three patients with OAG, aged 55 to 91 years, who underwent a combined phaco-ECP procedure and 58 biometry- and age matched control patients with OAG who underwent cataract surgery alone. METHODS: Patient records were retrospectively reviewed at the Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis (St. Louis, Mo.). The primary outcome was the difference in predicted and actual refractive outcomes in patients undergoing either phaco-ECP or standard cataract surgery. RESULTS: Compared with phaco alone, the difference in predicted versus actual postoperative results was more myopic in the phaco-ECP group (0.029, 0.110, and -0.095 vs -0.169, -0.325, and -0.312 [p < 0.05] for Sanders, Retzlaff, Kraff/Theoretical, Hoffer Q, and Holladay, respectively). Moreover, the F test for variability showed significantly more variability in refractive outcomes in the phaco-ECP group compared with standard cataract surgery. CONCLUSIONS: Patients undergoing phaco-ECP may have postoperative refractive errors that may vary from that predicted preoperatively more so than in cataract surgery alone. Surgeons may consider analyzing their results to determine whether any adjustment should be made to lens power selection when performing phaco-ECP. PMID- 26040220 TI - Comparison of glaucoma knowledge and referral practices among family physicians with ophthalmologists' expectations. AB - OBJECTIVE: To compare family physicians' glaucoma knowledge and clinical skills with ophthalmologists' expectations. DESIGN: An electronic cross-sectional survey of family physicians and ophthalmologists. PARTICIPANTS: Participants included members of the Canadian Ophthalmological Society, Canadian Glaucoma Society, and the American Glaucoma Society, as well as family physicians in the Canadian Medical Directory and the Society of Rural Physicians of Canada listserv. METHODS: Two complementary surveys were developed to evaluate family physicians' glaucoma knowledge and basic examination skills, and ophthalmologists' expected level of family physician clinical knowledge and skills. chi(2) tests identified differences between family physician and ophthalmologist responses. Differences in family physician knowledge based on practice location and frequency of patient visits with a diagnosis of glaucoma were also evaluated. RESULTS: A total of 142 ophthalmologists and 110 family physicians completed the survey. The majority (82%) of family physicians reported seeing patients with diagnosed glaucoma weekly, monthly, or semiannually. Significantly fewer family physicians than expected (p < 0.001) identified African descent (46%) and corticosteroid use (84%) as glaucoma risk factors. Family physicians were significantly less likely to refer based on risk factors (72%) than expected by ophthalmologists (91%; p < 0.001). Only 28% of family physicians were comfortable performing direct ophthalmoscopy, and 37% were comfortable checking for a relative afferent pupillary defect. A significant percentage of family physicians lacked knowledge of glaucoma medications (30%) and side effects (57%). CONCLUSIONS: This study revealed significant disparities in family physician glaucoma knowledge, clinical examination skills, and referral practices. Educational materials should target these knowledge gaps. PMID- 26040221 TI - Efficacy/safety of ranibizumab monotherapy or with laser versus laser monotherapy in DME. AB - OBJECTIVE: To compare the efficacy and safety of ranibizumab 0.5 mg intravitreal injection, as monotherapy or in combination with laser, with laser monotherapy in patients with visual impairment caused by diabetic macular edema. DESIGN: Twelve month, multicentre, open-label, parallel-group, randomized, active-control study. PARTICIPANTS: A total of 220 (ranibizumab monotherapy: n = 75, ranibizumab + laser: n = 73, laser monotherapy: n = 72) patients with a diagnosis of type I or II diabetes and visual impairment caused by macular edema were included in the efficacy analysis. METHODS: Ranibizumab was initiated with a fixed loading phase of 3 monthly injections followed by as needed therapy until stable vision achievement. Efficacy end points were the change in best corrected visual acuity (BCVA), change in central retinal thickness (CRT) measured by optical coherence tomography, proportion achieving a 15-letter BCVA gain, and 12-month Visual Function Questionnaire-25 (VFQ-25) score. Safety was assessed with the incidence and severity of adverse events. RESULTS: At 12 months, significant (p < 0.001) mean BCVA improvements were observed for both the ranibizumab monotherapy (+8.9 [95% confidence interval (CI) 7.0-10.7] letters) and the ranibizumab + laser (+8.2 [95% CI 6.0-10.4] letters) groups compared with the laser monotherapy group (+0.3 [95% CI -2.9 to 3.5] letters). Similarly, a better response in terms of CRT improvement, BCVA letter gain, and VFQ-25 was observed in both ranibizumab groups compared with laser monotherapy. The safety profile was comparable in the 2 ranibizumab groups. CONCLUSIONS: Ranibizumab as monotherapy or combined with laser resulted in significantly higher improvements in visual acuity and vision related quality of life at month 12 as compared with laser monotherapy. PMID- 26040222 TI - Medical student and patient perceptions of quality of life associated with vision loss. AB - OBJECTIVE: Because most medical schools in the United States and Canada require no formal ophthalmology training, the authors queried medical student and ophthalmic patients to compare their perceptions of the quality of life (QOL) associated with vision loss. DESIGN: Cross-sectional comparative study of consecutive medical students and patients with vision loss using a validated, reliable, time trade-off utility instrument. PARTICIPANTS: Consecutive Jefferson Medical College medical students (cohort 1: 145 second-year student; cohort 2: 112 third-year/fourth-year students) and 283 patients with vision loss (patient cohort). METHODS: Time trade-off vision utilities with anchors of 0.0 (death) to 1.0 (normal vision permanently) were used to quantify the QOL associated with vision loss. Students were asked to assume they had: (i) mild vision loss (20/40 to 20/50 vision in the better-seeing eye), (ii) legal blindness (20/200 in the better-seeing eye), and (iii) absolute blindness (no light perception bilaterally). RESULTS: Mean utilities for cohort 1/cohort 2 were 0.96/0.95 (p = 0.20) for mild vision loss, 0.88/0.84 for legal blindness (p = 0.009), and 0.80/0.67 (p < 0.0001) for absolute blindness. Medical student/patient mean utilities were 0.96/0.79 (p < 0.0001) for mild vision loss, 0.85/0.62 for legal blindness (p < 0.0001), and 0.74/0.26 (p < 0.0001) for absolute blindness. Overall, medical students underestimated the QOL associated with vision loss referent to patients with vision loss by 153%-425%. CONCLUSIONS: Medical students dramatically underestimated the impact of vision loss on patient QOL. Clinical training slightly improved medical student perceptions. Trivialization of vision loss could result in systemic health harm, less ophthalmic research dollars, loss of the finest medical students entering ophthalmology, and overall adverse financial effects for the field. PMID- 26040223 TI - SKread predicts handwriting performance in patients with low vision. AB - OBJECTIVE: To assess whether performance on the Smith-Kettlewell Reading (SKread) test is a reliable predictor of handwriting performance in patients with low vision. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty-six patients at their initial low-vision rehabilitation evaluation. METHODS: The patients completed all components of a routine low-vision appointment including logMAR acuity, performed the SKread test, and performed a handwriting task. Patients were timed while performing each task and their accuracy was recorded. The handwriting task was performed by having patients write 5 5-letter words into sets of boxes where each letter is separated by a box. The boxes were 15 * 15 mm, and accuracy was scored with 50 points possible from 25 letters: 1 point for each letter within the confines of a box and 1 point if the letter was legible. Correlation analysis was then performed. RESULTS: Median age of participants was 84 (range 54-97) years. Fifty-seven patients (86%) had age-related macular degeneration or some other maculopathy, whereas 9 patients (14%) had visual impairment from media opacity or neurologic impairment. Median Early Treatment Diabetic Retinopathy Study acuity was 20/133 (range 20/22 to 20/1000), and median logMAR acuity was 0.82 (range 0.04-1.70). SKread errors per block correlated with logMAR acuity (r = 0.6), and SKread time per block correlated with logMAR acuity (r = 0.51). SKread errors per block correlated with handwriting task time/accuracy ratio (r = 0.61). SKread time per block correlated with handwriting task time/accuracy ratio (r = 0.7). LogMAR acuity score correlated with handwriting task time/accuracy ratio (r = 0.42). All p values were < 0.01. CONCLUSIONS: SKread scores predict handwriting performance in patients with low vision better than logMAR acuity. PMID- 26040224 TI - Breaking down barriers to communicating complex retinoblastoma information: can graphics be the solution? AB - OBJECTIVE: To investigate the impact of a graphical timeline summarizing bilateral retinoblastoma disease and treatment outcomes on parents' understanding of complex medical information. DESIGN: Cross-sectional survey. PARTICIPANTS: Parents of children with retinoblastoma who were being actively managed at The Hospital for Sick Children were recruited. Forty-five parents from 42 families participated. METHODS: After a standardized presentation on retinoblastoma and visual tool named Disease-Specific electronic Patient Illustrated Clinical Timeline (DePICT), parents completed a 19-item questionnaire designed to assess their understanding of treatment choices for 2 eyes in bilateral retinoblastoma as communicated using DePICT. SPSS was used to perform statistical analysis. RESULTS: Forty-five parents from 42 families participated (65% female). Median age of participants was 34 years. Median level of participant education was completion of college/trade school. The median level of annual income was $40,000 to $70,000 CDN. Median time since diagnosis of retinoblastoma in their child was 13.5 months. Twenty-three (51%) participants were parents of children with unilateral retinoblastoma, and 22 (49%) were parents of children with bilateral retinoblastoma. Median number of correct answers was 15 of 19, and mean score was 77%. Normal distribution of scores was noted. English as a first language was significantly associated with score (p = 0.01). No significant association was observed between other variables and score in all analyses. CONCLUSIONS: This study builds on the validation of DePICT by demonstrating that parents can achieve good comprehension even when considering choices for treatment for 2 eyes with bilateral retinoblastoma. Clinical application of this tool can enhance the consent process. PMID- 26040225 TI - Efficacy and safety of dexamethasone intravitreal implant for refractory macular edema in children. AB - OBJECTIVE: To evaluate the efficacy and safety of dexamethasone (DEX) intravitreal implant (Ozurdex) in pediatric patients with cystoid macular edema (CME) refractory to conventional treatment. DESIGN: This study is a retrospective chart review. PARTICIPANTS: Four pediatric patients (5 eyes) with CME caused by uveitis, type I idiopathic macular telangiectasia (IMT), or Coats disease treated with DEX intravitreal implant. METHODS: Medical records of the 4 pediatric patients (5 eyes) with CME included in this study were reviewed. Data collected included details of the underlying diseases, treatments, and pretreatment and post-treatment central retinal thickness (CRT) measured by time-domain optical coherence tomography, visual acuity (VA), intraocular pressure (IOP), and lens status. The median follow-up time was 65 weeks (range, 59-93 weeks). RESULTS: Fifteen DEX intravitreal implants were injected into 5 eyes over the follow-up period. Reduction of CME was achieved in all eyes within 12 weeks after the initial injection. VA improved in 4 eyes and was unchanged in 1 eye at 12 weeks; VA improved in 2 eyes, decreased in 2 eyes, and was unchanged in 1 eye at 52 weeks. Three of 5 eyes experienced IOP elevation >= 10 mm Hg during the follow-up period. IOP was ultimately controlled medically in all eyes. Significant lens opacification was documented in 2 eyes. CONCLUSIONS: DEX intravitreal implant can be considered as an effective adjunctive off-label treatment to pediatric macular edema caused by uveitis or IMT/Coats disease; the safety profile of repeated treatment is acceptable. PMID- 26040226 TI - Swept source optical coherence tomography imaging of a series of choroidal tumours. AB - OBJECTIVE: This pilot study aimed to describe the swept-source optical coherence tomography (SS-OCT) features of a series of choroidal tumours. DESIGN: This was an observational case series. PARTICIPANTS: Patients in our ocular oncology unit were recruited: 32 eyes belonging to 31 patients. METHODS: All of the patients underwent fundus photography, ultrasonography (US), fundus autofluorescence (FAF), and SS-OCT. The main assessed characteristics were maximal tumour diameter and thickness, inner structure, and disturbances in the choroidal layers, sclera, retinal pigment epithelium, and retina. RESULTS: The tumours examined consisted of 16 nevi, 6 lesions with risk factors for growth, 4 melanomas, 4 hemangiomas, and 2 choroidal metastases. SS-OCT provided an accurate measurement of the tumour's maximum diameter in every case. Choroidal nevi displayed a compact, regular structure with a preserved choriocapillaris. Choroidal melanomas showed a more irregular inner structure, with an ablated choriocapillaris. Choroidal hemangiomas had a regular spongelike pattern. Choroidal metastases had an irregular inner structure organized in clumps and an ablated outer retina. In most of the pigmented tumours, the sclerochoroidal interface was not identifiable by SS-OCT. The presence of lipofuscin, detected by funduscopy and FAF, was also correlated with the SS-OCT findings. CONCLUSIONS: SS-OCT provided a view of the inner structures of a series of choroidal tumours and assessed their associated structural anomalies, as well as obtained measurements of the diameter and thickness in most cases. PMID- 26040227 TI - Emergent fibrinolysis for central artery occlusion is inappropriate after 2 hours' ischemia. PMID- 26040228 TI - Corneal Descemet's membrane rupture in a patient sustaining high-pressure water jet injury. PMID- 26040229 TI - Significant peripheral anterior synechiae after repeat selective laser trabeculoplasty. PMID- 26040230 TI - Tick infestation of the upper eyelid. PMID- 26040231 TI - Primary Langerhans cell histiocytosis of the lacrimal gland in an adult. PMID- 26040232 TI - Macular atrophy in a case of abetalipoproteinemia as only ocular clinical feature. PMID- 26040233 TI - Topiramate-induced myopic shift with associated retinal striae. PMID- 26040236 TI - Sensitive and homogeneous microRNA detection using branched cascade enzymatic amplification. AB - This assay, termed branched cascade enzymatic amplification (BCEA), can be a novel and straightforward method for sensitive and specific microRNA detection in crude cellular extracts of cancer cells at physiological temperature, by coupling two ordinary polymerases, Klenow fragment exo(-) and terminal deoxynucleotidyl transferase. PMID- 26040234 TI - Transmissible microbial and metabolomic remodeling by soluble dietary fiber improves metabolic homeostasis. AB - Dietary fibers are increasingly appreciated as beneficial nutritional components. However, a requisite role of gut microbiota in fiber function and the overall impact of fibers on metabolomic flux remain unclear. We herein showed enhancing effects of a soluble resistant maltodextrin (RM) on glucose homeostasis in mouse metabolic disease models. Remarkably, fecal microbiota transplantation (FMT) caused pronounced and time-dependent improvement in glucose tolerance in RM recipient mice, indicating a causal relationship between microbial remodeling and metabolic efficacy. Microbial 16S sequencing revealed transmissible taxonomic changes correlated with improved metabolism, notably enrichment of probiotics and reduction of Alistipes and Bacteroides known to associate with high fat/protein diets. Metabolomic profiling further illustrated broad changes, including enrichment of phenylpropionates and decreases in key intermediates of glucose utilization, cholesterol biosynthesis and amino acid fermentation. These studies elucidate beneficial roles of RM-dependent microbial remodeling in metabolic homeostasis, and showcase prevalent health-promoting potentials of dietary fibers. PMID- 26040235 TI - Genomic analysis in the clinic: benefits and challenges for health care professionals and patients in Brazil. AB - Despite significant advances in the diagnosis and treatment of genetic diseases in the last two decades, there is still a significant proportion where a causative mutation cannot be identified and a definitive genetic diagnosis remains elusive. New genome-wide or high-throughput multiple gene tests have brought new hope to the field, since they can offer fast, cost-effective and comprehensive analysis of genetic variation. This is particularly interesting in disorders with high genetic heterogeneity. There are, however, limitations and concerns regarding the implementation of genomic analysis in everyday clinical practice, including some particular to emerging and developing economies, as Brazil. They include the limited number of actionable genetic variants known to date, difficulties in determining the clinical validity and utility of novel variants, growth of direct-to-consumer genetic testing using a genomic approach and lack of proper training of health care professionals to adequately request, interpret and use genetic information. Despite all these concerns and limitations, the availability of genomic tests has grown at an extremely rapid pace and commercially available services include initiatives in almost all areas of clinical genetics, including newborn and carrier screening. We discuss the benefits and limitations of genomic testing, as well as the ethical implications and the challenges for genetic education and enough available and qualified health care professionals, to ensure the adequate process of informed consent, meaningful interpretation and use of genomic data and definition of a clear regulatory framework in the particular context of Brazil. PMID- 26040237 TI - Orthostatic response of cephalic blood flow using a mini laser Doppler blood flowmeter and hemodynamics of a new active standing test. AB - PURPOSE: Cephalic hemodynamic assessment is important in initial orthostatic hypotension. We sought to investigate cephalic blood flow (CBF) in the earlobe using a mini laser Doppler flowmeter (LDF) during orthostatic challenge. In addition, we clarified hemodynamic differences during a new active standing protocol using a footstool standing test (FST) with bending of the legs on the footstool in the sitting position to reduce the load of the squatting posture in the conventional squat standing test (SST). METHODS: Ten healthy men (21 +/- 0.5 years) performed the SST after a 1 min squat and the FST after a 1 min load consisting of bending the legs on a footstool in the sitting position. Earlobe CBF, beat-to-beat arterial blood pressure (ABP), mean arterial blood pressure (MAP), and heart rate (HR) were recorded during each test. RESULTS: Earlobe CBF showed a transient fall synchronized with the ABP during each test. No significant differences in the recovery times (RTs) of CBF and MAP were observed during the SST (CBF 12.9 +/- 0.6 s vs. MAP 12.1 +/- 0.5 s, P = 0.313) and FST (CBF 10.6 +/- 0.4 s vs. MAP 10.1 +/- 0.8 s, P = 0.552). Although the CBF and ABP decreases were not different in each test, the HR increase was significantly lower with the FST (24 +/- 2 bpm) than with the SST (31 +/- 3 bpm, P < 0.005). CONCLUSIONS: Earlobe CBF reflects the compensatory ABP regulatory response during standing and is potentially useful for estimating the orthostatic ABP response indirectly. Furthermore, the FST is a low-load protocol that can be an effective protocol for a standing test of cardiac function. PMID- 26040238 TI - Staging of early lymph node metastases with the sentinel lymph node technique and predictive factors in T1/T2 oral cavity cancer: A retrospective single-center study. AB - BACKGROUND: The purpose of this study was to examine the diagnostic accuracy of detecting lymph node metastases and to identify predictive and prognostic clinicopathological factors in patients with oral squamous cell carcinoma (OSCC) undergoing sentinel lymph node biopsy (SLNB). METHODS: All patients diagnosed with cT1 to T2N0 OSCC who underwent a diagnostic SLNB between 2007 and 2013 were included. RESULTS: We identified 253 patients, of whom 27% had a positive sentinel lymph node (SLB). The false-negative rate, sensitivity, and negative predictive value (NPV) were 5%, 88%, and 95%, respectively. Patients with micrometastases as well as macrometastases had a separately, significantly shorter disease-specific survival than patients with pN0 disease. In a logistic regression model, the maximum tumor thickness, perineural invasion, and differentiation grade were independent predictive factors for the presence of metastases. CONCLUSION: These data support the use of the SLNB technique as an accurate and safe staging tool in patients with OSCC with a cN0 neck. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1033-E1040, 2016. PMID- 26040239 TI - Traditional and environmentally preferable cleaning product exposure and health symptoms in custodians. AB - BACKGROUND: We investigated the associations between traditional and environmentally preferable cleaning product exposure and dermal, respiratory, and musculoskeletal symptoms in a population of custodians. METHODS: We analyzed associations between symptoms and exposure to traditional and environmentally preferable cleaning product exposure among 329 custodians. RESULTS: We observed increased odds of dermal (P < 0.01), upper (P = 0.01) and lower respiratory (P = 0.01), and upper extremity (P < 0.01), back (P < 0.01), and lower extremity (P = 0.01) musculoskeletal symptoms associated with increased typical traditional cleaning product exposure. We observed significant trends for increased odds of dermal (P = 0.03) and back (P = 0.04) and lower (P = 0.02) extremity musculoskeletal symptoms associated with increased typical environmentally preferable cleaning product exposure. CONCLUSIONS: Fewer positive associations and reduced odds of health symptoms associated with environmentally preferable cleaning product exposure suggest that these products may represent a safer alternative to traditional cleaning products. PMID- 26040240 TI - Evolution of the staminode in a representative sample of Scrophularia and its role as nectar safeguard in three widespread species. AB - Approximately 30% of the genera of Scrophulariaceae s.str. have a staminode, which is the remnant of a sterile stamen. However, there are no studies of the functionality or evolutionary pattern of staminodes in that family. This paper investigates three Scrophularia species with different staminode sizes to determine if the staminode safeguards nectar from dilution by rainwater and if it influences pollinator behavior. We also study staminode evolution and ancestral state reconstruction onto a phylogeny containing 71 species and subspecies with four different staminode developmental stages: tiny, large, enormous, and absent. The results showed that large staminodes did not hinder nectar collection or modify pollinator-visiting time but acted as a barrier to reduce rainwater entry. The latter reduced the dilution of nectar, which did not occur with tiny staminodes. The phylogenetic study revealed that the ancestral state in the genus corresponds with the presence of a large staminode vs. the tiny and enormous staminodes that are considered as derived. The complete disappearance of the staminode has occurred independently at least twice. Events occurred that increased or reduced the staminode size in one of the clades (Clade II), which includes species of sect. Caninae; most of these events occurred during the Pleistocene (0.6-2.7 Ma). PMID- 26040241 TI - Influence of task switching costs on colony homeostasis. AB - In social insects, division of labour allows colonies to optimise the allocation of workers across all available tasks to satisfy colony requirements. The maintenance of stable conditions within colonies (homeostasis) requires that some individuals move inside the nest to monitor colony needs and execute unattended tasks. We developed a simple theoretical model to explore how worker mobility inside the nest and task switching costs influence the maintenance of stable levels of task-associated stimuli. Our results indicate that worker mobility in large colonies generates important task switching costs and is detrimental to colony homeostasis. Our study suggests that the balance between benefits and costs associated with the mobility of workers patrolling inside the nest depends on colony size. We propose that several species of ants with diverse life-history traits should be appropriate to test the prediction that the proportion of mobile workers should vary during colony ontogeny. PMID- 26040243 TI - Allocation Costs Associated with Induced Defense in Phaeocystis globosa (Prymnesiophyceae): the Effects of Nutrient Availability. AB - Colony enlargement in Phaeocystis globosa has been considered as an induced defense strategy that reduces its susceptibility to grazers, but allocation costs inflicted by this plastic morphological defense are poorly understood. We conducted experiments in which P. globosa cultures were exposed to chemical cues from copepods, ciliates and heterotrophic dinoflagellates, respectively, under nutrient sufficient and deficient conditions to evaluate allocation costs associated with induced defense. Phaeocystis globosa responded to chemical cues from grazers by increasing colony diameter irrespective of nutrient conditions. We did not find trade-offs between induced defense and growth rate under nutrient sufficient conditions. Instead, induced defensive P. globosa had higher growth rates than non-induced P. globosa. When nutrient became limited, P. globosa exposed to grazing cues from copepods and dinoflagellates had significantly decreased growth rates when compared with non-induced P. globosa. We suggested that the decreased growth revealed allocation costs associated with induced defense that may influence on the trophic interactions between Phaeocystis and consumers. PMID- 26040242 TI - Can The EQ-5D Detect Meaningful Change? A Systematic Review. AB - BACKGROUND: The EQ-5D is one of the most frequently used, generic, preference based instruments for measuring the health utilities of patients in economic evaluations. It is recommended for health technology assessment by the National Institute for Health and Clinical Excellence. Because the EQ-5D plays such an important role in economic evaluations, useful information on its responsiveness to detect meaningful change in health status is required. OBJECTIVE: This study systematically reviewed and synthesized evidence on the responsiveness of the EQ 5D to detect meaningful change in health status for clinical research and economic evaluations. METHODS: We searched the EuroQol website, PubMed, PsychINFO, and EconLit databases to identify studies published in English from the inception of the EQ-5D until August 15, 2014 using keywords that were related to responsiveness. Studies that used only the EQ-VAS were excluded from the final analysis. Narrative synthesis was conducted to summarize evidence on the responsiveness of the EQ-5D by conditions or physiological functions. RESULTS: Of 1401 studies, 145 were included in the narrative synthesis and categorized into 19 categories for 56 conditions. The EQ-5D was found to be responsive in 25 conditions (45 %) with the magnitude of responsiveness varying from small to large depending on the condition. There was mixed evidence of responsiveness in 27 conditions (48 %). Only four conditions (7 %) (i.e., alcohol dependency, schizophrenia, limb reconstruction, and hearing impairment) were identified where the EQ-5D was not responsive. CONCLUSION: The EQ-5D is an appropriate measure for economic evaluation and health technology assessment in conditions where it has demonstrated evidence of responsiveness. In conditions with mixed evidence of responsiveness, researchers should consider using the EQ-5D with other condition specific measures to ensure appropriate estimates of effectiveness. These conditions should be a main focus for future research using the new EQ-5D version with five response levels. PMID- 26040244 TI - People's Judgments About Classic Property Law Cases. AB - People's judgments about property shape how they relate to other people with respect to resources. Property law cases can provide a valuable window into ownership judgments because disputants often use conflicting rules for ownership, offering opportunities to distinguish these basic rules. Here we report a series of ten studies investigating people's judgments about classic property law cases dealing with found objects. The cases address a range of issues, including the relativity of ownership, finder versus landowner rights, object location, objects below- versus above-ground, mislaid versus lost objects, contracts between landowners and finders, and the distinction between public and private space. The results show nuanced patterns in ownership judgments that are not well-explained by previous psychological theories. Also, people's judgments often conflict with court decisions and legal principles. These empirical patterns can be used to generate and test novel hypotheses about the intuitive logic of ownership. PMID- 26040245 TI - Biological Conditions and Economic Development: Nineteenth-Century Stature on the U.S. Great Plains. AB - Average stature is now a well-accepted measure of material and economic well being in development studies when traditional measures are sparse or unreliable, but little work has been done on the biological conditions for individuals on the nineteenth-century U.S. Great Plains. Records of 14,427 inmates from the Nebraska state prison are used to examine the relationship between stature and economic conditions. Statures of both black and white prisoners in Nebraska increased through time, indicating that biological conditions improved as Nebraska's output market and agricultural sectors developed. The effect of rural environments on stature is illustrated by the fact that farm laborers were taller than common laborers. Urbanization and industrialization had significant impacts on stature, and proximity to trade routes and waterways was inversely related to stature. PMID- 26040246 TI - How has soil carbon stock changed over recent decades? PMID- 26040247 TI - Clinical and In Vitro Studies on Impact of High-Dose Etoposide Pharmacokinetics Prior Allogeneic Hematopoietic Stem Cell Transplantation for Childhood Acute Lymphoblastic Leukemia on the Risk of Post-Transplant Leukemia Relapse. AB - The impact of etoposide (VP-16) plasma concentrations on the day of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on leukemia-free survival in children with acute lymphoblastic leukemia (ALL) was studied. In addition, the in vitro effects of VP-16 on the lymphocytes proliferation, cytotoxic activity and on Th1/Th2 cytokine responses were assessed. In 31 children undergoing allo-HSCT, VP-16 plasma concentrations were determined up to 120 h after the infusion using the HPLC-UV method. For mentioned in vitro studies, VP-16 plasma concentrations observed on allo-HSCT day were used. In 84 % of children, VP-16 plasma concentrations (0.1-1.5 MUg/mL) were quantifiable 72 h after the end of the drug infusion, i.e. when allo-HSCT should be performed. In 20 (65 %) children allo HSCT was performed 4 days after the end of the drug infusion, and VP-16 was still detectable (0.1-0.9 MUg/mL) in plasma of 12 (39 %) of them. Post-transplant ALL relapse occurred in four children, in all of them VP-16 was detectable in plasma (0.1-0.8 MUg/mL) on allo-HSCT day, while there was no relapse in children with undetectable VP-16. In in vitro studies, VP-16 demonstrated impact on the proliferation activity of stimulated lymphocytes depending on its concentration and exposition time. The presence of VP-16 in plasma on allo-HSCT day may demonstrate an adverse effect on graft-versus-leukemia (GvL) reaction and increase the risk of post-transplant ALL relapse. Therefore, if 72 h after VP-16 administration its plasma concentration is still above 0.1 MUg/mL then the postponement of transplantation for next 24 h should be considered to protect GvL effector cells from transplant material. PMID- 26040248 TI - Identification of Xenologs and Their Characteristic Low Expression Levels in the Cyanobacterium Synechococcus elongatus. AB - Horizontal gene transfer (HGT) is a central process in prokaryotic evolution. Once a gene is introduced into a genome by HGT, its contribution to the fitness of the recipient cell depends in part on its expression level. Here we show that in Synechococcus elongatus PCC 7942, xenologs derived from non-cyanobacterial sources exhibited lower expression levels than native genes in the genome. In accord with our observation, xenolog codon adaptation indexes also displayed relatively low expression values. These results are in agreement with previous reports that suggested the relative neutrality of most xenologs. However, we also demonstrated that some of the xenologs detected participated in cellular functions, including iron starvation acclimation and nitrate reduction, which corroborate the role of HGT in bacterial adaptation. For example, the expression levels of some of the xenologs detected are known to increase under iron-limiting conditions. We interpreted the overall pattern as an indication that there is a selection pressure against high expression levels of xenologs. However, when a xenolog protein product confers a selective advantage, natural selection can further modulate its expression level to meet the requirements of the recipient cell. In addition, we show that ORFans did not exhibit significantly lower expression levels than native genes in the genome, which suggested an origin other than xenology. PMID- 26040250 TI - Sickle Cell Trait Screening of Collegiate Athletes: Ethical Reasons for Program Reform. AB - The National Collegiate Athletic Association (NCAA) requires all student-athletes have their sickle cell trait (SCT) status confirmed prior to athletic participation. The NCAA approved the screening program in 2010 for institutions participating in Division I athletics and extended it in subsequent years to institutions at Division II and III levels. Ethical concerns about the controversial policy focus on its mandatory nature and potential impact on student-athletes, particularly through stigmatization of and discrimination against those with SCT. Organizations, such as the American Society of Hematology (ASH), oppose the imposition of SCT testing and instead recommend universal precautions that would protect the entire student-athlete population without revealing student-athletes' SCT statuses. This paper discusses these issues and offers recommendations, including genetic counseling, which would improve the current SCT screening program. It argues that implementation of universal precautions would ensure that the most ethically sound practices are afforded to every student-athlete. PMID- 26040251 TI - Post-stroke cognitive impairment is common even after successful clinical recovery. AB - BACKGROUND AND PURPOSE: Cognitive impairment is common after stroke, but the prevalence and long-term significance of the diverse neuropsychological deficits on functional outcome are still not well known. The frequency and prognostic value of domain-specific cognitive impairments were investigated in a large cohort of ischaemic stroke patients. METHODS: Consecutive patients (n = 409), aged 55-85 years, from the acute stroke unit of the Helsinki University Hospital, Finland, were evaluated with extensive clinical and neuropsychological assessments 3 months post-stroke. Impairments within nine cognitive domains were determined according to age-appropriate normative data from a random healthy population. Functional disability was evaluated with the modified Rankin scale (mRS) 3 and 15 months post-stroke. RESULTS: In all, 83% patients showed impairment in at least one cognitive domain, whereas 50% patients were impaired in multiple (>=3) domains. In cases with excellent clinical recovery at 3 months (mRS = 0-1, no disability), the occurrence of any cognitive impairment was 71%. Memory, visuoconstructional and executive functions were most commonly impaired. A substantially smaller proportion of patients scored below the conventional or more stringent cut-offs in the Mini-Mental State Examination (MMSE). Domain specific cognitive impairments were associated with functional dependence at 15 months regardless of stroke severity and other confounders. CONCLUSIONS: Cognitive impairment as evaluated with a comprehensive neuropsychological assessment is prevalent in stroke survivors even with successful clinical recovery. Typically multiple domains and complex cognitive abilities are affected. MMSE is not sensitive in detecting these symptoms. Post-stroke cognitive impairment is strongly related to poor functional outcome. PMID- 26040249 TI - Mechanisms and Consequences of Double-Strand DNA Break Formation in Chromatin. AB - All organisms suffer double-strand breaks (DSBs) in their DNA as a result of exposure to ionizing radiation. DSBs can also form when replication forks encounter DNA lesions or repair intermediates. The processing and repair of DSBs can lead to mutations, loss of heterozygosity, and chromosome rearrangements that result in cell death or cancer. The most common pathway used to repair DSBs in metazoans (non-homologous DNA end joining) is more commonly mutagenic than the alternative pathway (homologous recombination mediated repair). Thus, factors that influence the choice of pathways used DSB repair can affect an individual's mutation burden and risk of cancer. This review describes radiological, chemical, and biological mechanisms that generate DSBs, and discusses the impact of such variables as DSB etiology, cell type, cell cycle, and chromatin structure on the yield, distribution, and processing of DSBs. The final section focuses on nucleosome-specific mechanisms that influence DSB production, and the possible relationship between higher order chromosome coiling and chromosome shattering (chromothripsis). PMID- 26040252 TI - The effect of mobile app home monitoring on number of in-person visits following ambulatory surgery: protocol for a randomized controlled trial. AB - BACKGROUND: Women's College Hospital, Toronto, Canada, offers specialized ambulatory surgical procedures. Patients often travel great distances to undergo surgery. Most patients receiving ambulatory surgery have a low rate of postoperative events necessitating clinic visits. However, regular follow-up is still considered important in the early postoperative phase. Increasingly, telemedicine is used to overcome the distance patients must travel to receive specialized care. Telemedicine data suggest that mobile monitoring and follow-up care is valued by patients and can reduce costs to society. Women's College Hospital has used a mobile app (QoC Health Inc) to complement in-person postoperative follow-up care for breast reconstruction patients. Preliminary studies suggest that mobile app follow-up care is feasible, can avert in-person follow-up care, and is cost-effective from a societal and health care system perspective. OBJECTIVE: We hope to expand the use of mobile app follow-up care through its formal assessment in a randomized controlled trial. In postoperative ambulatory surgery patients at Women's College Hospital (WCH), can we avert in person follow-up care through the use of mobile app follow-up care compared to conventional, in-person follow-up care in the first 30 days after surgery. METHODS: This will be a pragmatic, single-center, open, controlled, 2-arm parallel-group superiority randomized trial comparing mobile app and in-person follow-up care over the first month following surgery. The patient population will comprise all postoperative ambulatory surgery patients at WCH undergoing breast reconstruction. The intervention consists of a postoperative mobile app follow-up care using the quality of recovery-9 (QoR9) and a pain visual analog scale (VAS), surgery-specific questions, and surgical site photos submitted daily for the first 2 weeks and weekly for the following 2 weeks. The primary outcome is the total number of physician visits related to the surgery over the first 30 days postoperative. The secondary outcomes include (1) the total number of phone calls and emails to a health care professional related to surgery, (2) complication rate, (3) societal and health care system costs, and (4) patient satisfaction over the first 30 days postoperative. Permutated-block randomization will be conducted by blocks of 4-6 using the program ralloc in Stata. This is an open study due to the nature of the intervention. RESULTS: A sample of 72 (36 patients per group) will provide an E-test for count data with a power of 95% (P=.05) to detect a difference of 1 visit between groups, assuming a 10% drop out rate. Count variables will be analyzed using Poisson regression. Categorical variables will be tested using a chi-square test. Cost-effectiveness will be analyzed using net benefit regression. Outcomes will be assessed over the first 30 days following surgery. CONCLUSIONS: We hope to show that the use of a mobile app in follow-up care minimizes the need for in-person visits for postoperative patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02318953; https://clinicaltrials.gov/ct2/show/NCT02318953 (Archived by WebCite at http://www.webcitation.org/6Yifzdjph). PMID- 26040253 TI - Prototheca wickerhamii algaemia: an emerging infection in solid organ transplant recipients. AB - Prototheca wickerhamii is an alga that rarely causes human disease but has been reported increasingly among immunocompromised individuals. We report a fatal case of P. wickerhamii in a renal transplant recipient who presented with a cutaneous lesion that led to disseminated disease despite treatment with voriconazole. We reviewed previous cases of protothecosis involving solid organ transplant recipients in the literature and discussed the value of newer microbiology platforms, i.e., matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF), to achieve early diagnosis and impact outcomes. PMID- 26040254 TI - The Impact of Aortic Occlusion Balloon on Mortality After Endovascular Repair of Ruptured Abdominal Aortic Aneurysms: A Meta-analysis and Meta-regression Analysis. AB - INTRODUCTION: We aimed to investigate whether the use of aortic occlusion balloon (AOB) has an impact on mortality of patients undergoing endovascular repair of ruptured abdominal aortic aneurysms (RAAAs). METHODS: A meta-analysis of the English-language literature was undertaken through February 2013. Articles reporting data on outcome after endovascular repair of RAAAs were identified and information regarding the use of AOB was sought. RESULTS: Included in this meta analysis were 39 eligible studies reporting 1277 patients. The pooled perioperative mortality was 21.6% (95% CI 18.1-25.1%). There was significant within-study heterogeneity (I(2) 50.2%, P < 0.001). A total of 200 patients required AOB with an estimated pooled proportion of 14.1% (8.9-19.3%). Individual random-effects meta-regression investigating the effect of AOB and other risk factors on mortality revealed a significant linear association of hemodynamic instability, bifurcated endograft approach, and primary conversion to open repair with mortality and a nonlinear (second degree polynomial) association of AOB with mortality. On multivariable meta-regression models, both hemodynamic instability and AOB were found to be statistically significant, independent predictors of mortality. In particular, there was a statistically significant negative correlation between AOB and mortality and a positive effect of hemodynamic instability on mortality. In practical terms, mortality was significantly higher in studies with a higher proportion of hemodynamically unstable patients and lower in studies with a higher rate of AOB use. CONCLUSION: This study provides meta-analytical evidence that the use of an AOB in unstable RAAA patients undergoing endovascular repair may improve the results. PMID- 26040255 TI - Endovascular Management of True Renal Arterial Aneurysms: Results from a Single Centre. AB - PURPOSE: To report a single centre's experience of the endovascular treatment of renal arterial aneurysms, including techniques and outcomes. MATERIALS AND METHODS: This is a retrospective analysis of true renal arterial aneurysms (TRAAs) treated using endovascular techniques over a period of 12 years and 10 months. The clinical presentations, aneurysm characteristics, endovascular techniques and outcomes are reported. RESULTS: There were nine TRAA cases with a mean aneurysm size of 21.0 mm, located at the main renal arterial bifurcation in all cases. Onyx((r)) was used as the embolic agent of choice (88.9 % cases), with concurrent balloon remodelling. The overall primary technical success rate was 100 %. Repeat intervention was carried out in 1 case, secondary to reperfusion >8 years post-initial treatment. Long-term clinical follow-up was available in 55.6 % of cases (mean 29.8 months; range 3.3-90.1 months). Early post-procedural renal function, as measured by serum creatinine, remained within the normal reference range. Renal parenchymal loss post-embolisation was <=20 % in 77.8 % of cases, as estimated on imaging. Minor complications included non-target embolization of Onyx((r)) with no clinical sequelae (n = 1), transient pain requiring only oral analgesia with no prolongation of hospital stay (n = 2). No major complications occurred as a consequence of embolisation. CONCLUSION: Endovascular therapy is an effective and safe primary therapy for TRAA with high success rate and low morbidity, supplanting surgery as primary therapy. Current experience in the use of Onyx((r)) in TRAA is primarily limited to individual case reports, and this represents the largest case series of Onyx((r))-treated TRAAs to date. PMID- 26040256 TI - Feasibility Study on MR-Guided High-Intensity Focused Ultrasound Ablation of Sciatic Nerve in a Swine Model: Preliminary Results. AB - INTRODUCTION: Spastic patients often seek neurolysis, the permanent destruction of the sciatic nerve, for better pain management. MRI-guided high-intensity focused ultrasound (MRgHIFU) may serve as a noninvasive alternative to the prevailing, more intrusive techniques. This in vivo acute study is aimed at performing sciatic nerve neurolysis using a clinical MRgHIFU system. METHODS: The HIFU ablation of sciatic nerves was performed in swine (n = 5) using a HIFU system integrated with a 3 T MRI scanner. Acute lesions were confirmed using T1 weighted contrast-enhanced (CE) MRI and histopathology using hematoxylin and eosin staining. The animals were euthanized immediately following post-ablation imaging. RESULTS: Reddening and mild thickening of the nerve and pallor of the adjacent muscle were seen in all animals. The HIFU-treated sections of the nerves displayed nuclear pyknosis of Schwann cells, vascular hyperemia, perineural edema, hyalinization of the collagenous stroma of the nerve, myelin sheet swelling, and loss of axons. Ablations were visible on CE MRI. Non-perfused volume of the lesions (5.8-64.6 cc) linearly correlated with estimated lethal thermal dose volume (4.7-34.2 cc). Skin burn adjacent to the largest ablated zone was observed in the first animal. Bilateral treatment time ranged from 55 to 138 min, and preparation time required 2 h on average. CONCLUSION: The acute pilot study in swine demonstrated the feasibility of a noninvasive neurolysis of the sciatic nerve using a clinical MRgHIFU system. Results revealed that acute HIFU nerve lesions were detectable on CE MRI, gross pathology, and histology. PMID- 26040257 TI - Direct and accelerated parameter mapping using the unscented Kalman filter. AB - PURPOSE: To accelerate parameter mapping using a new paradigm that combines image reconstruction and model regression as a parameter state-tracking problem. METHODS: In T2 mapping, the T2 map is first encoded in parameter space by multi TE measurements and then encoded by Fourier transformation with readout/phase encoding gradients. Using a state transition function and a measurement function, the unscented Kalman filter can describe T2 mapping as a dynamic system and directly estimate the T2 map from the k-space data. The proposed method was validated with a numerical brain phantom and volunteer experiments with a multiple-contrast spin echo sequence. Its performance was compared with a conjugate-gradient nonlinear inversion method at undersampling factors of 2 to 8. An accelerated pulse sequence was developed based on this method to achieve prospective undersampling. RESULTS: Compared with the nonlinear inversion reconstruction, the proposed method had higher precision, improved structural similarity and reduced normalized root mean squared error, with acceleration factors up to 8 in numerical phantom and volunteer studies. CONCLUSION: This work describes a new perspective on parameter mapping by state tracking. The unscented Kalman filter provides a highly accelerated and efficient paradigm for T2 mapping. PMID- 26040258 TI - Tumour depth of invasion of pT1 squamous cell carcinoma of the oral tongue and risk of pathologically detected neck metastases. AB - BACKGROUND: Tumour depth of invasion (TDI) is considered a predictor of pathologically detected neck metastases (PDNM) for squamous cell carcinoma (SCC), but different investigators have arrived at different cut-off of TDI. However, the relationship between TDI of pT1 SCC of the oral tongue and PDNM remains unknown. METHODS: Data was collected for patients with pT1SCC of the oral tongue. TDI, neurovascular invasion, pattern of invasion and presence of PDNM were recorded. The relationship between data was studied using logistic regression and ROC methods. RESULTS: With all other factors held constant, data showed that the odds ratio for each millimetre increase in TDI and risk of PDNM was 1.09 (95% CI: 0.95 - 1.25, p = 0.234), which was insignificant. CONCLUSION: TDI is not accurate and cannot be used as predictor of PDNM in patients with pT1 SCC of the tongue. Further, true TDI can only be assessed on resection specimens. This article is protected by copyright. All rights reserved. PMID- 26040260 TI - Biphasic Palladium-Catalyzed Hydroesterification in a Polyol Phase: Selective Synthesis of Derived Monoesters. AB - The palladium-catalyzed hydroesterification reaction was performed with polyols and olefins in a liquid/liquid biphasic system composed of unreacted polyol on the one hand and apolar reaction products/organic solvents on the other hand. The palladium-based catalyst was immobilized in the polyol phase thanks to the use of cationic triarylphosphines possessing pendent protonated amino groups in the acidic reaction medium or to the sulfonated phosphine TPPTS (trisodium triphenylphosphine-3,3',3''-trisulfonate). Owing to the insolubility of the products in the catalytic phase, this approach allowed the synthesis of monoesters of polyols with high selectivities as well as the easy separation of the catalyst through simple decantation. PMID- 26040261 TI - Synthesis of novel photofunctional multinuclear complexes using a coupling reaction. AB - Various photofunctional metal complexes with functional groups, i.e. bromo and vinyl groups, were integrated into hetero-multinuclear complexes using the Mizoroki-Heck reaction. The obtained trinuclear complexes absorb a wide range of visible light and have a long excited state lifetime and the photocatalytic ability to obtain CO2 reduction. PMID- 26040259 TI - MicroRNAs in cardiovascular ageing. AB - MicroRNAs (miRs) have emerged as potent regulators of pathways in physiological and disease contexts. This review focuses on the role of miRs in ageing of the cardiovascular system. Several miRs have been described to be regulated during ageing and some of these miRs are involved in the regulation of ageing-related processes. We discuss the roles of miR-34, miR-217 and miR-29, which are induced during ageing in the vasculature. The roles of miR-34, miR-29 (age-induced) and miR-18/19, which are decreased during ageing in the heart, are discussed as well. Furthermore, numerous miRs that play a role in diseases associated with ageing, like diabetes, atherosclerosis, hypertension, cardiac hypertrophy and atrial fibrillation, are also briefly discussed. miRs also serve as circulating biomarkers for cardiovascular ageing or ageing-associated diseases. Finally, pharmacological modulation of ageing-related miRs might become a promising strategy to combat cardiovascular ageing in a clinical setting. PMID- 26040263 TI - Adjuvant taxanes and the development of breast cancer-related arm lymphoedema. AB - BACKGROUND: Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL. METHODS: This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL. RESULTS: Some 27.1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33.5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2.82, 95 per cent c.i. 1.31 to 6.06). No such increase was observed when taxanes were administered in the neoadjuvant setting. CONCLUSION: The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting. PMID- 26040262 TI - The Value of Patient Reported Outcomes and Other Patient-Generated Health Data in Clinical Hematology. AB - With cures and long-term survival rates increasing in hematologic malignancies, increased focus has been placed on gaining a better understanding of the patient experience from disease and treatment effects. This has been the basis for the utilization of patient reported outcomes (PRO) and other patient-generated health data (PGHD) in efforts to improve long-term health-related quality of life (HRQOL). This review will summarize the impact PROs have had on the evolving standard of care for patients with hematologic malignant conditions and will conclude with a template for the integration of PRO and PGHD to enhance the patient experience, using stem cell transplantation as an example. PMID- 26040264 TI - Concentrations, bioaccumulation, and human health risk assessment of organochlorine pesticides and heavy metals in edible fish from Wuhan, China. AB - The objective of this study was to determine concentration and bioaccumulation of organochlorine pesticides and heavy metals in edible fish from Wuhan, China, in order to assess health risk to the human via fish consumption. Two edible fish species (Aristichthys nobilis and Hypophthalmichthys molitrix) were collected and analyzed for 11 organochlorine pesticides (OCPs) and eight heavy metals (HMs). Concentrations of ?HCHs, ?DDTs, and ?OCPs in fish samples were in the range of 0.37-111.20, not detected (nd)-123.61, and 2.04-189.04 ng g(-1) (wet weight), respectively. Bioaccumulation factors (BAFs) of OCPs in bighead carp (A. nobilis) were higher than those in silver carp (H. molitrix). Concentrations of ?HMs in bighead carp and silver carp were 352.48 and 345.20 mg kg(-1) (dw), respectively. Daily exposure of OCPs and HMs for consumers was estimated by comparing estimated daily intake (EDI) with different criteria. The results revealed that the EDIs in our study were all lower than those criteria. Target hazard quotient (THQ) and risk ratio (R) were used to evaluate non-carcinogenic and carcinogenic risks, respectively. As regard to non-carcinogenic effects of the contaminants, hazard quotients (THQ) of OCPs and HMs were both lower than 1.0, implying negligible non carcinogenic risk via fish consumption in study area. Nevertheless, in view of carcinogenic effects of the contaminants, the total value of risk ratio (R) of OCPs was lower than the threshold of tolerable risk while the total value of risk ratio (R) of HMs was higher than the threshold of tolerable risk due to the high carcinogenic risk ratios of As and Cr, indicating high carcinogenic risks via fish consumption. The results demonstrated that HMs in edible fish from Wuhan, China, especially As and Cr required more attention than OCPs. PMID- 26040265 TI - Removal of BrO3- from drinking water samples using newly developed agricultural waste-based activated carbon and its determination by ultra-performance liquid chromatography-mass spectrometry. AB - Activated carbon was prepared from date pits via chemical activation with H3PO4. The effects of activating agent concentration and activation temperature on the yield and surface area were studied. The optimal activated carbon was prepared at 450 degrees C using 55 % H3PO4. The prepared activated carbon was characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric-differential thermal analysis, and Brunauer, Emmett, and Teller (BET) surface area. The prepared date pit-based activated carbon (DAC) was used for the removal of bromate (BrO3 (-)). The concentration of BrO3 (-) was determined by ultra-performance liquid chromatography-mass tandem spectrometry (UPLC-MS/MS). The experimental equilibrium data for BrO3 (-) adsorption onto DAC was well fitted to the Langmuir isotherm model and showed maximum monolayer adsorption capacity of 25.64 mg g(-1). The adsorption kinetics of BrO3 (-) adsorption was very well represented by the pseudo-first-order equation. The analytical application of DAC for the analysis of real water samples was studied with very promising results. PMID- 26040266 TI - Selected issues related to the toxicity of ionic liquids and deep eutectic solvents--a review. AB - Green Chemistry plays a more and more important role in implementing rules of sustainable development to prevent environmental pollution caused by technological processes, while simultaneously increasing the production yield. Ionic liquids (ILs) and deep eutectic solvents (DESs) constitute a very broad group of substances. Apart from many imperfections, ILs and DESs have been the most promising discoveries in the world of Green Chemistry in recent years. The main advantage of ILs is their unique physicochemical properties-they are very desirable from the technological point of view, but apart from these benefits, ILs appear to be highly toxic towards organisms from different trophic levels. DES areas of usage are very spread, because they cover organic synthesis, extraction processes, electrochemistry, enzymatic reactions and many others. Moreover, DESs seem to be a less toxic alternative to ionic liquids. New possibilities of applications and future development trends are sought and presented, including such important solutions of life branches as pharmaceuticals' production and medicine. PMID- 26040267 TI - Direct synthesis of chiral 3-arylsuccinimides by rhodium-catalyzed enantioselective conjugate addition of arylboronic acids to maleimides. AB - Chiral rhodium catalysts comprising 2,5-diaryl- substituted bicyclo[2.2.1]diene ligands L1-L10 were utilized in the enantioselective 1,4-addition reaction of arylboronic acids to N-substituted maleimides. In the presence of 2.5 mol % of Rh(I) /L2, enantioenriched conjugate addition adducts were isolated in 72-99 % yields with 86-98 % ee. This protocol offers a convenient method to access a variety of 3-arylsuccinimides in a highly enantioselective manner. Maleimides with readily cleavable N-protecting groups were tolerated enabling the synthesis of useful synthetic intermediates. Pyrrolidine 4, a biologically active compound, and pyrrolidine 5, an ent-precursor to an HSD-1 inhibitor, were synthesized to demonstrate the utility of this method. PMID- 26040269 TI - Retraction Note to: The 'obesity paradox' and survival after colorectal cancer: true or false? PMID- 26040268 TI - Re: electroconvulsive therapy during pregnancy revisited. PMID- 26040270 TI - Synthesis and Biological Evaluation of N-Aryl-5-aryloxazol-2-amine Derivatives as 5-Lipoxygenase Inhibitors. AB - We describe the synthesis and biological evaluation of N-aryl-5-aryloxazol-2 amine derivatives that are able to inhibit 5-lipoxygenase (5-LOX), a key enzyme of leukotriene synthesis, for the treatment of inflammation-related diseases including asthma and rheumatoid arthritis. A novel structural moiety containing oxazole was initially identified from a chemical library using an in vitro enzymatic and cell-based assay, and its synthesized oxazole derivatives were further examined to develop a structure-activity relationship (SAR). SAR analysis demonstrated that a hydroxyl or amino group at the p-position on N-phenyl was essential for the 5-LOX-inhibitory activities of the derivatives, and that other halogen and methyl group-substituted derivatives affected the potency, positively or negatively. As a result, derivatives selected through first-round screening were further optimized using a cell-based assay and an in vivo assay to develop a potent, selective 5-LOX inhibitor. A final hit exhibited an improved efficacy in arachidonic acid-induced ear edema when applied topically but not orally. Moreover, it showed the additional advantage of sustainable antiinflammatory activity over a reference compound, zileuton. Taken together, chemical entities bearing an oxazole scaffold could be promising as therapeutic drugs for the treatment of chronic inflammatory skin disorders. PMID- 26040271 TI - Synthesis and Biological Evaluation of Novel Aryl-2H-pyrazole Derivatives as Potent Non-purine Xanthine Oxidase Inhibitors. AB - A series of aryl-2H-pyrazole derivatives were synthesized and evaluated for inhibitory activity against xanthine oxidase in vitro as potent xanthine oxidase inhibitors. Among them, 2 aryl-2H-pyrazole derivatives showed significant inhibitory activities against xanthine oxidase. Compound 19 emerged as the most potent xanthine oxidase inhibitor (IC50=9.8 uM) in comparison with allopurinol (IC50=9.5 uM). The docking study revealed that compound 19 might have strong interactions with the active site of xanthine oxidase. This compound is thus a new candidate for further development for the treatment of gout. PMID- 26040272 TI - Evolutionary analysis of the female-specific avian W chromosome. AB - The typically repetitive nature of the sex-limited chromosome means that it is often excluded from or poorly covered in genome assemblies, hindering studies of evolutionary and population genomic processes in non-recombining chromosomes. Here, we present a draft assembly of the non-recombining region of the collared flycatcher W chromosome, containing 46 genes without evidence of female-specific functional differentiation. Survival of genes during W chromosome degeneration has been highly non-random and expression data suggest that this can be attributed to selection for maintaining gene dose and ancestral expression levels of essential genes. Re-sequencing of large population samples revealed dramatically reduced levels of within-species diversity and elevated rates of between-species differentiation (lineage sorting), consistent with low effective population size. Concordance between W chromosome and mitochondrial DNA phylogenetic trees demonstrates evolutionary stable matrilineal inheritance of this nuclear-cytonuclear pair of chromosomes. Our results show both commonalities and differences between W chromosome and Y chromosome evolution. PMID- 26040273 TI - Self-illuminating quantum dots for non-invasive bioluminescence imaging of mammalian gametes. AB - BACKGROUND: The fertility performance of animals is still a mystery and the full comprehension of mammalian gametes maturation and early embryonic development remains to be elucidated. The recent development in nanotechnology offers a new opportunity for real-time study of reproductive cells in their physiological environments. As a first step toward that goal, we evaluated the effectiveness of a fluorescent and luminescent nanoparticle for in vitro and ex vivo imaging of porcine gametes. METHODS: Freshly harvested boar sperm were labeled with red shifted (655 nm) quantum dot nanoparticles conjugated (QD+) or not (QD-) with plasminogen antibody and evaluated. Subsets of labeled spermatozoa were loaded into straws and placed within the lumen of gilt reproductive tracts for ex vivo intra-uterine imaging. Porcine cumulus-oocyte complexes (COCs) were matured in the presence of QD- or QD+. Ovarian follicles were microinjected with QD- or QD+ and placed in culture for up to 4 days. After labeling, all samples were supplemented with coelenterazine, the luciferase substrate, and immediately submitted to bioluminescence analysis, followed by fluorescence and hyperspectral imaging. Data were analyzed with ANOVA and P < 0.05 indicated significant differences. RESULTS: All labeled-samples revealed bioluminescence emission that was confirmed by fluorescence and hyperspectral imaging of the QD localization within the cells and tissues. Over 76% of spermatozoa and both immature and mature COCs were successfully labeled with QD- or QD+. The QD- fluorescence appeared homogenously distributed in the oocytes, while found in the entire sperm length with a higher accumulation within the mid-piece. Labeled-follicles exhibited a progressive migration of QD nanoparticles within the follicle wall during culture. In contrast, QD+ fluorescence signals appeared condensed and stronger in the follicle cells, sperm head, and sub-plasma membrane area of mature oocytes. Weaker QD+ signals were detected in the cumulus cells. Fluorescence and hyperspectral microscope imaging showed comparable intracellular QD localization. Ex-vivo intra-uterine bioluminescence imaging of labeled spermatozoa revealed stronger signals captured over the oviducts, with uterine body allowing the lowest signal detection. CONCLUSION: Findings indicate that conjugated and non-conjugated fluorescent nanoparticles can be used for effective labeling of mammalian gametes for in vitro monitoring and potential in vivo targeted-imaging. PMID- 26040274 TI - Development of a genetic tool for functional screening of anti-malarial bioactive extracts in metagenomic libraries. AB - BACKGROUND: The chemical treatment of Plasmodium falciparum for human infections is losing efficacy each year due to the rise of resistance. One possible strategy to find novel anti-malarial drugs is to access the largest reservoir of genomic biodiversity source on earth present in metagenomes of environmental microbial communities. METHODS: A bioluminescent P. falciparum parasite was used to quickly detect shifts in viability of microcultures grown in 96-well plates. A synthetic gene encoding the Dermaseptin 4 peptide was designed and cloned under tight transcriptional control in a large metagenomic insert context (30 kb) to serve as proof-of-principle for the screening platform. RESULTS: Decrease in parasite viability consistently correlated with bioluminescence emitted from parasite microcultures, after their exposure to bacterial extracts containing a plasmid or fosmid engineered to encode the Dermaseptin 4 anti-malarial peptide. CONCLUSIONS: Here, a new technical platform to access the anti-malarial potential in microbial environmental metagenomes has been developed. PMID- 26040276 TI - Genome-wide expression patterns of calcium-dependent protein kinases in Toxoplasma gondii. AB - BACKGROUND: Calcium-dependent protein kinases (CDPKs) are found in plants and some Apicomplexan parasites but not in animals or fungi. CDPKs have been shown to play important roles in various calcium-signaling pathways such as host cell invasion, egress and protein secretion in Toxoplasma gondii. The objectives of the present study were to examine the T. gondii CDPK genes expression patterns during different development stages and stress responses. METHODS: We carried out a comprehensive expression analysis of CDPK genes based on previously published microarray datasets, and we also used real time quantitative RT-PCR to study ten T. gondii CDPK genes expression patterns under acid, alkali, high temperature and low temperature conditions. RESULTS: Microarrays analysis indicated that some TgCDPK genes exhibited different expression levels in IFN-gamma stimuli conditions or at different developmental stages, suggesting that CDPK genes may play different roles in these processes. Expression profiles under low temperature, high temperature, acid and alkaline indicated that most CDPK may be involved in regulating high temperature, acid and alkaline signaling pathways. CONCLUSIONS: We present a genome-wide expression analysis of CDPK genes in T. gondii for the first time, and the mRNA levels change with abiotic and biotic stresses, suggesting their functional roles in these processes. These results will provide a solid basis for future functional studies of the CDPK gene family in T. gondii. PMID- 26040275 TI - Reducing the global burden of type 2 diabetes by improving the quality of staple foods: The Global Nutrition and Epidemiologic Transition Initiative. AB - BACKGROUND: The prevalence of type 2 diabetes has been reaching epidemic proportions across the globe, affecting low/middle-income and developed countries. Two main contributors to this burden are the reduction in mortality from infectious conditions and concomitant negative changes in lifestyles, including diet. We aimed to depict the current state of type 2 diabetes worldwide in light of the undergoing epidemiologic and nutrition transition, and to posit that a key factor in the nutrition transition has been the shift in the type and processing of staple foods, from less processed traditional foods to highly refined and processed carbohydrate sources. DISCUSSION: We showed data from 11 countries participating in the Global Nutrition and Epidemiologic Transition Initiative, a collaborative effort across countries at various stages of the nutrition-epidemiologic transition whose mission is to reduce diabetes by improving the quality of staple foods through culturally-appropriate interventions. We depicted the epidemiologic transition using demographic and mortality data from the World Health Organization, and the nutrition transition using data from the Food and Agriculture Organization food balance sheets. Main staple foods (maize, rice, wheat, pulses, and roots) differed by country, with most countries undergoing a shift in principal contributors to energy consumption from grains in the past 50 years. Notably, rice and wheat products accounted for over half of the contribution to energy consumption from staple grains, while the trends for contribution from roots and pulses generally decreased in most countries. Global Nutrition and Epidemiologic Transition Initiative countries with pilot data have documented key barriers and motivators to increase intake of high-quality staple foods. Global research efforts to identify and promote intake of culturally-acceptable high-quality staple foods could be crucial in preventing diabetes. These efforts may be valuable in shaping future research, community interventions, and public health and nutritional policies. PMID- 26040277 TI - Elevated circulating vascular cell Adhesion Molecule-1 (sVCAM-1) is associated with concurrent depressive symptoms and cerebral white matter Hyperintensities in older adults. AB - BACKGROUND: Circulating vascular adhesion molecule-1 (sVCAM-1) is a presumed marker of endothelial activation and dysfunction, but little is known about its association with mood. We hypothesized that elevated plasma concentrations of sVCAM-1 may be a marker of depressive symptoms due to cerebral vascular disease. METHODS: We studied 680 community-dwelling participants in the MOBILIZE Boston Study, aged 65 years and older. sICAM-1 and sVCAM-1 were measured by ELISA assay and depressive symptoms were assessed during home interviews using the Revised Center for Epidemiological Studies Depression Scale (CESD-R). Cerebral White Matter Hyperintensities (WMHs) were quantified by MRI in a subgroup of 25 participants. RESULTS: One hundred seventy nine (27 %) subjects had a CESD-R Score >= 16, indicative of depressive symptoms. The mean sVCAM-1 concentration (+/-SD) was 1176 +/- 417 ng/mL in a group with CESD-R Scores <16 and 1239 +/- 451 ng/mL in those with CESD-R Scores >=16 (p = 0.036). CESD-R Score was positively associated with sVCAM-1 (r = 0.11, p = 0.004). The highest quintile of sVCAM-1, which is indicative of endothelial dysfunction, was significantly associated with depressive symptoms compared to the lowest quintile (OR = 1.97 (1.14-3.57) p = 0.015). In a subset of subjects, sVCAM-1 concentration was positively correlated with cerebral WMHs volume (p = 0.018). CONCLUSIONS: The association between high levels of sVCAM-1 and depressive symptoms may be due to endothelial dysfunction from cerebral microvascular damage. Future longitudinal studies are needed to determine whether sVCAM-1 can serve as a biomarker for cerebrovascular causes of depression. PMID- 26040278 TI - Feasibility of individual patient data meta-analyses in orthopaedic surgery. AB - BACKGROUND: The number of individual patient data meta-analyses published is very low especially in surgical domains. Our aim was to assess the feasibility of individual patient data (IPD) meta-analyses in orthopaedic surgery by determining whether trialists agree to send IPD for eligible trials. METHODS: We performed a literature search to identify relevant research questions in orthopaedic surgery. For each question, we developed a protocol synopsis for an IPD meta-analysis and identified all related randomized controlled trials (RCTs) with results published since 2000. Corresponding authors of these RCTs were sent personalized emails that presented a project for an IPD meta-analysis corresponding to one of the research questions, with a link to the protocol synopsis, and asking for IPD from their RCT. We guaranteed patient confidentiality and secure data storage, and offered co-authorship and coverage of costs related to extraction. RESULTS: We identified 38 research questions and 273 RCTs related to these questions. We could contact 217 of the 273 corresponding authors (79 %; 56 had unavailable or non-functional email addresses) and received 68/273 responses (25 %): 21 authors refused to share IPD, 10 stated that our request was under consideration and 37 agreed to send IPD. Four corresponding authors required authorship and three others asked for financial support to send the IPD. Overall, we could obtain IPD for 5,110 of 33,602 eligible patients (15 %). Among the 38 research questions, only one IPD meta-analysis could be potentially initiated because we could receive IPD for more than 50 % of participants. CONCLUSION: The present study illustrates the difficulties in initiating IPD meta-analyses in orthopaedic surgery. Significant efforts must be made to improve data sharing. PMID- 26040279 TI - Very low neighbourhood income limits participation post stroke: preliminary evidence from a cohort study. AB - BACKGROUND: Neighbourhood income level is associated with the incidence of stroke and stroke-related mortality. It has also been linked to receipt of appropriate services, post discharge motor recovery and functional status following a stroke. We examined the impact of neighbourhood income on participation among community dwelling stroke survivors during the two years following the stroke. METHODS: Secondary analysis of data from a prospective cohort study. Participants were 67 individuals who were treated in acute care or rehabilitation following a first ever stroke, and were discharged to the community with FIMTM scores of at least 3 for comprehension, memory and problem solving. On this functional independence measure, these scores indicate that assistance is needed with related tasks up to 50 % of the time. Participation at 6, 9, 12, 18 and 24-months post stroke was measured using the Reintegration to Normal Living Index (RNLI). Income was measured by median neighbourhood annual family income according to postal code. The impact of very low neighbourhood income (median family income $20,000 Cdn or less) on participation at each follow-up period was determined controlling for potential confounders. RESULTS: Six (9.0 %) of the participants lived in very low income neighbourhoods. These participants had average RNLI scores approximately 25 % lower at each follow-up period. While there was a trend for increasing participation with time among those in higher income neighbourhoods, this was not seen among very low-income neighbourhood participants. Very low me neighbourhood income had an independent effect on participation after controlling for discharge FIMTM, 2-min walk test, gender, self-rated health, age, and emotional well-being at all follow-up periods. CONCLUSIONS: Our results indicate that very low neighbourhood income is linked with decreased participation during the first two years following stroke. Our findings indicate the need for further investigation of this relationship, and the importance of close follow-up of stroke survivors living in very low-income contexts. PMID- 26040281 TI - Removing more tissue around breast tumour reduces need for further surgery. PMID- 26040280 TI - CD24(+) cells fuel rapid tumor growth and display high metastatic capacity. AB - INTRODUCTION: Breast tumors are comprised of distinct cancer cell populations which differ in their tumorigenic and metastatic capacity. Characterization of cell surface markers enables investigators to distinguish between cancer stem cells and their counterparts. CD24 is a well-known cell surface marker for mammary epithelial cells isolation, recently it was suggested as a potential prognostic marker in a wide variety of malignancies. Here, we demonstrate that CD24(+) cells create intra-tumor heterogeneity, and display highly metastatic properties. METHODS: The mammary carcinoma Mvt1 cells were sorted into CD24(-) and CD24(+) cells. Both subsets were morphologically and phenotypically characterized, and tumorigenic capacity was assessed via orthotopic inoculation of each subset into the mammary fat pad of wild-type and MKR mice. The metastatic capacity of each subset was determined with the tail vein metastasis assay. The role of CD24 in tumorigenesis was further examined with shRNA technology. GFP labeled cells were monitored in vivo for differentiation. The genetic profile of each subset was analyzed using RNA sequencing. RESULTS: CD24(+) cells displayed a more spindle-like cytoplasm. The cells formed mammospheres in high efficiency and CD24(+) tumors displayed rapid growth in both WT and MKR mice, and were more metastatic than CD24- cells. Interestingly, CD24-KD in CD24+ cells had no effect both in vitro and in vivo on the various parameters studied. Moreover, CD24(+) cells gave rise in vivo to the CD24(-) that comprised the bulk of the tumor. RNA seq analysis revealed enrichment of genes and pathways of the extracellular matrix in the CD24(+) cells. CONCLUSION: CD24(+) cells account for heterogeneity in mammary tumors. CD24 expression at early stages of the cancer process is an indication of a highly invasive tumor. However, CD24 is not a suitable therapeutic target; instead we suggest here new potential targets accounting for early differentiated cancer cells tumorigenic capacity. PMID- 26040282 TI - The effects of three different distraction methods on pain and anxiety in children. AB - This study aims to investigate of three different distraction methods (distraction cards, listening to the music of cartoon and balloon inflation) on pain and anxiety relief of children during phlebotomy. This study is a prospective, randomized, and controlled trial. The sample consisted of 6 to 12 years old children who require blood tests. Children were randomized into four groups as the distraction cards, the music, the balloon inflation, and the control. Data were obtained by conducting interviews with the children, their parents, and the observer before and after the procedure. The pain levels of the children were assessed by the parent and observer reports as well as self-report using the Wong-Baker FACES. The anxiety levels of children were assessed by parent and observer reports using Children Fear Scale. One hundred and twenty children (mean age: 9.1 +/- 1.6 years) were included. The self-reported procedural pain levels showed significant differences among the study groups (p = .040). The distraction card group (2.33 +/- 3.24) had significantly lower pain levels (p = .057) than the control group (4.53 +/- 3.23). The procedural child anxiety levels reported by the observer showed a significant difference among the study groups (p = .032). All the forms of distraction significantly reduced pain and anxiety perception. PMID- 26040283 TI - Gold Nanoparticles Inhibit Matrix Metalloproteases without Cytotoxicity. AB - Nanoparticles (NPs) are currently the focus of considerable attention for dental applications; however, their biological effects have not been fully elucidated. The long-term, slow release of matrix metalloproteases (MMPs) digests collagen fibrils within resin-dentin bonds. Therefore, MMP inhibitors can prolong the durability of resin-dentin bonds. However, there have been few reports evaluating the combined effect of MMP inhibition and the cytotoxic effects of NPs for dentin bonding. The aim of this study was to evaluate MMP inhibition and cytotoxic responses to gold (AuNPs) and platinum nanoparticles (PtNPs) stabilized by polyvinylpyrrolidone (PVP) in cultured murine macrophages (RAW264) by using MMP inhibition assays, measuring cell viability and inflammatory responses (quantitative reverse transcription polymerase chain reaction [RT-qPCR]), and conducting a micromorphological analysis by fluorescence and transmission electron microscopy. Cultured RAW264 cells were exposed to metal NPs at various concentrations (1, 10, 100, and 400 ug/mL). AuNPs and PtNPs markedly inhibited MMP-8 and MMP-9 activity. Although PtNPs were cytotoxic at high concentrations (100 and 400 ug/mL), no cytotoxic effects were observed for AuNPs at any concentration. Transmission electron microscopy images showed a significant nonrandom intercellular distribution for AuNPs and PtNPs, which were mostly observed to be localized in lysosomes but not in the nucleus. RT-qPCR analysis demonstrated inflammatory responses were not induced in RAW264 cells by AuNPs or PtNPs. The cytotoxicity of nanoparticles might depend on the core metal composition and arise from a "Trojan horse" effect; thus, MMP inhibition could be attributed to the surface charge of PVP, which forms the outer coating of NPs. The negative charge of the surface coating of PVP binds to Zn(2+) from the active center of MMPs by chelate binding and results in MMP inhibition. In summary, AuNPs are attractive NPs that effectively inhibit MMP activity without cytotoxicity or inflammatory responses. PMID- 26040284 TI - Inverse-model-based cuffless blood pressure estimation using a single photoplethysmography sensor. AB - This paper proposes an inverse-model-based cuffless method for estimating blood pressure using a single photoplethysmography sensor. The proposed method, which is based on the relationship between blood pressure and the features of pulse waves, employs an inverse estimation and uses the blood pressure as the explanatory variable. Using this method, the blood pressure can be estimated with high accuracy even in situations where the pulse wave features are scattered, as the method uses the dynamic signal-to-noise ratio of the Taguchi method. In order to verify the effectiveness of the proposed method, we employed it to measure the systolic blood pressure. It could be confirmed that the estimation accuracy of the proposed method is higher than that of similar methods. PMID- 26040285 TI - Comparative proteomics of cerebrospinal fluid reveals a predictive model for differential diagnosis of pneumococcal, meningococcal, and enteroviral meningitis, and novel putative therapeutic targets. AB - BACKGROUND: Meningitis is the inflammation of the meninges in response to infection or chemical agents. While aseptic meningitis, most frequently caused by enteroviruses, is usually benign with a self-limiting course, bacterial meningitis remains associated with high morbidity and mortality rates, despite advances in antimicrobial therapy and intensive care. Fast and accurate differential diagnosis is crucial for assertive choice of the appropriate therapeutic approach for each form of meningitis. METHODS: We used 2D-PAGE and mass spectrometry to identify the cerebrospinal fluid proteome specifically related to the host response to pneumococcal, meningococcal, and enteroviral meningitis. The disease-specific proteome signatures were inspected by pathway analysis. RESULTS: Unique cerebrospinal fluid proteome signatures were found to the three aetiological forms of meningitis investigated, and a qualitative predictive model with four protein markers was developed for the differential diagnosis of these diseases. Nevertheless, pathway analysis of the disease specific proteomes unveiled that Kallikrein-kinin system may play a crucial role in the pathophysiological mechanisms leading to brain damage in bacterial meningitis. Proteins taking part in this cellular process are proposed as putative targets to novel adjunctive therapies. CONCLUSIONS: Comparative proteomics of cerebrospinal fluid disclosed candidate biomarkers, which were combined in a qualitative and sequential predictive model with potential to improve the differential diagnosis of pneumococcal, meningococcal and enteroviral meningitis. Moreover, we present the first evidence of the possible implication of Kallikrein-kinin system in the pathophysiology of bacterial meningitis. PMID- 26040286 TI - Akt signaling dynamics in individual cells. AB - The protein kinase Akt (for which there are three isoforms) is a key intracellular mediator of many biological processes, yet knowledge of Akt signaling dynamics is limited. Here, we have constructed a fluorescent reporter molecule in a lentiviral delivery system to assess Akt kinase activity at the single cell level. The reporter, a fusion between a modified FoxO1 transcription factor and clover, a green fluorescent protein, rapidly translocates from the nucleus to the cytoplasm in response to Akt stimulation. Because of its long half life and the intensity of clover fluorescence, the sensor provides a robust readout that can be tracked for days under a range of biological conditions. Using this reporter, we find that stimulation of Akt activity by IGF-I is encoded into stable and reproducible analog responses at the population level, but that single cell signaling outcomes are variable. This reporter, which provides a simple and dynamic measure of Akt activity, should be compatible with many cell types and experimental platforms, and thus opens the door to new insights into how Akt regulates its biological responses. PMID- 26040287 TI - Rho-kinase-dependent actin turnover and actomyosin disassembly are necessary for mouse spinal neural tube closure. AB - The cytoskeleton is widely considered essential for neurulation, yet the mouse spinal neural tube can close despite genetic and non-genetic disruption of the cytoskeleton. To investigate this apparent contradiction, we applied cytoskeletal inhibitors to mouse embryos in culture. Preventing actomyosin cross-linking, F actin assembly or myosin II contractile activity did not disrupt spinal closure. In contrast, inhibiting Rho kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2) or blocking F-actin disassembly prevented closure, with apical F-actin accumulation and adherens junction disturbance in the neuroepithelium. Cofilin-1 null embryos yielded a similar phenotype, supporting the hypothesis that there is a key role for actin turnover. Co-exposure to Blebbistatin rescued the neurulation defects caused by RhoA inhibition, whereas an inhibitor of myosin light chain kinase, ML-7, had no such effect. We conclude that regulation of RhoA, Rho kinase, LIM kinase and cofilin signalling is necessary for spinal neural tube closure through precise control of neuroepithelial actin turnover and actomyosin disassembly. In contrast, actomyosin assembly and myosin ATPase activity are not limiting for closure. PMID- 26040288 TI - Single-cell polyadenylation site mapping reveals 3' isoform choice variability. AB - Cell-to-cell variability in gene expression is important for many processes in biology, including embryonic development and stem cell homeostasis. While heterogeneity of gene expression levels has been extensively studied, less attention has been paid to mRNA polyadenylation isoform choice. 3' untranslated regions regulate mRNA fate, and their choice is tightly controlled during development, but how 3' isoform usage varies within genetically and developmentally homogeneous cell populations has not been explored. Here, we perform genome-wide quantification of polyadenylation site usage in single mouse embryonic and neural stem cells using a novel single-cell transcriptomic method, BATSeq. By applying BATBayes, a statistical framework for analyzing single-cell isoform data, we find that while the developmental state of the cell globally determines isoform usage, single cells from the same state differ in the choice of isoforms. Notably this variation exceeds random selection with equal preference in all cells, a finding that was confirmed by RNA FISH data. Variability in 3' isoform choice has potential implications on functional cell-to cell heterogeneity as well as utility in resolving cell populations. PMID- 26040290 TI - Ultrastructure of the anterior organ and posterior funnel-shaped canal of Gyrocotyle urna Wagener, 1852 (Cestoda: Gyrocotylidea). AB - Using scanning and transmission electron microscopy, ultrastructure of the anterior organ and posterior funnel-shaped canal of Gyrocotyle urna Wagener, 1852 (Cestoda: Gyrocotylidea) from ratfish, Chimaera monstrosa (Holocephali), was studied for the first time. The proper anterior organ is localised at a short distance (about 170 um) from an apical pore surrounded by a receptor field, whereas its distal end is marked by a muscular sphincter. The tegumental surface of this organ is covered with short filitriches of irregular length; large area of muscle layers traverse beneath the tegumental layer. The funnel-shaped canal of G. urna (2.5-3.0 mm long) is a specialised, muscular part of the posterior attachment organ; it opens on the rounded elevation on the dorsal body surface. The tegumental layer bears conical sclerite-like structures (up to 1.5 um long). It produces electron-dense bodies that are transported into a canal lumen and surrounded thick muscle area mixed with numerous nerve fibres. The present ultrastructural study of G. urna indicates that gyrocotylideans share some ultrastructural characters of the anterior organ with spathebothriidean cestodes with a single anterior attachment sucker-like organ. In contrast, the unique posterior rosette attachment organ with funnel-shaped canal of the Gyrocotylidea resembles the haptor of polyopisthocotylean monogeneans in its position at the posterior end of the body and presumed origin. The above-mentioned features add more clarity to support the basal position of the Gyrocotylidea Poche, 1926 among cestodes. In addition, they also indicate a possible relationship of gyrocotylidean ancestors with monogeneans. PMID- 26040291 TI - Tip induced mechanical deformation of epitaxial graphene grown on reconstructed 6H-SiC(0001) surface during scanning tunneling and atomic force microscopy studies. AB - The structural and mechanical properties of an epitaxial graphene (EG) monolayer thermally grown on top of a 6H-SiC(0001) surface were studied by combined dynamic scanning tunneling microscopy (STM) and frequency modulation atomic force microscopy (FM-AFM). Experimental STM, dynamic STM and AFM images of EG on 6H SiC(0001) show a lattice with a 1.9 nm period corresponding to the (6 * 6) quasi cell of the SiC surface. The corrugation amplitude of this (6 * 6) quasi-cell, measured from AFM topographies, increases with the setpoint value of the frequency shift Deltaf (15-20 Hz, repulsive interaction). Excitation variations map obtained simultaneously with the AFM topography shows that larger dissipation values are measured in between the topographical bumps of the (6 * 6) quasi-cell. These results demonstrate that the AFM tip deforms the graphene monolayer. During recording in dynamic STM mode, a frequency shift (Deltaf) map is obtained in which Deltaf values range from 41 to 47 Hz (repulsive interaction). As a result, we deduced that the STM tip, also, provokes local mechanical distortions of the graphene monolayer. The origin of these tip-induced distortions is discussed in terms of electronic and mechanical properties of EG on 6H-SiC(0001). PMID- 26040289 TI - Phosphoproteome dynamics of Saccharomyces cerevisiae under heat shock and cold stress. AB - The ability of cells and organisms to survive and function through changes in temperature evolved from their specific adaptations to nonoptimal growth conditions. Responses to elevated temperatures have been studied in yeast and other model organisms using transcriptome profiling and provided valuable biological insights on molecular mechanisms involved in stress tolerance and adaptation to adverse environment. In contrast, little is known about rapid signaling events associated with changes in temperature. To gain a better understanding of global changes in protein phosphorylation in response to heat and cold, we developed a high temporal resolution phosphoproteomics protocol to study cell signaling in Saccharomyces cerevisiae. The method allowed for quantitative analysis of phosphodynamics on 2,777 phosphosites from 1,228 proteins. The correlation of kinetic profiles between kinases and their substrates provided a predictive tool to identify new putative substrates for kinases such as Cdc28 and PKA. Cell cycle analyses revealed that the increased phosphorylation of Cdc28 at its inhibitory site Y19 during heat shock is an adaptive response that delays cell cycle progression under stress conditions. The cellular responses to heat and cold were associated with extensive changes in phosphorylation on proteins implicated in transcription, protein folding and degradation, cell cycle regulation and morphogenesis. PMID- 26040292 TI - Global behaviour of a predator-prey like model with piecewise constant arguments. AB - The present study deals with the analysis of a predator-prey like model consisting of system of differential equations with piecewise constant arguments. A solution of the system with piecewise constant arguments leads to a system of difference equations which is examined to study boundedness, local and global asymptotic behaviour of the positive solutions. Using Schur-Cohn criterion and a Lyapunov function, we derive sufficient conditions under which the positive equilibrium point is local and global asymptotically stable. Moreover, we show numerically that periodic solutions arise as a consequence of Neimark-Sacker bifurcation of a limit cycle. PMID- 26040294 TI - Blood Urea Nitrogen/Creatinine Ratio in Acute Heart Failure Patients. PMID- 26040293 TI - Mediation analysis of decisional balance, sun avoidance and sunscreen use in the precontemplation and preparation stages for sun protection. AB - OBJECTIVE: Mediation analyses of sun protection were conducted testing structural equation models using longitudinal data with three waves. An effect was said to be mediated if the standardised path between processes of change, decisional balance and sun protection outcomes was significant. DESIGN: Longitudinal models of sun protection using data from individuals in the precontemplation (N = 964) and preparation (N = 463) stages who participated of an expert system intervention. MAIN OUTCOME MEASURES: Nine processes of change for sun protection, decisional balance constructs of sun protection (pros and cons), sun avoidance behaviour and sunscreen use. RESULTS: With the exception of two processes in the preparation stage, processes of change predicted the pros (r = .126-.614), and the pros predicted the outcomes (r = .181-.272). Three models with the cons as mediator in the preparation stage, and none in the precontemplation stage, showed a mediated relationship between processes and outcomes. CONCLUSION: In general, mediation analyses found both the process of change-to-pros and pros-to-behaviour paths significant for both precontemplation and preparation stages, and for both sun avoidance and sunscreen use outcomes. Findings provide support for the importance of assessing the role of underlying risk cognitions in improving sun protection adherence. PMID- 26040295 TI - Estimating the Prognosis of Patients With Aortic Stenosis in the Current Japanese Population. PMID- 26040296 TI - Visual Recognition of Aliphatic and Aromatic Amines Using a Fluorescent Gel: Application of a Sonication-Triggered Organogel. AB - A naphthalimide-based fluorescent gelator (N1) containing an alkenyl group has been designed and characterized. This material is able to gelate alcohols via a precipitate-to-gel transformation when triggered with ultrasound for less than 2 min (S-gel). The gelation process in n-propanol was studied by means of absorption, fluorescence, and IR spectra, scanning electron microscopy (SEM) images, and X-ray diffraction patterns. The fluorescence intensity of N1 decreased during the gelation process in a linear relationship with the sonication time. The S-gel of N1 could be used to sense aliphatic and aromatic amines by measuring the change in the signal output. For example, the addition of propylamine to the S-gel of N1 resulted in a dramatic enhancement of the fluorescence intensity, accompanied by a gel-to-sol transition. On the contrary, when the S-gel of N1 was treated with aromatic amines such as aniline, fluorescence was quenched and there was no gel collapse. The sensing mechanisms were studied by (1)H NMR, small-angle X-ray scattering, SEM and spectroscopic experiments. It is proposed that isomerization of the alkenyl group of N1 from the trans to cis form occurs when the S-gel is treated with propylamine, resulting in a gel-sol transition. However, the aromatic aniline molecules prefer to insert into the gel networks of N1 via hydrogen-bonding and charge-transfer interactions, maintaining the gel state. As potential applications, testing strips of N1 were prepared to detect aniline. PMID- 26040299 TI - Antimicrobial Effects of Nisin, Essential Oil, and gamma-Irradiation Treatments against High Load of Salmonella typhimurium on Mini-carrots. AB - This study aimed at using essential oil (EO) alone or combined EO with nisin and gamma-irradiation to control Salmonella Typhimurium during the refrigerated storage of mini-carrots. Peeled mini-carrots were inoculated with S. Typhimurium at a final concentration of approximately 7 log CFU/g. Inoculated samples were coated by 5 different coating solutions: (i) nisin solution at final concentration of 10(3) IU/mL; (ii) mountain savory EO solution at 0.35%; (iii) carvacrol solution at 0.35%; (iv) mountain savory EO at 0.35% plus nisin solution of 10(3) IU/mL; or (v) carvacrol at 0.35% plus nisin solution of 10(3) IU/mL. Coated mini-carrots were then irradiated at 0.5 or 1.0 kGy and compared to an unirradiated control sample. Samples were kept at 4 degrees C and microbial analyses were conducted at days 1, 3, 6, and 9. The results showed that mini carrots coated by carvacrol plus nisin solution or mountain savory EO plus nisin solution in combination with irradiation at 1.0 kGy completely eliminated S. Typhimurium to under the detection limit during the storage. Thus, the combined treatments using carvacrol plus nisin or mountain savory EO plus nisin coating solution and irradiation at 1.0 kGy could be used as an effective method for controlling S. Typhimurium in mini-carrots. PRACTICAL APPLICATION: This study shows the effect of using gamma irradiation at low dose (1 kGy) to reduce significantly the growth of Salmonella typhimurium in mini-carrots. It also shows that combination of nisin, essential oils with gamma irradiation have the best antibacterial effects against S. Typhimurium during the storage of mini-carrots. The results can be used for practical application in food industry in terms of food safety. PMID- 26040298 TI - Antiapoptotic efficacy of seed of Eugenia jambolana on testicular germ cell in experimental diabetic rat: a genomic study. AB - This study was designed to focus the genetic regulation of diabetes-induced testicular hypofunction and its amelioration by ethyl acetate fraction of seed of Eugenia jambolana. In this regard, we have assessed relevant biosensors such as biochemical, spermiological, histological and gene expression of antioxidant enzymes, germ cell apoptosis and androgenic key enzymes along with in situ end labelling and DNA fragmentation study. After 60 days administration of said fraction, significant recovery in the glycated haemoglobin, serum testosterone, sperm viability, hypo-osmotic swelling and nuclear chromatin decondensation were noted in fraction-treated diabetic group in comparison with diabetic control. Besides this, a significant recovery in the expression of Bax, Bcl-2, caspase-9, caspase-3, catalase, peroxidase, ?(5) , 3beta-hydroxy steroid dehydrogenase and 17beta-hydroxy steroid dehydrogenase genes was noted towards the control in ethyl acetate fraction-treated group. Testicular histology focused a significant recovery in the number of different generation of germ cells at stage VII of spermatogenesis in fraction-treated group. In situ end labelling and DNA fragmentation study of testicular tissues also showed a significant recovery in fraction-treated group towards the control. These findings indicate that the ethyl acetate fraction showed outstanding antiapoptotic activity by neutralising oxidative stress as well as by the improvement in glycaemic sensors. PMID- 26040300 TI - Unusual root development following surgical repositioning of horizontally developing central incisor. AB - Dilaceration is one of the causes of maxillary central incisor eruption failure. If the dilacerated maxillary permanent central incisor is in a horizontal or vertical position and root formation is in early stages, surgical repositioning is frequently the treatment of choice. In this article, the case of a horizontally impacted and dilacerated maxillary central incisor is presented which was treated by surgical repositioning. The tooth developed an unusual form of the root with discontinuity at the middle third region with the coronal and apical parts growing separately. Radiographic and clinical monitoring of the case was regularly performed. The tooth completely erupted in 2 years after the repositioning and even after 6 years of surgery is currently successfully functional in the arch with the malformed root. This article highlights the ability of Hertwig's epithelial root sheath to withstand trauma and its ability to recover. PMID- 26040297 TI - Neurorestoration induced by the HDAC inhibitor sodium valproate in the lactacystin model of Parkinson's is associated with histone acetylation and up regulation of neurotrophic factors. AB - BACKGROUND AND PURPOSE: Histone hypoacetylation is associated with Parkinson's disease (PD), due possibly to an imbalance in the activities of enzymes responsible for histone (de)acetylation; correction of which may be neuroprotective/neurorestorative. This hypothesis was tested using the anti epileptic drug sodium valproate, a known histone deacetylase inhibitor (HDACI), utilizing a delayed-start study design in the lactacystin rat model of PD. EXPERIMENTAL APPROACH: The irreversible proteasome inhibitor lactacystin was unilaterally injected into the substantia nigra of Sprague-Dawley rats that subsequently received valproate for 28 days starting 7 days after lactacystin lesioning. Longitudinal motor behavioural testing, structural MRI and post-mortem assessment of nigrostriatal integrity were used to track changes in this model of PD and quantify neuroprotection/restoration. Subsequent cellular and molecular analyses were performed to elucidate the mechanisms underlying valproate's effects. KEY RESULTS: Despite producing a distinct pattern of structural re modelling in the healthy and lactacystin-lesioned brain, delayed-start valproate administration induced dose-dependent neuroprotection/restoration against lactacystin neurotoxicity, characterized by motor deficit alleviation, attenuation of morphological brain changes and restoration of dopaminergic neurons in the substantia nigra. Molecular analyses revealed that valproate alleviated lactacystin-induced histone hypoacetylation and induced up-regulation of brain neurotrophic/neuroprotective factors. CONCLUSIONS AND IMPLICATIONS: The histone acetylation and up-regulation of neurotrophic/neuroprotective factors associated with valproate treatment culminate in a neuroprotective and neurorestorative phenotype in this animal model of PD. As valproate induced structural re-modelling of the brain, further research is required to determine whether valproate represents a viable candidate for disease treatment; however, the results suggest that HDACIs could hold potential as disease-modifying agents in PD. PMID- 26040301 TI - A multistate framework for the analysis of subsequent injury in sport (M-FASIS). AB - Physical activity is beneficial for many aspects of health but is associated with a risk of injury. Studies that assess causal risk factors of injury and reinjury provide valuable information to help develop and improve injury prevention programs. However, the underlying assumptions of analytical approaches often used to estimate causal factors in injury and subsequent injury research are often violated. This means that ineffective or even harmful interventions could be proposed because the underlying analyses produced unreliable or invalid causal effect estimates. We describe an adapted version of the multistate framework [multistate framework for the analysis of subsequent injury in sport (M-FASIS)] that makes investigator choices more transparent with respect to outcome and healing time. In addition, M-FASIS incorporates all previous sport injury analytical frameworks and accounts for injuries or conditions that heal or do not heal to 100%, acute and overuse injuries, illnesses, and competing event outcomes. PMID- 26040304 TI - Socio-economic disparities and functional limitations of children with cerebral palsy. PMID- 26040303 TI - Analysis of Swine Movements in a Province in Northern Vietnam and Application in the Design of Surveillance Strategies for Infectious Diseases. AB - While swine production is rapidly growing in South-East Asia, the structure of the swine industry and the dynamic of pig movements have not been well-studied. However, this knowledge is a prerequisite for understanding the dynamic of disease transmission in swine populations and designing cost-effective surveillance strategies for infectious diseases. In this study, we assessed the farming and trading practices in the Vietnamese swine familial farming sector, which accounts for most pigs in Vietnam, and for which disease surveillance is a major challenge. Farmers from two communes of a Red River Delta Province (northern Vietnam) were interviewed, along with traders involved in pig transactions. Major differences in the trade structure were observed between the two communes. One commune had mainly transversal trades, that is between farms of equivalent sizes, whereas the other had pyramidal trades, that is from larger to smaller farms. Companies and large familial farrow-to-finish farms were likely to act as major sources of disease spread through pig sales, demonstrating their importance for disease control. Familial fattening farms with high pig purchases were at greater risk of disease introduction and should be targeted for disease detection as part of a risk-based surveillance. In contrast, many other familial farms were isolated or weakly connected to the swine trade network limiting their relevance for surveillance activities. However, some of these farms used boar hiring for breeding, increasing the risk of disease spread. Most familial farms were slaughtering pigs at the farm or in small local slaughterhouses, making the surveillance at the slaughterhouse inefficient. In terms of spatial distribution of the trades, the results suggested that northern provinces were highly connected and showed some connection with central and southern provinces. These results are useful to develop risk-based surveillance protocols for disease detection in the swine familial sector and to make recommendations for disease control. PMID- 26040302 TI - Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo controlled trial. AB - AIMS: To investigate the efficacy and tolerability of empagliflozin added to basal insulin-treated type 2 diabetes. METHODS: Patients inadequately controlled [glycated haemoglobin (HbA1c) >7 to <=10% (>53 to <=86 mmol/mol)] on basal insulin (glargine, detemir, NPH) were randomized to empagliflozin 10 mg (n = 169), empagliflozin 25 mg (n = 155) or placebo (n = 170) for 78 weeks. The baseline characteristics were balanced among the groups [mean HbA1c 8.2% (67 mmol/mol), BMI 32.2 kg/m(2) ]. The basal insulin dose was to remain constant for 18 weeks, then could be adjusted at investigator's discretion. The primary endpoint was change from baseline in HbA1c at week 18. Key secondary endpoints were changes from baseline in HbA1c and insulin dose at week 78. RESULTS: At week 18, the adjusted mean +/- standard error changes from baseline in HbA1c were 0.0 +/- 0.1% (-0.1 +/- 0.8 mmol/mol) for placebo, compared with -0.6 +/- 0.1% (-6.2 +/- 0.8 mmol/mol) and -0.7 +/- 0.1% (-7.8 +/- 0.8 mmol/mol) for empagliflozin 10 and 25 mg, respectively (both p < 0.001). At week 78, empagliflozin 10 and 25 mg significantly reduced HbA1c, insulin dose and weight vs placebo (all p < 0.01), and empagliflozin 10 mg significantly reduced systolic blood pressure vs placebo (p = 0.004). Similar percentages of patients had confirmed hypoglycaemia in all groups (35-36%). Events consistent with urinary tract infection were reported in 9, 15 and 12% of patients on placebo, empagliflozin 10 and 25 mg, and events consistent with genital infection were reported in 2, 8 and 5%, respectively. CONCLUSIONS: Empagliflozin for 78 weeks added to basal insulin improved glycaemic control and reduced weight with a similar risk of hypoglycaemia to placebo. PMID- 26040306 TI - Stromal rejection in a deep anterior lamellar keratoplasty following influenza vaccination. PMID- 26040307 TI - Maternal emotion dysregulation is related to heightened mother-infant synchrony of facial affect. AB - A heightened synchrony between the mother's and infant's facial affect predicts adverse infant development. We know that maternal psychopathology is related to mother-infant facial affect synchrony, but it is unclear how maternal psychopathology is transmitted to mother-infant synchrony. One pathway might be maternal emotion dysregulation. We examined (a) whether maternal emotion dysregulation is positively related to facial affect synchrony and (b) whether maternal emotion dysregulation mediates the effect of maternal psychopathology on mother-infant facial affect synchrony. We observed 68 mothers with mood disorders and their 4- to 9-month-old infants in the Still-Face paradigm during two play interactions. The mother's and infant's facial affect were rated from high negative to high positive, and the degree of synchrony between the mother's and infant's facial affect was computed with a time-series analysis. Emotion dysregulation was measured with the Difficulties in Emotion Regulation Scale, and psychopathology was assessed with the Symptom Checklist-90-Revised. Higher maternal emotion dysregulation was significantly associated with higher facial affect synchrony; emotion dysregulation fully mediated the effect of maternal psychopathology on facial affect synchrony. Our findings demonstrate that maternal emotion dysregulation rather than maternal psychopathology per se places mothers and infants at risk for heightened facial affect synchrony. PMID- 26040308 TI - Early-life temperature modifies adult encapsulation response in an invasive ectoparasite. AB - Immunity of parasites has been studied amazingly little, in spite of the fact that parasitic organisms, especially the arthropod parasites, need immunity to survive their own infections to successfully complete life cycles. Long-term effects of challenging environmental temperatures on immunity have remained unstudied in insects and parasites. Our study species, the deer ked (Lipoptena cervi; Linnaeus 1758), is an invasive, blood-feeding parasitic fly of cervids. Here, it was studied whether thermal stress during the pupal diapause stage could modify adult immunity (encapsulation capacity) in L. cervi. The effect of either a low temperature or high temperature peak, experienced during winter dormancy, on encapsulation response of active adult was tested. It was found that low temperature exposure during diapause, as long as the temperature is not too harsh, had a favourable effect on adult immunity. An abnormal, high temperature peak during pupal winter diapause significantly deteriorated the encapsulation capacity of emerged adults. The frequency and intensity of extreme weather events such as high temperature fluctuations are likely to increase with climate change. Thus, the climate change might have previously unknown influence on host ectoparasite interactions, by affecting ectoparasite's immune defence and survival. PMID- 26040309 TI - Protocol and Research Perspectives of the ToMMo Child Health Study after the 2011 Great East Japan Earthquake. AB - Residents of areas affected by the Great East Japan Earthquake may suffer from diseases or health problems. We are conducting a cross-sectional study from 2012 to 2015 to investigate and address the health needs of schoolchildren affected by this disaster. In this paper, we describe the protocol and research perspectives of our long-term child health study, and present the results obtained immediately after the disaster. The parent-administered questionnaire includes the International Study of Asthma and Allergies in Childhood questionnaire for asthma and eczema symptoms, the Strengths and Difficulties Questionnaire (SDQ), and a questionnaire on influenza infection and vaccination status. In 2012, we distributed the questionnaire to 3,505 (2nd, 4th, 6th, and 8th graders) in three municipalities located in southern coastal area among the 28 municipalities, and 1,277 (36.4%) returned the completed questionnaire. Mean age was 11.1 +/- 2.2 years old. The number of children with symptoms of wheeze and eczema in the past 12 months was 146 (11.4%) and 199 (15.6%), respectively. The SDQ total difficulties score revealed 174 (13.6%) children with some form of difficulty in their daily lives. From May 2011 to April 2012, 195 (15.3%) and 649 (50.8%) children received the influenza vaccination once and twice, respectively, and 532 (41.7%) had suffered from influenza. The prevalence of eczema symptoms or some form of difficulty was higher than the Japanese average. However, careful interpretation was required because of potential self-selection bias from the low response rate. We will continue this study of schoolchildren to provide aggregate findings. PMID- 26040310 TI - Multimorbidity patterns in a primary care population aged 55 years and over. AB - BACKGROUND: To support the management of multimorbid patients in primary care, evidence is needed on prevalent multimorbidity patterns. OBJECTIVE: To identify the common and distinctive multimorbidity patterns. METHODS: Clinical data of 120480 patients (>=55 years) were extracted from 158 general practices in 2002 11. Prevalence rates of multimorbidity were analyzed (overall, and for 24 chronic diseases), adjusted for practice, number of diseases and patients' registration period; differentiated between patients 55-69 and >=70 years. To investigate multimorbidity patterns, prevalence ratios (prevalence rate index-disease group divided by that in the non-index-disease group) were calculated for patients with heart failure, diabetes mellitus, migraine or dementia. RESULTS: Multiple membership multilevel models showed that the overall adjusted multimorbidity rate was 86% in patients with >=1 chronic condition, varying from 70% (migraine) to 98% (heart failure), 38% had >=4 chronic diseases. In patients 55-69 years, 83% had multimorbidity. Numerous significant prevalence ratios were found for disease patterns in heart failure patients, ranging from 1.2 to 7.7, highest ratio for chronic obstructive pulmonary disease-cardiac dysrhythmia. For diabetes mellitus, dementia or migraine patients highest ratios were for heart failure-visual disorder (2.1), heart failure-depression (3.9) and depression-back/neck disorder (2.1), respectively (all P-values<0.001). CONCLUSIONS: Multimorbidity management in general practice can be reinforced by knowledge on the clinical implications of the presence of the comprehensive disease patterns among the elderly patients, and those between 55 and 69 years. Guideline developers should be aware of the complexity of multimorbidity. As a consequence of this complexity, it is even more important to focus on what matters to a patient with multimorbidity in general practice. PMID- 26040311 TI - Screening for postpartum depression in a private health care network in Chile. AB - BACKGROUND: It has been demonstrated that postpartum depression (PPD) has an impact on infant development with repercussions in the child's cognitive, socioemotional and conduct regulation. Screening for this disorder with the Edinburgh Postnatal Depression Scale (EPDS) has been recommended because this significantly identifies more cases of PPD than usual clinical evaluation. AIM: To evaluate the use of the EPDS to screen mothers attending well child care visits with their infants during the first 6 months of age and identifying the factors associated with its use in the largest private health care network in Chile. METHODS: Cross-sectional study, conducted by random sampling of the children's medical charts from a universe of 5700 infants aged 1-6 months that attended the health care network during 2009 and 2011. Estimated sample size: 500 medical charts, assuming a recording frequency of the EPDS of 5% (confidence level of 95% and power of 80%). The descriptive data analysis of the variables was carried out using a uni and multivariate analysis. All values of P < 0.05 were considered significant (Software SPSS 17.0). RESULTS: A total of 1940 visits, belonging to 503 medical charts of infants under 6 months of age were reviewed. The use of the EPDS to screen mothers was recorded in nine medical charts (1.7% of the infant population). The only variable that was significantly associated with the recording of the EPDS was the background of previous depression in the mother (P < 0.001). CONCLUSION: The record of the use of EPDS on mothers of infants seen in the private health care network is much less than what is recommended. PMID- 26040312 TI - Case-control association between CCT-associated variants and keratoconus in a Saudi Arabian population. AB - BACKGROUND: Keratoconus (KC) is the most common primary ectatic disease of the cornea and a major indication for corneal transplant. To date, limited KC associated-risk loci have been identified. Association has recently been suggested between KC and 8 single nucleotide polymorphisms (SNPs) in the genomic regions of FNDC3B, COL4A3, MPDZ-NF1B, RXRA-COL5A1, LCN12-PTGDS, FOXO1, and BANP ZNF469. These SNPs are associated with central corneal thickness (CCT), a known risk factor to KC. We are questioning whether these SNPs are significantly associated with KC in a Saudi Arabian population. The study included 108 unrelated KC cases and 300 controls. Patients were diagnosed with KC according to the Schimpff-flow based elevation map of the cornea. DNA genotyping was done using probe-based allelic discrimination TaqMan assays. Allele frequencies were compared between the cases and controls. RESULTS: All SNPs were successfully genotyped with high efficiency (>95 %). The SNPs had no significant deviation in cases or controls from Hardy-Weinberg Equilibrium (HWE, p value > 0.05). None of the selected SNPs were significantly associated with KC in the Saudi Arabian population. However, we replicated the same trend of minor allele frequency (MAF) between cases and controls reported by a recent GWAS regarding the 5 SNPs rs4894535 (FNDC3B, chr3: 171995605), rs1536482 (RXRA-COL5A1, chr9: 137440528), rs7044529 (COL5A1, chr9: 137568051), rs11145951 (LCN12-PTGDS, chr9: 139860264), and rs2721051 (FOXO1, chr13: 41110884). CONCLUSIONS: This is the first study investigating the association of these SNPs with KC in a population from Saudi Arabia. We replicated the same trend of MAF alteration of the association between the SNPs rs4894535 (FNDC3B, chr3: 171995605), rs7044529 (COL5A1, chr9: 137568051), rs11145951 (LCN12-PTGDS, chr9: 139860264) and rs2721051 (FOXO1, chr13: 41110884) and KC-risk as reported by a recently published GWAS. Consistently replicated population-based studies are necessary to identify and/or confirm genetic susceptibility for certain diseases. We acknowledge that the lack of significance in our study is due to our small sample size and insufficient statistical power; however our data still add to the body of evidence of potential KC-candidate SNPs. This report aims at supporting the possible association between CCT-associated SNPs and KC susceptibility. PMID- 26040313 TI - Use of Plasmodium falciparum culture-adapted field isolates for in vitro exflagellation-blocking assay. AB - BACKGROUND: A major requirement for malaria elimination is the development of transmission-blocking interventions. In vitro transmission-blocking bioassays currently mostly rely on the use of very few Plasmodium falciparum reference laboratory strains isolated decades ago. To fill a piece of the gap between laboratory experimental models and natural systems, the purpose of this work was to determine if culture-adapted field isolates of P. falciparum are suitable for in vitro transmission-blocking bioassays targeting functional maturity of male gametocytes: exflagellation. METHODS: Plasmodium falciparum isolates were adapted to in vitro culture before being used for in vitro gametocyte production. Maturation was assessed by microscopic observation of gametocyte morphology over time of culture and the functional viability of male gametocytes was assessed by microscopic counting of exflagellating gametocytes. Suitability for in vitro exflagellation-blocking bioassays was determined using dihydroartemisinin and methylene blue. RESULTS: In vitro gametocyte production was achieved using two isolates from French Guiana and two isolates from Cambodia. Functional maturity of male gametocytes was assessed by exflagellation observations and all four isolates could be used in exflagellation-blocking bioassays with adequate response to methylene blue and dihydroartemisinin. CONCLUSION: This work shows that in vitro culture-adapted P. falciparum field isolates of different genetic background, from South America and Southeast Asia, can successfully be used for bioassays targeting the male gametocyte to gamete transition, exflagellation. PMID- 26040314 TI - Up-regulation of iNOS by hypoxic postconditioning inhibits H9c2 cardiomyocyte apoptosis induced by hypoxia/re-oxygenation. AB - Apoptosis is a crucial mode of cell death induced by ischemia and reperfusion, and ischemic postconditioning (PostC) has been reported to inhibit cell apoptosis. Inducible nitric oxide synthase (iNOS) has been confirmed to play an important role in triggering and mediating the late cardio-protection against ischemia/hypoxia. In this study, we found that hypoxic PostC remarkably up regulated the expression of iNOS and decreased cardiomyocyte apoptosis. Pre treatment with 1400w (a highly selective inhibitor of iNOS) or iNOS siRNA weakened the anti-apoptotic effect of hypoxic PostC. These findings suggested that iNOS may be one of the key molecular mechanisms responsible for the inhibition of apoptosis by hypoxic PostC. PMID- 26040315 TI - Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms. AB - Tobacco usage is a major risk factor in the development, progression, and outcomes for lung cancer. Of the carcinogens associated with lung cancer, tobacco specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is among the most potent ones. The oncogenic mechanisms of NNK are not entirely understood, hindering the development of effective strategies for preventing and treating smoking-associated lung cancers. Here, we introduce the NNK-induced lung cancer animal models in different species and its potential mechanisms. Finally, we summarize several chemopreventive agents developed from these animal models. PMID- 26040316 TI - Corrigendum. PMID- 26040317 TI - Water-Aided Colonoscopy in Inflammatory Bowel Disease Patients-A Randomised, Single-Centre Trial. AB - BACKGROUND: Water-aided colonoscope insertion reduces patients' discomfort and need for sedation in unsedated and minimally sedated patients. However, water aided technique has never been studied in inflammatory bowel disease patients, characterised by younger age, structural changes of the colon and need for repeated colonoscopies. Our trial was designed to evaluate discomfort associated with water-aided colonoscopy compared with air insufflation in on-demand sedated patients with known inflammatory bowel disease. METHODS: In a randomised, single centre study, 92 patients were randomised to either water-aided insertion and air insufflation during withdrawal [Water] or air insufflation during both insertion and withdrawal [Air]. The main outcome measured was success rate of unsedated colonoscopy, defined as reaching the caecum without requiring sedation and with discomfort during insertion of less than or equal to 5 using 0-10 continuous scale [0 = none, 10 = maximum pain]. RESULTS: Success rate of caecal intubation without sedation or invoking a discomfort score greater than 5 was significantly higher in the Water arm compared with the Air arm [73.9 vs 45.7%, p = 0.01]. Discomfort score during insertion [mean +/- SD] was significantly lower in the Water than in the Air arm [3.8+/-2.4 vs 5.4+/-1.9, p < 0.001]. Other outcomes including procedural times, success rate of terminal ileum intubation, need for abdominal compression, and repositioning were comparable. There were no complications recorded in the study. CONCLUSIONS: Compared with air insufflation, water-aided colonoscopy significantly reduces discomfort in on-demand sedated patients with inflammatory bowel disease, achieving comparable procedural outcomes. PMID- 26040318 TI - Does Disease Extent Matter when Scoring the UCEIS? PMID- 26040319 TI - Prevention of transmission of Babesia canis by Dermacentor reticulatus ticks to dogs treated orally with fluralaner chewable tablets (BravectoTM). AB - BACKGROUND: The preventive effect of fluralaner chewable tablets (BravectoTM) against transmission of Babesia canis by Dermacentor reticulatus ticks was evaluated. METHODS: Sixteen dogs, tested negative for B. canis by PCR and IFAT, were allocated to two study groups. On day 0, dogs in one group (n = 8) were treated once orally with a fluralaner chewable tablet according to label recommendations and dogs in the control group (n = 8) remained untreated. On days 2, 28, 56, 70 and 84, dogs were infested with 50 (+/-4) B. canis infected D. reticulatus ticks with tick in situ thumb counts 48 +/- 4 h post-infestation. Prior to each infestation, the D. reticulatus ticks were confirmed to harbour B. canis by PCR analysis. On day 90, ticks were counted and removed from all dogs. Efficacy against ticks was calculated for each assessment time point. After treatment, all dogs were physically examined in conjunction with blood collection for PCR every 7 days, blood samples for IFAT were collected every 14 days and the dog's rectal body temperature was measured thrice weekly. From dogs displaying symptoms of babesiosis or were PCR positive, a blood smear was taken, and, if positive, dogs were rescue treated and replaced with a replacement dog. The preventive effect was evaluated by comparing infected dogs in the treated group with infected dogs in the untreated control group. RESULTS: All control dogs became infected with B. canis, as confirmed by PCR and IFAT. None of the 8 treated dogs became infected with B. canis, as IFAT and PCR were negative throughout the study until day 112. Fluralaner chewable tablet was 100 % effective against ticks on days 4, 30, 58, and 90 and an efficacy of 99.6 % and 99.2 % was achieved on day 72 and day 86 after treatment, respectively. Over the 12-week study duration, a 100 % preventive effect against B. canis transmission was demonstrated. CONCLUSIONS: A single oral administration of fluralaner chewable tablets effectively prevented the transmission of B. canis by infected D. reticulatus ticks over a 12-week period. PMID- 26040320 TI - Giant tubular adenoma of the accessory breast in the anterior chest wall occurred in a pregnant woman. AB - BACKGROUND: Tubular adenoma of the breast is a rare benign epithelial tumor and only a few literatures have been reported; so far, no cases of tubular adenoma occurred in the accessory breast have been reported in the English literature. Clinical presentation and management of our patient are discussed along with a review of the literature on accessory mammary and tubular adenoma. CASE PRESENTATION: We present a case of 26-year-old woman (gravid 4, para 1) at 37 weeks of pregnancy with rapid enlargement in left anterior chest wall during pregnancy. Physical examination showed the left accessory breast was obviously bigger than the right one that only had a light areola around a small nipple. An elastic, mobile well-circumscribed mass measuring approximately 15 cm * 15 cm was palpated. Moreover, it was edematous and congestive with an increase in local temperature. The breast ultrasound further demonstrated the mass was a relatively homogeneous solid with short stripe blood flow signal. A single live fetus of 37 weeks gestation was observed by abdominal ultrasound scan. After a 2850 g male neonate was delivered, the right accessory breast and the mass in left accessory breast were removed. The resected specimen appeared as a solid white elastic mass with a smooth surface and the cut surface was red-grayish. Microscopically, the lesion consisted of tightly packed homogenous glandular structures which are supported by a single layer of myoepithelial cells with sparse intervening stroma. CONCLUSIONS: We describe a very rare case of giant tubular adenoma arising within an accessory breast in the anterior chest wall in a late pregnancy woman. The high concentrations of estrogen, progesterone and prolactin might account for the significant tumor enlargement during pregnancy. To our knowledge, this is the first case of giant tubular adenoma occurred within the accessory breast in the anterior chest wall. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6210811191552106 . PMID- 26040321 TI - A spatiotemporal model to assess the introduction risk of African horse sickness by import of animals and vectors in France. AB - BACKGROUND: African horse sickness (AHS) is a major, Culicoides-borne viral disease in equines whose introduction into Europe could have dramatic consequences. The disease is considered to be endemic in sub-Saharan Africa. Recent introductions of other Culicoides-borne viruses (bluetongue and Schmallenberg) into northern Europe have highlighted the risk that AHS may arrive in Europe as well. The aim of our study was to provide a spatiotemporal quantitative risk model of AHS introduction into France. The study focused on two pathways of introduction: the arrival of an infectious host (PW-host) and the arrival of an infectious Culicoides midge via the livestock trade (PW-vector). The risk of introduction was calculated by determining the probability of an infectious animal or vector entering the country and the probability of the virus then becoming established: i.e., the virus's arrival in France resulting in at least one local equine host being infected by one local vector. This risk was assessed using data from three consecutive years (2010 to 2012) for 22 regions in France. RESULTS: The results of the model indicate that the annual risk of AHS being introduced to France is very low but that major spatiotemporal differences exist. For both introduction pathways, risk is higher from July to October and peaks in July. In general, regions with warmer climates are more at risk, as are colder regions with larger equine populations; however, regional variation in animal importation patterns (number and species) also play a major role in determining risk. Despite the low probability that AHSV is present in the EU, intra-EU trade of equines contributes most to the risk of AHSV introduction to France because it involves a large number of horse movements. CONCLUSION: It is important to address spatiotemporal differences when assessing the risk of ASH introduction and thus also when implementing efficient surveillance efforts. The methods and results of this study may help develop surveillance techniques and other risk reduction measures that will prevent the introduction of AHS or minimize AHS' potential impact once introduced, both in France and the rest of Europe. PMID- 26040323 TI - One-sided hip-preserving and concurrent contralateral total hip arthroplasty for the treatment of bilateral osteonecrosis of the femoral head in different stages: short-medium term outcomes. AB - BACKGROUND: We aimed to evaluate the clinical and radiological short-medium term outcomes for the treatment of bilateral osteonecrosis of the femoral head (ONFH) with hip-preserving surgery of core decompression followed by tightly impaction bone grafting combining with non-vascularized fibular allografting in one hip and concurrent one-stage total hip arthroplasty (THA) in the contralateral side. We hypothesized the aforementioned surgery showed benefits of protecting the preserved hip from collapsing and thereafter THA was delayed or avoided. METHODS: We retrospectively reviewed a consecutive series of 18 non-traumatic bilateral ONFH patients (36 hips) who had undergone previous mentioned surgeries between July 2004 and June 2013. Preoperative and the last follow-up Harris Hip Score (HHS) and Visual Analogue Scale (VAS) Score were obtained for clinical outcomes evaluation and X-rays of antero-posterior and frog-leg lateral views of bilateral hips were compared for radiological outcomes assessment. RESULTS: All patients were telephone contacted for out-patient clinic return visit at an average follow up time of 53.3 months (ranged from 20 months to 107 months). Of the 18 patients (15 men and 3 women), there were 5 patients were diagnosed preoperative IIB stages according to classification of the Association Research Circulation Osseuse classification (ARCO) and the remaining 13 patients were in ARCO IIIC stages. The mean age of the included patients was 40.7 years (range from 22 to 59 years). No age and followed-up time difference existed in genders. The postoperative HHS were 83.8 +/- 17.9 points, and it revealed statistical significance when compared to preoperative 61.6 +/- 17.0 points (p < 0.05). The VAS scores were reduced from preoperative 6.2 +/- 2.0 points to postoperative 2.8 +/- 2.3 points, which also manifested outcomes significance (p < 0.05). From radiological aspects, 14 patients acquired well repairmen of the necrotic areas of the femoral head. However, the other 4 patients ultimately suffered femoral head collapse, and the severe pain was gotten rid of after THA surgeries were performed. CONCLUSIONS: The un-collapsed hip can achieve biological stability and sufficient blood supply through the hip-preserving surgery and obtain longtime repairmen of the necrotic bone as well as early non-weight-bearing function training, which benefits from distributing the whole body weight load to the hip of one-stage THA. Consequently, we recommend this sort of surgery for clinical practice trial when faced bilateral ONFH in different stages though longer time follow-up and larger samples are essentially needed to address its efficacy. PMID- 26040325 TI - A strategy for analyzing bond strength and interaction kinetics between Pleckstrin homology domains and PI(4,5)P2 phospholipids using force distance spectroscopy and surface plasmon resonance. AB - Phospholipids are important membrane components involved in diverse biological activities ranging from cell signaling to infection by viral particles. A thorough understanding of protein-phospholipid interaction dynamics is thus crucial for deciphering basic cellular processes as well as for targeted drug discovery. For any specific phospholipid-protein binding experiment, various groups have reported different binding constants, which are strongly dependent on applied conditions of interactions. Here, we report a method for accurate determination of the binding affinity and specificity between proteins and phospholipids using a model interaction between PLC-delta1/PH and phosphoinositide phospholipid PtdIns(4,5)P2. We developed an accurate Force Distance Spectroscopy (FDS)-based assay and have attempted to resolve the problem of variation in the observed binding constant by directly measuring the bond force. We confirm the FDS findings of a high bond strength of ~0.19 +/- 0.04 nN by Surface Plasmon Resonance (SPR) data analysis, segregating non-specific interactions, which show a significantly lower K(D) suggesting tight binding. PMID- 26040324 TI - Whole exome sequencing confirms the clinical diagnosis of Marfan syndrome combined with X-linked hypophosphatemia. AB - BACKGROUND: To determine the genetic lesions and to modify the clinical diagnosis for a Chinese family with significant intrafamilial phenotypic diversities and unusual presentations. METHODS: Three affected patients and the asymptomatic father were included and received comprehensive systemic examinations. Whole exome sequencing (WES) was performed for mutation detection. Structural modeling test was applied to analyze the potential structural changes caused by the missense substitution. RESULTS: The proband showed a wide spectrum of systemic anomalies, including bilateral ectopia lentis, atrial septal defect, ventricular septal defect, widening of tibial metaphysis with medial bowing, and dolichostenomelia in digits, while her mother and elder brother only demonstrated similar skeletal changes. A recurrent mutation, PHEX p.R291*, was found in all patients, while a de novo mutation, FBN1 p.C792F, was only detected in the proband. The FBN1 substitution was also predicted to cause significant conformational change in fibrillin-1 protein, thus changing its physical and biological properties. CONCLUSIONS: Taken together, we finalized the diagnosis for this family as X-linked hypophosphatemia (XLH), and diagnosed this girl as Marfan syndrome combined with XLH, and congenital heart disease. Our study also emphasizes the importance of WES in assisting the clinical diagnosis for complicated cases when the original diagnoses are challenged. PMID- 26040322 TI - High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium. AB - INTRODUCTION: Mammographic density (MD), after adjustment for a women's age and body mass index, is a strong and independent risk factor for breast cancer (BC). Although the BC risk attributable to increased MD is significant in healthy women, the biological basis of high mammographic density (HMD) causation and how it raises BC risk remain elusive. We assessed the histological and immunohistochemical differences between matched HMD and low mammographic density (LMD) breast tissues from healthy women to define which cell features may mediate the increased MD and MD-associated BC risk. METHODS: Tissues were obtained between 2008 and 2013 from 41 women undergoing prophylactic mastectomy because of their high BC risk profile. Tissue slices resected from the mastectomy specimens were X-rayed, then HMD and LMD regions were dissected based on radiological appearance. The histological composition, aromatase immunoreactivity, hormone receptor status and proliferation status were assessed, as were collagen amount and orientation, epithelial subsets and immune cell status. RESULTS: HMD tissue had a significantly greater proportion of stroma, collagen and epithelium, as well as less fat, than LMD tissue did. Second harmonic generation imaging demonstrated more organised stromal collagen in HMD tissues than in LMD tissues. There was significantly more aromatase immunoreactivity in both the stromal and glandular regions of HMD tissues than in those regions of LMD tissues, although no significant differences in levels of oestrogen receptor, progesterone receptor or Ki-67 expression were detected. The number of macrophages within the epithelium or stroma did not change; however, HMD stroma exhibited less CD206(+) alternatively activated macrophages. Epithelial cell maturation was not altered in HMD samples, and no evidence of epithelial-mesenchymal transition was seen; however, there was a significant increase in vimentin(+)/CD45(+) immune cells within the epithelial layer in HMD tissues. CONCLUSIONS: We confirmed increased proportions of stroma and epithelium, increased aromatase activity and no changes in hormone receptor or Ki-67 marker status in HMD tissue. The HMD region showed increased collagen deposition and organisation as well as decreased alternatively activated macrophages in the stroma. The HMD epithelium may be a site for local inflammation, as we observed a significant increase in CD45(+)/vimentin(+) immune cells in this area. PMID- 26040326 TI - Novel compound heterozygous mutations in AMN cause Imerslund-Grasbeck syndrome in two half-sisters: a case report. AB - BACKGROUND: Imerslund-Grasbeck Syndrome (IGS) is a rare autosomal recessive disease characterized by intestinal vitamin B12 malabsorption. Clinical features include megaloblastic anemia, recurrent infections, failure to thrive, and proteinuria. Recessive mutations in cubilin (CUBN) and in amnionless (AMN) have been shown to cause IGS. To date, there are only about 300 cases described worldwide with only 37 different mutations found in CUBN and 30 different in the AMN gene. CASE PRESENTATION: We collected pedigree structure, clinical data, and DNA samples from 2 Caucasian English half-sisters with IGS. Molecular diagnostics was performed by direct Sanger sequencing of all 62 exons of the CUBN gene and 12 exons of the AMN gene. Because of lack of parental DNA, cloning, and sequencing of multiple plasmid clones was performed to assess the allele of identified mutations. Genetic characterization revealed 2 novel compound heterozygous AMN mutations in both half-sisters with IGS. Trans-configuration of the mutations was confirmed. CONCLUSION: We have identified novel compound heterozygous mutations in AMN in a family from the United Kingdom with clinical features of Imerslund Grasbeck Syndrome. PMID- 26040328 TI - High performance full color OLEDs based on a class of molecules with dual carrier transport channels and small singlet-triplet splitting. AB - Two deep blue emitting materials PPI-PPITPA and PPI-PPIPCz with dual carrier transport properties and small singlet-triplet splitting features are designed and synthesized. PPI-PPITPA and PPI-PPIPCz were used not only as non-doped emitting layers to fabricate highly efficient deep blue OLEDs, but also as hosts to construct high performance green, yellow and red phosphorescent OLEDs. PMID- 26040329 TI - DISMIRA: Prioritization of disease candidates in miRNA-disease associations based on maximum weighted matching inference model and motif-based analysis. AB - BACKGROUND: MicroRNAs (miRNAs) have increasingly been found to regulate diseases at a significant level. The interaction of miRNA and diseases is a complex web of multilevel interactions, given the fact that a miRNA regulates upto 50 or more diseases and miRNAs/diseases work in clusters. The clear patterns of miRNA regulations in a disease are still elusive. METHODS: In this work, we approach the miRNA-disease interactions from a network scientific perspective and devise two approaches - maximum weighted matching model (a graph theoretical algorithm which provides the result by solving an optimization equation of selecting the most prominent set of diseases) and motif-based analyses (which investigates the motifs of the miRNA-disease network and selects the most prominent set of diseases based on their maximum number of participation in motifs, thereby revealing the miRNA-disease interaction dynamics) to determine and prioritize the set of diseases which are most certainly impacted upon the activation of a group of queried miRNAs, in a miRNA-disease network. RESULTS AND CONCLUSION: Our tool, DISMIRA implements the above mentioned approaches and presents an interactive visualization which helps the user in exploring the networking dynamics of miRNAs and diseases by analyzing their neighbors, paths and topological features. A set of miRNAs can be used in this analysis to get the associated diseases for the input group of miRs with ranks and also further analysis can be done to find key miRs or diseases, shortest paths etc. DISMIRA can be accessed online for free at http://bnet.egr.vcu.edu:8080/dismira. PMID- 26040330 TI - Heliconema anguillae Yamaguti, 1935, a physalopterid nematode found in Japanese eels: taxonomic resurrection with a note on the third-stage larva from intertidal crabs in western Japan. AB - A parasitic nematode from the stomach of Japanese eel Anguilla japonica Temminck et Schlegel in western Japan, previously identified as Heliconema longissimum (Ortlepp, 1922), was morphologically re-examined and compared with the previous descriptions. In addition, the third-stage larva of this nematode is described, based on the specimens of encapsuled larvae found in musculature of two crabs, Hemigrapsus sp. and Perisesarma bidens (De Haan), caught from the upper intertidal zone of the same locality. As a result of the morphological observation, seven pairs of postcloacal papillae in adult males are confirmed. This matches with the character of H. longissimum, but the shape of the fifth postcloacal papillae differs between the present material and H. longissimum; the former possesses pedunculate papillae in the fifth pair whereas the latter has sessile papillae. Since the pedunculate papillae can be found in the original description and the syntype specimens of H. anguillae Yamaguti, 1935 that has been synonymised with H. longissimum, we thus here resurrect H. anguillae as an accepted species. For the life-cycle of the present nematode, littoral crabs, including the two infected species, are likely to be the source of infections for Japanese eels, acting as intermediate hosts. PMID- 26040331 TI - Urban soil exploration through multi-receiver electromagnetic induction and stepped-frequency ground penetrating radar. AB - In environmental assessments, the characterization of urban soils relies heavily on invasive investigation, which is often insufficient to capture their full spatial heterogeneity. Non-invasive geophysical techniques enable rapid collection of high-resolution data and provide a cost-effective alternative to investigate soil in a spatially comprehensive way. This paper presents the results of combining multi-receiver electromagnetic induction and stepped frequency ground penetrating radar to characterize a former garage site contaminated with petroleum hydrocarbons. The sensor combination showed the ability to identify and accurately locate building remains and a high-density soil layer, thus demonstrating the high potential to investigate anthropogenic disturbances of physical nature. In addition, a correspondence was found between an area of lower electrical conductivity and elevated concentrations of petroleum hydrocarbons, suggesting the potential to detect specific chemical disturbances. We conclude that the sensor combination provides valuable information for preliminary assessment of urban soils. PMID- 26040332 TI - Proprotein convertase subtilisin/kexin type 9 (PCSK9) in lipid metabolism, atherosclerosis and ischemic stroke. AB - Proprotein convertase subtilisin/kexin 9 (PCSK9) is the ninth member of the proprotein convertase family. It is an important regulator of cholesterol metabolism. PCSK9 can bind to low-density lipoprotein receptors (LDLRs) and induce the degradation of these receptors through the endosome/lysosome pathway, thus decreasing the LDLR levels on the cell surface of hepatocytes, resulting in increased serum low-density lipoprotein cholesterol (LDL-C) concentrations. Recent studies have found that gene polymorphisms of PCSK9 are associated with hypercholesterolemia, risk of atherosclerosis, and ischemic stroke. Furthermore, monoclonal antibodies, peptide mimetics, small molecule inhibitors and gene silencing agents that are associated with PCSK9 are some of the newer pharmaceutical therapeutic strategies and approaches for lowering serum LDL-C levels. In this review, we will discuss recent advances in PCSK9 research, which show that PCSK9 is correlated with lipid metabolism, atherosclerosis, and, in particular, ischemic stroke. We will also discuss the current state of PCSK9 therapeutics and their potential in modulating these diseases. PMID- 26040333 TI - Pre-Discharge Evaluation in Heart Failure - Additive Predictive Value of the 6 Minute Walking Test to Clinical Scores. AB - BACKGROUND: We aimed to investigate whether the assessment of functional capacity by the 6-minute walking test (6MWT) might improve the predictive ability of 2 validated clinical scores for risk stratification in heart failure (HF). METHODS AND RESULTS: The Cardiac and Comorbid Conditions HF (3C-HF) and the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) scores were evaluated in 466 consecutive HF patients who completed a pre-discharge 6MWT. The 12-month event rate was 7.7%. Both the 2 scores and the 6MWT predicted all-cause mortality (all P<0.0001), with a hazard ratio of 2.650 [95%CI 1.879-3.737], 2.754 [95%CI 1.870 4.056] for each one SD increase in the 3C-HF and MAGGIC, respectively, and of 2.080 [95% CI 1.619-2.671] for each one SD decrease in the meters walked. The addition of a 6MWT to both the 3C-HF and MAGGIC scores significantly improved predictive discrimination (c-index 0.793 [95% CI 0.722-0.864] and 0.802 [95% CI 0.733-0.871], respectively) and risk classification (integrated discrimination improvement, IDI 0.052 [95% CI 0.024-0.101] and 0.046 [95% CI 0.020-0.102], respectively). In the intermediate and high risk strata identified on the basis of both the 3C-HF and MAGGIC scores, mortality rates significantly differed according to a distance walked < or >=376 m. CONCLUSIONS: In HF patients, a pre discharge evaluation combining the 6MWT to clinical scores improves prediction of 12-month mortality. PMID- 26040334 TI - Impact of Arterial Access Route on Bleeding Complications in Japanese Patients Undergoing Percutaneous Coronary Intervention- Insight From the PRASFIT Trial. AB - BACKGROUND: Few large-scale studies have examined the relationship between bleeding events not related to coronary artery bypass grafting (CABG), and the vascular access route used in acute coronary syndrome (ACS) or in elective treatment of coronary artery disease (CAD). METHODS AND RESULTS: We compared the incidence of bleeding events occurring up to 3 days after percutaneous coronary intervention (PCI) or loading dose of prasugrel or clopidogrel in 2 studies of Japanese patients (PRASFIT-ACS, femoral and radial routes, n=683 and 531; PRASFIT Elective, femoral and radial routes, n=135 and 508). Rates of periprocedural bleeding, bleeding not related to CABG, and puncture site bleeding were consistently lower in the radial access route group than in the femoral access route group in both studies. Risk factors for periprocedural bleeding included sex, body weight, age, and access route in PRASFIT-ACS (femoral access: hazard ratio [HR], 3.739; 95% confidence interval [CI]: 1.727-8.094; radial access: HR, 0.288; 95% CI: 0.128-0.65), and body weight, age, and access route in PRASFIT Elective (femoral access: HR, 12.32; 95% CI 1.282->100; radial access: HR, 0.125; 95% CI: 0.013-1.205). CONCLUSIONS: The incidence of periprocedural bleeding is lower with a radial access route than with a femoral access route for PCI in Japanese patients with ACS or those undergoing elective PCI for CAD. PMID- 26040335 TI - Genetic Variation in Cardiomyopathy and Cardiovascular Disorders. AB - With the wider deployment of massively-parallel, next-generation sequencing, it is now possible to survey human genome data for research and clinical purposes. The reduced cost of producing short-read sequencing has now shifted the burden to data analysis. Analysis of genome sequencing remains challenged by the complexity of the human genome, including redundancy and the repetitive nature of genome elements and the large amount of variation in individual genomes. Public databases of human genome sequences greatly facilitate interpretation of common and rare genetic variation, although linking database sequence information to detailed clinical information is limited by privacy and practical issues. Genetic variation is a rich source of knowledge for cardiovascular disease because many, if not all, cardiovascular disorders are highly heritable. The role of rare genetic variation in predicting risk and complications of cardiovascular diseases has been well established for hypertrophic and dilated cardiomyopathy, where the number of genes that are linked to these disorders is growing. Bolstered by family data, where genetic variants segregate with disease, rare variation can be linked to specific genetic variation that offers profound diagnostic information. Understanding genetic variation in cardiomyopathy is likely to help stratify forms of heart failure and guide therapy. Ultimately, genetic variation may be amenable to gene correction and gene editing strategies. PMID- 26040336 TI - Pregnancy and Delivery in Women With Congenital Heart Disease. AB - Because of the growing population of patients with congenital heart disease (CHD), most maternal cardiac disease is now congenital in origin. For women with complex CHD, pregnancy poses an increased risk for both the mother, with complications of arrhythmias and heart failure being the most common, and the baby, with a higher chance of miscarriage, intrauterine growth retardation, and the need for early delivery. Pre-pregnancy counseling must be performed by cardiologists who have expertise in both CHD and pregnancy, with a detailed clinical assessment of the patient and the current hemodynamic situation, including echocardiography and an exercise test. In each case the approach must be individualized with consideration of the risks in each case. In some cases, such as Eisenmenger syndrome, pregnancy is contraindicated. Optimum outcomes in these complex patients are achieved when a multidisciplinary approach is used, involving maternal-fetal medicine specialists, cardiologists with expertise in CHD and obstetric anesthesia. PMID- 26040337 TI - Malnutrition, pharmaconutrition and other considerations in AL amyloidosis, a rare disease with masquerading symptoms and usually delayed diagnosis. AB - Amyloid Light-chain (AL) amyloidosis is a very rare disease. Nutritional and pharmaconutrional aspects are described. Nutrition repletion of malnourished AL patients is an essential strategy for improving treatment efficacy and clinical outcomes. Early diagnosis of AL amiloidosis is difficult to establish due to the fact that signs and symptoms appearing mimic other processes that delay the final correct histological diagnosis. Untreated patients with this disease have a dismal outcome, with a median survival of 10-14 months from diagnosis. The sooner the treatment is established the better the results are. Modern chemotherapeutical agents, based primarily in cyclophosphamide, bortethomid and dexametasone, produce a rapid, deep, and durable response in the majority of patients. Autologous stem cell transplantation remains restricted to selected patients who are generally without advanced cardiac amyloidosis. PMID- 26040338 TI - Nutritional implications for the patient undergoing extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) for cardiovascular collapse or catastrophic respiratory failure in the critically ill patient imposes a multidisciplinary approach. Nutritional support is one of the issues that must be faced, as this population presents a state of increased metabolic activity, elevated catabolism of protein and rapid accumulating energy deficiency. Provision of adequate nutritional therapy is hard to achieve due to different factors. This article provides a brief overview of the current literature regarding nutritional support during ECMO in adult patients, as no current guidelines address this issue. PMID- 26040339 TI - [Inflammation and obesity (lipoinflammation)]. AB - Obesity is a chronic disease with multiple origins. It is a widespread global phenomenon carrying potentially serious complications which requires a multidisciplinary approach due to the significant clinical repercussions and elevated health costs associated with the disease. The most recent evidence indicates that it shares a common characteristic with other prevalent, difficult to-treat pathologies: chronic, low-grade inflammation which perpetuates the disease and is associated with multiple complications. The current interest in lipoinflammation or chronic inflammation associated with obesity derives from an understanding of the alterations and remodelling that occurs in the adipose tissue, with the participation of multiple factors and elements throughout the process. Recent research highlights the importance of some of these molecules, called pro-resolving mediators, as possible therapeutic targets in the treatment of obesity. This article reviews the evidence published on the mechanisms that regulate the adipose tissue remodelling process and lipoinflammation both in obesity and in the mediators that are directly involved in the appearance and resolution of the inflammatory process. PMID- 26040340 TI - [A review of diseases related to the intake of gluten]. AB - Cereals are considered a basic food. Through the development of cooking, the human being has produced high- gluten-content food, so that it could make the most of its nutritional properties. Wheat is becoming one of the key elements of the Mediterranean diet. Amongst gluten- intake-related pathologies- gluten is present mainly in wheat, barley and rye- celiac disease (CD) is the most well known. CD is a chronic inflammatory condition which affects gastrointestinal tract which develops in genetically predisposed individuals. The most common manifestation of CD is nutrients malabsorption. This protein trigger other pathology, wheat allergy (WA), which is an adverse immunological effect to gluten due to E immunoglobulin. A recent increased in non celiac gluten sensitivity (NCGS) has also been noticed, defined as the emergence of a range of gluten intake related symptoms in patients for which celiac disease and wheat allergy have been ruled out. This article discusses these three conditions with their phatogenic mecanisms and the different clinic manifestations. PMID- 26040341 TI - [Fiber-type indication among different pathologies]. AB - INTRODUCTION: Fiber definition includes all those carbohydrates which are not digested nor absorbed in the upper gastrointestinal tract allowing them to reach the colon with no previous processing. Traditionally fiber has been classified according to their solubility into soluble and insoluble and different physiological properties have been defined for each type. The physiologic role of the fiber intake has been studied in diabetes, dyslipidemia or obesity. Fiber intake has also demonstrated to be beneficial in the prevention of many neoplastic diseases like colorectal cancer. It's also known that fiber plays an important role in the faecal excretion of nitrogen. AIM: To evaluate the current evidence that fiber intake plays in the management and prevention of several different diseases, being able to determine, if possible, the most recommended fiber type for each clinical condition. METHODS: A non-systematic review by searching the Medline and Pubmed was made and studies which met the inclusion criteria were identified and selected for analysis. RESULTS: Different fiber types can be useful for the treatment of several gastrointestinal diseases like constipation, diarrhea, irritable bowel syndrome, ulcerative colitis remission or short bowel syndrome. Patients diagnosed with diabetes, obesity, hyperlipidemia, hypertension and other cardiometabolic diseases can get a clinical improvement with soluble fiber intake. Dietary fiber has demonstrated to play a role in the prevention of colorrectal cancer and other neoplastic diseases. Patients with hepatic encephalopathy or chronic kidney disease will also benefit from fermentable fiber intake. DISCUSSION: Fiber plays an important role in the prevention and treatment of many clinical conditions. However further investigations are needed to establish specific fiber intake recommendations. PMID- 26040342 TI - [Exercise addiction: an emergent behavioral disorder]. AB - BACKGROUND: Regular physical activity plays a relevant role in health maintenance and disease prevention. However, excess exercise may generate adverse effects both on physical and mental activity. AIMS: To provide a state-of-the-art overview on exercise addiction, considering its concept, symptoms, diagnosis, epidemiological aspects, etiological factors, and potential interventions. METHODS: Articles related to the topic were reviewed through Pubmed, Sportdiscus, PsycINFO, Scopus and Web of Science databases, using combinations of the following keywords: "exercise", "addiction" and "dependence". RESULTS: Regular exercise taken into excess may result in adverse health consequences and quality of life impairment. Diagnosis of exercise addiction requires the employment of questionnaires such as the Exercise Dependence Scale (EDS) and the Exercise Addiction Inventory (EAI). These instruments have allowed the estimation of a 3% prevalence among exercise practitioners. Proposed hypotheses to explain the etiology of this disorder include both physiological and psychological mechanisms. Treatment is based on the cognitive-behavioral approach, but effectiveness needs to be evaluated. CONCLUSIONS: Although different hypotheses have been proposed to explain exercise dependence, integrative models are still necessary. A clinical validation of diagnostic instruments and a deepening into the relationship with behavioral eating disorders are also required. PMID- 26040343 TI - A strategy for weight loss based on healthy dietary habits and control of emotional response to food. AB - INTRODUCTION: A sedentary lifestyle and unhealthy eating habits are major causes of a negative energy balance and excess body weight. The lifestyle of the Mediterranean diet eating pattern significantly reduces risk factors for non communicable diseases. Moreover, emotions have a powerful effect on feeding behavior. There is a direct relationship between food choices (type and amount), emotions and increased energy intake. OBJECTIVE: To know the emotional behavior of individuals as a function of the relation between food intake and emotions to facilitate the establishment of personalized dietary guidelines based on healthy eating habits and increase the patient fidelity until the desired weight. SUBJECTS AND METHODS: 99 overweight adult people (81 women and 18 men) were subjected to a weight-reduction program based on the establishment of lifestyle and healthy eating habits. The adherence to Mediterranean dietary pattern and the effect of emotions on the choice of food and eating habits were determined using Mediterranean Diet Adherence Screener (MEDAS) and Emotional- Eater Questionnaire (EEQ) respectively. RESULTS: The studied population was sedentary, consumed an unhealthy diet and eating behavior was highly affected by emotions. The majority of participants, (66% of women and 71% of men) were classified as emotional eater. During the treatment program eating habits and lifestyle subjects were modified and reduced at least 10% of their body weight. CONCLUSION: Know the relation between food intake and emotions allows to personalize the dietary strategy for weight loss in overweight and obesity. PMID- 26040344 TI - [Changes in body weight of the university students at university]. AB - INTRODUCTION: One of the strategies for the prevention of the obesity is the identification of critical periods of gain weight. Some studies confirm gain weight during the university period. OBJECTIVE: The purpose of the present study was to determine the changes in the body weight of the university students in Navarre. METHODS: Prospective cohort study. Public University of Navarre and the University of Navarre, in Pamplona. Study examined weight change among 452 students attending at university in Pamplona, during first and third course. Four hundred and fifty two students completed the questionnaire. Weight and height were measures and body mass index was calculated. RESULTS: The mean body weight increased 0,600 kg, 1,8 kg for males and no change in body weight was observed in female. 44,7 % of students gained weight (60,8 % of men and 36,8 % of women), and the gain weight was of 3,4 kg. DISCUSSION: University years are a critical factor for the gain weight, particularly males. Consideration of this, is necessary the development of effective weight gain prevention strategies during the university. PMID- 26040345 TI - Association between serum uric acid levels and obesity among university students (China). AB - OBJECTIVE: To evaluate the association between serum uric acid and obesity among university students who participated in routine health screening in 2013. METHODS: In this cross-sectional study, 3529 subjects were analyzed. Obesity categories were classified by BMI levels references in China. And serum uric acid levels were classified by serum uric acid quartiles. Two-sample T-test and Wilcoxon Rank sum test were used to compare age, biochemical and anthropometric parameters of subjects of two genders. Rank correlation used to analyze relationship between serum uric acid and obesity. RESULTS: There were 1285 males (mean age, 19.8 +/- 1.3 years) and 2244 females (mean age, 19.9 +/- 1.3 years) in this study. Association between 2nd serum uric acid quartile and normal in male are significant and coefficient was 0.519. The 3rd serum uric acid quartile and normal in female was associated significantly (r = 0.173, p = 0.010). And associations between overweight and 3rd and 4th serum uric acid quartiles in female were significant (r = 0.128, p = 0.038 in 1st quartile and r = 0.282, p = 0.004 in 4th quartile). The 4th serum uric acid quartile and Obesity in two gender groups were significantly associated (r = 0.291, p = 0.000 in male and r = 0.484, p = 0.001 in female). CONCLUSION: High serum uric acid was positively associated with obesity in overweight and obesity group. However, the association was weak between two variables because serum uric acid influenced obesity with other related factors together. PMID- 26040346 TI - Iron status and dietary intakes of iron in normal-weight and obese young Mexican women. AB - INTRODUCTION: Obesity is reported to be a predictor of iron deficiency. In Mexico, 45.5% of women older than 20 years have obesity, and the prevalence of anemia is 10.2% in women 20 to 29 years. OBJECTIVE: To investigate the relation between body mass index (BMI), percentage of body fat (% BF), dietary intakes and iron status of healthy normal-weight and obese young women. METHODS: A total of 86 women [normal-weight (n = 46) and obese (n = 40)] completed the study. Intakes were evaluated by an 8-day food-record. Anthropometrics and blood collection (hemoglobin, hematocrit, ferritin and transferrin) were done on the luteal phase of menstrual cycle; menstrual characteristics were also reported. Iron status was determined according to stages of iron depletion. T-test and Mann-Whitney U test were used to compare groups' variables. Pearson correlation was used to determine relationships between variables. An odds ratio (OR) analysis was used to measure the association of BMI, % BF and dietary intakes with iron status. RESULTS: Biomarkers of iron were similar between groups. There was a positive correlation between % BF and ferritin (r = 0.222; p = 0.032). Similar intakes and menstrual periods may be the reason of similar iron status. BMI, % BF or dietary intakes were not independent contributors to stages of iron depletion. CONCLUSION: Guidance on dietary intakes is suggested for this population to avoid future iron deficiency complications. PMID- 26040347 TI - Prevalence of underweight, overweight, general and central obesity among 8-15 years old Bulgarian children and adolescents (Smolyan region, 2012-2014). AB - OBJECTIVE: The objective of this work is to investigate the distribution of underweight, overweight, the general and central obesity in 8-15-year-old Bulgarian children and adolescents, through the use of the anthropometric indices BMI and WHtR. MATERIALS AND METHODS: Subject of this study are 878 children and adolescents (437 boys and 441 girls) of Smolyan region, Bulgaria, at the age of 8 to 15 years. The study is cross-sectional and was conducted in the period 2012 2014. The body height, weight and waist circumference were measured. In addition, the body mass index (BMI) and waist to height ratio (WHtR) were calculated. Overweight and obesity were defined according to the cut-off points of BMI, recommended of IOTF and developed by Cole et al. (2000; 2007). The central obesity was defined according to the discriminatory values of 0.500 of WHtR. The collected data were analysed by statistical software packages STATISTICA 10.0 and SPSS 16. RESULTS: Overweight occurs among 18.8% of the boys and 17.0% of the girls, and obesity occurs among 7.6% of boys and 3.7% of the girls. The underweight are 8.0% of the boys and 10.4% of the girls. Central obesity (WHtR >= 0.500) occur among average 12.75% of all investigated children independently of their nutritional status (16.2% of boys and 9.3% of girls). With central obesity (WHtR >= 0.500) are on average 2.7% of all boys and girls with normal weight (n = 96) and an average 46.82% of all participants with overweight and with obesity (n = 205). With increased health risk (WHtR >= 0.500) are total of 2.01% (n=16) of all surveyed children (n = 793) from categories normal weight. CONCLUSION: There has been an increase in prevalence of overweight and obesity among Bulgarian children and adolescents from Smolyan region during the over one last decade. The relatively high percentage of underweight children, especially among in group of the girls alter puberty. The central obesity, as well as its combination with overweight or general obesity is more frequent in boys than in girls. PMID- 26040348 TI - Effect of calorie restriction on energy expenditure in overweight and obese adult women. AB - Energy expenditure (EE) may decrease in subjects on hypocaloric diets, in amounts that exceed body mass loss, favoring weight regain. OBJECTIVE: To verify if a short-term caloric restriction lowers Resting Energy Expenditure (REE) and Total Energy Expenditure (TEE) more than predicted by changes in body composition, and if this reduction of EE is related with compliance to the diet. METHODS: Twenty two women aged 23-44 years with a body mass index (BMI) of 25-32 kg/m2, underwent a three-month calorie restriction treatment (20 kcal/kg initial weight) and were encouraged to increase their physical activity. At the beginning and end of the intervention, body composition (DEXA), REE, Physical Activity Energy Expenditure (PAEE) and TEE were assessed, through a combination of indirect calorimetry and actigraphy. Participants, who lost more or equal than 5% of their initial weight were considered compliant with the diet. RESULTS: In the compliant group, REE decreased, when expressed in absolute numbers or when adjusted by fat free mass (FFM) [-164 +/- 168 kcal/day (10,6%) and -4,3 +/- 4,6 kcal/kg FFM (10,5%)]. This decline was significantly greater than that observed in the non-compliant group [ 6,2 +/- 1.42 Kcal/day (0.16%) and -0,5 +/- 3,4/Kg FFM (0.96%)]. FFM did not change in any of the two groups. At baseline, there was a significant correlation between FFM and REE (r = 0, 56 p < 0,05), which was lost at the end of the intervention. CONCLUSIONS: Compliant women showed a significant reduction in both absolute and adjusted REE, which together with the loss of correlation between REE and FFM at the end of the intervention suggests a metabolic adaptation. PMID- 26040349 TI - Psychometric characteristics of the Eating and Appraisal Due to Emotions and Stress Questionnaire and obesity in Mexican university students. AB - INTRODUCTION: Emotional eating has been defined as eating in a response to negative emotions and it is associated with weight gain. The English version of Eating Appraisal Due to Emotions and Stress Questionnaire (EADES) was developed to assess how individuals use food in order to cope with stress and emotions. OBJECTIVE: To analyze psychometric characteristics of Spanish version of EADES and to identify whether the constructs of EADES were associated with obesity in university students. METHODS: The EADES (Spanish version) was administered to 232 Mexican university students from 18 to 29 years old. Body Mass Index (BMI) was calculated. A test-retest evaluation was conducted with 75 participants. RESULTS: Cronbach's alpha of EADES was 0.92; the interclass correlation coefficient was 0.88. Regarding BMI and EADES results, the subscale Emotion and Stress Related Eating was significantly associated with obesity (p = 0.026). Through factor analysis of the instrument, three factors were extracted and items that showed factor loading < 0.40 were eliminated. 40 items remained in the questionnaire. With regard to obesity and the 40-items version of the instrument, a statistically significance association was found for the total score (OR = 0.973, p = 0.020) and for the factor Self-confidence related to Emotional Eating component (OR = 0.940, p = 0.026). CONCLUSIONS: A good internal consistency and temporal stability of the Spanish version of the instrument were found; the 40 item EADES version was positively associated with obesity. This instrument could be useful in assessing emotional eating. PMID- 26040350 TI - [Levels of obesity, fasting glycemia and physical condition in Chilean students]. AB - BACKGROUND: Chile has drastically altered eating patterns and physical activity. The main nutritional problem faced by Chilean society is overweight, which arises progressively from an early age. The aim of this study is to determine the nutritional status and compare fitness levels and fasting glucose in students. PATIENTS AND METHODS: A descriptive cross-sectional comparative study was conducted, making a comparison by gender and nutritional status, with 100 students (56 men and 44 women) aged 12-15 years old. Body composition, fasting glucose and fitness were evaluated. RESULTS: Women had a higher prevalence of overweight and obesity than men (22.73% and 19.65%). In the comparison of gender differences statistics were reported in one repetition maximum (1RM) (p = 0.001), abdominal strength (p = 0.004) and velocity (p = 0.001), there were no significant differences in body mass index (BMI) (p = 0.24) and fasting glucose (p = 0.99). In the comparison of nutritional status, the students classified as obese had a higher waist perimeter (p = 0.001), more time to walk 400 m (p = 0.008). There were no significant differences in other variables. CONCLUSIONS: Women have a higher prevalence of overweight and obesity than men. Obese students have a waist circumference more elevated, more time to walk 400 meters (p = <0.05) and they have increased levels of basal glucose. PMID- 26040351 TI - Association between serum Fe levels and obesity: a meta-analysis. AB - The purpose of this study is to clarify the association between serum Fe levels and Obesity using a meta-analysis approach. We searched eligible papers on the relevance published between 2006 and 2014 from the PubMed and the Chinese National Knowledge Infrastructure. Review Manage software was used to collect and analysis the date cited in the papers.6 eligible articles with 934 subjects from 40 case-control studies were identified. Overall,polled analysis indicated that subjects with obesity had lower Fe levels than healthy controls [standardized mean difference (SMD) = -0.738,95%confidence interval (CI) = (-1.228,-0.247)]. Thus, dietary supplement of Fe is recommended to prevent obesity. PMID- 26040352 TI - Lipid profile response to weight loss program in overweight and obese patient is related with gender and age. AB - INTRODUCTION: The risk of developing cardiovascular disease (CVD) increases with age, however CVD is markedly higher in men than in no-menopausal women. There are few interventions where compare the different effects to lose weight on lipid profile between men and women. OBJECTIVE: The aim of this study was to compare the response on the lipid profile by gender after a weight loss program, and determine whether there are differences by age group. METHODS: One hundred eighty (96 women and 84 men) overweight and obese participants (BMI 25-34.9 kg/m2) aged 18-50 years were randomised into treatment groups. The intervention period was 22 weeks (in all cases 3 times/wk of training for 22 weeks and 2 weeks for pre and post evaluation). All subjects followed a hypocaloric diet (25-30% less energy intake). Energy intake, body composition) and blood lipid profile were recorded at baseline and after of treatment. RESULTS: The response of HDL varied between men and women (p = 0.001). While in women it decreased (HDL: -2.94%, p = 0.02), HDL was elevated in men (HDL: 5% p = 0.02). After intervention men achieved decrease significantly LDL values a 6.65% more than women (p = 0.01). For TG concentrations there were significant differences between men and women in baseline however, only men had a significant chance in post-training measured (p = 0.001). TC showed significant differences between men and women in baseline (p = 0.013). After intervention, men and women showed a significant decreased to TC (p = 0.01). CONCLUSION: Men achieve a positive greater change on lipid profile than women. In addition, the favorable lipid profile response decreases with increasing age. PMID- 26040353 TI - [Nutritional status at the time of admission among patients admitted to a tertiary-care paediatric hospital]. AB - OBJECTIVE: To analyze the nutrition status of the pediatric patients at the time of hospital admission throughout a calendar year in a tertiary level hospital and to identify those patients and/or groups of pathologies with a higher risk of malnutrition. MATERIAL AND METHODS: Retrospective evaluation of nutrition status of 852 patients hospitalized in 2013 in a pediatric hospital (462 males and 390 females). Sex, age, body mass index at the moment of admission and days of hospitalization and diagnosis codified according to the International Classification of Diseases were registered. RESULTS: The prevalence of malnutrition patients registered at the moment of admission was 8.2%. Excess body weight (overweight and obesity) was detected in 18% of the patients. The diseases of the nervous system (22.9%), together with the diseases of the respiratory system, the infectious diseases (18.6%), the congenital malformations (11.4%) and the diseases of the genitorurinary system (8.6%) account for 84.4% of the cases with malnutrition. CONCLUSIONS: The overall prevalence rate for malnutrition in pediatric patients at the moment of admission in our hospital was 8.2%, being this figure similar to those published in occidental countries. It should be mandatory to accomplish an initial screening and follow up during hospitalization of younger patients and those suffering from diseases of the nervous and/or respiratory system and, especially, from congenital diseases. PMID- 26040354 TI - The distribution of the indicator height for age of Mexican children and adolescents with Down syndrome according to different reference standards. AB - OBJECTIVE: To compare the indicator height for age in Mexican children with Down Syndrome (DS) with two different reference patterns of growth (American and Spanish) that might be suitable for the Mexican population. METHODS: A cross sectional study was performed including 235 Mexican children and adolescents of both sexes with DS aged 45 days to 16 years enrolled in two specialized schools in the metropolitan area of Guadalajara. The dependent variables were weight/age; height/age; weight/ height and BMI. The data expressed was percentiles and the chi-square test was used to compare the distribution of the height/age index with American and Spanish reference patterns. In addition, a chi-square test was performed for the goodness of fit of the height/age index, with breakpoints lower and greater than the 50th percentile. RESULTS: The percentage of participants who were below the 50th percentile in the height/age index was significantly higher with the Spanish vs. the American reference pattern. The chi-square test for goodness of fit showed that the frequency of cases located below the 50th percentile in the height/age index was significantly higher with the American pattern in the age groups of 0 to 36 months (p = 0.022) and 37 to 72 months (p <0.001), but it was not significant (p = 0.225) in the older than 72 months age group. CONCLUSION: The American reference pattern is a better fit for the growth of Mexican children with DS compared with the Spanish reference pattern, and the distribution profile obtained with the standard growth and WHO reference was not suitable for the assessment of children with Down syndrome. PMID- 26040355 TI - [Demographic and socioeconomic differences in consumption of sugar-sweetened beverages among Colombian children and adolescents]. AB - INTRODUCTION: Sugar-sweetened beverages (SSB) are becoming a common component in the diets among children and adolescents, and its consumption is associated with an increased risk factors for cardiovascular disease. The aim of the present study was to describe the consumption of sugar-sweetened beverages among Colombian children and adolescents and to examine whether differences by demographic and socioeconomic according to gender. METHODS: We used data from the 2010 National Nutrition Survey of Colombia (ENSIN 2010) for 10,373 children and adolescents between 5 and 17 years old. SSB intake was based on intake from regular soda and/ or concentrated drinks. Demographic factors (sex, age, ethnicity, urbanicity, area and geographic region) and socioeconomic level (social class) were collected by structured questionnaire. Associations were established through a multivariate logistic regression. All analyzes were calculated by complex samples. RESULTS: Nationwide, 23% of girls and 22.4% of boys drank SSB at least once a week. Differences by demographic factors were observed for SSB consumption. In girls, factors associated with a greater odds for SSB intake (>= 1 time/week) were aged 14 to 17 years old [OR = 1.65 (95%CI = 1.32, 2.06)], living in the central region [OR = 2.42 (95%CI = 1.81, 3.25)] and urban area [OR = 1.77 (95%CI = 1.42, 2.20)]. In boys, the multivariate logistic regression shows that adolescents aged 14 to 17 years old [OR = 1.96 (95%CI = 1.58, 2.24)], living in the national territories (South) [OR = 2.42 (95%CI = 1.77, 3.32)] and urban area [OR = 1.79 (95%CI = 1.45, 2.20)] were associated with a higher probability of SSB consumption. Social class was not associated with SSB intake. CONCLUSIONS: SSB intake varies by certain demographic factors. Government can use findings from this study to tailor efforts to decrease SSB intake and to encourage consumption of more healthful beverages (e.g, water) among Colombian children and adolescents. PMID- 26040356 TI - Prenatal factors associated with birth weight and length and current nutritional status of hospitalized children aged 4-24 months. AB - The objective of the present study was to investigate the associations of prenatal factors with birth weight and length, as well as current nutritional status, of children hospitalized in southern Brazil. We conducted a cross sectional study of 300 child-mother pairs. Children were between 4 and 24 months old. They were at the inpatient unit or pediatric emergency department of the Hospital de Clinicas de Porto Alegre. Anthropometric data were collected, and a questionnaire on gestational data was answered by the children's mothers. Maternal variables of interest were: prepregnancy body mass index (BMI), gestational weight gain, smoking and/or use of alcohol, use of illicit drugs, gestational diabetes and/ or high blood pressure. Children's variables of interest were: sex, gestational age, birth weight (BW) and birth length (BL), and current anthropometric data [body mass index for age (BMI/A), height for age (H/A), and weight for age (W/A)]. The gestational weight gain and smoking were associated with BW. We also found that H/A was associated with BW and BL, W/A was associated with BW, and BMI/A was associated with BL. The gestational weight gain was associated with BL, diabetes was associated with BW and BL, and high blood pressure was associated with low height in the first two years of life. We concluded that prenatal factors may have an influence on both BW and BL, causing the birth of small and large for gestational age children, and thus affecting their growth rate during the first years of life. PMID- 26040357 TI - Predictive factors of non-alcoholic steatohepatitis: relationship with metabolic syndrome. AB - Non-alcoholic fatty liver disease (NAFLD) has been proposed as the hepatic manifestation of the metabolic syndrom (Ms), with insulin resistance (IR) as the common pathophysiological mechanism. METHODS: We included 145 patients with NAFLD proven liver biopsy. NAS-score was employed to grading NAFLD. We determined anthropometric measurements, basal blood pression (BP), biochemical measurements including high lipoprotein cholesterol (HDL-Chol), low-density lipoprotein cholesterol (LDL-Chol), triglycerides and leptin levels, homeostasis model assessment index (HOMA-IR), and abdominal ultrasound scan (US) was performed. Diagnosis of Ms was performed based on ATP III criteria. RESULTS: Average age was 43.6 + 11.2 years old and the mean body mass index (BMI) was 39 +/- 10.7 kg/m2. Sex distribution was: females 66 and males 79. Forty patients (27.5%) presented a NAS score > = 5. Waist circumference (p = 0.007), systolic and diastolic BP (p = 0.002 and p = 0.003 respectively), (HOMA-IR) (p = 5. Independent factors associated to NAS-score > = 5 were Ms and BMI > 30. Leptin levels were higher in patients with advanced fibrosis (>= F2) compared to patients with mild fibrosis (F0-F1) (75.5 + 50.2 ng/ml vs - 39.7 + 38.4 ng/ml respectively; p = 0.002). CONCLUSION: Presence of Ms and obesity (BMI >30) are the principal independent factors associated to NASH (NAS score > = 5). Leptin levels and BMI are higher in patients with advanced fibrosis. PMID- 26040358 TI - [Assessment of lipid profiles and bone mineral density in renal transplant patients]. AB - INTRODUCTION: Alterations in lipid metabolism and bone mineral metabolism disturbances are common disorders among renal transplant patients, contributing to the apparition of oxidative metabolic and cardiovascular diseases that threaten the integrity of the graft. AIMS: Describe and observe the evolution of alterations in bone mineral density (BMD) and lipid abnormalities in a population of kidney transplant patients. MATERIAL AND METHOD: The samples consisted of 119 kidney transplant patients of both sexes, measurements were performed pretransplant and posttransplant for five years of biochemical parameters, anthropometric measurements and measurement of bone mineral density at the lumbar spine, femur and radioulnar. RESULTS: During the five years after transplantation a significant increase in biochemical parameters, BMI, dyslipidemia, diabetes and hypertension occurs. At six months there is a high percentage of patients with pathologic BMD increase by 4.1% per year of transplantation. CONCLUSIONS: After kidney transplantation, a large increase of hyperlipidemia associated with a characteristic pattern of altered lipid with elevated total cholesterol, low density lipoprotein, high density lipoprotein, and the resulting increase in triglycerides, occurs despite statin therapy, leading to an increase in risk factors for diabetes, hypertension, diseases and cardiovascualres further loss of bone mass which carries a high risk of serious fractures occurs, threatening kidney graft and quality of life of patients. PMID- 26040359 TI - Reduction of serum advanced glycation end-products with a low calorie Mediterranean diet. AB - Dietary intake of advanced glycation end-products (AGEs) increases circulating and tissue levels of these substances, contributing to a state of increased oxidative stress and inflammation. A low dietary AGE intervention has been shown to reduce body AGE content. Mediterranean diets (MD) are theoretically considered low in AGEs, but the specific effects of a MD on AGEs serum levels has not been tested. METHODOLOGY: Forty-seven overweight and obese premenopausal women underwent a three-month calorie restriction treatment (20 kcal/kg initial weight) with a Mediterranean-type diet that excluded wine intake. The adherence to the MD was assessed before and at the end of treatment using an on-line questionnaire, which scores from 0 to 14 (minimal to maximal adherence). Body composition, insulin resistance, lipoproteins and carboxymethyl-lisine (CML) serum levels were measured at both time periods. Serum CML was assessed through ELISA (enzyme linked immunosorbent assay). Compliance to calorie restriction was assessed according to weight loss (< or > 5% initial weight). RESULTS: Mean body weight, body fat, waist circumference, total cholesterol, triglycerides and serum CML fell significantly, together with an increase in the Mediterranean score, although none of the patients reached the highest score. Significant changes in CML and insulin resistance were observed in 17 women classified as compliant to caloric restriction, but not in the 27 participants who were considered adherent to the MD (according to improvement of the Mediterranean Score). CONCLUSIONS: CML serum levels can be reduced through calorie restricted-Mediterranean-type diet. We could not reach a high enough MD score, so we cannot conclude whether the MD itself has an additive effect to caloric restriction. PMID- 26040360 TI - A home enteral nutrition (HEN); spanish registry of NADYA-SENPE group; for the year 2013. AB - AIM: To present the results of the Spanish home enteral nutrition (HEN) registry of the NADYA-SENPE group for the year 2013. MATERIAL AND METHODS: From January 1st to December 31st 2013 data was recorded for the HEN registry and further descriptive and analytical analysis was done. RESULTS: In this period 3 223 patients (50.6% men) and a total of 3 272 episodes of HEN were registered in 33 Spanish hospitals. The rate of prevalence was of 67,11 patients/million habitants/ year 2013. A high percentage of patients (98,24%) were older than 14 years. Adult's mean age was 69,14 years (sd 17,64) and men were younger than women p-value <0,001. Children mean age was 2,38 years (sd 4,35). The most frequent indication for HEN was neurological disease for children (49,1%). and for adults (60,6%). Gastrostomy was the most used administration route for children (51%) while younger ones were fed with NGT (p-value 0,003) also older adults (48%) were fed with this type of tube (p-value <0,001). The most frequent reasons for cessation of treatment was death, 44,4% were children and 54,7% were adults. CONCLUSIONS: The number of patients and hospitals registered increased in the last years while the other variables maintain steady. The registry developed allowing contrasted analysis of data in order to get more information. PMID- 26040361 TI - Mediterranean countries facing the Mediterranean Diet, are we still on track? The example of southern Spain midlife women. AB - INTRODUCTION AND OBJECTIVES: The overall intake of a cohort of middle aged women of Granada was studied along with their body composition, anthropometric and sociodemographic characteristics to evaluate if this population does really follow a Mediterranean Diet. METHODS: 206 women aged 53.3 +/- 5.5 years old, were evaluated for their body composition, anthropometric and sociodemographic characteristics, dietary patterns, Mediterranean diet score and bone mineral density. Results were additionally analyzed across weight status categories. RESULTS: 86% of the sample was overweight or obese and 14% was normal-weight (no woman was underweight). Mean body fat percentage of the sample was 40.3%. Values of bone mineral density showed a t-score average of -1.26 standard deviations. Energy intake decreased as weight status increased (p<0.05), as well as protein intake (p<0.05) but no differences were observed for carbohydrates or fat. Deviations from the Daily Recommended Intakes were observed as well as a moderate adherence (23% of the sample) to the Mediterranean Diet with no significant differences among weight status categories. CONCLUSIONS: Results indicated a progressive distancing from the Mediterranean dietary pattern and an unbalanced diet no correlated to the weight status group, so whether these dietary habits along with the unbalanced diet reported are prolonged over time the overweight and obese population will increase as well as the risk of developing chronic diseases, and will finally concur with the high prevalence of cardiovascular and osteoporosis risk over this population. PMID- 26040363 TI - Effect of the intake of liquids rich in polyphenols on blood pressure and fat liver deposition in rats submitted to high-fat diet. AB - INTRODUCTION: Seeking better quality of life, the number of studies on functional foods and disease prevention is growing fast. Whole red grape juice (WRGJ) and red wine (RW) stand out, which are rich in polyphenols, showing antioxidant and anti-inflammatory activity. OBJECTIVE: To evaluate the effect of WRGJ and RW intake and resveratrol solution (RS) on blood pressure and fat liver deposition of rats fed with high-fat diet. MATERIAL AND METHODS: During 60 days, 50 Rattus norvegicus Wistar Albino adults were divided into: control group (CG)--balanced diet, hyperlipidic group (HG), red wine group (RWG), grape juice group (JGG) and resveratrol group (RG)--hyperlipidic diet. Feed and water were offered ad libttum to all groups. WRGJ, RW and RS were offered daily to JG, WG and RG, respectively. Blood pressure was measured using tail plestimograph. The animals were anesthetized, sacrificed and the liver was removed, weighed and fat was extracted using Soxhlet extractor. RESULTS: No difference in weight gain, feed intake, liver weight and diastolic blood pressure among groups was observed. However, systolic blood pressure (mmHg) and liver fat concentration (g%) were lower (p<0.05) in JGG than in HG, WG and RG, but similar to CG. CONCLUSIONS: The daily consumption of WRGJ minimizes the effects of high-fat diet on systolic blood pressure and prevents nonalcoholic fatty infiltration in the liver of animals, which was not observed in the consumption of RW or resveratrol solution. PMID- 26040362 TI - A Home and Ambulatory Artificial Nutrition (NADYA) group report, Home Parenteral Nutrition in Spain, 2013. AB - AIM: To communicate the results of the Spanish Home Parenteral Nutrition (HPN) registry of the NADYA-SENPE group for the year 2013. MATERIAL AND METHODS: Data was recorded online by NADYA group collaborators that were responsible of the HPN follow-up from 1st January to 31st December 2013. RESULTS: A total of 197 patients and 202 episodes of HPN were registered from 35 hospitals that represents a rate of 4,22 patients/million habitants/year 2013. The median age was 53 years (IQR 40-64) for 189 adult patients and 7 months (IQR 6-35,5) for children. The most frequent disease in adults was neoplasm (30,7%) followed by other diseases (20,1%) and mesenteric ischemia (12,7%). Short bowel syndrome and intestinal obstruction (25,9%) were in 35.7% cases the indications for HPN. The most frequent diagnosis for children were the congenital intestinal disorders and other diagnosis, both with a (37,5%) and short bowel syndrome and intestinal obstruction were the indication for treatment, each was present in 50% of the sample. Tunneled catheters (50%) and subcutaneous reservoirs (27,7%) were frequently used. The septic complications related with catheter were commonly frequent with a rate of 0.74 infections/1000 HPN days. HPN duration presented a median of 1,69 days. A total of 86 episodes finalized during the year, death was the principal reason (45%), followed by "resumed oral via" (43,75%) while it happened inversely for children, 66,7% of them resumed oral via and 16,7% deceased. Fifteen per cent were considered for intestinal transplant, children were proportionally candidates, p-value 0.002. CONCLUSIONS: The number of participating centers and registered patients increased progressively respect to preceding years. Since 2003 Neoplasm is still being the principal pathological group. Death is adult's principal reason for finalizing HPN and "resuming oral via" for children. Despite that NADYA registry is consolidate as a essential source of relevant information about the advances in Home Artificial Nutrition in our country, currently is in an improvement process of the available information about patients characteristics with a special emphasis on children even though they still being a minority group. PMID- 26040364 TI - Adipose tissue redistribution caused by an early consumption of a high sucrose diet in a rat model. AB - INTRODUCTION: Obesity is a major public health problem worldwide. The quantity and site of accumulation of adipose tissue is of great importance for the physiopathology of this disease. OBJECTIVES: The aim of this study was to assess the effect of a high carbohydrate diet on adipose tissue distribution. METHODS: Male Wistar rats, control (CONT) and high sucrose diet (HSD; 30% sucrose in their drinking water), were monitored during 24 weeks and total energy and macronutrient intake were estimated by measuring daily average consumption. A bioelectrical impedance procedure was performed at 22 weeks of treatment to assess body compartments and systolic arterial blood pressure was measured. Serum was obtained and retroperitoneal adipose tissue was collected and weighed. RESULTS: HSD ingested less pellets and beverage, consuming less lipids and proteins than CONT, but the same amount of carbohydrates. Retroperitoneal adipose tissue was more abundant in HSD. Both groups were normoglycemic; triglycerides, adiponectin and leptin levels were higher, while total cholesterol and HDL cholesterol were lower in HSD; insulin, HOMA index and systolic blood pressure had a tendency of being higher in HSD. DISCUSSION: This model presents dyslipidemia and a strong tendency for insulin resistance and hypertension. Even though there was no difference in body compartments between groups, retroperitoneal adipose tissue was significantly increased in HSD. This suggests that a rearrangement of adipose tissue distribution towards the abdominal cavity takes place as a result of chronic high sucrose consumption, which contributes to a higher risk of suffering from metabolic and chronic degenerative diseases. PMID- 26040365 TI - [Anthropometric characterization, quality and lifestyles of the Chilean higher octogenarian old]. AB - INTRODUCTION: In Chile there has been an increase in the elderly population (AM). There is an interest in the group aged in 80 and older, because it has been described that they have different characteristics in relation to nutritional status, habits and quality of life. OBJECTIVE: To describe the characteristics of autonomous -AM of 80 years and over considering different aspects such as anthropometry, styles and quality of life. METHODS: Cross-sectional study, 271 AM of both genders, anthropometry was assessed by body mass index (BMI), two criteria for nutritional diagnosis were considered:, one from the Ministry of Health of Chile (MINSAL) and the other from the World Health Organization (WHO). Subsequently surveys of food frequency , Pittsburgh Sleep, sleepiness and quality of life perception were applied. RESULTS: The mean BMI was similar in both sexes (p = 0.06). However the intake of energy, macronutrients and micronutrients was higher in men (p <0.01). Considering both criterias MINSAL v/s International, it was found that nearly twenty times of the underweight AM proportion was detected by MINSAL criteria. Also, for the excess weight condition WHO classifies these cases with more frecuency (p <0.01). Moreover an excessive daytime sleepiness and moderate quality of life in the AM were perceived in the studied population. CONCLUSION: There is a significant prevalence of overweight in this age group, indepentently of criteria used. Although there are still some critical micronutrient deficiencies for this emerging age group. PMID- 26040366 TI - Impact of the consumption of a rich diet in butter and it replacement for a rich diet in extra virgin olive oil on anthropometric, metabolic and lipid profile in postmenopausal women. AB - OBJECTIVE: To analyze the impact of the substitution of a rich diet in saturated fats with a rich diet in monounsaturated fats on anthropometric, metabolic and lipid profile in postmenopausal women. MATERIAL AND METHODS: A prospective, longitudinal and comparative study where 18 postmenopausal women participated in two periods of dietary intervention of 28 days each one: 1) (SAT diet) consumed butter. Caloric formula (CF) = 15% protein, 38% fat. [20% saturated fat (SFA), 12% monounsaturated fat (MUFA) and 47% carbohydrates and 6% polyunsaturated (PUFA)]. b) Period MONO: with extra virgin olive oil (EVOO). CF = 15% protein, 38% fat (<10% SFA, 22% PUFA and 6% MUFA) and 47% carbohydrates. Size and body composition, glucose, insulin, HOMA, TC, HDL-C, LDL-C, VLDL-C, TG, TC/HDL-C, LDL C/HDL-C, TG/HDL-C and non-HDL-C/HDL.C were measured; dietary Anamnesis/24 hours, daily food record. ANOVA and Bonferroni statistical analysis (SPSS 20) was applied. RESULTS: The age was 56 +/- 5 years, BMI 29.8 +/- 3.1 kg/m2, waist circumference: 93.2 +/- 10.1 cm, waist/hip ratio: 0.86 +/- 0.14, waist/height: 0.59 +/- 0.06 and 38.6 +/- 4% body fat (NS). Lipid profile: SAT diet increased TC (p <0.001), LDL-C (p <0.002) and non HDL-Cholesterol (p <0.000), HDL-C increased in MONO diet (p <0.000). SAT diet: TC/HDL-c ratio, Non col HDL-c/HDL-c, LDL-c/HDL c (p <0.000) and TG/HDL-c (p <0.000). In MONO diet decreased TC/HDL-c (p <0.015) and TG/HDL-c (p <0.016). CONCLUSIONS: The SAT diet increased cardiovascular risk, while the MONO diet decreased the risk to develop the metabolic syndrome components and choronary heart disease. PMID- 26040367 TI - [Quality of the diet of the Spanish population over 80 years non institutionalized]. AB - INTRODUCTION: Non-institutionalized older adults are a group at high risk of malnutrition. Detect nutritional problems through indicators of overall diet quality is a challenge for health professionals, useful for the planning of nutritional policies. OBJECTIVE: Determine the overall quality of the diet of the Spanish population over 80 years non-institutionalized for the promotion and enhance the quality of life of the elderly. METHODOLOGY: People over 80 years from various Spanish regions, participants at the Longitudinal Aging Study from 2011 to 2013 (n = 159) were selected. Healthy Eating Index (HEI), the frequency of food consumption and the degree of adherence to the Mediterranean dietary pattern was used to assess the quality of the diet. RESULTS: The population had higher levels of HEI close to those corresponding to a healthy diet. A significant percentage of participants needed changes in the diet being older than 90 years who required a more significant dietary intervention. Most of the population met the recommendations of the Mediterranean Diet but low consumption of vegetables, nuts and wine and a high consumption of meats were observed. CONCLUSIONS: The customary diet of the non-institutionalized Spanish over 80 years has nutritional imbalances that could be corrected by making small changes in the diet pattern. Determine the overall quality of the diet allows planning intervention strategies to promote healthy dietary changes and take actions to maintain an optimal health during aging. PMID- 26040368 TI - [Association of intake macro and micronutrients with life quality of life in elderly]. AB - INTRODUCTION: The relationship between quality of life life quality and nutrients it is taking a special singular importance in this age group. OBJECTIVE: To determine the association between consumption of the macro and micronutrients with quality of life in elderly living in Santiago. MATERIALS AND METHODS: 1,704 autonomous elderly were assessed. Quality of life was measured by a Life style and Health promotion survey and food patterns were evaluated by a food frequency questionnaire. The quality of life and food intake were evaluated by the Survey of Life Style and Health Promoter and the Feeding and Food Survey were answered by 1,704 non-disabled participant of both sex. RESULTS: The 63.9% of the elderly were overweight or /obesity. Perform correlations between quality of life and nutrients consumption were; the vitamin A, which was is associated to better stress management (r = 0.166; p = 0.001), responsibility for health (0.171; p = 0.001) and exercise (r = 0.167; p = 0.001); the vitamin B12 was a protective factor to have a better quality of life OR = 0.78 (IC95% 0.67-0.90). On the other hand, the consumption of cola soft drinks OR = 1.92 (IC95% 1.42-2.60), the overweight OR = 1.77 (IC95% 1.02-3.06) and be male OR = 1.62 (IC95% 1.27-2.07) were risk factors for quality of life. CONCLUSIONS: The vitamin A and B12 consumption are protective factors for a better quality of life. Conversely, being a male, consumer cola soft drinks and the overweight are risk factors of quality of life in autonomous independent elderly. PMID- 26040369 TI - Anthropometric indicators of obesity as predictors of cardiovascular risk in the elderly. AB - BACKGROUND: Various anthropometric indicators can be used as predictors of cardiovascular risk in the elderly. OBJECTIVE: Evaluate the predictive capacity of anthropometric measurements in identifying cardiovascular risk in elderly patients at the Family Health Strategy of Vicosa-MG. METHODOLOGY: This was a cross-sectional epidemiological study with 349 elderly persons. Cardiovascular risk was calculated using the ratio of triglyceride levels with HDL-cholesterol (TG/HDL-c) levels. The anthropometric variables measured were waist circumference, body mass index, waist-to-height ratio, and conicity index. A biochemical assessment of triglycerides and HDL-cholesterol was performed. The anthropometric measurements were also related to cardiovascular risk using Receiver Operating Characteristic (ROC) curves. RESULTS: The observed results suggest that all these anthropometric indexes can be used to predict cardiovascular risk in males. However, in females, only BMI showed predictive capacity. The cutoff points identified appeared very close to the cutoffs recommended and recognized in other studies, with the exception of waist circumference measured at the midpoint between the last rib and the iliac crest, which showed a considerable difference. CONCLUSION: All anthropometric indices can be used to predict cardiovascular risk in males and females. Waist circumference at the midpoint between the last rib and the iliac crest was the best anthropometric measure to predict cardiovascular risk in males and smaller waist circumference and waist-height were the best anthropometric measures in females. PMID- 26040370 TI - [Prognostic value of serum homocysteine levels in elderly hospitalized patients]. AB - BACKGROUND AND OBJECTIVES: Increased serum homocysteine levels are related to vascular disease and increased mortality. The decrease of homocysteine is also associated with a worse prognosis in patients on hemodialysis; however, this relationship has not been well studied in other patients. Our goal is to study the prognosis of increased and decreased serum homocysteine levels in elderly patients admitted to a general internal medicine unit. PATIENTS AND METHODS: We included 239 patients (121 women and 118 men; mean age, 78 years) in which we determined serum homocysteine levels and study its relationship with vascular risk factors, vascular disease: ischemic heart disease, ischemic stroke and peripheral arterial disease, nutritional status, creatinine, albumin, folate and B12 vitamin. RESULTS: Mortality during hospitalization of patients with homocysteine levels below 9 MUmol/l was 33%, 9% for those with levels between 9 and 20 MUmol/l and 17% for those with levels above 20 MUmol/l. Low homocysteine values were related to increased comorbidity, higher degree of weight loss and decreased serum albumin levels. In a survival analysis using Kaplan-Meier curves, increased homocysteine was associated with increased mortality especially in patients with vascular disease. CONCLUSION: In elderly patients with multiple comorbidities, both decreased and increased serum homocysteine levels are associated with increased mortality. PMID- 26040371 TI - Food intake and nutritional status influence outcomes in hospitalized hematology oncology patients. AB - BACKGROUND: Malnutrition in oncology and hematology-oncology patients is important due to its prevalence and associated mortality and morbidity. The aims of the study were to assess the prevalence of malnutrition in oncology and hematology patients and determine if intake or malnutrition influences hospitalization outcomes. METHODOLOGY: A cohort study was performed in all patients admitted to the oncology and hematology wards in a 30-day period. Nutritional assessment was performed within 24-hours of admission and repeated after 7 days of hospitalization, including Subjective Global Assessment, anthropometry, dietary assessment (24-hour recall) and estimation of caloric and protein needs. Medical records were reviewed 30 days after discharge. RESULTS: Seventy-three patients were evaluated on admission and 29 on day 7 of hospitalization. The prevalence of malnutrition was 47.7%. On admission, patients consumed 71.6 (SD 22.0)% of the prescribed dietary calories and 68.2 (SD 23.5)% of prescribed proteins. The death rate was 2.8% among patients who ate >=75% and 17.9% among those who ate <75% (p = 0.040). No significant differences were observed between the intake of calories (p = 0.124) and protein (p = 0.126) on admission and on day 7 of hospitalization. Nutritional status was related to readmission rate, being 35.1% for malnourished vs. 8% for well-nourished (p = 0.014). Nutritional status and food intake were not related to the rest of the studied outcomes (length of stay and mechanical, metabolic or infectious complications). CONCLUSIONS: Intake did not decrease during hospitalization. There was an upward trend between reduced intake and mortality. Malnutrition was related to hospital readmission. PMID- 26040372 TI - Correlates of objectively measured physical activity in adolescents with Down syndrome: the UP & DOWN study. AB - INTRODUCTION: Correlates of physical activity (PA) have not been explored in adolescents with Down syndrome (DS). Understanding correlates of PA could provide information to develop strategies to increase levels of PA in this target population. OBJECTIVE: The aim of this study was to identify potential correlates of PA in adolescents with DS. METHOD: Information about levels of PA and their potential correlates was collected in 98 adolescents with DS (63 males, aged 11 20 years) using accelerometers and proxy-reported questionnaires. Analysis of covariance and multiple linear regression analyses were conducted to examine correlates of PA. RESULT: Our findings showed that participant's age and socioeconomic status were associated with levels of PA as non-modifiable correlates. Also, parental support, father PA, television-viewing time with siblings and with friends were associated with levels of PA as modifiable correlates. DISCUSSION AND CONCLUSION: Both modifiable and non-modifiable factors are associated with levels of PA in adolescents with DS. Therefore, a better understanding of correlates of PA could contribute to develop strategies on PA promotion in adolescents with DS. PMID- 26040373 TI - [The effect of a warm-up protocol on the sit-and-reach test score in adolescent students]. AB - INTRODUCTION: Sit-and-reach tests are often used in physical education classes for measurement of hamstring extensibility in students, without a standar protocol to perform it. OBJETIVE: To analyze the effect of a warm-up protocol based on locomotion activities and stretching in the sit-and-reach scores in adolescent students. METHOD: A total of 47 teenagers students (17 boys and 30 girls) performed the sit-and-reach test before, immediately after, and 5 and 10 minutes after completing a structured warm-up. The warm-up consisted on a part of continuous running, dynamic locomotor and mobility activities as well as static stretching of lower limbs (quadriceps, hamstrings, adductors, iliopsoas and gastrocnemius), with a total duration of 8 minutes. Between measurements after warm-up, the participants remained standing without performing any exercise and/or stretching. RESULTS AND DISCUSSION: After warm-up there was a significant improvement in the sit-and-reach score (+ 2.15 cm) (p < 0.001), being slightly higher at 5 and 10 minutes (+ 2.49 cm at 5 minutes and + 2.61 cm at 10 minutes) (p < 0.001 with respect to the pre-test). CONCLUSIONS: A warm-up protocol performed before the sit-and-reach test, comprised by locomotion, dynamic activities and stretching, improves significantly the distance achieved in this test. PMID- 26040374 TI - Physical fitness, adiposity and testosterone concentrations are associated to playing position in professional basketballers. AB - The effects of basketball on basal concentrations of testosterone and cortisol and its associations to body composition and physical performance remain to be determined. AIM: The main aim of this study was to determine the effects of playing position on physical fitness, percentage of body fat and hormonal profile in professional basketball players (BP). METHOD: Jump performance (SJ, CMJ and ABK), 30 m running speed and treadmill VO2max tests were conducted in 12 male BP (24.1 years) from the first division league of Spain (ACB). The percentage of body fat was determined from anthropometry, and hemoglobin, glucose, testosterone and cortisol concentrations were measured from fasting blood samples. BP were divided into 3 groups depending on playing positions: guards (GU), forwards (FW) and centers (CE) (n = 4 in each group). RESULTS: GU had greater percentage of body fat (%BF) than CE (p < 0.05). CE developed greater positive mechanical impulse than GU in all jump types (p < 0.05) and achieved higher maximal instantaneous power than GU and FW in the SJ and ABK (p < 0.05). Centers had more plasma testosterone than guards (p < 0.05). All groups a similar relative VO2max. CONCLUSION: Center position was associated to lower adiposity and higher jumping performance than playing as guards. All playing positions induced a similar effect on aerobic power. PMID- 26040375 TI - Effects of exercise on inflammation in cardiac rehabilitation. AB - BACKGROUND: Programs of weight loss and a healthy diet are recommended for patients with cardiovascular risk but the effectiveness of these programs in decreasing cardiovascular mortality is controversial. AIM: To examine the acute and long-term effects of a 2-month cardiac rehabilitation program on chemokines related to inflammation in subjects with cardiovascular disease. DESIGN: Prospective cohort study. METHODS: Twenty-six patients with cardiovascular disease enrolled in a cardiac rehabilitation program based on nutritional and exercise interventions were studied. Lifestyle and clinical, metabolic and inflammatory variables were analysed. RESULTS: 88.5% were men and the mean age was 54.9 +/- 7.8 years. At the end of the cardiac rehabilitation program the levels of carbohydrate and lipid metabolism were lower, except for high density lipoprotein cholesterol which was higher. The levels of uric acid, interleukin-6, interleukin-1Beta, adiponectin and leptin remained stable. Interleukin-6 correlated positively with levels of C-reactive protein and negatively with blood glucose. Interleukin-1Beta correlated positively with C-reactive protein levels and negatively with blood pressure figures. Significant correlations were seen between the changes in levels of interleukin-6 and interleukin-1Beta and changes in metabolic equivalents, and in C-reactive protein levels before and after the cardiac rehabilitation program. No significant correlations were observed with weight, waist circumference or fat mass. CONCLUSIONS: A cardiac rehabilitation program decreased anthropometric variables and blood pressure figures, and improved lipid metabolism and ergometry data. However, no changes regarding the inflammatory state were observed. PMID- 26040376 TI - [Consumption of nuts and vegetal oil in people with type 1 diabetes mellitus]. AB - INTRODUCTION: Recent studies have demonstrated the cardiovascular benefits of the Mediterranean Diet, enriched with olive oil and nuts. People with diabetes, who have an increased risk of cardiovascular complications, could benefit greatly from following this type of eating pattern. OBJECTIVE: Analysis of vegetable fats intake from nuts and olive oil in patients with 1 Diabetes Mellitus type (DM1). METHODS: Transverse descriptive study comparing 60 people with type 1 Diabetes Mellitus (DM1) with 60 healthy individuals. We collect the frequency of consumption of vegetable oils and nuts and calculate the contribution of these foods in mono and polyunsaturated fatty acids (oleic acid, linoleic acid and alpha-linolenic acid). For data collection we designed a food frequency questionnaire specifically. We also collect anthropometric variables, cardiovascular risk factors and diabetes-related variables. RESULTS: Vegetable fat intake from vegetable oils (3.02 +/- 1.14 vs 3.07 +/- 1.27 portions/day, P = 0.822) and nuts (1.35 +/- 2.24 vs 1.60 +/- 2.44 portions/week, P = 0.560), was similar in both groups. The DM1 group consumed fewer portions of olive oil daily than the control group (2.55 +/- 1.17 vs 3.02 +/- 1.34 portions/day, P = 0.046). We detected a significantly lower intake of alpha-linolenic acid in the control group (1.13 +/- 2.06 versus 2.64 +/- 4.37 g/day, p = 0.018) while there were not differences in the rest of fatty acids (oleic acid 28.30 +/- 18.13 vs 29.53 +/- 16.90 g/day, P = 0.703; linoleic 13.70 +/- 16.80 vs 15.45 +/- 19.90 g/day, P = 0.605). In DM1, it not demonstrated an influence of the intake of vegetable fats and oils from nuts in the anthropometric, metabolic and diabetes-specific variables. CONCLUSIONS: In people with DM1, total intake of vegetable oils and nuts do not differ from the general population. However, the consumption of olive oil and the contribution of alpha-linolenic fatty acid derived from such fats are slightly lower than the general population. Although intake of vegetable oils and nuts in people with DM1 is not related to metabolic parameters, or progression of complications of diabetes, it is reasonable to increase their intake, given the recognized benefits of this type of food. PMID- 26040377 TI - [Study of paracetamol levels in serum samples as predictive indicator of gastric emptying]. AB - INTRODUCTION: According to numerous studies, early initiation of nutrition in patients who have undergone surgery is essential. OBJETIVES: We analyzed the available techniques to assess gastric emptying in critically ill patients undergoing surgery, and holding the decision to introduce the type of feeding route. RESULTS: The measurement of gastric residual volume and auscultation are the standard tests used, but they have not shown great effectiveness. The acetaminophen absorption test seems to be a good predictive tool, that allows in 1 hour whether gastric emptying is right and thus, support the idea of continue with enteral nutrition, change to parenteral nutrition or evaluate the use of prokinetics drugs. DISCUSSION: Although there are studies whose final objective is the evaluation of the test as an indicator of tolerance of enteral nutrition, it is necessary to expand and standardize its use in order to include it in protocols for clinical practice. PMID- 26040378 TI - [Life style and monitoring of the dietary intake of students at the Melilla campus of the University of Granada]. AB - INTRODUCTION: University students represent a social group at risk, from the nutrionally point of view because they usually have inappropiate nutritional habits and lifestyle. OBJECTIVE: Analize the students' lifestyle from the Campus of University of Granada in Melilla. Analize the evolution of the eating habits of these students during the academic year 2013-2014. METHODS: A longitudinal study was carried out during the academic year 2013-2014, the lifestyle was evaluated and, in a ongoing way, the eating habits in a representative sample of 257 students, 90 men (35%) and 167 women (65%), all of them from the campus of University of Granada in Melilla. RESULTS: The results get worst as the academic year progresses and they are characterized by a significant reduction (p < 0.001) of carbohydrates intake as well as a significant increase (p < 0.001) of the lipido and proteina intake, especially, rich in saturated fat and a low-fiber diet. CONCLUSIONS: The population studied shows a sedentary lifestyle. As the academic year progresses, the students' eating habits get worst distance from the Mediterranian Diet pattern with the consequent risk at the development of cardiovascular diseases and metabolism disorder. So, it is necesary to get into these results in order to identify the influential factors in their eating habits and take the appropiate actions. PMID- 26040379 TI - [Estimation of the daily nutrients distribution in the Spanish standard diet]. AB - Based on the raw data from the Spanish intake, have made the necessary changes and groupings to establish nutritional content per serving as percentages, regarding the total daily intake of each individual surveyed (n = 3000). Also, it was found the effect of the rating factors (sex, age and location) on the distribution of these percentages. The result indicates that individuals below 25 year should be considered as different groups, front those above that age; and locality effect (treated as random factor rather than fixed) causes differences in the distribution of nutrients between food daily intakes. However, the sex was was not relevant to the anecdotal footage found in statistically significant differences. Percentage distribution of individual nutrients between different food outlets is proposed. PMID- 26040380 TI - Accuracy of body mass index for age to diagnose obesity in Mexican schoolchildren. AB - OBJECTIVE: To compare the accuracy of three BMI-forage references (World Health Organization reference, WHO; the updated International Obesity Task Force reference, IOTF; and Centers for Disease Control and Prevention (CDC) growth charts) to diagnose obesity in Mexican children. METHODS: A convenience sample of Mexican schoolchildren (n = 218) was assessed. The gold standard was the percentage of body fat estimated by deuterium dilution technique. Sensitivity and specificity of the classical cutoff point of BMI-for-age to identify obesity (i.e. > 2.00 standard deviation, SD) were estimated. The accuracy (i.e. area under the curve, AUC) of three BMI-for-age references for the diagnosis of obesity was estimated with the receiver operating characteristic (ROC) curves method. The optimal cutoff point (OCP) was determined. RESULTS: The cutoff points to identify obesity had low (WHO reference: 57.6%, CDC: 53.5%) to very low (IOTF reference: 40.4%) sensitivities, but adequate specificities (91.6%, 95.0%, and, 97.5%, respectively). The AUC of the three references were adequate (0.89). For the IOTF reference, the AUC was lower among the older children. The OCP for the CDC reference (1.24 SD) was lower than the OCP for WHO (1.53 SD) and IOTF charts (1.47 SD). CONCLUSIONS: The classical cutoff point for obesity has low sensitivity--especially for the IOTF reference. The accuracy of the three references was similar. However, to obtain comparable diagnosis of obesity different cutoff points should be used depending of the reference. PMID- 26040381 TI - [Prevalence of malnutrition in not critically ill older inpatients]. AB - BACKGROUND: Elder people suffer physiological changes and illnes that increase the risk of malnutrition. Nutritional status is a major prognosis factor in older people. This study is aimed at estimating the prevalence of malnutrition among the population of 65 and over inpatients as much at admission as at discharge. METHODS: We conducted a transversal observational study. 174 consecutive inpatients were examined using Nutritional Risk Screening 2002 (NRS-2002) and Mini Nutritional Assessment Short Form (MNA-SF) in the first 48 hours from admission. Patient Generated Subjective Global Assessment (PG-SGA) was applied to cancer patients. All patients were submitted the NRS-2002 at discharge. RESULTS: 29.31% of patients were at malnutrition risk according to the results of NRS-2002 at admission. This percentage increased up to 57.89% at discharge. The MNA-SF revealed nutritional alteration in 70.35% (54.65% with malnutrition risk, 15.7% with malnutrition). The NRS-2002 showed that 34.14% of cancer patients presented with nutritional risk; however, according to PG-SGA 56.41% of the cases presented with malnutrition to a certain extent (46.15% with moderate malnutrition and 10.26% with serious malnutrition). There are different groups of patients (older patients, transferred from emergency department, patients with heart failure) who present higher risk of nutritional deterioration while they are hospitalised (p < 0.05). CONCLUSIONS: There is a very high percentage of 65 and over patients at nutritional risk in our centre, as much at admission as at discharge. It is necessary to install a systematic screening of the nutritional status. PMID- 26040382 TI - [Nutritional status of two generations of brothers and sisters <5 years of age beneficiaries from opportunities living in marginalized rural communities in Chiapas, Mexico]. AB - Mexico, in recent decades, has developed several programs to eradicate the problem of infant malnutrition <5 years, primarily among those living in rural and indigenous areas. However, there is insufficient evidence on these programs' impact on child health and nutrition. OBJECTIVE: To describe the nutritional changes of two generations of brothers and sisters living in rural communities of Chiapas and who are Oportunidades beneficiaries. METHODS: Cross-sectional study. It was determined: underweight, stunting, wasting and overweight plus obesity. Older brothers and sisters were evaluated in 2002-2003, for 2010-2011 younger brothers and sisters were evaluated, both groups were <5 years of age at the time of data collection. RESULTS: Malnutrition, in its three types is a problem. 43.4% of brothers and sisters evaluated in 2010-2011 showed stunting, underweight prevalence declined from 18% to 13.2%, wasting (low weight for height) increased from 8.1% to 10.4%. Overweight and obesity increased significantly by 12 percentage points among brothers and sisters, from 24.8% in 2002-2003 to 36.8% in 2010-2011. Malnutrition among male children is lower than their brothers and sisters from the 2002-2003 generation (stunting p=<0.05), overweight and obesity was 10.9 percentage points higher than their brothers and sisters (26.4% to 37.3%). CONCLUSION: Children beneficiaries from Opportunities have not yet overcome chronic malnutrition problems. This study shows that there is not a clear impact in improving the nutritional status of the study population. PMID- 26040383 TI - Design of quality indicators for oral nutritional therapy. AB - OBJECTIVE: Quality indicators in nutritional therapy (NT) have been proposed as useful tools to improve clinical NT. This study was conducted to develop feasible quality indicators in oral nutritional therapy (QIONTs) to aid quality control. METHODS: A Clinical Nutrition Task Force composed of Brazilian NT experts from the International Life Science Institute (ILSI) developed QIONTs. In an internet based psychometric survey, 40 independent Brazilian NT practitioners assessed four attributes (simplicity, utility, objectivity, and low cost) of each QIONT using a five-point Likert scale. RESULTS: Independent NT experts consistently classified all 12 QIONTs developed by the ILSI team as good (mean Cronbach's alpha = 0.84). In ranked order, the QIONTs enable assessment of the frequency of nutritional screening, oral nutritional supplementation (ONS) prescription to malnourished patients receiving an oral diet, ONS prescription to patients receiving an oral diet but at risk of malnutrition, nutritional assessment, adhesion to ONS regime, hospitalized patients with insufficient oral dietary intake and ONS prescription, ICU patients with insufficient oral dietary intake and ONS prescription, oral intake assessment in ICU patients, oral intake assessment in ward patients, oral supplement volume intolerance due to inappropriate offering time, ONS flavor intolerance, and ONS volume intolerance. CONCLUSION: Twelve potentially feasible new QIONTs were developed and approved for clinical practice by experts. PMID- 26040384 TI - [Association between food behavior and hypercholesterolemia-LDL in university students]. AB - INTRODUCTION: Hypercholesterolemia-LDL (H-LDL) is associated with increased risk of cardiovascular disease. The association between H-LDL and feeding has focused on nutritional aspects. The study of the association between eating behavior (EB) and H-LDL in university students, could provide nutritional elements for correction and/or prevention in this population. OBJECTIVE: To assess the association between EB and H-LDL in university students. METHODS: A cross sectional study was carried out in a sample of 167 students from the Autonomous University of Guerrero, Mexico. LDL cholesterol in serum was measured and a concentration >=100 mg/dL was considered hypercholesterolemia. The EB was assessed using a previously validated questionnaire. The association between EB and H-LDL was determined with a bivariate logistic regression, adjusting for sex, age, socioeconomic status, smoking, energy intake, physical activity, presence or absence of obesity and family history. RESULTS: Eating lunch (morning snack) was related with 63% lower risk of H-LDL (OR 0.37; 95% CI 0.15, 0.90). Take food away from home once or twice a week was associated with a fourfold increased risk of H LDL (R 5.14; 95% CI 1.12, 23.62). Subjects who reported consuming excess food (1 or 2, and 3 or more times/week) had higher risk of H-LDL (OR 3.26; 95% CI 1.10, 9.64 and OR 10.52; 95% CI 2.66, 41.60 respectively). CONCLUSIONS: Some usual EB of the university students (Guerrero, Mexico) involve greater risk of H-LDL. To encourage actions corrective and/or preventive focused on these EB, could improve the health of this population. PMID- 26040385 TI - The understanding, attitude and use of nutrition label among consumers (China). AB - OBJECTIVE: The aim of this study was to investigate the understanding, attitude and use of nutrition label among consumers in china. METHODS: A cross-sectional survey with a self-structured questionnaire was conducted among 1153 consumers, who were recruited from different supermarkets during March to May 2014 in Wuhu city of china. RESULTS: The result shows that the subjective understanding of nutrition labels was moderate (62.8% of respondents) but the objective understanding was varied. The attitudes toward nutrition label was positive in participates who had a higher confidence and satisfaction of nutrition label. 59.2% of the respondents indicated 'sometimes' and 28.7% 'always' reading nutrition label. The most frequently reading of nutrition label food was milk (57.5%), followed by infant food (33.3%), and nutrient was protein 51.5%, vitamin (49.8%) and fat (29.4%). None of demographic characteristics was associated with the understanding, attitude and use of nutrition label except education. CONCLUSIONS: Participates of our study had a moderate understanding, positive attitude and higher frequent using nutrition label. Although the code of nutrition label became mandatory, more additional strategies for nutrition label are still needed, so as to improve consumers' the cognition of nutrition label. PMID- 26040386 TI - [Costs analysis system; its location within a program for food, nutrition and metabolic intervention]. AB - Every medical surgical action implies costs. Costs of medical provisions should be translated into tangible, and thus, measurable, benefits for the health status of the patient. Nutritional support therapies might increase the costs of medical provisions, but it is expected their implementation to result in lower morbidity and mortality rates as well as shortening of hospital stay, all of them leading to important savings. It is then required the assimilation of tools for costs analysis for a better management of nutritional support therapies. A proposal for the design of a hospital system (regarded anywhere in this text as SHACOST) for the analysis of the costs of interventions conducted in a patient in accordance with the guidelines included in the Metabolic, Nutrient and Food Intervention Program (referred everywhere for its Spanish acronym PRINUMA) is presented in this article. Hence, strategies are described to estimate the costs of a specified intervention. In addition, a primer on cost-effectiveness (ACE) and incremental cost-effectiveness (ACEI) analyses is shown relying on examples taken from the authors's experience in the provision of nutritional care to patients electively operated for a colorectal cancer. Finally, costs of surgical treatment of a mandibular tumor are described, followed by a discussion on how a better impact of the adopted surgical action could be achieved without considerable increases in total costs should a perioperatory nutritional support program be included. Implementation of SHACOST can provide the medical care teams with accounting tools required to assess the effectiveness of hospital nutritional support schemes, decide whether to acquire and introduce new technologies, and measure the impact of the performance of hospital forms for provision of nutritional care upon health management and perceived quality of life of the patient and their relatives. PMID- 26040387 TI - [Active interventions in hypercholesteroloemia patients with high cardiovascular risk in primary care; estudio ESPROCOL]. AB - INTRODUCTION: Hypercholesterolemia is a major modifiable risk factors for cardiovascular disease (CVD). Its reduction reduces morbidity and mortality from ischemic heart disease and CVD in general, primary prevention and secondary prevention especially. OBJECTIVE: To determine whether a notarized and intensive clinical practice can overcome inertia and achieve the therapeutic goal (OT) LDL C <100 mg/dL in high-risk patients attended in Primary Care (PC) in our country. METHODOLOGY: Epidemiological, prospective, multicenter study conducted in centers of different ACs By AP consecutive sampling 310 patients at high cardiovascular risk (diabetic or established CVD) previously treated with statins, which did not reach the OT included c-LDL. RESULTS: The study subjects had a mean age of 65.2 years, of which 60.32% were male. The 41.64% had a previous EVC, acute myocardial infarction (20.33%), angina (16.07%), stroke/TIA (9.19%), arthropathy (5.25%), diabetes (70.87%), hypertension (71.01%), and abdominal obesity (69.62%). The 43.57% (95% CI: 37,21; 50,08) of patients who performed the 2nd visit (241) got the OT. 62.50% (95% CI: 55.68, 68.98) of those who took the 3rd (216) got the OT. Finally, 77.56% (95% CI: 72.13, 83.08) patients who performed the last visit (205) got the OT. Throughout the study there was a reduction in LDL-C levels from 135.6 mg/dL at baseline, 107.4 mg dL in the 2nd visit, 97.3 mg/dL in the 3rd visit, up to 90.7 mg/dL at the final visit (p < 0.0001). The increase in HDL-C from baseline (50.9 mg/dL) and final (53.6 mg/dL) was also significant (p = 0.013). CONCLUSIONS: The reassessment and intensification of treatment in patients at high cardiovascular risk treated in primary care, applying the indications of the guides, achieves the OT in more than three quarters of the previously uncontrolled within half a year. These results should encourage us to overcome the therapeutic inertia in the control of CVD by early and energetic performance against hypercholesterolemia. PMID- 26040388 TI - Food intake reported versus nursing records: is there agreement in surgical patients? AB - OBJECTIVES: To evaluate the agreement between oral feeding by patients and chart records of this acceptance. METHOD: Besides the food intake surveys of surgical patients, the nursing records of nutrition were evaluated. Is was considered good oral feeding: intake >= 75% of total calories prescribed at the day; medium acceptance: 50 to 74.9%; low acceptance: < 50% and NPO (nothing per oral). The Kappa coefficient was adopted to assess agreement. RESULTS: There were similar answers between patient and nursing records in 91.3% of NPO situations, 87.1% for good oral feeding, 17.8% for medium acceptance and 16.5% for low acceptance (Kappa = 0.45). CONCLUSION: Agreement between patient's reports and nursing records was moderate to low. A higher proportion of similar answers were observed when the patients related good oral feeding or NPO. PMID- 26040389 TI - [Use of bacteriphages against Salmonella Enteritidis: a prevention tool]. AB - INTRODUCTION: Salmonellosis is a highly prevalent disease still searching for preventive tools to avoid contamination level priority public health. OBJECTIVE: The in vitro effect of bacteriophages against Salmonella enteritidis was evaluated as a prevention tool. METHOD: Two tests with three concentrations of bacteriophages were conducted against two strains of Salmonella Enteritidis inoculated in fresh faeces of laying hens. Each test had a positive control. Thus, four groups in each test were evaluated. Each experimental group included two replicates, and three plates were incubated per replicate. The concentrations tested were three: commercial solution (5 * 10(7) pfu/mL), and two dilutions (1/10 and 1/30). One of the strains tested was CECT 4300, a certified strain of Coleccion Espanola de Cultivo Tipo and the other a field isolated strain in a sacrificed hen farm. Both strains were inoculated at 1.3 * 10(5) cfu/g of faeces in each of the four groups. Isolation and identification of bacteria by ISO6579 was done at various times after inoculation: 1 minute, 24 hours and 7 days. RESULTS: In the first test, with certified strain, Salmonella was isolated in all groups at time 1 minute. After 24 hours, Salmonella was isolated in all groups except in one of the replicas treated with 1/10 dilution of bacteriophages, one of the other replica plate treated with 1/10 dilution, and two plates of the two replicas treated with the commercial solution. After 7 days, the bacteria were not isolated from any of the experimental groups. In the second test, with the field strain, Salmonella was isolated in all groups at time 1 minute. After 24 hours, Salmonella was isolated in all groups except in one of the replicas treated with 1/10 dilution of bacteriophages and the two replicas treated with the commercial solution. Salmonella was not isolated in any of the experimental groups at 7 days. CONCLUSIONS: The use of bacteriophages reduced Salmonella enteritidis isolates in faeces at 24 hours after the application, so it could be considered as a prevention tool. At 7 days after inoculation of bacteria, no one was isolated in any of the experimental groups. PMID- 26040390 TI - Presence of microorganisms from isolated Megaselia spp. in foodservice establishments. AB - INTRODUCTION: The transmission of harmful pathogens by arthropods is an increasing health concern. More concretely, flies are known to be able to transmit the infectious agent mechanically. OBJECTIVE: The present work shows a case report occurred from foodservice establishments where were isolated and identified, at the first time, Megaselia spp. in the food preparation place. Furthermore, microorganisms were analyzed from these flies. METHOD: It is based in entomological and microbiological analysis. RESULTS: Mesophilic aerobic flora and Enterobacteriaceae were found in all the samples, exceeding the limits established from food commodities on 41.7% (5/12) for mesophilic aerobic bacteria and 66.7% (8/12) for Enterobacteriaceae. Furthermore, 25% (3/12) of analyzed flies were found positive to Escherichia coli, data that can be linked with the microbiological food results. The most surprising results were the presence of S. aureus in 66.7% (8/12) of the analyzed flies. CONCLUSIONS: A binomial relationship among Megaselia spp. and bacteria is demonstrated being an important study to demonstrate that must be checked more hygienically measurement in foodservice. PMID- 26040391 TI - Anti-adipogenic activity of an olive seed extract in mouse fibroblasts. AB - The administration of different polyphenols protects against increased body weight and fat accumulation. The aim of the study was to determine the anti adipogenic activity of an olive-seed polyphenolic extract, by means of mouse fibroblast cell line 3T3-L1 adipocyte differentiation. MATERIAL AND METHODS: Cells were incubated and differentiated (6000 cells/cup) in the presence of olive seed extract at 10 and 50 mg/l biosecure concentrations of polyphenols, and with no extract in the control sample. After 5 to 7 days mature adipocytes are formed. The fat clusters are quantified by means of red-oil staining, 490 nm absorbance, and the expression of the leptin and PPARg genes, and then compared to the values obtained in the cultures before and after adipocyte differentiation. RESULTS: The control samples, with no extract, presented an accumulation of fat of 100%. By contrast, the addition of 50 mg/l of olive-seed extract polyphenols resulted in a 50% accumulation of fat, similar to that of the non-differentiated cells. A 10 mg/l extract concentration had no effect. Anti-adipogenic activity is thus confirmed, as the expression of the PPARg and leptin genes is reduced in adipocyte differentiation in the presence of extract at 50 mg/l. In conclusion, both the formation of fatty substances characteristic of adipogenesis, and the expression of the adipogenic PPARg and leptin genes are found to be inhibited by the prior addition of olive-seed extract polyphenols at a 50 mg/l concentration. PMID- 26040392 TI - Relationship between the domains of the Multidimensional Students' Life Satisfaction Scale, satisfaction with food-related life and happiness in university students. AB - AIM: To characterize types of university students based on satisfaction with life domains that affect eating habits, satisfaction with food-related life and subjective happiness. MATERIALS AND METHODS: A questionnaire was applied to a nonrandom sample of 305 students of both genders in five universities in Chile. The questionnaire included the abbreviated Multidimensional Student's Life Satisfaction Scale (MSLSS), Satisfaction with Food-related Life Scale (SWFL) and the Subjective Happiness Scale (SHS). Eating habits, frequency of food consumption in and outside the place of residence, approximate height and weight and sociodemographic variables were measured. RESULTS: Using factor analysis, the five-domain structure of the MSLSS was confirmed with 26 of the 30 items of the abbreviated version: Family, Friends, Self, Environment and University. Using cluster analysis four types of students were distinguished that differ significantly in the MSLSS global and domain scores, SWFL and SHS scores, gender, ownership of a food allowance card funded by the Chilean government, importance attributed to food for well-being and socioeconomic status. CONCLUSIONS: Higher levels of life satisfaction and happiness are associated with greater satisfaction with food-related life. Other major life domains that affect students' subjective well-being are Family, Friends, University and Self. Greater satisfaction in some domains may counterbalance the lower satisfaction in others. PMID- 26040393 TI - Protein intake, nitrogen balance and nutritional status in patients with Parkinson's disease; time for a change? AB - OBJECTIVE: To evaluate protein intake, nitrogen balance and nutritional status of clinically stable patients with Parkinson's disease (PD). METHODS: A cross sectional study of PD patients Hoehn-Yahr scale stage 1-3 and subjects with no neurologic disease (controls) matched for age and gender. All participants underwent a diet history interview, anthropometric measurements, bioelectrical impedance and food record over three non-consecutive days, including a weekend. A 24-hour urine collection and fasting venous blood sampling were collected from the participants for evaluation of creatinine clearance, creatinine height index and the nitrogen balance. RESULTS: The mean age of PD patients was 58.9 +/- 12.8 year compared to 54.7 +/- 12.6 year of the controls, P = 0.34. One third of PD group had symptoms of dysphagia and ingested less water and fibers when compared to controls. Calf circumference was small in PD group (35.5 +/- 2.8 vs. 38.4 +/- 3.5 cm, P = 0.012). Intake of nitrogen was significantly lower and nitrogen balance was negative in PD patients (-1.8 +/- 3.9 vs. 1.1 +/- 4.2 controls, P = 0.06). The antioxidants folate and vitamin E were consumed in small amounts in both groups, although significantly less in PD patients (P = 0.04 and 0.03, respectively). DISCUSSION: Daily intakes of protein of approximately 1.1 g/kg by clinically stable PD patients may not be enough to ensure a neutral calorie nitrogen balance and muscle tissue conservation. Larger studies are necessary to provide a more comprehensive picture of PD patients' metabolic status. PMID- 26040394 TI - Association between LAP Index (Lipid Accumulation Product) and metabolic profile in hospitalized patients. AB - INTRODUCTION: Lipid Accumulation Product (LAP) Index correlates to cardiovascular risk factors in general population but it has not been tested in hospitalized patients. OBJECTIVES: We aimed to evaluate associations between LAP Index and metabolic profile in a tertiary hospital. METHODS: Cross-sectional study with 90 inpatients. Lipid profile, fasting glucose, systolic and diastolic blood pressure measurements were obtained from electronic medical records. Weight, height and waist circumferences (WC) were assessed; Body Mass Index (BMI) and LAP Index were calculated. Data were expressed as mean +/- standard deviation or percentage. Pearson's correlation and Multiple Linear Regression were used to assess the objectives. RESULTS: Mean age of participants was 55.03 +/- 14.86 years and 47.8% (n = 43) were men. After adjustment for sex, age and physic activity LAP Index (log-transformed) was significantly associated with HDL-cholesterol (p < 0.001), fasting glucose (p = 0.02), systolic blood pressure (p = 0.03) and a trend toward total cholesterol (p = 0.07). CONCLUSION: There are independent association between LAP Index (log-transformed) and metabolic profile in hospitalized patients. PMID- 26040395 TI - Association of eating behaviors and BMI among elementary school students from Mexico. AB - The aim of this study was to analyze the association of cognitive restraint (CR), uncontrolled eating (UE), and emotional eating (EE) with body max index (BMI) among elementary schools children in Mexico. 5th and 6th grade students were recruited from two schools. Weight, height, and waist circumference were measured and BMI was calculated. Overweight and obese children were classified according to the World Health Organization's (WHO) BMI z-score. The TFEQ-R18 questionnaire was applied to assess behavioral patterns. Gender differences of UE and EE were observed. Private school children had higher scores of CR and UE. Children with CR were three times more likely to have abdominal obesity (AO) and children with OW or O were more likely to have UE. Children attending the private school and those with AO had higher CR scores; private school children, those with overweight or obesity and with AO had higher UE scores. PMID- 26040396 TI - [Body fat assessment by bioelectrical impedance and its correlation with anthropometric indicators]. PMID- 26040397 TI - [Frequency variability of eating disorders. Problem of population or instrument?]. PMID- 26040398 TI - [Nutritional screening in heart failure patients: 5 methods review]. PMID- 26040400 TI - A metallic metal oxide (Ti5O9)-metal oxide (TiO2) nanocomposite as the heterojunction to enhance visible-light photocatalytic activity. AB - Coupling titanium dioxide (TiO2) with other semiconductors is a popular method to extend the optical response range of TiO2 and improve its photon quantum efficiency, as coupled semiconductors can increase the separation rate of photoinduced charge carriers in photocatalysts. Differing from normal semiconductors, metallic oxides have no energy gap separating occupied and unoccupied levels, but they can excite electrons between bands to create a high carrier mobility to facilitate kinetic charge separation. Here, we propose the first metallic metal oxide-metal oxide (Ti5O9-TiO2) nanocomposite as a heterojunction for enhancing the visible-light photocatalytic activity of TiO2 nanoparticles and we demonstrate that this hybridized TiO2-Ti5O9 nanostructure possesses an excellent visible-light photocatalytic performance in the process of photodegrading dyes. The TiO2-Ti5O9 nanocomposites are synthesized in one step using laser ablation in liquid under ambient conditions. The as-synthesized nanocomposites show strong visible-light absorption in the range of 300-800 nm and high visible-light photocatalytic activity in the oxidation of rhodamine B. They also exhibit excellent cycling stability in the photodegrading process. A working mechanism for the metallic metal oxide-metal oxide nanocomposite in the visible-light photocatalytic process is proposed based on first-principle calculations of Ti5O9. This study suggests that metallic metal oxides can be regarded as partners for metal oxide photocatalysts in the construction of heterojunctions to improve photocatalytic activity. PMID- 26040401 TI - Femoral curvature variability in modern humans using three-dimensional quadric surface fitting. AB - INTRODUCTION: This study analysed femoral curvature in a population from Belgium in conjunction with other morphological characteristics by the use of three dimensional (3D) quadric surfaces (QS) modelled from the bone surface. METHODS: 3D models were created from computed tomography data of 75 femoral modern human bones. Anatomical landmarks (ALs) were palpated in specific bony areas of the femur (shaft, condyles, neck and head). QS were then created from the surface vertices which enclose these ALs. The diaphyseal shaft was divided into five QS shapes to analyse curvature in different parts of the shaft. RESULTS: Femoral bending differs in different parts of the diaphyseal shaft. The greatest degree of curvature was found in the distal shaft (mean 4.5 degrees range 0.2 degrees 10 degrees ) followed by the proximal (mean 4.4 degrees range 1.5 degrees -10.2 degrees ), proximal intermediate (mean 3.7 degrees range 0.9 degrees -7.9 degrees ) and distal intermediate (mean 1.8 degrees range 0.2 degrees -5.6 degrees ) shaft sections. The proximal and distal angles were significantly more bowed than the intermediate proximal and the intermediate distal angle. There was no significant difference between the proximal and distal angle. No significant correlations were found between morphological characteristics and femoral curvature. An extremely large variability of femoral curvature with several bones displaying very high or low degrees of femoral curvature was also found. CONCLUSION: 3D QS fitting enables the creation of accurate models which can discriminate between different patterns in similar curvatures and demonstrates there is a clear difference between curvature in different parts of the shaft. PMID- 26040402 TI - Visualizing biliary tracts with isosulphan blue to prevent injury during laparoscopic cholecystectomy: a preliminary cadaveric study. AB - BACKGROUND: Bile duct injury (BDI) as a complication of laparoscopic cholecystectomy may result in biliary cirrhosis with a high morbidity-mortality rate. Recurrent invasive procedures may be required for the optimum management. The most frequent causative factor in BDI is anatomical misidentification, particularly by inexperienced surgeons. Direct coloration of the cystic duct, bile duct, and gallbladder may decrease biliary tract injury. METHODS: This study was conducted during 10 standard, fresh cadaver autopsies at the Council of Forensic Medicine, Istanbul. Following needle puncture of the gallbladder fundus and aspiration of the bile content, identical quantities of isosulphan blue were injected into the gallbladder to visualize the biliary tract. RESULTS: Of the ten fresh cadavers, three were males and seven were females; the mean age at death was 43 years (range 22-76 years). Successful visualization of the colored biliary tract, encompassing the gallbladder, cystic duct, and bile duct, was achieved in all of the cadavers. CONCLUSIONS: Visualization of the biliary tract may reduce the risk associated with dissection of Calot's triangle. Surgical BDI risk following anatomical misidentification could be reduced by intraoperative injection of isosulphan blue; further studies are required to validate the clinical utility of this technique. PMID- 26040403 TI - Cadaveric preservation under adverse climatic conditions. PMID- 26040404 TI - Mapping a Type 1 FHB resistance on chromosome 4AS of Triticum macha and deployment in combination with two Type 2 resistances. AB - Markers closely flanking a Type 1 FHB resistance have been produced and the potential of combining this with Type 2 resistances to improve control of FHB has been demonstrated. Two categories of resistance to Fusarium head blight (FHB) in wheat are generally recognised: resistance to initial infection (Type 1) and resistance to spread within the head (Type 2). While numerous sources of Type 2 resistance have been reported, relatively fewer Type 1 resistances have been characterised. Previous study identified a Type 1 FHB resistance (QFhs.jic-4AS) on chromosome 4A in Triticum macha. Little is known about the effect of combining Type 1 and Type 2 resistances on overall FHB symptoms or accumulation of the mycotoxin deoxynivalenol (DON). QFhs.jic-4AS was combined independently with two Type 2 FHB resistances (Fhb1 and one associated with the 1BL/1RS translocation). While combining Type 1 and Type 2 resistances generally reduced visual symptom development, the effect on DON accumulation was marginal. A lack of polymorphic markers and a limited number of recombinants had originally prevented accurate mapping of the QFhs.jic-4AS resistance. Using an array of recently produced markers in combination with new populations, the position of QFhs.jic-4AS has been determined to allow this resistance to be followed in breeding programmes. PMID- 26040406 TI - Sample Collection Method Bias Effects in Quantitative Phosphoproteomics. AB - Current advances in selective enrichment, fractionation, and MS detection of phosphorylated peptides allowed identification and quantitation of tens of thousands phosphosites from minute amounts of biological material. One of the major challenges in the field is preserving the in vivo phosphorylation state of the proteins throughout the sample preparation workflow. This is typically achieved by using phosphatase inhibitors and denaturing conditions during cell lysis. Here we determine if the upstream cell collection techniques could introduce changes in protein phosphorylation. To evaluate the effect of sample collection protocols on the global phosphorylation status of the cell, we compared different sample workflows by metabolic labeling and quantitative mass spectrometry on Saccharomyces cerevisiae cell cultures. We identified highly similar phosphopeptides for cells harvested in ice cold isotonic phosphate buffer, cold ethanol, trichloroacetic acid, and liquid nitrogen. However, quantitative analyses revealed that the commonly used phosphate buffer unexpectedly activated signaling events. Such effects may introduce systematic bias in phosphoproteomics measurements and biochemical analysis. PMID- 26040405 TI - Population pharmacokinetics of oseltamivir in non-pregnant and pregnant women. AB - AIMS: Physiological changes in pregnancy are expected to alter the pharmacokinetics of various drugs. The objective of this study was to evaluate systematically the pharmacokinetics of oseltamivir (OS), a drug used in the treatment of influenza during pregnancy. METHODS: A multicentre steady-state pharmacokinetic study of OS was performed in 35 non-pregnant and 29 pregnant women. Plasma concentration-time profiles were analyzed using both non compartmental and population pharmacokinetic modelling (pop PK) and simulation approaches. A one compartment population pharmacokinetic model with first order absorption and elimination adequately described the pharmacokinetics of OS. RESULTS: The systemic exposure of oseltamivir carboxylate (OC, active metabolite of OS) was reduced approximately 30 (19-36)% (P < 0.001) in pregnant women. Pregnancy significantly (P < 0.001) influenced the clearance (CL/F) and volume of distribution (V/F) of OC. Both non-compartmental and population pharmacokinetic approaches documented approximately 45 (23-62)% increase in clearance (CL/F) of OC during pregnancy. CONCLUSION: Based on the decrease in exposure of the active metabolite, the currently recommended doses of OS may need to be increased modestly in pregnant women in order to achieve comparable exposure with that of non-pregnant women. PMID- 26040407 TI - DArT-based characterisation of genetic diversity in a Miscanthus collection from Poland. AB - MAIN CONCLUSION: Analysis of 180 accessions of Miscanthus using a DArT platform revealed high diversity. The phylogenetic analysis revealed that M. * giganteus accessions fall into two genetically distinct groups. Miscanthus is a genus of perennial rhizomatous grasses that has emerged in last 20 years as a feedstock for bioenergy and biofuel production. Currently, the most widely used accession for bioenergy purposes is Miscanthus * giganteus, a sterile triploid hybrid between Miscanthus sinensis and Miscanthus sacchariflorus. However, previous reports have shown that genetic diversity of Miscanthus * giganteus is limited. Here, we report development of Diversity Arrays Technology platform for the analysis of genetic structure of a Miscanthus collection of 180 accessions. A total of 906 markers were obtained of which around 25.5% exhibited polymorphism information content value in the range of 0.40 and 0.50 and are considered particularly informative. Newly developed marker system will serve as an additional resource to assist crop improvement, germplasm preservation and genetic studies. Three types of analysis indicated that 180 accessions from the collection were well differentiated and presented high diversity. Interestingly, the analysis revealed that there are two separate groups of plants, significantly differing in genetic diversity, that are commercially available as M. * giganteus. We suggest that one of these groups is most likely mutants or somaclonal variants of original M. * giganteus. The other group is recent hybrids of Miscanthus of higher genetic diversity. This study indicates that the diversity of commercially available M. * giganteus is higher than commonly assumed. Development of the new marker system can significantly assist breeding of new commercial cultivars of Miscanthus for bioenergy use. PMID- 26040408 TI - Role of peroxidase activity and Ca(2+) in axis growth during seed germination. AB - MAIN CONCLUSION: Axis growth during seed germination is mediated by reactive oxygen species and apoplastic peroxidase plays a role by producing OH(.) from H2O2. Ca (2+) activates both apoplastic peroxidase and NADPH oxidase. Role of reactive oxygen species (ROS) in seed germination and axis growth has been demonstrated in our earlier works with Vigna radiata seeds by studying superoxide generation and its metabolism in axes (Singh et al. in Plant Signal Behav doi: 10.4161/psb.29278 , 2014). In the present study, the participation of apoplastic peroxidase along with the involvement of Ca(2+) in axis growth during germination and post-germination stage has been investigated. Pharmacological studies using peroxidase (POX) inhibitors (salicylhydroxamic acid, SHAM; sodium azide, NaN3) and OH(.) scavenger (sodium benzoate, NaBz) indicated that seed germination and early axis growth (phase I) depend much on POX activity. Subapical region of axes corresponding to radicle that elongated much particularly in phase II suggested high POX activity as well as high NADPH oxidase (Respiratory burst oxidase homologue, Rboh, in plants) activity as indicated from localization by staining with TMB (3,3',5,5'-tetramethyl benzidine dihydrochloride hydrate) and NBT (nitroblue tetrazolium chloride), respectively. Apoplastic class III peroxidase (Prx) and also cellular POX activity reached maximum at the time of radicle emergence as revealed by TMB staining, spectrophotometric and in-gel assay for POX activity. Treatment with Ca(2+) antagonists (La(3+), plasma membrane-located Ca(2+) channel blocker and EGTA, Ca(2+) chelator in apoplast) retarded seed germination and strongly inhibited axis growth, while Li(+) (blocks endosomal Ca(2+) release) was effective only in retarding phase II axis growth suggesting an involvement of Ca(2+) influx during early axis growth. From the effect of Ca(2+) antagonists on the localization of activities of POX and Rboh using stains, it appears that Ca(2+) plays a dual role by activating Prx activity in apoplast while activating Rboh by entering into cytosol. PMID- 26040409 TI - Circulating sclerostin and dickkopf-1 levels in ossification of the posterior longitudinal ligament of the spine. AB - Sclerostin and dickkopf-1(DKK1) are Wnt/beta-catenin signal antagonists that play an important role in bone formation. Ossification of the posterior longitudinal ligament (OPLL) of the spine is characterized by pathological ectopic ossification of the posterior longitudinal ligament and ankylosing spinal hyperostosis. The aims of this study were to evaluate serum sclerostin and DKK1 levels in persons with OPLL and to identify its relationship with bone metabolism and bone mass in persons with OPLL. This was a case-control study, and 78 patients with OPLL were compared with 39 age- and sex-matched volunteers without OPLL. We analyzed the relationship with calciotropic hormones, bone turnover markers, OPLL localization, number of ossified vertebrae, and bone mineral density of total hip (TH-BMD). Serum sclerostin levels in men with OPLL were significantly higher than in men in the control group (control group: mean = 45.3 pmol/L; OPLL group: mean = 75.7 pmol/L; P = 0.002). Age and sclerostin levels were positively correlated in men with OPLL (r = 0.43; P = 0.002). Serum sclerostin levels in men with OPLL had a positive correlation with TH-BMD Z-score (r = 0.511; P = 0.011, n = 30). There was a strong negative correlation between serum sclerostin levels and serum DKK1 levels in men with OPLL (r = -0.506; P < 0.001). Bone and mineral metabolism in OPLL differs between men and women. In men with OPLL, systemic secretion of sclerostin increases with advancing age and with higher bone mass. These two Wnt/beta-catenin signal antagonists have the opposite effect in persons with OPLL, and higher serum sclerostin levels are counterbalanced by underproduction of DKK1. PMID- 26040410 TI - Can antiosteoporotic therapy reduce mortality in MRI-proved acute osteoporotic vertebral fractures? AB - Patients with MRI-proved acute painful vertebral fractures in whom conservative pain management fails are frequently referred for vertebroplasty. This study investigated the effects of treating osteoporosis on the mortality rate of patients with MRI-proved acute osteoporosis-related vertebral fractures who had undergone vertebroplasty. We retrospectively reviewed the cases of osteoporosis patients with MRI-proved acute vertebral fractures who had been treated with vertebroplasty from January 2001 to December 2007. The long-term outcomes of the patients who received antiosteoporotic therapy were compared with those of patients who received no therapy. A total of 304 patients (247 female patients and 57 male patients; mean age, 74.1 +/- 7.7 years) were enrolled in the study. The patients who received antiosteoporotic therapy had a significantly lower mortality rate than did patients who did not receive antiosteoporotic therapy (P = 0.001; hazard ratio, 0.396, 95 % confidence interval, 0.273-0.575). At the end of the study, 183 patients were alive, and 121 had died. Effective treatment for osteoporosis may improve survival in patients with osteoporosis-related vertebral fractures after vertebroplasty. PMID- 26040412 TI - Subgingival bacterial community profiles in HIV-infected Brazilian adults with chronic periodontitis. AB - BACKGROUND AND OBJECTIVE: To compare the subgingival microbial diversity between non-HIV-infected and HIV-infected individuals with chronic periodontitis using denaturing gradient gel electrophoresis (DGGE). MATERIAL AND METHODS: Thirty-two patients were selected: 11 were HIV-infected and 21 were non-HIV-infected, and all had chronic periodontitis. Periodontal measurements included probing depth, clinical attachment level, visible supragingival biofilm and bleeding on probing. Subgingival biofilm samples were collected from periodontal sites (50% with probing depth <= 4 mm and 50% with probing depth >= 5 mm) and whole-genomic amplified DNA was obtained. The DNA samples were subjected to amplification of a 16S rRNA gene fragment using universal bacterial primers, followed by DGGE analysis of the amplified gene sequences. RESULTS: The non-HIV-infected group presented higher mean full-mouth visible supragingival biofilm (p = 0.004), bleeding on probing (p = 0.006), probing depth (p < 0.001) and clinical attachment level (p = 0.001) in comparison with the HIV-infected group. DGGE analysis revealed 81 distinct bands from all 33 individuals. Banding profiles revealed a higher diversity of the bacterial communities in the subgingival biofilm of HIV-infected patients with chronic periodontitis. Moreover, cluster and principal component analyses demonstrated that the bacterial community profiles differed between these two conditions. High interindividual and intra individual variability in banding profiles were observed for both groups. CONCLUSION: HIV-infected patients with chronic periodontitis present greater subgingival microbial diversity. In addition, the bacterial communities associated with HIV-infected and non-HIV-infected individuals are different in structure. PMID- 26040411 TI - Identification of matrine as a promising novel drug for hepatic steatosis and glucose intolerance with HSP72 as an upstream target. AB - BACKGROUND AND PURPOSE: Matrine is a small molecule drug used in humans for the treatment of chronic viral infections and tumours in the liver with little adverse effects. The present study investigated its therapeutic efficacy for insulin resistance and hepatic steatosis in high-fat-fed mice. EXPERIMENTAL APPROACH: C57BL/J6 mice were fed a chow or high-fat diet for 10 weeks and then treated with matrine or metformin for 4 weeks. The effects on lipid metabolism and glucose tolerance were evaluated. KEY RESULTS: Our results first showed that matrine reduced glucose intolerance and plasma insulin level, hepatic triglyceride content and adiposity in high-fat-fed mice without affecting caloric intake. This reduction in hepatosteatosis was attributed to suppressed lipid synthesis and increased fatty acid oxidation. In contrast to metformin, matrine neither suppressed mitochondrial respiration nor activated AMPK in the liver. A computational docking simulation revealed HSP90, a negative regulator of HSP72, as a potential binding target of matrine. Consistent with the simulation results, matrine, but not metformin, increased the hepatic protein level of HSP72 and this effect was inversely correlated with both liver triglyceride level and glucose intolerance. CONCLUSIONS AND IMPLICATIONS: Taken together, these results indicate that matrine may be used for the treatment of type 2 diabetes and hepatic steatosis, and the molecular action of this hepatoprotective drug involves the activation of HSP72 in the liver. PMID- 26040414 TI - Effects of heterocycles containing different atoms as pi-bridges on the performance of dye-sensitized solar cells. AB - Two new D-pi-A zinc porphyrin dyes with thiophene and furan pi-bridges have been synthesized and employed in dye-sensitized solar cells (DSSCs). Here, the triphenylamine (TPA) moiety was used as the electron donor, and the hexylthiophene chromophores were introduced onto the donor groups, which effectively extended the pi-conjugation system. Although the two dyes had similar molecular structures, there was a significant difference between their optical and photoelectric properties. The EIS analysis suggested that the dye with the thiophene pi-bridge had a lower charge recombination rate compared to the dye with the furan pi-bridge. Based on their light-harvesting abilities, the power conversion efficiency (PCE) of dye JP-S was higher than that of dye JP-O. The JP S-based DSSC showed a PCE of 5.84%, whereas the PCE of the JP-O-based DSSC was 4.68%. Moreover, using the dye TTR1 as a co-sensitizer made up for the poor absorption of porphyrin dyes in the 480-600 nm range and reduced the charge recombination. The JP-S + TTR1-based DSSCs showed a higher PCE of 6.71%, and the Jsc and Voc values of the device were both increased using this strategy. PMID- 26040413 TI - Formula corrected maximal standardized uptake value in FDG-PET for partial volume effect and motion artifact is not a prognostic factor in stage I non-small cell lung cancer treated with stereotactic body radiotherapy. AB - OBJECTIVE: It is known that the partial volume effect and respiratory motion blur affect quantitative parameters such as the maximum standardized uptake value (SUVmax) in FDG-PET, especially in small lesions. The purpose of this study was to assess the prognostic value of corrected SUVmax, which was corrected SUVmax for the partial volume effect and respiratory motion blur, in patients with stage I non-small cell lung cancer (NSCLC) after treatment with stereotactic body radiotherapy (SBRT). METHODS: Fifty-one patients who were treated with SBRT between 2005 and 2011 in our institute were enrolled. The median tumor diameter was 2.2 cm (range 0.9-3.9 cm). The prescribed dose was typically 48 Gy in 4 fractions, 60 Gy in 8 fractions or 60 Gy in 15 fractions to the isocenter of irradiation fields. Each raw SUVmax was corrected using the recently proposed formula, and the correlations of raw SUVmax and corrected SUVmax with local control rate (LCR) were analyzed retrospectively. RESULTS: Median raw SUVmax before SBRT was 6.4 (range 0.6-22.8). Median corrected SUVmax was 8.0 (range 0.8 22.8), which was significantly increased (p < 0.01). The median follow-up period for survivors was 45.3 months (range 18.5-82.0 months). The 3-year LCR and overall survival rates were 81.8 and 65.2 %, respectively. In univariate analysis, raw SUVmax [per 1 increase; p = 0.02, hazard ratio (HR) 1.20, 95 % confidence interval (CI) 1.03-1.42] was significantly correlated with LCR, but corrected SUVmax did not show a significant correlation with LCR (per 1 increase; p = 0.15, HR 1.07, 95 % CI 0.96-1.19). Other factors significantly correlated with LCR were diagnosis (pathological diagnosis vs. clinical diagnosis; p = 0.04, HR 6.17, 95 % CI 1.08-116) and tumor diameter (per 1 mm increase; p < 0.01, HR 1.33, 95 % CI 1.15-1.61). CONCLUSIONS: Tumor diameter was the most significant predictor of LCR after SBRT. Correction for the partial volume effect and respiratory motion blur may weaken the prognostic value of SUVmax. PMID- 26040415 TI - Next generation sequencing search for uromodulin gene variants related with impaired renal function. AB - Uromodulin gene (UMOD) mutations have been linked to rare forms of mendelian dominant medullary cystic kidney disease and familial hyperuricemia. In addition, common single nucleotide polymorphisms in the UMOD promoter have been associated with the risk for impaired renal function and chronic kidney disease. Our main purpose was to identify UMOD variants related with impaired renal function in an elderly population. The UMOD gene was next generation sequenced in a total of 100 healthy individuals with normal or reduced renal function [measured as the rate of estimated glomerular filtration (eGFR)]. The identified missense changes and the common promoter rs12917707 polymorphism were determined in individuals with reduced (n = 88) and normal (n = 442) eGFR values. Allele and genotype frequencies were compared between the groups. We only identified a rare UMOD misense change, p.V458L, and the rare leu allele was significantly more frequent in a cohort of individuals with reduced (eGFR < 60) compared to normal eGFR (P = 0.02). The common rs12917707 polymorphism previously linked to renal function and kidney disease was not associated with impaired filtration rate in our cohort. We found a significant effect of the rare p.V458L variant on the value of estimated glomerular filtration. This finding deserves further validation in larger cohorts. PMID- 26040416 TI - NMR imaging estimates of muscle volume and intramuscular fat infiltration in the thigh: variations with muscle, gender, and age. AB - Muscle mass is particularly relevant to follow during aging, owing to its link with physical performance and autonomy. The objectives of this work were to assess muscle volume (MV) and intramuscular fat (IMF) for all the muscles of the thigh in a large population of young and elderly healthy individuals using magnetic resonance imaging (MRI) to test the effect of gender and age on MV and IMF and to determine the best representative slice for the estimation of MV and IMF. The study enrolled 105 healthy young (range 20-30 years) and older (range 70 80 years) subjects. MRI scans were acquired along the femur length using a three dimension three-point Dixon proton density-weighted gradient echo sequence. MV and IMF were estimated from all the slices. The effects of age and gender on MV and IMF were assessed. Predictive equations for MV and IMF were established using a single slice at various femur levels for each muscle in order to reduce the analysis process. MV was decreased with aging in both genders, particularly in the quadriceps femoris. IMF was largely increased with aging in men and, to a lesser extent, in women. Percentages of MV decrease and IMF increase with aging varied according to the muscle. Predictive equations to predict MV and IMF from single slices are provided and were validated. This study is the first one to provide muscle volume and intramuscular fat infiltration in all the muscles of the thigh in a large population of young and elderly healthy subjects. PMID- 26040417 TI - Phase and composition controllable synthesis of cobalt manganese spinel nanoparticles towards efficient oxygen electrocatalysis. AB - Spinel-type oxides are technologically important in many fields, including electronics, magnetism, catalysis and electrochemical energy storage and conversion. Typically, these materials are prepared by conventional ceramic routes that are energy consuming and offer limited control over shape and size. Moreover, for mixed-metal oxide spinels (for example, Co(x)Mn(3-x)O4), the crystallographic phase sensitively correlates with the metal ratio, posing great challenges to synthesize active product with simultaneously tuned phase and composition. Here we report a general synthesis of ultrasmall cobalt manganese spinels with tailored structural symmetry and composition through facile solution based oxidation-precipitation and insertion-crystallization process at modest condition. As an example application, the nanocrystalline spinels catalyse the oxygen reduction/evolution reactions, showing phase and composition co-dependent performance. Furthermore, the mild synthetic strategy allows the formation of homogeneous and strongly coupled spinel/carbon nanocomposites, which exhibit comparable activity but superior durability to Pt/C and serve as efficient catalysts to build rechargeable Zn-air and Li-air batteries. PMID- 26040418 TI - A large replum-valve joint area is associated with increased resistance to pod shattering in rapeseed. AB - The structure of the replum was studied in 64 rapeseed lines and in an F2 population derived from a cross between a high pod shattering resistance line, zy72360, and a susceptible line, R1. The dimensions of the replum close to the pedicel in lines with high silique shattering resistance index (SSRI) were greater than those with low SSRI. The replum-valve joint area index (RJAI) was used to investigate the relationship between the replum size and pod shattering. In the 64 accessions, RJAI displayed wide variation (0.50-4.12 mm(2)), with a variance coefficient of 45.4%. There were highly significant positive correlations between SSRI and RJAI, with a correlation coefficient of 0.6140. Analysis of RJAI in 276 F2 individuals further validated the positive correlations between SSRI and RJAI. These results revealed that replum structure was highly associated with pod shattering, and that a thick replum structure could produce high pod shatter resistance. The replum-valve joint area offers a good method to screen high resistance materials beneficial for breeding. PMID- 26040419 TI - Non-monophyly of Siberian Erythronium (Liliaceae) leads to the recognition of the formerly neglected Erythronium sajanense. AB - Four Erythronium species have been traditionally recognised within Eurasia based on their disjunct distributions and the slight morphological divergence between them: E. dens-canis, E. caucasicum, E. sibiricum and E. japonicum. The range of E. sibiricum includes adjacent parts of southern Siberia, Kazakhstan, China and Mongolia in the Altai-Sayan mountain region. Despite several recently proposed taxa within the range of E. sibiricum (E. sajanense, E. sibiricum subsp. altaicum, E. sibiricum subsp. sulevii), this species has never been tested for genetic subdivisions. We here used nucleotide sequence variation in one nuclear (internal transcribed spacer) and two plastid (rpl32-trnL, rps15-ycf1) regions to test for genetic divisions within Siberian Erythronium and, in particular, to examine the phylogenetic position of E. sajanense. The plastid phylogeny revealed a basal polytomy among E. japonicum, E. sibiricum populations pertaining to E. sajanense and a third strongly supported lineage that includes E. dens-canis, E. caucasicum and the remainder of E. sibiricum, thus rendering Siberian Erythronium non-monophyletic. The nuclear topology agrees with the plastid one in recovering E. sajanense as a distinct lineage that is weakly supported as sister to E. japonicum. Topological incongruences exist between the plastid and nuclear phylogenies but these do not affect the taxonomic recognition of E. sajanense (endemic to the Western Sayan Mts.). This species is morphologically distinguishable on the basis of its subulate stamen filaments. Whereas nuclear phylogeny failed to resolve any genetic grouping within E. sibiricum s. str., plastid data recovered a deep (possibly phylogeographically meaningful) lineage from samples referred to as E. sibiricum subsp. altaicum. PMID- 26040421 TI - Finding death in meaninglessness: Evidence that death-thought accessibility increases in response to meaning threats. AB - The meaning maintenance model proposes that violations to one's expectations will cause subsequent meaning restoration. In attempts to distinguish meaning maintenance mechanisms from mechanisms of terror management, previous research has failed to find increased death-thought accessibility (DTA) in response to various meaning threats. The present research suggests that this failure may have resulted from methodological differences in the way researchers measured DTA. Studies 1a and 1b found that by replacing this method with a standard method employed when studying worldview and self-esteem threats, DTA increased in response to two different meaning violations. Study 2 found increased DTA, but only among individuals high in personal need for structure, when using this standard DTA procedure, but not when using the procedure taken from previous meaning maintenance studies. Interestingly, these studies did not find increased meaning restoration, so an additional study (Study 3) was designed to provide a theoretically informed examination of this null effect. A meaning restoration effect was observed after removing the standard DTA assessment procedure, but only among participants high in personal need for structure. Implications for the threat-compensation literature are discussed. PMID- 26040420 TI - PI3 kinase is indispensable for oncogenic transformation by the V560D mutant of c Kit in a kinase-independent manner. AB - Oncogenic mutants of c-Kit are often found in mastocytosis, gastrointestinal stromal tumors and acute myeloid leukemia. The activation mechanism of the most commonly occurring mutation, D816V in exon 17 of c-Kit, has been well-studied while other mutations remain fairly uncharacterized in this respect. In this study, we show that the constitutive activity of the exon 11 mutant V560D is weaker than the D816V mutant. Phosphorylation of downstream signaling proteins induced by the ligand for c-Kit, stem cell factor, was stronger in c-Kit/V560D expressing cells than in cells expressing c-kit/D816V. Although cells expressing c-Kit/V560D showed increased ligand-independent proliferation and survival compared to wild-type c-Kit-expressing cells, these biological effects were weaker than in c-Kit/D816V-expressing cells. In contrast to cells expressing wild type c-Kit, cells expressing c-Kit/V560D were independent of Src family kinases for downstream signaling. However, the independence of Src family kinases was not due to a Src-like kinase activity that c-Kit/D816V displayed. Point mutations that selectively block the association of PI3 kinase with c-Kit/V560D inhibited ligand-independent activation of the receptor, while inhibition of the kinase activity of PI3 kinase with pharmacological inhibitors did not affect the kinase activity of the receptor. This suggests a lipid kinase-independent key role of PI3 kinase in c-Kit/V560D-mediated oncogenic signal transduction. Thus, PI3 kinase is an attractive therapeutic target in malignancies induced by c-Kit mutations independent of its lipid kinase activity. PMID- 26040422 TI - Stroke Research in China over the Past Decade: Analysis of NSFC Funding. AB - We analyzed the projects and published studies funded by NSFC (National Natural Science Foundation of China) in the field of stoke. Further more, we searched the published papers supported by NSFC in the last decade using the keywords of "stroke" or "cerebrovascular disease" and analyzed the results according to the topics associated with the mechanisms of ischemic brain injury, novel techniques and new drugs, medical imaging, translational medicine, and traditional Chinese medicine. PMID- 26040424 TI - Neurobehavioral and imaging correlates of hippocampal atrophy in a mouse model of vascular cognitive impairment. AB - Vascular cognitive impairment (VCI) is the second most common cause of dementia. Reduced cerebral blood flow is thought to play a major role in the etiology of VCI. Therefore, chronic cerebral hypoperfusion has been used to model VCI in rodents. The goal of the current study was to determine the histopathological and neuroimaging substrates of neurocognitive impairments in a mouse model of chronic cerebral hypoperfusion induced by unilateral common carotid artery occlusion (UCCAO). Mice were subjected to sham or right UCCAO (VCI) surgeries. Three months later, neurocognitive function was evaluated using the novel object recognition task, Morris water maze, and contextual and cued fear-conditioning tests. Next, cerebral perfusion was evaluated with dynamic susceptibility contrast magnetic resonance imaging (MRI) using an ultra-high field (11.75 T) animal MRI system. Finally, brain pathology was evaluated using histology and T2-weighted MRI. VCI, but not sham, mice had significantly reduced cerebral blood flow in the right vs. left cerebral cortex. VCI mice showed deficits in object recognition. T2-weighted MRI of VCI brains revealed enlargement of lateral ventricles, which corresponded to areas of hippocampal atrophy upon histological analysis. In conclusion, our data demonstrate that the UCCAO model of chronic hypoperfusion induces hippocampal atrophy and ventricular enlargement, resulting in neurocognitive deficits characteristic of VCI. PMID- 26040425 TI - Healable and Optically Transparent Polymeric Films Capable of Being Erased on Demand. AB - Different from living organisms, artificial materials can only undergo a limited number of damage/healing processes and cannot heal severe damage. As an alternative to solve this problem, we report in this study the fabrication of erasable, optically transparent and healable films by exponential layer-by-layer assembly of poly(acrylic acid) (PAA) and poly(ethylene oxide) (PEO). The hydrogen bonded PAA/PEO films are highly transparent, capable of conveniently healing damages and being erased under external stimuli. The PAA/PEO films can heal damages such as scratches and deep cuts for multiple times in the same location by exposure to pH 2.5 water or humid N2 flow. The healability of the PAA/PEO films originates from the reversibility of the hydrogen bonding interaction between PAA and PEO, and the tendency of films to flow upon adsorption of water. When the damage exceeds the capability of the films to repair, the damaged films can be conveniently erased from substrates to facilitate the replacement of the damaged films with new ones. The combination of healability and erasibility provides a new way to the design of transparent films with enhanced reliability and extended service life. PMID- 26040423 TI - Intranasal Insulin and Insulin-Like Growth Factor 1 as Neuroprotectants in Acute Ischemic Stroke. AB - Treatment options for stroke remain limited. Neuroprotective therapies, in particular, have invariably failed to yield the expected benefit in stroke patients, despite robust theoretical and mechanistic background and promising animal data. Insulin and insulin-like growth factor 1 (IGF-1) play a pivotal role in critical brain functions, such as energy homeostasis, neuronal growth, and differentiation. They may exhibit neuroprotective properties in acute ischemic stroke based upon their vasodilatory, anti-inflammatory and antithrombotic effects, as well as improvements of functional connectivity, neuronal metabolism, neurotransmitter regulation, and remyelination. Intranasally administered insulin has demonstrated a benefit for prevention of cognitive decline in older people, and IGF-1 has shown potential benefit to improve functional outcomes in animal models of acute ischemic stroke. The intranasal route presents a feasible, tolerable, safe, and particularly effective administration route, bypassing the blood-brain barrier and maximizing distribution to the central nervous system (CNS), without the disadvantages of systemic side effects and first-pass metabolism. This review summarizes the neuroprotective potential of intranasally administered insulin and IGF-1 in stroke patients. We present the theoretical background and pathophysiologic mechanisms, animal and human studies of intranasal insulin and IGF-1, and the safety and feasibility of intranasal route for medication administration to the CNS. PMID- 26040426 TI - Molecular cloning and promoter analysis of the specific salicylic acid biosynthetic pathway gene phenylalanine ammonia-lyase (AaPAL1) from Artemisia annua. AB - Phenylalanine ammonia-lyase (PAL) is the key enzyme in the biosynthetic pathway of salicylic acid (SA). In this study, a full-length cDNA of PAL gene (named as AaPAL1) was cloned from Artemisia annua. The gene contains an open reading frame of 2,151 bps encoding 716 amino acids. Comparative and bioinformatics analysis revealed that the polypeptide protein of AaPAL1 was highly homologous to PALs from other plant species. Southern blot analysis revealed that it belonged to a gene family with three members. Quantitative RT-PCR analysis of various tissues of A. annua showed that AaPAL1 transcript levels were highest in the young leaves. A 1160-bp promoter region was also isolated resulting in identification of distinct cis-regulatory elements including W-box, TGACG-motif, and TC-rich repeats. Quantitative RT-PCR indicated that AaPAL1 was upregulated by salinity, drought, wounding, and SA stresses, which were corroborated positively with the identified cis-elements within the promoter region. AaPAL1 was successfully expressed in Escherichia. coli and the enzyme activity of the purified AaPAL1 was approximately 287.2 U/mg. These results substantiated the involvement of AaPAL1 in the phenylalanine pathway. PMID- 26040427 TI - Electrode substrate innovation for electrochemical detection in microchip electrophoresis. AB - Microchip electrophoresis (MCE) represents the next generation of miniaturised electrophoretic devices and carry benefits such as significant improvement in analysis times, lower consumption of reagents and samples, flexibility and procedural simplicity. The devices provide a separation method for complex sample matrices and an on-board detection method for the analytical determination of a target compound. The detection part of MCE is increasingly leaning towards electrochemical methods, thus the selectivity and sensitivity of detection in MCE is dependent upon the chosen working electrode composition in addition to operating conditions of the chip such as separation voltage. Given the current plethora of electrode materials that are available, there exists a possibility to creatively integrate electrodes into MCE. This review will overview the application of several electrode materials, from the old through to the new. A particular recent focus has been the selectivity element of MCEs overcome with the use of enzymes, carbon composites and screen-printed technologies. PMID- 26040428 TI - Improve intra-uterine insemination in rabbits using ultra-high temperature skim milk as extender to keep semen at room temperature. AB - Two experiments were carried out to examine in vitro quality and in vivo fertility of rabbit semen diluted in ultra-high temperature (UHT) skim milk. In the first experiment, pooled ejaculates of 10 adult rabbits were divided in three aliquots. Each aliquot was diluted in saline solution, TrisC or UHTm extender and kept at room temperature for 24 h. Sperm quality assessment was performed during all the incubation periods. In the second experiment, 27 adult rabbit does were inseminated with semen incubated for 5 h. Embryo recovery was performed 96 h after insemination. Results showed that treatments diluted in UHTm registered the highest values of spermatozoon with total motility, intact and functional plasma membrane and greater number of embryos recovered in rabbit does. We conclude that UHT skim milk would be a good extender for improved intra-uterine insemination in rabbits and to keep sperm cells for several hours at room temperature. PMID- 26040430 TI - Erratum to: Southern Africa: the highest priority region for HIV prevention and care interventions. PMID- 26040429 TI - Fixed ratio dosing of pramlintide with regular insulin before a standard meal in patients with type 1 diabetes. AB - Amylin is co-secreted with insulin and is therefore lacking in patients with type 1 diabetes. Replacement with fixed ratio co-administration of insulin and the amylin analogue pramlintide may be superior to separate dosing. This concept was evaluated in a ratio-finding study. Patients with type 1 diabetes were enrolled in a randomized, single-masked, standard breakfast crossover study using regular human insulin injected simultaneously with pramlintide 6, 9 or 12 mcg/unit insulin or placebo. Insulin dosage was reduced by 30% from patients' usual estimates. Plasma glucose, glucagon and pramlintide and adverse events were assessed. All ratios reduced 0-3-h glucose and glucagon increments by >50%. No hypoglycaemia occurred. Adverse events were infrequent and generally mild. All pramlintide/insulin ratios markedly and safely reduced glycaemic excursions and suppressed glucagon secretion in the immediate postprandial state. Further study using one of these ratios to explore the efficacy and safety of longer-term meal time and basal hormone replacement is warranted. PMID- 26040431 TI - Prevalence of traumatic dental injuries and associated factors among preschool children in Amman, Jordan. AB - BACKGROUND/AIMS: Dental trauma is a major public health problem. However, baseline data regarding traumatic injuries to primary teeth in Jordan are lacking. The study aimed at evaluating the prevalence of traumatic dental injuries to primary anterior teeth among preschool children in Amman (Jordan), investigating the relationship between dental trauma and associated factors, and assessing the treatment provided and treatment need. MATERIALS AND METHODS: After obtaining ethical approval and parental consent, a cross-sectional population based study examined a total of 1198 children attending 39 preschools randomly selected from different areas of Amman. Chi-square test and stepwise logistic regression modeling were used for statistical analysis. RESULTS: The prevalence of traumatic dental injuries was 26.4%. The upper incisors were more likely to sustain dental trauma (91.7%). No statistically significant association was established between dental trauma and any of the socio-demographic variables. The most common type of dental trauma was enamel fracture (43.1%) followed by pulp injury (39.7%). The odds ratio suggested that the risk of dental trauma was 1.89 times greater if the overjet was >3 mm, 1.93 times greater if the child had an anterior open bite, and 2.56 times greater if the child had inadequate lip coverage. Only 25.3% of children diagnosed with a TDI visited a dentist following their trauma. CONCLUSIONS: The prevalence of dental trauma among preschool children in Amman (Jordan) was high; therefore, it is highly recommended to plan campaigns targeting parents, children, and medical/dental care providers that stress the importance of preventing dental trauma and treating it promptly. PMID- 26040432 TI - Electron spin coherence near room temperature in magnetic quantum dots. AB - We report on an example of confined magnetic ions with long spin coherence near room temperature. This was achieved by confining single Mn(2+) spins in colloidal semiconductor quantum dots (QDs) and by dispersing the QDs in a proton-spin free matrix. The controlled suppression of Mn-Mn interactions and minimization of Mn nuclear spin dipolar interactions result in unprecedentedly long phase memory (TM ~ 8 MUs) and spin-lattice relaxation (T1 ~ 10 ms) time constants for Mn(2+) ions at T = 4.5 K, and in electron spin coherence observable near room temperature (TM ~ 1 MUs). PMID- 26040433 TI - Secondary tracheoesophageal puncture using transnasal esophagoscopy in gastric pull-up reconstruction after total laryngopharyngoesophagectomy. AB - BACKGROUND: There is debate about the optimal voice restoration method and technique for patients who have undergone total laryngopharyngectomy, esophagectomy, and gastric pull-up. The purpose of this study was to report a series of patients who underwent awake, secondary tracheoesophageal puncture (TEP) after this procedure. METHODS: A retrospective chart review was performed at a tertiary referral center. All subjects who underwent TEP placement under transnasal esophagoscopy guidance between 2003 and 2013 were included. RESULTS: All patients underwent uncomplicated TEP in the clinic. At the time of last follow-up, all patients had functional TEP speech that they were using preferentially over an available electrolarynx. CONCLUSION: In-office placement of secondary TEP using transnasal esophagoscopy is an efficient means of providing a conduit for voice prostheses in patients who have undergone laryngopharyngectomy with gastric pull up reconstruction. This procedure can be performed with minimal complications and with expectation of voice outcomes comparable to that seen with standard laryngectomy. PMID- 26040434 TI - No solution yet for combining two independent studies in the presence of heterogeneity. PMID- 26040435 TI - Trauma-informed Day Services for Individuals with Intellectual/Developmental Disabilities: Exploring Staff Understanding and Perception within an Innovative Programme. AB - BACKGROUND: Trauma-informed care (TIC) is a systems-level philosophy of service delivery which integrates choice, collaboration, empowerment, safety and trust to create an organizational culture sensitive to trauma. This study explores staff understandings and perceptions within an innovative trauma-informed day program for individuals with Intellectual/developmental disabilities. METHODS: Semi structured interviews queried staff members (n = 20) regarding trauma and TIC, the integration of the five principles of TIC, associated challenges and recommendations for improvement. RESULTS: Inductive analyses revealed reasonable understandings of trauma and TIC, highlighting factors critical to the five principles of TIC. Differences were associated with duration of employment and the presence of specialized training. Challenges with TIC emerged at different system levels: individuals, staff, management and interorganizational. CONCLUSIONS: This study presents preliminary insight for the innovative and formative process of integrating TIC with intellectual/developmental disabilities services. PMID- 26040436 TI - Lateral assembly of oxidized graphene flakes into large-scale transparent conductive thin films with a three-dimensional surfactant 4-sulfocalix[4]arene. AB - Graphene is a promising candidate material for transparent conductive films because of its excellent conductivity and one-carbon-atom thickness. Graphene oxide flakes prepared by Hummers method are typically several microns in size and must be pieced together in order to create macroscopic films. We report a macro scale thin film fabrication method which employs a three-dimensional (3-D) surfactant, 4-sulfocalix[4]arene (SCX), as a lateral aggregating agent. After electrochemical exfoliation, the partially oxidized graphene (oGr) flakes are dispersed with SCX. The SCX forms micelles, which adsorb on the oGr flakes to enhance their dispersion, also promote aggregation into large-scale thin films under vacuum filtration. A thin oGr/SCX film can be shaved off from the aggregated oGr/SCX cake by immersing the cake in water. The oGr/SCX thin-film floating on the water can be subsequently lifted from the water surface with a substrate. The reduced oGr (red-oGr) films can be as thin as 10-20 nm with a transparency of >90% and sheet resistance of 890 +/- 47 kOmega/sq. This method of electrochemical exfoliation followed by SCX-assisted suspension and hydrazine reduction, avoids using large amounts of strong acid (unlike Hummers method), is relatively simple and can easily form a large scale conductive and transparent film from oGr/SCX suspension. PMID- 26040437 TI - Expression and Characterization of HA1 Protein of Highly Pathogenic H5N1 Avian Influenza Virus for Use in a Serodiagnostic Assay. AB - The hemagglutinin ectodomain (HA1 subunit) from highly pathogenic avian influenza (HPAI) isolate (A/chicken/Vietnam/14/2005) was cloned and expressed using a baculovirus expression vector. Biosynthesis, glycosylation and secretion of the HA1 proteins, with natural or a melittin signal peptide at the N-terminus and a six-histidine (6xHis) tag at the C-terminus, were examined in insect cells. A 40 kDa unglycosylated precursor and a fully processed, mature form of the HA1 protein migrated around 52 kDa were detected by SDS-PAGE and confirmed by Western blot using H5N1-specific antibody. Treatment of tunicamycin and peptide-N glycosidase F (PNGase F) further revealed that the recombinant HA1 proteins produced in insect cells were indeed glycosylated with N-linked oligosaccharide side chains. Time-course experiments showed that substitution of the HA natural sequence with the signal sequence from honeybee melittin promoted a high level of expression and efficient secretion of the HA1. A high yield, 37 MUg/ml, of HA1 protein was obtained from recombinant baculovirus-infected cell culture supernatant. In addition, the cell surface expression of rHA1 was detected by indirect immunofluorescent staining and showed biological activity on hemadsorption assays. Recombinant HA1 protein-based ELISA was evaluated and appeared to be sensitive and specific for the rapid detection of H5 subtype specific antibodies in serum samples. No cross-reactivity to antibodies from 15 other influenza A subtypes was detected. Taken together, the newly developed recombinant HA1-based ELISA could offer an alternative to other diagnostic approaches for the specific detection of H5 avian influenza virus infection. PMID- 26040438 TI - The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial. AB - Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure. PMID- 26040439 TI - Procalcitonin and Pentraxin-3: Current biomarkers in inflammation in white coat hypertension. AB - An association has been described between inflammation and the progression of hypertension (HT) and is shown with several biochemical parameters. Our aim was to examine the distribution of the serum procalcitonin (PCT), pentraxin (PTX)-3 and interleukin (IL)-33 levels and their relationship with carotid intima-media thickness (CIMT) in subjects with white coat HT (WCH), HT and normotension (NT) groups. Thirty-three patients with HT, 33 patients with WCH and 33 healthy subjects were enrolled in this study. PCT, PTX-3 and C-reactive protein (CRP) levels significantly increased in the HT group compared with the NT group. In addition, PCT and CRP levels were significantly higher in the WCH group than in the NT group. CIMT measurements were significantly higher in the WCH and HT groups than in the NT group. In the HT and WCH groups, there were significant positive correlations between PTX-3, PCT and CRP. In the WCH group, PTX-3 and PCT levels were significantly positively correlated with CIMT. PCT had area under the curve value of 0.817 which demonstrates its sufficiency to distinguish WCH from NT individuals. Our results suggest that in subjects with WCH and HT, which are characterized by increased cardiovascular risk, PTX-3 and PCT levels in the HT group and PCT levels in the WCH group are significantly and consistently higher than normotensives. Systemic inflammation moderately occurs in the WCH and HT groups. PCT monitoring may be a useful biomarker in inflammation related to atherosclerosis and early stage HT. PMID- 26040440 TI - The effect of obesity on electrocardiographic detection of hypertensive left ventricular hypertrophy: recalibration against cardiac magnetic resonance. AB - Electrocardiograph (ECG) criteria for left ventricular hypertrophy (LVH) are a widely used clinical tool. We recalibrated six ECG criteria for LVH against gold standard cardiac magnetic resonance (CMR) and assessed the impact of obesity. One hundred and fifty consecutive tertiary hypertension clinic referrals for CMR (1.5 T) were reviewed. Patients with cardiac pathology potentially confounding hypertensive LVH were excluded (n=22). The final sample size was 128 (age: 51.0+/ 15.2 years, 48% male). LVH was defined by CMR. From a 12-lead ECG, Sokolow-Lyon voltage and product, Cornell voltage and product, Gubner-Ungerleidger voltage and Romhilt-Estes score were evaluated, blinded to the CMR. ECG diagnostic performance was calculated. LVH by CMR was present in 37% and obesity in 51%. Obesity significantly reduced ECG sensitivity, because of significant attenuation in mean ECG values for Cornell voltage (22.2+/-5.7 vs 26.4+/-9.4 mm, P<0.05), Cornell product (2540+/-942 vs 3023+/-1185 mm * ms, P<0.05) and for Gubner Ungerleider voltage (18.2+/-7.1 vs 23.3+/-1.2 mm, P<0.05). Obesity also significantly reduced ECG specificity, because of significantly higher prevalence of LV remodeling (no LVH but increased mass-to-volume ratio) in obese subjects without LVH (36% vs 16%, P<0.05), which correlated with higher mean ECG LVH criteria values. Obesity-specific partition values were generated at fixed 95% specificity; Cornell voltage had highest sensitivity in non-obese (56%) and Sokolow-Lyon product in obese patients (24%). Obesity significantly lowers ECG sensitivity at detecting LVH, by attenuating ECG LVH values, and lowers ECG specificity through changes associated with LV remodeling. Our obesity-specific ECG partition values could improve the diagnostic performance in obese patients with hypertension. PMID- 26040441 TI - Prevalence of Zoonotic Giardia duodenalis Assemblage B and First Identification of Assemblage E in Rabbit Fecal Samples Isolates from Central China. AB - Giardia duodenalis is an important zoonotic pathogen, causes diarrhea in humans and animals worldwide. To date, few data are available on the prevalence of G. duodenalis in rabbits in China. In total, 955 fecal samples were collected from rabbits during 2008-2011 in Henan Province, Central China. The overall prevalence of G. duodenalis was 8.4% (80/955) on microscopic analysis, with the highest infection rate (11.3%) in rabbits aged 91-200 d. All G. duodenalis-positive isolates were characterized at the small subunit ribosomal RNA, beta-giardin (bg), glutamate dehydrogenase (gdh), and triosephosphate isomerase genes. Two assemblages and a mixed assemblage were detected in the rabbits: assemblage B (n = 26), assemblage E (n = 2), and a mixed assemblage of B and E (n = 4). Assemblage B isolates showed variability at the nucleotide sequences belonging to the so-called subtype BIV, based on analysis of multiple genes. This is the first report of G. duodenalis assemblage E in rabbits, and one novel subtype of assemblage E was identified through sequence analysis of gdh and bg genes, respectively. Our data suggest that rabbits may be reservoirs of G. duodenalis cysts potentially infectious to humans. PMID- 26040442 TI - Tracing CD34+ Stromal Fibroblasts in Palatal Mucosa and Periodontal Granulation Tissue as a Possible Cell Reservoir for Periodontal Regeneration. AB - The aim of the present research was to trace CD34+ stromal fibroblastic cells (CD34+ SFCs) in the palatal connective tissue harvested for muco-gingival surgical procedures and in granulation tissues from periodontal pockets using immunohistochemical and transmission electron microscopy. Immunohistochemical analysis targeted the presence of three antigens: CD31, alpha-smooth muscle actin (alpha-SMA), and CD34. In the palate, CD31 staining revealed a colored inner ring of the vessels representing the endothelium, alpha-SMA+ was located in the medial layer of the vasculature, and CD34 was intensely expressed by endothelial cells and artery adventitial cells (considered to be CD34+ SFCs). Granulation tissue showed the same pattern for CD31+ and alpha-SMA, but a different staining pattern for CD34. Ultrastructural examination of the palatal tissue highlighted perivascular cells with fibroblast-like characteristics and pericytes in close spatial relationship to endothelial cells. The ultrastructural evaluation of granulation tissue sections confirmed the presence of neovasculature and the inflammatory nature of this tissue. The present study traced the presence of CD34+ SFCs and of pericytes in the palatal connective tissue thus highlighting once more its intrinsic regenerative capabilities. The clinical and systemic factors triggering mobilization and influencing the fate of local CD34+SCFs and other progenitors are issues to be further investigated. PMID- 26040443 TI - Incorporation of diagnostic laparoscopy in the management algorithm for patients with peritoneal metastases: A multi-institutional analysis. AB - INTRODUCTION: Diagnostic laparoscopy (DL), which can predict complete cytoreduction (CC), is often considered unfeasible in patients with Peritoneal metastases (PM) due to a hostile abdomen, prior surgeries, incomplete assessment or risk of port site recurrence. We hypothesized that DL can be successfully incorporated into the management of patients with PM. METHODS: Retrospective review and data analysis of prospectively maintained databases from two high volume institutions was performed between 2007 and 2013. RESULTS: DL was successfully completed in 211/217 (92.6%) patients with PM. The technique for entry was the Hasson in 57%, optical trocar in 38% and Veress needle in 5%. Serosal injury from DL occurred in one patient (0.4%). Predominant histology included appendiceal (40%) and colorectal primaries (34%). Exclusion from cytoreduction by DL occurred in 68 (31.3%). Among those excluded, 7 (of 68, 10.3%) subsequently underwent CRS + HIPEC after receiving systemic chemotherapy. Overall survival (from laparoscopy) for those that underwent CRS + HIPEC at the original operation was 36 versus 12.7 months among those who were excluded by laparoscopy. There were no cases of port site recurrence. CONCLUSION: Diagnostic laparoscopy can be safely incorporated in the management of patients with peritoneal metastases, and can be especially beneficial in excluding patients from attempted incomplete cytoreduction. PMID- 26040444 TI - Police and mental health clinician partnership in response to mental health crisis: A qualitative study. AB - Police officers as first responders to acute mental health crisis in the community, commonly transport people in mental health crisis to a hospital emergency department. However, emergency departments are not the optimal environments to provide assessment and care to those experiencing mental health crises. In 2012, the Northern Police and Clinician Emergency Response (NPACER) team combining police and mental health clinicians was created to reduce behavioural escalation and provide better outcomes for people with mental health needs through diversion to appropriate mental health and community services. The aim of this study was to describe the perceptions of major stakeholders on the ability of the team to reduce behavioural escalation and improve the service utilization of people in mental health crisis. Responses of a purposive sample of 17 people (carer or consumer advisors, mental health or emergency department staff, and police or ambulance officers) who had knowledge of, or had interfaced with, the NPACER were thematically analyzed after one-to-one semistructured interviews. Themes emerged about the challenge created by a stand-alone police response, with the collaborative strengths of the NPACER (communication, information sharing, and knowledge/skill development) seen as the solution. Themes on improvements in service utilization were revealed at the point of community contact, in police stations, transition through the emergency department, and admission to acute inpatient units. The NPACER enabled emergency department diversion, direct access to inpatient mental health services, reduced police officer 'down-time', improved interagency collaboration and knowledge transfer, and improvements in service utilization and transition. PMID- 26040445 TI - Movement observation to identify ataxia: how well do experts agree? PMID- 26040446 TI - Comparison of striatal dopamine transporter levels in chronic heroin-dependent and methamphetamine-dependent subjects. AB - To compare the effects of heroin and methamphetamine (METH) addiction on dopamine transporters (DATs) in the same dose and duration, we assessed DAT levels in the striatum by 99m Tc-TRODAT-1 single-photon emission computed tomography (SPECT) brain images in people with heroin and METH dependence. We recruited 21 healthy human controls, 23 heroin-dependent subjects and 25 METH abusers. The heroin- and METH-dependent subjects exhibited negative urine toxicology after undergoing physiological detoxification. All subjects underwent SPECT brain imaging, and specific tracer uptake ratios (SURs) were assessed bilaterally in the regions of interest. A significant SUR reduction in heroin-dependent subjects and METH dependent subjects compared with healthy controls was found in the left striatum, right striatum, left caudate nucleus, right caudate nucleus, left putamen and right putamen. There were no significant differences in the heroin group and METH group for the left striatum, right striatum, left caudate nucleus, right caudate nucleus, left putamen and right putamen. The scores of craving, HAMA (Hamilton Anxiety Rating Scale), in heroin abusers were lower than in the METH abusers. Our results show that people with heroin and METH dependence who are currently abstinent had lower DAT levels in the striatum than healthy controls. There were no differences in striatal DAT in heroin and METH users. These results suggest that chronic heroin and METH abuse appears to produce similar effects in striatal DAT in humans. METH users may have more serious craving and anxiety symptoms than heroin users with prolonged abstinence. PMID- 26040447 TI - New diketopiperazine dimer from a filamentous fungal isolate of Aspergillus sydowii. PMID- 26040448 TI - Manual perineal support: learn the skills before you intervene. PMID- 26040450 TI - The emergence of macrocyclic lactone resistance in the canine heartworm, Dirofilaria immitis. AB - Prevention of heartworm disease caused by Dirofilaria immitis in domestic dogs and cats relies on a single drug class, the macrocyclic lactones (MLs). Recently, it has been demonstrated that ML-resistant D. immitis are circulating in the Mississippi Delta region of the USA, but the prevalence and impact of these resistant parasites remains unknown. We review published studies that demonstrated resistance in D.immitis, along with our current understanding of its mechanisms. Efforts to develop in vitro tests for resistance have not yet yielded a suitable assay, so testing infected animals for microfilariae that persist in the face of ML treatment may be the best current option. Since the vast majority of D. immitis populations continue to be drug-sensitive, protected dogs are likely to be infected with only a few parasites and experience relatively mild disease. In cats, infection with small numbers of worms can cause severe disease and so the clinical consequences of drug resistance may be more severe. Since melarsomine dihydrochloride, the drug used to remove adult worms, is not an ML, the ML-resistance should have no impact on our ability to treat diseased animals. A large refugium of heartworms that are not exposed to drugs exists in unprotected dogs and in wild canids, which may limit the development and spread of resistance alleles. PMID- 26040449 TI - Calorie seeking, but not hedonic response, contributes to hyperphagia in a mouse model for Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11 q13, the most recognised feature of which is hyperphagia. This is thought to arise as a consequence of abnormalities in both the physiological drive for food and the rewarding properties of food. Although a number of mouse models for PWS exist, the underlying variables dictating maladaptive feeding remain unknown. Here, feeding behaviour in a mouse model in which the imprinting centre (IC) of the syntenic PWS interval has been deleted (PWS(ICdel) mice) is characterised. It is demonstrated that PWS(ICdel) mice show hyperghrelinaemia and increased consumption of food both following overnight fasting and when made more palatable with sucrose. However, hyperphagia in PWS(ICdel) mice was not accompanied by any changes in reactivity to the hedonic properties of palatable food (sucrose or saccharin), as measured by lick-cluster size. Nevertheless, overall consumption by PWS(ICdel) mice for non-caloric saccharin in the licking test was significantly reduced. Combined with converging findings from a continuous reinforcement schedule, these data indicate that PWS(ICdel) mice show a marked heightened sensitivity to the calorific value of food. Overall, these data indicate that any impact of the rewarding properties of food on the hyperphagia seen in PWS(ICdel) mice is driven primarily by calorie content and is unlikely to involve hedonic processes. This has important implications for understanding the neural systems underlying the feeding phenotype of PWS and the contribution of imprinted genes to abnormal feeding behaviour more generally. PMID- 26040451 TI - Gut Catalase-Positive Bacteria Cross-Protect Adjacent Bifidobacteria from Oxidative Stress. AB - Bifidobacteria isolated from infant gut and breast milk exhibited different abilities to grow under microaerobic conditions, alone or in the presence of added catalase. In the present study, we demonstrated that some Bifidobacterium strains unable to grow under microaerobic conditions were cross-protected on solid media from oxidative stress by adjacent colonies of gut catalase-positive Staphylococcus epidermidis or Escherichia coli, but not by a catalase-deficient E. coli. The results of this study support the possible contribution of catalase positive bacteria to the establishment of certain bifidobacteria in non-anaerobic human niches of the infant gastrointestinal tract or mammary gland. PMID- 26040452 TI - Autoimmune diseases and pregnancy: analysis of a series of cases. AB - BACKGROUND: An autoimmune disease is characterized by tissue damage, caused by self-reactivity of different effector mechanisms of the immune system, namely antibodies and T cells. All autoimmune diseases, to some extent, have implications for fertility and obstetrics. Currently, due to available treatments and specialised care for pregnant women with autoimmune disease, the prognosis for both mother and child has improved significantly. However these pregnancies are always high risk. The purpose of this study is to analyse the fertility/pregnancy process of women with systemic and organ-specific autoimmune diseases and assess pathological and treatment implications. METHODS: The authors performed an analysis of the clinical records and relevant obstetric history of five patients representing five distinct autoimmune pathological scenarios, selected from Autoimmune Disease Consultation at the Hospital of Braga, and reviewed the literature. RESULTS: The five clinical cases are the following: Case 1-28 years old with systemic lupus erythematosus, and clinical remission of the disease, under medication with hydroxychloroquine, prednisolone and acetylsalicylic acid, with incomplete miscarriage at 7 weeks of gestation without signs of thrombosis. Case 2-44 years old with history of two late miscarriages, a single preterm delivery (33 weeks) and multiple thrombotic events over the years, was diagnosed with antiphospholipid syndrome after acute myocardial infarction. Case 3-31 years old with polymyositis, treated with azathioprine for 3 years with complete remission of the disease, took the informed decision to get pregnant after medical consultation and full weaning from azathioprine, and gave birth to a healthy term new-born. Case 4-38 years old pregnant woman developed Behcet's syndrome during the final 15 weeks of gestation and with disease exacerbation after delivery. Case 5-36 years old with autoimmune thyroiditis diagnosed during her first pregnancy, with difficult control over the thyroid function over the years and first trimester miscarriage, suffered a second miscarriage despite clinical stability and antibody regression. CONCLUSIONS: As described in literature, the authors found a strong association between autoimmune disease and obstetric complications, especially with systemic lupus erythematosus, antiphospholipid syndrome and autoimmune thyroiditis. PMID- 26040454 TI - FinisherSC: a repeat-aware tool for upgrading de novo assembly using long reads. AB - We introduce FinisherSC, a repeat-aware and scalable tool for upgrading de novo assembly using long reads. Experiments with real data suggest that FinisherSC can provide longer and higher quality contigs than existing tools while maintaining high concordance. AVAILABILITY AND IMPLEMENTATION: The tool and data are available and will be maintained at http://kakitone.github.io/finishingTool/ CONTACT: : dntse@stanford.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26040453 TI - Prognostic significance of clinical and pathological stages on locally advanced rectal carcinoma after neoadjuvant chemoradiotherapy. AB - OBJECTIVE: To investigate prognostic significance of clinical and pathological stages in patients with locally advanced rectal carcinoma treated with neoadjuvant chemoradiotherapy (neo-CRT) and total mesorectal excision. PATIENTS AND METHODS: 210 patients with locally advanced rectal carcinoma (cT3-4 or cN+) treated with neo-CRT followed by total mesorectal excision. Treatment outcomes were compared according to clinical and pathological stage. Overall survival (OS), disease free survival (DFS) among patients with different clinical stage and pathological stage after neo-CRT. RESULTS: The median follow-up time was 47 months (range, 14-98 months). Clinical T stage was associated with 5 year OS (p = 0.042) and 5 year DFS (p = 0.014) while clinical N stage was not associated with 5 year OS (p = 0.440), 5 year DFS (p = 0.711). Pathological T stage was associate with 5 year OS (p = 0.001) and 5 year DFS (p = 0.046); and N stage was associated with 5 year OS (p = 0.001), 5 year DFS (p = 0.002). The pathological stage was further classified into three groups: ypT0-2N0 in 91 patients (43.3 %), ypT3-4N0 in 69 patients (32.9 %) and ypT0-4N+ in 50 patients (23.8 %). While pathological stage (ypT0-2 vs ypT3-4N0 vs ypT0-4N+) was associated with 5 year OS (87.9 %, 75.5 %, 56.7 %, p = 0.000), 5 year DFS (74.5 %, 77.4 %, 50.5 %, p = 0.003). Multivariate analysis showed that ypN stage was an independent prognostic factor for patients 5 year DFS. CONCLUSIONS: Pathological stage is strongly associated with treatment outcomes in patients with locally advanced rectal carcinoma treated with neo-CRT followed by total mesorectal excision, which may be used as guidance for further individualized treatment. PMID- 26040455 TI - TiQuant: software for tissue analysis, quantification and surface reconstruction. AB - MOTIVATION: TiQuant is a modular software tool for efficient quantification of biological tissues based on volume data obtained by biomedical image modalities. It includes a number of versatile image and volume processing chains tailored to the analysis of different tissue types which have been experimentally verified. TiQuant implements a novel method for the reconstruction of three-dimensional surfaces of biological systems, data that often cannot be obtained experimentally but which is of utmost importance for tissue modelling in systems biology. AVAILABILITY AND IMPLEMENTATION: TiQuant is freely available for non-commercial use at msysbio.com/tiquant. Windows, OSX and Linux are supported. CONTACT: hoehme@uni-leipzig.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26040456 TI - Assembling short reads from jumping libraries with large insert sizes. AB - MOTIVATION: Advances in Next-Generation Sequencing technologies and sample preparation recently enabled generation of high-quality jumping libraries that have a potential to significantly improve short read assemblies. However, assembly algorithms have to catch up with experimental innovations to benefit from them and to produce high-quality assemblies. RESULTS: We present a new algorithm that extends recently described exSPAnder universal repeat resolution approach to enable its applications to several challenging data types, including jumping libraries generated by the recently developed Illumina Nextera Mate Pair protocol. We demonstrate that, with these improvements, bacterial genomes often can be assembled in a few contigs using only a single Nextera Mate Pair library of short reads. AVAILABILITY AND IMPLEMENTATION: Described algorithms are implemented in C++ as a part of SPAdes genome assembler, which is freely available at bioinf.spbau.ru/en/spades. CONTACT: ap@bioinf.spbau.ru SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26040457 TI - A web application for the unspecific detection of differentially expressed DNA regions in strand-specific expression data. AB - Genomic technologies allow laboratories to produce large-scale data sets, either through the use of next-generation sequencing or microarray platforms. To explore these data sets and obtain maximum value from the data, researchers view their results alongside all the known features of a given reference genome. To study transcriptional changes that occur under a given condition, researchers search for regions of the genome that are differentially expressed between different experimental conditions. In order to identify these regions several algorithms have been developed over the years, along with some bioinformatic platforms that enable their use. However, currently available applications for comparative microarray analysis exclusively focus on changes in gene expression within known transcribed regions of predicted protein-coding genes, the changes that occur in non-predictable genetic elements, such as non-coding RNAs. Here, we present a web application for the visualization of strand-specific tiling microarray or next generation sequencing data that allows customized detection of differentially expressed regions all along the genome in an unspecific manner, that allows identification of all RNA sequences, predictable or not. AVAILABILITY AND IMPLEMENTATION: The web application is freely accessible at http://tilingscan.uv.es/. TilingScan is implemented in PHP and JavaScript. CONTACT: vicente.arnau@uv.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26040458 TI - Uncovering distinct protein-network topologies in heterogeneous cell populations. AB - BACKGROUND: Cell biology research is fundamentally limited by the number of intracellular components, particularly proteins, that can be co-measured in the same cell. Therefore, cell-to-cell heterogeneity in unmeasured proteins can lead to completely different observed relations between the same measured proteins. Attempts to infer such relations in a heterogeneous cell population can yield uninformative average relations if only one underlying biochemical network is assumed. To address this, we developed a method that recursively couples an iterative unmixing process with a Bayesian analysis of each unmixed subpopulation. RESULTS: Our approach enables to identify the number of distinct cell subpopulations, unmix their corresponding observations and resolve the network structure of each subpopulation. Using simulations of the MAPK pathway upon EGF and NGF stimulations we assess the performance of the method. We demonstrate that the presented method can identify better than clustering approaches the number of subpopulations within a mixture of observations, thus resolving correctly the statistical relations between the proteins. CONCLUSIONS: Coupling the unmixing of multiplexed observations with the inference of statistical relations between the measured parameters is essential for the success of both of these processes. Here we present a conceptual and algorithmic solution to achieve such coupling and hence to analyze data obtained from a natural mixture of cell populations. As the technologies and necessity for multiplexed measurements are rising in the systems biology era, this work addresses an important current challenge in the analysis of the derived data. PMID- 26040459 TI - DNA-functionalized upconversion nanoparticles as biosensors for rapid, sensitive, and selective detection of Hg(2+) in complex matrices. AB - We have developed a facile one-step approach to make hydrophilic and DNA functionalizable upconversion nanoparticles (UCNPs), which are used to act as a biosensor for determining Hg(2+) in complex matrices. The proposed approach is simple and exhibits low background interference, high sensitivity and rapid response. PMID- 26040460 TI - quantro: a data-driven approach to guide the choice of an appropriate normalization method. AB - Normalization is an essential step in the analysis of high-throughput data. Multi sample global normalization methods, such as quantile normalization, have been successfully used to remove technical variation. However, these methods rely on the assumption that observed global changes across samples are due to unwanted technical variability. Applying global normalization methods has the potential to remove biologically driven variation. Currently, it is up to the subject matter experts to determine if the stated assumptions are appropriate. Here, we propose a data-driven alternative. We demonstrate the utility of our method (quantro) through examples and simulations. A software implementation is available from http://www.bioconductor.org/packages/release/bioc/html/quantro.html . PMID- 26040462 TI - Erratum to: Surgical evolution in the treatment of mandibular condyle fractures. PMID- 26040464 TI - Assessment of knowledge, attitude and practice about malaria and ITNs utilization among pregnant women in Shashogo District, Southern Ethiopia. AB - BACKGROUND: Malaria causes variety of adverse consequences in pregnant women due to invasion of the placenta by Plasmodium. It increases the risk of adverse pregnancy outcome for the mother, the foetus and the new-born. Therefore, knowledge, attitudes and practices of this vulnerable group about malaria and the effective use of insecticide-treated nets (ITNs) contribute to sustainable control of the disease and its effects. METHODS: A community based cross sectional study was carried out in May, 2014. A validated structured questionnaire was used for data collection. The data was analysed using logistic regression by means of STATA version 11 data analysis software. RESULTS: A total of 398 pregnant women participated in the study and their overall knowledge and attitude towards malaria and ITNs was fairly good; 74.3 % of the mothers had good knowledge and 51.1 % of them possessed positive attitude. Nevertheless, only 15.6 % of the mothers associated mosquitoes with malaria and majority of them (65.6 %) responded that it is transmitted due to poor personal hygiene and environmental sanitation. Younger age, receiving information and information obtained from health extension workers and media were found to be important predictors of pregnant women's attitude (P < 0.05). The ITNs utilization was poor. Only 15.8 % of 398 mothers owned at least one ITN. This was due to its unavailability in markets and unsustainable distribution. More than half of the mothers who owned the ITNs did not have a number proportional to their family size, and 52 % of the mothers had not slept under bed net the previous night. This was due to its being dirty, old, had holes and in some cases lack of awareness on how to install it and its importance to prevent malaria. Higher education was identified as the determining factor for ITNs utilization (P < 0.05). CONCLUSION: Even though the pregnant mothers' knowledge and attitude about malaria and ITNs was fairly good, its ownership and utilization was noticeably very low. Therefore, consistent and timely distribution by the government and other funding agencies is promptly needed. In addition, appropriate health education should be given on the link between malaria and mosquito, regular and correct use of ITNs with special focus to uneducated and elderly mothers. PMID- 26040463 TI - Natural killer (NK) cell profiles in blood and tumour in women with large and locally advanced breast cancer (LLABC) and their contribution to a pathological complete response (PCR) in the tumour following neoadjuvant chemotherapy (NAC): differential restoration of blood profiles by NAC and surgery. AB - BACKGROUND: NK cells contribute to tumour surveillance, inhibition of growth and dissemination by cytotoxicity, secretion of cytokines and interaction with immune cells. Their precise role in human breast cancer is unclear and the effect of therapy poorly studied. The purpose of our study was to characterise NK cells in women with large (>=3 cm) and locally advanced (T3-4, N1-2, M0) breast cancers (LLABCs) undergoing neoadjuvant chemotherapy (NAC) and surgery, and to ascertain their possible contribution to a pathological complete response (pCR). METHODS: Women with LLABCs (n = 25) and healthy female donors [HFDs (n = 10)] were studied. Pathological responses in the breast were assessed using established criteria. Blood samples were collected pre and post NAC and surgery. Flow cytometry and labelled monoclonal antibodies established absolute numbers (AbNs) and percentages (%) of NK cells, and expressing granzyme B/perforin and NKG2D. In vitro NK cytotoxicity was assessed and NK cells and cytokines (IL-2, INF-gamma, TGF-beta) documented in tumours using immunohistochemical techniques. Data was analysed by SPSS. RESULTS: Women with LLABCs had significantly reduced AbNs (160.00 +/- 40.00 cells/ul) but not % of NK cells, compared with HFDs (NK: 266.78 +/- 55.00 cells/ul; p = 0.020). NAC enhanced the AbN (p = 0.001) and % (p = 0.006) of NK cells in patients with good pathological responses. Granzyme B(+)/perforin(+) cells were significantly reduced (43.41 +/- 4.00%), compared with HFDs (60.26 +/- 7.00%; p = 0.003). NAC increased the % in good (p = 0.006) and poor (p = 0.005) pathological responders. Pretreatment NK cytotoxicity was significantly reduced in good (37.80 +/- 8.05%) and poor (22.80 +/- 7.97%) responders (p = 0.001) but remained unchanged following NAC. NK-NKG2D(+) cells were unaltered and unaffected by NAC; NKG2D expression was increased in patients with a pCR (p = 0.001). Surgery following NAC was not beneficial, except in those with a pCR. Tumour-infiltrating NK cells were infrequent but increased peritumourally (p = 0.005) showing a significant correlation (p = 0.004) between CD56(+) cells and grade of response. Tumour cytokines had no effect. CONCLUSION: Women with LLABCs have inhibited blood innate immunity, variably reversed by NAC (especially with tumour pCRs), which returned to pretreatment levels following surgery. These and in situ tumour findings suggest a role for NK cells in NAC induced breast pCR. PMID- 26040465 TI - Parasite richness in fish larvae from the nearshore waters of central and northern Chile. AB - In the present study, we determine the presence of parasites in fish larvae collected from nearshore waters along the northern and central coast of Chile. The parasites were identified to the lowest possible taxonomic level based on morphological and molecular analyses. The fish sample was composed of 5 574 fish larvae. Of these, 3% harboured only larval ectoparasitic copepods whereas no endoparasites were found in the 1 141 fish evaluated for this group of parasites. The parasitic copepods collected were initially classified as 'morphotypes' according to differences in morphological characteristics. They were then analysed using molecular techniques based on the 28S and COI genes. Seven morphotypes of parasitic copepods (mostly at chalimus stages) were recognised: two of the morphotypes belonged to Pennellidae Burmeister, 1835, three to Caligidae Burmeister, 1835 and two were not identified. Only five morphotypes of copepods were analysed using molecular sequences, which confirmed the existence of six species: two pennellids of the genus Trifur Wilson, 1917 and two caligids of the genus Caligus Muller, 1785, plus two additional species that were morphologically different from these taxa. The pennellids were present in several fish species, being generally more prevalent than the caligids, in both the central and northern localities of Chile. Multispecies infections in larval fish were infrequent (< 1%). We conclude that fish larvae were rich in parasites, considering that these hosts exhibited small body sizes and were very young. We suggest that fish larvae could play a role, as intermediate hosts, in the life cycle of the parasitic copepods found. PMID- 26040467 TI - Effect of cocoa products and flavanols on platelet aggregation in humans: a systematic review. AB - Previous evidence suggested an active role of cocoa products and flavanols in modulating platelet aggregation. However, cocoa flavanols are characterized by a low bioavailability that can deeply affect their presence in biological fluids and raise questions on their biological effect in humans. We performed a systematic search on Medline, Embase, Cochrane and ProQuest databases, until April 2015, on the effect of cocoa products on platelet aggregation in human intervention studies. We identified 13 interventions, of which only five involved repeated administration. Different effects were observed on the basis of the platelet aggregation test used, whereas neither a longer duration of treatment nor a higher dose was associated with a higher inhibition of platelet aggregation. In conclusion, the reviewed results suggest that consumption of cocoa products in bolus administration positively affects platelet aggregation in both healthy subjects and diseased patients. On the other hand, more evidence is required in order to assess the effect of long-term cocoa product ingestion and to identify the bioactive components involved. PMID- 26040466 TI - Integrative network-based approach identifies key genetic elements in breast invasive carcinoma. AB - BACKGROUND: Breast cancer is a genetically heterogeneous type of cancer that belongs to the most prevalent types with a high mortality rate. Treatment and prognosis of breast cancer would profit largely from a correct classification and identification of genetic key drivers and major determinants driving the tumorigenesis process. In the light of the availability of tumor genomic and epigenomic data from different sources and experiments, new integrative approaches are needed to boost the probability of identifying such genetic key drivers. We present here an integrative network-based approach that is able to associate regulatory network interactions with the development of breast carcinoma by integrating information from gene expression, DNA methylation, miRNA expression, and somatic mutation datasets. RESULTS: Our results showed strong association between regulatory elements from different data sources in terms of the mutual regulatory influence and genomic proximity. By analyzing different types of regulatory interactions, TF-gene, miRNA-mRNA, and proximity analysis of somatic variants, we identified 106 genes, 68 miRNAs, and 9 mutations that are candidate drivers of oncogenic processes in breast cancer. Moreover, we unraveled regulatory interactions among these key drivers and the other elements in the breast cancer network. Intriguingly, about one third of the identified driver genes are targeted by known anti-cancer drugs and the majority of the identified key miRNAs are implicated in cancerogenesis of multiple organs. Also, the identified driver mutations likely cause damaging effects on protein functions. The constructed gene network and the identified key drivers were compared to well established network-based methods. CONCLUSION: The integrated molecular analysis enabled by the presented network-based approach substantially expands our knowledge base of prospective genomic drivers of genes, miRNAs, and mutations. For a good part of the identified key drivers there exists solid evidence for involvement in the development of breast carcinomas. Our approach also unraveled the complex regulatory interactions comprising the identified key drivers. These genomic drivers could be further investigated in the wet lab as potential candidates for new drug targets. This integrative approach can be applied in a similar fashion to other cancer types, complex diseases, or for studying cellular differentiation processes. PMID- 26040469 TI - Cationic star copolymers based on beta-cyclodextrins for efficient gene delivery to mouse embryonic stem cell colonies. AB - A cationic star copolymer with a beta-cyclodextrin core was developed for nonviral gene transfer to mouse embryonic stem cells (mESCs). The copolymer comprises poly(2-dimethyl aminoethyl methacrylate) as the cationic component and poly(2-hydroxyethyl methacrylate) as the non-toxic stealth component. These materials have very low toxicity and show highly efficient transfection to mESC colonies. PMID- 26040470 TI - Vinflunine in routine clinical practice for the treatment of advanced or metastatic urothelial cell carcinoma - data from a prospective, multicenter experience. AB - BACKGROUND: Vinflunine is recommended in the European guideline for the treatment of advanced or metastatic urothelial cell carcinoma (UCC) after failure of platinum-based therapy. METHODS: This prospective, non-interventional study investigated the safety and efficacy of vinflunine in platinum-pretreated UCC patients in routine clinical practice. Data were prospectively collected on patients with advanced or metastatic UCC undergoing vinflunine treatment in 39 German hospitals and medical practices. Dosing of vinflunine, tumor assessments and concomitant medications followed physician's routine clinical practice. Primary endpoints were toxicity and assessment of vinflunine treatment modalities. Secondary aims included overall response rate (ORR), overall survival (OS) time and a prognostic risk-model. RESULTS: Seventy-seven platinum-pretreated patients were recruited. Vinflunine was predominantly administered as second-line (66%) therapy or in subsequent treatment lines (21%). One third of the patients received at least six cycles of vinflunine and the average number was 4.7 cycles. A vinflunine starting dose of 320 mg/m2 was chosen in 48% of patients and 280 mg/m2 in 39%. Grade 3/4 toxicities were leucopenia 16.9%, anemia 6.5%, elevated liver enzymes 6.5% and constipation 5.2%. ORR was 23.4% and OS was 7.7 (CI 4.1 to 10.4) months. Patients with zero, one, two or >=three risk factors displayed a median OS of 18.2, 9.5, 4.1 and 2.8 months, respectively (p=0.0005; HR=1.82). CONCLUSION: Vinflunine delivers a meaningful benefit to an unselected population of advanced platinum-pretreated UCC patients managed in routine clinical practice. PMID- 26040471 TI - Hospital population screening reveals overrepresentation of CD5(-) monoclonal B cell lymphocytosis and monoclonal gammopathy of undetermined significance of IgM type. AB - Monoclonal B-cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS) result from clonal expansions of mature B or plasma cells. Here, we set out to determine the immunophenotypic/monoclonal immunoglobulin (M protein) features and co-prevalence of MBL and MGUS in a hospital-based cohort of 1909 non-hematooncological patients. Of the evaluable cases, 3.8 % showed evidence for MBL by immunophenotyping, while 9.8 % were screened positive for M protein by immunofixation. With six concomitant cases (0.4 %), MBL and MGUS were not statistically associated. At least in two of these coincident cases, MBL and MGUS were of different clonal origin since both clones had divergent light chain restriction. CD5(-) MBL (57.1 %) and IgM+ MGUS (24.7 %) were strikingly overrepresented compared to population-based screenings and did not progress to overt lymphoma or myeloma during the observation period (mean follow-up of 117 weeks or 110 weeks, respectively). Prevalence and phenotypes suggest that a substantial proportion of incidental MBL and MGUS in hospitalized patients may be attributed to transiently expanded B-cell clones in the context of disease related immune stimulation rather than reflecting veritable precursors of clonal B-cell malignancies. PMID- 26040468 TI - Amyloid in dementia associated with familial FTLD: not an innocent bystander. AB - Patients with frontotemporal lobar degeneration (FTLD) can show superimposed amyloid pathology, though the impact of amyloid on the clinical presentation of FTLD is not well characterized. This cross-sectional case-control study compared clinical features, fluorodeoxyglucose-positron emission tomography metabolism and gray matter volume loss in 30 patients with familial FTLD in whom amyloid status was confirmed with autopsy or Pittsburgh compound B-PET. Compared to the amyloid negative patients, the amyloid-positive patients performed significantly worse on several cognitive tests and showed hypometabolism and volume loss in more temporoparietal regions. Our results suggest that in FTLD amyloid positivity is associated with a more Alzheimer's disease-like pattern of neurodegeneration. PMID- 26040472 TI - Predicting in vivo glioma growth with the reaction diffusion equation constrained by quantitative magnetic resonance imaging data. AB - Reaction-diffusion models have been widely used to model glioma growth. However, it has not been shown how accurately this model can predict future tumor status using model parameters (i.e., tumor cell diffusion and proliferation) estimated from quantitative in vivo imaging data. To this end, we used in silico studies to develop the methods needed to accurately estimate tumor specific reaction diffusion model parameters, and then tested the accuracy with which these parameters can predict future growth. The analogous study was then performed in a murine model of glioma growth. The parameter estimation approach was tested using an in silico tumor 'grown' for ten days as dictated by the reaction-diffusion equation. Parameters were estimated from early time points and used to predict subsequent growth. Prediction accuracy was assessed at global (total volume and Dice value) and local (concordance correlation coefficient, CCC) levels. Guided by the in silico study, rats (n = 9) with C6 gliomas, imaged with diffusion weighted magnetic resonance imaging, were used to evaluate the model's accuracy for predicting in vivo tumor growth. The in silico study resulted in low global (tumor volume error <8.8%, Dice >0.92) and local (CCC values >0.80) level errors for predictions up to six days into the future. The in vivo study showed higher global (tumor volume error >11.7%, Dice <0.81) and higher local (CCC <0.33) level errors over the same time period. The in silico study shows that model parameters can be accurately estimated and used to accurately predict future tumor growth at both the global and local scale. However, the poor predictive accuracy in the experimental study suggests the reaction-diffusion equation is an incomplete description of in vivo C6 glioma biology and may require further modeling of intra-tumor interactions including segmentation of (for example) proliferative and necrotic regions. PMID- 26040474 TI - Assessing embryo quality by combining non-invasive markers: early time-lapse parameters reflect gene expression in associated cumulus cells. AB - STUDY QUESTION: Are there associations between early time-lapse parameters, expression of candidate embryo viability genes in cumulus cells and embryo quality on Day 5? SUMMARY ANSWER: Early time-lapse parameters correlate to the expression levels of candidate embryo viability genes in cumulus cells but a combined analysis including both time-lapse and candidate gene expression did not identify significant predictors of embryo quality on Day 5. WHAT IS KNOWN ALREADY: Recent evidence suggests that early time-lapse parameters are predictive of blastocyst development. Similarly, a number of candidate genes in cumulus cells have been identified as potential markers of embryo viability. Relationships between time-lapse parameters and candidate gene expression in cumulus cells have not been investigated, and a combined analysis of these markers has not been attempted in relation to embryo quality. STUDY DESIGN, SIZE, DURATION: A total of 78 embryos obtained by ICSI from 22 patients were studied by time-lapse and measurement of cumulus cell gene expression of known markers of embryo viability. Time-lapse and cumulus cell gene expression data were assessed in relation to embryo quality on Day 5. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women, aged 32-40 years, underwent ICSI treatment for male infertility. Embryos with annotatable time to pronuclear breakdown (tPNB), division to two cells (t2C), three cells (t3C), four cells (t4C) and five cells (t5C) were included in the study. Expression levels of 27 candidate genes for embryo viability were measured in 78 associated cumulus cell masses using quantitative real-time PCR. MAIN RESULTS AND THE ROLE OF CHANCE: Cumulus cell expression of 11 candidate genes involved in energy metabolism (ATPase, H+ transporting, lysosomal 70 kDa, V1 subunit A (ATP6V1A), NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 1, 7.5 kDa (NDUFA1), lactate dehydrogenase A (LDHA), phosphofructokinase platelet (PFKP) and solute carrier family 2 member 4 (SLC2A4), mitochondrial biogenesis (DNA directed RNA polymerase, mitochondrial (POLRMT) and transcription factor A, mitochondrial (TFAM), signalling (prostaglandin-endoperoxide synthase 2), steroidogenesis (cytochrome P450, family 11, subfamily A, polypeptide 1 (CYP11A1) and cell stress (heat shock 70 kDa protein 5 (HSPA5) and peroxiredoxin 3 (PRDX3)) correlated to time-lapse parameters of the developing embryo, largely for t3C onwards (all P < 0.05). Expression of ATP synthase, H+ transporting, mitochondrial Fo complex, subunit E (ATP51), HSPA5, PFKP, PRDX3 and versican (VCAN) and the parameter t4C were also related to embryo quality on Day 5 (all P < 0.05). Ordinal logistic regression, where gene expression and time-lapse parameters were combined, did not identify any significant predictors of embryo quality on Day 5. LIMITATIONS AND REASON FOR CAUTION: Data are from a preliminary study, limited by a small sample size and using more than one ovarian stimulation protocol. A possible limitation is that each follicle was treated as an independent observation, although a considerable fraction of embryos were from the same patient. WIDER IMPLICATIONS OF THE FINDINGS: Results presented in this study suggest that some of the variation of time-lapse parameters may be related to cumulus cell gene expression and thus the ovarian microenvironment in which the oocyte developed. Although the current study did not identify significant predictors of embryo quality on Day 5, investigation in a larger cohort may determine whether cumulus cell gene expression and time-lapse parameters can be combined to predict embryo quality. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by Fertility Associates Ltd, the Auckland Medical Research Foundation and the University of Auckland. J.C.P. has a 0.5% shareholding in Fertility Associates. All other authors of this manuscript have nothing to declare and no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. PMID- 26040473 TI - Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway. AB - AIMS/HYPOTHESIS: This study investigated fibroblast growth factor 21 (FGF21) mediated cardiac protection against apoptosis caused by diabetic lipotoxicity and explored the protective mechanisms involved. METHODS: Cardiac Fgf21 mRNA expression was examined in a diabetic mouse model using real-time PCR. After pre incubation of palmitate-treated cardiac H9c2 cells and primary cardiomyocytes with FGF21 for 15 h, apoptosis and Fgf21-induced cell-survival signalling were investigated using small interfering (si)RNA and/or pharmacological inhibitors. We also examined the cardiac apoptotic signalling and structural and functional indices in wild-type and Fgf21-knockout (Fgf21-KO) diabetic mice. RESULTS: In a mouse model of type 1 diabetes, cardiac Fgf21 expression was upregulated about 40 fold at 2 months and 3-1.5-fold at 4 and 6 months after diabetes. FGF21 significantly reduced palmitate-induced cardiac apoptosis. Mechanistically, palmitate downregulated, but FGF21 upregulated, phosphorylation levels of extracellular signal-regulated kinase (ERK)1/2, mitogen-activated protein kinase 14 (p38 MAPK) and AMP-activated protein kinase (AMPK). Inhibition of each kinase with its inhibitor and/or siRNA revealed that FGF21 prevents palmitate-induced cardiac apoptosis via upregulating the ERK1/2-dependent p38 MAPK-AMPK signalling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic or fatty-acid-infused mice significantly prevented cardiac apoptosis and reduced inactivation of ERK1/2, p38 MAPK and AMPK and prevented cardiac remodelling and dysfunction. The Fgf21-KO mice were more susceptible to diabetes induced cardiac apoptosis, and this could be prevented by administration of FGF21. Deletion of Fgf21 did not further exacerbate cardiac dysfunction. CONCLUSIONS/INTERPRETATION: These results demonstrate that FGF21 prevents lipid- or diabetes-induced cardiac apoptosis by activating the ERK1/2-p38 MAPK-AMPK pathway. FGF21 may be a therapeutic target for the treatment of diabetes-related cardiac damage. PMID- 26040475 TI - Immune testing and treatment: still an open debate. PMID- 26040476 TI - Effect of religious rules on time of conception in Romania from 1905 to 2001. AB - STUDY QUESTION: Does the interdiction of sexual intercourse during Nativity and Lent fasting periods have any effect on when babies are conceived in Romania, in the 20th century? SUMMARY ANSWER: Based on date of birth records from the 20th century, Lent had a greater effect than the Nativity fast on conception within the Eastern Orthodox (ORTHD) population. WHAT IS KNOWN ALREADY: Seasonality of births (and therefore of conception) is affected by geographical factors (latitude, weather, day-length). Other demographic, economic and socio-cultural characteristics (education, ethnicity, religion) have been proved to have an influence on conception. STUDY DESIGN, SIZE, DURATION: The analyzed data consists of registered daily birth records for a long time series (35 429 points = 365 (days/year) * 97 years + 24 leap years), with 24 947 061 births in Romania over the period 1905-2001. The data were obtained from the 1992 and 2002 censuses. PARTICIPANTS/MATERIALS, SETTING, METHODS: Based on the reported birth date of each person, the estimated date of conception is computed using a standard gestation period of 280 days. The population was grouped into two categories (ORTHD and Non-Orthodox (NORTHD)) based on religious affiliation. Data analysis is performed in the same manner for both groups. Preliminary data analyses regarding seasonal variations in conception are considered first. Econometric models are applied and tested. The dependent variable in these models is the calculated date of conception, while the independent variables are: (i) religious affiliation; (ii) dates of Nativity and Lent fasts (the latter varies slightly from year to year); (iii) rural versus urban residence; (iv) length of day-light; (v) non-working days and (vi) trend. The models are tested for validity using analysis of variance while the regression coefficients are tested by the Student t-test. MAIN RESULTS AND THE ROLE OF CHANCE: All models are statistically valid (P < 0.01); all regression coefficients for the ORTHD group are valid (P < 0.01, except for rurality between 1990 and 2001, with P < 0.05). The data analysis indicates smaller standard error bars on the parameters for the ORTHD group as compared with the NORTHD group. The conclusion is that religious affiliation is an important factor in date of conception. LIMITATIONS, REASONS FOR CAUTION: The data do not refer to all births during the analyzed period, but only to those persons still alive at the 1992 and 2002 censuses. The date of conception was estimated assuming 280 days for gestation, which is a medically accepted time interval but will undoubtedly vary. However, the primary independent variables (Lent and Nativity fast at 48 and 40 days, respectively) are long enough to overlap the uncertainty in the conception date following the sexual intercourse event. We also must assume that the religious affiliation of the parents is well defined, based on the information given by their offspring at census time, and is the same for both parents. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are consistent with other studies, which show differences between religious groups on date of conception, although we reach different conclusions regarding the influence of weather on fertility in Romania. STUDY FUNDING/COMPETING INTERESTS: B.V.I., M.A. and G.R. have no competing interests to declare. There is no connection to the current paper, but C.H. declares that (i) he is currently conducting a research titled 'Chronic Diseases' Direct Costs within the Romanian Health System' funded by Local American Working Group; (ii) his wife is employed to a Romanian company (A&D Pharma) that does business in the pharmaceutical sector. This paper is a part of G.R. and M.A. scientific activities in COST Action TD1210. This work by C.H. was co-financed by the European Social Fund through project number POSDRU/1.5/S/59184. PMID- 26040477 TI - Association of serum levels of typical organic pollutants with polycystic ovary syndrome (PCOS): a case-control study. AB - STUDY QUESTION: Is polycystic ovary syndrome (PCOS) associated with increased serum levels of typical organic pollutants? SUMMARY ANSWER: PCOS in Han females from Northern China was significantly associated with elevated serum levels of pollutants, including polychlorinated biphenyls (PCBs), organochlorine pesticides and polycyclic aromatic hydrocarbons (PAHs). WHAT IS KNOWN ALREADY: PCOS is arguably the most common endocrinopathy in females of reproductive age. The etiology of PCOS is thought to be multifactorial. STUDY DESIGN, SIZE, DURATION: This was a preliminary case-control study undertaken at the Division of Reproductive Center, Peking University Third Hospital. Fifty participants affected by PCOS and 30 normal controls were recruited between August and October 2012 from Northern China. All participants were Han women. PARTICIPANTS/MATERIALS, SETTING, METHODS: PCOS participants were diagnosed according to the 2003 Rotterdam criteria. The control participants were non pregnant females unable to conceive solely due to male azoospermia. Serum levels of a wide range of organic pollutants, including PCBs, organochlorine pesticides, PAHs and more than 20 phenolic pollutants, were analyzed using gas chromatographic mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: Serum levels of PCBs, pesticides and PAHs were significantly higher in the PCOS group than the control group. Concentrations of PCBs, p,p' dichlorodiphenyldichloroethylene (p,p'-DDE) and PAHs in serum above median levels were associated with PCOS with odds ratios of 3.81 [95% confidence interval (CI), 1.45-10.0], 4.89 (95% CI, 1.81-13.2) and 2.39 (95% CI, 0.94-6.05), respectively. Partial least-squares-discriminant analysis (PLS-DA) confirmed that serum levels of organic pollutants were associated with PCOS, especially for p,p'-DDE and PCBs. LIMITATIONS, REASONS FOR CAUTION: Some other possible covariates (e.g. dietary and income) were missed in this study, although education and occupation have been considered as an indicator of personal income. The PLS-DA model allowed a quasi-exposome analysis with over 60 kinds of typical organic pollutants; however, the possibility of other pollutants involved in the PCOS still could not be excluded. WIDER IMPLICATIONS OF THE FINDINGS: Our study identified that bodily retention of environmental organic pollutants-including PCBs, pesticides (especially p,p'-DDE) and PAHs-was associated with PCOS. STUDY FUNDING/COMPETING INTERESTS: This research was supported by the Ministry of Science and Technology of China Grants (973 program; 2014CB943203 and 2015CB553401), National Natural Science Foundation of China (21322705, 21190051, 41121004 and 81170538), National Key Technology R&D Program in the Twelve Five-Year Plan (2012BAI32B01) and the Collaborative Innovation Center for Regional Environmental Quality. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: None. This is not a clinical trial. PMID- 26040478 TI - Effect of vaginal administration of misoprostol before intrauterine contraceptive insertion following previous insertion failure: a double blind RCT. AB - STUDY QUESTION: Is pretreatment with misoprostol useful in insertion of intrauterine contraceptives (IUCs) after insertion failure at the first attempt? SUMMARY ANSWER: Pretreatment with intravaginal administration of 200 mcg of misoprostol after IUC insertion failure 10 and 4 h before the second attempt of IUC placement was significantly better than placebo at facilitating the insertion of an IUC. WHAT IS KNOWN ALREADY: One of the reasons for low use of IUCs is the concept that insertion is difficult. Misoprostol was used in several randomized clinical trials (RCT) before IUC insertion to facilitate the insertion. In general, the results showed no significant differences when compared with placebo. However, most previous studies have been carried out among unselected women whereas the present study is among women with previous insertion failure. STUDY DESIGN, SIZE, DURATION: This was a double blind RCT conducted between February 2013 and October 2014. Participants were 104 women who requested an insertion of an IUC and the insertion failed at the first attempt. After insertion failure, the women received a sealed envelope with misoprostol or placebo. The randomization system (1: 1) in one block size was computer generated. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted at a tertiary care centre. The women were instructed to insert vaginally one tablet of misoprostol 200 ug (Prostokos, Hebron, Cariacica, PE, Brazil) or placebo 10 and 4 h before the woman returned to the clinic for a new insertion attempt. The outcomes were successful IUC insertion and the use of a cervical dilator immediately prior to the insertion procedure. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 2639 women requested the insertion of an IUC during the study period. The IUC was inserted at the first attempt in 2535 women (96%) and 104 women in whom we were unable to insert the device were eligible to participate in the RCT. Four women declined and 100 women were randomized (55 for the misoprostol group and 45 for the placebo group). From the 100 participating women, the levonorgestrel-releasing intrauterine system (LNG-IUS) was chosen by 55 and 37 women and the TCu380A intrauterine device (Cu-IUD) was chosen by none and 8 women in the misoprostol and placebo group, respectively. Seven and three women allocated to misoprostol and placebo, respectively, never returned to the clinic after randomization. We placed the IUC in 42 (87.5%) out of the 48 women and in 26 (61.9%) out of the 42 women randomized to misoprostol and placebo, respectively (P = 0.0066). Regarding the Evaluable Population the relative risk (RR) of successful insertions was 1.41 (95% confidence interval (CI) for absolute difference (8.2, 43.0), P = 0.0066); in the Intent-to-Treat Population the RR (95% CI) was 1.32 (0.3, 36.9). Multiple regression analysis showed that the significant variables associated with the insertion failure were the number of Caesarean section >=1 (P = 0.020) and the use of placebo (P = 0.026). Dilators were used in 21 (43.7%) out of the 48 and 21 (50%) out of the 42 women randomized to misoprostol and placebo, respectively (P = 0.804). LIMITATIONS, REASONS FOR CAUTION: The limitations were that the majority of the women chose the LNG-IUS, and consequently the data for the Cu-IUD were limited, and there was a small number of nulligravidas. WIDER IMPLICATIONS OF THE FINDINGS: The results show that IUC insertion difficulties and failures are not common. Pretreatment with intravaginal misoprostol facilitated IUC insertion after failure of insertion at the first attempt, and insertion failure was associated with number of Caesarean sections. STUDY FUNDING/COMPETING INTERESTS: This study received partial financial support from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), grant # 2012/10085-0, and from the National Research Council (CNPq), grant #573747/2008-3. All the TCu380A IUDs were donated by Injeflex, Sao Paulo, Brazil, and all the LNG-IUS were donated by the International Contraceptive Access Foundation (ICA), Turku, Finland. Both donations were provided in the form of unrestricted grants. The authors declare that there are no conflicts of interest associated with this study. TRIAL REGISTRATION NUMBER: ClinicalTrial.gov NCT01754649. PMID- 26040479 TI - In vitro maturation is associated with increased early embryo arrest without impairing morphokinetic development of useable embryos progressing to blastocysts. AB - STUDY QUESTIONS: Does polycystic ovarian syndrome (PCOS) or in vitro maturation (IVM) treatment affect embryo development events and morphokinetic parameters after time-lapse incubation? SUMMARY ANSWER: There was an increase in some abnormal phenotypic events in PCOS-IVM embryos as well as an increase in early arrest of PCOS-IVM and PCOS-ICSI embryos; however, IVM treatment or PCOS status did not alter morphokinetic development of embryos suitable for transfer of vitrification. WHAT IS KNOWN ALREADY: IVM has been less successful than standard IVF in terms of clinical pregnancy, implantation and live birth rates. There is currently no information available about the development of IVM embryos according to time-lapse analysis. STUDY DESIGN, SIZE AND DURATION: This article represents a prospective case-control study. The study involved 93 participants who underwent 93 treatment cycles. Cycles were completed between January 2013 and July 2014. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Participants were recruited for the study at Fertility Specialists of WA and Fertility Specialists South, Perth, Western Australia. Of the PCOS diagnosed patients, 32 underwent IVM treatment (PCOS-IVM) and 23 had standard ICSI treatment (PCOS-ICSI). There were 38 patients without PCOS who underwent standard ICSI treatment comprising the control group (control-ICSI). MAIN RESULTS AND THE ROLE OF CHANCE: The PCOS-IVM group showed significantly more embryos with multinucleated two cells (P = 0.041), multinucleated four cells (P = 0.001) and uneven two cells (P = 0.033) compared with the control-ICSI group, but not the PCOS-ICSI group. There were no significant differences in the rates of any abnormal events between the PCOS-ICSI and control-ICSI groups. Embryo arrest between Days 2 and 3 was higher in the PCOS-IVM and PCOS-ICSI groups compared with the control-ICSI group (P < 0.001 and P = 0.001). Embryo arrest from Days 3 to 4 was higher in the PCOS-IVM group compared with both the PCOS-ICSI and control-ICSI groups (P < 0.001). There were no differences in embryo arrest rates across all three groups at the compaction or blastulation stages. Cumulative rates of embryo arrest, from the time to second polar body extrusion (tPB2) to the time to formation of a blastocyst (tB), result in a decreased proportion of useable PCOS-IVM blastocysts compared with the other two treatment groups; however, of the embryos remaining, there was no significant difference in morphokinetic development between the three groups. LIMITATIONS AND REASONS FOR CAUTION: This was a small study using time-lapse analysis of embryo development as the primary end-point. Larger, randomized, clinical trials are required to clarify the implications of time-lapse incubation of IVM embryos and the effects on implantation and ongoing pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to compare the time-lapse analysis of IVM with standard ICSI for patients with and without PCOS. This allows for a more detailed and specific timeline of events from embryos generated using this approach for patients diagnosed with PCOS and shows that embryos generated from IVM have an increased rate of early embryo arrest, however; morphokinetic development is not impaired in embryos that progress to the useable blastocyst stage. STUDY FUNDING/COMPETING INTERESTS: The study was supported by the Women's and Infant's Research Foundation of Western Australia. R.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. The other authors have no competing interests. PMID- 26040481 TI - 'Friendly allies in raising a child': a survey of men and women seeking elective co-parenting arrangements via an online connection website. AB - STUDY QUESTION: What are the characteristics, motivations and expectations of men and women who search for a co-parent online? SUMMARY ANSWER: Male and female prospective co-parents differed in terms of their motivations, choice of co parent and expectations of co-parenting, while differences according to sexual orientation were less marked. WHAT IS KNOWN ALREADY: Very few studies have addressed the experiences of elective co-parents, i.e. men and women who are not in a relationship with each other creating and raising a child together. No study has examined the motivations and experiences of those who seek co-parents online. STUDY DESIGN, SIZE AND DURATION: An online survey was completed by 102 participants (61 men, 41 women) who were members of Pride Angel, an online connection website that facilitates contact between people looking for someone with whom to have a child. The survey was live for 7 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Details of the survey were emailed to all members of Pride Angel. The survey obtained data on participants' demographic characteristics, motivations, choice of co-parent and expectations of co parenting. Data were analysed to examine differences by gender and by sexual orientation within each gender. MAIN RESULTS AND THE ROLE OF CHANCE: Approximately one-third of men and one half of women seeking co-parenting arrangements were heterosexual. The majority (69, 68%) of participants were single, although significantly more gay and bisexual men (15, 36%) and lesbian and bisexual women (11, 55%) had a partner compared with heterosexual men (4, 20%) and heterosexual women (2, 12%), respectively. Overall, the most important motivation for seeking co-parenting arrangements was in order for both biological parents to be involved in the child's upbringing. Co-parents were looking for someone with a good medical history. Most female co-parents expected the child to live with them, whereas male co-parents either wished the child to reside with the mother or to live equally in both households. A higher proportion of gay and bisexual men than heterosexual men wanted daily contact with the child. LIMITATIONS, REASONS FOR CAUTION: Although this study presents data from the largest sample of elective co-parents to date, the main limitations were the low response rate and that only members of one website were approached. The findings may not be representative of all potential elective co-parents. WIDER IMPLICATIONS OF THE FINDINGS: This study provides important insights into the new phenomenon of elective co-parenting. With the increasing use of assisted reproductive technologies and the diversification of family forms, a growing number of people are seeking co-parenting arrangements to have children. While up until now, elective co-parenting has been principally associated with the gay and lesbian community, this study shows that, with the rise of co-parenting websites, increasing numbers of heterosexual men and women are seeking these types of parenting arrangements. This study generates the first findings on the expectations and motivations of those who seek co-parents online and examines whether these differ according to gender and sexual orientation. Future studies are needed to assess the impact of this new form of parenting on all involved, particularly the children. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Wellcome Trust (097857/Z/11/Z). Erika Tranfield is the co founder of the website Pride Angel, the remaining authors have no conflicts of interest to declare. PMID- 26040480 TI - Differential effects of estrogen and progesterone on development of primate secondary follicles in a steroid-depleted milieu in vitro. AB - STUDY QUESTION: What are the direct effects of progesterone (P4) and estradiol (E2) on the development and function of primate follicles in vitro from the pre antral to early antral stage? SUMMARY ANSWER: In a steroid-depleted milieu, E2 improved follicle survival, growth, antrum formation and oocyte health, whereas P4 exerted minimal beneficial effects on follicle survival and reduced oocyte health. WHAT IS KNOWN ALREADY: Effects of P4 and E2 on follicle development have been studied primarily in large antral and pre-ovulatory follicles. Chronic P4 exposure suppresses antral follicle growth, but acute P4 exposure promotes oocyte maturation in pre-ovulatory follicles. Effects of E2 can be stimulatory or inhibitory depending upon species, dose and duration of exposure. STUDY DESIGN, SIZE, DURATION: Non-human primate model, randomized, control versus treatment. Macaque (n = 6) secondary follicles (n = 24 per animal per treatment group) were cultured for 5 weeks. PARTICIPANTS/MATERIALS, SETTING, METHODS: Adult rhesus macaque secondary follicles were encapsulated in 0.25% alginate and cultured individually in media containing follicle stimulating hormone plus (i) vehicle, (ii) a steroid-synthesis inhibitor, trilostane (TRL, 250 ng/ml), (iii) TRL + low E2 (100 pg/ml) or progestin (P, 10 ng/ml R5020) and (iv) TRL + high E2 (1 ng/ml E2) or P (100 ng/ml R5020). Follicles reaching the antral stage (>=750 um) were treated with human chorionic gonadotrophin for 34 h. End-points included follicle survival, antrum formation, growth pattern, plus oocyte health and maturation status, as well as media concentrations of P4, E2 and anti-Mullerian hormone (AMH). MAIN RESULTS AND THE ROLE OF CHANCE: In a steroid-depleted milieu, low dose, but not high dose, P improved (P < 0.05) follicle survival, but had no effect (P > 0.05) on antrum formation and AMH production. Low-dose P increased (P < 0.05) P4 production in fast-grow follicles, and both doses of P elevated (P < 0.05) E2 production in slow-grow follicles. Additionally, low-dose P increased (P < 0.05) the percentage of no-grow follicles, and high-dose P promoted oocyte degeneration. In contrast, E2, in a steroid-depleted milieu, improved (P < 0.05) follicle survival, growth, antrum formation and oocyte health. E2 had no effect on P4 or E2 production. Follicles exposed to E2 yielded mature oocytes capable of fertilization and early cleavage, at a rate similar to untreated control follicles. LIMITATIONS, REASONS FOR CAUTION: This study is limited to in vitro effects of P and E2 during the interval from the secondary to small antral stage of macaque follicles. WIDER IMPLICATIONS OF THE FINDINGS: This study provides novel information on the direct actions of P4 and E2 on primate pre-antral follicle development. Combined with our previous report on the actions of androgens, our findings suggest that androgens appear to be a survival factor but hinder antral follicle differentiation, E2 appears to be a survival and growth factor at the pre-antral and early antral stage, whereas P4 may not be essential during early folliculogenesis in primates. STUDY FUNDING/COMPETING INTERESTS: NIH P50 HD071836 (NCTRI), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), ONPRC 8P51OD011092. There are no conflicts of interest. PMID- 26040482 TI - Role of folate-homocysteine pathway gene polymorphisms and nutritional cofactors in Down syndrome: A triad study. AB - STUDY QUESTION: Do gene-gene and gene-environment interactions in folate homocysteine (Hcy) pathway have a predisposing role for Down syndrome (DS)? SUMMARY ANSWER: The study provides evidence that in addition to advanced age, maternal genotype, micronutrient deficiency and elevated Hcy levels, individually and in combination, are risk factors for Down syndrome. WHAT IS KNOWN ALREADY: Polymorphisms in certain folate-Hcy-pathway genes (especially the T allele of MTHFR C677T), elevated Hcy and poor folate levels in mothers during pregnancy have been shown to be risk factors for Down syndrome in certain Asian populations (including the eastern region of India), while the same SNPs are not a risk factor in European populations. This conflicting situation alludes to differential gene-environment (nutrition) interactions in different populations which needs to be explored. STUDY DESIGN, SIZE, DURATION: Between 2008 and 2012, 151 Down syndrome triads and 200 age-matched controls (Control mothers n = 186) were included in the study. Seven polymorphisms in six genes of folate-Hcy metabolic pathway, along with Hcy, cysteine (Cys), vitamin B12 (vit-B12) and folate levels, were analysed and compared among the case and control groups. PARTICIPANTS/MATERIALS, SETTING, METHODS: Genotyping was performed by the PCR RFLP technique. Levels of homocysteine and cysteine were measured by HPLC while vitamin B12 and folate were estimated by chemiluminescence. MAIN RESULTS AND THE ROLE OF CHANCE: We demonstrate that polymorphisms in the folate-Hcy pathway genes in mothers collectively constitute a genotypic risk for DS which is effectively modified by interactions among genes and by the environment affecting folate, Hcy and vitamin B12 levels. The study also supports the idea that these maternal risk factors provide an adaptive advantage during pregnancy supporting live birth of the DS child. LIMITATIONS AND REASONS FOR CAUTION: Our inability to obtain genotype and nutritional assessments of unaffected siblings of the DS children was an important limitation of the study. Also, its confinement to a specific geographic region (the eastern part) of India, and relatively small sample size is a limitation. A parallel investigation on another population could add greater authenticity to the data. WIDER IMPLICATIONS OF THE FINDINGS: For mothers genetically susceptible to deliver a DS child (particularly in South Asia), peri conceptional nutritional supplementation and antenatal care could potentially reduce the risk of a DS child. Additionally, nutritional strategies could possibly be used for better management of the symptoms of DS children. STUDY FUNDING/COMPETING INTERESTS: The work is funded through Programme support for Genetic disorders by Department of Biotechnology, Government of India to R.R. The authors declare no conflict of interest. PMID- 26040483 TI - Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU. AB - The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA reactive agents. PMID- 26040484 TI - Palliative care costs in Canada: A descriptive comparison of studies of urban and rural patients near end of life. AB - BACKGROUND: Significant gaps in the evidence base on costs in rural communities in Canada and elsewhere are reported in the literature, particularly regarding costs to families. However, it remains unclear whether the costs related to all resources used by palliative care patients in rural areas differ to those resources used in urban areas. AIM: The study aimed to compare both the costs that occurred over 6 months of participation in a palliative care program and the sharing of these costs in rural areas compared with those in urban areas. DESIGN: Data were drawn from two prior studies performed in Canada, employing a longitudinal, prospective design with repeated measures. SETTING/PARTICIPANTS: The urban sample consisted of 125 patients and 127 informal caregivers. The rural sample consisted of 80 patients and 84 informal caregivers. Most patients in both samples had advanced cancer. RESULTS: The mean total cost per patient was CAD 26,652 in urban areas, while it was CAD 31,018 in rural areas. The family assumed 20.8% and 21.9% of costs in the rural and urban areas, respectively. The rural families faced more costs related to prescription medication, out-of-pocket costs, and transportation while the urban families faced more costs related to formal home care. CONCLUSION: Despite the fact that rural and urban families assumed a similar portion of costs, the distribution of these costs was somewhat different. Future studies would be needed to gain a better understanding of the dynamics of costs incurred by families taking care of a loved one at the end of life and the determinants of these costs in urban versus rural areas. PMID- 26040485 TI - 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-GH axis: the past 60 years. AB - At the time of the publication of Geoffrey Harris's monograph on 'Neural control of the pituitary gland' 60 years ago, the pituitary was recognised to produce a growth factor, and extracts administered to children with hypopituitarism could accelerate growth. Since then our understanding of the neuroendocrinology of the GH axis has included identification of the key central components of the GH axis: GH-releasing hormone and somatostatin (SST) in the 1970s and 1980s and ghrelin in the 1990s. Characterisation of the physiological control of the axis was significantly advanced by frequent blood sampling studies in the 1980s and 1990s; the pulsatile pattern of GH secretion and the factors that influenced the frequency and amplitude of the pulses have been defined. Over the same time, spontaneously occurring and targeted mutations in the GH axis in rodents combined with the recognition of genetic causes of familial hypopituitarism demonstrated the key factors controlling pituitary development. As the understanding of the control of GH secretion advanced, developments of treatments for GH axis disorders have evolved. Administration of pituitary-derived human GH was followed by the introduction of recombinant human GH in the 1980s, and, more recently, by long-acting GH preparations. For GH excess disorders, dopamine agonists were used first followed by SST analogues, and in 2005 the GH receptor blocker pegvisomant was introduced. This review will cover the evolution of these discoveries and build a picture of our current understanding of the hypothalamo-GH axis. PMID- 26040486 TI - Treatment and outcome of malignant giant cell tumor in the spine. AB - Malignant giant cell tumor (MGCT) in the spine is extremely rare and there is little published information regarding this subject in the literature. We attempted to correlate different treatment options and outcomes over time. A retrospective study of patients with spinal MGCT who were surgically treated in our center between 2006 and 2012 was performed. Overall, three surgical management strategies, including subtotal resection, piecemeal total resection, and total en bloc spondylectomy were applied. Postoperative radiotherapy was carried out in 4 cases. Clinical data and efficacy of surgical treatment strategy were analyzed via chart review. A total of 14 patients with spinal MGCT were included in the study. Three cases were diagnosed as primary MGCT (PMGCT), while the other 11 patients were secondary MGCT (SMGCT). The mean follow-up period was 41 (range 3-75) months. Recurrence was found in 7 patients after surgery in our center, while distant metastasis and death occurred in 4 and 6 cases, respectively. MGCT of bone is always a high-grade sarcoma with a poor prognosis and complete excision, while also preserving neural function, is recommended. In our study, patients who underwent total en bloc spondylectomy had significantly lower local recurrence rate for MGCT in the spine. PMID- 26040487 TI - Hypofractionated stereotactic radiation therapy in skull base meningiomas. AB - To investigate the role of hypo-fractionated stereotactic radiation treatment (HSRT) in the management of skull base meningioma. Twenty-six patients were included in the study and treated with a dose of 30 Gy in 5 fractions with volumetric modulated arc therapy (RapidArc). Eighteen patients were symptomatic before treatment. Endpoints were local toxicity and relief from symptoms. Tumors were located in anterior skull base in 4/27 cases, in middle skull base in 12/27 and in posterior skull base in 11/27. HSRT was performed as first treatment in 17 (65 %) patients, in 9 (35 %) patients it followed a previous partial resection. Median follow up was 24.5 months (range 5-57 months). clinical remission of symptoms, complete or partial, was obtained in the vast majority of patients after treatment. Out of the 18 symptomatic patients, partial remission occurred in 9 (50 %) patients and complete remission in 9 (50 %). All asymptomatic patients retained their status after treatment. No severe neurologic toxicity grade III-IV was recorded. No increase of meningioma in the same site of treatment occurred; 16 (62 %) patients had stable disease and 9 (38 %) patients had tumor reduction. The mean tumor volume after treatment was 10.8 +/- 17.8 cm(3) compared with 13.0 +/- 19.1 cm(3) before treatment (p = 0.02). The mean actuarial OS was 54.4 +/- 2.8 months. The 1- and 2-years OS was 92.9 +/- 0.7 %. HSRT proved to be feasible for these patients not eligible to full surgery or to ablative radiation therapy. Local control and durability of results suggest for a routine application of this approach in properly selected cases. PMID- 26040488 TI - Agents with vasodilator properties in acute heart failure: how to design successful trials. AB - Agents with vasodilator properties (AVDs) are frequently used in the treatment of acute heart failure (AHF). AVDs rapidly reduce preload and afterload, improve left ventricle to aorta and right ventricle to pulmonary artery coupling, and may improve symptoms. Early biomarker changes after AVD administration have suggested potentially beneficial effects on cardiac stretch, vascular tone, and renal function. AVDs that reduce haemodynamic congestion without causing hypoperfusion might be effective in preventing worsening organ dysfunction. Existing AVDs have been associated with different results on outcomes in randomized clinical trials, and observational studies have suggested that AVDs may be associated with a clinical outcome benefit. Lessons have been learned from past AVD trials in AHF regarding preventing hypotension, selecting the optimal endpoint, refining dyspnoea measurements, and achieving early randomization and treatment initiation. These lessons have been applied to the design of ongoing pivotal clinical trials, which aim to ascertain if AVDs improve clinical outcomes. The developing body of evidence suggests that AVDs may be a clinically effective therapy to reduce symptoms, but more importantly to prevent end-organ damage and improve clinical outcomes for specific patients with AHF. The results of ongoing trials will provide more clarity on the role of AVDs in the treatment of AHF. PMID- 26040489 TI - UNCLES: method for the identification of genes differentially consistently co expressed in a specific subset of datasets. AB - BACKGROUND: Collective analysis of the increasingly emerging gene expression datasets are required. The recently proposed binarisation of consensus partition matrices (Bi-CoPaM) method can combine clustering results from multiple datasets to identify the subsets of genes which are consistently co-expressed in all of the provided datasets in a tuneable manner. However, results validation and parameter setting are issues that complicate the design of such methods. Moreover, although it is a common practice to test methods by application to synthetic datasets, the mathematical models used to synthesise such datasets are usually based on approximations which may not always be sufficiently representative of real datasets. RESULTS: Here, we propose an unsupervised method for the unification of clustering results from multiple datasets using external specifications (UNCLES). This method has the ability to identify the subsets of genes consistently co-expressed in a subset of datasets while being poorly co expressed in another subset of datasets, and to identify the subsets of genes consistently co-expressed in all given datasets. We also propose the M-N scatter plots validation technique and adopt it to set the parameters of UNCLES, such as the number of clusters, automatically. Additionally, we propose an approach for the synthesis of gene expression datasets using real data profiles in a way which combines the ground-truth-knowledge of synthetic data and the realistic expression values of real data, and therefore overcomes the problem of faithfulness of synthetic expression data modelling. By application to those datasets, we validate UNCLES while comparing it with other conventional clustering methods, and of particular relevance, biclustering methods. We further validate UNCLES by application to a set of 14 real genome-wide yeast datasets as it produces focused clusters that conform well to known biological facts. Furthermore, in-silico-based hypotheses regarding the function of a few previously unknown genes in those focused clusters are drawn. CONCLUSIONS: The UNCLES method, the M-N scatter plots technique, and the expression data synthesis approach will have wide application for the comprehensive analysis of genomic and other sources of multiple complex biological datasets. Moreover, the derived in silico-based biological hypotheses represent subjects for future functional studies. PMID- 26040490 TI - Transoral robotic retropharyngeal node dissection. AB - BACKGROUND: Surgical access to metastases in the retropharyngeal lymph nodes (RPLNs) could be difficult. Transoral robotic surgery (TORS) can be utilized to access RPLNs. The purpose of this study was to describe a TORS approach to RPLN dissection. METHODS: A case series of patients undergoing RPLN dissection by TORS was conducted and compared to matched controls (1:2). RESULTS: Twelve patients underwent robotic RPLN dissection. Median age was 63 years (range, 43-73 years). Pathology was oropharyngeal squamous cell carcinoma (SCC) in 9 patients and papillary thyroid cancer (PTC) in 3 patients. The feeding tube dependence duration was 12 days (range, 1-46 days) on average. Complications occurred in 8 patients (66%); most commonly, aspiration pneumonitis in 6 patients. In comparison to the matched controls (24), there was no difference in length of stay or feeding tube dependence. Complications were higher in patients with oropharyngeal SCC. CONCLUSION: TORS is feasible for accessing RPLNs. The procedure is well tolerated in patients with PTC; whereas patients with oropharyngeal SCC are at increased risk of complications. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E981-E986, 2016. PMID- 26040491 TI - Postoperative analgesia after low-frequency electroacupuncture as adjunctive treatment in inguinal hernia surgery with abdominal wall mesh reconstruction. AB - OBJECTIVE: To determine whether an electroacupuncture (EA) technique that was developed for a surgical population under general anaesthesia reduces pain after mesh inguinal hernia open repair. METHODS: A total of 54 patients with right or left inguinal hernia were randomised to group I (preoperative, intraoperative, postoperative EA), group II (preoperative, postoperative EA), or a sham control group (group III; preoperative and postoperative placement of needles, but without skin penetration). The Visual Analogue Scale (VAS) (primary outcome) and the State-Trait Anxiety Spielberger Inventory were evaluated preoperatively and at 30 min, 90 min, 10 h and 24 h after surgery. Pain threshold and tolerance were evaluated using an algometer at these same time points and preoperatively before and after EA. Levels of the stress hormones cortisol, corticotrophin and prolactin were determined at 30 min, 90 min and 10 h after surgery and preoperatively before and after EA. RESULTS: The results showed significant differences between the true EA and control groups. The true EA groups (I and II) showed statistically significantly greater improvements in the primary (VAS pain, p<0.05) and secondary outcome measures (Anxiety scale; algometer measurements, p<0.05 and stress hormones, p<0.01) compared to the control group. There were no statistically significant differences between groups I and II. CONCLUSIONS: Electroacupuncture reduces postoperative pain after mesh inguinal hernia repair and decreases stress hormone levels and anxiety during the postoperative period. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT01722253. PMID- 26040492 TI - Effects of electroacupuncture on overactive bladder refractory to anticholinergics: a single-blind randomised controlled trial. AB - OBJECTIVE: To investigate the clinical effects and safety of electroacupuncture (EA) in the treatment of overactive bladder (OAB) refractory to first-line anticholinergic treatment. METHODS: Women diagnosed with OAB who were refractory to first-line anticholinergic treatment were referred for EA therapy. 50 women enrolled in this single-blind randomised controlled trial and were randomised 1:1 to EA or sham EA (SEA). The EA and SEA groups were treated with 30 sessions (5 sessions a week for 6 weeks), and each session lasted 30 min. OAB symptom scores (OABSS), King's Health Questionnaire scores (KHQ) and urodynamic parameters were used to assess treatment effects. Safety was also evaluated. RESULTS: 45 women completed all aspects of the study (23 in the EA group and 22 in the SEA group). The OABSS and KHQ showed statistically significant improvements in the EA group compared with the SEA group after 6 weeks of treatment (p<0.05). There were no statistical differences in the maximum flow rate and postvoid residual (p>0.05), but there were statistical improvements in the first sensation of bladder filling, first urge to void and maximum cystometric capacity (p<0.05) in the EA group compared with the SEA group. No serious adverse events occurred in either group. CONCLUSIONS: EA appears to be an effective, safe and minimally invasive treatment for women with OAB. Further studies with longer follow-up are needed to evaluate whether it could be a therapeutic option for OAB refractory to treatment with anticholinergics. PMID- 26040493 TI - Single base substitution in OsCDC48 is responsible for premature senescence and death phenotype in rice. AB - A premature senescence and death 128 (psd128) mutant was isolated from an ethyl methane sulfonate-induced rice IR64 mutant bank. The premature senescence phenotype appeared at the six-leaf stage and the plant died at the early heading stage. psd128 exhibited impaired chloroplast development with significantly reduced photosynthetic ability, chlorophyll and carotenoid contents, root vigor, soluble protein content and increased malonaldehyde content. Furthermore, the expression of senescence-related genes was significantly altered in psd128. The mutant trait was controlled by a single recessive nuclear gene. Using map-based strategy, the mutation Oryza sativa cell division cycle 48 (OsCDC48) was isolated and predicted to encode a putative AAA-type ATPase with 809 amino-acid residuals. A single base substitution at position C2347T in psd128 resulted in a premature stop codon. Functional complementation could rescue the mutant phenotype. In addition, RNA interference resulted in the premature senescence and death phenotype. OsCDC48 was expressed constitutively in the root, stem, leaf and panicle. Subcellular analysis indicated that OsCDC48:YFP fusion proteins were located both in the cytoplasm and nucleus. OsCDC48 was highly conserved with more than 90% identity in the protein levels among plant species. Our results indicated that the impaired function of OsCDC48 was responsible for the premature senescence and death phenotype. PMID- 26040494 TI - 15-Lipoxygenases regulate the production of chemokines in human lung macrophages. AB - BACKGROUND AND PURPOSE: 15-Lipoxygenase (15-LOX) activity is associated with inflammation and immune regulation. The objectives of the present study were to investigate the expression of 15-LOX-1 and 15-LOX-2 and evaluate the enzymes' roles in the polarization of human lung macrophages (LMs) in response to LPS and Th2 cytokines (IL-4/-13). EXPERIMENTAL APPROACH: LMs were isolated from patients undergoing surgery for carcinoma. The cells were cultured with a 15-LOX inhibitor (PD146176 or ML351), a COX inhibitor (indomethacin), a 5-LOX inhibitor (MK886) or vehicle and then stimulated with LPS (10 ng . mL(-1)), IL-4 (10 ng . mL(-1)) or IL-13 (50 ng . mL(-1)) for 24 h. Levels of ALOX15 (15-LOX-1) and ALOX15B (15-LOX 2) transcripts were determined by real-time quantitative PCR. Immunoassays were used to measure levels of LPS-induced cytokines (TNF-alpha, CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL10) and Th2 cytokine-induced chemokines (CCL13, CCL18 and CCL22) in the culture supernatant. KEY RESULTS: Stimulation of LMs with LPS was associated with increased expression of ALOX15B, whereas stimulation with IL-4/IL 13 induced the expression of ALOX15. PD146176 and ML351 (10 MUM) reduced the release of the chemokines induced by LPS and Th2 cytokines. The effects of these 15-LOX inhibitors were maintained in the presence of indomethacin and MK886. Furthermore, indomethacin revealed the inhibitory effect of PD146176 on TNF-alpha release. CONCLUSIONS AND IMPLICATIONS: Inhibition of the 15-LOX pathways is involved in the down-regulation of the in vitro production of chemokines in LMs. Our results suggest that the 15-LOX pathways have a role in the pathogenesis of inflammatory lung disorders and may thus constitute a potential drug target. PMID- 26040497 TI - [Not Available]. PMID- 26040495 TI - Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. AB - Long-term efficacy and safety of bosutinib (>=4 years follow-up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated-phase [AP, n = 79] chronic myeloid leukemia [CML], blast-phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1-88.6), 2.8 (0.03-55.9), 0.97 (0.3-89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan-Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib-related [AP] per investigator). Responses were durable in ~50% AP responders at 4 years (~25% BP patients responded at year 1, suggesting possible bridge-to-transplant role in BP patients); toxicity was manageable. PMID- 26040496 TI - Recent progress in understanding the molecular mechanisms of radioresistance in Deinococcus bacteria. AB - The deleterious effects of ionizing radiation are a major concern of the modern world. In the last decades, outstanding interest has been given to developing new therapeutic tools designed for protection against the toxic effects of ionizing radiation. Deinococcus spp. are among the most radioresistant organisms on Earth, being able to survive extreme doses of radiation, 1000-fold higher than most vertebrates. The molecular mechanisms underlying DNA repair and biomolecular protection, which are responsible for the remarkable radioresistance of Deinococcus bacteria, have been a debatable subject for the last 60 years. This paper is focused on the most recent findings regarding the molecular background of radioresistance and on Deinococcus bacteria response to oxidative stress. Novel proteins and genes involved in the highly regulated DNA repair processes, and enzymatic and non- enzymatic antioxidant systems are presented. In addition, a recently proposed mechanism that may contribute to oxidative damage protection in Deinococcus bacteria is discussed. A better understanding of these molecular mechanisms may draw future perspectives for counteracting radiation-related toxicity. PMID- 26040498 TI - Lipiodol injections for optimization of target volume delineation in a patient with a second tumor of the oropharynx: A case report. AB - BACKGROUND: Lipiodol injections were administered in the head and neck area to improve gross tumor volume (GTV) definition for small-volume re-irradiation of a 63-year-old previously irradiated patient with a second tumor of the oropharynx in the posterior wall with longitudinal ligament infiltration (cT4cN0cM0). METHODS: The patient had dialysis-depending renal failure. On diagnostic computed tomography (CT), which was performed with intravenous contrast agent, the tumor in the oropharynx was not detectable. Because of dialysis-depending renal failure comorbidity, no contrast agent was applied in the planning CT and in the diagnostic magnetic resonance imaging (MRI) study. In each cross-sectional imaging study performed, the GTV, especially in craniocaudal extensions, was not safely delineable. Therefore, craniocaudal tumor margins were pharyngoscopically marked with Lipiodol injections, an iodine-containing contrast agent. RESULTS: In a second planning CT, the GTV could be defined with the help of the Lipiodol marks and small-volume re-irradiation was performed. No Lipiodol-associated side effects occurred in the patient. CONCLUSION: In the present case, the use of Lipiodol injections at the tumor margins facilitated the definition of the GTV. PMID- 26040500 TI - Denosumab and fracture risk in women with breast cancer. PMID- 26040502 TI - Metal nano-film resistivity chemical sensor. AB - In this work, we present a study on reusable thin metal film resistivity-based sensor for direct measurement of binding of thiol containing molecules in liquid samples. While in bulk conductors the DC current is not influenced by the surface events to a measureable degree in a thin metal layer the electrons close to the surface conduct a significant part of electricity and are influenced by the surface interactions. In this study, the thickness of the gold layer was kept below 100 nm resulting in easily measureable resistivity changes of the metal element upon a surface SH-groups binding. No further surface modifications were necessary. Thin film gold layers deposited on a glass substrate by vacuum sputtering were photolithographically structured into four sensing elements arranged in a Wheatstone bridge to compensate for resistance fluctuations due to the temperature changes. Concentrations as low 100 pM provided measureable signals. The surface after the measurement could be electrolytically regenerated for next measurements. PMID- 26040501 TI - Apigenin, a Natural Flavonoid, Attenuates EAE Severity Through the Modulation of Dendritic Cell and Other Immune Cell Functions. AB - Apigenin, a natural flavonoid, found in several plants, fruits, vegetables, herbs, and spices, is known to have anti-oxidant and anti-inflammatory properties that are evident in the use of these substances for centuries as medicinal approaches to treat asthma, insomnia, Parkinson's disease, neuralgia, and shingles. However, there is a considerable dearth of information regarding its effect on immune cells, especially dendritic cells (DC) that maintain the critical balance between an immunogenic and tolerogenic immune response, in an immunospecialized location like the central nervous system (CNS). In this paper we looked at the anti-inflammatory properties of Apigenin in restoration of immune function and the resultant decrease in neuroinflammation. In vivo, a significant reduction in severity of experimental autoimmune encephalomyelitis (EAE) progression and relapse was observed in C57BL/6 (progressive) and SJL/J (relapse-remitting) mouse models of multiple sclerosis upon treatment with Apigenin. Apigenin treated EAE mice show decreased expression of alpha4 integrin and CLEC12A on splenic DCs and an increased retention of immune cells in the periphery compared to untreated EAE mice. This correlated consequently with immunohistochemistry findings of decreased immune cell infiltration and reduced demyelination in the CNS. These results indicate a protective role of Apigenin against the neurodegenerative effects resulting from the entry of DC stimulated pathogenic T cells into the CNS thus implicating a potential therapy for neuroinflammatory disease. PMID- 26040503 TI - Impulsivity and Aggression in Female BPD and ADHD Patients: Association with ACC Glutamate and GABA Concentrations. AB - Borderline personality disorder (BPD) and attention-deficit-hyperactivity disorder (ADHD) are both characterized by high impulsivity and difficulties in controlling anger and aggression. In BPD, comorbid ADHD may further increase impulsivity. For both disorders, altered MR spectroscopy levels of the neurotransmitters glutamate and GABA as well as some correlations with impulsivity were previously reported. The objective of this study was to investigate the neurotransmitters glutamate and GABA in relation to impulsivity and aggression as expressed in the anterior cingulate cortex (ACC) in groups of female patients with BPD and ADHD, respectively. Associations of glutamate and GABA levels with further BPD (symptom severity) and ADHD aspects (hyperactivity and inattention) were exploratively evaluated. 1H MR spectra were acquired at 3T to determine glutamate to total creatine ratios (Glu/tCr) and GABA levels from the ACC in a BPD group (n=26), an ADHD group (n=22), and a healthy control (HC) group (n=30); all participants were females. Both patient groups showed higher scores on self-reported impulsivity, anger, and aggression compared with HCs. ACC GABA levels were significantly lower in ADHD than HC. Although measures of impulsivity were positively related to glutamate and negatively to GABA, for aggression only a negative correlation with GABA could be demonstrated. These data provide human in vivo evidence for the role of ACC Glu/tCr and GABA in impulsivity and aggression. If distinct associations of Glu/tCr and GABA for BPD and ADHD can be confirmed in future studies, this might yield implications for more specific pharmacological treatments. PMID- 26040504 TI - Prognostic impact of residual normal metaphases in acute myeloid leukemia with t(8;21)(q22;q22). AB - Karyotyping makes it possible to stratify outcomes in acute myeloid leukemia (AML) patients. Previous studies have suggested that the presence of cells with normal metaphases negatively affects prognosis in patients with core-binding factor AML, especially in patients with inv(16), whereas no difference was noted for patients with t(8;21)(q22;q22). In the present study, we determined the influence of residual normal metaphases in 106 patients with AML patients with t(8;21)(q22;q22). The presence and total number of normal and abnormal metaphases were tallied for patients with AML patients with t(8;21)(q22;q22). There was no significant impact on complete remission rate between patients with one or more normal metaphases versus those with no normal metaphases (88.4 vs. 83.8 %, P = 0.503), whereas patients with one or more normal metaphases were noted to have a significantly worse 3-year overall survival than patients without normal metaphases (32 vs. 55 %, P = 0.017). Overall, these results suggest that the presence of cells with normal metaphases negatively affected the prognosis in AML patients with t(8;21). PMID- 26040505 TI - Platelet-rich plasma and its derivatives as promising bioactive materials for regenerative medicine: basic principles and concepts underlying recent advances. AB - Over the past decade, platelet-rich plasma (PRP), a platelet-concentrated plasma fraction, has been widely investigated and applied to regenerative medicine. The clinical utility of PRP is supported by evidence that PRP contains high concentrations of platelet-related growth factors and normal concentrations of plasma-derived fibrinogen, both of which contribute synergistically to the regenerative process. Additionally, its superior cost-efficacy versus conventional therapies is attractive to many clinicians. However, current disadvantages of PRP include a relatively complicated preparation procedure and variable operator-dependent efficacy. An additional disadvantage is the use of bovine thrombin, an animal-derived biological, as a coagulant. Many of these disadvantages are overcome by recent advances in preparation procedures and devices; for example, Joseph Choukroun simplified the platelet-rich fibrin preparation procedure and improved handling efficiency without the aid of animal derived factors. With advancements in cell processing technology, there has been a general shift in cell therapy from autologous to allogeneic treatment; however, autologous PRP therapy will not easily be replaced by allogeneic treatment in the near future. Therefore, to provide more predictable regenerative therapy outcomes using autologous PRP, further investigations should address developing a standardized procedure for PRP preparation to augment its efficacy and potency, independent of donor variability. We would then propose that operators and clinicians prepare PRP according to the standardized protocol and to carefully evaluate the clinical scenario (i.e., recipient factors comprising skeletal defects) to determine which factor(s) should be added to PRP preparations. This careful approach will lead to improved clinical outcomes for patients. PMID- 26040506 TI - Mechanical tissue resuscitation (MTR): a nonpharmacological approach to treatment of acute myocardial infarction. AB - BACKGROUND AND AIM: Myocardial ischemia-reperfusion injury is known to trigger an inflammatory response involving edema, apoptosis, and neutrophil activation/accumulation. Recently, mechanical tissue resuscitation (MTR) was described as a potent cardioprotective strategy for reduction of myocardial ischemia-reperfusion injury. Here, we further describe the protective actions of MTR and begin to define its therapeutic window. METHODS: A left ventricular, free wall ischemic area was created in anesthetized swine for 85 minutes and then reperfused for three hours. Animals were randomized to two groups: (1) untreated controls (Control) and (2) application of MTR that was delayed 90 minutes after the initiation of reperfusion (D90). Hemodynamics and regional myocardial blood flow were assessed at multiple time points. Infarct size and neutrophil accumulation were assessed following the reperfusion period. In separate cohorts, the effect of MTR on myocardial interstitial water (MRI imaging) and blood flow was examined. RESULTS: Both groups had similar areas at risk (AAR), hemodynamics, and arterial blood gas values. MTR, even when delayed 90 minutes into reperfusion (D90, 29.2 +/- 5.0% of AAR), reduced infarct size significantly compared to Controls (51.9 +/- 2.7%, p = 0.006). This protection was associated with a 33% decrease in neutrophil accumulation (p = 0.047). Improvements in blood flow and interstitial water were also observed. Moreover, we demonstrated that the therapeutic window for MTR lasts for at least 90 minutes following reperfusion. CONCLUSIONS: This study confirms our previous observations that MTR is an effective therapeutic approach to reducing reperfusion injury with a clinically useful treatment window. PMID- 26040507 TI - Adsorption of choline benzoate ionic liquid on graphene, silicene, germanene and boron-nitride nanosheets: a DFT perspective. AB - The adsorption of choline benzoate ([CH][BE]) ionic liquid (IL) on the surface of different hexagonal nanosheets has been studied using Density Functional Theory (DFT) methods. For this, the interaction mechanism, binding energies and electronic structure of [CH][BE] ionic liquid on four types of nanosheets, i.e., graphene, silicene, germanene and boron-nitride, were estimated and compared. The adsorption of [CH][BE] ionic liquid on different nanosheets is mainly featured by van der Waals forces, leading to strong benzoate ion-surface pi-stacking. Likewise, there is also an important charge transfer from the anion to the sheet. The electronic structure analysis shows that Si- and Ge-based sheets lead to the largest changes in the HOMO and LUMO levels of choline benzoate. This paper provides new insights into the capability of DFT methods to provide useful information about the adsorption of ionic liquids on nanosheets and how ionic liquid features could be tuned through the adsorption on the suitable nanosheet. PMID- 26040508 TI - Optimized protocols for cardiac magnetic resonance imaging in patients with thoracic metallic implants. AB - BACKGROUND: Cardiac magnetic resonance (MR) imaging is a valuable tool in congenital heart disease; however patients frequently have metal devices in the chest from the treatment of their disease that complicate imaging. Methods are needed to improve imaging around metal implants near the heart. Basic sequence parameter manipulations have the potential to minimize artifact while limiting effects on image resolution and quality. OBJECTIVE: Our objective was to design cine and static cardiac imaging sequences to minimize metal artifact while maintaining image quality. MATERIALS AND METHODS: Using systematic variation of standard imaging parameters on a fluid-filled phantom containing commonly used metal cardiac devices, we developed optimized sequences for steady-state free precession (SSFP), gradient recalled echo (GRE) cine imaging, and turbo spin-echo (TSE) black-blood imaging. We imaged 17 consecutive patients undergoing routine cardiac MR with 25 metal implants of various origins using both standard and optimized imaging protocols for a given slice position. We rated images for quality and metal artifact size by measuring metal artifact in two orthogonal planes within the image. RESULTS: All metal artifacts were reduced with optimized imaging. The average metal artifact reduction for the optimized SSFP cine was 1.5+/-1.8 mm, and for the optimized GRE cine the reduction was 4.6+/-4.5 mm (P < 0.05). Quality ratings favored the optimized GRE cine. Similarly, the average metal artifact reduction for the optimized TSE images was 1.6+/-1.7 mm (P < 0.05), and quality ratings favored the optimized TSE imaging. CONCLUSION: Imaging sequences tailored to minimize metal artifact are easily created by modifying basic sequence parameters, and images are superior to standard imaging sequences in both quality and artifact size. Specifically, for optimized cine imaging a GRE sequence should be used with settings that favor short echo time, i.e. flow compensation off, weak asymmetrical echo and a relatively high receiver bandwidth. For static black-blood imaging, a TSE sequence should be used with fat saturation turned off and high receiver bandwidth. PMID- 26040510 TI - Base of tongue squamous cell carcinoma with infiltrative bone marrow carcinomatosis after definitive chemoradiation: A case report. AB - BACKGROUND: Oropharyngeal squamous cell carcinoma (SCC) is known for its propensity for aggressive local progression and regional lymphatic spread. Distant metastases are relatively uncommon and the likelihood of hematogenous dissemination is primarily related to the extent and location of cervical lymph node metastases. Common sites of distant metastasis include the liver and lung. METHODS: We report an unusual case of base of tongue SCC with infiltrative bone marrow carcinomatosis presenting months after definitive chemoradiation despite locoregional control. RESULTS: Our patient exhibited an unusual pattern of distant dissemination after definitive chemoradiation had resulted in locoregional control. CONCLUSION: Patients who present with bone marrow failure after definitive treatment with apparent disease control should be monitored for bone marrow infiltration by the tumor and, if such infiltration is present, should be evaluated for palliative chemotherapy. Unfortunately, the prognosis for such patients is poor. (c) 2016 Wiley Periodicals, Inc. Head Neck 38: E2449 E2453, 2016. PMID- 26040509 TI - Clinical performance of a free-breathing spatiotemporally accelerated 3-D time resolved contrast-enhanced pediatric abdominal MR angiography. AB - BACKGROUND: Pediatric contrast-enhanced MR angiography is often limited by respiration, other patient motion and compromised spatiotemporal resolution. OBJECTIVE: To determine the reliability of a free-breathing spatiotemporally accelerated 3-D time-resolved contrast-enhanced MR angiography method for depicting abdominal arterial anatomy in young children. MATERIALS AND METHODS: With IRB approval and informed consent, we retrospectively identified 27 consecutive children (16 males and 11 females; mean age: 3.8 years, range: 14 days to 8.4 years) referred for contrast-enhanced MR angiography at our institution, who had undergone free-breathing spatiotemporally accelerated time resolved contrast-enhanced MR angiography studies. A radio-frequency-spoiled gradient echo sequence with Cartesian variable density k-space sampling and radial view ordering, intrinsic motion navigation and intermittent fat suppression was developed. Images were reconstructed with soft-gated parallel imaging locally low-rank method to achieve both motion correction and high spatiotemporal resolution. Quality of delineation of 13 abdominal arteries in the reconstructed images was assessed independently by two radiologists on a five point scale. Ninety-five percent confidence intervals of the proportion of diagnostically adequate cases were calculated. Interobserver agreements were also analyzed. RESULTS: Eleven out of 13 arteries achieved acceptable image quality (mean score range: 3.9-5.0) for both readers. Fair to substantial interobserver agreement was reached on nine arteries. CONCLUSION: Free-breathing spatiotemporally accelerated 3-D time-resolved contrast-enhanced MR angiography frequently yields diagnostic image quality for most abdominal arteries in young children. PMID- 26040513 TI - Reflecting on 'European policymaking on the tobacco advertising ban: the importance of escape routes'. PMID- 26040511 TI - Mutual enhancement between high-mobility group box-1 and NADPH oxidase-derived reactive oxygen species mediates diabetes-induced upregulation of retinal apoptotic markers. AB - The expression of the proinflammatory cytokine high-mobility group box-1 (HMGB1) is upregulated in epiretinal membranes and vitreous fluid from patients with proliferative diabetic retinopathy (PDR) and in the diabetic retina. We hypothesized that a novel mechanism exists where HMGB1 and NADPH oxidase (Nox) derived reactive oxygen species (ROS) are mutually enhanced in the diabetic retina, which may be a novel mechanism for promoting upregulation of retinal apoptotic markers induced by diabetes. Vitreous samples from 48 PDR and 34 nondiabetic patients, retinas from 1-month diabetic rats and from normal rats intravitreally injected with HMGB1 and human retinal microvascular endothelial cells (HRMEC) stimulated with HMGB1 were studied by enzyme-linked immunosorbent and spectrophotometric assays, Western blot analysis, RT-PCR, and immunofluorescence. We also studied the effect of the HMGB1 inhibitor glycyrrhizin and apocynin on diabetes-induced biochemical changes in the retinas of rats (n = 5-7 in each groups). HMGB1 and the oxidative stress marker protein carbonyl content levels in the vitreous fluid from PDR patients were significantly higher than in controls (p = 0.021; p = 0.005, respectively). There was a significant positive correlation between vitreous fluid levels of HMGB1 and the levels of protein carbonyl content (r = 0.62, p = 0.001). HMGB1 enhanced interleukin-1beta, ROS, Nox2, poly (ADP-ribose) polymerase (PARP)-1, and cleaved caspase-3 production by HRMEC. Diabetes and intravitreal injection of HMGB1 in normal rats induced significant upregulation of ROS, Nox2, PARP-1, and cleaved caspase-3 in the retina. Constant glycyrrhizin and apocynin intake from onset of diabetes did not affect the metabolic status of the diabetic rats, but restored these increased mediators to control values. The results of this study suggest that there is a mutual enhancement between HMGB1 and Nox-derived ROS in the diabetic retina, which may promote diabetes-induced upregulation of retinal apoptotic markers. PMID- 26040512 TI - Long-term tolerability of capnography and respiratory inductance plethysmography for respiratory monitoring in pediatric patients treated with patient-controlled analgesia. AB - BACKGROUND: The Anesthesia Patient Safety Foundation has advocated the use of continuous electronic monitoring of oxygenation and ventilation to preemptively identify opioid-induced respiratory depression. In adults, capnography is the gold standard in respiratory monitoring. An alternative technique used in sleep laboratories is respiratory inductance plethysmography (RIP). However, it is not known if either monitor is well tolerated by pediatric patients for prolonged periods of time. AIM: The goal of this study was to determine whether capnography or RIP is better tolerated in nonintubated, spontaneously breathing pediatric patients being treated with intravenous patient-controlled analgesia (IVPCA). METHODS: Nasal cannula capnography with oral sampling and thoracic and abdominal inductance plethysmography bands were placed along with the routine monitors on pediatric patients being treated for acute pain with IVPCA. Study monitors were left in place for as long as they were tolerated by the patient, up to a maximum of 24 consecutive hours. If the patient did not wear a particular study monitor for any reason, but tolerated the remaining monitor, participation in the study continued. If the patient would not wear either monitor, participation was terminated. RESULTS: Twenty-six patients (18 female, eight male, average age 10.1 +/- 5.5 years) consented to participate, but only 14 patients attempted to wear one or both the devices. Among those who wore either device, median time to device removal was 8.33 h (range 0.3-23.6 h) for capnography and 23.5 h (range 0.7-24 h) for RIP bands. CONCLUSION: Children did not tolerate wearing capnography cannulae for prolonged periods of time, limiting the usefulness of this device as a continuous monitor of ventilation in children. RIP bands were better tolerated; however, they require further assessment of their utility. Until more effective, child-friendly monitors are developed and their utility is validated, guidelines recommended for adult patients cannot be extended to children. PMID- 26040514 TI - The benefit of a geriatric nurse practitioner in a multidisciplinary diagnostic service for people with cognitive disorders. AB - BACKGROUND: The aim of the study was to evaluate whether adding a geriatric nurse practitioner (GNP) to an outpatient diagnostic multidisciplinary facility for patients with cognitive disorders (Diagnostic Observation Center for PsychoGeriatry, DOC-PG) could improve quality of care. DOC-PG combines hospital diagnostics and care assessment from a community mental health team and provides the general practitioner (GP) with advice for treatment and management. In a previous study, we found that 28.7% of the advice made by this service was not followed up on by the GP. METHODS: Two cohorts were studied: a group of patients with added GNP (n = 114) and a historical reference sample (n = 137). Both groups followed the same diagnostic protocol and care approach, but, in the GNP group, a care coordinator was added in order to communicate the advice from the DOC-PG to the GP. The primary outcome was the concordance rate of GPs regarding the advice. At the patient level, health-related quality of life (HRQoL) was assessed. Self Rated Burden and care-related quality of life were measured at the informal caregiver level. Measures were conducted immediately after DOC-PG diagnosis and after 6 and 12 months. Univariate analyses, logistic regression analyses, and mixed model multilevel analyses were used to test differences between both groups. RESULTS: Total concordance rates were significantly higher in the GNP group compared to the reference sample (82.1 and 71.3%, respectively; p < 0.001). No improvement in patient HRQoL was identified. Among the informal caregivers, a significant reduction of Self-Rated Burden was found in the GNP group at 12 months (adjusted mean difference -1.724, 95% CI -2.582 to -0.866; p < 0.001). CONCLUSIONS: Adding a GNP to an outpatient diagnostic multidisciplinary facility for patients with cognitive disorders may improve the GP concordance rate of the advice from the DOC-PG and reduce subjective burden of the informal caregiver. PMID- 26040515 TI - Microinvasion of liver metastases from colorectal cancer: predictive factors and application for determining clinical target volume. AB - OBJECTIVES: This study evaluates the microscopic characteristics of liver metastases from colorectal cancer (LMCRC) invasion and provides a reference for expansion from gross tumor volume (GTV) to clinical targeting volume (CTV). METHODS: Data from 129 LMCRC patients treated by surgical resection at our hospital between January 2008 and September 2009 were collected for study. Tissue sections used for pathology and clinical data were reviewed. Patient information used for the study included gender, age, original tumor site, number of tumors, tumor size, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199), synchronous or metachronous liver metastases, and whether patients received chemotherapy. The distance of liver microinvasion from the tumor boundary was measured microscopically by two senior pathologists. RESULTS: Of 129 patients evaluated, 81 (62.8 %) presented microinvasion distances from the tumor boundary ranging between 1.0 - 7.0 mm. A GTV-to-CTV expansion of 5, 6.7, or 7.0 mm was required to provide a 95, 99, or 100 % probability, respectively, of obtaining clear resection margins by microscopic observation. The extent of invasion was not related to gender, age, synchronous or metachronous liver metastases, tumor size, CA199 level, or chemotherapy. The extent of invasion was related to original tumor site, CEA level, and number of tumors. A scoring system was established based on the latter three positive predictors. Using this system, an invasion distance less than 3 mm was measured in 93.4 % of patients with a score of <=1 point, but in only 85.7 % of patients with a score of <=2 points. CONCLUSIONS: The extent of tumor invasion in our LMCRC patient cohort correlated with original tumor site, CEA level, and number of tumors. These positive predictors may potentially be used as a scoring system for determining GTV-to-CTV expansion. PMID- 26040516 TI - Prevalence and risk factors of posttraumatic stress disorder among survivors five years after the "Wenchuan" earthquake in China. AB - OBJECTIVE: The aim of this study was to investigate the prevalence of posttraumatic stress disorder (PTSD) and its risk factors among survivors in a heavily-hit area five years after the Wenchuan earthquake in 2008, China. METHODS: 684 survivors from Beichuan county, the center of the Wenchuan Earthquake in 2008, were evaluated using the PTSD Checklist-Civilian Version (PCL C) questionnaire in 2013. RESULTS: The prevalence of PTSD among survivors was 9.2% in 2013. Significant risk factors of PTSD included gender (females 12.1%, males 5.2%), age (18-35 y 0.8%, 36-59 y 9.7%, >=60 y 12.9%), occupation (farmers 12.2%, non-farmers 1.6%), education (less than high school 11.0%; > = high school 0.8%) and family member loss (yes: 12.4%, no: 7.3%). Multivariate logistic regression showed that females, older people, farmers and those with family member loss were significantly more likely to develop PTSD. CONCLUSIONS: Posttraumatic stress symptoms remained relatively common among survivors five years after the "5.12" Earthquake in Beichuan county, China. It is important to provide psychological aid and social support for survivors to decease health burden from PTSD, especially for females, farmers, old age survivors and those with family member loss. PMID- 26040518 TI - Editorial: diabetes and its association with hepatocellular carcinoma in chronic hepatitis B. PMID- 26040499 TI - Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double blind, placebo-controlled trial. AB - BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early stage hormone receptor-positive breast cancer. METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0.50 [95% CI 0.39-0.65], p<0.0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0.44 [95% CI 0.31-0.64], p<0.0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0.57 [95% CI 0.40-0.82], p=0.002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING: Amgen. PMID- 26040519 TI - Editorial: diabetes and its association with hepatocellular carcinoma in chronic hepatitis B - authors' reply. PMID- 26040521 TI - Editorial: diabetes and the risk of infections with immunomodulator therapy in inflammatory bowel diseases - author's reply. PMID- 26040520 TI - Editorial: diabetes and the risk of infections with immunomodulator therapy in inflammatory bowel diseases. PMID- 26040522 TI - Letter: serum I-FABP as marker for enterocyte damage in first-degree relatives of patients with coeliac disease. PMID- 26040523 TI - Letter: serum I-FABP as marker for enterocyte damage in first-degree relatives of patients with coeliac disease - authors' reply. PMID- 26040524 TI - Letter: what else can improve survival in cirrhotic patients with spontaneous bacterial peritonitis and associated septic shock? PMID- 26040525 TI - Letter: what else can improve survival in cirrhotic patients with spontaneous bacterial peritonitis and associated septic shock? Authors' reply. PMID- 26040526 TI - Letter: increasing incidence and prevalence of eosinophilic oesophagitis. PMID- 26040527 TI - Letter: increasing incidence and prevalence of eosinophilic oesophagitis - author's reply. PMID- 26040528 TI - Letter: scoring models in alcoholic hepatitis. PMID- 26040529 TI - Letter: scoring models in alcoholic hepatitis - authors' reply. PMID- 26040530 TI - Letter: cytomegalovirus infection in inflammatory bowel disease. PMID- 26040531 TI - Ab Initio Molecular-Dynamics Simulation of Neuromorphic Computing in Phase-Change Memory Materials. AB - We present an in silico study of the neuromorphic-computing behavior of the prototypical phase-change material, Ge2Sb2Te5, using ab initio molecular-dynamics simulations. Stepwise changes in structural order in response to temperature pulses of varying length and duration are observed, and a good reproduction of the spike-timing-dependent plasticity observed in nanoelectronic synapses is demonstrated. Short above-melting pulses lead to instantaneous loss of structural and chemical order, followed by delayed partial recovery upon structural relaxation. We also investigate the link between structural order and electrical and optical properties. These results pave the way toward a first-principles understanding of phase-change physics beyond binary switching. PMID- 26040532 TI - Multifactorial basis of epilepsy in patients with neurocysticercosis. PMID- 26040533 TI - In response: Multifactorial basis of epilepsy in patients with neurocysticercosis. PMID- 26040534 TI - In response: Talairach methodology in the era of 3D multimodal imaging: "The song remains the same," but catchier, and therefore more helpful for clinical decision making and surgical planning in epilepsy surgery. PMID- 26040535 TI - The terminology of psychogenic nonepileptic seizures: a historical perspective. PMID- 26040536 TI - In response: Terminology of PNES over time--the terms they are a-changin'. PMID- 26040538 TI - India is urged to make stents essential medicines to help control price. PMID- 26040539 TI - Vertically aligned P(VDF-TrFE) core-shell structures on flexible pillar arrays. AB - PVDF and P(VDF-TrFE) nano- and micro- structures have been widely used due to their potential applications in several fields, including sensors, actuators, vital sign transducers, and energy harvesters. In this study, we developed vertically aligned P(VDF-TrFE) core-shell structures using high modulus polyurethane acrylate (PUA) pillars as the support structure to maintain the structural integrity. In addition, we were able to improve the piezoelectric effect by 1.85 times from 40 +/- 2 to 74 +/- 2 pm/V when compared to the thin film counterpart, which contributes to the more efficient current generation under a given stress, by making an effective use of the P(VDF-TrFE) thin top layer as well as the side walls. We attribute the enhancement of piezoelectric effects to the contributions from the shell component and the strain confinement effect, which was supported by our modeling results. We envision that these organic-based P(VDF-TrFE) core-shell structures will be used widely as 3D sensors and power generators because they are optimized for current generations by utilizing all surface areas, including the side walls of core-shell structures. PMID- 26040537 TI - Emotion recognition deficits as predictors of transition in individuals at clinical high risk for schizophrenia: a neurodevelopmental perspective. AB - BACKGROUND: Schizophrenia is characterized by profound and disabling deficits in the ability to recognize emotion in facial expression and tone of voice. Although these deficits are well documented in established schizophrenia using recently validated tasks, their predictive utility in at-risk populations has not been formally evaluated. METHOD: The Penn Emotion Recognition and Discrimination tasks, and recently developed measures of auditory emotion recognition, were administered to 49 clinical high-risk subjects prospectively followed for 2 years for schizophrenia outcome, and 31 healthy controls, and a developmental cohort of 43 individuals aged 7-26 years. Deficit in emotion recognition in at-risk subjects was compared with deficit in established schizophrenia, and with normal neurocognitive growth curves from childhood to early adulthood. RESULTS: Deficits in emotion recognition significantly distinguished at-risk patients who transitioned to schizophrenia. By contrast, more general neurocognitive measures, such as attention vigilance or processing speed, were non-predictive. The best classification model for schizophrenia onset included both face emotion processing and negative symptoms, with accuracy of 96%, and area under the receiver-operating characteristic curve of 0.99. In a parallel developmental study, emotion recognition abilities were found to reach maturity prior to traditional age of risk for schizophrenia, suggesting they may serve as objective markers of early developmental insult. CONCLUSIONS: Profound deficits in emotion recognition exist in at-risk patients prior to schizophrenia onset. They may serve as an index of early developmental insult, and represent an effective target for early identification and remediation. Future studies investigating emotion recognition deficits at both mechanistic and predictive levels are strongly encouraged. PMID- 26040540 TI - Improved detection of Escherichia coli and coliform bacteria by multiplex PCR. AB - BACKGROUND: The presence of coliform bacteria is routinely assessed to establish the microbiological safety of water supplies and raw or processed foods. Coliforms are a group of lactose-fermenting Enterobacteriaceae, which most likely acquired the lacZ gene by horizontal transfer and therefore constitute a polyphyletic group. Among this group of bacteria is Escherichia coli, the pathogen that is most frequently associated with foodborne disease outbreaks and is often identified by beta-glucuronidase enzymatic activity or by the redundant detection of uidA by PCR. Because a significant fraction of essential E. coli genes are preserved throughout the bacterial kingdom, alternative oligonucleotide primers for specific E. coli detection are not easily identified. RESULTS: In this manuscript, two strategies were used to design oligonucleotide primers with differing levels of specificity for the simultaneous detection of total coliforms and E. coli by multiplex PCR. A consensus sequence of lacZ and the orphan gene yaiO were chosen as targets for amplification, yielding 234 bp and 115 bp PCR products, respectively. CONCLUSIONS: The assay designed in this work demonstrated superior detection ability when tested with lab collection and dairy isolated lactose-fermenting strains. While lacZ amplicons were found in a wide range of coliforms, yaiO amplification was highly specific for E. coli. Additionally, yaiO detection is non-redundant with enzymatic methods. PMID- 26040541 TI - Student perceptions of independent versus facilitated small group learning approaches to compressed medical anatomy education. AB - The purpose of this study was to compare student perceptions regarding two, small group learning approaches to compressed (46.5 prosection-based laboratory hours), integrated anatomy education at the University of Ottawa medical program. In the facilitated active learning (FAL) approach, tutors engage students and are expected to enable and balance both active learning and progression through laboratory objectives. In contrast, the emphasized independent learning (EIL) approach stresses elements from the "flipped classroom" educational model: prelaboratory preparation, independent laboratory learning, and limited tutor involvement. Quantitative (Likert-style questions) and qualitative data (independent thematic analysis of open-ended commentary) from a survey of students who had completed the preclerkship curriculum identified strengths from the EIL (promoting student collaboration and communication) and FAL (successful progression through objectives) approaches. However, EIL led to student frustration related to a lack of direction and impaired completion of objectives, whereas active learning opportunities in FAL were highly variable and dependent on tutor teaching style. A "hidden curriculum" was also identified, where students (particularly EIL and clerkship students) commonly compared their compressed anatomy education or their anatomy learning environment with other approaches. Finally, while both groups highly regarded the efficiency of prosection-based learning and expressed value for cadaveric-based learning, student commentary noted that the lack of grade value dedicated to anatomy assessment limited student accountability. This study revealed critical insights into small group learning in compressed anatomy education, including the need to balance student active learning opportunities with appropriate direction and feedback (including assessment). PMID- 26040542 TI - The changes in bone organic and inorganic matrix in newborn rats after maternal application of antiretroviral agents: Indinavir and zidovudine. AB - This work presents results concerning influence of indinavir (protease inhibitor, PI(1)) and zidovudine (nucleoside and nucleotide inhibitor of reverse transcriptase, NRTI) administered to pregnant Wistar rat females on organic and mineral constituents of bones and teeth (mandibles, skulls, tibiae, femurs, and incisors) of their offspring at the age of: 7, 14, and 28 days studied by means of induced laser and X-ray fluorescence spectroscopy supported by digital radiography. Influence of indinavir administered to pregnant female rats on bone of their offspring revealed mainly in changes of mineral concentration: lowered Ca concentration and disturbances of trace elements. Zidovudine influenced organic matter more than inorganic matrix which was seen in enhancement of LIF fluorescence. However, there was also an unexpected increase of bone density for rats from zidovudine group, unlike indinavir group, observed. Our studies suggest that studied antiretroviral agents given to pregnant women, may have different destructive impact on bone state of their offspring in the first period of life. Maternal administration of zidovudine may delay development of organic matrix, while indinavir may have adverse effects on inorganic structure. PMID- 26040543 TI - Evaluating rehabilitation following lumbar fusion surgery (REFS): study protocol for a randomised controlled trial. AB - BACKGROUND: The rate of lumbar fusion surgery (LFS) is increasing. Clinical recovery often lags technical outcome. Approximately 40% of patients undergoing LFS rate themselves as symptomatically unchanged or worse following surgery. There is little research describing rehabilitation following LFS with no clear consensus as to what constitutes the optimum strategy. It is important to develop appropriate rehabilitation strategies to help patients manage pain and recover lost function following LFS. METHODS/DESIGN: The study design is a randomised controlled feasibility trial exploring the feasibility of providing a complex multi-method rehabilitation intervention 3 months following LFS. The rehabilitation protocol that we have developed involves small participant groups of therapist led structured education utilising principles of cognitive behavioral therapy (CBT), progressive, individualised exercise and peer support. Participants will be randomly allocated to either usual care (UC) or the rehabilitation group (RG). We will recruit 50 subjects, planning to undergo LFS, over 30 months. Following LFS all participants will experience normal care for the first 3 months. Subsequent to a satisfactory 3 month surgical review they will commence their allocated post-operative treatment (RG or UC). Data collection will occur at baseline (pre-operatively), 3, 6 and 12 months post operatively. Primary outcomes will include an assessment of feasibility factors (including recruitment and compliance). Secondary outcomes will evaluate the acceptability and characteristics of a limited cluster of quantitative measures including the Oswestry Disability Index (ODI) and an aggregated assessment of physical function (walking 50 yards, ascend/descend a flight of stairs). A nested qualitative study will evaluate participants' experiences. DISCUSSION: This study will evaluate the feasibility of providing complex, structured rehabilitation in small groups 3 months following technically successful LFS. We will identify strengths and weakness of the proposed protocol and the usefulness and characteristics of the planned outcome measures. This will help shape the development of rehabilitation strategies and inform future work aimed at evaluating clinical efficacy. TRIAL REGISTRATION: ISRCTN60891364, 10/07/2014. PMID- 26040544 TI - Reproducibility and relative validity of a semi-quantitative food frequency questionnaire for Chinese pregnant women. AB - BACKGROUND: Food frequency questionnaire (FFQ) is a reliable tool to estimate dietary intake in large nutritional epidemiological studies, but there is lack of a current and validated FFQ for use in urban Chinese pregnant women. This study aimed to evaluate the reproducibility and validity of a semi-quantitative FFQ designed to estimate dietary intake among urban pregnant women in a cohort study conducted in central China. METHODS: In the reproducibility study, a sample of 123 healthy pregnant women completed the first FFQ at 12-13 weeks gestation and the second FFQ 3-4 weeks later. To validate the FFQ, the pregnant women completed three 24-h recalls (24HRs) between the intervals of two FFQs. RESULTS: The intraclass correlation coefficients of two administrations of FFQ for foods ranged from 0.23 (nuts) to 0.49 (fruits) and for nutrients from 0.24 (iodine) to 0.58 (selenium) and coefficients were all statistically significant. The unadjusted Pearson correlation coefficients between two methods ranged from 0.28 (beans) to 0.53 (fruits) for foods and from 0.15 (iodine) to 0.59 (protein) for nutrients. Energy-adjusted and de-attenuated correlation coefficients for foods ranged from 0.35 (beans) to 0.56 (fruits) and for nutrients from 0.11 (iodine) to 0.63 (protein), and all correlations being statistically significant except for iodine, sodium and riboflavin. On average, 67.0% (51.2%-80.5%) of women were classified by both methods into the same or adjacent quintiles based on their food intakes, while 68.5% (56.1%-77.2%) of women were classified as such based on nutrient intakes. Extreme misclassifications were very low for both foods (average of 2.0%) and nutrients (average of 2.2%). Bland-Altman Plots also showed reasonably acceptable agreement between two methods. CONCLUSION: This FFQ is a reasonably reliable and valid tool for assessing most food and nutrient intakes of urban pregnant women in central China. PMID- 26040545 TI - Chitosan/siCkip-1 biofunctionalized titanium implant for improved osseointegration in the osteoporotic condition. AB - Biofunctionalization with siRNA targeting the key negative modulators of bone turnover involved in the molecular mechanism of osteoporosis, such as casein kinase-2 interacting protein-1 (Ckip-1), may lead to enhanced Ti osseointegration in the osteoporotic condition. In this study, even siRNA loading was accomplished by the thermal alkali (TA) treatment to make the Ti ultrahydrophilic and negatively charged to facilitate the physical adsorption of the positively charged CS/siR complex, designated as TA-CS/siR. The intracellular uptake of the CS/siR complex and the gene knockdown efficiency were assessed with bone marrow mesenchymal stem cells (MSCs) as well as the green fluorescent protein (GFP) expressing H1299 cells. In vitro osteogenic activity of TA-CS/siCkip-1 targeting Ckip-1 was assessed with MSCs. In vivo osseointegration of TA-CS/siCkip-1 was assessed in the osteoporotic rat model. TA-CS/siR showed excellent siRNA delivery efficiency and gene silencing effect. TA-CS/siCkip-1 significantly improved the in vitro osteogenic differentiation of MSCs in terms of the enhanced alkaline phosphatase and collagen product and extracellular matrix mineralization, and led to dramatically enhanced in vivo osseointegration in the osteoporostic rat model, showing promising clinical potential for the osteoporotic condition application. TA-CS/siR may constitute a general approach for developing the advanced Ti implants targeting specific molecular mechanism. PMID- 26040546 TI - Model-free functional connectivity and impulsivity correlates of alcohol dependence: a resting-state study. AB - Alcohol dependence is characterized by impulsiveness toward consumption despite negative consequences. Although neuro-imaging studies have implicated some regions underlying this disorder, there is little information regarding its large scale connectivity pattern. This study investigated the within- and between network functional connectivity (FC) in alcohol dependence and examined its relationship with clinical impulsivity measures. Using probabilistic independent component analysis on resting-state functional magnetic resonance imaging (rs fMRI) data from 25 alcohol-dependent (AD) and 26 healthy control (HC) participants, we compared the within- and between-network FC between AD and HC. Then, the relationship between FC and impulsiveness as measured by the Barratt Impulsiveness Scale (BIS-11), the UPPS-P Impulsive Scale and the delay discounting task (DDT), was explored. Compared with HC, AD exhibited increased within-network FC in salience (SN), default mode (DMN), orbitofrontal cortex (OFCN), left executive control (LECN) and amygdala-striatum (ASN) networks. Increased between-network FC was found among LECN, ASN and SN. Between-network FC correlations were significantly negative between Negative-Urgency and OFCN pairs with right executive control network (RECN), anterior DMN (a-DMN) and posterior DMN (p-DMN) in AD. DDT was significantly correlated with the between-network FC among the LECN, a-DMN and SN in AD. These findings add evidence to the concept of altered within-network FC and also highlight the role of between-network FC in the pathophysiology of AD. Additionally, this study suggests differential neurobiological bases for different clinical measures of impulsivity that may be used as a systems-level biomarker for alcohol dependence severity and treatment efficacy. PMID- 26040549 TI - Ionic liquids enable accurate chromatographic analysis of polyelectrolytes. AB - The molecular weight distribution of polyelectrolytes was determined with high performance liquid chromatography using ionic liquids as eluents, because the electrostatic repulsion among polyelectrolytes was entirely suppressed in it. A mixed sample of polycation and polyanion was also analysed to detect them independently. PMID- 26040548 TI - Spontaneous lung and lymph node metastasis in transgenic breast cancer is independent of the urokinase receptor uPAR. AB - Urokinase-type plasminogen activator (uPA) is an extracellular protease that plays a pivotal role in tumor progression. uPA activity is spatially restricted by its anchorage to high-affinity uPA receptors (uPAR) at the cell surface. High tumor tissue expression of uPA and uPAR is associated with poor prognosis in lung, breast, and colon cancer patients in clinical studies. Genetic deficiency of uPA leads to a significant reduction in metastases in the murine transgenic MMTV-PyMT breast cancer model, demonstrating a causal role for uPA in cancer dissemination. To investigate the role of uPAR in cancer progression, we analyze the effect of uPAR deficiency in the same cancer model. uPAR is predominantly expressed in stromal cells in the mouse primary tumors, similar to human breast cancer. In a cohort of MMTV-PyMT mice [uPAR-deficient (n = 31) or wild type controls (n = 33)], tumorigenesis, tumor growth, and tumor histopathology were not significantly affected by uPAR deficiency. Lung and lymph node metastases were also not significantly affected by uPAR deficiency, in contrast to the significant reduction seen in uPA-deficient mice. Taken together, our data show that the genetic absence of uPAR does not influence the outcome of the MMTV-PyMT cancer model. PMID- 26040550 TI - Doxepin may be a useful pharmacotherapeutic agent in chronic urticaria. PMID- 26040551 TI - Bilateral removal of the mandibular and medial retropharyngeal lymph nodes through a single ventral midline incision for staging of head and neck cancers in dogs: a description of surgical technique. AB - Currently, there is no standard protocol for removal of regional lymph nodes for the staging of head and neck cancers in dogs. Palpation and fine needle aspiration of mandibular lymph nodes are most commonly performed for staging of head and neck cancers. Although cytology is commonly performed for staging of head and neck, cancers histopathology is required for definitive lymph node staging. When regional lymph node biopsy is performed, mandibular lymph nodes are most commonly sampled due to their accessibility. The medial retropharyngeal lymph nodes may be the most relevant draining lymph node of the head and neck, but they are not routinely sampled due to their anatomic location medial to the salivary glands. The technique described here will allow for a standardized surgical approach for the efficient removal of both mandibular and medial retropharyngeal lymph nodes for staging of head and neck tumours via a single ventral midline approach. PMID- 26040552 TI - Obesity: Lifestyle management, bariatric surgery, drugs, and the therapeutic exploitation of gut hormones. AB - Obesity is on the rise and the pursuit of efficient and safe treatment is ongoing. Available anti-obesity medical therapies have so far proved to be disappointing, whereas bariatric surgery is leading the way and offers long-term health benefits. Part of the success of bariatric surgery is thought to be mediated by gut hormones. A better understanding of the role of gut hormones within the gut-brain signaling pathway in the control of hunger, satiety, and energy homeostasis, has led to their therapeutic exploitation as possible anti obesity drugs. In this review, we provide a summary of currently available treatment options for obesity from simple lifestyle modifications and bariatric surgery to traditional and novel medical therapies. PMID- 26040553 TI - Oncologic outcome after local recurrence of chondrosarcoma: Analysis of prognostic factors. AB - BACKGROUND: Literature on outcome after local recurrence (LR) in chondrosarcoma is scarce and better appreciation of prognostic factors is needed. OBJECTIVES: (1) To evaluate post-LR oncologic outcomes of disease-specific survival and subsequent LR and (2) to identify prognostic factors for post-LR oncologic outcomes. PATIENTS AND METHODS: Review of 28 patients with locally recurrent chondrosarcoma from the original cohort of 150 patients, who were treated surgically with or without adjuvants between 1982 and 2011, was performed. Mean age was 46 years (range, 21-73) which included 20 males and 8 females with mean follow up of 8.4 +/- 7.5 years (range, 1.2-31.0). RESULTS: Post-LR survival at 5 years was 58.6 +/- 10.3%. Age greater than 50 years (P = 0.011) and LR occurring within 1 year of primary surgery (P = 0.011) independently predicted poor survival. Seven patients suffered subsequent LR, which was significantly affected by surgical margin for LR (P = 0.038). CONCLUSION: Long-term survival of locally recurrent chondrosarcoma is achievable in a substantial number of patients. Older age at onset of LR and shorter interval from primary surgery to LR identifies high risk patients for poor post-LR survival while, wide surgical margins at LR surgery reduces the risk of subsequent LR. PMID- 26040554 TI - Optimization of ultrasound-assisted extraction of gardenia fruit oil with bioactive components and their identification and quantification by HPLC-DAD/ESI MS(2). AB - Compounds in Fructus Gardeniae have been shown to possess a wide array of biological activities. However, Gardenia oil extracted from its fruit is less reported and its composition remains uncertain. To completely characterize lipophilic compounds in Gardenia oil, three conventional extraction (CE) and ultrasound-assisted extraction (UAE) methods were investigated. The oil extraction yield obtained by UAE was 51.8% higher than that acquired by cold pressed extraction (CPE). The fatty acid profile in UAE oil with different solvents was characterized by GC-MS. Petroleum ether was observed to be an ideal solvent with 8.59% extraction yield and 78.88% recovery rate and with a ratio of 3.11 of unsaturated fatty acids to saturated fatty acids. Response surface methodology (RSM) with Box-Behnken Design (BBD) was applied to optimize conditions in UEA of oil to maximize extraction yield. Furthermore, the bioactive components in oil extracted by UAE were qualitatively identified and quantified by HPLC-DAD/ESI-MS(2) and HPLC-DAD analysis. The eight compounds in Gardenia oil, including geniposide, trans/cis-crocin-1, crocin-2, crocin-3, crocin-4, and trans/cis-crocetin, were structurally revealed. The corresponding transfer rates of the bioactive components showed that the lipophilic trans/cis-crocetin could be completely transferred from fruit to oil, with the highest concentration of 11.38 MUg g(-1) oil among all compounds quantified. These findings could deliver potential application to a large-scale production of functional Gardenia oil whose bioactive components possess health benefits. PMID- 26040555 TI - Anti-dsDNA antibodies induce inflammation via endoplasmic reticulum stress in human mesangial cells. AB - BACKGROUND: Anti-dsDNA antibodies play an important role in the pathogenesis of lupus nephritis (LN). Endoplasmic reticulum (ER) stress is a physical reaction under stressful condition and can cause inflammation when stimulation is sustained. This study investigated the roles of ER stress in anti-dsDNA antibody induced inflammation response in human mesangial cells (HMCs). METHOD: Anti-dsDNA antibodies isolated from LN patients were used to stimulate HMCs. The expression of GRP78, PERK, p-PERK, p-eIF2alpha, ATF4, p-IRE1alpha, ATF6 and CHOP in HMCs was measured by western blot. NF-kappaB activation was detected by examining nuclear translocation of NF-kappaB p65. The expression and production of IL-1beta, TNF alpha and MCP-1 were examined by qPCR and ELISA. RESULTS: Flow cytometry and cellular ELISA showed that anti-dsDNA antibodies can bind to HMCs. The binding was not inhibited by blockage of Fc receptor. Anti-dsDNA antibody stimulation significantly enhanced the expression of GRP78, p-PERK, p-eIF2alpha and ATF4 in HMCs. However, no significant increase in the expression of p-IRE1alpha and ATF6 was found. In addition, anti-dsDNA antibodies also significantly increased the activation of NF-kappaB and upregulated the expression of IL-1beta, TNF-alpha and MCP-1, which were suppressed by pretreatment of HMCs with chemical ER stress inhibitor 4-PBA. Transfection of specific ATF4 siRNA also significantly reduced the activation of NF-kappaB and expression of proinflammatory cytokines. CONCLUSION: Anti-dsDNA antibodies induce NF-kappaB activation and inflammation in HMCs via PERK-eIF2alpha-ATF4 ER stress pathway. PMID- 26040556 TI - Identifying and assessing the impact of wine acid-related genes in yeast. AB - Saccharomyces cerevisiae strains used for winemaking show a wide range of fermentation phenotypes, and the genetic background of individual strains contributes significantly to the organoleptic properties of wine. This strain dependent impact extends to the organic acid composition of the wine, an important quality parameter. However, little is known about the genes which may impact on organic acids during grape must fermentation. To generate novel insights into the genetic regulation of this metabolic network, a subset of genes was identified based on a comparative analysis of the transcriptomes and organic acid profiles of different yeast strains showing different production levels of organic acids. These genes showed significant inter-strain differences in their transcription levels at one or more stages of fermentation and were also considered likely to influence organic acid metabolism based on existing functional annotations. Genes selected in this manner were ADH3, AAD6, SER33, ICL1, GLY1, SFC1, SER1, KGD1, AGX1, OSM1 and GPD2. Yeast strains carrying deletions for these genes were used to conduct fermentations and determine organic acid levels at various stages of alcoholic fermentation in synthetic grape must. The impact of these deletions on organic acid profiles was quantified, leading to novel insights and hypothesis generation regarding the role/s of these genes in wine yeast acid metabolism under fermentative conditions. Overall, the data contribute to our understanding of the roles of selected genes in yeast metabolism in general and of organic acid metabolism in particular. PMID- 26040557 TI - Analyse multiple disease subtypes and build associated gene networks using genome wide expression profiles. AB - BACKGROUND: Despite the large increase of transcriptomic studies that look for gene signatures on diseases, there is still a need for integrative approaches that obtain separation of multiple pathological states providing robust selection of gene markers for each disease subtype and information about the possible links or relations between those genes. RESULTS: We present a network-oriented and data driven bioinformatic approach that searches for association of genes and diseases based on the analysis of genome-wide expression data derived from microarrays or RNA-Seq studies. The approach aims to (i) identify gene sets associated to different pathological states analysed together; (ii) identify a minimum subset within these genes that unequivocally differentiates and classifies the compared disease subtypes; (iii) provide a measurement of the discriminant power of these genes and (iv) identify links between the genes that characterise each of the disease subtypes. This bioinformatic approach is implemented in an R package, named geNetClassifier, available as an open access tool in Bioconductor. To illustrate the performance of the tool, we applied it to two independent datasets: 250 samples from patients with four major leukemia subtypes analysed using expression arrays; another leukemia dataset analysed with RNA-Seq that includes a subtype also present in the previous set. The results show the selection of key deregulated genes recently reported in the literature and assigned to the leukemia subtypes studied. We also show, using these independent datasets, the selection of similar genes in a network built for the same disease subtype. CONCLUSIONS: The construction of gene networks related to specific disease subtypes that include parameters such as gene-to-gene association, gene disease specificity and gene discriminant power can be very useful to draw gene disease maps and to unravel the molecular features that characterize specific pathological states. The application of the bioinformatic tool here presented shows a neat way to achieve such molecular characterization of the diseases using genome-wide expression data. PMID- 26040558 TI - KIR3DL1*0250103: a novel three-domain KIR allele isolated in West African samples. AB - The full length sequence of KIR3DL1*0250103 differs from that of KIR3DL1*0150101 with nine single-nucleotide polymorphisms. PMID- 26040559 TI - Simultaneous juvenile polyposis syndrome and neurofibromatosis type 1--Response to Letter to the Editor. PMID- 26040560 TI - Mechanical properties of branched actin filaments. AB - Cells moving on a two dimensional substrate generate motion by polymerizing actin filament networks inside a flat membrane protrusion. New filaments are generated by branching off existing ones, giving rise to branched network structures. We investigate the force-extension relation of branched filaments, grafted on an elastic structure at one end and pushing with the free ends against the leading edge cell membrane. Single filaments are modeled as worm-like chains, whose thermal bending fluctuations are restricted by the leading edge cell membrane, resulting in an effective force. Branching can increase the stiffness considerably; however the effect depends on branch point position and filament orientation, being most pronounced for intermediate tilt angles and intermediate branch point positions. We describe filament networks without cross-linkers to focus on the effect of branching. We use randomly positioned branch points, as generated in the process of treadmilling, and orientation distributions as measured in lamellipodia. These networks reproduce both the weak and strong force response of lamellipodia as measured in force-velocity experiments. We compare properties of branched and unbranched networks. The ratio of the network average of the force per branched filament to the average force per unbranched filament depends on the orientation distribution of the filaments. The ratio exhibits compression dependence and may go up to about 4.5 in networks with a narrow orientation distribution. With orientation distributions measured in lamellipodia, it is about two and essentially independent from network compression, graft elasticity and filament persistence length. PMID- 26040561 TI - Aerobic Oxidative Cycloaddition of alpha-Chlorotosylhydrazones with Arylamines: General Chemoselective Construction of 1,4-Disubstituted and 1,5-Disubstituted 1,2,3-Triazoles under Metal-Free and Azide-Free Conditions. AB - A novel synthetic approach toward 1,4-disubstituted 1,2,3-triazoles and 1,5 disubstituted 1,2,3-triazoles by aerobic oxidative cycloaddition of alpha chlorotosylhydrazone with primary aryl amine has been developed. Significantly, the reaction proceeds smoothly to afford 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles under catalyst-free, metal-free, azide-free, and peroxide-free conditions. PMID- 26040562 TI - [Errors and complications associated with lower limb amputation]. AB - BACKGROUND: The newly launched "German law of patients' rights" strenghthens the rights of patients and places special emphasis on the right to full information. This includes information on errors, mistakes and complications due to surgery. ASSESSMENT: Surgery complications and mistakes are of main importance especially in the area of amputation because rehabilitation chances are dependent on good surgical quality. Therefore, it is necessary that surgeons know about these problems. Complications may be hematomas, bleeding, dysvascular problems, skin- or muscle-necrosis, and infections and wound healing problems, as well as neuromas or calcification of soft tissues. They are not totally preventable. CONSEQUENCES: Surgical mistakes may involve insufficient shaping of the bony stump end, incorrect treatment of soft tissue, wrong decisions regarding the amputation level, insufficient treatment of nerves and wound closure under tension of soft tissue. All surgical mistakes negatively influence the end bearing capability of the stump and, therefore, the prosthetic fit, and with this reduce rehabilitation chances. PURPOSE: It is necessary that surgeons know about these problems in order to avoid them. Therefore the typical complications and errors are demonstrated with case reports. PMID- 26040563 TI - Identification and validation of dysregulated MAPK7 (ERK5) as a novel oncogenic target in squamous cell lung and esophageal carcinoma. AB - BACKGROUND: MAPK7/ERK5 (extracellular-signal-regulated kinase 5) functions within a canonical three-tiered MAPK (mitogen activated protein kinase) signaling cascade comprising MEK (MAPK/ERK kinase) 5, MEKK(MEK kinase) 2/3 and ERK5 itself. Despite being the least well studied of the MAPK-modules, evidence supports a role for MAPK7-signaling in the pathology of several cancer types. METHODS AND RESULTS: Fluorescence in situ hybridization (FISH) analysis identified MAPK7 gene amplification in 4% (3/74) of non-small cell lung cancers (NSCLC) (enriched to 6% (3/49) in squamous cell carcinoma) and 2% (2/95) of squamous esophageal cancers (sqEC). Immunohistochemical (IHC) analysis revealed a good correlation between MAPK7 gene amplification and protein expression. MAPK7 was validated as a proliferative oncogenic driver by performing in vitro siRNA knockdown of MAPK7 in tumor cell lines. Finally, a novel MEK5/MAPK7 co-transfected HEK293 cell line was developed and used for routine cell-based pharmacodynamic screening. Phosphorylation antibody microarray analysis also identified novel downstream pharmacodynamic (PD) biomarkers of MAPK7 kinase inhibition in tumor cells (pMEF2A and pMEF2D). CONCLUSIONS: Together, these data highlight a broader role for dysregulated MAPK7 in driving tumorigenesis within niche populations of highly prevalent tumor types, and describe current efforts in establishing a robust drug discovery screening cascade. PMID- 26040564 TI - Spatial-Temporal Expression of Non-classical MHC Class I Molecules in the C57 Mouse Brain. AB - Recent studies clearly demonstrate major histocompatibility complex (MHC) class I expression in the brain plays an important functional role in neural development and plasticity. A previous study from our laboratory demonstrated the temporal and spatial expression patterns of classical MHC class I molecules in the brain of C57 mice. Studies regarding non-classical MHC class I molecules remain limited. Here we examine the expression of non-classical MHC class I molecules in mouse central nervous system (CNS) during embryonic and postnatal developmental stages using in situ hybridization and immunofluorescence. We find non-classical MHC class I molecules, M3/T22/Q1, are expressed in the cerebral cortex, neuroepithelium of the lateral ventricle, neuroepithelium of aquaeductus and developing cerebellum during embryonic developmental stages. During the postnatal period from P0 to adult, non-classical MHC class I mRNAs are detected in olfactory bulb, hippocampus, cerebellum and some nerve nuclei. Overall, the expression patterns of non-classical MHC class I molecules are similar to those of classical MHC class I molecules in the developing mouse brain. In addition, non-classical MHC class I molecules are present in the H2-K(b) and H2-D(b) double knock-out mice where their expression levels are greatly increased within the same locations as compared to wild type mice. The elucidation and discovery of the expression profile of MHC class I molecules during development is important for supporting an enhanced understanding of their physiological and potential pathological roles within the CNS. PMID- 26040565 TI - Linalool Inhibits LPS-Induced Inflammation in BV2 Microglia Cells by Activating Nrf2. AB - Linalool, a natural compound of the essential oils, has been reported to have anti-inflammatory effects. This study aimed to investigate the anti-inflammatory effects and mechanism of linalool in LPS-stimulated BV2 microglia cells. BV2 microglia cells were stimulated with LPS in the presence or absence of linalool. The production of inflammatory mediators TNF-alpha, IL-1beta, NO, and PGE2 as well as Nrf2, HO-1 expression were detected. Our results showed that linalool inhibited LPS-induced TNF-alpha, IL-1beta, NO, and PGE2 production in a dose dependent manner. Linalool also inhibited LPS-induced NF-kappaB activation. Treatment of linalool induced nuclear translocation of Nrf2 and expression of HO 1. In addition, our results showed that the anti-inflammatory effect of linalool was attenuated by transfection with Nrf2 siRNA. In conclusion, these results suggested that linalool inhibits LPS-induced inflammation in BV2 microglia cells by activating Nrf2/HO-1 signaling pathway. PMID- 26040566 TI - Overcoming the ethnic differences in patients hospitalized for heart failure: is there a need for international harmonization of clinical practice guidelines? PMID- 26040568 TI - Changes. PMID- 26040567 TI - Overview of surgery for oral cavity cancer in Ontario. AB - BACKGROUND: The pupose of this study was to describe variations in incidence and resection rates of patients with oral cavity squamous cell carcinoma (SCC) in Ontario. METHODS: All oral cavity SCCs in Ontario between 2003 and 2010 were identified from the Ontario Cancer Registry. Incidence and resection rates along with variations in care were compared by sociodemographic factors and Ontario health regions. RESULTS: The 8-year incidence rates for oral cavity SCC was 21.3 per 100,000 with variations by sex, age group, neighborhood income, and community size. Seventy-four percent of patients underwent an oral cavity cancer resection, of which 91% were at a regional head and neck cancer center. Variations in resection rates existed by region of residence and treatment. CONCLUSION: Oral cavity cancer incidence rates vary by sex, age, neighborhood income, community size, and health region. Resection rates vary by age and health region. Oral cavity cancer care is highly regionalized in Ontario. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: 1113-1118, 2016. PMID- 26040569 TI - Exploring Factors That Contribute to Positive Change in a Diverse, Group-Based Male Batterer Intervention Program: Using Qualitative Data to Inform Implementation and Adaptation Efforts. AB - Although batterer intervention programs (BIPs) are often mandated for perpetrators of intimate partner violence, the precursors and mechanisms of change operating within these programs remain unclear. The purpose of this qualitative study was to examine the perceptions and experiences of participants in a diverse, group-based male BIP to better understand factors facilitating positive change. Data were gathered through individual interviews with 15 men and were analyzed using grounded theory. Findings suggest that change is taking place through a reciprocal process in which change occurring via the group context facilitates change within participants and vice versa. The specific benefits of the group context and value of group diversity were emphasized. Factors supporting this change process include the role of group facilitators and providing group members with access to ongoing support. These results are useful for informing the continued implementation and adaptation of BIPs with the goal of reducing and ultimately terminating abusive behaviors. PMID- 26040570 TI - A 2-year review of the general internal medicine admissions to the British Role 3 Hospital in Camp Bastion, Afghanistan. AB - BACKGROUND: Detailed knowledge of the likely volume and nature of the diseases presenting to deployed secondary care facilities aids operational planning. Now the British operation in Afghanistan has ended and a record of the experience is useful to preserve the lessons learned. METHODS: Over a 2-year period from April 2011, prospective demographic and clinical data were collected on consecutive general internal medicine admissions to the Role 3 Hospital in Camp Bastion, Afghanistan. Up to four different symptoms and diagnoses were coded using the WHO International Classification of Disease, V.10 for each patient. RESULTS: A total of 1368 medical patients were admitted. Of 1131 military admissions, 612 were from the UK (54.1%) and the remainder from 13 allied countries; 237 civilians came from 23 countries. Civilians were older than the military patients (p<0.001) but included five children. The 20 most frequent presenting symptoms were identified and there were 1626 diagnoses made. The 10 most frequent diagnoses were infectious gastroenteritis (12.6%), heat illness (4.3%), pneumonia (3.6%), epilepsy (2.6%), cellulitis (2.7%), migraine (1.8%), peptic ulcer disease (1.2%), myocardial infarction (1.2%), venous thromboembolism (1.2%) and pericarditis (0.7%). In 252 cases (18.4%) a firm diagnosis was not reached and a symptom was recorded. The five most frequent of these were undifferentiated febrile illnesses (4.6%), syncope (3.7%), chest pain (2.8%), headache (0.8%) and palpitations (0.7%). The mean hospital length of stay was 1.59 days and 72.2% of UK military patients were 'returned to unit'. Three civilian patients died in hospital or following aeromedical evacuation and there were no deaths of any military patients. DISCUSSION: This study demonstrates the wide variety of presentations seen by physicians at an established military field hospital. This information informs the core syllabus of military physician training and will help facilitate planning for future medical support to similar military operations. TRIAL REGISTRATION NUMBER: RCDM/Res/Audit/1036/12/0305. PMID- 26040571 TI - Therapeutic targets of triple-negative breast cancer: a review. AB - Breast cancer (BC) is the second most common cause of cancer deaths. Triple negative breast cancer (TNBC) does not show immunohistochemical expression of oestrogen receptors, progesterone receptors or HER2. At present, no suitable treatment option is available for patients with TNBC. This dearth of effective conventional therapies for the treatment of advanced stage breast cancer has provoked the development of novel strategies for the management of patients with TNBC. This review presents recent information associated with different therapeutic options for the treatment of TNBC focusing on promising targets such as the Notch signalling, Wnt/beta-catenin and Hedgehog pathways, in addition to EGFR, PARP1, mTOR, TGF-beta and angiogenesis inhibitors. PMID- 26040573 TI - Elastofibroma dorsi: a case report with an immunohistochemical and ultrastructural studies. AB - Elastofibroma is a rare, benign, fibrous tumor formed by the proliferation of characteristic elastic fibers that commonly occurs between the lower margin of the scapula and the ribcage. We undertook a histochemical, immunohistochemical, and ultrastructural study of an elastofibroma dorsi beneath the right scapula of a 77-year-old woman. Tumor cells comprised collagen fiber bundles, numerous elastic fibers, and spindle cells resembling fibroblasts. The elastic and collagen fibers in the tumor were stained positively with Elastic van Gieson and Masson trichrome staining, respectively. Immunostaining showed that the fibroblasts were strongly positive for CD34, positive for vimentin, and weakly positive for alpha-smooth muscle actin. Ultrastructural observations revealed elastin and microfibrils between numerous irregularly arranged collagen fiber bundles. Signs suggestive of elastin deposition were also evident in the tangled collagen fibers themselves. The fibroblasts contained a large amount of rough endoplasmic reticulum and were surrounded on the outside of cells by microfibrils and collagen fibers. Although fibroblasts may produce large quantities of elastin, microfibrils, and collagen, our findings suggested that the deposition of elastin on collagen fibers may be involved in the formation of abnormal elastic fibers. PMID- 26040574 TI - Associations of EDNRA and EDN1 polymorphisms with carotid intima media thickness through interactions with gender, regular exercise, and obesity in subjects in Taiwan: Taichung Community Health Study (TCHS). AB - The aim of this study was to evaluate the interacted association between EDNRA and EDN1 polymorphisms and gender, regular exercise, and obesity status on carotid intima media thickness (IMT) in community- dwelling subjects of the Taichung Community Health Study. Five single-nucleotide polymorphisms (SNPs rs1395821, rs1878406, rs5333, rs1800541, and rs5370) of the EDNRA and EDN1 gene were examined in 480 participants from 160 families. The IMT protocol involves scanning the common carotid arteries (CCAs), the carotid bifurcations (bulb), and the origins (first 1 cm) of the internal carotid arteries (ICAs). Generalized linear models with a generalized estimating equation were employed to consider the dependence among family members. After multivariate adjustment, the effects of interactions between EDNRA and EDN1 gene with gender, obesity, and exercise were observed. For gene-gender interaction on CCA IMT, the adjusted mean for men carrying the GA/GG genotype of EDNRASNP rs1878406 was 1.18 times higher than that for men carrying the AA genotype (95% CI: 1.01, 1.37). As for bulb and ICA IMT, the adjusted mean values for women carrying the AC/AA genotype of EDN1 rs5370 was lower than those carrying the CC genotype: 0.89, [0.82, 0.98]; and 0.90 [0.83, 0.99], respectively. We did observe significant effects of EDNRA SNPs rs1395821 and rs5333 in individuals who regularly exercised. A significantly lower adjusted mean in CCA IMT for non-obese individuals carrying EDNRA SNP rs5333 was observed (0.92 [0.86, 0.99]) compared with non-obese individuals carrying the AA genotype. This study first reported significant interactions of EDNRA and EDN1 polymorphisms with gender, regular exercise, and obesity on carotid IMT in Han Chinese participants. PMID- 26040575 TI - Knowledge and perceptions of dementia and Alzheimer's disease in four ethnic groups in Copenhagen, Denmark. AB - OBJECTIVE: Older people from ethnic minorities are underrepresented in dementia care. Some of the determinants of access to care are knowledge and perceptions of dementia, which may vary between ethnic groups in the population. The aims of this study were to compare knowledge and perceptions of dementia and Alzheimer's disease (AD) among four ethnic groups in Copenhagen, Denmark, and to assess the influence of education and acculturation. METHODS: Quantitative survey data from 260 participants were analyzed: 100 native Danish, and 47 Polish, 51 Turkish, and 62 Pakistani immigrants. Knowledge and perceptions of dementia and AD were assessed with the Dementia Knowledge Questionnaire (DKQ) supplemented with two questions from the Alzheimer's Disease Awareness Test (ADAT). Knowledge and perceptions of dementia and AD in the four groups were compared, and the influence of education and acculturation was assessed. RESULTS: Group differences were found on the DKQ total score as well as all sub-domains. Turkish and Pakistani people were most likely to hold normalizing and stigmatizing views of AD. Level of education and acculturation had limited influence on dementia knowledge, accounting for 22% of the variance at most and had only minor influence on perceptions of AD. CONCLUSIONS: Lacking knowledge and certain perceptions of dementia and AD may hamper access to services in some ethnic minority groups. Ongoing efforts to raise awareness that dementia and AD are not part of normal aging, particularly among Turkish and Pakistani communities, should be a high priority for educational outreach. PMID- 26040576 TI - Fall and Fracture Risk in Sarcopenia and Dynapenia With and Without Obesity: the Role of Lifestyle Interventions. AB - Due to their differing etiologies and consequences, it has been proposed that the term "sarcopenia" should revert to its original definition of age-related muscle mass declines, with a separate term, "dynapenia", describing muscle strength and function declines. There is increasing interest in the interactions of sarcopenia and dynapenia with obesity. Despite an apparent protective effect of obesity on fracture, increased adiposity may compromise bone health, and the presence of sarcopenia and/or dynapenia ("sarcopenic obesity" and "dynapenic obesity") may exacerbate the risk of falls and fracture in obese older adults. Weight loss interventions are likely to be beneficial for older adults with sarcopenic and dynapenic obesity but may result in further reductions in muscle and bone health. The addition of exercise including progressive resistance training and nutritional strategies, including protein and vitamin D supplementation, may optimise body composition and muscle function outcomes thereby reducing falls and fracture risk in this population. PMID- 26040577 TI - Automaticity in fast lexical decision sequential effects: much like telling left from right. AB - Successive lexical decisions have shown sequential effects where faster word responses and slower nonword responses follow the same versus different prior response. To date, explanations of these effects have been based on processes specific to discriminating words from nonwords. However, a more parsimonious explanation is possible, based on generic choice processes that apply even to left/right discriminations. Under conditions that promote automaticity, this explanation distinctly predicts equal facilitation by response repetition for words and nonwords. This hypothesis was here tested in an experiment involving 82 participants completing 850-trial blocks of lexical decision with a 100 ms response-stimulus interval-a much faster rate of choice succession than previously used-and including a factor of word/nonword discriminability so as to further test the applicability of choice-specific processes. Distinct from earlier findings, sequential effects were found to be identical in sign and substance for words and nonwords. This reliably occurred as facilitation by repetition across the decile distribution of response-times, across high and low levels of word/nonword discriminability, within each block of the run, and in interaction with higher-order sequential effects involving up to four prior trials. The main effect of facilitation by repetition at the second-order was particularly strong, being equal in effect-size to the interactive effect of the word/nonword factor and word/nonword discriminability (eta (2) = 0.61). Hence, generic choice processes appeared to be sufficient to produce lexical decision sequential effects, independently of choice-specific processes. The findings particularly suggested a primary role for automatic response-facilitation, with accuracy-monitoring and expectancy contributing to higher-order effects. The further role of choice-specific processes in these and other findings, and the utility of lexical decision in studying generic choice processes, are discussed. PMID- 26040578 TI - Isothermal rolling circle amplification of virus genomes for rapid antigen detection and typing. AB - In this work, isothermal rolling circle amplification (RCA) of the multi-kilobase genome of engineered filamentous bacteriophage is used to report the presence and identification of specific protein analytes in solution. First, bacteriophages were chosen as sensing platforms because peptides or antibodies that bind medically relevant targets can be isolated through phage display or expressed as fusions to their p3 and p8 coat proteins. Second, the circular, single-stranded genome contained within the phage serves as a natural large DNA template for a RCA reaction to rapidly generate exponential amounts of double stranded DNA in a single isothermal step that can be easily detected using low-cost fluorescent nucleic acid stains. Amplifying the entire phage genome also provides high detection sensitivities. Furthermore, since the sequence of the viral DNA can be easily modified with multiple restriction enzyme sites, a simple DNA digest can be applied to detect and identify multiple antigens simultaneously. The methods developed here will lead to protein sensors that are highly scalable to produce, can be run without complex biological equipment and do not require the use of multiple antibodies or high-cost fluorescent DNA probes or nucleotides. PMID- 26040579 TI - Sphingopyxis fribergensis sp. nov., a soil bacterium with the ability to degrade styrene and phenylacetic acid. AB - Strain Kp5.2(T) is an aerobic, Gram-negative soil bacterium that was isolated in Freiberg, Saxony, Germany. The cells were motile and rod-shaped. Optimal growth was observed at 20-30 degrees C. The fatty acids of strain Kp5.2(T) comprised mainly C18 : 1omega7c and summed feature 3 (C16 : 1omega7c/iso-C15 : 0 2-OH). The major respiratory quinone was Q-10. The major polar lipids of strain Kp5.2(T) were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine and sphingoglycolipid. The G+C content of the genomic DNA was 63.7%. Sequencing of the 16S rRNA gene of strain Kp5.2(T) allowed its classification into the family Sphingomonadaceae, and the sequence showed the highest similarity to those of members of the genus Sphingopyxis, with Sphingopyxis italica SC13E-S71(T) (99.15% similarity), Sphingopyxis panaciterrae Gsoil 124(T) (98.96%), Sphingopyxis chilensis S37(T) (98.90%) and Sphingopyxis bauzanensis BZ30(T) (98.51%) as the nearest neighbours. DNA-DNA hybridization and further characterization revealed that strain Kp5.2(T) can be considered to represent a novel species of the genus Sphingopyxis. Hence, the name Sphingopyxis fribergensis sp. nov. is proposed, with the type strain Kp5.2(T) ( = DSM 28731(T) = LMG 28478(T)). PMID- 26040580 TI - Halovenus salina sp. nov., an extremely halophilic archaeon isolated from a saltern. AB - An extremely halophilic archaeon was isolated from a water sample of Isla Bacuta saltern in Huelva, Spain. Strain ASP54(T) is a novel red-pigmented, motile, rod shaped, Gram-stain-negative and strictly aerobic haloarchaeon. Strain ASP54(T) grew in media containing 15-30% (w/v) salts and optimally with 25% (w/v) salts. It grew between pH 5.0 and 9.0 (optimally at pH 7.5) and at 20-40 degrees C (optimally at 37 degrees C). Phylogenetic analysis based on multi-locus sequence analysis (MLSA) and the comparison of 16S rRNA gene sequences revealed that strain ASP54(T) is most closely related to the genus Halovenus. The closest relatives were Halovenus aranensis EB27(T) (92.1% 16S rRNA gene sequence similarity), Halorientalis regularis TNN28(T) (92.1%), and Halorientalis persicus D108(T) (92.0%). The polar lipid pattern of strain ASP54(T) consisted of biphosphatidylglycerol, phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate, sulfated mannosyl glucosyl diether and a minor-phospholipid. The predominant respiratory quinone was menaquinone-8 (MK-8) (83%), and a minor amount of MK-8(VIII-H2) (17%) was also detected. The G+C content of the genomic DNA of this strain was 63.1 mol%. Based on the phenotypic, chemotaxonomic and phylogenetic data presented in this study, strain ASP54(T) represents a novel species of the genus Halovenus, for which the name Halovenus salina sp. nov. is proposed. The type strain is ASP54(T) ( = CEC(T) 8749(T) = IBRC-M 10946(T) = JCM 30072(T)). PMID- 26040581 TI - Anxiety Among Patients Undergoing Nail Surgery and Skin Punch Biopsy: Effects of Age, Gender, Educational Status, and Previous Experience. AB - BACKGROUND: Patient anxiety about nail surgery relates mainly to pain associated with needle puncture, anesthetic flow during the procedure, and postoperative care, as well as possible past traumatic experience. OBJECTIVE: The aims of this study were to compare anxiety levels among patients undergoing nail surgery and skin punch biopsy and to assess the effects of demographic characteristics on anxiety. METHODS: Forty-eight consecutive patients who were referred to a dermatological surgery unit for nail surgery intervention (group 1) and 50 age- and sex-matched patients referred to the same unit for skin punch biopsy (group 2) were enrolled in the study. Patients' anxiety levels were measured using Spielberger's State-Trait Anxiety Inventory. RESULTS: There was no significant difference in median anxiety level between group 1 (42.00; interquartile range, 6.50) and group 2 (41.00; interquartile range, 8.25) (P = .517). The demographic factors of patient sex, educational status, and prior surgery showed no significant effects on anxiety levels. CONCLUSION: Nail surgery does not seem to cause significantly greater anxiety than skin punch biopsy. PMID- 26040582 TI - Helminth parasites of Artemia franciscana (Crustacea: Branchiopoda) in the Great Salt Lake, Utah: first data from the native range of this invader of European wetlands. AB - The present study is the first survey on the role of Artemia franciscana Kellogg as intermediate host of helminth parasites in its native geographical range in North America (previous studies have recorded nine cestode and one nematode species from this host in its invasive habitats in the Western Mediterranean). Samples of Artemia franciscana were collected from four sites in the Great Salt Lake (GSL), Utah, across several months (June-September 2009). A. franciscana serves as intermediate host of five helminth species in this lake. Four of them are cestodes: three hymenolepidids, i.e. Confluaria podicipina (Szymanski, 1905) (adults parasitic in grebes), Hymenolepis (sensu lato) californicus Young, 1950 (adults parasitic in gulls), Wardium sp. (definitive host unknown, probably charadriiform birds), and one dilepidid, Fuhrmannolepis averini Spassky et Yurpalova, 1967 (adults parasitic in phalaropes). In addition, an unidentified nematode of the family Acuariidae was recorded. Confluaria podicipina is the most prevalent and abundant parasite at all sampling sites, followed by H. (s. l.) californicus. The species composition of the parasites and the spatial variations in their prevalence and abundance reflect the abundance and distribution of aquatic birds serving as their definitive hosts. The temporal dynamics of the overall helminth infections exhibits the highest prevalence in the last month of study at each site (August or September). This native population of A. franciscana from GSL is characterised with higher prevalence, intensity and abundance of the overall cestode infection compared to the introduced populations of this species in the Palaearctic Region. The values of the infection descriptors in the native population of A. franciscana are slightly lower or in some cases similar to those of the Palaearctic species Artemia parthenogenetica Barigozzi (diploid populations) and Artemia salina (Linnaeus) in their native habitats. PMID- 26040583 TI - Isolation a new strain of Kocuria rosea capable of tolerating extreme conditions. PMID- 26040584 TI - Applying a low-flow CO2 removal device in severe acute hypercapnic respiratory failure. AB - A novel and portable extracorporeal CO2-removal device was evaluated to provide additional gas transfer, auxiliary to standard therapy in severe acute hypercapnic respiratory failure. A dual-lumen catheter was inserted percutaneously in five subjects (mean age 55 +/- 0.4 years) and, subsequently, connected to the CO2-removal device. The median duration on support was 45 hours (interquartile range 26-156), with a blood flow rate of approximately 500 mL/min. The mean PaCO2 decreased from 95.8 +/- 21.9 mmHg to 63.9 +/- 19.6 mmHg with the pH improving from 7.11 +/- 0.1 to 7.26 +/- 0.1 in the initial 4 hours of support. Three subjects were directly weaned from the CO2-removal device and mechanical ventilation, one subject was converted to ECMO and one subject died following withdrawal of support. No systemic bleeding or device complications were observed. Low-flow CO2 removal adjuvant to standard therapy was effective in steadily removing CO2, limiting the progression of acidosis in subjects with severe acute hypercapnic respiratory failure. PMID- 26040585 TI - Hybrid ECMO for a patient in respiratory failure developing cardiac insufficiency. AB - A 45-year-old patient in lung failure treated with veno-venous extracorporeal membrane oxygenation (VV ECMO) developed subsequent right heart failure and required cardiac support.We present a method of upgrading a VV ECMO to a hybrid system for simultaneous support for respiratory and cardiac failure. PMID- 26040586 TI - Evaluation of multiple comparison correction procedures in drug assessment studies using LORETA maps. AB - The identification of the brain regions involved in the neuropharmacological action is a potential procedure for drug development. These regions are commonly determined by the voxels showing significant statistical differences after comparing placebo-induced effects with drug-elicited effects. LORETA is an electroencephalography (EEG) source imaging technique frequently used to identify brain structures affected by the drug. The aim of the present study was to evaluate different methods for the correction of multiple comparisons in the LORETA maps. These methods which have been commonly used in neuroimaging and also simulated studies have been applied on a real case of pharmaco-EEG study where the effects of increasing benzodiazepine doses on the central nervous system measured by LORETA were investigated. Data consisted of EEG recordings obtained from nine volunteers who received single oral doses of alprazolam 0.25, 0.5, and 1 mg, and placebo in a randomized crossover double-blind design. The identification of active regions was highly dependent on the selected multiple test correction procedure. The combined criteria approach known as cluster mass was useful to reveal that increasing drug doses led to higher intensity and spread of the pharmacologically induced changes in intracerebral current density. PMID- 26040587 TI - Recognition and pseudonymisation of medical records for secondary use. AB - Health records rank among the most sensitive personal information existing today. An unwanted disclosure to unauthorised parties usually results in significant negative consequences for an individual. Therefore, health records must be adequately protected in order to ensure the individual's privacy. However, health records are also valuable resources for clinical studies and research activities. In order to make the records available for privacy-preserving secondary use, thorough de-personalisation is a crucial prerequisite to prevent re identification. This paper introduces MEDSEC, a system which automatically converts paper-based health records into de-personalised and pseudonymised documents which can be accessed by secondary users without compromising the patients' privacy. The system converts the paper-based records into a standardised structure that facilitates automated processing and the search for useful information. PMID- 26040588 TI - Calibration-free quantitation in microchip zone electrophoresis with conductivity detection. AB - The relationship between electrophoretic mobility and molar conductivity has previously led to speculation on achieving quantitation in zone electrophoresis without calibration curves when using conductivity detection. However, little work in this area has been pursued, possibly because of the breakdown of simple sensitivity-mobility relationships when working with partially protonated species. This topic is revisited with the aid of electrophoretic simulation software that produces facile predictions of analyte sensitivity relative to an internal standard. Calibration curve slopes for over 50 analyte/internal standard/BGE combinations were measured with both unbiased and electrokinetically biased injections using microchip electrophoresis with conductivity detection. The results were compared to theoretical expectations as computed with PeakMaster software. Good agreement was observed, with some systems being predicted with quantitative accuracy while others showed significant deviations. Some mechanisms that can lead to deviations from theory are demonstrated, but the causes for some discrepancies are still not understood. Overall, this work exhibits another useful application for simulation software, particularly for disposable devices where device-specific calibration curves cannot be collected. It also serves as quantitative validation for some outputs of PeakMaster simulation software. PMID- 26040589 TI - GH11 xylanase from Emericella nidulans with low sensitivity to inhibition by ethanol and lignocellulose-derived phenolic compounds. AB - An endo-beta-1,4-xylanase (X22) was purified from crude extract of Emericella nidulans when cultivated on submerged fermentation using sugarcane bagasse as the carbon source. The purified protein was identified by mass spectrometry and was most active at pH and temperature intervals of 5.0-6.5 and 50-60 degrees C, respectively. The enzyme showed half-lives of 40, 10 and 7 min at 28, 50 and 55 degrees C, respectively, and pH 5.0. Apparent Km and Vmax values on soluble oat spelt xylan were 3.39 mg/mL and 230.8 IU/mg, respectively, while Kcat and Kcat/Km were 84.6 s(-1) and 25.0 s(-1) mg(-1) mL. Incubation with phenolic compounds showed that tannic acid and cinnamic acid had an inhibitory effect on X22 but no time-dependent deactivation. On the other hand, ferulic acid, 4-hydroxybenzoic acid, vanillin and p-coumaric acid did not show any inhibitory effect on X22 activity, although they changed X22 apparent kinetic parameters. Ethanol remarkably increased enzyme thermostability and apparent Vmax and Kcat values, even though the affinity and catalytic efficiency for xylan were lowered. PMID- 26040590 TI - Knockout of the alanine racemase gene in Aeromonas hydrophila HBNUAh01 results in cell wall damage and enhanced membrane permeability. AB - This study focused on the alanine racemase gene (alr-2), which is involved in the synthesis of d-alanine that forms the backbone of the cell wall. A stable alr-2 knockout mutant of Aeromonas hydrophila HBNUAh01 was constructed. When the mutant was supplemented with d-alanine, growth was unaffected; deprivation of d-alanine caused the growth arrest of the starved mutant cells, but not cell lysis. No alanine racemase activity was detected in the culture of the mutant. Additionally, a membrane permeability assay showed increasing damage to the cell wall during d-alanine starvation. No such damage was observed in the wild type during culture. Scanning and transmission electron microscopy analyses revealed deficiencies of the cell envelope and perforation of the cell wall. Leakage of UV absorbing substances from the mutants was also observed. Thus, the partial viability of the mutants and their independence of d-alanine for growth indicated that inactivation of alr-2 does not impose an auxotrophic requirement for d alanine. PMID- 26040591 TI - A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity. AB - Acute myeloid leukaemia is characterized by marked inter- and intra-patient heterogeneity, the identification of which is critical for the design of personalized treatments. Heterogeneity of leukaemic cells is determined by mutations which ultimately affect the cell cycle. We have developed and validated a biologically relevant, mathematical model of the cell cycle based on unique cell-cycle signatures, defined by duration of cell-cycle phases and cyclin profiles as determined by flow cytometry, for three leukaemia cell lines. The model was discretized for the different phases in their respective progress variables (cyclins and DNA), resulting in a set of time-dependent ordinary differential equations. Cell-cycle phase distribution and cyclin concentration profiles were validated against population chase experiments. Heterogeneity was simulated in culture by combining the three cell lines in a blinded experimental set-up. Based on individual kinetics, the model was capable of identifying and quantifying cellular heterogeneity. When supplying the initial conditions only, the model predicted future cell population dynamics and estimated the previous heterogeneous composition of cells. Identification of heterogeneous leukaemia clones at diagnosis and post-treatment using such a mathematical platform has the potential to predict multiple future outcomes in response to induction and consolidation chemotherapy as well as relapse kinetics. PMID- 26040592 TI - Metachronal waves in the flagellar beating of Volvox and their hydrodynamic origin. AB - Groups of eukaryotic cilia and flagella are capable of coordinating their beating over large scales, routinely exhibiting collective dynamics in the form of metachronal waves. The origin of this behavior--possibly influenced by both mechanical interactions and direct biological regulation--is poorly understood, in large part due to a lack of quantitative experimental studies. Here we characterize in detail flagellar coordination on the surface of the multicellular alga Volvox carteri, an emerging model organism for flagellar dynamics. Our studies reveal for the first time that the average metachronal coordination observed is punctuated by periodic phase defects during which synchrony is partial and limited to specific groups of cells. A minimal model of hydrodynamically coupled oscillators can reproduce semi-quantitatively the characteristics of the average metachronal dynamics, and the emergence of defects. We systematically study the model's behaviour by assessing the effect of changing intrinsic rotor characteristics, including oscillator stiffness and the nature of their internal driving force, as well as their geometric properties and spatial arrangement. Our results suggest that metachronal coordination follows from deformations in the oscillators' limit cycles induced by hydrodynamic stresses, and that defects result from sufficiently steep local biases in the oscillators' intrinsic frequencies. Additionally, we find that random variations in the intrinsic rotor frequencies increase the robustness of the average properties of the emergent metachronal waves. PMID- 26040593 TI - The organization and control of an evolving interdependent population. AB - Starting with Darwin, biologists have asked how populations evolve from a low fitness state that is evolutionarily stable to a high fitness state that is not. Specifically of interest is the emergence of cooperation and multicellularity where the fitness of individuals often appears in conflict with that of the population. Theories of social evolution and evolutionary game theory have produced a number of fruitful results employing two-state two-body frameworks. In this study, we depart from this tradition and instead consider a multi-player, multi-state evolutionary game, in which the fitness of an agent is determined by its relationship to an arbitrary number of other agents. We show that populations organize themselves in one of four distinct phases of interdependence depending on one parameter, selection strength. Some of these phases involve the formation of specialized large-scale structures. We then describe how the evolution of independence can be manipulated through various external perturbations. PMID- 26040594 TI - Hysteretic dynamics of active particles in a periodic orienting field. AB - Active motion of living organisms and artificial self-propelling particles has been an area of intense research at the interface of biology, chemistry and physics. Significant progress in understanding these phenomena has been related to the observation that dynamic self-organization in active systems has much in common with ordering in equilibrium condensed matter such as spontaneous magnetization in ferromagnets. The velocities of active particles may behave similar to magnetic dipoles and develop global alignment, although interactions between the individuals might be completely different. In this work, we show that the dynamics of active particles in external fields can also be described in a way that resembles equilibrium condensed matter. It follows simple general laws, which are independent of the microscopic details of the system. The dynamics is revealed through hysteresis of the mean velocity of active particles subjected to a periodic orienting field. The hysteresis is measured in computer simulations and experiments on unicellular organisms. We find that the ability of the particles to follow the field scales with the ratio of the field variation period to the particles' orientational relaxation time, which, in turn, is related to the particle self-propulsion power and the energy dissipation rate. The collective behaviour of the particles due to aligning interactions manifests itself at low frequencies via increased persistence of the swarm motion when compared with motion of an individual. By contrast, at high field frequencies, the active group fails to develop the alignment and tends to behave like a set of independent individuals even in the presence of interactions. We also report on asymptotic laws for the hysteretic dynamics of active particles, which resemble those in magnetic systems. The generality of the assumptions in the underlying model suggests that the observed laws might apply to a variety of dynamic phenomena from the motion of synthetic active particles to crowd or opinion dynamics. PMID- 26040595 TI - Potential unsatisfiability of cyclic constraints on stochastic biological networks biases selection towards hierarchical architectures. AB - Constraints placed upon the phenotypes of organisms result from their interactions with the environment. Over evolutionary time scales, these constraints feed back onto smaller molecular subnetworks comprising the organism. The evolution of biological networks is studied by considering a network of a few nodes embedded in a larger context. Taking into account this fact that any network under study is actually embedded in a larger context, we define network architecture, not on the basis of physical interactions alone, but rather as a specification of the manner in which constraints are placed upon the states of its nodes. We show that such network architectures possessing cycles in their topology, in contrast to those that do not, may be subjected to unsatisfiable constraints. This may be a significant factor leading to selection biased against those network architectures where such inconsistent constraints are more likely to arise. We proceed to quantify the likelihood of inconsistency arising as a function of network architecture finding that, in the absence of sampling bias over the space of possible constraints and for a given network size, networks with a larger number of cycles are more likely to have unsatisfiable constraints placed upon them. Our results identify a constraint that, at least in isolation, would contribute to a bias in the evolutionary process towards more hierarchical modular versus completely connected network architectures. Together, these results highlight the context dependence of the functionality of biological networks. PMID- 26040596 TI - Edge effects in game-theoretic dynamics of spatially structured tumours. AB - Cancer dynamics are an evolutionary game between cellular phenotypes. A typical assumption in this modelling paradigm is that the probability of a given phenotypic strategy interacting with another depends exclusively on the abundance of those strategies without regard for local neighbourhood structure. We address this limitation by using the Ohtsuki-Nowak transform to introduce spatial structure to the go versus grow game. We show that spatial structure can promote the invasive (go) strategy. By considering the change in neighbourhood size at a static boundary--such as a blood vessel, organ capsule or basement membrane--we show an edge effect that allows a tumour without invasive phenotypes in the bulk to have a polyclonal boundary with invasive cells. We present an example of this promotion of invasive (epithelial-mesenchymal transition-positive) cells in a metastatic colony of prostate adenocarcinoma in bone marrow. Our results caution that pathologic analyses that do not distinguish between cells in the bulk and cells at a static edge of a tumour can underestimate the number of invasive cells. Although we concentrate on applications in mathematical oncology, we expect our approach to extend to other evolutionary game models where interaction neighbourhoods change at fixed system boundaries. PMID- 26040597 TI - Synthesis, characterization and modelling of zinc and silicate co-substituted hydroxyapatite. AB - Experimental chemistry and atomic modelling studies were performed here to investigate a novel ionic co-substitution in hydroxyapatite (HA). Zinc, silicate co-substituted HA (ZnSiHA) remained phase pure after heating to 1100 degrees C with Zn and Si amounts of 0.6 wt% and 1.2 wt%, respectively. Unique lattice expansions in ZnSiHA, silicate Fourier transform infrared peaks and changes to the hydroxyl IR stretching region suggested Zn and silicate co-substitution in ZnSiHA. Zn and silicate insertion into HA was modelled using density functional theory (DFT). Different scenarios were considered where Zn substituted for different calcium sites or at a 2b site along the c-axis, which was suspected in singly substituted ZnHA. The most energetically favourable site in ZnSiHA was Zn positioned at a previously unreported interstitial site just off the c-axis near a silicate tetrahedron sitting on a phosphate site. A combination of experimental chemistry and DFT modelling provided insight into these complex co-substituted calcium phosphates that could find biomedical application as a synthetic bone mineral substitute. PMID- 26040598 TI - The complex aerodynamic footprint of desert locusts revealed by large-volume tomographic particle image velocimetry. AB - Particle image velocimetry has been the preferred experimental technique with which to study the aerodynamics of animal flight for over a decade. In that time, hardware has become more accessible and the software has progressed from the acquisition of planes through the flow field to the reconstruction of small volumetric measurements. Until now, it has not been possible to capture large volumes that incorporate the full wavelength of the aerodynamic track left behind during a complete wingbeat cycle. Here, we use a unique apparatus to acquire the first instantaneous wake volume of a flying animal's entire wingbeat. We confirm the presence of wake deformation behind desert locusts and quantify the effect of that deformation on estimates of aerodynamic force and the efficiency of lift generation. We present previously undescribed vortex wake phenomena, including entrainment around the wing-tip vortices of a set of secondary vortices borne of Kelvin-Helmholtz instability in the shear layer behind the flapping wings. PMID- 26040599 TI - Unlimited multistability and Boolean logic in microbial signalling. AB - The ability to map environmental signals onto distinct internal physiological states or programmes is critical for single-celled microbes. A crucial systems dynamics feature underpinning such ability is multistability. While unlimited multistability is known to arise from multi-site phosphorylation seen in the signalling networks of eukaryotic cells, a similarly universal mechanism has not been identified in microbial signalling systems. These systems are generally known as two-component systems comprising histidine kinase (HK) receptors and response regulator proteins engaging in phosphotransfer reactions. We develop a mathematical framework for analysing microbial systems with multi-domain HK receptors known as hybrid and unorthodox HKs. We show that these systems embed a simple core network that exhibits multistability, thereby unveiling a novel biochemical mechanism for multistability. We further prove that sharing of downstream components allows a system with n multi-domain hybrid HKs to attain 3n steady states. We find that such systems, when sensing distinct signals, can readily implement Boolean logic functions on these signals. Using two experimentally studied examples of two-component systems implementing hybrid HKs, we show that bistability and implementation of logic functions are possible under biologically feasible reaction rates. Furthermore, we show that all sequenced microbial genomes contain significant numbers of hybrid and unorthodox HKs, and some genomes have a larger fraction of these proteins compared with regular HKs. Microbial cells are thus theoretically unbounded in mapping distinct environmental signals onto distinct physiological states and perform complex computations on them. These findings facilitate the understanding of natural two component systems and allow their engineering through synthetic biology. PMID- 26040600 TI - Quantification of the passive and active biaxial mechanical behaviour and microstructural organization of rat thoracic ducts. AB - Mechanical loading conditions are likely to play a key role in passive and active (contractile) behaviour of lymphatic vessels. The development of a microstructurally motivated model of lymphatic tissue is necessary for quantification of mechanically mediated maladaptive remodelling in the lymphatic vasculature. Towards this end, we performed cylindrical biaxial testing of Sprague-Dawley rat thoracic ducts (n = 6) and constitutive modelling to characterize their mechanical behaviour. Spontaneous contraction was quantified at transmural pressures of 3, 6 and 9 cmH2O. Cyclic inflation in calcium-free saline was performed at fixed axial stretches between 1.30 and 1.60, while recording pressure, outer diameter and axial force. A microstructurally motivated four-fibre family constitutive model originally proposed by Holzapfel et al. (Holzapfel et al. 2000 J. Elast. 61, 1-48. (doi:10.1023/A:1010835316564)) was used to quantify the passive mechanical response, and the model of Rachev and Hayashi was used to quantify the active (contractile) mechanical response. The average error between data and theory was 8.9 +/- 0.8% for passive data and 6.6 +/- 2.6% and 6.8 +/- 3.4% for the systolic and basal conditions, respectively, for active data. Multi-photon microscopy was performed to quantify vessel wall thickness (32.2 +/- 1.60 um) and elastin and collagen organization for three loading conditions. Elastin exhibited structural 'fibre families' oriented nearly circumferentially and axially. Sample-to-sample variation was observed in collagen fibre distributions, which were often non-axisymmetric, suggesting material asymmetry. In closure, this paper presents a microstructurally motivated model that accurately captures the biaxial active and passive mechanical behaviour in lymphatics and offers potential for future research to identify parameters contributing to mechanically mediated disease development. PMID- 26040601 TI - Microbuckling of fibrin provides a mechanism for cell mechanosensing. AB - Biological cells sense and respond to mechanical forces, but how such a mechanosensing process takes place in a nonlinear inhomogeneous fibrous matrix remains unknown. We show that cells in a fibrous matrix induce deformation fields that propagate over a longer range than predicted by linear elasticity. Synthetic, linear elastic hydrogels used in many mechanotransduction studies fail to capture this effect. We develop a nonlinear microstructural finite-element model for a fibre network to simulate localized deformations induced by cells. The model captures measured cell-induced matrix displacements from experiments and identifies an important mechanism for long-range cell mechanosensing: loss of compression stiffness owing to microbuckling of individual fibres. We show evidence that cells sense each other through the formation of localized intercellular bands of tensile deformations caused by this mechanism. PMID- 26040602 TI - Inflammation in intervertebral disc degeneration and regeneration. PMID- 26040604 TI - Ultrasound Evaluation of Carotid Intima-Media Thickness in Children. AB - AIM: The purpose of this study was to assess the association with automated US measurements of carotid artery intima-media thickness (cIMT) with anthropometric, laboratory data and ultrasonographic measurements of fat, in order to identify potential markers that could be used to prevent the development and progression of cardiovascular pathology in adolescents. METHOD: Forty-five patients aged 10 to 17 years were enrolled in this study. Blood samples and anthropometric measurements were obtained from all subjects. All patients underwent an ultrasonic assessment of subcutaneous tissue, pre-peritoneal fat, and intra abdominal fat. All patients received an US assessment of the common carotid artery intima-media thickness. RESULTS: There was a positive association of minimum beds of pre-peritoneal fat, on both sides, with cIMT. Additionally, cIMT on the right side was positively associated with HOMA-IR. In our multivariate analysis, HOMA-IR remained independently associated with cIMT (left) and measurement of the minimum bed of pre-peritoneal fat was associated with right cIMT. There was no association of cIMT with sex, BMI z-score, demographic variables or laboratory findings. CONCLUSION: Pre-peritoneal fat and HOMA-IR are associated with automated ultrasound measurements of both carotid intima-media thickness. Carotid intima-media thickness was not associated with any other demographic variables nor with other laboratory findings when assessed with our automated US method. PMID- 26040603 TI - Applications of the CRISPR-Cas9 system in cancer biology. AB - The prokaryotic type II CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR-associated 9) system is rapidly revolutionizing the field of genetic engineering, allowing researchers to alter the genomes of a large range of organisms with relative ease. Experimental approaches based on this versatile technology have the potential to transform the field of cancer genetics. Here, we review current approaches for functional studies of cancer genes that are based on CRISPR-Cas, with emphasis on their applicability for the development of next-generation models of human cancer. PMID- 26040605 TI - The use of radiation therapy in localized high-grade soft tissue sarcoma and potential impact on survival. AB - BACKGROUND: It is a consensus that radiation therapy (RT) should be applied for all large, deep, high-grade soft tissue sarcomas (STS). Therefore, we investigated the National Cancer Database (NCDB) to study how these guidelines are being followed, to determine what factors may be associated with the decision not to use RT, and to see whether there was an association of RT use and survival. METHODS: We retrospectively analyzed localized high-grade STS patients in the NCDB from 1998 through 2006. They were further stratified into two groups: no radiation (NRT) group and radiation (RT) group. Then, long-term survival between the two groups was evaluated using the Kaplan-Meier (KM) method with comparisons based on the log-rank test. Multiple variables were analyzed between the two groups. Propensity matching was performed secondarily to minimize the influence of confounding variables. RESULTS: A total of 3982 of 10,290 patients (37.8 %) did not receive RT and 6,308 patients (62.2 %) did receive RT. Patients in the NRT group were more likely to have a below-median education level (median 58.2 % vs. 60.7 %; p = 0.015) and a below-median income level (65.1 % vs. 68.6 %; p < 0.001). In addition, these patients lived farther from their treatment centers (20.2 vs. 14.8 miles, p = 0.002) and were more likely to be uninsured (5.3 % vs. 3.5 %, p < 0.001). They were less likely to receive a radical excision (55.2 % vs. 70.1 %; p < 0.001) and more likely to receive amputation (20.9 % vs. 3.3 %; p < 0.001). The 30-day mortality (1.2 % vs. 0.2 %; p < 0.001) and readmission rate (3.8 % vs. 2.8 %; p = 0.031) were higher for the NRT group. KM analysis showed that long-term survival for patients who did not receive RT was significantly lower, even after propensity score matching (p < 0.001). CONCLUSIONS: This large database review reveals a striking lack of utilization of RT to treat high-grade STS, which correlates with poorer survival even after propensity matching. Lower education and income levels and diminished access to medical care (insurance and distance to the facility) are associated with failing to receive RT. PMID- 26040606 TI - Intraperitoneal Vascular Endothelial Growth Factor: A Prognostic Factor and the Potential for Intraperitoneal Bevacizumab Use in Peritoneal Surface Malignancies. AB - INTRODUCTION: Intraperitoneal (IP) vascular endothelial growth factor (VEGF) levels have been shown to vary in the peritoneal cavity of patients with peritoneal surface malignancies. Our purpose was to correlate levels of IP VEGF with overall and disease-free survival to identify whether IP VEGF can be used to prognosticate patients and the possible role of IP bevacizumab. METHODS: From February to October 2012, 97 consecutive patients with peritoneal carcinomatosis were treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Intravenous (IV) VEGF levels were taken before surgery, whereas IP VEGF levels were taken at various time points during and after surgery. RESULTS: Median follow-up was 19.48 months. On univariate analysis, a lower IP VEGF taken just after incision (T1) was associated with improved overall (P = 0.0004) and disease-free survival (P = 0.0006) at 2 years. A lower T1/IV VEGF ratio also was associated with improved overall (P = 0.004) and disease-free survival (P = 0.0051). On multivariate analysis, a lower T1 was associated with improved overall survival, whereas a lower T1/IV VEGF was associated with improved disease free survival. On subset analysis, these two variables were associated with improved survival in colorectal cancers. CONCLUSIONS: A lower IP VEGF level prior to surgery is associated with improved survival. The use of preoperative intraperitoneal bevacizumab for patients with a heavy disease load should be considered, especially in colorectal cancers. PMID- 26040607 TI - Macroscopic Serosal Classification as a Prognostic Index in Radically Resected Stage pT3-pT4b Gastric Cancer. AB - BACKGROUND: Macroscopic serosal classification (MSC) is an important clinicopathologic index of gastric cancer (GC). To investigate the prognostic significance of MSC status in patients with radically resected stage pT3-pT4b GC, we examined the relationship between MSC type and pT stage. METHODS: Clinicopathologic and survival data of 1613 patients with stage pT3-pT4b GC were studied retrospectively, in the aftermath of radical surgery. RESULTS: MSC types, including reactive, nodular, tendonoid, and color-diffused type, correlated significantly with overall survival (OS) in this cohort, but prognosis was similar for all stages of color-diffused type GC. We proposed a revised pT stage in which color-diffused type cancers at pT3 or pT4a stage were reclassified into pT4b stage. In two-step multivariate analysis, revised pT stage (stage pT4b for all color-diffused types) proved more suitable for determining prognosis, surpassing both Union for International Cancer Control/American Joint Committee on Cancer pT stage and MSC type as an independent prognostic index. CONCLUSIONS: MSC type is a significant and independent prognostic index of OS in patients with radically resected stage pT3-pT4b GC. For prognostic purposes, tumors of color diffused type at pT3 or pT4a stage should be considered stage pT4b disease. PMID- 26040608 TI - Setting conservation management thresholds using a novel participatory modeling approach. AB - We devised a participatory modeling approach for setting management thresholds that show when management intervention is required to address undesirable ecosystem changes. This approach was designed to be used when management thresholds: must be set for environmental indicators in the face of multiple competing objectives; need to incorporate scientific understanding and value judgments; and will be set by participants with limited modeling experience. We applied our approach to a case study where management thresholds were set for a mat-forming brown alga, Hormosira banksii, in a protected area management context. Participants, including management staff and scientists, were involved in a workshop to test the approach, and set management thresholds to address the threat of trampling by visitors to an intertidal rocky reef. The approach involved trading off the environmental objective, to maintain the condition of intertidal reef communities, with social and economic objectives to ensure management intervention was cost-effective. Ecological scenarios, developed using scenario planning, were a key feature that provided the foundation for where to set management thresholds. The scenarios developed represented declines in percent cover of H. banksii that may occur under increased threatening processes. Participants defined 4 discrete management alternatives to address the threat of trampling and estimated the effect of these alternatives on the objectives under each ecological scenario. A weighted additive model was used to aggregate participants' consequence estimates. Model outputs (decision scores) clearly expressed uncertainty, which can be considered by decision makers and used to inform where to set management thresholds. This approach encourages a proactive form of conservation, where management thresholds and associated actions are defined a priori for ecological indicators, rather than reacting to unexpected ecosystem changes in the future. PMID- 26040609 TI - Towards an accurate and computationally-efficient modelling of Fe(II)-based spin crossover materials. AB - The DFT + U methodology is regarded as one of the most-promising strategies to treat the solid state of molecular materials, as it may provide good energetic accuracy at a moderate computational cost. However, a careful parametrization of the U-term is mandatory since the results may be dramatically affected by the selected value. Herein, we benchmarked the Hubbard-like U-term for seven Fe(ii)N6 based pseudo-octahedral spin crossover (SCO) compounds, using as a reference an estimation of the electronic enthalpy difference (DeltaHelec) extracted from experimental data (T1/2, DeltaS and DeltaH). The parametrized U-value obtained for each of those seven compounds ranges from 2.37 eV to 2.97 eV, with an average value of U = 2.65 eV. Interestingly, we have found that this average value can be taken as a good starting point since it leads to an unprecedented mean absolute error (MAE) of only 4.3 kJ mol(-1) in the evaluation of DeltaHelec for the studied compounds. Moreover, by comparing our results on the solid state and the gas phase of the materials, we quantify the influence of the intermolecular interactions on the relative stability of the HS and LS states, with an average effect of ca. 5 kJ mol(-1), whose sign cannot be generalized. Overall, the findings reported in this manuscript pave the way for future studies devoted to understand the crystalline phase of SCO compounds, or the adsorption of individual molecules on organic or metallic surfaces, in which the rational incorporation of the U-term within DFT + U yields the required energetic accuracy that is dramatically missing when using bare-DFT functionals. PMID- 26040610 TI - Magnetic nanoparticle based purification and enzyme-linked immunosorbent assay using monoclonal antibody against enrofloxacin. AB - Monoclonal anti-enrofloxacin antibody was prepared for a direct competitive enzyme-linked immunosorbent assay (ELISA) and purification system using monoclonal antibody (mAb) coupled magnetic nanoparticles (MNPs). The IC50 values of the developed mAb for enrofloxacin (ENR), ciprofloxacin, difloxacin, sarafloxacin, pefloxacin, and norfloxacin were 5.0, 8.3, 9.7, 21.7, 36.0, and 63.7 ng/mL, respectively. The lowest detectable level of ENR was 0.7 ng/mL in the prepared ELISA system. To validate the developed ELISA in the food matrix, known amounts of ENR were spiked in meat and egg samples at 10, 20 and 30 ng/mL. Recoveries for ENR ranged from 72.9 to 113.16% with a coefficient of variation (CV) of 2.42 to 10.11%. The applicability of the mAb-MNP system was verified by testing the recoveries for ENR residue in three different matrices. Recoveries for ENR ranged from 75.16 to 86.36%, while the CV ranged from 5.08 to 11.53%. Overall, ENR-specific monoclonal antibody was prepared and developed for use in competitive to ELISAs for the detection of ENR in animal meat samples. Furthermore, we suggest that a purification system for ENR using mAb-coupled MNPs could be useful for determination of ENR residue in food. PMID- 26040611 TI - A multiplex quantitative real-time polymerase chain reaction panel for detecting neurologic pathogens in dogs with meningoencephalitis. AB - Meningoencephalitis (ME) is a common inflammatory disorder of the central nervous system in dogs. Clinically, ME has both infectious and non-infectious causes. In the present study, a multiplex quantitative real-time polymerase chain reaction (mqPCR) panel was optimized for the detection of eight canine neurologic pathogens (Blastomyces dermatitidis, Cryptococcus spp., Neospora caninum, Borrelia burgdorferi, Bartonella spp., Toxoplasma gondii, Ehrlichia canis, and canine distemper virus [CDV]). The mqPCR panel was subsequently applied to 53 cerebrospinal fluid (CSF) samples collected from dogs with ME. The analytic sensitivity (i.e., limit of detection, expressed as molecules per 1 mL of recombinant vector) was 3.8 for CDV, 3.7 for Ehrlichia canis, 3.7 for Bartonella spp., 3.8 for Borrelia burgdorferi, 3.7 for Blastomyces dermatitidis, 3.7 for Cryptococcus spp., 38 for Neospora caninum, and 3.7 for Toxoplasma gondii. Among the tested CSF samples, seven (15%) were positive for the following pathogens in decreasing order of frequency: Cryptococcus spp. (3/7), Blastomyces dermatitidis (2/7), and Borrelia burgdorferi (2/7). In summary, use of an mqPCR panel with high analytic sensitivity as an initial screen for infectious agents in dogs with ME could facilitate the selection of early treatment strategies and improve outcomes. PMID- 26040612 TI - Tissue Doppler and strain imaging of left ventricle in Beagle dogs with iatrogenic hypercortisolism. AB - Changes in radial and longitudinal left ventricular (LV) function were investigated in beagles with iatrogenic hypercortisolism. A total of 11 normal dogs were used, and 2 mg/kg prednisone was administered per oral q12 h for 28 days to 7 out of 11 dogs to induce iatrogenic hypercortisolism. Body weight, blood pressure, conventional echocardiography and tissue Doppler imaging (TDI) of normal and iatrogenic hypercortisolism groups were conducted. The myocardial wall velocity of the LV was measured using color TDI and myocardial deformation was determined by the strain and strain rate. Conventional echocardiography revealed that the diastolic LV free wall and interventricular septum in the hypercortisolism group were thickened relative to those in the normal group. The peak early diastolic myocardial velocity and early to late diastolic myocardial velocity ratio of TDI in the hypercortisolism group were significantly lower than those in the normal group. The strain values in the hypercortisolism group were significantly lower than those in the normal group, particularly for longitudinal wall motion. The lower values of myocardium from TDI and strain imaging could be used to investigate subclinical LV systolic and diastolic dysfunction in dogs with the iatrogenic hypercortisolism. PMID- 26040613 TI - Quantitative CT assessment of bone mineral density in dogs with hyperadrenocorticism. AB - Canine hyperadrenocorticism (HAC) is one of the most common causes of general osteopenia. In this study, quantitative computed tomography (QCT) was used to compare the bone mineral densities (BMD) between 39 normal dogs and 8 dogs with HAC (6 pituitary-dependent hyperadrenocorticism [PDH]; pituitary dependent hyperadrenocorticism, 2 adrenal hyperadrenocorticism [ADH]; adrenal dependent hyperadrenocorticism) diagnosed through hormonal assay. A computed tomogaraphy scan of the 12th thoracic to 7th lumbar vertebra was performed and the region of interest was drawn in each trabecular and cortical bone. Mean Hounsfield unit values were converted to equivalent BMD with bone-density phantom by linear regression analysis. The converted mean trabecular BMDs were significantly lower than those of normal dogs. ADH dogs showed significantly lower BMDs at cortical bone than normal dogs. Mean trabecular BMDs of dogs with PDH using QCT were significantly lower than those of normal dogs, and both mean trabecular and cortical BMDs in dogs with ADH were significantly lower than those of normal dogs. Taken together, these findings indicate that QCT is useful to assess BMD in dogs with HAC. PMID- 26040614 TI - Effects of chelated Zn/Cu/Mn on redox status, immune responses and hoof health in lactating Holstein cows. AB - To evaluate the effects of chelated Zn/Cu/Mn on redox status, immune responses and hoof health in lactating Holstein cows, 48 head in early lactation were divided into healthy or lame groups according to their gait score. Cows were fed the same amount of Zn/Cu/Mn as sulfate salts or in chelated forms for 180 days, and foot-and-mouth disease (FMD) vaccine was injected at day 90. The results showed that lame cows had lower antioxidant function, serum Zn/Mn levels, hair Cu levels, and hoof hardness. Moreover, increased antioxidant status, FMD antibody titers, serum and hair levels of Zn/Cu/Mn, and hoof hardness and decreased milk fat percent and arthritis biomarkers were observed in cows fed chelated Zn/Cu/Mn. In summary, supplementation with chelated Zn/Cu/Mn improved antioxidant status and immune responses, reduced arthritis biomarkers, and increased accumulation of Zn/Cu/Mn in the body and hoof hardness in dairy cows. PMID- 26040615 TI - Discal cysts of the cervical spine in two dogs. AB - Discal cysts, which lie directly over intervertebral discs, are rare. Two old dogs with tetraparesis were referred to our facility. In both animals, magnetic resonance imaging revealed intraspinal extradural cystic mass lesions that were dorsal to degenerative intervertebral discs at the C3-C4 level. These lesions had low signal intensity on T1-weighted images, and high signal intensity on T2 weighted images. A ventral slot approach was used to perform surgical decompression, after which the symptoms improved remarkably. Discal cysts should be included in the differential diagnosis of dogs with cervical pain and tetraparesis. One effective treatment for discal cysts is surgical intervention. PMID- 26040616 TI - Immunization of BALB/c mice with Brucella abortus 2308DeltawbkA confers protection against wild-type infection. AB - Brucellosis is a zoonotic disease that causes animal and human diseases. Vaccination is a major measure for prevention of brucellosis, but it is currently not possible to distinguish vaccinated animals from those that have been naturally infected. Therefore, in this study, we constructed the Brucella (B.) abortus 2380 wbkA mutant (2308DeltawbkA) and evaluated its virulence. The survival of 2308DeltawbkA was attenuated in murine macrophage (RAW 264.7) and BALB/c mice, and it induced high protective immunity in mice. The wbkA mutant elicited an anti-Brucella-specific immunoglobulin G response and induced the secretion of gamma interferon. Antibodies to 2308DeltawbkA could be detected in sera from mice, implying the potential for use of this protein as a diagnostic antigen. The WbkA antigen would allow serological differentiation between infected and vaccinated animals. These results suggest that 2308DeltawbkA is a potential attenuated vaccine against 16M. This vaccine will be further evaluated in sheep. PMID- 26040617 TI - Osteogenic potential of mesenchymal cells derived from canine umbilical cord matrix co-cultured with platelet-rich plasma and demineralized bone matrix. AB - Canine mesenchymal cells (MSCs) derived from Wharton's jelly were co-cultured, then supplemented or not supplemented with platelet rich plasma (PRP) and demineralized bone matrix (DBM) to verify osteogenic differentiation. Osteoblastic differentiation followed by mineralized bone matrix production was found to be significantly higher (p < 0.05) when MSCs were associated with PRP/DBM in culture after 14-21-days of induction. Osteopontin and osteocalcin gene expression were significantly superior (p < 0.05) under the same culture conditions after 21 days of observation. In conclusion, addition of PRP to DBM co cultured with MSCs successfully induced osteogenesis in vitro. PMID- 26040618 TI - Anaplasma sp. and hemoplasma infection in leopard cats (Prionailurus bengalensis euptilurus) from Korea. AB - This study examined the occurrence of Anaplasma spp. and hemoplasma infection in leopard cats, Prionailurus bengalensis euptilurus, in Korea. Twenty-nine biological samples were tested by molecular analysis. Two (6.9%) and eight (27.6%) tested specimens were positive for Anaplasma bovis and hemoplasma infection, respectively. Based on our results, Anaplasma/Ehrlichia spp. and hemoplasma are regularly infecting leopard cat populations of Korea. Considering their endangered status, regular monitoring of infection by arthropod-borne pathogens known to cause clinical symptoms in feline hosts such as Anaplasma/Ehrlichia spp. and hemoplasma would be crucial as part of ongoing conservation efforts. PMID- 26040619 TI - Exceptional Responders Inspire Change: Lessons for Drug Development From the Bedside to the Bench and Back. PMID- 26040620 TI - Adjusting for the Confounding Effects of Treatment Switching-The BREAK-3 Trial: Dabrafenib Versus Dacarbazine. AB - BACKGROUND: Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48-1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS. MATERIALS AND METHODS: Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, "treatment group" (assumes treatment effect could continue until death) and "on-treatment observed" (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect. RESULTS: A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE "treatment group" and "on-treatment observed" analyses performed similarly well. CONCLUSION: RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to treat analysis will be confounded in the presence of treatment switching-a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making. IMPLICATIONS FOR PRACTICE: Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib. PMID- 26040621 TI - Chemotherapy Alone for Patients With Stage II/III Rectal Cancer Undergoing Radical Surgery. AB - PURPOSE: The purpose of this prospective pilot study was to determine the efficacy of preoperative chemotherapy with six cycles of FOLFOX 6 (without radiation therapy) followed by radical surgery followed by six additional cycles of FOLFOX 6 for patients with stage II/III rectal cancer. PATIENTS AND METHODS: From January 2010 to January 2014, patients with locally advanced rectal cancer who met the eligibility criteria were enrolled in this study. Patients received FOLFOX 6 chemotherapy comprising oxaliplatin and leucovorin calcium i.v. over 2 hours on day 1, then bolus, and then continuous fluorouracil i.v. over 46 hours on days 1 and 2. Treatment was repeated every 14 days for 6 courses followed by radical surgery followed by additional 6 cycles of FOLFOX 6. RESULTS: In total, 45 patients were enrolled in this study. In the preoperative re-evaluation, the overall response rate was 68.8% (clinical complete response was 4.4%, and the partial response was 64.4%). There were 14 cases (31.2%) of stable disease. No patients had progressive disease. Postoperatively, the pathologic complete response rate was 8 of 45 (17.8%; 95% confidence interval [CI]: 8.9%-28.9%). The median follow-up was 29 months (range 9-54 months). The actuarial 3-year overall survival and disease-free survival rates for all patients were 80.8% (standard error, 1.877; 95% CI: 69.3%-92.3%) and 67.9% (standard error, 2.319; 95% CI: 54.3%-81.5%), respectively. CONCLUSION: Neoadjuvant chemotherapy (FOLFOX) without radiotherapy is active and safe but cannot be considered a standard of care until the results of prospective randomized phase III trials are available. IMPLICATIONS FOR PRACTICE: Neoadjuvant radiotherapy of rectal cancer represents the current standard of care. However, its use is also associated with short-term toxicity and long-term morbidity. With the increasing use of total mesorectal resection resulting in better local control and advances in systemic therapy for colorectal cancer, this study highlights the question of whether radiation is a necessary component of neoadjuvant therapy for all patients with rectal cancer or whether select patients could be spared the additional toxicities and inconvenience of radiotherapy. This study suggests that neoadjuvant FOLFOX without radiotherapy is active and safe, but it could not be considered a standard of care till now. PMID- 26040622 TI - Phase II Clinical Trial of Ixabepilone in Metastatic Cervical Carcinoma. AB - LESSONS LEARNED: Accrual to cervical cancer studies remains a puzzling challenge given the lack of options and the dismal prognosis of this disease. The majority of patients referred for a trial such as this have very advanced disease that is difficult to manage.The observation of 4 partial responses among the 41 patients indicates that ixabepilone has some activity but not sufficient for further development without greater understanding of mechanisms of sensitivity and resistance. BACKGROUND: Ixabepilone is a microtubule-stabilizing agent approved for metastatic breast cancer. Preclinical data have shown that ixabepilone is active in taxane-sensitive and -resistant cells. Metastatic cervical carcinoma (mCC) has a poor prognosis and no established second-line therapies. This study assessed the efficacy and safety of ixabepilone in previously treated mCC. METHODS: Patients with histologically confirmed mCC and at least one prior cisplatin-containing regimen were treated with ixabepilone [6 mg/m(2) per day for 5 days] every 21 days. The primary endpoint was progression-free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints were response rate, rate of tumor growth, overall survival (OS), and safety. Levels of glu-terminated and acetylated tubulin, markers of microtubule stabilization, and surrogates for target engagement were assessed by Western blot. RESULTS: In total, 41 patients were enrolled; 34 had tumors with primarily squamous histology. The median number of prior therapies was 2 (range 1-6). Four patients (9.7%) had a partial response. Median PFS in months was 2.3 for all, 3.84 for taxane-naive, and 2.03 for taxane-pretreated patients (p = .13). Consistent with this, we found statistically similar (p = 1) rates of growth in taxane-naive patients (0.0035 per day) and taxane pretreated patients (0.0053 per day). Median OS was 5.84 months. G1/2 toxicities included vomiting (43%), sensory neuropathy (21%), and fatigue (60%). Bowel fistulas were observed in 7% of patients. Glu and acetylated tubulin were assessed in tumor samples from 11 patients during the first cycle of treatment. Although there was clear evidence of "target engagement" and microtubule stabilization in all tumors, a correlation between the extent of tubulin stabilization and response to therapy could not be demonstrated. CONCLUSION: Ixabepilone was well tolerated but showed very modest activity in second- or later-line mCC and cannot be recommended as a therapy. Target engagement was demonstrated but was not correlated with responses, suggesting that other factors mediate drug sensitivity. New strategies are needed for refractory mCC. PMID- 26040623 TI - Minimum absolute lymphocyte count during radiotherapy as a new prognostic factor for nasopharyngeal cancer. AB - BACKGROUND: The purpose of this study was to investigate whether the minimum absolute lymphocyte count (ALC) during radiotherapy (RT) could predict clinical outcome in patients with nasopharyngeal cancer (NPC). METHODS: We analyzed 70 patients with NPC including 63 patients treated with chemoradiotherapy and used multivariate analysis to determine whether minimum ALC affected clinical outcome. RESULTS: Patients were grouped by minimum ALC, with a cutoff of 245 cells/MUL. Five-year disease-specific survival (DSS) and progression-free survival (PFS) for patients with minimum ALC >=245 versus minimum ALC <245 were 88.1% versus 60.8% (p = .004) and 71.2% versus 35.2% (p = .004). All 10 patients with minimum ALC <120 experienced disease progression. Four of 6 patients (67%) with ALC <120 who died experienced disease progression within 6 months. CONCLUSION: Minimum ALC may predict poor 5-year DSS and should be evaluated by prospective studies. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1061-E1067, 2016. PMID- 26040624 TI - Eliminating residual iPS cells for safety in clinical application. PMID- 26040625 TI - Time-varying maximal proteinuria correlates with adverse cardiovascular events and graft failure in kidney transplant recipients. AB - AIM: In the general population, proteinuria is associated with progression to kidney failure, cardiovascular disease, and mortality. Here, we analyzed the effects of proteinuria on outcomes in kidney transplant recipients. METHODS: We performed a retrospective, multi-centre cohort study involving 2047 recipients to evaluate the effects of post-transplant proteinuria on adverse cardiovascular events, graft failure, and mortality. Patients were classified into two groups according to their levels of proteinuria: patients without proteinuria (<150 mg/day, n = 1113) and proteinuric patients (>= 150 mg/day, n = 934). Multivariate Cox hazard model was conducted with using the maximal proteinuria as time-varying covariate. RESULTS: During a median 55.3-month (range, 0.6-167.1) follow-up, there were 50 cases of major adverse cardiac events (cardiac death, nonfatal myocardial infarction, or coronary revascularization), 115 cases of graft failure, and 52 patient deaths. In multivariate Cox regression with time-varying covariate, proteinuric recipients were significantly associated with major adverse cardiac events (hazard ratio [HR] 8.689, 95% confidence interval [CI] 2.929-25.774, P < 0.001) compared to those without proteinuria. Recipients with proteinuria showed significantly higher incidences of acute rejection (23.1% vs. 9.4%, P < 0.001) and graft failure rate (HR 6.910, 95% CI 3.270-14.601, P < 0.001). In addition, mortality rate was also significantly higher in patients with proteinuria (HR 6.815, 95% CI 2.164-21.467, P = 0.001). CONCLUSION: Post transplant proteinuria correlates with adverse cardiovascular events, graft failure, and mortality. Therefore, proteinuria should be evaluated and managed to improve the outcomes of renal recipients. PMID- 26040626 TI - Lameness detection via leg-mounted accelerometers on dairy cows on four commercial farms. AB - Lameness in dairy herds is traditionally detected by visual inspection, which is time-consuming and subjective. Compared with healthy cows, lame cows often spend longer time lying down, walk less and change behaviour around feeding time. Accelerometers measuring cow leg activity may assist farmers in detecting lame cows. On four commercial farms, accelerometer data were derived from hind leg mounted accelerometers on 348 Holstein cows, 53 of them during two lactations. The cows were milked twice daily and had no access to pasture. During a lactation, locomotion score (LS) was assessed on average 2.4 times (s.d. 1.3). Based on daily lying duration, standing duration, walking duration, total number of steps, step frequency, motion index (MI, i.e. total acceleration) for lying, standing and walking, eight accelerometer means and their corresponding coefficient of variation (CV) were calculated for each week immediately before an LS. A principal component analysis was performed to evaluate the relationship between the variables. The effects of LS and farm on the principal components (PC) and on the variables were analysed in a mixed model. The first four PC accounted for 27%, 18%, 12% and 10% of the total variation, respectively. PC1 corresponded to Activity variability due to heavy loading by five CV variables related to standing and walking. PC2 corresponded to Activity level due to heavy loading by MI walking, MI standing and walking duration. PC3 corresponded to Recumbency due to heavy loading by four variables related to lying. PC4 corresponded mainly to Stepping due to heavy loading by step frequency. Activity variability at LS4 was significantly higher than at the lower LS levels. Activity level was significantly higher at LS1 than at LS2, which was significantly higher than at LS4. Recumbency was unaffected by LS. Stepping at LS1 and LS2 was significantly higher than at LS3 and LS4. Activity level was significantly lower on farm 3 compared with farms 1 and 2. Stepping was significantly lower on farms 1 and 3 compared with farms 2 and 4. MI standing indicated increased restlessness while standing when cows increased from LS3 to LS4. Lying duration was only increased in lame cows. In conclusion, Activity level differed already between LS1 and LS2, thus detecting early signs of lameness, particularly through contributions from walking duration and MI walking. Lameness detection models including walking duration, MI walking and MI standing seem worthy of further investigation. PMID- 26040628 TI - Monolayer Ti2CO2: A Promising Candidate for NH3 Sensor or Capturer with High Sensitivity and Selectivity. AB - Ti2C is one of the thinnest layers in MXene family with high potential for applications. In the present study, the adsorption of NH3, H2, CH4, CO, CO2, N2, NO2, and O2 on monolayer Ti2CO2 was investigated by using first-principles simulations to exploit its potential applications as gas sensor or capturer. Among all the gas molecules, only NH3 could be chemisorbed on Ti2CO2 with apparent charge transfer of 0.174 e. We further calculated the current-voltage (I V) relation using the nonequilibrium Green's function (NEGF) method. The transport feature exhibits distinct responses with a dramatic change of I-V relation before and after NH3 adsorption on Ti2CO2. Thus, we predict that Ti2CO2 could be a promising candidate for the NH3 sensor with high selectivity and sensitivity. On the other hand, the adsorption of NH3 on Ti2CO2 could be further strengthened with the increase of applied strain on Ti2CO2, while the adsorption of other gases on Ti2CO2 is still weak under the same strain, indicating that the capture of NH3 on Ti2CO2 under the strain is highly preferred over other gas molecules. Moreover, the adsorbed NH3 on Ti2CO2 could be escapable by releasing the applied strain, which indicates the capture process is reversible. Our study widens the application of monolayer Ti2CO2 not only as the battery material, but also as the potential gas sensor or capturer of NH3 with high sensitivity and selectivity. PMID- 26040627 TI - Randomised clinical study: Aspergillus niger-derived enzyme digests gluten in the stomach of healthy volunteers. AB - BACKGROUND: Aspergillus niger prolyl endoprotease (AN-PEP) efficiently degrades gluten molecules into non-immunogenic peptides in vitro. AIM: To assess the efficacy of AN-PEP on gluten degradation in a low and high calorie meal in healthy subjects. METHODS: In this randomised, double-blind, placebo-controlled, cross-over study 12 healthy volunteers attended to four test days. A liquid low or high calorie meal (4 g gluten) with AN-PEP or placebo was administered into the stomach. Via a triple-lumen catheter gastric and duodenal aspirates were sampled, and polyethylene glycol (PEG)-3350 was continuously infused. Acetaminophen in the meals tracked gastric emptying time. Gastric and duodenal samples were used to calculate 240-min area under the curve (AUC0-240 min ) of ? gliadin concentrations. Absolute ?-gliadin AUC0-240 min was calculated using duodenal PEG-3350 concentrations. RESULTS: AN-PEP lowered alpha-gliadin concentration AUC0-240 min, compared to placebo, from low and high calorie meals in stomach (low: 35 vs. 389 MUg * min/mL; high: 53 vs. 386 MUg * min/mL; P < 0.001) and duodenum (low: 7 vs. 168 MUg * min/mL; high: 4 vs. 32 MUg * min/mL; P < 0.001) and absolute alpha-gliadin AUC0-240 min in the duodenum from low (2813 vs. 31 952 MUg * min; P < 0.001) and high (2553 vs. 13 095 MUg * min; P = 0.013) calorie meals. In the placebo group, the high compared to low calorie meal slowed gastric emptying and lowered the duodenal alpha-gliadin concentration AUC0-240 min (32 vs. 168 MUg * min/mL; P = 0.001). CONCLUSIONS: AN-PEP significantly enhanced gluten digestion in the stomach of healthy volunteers. Increasing caloric density prolonged gastric residence time of the meal. Since AN-PEP already degraded most gluten from low calorie meals, no incremental effect was observed by increasing meal caloric density. ClinicalTrials.gov, Number: NCT01335503; www.trialregister.nl, Number: NTR2780. PMID- 26040629 TI - The health, education, and social care costs of school-aged children with active epilepsy: A population-based study. AB - OBJECTIVE: To provide data on the health, social care, and education costs of active childhood epilepsy and factors associated with these costs over an 18 month period in a population-based sample. METHODS: The Children with Epilepsy in Sussex Schools (CHESS) study is a population-based study involving school-aged children (5-15 years) with active epilepsy (taking one or more antiepileptic drug and/or had a seizure in the last year) in a defined geographical area in England. Clinical data were collected on 85 children (74% of eligible population) who underwent comprehensive psychological assessment. Health, education, and social care resource use was collected retrospectively over an 18-month period. Regression analysis was used to identify variables associated these with costs. RESULTS: The mean (standard deviation) 18-month cost of health care for a child with active epilepsy was L3,635 (L5,339), with mean education and social care cost of L11,552 (L8,937) and L1,742 (L8,158), respectively, resulting in total mean costs per participant of L16,931 (L14,764). Health care costs were significantly associated with seizure frequency and etiology (all p-values < 0.05). Combined health care, social care, and education costs were significantly related to cognitive impairment (intelligence quotient [IQ] <85) and seizure frequency (p < 0.05). The mean cost of health care, social care, and education over 18 months for participants with cognitive impairment was L23,579 (95% confidence interval [CI] L16,489-L30,670) compared to L7,785 (95% CI L4,943 L10,627) for those without impairment. SIGNIFICANCE: Active childhood epilepsy has significant health, social care, and education costs. This is the first study to comprehensively document the economic impact on these sectors as well as factors associated with these costs. When caring for children with epilepsy in England, costs incurred by education and social care sectors are approximately four times the costs incurred by the health care sector. Increased costs were associated with cognitive impairment (IQ <85) and weekly or greater seizure frequency. PMID- 26040630 TI - Transient and stable transformation of Ceratopteris richardii gametophytes. AB - BACKGROUND: Ferns, being vascular yet seedless, present unparalleled opportunities to investigate important questions regarding the evolution and development of land plants. Ceratopteris richardii, a diploid, homosporous fern has been advanced as a model fern system; however, the tenuous ability to transform the genome of this fern greatly limited its usefulness as a model organism. Here we report a simple and reliable Agrobacterium-mediated method for generating transient and stable transformants of mature C. richardii gametophytes. RESULTS: Transformation success was achieved by enzyme treatment that partially digested the cell walls of mature gametophytes to facilitate Agrobacteria infection. Co-incubation of Agrobacteria with enzymatically treated gametophytes was sufficient to generate transient transformants at a frequency of nearly 90% under optimal conditions. Stable transformation was achieved at a rate of nearly 3% by regenerating entire gametophytes from single transformed cells from T0 gametophytes on selective media. CONCLUSIONS: This transformation method will allow for the immediate observation of phenotypes in the haploid gametophytes of transformed plants, as well as the generation of stably transformed C. richardii lines for further analysis. Transformation capability will greatly facilitate gene functional studies in C. richardii, more fully realizing the potential of this model fern species. These protocols may be adapted to other plant species that are recalcitrant to Agrobacterium-mediated transformation. PMID- 26040631 TI - Modelling the cost-effectiveness of pharmacotherapy compared with cognitive behavioural therapy and combination therapy for the treatment of moderate to severe depression in the UK. AB - BACKGROUND: The National Institute of Health and Care Excellence (NICE) in England and Wales recommends the combination of pharmacotherapy and psychotherapy for the treatment of moderate to severe depression. However, the cost effectiveness analysis on which these recommendations are based has not included psychotherapy as monotherapy as a potential option. For this reason, we aimed to update, augment and refine the existing economic evaluation. METHOD: We constructed a decision analytic model with a 27-month time horizon. We compared pharmacotherapy with cognitive-behavioural therapy (CBT) and combination treatment for moderate to severe depression in secondary care from a healthcare service perspective. We reviewed the literature to identify relevant evidence and, where possible, synthesized evidence from clinical trials in a meta-analysis to inform model parameters. RESULTS: The model suggested that CBT as monotherapy was most likely to be the most cost-effective treatment option above a threshold of L 22,000 per quality-adjusted life year (QALY). It dominated combination treatment and had an incremental cost-effectiveness ratio of L 20,039 per QALY compared with pharmacotherapy. There was significant decision uncertainty in the probabilistic and deterministic sensitivity analyses. CONCLUSIONS: Contrary to previous NICE guidance, the results indicated that even for those patients for whom pharmacotherapy is acceptable, CBT as monotherapy may be a cost-effective treatment option. However, this conclusion was based on a limited evidence base, particularly for combination treatment. In addition, this evidence cannot easily be transferred to a primary care setting. PMID- 26040632 TI - A Japanese prospective multi-institutional feasibility study on accelerated partial breast irradiation using interstitial brachytherapy: treatment planning and quality assurance. AB - BACKGROUND: In Japan, breast-conserving surgery with closed cavity has generally been performed for breast cancer patients, and accelerated partial breast irradiation (APBI) is considered difficult because Asian females generally have smaller breast sizes than Western females. Therefore, common identification of target and treatment plan method in APBI is required. A prospective multicenter study was conducted in Japan to determine institutional compliance with APBI using high-dose-rate interstitial brachytherapy (ISBT) designed for Japanese female patients. METHODS: For this study, 46 patients were recruited at eight institutions from January 2009 to December 2011. The reproducibility of the ISBT APBI plan was evaluated using three criteria: (1) minimum clinical target volume dose with a clip dose >= 6 Gy/fraction, (2) irradiated volume constraint of 40 150 cm(3), and (3) uniformity of dose distribution, expressed as the dose non uniformity ratio (DNR, V150/V100) < 0.35. The ISBT-APBI plan for each patient was considered reproducible when all three criteria were met. When the number of non reproducible patients was <= 4 at study completion, APBI at this institution was considered statistically reproducible. RESULTS: Half of the patients (52 %) had a small bra size (A/B cup). The mean values of the dose-constrained parameters were as follows: Vref, 117 cm(3) (range, 40-282), DNR, 0.30 (range, 0.22-0.51), and clip dose, 784 cGy (range, 469-3146). A total of 43/46 treatment plans were judged to be compliant and ISBT-APBI was concluded to be reproducible. CONCLUSIONS: This study showed that multi-institutional ISBT-APBI treatment plan was reproducible for small breast patient with closed cavity. PMID- 26040633 TI - Research protocol for a randomized controlled trial of the health effects of volunteering for seniors. AB - BACKGROUND: A growing evidence base demonstrates that interventions that focus on participation in physical and social activities can assist in preventing and treating both physical and mental health problems. In addition, there is some evidence that engaging in volunteering activities can provide beneficial social, physical, psychological, and cognitive outcomes for older people. This study will use a randomized controlled trial approach to investigate the potential for interventions involving volunteer activities to produce positive physical and psychological outcomes for older people, thereby contributing to the limited evidence relating to the potential for volunteering to provide multiple health effects. METHODS/DESIGN: This randomized controlled trial will involve 400 retired/non-employed individuals in good health aged 60+ years living in the metropolitan area in Perth, Western Australia. Participants will be recruited from the Perth metropolitan area using a variety of recruitment methods to achieve a diverse sample in terms of age, gender, and socioeconomic status. Consenting and eligible participants will be randomly assigned to an intervention (n = 200) or control group (n = 200). Those in the intervention group will be asked to engage in a minimum 60 min of volunteer activities per week for a period of 6 months, while those in the control group will be asked to maintain their existing lifestyle or take on new activities as they see fit. Physical and psychological outcomes will be assessed. Primary physical outcomes will include physical activity and sedentary time (measured using pedometers and Actigraph monitors) and physical health (measured using a battery of physical functioning tests, resting heart rate, blood pressure, BMI, and girth). Primary psychological outcomes will include psychological well-being, depression, self-esteem, and quality of life (measured using the Warwick-Edinburgh Mental Well-Being Scale, Center for Epidemiologic Studies Depression Scale, the Rosenberg Self-Esteem Survey, and the Global Quality of Life Scale, respectively). Secondary outcomes of interest will include attitudes to volunteering (measured via open-ended interviews) and personal growth, purpose in life, social support, and self efficacy (measured using the Personal Growth and Purpose in Life subscales of Ryff's Psychological Well-Being Scale, the Social Provisions Scale, and the Generalized Self-Efficacy Scale, respectively). Participants will be re-assessed on these measures after 6 months. DISCUSSION: The results of this randomized controlled trial will generate new knowledge relating to the physical and psychological health benefits of different levels and types of volunteering for older people. In addition, insight will be provided into the major factors influencing the recruitment and retention of older volunteers. Understanding the full potential for volunteering to affect physical and mental well-being will provide policy makers with the evidence they require to determine appropriate investment in the volunteering sector, especially in relation to encouraging volunteering among older people who constitute an important resource for the community. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12615000091505. Date registered: 3 February, 2015. PMID- 26040634 TI - Internally architectured materials with directionally asymmetric friction. AB - Internally Architectured Materials (IAMs) that exhibit different friction forces for sliding in the opposite directions are proposed. This is achieved by translating deformation normal to the sliding plane into a tangential force in a manner that is akin to a toothbrush with inclined bristles. Friction asymmetry is attained by employing a layered material or a structure with parallel 'ribs' inclined to the direction of sliding. A theory of directionally asymmetric friction is presented, along with prototype IAMs designed, fabricated and tested. The friction anisotropy (the xi-coefficient) is characterised by the ratio of the friction forces for two opposite directions of sliding. It is further demonstrated that IAM can possess very high levels of friction anisotropy, with xi of the order of 10. Further increase in xi is attained by modifying the shape of the ribs to provide them with directionally dependent bending stiffness. Prototype IAMs produced by 3D printing exhibit truly giant friction asymmetry, with xi in excess of 20. A novel mechanical rectifier, which can convert oscillatory movement into unidirectional movement by virtue of directionally asymmetric friction, is proposed. Possible applications include locomotion in a constrained environment and energy harvesting from oscillatory noise and vibrations. PMID- 26040635 TI - Long-term effect of a short interprofessional education interaction between medical and physical therapy students. AB - Medicine is increasingly focused on team-based practice as interprofessional cooperation leads to better patient care. Thus, it is necessary to teach teamwork and collaboration with other health care professionals in undergraduate medical education to ensure that trainees entering the workforce are prepared to work in teams. Gross anatomy provides an opportunity to expose students to interprofessional education (IPE) early in their training. The purpose of this study is to describe an IPE experience and report if the experience has lasting influence on the participating students. The Readiness for Interprofessional Learning Scale (RIPLS) questionnaire was administered to first year medical (MD) and physical therapy (PT) students at Mayo Medical School and Mayo School of Health Sciences. Results demonstrated an openness on the part of the students to IPE. Interprofessional education experiences were incorporated into gross anatomy courses in both medical and PT curricula. The IPE experiences included a social event, peer-teaching, and collaborative clinical problem-solving sessions. These sessions enhanced gross anatomy education by reinforcing previous material and providing the opportunity to work on clinical cases from the perspective of two healthcare disciplines. After course completion, students again completed the RIPLS. Finally, one year after course completion, students were asked to provide feedback on their experience. The post-curricular RIPLS, similar to the pre curricular RIPLS, illustrated openness to IPE from both MD and PT students. There were however, significant differences in MD and PT perceptions of roles and responsibilities. One-year follow-up indicated long-term retention of lessons learned during IPE. PMID- 26040636 TI - Postexercise orthostatic intolerance: influence of exercise intensity. AB - NEW FINDINGS: What is the central question of this study? Following exercise, hypotension is often reported and syncope is more likely. It is unresolved whether the postexercise hypotension associated with different exercise intensities contributes to the rate at which syncope develops. What is the main finding and its importance? The physiological events that induce presyncope are the same both before and after exercise; however, more intense exercise accelerated the development of hypocapnia, hypotension and, ultimately, syncope. These data indicate that higher intensity exercise induces a postexercise hypotension that reduces cardiovascular reserve, an earlier development of hypocapnia and, ultimately, cerebral hypoperfusion. After exercise, a reduction in mean arterial pressure is often experienced and is referred to as postexercise hypotension. Whilst syncope is more likely following exercise, it is unknown whether orthostatic tolerance is impacted by any exercise intensity-mediated effect on postexercise hypotension. We examined the effect of exercise intensity on time to presyncope, induced via combined head-up tilt and lower body negative pressure following 1 h of cycling at 30 and 70% of heart rate range. Healthy participants (n = 8; mean +/- SD, 28 +/- 5 years old) completed orthostatic testing to presyncope before and after exercise. Beat-to-beat middle cerebral artery blood flow velocity (MCAv), mean arterial pressure and cerebral oxygenation (measured by near-infrared spectroscopy) were recorded continuously throughout orthostatic testing. During exercise, heart rates were 95 +/- 6 and 147 +/- 5 beats min(-1) for 30 and 70% heart rate range, respectively, with average power outputs of 103 +/- 22 and 221 +/- 45 W, respectively. Time to presyncope occurred 32% sooner after the 70% heart rate range trial (952 +/- 484 versus 1418 +/- 435 s; P = 0.004). Both before and after exercise, presyncope occurred at the same reduction in MCAv (grouped mean, -30 +/- 11 cm s(-1) ), mean arterial pressure (-18 +/- 13 mmHg), total oxygenation index (-6 +/- 2%) and partial pressure of end-tidal CO2 (-16 +/- 8 mmHg; all P > 0.1). At presyncope following exercise, the MCAv response was related more to the change in partial pressure of end-tidal CO2 from the baseline preceding orthostatic testing (r(2) = 0.50, P = 0.01) than to the hypotension (r(2) = 0.12, P = 0.17). Presyncope both before and after exercise occurred as a result of the same physiological perturbations, albeit greatly accelerated following more intense exercise. PMID- 26040637 TI - Substrate-mediated strain effect on the role of thermal heating and electric field on metal-insulator transition in vanadium dioxide nanobeams. AB - Single-crystalline vanadium dioxide (VO2) nanostructures have recently attracted great attention because of their single domain metal-insulator transition (MIT) nature that differs from a bulk sample. The VO2 nanostructures can also provide new opportunities to explore, understand, and ultimately engineer MIT properties for applications of novel functional devices. Importantly, the MIT properties of the VO2 nanostructures are significantly affected by stoichiometry, doping, size effect, defects, and in particular, strain. Here, we report the effect of substrate-mediated strain on the correlative role of thermal heating and electric field on the MIT in the VO2 nanobeams by altering the strength of the substrate attachment. Our study may provide helpful information on controlling the properties of VO2 nanobeam for the device applications by changing temperature and voltage with a properly engineered strain. PMID- 26040639 TI - Prepregnancy dietary patterns and risk of developing hypertensive disorders of pregnancy: results from the Australian Longitudinal Study on Women's Health. AB - BACKGROUND: Hypertensive disorders of pregnancy (HDPs), including gestational hypertension and pre-eclampsia, are common obstetric complications associated with adverse health outcomes for the mother and child. It remains unclear how dietary intake can influence HDP risk. OBJECTIVE: We investigated associations between prepregnancy dietary patterns and risk of HDPs. DESIGN: We selected 3582 women participating in the Australian Longitudinal Study on Women's Health, which is an observational population-based study. Women were not pregnant at baseline in 2003 and reported at least one live birth between 2003 and 2012. Diet was assessed by using a validated 101-item food-frequency questionnaire in 2003, and factor analysis was used to identify dietary patterns. HDPs were assessed by using the question, "Were you diagnosed or treated for hypertension during pregnancy?" Generalized estimating equation models were used to estimate RRs (95% CIs) adjusted for dietary, reproductive, sociodemographic, and lifestyle factors. RESULTS: During 9 y of follow-up of 3582 women, 305 women (8.5%) reported a first diagnosis of HDPs in 6149 pregnancies. We identified 4 dietary patterns labeled as meat, high-fat, and sugar; Mediterranean-style; fruit and low-fat dairy; and cooked vegetables. In the adjusted model, the meat, high-fat, and sugar, fruit and low-fat dairy, and cooked vegetable dietary patterns were not associated with HDP risk. The Mediterranean-style dietary pattern (characterized by vegetables, legumes, nuts, tofu, rice, pasta, rye bread, red wine, and fish) was inversely associated with risk of developing HDPs (quartile 4 compared with quartile 1: RR, 0.58; 95% CI, 0.42, 0.81). CONCLUSIONS: In this population-based study of Australian women, we observed an independent protective dose-response association between prepregnancy consumption of a Mediterranean-style dietary pattern and HDP risk. Additional studies are recommended to confirm our findings by prospectively examining whether the implementation of the Mediterranean-style dietary pattern before pregnancy has a role in the prevention of HDPs. PMID- 26040640 TI - Validation of an inexpensive and accurate mathematical method to measure long term changes in free-living energy intake. AB - BACKGROUND: Accurate measurement of free-living energy intake (EI) over long periods is imperative for understanding obesity and its treatment. Unfortunately, traditional methods rely on self-report and are notoriously inaccurate. Although EI can be indirectly estimated by the intake-balance method, this technique is prohibitively labor-intensive and expensive, requiring repeated measures of energy expenditure via doubly labeled water (DLW) along with multiple dual-energy X-ray absorptiometry (DXA) scans to measure changes in body energy stores. OBJECTIVE: Our objective was to validate a mathematical method to measure long term changes in free-living energy intake. DESIGN: We measured body weight and EI changes (DeltaEI) over 4 time intervals by using the intake-balance method in 140 individuals who underwent 2 y of caloric restriction as part of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy study. We compared the DeltaEI values calculated by using DLW/DXA with those obtained by using a mathematical model of human metabolism whose only inputs were the initial demographic information and repeated body weight data. RESULTS: The mean DeltaEI values calculated by the model were within 40 kcal/d of the DLW/DXA method throughout the 2-y study. For individual subjects, the overall root mean square deviation between the model and DLW/DXA method was 215 kcal/d, and most of the model-calculated DeltaEI values were within 132 kcal/d of the DLW/DXA method. CONCLUSIONS: Accurate and inexpensive estimates of DeltaEI that are comparable to the DLW/DXA method can be obtained by using a mathematical model and repeated body weight measurements. PMID- 26040641 TI - Association of dietary phosphate and serum phosphorus concentration by levels of kidney function. AB - BACKGROUND: The health implications of dietary phosphorus intake and the role of kidney function in managing serum phosphorus homeostasis are well studied. However, examining the source of dietary phosphorus intake and its impact on serum phosphorus has not been characterized in population studies. OBJECTIVE: This study aimed to distinguish the association of food sources of organic phosphorus and inorganic phosphate additives with serum phosphorus concentration. DESIGN: A cross-sectional analysis of 24-h food recall data from 7895 adult participants in the National Health and Nutrition Examination Survey 2003-2006 was performed. Phosphorus content of foods was categorized as organic or inorganic. Correlations of serum phosphorus to clinical and dietary intake variables were achieved by using multiple regression analysis. RESULTS: After controlling for estimated glomerular filtration rate (eGFR), body mass index (BMI; in kg/m2), and albumin-to-creatinine ratio, a significant increase in serum phosphorus occurred with dairy foods with inorganic phosphates [parameter estimate (PE) +/- SE: 0.07 +/- 0.02 mg/dL, P < 0.01] or without inorganic phosphates (PE: 0.02 +/- 0.01, P < 0.001) and cereals/grains with inorganic phosphates (PE: 0.005 +/- 0.002, P < 0.01). Significantly higher serum phosphorus occurred when eGRF was <30 (PE: 0.24 +/- 0.08, P < 0.0001), but eGFR 30-44 (PE: 0.11 +/- 0.04, P < 0.01) and 45-60 (PE: -0.10 +/- 0.04, P < 0.01) were associated with lower serum phosphorus; higher serum phosphorus was associated with BMI <18.5 (PE: 0.18 +/- 0.05, P = 0.0009) but lower with BMI >=35-39 (PE: -0.09 +/- 0.03, P = 0.0013) or >=40 (PE: -0.10 +/- 0.03, P = 0.014). CONCLUSIONS: This analysis shows that dairy products and cereals/grains having inorganic phosphate additives significantly increase serum phosphorus concentration, despite being consumed less frequently than foods without phosphate additives. It seems prudent for the Nutrient Facts Label to include phosphorus but also for food manufacturers to consider alternatives to phosphate additives. PMID- 26040642 TI - Effects of postnatal growth restriction and subsequent catch-up growth on neurodevelopment and glucose homeostasis in rats. AB - BACKGROUND: There is increasing evidence that poor growth of preterm infants is a risk factor for poor long-term development, while the effects of early postnatal growth restriction are not well known. We utilized a rat model to examine the consequences of different patterns of postnatal growth and hypothesized that early growth failure leads to impaired development and insulin resistance. Rat pups were separated at birth into normal (N, n = 10) or restricted intake (R, n = 16) litters. At d11, R pups were re-randomized into litters of 6 (R-6), 10 (R-10) or 16 (R-16) pups/dam. N pups remained in litters of 10 pups/dam (N-10). Memory and learning were examined through T-maze test. Insulin sensitivity was measured by i.p. insulin tolerance test and glucose tolerance test. RESULTS: By d10, N pups weighed 20% more than R pups (p < 0.001). By d15, the R-6 group caught up to the N-10 group in weight, the R-10 group showed partial catch-up growth and the R 16 group showed no catch-up growth. All R groups showed poorer scores in developmental testing when compared with the N-10 group during T-Maze test (p < 0.05). Although R-16 were more insulin sensitive than R-6 and R-10, all R groups were more glucose tolerant than N-10. CONCLUSION: In rats, differences in postnatal growth restriction leads to changes in development and in insulin sensitivity. These results may contribute to better elucidating the causes of poor developmental outcomes in human preterm infants. PMID- 26040643 TI - Health bodies resign from "charade" of EU alcohol forum. PMID- 26040645 TI - Four decades of National Blood Service in Iran: outreach, prospect and challenges. AB - OBJECTIVE: This study aims to compare the changes and progress made to Iranian Blood Transfusion Organization (IBTO) during 1974-2014 in order to identify the shortcomings. BACKGROUND: The History of Blood transfusion in Iran can be traced back to the 1940s. IBTO was established in 1974 as a national centralised organisation, supported by Iranian government for its budget and supplies and provides its products free of charge to both public and private hospitals. METHODS: The statistics have been derived from IBTO Statistical Center. Also related literature has been reviewed. RESULTS: From 1974 to 2014, donation per population has been increased about eight times. IBTO reached 100% voluntary blood donation in 2007, but the number of female blood donors in Iran is six times lower than average global rate. On one hand, the prevalence rate of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) in blood donors was dropped in to one fifth and one third, respectively during past 8 years. On the other hand, irrational blood usage and lack of integrated blood stock management systems and non self-sufficiency on plasma-derivedmedicines are considered as main challenges of IBTO. CONCLUSION: Forty years since the establishment, IBTO managed to achieve considerable improvements in different fields but many challenges still remain, which need to be addressed urgently. Great gap between the number of male and female blood donors in Iran has to be filled. The improvement of knowledge and practice on patient blood management and use of alternatives are on the agenda of IBTO in next coming years. PMID- 26040644 TI - Improving quality of care and long-term health outcomes through continuity of care with the use of an electronic or paper patient-held portable health file (COMMUNICATE): study protocol for a randomized controlled trial. AB - BACKGROUND: The advantages of patient-held portable health files (PHF) and personal health records (PHR), paper or electronic, are said to include improved health-care provider continuity-of-care and patient empowerment in maintaining health. Top-down approaches are favored by public sector government and health managers. Bottom-up approaches include systems developed directly by health-care providers, consumers and industry, implemented locally on devices carried by patient-consumers or shared via web-based portals. These allow individuals to access, manage and share their health information, and that of others for whom they are authorized, in a private, secure and confidential environment. Few medical record technologies have been evaluated in randomized trials to determine whether there are important clinical benefits of these interventions. The COMMUNICATE trial will assess the acceptability and long-term clinical outcomes of an electronic and paper patient-held PHF. METHODS/DESIGN: This is a 48-month, open-label pragmatic, superiority, parallel-group design randomized controlled trial. Subjects (n = 792) will be randomized in a 1:1:1 ratio to each of the trial arms: the electronic PHF added to usual care, the paper PHF added to usual care and usual care alone (no PHF). Inclusion criteria include those 60 years or older living independently in the community, but who have two or more chronic medical conditions that require prescription medication and regular care by at least three medical practitioners (general and specialist care). The primary objective is whether use of a PHF compared to usual care reduces a combined endpoint of deaths, overnight hospitalizations and blindly adjudicated serious out-of-hospital events. All primary analyses will be undertaken masked to randomized arm allocation using intention-to-treat principles. Secondary outcomes include quality of life and health literacy improvements. DISCUSSION: Lack of blinding creates potential for bias in trial conduct and ascertainment of clinical outcomes. Mechanisms are provided to reduce bias, including balanced study contact with all participants, a blinded adjudication committee determining which out-of-hospital events are serious and endpoints that are objective (overnight hospitalizations and mortality). The PRECIS tool provides a summary of the trial's design on the Pragmatic-Explanatory Continuum. TRIAL REGISTRATION: Registered with Clinicaltrials.gov (identifier: NCT01082978) on 8 March 2010. PMID- 26040646 TI - Acute alcohol intoxication and bispectral index monitoring. AB - BACKGROUND: Bispectral index (BIS) monitoring is commonly used to decrease the risk of awareness during anaesthesia. We aimed to determine the relationship between blood alcohol concentration and brain function (as measured by BIS) in healthy adults. METHODS: In this prospective observational study, 21 anaesthetic registrars self-regulated alcohol consumption over a 3-h period. Expired alcohol concentration (breathalyser) and BIS measurements were performed hourly for 4 h. A venous blood alcohol sample was taken at the conclusion of the study period. RESULTS: The main outcome measures were the correlation between blood alcohol and brain function as measured by BIS and the change in BIS from baseline (?BIS) at 4 h. The median number of standard drinks consumed was 9.1 (IQR 7.7-12.3), range 5.4-17. At 4 h, there was a moderate inverse correlation between BIS and blood alcohol (r = -0.49, P = 0.029) and between ?BIS and blood alcohol (r = -0.46, P =0.043). CONCLUSION: In healthy young adults, we found a moderate correlation between venous blood alcohol concentration and BIS. This suggests that acute alcohol consumption can decrease BIS. This information may be relevant when providing anaesthesia to intoxicated patients who require urgent or time-critical surgery, although certain limitations of this study should be kept in mind. PMID- 26040647 TI - Cerebral perfusion in the predementia stages of Alzheimer's disease. AB - OBJECTIVES: To investigate arterial spin-labelling (ASL) cerebral blood flow (CBF) changes in predementia stages of Alzheimer's disease (AD). METHODS: Data were obtained from 177 patients with subjective complaints, mild cognitive impairment and AD from the Amsterdam Dementia Cohort. AD stages were based on diagnosis and cerebrospinal fluid biomarkers amyloid-beta (Abeta) and total-tau (tau). General-linear-models were used to assess relationships between AD stages and total and regional CBF, correcting for age and sex. RESULTS: Decreasing CBF was related to more advanced AD stages in all supratentorial regions (p for trend < 0.05). Post-hoc testing revealed that CBF was lower in AD compared to controls and stage-1 predementia patients (i.e. abnormal Abeta and normal tau) in temporal and parietal regions, and compared to stage-2 predementia patients (i.e. abnormal Abeta and tau) in temporal regions. CBF values of stage-2 predementia patients were numerically in between those of stage-1 predementia patients and AD. CONCLUSION: The continuing decrease of CBF along the continuum of AD indicates the potential of ASL-CBF as a measure for disease progression. KEY POINTS: * Decreasing CBF relates to more advanced AD stages in all supratentorial regions. * The reduction of CBF does not reach a bottom level. * ASL-CBF has potential as a measure for disease progression in AD. PMID- 26040648 TI - Change in volume parameters induced by neoadjuvant chemotherapy provide accurate prediction of overall survival after resection in patients with oesophageal cancer. AB - OBJECTIVES: To assess the prognostic value of volumetric parameters measured with CT and PET/CT in patients with neoadjuvant chemotherapy (NACT) and resection for oesophageal cancer (EC). METHODS: Patients with locally advanced EC, who were treated with NACT and resection, were retrospectively analysed. Data from CT volumetry and (18) F-FDG PET/CT (maximum standardized uptake [SUVmax], metabolic tumour volume [MTV], and total lesion glycolysis [TLG]) were recorded before and after NACT. The impact of volumetric parameter changes induced by NACT (MTVRATIO, TLGRATIO, etc.) on overall survival (OS) was assessed using a Cox proportional hazards model. RESULTS: Eighty-four patients were assessed using CT volumetry; of those, 50 also had PET/CT before and after NACT. Low post-treatment CT volume and thickness, MTV, TLG, and SUVmax were all associated with longer OS (p < 0.05), as were CTthicknessRATIO, MTVRATIO, TLGRATIO, and SUVmaxRATIO (p < 0.05). In the multivariate analysis, only MTVRATIO (Hazard ratio, HR 2.52 [95% Confidence interval, CI 1.33-4.78], p = 0.005), TLGRATIO (HR 3.89 [95%CI 1.46-10.34], p = 0.006), and surgical margin status (p < 0.05), were independent predictors of OS. CONCLUSIONS: MTVRATIO and TLGRATIO are independent prognostic factors for survival in patients after NACT and resection for EC. KEY POINTS: * Change in PET parameters shows close correlation to survival in oesophageal cancer. * Association with OS is independent of changes in SUVmax and CT volume. * Metabolic parameters after NACT correlate with pathologic response and nodal status. * Metabolic parameters may be better suited than SUVmax for response assessment. PMID- 26040650 TI - Glioneuronal tumours with features of rosette-forming glioneuronal tumours of the fourth ventricle and dysembryoplastic neuroepithelial tumours: a report of three cases. AB - AIMS: To study three atypical glioneuronal tumours (GNTs), in order to shed light on the clinical and pathological features of this diverse tumour group. METHODS AND RESULTS: Clinical and neuropathological data for each case were retrospectively reviewed. Case 1 involved a 17-year-old boy with left leg movement difficulty. A mass lesion in the basal ganglia was detected radiologically; histopathological features included neurocytic/perivascular rosettes and a pilocytic astrocytoma component. Case 2 involved a 33-year-old man with intractable epilepsy. His left parietal lobe contained a cyst-like mass, resembling dysembryoplastic neuroepithelial tumour and rosette-forming glioneuronal tumour of the fourth ventricle microscopically. Case 3 involved a 21 year-old woman with a mass lesion in the mesencephalic tegmentum extending to the third and fourth ventricles and the suprasellar region. The lesion contained perivascular/neurocytic rosettes and an oligodendroglioma-like component. None of the tumours expressed an isocitrate dehydrogenase I mutation of the R132H type or contained a 1p/19q deletion, a BRAF(V600E) mutation, or KIAA1549-BRAF fusion. CONCLUSIONS: We describe three GNTs with atypical histopathology and locations. Additional cases and molecular studies are needed to better understand the biological nature of GNTs and to refine their classification system. PMID- 26040651 TI - Prognostic factors and follow-up strategy for superficial soft-tissue sarcomas: Analysis of 622 surgically treated patients from the scandinavian sarcoma group register. AB - BACKGROUND AND OBJECTIVES: Our study aimed to describe the clinical outcome of patients with superficial soft-tissue sarcomas (SSTS), define prognostic factors and provide evidence for a rational surveillance scheme. METHODS: Data for 622 consecutive, surgically treated SSTS patients were retrieved from the Scandinavian Sarcoma Group Register. We assessed the rates of local recurrence (LR) and metastasis (M), as well as overall survival (OS), local recurrence free survival (LRFS) and metastasis-free survival (MFS) of the cohort. RESULTS: The incidence of LR and M was 9% and 12%, respectively. OS at 5 years was 79%, LRFS was 74% and MFS 76%. Factors that affected OS, LRFS, and MFS were tumor size and patient age. Additionally, tumor grade was an independent prognostic factor for LRFS. The majority of LR and M events were observed the first 2 years of follow up. Clear surgical margins were correlated to lower risk for LR. Selected patients benefited from adjuvant radiotherapy. CONCLUSIONS: SSTS have a favourable prognosis, which is mainly determined by tumour-associated factors. Adequate surgical margins are important for local control, whereas radiotherapy has a secondary role. The data support current surveillance schemes, with a closer follow-up the first 2 years after surgery. PMID- 26040652 TI - Quantification of parasite shedding and horizontal transmission parameters in Histomonas meleagridis-infected turkeys determined by real-time quantitative PCR. AB - To gain more insight into the within flock transmission of Histomonas meleagridis, the shedding of parasites was quantified by a newly developed real time quantitative (q)PCR and the basic reproduction number (R0) and the mean number of secondary infections per infectious bird per day in a susceptible population (beta) of H. meleagridis in the absence of heterakis were assessed. Forty turkeys were divided into two groups of 10 and 30 birds at 14 days of age. Birds of the first group were inoculated with 200,000 histomonads each, the second group served as a susceptible contact group. Cloacal swabs were taken at 1, 1, 4, 7, 9, 11, 14, 18 and 21 days post inoculation (p.i.) to assess the shedding of the parasite by the qPCR (detection limit 330 histomonads/ml droppings). The experiment ended at 28 days p.i. Mortality was 100% in the inoculated birds and started at day 12 p.i., while in the contacts, it was 83% and started at 16 days p.i. Shedding started 1 day after the inoculation in both groups. The mean shedding levels (and 95% CI) expressed as parasite equivalents per gram cloacal content on a log10 scale in the inoculated, contact birds that died and contact birds alive were 2.0 (1.6-2.4), 1.6 (1.4-1.9) and 1.2 (0.5-2.0), respectively. Birds that died shed histomonas more often and were infectious for 13.4 days; in contrast, those that recovered were infectious for 5.7 days. R0 was estimated to be 8.4 and beta 0.70. Simulations made with the parameters obtained were in agreement with the experimental results, confirming their validity. PMID- 26040649 TI - Multiscale analysis of the murine intestine for modeling human diseases. AB - When functioning properly, the intestine is one of the key interfaces between the human body and its environment. It is responsible for extracting nutrients from our food and excreting our waste products. It provides an environment for a host of healthful microbes and serves as a first defense against pathogenic ones. These processes require tight homeostatic controls, which are provided by the interactions of a complex mix of epithelial, stromal, neural and immune cells, as well as the resident microflora. This homeostasis can be disrupted by invasive microbes, genetic lesions, and carcinogens, resulting in diseases such Clostridium difficile infection, inflammatory bowel disease (IBD) and cancer. Enormous strides have been made in understanding how this important organ functions in health and disease using everything from cell culture systems to animal models to human tissue samples. This has resulted in better therapies for all of these diseases, but there is still significant room for improvement. In the United States alone, 14,000 people per year die of C. difficile, up to 1.6 million people suffer from IBD, and more than 50,000 people die every year from colon cancer. Because these and other intestinal diseases arise from complex interactions between the different components of the gut ecosystem, we propose that systems approaches that address this complexity in an integrative manner may eventually lead to improved therapeutics that deliver lasting cures. This review will discuss the use of systems biology for studying intestinal diseases in vivo with particular emphasis on mouse models. Additionally, it will focus on established experimental techniques that have been used to drive this systems level analysis, and emerging techniques that will push this field forward in the future. PMID- 26040653 TI - Arthroscopic proximal versus open subpectoral biceps tenodesis with arthroscopic repair of small- or medium-sized rotator cuff tears. AB - PURPOSE: The study was aimed to compare arthroscopic proximal biceps tenodesis and open subpectoral biceps tenodesis in repair of small or medium rotator cuff tears. METHODS: Eighty-five patients underwent biceps tenodesis with arthroscopic repair of a rotator cuff tear, and 66 patients were followed for median of 26.8 (18-42) months with ultrasonography were reviewed. The arthroscopic biceps tenodesis group included 34 cases, and the open subpectoral biceps group included 32 cases. Patients were evaluated using visual analogue scale (VAS), American Shoulder and Elbow Surgeons (ASES), and constant scores. Rotator cuff repair and fixation of the biceps tendon were assessed by ultrasonography. Fixation failure and degree of deformity were evaluated by the pain in the bicipital groove and biceps apex distance (BAD). RESULTS: VAS score and tenderness at the bicipital groove decreased significantly in the open subpectoral group at 3 months postoperative. In both groups, the range of motion, ASES score, and constant score increased significantly (P < 0.05). Rotator cuff retear occurred in three cases (8.8 %) in the arthroscopic group and two cases in the open subpectoral group (6.2 %). There was no significant difference in BAD between the two groups. CONCLUSION: There was no difference between open subpectoral tenodesis and arthroscopic proximal tenodesis at the time of the final follow-up; however, open subpectoral tenodesis showed encouraging results at 3-month follow-up. This early result of subpectoral tenodesis was related to removing most part of biceps tendinitis and using intra-bicipital groove tenodesis technique. LEVEL OF EVIDENCE: III. PMID- 26040654 TI - Comparison of femur tunnel aperture location in patients undergoing transtibial and anatomical single-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: Although three-dimensional computed tomography (3D-CT) has been used to compare femoral tunnel position following transtibial and anatomical anterior cruciate ligament (ACL) reconstruction, no consensus has been reached on which technique results in a more anatomical position because methods of quantifying femoral tunnel position on 3D-CT have not been consistent. This meta-analysis was therefore performed to compare femoral tunnel location following transtibial and anatomical ACL reconstruction, in both the low-to-high and deep-to-shallow directions. METHODS: This meta-analysis included all studies that used 3D-CT to compare femoral tunnel location, using quadrant or anatomical coordinate axis methods, following transtibial and anatomical (AM portal or OI) single-bundle ACL reconstruction. RESULTS: Six studies were included in the meta-analysis. Femoral tunnel location was 18 % higher in the low-to-high direction, but was not significant in the deep-to-shallow direction, using the transtibial technique than the anatomical methods, when measured using the anatomical coordinate axis method. When measured using the quadrant method, however, femoral tunnel positions were significantly higher (21 %) and shallower (6 %) with transtibial than anatomical methods of ACL reconstruction. CONCLUSION: The anatomical ACL reconstruction techniques led to a lower femoral tunnel aperture location than the transtibial technique, suggesting the superiority of anatomical techniques for creating new femoral tunnels during revision ACL reconstruction in femoral tunnel aperture location in the low-to-high direction. However, the mean difference in the deep-to-shallow direction differed by method of measurement. LEVEL OF EVIDENCE: Meta-analysis, Level II. PMID- 26040655 TI - The correlation between femoral sulcus morphology and osteoarthritic changes in the patello-femoral joint. AB - PURPOSE: The purpose of this study was to reveal the correlation between the type of lesion and the depth of osteoarthritic (OA) changes in the patello-femoral (PF) joint and its bony morphological characteristics using computed tomography (CT) data. METHODS: Eighty-seven cadaveric knees were included in this study with median age of 83 years (62-97). OA depth evaluation was performed following Outerbridge's classification. Patella OA lesions were classified macroscopically using Han's method: type (1) no or minimal lesion, type (2) medial facet lesion without involvement of the ridge, type (3) lateral facet lesion without involvement of the ridge, type (4) lesion involving the ridge only, type (5) medial facet lesion with involvement of the ridge, type (6) lateral facet lesion with involvement of the ridge, and type (7) global lesion. Femoral-side OA lesions in the PF joint were classified using a modified Chang's method. Type (1) no or minimal lesion, type (2) medial facet lesion, type (3) centre of patella groove lesion, type (4) lateral facet lesion, and type (5) global lesion. Whole body CTs of all cadavers were taken before knee dissection. Using the CT data, patella morphology was evaluated following Wiberg's classification. Femoral sulcus angle (SA), sulcus depth (SD), and sulcus width (SW) were also measured using CT data. RESULTS: The measured SA, SD, and SW were 144.8 degrees +/- 7.2 degrees , 7.0 +/- 1.6 mm and 3.4 +/- 0.3 mm, respectively. When patella OA depth was divided into grades 1-2 (n = 30) and grades 3-4 (n = 57), the SD of grade 1-2 knees was 6.5 +/- 1.3 mm, and the SD of grade 3-4 knees was 7.3 +/- 1.6 mm, constituting a significant difference (p = 0.01). No significant difference in either SA or SW was observed between the two groups. Patella OA lesion, femoral side OA lesion, and depth were not affected by SA, SD, or SW. Wiberg's classification also showed no significant correlation with PF-OA. CONCLUSION: Deep SD was significantly correlated with the incidence of severe patella OA. Wiberg's classification, SA, and SW were not correlated with PF-OA. For clinical relevance, there is a risk of PF-OA progression in patients with deep SD, and treatment should be applied accordingly. PMID- 26040656 TI - Direct ChIP-Seq significance analysis improves target prediction. AB - BACKGROUND: Chromatin immunoprecipitation followed by sequencing of protein-bound DNA fragments (ChIP-Seq) is an effective high-throughput methodology for the identification of context specific DNA fragments that are bound by specific proteins in vivo. Despite significant progress in the bioinformatics analysis of this genome-scale data, a number of challenges remain as technology-dependent biases, including variable target accessibility and mappability, sequence dependent variability, and non-specific binding affinity must be accounted for. RESULTS AND DISCUSSION: We introduce a nonparametric method for scoring consensus regions of aligned immunoprecipitated DNA fragments when appropriate control experiments are available. Our method uses local models for null binding; these are necessary because binding prediction scores based on global models alone fail to properly account for specialized features of genomic regions and chance pull downs of specific DNA fragments, thus disproportionally rewarding some genomic regions and decreasing prediction accuracy. We make no assumptions about the structure or amplitude of bound peaks, yet we show that our method outperforms leading methods developed using either global or local null hypothesis models for random binding. We test prediction performance by comparing analyses of ChIP-seq, ChIP-chip, motif-based binding-site prediction, and shRNA assays, showing high reproducibility, binding-site enrichment in predicted target regions, and functional regulation of predicted targets. CONCLUSIONS: Given appropriate controls, a direct nonparametric method for identifying transcription-factor targets from ChIP-Seq assays may lead to both higher sensitivity and higher specificity, and should be preferred or used in conjunction with methods that use parametric models for null binding. PMID- 26040657 TI - GATE Monte Carlo simulations for variations of an integrated PET/MR hybrid imaging system based on the Biograph mMR model. AB - A simulation toolkit, GATE (Geant4 Application for Tomographic Emission), was used to develop an accurate Monte Carlo (MC) simulation of a fully integrated 3T PET/MR hybrid imaging system (Siemens Biograph mMR). The PET/MR components of the Biograph mMR were simulated in order to allow a detailed study of variations of the system design on the PET performance, which are not easy to access and measure on a real PET/MR system. The 3T static magnetic field of the MR system was taken into account in all Monte Carlo simulations. The validation of the MC model was carried out against actual measurements performed on the PET/MR system by following the NEMA (National Electrical Manufacturers Association) NU 2-2007 standard. The comparison of simulated and experimental performance measurements included spatial resolution, sensitivity, scatter fraction, and count rate capability. The validated system model was then used for two different applications. The first application focused on investigating the effect of an extension of the PET field-of-view on the PET performance of the PET/MR system. The second application deals with simulating a modified system timing resolution and coincidence time window of the PET detector electronics in order to simulate time-of-flight (TOF) PET detection. A dedicated phantom was modeled to investigate the impact of TOF on overall PET image quality. Simulation results showed that the overall divergence between simulated and measured data was found to be less than 10%. Varying the detector geometry showed that the system sensitivity and noise equivalent count rate of the PET/MR system increased progressively with an increasing number of axial detector block rings, as to be expected. TOF-based PET reconstructions of the modeled phantom showed an improvement in signal-to-noise ratio and image contrast to the conventional non TOF PET reconstructions. In conclusion, the validated MC simulation model of an integrated PET/MR system with an overall accuracy error of less than 10% can now be used for further MC simulation applications such as development of hardware components as well as for testing of new PET/MR software algorithms, such as assessment of point-spread function-based reconstruction algorithms. PMID- 26040658 TI - Canine small clear cell/T-zone lymphoma: clinical presentation and outcome in a retrospective case series. AB - Published studies, taken together, suggest the existence of a single canine lymphoma entity, with a small clear cell appearance by cytological evaluation, a histopathological T-zone pattern and an aberrant CD45-negative T-cell phenotype, mostly characterized by long-term survival. We describe clinical presentation and outcome in a retrospective case series of canine small clear cell/T-zone lymphoma. Despite the reported predisposition of Golden retriever, this breed was not represented in our case series. Most dogs presented with stage V disease, whereas only few had clinical signs or peripheral cytopenias. Blood was almost always more infiltrated than bone marrow. Median survival confirmed the favourable prognosis described in literature, but a few dogs died within a short time. Also, a subgroup of dogs developed second malignancies, eventually leading to death. We did not investigate possible prognostic factors because of the wide variety in treatments, and further studies are needed to identify high-risk animals. PMID- 26040660 TI - Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS Nebulisation in Baboon Monkeys. AB - PURPOSE: The objective of this study was to compare two different nebulizers: Eflow rapid(r) and Pari LC star(r) by scintigraphy and PK modeling to simulate epithelial lining fluid concentrations from measured plasma concentrations, after nebulization of CMS in baboons. METHODS: Three baboons received CMS by IV infusion and by 2 types of aerosols generators and colistin by subcutaneous infusion. Gamma imaging was performed after nebulisation to determine colistin distribution in lungs. Blood samples were collected during 9 h and colistin and CMS plasma concentrations were measured by LC-MS/MS. A population pharmacokinetic analysis was conducted and simulations were performed to predict lung concentrations after nebulization. RESULTS: Higher aerosol distribution into lungs was observed by scintigraphy, when CMS was nebulized with Pari LC(r) star than with Eflow Rapid(r) nebulizer. This observation was confirmed by the fraction of CMS deposited into the lung (respectively 3.5% versus 1.3%).CMS and colistin simulated concentrations in epithelial lining fluid were higher after using the Pari LC star(r) than the Eflow rapid(r) system. CONCLUSIONS: A limited fraction of CMS reaches lungs after nebulization, but higher colistin plasma concentrations were measured and higher intrapulmonary colistin concentrations were simulated with the Pari LC Star(r) than with the Eflow Rapid(r) system. PMID- 26040661 TI - Suppression of Remodeling Behaviors with Arachidonic Acid Modification for Enhanced in vivo Antiatherogenic Efficacies of Lovastatin-loaded Discoidal Recombinant High Density Lipoprotein. AB - PURPOSE: A series of in vitro evaluation in our previous studies had proved that arachidonic acid (AA) modification could suppress the remodeling behaviors of lovastatin-loaded discoidal reconstituted high density lipoprotein (LT-d-rHDL) by restraining the reactivity with lecithin cholesterol acyltransferase (LCAT) for reducing undesired drug leakage. This study focuses on the investigation of AA modified LT-d-rHDL (AA-LT-d-rHDL) in atherosclerotic New Zealand White (NZW) rabbit models to explore whether AA modification could enhance drug targeting delivery and improve antiatherogenic efficacies in vivo. METHODS: After pharmacokinetics of AA-LT-d-rHDL modified with different AA amount were investigated in atherosclerotic NZW rabbits, atherosclerotic lesions targeting property was assessed by ex vivo imaging of aortic tree and drug distribution. Furthermore, their antiatherogenic efficacies were elaborately evaluated and compared by typical biochemical indices. RESULTS: With AA modification amount augmenting, circulation time of AA-LT-d-rHDL was prolonged, and drug accumulation in the target locus was increased, eventually the significant appreciation in antiatherogenic efficacies were further supported by lower level of bad cholesterol, decreased atherosclerotic lesions areas and mean intima-media thickness (MIT), markedly attenuated matrix metalloproteinase-9 (MMP-9) protein expression and macrophage infiltration. CONCLUSION: This proof-of-concept study demonstrated that AA-LT-d-rHDL could enhance drug accumulation in atherosclerotic lesion and impede atherosclerosis progression more effectively. PMID- 26040662 TI - Structural Characterisation of Non-Deamidated Acidic Variants of Erwinia chrysanthemi L-asparaginase Using Small-Angle X-ray Scattering and Ion-Mobility Mass Spectrometry. AB - PURPOSE: Erwinia chrysanthemi L-asparaginase (ErA) is an enzyme commonly used in the treatment regimen for Acute Lymphoblastic Leukaemia (ALL). Biopharmaceutical products such as ErA must be monitored for modifications such as deamidation, typically using ion-exchange chromatography (IEX). Analysis of clinical-grade ErA using native IEX resolves a number of enzymatically-active, acidic variants that were poorly characterised. METHODS: ErA IEX variants were isolated and fully characterised using capillary electrophoresis (cIEF), LC-MS and LC-MS/MS of proteolytic digests, and structural techniques including circular dichroism, small-angle X-ray scattering (SAXS) and ion-mobility mass spectrometry (IM-MS). RESULTS: LC-MS, MS/MS and cIEF demonstrated that all ErA isolates consist mainly of enzyme lacking primary-sequence modifications (such as deamidation). Both SAXS and IM-MS revealed a different conformational state in the most prominent acidic IEX peak. However, SAXS data also suggested conformational differences between the main peak and major acidic variant were minor, based on comparisons with crystal structures. CONCLUSIONS: IEX data for biopharmaceuticals such as ErA should be thoroughly characterised, as the most common modifications, such as deamidation, may be absent. PMID- 26040664 TI - 17beta-Trenbolone exposure programs metabolic dysfunction in larval medaka. AB - Here, we used physiological and transcriptomic analyses to evaluate the effects of 17beta-trenbolone (TB) on metabolism during the early life stage of medaka (Oryzias latipes). In the physiological experiments, sex reversal rates increased continuously in proportion to TB concentrations (2-100 ng/L), and were 100% (all males) in the 200 ng/L treatment group. TB caused a significant increase in the gonadosomatic index of females at concentrations of 60 and 100 ng/L. These females exhibited swollen abdomens and decreased egg production and fertility. Significant increases were observed in the body mass index of these females. TB caused decreased fertility in males at concentrations >20 ng/L, but no other effects were observed. In the transcriptomic (microarray) experiments, larvae were exposed to TB for up to 7 d. Analyses using the KEGG Orthology Database revealed that predominant categories of significantly upregulated genes included "lipid metabolism" and "metabolism of terpenoids and polyketides." Thirteen genes (including those for hydroxymethylglutaryl-CoA synthase, cytoplasmic synthase, and lanosterol synthase) related to cholesterol biosynthesis via the mevalonate pathway were highlighted in these categories. Reverse transcriptase-polymerase chain reaction analyses were consistent with the microarray results, in terms of the direction and magnitude of change to gene expression. Among the downregulated genes, angiopoietin-like 4 and mitochondrial uncoupling protein 1, which are inversely correlated with obesity, were detected in the TB treatments. In conclusion, the results suggest that the exposure of females to TB during the early life stage may cause metabolic dysfunctions, including obesity and disrupted cholesterol synthesis. (c) 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1539-1551, 2016. PMID- 26040663 TI - Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice. AB - PURPOSE: To investigate protective effects of alisol B 23-acetate (AB23A) against hepatotoxity and cholestasis induced by 17alpha-ethinylestradiol (EE) in association with farnesoid X receptor (FXR) activation in vivo and in vitro. METHODS: The cholestatic liver injury model was established by subcutaneous injections of EE in C57BL/6 mice. Serum biomarkers, bile flow assay and H&E staining were used to identify the amelioration of cholestasis after AB23A treatment. Mice primary hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying AB23A hepatoprotection. RESULTS: AB23A treatment protected against liver injury induced by EE through increasing hepatic efflux and reducing uptake of bile acid via an induction in efflux transporters (Bsep and Mrp2) and an inhibition in hepatic uptake transporter (Ntcp) expression. AB23A also reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrated that the changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo and were abrogated after FXR was silenced in vitro. CONCLUSIONS: AB23A produces protective effects against EE-induced cholestasis, due to FXR-mediated gene regulation. PMID- 26040665 TI - Complications after CO2 laser surgery for early glottic cancer: An institutional experience. AB - BACKGROUND: Transoral laser microsurgery (TLM) of the glottis is increasingly utilized in the current management of early glottic cancer, its advantages being administrative ease, potential to be repeated, ability to keep radiotherapy and open laryngeal surgery available as salvage options, and low complication rates. METHODS: A retrospective chart review of prospectively gathered data on all patients over a 10-year period who had undergone TLM for Tis or early (T1-2) glottic squamous cell carcinomas (SCCs) was analyzed to examine the complications experienced. RESULTS: Of 132 patients undergoing TLM, complications were: edema requiring tracheostomy (n = 1), surgical emphysema (n = 1), pharyngeal bruising (n = 1), endotracheal tube cuff perforation (n = 1), anterior glottic web (n = 14), vocal cord granuloma (n = 14), laryngocele (n = 1), and none of airway fire or intraoperative or postoperative hemorrhage. CONCLUSION: Our results suggest that for early glottic cancers, and in skilled hands, with appropriate anesthetic and theater staff support, TLM is a safe and repeatable procedure. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E987-E990, 2016. PMID- 26040666 TI - Impact of heparanase on renal fibrosis. AB - Tubulo-interstitial fibrosis has been recognized as the hallmark of progression of chronic kidney disease, but, despite intensive research studies, there are currently no biomarkers or effective treatments for this condition. In this context, a promising candidate could be heparanase-1 (HPSE), an endoglycosidase that cleaves heparan sulfate chains and thus takes part in extracellular matrix remodeling. As largely described, it has a central role in the pathogenesis of cancer and inflammation, and it participates in the complex biological machinery involved in the onset of different renal proteinuric diseases (e.g., diabetic nephropathy, glomerulonephritis). Additionally, HPSE may significantly influence the progression of chronic kidney damage trough its major role in the biological pathway of renal fibrogenesis. Here, we briefly summarize data supporting the role of HPSE in renal damage, focusing on recent evidences that demonstrate the capability of this enzyme to modulate the signaling of pro-fibrotic factors such as FGF-2 and TGF-beta and consequently to control the epithelial-mesenchymal transition in renal tubular cells. We also emphasize the need of the research community to undertake studies and clinical trials to assess the potential clinical employment of this enzyme as diagnostic and prognostic tool and/or its role as therapeutic target for new pharmacological interventions. PMID- 26040667 TI - Salvinorin A analogues PR-37 and PR-38 attenuate compound 48/80-induced itch responses in mice. AB - BACKGROUND AND PURPOSE: The opioid system plays a crucial role in several physiological processes in the CNS and in the periphery. It has also been shown that selective opioid receptor agonists exert potent inhibitory action on pruritus and pain. In this study we examined whether two analogues of Salvinorin A, PR-37 and PR-38, exhibit antipruritic properties in mice. EXPERIMENTAL APPROACH: To examine the antiscratch effect of PR-37 and PR-38 we used a mouse model of compound 48/80-induced pruritus. In order to elucidate the mechanism of action of tested compounds, specific antagonists of opioid and cannabinoid receptors were used. The effect of PR-37 on the CNS was assessed by measuring motor parameters and exploratory behaviours in mice. KEY RESULTS: PR-37 and PR 38, jnjected s.c., significantly reduced the number of compound 48/80-induced scratching behaviours in mice in a dose- and time-dependent manner. PR-38 was also active when orally administered. The antiscratch activity of PR-37 was blocked by the selective kappa opioid receptor antagonist, nor-binaltorphimine, and that of PR-38 by the selective MU opioid receptor antagonist, beta funaltrexamine. CONCLUSION AND IMPLICATIONS: In conclusion, a novel framework for the development of new antipruritic drugs derived from salvinorin A has been validated. PMID- 26040668 TI - Polyinosinic-Polycytidylic Acid Perturbs Ovarian Functions Through Toll-Like Receptor 3-Mediated Tumor Necrosis Factor A Production in Female Mice. AB - Viral infections may perturb ovarian functions and female fertility. Mechanisms underlying viral perturbation of ovarian functions are incompletely understood. This study found that intraperitoneal injection of polyinosinic-polycytidylic acid [poly (I:C)] in female mice inhibits estradiol synthesis and induces ovarian granulosa cell apoptosis. Poly (I:C) is a synthetic viral double-stranded RNA analog, which induces innate antiviral responses mimicking a viral infection through activation of pattern recognition receptors, including toll-like receptor 3 (TLR3), retinoic acid-inducible gene I, and melanoma differentiation-associated gene 5. Injection of poly (I:C) significantly induced granulosa cell apoptosis in antral follicles and reduced antral follicle numbers. These effects were significantly diminished in Tlr3 knockout or tumor necrosis factor-alpha (Tnfa) knockout mice. We demonstrated that poly (I:C) induced TNFA production at a relatively high level in wild-type mice compared with that in Tlr3 knockout mice. Notably, TNFA neutralizing antibody significantly reduced poly (I:C)-induced ovarian dysfunction. In vitro assays confirmed that TNFA inhibits estradiol synthesis and induces granulosa cell apoptosis. Results provide novel insights into the mechanisms by which a mimicked viral infection perturbs ovarian functions in mice. PMID- 26040670 TI - An Alternative Model of Tubulobulbar Complex Internalization During Junction Remodeling in the Seminiferous Epithelium of the Rat Testis. AB - Tubulobulbar complexes (TBCs) are elongate subcellular machines responsible for internalizing intercellular junctions during sperm release. Each complex consists of a double-membrane tubular core terminating in a clathrin-coated pit. The core is surrounded by a network of actin filaments, and a distinct swelling or bulb, which lacks an association with actin, develops in the distal third of the structure. The bulb eventually buds from the complex and enters endocytic compartments of the Sertoli cell. The relationship of the actin cuff to the formation and budding of the bulb is not known. To gain insight into this relationship, we perturbed the actin networks of TBCs with cytochalasin D. When isolated testes were perfused with a physiological buffer containing cytochalasin D, apical TBCs at stage VII of spermatogenesis were associated with lower levels of actin compared to controls. At the ultrastructural level, the actin networks in cytochalasin D-treated testes appeared patchy, and ectopic bulbs and swollen tubular regions occurred. When normal untreated samples at early stage VII were analyzed, large elongate bulbs and short tubular sections were observed. Together, these results suggest a new model for TBC vesiculation in which the actin network begins to disassemble and the tubular region begins to swell into a bulb. As actin disassembly continues, the coated pit and most of the tubular region are incorporated into the enlarging bulb. The remaining short neck of the bulb near the base of the complex undergoes scission, and the bulb is internalized. PMID- 26040669 TI - Lats1 Deletion Causes Increased Germ Cell Apoptosis and Follicular Cysts in Mouse Ovaries. AB - The Hippo signaling pathway is essential for regulating proliferation and apoptosis in mammalian cells. The LATS1 kinase is a core member of the Hippo signaling pathway that phosphorylates and inactivates the transcriptional co activators YAP1 and WWTR1. Deletion of Lats1 results in low neonate survival and ovarian stromal tumors in surviving adults, but the effects of Lats1 on early follicular development are not understood. Here, the expression of Hippo pathway components including Wwtr1, Stk4, Stk3, Lats2, and Yap1 transcripts were decreased by 50% in mouse ovaries between 2 and 8 days of age while expression was maintained from 8 days to 21 days and after priming with eCG. LATS1, LATS2, and MOB1B were localized to both germ and somatic cells of primordial to antral follicles. Interestingly, YAP1 was predominantly cytoplasmic, whereas WWTR1 was nuclear in oocytes and somatic cells. Deletion of Lats1 caused an increase in germ cell apoptosis from 1.7% in control ovaries to 3.6% in Lats1 mutant ovaries and a 58% and 32% decrease in primordial and activated follicle numbers in cultured mutant ovaries. Surprisingly, there was an increase in Bmp15 but not Gdf9, Figla, Nobox transcripts or the somatic-specific transcripts Amh and Wnt4 in cultured Lats1 mutant ovaries. Last, Lats1 mutant ovaries developed ovarian cysts at a higher frequency (43%) than heterozygous (24%) and control ovaries (8%). Results showed that the Hippo pathway is active in ovarian follicles and that LATS1 is required to maintain the pool of germ cells and primordial follicles. PMID- 26040671 TI - Rbbp7 Is Required for Uterine Stromal Decidualization in Mice. AB - Uterine stromal cells undergo extensive proliferation and differentiation during postimplantation development, a process known as decidualization. While a range of signaling molecules have been demonstrated to play essential roles in this event, its potential epigenetic regulatory mechanisms remain largely unknown. Retinoblastoma binding protein 7 (Rbbp7) is a protein reported as a core component of many histone modification and chromatin remodeling complexes. In the present study, our in situ hybridization and immunochemistry analysis first reveals a spatiotemporal expression of Rbbp7 in the uterus during the peri implantation period. Observations of remarkable induction of Rbbp7 expression in uterine stromal cells in response to progesterone-nuclear receptor PR signaling point to its potential physiological significance during postimplantation uterine development. Employing a stealth RNA knockdown approach, combined with primary murine uterine stromal cell culture and an in vitro-induced decidualization model, we further demonstrate that Rbbp7 silencing compromises stromal cell decidualization via attenuating histone H4 acetylation and cyclin D3 expression. The results collectively suggest that Rbbp7 is a potentially functional player regulating normal histone acetylation modification and cyclin D3 expression in stromal cells during postimplantation decidual development. PMID- 26040672 TI - CYP26 Enzymes Are Necessary Within the Postnatal Seminiferous Epithelium for Normal Murine Spermatogenesis. AB - The active metabolite of vitamin A, retinoic acid (RA), is known to be essential for spermatogenesis. Changes to RA levels within the seminiferous epithelium can alter the development of male germ cells, including blocking their differentiation completely. Excess RA has been shown to cause germ cell death in both neonatal and adult animals, yet the cells capable of degrading RA within the testis have yet to be investigated. One previous study alluded to a requirement for one of the RA degrading enzymes, CYP26B1, in Sertoli cells but no data exist to determine whether germ cells possess the ability to degrade RA. To bridge this gap, the roles of CYP26A1 and CYP26B1 within the seminiferous epithelium were investigated by creating single and dual conditional knockouts of these enzymes in either Sertoli or germ cells. Analysis of these knockout models revealed that deletion of both Cyp26a1 and Cyp26b1 in either cell type resulted in increased vacuolization within the seminiferous tubules, delayed spermatid release, and an increase in the number of STRA8-positive spermatogonia, but spermatozoa were still produced and the animals were found to be fertile. However, elimination of CYP26B1 activity within both germ and Sertoli cells resulted in severe male subfertility, with a loss of advanced germ cells from the seminiferous epithelium. These data indicate that CYP26 activity within either Sertoli or germ cells is essential for the normal progression of spermatogenesis and that its loss can result in reduced male fertility. PMID- 26040674 TI - Analysis of the Effect of Leukemia Inhibitory Factor on Follicular Growth in Cultured Murine Ovarian Tissue. AB - Leukemia inhibitory factor (LIF) is expressed in the ovary and controls follicular growth. LIF has been reported to accelerate the primordial to primary follicle transition, the growth of cultured preantral follicles, and the maturation of oocytes. Previous reports on factors that regulate follicular growth have largely employed cultured follicles. However, there are several types of follicles and somatic cells in the ovary that are likely to interact with one another to regulate follicular growth. Therefore, a novel approach is essential for understanding the function of factors that regulate follicular growth in the ovary. In this study, we evaluated the function of LIF using cultured ovarian tissue. Ovarian tissue slices were cultured in the presence or absence of recombinant LIF and neutralizing anti-LIF antibody to enable continuous monitoring of follicular growth within the context of the ovary as well as analysis of the process of follicular growth. The results revealed that LIF inhibited the growth of primary, secondary, and antral follicles. Furthermore, we verified the inhibitory function of LIF using the neutralizing antibody, which accelerated follicular growth. These results suggest that LIF is likely to coordinate follicular growth in the ovary. The culture and analysis methods employed in this study are thus effective for clarifying the tissue-level functions of factors that regulate follicular growth within the ovary. PMID- 26040673 TI - Infertility in Female Mice with a Gain-of-Function Mutation in the Luteinizing Hormone Receptor Is Due to Irregular Estrous Cyclicity, Anovulation, Hormonal Alterations, and Polycystic Ovaries. AB - The luteinizing hormone receptor, LHCGR, is essential for fertility in males and females, and genetic mutations in the receptor have been identified that result in developmental and reproductive defects. We have previously generated and characterized a mouse model (KiLHR(D582G)) for familial male-limited precocious puberty caused by an activating mutation in the receptor. We demonstrated that the phenotype of the KiLHR(D582G) male mice is an accurate phenocopy of male patients with activating LHCGR mutations. In this study, we observed that unlike women with activating LHCGR mutations who are normal, female KiLHR(D582G) mice are infertile. Mice exhibit irregular estrous cyclicity, anovulation, and precocious puberty. A temporal study from 2-24 wk of age indicated elevated levels of progesterone, androstenedione, testosterone, and estradiol and upregulation of several steroidogenic enzyme genes. Ovaries of KiLHR(D582G) mice exhibited significant pathology with the development of large hemorrhagic cysts as early as 3 wk of age, extensive stromal cell hyperplasia and hypertrophy with luteinization, numerous atretic follicles, and granulosa cell tumors. Ovulation could not be rescued by the addition of exogenous gonadotropins. The body weights of the KiLHR(D582G) mice were higher than wild-type counterparts, but there was no increase in the body fat composition or metabolic abnormalities such as impaired glucose tolerance and insulin resistance. These studies demonstrate that activating LHCGR mutations do not produce the same phenotype in female mice as in humans and clearly illustrate species differences in the expression and regulation of LHCGR in the ovary, but not in the testis. PMID- 26040675 TI - Shaping of interphase chromosomes by the microtubule network. AB - It is well established that microtubule dynamics play a major role in chromosome condensation and localization during mitosis. During interphase, however, it is assumed that the metazoan nuclear envelope presents a physical barrier, which inhibits interaction between the microtubules located in the cytoplasm and the chromatin fibers located in the nucleus. In recent years, it has become apparent that microtubule dynamics alter chromatin structure and function during interphase as well. Microtubule motor proteins transport several transcription factors and exogenous DNA (such as plasmid DNA) from the cytoplasm to the nucleus. Various soluble microtubule components are able to translocate into the nucleus, where they bind various chromatin elements leading to transcriptional alterations. In addition, microtubules may apply force on the nuclear envelope, which is transmitted into the nucleus, leading to changes in chromatin structure. Thus, microtubule dynamics during interphase may affect chromatin spatial organization, as well as transcription, replication and repair. PMID- 26040676 TI - Age and amyloid effects on human central nervous system amyloid-beta kinetics. AB - OBJECTIVE: Age is the single greatest risk factor for Alzheimer's disease (AD), with the incidence doubling every 5 years after age 65. However, our understanding of the mechanistic relationship between increasing age and the risk for AD is currently limited. We therefore sought to determine the relationship between age, amyloidosis, and amyloid-beta (Abeta) kinetics in the central nervous system (CNS) of humans. METHODS: Abeta kinetics were analyzed in 112 participants and compared to the ages of participants and the amount of amyloid deposition. RESULTS: We found a highly significant correlation between increasing age and slowed Abeta turnover rates (2.5-fold longer half-life over five decades of age). In addition, we found independent effects on Abeta42 kinetics specifically in participants with amyloid deposition. Amyloidosis was associated with a higher (>50%) irreversible loss of soluble Abeta42 and a 10-fold higher Abeta42 reversible exchange rate. INTERPRETATION: These findings reveal a mechanistic link between human aging and the risk of amyloidosis, which may be owing to a dramatic slowing of Abeta turnover, increasing the likelihood of protein misfolding that leads to deposition. Alterations in Abeta kinetics associated with aging and amyloidosis suggest opportunities for diagnostic and therapeutic strategies. More generally, this study provides an example of how changes in protein turnover kinetics can be used to detect physiological and pathophysiological changes and may be applicable to other proteinopathies. PMID- 26040677 TI - TIF1gamma interferes with TGFbeta1/SMAD4 signaling to promote poor outcome in operable breast cancer patients. AB - BACKGROUND: The Transforming growth factor beta (TGFbeta) signaling has a paradoxical role in cancer development and outcome. Besides, the prognostic significance of the TGFbeta1, SMAD4 in breast cancer patients is an area of many contradictions. The transcriptional intermediary factor 1gamma (TIF1gamma) is thought to interact with the TGFbeta/SMAD signaling through different mechanisms. Our study aims to define the prognostic significance of TGFbeta1, SMAD4 and TIF1gamma expression in breast cancer patients and to detect possible interactions among those markers that might affect the outcome. METHODS: Immunohistochemistry was performed on tissue microarray (TMA) blocks prepared from samples of 248 operable breast cancer patients who presented at Centre Leon Berard (CLB) between 1998 and 2001. The intensity and the percentage of stained tumor cells were integrated into a single score (0-6) and a cutoff was defined for high or low expression for each marker. Correlation was done between TGFbeta1, SMAD4 and TIF1gamma expression with the clinico-pathologic parameters using Pearson's chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test. RESULTS: 223 cases were assessable for TIF1gamma, 204 for TGFbeta1 and 173 for SMAD4. Median age at diagnosis was 55.8 years (range: 27 to 89 years). Tumors were larger than 20 mm in 49.2% and 45.2% had axillary lymph node (LN) metastasis (N1a to N3). 19.4% of the patients had SBR grade I tumors, 46.8% grade II tumors and 33.9% grade III tumors. ER was positive in 85.4%, PR in 75.5% and Her2-neu was over-expressed in 10% of the cases. Nuclear TIF1gamma, cytoplasmic TGFbeta1, nuclear and cytoplasmic SMAD4 stainings were high in 35.9%, 30.4%, 27.7% and 52.6% respectively. TIF1gamma expression was associated with younger age (p=0.006), higher SBR grade (p<0.001), more ER negativity (p=0.035), and tumors larger than 2 cm (p=0.081), while TGFbeta1 was not associated with any of the traditional prognostic factors. TGFbeta1 expression in tumor cells was a marker of poor prognosis regarding DMFS (HR=2.28; 95% CI: 1.4 to 3.8; p=0.002), DFS (HR=2.00; 95% CI: 1.25 to 3.5; p=0.005) and OS (HR=1.89; 95 % CI: 1.04 to 3.43; p=0.037). TIF1gamma expression carried a tendency towards poorer DMFS (p=0.091), DFS (p=0.143) and OS (p=0.091). In the multivariate analysis TGFbeta1 remained an independent predictor of shorter DMFS, DFS and OS. Moreover, the prognostic significance of TGFbeta1 was more obvious in the TIF1gamma high patient subgroup than in the patients with TIF1gamma low expression. The subgroup expressing both markers had the worst DMFS (HR=3.2; 95% CI: 1.7 to 5.9; p<0.0001), DFS (HR=3.02; 95 % CI: 1.6 to 5.6; p<0.0001) and OS (HR=2.7; 95 % CI: 1.4 to 5.4; p=0.005). CONCLUSION: There is a crosstalk between the TIF1gamma and the TGFbeta1/SMAD4 signaling that deteriorates the outcome of operable breast cancer patients and when combined together they can serve as an effective prognostic tool for those patients. PMID- 26040679 TI - Breast cancer stem cells: current advances and clinical implications. AB - There is substantial evidence that many cancers, including breast cancer, are driven by a population of cells that display stem cell properties. These cells, termed cancer stem cells (CSCs) or tumor initiating cells, not only drive tumor initiation and growth but also mediate tumor metastasis and therapeutic resistance. In this chapter, we summarize current advances in CSC research with a major focus on breast CSCs (BCSCs). We review the prevailing methods to isolate and characterize BCSCs and recent evidence documenting their cellular origins and phenotypic plasticity that enables them to transition between mesenchymal and epithelial-like states. We describe in vitro and clinical evidence that these cells mediate metastasis and treatment resistance in breast cancer, the development of novel strategies to isolate circulating tumor cells (CTCs) that contain CSCs and the use of patient-derived xenograft (PDX) models in preclinical breast cancer research. Lastly, we highlight several signaling pathways that regulate BCSC self-renewal and describe clinical implications of targeting these cells for breast cancer treatment. The development of strategies to effectively target BCSCs has the potential to significantly improve the outcomes for patients with breast cancer. PMID- 26040678 TI - Comparative evaluation of several docking tools for docking small molecule ligands to DC-SIGN. AB - Five docking tools, namely AutoDock, FRED, CDOCKER, FlexX and GOLD, have been critically examined, with the aim of selecting those most appropriate for use as docking tools for docking molecules to the lectin dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). This lectin has been selected for its rather non-druggable binding site, which enables complex interactions that guide the binding of the core monosaccharide. Since optimal orientation is crucial for forming coordination bonds, it was important to assess whether the selected docking tools could reproduce the optimal binding conformation for several oligosaccharides that are known to bind DC-SIGN. Our results show that even widely used docking programs have certain limitations when faced with a rather shallow and featureless binding site, as is the case of DC SIGN. The FRED docking software (OpenEye Scientific Software, Inc.) was found to score as the best tool for docking ligands to DC-SIGN. The performance of FRED was further assessed on another lectin, Langerin. We have demonstrated that this validated docking protocol could be used for docking to other lectins similar to DC-SIGN. PMID- 26040680 TI - A protocol for studying embryonic mammary progenitor cells during mouse mammary primordial development in explant culture. AB - Embryonic explant culture is a powerful technique to observe tissue morphogenesis ex vivo, and is particularly useful for monitoring embryonic mammary gland development. It has been established that mammary cell lineage specification occurs during embryogenesis, although much remains to be elucidated with respect to how this occurs. During mammary specification, mammary progenitor cells are formed. Embryonic mammary development can proceed and be monitored in embryonic explant culture. Studies using explant culture will greatly enhance our understanding of the cellular mechanisms that regulate embryonic mammary primordial development and mammary progenitor cell specification. We present a protocol for culturing explants from mid-gestation mouse embryos so that morphogenetic processes and mammary epithelial progenitor cells can be studied during embryonic mammary development ex vivo. PMID- 26040681 TI - FACS Sorting Mammary Stem Cells. AB - Fluorescent-activated cell sorting (FACS) represents one of the key techniques that have been used to isolate and characterize stem cells, including cells from the mammary gland. A combination of approaches, including recognition of cell surface antigens and different cellular activities, has facilitated the identification of stem cells from the healthy mammary gland and from breast tumors. In this chapter we describe the protocol to use FACS to separate breast cancer stem cells, but most of the general principles discussed could be applied to sort other types of cells. PMID- 26040682 TI - Side population. AB - The side population (SP) assay has been utilized as a method for isolation and characterization of normal and cancer stem cells from a variety of tissues. However, the SP phenotype may not be a common property of all stem cells. This chapter reviews the principle and potential pitfalls of the SP assay with an emphasis on mammary gland SP cell analysis. PMID- 26040683 TI - Single-cell genome and transcriptome processing prior to high-throughput sequencing. AB - Single-cell genome and transcriptome characterizations will probe to be decisive within the stem cells research, especially to describe appropriately the genetic impact of the diverse stem cells populations that are present in each organism. In the present chapter, we describe in detail how to prepare sequencing libraries out of single cells, for whole genome DNA and mRNA sequencing. PMID- 26040684 TI - Shotgun proteomics on tissue specimens extracted with Acid guanidinium thiocyanate-phenol-chloroform. AB - Protein-containing organic fractions of acid guanidinium thiocyanate-phenol chloroform-extracted tissues are an interesting source of proteins as this method is widely used for RNA extraction for gene expression analysis. However, due to difficulties in redissolving pelleted proteins from the organic phase, protein analysis has only been limitedly reported. Current shotgun mass spectrometry based methods, however, require minute amounts of sample, and methods have been developed that allow SDS to be removed from an extraction buffer prior to protein digestion. The limited volume of starting material needed for shotgun proteomics facilitates redissolving proteins in SDS-containing buffers, allowing proteins to be readily extracted. Here we describe a protocol for an SDS-DTT-based extraction of proteins from the organic fraction of acid guanidinium-thiocyanate-phenol chloroform-extracted tissues that remain after RNA isolation for shotgun MS analysis. PMID- 26040685 TI - Antibody-based capture of target peptides in multiple reaction monitoring experiments. AB - Targeted quantitative mass spectrometry of immunoaffinity-enriched peptides, termed immuno-multiple reaction monitoring (iMRM), is a powerful method for determining the relative abundance of proteins in complex mixtures, like plasma or whole tissue. This technique combines 1,000-fold enrichment potential of antibodies for target peptides with the selectivity of multiple reaction monitoring mass spectrometry (MRM-MS). Using heavy isotope-labeled peptide counterparts as internal standards ensures high levels of precision. Further, LC MRM-MS selectivity allows for multiplexing; antibodies recognizing different peptides can be added directly to a single mixture without subjecting to interferences common to other multiple antibody protein assays. Integrated extracted ion chromatograms (XIC) of product ions from endogenous unlabeled "light" peptide and stable isotope-labeled internal standard "heavy" peptides are used to generate a light/heavy peak area ratio. This ratio is proportional to the amount of peptide in the digestion mixture and can be used to estimate the concentration of protein in the sample. PMID- 26040686 TI - Lentiviral transduction of mammary epithelial cells. AB - Lentiviral vectors are the workhorses of modern cell biology. They can infect a wide variety of cells including nondividing cells and stem cells. They integrate into the genome of infected cells leading to stable expression. It is easy to transduce 100 % of the cells in a culture and possible to infect cells simultaneously with multiple vectors, greatly facilitating studies on malignant transformation. We present simple protocols to produce and titrate lentiviral vectors, infect mammary epithelial cells, and check for contamination with replication-competent viruses. PMID- 26040687 TI - The transplantation of mouse mammary epithelial cells into cleared mammary fat pads. AB - The transplantation of mammary epithelial cells into the cleared fat pad allows their growth and differentiation in their normal physiological environment. This technique involves the grafting of tissue fragments or isolated cells into the mammary fat pads of prepubertal mice from which the endogenous epithelium has been surgically removed. Such transplantation assays are particularly useful for the analysis of morphogenetic potential and stem cell activity in normal mammary epithelium and breast tumors. We describe here the main steps in the transplantation of epithelial fragments and isolated cells from mouse mammary glands and the various approaches currently used to evaluate the regeneration and self-renewal properties of mammary stem cells. PMID- 26040688 TI - Humanization of the mouse mammary gland. AB - Although mouse models have provided invaluable information on the mechanisms of mammary gland development, anatomical and developmental differences between human and mice limit full understanding of this fundamental process. Humanization of the mouse mammary gland by injecting immortalized human breast stromal cells into the cleared murine mammary fat pad enables the growth and development of human mammary epithelial cells or tissue. This facilitates the characterization of human mammary gland development or tumorigenesis by utilizing the mouse mammary fat pad. Here we describe the process of isolating human mammary stromal and epithelial cells as well as their introduction into the mammary fat pads of immunocompromised mice. PMID- 26040689 TI - Lineage Tracing in the Mammary Gland Using Cre/lox Technology and Fluorescent Reporter Alleles. AB - Lineage tracing using Cre/lox technology has become a well-established technique to study the contribution of different (stem) cell populations to organ development and function. When used in the mammary gland, it forms a valuable addition to the already existing experimental toolbox and an important alternative to other readouts measuring stem cell potential, such as the fat pad transplantation assay.Here I describe how to set up and analyze an in vivo lineage tracing experiment using tamoxifen-inducible Cre/lox technology, highlighting the specific challenges that the investigator faces when employing this method and interpreting the results in the mammary gland. PMID- 26040690 TI - Modeling the breast cancer bone metastatic niche in complex three-dimensional cocultures. AB - Despite advances in early detection, prevention and treatment of breast cancer, the mortality of breast cancer patients did not decrease considerably in the last years. Metastatic breast cancer remains incurable. There is compelling evidence that dissemination of breast cancer cells at distant sites is an early event. At the time of detection and diagnosis, patients have disseminated breast cancer cells in the bone marrow. Only in half of these patients the disseminated cells proliferate and generate metastases, typically in 3-5 years for ER negative breast tumors and 10-15 years for ER positive breast tumors. In other patients metastases never develop. The ability to predict which patients will develop metastases and to devise strategies to interfere with this process hinges on understanding the mechanisms underlying growth at the metastatic site. In turn, this requires novel experimental systems that model in vitro the survival, dormancy and proliferation of disseminated cancer cells.We have established such experimental systems that model the bone microenvironment of the breast cancer metastatic niche. These systems are based on 3D complex cultures of human bone marrow stromal cells and breast cancer cell lines in collagen biomatrices. We identified conditions in which cancer cells are dormant, and conditions in which they proliferate and we validated the results in vivo. Dormant cancer cells were able to proliferate upon transfer into supportive microenvironment or upon manipulation of signaling pathways that control dormancy. These experimental systems will be instrumental in screening new compounds for metastasis studies and particularly in studying the pathways that control cellular dormancy. We provide in this chapter detailed protocols for these complex 3D coculture systems. PMID- 26040691 TI - Mammary cancer stem cells reinitiation assessment at the metastatic niche: the lung and bone. AB - Mammary cancer stem cells (MCSC) have been operationally defined as cells that re form secondary tumors upon transplantation into immunodeficient mice. Building on this observation, it has also been suggested that MCSCs are responsible for metastasis as well as evasion and resistance to therapeutic treatments. MCSC reinitiating potential is usually tested by implantation of limited amounts of cells orthotopically or subcutaneously, yet this poorly recapitulates the metastatic niche where truly metastatic reinitiation will occur. Herein, we describe the implantation of small amounts of MCSC selected populations in the bone (intra tibiae injection) and the lung (intra thoracic injection) to test for their metastatic reinitiation capabilities. PMID- 26040692 TI - Nanomechanical characterization of living mammary tissues by atomic force microscopy. AB - The mechanical properties of living cells and tissues are important for a variety of functional processes in vivo, including cell adhesion, migration, proliferation and differentiation. Changes in mechano-cellular phenotype, for instance, are associated with cancer progression. Atomic force microscopy (AFM) is an enabling technique that topographically maps and quantifies the mechanical properties of complex biological matter in physiological aqueous environments at the nanometer length scale. Recently we applied AFM to spatially resolve the distribution of nanomechanical stiffness across human breast cancer biopsies in comparison to healthy tissue and benign tumors. This led to the finding that AFM provides quantitative mechano-markers that may have translational significance for the clinical diagnosis of cancer. Here, we provide a comprehensive description of sample preparation methodology, instrumentation, data acquisition and analysis that allows for the quantitative nanomechanical profiling of unadulterated tissue at submicron spatial resolution and nano-Newton (nN) force sensitivity in physiological conditions. PMID- 26040693 TI - Mathematical Modelling as a Tool to Understand Cell Self-renewal and Differentiation. AB - Mathematical modeling is a powerful technique to address key questions and paradigms in a variety of complex biological systems and can provide quantitative insights into cell kinetics, fate determination and development of cell populations. The chapter is devoted to a review of modeling of the dynamics of stem cell-initiated systems using mathematical methods of ordinary differential equations. Some basic concepts and tools for cell population dynamics are summarized and presented as a gentle introduction to non-mathematicians. The models take into account different plausible mechanisms regulating homeostasis. Two mathematical frameworks are proposed reflecting, respectively, a discrete (punctuated by division events) and a continuous character of transitions between differentiation stages. Advantages and constraints of the mathematical approaches are presented on examples of models of blood systems and compared to patients data on healthy hematopoiesis. PMID- 26040694 TI - Mammary Stem Cells: A Clinician's View. AB - Mammary stem cells were identified and isolated more than a decade ago and, although much remains to be learned, a lot has been revealed about their properties and behavior. Yet there is a gap between the newly acquired knowledge and its successful clinical application. This chapter presented a critical view from the perspective of a clinician. PMID- 26040696 TI - The Burden of Low Back Pain Among Fishermen: A Survey in a Rural Fishing Settlement in Rivers State, Nigeria. AB - Although fishing is of great economic importance, it has been described as a very dangerous and strenuous occupation worldwide. The current study was designed to determine the prevalence of low back pain (LBP) and explore the coping strategies of fishermen in the Oyorokoto fishing settlement in Nigeria. Three hundred and eighty-four fishermen with an age range of 18 to 64 years and a mean age of 34.12 years (SD = 6.52) were recruited. LBP was identified in 262 (68.23%) of the participants. LBP was significantly associated with age, educational status, and body mass index (BMI; chi2 = 102.23, p < .001) but not with marital status (p = .211). Severe LBP was identified among participants who were in the age group 35 to 44 years (33.93%), married (79.46%), primary education (45.54%), and abnormal BMI (73.32%). Participants >=55 years (6.25%), widowers (1.79%), tertiary education (3.57%), and normal BMI (27.68%) had the least LBP. LBP was least prevalent in those who had practiced fishing for a duration of >=21 years (25.57%) as compared with other groups (chi2 = 10.49, p = .03). The number of fishing trips per week was not significantly associated with the severity of LBP. Significant difference was identified between those who used nonmotorized boats as compared with motorized types (chi2 = 12.75, p = .002). The coping strategy with the highest score was religion 7.23 (SD = 1.12). The coping strategy with the lowest score was substance abuse 3.01 (SD = 0.57). In conclusion, LBP is an important health problem among fishermen. Religion is the most common coping strategy used by the fishermen. PMID- 26040695 TI - Mitochondrial phylogenomics and genetic relationships of closely related pine moth (Lasiocampidae: Dendrolimus) species in China, using whole mitochondrial genomes. AB - BACKGROUND: Pine moths (Lepidoptera; Bombycoidea; Lasiocampidae: Dendrolimus spp.) are among the most serious insect pests of forests, especially in southern China. Although COI barcodes (a standardized portion of the mitochondrial cytochrome c oxidase subunit I gene) can distinguish some members of this genus, the evolutionary relationships of the three morphospecies Dendrolimus punctatus, D. tabulaeformis and D. spectabilis have remained largely unresolved. We sequenced whole mitochondrial genomes of eight specimens, including D. punctatus wenshanensis. This is an unambiguous subspecies of D. punctatus, and was used as a reference for inferring the relationships of the other two morphospecies of the D. punctatus complex. We constructed phylogenetic trees from this data, including twelve published mitochondrial genomes of other Bombycoidea species, and examined the relationships of the Dendrolimus taxa using these trees and the genomic features of the mitochondrial genome. RESULTS: The eight fully sequenced mitochondrial genomes from the three morphospecies displayed similar genome structures as other Bombycoidea species in terms of gene content, base composition, level of overall AT-bias and codon usage. However, the Dendrolimus genomes possess a unique feature in the large ribosomal 16S RNA subunits (rrnL), which are more than 60 bp longer than other members of the superfamily and have a higher AC proportion. The eight mitochondrial genomes of Dendrolimus were highly conservative in many aspects, for example with identical stop codons and overlapping regions. But there were many differences in start codons, intergenic spacers, and numbers of mismatched base pairs of tRNA (transfer RNA genes). Our results, based on phylogenetic trees, genetic distances, species delimitation and genomic features (such as intergenic spacers) of the mitochondrial genome, indicated that D. tabulaeformis is as close to D. punctatus as is D. punctatus wenshanensis, whereas D. spectabilis evolved independently from D. tabulaeformis and D. punctatus. Whole mitochondrial DNA phylogenies showed that D. spectabilis formed a well-supported monophyletic clade, with a clear species boundary separating it from the other congeners examined here. However, D. tabulaeformis often clustered with D. punctatus and with the subspecies D. punctatus wenshanensis. Genetic distance analyses showed that the distance between D. tabulaeformis and D. punctatus is generally less than the intraspecific distance of D. punctatus and its subspecies D. punctatus wenshanensis. In the species delimitation analysis of Poisson Tree Processes (PTP), D. tabulaeformis, D. punctatus and D. punctatus wenshanensis clustered into a putative species separated from D. spectabilis. In comparison with D. spectabilis, D. tabulaeformis and D. punctatus also exhibit a similar structure in intergenic spacer characterization. These different types of evidence suggest that D. tabulaeformis is very close to D. punctatus and its subspecies D. punctatus wenshanensis, and is likely to be another subspecies of D. punctatus. CONCLUSIONS: Whole mitochondrial genomes possess relatively rich genetic information compared with the traditional use of single or multiple genes for phylogenetic purposes. They can be used to better infer phylogenetic relationships and degrees of relatedness of taxonomic groups, at least from the aspect of maternal lineage: caution should be taken due to the maternal-only inheritance of this genome. Our results indicate that D. spectabilis is an independent lineage, while D. tabulaeformis shows an extremely close relationship to D. punctatus. PMID- 26040697 TI - Context-specific role of SOX9 in NF-Y mediated gene regulation in colorectal cancer cells. AB - Roles for SOX9 have been extensively studied in development and particular emphasis has been placed on SOX9 roles in cell lineage determination in a number of discrete tissues. Aberrant expression of SOX9 in many cancers, including colorectal cancer, suggests roles in these diseases as well and recent studies have suggested tissue- and context-specific roles of SOX9. Our genome wide approach by chromatin immunoprecipitation sequencing (ChIP-seq) in human colorectal cancer cells identified a number of physiological targets of SOX9, including ubiquitously expressed cell cycle regulatory genes, such as CCNB1 and CCNB2, CDK1, and TOP2A. These novel high affinity-SOX9 binding peaks precisely overlapped with binding sites for histone-fold NF-Y transcription factor. Furthermore, our data showed that SOX9 is recruited by NF-Y to these promoters of cell cycle regulatory genes and that SOX9 is critical for the full function of NF Y in activation of the cell cycle genes. Mutagenesis analysis and in vitro binding assays provided additional evidence to show that SOX9 affinity is through NF-Y and that SOX9 DNA binding domain is not necessary for SOX9 affinity to those target genes. Collectively, our results reveal possibly a context-dependent, non classical regulatory role for SOX9. PMID- 26040698 TI - A fine balance: epigenetic control of cellular quiescence by the tumor suppressor PRDM2/RIZ at a bivalent domain in the cyclin a gene. AB - Adult stem cell quiescence is critical to ensure regeneration while minimizing tumorigenesis. Epigenetic regulation contributes to cell cycle control and differentiation, but few regulators of the chromatin state in quiescent cells are known. Here we report that the tumor suppressor PRDM2/RIZ, an H3K9 methyltransferase, is enriched in quiescent muscle stem cells in vivo and controls reversible quiescence in cultured myoblasts. We find that PRDM2 associates with >4400 promoters in G0 myoblasts, 55% of which are also marked with H3K9me2 and enriched for myogenic, cell cycle and developmental regulators. Knockdown of PRDM2 alters histone methylation at key promoters such as Myogenin and CyclinA2 (CCNA2), and subverts the quiescence program via global de repression of myogenesis, and hyper-repression of the cell cycle. Further, PRDM2 acts upstream of the repressive PRC2 complex in G0. We identify a novel G0 specific bivalent chromatin domain in the CCNA2 locus. PRDM2 protein interacts with the PRC2 protein EZH2 and regulates its association with the bivalent domain in the CCNA2 gene. Our results suggest that induction of PRDM2 in G0 ensures that two antagonistic programs-myogenesis and the cell cycle-while stalled, are poised for reactivation. Together, these results indicate that epigenetic regulation by PRDM2 preserves key functions of the quiescent state, with implications for stem cell self-renewal. PMID- 26040699 TI - Characterization of fusion genes and the significantly expressed fusion isoforms in breast cancer by hybrid sequencing. AB - We developed an innovative hybrid sequencing approach, IDP-fusion, to detect fusion genes, determine fusion sites and identify and quantify fusion isoforms. IDP-fusion is the first method to study gene fusion events by integrating Third Generation Sequencing long reads and Second Generation Sequencing short reads. We applied IDP-fusion to PacBio data and Illumina data from the MCF-7 breast cancer cells. Compared with the existing tools, IDP-fusion detects fusion genes at higher precision and a very low false positive rate. The results show that IDP fusion will be useful for unraveling the complexity of multiple fusion splices and fusion isoforms within tumorigenesis-relevant fusion genes. PMID- 26040700 TI - SNiPlay3: a web-based application for exploration and large scale analyses of genomic variations. AB - SNiPlay is a web-based tool for detection, management and analysis of genetic variants including both single nucleotide polymorphisms (SNPs) and InDels. Version 3 now extends functionalities in order to easily manage and exploit SNPs derived from next generation sequencing technologies, such as GBS (genotyping by sequencing), WGRS (whole gre-sequencing) and RNA-Seq technologies. Based on the standard VCF (variant call format) format, the application offers an intuitive interface for filtering and comparing polymorphisms using user-defined sets of individuals and then establishing a reliable genotyping data matrix for further analyses. Namely, in addition to the various scaled-up analyses allowed by the application (genomic annotation of SNP, diversity analysis, haplotype reconstruction and network, linkage disequilibrium), SNiPlay3 proposes new modules for GWAS (genome-wide association studies), population stratification, distance tree analysis and visualization of SNP density. Additionally, we developed a suite of Galaxy wrappers for each step of the SNiPlay3 process, so that the complete pipeline can also be deployed on a Galaxy instance using the Galaxy ToolShed procedure and then be computed as a Galaxy workflow. SNiPlay is accessible at http://sniplay.southgreen.fr. PMID- 26040701 TI - Sequence-independent characterization of viruses based on the pattern of viral small RNAs produced by the host. AB - Virus surveillance in vector insects is potentially of great benefit to public health. Large-scale sequencing of small and long RNAs has previously been used to detect viruses, but without any formal comparison of different strategies. Furthermore, the identification of viral sequences largely depends on similarity searches against reference databases. Here, we developed a sequence-independent strategy based on virus-derived small RNAs produced by the host response, such as the RNA interference pathway. In insects, we compared sequences of small and long RNAs, demonstrating that viral sequences are enriched in the small RNA fraction. We also noted that the small RNA size profile is a unique signature for each virus and can be used to identify novel viral sequences without known relatives in reference databases. Using this strategy, we characterized six novel viruses in the viromes of laboratory fruit flies and wild populations of two insect vectors: mosquitoes and sandflies. We also show that the small RNA profile could be used to infer viral tropism for ovaries among other aspects of virus biology. Additionally, our results suggest that virus detection utilizing small RNAs can also be applied to vertebrates, although not as efficiently as to plants and insects. PMID- 26040703 TI - Improving medication adherence in migraine treatment. AB - Medication adherence is integral to successful treatment of migraine and other headache. The existing literature examining medication adherence in migraine is small, and the methodologies used to assess adherence are limited. However, these studies broadly suggest poor adherence to both acute and preventive migraine medications, with studies using more objective monitoring reporting lower adherence rates. Methods for improving medication adherence are described, including organizational strategies, provider-monitoring and self-monitoring of adherence, regimen strategies, patient education, self-management skills training (e.g., stimulus control, behavioral contracts), and cognitive-behavioral therapy techniques. The article concludes by discussing the future of research regarding adherence to medications for migraine and other headaches. PMID- 26040705 TI - Sirolimus for the treatment of children with various complicated vascular anomalies. AB - Vascular anomalies include a heterogeneous group of disorders that are categorized as vascular tumors or vascular malformations. Treatment options include resection, embolization, laser therapy, and sclerotherapy or medical treatment such as propranolol, steroids, interferon, and cytostatic chemotherapy. Mammalian target of rapamycin seems to play a key role in the signal pathway of angiogenesis and subsequently in the development of vascular anomalies. Recently, the successful use of sirolimus has been reported in children with lymphatic malformations and kaposiform hemangioendotheliomas. We report on six patients with different vascular anomalies (kaposiform hemangioendothelioma n = 2, combined lymphatico-venous malformation n = 2, pulmonary lymphangiectasia n = 1, and orbital lymphatic malformation n = 1) who were treated with peroral sirolimus. Three of the children initially presented with a Kasabach-Merrit phenomenon. Median duration of treatment was 10 months; two children are still on treatment. Three children each achieved complete and partial remission. Kasabach Merrit phenomenon resolved within 1 month in all patients. Treatment with sirolimus was tolerated well; only mild reversible leukopenia was observed. CONCLUSION: Sirolimus proved to be effective in children with complicated lymphatic or lymphatico-venous malformations and kaposiform hemangioendotheliomas. Treatment was tolerated well with acceptable side effects. The optimum length of treatment and possible long-term side effects have to be evaluated. WHAT IS KNOWN: * Vascular anomalies including vascular tumors and vascular malformations may lead to life-threatening conditions.* Some patients are refractory to established treatment and/or are not available for local invasive procedures. WHAT IS NEW: * We reviewed the literature focusing treatment of vascular anomalies inc hildren and adolescents.* Our data support recent studies that sirolimus is an effective treatment option in patients with complicated vascular tumors andmalformations PMID- 26040702 TI - Partitioning between recoding and termination at a stop codon-selenocysteine insertion sequence. AB - Selenocysteine (Sec) is inserted into proteins by recoding a UGA stop codon followed by a selenocysteine insertion sequence (SECIS). UGA recoding by the Sec machinery is believed to be very inefficient owing to RF2-mediated termination at UGA. Here we show that recoding efficiency in vivo is 30-40% independently of the cell growth rate. Efficient recoding requires sufficient selenium concentrations in the medium. RF2 is an unexpectedly poor competitor of Sec. We recapitulate the major characteristics of SECIS-dependent UGA recoding in vitro using a fragment of fdhF-mRNA encoding a natural bacterial selenoprotein. Only 40% of actively translating ribosomes that reach the UGA codon insert Sec, even in the absence of RF2, suggesting that the capacity to insert Sec into proteins is inherently limited. RF2 does not compete with the Sec incorporation machinery; rather, it terminates translation on those ribosomes that failed to incorporate Sec. The data suggest a model in which early recruitment of Sec-tRNA(Sec)-SelB-GTP to the SECIS blocks the access of RF2 to the stop codon, thereby prioritizing recoding over termination at Sec-dedicated stop codons. PMID- 26040706 TI - Hospitalization and 1-year all-cause mortality in type 2 diabetic patients with chronic kidney disease at Stages 1 and 2: Effect of mild anemia. AB - BACKGROUND: The effect of anemia in advanced chronic kidney disease (CKD) on morbidity and mortality is known. The aim of the present study was to assess the effect of mild anemia on hospitalization and 1-year all-cause mortality in type 2 diabetes mellitus (T2DM) patients with Stage 1 and 2 CKD. METHODS: Hospitalized T2DM patients (n = 307) with a glomerular filtration rate >= 60 mL/min per 1.73 m(2) and urinary albumin excretion > 30 mg/24 h (Stage 1 and 2 CKD) were enrolled in the study and divided into two groups based on hemoglobin (Hb) concentrations: those with (mean [ +/- SD] Hb 10.7 +/- 0.7 g/dL) and without (mean Hb 13.3 +/- 1.28 g/dL) anemia. RESULTS: There was no significant difference between patients with and without anemia in terms of age, gender, body mass index, HbA1c, and cardiovascular diseases. The mean length of hospitalization of the 130 anemic and 177 non-anemic patients was 4.3 +/- 3.5 and 3.5 +/- 1.9 days, respectively (P < 0.001). Twelve anemic patients died within 1 year, compared with three patients without anemia (9.2% vs 1.7%, respectively; P = 0.002). After adjusting for confounding variables, multivariate Cox regression analysis revealed that mild anemia was significantly associated with 1-year all-cause mortality (hazard ratio 2.15, 95% confidence interval 1.92-2.54; P = 0.033). CONCLUSIONS: Mild anemia may increase the length of hospitalization and was associated with 1-year all-cause mortality among hospitalized T2DM patients with Stage 1 and 2 CKD. PMID- 26040707 TI - Fusion of microlitre water-in-oil droplets for simple, fast and green chemical assays. AB - A simple format for microscale chemical assays is proposed. It does not require the use of test tubes, microchips or microtiter plates. Microlitre-range (ca. 0.7 5.0 MUL) aqueous droplets are generated by a commercial micropipette in a non polar matrix inside a Petri dish. When two droplets are pipetted nearby, they spontaneously coalesce within seconds, priming a chemical reaction. Detection of the reaction product is accomplished by colorimetry, spectrophotometry, or fluorimetry using simple light-emitting diode (LED) arrays as the sources of monochromatic light, while chemiluminescence detection of the analytes present in single droplets is conducted in the dark. A smartphone camera is used as the detector. The limits of detection obtained for the developed in-droplet assays are estimated to be: 1.4 nmol (potassium permanganate by colorimetry), 1.4 pmol (fluorescein by fluorimetry), and 580 fmol (sodium hypochlorite by chemiluminescence detection). The format has successfully been used to monitor the progress of chemical and biochemical reactions over time with sub-second resolution. A semi-quantitative analysis of ascorbic acid using Tillman's reagent is presented. A few tens of individual droplets can be scanned in parallel. Rapid switching of the LED light sources with different wavelengths enables a spectral analysis of multiple droplets. Very little solid waste is produced. The assay matrix is readily recycled, thus the volume of liquid waste produced each time is also very small (typically, 1-10 MUL per analysis). Various water-immiscible translucent liquids can be used as the reaction matrix: including silicone oil, 1 octanol as well as soybean cooking oil. PMID- 26040708 TI - Overview of hydrogel-based strategies for application in cardiac tissue regeneration. AB - Cardiovascular diseases remain the leading cause of death globally. Since the adult heart lacks the capacity to regenerate, loss of myocardium following myocardial infarction is irreversible and ultimately leads to failure to maintain cardiac function. In order to repopulate the areas of cell loss in the damaged hearts for restoration of cardiac function, cell transplantation/replacement has been extensively investigated. Recently, biomaterials have emerged as an approach to improve delivery and viability of cells for the regeneration of the damaged heart. Here we review the most common approaches in hydrogel-based cardiac tissue regeneration with particular focus on the implementation of hydrogels to improve cell delivery. PMID- 26040709 TI - Feasibility of use of probabilistic reversal learning and serial reaction time tasks in clinical trials of Parkinson's disease. AB - INTRODUCTION: The aim of this study was to investigate the feasibility of using two computer-administered neuropsychological tasks in a clinical trial involving participants with Parkinson's disease without dementia. The tasks, probabilistic reversal learning (PRL) and serial reaction time (SRT), target dorsolateral prefrontal cortex (SRT) and ventral striatal-orbitofrontal (PRL) functioning respectively. METHODS: Participants were 53 adults with idiopathic Parkinson's disease who completed both the SRT and PRL tasks at baseline in a clinical trial. Repeated measures were examined only for the placebo group (n = 20). RESULTS: No participants were removed from analyses due to inability to complete the tasks, and most had fewer than 10% of trials culled due to slow reaction times. Response accuracy on PRL was 81.98% and 66.65% for the two stages of the task respectively. Disease duration was associated with SRT relearning. Disease duration and stage were associated with initial learning on PRL, and there was a trend towards disease stage predicting greater errors on PRL. Among participants in the placebo group, practice effects were seen on PRL (Phase 1 errors) and SRT (relearning). CONCLUSIONS: These results provide initial evidence for the clinical feasibility of computerized PRL and SRT tasks in clinical trials in Parkinson's disease. PMID- 26040710 TI - Model-based segmentation in orbital volume measurement with cone beam computed tomography and evaluation against current concepts. AB - PURPOSE: Objective determination of the orbital volume is important in the diagnostic process and in evaluating the efficacy of medical and/or surgical treatment of orbital diseases. Tools designed to measure orbital volume with computed tomography (CT) often cannot be used with cone beam CT (CBCT) because of inferior tissue representation, although CBCT has the benefit of greater availability and lower patient radiation exposure. Therefore, a model-based segmentation technique is presented as a new method for measuring orbital volume and compared to alternative techniques. METHODS: Both eyes from thirty subjects with no known orbital pathology who had undergone CBCT as a part of routine care were evaluated (n = 60 eyes). Orbital volume was measured with manual, atlas based, and model-based segmentation methods. Volume measurements, volume determination time, and usability were compared between the three methods. Differences in means were tested for statistical significance using two-tailed Student's t tests. RESULTS: Neither atlas-based (26.63 +/- 3.15 mm(3)) nor model based (26.87 +/- 2.99 mm(3)) measurements were significantly different from manual volume measurements (26.65 +/- 4.0 mm(3)). However, the time required to determine orbital volume was significantly longer for manual measurements (10.24 +/- 1.21 min) than for atlas-based (6.96 +/- 2.62 min, p < 0.001) or model-based (5.73 +/- 1.12 min, p < 0.001) measurements. CONCLUSION: All three orbital volume measurement methods examined can accurately measure orbital volume, although atlas-based and model-based methods seem to be more user-friendly and less time consuming. The new model-based technique achieves fully automated segmentation results, whereas all atlas-based segmentations at least required manipulations to the anterior closing. Additionally, model-based segmentation can provide reliable orbital volume measurements when CT image quality is poor. PMID- 26040711 TI - Sequential capillary electrophoresis analysis using optically gated sample injection and UV/vis detection. AB - We present sequential CE analysis of amino acids and L-asparaginase-catalyzed enzyme reaction, by combing the on-line derivatization, optically gated (OG) injection and commercial-available UV-Vis detection. Various experimental conditions for sequential OG-UV/vis CE analysis were investigated and optimized by analyzing a standard mixture of amino acids. High reproducibility of the sequential CE analysis was demonstrated with RSD values (n = 20) of 2.23, 2.57, and 0.70% for peak heights, peak areas, and migration times, respectively, and the LOD of 5.0 MUM (for asparagine) and 2.0 MUM (for aspartic acid) were obtained. With the application of the OG-UV/vis CE analysis, sequential online CE enzyme assay of L-asparaginase-catalyzed enzyme reaction was carried out by automatically and continuously monitoring the substrate consumption and the product formation every 12 s from the beginning to the end of the reaction. The Michaelis constants for the reaction were obtained and were found to be in good agreement with the results of traditional off-line enzyme assays. The study demonstrated the feasibility and reliability of integrating the OG injection with UV/vis detection for sequential online CE analysis, which could be of potential value for online monitoring various chemical reaction and bioprocesses. PMID- 26040712 TI - Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing. AB - At the onset of metazoan cell division the nuclear envelope breaks down to enable capture of chromosomes by the microtubule-containing spindle apparatus. During anaphase, when chromosomes have separated, the nuclear envelope is reassembled around the forming daughter nuclei. How the nuclear envelope is sealed, and how this is coordinated with spindle disassembly, is largely unknown. Here we show that endosomal sorting complex required for transport (ESCRT)-III, previously found to promote membrane constriction and sealing during receptor sorting, virus budding, cytokinesis and plasma membrane repair, is transiently recruited to the reassembling nuclear envelope during late anaphase. ESCRT-III and its regulatory AAA (ATPase associated with diverse cellular activities) ATPase VPS4 are specifically recruited by the ESCRT-III-like protein CHMP7 to sites where the reforming nuclear envelope engulfs spindle microtubules. Subsequent association of another ESCRT-III-like protein, IST1, directly recruits the AAA ATPase spastin to sever microtubules. Disrupting spastin function impairs spindle disassembly and results in extended localization of ESCRT-III at the nuclear envelope. Interference with ESCRT-III functions in anaphase is accompanied by delayed microtubule disassembly, compromised nuclear integrity and the appearance of DNA damage foci in subsequent interphase. We propose that ESCRT-III, VPS4 and spastin cooperate to coordinate nuclear envelope sealing and spindle disassembly at nuclear envelope-microtubule intersection sites during mitotic exit to ensure nuclear integrity and genome safeguarding, with a striking mechanistic parallel to cytokinetic abscission. PMID- 26040713 TI - ESCRT-III controls nuclear envelope reformation. AB - During telophase, the nuclear envelope (NE) reforms around daughter nuclei to ensure proper segregation of nuclear and cytoplasmic contents. NE reformation requires the coating of chromatin by membrane derived from the endoplasmic reticulum, and a subsequent annular fusion step to ensure that the formed envelope is sealed. How annular fusion is accomplished is unknown, but it is thought to involve the p97 AAA-ATPase complex and bears a topological equivalence to the membrane fusion event that occurs during the abscission phase of cytokinesis. Here we show that the endosomal sorting complex required for transport-III (ESCRT-III) machinery localizes to sites of annular fusion in the forming NE in human cells, and is necessary for proper post-mitotic nucleo cytoplasmic compartmentalization. The ESCRT-III component charged multivesicular body protein 2A (CHMP2A) is directed to the forming NE through binding to CHMP4B, and provides an activity essential for NE reformation. Localization also requires the p97 complex member ubiquitin fusion and degradation 1 (UFD1). Our results describe a novel role for the ESCRT machinery in cell division and demonstrate a conservation of the machineries involved in topologically equivalent mitotic membrane remodelling events. PMID- 26040714 TI - Materials science: Round the bend with microwaves. PMID- 26040715 TI - Erratum: Mutant MHC class II epitopes drive therapeutic immune responses to cancer. PMID- 26040716 TI - Cloning and variation of ground state intestinal stem cells. AB - Stem cells of the gastrointestinal tract, pancreas, liver and other columnar epithelia collectively resist cloning in their elemental states. Here we demonstrate the cloning and propagation of highly clonogenic, 'ground state' stem cells of the human intestine and colon. We show that derived stem-cell pedigrees sustain limited copy number and sequence variation despite extensive serial passaging and display exquisitely precise, cell-autonomous commitment to epithelial differentiation consistent with their origins along the intestinal tract. This developmentally patterned and epigenetically maintained commitment of stem cells is likely to enforce the functional specificity of the adult intestinal tract. Using clonally derived colonic epithelia, we show that toxins A or B of the enteric pathogen Clostridium difficile recapitulate the salient features of pseudomembranous colitis. The stability of the epigenetic commitment programs of these stem cells, coupled with their unlimited replicative expansion and maintained clonogenicity, suggests certain advantages for their use in disease modelling and regenerative medicine. PMID- 26040718 TI - Cell biology: nuclear dilemma resolved. PMID- 26040717 TI - Receptor-mediated selective autophagy degrades the endoplasmic reticulum and the nucleus. AB - Macroautophagy (hereafter referred to as autophagy) degrades various intracellular constituents to regulate a wide range of cellular functions, and is also closely linked to several human diseases. In selective autophagy, receptor proteins recognize degradation targets and direct their sequestration by double membrane vesicles called autophagosomes, which transport them into lysosomes or vacuoles. Although recent studies have shown that selective autophagy is involved in quality/quantity control of some organelles, including mitochondria and peroxisomes, it remains unclear how extensively it contributes to cellular organelle homeostasis. Here we describe selective autophagy of the endoplasmic reticulum (ER) and nucleus in the yeast Saccharomyces cerevisiae. We identify two novel proteins, Atg39 and Atg40, as receptors specific to these pathways. Atg39 localizes to the perinuclear ER (or the nuclear envelope) and induces autophagic sequestration of part of the nucleus. Atg40 is enriched in the cortical and cytoplasmic ER, and loads these ER subdomains into autophagosomes. Atg39 dependent autophagy of the perinuclear ER/nucleus is required for cell survival under nitrogen-deprivation conditions. Atg40 is probably the functional counterpart of FAM134B, an autophagy receptor for the ER in mammals that has been implicated in sensory neuropathy. Our results provide fundamental insight into the pathophysiological roles and mechanisms of 'ER-phagy' and 'nucleophagy' in other organisms. PMID- 26040719 TI - Corrigendum: A new arboreal haramiyid shows the diversity of crown mammals in the Jurassic period. PMID- 26040721 TI - Cell biology: Receptors for selective recycling. PMID- 26040720 TI - Regulation of endoplasmic reticulum turnover by selective autophagy. AB - The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans. PMID- 26040722 TI - A noisy linear map underlies oscillations in cell size and gene expression in bacteria. AB - During bacterial growth, a cell approximately doubles in size before division, after which it splits into two daughter cells. This process is subjected to the inherent perturbations of cellular noise and thus requires regulation for cell size homeostasis. The mechanisms underlying the control and dynamics of cell size remain poorly understood owing to the difficulty in sizing individual bacteria over long periods of time in a high-throughput manner. Here we measure and analyse long-term, single-cell growth and division across different Escherichia coli strains and growth conditions. We show that a subset of cells in a population exhibit transient oscillations in cell size with periods that stretch across several (more than ten) generations. Our analysis reveals that a simple law governing cell-size control-a noisy linear map-explains the origins of these cell-size oscillations across all strains. This noisy linear map implements a negative feedback on cell-size control: a cell with a larger initial size tends to divide earlier, whereas one with a smaller initial size tends to divide later. Combining simulations of cell growth and division with experimental data, we demonstrate that this noisy linear map generates transient oscillations, not just in cell size, but also in constitutive gene expression. Our work provides new insights into the dynamics of bacterial cell-size regulation with implications for the physiological processes involved. PMID- 26040723 TI - Self-Care Behaviors and Glycemic Control in Low-Income Adults in Mexico With Type 2 Diabetes Mellitus May Have Implications for Patients of Mexican Heritage Living in the United States. AB - This study examined self-care behaviors and their relationship to glycemic control in low-income Mexican adults with type 2 diabetes in Southeastern Tamaulipas, Mexico. A total of 135 patients were enrolled from 17 community health centers. The most frequent self-care behavior was medication management (80%), and the least frequent self-care behavior was self blood glucose monitoring (7%). All the patients demonstrated poor glycemic control, with glycated hemoglobin > 7%. Self-care behaviors were associated with fasting blood glucose (rs = .223, p = .005). Medication management was influenced by cognitive performance, F(1, 130) = 4.49, p = .036, and depression, F(1, 130) = 8.22, p = .005. Dietary behaviors were influenced by previous diabetes education, F(1, 130) = 6.73, p = .011. These findings indicate that education and cognitive behavioral interventions in Spanish for Mexican adults with type 2 diabetes are urgently needed. PMID- 26040724 TI - Microparticles Containing Curcumin Solid Dispersion: Stability, Bioavailability and Anti-Inflammatory Activity. AB - This work aimed at improving the solubility of curcumin by the preparation of spray-dried ternary solid dispersions containing Gelucire(r)50/13-Aerosil(r) and quantifying the resulting in vivo oral bioavailability and anti-inflammatory activity. The solid dispersion containing 40% of curcumin was characterised by calorimetry, infrared spectroscopy and X-ray powder diffraction. The solubility and dissolution rate of curcumin in aqueous HCl or phosphate buffer improved up to 3600- and 7.3-fold, respectively. Accelerated stability test demonstrated that the solid dispersion was stable for 9 months. The pharmacokinetic study showed a 5.5-fold increase in curcumin in rat blood plasma when compared to unprocessed curcumin. The solid dispersion also provided enhanced anti-inflammatory activity in rat paw oedema. Finally, the solid dispersion proposed here is a promising way to enhance curcumin bioavailability at an industrial pharmaceutical perspective, since its preparation applies the spray drying, which is an easy to scale up technique. The findings herein stimulate further in vivo evaluations and clinical tests as a cancer and Alzheimer chemoprevention agent. PMID- 26040725 TI - Membrane fouling controlled by coagulation/adsorption during direct sewage membrane filtration (DSMF) for organic matter concentration. AB - Unlike the role of the membrane in a membrane bioreactor, which is designed to replace a sediment tank, direct sewage membrane filtration (DSMF), with the goal of concentrating organic matters, is proposed as a pretreatment process in a novel sewage treatment concept. The concept of membrane-based pretreatment is proposed to divide raw sewage into a concentrated part retaining most organics and a filtered part with less pollutant remaining, so that energy recovery and water reuse, respectively, could be realized by post-treatment. A pilot-scale experiment was carried out to verify the feasibility of coagulant/adsorbent addition for membrane fouling control, which has been the main issue during this DSMF process. The results showed that continuous coagulant addition successfully slowed down the increase in filtration resistance, with the resistance maintained below 1.0*10(13) m(-1) in the first 70 hr before a jump occurred. Furthermore, the adsorbent addition contributed to retarding the occurrence of the filtration resistance jump, achieving simultaneous fouling control and chemical oxygen demand (COD) concentration improvement. The final concentrated COD amounted to 7500 mg/L after 6 days of operation. PMID- 26040726 TI - Photodegradation of methylmercury in Jialing River of Chongqing, China. AB - Photodegradation (PD) of methylmercury (MMHg) is a key process of mercury (Hg) cycling in water systems, maintaining MMHg at a low level in water systems. However, we possess little knowledge of this important process in the Jialing River of Chongqing, China. In situ incubation experiments were thus performed to measure temporal patterns and influencing factors of MMHg PD in this river. The results showed that MMHg underwent a net demethylation process under solar radiation in the water column, which predominantly occurred in surface waters. For surface water, the highest PD rate constants were observed in spring (12*10( 3)+/-1.5*10(-3) m2/E), followed by summer (9.0*10(-3)+/-1.2*10(-3) m2/E), autumn (1.4*10(-3)+/-0.12*10(-3) m2/E), and winter (0.78*10(-3)+/-0.11*10(-3) m2/E). UV A radiation (320-400 nm), UV-B radiation (280-320 nm), and photosynthetically active radiation (PAR, 400-700 nm) accounted for 43%-64%, 14%-31%, and 16%-45% of MMHg PD, respectively. PD rate constants varied substantially with the treatments that filtered the river water and amended it with chemicals (i.e., Cl-, NO3-, dissolved organic matter (DOM), Fe(III)), which reveals that suspended particulate matter and water components are important factors in affecting the PD process. For the entire water column, the PD rate constant determined for each wavelength range decreased rapidly with water depth. UV-A, UV-B, and PAR contributed 27%-46%, 6.2%-12%, and 42%-65% to the PD process, respectively. PD flux was estimated to be 4.7 MUg/(m2.year) in the study site. Our results are very important to understand the cycling characteristics of MMHg in the Jialing River of Chongqing, China. PMID- 26040727 TI - Powdered activated carbon adsorption of two fishy odorants in water: Trans,trans 2,4-heptadienal and trans,trans-2,4-decadienal. AB - Powdered activated carbon (PAC) adsorption of two fishy odorants, trans,trans-2,4 heptadienal (HDE) and trans,trans-2,4-decadienal (DDE), was investigated. Both the pseudo first-order and the pseudo second-order kinetic models well described the kinetics curves, and DDE was more readily removed by PAC. In isotherm tests, both Freundlich and Modified Freundlich isotherms fitted the experimental data well. PAC exhibited a higher adsorption capacity for DDE than for HDE, which could be ascribed to the difference in their hydrophobicity. The calculated thermodynamic parameters (DeltaG0, DeltaH0, and DeltaS0) indicated an exothermic and spontaneous adsorption process. PAC dosage, pH, and natural organic matter (NOM) presence were found to influence the adsorption process. With increasing PAC dosage, the pseudo first-order and pseudo second-order rate constants both increased. The value of pH had little influence on HDE or DDE molecules but altered the surface charge of PAC, and the maximum adsorption capacity occurred at pH9. The presence of NOM, especially the fraction with molecular weight less than 1k Dalton, hindered the adsorption. The study showed that preloaded NOM impaired the adsorption capacity of HDE or DDE more severely than simultaneously fed NOM did. PMID- 26040728 TI - Toxic effects of perfluorononanoic acid on the development of Zebrafish (Danio rerio) embryos. AB - Perfluorononanoic acid (PFNA) is a nine-carbon perfluoroalkyl acid widely used in industrial and domestic products. It is a persistent organic pollutant found in the environment as well as in the tissues of humans and wildlife. There is a concern that this chemical might be a developmental toxicant and teratogen in various ecosystems. In the present study, the toxic effects of PFNA were evaluated in zebrafish (Danio rerio) embryos. One hour post-fertilization embryos were treated with 0, 25, 50, 100, 200, 300, 350, and 400 MUmol/L PFNA for 96 hr in 6-well plates. Developmental phenotypes and hatching rates were observed and recorded. Nineteen genes related to oxidative stress and lipid metabolism were examined using Quantitative RT-PCR and confirmed by whole mount in situ hybridization (WISH). Results showed that PFNA delayed the development of zebrafish embryos, reduced the hatching rate, and caused ventricular edema and malformation of the spine. In addition, the amount of reactive oxygen species in the embryo bodies increased significantly after exposure to PFNA compared with that of the control group. The Quantitative RT-PCR and WISH experiments demonstrated that mRNA expression of the lfabp and ucp2 genes increased significantly while that of sod1 and mt-nd1 decreased significantly after PFNA exposure. The mRNA expression levels of gpx1 and mt-atp6 decreased significantly in the high concentration group. However, the mRNA expression levels of both ppara and pparg did not show any significant variation after exposure. These findings suggest that PFNA affected the development of zebrafish embryos at relatively low concentrations. PMID- 26040729 TI - Denitrification and biofilm growth in a pilot-scale biofilter packed with suspended carriers for biological nitrogen removal from secondary effluent. AB - Tertiary denitrification is an effective method for nitrogen removal from wastewater. A pilot-scale biofilter packed with suspended carriers was operated for tertiary denitrification with ethanol as the organic carbon source. Long-term performance, biokinetics of denitrification and biofilm growth were evaluated under filtration velocities of 6, 10 and 14 m/hr. The pilot-scale biofilter removed nitrate from the secondary effluent effectively, and the nitrate nitrogen (NO3-N) removal percentage was 82%, 78% and 55% at the filtration velocities of 6, 10 and 14 m/hr, respectively. At the filtration velocities of 6 and 10 m/hr, the nitrate removal loading rate increased with increasing influent nitrate loading rates, while at the filtration velocity of 14 m/hr, the removal loading rate and the influent loading rate were uncorrelated. During denitrification, the ratio of consumed chemical oxygen demand to removed NO3-N was 3.99-4.52 mg/mg. Under the filtration velocities of 6, 10 and 14 m/hr, the maximum denitrification rate was 3.12, 4.86 and 4.42 g N/(m2.day), the half-saturation constant was 2.61, 1.05 and 1.17 mg/L, and the half-order coefficient was 0.22, 0.32 and 0.24(mg/L)1/2/min, respectively. The biofilm biomass increased with increasing filtration velocity and was 2845, 5124 and 7324 mg VSS/m2 at filtration velocities of 6, 10 and 14 m/hr, respectively. The highest biofilm density was 44 mg/cm3 at the filtration velocity of 14 m/hr. Due to the low influent loading rate, biofilm biomass and thickness were lowest at the filtration velocity of 6m/hr. PMID- 26040730 TI - Groundwater arsenic removal by coagulation using ferric(III) sulfate and polyferric sulfate: A comparative and mechanistic study. AB - Elevated arsenic (As) in groundwater poses a great threat to human health. Coagulation using mono- and poly-Fe salts is becoming one of the most cost effective processes for groundwater As removal. However, a limitation comes from insufficient understanding of the As removal mechanism from groundwater matrices in the coagulation process, which is critical for groundwater treatment and residual solid disposal. Here, we overcame this hurdle by utilizing microscopic techniques to explore molecular As surface complexes on the freshly formed Fe flocs and compared ferric(III) sulfate (FS) and polyferric sulfate (PFS) performance, and finally provided a practical solution in As-geogenic areas. FS and PFS exhibited a similar As removal efficiency in coagulation and coagulation/filtration in a two-bucket system using 5mg/L Ca(ClO)2. By using the two-bucket system combining coagulation and sand filtration, 500 L of As-safe water (<10 MUg/L) was achieved during five treatment cycles by washing the sand layer after each cycle. Fe k-edge X-ray absorption near-edge structure (XANES) and As k-edge extended X-ray absorption fine structure (EXAFS) analysis of the solid residue indicated that As formed a bidentate binuclear complex on ferrihydrite, with no observation of scorodite or poorly-crystalline ferric arsenate. Such a stable surface complex is beneficial for As immobilization in the solid residue, as confirmed by the achievement of much lower leachate As (0.9 MUg/L-0.487 mg/L) than the US EPA regulatory limit (5 mg/L). Finally, PFS is superior to FS because of its lower dose, much lower solid residue, and lower cost for As-safe drinking water. PMID- 26040731 TI - Diurnal and spatial variations of soil NOx fluxes in the northern steppe of China. AB - NOx emissions from biogenic sources in soils play a significant role in the gaseous loss of soil nitrogen and consequent changes in tropospheric chemistry. In order to investigate the characteristics of NOx fluxes and factors influencing these fluxes in degraded sandy grasslands in northern China, diurnal and spatial variations of NOx fluxes were measured in situ. A dynamic flux chamber method was used at eight sites with various vegetation coverages and soil types in the northern steppe of China in the summer season of 2010. Fluxes of NOx from soils with plant covers were generally higher than those in the corresponding bare vegetation-free soils, indicating that the canopy plays an important role in the exchange of NOx between soil and air. The fluxes of NOx increased in the daytime, and decreased during the nighttime, with peak emissions occurring between 12:00 and 14:00. The results of multiple linear regression analysis indicated that the diurnal variation of NOx fluxes was positively correlated with soil temperature (P<0.05) and negatively with soil moisture content (P<0.05). Based on measurement over a season, the overall variation in NOx flux was lower than that of soil nitrogen contents, suggesting that the gaseous loss of N from the grasslands of northern China was not a significant contributor to the high C/N in the northern steppe of China. The concentration of NOx emitted from soils in the region did not exceed the 1-hr National Ambient Air Quality Standard (0.25 mg/m3). PMID- 26040732 TI - Effects of elevated atmospheric CO2 concentration and temperature on the soil profile methane distribution and diffusion in rice-wheat rotation system. AB - The aim of this experiment was to determine the impacts of climate change on soil profile concentrations and diffusion effluxes of methane in a rice-wheat annual rotation ecosystem in Southeastern China. We initiated a field experiment with four treatments: ambient conditions (CKs), CO2 concentration elevated to ~500 MUmol/mol (FACE), temperature elevated by ca. 2 degrees C (T) and combined elevation of CO2 concentration and temperature (FACE+T). A multilevel sampling probe was designed to collect the soil gas at four different depths, namely, 7 cm, 15 cm, 30 cm and 50 cm. Methane concentrations were higher during the rice season and decreased with depth, while lower during the wheat season and increased with depth. Compared to CK, mean methane concentration was increased by 42%, 57% and 71% under the FACE, FACE+T and T treatments, respectively, at the 7 cm depth during the rice season (p<0.05). Mean methane diffusion effluxes to the 7 cm depth were positive in the rice season and negative in the wheat season, resulting in the paddy field being a source and weak sink, respectively. Moreover, mean methane diffusion effluxes in the rice season were 0.94, 1.19 and 1.42 mg C/(m2.hr) in the FACE, FACE+T and T treatments, respectively, being clearly higher than that in the CK. The results indicated that elevated atmospheric CO2 concentration and temperature could significantly increase soil profile methane concentrations and their effluxes from a rice-wheat field annual rotation ecosystem (p<0.05). PMID- 26040733 TI - The potential leaching and mobilization of trace elements from FGD-gypsum of a coal-fired power plant under water re-circulation conditions. AB - Experimental and geochemical modelling studies were carried out to identify mineral and solid phases containing major, minor, and trace elements and the mechanism of the retention of these elements in Flue Gas Desulphurisation (FGD) gypsum samples from a coal-fired power plant under filtered water recirculation to the scrubber and forced oxidation conditions. The role of the pH and related environmental factors on the mobility of Li, Ni, Zn, As, Se, Mo, and U from FGD gypsums for a comprehensive assessment of element leaching behaviour were also carried out. Results show that the extraction rate of the studied elements generally increases with decreasing the pH value of the FGD-gypsum leachates. The increase of the mobility of elements such as U, Se, and As in the FGD-gypsum entails the modification of their aqueous speciation in the leachates; UO2SO4, H2Se, and HAsO2 are the aqueous complexes with the highest activities under acidic conditions. The speciation of Zn, Li, and Ni is not affected in spite of pH changes; these elements occur as free cations and associated to SO4(2) in the FGD-gypsum leachates. The mobility of Cu and Mo decreases by decreasing the pH of the FGD-gypsum leachates, which might be associated to the precipitation of CuSe2 and MoSe2, respectively. Time-of-Flight mass spectrometry of the solid phase combined with geochemical modelling of the aqueous phase has proved useful in understanding the mobility and geochemical behaviour of elements and their partitioning into FGD-gypsum samples. PMID- 26040734 TI - Unraveling the size distributions of surface properties for purple soil and yellow soil. AB - Soils contain diverse colloidal particles whose properties are pertinent to ecological and human health, whereas few investigations systematically analyze the surface properties of these particles. The objective of this study was to elucidate the surface properties of particles within targeted size ranges (i.e. >10, 1-10, 0.5-1, 0.2-0.5 and <0.2 MUm) for a purple soil (Entisol) and a yellow soil (Ultisol) using the combined determination method. The mineralogy of corresponding particle-size fractions was determined by X-ray diffraction. We found that up to 80% of the specific surface area and 85% of the surface charge of the entire soil came from colloidal-sized particles (<1 MUm), and almost half of the specific surface area and surface charge came from the smallest particles (<0.2 MUm). Vermiculite, illite, montmorillonite and mica dominated in the colloidal-sized particles, of which the smallest particles had the highest proportion of vermiculite and montmorillonite. For a given size fraction, the purple soil had a larger specific surface area, stronger electrostatic field, and higher surface charge than the yellow soil due to differences in mineralogy. Likewise, the differences in surface properties among the various particle-size fractions can also be ascribed to mineralogy. Our results indicated that soil surface properties were essentially determined by the colloidal-sized particles, and the <0.2 MUm nanoparticles made the largest contribution to soil properties. The composition of clay minerals within the diverse particle-size fractions could fully explain the size distributions of surface properties. PMID- 26040735 TI - Prediction of effluent concentration in a wastewater treatment plant using machine learning models. AB - Of growing amount of food waste, the integrated food waste and waste water treatment was regarded as one of the efficient modeling method. However, the load of food waste to the conventional waste treatment process might lead to the high concentration of total nitrogen (T-N) impact on the effluent water quality. The objective of this study is to establish two machine learning models-artificial neural networks (ANNs) and support vector machines (SVMs), in order to predict 1 day interval T-N concentration of effluent from a wastewater treatment plant in Ulsan, Korea. Daily water quality data and meteorological data were used and the performance of both models was evaluated in terms of the coefficient of determination (R2), Nash-Sutcliff efficiency (NSE), relative efficiency criteria (drel). Additionally, Latin-Hypercube one-factor-at-a-time (LH-OAT) and a pattern search algorithm were applied to sensitivity analysis and model parameter optimization, respectively. Results showed that both models could be effectively applied to the 1-day interval prediction of T-N concentration of effluent. SVM model showed a higher prediction accuracy in the training stage and similar result in the validation stage. However, the sensitivity analysis demonstrated that the ANN model was a superior model for 1-day interval T-N concentration prediction in terms of the cause-and-effect relationship between T-N concentration and modeling input values to integrated food waste and waste water treatment. This study suggested the efficient and robust nonlinear time-series modeling method for an early prediction of the water quality of integrated food waste and waste water treatment process. PMID- 26040736 TI - Cu-Mn-Ce ternary mixed-oxide catalysts for catalytic combustion of toluene. AB - Cu-Mn, Cu-Mn-Ce, and Cu-Ce mixed-oxide catalysts were prepared by a citric acid sol-gel method and then characterized by XRD, BET, H2-TPR and XPS analyses. Their catalytic properties were investigated in the toluene combustion reaction. Results showed that the Cu-Mn-Ce ternary mixed-oxide catalyst with 1:2:4 mole ratios had the highest catalytic activity, and 99% toluene conversion was achieved at temperatures below 220 degrees C. In the Cu-Mn-Ce catalyst, a portion of Cu and Mn species entered into the CeO2 fluorite lattice, which led to the formation of a ceria-based solid solution. Excess Cu and Mn oxides existed on the surface of the ceria-based solid solution. The coexistence of Cu-Mn mixed oxides and the ceria-based solid solution resulted in a better synergetic interaction than the Cu-Mn and Cu-Ce catalysts, which promoted catalyst reducibility, increased oxygen mobility, and enhanced the formation of abundant active oxygen species. PMID- 26040737 TI - Immobilization of self-assembled pre-dispersed nano-TiO2 onto montmorillonite and its photocatalytic activity. AB - The immobilization of pre-dispersed TiO2 colloids onto the external surface of the clay mineral montmorillonite (Mt) was accomplished and regulated via a self assembly method employing the cationic surfactant cetyltrimethylammonium bromide (CTAB). The role of CTAB in the synthesis process was investigated by preparing a series of TiO2-CTAB-Mt composites (TCM) with various CTAB doses. The results indicated that a uniform and continuous TiO2 film was deposited on the external surface of montmorillonite in the composite synthesized with 0.1 wt.% of CTAB, and the TCM nano-composites showed much higher values for specific surface area, average pore size and pore volume than the raw montmorillonite clay. Then, the formed TCM materials were applied in photocatalytic degradation of 2,4 dichlorophenol (2,4-DCP) in aqueous solution. The degradation efficiency reached as high as 94.7%. Based on the degradation intermediates benezoquinone, fumaric acid and oxalic acid identified by LC-MS analysis, a mechanism for the photocatalytic oxidation of 2,4-DCP on TiO2/Mt nano-composites is proposed. PMID- 26040738 TI - Effects of fluoride on the removal of cadmium and phosphate by aluminum coagulation. AB - This study focuses on the effects of pH and fluoride at different molar ratios of fluoride to Al (RF:Al) on the removal of cadmium (Cd2+) and phosphate by Al coagulation. Fluoride at RF:Al>=3:1 inhibits the removal of Cd over wide Al dose ranges from 5 to 10 mg/L as Al. The removal of phosphate decreases significantly at high RF:Al of 10:1 whereas at lowered RF:Al (i.e., <=6:1), an adverse effect is observed only at insufficient Al doses below 2 mg/L. Fluoride shows inhibitive effects towards the removal of Cd at pH7 and 8 and that of phosphate at pH6. Fluoride decreases the zeta-potential in both systems, and the decreasing extent is positively correlated to the elevated RF:Al. The Al fluoride interactions include the formation of Al-F complexes and the adsorption of fluoride onto Al(OH)3 precipitates, i.e., the formation of Al(OH)nFm. Al-F complex formation inhibits Al hydrolysis and increases residual Al levels, and a more significant increase was observed at lower pH. Al-F complexes at high RF:Al complicate the coagulation behavior of Al towards both negative and positive ionic species. Moreover, fluoride at low RF:Al shows little effect on Al coagulation behavior towards Cd2+ and phosphate, and the spent defluoridation adsorbent, i.e., aluminum (Al) hydro(oxide) with adsorbed fluoride at RF:Al of below 0.1:1, may be reclaimed as a coagulant after being dissolved. PMID- 26040739 TI - Structure and function of rhizosphere and non-rhizosphere soil microbial community respond differently to elevated ozone in field-planted wheat. AB - To assess the responses of the soil microbial community to chronic ozone (O3), wheat seedlings (Triticum aestivum Linn.) were planted in the field and exposed to elevated O3 (eO3) concentration. Three treatments were employed: (1) Control treatment (CK), AOT40=0; (2) O3-1, AOT40=1.59 ppm*h; (3) O3-2, AOT40=9.17 ppm*h. Soil samples were collected for the assessment of microbial biomass C, community level physiological profiles (CLPPs), and phospholipid fatty acids (PLFAs). EO3 concentration significantly reduced soil microbial carbon and changed microbial CLPPs in rhizosphere soil, but not in non-rhizosphere soil. The results of the PLFAs showed that eO3 concentrations had significant effects on soil community structure in both rhizosphere and non-rhizosphere soils. The relative abundances of fungal and actinomycetous indicator PLFAs decreased in both rhizosphere and non-rhizosphere soils, while those of bacterial PLFAs increased. Thus the results proved that eO3 concentration significantly changed the soil microbial community function and composition, which would influence the soil nutrient supply and carbon dynamics under O3 exposure. PMID- 26040740 TI - Chemical looping combustion: A new low-dioxin energy conversion technology. AB - Dioxin production is a worldwide concern because of its persistence and carcinogenic, teratogenic, and mutagenic effects. The pyrolysis-chemical looping combustion process of disposing solid waste is an alternative to traditional solid waste incineration developed to reduce the dioxin production. Based on the equilibrium composition of the Deacon reaction, pyrolysis gas oxidized by seven common oxygen carriers, namely, CuO, NiO, CaSO4, CoO, Fe2O3, Mn3O4, and FeTiO3, is studied and compared with the pyrolysis gas directly combusted by air. The result shows that the activity of the Deacon reaction for oxygen carriers is lower than that for air. For four typical oxygen carriers (CuO, NiO, Fe2O3, and FeTiO3), the influences of temperature, pressure, gas composition, and tar on the Deacon reaction are discussed in detail. According to these simulation results, the dioxin production in China, Europe, the United States, and Japan is predicted for solid waste disposal by the pyrolysis-chemical looping combustion process. Thermodynamic analysis results in this paper show that chemical looping combustion can reduce dioxin production in the disposal of solid waste. PMID- 26040741 TI - Picoplankton and virioplankton abundance and community structure in Pearl River Estuary and Daya Bay, South China. AB - By using flow cytometry techniques, we investigated the abundance and composition of the heterotrophic prokaryotes, virioplankton and picophytoplankton community in the Pearl River Estuary and Daya Bay in the summer of 2012. We identified two subgroups of prokaryotes, high nucleic acid (HNA) and low nucleic acid (LNA), characterized by different nucleic acid contents. HNA abundance was significantly correlated with larger phytoplankton and Synechococcus (Syn) abundance, which suggested the important role of organic substrates released from primary producers on bacterial growth. Although LNA did not show any association with environmental variables, it was a vital component of the microbial community. In contrast to previous studies, the total virioplankton concentration had a poor relationship with nutrient availability. The positive relationship between large sized phytoplankton abundance and the V-I population confirmed that V-I was a phytoplankton-infecting viral subgroup. Although the V-II group (bacteriophages) was dominant in the virioplankton community, it was not related with prokaryotic abundance, which indicated factors other than hosts controlling V-II abundance or the uncertainty of virus-host coupling. With respect to the picophytoplankton community, our results implied that river input exerted a strong limitation to Syn distribution in the estuary, while picoeukaryotes (Euk) were numerically less abundant and showed a quite different distribution pattern from that of Syn, and hence presented ecological properties distinct from Syn in our two studied areas. PMID- 26040742 TI - Chemical characterization of size-resolved aerosols in four seasons and hazy days in the megacity Beijing of China. AB - Size-resolved aerosol samples were collected by MOUDI in four seasons in 2007 in Beijing. The PM10 and PM1.8 mass concentrations were 166.0+/-120.5 and 91.6+/ 69.7 MUg/m3, respectively, throughout the measurement, with seasonal variation: nearly two times higher in autumn than in summer and spring. Serious fine particle pollution occurred in winter with the PM1.8/PM10 ratio of 0.63, which was higher than other seasons. The size distribution of PM showed obvious seasonal and diurnal variation, with a smaller fine mode peak in spring and in the daytime. OM (organic matter=1.6*OC (organic carbon)) and SIA (secondary inorganic aerosol) were major components of fine particles, while OM, SIA and Ca2+ were major components in coarse particles. Moreover, secondary components, mainly SOA (secondary organic aerosol) and SIA, accounted for 46%-96% of each size bin in fine particles, which meant that secondary pollution existed all year. Sulfates and nitrates, primarily in the form of (NH4)2SO4, NH4NO3, CaSO4, Na2SO4 and K2SO4, calculated by the model ISORROPIA II, were major components of the solid phase in fine particles. The PM concentration and size distribution were similar in the four seasons on non-haze days, while large differences occurred on haze days, which indicated seasonal variation of PM concentration and size distribution were dominated by haze days. The SIA concentrations and fractions of nearly all size bins were higher on haze days than on non-haze days, which was attributed to heterogeneous aqueous reactions on haze days in the four seasons. PMID- 26040743 TI - Numerical study of the effects of Planetary Boundary Layer structure on the pollutant dispersion within built-up areas. AB - The effects of different Planetary Boundary Layer (PBL) structures on pollutant dispersion processes within two idealized street canyon configurations and a realistic urban area were numerically examined by a Computational Fluid Dynamics (CFD) model. The boundary conditions of different PBL structures/conditions were provided by simulations of the Weather Researching and Forecasting model. The simulated results of the idealized 2D and 3D street canyon experiments showed that the increment of PBL instability favored the downward transport of momentum from the upper flow above the roof to the pedestrian level within the street canyon. As a result, the flow and turbulent fields within the street canyon under the more unstable PBL condition are stronger. Therefore, more pollutants within the street canyon would be removed by the stronger advection and turbulent diffusion processes under the unstable PBL condition. On the contrary, more pollutants would be concentrated in the street canyon under the stable PBL condition. In addition, the simulations of the realistic building cluster experiments showed that the density of buildings was a crucial factor determining the dynamic effects of the PBL structure on the flow patterns. The momentum field within a denser building configuration was mostly transported from the upper flow, and was more sensitive to the PBL structures than that of the sparser building configuration. Finally, it was recommended to use the Mellor-Yamada Nakanishi-Niino (MYNN) PBL scheme, which can explicitly output the needed turbulent variables, to provide the boundary conditions to the CFD simulation. PMID- 26040744 TI - Interaction between Cu2+ and different types of surface-modified nanoscale zero valent iron during their transport in porous media. AB - This study investigated the interaction between Cu2+ and nano zero-valent iron (NZVI) coated with three types of stabilizers (i.e., polyacrylic acid [PAA], Tween-20 and starch) by examining the Cu2+ uptake, colloidal stability and mobility of surface-modified NZVI (SM-NZVI) in the presence of Cu2+. The uptake of Cu2+ by SM-NZVI and the colloidal stability of the Cu-bearing SM-NZVI were examined in batch tests. The results showed that NZVI coated with different modifiers exhibited different affinities for Cu2+, which resulted in varying colloidal stability of different SM-NZVI in the presence of Cu2+. The presence of Cu2+ exerted a slight influence on the aggregation and settling of NZVI modified with PAA or Tween-20. However, the presence of Cu2+ caused significant aggregation and sedimentation of starch-modified NZVI, which is due to Cu2+ complexation with the starch molecules coated on the surface of the particles. Column experiments were conducted to investigate the co-transport of Cu2+ in association with SM-NZVI in water-saturated quartz sand. It was presumed that a physical straining mechanism accounted for the retention of Cu-bearing SM-NZVI in the porous media. Moreover, the enhanced aggregation of SM-NZVI in the presence of Cu2+ may be contributing to this straining effect. PMID- 26040745 TI - Tricrystalline TiO2 with enhanced photocatalytic activity and durability for removing volatile organic compounds from indoor air. AB - It is important to develop efficient and economic techniques for removing volatile organic compounds (VOCs) in indoor air. Heterogeneous TiO2-based semiconductors are a promising technology for achieving this goal. Anatase/brookite/rutile tricrystalline TiO2 with mesoporous structure was synthesized by a low-temperature hydrothermal route in the presence of HNO3. The obtained samples were characterized by X-ray diffraction and N2 adsorption desorption isotherm. The photocatalytic activity was evaluated by photocatalytic decomposition of toluene in air under UV light illumination. The results show that tricrystalline TiO2 exhibited higher photocatalytic activity and durability toward gaseous toluene than bicrystalline TiO2, due to the synergistic effects of high surface area, uniform mesoporous structure and junctions among mixed phases. The tricrystalline TiO2 prepared at RHNO3=0.8, containing 80.7% anatase, 15.6% brookite and 3.7% rutile, exhibited the highest photocatalytic activity, about 3.85-fold higher than that of P25. The high activity did not significantly degrade even after five reuse cycles. In conclusion, it is expected that our study regarding gas-phase degradation of toluene over tricrystalline TiO2 will enrich the chemistry of the TiO2-based materials as photocatalysts for environmental remediation and stimulate further research interest on this intriguing topic. PMID- 26040746 TI - Biogenic volatile organic compound analyses by PTR-TOF-MS: Calibration, humidity effect and reduced electric field dependency. AB - Green leaf volatiles (GLVs) emitted by plants after stress or damage induction are a major part of biogenic volatile organic compounds (BVOCs). Proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) is a high-resolution and sensitive technique for in situ GLV analyses, while its performance is dramatically influenced by humidity, electric field, etc. In this study the influence of gas humidity and the effect of reduced field (E/N) were examined in addition to measuring calibration curves for the GLVs. Calibration curves measured for seven of the GLVs in dry air were linear, with sensitivities ranging from 5 to 10 ncps/ppbv (normalized counts per second/parts per billion by volume). The sensitivities for most GLV analyses were found to increase by between 20% and 35% when the humidity of the sample gas was raised from 0% to 70% relative humidity (RH) at 21 degrees C, with the exception of (E)-2-hexenol. Product ion branching ratios were also affected by humidity, with the relative abundance of the protonated molecular ions and higher mass fragment ions increasing with humidity. The effect of reduced field (E/N) on the fragmentation of GLVs was examined in the drift tube of the PTR-TOF-MS. The structurally similar GLVs are acutely susceptible to fragmentation following ionization and the fragmentation patterns are highly dependent on E/N. Overall the measured fragmentation patterns contain sufficient information to permit at least partial separation and identification of the isomeric GLVs by looking at differences in their fragmentation patterns at high and low E/N. PMID- 26040747 TI - Enhancement of elemental mercury adsorption by silver supported material. AB - Mercury, generally found in natural gas, is extremely hazardous. Although average mercury levels are relatively low, they are further reduced to comply with future mercury regulations, which are stringent in order to avoid releasing to the environment. Herein, vapor mercury adsorption was therefore investigated using two kinds of supports, granular activated carbon (GAC) and titanium dioxide (TiO2). Both supports were impregnated by silver (5 and 15 wt.%), before testing against a commercial adsorbent (sulfur-impregnated activated carbon, SAC). The adsorption isotherm, kinetics, and its thermodynamics of mercury adsorption were reported. The results revealed that Langmuir isotherm provided a better fit to the experimental data. Pseudo second-order was applicable to describe adsorption kinetics. The higher uniform Ag dispersion was a key factor for the higher mercury uptake. TiO2 supported silver adsorbent showed higher mercury adsorption than the commercial one by approximately 2 times. Chemisorption of mercury onto silver active sites was confirmed by an amalgam formation found in the spent adsorbents. PMID- 26040748 TI - Characterization of soil fauna under the influence of mercury atmospheric deposition in Atlantic Forest, Rio de Janeiro, Brazil. AB - The increasing levels of mercury (Hg) found in the atmosphere arising from anthropogenic sources, have been the object of great concern in the past two decades in industrialized countries. Brazil is the seventh country with the highest rate of mercury in the atmosphere. The major input of Hg to ecosystems is through atmospheric deposition (wet and dry), being transported in the atmosphere over large distances. The forest biomes are of strong importance in the atmosphere/soil cycling of elemental Hg through foliar uptake and subsequent transference to the soil through litter, playing an important role as sink of this element. Soil microarthropods are keys to understanding the soil ecosystem, and for such purpose were characterized by the soil fauna of two Units of Forest Conservation of the state of the Rio de Janeiro, inwhich one of the areas suffer quite interference from petrochemicals and industrial anthropogenic activities and other area almost exempts of these perturbations. The results showed that soil and litter of the Atlantic Forest in Brazil tend to stock high mercury concentrations, which could affect the abundance and richness of soil fauna, endangering its biodiversity and thereby the functioning of ecosystems. PMID- 26040749 TI - Particle size distribution and characteristics of heavy metals in road-deposited sediments from Beijing Olympic Park. AB - Due to rapid urbanization and industrialization, heavy metals in road-deposited sediments (RDSs) of parks are emitted into the terrestrial, atmospheric, and water environment, and have a severe impact on residents' and tourists' health. To identify the distribution and characteristic of heavy metals in RDS and to assess the road environmental quality in Chinese parks, samples were collected from Beijing Olympic Park in the present study. The results indicated that particles with small grain size (<150 MUm) were the dominant fraction. The length of dry period was one of the main factors affecting the particle size distribution, as indicated by the variation of size fraction with the increase of dry days. The amount of heavy metal (i.e., Cu, Zn, Pb and Cd) content was the largest in particles with small size (<150 MUm) among all samples. Specifically, the percentage of Cu, Zn, Pb and Cd in these particles was 74.7%, 55.5%, 56.6% and 71.3%, respectively. Heavy metals adsorbed in sediments may mainly be contributed by road traffic emissions. The contamination levels of Pb and Cd were higher than Cu and Zn on the basis of the mean heavy metal contents. Specifically, the geoaccumulation index (Igeo) decreased in the order: Cd>Pb>Cu>Zn. This study analyzed the mobility of heavy metals in sediments using partial sequential extraction with the Tessier procedure. The results revealed that the apparent mobility and potential metal bioavailability of heavy metals in the sediments, based on the exchangeable and carbonate fractions, decreased in the order: Cd>Zn~Pb>Cu. PMID- 26040751 TI - Cyanobacterial bloom dynamics in Lake Taihu. PMID- 26040750 TI - Mesoporous carbon adsorbents from melamine-formaldehyde resin using nanocasting technique for CO2 adsorption. AB - Mesoporous carbon adsorbents, having high nitrogen content, were synthesized via nanocasting technique with melamine-formaldehyde resin as precursor and mesoporous silica as template. A series of adsorbents were prepared by varying the carbonization temperature from 400 to 700 degrees C. Adsorbents were characterized thoroughly by nitrogen sorption, X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), thermogravimetric analysis (TGA), elemental (CHN) analysis, Fourier transform infrared (FTIR) spectroscopy and Boehm titration. Carbonization temperature controlled the properties of the synthesized adsorbents ranging from surface area to their nitrogen content, which play major role in their application as adsorbents for CO2 capture. The nanostructure of these materials was confirmed by XRD and TEM. Their nitrogen content decreased with an increase in carbonization temperature while other properties like surface area, pore volume, thermal stability and surface basicity increased with the carbonization temperature. These materials were evaluated for CO2 adsorption by fixed-bed column adsorption experiments. Adsorbent synthesized at 700 degrees C was found to have the highest surface area and surface basicity along with maximum CO2 adsorption capacity among the synthesized adsorbents. Breakthrough time and CO2 equilibrium adsorption capacity were investigated from the breakthrough curves and were found to decrease with increase in adsorption temperature. Adsorption process for carbon adsorbent-CO2 system was found to be reversible with stable adsorption capacity over four consecutive adsorption-desorption cycles. From three isotherm models used to analyze the equilibrium data, Temkin isotherm model presented a nearly perfect fit implying the heterogeneous adsorbent surface. PMID- 26040752 TI - Transcriptome Analysis of K-877 (a Novel Selective PPARalpha Modulator (SPPARMalpha))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver. AB - AIM: Selective PPARalpha modulators (SPPARMalpha) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARMalpha K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. METHODS: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARMalpha on the liver gene expression. RESULTS: Consequently, a cell based transactivation assay showed that K-877 activates PPARalpha with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid beta-oxidative genes in human hepatocytes and the mouse liver. Almost all genes up- or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly induced in the K-877-treated mouse liver, but not human hepatocytes, thus suggesting that the clinical dose of K-877 may not induce peroxisome proliferation or liver toxicity in humans. Notably, K-877 significantly induces the expression of clinically beneficial target genes (VLDLR, FGF21, ABCA1, MBL2, ENPEP) in human hepatocytes. CONCLUSION: These results indicate that changes in the gene expression induced by K-877 treatment are mainly mediated through PPARalpha activation. K-877 regulates the hepatic gene expression as a SPPARMalpha and thus may improve dyslipidemia as well as metabolic disorders, such as metabolic syndrome and type 2 diabetes, without untoward side effects. PMID- 26040754 TI - Adrenomedullin-RAMP2 System in Vascular Endothelial Cells. AB - Vascular endothelial cells play key roles in maintaining vascular and organ homeostasis. Adrenomedullin (AM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic molecule involved in both circulatory homeostasis and the pathogenesis of cardiovascular diseases. We have reported that knockout mice deficient in AM or receptor activity-modifying protein 2 (RAMP2), an AM-receptor accessory protein, show vascular endothelial cell deformities that are embryonically lethal. To directly clarify the pathophysiological functions of the vascular AM-RAMP2 system, we generated vascular endothelial cell-specific RAMP2 knockout mice. Using these mice, we found that the AM-RAMP2 system is a key determinant of vascular integrity and homeostasis from prenatal stages through adulthood. This review highlights the functions of AM-RAMP2 in vascular endothelial cells. PMID- 26040753 TI - UFM1 Protects Macrophages from oxLDL-Induced Foam Cell Formation Through a Liver X Receptor alpha Dependent Pathway. AB - AIM: Macrophage foam cell formation is the most prominent characteristic of the early stages of atherosclerosis. Ubiquitin Fold Modifier 1 (UFM1) is a new member of the ubiquitin-like protein family, and its underlying mechanism of action in macrophage foam cell formation is poorly understood. Our current study focuses on UFM1 and investigates its role in macrophage foam cell formation. METHODS: Using real-time quantitative PCR (qRT-PCR) and western blot analysis, we first analyzed the UFM1 expression in mouse peritoneal macrophages (MPMs) from ApoE-/- mice in vivo and in human macrophages treated with oxLDL in vitro. Subsequently, the effects of UFM1 on macrophages foam cell formation were determined by Nile Red staining and direct lipid analysis. We then examined whether UFM1 affects the process of lipid metabolism in macrophages. Lastly, with the method of small interfering RNA (siRNA), we delineated the mechanism of UFM1 to attenuate lipid accumulation in THP-1 macrophages. RESULTS: UFM1 is dramatically upregulated under atherosclerosis conditions both in vivo and in vitro. Moreover, UFM1 markedly decreased macrophage foam cell formation. Mechanistic studies revealed that UFM1 increased the macrophage cholesterol efflux, which was due to the increased expression of ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1). Furthermore, the upregulation of ABCA1 and ABCG1 by UFM1 resulted from liver X receptor alpha (LXRalpha) activation, which was confirmed by the observation that LXRalpha siRNA prevented the expression of ABCA1 and ABCG1. Consistent with this, the UFM1-mediated attenuation of lipid accumulation was abolished by such inhibition. CONCLUSIONS: Taken together, our results showed that UFM1 could suppress foam cell formation via the LXRalpha-dependent pathway. PMID- 26040755 TI - Bone Tissue Engineering by Using Calcium Phosphate Glass Scaffolds and the Avidin Biotin Binding System. AB - Highly porous and interconnected scaffolds were fabricated using calcium phosphate glass (CPG) for bone tissue engineering. An avidin-biotin binding system was used to improve osteoblast-like cell adhesion to the scaffold. The scaffolds had open macro- and micro-scale pores, and continuous struts without cracks or defects. Scaffolds prepared using a mixture (amorphous and crystalline CPG) were stronger than amorphous group and crystalline group. Cell adhesion assays showed that more cells adhered, with increasing cell seeding efficiency to the avidin-adsorbed scaffolds, and that cell attachment to the highly porous scaffolds significantly differed between avidin-adsorbed scaffolds and other scaffolds. Proliferation was also significantly higher for avidin-adsorbed scaffolds. Osteoblastic differentiation of MG-63 cells was observed at 3 days, and MG-63 cells in direct contact with avidin-adsorbed scaffolds were positive for type I collagen, osteopontin, and alkaline phosphatase gene expression. Osteocalcin expression was observed in the avidin-adsorbed scaffolds at 7 days, indicating that cell differentiation in avidin-adsorbed scaffolds occurred faster than the other scaffolds. Thus, these CPG scaffolds have excellent biological properties suitable for use in bone tissue engineering. PMID- 26040756 TI - A meta-analysis of functional group responses to forest recovery outside of the tropics. AB - Both active and passive forest restoration schemes are used in degraded landscapes across the world to enhance biodiversity and ecosystem service provision. Restoration is increasingly also being implemented in biodiversity offset schemes as compensation for loss of natural habitat to anthropogenic development. This has raised concerns about the value of replacing old-growth forest with plantations, motivating research on biodiversity recovery as forest stands age. Functional diversity is now advocated as a key metric for restoration success, yet it has received little analytical attention to date. We conducted a meta-analysis of 90 studies that measured differences in species richness for functional groups of fungi, lichens, and beetles between old-growth control and planted or secondary treatment forests in temperate, boreal, and Mediterranean regions. We identified functional-group-specific relationships in the response of species richness to stand age after forest disturbance. Ectomycorrhizal fungi averaged 90 years for recovery to old-growth values (between 45 years and unrecoverable at 95% prediction limits), and epiphytic lichens took 180 years to reach 90% of old-growth values (between 140 years and never for recovery to old growth values at 95% prediction limits). Non-saproxylic beetle richness, in contrast, decreased as stand age of broadleaved forests increased. The slow recovery by some functional groups essential to ecosystem functioning makes old growth forest an effectively irreplaceable biodiversity resource that should be exempt from biodiversity offsetting initiatives. PMID- 26040757 TI - Predicting and Improving Recognition Memory Using Multiple Electrophysiological Signals in Real Time. AB - Although people are capable of storing a virtually infinite amount of information in memory, their ability to encode new information is far from perfect. The quality of encoding varies from moment to moment and renders some memories more accessible than others. Here, we were able to forecast the likelihood that a given item will be later recognized by monitoring two dissociable fluctuations of the electroencephalogram during encoding. Next, we identified individual items that were poorly encoded, using our electrophysiological measures in real time, and we successfully improved the efficacy of learning by having participants restudy these items. Thus, our memory forecasts using multiple electrophysiological signals demonstrate the feasibility and the effectiveness of using real-time monitoring of the moment-to-moment fluctuations of the quality of memory encoding to improve learning. PMID- 26040758 TI - Novel AgI-decorated beta-Bi2O3 nanosheet heterostructured Z-scheme photocatalysts for efficient degradation of organic pollutants with enhanced performance. AB - The low photocatalytic activity of single semiconductor photocatalysts mainly originates from their fast recombination of photogenerated electron-hole pairs. Constructing nanosheet-based composite photocatalysts is an effective way to enhance the charge separation efficiency of photogenerated electron-hole pairs. In this work, AgI-decorated beta-Bi2O3 nanosheet heterostructured photocatalysts were prepared by a facile method. The as-obtained AgI/beta-Bi2O3 heterostructures exhibited enhanced visible-light-driven photocatalytic activity towards the degradation of methyl orange (MO) and tetracycline hydrochloride (TC) in aqueous solution. The optimum photocatalytic activity of 20%-AgI/beta-Bi2O3 for the degradation of MO was about 4.1 and 6.2 times higher than that of AgI and beta Bi2O3. The photocatalytic activity enhancement of AgI/beta-Bi2O3 heterostructures could be ascribed to the formation of a Z-scheme system, which results in the efficient space separation of photo-induced charge carriers. PMID- 26040759 TI - Young adult gender differences in forearm skin-to-fat tissue dielectric constant values measured at 300 MHz. AB - BACKGROUND/PURPOSE: Skin-to-fat tissue dielectric constant (TDC) values depend on measurement depth and gender. Our goal was to assess male-female differences in TDC values associated with differing skin depths. METHODS: Bilateral forearm TDC measurements were made on young adult male and females with mean ages from 24.7 to 27.3 years. There were four measurement groups distinguished by the TDC measurement depth and include the following numbers of subjects for each gender; 30, 150, 60, and 50 for probe-measurement depths of 0.5, 1.5, 2.5, and 5.0 mm. Data were subsequently compared with values calculated with a simple two-layer model. RESULTS: For females and males, there was a significant difference in TDC values among depths (P < 0.001) with TDC values decreasing with increasing depth. Gender comparisons showed that TDC values of males were significantly (P < 0.001) greater than values for females at each depth. Male-female percentage differences ranged from 14.8% to 22.0%. Model calculations suggest that gender differences might be explained by skin thickness differences. CONCLUSION: Findings indicate that decisions with regard to skin water content among or between groups based on TDC measurements need to account for gender and are best made when corresponding skin thickness measurements are available. However, changes in TDC values assessed in individual patients and comparisons between corresponding skin areas in affected and non-affected sites are not limited. Thus, assessments of acute treatment effects and assessments of inter-arm or inter-leg TDC differences or ratios within genders are a useful and suitable method to characterize edema and lymphedema features. PMID- 26040761 TI - Comparative analysis of the Mycoplasma capricolum subsp. capricolum GM508D genome reveals subrogation of phase-variable contingency genes and a novel integrated genetic element. AB - Mycoplasma capricolum subspecies capricolum is both a pathogen of small ruminants and a model recipient organism for gene transplantation and synthetic biology. With the availability of the complete genome of the type strain California kid (released in 2005), a draft genome of strain GM508D was determined to investigate genomic variation in this subspecies. Differences in mobile genetic element location and complement, catabolic pathway genes, contingency loci, surface antigen genes and type II restriction-modification systems highlight the plasticity and diversity within this taxon. PMID- 26040760 TI - Targeting of Helicobacter pylori thymidylate synthase ThyX by non-mitotoxic hydroxy-naphthoquinones. AB - ThyX is an essential thymidylate synthase that is mechanistically and structurally unrelated to the functionally analogous human enzyme, thus providing means for selective inhibition of bacterial growth. To identify novel compounds with anti-bacterial activity against the human pathogenic bacterium Helicobacter pylori, based on our earlier biochemical and structural analyses, we designed a series of eighteen 2-hydroxy-1,4-naphthoquinones (2-OH-1,4-NQs) that target HpThyX. Our lead-like molecules markedly inhibited the NADPH oxidation and 2' deoxythymidine-5'-monophosphate-forming activities of HpThyX enzyme in vitro, with inhibitory constants in the low nanomolar range. The identification of non cytotoxic and non-mitotoxic 2-OH-1,4-NQ inhibitors permitted testing their in vivo efficacy in a mouse model for H. pylori infections. Despite the widely assumed toxicity of naphthoquinones (NQs), we identified tight-binding ThyX inhibitors that were tolerated in mice and can be associated with a modest effect in reducing the number of colonizing bacteria. Our results thus provide proof-of concept that targeting ThyX enzymes is a highly feasible strategy for the development of therapies against H. pylori and a high number of other ThyX dependent pathogenic bacteria. We also demonstrate that chemical reactivity of NQs does not prevent their exploitation as anti-microbial compounds, particularly when mitotoxicity screening is used to prioritize these compounds for further experimentation. PMID- 26040762 TI - Neutrophil-to-lymphocyte ratio and overall survival in all sites of head and neck squamous cell carcinoma. AB - BACKGROUND: Current prognostic criteria are insufficient in predicting outcomes in head and neck cancer, necessitating new, readily available biomarkers. METHODS: Pretreatment neutrophil and lymphocyte counts and their ratio (NLR) were retrospectively investigated for correlation with overall survival while controlling for demographic and clinical confounders. RESULTS: Patients in the highest tertile of neutrophil counts and those in the lowest tertile of lymphocytes experienced shorter survival than the rest of the population. Patients in the highest tertile of the NLR were at a higher risk compared with those in the lowest tertile after multivariate analysis (hazard ratio [HR] = 2.39; p = .0001). Additionally, NLR was lower in patients with human papillomavirus (HPV)-positive tumors compared to HPV-negative tumors and predicted survival in both tumor types. CONCLUSION: Neutrophil and lymphocyte counts are strong biomarkers with opposing prognostic significance and the NLR is a robust predictor of overall survival in oral, pharyngeal, and laryngeal squamous cell carcinomas. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1068 E1074, 2016. PMID- 26040763 TI - The location of coenzyme Q10 in phospholipid membranes made of POPE: a small angle synchrotron X-ray diffraction study. AB - The location of coenzyme Q10 (Q10) inside the inner mitochondrial membrane is a topic of research aiming at a deeper understanding of the function of the mitochondrial respiratory chain. We investigated the location of Q10 inside model membranes made of 1-palmitoyl-2-oleoyl-phosphatidylethanolamine by means of small angle synchrotron X-ray diffraction. Q10, which stands for ubiquinone-10 (UQ) or ubihydroquinone-10 (UH), did not remarkably influence the main phase transition temperature, but significantly decreased the lamellar-inverse hexagonal phase transition temperature (T(h)). The effect of UH on T(h) was stronger than the effect of UQ and the effect of liquid Q10 on T(h) was stronger than the effect of crystalline Q10. In the presence of Q10, the lattice parameters of the lamellar phases remained unchanged, whereas the H II lattice parameter was clearly influenced: While UQ had an increasing effect, UH had a decreasing effect. Furthermore, Q10 prevented the formation of cubic phases. The results give new evidence that the headgroup of Q10 is distant from the center of the membrane, which might be important for the function of the mitochondrial respiratory chain. PMID- 26040764 TI - SOX 1, contrary to SOX 2, suppresses proliferation, migration, and invasion in human laryngeal squamous cell carcinoma by inhibiting the Wnt/beta-catenin pathway. AB - Sex-determining region Y (SRY)-box protein 1 (SOX 1) has been reported to have the inhibiting effects on various cancer cells; however, the expression and effect of SOX 1 on laryngeal squamous cell carcinoma (LSCC) have not been determined. Therefore, the aim of this study was to assess the anti-proliferation and metastatic effects of SOX 1 and its related mechanisms on LSCC. According to our present study, first, we found that overexpression of SOX 1 could significantly inhibit proliferation and promote apoptosis in Tu212 cells. Additionally, overexpression of SOX 1 suppressed the migration and invasion potential of Tu212 cells via regulating Wnt/beta-catenin pathway. Finally, we demonstrated for the first time that overexpression of SOX 1 could downregulate the expression of SOX 2, and co-expression of SOX 1 and SOX 2 could reverse the anti-tumor effect of SOX 1. In conclusion, our studies suggested that SOX 1 suppressed cell growth and invasion in Tu212 cells by inhibiting Wnt/beta-catenin pathway, and the anti-tumor effect of SOX 1 could be weakened by SOX 2, which may be a potential molecular basis for clinical treatment of LSCC. PMID- 26040765 TI - Thyroid carcinoma cells produce PLGF to enhance metastasis. AB - Cancer neovascularization is essential for metastasis of thyroid carcinoma. However, the underlying molecular mechanisms are ill-defined. Recently, placental growth factor (PLGF) has been shown to play critical roles in the pathological angiogenesis through regulating matrix metalloproteinases (MMPs); here, we were prompted to examine the role of PLGF in the metastasis of thyroid carcinoma. We found that the PLGF and MMP9 levels strongly correlated in the thyroid carcinoma specimen. Higher PLGF and MMP9 levels were detected in the thyroid carcinoma with metastasis. Using a human thyroid carcinoma cell line, TT, we found that overexpression of PLGF in TT cells increased expression of MMP9, while inhibition of PLGF in TT cells decreased expression of MMP9. However, modification of MMP9 levels in TT cells did not affect PLGF levels, suggesting that PLGF may regulate MMP9 in thyroid carcinoma cells. Moreover, application of a specific MAPK p42/p44 inhibitor, but not the application of a specific MAPK p38 inhibitor or specific Akt or JNK inhibitors, substantially abolished the effect of PLGF on MMP9 activation, suggesting that PLGF may increase expression of MMP9 via p42/p44 signaling pathway. Together, these data suggest that antagonizing PLGF in thyroid carcinoma cells may be a promising therapy to suppress cancer metastasis. PMID- 26040766 TI - PARP3 interacts with FoxM1 to confer glioblastoma cell radioresistance. AB - Poly(ADP-ribose) polymerase 3 (PARP3), a critical player in cellular response to DNA double-strand breaks (DSBs), plays an essential role in the maintenance of genome integrity. However, the role of PARP3 in tumorigenesis especially in glioblastoma remains largely unknown. In the present study, we found that the mRNA and protein levels of PARP3 were upregulated in primary glioblastoma tissues. Knockdown of PARP3 expression by lentivirus-based shRNA decreased cell glioblastoma proliferation and inhibited tumor growth in vivo by using a xenograft mouse model. Furthermore, we found that silencing the expression of PARP3 resulted in a synergistic radiosensitizing effect when combined with radiotherapy in glioblastoma cell lines. At the molecular level, we found that PARP3 interacted with FoxM1 to enhance its transcriptional activity and conferred glioblastoma cell radioresistance. Thus, our data suggest that PARP3 could be a therapeutic target to overcome radioresistance in glioblastoma. PMID- 26040767 TI - A role of MMP-14 in the regulation of invasiveness of nasopharyngeal carcinoma. AB - Although matrix metalloproteinase 14 (MMP-14) has been shown to play a substantial role in the carcinogenesis of some types of cancer, its involvement in the pathogenesis of nasopharyngeal carcinoma (NPC) has not been reported. Here, we analyzed MMP-14 levels in the NPC specimens from patients and compared with the paired normal nasopharynx (NNP) tissues. We found that NPC had significantly higher messenger RNA (mRNA) and protein levels of MMP-14. Moreover, higher levels of MMP-14 correlated with more advanced status of clinical stage and lymphatic metastasis. In vitro, MMP-14 levels determined the potential of invasiveness of NPC cells, possibly through induction of EMT-associated genes. Our data thus highlight MMP-14 as a novel therapeutic target for NPC. PMID- 26040768 TI - Interference with HMGB1 increases the sensitivity to chemotherapy drugs by inhibiting HMGB1-mediated cell autophagy and inducing cell apoptosis. AB - Non-small cell lung cancer is commonly seen with higher morbidity and mortality. High-mobility group protein 1 (HMGB1) is a highly conserved nuclear protein, which is involved in multiple human diseases including cancers. However, the mechanisms of HMGB1 in non-small cell lung cancer remain unclear. The goal of the present study is to identify the relationship between HMGB1 and the progresssion of non-small cell lung cancer and investigate the molecular mechanism of HMGB1 in non-small lung cancer cell lines. Firstly, we detected the expression levels of HMGB1 by by real-time PCR and western blotting analysis, and the results demonstrated that HMGB1 was much higher expressed in non-small cell lung cancer cell lines, including A549, SPC-1-1, NCI-2170, SK-MES-1, and NCI-H1299, compared with that of WI-38. Next, 5 MUM of adriamycin (AMD), 20 MUM of cisplatin (DDP), and 50 MUM of methotrexate (MTX) were used to treat A549 cells and SPC-A-1 cells for 48 h. The results showed that treatment with chemotherapy drugs significantly increased the levels of HMGB1 in A549 cells and SPC-A-1 cells. Moreover, the expression levels of HMGB1 increased in a time-dependent manner being treated with DDP. Then, the endogenous HMGB1 expression was successfully interferred with shRNA specific to HMGB1 in A549 and SPC-A-1 cells, which was detected by western blotting analysis. Then, the cisplatin-sensitive A549 cells and cisplatin resistant A549/DDP cells were treated with increasing concentrations of cisplatin for 24, 48, and 72 h; cell viability were analyzed by MTT assay; and IC50 values were calculated. The results demonstrated that the expression level of HMGB1 in A549/DDP cells was much higher than that of A549 cells; moreover, transfection with HMGB1 shRNA in A549/DDP cells decreased the IC50 value of cisplatin in A549/DDP cells. The expression levels of autophagy-related proteins beclin-1 and LC3-II were significantly higher in A549/DDP cells or the A549 cells treated with chemotherapeutic drugs, compared with that in A549 cells. However, interference with endogenous HMGB1 obviously suppressed autophagy-related proteins and increased cell apoptosis rate and the expression of cleaved caspase-3 in A549/DDP cells. All of the data suggested that interference with the endogenous HMGB1 significantly inhibited cell autophagy and increased cell apoptosis of A549/DDP cells. Thus, the study on the resistance of chemotherapy drugs would provide a theoretical reference for clinical treatment of non-small cell lung cancer. PMID- 26040770 TI - Biologic agents in the treatment of glomerulonephritides. AB - Current immunosuppression strategies in the treatment of glomerulonephritides remain unsatisfactory, especially in glomerular diseases that are frequently relapsing or are resistant to treatment. Toxicities associated with the use of drugs with non-specific targets for the immune response result in treatment non compliance, and increase morbidity and mortality in these patients. Advances in our understanding of the immunopathogenesis of glomerulonephritis and the availability of biologics have led to their successful use in the treatment of immune-mediated glomerular diseases. Biologics are usually very large complex molecules, often produced using recombinant DNA technology and manufactured in a living system such as a microorganism, or plant or animal cells. They are novel agents that can target specific immune cell types, cytokines or immune pathways involved in the pathogenesis of these disorders. It is attractive to consider that, given their specific mode of action, these agents can potentially offer a more directed and effective immunosuppression, with side-effect profiles that are much more desirable. However, there have been few randomized controlled trials comparing biologic agents to conventional immunosuppression, and in many of these studies the side-effect profiles have been disappointingly similar. In this review, we will examine the rationale, efficacy and safety of some commonly used biologics in the treatment of primary and secondary glomerulonephritides. We will also discuss some of the key challenges that may be encountered with the use of biologics in treating glomerulonephritis in the future. PMID- 26040769 TI - Matrix metalloproteinase-12 expression is increased in cutaneous melanoma and associated with tumor aggressiveness. AB - Cutaneous melanoma is the most malignant form of skin cancer characterized by aggressive invasion. Matrix metalloproteinases play essential roles in tumor invasion due to their ECM degrading capacity. However, the clinical significance of matrix metalloproteinasis (MMP)-12 in human cutaneous melanoma has not been addressed yet. In the present study, we investigated MMP-12 expression level in 298 patients with cutaneous melanoma and 60 normal skin tissue specimens by immunohistochemistry assay. Appropriate statistical analysis was utilized to determine the association of MMP-12 with clinical features and prognosis of melanoma. Results showed that MMP-12 expression was increased in cutaneous melanoma compared with that in normal skin. It was also found that MMP-12 expression in melanoma was significantly associated with tumor invasion and metastasis. Univariate survival analysis indicated that patients with melanoma of high MMP-12 expression had unfavorable overall survival compared with those of low MMP-12 expression. Cox's proportional hazards analysis showed that MMP-12 expression was an independent prognostic marker of overall survival for patients with cutaneous melanoma. These results proved that MMP-12 expression was increased in cutaneous melanoma and associated with tumor progression. It also provided the first evidence that MMP-12 level could be an independent prognostic marker for patients with cutaneous melanoma. PMID- 26040771 TI - Aberrant GSTP1 promoter methylation predicts short-term prognosis in acute-on chronic hepatitis B liver failure. AB - BACKGROUND: Glutathione-S-transferase P1 (GSTP1) methylation has been demonstrated to be associated with oxidative stress induced liver damage in acute on-chronic hepatitis B liver failure (ACHBLF). AIM: To evaluate the methylation level of GSTP1 promoter in acute-on-chronic hepatitis B liver failure and determine its predictive value for prognosis. METHODS: One hundred and five patients with acute-on-chronic hepatitis B liver failure, 86 with chronic hepatitis B (CHB) and 30 healthy controls (HC) were retrospectively enrolled. GSTP1 methylation level in peripheral mononuclear cells (PBMC) was detected by MethyLight. Clinical and laboratory parameters were obtained. RESULTS: GSTP1 methylation levels were significantly higher in patients with acute-on-chronic hepatitis B liver failure (median 16.84%, interquartile range 1.83-59.05%) than those with CHB (median 1.25%, interquartile range 0.48-2.47%; P < 0.01) and HC (median 0.80%, interquartile range 0.67-1.27%; P < 0.01). In acute-on-chronic hepatitis B liver failure group, nonsurvivors showed significantly higher GSTP1 methylation levels (P < 0.05) than survivors. GSTP1 methylation level was significantly correlated with total bilirubin (r = 0.29, P < 0.01), prothrombin time activity (r = -0.24, P = 0.01) and model for end-stage liver disease (MELD) score (r = 0.26, P = 0.01). When used to predict 1- or 2-month mortality of acute on-chronic hepatitis B liver failure, GSTP1 methylation showed significantly better predictive value than MELD score [area under the receiver operating characteristic curve (AUC) 0.89 vs. 0.72, P < 0.01; AUC 0.83 vs. 0.70, P < 0.05 respectively]. Meanwhile, patients with GSTP1 methylation levels above the cut off points showed significantly poorer survival than those below (P < 0.05). CONCLUSIONS: Aberrant GSTP1 promoter methylation exists in acute-on-chronic hepatitis B liver failure and shows high predictive value for short-term mortality. It might serve as a potential prognostic marker for acute-on-chronic hepatitis B liver failure. PMID- 26040772 TI - Reduced Cytotoxicity of Graphene Nanosheets Mediated by Blood-Protein Coating. AB - The advent and pending wide use of nanoscale materials urges a biosafety assessment and safe design of nanomaterials that demonstrate applicability to human medicine. In biological microenvironment, biomolecules will bind onto nanoparticles forming corona and endow nanoparticles new biological identity. Since blood-circulatory system will most likely be the first interaction organ exposed to these nanomaterials, a deep understanding of the basic interaction mechanisms between serum proteins and foreign nanoparticles may help to better clarify the potential risks of nanomaterials and provide guidance on safe design of nanomaterials. In this study, the adsorption of four high-abundance blood proteins onto the carbon-based nanomaterial graphene oxide (GO) and reduced GO (rGO) were investigated via experimental (AFM, florescence spectroscopy, SPR) and simulation-based (molecular dynamics) approaches. Among the proteins in question, we observe competitive binding to the GO surface that features a melange of distinct packing modes. Our MD simulations reveal that the protein adsorption is mainly enthalpically driven through strong pi-pi stacking interactions between GO and aromatic protein residues, in addition to hydrophobic interactions. Overall, these results were in line with previous findings related to adsorption of serum proteins onto single-walled carbon nanotubes (SWCNTs), but GO exhibits a dramatic enhancement of adsorption capacity compared to this one-dimensional carbon form. Encouragingly, protein-coated GO resulted in a markedly less cytotoxicity than pristine and protein-coated SWCNTs, suggesting a useful role for this planar nanomaterial in biomedical applications. PMID- 26040773 TI - Shizuoka Prefecture Disaster Drill Involving the Japanese and US Military. PMID- 26040774 TI - Ureteral Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue, Chronic Inflammation, and Renal Artery Atherosclerosis. PMID- 26040775 TI - A Rare Case of Primary Tubular Adenocarcinoma of the Thymus, Enteric Immunophenotype: A Case Study and Review of the Literature. AB - Thymic carcinomas are uncommon malignant tumors, and thymic adenocarcinomas are extremely rare. Here, we describe a case of primary thymic adenocarcinoma in a 59 year-old woman. Histological examination of the tumor revealed tubular morphology with expression of cytokeratin 20 and caudal-type homeobox 2 according to immunohistochemistry, suggesting enteric features. Extensive clinical and radiological studies excluded the possibility of an extrathymic primary tumor. A review of the literature revealed only two global cases of primary tubular adenocarcinomas of the thymus with enteric immunophenotype. PMID- 26040776 TI - Necrotizing Sarcoid Granulomatosis: Possibly Veiled Disease in Endemic Area of Mycobacterial Infection. PMID- 26040777 TI - Anti-absence activity of mGlu1 and mGlu5 receptor enhancers and their interaction with a GABA reuptake inhibitor: Effect of local infusions in the somatosensory cortex and thalamus. AB - OBJECTIVE: Glutamate and gamma-aminobutyric acid (GABA) are the key neurotransmitter systems in the cortical-thalamocortical network, involved in normal and pathologic oscillations such as spike-wave discharges (SWDs), which characterize different forms of absence epilepsy. Metabotropic glutamate (mGlu) and GABA receptors are widely expressed within this network. Herein, we examined the effects of two selective positive allosteric modulators (PAMs) of mGlu1 and mGlu5 receptors, the GABA reuptake inhibitor, tiagabine, and their interaction in the somatosensory cortex and thalamus on SWDs in WAG/Rij rats. METHODS: Male WAG/Rij rats were equipped with bilateral cannulas in the somatosensory cortex (S1po) or the ventrobasal (VB) thalamic nuclei, and with cortical electroencephalography (EEG) electrodes. Rats received a single dose of the mGlu1 receptor PAM, RO0711401, or the mGlu5 receptor PAM, VU0360172, various doses of tiagabine, or VU0360172 combined with tiagabine. RESULTS: Both PAMs suppressed SWDs regardless of the site of injection. Tiagabine enhanced SWDs when injected into the thalamus, but, unexpectedly, suppressed SWDs in a dose-dependent manner when injected into the cortex. Intracortical co-injection of VU0360172 and tiagabine produced slightly larger effects as compared to either VU0360172 or tiagabine alone. Intrathalamic co-injections of VU0360172 and subthreshold doses of tiagabine caused an antiabsence effect similar to that exhibited by VU0360172 alone in the first 10 min. At 30 min, however, the antiabsence effect of VU0360172 was prevented by subthreshold doses of tiagabine, and the combination produced a paradoxical proabsence effect at 40 and 50 min. SIGNIFICANCE: These data (1) show that mGlu1 and mGlu5 receptor PAMs reduce absence seizures acting at both thalamic and cortical levels; (2) demonstrate for the first time that tiagabine, despite its established absence-enhancing effect, reduces SWDs when injected into the somatosensory cortex; and (3) indicate that the efficacy of VU0360172 in the thalamus may be critically affected by the availability of (extra)synaptic GABA. PMID- 26040778 TI - The development and first validation of the Manchester Early Morning Symptoms Index (MEMSI) for patients with COPD. AB - AIM: Early morning symptoms (EMS) in people with COPD are associated with poor health, impaired activities and increased exacerbation risk. We describe the development and preliminary validation of the Manchester Early Morning Symptom Index (MEMSI) to quantify EMS in COPD. METHODS: Focus groups and cognitive debriefing with patients with COPD were used to develop the potential item list, followed by a cross-sectional study to finalise the items for inclusion. In addition to test-retest reliability, comparisons with the St George's Respiratory Questionnaire-C (SGRQ-C), modified Medical Research Council Dyspnoea Scale, Functional Assessment of Chronic Illness Therapy Fatigue Scale (FACIT-F) and Hospital Anxiety and Depression Scale (HADS) evaluated construct validity. Hierarchical methods informed item deletion and Rasch analysis was applied to assess scale unidimensionality. RESULTS: 23 items were identified from the focus groups and debriefings. The cross-sectional study involved 203 patients with COPD (mean age 64.7 SD 7.5 years, male 63%, Global Initiative for Chronic Obstructive Lung Disease (GOLD): 1:14% 2:41% 3:25% 4: 7%). 13 items were removed during item reduction. MEMSI contains 10 items, demonstrates good overall fit to the Rasch model (chi(2) p=0.26) and item score distribution; excellent reliability (Person Separation Index: 0.91) and good test-retest repeatability (r=0.82). It correlates with the SGRQ-C (r=0.73), FACIT-F (r=-0.65) and HADS (r=0.53-0.54) indicating good construct validity. CONCLUSIONS: MEMSI is a reliable and valid unidimensional measure of EMS for patients with COPD. It is simple to use and score supporting its suitability for research and clinical use. Work is underway to determine the minimal clinical important difference and cross-cultural validity. PMID- 26040779 TI - Neighborhood as a predictor of non-aggressive, but not aggressive, antisocial behaviors in adulthood. AB - BACKGROUND: Prior meta-analytic work has highlighted important etiological distinctions between aggressive (AGG) and non-aggressive rule-breaking (RB) dimensions of antisocial behavior. Among these is the finding that RB is influenced by the environment more than is AGG. Relatively little research, however, has sought to identify the specific environmental experiences that contribute to this effect. The current study sought to do just this. METHOD: We examined whether unrelated adults residing in the same neighborhood (n = 1915 participants in 501 neighborhoods) were more similar in their AGG and RB than would be expected by chance. Analyses focused on simple multi-level models, with the participant as the lower-level unit and the neighborhood as the upper-level unit. RESULTS: Results revealed little to no evidence of neighborhood-level variance in AGG. By contrast, 11+% of the variance in RB could be predicted from participant neighborhood, results that persisted even when considering the possibility of genetic relatedness across participants and neighborhood selection effects. Moreover, 17% of this neighborhood-level variance in RB was accounted for by neighborhood structural characteristics and social processes. CONCLUSIONS: Findings bolster prior suggestions that broader contextual experiences, like the structural and social characteristics of one's neighborhood, contribute in a meaningful way to RB in particular. Our results also tentatively imply that this association may be environmental in origin. Future work should seek to develop additional, stronger designs capable of more clearly leveraging genetic un relatedness to improve causal inferences regarding the environment. PMID- 26040781 TI - Student perceptions of an interprofessional educational experience: The importance of goal articulation. AB - The education of future health care professionals must involve activities where interprofessional collaboration and the functioning of interdisciplinary teams are the goals and not the exceptions. This type of interprofessional education (IPE) will benefit students as they will be better able to communicate with and mobilize the skills of other health care workers, work toward common goals related to patient care, and develop a more cost-effective treatment strategy in the long term. Such an IPE program was initiated in the clinical anatomy course for physician assistant students from the University of Mount Union that was taught, in part, by medical students from the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. Surveys of both student groups at the end of the course indicated that although this was a useful IPE experience, the value of this program as an IPE experience was not entirely appreciated by the participating students. It turned out that although the goals and importance of these types of IPE activities are clear to the faculty, they must also be made clear to all of the students. PMID- 26040780 TI - Flux balance analysis predicts essential genes in clear cell renal cell carcinoma metabolism. AB - Flux balance analysis is the only modelling approach that is capable of producing genome-wide predictions of gene essentiality that may aid to unveil metabolic liabilities in cancer. Nevertheless, a systemic validation of gene essentiality predictions by flux balance analysis is currently missing. Here, we critically evaluated the accuracy of flux balance analysis in two cancer types, clear cell renal cell carcinoma (ccRCC) and prostate adenocarcinoma, by comparison with large-scale experiments of gene essentiality in vitro. We found that in ccRCC, but not in prostate adenocarcinoma, flux balance analysis could predict essential metabolic genes beyond random expectation. Five of the identified metabolic genes, AGPAT6, GALT, GCLC, GSS, and RRM2B, were predicted to be dispensable in normal cell metabolism. Hence, targeting these genes may selectively prevent ccRCC growth. Based on our analysis, we discuss the benefits and limitations of flux balance analysis for gene essentiality predictions in cancer metabolism, and its use for exposing metabolic liabilities in ccRCC, whose emergent metabolic network enforces outstanding anabolic requirements for cellular proliferation. PMID- 26040782 TI - Expanding the chemical space for natural products by Aspergillus-Streptomyces co cultivation and biotransformation. AB - Actinomycetes and filamentous fungi produce a wide range of bioactive compounds, with applications as antimicrobials, anticancer agents or agrochemicals. Their genomes contain a far larger number of gene clusters for natural products than originally anticipated, and novel approaches are required to exploit this potential reservoir of new drugs. Here, we show that co-cultivation of the filamentous model microbes Streptomyces coelicolor and Aspergillus niger has a major impact on their secondary metabolism. NMR-based metabolomics combined with multivariate data analysis revealed several compounds that correlated specifically to co-cultures, including the cyclic dipeptide cyclo(Phe-Phe) and 2 hydroxyphenylacetic acid, both of which were produced by A. niger in response to S. coelicolor. Furthermore, biotransformation studies with o-coumaric acid and caffeic acid resulted in the production of the novel compounds (E)-2-(3 hydroxyprop-1-en-1-yl)-phenol and (2E,4E)-3-(2-carboxy-1-hydroxyethyl)-2,4 hexadienedioxic acid, respectively. This highlights the utility of microbial co cultivation combined with NMR-based metabolomics as an efficient pipeline for the discovery of novel natural products. PMID- 26040783 TI - Glucocorticoids as regulatory signals during intrauterine development. AB - NEW FINDINGS: What is the topic of this review? This review discusses the role of the glucocorticoids as regulatory signals during intrauterine development. It examines the functional significance of these hormones as maturational, environmental and programming signals in determining offspring phenotype. What advances does it highlight? It focuses on the extensive nature of the regulatory actions of these hormones. It highlights the emerging data that these actions are mediated, in part, by the placenta, other endocrine systems and epigenetic modifications of the genome. Glucocorticoids are important regulatory signals during intrauterine development. They act as maturational, environmental and programming signals that modify the developing phenotype to optimize offspring viability and fitness. They affect development of a wide range of fetal tissues by inducing changes in cellular expression of structural, transport and signalling proteins, which have widespread functional consequences at the whole organ and systems levels. Glucocorticoids, therefore, activate many of the physiological systems that have little function in utero but are vital at birth to replace the respiratory, nutritive and excretory functions previously carried out by the placenta. However, by switching tissues from accretion to differentiation, early glucocorticoid overexposure in response to adverse conditions can programme fetal development with longer term physiological consequences for the adult offspring, which can extend to the next generation. The developmental effects of the glucocorticoids can be direct on fetal tissues with glucocorticoid receptors or mediated by changes in placental function or other endocrine systems. At the molecular level, glucocorticoids can act directly on gene transcription via their receptors or indirectly by epigenetic modifications of the genome. In this review, we examine the role and functional significance of glucocorticoids as regulatory signals during intrauterine development and discuss the mechanisms by which they act in utero to alter the developing epigenome and ensuing phenotype. PMID- 26040785 TI - Organotellurium scaffolds for mass cytometry reagent development. AB - Mass cytometry (MC) is a powerful tool for studying heterogeneous cell populations. In previous work, our laboratory has developed an MC probe for hypoxia bearing a methyl telluride mass tag. The methyl telluride was unoptimized, displaying stability and toxicity limitations. Here, we investigate three classes of organotelluriums as MC mass tags: methyl tellurides, trifluoromethyl tellurides and 2-alkyl-tellurophenes. NMR was used to compare the stability of these compounds in aqueous and organic solutions and the compounds were analysed for toxicity in Jurkat cells. The methyl tellurides were moderately stable to aerobic oxidation in organic solution under dry ambient conditions. The trifluoromethyl tellurides were stable to aerobic oxidation in organic solution but decomposed in aqueous solution. The 2-alkyl-tellurophenes proved to be stable in both organic and aqueous solutions under ambient conditions and showed limited toxicity (IC50 > 200 MUM) in cell based assays. The synthetic feasibility, chemically stability, and limited toxicity of tellurophenes suggests these groups will be good choices for MC reagent development. PMID- 26040784 TI - Awareness and practice of emergency contraception at a private university in Nigeria. AB - BACKGROUND: The pursuit of formal education now causes many people in developing countries to marry later in life, thereby leading to increased premarital sex and unintended pregnancies. Efforts have been made to characterize awareness and use of emergency contraception (EC) among undergraduate students in public universities in Nigeria; however, it is not known if students in private tertiary institutions adopt different practices or if having an affluent family background plays a role. This pilot study therefore aimed to assess the awareness and use of EC among students at a private Nigerian university toward assisting education planners in developing strategies in improving students' reproductive well-being. RESULTS: Out of 94 female students, 42 (44.7%) had sexual experience, but only 32 (34.0%) were currently sexually active. Six students (6.4%) had had unwanted pregnancies, of which all but one were terminated. Fifty-seven respondents (60.6%) were aware of EC, though only 10 (10.6%) ever practiced it. The greatest source of EC information was from health workers and peers; the lowest source was family or relatives. Most respondents desired orientation and availability of EC on campus. EC awareness among the students was predicted by upper social class background (adjusted odds ratio [OR], 2.73; 95% confidence interval [CI], 1.06 7.45) and upbringing in the Federal Capital Territory (adjusted OR, 4.45; 95% CI, 1.56-14.22). CONCLUSIONS: Though awareness of EC was higher among the private university students in this study than at most public universities, there was no difference in EC usage. A high pregnancy termination rate was observed; dilatation and curettage were mainly adopted. In Nigeria, youth-friendly reproductive health information and access should not be limited to government owned tertiary institutions but also extended to private ones. PMID- 26040786 TI - A warning about tuberculosis. PMID- 26040787 TI - CARMO: a comprehensive annotation platform for functional exploration of rice multi-omics data. AB - High-throughput technology is gradually becoming a powerful tool for routine research in rice. Interpretation of biological significance from the huge amount of data is a critical but non-trivial task, especially for rice, for which gene annotations rely heavily on sequence similarity rather than direct experimental evidence. Here we describe the annotation platform for comprehensive annotation of rice multi-omics data (CARMO), which provides multiple web-based analysis tools for in-depth data mining and visualization. The central idea involves systematic integration of 1819 samples from omics studies and diverse sources of functional evidence (15 401 terms), which are further organized into gene sets and higher-level gene modules. In this way, the high-throughput data may easily be compared across studies and platforms, and integration of multiple types of evidence allows biological interpretation from the level of gene functional modules with high confidence. In addition, the functions and pathways for thousands of genes lacking description or validation may be deduced based on concerted expression of genes within the constructed co-expression networks or gene modules. Overall, CARMO provides comprehensive annotations for transcriptomic datasets, epi-genomic modification sites, single nucleotide polymorphisms identified from genome re-sequencing, and the large gene lists derived from these omics studies. Well-organized results, as well as multiple tools for interactive visualization, are available through a user-friendly web interface. Finally, we illustrate how CARMO enables biological insights using four examples, demonstrating that CARMO is a highly useful resource for intensive data mining and hypothesis generation based on rice multi-omics data. CARMO is freely available online (http://bioinfo.sibs.ac.cn/carmo). PMID- 26040788 TI - Obesity in regional anesthesia--a risk factor for peripheral catheter-related infections. AB - BACKGROUND: Obesity is believed to increase the risk of surgical site infections and possibly increase the risk of catheter-related infections in regional anesthesia. We, therefore, analyzed the influence of obesity on catheter-related infections defined within a national registry for regional anesthesia. METHODS: The German Network for Regional Anesthesia database with 25 participating clinical centers was analyzed between 2007 and 2012. Exactly, 28,249 cases (13,239 peripheral nerve and 15,010 neuraxial blocks) of patients >= 14 years were grouped in I: underweight (BMI 13.2-18.49 kg/m(2) , n = 597), II: normal weight (BMI 18.5-24.9 kg/m(2) , n = 9272), III: overweight (BMI 25.0-29.9 kg/m(2) , n = 10,632), and IV: obese (BMI 30.0-70.3 kg/m(2) , n = 7,744). The analysis focused on peripheral and neuraxial catheter-related infections. Differences between the groups were tested with non-parametric ANOVA and chi-square (P < 0.05). Binary logistic regression was used to compare obese, overweight, or underweight patients with normal weight patients. Odds ratios (OR and 95% confidence interval) were calculated and adjusted for potential confounders. RESULTS: Confounders with significant influence on the risk for catheter-related infections were gender, age, ASA score, diabetes, preoperative infection, multiple skin puncture, and prolonged catheter use. The incidence (normal weight: 2.1%, obese: 3.6%; P < 0.001) and the risk of peripheral catheter-related infection was increased in obese compared to normal weight patients [adjusted OR: 1.69 (1.25-2.28); P < 0.001]. In neuraxial sites, the incidence of catheter related infections differed significantly between normal weight and obese patients (normal weight: 3.2%, obese: 2.3%; P = 0.01), whereas the risk was comparable [adjusted OR: 0.95 (0.71-1.28); P = 0.92]. CONCLUSION: This retrospective cohort study suggests that obesity is an independent risk factor for peripheral, but not neuraxial, catheter-related infections. PMID- 26040789 TI - Effects of exercise training and photobiomodulation therapy (EXTRAPHOTO) on pain in women with fibromyalgia and temporomandibular disorder: study protocol for a randomized controlled trial. AB - BACKGROUND: Fibromyalgia (FM) is a syndrome most prevalent in women, in whom it is characterized mainly by chronic pain. An important issue is that many patients with FM are reported to have temporomandibular dysfunction (TMD), and the coexistence of these pathologies generates a clinical outcome of high complexity. The literature is unclear regarding an effective therapy for reducing pain in patients with both comorbidities. Exercise training and phototherapy (low-level laser therapy with light-emitting diode) are two of the approaches used to treat pain. Thus, the aim of this study is to assess the potential role of exercise training plus phototherapy in reducing chronic pain in women with FM and TMD. A further aim is to determine whether the interventions can improve quality of life and modulate endogenous serotonin. METHODS/DESIGN: A randomized controlled clinical trial will be conducted. It will involve 60 women >= 35 years of age with a diagnosis of FM and TMD. After recruitment, patients will be randomly allocated to one of four groups: a control group (no intervention), a group that will receive a phototherapy intervention (PHO), a group that will be prescribed muscle-stretching, aerobic, and facial exercises (EXT), or a group that will receive phototherapy plus exercise interventions (PHO + EXT). The trial will last 10 weeks, and the following outcomes will be evaluated on two separate occasions (baseline and within 24 h after the last day of the protocol). Pain intensity will be analyzed using a visual analogue scale and the McGill Pain Questionnaire, and pain thresholds will be punctuated using a digital algometer. FM symptoms will be assessed using the Fibromyalgia Impact Questionnaire, and quality of life will be determined with the 36-item Short Form Health Survey. Serotonin levels will be evaluated in salivary samples using a competitive enzyme-linked immunosorbent assay. DISCUSSION: This is the first randomized controlled trial in which the role of phototherapy, exercise training, and a combination of these interventions will be evaluated for chronic pain in patients with FM and TMD. The results will offer valuable clinical evidence for objective assessment of the potential benefits and risks of procedures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02279225. Registered 27 October 2014. PMID- 26040790 TI - [Electrophysiology in ophthalmology]. AB - Electrophysiology is an objective functional test of the visual pathway and allows the location of visual dysfunctions to be detected. The flash electroretinogram (ERG) allows recognition of large area damage to the retina and can distinguish between rod and cone diseases by recording under both dark and light-adapted conditions. Specific stimulation techniques are used for the multifocal ERG (mfERG) which reveals localized retinal dysfunction, e. g. in maculopathies. The pattern ERG (PERG) is an indicator of ganglion cell function and can be used for early detection of glaucoma. The visual evoked potential (VEP) is a cortical response and serves as a functional test of the entire visual pathway from the eye to the visual system of the brain. After presenting each of these methods individually, the article gives assistance in situations where the appropriate electrophysiological method for a given clinical hypothesis is to be selected and explains how the methods can be combined in a reasonable way. PMID- 26040791 TI - [Requirements for low vision magnification aids in age-related macular degeneration: Data from the Tubingen low vision clinic (comparison of 2007-2011 with 1999-2005)]. AB - BACKGROUND: The purpose of this study was to investigate if there has been a change in requirements for low vision magnification aids in recent years. PATIENTS AND METHODS: The collective data from age-related macular degeneration (AMD) patients from the Tubingen low vision clinic from the years 2007-2011 were compared with the patient collective from the years 1999-2005. Magnification needs and the prescribed magnifying aids for reading in the categories magnifying spectacles, hand-held magnifiers, monocular telescopes, electronic magnifiers and electronic reading devices were evaluated. In addition patients from 2010 and 2011 were divided into dry and neovascular AMD and the prescribed magnification aids were compared for these AMD forms. RESULTS: There was no significant change in in the prescribed magnification reading aids for AMD patients between the years 1999-2005 and 2007-2011. An electronic magnifier was prescribed most often (both collectives 43 %), followed by hand-held magnifiers (32 and 29.5 %, respectively) and magnifying spectacles (17 and 18.8 %, respectively). Also the magnifying needs and mean age of the AMD patients did not change significantly between the two periods (2007-2011 versus 1999-2005). The detailed analysis for dry and neovascular AMD for the years 2010 and 2011 showed no significant differences for the most commonly prescribed low vision aids. The prescription of low vision aids is not influenced by the AMD classification (dry or neovascular), only by the magnification needs. CONCLUSION: There is an unchanged and still high demand for rehabilitation aids of AMD patients, for dry as well as for neovascular AMD even after the introduction of anti-vascular endothelial growth factor (anti-VEGF) therapy. PMID- 26040792 TI - [Endogenous Candida lens abscess in a premature infant]. AB - BACKGROUND: This case report describes an extremely rare Candida lens abscess in a premature infant (gestational age 24 weeks at birth). CASE REPORT: After birth the infant suffered from Candida sepsis which was successfully treated with an antifungal medication. The patient was referred at the age of 6 months because of greyish alterations in the pupils but an absence of other symptoms. The examination with the patient under general anesthesia revealed a grey pupillary membrane and behind it a whitish swollen lens. A lensectomy was performed. The vitreous body was inconspicuous. Candida albicans was identified microbiologically. CONCLUSIONS: In preterm infants dissemination of pathogens into the lens through the vascular coat of the lens is possible, which after regression of the coat is no longer accessible to systemic treatment and may thus be manifested as delayed abscess formation. PMID- 26040793 TI - [MD PhD programs: Providing basic science education for ophthalmologists]. AB - BACKGROUND: Enrollment in MD PhD programs offers the opportunity of a basic science education for medical students and doctors. These programs originated in the USA where structured programs have been offered for many years, but now German universities also run MD PhD programs. OBJECTIVE: The MD PhD programs provided by German universities were investigated regarding entrance requirements, structure and financing modalities. MATERIAL AND METHODS: An internet and telephone-based search was carried out. RESULTS: Out of 34 German universities 22 offered MD PhD programs. At 15 of the 22 universities a successfully completed course of studies in medicine was required for enrollment, 7 programs admitted medical students in training and 7 programs required a medical doctoral thesis, which had to be completed with at least a grade of magna cum laude in 3 cases. Financing required scholarships in many cases. CONCLUSION: Several German universities currently offer MD PhD programs; however, these differ considerably regarding entrance requirements, structure and financing. A detailed analysis investigating the success rates of these programs (e.g. successful completion and career paths of graduates) would be of benefit. PMID- 26040795 TI - Sarah Clarke: Determined and convivial. PMID- 26040794 TI - [Influence of corneal pachymetric changes on functional results after cataract surgery]. AB - BACKGROUND: In the early postoperative period following uncomplicated cataract surgery, the correlation of corrected distance visual acuity (CDVA) and the increase in corneal thickness and anterior chamber depth (ACD) are investigated. PATIENTS AND METHODS: A total of 54 cataract patients with a mean age of 70 +/- 8.4 years were included in this prospective study. Surgery was carried out on one eye of each patient according to the study protocol. Refraction, CDVA and ACD were evaluated 1 day and 1 week postoperatively and compared with the pachymetry results measured with the Pentacam. RESULTS: The mean postoperative CDVA significantly improved from 0.31 +/- 0.24 logMAR to 0.18 +/- 0.22 logMAR after one day and up to 0.06 +/- 0.13 logMAR one week after surgery (p < 0.05). The mean spherical equivalent was - 0.52 +/- 0.69 D after one day and - 0.50 +/- 0.82 D one week after surgery and showed only minimal differences compared to the mean target refraction of - 0.39 +/- 0.70 D. Postoperative corneal thickness showed a significant increase compared to the preoperative results (p < 0.05) on both visits: the mean difference was 33.26 +/- 50.20 um (- 17 to 315 um) on the first day and 20.22 +/- 23.15 um (- 10 to 99 um) one week after surgery. Up to 7 days postoperatively the increase in corneal thickness and CDVA showed only moderate or no correlations (r = 0.465 vs. r = 0.072, respectively). Regarding pachymetry and ACD values, no or only low correlations were found. CONCLUSION: The significant increase in corneal thickness on the first and seventh day shows no to moderate correlation to the CDVA. Nevertheless, a good and early rehabilitation of visual acuity following uncomplicated cataract surgery is possible. Intraocular pressure measurement can lead to false high results due to an increase in corneal thickness. PMID- 26040796 TI - Fast electrically assisted regeneration of on-chip SERS substrates. AB - A microfluidic chip approach utilising integrated electrically connected stationary SERS targets based on inkjet-printed silver nanoparticles is presented. It enables multiple interference-free consecutive surface-enhanced Raman measurements inside chip channels by electrically assisted regeneration of the stationary SERS substrate. Thereby it circumvents common adsorption and memory effect problems associated with stationary SERS targets allowing multiple consecutive measurements in a continuous-flow system. PMID- 26040797 TI - New report of additional enterobacterial species causing wilt in West Bengal, India. AB - Ralstonia solanacearum is known to be the most prominent causal agent of bacterial wilt worldwide. It has a wide host range comprising solanaceous and nonsolanaceous plants. Typical symptoms of the disease are leaf wilt, browning of vascular tissues, and collapsing of the plant. With the objective of studying the diversity of pathogens causing bacterial wilt in West Bengal, we collected samples of diseased symptomatic crops and adjacent symptomatic and asymptomatic weeds from widespread locations in West Bengal. By means of a routine molecular identification test specific to "R. solanacearum species complex", the majority of these strains (68 out of 71) were found to not be R. solanacearum. Presumptive identification of these isolates with conventional biochemicals, extensive testing of pathogenicity of a subset involving greenhouse trials fulfilling Koch's postulate test, and scanning electron microscopic analysis for the presence of pathogen in diseased plants were done. 16S rDNA sequencing of a subset of these strains (GenBank accession Nos. JX880249-JX880251) and analysis of sequences with the nBLAST programme showed a high similarity (97%-99%) to sequences of the Enterobacteriaceae group available in GenBank. Molecular phylogeny further established the taxonomic position of the strains. The 3 bacterial strain cultures have been submitted to MTCC, Institute of Microbial Technology, Chandigarh, India, and were identified as Klebsiella oxytoca, Enterobacter cowanii, and Klebsiella oxytoca, respectively. Although Enterobacter sp. has previously been reported to cause wilt in many plants, susceptibility of most of the dedicated hosts of R. solanacearum to wilt caused by Enterobacter and other bacteria from Enterobacteriaceae is being reported for the first time in this work. PMID- 26040798 TI - Reclassification of low-gradient aortic stenosis severity in patients with preserved ejection fraction: when is severe truly severe? PMID- 26040799 TI - X-ray-free implantation of a permanent pacemaker during pregnancy using a 3D electro-anatomic mapping system. PMID- 26040800 TI - Rare case of a multilocular primary cardiac intimal sarcoma presenting as left atrial mass with new onset atrial fibrillation. PMID- 26040801 TI - Turned, wedged, but still no feeling: asymptomatic late transcatheter aortic valve dislocation into the LVOT. PMID- 26040802 TI - Triple transcatheter and surgical valve replacement: a 'hybrid' approach to valvular heart disease. PMID- 26040803 TI - Optical coherence tomography follow-up after bioresorbable in metallic and metallic in bioresorbable stenting: tackling in-stent restenosis in the era of bioresorbable vascular scaffolds. PMID- 26040804 TI - Lipoma of the interventricular septum. PMID- 26040805 TI - Survival of adults with ASD2: a call for a longitudinal clinical registry. PMID- 26040806 TI - The association between in-stent neoatherosclerosis and native coronary artery disease progression: a long-term angiographic and optical coherence tomography cohort study. AB - AIMS: The purpose of the present study was to investigate the relationship between in-stent neoatherosclerosis (NA) and native atherosclerosis progression of untreated coronary segments. METHODS AND RESULTS: In-stent NA was assessed by optical coherence tomography (OCT) among patients included in the SIRTAX-LATE OCT study 5 years after drug-eluting stent (DES) (sirolimus-eluting and paclitaxel eluting stents) implantation. Neoatherosclerosis was defined as the presence of fibroatheroma or fibrocalcific plaque within the neointima of stented segments with a longitudinal extension >1.0 mm. Atherosclerosis progression in untreated native coronary segments was evaluated by serial quantitative coronary angiography (QCA). The change in minimal lumen diameter (MLD) was serially assessed within matched segments at baseline and 5-year angiographic follow-up. The key clinical endpoint was non-target lesion (non-TL) revascularization throughout 5 years. A total of 88 patients with 88 lesions were available for OCT analysis 5 years after DES implantation. In-stent NA was observed in 16% of lesions with the majority of plaques being fibroatheromas (11.4%) followed by fibrocalcific plaques (5.7%). A total of 704 non-TL segments were serially evaluated by QCA. Between baseline and 5-year follow-up, the reduction in MLD was significantly more pronounced in patients with NA (-0.25 mm, 95% CI -0.36 to 0.17 mm) when compared with patients without NA (-0.13 mm, 95% CI -0.17 to -0.10 mm, P = 0.002). Similarly, non-TL revascularization was more frequent in patients with NA (78.6%) when compared with patients without NA (44.6%, P = 0.028) throughout 5 years. CONCLUSIONS: In-stent NA is more common among patients with angiographic and clinical evidence of native atherosclerosis progression suggesting similar pathophysiological mechanisms.SIRTAX trial is registered at http://www.clinicaltrials.gov/ct2/show/NCT00617084. PMID- 26040807 TI - First report of simultaneous transcatheter aortic valve replacement, endovascular aortic aneurysm repair, and permanent pacemaker implantation after multi-vessel coronary stenting and left atrial appendage occlusion. PMID- 26040808 TI - Atypical position of subcutaneus implantable cardioverter-defibrillator as a solution in hypertrophic cardiomyopathy patient with initially negative electrocardiographic screening. PMID- 26040809 TI - The role of multi-modality imaging to investigate and manage anomalous right coronary artery originating from the pulmonary artery (ARCAPA) anomaly with associated coronary aneurysms presenting as acute left ventricular failure. PMID- 26040810 TI - Unique coronary artery anomaly: three separate coronary artery ostia within one coronary sinus. PMID- 26040811 TI - Neoatherosclerosis: mirage of an ancient illness or genuine disease condition? PMID- 26040812 TI - Clinical symptoms related to anal sphincter defects and atrophy on external phased-array MR imaging. AB - INTRODUCTION AND HYPOTHESIS: Defecatory complaints have a severe impact on quality of life. The additional value of pelvic floor MRI in patients with defecatory complaints is unclear. Our aim was to correlate the presence of defects and atrophy of the anal sphincter complex using pelvic floor MRI in women with mixed pelvic floor symptoms and to establish patient characteristics and self reported complaints predictive of pathology. METHODS: This is a retrospective study among women with mixed pelvic floor symptoms who underwent external phased-array MRI and completed a questionnaire on bothersome defecatory complaints. Data on patient characteristics, including obstetrical history and questionnaire scores were correlated with the assessment of anal sphincter defects and atrophy on pelvic floor MRI. RESULTS: One hundred and fifty-eight women were included. A defect of the external anal sphincter (EAS) and internal anal sphincter (IAS) was found in 18 (11%) and 5 (3%) patients respectively. Atrophy of the EAS was present in 72 patients (46%), with more cases of mild (n = 52, 33%) than severe atrophy (n = 20, 13%). The variable "previous third or fourth degree tear" had a significant positive association with an IAS defect on MRI, with an OR of 9.533 (1.425-63.776). Patients with EAS atrophy had higher scores for fecal incontinence (indicating more bother) than patients without EAS atrophy. Higher age and BMI were true predictors of the presence of more severe EAS atrophy. CONCLUSION: Atrophy of the EAS was highly prevalent in this population and was associated with bothersome symptoms of fecal incontinence. PMID- 26040813 TI - Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II. AB - BACKGROUND AND PURPOSE: Calcium/calmodulin-dependent protein kinase IIdelta (CaMKIIdelta) is an important regulator of cardiac contractile function and dysfunction and may be an unwanted secondary target for anti-cancer drugs such as sunitinib and imatinib that have been reported to alter cardiac performance. This study aimed to determine whether anti-cancer kinase inhibitors may affect CaMKII activity and expression when administered in vivo. EXPERIMENTAL APPROACH: Cardiovascular haemodynamics in response to acute and chronic sunitinib treatment, and chronic imatinib treatment, were assessed in guinea pigs and the effects compared with those of the known positive and negative inotropes, isoprenaline and verapamil. Parallel studies from the same animals assessed CaMKIIdelta expression and CaMKII activity following drug treatments. KEY RESULTS: Acute administration of sunitinib decreased left ventricular (LV) dP/dtmax. Acute administration of isoprenaline increased LVdP/dtmax dose dependently, while LVdP/dtmax was decreased by verapamil. CaMKII activity was decreased by acute administration of sunitinib and was increased by acute administration of isoprenaline, and decreased by acute administration of verapamil. CaMKIIdelta expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKIIdelta expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKIIdelta expression and CaMKII activity. CONCLUSIONS AND IMPLICATIONS: Chronic sunitinib and imatinib treatment increased CaMKIIdelta expression and CaMKII activity. As these compounds are associated with cardiac dysfunction, increased CaMKII expression could be an early indication of cellular cardiotoxicity marking potential progression of cardiac contractile dysfunction. PMID- 26040814 TI - Biomarkers for differentiation of causes of respiratory distress in dogs and cats: Part 1--Cardiac diseases and pulmonary hypertension. AB - OBJECTIVE: To review the current veterinary and relevant human literature regarding biomarkers of cardiac disease leading to respiratory compromise. DATA SOURCES: Veterinary and human medical literature: original research articles, scientific reviews, consensus statements, and recent textbooks. HUMAN DATA SYNTHESIS: Cardiac troponins (cTn) and natriuretic peptides are routinely used in human medicine. VETERINARY DATA SYNTHESIS: Although biomarkers should not be accepted in lieu of gold standard diagnostics, they may be useful in directing care in the stabilization process. Biomarkers of congestive heart failure (CHF) include natriuretic peptides, cTn, and endothelin. cTnI is useful in differentiating causes of pericardial effusion, but is unlikely to be useful in differentiating CHF from other causes of respiratory distress. The most extensively studied and promising cardiac biomarker is amino-terminal probrain natriuretic peptide, although a bedside test is not currently available. Other natriuretic peptides have also proven useful, but have lower availability. Endothelin is unlikely to be clinically useful. Although critically evaluated for their use in cardiac diseases, many of the biomarkers are affected by more than one type of respiratory or systemic disease. Several cardiac biomarkers are increased in cases of pulmonary hypertension (PH), but discerning CHF alone from PH or a combination of heart disease and PH is challenging when evaluating biomarkers alone. CONCLUSION: At this time, there are no point-of-care tests for biomarkers that can reliably differentiate among causes of dyspnea of cardiac origin in dogs and cats, although there are reference laboratory tests that show promise and future development of point-of-care tests that may be useful in certain situations. PMID- 26040815 TI - Biomarkers for differentiation of causes of respiratory distress in dogs and cats: Part 2--Lower airway, thromboembolic, and inflammatory diseases. AB - OBJECTIVES: To review the current veterinary and relevant human literature regarding biomarkers of respiratory diseases leading to dyspnea and to summarize the availability, feasibility, and practicality of using respiratory biomarkers in the veterinary setting. DATA SOURCES: Veterinary and human medical literature: original research articles, scientific reviews, consensus statements, and recent textbooks. HUMAN DATA SYNTHESIS: Numerous biomarkers have been evaluated in people for discriminating respiratory disease processes with varying degrees of success. VETERINARY DATA SYNTHESIS: Although biomarkers should not dictate clinical decisions in lieu of gold standard diagnostics, their use may be useful in directing care in the stabilization process. Serum immunoglobulins have shown promise as an indicator of asthma in cats. A group of biomarkers has also been evaluated in exhaled breath. Of these, hydrogen peroxide has shown the most potential as a marker of inflammation in asthma and potentially aspiration pneumonia, but methods for measurement are not standardized. D-dimers may be useful in screening for thromboembolic disease in dogs. There are a variety of markers of inflammation and oxidative stress, which are being evaluated for their ability to assess the severity and type of underlying disease process. Of these, amino terminal pro-C-type natriuretic peptide may be the most useful in determining if antibiotic therapy is warranted. Although critically evaluated for their use in respiratory disorders, many of the biomarkers which have been evaluated have been found to be affected by more than one type of respiratory or systemic disease. CONCLUSION: At this time, there are point-of-care biomarkers that have been shown to reliably differentiate between causes of dyspnea in dogs and cats. Future clinical research is warranted to understand of how various diseases affect the biomarkers and more bedside tests for their utilization. PMID- 26040823 TI - Intestinal type adenocarcinoma of the ethmoid: Outcomes of a treatment regimen based on endoscopic surgery with or without radiotherapy. AB - BACKGROUND: The purpose of this study was to assess survival, prognostic factors, and complications in a cohort of patients with intestinal-type adenocarcinoma (ITAC) treated with transnasal endoscopic surgery +/- radiotherapy (RT). METHODS: Patients with ITAC who underwent endoscopic surgery +/- RT at 2 tertiary centers were retrospectively reviewed. Overall survival (OS) and event-free survival were calculated, and statistically significant variables were entered in a multivariate Cox regression model. Complications were also analyzed. RESULTS: One hundred-sixty-nine patients were included. Major complications occurred in 9.5% of patients. Adjuvant RT was delivered in 58.6% of patients. Five-year OS and event-free survival were 68.9% and 63.6%, respectively. Advanced pT classification, high-grade, and positive surgical margins were independently predictive of poor survival. CONCLUSION: Endoscopic surgery +/- RT is a valid treatment option in most cases of ITAC. When compared with series based on external surgery, our results support a definitive paradigm shift in the management of ITAC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E996-E1003, 2016. PMID- 26040824 TI - A rare presentation of complication arising from Meckel's diverticulum in the form of diverticulotransverse colonic fistula in an adult. AB - Meckel's diverticulum is a common congenital malformation of the gastrointestinal tract, reported to be present in 2-4% of the population. Although most patients with Meckel's diverticulum remain asymptomatic throughout life, reports of acute inflammation, perforation, haemorrhage, intussusception, intestinal obstruction, vesicodiverticular fistulae and primary tumours are described. We present a rare diagnosis of diverticulotransverse colonic fistula and its management. PMID- 26040825 TI - Can maintenance trastuzumab be stopped in patients with HER2-positive metastatic breast cancer? AB - Trastuzumab has significantly improved the median survival of patients with HER2 positive breast cancer. In metastatic disease, maintenance trastuzumab is usually given after tumour response has been achieved with the combination of chemotherapy and trastuzumab, with the aim of prolonging time to disease progression. We report a case where a durable complete response (CR) was achieved without maintenance trastuzumab. In the absence of consensus guidelines, it is difficult to recommend which HER2-positive patients with metastatic breast cancer after CR will benefit from withdrawing maintenance trastuzumab therapy and when this could be considered. PMID- 26040826 TI - Catheter ablation targeting Purkinje potentials controlled ventricular fibrillation in a patient with a malignant lymphoma occurring in the ventricular septum. AB - Malignant lymphoma is known to cause various types of arrhythmia, including ventricular fibrillation. However, radiofrequency catheter ablation of ventricular fibrillation associated with malignant lymphoma has never been reported. We describe the case of a 53-year-old man with refractory ventricular fibrillation that was associated with malignant lymphoma. Electrophysiological testing revealed that a Purkinje potential appeared before ventricular contraction at the tumour site. We successfully treated the ventricular fibrillation with radiofrequency catheter ablation, using the Purkinje potential as an indicator. Physicians should consider this treatment if ventricular fibrillation cannot be controlled using other strategies. PMID- 26040827 TI - A chemical mixer with dark-green nails. AB - Nails are integral extensions of the skin and they together form the largest organ of the human body. Changes in nail appearance can be due to external insults or internal pathologies, and nail signs have to be interpreted in light of a good history. We present an interesting case of a man who developed dark green discolouration of his nails over a short period of time. His work as a chemical mixer rendered him susceptible to hazardous chemical exposure. A notification was filed and the local Occupational Health Department discovered insufficient protective gear and lack of protocols regarding hazards of isocyanate-based resin. The patient also reported washing utensils with bare hands. Based on the meniscal demarcation borders between the discoloured and normal areas, plus a positive bacterial culture from nail clippings, the final diagnosis of isocyanate-resin-induced onycholysis with secondary Pseudomonas infection remained as the most likely clinical diagnosis. PMID- 26040828 TI - Successful treatment of a giant pediatric fusiform basilar trunk aneurysm with surpass flow diverter. AB - Fusiform aneurysms present a unique challenge to traditional microsurgical and endovascular treatment because of the lack of a discernible neck and the involvement of parent vessel. Flow diversion has increasingly become the treatment of choice for fusiform aneurysms in the anterior circulation, but its results in the posterior circulation are variable. We report successful treatment of a giant fusiform upper basilar trunk aneurysm with the Surpass flow diverter in an adolescent, and discuss the potential advantages of this emerging technology in the treatment of fusiform posterior circulation aneurysms. PMID- 26040829 TI - Paediatric splenic and rectovesical pouch abscesses caused by Eggerthella lenta. AB - Paediatric splenic abscesses are rare, but can be fatal. An 8-year-old boy developed recurrent fever and abdominal pain 5 months after undergoing an appendectomy. A CT scan showed splenic and rectovesical pouch abscesses. The patient was successfully treated with antibiotics, and laparoscopic drainage and debridement of pus from the rectovesical pouch abscess. Eggerthella lenta was cultured from the latter lesion. Early diagnosis and treatment resulted in the satisfactory resolution of the infection. PMID- 26040831 TI - A diagnostic challenge: pyogenic granuloma or oral focal mucinosis. PMID- 26040830 TI - Chronic enterococcal spinal implant infection 6 years after instrumentation of a severe scoliosis in a 22-year-old woman. PMID- 26040832 TI - Unilateral congenital buphthalmos. PMID- 26040833 TI - A simple and fast physics-based analytical method to calculate therapeutic and stray doses from external beam, megavoltage x-ray therapy. AB - State-of-the-art radiotherapy treatment planning systems provide reliable estimates of the therapeutic radiation but are known to underestimate or neglect the stray radiation exposures. Most commonly, stray radiation exposures are reconstructed using empirical formulas or lookup tables. The purpose of this study was to develop the basic physics of a model capable of calculating the total absorbed dose both inside and outside of the therapeutic radiation beam for external beam photon therapy. The model was developed using measurements of total absorbed dose in a water-box phantom from a 6 MV medical linear accelerator to calculate dose profiles in both the in-plane and cross-plane direction for a variety of square field sizes and depths in water. The water-box phantom facilitated development of the basic physical aspects of the model. RMS discrepancies between measured and calculated total absorbed dose values in water were less than 9.3% for all fields studied. Computation times for 10 million dose points within a homogeneous phantom were approximately 4 min. These results suggest that the basic physics of the model are sufficiently simple, fast, and accurate to serve as a foundation for a variety of clinical and research applications, some of which may require that the model be extended or simplified based on the needs of the user. A potentially important advantage of a physics based approach is that the model is more readily adaptable to a wide variety of treatment units and treatment techniques than with empirical models. PMID- 26040835 TI - Alexithymia and Early Maladaptive Schemas in chronic pain patients. AB - Psychological factors have an impact on subjective pain experience. The aim of this study was to explore the occurrence of alexithymia and Early Maladaptive Schemas in a sample of 271 first visit chronic pain patients of six pain clinics. The patients completed the study questionnaire consisting of the Toronto Alexithymia Scale-20, the Finnish version of the Young Schema Questionnaire short form-extended, the Beck Depression Inventory-II, and pain variables. Alexithymic patients scored higher on Early Maladaptive Schemas and had more pain intensity, pain disability and depression than nonalexithymic patients. Both alexithymia and depression correlated significantly with most Early Maladaptive Schemas. The co occurrence of alexithymia, Early Maladaptive Schemas and depression seems to worsen the pain experience. Screening of alexithymia, depression and Early Maladaptive Schemas may help to plan psychological treatment interventions for chronic pain patients. PMID- 26040834 TI - Memory acquisition and retrieval impact different epigenetic processes that regulate gene expression. AB - BACKGROUND: A fundamental question in neuroscience is how memories are stored and retrieved in the brain. Long-term memory formation requires transcription, translation and epigenetic processes that control gene expression. Thus, characterizing genome-wide the transcriptional changes that occur after memory acquisition and retrieval is of broad interest and importance. Genome-wide technologies are commonly used to interrogate transcriptional changes in discovery-based approaches. Their ability to increase scientific insight beyond traditional candidate gene approaches, however, is usually hindered by batch effects and other sources of unwanted variation, which are particularly hard to control in the study of brain and behavior. RESULTS: We examined genome-wide gene expression after contextual conditioning in the mouse hippocampus, a brain region essential for learning and memory, at all the time-points in which inhibiting transcription has been shown to impair memory formation. We show that most of the variance in gene expression is not due to conditioning and that by removing unwanted variance through additional normalization we are able provide novel biological insights. In particular, we show that genes downregulated by memory acquisition and retrieval impact different functions: chromatin assembly and RNA processing, respectively. Levels of histone 2A variant H2AB are reduced only following acquisition, a finding we confirmed using quantitative proteomics. On the other hand, splicing factor Rbfox1 and NMDA receptor-dependent microRNA miR 219 are only downregulated after retrieval, accompanied by an increase in protein levels of miR-219 target CAMKIIgamma. CONCLUSIONS: We provide a thorough characterization of coding and non-coding gene expression during long-term memory formation. We demonstrate that unwanted variance dominates the signal in transcriptional studies of learning and memory and introduce the removal of unwanted variance through normalization as a necessary step for the analysis of genome-wide transcriptional studies in the context of brain and behavior. We show for the first time that histone variants are downregulated after memory acquisition, and splicing factors and microRNAs after memory retrieval. Our results provide mechanistic insights into the molecular basis of cognition by highlighting the differential involvement of epigenetic mechanisms, such as histone variants and post-transcriptional RNA regulation, after acquisition and retrieval of memory. PMID- 26040836 TI - Benzodiazepine prescribing guideline adherence and misuse potential in Irish minors. AB - BACKGROUND: The Good Prescribing Practice for Clinicians guidelines were published in 2002 in Ireland to guide General Practitioners about prescribing benzodiazepines. There has been no research to-date to measure compliance by General Practitioners. Inappropriate prescribing to minors may result in increased use or misuse of benzodiazepines. OBJECTIVE: The purpose of this study was to evaluate the prescribing of benzodiazepines to minors in Ireland against the Good Prescribing Practice for Clinicians guidelines. METHOD: Data for medicines dispensed between January 2009 and December 2012 from the Health Intelligence Ireland database were accessed and analysed. This database contains information about government-subsidised community-pharmacy-dispensed medicines. RESULTS: Benzodiazepine prescribing to minors increased by 10.2% between 2009 and 2012. Almost 15% of patients (n = 2193) were prescribed benzodiazepines for greater than four weeks; which contravenes the guidelines. Approximately half (51.4%) of prescribers who contravened this guideline, prescribed all their benzodiazepines in quantities of greater than one week, against the recommendations of the guidelines. CONCLUSION: The consequences of prescribing against National Guidelines can result in patients who become long-term benzodiazepine users and thus place an increased burden upon the healthcare system. The reasons for non-compliance by GPs should be investigated to find solutions. PMID- 26040837 TI - Implementation of medication review with follow-up in a Spanish community pharmacy and its achieved outcomes. AB - BACKGROUND: Despite many research studies demonstrating the benefit in clinical, economic, and humanistic outcomes of professional pharmacy services, there is a paucity of evidence when these services become incorporated into the usual practice of a community pharmacy. OBJECTIVE: The objective of the present study was to evaluate the clinical, economic, and humanistic impact of a pharmacist conducted medication review with follow-up following 18 months implementation. SETTING: Community pharmacies in Spain. METHOD: The study used an effectiveness implementation hybrid design. During the follow-up, patients attended the pharmacy on a monthly basis and received the medication review with follow-up service. MAIN OUTCOME MEASURE: Economic, clinical, and humanistic measures were used to assess the impact of the service. RESULTS: 132 patients received the service. During the 18 months of follow-up, 408 negative outcomes related to medicines (which are uncontrolled health problems) were identified, of which 393 were resolved. The average number of medicines used by patients significantly decreased from 6.1 (SD: 2.9) to 3.3 (SD: 2.2). A significant decrease was also observed in hospitalizations [OR = 0.31 (IC 95% = 0.10-0.99)] and in emergency department visits [OR = 0.16 (IC 95% = 0.05-0.55); p = 0.001]. A general trend to increase all quality of life domains was observed over time. The higher increase was observed in the construct health transition [mean increase: 30.7 (SD: 25.4)], followed by bodily pain [mean increase: 22.3 (SD: 25.4)], and general health [mean increase: 20.7 (SD: 23.7)]. Medication knowledge significantly increased in terms of aggregated domains of dose, frequency, drug indication [from 8.9 (SD: 17.5) to 87.9 (SD: 25.0)], and dose and frequency [from 9.3 (SD: 17.9) to 92.5 (22.1)]. Although a slight improvement was observed in terms of drug indication, this increase was not statistically significant. 68 out of 132 patients (51.5%) were non-adherent to their treatment. This number decreased to 1 (0.8%) after the follow-up [OR = 0.007 (IC 95%: 0.001-0.053) p < 0.001]. CONCLUSION: A community pharmacy based medication review with follow-up service delivered by a trained pharmacist, has positive effects across clinical, economic, and humanistic outcomes. These results are consistent with previous studies. Incorporating community pharmacists into the multidisciplinary team is a reliable solution to improve health care. PMID- 26040838 TI - Structural flexibility of the heme cavity in the cold-adapted truncated hemoglobin from the Antarctic marine bacterium Pseudoalteromonas haloplanktis TAC125. AB - Truncated hemoglobins build one of the three branches of the globin protein superfamily. They display a characteristic two-on-two alpha-helical sandwich fold and are clustered into three groups (I, II and III) based on distinct structural features. Truncated hemoglobins are present in eubacteria, cyanobacteria, protozoa and plants. Here we present a structural, spectroscopic and molecular dynamics characterization of a group-II truncated hemoglobin, encoded by the PSHAa0030 gene from Pseudoalteromonas haloplanktis TAC125 (Ph-2/2HbO), a cold adapted Antarctic marine bacterium hosting one flavohemoglobin and three distinct truncated hemoglobins. The Ph-2/2HbO aquo-met crystal structure (at 2.21 A resolution) shows typical features of group-II truncated hemoglobins, namely the two-on-two alpha-helical sandwich fold, a helix Phi preceding the proximal helix F, and a heme distal-site hydrogen-bonded network that includes water molecules and several distal-site residues, including His(58)CD1. Analysis of Ph-2/2HbO by electron paramagnetic resonance, resonance Raman and electronic absorption spectra, under varied solution conditions, shows that Ph-2/2HbO can access diverse heme ligation states. Among these, detection of a low-spin heme hexa coordinated species suggests that residue Tyr(42)B10 can undergo large conformational changes in order to act as the sixth heme-Fe ligand. Altogether, the results show that Ph-2/2HbO maintains the general structural features of group-II truncated hemoglobins but displays enhanced conformational flexibility in the proximity of the heme cavity, a property probably related to the functional challenges, such as low temperature, high O2 concentration and low kinetic energy of molecules, experienced by organisms living in the Antarctic environment. PMID- 26040840 TI - Antibiotic lock for the prevention of catheter-related infection in neonates. AB - BACKGROUND: Use of a central venous catheter (CVC) in neonates is associated with an increase in nosocomial infection. Numerous strategies exist to prevent catheter-related bloodstream infection (CRBSI); however, CRBSI continues to be a major problem. Antibiotic locking catheters is a new and promising treatment that potentially prevents this severe condition. OBJECTIVES: To assess the effectiveness of antibiotic lock versus no antibiotic lock or alternative antibiotic lock in the prevention of catheter-related infections in newborn infants of any gestational age during their initial stay in the neonatal unit and to study any relevant adverse effects from antibiotic lock therapy. SEARCH METHODS: Methods followed those of the Cochrane Neonatal Review Group (CNRG). We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 5); MEDLINE (via PubMed); EMBASE (hosted by EBCHOST); CINAHL; abstracts from Pediatric Academic Societies, European Society for Paediatric Research and trials registries; and references cited in our short listed articles using keywords and MeSH headings, up to April 2015. SELECTION CRITERIA: We considered all trials utilising random or quasi-random participant allocation. Participants included all newborn infants of any postmenstrual age who required any type of CVC. We compared an antibiotic lock technique with no antibiotic lock or placebo, such as heparinised saline, for any duration of time. DATA COLLECTION AND ANALYSIS: We extracted data using the standard methods of the CNRG. Two review authors independently assessed the relevance and risk of bias of the retrieved records. We expressed our dichotomous results using risk ratio (RR) with their 95% confidence intervals (CIs). We assessed for heterogeneity using the I(2) statistic. MAIN RESULTS: We included three trials (271 infants) in this review. Two of the three included studies had an overall low risk of bias and the remaining study had high risk of selection and performance biases. The use of an antibiotic lock decreased the incidence of confirmed catheter-related infection (typical RR 0.15, 95% CI 0.06 to 0.40; 3 studies, 271 infants) (high-quality evidence). The typical absolute risk reduction (ARR) was 18.5% and the number needed to treat for an additional beneficial outcome (NNTB) was 5. The effect of use of an antibiotic lock on suspected catheter infection was imprecise (typical RR 0.65, 95% CI 0.22 to 1.92) (moderate quality evidence). Confirmed and suspect infection rates combined were lower in the antibiotic lock group (absolute rates, RR 0.25, 95% CI 0.12 to 0.49; rate per 1000 catheter days, RR 0.17, 95% CI 0.07 to 0.40). The ARR was 20.5% and the NNTB was 5. None of the studies report resistance to the antibiotic used during the lock treatment. There was no significant difference in the detectable serum levels of antibiotic. When the data from two studies were pooled, there were significantly fewer episodes of hypoglycaemia in the treatment arm (typical RR 0.51, 95% CI 0.28 to 0.92). There was no statistically significant difference for mortality due to sepsis between the control and intervention group. AUTHORS' CONCLUSIONS: Based on a small number of trials and neonates, antibiotic lock solution appeared to be effective in preventing CRBSI in the neonatal population. However, as each included study used a different antibiotics and antibiotic resistance could not be reliably assessed, the evidence to-date is insufficient to determine the effects of antibiotic lock on infections in neonates. PMID- 26040841 TI - Creating Inquiry Between Technology Developers and Civil Society Actors: Learning from Experiences Around Nanotechnology. AB - Engaging civil society actors as knowledgeable dialogue partners in the development and governance of emerging technologies is a new challenge. The starting point of this paper is the observation that the design and orchestration of current organized interaction events shows limitations, particularly in the articulation of issues and in learning how to address the indeterminacies that go with emerging technologies. This paper uses Dewey's notion of 'publics' and 'reflective inquiry' to outline ways of doing better and to develop requirements for a more productive involvement of civil society actors. By studying four novel spaces for interaction in the domain of nanotechnology, this paper examines whether and how elements of Dewey's thought are visible and under what conditions. One of the main findings is that, in our society, special efforts are needed in order for technology developers and civil society actors to engage in a joint inquiry on emerging nanotechnology. Third persons, like social scientists and philosophers, play a role in this respect in addition to external input such as empirically informed scenarios and somewhat protected spaces. PMID- 26040842 TI - Distribution and sources of the polycyclic aromatic hydrocarbons in the sediments of the Pearl River estuary, China. AB - The Pearl River delta, one of the most prosperous economically region in China, has experienced significant contaminant inputs. However, the dynamics of pollutants in the Pearl River estuary and the adjacent coastal areas are still unclear at present. In the paper, distribution and sources of polycyclic aromatic hydrocarbons (PAHs) were investigated in the surface sediments of the Pearl River estuary. The total PAHs concentrations ranged from 126.08 to 3828.58 ng/g with a mean value of 563.52 ng/g, whereas the highest PAHs were observed in Guangzhou channel. Among the U.S. Environmental Protection Agency's 16 priority PAHs, PAHs with 3-4 rings exhibited relative higher levels. A positive relationship was found between PAHs and total organic carbon. The source analysis further showed that the major sources of PAHs in the Pearl River estuary were originated from the pyrolytic inputs, reflecting a mixed energy structure such as wood, coal and petroleum combustion. In summary, although PAHs in Lingding Bay and the adjacent coastal areas of the Pearl River estuary exhibited a relatively low pollution level, the relatively high pollution level of PAHs in Guangzhou channel will be attended. PMID- 26040843 TI - Acaricidal activity of thymol against larvae of Rhipicephalus microplus (Acari: Ixodidae) under semi-natural conditions. AB - This is the first study to investigate the activity of thymol on Rhipicephalus microplus larvae under semi-natural conditions. For this purpose, tests were conducted in pots with Brachiaria decumbens seedlings containing cattle tick larvae. Thymol, diluted in ethanol 50 degrees GL, was tested at concentrations of 2.5, 5.0, 10.0, 15.0, and 20.0 mg/mL, along with the control group treated with the solvent alone. Each treatment was composed of five pots (1 pot = a repetition). The experiment was performed in three steps. On the first day, the larvae were applied at the base of the signalgrass. Twenty-four hours later, approximately 25 mL of the solution was applied with thymol on the top of the vegetation in each pot. The survival of the larvae was measured 24 h after application of the solutions. Each pot was analyzed individually, and the grass fillets contained larvae were cut with scissors, placed in Petri dishes, and taken to the laboratory to count the number of living larvae. At the highest concentrations (10, 15, and 20 mg /mL), the number of live larvae declined by more than 95 % in relation to the control group. The lethal concentration 50 % (LC50) and LC90 values were 3.45 and 9.25 mg/ml, respectively. The application of thymol in semi-natural conditions starting concentration of 10 mg/mL significantly reduced the number of living R. microplus larvae. PMID- 26040844 TI - The brown hare (Lepus europaeus) as a novel intermediate host for Echinococcus multilocularis in Europe. AB - A typical multivesiculated metacestode tissue has been found in the liver of a European brown hare (Lepus europaeus) originating from a northern area of Switzerland. In this study, the causative species was identified as Echinococcus multilocularis by appropriate histological and molecular analyses and corresponding DNA sequencing. This is the first confirmation of larval E. multilocularis from hares in central Europe. The metacestode tissue contained protoscolices, suggesting that the hare may contribute to the transmission of E. multilocularis in Switzerland. PMID- 26040845 TI - Tsetse diversity and abundance in Southern Burkina Faso in relation with the vegetation. AB - The increase of human population, combined with climatic changes, contributed to the modification of spatial distribution of tsetse flies, main vector of trypanosomiasis. In order to establish and compare tsetse presence and their relationship with vegetation, entomological survey was performed using biconical traps deployed in transects, simultaneously with phyto-sociological study, on the Comoe river at its source in the village of Moussodougou, and in the semi protected area of Folonzo, both localities in Southern Burkina Faso. In Folonzo, the survey revealed a diversity of tsetse with 4 species occurring with apparent densities as follows: Glossina tachinoides (8.9 tsetse/trap/day); G. morsitans submorsitans (1.8 tsetse/trap/day); G. palpalis gambiensis (0.6/trap/day) and G. medicorum (0.15 tsetse/trap/day). In Moussodougou, a highly anthropized area, mainly G. p. gambiensis was caught (2.06 tsetse/trap/day), and rarely G. tachinoides. The phyto-sociological study allowed discrimination of 6 types of vegetation in both localities, with 3 concordances that are riparian forest, shrubby and woody savannah. In Moussodougou, all tsetse were caught in the riparian forest. That was also the case in Folonzo where a great proportion (95 to 99 % following the season) of G. p. gambiensis and G. tachinoides were caught in the gallery, while G. m. submorsitans was occurring as well in the gallery as in the savannah, and G. medicorum in the forest gallery. This study showed that although G. tachinoides and G.p. gambiensis are both riparian, they do not have the same preference in terms of biotope. PMID- 26040846 TI - Parental determinants of metabolic syndrome among adolescent Asian Indians: A cross-sectional analysis of parent-offspring trios. AB - BACKGROUND: The aim of the present study was to investigate the relationship between parental metabolic syndrome (MS) and the risk of MS and associated abnormalities in adolescent offspring. METHODS: This cross-sectional study was performed on 304 adolescents (12-16 years; 236 children with at least one parent and 124 father-mother-child trios) recruited from four schools representing different socioeconomic strata from Vellore, India. Anthropometric data was collected and blood pressure, blood glucose, and lipids were measured. RESULTS: The prevalence of MS in adolescent offspring, fathers, and mothers was 3.3%, 52.5%, and 48.7% respectively. The most commonly observed metabolic abnormality among adolescents was lower high-density lipoprotein. Maternal waist circumference (WC) was strongly correlated with adolescent body mass index (P = 0.007), WC (P < 0.001), serum triglycerides (P = 0.02), and systolic (P = 0.005) and diastolic (P = 0.01) blood pressure. Maternal MS status was significantly associated with a greater risk of central obesity (WC odds ratio [OR] 2.02; 95% confidence interval [CI] 1.21-3.17) in offspring. Both parents having MS conferred a significant effect on the child's WC (OR 1.21; 95% CI 1.72-2.07) and increased risk of MS (OR 6.19; 95% CI 1.64-23.26). CONCLUSIONS: This study highlights the possible heritable parental components that may contribute to the MS phenotype in offspring: MS in adolescent offspring is related to parental MS status, and maternal traits reflect offspring adiposity and metabolic traits more strongly than paternal factors. Therefore, adolescent children of parents with MS should be targets for primordial prevention of cardiometabolic disease. PMID- 26040847 TI - An anionic conjugated polymer as a multi-action sensor for the sensitive detection of Cu(2+) and PPi, real-time ALP assaying and cell imaging. AB - A Cu(2+) ensemble polyfluorene derivative, poly[5,5'-(((9H-fluorene-9,9 diyl)bis(hexane-6,1-diyl))bis(oxy))diisophthalate] sodium salt (PFT), displays unprecedented selectivity for PPi (LOD = 2.26 ppb) in aqueous solution as well as in random urine samples at physiological pH vis-a-vis monitoring ALP activity. Furthermore, intracellular imaging of Cu(2+) and PPi in mouse macrophage (J774A.1) and human breast cancer cells (MDA-MB231) was achieved to confirm the viability of PFT in biological systems. PMID- 26040848 TI - A workflow-driven approach to integrate generic software modules in a Trusted Third Party. AB - BACKGROUND: Cohort studies and registries rely on massive amounts of personal medical data. Therefore, data protection and information security as well as ethical aspects gain in importance and need to be considered as early as possible during the establishment of a study. Resulting legal and ethical obligations require a precise implementation of appropriate technical and organisational measures for a Trusted Third Party. METHODS: This paper defines and organises a consistent workflow-management to realize a Trusted Third Party. In particular, it focusses the technical implementation of a Trusted Third Party Dispatcher to provide basic functionalities (including identity management, pseudonym administration and informed consent management) and measures required to meet study specific conditions of cohort studies and registries. Thereby several independent open source software modules developed and provided by the MOSAIC project are used. This technical concept offers the necessary flexibility and extensibility to address legal and ethical requirements of individual scenarios. RESULTS: The developed concept for a Trusted Third Party Dispatcher allows mapping single process steps as well as individual requirements and characteristics of particular studies to workflows, which in turn can be combined to model complex Trusted Third Party processes. The uniformity of this approach permits unrestricted re-combination of the available functionalities (depending on the applied software modules) for various research projects. CONCLUSION: The proposed approach for the technical implementation of an independent Trusted Third Party reduces the effort for scenario specific implementations as well as for maintenance. The applicability and the efficacy of the concept for a workflow driven Trusted Third Party could be confirmed during the establishment of several nationwide studies (e.g. German Centre for Cardiovascular Research and the National Cohort). PMID- 26040849 TI - Interdisciplinary approach to cell-biomaterial interactions: biocompatibility and cell friendly characteristics of RKKP glass-ceramic coatings on titanium. AB - In this work, titanium (Ti) supports have been coated with glass-ceramic films for possible applications as biomedical implant materials in regenerative medicine. For the film preparation, a pulsed laser deposition (PLD) technique has been applied. The RKKP glass-ceramic material, used for coating deposition, was a sol-gel derived target of the following composition: Ca-19.4, P-4.6, Si-17.2, O 43.5, Na-1.7, Mg-1.3, F-7.2, K-0.2, La-0.8, Ta-4.1 (all in wt%). The prepared coatings were compact and uniform, characterised by a nanometric average surface roughness. The biocompatibility and cell-friendly properties of the RKKP glass ceramic material have been tested. Cell metabolic activity and proliferation of human colon carcinoma CaCo-2 cells seeded on RKKP films showed the same exponential trend found in the control plastic substrates. By the phalloidin fluorescence analysis, no significant modifications in the actin distribution were revealed in cells grown on RKKP films. Moreover, in these cells a high mRNA expression of markers involved in protein synthesis, proliferation and differentiation, such as villin (VIL1), alkaline phosphatase (ALP1), beta-actin (beta-ACT), Ki67 and RPL34, was recorded. In conclusion, the findings, for the first time, demonstrated that the RKKP glass-ceramic material allows the adhesion, growth and differentiation of the CaCo-2 cell line. PMID- 26040851 TI - Too many die without dignity. PMID- 26040850 TI - RNA-seq analysis reveals genetic response and tolerance mechanisms to ozone exposure in soybean. AB - BACKGROUND: Oxidative stress caused by ground level ozone is a contributor to yield loss in a number of important crop plants. Soybean (Glycine max) is considered to be ozone sensitive, and current research into its response to oxidative stress is limited. To better understand the genetic response in soybean to oxidative stress, an RNA-seq analysis of two soybean cultivars was performed comparing an ozone intolerant cultivar (Mandarin-Ottawa) and an ozone resistant cultivar (Fiskeby III) following exposure to ozone. RESULTS: Analysis of the transcriptome data revealed cultivar-specific expression level differences of genes previously implicated in oxidative stress responses, indicating unique cultivar-specific responses. Both Fiskeby III and Mandarin (Ottawa) exhibit an increased expression of oxidative response genes as well as glutathiones, phenylpropanoids, and phenylalanine ammonia-lyases. Mandarin (Ottawa) exhibited more general stress response genes whereas Fiskeby III had heightened expression of metabolic process genes. An examination of the timing of gene responses over the course of ozone exposure identified significantly more differentially expressed genes across all time points in Mandarin (Ottawa) than in Fiskeby III. The timing of expression was also considered to identify genes that may be indicative of a delayed response to ozone stress in Fiskeby III, We found that Mandarin (Ottawa) exhibits an higher level of expression in early time points for oxidative and general stress response genes while Fiskeby III seems to maintain expression of defense and stress response genes. Of particular interest was the expression of wax and cutin biosynthetic genes that we found to be expressed in Mandarin (Ottawa) in all sampled time points, whereas the expression of this pathway is only in the first time point for Fiskeby III. CONCLUSIONS: We were able to identify differentially expressed genes that correspond to each of the known or expected categories of genes previously implicated in other species for ozone stress. Our study shows evidence that at least part of the observed ozone tolerance of Fiskeby III may be due to its thicker, denser leaves providing passive resistance thereby limiting the degree of ozone exposure. The observed diminished genetic response is then likely a consequence of this reduced exposure. PMID- 26040852 TI - Future of clinical research in the NHS. PMID- 26040853 TI - Targetable mutations found in metastatic prostate cancer. PMID- 26040855 TI - Structured Pd-Au/Cu-fiber catalyst for gas-phase hydrogenolysis of dimethyl oxalate to ethylene glycol. AB - Galvanic co-deposition of 0.5 wt% Au and 0.1 wt% Pd on a microfibrous-structure using 8 MUm Cu-fibers delivers a Pd-Au/Cu-fiber catalyst, which is highly active, selective and stable for the hydrogenolysis of dimethyl oxalate to ethylene glycol. Au and Pd synergistically promote the hydrogenolysis activity of Cu(+) sites, while Au also critically stabilizes Cu(+) sites to prevent deep reductive deactivation. PMID- 26040854 TI - Laparoscopic Versus Open Surgery for Mid-Low Rectal Cancer: a Systematic Review and Meta-Analysis on Short- and Long-Term Outcomes. AB - BACKGROUND: The safety of laparoscopic surgery for mid-low rectal cancer treatment has remained controversial, especially regarding the long-term outcomes. The aim of this study was to demonstrate whether the laparoscopic technique is feasible. METHODS: We searched all of studies that compared the short- or long-term outcomes regarding laparoscopic and open rectal cancer surgeries (the tumour distance from anal verge within 10 cm). The data sources included PubMed, EMBASE, OVID, Web of Science and the Cochrane Library databases. The combined outcome of the dichotomous variables was expressed as an estimation of the odds ratios and continuous variables were presented in the form of weighted mean differences with 95% credible intervals. Subgroup, publication bias and sensitivity analyses were performed. RESULTS: Thirteen studies met the final inclusion criteria (total n = 3,678). The pooled analyses showed, despite longer operation times, that there were significantly less blood loss, fewer transfusions, shorter times to bowel function recovery, resumed diet and hospital durations, and lower overall complication and wound infection rates. The compared results of the lymph node harvest number, distal resection margin, circumferential resection margin involvement, local and distant recurrences, disease-free survival and overall survival were similar between both groups. CONCLUSIONS: This study suggests that the safety and feasibility of laparoscopic surgery appear to be equivalent to open surgery for treatment of mid- low rectal cancer, with the more favourable short-term benefits, fewer complications, comparable pathological outcomes and long-term outcomes. PMID- 26040856 TI - The Reaction between Bromine and the Water Dimer and the Highly Exothermic Reverse Reaction. AB - The entrance complex, transition state, and exit complex for the bromine atom plus water dimer reaction Br + (H2O)2 -> HBr + (H2O)OH and its reverse reaction have been investigated using the CCSD(T) method with correlation consistent basis sets up to cc-pVQZ-PP. Based on the CCSD(T)/cc-pVQZ-PP results, the reaction is endothermic by 31.7 kcal/mol. The entrance complex Br?(H2O)2 is found to lie 6.5 kcal/mol below the separated reactants. The classical barrier lies 28.3 kcal/mol above the reactants. The exit complex HBr?(H2O)OH is bound by 6.0 kcal/mol relative to the separated products. Compared with the corresponding water monomer reaction Br + H2 O -> HBr + OH, the second water molecule lowers the relative energies of the entrance complex, transition state, and exit complex by 3.0, 3.8, and 3.7 kcal/mol, respectively. Both zero-point vibrational energies and spin orbit coupling effects make significant changes to the above classical energetics. Including both effects, the predicted energies relation to separated Br + (H2O)2 are -3.0 kcal/mol [Br...(H2O)2 ], 28.2 kcal/mol [transition state], 26.4 kcal/mol [HBr...(H2O)OH], and 30.5 kcal/mol [separated HBr + (H2O)OH]. The potential energy surface for the Br + (H2O)2 reaction is related to that for the valence isoelectronic Cl + (H2O)2 system but radically different from the F + (H2O)2 system. PMID- 26040857 TI - Health plan. PMID- 26040859 TI - To pluto. PMID- 26040858 TI - Misplaced faith. PMID- 26040860 TI - Take concepts of chemistry out of the classroom. PMID- 26040872 TI - Scientists blamed for olive-tree ruin. PMID- 26040873 TI - Retracted gay-marriage study debated at misconduct meet-up. PMID- 26040875 TI - Atomic clocks face off. PMID- 26040874 TI - Hawaiian telescopes pruned. PMID- 26040876 TI - MSF takes bigger global-health role. PMID- 26040877 TI - CRISPR, the disruptor. PMID- 26040878 TI - Business: The billion-dollar biotech. PMID- 26040879 TI - Pregnancy: Prepare for unexpected prenatal test results. PMID- 26040881 TI - Q&A: The dinosaur doctor. PMID- 26040883 TI - Genomics: Bird sequencing project takes off. PMID- 26040884 TI - Research reforms: Ukrainian science needs elixir of youth. PMID- 26040885 TI - Seismology: Improve oversight of fracking in China. PMID- 26040886 TI - Research rigour: Use '4Rs' criteria to assess papers. PMID- 26040887 TI - Breast cancer: Diagnostic service shares BRCA data. PMID- 26040888 TI - Astronomy: Pluto leads the way in planet formation. PMID- 26040889 TI - Resonant interactions and chaotic rotation of Pluto's small moons. AB - Four small moons--Styx, Nix, Kerberos and Hydra--follow near-circular, near equatorial orbits around the central 'binary planet' comprising Pluto and its large moon, Charon. New observational details of the system have emerged following the discoveries of Kerberos and Styx. Here we report that Styx, Nix and Hydra are tied together by a three-body resonance, which is reminiscent of the Laplace resonance linking Jupiter's moons Io, Europa and Ganymede. Perturbations by the other bodies, however, inject chaos into this otherwise stable configuration. Nix and Hydra have bright surfaces similar to that of Charon. Kerberos may be much darker, raising questions about how a heterogeneous satellite system might have formed. Nix and Hydra rotate chaotically, driven by the large torques of the Pluto-Charon binary. PMID- 26040890 TI - Greenland supraglacial lake drainages triggered by hydrologically induced basal slip. AB - Water-driven fracture propagation beneath supraglacial lakes rapidly transports large volumes of surface meltwater to the base of the Greenland Ice Sheet. These drainage events drive transient ice-sheet acceleration and establish conduits for additional surface-to-bed meltwater transport for the remainder of the melt season. Although it is well established that cracks must remain water-filled to propagate to the bed, the precise mechanisms that initiate hydro-fracture events beneath lakes are unknown. Here we show that, for a lake on the western Greenland Ice Sheet, drainage events are preceded by a 6-12 hour period of ice-sheet uplift and/or enhanced basal slip. Our observations from a dense Global Positioning System (GPS) network allow us to determine the distribution of meltwater at the ice-sheet bed before, during, and after three rapid drainages in 2011-2013, each of which generates tensile stresses that promote hydro-fracture beneath the lake. We hypothesize that these precursors are associated with the introduction of meltwater to the bed through neighbouring moulin systems (vertical conduits connecting the surface and base of the ice sheet). Our results imply that as lakes form in less crevassed, interior regions of the ice sheet, where water at the bed is currently less pervasive, the creation of new surface-to-bed conduits caused by lake-draining hydro-fractures may be limited. PMID- 26040891 TI - How to catch a cloud. PMID- 26040893 TI - Monoclonal neutralizing antibodies against EV71 screened from mice immunized with yeast-produced virus-like particles. AB - Periodic outbreaks of hand, foot and mouth disease (HFMD) occur in children under 5 years old, and can cause death in some cases. The C4 strain of enterovirus 71 (EV71) is the main pathogen that causes HFMD in China. Although no drugs against EV71 are available, some studies have shown that candidate vaccines or viral capsid proteins can produce anti-EV71 immunity. In this study, female BABL/c mice (6-8 weeks old) were immunized with virus-like particles (VLPs) of EV71 produced in yeast to screen for anti-EV71 antibodies. Two hybridomas that could produce neutralizing antibodies against EV71 were obtained. Both neutralizing mAbs (D4 and G12) were confirmed to bind the VP1 capsid protein of EV71, and could protect >95% cells from 100 TCID50 EV71 infection at 25 ug/mL solution (lowest concentration). Those two neutralizing mAbs identified in the study may be promising candidates in development for mAbs to treat EV71 infection, and utilized as suitable reagents for use in diagnostic tests and biological studies. PMID- 26040894 TI - Bicarbonate transporters in corals point towards a key step in the evolution of cnidarian calcification. AB - The bicarbonate ion (HCO3(-)) is involved in two major physiological processes in corals, biomineralization and photosynthesis, yet no molecular data on bicarbonate transporters are available. Here, we characterized plasma membrane type HCO3(-) transporters in the scleractinian coral Stylophora pistillata. Eight solute carrier (SLC) genes were found in the genome: five homologs of mammalian type SLC4 family members, and three of mammalian-type SLC26 family members. Using relative expression analysis and immunostaining, we analyzed the cellular distribution of these transporters and conducted phylogenetic analyses to determine the extent of conservation among cnidarian model organisms. Our data suggest that the SLC4gamma isoform is specific to scleractinian corals and responsible for supplying HCO3(-) to the site of calcification. Taken together, SLC4gamma appears to be one of the key genes for skeleton building in corals, which bears profound implications for our understanding of coral biomineralization and the evolution of scleractinian corals within cnidarians. PMID- 26040896 TI - Potential therapeutics for myocardial ischemia-reperfusion injury. Focus on "Induction of cardioprotection by small netrin-1-derived peptides". PMID- 26040895 TI - The exocyst gene Sec10 regulates renal epithelial monolayer homeostasis and apoptotic sensitivity. AB - The highly conserved exocyst protein complex regulates polarized exocytosis of subsets of secretory vesicles. A previous study reported that shRNA knockdown of an exocyst central subunit, Sec10 (Sec10-KD) in Madin-Darby canine kidney (MDCK) cells disrupted primary cilia assembly and 3D cyst formation. We used three dimensional collagen cultures of MDCK cells to further investigate the mechanisms by which Sec10 and the exocyst regulate epithelial polarity, morphogenesis, and homeostasis. Sec10-KD cysts initially demonstrated undisturbed lumen formation although later displayed significantly fewer and shorter primary cilia than controls. Later in cystogenesis, control cells maintained normal homeostasis, while Sec10-KD cysts displayed numerous apoptotic cells extruded basally into the collagen matrix. Sec10-KD MDCK cells were also more sensitive to apoptotic triggers than controls. These phenotypes were reversed by restoring Sec10 expression with shRNA-resistant human Sec10. Apico-basal polarity appeared normal in Sec10-KD cysts, whereas mitotic spindle angles differed significantly from controls, suggesting a planar cell polarity defect. In addition, analysis of renal tubules in a newly generated kidney-specific Sec10-knockout mouse model revealed significant defects in primary cilia assembly and in the targeted renal tubules; abnormal epithelial cell extrusion was also observed, supporting our in vitro results. We hypothesize that, in Sec10-KD cells, the disrupted exocyst activity results in increased apoptotic sensitivity through defective primary cilia signaling and that, in combination with an increased basal cell extrusion rate, it affects epithelial barrier integrity and homeostasis. PMID- 26040897 TI - PEDF-derived peptide promotes skeletal muscle regeneration through its mitogenic effect on muscle progenitor cells. AB - In response injury, intrinsic repair mechanisms are activated in skeletal muscle to replace the damaged muscle fibers with new muscle fibers. The regeneration process starts with the proliferation of satellite cells to give rise to myoblasts, which subsequently differentiate terminally into myofibers. Here, we investigated the promotion effect of pigment epithelial-derived factor (PEDF) on muscle regeneration. We report that PEDF and a synthetic PEDF-derived short peptide (PSP; residues Ser(93)-Leu(112)) induce satellite cell proliferation in vitro and promote muscle regeneration in vivo. Extensively, soleus muscle necrosis was induced in rats by bupivacaine, and an injectable alginate gel was used to release the PSP in the injured muscle. PSP delivery was found to stimulate satellite cell proliferation in damaged muscle and enhance the growth of regenerating myofibers, with complete regeneration of normal muscle mass by 2 wk. In cell culture, PEDF/PSP stimulated C2C12 myoblast proliferation, together with a rise in cyclin D1 expression. PEDF induced the phosphorylation of ERK1/2, Akt, and STAT3 in C2C12 myoblasts. Blocking the activity of ERK, Akt, or STAT3 with pharmacological inhibitors attenuated the effects of PEDF/PSP on the induction of C2C12 cell proliferation and cyclin D1 expression. Moreover, 5-bromo 2'-deoxyuridine pulse-labeling demonstrated that PEDF/PSP stimulated primary rat satellite cell proliferation in myofibers in vitro. In summary, we report for the first time that PSP is capable of promoting the regeneration of skeletal muscle. The signaling mechanism involves the ERK, AKT, and STAT3 pathways. These results show the potential utility of this PEDF peptide for muscle regeneration. PMID- 26040899 TI - Liraglutide Activates AMPK Signaling and Partially Restores Normal Circadian Rhythm and Insulin Secretion in Pancreatic Islets in Diabetic Mice. AB - beta-Cell insufficiency plays an important role in the development of diabetes. Environmental factors, including lifestyle, play a critical role in beta-cell dysfunction. Modern lifestyles affect the inherent circadian clock in central and peripheral organs. Recent studies have demonstrated that the normal intrinsic circadian clock in islets was essential for the viability of beta cells and their insulin secretory function. Overall, however, the data are inconclusive. Our study demonstrated that the disrupted circadian rhythm of islets in streptozotocin induced type1 diabetic mice may be associated with impaired beta cell function and glucose intolerance. Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, could partially restore the normal circadian rhythm and activate the 5' AMP-activated protein kinase (AMPK) signaling pathway. Our study provided evidence demonstrating that Liraglutide might restore beta-cell function and protect against the development of diabetes in a mouse model by attenuating the disruption of the intrinsic circadian rhythm in islets and by activating AMPK signaling. PMID- 26040898 TI - Role of nitric oxide in murine conventional outflow physiology. AB - Elevated intraocular pressure (IOP) is the main risk factor for glaucoma. Exogenous nitric oxide (NO) decreases IOP by increasing outflow facility, but whether endogenous NO production contributes to the physiological regulation of outflow facility is unclear. Outflow facility was measured by pressure-controlled perfusion in ex vivo eyes from C57BL/6 wild-type (WT) or transgenic mice expressing human endothelial NO synthase (eNOS) fused to green fluorescent protein (GFP) superimposed on the endogenously expressed murine eNOS (eNOS GFPtg). In WT mice, exogenous NO delivered by 100 MUM S-nitroso-N acetylpenicillamine (SNAP) increased outflow facility by 62 +/- 28% (SD) relative to control eyes perfused with the inactive SNAP analog N-acetyl-d-penicillamine (NAP; n = 5, P = 0.016). In contrast, in eyes from eNOS-GFPtg mice, SNAP had no effect on outflow facility relative to NAP (-9 +/- 4%, P = 0.40). In WT mice, the nonselective NOS inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 10 MUM) decreased outflow facility by 36 +/- 13% (n = 5 each, P = 0.012), but 100 MUM l NAME had no detectable effect on outflow facility (-16 +/- 5%, P = 0.22). An eNOS selective inhibitor (cavtratin, 50 MUM) decreased outflow facility by 19 +/- 12% in WT (P = 0.011) and 39 +/- 25% in eNOS-GFPtg (P = 0.014) mice. In the conventional outflow pathway of eNOS-GFPtg mice, eNOS-GFP expression was localized to endothelial cells lining Schlemm's canal and the downstream vessels, with no apparent expression in the trabecular meshwork. These results suggest that endogenous NO production by eNOS within endothelial cells of Schlemm's canal or downstream vessels contributes to the physiological regulation of aqueous humor outflow facility in mice, representing a viable strategy to more successfully lower IOP in glaucoma. PMID- 26040900 TI - Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer. AB - Angiogenesis, a crucial step in tumor growth and metastasis, is regulated by various pro- or anti-angiogenic factors. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, roles of tumor-derived microRNAs in regulating tumor vascularization remain to be elucidated. In this study, we found that delivery of miR-494 into human vascular endothelial cells (ECs) enhanced the EC migration and promoted angiogenesis. The angiogenic effect of miR-494 was mediated by the targeting of PTEN and the subsequent activation of Akt/eNOS pathway. Importantly, co-culture experiments demonstrated that a lung cancer cell line, A549, secreted and delivered miR-494 into ECs via a microvesicle-mediated route. In addition, we found that the expression of miR-494 was induced in the tumor cells in response to hypoxia, likely via a HIF-1alpha-mediated mechanism. Furthermore, a specific miR-494 antagomiR effectively inhibited angiogenesis and attenuated the growth of tumor xenografts in nude mice. Taken together, these results demonstrated that miR-494 is a novel tumor-derived paracrine signal to promote angiogenesis and tumor growth under hypoxic condition. PMID- 26040901 TI - Introduction for the Special Issue of METHODS on Detection and quantification of proteins in clinical samples by mass spectrometry. PMID- 26040902 TI - Omega-3 polyunsaturated fatty acid supplementation and cognition: A systematic review and meta-analysis. AB - BACKGROUND: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are promoted as cognitive enhancers with consumption recommended in the general population and those with neurocognitive deficits such as attention deficit hyperactivity disorder (ADHD). However, evidence from randomised placebo-controlled trials is inconclusive. AIMS: This study aimed to conduct a systematic review and meta analysis examining the effect of n-3 PUFA supplementation on cognition in healthy populations and those with ADHD and related disorders (RDs). METHODS: Databases were searched for randomised controlled trials (RCTs) in adults and school-aged children (who were healthy and typically developing (TD) or had ADHD or a related neurodevelopmental disorder (ADHD+RD) which assessed the effects of n-3 PUFA on cognition. RESULTS: In the 24 included studies n-3 PUFA supplementation, in the whole sample and the TD and ADHD+RD subgroup, did not show improvements in any of the cognitive performance measures. In those with low n-3 PUFA status, supplementation improved short-term memory. CONCLUSIONS: There is marginal evidence that n-3 PUFA supplementation effects cognition in those who are n-3 PUFA deficient. However, there is no evidence of an effect in the general population or those with neurodevelopmental disorders. This has important implications given the widespread advertisement and consumption of n-3 PUFA; claims of cognitive benefit should be narrowed. PMID- 26040903 TI - Olanzapine and risperidone plasma concentration therapeutic drug monitoring: A feasibility study. AB - BACKGROUND: This study aimed to develop a clinically acceptable method of therapeutic drug monitoring (TDM) for olanzapine and risperidone and to evaluate the feasibility of its implementation. METHOD: A non-randomised study of inpatients from five Mental Health Trusts was conducted, with a clinical interview at the time of TDM and a subsequent 6-week follow-up review of clinical notes. The TDM intervention comprised: (a) a venous blood sample taken 12 hours post-dose, 7-10 days after drug initiation, and (b) rapid results feedback, with interpretation algorithm guidance. RESULTS: Thirty-two participants provided samples (19 prescribed olanzapine, 13 risperidone). Twenty-six participants remained on the target drug at study end, with seven experiencing a dose change, for whom only four of the TDM results were confirmed as having been checked. Mean dose increased for olanzapine (0.9 mg/day, range 0-10) and decreased for risperidone (-0.3 mg/day, range -4-3). CONCLUSION: TDM can be implemented as part of routine clinical practice for both drugs. However, the lack of robust supporting evidence for or against antipsychotic TDM has probably led to a lack of enthusiasm for and interest in the results. Nevertheless, the advent of less invasive measures and the targeting of patients who might be more likely to benefit may facilitate uptake. PMID- 26040904 TI - miR-29c in urinary exosomes as predictor of early renal fibrosis in lupus nephritis. AB - BACKGROUND: Despite overall improvement in prognosis, 10-30% of patients with lupus nephritis (LN) will develop end-stage renal disease. To date, renal biopsy is still the 'gold standard' test used to predict renal outcome. However, due to its invasive nature, new non-invasive biomarkers are required. Urinary exosomes, microvesicles released by every epithelial cell facing the urinary space, represent an ideal source of markers for renal dysfunction and injury. Here, we sought to evaluate miR-29c expression levels in urinary exosomes as a novel biomarker of renal fibrosis in LN. METHODS: Urinary exosomes were isolated from 32 samples of patients with biopsy-proven LN, 15 non-lupus chronic kidney diseases and 20 healthy controls. Electronic microscopy and western blot were used to characterize the exosomes. Expression levels of miR-29c were detected by RT-PCR quantitative and correlated with clinical and histological parameters along with the expression levels of Smad2/3, TGF-beta and MMP2/9. For comparison, miRNA expression was also evaluated in the urinary pellet. RESULTS: MiR-29c levels in urinary exosomes showed a negatively strong correlation with the histological chronicity index (r = -0.898, P = 0.001) and glomerular sclerosis (r = -0.555, P = 0.007). No correlation with eGFR and creatinine levels was found. MiR-29c expression levels could predict the degree of chronicity in patients with LN with an area under the curve (AUC) of 0.946 (P < 0.001) and with high sensitivity and specificity (94% and 82%). Smad3 and MMP2 expression in urinary exosomes correlated negatively with miR-29c expression (r = -0.737 and -0.856, respectively). In the urinary pellet, no miR-29c expression was detected; however, upregulation of Smad3 and MMP2 was observed (3.54- and 5.85-fold increase). CONCLUSIONS: Overall, miR-29c correlated with the degree of renal chronicity but not with renal function, suggesting it could be used as a novel non-invasive marker of early progression to fibrosis in patients with LN. PMID- 26040905 TI - Factors influencing incidental representation of previously unknown conservation features in marine protected areas. AB - Spatially explicit information on species distributions for conservation planning is invariably incomplete; therefore, the use of surrogates is required to represent broad-scale patterns of biodiversity. Despite significant interest in the effectiveness of surrogates for predicting spatial distributions of biodiversity, few researchers have explored questions involving the ability of surrogates to incidentally represent unknown features of conservation interest. We used the Great Barrier Reef marine reserve network to examine factors affecting incidental representation of conservation features that were unknown at the time the reserve network was established. We used spatially explicit information on the distribution of 39 seabed habitats and biological assemblages and the conservation planning software Marxan to examine how incidental representation was affected by the spatial characteristics of the features; the conservation objectives (the minimum proportion of each feature included in no take areas); the spatial configuration of no-take areas; and the opportunity cost of conservation. Cost was closely and inversely correlated to incidental representation. However, incidental representation was achieved, even in a region with only coarse-scale environmental data, by adopting a precautionary approach that explicitly considered the potential for unknown features. Our results indicate that incidental representation is enhanced by partitioning selection units along biophysical gradients to account for unknown within-feature variability and ensuring that no-take areas are well distributed throughout the region; by setting high conservation objectives that (in this case >33%) maximize the chances of capturing unknown features incidentally; and by carefully considering the designation of cost to planning units when using decision-support tools for reserve design. The lessons learned from incidental representation in the Great Barrier Reef have implications for conservation planning in other regions, particularly those that lack detailed environmental and ecological data. PMID- 26040906 TI - Probing ferroic transitions in a multiferroic framework family: a neutron diffraction study of the ammonium transition metal formates. AB - This study probes the magnetic and ferroelectric ordering of the NH4M(HCO2)3 (M = Mn(2+), Fe(2+), Co(2+) and Ni(2+)) frameworks using neutron diffraction, improving the understanding of the origins of the properties of these fascinating multiferroics. This rare study of the magnetic structure of a family of metal organic frameworks shows that all four compounds exhibit antiferromagnetic coupling between neighbouring cations bridged by formate ligands. The orientation of the spin, however, changes in a highly unusual way across the series with the spins aligned along the c-axis for the Fe(2+) and Ni(2+) frameworks but lying in the ab plane for the other members of the series. This work also sheds new light on the nature of the ferroelectric order-disorder transition in these materials; probing changes in the ammonium cation across the transition and also shows that the Ni(2+) framework does not undergo a transition to the polar P63 phase due to the smaller size of the Ni(2+) cation. Finally trends in their anisotropic negative thermal expansion, which potentially enhances their ferroic behaviour, are quantified. PMID- 26040907 TI - First-Line Antimicrobial Resistance Patterns of Escherichia coli in Children With Urinary Tract Infection in Emergency Department and Primary Care Clinics. AB - OBJECTIVE: To identify risk factors for antibiotic resistance to Escherichia coli (E. coli) in children with urinary tract infections (UTIs) in emergency room and primary care clinics. METHOD: This is a cross-sectional study of children 0 to 18 years of age reported to have E coli-positive UTIs whose medical and laboratory records were systematically reviewed. RESULT: Compared with girls, boys were 2.29 times (confidence interval [CI] = 1.30-4.02) more likely to have E coli isolates resistant to ampicillin and 2 times more likely (CI = 1.13-3.62) to have isolates resistant to trimethoprim-sulfamethoxazole (TMP/SMX). Patients with genitourinary abnormalities were 1.57 times more likely to be resistant to ampicillin (CI = 1.03-2.41) and 1.86 times to TMP/SMX (CI = 1.18-2.94). CONCLUSION: Higher rates of ampicillin and TMP/SMX resistant urinary E coli isolates were observed among boys and children with a history of genitourinary abnormality. Age and recent antibiotic prescription are also potential risk factors for resistance. PMID- 26040908 TI - Effect of potassium present in stratum corneum during non-invasive measurement of potassium in human subjects using reverse iontophoresis. AB - PURPOSE: Reverse iontophoresis (RI) is one of the potential techniques used to monitor the concentration of various analytes in body fluids non-invasively. Transdermal extraction of potassium is investigated using RI. In the present work, the effect of potassium on stratum corneum (SC) during RI, feasibility of RI for continuous monitoring of potassium, and use of potassium as internal standard in RI, are investigated. METHODS: Tape stripping experiment is carried out to find potassium concentration in SC. RI is carried out continuously for 180 min without passive diffusion and after passive diffusion for 60 min. Skin impedance measurements are done at 20 Hz and 20 kHz. RESULTS: Potassium is found to be in the range 300-650 nmol/cm(2) on SC by tape stripping experiment. Correlation coefficient between blood potassium and extracted potassium through RI after passive diffusion (R(2) = 0.5870) is more than without passive diffusion (R(2) = 0.5117). The skin impedance measurement shows that RI has more effect on SC than superficial layer of SC during RI. CONCLUSION: The present investigations conclude that it is possible to monitor potassium continuously through RI and using potassium as internal standard in RI. PMID- 26040909 TI - Glycosylated Benzoxazinoids Are Degraded during Fermentation of Wheat Bran. AB - Benzoxazinoids are plant secondary metabolites found in whole grain cereal foods including bread. They are bioavailable and metabolized in humans, and therefore their potential bioactivity is of interest. However, effects of food processing on their content and structure are not yet studied. This study reports effects of bioprocessing on wheat bran benzoxazinoid content. Benzoxazinoid glycosides were completely degraded during fermentation, whereas metabolites of benzoxazinoid aglycones were formed. Fermentation conditions did not affect the conversion process, as both yeast and yeast/lactic acid bacteria mediated fermentations had generally similar impacts. Likewise, enzymatic treatment of the bioprocess samples did not affect the conversion, suggesting that these compounds most likely are freely bioavailable from the grain matrix and not linked to the cell wall polymers. Additionally, the results show that benzoxazinoids undergo structural conversion during the fermentation process, resulting in several unknown compounds that contribute to the phytochemical intake and necessitate further analysis. PMID- 26040910 TI - Discriminative variable subsets in Bayesian classification with mixture models, with application in flow cytometry studies. AB - We discuss the evaluation of subsets of variables for the discriminative evidence they provide in multivariate mixture modeling for classification. The novel development of Bayesian classification analysis presented is partly motivated by problems of design and selection of variables in biomolecular studies, particularly involving widely used assays of large-scale single-cell data generated using flow cytometry technology. For such studies and for mixture modeling generally, we define discriminative analysis that overlays fitted mixture models using a natural measure of concordance between mixture component densities, and define an effective and computationally feasible method for assessing and prioritizing subsets of variables according to their roles in discrimination of one or more mixture components. We relate the new discriminative information measures to Bayesian classification probabilities and error rates, and exemplify their use in Bayesian analysis of Dirichlet process mixture models fitted via Markov chain Monte Carlo methods as well as using a novel Bayesian expectation-maximization algorithm. We present a series of theoretical and simulated data examples to fix concepts and exhibit the utility of the approach, and compare with prior approaches. We demonstrate application in the context of automatic classification and discriminative variable selection in high-throughput systems biology using large flow cytometry datasets. PMID- 26040911 TI - Modelling the effect of antimicrobial treatment on carriage of hospital pathogens with application to MRSA. AB - Numerous studies have sought to assess the effectiveness of control measures aimed at reducing the spread of pathogens such as Methicillin-resistant Staphylococcus aureus (MRSA) in hospital settings. Far less is known about possible short-term effects of antibiotics and other antimicrobial treatments on pathogen carriage in patients. This paper is concerned with developing and applying methods for the analysis of detailed data on hospital patients which include information on patient treatments and screening tests for the pathogen in question. The carriage status (colonized, or not) of each patient is modelled as a Markov chain, and models for both perfect and imperfect test sensitivity are developed. Goodness-of-fit procedures based on simulation are also proposed. The methods are illustrated using both simulated data and data on MRSA. PMID- 26040912 TI - The projack: a resampling approach to correct for ranking bias in high-throughput studies. AB - The problem of ranked inference arises in a number of settings, for which the investigator wishes to perform parameter inference after ordering a set of [Formula: see text] statistics. In contrast to inference for a single hypothesis, the ranking procedure introduces considerable bias, a problem known as the "winner's curse" in genetic association. We introduce the projack (for Prediction by Re- Ordered Jackknife and Cross-Validation, [Formula: see text]-fold). The projack is a resampling-based procedure that provides low-bias estimates of the expected ranked effect size parameter for a set of possibly correlated [Formula: see text] statistics. The approach is flexible, and has wide applicability to high-dimensional datasets, including those arising from genomics platforms. Initially, motivated for the setting where original data are available for resampling, the projack can be extended to the situation where only the vector of [Formula: see text] values is available. We illustrate the projack for correction of the winner's curse in genetic association, although it can be used much more generally. PMID- 26040913 TI - Zooming into the binding groove of HLA molecules: which positions and which substitutions change peptide binding most? AB - Human leukocyte antigen (HLA) genes are the most polymorphic genes in the human genome. Almost all polymorphic residues are located in the peptide-binding groove, resulting in different peptide-binding preferences. Whether a single amino acid change can alter the peptide-binding repertoire of an HLA molecule has never been shown. To experimentally quantify the contribution of a single amino acid change to the peptide repertoire of even a single HLA molecule requires an immense number of HLA peptide-binding measurements. Therefore, we used an in silico method to study the effect of single mutations on the peptide repertoires. We predicted the peptide-binding repertoire of a large set of HLA molecules and used the overlap of the peptide-binding repertoires of each pair of HLA molecules that differ on a single position to measure how much single substitutions change the peptide binding. We found that the effect of a single substitution in the peptide-binding groove depends on the substituted position and the amino acids involved. The positions that alter peptide binding most are the most polymorphic ones, while those that are hardly variable among HLA molecules have the lowest effect on the peptide repertoire. Although expected, the relationship between functional divergence and polymorphism of HLA molecules has never been shown before. Additionally, we show that a single substitution in HLA-B molecules has more effect on the peptide-binding repertoire compared to that in HLA-A molecules. This provides an (alternative) explanation for the larger polymorphism of HLA-B molecules compared to HLA-A molecules. PMID- 26040914 TI - Improved Treatment Satisfaction and Self-reported Health Status after Introduction of Basal-Supported Oral Therapy Using Insulin Glargine in Patients with Type 2 Diabetes: Sub-Analysis of ALOHA2 Study. AB - INTRODUCTION: This study aimed to assess treatment satisfaction and self-reported health status in insulin-naive patients with type 2 diabetes mellitus (T2DM) who started insulin glargine basal-supported oral therapy (BOT) with glycated hemoglobin (HbA1c) value of >=6.5%, using data from Add-on Lantus((r)) to Oral Hypoglycemic Agents 2 (ALOHA2) study, a 24-week single-arm, observational study of Japanese patients with T2DM, conducted as drug use surveillance in Japan. METHODS: Treatment satisfaction was measured using the Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) and change version (DTSQc) and self-reported health status using EuroQol 5 Dimension (EQ-5D). The results were compared between the groups stratified by HbA1c level at the final evaluation point: target-achieved (<7.0%) and target-not-achieved groups (>=7.0%). RESULTS: In 1251 patients (336 in the target-achieved group), scores of DTSQs, DTSQc, and EQ-5D indicated significant improvement from baseline to the final evaluation point (both P < 0.01). The mean change in DTSQs scale score, DTSQs item score, and EQ-5D index score, and mean DTSQc scale score were significantly improved in the target-achieved group compared with the target-not-achieved group (P < 0.05 for all). DTSQs scale score and HbA1c level showed the same pattern of chronological change. Data analysis in patients stratified by DTSQs score showed better glycemic control in the high satisfaction group. CONCLUSION: Following insulin glargine BOT introduction, treatment satisfaction and health status were improved from patients' perspectives despite the need for daily injections. Based on the possible association between HbA1c 7.0% level achievement, treatment satisfaction, and health status, better glycemic control may be a key to successful treatment. PMID- 26040915 TI - Association of herbal and dietary supplements with progression and complications of chronic kidney disease: A prospective cohort study. AB - AIM: To determine associations between herbal and dietary supplement (HDS) use and the progression of chronic kidney disease (CKD), and associations of HDS with uncontrolled hyperphosphataemia in patients with CKD. METHOD: The cohort study recruited 406 Thai outpatients with stage 3-5 CKD from two kidney clinics of which 357 were followed up over 12 months. Patients receiving renal replacement therapy prior to recruitment were excluded. Participants were interviewed regarding their HDS use, dietary intake and conventional medication adherence using a questionnaire. The primary outcome was a composite of a decline of at least 5 mL/min per 1.73 m2 per year of estimated glomerular filtration rate and end stage renal disease. Serum creatinine, serum levels of potassium and phosphate were extracted from their medical notes over the 12 months. chi2 tests and multiple logistic regression analyses were performed to ascertain any associations. RESULTS: Despite no association between HDS and the progression of CKD over a one-year period (adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 0.66-2.03), two patients had acute kidney injury, which may be related to an unknown Chinese herbal medicine, or river spiderwort combined with diclofenac reported in the medical notes. The use of HDS was associated with uncontrolled hyperphosphataemia (adjusted OR 3.53, 95%CI 1.20-10.43). CONCLUSIONS: The findings suggest that HDS are likely to be related to acute kidney injury rather than the progression of CKD in Thai patients with CKD. The products were associated with uncontrolled hyperphosphataemia. Patients who have CKD and use HDS should be closely monitored regarding their kidney function and electrolytes. PMID- 26040916 TI - Meta-Analysis Methods to Estimate the Shape and Uncertainty in the Association Between Long-Term Exposure to Ambient Fine Particulate Matter and Cause-Specific Mortality Over the Global Concentration Range. AB - Estimates of excess mortality associated with exposure to ambient concentrations of fine particulate matter have been obtained from either a single cohort study or pooling information from a small number of studies. However, standard frequentist methods of pooling are known to underestimate statistical uncertainty in the true risk distribution when the number of studies pooled is small. Alternatively, Bayesian pooling methods using noninformative priors yield unrealistically large amounts of uncertainty in this case. We present a new hybrid frequentist-bayesian framework for meta-analysis that incorporates features of both frequentist and Bayesian approaches, yielding estimated uncertainty distributions that are more useful for burden estimation. We also present an example of mortality risk due to long-term exposure to ambient fine particulate matter obtained from a small number of cohort studies conducted in the United States and Europe. We compare our new risk uncertainty distribution to that obtained by the integrated exposure-response (IER) model used in the Global Burden of Disease 2010 project for which risk was modeled over the entire global concentration range. We suggest a method to incorporate our new risk uncertainty distribution based on the relatively low concentrations observed in the United States and western Europe into the IER model, thus extending risk estimation to the global concentration range. PMID- 26040917 TI - Physical activity and sedentary behaviour among Asian and Anglo-Australian adolescents. AB - ISSUE ADDRESSED: Evidence suggests that physical activity (PA) and sedentary behaviour (SB) participation varies among culturally and linguistically diverse (CALD) adolescents. The present study examined differences in PA and SB among a CALD sample of Chinese Australian, South-east Asian and Anglo-Australian adolescents. METHODS: Data from 286 adolescents aged 12-16 years involved in the Chinese and Australian Adolescent Health Survey in metropolitan Melbourne, Australia, were analysed. Accelerometry outcomes included median activity counts per minute (counts x min(-1)) and minutes per day (min x day(-1)) spent in light intensity PA (LPA), moderate-to-vigorous-intensity PA (MVPA) and sedentary time (ST). Kruskal-Wallis one-way analysis of variance and sequential multiple hierarchical linear regressions were used to examine CALD differences in PA and ST. RESULTS: Multivariate analyses of accelerometry data found Chinese Australian and South-east Asian adolescents engaged in significantly less daily MVPA (5-8 min x day(-1)) and LPA (50-58 min x day(-1); P < 0.05), but greater daily ST (40 41 min x day(-1)), than Anglo-Australian adolescents, after adjusting for age, gender and socioeconomic category. CONCLUSION: The results demonstrate lower engagement in daily MVPA and LPA and greater engagement in ST using accelerometry among Chinese Australian and South-east Asian adolescents compared with Anglo Australian adolescents. These findings have important public health implications in furthering our understanding of CALD differences in PA and SB. SO WHAT? An understanding of the CALD differences in physical activity and sedentary behaviour among Australian adolescents has important implications for intervention planning and delivery as well as the wider health implications of these behaviours. This article furthers the current understanding of CALD adolescents' participation in physical activity and sedentary behaviour, of which limited information is available. PMID- 26040918 TI - A patient with urinary tract tuberculosis during treatment with etanercept. AB - BACKGROUND: Tumor necrosis factor (TNF)-alpha inhibitors are widely used for rheumatoid arthritis (RA). However, there are several risks to use TNFalpha inhibitors. Given the properties of TNF-alpha inhibitors, prevention and early detection of tuberculosis (TB) are especially important. Even among TNF-alpha inhibitors, the risk of TB infection differs according to each drug. The incidence of TB is lowest with etanercept (ETN). We present a case of urinary tract TB during treatment with ETN. CASE REPORT: A 58-year-old woman was receiving ETN for RA. Before starting ETN, isoniazid (INH) prophylaxis was started. RA was well controlled by ETN. However, 32 months after starting ETN, she noticed urinary frequency and a sensation of residual urine. The diagnosis was elusive, and it took 3 months until urinary tract TB was finally diagnosed. The TB resolved with antituberculosis medication, but RA disease activity flared up after ETN was discontinued. ETN was resumed with careful monitoring for TB recurrence. After resuming ETN, the RA was again well controlled, with no recurrence of TB. CONCLUSIONS: Patients should be monitored for development of TB during ETN treatment, but ETN can be used safely with careful management. PMID- 26040920 TI - Effect of gastric lavage on feeding in neonates born through meconium-stained liquor: a systematic review. AB - OBJECTIVE: To evaluate the efficacy and safety of gastric lavage (GL) in neonates born through meconium-stained liquor (MSL). DESIGN: A systematic review of randomised controlled trials by searching databases MEDLINE (from 1966), EMBASE (from1980), CINAHL, Cochrane Central Register of Controlled Trials, Google Scholar and proceedings of Pediatric Academic Society meetings (2002-2014). SETTING: Delivery room/Neonatal ward. PATIENTS: Neonates with gestation >34 weeks and birth weight >=1800 g born through MSL. INTERVENTIONS: Prophylactic GL versus no intervention before first feed. MAIN OUTCOME MEASURE: Feeding intolerance, defined as inability to initiate/upgrade feeds due to problems such as retching, vomiting, regurgitation and gastric residuals. RESULTS: A total of six studies (GL: 918, no GL: 966) were included in the review. Meta-analysis using fixed effects model showed decreased incidence of feed intolerance following GL ((81/918 (8.8%) vs 114/966 (11.8%); risk ratio (RR): 0.71 (95% CI 0.55 to 0.93)). However, the results were not significant when random-effects model was used (RR: 0.78 (95% CI 0.55 to 1.09)). No significant adverse effects of GL were reported. CONCLUSIONS: Routine GL immediately after birth may improve feed tolerance in neonates born through MSL. However, the evidence is limited, with probable small study bias and high risk of bias in a number of the included studies. Well designed studies with adequate sample size are essential to confirm these findings. PMID- 26040919 TI - Genetic variation in the adenosine regulatory cycle is associated with posttraumatic epilepsy development. AB - OBJECTIVE: Determine if genetic variation in enzymes/transporters influencing extracellular adenosine homeostasis, including adenosine kinase (ADK), [ecto-5' nucleotidase (NT5E), cluster of differentiation 73 (CD73)], and equilibrative nucleoside transporter type-1 (ENT-1), is significantly associated with epileptogenesis and posttraumatic epilepsy (PTE) risk, as indicated by time to first seizure analyses. METHODS: Nine ADK, three CD73, and two ENT-1 tagging single nucleotide polymorphisms (SNPs) were genotyped in 162 white adults with moderate/severe traumatic brain injury (TBI) and no history of premorbid seizures. Kaplan-Meier models were used to screen for genetic differences in time to first seizure occurring >1 week post-TBI. SNPs remaining significant after correction for multiple comparisons were examined using Cox proportional hazards analyses, adjusting for subdural hematoma, injury severity score, and isolated TBI status. SNPs significant in multivariate models were then entered simultaneously into an adjusted Cox model. RESULTS: Comparing Kaplan-Meier curves, rs11001109 (ADK) rare allele homozygosity and rs9444348 (NT5E) heterozygosity were significantly associated with shorter time to first seizure and an increased seizure rate 3 years post-TBI. Multivariate Cox proportional hazard models showed that these genotypes remained significantly associated with increased PTE hazard up to 3 years post-TBI after controlling for variables of interest (rs11001109: hazard ratio (HR) 4.47, 95% confidence interval (CI) 1.27 15.77, p = 0.020; rs9444348: HR 2.95, 95% CI 1.19-7.31, p = 0.019) . SIGNIFICANCE: Genetic variation in ADK and NT5E may help explain variability in time to first seizure and PTE risk, independent of previously identified risk factors, after TBI. Once validated, identifying genetic variation in adenosine regulatory pathways relating to epileptogenesis and PTE may facilitate exploration of therapeutic targets and pharmacotherapy development. PMID- 26040921 TI - Pseudocarcinomatous hyperplasia in anaplastic large cell lymphoma, a mimicker of poorly differentiated squamous cell carcinoma: report of a case and review of the literature. AB - Pseudocarcinomatous hyperplasia can occasionally be observed in biopsies of CD30 positive lymphoproliferative disorders. It is important to be cognizant of this association, because epithelial hyperproliferation can overshadow large atypical lymphoid cells, leading to an erroneous diagnosis of squamous cell carcinoma (SCC) or keratoacanthoma. Herein, we present a case of anaplastic large cell lymphoma (ALCL) with pseudocarcinomatous hyperplasia simulating a poorly differentiated carcinoma and review the literature on this subject. Immunohistochemical staining with p63 helped delineate the infiltrating tongues of pseudocarcinomatous hyperplasia from the malignant infiltrate. We present this case to raise awareness of the potential for pseudocarcinomatous hyperplasia to occur in the setting of CD30+ lymphoproliferative disorders. Clinicians and dermatopathologists should consider the possibility of ALCL or lymphomatoid papulosis when examining lesions with features of inflamed SCC, especially if the tumor presents on a site or in a patient that is not typical of SCC. PMID- 26040922 TI - A RP-UFLC Assay for Protein Tyrosine Phosphatases: Focus on Protein Tyrosine Phosphatase Non-Receptor Type 2 (PTPN2). AB - Protein tyrosine phosphatases (PTPs) are involved in numerous signaling pathways and dysfunctions of certain of these enzymes have been linked to several human diseases including cancer and autoimmune diseases. PTPN2 is a PTP mainly expressed in hematopoietic cells and involved in growth factor and JAK/STAT signaling pathways. Loss of function analyses in patients with mutation/deletion of the PTPN2 gene and knock-out mouse models indicate that PTPN2 acts as a tumor suppressor in T-cell malignancies and as a regulator of inflammation and immunity. The use of sensitive and quantitative assays is of prime importance to better characterize the biochemical properties of PTPN2 and its biological roles. We report a highly sensitive non-radioactive assay that allows the measurement of the activity of purified PTPN2 and of endogenous PTPN2 immunoprecipitated on agarose beads. The assay relies on separation and quantitation by reverse-phase ultra fast liquid chromatography (RP-UFLC) of a fluorescein-labeled phosphotyrosine peptide substrate derived from the sequence of STAT1. The applicability and reliability of this approach is supported by kinetic and mechanistic studies using PTP inhibitors. More broadly, our PTPN2 assay provides the basis for the design of flexible methods for the measurement of other PTPs. PMID- 26040924 TI - Elimination of strength degrading effects caused by surface microdefect: A prevention achieved by silicon nanotexturing to avoid catastrophic brittle fracture. AB - The unavoidable occurrence of microdefects in silicon wafers increase the probability of catastrophic fracture of silicon-based devices, thus highlighting the need for a strengthening mechanism to minimize fractures resulting from defects. In this study, a novel mechanism for manufacturing silicon wafers was engineered based on nanoscale reinforcement through surface nanotexturing. Because of nanotexturing, different defect depths synthetically emulated as V notches, demonstrated a bending strength enhancement by factors of 2.5, 3.2, and 6 for 2-, 7-, and 14-MUm-deep V-notches, respectively. A very large increase in the number of fragments observed during silicon fracturing was also indicative of the strengthening effect. Nanotextures surrounding the V-notch reduced the stress concentration factor at the notch tip and saturated as the nanotexture depth approached 1.5 times the V-notch depth. The stress reduction at the V-notch tip measured by micro-Raman spectroscopy revealed that nanotextures reduced the effective depth of the defect. Therefore, the nanotextured samples were able to sustain a larger fracture force. The enhancement in Weibull modulus, along with an increase in bending strength in the nanotextured samples compared to polished single-crystal silicon samples, demonstrated the reliability of the strengthening method. These results suggest that this method may be suitable for industrial implementation. PMID- 26040925 TI - Surface-promoted aggregation of amphiphilic quadruplex ligands drives their selectivity for alternative DNA structures. AB - Scientists are currently truly committed to enhance the specificity of chemotherapeutics that target DNA. To this end, sequence-specific drugs have progressively given way to structure-specific therapeutics. However, while numerous strategies have been implemented to design high-affinity candidates, strategies devoted to the design of high-selectivity ligands are still rare. Here we report on such an approach via the study of an amphiphilic compound, TEGPy, that self-assembles at a liquid/solid interface to provide nanosized objects that are stable in water. The resulting aggregates, identified through atomic force microscopy measurements, were found to disassemble upon interaction with DNA in a structure-specific manner (quadruplex- versus duplex-DNA). Our results provide a fertile ground for devising new strategies aiming at concomitantly enhancing DNA structural specificity and the water-solubility of aggregation-prone ligands. PMID- 26040926 TI - National cancer intelligence network cancer outcomes conference 2015, 8-10 june 2015, europa hotel, belfast. PMID- 26040927 TI - Conference and issue details. PMID- 26040923 TI - Behavioral and neurodevelopmental precursors to binge-type eating disorders: support for the role of negative valence systems. AB - BACKGROUND: Pediatric loss-of-control (LOC) eating is a robust behavioral precursor to binge-type eating disorders. Elucidating precursors to LOC eating and binge-type eating disorders may refine developmental risk models of eating disorders and inform interventions. METHOD: We review evidence within constructs of the Negative Valence Systems (NVS) domain, as specified by the Research Domain Criteria framework. Based on published studies, we propose an integrated NVS model of binge-type eating-disorder risk. RESULTS: Data implicate altered corticolimbic functioning, neuroendocrine dysregulation, and self-reported negative affect as possible risk factors. However, neuroimaging and physiological data in children and adolescents are sparse, and most prospective studies are limited to self-report measures. CONCLUSIONS: We discuss a broad NVS framework for conceptualizing early risk for binge-type eating disorders. Future neural and behavioral research on the developmental trajectory of LOC and binge-type eating disorders is required. PMID- 26040928 TI - Does previous chemotherapy-induced nausea and vomiting predict postoperative nausea and vomiting? AB - BACKGROUND: Postoperative nausea and vomiting (PONV) remains a problem in the postoperative period. Previous PONV in oncology patients has recently been associated with chemotherapy-induced nausea and vomiting (CINV). We assessed if CINV could improve Apfel's heuristic for predicting PONV. METHODS: We conducted a retrospective study of 1500 consecutive patients undergoing intermediate or major cancer surgery between April and July 2011. PONV was assessed in the first postoperative day during post-anaesthesia care. The assigned anaesthetist completed an electronic medical record with all of the studied variables. Multiple logistic regression analyses were performed to assess whether any of the variables could add predictive ability to Apfel's tallying heuristic, and receiver operating characteristic (ROC) curves were modelled. The areas under the curve (AUC) were used to compare the model's discriminating ability for predicting patients who vomited from those who did not vomit. RESULTS: The overall incidence of PONV was 26%. Multiple logistic regressions identified two independent predictors for PONV (odds ratio; 95% CI), Apfel's score (1.78; 1.23 2.63) and previous chemotherapy-induced vomiting (3.15; 1.71-5.9), Hosmer Lemeshow's P < 0.0001. Previous CINV was the most significant predictor to be added to Apfel's heuristic in this population. CONCLUSIONS: A history of chemotherapy-induced nausea vomiting was a strong predictor for PONV and should be investigated as an added risk factor for PONV in the preoperative period of oncology surgery in prospective studies. PMID- 26040929 TI - Masked hypertension in extremely preterm adolescents. AB - AIM: Extremely preterm (EPT, born <28 weeks gestation) or extremely low birthweight (ELBW, birthweight <1000 g) individuals are at increased risk of high blood pressure (BP) and cardiovascular disease. We compared office BP measurements with 24-h ambulatory BP measurement (ABP) in EPT/ELBW individuals at age 18 years and term controls, and determined the sensitivity and specificity of office BP in predicting masked hypertension (24-h ABP measurements > 130/80). METHODS: All EPT/ELBW individuals and matched term control adolescents born in Victoria, Australia, between 1991 and 1992 were recruited. A subset of this cohort was seen at 18 years, and researchers blinded to birth status measured office BP and ABP. We established the office BP thresholds that had the highest sensitivity and specificity in predicting masked hypertension. RESULTS: EPT/ELBW (N = 120) individuals had higher mean BP measurements at 18 years, compared with controls (N = 71). Although there were no significant differences in rates of high BP between groups, high proportions of both EPT/ELBW (43.3%) and term control (36.6%) participants met criteria for masked systolic hypertension. In EPT/ELBW individuals, office systolic BP measurement of >=122.5 mmHg predicted masked systolic hypertension (sensitivity 79%, specificity 74%). Office diastolic BP measurement of >=75.5 mmHg predicted masked diastolic hypertension (sensitivity 77%, specificity, 77%). CONCLUSIONS: At age 18 years, EPT/ELBW individuals have higher systolic and diastolic BP, compared with controls. Office BP may be an adequate screen for masked hypertension in EPT/ELBW survivors, but further research is needed to identify accurate ABP thresholds for masked hypertension for young Australians. PMID- 26040930 TI - A large primary retroperitoneal vaginal leiomyosarcoma: a case report. AB - INTRODUCTION: Primary vaginal leiomyosarcomas are uncommon, especially those growing outside the vagina.Out of all malignant vaginal neoplasms, leiomyosarcomas account for about 2%. Reports in the literature mostly concern the pathology of these tumors; few reports have been published that discuss how to surgically remove them. CASE PRESENTATION: A 69-year-old Chinese woman presented with a mass in her buttocks that had been present for more than four months. Computed tomography demonstrated a mass of approximately 12.0*9.5*8.0cm in her retroperitoneal space. We resected the tumor via a posterior incision, and resected part of her sacrum and coccyx. The resected tumor was diagnosed by its pathological features as a leiomyosarcoma. Our patient received adjuvant chemotherapy after surgery. She was free of disease at a one-year follow-up and her general condition is good. CONCLUSIONS: We report a rare case of a primary vaginal leiomyosarcoma that was resected through an approach that has not, to the best of our knowledge, been previously reported. This case report adds valuable knowledge to the sparse available literature on the surgical treatment of vaginal leiomyosarcomas. PMID- 26040931 TI - Navigation strategy training using virtual reality in six chronic stroke patients: A novel and explorative approach to the rehabilitation of navigation impairment. AB - Recent studies have shown that navigation impairment is a common complaint after brain injury. Effective training programmes aiming to improve navigation ability in neurological patients are, however, scarce. The few reported programmes are merely focused on recalling specific routes rather than encouraging brain-damaged patients to use an alternative navigation strategy, applicable to any route. Our aim was therefore to investigate the feasibility of a (virtual reality) navigation training as a tool to instruct chronic stroke patients to adopt an alternative navigation strategy. Navigation ability was systematically assessed before the training. The training approach was then determined based on the individual pattern of navigation deficits of each patient. The use of virtual reality in the navigation strategy training in six middle-aged stroke patients was found to be highly feasible. Furthermore, five patients learned to (partially) apply an alternative navigation strategy in the virtual environment, suggesting that navigation strategies are mouldable rather than static. In the evaluation of their training experiences, the patients judged the training as valuable and proposed some suggestions for further improvement. The notion that the navigation strategy people use can be influenced after a short training procedure is a novel finding and initiates a direction for future studies. PMID- 26040932 TI - The prognostic significance of a postoperative systemic inflammatory response in patients with colorectal cancer. AB - BACKGROUND: Recently, a preoperative systemic inflammatory response has been reported to be a prognostic factor in patients with colorectal cancer (CRC). However, the prognostic significance of a systemic inflammatory response in the early stage after surgery in patients with CRC is unknown. The aim of this retrospective study was to evaluate the prognostic significance of a postoperative systemic inflammatory response in patients with CRC. METHODS: Two hundred and fifty-four patients who underwent potentially curative surgery for stage II/III CRC were enrolled in this study. Univariate and multivariate analyses were performed to evaluate the relationship between the prognosis and clinicopathological factors, including the neutrophil-to-lymphocyte ratio (NLR) and Glasgow Prognostic Score (GPS), which were measured within two weeks before operation and at the first visit after leaving the hospital. RESULTS: The overall survival rates were significantly worse in the high preoperative NLR/preoperative GPS/postoperative NLR group. A multivariate analysis indicated that only preoperative GPS, postoperative NLR, and the number of lymph node metastases were independent prognostic factors for a poor survival. CONCLUSIONS: The postoperative NLR is an independent prognostic factor in patients with CRC who underwent potentially curative surgery. PMID- 26040933 TI - Epigenetics of Notch1 regulation in pulmonary microvascular rarefaction following extrauterine growth restriction. AB - BACKGROUND: Extrauterine growth restriction (EUGR) plays an important role in the developmental origin of adult cardiovascular diseases. In an EUGR rat model, we reported an elevated pulmonary arterial pressure in adults and genome-wide epigenetic modifications in pulmonary vascular endothelial cells (PVECs). However, the underlying mechanism of the early nutritional insult that results in pulmonary vascular consequences later in life remains unclear. METHODS: A rat model was used to investigate the physiological and structural effect of EUGR on early pulmonary vasculature by evaluating right ventricular systolic pressure and pulmonary vascular density in male rats. Epigenetic modifications of the Notch1 gene in PVECs were evaluated. RESULTS: EUGR decreased pulmonary vascular density with no significant impact on right ventricular systolic pressure at 3 weeks. Decreased transcription of Notch1 was observed both at 3 and 9 weeks, in association with decreased downstream target gene, Hes-1. Chromatin immunoprecipitation and bisulfite sequencing were performed to analyze the epigenetic modifications of the Notch1 gene promoter in PVECs. EUGR caused a significantly increased H3K27me3 in the proximal Notch1 gene promoter, and increased methylation of single CpG sites in the distal Notch1 gene promoter, both at 3 and 9 weeks. CONCLUSIONS: We conclude that EUGR results in decreased pulmonary vascular growth in association with decreased Notch1 in PVECs. This may be mediated by increased CpG methylation and H3K27me3 in the Notch1 gene promoter region. PMID- 26040934 TI - Treatment outcome and patterns of failure in patients of pinealoblastoma: review of literature and clinical experience from a regional cancer centre in north India. AB - PURPOSE: Pinealoblastoma is a highly malignant embryonal tumour of the pineal region affecting children and young adults. We herein intend to report the clinical features and treatment outcome of patients of pinealoblastoma treated at our institute. METHODS: Clinical data was collected by retrospective chart review from 2003-2012. Histopathology slides were reviewed, and relevant immunohistochemistry stains were done. Overall survival (OS) and recurrence-free survival (RFS) were analysed by Kaplan-Meier product-limit method. Univariate and multivariate analyses of prognostic factors were done by log rank test and Cox proportional hazard regression model, respectively. RESULTS: Seventeen patients met the study criterion (male:female = 11:6). Median age at presentation was 14 years (range 4-47 years). Surgical resection was gross total in 6 (35.29%), near total in 2 (11.76%), sub-total in 2 (11.76%), and limited to biopsy in 7 (41.18 %) patients. At presentation, 4 patients had leptomeningeal dissemination. Radiation therapy was delivered in all patients-craniospinal irradiation in 15 (88.24%), whole brain irradiation in 1 (5.88%), and whole ventricular irradiation followed by boost in 1 (5.88%) patient. Systemic chemotherapy (median 6 cycles) was given in 14 (82.35%) patients. The most common regimen was a combination of carboplatin and etoposide, used in 10 (58.82%) patients. After a median follow-up of 30.3 months (mean 32.01 months), death and disease recurrences were noted in 3 (17.65%) and 7 (41.18%) patients. Amongst the patients with recurrent disease, 4 had spinal drop metastases and 3 had local recurrence along with spinal drop metastases. Median OS was not reached, and estimated median RFS was noted to be 5.49 years. The actuarial rates of OS and RFS at 2 years were 85.6 and 73.1%, respectively. On univariate analysis, age more than 8 years (P = 0.0071) and M0 stage (P = 0.0483) were significant predictors of improved RFS. Age retained significance on multivariate analysis of RFS (P = 0.02932). CONCLUSION: Maximal safe resection followed by craniospinal irradiation and systemic chemotherapy with 6 cycles of carboplatin-etoposide regimen is a reasonable treatment strategy in patients of pinealoblastoma more than 8 years of age in a developing nation. However, the same strategy is less effective in younger children and innovative study designs of intensification of post-operative treatment must be explored in this age group. PMID- 26040935 TI - Sublaminar wiring for odontoid synchondrotic fracture stabilization in a 4-year old: a case report. AB - BACKGROUND: The pediatric age group presents a challenge in diagnosis and management of upper cervical injuries. Cervical spine injuries are relatively rare in children as compared to adults and C2 vertebra is the commonly affected site for fracture and injury. METHODS: In our case, a 4-year-old female child was brought to the emergency after being hit over the head and neck by a falling wooden beam. Patient had associated minimal neurological deficits. Urgent CT scan of the head and cervical spine were done. CT spine suggested instability as there was anterior angulation of the odontoid process with anterior displacement and associated occipital fracture. Patient underwent a sublaminar wiring at C1-C2 vertebra. RESULTS: There was neurological improvement following surgery and patient was discharged after 2 weeks on soft cervical collar. Synchondrotic odontoid fracture is traditionally managed with closed reduction and external stabilization due to high rates of fusion in children. CONCLUSIONS: However, early surgical intervention has an important role in management of unstable injuries. Sublaminar wiring though not as stable as rigid instrumentation can be done in pediatric patients where even the smallest instrumentation is too invasive. Management of the odontoid synchondrosis fracture remains a controversial topic in children of younger age group. PMID- 26040937 TI - J. Gordon McComb, MD: President of the ISPN, 2013-2014. PMID- 26040936 TI - Challenges and opportunities to advance pediatric neuro-oncology care in the developing world. AB - PURPOSE: As the morbidity and mortality associated with communicable diseases continue to decrease in the developing world, the medical burden of childhood cancer continues to expand. Although international aid and relief groups such as the World Health Organization recognize the importance of childhood cancer, their main emphasis is on the more easily treated malignancies, such as leukemias and lymphomas, and not pediatric brain tumors, which are the second most common malignancy in children and the leading cause of cancer-related deaths in the pediatric population. Addressing the needs of these children is a growing concern of several professional neuro-oncology-related societies. Thus, the goal of this review is to describe the current state of pediatric neuro-oncology care in the developing world, address the current and future needs of the field, and help guide professional societies' efforts to contribute in a more holistic and multidisciplinary manner. METHODS: We reviewed the literature to compare the availability of neuro-oncology care in various regions of the developing world with that in higher income nations, to describe examples of successful initiatives, and to present opportunities to improve care. RESULTS: The current challenges, previous successes, and future opportunities to improve neuro oncology care are presented. The multidisciplinary nature of neuro-oncology depends on large teams of highly specialized individuals, including neuro oncologists, neurosurgeons, neurologists, radiologists, radiation oncologists, pathologists, palliative care specialists, oncology nurses, physical therapists, occupational therapists, speech therapists, pediatric intensivists, and social workers, among others. CONCLUSION: Pediatric neuro-oncology is one of the most complex types of medical care to deliver, as it relies on numerous specialists, subspecialists, support staff, and physical resources and infrastructure. However, with increasing collaboration and advancing technologies, developed nations can help substantially improve neuro-oncology care for children in developing nations. PMID- 26040938 TI - Intravaginal practices and lactobacilli colonization among women in Accra, Ghana. AB - BACKGROUND: Intravaginal practices may affect the colonization of vaginal flora and lead to vaginal infections due to the potential effects on the vaginal environment. This study investigated the vaginal practices and their possible effects on vaginal lactobacilli flora colonization in women in Accra. METHODS: A cross-sectional, descriptive single-site study was carried out on 141 women assessing medical care at the Obstetrics and Gynaecology Department of the Korle Bu Teaching Hospital (KBTH) in Accra. Study-relevant information on participants was obtained by means of questionnaire. Vaginal swab samples were collected and processed for laboratory analyses. RESULTS: All the participants (141/141, 100.0 %) indicated they performed intravaginal practices using various methods. Almost half (46.1 %) of these women were between the ages of 25-34 years and 65.0 % were married. Internal douching (82.3 %; p > 0.05) was the commonest practice reported. Other practices such as insertion and wiping with hands and objects, as well as use of locally prepared concoctions and certain commercial products were also reported. The reason most commonly given was for hygienic purpose (83.0 %); a few (10.6 %) did it for sexual satisfaction, while others indicated vaginal tightness (5.7 %) and wound healing (0.7 %) as reasons for their practice. No Lactobacillus sp. was detected in as many as 78.7 % of the sample. Association tests by the Pearson correlation analysis showed strong significant negative correlation (r = -0.954, p < 0.05) between use of traditional herbs/concoction and vaginal lactobacilli colonization; and douching being the least negatively (r = -0.601, p > 0.05) correlated practice. CONCLUSIONS: Vaginal practices were common among the women studied. A more elaborate prospective, case-control study into intravaginal practices and their impact on the health of women in Ghana should be explored. PMID- 26040939 TI - Effects of a Levonorgestrel-Releasing Intrauterine System on the Expression of Steroid Receptor Coregulators in Adenomyosis. AB - Although the pathophysiology of adenomyosis has not been clarified, it is thought to be related to ectopic endometrium, which depends on hormonal regulation. The levonorgestrel-releasing intrauterine system (LNG-IUS) is effective for the medical treatment of adenomyosis. However, the underlying molecular mechanisms by which LNG-IUS ameliorates adenomyosis pathology remain unclear. This study was designed to compare the expression levels of steroid receptor coregulators in human endometrium of control and participants with adenomyosis and to determine whether LNG-IUS modulated their expression. Immunohistochemistry with H-scores was performed. Steroid receptor coactivators were shown to have significantly decreased expressions at the secretory phase in the LNG-IUS group when compared to the other groups. Expression of transcriptional intermediary factor 2 was lower in the LNG-IUS group than in both the control group (P = .015) and the untreated adenomyosis group (P = .019) during the secretory phase. Amplified in breast cancer 1 expression was higher in the stromal cells of the untreated adenomyosis group than in those of the controls (P = .017) during the secretory phase; however, levels were lower in the LNG-IUS group (P = .005). Nuclear receptor corepressor expression increased during the proliferative phase and decreased during the secretory phase in untreated adenomyosis; this pattern was reversed in the control and LNG-IUS groups. Thus, an altered expression of steroid receptor coregulators may play a role in adenomyosis development and treatment. PMID- 26040940 TI - Increased Levels of Cell-Free miR-517a and Decreased Levels of Cell-Free miR-518b in Maternal Plasma Samples From Placenta Previa Pregnancies at 32 Weeks of Gestation. AB - OBJECTIVE: The aim of this study was to clarify the association between placenta previa and circulating levels of cell-free pregnancy-associated placenta-specific microRNAs (miRNAs) in maternal plasma. METHOD: Twenty singleton pregnancies with placenta previa (placenta previa group) and 26 uncomplicated pregnancies (control group) were recruited. Blood sampling was performed at 32 weeks of gestation, and cesarean delivery in all cases of placenta previa was performed at a mean gestational age of 37 weeks. The maternal plasma concentrations of cell-free pregnancy-associated placenta-specific miRNAs (miR-517a and miR-518b) were measured by absolute quantitative real-time reverse transcription-polymerase chain reaction. RESULTS: Plasma concentrations of cell-free miR-517a were significantly higher in the placenta previa group than that in the control group (P = .011), while the plasma concentration of cell-free miR-518b was significantly lower in the placenta previa group than that in the control group (P = .004). Plasma concentrations of cell-free miR-517a in placenta previa were significantly higher in placenta previa with alert bleeding later group than those in placenta previa without alert bleeding group or control group (P = .030 or .047, respectively) and correlated with the volume of hemorrhage at delivery (R and P value: .512 and .025). CONCLUSION: Plasma concentrations of cell-free miR-517a and miR-518b at 32 weeks of gestation were altered in pregnant women with placenta previa, and the circulating level of cell-free miR-517a in placenta previa may be a predictive marker for the risks of alert bleeding later and massive hemorrhage at delivery. PMID- 26040941 TI - The Effects of Heme Oxygenase By-Products on the Proliferation and Invasion of HUVECs, HTR-8/SVneo Cells, 3A(tPA 30-1) Cells, and HESCs Under Varying Oxygen Concentrations. AB - OBJECTIVE: Abnormal spiral artery remodeling during early pregnancy leads to preeclampsia. The proliferation and invasion of trophoblasts in pregnancy are important for spiral artery remodeling. This study examined whether heme oxygenase (HO) by-products (carbon monoxide biliverdin, and iron) play roles in regulating the restoration of proliferation and invasion of human umbilical vein endothelial cells (HUVECs), HTR-8/SV-neo cells originating from first-trimester trophoblasts, 3A(tPA 30-1) obtained from term trophoblasts, and human endometrial stromal cells (HESCs) inhibited by zinc protoporphyrin IX (Znpp-9). STUDY DESIGN: We explored whether HO by-products restored the proliferation and invasion of HUVECs, HTR-8/SVneo cells, 3A(tPA 30-1) cells, and HESCs inhibited by Znpp-9 depending on the oxygen concentration. RESULTS: Bilirubin promoted proliferation of HUVECs, HTR-8/SVneo cells, 3A(tPA-30-1) cells, and HESCs under both hypoxic and normoxic conditions. Biliverdin also promoted invasion of HUVECs, HTR-8/SVneo cells, 3A(tPA30-1) cells, and HESCs under both hypoxic and normoxic conditions. Carbon monoxide-releasing molecule 2 promoted the proliferation and invasion of specific cell types depending on the oxygen concentration. CONCLUSION: Our data suggest that HO by-products differentially stimulate the proliferation and invasion of cells involved in pregnancy maintenance. When HO by-products are considered to be stimulants during the invasion and proliferation of such cells, both target cells and the gestational period should be considered. PMID- 26040942 TI - Capture and enumeration of mRNA transcripts from single cells using a microfluidic device. AB - Accurate measurement of RNA transcripts from single cells will enable the precise classification of cell types and characterization of the heterogeneity in cell populations that play key roles in normal cellular physiology and diseases. As a step towards this end, we have developed a microfluidic device and methods for automatic hydrodynamic capture of single mammalian cells and subsequent immobilization and digital counting of polyadenylated mRNA molecules released from the individual cells. Using single-molecule fluorescence imaging, we have demonstrated that polyadenylated mRNA molecules from single HeLa cells can be captured within minutes by hybridization to polydeoxyribothymidine oligonucleotides covalently attached on the glass surface in the device. The total mRNA molecule counts in the individual HeLa cells are found to vary significantly from one another. Our technology opens up the possibility of direct digital enumeration of RNA transcripts from single cells with single-molecule sensitivity using a single integrated microfluidic device. PMID- 26040943 TI - Europium(III)-beta-diketonate complex-containing nanohybrid luminescent pH detector. AB - In this work, by loading an Eu(3+)-beta-diketonate complex into LAPONITE(r), we report an organic-inorganic hybrid pH detection system Eu(3+)(TTA)n@Lap that is valid under acid conditions, which can serve as highly robust, reliable, rapid responsive and sensitive fluorescent pH detector. In addition, this hybrid pH detector can be easily recovered and reused by simply treating with Et3N vapor. PMID- 26040945 TI - Atypical femur fractures in a patient with pycnodysostosis: a case report. AB - Pycnodysostosis is a rare autosomal recessive disease due to a mutation in the gene for the enzyme Cathepsin K. It is characterized by short stature, craniofacial dysmorphias, osteosclerosis, and brittle bones. There are only a few reports in the literature describing surgical interventions for long bone fractures in pycnodysostosis patients, most of which describe intramedullary nail treatment of isolated long bone fractures. We describe a case in which a pregnant female with pycnodysostosis presented with a shaft fracture of the left femur following minor trauma and a history of increasing thigh pain. Radiographs obtained in the emergency room also revealed an impending subtrochanteric fracture of the contralateral side. The acute left femoral shaft fracture was treated with an adolescent-sized intramedullary nail; it was decided to defer surgery on the contralateral side until after pregnancy. Three months later, the patient had the contralateral femur prophylactically fixated with a plate and screws. One year after the index surgery, both methods demonstrated satisfactory healing both clinically and radiographically. Although we recommend use of an intramedullary nail for long bone fractures in patients with pycnodysostosis, a plate can be utilized if health conditions or skeletal morphology precludes use of a nail. PMID- 26040946 TI - Health-social partnership intervention programme for community-dwelling older adults: a research protocol for a randomized controlled trial. AB - AIM: This paper aims to describe the research protocol that will be used to determine the effectiveness of a health-social partnership intervention programme among community-dwelling older adults. BACKGROUND: Ageing in place is a preferred option for overcoming challenges of the increasing prevalence of chronic diseases and the risk for hospitalization associated with the ageing population. Nevertheless, our knowledge of how to implement this concept is limited. The integrated efforts of health and social services may help to enable older adults to live with a sense of control over their daily life and to be independent to the fullest extent possible in the community. DESIGN: This is a randomized, controlled trial. METHODS: Participants are community-dwelling older adults referred from a community centre. Sample size calculation was based on power analysis. The intervention group will receive the programme with the standard protocols guided by a comprehensive assessment-intervention-evaluation framework. Home visits and telephones follow-up will be employed as means of conducting the interventions and monitoring their progress. The customary care group will receive placebo social calls. The duration of the interventions will be 3 months. The study was funded by the School of Nursing in Hong Kong. Research Ethics Committee approval was obtained in September 2014. DISCUSSION: The results of this research are expected to enable older adults to stay in the community with optimal health and well-being. Health and social sciences are integrated into the practice in this research protocol. The scarce literature on this topic means that this study can also provide an opportunity to bridge the caring gap among older adults. PMID- 26040944 TI - Head Position in Stroke Trial (HeadPoST)--sitting-up vs lying-flat positioning of patients with acute stroke: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Positioning a patient lying-flat in the acute phase of ischaemic stroke may improve recovery and reduce disability, but such a possibility has not been formally tested in a randomised trial. We therefore initiated the Head Position in Stroke Trial (HeadPoST) to determine the effects of lying-flat (0 degrees ) compared with sitting-up (>= 30 degrees ) head positioning in the first 24 hours of hospital admission for patients with acute stroke. METHODS/DESIGN: We plan to conduct an international, cluster randomised, crossover, open, blinded outcome-assessed clinical trial involving 140 study hospitals (clusters) with established acute stroke care programs. Each hospital will be randomly assigned to sequential policies of lying-flat (0 degrees ) or sitting-up (>= 30 degrees ) head position as a 'business as usual' stroke care policy during the first 24 hours of admittance. Each hospital is required to recruit 60 consecutive patients with acute ischaemic stroke (AIS), and all patients with acute intracerebral haemorrhage (ICH) (an estimated average of 10), in the first randomised head position policy before crossing over to the second head position policy with a similar recruitment target. After collection of in-hospital clinical and management data and 7-day outcomes, central trained blinded assessors will conduct a telephone disability assessment with the modified Rankin Scale at 90 days. The primary outcome for analysis is a shift (defined as improvement) in death or disability on this scale. For a cluster size of 60 patients with AIS per intervention and with various assumptions including an intracluster correlation coefficient of 0.03, a sample size of 16,800 patients at 140 centres will provide 90 % power (alpha 0.05) to detect at least a 16 % relative improvement (shift) in an ordinal logistic regression analysis of the primary outcome. The treatment effect will also be assessed in all patients with ICH who are recruited during each treatment study period. DISCUSSION: HeadPoST is a large international clinical trial in which we will rigorously evaluate the effects of different head positioning in patients with acute stroke. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02162017 (date of registration: 27 April 2014); ANZCTR identifier: ACTRN12614000483651 (date of registration: 9 May 2014). Protocol version and date: version 2.2, 19 June 2014. PMID- 26040947 TI - Rapid, metal-free hydrosilanisation chemistry for porous silicon surface modification. AB - Here, we report a novel surface modification for porous silicon (pSi). Hydroxyl terminated pSi surfaces are modified with a hydrosilane via Si-H activation using the Lewis acid catalyst tris(pentafluorophenyl) borane. This surface reaction is fast and efficient at room temperature, and leads to a surface stabilised against hydrolytic attack in aqueous media. The resulting surface shows promise as a substrate for surface-assisted laser desorption/ionisation mass spectrometry. PMID- 26040948 TI - Dynamic curvature topography for evaluating the anterior corneal surface change with Corvis ST. AB - BACKGROUND: The measurement of dynamic parameters, such as the length of applanation and the amplitude of deformation, is significant for evaluating corneal properties. Most of the corneal properties (related to shape) including the anterior corneal curvature and the thickness of cornea can be easily measured using some existing techniques. However, they only provide the static or pseudo dynamic analysis. Based on Corvis ST images, the dynamic features after corneal boundaries detection and parameter estimation will be helpful for corneal analysis. MATERIAL: The study included 40 eyes in normal group (ranging from 19 to 45 years old) and 30 eyes in keratoconus group (ranging from 16 to 40 years old). These eyes were examined by Corvis ST and for each one a sequence of 140 images was obtained. Besides, 11 subjects of each group were also tested by Pentacam. METHODS: By analyzing the video from the Corvis ST imaging, the fully dynamic curvature topography is proposed to evaluate the response of the anterior corneal surface to the air puff. The new method not only quantitatively measures the intact variation of anterior corneal surface but also provides an intuitive way to observe the dynamic change of the anterior corneal surface in the whole air stream process. The proposed method consists of three main steps: cornea segmentation, curvature estimation and integrated visualization. An automatic segmentation method based on the combination of prior knowledge with phase symmetry and asymmetry theory is firstly presented to detect the corneal boundaries. The Landau-new method is then used to estimate the anterior corneal surface. The corneal dynamic topography is finally obtained by combining the dynamic parameters with the original Corvis ST video, which is an improvement of the fusion technique proposed by Li et al. RESULTS AND CONCLUSION: By comparing the segmentation results with manual method and built-in method of Corvis ST, the accuracy and robustness of our proposed segmentation method is demonstrated. The correctness of the estimated corneal anterior curvatures is also evaluated by comparing it with that of Pentacam which is considered to be able to provide the first-class measurement currently. The dynamic topography may be used to distinguish the dynamic behavior of normal corneas from that of keratoconus. PMID- 26040950 TI - White House forum promotes responsible use of antibiotics. PMID- 26040949 TI - The activity and inhibition of poly(ADP-ribose) polymerase-1 in equine peripheral blood mononuclear cells in vitro. AB - OBJECTIVES: To evaluate the poly (ADP-ribose) polymerase-1 (PARP1) enzyme and its inhibition in horses and explore its potential as a novel therapeutic target for equine intestinal ischemia-reperfusion injury by (1) identifying poly (ADP ribose) (PAR) as an indication of PARP1 activation in equine cells using available immunoblot analytical techniques, (2) inducing PARP1 activation in an in vitro oxidative DNA damage model, (3) and demonstrating the inhibition of PARP1 in equine cells using commercially available PARP1 inhibitors. DESIGN: Experimental study. ANIMALS: Blood samples were collected from systemically healthy ponies (n = 3) and horses (n = 3). INTERVENTIONS: (1) Equine peripheral blood mononuclear cells were exposed to 3 different concentrations of hydrogen peroxide (H2 O2 ) and were lysed at specific time points. PARP1 activity was then assessed by using immunoblot analyses to determine PAR levels. (2) Equine peripheral blood mononuclear cells were preincubated with defined concentrations of PARP1 inhibitors prior to H2 O2 -mediated PARP1 stimulation. PAR levels reflecting PARP1 activity were determined using immunoblot analyses. MEASUREMENTS AND MAIN RESULTS: Commercially available anti-PAR antibodies were used successfully to identify equine PAR. There was a significant increase in PAR accumulation following treatment with H2 O2 . All of the tested PARP inhibitors significantly reduced PAR accumulation to or below basal levels following treatment with H2 O2 . CONCLUSIONS: This proof of principle study demonstrated that PAR, an indicator of PARP1 activity, can be identified in the equine species using immunoblot techniques, that equine PARP1 can be activated by H2 O2 -induced DNA damage, and that this activation can be inhibited by PARP1 enzyme inhibitors. The data suggest that the PARP1 pathway plays a role in the equine cellular response to oxidative DNA damage and supports its potential as a novel therapeutic target. Further research documenting an increase in PAR levels in vivo and the efficacy of PARP1 inhibitors in an equine intestinal ischemia reperfusion model is needed. PMID- 26040951 TI - A large left ventricular pseudoaneurysm. PMID- 26040952 TI - Mesenchymal Stem Cells as a Source of Repair Cytokines: Mesenchymal Stem Cells as the Conductor. PMID- 26040953 TI - Contemporary Medical and Surgical Management of X-linked Hypophosphatemic Rickets. AB - X-linked hypophosphatemia is an inheritable disorder of renal phosphate wasting that clinically manifests with rachitic bone pathology. X-linked hypophosphatemia is frequently misdiagnosed and mismanaged. Optimized medical therapy is the cornerstone of treatment. Even with ideal medical management, progressive bony deformity may develop in some children and adults. Medical treatment is paramount to the success of orthopaedic surgical procedures in both children and adults with X-linked hypophosphatemia. Successful correction of complex, multiapical bone deformities found in patients with X-linked hypophosphatemia is possible with careful surgical planning and exacting surgical technique. Multiple methods of deformity correction are used, including acute and gradual correction. Treatment of some pediatric bony deformity with guided growth techniques may be possible. PMID- 26040954 TI - Novel Strategies for the Diagnosis of Posttraumatic Infections in Orthopaedic Trauma Patients. AB - Orthopaedic infections that occur after trauma are common. Clinical examination, laboratory markers, imaging modalities, and culture and molecular technologies are used to aid the diagnosis of infection. Culture methods comprise the backbone of diagnostic systems used in hospital laboratory settings; however, several studies have questioned the ability of these techniques to adequately identify infections, particularly in cases where orthopaedic implants were used or when the presence of biofilm bacteria is suspected. Advances in imaging and molecular diagnostics can provide orthopaedic surgeons with an improved means of diagnosing and treating infections. PMID- 26040955 TI - Impact of positional changes in neural monitoring endotracheal tube on amplitude and latency of electromyographic response in monitored thyroid surgery: Results from the Porcine Experiment. AB - BACKGROUND: The purpose of this study was to evaluate electromyography (EMG) amplitude and latency changes during tube dislocation in monitored thyroid surgery, which may be observed without recurrent laryngeal nerve injury. METHODS: Duroc-Landrace piglets were intubated with the TriVantage EMG tube. We measured EMG changes during both upward and downward tube dislocation (10-20 mm) and rotation (45-90 degrees ) with continuous neuromonitoring. RESULTS: The EMG amplitude varied significantly with induced endotracheal tube rotation and depth changes. However, the EMG latency was relatively unaffected by such tube dislocation, just a transient artifactual latency change was observed in the situation of extreme amplitude variation. CONCLUSION: Amplitude changes without latency changes may be due to changes in tube position alone during surgery, but could still reflect a neurophysiologic event; amplitude changes during neuropraxic injury merit additional investigation. Thus, the combined event (concordant amplitude decrease and latency increase) serves as an appropriate adverse EMG event correlating with impending neural injury. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1004-E1008, 2016. PMID- 26040956 TI - Sub-second pencil beam dose calculation on GPU for adaptive proton therapy. AB - Although proton therapy delivered using scanned pencil beams has the potential to produce better dose conformity than conventional radiotherapy, the created dose distributions are more sensitive to anatomical changes and patient motion. Therefore, the introduction of adaptive treatment techniques where the dose can be monitored as it is being delivered is highly desirable. We present a GPU-based dose calculation engine relying on the widely used pencil beam algorithm, developed for on-line dose calculation. The calculation engine was implemented from scratch, with each step of the algorithm parallelized and adapted to run efficiently on the GPU architecture. To ensure fast calculation, it employs several application-specific modifications and simplifications, and a fast scatter-based implementation of the computationally expensive kernel superposition step. The calculation time for a skull base treatment plan using two beam directions was 0.22 s on an Nvidia Tesla K40 GPU, whereas a test case of a cubic target in water from the literature took 0.14 s to calculate. The accuracy of the patient dose distributions was assessed by calculating the gamma index with respect to a gold standard Monte Carlo simulation. The passing rates were 99.2% and 96.7%, respectively, for the 3%/3 mm and 2%/2 mm criteria, matching those produced by a clinical treatment planning system. PMID- 26040957 TI - Pigeons (Columba livia) fail to connect dots in learning biological motion. AB - Biological motion point-light displays provide a powerful method for studying motion perception. Nonhuman animals are capable of discriminating point-light displays, but it remains unknown how they perceive biological motion in these displays. We trained two groups of pigeons to discriminate video stimuli using two different classification rules. The motion-congruent group was trained to discriminate full-detail and corresponding point-light displays of pigeons from full-detail and point-light displays of humans. The motion-incongruent group was trained to discriminate full-detail pigeons and point-light humans from the other displays. Both groups acquired the discrimination. When tested with novel displays, pigeons showed good transfer of learning. Transfer was poorest with the point-light displays in the motion-congruent group. The results indicate that the pigeons failed to make the connection between the full-detail displays and their point-light counterparts even when the common motion was available as a cue. PMID- 26040958 TI - ProCARs: Progressive Reconstruction of Ancestral Gene Orders. AB - BACKGROUND: In the context of ancestral gene order reconstruction from extant genomes, there exist two main computational approaches: rearrangement-based, and homology-based methods. The rearrangement-based methods consist in minimizing a total rearrangement distance on the branches of a species tree. The homology based methods consist in the detection of a set of potential ancestral contiguity features, followed by the assembling of these features into Contiguous Ancestral Regions (CARs). RESULTS: In this paper, we present a new homology-based method that uses a progressive approach for both the detection and the assembling of ancestral contiguity features into CARs. The method is based on detecting a set of potential ancestral adjacencies iteratively using the current set of CARs at each step, and constructing CARs progressively using a 2-phase assembling method. CONCLUSION: We show the usefulness of the method through a reconstruction of the boreoeutherian ancestral gene order, and a comparison with three other homology based methods: AnGeS, InferCARs and GapAdj. The program, written in Python, and the dataset used in this paper are available at http://bioinfo.lifl.fr/procars/. PMID- 26040959 TI - Next generation transcriptomics and genomics elucidate biological complexity of microglia in health and disease. AB - Genome-wide expression profiling technology has resulted in detailed transcriptome data for a wide range of tissues, conditions and diseases. In neuroscience, expression datasets were mostly generated using whole brain tissue samples, resulting in data from a mixture of cell types, including glial cells and neurons. Over the past few years, a rapidly increasing number of expression profiling studies using isolated microglial cell populations have been reported. In these studies, the microglia transcriptome was compared to other cell types, such as other brain cells and peripheral tissue macrophages, and related to aging and neurodegenerative conditions. A commonality found in many of these studies was that microglia possess distinct gene expression signatures. This repertoire of selectively-expressed microglial genes highlight functions beyond immune responses, such as synaptic modulation and neurotrophic support, and open up avenues to explore as-yet-unexpected roles. These data provide improved understanding of disease pathology, and complement not only the aforementioned whole brain tissue transcriptome studies, but also genome- and epigenome-wide association studies. In this review, insights obtained from isolated microglia transcriptome studies are presented, and compared to studies using other genome wide approaches. The relation of microglia to other tissue macrophages and glial cell populations, as well as the role of microglia in the aging brain and in neurodegenerative conditions, will be discussed. Many more of these types of studies are expected in the near future, hopefully leading to the identification of novel genes and targets for neurodegenerative conditions. PMID- 26040961 TI - The New York State Collaborative Care Initiative: 2012-2014. AB - We report on a partnership between the NYS Department of Health and Office of Mental Health that delivered the full integration of depression care into primary medical care. Called the NYS Collaborative Care Initiative (NYS-CCI), nineteen NYS academic medical centers participated. Based on principles of chronic illness care, Collaborative Care detects and manages depression in primary care using a highly prescriptive protocol (University of Washington AIMS Center website: http://uwaims.org/ ). Fidelity was ensured by measuring screening rates, diagnosis, enrollment, and improvement among those in treatment for 16 weeks. There was significant, progressive performance improvement in sites that served over 1 million patients over the course of the two and a half year grant. Clinics also reported satisfaction with the CC model. Based on the experience gained, we recommend a number of critical actions necessary for the successful implementation and scaling-up of CC throughout any state undertaking this endeavor. PMID- 26040962 TI - Leading with Lean: Getting the Outcomes we Need with the Funding we Have. AB - Lean and other quality management methodologies have been used by industry and manufacturing for many years. More recently they have been adopted by health care. The authors describe their experience with the lean way of continuous quality improvement, first developed by Toyota, at one of New York's largest behavioral health departments. The relevance and application of these methodologies to the mental health sector is presented. PMID- 26040963 TI - Effects of deer age on the physicochemical properties of deproteinized antler cancellous bone: an approach to optimize osteoconductivity of bone graft. AB - Inorganic bone xenograft materials have recently found extensive surgical application in the clinic. Previously we have demonstrated that calcinated antler cancellous bone (CACB) has great potential for bone defect repair, due to the similar structure and composition compared with human bone. However, the effect of intrinsic material characteristics, particularly deer age, on the physicochemical and biological properties of CACB scaffolds has not been clarified. The aim of this study is to investigate the structure, composition and in vitro solubility of CACB scaffolds derived from deer of varying ages, including young (CACB-Y), middle-aged (CACB-M), and old (CACB-O) deer, and to determine subsequent biological performance. Microstructural analyses showed looser crystal arrangement and lower porosity in CACB-M compared to CACB-Y and CACB-O. Phase-structure analysis showed that CACB-M had the largest crystal size. Component characterization results showed that CACB-M had the most carbonated substitute and the highest content of trace elements (Na, Fe). The in vitro solubility test showed that CACB-M had the fastest dissolution and apatite deposition rates with new crystalline phases. In addition, CACB-M could be conducive for attachment, proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells in vitro, as well as conducive for bone regeneration in vivo. These findings indicate that animal age should be seriously considered as a key parameter in optimizing the physicochemical and biological properties of deproteinized antler cancellous bone substitutes for bone regeneration applications. PMID- 26040964 TI - Chinese herbal medicine for treating recurrent urinary tract infections in women. AB - BACKGROUND: Acute urinary tract infection (UTI) is a common bacterial infection that affects 40% to 50% of women. Between 20% and 30% of women who have had a UTI will experience a recurrence, and around 25% will develop ongoing recurrent episodes with implications for individual well-being and healthcare costs. Prophylactic antibiotics can prevent recurrent UTIs but there are growing concerns about microbial resistance, side effects from treatment and lack of long term benefit. Consequently, alternative treatments are being investigated. Chinese herbal medicine (CHM) has a recorded history of treating UTI symptoms and more recent research suggests a potential role in the management of recurrent UTIs. This review aimed to evaluate CHM for recurrent UTI. OBJECTIVES: This review assessed the benefits and harms of CHM for the treatment of recurrent UTIs in adult women, both as a stand-alone therapy and in conjunction with other pharmaceutical interventions. SEARCH METHODS: We searched the Cochrane Kidney and Transplant's Specialised Register to 7 May 2015 through contact with the Trials Search Co-ordinator, using search terms relevant to this review. We also searched AMED, CINAHL and the Chinese language electronic databases Chinese BioMedical Literature Database (CBM), China Network on Knowledge Infrastructure (CNKI), VIP and Wan Fang Databases to July 2014. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing treatments using CHM with either an inactive placebo or conventional biomedical treatment. RCTs comparing different CHM strategies and treatments were eligible for inclusion. Quasi-randomised studies were excluded. DATA COLLECTION AND ANALYSIS: Data extraction was carried out independently by two authors. Where more than one publication of one study existed, these were grouped and the publication with the most complete data was used in the analyses. Where relevant outcomes were only published in earlier versions these data were used. All meta-analyses were performed using relative risk (RR) for dichotomous outcomes with 95% confidence intervals (CI). MAIN RESULTS: We included seven RCTs that involved a total of 542 women; of these, five recruited post-menopausal women (aged from 56 to 70 years) (422 women). We assessed all studies to be at high risk of bias. Meta-analyses comparing the overall effectiveness of treatments during acute phases of infection and rates of recurrence were conducted. Analysis of three studies involving 282 women that looked at CHM versus antibiotics suggested that CHM had a higher rate of effectiveness for acute UTI (RR 1.21, 95% CI 1.11 to 33) and reduced recurrent UTI rates (RR 0.28, 95% CI 0.09 to 0.82). Analysis of two studies involving 120 women that compared CHM plus antibiotics versus antibiotics alone found the combined intervention had a higher rate of effectiveness for acute UTI (RR 1.24, 95% CI 1.04 to 1.47) and resulted in lower rates of recurrent infection six months after the study (RR 0.53, 95% CI 0.35 to 0.80).One study comparing different CHM treatments found Er Xian Tang was more effective in treating acute infection in post-menopausal women than San Jin Pian (80 women: RR 1.28, 95% CI 1.03 to 1.57). Analysis showed that active CHM treatments specifically formulated for recurrent UTI were more effective in reducing infection incidence than generic CHM treatments that were more commonly used for acute UTI (RR 0.40, 95% CI 0.21 to 0.77).Only two studies undertook to report adverse events; neither reported the occurrence of any adverse events. AUTHORS' CONCLUSIONS: Evidence from seven small studies suggested that CHM as an independent intervention or in conjunction with antibiotics may be beneficial for treating recurrent UTIs during the acute phase of infection and may reduce the recurrent UTI incidence for at least six months post-treatment. CHM treatments specifically formulated for recurrent UTI may be more effective than herbal treatments designed to treat acute UTI. However, the small number and poor quality of the included studies meant that it was not possible to formulate robust conclusions on the use of CHM for recurrent UTI in women either alone or as an adjunct to antibiotics. PMID- 26040965 TI - [Pressure and gases: Current guidelines on diving accidents]. PMID- 26040966 TI - Complications of Total Hip Arthroplasty: Standardized List, Definitions, and Stratification Developed by The Hip Society. AB - BACKGROUND: Reporting of complications after total hip arthroplasty (THA) is not standardized, and it is done inconsistently across various studies on the topic. Advantages of standardizing complications include improved patient safety and outcomes and better reporting in comparative studies. QUESTIONS/PURPOSES: The purpose of this project was to develop a standardized list of complications and adverse events associated with THA, develop standardized definitions for each complication, and stratify the complications. A further purpose was to validate these standardized THA complications. METHODS: The Hip Society THA Complications Workgroup proposed a list of THA complications, definitions for each complication, and a stratification scheme for the complications. The stratification system was developed from a previously validated grading system for complications of hip preservation surgery. The proposed complications, definitions, and stratification were validated with an expert opinion survey of members of The Hip Society, a case study evaluation, and analysis of a large administrative hospital system database with a focus on readmissions. RESULTS: One hundred five clinical members (100%) of The Hip Society responded to the THA complications survey. Initially, 21 THA complications were proposed. The validation process reduced the 21 proposed complications to 19 THA complications with definitions and stratification that were endorsed by The Hip Society (bleeding, wound complication, thromboembolic disease, neural deficit, vascular injury, dislocation/instability, periprosthetic fracture, abductor muscle disruption, deep periprosthetic joint infection, heterotopic ossification, bearing surface wear, osteolysis, implant loosening, cup-liner dissociation, implant fracture, reoperation, revision, readmission, death). CONCLUSIONS: Acceptance and use of these standardized, stratified, and validated THA complications and adverse events could advance reporting of outcomes of THA and improve assessment of THA by clinical investigators. LEVEL OF EVIDENCE: Level V, therapeutic study. PMID- 26040967 TI - Is MR-guided High-intensity Focused Ultrasound a Feasible Treatment Modality for Desmoid Tumors? AB - BACKGROUND: MR-guided high-intensity focused ultrasound is a noninvasive treatment modality that uses focused ultrasound waves to thermally ablate tumors within the human body while minimizing side effects to surrounding healthy tissues. This technology is FDA-approved for certain tumors and has potential to be a noninvasive treatment option for extremity soft tissue tumors. Development of treatment modalities that achieve tumor control, decrease morbidity, or both might be of great benefit for patients. We wanted to assess the potential use of this technology in the treatment of extremity desmoid tumors. QUESTIONS/PURPOSES: (1) Can we use MR-guided high-intensity focused ultrasound to accurately ablate a predetermined target volume within a human cadaver extremity? (2) Does MR-guided high-intensity focused ultrasound treatment stop progression and/or cause regression of extremity desmoid tumors? METHODS: Simulated tumor volumes in four human cadavers, created by using plastic markers, were ablated using a commercially available focused ultrasound system. Accuracy was determined in accordance with the International Organization of Standards location error by measuring the farthest distance between the ablated tissue and the plane corresponding to the target. Between 2012 and 2014, we treated nine patients with desmoid tumors using focused ultrasound ablation. Indications for this were tumor related symptoms or failure of conventional treatment. Of those, five of them were available for MRI followup at 12 months or longer (mean, 18.2 months; range, 12-23 months). The radiographic and clinical outcomes of five patients who had desmoid tumors treated with focused ultrasound were prospectively recorded. Patients were assessed preoperatively with MRI and followed at routine intervals after treatment with MRI scans and clinical examination. RESULTS: The ablation accuracy for the four cadaver extremities was 5 mm, 3 mm, 8 mm, and 8 mm. Four patients' tumors became smaller after treatment and one patient has slight progression at the time of last followup. The mean decrease in tumor size determined by MRI measurements was 36% (95% confidence interval, 7%-66%). No patient has received additional adjuvant systemic or local treatment. Treatment related adverse events included first- and second-degree skin burns occurring in four patients, which were managed successfully without further surgery. CONCLUSIONS: This preliminary investigation provides some evidence that MR-guided high-intensity focused ultrasound may be a feasible treatment for desmoid tumors. It may also be of use for other soft tissue neoplasms in situations in which there are limited traditional treatment options such as recurrent sarcomas. Further investigation is necessary to better define the indications, efficacy, role, and long-term oncologic outcomes of focused ultrasound treatment. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26040968 TI - Do Upper Extremity Trauma Patients Have Different Preferences for Shared Decision making Than Patients With Nontraumatic Conditions? AB - BACKGROUND: Shared decision-making is a combination of expertise, available scientific evidence, and the preferences of the patient and surgeon. Some surgeons contend that patients are less capable of participating in decisions about traumatic conditions than nontraumatic conditions. QUESTIONS/PURPOSES: (1) Do patients with nontraumatic conditions have different preferences for shared decision-making when compared with those who sustained acute trauma? (2) Do disability, symptoms of depression, and self-efficacy correlate with preference for shared decision-making? METHODS: In this prospective, comparative trial, we evaluated a total of 133 patients presenting to the outpatient practices of two university-based hand surgeons with traumatic or nontraumatic hand and upper extremity illnesses or conditions. Each patient completed questionnaires measuring their preferred role in healthcare decision-making (Control Preferences Scale [CPS]), symptoms of depression (Patients' Health Questionnaire), and pain self-efficacy (confidence that one can achieve one's goals despite pain; measured using the Pain Self-efficacy Questionnaire). Patients also completed a short version of the Disabilities of the Arm, Shoulder, and Hand questionnaire and an ordinal rating of pain intensity. RESULTS: There was no difference in decision making preferences between patients with traumatic (CPS: 3 +/- 2) and nontraumatic conditions (CPS: 3 +/- 1 mean difference = 0.2 [95% confidence interval, -0.4 to 0.7], p = 0.78) with most patients (95 versus 38) preferring shared decision-making. More educated patients preferred a more active role in decision-making (beta = -0.1, r = 0.08, p = 0.001); however, differences in levels of disability, pain and function, depression, and pain-related self efficacy were not associated with differences in patients' preferences in terms of shared decision-making. CONCLUSIONS: Patients who sustained trauma have on average the same preference for shared decision-making compared with patients who sustained no trauma. Now that we know the findings of this study, clinicians might be motivated to share their expertise about the treatment options, potential outcomes, benefits, and harms with the patient and to discuss their preference as well in a semiacute setting, resulting in a shared decision. PMID- 26040969 TI - The Minimum Clinically Important Difference of the Patient-rated Wrist Evaluation Score for Patients With Distal Radius Fractures. AB - BACKGROUND: The Patient-rated Wrist Evaluation (PRWE) is a commonly used instrument in upper extremity surgery and in research. However, to recognize a treatment effect expressed as a change in PRWE, it is important to be aware of the minimum clinically important difference (MCID) and the minimum detectable change (MDC). The MCID of an outcome tool like the PRWE is defined as the smallest change in a score that is likely to be appreciated by a patient as an important change, while the MDC is defined as the smallest amount of change that can be detected by an outcome measure. A numerical change in score that is less than the MCID, even when statistically significant, does not represent a true clinically relevant change. To our knowledge, the MCID and MDC of the PRWE have not been determined in patients with distal radius fractures. QUESTIONS/PURPOSES: We asked: (1) What is the MCID of the PRWE score for patients with distal radius fractures? (2) What is the MDC of the PRWE? METHODS: Our prospective cohort study included 102 patients with a distal radius fracture and a median age of 59 years (interquartile range [IQR], 48-66 years). All patients completed the PRWE questionnaire during each of two separate visits. At the second visit, patients were asked to indicate the degree of clinical change they appreciated since the previous visit. Accordingly, patients were categorized in two groups: (1) minimally improved or (2) no change. The groups were used to anchor the changes observed in the PRWE score to patients' perspectives of what was clinically important. We determined the MCID using an anchor-based receiver operator characteristic method. In this context, the change in the PRWE score was considered a diagnostic test, and the anchor (minimally improved or no change as noted by the patients from visit to visit) was the gold standard. The optimal receiver operator characteristic cutoff point calculated with the Youden index reflected the value of the MCID. RESULTS: In our study, the MCID of the PRWE was 11.5 points. The area under the curve was 0.54 (95% CI, 0.37-0.70) for the pain subscale and 0.71 (95% CI, 0.57-0.85) for the function subscale. We determined the MDC to be 11.0 points. CONCLUSIONS: We determined the MCID of the PRWE score for patients with distal radius fractures using the anchor-based approach and verified that the MDC of the PRWE was sufficiently small to detect our MCID. CLINICAL RELEVANCE: We recommend using an improvement on the PRWE of more than 11.5 points as the smallest clinically relevant difference when evaluating the effects of treatments and when performing sample-size calculations on studies of distal radius fractures. PMID- 26040970 TI - T-cell subsets in autologous and allogeneic peripheral blood stem cell concentrates. AB - BACKGROUND AND OBJECTIVES: Regulatory T cells (Tregs) and other T-cell subsets are of importance in the setting of autologous and allogeneic stem cell transplantations. We conducted a study to assess the content of peripheral blood stem cell concentrates and related apheresis parameters in the autologous and allogeneic setting. MATERIAL AND METHODS: We characterized 53 donors, patients and peripheral blood stem cell concentrates (PBSC) regarding the content of CD45(+) cells, lymphocytes, CD3(+) cells, CD3(+) CD4(+) T cells, CD3(+) CD4(+) CD25(+) T cells, CD3(+) CD4(+) CD25(+) CD127(low/negative) Tregs and CD34(+) cells and calculated cell yields, recruitment factors and collection efficiency for all cell types. We compared allogeneic data with autologous data. RESULTS: Autologous PBSC show significantly lower concentrations of T-cell subsets compared to allogeneic PBSC (17,112/MUl CD4(+), 14,858/MUl CD4(+) CD25(+) and 1579/MUl CD3(+) CD4(+) CD25(+) CD127(low/negative) Tregs in autologous compared to 65,539/MUl CD4(+), 44,208(+) /MUl CD4(+) CD25(+) and 5040/MUl CD3(+) CD4(+) CD25(+) CD127(low/negative) Tregs in allogeneic PBSC, respectively), in contrast to CD34(+) concentrations (5342/MUl CD34(+) in autologous compared to 2367/MUl CD34(+) in allogeneic PBSC, respectively). Accordantly, all T-cell yields are lower in the autologous setting compared to allogeneic PBSC. However, recruitment factor and collection efficiency of all cell types are higher in autologous compared to allogeneic PBSC, but not all parameters differ significantly when groups are compared. CONCLUSION: T-cell subsets and especially Tregs are a substantial part of PBSC transplantation, as considerable recruitment during apheresis occurs. In large volume apheresis, the collection efficiency of Treg is comparable to that of CD34(+) cells, while recruitment factors are even higher. PMID- 26040971 TI - Quantitative analysis of the size effect of room temperature nanoimprinted P3HT nanopillar arrays on the photovoltaic performance. AB - We develop a solvent-assisted room temperature nanoimprint lithography (SART-NIL) technique to fabricate an ideal active layer consisting of poly(3-hexylthiophene) nanopillar arrays surrounded by [6,6]-phenyl-C61-butyric acid methyl ester. Characterization by scanning electron microscopy, two-dimensional grazing incidence wide angle X-rays diffraction, and conducting atomic force microscopy reveals that the SART-NIL technique can precisely control the size of P3HT nanopillar arrays. With the decrease in diameters of P3HT nanopillar arrays, the P3HT nanopillar arrays exhibit a more preferable face-on molecular orientation, enhanced UV-vis absorption and higher conducting ability along the direction perpendicular to the substrate. The ordered bulk heterojunction film consisting of P3HT nanopillar arrays with a diameter of ~45 nm (OBHJ-45) gives face-on orientation, a high interfacial area of 2.87, a high conducting ability of ~130 pA and efficient exciton diffusion and dissociation. The polymer solar cell (PSC) based on an OBHJ-45 film exhibits a significantly improved device performance compared with those of PSCs based on the P3HT nanoapillar arrays with diameters ~100 nm and ~60 nm. We believe that the SART-NIL technique is a powerful tool for fabricating an ideal active layer for high performance PSCs. PMID- 26040972 TI - Chromothripsis with at least 12 breaks at 1p36.33-p35.3 in a boy with multiple congenital anomalies. AB - Terminal deletion in the short arm of chromosome 1 results in a disorder described as 1p36 deletion syndrome. The resulting phenotype varies among patients including mental retardation, developmental delay, sensorineural hearing loss, seizures, heart defects, and distinct facies. In the present case, we performed array-comparative genomic hybridization in a boy with multiple congenital malformations presenting some features overlapping the 1p36 deletion phenotype for whom chromosomal analysis did not reveal a terminal deletion in 1p. Results showed complex chromosome rearrangements involving the 1p36.33-p35.3 region. While the mechanism of origin of these rearrangements is still unclear, chromothripsis-a single catastrophic event leading to shattering chromosomes or chromosome regions and rejoining of the segments-has been described to occur in a fraction of cancers. The presence of at least 12 clustered breaks at 1p and apparent lack of mosaicism in the present case suggests that a single event like chromothripsis occurred. This finding suggests that chromothripsis is responsible for some constitutive complex chromosome rearrangements. PMID- 26040973 TI - Evaluation of phosphorus adsorption capacity of sesame straw biochar on aqueous solution: influence of activation methods and pyrolysis temperatures. AB - The phosphorus (P) adsorption characteristic of sesame straw biochar prepared with different activation agents and pyrolysis temperatures was evaluated. Between 0.109 and 0.300 mg L(-1) in the form of inorganic phosphate was released from raw sesame straw biochar in the first 1 h. The release of phosphate was significantly enhanced from 62.6 to 168.2 mg g(-1) as the pyrolysis temperature increased. Therefore, sesame straw biochar cannot be used as an adsorbent for P removal without change in the physicochemical characteristics. To increase the P adsorption of biochar in aqueous solution, various activation agents and pyrolysis temperatures were applied. The amount of P adsorbed from aqueous solution by biochar activated using different activation agents appeared in the order ZnCl2 (9.675 mg g(-1)) > MgO (8.669 mg g(-1)) ? 0.1N-HCl > 0.1N-H2SO4 > K2SO4 >= KOH >= 0.1N-H3PO4, showing ZnCl2 to be the optimum activation agent. Higher P was adsorbed by the biochar activated using ZnCl2 under different pyrolysis temperatures in the order 600 degrees C > 500 degrees C > 400 degrees C > 300 degrees C. Finally, the amount of adsorbed P by activated biochar at different ratios of biochar to ZnCl2 appeared in the order 1:3 ? 1:1 > 3:1. As a result, the optimum ratio of biochar to ZnCl2 and pyrolysis temperature were found to be 1:1 and 600 degrees C for P adsorption, respectively. The maximum P adsorption capacity by activated biochar using ZnCl2 (15,460 mg kg(-1)) was higher than that of typical biochar, as determined by the Langmuir adsorption isotherm. Therefore, the ZnCl2 activation of sesame straw biochar was suitable for the preparation of activated biochar for P adsorption. PMID- 26040974 TI - Phytoextraction of potentially toxic elements by Indian mustard, rapeseed, and sunflower from a contaminated riparian soil. AB - The objective of this study was to quantify the phytoextraction of the potentially toxic elements Al, As, Cd, Co, Cr, Cu, Mo, Ni, Pb, Se, V, and Zn by Indian mustard, rapeseed, and sunflower from a contaminated riparian soil. To achieve this goal, a greenhouse pot experiment was established using a highly contaminated grassland soil collected at the Wupper River (Germany). The impact of ethylene-diamine-tetra-acetic acid (EDTA), humate (HK), and phosphate potassium (PK) on the mobility and uptake of the elements by rapeseed also was investigated. Indian mustard showed the highest efficiency for phytoextraction of Al, Cr, Mo, Se, and V; sunflower for Cd, Ni, Pb, and Zn, and rapeseed for Cu. The bioconcentration ratios were higher than 1 for the elements (except As and Cu), indicating the suitability of the studied plants for phytoextraction. Application of EDTA to the soil increased significantly the solubility of Cd, Co, Cr, Ni, and Pb and decreased the solubility of Al, As, Se, V, and Mo. Humate potassium decreased significantly the concentrations of Al and As in rapeseed but increased the concentrations of Cu, Se, and Zn. We may conclude that HK can be used for immobilization of Al and As, while it can be used for enhancing the phytoextraction of Cu, Se, and Zn by rapeseed. Phosphate potassium immobilized Al, Cd, Pb, and Zn, but enhanced phytoextraction of As, Cr, Mo, and Se by rapeseed. PMID- 26040975 TI - Hydrogeochemical tracing of mineral water in Jingyu County, Northeast China. AB - The east Jilin Province in China, Jingyu County has been explored as a potential for enriching mineral water. In order to assess the water quality and quantity, it is of crucial importance to investigate the origin of the mineral water and its flow paths. In this study, eighteen mineral springs were sampled in May and September of 2012, May and September of 2013, and May 2014 and the environment, evolvement, and reaction mechanism of mineral water formation were analysed by hydrochemical data analysis, geochemical modelling and multivariate statistical analysis. The results showed that the investigated mineral water was rich in calcium, magnesium, potassium, sodium, bicarbonate, chloride, sulphate, fluoride, nitrate, total iron, silicate, and strontium, and mineral water ages ranged from 11.0 to more than 61.0 years. The U-shape contours of the mineral ages indicate a local and discrete recharge. The mineral compositions of the rocks were olivine, potassium feldspar, pyroxene, albite, and anorthite and were under-saturated in the mineral water. The origin of mineral water was from the hydrolysis of basalt minerals under a neutral to slightly alkaline and CO2-rich environment. PMID- 26040977 TI - White and grey matter relations to simple, choice, and cognitive reaction time in spina bifida. AB - Elevated reaction time (RT) is common in brain disorders. We studied three forms of RT in a neurodevelopmental disorder, spina bifida myelomeningocele (SBM), characterized by regional alterations of both white and grey matter, and typically developing individuals aged 8 to 48 years, in order to establish the nature of the lifespan-relations of RT and brain variables. Cognitive accuracy and RT speed and variability were all impaired in SBM relative to the typically developing group, but the most important effects of SBM on RT are seen on tasks that require a cognitive decision rule. Individuals with SBM are impaired not only in speeded performance, but also in the consistency of their performance on tasks that extend over time, which may contribute to poor performance on a range of cognitive tasks. The group with SBM showed smaller corrected corpus callosum proportions, larger corrected cerebellar white matter proportions, and larger corrected proportions for grey matter in the Central Executive and Salience networks. There were clear negative relations between RT measures and corpus callosum, Central Executive, and Default Mode networks in the group with SBM; relations were not observed in typically developing age peers. Statistical mediation analyses indicated that corpus callosum and Central Executive Network were important mediators. While RT is known to rely heavily on white matter under conditions of typical development and in individuals with adult-onset brain injury, we add the new information that additional involvement of grey matter may be important for a key neuropsychological function in a common neurodevelopmental disorder. PMID- 26040978 TI - Effects of oxytocin and vasopressin on the neural response to unreciprocated cooperation within brain regions involved in stress and anxiety in men and women. AB - Anxiety disorders are characterized by hyperactivity in both the amygdala and the anterior insula. Interventions that normalize activity in these areas may therefore be effective in treating anxiety disorders. Recently, there has been significant interest in the potential use of oxytocin (OT), as well as vasopressin (AVP) antagonists, as treatments for anxiety disorders. In this double-blind, placebo-controlled, pharmaco- fMRI study, 153 men and 151 women were randomized to treatment with either 24 IU intranasal OT, 20 IU intranasal AVP, or placebo and imaged with fMRI as they played the iterated Prisoner's Dilemma game with same-sex human and computer partners. In men, OT attenuated the fMRI response to unreciprocated cooperation (CD), a negative social interaction, within the amygdala and anterior insula. This effect was specific to interactions with human partners. In contrast, among women, OT unexpectedly attenuated the amygdala and anterior insula response to unreciprocated cooperation from computer but not human partners. Among women, AVP did not significantly modulate the response to unreciprocated cooperation in either the amygdala or the anterior insula. However, among men, AVP attenuated the BOLD response to CD outcomes with human partners across a relatively large cluster including the amygdala and the anterior insula, which was contrary to expectations. Our results suggest that OT may decrease the stress of negative social interactions among men, whereas these effects were not found in women interacting with human partners. These findings support continued investigation into the possible efficacy of OT as a treatment for anxiety disorders. PMID- 26040976 TI - Air pollution and public health: emerging hazards and improved understanding of risk. AB - Despite past improvements in air quality, very large parts of the population in urban areas breathe air that does not meet European standards let alone the health-based World Health Organisation Air Quality Guidelines. Over the last 10 years, there has been a substantial increase in findings that particulate matter (PM) air pollution is not only exerting a greater impact on established health endpoints, but is also associated with a broader number of disease outcomes. Data strongly suggest that effects have no threshold within the studied range of ambient concentrations, can occur at levels close to PM2.5 background concentrations and that they follow a mostly linear concentration-response function. Having firmly established this significant public health problem, there has been an enormous effort to identify what it is in ambient PM that affects health and to understand the underlying biological basis of toxicity by identifying mechanistic pathways-information that in turn will inform policy makers how best to legislate for cleaner air. Another intervention in moving towards a healthier environment depends upon the achieving the right public attitude and behaviour by the use of optimal air pollution monitoring, forecasting and reporting that exploits increasingly sophisticated information systems. Improving air quality is a considerable but not an intractable challenge. Translating the correct scientific evidence into bold, realistic and effective policies undisputedly has the potential to reduce air pollution so that it no longer poses a damaging and costly toll on public health. PMID- 26040979 TI - Is the Alzheimer's disease cortical thickness signature a biological marker for memory? AB - Recent work suggests that analysis of the cortical thickness in key brain regions can be used to identify individuals at greatest risk for development of Alzheimer's disease (AD). It is unclear to what extent this "signature" is a biological marker of normal memory function - the primary cognitive domain affected by AD. We examined the relationship between the AD signature biomarker and memory functioning in a group of neurologically healthy young and older adults. Cortical thickness measurements and neuropsychological evaluations were obtained in 110 adults (age range 21-78, mean = 46) drawn from the Brain Resource International Database. The cohort was divided into young adult (n = 64, age 21 50) and older adult (n = 46, age 51-78) groups. Cortical thickness analysis was performed with FreeSurfer, and the average cortical thickness extracted from the eight regions that comprise the AD signature. Mean AD-signature cortical thickness was positively associated with performance on the delayed free recall trial of a list learning task and this relationship did not differ between younger and older adults. Mean AD-signature cortical thickness was not associated with performance on a test of psychomotor speed, as a control task, in either group. The results suggest that the AD signature cortical thickness is a marker for memory functioning across the adult lifespan. PMID- 26040980 TI - Neurobiological mechanisms associated with facial affect recognition deficits after traumatic brain injury. AB - The neurobiological mechanisms that underlie facial affect recognition deficits after traumatic brain injury (TBI) have not yet been identified. Using functional magnetic resonance imaging (fMRI), study aims were to 1) determine if there are differences in brain activation during facial affect processing in people with TBI who have facial affect recognition impairments (TBI-I) relative to people with TBI and healthy controls who do not have facial affect recognition impairments (TBI-N and HC, respectively); and 2) identify relationships between neural activity and facial affect recognition performance. A facial affect recognition screening task performed outside the scanner was used to determine group classification; TBI patients who performed greater than one standard deviation below normal performance scores were classified as TBI-I, while TBI patients with normal scores were classified as TBI-N. An fMRI facial recognition paradigm was then performed within the 3T environment. Results from 35 participants are reported (TBI-I = 11, TBI-N = 12, and HC = 12). For the fMRI task, TBI-I and TBI-N groups scored significantly lower than the HC group. Blood oxygenation level-dependent (BOLD) signals for facial affect recognition compared to a baseline condition of viewing a scrambled face, revealed lower neural activation in the right fusiform gyrus (FG) in the TBI-I group than the HC group. Right fusiform gyrus activity correlated with accuracy on the facial affect recognition tasks (both within and outside the scanner). Decreased FG activity suggests facial affect recognition deficits after TBI may be the result of impaired holistic face processing. Future directions and clinical implications are discussed. PMID- 26040982 TI - A microwave-facilitated rapid synthesis of gold nanoclusters with tunable optical properties for sensing ions and fluorescent ink. AB - Luminescent glutathione-capped gold nanoclusters (GS-AuNCs) with tunable emissions have been efficiently synthesized by a solution-based microwave method. PMID- 26040981 TI - Loss of SOX2 expression induces cell motility via vimentin up-regulation and is an unfavorable risk factor for survival of head and neck squamous cell carcinoma. AB - Recurrent gain on chromosome 3q26 encompassing the gene locus for the transcription factor SOX2 is a frequent event in human squamous cell carcinoma, including head and neck squamous cell carcinoma (HNSCC). Numerous studies demonstrated that SOX2 expression and function is related to distinct aspects of tumor cell pathophysiology. However, the underlying molecular mechanisms are not well understood, and the correlation between SOX2 expression and clinical outcome revealed conflicting data. Transcriptional profiling after silencing of SOX2 expression in a HNSCC cell line identified a set of up-regulated genes related to cell motility (e.g. VIM, FN1, CDH2). The inverse regulation of SOX2 and aforementioned genes was validated in 18 independent HNSCC cell lines from different anatomical sites. The inhibition of cell migration and invasion by SOX2 was confirmed by constant or conditional gene silencing and accelerated motility of HNSCC cells after SOX2 silencing was partially reverted by down-regulation of vimentin. In a retrospective study, SOX2 expression was determined by immunohistochemical staining on tissue microarrays containing primary tumor specimens of two independent HNSCC patient cohorts. Low SOX2 expression was found in 19.3% and 44.9% of primary tumor specimens, respectively. Univariate analysis demonstrated a statistically significant correlation between low SOX2 protein levels and reduced progression-free survival (Cohort I 51 vs. 16 months; Cohort II 33 vs. 12 months) and overall survival (Cohort I 150 vs. 37 months; Cohort II 33 vs. 16 months). Multivariate Cox proportional hazard model analysis confirmed that low SOX2 expression serves as an independent prognostic marker for HNSCC patients. We conclude that SOX2 inhibits tumor cell motility in HNSCC cells and that low SOX2 expression serves as a prognosticator to identify HNSCC patients at high risk for treatment failure. PMID- 26040984 TI - Target deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery. AB - Identification of the target proteins of bioactive small molecules isolated from phenotypic screens plays an important role in chemical biology and drug discovery. However, discovering the targets of small molecules is often the most challenging and time-consuming step for chemical biology researchers. To overcome the bottlenecks in target identification, many new approaches based on genomics, proteomics, and bioinformatics technologies have been developed. Here, we provide an overview of the current major methodologies for target deconvolution of bioactive small molecules. To obtain an integrated view of the mechanisms of action of small molecules, we propose a systematic approach that involves the combination of multi-omics-based target identification and validation and preclinical target validation. PMID- 26040983 TI - Intraoperative, real-time monitoring of blood flow dynamics associated with laser surgery of port wine stain birthmarks. AB - BACKGROUND AND OBJECTIVE: Port-wine stain (PWS) birthmarks affect ~22 million people worldwide. After several treatment sessions, complete disappearance of the PWS occurs in only ~10% of treated patients. There is a need to develop a new strategy to improve the efficacy of each treatment session and the overall treatment outcome. The study objective was to determine how intraoperative measurements of blood flow correlate with treatment response assessed several weeks post treatment. STUDY DESIGN/MATERIALS AND METHODS: We employed Laser Speckle Imaging (LSI) to measure intraoperative blood-flow dynamics. We collected data from 24 subjects undergoing laser therapy for facial PWS birthmarks. Photographs were taken before treatment and at a follow-up visit, and analyzed by two expert observers. RESULTS: Intraoperative LSI enables real-time monitoring of blood-flow dynamics in response to laser treatment and can inform clinicians on the need for focused re-treatment. The degree of PWS blanching achieved is positively correlated with the log-transformed acute blood-flow reduction (P = 0.022). CONCLUSION: LSI is a simple, intraoperative monitoring tool during laser therapy of PWS birthmarks. LSI provides a single value for blood flow that correlates well with the degree of blanching achieved with laser therapy. PMID- 26040985 TI - Discovery and characterization of novel small-molecule inhibitors targeting nicotinamide phosphoribosyltransferase. AB - Nicotinamide phosphoribosyltransferase (NAMPT) is a promising anticancer target. Using high throughput screening system targeting NAMPT, we obtained a potent NAMPT inhibitor MS0 (China Patent ZL201110447488.9) with excellent in vitro activity (IC50 = 9.87 +/- 1.15 nM) and anti-proliferative activity against multiple human cancer cell lines including stem-like cancer cells. Structure activity relationship studies yielded several highly effective analogues. These inhibitors specifically bound NAMPT, rather than downstream NMNAT. We provided the first chemical case using cellular thermal shift assay to explain the difference between in vitro and cellular activity; MS7 showed best in vitro activity (IC50 = 0.93 +/- 0.29 nM) but worst cellular activity due to poor target engagement in living cells. Site-directed mutagenesis studies identified important residues for NAMPT catalytic activity and inhibitor binding. The present findings contribute to deep understanding the action mode of NAMPT inhibitors and future development of NAMPT inhibitors as anticancer agents. PMID- 26040986 TI - Circadian control of bile acid synthesis by a KLF15-Fgf15 axis. AB - Circadian control of nutrient availability is critical to efficiently meet the energetic demands of an organism. Production of bile acids (BAs), which facilitate digestion and absorption of nutrients, is a major regulator of this process. Here we identify a KLF15-Fgf15 signalling axis that regulates circadian BA production. Systemic Klf15 deficiency disrupted circadian expression of key BA synthetic enzymes, tissue BA levels and triglyceride/cholesterol absorption. Studies in liver-specific Klf15-knockout mice suggested a non-hepatic basis for regulation of BA production. Ileal Fgf15 is a potent inhibitor of BA synthesis. Using a combination of biochemical, molecular and functional assays (including ileectomy and bile duct catheterization), we identify KLF15 as the first endogenous negative regulator of circadian Fgf15 expression. Elucidation of this novel pathway controlling circadian BA production has important implications for physiologic control of nutrient availability and metabolic homeostasis. PMID- 26040987 TI - HMGB1 Neutralizing Antibody Attenuates Cardiac Injury and Apoptosis Induced by Hemorrhagic Shock/Resuscitation in Rats. AB - High-mobility group box 1 (HMGB1) and its natural receptor, Toll-like receptor-4 (TLR4), are involved in various infectious or noninfectious diseases including hemorrhagic shock. HMGB1 neutralizing antibody (anti-HMGB1 monoclonal antibody (mAb)) treatment was shown to alleviate ischemia-reperfusion injury effectively. The aim of this study was to explore whether and by what mechanisms anti-HMGB1 mAb attenuates hemorrhagic shock and resuscitation (HS/R)-induced cardiac injury. Employing rat HS/R models, we found that anti-HMGB1 mAb treatment improved HS/R induced cardiac function deterioration, attenuated cardiac enzyme elevation, improved ATP loss, and protected cardiac tissue. Anti-HMGB1 mAb also inhibited the production of inflammatory factors interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha). Moreover, anti-HMGB1 mAb reduced apoptotic responses by suppressing activated caspase-3 and reversing apoptotic gene expression of capase-3, Bax, and Bcl-2 in rat cardiac tissue. Moreover, anti HMGB1 mAb decreased HS/R-induced HMGB1 and TLR4 expression elevation. We further confirmed that anti-HMGB1 mAb inhibited lipopolysaccharide-activated HGMB1 and TLR4 expression and decreased inflammatory factors IL-1beta, IL-6, and TNF-alpha at the cellular level. It was concluded that anti-HMGB1 mAb treatment protects rats from cardiac injury induced by HS/R, and the beneficial effects may be related to its inhibitory effects on the HMGB1-TLR4 axis. PMID- 26040988 TI - The effects of phosphodiesterase-5 inhibitor sildenafil against post resuscitation myocardial and intestinal microcirculatory dysfunction by attenuating apoptosis and regulating microRNAs expression: essential role of nitric oxide syntheses signaling. AB - BACKGROUND: Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion (I/R) injury. Sildenafil has been shown to attenuate postresuscitation myocardial dysfunction in piget models of ventricular fibrillation. This study was designed to investigate if administration of sildenafil will attenuate post-resuscitation myocardial dysfunction by attenuating apoptosis and regulating miRNA expressions, furthermore, ameliorating the severity of post-microcirculatory dysfunction. METHODS: Twenty-four male pigs (weighing 30 +/- 2 kg) were randomly divided into groups, sildenafil pretreatment (n = 8), saline (n = 8) and sham operation (sham, n = 8). Sildenafil pretreatment consisted of 0.5 mg/kg sildenafil, administered once intraperitoneally 30 min prior to ventricular fibrillation (VF). Eight minutes of untreated VF was followed by defibrillation in anesthetized, closed chest pigs. Hemodynamic status and blood samples were obtained at 0 min, 0.5, 1, 2, 4 and 6 h after return of spontaneous circulation (ROSC). Surviving pigs were euthanatized at 24 h after ROSC, and hearts were removed for analysis by electron microscopy, western blotting, quantitative real-time polymerase chain reaction (PCR), and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Intestinal microcirculatory blood flow was visualized by a sidestream dark-field imaging device at baseline and 0.5, 1, 2, 4, and 6 h after ROSC. RESULTS: Compared with the saline group, the sildenafil group had a higher 24-hour survival (7/8 versus 3/8 survivors, p < 0.05) and a better outcome in hemodynamic parameters. The protective effect of sildenafil also correlated with reduced cardiomyocyte apoptosis, as evidenced by reduced TUNEL-positive cells, increased anti-apoptotic Bcl-2/Bax ratio and inhibited caspase-3 activity in myocardium. Additionally, sildenafil treatment inhibited the increases in the microRNA-1 levels and alleviated the decreases in the microRNA-133a levels which negatively regulates pro-apoptotic genes. At 6 h after ROSC, post-resuscitation perfused vessel density and microcirculatory flow index were significantly lower in the saline group than in the sildenafil group. CONCLUSIONS: The major findings of this study are as follows: (1) sildenafil improved post-resuscitation perfusion of the heart, and thus reduced cardiac myocyte apoptosis and improved cardiac function; (2) sildenafil treatment inhibited the increases in the microRNA-1 levels, but alleviated the decreases in the microRNA-133a levels. PMID- 26040989 TI - High Prevalence of Assisted Injection Among Street-Involved Youth in a Canadian Setting. AB - Many people who inject illicit drugs receive manual assistance when injecting, and this practice has been linked to increased risk of HIV infection and other harms. Little is known, however, about this practice among youth. This study uses a multivariate generalized estimating equation to identify factors associated with receiving assistance with injecting among a cohort of street-involved youth aged 14-26 in Vancouver, Canada. A total of 253 participants reported injecting drugs during the study period, and 49 % (n = 125) of these youth reported receiving assistance with injecting in the past 6 months. In multivariate analysis, younger age, female gender, binge drug use, heroin injecting, cocaine injecting, crystal methamphetamine injecting, and syringe sharing were positively and independently associated with assisted injection (all p < 0.05). These findings underscore the need for expanding substance abuse treatment alongside HIV prevention and health promotion interventions to empower youth to enact safer injection practices. PMID- 26040990 TI - Partial depletion of yolk during zebrafish embryogenesis changes the dynamics of methionine cycle and metabolic genes. AB - BACKGROUND: Limited nutrient availability during development is associated with metabolic diseases in adulthood. The molecular cause for these defects is unclear. Here, we investigate if transcriptional changes caused by developmental malnutrition reveal an early response that can be linked to metabolism and metabolic diseases. RESULTS: We limited nutrient availability by removing yolk from zebrafish (Danio rerio) embryos. We then measured genome expression after 8, 24, 32 h post-fertilization (hpf) by RNA sequencing and 48 hpf by microarray profiling. We assessed the functional impact of deregulated genes by enrichment analysis of gene ontologies, pathways and CpG sites around the transcription start sites. Nutrient depletion during embryogenesis does not affect viability, but induces a bias towards female development. It induces subtle expression changes of metabolic genes: lipid transport, oxidative signaling, and glycolysis are affected during earlier stages, and hormonal signaling at 48 hpf. Co-citation analysis indicates association of deregulated genes to the metabolic syndrome, a known outcome of early-life nutrient depletion. Notably, deregulated methionine cycle genes indicate altered methyl donor availability. We find that the regulation of deregulated genes may be less dependent on methyl donor availability. CONCLUSIONS: The systemic response to reduced nutrient availability in zebrafish embryos affects metabolic pathways and can be linked to metabolic diseases. Further exploration of the reported zebrafish model system may elucidate the consequences of reduced nutrient availability during embryogenesis. PMID- 26040991 TI - Zn(II) and Hg(II) binding to a designed peptide that accommodates different coordination geometries. AB - Designed metal ion binding peptides offer a variety of applications in both basic science as model systems of more complex metalloproteins, and in biotechnology, e.g. in bioremediation of toxic metal ions, biomining or as artificial enzymes. In this work a peptide (HS: Ac-SCHGDQGSDCSI-NH2) has been specifically designed for binding of both Zn(II) and Hg(II), i.e. metal ions with different preferences in terms of coordination number, coordination geometry, and to some extent ligand composition. It is demonstrated that HS accommodates both metal ions, and the first coordination sphere, metal ion exchange between peptides, and speciation are characterized as a function of pH using UV-absorption-, synchrotron radiation CD-, (1)H-NMR-, and PAC-spectroscopy as well as potentiometry. Hg(II) binds to the peptide with very high affinity in a {HgS2} coordination geometry, bringing together the two cysteinates close to each end of the peptide in a loop structure. Despite the high affinity, Hg(II) is kinetically labile, exchanging between peptides on the subsecond timescale, as indicated by line broadening in (1)H-NMR. The Zn(II)-HS system displays more complex speciation, involving monomeric species with coordinating cysteinates, histidine, and a solvent water molecule, as well as HS-Zn(II)-HS complexes. In summary, the HS peptide displays conformational flexibility, contains many typical metal ion binding groups, and is able to accommodate metal ions with different structural and ligand preferences with high affinity. As such, the HS peptide may be a scaffold offering binding of a variety of metal ions, and potentially serve for metal ion sequestration in biotechnological applications. PMID- 26040992 TI - Possible effect of lysophosphatidic acid on cell proliferation and involvement of lysophosphatidic acid and lysophosphatidic acid receptors in mechanical stretch induced mitogen-activated protein kinase. AB - OBJECTIVES: To determine whether lysophosphatidic acid activates the mitogen activated protein kinase and increases DNA synthesis in human bladder smooth muscle cells, and to examine the involvement of lysophosphatidic acid and lysophosphatidic acid receptor in mechanical stretch-induced mitogen-activated protein kinase activation in cultured human bladder smooth muscle cells. METHODS: TaqMan reverse transcription polymerase chain reaction was used to determine the mRNA expression levels of six lysophosphatidic acid receptor subtypes. Mitogen activated protein kinase activity enhanced by either lysophosphatidic acid or mechanical stretch was measured by western blotting. The effect of lysophosphatidic acid on DNA synthesis was assessed by 5-bromo-2'-deoxy-uridine incorporation assay. RESULTS: Lysophosphatidic acid 1 subtype mRNA was predominantly expressed (96%). Lysophosphatidic acid activated the mitogen activated protein kinase in a concentration-dependent manner. C-jun NH2 -terminal kinase showed the highest activity among the three subsets of the mitogen activated protein kinase family members (c-jun NH2 -terminal kinase, extracellular signal-regulated kinases, p38). Lysophosphatidic acid also increased incorporation of 5-bromo-2'-deoxy-uridine. These responses were suppressed by Ki16425 (lysophosphatidic acid receptor antagonist). Mechanical stretch mainly induced c-jun NH2 -terminal kinase activation. This activation was partially inhibited by Ki16425. CONCLUSIONS: Lysophosphatidic acid might activate the c-jun NH2 -terminal kinase component of the mitogen-activated protein kinase family and DNA synthesis through lysophosphatidic acid receptors (presumably, through lysophosphatidic acid 1) in human bladder smooth muscle cells. The present study also implicates the involvement of lysophosphatidic acid and lysophosphatidic acid receptors in mechanical stretch-induced c-jun NH2 -terminal kinase activation. Lysophosphatidic acid receptor can be partially activated by mechanical stretching through lysophosphatidic acid-dependent or independent mechanism. PMID- 26040993 TI - A novel salt-tolerant chitobiosidase discovered by genetic screening of a metagenomic library derived from chitin-amended agricultural soil. AB - Here, we report on the construction of a metagenomic library from a chitin amended disease-suppressive agricultural soil and its screening for genes that encode novel chitinolytic enzymes. The library, constructed in fosmids in an Escherichia coli host, comprised 145,000 clones containing inserts of sizes of 21 to 40 kb, yielding a total of approximately 5.8 GB of cloned soil DNA. Using genetic screenings by repeated PCR cycles aimed to detect gene sequences of the bacterial chitinase A-class (hereby named chi A genes), we identified and characterized five fosmids carrying candidate genes for chitinolytic enzymes. The analysis thus allowed access to the genomic (fosmid-borne) context of these genes. Using the chiA-targeted PCR, which is based on degenerate primers, the five fosmids all produced amplicons, of which the sequences were related to predicted chitinolytic enzyme-encoding genes of four different host organisms, including Stenotrophomonas maltophilia. Sequencing and de novo annotation of the fosmid inserts confirmed that each one of these carried one or more open reading frames that were predicted to encode enzymes active on chitin, including one for a chitin deacetylase. Moreover, the genetic contexts in which the putative chitinolytic enzyme-encoding genes were located were unique per fosmid. Specifically, inserts from organisms related to Burkholderia sp., Acidobacterium sp., Aeromonas veronii, and the chloroflexi Nitrolancetus hollandicus and/or Ktedonobacter racemifer were obtained. Remarkably, the S. maltophilia chiA-like gene was found to occur in two different genetic contexts (related to N. hollandicus/K. racemifer), indicating the historical occurrence of genetic reshufflings in this part of the soil microbiota. One fosmid containing the insert composed of DNA from the N. hollandicus-like organism (denoted 53D1) was selected for further work. Using subcloning procedures, its putative gene for a chitinolytic enzyme was successfully brought to expression in an E. coli host. On the basis of purified protein preparations, the produced protein was characterized as a chitobiosidase of 43.6 kDa, with a pI of 4.83. Given its activity spectrum, it can be typified as a halotolerant chitobiosidase. PMID- 26040994 TI - Angelman Syndrome. AB - In this review we summarize the clinical and genetic aspects of Angelman syndrome (AS), its molecular and cellular underpinnings, and current treatment strategies. AS is a neurodevelopmental disorder characterized by severe cognitive disability, motor dysfunction, speech impairment, hyperactivity, and frequent seizures. AS is caused by disruption of the maternally expressed and paternally imprinted UBE3A, which encodes an E3 ubiquitin ligase. Four mechanisms that render the maternally inherited UBE3A nonfunctional are recognized, the most common of which is deletion of the maternal chromosomal region 15q11-q13. Remarkably, duplication of the same chromosomal region is one of the few characterized persistent genetic abnormalities associated with autistic spectrum disorder, occurring in >1-2% of all cases of autism spectrum disorder. While the overall morphology of the brain and connectivity of neural projections appear largely normal in AS mouse models, major functional defects are detected at the level of context-dependent learning, as well as impaired maturation of hippocampal and neocortical circuits. While these findings demonstrate a crucial role for ubiquitin protein ligase E3A in synaptic development, the mechanisms by which deficiency of ubiquitin protein ligase E3A leads to AS pathophysiology in humans remain poorly understood. However, recent efforts have shown promise in restoring functions disrupted in AS mice, renewing hope that an effective treatment strategy can be found. PMID- 26040995 TI - Increases in peripheral SIRT1: a new biological characteristic of asthma. AB - BACKGROUND AND OBJECTIVE: Silent information regulator 1 (SIRT1) is a class III histone deacetylase that exerts both anti-inflammatory and anti-aging effects. However, no data are available regarding SIRT1 expression in patients with asthma. Here, we studied SIRT1 levels in the serum of patients with asthma and analysed the distribution of SIRT1 in both the serum and the lungs in an asthmatic mouse model to determine its clinical significance. METHODS: Serum SIRT1 levels, total immunoglobulin E (IgE) levels and peripheral blood eosinophil percentages as well as pulmonary function were quantified in 97 patients with asthma and 118 healthy volunteers. BALB/c mice were sensitized and challenged using ovalbumin (OVA) to produce the asthmatic model, and SIRT1 levels in both the serum and the lung tissues were subsequently measured. RESULTS: The serum SIRT1 levels were significantly elevated in the patients with asthma compared with the controls. Serum SIRT1 levels positively correlated with total IgE levels and negatively correlated with pulmonary function. In the OVA-sensitized and challenged mice, an increased serum SIRT1 level was confirmed, whereas decreased SIRT1 expression was observed in the lung tissues. CONCLUSIONS: These data indicate that lung SIRT1 expression decreased while serum SIRT1 increased in the setting of asthma. Serum SIRT1 levels correlate positively with both IgE levels and negatively with pulmonary function, suggesting that increased peripheral SIRT1 levels represent a new biological characteristic of asthma. Increased serum SIRT1 may be an auxiliary index for the diagnosis of asthma and elevating lung SIRT1 levels may be a new strategy for asthma therapy. PMID- 26040996 TI - In the Opponent's Shoes: Increasing the Behavioral Validity of Attackers' Judgments in Counterterrorism Models. AB - A key objective for policymakers and analysts dealing with terrorist threats is trying to predict the actions that malicious agents may take. A recent trend in counterterrorism risk analysis is to model the terrorists' judgments, as these will guide their choices of such actions. The standard assumptions in most of these models are that terrorists are fully rational, following all the normative desiderata required for rational choices, such as having a set of constant and ordered preferences, being able to perform a cost-benefit analysis of their alternatives, among many others. However, are such assumptions reasonable from a behavioral perspective? In this article, we analyze the types of assumptions made across various counterterrorism analytical models that represent malicious agents' judgments and discuss their suitability from a descriptive point of view. We then suggest how some of these assumptions could be modified to describe terrorists' preferences more accurately, by drawing knowledge from the fields of behavioral decision research, politics, philosophy of choice, public choice, and conflict management in terrorism. Such insight, we hope, might help make the assumptions of these models more behaviorally valid for counterterrorism risk analysis. PMID- 26040998 TI - Possible Sulfamethoxazole/Trimethoprim-Induced Pancreatitis in a Complicated Adolescent Patient Posttraumatic Injury. AB - INTRODUCTION: Multiple medications have been associated with pancreatitis, however, data in the pediatric population are scarce secondary to the nonspecific presentation and infrequent diagnosis. The aim of this report is to characterize drug-induced pancreatitis in an adolescent patient. CASE PRESENTATION: A 16-year old African-American female presented with a surgical site infection 8 weeks after a motor vehicle accident with multiple traumas. Two weeks prior to the admission, the patient was hospitalized for a urinary tract infection (UTI) and was initiated on sulfamethoxazole/trimethoprim (TMP/SMX) daily for UTI prophylaxis. On day 13, the patient was diagnosed with acute pancreatitis with an amylase level of 187 units/L (normal = 30-110) and a lipase level of 987 units/L (normal = 23-208). TMP/SMX was discontinued, and pancreatic enzyme levels decreased but did not reach normal. The patient was asymptomatic at discharge. DISCUSSION: TMP/SMX was identified as the likely etiology of pancreatitis by the medical team. Evaluation with the Naranjo algorithm indicated a "possible" adverse drug reaction. CONCLUSION: Acute pancreatitis can have significant morbidity and mortality in the pediatric population but can go undiagnosed due to its lower incidence. Pediatric patients presenting with idiopathic abdominal pain should be evaluated for pancreatitis and drug therapy should be reviewed for potential causative agents. PMID- 26040997 TI - Resistive-Pulse Measurements with Nanopipettes: Detection of Vascular Endothelial Growth Factor C (VEGF-C) Using Antibody-Decorated Nanoparticles. AB - Quartz nanopipettes have recently been employed for resistive-pulse sensing of Au nanoparticles (AuNP) and nanoparticles with bound antibodies. The analytical signal in such experiments is the change in ionic current caused by the nanoparticle translocation through the pipette orifice. This paper describes resistive-pulse detection of cancer biomarker (Vascular Endothelial Growth Factor C, VEGF-C) through the use of antibody-modified AuNPs and nanopipettes. The main challenge was to differentiate between AuNPs with attached antibodies for VEGF-C and antigen-conjugated particles. The zeta-potentials of these types of particles are not very different, and, therefore, carefully chosen pipettes with well characterized geometry were necessary for selective detection of VEGF-C. PMID- 26040999 TI - Cardiovascular risk estimation in older persons: SCORE O.P. AB - AIMS: Estimation of cardiovascular disease risk, using SCORE (Systematic COronary Risk Evaluation) is recommended by European guidelines on cardiovascular disease prevention. Risk estimation is inaccurate in older people. We hypothesized that this may be due to the assumption, inherent in current risk estimation systems, that risk factors function similarly in all age groups. We aimed to derive and validate a risk estimation function, SCORE O.P., solely from data from individuals aged 65 years and older. METHODS AND RESULTS: 20,704 men and 20,121 women, aged 65 and over and without pre-existing coronary disease, from four representative, prospective studies of the general population were included. These were Italian, Belgian and Danish studies (from original SCORE dataset) and the CONOR (Cohort of Norway) study. The variables which remained statistically significant in Cox proportional hazards model and were included in the SCORE O.P. model were: age, total cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, smoking status and diabetes. SCORE O.P. showed good discrimination; area under receiver operator characteristic curve (AUROC) 0.74 (95% confidence interval: 0.73 to 0.75). Calibration was also reasonable, Hosmer Lemeshow goodness of fit test: 17.16 (men), 22.70 (women). Compared with the original SCORE function extrapolated to the >=65 years age group discrimination improved, p = 0.05 (men), p < 0.001 (women). Simple risk charts were constructed. On simulated external validation, performed using 10-fold cross validation, AUROC was 0.74 and predicted/observed ratio was 1.02. CONCLUSION: SCORE O.P. provides improved accuracy in risk estimation in older people and may reduce excessive use of medication in this vulnerable population. PMID- 26041000 TI - A tertiary care center's experience with febrile seizures: evaluation of 632 cases. AB - BACKGROUND: The aim of this paper was to evaluate demographic and prognostic features of febrile seizures (FSs) in a tertiary center in Turkey. METHODS: A retrospective study of 632 children with FS was conducted from January 1995 to January 2002 in the pediatric neurology and general pediatrics departments of Istanbul University, Istanbul Medical School. Patients data was collected and eligible patients were included in the study. RESULTS: There were 386 male (61.1%) and 246 female (38.9%) patients, with a male-to-female ratio of 1.57. Twenty six (4.1%) patients had prenatal, 104 (16.5%) patients had perinatal neonatal problems. Age at first seizure was 3-72 months with an average of 20.1 months. While 193 patients (30%) were admitted with two seizures, 246 (39%) were admitted with three or more. Out of 632 patients, 501 (79.2%) had recurrences. In an average of 5.8 years (4-8.8), 30 out of 632 patients (4.7%) were diagnosed with epilepsy. First degree relative with FS, age at first FS less than 18 months, height of peak temperature (<38.5 degrees C), less than 1 or 3 hours between onset of fever and seizure, complex first seizure, complex FS were all related to febrile seizure recurrence in a statistically significant way. Some risk factors for subsequent epilepsy development included complex FS and less than one hour of fever before FS. No patient with FS had died. CONCLUSIONS: Complex FS and less than 1 hour of fever before FS are common risk factors for both epilepsy and FS recurrence. PMID- 26041001 TI - Recurrence of nephrotic proteinuria in children with focal segmental glomerulosclerosis: early treatment with plasmapheresis and immunoadsorption should be associated with better prognosis. AB - BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease, characterized by progressive renal function deterioration, nephrotic proteinuria, and risk of chronic renal failure. We present long-term results of 5 patients with primary FSGS and recurrence of nephrotic proteinuria after renal transplantation treated with plasma exchange (PE) and immunoadsorption (IA). METHODS: We retrospectively investigated the relationship between the delay in initiation of the therapy and treatment outcomes, particularly achievement of remission of proteinuria. RESULTS: Remission occurred in all three patients who started PE/IA in interval 3-7 days after diagnosis of recurrence of FSGS. Remission was achieved after 3-4 weeks in two patients with 3 days of delay to the start of PE. The third patient (PE started with 7 days of delay) reached complete remission after 6 months of PE/IA treatment. All these patients had remission sustainable for a long time. The remaining two patients with 14 and 406 days of delay to PE treatment did not achieve remission sustainable for a long time. The two patients who did not achieve remission developed end-stage renal disease with graft loss (1 and 6.7 years after transplantation). Patients who achieved remission of proteinuria during PE/IA treatment have still functioning grafts (2.8, 9.7 and 3.8 years after renal transplantation). All these patients are still treated with PE/IA. CONCLUSIONS: The present 5 cases suggest that if recurrence of FSGS occurs, the probability of achieving remission is dependent on the early initiation of PE/IA therapy. Therefore, we suggest that PE/IA treatment might be started as soon as possible after recurrence of FSGS. PMID- 26041002 TI - Headache and psychological disorders in children and adolescents: a cross generational study. AB - BACKGROUND: Headache and psychopathology (especially anxiety and mood disorders) are comorbid across the life span. The present study is a clinical contribution in the direction of studying the familial recurrence of headache, and the interplay of headache and psychopathology in children. METHODS: The clinical sample is composed by 130 headache patients (53 boys and 77 girls, age range 8 18), while the control group is composed by 87 healthy subjects from the general population (39 boys and 48 girls, age range 8-18). A structured interview according to International Classification for Headache Disorders-II criteria has been administered to the clinical group; the Child Behavior Checklist (CBCL) and the Self Administrated Psychiatric Scales for Children and Adolescents (SAFA) have been used in order to assess psychopathology in both groups. RESULTS: The recurrence of headache in family members is confirmed by the present study, albeit limited to paternal side, chi2 (4, N.=130)=10.47, P=0.033. Results also showed that scores obtained by the clinical sample in CBCL and SAFA are generally higher than scores obtained by the control group, but without differences between headache sub-types. Finally, internalizing symptoms (anxiety and depression) in children correlate with mothers' point of view, r>=0.23, P<0.05, outlining a specific attunement between headache patients and their mothers. CONCLUSIONS: Headache runs in families, with high level of psychological disorders. Mothers are particularly attuned with the psychological needs of their headache children. PMID- 26041004 TI - Neuroendoscopic treatment for hydrocephalus associated to midline arachnoid cysts in a series of nine pediatric patients. AB - BACKGROUND: Arachnoid cysts are extra-axial cerebrospinal fluid (CSF) collections surrounded by a membrane. Occasionally, hydrocephalus is associated due to a change in CSF circulatory dynamics. Neuroendoscopic treatment has been recommended for patients who develop symptoms resulting from the cyst location. METHODS: We retrospectively evaluate the results in our series of 9 patients with hydrocephalus associated to midline arachnoid cysts treated endoscopically. Success was rated on a scale of five degrees of neuroendoscopical success. RESULTS: We performed endoscopic third ventriculostomy (ETV) in three cases; ETV was associated to ventriculocystostomy (VC) in three cases; ETV, VC and septostomy (SPT) were performed in one patient; neuroendoscopic Monro foraminoplasty (NEFPMO) plus SPT were associated in one case; last patient was performed ETV, VC and cystocysternostomy (CC). For first procedures, 6 patients completed permanent Success (grade I). In one case success was transitory (grade II) and required a second procedure (ETV). In one patient VC success and ETV failure implied partial success (grade III). One patient's early failure (grade V) required a second procedure (ETV + NEFPMO). Success in second procedures was grade I in both patients. Follow-up period was over 12 months and altogether success was grade I in 8/9 patients and grade III in 1/9 patients. Shunt independency went over 88%. CONCLUSIONS: Endoscopy allows a solution avoiding the implantation of cerebrospinal fluid shunt devices. When possible, we likely approach both, hydrocephalus and arachnoid cyst, with different endoscopic maneuvers in a single procedure. It is important to expand the usage of success classifications for combined procedures. PMID- 26041003 TI - Neurodevelopmental evaluation of children with cyanotic congenital heart disease. AB - BACKGROUND: The aim of the study was to perform a neurodevelopmental evaluation of the children with cyanotic congenital heart disease and to determine the factors that affect the neurodevelopmental status. METHODS: The study was performed in the Pediatric Cardiology Department of Behcet Uz Children's Hospital between February and August 2013. Children between the age of six to forty-two months were included in the study and were evaluated in three groups (two patient groups and the control group). In group A, patients with isolated cyanotic congenital heart disease were enrolled. Group B consisted of the patients with cyanotic congenital heart disease with other concomitant diseases. Group C included the healthy control group. For the neurodevelopmental evaluation Bayley Scale of Infant Development- II (BSID-II) was used. Mental Developmental Index (MDI) and Psychmotor Developmental Index (PDI) scores were calculated. Factors possibly effective on neurodevelopment were evaluated. RESULTS: Thirty eight patients (32 in group A and 6 in group B) and 33 healthy subjects in group C were included in the study. Mean age of the patient group was 22.5+/-11.2 months. In group A mean MDI Score (82.5+/-14.7) was significantly lower than group C (92.3+/ 6.9) (P=0.001). Similarly mean PDI Score in group A (82.0+/-18.2) was found significantly lower than group C (92.5+/-7.4) (P=0.003). When group A and B were compared, mean MDI and PDI scores were lower in group B, but the difference was not statistically significant. For group A, according to the psychomotor development index, 41.6% of the patients were found to be mildly to severely retarded. In terms of the mental development index, 34.4% of the patients had moderate or mild retardation. The sex, socioeconomic status, gestational age, birth weight, comorbidities, history of surgery and reoperation, length of stay in intensive care unit were not found influential on the MDI and PDI scores of the patients. CONCLUSIONS: Mental-motor retardation is frequently encountered in children with cyanotic congenital heart disease. These patients may benefit from motor, language, speech, developmental and educational therapies. For this reason, these children have to be under regular follow up for neurodevelopmental status. PMID- 26041005 TI - Spectrum of cystic fibrosis mutations in Syrian patients. AB - BACKGROUND: Cystic fibrosis (CF) is the most common autosomal recessive disease in Caucasians. However, it is considered to be rare in Arabs. Reports of the cystic fibrosis transmembrane regulator (CFTR) mutations from Syrians are limited. The main aim of this study was to identify the frequency of CFTR mutations in 25 CF patients. To the best of our knowledge, this is the first comprehensive report about CF in Syrian patients. METHODS: The main clinical presentations were respiratory system symptoms (recurrent pneumonia and chronic cough) in 16 (64%) patients, failure to thrive in 15 (60%), GI system symptoms (diarrhea, steatorrhea) in 15 (60%) and nasal polyps in 1 (4%). RESULTS: A total of 36 known mutations in the CFTR gene were screened among 25 CF Syrian patients. However, 13 different CFTR mutations were identified. These mutations in order of frequency were: DeltaF508 (18%), W1282X (12%), I148T (6%), CFTRdel 2.3 (6%), 2182AA->G (6%), G542X (6%), N1303K (6%), G551D (4%), G85E (4%), R117H (4%), G85E (4%), R347P (2%), M.2183AA>G (2%) and 3199del6 (2%). However, 22% of the total mutations could not be detected in this study. Moreover, 142 healthy Syrian individuals were tested for DeltaF508 and G551D mutations in an attempt to determine the carrier rate in the Syrian population. These two mutations were not detected in this cohort of healthy Syrians. CONCLUSIONS: These results provide important tools for adapting a molecular diagnostic test and prenatal diagnosis for the Syrian population. PMID- 26041006 TI - Sleep disordered breathing in a cohort of children with achondroplasia: correlation between clinical and instrumental findings. AB - BACKGROUND: The aim of the present study was to show the results of an overnight polysomnography in a cohort of 9 children (7 females and 2 males) with achondroplasia, aged between 1 and 12 years (5.56+/-4.7 years). All of the children carried the Gly380Arg (G380R) mutation on the FGFR3 gene. METHODS: All the young patients underwent nocturnal polysomnography without sleep deprivation. Sleep staging was noted according to the guidelines of the American Academy of Sleep Medicine. At the time of registration, the parents answered to a Sleep Control Test questionnaire regarding medical history and diurnal and nocturnal symptoms of their children. RESULTS: Respiratory sleep disorder was present in 78% of cases, and was generally mild. In 67% of the children there was respiratory effort for more than 30% of the total sleep time. The sample was divided into two age categories: 5 children under the age of 3 years and 4 children over 10 years old. A higher incidence of sleep disorder was found in the first few years of life, where the obstructive pattern predominates. Regarding sleep architecture, we did not find macroscopic alterations of sleep architecture and its phasic manifestations in our paediatric group. However, parents have not been referred daytime sleepiness, attention deficiency, hyperactivity and nocturnal enuresis. Only one had referred recurrent respiratory infections. CONCLUSIONS: Polysomnography is a very useful tool in the evaluation of sleep disordered breathing in children with achondroplasia. PMID- 26041007 TI - Deep brain stimulation of anterior nucleus thalami disrupts sleep in epilepsy patients. AB - In view of the regulatory function of the thalamus in the sleep-wake cycle, the impact of deep brain stimulation (DBS) of the anterior nucleus thalami (ANT) on sleep was assessed in a small consecutive cohort of epilepsy patients with standardized polysomnography (PSG). In nine patients treated with ANT-DBS (voltage 5 V, frequency 145 Hz, cyclic mode), the number of arousals during stimulation and nonstimulation periods, neuropsychiatric symptoms (npS), and seizure frequency were determined. Electroclinical arousals were triggered in 14.0 to 67.0% (mean 42.4 +/- SD 16.8%) of all deep brain stimuli. Six patients reported npS. Nocturnal DBS voltages were reduced in eight patients (one patient without npS refused) and PSGs were repeated. Electroclinical arousals occurred between 1.4 and 6.7 (mean 3.3 +/- 1.7) times more frequently during stimulation periods compared to nonstimulation periods; the number of arousals positively correlated with the level of DBS voltage (range 1 V to 5 V) (Spearman's rank coefficient 0.53121; p < 0.05). No patient experienced seizure deterioration and four patients reported remission of npS. This case-cohort study provides evidence that ANT-DBS interrupts sleep in a voltage-dependent manner, thus putatively resulting in an increase of npS. Reduction of nocturnal DBS voltage seems to lead to improvement of npS without hampering efficacy of ANT-DBS. PMID- 26041008 TI - Quantile regression in the presence of monotone missingness with sensitivity analysis. AB - In this paper, we develop methods for longitudinal quantile regression when there is monotone missingness. In particular, we propose pattern mixture models with a constraint that provides a straightforward interpretation of the marginal quantile regression parameters. Our approach allows sensitivity analysis which is an essential component in inference for incomplete data. To facilitate computation of the likelihood, we propose a novel way to obtain analytic forms for the required integrals. We conduct simulations to examine the robustness of our approach to modeling assumptions and compare its performance to competing approaches. The model is applied to data from a recent clinical trial on weight management. PMID- 26041009 TI - Socio-economic status and ethnicity are independently associated with dietary patterns: the HELIUS-Dietary Patterns study. AB - BACKGROUND: Differences in dietary patterns between ethnic groups have often been observed. These differences may partially be a reflection of differences in socio economic status (SES) or may be the result of differences in the direction and strength of the association between SES and diet. OBJECTIVE: We aimed to examine ethnic differences in dietary patterns and the role of socio-economic indicators on dietary patterns within a multi-ethnic population. DESIGN: Cross-sectional multi-ethnic population-based study. SETTING: Amsterdam, the Netherlands. SUBJECTS: Principal component analysis was used to identify dietary patterns among Dutch (n=1,254), South Asian Surinamese (n=425), and African Surinamese (n=784) participants. Levels of education and occupation were used to indicate SES. Linear regression analysis was used to examine the association between ethnicity and dietary pattern scores first and then between socio-economic indicators and dietary patterns within and between ethnic groups. RESULTS: 'Noodle/rice dishes and white meat', 'red meat, snacks, and sweets' and 'vegetables, fruit and nuts' patterns were identified. Compared to the Dutch origin participants, Surinamese more closely adhered to the 'noodle/rice dishes and white meat' pattern which was characterized by foods consumed in a 'traditional Surinamese diet'. Closer adherence to the other two patterns was observed among Dutch compared to Surinamese origin participants. Ethnic differences in dietary patterns persisted within strata of education and occupation. Surinamese showed greater adherence to a 'traditional' pattern independent of SES. Among Dutch participants, a clear socio-economic gradient in all dietary patterns was observed. Such a gradient was only present among Surinamese dietary oatterns to the 'vegetables, fruit and nuts' pattern. CONCLUSIONS: We found a selective change in the adherence to dietary patterns among Surinamese origin participants, presumably a move towards more vegetables and fruits with higher SES but continued fidelity to the traditional diet. PMID- 26041010 TI - Pleomorphic spindle cell dermal neoplasm with dot-like keratin reactivity: keratin-positive AFX or carcinoma? AB - Atypical fibroxanthoma (AFX) is an uncommon cutaneous neoplasm of pleomorphic myofibroblast-like cells. Diagnosis requires exclusion of other undifferentiated spindle and pleomorphic cell neoplasms by immunohistochemistry. We report two patients with p63-non-reactive spindle cell neoplasms which resembled AFX but demonstrated anomalous dot-like immunolabeling with antibodies to high molecular weight keratin and keratin 5. One case recurred locally, suggesting such lesions may behave aggressively. Whether these lesions represent keratin-positive dermal sarcomas or poorly differentiated carcinomas is debatable. Regardless of exact classification, our experience suggests such cases should be managed as high-risk non-melanoma skin cancers. PMID- 26041011 TI - Facilitated Tau Degradation by USP14 Aptamers via Enhanced Proteasome Activity. AB - The ubiquitin-proteasome system (UPS) is the primary mechanism by which intracellular proteins, transcription factors, and many proteotoxic proteins with aggregation-prone structures are degraded. The UPS is reportedly downregulated in various neurodegenerative disorders, with increased proteasome activity shown to be beneficial in many related disease models. Proteasomes function under tonic inhibitory conditions, possibly via the ubiquitin chain-trimming function of USP14, a proteasome-associated deubiquitinating enzyme (DUB). We identified three specific RNA aptamers of USP14 (USP14-1, USP14-2, and USP14-3) that inhibited its deubiquitinating activity. The nucleotide sequences of these non-cytotoxic USP14 aptamers contained conserved GGAGG motifs, with G-rich regions upstream, and similar secondary structures. They efficiently elevated proteasomal activity, as determined by the increased degradation of small fluorogenic peptide substrates and physiological polyubiquitinated Sic1 proteins. Additionally, proteasomal degradation of tau proteins was facilitated in the presence of the UPS14 aptamers in vitro. Our results indicate that these novel inhibitory UPS14 aptamers can be used to enhance proteasome activity, and to facilitate the degradation of proteotoxic proteins, thereby protecting cells from various neurodegenerative stressors. PMID- 26041012 TI - Reversed-phase ion-pair chromatography-diode array detection of the bispyridinium compound MB327: plasma analysis of a potential novel antidote for the treatment of organophosphorus poisoning. AB - In the case of poisoning by organophosphorus nerve agents or pesticides, there is still a lack of pharmacological treatment of the cholinergic crisis selectively targeting the nicotinic acetylcholine receptor. Recently, the compound MB327 was identified as a potential novel lead structure to close this gap, thus demanding a quantitative assay for initial pharmacokinetic (PK) studies. MB327 is a salt consisting of the dicationic bispyridinium compound (BPC) 1,1'-(propane-1,3 diyl)bis(4-tert-butylpyridinium) and two iodide counter ions. Due to the permanent positive charge of the BPC, an isocratic reversed-phase ion-pair chromatographic separation (RPIPC) was developed using heptanesulfonic acid as ion-pairing reagent and 45% v/v methanol as organic modifier (1 mL/min). Selective UV-detection (230 nm) was done by a diode array detector (DAD) for reliable, rugged, precise (RSD < 7%) and accurate (96-104%) quantitative analysis of 50 MUL swine plasma (linear range 1-1000 ug BPC/mL plasma, lower limit of quantification 2 ug/mL). During method validation, diverse parameters essential for the chromatographic process were investigated to generate van't Hoff, van Deemter and width plots allowing calculation of thermodynamic data like the distribution constant K (5.7 +/- 0.3), change in enthalpy, DeltaH(0) : -23.66 kJ/mol, and entropy, DeltaS(0) : -65 J/(mol*K). In addition, RPIPC-DAD analysis enabled calculation of molar absorptivities of the BPC, epsilon230 : 17 400 +/- 1100 L/(mol*cm), and iodide, epsilon230 : 9900 +/- 400 L/(mol*cm), which determination was hampered by interference with each other in conventional cuvette UV-spectrophotometric measurements. Finally, the RPIPC-DAD procedure was applied to samples from an in vivo study of swine. PMID- 26041013 TI - A parent-directed language intervention for children of low socioeconomic status: a randomized controlled pilot study. AB - We designed a parent-directed home-visiting intervention targeting socioeconomic status (SES) disparities in children's early language environments. A randomized controlled trial was used to evaluate whether the intervention improved parents' knowledge of child language development and increased the amount and diversity of parent talk. Twenty-three mother-child dyads (12 experimental, 11 control, aged 1;5-3;0) participated in eight weekly hour-long home-visits. In the experimental group, but not the control group, parent knowledge of language development increased significantly one week and four months after the intervention. In lab based observations, parent word types and tokens and child word types increased significantly one week, but not four months, post-intervention. In home-based observations, adult word tokens, conversational turn counts, and child vocalization counts increased significantly during the intervention, but not post intervention. The results demonstrate the malleability of child-directed language behaviors and knowledge of child language development among low-SES parents. PMID- 26041014 TI - Placental magnetic resonance imaging T2* measurements in normal pregnancies and in those complicated by fetal growth restriction. AB - OBJECTIVES: The magnetic resonance imaging (MRI) variable transverse relaxation time (T2*) depends on multiple factors, one important one being the presence of deoxyhemoglobin. We aimed to describe placental T2* measurements in normal pregnancies and in those with fetal growth restriction (FGR). METHODS: We included 24 normal pregnancies at 24-40 weeks' gestation and four FGR cases with an estimated fetal weight below the 1(st) centile. Prior to MRI, an ultrasound examination, including Doppler flow measurements, was performed. The T2* value was calculated using a gradient echo MRI sequence with readout at 16 different echo times. In normal pregnancies, repeat T2* measurements were performed and interobserver reproducibility was assessed in order to estimate the reproducibility of the method. Placental histological examination was performed in the FGR cases. RESULTS: The method was robust regarding the technical and interobserver reproducibility. However, some slice-to-slice variation existed owing to the heterogeneous nature of the normal placenta. We therefore based T2* estimations on the average of two slices from each placenta. In normal pregnancies, the placental T2* value decreased significantly with increasing gestational age, with mean +/- SD values of 120 +/- 17 ms at 24 weeks' gestation, 84 +/- 16 ms at 32 weeks and 47 +/- 17 ms at 40 weeks. Three FGR cases had abnormal Doppler flow, histological signs of maternal hypoperfusion and a reduced T2* value (Z-score < -3.5). In the fourth FGR case, Doppler flow, placental histology and T2* value (Z-score, -0.34) were normal. CONCLUSIONS: The established reference values for placental T2* may be clinically useful, as T2* values were significantly lower in FGR cases with histological signs of maternal hypoperfusion. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26041015 TI - Surface Curvature Relation to Protein Adsorption for Carbon-based Nanomaterials. AB - The adsorption of proteins onto carbon-based nanomaterials (CBNs) is dictated by hydrophobic and pi-pi interactions between aliphatic and aromatic residues and the conjugated CBN surface. Accordingly, protein adsorption is highly sensitive to topological constraints imposed by CBN surface structure; in particular, adsorption capacity is thought to increase as the incident surface curvature decreases. In this work, we couple Molecular Dynamics (MD) simulations with fluorescence spectroscopy experiments to characterize this curvature dependence in detail for the model protein bovine serum albumin (BSA). By studying BSA adsorption onto carbon nanotubes of increasing radius (featuring descending local curvatures) and a flat graphene sheet, we confirm that adsorption capacity is indeed enhanced on flatter surfaces. Naive fluorescence experiments featuring multi-walled carbon nanotubes (MWCNTs), however, conform to an opposing trend. To reconcile these observations, we conduct additional MD simulations with MWCNTs that match those prepared in experiments; such simulations indicate that increased mass to surface area ratios in multi-walled systems explain the observed discrepancies. In reduction, our work substantiates the inverse relationship between protein adsorption capacity and surface curvature and further demonstrates the need for subtle consideration in experimental and simulation design. PMID- 26041016 TI - Nursing educator perspectives of overseas qualified nurses' intercultural clinical communication: barriers, enablers and engagement strategies. AB - AIMS AND OBJECTIVES: To understand the intercultural communication experiences and associated communication training needs of overseas qualified nurses in the Australian healthcare system from the unique perspectives of nurse educators teaching in accredited bridging programmes. BACKGROUND: Overseas qualified nurses are an integral part of the nursing workforce in migration destination countries. Communication training needs are more complex when there are cultural, ethnic and language differences between nurses, other health professionals and patients. DESIGN: A qualitative, exploratory research design using semi-structured interviews. METHODS: All (nine) organisations involved in conducting the Australian Health Practitioner Regulation Agency approved preregistration bridging programmes for overseas qualified nurses within the state of Victoria, Australia, were involved in the study. Participants were 12 nurse educators employed in these organisations. Thematic analysis was undertaken. RESULTS: Three macro themes emerged about the overseas qualified nurses' intercultural communication: (1) pre-existing barriers and enablers to intercultural communication, for example, nurses' reluctance to engage in communicative strategies that build rapport with patients, (2) transitional behaviours and impact on communication, including maintenance of perceived cultural hierarchies between health professionals and (3) development of communicative competence, including expanding one's repertoire of conversational gambits. CONCLUSIONS: The findings point to the domains and causes of communication challenges facing overseas qualified nurses in new healthcare settings as well as strategies that the nurse educators and nurses can adopt. Communication cannot be merely regarded as a skill that can be taught in a didactic programme. Comprehensive understanding is needed about the sociocultural dimensions of these nurses' orientation, which can impact on how they communicate in their new healthcare settings. RELEVANCE TO CLINICAL PRACTICE: The findings can act as triggers for discussion with overseas qualified nurses and other health professionals to raise awareness about the aspects of intercultural communication and to debate alternative viewpoints and explanations. They can also inform changes in the structure and content of the bridging programmes. PMID- 26041017 TI - An efficient and practical approach to trifluoromethylthiolation of alpha haloketones/alpha-haloarylmethanes. AB - An efficient and practical approach to trifluoromethylthiolation of alpha haloketones/alpha-haloarylmethanes was developed. The transformation employs only AgSCF3 and KI in situ generated active nucleophilic trifluoromethylthio species and cleanly occurs in up to quantitative yield at room temperature, thereby providing an unprecedentedly easy entry to various alpha-SCF3-substituted ketones/arylmethanes. PMID- 26041018 TI - In-hospital vs. 30-day mortality in the critically ill - a 2-year Swedish intensive care cohort analysis. AB - BACKGROUND: Standardised mortality ratio (SMR) is a common quality indicator in critical care and is the ratio between observed mortality and expected mortality. Typically, in-hospital mortality is used to derive SMR, but the use of a time fixed, more objective, end-point has been advocated. This study aimed to determine the relationship between in-hospital mortality and 30-day mortality on a comprehensive Swedish intensive care cohort. METHODS: A retrospective study on patients >15 years old, from the Swedish Intensive Care Register (SIR), where intensive care unit (ICU) admissions in 2009-2010 were matched with the corresponding hospital admissions in the Swedish Hospital Discharge Register. Recalibrated SAPS (Simplified Acute Physiology Score) 3 models were developed to predict and compare in-hospital and 30-day mortality. SMR based on in-hospital mortality and on 30-day mortality were compared between ICUs and between groups with different case-mixes, discharge destinations and length of hospital stays. RESULTS: Sixty-five ICUs with 48861 patients, of which 35610 were SAPS 3 scored, were included. Thirty-day mortality (17%) was higher than in-hospital mortality (14%). The SMR based on 30-day mortality and that based on in-hospital mortality differed significantly in 7/53 ICUs, for patients with sepsis, for elective surgery-admissions and in groups categorised according to discharge destination and hospital length of stay. CONCLUSION: Choice of mortality end-point influences SMR. The extent of the influence depends on hospital-, ICU- and patient cohort characteristics as well as inter-hospital transfer rates, as all these factors influence the difference between SMR based on 30-day mortality and SMR based on in-hospital mortality. PMID- 26041020 TI - Inhibitory phonetic priming: Where does the effect come from? AB - Both phonological and phonetic priming studies reveal inhibitory effects that have been interpreted as resulting from lexical competition between the prime and the target. We present a series of phonetic priming experiments that contrasted this lexical locus explanation with that of a prelexical locus by manipulating the lexical status of the prime and the target and the task used. In the related condition of all experiments, spoken targets were preceded by spoken primes that were phonetically similar but shared no phonemes with the target (/bak/ /depsilont/). In Experiments 1 and 2, word and nonword primes produced an inhibitory effect of equal size in shadowing and same-different tasks respectively. Experiments 3 and 4 showed robust inhibitory phonetic priming on both word and nonword targets in the shadowing task, but no effect at all in a lexical decision task. Together, these findings show that the inhibitory phonetic priming effect occurs independently of the lexical status of both the prime and the target, and only in tasks that do not necessarily require the activation of lexical representations. Our study thus argues in favour of a prelexical locus for this effect. PMID- 26041019 TI - Yield of coeliac screening in abdominal pain-associated functional gastrointestinal system disorders. AB - AIM: Chronic abdominal pain (CAP) in childhood is common and in the majority functional. While CAP is one of the complaints of coeliac disease (CD), whether CAP as a sole complaint is indicative of CD is unclear. Our aim was to evaluate the relationship between CAP and CD. METHODS: The study was conducted on 1047 children (61.1% female, mean age 9.6 +/- 4.1 years) with CAP. Patients were evaluated according to the Rome III criteria. Patients with alarm symptoms and conditions known to be associated with CD were excluded. Patients were screened for CD using a rapid tissue transglutaminase (tTG) test; positive cases were tested by tTG ELISA, and duodenal biopsies were obtained if tTG was above the normal limit. RESULTS: Functional dyspepsia (FD), irritable bowel syndrome (IBS) and functional abdominal pain (FAP) were diagnosed in 384 (36.7%), 274 (26.2%) and 389 (37.2%) patients, respectively. In 13 patients, the tTG rapid test was positive; 10 were also positive for tTG by ELISA and histopathological evaluations diagnosed CD in all 10 patients. The overall prevalence of CD was 0.95% (2.2%, 0.5% and 0.5% in patients with IBS, FD and FAP, respectively). The prevalence of CD in patients with IBS was higher than expected but with borderline statistical significance (P = 0.053). CONCLUSIONS: CD is found as common in children with FD and FAP as in the general population. CD was more commonly diagnosed in IBS patients with borderline statistical significance. We suggest that particular attention be paid to children with IBS. PMID- 26041021 TI - Ga-68 octreotate PET/CT and Tc-99m heat-denatured red blood cell SPECT/CT imaging of an intrapancreatic accessory spleen. AB - Intrapancreatic accessory spleens are relatively uncommon and can be difficult to distinguish from neuroendocrine tumours on CT, MRI and somatostatin receptor scintigraphy. We present the case of a 26-year-old woman with an incidentally diagnosed pancreatic lesion confirmed to be an intrapancreatic accessory spleen on Tc-99m heat-denatured red blood cell single photon emission computed tomography/CT. PMID- 26041022 TI - Colorectal surgery in Parkinson's disease--outcomes and predictors of mortality. AB - PURPOSE: Although diseases of the lower gastrointestinal tract are common in patients with Parkinson's disease, there is a paucity of data regarding postoperative outcomes after colorectal surgery. METHODS: The Nationwide Inpatient Sample database (2007-2011) was utilized to analyze outcomes in patients with Parkinson's disease (PD) undergoing colorectal surgery. Main outcomes were risk-adjusted inpatient morbidity, mortality, hospital charge, and length of hospital stay. RESULTS: A total of 6490 patients were identified. Utilization of laparoscopic surgery in Parkinson's patients has progressively increased in frequency over the latest 5 years analyzed. The most common diagnoses were colorectal malignancy (39 %) and intestinal obstruction (20 %). Right hemicolectomy (37 %) and sigmoidectomy (30 %) were the most common operations. Laparoscopy was used in 18 % of Parkinson's patients and most commonly in the elective setting. 54.3 % of Parkinson's patients had emergency surgery compared to 38.6 % in non-Parkinson's. Overall morbidity and mortality were significantly lower after laparoscopic surgery compared to open (20 vs. 25 % and 2.1 vs. 6.6 %, respectively). Length of stay was significantly shorter (OR 1.86; p < 0.01) for laparoscopic operations, but there were no significant differences in risk-adjusted outcomes between laparoscopic and open groups. CONCLUSION: PD patients have high rates of morbidity and mortality after colorectal surgery; this may be because more than half of all patients in this population undergo emergent surgery. The laparoscopic approach appears to have short-term benefits in this patient population. PMID- 26041023 TI - 99m-Technetium binding site in bone marrow mononuclear cells. AB - INTRODUCTION: The increasing interest in 99m-technetium ((99m)Tc)-labeled stem cells encouraged us to study the (99m)Tc binding sites in stem cell compartments. METHODS: Bone marrow mononuclear cells were collected from femurs and tibia of rats. Cells were labeled with (99m)Tc by a direct method, in which reduced molecules react with (99m)Tc with the use of chelating agents, and lysed carefully in an ultrasonic apparatus. The organelles were separated by means of differential centrifugation. At the end of this procedure, supernatants and pellets were counted, and the percentages of radioactivity (in megabecquerels) bound to the different cellular fractions were determined. Percentages were calculated by dividing the radioactivity in each fraction by total radioactivity in the sample. The pellets were separated and characterized by their morphology on electron microscopy. RESULTS: The labeling procedure did not affect viability of bone marrow mononuclear cells. Radioactivity distributions in bone marrow mononuclear cell organelles, obtained in five independent experiments, were approximately 38.5 % in the nuclei-rich fraction, 5.3 % in the mitochondria-rich fraction, 2.2 % in microsomes, and 54 % in the cytosol. Our results showed that most of the radioactivity remained in the cytosol; therefore, this is an intracellular labeling procedure that has ribosomes unbound to membrane and soluble molecules as targets. However, approximately 39 % of the radioactivity remained bound to the nuclei-rich fraction. To confirm that cell disruption and organelle separation were efficient, transmission electron microscopy assays of all pellets were performed. CONCLUSIONS: Our results showed that most of the radioactivity was present in the cytosol fraction. More studies to elucidate the mechanisms involved in the cellular uptake of (99m)Tc in bone marrow cells are ongoing. PMID- 26041024 TI - Follicular thyroid carcinoma: differences in clinical relevance between minimally invasive and widely invasive tumors. AB - BACKGROUND: Evidence on the biological behavior and clinical courses of minimally invasive and widely invasive follicular thyroid carcinoma (MI-FTC, WI-FTC) is still debatable. The current study was conducted to identify differences between MI and WI tumors and those prognostic parameters influencing late outcome such as local recurrence and survival. METHODS: From January 1998 to October 2013, 71 patients were operated on in our department because of a FTC. A retrospective cohort study was carried out to compare 42 MI-FTC and 29 WI-FTC. The comparison involved evaluation of patient characteristics, tumor characteristics, tumor staging, and risk assessment. RESULTS: A diameter greater than 4.0 cm, the presence of vascular invasion, the TNM stage III-IVA, and the high risk at AMES system risk stratification were independent factors significantly related to the presence of a WI-FTC. The only independent predictor of recurrence and disease free survival at 10-year follow-up was a tumor size greater than 4.0 cm. CONCLUSIONS: More attention must be paid in the postoperative tumor re-staging of those patients with tumor size larger than 4.0 cm, which was the only parameter predicting recurrence and influencing disease-free survival. Nevertheless, definitive recommendations cannot be made without a longer follow-up. PMID- 26041025 TI - Outcome analysis of cubital tunnel decompression. AB - BACKGROUND: Cubital tunnel decompression is a commonly undertaken upper limb procedure. Most studies compare the different techniques of decompression; however, only a few have specifically investigated the outcome of ulnar nerve decompression. AIM: The aim of this study was to investigate the outcome of ulnar nerve decompression following cubital tunnel syndrome. METHODS AND RESULTS: A total of 174 ulnar nerve decompression cases were identified from the upper limb surgery database with complete data available for 136 cases. Simple decompression was performed in 110 (80.88%) cases, and in 26 (19.12%), anterior subcutaneous transposition was also supplemented. These operations were performed at three different hospitals by surgeons of different levels of experience. The most common cause of cubital tunnel syndrome was idiopathic. The outcome was satisfactory in 86% of cases. No obvious association was demonstrated between the outcome of surgery and duration of symptoms, presence of co-morbidities or the type of surgery performed. CONCLUSION: This is the largest outcome analysis of the results of ulnar nerve decompression at the elbow. Good results following nerve decompression were attained in 86% of cases without any significant effect of duration of symptoms or co-morbidities on the outcome of surgery. It is hoped that the findings of the current study will help general practitioners, junior doctors and surgeons in their management and pre-operative consultation with patients having cubital tunnel syndrome. PMID- 26041026 TI - Cogon grass (Imperata cylindrica), a potential biomass candidate for bioethanol: cell wall structural changes enhancing hydrolysis in a mild alkali pretreatment regime. AB - BACKGROUND: Imperata cylindrica is being considered as a biomass candidate for bioethanol. This work aimed to evaluate a mild alkali pretreatment effect on the Imperata recalcitrant structure. Therefore, varied concentrations of NaOH (0, 7.5, 15, 20, and 25 g L(-1) ) were applied as treatments to Imperata at 105 degrees C for 10 min. RESULTS: Scanning electron microscopy, atomic force microscopy, and Fourier transform infrared spectroscopy studies revealed that 20 to 25 g L(-1) NaOH-treated Imperata exposed amorphous cellulose on surface granules composed of lignin, waxes, and partly hemicelluloses were abolished due to the comprehensive disruption of the linkages between lignin and carbohydrates. The cellulose crystalline index was increased with 7.5 to 20 g L(-1) NaOH treatments and reduced with a 25 g L(-1) NaOH treatment. In fact, the cellulose content in solids increased with the increasing NaOH concentration and was estimated to be 720 and 740 g kg(-1) for the 20 and 25 g L(-1) NaOH treatments, respectively. The yield of the reducing sugar was obtained 805 and 813 mg g(-1) from 20 and 25 g L(-1) NaOH-treated Imperata, respectively. CONCLUSION: Considering the cost of pretreatment, the 20 g L(-1) NaOH treatment is judged to be effective for disrupting Imperata recalcitrance in this pretreatment regime. PMID- 26041027 TI - Novel antimicrobial peptide specifically active against Porphyromonas gingivalis. AB - Porphyromonas gingivalis, the major etiologic agent of chronic periodontitis, produces a broad spectrum of virulence factors, including outer membrane vesicles, lipopolysaccharides, hemolysins and proteinases. Antimicrobial peptides (AMPs) including bacteriocins have been found to inhibit the growth of P. gingivalis; however, these peptides are relatively large molecules. Hence, it is difficult to synthesize them by a scale-up production. Therefore, this study aimed to synthesize a shorter AMP that was still active against P. gingivalis. A peptide that contained three cationic amino acids (Arg, His and Lys), two anionic amino acids (Glu and Asp), hydrophobic amino acids residues (Leu, Ile, Val, Ala and Pro) and hydrophilic residues (Ser and Gly) was obtained and named Pep-7. Its bioactivity and stability were tested after various treatments. The mechanism of action of Pep-7 and its toxicity to human red blood cells were investigated. The Pep-7 inhibited two pathogenic P. gingivalis ATCC 33277 and P. gingivalis ATCC 53978 (wp50) strains at a minimum bactericidal concentration (MBC) of 1.7 uM, but was ineffective against other oral microorganisms (P. intermedia, Tannerella forsythensis, Streptococcus salivarius and Streptococcus sanguinis). From transmission electron microscopy studies, Pep-7 caused pore formation at the poles of the cytoplasmic membranes of P. gingivalis. A concentration of Pep-7 at four times that of its MBC induced some hemolysis but only at 0.3%. The Pep-7 was heat stable under pressure (autoclave at 110 and 121 degrees C) and possessed activity over a pH range of 6.8-8.5. It was not toxic to periodontal cells over a range of 70.8-4.4 MUM and did not induce toxic pro-inflammatory cytokines. The Pep-7 showed selective activity against Porphyromonas sp. by altering the permeability barriers of P. gingivalis. The Pep-7 was not mutagenic in vitro. This work highlighted the potential for the use of this synthetic Pep-7 against P. gingivalis. PMID- 26041028 TI - PREVENTT: preoperative intravenous iron to treat anaemia in major surgery: study protocol for a randomised controlled trial. AB - BACKGROUND: Anaemia is common in patients undergoing major surgery. The current standard of care for patients with low haemoglobin in the peri-operative period is blood transfusion. The presence of preoperative anaemia is associated with an increased likelihood of the patient receiving peri-operative transfusion and worsened outcomes following surgery, more post-operative complications, delayed recovery and greater length of hospital stay. Intravenous iron, if applied in the preoperative setting, may correct anaemia by the time of surgery and reduce the need for blood transfusion and improve outcomes. METHODS/DESIGN: PREVENTT is a phase III double-blind randomised controlled trial that will compare the use of intravenous ferric carboxymaltose (dose 1000 mg) with placebo 10-42 days before major open abdominal surgery in 500 patients with anaemia (haemoglobin < 120 g/L). The primary outcome measure will be the need for blood transfusion and secondary endpoints will include post-operative recovery, length of hospital stay, health care utilisation and cost analysis. TRIAL REGISTRATION: ISRCTN67322816--registered 9 October 2012. ClinicalTrials.gov identifier: NCT01692418. PMID- 26041030 TI - Embryo oxygenation in pipefish brood pouches: novel insights. AB - The pipefish brood pouch presents a unique mode of parental care that enables males to protect, osmoregulate, nourish and oxygenate the developing young. Using a very fine O2 probe, we assessed the extent to which males of the broad-nosed pipefish (Syngnathus typhle) oxygenate the developing embryos and are able to maintain pouch fluid O2 levels when brooding in normoxia (100% O2 saturation) and hypoxia (40% O2 saturation) for 24 days. In both treatments, pouch fluid O2 saturation levels were lower compared with the surrounding water and decreased throughout the brooding period, reflecting greater offspring demand for O2 during development and/or decreasing paternal ability to provide O2 to the embryos. Male condition (hepatosomatic index) was negatively affected by hypoxia. Larger males had higher pouch fluid O2 saturation levels compared with smaller males, and levels were higher in the bottom section of the pouch compared with other sections. Embryo size was positively correlated with O2 availability, irrespective of their position in the pouch. Two important conclusions can be drawn from our findings. First, our results highlight a potential limitation to brooding within the pouch and dismiss the notion of closed brood pouches as well oxygenated structures promoting the evolution of larger eggs in syngnathids. Second, we provide direct evidence that paternal care improves with male size in this species. This finding offers an explanation for the documented strong female preference for larger partners because, in terms of oxygenation, the brood pouch can restrict embryo growth. PMID- 26041031 TI - Oxygen safety margins set thermal limits in an insect model system. AB - A mismatch between oxygen availability and metabolic demand may constrain thermal tolerance. While considerable support for this idea has been found in marine organisms, results from insects are equivocal and raise the possibility that mode of gas exchange, oxygen safety margins and the physico-chemical properties of the gas medium influence heat tolerance estimates. Here, we examined critical thermal maximum (CTmax) and aerobic scope under altered oxygen supply and in two life stages that varied in metabolic demand in Bombyx mori (Lepidoptera: Bombycidae). We also systematically examined the influence of changes in gas properties on CTmax. Larvae have a lower oxygen safety margin (higher critical oxygen partial pressure at which metabolism is suppressed relative to metabolic demand) and significantly higher CTmax under normoxia than pupae (53 degrees C vs 50 degrees C). Larvae, but not pupae, were oxygen limited with hypoxia (2.5 kPa) decreasing CTmax significantly from 53 to 51 degrees C. Humidifying hypoxic air relieved the oxygen limitation effect on CTmax in larvae, whereas variation in other gas properties did not affect CTmax. Our data suggest that oxygen safety margins set thermal limits in air-breathing invertebrates and the magnitude of this effect potentially reconciles differences in oxygen limitation effects on thermal tolerance found among diverse taxa to date. PMID- 26041029 TI - Structural equation modeling of immunotoxicity associated with exposure to perfluorinated alkylates. AB - BACKGROUND: Exposure to perfluorinated alkylate substances (PFASs) is associated with immune suppression in animal models, and serum concentrations of specific antibodies against certain childhood vaccines tend to decrease at higher exposures. As such, we investigated the immunotoxic impacts of the three major PFASs in a Faroese birth cohort. METHODS: A total of 464 children contributed blood samples collected at age 7 years. PFAS concentrations and concentrations of antibodies against diphtheria and tetanus were assessed in serum at age 7 years, and results were available from samples collected at age 5. In addition to standard regressions, structural equation models were generated to determine the association between three major PFASs measured at the two points in time and the two antibody concentrations. RESULTS: Concentrations of all three 7-year PFAS concentrations were individually associated with a decrease in concentrations of antibodies, however, it was not possible to attribute causality to any single PFAS concentration. Hence, the three 7-year concentrations were combined and showed that a 2-fold increase in PFAS was associated with a decrease by 54.4% (95% CI: 22.0%, 73.3%) in the antibody concentration. If considering both the age 5 and age-7 concentrations of the three major PFASs, the exposure showed a slightly greater loss. CONCLUSIONS: These analyses strengthen the evidence of human PFAS immunotoxicity at current exposure levels and reflect the usefulness of structural equation models to adjust for imprecision in the exposure variables. PMID- 26041032 TI - Avian thermoregulation in the heat: scaling of heat tolerance and evaporative cooling capacity in three southern African arid-zone passerines. AB - Many birds can defend body temperature (Tb) far below air temperature (Ta) during acute heat exposure, but relatively little is known about how avian heat tolerance and evaporative cooling capacity varies with body mass (Mb), phylogeny or ecological factors. We determined maximum rates of evaporative heat dissipation and thermal end points (Tb and Ta associated with thermoregulatory failure) in three southern African ploceid passerines, the scaly-feathered weaver (Sporopipes squamifrons, Mb~10 g), sociable weaver (Philetairus socius, Mb~25 g) and white-browed sparrow-weaver (Plocepasser mahali, Mb~40 g). Birds were exposed to a ramped profile of progressively increasing Ta, with continuous monitoring of behaviour and Tb used to identify the onset of severe hyperthermia. The maximum Ta birds tolerated ranged from 48 degrees C to 54 degrees C, and was positively related to Mb. Values of Tb associated with severe heat stress were in the range of 44 to 45 degrees C. Rates of evaporative water loss (EWL) increased rapidly when Ta exceeded Tb, and maximum evaporative heat dissipation was equivalent to 141-222% of metabolic heat production. Fractional increases in EWL between Ta<40 degrees C and the highest Ta reached by each species were 10.8 (S. squamifrons), 18.4 (P. socius) and 16.0 (P. mahali). Resting metabolic rates increased more gradually with Ta than expected, probably reflecting the very low chamber humidity values we maintained. Our data suggest that, within a taxon, larger species can tolerate higher Ta during acute heat stress. PMID- 26041033 TI - Locomotor corollary activation of trigeminal motoneurons: coupling of discrete motor behaviors. AB - During motor behavior, corollary discharges of the underlying motor commands inform sensory-motor systems about impending or ongoing movements. These signals generally limit the impact of self-generated sensory stimuli but also induce motor reactions that stabilize sensory perception. Here, we demonstrate in isolated preparations of Xenopus laevis tadpoles that locomotor corollary discharge provokes a retraction of the mechanoreceptive tentacles during fictive swimming. In the absence of sensory feedback, these signals activate a cluster of trigeminal motoneurons that cause a contraction of the tentacle muscle. This corollary discharge encodes duration and strength of locomotor activity, thereby ensuring a reliable coupling between locomotion and tentacle motion. The strict phase coupling between the trigeminal and spinal motor activity, present in many cases, suggests that the respective corollary discharge is causally related to the ongoing locomotor output and derives at least in part from the spinal central pattern generator; however, additional contributions from midbrain and/or hindbrain locomotor centers are likely. The swimming-related retraction might protect the touch-receptive Merkel cells on the tentacle from sensory over stimulation and damage and/or reduce the hydrodynamic drag. The intrinsic nature of the coupling of tentacle retraction to locomotion is an excellent example of a context-dependent, direct link between otherwise discrete motor behaviors. PMID- 26041034 TI - Size dependence in non-sperm ejaculate production is reflected in daily energy expenditure and resting metabolic rate. PMID- 26041035 TI - Pharmacovigilance in resource-limited countries. AB - In the past 20 years, many low- and middle-income countries have created national pharmacovigilance (PV) systems and joined the WHO's global PV network. However, very few of them have fully functional systems. Scientific evidence on the local burden of medicine-related harm and their preventability is missing. Legislation and regulatory framework as well as financial support to build sustainable PV systems are needed. Public health programs need to integrate PV to monitor new vaccines and medicines introduced through these programs. Signal analysis should focus on high-burden preventable adverse drug problems. Increased involvement of healthcare professionals from public and private sectors, pharmaceutical companies, academic institutions and the public at large is necessary to assure a safe environment for drug therapy. WHO has a major role in supporting and coordinating these developments. PMID- 26041037 TI - Evaluation of the Surface Treatment on Bone Healing in a Transmucosal 1-mm Area of Implant Abutment: An Experimental Study in the Rabbit Tibia. AB - PURPOSE: The objective of the present study was to investigate the effect on bone tissue healing patterns in 1-mm area treated in the transmucosal surface of the abutment in the tibia of rabbits. MATERIALS AND METHODS: Forty-six abutments were divided into two groups: control group (CG) with 14 abutments with smooth surface and experimental group (EG) with 32 abutments presenting a 1-mm area of the transmucosal surface treated through sandblasting with microparticles of titanium oxide followed by acid etching. Five samples of each group were analyzed using an optical laser profilometer for surface roughness characterization. Thirty-six Morse taper implants (3.5 mm in diameter and 7 mm in length) were inserted 1.5 mm subcrestal into the tibiae of nine rabbits. The implants were removed after 8, 10, and 12 weeks for histological analysis. The histological slides were prepared and analyzed qualitatively in relation to the new bone at the interface bone abutment and quantitatively, in relation to bone height from the base of the implant. These data were computed and statistically compared inside the groups using analysis of variance and the U-test between groups for same time. RESULTS: Both groups exhibited bone growth in the direction and over the surface of the abutments, with good healing. However, the EG group showed an increased height of bone formation in the crestal direction, and highly significant differences were observed (p < .001) between these measured values. CONCLUSIONS: Under the limitations of the present study, histological follow-up at 8, 10, and 12 weeks showed that transmucosal 1-mm area of implant abutment with treatment of the surface facilitated the maintenance of bone height around the abutment compared with the same abutment with the totally smooth surface. PMID- 26041036 TI - Credibility and advocacy in conservation science. AB - Conservation policy sits at the nexus of natural science and politics. On the one hand, conservation scientists strive to maintain scientific credibility by emphasizing that their research findings are the result of disinterested observations of reality. On the other hand, conservation scientists are committed to conservation even if they do not advocate a particular policy. The professional conservation literature offers guidance on negotiating the relationship between scientific objectivity and political advocacy without damaging conservation science's credibility. The value of this guidance, however, may be restricted by limited recognition of credibility's multidimensionality and emergent nature: it emerges through perceptions of expertise, goodwill, and trustworthiness. We used content analysis of the literature to determine how credibility is framed in conservation science as it relates to apparent contradictions between science and advocacy. Credibility typically was framed as a static entity lacking dimensionality. Authors identified expertise or trustworthiness as important, but rarely mentioned goodwill. They usually did not identify expertise, goodwill, or trustworthiness as dimensions of credibility or recognize interactions among these 3 dimensions of credibility. This oversimplification may limit the ability of conservation scientists to contribute to biodiversity conservation. Accounting for the emergent quality and multidimensionality of credibility should enable conservation scientists to advance biodiversity conservation more effectively. PMID- 26041038 TI - Cytokine Profiles from Antigen-Stimulated Whole-Blood Samples among Patients with Pulmonary or Nonmeningeal Disseminated Coccidioidomycosis. AB - The outcome of coccidioidomycosis depends on a robust specific cellular immune response. A T-helper type 1 (Th1) cellular immune response has been previously associated with resolution of clinical illness. However, the precise elements of this response and whether cytokines not involved with the Th1 response play a role in coccidioidomycosis are not known. Whole-blood samples were obtained from subjects with active coccidioidomycosis and controls and incubated for 18 h with T27K, a coccidioidal antigen preparation. The supernatant was then assayed for gamma interferon (IFN-gamma), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-alpha), IL-4, IL-6, IL-10, and IL-17A. A total of 43 subjects, 16 with acute pneumonia, 9 with pulmonary sequelae of nodules and cavities, and 18 with nonmeningeal disseminated coccidioidomycosis, were studied. Compared to concentrations in healthy immune and nonimmune donors, the median concentration of IL-17A was significantly higher in those with active coccidioidomycosis (for both, P < 0.01). In addition, IL-6 concentrations were higher while IL-2 and IFN gamma concentrations were significantly lower in those with nonmeningeal disseminated disease diagnosed within 12 months than in those with acute pneumonia (for all, P < 0.05). The cytokine profile among patients with active coccidioidomycosis is distinct in that IL-17A is persistently present. In addition, those with nonmeningeal disseminated disease have an increased inflammatory cytokine response and diminished Th1 responses that modulate over time. PMID- 26041039 TI - Bacillus anthracis Capsular Conjugates Elicit Chimpanzee Polyclonal Antibodies That Protect Mice from Pulmonary Anthrax. AB - The immunogenicity of Bacillus anthracis capsule (poly-gamma-D-glutamic acid [PGA]) conjugated to recombinant B. anthracis protective antigen (rPA) or to tetanus toxoid (TT) was evaluated in two anthrax-naive juvenile chimpanzees. In a previous study of these conjugates, highly protective monoclonal antibodies (MAbs) against PGA were generated. This study examines the polyclonal antibody response of the same animals. Preimmune antibodies to PGA with titers of >10(3) were detected in the chimpanzees. The maximal titer of anti-PGA was induced within 1 to 2 weeks following the 1st immunization, with no booster effects following the 2nd and 3rd immunizations. Thus, the anti-PGA response in the chimpanzees resembled a secondary immune response. Screening of sera from nine unimmunized chimpanzees and six humans revealed antibodies to PGA in all samples, with an average titer of 10(3). An anti-PA response was also observed following immunization with PGA-rPA conjugate, similar to that seen following immunization with rPA alone. However, in contrast to anti-PGA, preimmune anti-PA antibody titers and those following the 1st immunization were <=300, with the antibodies peaking above 10(4) following the 2nd immunization. The polyclonal anti-PGA shared the MAb 11D epitope and, similar to the MAbs, exerted opsonophagocytic killing of B. anthracis. Most important, the PGA-TT-induced antibodies protected mice from a lethal challenge with virulent B. anthracis spores. Our data support the use of PGA conjugates, especially PGA-rPA targeting both toxin and capsule, as expanded-spectrum anthrax vaccines. PMID- 26041040 TI - T(H)17-Mediated Protection against Pneumococcal Carriage by a Whole-Cell Vaccine Is Dependent on Toll-Like Receptor 2 and Surface Lipoproteins. AB - A pneumococcal whole-cell vaccine (WCV) confers T(H)17-mediated immunogenicity and reduces nasopharyngeal (NP) carriage in mice. Activation of Toll-like receptor 2 (TLR2) has been shown to be important for generating T(H)17 responses, and several lipidated pneumococcal proteins have TLR2-activating properties. Here we investigated the roles of TLR2 and lipidation of proteins in WCV-induced interleukin-17A (IL-17A) responses and protection against NP carriage. Immunization of Tlr2(-/-) mice with WCV conferred significantly lower IL-17A levels and reduced protection against NP carriage, compared to wild-type (WT) mice, suggesting that host TLR2 engagement is required for effective immunity and protection elicited by WCV immunization. Using a WCV with deletion of lgt, the gene encoding the enzyme required for lipidation and membrane attachment of prolipoproteins, we show that lipidation and membrane localization of these proteins are critical for the immunogenicity and protective efficacy of the WCV. To evaluate the roles of diacylglyceryl transferase (Lgt)-mediated processes in the recall of WCV-induced protective responses, we colonized WCV-immunized animals with a strain in which lgt was deleted. WCV-immunized animals still had significantly reduced colonization burdens, compared to control animals, which suggests that lipidation and membrane localization of pneumococcal prolipoproteins are less critical for the recall of the immune responses elicited by WCV immunization than for the priming of such responses. Elucidation of underlying immune mechanisms and the optimal characteristics of WCV formulations can help guide vaccine development and enhance our understanding of host pneumococcus interactions. PMID- 26041041 TI - Serological Correlates of Protection against a GII.4 Norovirus. AB - Noroviruses are the leading cause of acute gastroenteritis worldwide, and norovirus vaccine prevention strategies are under evaluation. The immunogenicity of two doses of bivalent genogroup 1 genotype 1 (GI.1)/GII.4 (50 MUg of virus like particles [VLPs] of each strain adjuvanted with aluminum hydroxide and 3-O desacyl-4'monophosphoryl lipid A [MPL]) norovirus vaccine administered to healthy adults in a phase 1/2 double-blind placebo-controlled trial was determined using virus-specific serum total antibody enzyme-linked immunosorbent assay (ELISA), IgG, IgA, and histoblood group antigen (HBGA)-blocking assays. Trial participants subsequently received an oral live virus challenge with a GII.4 strain, and the vaccine efficacy results were reported previously (D. I. Bernstein et al., J Infect Dis 211:870-878, 2014, doi:10.1093/infdis/jiu497). This report assesses the impact of prechallenge serum antibody levels on infection and illness outcomes. Serum antibody responses were observed in vaccine recipients by all antibody assays, with first-dose seroresponse frequencies ranging from 88 to 100% for the GI.1 antigen and from 69 to 84% for the GII.4 antigen. There was little increase in antibody levels after the second vaccine dose. Among the subjects receiving the placebo, higher prechallenge serum anti-GII.4 HBGA-blocking and IgA antibody levels, but not IgG or total antibody levels, were associated with a lower frequency of virus infection and associated illness. Notably, some placebo subjects without measurable serum antibody levels prechallenge did not become infected after norovirus challenge. In vaccinees, anti-GII.4 HBGA-blocking antibody levels of >1:500 were associated with a lower frequency of moderate-to severe vomiting or diarrheal illness. In this study, prechallenge serum HBGA antibody titers correlated with protection in subjects receiving the placebo; however, other factors may impact the likelihood of infection and illness after virus exposure. (This study is registered at ClinicalTrials.gov under registration number NCT1609257.). PMID- 26041043 TI - Effect of the efflux pump QepA2 combined with chromosomally mediated mechanisms on quinolone resistance and bacterial fitness in Escherichia coli. AB - OBJECTIVES: The aim of the study was to determine the interplay between the plasmid-mediated qepA2 gene and multiple chromosomally mediated fluoroquinolone resistance determinants in the development of fluoroquinolone resistance in Escherichia coli and its influence on bacterial fitness. METHODS: E. coli ATCC 25922 and derived isogenic strains harbouring different chromosomally mediated fluoroquinolone resistance determinants were electroporated with pBK-CMV vector encoding QepA2. The MICs of fluoroquinolones were determined by standardized microdilution. The mutant prevention concentration (MPC) was evaluated. Bacterial fitness was analysed using DeltalacZ system competition assays. RESULTS: The ciprofloxacin MIC for strains harbouring the qepA2 gene was 4- to 8-fold higher compared with strains without the qepA2 gene. The qepA2 gene also increased the MPC of ciprofloxacin 4- to 16-fold. Combination of the qepA2 gene plus two to three additional mechanisms conferred a clinically relevant resistance level. The presence of the qepA2 gene was associated with fitness costs in strains with mutations in the gyrA and/or parC genes, although the presence of an additional deletion of the marR gene compensated for this fitness cost by increasing bacterial fitness by 5%-23%. CONCLUSIONS: The additive effect of chromosomally mediated fluoroquinolone resistance mechanisms and the qepA2 gene led to clinical levels of fluoroquinolone resistance. Under competitive conditions, the qepA2 gene had a biological cost in E. coli that was compensated for by the presence of an additional deletion in the marR gene. PMID- 26041044 TI - Reconstruction of an inferior orbital rim and cheek defect with a pedicled osteomyocutaneous submental flap. AB - BACKGROUND: The purpose of this study was to present the feasibility of reconstructing an inferior orbital rim and cheek defect with a pedicled osteomyocutaneous submental flap. METHOD: A 77-year-old women with a right nasosinusal adenoid cystic carcinoma invading soft tissues and skin of the cheek, the inferior rim of the orbit, the hard palate, and the middle turbinate is presented. A right radical maxillectomy with preservation of the eye was performed. A pedicled osteomyocutaneous submental island flap was used to reconstruct the defect. An inferior marginal mandibular section was incorporated with the flap and used to reconstruct the inferior orbital rim. RESULTS: Satisfactory cosmetic and functional results were reached by reconstructing the inferior rim of the orbit and the cheek skin using this flap. CONCLUSION: This is the first case report of an osteomyocutaneous submental flap for reconstruction of an inferior orbital rim defect. PMID- 26041045 TI - Recurrent abducens nerve palsy due to basilar venous plexus engorgement. PMID- 26041042 TI - Evaluation of the Efficacy, Potential for Vector Transmission, and Duration of Immunity of MP-12, an Attenuated Rift Valley Fever Virus Vaccine Candidate, in Sheep. AB - Rift Valley fever virus (RVFV) causes serious disease in ruminants and humans in Africa. In North America, there are susceptible ruminant hosts and competent mosquito vectors, yet there are no fully licensed animal vaccines for this arthropod-borne virus, should it be introduced. Studies in sheep and cattle have found the attenuated strain of RVFV, MP-12, to be both safe and efficacious based on early testing, and a 2-year conditional license for use in U.S. livestock has been issued. The purpose of this study was to further determine the vaccine's potential to infect mosquitoes, the duration of humoral immunity to 24 months postvaccination, and the ability to prevent disease and viremia from a virulent challenge. Vaccination experiments conducted in sheep found no evidence of a potential for vector transmission to 4 North American mosquito species. Neutralizing antibodies were elicited, with titers of >1:40 still present at 24 months postvaccination. Vaccinates were protected from clinical signs and detectable viremia after challenge with virulent virus, while control sheep had fever and high-titered viremia extending for 5 days. Antibodies to three viral proteins (nucleocapsid N, the N-terminal half of glycoprotein GN, and the nonstructural protein from the short segment NSs) were also detected to 24 months using competitive enzyme-linked immunosorbent assays. This study demonstrates that the MP-12 vaccine given as a single dose in sheep generates protective immunity to a virulent challenge with antibody duration of at least 2 years, with no evidence of a risk for vector transmission. PMID- 26041046 TI - Prevalence and etiology of subclinical mastitis in dairy ewes in two seasons in Semnan province, Iran. AB - Twenty-one dairy ewe flocks selected by stratified random sampling were subjected to study the prevalence and etiology of subclinical intramammary infections and to assess the influence of parity on the prevalence of intramammary infections. Also, spontaneous cure rates were determined over study period. A total of 1192 milk samples were collected at 2 weeks after lambing until tenth-week postpartum. All flocks had hand milking; those which were classified by bacterial culture and California Mastitis Test (CMT) as positive were deemed to have glands with subclinical mastitis (SCM). Of 1192 halves examined, 791 samples were collected during spring and 401 samples were collected during summer. Prevalence rate of SCM in spring was 14.7 %; and spontaneous cure that occurred in this season was 88.8 %; coagulase-negative staphylococci (CNS) were the most common isolates (66.6 %). Samples collected in spring showed higher prevalence rate of SCM than summer samples. This rate was 8.9 % in summer. Spontaneous cure rate in this season was 69.4 %, and Staphylococcus aureus (72.2 %) was the most common isolates. SCM was seen at significantly lower rates in left half than in right one (p < 0.05). Multiparous ewes had significantly higher (p < 0.05) SCM prevalence rates than primiparous ewes. The incidence of clinical mastitis (defined as number of clinical cases per 100 ewe-months) was 0.21 and 0.74 in spring and summer, respectively. The isolates from clinical cases in spring were fungi and, from summer, were S. aureus. Also, S. aureus SCM cases were not significantly severe than other SCM cases. In conclusion, multiparous ewes were most at risk, and severity of infection was higher in summer. PMID- 26041047 TI - Fetal magnetocardiography measurements with an array of microfabricated optically pumped magnetometers. AB - Following the rapid progress in the development of optically pumped magnetometer (OPM) technology for the measurement of magnetic fields in the femtotesla range, a successful assembly of individual sensors into an array of nearly identical sensors is within reach. Here, 25 microfabricated OPMs with footprints of 1 cm(3) were assembled into a conformal array. The individual sensors were inserted into three flexible belt-shaped holders and connected to their respective light sources and electronics, which reside outside a magnetically shielded room, through long optical and electrical cables. With this setup the fetal magnetocardiogram of a pregnant woman was measured by placing two sensor belts over her abdomen and one belt over her chest. The fetal magnetocardiogram recorded over the abdomen is usually dominated by contributions from the maternal magnetocardiogram, since the maternal heart generates a much stronger signal than the fetal heart. Therefore, signal processing methods have to be applied to obtain the pure fetal magnetocardiogram: orthogonal projection and independent component analysis. The resulting spatial distributions of fetal cardiac activity are in good agreement with each other. In a further exemplary step, the fetal heart rate was extracted from the fetal magnetocardiogram. Its variability suggests fetal activity. We conclude that microfabricated optically pumped magnetometers operating at room temperature are capable of complementing or in the future even replacing superconducting sensors for fetal magnetocardiography measurements. PMID- 26041048 TI - Study on the influence of leucine-rich amelogenin peptide (LRAP) on the remineralization of enamel defects via micro-focus x-ray computed tomography and nanoindentation. AB - Regeneration of severely damaged enamel (e.g. deep demineralized lesions) is currently not possible, because the structural units of enamel crystal construction are removed after its maturation. The aim of this in vitro study was to evaluate the effect of surface impregnation by leucine-rich amelogenin peptide (LRAP) on the remineralization of eroded enamel using micro-focus x-ray computed tomography (uCT). Fifteen bovine enamel blocks were embedded in resin and three zones (sound, demineralization, and remineralization) were defined on each specimen. Lesions were prepared by immersing the samples in demineralization solution for 7 d. The samples were soaked in distilled water or 60 or 120 ug mL( 1) solution of LRAP in water for 30 min. After the surface treatment, specimens were incubated in artificial saliva for either 5 or 10 d at 37 degrees C. The amount of mineral gain (dDeltaZ%) and the relative changes in the lesion depth (dLD%), obtained from uCT, were used to evaluate the effect of LRAP on the remineralization of lesions. The effects of LRAP on cross-sectional integrated hardness DeltaINH were studied after 10 d using nanoindentation. ANOVA test was used to determine the effect of time and/or LRAP concentration on dDeltaZ%, dLD% and DeltaINH mean values. Tukey's analysis was used for multiple comparison testing (alpha = 0.05). Analysis of uCT data showed significant effect of time and LRAP concentration on the dDeltaZ% (p = 0.013, p = 0.003) and the dLD% (p < 0.001, p = 0.002) mean values. The nanoindentation hardness was significantly improved by 120 ug mL(-1) LRAP (p = 0.02). Also, the peptide treatment affected the mineral distribution throughout the lesion by inhibiting of superficial deposition. This study showed that the treatment of eroded lesions in enamel by LRAP can improve and regulate the pattern of remineralization in vitro. PMID- 26041049 TI - Use and risks of surgical mesh for pelvic organ prolapse surgery in women in New York state: population based cohort study. PMID- 26041050 TI - Chronic reactive gliosis following regulatory T cell depletion during acute MCMV encephalitis. AB - Long-term, persistent central nervous system inflammation is commonly seen following brain infection. Using a murine model of viral encephalitis (murine cytomegalovirus, MCMV) we have previously shown that post-encephalitic brains are maintained in an inflammatory state consisting of glial cell reactivity, retention of brain-infiltrating tissue-resident memory CD8+ T-cells, and long term persistence of antibody-producing cells of the B-lineage. Here, we report that this neuroinflammation occurs concomitantly with accumulation and retention of immunosuppressive regulatory T-cells (Tregs), and is exacerbated following their ablation. However, the extent to which these Tregs function to control neuroimmune activation following MCMV encephalitis is unknown. In this study, we used Foxp3-diphtheria toxin receptor-GFP (Foxp3-DTR-GFP) transgenic mice, which upon administration of low-dose diphtheria toxin (DTx) results in the specific depletion of Tregs, to investigate their function. We found treatment with DTx during the acute phase of viral brain infection (0-4 dpi) resulted in depletion of Tregs from the brain, exacerbation of encephalitis (i.e., increased presence of CD4+ and CD8+ T-cells), and chronic reactive phenotypes of resident glial cells (i.e., elevated MHC Class II as well as PD-L1 levels, sustained microgliosis, and increased glial fibrillary acidic protein (GFAP) expression on astrocytes) versus untreated, infected animals. This chronic proinflammatory environment was associated with reduced cognitive performance in spatial learning and memory tasks (Barnes Maze) by convalescent animals. These data demonstrate that chronic glial cell activation, unremitting post-encephalitic neuroinflammation, and its associated long-term neurological sequelae in response to viral brain infection are modulated by the immunoregulatory properties of Tregs. GLIA 2015;63:1982-1996. PMID- 26041051 TI - Genome informatics and vaccine targets in Corynebacterium urealyticum using two whole genomes, comparative genomics, and reverse vaccinology. AB - BACKGROUND: Corynebacterium urealyticum is an opportunistic pathogen that normally lives on skin and mucous membranes in humans. This high Gram-positive bacteria can cause acute or encrusted cystitis, encrusted pyelitis, and pyelonephritis in immunocompromised patients. The bacteria is multi-drug resistant, and knowledge about the genes that contribute to its virulence is very limited. Two complete genome sequences were used in this comparative genomic study: C. urealyticum DSM 7109 and C. urealyticum DSM 7111. RESULTS: We used comparative genomics strategies to compare the two strains, DSM 7109 and DSM 7111, and to analyze their metabolic pathways, genome plasticity, and to predict putative antigenic targets. The genomes of these two strains together encode 2,115 non-redundant coding sequences, 1,823 of which are common to both genomes. We identified 188 strain-specific genes in DSM 7109 and 104 strain-specific genes in DSM 7111. The high number of strain-specific genes may be a result of horizontal gene transfer triggered by the large number of transposons in the genomes of these two strains. Screening for virulence factors revealed the presence of the spaDEF operon that encodes pili forming proteins. Therefore, spaDEF may play a pivotal role in facilitating the adhesion of the pathogen to the host tissue. Application of the reverse vaccinology method revealed 19 putative antigenic proteins that may be used in future studies as candidate drug or vaccine targets. CONCLUSIONS: The genome features and the presence of virulence factors in genomic islands in the two strains of C. urealyticum provide insights in the lifestyle of this opportunistic pathogen and may be useful in developing future therapeutic strategies. PMID- 26041053 TI - Strategies for the discontinuation of humidified high flow nasal cannula (HHFNC) in preterm infants. AB - BACKGROUND: Humidified high flow nasal cannula (HHFNC) delivers humidified gas at increased flow rates via binasal prongs and is becoming widely accepted as a method of non-invasive respiratory support for preterm infants. While indications for the use of (HHFNC) and its associated risks and benefits are being investigated, the best strategy for the discontinuation of HHFNC remains unknown. At what point an infant is considered stable enough to attempt to start withdrawing their HHFNC is not known. The criteria for a failed attempt at HHFNC discontinuation is also unclear. OBJECTIVES: To determine the risks and benefits of different strategies used for the discontinuation of HHFNC in preterm infants. SEARCH METHODS: We searched the Cochrane Neonatal Review Group Specialized Register, PubMed (1966 to March 2015), CINAHL (1982 to March 2015), EMBASE (1980 to March 2015), and the Cochrane Central Register of Controlled Trials (CENTRAL). Also, we checked previous reviews, including cross references. We searched for following web sites for ongoing trials: ClinicalTrials.gov and controlled trials.com. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in which either individual newborn infants or clusters of infants (such as separate neonatal units) were randomised to different HHFNC withdrawal strategies (from the first time they come off HHFNC and any subsequent weaning, or withdrawal attempt, or both). DATA COLLECTION AND ANALYSIS: We used standard methods of Cochrane and the Cochrane Neonatal Review Group. MAIN RESULTS: We identified no eligible studies examining the best strategy to wean or withdraw HHFNC once started as respiratory support in preterm infants AUTHORS' CONCLUSIONS: There is currently no evidence available to suggest the best strategy for weaning and withdrawing HHFNC as a respiratory support in preterm infants. Research is required into the best strategy for withdrawal of HHFNC and to which subgroups this applies. Clear criteria for the definition of stability prior to attempting to withdraw HHFNC needs to be established. Furthermore, clear definitions are needed as to what constitutes failure of HHFNC. PMID- 26041054 TI - What does cognitive control feel like? Effective and ineffective cognitive control is associated with divergent phenomenology. AB - Cognitive control is accompanied by observable negative affect. But how is this negative affect experienced subjectively, and are these feelings related to variation in cognitive control? To address these questions, 42 participants performed a punished inhibitory control task while periodically reporting their subjective experience. We found that within-subject variation in subjective experience predicted control implementation, but not neural monitoring (i.e., the error-related negativity, ERN). Specifically, anxiety and frustration predicted increased and decreased response caution, respectively, while hopelessness accompanied reduced inhibitory control, and subjective effort coincided with the increased ability to inhibit prepotent responses. Clarifying the nature of these phenomenological results, the effects of frustration, effort, and hopelessness but not anxiety-were statistically independent from the punishment manipulation. Conversely, while the ERN was increased by punishment, the lack of association between this component and phenomenology suggests that early monitoring signals might precede the development of control-related subjective experience. Our results indicate that the types of feelings experienced during cognitively demanding tasks are related to different aspects of controlled performance, critically suggesting that the relationship between emotion and cognitive control extends beyond the dimension of valence. PMID- 26041055 TI - Hydrophobic Mutagenesis and Semi-rational Engineering of Arginine Deiminase for Markedly Enhanced Stability and Catalytic Efficiency. AB - Due to its systemic arginine degradation, arginine deiminase (ADI) has attracted attentions as an anti-tumor drug. Its low activity at physiological conditions among other limitations has necessitated its engineering for improved properties. The present study describes the hydrophobic mutagenesis and semi-rational engineering of ADI from Pseudomonas plecoglossicida (PpADI). Using an improved ADI variant M13 (D38H/A128T/E296K/H404R/I410L) as parent, site saturation mutagenesis at position 162 resulted in an over 20 % increase in protein solubility. Compared with M13 (15.23 U/mg), mutants M13-2 (M13+S245D) and M13-5 (M13+R243L) exhibited enhanced specific activity of 21.19 and 31.20 U/mg at physiological conditions. M13-5 displayed enhanced substrate specificity with a dramatic reduction in its K m value (from 0.52 to 0.16 mM). It is speculated that the improvements in M13-5 could mainly be attributed to the enhanced structural stability due to an R243L substitution. The hydrophobic contribution of Leu 243 was supported by mutant M13-9 (M13+A276W) generated based on the hydrophobic mutagenesis concept. M13-9 showed a specific activity of 18.68 U/mg, as well as remarkable thermal and pH stability. It retained over 90 % activity over pH range from 4.5 to 8.5. At 60 degrees C, the half-life of M13-9 was enhanced from 4 to 17.5 min in comparison with M13, and its specific activity at 62 degrees C (93.0 U/mg) was approximately fivefold of that determined at 37 degrees C. Our results suggest that the increased hydrophobicity around the active regions of PpADI might be crucial in improving its structural stability and ultimately catalytic efficiency. PMID- 26041056 TI - Expression Analysis of Phenylalanine Ammonia Lyase Gene and Rosmarinic Acid Production in Salvia officinalis and Salvia virgata Shoots Under Salicylic Acid Elicitation. AB - Partial fragments of phenylalanine ammonia lyase (PAL) genes were cloned and characterized from Salvia officinalis (SoPAL) and Salvia virgata (SvPAL). Different concentrations (250 and 500 MUM) of exogenous salicylic acid (SA) were used when correlation between PAL expression and rosmarinic acid (RA) accumulation was compared. The results showed that the deduced cDNA sequences of the partial genes had high similarities with those of known PAL gene from other plant species. Semi-quantitative reverse transcription PCR (RT-PCR) analysis revealed that exogenous application of SA led to up-regulating of the PAL expression. Further analysis showed that in S. virgata, at higher concentration of SA, higher accumulation of RA was achieved, while in S. officinalis, the higher RA accumulation was observed at lower concentration of SA. It was concluded that there was no positive correlation between the intensity of PAL transcription and the RA accumulation in the studied species. Therefore, despite of the increase in transcription rate of the PAL at the higher concentration of SA, the lower amounts of RA were accumulated in the case of S. officinalis. Consequently, the hypothesis that PAL is the rate-determining step in RA biosynthesis is not always valid and probably some other unknown factors participate in the synthesis of phenolics. PMID- 26041057 TI - Overview of Antioxidant Peptides Derived from Marine Resources: The Sources, Characteristic, Purification, and Evaluation Methods. AB - Marine organisms are rich sources of structurally diverse bioactive nitrogenous components. In recent years, numerous bioactive peptides have been identified in a range of marine protein resources, such as antioxidant peptides. Many studies have approved that marine antioxidant peptides have a positive effect on human health and the food industry. Antioxidant activity of peptides can be attributed to free radicals scavenging, inhibition of lipid peroxidation, and metal ion chelating. Moreover, it has also been verified that peptide structure and its amino acid sequence can mainly affect its antioxidant properties. The aim of this review is to summarize kinds of antioxidant peptides from various marine resources. Additionally, the relationship between structure and antioxidant activities of peptides is discussed in this paper. Finally, current technologies used in the preparation, purification, and evaluation of marine-derived antioxidant peptides are also reviewed. PMID- 26041058 TI - A Simple Green Synthesis of Palladium Nanoparticles with Sargassum Alga and Their Electrocatalytic Activities Towards Hydrogen Peroxide. AB - This study presents the synthesis of palladium nanoparticles (PdNPs) using the extract derived from the marine alga, Sargassum bovinum, collected from Persian Gulf area. Water-soluble compounds that exist in the marine alga extract were the main cause of the reduction of palladium ions to Pd nanoparticles. The basic properties of PdNPs produced in this method were confirmed by UV-visible spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD), energy-dispersive X-ray (EDX) analysis, and Fourier transform infrared spectroscopy (FTIR). TEM confirmed the monodispersed and octahedral shape of PdNPs within the size ranges from 5 to 10 nm. Catalytic performance of the biosynthetic PdNPs was investigated by electrochemical reduction of hydrogen peroxide (H2O2). PdNP-modified carbon ionic liquid electrode (PdNPs/CILE) was developed as a nonenzymatic sensor for the determination of hydrogen peroxide. Amperometric measurements showed that PdNPs/CILE is a reliable sensor for the detection of hydrogen peroxide in the range of 5.0 MUM-15.0 mM with a sensitivity of 284.35 mAmM(-1) cm(-2) and a detection limit of 1.0 MUM. Moreover, PdNPs/CILE exhibits a wide linear range, high sensitivity and selectivity, and excellent stability for the detection of H2O2 in aqueous solutions. PMID- 26041059 TI - Characterization and Optimization of Bioflocculant Exopolysaccharide Production by Cyanobacteria Nostoc sp. BTA97 and Anabaena sp. BTA990 in Culture Conditions. AB - Bioflocculant exopolysaccharide (EPS) production by 40 cyanobacterial strains during their photoautotrophic growth was investigated. Highest levels of EPS were produced by Nostoc sp. BTA97 and Anabaena sp. BTA990. EPS production was maximum during stationary growth phase, when nitrogenase activity was very low. Maximum EPS production occurred at pH 8.0 in the absence of any combined nitrogen source. The cyanobacterial EPS consisted of soluble protein and polysaccharide that included substantial amounts of neutral sugars and uronic acid. The EPS isolated from Anabaena sp. BTA990 and Nostoc sp. BTA97 demonstrated high flocculation capacity. There was a positive correlation between uronic acid content and flocculation activity. The flocculant bound a cationic dye, Alcian Blue, indicating it to be polyanionic. The 16S rRNA gene sequences for Nostoc sp. BTA97 and Anabaena sp. BTA990 were deposited at NCBI GenBank, and accession numbers were obtained as KJ830951 and KJ830948, respectively. The results of these experiments indicate that strains Anabaena sp. BTA990 and Nostoc sp. BTA97 are good candidates for the commercial production of EPS and might be utilized in industrial applications as an alternative to synthetic and abiotic flocculants. PMID- 26041060 TI - Endophyte-mediated interactions between cauliflower, the herbivore Spodoptera litura, and the ectoparasitoid Bracon hebetor. AB - Fungal endosymbionts in plants may influence interactions among plants, herbivores and their parasitoids through the production of secondary metabolites. We used a lepidopteran pest and its generalist parasitoid to test the effect of endophyte-infected plants on a third trophic level. Endophytic fungi, Aspergillus flavus and Aspergillus niger, isolated from Acacia arabica, were used to infect cauliflower plants. We found that the presence of the endophyte in the plants significantly extended the development period of Spodoptera litura (Fab.) larvae. Feeding of the host on endophyte-infected plants further adversely affected the development and performance of its parasitoid, Bracon hebetor (Say). A negative impact was also recorded for longevity and fecundity of endophyte-naive parasitoid females due to the parasitization of host larvae fed on endophyte infected plants. The presence of endophytes in the diet of the host larvae significantly prolonged the development of the parasitoid. A strong detrimental effect was also recorded for larval survival and emergence of parasitoid adults. The longevity and parasitism rate of female wasps were reduced significantly due to the ingestion of endophyte-infected cauliflower plants by S. litura larvae. Overall, we found that both endophytic fungi had a negative impact on the parasitoid. PMID- 26041061 TI - Fraction distribution and risk assessment of heavy metals in waste clay sediment discharged through the phosphate beneficiation process in Jordan. AB - Heavy metal contamination of clay waste through the phosphate beneficiation process is a serious problem faced by scientists and regulators worldwide. Through the beneficiation process, heavy metals naturally present in the phosphate rocks became concentrated in the clay waste. This study evaluated the concentration of heavy metals and their fractions in the clay waste in order to assess the risk of environmental contamination. A five-step sequential extraction method, the risk assessment code (RAC), effects range low (ERL), effects range medium (ERM), the lowest effect level (LEL), the severe effect level (SEL), the redistribution index (U tf), the reduced partition index (I), residual partition index (I R), and the Nemerow multi-factor index (PC) were used to assess for clay waste contamination. Heavy metals were analyzed using high-resolution inductively coupled plasma mass spectrometry (HR-ICP-MS) and inductively coupled plasma optical emission spectroscopy (ICP-OES). Correlation analyses were carried out to better understand the relationships between the chemical characteristics and the contents of the different phase fractions. Concentrations of Cd and Cu confirmed that both were bound to the exchangeable fraction (F1) and the carbonate fraction (F2), presenting higher mobility, whereas Pb was most abundant in the Fe-Mn oxide fraction (F3) and organic matter fraction (F4). The residual fraction (F5) contained the highest concentrations (>60%) of As, Cr, Mo, V, and Zn, with lower mobility. Application of the RAC index showed that Cd and Cu should be considered a moderate risk, whereas As, Cr, Mo, Pb, and Zn presented a low risk. Cadmium and Cu contents in mobile fractions F1 and F2 were higher than ERL but lower than ERM. On the other hand, As, Pb, and Zn contents of mobile fractions F1 and F2 were lower than ERL and ERM guideline values. Moreover, total Pb concentrations in the clay waste were below the lowest effect level (LEL) threshold value period, Cr and Zn values in the clay waste were determined to have exceeded the severe effect level (SEL) limit values, whereas Cd and Cu level ranges between LEL and SEL indicate moderate contamination. I R values of heavy metals in the clay waste confirmed that Cd and Cu were bound to the exchangeable and carbonate fractions and presented higher mobility, whereas As, Cr, Mo, Pb, V, and Zn were bound to organic or residual fractions and consequently exhibit lower mobility. A Nemerow multi-factor index revealed that the mine site contains high levels of Cd, Cu, V, and Zn pollution. As and Cr were found at a moderate level of contamination, whereas Pb was present at a safe level of contamination. The order of the comprehensive contamination indices was Cd > Cu > Mo > Zn > V > Cr > As > Pb, indicating that the assessment of clay waste, especially with Cd and Cu, should be undertaken to control heavy metal contamination in adjacent urban and mine areas at the Eshidiya mines. PMID- 26041062 TI - Managing shallow aquifers in the dry zone of Sri Lanka. AB - This study looks at the groundwater issues in the dry zone of Sri Lanka and shows how the use of remote sensing with high-resolution images can help in groundwater management. A new approach is developed for automatic extraction of the location of agro-wells using high-spatial-resolution satellite imageries. As an example, three pilot sites in three different aquifer systems in the country are considered, and their high-resolution images are analyzed over two temporal time periods. The analysis suggests that the well density in all three regions has increased over the last few years, indicating higher levels of groundwater extraction. Using the well inventory developed by this new approach, the water budgeting was prepared for the mainland of Jaffna Peninsula. The analysis shows a wide variation in well density in the Jaffna Peninsula, ranging from (as little as) less than 15 wells per square kilometer to (as high as) more than 200 wells per square kilometer. Calculations made for the maximum allowable water extraction in each administrative division of Jaffna show that less than 3 h of daily extraction per well is possible in some districts. This points to an increasing pressure on groundwater resources in the region and thus highlights the importance of understanding groundwater budgets for sustainable development of the aquifers. PMID- 26041063 TI - Effect of soil type and organic manure on adsorption-desorption of flubendiamide. AB - Laboratory study on adsorption-desorption of flubendiamide was conducted in two soil types, varying in their physical and chemical properties, by batch equilibrium method. After 4 h of equilibrium time, adsorption of flubendiamide on soil matrix exhibited moderately low rate of accumulation with 4.52 +/- 0.21% in red soil and low rate with 3.55 +/- 0.21% in black soil. After amending soils with organic manure, adsorption percentage increased to 6.42 +/- 0.21% in red soil and (4.18 +/- 0.21%) in black soil indicating that amendment significantly increased sorption. Variation in sorption affinities of the soils as indicated by distribution coefficient (K d) for sorption was in the range of 2.98-4.32, 4.91 6.64, 1.04-1.45 and 1.92-2.81 ml/g for red soil, organic manure-treated red soil, black soil and organic manure-treated black soil, respectively. Desorption was slightly slower than adsorption indicating a hysteresis effect having hysteresis coefficient ranges between 0.023 and 0.149 in two test soils. The adsorption data for the insecticide fitted well the Freundlich equation. Results revealed that adsorption-desorption was influenced by soil types and showed that the maximum sorption and minimum desorption of the insecticide was observed in soils with higher organic carbon and clay content. It can be inferred that crystal lattice of the clay soil plays a significant role in flubendiamide adsorption and desorption. Adsorption was lower at acidic pH and gradually increased towards alkaline pH. As this insecticide is poorly sorbed in the two Indian soil types, there may be a possibility of their leaching to lower soil profiles. PMID- 26041064 TI - Spatial monitoring of arsenic and heavy metals in the Almyros area, Central Greece. Statistical approach for assessing the sources of contamination. AB - The purpose of this work was to provide information on As and heavy metals content in surface soils of the Almyros area, in Central Greece. A 3-year (2009 2011) research was conducted, in order to investigate the possible temporal variation of As and heavy metal levels. Each year, a number of 251 soil samples (753 totally number of samples) were collected from the area studied, using a Differential Global Positioning System (D.G.P.S.). Soil samples were analyzed for physicochemical parameters and for pseudo-total content of metals, after digestion with Aqua Regia. Thematic maps were created, with Geographic Information Systems (GIS) techniques, using geostatistical tools. The corresponding topographical diagrams covering 15,000 ha of the study area were digitized. The thematic maps and the geostatistical analysis tools were conducted with the use of ArcGIS and the extensions Geostatistical Analyst, Spatial Analyst, and 3D analyst. Factor analysis was conducted in order to assess the possible sources of the pollution. The levels of As and metals determined were lower than the maximum permitted, except for Cd, which content was, in some cases, higher than the critical limits for soils. No statistical differences were observed among the years of the study, although a trend of continuous increasing of their content was detected. Significant correlations between heavy metal fractions and soil physicochemical parameters were obtained and discussed. PMID- 26041065 TI - The effect of climate and meteorological changes on particulate matter in Pune, India. AB - This paper presents the distinctiveness of particulate matter (PM) mass concentrations (PM10, PM2.5, and PM10-2.5) and meteorological effect in Pune city during 2011-2012. The PM samples were collected using Mini-Vol TAS air sampler (Airmetrics Co. Inc., 5 l min(-1) flow rate). The meteorological parameters were also measured during the study period. The analysis of 24-h average PM10, PM2.5, and PM10-2.5 concentrations showed the maximum during winter (267.2-67.2, 180.6 55.6, 138.9-11.7 MUg m(-3)) followed by summer (236.1-55.5, 138.8-27.7, 125-13.8 MUg m(-3)) and post-monsoon (153.3-82.3, 138.9-41.7, 41.7-14.4 MUg m(-3)) and showed the lowest concentration during monsoon (98.9-27.8, 83.3-13.9, 40.0-6.0 MUg m(-3)) seasons in the entire study. PM10 comprised a vast fraction of PM2.5 (61% of PM2.5), while the estimated PM2.5/PM10 ratios for monsoon, post-monsoon, winter, and summer seasons were ranged between 0.5 and 0.9, 0.51 and 0.91, 0.3 and 0.9, and 0.3 and 0.8, respectively. The 7-day back trajectories analysis for whole year shows that the air masses transported to Pune were mixed mainland maritime such as from southwesterly, north, northwest. Chemometric analysis was applied as a tool to evaluate and predict the particulate mass concentration from available meteorological data. To achieve this, a calibration model was developed by partial least squares regression (PLSR) method and was further used to predict the PM concentrations based on meteorological data. On predicting the PM concentration from local meteorological data, the model performance and quality was found very good in case of PM10 compared to PM2.5. PMID- 26041066 TI - Internal Hernia in Pregnant Women After Gastric Bypass: a Retrospective Register Based Cohort Study. AB - BACKGROUND AND AIMS: Pregnant women who have previously had laparoscopic Roux-en Y gastric bypass surgery are increasingly seen in the acute surgical care setting with abdominal pain due to internal hernia. With this study, we want to contribute with our experience and to present our local surgical guidelines concerning this particularly vulnerable patient group. MATERIALS AND METHOD: This article is a retrospective study on prospectively collected data. Using data from the Danish National Health Register, we identified 23 women who had bariatric surgery previously and who were admitted to our surgical department and operated on for suspicion of internal hernia. Additional data was collected from patient files and surgical files. RESULTS: We identified 23 women who all during pregnancy underwent surgery on suspicion of internal hernia; in 17 patients, the diagnosis was confirmed. We found that laparoscopic approach in our sample was performed as late as the 31st gestational week. All women and foetuses survived this dangerous condition, and none suffered from serious complications, nor did any of the patients have a bowel resection due to small bowel strangulation. CONCLUSION: In skilled clinical hands, internal hernia has a good prognosis in pregnant patients. Surgery may be performed subacutely or even electively, depending on the condition of patient and foetus, and straightforward clinical assessment is adequate, and imaging studies, e.g. CT, are not necessary. PMID- 26041067 TI - Use of panoramic radiography to predict postsurgical sensory impairment following extraction of impacted mandibular third molars. AB - BACKGROUND: The purpose of this study was to use panoramic radiographic findings to predict postsurgical sensory impairment following the extraction of impacted mandibular third molars. METHODS: There were 120 patients enrolled in this study (55 male and 65 female). A total of 120 impacted mandibular third molars were included due to the proximity between the inferior alveolar nerve (IAN) canal and the roots of the impacted third molar on the panoramic radiograph. Seven radiographic signs were the predictor variables: (1) darkening of the root(s); (2) interruption of the radiopaque line of the inferior alveolar canal; (3) diversion of the inferior alveolar canal; (4) dark and bifid apex; (5) deflection of the root(s); (6) narrowing of the inferior alveolar canal; and (7) narrowing of the root(s). The outcome variable was the postoperative IAN sensory impairment. The retrospective cohort study model was used, and univariable and bivariable statistics was computed with the statistically significant level at p <= 0.05. RESULTS: Three of the radiographic signs were statistically associated with IAN sensory impairment (p<0.05). They include: (1) interruption of the radiopaque line [sensitivity = 0.92, specificity = 0.45, positive predictive value (PPV) = 0.17, negative predictive value (NPV) = 0.02]; (2) diversion of the IAN canal (sensitivity = 0.77, specificity = 0.84, PPV = 0.37, NPV = 0.03); and (3) narrowing of the IAN canal (sensitivity = 0.69, specificity = 0.65, PPV = 0.19, NPV = 0.05). However, the other four radiographic signs, namely darkening of the root(s), dark and bifid apex, deflection of the root(s), and narrowing of the root(s), were not statistically associated with IAN sensory impairment (p>0.05). CONCLUSION: There are three radiographic signs: (1) interruption of the radiopaque line; (2) diversion of the IAN canal; and (3) narrowing of the IAN canal. These signs are valuable in presurgical evaluation of the risk of postoperative sensory impairment after surgical removal of impacted mandibular third molar. PMID- 26041068 TI - Catalytic asymmetric desymmetrization of N-arylmaleimides: efficient construction of both atom chirality and axial chirality. AB - The catalytic asymmetric Michael addition/desymmetrization reaction of N-(2-t butylphenyl)maleimides with unprotected 3-substituted-2-oxindoles was successfully realized using a chiral N,N'-dioxide-Sc(III) complex, leading to succinimides with two kinds of stereogenic elements-atom chirality and axial chirality-in up to 99% yield, 99% ee and >19 : 1 d.r. PMID- 26041069 TI - Effect of mechanical optical clearing on near-infrared spectroscopy. AB - Near-infrared Spectroscopy (NIRS) is a broadly utilized technology with many emerging applications including clinical diagnostics, sports medicine, and functional neuroimaging, to name a few. For functional brain imaging NIR light is delivered at multiple wavelengths through the scalp and skull to the brain to enable spatial oximetry measurements. Dynamic changes in brain oxygenation are highly correlated with neural stimulation, activation, and function. Unfortunately, NIRS is currently limited by its low spatial resolution, shallow penetration depth, and, perhaps most importantly, signal corruption due to light interactions with superficial non-target tissues such as scalp and skull. In response to these issues, we have combined the non-invasive and rapidly reversible method of mechanical tissue optical clearing (MOC) with a commercially available NIRS system. MOC utilizes a compressive loading force on tissue, causing the lateral displacement of blood and water, while simultaneously thinning the tissue. A MOC-NIRS Breath Hold Test displayed a ~3.5-fold decrease in the time-averaged standard deviation between channels, consequentially promoting greater channel agreement. A Skin Pinch Test was implemented to negate brain and muscle activity from affecting the recorded signal. These results displayed a 2.5-3.0 fold increase in raw signal amplitude. Existing NIRS instrumentation has been further integrated within a custom helmet device to provide a uniform force distribution across the NIRS sensor array. These results showed a gradual decrease in time-averaged standard deviation among channels with an increase in applied pressure. Through these experiments, and the development of the MOC-NIRS helmet device, MOC appears to provide enhancement of NIRS technology beyond its current limitations. PMID- 26041070 TI - Biomimetic mineralization of metal-organic frameworks as protective coatings for biomacromolecules. AB - Enhancing the robustness of functional biomacromolecules is a critical challenge in biotechnology, which if addressed would enhance their use in pharmaceuticals, chemical processing and biostorage. Here we report a novel method, inspired by natural biomineralization processes, which provides unprecedented protection of biomacromolecules by encapsulating them within a class of porous materials termed metal-organic frameworks. We show that proteins, enzymes and DNA rapidly induce the formation of protective metal-organic framework coatings under physiological conditions by concentrating the framework building blocks and facilitating crystallization around the biomacromolecules. The resulting biocomposite is stable under conditions that would normally decompose many biological macromolecules. For example, urease and horseradish peroxidase protected within a metal-organic framework shell are found to retain bioactivity after being treated at 80 degrees C and boiled in dimethylformamide (153 degrees C), respectively. This rapid, low-cost biomimetic mineralization process gives rise to new possibilities for the exploitation of biomacromolecules. PMID- 26041071 TI - Effect of various surface preparations on bond strength of a gingiva-colored indirect composite to zirconia framework for implant-supported prostheses. AB - To evaluate the effects of various surface preparations on shear bond strength of a gingiva-colored indirect composite material and zirconia framework. Zirconia disks were prepared with one of nine surface treatments: hydrofluoric acid etching (HF), heating at 1,000 degrees C for 10 min (HT), wet-grinding with 600- and 1500-grit SiC paper (SiC 600 and 1500), alumina-blasting at 0.1, 0.2, 0.4 and 0.6 MPa (AB 0.1, 0.2, 0.4, and 0.6), and no treatment (NT). An indirect composite material was bonded to zirconia. Shear bond strengths were measured. Bond strength was significantly higher in AB 0.2, 0.4, and 0.6 groups than in other groups at 0 and 20,000 thermocycles. Post-thermocycling bond strength was lower in NT, HF, and HT groups than in other groups. Alumina-blasting with 0.2 MPa or higher yielded sufficient durable bond strength between gingiva-colored indirect composite and zirconia frameworks. Hydrofluoric acid etching and heat treatment did not achieve durable bond strengths. PMID- 26041072 TI - Retraction: Fluoride release and recharge abilities of contemporary fluoride containing restorative materials and dental adhesives. PMID- 26041073 TI - The Usefulness of the TOAST Classification and Prognostic Significance of Pyramidal Symptoms During the Acute Phase of Cerebellar Ischemic Stroke. AB - Cerebellar stroke is a rare condition with very nonspecific clinical features. The symptoms in the acute phase could imitate acute peripheral vestibular disorders or a brainstem lesion. The aim of this study was to assess the usefulness of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification in cerebellar stroke and the impact of clinical features on the prognosis. We retrospectively analyzed 107 patients with diagnosed ischemic cerebellar infarction. We studied the clinical features and compared them based on the location of the ischemic lesion and its distribution in the posterior interior cerebellar artery (PICA), superior cerebellar artery (SCA), and anterior inferior cerebellar artery (AICA) territories. According to the TOAST classification, stroke was more prevalent in atrial fibrillation (26/107) and when the lesion was in the PICA territory (39/107). Pyramidal signs occurred in 29/107 of patients and were more prevalent when the lesion was distributed in more than two vascular regions (p = 0.00640). Mortality was higher among patients with ischemic lesion caused by cardiac sources (p = 0.00094) and with pyramidal signs (p = 0.00640). The TOAST classification is less useful in assessing supratentorial ischemic infarcts. Cardioembolic etiology, location of the ischemic lesion, and pyramidal signs support a negative prognosis. PMID- 26041074 TI - Perverted Head-Shaking and Positional Downbeat Nystagmus in Essential Tremor. AB - Even though the pathophysiology is not completely understood, cerebellar dysfunction has been invoked in essential tremor (ET). We evaluated cerebellar dysfunction in ET with the presence of perverted head-shaking (pHSN) and positional downbeat nystagmus (pDBN) which are known to reflect cerebellar dysfunction. First, we reviewed the videooculography (VOG) of 185 patients with ET from March 2007 to April 2010. Seventeen of 28 patients with pHSN and pDBN were followed up for at least a 1.8-year interval from baseline to determine the clinical course. And then, we recruited 52 consecutive patients with ET and compared their ocular motor findings with 51 normal controls using VOG. Among the 185 patients with ET, 28 (15.1 %) showed pHSN (n = 23, 12.4 %) or pDBN (n = 8, 4.3 %). Seventeen of them who were followed up did not develop Parkinsonism or other neurologic deficits during the observation period. The subsequent case control study showed a higher prevalence of pHSN or pDBN (11/52, 21.2 %, pHSN in nine and pDBN in five) in patients with ET than in the normal controls (2/51, 3.9 %, pHSN only, P = 0.015). The tremor rating scale or involved body sites did not differ between the patients with and without pHSN/pDBN. pHSN and pDBN were more common in patients with ET than in the normal controls. This result supports that cerebellar dysfunction is associated with ET. PMID- 26041075 TI - TROL-FNR interaction reveals alternative pathways of electron partitioning in photosynthesis. AB - In photosynthesis, final electron transfer from ferredoxin to NADP(+) is accomplished by the flavo enzyme ferredoxin:NADP(+) oxidoreductase (FNR). FNR is recruited to thylakoid membranes via integral membrane thylakoid rhodanase-like protein TROL. We address the fate of electrons downstream of photosystem I when TROL is absent. We have employed electron paramagnetic resonance (EPR) spectroscopy to study free radical formation and electron partitioning in TROL depleted chloroplasts. DMPO was used to detect superoxide anion (O2(.-)) formation, while the generation of other free radicals was monitored by Tiron. Chloroplasts from trol plants pre-acclimated to different light conditions consistently exhibited diminished O2(.-) accumulation. Generation of other radical forms was elevated in trol chloroplasts in all tested conditions, except for the plants pre-acclimated to high-light. Remarkably, dark- and growth light acclimated trol chloroplasts were resilient to O2(.-) generation induced by methyl-viologen. We propose that the dynamic binding and release of FNR from TROL can control the flow of photosynthetic electrons prior to activation of the pseudo-cyclic electron transfer pathway. PMID- 26041076 TI - Coronary artery disease risk among obese metabolically healthy young men. AB - OBJECTIVE: The aim of this study was to assess coronary artery disease (CAD) risk among obese young men without metabolic risk factors. DESIGN: A longitudinal study in a historical cohort. METHODS: Incident CAD during a median follow-up of 6.1 years was assessed among 31,684 young men (mean age 31.2 +/- 5.7 years) of the Metabolic, Lifestyle and Nutrition Assessment in Young Adults (MELANY) cohort. Participants were categorized by BMI and the number of metabolic abnormalities (based on the Adult Treatment Panel-III). Metabolically healthy (MH) obesity was defined as BMI >= 30 kg/m(2) in the presence of normal blood pressure (BP) and normal levels of fasting glucose, triglyceride, and HDL cholesterol (HDL-c) levels (n = 599; 1.9%). Cox proportional hazard models were applied. RESULTS: There were 198 new cases of CAD that were diagnosed during 209,971 person-years of follow-up, of which six cases occurred among MH obese. The incidence of CAD among MH lean, overweight, and obese participants was 0.23, 0.45, and 1.0/1000 person-years respectively. In a multivariable model adjusted for clinical and biochemical CAD risk factors, a higher CAD risk was observed among MH-obese (hazard ratio = 3.08; 95% CI = 1.10-8.68, P = 0.033), compared to MH-normal weight subjects. This risk persisted when BMI was treated as a time dependent variable, or when fasting glucose, HDL-c, triglycerides, or BP were added to the model. Similar results were also obtained when a more permissive definition of MH was used. CONCLUSIONS: Obesity may continue to contribute to increased risk for incident CAD in young men even in the presence of a healthy metabolic profile. PMID- 26041077 TI - ENDOCRINOLOGY AND ADOLESCENCE: Osteoporosis in children: diagnosis and management. AB - Osteoporosis in children can be primary or secondary due to chronic disease. Awareness among paediatricians is vital to identify patients at risk of developing osteoporosis. Previous fractures and backaches are clinical predictors, and low cortical thickness and low bone density are radiological predictors of fractures. Osteogenesis Imperfecta (OI) is a rare disease and should be managed in tertiary paediatric units with the necessary multidisciplinary expertise. Modern OI management focuses on functional outcomes rather than just improving bone mineral density. While therapy for OI has improved tremendously over the last few decades, this chronic genetic condition has some unpreventable, poorly treatable and disabling complications. In children at risk of secondary osteoporosis, a high degree of suspicion needs to be exercised. In affected children, further weakening of bone should be avoided by minimising exposure to osteotoxic medication and optimising nutrition including calcium and vitamin D. Early intervention is paramount. However, it is important to identify patient groups in whom spontaneous vertebral reshaping and resolution of symptoms occur to avoid unnecessary treatment. Bisphosphonate therapy remains the pharmacological treatment of choice in both primary and secondary osteoporosis in children, despite limited evidence for its use in the latter. The duration and intensity of treatment remain a concern for long-term safety. Various new potent antiresorptive agents are being studied, but more urgently required are studies using anabolic medications that stimulate bone formation. More research is required to bridge the gaps in the evidence for management of paediatric osteoporosis. PMID- 26041079 TI - Insertion, elimination and isomerisation of olefins at alkylaluminium hydride: an experimental and theoretical study. AB - The insertion, elimination and isomerisation of octenes with di-n-octylaluminium hydride [HAl(Oct)2], tri-n-octylaluminium [Al(Oct)3] and sec-octylaluminium species have been studied as individual steps in a putative aluminium based contrathermodynamic olefin isomerisation process. While elimination of 1-octene from [Al(Oct)3] is energetically unfavourable, the process is driven by high temperature vacuum distillation, leading to very high selectivity to 1-octene (>97%). At high conversions the [HAl(Oct)2] so obtained exists predominately as hydride-bridged cyclic oligomers, whereas at low conversion the mixed alkyl/hydride-bridged dimer [(Oct)2Al(MU-H)(MU-Oct)Al(Oct)2] is the major species. Di-n-octylaluminium hydride recovered after olefin elimination may be recycled and is active toward re-insertion of octenes. Internal octenes (cis- and trans-2-, 3- and 4-octene) only partially insert however, and even after prolonged heating there is no significant secondary to primary alkyl isomerisation evident. PMID- 26041078 TI - Projected Spending on Psychotropic Medications 2013-2020. AB - Spending on psychotropic medications has grown rapidly in recent decades. Using national data on drug expenditures, patent expirations, future drug development and expert interviews, we project that spending will grow more slowly over the period 2012-2020. The average annual increase is projected to be just 3.0 % per year, continuing the steady deceleration in recent years. The main drivers of this expected deceleration include slower development of new drugs, upcoming patent expirations which will lower prices, and payers' growing ability to manage utilization and promote generic use. The slowdown will relieve some cost pressures on payers, particularly Medicare and Medicaid. PMID- 26041080 TI - Paeoniflorin selectively inhibits LPS-provoked B-cell function. AB - B cells are important in the development of autoimmune disorders through mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and targeting which reduces inflammation and tissue damage effectively but often leads to patients suffering from secondary infection. Paeoniflorin (PF) is the main substance of the Total glucosides of peony and has been widely used to treat autoimmune diseases for years. However, whether PF affects B cell activity remains unknown. In this study, using purified murine spleen B cells, we analyzed the effects of PF on B-cell function in vitro. We found that PF inhibited the expression of CD69/CD86 and the proliferation of B cells stimulated by LPS. In addition, PF reduced the B-cell differentiation and immunoglobulin production that was stimulated by LPS. Interestingly, PF did not alter B-cell activation and proliferation provoked by anti-CD40 or IL-4. These results indicated for the first time that PF inhibits B-cell activation, proliferation and differentiation by selectively blocking the LPS/TLR4 signaling pathway. Furthermore, our data suggest that PF selectively inhibits inflammation and tissue damage mediated by LPS-activated B cells but does not alter CD40/CD40L or IL-4-provoked B-cell function in autoimmune diseases treatment, which might aid in protecting patients from secondary infection. PMID- 26041081 TI - DNA Oligonucleotide Fragment Ion Rearrangements Upon Collision-Induced Dissociation. AB - Collision-induced dissociation (CID) of m/z-isolated w type fragment ions and an intact 5' phosphorylated DNA oligonucleotide generated rearranged product ions. Of the 21 studied w ions of various nucleotide sequences, fragment ion sizes, and charge states, 18 (~86%) generated rearranged product ions upon CID in a Synapt G2-S HDMS (Waters Corporation, Manchester, England, UK) ion mobility-mass spectrometer. Mass spectrometry (MS), ion mobility spectrometry (IMS), and theoretical modeling data suggest that purine bases can attack the free 5' phosphate group in w type ions and 5' phosphorylated DNA to generate sequence permuted [phosphopurine](-) fragment ions. We propose and discuss a potential mechanism for generation of rearranged [phosphopurine](-) and complementary y-B type product ions. PMID- 26041082 TI - Anomerization of Acrylated Glucose During Traveling Wave Ion Mobility Spectrometry. AB - Anomerization of simple sugars in the liquid phase is known as an acid- and base catalyzed process, which highly depends on solvent polarity. This reaction is reported here to occur in the gas phase, during traveling wave ion mobility spectrometry (TWIMS) experiments aimed at separating alpha- and beta-anomers of penta-acrylated glucose generated as ammonium adducts in electrospray ionization. This compound was available in two samples prepared from glucose dissolved in solvents of different polarity, namely tetrahydrofuran (THF) and N,N dimethylacetamide (DMAC), and analyzed by electrospray tandem mass spectrometry (ESI-MS/MS) as well as traveling wave ion mobility (ESI-TWIMS-MS). In MS/MS, an anchimerically-assisted process was found to be unique to the electrosprayed alpha-anomer, and was only observed for the THF sample. In ESI-TWIMS-MS, a signal was measured at the drift time expected for the alpha-anomer for both the THF and DMAC samples, in apparent contradiction to the MS/MS results, which indicated that the alpha-anomer was not present in the DMAC sample. However, MS/MS experiments performed after TWIMS separation revealed that ammonium adducts of the alpha-anomer produced from each sample, although exhibiting the same collision cross section, were clearly different. Indeed, while the alpha-anomer actually present in the THF sample was electrosprayed with the ammonium adducted at the C2 acrylate, its homologue only observed when the DMAC sample was subjected to TWIMS hold the adducted ammonium at the C1 acrylate. These findings were explained by a beta/alpha inter-conversion upon injection in the TWIMS cell, as supported by theoretical calculation and dynamic molecular modeling. PMID- 26041083 TI - Pharmacokinetic analysis of cyclosporine in a renal transplant recipient with congenital absence of the portal vein. AB - Here we report therapeutic drug monitoring of cyclosporine in a kidney transplant recipient lacking enterohepatic circulation. The patient developed steroid resistant nephrotic syndrome at age 14 years, and was medicated with an oral cyclosporine microemulsion. However, her cyclosporine trough level was unexpectedly elevated, and subsequent investigations showed that she was deficient in drug metabolism as a result of the congenital absence of the portal vein. Her renal function gradually decreased and she became dialysis-dependent at the age of 21 years, and kidney transplantation was planned. Based on pretransplant therapeutic drug monitoring, we started cyclosporine microemulsion at half of the conventional dosage. After transplantation, the dosage was successfully adjusted to achieve a target trough level. The post-transplant course was stable with no symptoms of rejection or cyclosporine-associated nephrotoxicity. PMID- 26041085 TI - Health damage from current air pollution levels. PMID- 26041084 TI - Metabolic patterns in prion diseases: an FDG PET voxel-based analysis. AB - PURPOSE: Clinical diagnosis of human prion diseases can be challenging since symptoms are common to other disorders associated with rapidly progressive dementia. In this context, (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) might be a useful complementary tool. The aim of this study was to determine the metabolic pattern in human prion diseases, particularly sporadic Creutzfeldt-Jakob disease (sCJD), the new variant of Creutzfeldt-Jakob disease (vCJD) and fatal familial insomnia (FFI). METHODS: We retrospectively studied 17 patients with a definitive, probable or possible prion disease who underwent FDG PET in our institution. Of these patients, 12 were diagnosed as sCJD (9 definitive, 2 probable and 1 possible), 1 was diagnosed as definitive vCJD and 4 were diagnosed as definitive FFI. The hypometabolic pattern of each individual and comparisons across the groups of subjects (control subjects, sCJD and FFI) were evaluated using a voxel-based analysis. RESULTS: The sCJD group exhibited a pattern of hypometabolism that affected both subcortical (bilateral caudate, thalamus) and cortical (frontal cortex) structures, while the FFI group only presented a slight hypometabolism in the thalamus. Individual analysis demonstrated a considerable variability of metabolic patterns among patients, with the thalamus and basal ganglia the most frequently affected areas, combined in some cases with frontal and temporal hypometabolism. CONCLUSION: Patients with a prion disease exhibit a characteristic pattern of brain metabolism presentation in FDG PET imaging. Consequently, in patients with rapidly progressive cognitive impairment, the detection of these patterns in the FDG PET study could orient the diagnosis to a prion disease. PMID- 26041086 TI - Evaluation of an intervention for patients with alcohol-related injuries: results of a mixed methods study. AB - OBJECTIVE: To explore the effect of education and training on the delivery of alcohol screening and brief intervention and referral to high-risk patients in a hospital setting. Main outcome measures included; delivery of training; practice change in relation to staff performing alcohol screening, brief intervention and referrals. METHODS: Observational study design using mixed methods set in a tertiary referral hospital. Pre-post assessment of medical records and semi structured interviews with key informants. RESULTS: Routine screening for substance misuse (9% pre / 71.4% post) and wellbeing concerns (6.6% pre / 15 % post) was more frequent following the introduction of resources and staff participation in educational workshops. There was no evidence of a concomitant increase in delivery of brief intervention or referrals to services. Implementation challenges, including time constraints and staff attitudes, and enablers such as collaboration and visible pathways, were identified. CONCLUSION: Rates of patient screening increased, however barriers to delivery of brief intervention and referrals remained. Implementation strategies targeting specific barriers and enablers to introducing interventions are both required to improve the application of secondary prevention for patients in acute settings. IMPLICATIONS: Educational training, formalised liaison between services, systematised early intervention protocols, and continuous quality improvement processes will progress service delivery in this area. PMID- 26041087 TI - Erratum. PMID- 26041091 TI - The unexpected epidural: a case report. AB - BACKGROUND: We report the peculiar case of a patient with a retained large epidural catheter fragment, incidentally found 12 years after its placement. Our primary aim is to emphasize how the breakage and retention of even exceptionally large portions of this device can go undetected. The patient can be completely asymptomatic and, with no clue that such a foreign body exists, the presentation of its potential complications can be subtle and misleading. To our knowledge, this is the first reported case of the incidental discovery of such a large fragment so many years after its placement. No consensus exists about how to handle this complication, therefore our report adds to the amount of available evidence. CASE PRESENTATION: A 53-year-old caucasian female with a history of diverticulitis requiring multiple hospitalizations underwent laparoscopic sigmoidectomy. The early postoperative period was complicated by peritonitis, demanding an urgent "second-look" exploratory laparoscopy. Nine days post operatively, a filiform metallic object in the upper-quadrant was noted on x-ray. No epidural had been placed for either one of her recent surgeries. Given the patient's history, the object was initially thought to be a retained surgical sponge. Previous studies, however, showed that the same image was already present preoperatively. Upon further questioning, the patient reported an epidural being placed twelve years before, at the time of her pregnancy. No mention of breakage had been made to her at that time, nor a retained foreign body was ever reported afterwards, despite her many imaging exams. She also never experienced any symptoms. A 15 cm fragment of a wire-reinforced catheter was surgically retrieved under local anesthesia and fluoroscopic guidance. CONCLUSION: Breakage of the epidural catheter with fragment retention is a known complication of this device, possibly leading to devastating sequelae. The fragment can go undetected for years. In this case our finding was incidental and the patient was asymptomatic. However, in the event a neurologic complication arose, the identification of the unknowingly retained epidural as the causative agent could have been difficult and delayed, with potential harm to the patient. PMID- 26041092 TI - Current perspectives toward the identification of key players in gastric cancer microRNA dysregulation. AB - Acquired genetic and epigenetic alterations in normal cells give rise to transformed cells, which lead to tumor development. Elucidation of the precise mechanisms underlying primary and metastatic tumor formation is required. MicroRNAs (miRNAs) are small noncoding RNAs that play a major role in post transcriptional gene regulation during various biological processes. Accumulating evidence suggests that dysregulation of miRNAs is intimately involved in the carcinogenesis, progression and metastasis of many cancers, including gastric cancers (GCs), while the alteration of certain miRNAs provides biomarkers to detect early GCs. This review summarizes the most recent findings into the mechanisms of miRNA-mediated regulation of GCs, which will support the development of diagnostic biomarkers and novel therapeutic strategies. PMID- 26041093 TI - Evolution in the smallest valves (stomata) guides even the biggest trees. PMID- 26041094 TI - Nanopillar Based Enhanced-Fluorescence Detection of Surface-Immobilized Beryllium. AB - The unique properties associated with beryllium metal ensures the continued use in many industries despite the documented health and environmental risks. While engineered safeguards and personal protective equipment can reduce risks associated with working with the metal, it has been mandated by the Environmental Protection Agency (EPA) and Occupational Safety and Health Administration (OSHA) that the workplace air and surfaces must be monitored for toxic levels. While many methods have been developed to monitor levels down to the low MUg/m(3), the complexity and expense of these methods have driven the investigation into alternate methodologies. Herein, we use a combination of the previously developed fluorescence Be(II) ion detection reagent, 10-hydroxybenzo[h]quinoline (HBQ), with an optical field enhanced silicon nanopillar array, creating a new surface immobilized (si-HBQ) platform. The si-HBQ platform allows the positive control of the reagent for demonstrated reusability and a pillar diameter based tunable enhancement. Furthermore, native silicon nanopillars are overcoated with thin layers of porous silicon oxide to develop an analytical platform capable of a 0.0006 MUg/L limit of detection (LOD) using sub-MUL sample volumes. Additionally, we demonstrate a method to multiplex the introduction of the sample to the platform, with minimal 5.2% relative standard deviation (RSD) at 0.1 MUg/L, to accommodate the potentially large number of samples needed to maintain industrial compliance. The minimal sample and reagent volumes and lack of complex and highly specific instrumentation, as well as positive control and reusability of traditionally consumable reagents, create a platform that is accessible and economically advantageous. PMID- 26041095 TI - Flow diversion in vasculitic intracranial aneurysms? Repair of giant complex cavernous carotid aneurysm in polyarteritis nodosa using Pipeline embolization devices: first reported case. AB - Intracranial aneurysms in polyarteritis nodosa (PAN) are exceedingly rare lesions with unpredictable behavior that pose real challenges to microsurgical and endovascular interventions owing to their inflammatory nature. We introduce a safe and effective alternative for treating these aneurysms using Pipeline embolization devices (PEDs). A 20-year-old man presented with diplopia, headaches, chronic abdominal pain, and weight loss. Diagnostic evaluations confirmed PAN, including bilateral giant cavernous carotid aneurysms. Cyclophosphamide and steroids achieved significant and sustained clinical improvement, with a decision to follow the aneurysms serially. Seven years later the left unruptured aneurysm enlarged, causing a sudden severe headache and a cavernous sinus syndrome. Treatment of the symptomatic aneurysm was pursued using flow diversion (PED) and the internal carotid artery was successfully reconstructed with a total of four overlapping PEDs. At 6 months follow-up, complete exclusion of the aneurysm was demonstrated, with symptomatic recovery. This is the first description of using a flow-diverting technique in an inflammatory vasculitis. In this case, PEDs not only attained a definitive closure of the aneurysm but also reconstructed the damaged and fragile arterial segment affected with vasculitis. PMID- 26041096 TI - Solitaire stents for the treatment of complex symptomatic intracranial stenosis after antithrombotic failure: safety and efficacy evaluation. AB - OBJECTIVES: To evaluate the feasibility, safety, and efficacy of Solitaire stent placement after balloon angioplasty for the treatment of complex symptomatic intracranial atherosclerotic stenosis (ICAS). METHODS: We retrospectively reviewed the clinical data from 44 patients who underwent Solitaire stent placement for complex symptomatic ICAS at our department between November 2010 and March 2014, with focus on the clinical factors, lesion characteristics, treatment results, and periprocedural complications. We also summarized the early outcomes and imaging findings during the follow-up period. RESULTS: Overall, the technical success rate was 100% (44/44). Post-stenting residual stenosis ranged from 0% to 40% (mean 15.00+/-12.94%). The overall 30-day rate of procedure related complications was 9.09% (4/44). The incidence of recurrent ischemic events related to the territory artery was 4.55% during a mean clinical follow-up period of 25.5 months. Five patients (11.36%) developed in-stent restenosis during a mean angiographic follow-up period of 9.3 months. CONCLUSIONS: This is the first case series study of ICAS treated by Solitaire stent placement. Deployment of a Solitaire stent with balloon angioplasty in the treatment of complex severe intracranial stenosis appears safe and effective, with a high technical success rate, relatively low periprocedural complication rate, and favorable outcome during follow-up. PMID- 26041097 TI - Stent-assisted coil embolization of aneurysms with small parent vessels: safety and efficacy analysis. AB - BACKGROUND: Stent-assisted coil embolization (SACE) is a viable therapeutic approach for wide-neck intracranial aneurysms. However, it can be technically challenging in small cerebral vessels (<=2 mm). OBJECTIVE: To present our experience with stents approved for SACE in aneurysms with small parent arteries. METHODS: All patients who underwent stent-assisted aneurysm treatment with either a Neuroform or an Enterprise stent device at our institution between June 2006 and October 2012 were identified. Additionally, we evaluated each patient's vascular risk factors, aneurysm characteristics (ruptured vs non-ruptured, incidental finding, recanalized) and follow-up angiography data. RESULTS: A total of 41 patients with 44 aneurysms met our criteria, including 31 women and 10 men. Most of the aneurysms were located in the anterior circulation (75%). Stent placement in vessels 1.2-2 mm in diameter was successful in 93.2%. Thromboembolic complications occurred in 6 cases and vessel straightening was seen in 1 case only. Initial nearly complete to complete aneurysm obliteration was achieved in 88.6%. Six-month follow-up angiography showed coil compaction in three cases, one asymptomatic in-stent stenosis and stent occlusion. Twelve to 20-months' follow up showed stable coil compaction in two patients compared with previous follow up, and aneurysm recanalization in two patients. Twenty-four to 36-months' follow up showed further coil compaction in one of these patients and aneurysm recanalization in a previous case of stable coil compaction on mid-term follow up. CONCLUSIONS: Our results suggest that SACE of aneurysms with small parent vessels is feasible in selected cases and shows good long-term patency rates of parent arteries. PMID- 26041098 TI - Use of flow-diverting stents as salvage treatment following failed stent-assisted embolization of intracranial aneurysms. AB - Flow-diverting stents, including the Pipeline embolization device (PED) and Silk, have been beneficial in the treatment of aneurysms previously unable to be approached via endovascular techniques. Recurrent aneurysms for which stent assisted embolization has failed are a therapeutic challenge, given the existing intraluminal construct with continued blood flow into the aneurysm. We report our experience using flow-diverting stents in the repair of 25 aneurysms for which stent-assisted embolization had failed. Nineteen (76%) of these aneurysms at the 12-month follow-up showed improved Raymond class occlusion, with 38% being completely occluded, and all aneurysms demonstrated decreased filling. One patient developed a moderate permanent neurologic deficit. Appropriate stent sizing, proximal and distal construct coverage, and preventing flow diverter deployment between the previously deployed stent struts are important considerations to ensure wall apposition and prevention of endoleak. Flow diverters are shown to be a reasonable option for treating previously stented recurrent cerebral aneurysms. PMID- 26041099 TI - Dural arteriovenous fistulas at the craniocervical junction: a systematic review. AB - BACKGROUND: Dural arteriovenous fistulas (DAVFs) at the craniocervical junction are uncommon but clinically important abnormalities. OBJECTIVE: To investigate the clinical characteristics of patients with DAVFs at the craniocervical junction and assess angiographic features associated with bleeding at presentation. METHODS: We systematically reviewed the literature and searched PubMed and EMBASE for all relevant English language articles published between 1980 and 2014. The clinical presentation, angiographic characteristics, and treatment were assessed. The clinical differences between a subarachnoid hemorrhage (SAH) group and a non-SAH group were statistically examined. RESULTS: Fifty-six patients were identified after a review of the literature (mean age 55.6 years; male to female ratio=3:1). Twenty-one patients (37.5%) presented with hemorrhage including SAH and posterior fossa hemorrhage. There was no significant difference in patient age, sex, or location of the DAVF between the SAH group and the non-SAH group. Intracranial venous drainage was significantly associated with SAH (p<0.001). The presence of a varix was significantly associated with SAH (p=0.001). Open surgery had a significantly higher efficacy of initial complete obliteration than embolization (100% vs 71.4%, p<0.01). CONCLUSIONS: DAVFs at the craniocervical junction are rare lesions, which often present with hemorrhage. Intracranial venous drainage and a venous varix are associated with increased risk of SAH. Surgical interruption of the feeding arteries or draining veins is an effective and reliable method for treating DAVFs at the craniocervical junction. Embolization is a feasible alternative to surgery in the treatment of selective DAVFs. PMID- 26041101 TI - Interview with Matthew Diamond, 2014 Epilepsia prize winner. PMID- 26041100 TI - Association of thrombelastographic parameters with post-stenting ischemic events. AB - BACKGROUND AND PURPOSE: Thrombelastography (TEG) is widely used for the measurement of platelet function. However, few studies have investigated the TEG parameters in patients receiving extracranial or intracranial artery stenting for ischemic cerebrovascular disease. This study sought to describe the association of TEG parameters before the procedure with post-procedural ischemic events after extracranial or intracranial artery stenting. METHODS: Patients in whom stenting was performed for extracranial or intracranial artery stenosis (70-99%) were recruited into the study. Blood samples were obtained for TEG to assess platelet function before stenting. The primary endpoint was ischemic stroke or transient ischemic attack in the territory of the stented artery. RESULTS: A total of 218 patients were included in the study. During a mean follow-up period of 132 days (range 98-226 days), 18 (8.3%) primary endpoint events were recorded. Compared with patients without ischemic events, the ADP-induced platelet-fibrin clot strength (MAADP) was significantly higher (41.57+/-15.10 vs 33.50+/-13.86, p=0.020) and the ADP inhibition rate (ADP%) was significantly lower in patients with ischemic events (39.54+/-23.15 vs 55.29+/-24.43, p=0.009). Multivariate analysis identified MAADP and ADP% as significant independent predictors of subsequent ischemic events with HRs of 1.036 and 0.965, respectively. From receiver operating characteristic curve analysis, MAADP >49.95 mm had the best predictive value of ischemic events. CONCLUSIONS: Our study suggests that TEG parameters MAADP and ADP% are associated with subsequent ischemic events in patients with extracranial or intracranial stents. CLINICAL TRIAL NUMBER: NCT01925872. PMID- 26041103 TI - Mental health recovery: lived experience of consumers, carers and nurses. AB - Background Mental health recovery is a prominent topic of discussion in the global mental health settings. The concept of mental health recovery brought about a major shift in the traditional philosophical views of many mental health systems. Aim The purpose of this article is to outline the results of a qualitative study on mental health recovery, which involved mental health consumers, carers and mental health nurses from an Area Mental Health Service in Victoria, Australia. This paper is Part One of the results that explored the meaning of recovery. Methods The study used van Manen's hermeneutic phenomenology to analyse the data. Findings Themes suggested that the cohort had varying views on recovery that were similar and dissimilar. The similar views were categorised under two processes involving the self, an internal process and an external process. These two processes involved reclaiming various aspects of oneself, living life, cure or absence of symptoms and contribution to community. The dissimilar views involved returning to pre-illness state and recovery was impossible. Conclusion This study highlights the need for placing importance on the person's sense of self in the recovery process. PMID- 26041102 TI - A new arylbenzofuran derivative functions as an anti-tumour agent by inducing DNA damage and inhibiting PARP activity. AB - We previously reported that 7-hydroxy-5, 4'-dimethoxy-2-arylbenzofuran (HDAB) purified from Livistona chinensis is a key active agent. The present study investigated the function and molecular mechanism of HDAB. HDAB treatment of cervical cancer cells resulted in S phase arrest and apoptosis, together with cyclin A2 and CDK2 upregulation. Cyclin A2 siRNA and a CDK inhibitor efficiently relieved S phase arrest but increased the apoptosis rate. Mechanistic studies revealed that HDAB treatment significantly increased DNA strand breaks in an alkaline comet assay and induced ATM, CHK1, CHK2 and H2A.X phosphorylation. Wortmannin (a broad inhibitor of PIKKs) and CGK733 (a specific ATM inhibitor), but not LY294002 (a phosphatidylinositol 3-kinase inhibitor) or NU7026 (a DNA-PK specific inhibitor), prevented H2A.X phosphorylation and gammaH2A.X-positive foci formation in the nuclei, reversed S phase arrest and promoted the HDAB-induced apoptosis, suggesting that HDAB is a DNA damaging agent that can activate the ATM dependent DNA repair response, thereby contributing to cell cycle arrest. In addition, molecular docking and in vitro activity assays revealed that HDAB can correctly dock into the hydrophobic pocket of PARP-1 and suppress PARP-1 ADP ribosylation activity. Thus, the results indicated that HDAB can function as an anti-cancer agent by inducing DNA damage and inhibiting PARP activity. PMID- 26041104 TI - Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations. AB - The development of our understanding of frontotemporal dementia (FTD) has gathered pace over the last 10 years. After taking a back seat to Alzheimer's disease for many years FTD has emerged as a significant group of heterogeneous diseases often affecting people under the age of 65. FTD has also been brought into the spotlight as the major disease entities of the group have clinical, genetic and pathological links to motor neuron disease/amyotrophic lateral sclerosis, indicating that they form a disease spectrum. In this review, we overview how the pathological concept of frontotemporal lobar degeneration (FTLD) and the clinical concept of FTD evolved and show that FTLD, once thought of as a single disorder, represents a heterogeneous group of diseases with overlapping clinical symptoms, multiple causative genes and varying underlying pathology. We also provide a brief summary of the clinical manifestations, summarize the major genetic aspects and describe the main pathological features seen in the different subtypes of FTLD. We also summarize the correlations that exist between clinical presentations and pathological variants. An overview of the main pathogenic mechanisms is also provided. PMID- 26041105 TI - Mid-infrared passively switched pulsed dual wavelength Ho(3+)-doped fluoride fiber laser at 3 MUm and 2 MUm. AB - Cascade transitions of rare earth ions involved in infrared host fiber provide the potential to generate dual or multiple wavelength lasing at mid-infrared region. In addition, the fast development of saturable absorber (SA) towards the long wavelengths motivates the realization of passively switched mid-infrared pulsed lasers. In this work, by combing the above two techniques, a new phenomenon of passively Q-switched ~3 MUm and gain-switched ~2 MUm pulses in a shared cavity was demonstrated with a Ho(3+)-doped fluoride fiber and a specifically designed semiconductor saturable absorber (SESAM) as the SA. The repetition rate of ~2 MUm pulses can be tuned between half and same as that of ~3 MUm pulses by changing the pump power. The proposed method here will add new capabilities and more flexibility for generating mid-infrared multiple wavelength pulses simultaneously that has important potential applications for laser surgery, material processing, laser radar, and free-space communications, and other areas. PMID- 26041106 TI - The role of elicited verbal imitation in toddlers' word learning. AB - This study is about the role of elicited verbal imitation in toddler word learning. Forty-eight toddlers were taught eight nonwords linked to referents. During training, they were asked to imitate the nonwords. Naming of the referents was tested at three intervals (one minute later [uncued], five minutes, and 1-7 days later [cued]) and recognition at the last two intervals. Receptive vocabulary, nonword repetition, and expressive phonology were assessed. The accuracy of elicited imitation during training predicted naming at one and five minutes, but not 1-7 days later. Neither nonword repetition nor expressive phonology was associated with naming over time but extant vocabulary predicted performance at all time intervals. We hypothesize that elicited imitation facilitates word learning in its earliest stages by supporting encoding of the word form into memory and allowing practice of the articulatory-phonological plan. At later stages, vocabulary facilitates integration of the word form into the lexical network. PMID- 26041107 TI - Glucose-dependent insulinotropic polypeptide directly induces glucose transport in rat skeletal muscle. AB - Several gastrointestinal proteins have been identified to have insulinotropic effects, including glucose-dependent insulinotropic polypeptide (GIP); however, the direct effects of incretins on skeletal muscle glucose transport remain largely unknown. Therefore, the purpose of the current study was to examine the role of GIP on skeletal muscle glucose transport and insulin signaling in rats. Relative to a glucose challenge, a mixed glucose+lipid oral challenge increased circulating GIP concentrations, skeletal muscle Akt phosphorylation, and improved glucose clearance by ~35% (P < 0.05). These responses occurred without alterations in serum insulin concentrations. In an incubated soleus muscle preparation, GIP directly stimulated glucose transport and increased GLUT4 accumulation on the plasma membrane in the absence of insulin. Moreover, the ability of GIP to stimulate glucose transport was mitigated by the addition of the PI 3-kinase (PI3K) inhibitor wortmannin, suggesting that signaling through PI3K is required for these responses. We also provide evidence that the combined stimulatory effects of GIP and insulin on soleus muscle glucose transport are additive. However, the specific GIP receptor antagonist (Pro(3))GIP did not attenuate GIP-stimulated glucose transport, suggesting that GIP is not signaling through its classical receptor. Together, the current data provide evidence that GIP regulates skeletal muscle glucose transport; however, the exact signaling mechanism(s) remain unknown. PMID- 26041108 TI - Regular postexercise cooling enhances mitochondrial biogenesis through AMPK and p38 MAPK in human skeletal muscle. AB - This study investigated the effect of regular postexercise cold water immersion (CWI) on muscle aerobic adaptations to endurance training. Eight males performed 3 sessions/wk of endurance training for 4 wk. Following each session, subjects immersed one leg in a cold water bath (10 degrees C; COLD) for 15 min, while the contralateral leg served as a control (CON). Muscle biopsies were obtained from vastus lateralis of both CON and COLD legs prior to training and 48 h following the last training session. Samples were analyzed for signaling kinases: p38 MAPK and AMPK, peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), enzyme activities indicative of mitochondrial biogenesis, and protein subunits representative of respiratory chain complexes I-V. Following training, subjects' peak oxygen uptake and running velocity were improved by 5.9% and 6.2%, respectively (P < 0.05). Repeated CWI resulted in higher total AMPK, phosphorylated AMPK, phosphorylated acetyl-CoA carboxylase, beta-3-hydroxyacyl CoA-dehydrogenase and the protein subunits representative of complex I and III (P < 0.05). Moreover, large effect sizes (Cohen's d > 0.8) were noted with changes in protein content of p38 (d = 1.02, P = 0.064), PGC-1alpha (d = 0.99, P = 0.079), and peroxisome proliferator-activated receptor alpha (d = 0.93, P = 0.10) in COLD compared with CON. No differences between conditions were observed in the representative protein subunits of respiratory complexes II, IV, and V and in the activities of several mitochondrial enzymes (P > 0.05). These findings indicate that regular CWI enhances p38, AMPK, and possibly mitochondrial biogenesis. PMID- 26041109 TI - Central mechanisms regulating coordinated cardiovascular and respiratory function during stress and arousal. AB - Actual or potentially threatening stimuli in the external environment (i.e., psychological stressors) trigger highly coordinated defensive behavioral responses that are accompanied by appropriate autonomic and respiratory changes. As discussed in this review, several brain regions and pathways have major roles in subserving the cardiovascular and respiratory responses to threatening stimuli, which may vary from relatively mild acute arousing stimuli to more prolonged life-threatening stimuli. One key region is the dorsomedial hypothalamus, which receives inputs from the cortex, amygdala, and other forebrain regions and which is critical for generating autonomic, respiratory, and neuroendocrine responses to psychological stressors. Recent studies suggest that the dorsomedial hypothalamus also receives an input from the dorsolateral column in the midbrain periaqueductal gray, which is another key region involved in the integration of stress-evoked cardiorespiratory responses. In addition, it has recently been shown that neurons in the midbrain colliculi can generate highly synchronized autonomic, respiratory, and somatomotor responses to visual, auditory, and somatosensory inputs. These collicular neurons may be part of a subcortical defense system that also includes the basal ganglia and which is well adapted to responding to threats that require an immediate stereotyped response that does not involve the cortex. The basal ganglia/colliculi system is phylogenetically ancient. In contrast, the defense system that includes the dorsomedial hypothalamus and cortex evolved at a later time, and appears to be better adapted to generating appropriate responses to more sustained threatening stimuli that involve cognitive appraisal. PMID- 26041110 TI - The interaction between peripheral and central fatigue at different muscle temperatures during sustained isometric contractions. AB - Changes in central fatigue have been linked to active and passive changes in core temperature, as well as integration of sensory feedback from thermoreceptors in the skin. However, the effects of muscle temperature (Tm), and thereby metaboreceptor and local afferent nerve temperature, on central fatigue (measured using voluntary activation percentage) during sustained, high muscle fatigue exercise remain unexamined. In this study, we investigated Tm across the range of cold to hot, and its effect on voluntary activation percentage during sustained isometric contractions of the knee extensors. The results suggest that contrary to brief contractions, during a sustained fatiguing contraction Tm significantly (P < 0.001) influences force output (-0.7%/ degrees C increase) and central fatigue (-0.5%/ degrees C increase), showing a negative relationship across the Tm continuum in moderately trained individuals. The negative relationship between voluntary activation percentage and Tm indicates muscle temperature may influence central fatigue during sustained and high muscle fatigue exercise. On the basis of on an integrative analysis between the present data and previous literature, the impact of core and muscle temperature on voluntary muscle activation is estimated to show a ratio of 5.5 to 1, respectively. Accordingly, Tm could assume a secondary or tertiary role in the reduction of voluntary muscle activation when body temperature leaves a thermoneutral range. PMID- 26041113 TI - Vitamin D deficiency is a potential risk factor for contrast-induced nephropathy. AB - Vitamin D deficiency (VDD) is widespread in the general population. Iodinated (IC) or gadolinium-based contrast media (Gd) may decrease renal function in high risk patients. This study tested the hypothesis that VDD is a predisposing factor for IC- or Gd-induced nephrotoxicity. To this end, male Wistar rats were fed standard (SD) or vitamin D-free diet for 30 days. IC (diatrizoate), Gd (gadoterate meglumine), or 0.9% saline was then administered intravenously and six groups were obtained as the following: SD plus 0.9% saline (Sham-SD), SD plus IC (SD+IC), SD plus Gd (SD+Gd), vitamin D-free diet for 30 days plus 0.9% saline (Sham-VDD30), vitamin D-free diet for 30 days plus IC (VDD30+IC), and vitamin D free diet for 30 days plus Gd (VDD30+Gd). Renal hemodynamics, redox status, histological, and immunoblot analysis were evaluated 48 h after contrast media (CM) or vehicle infusion. VDD rats showed lower levels of total serum 25 hydroxyvitamin D [25(OH)D], similar plasma calcium and phosphorus concentration, and higher renal renin and angiotensinogen protein expression compared with rats fed SD. IC or Gd infusion did not affect inulin clearance-based estimated glomerular filtration rate (GFR) in rats fed SD but significantly decreased GFR in rats fed vitamin D-free diet. Both CM increased renal angiotensinogen, and the interaction between VDD and CM triggered lower renal endothelial nitric oxide synthase abundance and higher renal thiobarbituric acid reactive substances-to glutathione ratio (an index of oxidative stress) on VDD30+IC and VDD30+Gd groups. Conversely, worsening of renal function was not accompanied by abnormalities on kidney structure. Additionally, rats on a VDD for 60 days displayed a greater fall in GFR after CM administration. Collectively, our findings suggest that VDD is a potential risk factor for IC- or Gd-induced nephrotoxicity most likely due to imbalance in intrarenal vasoactive substances and oxidative stress. PMID- 26041112 TI - Impact of age on exercise-induced ATP supply during supramaximal plantar flexion in humans. AB - Currently, the physiological factors responsible for exercise intolerance and bioenergetic alterations with age are poorly understood due, at least in art, to the confounding effect of reduced physical activity in the elderly. Thus, in 40 healthy young (22 +/- 2 yr) and old (74 +/- 8 yr) activity-matched subjects, we assessed the impact of age on: 1) the relative contribution of the three major pathways of ATP synthesis (oxidative ATP synthesis, glycolysis, and the creatine kinase reaction) and 2) the ATP cost of contraction during high-intensity exercise. Specifically, during supramaximal plantar flexion (120% of maximal aerobic power), to stress the functional limits of the skeletal muscle energy systems, we used (31)P-labeled magnetic resonance spectroscopy to assess metabolism. Although glycolytic activation was delayed in the old, ATP synthesis from the main energy pathways was not significantly different between groups. Similarly, the inferred peak rate of mitochondrial ATP synthesis was not significantly different between the young (25 +/- 8 mM/min) and old (24 +/- 6 mM/min). In contrast, the ATP cost of contraction was significantly elevated in the old compared with the young (5.1 +/- 2.0 and 3.7 +/- 1.7 mM.min(-1).W(-1), respectively; P < 0.05). Overall, these findings suggest that, when young and old subjects are activity matched, there is no evidence of age-related mitochondrial and glycolytic dysfunction. However, this study does confirm an abnormal elevation in exercise-induced skeletal muscle metabolic demand in the old that may contribute to the decline in exercise capacity with advancing age. PMID- 26041111 TI - Genetic approaches in comparative and evolutionary physiology. AB - Whole animal physiological performance is highly polygenic and highly plastic, and the same is generally true for the many subordinate traits that underlie performance capacities. Quantitative genetics, therefore, provides an appropriate framework for the analysis of physiological phenotypes and can be used to infer the microevolutionary processes that have shaped patterns of trait variation within and among species. In cases where specific genes are known to contribute to variation in physiological traits, analyses of intraspecific polymorphism and interspecific divergence can reveal molecular mechanisms of functional evolution and can provide insights into the possible adaptive significance of observed sequence changes. In this review, we explain how the tools and theory of quantitative genetics, population genetics, and molecular evolution can inform our understanding of mechanism and process in physiological evolution. For example, lab-based studies of polygenic inheritance can be integrated with field based studies of trait variation and survivorship to measure selection in the wild, thereby providing direct insights into the adaptive significance of physiological variation. Analyses of quantitative genetic variation in selection experiments can be used to probe interrelationships among traits and the genetic basis of physiological trade-offs and constraints. We review approaches for characterizing the genetic architecture of physiological traits, including linkage mapping and association mapping, and systems approaches for dissecting intermediary steps in the chain of causation between genotype and phenotype. We also discuss the promise and limitations of population genomic approaches for inferring adaptation at specific loci. We end by highlighting the role of organismal physiology in the functional synthesis of evolutionary biology. PMID- 26041115 TI - A novel continuous capnodynamic method for cardiac output assessment in a porcine model of lung lavage. AB - BACKGROUND: We have evaluated a new method for continuous monitoring of effective pulmonary blood flow (COEPBF ), i.e. cardiac output (CO) minus intra-pulmonary shunt, during mechanical ventilation. The method has shown good trending ability during severe hemodynamic challenges in a porcine model with intact lungs. In this study, we further evaluate the COEPBF method in a model of lung lavage. METHODS: COEPBF was compared to a reference method for CO during hemodynamic and PEEP alterations, 5 and 12 cmH2 O, before and after repeated lung lavages in 10 anaesthetised pigs. Bland-Altman, four-quadrant and polar plot methodologies were used to determine agreement and trending ability. RESULTS: After lung lavage at PEEP 5 cmH2 O, the ratio of arterial oxygen partial pressure related to inspired fraction of oxygen significantly decreased. The mean difference (limits of agreement) between methods changed from 0.2 (-1.1 to 1.5) to -0.9 (-3.6 to 1.9) l/min and percentage error increased from 34% to 70%. Trending ability remained good according to the four-quadrant plot (concordance rate 94%), whereas mean angular bias increased from 4 degrees to -16 degrees when using the polar plot methodology. CONCLUSION: Both agreement and precision of COEPBF were impaired in relation to CO when the shunt fraction was increased after lavage at PEEP 5 cmH2 O. However, trending ability remained good as assessed by the four-quadrant plot, whereas the mean polar angle, calculated by the polar plot, was wide. PMID- 26041114 TI - Antineoplastic drugs determination by HPLC-HRMS(n) to monitor occupational exposure. AB - The purpose of this study was to develop a simple, direct, multiresidue highly specific procedure to evaluate the possible surface contamination of selected antineoplastic drugs in several hospital environment sites by using wipe test sampling. 5-fluorouracil (5-FU), carboplatin (C-Pt), cyclophosphamide (CYC), cytarabine (CYT), doxorubicin (DOX), gemcitabine (GEM), ifosfamide (IFO), methotrexate (MET), and mitomycin C (MIT) belong to very different chemical classes but show good ionization properties under electrospray ionization (ESI) conditions (negative ion mode for 5-FU and positive ion mode in all other cases). HPLC (high performance liquid chromatography) coupled with HRMS (high resolution mass spectrometry) appears to be the best technique for direct analysis of these analytes, because neither derivatization nor complex extraction procedure for polar compounds in samples is requested prior the analysis. Sample preparation was limited to washing wipes with appropriate solvents. Chromatographic separation was achieved on C18 reversed phase columns. The HPLC-HRMS/MS method was validated in order to obtain robustness, sensitivity and selectivity. LLOQ (lower limit of quantitation) values provided a sensitivity good enough to evidence the presence of the drugs in a very low concentration range (<1 pg/cm(2) ). The method was applied for a study of real wipe tests coming from many areas from a hospital showing some positive samples. The low quantitation limits and the high specificity due to the high resolution approach of the developed method allowed an accurate description of the working environment that can be used to define procedural rules to limit working place contamination to a minimum. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26041116 TI - Breath-holding times in various phases of respiration and effect of respiratory training in lung cancer patients. AB - INTRODUCTION: Breath-holding (BH) technique is used for reducing the intrafraction-tumour motion in mobile lung tumours treated with radiotherapy (RT). There is paucity of literature evaluating differences in BH times in various phases of respiration in patients with lung cancer. METHODS: One hundred consecutive patients with lung cancer planned for radical RT/chemoradiation were accrued in the study. Eighty-seven patients were eligible for analysis at RT conclusion. Baseline pulmonary function test (PFT) were performed in all patients, and respiratory training was given from the day of RT planning. Deep inspiration breath hold (DIBH), deep expiration breath hold (DEBH) and mid ventilation breath hold (MVBH) were recorded manually with a stopwatch for each patient at four time points (RT planning/baseline, RT starting, during RT and RT conclusion). RESULTS: Median DIBH times at RT planning, RT starting, during RT and RT conclusion were 21.2, 20.6, 20.1 and 21.1 s, respectively. The corresponding median DEBH and MVBH times were 16.3, 18.2, 18.3, 18.5 s and 19.9, 20.5, 21.3, 22.1 s, respectively. Respiratory training increased MVBH time at RT conclusion compared to baseline, which was statistically significant (19.9-22.1 s, P = 0.002). DIBH or DEBH times were stable at various time points with neither a significant improvement nor decline. Among various patient and tumour factors Forced Vital Capacity pre-bronchodilation (FVCpre ) was the only factor that consistently predicted DIBH, DEBH and MVBH at all four time points with P value <0.05. CONCLUSIONS: BH was well tolerated by most lung cancer patients with minimum median BH time of at least 16 s in any of the three phases of respiration. Respiratory training improved MVBH time while consistently maintaining DIBH and DEBH times throughout the course of radiotherapy. PMID- 26041118 TI - Geographical variation in the incidence of childhood leukaemia in Manitoba. AB - BACKGROUND: Identification of geographical areas and ecological factors associated with higher incidence of childhood leukaemias can direct further study for preventable factors and location of health services to manage such individuals. AIM: The aim of this study was to describe the geographical variation and the socio-demographic factors associated with childhood leukaemia in Manitoba. METHODS: Information on childhood leukaemia incidence between 1992 and 2008 was obtained from the Canadian Cancer Registry and the socio-demographic characteristics for the area of residence from the 2006 Canadian Census. Bayesian spatial Poisson mixed models were used to describe the geographical variation of childhood leukaemia and to determine the association between childhood leukaemia and socio-demographic factors. RESULTS: The south-eastern part of the province had a higher incidence of childhood leukaemia than other parts of the province. In the age and sex-adjusted Poisson regression models, areas with higher proportions of visible minorities and immigrant residents had higher childhood leukaemia incidence rate ratios. In the saturated Poisson regression model, the childhood leukaemia rates were higher in areas with higher proportions of immigrant residents. Unemployment rates were not a significant factor in leukaemia incidence. CONCLUSION: In Manitoba, areas with higher proportions of immigrants experience higher incidence rates of childhood leukaemia. We have identified geographical areas with higher incidence, which require further study and attention. PMID- 26041117 TI - [ICD therapy in the primary prevention of sudden cardiac death: Risk stratification and patient selection]. AB - Without the concept of primary prevention of sudden cardiac death, therapy with implantable defibrillators would not have reached the current distribution and clinical importance. Most of the scientific evidence of the concept is based on clinical studies from 1996-2005. More than 75 % of all defibrillator implantations are currently indicated as primary prevention. Implantable converter-defibrillator (ICD) therapy in the primary prevention of sudden cardiac death was incorporated into scientific guidelines starting in 1998. The historical development of the indications for ICD therapy in the primary prevention of sudden cardiac death is presented, reflecting major results of controlled, randomized clinical studies and guideline discussions. PMID- 26041119 TI - Occurrence of respiratory symptoms in persons with restrictive ventilatory impairment compared with persons with chronic obstructive pulmonary disease: The PLATINO study. AB - Patients with chronic obstructive pulmonary disease (COPD) usually complain of symptoms such as cough, sputum, wheezing, and dyspnea. Little is known about clinical symptoms in individuals with restrictive ventilatory impairment. The aim of this study was to compare the prevalence and type of respiratory symptoms in patients with COPD to those reported by individuals with restrictive ventilatory impairment in the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar study. Between 2002 and 2004, individuals >=40 years of age from five cities in Latin America performed pre and post-bronchodilator spirometry and had their respiratory symptoms recorded in a standardized questionnaire. Among the 5315 individuals evaluated, 260 (5.1%) had a restrictive spirometric diagnosis (forced vital capacity (FVC) < lower limit of normal (LLN) with forced expiratory volume in the first second to forced vital capacity ratio (FEV1/FVC) >= LLN; American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005) and 610 (11.9%) were diagnosed with an obstructive pattern (FEV1/FVC < LLN; ATS/ERS 2005). Patients with mild restriction wheezed more ((30.8%) vs. (17.8%); p < 0.028). No difference was seen in dyspnea, cough, and sputum between the two groups after adjusting for severity stage. The health status scores for the short form 12 questionnaire were similar in restricted and obstructed patients for both physical (48.4 +/- 9.4 vs. 48.3 +/- 9.8) and mental (50.8 +/- 10.6 vs. 50.0 +/- 11.5) domains. Overall, respiratory symptoms are not frequently reported by patients with restricted and obstructed patterns as defined by spirometry. Wheezing was more frequent in patients with restricted pattern compared with those with obstructive ventilatory defect. However, the prevalence of cough, sputum production, and dyspnea are not different between the two groups when adjusted by the same severity stage. PMID- 26041120 TI - Tuning assembly and enzymatic degradation of silk/poly(N-vinylcaprolactam) multilayers via molecular weight and hydrophobicity. AB - We report on enzymatically degradable nanothin coatings obtained by layer-by layer (LbL) assembly of silk fibroin with poly(N-vinylcaprolactam) (PVCL) via hydrogen bonding and hydrophobic interactions. We found that both silk beta-sheet content, controlled through dipping and spin-assisted LbL, and PVCL molecular weight regulate film thickness, microstructure, pH-stability, and biodegradability with a nanoscale precision. Thickness of (silk/PVCL) films increased with increase in PVCL molecular weight and decrease in deposition pH. The impact of assembly pH on film growth was more dramatic for dipped films. These systems show a significant rise in thickness with increase in PVCL molecular weight at pH < 5 but become independent on polymer chain length at pH >= 5. We also found that spin-assisted films exhibited a greater stability at elevated pH and against enzymatic degradation as compared to their dipped counterparts. For both film types, the pH and enzymatic stability was improved with increasing PVCL length and beta-sheet content, indicating enhanced hydrophobic and hydrogen-bonded interactions between PVCL and silk. Finally, we fabricated spherical and cubical (silk/PVCL) LbL capsules of regulated permeability and enzymatic degradation. Our approach gives a unique opportunity to tune thickness, morphology, structure, and biodegradability rate of silk films and capsules by varying silk secondary structure and PVCL length. Accounting for all-aqueous fabrication and the biocompatibility of both polymers these biodegradable materials provide novel platforms for delivery systems and medical devices. PMID- 26041121 TI - The use of smartphones by junior doctors. PMID- 26041122 TI - Exploring nurses' reactions to a novel technology to support acute health care delivery. AB - AIMS AND OBJECTIVES: To explore nurses' reactions to new novel technology for acute health care. BACKGROUND: Past failures of technology developers to deliver products that meet nurses' needs have led to resistance and reluctance in the technology adoption process. Thus, involving nurses in a collaborative process from early conceptualisation serves to inform design reflective upon current clinical practice, facilitating the cementing of 'vision' and expectations of the technology. DESIGN: An exploratory descriptive design to capture nurses' immediate impressions. METHODS: Four focus groups (52 nurses from medical and surgical wards at two hospitals in Australia; one private and one public). RESULTS: Nursing reactions towards the new technology illustrated a variance in barrier and enabler comments across multiple domains of the Theoretical Domains Framework. Most challenging for nurses were the perceived threat to their clinical skill, and the potential capability of the novel technology to capture their clinical workflow. Enabling reactions included visions that this could help integrate care between departments; help management and support of nursing processes; and coordinating their patients care between clinicians. Nurses' reactions differed across hospital sites, influenced by their experiences of using technology. For example, Site 1 nurses reported wide variability in their distribution of barrier and enabling comments and nurses at Site 2, where technology was prevalent, reported mostly positive responses. CONCLUSION: This early involvement offered nursing input and facilitated understanding of the potential capabilities of novel technology to support nursing work, particularly the characteristics seen as potentially beneficial (enabling technology) and those conflicting (barrier technology) with the delivery of both safe and effective patient care. RELEVANCE TO CLINICAL PRACTICE: Collaborative involvement of nurses from the early conceptualisation of technology development brings benefits that increase the likelihood of successful use of a tool intended to support the delivery of safe and efficient patient care. PMID- 26041123 TI - Chronic anophthalmic socket pain treated by implant removal and dermis fat graft. AB - AIMS: To report the outcome of orbital implant removal and dermis fat graft (DFG) implantation in patients with chronic anophthalmic socket pain (ASP), in whom all detectable causes of pain had been ruled out and medical management had failed. METHODS: Retrospective, multicentre case series. A review of all cases undergoing orbital implant replacement with DFG between 2007 and 2013 was conducted at the University of Iowa Hospitals and Clinics (UIHC), USA, and St. Erik Eye Hospital, Sweden. Inclusion criteria included (1) chronic ASP >2 years and unresponsive to treatment, (2) absence of pathological or structural cause for pain established by socket examination and orbital imaging, and (3) minimum 12-month post-surgical follow-up. RESULTS: Six cases with chronic ASP were identified, four were post enucleation and two were eviscerated at an average age of 45 years. The incidence of chronic ASP among enucleations at UIHC over a 6-year period was 0.7%. Indications for enucleation and evisceration included tumours and glaucoma. Intractable ASP had been present for an average of 11 years and persisted despite medical management. All patients were free of pain within 3 months of implant removal and DFG placement and remained pain free at an average 24 months following surgery. CONCLUSIONS: Orbital implant replacement with DFG was effective at relieving chronic ASP, and pain resolution was sustained in all cases. This surgical intervention may be a useful management option for patients in whom all detectable causes of chronic pain have been excluded and have failed medical pain management. PMID- 26041124 TI - Attributes of God: Conceptual Foundations of a Foundational Belief. AB - Anthropomorphism, or the attribution of human properties to nonhuman entities, is often posited as an explanation for the origin and nature of God concepts, but it remains unclear which human properties we tend to attribute to God and under what conditions. In three studies, participants decided whether two types of human properties-psychological (mind-dependent) properties and physiological (body dependent) properties-could or could not be attributed to God. In Study 1 (n = 1,525), participants made significantly more psychological attributions than physiological attributions, and the frequency of those attributions was correlated both with participants' religiosity and with their attribution of abstract, theological properties. In Study 2 (n = 99) and Study 3 (n = 138), participants not only showed the same preference for psychological properties but were also significantly faster, more consistent, and more confident when attributing psychological properties to God than when attributing physiological properties. And when denying properties to God, they showed the reverse pattern that is, they were slower, less consistent, and less confident when denying psychological properties than when denying physiological properties. These patterns were observed both in a predominantly Christian population (Study 2) and a predominantly Hindu population (Study 3). Overall, we argue that God is conceptualized not as a person in general but as an agent in particular, attributed a mind by default but attributed a body only upon further consideration. PMID- 26041125 TI - Proanthocyanidins in an astringent persimmon inhibit Salmonella pathogenicity island 1 (SPI1) secretion. AB - BACKGROUND: Astringent compounds contained in persimmon fruits have been widely used in Japan as food preservatives and thus as anti-bacterial and anti-fungi reagents. However, the molecular mechanism of the anti-microbial activity has been unclear. One of the virulence secretion systems in Salmonella enterica was used to test the anti-microbial activity of extracts from a persimmon (Diospyros kaki Thunb 'Saijo'). RESULTS: We found that the extract could inhibit the secretion of virulence proteins but did not affect cell growth and determined the critical concentrations of the extract to show the effect. Then, the effective fraction on the suppression of secretion of virulence proteins was purified from the crude extracts using solvent partition, absorption chromatography and gel filtration chromatography. The anti-bacterial fraction was analysed by HCl butanol treatment and gel permeation chromatography followed by nuclear magnetic resonance and identified as the octamers of epigallocatechin and its gallate as major components. CONCLUSION: Proanthocyanidins suppress the secretion of Salmonella pathogenicity island 1 virulence proteins. PMID- 26041126 TI - Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria. AB - The metabolically inert perfluorinated fatty acids perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) can display fatty acid-like activity in biological systems. The uncoupling protein 1 (UCP1) in brown adipose tissue is physiologically (re)activated by fatty acids, including octanoate. This leads to bioenergetically uncoupled energy dissipation (heat production, thermogenesis). We have examined here the possibility that PFOA/PFOS can directly (re)activate UCP1 in isolated mouse brown-fat mitochondria. In wild-type brown-fat mitochondria, PFOS and PFOA overcame GDP-inhibited thermogenesis, leading to increased oxygen consumption and dissipated membrane potential. The absence of this effect in brown-fat mitochondria from UCP1-ablated mice indicated that it occurred through activation of UCP1. A competitive type of inhibition by increased GDP concentrations indicated interaction with the same mechanistic site as that utilized by fatty acids. No effect was observed in heart mitochondria, i.e., in mitochondria without UCP1. The stimulatory effect of PFOA/PFOS was not secondary to non-specific mitochondrial membrane permeabilization or to ROS production. Thus, metabolic effects of perfluorinated fatty acids could include direct brown adipose tissue (UCP1) activation. The possibility that this may lead to unwarranted extra heat production and thus extra utilization of food resources, leading to decreased fitness in mammalian wildlife, is discussed, as well as possible negative effects in humans. However, a possibility to utilize PFOA-/PFOS-like substances for activating UCP1 therapeutically in obesity-prone humans may also be envisaged. PMID- 26041127 TI - Real-time monitoring of oxygen uptake in hepatic bioreactor shows CYP450 independent mitochondrial toxicity of acetaminophen and amiodarone. AB - Prediction of drug-induced toxicity is complicated by the failure of animal models to extrapolate human response, especially during assessment of repeated dose toxicity for cosmetic or chronic drug treatments. In this work, we present a 3D microreactor capable of maintaining metabolically active HepG2/C3A spheroids for over 28 days in vitro under stable oxygen gradients mimicking the in vivo microenvironment. Mitochondrial respiration was monitored using two-frequency phase modulation of phosphorescent microprobes embedded in the tissue. Phase modulation is focus independent and unaffected by cell death or migration. This sensitive measurement of oxygen dynamics revealed important information on the drug mechanism of action and transient subthreshold effects. Specifically, exposure to antiarrhythmic agent, amiodarone, showed that both respiration and the time to onset of mitochondrial damage were dose dependent showing a TC50 of 425 MUm. Analysis showed significant induction of both phospholipidosis and microvesicular steatosis during long-term exposure. Importantly, exposure to widely used analgesic, acetaminophen, caused an immediate, reversible, dose dependent loss of oxygen uptake followed by a slow, irreversible, dose independent death, with a TC50 of 12.3 mM. Transient loss of mitochondrial respiration was also detected below the threshold of acetaminophen toxicity. The phenomenon was repeated in HeLa cells that lack CYP2E1 and 3A4, and was blocked by preincubation with ascorbate and TMPD. These results mark the importance of tracing toxicity effects over time, suggesting a NAPQI-independent targeting of mitochondrial complex III might be responsible for acetaminophen toxicity in extrahepatic tissues. PMID- 26041128 TI - Association of angiotensin II type 1 receptor (A1166C) polymorphism with breast cancer risk: An update meta-analysis. AB - OBJECTIVE: Previous studies on the relationship between angiotensin II type 1 receptor (AT1R) gene (A1166C) polymorphism and breast cancer did not reach the same conclusion. In the present study, we aimed to further evaluate the relationship between the AT1R gene A1166C polymorphism and breast cancer risk. METHODS: We selected five case-control studies related to AT1R gene A1166C polymorphism and breast cancer by searching PubMed, EMBase, Chinese Biomedical Literature Database, Chinese CNKI, Web of Science, and the Wanfang database. We utilized Q-test and I(2) test to detect the heterogeneity between each study. A random-effects model (I(2) > 50%; p < 0.10) or a fixed-effects model (I(2) < 50%; p > 0.10) was utilized to merge the odds ratio (OR) and 95% confidence interval (CI) during the meta- analyses. RESULTS: The present study included 972 patients with breast cancer and 1336 cancer-free control subjects. By meta-analysis, we found A1166C polymorphism was associated with decreased risk for breast cancer in Caucasian population in an additive model (C vs. T: OR = 0.77, 95% CI: 0.62-0.96, p = 0.02). However, we did not find associations in other genetic models (AC+CC vs. AA: OR = 0.78, 95% CI: 0.50-1.22, p = 0.28; CC vs. AA+AC: OR = 1.64, 95% CI: 0.94-2.85, p = 0.08). CONCLUSION: We concluded that AT1R gene A1166C polymorphism was associated with reduced risk for breast cancer. PMID- 26041129 TI - Angiotensin-converting enzyme insertion/deletion gene polymorphisms associated with risk of atrial fibrillation: A meta-analysis of 23 case-control studies. AB - AIMS: The renin-angiotensin-aldosterone system is important to the development of atrial fibrillation (AF). A lot of research has focused on the relationship between angiotensin-converting enzyme (ACE) insertion (I) /deletion (D) gene polymorphisms and AF, with inconsistent results. A meta-analysis was carried out to find the correlation between ACE I/D gene polymorphisms and AF. METHODS: Data were extracted from articles published before September 2013 on ACE I/D polymorphisms and AF in Embase, PubMed, WanFangData, and China National Knowledge Infrastructure. RESULTS: The recessive model found that ACE I/D gene polymorphisms were related to AF (odds ratio (OR) = 1.61, 95% confidence interval (CI) = 1.16-1.72). Subgroup analysis showed a significant association in the recessive model for Asian (OR = 1.40, 95% CI = 1.19-1.80) and Caucasian (OR = 1.42, 95% CI = 1.01-1.99) populations. CONCLUSIONS: ACE I/D gene polymorphisms and AF are significantly related to ethnicity. Individuals with the ACE D/D genotype appear to be at higher risk of AF. PMID- 26041130 TI - The association between glycemic variability and diabetic cardiovascular autonomic neuropathy in patients with type 2 diabetes. AB - BACKGROUND: It is presently unclear whether glycemic variability is associated with diabetic cardiovascular autonomic neuropathy (CAN). The aim of this study was to examine whether short- and/or long-term glycemic variability (GV) contribute to CAN. METHODS: A total of 110 patients with type 2 diabetes who underwent three-day continuous glucose monitoring (CGM) completed five standardized autonomic neuropathy tests. Short-term GV was measured by the standard deviation (SD), coefficient of variation (CV) of glucose, and the mean amplitude of glycemic excursions (MAGE) in CGM. HbA1c variability was calculated from the intrapersonal SD, adjusted SD, and CV of serial HbA1c over 2-year period. CAN was defined as the presence of at least two abnormal parasympathetic function tests. The severity of CAN was evaluated by total scores of five autonomic function tests. RESULTS: In univariate analysis, not only SD and CV in CGM but also all parameters of HbA1c variability were significantly higher in the patients with CAN (n = 47, 42.7 %) than in those without CAN. In multivariate analysis, CV (Odds ratio [OR] 1.07, 95 % confidence interval [CI] 1.01-1.13; p = 0.033), but neither SD nor MAGE in CGM, independently correlated with the presence of CAN. All parameters of HbA1c variability, such as SD of HbA1c (OR 12.10 [95 % CI 2.29-63.94], p = 0.003), adjusted SD of HbA1c (OR 17.02 [95 % CI 2.66-108.86], p = 0.003), and log CV of HbA1c (OR 24.00 [95 % CI 3.09-186.48], p = 0.002), were significantly associated with the presence of CAN. The patients with higher HbA1c variability had an increased risk of advanced CAN. CONCLUSION: CV in CGM and all parameters of HbA1c variability were independently associated with the presence of CAN in patients with inadequately controlled type 2 diabetes requiring CGM. PMID- 26041131 TI - Effectiveness of a Smartphone application and wearable device for weight loss in overweight or obese primary care patients: protocol for a randomised controlled trial. AB - BACKGROUND: To evaluate the effectiveness of an experimental intervention based on standard diet recommendations plus free Smartphone application (app) and wearable device for weight loss, compared with the standard diet intervention alone, in primary care patients aged 18 years or older who are overweight or obese. METHODS/DESIGN: Multicentre randomized, controlled clinical trial. LOCATION: Primary health care centres in the city of Tarragona and surrounding areas. SUBJECTS: 70 primary care patients, aged 18 years or older, with body mass index of 25 g/m2 or greater who wish to lose weight. Description of the intervention: 12 months of standard diet recommendations without (n = 35) or with (n = 35) assistance of a free Smartphone app that allows the participant to maintain a record of dietary intake and a bracelet monitor that records physical activity. The outcomes will be weight loss at 12 months (primary outcome), changes in physical activity and cardiometabolic risk factors, frequency of app use, and participant satisfaction after 12 months. DISCUSSION: The results of our study will offer evidence of the effectiveness of an intervention using one of the most popular free apps and wearable devices in achieving weight loss among patients who are overweight or obese. If these new technologies are proven effective in our population, they could be readily incorporated into primary care interventions promoting healthy weight. The open design and study characteristics make it impossible for the participants and researchers to be blinded to study group assignment. Researchers responsible for data analysis will be blinded to participant allocation. TRIAL REGISTRATION: Clinical Register: NCT02417623. Registered 26 March 2015. PMID- 26041133 TI - Measuring mental well-being: A validation of the Short Warwick-Edinburgh Mental Well-Being Scale in Norwegian and Swedish. AB - AIMS: Mental health, currently one of the biggest challenges worldwide, requires attention and research. The aim of this study was to examine the psychometric properties of the Short Warwick-Edinburgh Mental Well-Being Scale (SWEMWBS), and validate the scale for use in Norway and Sweden. SWEMWBS, which includes both hedonic and eudemonic principles of mental well-being, could facilitate useful future studies. METHOD: Data were collected among Norwegian and Swedish hotel managers (N=600) through self-rated online questionnaires. Tests used to examine the psychometric properties of the scale included descriptive statistics, correlations, reliability analyses, and explorative factor analyses in SPSS, as well as confirmatory factor analyses in AMOS. Robustness tests were run for gender and country subsamples. RESULTS: The scale showed adequate internal consistency and reliability. Results of the confirmatory factor analysis showed moderate fit in Norway and Sweden. In addition, the scale showed acceptable construct, criterion-related, and discriminant validity. CONCLUSION: The psychometric properties of the SWEMWBS were acceptable in both the Norwegian and the Swedish translations of the scale. PMID- 26041132 TI - The positive impact of interprofessional education: a controlled trial to evaluate a programme for health professional students. AB - BACKGROUND: Collaborative interprofessional practice is an important means of providing effective care to people with complex health problems. Interprofessional education (IPE) is assumed to enhance interprofessional practice despite challenges to demonstrate its efficacy. This study evaluated whether an IPE programme changed students' attitudes to interprofessional teams and interprofessional learning, students' self-reported effectiveness as a team member, and students' perceived ability to manage long-term conditions. METHODS: A prospective controlled trial evaluated an eleven-hour IPE programme focused on long-term conditions' management. Pre-registration students from the disciplines of dietetics (n = 9), medicine (n = 36), physiotherapy (n = 12), and radiation therapy (n = 26) were allocated to either an intervention group (n = 41) who received the IPE program or a control group (n = 42) who continued with their usual discipline specific curriculum. Outcome measures were the Attitudes Toward Health Care Teams Scale (ATHCTS), Readiness for Interprofessional Learning Scale (RIPLS), the Team Skills Scale (TSS), and the Long-Term Condition Management Scale (LTCMS). Analysis of covariance compared mean post-intervention scale scores adjusted for baseline scores. RESULTS: Mean post-intervention attitude scores (all on a five-point scale) were significantly higher in the intervention group than the control group for all scales. The mean difference for the ATHCTS was 0.17 (95 %CI 0.05 to 0.30; p = 0.006), for the RIPLS was 0.30 (95 %CI 0.16 to 0.43; p < 0.001), for the TSS was 0.71 (95 %CI 0.49 to 0.92; p < 0.001), and for the LTCMS was 0.75 (95 %CI 0.56 to 0.94; p < 0.001). The mean effect of the intervention was similar for students from the two larger disciplinary sub-groups of medicine and radiation therapy. CONCLUSIONS: An eleven-hour IPE programme resulted in improved attitudes towards interprofessional teams and interprofessional learning, as well as self-reported ability to function within an interprofessional team, and self-reported confidence, knowledge, and ability to manage people with long-term conditions. These findings indicate that a brief intervention such as this can have immediate positive effects and contribute to the development of health professionals who are ready to collaborate with others to improve patient outcomes. PMID- 26041134 TI - Colistin: efficacy and safety in different populations. AB - This article reviews mechanisms, incidences, risk factors and preventive modalities of colistin toxicity as well as colistin use in special populations and through special routes. All clinical studies that examined the pharmacokinetic/pharmacodynamic, efficacy and side effects of colistin in the management of multidrug-resistant organisms in different patient population including pediatrics, adults, obese, critically ill, burn or cancer patients with any route of drug administration were considered. Compared with older recommended doses, current dosing approach improves cure rate without significant increase in the rate of colistin-induced nephrotoxicity. Efficacy and safety of high doses of colistin should be considered in the future studies. Also comparing efficacy and safety of different doses of aerosolized colistin and defining the appropriate dose in different populations is another open area of future researches. PMID- 26041135 TI - Synergies and trade-offs in achieving global biodiversity targets. AB - After their failure to achieve a significant reduction in the global rate of biodiversity loss by 2010, world governments adopted 20 new ambitious Aichi biodiversity targets to be met by 2020. Efforts to achieve one particular target can contribute to achieving others, but different targets may sometimes require conflicting solutions. Consequently, lack of strategic thinking might result, once again, in a failure to achieve global commitments to biodiversity conservation. We illustrate this dilemma by focusing on Aichi Target 11. This target requires an expansion of terrestrial protected area coverage, which could also contribute to reducing the loss of natural habitats (Target 5), reducing human-induced species decline and extinction (Target 12), and maintaining global carbon stocks (Target 15). We considered the potential impact of expanding protected areas to mitigate global deforestation and the consequences for the distribution of suitable habitat for >10,000 species of forest vertebrates (amphibians, birds, and mammals). We first identified places where deforestation might have the highest impact on remaining forests and then identified places where deforestation might have the highest impact on forest vertebrates (considering aggregate suitable habitat for species). Expanding protected areas toward locations with the highest deforestation rates (Target 5) or the highest potential loss of aggregate species' suitable habitat (Target 12) resulted in partially different protected area network configurations (overlapping with each other by about 73%). Moreover, the latter approach contributed to safeguarding about 30% more global carbon stocks than the former. Further investigation of synergies and trade-offs between targets would shed light on these and other complex interactions, such as the interaction between reducing overexploitation of natural resources (Targets 6, 7), controlling invasive alien species (Target 9), and preventing extinctions of native species (Target 12). Synergies between targets must be identified and secured soon and trade-offs must be minimized before the options for co-benefits are reduced by human pressures. PMID- 26041136 TI - Inter-Arm Blood Pressure Difference in Hospitalized Elderly Patients Is Not Associated With Excess Mortality. AB - Inter-arm blood pressure difference (IAD) has been found to be associated with cardiovascular mortality. Its clinical significance and association with mortality in the elderly is not well defined. This study evaluated the association of IAD with mortality in a cohort of hospitalized elderly individuals. Blood pressure (BP) was measured simultaneously in both arms in elderly individuals (older than 65 years) hospitalized in a geriatric ward from October 2012 to July 2014. During the study period, 445 patients, mostly women (54.8%) with a mean age of 85+/-5 years, were recruited. Systolic and diastolic IAD were >10 mm Hg in 102 (22.9%) and 76 (17.1%) patients, respectively. Patients were followed for an average of 342+/-201 days. During follow-up, 102 patients (22.9%) died. Mortality was not associated with systolic or diastolic IAD. It is therefore questionable whether BP should be routinely measured in both arms in the elderly. PMID- 26041137 TI - Simple bedside score to optimize the time and the decision to initiate appropriate therapy for carbapenem-resistant Enterobacteriaceae. AB - BACKGROUND: Epidemiological characteristics of patients with bloodstream infections (BSI) due to extended-spectrum beta-lactamase producing (ESBL) and carbapenem-resistant (CRE) strains are often similar. Mortality rates for CRE BSI are 70%, and mean time to initiation of appropriate therapy is ~5 days. A bedside score was developed to differentiate CRE-BSIs from ESBL-BSIs, in order to help decrease the time to initiation of appropriate therapy for CRE and mortality rates. FINDINGS: Score was developed based of data (2007-2010) abstracted from charts of adult patients from Assaf Harofeh Medical Center (AHMC, Zeriffin, Israel), and validated on a cohort of patients from Detroit Medical Center (DMC, MI, USA). A multivariate model for presence of CRE was generated. A clinical prediction score and ROC curve was derived. 451 patients with ESBL BSIs (285 from AHMC and 166 from DMC) and 74 patients with CRE BSIs (58 from AHMC and 16 from DMC) were included. The prediction score included chemotherapy in the past 3 months (19 points), presence of foreign invasive devices (10 points), no peripheral vascular disease (10 points), reduced consciousness or cognition at time of acute illness (9 points), time in hospital prior to BSI >= 3 days (7 points), and age younger than 65 years (6 points). A score of >=32 to define "high CRE risk" had sensitivity of 59%, specificity of 76%, PPV of 34% and NPV of 90%. CONCLUSIONS: The score's 90% NPV implies it could reduce un-necessary (and toxic) empiric use of anti-CRE therapeutics, but this should be studied prospectively and on broader populations in order to test its potential role in reducing mortality. PMID- 26041138 TI - Health care-associated infections in patients with head and neck cancer treated with chemotherapy and/or radiotherapy. AB - BACKGROUND: The incidence of health care-associated infections in patients with head and neck cancer receiving chemotherapy and/or radiotherapy (RT) is unknown. This retrospective study investigated the most common pathogens and their antibiotic sensitivity/resistance patterns in patients with head and neck cancer. METHODS: Infection rates in patients with head and neck cancer were analyzed over 2 periods (January 2005 to December 2009 and January 2010 to November 2012). RESULTS: In the first period, 140 health care-associated infections were observed among 2288 admissions, mostly because of gram-negative pathogens affecting the respiratory tract. In the second period, 212 health care-associated infections were observed. An increase in antibiotic resistance was reported. Health care associated infections were more frequent with: male sex, age <65 years, important comorbidities, smoking, proton pump inhibitors (PPIs), prophylaxis, and/or central venous catheter (CVC), locally advanced disease, and chemotherapy/RT, especially after the third week of treatment. CONCLUSION: Health care-associated infections increased over time, with corresponding increases in gram-negative pathogens and resistant strains. Prevention and treatment protocols should be implemented in institutions treating patients with head and neck cancer. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1009-E1013, 2016. PMID- 26041139 TI - A novel mycovirus identified from the rice false smut fungus Ustilaginoidea virens. AB - The complete sequence of a novel mycovirus infecting Ustilaginoidea virens, the causal agent of false smut of rice, is reported here and designated as Ustilaginoidea virens unassigned RNA virus HNND-1 (UvURV-HNND-1). This virus has an undivided dsRNA genome of 2903 nt in length and contains two non-overlapping open reading frames (ORF1 and 2), with the small ORF1 encoding a protein of unknown function that showed sequence similarity to the comparable protein in virus Alternaria longipes dsRNA virus 1(AlRV1) and a larger ORF2 encoded the protein showing identities to the RNA-dependent RNA polymerases of AlRV1 and some other unassigned dsRNA viruses. Phylogenetic analysis showed that UvURV-HNND-1 is more closely related to unclassified viruses such as AlRV1 and distinct from distantly related members of the family Partitiviridae. Here, we propose in accordance with previous reports that UvURV-HNND-1 might belong to a new mycovirus genus together with AlRV1 and other similar viruses. PMID- 26041140 TI - Simultaneous EEG-fMRI: evaluating the effect of the cabling configuration on the gradient artefact. AB - EEG recordings made in combined EEG-fMRI studies are corrupted by gradient artefacts (GAs) resulting from the interaction of the EEG system with the time varying magnetic field gradients used in MRI. The dominant contribution to the GA arises from interaction with the leads of the EEG cap and the human head, but artefacts are also produced in the cables used to connect the EEG cap to the amplifier. The aim of this study is to measure the effects of the connecting cable configuration on the characteristics of the GA. We measured the GA produced on two different cable configurations (a ribbon cable and a cable consisting of wires that are twisted together to form a cylindrical bundle) by gradient pulses applied on three orthogonal axes and also characterized the effect of each cable configuration on the GA generated by a multi-slice echo planar imaging sequence, as employed in typical EEG-fMRI studies. The results demonstrate that the cabling that connects the EEG cap to the amplifier can make a significant contribution to the GA recorded during EEG-fMRI studies. In particular, we demonstrate that the GA generated by a ribbon cable is larger than that produced using a twisted cable arrangement and that changes in the GA resulting from variation in the cable position are also greater for the ribbon cable. PMID- 26041141 TI - Size-Dependent Enantioselective Adsorption of Racemic Molecules through Homochiral Metal-Organic Frameworks Embedding Helicity. AB - Homochiral metal-organic frameworks (HMOFs) are efficient materials for enantioselective adsorption. However, the combination of size selectivity and enantioselectivity is still a major challenge in the field of HMOFs. Herein, two enantiomorphic HMOFs built from predesigned proline-derived ligands are presented. Both of them show multiple homochiral features: they contain four different helical chains and three types of helical channels. Due to the size effect of the helical channels, each HMOF can enantioselectively adsorb methyl lactate with high ee. The results reveal a new approach toward size-dependent enantioselective separation of racemic compounds by using HMOFs built from inexpensive proline derivatives. PMID- 26041142 TI - An Asymmetrical Network: National and International Dimensions of the Development of Mexican Physiology. AB - This article examines the history of Mexican physiology during the period 1910-60 when two noted investigators, Jose J. Izquierdo, first, and Arturo Rosenblueth, second, inscribed their work into an international network of medical research. The network had at its center the laboratory of Walter B. Cannon at Harvard University. The Rockefeller Foundation was its main supporter. Rosenblueth was quite familiar with the network because he worked with Cannon at Harvard for over ten years before returning to Mexico in the early 1940s. Izquierdo and Rosenblueth developed different strategies to face adverse conditions such as insufficient laboratory equipment, inadequate library resources, a small scientific community, and ephemeral political support. Both acquired local influence and international prestige, but the sources of financial and academic power remained in the United States. This case study provides insight into the circulation of scientific ideas and practices in an important Latin American country and suggests that the world's circulation of science among industrial and developing nations during the mid-twentieth century was intrinsically asymmetric but opened temporary opportunities for talented individuals and groups of researchers. PMID- 26041143 TI - Heparin-conjugated alginate multilayered microspheres for controlled release of bFGF. AB - In order to effectively immobilize and control release of basic fibroblast growth factor (bFGF) from alginate microspheres, heparin-conjugated alginate (H-Alg) was first synthesized by covalent binding. Then multilayered H-Alg microspheres (multilayered microspheres) were fabricated via an electrostatic droplet generation technique followed by a layer-by-layer (LbL) self-assembly technique. Several techniques such as Fourier transform infrared spectroscopy (FTIR), (1)H NMR, zeta potential analysis and scanning electron microscopy (SEM) were used to characterize the properties of H-Alg (FTIR and (1)H-NMR) and multilayered microspheres (FTIR, zeta potential analysis and SEM). bFGF binding efficiency, release profiles of bFGF from multilayered microspheres and the biological activity of released bFGF were well investigated. It was found that the bFGF binding efficiency of H-Alg microspheres was increased up to five times higher than that of the alginate microspheres. Additionally, the release profiles of bFGF from multilayered microspheres were sustained for two weeks with relieved initial burst release, and the release rate to bFGF could be regulated by controlling the number of deposited layers. Importantly, the released bFGF still retained its biological activity as assessed by the in vitro proliferation of NIH 3T3 mouse fibroblasts. In conclusion, this study presented an easy yet effective method for the controlled, sustained release of heparin-binding growth factors, using polyelectrolyte multilayer-coated heparin-conjugated alginate microspheres. PMID- 26041144 TI - Cross-priming amplification for detection of bovine viral diarrhoea virus species 1 and 2. AB - AIMS: The aim of the study was the development of cross-priming amplification for ubiquitous detection of bovine viral diarrhoea virus (BVDV) species 1 and 2. METHODS AND RESULTS: Three and five specific primers, respectively, for the detection of BVDV-1 and BVDV-2, were designed on the basis of the sequences of the 5'UTR region. Incubation temperature and reaction time were determined. The optimal incubation conditions using water bath were 63 degrees C for 75 min. Reverse transcription step (RT) was not required. The results were visualized under UV-light as a bright yellow fluorescence in positive samples. Additional method for results interpretation was agarose gel electrophoresis. Positive samples showed the presence of ladder-like banding patterns, formed by harpin like cross-priming amplification (CPA) products. Sensitivity of CPA was compared with conventional RT-PCR and real-time RT-PCR. The CPA detection limit was 3500 copies for BVDV-1 and 80000 copies for BVDV-2 per reaction. For RT-PCR it was 350 and 80 copies for BVDV-1 and BVDV-2, respectively, and for real-time RT-PCR it was 35 copies for BVDV-1 and 80 copies for BVDV-2. The sensitivity of the developed method is sufficient to detect persistently infected (PI) animals. Positive results were found in 24 of 25 BVDV isolates belonging to species 1 and 2. Additionally, one false-negative result for BVDV-2 was detected. There were no false-positive results in negative samples and in the negative control. Both sets of primers used for the detection of BVDV-1 and BVDV-2 were not able to detect atypical pestiviruses. CPA positive results were confirmed by RT-PCR and real time RT-PCR. CONCLUSIONS: CPA is a rapid method for the detection of BVDV-1 and BVDV-2 in field samples from PI animals. SIGNIFICANCE AND IMPACT OF STUDY: This is the first report on the application of the CPA method for the detection of BVDV. PMID- 26041145 TI - Structural investigations of T854A mutation in EGFR and identification of novel inhibitors using structure activity relationships. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is a member of the ErbB family that is involved in a number of processes responsible for cancer development and progression such as angiogenesis, apoptosis, cell proliferation and metastatic spread. Malfunction in activation of protein tyrosine kinases has been shown to result in uncontrolled cell growth. The EGFR TK domain has been identified as suitable target in cancer therapy and tyrosine kinase inhibitors such as erlotinib have been used for treatment of cancer. Mutations in the region of the EGFR gene encoding the tyrosine kinase (TK) domain causes altered responses to EGFR TK inhibitors (TKI). In this paper we perform molecular dynamics simulations and PCA analysis on wild-type and mutant (T854A) structures to gain insight into the structural changes observed in the target protein upon mutation. We also report two novel inhibitors identified by combined approach of QSAR model development. RESULTS: The wild-type and mutant structure was observed to be stable for 26 ns and 24 ns respectively. In PCA analysis, the mutant structure proved to be more flexible than wild-type. We developed a 3D-QSAR model using 38 thiazolyl-pyrazoline compounds which was later used for prediction of inhibitory activity of natural compounds of ZINC library. The 3D-QSAR model was proved to be robust by the statistical parameters such as r2 (0.9751), q2(0.9491) and pred_r2(0.9525). CONCLUSION: Analysis of molecular dynamics simulations results indicate stability loss and increased flexibility in the mutant structure. This flexibility results in structural changes which render the mutant protein drug resistant against erlotinib. We report two novel compounds having high predicted inhibitory activity to EGFR TK domain with both wild-type and mutant structure. PMID- 26041147 TI - In vitro effects of glutamate and N-methyl-D-aspartate receptor (NMDAR) antagonism on human tendon derived cells. AB - It is known that extracellular glutamate concentrations are increased in tendinopathy but the effects of glutamate upon human tendon derived cells are unknown. The primary purpose was to investigate the effect of glutamate exposure on human tendon-derived cells in terms of viability, protein, and gene expression. The second purpose was to assess whether NMDAR antagonism would affect the response of tendon-derived cells to glutamate exposure. Human tendon derived cells were obtained from supraspinatus tendon tissue obtained during rotator cuff repair (tendon tear derived cells) and from healthy hamstring tendon tissue (control cells). The in vitro impact of glutamate exposure and NMDAR antagonism (MK-801) was measured using the Alamar blue cell viability assay, immunocytochemistry, and quantitative real-time PCR. Glutamate reduced cell viability at 24 h in tendon tear derived cells but not in control cells at concentrations of 7.5 mM and above. Cell viability was significantly reduced after 72 h of 1.875 mM glutamate in both cell groups; this deleterious effect was attenuated by NMDAR antagonism with 10 uM MK-801. Both 24 and 72 h of 1.875 mM glutamate exposure reduced Type 1 alpha 1 collagen (COL1A1) and Type 3 alpha 1 collagen (COL3A1) gene expression, but increased Aggrecan gene expression. We propose that these effects of glutamate on tendon derived cells including reduced cell viability and altered matrix gene expression contribute to the pathogenesis of tendinopathy. PMID- 26041149 TI - [Learning curve for transaxillary endoscopic thyroidectomy]. PMID- 26041148 TI - Association analysis of -416 G>C polymorphism of T-cell immunoglobulin and mucin domain-1 gene with asthma in Iran. AB - TIM (T-cell immunoglobulin (Ig) and mucin domain)-1, one of the members of TIM family, expresses on Th2 cells and promotes the production of Th2 signature cytokines. This can increase a series of responses in these cells which could be one of the causes of asthma or asthma-related phenotypes. The aim of this study was to investigate whether a TIM-1 promoter single nucleotide polymorphism (SNP), -416 G>C, is associated with asthma in Iranian population. In this case-control study, existence of the -416 G>C polymorphism was assessed using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) in 300 patients with asthma (97 atopic, 203 nonatopic) and 309 healthy volunteers. Additionally, the relationship between these polymorphism genotypes and total serum IgE levels in this Iranian population was evaluated. We discovered a significant association between the -416 G>C polymorphism and atopic asthma susceptibility in the population, but this SNP showed no connection with nonatopic asthma (P < 0.05). However, our results showed significant relation between this polymorphism and serum IgE level (P < 0.05). Our results suggest that -416 G>C polymorphism in TIM-1 gene could be a predisposing factor for atopic asthma in Iranian population, and CC genotype of this SNP can be associated with increased level of IgE in patients with asthma in the same population. PMID- 26041150 TI - [Management of complications after reconstruction of mesenteric arteries]. AB - Because of the low ischemia tolerance of abdominal organs and the comorbidities of patients with abdominal ischemic syndromes, complications after the reconstruction of visceral arteries are often severe and associated with a significant mortality rate. The possible complications after interventions on the visceral arteries and their treatment are presented. Endovascular procedures have gained an increasingly important role in many primary interventions as well as in the treatment of complications. PMID- 26041152 TI - Angiotensin-converting enzyme (ACE) inhibitors for proteinuria and microalbuminuria in people with sickle cell disease. AB - BACKGROUND: Sickle cell disease is a group of disorders characterized by deformation of erythrocytes. Renal damage is a frequent complication in sickle cell disease as a result of long-standing anemia and disturbed circulation through the renal medullary capillaries. Due to the improvement in life expectancy of people with sickle cell disease, there has been a corresponding significant increase in the incidence of renal complications. Microalbuminuria and proteinuria are noted to be a strong predictor of subsequent renal failure. There is extensive experience and evidence with angiotensin-converting enzyme (ACE) inhibitors over many years in a variety of clinical situations for patients who do not have sickle cell disease, but their effect in people with this disease is unknown. It is common practice to administer ACE inhibitors for sickle nephropathy due to their renoprotective properties; however, little is known about their effectiveness and safety in this setting. This is an update of a Cochrane Review first published in 2013. OBJECTIVES: To determine the effectiveness of ACE inhibitor administration in people with sickle cell disease for decreasing intraglomerular pressure, microalbuminuria and proteinuria and to to assess the safety of ACE inhibitors as pertains to their adverse effects. SEARCH METHODS: The authors searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Hameoglobinopathies Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 03 June 2015. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of ACE inhibitors designed to reduce microalbuminuria and proteinuria in people with sickle cell disease compared to either placebo or standard treatment regimen. DATA COLLECTION AND ANALYSIS: Three authors independently applied the inclusion criteria in order to select studies for inclusion in the review. Two authors assessed the risk of bias of studies and extracted data and the third author verified these assessments. MAIN RESULTS: Five studies were identified through the searches, only one met our inclusion criteria. The included study randomized 22 participants (seven males and 15 females) having proteinuria or microalbuminuria with sickle cell disease and treated the participants for six months (median length of follow up of three months) with captopril or placebo. The overall quality of the outcomes reported was high, since most aspects that may contribute to bias were regarded to be of low risk, although allocation concealment was not reported. At six months, the study reported no significant difference in urinary albumin excretion between the captopril group and the placebo group, although the mean urinary albumin excretion in the captopril group was lower by a mean difference of -49.00 (95% confidence interval -124.10 to 26.10) compared to that of placebo. However, our analysis on the absolute change score showed significant changes between the two groups by a mean difference of -63.00 (95% confidence interval -93.78 to -32.22). At six months albumin excretion in the captopril group was noted to decrease from baseline by a mean of 45 +/- 23 mg/day and the placebo group was noted to increase by 18 +/- 45 mg/day. Serum creatinine and potassium levels were reported constant throughout the study. The potential for inducing hypotension should be highlighted; the study reported a decrease of 8 mmHg in systolic pressure and 5 mmHg in diastolic and mean blood pressure. AUTHORS' CONCLUSIONS: There is not enough evidence to show that the administration of ACE inhibitors is associated with a reduction of microalbuminuria and proteinuria in people with sickle cell disease, although a potential for this was seen. More long-term studies involving multiple centers and larger cohorts using a randomized-controlled design are warranted, especially among the pediatric age group. Detailed reporting of each outcome measure is necessary to allow a clear cut interpretation in a systematic review. One of the difficulties encountered in this review was the lack of detailed data reported in the included study. PMID- 26041151 TI - Outcome of delirium in critically ill patients: systematic review and meta analysis. AB - OBJECTIVES: To determine the relation between delirium in critically ill patients and their outcomes in the short term (in the intensive care unit and in hospital) and after discharge from hospital. DESIGN: Systematic review and meta-analysis of published studies. DATA SOURCES: PubMed, Embase, CINAHL, Cochrane Library, and PsychINFO, with no language restrictions, up to 1 January 2015. ELIGIBILITY CRITERIA FOR SELECTION STUDIES: Reports were eligible for inclusion if they were prospective observational cohorts or clinical trials of adults in intensive care units who were assessed with a validated delirium screening or rating system, and if the association was measured between delirium and at least one of four clinical endpoints (death during admission, length of stay, duration of mechanical ventilation, and any outcome after hospital discharge). Studies were excluded if they primarily enrolled patients with a neurological disorder or patients admitted to intensive care after cardiac surgery or organ/tissue transplantation, or centered on sedation management or alcohol or substance withdrawal. Data were extracted on characteristics of studies, populations sampled, identification of delirium, and outcomes. Random effects models and meta regression analyses were used to pool data from individual studies. RESULTS: Delirium was identified in 5280 of 16,595 (31.8%) critically ill patients reported in 42 studies. When compared with control patients without delirium, patients with delirium had significantly higher mortality during admission (risk ratio 2.19, 94% confidence interval 1.78 to 2.70; P<0.001) as well as longer durations of mechanical ventilation and lengths of stay in the intensive care unit and in hospital (standard mean differences 1.79 (95% confidence interval 0.31 to 3.27; P<0.001), 1.38 (0.99 to 1.77; P<0.001), and 0.97 (0.61 to 1.33; P<0.001), respectively). Available studies indicated an association between delirium and cognitive impairment after discharge. CONCLUSIONS: Nearly a third of patients admitted to an intensive care unit develop delirium, and these patients are at increased risk of dying during admission, longer stays in hospital, and cognitive impairment after discharge. PMID- 26041153 TI - Effect of Chromium Supplementation on Element Distribution in a Mouse Model of Polycystic Ovary Syndrome. AB - Polycystic ovary syndrome (PCOS) is a complex endocrine disorder and one of the most common causes of anovulatory infertility. In addition, insulin resistance is commonly associated with PCOS and contributed to pathophysiology connected to dietary minerals including chromium (Cr), copper (Cu), iron (Fe), and zinc (Zn). The aims of this study were to explore whether PCOS in mice alters levels of these elements and determine if Cr supplementation resolves changes. Twenty-four female BALB/c mice were divided into three groups of eight mice [normal control (NC), PCOS+placebo milk (PP), and PCOS+Cr-containing milk (PCr)]. Each group received a high-fat diet for 4 weeks. Our results show significantly higher levels of dehydroepiandrosterone (DHEA) (p<0.001), fasting glucose (p<0.05), and fasting insulin (p<0.05) in the PP group compared with both NC and PCr group. However, Cr levels were significantly lower in muscle, bone, and serum in the PP group (p<0.05) compared with NC and PCr groups. In liver, bone, and serum, Fe levels were significantly higher in the PP group compared with the NC group (p<0.05). In addition, we found significant correlations between Cu/Zn ratio and fasting insulin in all mice (r=0.61; p=0.002). Given that significant research shows that Cr supplementation improves fasting glucose, fasting insulin, and metal metabolism disorders for PCOS mice, our data suggest that trace element levels can serve as biomarkers to prescribe therapeutic supplementation to maintain a healthy metabolic balance and treat disease conditions. PMID- 26041154 TI - Autophagy Plays a Cytoprotective Role During Cadmium-Induced Oxidative Damage in Primary Neuronal Cultures. AB - Cadmium (Cd) induces significant oxidative damage in cells. Recently, it was reported that autophagy could be induced by Cd in neurons. However, little is known about the role of reactive oxygen species (ROS) during Cd-induced autophagy. In our study, we examined the cross-talk between ROS and autophagy by using N-acetyl cysteine (NAC, an antioxidant) and chloroquine (CQ, a pharmacological inhibitor of autophagy) in a primary rat neuronal cell cultures. We observed accumulation of acidic vesicular organelles and the increased expression of endogenous protein light chain 3 (LC3) in Cd-treated neurons, revealing that Cd induced a high level of autophagy. Moreover, increased levels of ROS were observed in neurons treated with Cd, showing that ROS accumulation was closely associated with neuron's exposure to Cd. Furthermore, we found that autophagy was inhibited by using CQ and/or NAC with further aggravation of mitochondrial damage, lactate dehydrogenase (LDH) leakage and hypoploid apoptotic cell number in Cd-treated neurons. These results proved that autophagy has a cytoprotective role during Cd-induced toxicity in neurons, and it can prevent the oxidative damage. These findings may enable the development of novel therapeutic strategies for neurological diseases. PMID- 26041155 TI - Impacts of Mercury Pollution Controls on Atmospheric Mercury Concentration and Occupational Mercury Exposure in a Hospital. AB - Mercury (Hg) and Hg-containing products are used in a wide range of settings in hospitals. Hg pollution control measures were carried out in the pediatric ward of a hospital to decrease the possibility of Hg pollution occurring and to decrease occupational Hg exposure. Total gaseous Hg (TGM) concentrations in the pediatric ward and hair and urine Hg concentrations for the pediatric staff were determined before and after the Hg pollution control measures had been implemented. A questionnaire survey performed indicated that the pediatric staff had little understanding of Hg pollution and that appropriate disposal techniques were not always used after Hg leakage. TGM concentrations in the pediatric ward and urine Hg (UHg) concentrations for the pediatric staff were 25.7 and 22.2% lower, respectively, after the Hg pollution control measures had been implemented than before, which indicated that the control measures were effective. However, TGM concentrations in the pediatric ward remained significantly higher than background concentrations and UHg concentrations for the pediatric staff were remained significantly higher than the concentrations in control group, indicating continued existence of certain Hg pollution. PMID- 26041156 TI - Combined chemometric analysis of (1)H NMR, (13)C NMR and stable isotope data to differentiate organic and conventional milk. AB - The increased sales of organically produced food create a strong need for analytical methods, which could authenticate organic and conventional products. Combined chemometric analysis of (1)H NMR-, (13)C NMR-spectroscopy data, stable isotope data (IRMS) and alpha-linolenic acid content (gas chromatography) was used to differentiate organic and conventional milk. In total 85 raw, pasteurized and ultra-heat treated (UHT) milk samples (52 organic and 33 conventional) were collected between August 2013 and May 2014. The carbon isotope ratios of milk protein and milk fat as well as the alpha-linolenic acid content of these samples were determined. Additionally, the milk fat was analyzed by (1)H and (13)C NMR spectroscopy. The chemometric analysis of combined data (IRMS, GC, NMR) resulted in more precise authentication of German raw and retail milk with a considerably increased classification rate of 95% compared to 81% for NMR and 90% for IRMS using linear discriminate analysis. PMID- 26041157 TI - Tunisian date (Phoenix dactylifera L.) by-products: Characterization and potential effects on sensory, textural and antioxidant properties of dairy desserts. AB - Three Tunisian date varieties, Deglet Nour, Kentichi and Allig, served to produce syrups and powders, which were then examined for their physico-chemical composition and antioxidant properties. Different proportions of these sweetening like agents were incorporated to produce nine different formulations of dairy desserts, with lower amount of added sugars to avoid any artificial flavoring or coloring agents. Sensory and color evaluation data revealed that incorporating Deglet Nour and Kentichi syrup offers the most desirable formulation. Furthermore, syrup polysaccharides and fibers contribute to better maintain the final product texture. In addition, date by-products create a good source of natural thickening agents, involved in enhancing apparent viscosity and spontaneous exudation. Thanks to their high content in phenolic compounds, date by-products considerably improve antioxidant activities of the formulated desserts. Therefore, they could be valued as natural ingredients in the formulation of novel dairy products with high nutritional-properties. PMID- 26041158 TI - Visualization of calcium and zinc ions in Saccharomyces cerevisiae cells treated with PEFs (pulse electric fields) by laser confocal microscopy. AB - The aim of the present work was to visualize the areas of increased concentration of calcium and zinc ions inside Saccharomyces cerevisiae cells with the use of confocal microscopy and to make an attempt to asses semi-quantitatively their concentration within the limits of the cells. Semi-quantitative analysis revealed that fluorescence inside cells from control samples was three-times lower than that observed for cells from the sample enriched with calcium. Differences in distribution of fluorescence intensity between cells originated from the samples enriched with zinc and control samples were also observed. On the basis of the optical sections, the 3D reconstructions of ion-rich areas distribution in the cell were made. The obtained results showed that confocal microscopy is a useful technique for visualization of the areas in S. cerevisiae cells which contain higher amount of calcium and zinc and it may be also used for semi-quantitative analysis. PMID- 26041159 TI - Binding, stability, and antioxidant activity of quercetin with soy protein isolate particles. AB - This work is to study the potential of particles fabricated from soy protein isolate (SPI) as a protective carrier for quercetin. When the concentration of SPI particles increases from 0 to 0.35 g/L, quercetin gives a gradually increased fluorescence intensity and fluorescence anisotropy. The addition of quercetin can highly quench the intrinsic fluorescence of SPI particles. These results are explained in terms of the binding of quercetin to the hydrophobic pockets of SPI particles mainly through the hydrophobic force together with the hydrogen bonding. The small difference in the binding constants at 25 and 40 degrees C suggests the structural stability of SPI particles. The relative changes in values of Gibbs energy, enthalpy, and entropy indicate that the binding of quercetin with SPI particles is spontaneous and hydrophobic interaction is the major force. Furthermore, SPI particles are superior to native SPI for improving the stability and radical scavenging activity of quercetin. PMID- 26041160 TI - A novel ultrasound-assisted back extraction reverse micelles method coupled with gas chromatography-flame ionization detection for determination of aldehydes in heated edibles oils. AB - A novel ultrasound-assisted back extraction reverse micelles coupled with gas chromatography-flame ionization detection has been developed for the extraction and determination of some short chain aldehydes in different heated edible oil samples. After the homogenization of the oil samples with Triton X-100, 200 MUL of methanol was added to facilitate the phase separation. The aqueous micelle phase has been separated by centrifugation, then it was treated with a mixture of H2O: CHCl3 and ultrasonic vibration, were used to effectively back-extraction of the analytes into the chloroform phase. The sedimented organic phase was obtained after centrifugation, withdrawn into the microsyringe and directly injected into the GC-FID system. The calibration graphs were linear in the range 0.05-20 mg L( 1). The limits of detection were in the range of 0.02-0.15 mg L(-1). This procedure was successfully applied for determination of propanal, butanal, hexanal and heptanal in real heated oil samples. PMID- 26041161 TI - Effect of green Spanish-style processing (Manzanilla and Hojiblanca) on the quality parameters and fatty acid and triacylglycerol compositions of olive fat. AB - This work studies the effect of processing Manzanilla and Hojiblanca olives as green Spanish-style on the quality parameters and fatty acid and triacylglycerol compositions of their oils. Lye treatment reduced the values of most quality parameters while fermentation/packaging increased acidity, K232 and K270. Processing did not cause any systematic effect on fatty acids (FA), triacylglycerols or nutritional fat subclasses but significant differences between cultivars were observed. Principal component analysis (PCA) confirmed that most of the variation among oil characteristics was due to cultivars and only a limited proportion (~22% and ~14% variance for FA and triacylglycerols, respectively) to processing. Furthermore, the levels of the quality parameters and fatty acids with restrictions in the legislation were below the limits established in the Commission Implementing Regulation (EU) 1348/2013 for extra virgin olive oil (EVOO), except for C18:3n-3 in Hojiblanca. Therefore, the fat of processed olives was compatible with EVOO. PMID- 26041162 TI - Health Risk Assessment using in vitro digestion model in assessing bioavailability of heavy metal in rice: A preliminary study. AB - Little is known about the bioavailability of heavy metal contamination and its health risks after rice ingestion. This study aimed to determine bioavailability of heavy metal (As, Cd, Cu, Cr, Co, Al, Fe, Zn and Pb) concentrations in cooked rice and human Health Risk Assessment (HRA). The results found Zn was the highest (4.3+/-0.1 mg/kg), whereas As showed the lowest (0.015+/-0.001 mg/kg) bioavailability of heavy metal concentration in 22 varieties of cooked rice. For single heavy metal exposure, no potential of non carcinogenic health risks was found, while carcinogenic health risks were found only for As. Combined heavy metal exposures found that total Hazard Quotient (HQtotal) values for adult were higher than the acceptable range (HQTotal<1), whereas total Lifetime Cancer Risk (LCRTotal) values were higher than the acceptable range (LCRTotal values >1*10( 4)) for both adult and children. This study is done to understand that the inclusion of bioavailability heavy metal into HRA produces a more realistic estimation of human heavy metal exposure. PMID- 26041163 TI - Determination of the total content of some sulfonamides in milk using solid-phase extraction coupled with off-line derivatization and spectrophotometric detection. AB - A simple screening method for isolation and determination of the total content of some sulfonamides in milk using solid-phase extraction and a color reaction is described. This procedure is based on SPE of sulfonamides on hypercrosslinked polystyrene, elution with acetonitrile and off-line derivatization with p dimethylaminocinnamaldehyde in acetonitrile followed by spectrophotometric determination. The reaction produces intense violet-red color and can be easily used both for quantitation of sulfonamides using spectrophotometry and for naked eye semi-quantitative estimation. Maximum absorption of the reaction product was determined at 540 nm. The Lambert-Beer's law was obeyed in the range of 0.07-3.0 MUg mL(-1) in eluate, with the squared correlation coefficient (R(2)) of 0.9875 0.9995, and the relative standard deviation (RSD) of 3-4%. The limits of SAs detection using preconcentration were of 0.02-0.03 MUg mL(-1). The proposed method can be recommended as a routine screening method for quantitation of sulfonamides in milk. PMID- 26041165 TI - Dynamic controlled atmosphere and ultralow oxygen storage on 'Gala' mutants quality maintenance. AB - The aim of the present work was to compare the effect of ultralow oxygen (ULO) with dynamic controlled atmosphere (DCA) and controlled atmosphere (CA) on the post storage quality of 'Royal Gala' and 'Galaxy' apples after long-term storage. Two experiments were carried out with 'Royal Gala' and 'Galaxy' apples, in the years 2012 and 2013, respectively. A higher internal ethylene concentration was observed in fruits stored under CA; intermediate concentration in fruits under ULO; and the lowest by fruits stored under DCA-CF (DCA based on chlorophyll fluorescence). Flesh firmness was higher in fruits stored under DCA-CF and ULO differing from CA, in the year 2012, but in 2013 fruits stored under ULO showed the highest flesh firmness, differing from CA fruits. DCA-CF is efficient in quality maintenance of 'Royal Gala' and 'Galaxy' apples. Both 'Gala' mutants stored under ULO show a similar quality maintenance to those stored under DCA-CF. PMID- 26041164 TI - Solubility and thermodynamic behavior of vanillin in propane-1,2-diol+water cosolvent mixtures at different temperatures. AB - The solubilities of bioactive compound vanillin were measured in various propane 1,2-diol+water cosolvent mixtures at T=(298-318)K and p=0.1 MPa. The experimental solubility of crystalline vanillin was determined and correlated with calculated solubility. The results showed good correlation of experimental solubilities of crystalline vanillin with calculated ones. The mole fraction solubility of crystalline vanillin was recorded highest in pure propane-1,2-diol (7.06*10(-2) at 298 K) and lowest in pure water (1.25*10(-3) at 298 K) over the entire temperature range investigated. Thermodynamic behavior of vanillin in various propane-1,2-diol+water cosolvent mixtures was evaluated by Van't Hoff and Krug analysis. The results showed an endothermic, spontaneous and an entropy-driven dissolution of crystalline vanillin in all propane-1,2-diol+water cosolvent mixtures. Based on solubility data of this work, vanillin has been considered as soluble in water and freely soluble in propane-1,2-diol. PMID- 26041166 TI - Carbon disulfide formation in papaya under conditions of dithiocarbamate residue analysis. AB - Golden, Sunrise Solo and Tainung cultivars of papaya were found to release CS2 when submitted to experimental conditions of dithiocarbamate residue analysis. Three common analytical methods were used to quantitate CS2; one spectrophotometric method and two chromatographic methods. All three methods gave positive CS2 results for all three papaya varieties. Other endogenous compounds present in isooctane extracts of papaya fractions detected via gas chromatography (GC/ITD) using electron ionization (EI) were: carbonyl sulfide, dimethyl sulfide, carbon disulfide, 2-methylthiophene, 3-methylthiophene, 2-ethylthiophene, 3 ethylthiophene, benzylisothiocyanate, benzylthiocyanate and benzonitrile. Control samples were obtained from papaya plantations cultivated in experimental areas, in which no treatment with fungicides of the dithiocarbamate group was applied. Endogenous CS2 levels were compared with true dithiocarbamate residues measured in papaya samples from the field trials following applications of the mancozeb fungicide. Three days after application, true dithiocarbamate residues, measured by the procedure with isooctane partitioning and GC-ITD, were at the average level of 2 mg kg(-1). PMID- 26041167 TI - Ethylene degreening modulates health promoting phytochemicals in Rio Red grapefruit. AB - In the current study, we examined the effects of postharvest degreening and storage on phytochemicals in Rio Red grapefruit. Grapefruits were degreened with 3.5 MUl/l of ethylene at 21 degrees C and 80% relative humidity for 72 h, while non-degreened fruits were used as the control. Furthermore, the grapefruits were stored at 11 degrees C for 3 weeks and then at 21 degrees C for 2 weeks. Degreening improved the peel colour of the grapefruit without affecting total soluble solids or acidity of the juice. Degreened fruits had significantly more ascorbic acid after 35 days of storage. Degreening had no significant effect on the levels of carotenoids, limonoids and flavonoids as compared to the non degreened fruits, after 35 days of storage. However, after 7 days, degreened fruits had more limonin and flavonoids and less furocoumarin, namely 6',7' dihydroxybergamottin. Overall, ethylene treatment had a significant effect on the phytochemical contents of Rio Red grapefruit, especially after 7 days of storage. PMID- 26041168 TI - Optimization of extraction of high purity all-trans-lycopene from tomato pulp waste. AB - The aim of this work was to optimize the extraction of pure all-trans-lycopene from the pulp fractions of tomato processing waste. A full factorial design (FFD) consisting of four independent variables including extraction temperature (30-50 degrees C), time (1-60 min), percentage of acetone in n-hexane (25-75%, v/v) and solvent volume (10-30 ml) was used to investigate the effects of process variables on the extraction. The absolute amount of lycopene present in the pulp waste was found to be 0.038 mg/g. The optimal conditions for extraction were as follows: extraction temperature 20 degrees C, time 40 min, a solvent composition of 25% acetone in n-hexane (v/v) and solvent volume 40 ml. Under these conditions, the maximal recovery of lycopene was 94.7%. The HPLC-DAD analysis demonstrated that, lycopene was obtained in the all-trans-configuration at a very high purity grade of 98.3% while the amount of cis-isomers and other carotenoids were limited. PMID- 26041169 TI - Determination of melamine in dairy products using electromembrane-LPME followed by HPLC. AB - This study presents the application of electromembrane microextraction technique combined with HPLC-UV detection for fast extraction-preconcentration and determination of melamine in dairy products. It is based on the extraction of charged melamine molecules migrated from 6.5 mL feed solution through a liquid membrane immobilized in the pores of a hollow fiber into 20 MUL of the acceptor solution. The best performance was achieved by using 2-nitrophenyloctylether, tris-(2-ethylhexyl) phosphate (10%) and di-(2-ethylhexyl)phosphate (10%) as the extraction solvent; application of a potential of 90 V as the driving force and by adjusting the pH of feed and receiving phases at 5.5 and 1, respectively. The working range was 7-8000 ng mL(-1), with detection limit of 2.0-5.8 ng mL(-1). The enrichment factor was in the range 82-192. Intra- and inter-day relative standard deviations were less than 6.6%. Extraction and relative recoveries for different samples were between 25-59% and 85-95%, respectively. PMID- 26041170 TI - Antioxidant activities and antiproliferative activity of Thai purple rice cooked by various methods on human colon cancer cells. AB - The changes in anthocyanins, phenolic compounds, and antioxidant activities of Thai purple rice cooked by various cooking devices, including an electric rice cooker, an autoclave and a microwave oven, were investigated. In raw rice, cyanidin-3-glucoside (cy-3-glu) and peonidin-3-glucoside (pn-3-glu) are predominant anthocyanins, whereas protocatechuic acid (PCA) and vanillic acid (VA) are major free phenolic acids, and ferulic acid (FA) and VA are major bound phenolic acids. The microwave cooking method resulted in a marked loss of phenolics, anthocyanins and antioxidant activities (p<0.05). A decrease of cy-3 glu occurred concomitantly with an increase of PCA upon any cooking methods applied. A methanolic extract of rice cooked under sterilization exhibited the highest content of PCA and the highest inhibition of Caco-2 cell proliferation with an IC50 (16.11 MUg/mL) comparable to that of raw rice. Thai purple rice cooked under sterilization could be a potential source of PCA exerting high antiproliferative activity. PMID- 26041171 TI - Tubular cellulose/starch gel composite as food enzyme storehouse. AB - The objective of this study was to produce a composite biocatalyst, based on porous cellulosic material, produced after wood sawdust delignification (tubular cellulose; TC) and starch gel (SG), for the development of bioprocesses related to enzyme applications. The composite biocatalyst was studied by Scanning Electron Microscopy to observe the SG deposition in the TC pores, and porosimetry analysis to determine the average pore diameter and surface area. The deposition of SG into the TC tubes provided a TC/SG composite with reduced pore sizes. X-ray powder diffractometry showed a decrease of crystallinity with increased SG ratio in the composite. The composite was used as an insoluble carrier for entrapment of the dairy enzyme rennin, leading to the production of an active biocatalyst for milk coagulation (initiation of milk clotting at about 20 min and full coagulation at about 200 min), creating perspectives for several applications in food enzyme research and technology. PMID- 26041172 TI - Chemical forces and water holding capacity study of heat-induced myofibrillar protein gel as affected by high pressure. AB - The effects of high pressure (100-500 MPa) on chemical forces and water holding capacity of heat-induced myofibrillar protein (MP) gel were investigated. As pressure increased, total sulfhydryl (SH) group content decreased and absolute value of zeta potential increased, which suggested the formation of disulfide bonds and increased the strength of electrostatic repulsion. Surface hydrophobicity and normalized intensity of the 760 cm(-1) band showed a maximum value at 200 MPa, indicating that 200 MPa was the optimum pressure for hydrophobic interactions. Hydrogen bonding of MP gel was strengthened at pressures of 300 MPa and above. Bound water (T2b) had lower water mobility and was more closely associated with proteins. Free water (T22) had higher water mobility. More free water was attracted by proteins or trapped in gel structure, and transferred to bound or immobilized water as pressure increased. A value of 200 MPa was the optimum pressure for the water holding capacity of MP gel. PMID- 26041173 TI - Assessment of phytochemical composition and antioxidant potential in some indigenous chilli genotypes from North East India. AB - Twenty five chilli genotypes from North East region of India evaluated showed variation for capsaicin from 0.27% (CHF-CA-1) to 3.03% (CHF-CA-21), oleoresin content from 2.49% (CHF-CA-5) to 9.26% (CHF-CA-18) with high to moderate ascorbic acid. Total phenolics ranged from 5.1 (CHF-CA-8) to 26.8 (CHF-CA-23) mg GAE/g and total carotenoids from 0.09 (CHF-CA-16) to 7.72 (CHF-CA-17) mg/g dry weight. The antioxidant activity varied from 15.3% (CHF-CA-4) to 60.7% (CHF-CA-21). Free radical scavenging activity using DPPH assay showed low IC50 ranging from 0.021 to 0.041 mg/mg, low EC50 from 0.92 to 1.78 mg/mg DPPH, high ARP values (56.17 109.52) in CHF-CA-6, CHF-CA-7, CHF-CA-17, CHF-CA-21, CHF-CA-22 and CHF-CA-23 genotypes. The reducing power ranged from 0.92 to 4.10 ASE/ml and specific phenolic composition showed presence of gallic acid with other hydroxycinnamic acid. Among the flavonoids, presence of catechin was maximum followed by quercetin and rutin. PMID- 26041174 TI - Microscopic evidence for Ca(2+) mediated pectin-pectin interactions in carrot based suspensions. AB - This study explored the use of fluorescently labeled pectin to obtain evidence for Ca(2+) mediated pectin-pectin interactions in situ. Specifically, carrots were either blanched at low temperature (LTB) or blanched at high temperature (HTB) to activate or inactivate endogenous pectin methylesterase, respectively. Consequently, pectin in tissue particles of LTB and HTB carrots exhibited low degree of methylesterification (DM) and high DM, respectively. Pectin present in the LTB carrot serum exhibited a lower DM, was more branched, and showed a higher molar mass compared to HTB carrot serum pectin. Ca(2+) mediated pectin-pectin interactions were influenced by serum pectin molecular structure, increased with increasing pH and Ca(2+) concentration, and decreasing DM. Presence of more linear pectin in the serum created a competition, leading to less intense interactions between labeled pectin and pectin at tissue particle surfaces. Generally, the most intense Ca(2+) mediated pectin-pectin interactions were observed for pectin of LTB carrot particles. PMID- 26041175 TI - Optimized core-shell Au@Ag nanoparticles for label-free Raman determination of trace Rhodamine B with cancer risk in food product. AB - A simple and reliable method based on surface-enhanced Raman scattering (SERS) with a portable Raman system is described for sensitive determination of trace levels of Rhodamine B (RB) in hot sauce samples. The sodium salt of phytic acid (IP6) stabilized Au@Ag core-shell bimetallic nanoparticles are constructed and used as SERS substrate, yielding high Raman enhancement of RB. The limit of detection for RB in water is 5 nM (2 ppb), which is below China Exit and Entry Inspection and Quarantine Bureau's tolerance level of 5 ppb. Also, the proposed easy assay of IP6-Au@Ag NPs combining with portable Raman system could be applied for on-site monitoring RB in hot sauce. PMID- 26041176 TI - Extraction of trace elements by ultrasound-assisted emulsification from edible oils producing detergentless microemulsions. AB - The aim of this study is to develop a new method for the extraction and preconcentration of trace elements from edible oils via an ultrasound-assisted extraction using ethylenediaminetetraacetic acid (EDTA) producing detergentless microemulsions. These were then analyzed using ICP-MS against matrix matched standards. Optimum experimental conditions were determined and the applicability of the proposed ultrasound-assisted extraction method was investigated. Under the optimal conditions, the detection limits (MUg kg(-1)) were 2.47, 2.81, 0.013, 0.037, 1.37, 0.050, 0.049, 0.47, 0.032 and 0.087 for Al, Ca, Cd, Cu, Mg, Mn, Ni, Ti, V and Zn respectively for edible oils (3Sb/m). The accuracy of the developed method was checked by analyzing certified reference material. The proposed method was applied to different edible oils such as sunflower seed oil, rapeseed oil, olive oil and cod liver oil. PMID- 26041177 TI - Glucose: Detection and analysis. AB - Glucose is an aldosic monosaccharide that is centrally entrenched in the processes of photosynthesis and respiration, serving as an energy reserve and metabolic fuel in most organisms. As both a monomer and as part of more complex structures such as polysaccharides and glucosides, glucose also plays a major role in modern food products, particularly where flavor and or structure are concerned. Over the years, many diverse methods for detecting and quantifying glucose have been developed; this review presents an overview of the most widely employed and historically significant, including copper iodometry, HPLC, GC, CZE, and enzyme based systems such as glucose meters. The relative strengths and limitations of each method are evaluated, and examples of their recent application in the realm of food chemistry are discussed. PMID- 26041178 TI - Adsorption of nisin and pediocin on nanoclays. AB - Three different nanoclays (bentonite, octadecylamine-modified montmorillonite and halloysite) were studied as potential carriers for the antimicrobial peptides nisin and pediocin. Adsorption occurred from peptide solutions in contact with nanoclays at room temperature. Higher adsorption of nisin and pediocin was obtained on bentonite. The antimicrobial activity of the resultant bacteriocin nanoclay systems was analyzed using skimmed milk agar as food simulant and the largest inhibition zones were observed against Gram-positive bacteria for halloysite samples. Bacteriocins were intercalated into the interlayer space of montmorillonites as deduced from the increase of the basal spacing measured by X ray diffraction (XRD) assay. Infrared spectroscopy suggested non-electrostatic interactions, such as hydrogen bonding between siloxane groups from clays and peptide molecules. Transmission electron microscopy did not show any alteration in morphologies after adsorption of antimicrobial peptides on bentonite and halloysite. These results indicate that nanoclays, especially halloysite, are suitable nanocarriers for nisin and pediocin adsorption. PMID- 26041179 TI - Preparation and thermo-reversible gelling properties of protein isolate from defatted Antarctic krill (Euphausia superba) byproducts. AB - Protein isolate was prepared from defatted Antarctic krill (Euphausia superba) byproducts by 0.1 M NaOH extraction. Maximum yield of krill protein isolate reached 28.66% by precipitation at pH 4.6. Krill protein isolate demonstrated its excellent nutritional values through amino acid composition and in vitro digestibility. Thermal transition of krill protein isolate was determined by differential scanning calorimetry measurement. Extrapolated values of glass transition temperature (Tg) and denaturation temperature (Td) of krill protein isolate were 33.8 degrees C and 80.3 degrees C when the heating rate was 2 degrees C/min. Dispersions of krill protein isolate generated self-supported gels at concentrations above 100 g/L without the addition of salt or other additives. A noticeable enhancement of gel strength was induced through cooling. Gels with krill protein isolate displayed a thermo-reversible behavior under repeating heating/cooling cycles, which was primarily due to the formation and disruption of hydrogen bonds. Network strength of protein gels was strongly dependent on protein concentrations. PMID- 26041180 TI - Inhibitory effects of alpha-Na8SiW11CoO40 on tyrosinase and its application in controlling browning of fresh-cut apples. AB - alpha-Na8SiW11CoO40 was synthesized and characterized. The inhibitory effects of alpha-Na8SiW11CoO40 on the activity of mushroom tyrosinase and the effects of alpha-Na8SiW11CoO40 on the browning of fresh-cut apples were studied. The Native PAGE result showed that alpha-Na8SiW11CoO40 had a significant inhibitory effect on tyrosinase. Kinetic analyses showed that alpha-Na8SiW11CoO40 was an irreversible and competitive inhibitor. The inhibitor concentration leading to a 50% reduction in activity (IC50) was estimated to be 0.239 mM. Additionally, the results also showed that alpha-Na8SiW11CoO40 treatment could significantly decrease the browning process of apple slices and inhibit the polyphenol oxidase (PPO) activity. Moreover, application of alpha-Na8SiW11CoO40 resulted in higher peroxidase activity and promoted high amounts of phenolic compounds and ascorbic acid. This study may provide a promising method for the use of polyoxometalates to inhibit tyrosinase activity and control the browning of fresh-cut apples. PMID- 26041182 TI - Blueberry polyphenol oxidase: Characterization and the kinetics of thermal and high pressure activation and inactivation. AB - Partially purified blueberry polyphenol oxidase (PPO) in Mcllvaine buffer (pH=3.6, typical pH of blueberry juice) was subjected to processing at isothermal isobaric conditions at temperatures from 30 to 80 degrees C and pressure from 0.1 to 700 MPa. High pressure processing at 30-50 degrees C at all pressures studied caused irreversible PPO activity increase with a maximum of 6.1 fold increase at 500 MPa and 30 degrees C. Treatments at mild pressure-mild temperature conditions (0.1-400 MPa, 60 degrees C) also caused up to 3 fold PPO activity increase. Initial activity increase followed by a decrease occurred at relatively high pressure-mild temperature (400-600 MPa, 60 degrees C) and mild pressure-high temperature (0.1-400 MPa, 70-80 degrees C) combinations. At temperatures higher than 76 degrees C, monotonic decrease in PPO activity occurred at 0.1 MPa and pressures higher than 500 MPa. The activation/inactivation kinetics of the enzyme was successfully modelled assuming consecutive reactions in series with activation followed by inactivation. PMID- 26041181 TI - Some physicochemical characteristics of pinus (Pinus halepensis Mill., Pinus pinea L., Pinus pinaster and Pinus canariensis) seeds from North Algeria, their lipid profiles and volatile contents. AB - Physicochemical characteristics of seeds of some pinus species (Pinus halepensis Mill., Pinus pinea L., Pinus pinaster and Pinus canariensis) grown in North Algeria were determined. The results showed that the seeds consist of 19.8-36.7% oil, 14.25-26.62% protein, 7.8-8.6% moisture. Phosphorus, potassium and magnesium were the predominant elements present in seeds. Pinus seed's oil physicochemical properties show acid values (4.9-68.9), iodine values (93.3-160.4) and saponification values (65.9-117.9). Oil analysis showed that the major unsaturated fatty acids for the four species were linoleic acid (30-59%) and oleic acid (17.4-34.6%), while the main saturated fatty acid was palmitic acid (5 29%). Gas Chromatography and Mass Spectrometry analysis of P. halepensis Mill., P. pinaster and P. canariensis volatile oils indicated that the major volatile compound was the limonene with relative percentage of 3.1, 7.5 and 10.8, respectively. PMID- 26041183 TI - Circular dichroism and infrared spectroscopic characterization of secondary structure components of protein Z during mashing and boiling processes. AB - In beer brewing, protein Z is hypothesized to stabilize beer foam. However, few investigations have revealed the relationship between conformational alterations to protein Z during the brewing process and beer foam. In this report, protein Z from sweet wort was isolated during mashing and boiling processes. Circular dichroism (CD) and Fourier transform infrared spectroscopy (FTIR) were used to monitor the structural characteristics of protein Z. The results showed that the alpha-helix and beta-sheet content decreased, whereas the content of beta-turn and random coil increased. The complex environment rich in polysaccharides may facilitate conformational alterations and modifications to protein Z. Additionally, the formation of extended structural features to protein Z provides access to reactive amino acid side chains that can undergo modifications and the exposure of hydrophobic core regions of the protein. Analyzing structural transformations should provide a deeper understanding of the mechanism of protein Z on maintaining beer foam. PMID- 26041184 TI - Peptide identification and angiotensin converting enzyme (ACE) inhibitory activity in prolyl endoproteinase digests of bovine alpha(s)-casein. AB - Incubation of sodium caseinate (NaCN) and purified alpha-casein (alphas-CN) with an Aspergillus niger derived prolyl endoproteinase (An-PEP) for 1, 2, 3, 4, 8 and 24 h resulted in the generation of potent angiotensin converting enzyme (ACE) inhibitory hydrolysates. An ACE IC50 of 21.1+/-5.1 MUg/ml was obtained on incubation of An-PEP with NaCN for 4 h. Fractionation of the NaCN hydrolysates using 3 kDa centrifugal filters resulted in highly active permeate fractions, the most potent being obtained from the 3 h hydrolysate (ACE IC50=2.9+/-0.3 MUg/ml). The hydrolytic specificity of An-PEP for purified alpha-CN was assessed using UPLC ESI MS/MS. The analysis confirmed An-PEP's cleavage preference for the C terminal side of Pro and also confirmed that An-PEP has the ability to cleave at the C-terminal of Ala, Leu, Arg and His residues. PMID- 26041185 TI - Polyamines in conventional and organic vegetables exposed to exogenous ethylene. AB - Relationships between endogenous levels of polyamines by thin layer chromatography (TLC) and gas chromatography (GC), nitrate and response to the application of ethylene were established between organic and conventional vegetables (broccoli, collard greens, carrots and beets), both raw and cooked. Responses to ethylene showed that organic plants were less responsive to the growth regulator. The levels of free polyamines obtained by TLC were higher in organic vegetables. Organic broccoli showed higher levels of putrescine (Put), and cooking resulted in lowering the overall content of these amines. Conventional collard green showed the highest level of putrescine in the leaves compared with organic. Tubers of carrots and beets contain the highest levels of Put. These plants also contain high levels of spermine. GC analysis showed the highest polyamines contents compared with those obtained by TLC. Cooking process decreased putrescine and cadaverine content, both in conventionally and organically grown vegetables. Organic beets contain lower NO3(-) compared with its conventional counterpart. PMID- 26041186 TI - Identification of innovative potential quality markers in rocket and melon fresh cut produce. AB - Ready-to-eat fresh cut produce are exposed to pre- and postharvest abiotic stresses during the production chain. Our work aimed to identify stress responsive genes as new molecular markers of quality that can be widely applied to leaves and fruits and easily determined at any stage of the production chain. Stress responsive genes associated with quality losses were isolated in rocket and melon fresh-cut produce and their expression levels analyzed by quantitative real time PCR (qRT-PCR) at different time points after harvest at 20 degrees C and 4 degrees C. qRT-PCR results were supported by correlation analysis with physiological and biochemical determinations evaluated at the same conditions such as chlorophyll a fluorescence indices, total, reducing sugars, sucrose, ethylene, ascorbic acid, lipid peroxidation and reactive oxygen species. In both species the putative molecular markers increased their expression soon after harvest suggesting a possible use as novel and objective quality markers of fresh cut produces. PMID- 26041187 TI - Study of the effect of different fermenting microorganisms on the Se, Cu, Cr, and Mn contents in fermented goat and cow milks. AB - The aim of this study was to determine the Se, Cu, Cr, and Mn concentrations of different types of goat- and cow-milk fermented products and evaluate the influence of fermenting bacteria (classical fermenting starters and a probiotic strain) on these concentrations. Atomic absorption spectrometry with hydride generation was used to measure Se and electrothermal atomization to measure Cu, Cr and Mn. Analytical parameters determined in the fermented milks demonstrated that the procedures used were adequate for Se, Cu, Cr, and Mn analyses. Se levels were significantly lower in fermented goat milk products than in fermented cow milk products (p<0.05). Se, Cu, Cr, and Mn levels did not differ as a function of the fermenting bacteria used in commercial fermented goat or cow milks or in the lab-produced goat yoghurt. Given the Se, and Cr intakes for healthy adults, goat and cow yogurts may be important dietary sources. PMID- 26041188 TI - Chitosan-based adsorption and freeze deproteinization: Improved extraction and purification of synthetic colorants from protein-rich food samples. AB - A freeze method for deproteinization coupling with the chitosan purification process was developed for the determination of 8 synthetic food colorants in protein-rich samples. The solvents for extraction and different methods for deproteinization were examined and selected. Chitosan was employed for the purification after deproteinization, and further compared with the traditional polyamine purification method. Determination of the purified extract was conducted through the separation using high performance liquid chromatography and detection by multi-wavelength mode. Under the optimum conditions, the method showed good linearity between 0.6 and 10mg/kg, for the 8 synthetic colorants, and the limit of detection was between 0.1 and 0.4 mg/kg as was defined when the ratio of signal to noise was three. The recoveries of the spiked samples were found to be between 83% and 91%. The intra-day precision and inter-day precision was estimated to be 3-10% and 6-12%, respectively. The developed method could be applied to deproteinization and clean-up for pretreatment of protein-rich samples. PMID- 26041189 TI - Effect of pH shifts on IgE-binding capacity and conformational structure of tropomyosin from short-neck clam (Ruditapes philippinarum). AB - The aim of the present study was to assess pH-induced changes in conformational structures and potential allergenicity of tropomyosin from short-neck clams. As defined with circular dichroism (CD), an unfolded structure was found at pH values ranging from 2.0 to 5.0, followed by the loss of secondary structure at pH of 1.0. Correspondingly, surface hydrophobicity was reduced by 97.7% when pH was reduced from 7.0 to 1.0. Further indirect ELISA and dot-blot results of pH shifted tropomyosin showed that potential allergenicity correlated well with structural changes, as well as with SGF digestibility. Allergenicity decreased significantly with unfolding of the protein and was stable when surface hydrophobicity recovered back to neutral conditions. These results showed that conformational changes in tropomyosin induced by pH shifting significantly influenced the allergenicity of tropomyosin, and that the resulting changes occurred predominately in the acidic pH range. PMID- 26041190 TI - Formation and stabilization of nanoemulsion-based vitamin E delivery systems using natural biopolymers: Whey protein isolate and gum arabic. AB - Natural biopolymers, whey protein isolate (WPI) and gum arabic (GA), were used to fabricate emulsion-based delivery systems for vitamin E-acetate. Stable delivery systems could be formed when vitamin E-acetate was mixed with sufficient orange oil prior to high pressure homogenization. WPI (d32=0.11 MUm, 1% emulsifier) was better than GA (d32=0.38 MUm, 10% emulsifier) at producing small droplets at low emulsifier concentrations. However, WPI-stabilized nanoemulsions were unstable to flocculation near the protein isoelectric point (pH 5.0), at high ionic strength (>100mM), and at elevated temperatures (>60 degrees C), whereas GA-stabilized emulsions were stable. This difference was attributed to differences in emulsifier stabilization mechanisms: WPI by electrostatic repulsion; GA by steric repulsion. These results provide useful information about the emulsifying and stabilizing capacities of natural biopolymers for forming food-grade vitamin enriched delivery systems. PMID- 26041191 TI - Development of an effective and efficient DNA isolation method for Cinnamomum species. AB - Different species of Cinnamomum are rich in polysaccharide's and secondary metabolites, which hinder the process of DNA extraction. High quality DNA is the pre-requisite for any molecular biology study. In this paper we report a modified method for high quality and quantity of DNA extraction from both lyophilized and non-lyophilized leaf samples. Protocol reported differs from the CTAB procedure by addition of higher concentration of salt and activated charcoal to remove the polysaccharides and polyphenols. Wide utility of the modified protocol was proved by DNA extraction from different woody species and 4 Cinnamomum species. Therefore, this protocol has also been validated in different species of plants containing high levels of polyphenols and polysaccharides. The extracted DNA showed perfect amplification when subjected to RAPD, restriction digestion and amplification with DNA barcoding primers. The DNA extraction protocol is reproducible and can be applied for any plant molecular biology study. PMID- 26041192 TI - Vis-NIR hyperspectral imaging in visualizing moisture distribution of mango slices during microwave-vacuum drying. AB - Mango slices were dried by microwave-vacuum drying using a domestic microwave oven equipped with a vacuum desiccator inside. Two lab-scale hyperspectral imaging (HSI) systems were employed for moisture prediction. The Page and the Two term thin-layer drying models were suitable to describe the current drying process with a fitting goodness of R(2)=0.978. Partial least square (PLS) was applied to correlate the mean spectrum of each slice and reference moisture content. With three waveband selection strategies, optimal wavebands corresponding to moisture prediction were identified. The best model RC-PLS-2 (Rp(2)=0.972 and RMSEP=4.611%) was implemented into the moisture visualization procedure. Moisture distribution map clearly showed that the moisture content in the central part of the mango slices was lower than that of other parts. The present study demonstrated that hyperspectral imaging was a useful tool for non destructively and rapidly measuring and visualizing the moisture content during drying process. PMID- 26041193 TI - Origin assessment of EV olive oils by esterified sterols analysis. AB - In this study extra virgin olive oils of Italian and non-Italian origin (from Spain, Tunisia and blends of EU origin) were differentiated by GC-FID analysis of sterols and esterified sterols followed by chemometric tools. PCA allowed to highlight the high significance of esterified sterols to characterise extra virgin olive oils in relation to their origin. SIMCA provided a sensitivity and specificity of 94.39% and 91.59% respectively; furthermore, an external set of 54 extra virgin olive oils bearing a designation of Italian origin on the labelling was tested by SIMCA. Prediction results were also compared with organoleptic assessment. Finally, the poor correlation found between ethylesters and esterified sterols allowed to hazard the guess, worthy of further investigations, that esterified sterols may prove to be promising in studies of geographical discrimination: indeed they appear to be independent of those factors causing the formation of ethyl esters and related to olive oil production. PMID- 26041194 TI - Heat damage and in vitro starch digestibility of puffed wheat kernels. AB - The effect of processing conditions on heat damage, starch digestibility, release of advanced glycation end products (AGEs) and antioxidant capacity of puffed cereals was studied. The determination of several markers arising from Maillard reaction proved pyrraline (PYR) and hydroxymethylfurfural (HMF) as the most reliable indices of heat load applied during puffing. The considerable heat load was evidenced by the high levels of both PYR (57.6-153.4 mg kg(-1) dry matter) and HMF (13-51.2 mg kg(-1) dry matter). For cost and simplicity, HMF looked like the most appropriate index in puffed cereals. Puffing influenced starch in vitro digestibility, being most of the starch (81-93%) hydrolyzed to maltotriose, maltose and glucose whereas only limited amounts of AGEs were released. The relevant antioxidant capacity revealed by digested puffed kernels can be ascribed to both the new formed Maillard reaction products and the conditions adopted during in vitro digestion. PMID- 26041195 TI - Study of heavy metal concentrations in wild edible mushrooms in Yunnan Province, China. AB - Contamination with heavy metals in several species of edible mushrooms from the Yunnan Province in China was determined. Samples were collected from 16 locations in the Yunnan Province, and the contamination levels of Mn, Fe, Cu, Zn, As, Cd, and Pb were analyzed. The results demonstrated that the concentrations of essential elements (Mn, Fe, Cu, and Zn) in the mushrooms were at typical levels. The concentrations of potentially toxic metals (As, Pb and Cd) were higher than the national standard values of China (1.0 mg/kg for As, 0.2 mg/kg for Cd, and 2.0 mg/kg for Pb) in most cases. Bio-concentration factors suggested that it was easier for As and Cd to be accumulated in mushrooms than Pb, and a Health Risk Index assessment also suggested that As and Cd are greater risks to health than Pb. In conclusion, heavy metal pollution in wild edible mushrooms is a serious problem in the Yunnan Province. Among the toxic metals, As and Cd in the edible mushrooms in the area are the main sources of risk, as they may cause severe health problems. The local government needs to take measures in the form of concrete policies to protect the wild edible mushroom resources in the Yunnan Province. PMID- 26041196 TI - Analytical strategy based on the combination of gas chromatography coupled to time-of-flight and hybrid quadrupole time-of-flight mass analyzers for non-target analysis in food packaging. AB - The potential of an advanced analytical strategy based on the use of gas chromatography (GC) coupled to high resolution mass spectrometry (HRMS) with two different analyzers and ionization sources has been investigated and applied to the non-target analysis of food packaging contaminants. Initially, the approach based on GC-time-of-flight (TOF) MS with electron ionization (EI) source allowed performing a library search and mass accurate measurements of selected ions. Then, a second analysis was performed using hybrid quadrupole (Q) TOF MS with an atmospheric pressure chemical ionization (APCI) source in order to search for the molecular ion or the protonated molecule and study the fragmentation behavior. This analytical strategy was applied to the analysis of four polypropylene/ethylene vinyl alcohol/polypropylene (PP/EVOH/PP) multilayer trays and one PP/Al foil/PP film, each one subjected to migration assays with the food simulants isooctane and Tenax(r), in order to investigate its potential on the determination of migrant substances. PMID- 26041197 TI - Chemical composition of volatile aroma metabolites and their glycosylated precursors that can uniquely differentiate individual grape cultivars. AB - Every grape cultivar has its own unique genetic characteristics, leading to the production of a different secondary metabolite profile. Aroma is one of the most important aspects in terms of the quality of grapes and previous studies have assigned specific aromas to particular grape cultivars. In this study we present the molecular profiling of volatile aroma metabolites and their precursors in ten selected genotypes, including six Vitis vinifera cultivars, two American species (Arizonica Texas, Vitis cinerea) and two interspecific crosses. Chemical profiling was achieved through combined use of two orthogonal techniques, GC-MS and LC-HRMS, before and after enzymatic hydrolysis. The results show that both free and glycosidically bound aroma precursors behave differently in each different grape cultivar and species. As many as 66 free aroma volatile molecules (originally existing and released after hydrolysis) were profiled through GC-MS analysis, while 15 glycosylated precursors of volatiles were identified through LC-HRMS and correlation with GC-MS data. PMID- 26041198 TI - Development of a novel biosensor based on F(0)F(1)-ATPase for the detection of 2 dodecylcyclobutanone in irradiated beef. AB - A novel biosensor regulated by the rotator of F0F1-ATPase was developed to analyze 2-dodecylcyclobutanone (2-DCB) to detect gamma-ray irradiated beef rapidly. The biosensor was assembled by conjugating 2-DCB monoclonal antibodies with the "rotator" epsilon-subunit of F0F1-ATPase within chromatophores through an epsilon-subunit monoclonal antibody-biotin-avidin-biotin linker. The limit of detection (LOD) of 2-DCB was approximately 10(-8) MUg/mL. The recovery ratio of 2 DCB from ground beef patties ranged from 75.1% to 116.4%. The intra-assay and inter-assay coefficients of variation were both <15.0%. The proposed method was validated by gas chromatography-mass spectrometry with high correlation. The biosensor was used to detect 2-DCB in ground beef patties with different fat contents (10%, 20%, and 30%) irradiated at 0.5, 1.0, 3.0, 5.0, and 7.0 kGy. The 2 DCB concentration linearly increased with the radiation dose in all the beef samples. 2-DCB concentration increased with fat levels in the three samples. PMID- 26041199 TI - Alternative to decrease cholesterol in sheep milk cheeses. AB - The presence of cholesterol in foods is of nutritional interest because high levels of this molecule in human plasma are associated with an increasing risk of cardiovascular disease and nowadays consumers are demanding healthier products. The goal of this experiment was to diminish the cholesterol content of Manchego, the most popular Spanish cheese manufactured from ewes milk. For this purpose three bulk milks coming from dairy ewe fed with 0 (Control), 3 and 6% of linseed supplement on their diet were used. Nine cheeses (3 per bulk milk) were manufactured and ripened for 3 months. Cholesterol of ewes milk cheese from 6% to 12% linseed supplemented diets decreased by 9.6% and 16.1% respectively, therefore supplying a healthier profile. In a second experiment, different sources of unsaturated fatty acids (rich in oleic, linoleic and alpha-linolenic acids) were supplemented to dairy ewes and no significant differences were found on cheese cholesterol levels. PMID- 26041200 TI - Effect of mixing time on the structural characteristics of noodle dough under vacuum. AB - The structural characteristics of noodle dough under different vacuum mixing times were investigated using three flour samples by texture profile analysis (TPA), SEM, FTIR micro-imaging, and by measuring the glutenin macropolymer and free -SH content. The sheeted dough mixed for 8 min presented better textural properties and a more compact and even microstructure. Insufficient mixing resulted in an uneven distribution and an inadequately developed gluten network, especially for weak-gluten flour (Jimai 22). Excessive mixing was detrimental to the developed dough network and decreased the uniformity of component spatial distribution. Furthermore, excessive mixing led to a decrease in GMP content as well as the increase in free -SH content. Flours with different protein characteristics behaved differently. The TPA, microstructure and free -SH content of dough of Zhengmai 366 was less affected by mixing time than that of Jimai 22, suggesting that strong-gluten flour has better noodle dough mixing tolerance. PMID- 26041201 TI - Hydrogenolytic depolymerization of procyanidin polymers from hi-tannin sorghum bran. AB - Depolymerization of procyanidin polymers into oligomers enhances their bioavailability and bioactivity because oligomers are bioavailable. Hydrogenolysis was applied in this study to depolymerize hi-tannin sorghum bran procyanidin polymers into oligomers. The yield and composition of oligomers under different hydrogenolysis conditions was investigated. Results showed that raising temperature from 50 to 100 degrees C significantly increased total yield of oligomers. Higher temperatures (150 and 200 degrees C) produced monomers with lower yield. The highest yield of oligomers (38.8%) was obtained using 1 MPa hydrogen whereas 3 MPa hydrogen in reaction vessel decreased yield. Total yield of oligomers reached the highest at 1-3 h and then decreased with prolonged reaction time. Yield increased with palladium-on-carbon (Pd/C, a catalyst) amount from 0.5 to 3 mg and plateaued with Pd/C amount from 3 to 10 mg. The maximum yield of produced oligomers was achieved under 100 degrees C, 1 MPa hydrogen pressure, 1-3 h, and 3-10 mg Pd/C. PMID- 26041202 TI - Discrimination of geographical origin of lentils (Lens culinaris Medik.) using isotope ratio mass spectrometry combined with chemometrics. AB - The aim of this study was to predict the geographic origin of lentils by using isotope ratio mass spectrometry (IRMS) in combination with chemometrics. Lentil samples from two origins, i.e. Italy and Canada, were analysed obtaining the stable isotope ratios of delta(13)C, delta(15)N, delta(2)H, delta(18)O, and delta(34)S. A comparison between median values (U-test) highlighted statistically significant differences (p<0.05) for all isotopic parameters between the lentils produced in these two different geographic areas, except for delta(15)N. Applying principal component analysis, grouping of samples was observed on the basis of origin but with overlapping zones; consequently, two supervised discriminant techniques, i.e. partial least squares discriminant analysis and k-nearest neighbours algorithm were used. Both models showed good performances with external prediction abilities of about 93% demonstrating the suitability of the methods developed. Subsequently, isotopic determinations were also performed on the protein and starch fractions and the relevant results are reported. PMID- 26041203 TI - Separation and characterization of alpha-chain subunits from tilapia (Tilapia zillii) skin gelatin using ultrafiltration. AB - Alpha-chain subunits were separated from tilapia skin gelatin using ultrafiltration, and the physicochemical properties of obtained subunits were investigated. As a result, alpha1-subunit and alpha2-subunit could be successfully separated by 100 kDa MWCO regenerated cellulose membranes and 150 kDa MWCO polyethersulfone membranes, respectively. Glycine was the most dominant amino acid in both alpha1-subunit and alpha2-subunit. However, the tyrosine content was higher in alpha2-subunit than in alpha1-subunit, resulting in strong absorption near 280 nm observed in the UV absorption spectrum. Based on the DSC analysis, it was found that the glass transition temperatures of gelatin, alpha1 subunit and alpha2-subunit were 136.48 degrees C, 126.77 degrees C and 119.43 degrees C, respectively. Moreover, the reduced viscosity and denaturation temperature of alpha1-subunit were higher than those of alpha2-subunit, and the reduced viscosity reached the highest when alpha-subunits were mixed with alpha1/alpha2 ratio of approximately 2, suggesting that alpha1-subunit plays a more important role in the thermostability of gelatin than alpha2-subunit. PMID- 26041204 TI - Quantification of Nepsilon-(2-Furoylmethyl)-L-lysine (furosine), Nepsilon (Carboxymethyl)-L-lysine (CML), Nepsilon-(Carboxyethyl)-L-lysine (CEL) and total lysine through stable isotope dilution assay and tandem mass spectrometry. AB - The control of Maillard reaction (MR) is a key point to ensure processed foods quality. Due to the presence of a primary amino group on its side chain, lysine is particularly prone to chemical modifications with the formation of Amadori products (AP), Nepsilon-(Carboxymethyl)-L-lysine (CML), Nepsilon-(Carboxyethyl)-L lysine (CEL). A new analytical strategy was proposed which allowed to simultaneously quantify lysine, CML, CEL and the Nepsilon-(2-Furoylmethyl)-L lysine (furosine), the indirect marker of AP. The procedure is based on stable isotope dilution assay followed by liquid chromatography tandem mass spectrometry. It showed high sensitivity and good reproducibility and repeatability in different foods. The limit of detection and the RSD% were lower than 5 ppb and below 8%, respectively. Results obtained with the new procedure not only improved the knowledge about the reliability of thermal treatment markers, but also defined new insights in the relationship between Maillard reaction products and their precursors. PMID- 26041205 TI - Acetylated adipate of retrograded starch as RS 3/4 type resistant starch. AB - This study was aimed at producing acetylated adipate of retrograded starch (ADA R) with various degrees of substitution with functional groups and at determining the effect of esterification degree on resistance and pasting characteristics of the produced preparations. Paste was prepared from native potato starch, and afterwards frozen and defrosted. After drying and disintegration, the paste was acetylated and crosslinked using various doses of reagents. An increase in the total degree of esterification of the produced ADA-R-preparation caused an increase in its resistance to the action of amyloglucosidase. Viscosity of the paste produced from ADA-R-preparation in a wide range of acetylation degrees was increasing along with increasing crosslinking of starch. The study demonstrated that acetylated adipate of retrograded starch may be classified as a preparation of RS 3/4 type resistant starch (retrograded starch/chemically-modified starch) with good texture-forming properties. The conducted modification offers the possibility of modeling the level of resistance of the produced preparation. PMID- 26041206 TI - Binding properties and structure-affinity relationships of food antioxidant butylated hydroxyanisole and its metabolites with lysozyme. AB - Considering the harmful impact of food antioxidants on human bodies, thoroughly exposing their potential effects at the molecular level is important. In this study, the binding interactions of butylated hydroxyanisole (BHA), a phenolic antioxidant, and its different major metabolites tert-butylhydroquinone (TBHQ) and tert-butylbenzoquinone (TBQ) with lysozyme were examined via fluorescence, three-dimensional fluorescence, circular dichroism (CD), and ligand-protein docking studies. The three compounds caused strong quenching of lysozyme fluorescence by a static quenching mechanism but with different quenching efficiencies and different effects on the alpha-helix content of the lysozyme. The order of binding affinity of lysozyme for all test compounds is as follows: BHA>TBQ>TBHQ. Thermodynamic parameters indicated that hydrogen bonding and van der Waals forces perform dominant functions in the binding between these compounds and lysozyme. Furthermore, structure-affinity relationships between the model compounds and lysozyme were established on the basis of computational analyses. PMID- 26041207 TI - The stability of tryptophan, 5-methyl-tryptophan and alpha-methyl-tryptophan during NaOH hydrolysis of selected foods. AB - This study evaluated the use of 5-methyl-tryptophan, alpha-methyl-tryptophan or synthetic tryptophan to correct for the losses of protein-bound tryptophan in foods during NaOH hydrolysis. Synthetic tryptophan and each protein source was incubated in 4.5M NaOH containing 5-methyl-tryptophan and alpha-methyl-tryptophan in nitrogen gas-sparged Teflon vials for 0-144 h at 110 degrees C. The hydrolysis and loss rates of protein-bound tryptophan, 5-methyl-tryptophan, alpha methyl-tryptophan and synthetic tryptophan were predicted using least-squares nonlinear regression. Using 5-methyl-tryptophan or synthetic tryptophan to correct for hydrolytic losses of tryptophan overestimated the tryptophan content by 8.2-19% and -0.3-8.8% respectively, while correction using alpha-methyl tryptophan underestimated tryptophan by between 0.2% and 8.1% across the protein sources. Correction using alpha-methyl-tryptophan or synthetic tryptophan was more accurate than using 5-methyl-tryptophan, but when highly accurate tryptophan composition data are required, least-squares nonlinear regression is the best approach as it removes the need for a hydrolysis correction factor. PMID- 26041208 TI - Phenolic compounds, organic acids and antioxidant activity of grape juices produced in industrial scale by different processes of maceration. AB - The effect of maceration process on the profile of phenolic compounds, organic acids composition and antioxidant activity of grape juices from new varieties of Vitis labrusca L. obtained in industrial scale was investigated. The extraction process presented a high yield without pressing the grapes. The use of a commercial pectinase resulted in an increase on extraction yield and procyanidins B1 and B2 concentrations and a decrease on turbidity and concentration of catechins. The combination of 60 degrees C and 3.0 mL 100 kg(-1) of enzyme resulted in the highest extraction of phenolic compounds, reducing the content of acetic acid. The juices presented high antioxidant activity, related to the great concentration of malvidin, cyanidin, catechin and caffeic, cinnamic and gallic acids. Among the bioactive compounds, the juices presented high concentration of procyanidin B1, caffeic acid and trans-resveratrol, with higher levels compared to those reported in the literature. PMID- 26041209 TI - Physicochemical characterization of cactus pads from Opuntia dillenii and Opuntia ficus indica. AB - Physicochemical characteristics (weight, length, width, thickness, moisture, Brix degree, total fiber, protein, ash, pH, acidity, ascorbic acid, total phenolic compounds, P, Na, K, Ca, Mg, Fe, Cu, Zn, Mn and Cr) were determined in cactus pads from Opuntia dillenii and Opuntia ficus indica. The physicochemical characteristics of both species were clearly different. There were important differences between the orange and green fruit pulp of O. ficus indica; the cactus pads of O. dillenii could be differentiated according to the region (North and South). Consumption of cactus pads contributes to the intake of dietary fiber, total phenolic compounds, K, Mg, Mn and Cr. Applying factor and/or discriminant analysis, the cactus pad samples were clearly differentiated according to the species, the fruit pulp color and production region. PMID- 26041210 TI - Higher transcription levels in ascorbic acid biosynthetic and recycling genes were associated with higher ascorbic acid accumulation in blueberry. AB - In our preliminary study, the ripe fruits of two highbush blueberry (Vaccinium corymbosum L.) cultivars, cv 'Berkeley' and cv 'Bluecrop', were found to contain different levels of ascorbic acid. However, factors responsible for these differences are still unknown. In the present study, ascorbic acid content in fruits was compared with expression profiles of ascorbic acid biosynthetic and recycling genes between 'Bluecrop' and 'Berkeley' cultivars. The results indicated that the l-galactose pathway was the predominant route of ascorbic acid biosynthesis in blueberry fruits. Moreover, higher expression levels of the ascorbic acid biosynthetic genes GME, GGP, and GLDH, as well as the recycling genes MDHAR and DHAR, were associated with higher ascorbic acid content in 'Bluecrop' compared with 'Berkeley', which indicated that a higher efficiency ascorbic acid biosynthesis and regeneration was likely to be responsible for the higher ascorbic acid accumulation in 'Bluecrop'. PMID- 26041211 TI - High pressure treatments accelerate changes in volatile composition of sulphur dioxide-free wine during bottle storage. AB - The impact of high hydrostatic pressure (HHP) treatments on volatile composition of sulphur dioxide-free wines during bottle storage was studied. For this purpose, white and red wines were produced without sulphur dioxide (SO2) and, at the end of the alcoholic fermentation, the wines were pressurised at 500 MPa and 425 MPa for 5 min. Wine with 40 ppm of SO2 and a wine without a preservation treatment were used as controls. More than 160 volatile compounds, distributed over 12 chemical groups, were identified in the wines by an advanced gas chromatography technique. The pressurised wines contained a higher content of furans, aldehydes, ketones, and acetals, compared with unpressurised wines after 9 months of storage. The changes in the volatile composition indicate that HHP treatments accelerated the Maillard reaction, and alcohol and fatty acid oxidation, leading to wines with a volatile composition similar to those of faster aged and/or thermally treated wines. PMID- 26041212 TI - Detection and quantification of adulteration of sesame oils with vegetable oils using gas chromatography and multivariate data analysis. AB - This study was performed to develop a hierarchical approach for detection and quantification of adulteration of sesame oil with vegetable oils using gas chromatography (GC). At first, a model was constructed to discriminate the difference between authentic sesame oils and adulterated sesame oils using support vector machine (SVM) algorithm. Then, another SVM-based model is developed to identify the type of adulterant in the mixed oil. At last, prediction models for sesame oil were built for each kind of oil using partial least square method. To validate this approach, 746 samples were prepared by mixing authentic sesame oils with five types of vegetable oil. The prediction results show that the detection limit for authentication is as low as 5% in mixing ratio and the root-mean-square errors for prediction range from 1.19% to 4.29%, meaning that this approach is a valuable tool to detect and quantify the adulteration of sesame oil. PMID- 26041213 TI - Preparative HSCCC isolation of phloroglucinolysis products from grape seed polymeric proanthocyanidins as new powerful antioxidants. AB - Polymeric proanthocyanidins isolated from a grape seed phenolic extract were hydrolysed in the presence of phloroglucinol into monomer catechins and their nucleophile derivatives. Each of the phloroglucinolysis products was successfully separated and isolated in large amount by semi-preparative HSCCC technique under the optimized conditions based on a selection of suitable solvent system. The optimized solvent system consisted of n-hexane-ethyl acetate-water (1:80:80, v/v/v) with a combination of head-tail and tail-head elution modes. By only one step HSCCC separation, the purity of each obtained phloroglucinolysis product, including monomer catechins and their nucleophile derivatives was above 76%, verified by UPLC. The structures of these products were tentatively identified by UPLC based on their retention time and further confirmed by MS and (1)H NMR analysis. Furthermore, by DPPH, ABTS and FRAP assays, it was verified that all these phloroglucinolysis products possessed strong antioxidant activities, being catechin-nucleophile derivatives more powerful than free catechins. PMID- 26041215 TI - Characterization of an acidic cold-adapted cutinase from Thielavia terrestris and its application in flavor ester synthesis. AB - An acidic cutinase (TtcutB) from Thielavia terrestris CAU709 was purified to apparent homogeneity with 983 Um g(-1) specific activity. The molecular mass of the enzyme was estimated to be 27.3 and 27.9 kDa by SDS-PAGE and gel filtration, respectively. A peptide sequence homology search revealed no homologous cutinases from T. terrestris, except for one putative cutinase gene (XP003656017.1), indicating that TtcutB is a novel enzyme. TtcutB exhibited an acidic pH optimum of 4.0, and stability at pH 2.5-10.5. Optimal activity was at 55 degrees C, it was stable up to 65 degrees C, and retained over 30% activity at 0 degrees C. Km values toward p-nitrophenyl (pNP) acetate, pNP-butyrate and pNP-caproate were 8.3, 1.1 and 0.88 mM, respectively. The cutinase exhibited strong synthetic activity on flavor ester butyl butyrate under non-aqueous environment, and the highest esterification efficiency of 95% was observed under the optimized reaction conditions. The enzyme's unique biochemical properties suggest great potential in flavor esters-producing industries. PMID- 26041214 TI - Phenols and the antioxidant capacity of Mediterranean vegetables prepared with extra virgin olive oil using different domestic cooking techniques. AB - Potato, tomato, eggplant and pumpkin were deep fried, sauteed and boiled in Mediterranean extra virgin olive oil (EVOO), water, and a water/oil mixture (W/O). We determined the contents of fat, moisture, total phenols (TPC) and eighteen phenolic compounds, as well as antioxidant capacity in the raw vegetables and compared these with contents measured after cooking. Deep frying and sauteing led to increased fat contents and TPC, whereas both types of boiling (in water and W/O) reduced the same. The presence of EVOO in cooking increased the phenolics identified in the raw foods as oleuropein, pinoresinol, hydroxytyrosol and tyrosol, and the contents of vegetable phenolics such as chlorogenic acid and rutin. All the cooking methods conserved or increased the antioxidant capacity measured by DPPH, FRAP and ABTS. Multivariate analyses showed that each cooked vegetable developed specific phenolic and antioxidant activity profiles resulting from the characteristics of the raw vegetables and the cooking techniques. PMID- 26041216 TI - Sensitive simultaneous determination of three sulfanilamide artificial sweeters by capillary electrophoresis with on-line preconcentration and contactless conductivity detection. AB - A sensitive method followed by capillary electrophoresis with on-line perconcentration and capacitively coupled contactless conductivity detection (CE C(4)D) was evaluated as a novel approach for the determination of three sulfanilamide artificial sweeteners (acesulfame-K, sodium saccharin and sodium cyclamate) in beverages. The on-line preconcentration technique, namely field amplified sample injection, coupled with CE-C(4)D were successfully developed and optimized. The separation was achieved within 10 min under the following conditions: an uncoated fused-silica capillary (45 cm * 50 MUm i.d., Leff=40 cm), 20 mmol L(-1) HAc as running buffer, separation voltage of -12 kV, electrokinetic injection of -11 kV * 8 s. The detection limits of acesulfame-K, sodium saccharin and sodium cyclamate were 4.4, 6.7 and 8.8 MUg L(-1), respectively. The relative standard deviation varied in the range of 3.0-5.0%. Results of this study show a great potential method for the fast screening of these artificial sweeteners contents in commercial beverages. PMID- 26041217 TI - Subcritical extraction of flaxseed oil with n-propane: Composition and purity. AB - Flaxseed (Linum usitatissimum L.) oil was obtained via subcritical n-propane fluid extraction (SubFE) under different temperatures and pressures with an average yield of 28% and its composition, purity and oxidative stability were compared to oils obtained via conventional solvent extraction methods (SEMs). When the oxidative stability was measured by differential scanning calorimetry, the oil was found to be up to 5 times more resistant to lipid oxidation as compared to the SEM oils. Direct infusion electrospray ionization mass spectrometry (ESI-MS) analysis showed characteristic and similar TAG profiles for SubFE and SEMs oils but higher purity for the SubFE oil. The flaxseed oil content of beta-tocopherol, campesterol, stigmasterol and sitosterol were quantified via GC-MS. SubFE showed to be a promising alternative to conventional SEM since SubFE provides an oil with higher purity and higher oxidation stability and with comparable levels of biologically active components. PMID- 26041218 TI - Characteristics of rose hip (Rosa canina L.) cold-pressed oil and its oxidative stability studied by the differential scanning calorimetry method. AB - Two new commercially available high linolenic oils, pressed at low temperature from rose hip seeds, were characterised for their composition, quality and DPPH radical scavenging activity. The oxidative stability of oils was assessed using differential scanning calorimetry (DSC). Phytosterols, tocopherols and carotenoids contents were up to 6485.4; 1124.7; and 107.7 mg/kg, respectively. Phenolic compounds determined for the first time in rose hip oil totalled up to 783.55 MUg/kg, with a predominant presence of p-coumaric acid methyl ester. Antiradical activity of the oils reached up to 3.00 mM/kg TEAC. The acid, peroxide and p-anisidine values as well as iron and copper contents indicated good quality of the oils. Relatively high protection against oxidative stress in the oils seemed to be a result of their high antioxidant capacity and the level of unsaturation of fatty acids. PMID- 26041219 TI - Purification and characterization of antioxidant peptides from enzymatically hydrolyzed chicken egg white. AB - Egg white is considered as a rich source of high quality proteins with various bioactive peptide fractions. Enzymatic hydrolysis of proteins can be used to release bioactive fractions and different enzymes have different abilities in releasing such bioactive fractions depending on the enzyme's site of activity on a protein. In this study, several proteases were examined for their ability to release antioxidant peptides from hen egg white and protease P was selected based on the antioxidant activity and the digestion yield of the crude protein hydrolysate. A combination of several purification steps including ultrafiltration with low molecular weight cut-off membranes, cation exchange chromatography and reversed phase high performance liquid chromatography was used to purify 'protease P egg white hydrolysate'. Sixteen antioxidant peptides, which were derived from ovalbumin, ovotransferrin and cystatin were isolated from the most active fractions. Amino acid sequences of those peptides were determined using LC-MS/MS. Oxygen radical absorbance capacity (ORAC) values of selected short chain peptides were determined using synthetic peptides. Two peptides AEERYP and DEDTQAMP (Ala-Glu-Glu-Arg-Tyr-Pro and Asp-Glu-Asp-Thr-Gln-Ala-Met-Pro) showed the highest ORAC values. The results from this study indicate that egg white is rich in antioxidant peptides which can be used as a potential source for preparing bioactive ingredients using enzymatic hydrolysis followed by purification techniques. PMID- 26041220 TI - Suitability of bovine bile compared to urine for detection of free, sulfate and glucuronate boldenone, androstadienedione, cortisol, cortisone, prednisolone, prednisone and dexamethasone by LC-MS/MS. AB - The administration of boldenone and androstadienedione to cattle is forbidden in the European Union, while prednisolone is permitted for therapeutic purposes. They are pseudoendogenous substances (endogenously produced under certain circumstances). The commonly used matrices in control analyses are urine or liver. With the aim of improving the residue controls, we previously validated a method for steroid analysis in bile. We now compare urine (a 'classic' matrix) to bile, both collected at the slaughterhouse, to understand whether the detection of steroids in the latter is easier. With the aim of having clearer results, we tested the presence of the synthetic corticosteroid dexamethasone. The results show that bile does not substantially improve the detection of boldenone, or its conjugates, prednisolone and prednisone. Dexamethasone, instead, was found in 10 out of 53 bovine bile samples, but only in one urine sample from the same animals. Bile could constitute a novel matrix for the analysis of residues in food-producing animals, and possibly not only of synthetic corticosteroids. PMID- 26041221 TI - Meat composition, fatty acid profile and oxidative stability of meat from broilers supplemented with pomegranate (Punica granatum L.) by-products. AB - The effects of diets supplemented with four levels (0%, 0.5%, 1.0% and 2.0%) of pomegranate by-product (PB) on meat composition, fatty acid profile and oxidative stability of broiler meat were evaluated. The crude protein and moisture contents increased, whereas ether extract in breast and thigh meat and cholesterol in breast meat decreased in response to dietary PB supplementation (p<0.05). In breast and thigh meat, the sum of saturated fatty acids was lower, while the sum of mono-unsaturated and n-3 fatty acids were higher, alongside lower n-6/n-3 ratio in the 1.0% and 2.0% PB supplemented group (p<0.05). The TBARS values and pH of breast and thigh meat were reduced in the PB supplemented groups (p<0.05). Overall, the results presented herein indicate that supplementation of diets with up to 2% pomegranate by-products improved the meat composition, fatty acid profile and reduced lipid oxidation of broiler meat. PMID- 26041222 TI - Determination of melamine in milk and dairy products by microchip-based high field asymmetric ion mobility spectrometry combined with solid-phase extraction. AB - This article presents a method for sensitive, fast and quantitative determination of melamine in milk and dairy products using high-field asymmetric ion mobility spectrometry (FAIMS). The solid-phase extraction (SPE) technology was used for purification after the sample was extracted by organic solvents, and followed by the analysis of FAIMS. The measurement parameters and variables that affect the FAIMS detection have been investigated, and optimum conditions have been obtained as follows: the carrier gas flow rate is 1.6 L min(-1), the headspace sampler temperature is 150 degrees C, the pressure is 1 atm, and the humidity is 2.0 g m(-3). The results showed that the SPE-FAIMS method can detect melamine in samples with a concentration down to 0.1 mg kg(-1). The ion intensity has a linear relationship with melamine concentration in the range from 0.3 mg L(-1) to 25 mg L(-1), with a good linearity of 0.9975. The limits of detection (LOD) and limits of quantification (LOQ) are 0.1 mg kg(-1) and 0.3 mg kg(-1) in milk and dairy products, respectively, and the relative standard deviation is less than 8.0%. The results demonstrated that FAIMS has great potential as a powerful tool for food analysis and safety inspection. PMID- 26041223 TI - Assessing the bioavailability of polyphenols and antioxidant properties of extra virgin argan oil by simulated digestion and Caco-2 cell assays. Comparative study with extra virgin olive oil. AB - Argan oil is becoming increasingly popular in the edible-oil market as a luxury food with healthy properties. This paper analyzes (i) the bioavailability of the polyphenol content and antioxidant properties of extra virgin argan oil (EVA) by the combination of in vitro digestion and absorption across Caco-2 cells and (ii) the protective role of the oil bioaccessible fraction (BF) against induced oxidative stress. Results were compared with those obtained with extra virgin olive oil (EVO). Higher values of polyphenols and antioxidant activity were observed in the BF obtained after the in vitro digestion of oils compared with the initial chemical extracts; the increase was higher for EVA but absolute BF values were lower than EVO. Bioaccessible polyphenols from EVA were absorbed by Caco-2 cells in higher proportions than from EVO, and minor differences were observed for antioxidant activity. Preincubation of cell cultures with BF from both oils significantly protected against oxidation, limiting cell damage and reducing reactive oxygen species generation. PMID- 26041224 TI - Antioxidant properties of sterilized yacon (Smallanthus sonchifolius) tuber flour. AB - The objective of this research work was to investigate the antioxidant properties of sterilized yacon tuber flour. The results revealed for the first time the high antioxidant activity of sterilized yacon flour. The best extract obtained by boiling 8.9% (w/v) of yacon flour in deionised water for 10 min exhibited a total antioxidant capacity of 222+/-2 mg (ascorbic acid equivalent)/100 g DW and a total polyphenol content of 275+/-3 mg (gallic acid equivalent)/100 g DW associated to the presence of four main phenolic compounds: chlorogenic acid, caffeic acid, coumaric acid and protocatechuic acid, as well as the amino acid tryptophan. The most abundant was chlorogenic acid, followed by caffeic acid. Biological assays revealed that the extract had indeed antioxidant protection, and no pro-oxidant activity. In conclusion, sterilized yacon tuber flour has the potential to be used in the food industry as a food ingredient to produce functional food products. PMID- 26041225 TI - Enzymatic protein hydrolysates from high pressure-pretreated isolated pea proteins have better antioxidant properties than similar hydrolysates produced from heat pretreatment. AB - Isolated pea protein (IPP) dispersions (1%, w/v) were pretreated with high pressure (HP) of 200, 400, or 600 MPa for 5 min at 24 degrees C or high temperature (HT) for 30 min at 100 degrees C prior to hydrolysis with 1% (w/w) Alcalase. HP pretreatment of IPP at 400 and 600 MPa levels led to significantly (P<0.05) improved (>40%) oxygen radical absorption capacity (ORAC) of hydrolysates. 2,2-Diphenyl-1-picrylhydrazyl, superoxide radical and hydroxyl radical scavenging activities of pea protein hydrolysates were also significantly (P<0.05) improved (25%, 20%, and 40%, respectively) by HP pretreatment of IPP. Protein hydrolysates from HT IPP showed no ORAC, superoxide or hydroxyl scavenging activity but had significantly (P<0.05) improved (80%) ferric reducing antioxidant power. The protein hydrolysates had weaker antioxidant properties than glutathione but overall, the HP pretreatment was superior to HT pretreatment in facilitating enzymatic release of antioxidant peptides from IPP. PMID- 26041226 TI - Relationship of various flour properties with noodle making characteristics among durum wheat varieties. AB - The grain, flour, dough and noodle making properties of Indian durum wheat varieties were evaluated. Varieties having higher grain weight had lower hardness and higher yellow pigment content. Gluten performance index showed positive correlation with alpha-helix and negative with intermolecular+antiparallel-beta sheets in gluten. The proportion of extracted polymeric proteins was related to dough strength. Elastic (G') and loss (G") modulus of dough were positively correlated to intermolecular+antiparallel-beta-sheets and negatively with beta turn+ beta-sheets proportion of dough and gluten. PDW291 with exceptionally higher G' and G" and best noodle making properties showed the presence 90 kDa and 88 kDa polypeptides corresponding to 14+15 and type 2 banding pattern. PMID- 26041227 TI - Simultaneous extraction, identification and quantification of phenolic compounds in Eclipta prostrata using microwave-assisted extraction combined with HPLC-DAD ESI-MS/MS. AB - A simple and rapid method was developed using microwave-assisted extraction (MAE) combined with HPLC-DAD-ESI-MS/MS for the simultaneous extraction, identification, and quantification of phenolic compounds in Eclipta prostrata, a common herb and vegetable in China. The optimized parameters of MAE were: employing 50% ethanol as solvent, microwave power 400 W, temperature 70 degrees C, ratio of liquid/solid 30 mL/g and extraction time 2 min. Compared to conventional extraction methods, the optimized MAE can avoid the degradation of the phenolic compounds and simultaneously obtained the highest yields of all components faster with less consumption of solvent and energy. Six phenolic acids, six flavonoid glycosides and one coumarin were firstly identified. The phenolic compounds were quantified by HPLC-DAD with good linearity, precision, and accuracy. The extract obtained by MAE showed significant antioxidant activity. The proposed method provides a valuable and green analytical methodology for the investigation of phenolic components in natural plants. PMID- 26041228 TI - Onion skin waste as a valorization resource for the by-products quercetin and biosugar. AB - Onion skin waste (OSW), which is produced from processed onions, is a major industrial waste. We evaluated the use of OSW for biosugar and quercetin production. The carbohydrate content of OSW was analyzed, and the optimal conversion conditions were evaluated by varying enzyme mixtures and loading volumes for biosugar production and quercetin extraction. The enzymatic conversion rate of OSW to biosugar was 98.5% at 0.72 mg of cellulase, 0.16 mg of pectinase, and 1.0mg of xylanase per gram of dry OSW. Quercetin extraction also increased by 1.61-fold after complete enzymatic hydrolysis. In addition, the newly developed nano-matrix (terpyridine-immobilized silica-coated magnetic nanoparticles-zinc (TSMNP-Zn matrix) was utilized to separate quercetin from OSW extracts. The nano-matrix facilitated easy separation and purification of quercetin. Using the TSMNP-Zn matrix the quercetin was approximately 90% absorbed. In addition, the recovery yield of quercetin was approximately 75% after treatment with ethylenediaminetetraacetic acid. PMID- 26041229 TI - Biopolymer nanoparticles designed for polyunsaturated fatty acid vehiculization: Protein-polysaccharide ratio study. AB - Information about the design of biopolymer nanoparticles (BNPs) for polyunsaturated fatty acid (PUFA) vehiculization is provided. Linoleic acid (LA) was used as a model PUFA. The binding ability of LA to beta-lactoglobulin (BLG) was applied for obtaining BLG-LA complexes. BLG-LA complex formation was monitored by fluorimetry and it was observed that a moderate heat treatment (60 degrees C, 10 min) enhanced BLG-LA complexation. Obtaining BNPs involved the electrostatic deposition of high methoxyl pectin (HMP) onto the BLG-LA complex surface. The phase behavior of biopolymer systems was discussed at different Prot:HMP ratio (RProt:HMP, wt.%) levels (1:1-6:1). Absorbance at 600 nm, particle size, and zeta potential were analyzed at pH 4.0. At 1:1-2:1 RProt:HMP, BNPs showed appreciable turbidity, a nanometric diameter (337-364 nm), and a negative zeta potential. Finally, intrinsic and extrinsic fluorimetry was used for examining the HMP protective role at the LA binding site. At 2:1 RProt:HMP, HMP cover could promote significant LA protection in BNPs. PMID- 26041230 TI - Simultaneous determination of acrylamide, asparagine and glucose in food using short chain methyl imidazolium ionic liquid based ultrasonic assisted extraction coupled with analyte focusing by ionic liquid micelle collapse capillary electrophoresis. AB - Acrylamide (AA) is a known lethal neurotoxin and carcinogen. AA is formed in foods during the browning process by the Maillard reaction of glucose (GL) with asparagine (AS). For the first time, the simultaneous online preconcentration and separation of AA, AS and GL using analyte focusing by ionic liquid micelle collapse capillary electrophoresis (AFILMC) was presented. Samples were prepared in a 1-butyl-3-methylimidazolium bromide (BMIMBr) micellar matrix with a conductivity 4 times greater than that of the running buffer (12.5 mmol L(-1) phosphate buffer at pH 8.5). Samples were hydrodynamically injected into a fused silica capillary at 25.0 mbar for 25.0 s. Separations were performed by applying a voltage of 25.0 kV and a detection at 200.0 nm. To sufficiently reduce BMIMBr adsorption on the interior surface of capillary, an appropriate rinsing procedure by hydrochloric acid and water was optimized. AFILMC measurements of analytes within the concentration range of 0.05-10.0 MUmol L(-1) achieved adequate reproducibility and accuracy with RSD 1.14-3.42% (n=15) and recovery 98.0-110.0%, respectively. Limits of detections were 0.71 ng g(-1) AA, 1.06 ng g(-1) AS and 27.02 ng g(-1) GL with linearity ranged between 2.2 and 1800 ng g(-1). The coupling of AFILMC with IL based ultrasonic assisted extraction (ILUAE) was successfully applied to the efficient extraction and determination of AA, AS and GL in bread samples. The structure of ILs has significant effects on the extraction efficiency of analytes. The optimal extraction efficiency (97.8%) was achieved by an aqueous extraction with 4:14 ratio of sample: 3.0 mol L(-1) BMIMBr followed by sonication at 35 degrees C. The proposed combination of ILUAE and AFILMC was simple, ecofriendly, reliable and inexpensive to analyze a toxic compound and its precursors in bread which is applicable to food safety. PMID- 26041231 TI - Combined techniques for characterising pasta structure reveals how the gluten network slows enzymic digestion rate. AB - The aim of the present study is to characterise the influence of gluten structure on the kinetics of starch hydrolysis in pasta. Spaghetti and powdered pasta were prepared from three different cultivars of durum semolina, and starch was also purified from each cultivar. Digestion kinetic parameters were obtained through logarithm-of-slope analysis, allowing identification of sequential digestion steps. Purified starch and semolina were digested following a single first-order rate constant, while pasta and powdered pasta followed two sequential first-order rate constants. Rate coefficients were altered by pepsin hydrolysis. Confocal microscopy revealed that, following cooking, starch granules were completely swollen for starch, semolina and pasta powder samples. In pasta, they were completely swollen in the external regions, partially swollen in the intermediate region and almost intact in the pasta strand centre. Gluten entrapment accounts for sequential kinetic steps in starch digestion of pasta; the compact microstructure of pasta also reduces digestion rates. PMID- 26041232 TI - Biochemical characterization of three distinct polygalacturonases from Neosartorya fischeri P1. AB - Polygalacturonase is one of the most important industrial pectinases. To enrich the genetic resources and develop new enzyme candidates, three polygalacturonase genes (Nfpg I-III) of glycosyl hydrolase family 28 were cloned from Neosartorya fischeri P1 and functionally expressed in Pichia pastoris. The purified recombinant proteins exhibited some distinguished properties. In comparison with other counterparts, NfPG I showed the highest specific activity (40, 123 U/mg), NfPG II had the highest temperature optimum (65 degrees C), and the pH optimum of NfPG III was the lowest (3.5). The orders of their thermostability and resistance to chemicals tested were NfPG II>NfPG III>NfPG I and NfPG II>NfPG I>NfPG III, respectively. Combinations of these enzymes showed better performance than individuals in the processing and clarification of apple and strawberry juice. These results suggest that N. fischeri polygalacturonases have great application potentials in the food industry for juice production. PMID- 26041233 TI - Multi-element, multi-compound isotope profiling as a means to distinguish the geographical and varietal origin of fermented cocoa (Theobroma cacao L.) beans. AB - Multi-element stable isotope ratios have been assessed as a means to distinguish between fermented cocoa beans from different geographical and varietal origins. Isotope ratios and percentage composition for C and N were measured in different tissues (cotyledons, shells) and extracts (pure theobromine, defatted cocoa solids, protein, lipids) obtained from fermented cocoa bean samples. Sixty-one samples from 24 different geographical origins covering all four continental areas producing cocoa were analyzed. Treatment of the data with unsupervised (Principal Component Analysis) and supervised (Partial Least Squares Discriminant Analysis) multiparametric statistical methods allowed the cocoa beans from different origins to be distinguished. The most discriminant variables identified as responsible for geographical and varietal differences were the delta(15)N and delta(13)C values of cocoa beans and some extracts and tissues. It can be shown that the isotope ratios are correlated with the altitude and precipitation conditions found in the different cocoa-growing regions. PMID- 26041234 TI - Antioxidant properties, phenolic composition and potentiometric sensor array evaluation of commercial and new blueberry (Vaccinium corymbosum) and bog blueberry (Vaccinium uliginosum) genotypes. AB - Antioxidant properties of juices of newly bred and known blueberry (Vaccinium corymbosum) genotypes and wild bog blueberry (Vaccinium uliginosum) were evaluated by ABTS(+) scavenging capacity (RSC), ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), total phenolic content (TPC) and total anthocyanin content (TAC) assays. TPC varied in the range of 0.85-2.81 mg gallic acid equiv./mL, RSC, FRAP and ORAC values were 6.38-20.9, 3.07-17.8 and 4.21-45.68 MUmol Trolox equiv./g, respectively. New blueberry genotypes and bog blueberry demonstrated stronger antioxidant properties and TAC than other studied genotypes. The content of quinic (203-3614 MUg/mL), chlorogenic (20.0-346.8 MUg/mL) acids and rutin (0.00-26.88 MUg/mL) measured by UPLC/ESI-QTOF-MS varied depending on the genotype. Juices were evaluated by electronic tongue; PCA score plot showed that the method discriminates different genotypes although some juice samples were located very closely and overlapping. Significant differences were observed between L(*), a(*), b(*) colour parameters of some genotypes. PMID- 26041235 TI - Amino acid-catalyzed formation of 2-vinylfuran from lipid-derived 4-oxo-2 hexenal. AB - The formation of 2-vinylfuran from the corresponding 4-oxo-2-hexenal (OHE, a lipid oxidation product) under the catalysis of amino acid were studied. The effects of amino acids, reaction temperature, reaction time, water content, pH, metallic ions and some food additives on the formation of 2-vinylfuran were investigated. Amino acids promoted the formation of 2-vinylfuran except aspartic acid, histidine and glutamine. Cysteine showed the strongest catalytic activity among the amino acids tested. Further investigation indicated that the intermediate 1-(furan-2-yl)ethanol played an very important role in the formation of 2-vinylfuran. Both higher temperature and acidic condition favored the transformation of OHE into 2-vinylfuran. The reaction time, water content, metallic ions and food additives also influenced the reaction to certain extent. PMID- 26041236 TI - Quality control of fruit juices by using organic acids determined by capillary zone electrophoresis with poly(vinyl alcohol)-coated bubble cell capillaries. AB - An enhanced method for the determination of organic acids in several fruit juices by capillary zone electrophoresis (CZE) with direct UV-Vis detection has been developed in this work. First, a study with simulated real juice samples was done to find the best separation conditions. Next, several commercial fruit juices were analyzed, and the organic acid contents were quantified in less than 12 min using a poly(vinyl alcohol)-coated fused-silica 'bubble cell' capillary. The present method is reliable, fast and provides detection limits comprised between 0.1 and 2.5 MUg mL(-1). Moreover, different chemometric techniques, based on CZE data, were examined. Linear discriminant analysis allowed the differentiation of fruit juices according to the fruit type, whereas multiple linear regression models predicted the percentages of orange and pineapple juices in binary blends with grape. Thus, the present methodology is of utmost interest for routine and quality control purposes in food industries. PMID- 26041237 TI - Affinity maturation of single-chain variable fragment specific for aflatoxin B(1) using yeast surface display. AB - As aflatoxin B1 is one of the most toxic mycotoxins, it is important to detect and to quantify aflatoxin B1 accurately by immunological methods. To enhance aflatoxin B1-binding affinity of the single-chain variable fragment, yeast surface display technique combined with fluorescence-activated cell sorting was applied. A randomly mutated scFv library was subjected to 4 rounds of fluorescence-activated cell sorting, resulting in isolation of 5 scFv variants showing an affinity improvement compared to the parental wild type scFv. The best scFv with a 9-fold improvement in affinity for aflatoxin B1 exhibited similar specificity to the monoclonal antibody. Most of the mutations in scFv-M37 were located outside of the canonical antigen-contact loops, suggesting that its affinity improvement might be driven by an allosteric effect inducing scFv-M37 to form a more favorable binding pocket for aflatoxin B1 than the wild type scFv. PMID- 26041238 TI - Spray-drying microencapsulation of synergistic antioxidant mushroom extracts and their use as functional food ingredients. AB - In this work, hydroalcoholic extracts of two mushrooms species, Suillus luteus (L.: Fries) (Sl) and Coprinopsis atramentaria (Bull.) (Ca), were studied for their synergistic antioxidant effect and their viability as functional food ingredients tested by incorporation into a food matrix (cottage cheese). In a first step, the individual extracts and a combination of both, showing synergistic effects (Sl:Ca, 1:1), were microencapsulated by spray-drying using maltodextrin as the encapsulating material. The incorporation of free extracts resulted in products with a higher initial antioxidant activity (t0) but declining after 7 days (t7), which was associated with their degradation. However, the cottage cheese enriched with the microencapsulated extracts, that have revealed a lower activity at the initial time, showed an increase at t7. This improvement can be explained by an effective protection provided by the microspheres together with a sustained release. Analyses performed on the studied cottage cheese samples showed the maintenance of the nutritional properties and no colour modifications were noticed. PMID- 26041239 TI - Ultrasound-assisted ionic liquid dispersive liquid-liquid microextraction combined with graphite furnace atomic absorption spectrometric for selenium speciation in foods and beverages. AB - A rapid and environmentally friendly ultrasound assisted ionic liquid dispersive liquid liquid microextraction (USA-IL-DLLME) was developed for the speciation of inorganic selenium in beverages and total selenium in food samples by using graphite furnace atomic absorption spectrometry. Some analytical parameters including pH, amount of complexing agent, extraction time, volume of ionic liquid, sample volume, etc. were optimized. Matrix effects were also investigated. Enhancement factor (EF) and limit of detection (LOD) for Se(IV) were found to be 150 and 12 ng L(-1), respectively. The relative standard deviation (RSD) was found 4.2%. The accuracy of the method was confirmed with analysis of LGC 6010 Hard drinking water and NIST SRM 1573a Tomato leaves standard reference materials. Optimized method was applied to ice tea, soda and mineral water for the speciation of Se(IV) and Se(VI) and some food samples including beer, cow's milk, red wine, mixed fruit juice, date, apple, orange, grapefruit, egg and honey for the determination of total selenium. PMID- 26041240 TI - A review of modern instrumental techniques for measurements of ice cream characteristics. AB - There is an increasing demand of the food industries and research institutes to have means of measurement allowing the characterization of foods. Ice cream, as a complex food system, consists of a frozen matrix containing air bubbles, fat globules, ice crystals, and an unfrozen serum phase. Some deficiencies in conventional methods for testing this product encourage the use of alternative techniques such as rheometry, spectroscopy, X-ray, electro-analytical techniques, ultrasound, and laser. Despite the development of novel instrumental applications in food science, use of some of them in ice cream testing is few, but has shown promising results. Developing the novel methods should increase our understanding of characteristics of ice cream and may allow online testing of the product. This review article discusses the potential of destructive and non-destructive methodologies in determining the quality and characteristics of ice cream and similar products. PMID- 26041241 TI - Ultrastructure of underutilized tuber starches and its relation to physicochemical properties. AB - Starches from five underutilized tubers (canna, potato, Chinese yam, water chestnut, and taro) were extracted to investigate quantitative structure-property relationships (QSPR) in each starch using a combination of X-ray diffraction (XRD) and small-angle X-ray scattering (SAXS). Structural parameters of the tuber starches were determined using the paracrystalline model. Swelling power (SP), water solubility index (WSI), amylose leaching (AML), and thermal properties were also measured. The XRD results indicated that starches from Chinese yam, water chestnut, and taro are C-type starches with relatively high crystallinity (29.23 35.02%). In contrast, canna and potato starches are B-type starches exhibiting lower crystallinity and higher amylose content. The paracrystalline model provided a better fit for the C-type starches than for the B-type starches because the former was highly compressible (indicated by a higher "beta" value). B-type starches, on the other hand, tend to be more rigid along the lamellar repeat direction, requiring the layers to bend to accommodate internal stress. The QSPR analysis showed that three structural parameters, "O", "beta", and "Deltarhou", correlate well with the SP and WSI, and thus can be used to predict certain physicochemical properties. PMID- 26041242 TI - Ozone fumigation for safety and quality of wine grapes in postharvest dehydration. AB - This paper proposes postharvest ozone fumigation (as a method) to control microorganisms and evaluate the effect on polyphenols, anthocyanins, carotenoids and cell wall enzymes during the grape dehydration for wine production. Pignola grapes were ozone-treated (1.5 g/h) for 18 h (A=shock treatment), then dehydrated or ozone-treated (1.5 g/h) for 18 h and at 0.5 g/h for 4 h each day (B=long-term treatment) during dehydration. Treatment and dehydration were performed at 10 degrees C. No significant difference was found for total carotenoid, total phenolic and total anthocyanin contents after 18 h of O3 treatment. A significant decrease in phenolic and anthocyanin contents occurred during treatment B. Also carotenoids were affected by B ozone treatment. Pectin methylesterase (PME) and polygalacturonase (PG) activities were higher in A-treated grapes during dehydration. Finally, ozone reduced fungi and yeasts by 50%. Shock ozone fumigation (A treatment) before dehydration can be used to reduce the microbial count during dehydration without affecting polyphenol and carotenoid contents. PMID- 26041243 TI - Chemical fingerprinting of Gardenia jasminoides Ellis by HPLC-DAD-ESI-MS combined with chemometrics methods. AB - A fingerprint analysis method has been developed for characterization and discrimination of Gardenia jasminoides Ellis from different areas. The chemometrics methods including similarity evaluation, principal components analysis (PCA) and hierarchical clustering analysis (HCA) were introduced to identify more useful chemical markers for improving the quality control standard of dried ripe fruits of G. jasminoides Ellis. Then the selected chemical markers were analyzed by high performance liquid chromatography-diode array detection electrospray ionization mass spectrometry (HPLC-DAD-ESI-MS) qualitatively and quantitatively. 23 characteristic peaks were assigned while 19 peaks of them were identified by comparing retention times, UV and MS spectra with authentic compounds or literature data. Moreover, 14 of them were determined quantitatively which could effectively evaluate the quality of G. jasminoides Ellis. This study was expected to provide comprehensive information for the quality evaluation of G. jasminoides Ellis, which would be a valuable reference for further study and development of this herb and related medicinal products. PMID- 26041244 TI - Comparative study on the effects of nystose and fructofuranosyl nystose in the glycation reaction on the antigenicity and conformation of beta-lactoglobulin. AB - Our previous work indicated that the antigenicity of bovine beta-lactoglobulin (beta-LG) decreased after conjugation with fructo-oligosaccharides (FOS) which was related to its conformational changes. In attempt to unravel further changes of beta-LG antigenicity, nystose (GF3) and 1(F)-beta-fructofuranosyl nystose (GF4) of FOS were used to investigate the relationship between conformation and antigenicity. The antigenicity of beta-LG after conjugated with GF3 and GF4 decreased from 143.4 to 29.5 and 31.6 MUg/mL, respectively. The results of mass spectrometry revealed that the molecular weight of beta-LG increased from 18.4 to 19.8 and 19.1 kDa after conjugation with GF3 and GF4, respectively. It was shown that the conformational changes of beta-LG after conjugation with GF3 were bigger than that with GF4, including quenching of fluorescence intensity, the red-shift of fluorescence spectra, and the increase in sulfhydryl content. However, there was no significant difference in the antigenicity between beta-LG-GF3 and beta-LG GF4 conjugates (P>0.05). PMID- 26041245 TI - The effects of pre-salting methods on salt and water distribution of heavily salted cod, as analyzed by (1)H and (23)Na MRI, (23)Na NMR, low-field NMR and physicochemical analysis. AB - The effect of different pre-salting methods (brine injection with salt with/without polyphosphates, brining and pickling) on the water and salt distribution in dry salted Atlantic cod (Gadus morhua) fillets was studied with proton and sodium NMR and MRI methods, supported by physicochemical analysis of salt and water content as well as water holding capacity. The study indicated that double head brine injection with salt and phosphates lead to the least heterogeneous water distribution, while pickle salting had the least heterogeneous salt distribution. Fillets from all treatments contained spots with unsaturated brine, increasing the risk of microbial denaturation of the fillets during storage. Since a homogeneous water and salt distribution was not achieved with the studied pre-salting methods, further optimizations of the salting process, including the pre-salting and dry salting steps, must be made in the future. PMID- 26041246 TI - Improving and sustaining a reduction in iatrogenic pneumothorax through a multifaceted quality-improvement approach. AB - BACKGROUND: The Agency for Healthcare Research and Quality has adopted iatrogenic pneumothorax (IAP) as a Patient Safety Indicator. In 2006, in response to a low performance ranking for IAP rate from the University Healthsystem Consortium (UHC), the authors established a multidisciplinary team to reduce our institution's IAP rate. Root-cause analysis found that subclavian insertion of central venous catheterization (CVC) was the most common procedure associated with IAP OBJECTIVE: Our short-term goal was a 50% reduction of both CVC associated and all-cause IAP rates within 18 months, with long-term goals of sustained reduction. DESIGN: Observational study. SETTING: Academic tertiary care hospital. PATIENTS: Consecutive inpatients from 2006 to 2014. INTERVENTION: Our multifaceted intervention included: (1) clinical and documentation standards based on evidence, (2) cognitive aids, (3) simulation training, (4) purchase and deployment of ultrasound equipment, and (5) feedback to clinical services. MEASUREMENTS: CVC-associated IAP, all-cause IAP rate. RESULTS: We achieved both a short-term (years 2006 to 2008) and long-term (years 2006 to 2008-2014) reduction in our CVC-associated and all-cause IAP rates. Our short-term reduction in our CVC-associated IAP was 53% (P = 0.088), and our long-term reduction was 85% (P < 0.0001). Our short-term reduction in the all-cause IAP rate was 26% (P < 0.0001), and our long-term reduction was 61% (P < 0.0001). CONCLUSIONS: A multidisciplinary team, focused on evidence, patient safety, and standardization, can use a set of multifaceted interventions to sustainably improve patient outcomes for several years after implementation. Our hospital was in the highest performance UHC quartile for all-cause IAP in 2012 to 2014. PMID- 26041247 TI - Validation and application of a multi-residue method, using accelerated solvent extraction followed by gas chromatography, for pesticides quantification in soil. AB - A multi-residue method was developed to determine different types of pesticides in soils. An extraction with pressure and temperature, through accelerated solvent extraction (dichloromethane:acetone, 50:50, v/v). The pesticides were determined by gas chromatography with several selective detectors: electron capture detector, pulsed flame photometric detector and thermionic specific detector. The following parameters were determined: limit of detection, limit of quantification, equipment linearity (working interval), method linearity as well as, method accuracy and precision. The average recoveries ranged between 76 and 106%, with the exception of chlorothalonil, which had an average recovery of 46%. Additionally, detection limits from 0.9 to 7.6ng g -: (1) and the quantification limits from 3.00 to 25.47ng g -: (1) were estimated. In terms of linearity and precision, the results obtained were in the ranges considered adequate (R(2) >= 0.98 and coefficient of variation (CV) <= 20%), with the exception of aldrin (R(2) = 0.946, CV = 35.79%), lindane (R(2) = 0.917, CV = 32.91%) and chlorothalonil (R(2) = 0.8184, CV = 81.35%). The proposed method was used to evaluate pesticides in real soil samples, detecting concentrations over 1000ng g : (1) for some pesticides. The method was correctly validated and provided for the rapid determination of pesticides in soil. PMID- 26041248 TI - The simple determination method for anthocyanidin aglycones in fruits using ultra high-performance liquid chromatography. AB - The simple determination method for anthocyanidin aglycones in fruits using ultra high-performance liquid chromatography (UHPLC) coupled with the heating-block acidic hydrolysis method was validated through the precision, accuracy and linearity. The UHPLC separation was performed on a reversed-phase C18 column (particle size 2 MUm, i.d. 2 mm, length 100 mm) with a photodiode-array detector. The limits of detection and quantification of the UHPLC analyses were 0.09 and 0.29 mg/kg for delphinidin, 0.08 and 0.24 mg/kg for cyanidin, 0.09 and 0.26 mg/kg for petunidin, 0.14 and 0.42 mg/kg for pelargonidin, 0.16 and 0.48 mg/kg for peonidin and 0.30 and 0.91 mg/kg for malvidin, respectively. The intra- and inter day precisions of individual anthocyanidin aglycones were <10.3%. All calibration curves exhibited good linearity (r = 0.999) within the tested ranges. The total run time of UHPLC was 8 min. The simple preparation method with UHPLC detection in this study presented herein significantly improved the speed and the simplicity for preparation step of delphinidin, cyanidin, petunidin, pelargonidin, peonidin and malvidin in fruits. Especially, the UHPLC detection exhibited good resolution in spite of shorter run time about four times than conventional HPLC detection. PMID- 26041249 TI - Alpha-Synuclein Pathology in Sensory Nerve Terminals of the Upper Aerodigestive Tract of Parkinson's Disease Patients. AB - Dysphagia is common in Parkinson's disease (PD) and causes significant morbidity and mortality. PD dysphagia has usually been explained as dysfunction of central motor control, much like other motor symptoms that are characteristic of the disease. However, PD dysphagia does not correlate with severity of motor symptoms nor does it respond to motor therapies. It is known that PD patients have sensory deficits in the pharynx, and that impaired sensation may contribute to dysphagia. However, the underlying cause of the pharyngeal sensory deficits in PD is not known. We hypothesized that PD dysphagia with sensory deficits may be due to degeneration of the sensory nerve terminals in the upper aerodigestive tract (UAT). We have previously shown that Lewy-type synucleinopathy (LTS) is present in the main pharyngeal sensory nerves of PD patients, but not in controls. In this study, the sensory terminals in UAT mucosa were studied to discern the presence and distribution of LTS. Whole-mount specimens (tongue-pharynx-larynx upper esophagus) were obtained from 10 deceased human subjects with clinically diagnosed and neuropathologically confirmed PD (five with dysphagia and five without) and four age-matched healthy controls. Samples were taken from six sites and immunostained for phosphorylated alpha-synuclein (PAS). The results showed the presence of PAS-immunoreactive (PAS-ir) axons in all the PD subjects and in none of the controls. Notably, PD patients with dysphagia had more PAS-ir axons in the regions that are critical for initiating the swallowing reflex. These findings suggest that Lewy pathology affects mucosal sensory axons in specific regions of the UAT and may be related to PD dysphagia. PMID- 26041250 TI - Activity of the hypothalamus-pituitary-interrenal axis (HPI axis) and immune response in carp lines with different susceptibility to disease. AB - The stress response transmitted by the HPA axis is one of the best examples of neuroendocrine-immune interactions that are critical for survival. Analogous to the situation in mammals, the stress response in fish is characterized by the activation of the hypothalamo-pituitary-interrenal axis (HPI). Effects of cortisol on the fish immune system comply with findings in mammals and suggest that the differences in sensitivity to stress will influence the immune response and as a consequence of survival. Therefore, we studied the stress response and its immunity-related effects in four different carp lines (R3, R3xR8, K and R2) that display a differential pathogen susceptibility. Previous studies indicate that R3xR8 and R3 carp are susceptible to bacterial and parasite infection, while R2 and K are relatively resistant to infection. Interestingly, the most striking effect of stress on leukocyte composition and activity was observed in the pathogen-resistant K carp, even though no robust changes in gene expression of stress-involved factors were observed. In contrast, R3 carp showed no spectacular stress-induced changes in their immunological parameters with concurrent significant activation of the HPI axis. Upon stress, the R3 carp showed up regulation of crf, pomc and gr2 gene expression in the hypothalamus. Furthermore in R3 carp, at all levels of the HPI axis, stress induced the highest up regulation of il-1beta gene expression. Although we are aware of the complexity of the interactions between stress and pathogen susceptibility and of the risk of interpretation based on correlations, it is noteworthy that the fish more susceptible to infection also exhibited the highest response to stress. PMID- 26041251 TI - Perfusion dynamics in lower limb reconstruction: Investigating postoperative recovery and training using combined white light photospectroscopy and laser Doppler (O2C((r))). AB - BACKGROUND: Postoperative regimes designed to acclimatise lower limb free flaps to the changing flow dynamics of standing (flap training exercises) are widely employed despite a paucity of evidence for their use. This study utilises non invasive monitoring of perfusion parameters to investigate flap training at the microcirculatory level. METHODS: Eight prospective patients undergoing lower limb reconstruction with anterolateral thigh fasciocutaneous free flaps were enrolled. Combined tissue photospectroscopy and laser Doppler (O2C, LEA, Germany) was used to assess perfusion during five days of postoperative limb elevation and a subsequent three day flap training regime. Superficial Oxygen saturation (SO2), Haemoglobin concentration (rHb) and Flow measurements were taken. Readings were compared to pre-training control measurements. RESULTS: In the first five postoperative days of limb elevation, there were no significant changes in perfusion parameters. On commencement of flap training, 5 min of leg dependency resulted in mean decreases in SO2 of 45% on day 1 (p = 0.05) and 56% on day 2 (p = 0.02). Haemoglobin concentrations increased by 20% on day 1 (p = 0.01) and 26% on day 2 (p = 0.02). Flow decreased by 67% on day 1 (p = 0.19) and 78% day 2 (p = 0.03). On day 3 changes were observed to a lesser degree and only rHb increases remained statistically significant (p = 0.01). CONCLUSIONS: Prior to flap training, lower limb dependency causes reduced oxygenation, increased venous pooling and decreased flow consistent with venous congestion. Following a three day training regime, flap perfusion begins to accommodate for these changes. These findings provide a rationale for flap training, although further work is required to explain the mechanisms. PMID- 26041252 TI - Real time chemical imaging of a working catalytic membrane reactor during oxidative coupling of methane. AB - We report the results from an operando XRD-CT study of a working catalytic membrane reactor for the oxidative coupling of methane. These results reveal the importance of the evolving solid state chemistry during catalytic reaction, particularly the chemical interaction between the catalyst and the oxygen transport membrane. PMID- 26041253 TI - The 2014 Malcolm Ferguson-Smith Young Investigator Award. PMID- 26041254 TI - Comment on "Outcomes of critical congenital heart disease requiring emergent neonatal cardiac intervention": a new classification of congenital heart disease. PMID- 26041255 TI - A Case of Mediastinal Granular Cell Tumor with Horner's Syndrome. AB - Granular cell tumor (GCT) is found in various organs but is rare in the mediastinum. We report a case of mediastinal GCT in a 19-year-old woman who presented with left ptosis and miosis. CT and MRI revealed a 29-mm well circumscribed tumor located close to the first thoracic vertebra with features suggesting a neurogenic tumor. The tumor was completely excised using single-port video-assisted thoracoscopic surgery. Histopathological and immunohistochemical analysis revealed that the tumor was a benign GCT. Postoperatively, left ptosis and miosis had improved slightly. To our knowledge, this is the first report regarding mediastinal GCT presenting with preoperative Horner's syndrome. PMID- 26041256 TI - Sympathicotomy for palmar hyperhidrosis: the association between intraoperative palm temperature change and the curative effect. AB - PURPOSE: To investigate the association between intraoperative palm temperature change and the curative effect of sympathicotomy. METHODS: 49 patients with palmar hyperhidrosis were treated with bilateral endoscopic sympathicotomy. Ipsilateral palm temperature was monitored before and at 3-5 min increments after the sympathetic trunk was transected. The maximum temperature elevation (Tmax) was calculated and used to evaluate the effect on postoperative cure rates. RESULTS: Forty-nine patients underwent 98 sympathicotomies. There were 77 T4 sympathicotomies, 15 T4 + T5 sympathicotomies, and six T3 sympathicotomies due to pleural adhesions or neurovascular proximity. The Tmax was <=1 degrees C in 49 (50.0%), 1-1.5 degrees C in 17 (17.3%), and >1.5 degrees C in 32 (32.7%) palms. Ninety-two palms of 46 patients were followed with complete efficacy, and three patients were lost to follow up. Cure was achieved in 86 palms (93.4%). Of the 71 palms which underwent T4 sympathicotomy, cure was achieved in 67 palms (94.3%). In those palms which did not achieve cure, the Tmax was less than 1 degrees C in each case, while in palms with a Tmax <=1 degrees C, 32 of 36 (88.9%) were cured. CONCLUSION: There is an association between intraoperative palmar temperature change and curative effect. However, palmar temperature change cannot be used to predict cure or guide surgical approach. PMID- 26041257 TI - Imaging screw dislocations at atomic resolution by aberration-corrected electron optical sectioning. AB - Screw dislocations play an important role in materials' mechanical, electrical and optical properties. However, imaging the atomic displacements in screw dislocations remains challenging. Although advanced electron microscopy techniques have allowed atomic-scale characterization of edge dislocations from the conventional end-on view, for screw dislocations, the atoms are predominantly displaced parallel to the dislocation line, and therefore the screw displacements are parallel to the electron beam and become invisible when viewed end-on. Here we show that screw displacements can be imaged directly with the dislocation lying in a plane transverse to the electron beam by optical sectioning using annular dark field imaging in a scanning transmission electron microscope. Applying this technique to a mixed [a+c] dislocation in GaN allows direct imaging of a screw dissociation with a 1.65-nm dissociation distance, thereby demonstrating a new method for characterizing dislocation core structures. PMID- 26041258 TI - Erratum to: High performances of (18)F-fluorodeoxyglucose PET-CT in cardiac implantable device infections: A study of 40 patients. PMID- 26041259 TI - Heralded Quantum Entanglement between Distant Matter Qubits. AB - We propose a scheme to realize heralded quantum entanglement between two distant matter qubits using two Lambda atom systems. Our proposal does not need any photon interference. We also present a general theory of outcome state of non monochromatic incident light and finite interaction time. PMID- 26041260 TI - Criteria of Glycemic Control in Type 2 Diabetes Mellitus. AB - The paper presents the basic criteria for glycemic control in type 2 diabetes mellitus, the data on the relationship between postprandial glycemia and the development of the late vascular complications, and methods for evaluating the glycemic index of foodstuffs and dishes in order to optimize the diets and improve the efficiency of therapeutic measures in this disease. PMID- 26041261 TI - A TpyRu2+-based bismetallopolymer and its performance in catalytic water oxidation (Tpy = 4-(p-methoxyphenyl)-2,2':6',2''-terpyridine). AB - A bismetallo-organic polymer was successfully prepared by treating a metallo ligand with Ag(+); characterization was accomplished by NMR, UV-vis, and single crystal X-ray analyses. This heteronuclear polymer achieved more than a two-fold turnover number (TON) and a faster reaction rate in comparison to a Ce-driven Ru monomer in catalytic water oxidation. PMID- 26041262 TI - Genome-based, mechanism-driven computational modeling of risks of ionizing radiation: The next frontier in genetic risk estimation? AB - Research activity in the field of estimation of genetic risks of ionizing radiation to human populations started in the late 1940s and now appears to be passing through a plateau phase. This paper provides a background to the concepts, findings and methods of risk estimation that guided the field through the period of its growth to the beginning of the 21st century. It draws attention to several key facts: (a) thus far, genetic risk estimates have been made indirectly using mutation data collected in mouse radiation studies; (b) important uncertainties and unsolved problems remain, one notable example being that we still do not know the sensitivity of human female germ cells to radiation induced mutations; and (c) the concept that dominated the field thus far, namely, that radiation exposures to germ cells can result in single gene diseases in the descendants of those exposed has been replaced by the concept that radiation exposure can cause DNA deletions, often involving more than one gene. Genetic risk estimation now encompasses work devoted to studies on DNA deletions induced in human germ cells, their expected frequencies, and phenotypes and associated clinical consequences in the progeny. We argue that the time is ripe to embark on a human genome-based, mechanism-driven, computational modeling of genetic risks of ionizing radiation, and we present a provisional framework for catalyzing research in the field in the 21st century. PMID- 26041263 TI - How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models. AB - Several mutations in nuclear genes encoding for mitochondrial components have been associated with an increased cancer risk or are even causative, e.g. succinate dehydrogenase (SDHB, SDHC and SDHD genes) and iso-citrate dehydrogenase (IDH1 and IDH2 genes). Recently, studies have suggested an eminent role for mitochondrial DNA (mtDNA) mutations in the development of a wide variety of cancers. Various studies associated mtDNA abnormalities, including mutations, deletions, inversions and copy number alterations, with mitochondrial dysfunction. This might, explain the hampered cellular bioenergetics in many cancer cell types. Germline (e.g. m.10398A>G; m.6253T>C) and somatic mtDNA mutations as well as differences in mtDNA copy number seem to be associated with cancer risk. It seems that mtDNA can contribute as driver or as complementary gene mutation according to the multiple-hit model. This can enhance the mutagenic/clonogenic potential of the cell as observed for m.8993T>G or influences the metastatic potential in later stages of cancer progression. Alternatively, other mtDNA variations will be innocent passenger mutations in a tumor and therefore do not contribute to the tumorigenic or metastatic potential. In this review, we discuss how reported mtDNA variations interfere with cancer treatment and what implications this has on current successful pharmaceutical interventions. Mutations in MT-ND4 and mtDNA depletion have been reported to be involved in cisplatin resistance. Pharmaceutical impairment of OXPHOS by metformin can increase the efficiency of radiotherapy. To study mitochondrial dysfunction in cancer, different cellular models (like rho(0) cells or cybrids), in vivo murine models (xenografts and specific mtDNA mouse models in combination with a spontaneous cancer mouse model) and small animal models (e.g. Danio rerio) could be potentially interesting to use. For future research, we foresee that unraveling mtDNA variations can contribute to personalized therapy for specific cancer types and improve the outcome of the disease. PMID- 26041265 TI - Error-free DNA-damage tolerance in Saccharomyces cerevisiae. AB - DNA-damage tolerance (DDT) is an important mechanism for living cells to bypass replication blocks on the template strand. In Saccharomyces cerevisiae, DDT is mediated by the RAD6 epistasis group of genes, consisting of two parallel pathways: error-prone translesion DNA synthesis (TLS), and error-free lesion bypass. The two pathways are activated by sequential ubiquitination of PCNA on the Lys164 residue. When a replication fork is stalled at a lesion, PCNA is first monoubiquitinated by Rad6-Rad18, which leads to the TLS pathway. The subsequent ubiquitination by the Mms2-Ubc13-Rad5 complex on the monoubiquitinated PCNA is to form a Lys63-linked polyubiquitin chain that promotes error-free lesion bypass. While the TLS pathway has been extensively characterized, the molecular events leading to error-free lesion bypass by polyubiquitinated PCNA are largely obscure. Furthermore, PCNA can also be sumoylated at the same Lys164 residue, which helps to recruit Srs2, a helicase and anti-recombinase. This review summarizes recent advances in our understanding of error-free DDT and its interplay with Srs2 and homologous recombination. PMID- 26041266 TI - Magnetic resonance imaging (MRI): A review of genetic damage investigations. AB - Magnetic resonance imaging (MRI) is a powerful, non-invasive diagnostic medical imaging technique widely used to acquire detailed information about anatomy and function of different organs in the body, in both health and disease. It utilizes electromagnetic fields of three different frequency bands: static magnetic field (SMF), time-varying gradient magnetic fields (GMF) in the kHz range and pulsed radiofrequency fields (RF) in the MHz range. There have been some investigations examining the extent of genetic damage following exposure of bacterial and human cells to all three frequency bands of electromagnetic fields, as used during MRI: the rationale for these studies is the well documented evidence of positive correlation between significantly increased genetic damage and carcinogenesis. Overall, the published data were not sufficiently informative and useful because of the small sample size, inappropriate comparison of experimental groups, etc. Besides, when an increased damage was observed in MRI-exposed cells, the fate of such lesions was not further explored from multiple 'down-stream' events. This review provides: (i) information on the basic principles used in MRI technology, (ii) detailed experimental protocols, results and critical comments on the genetic damage investigations thus far conducted using MRI equipment and, (iii) a discussion on several gaps in knowledge in the current scientific literature on MRI. Comprehensive, international, multi-centered collaborative studies, using a common and widely used MRI exposure protocol (cardiac or brain scan) incorporating several genetic/epigenetic damage end-points as well as epidemiological investigations, in large number of individuals/patients are warranted to reduce and perhaps, eliminate uncertainties raised in genetic damage investigations in cells exposed in vitro and in vivo to MRI. PMID- 26041267 TI - Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment. AB - Benzo[a]pyrene (BaP) is a well-studied environmental compound that requires metabolic activation to have a carcinogenic effect. The neurotoxicity of BaP has received considerably less attention than its carcinogenicity. Environmental exposure to BaP correlates with impaired learning and memory in adults, and poor neurodevelopment in children. We carried out a comprehensive literature review to examine the neurotoxicity of BaP. The data were used to identify potential point of departure (POD) values for cancer and neurotoxicity endpoints using benchmark dose (BMD) modelling to compare the utility of both endpoints in the risk assessment of BaP. The POD for neurotoxicity in rodents, based on a standard behavioural test (Morris water maze), was 0.025 mg BaP/kg-bw-day compared to 0.54 mg BaP/kg-bw-day for rodent forestomach carcinogenicity, suggesting that neurotoxic endpoints are more sensitive than cancer endpoints for health risks associated with BaP exposure. Using the limited number of published studies on this topic, we propose a preliminary mode of action (MOA) to explain BaP-induced neurotoxicity in rodents. The MOA includes: (1) BaP binding to the aryl hydrocarbon receptor (AHR); (2) AHR-dependent modulation of the transcription of N-methyl-d-aspartate glutamate receptor (NMDAR) subunits; (3) NMDAR-mediated loss of neuronal activity and decreased long-term potentiation; and (4) compromised learning and memory. More data are needed to explore the proposed neurotoxic MOA. In addition, we consider alternative MOAs, including the hypothesis that BaP mediated DNA damage may lead to either carcinogenicity or neurotoxicity, depending on the tissue. Our proposed MOA is intended to serve as a basis for hypothesis testing in future studies. We emphasise that further studies are needed to validate the proposed MOA, to evaluate its human relevance, and to explore other potential mechanisms of BaP neurotoxicity. PMID- 26041264 TI - Functional genomic screening approaches in mechanistic toxicology and potential future applications of CRISPR-Cas9. AB - Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. Chemical toxicants act by many different mechanisms, however, and the genes involved in adverse outcome pathways (AOPs) and AOP networks are not yet characterized. Functional genomic approaches can reveal both toxicity pathways and susceptibility genes, through knockdown or knockout of all non-essential genes in a cell of interest, and identification of genes associated with a toxicity phenotype following toxicant exposure. Screening approaches in yeast and human near-haploid leukemic KBM7 cells have identified roles for genes and pathways involved in response to many toxicants but are limited by partial homology among yeast and human genes and limited relevance to normal diploid cells. RNA interference (RNAi) suppresses mRNA expression level but is limited by off-target effects (OTEs) and incomplete knockdown. The recently developed gene editing approach called clustered regularly interspaced short palindrome repeats associated nuclease (CRISPR)-Cas9, can precisely knock-out most regions of the genome at the DNA level with fewer OTEs than RNAi, in multiple human cell types, thus overcoming the limitations of the other approaches. It has been used to identify genes involved in the response to chemical and microbial toxicants in several human cell types and could readily be extended to the systematic screening of large numbers of environmental chemicals. CRISPR-Cas9 can also repress and activate gene expression, including that of non-coding RNA, with near saturation, thus offering the potential to more fully characterize AOPs and AOP networks. Finally, CRISPR-Cas9 can generate complex animal models in which to conduct preclinical toxicity testing at the level of individual genotypes or haplotypes. Therefore, CRISPR-Cas9 is a powerful and flexible functional genomic screening approach that can be harnessed to provide unprecedented mechanistic insight in the field of modern toxicology. PMID- 26041268 TI - Low-dose ionising radiation and cardiovascular diseases--Strategies for molecular epidemiological studies in Europe. AB - It is well established that high-dose ionising radiation causes cardiovascular diseases. In contrast, the evidence for a causal relationship between long-term risk of cardiovascular diseases after moderate doses (0.5-5 Gy) is suggestive and weak after low doses (<0.5 Gy). However, evidence is emerging that doses under 0.5 Gy may also increase long-term risk of cardiovascular disease. This would have major implications for radiation protection with respect to medical use of radiation for diagnostic purposes and occupational or environmental radiation exposure. Therefore, it is of great importance to gain information about the presence and possible magnitude of radiation-related cardiovascular disease risk at doses of less than 0.5 Gy. The biological mechanisms implicated in any such effects are unclear and results from epidemiological studies are inconsistent. Molecular epidemiological studies can improve the understanding of the pathogenesis and the risk estimation of radiation-induced circulatory disease at low doses. Within the European DoReMi (Low Dose Research towards Multidisciplinary Integration) project, strategies to conduct molecular epidemiological studies in this field have been developed and evaluated. Key potentially useful European cohorts are the Mayak workers, other nuclear workers, uranium miners, Chernobyl liquidators, the Techa river residents and several diagnostic or low-dose radiotherapy patient cohorts. Criteria for informative studies are given and biomarkers to be investigated suggested. A close collaboration between epidemiology, biology and dosimetry is recommended, not only among experts in the radiation field, but also those in cardiovascular diseases. PMID- 26041269 TI - G-quadruplexes: A possible epigenetic target for nutrition. AB - G-quadruplexes (G4) are highly stable tetra-stranded secondary DNA structures known to mediate gene regulation. These structures are resolved by DNA helicases and are believed to be a causal factor in the phenotype of premature ageing disorders following mutations in DNA helicase genes. The relevance of G4 structures in ageing may be further implicated by their dynamic relationship with DNA modification mechanisms. When DNA methylation and oxidation occur at the vicinity of G4 elements, they can affect the stability of G4 structures which may in turn mediate gene expression resulting in deleterious effects on genome integrity. Therefore, the influence of nutritional deficiencies or excess on oxidation and methylation mechanisms may be contributing factors affecting the stability of G4 structures and their balance in the human genome. We propose that dietary nutrients such as folate and antioxidants may play a beneficial role in reducing G4-induced DNA damage through changes in G4 structure stability. The current knowledge advocates the importance of resolving G4 structures by DNA helicases for sustained genome integrity, and the existence of stability changes in G4 structures when associated with DNA methylation and oxidation modifications. PMID- 26041270 TI - Protection of the genome and central protein-coding sequences by non-coding DNA against DNA damage from radiation. AB - Non-coding DNA comprises a very large proportion of the total genomic content in higher organisms, but its function remains largely unclear. Non-coding DNA sequences constitute the majority of peripheral heterochromatin, which has been hypothesized to be the genome's 'bodyguard' against DNA damage from chemicals and radiation for almost four decades. The bodyguard protective function of peripheral heterochromatin in genome defense has been strengthened by the results from numerous recent studies, which are summarized in this review. These data have suggested that cells and/or organisms with a higher level of heterochromatin and more non-coding DNA sequences, including longer telomeric DNA and rDNAs, exhibit a lower frequency of DNA damage, higher radioresistance and longer lifespan after IR exposure. In addition, the majority of heterochromatin is peripherally located in the three-dimensional structure of genome organization. Therefore, the peripheral heterochromatin with non-coding DNA could play a protective role in genome defense against DNA damage from ionizing radiation by both absorbing the radicals from water radiolysis in the cytosol and reducing the energy of IR. However, the bodyguard protection by heterochromatin has been challenged by the observation that DNA damage is less frequently detected in peripheral heterochromatin than in euchromatin, which is inconsistent with the expectation and simulation results. Previous studies have also shown that the DNA damage in peripheral heterochromatin is rarely repaired and moves more quickly, broadly and outwardly to approach the nuclear pore complex (NPC). Additionally, it has been shown that extrachromosomal circular DNAs (eccDNAs) are formed in the nucleus, highly detectable in the cytoplasm (particularly under stress conditions) and shuttle between the nucleus and the cytoplasm. Based on these studies, this review speculates that the sites of DNA damage in peripheral heterochromatin could occur more frequently and may be removed by repetitive elements in non-coding DNA through the formation of eccDNAs and expelled out of the nucleus to the cytoplasm via the NPC. Therefore, this review proposes that the genome and central protein-coding sequences are doubly protected by non coding DNA in peripheral heterochromatin against DNA damage from radiation, which may be a novel protective role of non-coding DNA in genome defense. PMID- 26041271 TI - Strength of object representation: its key role in object-based attention for determining the competition result between Gestalt and top-down objects. AB - It was found in previous studies that two types of objects (rectangles formed according to the Gestalt principle and Chinese words formed in a top-down fashion) can both induce an object-based effect. The aim of the present study was to investigate how the strength of an object representation affects the result of the competition between these two types of objects based on research carried out by Liu, Wang and Zhou [(2011) Acta Psychologica, 138(3), 397-404]. In Experiment 1, the rectangles were filled with two different colors to increase the strength of Gestalt object representation, and we found that the object effect changed significantly for the different stimulus types. Experiment 2 used Chinese words with various familiarities to manipulate the strength of the top-down object representation. As a result, the object-based effect induced by rectangles was observed only when the Chinese word familiarity was low. These results suggest that the strength of object representation determines the result of competition between different types of objects. PMID- 26041272 TI - Selective visual scaling of time-scale processes facilitates broadband learning of isometric force frequency tracking. AB - The experiment investigated the effect of selectively augmenting faster time scales of visual feedback information on the learning and transfer of continuous isometric force tracking tasks to test the generality of the self-organization of 1/f properties of force output. Three experimental groups tracked an irregular target pattern either under a standard fixed gain condition or with selectively enhancement in the visual feedback display of intermediate (4-8 Hz) or high (8-12 Hz) frequency components of the force output. All groups reduced tracking error over practice, with the error lowest in the intermediate scaling condition followed by the high scaling and fixed gain conditions, respectively. Selective visual scaling induced persistent changes across the frequency spectrum, with the strongest effect in the intermediate scaling condition and positive transfer to novel feedback displays. The findings reveal an interdependence of the timescales in the learning and transfer of isometric force output frequency structures consistent with 1/f process models of the time scales of motor output variability. PMID- 26041273 TI - Strategic top-down control versus attentional bias by previous reward history. AB - Rewards modify performance so that attentional priority is given to stimuli associated with a higher probability of reward. A stimulus associated with reward attracts attention even when it is no longer relevant. In this study, we explored whether or not strategic top-down control can be employed to overcome the attentional bias from a recent reward-stimulus association. Four groups of 12 participants completed a spatial-cueing task involving two phases, in which the cue associated with the target location changed from Phase 1 to Phase 2. Attentional-bias effects toward a previously rewarded cue were demonstrated when the rewarded cue from Phase 1 interfered with the orienting toward a nonrewarded but valid cue in Phase 2. Associating the Phase 2 cue with a higher reward than had been used in Phase 1 resulted in a rapid orientation of attention to the new cue. These findings suggest that pathologies characterized by maladaptive attentional biases (e.g., addiction) may be counteracted by treatments that manipulate motivation by enhancing the subjective relevance of rewards that are less harmful. PMID- 26041274 TI - Botulinum toxin type A injection for refractory interstitial cystitis: A randomized comparative study and predictors of treatment response. AB - OBJECTIVES: To determine whether botulinum toxin type A can represent an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies. METHODS: This is a single-center, prospective, open labeled, randomized comparative study. Patients with refractory interstitial cystitis were randomly divided into two groups: immediate injection (group A) or 1-month delayed injection (group B) of botulinum toxin type A after allocation. The rate of treatment response (global response assessment >=+1: slightly improved), and changes in symptom scores and frequency volume chart variables were compared between groups 1 month after allocation. Using subjects of both groups as a single cohort, predictive factors for treatment response at 1 month post-injection and the duration of response were explored. RESULTS: A total of 34 patients (group A n = 18, group B n = 16) were allocated. The response rate was significantly higher in group A than group B (72.2% vs 25.0%, P = 0.01). All symptom measures showed significant improvement in group A than group B. When both groups were combined as a single cohort, the response rate was 73.5% at 1 month, 58.8% at 3 months, 38.2% at 6 months and 20.6% at 12 months. The mean duration of response was 5.4 months. Multivariate analysis showed that past exposure to hydrodistension more than three times correlated with better outcomes. CONCLUSIONS: Botulinum toxin type A injection could be an alternative treatment option for patients with interstitial cystitis refractory to conventional therapies, especially for those who have received repeated hydrodistensions and transurethral fulguration. PMID- 26041275 TI - Is Seeing Believing? The Process of Change During Cognitive-behavioural Therapy for Distressing Visual Hallucinations. AB - People with psychosis often report distressing visual hallucinations (VH). In contrast to auditory hallucinations, there is little empirical evidence on effective interventions. The effectiveness of a novel-focused cognitive behavioural therapy (CBT) intervention for VH was explored using a multiple baseline single case design with four participants. Change to individual appraisals, emotional and behavioural responses to VH were measured with daily diaries kept throughout the baseline and intervention phase lasting up to 16 sessions. Maintenance of change was tracked during a follow-up period of one month. Changes in appraisals, distress and response in accordance with the theory was evident in two out of four of the cases. However, change occurred within the baseline phase that limited the conclusions that change could be attributed to CBT alone. There was some evidence of clinically significant change and reliable change for two out of four of the cases at follow-up on one of the standardized psychiatric assessments. The research reported here has theoretical and clinical implications for refinement of the model and interventions for distressing VH. Copyright (c) 2015 John Wiley & Sons, Ltd. KEY PRACTITIONER MESSAGE: Distressing visual hallucinations (VH) are a relatively common symptom of psychosis. Visual hallucinations seem to be associated with greater impairment and disability. We have no specific treatment for VH. The appraisal of the visual experience and the behavioural response is important in maintaining the distress. Cognitive behavioural therapy for VH at present has limited value. PMID- 26041276 TI - Epithelial Cadherin Determines Resistance to Infectious Pancreatic Necrosis Virus in Atlantic Salmon. AB - Infectious pancreatic necrosis virus (IPNV) is the cause of one of the most prevalent diseases in farmed Atlantic salmon (Salmo salar). A quantitative trait locus (QTL) has been found to be responsible for most of the genetic variation in resistance to the virus. Here we describe how a linkage disequilibrium-based test for deducing the QTL allele was developed, and how it was used to produce IPN resistant salmon, leading to a 75% decrease in the number of IPN outbreaks in the salmon farming industry. Furthermore, we describe how whole-genome sequencing of individuals with deduced QTL genotypes was used to map the QTL down to a region containing an epithelial cadherin (cdh1) gene. In a coimmunoprecipitation assay, the Cdh1 protein was found to bind to IPNV virions, strongly indicating that the protein is part of the machinery used by the virus for internalization. Immunofluorescence revealed that the virus colocalizes with IPNV in the endosomes of homozygous susceptible individuals but not in the endosomes of homozygous resistant individuals. A putative causal single nucleotide polymorphism was found within the full-length cdh1 gene, in phase with the QTL in all observed haplotypes except one; the absence of a single, all-explaining DNA polymorphism indicates that an additional causative polymorphism may contribute to the observed QTL genotype patterns. Cdh1 has earlier been shown to be necessary for the internalization of certain bacteria and fungi, but this is the first time the protein is implicated in internalization of a virus. PMID- 26041277 TI - Adrenal (131)I-6beta-iodomethylnorcholesterol scintigraphy in choosing the side for adrenalectomy in bilateral adrenal tumors with subclinical hypercortisolemia. AB - PURPOSE: Adrenal scintigraphy with 131I-6beta-iodomethylnorcholesterol is considered by several authors the gold standard for assessing tumors with subclinical hypercortisolemia. However, most of the described series consist mainly of cases with unilateral lesions. The aim of our study was to assess whether scintigraphy is useful in choosing the adrenalectomy side in the case of bilateral adrenal tumors with subclinical hypercortisolemia. METHODS: The study focused on 15 consecutive patients with benign bilateral adrenal tumors and subclinical hypercortisolemia. The scintigraphy with 131I-6beta iodomethylnorcholesterol was performed. Fourteen patients underwent unilateral adrenalectomy; the gland with predominant uptake on scintigraphy was removed. Cortisol and ACTH concentrations were measured one and six months after surgery. Post-dexamethasone cortisolemia was assessed six months after surgery. To date, the patients have been under postoperative observation for 1-4 years. RESULTS: Four patients showed unilateral uptake of radiotracer, and nine patients showed predominant accumulation of radiotracer in one of the adrenal glands. The smaller tumor was predominant in 2 cases. Percentage of activity on the predominant side correlates positively with the difference between tumors' diameters. Unilateral uptake of radiotracer predicts long-lasting postoperative insufficiency of the second adrenal gland. Excision of predominating tumor led to cessation of hypercortisolemia in all patients. CONCLUSIONS: The corticoadrenal scintigraphy is useful in choosing the side for operation in the case of bilateral adrenal tumors with subclinical hypercortisolemia. PMID- 26041278 TI - Combination with third-generation bisphosphonate (YM529) and interferon-alpha can inhibit the progression of established bone renal cell carcinoma. AB - The aim of this study was to investigate whether the third-generation nitrogen containing bisphosphonate (YM529) can inhibit the progression of established bone renal cell carcinoma (RCC) and to elucidate its mechanism. Antiproliferative effect and apoptosis induction of RCC cells and mouse osteoclasts by YM529 and/or interferon-alpha (IFN-alpha) were evaluated in vitro using cell counting and in vivo using soft X-ray, the TUNEL method and tartrate-resistant acid phosphatase stain. For the in vivo study, male athymic BALB/cA Jc1-nu nude mice bearing human RCC cell line RBM1-IT4 cells were treated with YM529 and/or IFN-alpha. The biological activity of osteoclasts was evaluated using the pit formation assay. The antiangiogenetic effect by YM529 and/or IFN-alpha was analyzed using micro vessel density and in situ mRNA hybridization. Osteoclast number in bone tumors was decreased in YM529-treated mouse. YM529 also inhibited osteoclast activity and proliferation in vitro, whereas basic fibroblast growth factor expressions and micro-vessel density within tumors were inhibited by IFN-alpha. Neither YM529 nor IFN-alpha alone significantly inhibited the growth of established bone metastatic tumors. Combined treatment with YM529 and IFN-alpha may be beneficial in patients with human RCC bone metastasis. Their effects are mediated by osteoclast recruitment inhibition and inactivation by YM529 and antiangiogenesis by IFN-alpha. PMID- 26041279 TI - Robust Protection against Highly Virulent Foot-and-Mouth Disease Virus in Swine by Combination Treatment with Recombinant Adenoviruses Expressing Porcine Alpha and Gamma Interferons and Multiple Small Interfering RNAs. AB - Because the currently available vaccines against foot-and-mouth disease (FMD) provide no protection until 4 to 7 days postvaccination, the only alternative method to halt the spread of the FMD virus (FMDV) during outbreaks is the application of antiviral agents. Combination treatment strategies have been used to enhance the efficacy of antiviral agents, and such strategies may be advantageous in overcoming viral mechanisms of resistance to antiviral treatments. We have developed recombinant adenoviruses (Ads) for the simultaneous expression of porcine alpha and gamma interferons (Ad-porcine IFN-alphagamma) as well as 3 small interfering RNAs (Ad-3siRNA) targeting FMDV mRNAs encoding nonstructural proteins. The antiviral effects of Ad-porcine IFN-alphagamma and Ad 3siRNA expression were tested in combination in porcine cells, suckling mice, and swine. We observed enhanced antiviral effects in porcine cells and mice as well as robust protection against the highly pathogenic strain O/Andong/SKR/2010 and increased expression of cytokines in swine following combination treatment. In addition, we showed that combination treatment was effective against all serotypes of FMDV. Therefore, we suggest that the combined treatment with Ad porcine IFN-alphagamma and Ad-3siRNA may offer fast-acting antiviral protection and be used with a vaccine during the period that the vaccine does not provide protection against FMD. IMPORTANCE: The use of current foot-and-mouth disease (FMD) vaccines to induce rapid protection provides limited effectiveness because the protection does not become effective until a minimum of 4 days after vaccination. Therefore, during outbreaks antiviral agents remain the only available treatment to confer rapid protection and reduce the spread of foot-and mouth disease virus (FMDV) in livestock until vaccine-induced protective immunity can become effective. Interferons (IFNs) and small interfering RNAs (siRNAs) have been reported to be effective antiviral agents against FMDV, although the virus has associated mechanisms of resistance to type I interferons and siRNAs. We have developed recombinant adenoviruses for the simultaneous expression of porcine alpha and gamma interferons (Ad-porcine IFN-alphagamma) as well as 3 small interfering RNAs (Ad-3siRNA) to enhance the inhibitory effects of these antiviral agents observed in previous studies. Here, we show enhanced antiviral effects against FMDV by combination treatment with Ad-porcine IFN-alphagamma and Ad 3siRNA to overcome the mechanisms of resistance of FMDV in swine. PMID- 26041280 TI - Tracking the Emergence of Host-Specific Simian Immunodeficiency Virus env and nef Populations Reveals nef Early Adaptation and Convergent Evolution in Brain of Naturally Progressing Rhesus Macaques. AB - While a clear understanding of the events leading to successful establishment of host-specific viral populations and productive infection in the central nervous system (CNS) has not yet been reached, the simian immunodeficiency virus (SIV) infected rhesus macaque provides a powerful model for the study of human immunodeficiency virus (HIV) intrahost evolution and neuropathogenesis. The evolution of the gp120 and nef genes, which encode two key proteins required for the establishment and maintenance of infection, was assessed in macaques that were intravenously inoculated with the same viral swarm and allowed to naturally progress to simian AIDS and potential SIV-associated encephalitis (SIVE). Longitudinal plasma samples and immune markers were monitored until terminal illness. Single-genome sequencing was employed to amplify full-length env through nef transcripts from plasma over time and from brain tissues at necropsy. nef sequences diverged from the founder virus faster than gp120 diverged. Host specific sequence populations were detected in nef (~92 days) before they were detected in gp120 (~182 days). At necropsy, similar brain nef sequences were found in different macaques, indicating convergent evolution, while gp120 brain sequences remained largely host specific. Molecular clock and selection analyses showed weaker clock-like behavior and stronger selection pressure in nef than in gp120, with the strongest nef selection in the macaque with SIVE. Rapid nef diversification, occurring prior to gp120 diversification, indicates that early adaptation of nef in the new host is essential for successful infection. Moreover, the convergent evolution of nef sequences in the CNS suggests a significant role for nef in establishing neurotropic strains. IMPORTANCE: The SIV infected rhesus macaque model closely resembles HIV-1 immunopathogenesis, neuropathogenesis, and disease progression in humans. Macaques were intravenously infected with identical viral swarms to investigate evolutionary patterns in the gp120 and nef genes leading to the emergence of host-specific viral populations and potentially linked to disease progression. Although each macaque exhibited unique immune profiles, macaque-specific nef sequences evolving under selection were consistently detected in plasma samples at 3 months postinfection, significantly earlier than in gp120 macaque-specific sequences. On the other hand, nef sequences in brain tissues, collected at necropsy of two animals with detectable infection in the central nervous system (CNS), revealed convergent evolution. The results not only indicate that early adaptation of nef in the new host may be essential for successful infection, but also suggest that specific nef variants may be required for SIV to efficiently invade CNS macrophages and/or enhance macrophage migration, resulting in HIV neuropathology. PMID- 26041281 TI - Poxvirus Protein MC132 from Molluscum Contagiosum Virus Inhibits NF-B Activation by Targeting p65 for Degradation. AB - Molluscum contagiosum virus (MCV) is unique in being the only known extant, human adapted poxvirus, yet to date, it is very poorly characterized in terms of host pathogen interactions. MCV causes persistent skin lesions filled with live virus, but these are generally immunologically silent, suggesting the presence of potent inhibitors of human antiviral immunity and inflammation. Fewer than five MCV immunomodulatory genes have been characterized in detail, but it is likely that many more remain to be discovered given the density of such sequences in all well characterized poxviruses. Following virus infection, NF-B activation occurs in response to both pattern recognition receptor (PRR) signaling and cellular activation by virus-elicited proinflammatory cytokines, such as tumor necrosis factor (TNF). As such, NF-B activation is required for virus detection, antiviral signaling, inflammation, and clearance of viral infection. Hence, we screened a library of MCV genes for effects on TNF-stimulated NF-B activation. This revealed MC132, a unique protein with no orthologs in other poxviral genomes, as a novel inhibitor of NF-B. Interestingly, MC132 also inhibited PRR- and virus-activated NF-B, since MC132 interacted with the NF-B subunit p65 and caused p65 degradation. Unbiased affinity purification to identify host targets of MC132 revealed that MC132 acted by targeting NF-B p65 for ubiquitin-dependent proteasomal degradation by recruiting p65 to a host Cullin-5/Elongin B/Elongin C complex. These data reveal a novel mechanism for poxviral inhibition of human innate immunity and further clarify how the human-adapted poxvirus MCV can so effectively evade antiviral immunity to persist in skin lesions. PMID- 26041282 TI - New Insights into the Understanding of Hepatitis C Virus Entry and Cell-to-Cell Transmission by Using the Ionophore Monensin A. AB - In our study, we characterized the effect of monensin, an ionophore that is known to raise the intracellular pH, on the hepatitis C virus (HCV) life cycle. We showed that monensin inhibits HCV entry in a pangenotypic and dose-dependent manner. Monensin induces an alkalization of intracellular organelles, leading to an inhibition of the fusion step between viral and cellular membranes. Interestingly, we demonstrated that HCV cell-to-cell transmission is dependent on the vesicular pH. Using the selective pressure of monensin, we selected a monensin-resistant virus which has evolved to use a new entry route that is partially pH and clathrin independent. Characterization of this mutant led to the identification of two mutations in envelope proteins, the Y297H mutation in E1 and the I399T mutation in hypervariable region 1 (HVR1) of E2, which confer resistance to monensin and thus allow HCV to use a pH-independent entry route. Interestingly, the I399T mutation introduces an N-glycosylation site within HVR1 and increases the density of virions and their sensitivity to neutralization with anti-apolipoprotein E (anti-ApoE) antibodies, suggesting that this mutation likely induces conformational changes in HVR1 that in turn modulate the association with ApoE. Strikingly, the I399T mutation dramatically reduces HCV cell-to-cell spread. In summary, we identified a mutation in HVR1 that overcomes the vesicular pH dependence, modifies the biophysical properties of particles, and drastically reduces cell-to-cell transmission, indicating that the regulation by HVR1 of particle association with ApoE might control the pH dependence of cell free and cell-to-cell transmission. Thus, HVR1 and ApoE are critical regulators of HCV propagation. IMPORTANCE: Although several cell surface proteins have been identified as entry factors for hepatitis C virus (HCV), the precise mechanisms regulating its transmission to hepatic cells are still unclear. In our study, we used monensin A, an ionophore that is known to raise the intracellular pH, and demonstrated that cell-free and cell-to-cell transmission pathways are both pH dependent processes. We generated monensin-resistant viruses that displayed different entry routes and biophysical properties. Thanks to these mutants, we highlighted the importance of hypervariable region 1 (HVR1) of the E2 envelope protein for the association of particles with apolipoprotein E, which in turn might control the pH dependency of cell-free and cell-to-cell transmission. PMID- 26041284 TI - Careers in Virology: Science Writing and Journalism. AB - This article condenses some highlights from a presentation that I have now given at several universities about the bench-to-newsroom career path. For readers who simply want a short explanation of how to parlay their hard-earned critical thinking skills from graduate school into a lucrative job in a growing industry, go to law school. PMID- 26041283 TI - mRNA Capping by Venezuelan Equine Encephalitis Virus nsP1: Functional Characterization and Implications for Antiviral Research. AB - Alphaviruses are known to possess a unique viral mRNA capping mechanism involving the viral nonstructural protein nsP1. This enzyme harbors methyltransferase (MTase) and nsP1 guanylylation (GT) activities catalyzing the transfer of the methyl group from S-adenosylmethionine (AdoMet) to the N7 position of a GTP molecule followed by the formation of an m(7)GMP-nsP1 adduct. Subsequent transfer of m(7)GMP onto the 5' end of the viral mRNA has not been demonstrated in vitro yet. Here we report the biochemical characterization of Venezuelan equine encephalitis virus (VEEV) nsP1. We have developed enzymatic assays uncoupling the different reactions steps catalyzed by nsP1. The MTase and GT reaction activities were followed using a nonhydrolyzable GTP (GIDP) substrate and an original Western blot assay using anti-m3G/m(7)G-cap monoclonal antibody, respectively. The GT reaction is stimulated by S-adenosyl-l-homocysteine (Ado-Hcy), the product of the preceding MTase reaction, and metallic ions. The covalent linking between nsP1 and m(7)GMP involves a phosphamide bond between the nucleotide and a histidine residue. Final guanylyltransfer onto RNA was observed for the first time with an alphavirus nsP1 using a 5'-diphosphate RNA oligonucleotide whose sequence corresponds to the 5' end of the viral genome. Alanine scanning mutagenesis of residues H37, H45, D63, E118, Y285, D354, R365, N369, and N375 revealed their respective roles in MT and GT reactions. Finally, the inhibitory effects of sinefungin, aurintricarboxylic acid (ATA), and ribavirin triphosphate on MTase and capping reactions were investigated, providing possible avenues for antiviral research. IMPORTANCE: Emergence or reemergence of alphaviruses represents a serious health concern, and the elucidation of their replication mechanisms is a prerequisite for the development of specific inhibitors targeting viral enzymes. In particular, alphaviruses are able, through an original reaction sequence, to add to their mRNA a cap required for their protection against cellular nucleases and initiation of viral proteins translation. In this study, the capping of a 5' diphosphate synthetic RNA mimicking the 5' end of an alphavirus mRNA was observed in vitro for the first time. The different steps for this capping are performed by the nonstructural protein 1 (nsP1). Reference compounds known to target the viral capping inhibited nsP1 enzymatic functions, highlighting the value of this enzyme in antiviral development. PMID- 26041285 TI - Influenza A Virus Coinfection through Transmission Can Support High Levels of Reassortment. AB - The reassortment of gene segments between influenza viruses increases genomic diversity and plays an important role in viral evolution. We have shown previously that this process is highly efficient within a coinfected cell and, given synchronous coinfection at moderate or high doses, can give rise to ~60 to 70% of progeny shed from an animal host. Conversely, reassortment in vivo can be rendered undetectable by lowering viral doses or extending the time between infections. One might also predict that seeding of transmitted viruses into different sites within the target tissue could limit subsequent reassortment. Given the potential for stochastic factors to restrict reassortment during natural infection, we sought to determine its efficiency in a host coinfected through transmission. Two scenarios were tested in a guinea pig model, using influenza A/Panama/2007/99 (H3N2) virus (wt) and a silently mutated variant (var) thereof as parental virus strains. In the first, coinfection was achieved by exposing a naive guinea pig to two cagemates, one infected with wt and the other with var virus. When such exposure led to coinfection, robust reassortment was typically seen, with 50 to 100% of isolates carrying reassortant genomes at one or more time points. In the second scenario, naive guinea pigs were exposed to a cagemate that had been coinoculated with wt and var viruses. Here, reassortment occurred in the coinoculated donor host, multiple variants were transmitted, and reassortants were prevalent in the recipient host. Together, these results demonstrate the immense potential for reassortment to generate viral diversity in nature. IMPORTANCE: Influenza viruses evolve rapidly under selection due to the generation of viral diversity through two mechanisms. The first is the introduction of random errors into the genome by the viral polymerase, which occurs with a frequency of approximately 10(-5) errors/nucleotide replicated. The second is reassortment, or the exchange of gene segments between viruses. Reassortment is known to occur readily under well-controlled laboratory conditions, but its frequency in nature is not clear. Here, we tested the hypothesis that reassortment efficiency following coinfection through transmission would be reduced compared to that seen with coinoculation. Contrary to this hypothesis, our results indicate that coinfection achieved through transmission supports high levels of reassortment. These results suggest that reassortment is not exquisitely sensitive to stochastic effects associated with transmission and likely occurs in nature whenever a host is infected productively with more than one influenza A virus. PMID- 26041286 TI - Intracellular Transport of Vaccinia Virus in HeLa Cells Requires WASH-VPEF/FAM21 Retromer Complexes and Recycling Molecules Rab11 and Rab22. AB - Vaccinia virus, the prototype of the Orthopoxvirus genus in the family Poxviridae, infects a wide range of cell lines and animals. Vaccinia mature virus particles of the WR strain reportedly enter HeLa cells through fluid-phase endocytosis. However, the intracellular trafficking process of the vaccinia mature virus between cellular uptake and membrane fusion remains unknown. We used live imaging of single virus particles with a combination of various cellular vesicle markers, to track fluorescent vaccinia mature virus particle movement in cells. Furthermore, we performed functional interference assays to perturb distinct vesicle trafficking processes in order to delineate the specific route undertaken by vaccinia mature virus prior to membrane fusion and virus core uncoating in cells. Our results showed that vaccinia virus traffics to early endosomes, where recycling endosome markers Rab11 and Rab22 are recruited to participate in subsequent virus trafficking prior to virus core uncoating in the cytoplasm. Furthermore, we identified WASH-VPEF/FAM21-retromer complexes that mediate endosome fission and sorting of virus-containing vesicles prior to virus core uncoating in the cytoplasm. IMPORTANCE: Vaccinia mature virions of the WR strain enter HeLa cells through fluid phase endocytosis. We previously demonstrated that virus-containing vesicles are internalized into phosphatidylinositol 3-phosphate positive macropinosomes, which are then fused with Rab5-positive early endosomes. However, the subsequent process of sorting the virion-containing vesicles prior to membrane fusion remains unclear. We dissected the intracellular trafficking pathway of vaccinia mature virions in cells up to virus core uncoating in cytoplasm. We show that vaccinia mature virions first travel to early endosomes. Subsequent trafficking events require the important endosome-tethered protein VPEF/FAM21, which recruits WASH and retromer protein complexes to the endosome. There, the complex executes endosomal membrane fission and cargo sorting to the Rab11-positive and Rab22-positive recycling pathway, resulting in membrane fusion and virus core uncoating in the cytoplasm. PMID- 26041287 TI - H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4+ T Cells. AB - Histone methyltransferase inhibitors (HMTis) and histone deacetylase inhibitors (HDACis) are reported to synergistically induce the expression of latent human immunodeficiency virus type 1 (HIV-1), but studies have largely been performed with cell lines. As specific and potent HMTis directed at EZH1 (enhancer of zeste 2 Polycomb repressive complex 2 subunit 1)/EZH2 are now in human testing, we wished to rigorously test such an inhibitor in a primary resting T-cell model of HIV latency. We found that GSK343, a potent and selective EZH2/EZH1 inhibitor, reduced trimethylation of histone 3 at lysine 27 (H3K27) of the HIV provirus in resting cells. Remarkably, this epigenetic change was not associated with increased proviral expression in latently infected resting cells. However, following the reduction in H3K27 at the HIV long terminal repeat (LTR), subsequent exposure to the HDACi suberoylanilide hydroxamic acid or vorinostat (VOR) resulted in increases in HIV gag RNA and HIV p24 antigen production that were up to 2.5-fold greater than those induced by VOR alone. Therefore, in primary resting CD4(+) T cells, true mechanistic synergy in the reversal of HIV latency may be achieved by the combination of HMTis and HDACis. Although other cellular effects of EZH2 inhibition may contribute to the sensitization of the HIV LTR to subsequent exposure to VOR, and to increase viral antigen production, this synergistic effect is directly associated with H3K27 demethylation at nucleosome 1 (Nuc-1). Based upon our findings, the combination of HMTis and HDACis should be considered for testing in animal models or clinical trials. IMPORTANCE: Demethylation of H3K27 mediated by the histone methyltransferase inhibitor GSK343 in primary resting T cells is slow, occurring over 96 h, but by itself does not result in a significant upregulation of cell-associated HIV RNA expression or viral antigen production. However, following H3K27 demethylation, latent viral expression within infected primary resting CD4(+) T cells is synergistically increased upon exposure to the histone deacetylase inhibitor vorinostat. Demethylation at H3K27 sensitizes the HIV promoter to the effects of an HDACi and provides a proof-of-concept for the testing of combination epigenetic approaches to disrupt latent HIV infection, a necessary step toward the eradication of HIV infection. PMID- 26041288 TI - The Torsin Activator LULL1 Is Required for Efficient Growth of Herpes Simplex Virus 1. AB - TorsinA is a membrane-tethered AAA+ ATPase implicated in nuclear envelope dynamics as well as the nuclear egress of herpes simplex virus 1 (HSV-1). The activity of TorsinA and the related ATPase TorsinB strictly depends on LAP1 and LULL1, type II transmembrane proteins that are integral parts of the Torsin/cofactor AAA ring, forming a composite, membrane-spanning assembly. Here, we use CRISPR/Cas9-mediated genome engineering to create single- and double knockout (KO) cell lines of TorA and TorB as well as their activators, LAP1 and LULL1, to investigate the effect on HSV-1 production. Consistent with LULL1 being the more potent Torsin activator, a LULL1 KO reduces HSV-1 growth by one order of magnitude, while the deletion of other components of the Torsin system in combination causes subtle defects. Notably, LULL1 deficiency leads to a 10-fold decrease in the number of viral genomes per host cell without affecting viral protein production, allowing us to tentatively assign LULL1 to an unexpected role that precedes HSV-1 nuclear egress. IMPORTANCE: In this study, we conduct the first comprehensive genetic and phenotypic analysis of the Torsin/cofactor system in the context of HSV-1 infection, establishing LULL1 as the most important component of the Torsin system with respect to viral production. PMID- 26041289 TI - Early Steps of Jaagsiekte Sheep Retrovirus-Mediated Cell Transformation Involve the Interaction between Env and the RALBP1 Cellular Protein. AB - Ovine pulmonary adenocarcinoma is a naturally occurring lung cancer in sheep induced by the Jaagsiekte sheep retrovirus (JSRV). Its envelope glycoprotein (Env) carries oncogenic properties, and its expression is sufficient to induce in vitro cell transformation and in vivo lung adenocarcinoma. The identification of cellular partners of the JSRV envelope remains crucial for deciphering mechanisms leading to cell transformation. We initially identified RALBP1 (RalA binding protein 1; also known as RLIP76 or RIP), a cellular protein implicated in the ras pathway, as a partner of JSRV Env by yeast two-hybrid screening and confirmed formation of RALBP1/Env complexes in mammalian cells. Expression of the RALBP1 protein was repressed in tumoral lungs and in tumor-derived alveolar type II cells. Through its inhibition using specific small interfering RNA (siRNA), we showed that RALBP1 was involved in envelope-induced cell transformation and in modulation of the mTOR (mammalian target of rapamycin)/p70S6K pathway by the retroviral envelope. IMPORTANCE: JSRV-induced lung adenocarcinoma is of importance for the sheep industry. While the envelope has been reported as the oncogenic determinant of the virus, the cellular proteins directly interacting with Env are still not known. Our report on the formation of RALBP/Env complexes and the role of this interaction in cell transformation opens up a new hypothesis for the dysregulation observed upon virus infection in sheep. PMID- 26041290 TI - Arenavirus Coinfections Are Common in Snakes with Boid Inclusion Body Disease. AB - Recently, novel arenaviruses were found in snakes with boid inclusion body disease (BIBD); these form the new genus Reptarenavirus within the family Arenaviridae. We used next-generation sequencing and de novo sequence assembly to investigate reptarenavirus isolates from our previous study. Four of the six isolates and all of the samples from snakes with BIBD contained at least two reptarenavirus species. The viruses sequenced comprise four novel reptarenavirus species and a representative of a new arenavirus genus. PMID- 26041291 TI - A Kinome-Wide Small Interfering RNA Screen Identifies Proviral and Antiviral Host Factors in Severe Acute Respiratory Syndrome Coronavirus Replication, Including Double-Stranded RNA-Activated Protein Kinase and Early Secretory Pathway Proteins. AB - To identify host factors relevant for severe acute respiratory syndrome coronavirus (SARS-CoV) replication, we performed a small interfering RNA (siRNA) library screen targeting the human kinome. Protein kinases are key regulators of many cellular functions, and the systematic knockdown of their expression should provide a broad perspective on factors and pathways promoting or antagonizing coronavirus replication. In addition to 40 proteins that promote SARS-CoV replication, our study identified 90 factors exhibiting an antiviral effect. Pathway analysis grouped subsets of these factors in specific cellular processes, including the innate immune response and the metabolism of complex lipids, which appear to play a role in SARS-CoV infection. Several factors were selected for in depth validation in follow-up experiments. In cells depleted for the beta2 subunit of the coatomer protein complex (COPB2), the strongest proviral hit, we observed reduced SARS-CoV protein expression and a >2-log reduction in virus yield. Knockdown of the COPB2-related proteins COPB1 and Golgi-specific brefeldin A-resistant guanine nucleotide exchange factor 1 (GBF1) also suggested that COPI coated vesicles and/or the early secretory pathway are important for SARS-CoV replication. Depletion of the antiviral double-stranded RNA-activated protein kinase (PKR) enhanced virus replication in the primary screen, and validation experiments confirmed increased SARS-CoV protein expression and virus production upon PKR depletion. In addition, cyclin-dependent kinase 6 (CDK6) was identified as a novel antiviral host factor in SARS-CoV replication. The inventory of pro- and antiviral host factors and pathways described here substantiates and expands our understanding of SARS-CoV replication and may contribute to the identification of novel targets for antiviral therapy. IMPORTANCE: Replication of all viruses, including SARS-CoV, depends on and is influenced by cellular pathways. Although substantial progress has been made in dissecting the coronavirus replicative cycle, our understanding of the host factors that stimulate (proviral factors) or restrict (antiviral factors) infection remains far from complete. To study the role of host proteins in SARS-CoV infection, we set out to systematically identify kinase-regulated processes that influence virus replication. Protein kinases are key regulators in signal transduction, controlling a wide variety of cellular processes, and many of them are targets of approved drugs and other compounds. Our screen identified a variety of hits and will form the basis for more detailed follow-up studies that should contribute to a better understanding of SARS-CoV replication and coronavirus-host interactions in general. The identified factors could be interesting targets for the development of host-directed antiviral therapy to treat infections with SARS-CoV or other pathogenic coronaviruses. PMID- 26041292 TI - A Dual-Modality Herpes Simplex Virus 2 Vaccine for Preventing Genital Herpes by Using Glycoprotein C and D Subunit Antigens To Induce Potent Antibody Responses and Adenovirus Vectors Containing Capsid and Tegument Proteins as T Cell Immunogens. AB - We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4(+) and CD8(+) T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model. IMPORTANCE: HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs. PMID- 26041293 TI - Coronavirus nsp10/nsp16 Methyltransferase Can Be Targeted by nsp10-Derived Peptide In Vitro and In Vivo To Reduce Replication and Pathogenesis. AB - The 5' cap structures of eukaryotic mRNAs are important for RNA stability and protein translation. Many viruses that replicate in the cytoplasm of eukaryotes have evolved 2'-O-methyltransferases (2'-O-MTase) to autonomously modify their mRNAs and carry a cap-1 structure (m7GpppNm) at the 5' end, thereby facilitating viral replication and escaping innate immune recognition in host cells. Previous studies showed that the 2'-O-MTase activity of severe acute respiratory syndrome coronavirus (SARS-CoV) nonstructural protein 16 (nsp16) needs to be activated by nsp10, whereas nsp16 of feline coronavirus (FCoV) alone possesses 2'-O-MTase activity (E. Decroly et al., J Virol 82:8071-8084, 2008, http://dx.doi.org/10.1128/JVI.00407-08; M. Bouvet et al., PLoS Pathog 6:e1000863, 2010, http://dx.doi.org/10.1371/journal.ppat.1000863; E. Decroly et al., PLoS Pathog 7:e1002059, 2011, http://dx.doi.org/10.1371/journal.ppat.1002059; Y. Chen et al., PLoS Pathog 7:e1002294, 2011, http://dx.doi.org/10.1371/journal.ppat.1002294) . In this study, we demonstrate that stimulation of nsp16 2'-O-MTase activity by nsp10 is a universal and conserved mechanism in coronaviruses, including FCoV, and that nsp10 is functionally interchangeable in the stimulation of nsp16 of different coronaviruses. Based on our current and previous studies, we designed a peptide (TP29) from the sequence of the interaction interface of mouse hepatitis virus (MHV) nsp10 and demonstrated that the peptide inhibits the 2'-O-MTase activity of different coronaviruses in biochemical assays and the viral replication in MHV infection and SARS-CoV replicon models. Interestingly, the peptide TP29 exerted robust inhibitory effects in vivo in MHV-infected mice by impairing MHV virulence and pathogenesis through suppressing virus replication and enhancing type I interferon production at an early stage of infection. Therefore, as a proof of principle, the current results indicate that coronavirus 2'-O-MTase activity can be targeted in vitro and in vivo. IMPORTANCE: Coronaviruses are important pathogens of animals and human with high zoonotic potential. SARS-CoV encodes the 2'-O-MTase that is composed of the catalytic subunit nsp16 and the stimulatory subunit nsp10 and plays an important role in virus genome replication and evasion from innate immunity. Our current results demonstrate that stimulation of nsp16 2'-O-MTase activity by nsp10 is a common mechanism for coronaviruses, and nsp10 is functionally interchangeable in the stimulation of nsp16 among different coronaviruses, which underlies the rationale for developing inhibitory peptides. We demonstrate that a peptide derived from the nsp16-interacting domain of MHV nsp10 could inhibit 2'-O-MTase activity of different coronaviruses in vitro and viral replication of MHV and SARS-CoV replicon in cell culture, and it could strongly inhibit virus replication and pathogenesis in MHV-infected mice. This work makes it possible to develop broad-spectrum peptide inhibitors by targeting the nsp16/nsp10 2'-O-MTase of coronaviruses. PMID- 26041294 TI - Herpes Simplex Virus 1 Reactivates from Autonomic Ciliary Ganglia Independently from Sensory Trigeminal Ganglia To Cause Recurrent Ocular Disease. AB - Herpes simplex virus 1 (HSV-1) and HSV-2 establish latency in sensory and autonomic neurons after ocular or genital infection, but their recurrence patterns differ. HSV-1 reactivates from latency to cause recurrent orofacial disease, and while HSV-1 also causes genital lesions, HSV-2 recurs more efficiently in the genital region and rarely causes ocular disease. The mechanisms regulating these anatomical preferences are unclear. To determine whether differences in latent infection and reactivation in autonomic ganglia contribute to differences in HSV-1 and HSV-2 anatomical preferences for recurrent disease, we compared HSV-1 and HSV-2 clinical disease, acute and latent viral loads, and viral gene expression in sensory trigeminal and autonomic superior cervical and ciliary ganglia in a guinea pig ocular infection model. HSV-2 produced more severe acute disease, correlating with higher viral DNA loads in sensory and autonomic ganglia, as well as higher levels of thymidine kinase expression, a marker of productive infection, in autonomic ganglia. HSV-1 reactivated in ciliary ganglia, independently from trigeminal ganglia, to cause more frequent recurrent symptoms, while HSV-2 replicated simultaneously in autonomic and sensory ganglia to cause more persistent disease. While both HSV-1 and HSV-2 expressed the latency-associated transcript (LAT) in the trigeminal and superior cervical ganglia, only HSV-1 expressed LAT in ciliary ganglia, suggesting that HSV-2 is not reactivation competent or does not fully establish latency in ciliary ganglia. Thus, differences in replication and viral gene expression in autonomic ganglia may contribute to differences in HSV-1 and HSV-2 acute and recurrent clinical disease. PMID- 26041295 TI - Mapping of a Region of the PA-X Protein of Influenza A Virus That Is Important for Its Shutoff Activity. AB - Influenza A virus PA-X comprises an N-terminal PA endonuclease domain and a C terminal PA-X-specific domain. PA-X reduces host and viral mRNA accumulation via its endonuclease function. Here, we found that the N-terminal 15 amino acids, particularly six basic amino acids, in the C-terminal PA-X-specific region are important for PA-X shutoff activity. These six basic amino acids enabled a PA deletion mutant to suppress protein expression at a level comparable to that of wild-type PA-X. PMID- 26041296 TI - Novel Arenavirus Entry Inhibitors Discovered by Using a Minigenome Rescue System for High-Throughput Drug Screening. AB - Certain members of the Arenaviridae family are category A agents capable of causing severe hemorrhagic fevers in humans. Specific antiviral treatments do not exist, and the only commonly used drug, ribavirin, has limited efficacy and can cause severe side effects. The discovery and development of new antivirals are inhibited by the biohazardous nature of the viruses, making them a relatively poorly understood group of human pathogens. We therefore adapted a reverse genetics minigenome (MG) rescue system based on Junin virus, the causative agent of Argentine hemorrhagic fever, for high-throughput screening (HTS). The MG rescue system recapitulates all stages of the virus life cycle and enables screening of small-molecule libraries under biosafety containment level 2 (BSL2) conditions. The HTS resulted in the identification of four candidate compounds with potent activity against a broad panel of arenaviruses, three of which were completely novel. The target for all 4 compounds was the stage of viral entry, which positions the compounds as potentially important leads for future development. IMPORTANCE: The arenavirus family includes several members that are highly pathogenic, causing acute viral hemorrhagic fevers with high mortality rates. No specific effective treatments exist, and although a vaccine is available for Junin virus, the causative agent of Argentine hemorrhagic fever, it is licensed for use only in areas where Argentine hemorrhagic fever is endemic. For these reasons, it is important to identify specific compounds that could be developed as antivirals against these deadly viruses. PMID- 26041297 TI - Inhibition of O-Linked N-Acetylglucosamine Transferase Reduces Replication of Herpes Simplex Virus and Human Cytomegalovirus. AB - O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential cellular enzyme that posttranslationally modifies nuclear and cytoplasmic proteins via O-linked addition of a single N-acetylglucosamine (GlcNAc) moiety. Among the many targets of OGT is host cell factor 1 (HCF-1), a transcriptional regulator that is required for transactivation of the immediate-early genes of herpes simplex virus (HSV). HCF-1 is synthesized as a large precursor that is proteolytically cleaved by OGT, which may regulate its biological function. In this study, we tested whether inhibition of the enzymatic activity of OGT with a small molecule inhibitor, OSMI-1, affects initiation of HSV immediate-early gene expression and viral replication. We found that inhibiting OGT's enzymatic activity significantly decreased HSV replication. The major effect of the inhibitor occurred late in the viral replication cycle, when it reduced the levels of late proteins and inhibited capsid formation. However, depleting OGT levels with small interfering RNA (siRNA) reduced the expression of HSV immediate early genes, in addition to reducing viral yields. In this study, we identified OGT as a novel cellular factor involved in HSV replication. Our results obtained using a small molecule inhibitor and siRNA depletion suggest that OGT's glycosylation and scaffolding functions play distinct roles in the replication cycle of HSV. IMPORTANCE: Antiviral agents can target viral or host gene products essential for viral replication. O-GlcNAc transferase (OGT) is an important cellular enzyme that catalyzes the posttranslational addition of GlcNAc sugar residues to hundreds of nuclear and cytoplasmic proteins, and this modification regulates their activity and function. Some of the known OGT targets are cellular proteins that are critical for the expression of herpes simplex virus (HSV) genes, suggesting a role for OGT in the replication cycle of HSV. In this study, we found that OGT is required for efficient expression of viral genes and for assembly of new virions. Thus, we identify OGT as a novel host factor involved in the replication of HSV and a potential target for antiviral therapy. PMID- 26041298 TI - Distinct Immune Responses in Resistant and Susceptible Strains of Mice during Neurovirulent Alphavirus Encephalomyelitis. AB - Susceptibility to alphavirus encephalomyelitis is dependent on a variety of factors, including the genetic background of the host. Neuroadapted Sindbis virus (NSV) causes uniformly fatal disease in adult C57BL/6 (B6) mice, but adult BALB/c (Bc) mice recover from infection. In B6 mice, fatal encephalomyelitis is immune mediated rather than a direct result of virus infection. To identify the immunological determinants of host susceptibility to fatal NSV-induced encephalomyelitis, we compared virus titers and immune responses in adult B6 and Bc mice infected intranasally with NSV. B6 mice had higher levels of virus replication, higher levels of type I interferon (IFN), and slower virus clearance than did Bc mice. B6 mice had more neuronal apoptosis, more severe neurologic disease, and higher mortality than Bc mice. B6 mice had more infiltration of inflammatory cells and higher levels of IL1b, IL-6, TNFa, Csf2, and CCL2 mRNAs and interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), IFN-gamma, and C-C motif ligand 2 (CCL2) protein in brains than Bc mice. However, Bc mice had more brain antibody at day 7 and a higher percentage of CD4(+) T cells. CD4(+) T cells in the brains of Bc mice included fewer Th17 cells and more regulatory T cells (Tregs) producing IL-10 than B6 mice, accompanied by higher levels of Il2 and Cxcl10 mRNAs. In the absence of IL-10, resistant Bc mice became susceptible to fatal encephalomyelitis after NSV infection. These studies demonstrate the importance of the immune response and its regulation in determining host survival during alphavirus encephalomyelitis. IMPORTANCE: Mosquito-borne alphavirus infections are an important cause of encephalomyelitis in humans. The severity of disease is dependent both on the strain of the virus and on the age and genetic background of the host. A neurovirulent strain of Sindbis virus causes immune mediated fatal encephalomyelitis in adult C57BL/6 mice but not in BALB/c mice. To determine the host-dependent immunological mechanisms underlying the differences in susceptibility between these two strains of mice, we compared their immune responses to infection. Resistance to fatal disease in BALB/c mice was associated with better antibody responses, more-rapid virus clearance, fewer Th17 cells, and more-potent regulatory T cell responses than occurred in susceptible C57BL/6 mice. In the absence of interleukin-10, a component of the regulatory immune response, resistant mice became susceptible to lethal disease. This study demonstrates the importance of the immune response and its regulation for host survival during alphavirus encephalomyelitis. PMID- 26041299 TI - Primer ID Validates Template Sampling Depth and Greatly Reduces the Error Rate of Next-Generation Sequencing of HIV-1 Genomic RNA Populations. AB - Validating the sampling depth and reducing sequencing errors are critical for studies of viral populations using next-generation sequencing (NGS). We previously described the use of Primer ID to tag each viral RNA template with a block of degenerate nucleotides in the cDNA primer. We now show that low abundance Primer IDs (offspring Primer IDs) are generated due to PCR/sequencing errors. These artifactual Primer IDs can be removed using a cutoff model for the number of reads required to make a template consensus sequence. We have modeled the fraction of sequences lost due to Primer ID resampling. For a typical sequencing run, less than 10% of the raw reads are lost to offspring Primer ID filtering and resampling. The remaining raw reads are used to correct for PCR resampling and sequencing errors. We also demonstrate that Primer ID reveals bias intrinsic to PCR, especially at low template input or utilization. cDNA synthesis and PCR convert ca. 20% of RNA templates into recoverable sequences, and 30-fold sequence coverage recovers most of these template sequences. We have directly measured the residual error rate to be around 1 in 10,000 nucleotides. We use this error rate and the Poisson distribution to define the cutoff to identify preexisting drug resistance mutations at low abundance in an HIV-infected subject. Collectively, these studies show that >90% of the raw sequence reads can be used to validate template sampling depth and to dramatically reduce the error rate in assessing a genetically diverse viral population using NGS. IMPORTANCE: Although next-generation sequencing (NGS) has revolutionized sequencing strategies, it suffers from serious limitations in defining sequence heterogeneity in a genetically diverse population, such as HIV-1 due to PCR resampling and PCR/sequencing errors. The Primer ID approach reveals the true sampling depth and greatly reduces errors. Knowing the sampling depth allows the construction of a model of how to maximize the recovery of sequences from input templates and to reduce resampling of the Primer ID so that appropriate multiplexing can be included in the experimental design. With the defined sampling depth and measured error rate, we are able to assign cutoffs for the accurate detection of minority variants in viral populations. This approach allows the power of NGS to be realized without having to guess about sampling depth or to ignore the problem of PCR resampling, while also being able to correct most of the errors in the data set. PMID- 26041300 TI - Broadly Neutralizing Human Immunodeficiency Virus Type 1 Antibody Gene Transfer Protects Nonhuman Primates from Mucosal Simian-Human Immunodeficiency Virus Infection. AB - Broadly neutralizing antibodies (bnAbs) can prevent lentiviral infection in nonhuman primates and may slow the spread of human immunodeficiency virus type 1 (HIV-1). Although protection by passive transfer of human bnAbs has been demonstrated in monkeys, durable expression is essential for its broader use in humans. Gene-based expression of bnAbs provides a potential solution to this problem, although immune responses to the viral vector or to the antibody may limit its durability and efficacy. Here, we delivered an adeno-associated viral vector encoding a simianized form of a CD4bs bnAb, VRC07, and evaluated its immunogenicity and protective efficacy. The expressed antibody circulated in macaques for 16 weeks at levels up to 66 g/ml, although immune suppression with cyclosporine (CsA) was needed to sustain expression. Gene-delivered simian VRC07 protected against simian-human immunodeficiency virus (SHIV) infection in monkeys 5.5 weeks after treatment. Gene transfer of an anti-HIV antibody can therefore protect against infection by viruses that cause AIDS in primates when the host immune responses are controlled. PMID- 26041301 TI - Frequency, Private Specificity, and Cross-Reactivity of Preexisting Hepatitis C Virus (HCV)-Specific CD8+ T Cells in HCV-Seronegative Individuals: Implications for Vaccine Responses. AB - T cell responses play a critical role in controlling or clearing viruses. Therefore, strategies to prevent or treat infections include boosting T cell responses. T cells specific for various pathogens have been reported in unexposed individuals and an influence of such cells on the response toward vaccines is conceivable. However, little is known about their frequency, repertoire, and impact on vaccination. We performed a detailed characterization of CD8(+) T cells specific to a hepatitis C virus (HCV) epitope (NS3-1073) in 121 HCV-seronegative individuals. We show that in vitro HCV NS3-1073-specific CD8(+) T cell responses were rather abundantly detectable in one-third of HCV-seronegative individuals irrespective of risk factors for HCV exposure. Ex vivo, these NS3-1073-specific CD8(+) T cells were found to be both naive and memory cells. Importantly, recognition of various peptides derived from unrelated viruses by NS3-1073 specific CD8(+) T cells showed a considerable degree of T cell cross-reactivity, suggesting that they might in part originate from previous heterologous infections. Finally, we further provide evidence that preexisting NS3-1073 specific CD8(+) T cells can impact the T cell response toward peptide vaccination. Healthy, vaccinated individuals who showed an in vitro response toward NS3-1073 already before vaccination displayed a more vigorous and earlier response toward the vaccine. IMPORTANCE: Preventive and therapeutic vaccines are being developed for many viral infections and often aim on inducing T cell responses. Despite effective antiviral drugs against HCV, there is still a need for a preventive vaccine. However, the responses to vaccines can be highly variable among different individuals. Preexisting T cells in unexposed individuals could be one reason that helps to explain the variable T cell responses to vaccines. Based on our findings, we suggest that HCV CD8(+) T cells are abundant in HCV-seronegative individuals but that their repertoire is highly diverse due to the involvement of both naive precursors and cross-reactive memory cells of different specificities, which can influence the response to vaccines. The data may emphasize the need to personalize immune-based therapies based on the individual's T cell repertoire that is present before the immune intervention. PMID- 26041302 TI - Head-to-Head Comparison of Poxvirus NYVAC and ALVAC Vectors Expressing Identical HIV-1 Clade C Immunogens in Prime-Boost Combination with Env Protein in Nonhuman Primates. AB - We compared the HIV-1-specific cellular and humoral immune responses elicited in rhesus macaques immunized with two poxvirus vectors (NYVAC and ALVAC) expressing the same HIV-1 antigens from clade C, Env gp140 as a trimeric cell-released protein and a Gag-Pol-Nef polyprotein as Gag-induced virus-like particles (VLPs) (referred to as NYVAC-C and ALVAC-C). The immunization protocol consisted of two doses of the corresponding poxvirus vector plus two doses of a combination of the poxvirus vector and a purified HIV-1 gp120 protein from clade C. This immunogenicity profile was also compared to that elicited by vaccine regimens consisting of two doses of the ALVAC vector expressing HIV-1 antigens from clades B/E (ALVAC-vCP1521) plus two doses of a combination of ALVAC-vCP1521 and HIV-1 gp120 protein from clades B/E (similar to the RV144 trial regimen) or clade C. The results showed that immunization of macaques with NYVAC-C stimulated at different times more potent HIV-1-specific CD4(+) T-cell responses and induced a trend toward higher-magnitude HIV-1-specific CD8(+) T-cell immune responses than did ALVAC-C. Furthermore, NYVAC-C induced a trend toward higher levels of binding IgG antibodies against clade C HIV-1 gp140, gp120, or murine leukemia virus (MuLV) gp70-scaffolded V1/V2 and toward best cross-clade-binding IgG responses against HIV-1 gp140 from clades A, B, and group M consensus, than did ALVAC-C. Of the linear binding IgG responses, most were directed against the V3 loop in all immunization groups. Additionally, NYVAC-C and ALVAC-C also induced similar levels of HIV-1-neutralizing antibodies and antibody-dependent cellular cytotoxicity (ADCC) responses. Interestingly, binding IgA antibody levels against HIV-1 gp120 or MuLV gp70-scaffolded V1/V2 were absent or very low in all immunization groups. Overall, these results provide a comprehensive survey of the immunogenicity of NYVAC versus ALVAC expressing HIV-1 antigens in nonhuman primates and indicate that NYVAC may represent an alternative candidate to ALVAC in the development of a future HIV-1 vaccine. IMPORTANCE: The finding of a safe and effective HIV/AIDS vaccine immunogen is one of the main research priorities. Here, we generated two poxvirus-based HIV vaccine candidates (NYVAC and ALVAC vectors) expressing the same clade C HIV-1 antigens in separate vectors, and we analyzed in nonhuman primates their immunogenicity profiles. The results showed that immunization with NYVAC-C induced a trend toward higher HIV-1-specific cellular and humoral immune responses than did ALVAC-C, indicating that this new NYVAC vector could be a novel optimized HIV/AIDS vaccine candidate for human clinical trials. PMID- 26041303 TI - Thioredoxin 2 Is a Novel E2-Interacting Protein That Inhibits the Replication of Classical Swine Fever Virus. AB - The E2 protein of classical swine fever virus (CSFV) is an envelope glycoprotein that is involved in virus attachment and entry. To date, the E2-interacting cellular proteins and their involvement in viral replication have been poorly documented. In this study, thioredoxin 2 (Trx2) was identified to be a novel E2 interacting partner using yeast two-hybrid screening from a porcine macrophage cDNA library. Trx2 is a mitochondrion-associated protein that participates in diverse cellular events. The Trx2-E2 interaction was further confirmed by glutathione S-transferase (GST) pulldown, in situ proximity ligation, and laser confocal assays. The thioredoxin domain of Trx2 and the asparagine at position 37 (N37) in the E2 protein were shown to be critical for the interaction. Silencing of the Trx2 expression in PK-15 cells by small interfering RNAs significantly promotes CSFV replication, and conversely, overexpression of Trx2 markedly inhibits viral replication of the wild-type (wt) CSFV and to a greater extent that of the CSFV N37D mutant, which is defective in binding Trx2. The wt CSFV but not the CSFV N37D mutant was shown to reduce the Trx2 protein expression in PK-15 cells. Furthermore, we demonstrated that Trx2 increases nuclear factor kappa B (NF-kappaB) promoter activity by promoting the nuclear translocation of the p65 subunit of NF-kappaB. Notably, activation of the NF-kappaB signaling pathway induced by tumor necrosis factor alpha (TNF-alpha) significantly inhibits CSFV replication in PK-15 cells, whereas blocking the NF-kappaB activation in Trx2 overexpressing cells no longer suppresses CSFV replication. Taken together, our findings reveal that Trx2 inhibits CSFV replication via the NF-kappaB signaling pathway. IMPORTANCE: Thioredoxin 2 (Trx2) is a mitochondrion-associated protein that participates in diverse cellular events, such as antioxidative and antiapoptotic processes and the modulation of transcription factors. However, little is known about the involvement of Trx2 in viral replication. Here, we investigated, for the first time, the role of Trx2 in the replication of classical swine fever virus (CSFV), a devastating pestivirus of pigs. By knockdown and overexpression, we showed that Trx2 negatively regulates CSFV replication. Notably, we demonstrated that Trx2 inhibits CSFV replication by promoting the nuclear translocation of the p65 subunit of NF-kappaB, a key regulator of the host's innate immunity and inflammatory response. Our findings reveal a novel role of Trx2 in the host's antiviral response and provide new insights into the complex mechanisms by which CSFV interacts with the host cell. PMID- 26041304 TI - The Fc-alpha receptor is a new target antigen for immunotherapy of myeloid leukemia. AB - Antibody-based immunotherapy of leukemia requires the targeting of specific antigens on the surface of blasts. The Fc gamma receptor (CD64) has been investigated in detail, and CD64-targeting immunotherapy has shown promising efficacy in the targeted ablation of acute myeloid leukemia (AML), acute myelomonocytic leukemia (AMML) and chronic myeloid leukemia cells (CML). Here we investigate for the first time the potential of FcalphaRI (CD89) as a new target antigen expressed by different myeloid leukemic cell populations. For specific targeting and killing, we generated a recombinant fusion protein comprising an anti-human CD89 single-chain Fragment variable and the well-characterized truncated version of the potent Pseudomonas aeruginosa exotoxin A (ETA'). Our novel therapeutic approach achieved in vitro EC50 values in range 0.2-3 nM depending on the applied stimuli, that is, interferon gamma or tumor necrosis factor alpha. We also observed a dose-dependent apoptosis-mediated cytotoxicity, which resulted in the elimination of up to 90% of the target cells within 72 hr. These findings were also confirmed ex vivo using leukemic primary cells from peripheral blood samples of three previously untreated patients. We conclude that CD89-specific targeting of leukemia cell lines can be achieved in vitro and that the efficient elimination of leukemic primary cells supports the potential of CD89-ETA' as a potent, novel immunotherapeutic agent. PMID- 26041305 TI - High Temporal Resolution Detection of Patient-Specific Glucose Uptake from Human ex Vivo Adipose Tissue On-Chip. AB - Human tissue in vitro models on-chip are highly desirable to dissect the complexity of a physio-pathological in vivo response because of their advantages compared to traditional static culture systems in terms of high control of microenvironmental conditions, including accurate perturbations and high temporal resolution analyses of medium outflow. Human adipose tissue (hAT) is a key player in metabolic disorders, such as Type 2 Diabetes Mellitus (T2DM). It is involved in the overall energy homeostasis not only as passive energy storage but also as an important metabolic regulator. Here, we aim at developing a large scale microfluidic platform for generating high temporal resolution of glucose uptake profiles, and consequently insulin sensitivity, under physio-pathological stimulations in ex vivo adipose tissues from nondiabetic and T2DM individuals. A multiscale mathematical model that integrates fluid dynamics and an intracellular insulin signaling pathway description was used for assisting microfluidic design in order to maximize measurement accuracy of tissue metabolic activity in response to perturbations. An automated microfluidic injection system was included on-chip for performing precise dynamic biochemical stimulations. The temporal evolution of culture conditions could be monitored for days, before and after perturbation, measuring glucose concentration in the outflow with high temporal resolution. As a proof of concept for detection of insulin resistance, we measured insulin-dependent glucose uptake by hAT from nondiabetic and T2DM subjects, mimicking the postprandial response. The system presented thus represents an important tool in dissecting the role of single tissues, such as hAT, in the complex interwoven picture of metabolic diseases. PMID- 26041306 TI - Significant association between vitamin D deficiency and sepsis: a systematic review and meta-analysis. AB - BACKGROUND: A number of observational studies have found an association between low vitamin D levels and risk of sepsis. We conducted a systematic review and meta-analysis to determine the overall estimate of risk. METHODS: This was a systematic review and meta-analysis conducted by online searches (CENTRAL, PubMed/MEDLINE, and EMBASE) was registered in PROSPERO (CRD42014014767). Primary outcome was incidence, prevalence, relative risk or odds ratio of having sepsis or bloodstream infection between patients with vitamin D deficiency and controls. RESULTS: The initial search yielded 647 articles. Twenty-one articles underwent full-length review and data were extracted from 10 observational studies. Pooled odds ratio of sepsis in participants with vitamin D deficiency was 1.78 (95% confidence interval [CI] = 1.55 to 2.03, p < 0.01) compared with controls in studies that reported participant numbers and was 1.45 (95% CI = 1.26 to 1.66, p < 0.01) in studies that reported an adjusted odds ratio of vitamin D deficiency for developing sepsis. Statistical between-study heterogeneity was low (I(2) = 0% and 5%, respectively). Standardized mean difference of 25-hydroxyvitamin D levels in patients with sepsis and controls was -0.24 (95% CI = -0.49 to 0.00, p = 0.05) and lower in the sepsis group compared with non-sepsis or control participants. The statistical between-study heterogeneity (I(2)) was 0%. CONCLUSION: Vitamin D deficiency were associated with an increased susceptibility of sepsis. PMID- 26041308 TI - Development and validation of a self-reported periodontal disease measure among Jordanians. AB - BACKGROUND: The development of self-reported measures of periodontal disease would be of great benefit to facilitate epidemiological studies of periodontal disease on a larger scale, and to allow for surveillance of the periodontal condition of populations over time. OBJECTIVES: To develop a culturally adapted self-reported measure of periodontal disease, test its predictive and discriminative validity and establish a cut-off value for this measure to diagnose periodontal disease. METHODS: A total of 288 Jordanian adults completed the questionnaire assessing self-reported periodontal health (18 questions) and underwent periodontal examination. Of the 18 questions, six were significantly associated with at least one clinical definition of periodontitis and were used to constitute the self-reported periodontal disease measure. Receiver-operating characteristics (ROC) curve analyses were used to examine the overall discriminatory power, sensitivity and specificity, and corresponding cut-off points of the self-reported periodontal disease measure. RESULTS: ROC analysis showed that the self-reported periodontal disease measure had an excellent performance to discriminate between those with and without periodontal disease, regardless of the clinical definition used. A score of 2, on a scale of 0 to 6, had the highest sensitivity and specificity to detect periodontal disease when defined by all study criteria. Significant associations were observed between self-reported periodontal disease measures and all clinical definitions in the regression analysis (the odds ratio ranged from 8.31 to 18.96), according to the clinical definition to be predicted. CONCLUSION: Self-reported periodontal disease measures have excellent predictive and discriminative validity when tested against clinical definitions, and severity and extent of periodontal disease. PMID- 26041307 TI - CagA of Helicobacter pylori interacts with and inhibits the serine-threonine kinase PRK2. AB - CagA is a multifunctional toxin of Helicobacter pylori that is secreted into host epithelial cells by a type IV secretion system. Following host cell translocation, CagA interferes with various host-cell signalling pathways. Most notably this toxin is involved in the disruption of apical-basolateral cell polarity and cell adhesion, as well as in the induction of cell proliferation, migration and cell morphological changes. These are processes that also play an important role in epithelial-to-mesenchymal transition and cancer cell invasion. In fact, CagA is considered as the only known bacterial oncoprotein. The cellular effects are triggered by a variety of CagA activities including the inhibition of serine-threonine kinase Par1b/MARK2 and the activation of tyrosine phosphatase SHP-2. Additionally, CagA was described to affect the activity of Src family kinases and C-terminal Src kinase (Csk) suggesting that interference with multiple cellular kinase- and phosphatase-associated signalling pathways is a major function of CagA. Here, we describe the effect of CagA on protein kinase C related kinase 2 (PRK2), which acts downstream of Rho GTPases and is known to affect cytoskeletal rearrangements and cell polarity. CagA interacts with PRK2 and inhibits its kinase activity. Because PRK2 has been linked to cytoskeletal rearrangements and establishment of cell polarity, we suggest that CagA may hijack PRK2 to further manipulate cancer-related signalling pathways. PMID- 26041309 TI - Appearances can be deceiving. PMID- 26041310 TI - Cardiac CT in asymptomatic diabetes mellitus: role of non-invasive atherosclerosis imaging in high-risk asymptomatic individuals. PMID- 26041311 TI - A putative multicopper oxidase, IoxA, is involved in iodide oxidation by Roseovarius sp. strain A-2. AB - Roseovarius sp. strain A-2 is an aerobic heterotrophic bacterium with a capacity for oxidizing iodide ion (I(-)) to form molecular iodine (I2). In this study, iodide-oxidizing enzyme of strain A-2 was characterized. The enzyme was an extracellular protein, and Cu(2+) ion significantly enhanced the enzyme activity in the culture supernatant. When iodide was used as the substrate, the crude enzyme showed Km and Vmax values of 4.78 mM and 25.1 U mg(-1), respectively. The enzyme was inhibited by NaN3, EDTA, KCN, and o-phenanthroline, and also had significant activities toward p-phenylenediamine and hydroquinone. Tandem mass spectrometric analysis of an active band excised from SDS-PAGE gel revealed that at least two proteins are involved in the enzyme. One of these proteins was closely related with IoxA, a multicopper oxidase previously found as a component of iodide-oxidizing enzyme of Alphaproteobacterium strain Q-1. Furthermore, a terrestrial bacterium Rhodanobacter denitrificans 116-2, which possesses an ioxA like gene in its genome, was found to oxidize iodide. These results suggest that IoxA catalyzes the oxidation of iodide in phylogenetically distinct bacteria. PMID- 26041312 TI - Honey feeding protects kidney against cisplatin nephrotoxicity through suppression of inflammation. AB - Cisplatin is a highly effective chemotherapeutic drug used to treat a wide variety of solid tumors. However, its use was limited due its dose-limiting toxicity to the kidney. Currently, there are no therapies available to treat or prevent cisplatin nephrotoxicity. Honey is a naturally occurring complex liquid and widely used in traditional Ayurvedic medicine to treat many illnesses. However, its effect on cisplatin nephrotoxicity is unknown. To determine the role of honey in cisplatin nephrotoxicity, animals were pretreated orally for a week and then cisplatin was administered. Honey feeding was continued for another 3 days. Our results show that animals with cisplatin-induced kidney dysfunction, as determined by increased serum creatinine, which received honey feeding had less kidney dysfunction. Improved kidney function was associated with better preservation of kidney morphology in honey-treated group as compared to the cisplatin alone-treated group. Interestingly, honey feeding significantly reduced cisplatin-induced tubular epithelial cell death, immune infiltration into the kidney as well as cytokine and chemokine expression and excretion as compared to cisplatin treated animals. Western blot analysis shows that cisplatin-induced increase in phosphorylation of NFkB was completely suppressed with honey feeding. In conclusion, honey feeding protects the kidney against cisplatin nephrotoxicity through suppression of inflammation and NFkB activation. PMID- 26041313 TI - Transcriptional responses of invasive and indigenous whiteflies to different host plants reveal their disparate capacity of adaptation. AB - The whitefly Bemisia tabaci contains more than 35 cryptic species. The higher adaptability of Middle East-Asia Minor 1 (MEAM1) cryptic species has been recognized as one important factor for its invasion and displacement of other indigenous species worldwide. Here we compared the performance of the invasive MEAM1 and the indigenous Asia II 3 whitefly species following host plant transfer from a suitable host (cotton) to an unsuitable host (tobacco) and analyzed their transcriptional responses. After transfer to tobacco for 24 h, MEAM1 performed much better than Asia II 3. Transcriptional analysis showed that the patterns of gene regulation were very different with most of the genes up-regulated in MEAM1 but down-regulated in Asia II 3. Whereas carbohydrate and energy metabolisms were repressed in Asia II 3, the gene expression and protein metabolisms were activated in MEAM1. Compared to the constitutive high expression of detoxification genes in MEAM1, most of the detoxification genes were down regulated in Asia II 3. Enzymatic activities of P450, GST and esterase further verified that the detoxification of MEAM1 was much higher than that of Asia II 3. These results reveal obvious differences in responses of MEAM1 and Asia II 3 to host transfer. PMID- 26041314 TI - Neuroprotection of Early Locomotor Exercise Poststroke: Evidence From Animal Studies. AB - Early locomotor exercise after stroke has attracted a great deal of attention in clinical and animal research in recent years. A series of animal studies showed that early locomotor exercise poststroke could protect against ischemic brain injury and improve functional outcomes through the promotion of angiogenesis, inhibition of acute inflammatory response and neuron apoptosis, and protection of the blood-brain barrier. However, to date, the clinical application of early locomotor exercise poststroke was limited because some clinicians have little confidence in its effectiveness. Here we review the current progress of early locomotor exercise poststroke in animal models. We hope that a comprehensive awareness of the early locomotor exercise poststroke may help to implement early locomotor exercise more appropriately in treatment for ischemic stroke. PMID- 26041315 TI - Vasectomy and risk of prostate cancer: a systematic review and meta-analysis of cohort studies. AB - The results of published literature focusing on the association between vasectomy and the incidence of prostate cancer are often inconsistent. We conducted a meta analysis to provide a quantitative assessment of the association between vasectomy and the risk of prostate cancer. We identified all cohort studies by searching the PubMed, Embase, and Cochrane Library before August 2014. The quality of the studies was evaluated using the Newcastle-Ottawa Scale checklist. Summary effect estimates with 95% confidence intervals (CI) were derived using a fixed or random effects model, depending on the heterogeneity of the included studies. Nine cohort studies that spanned across two continents involving 1 127 096 participants (ages 20-75) with 7539 cases of prostate cancer cases were included in the meta-analysis. The overall combined relative risks for men with the reference group were 1.08 (95% CI: 0.87-1.34) in a random effects, however, the association was not statistically significant (p = 0.48). Estimates of total effects were generally consistent in the sensitivity and subgroup analyses. No evidence of publication bias was observed. This meta-analysis indicated that vasectomy may not contribute to the risk of prostate cancer. The conclusion might have a far-reaching significance for the public health, especially in countries with high prevalence rates of vasectomy. PMID- 26041316 TI - A randomized clinical trial of the effects of ultra-low-dose naloxone infusion on postoperative opioid requirements and recovery. AB - BACKGROUND: Tolerance to remifentanil during sevoflurane anesthesia may increase postoperative analgesic requirements. Low-dose naloxone not only has been shown to block the development of acute opioid tolerance but also to ameliorate undesired opioid-induced side effects. We hypothesized that naloxone prevents the acute opioid tolerance produced by a large dose of remifentanil, and reduces the incidence of opioid-induced side effects. METHODS: Seventy-two patients undergoing open colorectal surgery were randomly assigned to receive intraoperative remifentanil (1) small dose at 0.1 MUg/kg/min; (2) large dose at 0.30 MUg/kg/min; or (3) large dose at 0.30 MUg/kg/min combined with low-dose naloxone at 0.25 MUg/kg/h just after the induction. Cumulative morphine consumption, postoperative pain scores, incidence of opioid-related side effects, time to recovery of bowel function, and length of hospital stay were recorded. RESULTS: Cumulative morphine consumption at 24 h after surgery was higher in the large-dose remifentanil group (28 +/- 12 mg) compared with the small-dose remifentanil group (17 +/- 12 mg), and large-dose remifentanil-naloxone group (18 +/- 9 mg), (P < 0.001). The median time to return of bowel function was shorter in the large-dose remifentanil-naloxone group than the other two groups (P < 0.05). The median length of hospital stay was lower in the large-dose remifentanil-naloxone group (8 [interquartile range: 8-12] days) compared with the small-dose remifentanil group (12 [interquartile range: 9-15] days) and large dose remifentanil group (12 [interquartile range: 10-13] days), (P < 0.001). CONCLUSION: Naloxone infusion prevented the acute opioid tolerance, provided a quicker recovery of bowel function, and reduced the length of hospital stay after open colorectal surgery. PMID- 26041317 TI - Intensive field phenotyping of maize (Zea mays L.) root crowns identifies phenes and phene integration associated with plant growth and nitrogen acquisition. AB - Root architecture is an important regulator of nitrogen (N) acquisition. Existing methods to phenotype the root architecture of cereal crops are generally limited to seedlings or to the outer roots of mature root crowns. The functional integration of root phenes is poorly understood. In this study, intensive phenotyping of mature root crowns of maize was conducted to discover phenes and phene modules related to N acquisition. Twelve maize genotypes were grown under replete and deficient N regimes in the field in South Africa and eight in the USA. An image was captured for every whorl of nodal roots in each crown. Custom software was used to measure root phenes including nodal occupancy, angle, diameter, distance to branching, lateral branching, and lateral length. Variation existed for all root phenes within maize root crowns. Size-related phenes such as diameter and number were substantially influenced by nodal position, while angle, lateral density, and distance to branching were not. Greater distance to branching, the length from the shoot to the emergence of laterals, is proposed to be a novel phene state that minimizes placing roots in already explored soil. Root phenes from both older and younger whorls of nodal roots contributed to variation in shoot mass and N uptake. The additive integration of root phenes accounted for 70% of the variation observed in shoot mass in low N soil. These results demonstrate the utility of intensive phenotyping of mature root systems, as well as the importance of phene integration in soil resource acquisition. PMID- 26041318 TI - Novel imaging-based phenotyping strategies for dissecting crosstalk in plant development. AB - In an era of genomics, proteomics, and metabolomics a large number of mutants are available. The discovery of their phenotypes is fast becoming the bottleneck of molecular plant physiology. This crisis can be overcome by imaging-based phenotyping, an emerging, rapidly developing and innovative approach integrating plant and computer science. A tremendous amount of digital image data are automatically analysed using techniques of 'machine vision'. This minireview will shed light on the available imaging strategies and discuss standard methods for the automated analysis of images to give the non-bioinformatic reader an idea how the new technology works. A number of successful platforms will be described and the prospects that image-based phenomics may offer for elucidating hormonal cross talk and molecular growth physiology will be discussed. PMID- 26041319 TI - Post-translational modifications of hormone-responsive transcription factors: the next level of regulation. AB - Plants exhibit a high level of developmental plasticity and growth is responsive to multiple developmental and environmental cues. Hormones are small endogenous signalling molecules which are fundamental to this phenotypic plasticity. Post translational modifications of proteins are a central feature of the signal transduction pathways that regulate gene transcription in response to hormones. Modifications that affect the function of transcriptional regulators may also serve as a mechanism to incorporate multiple signals, mediate cross-talk, and modulate specific responses. This review discusses recent research that suggests hormone-responsive transcription factors are subject to multiple modifications which imply an additional level of regulation conferred by enzymes that mediate specific modifications, such as phosphorylation, ubiquitination, SUMOylation, and S-nitrosylation. These modifications can affect protein stability, sub-cellular localization, interactions with co-repressors and activators, and DNA binding. The focus here is on direct cross-talk involving transcription factors downstream of auxin, brassinosteroid, and gibberellin signalling. However, many of the concepts discussed are more broadly relevant to questions of how plants can modify their growth by regulating subsets of genes in response to multiple cues. PMID- 26041320 TI - Tricho- and atrichoblast cell files show distinct PIN2 auxin efflux carrier exploitations and are jointly required for defined auxin-dependent root organ growth. AB - The phytohormone auxin is a vital growth regulator in plants. In the root epidermis auxin steers root organ growth. However, the mechanisms that allow adjacent tissues to integrate growth are largely unknown. Here, the focus is on neighbouring epidermal root tissues to assess the integration of auxin-related growth responses. The pharmacologic, genetic, and live-cell imaging approaches reveal that PIN2 auxin efflux carriers are differentially controlled in tricho- and atrichoblast cells. PIN2 proteins show lower abundance at the plasma membrane of trichoblast cells, despite showing higher rates of intracellular trafficking in these cells. The data suggest that PIN2 proteins display distinct cell-type dependent trafficking rates to the lytic vacuole for degradation. Based on this insight, it is hypothesized that auxin-dependent processes are distinct in tricho and atrichoblast cells. Moreover, genetic interference with epidermal patterning supports this assumption and suggests that tricho- and atrichoblasts have distinct importance for auxin-sensitive root growth and gravitropic responses. PMID- 26041322 TI - What the radiologist needs to know about Charcot foot. AB - Charcot neuropathic osteoarthropathy (CN) is a progressive disease affecting the bones, joints and soft tissue of the foot and ankle, most commonly associated with diabetic neuropathy. Patients with diabetes complicated by CN have especially high morbidity, frequency of hospitalisation, and therefore, significant utilisation of expensive medical resources. The diagnosis of early CN can be challenging and is based on clinical presentation supported by various imaging modalities. Imaging is important for the detection of early CN and is useful in monitoring progression and complications of the disease. The later stages of CN are potentially devastating for individuals and present an increasing socioeconomic challenge for health systems. The astute radiologist, particularly in the context of a multidisciplinary team, plays a critical role in diagnosis of the primary disease and its complications. This review article aims to outline the key features of CN, emphasising current clinical and radiologic concepts as an aid for the practising radiologist. PMID- 26041323 TI - Diagnosis and treatment of perineal endometriosis: review of 17 cases. AB - PURPOSE: To demonstrate the appropriate diagnosis and treatment of perineal endometriosis. METHODS: Seventeen patients who presented with a tender perineal mass coinciding with the menstrual cycle on the scar of a previous vaginally procedure were examined retrospectively. Their clinical features and treatment were analyzed. RESULTS: All patients presented with a palpable painful lesion. All of them had had vaginal delivery with episiotomy. The mean age of the patients was 34.35 years. The mean latent period was 46.82 months. The mean size was 2.38 cm. Thirteen patients presented with one subcutaneous nodule and four had multiple nodules. Color Doppler ultrasound revealed a subcutaneous nodule with an irregular outline and echo-complex density underlying the episiotomy scar. Only one patient suffered from perineal endometriosis combined with pelvic endometriosis. All endometriotic masses in perineum were completely excised and cured, and confirmed by the microscopic examination. CONCLUSIONS: A detailed history and thorough pelvic examination are essential in diagnosing perineal endometriosis. Surgical intervention is the first choice of treatment. PMID- 26041321 TI - SCF E3 ligase PP2-B11 plays a positive role in response to salt stress in Arabidopsis. AB - Skp1-Cullin-F-box (SCF) E3 ligases are essential to the post-translational regulation of many important factors involved in cellular signal transduction. In this study, we identified an F-box protein from Arabidopsis thaliana, AtPP2-B11, which was remarkably induced with increased duration of salt treatment in terms of both transcript and protein levels. Transgenic Arabidopsis plants overexpressing AtPP2-B11 exhibited obvious tolerance to high salinity, whereas the RNA interference line was more sensitive to salt stress than wild-type plants. Isobaric tag for relative and absolute quantification analysis revealed that 4311 differentially expressed proteins were regulated by AtPP2-B11 under salt stress. AtPP2-B11 could upregulate the expression of annexin1 (AnnAt1) and function as a molecular link between salt stress and reactive oxygen species accumulation in Arabidopsis. Moreover, AtPP2-B11 influenced the expression of Na(+) homeostasis genes under salt stress, and the AtPP2-B11 overexpressing lines exhibited lower Na(+) accumulation. These results suggest that AtPP2-B11 functions as a positive regulator in response to salt stress in Arabidopsis. PMID- 26041324 TI - Predictors of severity in primary postpartum hemorrhage. AB - PURPOSE: To identify risk factors and etiologies leading to severe primary postpartum hemorrhage (PPH) in women with PPH. METHODS: Women who experienced PPH within the first 24 h after delivery over a 3-year period were retrospectively evaluated. Patients were divided into two groups on the basis of severe PPH (n = 125) or non-severe PPH (n = 411). Risk factors and etiologies for severe PPH were explored using univariate and multivariate logistic regression analyses. RESULTS: PPH and severe PPH complicated 2.1 and 0.49 % of all deliveries, respectively. Previous cesarean delivery (OR = 3.15, 95 % CI = 1.02-10.3; p = 0.001), prolonged labor (OR = 3.62, 95 % CI = 3.21-4.03; p < 0.001), oxytocin augmentation (OR = 3.32, 95 % CI 2.05-5.93; p < 0.001) and emergency cesarean delivery (OR = 4.75, 95 % CI 1.32-12.96; p < 0.001) were the factors independently associated with severe PPH. Etiologies significantly associated with severe PPH are uterine atony (OR = 2.72, 95 % CI 1.64-4.55; p < 0.001) and abnormal placentation (OR = 3.05, 95 % CI 1.56-6.27; p = 0.006). CONCLUSION: Previous cesarean delivery, prolonged labor, oxytocin augmentation and emergency cesarean delivery are strongest predictors of severe blood loss in women with PPH. In addition, uterine atony and abnormal placentation are the etiologies significantly associated with severe PPH. PMID- 26041325 TI - To do or not to do emergency cervical cerclage (a rescue stitch) at 24-28 weeks gestation in addition to progesterone for patients coming early in labor? A prospective randomized trial for efficacy and safety. AB - PURPOSE: To measure the outcome of emergency cervical cerclage (ECC) combined with progesterone vs. progesterone alone in pregnancy prolongation for preterm labor at 24-28 weeks. METHODS: One hundred patients in early labor were allocated randomly into two equal groups. Group A were treated by ECC and progesterone, and group B were on the same progesterone dose only treatment. RESULTS: No significant differences were observed in both groups as regard demographic data, fetal gestational age or cervical state on admission. However, a significant pregnancy prolongation was observed in group A (28.44 +/- 12.73 days vs. 9.96 +/- 3.27 in group B, p < 0.001) with subsequent increase in fetal gestational age (32.04 +/- 3.2 vs. 27.86 +/- 3.213, p < 0.001), heavier weight, higher Apgar score at 1 and 5 min, and lower rate of cesarean delivery (1033.1 +/- 170.83 vs. 715.1 +/- 138.73, p < 0.001) (2.68 +/- 1.132 vs. 2.14 +/- 0.93, p < 0.001), (5.48 +/- 2.6 vs. 2.38 +/- 1.59, p = 0.01) and (16 vs. 62 %, p = 0.01), respectively. Also neonatal outcomes in terms of early neonatal deaths were lower in this group (18 vs. 46 %, p = 0.049). CONCLUSIONS: ECC is effective in pregnancy prolongation when judiciously used in combination with progesterone compared to progesterone alone. PMID- 26041326 TI - The dynamic changes of vaginal microecosystem in patients with recurrent vulvovaginal candidiasis: a retrospective study of 800 patients. AB - PURPOSE: Vaginal microecological environment is an important factor of recurrent vulvovaginal candidiasis (RVVC). This study was undertaken to investigate dynamic changes of vaginal microecosystem in patients with RVVC. METHODS: Four hundred patients with VVC and 400 healthy women of reproductive age who admitted to the hospital from January 2012 to December 2013 were evaluated retrospectively. Vaginal microecological factors were evaluated before and after treatment until no recurrence, including vaginal cleanliness, white blood cells, Lactobacillus, Lactobacillus classification, bacteria density, flora diversity, Nugent scores, etc. The grouping was done according to the recurrence of the disease. Every time after treatment, the relapsing patients were defined as case group and the cured patients without recurrence were defined as control group. The differences in the results between the case and the control groups were analyzed by t test. RESULTS: With the development of RVVC, the ages of all case groups were lower than the corresponding control groups. In different stages of the disease, the bacteria density of the case groups and their corresponding control groups had no significant difference (P > 0.05). Most of the microecological indicators of the first occurring group were significantly different (P < 0.05) from that of the control group. In the recurrence groups, only a few indicators were significantly different from the control groups. The values of all vaginal microecological indicators (except Lactobacillus) of all case groups were higher than that of the control groups. The values of Lactobacillus of all RVVC case groups were lower than that of the RVVC control groups. CONCLUSIONS: There were vaginal microecological imbalances in all developing stages of RVVC. As for vaginal flora, diverse sorts changed to normal Lactobacillus dominantly with the development of RVVC. In the first occurrence of RVVC, after antifungal treatment, Lactobacillus is suggested to be timely supplemented to restore vaginal microecological balance. PMID- 26041327 TI - Continuous versus cyclic oral contraceptives for endometriosis: any conclusive evidence? PMID- 26041328 TI - Use of misoprostol in myomectomy: a systematic review and meta-analysis. AB - INTRODUCTION: Misoprostol, a prostaglandin derivative, reduces blood flow to uterus, facilitating every surgical operation on myometrium. METHOD: PubMed, Scopus and Cochrane databases were systematically searched and five studies met the inclusion criteria for our meta-analysis. RESULTS: In total, 283 patients were included. The intention to treat population included 142 patients. The mean age of the patients was 34 years old. The vaginal route of administration was preferred in 117 out of 142 patients and the rectal route in 25 patients. Three studies were included in the analysis regarding duration of operation, estimated blood loss, preoperative/postoperative hemoglobin, transfusions needed and febrile morbidity. No significant difference was observed between vaginal suppository and placebo group concerning the duration of operation, the fall of preoperative hemoglobin, transfusions needed and the febrile morbidity. Regarding the estimated blood loss, the mean difference observed between the misoprostol and placebo groups was -148.55 mL per operation (95 % CI, -233.10 to -64), p < 0.001. As far as the postoperative Hgb, the misoprostol group presented significantly smaller reduction, 0.68 gr/dL per operation (95 % CI, 0.38-0.97), p < 0.001. CONCLUSION: Easy to use, minor or no side effects, and good clinical outcomes are the properties that render misoprostol useful in the realization myomectomy independently of the surgical technique applied. PMID- 26041329 TI - Clinical and immunologic effects of maraviroc in progressive multifocal leukoencephalopathy. PMID- 26041330 TI - Unusual cause of hyperbilirubinaemia in a preterm baby. PMID- 26041331 TI - Effect of surface modification on interfacial nanobubble morphology and contact line tension. AB - Past research has confirmed the existence of surface nanobubbles on various hydrophobic substrates (static contact angle >90 degrees ) when imaged in air equilibrated water. Additionally, the use of solvent exchange techniques (based on the difference in saturation levels of air in various solvents) also introduced surface nanobubbles on hydrophilic substrates (static contact angle <90 degrees ). In this work, tapping mode atomic force microscopy was used to image interfacial nanobubbles formed on bulk polycarbonate (static contact angle of 81.1 degrees ), bromo-terminated silica (BTS; static contact angle of 85.5 degrees ), and fluoro-terminated silica (FTS; static contact angle of 105.3 degrees ) surfaces when immersed in air-equilibrated water without solvent exchange. Nanobubbles formed on the above three substrates were characterized on the basis of Laplace pressure, bubble density, and contact line tension. Results reported here show that (1) the Laplace pressures of all nanobubbles formed on both BTS and polycarbonate were an order of magnitude higher than those of FTS, (2) the nanobubble number density per unit area decreased with an increase in substrate contact angle, and (3) the contact line tension of the nanobubbles was calculated to be positive for both BTS and polycarbonate (lateral radius, Rs < 50 nm for all nanobubbles), and negative for FTS (Rs > 50 nm for all nanobubbles). The nanobubble morphology and distribution before and after using the solvent exchange method (ethanol-water), on the bulk polycarbonate substrate was also characterized. Analysis for these polycarbonate surface nanobubbles showed that both the Laplace pressure and nanobubble density reduced by ~98% after ethanol water exchange, accompanied by a flip in the magnitude of contact line tension from positive (0.19 nN) to negative (-0.11 nN). PMID- 26041332 TI - Correction: Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate. PMID- 26041333 TI - The secret lives of Drosophila flies. AB - Flies of the genus Drosophila, and particularly those of the species Drosophila melanogaster, are best known as laboratory organisms. As with all model organisms, they were domesticated for empirical studies, but they also continue to exist as wild populations. Decades of research on these flies in the laboratory have produced astounding and important insights into basic biological processes, but we have only scratched the surface of what they have to offer as research organisms. An outstanding challenge now is to build on this knowledge and explore how natural history has shaped D. melanogaster in order to advance our understanding of biology more generally. PMID- 26041334 TI - The reliability and validity of the pain items of the Hong Kong version interRAI community health assessment for community-dwelling elders in Hong Kong. PMID- 26041335 TI - Deficit irrigation strategies enhance health-promoting compounds through the intensification of specific enzymes in early peaches. AB - BACKGROUND: Biochemical and enzymatic responses to long-term regulated deficit irrigation (RDI) at harvest, during cold storage and after the retail sale period of 'Flordastar' early peaches were evaluated. Irrigation strategies were Control, and two RDI applied during post-harvest period (RDI1 , severe; RDI2 , moderate), based on different thresholds of maximum daily shrinkage signal intensity (RDI1 , 1.4 to dry; RDI2 , 1.3 to 1.6). RESULTS: Both RDI provoked stress in the plant. This meant higher antioxidant concentration [averaging 1.30 +/- 0.27 g ascorbic acid equivalents (AAE) kg(-1) fresh weight (FW) for control and 1.77 +/- 0.35 and 1.50 +/- 0.30 g AAE kg(-1) FW for RDI1 and RDI2 , respectively]. Antioxidant levels decreased with storage by polyphenoloxydase action, which increased (from 0.04 +/- 0.01 U mg(-1) protein to 0.32 +/- 0.08 U mg(-1) protein). Vitamin C was initially higher in RDI samples (44.22 +/- 0.05 g total vitamin C kg(-1) FW for control vs. 46.77 +/- 0.02 and 46.27 +/- 0.03 g total vitamin C kg(-1) FW for RDI1 and RDI2 , respectively). CONCLUSION: The way RDI was applied affected bioactive fruit composition, being catalase and dehydroascorbic acid good water stress indicators. RDI strategies can be used as field practice, allowing water savings while enhanced healthy compound content in early peaches. PMID- 26041337 TI - Behavioral and neurophysiological effects of Ro 10-5824, a dopamine D4 receptor partial agonist, in common marmosets. AB - RATIONALE: Growing evidence suggests that dopamine D4 receptors (D4Rs) are involved in controlling executive functions. We have previously demonstrated that Ro 10-5824, a D4R partial agonist, improves the performance of common marmosets in the object retrieval detour (ORD) task. However, the neural mechanisms underlying this improvement are unknown. OBJECTIVES: We investigated the behavioral and neurophysiological effects of Ro 10-5824 in common marmosets. METHODS: The effects of Ro 10-5824 on cognitive function were evaluated using the ORD task. The neurophysiological effects of Ro 10-5824 were investigated by quantitative electroencephalography, especially on baseline gamma band activity in the frontal cortex. The effects of Ro 10-5824 on spontaneous locomotion were also assessed. RESULTS: Systemic administration of Ro 10-5824 at 3 mg/kg significantly increased the success rate in the ORD task. At doses of 1 and 3 mg/kg, Ro 10-5824 increased baseline gamma band activity in the frontal cortex. Ro 10-5824 had no effect on spontaneous locomotion. CONCLUSIONS: Activation of D4R by Ro 10-5824 improves the success rate in the ORD task and increases baseline gamma band activity in the frontal cortex without affecting locomotion in common marmosets. These findings highlight the role of D4R in gamma oscillations of non-human primates. As gamma oscillations are thought to be involved in attention and behavioral inhibition, our results suggest D4R agonists may improve these cognitive functions by modulating baseline gamma band activity in the frontal cortex. PMID- 26041336 TI - Negative mood reverses devaluation of goal-directed drug-seeking favouring an incentive learning account of drug dependence. AB - BACKGROUND: Two theories explain how negative mood primes smoking behaviour. The stimulus-response (S-R) account argues that in the negative mood state, smoking is experienced as more reinforcing, establishing a direct (automatic) association between the negative mood state and smoking behaviour. By contrast, the incentive learning account argues that in the negative mood state smoking is expected to be more reinforcing, which integrates with instrumental knowledge of the response required to produce that outcome. OBJECTIVES: One differential prediction is that whereas the incentive learning account anticipates that negative mood induction could augment a novel tobacco-seeking response in an extinction test, the S-R account could not explain this effect because the extinction test prevents S-R learning by omitting experience of the reinforcer. METHODS: To test this, overnight-deprived daily smokers (n = 44) acquired two instrumental responses for tobacco and chocolate points, respectively, before smoking to satiety. Half then received negative mood induction to raise the expected value of tobacco, opposing satiety, whilst the remainder received positive mood induction. Finally, a choice between tobacco and chocolate was measured in extinction to test whether negative mood could augment tobacco choice, opposing satiety, in the absence of direct experience of tobacco reinforcement. RESULTS: Negative mood induction not only abolished the devaluation of tobacco choice, but participants with a significant increase in negative mood increased their tobacco choice in extinction, despite satiety. CONCLUSIONS: These findings suggest that negative mood augments drug seeking by raising the expected value of the drug through incentive learning, rather than through automatic S-R control. PMID- 26041338 TI - Role of 5-HT2C receptors in effects of monoamine releasers on intracranial self stimulation in rats. AB - RATIONALE: Many monoamine releasers are abused by humans and produce abuse related facilitation of intracranial self-stimulation (ICSS) in rats. Facilitation of ICSS in rats can be limited by monoamine releaser-induced serotonin (5-HT) release, but receptors that mediate 5-HT effects of monoamine releasers are unknown. OBJECTIVES: The aim of this study is to investigate whether 5-HT2C receptor activation is necessary for rate-decreasing effects produced in an ICSS procedure in rats by the 5-HT-selective monoamine releaser fenfluramine and the non-selective releasers napthylisopropylamine (PAL-287) and (+)-3,4-methylenedioxymethamphetamine ((+)-MDMA). METHODS: Adult male Sprague Dawley rats with electrodes implanted in the medial forebrain bundle were trained to lever press for brain stimulation under a "frequency-rate" ICSS procedure. Effectiveness of the 5-HT2C antagonist SB 242,084 was evaluated to block rate decreasing effects produced by (1) the 5-HT2C agonist Ro 60-0175, (2) the 5-HT selective releaser fenfluramine, and (3) the mixed-action dopamine (DA)/norepinephrine (NE)/5-HT releasers PAL-287 (1.0-5.6 mg/kg) and (+)-MDMA (1.0 3.2 mg/kg). For comparison, effectiveness of SB 242,084 to alter rate-decreasing effects of the kappa-opioid receptor agonist U69,593 and rate-increasing effects of the DA>5-HT releaser amphetamine was also examined. RESULTS: SB 242,084 pretreatment blocked rate-decreasing effects of Ro 60-0175 and fenfluramine, but not the rate-decreasing effects of U69,593 or the rate-increasing effects of amphetamine. SB 242,084 blunted the rate-decreasing effects and enhanced expression of rate-increasing effects of PAL-287 and (+)-MDMA. CONCLUSIONS: These data suggest that 5-HT2C receptor activation contributes to rate-decreasing effects that are produced by selective and mixed-action 5-HT releasers in rats and that may oppose and limit the expression of abuse-related ICSS facilitation by these compounds. PMID- 26041339 TI - High copy wildtype human 1N4R tau expression promotes early pathological tauopathy accompanied by cognitive deficits without progressive neurofibrillary degeneration. AB - INTRODUCTION: Accumulation of insoluble conformationally altered hyperphosphorylated tau occurs as part of the pathogenic process in Alzheimer's disease (AD) and other tauopathies. In most AD subjects, wild-type (WT) tau aggregates and accumulates in neurofibrillary tangles and dystrophic neurites in the brain; however, in some familial tauopathy disorders, mutations in the gene encoding tau cause disease. RESULTS: We generated a mouse model, Tau4RTg2652, that expresses high levels of normal human tau in neurons resulting in the early stages of tau pathology. In this model, over expression of WT human tau drives pre-tangle pathology in young mice resulting in behavioral deficits. These changes occur at a relatively young age and recapitulate early pre-tangle stages of tau pathology associated with AD and mild cognitive impairment. Several features distinguish the Tau4RTg2652 model of tauopathy from previously described tau transgenic mice. Unlike other mouse models where behavioral and neuropathologic changes are induced by transgenic tau harboring MAPT mutations pathogenic for frontotemporal lobar degeneration (FTLD), the mice described here express the normal tau sequence. CONCLUSIONS: Features of Tau4RTg2652 mice distinguishing them from other established wild type tau overexpressing mice include very early phenotypic manifestations, non-progressive tau pathology, abundant pre-tangle and phosphorylated tau, sparse oligomeric tau species, undetectable fibrillar tau pathology, stability of tau transgene copy number/expression, and normal lifespan. These results suggest that Tau4RTg2652 animals may facilitate studies of tauopathy target engagement where WT tau is driving tauopathy phenotypes. PMID- 26041341 TI - Erratum. Correction to: Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. PMID- 26041340 TI - Knowledge co-production and boundary work to promote implementation of conservation plans. AB - Knowledge co-production and boundary work offer planners a new frame for critically designing a social process that fosters collaborative implementation of resulting plans. Knowledge co-production involves stakeholders from diverse knowledge systems working iteratively toward common vision and action. Boundary work is a means of creating permeable knowledge boundaries that satisfy the needs of multiple social groups while guarding the functional integrity of contributing knowledge systems. Resulting products are boundary objects of mutual interest that maintain coherence across all knowledge boundaries. We examined how knowledge co-production and boundary work can bridge the gap between planning and implementation and promote cross-sectoral cooperation. We applied these concepts to well-established stages in regional conservation planning within a national scale conservation planning project aimed at identifying areas for conserving rivers and wetlands of South Africa and developing an institutional environment for promoting their conservation. Knowledge co-production occurred iteratively over 4 years in interactive stake-holder workshops that included co-development of national freshwater conservation goals and spatial data on freshwater biodiversity and local conservation feasibility; translation of goals into quantitative inputs that were used in Marxan to select draft priority conservation areas; review of draft priority areas; and packaging of resulting map products into an atlas and implementation manual to promote application of the priority area maps in 37 different decision-making contexts. Knowledge co production stimulated dialogue and negotiation and built capacity for multi-scale implementation beyond the project. The resulting maps and information integrated diverse knowledge types of over 450 stakeholders and represented >1000 years of collective experience. The maps provided a consistent national source of information on priority conservation areas for rivers and wetlands and have been applied in 25 of the 37 use contexts since their launch just over 3 years ago. When framed as a knowledge co-production process supported by boundary work, regional conservation plans can be developed into valuable boundary objects that offer a tangible tool for multi-agency cooperation around conservation. Our work provides practical guidance for promoting uptake of conservation science and contributes to an evidence base on how conservation efforts can be improved. PMID- 26041342 TI - Elevational differences in developmental plasticity determine phenological responses of grasshoppers to recent climate warming. AB - Annual species may increase reproduction by increasing adult body size through extended development, but risk being unable to complete development in seasonally limited environments. Synthetic reviews indicate that most, but not all, species have responded to recent climate warming by advancing the seasonal timing of adult emergence or reproduction. Here, we show that 50 years of climate change have delayed development in high-elevation, season-limited grasshopper populations, but advanced development in populations at lower elevations. Developmental delays are most pronounced for early-season species, which might benefit most from delaying development when released from seasonal time constraints. Rearing experiments confirm that population, elevation and temperature interact to determine development time. Population differences in developmental plasticity may account for variability in phenological shifts among adults. An integrated consideration of the full life cycle that considers local adaptation and plasticity may be essential for understanding and predicting responses to climate change. PMID- 26041344 TI - Delay of gratification is associated with white matter connectivity in the dorsal prefrontal cortex: a diffusion tensor imaging study in chimpanzees (Pan troglodytes). AB - Individual variability in delay of gratification (DG) is associated with a number of important outcomes in both non-human and human primates. Using diffusion tensor imaging (DTI), this study describes the relationship between probabilistic estimates of white matter tracts projecting from the caudate to the prefrontal cortex (PFC) and DG abilities in a sample of 49 captive chimpanzees (Pan troglodytes). After accounting for time between collection of DTI scans and DG measurement, age and sex, higher white matter connectivity between the caudate and right dorsal PFC was found to be significantly associated with the acquisition (i.e. training phase) but not the maintenance of DG abilities. No other associations were found to be significant. The integrity of white matter connectivity between regions of the striatum and the PFC appear to be associated with inhibitory control in chimpanzees, with perturbations on this circuit potentially leading to a variety of maladaptive outcomes. Additionally, results have potential translational implications for understanding the pathophysiology of a number of psychiatric and clinical outcomes in humans. PMID- 26041343 TI - The role of ontogeny in physiological tolerance: decreasing hydrostatic pressure tolerance with development in the northern stone crab Lithodes maja. AB - Extant deep-sea invertebrate fauna represent both ancient and recent invasions from shallow-water habitats. Hydrostatic pressure may present a significant physiological challenge to organisms seeking to colonize deeper waters or migrate ontogenetically. Pressure may be a key factor contributing to bottlenecks in the radiation of taxa and potentially drive speciation. Here, we assess shifts in the tolerance of hydrostatic pressure through early ontogeny of the northern stone crab Lithodes maja, which occupies a depth range of 4-790 m in the North Atlantic. The zoea I, megalopa and crab I stages were exposed to hydrostatic pressures up to 30.0 MPa (equivalent of 3000 m depth), and the relative fold change of genes putatively coding for the N-methyl-D-aspartate receptor-regulated protein 1 (narg gene), two heat-shock protein 70 kDa (HSP70) isoforms and mitochondrial Citrate Synthase (CS gene) were measured. This study finds a significant increase in the relative expression of the CS and hsp70a genes with increased hydrostatic pressure in the zoea I stage, and an increase in the relative expression of all genes with increased hydrostatic pressure in the megalopa and crab I stages. Transcriptional responses are corroborated by patterns in respiratory rates in response to hydrostatic pressure in all stages. These results suggest a decrease in the acute high-pressure tolerance limit as ontogeny advances, as reflected by a shift in the hydrostatic pressure at which significant differences are observed. PMID- 26041346 TI - Risk-spreading by mating multiply is plausible and requires empirical attention. PMID- 26041345 TI - Vitellogenin and vitellogenin receptor gene expression is associated with male and female parenting in a subsocial insect. AB - Complex social behaviour in Hymenoptera has been hypothesized to evolve by co opting reproductive pathways (the ovarian ground plan hypothesis, OGPH) and gene networks (the reproductive ground plan hypothesis, RGPH). In support of these hypotheses, in eusocial Hymenoptera where there is reproductive division of labour, the yolk precursor protein vitellogenin (Vg) influences the expression of worker social behaviour. We suggest that co-opting genes involved in reproduction may occur more generally than just in the evolution of eusociality; i.e. underlie earlier stages of social evolution such as the evolution of parental care, given that reproduction and parental care rarely overlap. We therefore examined vitellogenin (vg) gene expression associated with parental care in the subsocial beetle Nicrophorus vespilloides. We found a significant reduction in the expression of vg and its receptor, vgr, in head tissue during active parental care, and confirmed that the receptor is expressed in the brains of both sexes. Ours is the first study to show that vgr is expressed in the brain of a non eusocial insect. Given the association between behaviour and gene expression in both sexes, and the presence of vitellogenin receptors in the brain, we suggest that Vg was co-opted early in the evolution of sociality to have a regulatory function. This extends the association of Vg in parenting to subsocial species and outside of the Hymenoptera, and supports the hypothesis that the OGPH is general and that heterochrony in gene expression is important in the evolution of social behaviour and precedes subsequent evolutionary specialization of social roles. PMID- 26041347 TI - Cognitive ability is heritable and predicts the success of an alternative mating tactic. AB - The ability to attract mates, acquire resources for reproduction, and successfully outcompete rivals for fertilizations may make demands on cognitive traits--the mechanisms by which an animal acquires, processes, stores and acts upon information from its environment. Consequently, cognitive traits potentially undergo sexual selection in some mating systems. We investigated the role of cognitive traits on the reproductive performance of male rose bitterling (Rhodeus ocellatus), a freshwater fish with a complex mating system and alternative mating tactics. We quantified the learning accuracy of males and females in a spatial learning task and scored them for learning accuracy. Males were subsequently allowed to play the roles of a guarder and a sneaker in competitive mating trials, with reproductive success measured using paternity analysis. We detected a significant interaction between male mating role and learning accuracy on reproductive success, with the best-performing males in maze trials showing greater reproductive success in a sneaker role than as a guarder. Using a cross classified breeding design, learning accuracy was demonstrated to be heritable, with significant additive maternal and paternal effects. Our results imply that male cognitive traits may undergo intra-sexual selection. PMID- 26041348 TI - A strong genetic correlation underlying a behavioural syndrome disappears during development because of genotype-age interactions. AB - In animal populations, as in humans, behavioural differences between individuals that are consistent over time and across contexts are considered to reflect personality, and suites of correlated behaviours expressed by individuals are known as behavioural syndromes. Lifelong stability of behavioural syndromes is often assumed, either implicitly or explicitly. Here, we use a quantitative genetic approach to study the developmental stability of a behavioural syndrome in a wild population of blue tits. We find that a behavioural syndrome formed by a strong genetic correlation of two personality traits in nestlings disappears in adults, and we demonstrate that genotype-age interaction is the likely mechanism underlying this change during development. A behavioural syndrome may hence change during organismal development, even when personality traits seem to be strongly physiologically or functionally linked in one age group. We outline how such developmental plasticity has important ramifications for understanding the mechanistic basis as well as the evolutionary consequences of behavioural syndromes. PMID- 26041349 TI - Mountain uplift explains differences in Palaeogene patterns of mammalian evolution and extinction between North America and Europe. AB - Patterns of late Palaeogene mammalian evolution appear to be very different between Eurasia and North America. Around the Eocene-Oligocene (EO) transition global temperatures in the Northern Hemisphere plummet: following this, European mammal faunas undergo a profound extinction event (the Grande Coupure), while in North America they appear to pass through this temperature event unscathed. Here, we investigate the role of surface uplift to environmental change and mammalian evolution through the Palaeogene (66-23 Ma). Palaeogene regional surface uplift in North America caused large-scale reorganization of precipitation patterns, particularly in the continental interior, in accord with our combined stable isotope and ecometric data. Changes in mammalian faunas reflect that these were dry and high-elevation palaeoenvironments. The scenario of Middle to Late Eocene (50-37 Ma) surface uplift, together with decreasing precipitation in higher altitude regions of western North America, explains the enigma of the apparent lack of the large-scale mammal faunal change around the EO transition that characterized western Europe. We suggest that North American mammalian faunas were already pre-adapted to cooler and drier conditions preceding the EO boundary, resulting from the effects of a protracted history of surface uplift. PMID- 26041350 TI - More than one way to spin a crystallite: multiple trajectories through liquid crystallinity to solid silk. AB - Arthropods face several key challenges in processing concentrated feedstocks of proteins (silk dope) into solid, semi-crystalline silk fibres. Strikingly, independently evolved lineages of silk-producing organisms have converged on the use of liquid crystal intermediates (mesophases) to reduce the viscosity of silk dope and assist the formation of supramolecular structure. However, the exact nature of the liquid-crystal-forming-units (mesogens) in silk dope, and the relationship between liquid crystallinity, protein structure and silk processing is yet to be fully elucidated. In this review, we focus on emerging differences in this area between the canonical silks containing extended-beta-sheets made by silkworms and spiders, and 'non-canonical' silks made by other insect taxa in which the final crystallites are coiled-coils, collagen helices or cross-beta sheets. We compared the amino acid sequences and processing of natural, regenerated and recombinant silk proteins, finding that canonical and non canonical silk proteins show marked differences in length, architecture, amino acid content and protein folding. Canonical silk proteins are long, flexible in solution and amphipathic; these features allow them both to form large, micelle like mesogens in solution, and to transition to a crystallite-containing form due to mechanical deformation near the liquid-solid transition. By contrast, non canonical silk proteins are short and have rod or lath-like structures that are well suited to act both as mesogens and as crystallites without a major intervening phase transition. Given many non-canonical silk proteins can be produced at high yield in E. coli, and that mesophase formation is a versatile way to direct numerous kinds of supramolecular structure, further elucidation of the natural processing of non-canonical silk proteins may to lead to new developments in the production of advanced protein materials. PMID- 26041351 TI - Bet-hedging via polyandry: a comment on 'Mating portfolios: bet-hedging, sexual selection and female multiple mating'. PMID- 26041352 TI - Ectopic expression of ecdysone oxidase impairs tissue degeneration in Bombyx mori. AB - Metamorphosis in insects includes a series of programmed tissue histolysis and remolding processes that are controlled by two major classes of hormones, juvenile hormones and ecdysteroids. Precise pulses of ecdysteroids (the most active ecdysteroid is 20-hydroxyecdysone, 20E), are regulated by both biosynthesis and metabolism. In this study, we show that ecdysone oxidase (EO), a 20E inactivation enzyme, expresses predominantly in the midgut during the early pupal stage in the lepidopteran model insect, Bombyx mori. Depletion of BmEO using the transgenic CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/RNA-guided Cas9 nucleases) system extended the duration of the final instar larval stage. Ubiquitous transgenic overexpression of BmEO using the Gal4/UAS system induced lethality during the larval-pupal transition. When BmEO was specifically overexpressed in the middle silk gland (MSG), degeneration of MSG at the onset of metamorphosis was blocked. Transmission electron microscope and LysoTracker analyses showed that the autophagy pathway in MSG is inhibited by BmEO ectopic expression. Furthermore, RNA-seq analysis revealed that the genes involved in autophagic cell death and the mTOR signal pathway are affected by overexpression of BmEO. Taken together, BmEO functional studies reported here provide insights into ecdysone regulation of tissue degeneration during metamorphosis. PMID- 26041353 TI - Crying wolf to a predator: deceptive vocal mimicry by a bird protecting young. AB - Animals often mimic dangerous or toxic species to deter predators; however, mimicry of such species may not always be possible and mimicry of benign species seems unlikely to confer anti-predator benefits. We reveal a system in which a bird mimics the alarm calls of harmless species to fool a predator 40 times its size and protect its offspring against attack. Our experiments revealed that brown thornbills (Acanthiza pusilla) mimic a chorus of other species' aerial alarm calls, a cue of an Accipiter hawk in flight, when predators attack their nest. The absence of any flying predators in this context implies that these alarms convey deceptive information about the type of danger present. Experiments on the primary nest predators of thornbills, pied currawongs (Strepera graculina), revealed that the predators treat these alarms as if they themselves are threatened by flying hawks, either by scanning the sky for danger or fleeing, confirming a deceptive function. In turn, these distractions delay attack and provide thornbill nestlings with an opportunity to escape. This sophisticated defence strategy exploits the complex web of interactions among multiple species across several trophic levels, and in particular exploits a predator's ability to eavesdrop on and respond appropriately to heterospecific alarm calls. Our findings demonstrate that prey can fool predators by deceptively mimicking alarm calls of harmless species, suggesting that defensive mimicry could be more widespread because of indirect effects on predators within a web of eavesdropping. PMID- 26041354 TI - Investigating the causes and consequences of symbiont shuffling in a multi partner reef coral symbiosis under environmental change. AB - Dynamic symbioses may critically mediate impacts of climate change on diverse organisms, with repercussions for ecosystem persistence in some cases. On coral reefs, increases in heat-tolerant symbionts after thermal bleaching can reduce coral susceptibility to future stress. However, the relevance of this adaptive response is equivocal owing to conflicting reports of symbiont stability and change. We help reconcile this conflict by showing that change in symbiont community composition (symbiont shuffling) in Orbicella faveolata depends on the disturbance severity and recovery environment. The proportion of heat-tolerant symbionts dramatically increased following severe experimental bleaching, especially in a warmer recovery environment, but tended to decrease if bleaching was less severe. These patterns can be explained by variation in symbiont performance in the changing microenvironments created by differentially bleached host tissues. Furthermore, higher proportions of heat-tolerant symbionts linearly increased bleaching resistance but reduced photochemical efficiency, suggesting that any change in community structure oppositely impacts performance and stress tolerance. Therefore, even minor symbiont shuffling can adaptively benefit corals, although fitness effects of resulting trade-offs are difficult to predict. This work helps elucidate causes and consequences of dynamism in symbiosis, which is critical to predicting responses of multi-partner symbioses such as O. faveolata to environmental change. PMID- 26041355 TI - Negative effects of pesticides on wild bee communities can be buffered by landscape context. AB - Wild bee communities provide underappreciated but critical agricultural pollination services. Given predicted global shortages in pollination services, managing agroecosystems to support thriving wild bee communities is, therefore, central to ensuring sustainable food production. Benefits of natural (including semi-natural) habitat for wild bee abundance and diversity on farms are well documented. By contrast, few studies have examined toxicity of pesticides on wild bees, let alone effects of farm-level pesticide exposure on entire bee communities. Whether beneficial natural areas could mediate effects of harmful pesticides on wild bees is also unknown. Here, we assess the effect of conventional pesticide use on the wild bee community visiting apple (Malus domestica) within a gradient of percentage natural area in the landscape. Wild bee community abundance and species richness decreased linearly with increasing pesticide use in orchards one year after application; however, pesticide effects on wild bees were buffered by increasing proportion of natural habitat in the surrounding landscape. A significant contribution of fungicides to observed pesticide effects suggests deleterious properties of a class of pesticides that was, until recently, considered benign to bees. Our results demonstrate extended benefits of natural areas for wild pollinators and highlight the importance of considering the landscape context when weighing up the costs of pest management on crop pollination services. PMID- 26041356 TI - Cognitive capacities for cooking in chimpanzees. AB - The transition to a cooked diet represents an important shift in human ecology and evolution. Cooking requires a set of sophisticated cognitive abilities, including causal reasoning, self-control and anticipatory planning. Do humans uniquely possess the cognitive capacities needed to cook food? We address whether one of humans' closest relatives, chimpanzees (Pan troglodytes), possess the domain-general cognitive skills needed to cook. Across nine studies, we show that chimpanzees: (i) prefer cooked foods; (ii) comprehend the transformation of raw food that occurs when cooking, and generalize this causal understanding to new contexts; (iii) will pay temporal costs to acquire cooked foods; (iv) are willing to actively give up possession of raw foods in order to transform them; and (v) can transport raw food as well as save their raw food in anticipation of future opportunities to cook. Together, our results indicate that several of the fundamental psychological abilities necessary to engage in cooking may have been shared with the last common ancestor of apes and humans, predating the control of fire. PMID- 26041357 TI - Reproductive skew drives patterns of sexual dimorphism in sponge-dwelling snapping shrimps. AB - Sexual dimorphism is typically a result of strong sexual selection on male traits used in male-male competition and subsequent female choice. However, in social species where reproduction is monopolized by one or a few individuals in a group, selection on secondary sexual characteristics may be strong in both sexes. Indeed, sexual dimorphism is reduced in many cooperatively breeding vertebrates and eusocial insects with totipotent workers, presumably because of increased selection on female traits. Here, we examined the relationship between sexual dimorphism and sociality in eight species of Synalpheus snapping shrimps that vary in social structure and degree of reproductive skew. In species where reproduction was shared more equitably, most members of both sexes were physiologically capable of breeding. However, in species where reproduction was monopolized by a single individual, a large proportion of females--but not males- were reproductively inactive, suggesting stronger reproductive suppression and conflict among females. Moreover, as skew increased across species, proportional size of the major chela--the primary antagonistic weapon in snapping shrimps- increased among females and sexual dimorphism in major chela size declined. Thus, as reproductive skew increases among Synalpheus, female-female competition over reproduction appears to increase, resulting in decreased sexual dimorphism in weapon size. PMID- 26041358 TI - Responses of tadpoles to hybrid predator odours: strong maternal signatures and the potential risk/response mismatch. AB - Previous studies have established that when a prey animal knows the identity of a particular predator, it can use this knowledge to make an 'educated guess' about similar novel predators. Such generalization of predator recognition may be particularly beneficial when prey are exposed to introduced and invasive species of predators or hybrids. Here, we examined generalization of predator recognition for woodfrog tadpoles exposed to novel trout predators. Tadpoles conditioned to recognize tiger trout, a hybrid derived from brown trout and brook trout, showed generalization of recognition of several unknown trout odours. Interestingly, the tadpoles showed stronger responses to odours of brown trout than brook trout. In a second experiment, we found that tadpoles trained to recognize brown trout showed stronger responses to tiger trout than those tadpoles trained to recognize brook trout. Given that tiger trout always have a brown trout mother and a brook trout father, these results suggest a strong maternal signature in trout odours. Tadpoles that were trained to recognize both brown trout and brook trout showed stronger response to novel tiger trout than those trained to recognize only brown trout or only brook trout. This is consistent with a peak shift in recognition, whereby cues that are intermediate between two known cues evoke stronger responses than either known cue. Given that our woodfrog tadpoles have no evolutionary or individual experience with trout, they have no way of knowing whether or not brook trout, brown trout or tiger trout are more dangerous. The differential intensity of responses that we observed to hybrid trout cues and each of the parental species indicates that there is a likely mismatch between risk and anti-predator response intensity. Future work needs to address the critical role of prey naivety on responses to invasive and introduced hybrid predators. PMID- 26041360 TI - Behavioural mimicry in flight path of Batesian intraspecific polymorphic butterfly Papilio polytes. AB - Batesian mimics that show similar coloration to unpalatable models gain a fitness advantage of reduced predation. Beyond physical similarity, mimics often exhibit behaviour similar to their models, further enhancing their protection against predation by mimicking not only the model's physical appearance but also activity. In butterflies, there is a strong correlation between palatability and flight velocity, but there is only weak correlation between palatability and flight path. Little is known about how Batesian mimics fly. Here, we explored the flight behaviour of four butterfly species/morphs: unpalatable model Pachliopta aristolochiae, mimetic and non-mimetic females of female-limited mimic Papilio polytes, and palatable control Papilio xuthus. We demonstrated that the directional change (DC) generated by wingbeats and the standard deviation of directional change (SDDC) of mimetic females and their models were smaller than those of non-mimetic females and palatable controls. Furthermore, we found no significant difference in flight velocity among all species/morphs. By showing that DC and SDDC of mimetic females resemble those of models, we provide the first evidence for the existence of behavioural mimicry in flight path by a Batesian mimic butterfly. PMID- 26041361 TI - A preliminary study of the mechanism of nitrate-stimulated remarkable increase of rifamycin production in Amycolatopsis mediterranei U32 by RNA-seq. AB - BACKGROUND: Rifamycin is an important antibiotic for the treatment of infectious disease caused by Mycobacteria tuberculosis. It was found that in Amycolatopsis mediterranei U32, an industrial producer for rifamycin SV, supplementation of nitrate into the medium remarkably stimulated the yield of rifamycin SV. However, the molecular mechanism of this nitrate-mediated stimulation remains unknown. RESULTS: In this study, RNA-sequencing (RNA-seq) technology was employed for investigation of the genome-wide differential gene expression in U32 cultured with or without nitrate supplementation. In the presence of nitrate, U32 maintained a high transcriptional level of genes both located in the rifamycin biosynthetic cluster and involved in the biosynthesis of rifamycin precursors, including 3-amino-5-dihydroxybenzoic acid, malonyl-CoA and (S)-methylmalonyl-CoA. However, when nitrate was omitted from the medium, the transcription of these genes declined sharply during the transition from the mid-logarithmic phase to the early stationary phase. With these understandings, one may easily propose that nitrate stimulates the rifamycin SV production through increasing both the precursors supply and the enzymes for rifamycin biosynthesis. CONCLUSION: It is the first time to thoroughly illustrate the mechanism of the nitrate-mediated stimulation of rifamycin production at the transcriptional level, which may facilitate improvement of the industrial production of rifamycin SV, e.g. through optimizing the global rifamycin biosynthetic pathways on the basis of RNA-seq data. PMID- 26041359 TI - Hybridization masks speciation in the evolutionary history of the Galapagos marine iguana. AB - The effects of the direct interaction between hybridization and speciation-two major contrasting evolutionary processes--are poorly understood. We present here the evolutionary history of the Galapagos marine iguana (Amblyrhynchus cristatus) and reveal a case of incipient within--island speciation, which is paralleled by between-island hybridization. In-depth genome-wide analyses suggest that Amblyrhynchus diverged from its sister group, the Galapagos land iguanas, around 4.5 million years ago (Ma), but divergence among extant populations is exceedingly young (less than 50,000 years). Despite Amblyrhynchus appearing as a single long-branch species phylogenetically, we find strong population structure between islands, and one case of incipient speciation of sister lineages within the same island--ostensibly initiated by volcanic events. Hybridization between both lineages is exceedingly rare, yet frequent hybridization with migrants from nearby islands is evident. The contemporary snapshot provided by highly variable markers indicates that speciation events may have occurred throughout the evolutionary history of marine iguanas, though these events are not visible in the deeper phylogenetic trees. We hypothesize that the observed interplay of speciation and hybridization might be a mechanism by which local adaptations, generated by incipient speciation, can be absorbed into a common gene pool, thereby enhancing the evolutionary potential of the species as a whole. PMID- 26041362 TI - Nocturnal Hypertension Correlates Better With Target Organ Damage in Patients With Chronic Kidney Disease than a Nondipping Pattern. AB - Both nocturnal hypertension and nondipping pattern are associated with target organ damages (TODs); however, no data exist with respect to Chinese patients with chronic kidney disease (CKD). The authors recruited 1322 patients with CKD admitted to our hospital division and referred with data in this cross-sectional study. Patients with nocturnal systolic hypertension had a lower estimated glomerular filtration rate (eGFR) and higher left ventricular mass index (LVMI) and carotid intima-media thickness (cIMT) compared with patients with normal nocturnal systolic blood pressure (SPB; all, P<.001), while patients in the dipper and nondipper groups had similar levels of eGFR, LVMI, and cIMT when the patients had a similar nocturnal SBP. Factorial-designed analysis of variance indicated that the main effect of nocturnal SBP was significant for all TOD differences (all, P<.001), but no significance existed with respect to the main effect of the dipper pattern and an interaction between the two factors (all, P>.05). Nocturnal systolic hypertension, rather than nondipping pattern, was an independent risk factor for TOD in CKD patients. Nocturnal hypertension, rather than a nondipping pattern, was better associated with TOD in CKD patients. PMID- 26041363 TI - Evaluation of work-based screening for early signs of alcohol-related liver disease in hazardous and harmful drinkers: the PrevAIL study. AB - BACKGROUND: The direct cost of excessive alcohol consumption to health services is substantial but dwarfed by the cost borne by the workplace as a result of lost productivity. The workplace is also a promising setting for health interventions. The Preventing Alcohol Harm in Liverpool and Knowsley (PrevAIL) project aimed to evaluate a mechanism for detecting the prevalence of alcohol related liver disease using fibrosis biomarkers. Secondary aims were to identify the additive effect of obesity as a risk factor for early liver disease; to assess other impacts of alcohol on work, using a cross-sectional survey. METHODS: Participants (aged 36-55 y) from 13 workplaces participated (March 2011-April 2012). BMI, waist circumference, blood pressure and self-reported alcohol consumption in the previous week was recorded. Those consuming more than the accepted UK threshold (men: >21 units; female: >14 units alcohol) provided a 20 ml venous blood sample for a biomarker test (Southampton Traffic Light Test) and completed an alcohol questionnaire (incorporating the Severity of Alcohol Dependence Questionnaire). RESULTS: The screening mechanism enrolled 363 individuals (52 % women), 39 % of whom drank above the threshold and participated in the liver screen (n = 141, complete data = 124 persons). Workplaces with successful participation were those where employers actively promoted, encouraged and facilitated attendance. Biomarkers detected that 30 % had liver disease (25 %, intermediate; 5 % probable). Liver disease was associated with the frequency of visits to the family physician (P = 0.036) and obesity (P = 0.052). CONCLUSIONS: The workplace is an important setting for addressing alcohol harm, but there are barriers to voluntary screening that need to be addressed. Early detection and support of cases in the community could avert deaths and save health and social costs. Alcohol and obesity should be addressed simultaneously, because of their known multiplicative effect on liver disease risk, and because employers preferred a general health intervention to one that focused solely on alcohol consumption. PMID- 26041364 TI - Making medical student course evaluations meaningful: implementation of an intensive course review protocol. AB - BACKGROUND: Ongoing course evaluation is a key component of quality improvement in higher education. The complexities associated with delivering high quality medical education programs involving multiple lecturers can make course and instructor evaluation challenging. We describe the implementation and evaluation of an "intensive course review protocol" in an undergraduate medical program METHODS: We examined pre-clerkship courses from 2006 to 2011 - prior to and following protocol implementation. Our non-parametric analysis included Mann Whitney U tests to compare the 2006/07 and 2010/11 academic years. RESULTS: We included 30 courses in our analysis. In the 2006/07 academic year, 13/30 courses (43.3 %) did not meet the minimum benchmark and were put under intensive review. By 2010/11, only 3/30 courses (10.0 %) were still below the minimum benchmark. Compared to 2006/07, courses ratings in the 2010/11 year were significantly higher (p = 0.004). However, during the study period mean response rates fell from 76.5 % in 2006/07 to 49.7 % in 2010/11. CONCLUSION: These results suggest an intensive course review protocol can have a significant impact on pre-clerkship course ratings in an undergraduate medical program. Reductions in survey response rates represent an ongoing challenge in the interpretation of student feedback. PMID- 26041365 TI - Patterned feeding experience for preterm infants: study protocol for a randomized controlled trial. AB - BACKGROUND: Neurobehavioral disabilities occur in 5-15% of preterm infants with an estimated 50-70% of very low birth weight preterm infants experiencing later dysfunction, including cognitive, behavioral, and social delays that often persist into adulthood. Factors implicated in poor neurobehavioral and developmental outcomes are hospitalization in the neonatal intensive care unit (NICU) and inconsistent caregiving patterns. Although much underlying brain damage occurs in utero or shortly after birth, neuroprotective strategies can stop lesions from progressing, particularly when these strategies are used during the most sensitive periods of neural plasticity occurring months before term age. The purpose of this randomized trial is to test the effect of a patterned feeding experience on preterm infants' neurobehavioral organization and development, cognitive function, and clinical outcomes. METHODS: This trial uses an experimental, longitudinal, 2-group design with 120 preterm infants. Infants are enrolled within the first week of life and randomized to an experimental group receiving a patterned feeding experience from the first gavage feeding through discharge or to a control group receiving usual feeding care experience. The intervention involves a continuity of tactile experiences associated with feeding to train and build neuronal networks supportive of normal infant feeding experience. Primary outcomes are neurobehavioral organization as measured by Neurobehavioral Assessment of the Preterm Infant at 3 time points: the transition to oral feedings, NICU discharge, and 2 months corrected age. Secondary aims are cognitive function measured using the Bayley Scales of Infant and Toddler Development, Third Edition at 6 months corrected age, neurobehavioral development (sucking organization, feeding performance, and heart rate variability), and clinical outcomes (length of NICU stay and time to full oral feeding). The potential effects of demographic and biobehavioral factors (perinatal events and conditions of maternal or fetal/newborn origin and immunologic and genetic biomarkers) on the outcome variables will also be considered. DISCUSSION: Theoretically, the intervention provided at a critical time in neurologic system development and associated with a recurring event (feeding) should enhance neural connections that may be important for later development, particularly language and other cognitive and neurobehavioral organization skills. TRIAL REGISTRATION: NCT01577615 11 April 2012. PMID- 26041367 TI - Merkel cell carcinoma: Overall survival after open biopsy versus wide local excision. AB - BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin with a dismal prognosis. METHODS: We conducted a retrospective medical chart review of patients with MCC who were initially diagnosed with an open biopsy (n = 30) or wide local excision (n = 24). RESULTS: Stages I, II, and III disease was found in 38%, 20%, and 16%, respectively. The 2-year and 5-year overall and disease-specific survival rates were 64.8% and 38.8% versus 45.2% and 26.4%, respectively. Cox regression multivariate model, including tissue sampling technique, re-resection, therapy modalities, pathological staging, and T and N classifications, showed that patients diagnosed initially with an open biopsy have significant worse overall (p = .014) and disease-free (p = .005) survival rates compared with patients who had a wide local excision. CONCLUSION: This study showed an improved overall survival in patients with MCC after wide local excision compared to open biopsy of the primary site at first diagnosis. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1014-E1018, 2016. PMID- 26041369 TI - The adpA-like regulatory gene from Actinoplanes teichomyceticus: in silico analysis and heterologous expression. AB - Analysis of the draft sequence of the genome of teicoplanin producer Actinoplanes teichomyceticus (NRRL-B16726) led to identification of several genes encoding AraC-family regulators that resemble AdpA, master regulator of transcription in Streptomyces. We elucidated possible regulatory functions of one of the identified genes, adpA19(at), most similar to archetypal adpA from model Streptomyces species, in a series of expression experiments. Introduction of adpA19 at under control of its own promoter on moderate copy number vector pKC1139 into NRRL-B16726 had no influence on antibiotic production and sporulation. Introduction of adpA19 at into Streptomyces coelicolor M145 and several S. ghanaensis strains had major influence on antibiotic production by these bacteria. Finally, adpA19 at expression in a set of soil actinomycete isolates led to induction of synthesis of antibiotic compounds. Our data point to pleiotropic regulatory role of adpA19(at), warranting its use as a tool to manipulate secondary metabolome of actinomycetes. PMID- 26041370 TI - Steric Enhancement of the Chemiluminescence of Luminols. AB - A surprising 20-fold increase in chemiluminescence efficiency was observed for dialkyl luminol derivatives in comparison with the parent compound. This effect could be a direct consequence of steric gearing which facilitates the transition from the intermediate endoperoxide to the electronically excited phthalate. Mechanistic aspects of this process have been supported by computational calculations (CASPT2//CASSCF). PMID- 26041371 TI - Diverticulitis of the appendix, a distinctive entity: preoperative diagnosis by computed tomography. AB - Diverticular disease of the appendix is rare and is usually diagnosed during surgery. We report a case of a 50-year-old man who presented to the emergency department with right lower quadrant pain of 1-day duration. A preoperative diagnosis of appendiceal diverticulitis was made by computed tomography of the abdomen. The patient underwent emergency laparoscopic appendectomy, which confirmed the diagnosis. PMID- 26041368 TI - Therapeutic cyclic lipopeptides mining from microbes: latest strides and hurdles. AB - Infectious diseases impose serious public health burdens and often have devastating consequences. The cyclic lipopeptides elaborated by bacteria Bacillus, Paenibacillus, Pseudomonas, Streptomyces, Serratia, Propionibacterium and fungus Fusarium are very crucial in restraining the pathogens. Composed of a peptide and a fatty acyl moiety these amphiphilic metabolites exhibit broad spectrum antimicrobial effects. Among the plethora of cyclic lipopeptides, only selective few have emerged as robust antibiotics. For their functional vigor, polymyxin, daptomycin, surfactin, iturin, fengysin, paenibacterin and pseudofactin have been integrated in mainstream healthcare. Daptomycin has been a significant part of antimicrobial arsenal since the past decade. As the magnitude of drug resistance rises in unprecedented manner, the urgency of prospecting novel cyclic lipopeptides is being perceived. Intense research has revealed the implication of these bioactive compounds stretching beyond antibacterial and antifungal. Anticancer, immunomodulatory, prosthetic parts disinfection and vaccine adjuvancy are some of the validated prospects. This review discusses the emerging applications, mechanisms governing the biological actions, role of genomics in refining structure and function, semi-synthetic analog discovery, novel strain isolation, setbacks etc. Though its beyond the scope of the current topic, for holistic purpose, the role of lipopeptides in bioremediation and crop biotechnology has been briefly outlined. This updated critique is expected to galvanize innovations and diversify therapeutic recruitment of microbial lipopeptides. PMID- 26041372 TI - Chelerythrine-lysozyme interaction: spectroscopic studies, thermodynamics and molecular modeling exploration. AB - The binding of the iminium and alkanolamine forms of chelerythrine to lysozyme (Lyz) was investigated by spectroscopy and docking studies. The thermodynamics of the binding was studied by calorimetry. Spectroscopic evidence suggested that Trp 62 and Trp-63 in the beta-domain of the protein are closer to the binding site; moreover, the binding site was at a distance of 2.27 and 2.00 nm from the iminium and alkanolamine forms, respectively, according to the Forster theory of non radiation energy transfer. The equilibrium binding constants for the iminium and alkanolamine forms at 298 K were evaluated to be 1.29 * 10(5) and 7.79 * 10(5) M( 1), respectively. The binding resulted in an alteration of the secondary structure of the protein with a distinct reduction of the helical organization. The binding of iminium was endothermic, involving electrostatic and hydrophobic interactions, while that of alkanolamine form was exothermic and dominated by hydrogen bonding interactions. Docking studies provided the atomistic details pertaining to the binding of both forms of chelerythrine and supported the higher binding in favour of the alkanolamine over the iminium. Furthermore, molecular dynamics study provided accurate insights regarding the binding of both chelerythrine forms in accordance with the experimental results obtained. Chelerythrine binding pocket involves the catalytic region and aggregation prone K-peptide region, which are sandwiched between one another. Overall, these results suggest that both the forms of the alkaloid bind to the protein but the neutral form has higher affinity than the cationic form. PMID- 26041373 TI - Increased CD1D polymorphism: identification of two novel alleles, CD1D*03 and *04, in individuals from Morocco. AB - Two novel CD1D alleles were identified in unrelated individuals from Morocco. They differ each from the common CD1D*01 allele by one nucleotide substitution in exon 2 resulting in one amino acid change in the G-ALPHA1-LIKE domain. According to the IMGT unique numbering for G domain, CD1D*03 has one nucleotide transition c136 > t in codon 46, with an arginine-to-cysteine amino acid change (R46 > C) in the D-STRAND, whereas CD1D*04 has one transition c98 > t in codon 33, with a threonine-to-methionine amino acid change (T33 > M) in the C-STRAND. This suggests that CD1D is more polymorphic than previously assumed. PMID- 26041374 TI - Characteristics of patients with late manifestation of resistance thyroid hormone syndrome: a single-center experience. AB - Resistance to thyroid hormone (RTH) is a rare genetic disease caused by reduced tissue sensitivity to thyroid hormone. The hallmark of RTH is elevated serum levels of thyroid hormone with unsuppressed thyrotropin (TSH). However, the most common form of RTH results from minor defects in the ligand-binding domain or hinge domain of the TRbeta gene, resulting in impaired T3-induced transcriptional activity, often showing mild presentation. Early diagnosis can be challenging. The objective of the current study was to characterize this specific group of RTH patients. This was a retrospective study. Patients diagnosed as RTH with TRbeta mutations were enrolled in a single institute between 2004 and 2014. A total of 14 patients were diagnosed as RTH with mutation in THbeta gene. The median age at diagnosis was 22.5 (IQR: 13.25-32.75). Goiter was the most common clinical finding. TSH was significantly elevated after TRH injection (median peak was 21.83 MUIU/l, IQR: 13.59-31.48), 9.2-fold compared to the basal level. We found 10 mutations in TRbeta gene, all located in the last four exons, and including one novel mutation, H271D. In vitro study found that H271D mutation reduced TR affinity to T3. Four patients with intact thyroid were diagnosed after 16 years old, defined as late manifestation. Compared to those diagnosed before 10 years old, patients with late manifestation presented with normal growth and mental development. Interestingly, three of them carried R438H mutation. We identified a novel p.H271D mutation in TRbeta associated with RTH. Endocrinologists should be alert that RTH is frequently found in euthyroid patients with mild symptoms and often leads to misleading diagnosis as well as inappropriate treatment. PMID- 26041375 TI - A gene-disease association study of IL18 in thyroid cancer: genotype and haplotype analyses. AB - Thyroid cancer is the most common malignancy of the endocrine system, and genetic factors have been shown to be associated with its risk. Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine that induces IFN-gamma production and is involved in T helper type 1 development. To determine the role of IL-18 gene in thyroid cancer susceptibility, we conducted a case-control study, and genotyped five single nucleotide polymorphisms (SNPs) in IL-18 gene (-656 G/T (rs1946519), 607 C/A (rs1946518), and -137 G/C (rs187238) in the promoter region and +113 T/G (rs360718) and +127 C/T (rs360717) in 5'-untranslated region) in 105 patients with thyroid cancer and 148 healthy controls from Iranian population. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific primer-PCR were used for genotyping. The association of different genotypes with thyroid cancer, tumor type, and the tumor stage was analyzed. Comparing all of the patient population with the controls, TT genotype at position -656 G/T was observed to be associated with a significantly increased risk of thyroid cancer [31/105 (30.1 %) vs 19/148 (13.1 %), p = 0.002, OR 2.90, CI 1.40-5.70]. No association with thyroid cancer was found at other positions ( 607 C/A, -137 G/C, +113 T/G, and +127 C/T). Excluding the patients with medullary carcinoma, and including only the ones with thyroid cancer derived from the follicular epithelium, nearly the same results were observed regarding the genotypes at position -656 G/T. Furthermore, significantly decreased risk of thyroid cancer derived from the follicular epithelium was observed upon inheritance of the homozygote genotype (CC) at position +127 C/T (40/94 (42.5 %) versus 84/148 (56.8 %) in patients and controls, respectively (OR 0.56, 95 % CI for OR 0.32-0.98, p = 0.04). Haplotype analysis indicated that among 32 possible haplotypes, TAGTT haplotype frequency was significantly higher in patients than in controls [12/188 (6.4 %) vs 2/292 (0.7 %), p = 0.0008] and this difference resisted Bonferroni correction (n = 19) and significant level set at 0.003. Nearly the same results were observed after excluding the patients with medullary carcinoma. No association was found between the SNPs and the stage of tumor. Our results suggest the increased susceptibility to thyroid cancer in subjects with TT genotype at position -656 G/T of the promoter of IL-18 gene, as well as TAGTT haplotype emerged from five studied SNPs in IL-18 gene. The data also suggest that the inheritance of +127 CC genotype may protect individuals from thyroid cancer derived from follicular epithelium. PMID- 26041376 TI - Bisphosphonates and glucocorticoid-induced osteoporosis: cons. AB - During the use of glucocorticoids (GCs), both vertebral and nonvertebral fracture risk are increased, due to the direct and indirect negative effects of GCs on bone, muscles, and the activity of the underlying inflammatory diseases. Inhibition of bone formation and increased apoptosis of osteocytes play a consistent and crucial role in the pathogenesis of glucocorticoid-induced osteoporosis (GIO), while changes in bone resorption during GC-use are variable. To prevent fractures, important general measures include using the lowest possible dose of GCs, treating the underlying disease adequately, a healthy life style, adequate calcium and vitamin D supplementation, and regular exercise. Although it has been shown that bisphosphonates reduce vertebral fractures during the first 2 years of GC-treatment, there are no data on long-term use of bisphosphonates during GC-treatment. Of some concern in GIO, bisphosphonates reduce bone turnover, including bone formation, which is already downregulated by GCs. In contrast, the use of the anabolic agent teriparatide is more effective in reducing vertebral fractures than alendronate. In summary, bisphosphonates remain the first choice in the first two years of treatment in GC-treated patients with high fracture risk, but their long-term effects on bone quality and fracture risk reduction remain uncertain. PMID- 26041377 TI - Body composition in prostate cancer patients: novel insights suggest diverse prognostic roles of lean and fat mass. PMID- 26041378 TI - Activated air produced by shielded sliding discharge plasma mediates plasmid DNA delivery to mammalian cells. AB - Cold plasma is emerging as a potential method for medical applications. The current study assessed the efficacy of a novel cold plasma reactor based on shielded sliding discharge producing cathode-directed streamers generated in ambient air for the delivery of plasmid DNA. Experiments were performed with mouse melanoma cells (B16F10) and human keratinocyte cells (HaCaT) inoculated with plasmid DNA encoding luciferase. Quantitative results measured over a 72-h period displayed luciferase expression levels as high as 5-fold greater in cells exposed to plasma-activated air (PAA) than levels obtained from the inoculation of plasmid DNA alone (P < 0.05, P < 0.01). No effect on cell viability was observed. Delivery of plasmid encoding GFP to HaCaT cells seeded on polycaprolactone (PCL) scaffolds was confirmed by immunostaining. The use of cold plasma for DNA delivery is attractive as it provides a non-viral, non-invasive method where the electrode or the plasma itself never directly contacts the exposed site. The current device design provides localized DNA transfer using a novel technology. Our report suggests PAA warrants further exploration as an alternative or supplemental approach for DNA transfer. PMID- 26041379 TI - Gross classification of solitary small hepatocellular carcinoma on preoperative computed tomography: Prognostic significance after radiofrequency ablation. AB - AIM: The prognostic significance of the gross classification of hepatocellular carcinoma (HCC) has been confirmed in both hepatectomy and living donor liver transplantation. However, the role of this type of classification in HCC treated with radiofrequency ablation (RFA) has rarely been reported. The aim of this study was to investigate the role of preoperative gross classification in cases of solitary small HCC treated with RFA. METHODS: From January 2007 to September 2013, 103 patients with solitary small HCC treated with RFA were retrospectively reviewed. The lesions were classified into three types according to gross appearance in preoperative contrast-enhanced computed tomography (CT) scans. Clinicopathological variables and survival information were compared among these three types. Univariate and multivariate analyses were performed to clarify the long-term prognostic factors. RESULTS: The group of 103 tumors comprised 34 type 1, 49 type 2 and 20 type 3 tumors. The level of preoperative serum alpha fetoprotein in the type 3 tumors was significantly higher than that in types 1 and 2 (P < 0.05). The overall survival of the patients with type 3 HCC was the poorest among the three types. The tumor-free survival of the patients with types 3 and 2 HCC were significantly poorer than those with type 1 (P < 0.05). The univariate analysis showed that gross classification, alpha-fetoprotein level, tumor size and degree of enhancement were poor prognostic factors. The multivariate analysis indicated that the gross classification was the only independent prognostic indicator. CONCLUSION: The preoperative gross classification was of great prognostic significance in solitary small HCC treated with RFA. PMID- 26041380 TI - Pseudo-binary electrolyte, LiBH4-LiCl, for bulk-type all-solid-state lithium sulfur battery. AB - The ionic conduction and electrochemical and thermal stabilities of the LiBH4 LiCl solid-state electrolyte were investigated for use in bulk-type all-solid state lithium-sulfur batteries. The LiBH4-LiCl solid-state electrolyte exhibiting a lithium ionic conductivity of [Formula: see text] at 373 K, forms a reversible interface with a lithium metal electrode and has a wide electrochemical potential window up to 5 V. By means of the high-energy mechanical ball-milling technique, we prepared a composite powder consisting of elemental sulfur and mixed conductive additive, i.e., Ketjen black and Maxsorb. In that composite powder, homogeneous dispersion of the materials is achieved on a nanometer scale, and thereby a high concentration of the interface among them is induced. Such nanometer-scale dispersals of both elemental sulfur and carbon materials play an important role in enhancing the electrochemical reaction of elemental sulfur. The highly deformable LiBH4-LiCl electrolyte assists in the formation of a high concentration of tight interfaces with the sulfur-carbon composite powder. The LiBH4-LiCl electrolyte also allows the formation of the interface between the positive electrode and the electrolyte layers, and thus the Li-ion transport paths are established at that interface. As a result, our battery exhibits high discharge capacities of 1377, 856, and 636 mAh g(-1) for the 1st, 2nd, and 5th discharges, respectively, at 373 K. These results imply that complex hydride based solid-state electrolytes that contain Cl-ions in the crystal would be integrated into rechargeable batteries. PMID- 26041381 TI - An integrated structural proteomics approach along the druggable genome of Corynebacterium pseudotuberculosis species for putative druggable targets. AB - BACKGROUND: The bacterium Corynebacterium pseudotuberculosis (Cp) causes caseous lymphadenitis (CLA), mastitis, ulcerative lymphangitis, and oedema in a number of hosts, comprising ruminants, thereby intimidating economic and dairy industries worldwide. So far there is no effective drug or vaccine available against Cp. Previously, a pan-genomic analysis was performed for both biovar equi and biovar ovis and a Pathogenicity Islands (PAIS) analysis within the strains highlighted a large set of proteins that could be relevant therapeutic targets for controlling the onset of CLA. In the present work, a structural druggability analysis pipeline was accomplished along 15 previously sequenced Cp strains from both biovar equi and biovar ovis. METHODS AND RESULTS: We computed the whole modelome of a reference strain Cp1002 (NCBI Accession: NC_017300.1) and then the homology models of proteins, of 14 different Cp strains, with high identity (>= 85%) to the reference strain were also done. Druggability score of all proteins pockets was calculated and only those targets that have a highly druggable (HD) pocket in all strains were kept, a set of 58 proteins. Finally, this information was merged with the previous PAIS analysis giving two possible highly relevant targets to conduct drug discovery projects. Also, off-targeting information against host organisms, including Homo sapiens and a further analysis for protein essentiality provided a final set of 31 druggable, essential and non-host homologous targets, tabulated in table S4, additional file 1. Out of 31 globally druggable targets, 9 targets have already been reported in other pathogenic microorganisms, 3 of them (3-isopropylmalate dehydratase small subunit, 50S ribosomal protein L30, Chromosomal replication initiator protein DnaA) in C. pseudotuberculosis. CONCLUSION: Overall we provide valuable information of possible targets against C. pseudotuberculosis where some of these targets have already been reported in other microorganisms for drug discovery projects, also discarding targets that might be physiologically relevant but are not amenable for drug binding. We propose that the constructed in silico dataset might serve as a guidance for the scientific community to have a better understanding while selecting putative therapeutic protein candidates as druggable ones as effective measures against C. pseudotuberculosis. PMID- 26041382 TI - TRPC3-dependent synaptic transmission in central mammalian neurons. AB - The transient receptor potential (TRPC) proteins form non-selective cation channels that are activated downstream of Gq-phospholipase C-coupled receptors. TRPC3, one of the seven members of the TRPC subfamily, combines functions of an unspecific ion channel and a signal transducer. In the mammalian brain, the expression of TRPC3 is highest in cerebellar Purkinje cells, the principal neurons, and the sole output of the cerebellar cortex. In this review, we summarize findings identifying TRPC3 channels as integral components of glutamatergic metabotropic synaptic transmission. We give an overview of postsynaptic interaction partners and activation mechanisms of TRPC3 in central neurons. Finally, we address the deleterious consequences of distorted TRPC3 synaptic signaling for cerebellar function in different mouse models and present TRPC3 as an emerging candidate protein implicated in various forms of ataxia in humans. PMID- 26041384 TI - International prevalence of the use of peripheral intravenous catheters. AB - Over a billion peripheral intravenous catheters (PIVCs) are inserted each year in hospitalized patients worldwide. However, international data on prevalence and management of these devices are lacking. The study assessed the prevalence of PIVCs and their management practices across different regions of the world. This global audit involved 14 hospitals across 13 countries, with 479 patients screened for the presence of a PIVC. We found 59% of patients had at least 1 PIVC in place, and 16% had other types of vascular devices. We also found that overall, 25% of patients had no vascular device in place. The majority of PIVCs were inserted by nursing staff or a specialist team. The prevalence of idle PIVCs in place with no fluid or medication orders was 16%, and 12% of PIVCs had at least 1 symptom of phlebitis. PMID- 26041383 TI - Estrogen receptor alpha promotes smoking-carcinogen-induced lung carcinogenesis via cytochrome P450 1B1. AB - Smoking carcinogen N-nitrosamines such as 4-methylnitrosamino-l-3-pyridyl butanone (NNK) require metabolic activation to exert their genotoxicity. The first activation step is mainly catalyzed by cytochrome P450 (CYP) family. Estrogen receptor alpha (ERalpha) plays a role in lung pathology. The association between them is unknown. In this study, we explored the relationship and function of CYP1B1 and ERalpha in NNK-induced lung tumorigenesis. CYP1B1 and ERalpha expression was analyzed in human lung cancer tissues and NNK-induced lung tumor of A/J mice. Cell lines NCI-H23 and NCI-H460 were employed to further study the responsible mechanisms using various cellular and molecular approaches. Our in vivo experiments demonstrated that CYP1B1 and ERalpha were over-expressed at the early stage of NNK-induced lung tumorigenesis. Microarray analysis found that ERalpha was involved in the extracellular-signal-regulated kinase (ERK)/MAPK pathway. NNK activated RAS/ERK/AP1 as it remarkably increased the levels of p ERK, c-Fos, and c-Jun but inhibited multiple negative regulators of Ras/ERK/AP1, Pdcd4, Spry1, Spry2, and Btg2 through up-regulating miR-21. Both CYP1B1 siRNA and ERK-specific inhibitor U0126 suppressed NNK-mediated ERalpha up-regulation, suggesting that ERalpha was downstream of CYP1B1 and ERK. ERK inactivation led to the accumulation of CYP1B1, indicating that CYP1B1 was upstream of ERK activation. Inhibition of ERK or ERalpha decreased NNK-induced cell proliferation. Blockage of CYP1B1 or ERalpha induced apoptosis of lung cancer cells. Collectively, NNK-mediated ERalpha induction is via CYP1B1 and ERK and contributes to the lung carcinogenesis. The inhibition of CYP1B1, ERK, or ERalpha may arrest the lung cancer cell growth, implicating a pivotal strategy for the treatment of lung cancer. KEY MESSAGES: Smoking carcinogen NNK requires metabolic activation to exert their genotoxicity. CYP1B1 is the enzyme to catalyze NNK. NNK activates CYP1B1 and ERK to induce ERalpha. Inhibition of CYP1B1, ERK, or ERalpha arrests the lung cancer cell growth. PMID- 26041385 TI - Thermal comfort indices of female Murrah buffaloes reared in the Eastern Amazon. AB - The study aimed to develop new and more specific thermal comfort indices for buffaloes reared in the Amazon region. Twenty female Murrah buffaloes were studied for a year. The animals were fed in pasture with drinking water and mineral supplementation ad libitum. The following parameters were measured twice a week in the morning (7 AM) and afternoon (1 PM): air temperature (AT), relative air humidity (RH), dew point temperature (DPT), wet bulb temperature (WBT), black globe temperature (BGT), rectal temperature (RT), respiratory rate (RR), and body surface temperature (BST). The temperature and humidity index (THI), globe temperature and humidity index (GTHI), Benezra's comfort index (BTCI), and Iberia's heat tolerance index (IHTI) were calculated so they could be compared to the new indices. Multivariate regression analyses were carried out using the canonical correlation model, and all indices were correlated with the physiological and climatic variables. Three pairs of indices (general, effective, and practical) were determined comprising the buffalo comfort climatic condition index (BCCCI) and the buffalo environmental comfort index (BECI). The indices were validated and a great agreement was found among the BCCCIs (general, effective, and practical), with 98.3 % between general and effective a.nd 92.6 % between general and practical. A significant correlation (P < 0.01) was found between the new indices and the physiological and climatic variables, which indicated that these may be used in pairs to diagnose thermal stress in buffaloes reared in the Amazon. PMID- 26041386 TI - Birth month affects lifetime disease risk: a phenome-wide method. AB - OBJECTIVE: An individual's birth month has a significant impact on the diseases they develop during their lifetime. Previous studies reveal relationships between birth month and several diseases including atherothrombosis, asthma, attention deficit hyperactivity disorder, and myopia, leaving most diseases completely unexplored. This retrospective population study systematically explores the relationship between seasonal affects at birth and lifetime disease risk for 1688 conditions. METHODS: We developed a hypothesis-free method that minimizes publication and disease selection biases by systematically investigating disease birth month patterns across all conditions. Our dataset includes 1 749 400 individuals with records at New York-Presbyterian/Columbia University Medical Center born between 1900 and 2000 inclusive. We modeled associations between birth month and 1688 diseases using logistic regression. Significance was tested using a chi-squared test with multiplicity correction. RESULTS: We found 55 diseases that were significantly dependent on birth month. Of these 19 were previously reported in the literature (P < .001), 20 were for conditions with close relationships to those reported, and 16 were previously unreported. We found distinct incidence patterns across disease categories. CONCLUSIONS: Lifetime disease risk is affected by birth month. Seasonally dependent early developmental mechanisms may play a role in increasing lifetime risk of disease. PMID- 26041387 TI - T-wave oversensing in patients with Brugada syndrome: true bipolar versus integrated bipolar implantable cardioverter defibrillator leads: multicenter retrospective study. AB - BACKGROUND: It is thought that dedicated bipolar are more susceptible to T-wave oversensing when compared with integrated bipolar leads. This could be of extreme importance in patients with Brugada syndrome (BrS) because T-wave oversensing in this population is more frequent when compared with other implantable cardioverter defibrillator (ICD) recipients without BrS. We aimed to compare the incidence of T-wave oversensing in patients with BrS according to the type of lead (integrated bipolar versus true/dedicated bipolar). METHODS AND RESULTS: All patients diagnosed with BrS with an ICD implant in 10 tertiary hospitals between 1993 and 2013 were included in the study. A total of 480 patients were included (mean age, 45.6+/-14 years). During a mean follow-up of 74.9+/-51.7 months (median, 69; range, 2-236), 28 patients had T-wave oversensing (5.8%), leading to inappropriate shock in 18 (3.8%). All these events occurred in patients with true bipolar ICD leads (P=0.01) and in 2 patients it was solved instantaneously by changing the configuration from a dedicated to an integrated bipolar sensing configuration. In the stepwise multivariate models, only integrated bipolar ICD leads (hazard ratio, 0.34; 95% confidence interval, 0.171-0.675; P=0.002) was independent predictor of non-T-wave oversensing. CONCLUSIONS: T-wave oversensing is a potential reason of inappropriate shocks in patients with BrS receiving ICDs. In the vast majority it can be solved by reprogramming. However, in some patients it still requires invasive intervention. Importantly, incidence is significantly lower using an integrated bipolar lead system when compared with a dedicated bipolar lead system and hence the latter should be routinely used in BrS cases. PMID- 26041388 TI - Effects of total gastrectomy on plasma silicon and amino acid concentrations in men. AB - The aim of the study was to determine one-year effects of total gastrectomy on plasma silicon and free amino acid concentrations in patients and evaluate changes of volumetric bone mineral density (vBMD) in lumbar spine. Eight patients were enrolled to the control (CTR) group. Six patients subjected to total gastrectomy (GX group) were included to the experimental group. vBMD in trabecular and cortical bone was measured in lumbar vertebrae at baseline (before surgery) and one year later using quantitative computed tomography. Plasma concentrations of silicon and free amino acids were determined at baseline and one year later using photometric method and ion-exchange chromatography. Body weights within CTR and GX groups were not different after one-year follow-up when compared to the baseline values (P > 0.05). An average annual decrease of vBMD in the trabecular bone in the gastrectomized patients reached 15.0% in lumbar spine and was significantly different in comparison to the percentage changes observed in CTR group (P = 0.02). One-year percentage change of vBMD in the cortical bone in L1 and L2 has shown significantly decreased values by 10.5 and 9.1% in the GX group when compared to the percentage change observed in the controls (P < 0.05). Plasma concentration of adipic acid was significantly higher by 101.6% one year after total gastrectomy procedure in the patients when compared to the baseline value (P = 0.01). Plasma concentration of silicon was significantly lowered by 26.7% one year after the total gastrectomy when compared to the baseline value (P = 0.009). Total gastrectomy in patients has induced severe osteoporotic changes in lumbar spine within one-year period. The observed osteoporotic changes were associated with decreased plasma concentration of silicon indicating importance of exocrine and endocrine functions of stomach for silicon homeostasis maintenance. Gastrectomy-induced bone loss was not related to decreased amino acid concentration in plasma obtained from overnight fasted patients. PMID- 26041389 TI - RTEF-1 protects against oxidative damage induced by H2O2 in human umbilical vein endothelial cells through Klotho activation. AB - Oxidative stress is a main risk factor of vascular aging, which may lead to age associated diseases. Related transcriptional enhancer factor-1 (RTEF-1) has been suggested to regulate many genes expression which are involved in the endothelial angiogenesis and vasodilation. However, whether RTEF-1 has a direct role in anti oxidation and what specific genes are involved in RTEF-1-driven anti-oxidation have not been elucidated. In this study, we found that overexpressing RTEF-1 in H2O2-treated human umbilical vein endothelial cells decreased senescence associated-beta-galactosidase (SA-beta-gal)-positive cells and G0/G1 cells population. The expressions of p53 and p21 were decreased in H2O2-treated RTEF-1 o/e human umbilical vein endothelial cells. However, specific small interfering RNA of RTEF-1 totally reversed the anti-oxidation effect of RTEF-1 and inhibited RTEF-1-induced decreased p53 and p21 expressions. It demonstrated that RTEF-1 could protect cells from H2O2-induced oxidative damage. In addition, we demonstrated that RTEF-1 could up-regulate Klotho gene expression and activate its promoter. Furthermore, Klotho small interfering RNA significantly blocked RTEF-1-driven endothelial cell protection from H2O2-induced oxidative damage and increased p53 and p21 expressions. These results reveal that RTEF-1 is a potential anti-oxidation gene and can prevent H2O2-induced endothelial cell oxidative damage by activating Klotho. PMID- 26041390 TI - Retinal pigment epithelial cell proliferation. AB - The human retinal pigment epithelium forms early in development and subsequently remains dormant, undergoing minimal proliferation throughout normal life. Retinal pigment epithelium proliferation, however, can be activated in disease states or by removing retinal pigment epithelial cells into culture. We review the conditions that control retinal pigment epithelial proliferation in culture, in animal models and in human disease and interpret retinal pigment epithelium proliferation in context of the recently discovered retinal pigment epithelium stem cell that is responsible for most in vitro retinal pigment epithelial proliferation. Retinal pigment epithelial proliferation-mediated wound repair that occurs in selected macular diseases is contrasted with retinal pigment epithelial proliferation-mediated fibroblastic scar formation that underlies proliferative vitreoretinopathy. We discuss the role of retinal pigment epithelial proliferation in age-related macular degeneration which is reparative in some cases and destructive in others. Macular retinal pigment epithelium wound repair and regression of choroidal neovascularization are more pronounced in younger than older patients. We discuss the possibility that the limited retinal pigment epithelial proliferation and latent wound repair in older age-related macular degeneration patients can be stimulated to promote disease regression in age-related macular degeneration. PMID- 26041392 TI - [Extended voriconazole theraphy and long term survival of a patient with invasive central aspergillosis causing stroke]. AB - Central nervous system (CNS) aspergillosis with stroke has a high mortality and poor prognosis generally. We report a 78-years-old woman with diabetes mellitus, who developed invasive paranasal sinus aspergillosis with the orbital apex syndrome on the right side and cerebral infarction caused by intracranial occlusion of the right internal carotid artery. Based on the presence of a mass lesion in the ethmoid sinus extending to the orbital apex on the right side with cranial CT, the mass lesion was surgically removed and the pathological examination of the surgical specimen revealed aspergillus mold. Immediately after surgery, we initiated treatment with voriconazole 200 mg * 2/day intravenously for 38 days, and then via feeding tube for 86 days until the galactomannan aspergillus antigen level in the cerebrospinal fluid became negative at 132 days. She is alive now for almost two years without relapse of aspergillosis. There is no definitive guideline for management of patients with CNS aspergillosis concerning the length of drug treatment and the method for monitoring the response for treatment. We believe that measurement of the galactomannan aspergillus antigen level in the cerebrospinal fluid might be a useful way of monitoring the efficacy of treatment for CNS aspergillosis. PMID- 26041391 TI - Dietary essentiality of "nutritionally non-essential amino acids" for animals and humans. AB - Based on growth or nitrogen balance, amino acids (AA) had traditionally been classified as nutritionally essential (indispensable) or non-essential (dispensable) for animals and humans. Nutritionally essential AA (EAA) are defined as either those AA whose carbon skeletons cannot be synthesized de novo in animal cells or those that normally are insufficiently synthesized de novo by the animal organism relative to its needs for maintenance, growth, development, and health and which must be provided in the diet to meet requirements. In contrast, nutritionally non-essential AA (NEAA) are those AA which can be synthesized de novo in adequate amounts by the animal organism to meet requirements for maintenance, growth, development, and health and, therefore, need not be provided in the diet. Although EAA and NEAA had been described for over a century, there are no compelling data to substantiate the assumption that NEAA are synthesized sufficiently in animals and humans to meet the needs for maximal growth and optimal health. NEAA play important roles in regulating gene expression, cell signaling pathways, digestion and absorption of dietary nutrients, DNA and protein synthesis, proteolysis, metabolism of glucose and lipids, endocrine status, men and women fertility, acid-base balance, antioxidative responses, detoxification of xenobiotics and endogenous metabolites, neurotransmission, and immunity. Emerging evidence indicates dietary essentiality of "nutritionally non-essential amino acids" for animals and humans to achieve their full genetic potential for growth, development, reproduction, lactation, and resistance to metabolic and infectious diseases. This concept represents a new paradigm shift in protein nutrition to guide the feeding of mammals (including livestock), poultry, and fish. PMID- 26041393 TI - [A case with both infectious cavernous sinus thrombosis and Lemierre syndrome due to intraoral resident flora]. AB - The present report describes a 54-year-old woman with cavernous sinus thrombosis (CST) presenting with fever, and marked periorbital swelling. There is a history of untreated periodontal disease. On initial examination, periorbital pain associated with bilateral blephaloptosis, chemosis, and disturbed eye movement was present. The laboratory evaluation showed significant elevations in inflammatory and fibrinolytic markers. Diffusion-weighted MRI revealed high signal intensities in the bilateral superior ophthalmic veins (SOV). Contrast enhanced computed tomography (CT) of the cranium showed an enlarged right SOV and a non-enhancing lesion within the right SOV and bilateral cavernous sinus, indicating cavernous sinus thrombosis with diffuse SOV thrombosis. Blood culture performed on admission showed bacterial infection by intraoral resident flora; therefore, the CST was attributed to untreated periodontal disease. Contrast enhanced CT of the case also revealed the presence of thrombosis in the jugular vein associated with micropulmonary embolus, indicating co-occurrence of Lemierre's syndrome. Antibiotic and anticoagulant treatment were initiated, and the tooth decay was treated; all clinical symptoms and signs subsequently improved. Additional neuroimaging showed that the thrombus was absent from both SOV and the cavernous sinus. Infectious CST is life threatening; therefore, laboratory and imaging examination should be performed quickly, and antibiotic and anticoagulant therapy administrated immediately. PMID- 26041394 TI - [Aggregatibacter segnis endocarditis mimicking antineutrophil cytoplasmic antibody-associated vasculitis presenting with cerebral hemorrhage: a case report]. AB - A 56-year-old man who underwent a tooth extraction in the previous year presented with weakness of the right upper extremity. Brain CT and MRI scans showed subcortical hemorrhage in the left frontal lobe. His body temperature was 37.5 degrees C. Blood examination revealed anemia, elevated levels of C-reactive protein, and a positive result for PR3-ANCA. Aggregatibacter segnis was identified in the incubated blood cultures, and transesophageal echocardiograms showed infectious growth in the anterior mitral leaflet. He was diagnosed with infectious endocarditis. After treatment with ceftriaxione, the clinical symptoms were improved. We concluded that infectious endocarditis caused cerebral hemorrhage and that the positive result for PR3-ANCA was a false positive. Infectious endocarditis can mimic ANCA-associated vasculitis. When ANCA associated vasculitis is suspected, infectious endocarditis must be ruled out. PMID- 26041395 TI - [Chronic intracerebral hemorrhage in the basal ganglia: Report of two cases and prevalence]. AB - Two patients presented with chronic intracerebral hemorrhage (CIH) in the basal ganglia. A 48-year-old man (Case 1) was admitted to our hospital because of hypertensive right putaminal hemorrhage. On day 14, his hematoma surrounding the edema had grown without re-bleeding as seen on head CT, which was then removed endoscopically on day 28. Biopsied specimen of the hematoma capsule showed granulomatous tissue with vascularity. A 54-year-old man (Case 2) was admitted to our hospital because of bilateral intracerebral hemorrhage in the basal ganglia of the right putamen and left thalamus. On head CT, both hematomas were found to be enlarged without change in his symptoms on the 11th day after onset. His symptoms and signs subsided with medical treatment for 4 weeks. Cerebral angiography showed no abnormality of cerebral vessels. The patient had intracerebral hemorrhage in the basal ganglia or cerebral lobes 5 times in the past 10 years. Although no arterial or venous abnormality was detected by cerebral angiography and MRI/MRA, the abnormality of vessels including capillaries was strongly suggested. CIH should be considered a possibility when the symptom or hematoma does not improve even 2 weeks after the onset. The prevalence of CIH in our hospital was 0.08% of total intracerebral hemorrhages and 0.15% of hemorrhages in the basal ganglia. PMID- 26041396 TI - [A child who developed internal carotid artery obstruction 2 weeks after incurring an intraoral blunt injury: A case report]. AB - This report describes a 9-year-old boy with an internal carotid artery (ICA) injury caused by a fall with the blunt edge of a toothbrush held in the mouth. The initial injury appeared trivial, but 2 weeks later, generalized convulsion and left hemiparesis occurred. Magnetic resonance imaging and magnetic resonance angiography revealed an infarction of the right striatum, right ICA occlusion, and stenosis of the right middle cerebral artery, which were caused by the dissection or intimal damage of the ICA due to the blunt trauma. For children, intraoral blunt trauma sometimes causes ICA occlusion and consecutive strokes after the latent interval of days to weeks. Therefore, a careful clinical observation is essential to prevent overlooking strokes. This patient was an unique case with a long latent interval among the past literatures. PMID- 26041397 TI - Association mapping for frost tolerance using multi-parent advanced generation inter-cross (MAGIC) population in faba bean (Vicia faba L.). AB - A multi-parent advanced generation inter-cross (MAGIC) derived from 11 founder lines in faba bean was used in this study to identify quantitative trait loci (QTL) for frost tolerance traits using the association mapping method with 156 SNP markers. This MAGIC population consists of a set of 189 genotypes from the Gottingen Winter Bean Population. The association panel was tested in two different experiments, i.e. a frost and a hardening experiment. Six morphological traits, leaf fatty acid composition, relative water content in shoots were scored in this study. The genotypes presented a large genetic variation for all traits that were highly heritable after frost and after hardening. High phenotypic significant correlations were established between traits. The principal coordinates analysis resulted in no clear structure in the current population. Association mapping was performed using a general linear model and mixed linear model with kinship. A False discovery rate of 0.20 (and 0.05) was used to test the significance of marker-trait association. As a result, many putative QTLs for 13 morphological and physiological traits were detected using both models. The results reveal that QTL mapping by association analysis is a powerful method of detecting the alleles associated with frost tolerance in the winter faba bean which can be used in accelerating breeding programs. PMID- 26041398 TI - Management of Brain Metastasis in Patients With Pulmonary Neuroendocrine Carcinomas. AB - BACKGROUND: The patterns of intracranial failure in patients with brain metastasis from pulmonary neuroendocrine carcinoma (PNEC) remain unknown. METHODS: From 1998 to 2013, 29 patients with the diagnosis of PNEC were treated for brain metastasis: 16 patients (55%) underwent whole-brain radiation therapy (WBRT), 5 (17%) patients underwent WBRT with a stereotactic radiosurgery (SRS) boost, and 8 (28%) patients underwent primary SRS alone. RESULTS: The median age at treatment was 61 years (range: 44-84 years) and the median follow-up was 9.6 months (0-157.4 months). Of the patients treated with SRS alone, 1 patient had radiographic local progression of disease and 1 patient had a distant intracranial failure. Of the patients treated with WBRT with or without an SRS boost, 9 patients developed intracranial progression, including 1 local failure. No differences in rates of intracranial progression or local failure between the 2 groups (P = .94 and P = .44, respectively) were observed. The actuarial rates of distant intracranial failure at 12 months were 32.9% (95% confidence interval [95% CI] 8.9%-56.8%) and 25% (95% CI 0.0%-67.4%) in patients undergoing primary WBRT or SRS, respectively (P = .31). The median overall survival was 15.8 months in patients treated with WBRT and 20.4 months in patients treated with primary SRS (P = .78). CONCLUSION: Patients with brain metastasis from PNECs can be effectively treated with either WBRT or SRS alone, with a pattern of failure more consistent with non-small cell lung cancer than small cell lung cancer. In this series, there was not a statistically significant increased risk of distant intracranial failure when patients were treated with primary SRS. PMID- 26041399 TI - Radix Astragali and Tanshinone Help Carboplatin Inhibit B16 Tumor Cell Growth. AB - BACKGROUND: Excessive UV radiation causes increased melanoma incidence. Postoperation chemotherapy will destroy lymphocytes and compromise immune response. Immunodepression is also detected in patients with cancers. Previous studies suggested that polysaccharide-protein complexes manifested immunomodulatory and antitumor activities. Radix Astragali (RA) extract is a product of polysaccharide-protein complexes, which has been used in the treatment of a variety of diseases because of its low toxicity to the host. Tanshinone (TA) is a derivative of phenanthrenequinone isolated from Danshen, which is suggested to inhibit tumor growth by inducing apoptosis in tumor cells. Carboplatin (CA) is a commonly used chemotherapeutic drug in melanoma treatment. Therefore, we hypothesized that the combination of RA and TA will help CA better inhibit the B16 cell growth. PURPOSE: The study will test that the efficacy of growth inhibition of tumor cell produced by CA + RA + TA is better than CA + RA or CA + TA. METHODS: The B16 tumor cells were injected to Swiss-Hauschka (ICR) mice subcutaneously. Twenty-four hours later, mice received CA intraperitoneally, CA + RA (RA were administered gastrically at the dosage of 10 g/kg body weight), CA + TA (TA were administered gastrically at the dosage of 0.5 g/kg body weight), or no treatment (model group). Tumor weight, volume, latency, incidence, the percentage of CD4(+) and CD8(+) in spleen, and natural killer (NK), and cytotoxic lymphocyte (CTL) activities were measured and compared among different groups. RESULTS: Compared with mice treated with CA + RA, CA + TA, or CA alone, the mice treated with CA + RA + TA showed (1) significantly smaller tumor weight and tumor volume; (2) significantly longer tumor latency; (3) significantly lower tumor incidence; and (4) significantly increased percentage of CD4(+) and CD8(+) in spleen and increased activities of NK and CTL. CONCLUSION: Combination of RA and TA can help CA produce more effective inhibition on B16 cell growth. PMID- 26041401 TI - The importance of second shell effects in the simulation of hydrated Sr2+ hydroxide complexes. AB - Density functional theory at the meta-GGA level is employed to study the microsolvation of Sr(2+) hydroxides, in order to establish likely candidate species for the interaction of nuclear fission-generated strontium with corroded Magnox fuel cladding in high pH spent nuclear fuel storage ponds. A combination of the COSMO continuum solvation model and one or two shells of explicit water molecules is employed. Inclusion of only a single explicit solvation shell is unsatisfactory; open regions are present in the strontium coordination shell which would not exist in real aqueous complexes, and many optimised structures possess unavoidable energetic instabilities. Incorporation of a second shell of explicit waters, however, yields energetically minimal structures without open regions in the first strontium coordination shell. The most stable systems with one, two or three hydroxide ions are all 6-coordinated with a distorted trigonal antiprismatic geometry, whereas systems with four OH(-) ions have a most stable coordination number of five. Transformation, via a proton transfer mechanism, from one coordination mode to another (e.g. from a system with two hydroxides bound directly to the strontium to one in which a hydroxide ion migrates into the second coordination shell) is found to be energetically facile. It is concluded that the most likely strontium-hydroxide complexes to be found in high pH aqueous solutions are mono- and dihydroxides, and that these coexist. PMID- 26041400 TI - Anti-HER3 Monoclonal Antibody Inhibits Acquired Trastuzumab-Resistant Gynecologic Cancers. AB - BACKGROUND: Antibody resistance, both de novo and acquired, is usually related to high risk of recurrence and lower survival rate in gynecologic cancers. Prevention or reversal of the resistance often yields beneficial clinical results. It was reported that anti-human epidermal growth factor receptor 3 monoclonal antibody was effective against trastuzumab-resistant breast cancer cells. Here in our laboratory, an acquired trastuzumab-resistant ovarian cancer cell line, SKOV3-T, was established previously. Further, human epidermal growth factor receptor 3 was observed to be upregulated in this cell line by microarray detection, suggesting that the antagonist against human epidermal growth factor receptor 3 might be effective to inhibit the resistant cells. METHODS: We developed an anti-human epidermal growth factor receptor 3 monoclonal antibody, LMAb3, and its affinity to bind human epidermal growth factor receptor 3 was calculated by the Biacore method. Preliminarily, LMAb3's antitumor activity was evaluated in vitro using cell growth/proliferation and clone formation assays in the breast cancer cell line MCF-7. Furthermore, LMAb3 was also evaluated for its inhibitory effect on the carcinogenicity of the SKOV3-T cells, which were induced to overexpress human epidermal growth factor receptor 3, both in vitro and in vivo. The possible underlying signal transduction mechanisms were also identified by Western blot in the MCF-7 and SKOV3-T cells. RESULTS: LMAb3 was able to inhibit the cell growth/proliferation, clone, and tumor formation both in vitro (in the MCF-7 and SKOV3-T cells) and in vivo. The underlying mechanism of LMAb3 possibly involves inactivation of the HER family proteins (human epidermal growth factor receptor 1, human epidermal growth factor receptor 2, and especially human epidermal growth factor receptor 3) as well as the downstream mitogen-activated protein kinase and protein kinase B pathways. CONCLUSION: Our work suggests that satisfactory curative effects might be achieved with LMAb3 to treat the trastuzumab-resistant, human epidermal growth factor receptor 3-positive cases of gynecologic cancers. PMID- 26041402 TI - Plain packaging for tobacco products faces UK legal challenge. PMID- 26041404 TI - Organometallic rhenium(III) chalcogenide clusters: coordination of N-heterocyclic carbenes. AB - The preparation of rhenium based octahedral clusters containing N-heterocyclic carbenes is described. These represent the first examples of [M6(MU3-Q)8](n+) or [M6(MU3-X)8](n+) clusters to contain a carbene ligand of any type (NHC, Fischer or Schrock). Surprisingly, the NHC ligands attenuate their luminescent properties. PMID- 26041405 TI - Anomalies of a topologically ordered surface. AB - Bulk insulators with strong spin orbit coupling exhibit metallic surface states possessing topological order protected by the time reversal symmetry. However, experiments show vulnerability of topological states to aging and impurities. Different studies show contrasting behavior of the Dirac states along with plethora of anomalies, which has become an outstanding problem in material science. Here, we probe the electronic structure of Bi(2)Se(3) employing high resolution photoemission spectroscopy and discover the dependence of the behavior of Dirac particles on surface terminations. The Dirac cone apex appears at different binding energies and exhibits contrasting shift on Bi and Se terminated surfaces with complex time dependence emerging from subtle adsorbed oxygen surface atom interactions. These results uncover the surface states behavior of real systems and the dichotomy of topological and normal surface states important for device fabrication as well as realization of novel physics such as Majorana Fermions, magnetic monopole, etc. PMID- 26041406 TI - The diagnosis of left ventricular assist device thrombosis. AB - The clinical course of a patient with a left ventricular assist device is described. A total of 6 weeks after device insertion, the lactate dehydrogenase (LDH) level increased to 2801 U/l despite adding low-molecular-weight heparin to acenocoumarol and aspirin. Pump thrombosis was suspected but unconfirmed by computed tomography. Increased pump power requirement did not occur. Instituting unfractionated heparin caused a drop in the LDH level. After discontinuing heparin, the LDH levels rose to 5529 U/l whereupon pump replacement was performed. LDH levels, combined with clinical deterioration and right heart catheterisation, led to the diagnosis of pump thrombosis. PMID- 26041407 TI - Heart failure in 2015: let's get organised! PMID- 26041403 TI - Acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with Ebola virus disease contracted in Madrid, Spain. AB - BACKGROUND: In the current epidemic of Ebola virus disease, health-care workers have been transferred to Europe and the USA for optimised supportive care and experimental treatments. We describe the clinical course of the first case of Ebola virus disease contracted outside of Africa, in Madrid, Spain. METHODS: Herein we report clinical, laboratory, and virological findings of the treatment of a female nurse assistant aged 44 years who was infected with Ebola virus around Sept 25-26, 2014, while caring for a Spanish missionary with confirmed Ebola virus disease who had been medically evacuated from Sierra Leone to La Paz Carlos III University Hospital, Madrid. We also describe the use of experimental treatments for Ebola virus disease in this patient. FINDINGS: The patient was symptomatic for 1 week before first hospital admission on Oct 6, 2014. We used supportive treatment with intravenous fluids, broad-spectrum antibiotics, and experimental treatments with convalescent plasma from two survivors of Ebola virus disease and high-dose favipiravir. On day 10 of illness, she had acute respiratory distress syndrome, possibly caused by transfusion-related acute lung injury, which was managed without mechanical ventilation. Discharge was delayed because of the detection of viral RNA in several bodily fluids despite clearance of viraemia. The patient was discharged on day 34 of illness. At the time of discharge, the patient had possible subacute post-viral thyroiditis. None of the people who had contact with the patient before and after admission became infected with Ebola virus. INTERPRETATION: This report emphasises the uncertainties about the efficacy of experimental treatments for Ebola virus disease. Clinicians should be aware of the possibility of transfusion-related acute lung injury when using convalescent plasma for the treatment of Ebola virus disease. FUNDING: La Paz-Carlos III University Hospital. PMID- 26041408 TI - Clinical Pharmacokinetic, Pharmacodynamic, and Drug-Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor. AB - The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RTG throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RTG is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen. PMID- 26041411 TI - Adoptive immunotherapy of cancer utilizing genetically engineered lymphocytes. AB - It is becoming increasingly clear that adoptive immunotherapy with genetically engineered T cells has the potential to control and even cure cancer in some patients. On the other hand, severe adverse events associated with efficacy have frequently been reported in clinical trials. Current and near-future challenges for the development of adoptive immunotherapy of cancer using genetically engineered T cells include minimization and prediction of adverse events; identification of new and effective targets, including patient-specific mutations; improvement in T cell functionality, persistence, and memory formation capacity; and utilization of allogeneic or cell line-based T cells. PMID- 26041409 TI - Src/STAT3-dependent heme oxygenase-1 induction mediates chemoresistance of breast cancer cells to doxorubicin by promoting autophagy. AB - Chemotherapeutic resistance in breast cancer, whether acquired or intrinsic, remains a major clinical obstacle. Thus, increasing tumor cell sensitivity to chemotherapeutic agents will be helpful in improving the clinical management of breast cancer. In the present study, we found an induction of HO-1 expression in doxorubicin (DOX)-treated MDA-MB-231 human breast adenocarcinoma cells, which showed insensitivity to DOX treatment. Knockdown HO-1 expression dramatically upregulated the incidence of MDA-MB-231 cell death under DOX treatment, indicating that HO-1 functions as a critical contributor to drug resistance in MDA-MB-231 cells. We further observed that DOX exposure induced a cytoprotective autophagic flux in MDA-MB-231 cells, which was dependent on HO-1 induction. Moreover, upregulation of HO-1 expression required the activation of both signal transducer and activator of transcription (STAT)3 and its upstream regulator, protein kinase Src. Abrogating Src/STAT3 pathway activation attenuated HO-1 and autophagy induction, thus increasing the chemosensitivity of MDA-MB-231 cells. Therefore, we conclude that Src/STAT3-dependent HO-1 induction protects MDA-MB 231 breast cancer cells from DOX-induced death through promoting autophagy. In the following study, we further demonstrated the contribution of Src/STAT3/HO 1/autophagy pathway activation to DOX resistance in another breast cancer cell line, MDA-MB-468, which bears a similar phenotype to MDA-MB-231 cells. Therefore, activation of Src/STAT3/HO-1/autophagy signaling pathway might play a general role in protecting certain subtypes of breast cancer cells from DOX-induced cytotoxicity. Targeting this signaling event may provide a potential approach for overcoming DOX resistance in breast cancer therapeutics. PMID- 26041410 TI - Molecular architecture of native fibronectin fibrils. AB - Fibronectin fibrils within the extracellular matrix play central roles in physiological and pathological processes, yet many structural details about their hierarchical and molecular assembly remain unknown. Here we combine site-specific protein labelling with single-molecule localization by stepwise photobleaching or direct stochastic optical reconstruction microscopy (dSTORM), and determine the relative positions of various labelled sites within native matrix fibrils. Single end-labelled fibronectin molecules in fibrils display an average end-to-end distance of ~133 nm. Sampling of site-specific antibody epitopes along the thinnest fibrils (protofibrils) shows periodic punctate label patterns with ~95 nm repeats and alternating N- and C-terminal regions. These measurements suggest an antiparallel 30-40 nm overlap between N-termini, suggesting that the first five type I modules bind type III modules of the adjacent molecule. Thicker fibres show random bundling of protofibrils without a well-defined line-up. This super-resolution microscopy approach can be applied to other fibrillar protein assemblies of unknown structure. PMID- 26041412 TI - The mammalian target of rapamycin signaling pathway regulates myocyte enhancer factor-2C phosphorylation levels through integrin-linked kinase in goat skeletal muscle satellite cells. AB - Mammalian target of rapamycin (mTOR) signaling pathway plays a key role in muscle development and is involved in multiple intracellular signaling pathways. Myocyte enhancer factor-2 (MEF2) regulates muscle cell proliferation and differentiation. However, how the mTOR signaling pathway regulates MEF2 activity remains unclear. We isolated goat skeletal muscle satellite cells (gSSCs) as model cells to explore mTOR signaling pathway regulation of MEF2C. We inhibited mTOR activity in gSSCs with PP242 and found that MEF2C phosphorylation was decreased and that muscle creatine kinase (MCK) expression was suppressed. Subsequently, we detected integrin-linked kinase (ILK) using MEF2C coimmunoprecipitation; ILK and MEF2C were colocalized in the gSSCs. We found that inhibiting mTOR activity increased ILK phosphorylation levels and that inhibiting ILK activity with Cpd 22 and knocking down ILK with small interfering RNA increased MEF2C phosphorylation and MCK expression. In the presence of Cpd 22, mTOR activity inhibition did not affect MEF2C phosphorylation. Moreover, ILK dephosphorylated MEF2C in vitro. These results suggest that the mTOR signaling pathway regulates MEF2C positively and regulates ILK negatively and that ILK regulates MEF2C negatively. It appears that the mTOR signaling pathway regulates MEF2C through ILK, further regulating the expression of muscle-related genes in gSSCs. PMID- 26041413 TI - Dedication and work. PMID- 26041414 TI - Fetal hemoglobin and hemolysis markers in sickle cell anemia. PMID- 26041415 TI - The compound state: Hb S/beta-thalassemia. PMID- 26041416 TI - Evaluation of the effectiveness of packed red blood cell irradiation by a linear accelerator. AB - Irradiation of blood components with ionizing radiation generated by a specific device is recommended to prevent transfusion-associated graft-versus-host disease. However, a linear accelerator can also be used in the absence of such a device, which is the case of the blood bank facility studied herein. In order to evaluate the quality of the irradiated packed red blood cells, this study aimed to determine whether the procedure currently employed in the facility is effective in inhibiting the proliferation of T lymphocytes without damaging blood components. The proliferation of T lymphocytes, plasma potassium levels, and the degree of hemolysis were evaluated and compared to blood bags that received no irradiation. Packed red blood cell bags were irradiated at a dose of 25Gy in a linear accelerator. For this purpose, a container was designed to hold the bags and to ensure even distribution of irradiation as evaluated by computed tomography and dose-volume histogram. Irradiation was observed to inhibit the proliferation of lymphocytes. The percentage of hemolysis in irradiated bags was slightly higher than in non-irradiated bags (p-value >0.05), but it was always less than 0.4% of the red cell mass. Although potassium increased in both groups, it was more pronounced in irradiated red blood cells, especially after seven days of storage, with a linear increase over storage time. The findings showed that, at an appropriate dosage and under validated conditions, the irradiation of packed red blood cells in a linear accelerator is effective, inhibiting lymphocyte proliferation but without compromising the viability of the red cells. PMID- 26041417 TI - Mobilization and collection of CD34(+) cells for autologous transplantation of peripheral blood hematopoietic progenitor cells in children: analysis of two different granulocyte-colony stimulating factor doses. AB - INTRODUCTION: The use of peripheral hematopoietic progenitor cells (HPCs) is the cell choice in autologous transplantation. The classic dose of granulocyte-colony stimulating factor (G-CSF) for mobilization is a single daily dose of 10MUg/kg of patient body weight. There is a theory that higher doses of granulocyte-colony stimulating factor applied twice daily could increase the number of CD34(+) cells collected in fewer leukapheresis procedures. OBJECTIVE: The aim of this study was to compare a fractionated dose of 15MUg G-CSF/kg of body weight and the conventional dose of granulocyte-colony stimulating factor in respect to the number of leukapheresis procedures required to achieve a minimum collection of 3*10(6) CD34(+) cells/kg body weight. METHODS: Patients were divided into two groups: Group 10 - patients who received a single daily dose of 10MUg G-CSF/kg body weight and Group 15 - patients who received a fractioned dose of 15MUg G CSF/kg body weight daily. The leukapheresis procedure was carried out in an automated cell separator. The autologous transplantation was carried out when a minimum number of 3*10(6) CD34(+) cells/kg body weight was achieved. RESULTS: Group 10 comprised 39 patients and Group 15 comprised 26 patients. A total of 146 apheresis procedures were performed: 110 (75.3%) for Group 10 and 36 (24.7%) for Group 15. For Group 10, a median of three (range: 1-7) leukapheresis procedures and a mean of 8.89*10(6) CD34(+) cells/kg body weight (+/-9.59) were collected whereas for Group 15 the corresponding values were one (range: 1-3) and 5.29*10(6) cells/kg body weight (+/-4.95). A statistically significant difference was found in relation to the number of apheresis procedures (p-value <0.0001). CONCLUSIONS: To collect a minimum target of 3*10(6) CD34(+) cells/kg body weight, the administration of a fractionated dose of 15MUg G-CSF/kg body weight significantly decreased the number of leukapheresis procedures performed. PMID- 26041418 TI - Pattern of hemolysis parameters and association with fetal hemoglobin in sickle cell anemia patients in steady state. AB - OBJECTIVE: This study aimed to evaluate the influence of fetal hemoglobin (Hb F) on hemolysis biomarkers in sickle cell anemia patients. METHODS: Fifty adult sickle cell anemia patients were included in the study. All patients were taking hydroxyurea for at least six months and were followed at the outpatient clinic of a hospital in Fortaleza, Ceara, Brazil. The control group consisted of 20 hemoglobin AA individuals. The reticulocyte count was performed by an automated methodology, lactate dehydrogenase and uric acid were measured by spectrophotometry and arginase I by enzyme-linked immunosorbent assay (ELISA). The presence of Hb S was detected by high-performance liquid chromatography. The level of significance was set for a p-value <0.05. RESULTS: A significant increase was observed in the reticulocyte count and lactate dehydrogenase, uric acid and arginase I levels in sickle cell anemia patients compared to the control group (p-value <0.05). Patients having Hb F levels greater than 10% showed a significant decrease in the reticulocyte count, arginase I and lactate dehydrogenase. A significant decrease was observed in arginase I levels in patients taking hydroxyurea at a dose greater than 20mg/kg/day. CONCLUSION: The results of this study show that sickle cell anemia patients have increases in the hemolysis biomarkers, lactate dehydrogenase, reticulocyte count, arginase I, uric acid and increases in Hb F can reduce the reticulocyte count and arginase I and lactate dehydrogenase levels. PMID- 26041419 TI - Socioeconomic and demographic characteristics of sickle cell disease patients from a low-income region of northeastern Brazil. AB - OBJECTIVE: To characterize the socioeconomic and demographic aspects of sickle cell disease patients from the state of Rio Grande do Norte (RN), Northeast Brazil, and their adherence to the recommended treatment. METHODS: This cross sectional descriptive study was performed at referral centers for the treatment of hematological diseases. One hundred and fifty-five unrelated individuals with sickle cell disease who went to these centers for outpatient visits were analyzed. All the patients, or their caregivers, were informed about the research procedures and objectives, and answered a standardized questionnaire. RESULTS: The patients were predominantly younger than 12 years old, self-declared as mulatto, lived in small towns fairly distant from the referral center, and had low education and socioeconomic levels. Individuals who were ten or younger were diagnosed at an earlier age. Almost 50% of the patients were taking hydroxyurea, 91.4% reported having received pneumococcal/meningococcal vaccinations and 76.1% received penicillin as antibiotic prophylaxis. However, the majority of them reported having difficulties following the recommendations of the physicians, mainly in respect to attaining the prescribed medications and transportation to the referral centers. CONCLUSION: These individuals have a vulnerable socioeconomic situation that can lead to an aggravation of their general health and thus deserve special attention from the medical and psychosocial perspectives. Thus, it is necessary to improve public policies that provide Brazilian sickle cell disease patients with better access to medical treatment, living conditions, and integration into society. PMID- 26041420 TI - Evaluation of hemoglobin performance in the assessment of iron stores in feto maternal pairs in a high-risk population: receiver operating characteristic curve analysis. AB - OBJECTIVE: By applying receiver operating characteristic curve analysis, the objective of this study was to see whether hemoglobin levels reflect body iron stores in a group of pregnant women at term who, by using serum ferritin as the reference test, had a high pre-test probability of having iron deficiency anemia. Likewise, we evaluated the ability of hemoglobin and maternal serum ferritin levels to predict iron deficiency anemia in newborns. METHODS: Hemoglobin and serum ferritin were measured in 187 pregnant women at term belonging to a group with a high pre-test probability of iron deficiency anemia and their newborns. Women with Hb <11.0g/dL and newborns with cord Hb <13.0g/dL were classified as anemic. A serum ferritin <12.0MUg/L in women and a cord blood serum ferritin <35.0MUg/L were considered to reflect empty iron stores. Receiver operating characteristic curve analysis was applied to select the cut-off points that better reflected iron stores. RESULTS: The Hb cut-off point selected by receiver operating characteristic curve analysis in women was <11.5g/dL (sensitivity: 60.82, specificity: 53.33%, Youden Index: 0.450). Most of the newborns had normal Hb which precluded this analysis. Maternal Hb <11.0g/dL was the cut-off point that best reflected iron deficiency anemia in newborns (sensitivity: 55.88%, specificity: 57.24%, Youden Index: 0.217). The best cut-off point of maternal serum ferritin to reflect empty iron stores in newborns was <6.0MUg/L (sensitivity: 76.47%, specificity: 31.58%, Youden Index: 0.200). CONCLUSION: Hemoglobin concentration performed poorly to detect iron deficiency anemia in women at term with high risk for iron deficiency and their newborns. PMID- 26041421 TI - Outcomes in relapsed Hodgkin's lymphoma treated with autologous and allogeneic hematopoietic cell transplantation at the Pontificia Universidad Catolica de Chile. AB - INTRODUCTION: Hodgkin's lymphoma is a highly curable disease. Autologous and reduced intensity allogeneic hematopoietic cell transplantations are alternatives to treat relapsed patients. Here, we report on the results of one service using these procedures. METHODS: All patients who underwent transplantations in our institution between 1996 and 2014 were retrospectively studied and demographics, toxicities and survival rate were analyzed. RESULTS: This study evaluated 24 autologous and five reduced intensity allogeneic transplantations: the median ages of the patients were 29 and 32 years, respectively. At the time of autologous transplantation, ten patients were in complete remission, nine had chemosensitive disease but were not in complete remission, three had refractory disease and the status of two is unknown. In the allogeneic group, two were in complete remission and three had chemosensitive disease. The 5-year overall survival after autologous transplantation was 42% (66% patients were in complete remission, 37% had chemosensitive disease with incomplete remission and 0% had refractory disease) and 1-year overall survival after allogeneic transplantation was 80%. Transplant-related mortality was 0% in patients conditioned with the ifosfamide/carboplatin/etoposide (ICE), carmustine/etoposide/cyclophosphamide (BEC) and carmustine/etoposide/cytarabine/melphalan (BEAM) regimens, 37% in patients conditioned with busulfan-based regimens and 20% in allogeneic transplantations. CONCLUSIONS: Hematopoietic cell transplantation for relapsed Hodgkin's lymphoma is a potentially curative procedure especially in patients in complete remission at the time of autologous transplantations, and possibly after allogeneic transplantations. Further studies are necessary to clarify the role of allogeneic transplantations in the treatment of relapsed Hodgkin's lymphoma. PMID- 26041423 TI - Very mild forms of Hb S/beta(+)-thalassemia in Brazilian children. PMID- 26041422 TI - Resistance of dialyzed patients to erythropoietin. AB - Resistance to recombinant human erythropoietin is a common condition in dialyzed patients with chronic kidney disease and is associated with more hospitalizations, increased mortality and frequent blood transfusions. The main cause of hyporesponsiveness to recombinant human erythropoietin in these patients is iron deficiency. However, a high proportion of patients does not respond to treatment, even to the use of intravenous iron, which indicates the presence of other important causes of resistance. In addition to the iron deficiency, the most common causes of resistance include inflammation, infection, malnutrition, inadequate dialysis, and hyperparathyroidism, although other factors may be associated. In the presence of adequate iron stores, other causes should be investigated and treated appropriately. PMID- 26041425 TI - Central retinal vein occlusion as first manifestation of relapse in acute lymphoblastic leukemia. PMID- 26041424 TI - Compound heterozygous state of beta-thalassemia with IVS1-5 (G->C) mutation and Indian deletion-inversion Ggamma(Agammadeltabeta)(0)-thalassemia in eastern India. PMID- 26041426 TI - Somatic mutations of calreticulin in a Brazilian cohort of patients with myeloproliferative neoplasms. PMID- 26041428 TI - The implications of maternal grandmother coresidence and involvement for adolescent adjustment in South Africa. AB - Maternal grandmothers residing in 3-generation households often provide care and support to their grandchildren. However, the implications of grandmother coresidence and involvement for adolescent adjustment have been neglected in the South African literature. This study examined whether the involvement of maternal grandmothers who coreside with grandchildren and their parents differed from that of non-coresident grandmothers. In addition, we assessed the associations between maternal grandmother coresidence and involvement, and adolescents' internalising problems, externalising problems and prosocial behaviour. Self-report survey data were obtained from a sample of 384 "coloured" (mixed-race) and black African Grade 8 and Grade 9 students in Cape Town. The mean age of the participants was 13.96 years, 58% were females and 27% lived in 3-generation households. Results indicated that there was no significant difference in the involvement of coresident and non-coresident grandmothers, and that adolescents in 3-generation and 2-generation households displayed similar levels of adjustment. Hierarchical multiple regression analyses revealed that greater maternal grandmother involvement was associated with more adolescent prosocial behaviour (p < .001) regardless of household structure, and with fewer adolescent internalising problems in 3-generation households (p = .03). Findings underscore the need to move beyond the immediate family to consider how grandparents may influence adolescent development. PMID- 26041427 TI - Resveratrol Decreases TXNIP mRNA and Protein Nuclear Expressions With an Arterial Function Improvement in Old Mice. AB - Aging leads to a high prevalence of glucose intolerance and cardiovascular diseases, with oxidative stress playing a potential role. Resveratrol has shown promising effects on glucose tolerance and tends to improve endothelial function in elderly patients. Thioredoxin-interacting protein (TXNIP) was recently proposed as a potential link connecting glucose metabolism to oxidative stress. Here, we investigated the resveratrol-induced improvement of arterial aging phenotype in old mice and the expression of aortic TXNIP. Using an in vivo model of old mice with or without 3-month resveratrol treatment, we investigated the effects of resveratrol on age-related impairments from a cardiovascular Doppler analysis, to a molecular level, by studying inflammation and oxidative stress factors. We found a dual effect of resveratrol, with a decrease of age-related glucose intolerance and oxidative stress imbalance leading to reduced matrix remodeling that forestalls arterial aging phenotype in terms of intima-media thickness and arterial distensibility. These results provide the first evidence that aortic TXNIP mRNA and protein nuclear expressions are increased in the arterial aging and decreased by resveratrol treatment. In conclusion, we demonstrated that resveratrol helped to restore several aging impaired processes in old mice, with a decrease of aortic TXNIP mRNA and protein nuclear expressions. PMID- 26041430 TI - Design of C18 Organic Phases with Multiple Embedded Polar Groups for Ultraversatile Applications with Ultrahigh Selectivity. AB - For the first time, we synthesized multiple embedded polar groups (EPGs) containing linear C18 organic phases. The new materials were characterized by elemental analysis, IR spectroscopy, (1)H NMR, diffuse reflectance infrared Fourier transform (DRIFT), solid-state (13)C cross-polarization magic angle spinning (CP/MAS) NMR, suspended-state (1)H NMR, and differential scanning calorimetry (DSC). (29)Si CP/MAS NMR was carried out to investigate the degree of cross-linking of the silane and silane functionality of the modified silica. Solid-state (13)C CP/MAS NMR and suspended-state (1)H NMR spectroscopy indicated a higher alkyl chain order for the phase containing four EPGs than for the phase with three EPGs. To correlate the NMR results with temperature-dependent chromatographic studies, standard reference materials (SRM 869b and SRM 1647e), a column selectivity test mixture for liquid chromatography was employed. A single EPG containing the C18 phase was also prepared in a similar manner to be used as a reference column especially for the separation of basic and polar compounds in reversed-phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC), respectively. Detailed chromatographic characterization of the new phases was performed in terms of their surface coverage, hydrophobic selectivity, shape selectivity, hydrogen bonding capacity, and ion-exchange capacity at pH 2.7 and 7.6 for RPLC as well as their hydrophilicity, the selectivity for hydrophilic-hydrophobic substituents, the selectivity for the region and configurational differences in hydrophilic substituents, the evaluation of electrostatic interactions, and the evaluation of the acidic-basic nature for HILIC-mode separation. Furthermore, peak shapes for the basic analytes propranolol and amitriptyline were studied as a function of the number of EPGs on the C18 phases in the RPLC. The chromatographic performance of multiple EPGs containing C18 HILIC phases is illustrated by the separation of sulfa drugs, beta blockers, xanthines, nucleic acid bases, nucleosides, and water-soluble vitamins. Both of the phases showed the best performance for the separation of shape constrained isomers, nonpolar, polar, and basic compounds in RPLC- and HILIC-mode separation of sulfa drugs, and other polar and basic analytes compared to the conventional alkyl phases with and without embedded polar groups and HILIC phases. Surprisingly, one phase would be able to serve the performance of three different types of phases with very high selectivity, and we named this phase the "smart phase". Versatile applications with a single column will reduce the column purchasing cost for the analyst as well as achieve high separation, which is challenging with the commercially available columns. PMID- 26041429 TI - High doses of caffeine reduce in vivo osteogenic activity in prepubertal rats. AB - Caffeine adversely affects endochondral ossification during fetal skeletal growth, and results in increased incidence of delayed and abnormal fetal skeletal development. Chronic caffeine intake also decreases growth hormone secretion. Thus, it is conceivable that caffeine may disrupt bone growth during the peripubertal period. This study aimed to investigate the impact of high-caffeine consumption on bone growth throughout puberty. A total of 51 male rats (21 days old) were divided randomly into three groups: a control group and two groups fed caffeine via gavage with 120 and 180 mg kg(-1) day(-1) for 4 weeks. After death, the final length and weight of leg bones were measured, and the tibia processed for histomorphometric analysis. Caffeine caused a significant decrease in body mass gain. This was accompanied with proportional decreases in lean body mass and body fat. In addition, bone mass and osteogenic activity in vivo were assessed using dual-energy X-ray absorptiometry and (18) F-NaF positron emission tomography. The results showed significant decreases of bone mass and in vivo osteogenic activity in the caffeine-fed groups. Rats fed with caffeine showed a significantly shorter and lighter tibia and femur and the vertebral column compared with controls. In addition, caffeine does not increase the width of the growth plates (GPs), it slows the rate at which the GP closes due to a slower rate of growth. These results demonstrated that caffeine altered osteogenic activity, leading to delayed peripubertal longitudinal bone growth and maturation. Given that osteogenic cells undergo dynamic changes in metabolic activity and that the pubertal growth spurt is mainly stimulated by growth hormone/insulin-like growth factor-1 and sex steroids during pubertal development, caffeine could suppress ossification by interfering with both physiological changes in hormonal secretion and osteogenic activity during this critical period. Further study will be needed to investigate the cellular/molecular mechanism by which caffeine affects osteogenesis using in vitro experimental models. PMID- 26041431 TI - Effect of atovastatin treatment on porcine circovirus 2 infection in BALB/c mice. AB - The HMG-CoA reductase (HMGCR) pathway is an important metabolic route, which is not only present in almost every organism, but also involves virus infection. It has recently been shown that expression levels of IFN-responsive genes were significantly increased in HMGCR-downregulated cells and HMGCR inhibitor-treated cells. The aim of this study was to determine whether inhibition of HMGCR by atovastatin would significantly affect Porcine circovirus type 2 (PCV2) infection and immunological reaction in BALB/c mice. The results showed atovastatin significantly stimulated PCV2 replication in vivo. Immunological reaction in atovastatin-treated mice was also significantly enhanced during PCV2 infection. Atovastatin also enhanced PCV2-induced illness in mice. The results of this study will provide new insight into the role of atovastatin in PCV2 infection. PMID- 26041433 TI - The nucleolar interface of RNA viruses. AB - In recent years, understanding of the nucleolus has undergone a renaissance. Once considered primarily as the sites of ribosome biogenesis, nucleoli are now understood to be highly dynamic, multifunctional structures that participate in a plethora of cellular functions including regulation of the cell cycle, signal recognition particle assembly, apoptosis and stress responses. Although the molecular/mechanistic details of many of these functions remain only partially resolved, it is becoming increasingly apparent that nucleoli are also common targets of almost all types of viruses, potentially allowing viruses to manipulate cellular responses and the intracellular environment to facilitate replication and propagation. Importantly, a number of recent studies have moved beyond early descriptive observations to identify key roles for nucleolar interactions in the viral life cycle and pathogenesis. While it is perhaps unsurprising that many viruses that replicate within the nucleus also form interactions with nucleoli, the roles of nucleoli in the biology of cytoplasmic viruses is less intuitive. Nevertheless, a number of positive-stranded RNA viruses that replicate exclusively in the cytoplasm are known to express proteins that enter the nucleus and target nucleoli, and recent data have indicated similar processes in several cytoplasmic negative-sense RNA viruses. Here, we review this emerging aspect of the virus-host interface with a focus on examples where virus-nucleolus interactions have been linked to specific functional outcomes/mechanistic processes in infection and on the nucleolar interfaces formed by viruses that replicate exclusively in the cytoplasm. PMID- 26041432 TI - Metal rich particulate matter impairs acetylcholine-mediated vasorelaxation of microvessels in mice. AB - BACKGROUND: Exposure to PM2.5 (particulate matter<2.5 MUm) has been associated with changes in endothelial function. PM2.5 was collected from two Chinese cities, Jinchang (JC) and Zhangye (ZH), both with similar PM2.5 concentrations. However, JC had levels of nickel (Ni), selenium (Se), copper (Cu), and arsenic (As) that were 76, 25, 17, and 7 fold higher than that measured in ZH, respectively. We used this unique PM sample to delineate the chemical components that drive pulmonary and systemic effects and explore the mechanism(s) by which vascular dysfunction is caused. METHODS: Male FVB/N mice received oropharyngeal aspiration of water or PM2.5 from JC, ZH or ZH spiked with one of the following elements at the same concentrations found in the JC PM (Ni=4.76; As=2.36; Se=0.24; Cu=2.43 MUg/mg) followed by evaluation of markers of pulmonary and systemic inflammation. Mesenteric arteries were isolated for gene expression or functional response to various agonists (Phenylephrine, Acetylcholine, and Sodium Nitroprusside) and inhibitors (L-NAME, Apocynin, and VAS2870) ex vivo. RESULTS: Protein and total cell counts from lung lavage revealed significant pulmonary inflammation from ZH (p<0.01) and JC and ZH+NiSO4 (p<0.001) as compared to control and a significant decrease in mesenteric artery relaxation (p<0.001) and this decrease is blunted in the presence of NADPH oxidase inhibitors. Significant increases in gene expression (TNF-alpha, IL-6, Nos3; p<0.01; NOX4; p<0.05) were observed in JC and ZH+NiSO4, as well as significantly higher concentrations of VEGF and IL-10 (p<0.01, p<0.001; respectively). CONCLUSIONS: Our results indicate that the specific toxicity observed in PM from JC is likely due to the nickel component in the PM. Further, since VAS2870 was the most successful inhibitor to return vessels to baseline relaxation values, NADPH Oxidase is implicated as the primary source of PM-induced O2*-. PMID- 26041434 TI - Activation of Transcription Factor GAX and Concomitant Downregulation of IL-1beta and ERK1/2 Modulate Vascular Smooth Muscle Cell Phenotype in 3D Fibrous Scaffolds. AB - Since vascular smooth muscle cells (VSMCs) display phenotypic plasticity in response to changing environmental cues, understanding the molecular mechanisms underlying the phenotypic modulation mediated by a three-dimensional (3D) scaffold is important to engineer functional vasculature. Following cell seeding into 3D scaffolds, the synthetic phenotype is desired to enable cells to expand rapidly and produce and assemble extracellular matrix components, but must revert to a quiescent contractile phenotype after tissue fabrication to impart the contractile properties found in native blood vessels. This study shows that 3D electrospun fibrous scaffolds regulate human coronary artery smooth muscle cells (HCASMCs) toward a more synthetic phenotype characterized by reduced contractile markers, such as smooth muscle alpha-actin and calponin. The reduction in contractile markers expression was mediated by endogenously expressed proinflammatory cytokine interleukin-1beta (IL-1beta). 3D topography transiently induces concomitant upregulation of IL-1beta and MAPK ERK1/2 through nuclear factor-kappaB-dependent signaling pathway. An early burst of expression of IL 1beta is essential for suppression of the homeobox transcription factor Gax and related cyclin-dependent kinase inhibitor p21(Cip1), which are key regulators for cells exiting from cell cycle. Our findings provide new insights for understanding signaling mechanisms of HCASMCs in electrospun 3D fibrous scaffolds, which have considerable value for application in vascular tissue engineering. PMID- 26041435 TI - Quality of life is associated with chronic inflammation in schizophrenia: a cross sectional study. AB - Inflammation may play a crucial role in the pathogenesis of schizophrenia. However, the association between chronic inflammation and health outcomes in schizophrenia remains unclear, particularly for patient-reported outcomes. The aim of this study was to investigate the relationship between quality of life (QoL) and chronic inflammation assessed using C -Reactive Protein (CRP) in patients with schizophrenia. Two hundred and fifty six patients with schizophrenia were enrolled in this study. After adjusting for key socio demographic and clinical confounding factors, patients with high levels of CRP (>3.0 mg/l) had a lower QoL than patients with normal CRP levels (OR = 0.97, 95% CI = 0.94-0.99). An investigation of the dimensions of QoL revealed that psychological well-being, physical well-being and sentimental life were the most salient features of QoL associated with CRP. Significant associations were found between lower educational level (OR = 4.15, 95% CI = 1.55-11.07), higher body mass index (OR = 1.16, 95% CI = 1.06-1.28), higher Fagerstrom score (OR = 1.22, 95% CI = 1.01-1.47) and high levels of CRP. After replications with longitudinal approaches, the association between QoL and chronic inflammation may offer interesting interventional prospects to act both on inflammation and QoL in patients with schizophrenia. PMID- 26041436 TI - The Magnitude of Time-Dependent Bias in the Estimation of Excess Length of Stay Attributable to Healthcare-Associated Infections. AB - BACKGROUND Estimates of the excess length of stay (LOS) attributable to healthcare-associated infections (HAIs) in which total LOS of patients with and without HAIs are biased because of failure to account for the timing of infection. Alternate methods that appropriately treat HAI as a time-varying exposure are multistate models and cohort studies, which match regarding the time of infection. We examined the magnitude of this time-dependent bias in published studies that compared different methodological approaches. METHODS We conducted a systematic review of the published literature to identify studies that report attributable LOS estimates using both total LOS (time-fixed) methods and either multistate models or matching patients with and without HAIs using the timing of infection. RESULTS Of the 7 studies that compared time-fixed methods to multistate models, conventional methods resulted in estimates of the LOS to HAIs that were, on average, 9.4 days longer or 238% greater than those generated using multistate models. Of the 5 studies that compared time-fixed methods to matching on timing of infection, conventional methods resulted in estimates of the LOS to HAIs that were, on average, 12.6 days longer or 139% greater than those generated by matching on timing of infection. CONCLUSION Our results suggest that estimates of the attributable LOS due to HAIs depend heavily on the methods used to generate those estimates. Overestimation of this effect can lead to incorrect assumptions of the likely cost savings from HAI prevention measures. PMID- 26041438 TI - High prevalence of primary focal dystonia in the Faroe Islands. AB - OBJECTIVE: There are no previous studies undertaken about primary focal dystonia in the Faroe Islands. The aim of this study was to establish the prevalence of these diseases in the Faroese population. METHODS: Patients were ascertained and registered prospectively from January 1, 1994, through 2013 when they were examined at the Neurological Clinic of the Faroese National Hospital or at a private neurological practice, which together constitutes all the available neurological services in the Faroe Islands. RESULT: On January 1, 2014, there were 29 individuals within the entire Faroese population of 48,100 with primary focal dystonia: 23 with torticollis, four with writer's cramp, one with oromandibular dystonia, and one with laryngeal dystonia; no one had blepharospasm. The prevalence of primary focal dystonia was 602 per million (395 873) (95% confidence limit). The most common subtype was cervical dystonia with a prevalence of 478 (332-728) per million. CONCLUSION: The study yielded that (i) the prevalence of primary focal dystonia of 602 (395-873) per million is far higher in the Faroe Islands than that revealed in most other regions studied and (ii) the prevalence of the cervical dystonia subtype is far more common than elsewhere with the highest prevalence of 478 (332-728), which is higher than described in any previously published survey. As the study is serviced-based, the result may underestimate actual occurrence; thus, prevalence rates may be even higher. PMID- 26041437 TI - Continuous central venous oxygen saturation assisted intraoperative hemodynamic management during major abdominal surgery: a randomized, controlled trial. AB - BACKGROUND: Major abdominal surgery is associated with significant risk of morbidity and mortality in the perioperative period. Optimising intraoperative fluid administration may result in improved outcomes. Our aim was to compare the effects of central venous pressure (CVP), and central venous oxygen saturation (ScvO2)-assisted fluid therapy on postoperative complications in patients undergoing high risk surgery. METHODS: Patients undergoing elective major abdominal surgery were randomised into control and ScvO2 groups. The target level of mean arterial pressure (MAP) was >= 60 mmHg in both groups. In cases of MAP < 60 mmHg patients received either a fluid or vasopressor bolus according to the CVP < 8 mmHg in the control group. In the ScvO2 group, in addition to the MAP, an ScvO2 of <75% or a >3% decrease indicated need for intervention, regardless of the actual MAP. Data are presented as mean +/- standard deviation or median (interquartile range). RESULTS: We observed a lower number of patients with complications in the ScvO2 group compared to the control group, however it did not reach statistical significance (ScvO2 group: 10 vs. CONTROL GROUP: 19; p = 0.07). Patients in the ScvO2 group (n = 38) received more colloids compared to the control group (n = 41) [279(161) vs. 107(250) ml/h; p < 0.001]. Both groups received similar amounts of crystalloid (1126 +/- 471 vs. 1049 +/- 431 ml/h; p = 0.46) and norepinephrine [37(107) vs. 18(73) mcg/h; p = 0.84]. Despite similar blood loss in both groups, the ScvO2 group received more blood transfusions (63% vs. 37%; p = 0.018). More patients in the control group had a postoperative PaO2/FiO2 < 200 mmHg (23 vs. 10, p < 0.01). Twenty eight day survival was significantly higher in the ScvO2 group (37/38 vs. 33/41 p = 0.018). CONCLUSION: ScvO2-assisted intraoperative haemodynamic support provided some benefits, including significantly better postoperative oxygenation and 28 day survival rate, compared to CVP-assisted therapy without a significant effect on postoperative complications during major abdominal surgery. TRIAL REGISTRATION: ClinicalTrials.gov NCT02337010. PMID- 26041439 TI - Relaxin affects cell organization and early and late stages of spermatogenesis in a coculture of rat testicular cells. AB - Relaxin and its receptor RXFP1 are co-expressed in Sertoli cells, and relaxin can stimulate proliferation of Sertoli cells. In this study, we investigated a role of relaxin in spermatogenesis, using a short-term culture of testicular cells of the rat that allowed differentiation of spermatogonia to spermatids. Sertoli, germ, and peritubular myoid cells were the predominant cell types in the culture. Sertoli and germ cells expressed RXFP1. Cultures were incubated without (control) or with 0.5% fetal bovine serum (FBS) or 100 ng/mL H2 relaxin (RLN) for 2 days. Cell organization, number, and differentiation were analyzed after 2 (D2), 5 (D5) or 8 (D8) days of culturing. Although the proportion of germ cells decayed from D2 to D5, the relative contribution of HC, 1C, 2C, and 4C germ cell populations remained constant in the control group during the whole culture. RLN did not affect the proportion of germ cell populations compared with control, but increased gene and/or protein expression of the undifferentiated and differentiated spermatogonia markers PLZF and c-KIT, and of the post-meiotic marker Odf2 in D5. RLN favored organization of cells in tubule-like structures, the arrangement of myoid cells around the tubules, arrangement of c-KIT-positive spermatogonia at the basal region of the tubules, and expression of the cell junction protein beta-catenin close to the plasma membrane region. Knockdown of relaxin with small interfering RNA (siRNA) reduced expression of beta-catenin at the cell junctions, and shifted its expression to the nucleus. We propose that relaxin may affect spermatogenesis by modulating spermatogonial self renewal and favoring cell contact. PMID- 26041440 TI - Esthesioneuroblastoma with large intracranial extension treated with Induction chemotherapy, de-bulking surgery and image guided intensity modulated radiotherapy. AB - INTRODUCTION: Esthesioneuroblastoma is a rare tumour of the sino-nasal tract. One third cases present with intracranial extension. However, treatment options are limited for such cases. METHODOLOGY: We herein report a case with large intracranial extension treated with Induction chemotherapy, de-bulking surgery, and image guided intensity modulated radiotherapy. RESULTS: The patient was treated with IGIMRT technique to a dose of 64 Gy in 32 fractions. Cone bean CT verification was done twice a week to eliminate set up error. The patient achieved complete resolution of the disease and was disease free 6 months after completion of treatment. CONCLUSION: IGIMRT even after a de-bulking surgery may help to achieve long-term disease control for patients with large intracranial extension with minimal morbidity. PMID- 26041441 TI - Prospective surveillance of hospitalisations associated with varicella in New Zealand children. AB - AIM: Varicella is a vaccine-preventable disease not notifiable in New Zealand (NZ), and varicella vaccine is not funded in the National Immunisation Schedule (NIS). Hospitalisations can occur because of bacterial secondary infection and other complications, which can result in long-term sequelae. Varicella may not be acknowledged in discharge coding when complications occur weeks after infection. Using the New Zealand Paediatric Surveillance Unit (NZPSU), the aim of this study was to document the hospitalisation burden of this disease. METHODS: Cases (0-14 years) of varicella and post-varicella complications requiring hospitalisation, including stroke syndromes where varicella occurred in the preceding 6 months, were notified to NZPSU between 1 November 2011 and 31 October 2013. Herpes zoster cases were excluded. Questionnaires were used to capture demographics, clinical features, management and short-term outcomes. RESULTS: One hundred seventy-eight notifications were received and 144 were confirmed cases. Overall incidence was 8.3/100,000 children per year. Fifty-two percent were women with a median age of 2.4 years. Maori and Pacific Island (PI) children accounted for 74% of hospitalisations, with incidence rate ratios compared with European children of 2.8 and 3.9, respectively (P < 0.01). Complications included: infection (75%), respiratory (11%), neurological (11%), electrolyte disturbance (6%) and haemorrhagic varicella (4%). Nine percent were immunocompromised. Median duration of hospital admission was 4 days with 9% requiring intensive care admission. There were no reported deaths; however, 19% had ongoing problems at discharge. CONCLUSION: Varicella has more associated morbidity than commonly perceived in immunocompetent children. Maori and PI children are more likely to have complications. This surveillance gives support for inclusion of universal varicella vaccine in the NZ NIS. PMID- 26041442 TI - Four-dimensional computed tomography (4DCT): A review of the current status and applications. AB - The applications of conventional computed tomography (CT) have been widely researched and implemented in clinical practice. A recent technological innovation in the field of CT is the emergence of four-dimensional computed tomography (4DCT), where a three-dimensional computed tomography volume containing a moving structure is imaged over a period of time, creating a dynamic volume data set. 4DCT has previously been mainly utilised in the setting of radiation therapy planning, but with the development of wide field of view CT, 4DCT has opened major avenues in the diagnostic arena. The aim of this study is to provide a comprehensive narrative review of the literature regarding the current clinical applications of 4DCT. The applications reviewed include both routine diagnostic usage as well as an appraisal of the current research literature. A systematic review of the studies related to 4DCT was conducted. The Medline database was searched using the MeSH subject heading 'Four-Dimensional Computed Tomography'. After excluding non-human and non-English papers, 2598 articles were found. Further exclusion criteria were applied, including date range (since wide field of view CT was introduced in 2007), and exclusion of technical/engineering/physics papers. Further filtration of papers included identification of Review papers. This process yielded 67 papers. Of these, exclusion of papers not specifically discussing 4DCT (cone beam, 4D models) yielded 38 papers. As part of the review, the technique for 4DCT is described, with perspectives as to how it has evolved and its benefits in different clinical indications. PMID- 26041443 TI - Vasopressin regulation of sodium transport in the distal nephron and collecting duct. AB - Arginine vasopressin (AVP) is released from the posterior pituitary gland during states of hyperosmolality or hypovolemia. AVP is a peptide hormone, with antidiuretic and antinatriuretic properties. It allows the kidneys to increase body water retention predominantly by increasing the cell surface expression of aquaporin water channels in the collecting duct alongside increasing the osmotic driving forces for water reabsorption. The antinatriuretic effects of AVP are mediated by the regulation of sodium transport throughout the distal nephron, from the thick ascending limb through to the collecting duct, which in turn partially facilitates osmotic movement of water. In this review, we will discuss the regulatory role of AVP in sodium transport and summarize the effects of AVP on various molecular targets, including the sodium-potassium-chloride cotransporter NKCC2, the thiazide-sensitive sodium-chloride cotransporter NCC, and the epithelial sodium channel ENaC. PMID- 26041444 TI - Arginase inhibition: a new treatment for preventing progression of established diabetic nephropathy. AB - Our previous publication showed that inhibition of arginase prevents the development of diabetic nephropathy (DN). However, identification of targets that retard the progression of established DN-which is more clinically relevant-is lacking. Therefore, we tested the hypothesis that arginase inhibition would prevent the progression of established DN. Effects of arginase inhibition were compared with treatment with the angiotensin-converting enzyme inhibitor captopril, a current standard of care in DN. Experiments were conducted in Ins2(Akita) mice treated with the arginase inhibitor S-(2-boronoethyl)-l-cysteine (BEC) or captopril starting at 6 wk of age for 12 wk (early treatment) or starting at 12 wk of age for 6 wk (late treatment). Early and late treatment with BEC resulted in protection from DN as indicated by reduced albuminuria, histological changes, kidney macrophage infiltration, urinary thiobarbituric acid reactive substances, and restored nephrin expression, kidney nitrate/nitrite, kidney endothelial nitric oxide synthase phosphorylation, and renal medullary blood flow compared with vehicle-treated Ins2(Akita) mice at 18 wk of age. Interestingly, early treatment with captopril reduced albuminuria, histological changes, and kidney macrophage infiltration without affecting the other parameters, but late treatment with captopril was ineffective. These findings highlight the importance of arginase inhibition as a new potential therapeutic intervention in both early and late stages of diabetic renal injury. PMID- 26041445 TI - Kidney glycosphingolipids are elevated early in diabetic nephropathy and mediate hypertrophy of mesangial cells. AB - Glycosphingolipids (GSLs) play a role in insulin resistance and diabetes, but their role in diabetic nephropathy (DN) has received limited attention. We used 9 and 17-wk-old nondiabetic db/m and diabetic db/db mice to examine the role of GSLs in DN. Cerebrosides or monoglycosylated GSLs [hexosylceramides (HexCers); glucosyl- and galactosylceramides] and lactosylceramide (LacCers) were elevated in db/db mouse kidney cortices, specifically in glomeruli, and also in urine. In our recent paper (25), we observed that the kidneys exhibited glomerular hypertrophy and proximal tubular vacuolization and increased fibrosis markers at these time points. Mesangial cells contribute to hyperglycemia-induced glomerular hypertrophy in DN. Hyperglycemic culture conditions, similar to that present in diabetes, were sufficient to elevate mesangial cell HexCers and increase markers of fibrosis, extracellular matrix proteins, and cellular hypertrophy. Inhibition of glucosylceramide synthase or lowering glucose levels decreased markers of fibrosis and extracellular matrix proteins and reversed mesangial cell hypertrophy. Hyperglycemia increased phosphorylated (p)SMAD3 and pAkt levels and reduced phosphatase and tensin homolog levels, which were reversed with glucosylceramide synthase inhibition. These data suggest that inhibition of glucosylceramide synthase reversed mesangial cell hypertrophy through decreased pAkt and pSmad3 and increased pathways responsible for protein degradation. Importantly, urinary GSL levels were higher in patients with DN compared with healthy control subjects, implicating a role for these lipids in human DN. Thus, hyperglycemia in type II diabetes leads to renal dysfunction at least in part by inducing accumulation of HexCers and LacCers in mesangial cells, resulting in fibrosis, extracellular matrix production, and hypertrophy. PMID- 26041446 TI - Carbonic anhydrase II binds to and increases the activity of the epithelial sodium-proton exchanger, NHE3. AB - Two-thirds of sodium filtered by the renal glomerulus is reabsorbed from the proximal tubule via a sodium/proton exchanger isoform 3 (NHE3)-dependent mechanism. Since sodium and bicarbonate reabsorption are coupled, we postulated that the molecules involved in their reabsorption [NHE3 and carbonic anhydrase II (CAII)] might physically and functionally interact. Consistent with this, CAII and NHE3 were closely associated in a renal proximal tubular cell culture model as revealed by a proximity ligation assay. Direct physical interaction was confirmed in solid-phase binding assays with immobilized CAII and C-terminal NHE3 glutathione-S-transferase fusion constructs. To assess the effect of CAII on NHE3 function, we expressed NHE3 in a proximal tubule cell line and measured NHE3 activity as the rate of intracellular pH recovery, following an acid load. NHE3 expressing cells had a significantly greater rate of intracellular pH recovery than controls. Inhibition of endogenous CAII activity with acetazolamide significantly decreased NHE3 activity, indicating that CAII activates NHE3. To ascertain whether CAII binding per se activates NHE3, we expressed NHE3 with wild type CAII, a catalytically inactive CAII mutant (CAII-V143Y), or a mutant unable to bind other transporters (CAII-HEX). NHE3 activity increased upon wild-type CAII coexpression, but not in the presence of the CAII V143Y or HEX mutant. Together these studies support an association between CAII and NHE3 that alters the transporter's activity. PMID- 26041448 TI - Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. AB - Early stage diabetic nephropathy is characterized by glomerular hyperfiltration and reduced renal tissue Po2. Recent observations have indicated that increased tubular Na(+)-glucose linked transport (SGLT) plays a role in the development of diabetes-induced hyperfiltration. The aim of the present study was to determine how inhibition of SLGT impacts upon Po2 in the diabetic rat kidney. Diabetes was induced by streptozotocin in Sprague-Dawley rats 2 wk before experimentation. Renal hemodynamics, excretory function, and renal O2 homeostasis were measured in anesthetized control and diabetic rats during baseline and after acute SGLT inhibition using phlorizin (200 mg/kg ip). Baseline arterial pressure was similar in both groups and unaffected by SGLT inhibition. Diabetic animals displayed reduced baseline Po2 in both the cortex and medulla. SGLT inhibition improved cortical Po2 in the diabetic kidney, whereas it reduced medullary Po2 in both groups. SGLT inhibition reduced Na(+) transport efficiency [tubular Na(+) transport (TNa)/renal O2 consumption (Qo2)] in the control kidney, whereas the already reduced TNa/Qo2 in the diabetic kidney was unaffected by SGLT inhibition. In conclusion, these data demonstrate that when SGLT is inhibited, renal cortex Po2 in the diabetic rat kidney is normalized, which implies that increased proximal tubule transport contributes to the development of hypoxia in the diabetic kidney. The reduction in medullary Po2 in both control and diabetic kidneys during the inhibition of proximal Na(+) reabsorption suggests the redistribution of active Na(+) transport to less efficient nephron segments, such as the medullary thick ascending limb, which results in medullary hypoxia. PMID- 26041447 TI - Obesity and renovascular disease. AB - Obesity remains a prominent public health concern. Obesity not only contributes greatly to cardiovascular events but has also been identified to initiate and affect the progression of preexisting chronic kidney disease. The prevalence of renal artery stenosis is growing world-wide, especially in the elderly population and in individuals with atherosclerotic risk factors such as obesity. Prolonged renovascular disease causes inflammation and microvascular remodeling within the post-stenotic kidney, which promote tissue scarring and may account for irreversible renal damage. Obesity has been shown to aggravate kidney damage via several pathways, including exacerbation of microvascular regression and renal cell injury mediated by adipocytes and insulin resistance, thereby worsening the structural and functional outcomes of the kidney in renovascular disease. Dietary modification and inhibition of the renin-angiotensin-aldosterone system have been shown to alleviate obesity-induced tissue injury and remodeling. Possibly, angiogenic factors may boost microvascular repair in the ischemic kidney in the obesity milieu. Novel therapeutic interventions targeting deleterious pathways that are activated by obesity and responsible for kidney damage need to be explored in future studies. PMID- 26041450 TI - Hyperimmunised bovine milk and whey: influence of pH and enzymatic treatments on the antigen-binding capacity of immunoglobulin G. AB - BACKGROUND: Hyperimmunised bovine milk and whey (whole and defatted) were submitted at 37 degrees C to different pH values (between 1 and 10) and enzymes (pepsin, trypsin and chymotrypsin) at their optimum pH and the IgG immunoactivity against Campylobacter jejuni was measured by means of ELISA assays. RESULTS: The kinetic antigen-binding capacity (ABC) losses follow a hyperbolic-type equation. The ABC of IgG is strongly reduced at low pH (1 and 2) and the effect is lower at alkaline pH (8 and 10). The presence of pepsin (at their optimum pH of 2) almost completely reduced the IgG ABC after 2 h of treatment. The ABCs are higher in whole products (milk and whey). The influence of trypsin and quimotrypsin on the ABCs is moderate (ABC losses lower that 25%). CONCLUSIONS: The ABC of IgG obtained from hyperimmunised bovine defatted milk and whey is largely reduced in conditions similar to those found in the human digestive tract. Only whole milk can maintain around 40% of their initial ABC. IgG encapsulation or other methods to protect the immunoglobulin activities could be an alternative to use these type of products in final foods formulae. PMID- 26041449 TI - Gender-specific factors associated with shorter sleep duration at age 3 years. AB - Total sleep duration has been decreasing among children in the last decades. Short sleep duration (SSD) has been associated with deleterious health consequences, such as excess weight/obesity. Risk factors for SSD have already been studied among school-aged children and adolescents, but inconsistent results have been reported regarding possible gender differences. Studies reporting such relationships are scarce in preschoolers, despite the importance of this period for adopting healthy behaviour. We aimed to investigate factors associated with SSD in 3-year-old boys (n = 546) and girls (n = 482) in a French Mother-Child Cohort (EDEN Study). Children were born between 2003 and 2006 in two French university hospitals. Clinical examinations and parent self-reported questionnaires allowed us to collect sociodemographic (e.g. income, education, family situation, child-minding system), maternal [e.g. body mass index (BMI), parity, depression, breastfeeding duration] and child's characteristics (e.g. gender, birth weight, term, physical activity and TV viewing duration, food consumption, usual sleep time). Sleep duration/24-h period was calculated and SSD was defined as <12 h. Analyses were performed using logistic regression. The mean sleep duration was 12 h 35 +/- 56 min, with 91% of the children napping. Patterns of risk factors associated with SSD differed according to gender. In addition to parental presence when falling asleep, short sleep duration was associated strongly positively with high BMI Z-score and TV viewing duration among boys and with familial home child-minding and lower scores on the 'fruits and vegetables' dietary pattern among girls. These results suggest either a patterning of parental behaviours that differs according to gender, or a gender-specific sleep physiology, or both. PMID- 26041451 TI - British society of breast radiology annual scientific meeting 2014. PMID- 26041452 TI - Tuning polymer architecture to manipulate the relative stability of different colloid crystal morphologies. AB - Polymers dilutely adsorbed in colloidal crystals play an underappreciated role in determining the stability of the crystal phase. Recent work has shown that tailoring the size and shape of the adsorbing polymer can help tune the relative thermodynamic stability of the face-centered cubic (FCC) and hexagonal close packed (HCP) polymorphs [N. A. Mahynski, A. Z. Panagiotopoulos, D. Meng, and S. K. Kumar, Nat. Commun., 2014, 5, 4472]. This is a consequence of how different polymorphs uniquely distribute their interstitial voids. By engineering an adsorbent's morphology to be complementary to the interstices in a desired crystal form, other competing forms may be thermodynamically suppressed. Previous investigations into this effect focused solely on linear polymers, while here we investigate the effects of more complex polymer architectures, namely that of star polymers. We find that even small perturbations to an adsorbing polymer's architecture lead to significant, qualitative changes in the relative stability of close-packed colloidal crystal polymorphs. In contrast to the linear homopolymer case, the FCC phase may be re-stabilized over the HCP with sufficiently large star polymers, and as a result, solvent quality may be used as a polymorphic "switch" between the two forms. This suggests that star polymers can be engineered to stabilize certain crystal phases at will using experimentally accessible parameters such as temperature. PMID- 26041453 TI - Destruction-free procedure for the isolation of bacteria from sputum samples for Raman spectroscopic analysis. AB - Lower respiratory tract infections are the fourth leading cause of death worldwide. Here, a timely identification of the causing pathogens is crucial to the success of the treatment. Raman spectroscopy allows for quick identification of bacterial cells without the need for time-consuming cultivation steps, which is the current gold standard to detect pathogens. However, before Raman spectroscopy can be used to identify pathogens, they have to be isolated from the sample matrix, i.e., sputum in case of lower respiratory tract infections. In this study, we report an isolation protocol for single bacterial cells from sputum samples for Raman spectroscopic identification. Prior to the isolation, a liquefaction step using the proteolytic enzyme mixture Pronase E is required in order to deal with the high viscosity of sputum. The extraction of the bacteria was subsequently performed via different filtration and centrifugation steps, whereby isolation ratios between 46 and 57 % were achieved for sputa spiked with 6.10(7) to 6.10(4) CFU/mL of Staphylococcus aureus. The compatibility of such a liquefaction and isolation procedure towards a Raman spectroscopic classification was shown for five different model species, namely S. aureus, Staphylococcus epidermidis, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa. A classification of single-cell Raman spectra of these five species with an accuracy of 98.5 % could be achieved on the basis of a principal component analysis (PCA) followed by a linear discriminant analysis (LDA). These classification results could be validated with an independent test dataset, where 97.4 % of all spectra were identified correctly. Graphical Abstract Development of an isolation protocol of bacterial cells out of sputum samples followed by Raman spectroscopic measurement and species identification using chemometrical models. PMID- 26041454 TI - Quantification of circulating steroids in individual zebrafish using stacking to achieve nanomolar detection limits with capillary electrophoresis and UV-visible absorbance detection. AB - Capillary electrophoresis and UV-visible absorbance detection are used with sample stacking to achieve detection limits ranging from 0.2 to 2 ng/mL (0.8 to 6 nM) for steroids. Stacking is accomplished using negatively charged cyclodextrin steroid-carrier molecules at a discrete pH interface between the reconstituted sample and the separation electrolyte. Steroids are then separated in under 5 min using capillary electrophoresis that incorporates secondary equilibria via sodium dodecyl sulfate and cyclodextrin. The effectiveness of the method for measurements of multiple steroids in limited sample volumes is demonstrated in individual female fish with total circulating blood volumes of 5 MUL or less. Steroid recoveries from plasma following a sample processing method developed with commercial extraction cartridges range from 81 to 109 % for 17alpha,20beta dihydroxy-pregn-4-en-3-one, testosterone, 11-ketotestosterone, estrone, 17beta estradiol, and 17alpha-ethinyl estradiol. When applied to reproductively active female zebrafish, changes were detected in the levels of circulating steroids as a result of exposure to different solvents and 17beta-estradiol. PMID- 26041455 TI - Time-of-flight accurate mass spectrometry identification of quinoline alkaloids in honey. AB - Time-of-flight accurate mass spectrometry (TOF-MS), following a previous chromatographic (gas or liquid chromatography) separation step, is applied to the identification and structural elucidation of quinoline-like alkaloids in honey. Both electron ionization (EI) MS and positive electrospray (ESI+) MS spectra afforded the molecular ions (M(.+) and M+H(+), respectively) of target compounds with mass errors below 5 mDa. Scan EI-MS and product ion scan ESI-MS/MS spectra permitted confirmation of the existence of a quinoline ring in the structures of the candidate compounds. Also, the observed fragmentation patterns were useful to discriminate between quinoline derivatives having the same empirical formula but different functionalities, such as aldoximes and amides. In the particular case of phenylquinolines, ESI-MS/MS spectra provided valuable clues regarding the position of the phenyl moiety attached to the quinoline ring. The aforementioned spectral information, combined with retention times matching, led to the identification of quinoline and five quinoline derivatives, substituted at carbon number 4, in honey samples. An isomer of phenyquinoline was also noticed; however, its exact structure could not be established. Liquid-liquid microextraction and gas chromatography (GC) TOF-MS were applied to the screening of the aforementioned compounds in a total of 62 honeys. Species displaying higher occurrence frequencies were 4-quinolinecarbonitrile, 4 quinolinecarboxaldehyde, 4-quinolinealdoxime, and the phenylquinoline isomer. The Pearson test revealed strong correlations among the first three compounds. PMID- 26041456 TI - RPA prevents G-rich structure formation at lagging-strand telomeres to allow maintenance of chromosome ends. AB - Replication protein A (RPA) is a highly conserved heterotrimeric single-stranded DNA-binding protein involved in DNA replication, recombination, and repair. In fission yeast, the Rpa1-D223Y mutation provokes telomere shortening. Here, we show that this mutation impairs lagging-strand telomere replication and leads to the accumulation of secondary structures and recruitment of the homologous recombination factor Rad52. The presence of these secondary DNA structures correlates with reduced association of shelterin subunits Pot1 and Ccq1 at telomeres. Strikingly, heterologous expression of the budding yeast Pif1 known to efficiently unwind G-quadruplex rescues all the telomeric defects of the D223Y cells. Furthermore, in vitro data show that the identical D to Y mutation in human RPA specifically affects its ability to bind G-quadruplex. We propose that RPA prevents the formation of G-quadruplex structures at lagging-strand telomeres to promote shelterin association and facilitate telomerase action at telomeres. PMID- 26041458 TI - Important considerations in the management of Graves' disease in pregnant women. AB - Graves' disease is an autoimmune disorder in which autoantibodies to the thyroid stimulating hormone receptor cause hyperthyroidism through unregulated stimulation of the thyroid-stimulating hormone receptor. Effective management of Graves' disease in pregnancy must address the competing fetal and maternal priorities of controlling hyperthyroidism in the mother on the one hand, and on the other, minimizing the impact of maternal disease and antithyroid drugs on the well-being of the fetus. Optimal strategies for achieving this intricate balance are currently a source of continued debate among thyroid experts and studies in recent decades are now providing greater clarity into the risk posed to the unborn baby by the combination of biochemical, immunological and pharmacological hazards arising from Graves' disease and its therapy. This review summarizes the current best practice and highlights important considerations and areas of uncertainty in the management of Graves' disease in pregnant women. PMID- 26041457 TI - ER-endosome contact sites: molecular compositions and functions. AB - Recent studies have revealed the existence of numerous contact sites between the endoplasmic reticulum (ER) and endosomes in mammalian cells. Such contacts increase during endosome maturation and play key roles in cholesterol transfer, endosome positioning, receptor dephosphorylation, and endosome fission. At least 7 distinct contact sites between the ER and endosomes have been identified to date, which have diverse molecular compositions. Common to these contact sites is that they impose a close apposition between the ER and endosome membranes, which excludes membrane fusion while allowing the flow of molecular signals between the two membranes, in the form of enzymatic modifications, or ion, lipid, or protein transfer. Thus, ER-endosome contact sites ensure coordination of molecular activities between the two compartments while keeping their general compositions intact. Here, we review the molecular architectures and cellular functions of known ER-endosome contact sites and discuss their implications for human health. PMID- 26041459 TI - Effects of the DASH Diet and Walking on Blood Pressure in Patients With Type 2 Diabetes and Uncontrolled Hypertension: A Randomized Controlled Trial. AB - Data on the potential beneficial effects of combining diet and exercise on blood pressure (BP) are still scarce. A 4-week randomized controlled clinical trial was undertaken in 40 hypertensive patients with type 2 diabetes with uncontrolled blood pressure (BP) in office and daytime ambulatory BP monitoring (ABPM). Patients were assigned to follow a Dietary Approaches to Stop Hypertension (DASH) diet associated with advice to increase walking using a pedometer (intervention group) or a diet based on the American Diabetes Association recommendations (control group). The lifestyle intervention caused a greater ABPM (mm Hg) reduction in systolic 24-hour, diastolic 24-hour, nighttime systolic, daytime systolic, and daytime diastolic measurements than observed in the control group. In the intervention group there was a decrease in urinary sodium and an increase in urinary potassium, plasma aldosterone, and the number of steps per day (P<.05). The DASH diet and increased walking were associated with clinically significant reductions in ABPM values in hypertensive patients with type 2 diabetes. PMID- 26041460 TI - PRL-3 promotes migration and invasion and is associated with poor prognosis in salivary adenoid cystic carcinoma. AB - BACKGROUND: PRL-3 had been found to be involved in tumorigenesis in various malignancies. In this study, we investigated the role of PRL-3 in the development, migration, and invasion of salivary adenoid cystic carcinoma (SACC). METHODS: Immunohistochemistry (IHC) was used to analyze the role of PRL-3 in the development and prognosis of SACC. Then, we overexpressed or inhibited the expression of PRL-3 in paired SACC cells to analyze the role of PRL-3 in the migration and invasion of SACC. In vitro migration and invasion assays were used. Western blotting was used to detect metastasis-related protein levels. RESULTS: IHC results confirmed that the deregulation of PRL-3 was a frequent event in SACC; the upregulation of PRL-3 was related to clinical stages, vital status, and distant metastasis, which was associated with reduced overall survival and disease-free survival. SACC-LM cells with higher migratory and invasive abilities had more robust PRL-3 protein expression than SACC-83 cells with lower migratory and invasive abilities. PRL-3 overexpression promoted cell migration, invasion, and proliferation, led to simultaneous upregulation of phosphorylated PRL-3, pERK1/2, Slug, vimentin, and downregulation of E-cadherin in SACC-83 cells. However, the inhibition of PRL-3 by PRL-3 inhibitor or PRL-3 siRNA in SACC-LM cells inhibited cell migration, invasion, and proliferation, resulted in simultaneous downregulation of phosphorylated PRL-3, pERK1/2, Slug, vimentin, and upregulation of E-cadherin. CONCLUSIONS: Our results confirm that PRL-3 plays an important role in the development of SACC and contributes to the migratory and invasive abilities of SACC. PMID- 26041461 TI - Potential relationship between Hashimoto's thyroiditis and BRAF(V600E) mutation status in papillary thyroid cancer. AB - BACKGROUND: The purpose of this study was to evaluate the potential relationship between Hashimoto's thyroiditis and BRAF(V600E) mutation status in patients with papillary thyroid carcinoma (PTC). METHODS: A total of 619 patients with PTC who underwent total thyroidectomy with lymph node dissection were enrolled in this study. Univariable and multivariate analyses were used. RESULTS: Hashimoto's thyroiditis was present in 35.9% (222 of 619) of PTCs. Multivariate logistic regressions showed that BRAF(V600E) mutation, sex, extrathyroidal extension, and lymph node metastasis were independent factors for Hashimoto's thyroiditis. Female sex, more frequent extrathyroidal extension, and a higher incidence of lymph node metastasis were significantly associated with PTCs accompanied by BRAF(V600E) mutation without Hashimoto's thyroiditis compared with PTCs accompanied by BRAF(V600E) mutation with Hashimoto's thyroiditis. CONCLUSION: Hashimoto's thyroiditis was negatively associated with BRAF(V600E) mutation, extrathyroidal extension, and lymph node metastasis. In addition, Hashimoto's thyroiditis was related to less lymph node metastasis and extrathyroidal extension in PTCs with BRAF(V600E) mutation. Therefore, Hashimoto's thyroiditis is a potentially protective factor in PTC. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1019-E1025, 2016. PMID- 26041463 TI - [Features of occupational health nurse support for the improvement of psychosocial working environments and related factors: Focusing on required knowledge and skills, and measures to develop them]. AB - OBJECTIVE: The purpose of this study was to examine the support activities provided for occupational health nurses aimed at improving psychosocial working environments, related knowledge and skills, and learning environments as well as associations among these factors. In addition, we aimed to create correlated factor models to describe the support activities in order to identify ways to promote these activities among occupational health nurses. METHODS: An anonymous mail-based questionnaire survey was conducted of occupational health nurses who were members of the Japan Society for Occupational Health and belonged to enterprises or independent health insurance societies. Among 356 returned questionnaires (response rate: 46.4%), all the main items were answered in 329 (valid response rate: 92.4%), and these questionnaires were analyzed. Factor analysis was performed for the seven items pertaining to support activities for the improvement of psychosocial working environments and models of each factor of the support activities were developed using covariance structure analysis. RESULTS: In the factor analysis, [Clarifying a stress-related situation and providing advice] and [Facilitating workplace involvement] were identified as support-related factors. The mean implementation rates for these approaches were approximately 50 to 80%, and less than 40%, respectively. [Clarifying a stress related situation and providing advice] was associated with skills of "providing superiors with explanations to enhance their understanding" and "collecting and analyzing stress survey results by department", and knowledge of "personal stress questionnaires" and "common stress factors in working environments". The above mentioned knowledge and skills were associated with self-learning of "examining and reporting daily activities for the improvement of working environments" and "reviewing related papers". [Facilitating workplace involvement] was associated with skills of "indirectly supporting discussions led by key persons in working environments" and "giving feedback regarding occupational stress survey results to superiors", and knowledge of "tools for the improvement of working environments" and "appropriate methods to use stress questionnaires". In addition, such knowledge and skills were associated with self-learning and learning environments of "participating in seminars to learn effective methods to use group-work approaches" and "receiving support and advice from mentors of universities and research institutions". DISCUSSION: The features of occupational health nurse support for the improvement of psychosocial working environments were revealed by this study. The implementation rates suggest that it is particularly necessary to promote [Facilitating workplace involvement]. It will be necessary to encourage the acquisition of associated knowledge and skills in order to promote occupational health nurse support for the improvement of psychosocial working environments. PMID- 26041462 TI - Gut and sublingual microvascular effect of esmolol during septic shock in a porcine model. AB - INTRODUCTION: Esmolol may efficiently reduce heart rate (HR) and decrease mortality during septic shock. An improvement of microcirculation dissociated from its macrocirculatory effect may a role. The present study investigated the effect of esmolol on gut and sublingual microcirculation in a resuscitated piglet model of septic shock. METHODS: Fourteen piglets, anesthetized and mechanically ventilated, received a suspension of live Pseudomonas aeruginosa. They were randomly assigned to two groups: the esmolol (E) group received an infusion of esmolol, started at 7.5 MUg?kg(-1)?min(-1), and progressively increased to achieve a HR below 90 beats?min(-1). The control (C) group received an infusion of Ringer's lactate solution. HR, mean arterial pressure (MAP), cardiac index (CI), stroke index (SI), systemic vascular resistance (SVR), arterio-venous blood gas and lactate were recorded. Oxygen consumption (VO2), delivery (DO2) and peripheral extraction (O2ER) were computed. Following an ileostomy, a laser Doppler probe was applied on ileal mucosa to monitor gut microcirculatory laser Doppler flow (GMLDF). Videomicroscopy was also used on ileal mucosa and sublingual areas to evaluate mean flow index (MFI), heterogeneity, ratio of perfused villi and proportion of perfused vessels. Resuscitation maneuvers were performed following a defined algorithm. RESULTS: Bacterial infusion induced a significant alteration of the gut microcirculation with an increase in HR. Esmolol produced a significant time/group effect with a decrease in HR (P <0.004) and an increase in SVR (P <0.004). Time/group effect was not significant for CI and MAP, but there was a clear trend toward a decrease in CI and MAP in the E group. Time/group effect was not significant for SI, O2ER, DO2, VO2, GMLDF and lactate. A significant time/group effect of ileal microcirculation was found with a lower ileal villi perfusion (P <0.025) in the C group, and a trend toward a better MFI in the E group. No difference between both groups was found regarding microcirculatory parameters in the sublingual area. CONCLUSIONS: Esmolol provided a maintenance of microcirculation during sepsis despite its negative effects on macrocirculation. Some parameters even showed a trend toward an improvement of the microcirculation in the gut area in the esmolol group. PMID- 26041464 TI - Amyloidosis and the risk of cancer: a nationwide population-based study. AB - BACKGROUND: The association between amyloidosis and cancer remains unclear. PARTICIPANTS AND METHODS: Using the Taiwan National Health Insurance Research Database we conducted a population-based cohort study. Patients newly diagnosed with amyloidosis between 1997 and 2009 were enrolled. Patients with antecedent cancer were excluded. Standardized incidence ratios (SIR) of cancers were calculated for the study cohort and compared with cancer incidence among the general population. We used a multivariate Cox regression model to evaluate the predictors of cancer development for patients with amyloidosis. RESULTS: The study included 1,693 subjects with median follow-up of 5.63 years. A total of 68 patients developed cancer. The incidence of kidney cancer (SIR 3.42; 95 % CI 1.11 7.97; p = 0.034) and hematologic malignancies (SIR 3.88; 95 % CI 1.86-7.14; p < 0.001) were significantly higher for patients with amyloidosis. CONCLUSION: This is currently the largest study to evaluate cancer risk among patients with amyloidosis. The results indicate that amyloidosis may be associated with an increased risk of kidney cancer and hematologic malignancies. PMID- 26041465 TI - Doctors as the governing body of the Kurdish health system: exploring upward and downward accountability among physicians and its influence on the adoption of coping behaviours. AB - BACKGROUND: The health system of Iraqi Kurdistan is severely understudied, particularly with regard to patient-physician interactions and their effects. We examine patterns of behaviour among physicians in Kurdistan, the justifications given and possible enabling factors, with a view to understanding accountability both from above and below. METHODS: An ethnographic study was conducted in the Sulaimaniyah Teaching Hospital in the Kurdistan Region of Iraq. Data was collected through negotiated interactive observation, and interviews were conducted with 10 participants, 5 physicians and 5 patients. Data collected was analysed using thematic analysis. RESULTS: Common patterns of practice among physicians in Kurdistan include displays of discontent, reluctance to negotiate decisions with patients and unfavourable behaviours including dual practice and predatory behaviours towards patients. These behaviours are justified as a mechanism of dealing with negative aspects of their work, including overcrowding, low salaries and social pressure to live up to socially conceived ideas of a physician's identity. CONCLUSIONS: Michael Lipsky's theory of street-level bureaucrats and their coping behaviours is a useful way to analyse the Kurdish health system. Physician behaviours are enabled by a number of factors that work to enhance physician discretion through lowering of upward and downward accountability. Physicians are under very little pressure to change their behaviour, and as a result, they effectively become the street-level governing body of the Kurdish health system. PMID- 26041466 TI - Electron transfer within a reaction path model calibrated by constrained DFT calculations: application to mixed-valence organic compounds. AB - The quantum dynamics of electron transfer in mixed-valence organic compounds is investigated using a reaction path model calibrated by constrained density functional theory (cDFT). Constrained DFT is used to define diabatic states relevant for describing the electron transfer, to obtain equilibrium structures for each of these states and to estimate the electronic coupling between them. The harmonic analysis at the diabatic minima yields normal modes forming the dissipative bath coupled to the electronic states. In order to decrease the system-bath coupling, an effective one dimensional vibronic Hamiltonian is constructed by partitioning the modes into a linear reaction path which connects both equilibrium positions and a set of secondary vibrational modes, coupled to this reaction coordinate. Using this vibronic model Hamiltonian, dissipative quantum dynamics is carried out using Redfield theory, based on a spectral density which is determined from the cDFT results. In a first benchmark case, the model is applied to a series of mixed-valence organic compounds formed by two 1,4 dimethoxy-3-methylphenylene fragments linked by an increasing number of phenylene bridges. This allows us to examine the coherent electron transfer in extreme situations leading to a ground adiabatic state with or without a barrier and therefore to the trapping of the charge or to an easy delocalization. PMID- 26041467 TI - Design, Synthesis, and Antitumor Activity of (E,Z)-1-(dihydrobenzofuran-5-yl)-3 phenyl-2-(1,2,4-triazol-1-yl)-2-propen-1-ones. AB - A series of (E,Z)-1-(dihydrobenzofuran-5-yl)-3-phenyl-2-(1,2,4-triazol-1-yl)-2 propen-1-ones (C1-C35) were designed and synthesized, and the structures of compounds (Z)-C27 and (Z)-C29 were confirmed by single-crystal X-ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF-7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)-C24 exhibited the most consistent potent activities against three neoplastic cells with IC50 values ranging from 3.2 to 7.1 MUm. Further researches demonstrated that compounds (E,Z)-C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure-activity relationship between the configurations and cytotoxicity of the compounds was also investigated. PMID- 26041468 TI - Erythema ab igne. PMID- 26041469 TI - Systematic review of models assessing the economic value of routine varicella and herpes zoster vaccination in high-income countries. AB - BACKGROUND: A systematic review was conducted to assess the cost-effectiveness of routine varicella and herpes zoster (HZ) vaccination in high-income countries estimated by modelling studies. METHODS: A PubMed search was performed to identify relevant studies published before October 2013. Studies were included in the review if they (i) evaluated the cost-effectiveness of routine childhood or adolescent varicella vaccination and/or HZ vaccination targeting the elderly, and if they (ii) reported results for high-income countries. RESULTS: A total of 38 model-based studies were identified that fulfilled the inclusion criteria. Routine childhood or adolescent varicella vaccination was cost-effective or cost saving from a payer perspective and always cost-saving from a societal perspective when ignoring its potential impact on HZ incidence due to reduced or absent exogenous boosting. The inclusion of the potential impact of childhood varicella vaccination on HZ led to net quality-adjusted life-year (QALY) losses or incremental cost-effectiveness ratios exceeding commonly accepted thresholds. Additional HZ vaccination could partially mitigate this effect. Studies focusing only on the evaluation of HZ vaccination reported a wide range of results depending on the selected target age-group and the vaccine price, but most found HZ vaccination to be a cost-effective or marginally cost-effective intervention. Cost-effectiveness of HZ vaccination was strongly dependent on the age at vaccination, the price of the vaccine, the assumed duration of protection and the applied cost per QALY threshold. CONCLUSIONS: While HZ vaccination is mostly considered cost-effective, cost-effectiveness of varicella vaccination primarily depends on the in- or exclusion of exogenous boosting in the model. As a consequence, clarification on the role of exogenous boosting is crucial for decision-making regarding varicella vaccination. PMID- 26041470 TI - Effect of distance to health facility on the maintenance of INR therapeutic ranges in rheumatic heart disease patients from Cape Town: no evidence for an association. AB - BACKGROUND: Lack of adherence to international normalised ratio (INR) monitoring in rheumatic heart disease (RHD) patients is a contributor to cardio-embolic complications. This population-based observational study investigated whether the distance between home and an INR clinic affects the maintenance of therapeutic INR in RHD patients on warfarin. METHODS: Residential addresses, INR clinics, and INR results of patients with RHD were extracted from the Cape Town component of the Global Rheumatic Heart Disease Registry (REMEDY) database. Addresses of homes and INR clinics were converted to geographical coordinates and verified in ArcGIS 10(r). ArcGIS 10(r) and Google Maps(r) were used for spatial mapping and obtaining shortest road distances respectively. The travel distance between the home and INR clinic was correlated with time within therapeutic range (TTR) using the Rosendaal linear interpolation method, and with the fraction of INR within range, based on an average of three INR readings of patients and compared with recommended therapeutic ranges. RESULTS: RHD patients (n = 133) resided between 0.2 km and 50.8 km (median distance, 3.60 km) from one of 33 INR clinics. There was no significant difference in the achievement of the therapeutic INR between patients who travelled a shorter distance compared to those who travelled a longer distance (in range = 3.50 km versus out of range = 3.75 km, p = 0.78). This finding was the same for patients with mechanical valve replacement (n = 105) (3.50 km versus 3.90 km, p = 0.81), and native valves (3.45 km versus 2.75 km, p = 0.84). CONCLUSIONS: There is no association between the maintenance of INR within therapeutic range amongst RHD patients in Cape Town and distance from patients' residence to the INR clinic. PMID- 26041472 TI - Dynamic modelling of high biomass density cultivation and biohydrogen production in different scales of flat plate photobioreactors. AB - This paper investigates the scaling-up of cyanobacterial biomass cultivation and biohydrogen production from laboratory to industrial scale. Two main aspects are investigated and presented, which to the best of our knowledge have never been addressed, namely the construction of an accurate dynamic model to simulate cyanobacterial photo-heterotrophic growth and biohydrogen production and the prediction of the maximum biomass and hydrogen production in different scales of photobioreactors. To achieve the current goals, experimental data obtained from a laboratory experimental setup are fitted by a dynamic model. Based on the current model, two key original findings are made in this work. First, it is found that selecting low-chlorophyll mutants is an efficient way to increase both biomass concentration and hydrogen production particularly in a large scale photobioreactor. Second, the current work proposes that the width of industrial scale photobioreactors should not exceed 0.20 m for biomass cultivation and 0.05 m for biohydrogen production, as severe light attenuation can be induced in the reactor beyond this threshold. PMID- 26041474 TI - Deposition of uniform Pt nanoparticles with controllable size on TiO2-based nanowires by atomic layer deposition and their photocatalytic properties. PMID- 26041471 TI - Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden. AB - BACKGROUND: Redox stress is a hallmark of the rewired metabolic phenotype of cancer. The underlying dysregulation of reactive oxygen species (ROS) is interconnected with abnormal mitochondrial biogenesis and function. In chronic lymphocytic leukemia (CLL), elevated ROS are implicated in clonal outgrowth and drug resistance. The pro-survival oncogene T-cell leukemia 1 (TCL1) is causally linked to the high threshold towards classical apoptosis in CLL. We investigated how aberrant redox characteristics and bioenergetics of CLL are impacted by TCL1 and if this is therapeutically exploitable. METHODS: Bio-organometallic chemistry provided compounds containing a cytosine nucleobase, a metal core (ferrocene, ruthenocene, Fe(CO)3), and a 5'-CH2O-TDS substituent. Four of these metal containing nucleoside analogues (MCNA) were tested for their efficacy and mode of action in CLL patient samples, gene-targeted cell lines, and murine TCL1 transgenic splenocytes. RESULTS: The MCNA showed a marked and selective cytotoxicity towards CLL cells. MCNA activity was equally observed in high-risk disease groups, including those of del11q/del17p cytogenetics and of clinical fludarabine resistance. They overcame protective stromal cell interactions. MCNA evoked PARP-mediated cell death was non-autophagic and non-necrotic as well as caspase- and P53-independent. This unconventional apoptosis involved early increases of ROS, which proved indispensible based on mitigation of MCNA triggered death by various scavengers. MCNA exposure reduced mitochondrial respiration (oxygen consumption rate; OCR) and induced a rapid membrane depolarization (?PsiM). These characteristics distinguished the MCNA from the alkylator bendamustine and from fludarabine. Higher cellular ROS and increased MCNA sensitivity were linked to TCL1 expression. The presence of TCL1 promoted a mitochondrial release of in part caspase-independent apoptotic factors (AIF, Smac, Cytochrome-c) in response to MCNA. Although basal mitochondrial respiration (OCR) and maximal respiratory capacity were not affected by TCL1 overexpression, it mediated a reduced aerobic glycolysis (lactate production) and a higher fraction of oxygen consumption coupled to ATP-synthesis. CONCLUSIONS: Redox active substances such as organometallic nucleosides can confer specific cytotoxicity to ROS-stressed cancer cells. Their P53- and caspase-independent induction of non-classical apoptosis implicates that redox-based strategies can overcome resistance to conventional apoptotic triggers. The high TCL1-oncogenic burden of aggressive CLL cells instructs their particular dependence on mitochondrial energetic flux and renders them more susceptible towards agents interfering in mitochondrial homeostasis. PMID- 26041473 TI - Ectopic expression of N-acetylglucosaminyltransferase V accelerates hepatic triglyceride synthesis. AB - AIM: Glycosylation changes induce various types of biological phenomena in human diseases. N-Acetylglucosaminyltransferase V (GnT-V) is one of the most important glycosyltransferases involved in cancer biology. Recently, many researchers have challenged studies of lipid metabolism in cancer. To elucidate the relationships between cancer and lipid metabolism more precisely, we investigated the effects of GnT-V on lipid metabolism. In this study, we investigated the effects of aberrant glycosylation by GnT-V on hepatic triglyceride production. METHODS: We compared lipid metabolism in GnT-V transgenic (Tg) mice with that of wild-type (WT) mice fed with normal chow or a choline-deficient amino acid-defined (CDAA) diet in vivo. HepG2 cells and GnT-V transfectants of Hep3B cells were used in an in vitro study. RESULTS: Serum triglyceride levels and hepatic very low-density lipoprotein (VLDL) secretion in Tg mice were significantly elevated compared with that of WT mice. Hepatic lipogenic genes (Lxralpha, Srebp1, Fas and Acc) and VLDL secretion-related gene (Mttp1) were significantly higher in Tg mice. Expression of these genes was also significantly higher in GnT-V transfectants than in mock cells. Knockdown of GnT-V decreased, while both epidermal growth factor and transforming growth factor-beta1 stimulation increased LXRalpha gene expression in HepG2 cells. Finally, we found that the blockade of VLDL secretion by CDAA diet induced massive hepatic steatosis in Tg mice. CONCLUSION: Our study demonstrates that enhancement of hepatic GnT-V activity accelerates triglyceride synthesis and VLDL secretion. Glycosylation modification by GnT-V regulation could be a novel target for a therapeutic approach to lipid metabolism. PMID- 26041475 TI - Exposure of personnel and public due to using 153Sm-labelled EDTMP-Quadramet(r) in nuclear medicine procedures. AB - The main aim of this study was to highlight the problems of personnel exposure when administering (153)Sm-labelled ethylene diamine tetramethylene phosphonate Quadramet((r)) to patients and especially to evaluate hand exposure of the personnel. The exposure levels of patients' families and the people who takes care of the patients treated by Quadramet((r)) were also estimated. Thermoluminescent detectors were used to measure the doses. The doses received during the injection of the Quadramet((r)) by the nursing staff have been determined at the level of 1/150 dose limit for the skin. Exposure of members of the patient's family staying 1.5 m away from the patient being treated with Quadramet((r)) has been estimated to be 0.40 mGy. PMID- 26041476 TI - Radiation dosimetry properties of smartphone CMOS sensors. AB - During the past years, several smartphone applications have been developed for radiation detection. These applications measure radiation using the smartphone camera complementary metal-oxide-semiconductor sensor. They are potentially useful for data collection and personal dose assessment in case of a radiological incident. However, it is important to assess these applications. Six applications were tested by means of irradiations with calibrated X-ray and gamma sources. It was shown that the measurement stabilises only after at least 10-25 min. All applications exhibited a flat dose rate response in the studied ambient dose equivalent range from 2 to 1000 MUSv h(-1). Most applications significantly over- or underestimate the dose rate or are not calibrated in terms of dose rate. A considerable energy dependence was observed below 100 keV but not for the higher energy range more relevant for incident scenarios. Photon impact angle variation gave a measured signal variation of only about 10 %. PMID- 26041477 TI - Isolation and purification of prenylated phenolics from Amorpha fruticosa by high speed counter-current chromatography. AB - Prenylated phenolics such as amorfrutins are recently identified potent anti inflammatory and antidiabetic natural products. In this work, high-speed counter current chromatography was investigated for the isolation and purification of prenylated phenolics from the fruits of Amorpha fruticosa by using a two-phase solvent system composed of n-hexane/ethanol/water (5:4:1, v/v). As a result, 14.2 mg of 5,7-dihydroxy-8-geranylflavanone, 10.7 mg of amorfrutin A and 17.4 mg of amorfrutin B were obtained from 200 mg of n-hexane-soluble crude extract in one step within 250 min. The purities of 5,7-dihydroxy-8-geranylflavanone, amorfrutins A and B were 95.2, 96.7 and 97.1%, respectively, as determined by ultra high performance liquid chromatography. The structural identification was performed by mass spectrometry and (1) H and (13) C NMR spectroscopy. The results indicated that the established method is an efficient and convenient way to purified prenylated phenolics from A. fruticosa extract. PMID- 26041478 TI - Abstracts of the 4th Meeting of the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. PMID- 26041479 TI - Timing of blood pressure lowering in acute ischemic stroke. AB - Whether there are any benefits without harm from early lowering of blood pressure (BP) in the setting of acute ischemic stroke (AIS) has been a longstanding controversy in medicine. Whilst most studies have consistently shown associations between elevated BP, particularly systolic BP, and poor outcome, some also report that very low BP (systolic <130 mmHg) and large reductions in systolic BP are associated with poor outcomes in AIS. However, despite these associations, the observed U- or J-shaped relationship between BP and outcome in these patients may not be causally related. Patients with more severe strokes may have a more prominent autonomic response and later lower BP as their condition worsens, often pre-terminally. Fortunately, substantial progress has been made in recent years with new evidence arising from well-conducted randomized trials. This review outlines new evidence and recommendations for clinical practice over BP management in AIS. PMID- 26041480 TI - Prophylactic treatment for delayed chemotherapy-induced nausea and vomiting after non-AC based moderately emetogenic chemotherapy: a systematic review of randomized controlled trials. AB - PURPOSE: Delayed chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of moderately emetogenic chemotherapy not containing anthracyclines and cyclophosphamide (non-AC MEC). In this review, we summarize current literature to update recommendations for delayed CINV prophylaxis after non-AC MEC. METHODS: We conducted a systematic search in PubMed and conference proceedings from ASCO, ESMO, and MASCC. Included randomized controlled trials (RCTs) aimed to prospectively evaluate the efficacy of two or more antiemetic strategies in the prevention of delayed CINV after the administration of non-AC MEC. At least one of the following endpoints was used: complete response, complete control, no nausea, no vomiting, and/or no use of rescue medication. RESULTS: Our search provided 247 publications. Nine met the predefined criteria. Included RCTs reported outcomes on palonosetron, aprepitant, casopitant, netupitant/palonosetron (NEPA), olanzapine, and megestrol acetate. CONCLUSIONS: Superiority of palonosetron over first-generation 5-HT3 receptor antagonists for the prevention of acute and delayed CINV after non-AC MEC has not been proven. The addition of an NK1 receptor antagonist to first-generation 5-HT3 receptor antagonists does not significantly improve the incidence of delayed CINV after non-AC MEC. The efficacy of a single-day regimen of dexamethasone with palonosetron is non-inferior to multiday dexamethasone. NEPA, olanzapine, and megestrol acetate show highly effective complete response (CR) rates. PMID- 26041482 TI - A novel tissue-engineered trachea with a mechanical behavior similar to native trachea. AB - A novel tissue-engineered trachea was developed with appropriate mechanical behavior and substantial regeneration of tracheal cartilage. We designed hollow bellows scaffold as a framework of a tissue-engineered trachea and demonstrated a reliable method for three-dimensional (3D) printing of monolithic bellows scaffold. We also functionalized gelatin sponge to allow sustained release of TGF beta1 for stimulating tracheal cartilage regeneration and confirmed that functionalized gelatin sponge induces cartilaginous tissue formation in vitro. A tissue-engineered trachea was then created by assembling chondrocytes-seeded functionalized gelatin sponges into the grooves of bellows scaffold and it showed very similar mechanical behavior to that of native trachea along with substantial regeneration of tracheal cartilage in vivo. The tissue-engineered trachea developed here represents a novel concept of tracheal substitute with appropriate mechanical behavior similar to native trachea for use in reconstruction of tracheal stenosis. PMID- 26041481 TI - Phase II trial of epidermal growth factor ointment for patients with Erlotinib related skin effects. AB - PURPOSE: The efficacy of erlotinib, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated in patients with non-small cell lung cancer (NSCLC) and pancreatic cancer (PC). In the present study, we evaluated the effect of epidermal growth factor (EGF) ointment on erlotinib related skin effects (ERSEs). METHODS: This was an open-label, non-comparative, multicenter, phase II trial. The patients included those diagnosed with NSCLC or PC who were treated with erlotinib. The effectiveness of the ointment was defined as follows: (1) grade 2, 3, or 4 ERSEs downgraded to <= grade 1 or (2) grade 3 or 4 ERSEs downgraded to grade 2 and persisted for at least 2 weeks. RESULTS: Fifty two patients from seven institutes in Korea were enrolled with informed consent. The final assessment included 46 patients (30 males, 16 females). According to the definition of effectiveness, the EGF ointment was effective in 36 (69.2%) intention to treat patients. There were no statistically significant differences in the effectiveness of the EGF ointment by gender (p = 0.465), age (p = 0.547), tumor type (p = 0.085), erlotinib dosage (p = 0.117), and number of prior chemotherapy sessions (p = 0.547). The grading for the average National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) rating of rash/acne and itching improved from 2.02 +/- 0.83 to 1.13 +/- 0.89 and 1.52 +/- 0.84 to 0.67 +/- 0.90, respectively (p < 0.001). The most common reason for discontinuing the study was progression of cancer (37%). CONCLUSIONS: Based on the results, the EGF ointment is effective for ERSEs, regardless of gender, age, type of tumor, and dosage of erlotinib. The EGF ointment evenly improved all kinds of symptoms of ERSEs. CLINICAL TRIAL REGISTRATION NO: ClinicalTrials.gov identifier: NCT01593995. PMID- 26041483 TI - Activated carbon for aerobic oxidation: Benign approach toward 2 benzoylbenzimidazoles and 2-benzoylbenzoxazoles synthesis. AB - A general strategy involving a novel and highly efficient aerobic benzylic oxidation promoted by cheap, reusable activated carbon in water is developed. Application of this method has been demonstrated in the benign synthesis of bioactive 2-benzoylbenzimidazoles and 2-benzoylbenzoxazoles derivatives. Furthermore, the activated carbon catalyst could be recovered and reused at least three times without significantly losing its activity. Preliminary research suggests that the oxidation mechanism may involve intermediate hydroperoxidation and that a portion of the final carbonyl product is obtained through a secondary benzylic alcohol intermediate. Finally, theoretical calculations reveal that the oxidation yield is closely associated with the electric density at the benzylic position of the substrate. PMID- 26041484 TI - The Principle-Based Method of Practical Ethics. AB - This paper is about the methodology of doing practical ethics. There is a variety of methods employed in ethics. One of them is the principle-based approach, which has an established place in ethical reasoning. In everyday life, we often judge the rightness and wrongness of actions by their conformity to principles, and the appeal to principles plays a significant role in practical ethics, too. In this paper, I try to provide a better understanding of the nature of principle-based reasoning. To accomplish this, I show in the first section that these principles can be applied to cases in a meaningful and sufficiently precise way. The second section discusses the question how relevant applying principles is to the resolution of ethical issues. This depends on their nature. I argue that the principles under consideration in this paper should be interpreted as presumptive principles and I conclude that although they cannot be expected to bear the weight of definitely resolving ethical problems, these principles can nevertheless play a considerable role in ethical research. PMID- 26041485 TI - Synthesis of high aspect ratio (K, Na)NbO3 plate-like particles and study on the synthesis mechanism. AB - Plate-like NaNbO3 (NN) templates have been successfully synthesized via a two step molten salt method using K2CO3 as a raw material at 970 degrees C, which is below the topochemical reaction temperature using Na2CO3 as the raw material (higher than 1000 degrees C). The synthesized plate-like NN particles have a higher aspect ratio with a thickness of 0.5-1 MUm, a width of 5-10 MUm and a length of 15-25 MUm. In this process, we found that Na2CO3 or K2CO3 plays an important role in removing the (Bi2O2)(2+) layers in the substitution process and the final composition is decided by the type of molten salt. Using KCl as molten salt and Na2CO3 or K2CO3 as raw material, the (Bi2O2)(2+) layers could be removed by Na2CO3 or K2CO3 and K(+) ions can be incorporated into the template during the topochemical reaction and thus (K, Na)NbO3 (KNN) plate-like particles can be fabricated. The growth process is reasonably elucidated by this growth mechanism. PMID- 26041486 TI - Mouse genetic background impacts both on iron and non-iron metals parameters and on their relationships. AB - Iron is reported to interact with other metals. In addition, it has been shown that genetic background may impact iron metabolism. Our objective was to characterize, in mice of three genetic backgrounds, the links between iron and several non-iron metals. Thirty normal mice (C57BL/6, Balb/c and DBA/2; n = 10 for each group), fed with the same diet, were studied. Quantification of iron, zinc, cobalt, copper, manganese, magnesium and rubidium was performed by ICP/MS in plasma, erythrocytes, liver and spleen. Transferrin saturation was determined. Hepatic hepcidin1 mRNA level was evaluated by quantitative RT-PCR. As previously reported, iron parameters were modulated by genetic background with significantly higher values for plasma iron parameters and liver iron concentration in DBA/2 and Balb/c strains. Hepatic hepcidin1 mRNA level was lower in DBA/2 mice. No iron parameter was correlated with hepcidin1 mRNA levels. Principal component analysis of the data obtained for non-iron metals indicated that metals parameters stratified the mice according to their genetic background. Plasma and tissue metals parameters that are dependent or independent of genetic background were identified. Moreover, relationships were found between plasma and tissue content of iron and some other metals parameters. Our data: (i) confirms the impact of the genetic background on iron parameters, (ii) shows that genetic background may also play a role in the metabolism of non-iron metals, (iii) identifies links between iron and other metals parameters which may have implications in the understanding and, potentially, the modulation of iron metabolism. PMID- 26041487 TI - Is traditional Chinese medicine recommended in Western medicine clinical practice guidelines in China? A systematic analysis. AB - BACKGROUND: Evidence-based medicine promotes and relies on the use of evidence in developing clinical practice guidelines (CPGs). The Chinese healthcare system includes both traditional Chinese medicine (TCM) and Western medicine, which are expected to be equally reflected in Chinese CPGs. OBJECTIVE: To evaluate the inclusion of TCM-related information in Western medicine CPGs developed in China and the adoption of high level evidence. METHODS: All CPGs were identified from the China Guideline Clearinghouse (CGC), which is the main Chinese organisation maintaining the guidelines issued by the Ministry of Health of China, the Chinese Medical Association and the Chinese Medical Doctors' Association.TCM-related contents were extracted from all the CPGs identified. Extracted information comprised the institution issuing the guideline, date of issue, disease, recommendations relating to TCM, evidence level of the recommended content and references supporting the recommendations. RESULTS: A total of 604 CPGs were identified, only a small number of which (74/604; 12%) recommended TCM therapy and only five guidelines (7%) had applied evidence grading. The 74 CPGs involved 13 disease systems according to the International Classification of Diseases 10th edition. TCM was mainly recommended in the treatment part of the guidelines (73/74, 99%), and more than half of the recommendations (43/74, 58%) were related to Chinese herbal medicine (single herbs or herbal treatment based on syndrome differentiation). CONCLUSIONS: Few Chinese Western medicine CPGs recommend TCM therapies and very few provide evidence grading for the TCM recommendation. We suggest that future guideline development should be based on systematic searches for evidence to support CPG recommendations and involve a multidisciplinary approach including TCM expertise. PMID- 26041488 TI - A long-term, observational cohort study on the safety of low-dose glucocorticoids in ankylosing spondylitis: adverse events and effects on bone mineral density, blood lipid and glucose levels and body mass index. AB - OBJECTIVES: This study aimed to investigate the risk of adverse events and effects on bone mineral density (BMD), blood lipid and glucose levels and body mass index (BMI) of low-dose glucocorticoid (GC) treatment in ankylosing spondylitis. DESIGN: We performed a retrospective, observational cohort study. Adverse effects were compared between GC users and non-GC users, and we analysed differences in the duration of GC exposure (no GC exposure, <6 months, 6 months to 2 years and >2 years). SETTING: Outpatient clinic in a tertiary general hospital in China, rheumatology follow-up visits over the past 30 years. PARTICIPANTS: We included 830 patients with ankylosing spondylitis who were followed up for at least 6 months without a previous history or current complications of active gastrointestinal problems, hypertension, psychiatric or mental problems, diabetes mellitus, tuberculosis and hepatitis. The median follow up time was 1.6 years (range 0.5-15 years, a total of 1801 patient-years). RESULTS: A total of 555 (66.9%) patients were treated with low-dose GCs, and the median cumulative duration of GC therapy was 1.3 years (range 0.1-8.5 years). Dermatological incidents, including acne, bruisability and cutaneous infections, were the most common adverse events, with a cumulative incidence rate of 5.4% (22.2 events per 1000 patient-years), followed by a puffy and rounded face (1.6%), symptoms of weight gain (1.1%) and serious infections (1.0%). The rates of all other types of adverse events were less than 1%. The GC groups (GC users and non-GC users) and the duration of GC therapy were not associated with the frequency of low BMD, dyslipidaemia, hyperglycaemia or obesity (p<0.05). CONCLUSIONS: Adverse events during long-term treatment of low-dose GCs are limited. Low-dose GCs do not have an adverse effect on BMD, blood lipid and glucose levels and BMI. PMID- 26041489 TI - Do patterns of mental healthcare predict treatment failure in young people with schizophrenia? Evidence from an Italian population-based cohort study. AB - OBJECTIVE: Little is known about the practice of predicting community-based care effectiveness of patients affected by schizophrenic disorders. We assessed predictors of treatment failure in a large sample of young people affected by schizophrenia. METHODS: A cohort of 556 patients aged 18-35 years who were originally diagnosed with schizophrenia during 2005-2009 in a Mental Health Service (MHS) of the Italian Lombardy Region was identified. Intensity of mental healthcare received during the first year after index visit (exposure) was measured by patients' regularity in MHS attendance and the length of time covered with antipsychotic drug therapy. Patients were followed from index visit until 2012 for identifying hospital admission for mental disorder (outcome). A proportional hazards model was fitted to estimate the HR and 95% CIs for the exposure-outcome association, after adjusting for several covariates. A set of sensitivity analyses were performed in order to account for sources of systematic uncertainty. RESULTS: During follow-up, 144 cohort members experienced the outcome. Compared with patients on low coverage with antipsychotic drugs (<= 4 months), those on intermediate (5-8 months) and high (>= 9 months) coverage, had HRs (95% CI) of 0.94 (0.64 to 1.40) and 0.69 (0.48 to 0.98), respectively. There was no evidence that regular attendance at the MHS affected the outcome. CONCLUSIONS: Patients in the early phase of schizophrenia and their families should be cautioned about the possible consequences of poor antipsychotic adherence. Physicians and decision makers should increase their contribution towards improving mental healthcare. PMID- 26041490 TI - Quantifying uncertainty in intervention effectiveness with structured expert judgement: an application to obstetric fistula. AB - OBJECTIVE: To demonstrate a new application of structured expert judgement to assess the effectiveness of surgery to correct obstetric fistula in a low-income setting. Intervention effectiveness is a major input of evidence-informed priority setting in healthcare, but information on intervention effectiveness is generally lacking. This is particularly problematic in the context of poorly resourced healthcare settings where even efficacious interventions fail to translate into improvements in health. The few intervention effectiveness studies related to obstetric fistula treatment focus on the experience of single facilities and do not consider the impact of multiple factors that may affect health outcomes. DESIGN: We use the classical model of structured expert judgement, a method that has been used to quantify uncertainty in the areas of engineering and environmental risk assessment when data are unavailable. Under this method, experts quantify their uncertainty about rates of long-term disability in patients with fistula following treatment in different contexts, but the information content drawn from their responses is statistically conditioned on the accuracy and informativeness of their responses to a set of calibration questions. Through this method, we develop best estimates and uncertainty bounds for the rate of disability associated with each treatment scenario and setting. PARTICIPANTS: Eight experts in obstetric fistula repair in low and middle income countries. RESULTS: Estimates developed using performance weights were statistically superior to those involving a simple averaging of expert responses. The performance-weight decision maker's assessments are narrower for 9 of the 10 calibration questions and 21 of 23 variables of interest. CONCLUSIONS: We find that structured expert judgement is a viable approach to investigating the effectiveness of medical interventions where randomised controlled trials are not possible. Understanding the effectiveness of surgery performed at different types of facilities can guide programme planning to increase access to fistula treatment. PMID- 26041491 TI - Welfare state retrenchment and increasing mental health inequality by educational credentials in Finland: a multicohort study. AB - OBJECTIVES: Epidemiological studies have shown an association between educational credentials and mental disorders, but have not offered any explanation for the varying strength of this association in different historical contexts. In this study, we investigate the education-specific trends in hospitalisation due to psychiatric disorders in Finnish working-age men and women between 1976 and 2010, and offer a welfare state explanation for the secular trends found. SETTING: Population-based setting with a 25% random sample of the population aged 30-65 years in 7 independent consecutive cohorts (1976-1980, 1981-1985, 1986-1990, 1991 1995, 1996-2000, 2001-2005, 2006-2010). PARTICIPANTS: Participants were randomly selected from the Statistics Finland population database (n=2,865,746). These data were linked to diagnosis-specific records on hospitalisations, drawn from the National Hospital Discharge Registry using personal identification numbers. Employment rates by educational credentials were drawn from the Statistics Finland employment database. PRIMARY AND SECONDARY OUTCOME MEASURES: Hospitalisation and employment. RESULTS: We found an increasing trend in psychiatric hospitalisation rates among the population with only an elementary school education, and a decreasing trend in those with higher educational credentials. The employment rate of the population with only an elementary school education decreased more than that of those with higher educational credentials. CONCLUSIONS: We propose that restricted employment opportunities are the main mechanism behind the increased educational inequality in hospitalisation for psychiatric disorders, while several secondary mechanisms (lack of outpatient healthcare services, welfare cuts, decreased alcohol duty) further accelerated the diverging long-term trends. All of these inequality-increasing mechanisms were activated by welfare state retrenchment, which included the liberalisation of financial markets and labour markets, severe austerity measures and narrowing down of public sector employment commitment. PMID- 26041492 TI - Does suicide have a stronger association with seasonality than sunlight? AB - OBJECTIVES: Suicide rates have widely been reported to peak in spring and summer. A frequent hypothesis is that increased sunlight exposure alters biological mechanisms. However, few attempts have been made to systematically untangle the putative suicidogenic risk of sunlight exposure from that of seasonality. We examined whether average hours of daily sunlight in a month confer additional risk over month of year when predicting monthly suicide rates. DESIGN: Historical population-based ecological longitudinal study. SETTING AND PARTICIPANTS: We used 3 longitudinal studies (n=31,060 suicides) with monthly suicide and meteorological data from Greece (1992-2001), Victoria, Australia (1990-1998) and Norway (1969-2009). INTERVENTION: We used a negative binomial regression to observe (1) the association of month of year with suicides, adjusting for different sunlight exposures, and (2) the association of sunlight exposure with suicides, adjusting for month of year. We then investigated claims that suicides were associated with daily sunlight exposures, defined by us as 2550 sunlight exposure combinations corresponding to a 1-50 days exposure window with lags of 0 50 days. RESULTS: Using monthly data, the association between month of year and suicides remained after adjusting for mean daily hours of sunlight and change in the mean daily hours of sunlight. Adjusted for month of year, the associations between sunlight exposure and suicides became non-significant and attenuated towards the null (the coefficient estimate for mean daily hours of sunlight decreased in absolute magnitude by 72%). The findings were consistent across all 3 cohorts, both when analysed separately and combined. When investigating daily sunlight exposures, we found no significant results after correcting for multiple testing. CONCLUSIONS: Using monthly data, the robustness of our month of year effects, combined with the transient and modest nature of our sunlight effects, suggested that the association between sunlight exposure and suicide was a proxy for the association between seasonality and suicide. PMID- 26041494 TI - Reaction Path Bifurcation in an Electrocyclic Reaction: Ring-Opening of the Cyclopropyl Radical. AB - Following previous work [J. Chem. Phys. 2013, 139, 154108] on a simple model of a reaction with a post-transition state valley ridge inflection point, we study the chemically important example of the electrocyclic cyclopropyl radical ring opening reaction using direct dynamics and a reduced dimensional potential energy surface. The overall reaction requires con- or disrotation of the methylenes, but the initial stage of the ring-opening involves substantial internal rotation of only one methylene. The reaction path bifurcation is then associated with the relative sense of rotation of the second methylene. Clear deviations of reactive trajectories from the disrotatory intrinsic reaction coordinate (IRC) for the ring-opening are observed and the dynamical mechanism is discussed. Several features observed in the model system are found to be preserved in the more complex and higher dimensional ring-opening reaction. Most notable is the sensitivity of the reaction mechanism to the shape of the potential manifested as a Newtonian kinetic isotope effect upon deuterium substitution of one of the methylene hydrogens. Dependence of the product yield on frictional dissipation representing external environmental effects is also presented. The dynamics of the post-transition state cyclopropyl radical ring-opening are discussed in detail, and the use of low dimensional models as tools to analyze complicated organic reaction mechanisms is assessed in the context of this reaction. PMID- 26041493 TI - Patient information leaflets to reduce antibiotic use and reconsultation rates in general practice: a systematic review. AB - OBJECTIVE: Patients' knowledge and expectations may influence prescription of antibiotics. Therefore, providing evidence-based information on cause of symptoms, self-management and treatment is essential. However, providing information during consultations is challenging. Patient information leaflets could facilitate consultations by increasing patients' knowledge, decrease unnecessary prescribing of antibiotics and decrease reconsultations for similar illnesses. Our objective was to systematically review effectiveness of information leaflets used for informing patients about common infections during consultations in general practice. DESIGN, SETTING AND PARTICIPANTS: We systematically searched PubMed/MEDLINE and EMBASE for studies evaluating information leaflets on common infections in general practice. Two reviewers extracted data and assessed article quality. PRIMARY AND SECONDARY OUTCOME MEASURES: Antibiotic use and reconsultation rates. RESULTS: Of 2512 unique records, eight studies were eligible (7 randomised, controlled trials, 1 non randomised study) accounting for 3407 patients. Study quality varied from reasonable to good. Five studies investigated effects of leaflets during consultations for respiratory tract infections; one concerned conjunctivitis, one urinary tract infections and one gastroenteritis and tonsillitis. Three of four studies presented data on antibiotic use and showed significant reductions of prescriptions in leaflet groups with a relative risk (RR) varying from 0.53 (0.40 to 0.69) to 0.96 (0.83 to 1.11). Effects on reconsultation varied widely. One large study showed lower reconsultation rates (RR 0.70 (0.53 to 0.91), two studies showed no effect, and one study showed increased reconsultation rates (RR 1.53 (1.03 to 2.27)). Studies were too heterogenic to perform a meta-analysis. CONCLUSIONS: Patient information leaflets during general practitioners consultations for common infections are promising tools to reduce antibiotic prescriptions. Results on reconsultation rates for similar symptoms vary, with a tendency toward fewer reconsultations when patients are provided with a leaflet. Use of information leaflets in cases of common infections should be encouraged. Their contributing role in multifaceted interventions targeting management of common infections in primary care needs to further exploration. PMID- 26041495 TI - Diagnosis and management of fulminant Wilson's disease: a single center's experience. AB - BACKGROUND: Medical therapy is rarely effective in patients with fulminant Wilson's disease (FWD). Liver transplantation is limited by the lack of donor liver in most patients with FWD at the time of diagnosis. New Wilson's index, model for end-stage liver disease (MELD) and Child-Pugh score are useful tools for decision-making of liver transplantation; however, none of them is an independent decisive tool. It is worthwhile to explore a more effective and practical therapeutic strategy and reevaluate the prediction systems for patients with FWD. METHODS: Nine patients with FWD associated with hemolytic crisis and fulminant hepatic failure (FHF) were investigated. The clinical presentation, prognostic score and medical therapies of the patients were analyzed. RESULTS: In 7 of the 9 patients with FWD who received the comprehensive therapy of corticosteroid, copper-chelating agent (dimercaptopropansulfonate sodium) and therapeutic plasma exchange (TPE), 6 patients recovered from FHF. The remaining one had been improved through the comprehensive therapy but died of septicemia 51 days later. Two patients with spontaneous bacterial peritonitis (SBP) died from liver failure in three or five hospital days without plasma exchange or chelating therapy. All of the 9 patients with FWD presented with acute hepatic failure, severe jaundice and mild to severe hemolytic anemia. No marked difference in the incidence of severe hemolytic anemia was detected between the survival and deceased groups. However, the incidence and the degree of hepatic encephalopathy (HE) in the non-survival group were higher than those in the survival group. Unlike the deceased group, the survival group had no complications induced by bacterial infection. Compared to new Wilson's index, Child-Pugh score and MELD score, the variation of prothrombin activity (PTA) between the survival and deceased groups was more evident. CONCLUSION: For patients with FWD, the episode of severe hepatic encephalopathy or/and spontaneous bacterial peritonitis indicates worse prognosis, and PTA is a recommendable predictor. An emergent liver transplantation should be considered for patients whose PTA is below 20%, or for those with severe HE or/and SBP. The comprehensive therapy of corticosteroid, copper-chelating agent and TPE is effective for patients without SBP and whose PTA is higher than 20%. PMID- 26041496 TI - Posterior reversible encephalopathy syndrome in patients with hematologic tumor confers worse outcome. AB - BACKGROUND: This study aimed to evaluate the clinical features of posterior reversible encephalopathy syndrome (PRES) in children. METHODS: The medical records of 31 patients from five medical centers who were diagnosed with PRES from 2001 to 2013 were retrospectively analyzed. In the 31 patients, 16 were males, and 15 females, with a median age of 7 years (3-12 years). Patients younger than 10 years accounted for 74.2% of the 31 patients. RESULTS: Seizure, the most common clinical sign, occurred in 29 of the 31 patients. Visual disturbances were also observed in 20 patients. Cerebral imaging abnormalities were bilateral and predominant in the parietal and occipital white matter. In this series, three patients died in the acute phase of PRES. One patient had resolution of neurologic presentation within one week, but no apparent improvement in radiological abnormalities was observed at eight months. One patient showed gradual recovery of both neurologic presentation and radiological abnormalities during follow-up at eight months. One patient developed long-term cortical blindness. All of the PRES patients with hematologic tumor had a worse prognosis than those without hematologic tumor. CONCLUSIONS: Seizure is a prevalent characteristic of children with PRES. Poor prognosis can be seen in PRES patients with hematologic tumor. PMID- 26041498 TI - Antinuclear antibodies in neuromyelitis optica: guardians of the brain? PMID- 26041497 TI - Actual Use of Medications Prescribed During Pregnancy: A Cross-Sectional Study Using Data from a Population-Based Congenital Anomaly Registry. AB - INTRODUCTION AND AIM: Data from prescription databases are increasingly being used to study associations between maternal medications used in pregnancy and congenital anomalies. We therefore investigated the extent to which prescriptions reflect the actual use of medication during pregnancy, and whether medicines used during pregnancy are taken according to the prescribed dosage and duration. METHODS: We performed a cross-sectional study in a population-based congenital anomaly register (EUROCAT Northern Netherlands). We included 202 women who had at least one prescription during their pregnancy and who gave birth between 2009 and 2011. Compliance with the prescribed medication was verified by telephone interview. We calculated the compliance rates for several medication groups by dividing the number of mothers who confirmed they had taken the medication by the total number to whom it had been prescribed. Compliance was positive if the mother confirmed she took the medication, even if she only took one of several prescriptions from the same medication group. For each prescription taken, we also determined whether her use conformed to the prescribed dosage and duration. RESULTS: During the first trimester, the compliance rates ranged from 0.84 (for chronic diseases) to 0.92 (for pregnancy-related symptoms). Most of the medications actually taken were used at the prescribed dosage or lower. More than half of the medications actually taken were used for the duration prescribed or shorter. CONCLUSION: Prescription records are generally a relatively reliable source of data for research into associations between medication use in pregnancy and congenital anomalies compared with other data sources. Pharmacy records of medication use in pregnancy might represent an overestimation, which should be taken into account. However, our results show that, except for 'corticosteroids, dermatological preparations'; 'ear, eye, nose and throat preparations'; and 'anxiolytics, hypnotics and sedatives', this overestimation generally seems minimal. PMID- 26041499 TI - A network comprising short and long noncoding RNAs and RNA helicase controls mouse retina architecture. AB - Brain regions, such as the cortex and retina, are composed of layers of uniform thickness. The molecular mechanism that controls this uniformity is not well understood. Here we show that during mouse postnatal development the timed expression of Rncr4, a retina-specific long noncoding RNA, regulates the similarly timed processing of pri-miR-183/96/182, which is repressed at an earlier developmental stage by RNA helicase Ddx3x. Shifting the timing of mature miR-183/96/182 accumulation or interfering with Ddx3x expression leads to the disorganization of retinal architecture, with the photoreceptor layer being most affected. We identify Crb1, a component of the adhesion belt between glial and photoreceptor cells, as a link between Rncr4-regulated miRNA metabolism and uniform retina layering. Our results suggest that the precise timing of glia neuron interaction controlled by noncoding RNAs and Ddx3x is important for the even distribution of cells across layers. PMID- 26041500 TI - Safe limits of contrast vary with hydration volume for prevention of contrast induced nephropathy after coronary angiography among patients with a relatively low risk of contrast-induced nephropathy. AB - BACKGROUND: Few studies have investigated the safe limits of contrast to prevent contrast-induced nephropathy (CIN) based on hydration data. We aimed to investigate the relative safe maximum contrast volume adjusted for hydration volume in a population with a relatively low risk of CIN. METHODS AND RESULTS: The ratios of contrast volume-to-creatinine clearance (V/CrCl) and hydration volume to body weight (HV/W) were determined in patients undergoing cardiac catheterization. Receiver-operator characteristic curve analysis based on the maximum Youden index was used to identify the optimal cutoff for V/CrCl in all patients and in HV/W subgroups. Eighty-six of 3273 (2.6%) patients with mean CrCl 71.89+/-27.02 mL/min developed CIN. Receiver-operator characteristic curve analysis indicated that a V/CrCl ratio of 2.44 was a fair discriminator for CIN in all patients (sensitivity, 73.3%; specificity, 70.4%). After adjustment for other confounders, V/CrCl >2.44 continued to be significantly associated with CIN (adjusted odds ratio, 4.12; P<0.001) and the risk of death (adjusted hazard ratio, 2.62; P<0.001). The mean HV/W was 12.18+/-7.40. We divided the patients into 2 groups (HV/W <=12 and >12 mL/kg). The best cutoff value for V/CrCl was 1.87 (sensitivity, 67.9%; specificity, 64.4%; adjusted odds ratio, 3.24; P=0.011) in the insufficient hydration subgroup (HV/W, <=12 mL/kg; CIN, 1.32%) and 2.93 (sensitivity, 69.0%; specificity, 65.0%; adjusted odds ratio, 3.04; P=0.004) in the sufficient hydration subgroup (HV/W, >12 mL/kg; CIN, 5.00%). CONCLUSIONS: The V/CrCl ratio adjusted for HV/W may be a more reliable predictor of CIN and even long-term outcomes after cardiac catheterization. We also found a higher best cutoff value for V/CrCl to predict CIN in patients with a relatively sufficient hydration status, which may be beneficial during decision-making about contrast dose limits in relatively low-risk patients with different hydration statuses. PMID- 26041501 TI - A Review of Environmental Life Cycle Assessments of Liquid Transportation Biofuels in the Pan American Region. AB - Life-cycle assessment (LCA) has been applied to many biofuel and bioenergy systems to determine potential environmental impacts, but the conclusions have varied. Different methodologies and processes for conducting LCA of biofuels make the results difficult to compare, in-turn making it difficult to make the best possible and informed decision. Of particular importance are the wide variability in country-specific conditions, modeling assumptions, data quality, chosen impact categories and indicators, scale of production, system boundaries, and co-product allocation. This study has a double purpose: conducting a critical evaluation comparing environmental LCA of biofuels from several conversion pathways and in several countries in the Pan American region using both qualitative and quantitative analyses, and making recommendations for harmonization with respect to biofuel LCA study features, such as study assumptions, inventory data, impact indicators, and reporting practices. The environmental management implications are discussed within the context of different national and international regulatory environments using a case study. The results from this study highlight LCA methodology choices that cause high variability in results and limit comparability among different studies, even among the same biofuel pathway, and recommendations are provided for improvement. PMID- 26041502 TI - What did you say? Self-regulatory depletion impairs interpretation of vocal cues. AB - Evidence indicates that people are motivated to interpret environmental cues to belongingness, but doing so can be challenging. Prior evidence shows that the self's regulatory resources are consumed when interpreting complex facial displays; with this study, we examined how the depletion of such resources may impact the ability to interpret vocal tones. Results showed that depletion decreased accuracy in identifying complex (vs. simple) vocal cues, which extends prior work and offers a more comprehensive understanding of the relationship between self-regulatory resources and the ability to effectively interpret one's social environment. PMID- 26041503 TI - Role of RAI in the management of incidental N1a disease in papillary thyroid cancer. AB - BACKGROUND: Following total thyroidectomy (TT) for papillary thyroid cancer (PTC), pathological assessment can occasionally reveal incidental perithyroidal lymph nodes (LNs) with occult metastases. These cN0pN1a patients often receive radioactive iodine (RAI) therapy for this indication alone. The aim of this study was to determine the central compartment nodal recurrence-free survival in patients treated without RAI compared to those who received RAI treatment. METHODS: An institutional database of 3664 previously untreated patients with differentiated thyroid cancer operated between 1986 and 2010 was reviewed. A total of 232 pT1-3 patients managed with TT and no neck dissection were subsequently found to have incidental level 6 LNs on pathology. Patients with other indications for RAI, such as extrathyroidal extension and close or positive margins, were excluded. One hundred and four patients remained for analysis. Kaplan-Meier method was used to determine central neck LN recurrence-free survival (RFS). RESULTS: The median age of the cohort was 40 years (range 17-83). The median follow-up was 53 months (range 1-211). The median number of positive LNs removed and maximum LN diameter were 1 (range 1-8) and 5 mm (range 1-16 mm), respectively. A total of 67 (64%) patients had adjuvant RAI and 37 (36%) did not. Patients with vascular invasion (P = 0.01), LNs >2 mm (P = 0.07) and >2 positive nodes (P = 0.06) were more likely to be selected for adjuvant RAI therapy. Patients without RAI therapy had similar 5-year central neck LN RFS compared to those treated with RAI: 96.2% vs 94.6%, respectively (P = 0.92). CONCLUSION: There is no difference in the 5-year central compartment nodal recurrence-free survival in patients treated without RAI compared to those who received RAI treatment. PMID- 26041504 TI - Subregional differences in the generation of fast network oscillations in the rat medial prefrontal cortex (mPFC) in vitro. AB - KEY POINTS: Fast network oscillations in the beta (20-30 Hz) frequency range can be evoked with combined activation of muscarinic and kainate receptors in different subregions of the medial prefrontal cortex (mPFC). Subregional differences were observed as the oscillations in the dorsal prelimbic cortex (PrL) were smaller in magnitude than those in the ventral dorsopeduncular (DP) region, and these differences persisted in trimmed slices containing only PrL and DP regions. Oscillations in both regions were dependent upon GABAA and AMPA receptor activation but NMDA receptor blockade decreased oscillations only in the DP region. Subregional differences in neuronal properties of the presumed pyramidal cells were found between PrL and DP, with many more cells in DP firing rhythmically compared to the PrL region. Presumed inhibitory synaptic potentials (IPSPs) recorded from principal cells were more rhythmic and coherent, and significantly larger in amplitude, in the DP region; the data suggest that variation in the patterns of activity between subregions may reflect distinct functional roles. ABSTRACT: Fast network oscillations in the beta (20-30 Hz) and low gamma (30-80 Hz) range underlie higher cognitive functions associated with the medial prefrontal cortex (mPFC) including attention and working memory. Using a combination of kainate (KA, 200 nm) and the cholinergic agonist carbachol (Cb, 10 MUm) fast network oscillations, in the beta frequency range, were evoked in the rat mPFC in vitro. Oscillations were elicited in the prelimbic (PrL), infralimbic (IL) and the dorsopeduncular (DP) cortex, with the largest oscillations observed in DP cortex. Oscillations in both the PrL and DP were dependent, with slightly different sensitivities, on gamma-aminobutyric acid (GABA)A , alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors, but only oscillations in the DP were significantly reduced by N-methyl-d-aspartate (NMDA) receptor blockade. Intracellular recordings showed that 9/20 regular spiking (RS) cells in the PrL exhibited a notable cAMP dependent hyperpolarisation activated current (Ih ) in contrast to 16/17 in the DP cortex. Extracellular single unit recordings showed that the majority of cells in the PrL, and DP regions had interspike firing frequencies (IFFs) at beta (20 30 Hz) frequencies and fired at the peak negativity of the field oscillation. Recordings in DP revealed presumed inhibitory postsynaptic potentials (IPSPs) that were larger in amplitude and more rhythmic than those in the PrL region. Our data suggest that each PFC subregion may be capable of generating distinct patterns of network activity with different cell types involved. Variation in the properties of oscillations evoked in the PrL and DP probably reflects the distinct functional roles of these different PFC regions. PMID- 26041505 TI - Polymer-Free Drug-Eluting Stents: An Overview of Coating Strategies and Comparison with Polymer-Coated Drug-Eluting Stents. AB - Clinical evaluations have proven the efficacy of drug-elution stents (DES) in reduction of in-stent restenosis rates as compared to drug-free bare metal stents (BMS). Typically, DES are metal stents that are covered with a polymer film loaded with anti-inflammatory or antiproliferative drugs that are released in a sustained manner. However, although favorable effects of the released drugs have been observed, the polymer coating as such has been associated with several adverse clinical effects, such as late stent thrombosis. Elimination of the polymeric carrier of DES may therefore potentially lead to safer DES. Several technologies have been developed to design polymer-free DES, such as the use of microporous stents and inorganic coatings that can be drug loaded. Several drugs, including sirolimus, tacrolimus, paclitaxel, and probucol have been used in the design of carrier-free stents. Due to the function of the polymeric coating to control the release kinetics of a drug, polymer-free stents are expected to have a faster drug elution rate, which may affect the therapeutic efficacy. However, several polymer-free stents have shown similar efficacy and safety as the first generation DES, although the superiority of polymer-free DES has not been established in clinical trials. PMID- 26041506 TI - Atorvastatin attenuates homocysteine-induced migration of smooth muscle cells through mevalonate pathway involving reactive oxygen species and p38 MAPK. AB - Statins have been reported to have an antioxidant effect against homocysteine (Hcy)-induced endothelial dysfunction. It is unknown whether they have the same effect against migration of vascular smooth muscle cells (VSMCs) induced by Hcy. In this study, it was investigated whether and how atorvastatin could inhibit the Hcy-induced migration in cultured VSMCs and revealed the possible redox mechanism. VSMCs were isolated from the thoracic aortas of Sprague-Dawley rats. The migration of VSMCs was examined using a transwell technique and cell viability was determined by 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazoliumbromide (MTT) assay. Reactive oxygen species (ROS) were measured using the fluoroprobe 2'7'-dichlorodihydrofluorescein diacetate. The activity of NADPH oxidase was assessed by lucigenin enhanced chemiluminescence. Expressions of Nox1 mRNA and p-p38MAPK protein were measured by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis, respectively. The results showed that atorvastatin inhibited the migration of VSMCs induced by Hcy, which was reversed by the mevalonate. In addition, pretreatment with the NADPH oxidase inhibitor DPI, the free radical scavenger NAC and the p38 MAPK inhibitor SB203580 blocked Hcy-induced VSMCs migration. Furthermore, atorvastatin suppressed Hcy-induced activation of NADPH oxidase and ROS, attenuated Hcy-induced overexpression of Nox1mRNA. Similar effects occurred with VSMCs transfected with Nox1 siRNA. Moreover, atorvastatin other than DPI, NAC, SB203580 and Nox1 siRNA transfection blocked Hcy-induced p38 MAPK phosphorylation, which was also reversed by the mevalonate. The data demonstrates that atorvastatin inhibits Hcy-induced VSMCs migration in a mevalonate pathway. Furthermore, a part of the biological effect of atorvastatin involves a decrease in the levels of Nox1-dependent ROS generation and p38 MAPK activation. PMID- 26041507 TI - High salinity effect on bioremediation of pretreated pesticide lixiviates from greenhouses. AB - Hydroponics culture greenhouses usually work in closed and semi-closed irrigation systems for nutrients and water-saving purposes. Photo-Fenton reaction has been revealed as an efficient way to depollute that kind of recycled effluents containing pesticides, even for high salinity concentrations. However, the inefficacy of organic matter chemical depletion imposes the use of a subsequent treatment. This work proposes the suitability of an integration of advanced oxidation process with a subsequent bioreactor to treat greenhouse lixiviates effluents at high or extremely high conductivity (salts concentration: up to 42 g L-1). As a first step in this study, the performance of a series of sequencing batch reactors was monitored in order to check the biocompatibility of photo Fenton pretreated effluents depending on their salinity content. In the second step, those same pretreated effluents were loaded to a biofiltration column filled with expanded clay. Finally, bacterial 16S rRNA gene sequencing was carried out to analyse microbial diversity of the biomass developed in the column. Results stated that the chemical-biological coupled system is effective for the treatment of water effluents containing pesticides. The integrated system is able to deplete more than 80% of the organic load, even under extremely high salinity. PMID- 26041508 TI - A biologically inspired network design model. AB - A network design problem is to select a subset of links in a transport network that satisfy passengers or cargo transportation demands while minimizing the overall costs of the transportation. We propose a mathematical model of the foraging behaviour of slime mould P. polycephalum to solve the network design problem and construct optimal transport networks. In our algorithm, a traffic flow between any two cities is estimated using a gravity model. The flow is imitated by the model of the slime mould. The algorithm model converges to a steady state, which represents a solution of the problem. We validate our approach on examples of major transport networks in Mexico and China. By comparing networks developed in our approach with the man-made highways, networks developed by the slime mould, and a cellular automata model inspired by slime mould, we demonstrate the flexibility and efficiency of our approach. PMID- 26041509 TI - A large Great Britain-wide outbreak of STEC O157 phage type 8 linked to handling of raw leeks and potatoes. AB - Between December 2010 and July 2011, 252 cases of STEC O157 PT8 stx1 + 2 infection were reported in England, Scotland and Wales. This was the largest outbreak of STEC reported in England and the second largest in the UK to date. Eighty cases were hospitalized, with two cases of haemolytic uraemic syndrome and one death reported. Routine investigative data were used to generate a hypothesis but the subsequent case-control study was inconclusive. A second, more detailed, hypothesis generation exercise identified consumption or handling of vegetables as a potential mode of transmission. A second case-control study demonstrated that cases were more likely than controls to live in households whose members handled or prepared leeks bought unwrapped [odds ratio (OR) 40, 95% confidence interval (CI) 2.08-769.4], and potatoes bought in sacks (OR 13.13, 95% CI 1.19 145.3). This appears to be the first outbreak of STEC O157 infection linked to the handling of leeks. PMID- 26041511 TI - Contemporary author guidelines for a journal with tradition and some issues on clinical research. PMID- 26041510 TI - Sleep, Pain Catastrophizing, and Central Sensitization in Knee Osteoarthritis Patients With and Without Insomnia. AB - OBJECTIVE: Osteoarthritis (OA), a chronic degenerative joint disorder, is characterized by joint pain. Emerging research demonstrates that a significant number of patients evidence central sensitization (CS), a hyperexcitability in nociceptive pathways, which is known to amplify and maintain clinical pain. The clinical correlates of CS in OA, however, are poorly understood. Insomnia is prevalent in older adults with OA, and recent experiments suggest associations between poor sleep and measures of CS. Catastrophizing, a potent predictor of pain outcomes, has also been associated with CS, but few studies have investigated possible interactions between catastrophizing, sleep, and CS. METHODS: We conducted a case-control study of 4 well-characterized groups of adults with insomnia and/or knee OA. A total of 208 participants completed multimodal sleep assessments (questionnaire, diary, actigraphy, and polysomnography) and extensive evaluation of pain using clinical measures and quantitative sensory testing to evaluate associations between CS, catastrophizing, and insomnia. Descriptive characterization of each measure is presented, with specific focus on sleep efficiency and CS. RESULTS: The knee OA insomnia group demonstrated the greatest degree of CS compared to controls. In the overall sample, we found that catastrophizing moderated the relationship between sleep efficiency and CS. Specifically those with low sleep efficiency and high catastrophizing scores reported increased levels of CS. In addition, CS was significantly associated with increased clinical pain. CONCLUSION: These findings highlight the importance of assessing sleep efficiency, CS, and catastrophizing in chronic pain patients and have important clinical implications for treatment planning. PMID- 26041512 TI - Renal scarring and chronic kidney disease in children with spina bifida in a multidisciplinary Malaysian centre. AB - AIMS: The aim of this study was to determine the occurrence of renal cortical scarring and chronic kidney disease (CKD) in children with neurogenic bladder secondary to spina bifida (SB) managed at the Universiti Kebangsaan Malaysia Medical Centre. The secondary objective was to identify the clinical factors associated with these adverse outcomes. METHODS: The medical records of 56 children managed from 1997 were available. Socio-demographic and clinical data for SB children managed for a minimum of 2 years (n = 45) were reviewed. This included age at referral, gender, ethnicity, duration of care, type of SB lesion, presence of vesico-ureteric reflux (VUR), symptomatic urinary tract infections, bladder trabeculation, catheterisations and renal function. RESULTS: Forty-nine per cent of SB lesions were open myelomeningocoele, 40% were closed lesions and 11% were occult. Majority (96%) were at lumbar L3 or below. Twenty-nine children (64.5%) were referred before 6 months of age (mean15.8 months; range newborn to 125 months). Thirty-five (77.8%) had neurogenic bladder and 31(69%) had neurogenic bowel. Sixteen developed renal scarring and six, CKD. Late referral (>=6 months of age), small kidneys at referral, dilating VUR and bladder trabeculation were significant independent factors associated with scarring. On multivariate analysis, late referral (odds ratio (OR) 17.4; 95% confidence interval (CI) 1.26-238.7) and dilating VUR (OR 137.0; CI 6.4-2921.1) remained significant. CONCLUSION: Prevention of renal scarring and CKD remains a challenge in Malaysia even with multidisciplinary proactive care of SB children. Early referrals and more stringent management strategies for dilating VUR are still required. PMID- 26041513 TI - Suicidal chemistry: combined intoxication with carbon monoxide and formic acid. AB - Herein, we present a rare case of suicidal intoxication with carbon monoxide produced via reaction of formic and sulphuric acid with additional toxic effect of formic acid. The deceased was a 22-year-old men found dead in the bathroom locked from the inside. A bucket filled with liquid was found next to him, together with an almost empty canister labeled "formic acid" and another empty unlabeled canister. The postmortem examination revealed corrosive burns of the face, neck and chest, cherry-pink livor mortis, corrosive injury to the oropharyngeal area and trachea, subpleural petechiae, 100 mL of blood in stomach and superficial erosions of stomach mucosa. Toxicology analysis revealed 30% of carboxyhemoglobin in the femoral blood and the presence of the formic acid in various samples. Quantitative analysis of formic acid was performed by measuring methyl ester derivative of formic acid by using headspace gas chromatography with flame ionization detection. The highest concentration of formic acid was measured in the lungs (0.55 g/kg), gastric content (0.39 g/L), and blood (0.28 g/L). In addition, it was established that content of the unlabeled canister had a pH value of 0.79 and contained sulphuric ions. Morphological and toxicology findings suggested that the main route of exposure to formic acid was inhalation of vapors with a possible ingestion of only small amount of liquid acid. The cause of death was determined to be combined intoxication with carbon monoxide and formic acid. PMID- 26041514 TI - Postmortem degradation of skeletal muscle proteins: a novel approach to determine the time since death. AB - Estimating the time since death is a very important aspect in forensic sciences which is pursued by a variety of methods. The most precise method to determine the postmortem interval (PMI) is the temperature method which is based on the decrease of the body core temperature from 37 degrees C. However, this method is only useful in the early postmortem phase (~0-36 h). The aim of the present work is to develop an accurate method for PMI determination beyond this present limit. For this purpose, we used sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), Western blotting, and casein zymography to analyze the time course of degradation of selected proteins and calpain activity in porcine biceps femoris muscle until 240 h postmortem (hpm). Our results demonstrate that titin, nebulin, desmin, cardiac troponin T, and SERCA1 degraded in a regular and predictable fashion in all samples investigated. Similarly, both the native calpain 1 and calpain 2 bands disintegrate into two bands subsequently. This degradation behavior identifies muscular proteins and enzymes as promising substrates for future molecular-based PMI determination technologies. PMID- 26041515 TI - When is an acoustic neuroma not an acoustic neuroma? Pitfalls for radiosurgeons. AB - INTRODUCTION: Because acoustic neuroma (AN), also termed vestibular schwannoma, constitutes by far the commonest intracranial schwannoma and cerebello-pontine angle (CPA) tumour, there is a risk of overlooking rarer alternative diagnoses with similar clinical and/or radiological features. The purpose of this article is to highlight to radiosurgeons the potentially serious implications of this problem through illustrative case studies. METHODS: Our linac stereotactic radiosurgery (SRS) technique has been previously described, with stereotactic headring fixation and treatment delivered via cones or micro-multileaf collimators using multiple arcs or static beams. RESULTS: Between November 1993 and October 2014, we treated 132 patients referred with a clinical diagnosis of AN, the vast majority with 12 Gy marginal dose. Three of these (2.3%), evident either at the time of treatment (2) or subsequently (1), had features instead consistent with cochlear schwannoma, facial schwannoma and meningioma, respectively. Each warranted significant modification to standard AN outlining and fields. The meningioma progressed due to geographic miss. One other patient with recurrent facial schwannoma (not yet needing SRS) was also referred with an incorrect diagnosis of AN. CONCLUSION: When rare variants of common medical problems are not identified before referral, there is a risk that 'blinkering' can lead to misdiagnosis and suboptimal treatment. Radiosurgeons need to be particularly mindful of this issue with AN, which can mimic several other tumours occurring in the CPA region, albeit with different patterns of spread. Optimal imaging, high-quality radiology reporting and neuroradiology input at the time of SRS planning within the setting of a specialised multidisciplinary team are highly desirable. PMID- 26041516 TI - Electrochemical sensors and biosensors based on redox polymer/carbon nanotube modified electrodes: a review. AB - The aim of this review is to present the contributions to the development of electrochemical sensors and biosensors based on polyphenazine or polytriphenylmethane redox polymers together with carbon nanotubes (CNT) during recent years. Phenazine polymers have been widely used in analytical applications due to their inherent charge transport properties and electrocatalytic effects. At the same time, since the first report on a CNT-based sensor, their application in the electroanalytical chemistry field has demonstrated that the unique structure and properties of CNT are ideal for the design of electrochemical (bio)sensors. We describe here that the specific combination of phenazine/triphenylmethane polymers with CNT leads to an improved performance of the resulting sensing devices, because of their complementary electrical, electrochemical and mechanical properties, and also due to synergistic effects. The preparation of polymer/CNT modified electrodes will be presented together with their electrochemical and surface characterization, with emphasis on the contribution of each component on the overall properties of the modified electrodes. Their importance in analytical chemistry is demonstrated by the numerous applications based on polymer/CNT-driven electrocatalytic effects, and their analytical performance as (bio) sensors is discussed. PMID- 26041517 TI - Combining multiset resolution and segmentation for hyperspectral image analysis of biological tissues. AB - Hyperspectral images can provide useful biochemical information about tissue samples. Often, Fourier transform infrared (FTIR) images have been used to distinguish different tissue elements and changes caused by pathological causes. The spectral variation between tissue types and pathological states is very small and multivariate analysis methods are required to describe adequately these subtle changes. In this work, a strategy combining multivariate curve resolution alternating least squares (MCR-ALS), a resolution (unmixing) method, which recovers distribution maps and pure spectra of image constituents, and K-means clustering, a segmentation method, which identifies groups of similar pixels in an image, is used to provide efficient information on tissue samples. First, multiset MCR-ALS analysis is performed on the set of images related to a particular pathology status to provide basic spectral signatures and distribution maps of the biological contributions needed to describe the tissues. Later on, multiset segmentation analysis is applied to the obtained MCR scores (concentration profiles), used as compressed initial information for segmentation purposes. The multiset idea is transferred to perform image segmentation of different tissue samples. Doing so, a difference can be made between clusters associated with relevant biological parts common to all images, linked to general trends of the type of samples analyzed, and sample-specific clusters, that reflect the natural biological sample-to-sample variability. The last step consists of performing separate multiset MCR-ALS analyses on the pixels of each of the relevant segmentation clusters for the pathology studied to obtain a finer description of the related tissue parts. The potential of the strategy combining multiset resolution on complete images, multiset segmentation and multiset local resolution analysis will be shown on a study focused on FTIR images of tissue sections recorded on inflamed and non-inflamed palatine tonsils. PMID- 26041518 TI - Sensitive determination of 17beta-estradiol in river water using a graphene based electrochemical sensor. AB - In this study, a novel material for the electrochemical determination of 17beta estradiol using an electrode based on reduced graphene oxide and a metal complex porphyrin has been applied to environmental monitoring. The electrochemical profile of the proposed electrode was analyzed by differential pulse voltammetry, which showed a shift of the oxidation peak potential of 17beta-estradiol to 150mV in a less positive direction compared to the bare reduced graphene oxide electrode. DPV experiments were performed in PBS at pH 7.0 to determine 17beta estradiol without any previous step of extraction, cleanup, or derivatization, in the range of 0.1-1.0MUmolL(-1) with a detection limit archived at 5.3nmolL(-1) (1.4MUgL(-1)). The proposed sensor was successfully applied in the determination of 17beta-estradiol in a river water sample without any purification step and was successfully analyzed under the standard addition method. All the obtained results were in agreement with those from the HPLC procedure. PMID- 26041519 TI - The renewable bismuth bulk annular band working electrode: fabrication and application in the adsorptive stripping voltammetric determination of nickel(II) and cobalt(II). AB - The paper presents the first report on fabrication and application of a user friendly and mercury free electrochemical sensor, with the renewable bismuth bulk annular band working electrode (RBiABE), in stripping voltammetry (SV). The sensor body is partly filled with the internal electrolyte solution, in which the RBiABE is cleaned and activated before each measurement. Time of the RBiABE contact with the sample solution is precisely controlled. The usefulness of this sensor was tested by Ni(II) and Co(II) traces determination by means of differential pulse adsorptive stripping voltammetry (DP AdSV), after complexation with dimethylglyoxime (DMG) in ammonia buffer (pH 8.2). The experimental variables (composition of the supporting electrolyte, pre-concentration potential and time, potential of the RBiABE activation, and DP parameters), as well as possible interferences, were investigated. The linear calibration graphs for Ni(II) and Co(II), determined individually and together, in the range from 1*10( 8) to 70*10(-8)molL(-1) and from 1*10(-9) to 70*10(-9)molL(-1) respectively, were obtained. The calculated limit of detection (LOD), for 30s of the accumulation time, was 3*10(-9)molL(-1) for Ni(II) in case of a single element's analysis, whereas the LOD was 5*10(-9)molL(-1) for Ni(II) and 3*10(-10)molL(-1) for Co(II), when both metal ions were measured together. The repeatability of the Ni(II) and Co(II) adsorptive stripping voltammetric signals obtained at the RBiABE were equal to 5.4% and 2.5%, respectively (n=5). Finally, the proposed method was validated by determining Ni(II) and Co(II) in the certified reference waters (SPS SW1 and SPS-SW2) with satisfactory results. PMID- 26041520 TI - CoFe2O4 nano-particles functionalized with 8-hydroxyquinoline for dispersive solid-phase micro-extraction and direct fluorometric monitoring of aluminum in human serum and water samples. AB - A simple dispersive solid-phase micro-extraction method based on CoFe2O4 nano particles (NPs) functionalized with 8-hydroxyquinoline (8-HQ) with the aid of sodium dodecyl sulfate (SDS) was developed for separation of Al(III) ions from aqueous solutions. Al(III) ions are separated at pH 7 via complex formation with 8-HQ using the functionalized CoFe2O4 nano-particles sol solution as a dispersed solid-phase extractor. The separated analyte is directly quantified by a spectrofluorometric method at 370nm excitation and 506nm emission wavelengths. A comparison of the fluorescence of Al(III)-8-HQ complex in bulk solution and that of Al(III) ion interacted with 8-HQ/SDS/CoFe2O4 NPs revealed a nearly 5-fold improvement in intensity. The experimental factors influencing the separation and in situ monitoring of the analyte were optimized. Under these conditions, the calibration graph was linear in the range of 0.1-300ngmL(-1) with a correlation coefficient of 0.9986. The limit of detection and limit of quantification were 0.03ngmL(-1) and 0.10ngmL(-1), respectively. The inter-day and intra-day relative standard deviations for six replicate determinations of 150ngmL(-1) Al(III) ion were 2.8% and 1.7%, respectively. The method was successfully applied to direct determine Al(III) ion in various human serum and water samples. PMID- 26041521 TI - Does volumetric absorptive microsampling eliminate the hematocrit bias for caffeine and paraxanthine in dried blood samples? A comparative study. AB - Volumetric absorptive microsampling (VAMS) is a novel sampling technique that allows the straightforward collection of an accurate volume of blood (approximately 10MUL) from a drop or pool of blood by dipping an absorbent polymeric tip into it. The resulting blood microsample is dried and analyzed as a whole. The aim of this study was to evaluate the potential of VAMS to overcome the hematocrit bias, an important issue in the analysis of dried blood microsamples. An LC-MS/MS method for analysis of the model compounds caffeine and paraxanthine in VAMS samples was fully validated and fulfilled all pre established criteria. In conjunction with previously validated procedures for dried blood spots (DBS) and blood, this allowed us to set up a meticulous comparative study in which both compounds were determined in over 80 corresponding VAMS, DBS and liquid whole blood samples. These originated from authentic human patient samples, covering a wide hematocrit range (0.21-0.50). By calculating the differences with reference whole blood concentrations, we found that analyte concentrations in VAMS samples were not affected by a bias that changed over the evaluated hematocrit range, in contrast to DBS results. However, VAMS concentrations tend to overestimate whole blood concentrations, as a consistent positive bias was observed. A different behavior of VAMS samples prepared from incurred and spiked blood, combined with a somewhat reduced recovery of caffeine and paraxanthine from VAMS tips at high hematocrit values, an effect that was not observed for DBS using a very similar extraction procedure, was found to be at the basis of the observed VAMS-whole blood deviations. Based on this study, being the first in which the validity and robustness of VAMS is evaluated by analyzing incurred human samples, it can be concluded that VAMS effectively assists in eliminating the effect of hematocrit. PMID- 26041522 TI - On-line monitoring of Soxhlet extraction by chromatography and mass spectrometry to reveal temporal extract profiles. AB - Soxhlet extraction is a popular sample preparation technique used in chemical analysis. It enables liberation of molecules embedded in complex matrices (for example, plant tissues, foodstuffs). In most protocols, samples are analyzed after the extraction process is complete. However, in order to optimize extraction conditions and enable comparisons between different types of extraction, it would be desirable to monitor it in real time. The main development of this work is the design and construction of the interface between Soxhlet extractor and GC-MS as well as ESI-MS system. The temporal extract profiles, obtained in the course of real-time GC-MS monitoring, have been fitted with mathematical functions to analyze extraction kinetics of different analytes. For example, the mass transfer coefficients of pinene, limonene and terpinene in lemon sample, estimated using the first-order kinetic model, are 0.540h(-1), 0.507h(-1) and 0.722h(-1), respectively. On the other hand, the Peleg model provides the following extraction rates of pinene, limonene and terpinene: 0.370nMh(-1), 0.216nMh(-1) and 0.596nMh(-1), respectively. The results suggest that both first-order kinetic and Peleg equations can be used to describe the progress of Soxhlet extraction. On-line monitoring of Soxhlet extraction reveals extractability of various analytes present in natural samples (plant tissue), and can potentially facilitate optimization of the extraction process. PMID- 26041523 TI - A bare-eye based one-step signal amplified semiquantitative immunochromatographic assay for the detection of imidacloprid in Chinese cabbage samples. AB - A novel bare-eye based one-step signal amplified semi-quantitative immunochromatographic assay (SAS-ICA) was developed for detection of the pesticide imidacloprid. This method was based on competitive immunoreactions. Signal amplification was achieved by dual labeling of the test lines (TLs) on the strip using high affinity nanogold-biotinylated anti-imidacloprid mAb (BAb) and nanogold-streptavidin (Sa) probes. The relative color intensities of three TLs (TL-I, TL-II and TL-III) on a nitrocellulose (NC) membrane were used for direct visual analysis of the SAS-ICA strips, and could be used for semi-quantitation of analyte concentrations by observing what TLs disappeared in the amplification zone. Under optimized conditions, the following imidacloprid concentration ranges would be detected by visual examination of the SAS-ICA strip: 0-5ngmL(-1) (negative samples), and 5-25ngmL(-1), 25-250ngmL(-1), 250-1000ngmL(-1) and >1000ngmL(-1) (positive samples). The sensitivity (the visual detection limit (VDL) of TL-III) and semi-quantitative analytical capacity (when TL-III disappeared completely) of the SAS-ICA strip were 10-fold and 160-fold higher than those of traditional ICA, respectively. The developed SAS-ICA strip was applied to the analysis of spiked and authentic contaminated Chinese cabbage samples in the laboratory and under field conditions, and the results were validated by high-performance liquid chromatography (HPLC). This process could be adopted as a potential generous technique for all ICA-based detection methods. PMID- 26041524 TI - Dispersion in cylindrical channels on the laminar flow at low Fourier numbers. AB - A numerical solution of the uniform dispersion model in cylindrical channels at low Fourier numbers is presented. The presented setup allowed to eliminate experimental non-idealities interfering the laminar flow. Double-humped responses measured in a flow injection system with impedance detection agreed with those predicted by theory. Simulated concentration profiles as well as flow injection analysis (FIA) responses show the predictive and descriptive power of the numerical approach. A strong dependence of peak shapes on Fourier numbers, at its low values, makes the approach suitable for determination of diffusion coefficients. In the work, the uniform dispersion model coupled with the Levenberg-Marquardt method of optimization allowed to determine the salt diffusion coefficient for KCl, NaCl, KMnO4 and CuSO4 in water. The determined values (1.83, 1.53, 1.57 and 0.90)*10(-9)m(2)s(-1), respectively, agree well with the literature data. PMID- 26041525 TI - Quantitative analysis of poly- and perfluoroalkyl compounds in water matrices using high resolution mass spectrometry: optimization for a laser diode thermal desorption method. AB - An alternative analysis technique for the quantitation of 15 poly- and perfluoroalkyl substances (PFASs) in water matrices is reported. Analysis time between each sample was reduced to less than 20s, all target molecules being analyzed in a single run with the use of laser diode thermal desorption atmospheric pressure chemical ionization (LDTD/APCI) coupled with high resolution accurate mass (HRMS) orbitrap mass spectrometry. LDTD optimal settings were investigated using either one-factor-at-a-time or experimental design methodologies, while orbitrap parameters were optimized simultaneously by means of a Box-Behnken design. Following selection of an adequate sample concentration and purification procedure based on solid-phase extraction and graphite clean-up, the method was validated in an influent wastewater matrix. Environmentally significant limits of detection were reported (0.3-4ngL(-1) in wastewater and 0.03-0.2ngL(-1) in surface water) and out of the 15 target analytes, 11 showed excellent accuracies (+/-20% of the target values) and recovery rates (75-125%). The method was successfully applied to a selection of environmental samples, including wastewater samples in 7 locations across Canada, as well as surface and tap water samples from the Montreal region, providing insights into the degree of PFAS contamination in this area. PMID- 26041526 TI - Development of versatile isotopic labeling reagents for profiling the amine submetabolome by liquid chromatography-mass spectrometry. AB - Metabolomic profiling involves relative quantification of metabolites in comparative samples and identification of the significant metabolites that differentiate different groups (e.g., diseased vs. controls). Chemical isotope labeling (CIL) liquid chromatography-mass spectrometry (LC-MS) is an enabling technique that can provide improved metabolome coverage and metabolite quantification. However, chemical identification of labeled metabolites can still be a challenge. In this work, a new set of isotopic labeling reagents offering versatile properties to enhance both detection and identification are described. They were prepared by a glycine molecule (or its isotopic counterpart) and an aromatic acid with varying structures through a simple three-step synthesis route. In addition to relatively low costs of synthesizing the reagents, this reaction route allows adjusting reagent property in accordance with the desired application objective. To date, two isotopic reagents, 4 dimethylaminobenzoylamido acetic acid N-hydroxylsuccinimide ester (DBAA-NHS) and 4-methoxybenzoylamido acetic acid N-hydroxylsuccinimide ester (MBAA-NHS), for labeling the amine-containing metabolites (i.e., amine submetabolome) have been synthesized. The labeling conditions and the related LC-MS method have been optimized. We demonstrate that DBAA labeling can increase the metabolite detectability because of the presence of an electrospray ionization (ESI)-active dimethylaminobenzoyl group. On the other hand, MBAA labeled metabolites can be fragmented in MS/MS and pseudo MS(3) experiments to provide structural information on metabolites of interest. Thus, these reagents can be tailored to quantitative profiling of the amine submetabolome as well as metabolite identification in metabolomics applications. PMID- 26041527 TI - Nucleic acid quantification using nicking-displacement, rolling circle amplification and bio-bar-code mediated triple-amplification. AB - In the present study, an inductively-coupled plasma-mass spectrometry (ICP-MS) based triple-amplification system, by combination of nicking-displacement, rolling circle amplification (RCA) and bio-bar-code probes, was fabricated for the detection of DNA target. By using this system, hepatitis B virus (HBV) DNA target down to 3.2*10(-17)M was detected by DNA probes labeled with Au nanoparticles (AuNPs). Single nucleotide polymorphisms in genes can also be effectively discriminated. In addition, we proved that this strategy is capable of detecting the target in complicated biological samples and holds great potential application in biomedical research. PMID- 26041528 TI - Strand displacement amplification for ultrasensitive detection of human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs), such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide a powerful model system for studies of cellular identity and early mammalian development, which hold great promise for regenerative medicine. It is necessary to develop a convenient method to discriminate hPSCs from other cells in clinics and basic research. Herein, a simple and reliable biosensor for stem cell detection was established. In this biosensor system, stage-specific embryonic antigen-3 (SSEA-3) and stage-specific embryonic antigen-4 (SSEA-4) were used to mark human pluripotent stem cells (hPSCs). Antibody specific for SSEA-3 was coated onto magnetic beads for hPSCs enrichment, and antibody specific for SSEA-4 was conjugated with carboxyl modified tDNA sequence which was used as template for strand displacement amplification (SDA). The amplified single strand DNA (ssDNA) was detected with a lateral flow biosensor (LFB). This biosensor is capable of detecting a minimum of 19 human embryonic stem cells by a strip reader and 100 human embryonic stem cells by the naked eye within 80min. This approach has also shown excellent specificity to distinguish hPSCs from other types of cells, showing that it is promising for specific and handy detection of human pluripotent stem cells. PMID- 26041529 TI - Application of photocatalytic cadmium sulfide nanoparticles to detection of enzymatic activities of glucose oxidase and glutathione reductase using oxidation of 3,3',5,5'-tetramethylbenzidine. AB - It was found out that semiconductor CdS nanoparticles (NPs) are able to catalyze photooxidation of the well known chromogenic enzymatic substrate 3,3',5,5' tetramethylbenzidine (TMB) by oxygen. The photocatalytical oxidation of TMB does not require hydrogen peroxide and its rate is directly proportional to the quantity of CdS NPs produced in situ through the interaction of Cd(2+) and S(2-) ions in an aqueous medium. This phenomenon was applied to development of colorimetric sensitive assays for glucose oxidase and glutathione reductase based on enzymatic generation of CdS NPs acting as light-powered catalysts. Sensitivity of the developed chromogenic assays was of the same order of magnitude or even better than that of relevant fluorogenic assays. The present approach opens the possibility for the design of simple and sensitive colorimetric assays for a number of enzymes using inexpensive and available TMB as a universal chromogenic compound. PMID- 26041530 TI - Determination of human serum semicarbazide-sensitive amine oxidase activity via flow injection analysis with fluorescence detection after online derivatization of the enzymatically produced benzaldehyde with 1,2-diaminoanthraquinone. AB - A fast, simple, and sensitive flow injection analysis method was developed for the measurement of semicarbazide-sensitive amine oxidase (SSAO) activity in human serum. Benzaldehyde, generated by the action of SSAO after incubation of serum with benzylamine, was derivatized with a novel aromatic aldehyde-specific reagent (1,2-diaminoanthraquinone) and the fluorescent product was measured by fluorescence detection at excitation and emission wavelengths of 390 and 570nm, respectively. Serum SSAO activity was defined as benzaldehyde (nmol) formed per milliliter serum per hour. The method was linear over SSAO activity of 0.2 150.0nmolmL(-1)h(-1) with a detection limit of 0.06nmolmL(-1)h(-1). The %RSD of intra-day and inter-day precision did not exceed 9.4% and the accuracy ranged from -6.5 to -0.6%. The method was applied for the determination of the serum SSAO activity in healthy controls (C, n=24) and diabetes mellitus patients (DM, n=18). It was demonstrated that the activity (mean+/-SE) of SSAO in diabetics sera was significantly higher than that in healthy subjects' ones (DM; 73.3+/ 1.8nmolmL(-1)h(-1)vs C; 58.9+/-2.2nmolmL(-1)h(-1), P<0.01). PMID- 26041531 TI - A sensitive electrochemiluminescence cytosensor for quantitative evaluation of epidermal growth factor receptor expressed on cell surfaces. AB - A sensitive electrochemiluminescence (ECL) strategy for evaluating the epidermal growth factor receptor (EGFR) expression level on cell surfaces was designed by integrating the specific recognition of EGFR expressed on MCF-7 cell surfaces with an epidermal growth factor (EGF)-funtionalized CdS quantum dots (CdSQDs) capped magnetic bead (MB) probe. The high sensitivity of ECL probe of EGF funtionalized CdSQD-capped-MB was used for competitive recognition with EGFR expressed on cell surfaces with recombinant EGFR protein. The changes of ECL intensity depended on both the cell number and the expression level of EGFR receptor on cell surfaces. A wide linear response to cells ranging from 80 to 4*10(6)cellsmL(-1) with a detection limit of 40cellsmL(-1) was obtained. The EGF cytosensor was used to evaluate EGFR expression levels on MCF-7 cells, and the average number of EGFR receptor on single MCF-7 cells was 1.35*10(5) with the relative standard deviation of 4.3%. This strategy was further used for in-situ and real-time evaluating EGFR receptor expressed on cell surfaces in response to drugs stimulation at different concentration and incubation time. The proposed method provided potential applications in the detection of receptors on cancer cells and anticancer drugs screening. PMID- 26041532 TI - REM sleep behaviour disorder is associated with lower fast and higher slow sleep spindle densities. AB - To investigate differences in sleep spindle properties and scalp topography between patients with rapid eye movement sleep behaviour disorder (RBD) and healthy controls, whole-night polysomnograms of 35 patients diagnosed with RBD and 35 healthy control subjects matched for age and sex were compared. Recordings included a 19-lead 10-20 electroencephalogram montage and standard electromyogram, electrooculogram, electrocardiogram and respiratory leads. Sleep spindles were automatically detected using a standard algorithm, and their characteristics (amplitude, duration, density, frequency and frequency slope) compared between groups. Topological analyses of group-discriminative features were conducted. Sleep spindles occurred at a significantly (e.g. t34 = -4.49; P = 0.00008 for C3) lower density (spindles ? min(-1) ) for RBD (mean +/- SD: 1.61 +/ 0.56 for C3) than for control (2.19 +/- 0.61 for C3) participants. However, when distinguishing slow and fast spindles using thresholds individually adapted to the electroencephalogram spectrum of each participant, densities smaller (31-96%) for fast but larger (20-120%) for slow spindles were observed in RBD in all derivations. Maximal differences were in more posterior regions for slow spindles, but over the entire scalp for fast spindles. Results suggest that the density of sleep spindles is altered in patients with RBD and should therefore be investigated as a potential marker of future neurodegeneration in these patients. PMID- 26041534 TI - Proceedings of the International Cancer Imaging Society (ICIS) 14th Annual Teaching Course. PMID- 26041533 TI - Rapid and non-destructive determination of rancidity levels in butter cookies by multi-spectral imaging. AB - BACKGROUND: Rancidity is an important attribute for quality assessment of butter cookies, while traditional methods for rancidity measurement are usually laborious, destructive and prone to operational error. In the present paper, the potential of applying multi-spectral imaging (MSI) technology with 19 wavelengths in the range of 405-970 nm to evaluate the rancidity in butter cookies was investigated. RESULTS: Moisture content, acid value and peroxide value were determined by traditional methods and then related with the spectral information by partial least squares regression (PLSR) and back-propagation artificial neural network (BP-ANN). The optimal models for predicting moisture content, acid value and peroxide value were obtained by PLSR. The correlation coefficient (r) obtained by PLSR models revealed that MSI had a perfect ability to predict moisture content (r = 0.909), acid value (r = 0.944) and peroxide value (r = 0.971). CONCLUSION: The study demonstrated that the rancidity level of butter cookies can be continuously monitored and evaluated in real-time by the multi spectral imaging, which is of great significance for developing online food safety monitoring solutions. PMID- 26041535 TI - B Lymphocytes Are Required during the Early Priming of CD4+ T Cells for Clearance of Pneumocystis Infection in Mice. AB - B cells play a critical role in the clearance of Pneumocystis. In addition to production of Pneumocystis-specific Abs, B cells are required during the priming phase for CD4(+) T cells to expand normally and generate memory. Clearance of Pneumocystis was found to be dependent on Ag specific B cells and on the ability of B cells to secrete Pneumocystis-specific Ab, as mice with B cells defective in these functions or with a restricted BCR were unable to control Pneumocystis infection. Because Pneumocystis-specific antiserum was only able to partially protect B cell-deficient mice from infection, we hypothesized that optimal T cell priming requires fully functional B cells. Using adoptive transfer and B cell depletion strategies, we determined that optimal priming of CD4(+) T cells requires B cells during the first 2-3 d of infection and that this was independent of the production of Ab. T cells that were removed from Pneumocystis infected mice during the priming phase were fully functional and able to clear Pneumocystis infection upon adoptive transfer into Rag1(-/-) hosts, but this effect was ablated in mice that lacked fully functional B cells. Our results indicate that T cell priming requires a complete environment of Ag presentation and activation signals to become fully functional in this model of Pneumocystis infection. PMID- 26041537 TI - Vitamin E Isoform gamma-Tocotrienol Downregulates House Dust Mite-Induced Asthma. AB - Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform gamma-tocotrienol possesses both antioxidative and anti inflammatory properties, we sought to determine protective effects of gamma tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and gamma-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. gamma-Tocotrienol displayed better free radical-neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including alpha-tocopherol. Besides, gamma-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, gamma-tocotrienol was found to block nuclear NF kappaB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did alpha-tocopherol and prednisolone. More importantly, gamma-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform gamma-tocotrienol in allergic asthma. PMID- 26041536 TI - CARMA3 Is Critical for the Initiation of Allergic Airway Inflammation. AB - Innate immune responses to allergens by airway epithelial cells (AECs) help initiate and propagate the adaptive immune response associated with allergic airway inflammation in asthma. Activation of the transcription factor NF-kappaB in AECs by allergens or secondary mediators via G protein-coupled receptors (GPCRs) is an important component of this multifaceted inflammatory cascade. Members of the caspase recruitment domain family of proteins display tissue specific expression and help mediate NF-kappaB activity in response to numerous stimuli. We have previously shown that caspase recruitment domain-containing membrane-associated guanylate kinase protein (CARMA)3 is specifically expressed in AECs and mediates NF-kappaB activation in these cells in response to stimulation with the GPCR agonist lysophosphatidic acid. In this study, we demonstrate that reduced levels of CARMA3 in normal human bronchial epithelial cells decreases the production of proasthmatic mediators in response to a panel of asthma-relevant GPCR ligands such as lysophosphatidic acid, adenosine triphosphate, and allergens that activate GPCRs such as Alternaria alternata and house dust mite. We then show that genetically modified mice with CARMA3 deficient AECs have reduced airway eosinophilia and proinflammatory cytokine production in a murine model of allergic airway inflammation. Additionally, we demonstrate that these mice have impaired dendritic cell maturation in the lung and that dendritic cells from mice with CARMA3-deficient AECs have impaired Ag processing. In conclusion, we show that AEC CARMA3 helps mediate allergic airway inflammation, and that CARMA3 is a critical signaling molecule bridging the innate and adaptive immune responses in the lung. PMID- 26041538 TI - Essential Function for the Nuclear Protein Akirin2 in B Cell Activation and Humoral Immune Responses. AB - Akirin2, an evolutionarily conserved nuclear protein, is an important factor regulating inflammatory gene transcription in mammalian innate immune cells by bridging the NF-kappaB and SWI/SNF complexes. Although Akirin is critical for Drosophila immune responses, which totally rely on innate immunity, the mammalian NF-kappaB system is critical not only for the innate but also for the acquired immune system. Therefore, we investigated the role of mouse Akirin2 in acquired immune cells by ablating Akirin2 function in B lymphocytes. B cell-specific Akirin2-deficient (Cd19(Cre/+)Akirin2(fl/fl)) mice showed profound decrease in the splenic follicular (FO) and peritoneal B-1, but not splenic marginal zone (MZ), B cell numbers. However, both Akirin2-deficient FO and MZ B cells showed severe proliferation defect and are prone to undergo apoptosis in response to TLR ligands, CD40, and BCR stimulation. Furthermore, B cell cycling was defective in the absence of Akirin2 owing to impaired expression of genes encoding cyclin D and c-Myc. Additionally, Brg1 recruitment to the Myc and Ccnd2 promoter was severely impaired in Akirin2-deficient B cells. Cd19(Cre/+)Akirin2(fl/fl) mice showed impaired in vivo immune responses to T-dependent and -independent Ags. Collectively, these results demonstrate that Akirin2 is critical for the mitogen induced B cell cycle progression and humoral immune responses by controlling the SWI/SNF complex, further emphasizing the significant function of Akirin2 not only in the innate, but also in adaptive immune cells. PMID- 26041539 TI - Critical Roles of Chemoresistant Effector and Regulatory T Cells in Antitumor Immunity after Lymphodepleting Chemotherapy. AB - Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8(+) T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4(+)CD25(+) Foxp3(+) Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4(+) T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8(+) T cells were responsible for this augmentation. Using Rag2(-/-) mice or depletion of recipient CD8(+) T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4(+) T cells enhanced the proliferation of CD8(+) T cells and the priming of tumor specific CD8(+) T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies. PMID- 26041540 TI - CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28-CD8+ T Cells. AB - A substantial proportion of CD8(+) T cells in adults lack the expression of the CD28 molecule, and the aging of the immune system is associated with a steady expansion of this T cell subset. CD28(-)CD8(+) T cells are characterized by potent effector functions but impaired responses to antigenic challenge. CD28 acts as the primary T cell costimulatory receptor, but there are numerous additional receptors that can costimulate the activation of T cells. In this study, we have examined such alternative costimulatory pathways regarding their functional role in CD28(-)CD8(+) T cells. Our study showed that most costimulatory molecules have a low capacity to activate CD28-deficient T cells, whereas the engagement of the CD2 molecule by its ligand CD58 clearly costimulated proliferation, cytokine production, and effector function in this T cell subset. CD58 is broadly expressed on APCs including dendritic cells. Blocking CD58 mAb greatly reduced the response of human CD28(-)CD8(+) T cells to allogeneic dendritic cells, as well as to viral Ags. Our results clearly identify the CD58/CD2 axis as the primary costimulatory pathway for CD8 T cells that lack CD28. Moreover, we show that engagement of CD2 amplifies TCR signals in CD28( )CD8(+) T cells, demonstrating that the CD2-CD58 interaction has a genuine costimulatory effect on this T cell subset. CD2 signals might promote the control of viral infection by CD28(-)CD8(+) T cells, but they might also contribute to the continuous expansion of CD28(-)CD8(+) T cells during chronic stimulation by persistent Ag. PMID- 26041541 TI - Pollensomes as Natural Vehicles for Pollen Allergens. AB - Olive (Olea europaea) pollen constitutes one of the most important allergen sources in the Mediterranean countries and some areas of the United States, South Africa, and Australia. Recently, we provided evidence that olive pollen releases nanovesicles of respirable size, named generically pollensomes, during in vitro germination. Olive pollensomes contain allergens, such as Ole e 1, Ole e 11, and Ole e 12, suggesting a possible role in allergy. The aim of this study was to assess the contribution of pollensomes to the allergic reaction. We show that pollensomes exhibit allergenic activity in terms of patients' IgE-binding capacity, human basophil activation, and positive skin reaction in sensitized patients. Furthermore, allergen-containing pollensomes have been isolated from three clinically relevant nonphylogenetically related species: birch (Betula verrucosa), pine (Pinus sylvestris), and ryegrass (Lolium perenne). Most interesting, pollensomes were isolated from aerobiological samples collected with an eight-stage cascade impactor collector, indicating that pollensomes secretion is a naturally occurring phenomenon. Our findings indicate that pollensomes may represent widespread vehicles for pollen allergens, with potential implications in the allergic reaction. PMID- 26041542 TI - Mid-term Results of Intramuscular Lengthening of Gastrocnemius and/or Soleus to Correct Equinus Deformity in Flatfoot. AB - BACKGROUND: Intramuscular lengthening of the gastrocnemius and/or soleus (Baumann procedure) is widely used in patients who have cerebral palsy, with several advantages over other lengthening techniques. Tightness of the gastrocnemius or gastrocnemius-soleus complex has been confirmed to be related to flatfoot deformity. The purpose of this study was to evaluate the mid-term results of the Baumann procedure as a part of the treatment of flatfoot with equinus deformity. METHODS: We reviewed 35 pediatric and adult patients (43 feet) with flatfoot who underwent the Baumann procedure for the concomitant equinus deformity. The mean duration of follow-up was 39.4 months. Preoperative and follow-up evaluations included the maximal angle of dorsiflexion of the ankle with the knee fully extended and with the knee flexed to 90 degrees, the American Orthopaedic Foot & Ankle Society ankle-hindfoot (AOFAS-AH) scores, and postoperative complications. RESULTS: Preoperatively, the mean angle of passive ankle dorsiflexion with the knee extended was -4.7 +/- 2.7 degrees and that with the knee flexed was 2.3 +/- 2.5 degrees. At the final follow-up, both values improved significantly by a mean of 13.6 degrees (P < .001) and 9.7 degrees (P < .001), respectively. The average AOFAS-AH scores improved from 56.8 points preoperatively to 72.1 at the final follow-up. Recurrence of equinus was observed in 3 patients (4 feet). There were no cases of overcorrection, neurovascular injury, or healing problems. CONCLUSIONS: Our results indicate that the Baumann procedure can effectively and sequentially correct the tightness of the gastrocnemius or the gastrocnemius soleus complex in patients with flatfoot deformity, without obvious postoperative complications. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26041543 TI - Concomitant Ankle Injuries Associated With Tibial Shaft Fractures. AB - BACKGROUND: Ankle injuries associated with tibial shaft fractures can cause postoperative ankle pain and stiffness even when satisfactory bony union has been achieved. Although several previous studies have described these injuries, they have not been clearly defined or classified in terms of ankle injury type or need for surgical fixation. METHODS: Seventy-one consecutive patients (mean +/- SD age, 48.3 +/- 16.7 years; 37 men and 34 women) with tibial shaft fractures who underwent computed tomography examination were included. Data were collected including age, sex, body mass index, fracture location of the tibia and fibula (in percentile of length), tibial fracture shape (spiral, oblique, transverse), presence and pattern of concomitant ankle injuries (on the distal tibial articular surface), and necessity for surgical fixation of ankle injuries. Factors associated with concomitant ankle injuries associated with tibial shaft fractures were analyzed by logistic regression analysis. RESULTS: A total of 47 (64.7%) of the 71 tibial shaft fractures involved concomitant ankle injuries, including 8 cases of combined lateral malleolar fracture, posterior malleolar fracture, and anterior inferior tibiofibular ligament (AITFL) avulsion fracture; 9 cases of combined posterior malleolar fracture and AITFL avulsion fracture; 6 cases of combined lateral malleolar fracture and posterior malleolar fracture; 1 case of combined lateral malleolar fracture and AITFL avulsion fracture; 10 cases of posterior malleolar fracture; 7 cases of lateral malleolar fracture; 5 cases of AITFL avulsion fracture; and 1 unclassified fracture. Of these, 34 of the ankle injuries required surgical fixation. Spiral-type tibial shaft fracture was significantly associated with concomitant ankle injury (P = .001). CONCLUSIONS: Orthopaedic surgeons should be aware that tibial shaft fractures, especially spiral-type fractures, are frequently associated with ankle injuries, such as lateral malleolar fractures, posterior malleolar fractures, and AITFL avulsion fractures. A considerable portion of these cases may necessitate surgical fixation. We recommend all spiral-type tibial shaft fractures routinely undergo computed tomography examination. LEVEL OF EVIDENCE: Level III, comparative series. PMID- 26041544 TI - Allograft Reconstruction of Chronic Tibialis Anterior Tendon Ruptures. AB - BACKGROUND: Chronic ruptures of the tibialis anterior tendon are often associated with tendon retraction and poor-quality tissue, resulting in large segmental defects that make end-to-end repair impossible. Interpositional allograft reconstruction has previously been described as an operative option in these cases; however, there are no reports of the clinical outcomes of this technique in the literature. METHODS: Eleven patients with chronic tibialis anterior tendon ruptures underwent intercalary allograft recon-struction between 2006 and 2013. Patient demographics, injury presentation, and details of surgery were reviewed. Postoperative outcomes at a mean follow-up of 43.8 (range, 6-105) months included the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot score, Short Form-12 (SF-12) physical health score, Lower Extremity Functional Score (LEFS), visual analog scale (VAS) pain rating, dorsiflexion strength, gait analysis, and complications. RESULTS: The average postoperative dorsiflexion strength, as categorized by the Medical Council grading scale, was 4.8 +/- 0.45. The average postoperative VAS score was 0.8 +/- 1.1. The average LEFS was 66.9 +/- 17.2, SF 12 physical health score was 40.1 +/- 14.4, and AOFAS score was 84.3 +/- 7.7. One complication occurred, consisting of transient neuritic pain in the superficial peroneal nerve distribution. There were no postoperative infections, tendon reruptures, reoperations, or allograft-associated complications. CONCLUSION: Allograft reconstruction of chronic irreparable tibialis anterior tendon ruptures yielded satisfactory strength, pain, and patient-reported functional outcomes. This technique offers a safe and reliable alternative, without the donor site morbidity associated with tendon transfer or autograft harvest. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26041545 TI - The Fate of the Fixed Syndesmosis Over Time. AB - BACKGROUND: A prior study demonstrated statistical widening of the syndesmosis within weeks of elective screw removal. However, no information is available as to the radiographic outcomes of screw retention. The aim of this study was to evaluate radiographic syndesmotic widening and talar shift over time in patients treated with syndesmotic screws and to compare screw removal with retention along with other potential risk factors that may have led to tibia-fibula diastasis after weightbearing. METHODS: One hundred sixty-six skeletally mature patients with ankle fractures and concomitant syndesmotic injuries were treated with syndesmotic reduction and screw fixation. The syndesmosis was evaluated intraoperatively either by a stress test or direct visualization. If the syndesmosis was incompetent, it was reduced and stabilized with syndesmotic screws to maintain reduction. Anteroposterior, mortise, and lateral radiographs at presentation, postoperatively, and at follow-up after weightbearing were evaluated. We measured the medial clear space (MCS), tibia-fibula overlap (OL), and tibia-fibula clear space (CS). Screws that were retained were graded as loose/broken or intact. RESULTS: The fibula shifted an insignificant amount on postoperative mortise radiographs after elective syndesmotic screw removal at 3 months or more after initial fixation, indicated by a slightly greater CS and lower OL. The MCS did not change from preoperative to postoperative screw removal. There was no change in the radiographic markers from the postoperative to final follow-up images in those whose screws became loose or broken. Likewise, there was no radiographic difference if screws remained intact versus those that were loose or broken. CONCLUSION: In contradistinction to prior work, we found that only very mild widening (0.5 mm) of the tibia-fibula space occurred after weightbearing following syndesmotic fixation. The removal of syndesmotic screws at 3 months resulted in a slightly lower OL (<1 mm) and greater CS (0.5 mm) on mortise radiographs than screw retention even if the retained screws loosened or broke. This was not associated with any talar subluxation, and these differences were not statistically significant. The mortise remained intact whether the syndesmotic screws were removed, were loosened or broken, or remained solid. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 26041546 TI - Effect of new training technique on affinity of cynomolgus monkeys for animal care personnel. AB - To confirm our hypothesis that the sex and age of cynomolgus monkeys influences the effect of training, we employed a new training technique designed to increase the animal's affinity for animal care personnel. During 151 days of training, monkeys aged 2 to 10 years accepted each 3 raisins/3 times/day, and communicated with animal care personnel (5 times/day). Behavior was scored using integers between -1 and 5. Before training, 35 of the 61 monkeys refused raisins offered directly by animal care personnel (Score -1, 0 and 1). After training, 28 of these 35 monkeys (80%) accepted raisins offered directly by animal care personnel (>Score 2). The mean score of monkeys increased from 1.2 +/- 0.1 to 4.3 +/- 0.2. The minimum training period required for monkeys to reach Score 2 was longer for females than for males. After 151 days, 6 of the 31 females and 1 of the 30 males still refused raisins offered directly by animal care personnel. Beneficial effects of training were obtained in both young and adult monkeys. These results indicate that our new training technique markedly improves the affinity of monkeys for animal care personnel, and that these effects tend to vary by sex but not age. In addition, abnormal behavior and symptoms of monkeys were improved by this training. PMID- 26041547 TI - Effect of BMP4 preceded by retinoic acid and co-culturing ovarian somatic cells on differentiation of mouse embryonic stem cells into oocyte-like cells. AB - Bone morphogenetic protein 4 (BMP4) and retinoic acid (RA) signaling are the key regulators for germ cell and meiosis induction, respectively. Gonadal tissue also provides an appropriate microenvironment for oocyte differentiation in vivo. The current study aimed to determine whether mimicking in vivo niche is more efficient for oocyte differentiation from embryonic stem (ES) cells. Here, differentiation of mouse ES cells toward oocyte-like cells using embryoid body (EB) and monolayer protocols was induced in the presence (+BMP4) or absence ( BMP4) of BMP4. On day 5, each group was co-cultured with ovarian somatic cells in the presence or absence of RA (+RA or -RA) for an additional 14 days. Our results showed a significant increase in expression of meiotic markers in the +BMP4 condition in EB differentiation protocol. Further differentiation with ovarian somatic cells led to a subpopulation of oocyte-like cell formation. Compared to the controls, the +RA condition resulted in a significant elevation of the meiotic gene expression in contrast to Oct4 that significantly decreased in both protocols. In the cells pre-treated with BMP4 and then exposed to RA in the monolayer differentiation protocol, the gene expression levels of germ cell, Mvh, and maturation markers, Cx37, Zp2, and Gdf9, were also upregulated significantly. Therefore, it can be concluded that +BMP4 and +RA along with ovarian somatic cell co-culture improved the rate of in vitro oocyte differentiation. PMID- 26041548 TI - Long-term late toxicities and quality of life for survivors of nasopharyngeal carcinoma treated with intensity-modulated radiotherapy versus non-intensity modulated radiotherapy. AB - BACKGROUND: The purpose of this study was to investigate late toxicities and quality of life (QOL) of patients with nasopharyngeal carcinoma (NPC) with long term survival after treatment by intensity-modulated radiotherapy (IMRT) versus non-IMRT. METHODS: An observational, cross-sectional study of QOL and late toxicities was conducted in 242 patients with NPC with survival of >5 years after treatment with IMRT (n = 100) or non-IMRT (n = 142) by using physician-assessed toxicities (Common Terminology Criteria for Adverse Events [CTCAE] version 4) and the patient-reported European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30-questions (EORTC QLQ-C30) and the Head and Neck 35-questions (EORTC QLQ-C30-H&N35) module. RESULTS: The IMRT group had both statistically (p < .05) and clinically (difference of predicted mean scores >=10 points) better outcome in global QOL, cognitive functioning, social functioning, fatigue, and 11 scales of the head and neck module. Late toxicities, including neuropathy, hearing loss, dysphagia, xerostomia, and neck fibrosis were significantly less severe in the IMRT group. Multivariate analysis revealed that the radiotherapy (RT) technique was statistically significantly associated with late toxicities and QOL outcome after adjusting for other clinical and demographic variables. CONCLUSION: The use of the IMRT technique was associated with the improvement of physician-assessed late toxicities and patient-reported QOL in NPC survivors. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1026-E1032, 2016. PMID- 26041549 TI - Precision Medicine...Visualized-a Message from the President of the WMIC. PMID- 26041551 TI - Industry-sponsored clinical research outside high-income countries: an empirical analysis of registered clinical trials from 2006 to 2013. AB - BACKGROUND: Industry-sponsored clinical trials, in the past performed almost exclusively in more developed countries, now often recruit participants globally. However, recruitment from outside high-income countries may not represent the ultimate target population for the intervention. Clinical trial registries provide an opportunity to quantify and examine the type of clinical research performed in various geographic regions. We sought to characterize industry sponsored randomized controlled trials conducted in high-income countries and to compare these trials to those performed outside high-income countries. METHODS: Clinical trial data on all industry-funded randomized controlled trials conducted between 2006 and 2014 were obtained from the registry ClinicalTrials.gov. Trials were classified according to their study sites as conducted in high or non-high income countries, and data on trial characteristics were collected. RESULTS: Of 22,511 relevant trials, a total of 6,085 (27.0 %) trials included study sites outside a high-income country, and 2,045 (9.1 %) were conducted exclusively outside high-income countries. Of country groups, Central Europe had the greatest number of trials (3,127), followed by Eastern Europe (2,075). The percentage of trials with study sites outside high-income countries remained relatively constant over the study period. Studies with sites outside high-income countries tended to recruit more participants (median enrolled participants 265 vs. 71, P <0.001), to be longer (median study duration 20 vs. 13 months, P <0.05), and to study more advanced phase interventions (Phase 3 or 4 trial 58 % vs. 33 %, P <0.001). CONCLUSIONS: More than a quarter of industry-sponsored trials include participants from outside high-income countries and this rate remained stable over the 7-year study period. Trials conducted outside high-income countries tend to be larger, have a longer duration, and study later phase interventions compared to studies performed exclusively in high-income countries. PMID- 26041552 TI - Patterns of suicide in Kuwait: a retrospective descriptive study from 2003-2009. AB - BACKGROUND: Prior to the invasion of Kuwait by Iraq in 1990, suicides were almost unheard of in Kuwait. However, there has been a notable increase in the referrals of suicide cases to the forensic authorities since then. A review of suicide cases was performed to investigate the demographics of this phenomenon and the suicide modalities used and to uncover issues that can be addressed by the region's government. METHODS: The sole source of data was the general department of criminal evidence (GDCE), where cases are referred by police authorities and by hospital investigators from the entire country. All cases signed out by forensic investigators as "suicide" during the time period 2003-2009 were retrieved. A full review of the data from the case files was made. This included demographic data, scene examination, radiographic investigations, autopsies with histo-pathological examination findings and toxicological screening results in each case. RESULTS: A total of 347 cases were retrieved and studied. Hanging was found to be the most common suicide modality used by subjects (60 %). Non citizens constituted 87 % of cases, and no significant difference was found between married and single subjects or between Muslims and non-Muslims. Regions that were more populated with an expatriate labour force had the highest suicide prevalence. CONCLUSION: The government of Kuwait needs to investigate the dire conditions in which some expatriates live and to improve their situation. More control over the dispensing of certain medications needs to be enforced. Finally, strict firearm control could help reduce the suicide rates in Kuwait. PMID- 26041550 TI - Molecular drivers of lobular carcinoma in situ. AB - Lobular carcinoma in situ (LCIS) is considered to be a risk factor for the development of invasive breast carcinoma, but it may also be a non-obligate precursor to invasive lobular carcinoma (ILC). Many LCIS lesions do not progress to ILC, and the molecular changes that are necessary for progression from LCIS to ILC are poorly understood. Disruption in the E-cadherin complex is the hallmark of lobular lesions, but other signaling molecules, such as PIK3CA and c-src, are consistently altered in LCIS. This review focuses on the molecular drivers of lobular carcinoma, a more complete understanding of which may give perspective on which LCIS lesions progress, and which will not, thus having immense clinical implications. PMID- 26041553 TI - Tunable structures of mixtures of magnetic particles in liquid-crystalline matrices. AB - We investigate the self-organization of a binary mixture of similar sized rods and dipolar soft spheres by means of Monte-Carlo simulations. We model interparticle interactions by employing anisotropic Gay-Berne, dipolar and soft sphere interactions. In the limit of vanishing magnetic moments we obtain a variety of fully miscible liquid crystalline phases including nematic, smectic and lamellar phases. For the magnetic mixture, we find that the liquid crystalline matrix supports the formation of orientationally ordered ferromagnetic chains. Depending on the relative size of the species the chains align parallel or perpendicular to the director of the rods forming uniaxial or biaxial nematic, smectic and lamellar phases. As an exemplary external perturbation we apply a homogeneous magnetic field causing uniaxial or biaxial ordering to an otherwise isotropic state. PMID- 26041554 TI - Similar frequency of the McGurk effect in large samples of native Mandarin Chinese and American English speakers. AB - Humans combine visual information from mouth movements with auditory information from the voice to recognize speech. A common method for assessing multisensory speech perception is the McGurk effect: When presented with particular pairings of incongruent auditory and visual speech syllables (e.g., the auditory speech sounds for "ba" dubbed onto the visual mouth movements for "ga"), individuals perceive a third syllable, distinct from the auditory and visual components. Chinese and American cultures differ in the prevalence of direct facial gaze and in the auditory structure of their languages, raising the possibility of cultural and language-related group differences in the McGurk effect. There is no consensus in the literature about the existence of these group differences, with some studies reporting less McGurk effect in native Mandarin Chinese speakers than in English speakers and others reporting no difference. However, these studies sampled small numbers of participants tested with a small number of stimuli. Therefore, we collected data on the McGurk effect from large samples of Mandarin-speaking individuals from China and English-speaking individuals from the USA (total n = 307) viewing nine different stimuli. Averaged across participants and stimuli, we found similar frequencies of the McGurk effect between Chinese and American participants (48 vs. 44 %). In both groups, we observed a large range of frequencies both across participants (range from 0 to 100 %) and stimuli (15 to 83 %) with the main effect of culture and language accounting for only 0.3 % of the variance in the data. High individual variability in perception of the McGurk effect necessitates the use of large sample sizes to accurately estimate group differences. PMID- 26041557 TI - Abstracts of the XXV Congress of the International Society on Thrombosis and Haemostasis, June 20-25, 2015. PMID- 26041556 TI - Relationship between serum secreted frizzled-related protein 4 levels and the first-phase of glucose-stimulated insulin secretion in individuals with different glucose tolerance. AB - Recent evidence suggests that serum secreted frizzled-related protein (SFRP) 4 may affect beta-cell function. In a cross-sectional clinical study, 56 subjects with type 2 diabetes mellitus (T2DM), 52 subjects with impaired glucose tolerance (IGT) and 42 normal glucose tolerance (NGT) subjects were enrolled to investigate the relationship between SFRP4 levels and the first-phase of glucose-stimulated insulin secretion, glucose metabolism and inflammation. Intravenous glucose tolerance tests were conducted, and acute insulin response (AIR), the area under the curve of the first-phase (0-10 min) insulin secretion (AUC), and the glucose disposition index (GDI) were calculated. The serum levels of SFRP4, IL-1beta, plasma glucose, serum lipid, and glycated hemoglobin (HbA1c) were measured. Levels of serum SFRP4 and IL-1beta in the T2DM group and IGT group were significantly higher than those in the NGT group (P < 0.01). The AIR, AUC and GDI between the three groups showed a progressive decrease from the NGT to IGT groups with the lowest value in the T2DM groups (P < 0.01). The serum SFRP4 levels were negatively correlated with AIR, AUC, GDI and HOMA-beta (P < 0.01) and were positively correlated with fasting plasma glucose, HbA1c, hs-CRP, and IL-1beta (P < 0.01). Our study provides evidence that the concentrations of serum SFRP4 in T2DM and IGT subjects were increased and were correlated closely with glycose metabolic disorder, the first-phase of glucose-stimulated insulin secretion and chronic low-grade inflammation. SFRP4 may participate in the development of type 2 diabetes mellitus. PMID- 26041555 TI - LeishVet update and recommendations on feline leishmaniosis. AB - Limited data is available on feline leishmaniosis (FeL) caused by Leishmania infantum worldwide. The LeishVet group presents in this report a review of the current knowledge on FeL, the epidemiological role of the cat in L. infantum infection, clinical manifestations, and recommendations on diagnosis, treatment and monitoring, prognosis and prevention of infection, in order to standardize the management of this disease in cats. The consensus of opinions and recommendations was formulated by combining a comprehensive review of evidence based studies and case reports, clinical experience and critical consensus discussions. While subclinical feline infections are common in areas endemic for canine leishmaniosis, clinical illness due to L. infantum in cats is rare. The prevalence rates of feline infection with L. infantum in serological or molecular based surveys range from 0% to more than 60%. Cats are able to infect sand flies and, therefore, they may act as a secondary reservoir, with dogs being the primary natural reservoir. The most common clinical signs and clinicopathological abnormalities compatible with FeL include lymph node enlargement and skin lesions such as ulcerative, exfoliative, crusting or nodular dermatitis (mainly on the head or distal limbs), ocular lesions (mainly uveitis), feline chronic gingivostomatitis syndrome, mucocutaneous ulcerative or nodular lesions, hypergammaglobulinaemia and mild normocytic normochromic anaemia. Clinical illness is frequently associated with impaired immunocompetence, as in case of retroviral coinfections or immunosuppressive therapy. Diagnosis is based on serology, polymerase chain reaction (PCR), cytology, histology, immunohistochemistry (IHC) or culture. If serological testing is negative or low positive in a cat with clinical signs compatible with FeL, the diagnosis of leishmaniosis should not be excluded and additional diagnostic methods (cytology, histology with IHC, PCR, culture) should be employed. The most common treatment used is allopurinol. Meglumine antimoniate has been administered in very few reported cases. Both drugs are administered alone and most cats recover clinically after therapy. Follow-up of treated cats with routine laboratory tests, serology and PCR is essential for prevention of clinical relapses. Specific preventative measures for this infection in cats are currently not available. PMID- 26041558 TI - M2 macrophages and inflammatory cells in oral lesions of chronic paracoccidioidomycosis. AB - BACKGROUND: Paracoccidioidomycosis (PCM) is a systemic fungal infection caused by Paracoccidioides brasiliensis (Pb) and associated with deficient cellular immune response, which is modulated by inflammatory cells, mainly macrophages, and cytokines. Recently, the comprehension of the macrophage polarization mediated by Th1 and Th2 cytokines has contributed to elucidate the immune response that takes part in some diseases. Thus, the aim of this study was to assess the presence of Th1- and Th2-immune response and also Pb counting in oral lesions of chronic PCM. METHODS: Forty-eight cases of chronic PCM oral lesions were included. All cases were classified as loose or dense granulomas. S100 protein, IL-1beta, IL-6, TNF alpha, CD163 and CD68 immunoexpressions, and Pb localization were evaluated. The fungi present in the tissue were quantified by anti-Pb antibody. RESULTS: Most patients were white men with mean age of 47 years old and showed higher incidence of multiple lesions. Loose granulomas were predominant and exhibited a great amount of M2 macrophages, which were visualized with anti-CD163 antibody. The expression for CD163 and CD68 was similar (P = 0.05), highlighting the predominance of M2 macrophages in PCM. IL-1beta, IL-6, and TNF-alpha immunoexpression did not significantly change with CD163, CD68, and S100 protein. The number of fungi was significantly higher in cases with intense IL-1beta immunoexpression (P = 0.003). CONCLUSIONS: M2-activated macrophages were the majority among inflammatory cells in chronic PCM, characterizing the action of a Th2-immune response. Nevertheless, Th1 cytokines were also found; mainly IL 1beta, which was associated with fungi counting in oral lesions. PMID- 26041560 TI - Branchlike nano-electrodes for enhanced terahertz emission in photomixers. AB - Branchlike nano-electrode structures were found to improve the THz emission intensity of a photomixer by approximately one order of magnitude higher than that of a photomixer with one row of nano-electrodes separated by the same 100 nm gap. The enhancement is attributed to a more efficient collection of generated carriers, which is in turn due to a more intense electric field under the branchlike nano-electrodes' structures. This is coupled with an increased number of effective areas where strong tip-to-tip THz field enhancements were observed. The optical-to-THz conversion efficiency of the photomixers with the new branchlike nano-electrodes was found to be 10 times higher. The more efficient THz photomixer will greatly benefit the development of continuous-wave THz imaging and spectroscopy systems. PMID- 26041559 TI - Is robotic ventral mesh rectopexy better than laparoscopy in the treatment of rectal prolapse and obstructed defecation? A meta-analysis. AB - Ventral mesh rectopexy is an approach in the treatment of internal and external rectal prolapse and rectocele. Our aim was to assess whether robotic surgery confers any significant advantages over laparoscopy, and the associated complication rate. Two reviewers performed a literature search using MEDLINE and PubMed databases for studies comparing robotic versus laparoscopic surgery. Five prospective, non-randomised studies were identified and included. A total of 244 patients (101 robotic and 143 laparoscopic) were included in the analysis. Operative time was shorter with laparoscopic surgery, mean weighted difference 27.94 [confidence interval (CI) 19.30-36.57; p < 0.00001]. The conversion rate was not significantly different between groups. There was a trend towards a reduction in length of inpatient stay and early post-operative complications in the robotic group; however, these did not reach statistical significance. Recurrence rates were similar between groups (odds ratio 0.91, CI 0.32-2.63; p = 0.87). Functional results were comparable between groups. Early studies show that robotic ventral rectopexy is a safe option compared to the laparoscopic approach, with overall comparable results. There appeared to be a trend towards a reduction in length of inpatient stay and post-operative complications. These perceived benefits may offset the longer operative times and outlay costs. Larger randomised controlled trials are needed to further evaluate clinical value and cost-effectiveness. PMID- 26041561 TI - CASPT2 study of inverse sandwich-type dinuclear 3d transition metal complexes of ethylene and dinitrogen molecules: similarities and differences in geometry, electronic structure, and spin multiplicity. AB - The spin multiplicities and coordination structures of inverse sandwich-type complexes (ISTCs) of ethylene and dinitrogen molecules with 3d transition metal elements (Sc to Ni), (MU-C2H4)[M(AIP)]2 and (MU-N2)[M(AIP)]2 (AIPH = (Z)-1-amino 3-iminoprop-1-ene; M = Sc to Ni) were investigated by the CASPT2 method. In both ethylene and dinitrogen ISTCs of the early 3d transition metals (Sc to Cr), sandwiched ethylene and dinitrogen ligands coordinate with two metal atoms in an eta(2)-side-on form and their ground states have an open-shell singlet spin multiplicity. The eta(1)-end-on coordination structure of dinitrogen ISTCs is considerably less stable than the eta(2)-side-on form in these metals. For the late 3d transition metals (Mn to Ni), ethylene and dinitrogen ISTCs exhibit interesting similarities and differences in spin multiplicity and structure as follows: in ethylene ISTCs of Mn to Ni, the ground state has an open-shell singlet spin multiplicity like those of the ISTCs of early transition metals. However, the ethylene ligand is considerably distorted, in which the ethylene carbon atoms have a tetrahedral-like structure similar to sp(3) carbon and each of them coordinates with one metal in a MU-eta(1):eta(1) structure. These geometrical features are completely different from those of ISTCs of the early transition metals. In dinitrogen ISTCs of Mn to Ni, on the other hand, the ground state has a high spin multiplicity from nonet (Mn) to triplet (Ni). The eta(2) side-on coordination structure of the dinitrogen ligand is as stable as the eta(1)-end-on form in the Mn complex but the eta(1)-end-on structure is more stable than the eta(2)-side-on form in the Fe to Ni complexes. All these interesting similarities and differences between ethylene and dinitrogen ISTCs and between the early and late transition metal elements arise from the occupation of several important molecular orbitals. PMID- 26041562 TI - Occupational asthma contribution in phenotyping adult asthma by using age-of asthma onset clustering. PMID- 26041564 TI - Response Evaluation Criteria in Cancer of the Liver (RECICL) (2015 Revised version). AB - The Response Evaluation Criteria in Solid Tumors (RECIST) is inappropriate to assess the direct effects of treatment on hepatocellular carcinoma (HCC) by locoregional therapies such as radiofrequency ablation (RFA) and transarterial chemoembolization (TACE). Therefore, establishment of response evaluation criteria solely devoted to HCC is needed urgently in clinical practice as well as in clinical trials of HCC treatment, such as molecular-targeted therapies, which cause necrosis of the tumor. The Response Evaluation Criteria in Cancer of the Liver (RECICL) was revised in 2015 by the Liver Cancer Study Group of Japan based on the 2009 version of RECICL, which was commonly used in Japan. Major revised points of the RECICL 2015 is to define the target lesions of two lesions per organ or three lesions per liver, up to a maximum of five lesions. The second revised point is that setting the timing at which the overall treatment response has been changed. The third point is that the definition of treatment effect 1 has been changed to more than 50% tumor enlargement, excluding the area of necrosis after treatment. Overall evaluation of treatment response has been amended to make it possible to evaluate the overall response including extrahepatic lesions by systemic therapy, which is similar to RECIST or modified RECIST. We hope this new treatment response criteria, RECICL, proposed by the Liver Cancer Study Group of Japan will benefit HCC treatment response evaluation in the setting of daily clinical practice and clinical trials, not only in Japan, but also internationally. PMID- 26041563 TI - HGF and TGFbeta1 differently influenced Wwox regulatory function on Twist program for mesenchymal-epithelial transition in bone metastatic versus parental breast carcinoma cells. AB - BACKGROUND: Much effort has been devoted to determining how metastatic cells and microenvironment reciprocally interact. However, the role of biological stimuli of microenvironment in controlling molecular events in bone metastasis from breast carcinoma for mesenchymal-epithelial transition (MET) is largely unknown. The purpose of the present paper was to clarify (1) the influence of hepatocyte growth factor (HGF) and transforming growth factorbeta1 (TGFbeta1) on the phenotype of bone-metastatic 1833 and parental MDA-MB231 cells; (2) the hierarchic response of Twist and Snail controlled by Wwox co-factor, that might be critical for the control of 1833-adhesive properties via E-cadherin. METHODS: We studied under HGF and TGFbeta1 the gene profiles-responsible for epithelial mesenchymal transition (EMT), versus the revertant MET phenotype-making the correspondence with 1833 morphology and the relation to HGF-dependent control of TGFbeta1 signalling. In particular, the activation of Twist program and the underlying molecular mechanisms were investigated, considering the role of endogenous and exogenous Wwox with siRNAWWOX and the expression vector transfection, to clarify whether Twist affected E-cadherin transactivation through a network of transcription factors and regulators. RESULTS: HGF and TGFbeta1 oppositely affected the expression of Wwox in 1833 cells. Under HGF, endogenous Wwox decreased concomitant with Twist access to nuclei and its phosphorylation via PI3K/Akt pathway. Twist activated by HGF did not influence the gene profile through an E-box mechanism, but participated in the interplay of PPARgamma/Ets1/NF-kB-transcription factors, triggering E-cadherin transactivation. Altogether, HGF conferred MET phenotype to 1833 cells, even if this was transient since followed by TGFbeta1-signalling activation. TGFbeta1 induced Snail in both the cell lines, with E-cadherin down-regulation only in 1833 cells because in MDA-MB231 cells E-cadherin was practically absent. Exogenous Wwox activated metastatic HIF-1, with Twist as co-factor. CONCLUSIONS: HGF and TGFbeta1 of bone-metastasis microenvironment acted co-ordinately, influencing non redundant pathways regulated by Twist program or Snail transcription factor, with reversible MET switch. This process implicated different roles for Wwox in the various steps of the metastatic process including colonization, with microenvironmental/exogenous Wwox that activated HIF-1, important for E-cadherin expression. Interfering with the Twist program by targeting the pre-metastatic niche stimuli could be an effective anti-bone metastasis therapy. PMID- 26041565 TI - Systematic review of intervention design and delivery in pragmatic and explanatory surgical randomized clinical trials. AB - BACKGROUND: Surgical interventions are complex, with multiple components that require consideration in trial reporting. This review examines the reporting of details of surgical interventions in randomized clinical trials (RCTs) within the context of explanatory and pragmatic study designs. METHODS: Systematic searches identified RCTs of surgical interventions published in 2010 and 2011. Included studies were categorized as predominantly explanatory or pragmatic. The extent of intervention details in the reports were compared with the CONSORT statement for reporting trials of non-pharmacological treatments (CONSORT-NPT). CONSORT-NPT recommends reporting the descriptions of surgical interventions, whether they were standardized and adhered to (items 4a, 4b and 4c). Reporting of the context of intervention delivery (items 3 and 15) and operator expertise (item 15) were assessed. RESULTS: Of 4541 abstracts and 131 full-text articles, 80 were included (of which 39 were classified as predominantly pragmatic), reporting 160 interventions. Descriptions of 129 interventions (80.6 per cent) were provided. Standardization was mentioned for 47 (29.4 per cent) of the 160 interventions, and 22 articles (28 per cent) reported measurement of adherence to at least one aspect of the intervention. Seventy-one papers (89 per cent) provided some information about context. For one-third of interventions (55, 34.4 per cent), some data were provided regarding the expertise of personnel involved. Reporting standards were similar in trials classified as pragmatic or explanatory. CONCLUSION: The lack of detail in trial reports about surgical interventions creates difficulties in understanding which operations were actually evaluated. Methods for designing and reporting surgical interventions in RCTs, contributing to the quality of the overall study design, are required. This should allow better implementation of trial results into practice. PMID- 26041566 TI - ALFF Value in Right Parahippocampal Gyrus Acts as a Potential Marker Monitoring Amyotrophic Lateral Sclerosis Progression: a Neuropsychological, Voxel-Based Morphometry, and Resting-State Functional MRI Study. AB - The aim of this study is to analyze cognitive impairment in amyotrophic lateral sclerosis (ALS). Forty-four participants matched for age, sex, and educational background were enrolled as the sporadic ALS group (n = 22) and the control group (n = 22). All participants completed comprehensive neuropsychological tests, including the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Stroop Color-Word Interference Test (SCWT), the Wisconsin Card Sorting Test (WCST), and the Frontal Assessment Battery. The participants underwent a series of 3.0 Tesla magnetic resonance imaging (MRI) scans. Resting state functional MRI (Rs-fMRI) using the amplitude of low-frequency fluctuation (ALFF) was performed. Three-dimensional T1-weighted anatomical images obtained by voxel-based morphometry (VBM) were used to conduct correlation analyses and group comparisons with the demographic and neuropsychological characteristics. The results indicated that the decreased gray matter (GM) volume in the bilateral precentral gyri and increased ALFF values in the right parahippocampal gyrus, left inferior temporal gyrus, left anterior cingulate gyrus, right superior frontal gyrus, and left middle occipital gyrus were identified in the sporadic ALS group. The increased ALFF value in the right parahippocampal gyrus was positively correlated with ALS progression rate. The ALS patients exhibited poor performances on cognitive and executive tests, which were significantly or marginally significantly correlated with the ALFF values in the anterior cingulate gyrus and the frontal, temporal, and parahippocampal cortices. In conclusion, these findings provide evidence of an extramotor involvement and suggest that the ALFF value in the right parahippocampal gyrus could represent a potential marker to monitor disease progression. PMID- 26041567 TI - ETHNICITY AND INCOME IMPACT ON BMI AND STATURE OF SCHOOL CHILDREN LIVING IN URBAN SOUTHERN MEXICO. AB - Obesity affects quality of life and increases the risk of morbidity and mortality. Mexico, a middle-income country, has a high prevalence of overweight and obesity among urban children. Merida is the most populated and growing city in southern Mexico with a mixed Mayan and non-Maya population. Local urbanization and access to industrialized foods have impacted the eating habits and physical activity of children, increasing the risk of overweight and obesity. This study aimed to contribute to the existing literature on the global prevalence of overweight and obesity and examined the association of parental income, ethnicity and nutritional status with body mass index (BMI) and height in primary school children in Merida. The heights and weights of 3243 children aged 6-12 from sixteen randomly selected schools in the city were collected between April and December 2012. Multinomial logistic regression models were used to examine differences in the prevalence of BMI and height categories (based on WHO reference values) by ethnicity and income levels. Of the total students, 1648 (50.9%) were overweight or obese. Stunting was found in 227 children (7%), while 755 (23.3%) were defined as having short stature. Combined stunting and overweight/obesity was found in 301 students (9.3%) and twelve (0.4%) were classified as stunted and of low weight. Having two Mayan surnames was inversely associated with having adequate height (OR=0.69, p<0.05) and the presence of two Maya surnames in children increased the odds of short stature and stunting. Children from lower income families had twice the odds of being stunted and obese. Overweight, obesity and short stature were frequent among the studied children. A significant proportion of Meridan children could face an increased risk of developing cardiovascular disease and its associated negative economic and social outcomes unless healthier habits are adopted. Action is needed to reduce the prevalence of obesity among southern Mexican families of all ethnic groups, particularly those of lower income. PMID- 26041569 TI - Application of mesoporous carbon as a solid-phase microextraction fiber coating for the extraction of volatile aromatic compounds. AB - A mesoporous carbon was fabricated using MCM-41 as a template and sucrose as a carbon source. The carbon material was coated on stainless-steel wires by using the sol-gel technique. The prepared solid-phase microextraction fiber was used for the extraction of five volatile aromatic compounds (chlorobenzene, ethylbenzene, o-xylene, bromobenzene, and 4-chlorotoluene) from tea beverage samples (red tea and green tea) prior to gas chromatography with mass spectrometric detection. The main experimental parameters affecting the extraction of the volatile aromatic compounds by the fiber, including the extraction time, sample volume, extraction temperature, salt addition, and desorption conditions, were investigated. The linearity was observed in the range from 0.1 to 10.0 MUg/L with the correlation coefficients (r) ranging from 0.9923 to 0.9982 and the limits of detection were less than 10.0 ng/L. The recoveries of the volatile aromatic compounds by the method from tea beverage samples at spiking levels of 1.0 and 10.0 MUg/L ranged from 73.1 to 99.1%. PMID- 26041568 TI - Arbuscular mycorrhiza affects nickel translocation and expression of ABC transporter and metallothionein genes in Festuca arundinacea. AB - Mycorrhizal fungi are key microorganisms for enhancing phytoremediation of soils contaminated with heavy metals. In this study, the effects of the arbuscular mycorrhizal fungus (AMF) Funneliformis mosseae (=Glomus mosseae) on physiological and molecular mechanisms involved in the nickel (Ni) tolerance of tall fescue (Festuca arundinacea = Schedonorus arundinaceus) were investigated. Nickel addition had a pronounced negative effect on tall fescue growth and photosynthetic pigment contents, as well as on AMF colonization. Phosphorus content increased markedly in mycorrhizal plants (M) compared to non-inoculated (NM) ones. However, no significant difference was observed in root carbohydrate content between AMF-inoculated and non-inoculated plants. For both M and NM plants, Ni concentrations in shoots and roots increased according to the addition of the metal into soil, but inoculation with F. mosseae led to significantly lower Ni translocation from roots to the aboveground parts compared to non inoculated plants. ABC transporter and metallothionein transcripts accumulated to considerably higher levels in tall fescue plants colonized by F. mosseae than in the corresponding non-mycorrhizal plants. These results highlight the importance of mycorrhizal colonization in alleviating Ni-induced stress by reducing Ni transport from roots to shoots of tall fescue plants. PMID- 26041570 TI - COCATS 4 Task Force 5: Training in Echocardiography: Endorsed by the American Society of Echocardiography. PMID- 26041571 TI - Jill (or Jack) of All Trades, Master of None? PMID- 26041572 TI - Strain imaging in echocardiography: converging on congruence? PMID- 26041573 TI - If Life Was a Movie: Reflections from a Year as ASE President. PMID- 26041574 TI - Two years in review. PMID- 26041575 TI - Pediatric and congenital echocardiography: how far have we gone, and what is ahead? PMID- 26041576 TI - Atorvastatin alleviates experimental diabetic cardiomyopathy by suppressing apoptosis and oxidative stress. AB - Diabetic hazard on the myocardium is a complication of diabetes that intensifies its morbidity and increases its mortality. Therefore, alleviation of diabetic cardiomyopathy (DCM) by a reliable drug remains a matter of interest in experimental research. The aim of this study was to explore the structural alterations in the myocardium induced by atorvastatin (ATOR) in DCM, induced by streptozotocin (STZ), along with the associated changes occurring in apoptosis and oxidative stress markers. Thirty-two rats were divided into four groups; group A (control), group B (non-diabetic, received ATOR, orally, 50 mg/kg daily), group C (DCM, received STZ 70 mg/kg, single i.p. injection) and group D (DCM + ATOR). After 6 weeks, left ventricle (LV) specimens were prepared for histological and immunohistochemical study by hematoxlyin and eosin, Masson's trichrome, anti-cleaved caspase-3 stains as well as for assays of oxidative stress markers. All data were measured morphometrically and statistically analyzed. The DCM group showed disorganization of the cardiomyocytes, interstitial edema, numerous fibroblasts, significant increases in the collagen volume fraction (p < 0.001), cleaved caspase-3 expression % area (p < 0.001) and, malondialdehyde in blood (p < 0.001), in LV (p < 0.05) compared with DCM + ATOR group. The latter has LV wall thickness, relative heart weight and antioxidant activities nearly similar to the control, independent from ATOR lipid-lowering effect. Therefore, ATOR can preserve myocardial structure in DCM nearly similar to normal. This may be achieved by suppressing apoptosis that parallels the correction of the antioxidant markers, which can be considered as non-lipid lowering benefit of statins. PMID- 26041577 TI - Synthesis and structure-activity relationship of aminoarylthiazole derivatives as correctors of the chloride transport defect in cystic fibrosis. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity. PMID- 26041579 TI - A high surface area flower-like Ni-Fe layered double hydroxide for electrocatalytic water oxidation reaction. AB - Layered double hydroxide has been used in a variety of areas, including but not limited to catalysis, energy storage, drug or gene delivery, water treatment, etc. Herein, we report a new simple hydrothermal method to prepare a high surface area flower-like Ni-Fe layered double hydroxide (LDH) assembled by nanosheets by using nickel alkoxide and FeSO4 as the only starting materials. It is free of alkaline solution and other additives for directing or supporting in the synthesis procedure. The formation mechanism of this flower-like LDH formed by ultrathin nanosheets is also discussed. Moreover, the as-obtained LDH material shows increased electrocatalytic activity and stability toward WOR in alkaline media compared with the materials prepared without a Ni alkoxide precursor or Fe precursor, namely alpha-Fe2O3 and Ni(OH)2, respectively. In addition, the electrocatalytic activity is demonstrated to be related to the molar ratio of Fe and Ni in the final Ni-Fe material, and the best activity is achieved when the ratio reaches 0.52 : 1. The phase compositions of the resulting Ni-Fe(x) are discussed. Furthermore, the Ni-Fe LDH material reported herein might be employed as a promising noble-metal-free water oxidation catalyst to replace the IrOx material-the state-of-the-art water oxidation catalyst. PMID- 26041578 TI - Prevention of acute exacerbation of chronic hepatitis B infection in cancer patients receiving chemotherapy in a hepatitis B virus endemic area. AB - Reactivation of hepatitis B viral (HBV) infection in cancer patients undergoing chemotherapy may cause interruption of chemotherapy and lead to liver failure and death. In our institute, a computerized order entry-based alert system was introduced in September 2011 to remind healthcare providers of HBV testing when prescribing chemotherapy. Since August 2012, an order entry-based therapeutic control system has been applied to ensure HBV prophylaxis during chemotherapy. This retrospective cohort study included cancer patients receiving chemotherapy in the Kaohsiung Veterans General Hospital from November 2009 to June 2013. The prechemotherapy HBV screening rate, HBV prophylactic rate, and severe HBV acute exacerbation rate were compared between stages with different order systems. Newly diagnosed cancer patients (n = 2512) were included. The HBV testing rate in the screening reminder stage was higher than that in the educational stage (93.5% versus 40.2%, P < 0.001), whereas the adequate HBV prophylactic rates in the two order entry-based stages were comparable (41.1% versus 39.2%). Patients in the order entry-based therapeutic control stage had a higher HBV screening rate (99.3% versus 40.2%, P < 0.001) and a higher HBV prophylactic rate (95.8% versus 39.2%, P < 0.001) than those in the educational stage. Additionally, the severe HBV acute exacerbation rate in the therapeutic control stage was lower than those in the educational and screening reminder stages (0% versus 1.2% and 1.2%, respectively; both P < 0.01). CONCLUSION: A computerized order entry-based therapeutic control system can provide excellent prechemotherapy HBV screening for cancer patients undergoing chemotherapy and can effectively prevent severe acute exacerbation of HBV infection in hospitals among HBV endemic areas. PMID- 26041580 TI - Adaptive Spontaneous Transitions between Two Mechanisms of Numerical Averaging. AB - We investigated the mechanism with which humans estimate numerical averages. Participants were presented with 4, 8 or 16 (two-digit) numbers, serially and rapidly (2 numerals/second) and were instructed to convey the sequence average. As predicted by a dual, but not a single-component account, we found a non monotonic influence of set-size on accuracy. Moreover, we observed a marked decrease in RT as set-size increases and RT-accuracy tradeoff in the 4-, but not in the 16-number condition. These results indicate that in accordance with the normative directive, participants spontaneously employ analytic/sequential thinking in the 4-number condition and intuitive/holistic thinking in the 16 number condition. When the presentation rate is extreme (10 items/sec) we find that, while performance still remains high, the estimations are now based on intuitive processing. The results are accounted for by a computational model postulating population-coding underlying intuitive-averaging and working-memory mediated symbolic procedures underlying analytical-averaging, with flexible allocation between the two. PMID- 26041581 TI - Disturbance of redox homeostasis as a contributing underlying pathomechanism of brain and liver alterations in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. AB - 3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is an inherited disorder of organic acid metabolism biochemically characterized by tissue accumulation and high urinary excretion of 3-hydroxy-3-methylgutarate, 3-methylglutarate, 3 methylglutaconate and 3-hydroxyisovalerate. Affected patients predominantly present neurological symptoms that are accompanied by mild hepatopathy during episodes of catabolic crisis. The pathophysiology of this disease is poorly known, although recent animal and human in vitro and in vivo studies have suggested that oxidative stress caused by the major accumulating organic acids may represent a pathomechanism of brain and liver damage in HL deficiency. In this review we focus on the deleterious effects of these carboxylic acids on redox homeostasis in rat and human tissues that may offer new perspectives for potential novel adjuvant therapeutic strategies in this disorder. PMID- 26041582 TI - Acceptance as a Mediator for Change in Acceptance and Commitment Therapy for Persons with Chronic Pain? AB - BACKGROUND: Cognitive behavior therapy (CBT) is considered effective for chronic pain, but little is known about active treatment components. Although acceptance correlates with better health outcomes in chronic pain patients, no study has examined its mediating effect in an experimental design. PURPOSE: The aim of the present study is to investigate acceptance as a mediator in acceptance and commitment therapy (ACT), a third wave CBT intervention, for chronic pain. METHOD: A bootstrapped cross product of coefficients approach was used on data from a previously published RCT evaluating ACT for chronic pain. To address the specificity of acceptance as a mediator, anxiety and depression were also tested as mediators. Outcome variables were satisfaction with life and physical functioning. Two change scores, pre-assessment to 6-month follow-up (n = 53) and pre-assessment to 12-month follow-up (n = 32), were used. RESULTS: Acceptance was found to mediate the effect of treatment on change in physical functioning from pre-assessment to follow-up at 6 months. Further, a trend was shown from pre assessment to follow-up at 12 months. No indirect effect of treatment via acceptance was found for change in satisfaction with life. CONCLUSION: This study adds to a small but growing body of research using mediation analysis to investigate mediating factors in the treatment of chronic pain. In summary, the results suggest that acceptance may have a mediating effect on change in physical functioning in ACT for persons with chronic pain. However, given the small sample size of the study, these findings need to be replicated. PMID- 26041583 TI - Engagement in New Dietary Habits-Obese Women's Experiences from Participating in a 2-Year Diet Intervention. AB - BACKGROUND: Dietary weight loss interventions most often result in weight loss, but weight maintenance on a long-term basis is the main problem in obesity treatment. There is a need for an increased understanding of the behaviour patterns involved in adopting a new dietary behavior and to maintain the behaviour over time. PURPOSE: The purpose of this paper is to explore overweight and obese middle-aged women's experiences of the dietary change processes when participating in a 2-year-long diet intervention. METHODS: Qualitative semi structured interviews with 12 overweight and obese women (54-71 years) were made after their participation in a diet intervention programme. The programme was designed as a RCT study comparing a diet according to the Nordic nutrition recommendations (NNR diet) and a Palaeolithic diet (PD). Interviews were analysed according to Grounded Theory principles. RESULTS: A core category "Engagement phases in the process of a diet intervention" concluded the analysis. Four categories included the informants' experiences during different stages of the process of dietary change: "Honeymoon phase", "Everyday life phase", "It's up to you phase" and "Crossroads phase". The early part of the intervention period was called "Honeymoon phase" and was characterised by positive experiences, including perceived weight loss and extensive support. The next phases, the "Everyday life phase" and "It's up to you phase", contained the largest obstacles to change. The home environment appeared as a crucial factor, which could be decisive for maintenance of the new dietary habits or relapse into old habits in the last phase called "Crossroads phase". CONCLUSION: We identified various phases of engagement in the process of a long-term dietary intervention among middle-aged women. A clear personal goal and support from family and friends seem to be of major importance for long-term maintenance of new dietary habits. Gender relations within the household must be considered as a possible obstacle for women engaging in diet intervention. PMID- 26041584 TI - Epidemiology of classical risk factors in stroke patients in the Middle East. AB - The Middle East (ME) is an ethnically and economically diverse region. A systematic review of all stroke studies conducted in the ME was carried out, with the aim of determining the prevalence of classic vascular risk factors (CRFs) across this region. Additionally, the prevalence of CRFs in the ME was compared to that of a US cohort. Prospective and retrospective ME stroke studies published from 1994 to 2014 were searched for that specifically reported on the prevalence of CRFs. The Z test for proportions was used to determine the significance of differences in CRF rates between the ME and non-ME studies. A total of 21,724 stroke patients from 13 nations in the ME were included. The prevalence rates for CRFs in the ME stroke population were hypertension, 62.1%; diabetes, 33.1%; dyslipidaemia, 36.8%; ischaemic heart disease, 24.6%; smoking, 19.3%; and atrial fibrillation, 13.6%. Compared to the US cohort, ME patients had a lower prevalence of all CRFs except diabetes (P < 0.0001) and smoking (P = 0.05). Compared with stroke patients in the USA, those in the ME have a significantly higher prevalence of diabetes and smoking. Education and lifestyle modification is perhaps the most effective strategy in reducing the risk of stroke in this population. PMID- 26041585 TI - Efficacy and Tolerability of Sitagliptin Compared with Glimepiride in Elderly Patients with Type 2 Diabetes Mellitus and Inadequate Glycemic Control: A Randomized, Double-Blind, Non-Inferiority Trial. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus (T2DM) and inadequate glycemic control with diet and exercise alone. METHODS: This was a randomized, parallel-group, multinational, non-inferiority clinical trial with an active-controlled, double-blind treatment period in which patients >= 65 and <= 85 years of age with T2DM were screened at 85 sites. Patients were randomized to once-daily sitagliptin (100 or 50 mg, depending on renal function) or glimepiride (in titrated doses) for 30 weeks. The main outcome measures were change from baseline in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and body weight; and the incidence of symptomatic hypoglycemia. RESULTS: The mean baseline HbA1c was 7.8% in both the sitagliptin group (n = 197) and the glimepiride group (n = 191). After 30 weeks, the least squares (LS) mean change in HbA1c baseline was -0.32% with sitagliptin and -0.51 % with glimepiride, for a between-group difference (95% CI) of 0.19% (0.03-0.34). This result met the pre-specified criterion for declaring non-inferiority, which required that the upper 95% confidence limit lie below 0.4%. The LS mean change in FPG from baseline was -14.5 mg/dL with sitagliptin and -21.2 mg/dL with glimepiride, for a between-group difference (95% CI) of 6.7 mg/dL (0.7-12.7). The percentages of patients with adverse events of symptomatic hypoglycemia were 0.8% in the sitagliptin group and 4.7% in the glimepiride group (between-treatment difference = -3.9%, p = 0.009). The LS mean change in body weight from baseline was 0.4 kg with sitagliptin and 1.1 kg with glimepiride, for a between-group difference of -0.7 kg (p = 0.011). CONCLUSION: In elderly patients with T2DM and inadequate glycemic control with diet and exercise alone, sitagliptin provided non-inferior glycemic control after 30 weeks of treatment compared with glimepiride. Compared with glimepiride, sitagliptin had a lower risk of hypoglycemia. Sitagliptin was weight-neutral; while the between-group difference in change from baseline in body weight was statistically significant, the modest difference may not be clinically meaningful. STUDY IDENTIFIER: ClinicalTrials.gov NCT01189890. PMID- 26041586 TI - High-performance ternary blend polymer solar cells involving both energy transfer and hole relay processes. AB - The integration of multiple materials with complementary absorptions into a single junction device is regarded as an efficient way to enhance the power conversion efficiency (PCE) of organic solar cells (OSCs). However, because of increased complexity with one more component, only limited high-performance ternary systems have been demonstrated previously. Here we report an efficient ternary blend OSC with a PCE of 9.2%. We show that the third component can reduce surface trap densities in the ternary blend. Detailed studies unravel that the improved performance results from synergistic effects of enlarged open circuit voltage, suppressed trap-assisted recombination, enhanced light absorption, increased hole extraction, efficient energy transfer and better morphology. The working mechanism and high device performance demonstrate new insights and design guidelines for high-performance ternary blend solar cells and suggest that ternary structure is a promising platform to boost the efficiency of OSCs. PMID- 26041588 TI - Reproduction. Introduction. PMID- 26041587 TI - Safety and Hemostatic Effectiveness of the Fibrin Pad for Severe Soft-Tissue Bleeding During Abdominal, Retroperitoneal, Pelvic, and Thoracic (Non-cardiac) Surgery: A Randomized, Controlled, Superiority Trial. AB - BACKGROUND: In surgery, rapid hemostasis can be required in various settings and bleeding intensities to minimize complications related to blood loss. While effective hemostats are available for mild-to-moderate surgical bleeding, few are effective against challenging severe hemorrhage. We report the effectiveness and safety of the fibrin pad (FP), a novel combination hemostat (device/human biologic), in controlling severe soft-tissue bleeding as compared to the standard of care (SoC). METHODS: This randomized, controlled, superiority study enrolled subjects >=18 years, requiring elective abdominal, retroperitoneal, pelvic, or thoracic (non-cardiac) surgery. A severe target bleeding site (TBS) was identified intra-operatively following which, subjects were randomized to the FP or the SoC group. Hemostatic status was observed at 4 min (primary endpoint) and 10 min post-randomization. Safety variables included TBS-related bleeding and thrombotic events. RESULTS: At 4 min post-randomization, 50/59 (84.7 %) subjects in the FP group and 10/32 (31.3%) [Corrected] subjects in the SoC group achieved hemostasis without needing re-treatment (P < 0.0001). Compared to the SoC group, the FP group showed better hemostasis at 10 min post-randomization [58/59 (98.3 %) vs. 28/32 (87.5 %); P = 0.01], lower mean time to hemostasis (6.1 +/- 13.5 vs. 17.8 +/- 32.0 min), and a less frequent need for re-treatment (5.1 vs. 53.1 %). The triangular test for binary response demonstrated the FP to be superior to SoC (95 % CI 1.474-3.290; P < 0.0001). Safety profiles in both groups were similar to those typically observed after long-duration surgery. CONCLUSION: The FP is safe and superior to SoC for controlling challenging severe soft-tissue bleeding encountered during intra-abdominal and thoracic surgical procedures. PMID- 26041589 TI - Tocodynamometry detects preterm labor in the bitch before luteolysis. AB - Preterm labor (PTL), myometrial activity, and accompanying cervical changes can lead to the loss of pregnancy via resorption or abortion before term gestation. Idiopathic PTL has no metabolic, infectious, congenital, traumatic, or toxic cause identified; however, hypoluteoidism has been hypothesized to cause PTL in the bitch, based on progesterone measurements at the time of clinical pregnancy loss. This study documents the use of tocodynamometry to detect PTL in 5 bitches; progesterone measurements in these bitches were normal for pregnancy at the time PTL was diagnosed. PMID- 26041590 TI - Canine neonatal transcranial ultrasonography from birth until closure of bregmatic fontanelle. AB - Ultrasonography is a valuable diagnostic tool that has been used for diagnosis of neonatal brain diseases. The purpose of the present study was to describe the sequential ultrasonographic appearance of the normal canine neonatal brain from birth till closure of the bregmatic fontanelle. In total, 16 clinically normal neonates of mixed breed dogs were used. The bregmatic fontanelle was used as an acoustic window to record 5 transcranial scans (3 transverse, 1 sagittal, and 1 parasagittal scans) at 3, 10, 20, and 30 days of age. The appearance, echogenicity, and developmental differentiation of the structures within the cranium were described. Good images were obtained at 10 and 20 days of age. At 30 days of age, the obtained images presented poor details, as the fontanelle was small. Data obtained from this study represent the basis of brain ultrasound in neonates until 30 days of age, which could be beneficial in diagnosing congenital brain diseases. PMID- 26041591 TI - Lumbosacral transitional vertebrae, canine hip dysplasia, and sacroiliac joint degenerative changes on ventrodorsal radiographs of the pelvis in police working German shepherd dogs. AB - Lumbosacral transitional vertebrae (LTV) frequently occur in German shepherd dogs. The aim of the study was to evaluate the prevalence and interdependence between LTV and canine hip dysplasia (CHD) as well as sacroiliac joint degenerative changes visualized on ventrodorsal radiographs of the pelvis in both working and companion German shepherd dogs. The presence of LTV was found in 12% of working dogs and in 33% of companion dogs. Similar incidence of hip dysplasia in both the groups was found. It has been shown that dogs with LTV have a higher frequency of severe CHD. A higher percentage of sacroiliac joint degenerative changes was observed in dogs with no signs of LTV and in working dogs. PMID- 26041592 TI - Topics in the routine assessment of newborn puppy viability. AB - Neonatal veterinarians still observe higher mortality rates among their patients than those observed among humans. Establishment of a neonatal assessment protocol is fundamental to the identification of the medical status of the neonate and the need for medical intervention. The neonatal Apgar score evaluation, which is commonly used in clinical practice, should be complemented by other methods of analysis. This study proposes, in addition to an Apgar score analysis, the evaluation of laboratory parameters and weight. We believe that knowledge of these reference values is essential for diagnosing at-risk neonates and for establishing suitable treatments. PMID- 26041593 TI - Gastroesophageal intussusception in a 50-day-old German shepherd dog. AB - Gastroesophageal intussusception is a rare but life-threatening condition that requires immediate diagnosis and urgent surgical intervention. We describe the clinical, radiographic, ultrasonographic, and gross pathologic examinations of a 50-day-old German Shepherd dog with gastroesophageal intussusception associated with esophageal dilatation. The dog was brought to the clinic 10 days after weaning with a history of regurgitation, persistent vomiting, hematemesis, and dyspnea. On admission, the dog was lethargic with signs of shock and died just before surgery. Gastroesophageal intussusception should be considered in the differential diagnosis in dogs with progressive vomiting or regurgitation especially at the weaning time. PMID- 26041594 TI - Treatment of canine pyometra with the gonadotropin-releasing hormone antagonist acyline: a case series. AB - To describe the effect of the third-generation gonadotropin-releasing hormone antagonist acyline in the treatment of 4 diestrous bitches with the cystic endometrial hyperplasia-pyometra complex. The 4 bitches were treated with 330 MUg/kg of subcutaneous acyline on day 0 and antibiotics, and followed up for 2 weeks. One closed-cervix case showed cervical dilatation 36 hours after treatment, and all the 4 animals showed resolution of clinical signs starting on day 3 posttreatment. Ultrasonographic uterine diameters and luminal contents decreased in the bitches having high progesterone serum concentrations before treatment but not in those with low levels. Serum progesterone importantly decreased from high to basal concentrations in the 3 "ultrasonographically cured" animals. No local or systemic side effects related to the treatment were observed. The gonadotropin-releasing hormone antagonist acyline may have a promising place for the medical treatment of cystic endometrial hyperplasia pyometra complex in dogs. PMID- 26041595 TI - Spermatocele in a South African Boerboel dog. AB - A 2-year-old intact male South African Boerboel presented for semen cryopreservation and was discovered to be azoospermic. The dog had excellent libido and had sired litters within 6 months, so a further investigation of why his collection lacked sperm was warranted. On further examination of his scrotal contents, his right epididymis had an enlarged area with a hard texture. Ultrasonography revealed that the enlarged area of the right epididymis was fluid filled. A sample of the fluid was aspirated for aerobic culture. No bacteria showed growth. Although the culture was negative, it was suspected that this dog had an epididymitis or epididymal abscess, and treatment with enrofloxacin at 10mg/kg orally was initiated for 4 weeks. The abnormal texture and fluid-filled cavity in the right epididymis persisted, despite antibiotic therapy. Cytology of a repeat aspiration of the fluid-filled area after antibiotic therapy revealed a mixture of red blood cells and sperm. Owing to the potential for blood-testis barrier disruption, a unilateral orchiectomy of the right testicle was performed, as an attempt to protect future sperm production of the remaining testicle. A spermatocele was confirmed on histopathology. After another month, an excellent quality semen sample was collected, with 90% progressive motility, good concentration, and few morphologic abnormalities. A subsequent collection was acquired and was successfully cryopreserved for future breeding. In dogs with spermatoceles, semen quality can be preserved with aggressive treatment to remove the affected testicle. The disruption of the blood-testis barrier in spermatoceles may result in antisperm antibody production and eventual infertility; however, cryopreservation can result in long-term options for owners seeking to continue using an animal in their breeding program. PMID- 26041596 TI - Adult-onset lymphoplasmacytic orchitis in a Labrador retriever stud dog. AB - A formerly fertile 5-year-old 45-kg Labrador retriever was evaluated for azoospermia noted during routine semen collection for an artificial insemination. Over the past 3 years, the dog had sired 4 litters of anticipated size for the breed out of 5 breedings, the most recent a litter of 10 conceived and whelped 2 months previously. Physical examination findings were normal with the exception of bilaterally small and soft testes. An open excisional wedge biopsy of the right testis was performed under general anesthesia. Histopathology findings supported an immunologic, autoimmune pathogenesis that had resulted in infertility over the previous 4 months. PMID- 26041597 TI - Palatability assessment of an oral recuperation fluid in healthy dogs during the perioperative period. AB - The objective of this study was to determine whether healthy dogs undergoing elective surgery will accept and prefer an oral recuperation fluid (ORF) to water during the perioperative time period and if the consumption of an ORF would lead to increased caloric intake during the final preoperative and first postoperative periods. This prospective, observational study was performed in the setting of a University Veterinary Teaching Hospital. A total of 67 healthy dogs were presented for routine ovariectomy (n = 30) or castration (n = 37). Before surgical intervention, dogs were offered an ORF to assess their voluntary acceptance of the fluid. After 2 hours, the ORF was offered alongside water to assess fluid preference. Routine castration or ovariectomy was then performed. During the immediate postoperative period, dogs were reassessed as to their acceptance and preference of the ORF. A high percentage of dogs accepted the ORF in both the preoperative (55/67, 82%) and postoperative (42/67, 63%) periods (P < .01 and P = .04, respectively). Of dogs that demonstrated a preference between the ORF and water, 87% (95% CI: 77%-93%) chose the ORF preoperatively, whereas 98% (95% CI: 87%-99.5%) chose the ORF postoperatively (P < .01 and P < .01, respectively). Dogs that consumed the ORF in each measurement period ingested a higher amount of food (measured as percentage of kilocalories offered) when compared with those that did not consume the ORF (preoperatively 83% vs. 49%, P < .01; postoperatively 51% vs. 27%, P = .01). A commercially manufactured veterinary ORF was found to be palatable, as determined by acceptance and preference testing, in healthy dogs during the preoperative and postoperative phases of routine sterilization. Further studies in dogs undergoing more intensive surgical procedures or recovering from nonsurgical illness or both are warranted. PMID- 26041598 TI - Graves' disease and Gitelman syndrome. PMID- 26041601 TI - Younger children experience lower levels of language competence and academic progress in the first year of school: evidence from a population study. AB - BACKGROUND: The youngest children in an academic year are reported to be educationally disadvantaged and overrepresented in referrals to clinical services. In this study we investigate for the first time whether these disadvantages are indicative of a mismatch between language competence at school entry and the academic demands of the classroom. METHODS: We recruited a population sample of 7,267 children aged 4 years 9 months to 5 years 10 months attending state-maintained reception classrooms in Surrey, England. Teacher ratings on the Children's Communication Checklist-Short (CCC-S), a measure of language competence, the Strengths and Difficulties Questionnaire-Total Difficulties Score (SDQ), a measure of behavioural problems, and the Early Years Foundation Stage Profile (EYFSP), a measure of academic attainment, were obtained at the end of the reception year. RESULTS: The youngest children were rated by teachers as having more language deficits, behaviour problems, and poorer academic progress at the end of the school year. Language deficits were highly associated with behaviour problems; adjusted odds ratio 8.70, 95% CI [7.25 10.45]. Only 4.8% of children with teacher-rated language deficits and 1.3% of those with co-occurring language and behaviour difficulties obtained a 'Good Level of Development' on the EYFSP. While age predicted unique variance in academic attainment (1%), language competence was the largest associate of academic achievement (19%). CONCLUSION: The youngest children starting school have relatively immature language and behaviour skills and many are not yet ready to meet the academic and social demands of the classroom. At a population level, developing oral language skills and/or ensuring academic targets reflect developmental capacity could substantially reduce the numbers of children requiring specialist clinical services in later years. PMID- 26041600 TI - Relief and Recurrence of Congestion During and After Hospitalization for Acute Heart Failure: Insights From Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF). AB - BACKGROUND: Congestion is the most frequent cause for hospitalization in acute decompensated heart failure. Although decongestion is a major goal of acute therapy, it is unclear how the clinical components of congestion (eg, peripheral edema, orthopnea) contribute to outcomes after discharge or how well decongestion is maintained. METHODS AND RESULTS: A post hoc analysis was performed of 496 patients enrolled in the Diuretic Optimization Strategy Evaluation in Acute Decompensated Heart Failure (DOSE-AHF) and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trials during hospitalization with acute decompensated heart failure and clinical congestion. A simple orthodema congestion score was generated based on symptoms of orthopnea (>=2 pillows=2 points, <2 pillows=0 points) and peripheral edema (trace=0 points, moderate=1 point, severe=2 points) at baseline, discharge, and 60-day follow-up. Orthodema scores were classified as absent (score of 0), low-grade (score of 1-2), and high grade (score of 3-4), and the association with death, rehospitalization, or unscheduled medical visits through 60 days was assessed. At baseline, 65% of patients had high-grade orthodema and 35% had low-grade orthodema. At discharge, 52% patients were free from orthodema at discharge (score=0) and these patients had lower 60-day rates of death, rehospitalization, or unscheduled visits (50%) compared with those with low-grade or high-grade orthodema (52% and 68%, respectively; P=0.038). Of the patients without orthodema at discharge, 27% relapsed to low-grade orthodema and 38% to high-grade orthodema at 60-day follow up. CONCLUSIONS: Increased severity of congestion by a simple orthodema assessment is associated with increased morbidity and mortality. Despite intent to relieve congestion, current therapy often fails to relieve orthodema during hospitalization or to prevent recurrence after discharge. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00608491, NCT00577135. PMID- 26041599 TI - Force and number of myosin motors during muscle shortening and the coupling with the release of the ATP hydrolysis products. AB - KEY POINTS: Muscle contraction is due to cyclical ATP-driven working strokes in the myosin motors while attached to the actin filament. Each working stroke is accompanied by the release of the hydrolysis products, orthophosphate and ADP. The rate of myosin-actin interactions increases with the increase in shortening velocity. We used fast half-sarcomere mechanics on skinned muscle fibres to determine the relation between shortening velocity and the number and strain of myosin motors and the effect of orthophosphate concentration. A model simulation of the myosin-actin reaction explains the results assuming that orthophosphate and then ADP are released with rates that increase as the motor progresses through the working stroke. The ADP release rate further increases by one order of magnitude with the rise of negative strain in the final motor conformation. These results provide the molecular explanation of the relation between the rate of energy liberation and shortening velocity during muscle contraction. The chemo mechanical cycle of the myosin II--actin reaction in situ has been investigated in Ca(2+)-activated skinned fibres from rabbit psoas, by determining the number and strain (s) of myosin motors interacting during steady shortening at different velocities (V) and the effect of raising inorganic phosphate (Pi) concentration. It was found that in control conditions (no added Pi ), shortening at V <= 350 nm s(-1) per half-sarcomere, corresponding to force (T) greater than half the isometric force (T0 ), decreases the number of myosin motors in proportion to the reduction of T, so that s remains practically constant and similar to the T0 value independent of V. At higher V the number of motors decreases less than in proportion to T, so that s progressively decreases. Raising Pi concentration by 10 mM, which reduces T0 and the number of motors by 40-50%, does not influence the dependence on V of number and strain. A model simulation of the myosin-actin reaction in which the structural transitions responsible for the myosin working stroke and the release of the hydrolysis products are orthogonal explains the results assuming that Pi and then ADP are released with rates that increase as the motor progresses through the working stroke. The rate of ADP release from the conformation at the end of the working stroke is also strain-sensitive, further increasing by one order of magnitude within a few nanometres of negative strain. These results provide the molecular explanation of the relation between the rate of energy liberation and the load during muscle contraction. PMID- 26041602 TI - Randomized trial comparing the velocities of the antihypertensive effects on home blood pressure of candesartan and candesartan with hydrochlorothiazide. AB - We aimed to evaluate the hypotensive effect and the time to attain the maximal antihypertensive effect (stabilization time) of 8 mg candesartan/6.25 mg hydrochlorothiazide (HCTZ) combination therapy (combination regimen) and therapy with an increased candesartan dose (12 mg; maximum dose regimen) using home blood pressure (BP) measurements. A prospective, multicenter, open-label, randomized, comparative trial was conducted. Essential hypertensive patients who failed to achieve adequate BP control (systolic BP (SBP) ? 135 mm Hg) on 8 mg candesartan alone were randomized to two groups: the combination regimen (n=103) and the maximum dose regimen (n=103). Home morning SBP reduction at 8 weeks after randomization was 11.4 +/- 1.3 mm Hg in the combination regimen and 7.8 +/- 1 .2 mm Hg in the maximum dose regimen. The combination regimen provided additional reduction of 4.0 mm Hg (95% confidence interval (CI): 0.8-7.2 mm Hg, P=0.01) in home morning SBP over the maximum dose regimen at 8 weeks after randomization. The maximal antihypertensive effect and stabilization time for home SBP were 9.4 mm Hg and 37.1 days (P<0.0001), respectively, with the combination regimen. The maximum dose regimen decreased home SBP with a very gentle slope, and estimated maximal effect and estimated stabilization time were not significant (P>0.2). The rate of achieving target BP (home morning SBP <135 mm Hg) was significantly higher with the combination regimen than with the maximum dose regimen (52.4 vs. 30.1%, P=0.002). In conclusion, changing from 8 mg candesartan to combination therapy was more effective in reducing home SBP and achieving goal BP more rapidly than increasing the candesartan dose. PMID- 26041604 TI - Induction chemotherapy with concurrent chemoradiotherapy versus concurrent chemoradiotherapy for locally advanced squamous cell carcinoma of head and neck: a meta-analysis. AB - Concurrent chemoradiotherapy (CCRT) has been considered to be the standard of care for locally advanced squamous cell carcinoma of head and neck (LA-SCCHN). Whether induction chemotherapy (IC) with CCRT will further improve the clinical outcomes or not is still unclear. We conducted a meta-analysis to compare the two regimens for LA-SCCHN. Literature searches were carried out in PubMed, Embase, Cochrane Library and Chinese Biology Medicine from inception to November 2014. Five prospective randomized controlled trials (RCTs) with 922 patients were included in meta-analysis. Results were expressed as hazard ratios (HRs) or relative risks (RRs) with 95% confidence intervals (CIs). Compared with CCRT, IC with CCRT showed no statistically significant differences in overall survival (OS), progression-free survival (PFS), overall response rate (ORR) or locoregional recurrence rate (LRR), but could increase risks of grade 3-4 febrile neutropenia (P = 0.0009) and leukopenia (P = 0.04). In contrast, distant metastasis rate (DMR) decreased (P = 0.006) and complete response rate (CR) improved (P = 0.010) for IC with CCRT. In conclusion, the current studies do not support the use of IC with CCRT over CCRT, and the further positioning of IC with CCRT as standard treatment for LA-SCCHN will come from more RCTs directly comparing IC followed by CCRT with CCRT. PMID- 26041603 TI - Plasma insulin profiles after subcutaneous injection: how close can we get to physiology in people with diabetes? AB - Many people with diabetes rely on insulin therapy to achieve optimal blood glucose control. A fundamental aim of such therapy is to mimic the pattern of 'normal' physiological insulin secretion, thereby controlling basal and meal-time plasma glucose and fatty acid turnover. In people without diabetes, insulin release is modulated on a time base of 3-10 min, something that is impossible to replicate without intravascular glucose sensing and insulin delivery. Overnight physiological insulin delivery by islet beta cells is unchanging, in contrast to requirements once any degree of hyperglycaemia occurs, when diurnal influences are evident. Subcutaneous pumped insulin or injected insulin analogues can approach the physiological profile, but there remains the challenge of responding to day-to-day changes in insulin sensitivity. Physiologically, meal-time insulin release begins rapidly in response to reflex activity and incretins, continuing with the rise in glucose and amino acid concentrations. This rapid response reflects the need to fill the insulin space with maximum concentration as early as 30 min after starting the meal. Current meal-time insulins, by contrast, are associated with a delay after injection before absorption begins, and a delay to peak because of tissue diffusion. While decay from peak for monomeric analogues is not dissimilar to average physiological needs, changes in meal type and, again, in day-to-day insulin sensitivity, are difficult to match. Recent and current developments in insulin depot technology are moving towards establishing flatter basal and closer-to-average physiological meal-time plasma insulin profiles. The present article discusses the ideal physiological insulin profile, how this can be met by available and future insulin therapies and devices, and the challenges faced by healthcare professionals and people with diabetes in trying to achieve an optimum plasma insulin profile. PMID- 26041605 TI - Exposure to cows is not associated with diarrhoea or impaired child growth in rural Odisha, India: a cohort study. AB - Exposure to animal livestock has been linked to zoonotic transmission, especially of gastrointestinal pathogens. Exposure to animals may contribute to chronic asymptomatic intestinal infection, environmental enteropathy and child under nutrition in low-income settings. We conducted a cohort study to explore the effect of exposure to cows on growth and endemic diarrhoea in children aged <5 years in a rural, low-income setting in the Indian state of Odisha. The study enrolled 1992 households with 2739 children. Height measurements were available for 824 children. Exposure to cows was measured as (1) the presence of a cowshed within or outside the compound, (2) the number of cows owned by a household, and (3) the number of cowsheds located within 50 m of a household. In a sub-study of 518 households, fly traps were used to count the number of synanthropic flies that may act as vectors for gastrointestinal pathogens. We found no evidence that environmental exposure to cows contributes to growth deficiency in children in rural India, neither directly by affecting growth, nor indirectly by increasing the risk of diarrhoea. We found no strong evidence that the presence of a cowshed increased the number synanthropic flies in households. PMID- 26041606 TI - Mortality Risk in Alcoholic Patients in Northern Italy: Comorbidity and Treatment Retention Effects in a 30-Year Follow-Up Study. AB - AIMS: To analyse the general and cause-specific mortality over the course of 30 years among subjects treated for alcohol use disorders (AUD) in Northern Italy. METHODS: Cohort of 2499 subjects followed-up for mortality until 31 December 2012. Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were computed to compare the mortality in the cohort with the general population. Cox regression was used to study the effect of psychiatric disorders, burden of physical comorbidity and retention in treatment on mortality, controlling for socio-demographic factors. RESULTS: During the follow-up, 435 deaths occurred. Compared with the general population, alcoholics experienced a 5-fold increased mortality (SMR: 5.53; 95% CI: 5.03, 6.07). Significant excess mortality was observed for a range of specific causes: infections, cancers, cardiovascular, respiratory and digestive system diseases as well as violent causes. In multivariate analysis, the hazard of dying was lower for female gender (hazard ratio [HR]: 0.62; 95% CI: 0.46, 0.84) and for increasing length of retention in treatment (HR for third tertile vs first tertile: 0.43; 95% CI: 0.32, 0.57). Burden of physical comorbidity was associated with increased hazard of dying (HR for 3+ comorbidities vs no comorbidities: 4.40; 95% CI: 2.91, 6.66). Psychiatric comorbidity was not associated with mortality. CONCLUSIONS: Despite the harmful effect of AUD, retention in treatment represented a protective factor against death, suggesting that strategies supporting primary medical- and social-care may effectively reduce premature mortality. PMID- 26041607 TI - Serotonin and Dopamine Candidate Gene Variants and Alcohol- and Non-Alcohol Related Aggression. AB - AIMS: Aggressive and criminal traits have a complex genetic background which interacts with environmental factors. Alcohol intoxication has been related to lower thresholds of aggressive behaviors. In this association study of two independent samples, a number of candidate gene variants (5HT2A T102C, 5-HTTLPR, DRD Ins-141Del, DAT1 VNTR) were related to violent criminal behavior and alcohol related aggressive traits. METHOD: Treatment-seeking alcohol-dependent individuals (293 patients and 499 controls from Germany, 180 patients and 402 controls from Poland) underwent a Semi-Structured Assessment for the Genetics of Alcoholism interview which gathered information on alcohol-related violence and criminal behaviors, beside alcohol dependence characteristics. RESULTS: Patients with a history of violent or non-violent crime were more often male, had an earlier onset of alcoholism, more withdrawal seizures and delirium tremens, and were more likely to have a history of suicide attempts. No significant association between candidate gene variants and criminal behavior was detected. 5HTTLPR variant was related to one characteristic of alcohol-related violence. CONCLUSIONS: With findings from genome-wide association studies linking aggression-related traits to second messenger systems, further studies are needed to determine the genetic underpinnings of non-alcohol and alcohol-related aggression. PMID- 26041608 TI - PPARalpha Agonists Reduce Alcohol Drinking: Do They Act in the Brain or in the Liver? PMID- 26041609 TI - Surveillance of US Death Rates from Chronic Diseases Related to Excessive Alcohol Use. AB - AIMS: To assess the utility of multiple-cause (MC) death records for surveillance of US mortality rates from chronic causes related to excessive alcohol use. METHODS: The Alcohol-Related Disease Impact (ARDI) resource produced estimates of the population 'alcohol attributable fraction' (AAF) due to excessive drinking for each alcohol-related (AAF > 0%) cause of death, and used AAFs to estimate numbers of alcohol-related deaths from alcohol-related underlying causes (UC) in adults age 20-64 and 65+ years in 2006-2010. For surveillance, this study used MC death file to identify individual deaths (2006-2010) with an 'alcohol-induced' cause (AAF = 100%) anywhere on the certificate, and to obtain US rates of premature death (ages 15-64 and 65-74 years) for 1999-2012. RESULTS: Using the selected MC records, numbers of deaths from alcohol-related chronic UC (2006 2010) were 81% of ARDI estimates for age 20-64, but only 40% for 65+ years. The MC records identified substantial numbers of deaths from causes (e.g. certain infectious diseases) not included as alcohol-related in ARDI, but included in surveillance of premature death rates for chronic UC. Also, premature death rates for chronic alcohol-induced causes using only the UC (as in routine mortality statistics) were only about half the rates based on MC; all rates increased in recent years but some reached statistical significance only by using MC. CONCLUSIONS: Using MC records underestimated total US deaths from alcohol-related chronic causes as the UC, but enhanced surveillance of rates for premature deaths involving chronic causes that may be related to excessive alcohol use. PMID- 26041610 TI - Risk Factors Measured During Medical School for Later Hazardous Drinking: A 10 year, Longitudinal, Nationwide Study (NORDOC). AB - AIMS: To investigate the prevalence and temporal patterns of hazardous drinking and risk factors during medical school for future hazardous drinking among doctors. METHODS: Two cohorts of graduating medical students (N = 1052) from all four Norwegian universities (NORDOC) were surveyed in their final year of medical school training (1993/94 and 1999) (T1) and again 4 (T2) and 10 (T3) years later. Longitudinally, 53% (562/1052) of the sample responded at all three time points. Hazardous drinking was defined as drinking five or more drinks during one session at least 2-3 times per month. Predictors of hazardous drinking, identified by logistic regression models after controlling for cohort, included a parental history of alcohol problems, having children, no religious activity, use of alcohol to cope with tension and some personality traits. RESULTS: There was a significant decline in the prevalence of hazardous drinking from T1 (14%) to T2 (10%) but not from T2 to T3 (8%). Approximately 23% of hazardous drinkers at T1 remained hazardous drinkers at T3 (N = 18). At T2, significant adjusted predictors included male gender (OR = 2.0, P = 0.04), use of alcohol as a coping strategy (OR = 2.2, P = 0.03) and hazardous drinking at T1 (OR = 9.8, P < 0.001). The significant adjusted predictors at T3 included older age (OR = 1.1, P = 0.01), male gender (OR = 3.6, P = 0.002) and hazardous drinking at T1 (OR = 7.5, P < 0.001). CONCLUSIONS: Hazardous drinking and drinking to cope with tension during medical school were the most important predictors of later hazardous drinking and should be targets of preventive efforts in medical schools. PMID- 26041611 TI - Why musical memory can be preserved in advanced Alzheimer's disease. AB - Musical memory is considered to be partly independent from other memory systems. In Alzheimer's disease and different types of dementia, musical memory is surprisingly robust, and likewise for brain lesions affecting other kinds of memory. However, the mechanisms and neural substrates of musical memory remain poorly understood. In a group of 32 normal young human subjects (16 male and 16 female, mean age of 28.0 +/- 2.2 years), we performed a 7 T functional magnetic resonance imaging study of brain responses to music excerpts that were unknown, recently known (heard an hour before scanning), and long-known. We used multivariate pattern classification to identify brain regions that encode long term musical memory. The results showed a crucial role for the caudal anterior cingulate and the ventral pre-supplementary motor area in the neural encoding of long-known as compared with recently known and unknown music. In the second part of the study, we analysed data of three essential Alzheimer's disease biomarkers in a region of interest derived from our musical memory findings (caudal anterior cingulate cortex and ventral pre-supplementary motor area) in 20 patients with Alzheimer's disease (10 male and 10 female, mean age of 68.9 +/- 9.0 years) and 34 healthy control subjects (14 male and 20 female, mean age of 68.1 +/- 7.2 years). Interestingly, the regions identified to encode musical memory corresponded to areas that showed substantially minimal cortical atrophy (as measured with magnetic resonance imaging), and minimal disruption of glucose metabolism (as measured with (18)F-fluorodeoxyglucose positron emission tomography), as compared to the rest of the brain. However, amyloid-beta deposition (as measured with (18)F-flobetapir positron emission tomography) within the currently observed regions of interest was not substantially less than in the rest of the brain, which suggests that the regions of interest were still in a very early stage of the expected course of biomarker development in these regions (amyloid accumulation -> hypometabolism -> cortical atrophy) and therefore relatively well preserved. Given the observed overlap of musical memory regions with areas that are relatively spared in Alzheimer's disease, the current findings may thus explain the surprising preservation of musical memory in this neurodegenerative disease. PMID- 26041612 TI - The strange case of Dr. William Gowers and Mr. Sherlock Holmes. PMID- 26041613 TI - Cerebellar neurochemical alterations in spinocerebellar ataxia type 14 appear to include glutathione deficiency. AB - Autosomal dominant ataxia type 14 (SCA14) is a rare usually adult-onset progressive disorder with cerebellar neurodegeneration caused by mutations in protein kinase C gamma. We set out to examine cerebellar and extracerebellar neurochemical changes in SCA14 by MR spectroscopy. In 13 SCA14 patients and 13 healthy sex- and age-matched controls, 3-T single-voxel brain proton MR spectroscopy was performed in a cerebellar voxel of interest (VOI) at TE = 30 ms to obtain a neurochemical profile of metabolites with short relaxation times. In the cerebellum and in additional VOIs in the prefrontal cortex, motor cortex, and somatosensory cortex, a second measurement was performed at TE = 144 ms to mainly extract the total N-acetyl-aspartate (tNAA) signal besides the signals for total creatine (tCr) and total choline (tCho). The cerebellar neurochemical profile revealed a decrease in glutathione (6.12E-06 +/- 2.50E-06 versus 8.91E-06 +/- 3.03E-06; p = 0028) and tNAA (3.78E-05 +/- 5.67E-06 versus 4.25E-05 +/- 5.15E-06; p = 0023) and a trend for reduced glutamate (2.63E-05 +/- 6.48E-06 versus 3.15E 05 +/- 7.61E-06; p = 0062) in SCA14 compared to controls. In the tNAA-focused measurement, cerebellar tNAA (296.6 +/- 42.6 versus 351.7 +/- 16.5; p = 0004) and tCr (272.1 +/- 25.2 versus 303.2 +/- 31.4; p = 0004) were reduced, while the prefrontal, somatosensory and motor cortex remained unaffected compared to controls. Neuronal pathology in SCA14 detected by MR spectroscopy was restricted to the cerebellum and did not comprise cortical regions. In the cerebellum, we found in addition to signs of neurodegeneration a glutathione reduction, which has been associated with cellular damage by oxidative stress in other neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia. PMID- 26041614 TI - Magnetization transfer ratio in lesions rather than normal-appearing brain relates to disability in patients with multiple sclerosis. AB - Magnetization transfer ratio (MTR) is a semi-quantitative measure that seems to correlate with the degree of myelin loss and generally tissue destruction in multiple sclerosis (MS). Our objective was to comprehensively assess the MTR of lesions and normal appearing (NA) tissue separately in the white matter (WM), the cortex, the thalamus and the basal ganglia (BG) and determine their relative contribution to disability. In this cross-sectional study 71 patients were included (59 with relapsing-remitting MS, 12 with secondary progressive MS). We used a three-dimensional MTR sequence with high spatial resolution, based on balanced steady-state free precession. Mean MTR was calculated for lesions and NA tissue separately for each tissue type. Lesional MTR was lower than normal appearing MTR in WM, cortex and thalamus. In the regression analysis, MTR of cortical lesions (beta = -0.23, p = 0.05) and MTR of WML (beta = -0.21, p = 0.08) were related by trend to the expanded disability status scale. MTR of WML significantly predicted the paced auditory serial-addition test (beta = 0.35, p = 0.004). MTR of normal-appearing tissue did not relate to any outcome. Our results suggest that MTR of lesions in the white matter and cortex rather than of normal appearing tissue relates to disability in patients with MS. PMID- 26041615 TI - Eye-tracking controlled cognitive function tests in patients with amyotrophic lateral sclerosis: a controlled proof-of-principle study. AB - Amyotrophic lateral sclerosis (ALS) primarily affects motor and speech abilities. In addition, cognitive functions are impaired in a subset of patients. There is a need to establish an eye movement-based method of neuropsychological assessment suitable for severely physically impaired patients with ALS. Forty-eight ALS patients and thirty-two healthy controls matched for age, sex and education performed a hand and speech motor-free version of the Raven's coloured progressive matrices (CPM) and the D2-test which had been especially adapted for eye-tracking control. Data were compared to a classical motor-dependent paper pencil version. The association of parameters of the eye-tracking and the paper pencil version of the tests and the differences between and within groups were studied. Subjects presented similar results in the eye-tracking and the corresponding paper-pencil versions of the CPM and D2-test: a correlation between performance accuracy for the CPM was observed for ALS patients (p < 0.001) and controls (p < 0.001) and in the D2-test for controls (p = 0.048), whereas this correlation did not reach statistical significance for ALS patients (p = 0.096). ALS patients performed worse in the CPM than controls in the eye-tracking (p = 0.053) and the paper-pencil version (p = 0.042). Most importantly, eye-tracking versions of the CPM (p < 0.001) and the D2-test (p = 0.024) reliably distinguished between more and less cognitively impaired patients. Eye-tracking based neuropsychological testing is a promising approach for assessing cognitive deficits in patients who are unable to speak or write such as patients with severe ALS. PMID- 26041616 TI - Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life. AB - Sustained-release fampridine (fampridine-SR) improves gait velocity and self perceived capacities in people with multiple sclerosis (MS). However, little is known about the treatment's effect on temporospatial gait parameters, walking endurance, general fatigue, hand function and quality of life (QoL). We therefore sought to evaluate these parameters in a real-world setting: 120 consecutive, eligible patients with MS were evaluated at baseline (D0) and after two weeks (D14) of fampridine-SR. Lastly, D14 responders were again evaluated after three months (M3). Response to treatment was defined as a 15% improvement in at least one of the following tests: the Timed 25-Foot-Walk (T25FW), the 2-min walk test (2MWT) and the Multiple Sclerosis Walking Scale (MSWS-12). Eighty-three patients (74%) were found to be responders. The response rate was lower when assessed as a 20% improvement in the T25FW (50.9%), and this difference was particularly marked for fast-walking subjects (i.e. T25FW <8 s at baseline). Responders displayed mean improvements (at D14 and M3, respectively) of 34.5 and 35.5% in the T25FW, 39 and 36.7% in the 2MWT and 19 and 11.6% in the MSWS-12. The increase in gait velocity was due to both a higher cadence and a greater step length. Responders showed also significant, lasting reductions in fatigue (visual analogue scale and the Fatigue Severity Scale; p < 10(-4) at D14 and <0.01 at M3) and significant, lasting improvements in hand function (9 Hole Peg Test; p < 0.05) and QoL (SF-12; p < 0.01). In conclusion, several MS-induced symptoms other than gait velocity may be improved by fampridine-SR, even if this remains to be more specifically evaluated in future studies. PMID- 26041619 TI - Novel photochromic infinite coordination polymer particles derived from a diarylethene photoswitch. AB - A novel infinite coordination polymer (DAE-ICP) based on zinc nitrite and a diarylethene photoswitch, with reversible photochromic properties in solution and the solid state upon applying photostimuli, was synthesized and characterized by FT-IR, EDX, FE-SEM and FE-TEM. PMID- 26041618 TI - Would you bet on PET? Evaluation of the significance of positive PET scan results post-microwave ablation for non-small cell lung cancer. AB - Fluodeoxyglucose-positron emission tomography (FDG-PET) imaging is an acknowledged modality for the follow-up of solid tumours treated with thermal ablation, with persistent or new FDG uptake at the ablation site considered to be a reliable indicator of local recurrence. Several cases of proven false-positive FDG-PET scans are illustrated in this pictorial essay with uptake at the site of the ablated tumour, remote from the ablated lesion and in mediastinal and hilar lymph nodes. Positive FDG-PET scans post-thermal ablation of lung tumours therefore cannot always reliably predict local tumour recurrence or nodal spread. It is important to be familiar with FDG uptake patterns post-ablation and their significance. FDG-PET avid lesions post-ablation may require histological confirmation before further therapy is planned or management is changed. PMID- 26041617 TI - Treating relapsing-remitting multiple sclerosis: therapy effects on brain atrophy. AB - Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system with a complex and heterogeneous pathology that may ultimately lead to neurodegeneration and brain atrophy. Brain volume loss in MS is known to occur early in the disease course and to be clinically relevant, as it has been related to disability progression. Nowadays, brain volume loss is relatively easy to measure with different automated, reproducible and accurate software tools. Therefore, most of (if not all) the newest clinical trials have incorporated brain volume outcomes as a measure of treatment effect. With this review, we aimed to update and summarize all existing data regarding brain volume and RRMS treatment in clinical trials as well as in open-label observational studies of drugs with positive results in its primary outcome in at least one phase III trial as of March 2014. PMID- 26041620 TI - Sequential culture with Torulaspora delbrueckii and Saccharomyces cerevisiae and management of fermentation temperature to improve cherry wine quality. AB - BACKGROUND: There has been limited research on the use of non-Saccharomyces yeasts for the production of cherry wines. This work used an autochthonous Torulaspora delbrueckii strain 49 (TD49) in association with a commercial S. cerevisiae RC212 yeast, to investigate the effect of multi-starter culture (sequential inoculation and simultaneous inoculation) and fermentation temperature on the quality of cherry wines. RESULTS: Both TD49 and RC212 proliferated during alcoholic fermentation (AF) under sequential inoculation conditions, whereas in the case of simultaneous inoculation, TD49 increased slowly at first and then declined sharply near the fermentation end. The analytical profile showed that both mixed fermentations produced lower levels of volatile acidy and higher levels of aromatic compounds than those from RC212 mono culture. During sensory analysis, wines from sequential fermentation obtained the highest score, mainly due to the higher intensity in 'fruity' and 'floral' characters. As for the influence of temperature, a low temperature (20 degrees C) enhanced TD49 persistence during AF, but the sensory quality decreased anyway; 30 degrees C resulted in decreases in most measured descriptors. Therefore, 25 degrees C was selected as the best culture temperature. CONCLUSION: TD49/RC212 sequential inoculation and fermentation at 25 degrees C significantly enhanced the cherry wine quality. PMID- 26041621 TI - Individual, social and contextual factors associated with psychiatric care outcomes among patients with intellectual disabilities in the emergency department. AB - BACKGROUND: Individuals with intellectual disabilities (ID) are disproportionately high users of psychiatric emergency services. Despite the demand for psychiatric assessments in the emergency department (ED), no clear guidelines have been established as to what factors should guide clinical decision-making processes. The current study aimed to explore individual, social and contextual factors related to psychiatric care outcomes among patients with ID in the emergency department. METHOD: Emergency department charts were reviewed for 66 individuals with ID who visited the emergency department during a psychiatric crisis. RESULTS: Standardised crisis severity scores were significantly higher in patients seen by psychiatrists as compared with patients who did not receive psychiatric consultations in the emergency department. A significantly greater proportion of patients with moderate or severe levels of ID (vs. borderline/mild) received psychiatric consultations. Emergency department visits resulting in inpatient hospital admission did not differ from those that did not, with the exception of the level of ID: patients admitted to psychiatric inpatient care were more likely to have moderate or severe levels of ID. CONCLUSIONS: The psychiatric care experiences of patients with ID in the emergency department appear highly variable. Further research focused on emergency department clinical decision-making practices concerning this population is warranted. PMID- 26041622 TI - Revisiting molecular serotyping of Streptococcus pneumoniae. AB - BACKGROUND: Ninety-two Streptococcus pneumoniae serotypes have been described so far, but the pneumococcal conjugate vaccine introduced in the Brazilian basic vaccination schedule in 2010 covers only the ten most prevalent in the country. Pneumococcal serotype-shifting after massive immunization is a major concern and monitoring this phenomenon requires efficient and accessible serotyping methods. Pneumococcal serotyping based on antisera produced in animals is laborious and restricted to a few reference laboratories. Alternatively, molecular serotyping methods assess polymorphisms in the cps gene cluster, which encodes key enzymes for capsular polysaccharides synthesis in pneumococci. In one such approach, cps RFLP, the PCR amplified cps loci are digested with an endonuclease, generating serotype-specific fingerprints on agarose gel electrophoresis. METHODS: In this work, in silico and in vitro approaches were combined to demonstrate that XhoII is the most discriminating endonuclease for cps-RFLP, and to build a database of serotype-specific fingerprints that accommodates the genetic diversity within the cps locus of 92 known pneumococci serotypes. RESULTS: The expected specificity of cps-RFLP using XhoII was 76% for serotyping and 100% for serogrouping. The database of cps-RFLP fingerprints was integrated to Molecular Serotyping Tool (MST), a previously published web-based software for molecular serotyping. In addition, 43 isolates representing 29 serotypes prevalent in the state of Minas Gerais, Brazil, from 2007 to 2013, were examined in vitro; 11 serotypes (nine serogroups) matched the respective in silico patterns calculated for reference strains. The remaining experimental patterns, despite their resemblance to their expected in silico patterns, did not reach the threshold of similarity score to be considered a match and were then added to the database. CONCLUSION: The cps RFLP method with XhoII outperformed the antisera-based and other molecular serotyping methods in regard of the expected specificity. In order to accommodate the genetic variability of the pneumococci cps loci, the database of cps-RFLP patterns will be progressively expanded to include new variant in vitro patterns. The cps-RFLP method with endonuclease XhoII coupled with MST for computer assisted interpretation of results may represent a relevant contribution to the real time detection of changes in regional pneumococci population diversity in response to mass immunization programs. PMID- 26041623 TI - The Roles of Endoscope in Aneurysmal Surgery. AB - The neuroendoscope, with its higher magnification, better observation, and additional illumination, can provide us information that may not be available with the microscope in aneurysm surgery. Furthermore, recent advancement of the holding systems for the endoscope allows surgeons to perform microsurgical manipulation using both hands under the simultaneous endoscopic and microscopic monitoring. With this procedure, surgeons can inspect hidden structures, dissect perforators at the back of the aneurysm, identify important vessel segments without retraction of the aneurysm or arteries, and check for completion of clipping. In addition, we have recently applied endoscopic indocyanine green video angiography to aneurysm surgery. This newly developed technique can offer real-time assessment of the blood flow of vasculatures in the dead angles of the microscope, and will reduce operative morbidity related to vascular occlusion, improve the durability of aneurysm surgery by reducing incomplete clipping, and thus promote the outcome of aneurysm surgery. PMID- 26041624 TI - Morphology Parameters for Mirror Posterior Communicating Artery Aneurysm Rupture Risk Assessment. AB - Recent studies have shown that posterior communicating artery (PComA) aneurysms are more likely to rupture. However, surgical intervention for PComA aneurysms may be associated with increased treatment-related morbidity rate. Therefore, it is meaningful to investigate the factors related to PComA aneurysm rupture. The purpose of this study was to identify morphological parameters that significantly correlate with PComA aneurysm rupture. We divided 14 pairs of mirror posterior communicating artery aneurysms (PComA-MANs) into ruptured and unruptured groups. Computed tomography angiography (CTA) imaging was evaluated with three dimensional (3D) Slicer to generate models of the aneurysms and surrounding vasculature. Nine morphological parameters [size, height, width, neck width, aspect ratio (AR), bottleneck factor (BNF), height/width ratio (H/W), size ratio (SR), and bleb formation] were examined in the two groups for significance with respect to rupture. By contrast, statistically significant differences were found in ruptured and unruptured group for size, AR, BNF, SR, and bleb formation (P < 0.05). Parameters that had no significant differences between the two groups were height (P = 0.103), width (P = 0.078), neck width (P = 0.808), and H/W (P = 0.417). We conclude that MANs may be a useful model for the morphological analysis of intracranial aneurysm rupture. Larger size, higher AR, BNF, SR, and bleb formation may be related to rupture of PComA aneurysms. Larger sample studies minimizing the interference from patient-related factors and aneurysm type were expected for acquiring more accurate assessment of the relationship between these parameters and PComA aneurysm rupture. PMID- 26041625 TI - Intraoperative Angiography Using Portable Fluoroscopy Unit in the Treatment of Vascular Malformation. AB - Intraoperative angiography (IOA) is employed for the treatment of the complicated cases in neurological surgery. The IOA is usually performed with OEC portable digital subtraction angiography (DSA) unit. We are performing IOA with portable fluoroscopy unit with simple DSA function and report its usefulness on neurosurgical treatment. IOA or hybrid treatment with mobile fluoroscopy system was performed for 9 cases [cerebral arteriovenous malformation (AVM), 3; cranial dural arteriovenous fistula (AVF), 2; and spinal AVM/AVF, 4]. Thus, ex vivo analysis was performed comparing image quality of portable fluoroscopy unit and conventional DSA system. Although the resolution of portable fluoroscopy unit is not so high compared to conventional DSA system, the existence of the vascular lesions such as cerebral aneurysm, cerebral AVM, and spinal dural AVF were detected. The operation of portable fluoroscopy unit was simple and no special assistance was required. The complication related to the catheterization or IOA did not occur. IOA with portable fluoroscopy unit was useful for the identification of vascular lesion and has advantage on the cost benefit. PMID- 26041626 TI - Cerebral Infarction following Acute Subdural Hematoma in Infants and Young Children: Predictors and Significance of FLAIR Vessel Hyperintensity. AB - A phenomenon of cerebral infarction following acute subdural hematoma (ASDH) in infants and young children, termed cerebral infarction following ASDH (CIASDH), has been well recognized, though both its mechanisms and risk factors have been poorly understood. The purpose of the present study was to investigate the predictors for CIASDH in a population of ASDH, and to evaluate the imaging studies to presume the mechanisms of CIASDH. We retrospectively examined consecutive children 6 years of age or younger, who were diagnosed with ASDH and were admitted to our hospital between 2000 and 2014. In 57 consecutive children with ASDH, 12 (21.1%) developed CIASDH. The multivariate analysis revealed five predictors for CIASDH: presence of seizure, consciousness disturbance at admission, absence of skull fracture, hematoma thickness >= 5 mm on computed tomography (CT), and midline shift >= 3 mm on CT (p < 0.05). In three of six patients (50%) undergoing magnetic resonance (MR) imaging/fluid-attenuated inversion recovery (FLAIR) within 5 days of admission, serpentine hyperintensities in the subarachnoid space (FLAIR vessel hyperintensities) were demonstrated. MR angiography showed neither occlusion nor stenosis of the cerebral arteries. Single photon emission CT performed at admission in one patient showed a cerebral blood flow reduction in the ASDH side. All the children with CIASDH showed unfavorable outcomes at discharge. Children showing multiple predictors at admission should be carefully observed for development of CIASDH. Evaluation of the imaging studies suggested that a blood flow disturbance in the level of peripheral arteries to microcirculation was one candidate for possible mechanisms to induce the CIASDH. PMID- 26041627 TI - Effectiveness of Acute Phase Hybrid Assistive Limb Rehabilitation in Stroke Patients Classified by Paralysis Severity. AB - The purpose of the present study was to investigate the effectiveness of acute phase hybrid assistive limb (HAL) rehabilitation training for patients after stroke by measuring the difference in the severity of paralysis. Fifty-three acute stroke patients were enrolled in this prospective cohort study. HAL training was administered about twice per week, and the mean number of sessions was 3.9 +/- 2.7. The walking training was performed on a treadmill with individually adjustable body weight support and speed and there was a 10-m walk test (10MWT) before and after each session. Assessment at baseline and at endpoint consisted of the Glasgow Coma Scale (GCS), Revised Hasegawa's Dementia Scale (HDS-R), Brunnstrom stage (Brs), Functional Independence Measure (FIM), Barthel index (BI), and 10MWT. We measured these assessments at the first walking training session and at the end of the final training session without the HAL. To evaluate the feasibility of training with the HAL, the outcome measures of BI, FIM, and speed and number of steps of 10MWT were compared before and after training using a paired Wilcoxon's signed-rank test in different Brs. Except for Brs IV, the Brs III or higher subgroups displayed significant amelioration in BI, and the Brs III subgroup displayed significant amelioration in FIM. The Brs V and VI subgroups displayed significant amelioration in 10-m walking speed and steps. In acute phase rehabilitation after stroke, it is thought that the HAL is more effective for patients with less lower-limb paralysis, such as Brs III or higher. PMID- 26041628 TI - Results of Prospective Cohort Study on Symptomatic Cerebrovascular Occlusive Disease Showing Mild Hemodynamic Compromise [Japanese Extracranial-Intracranial Bypass Trial (JET)-2 Study]. AB - The purpose of this study is to determine the true threshold of cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) for subsequent ischemic stroke without extracranial-intracranial (EC-IC) bypass surgery in patients with hemodynamic ischemia due to symptomatic major cerebral arterial occlusive diseases. Patients were categorized based on rest CBF and CVR into four subgroups as follows: Group A, 80% < CBF < 90% and CVR < 10%; Group B, CBF < 80% and 10% < CVR < 20%; Group C, 80% < CBF < 90% and 10% < CVR < 20%; and Group D, CBF < 90% and 20% < CVR < 30%. Patients were followed up for 2 years under best medical treatment by the stroke neurologists. Primary and secondary end points were defined as all adverse events and ipsilateral stroke recurrence respectively. A total of 132 patients were enrolled. All adverse events were observed in 9 patients (3.5%/year) and ipsilateral stroke recurrence was observed only in 2 patients (0.8%/year). There was no significant difference among the four subgroups in terms of the rate of both primary and secondary end points. Compared with the medical arm of the Japanese EC-IC bypass trial (JET) study including patients with CBF < 80% and CVR < 10% as a historical control, the incidence of ipsilateral stroke recurrence was significantly lower in the present study. Patients with symptomatic major cerebral arterial occlusive diseases and mild hemodynamic compromise have a good prognosis under medical treatment. EC-IC bypass surgery is unlikely to benefit patients with CBF > 80% or CVR > 10%. PMID- 26041629 TI - Intraoperative Arachnoid Plasty Has Possibility to Prevent Chronic Subdural Hematoma after Surgery for Unruptured Cerebral Aneurysms. AB - Some patients develop chronic subdural hematomas (CSDHs) after the clipping/coating of unruptured aneurysms. The risk factors are not well understood and while no preventive methods are currently available, arachnoid plasty (ARP) may intercept the development of postoperative CSDH. We investigated the risk factors for CSDH and the usefulness of ARP to prevent postoperative CSDH. Between January 2009 and June 2013, 393 patients underwent 416 aneurysm surgeries via the pterional approach at Kushiro Kojinkai Memorial Hospital. Of these, 394 aneurysms (371 patients) were included in this study. Using multivariate analysis we evaluated the relationship between the patient demographics and clinical characteristics, and the development of postoperative symptomatic CSDH. We also studied the effect of ARP performed during aneurysm surgery. We found that symptomatic CSDH developed after 20 (5.1%) of the 394 operations; it was addressed by burr hole surgery and evacuation/irrigation. Male gender, advanced age, and oral anticoagulant therapy were significant risk factors for CSDH. Additive ARP, performed in the course of 132 surgeries (33.5%) was found to be a significant negative risk factor. The incidence of CSDH was significantly lower in patients who had undergone ARP than in patients who had not undergone it (0.8% vs. 7.3%, p < 0.01). We first report that ARP is useful for the prevention of CSDH in patients treated by aneurysm surgery. PMID- 26041630 TI - Neuroradiological Manifestations of Hereditary Hemorrhagic Telangiectasia in 139 Japanese Patients. AB - The purpose of this study is to report the neuroradiological manifestations of hereditary hemorrhagic telangiectasia (HHT). One hundred and thirty-nine Japanese HHT patients (73 men and 66 women, aged 2-78 years) were included in this study. Diagnosis of HHT was based on genetic analysis and/or clinical diagnosis of Curacao. They included 68 HHT1 and 37 HHT2 patients. Essentially, all patients underwent brain magnetic resonance imaging (MRI) and pulmonary computed tomography (CT). Contrast enhanced studies of brain MRI and hepatic CT were performed in a subset of patients. Catheter cerebral angiography was performed when indicated. Their neuroradiological features were reviewed retrospectively. Various imaging abnormalities were found. Brain arteriovenous malformations (AVMs) were observed in 27/136 patients (19.9%, 21 patients with HHT1 and 1 patient with HHT2). Pulmonary arteriovenous fistulas (AVFs) were found in 73/137 patients (65.2%, 45 patients with HHT1 and 6 patients with HHT2). Cerebral infarction and brain abscess were found in 17 patients and 3 patients with pulmonary AVFs, respectively. T1 high lesions in the basal ganglia suggestive of porto-venous shunts were observed in 51/136 patients (37.5%, 9 patients with HHT1 and 28 patients with HHT2). Hepatic AVMs were observed in 61/136 patients (44.9%, 15 patients in HHT1 and 29 patients in HHT2). Brain AVMs and pulmonary AVFs were more common in HHT1 than in HHT2 (both p < 0.01), but hepatic AVMs were conversely more common in HHT2 than in HHT1 (p < 0.01). In conclusion, HHT patients present with a variety of neuroradiological manifestations, which are related to substantial causes of morbid-mortality in HHT. PMID- 26041631 TI - Evidence for Cerebral Hemodynamic Measurement-based Therapy in Symptomatic Major Cerebral Artery Disease. AB - In patients with atherosclerotic internal carotid artery or middle cerebral artery occlusive disease, chronic reduction in cerebral perfusion pressure (chronic hemodynamic compromise) increases the risk of ischemic stroke and can be detected by directly measuring hemodynamic parameters. However, strategies for selecting treatments based on hemodynamic measurements have not been clearly established. Bypass surgery has been proven to improve hemodynamic compromise. However, the benefit of bypass surgery for reducing the stroke risk in patients with hemodynamic compromise is controversial. The results of the two randomized controlled trials were inconsistent. Hypertension is a major risk factor for stroke, and antihypertensive therapy provides general benefit to patients with symptomatic atherosclerotic major cerebral artery disease. However, the benefit of strict control of blood pressure for reducing the stroke risk in patients with hemodynamic compromise is a matter of debate. The results of the two observational studies were different. We must establish strategies for selecting treatments based on hemodynamic measurements in atherosclerotic major cerebral artery disease. PMID- 26041632 TI - High-resolution MRI using orbit surface coils for the evaluation of metastatic risk factors in 143 children with retinoblastoma: Part 1: MRI vs. histopathology. AB - INTRODUCTION: A reliable detection of metastatic risk factors is important for children with retinoblastoma to choose the right therapeutic regimen. First studies using high-resolution magnetic resonance imaging (MRI) with orbit surface coils were promising. The aim of this study was therefore to evaluate the ability of high-resolution MRI to detect metastatic and especially advanced metastatic risk factors in a large group of children with retinoblastoma. METHODS: One hundred forty-three consecutive children with retinoblastoma (148 enucleated eyes, 64 girls, 79 boys, mean age 19.7 +/- 15.3) who received pretherapeutical high-resolution MRI with orbit surface coils on 1.5 T MR scanner systems between 2007 and 2012 and subsequent primary enucleation within 14 days were included in this retrospective study. Image analysis was performed by two neuroradiologists experienced in ocular imaging in consensus. Histopathology served as gold standard. RESULTS: Sensitivity/specificity for the detection of metastatic risk factors using high-resolution MRI with orbit surface coils were 60 %/88.7 % for postlaminar optic nerve infiltration, 65.5 %/95.6 % for choroidal invasion, 100 %/99.3 % for scleral invasion, and 100 %/100 % for peribulbar fat invasion, respectively. The results increased for the detection of advanced metastatic risk factors, 81.8 %/89.1 % for deep postlaminar optic nerve infiltration, 70.6 %/97.6 % for massive choroidal invasion. CONCLUSIONS: High-resolution MRI is clinically valuable for the detection of metastatic, especially of advanced metastatic risk factors in children with retinoblastoma. PMID- 26041633 TI - Erratum to: State-of-the-art MRI techniques in neuroradiology: principles, pitfalls, and clinical applications. PMID- 26041634 TI - A decade of progress in the understanding, prevention and treatment of age related macular degeneration in Singapore. PMID- 26041635 TI - Anti-BP180 NC16A IgG Titres as an Indicator of Disease Activity and Outcome in Asian Patients with Bullous Pemphigoid. AB - INTRODUCTION: Anti-BP180 IgG titres were observed to parallel disease activity in case series of bullous pemphigoid (BP). This study aimed to examine whether anti BP180 titres are an indicator of disease severity, clinical course and outcome in Asian patients with BP. MATERIALS AND METHODS: This was a prospective observational study conducted between March 2005 and March 2008 in the Immunodermatology Clinic at the National Skin Centre, Singapore. Disease activity and anti-BP180 IgG titres were measured 4-weekly for 12 weeks and during disease flares and clinical remission. Associations between anti-BP180 titres and disease activity, disease flare, clinical remission and cumulative prednisolone dose were examined. RESULTS: Thirty-four patients with newly diagnosed BP were recruited. Median follow-up duration was 3 years. Notable correlations between disease activity and anti-BP180 titres were at baseline (r = 0.51, P = 0.002), and disease flare (r = 0.85, P <0.001). Lower titres at Week 12 were associated with greater likelihood of clinical remission (P = 0.036). Post hoc, patients with anti-BP180 titres above 87.5 U/mL at time of diagnosis who reached remission within 2 years of diagnosis received significantly higher cumulative doses (mg/kg) of prednisolone (median, 72.8; range, 56.5 to 127.1) than those with titres <87.5 U/mL (median, 44.6; range, 32.5 to 80.8); P = 0.025). CONCLUSION: Anti-BP180 titres may be a useful indicator of disease activity at time of diagnosis and at disease flare. Lower titres at Week 12 may predict greater likelihood of clinical remission. Titres above 87.5 U/mL at time of diagnosis may suggest the need for higher cumulative doses of prednisolone to achieve remission within 2 years. PMID- 26041636 TI - An External Independent Validation of APACHE IV in a Malaysian Intensive Care Unit. AB - INTRODUCTION: Intensive care unit (ICU) prognostic models are predominantly used in more developed nations such as the United States, Europe and Australia. These are not that popular in Southeast Asian countries due to costs and technology considerations. The purpose of this study is to evaluate the suitability of the acute physiology and chronic health evaluation (APACHE) IV model in a single centre Malaysian ICU. MATERIALS AND METHODS: A prospective study was conducted at the single centre ICU in Hospital Sultanah Aminah (HSA) Malaysia. External validation of APACHE IV involved a cohort of 916 patients who were admitted in 2009. Model performance was assessed through its calibration and discrimination abilities. A first-level customisation using logistic regression approach was also applied to improve model calibration. RESULTS: APACHE IV exhibited good discrimination, with an area under receiver operating characteristic (ROC) curve of 0.78. However, the model's overall fit was observed to be poor, as indicated by the Hosmer-Lemeshow goodness-of-fit test (C = 113, P <0.001). Predicted in-ICU mortality rate (28.1%) was significantly higher than the actual in-ICU mortality rate (18.8%). Model calibration was improved after applying first-level customisation (C = 6.39, P = 0.78) although discrimination was not affected. CONCLUSION: APACHE IV is not suitable for application in HSA ICU, without further customisation. The model's lack of fit in the Malaysian study is attributed to differences in the baseline characteristics between HSA ICU and APACHE IV datasets. Other possible factors could be due to differences in clinical practice, quality and services of health care systems between Malaysia and the United States. PMID- 26041637 TI - Prevalence of Chronic Mental and Physical Disorders, Impact on Work Productivity and Correlates of Alcohol Use Disorders and Nicotine Dependence across Occupations. AB - INTRODUCTION: This study assessed occupational differences in the prevalence of mental and physical disorders in an employed general population sample in Singapore and investigated the impact of these disorders on work productivity losses in terms of work-loss days and work-cutback days. The association of occupation with alcohol use disorders (AUD) and nicotine dependence (ND) was also investigated. MATERIALS AND METHODS: Data from a population-based mental health survey of a representative sample of multi-ethnic residents aged 18 years and above were used. The World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI) was administered to establish the lifetime diagnosis of key mental disorders. Self-report on sociodemographic characteristics, productivity loss, ND, and lifetime physical conditions were obtained. Nine occupational groups were included in this analysis. RESULTS: The sample comprised 4361 participants with a mean (SD) age of 42.2 (11.9) years, ranging between 19 to 80 years. 'Associate professionals and technicians' (26.2%), 'Services and sales workers' (17.7%) and 'Professionals' (15.4%) were the 3 predominant occupational categories. Sociodemographic characteristics differed significantly across occupations (P <0.001). The lifetime prevalences of having 'any mental disorder' and 'any physical disorder' were 13.0% and 37.9%, respectively; major depressive disorder was the most prevalent mental disorder (5.9%) and hypertension was the most common physical disorder (15.6%). There were no significant differences in work productivity loss across occupations. Sociodemographic and occupational correlates for AUD and ND were identified. CONCLUSION: Sociodemographic and health disparities exist in the major occupational categories in Singapore. The strength of the associations between occupation and AUD and ND are significant, indicating the need for preventative measures in select occupations. PMID- 26041638 TI - Dietary Protein Intake in a Multi-ethnic Asian Population of Healthy Participants and Chronic Kidney Disease Patients. AB - INTRODUCTION: Clinical practice guidelines recommend different levels of dietary protein intake in predialysis chronic kidney disease (CKD) patients. It is unknown how effectively these recommendations perform in a multi-ethnic Asian population, with varied cultural beliefs and diets. We assess the profi le of protein intake in a multi-ethnic Asian population, comparing healthy participants and CKD patients. MATERIALS AND METHODS: We analysed the 24-hour urine collections of the Asian Kidney Disease Study (AKDS) and the Singapore Kidney Function Study (SKFS) to estimate total protein intake (TPI; g/day). We calculated ideal body weight (IDW; kg): 22.99 * height2 (m). Standard statistical tests were applied where appropriate, and linear regression was used to assess associations of continuous variables with protein intake. RESULTS: There were 232 CKD patients and 103 healthy participants with 35.5% diabetics. The mean TPI in healthy participants was 58.89 +/- 18.42 and the mean TPI in CKD patients was 53.64 +/- 19.39. By US National Kidney Foundation (NKF) guidelines, 29/232 (12.5%) of CKD patients with measured glomerular filtration rate (GFR) <25 (in mL/min/1.73 m2) had a TPI-IDW of <0.6 g/kg/day. By Caring for Australasians with Renal Impairment (CARI) guidelines, 76.3% (177/232) of CKD patients had TPI-IDW >0.75g/kg/ day. By American Dietetic Association (ADA) guidelines, 34.7% (44/127) of CKD patients with GFR <50 had TPI-IDW between 0.6 to 0.8 g/kg/day. Only 1/6 non-diabetic CKD patients with GFR <20 had a protein intake of between 0.3 to 0.5 g/kg/day. A total of 21.9% (25/114) of diabetic CKD patients had protein intake between 0.8 to 0.9 g/kg/day. CONCLUSION: On average, the protein intake of most CKD patients exceeds the recommendations of guidelines. Diabetic CKD patients should aim to have higher protein intakes. PMID- 26041639 TI - Pyoderma gangrenosum mimicking early acute infection following total knee arthroplasty. PMID- 26041640 TI - Diagnosing bacteraemia early in older adults. PMID- 26041641 TI - Iron-induced myocardial injury: an alarming side effect of superparamagnetic iron oxide nanoparticles. PMID- 26041642 TI - Cation-Transporting Peptides: Scaffolds for Functionalized Pores? AB - Protein pores that selectively transport ions across membranes are among nature's most efficient machines. The selectivity of these pores can be exploited for ion sensing and water purification. Since it is difficult to reconstitute membrane proteins in their active form for practical applications it is desirable to develop robust synthetic compounds that selectively transport ions across cell membranes. One can envision tuning the selectivity of pores by incorporating functional groups inside the pore. Readily accessible octapeptides containing (aminomethyl)benzoic acid and alanine are reported here that preferentially transport cations over halides across the lipid bilayer. Ion transport is hypothesized through pores formed by stable assemblies of the peptides. The aromatic ring(s) appear to be proximal to the pore and could be potentially utilized for functionalizing the pore interior. PMID- 26041644 TI - Epidemiological survey and clinical investigation of pediatric IgA nephropathy. AB - BACKGROUND: Since school urinalysis screening was introduced in 1974, the number of cases requiring initiation of dialysis due to glomerulonephritis has been steadily decreasing and school urinalysis screening has been praised for contributing to the early detection and treatment of glomerulonephritis. However, the lack of nationwide epidemiological surveys is also a problem. METHODS: We conducted an epidemiological survey focusing on the frequency of occurrence of pediatric IgA nephropathy in Nishinomiya City. Subjects comprised 374,846 children who underwent school urinalysis screening from 2003 to 2012. Renal biopsy findings and clinical findings of these pediatric IgA nephropathy cases were retrospectively investigated. RESULTS: There were 37 (mean 3.7/year) newly diagnosed cases of pediatric IgA nephropathy in Nishinomiya City. The IgA nephropathy onset rate per 100,000 children who underwent school urinalysis screening was 9.9 cases/year. Compared to the histologic low grade group, the histologic high grade group had significantly higher urinary P/C ratio (P < 0.001). In the histologic high grade group, the number of cases of proteinuria remission 3 years after starting treatment was significantly higher in the group treated with steroids (P = 0.045). CONCLUSIONS: Our study found that 9.9 cases of pediatric IgA nephropathy were diagnosed per 100,000 in the pediatric population, which is equivalent to or slightly more than past reports. IgA nephropathy, which poses a high histologic risk, presents with heavy proteinuria; but the proteinuria remission rate following steroid therapy is high 3 years after treatment, which suggests that administration of steroids results in an improved clinical outcome. PMID- 26041645 TI - Sports and physical activity after cementless total hip arthroplasty with a minimum follow-up of 10 years. AB - The present retrospective cohort study was conducted to compare sporting activity levels before and a minimum of 10 years after primary cementless total hip arthroplasty (THA). A consecutive series of 86 patients with a mean age at surgery of 52 years (range, 21-60 years) was evaluated 11 years after surgery (range, 10-12 years). Pre- and post-operative sporting activities were assessed at routine follow-up using the University of California, Los Angeles activity score and the Schulthess Clinic sports and activity questionnaire. Post-operative health-related quality of life was measured using the Short-Form 36 (SF-36) questionnaire and compared with age-matched reference populations from the SF-36 database. Eleven years after THA, 89% of preoperatively active patients had returned to sport. Comparing sports activity preoperatively (before the onset of symptoms) and 11 years after THA, no significant difference was found for the mean number of disciplines or session length. A significant decline in high impact activities was observed, while participation in low-impact activities significantly increased. Health-related quality of life compared well against a healthy age-matched reference population and was significantly higher than in a reference group of patients with osteoarthritis. The majority of patients were able to maintain their physical activity level in the long term after primary cementless THA, compared with the activity level before the onset of restricting osteoarthritis symptoms. However, a change in disciplines toward low-impact activities was observed. PMID- 26041646 TI - Can CPAP be indicated in adult patients with suspected obstructive sleep apnea only on the basis of clinical data? AB - BACKGROUND: There is scarce information about whether the diagnosis of OSA supported only by medical record data can be a useful and reliable tool to initiate a CPAP treatment. OBJECTIVES: The aim of this study is to develop and assess the accuracy of clinical parameters for the diagnosis and prescription of CPAP in patients with suspected OSA. METHODS: Adult patients who underwent polysomnography and completed the Berlin questionnaire, a clinical record, and the Epworth sleepiness scale were included in the study. A situation was simulated in which two blinded and independent observers would be able to indicate CPAP treatment if the patients were snorers with frequent apnea reports (>=3-4 times a week) and overweight (BMI > 25 kg/m(2)) plus one of the following: diurnal symptoms (tiredness after sleeping or at waking time >=3-4 times a week or Epworth sleepiness scale >11), arterial hypertension, cerebrovascular accident, coronary event, type II diabetes or cardiac arrhythmias (observer 1, clinical criteria) or on the basis of the respiratory disturbance index, significant tiredness (>=3-4 times a week) or sleepiness (Epworth >11) and associated comorbidities (observer 2, reference method). The area under the ROC curve (ABC-ROC), sensitivity, specificity, and likelihood ratios were calculated. RESULTS: Among 516 subjects (72 % men), the median age was 52 years, BMI 28.3 kg/m(2), and RDI 19.7 events/h. The ABC-ROC, sensitivity, specificity, and positive likelihood ratio of the clinical parameters were of 0.64 to 0.65, 31 to 33 %, 97 to 98 %, and 11 to15 respectively. No differences in the diagnostic performance of the clinical criteria were observed between men and women. CONCLUSIONS: These clinical parameters made it possible to indicate CPAP in approximately one third of the population with OSA which would have required it on the basis of their PSG and clinical history. This approach showed high specificity; hence, few patients who did not meet the criteria for CPAP use would have received this treatment. PMID- 26041648 TI - Study of sleep microstructure in patients of migraine without aura. AB - PURPOSE: Although the relationship between sleep and migraine has been widely reported, studies on sleep microstructure are few. The aim was to study and compare microstructural polysomnographic characteristics in patients of "migraine without aura" (MOA) with controls. METHODS: Twenty-five patients of MOA and 25 age- and gender-matched healthy controls were subjected to overnight polysomnography. Microstructural sleep analysis, including arousal and cyclic alternating pattern (CAP) analysis was performed. Arousals and CAP parameters were compared between the two groups using the Mann-Whitney U test (p <= 0.05). RESULTS: The overall arousal index (p = 0.528) and that during non-rapid eye movement (NREM) sleep (p = 0.503) were comparable between the two groups. However, the arousal index was lower in migraineurs during rapid eye movement (REM) sleep (p = 0.001). The overall CAP rate (p = 0.020) as well as the number of CAP cycles and sequences (p = 0.032) was lower among migraineurs. The total phase A duration (p < 0.0001) was increased, and conversely, phase B duration (p = 0.001) was decreased in migraineurs. The phase A1 duration (p = 0.036) was higher in migraineurs. Finally, phase A1 (p = 0.357) index was comparable, and conversely, A2 (p < 0.0001) and A3 (p = 0.020) indices were decreased in migraineurs. CONCLUSIONS: This study showed a decreased REM arousability as well as a decreased overall CAP rate and CAP cycling in patients with migraine as compared to controls. This indicates that there is probably an alteration of the arousal mechanisms in patients with migraine that may facilitate the occurrence of headache paroxysms during sleep. PMID- 26041647 TI - Heart rate variability during sleep at high altitude: effect of periodic breathing. AB - BACKGROUND: Heart rate variability (HRV) during sleep in normal subjects at high altitude shows a decrease in parasympathetic tone associated with an increase in the sympathetic one, which tends to be reversed with acclimatization. However, periodic breathing (PB) during sleep may influence this effect detected by HRV spectral analysis. PURPOSE: The aim of our study was to investigate HRV during sleep periodic breathing (PB) at high altitude in normal subjects at two different times of acclimatization, i.e., two different levels of hypoxemia. METHODS: Recordings of six healthy climbers (aged between 33 and 40 years), at sea level (SL) and at Everest North Base Camp (5180 m), during the first (BC1) and the tenth (BC2) overnight unattended polygraphy, were analyzed. PB was commonplace in all subjects at high altitude to a variable extent. At SL and at BC1 and BC2, HRV was evaluated overnight and separately during clear regular breathing (RB) and PB. RESULTS: A mean overnight beat-by-beat series interval (RR) reduction at acute environmental hypoxic exposure that resumed to SL values after 10-day sojourn was observed. This reduction was mostly due to RR during RB, while during PB, RR values were not different from SL. Higher peaks of tidal volume were associated with higher HRV. CONCLUSIONS: The present study shows that in healthy subjects, PB with central apneas increases the amplitude of RR oscillations, and these oscillations are tightly related to respiratory amplitude. Oxygenation does not influence this phenomenon. Therefore, oscillations in ventilation itself should be taken into account when investigating HRV. PMID- 26041649 TI - Extremely strong organic-metal oxide electronic coupling caused by nucleophilic addition reaction. AB - Electronic interactions between organic materials and inorganic semiconductors play important roles in various electronic and optoelectronic functions and also provide new functions such as optical interfacial charge-transfer (ICT) transitions having the following features. ICT transitions enable the capture of lower-energy photons than HOMO-LUMO gaps or band gaps and allow one-step charge separation without loss of energy. The hybrid material generated by the nucleophilic addition reaction between TiO2 and TCNQ exclusively exhibits strong ICT transitions. In this study, we report that strong organic-metal oxide electronic coupling is caused by the nucleophilic addition reaction, which enhances the ICT transitions. The electronic coupling between TiO2 and TCNQ occurs according to a two-step mechanism. First, the lowest unoccupied molecular orbital (LUMO (pi*)) of TCNQ is elevated by the nucleophilic attack of a deprotonated hydroxy group on TiO2 to TCNQ and the electron distribution is moved toward TiO2. By this elevation and redistribution, the LUMO (pi*) strongly interacts with the d(t2g) orbitals of a surface Ti atom. From avoided-crossing behavior with a large splitting energy of ca. 0.95 eV, the coupling energy was estimated to be as much as 0.5 eV in the mono-Ti model complex. This strong d-pi* electronic coupling leads to strong coupling between complete ICT excited states and partial ICT excited states with a large splitting energy of ca. 0.92 eV, which considerably increases the probabilities of ICT transition. This study clarified the mechanisms of the strong organic-inorganic electronic coupling and the enhancement of ICT absorption in the TiO2-TCNQ hybrid material. PMID- 26041650 TI - Ultrahigh field single-refocused diffusion weighted imaging using a matched-phase adiabatic spin echo (MASE). AB - PURPOSE: To improve ultrahigh field diffusion-weighted imaging (DWI) in the presence of inhomogeneous transmit B1 field by designing a novel semi-adiabatic single-refocused DWI technique. METHODS: A 180 degrees slice-selective, adiabatic radiofrequency (RF) pulse of 4 ms duration was designed using the adiabatic Shinnar-Le Roux algorithm. A matched-phase slice-selective 90 degrees RF pulse of 8 ms duration was designed to compensate the nonlinear phase of the adiabatic 180 degrees RF pulse. The resulting RF pulse combination, matched phase adiabatic spin echo (MASE), was integrated into a single-shot echo planar DWI sequence. The performance of this sequence was compared with single-refocused Stejskal-Tanner (ST), twice-refocused spin echo (TRSE) and twice-refocused adiabatic spin echo (TRASE) in simulations, phantoms, and healthy volunteers at 7 Tesla (T). RESULTS: In regions with inhomogeneous B1 , MASE resulted in increased signal intensity compared with ST (up to 64%). Moderate increase in specific absorption rate (35-39%) was observed for adiabatic RF pulses. MASE resulted in higher signal homogeneity at 7T, leading to improved visualization of measures derived from diffusion-weighted images such as white matter tractography and track density images. CONCLUSION: Efficient adiabatic SLR pulses can be adapted to single-refocused DWI, leading to substantially improved signal uniformity when compared with conventional acquisitions. PMID- 26041651 TI - Adolescent endogenous sex hormones and breast density in early adulthood. AB - INTRODUCTION: During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer. METHODS: Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25-29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV. RESULTS: Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all P trend <=0.03) but not when measured in postmenarche samples (all P trend >=0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all P trend >=0.16). CONCLUSIONS: Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999. PMID- 26041652 TI - From the concrete to the intangible: understanding the diverse experiences and impacts of new transport infrastructure. AB - BACKGROUND: Changes to the environment that support active travel have the potential to increase population physical activity. The Cambridgeshire Guided Busway is an example of such an intervention that provides new traffic-free infrastructure for walking, cycling and public transport. This qualitative investigation explored the diverse experiences of new transport infrastructure and its impacts on active travel behaviours. METHODS: Thirty-eight adult participants from the Commuting and Health in Cambridge natural experimental study were purposively selected according to their demographic and travel behaviour change characteristics and invited to participate in semi-structured interviews between February and June 2013. A mixed-method, following-a-thread approach was used to construct two contrasting vignettes (stories) to which the participants were asked to respond as part of the interviews. Inductive thematic qualitative analysis of the interview data was performed with the aid of QSR NVivo8. RESULTS: Perceptions of the busway's attributes were important in shaping responses to it. Some participants rarely considered the new transport infrastructure or described it as unappealing because of its inaccessibility or inconvenient routing. Others located more conveniently for access points experienced the new infrastructure as an attractive travel option. Likewise, the guided buses and adjacent path presented ambiguous spaces which were received in different ways, depending on travel preferences. While new features such as on board internet access or off-road cycling were appreciated, shortcomings such as overcrowded buses or a lack of path lighting were barriers to use. The process of adapting to the environmental change was discussed in terms of planning and trialling new behaviours. The establishment of the busway in commuting patterns appeared to be influenced by whether the anticipated benefits of change were realised. CONCLUSIONS: This study examined the diverse responses to an environmental intervention that may help to explain small or conflicting aggregate effects in quantitative outcome evaluation studies. Place and space features, including accessibility, convenience, pleasantness and safety relative to the alternative options were important for the acceptance of the busway. Our findings show how environmental change supporting active travel and public transport can encourage behaviour change for some people in certain circumstances. PMID- 26041653 TI - Study protocol: the effectiveness and cost effectiveness of a brief behavioural intervention to promote regular self-weighing to prevent weight regain after weight loss: randomised controlled trial (The LIMIT Study). AB - BACKGROUND: Although obesity causes many adverse health consequences, modest weight loss reduces the incidence. There are effective interventions that help people to lose weight but weight regain is common and long term maintenance remains a critical challenge. As a high proportion of the population of most high and middle income countries are overweight, there are many people who would benefit from weight loss and its maintenance. Therefore, we need to find effective low cost scalable interventions to help people achieve this. One such intervention that has shown promise is regular self-weighing, to check progress against a target, however there is no trial that has tested this using a randomised controlled design (RCT). The aim of this RCT is to evaluate the effectiveness and cost effectiveness of a brief behavioural intervention delivered by non-specialist staff to promote regular self-weighing to prevent weight regain after intentional weight loss. METHODS: A randomised trial of 560 adults who have lost >= 5 % of their initial body weight through a 12 week weight loss programme. The comparator group receive a weight maintenance leaflet, a diagram representing healthy diet composition, and a list of websites for weight control. The intervention group receive the same plus minimally trained telephonists will ask participants to set a weight target and encourage them to weigh themselves daily, and provide support materials such as a weight record card. The primary outcome is the difference between groups in weight change from baseline to 12 months. DISCUSSION: If effective, this study will provide public health agencies with a simple, low cost maintenance intervention that could be implemented immediately. TRIAL REGISTRATION: ISRCTN52341938 Date Registered: 31/03/2014. PMID- 26041654 TI - Management of paediatric illnesses by patent and proprietary medicine vendors in Nigeria. AB - BACKGROUND: In Nigeria and elsewhere, informal drug sellers, or patent and proprietary medicine vendors (PPMVs), are a common source of care for children with malaria, diarrhoea, and pneumonia. However, their knowledge and stocking of recommended treatments for these common childhood illnesses are not well understood. METHODS: A census of PPMV shops was conducted in Kogi and Kwara states. A shop survey was conducted on a subset of 250 shops. Multivariate regression analysis was used to assess associations between shop worker characteristics and (1) knowledge of optimal treatments for malaria, diarrhoea, and pneumonia, and (2) stocking of essential medicines to treat these illnesses. RESULTS: From the census, 89.9% of shops stocked oral rehydration solution (ORS), while 61.1% of shops stocked artemisinin-based combination therapies and 72.2% of shops stocked amoxicillin. Stocking patterns varied by state, urban/rural location, and according to whether or not the shop was headed by someone with formal health training (e.g. having a professional health education degree). In multivariate analyses, selling drugs wholesale and participating in any training in the past year was associated with a higher likelihood of naming the correct treatment for malaria, and having formal health training was associated with stocking ORS. However, few other PPMV characteristics were predictive of correct knowledge of optimal treatments and stocking behaviour. CONCLUSION: Many PPMVs lack the knowledge and tools to properly treat common childhood illnesses. PPMV knowledge and selling of essential medicines for these illnesses should be strengthened to improve child health in Nigeria. PMID- 26041655 TI - Preparation of fluorescent mesoporous hollow silica-fullerene nanoparticles via selective etching for combined chemotherapy and photodynamic therapy. AB - Well-dispersed mesoporous hollow silica-fullerene nanoparticles with particle sizes of ~50 nm have been successfully prepared by incorporating fullerene molecules into the silica framework followed by a selective etching method. The fabricated fluorescent silica-fullerene composite with high porosity demonstrates excellent performance in combined chemo/photodynamic therapy. PMID- 26041656 TI - Biting midges (Culicoides, Diptera) transmit Haemoproteus parasites of owls: evidence from sporogony and molecular phylogeny. AB - BACKGROUND: Haemoproteus parasites are widespread, and several species cause diseases both in birds and blood-sucking insects. These pathogens are transmitted by dipterans belonging to the Ceratopogonidae and Hippoboscidae, however certain vector species remain unknown for the majority of Haemoproteus spp. Owls are often infected by Haemoproteus parasites, but experimental studies on vectors of these infections are lacking. The aim of this study was to investigate sporogonic development of two widespread Haemoproteus parasites of owls, H. noctuae and H. syrnii in experimentally infected biting midges Culicoides impunctatus and Culicoides nubeculosus. We also followed in vitro sporogonic development of these infections and determined their phylogenetic relationships with Haemoproteus spp., for which vectors have been identified. METHODS: Wild-caught C. impunctatus and laboratory reared C. nubeculosus were infected experimentally by allowing them to take blood meals on one individual long-eared owl (Asio otus) and one tawny owl (Strix aluco) harbouring mature gametocytes of H. noctuae (lineage hCIRCUM01) and H. syrnii (hCULCIB01), respectively. The engorged insects were maintained in the laboratory at 16-18 degrees C, and dissected at intervals in order to follow the development of ookinetes, oocysts and sporozoites. We also observed in vitro development of sexual stages of both parasites by exposure of infected blood to air. The parasite lineages were determined by polymerase chain reaction-based methods. Bayesian phylogeny was constructed in order to determine the relationships of owl parasites with other avian Haemoproteus spp., for which vectors have been identified. RESULTS: Both H. noctuae and H. syrnii completed sporogony in C. nubeculosus, and H. noctuae completed sporogony in C. impunctatus. Ookinetes, oocysts and sporozoites of these parasites were reported and described. Gametes and ookinetes of both species readily developed in vitro. In accordance with sporogony data, the phylogenetic analysis placed both parasite lineages in a clade of Culicoides spp.-transmitted avian Haemoproteus (Parahaemoproteus) spp. CONCLUSIONS: Culicoides nubeculosus and C. impunctatus are vectors of H. noctuae and H. syrnii. Phylogenies based on cytochrome b gene indicate parasite-vector relationships, and we recommend using them in predicting possible parasite-vector relationships and planning research on avian Haemoproteus spp. vectors in wildlife. PMID- 26041657 TI - In situ microfluidic SERS assay for monitoring enzymatic breakdown of organophosphates. AB - In this paper, we report on a method to probe the breakdown of the organophosphate (OP) simulants o,s-diethyl methyl phosphonothioate (OSDMP) and demeton S by the enzyme organophosphorous hydrolase (OPH) in a microfluidic device by surface enhanced Raman spectroscopy (SERS). SERS hotspots were formed on-demand inside the microfluidic device by laser-induced aggregation of injected Ag NPs suspensions. The Ag NP clusters, covering micron-sized areas, were formed within minutes using a conventional confocal Raman laser microscope. These Ag NP clusters were used to enhance the Raman spectra of the thiol products of OP breakdown in the microfluidic device: ethanethiol (EtSH) and (ethylsulfanyl) ethane-1-thiol (2-EET). When the OPH enzyme and its substrates OSDMP and demeton S were introduced, the thiolated breakdown products were generated, resulting in changes in the SERS spectra. With the ability to analyze reaction volumes as low as 20 nL, our approach demonstrates great potential for miniaturization of SERS analytical protocols. PMID- 26041659 TI - Elevated Serum Levels of Neopterin at Admission Predicts Depression After Acute Ischemic Stroke: a 6-Month Follow-Up Study. AB - Inflammation and cell-mediated immune activation are attributed to the pathogenesis and pathophysiology in depression. Our aim was to test the possible association between serum levels of neopterin and the development of post-stroke depression (PSD) in Chinese patients. The subjects were first-ever acute ischemic stroke patients who were hospitalized at the First Affiliated Hospital of Xinxiang Medical University during the period from December 2012 to December 2013. Clinical information and stroke severity were collected at admission. Neurological and neuropsychological evaluations were conducted at the 6-month follow-up. Serum neopterin levels were measured using fluorometry and a high performance liquid chromatography (HPLC) method. Multivariate analyses were performed using logistic regression models. During the study period, 226 patients were included and finished the 6-month follow-up. Sixty-nine patients (30.5 %) were diagnosed as having major depression at 6 months. Patients with major depression showed higher levels of serum neopterin (21.6[IQR, 18.9-25.7]nmol/L vs. 14.6[IQR, 12.2-18.4]nmol/L, P < 0.0001) at admission. In multivariate analyses, serum neopterin was an independent predictor of PSD at 6 months [odds ratio (OR): 1.952 (95 % CI, 1.358-2.805), P < 0.0001]. With an AUC of 0.850 (95 % CI, 0.797-0.902), neopterin showed a significantly greater discriminatory ability as compared with high-sensitivity C-reactive protein, age, body mass index, and National Institutes of Health and Stroke Scale score. Neopterin is a novel, independent predictor of the development of depression 6 months after stroke. This indicated that the elevated neopterin levels may play a significant role in the pathology of depression and that the pathways leading to inflammation and cell-mediated immune activation warrant further exploration. PMID- 26041658 TI - An Overview on Human Umbilical Cord Blood Stem Cell-Based Alternative In Vitro Models for Developmental Neurotoxicity Assessment. AB - The developing brain is found highly vulnerable towards the exposure of different environmental chemicals/drugs, even at concentrations, those are generally considered safe in mature brain. The brain development is a very complex phenomenon which involves several processes running in parallel such as cell proliferation, migration, differentiation, maturation and synaptogenesis. If any step of these cellular processes hampered due to exposure of any xenobiotic/drug, there is almost no chance of recovery which could finally result in a life-long disability. Therefore, the developmental neurotoxicity (DNT) assessment of newly discovered drugs/molecules is a very serious concern among the neurologists. Animal-based DNT models have their own limitations such as ethical concerns and lower sensitivity with less predictive values in humans. Furthermore, non availability of human foetal brain tissues/cells makes job more difficult to understand about mechanisms involve in DNT in human beings. Although, the use of cell culture have been proven as a powerful tool for DNT assessment, but many in vitro models are currently utilizing genetically unstable cell lines. The interpretation of data generated using such terminally differentiated cells is hard to extrapolate with in vivo situations. However, human umbilical cord blood stem cells (hUCBSCs) have been proposed as an excellent tool for alternative DNT testing because neuronal development from undifferentiated state could exactly mimic the original pattern of neuronal development in foetus when hUCBSCs differentiated into neuronal cells. Additionally, less ethical concern, easy availability and high plasticity make them an attractive source for establishing in vitro model of DNT assessment. In this review, we are focusing towards recent advancements on hUCBSCs-based in vitro model to understand DNTs. PMID- 26041660 TI - Rescue of Brain Function Using Tunneling Nanotubes Between Neural Stem Cells and Brain Microvascular Endothelial Cells. AB - Evidence indicates that neural stem cells (NSCs) can ameliorate cerebral ischemia in animal models. In this study, we investigated the mechanism underlying one of the neuroprotective effects of NSCs: tunneling nanotube (TNT) formation. We addressed whether the control of cell-to-cell communication processes between NSCs and brain microvascular endothelial cells (BMECs) and, particularly, the control of TNT formation could influence the rescue function of stem cells. In an attempt to mimic the cellular microenvironment in vitro, a co-culture system consisting of terminally differentiated BMECs from mice in a distressed state and NSCs was constructed. Additionally, engraftment experiments with infarcted mouse brains revealed that control of TNT formation influenced the effects of stem cell transplantation in vivo. In conclusion, our findings provide the first evidence that TNTs exist between NSCs and BMECs and that regulation of TNT formation alters cell function. PMID- 26041661 TI - Efficient Docosahexaenoic Acid Uptake by the Brain from a Structured Phospholipid. AB - Docosahexaenoic acid (DHA) is the main essential omega-3 fatty acid in brain tissues required for normal brain development and function. An alteration of brain DHA in neurodegenerative diseases such as Alzheimer's and Parkinson's is observed. Targeted intake of DHA to the brain could compensate for these deficiencies. Blood DHA is transported across the blood-brain barrier more efficiently when esterified at the sn-2 position of lyso-phosphatidylcholine. We used a structured phosphatidylcholine to mimic 2-docosahexaenoyl-lysoPC (lysoPC DHA), named AceDoPC (1-acetyl,2-docosahexaenoyl-glycerophosphocholine), that may be considered as a stabilized form of the physiological lysoPC-DHA and that is neuroprotective in experimental ischemic stroke. The aim of the present study was to investigate whether AceDoPC is a relevant delivery form of DHA to the brain in comparison with other forms of the fatty acid. By combining in vitro and in vivo experiments, our findings report for the first time that AceDoPC is a privileged and specific carrier of DHA to the brain, when compared with DHA-containing PC and non-esterified DHA. We also show that AceDoPC was hydrolyzed, in part, into lysoPC-DHA. Ex vivo autoradiography of rat brain reveals that DHA from AceDoPC was localized in specific brain regions playing key roles in memory, thoughts, and cognitive functions. Finally, using molecular modeling approaches, we demonstrate that electrostatic and lipophilic potentials are distributed very similarly at the surfaces of AceDoPC and lysoPC-DHA. Our findings identify AceDoPC as an efficient way to specifically target DHA to the brain, which would allow potential preventive and therapeutic approaches for neurological diseases. PMID- 26041662 TI - Topographical Distribution of Morphological Changes in a Partial Model of Parkinson's Disease--Effects of Nanoencapsulated Neurotrophic Factors Administration. AB - Administration of various neurotrophic factors is a promising strategy against Parkinson's disease (PD). An intrastriatal infusion of 6-hydroxidopamine (6-OHDA) in rats is a suitable model to study PD. This work aims to describe stereological parameters regarding rostro-caudal gradient, in order to characterize the model and verify its suitability for elucidating the benefits of therapeutic strategies. Administration of 6-OHDA induced a reduction in tyrosine hidroxylase (TH) reactivity in the dorsolateral part of the striatum, being higher in the caudal section than in the rostral one. Loss of TH-positive neurons and axodendritic network was highly significant in the external third of substantia nigra (e-SN) in the 6-OHDA group versus the saline one. After the administration of nanospheres loaded with neurotrophic factors (NTF: vascular endothelial growth factor (VEGF) + glial cell line-derived neurotrophic factor (GDNF)), parkinsonized rats showed more TH-positive fibers than those of control groups; this recovery taking place chiefly in the rostral sections. Neuronal density and axodendritic network in e-SN was more significant than in the entire SN; the topographical analysis showed that the highest difference between NTF versus control group was attained in the middle section. A high number of bromodeoxyuridine (BrdU)-positive cells were found in sub- and periventricular areas in the group receiving NTF, where most of them co-expressed doublecortin. Measurements on the e-SN achieved more specific and significant results than in the entire SN. This difference in rostro-caudal gradients underpins the usefulness of a topological approach to the assessment of the lesion and therapeutic strategies. Findings confirmed the neurorestorative, neurogenic, and synergistic effects of VEGF+GDNF administration. PMID- 26041663 TI - The Carnitine Palmitoyl Transferase (CPT) System and Possible Relevance for Neuropsychiatric and Neurological Conditions. AB - The carnitine palmitoyl transferase (CPT) system is a multiprotein complex with catalytic activity localized within a core represented by CPT1 and CPT2 in the outer and inner membrane of the mitochondria, respectively. Two proteins, the acyl-CoA synthase and a translocase also form part of this system. This system is crucial for the mitochondrial beta-oxidation of long-chain fatty acids. CPT1 has two well-known isoforms, CPT1a and CPT1b. CPT1a is the hepatic isoform and CPT1b is typically muscular; both are normally utilized by the organism for metabolic processes throughout the body. There is a strong evidence for their involvement in various disease states, e.g., metabolic syndrome, cardiovascular diseases, and in diabetes mellitus type 2. Recently, a new, third isoform of CPT was described, CPT1c. This is a neuronal isoform and is prevalently localized in brain regions such as hypothalamus, amygdala, and hippocampus. These brain regions play an important role in control of food intake and neuropsychiatric and neurological diseases. CPT activity has been implicated in several neurological and social diseases mainly related to the alteration of insulin equilibrium in the brain. These pathologies include Parkinson's disease, Alzheimer's disease, and schizophrenia. Evolution of both Parkinson's disease and Alzheimer's disease is in some way linked to brain insulin and related metabolic dysfunctions with putative links also with the diabetes type 2. Studies show that in the CNS, CPT1c affects ceramide levels, endocannabionoids, and oxidative processes and may play an important role in various brain functions such as learning. PMID- 26041665 TI - Erratum to: Resveratrol Represses Pokemon Expression in Human Glioma Cells. PMID- 26041664 TI - Estrogen Selectively Mobilizes Neural Stem Cells in the Third Ventricle Stem Cell Niche of Postnatal Day 21 Rats. AB - The neuroprotective properties of stem cells have been described for various pathophysiological states. Here, we determined the effects of exogenous perinatal estrogen treatment on endogenous neural stem cell activity in the third ventricle stem cell niche (3VSCN) and the caudal third ventricle (C3V). Pregnant Sprague Dawley rats were gavaged with ethinyl estradiol (EE2, 10 MUg/kg/day) or vehicle on gestational days 6-21, and their offspring were similarly treated from birth to weaning on postnatal day 21. At weaning, neural stem cell activity was investigated using the stem cell markers nestin, Ki-67, phosphohistone H3 (PHH3), and doublecortin (DCX). The 3VSCN was characterized by nestin labeling, but little DCX labeling, while both the subventricular (SVZ) and subgranular zones (SGZ) displayed robust DCX expression. Ki-67 cell counts in the 3VSCN were 2.2 to 6.4 times those of the C3V. In the 3VSCN, EE2 treatment significantly increased Ki-67, PHH3, and co-labeled cell counts by 135-207 %, effects which appeared stronger in females. EE2 treatment had only marginally significant effects in the C3V, mildly increasing PHH3 and co-labeled cell counts. Perinatal estrogen treatment selectively increased and mobilized proliferative cells in the 3VSCN at weaning, potentially providing increased neuroprotection. Because PHH3 cells are thought to be in the mitotic phase of the cell cycle and Ki-67 cells can be found in most phases of the cycle, the effect of estrogen treatment on 3VSCN cells appears to involve enhancement of mitosis. PMID- 26041666 TI - Meta-analysis of surgical outcome after enucleation versus standard resection for pancreatic neoplasms. AB - BACKGROUND: Pancreatic enucleation is a tissue-sparing approach to pancreatic neoplasms and may result in better postoperative pancreatic function than standard pancreatic resection. The objective of this review was to compare the postoperative outcome after pancreatic enucleation versus standard resection. METHODS: MEDLINE, Embase and the Cochrane Library were searched systematically until February 2015 to identify studies comparing the outcome of enucleation versus standard resection for pancreatic neoplasms. After critical appraisal, meta-analysis was performed and the findings were presented as odds ratios or weighted mean differences with corresponding 95 per cent c.i. RESULTS: Twenty-two observational studies (1148 patients) were included. Duration of surgery (P < 0.001), blood loss (P < 0.001), length of hospital stay (P = 0.04), and postoperative endocrine (P < 0.001) and exocrine (P = 0.01) insufficiency were lower after enucleation than after standard resection. Mortality (P = 0.44), overall complications (P = 0.74), reoperation rate (P = 0.93) and delayed gastric emptying (P = 0.15) were not significantly different between the two approaches. The overall rate of postoperative pancreatic fistula (POPF) was higher after enucleation than after standard resection (P < 0.001). However, the raised POPF rate did not result in higher mortality or overall morbidity. Sensitivity analysis of high-volume studies (total of more than 20 enucleations and more than 4 per year) showed that, in specialized centres, enucleation can be performed with no increased risk of POPF (P = 0.12). CONCLUSION: Compared with standard resection, pancreatic enucleation can be performed effectively and with comparable safety in high-volume institutions. Enucleation should be considered instead of standard resection for selected pancreatic neoplasms. PMID- 26041667 TI - A Japanese single-hospital observational trial with a retrospective case-control analysis of varicella zoster virus reactivation after autologous peripheral blood stem cell transplantation. AB - BACKGROUND: Varicella zoster virus (VZV) reactivation following hematopoietic stem cell transplantation (SCT) is common. To help reduce its incidence and to identify predictive factors for VZV reactivation after autologous SCT (auto-SCT), we conducted a retrospective analysis in patients with hematologic malignancy at our hospital. METHODS: We conducted a single-hospital observational trial with a retrospective case-control analysis of post-auto-SCT VZV reactivation in patients with malignant lymphoma (ML) and multiple myeloma (MM) between January 2001 and December 2010, in the Department of Hematology at our hospital. First, we analyzed the cumulative incidence of VZV reactivation during the post-SCT period. Second, we conducted a case-control analysis to identify the risk factors for VZV reactivation within 1 year after SCT. Univariate analyses were performed using Fisher's exact test for categorical variables. A multivariable model and logistic regression were used to assess the risk factors for VZV reactivation. RESULTS: We included 97 patients in this study. The median duration of follow-up was 1027 days. Forty-two patients experienced VZV reactivation after SCT, while 29 (69.0%) experienced reactivation within 1 year after SCT. The cumulative incidence was 30.7% at 1 year and 51.2% for the total observation period. Multivariate analysis showed that engraftment after day 10 was an independent risk factor for VZV reactivation (P = 0.03). CONCLUSIONS: Our study showed a high incidence of VZV reactivation in the first year after auto-SCT in ML and MM patients. Patients with delayed engraftment are at high risk for VZV reactivation and should be considered for prolonged VZV prophylaxis. PMID- 26041668 TI - Acute hypernatremia after voluntary saline intake leading to intracerebral haemorrhage: neuroimaging confirms diagnosis. PMID- 26041669 TI - Response to microsurgical anatomy of lumbosacral spinal roots. PMID- 26041670 TI - Role of Imaging Techniques for Diagnosis, Prognosis and Management of Heart Failure Patients: Cardiac Magnetic Resonance. AB - Cardiac magnetic resonance (CMR) has evolved into a major tool for the diagnosis and assessment of prognosis of patients suffering from heart failure. Anatomical and structural imaging, functional assessment, T1 and T2 mapping tissue characterization, and late gadolinium enhancement (LGE) have provided clinicians with tools to distinguish between non-ischemic and ischemic cardiomyopathies and to identify the etiology of non-ischemic cardiomyopathies. LGE is a useful tool to predict the likelihood of functional recovery after revascularization in patients with CAD and to guide the left ventricular (LV) lead placement in those who qualify for cardiac resynchronization (CRT) therapy. In addition, the presence of LGE and its extent in myocardial tissue relate to overall cardiovascular outcomes. Emerging roles for cardiac imaging in heart failure with preserved ejection fraction (HFpEF) are being studied, and CMR continues to be among the most promising noninvasive imaging alternatives in the diagnosis of this disease. PMID- 26041672 TI - Regulation profiles of e-cigarettes in the United States: a critical review with qualitative synthesis. AB - BACKGROUND: Electronic cigarettes (e-cigarettes) have been steadily increasing in popularity since their introduction to US markets in 2007. Debates surrounding the proper regulatory mechanisms needed to mitigate potential harms associated with their use have focused on youth access, their potential for nicotine addiction, and the renormalization of a smoking culture. The objective of this study was to describe the enacted and planned regulations addressing this novel public health concern in the US. METHODS: We searched LexisNexis Academic under Federal Regulations and Registers, as well as State Administrative Codes and Registers. This same database was also used to find information about planned regulations in secondary sources. The search was restricted to US documents produced between January 1(st), 2004, and July 14(th), 2014. RESULTS: We found two planned regulations at the federal level, and 74 enacted and planned regulations in 44 states. We identified six state-based regulation types, including i) access, ii) usage, iii) marketing and advertisement, iv) packaging, v) taxation, and vi) licensure. These were further classified into 10 restriction subtypes: sales, sale to minors, use in indoor public places, use in limited venues, use by minors, licensure, marketing and advertising, packaging, and taxation. Most enacted restrictions aimed primarily to limit youth access, while few regulations enforced comprehensive restrictions on product use and availability. CONCLUSIONS: Current regulations targeting e-cigarettes in the US are varied in nature and scope. There is greater consensus surrounding youth protection (access by minors and/or use by minors, and/or use in limited venues), with little consensus on multi-level regulations, including comprehensive use bans in public spaces. PMID- 26041671 TI - Targeting the insulin-like growth factor receptor and Src signaling network for the treatment of non-small cell lung cancer. AB - BACKGROUND: Therapeutic interventions in the insulin-like growth factor receptor (IGF-1R) pathway were expected to provide clinical benefits; however, IGF-1R tyrosine kinase inhibitors (TKIs) have shown limited antitumor efficacy, and the mechanisms conveying resistance to these agents remain elusive. METHODS: The expression and activation of the IGF-1R and Src were assessed via the analysis of a publicly available dataset, as well as immunohistochemistry, Western blotting, RT-PCR, and in vitro kinase assays. The efficacy of IGF-1R TKIs alone or in combination with Src inhibitors was analyzed using MTT assays, colony formation assays, flow cytometric analysis, and xenograft tumor models. RESULTS: The co activation of IGF-1R and Src was observed in multiple human NSCLC cell lines as well as in a tissue microarray (n = 353). The IGF-1R and Src proteins mutually phosphorylate on their autophosphorylation sites. In high-pSrc-expressing NSCLC cells, linsitinib treatment initially inactivated the IGF-1R pathway but led a Src-dependent reactivation of downstream effectors. In low-pSrc-expressing NSCLC cells, linsitinib treatment decreased the turnover of the IGF-1R and Src proteins, ultimately amplifying the reciprocal co-activation of IGF-1R and Src. Co-targeting IGF-1R and Src significantly suppressed the proliferation and tumor growth of both high-pSrc-expressing and low-pSrc-expressing NSCLC cells in vitro and in vivo and the growth of patient-derived tissues in vivo. CONCLUSIONS: Reciprocal activation between Src and IGF-1R occurs in NSCLC. Src causes IGF-1R TKI resistance by acting as a key downstream modulator of the cross-talk between multiple membrane receptors. Targeting Src is a clinically applicable strategy to overcome resistance to IGF-1R TKIs. PMID- 26041673 TI - Dietary alpha-Linolenic Acid and Total omega-3 Fatty Acids Are Inversely Associated with Abdominal Aortic Calcification in Older Women, but Not in Older Men. AB - BACKGROUND: Associations of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) plus decosahexaenoic acid (DHA), and total omega-3 (n-3) fatty acid (FA) intakes with abdominal aortic calcification (AAC) are not well understood. OBJECTIVE: This study explored the associations between baseline and long-term changes in omega-3 FA consumption and AAC severity among community-dwelling older men and women. METHODS: The present study used a subset of the Melbourne Collaborative Cohort Study in which participants were interviewed in 1990-1994 and again in 2010-2011. Dietary intake was evaluated at both baseline and follow up with use of food-frequency questionnaires. AAC severity was assessed by both lateral thoraco-lumbar radiography and dual-energy X-ray absorptiometry (DXA) at follow-up. RESULTS: A total of 312 participants aged 45-64 y old at baseline were followed for a duration of (mean +/- SD) 18 +/- 1 y. Baseline energy-adjusted ALA intake tended to be inversely associated with AAC severity by radiography [OR (95% CI) for tertile 3 vs. tertile 1: 0.49 (0.23, 1.02), P-trend: 0.06] and was inversely associated with AAC severity by DXA [OR (95% CI) for tertile 3 vs. tertile 1: 0.37 (0.16, 0.83)] in women, after adjustment for confounders. Women in the third tertile of total omega-3 FA intake had significantly lower AAC severity by radiography [OR (95% CI): 0.33 (0.16, 0.71)] and DXA [OR (95% CI): 0.27 (0.12, 0.62)] than those in the first tertile. Changes in tertile of omega-3 FA intake over 18 y were not found to be associated with AAC severity in either men or women. CONCLUSION: The results of our study suggest that dietary ALA and total omega-3 FA intakes are both important predictors of the development of AAC in older women, but not in older men. PMID- 26041676 TI - Toward a Just, Nutritious, and Sustainable Food System: The False Dichotomy of Localism versus Supercenterism. PMID- 26041674 TI - Protein and Calorie Restriction Contribute Additively to Protection from Renal Ischemia Reperfusion Injury Partly via Leptin Reduction in Male Mice. AB - BACKGROUND: Short-term dietary restriction (DR) without malnutrition preconditions against surgical stress in rodents; however, the nutritional basis and underlying nutrient/energy-sensing pathways remain poorly understood. OBJECTIVES: We investigated the relative contribution of protein restriction (PR) vs. calorie restriction (CR) to protection from renal ischemia reperfusion injury (IRI) and changes in organ-autonomous nutrient/energy-sensing pathways and hormones underlying beneficial effects. METHODS: Mice were preconditioned on experimental diets lacking total calories (0-50% CR) or protein/essential amino acids (EAAs) vs. complete diets consumed ad libitum (AL) for 1 wk before IRI. Renal outcome was assessed by serum markers and histology and integrated over a 2 dimensional protein/energy landscape by geometric framework analysis. Changes in renal nutrient/energy-sensing signal transduction and systemic hormones leptin and adiponectin were also measured. The genetic requirement for amino acid sensing via general control non-derepressible 2 (GCN2) was tested with knockout vs. control mice. The involvement of the hormone leptin was tested by injection of recombinant protein vs. vehicle during the preconditioning period. RESULTS: CR mediated protection was dose dependent up to 50% with maximal 2-fold effect sizes. PR benefits were abrogated by EAA re-addition and additive with CR, with maximal benefits at any given amount of CR occurring with a protein-free diet. GCN2 was not required for functional benefits of PR. Activation and repression of nutrient/energy-sensing kinases, AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin complex 1 (mTORC1), respectively, on PR reflected a state of negative energy balance, paralleled by 13% weight loss and an 87% decrease in leptin, independent of calorie intake. Recombinant leptin administration partially abrogated benefits of dietary preconditioning against renal IRI. CONCLUSIONS: In male mice, PR and CR both contributed to the benefits of short-term DR against renal IRI independent of GCN2 but partially dependent on reduced circulating leptin and coincident with AMPK activation and mTORC1 repression. PMID- 26041675 TI - Infant Maturity at Birth Reveals Minor Differences in the Maternal Milk Metabolome in the First Month of Lactation. AB - BACKGROUND: Human milk is the gold standard of nutrition for infants, providing both protective and essential nutrients. Although much is known about milk from mothers giving birth to term infants, less is known about milk from mothers giving birth to premature infants. In addition, little is known about the composition and diversity of small molecules in these milks and how they change over the first month of lactation. OBJECTIVE: The objective was to understand how milk metabolites vary over the first month of lactation in mothers giving birth to term and preterm infants. METHODS: (1)H nuclear magnetic resonance (NMR) metabolomics was used to characterize metabolites that were present in micromolar to molar concentrations in colostrum (day 0-5 postpartum), transition milk (day 14), and mature milk (day 28) from mothers who delivered term (n = 15) and preterm (n = 13) infants. Principal components analysis, linear mixed-effects models (LMMs), and linear models (LMs) were used to explore the relation between infant maturity and the postpartum day of collection of milk samples. RESULTS: By using a standard NMR metabolite library, 69 metabolites were identified in the milks, including 15 sugars, 23 amino acids and derivatives, 11 energy-related metabolites, 10 fatty acid-associated metabolites, 3 nucleotides and derivatives, 2 vitamins, and 5 bacteria-associated metabolites. Many metabolite concentrations followed a similar progression over time in both term and preterm milks, with more biological variation in metabolite concentrations in preterm milk. However, although lacto-N-neotetraose (LMM, P = 4.0 * 10(-5)) and lysine (LM, P = 1.5 * 10(-4)) significantly decreased in concentration in term milk over time, they did not significantly change in preterm milk. CONCLUSION: Overall, the metabolic profile of human milk is dynamic throughout the first month of lactation, with more variability in preterm than in term milk and subtle differences in some metabolite concentrations. This trial was registered at clinicaltrials.gov as NCT01841268. PMID- 26041677 TI - Regular Consumption of a High-Phytate Diet Reduces the Inhibitory Effect of Phytate on Nonheme-Iron Absorption in Women with Suboptimal Iron Stores. AB - BACKGROUND: High phytate (HP) consumption is a concern in developing countries because of the high prevalence of iron deficiency in these countries. OBJECTIVE: We investigated whether habitual consumption of an HP diet reduces the inhibitory effect of phytate on nonheme-iron absorption. METHODS: Thirty-two nonanemic females, 18-35 y of age, with normal body mass index but with suboptimal iron stores (serum ferritin, <=30 MUg/L), were matched for serum ferritin concentration and randomly assigned to HP and low-phytate (LP) groups, in a parallel design study. Each subject consumed HP or LP foods with at least 2 of their daily meals for 8 wk, resulting in a change in phytate intake (from 718 to 1190 mg/d in the HP group and 623 to 385 mg/d in the LP group). The serum iron response over 4 h after a test meal containing 350 mg of phytate was measured at baseline and postintervention. Ferritin, transferrin receptor, and hepcidin concentrations were measured at baseline and 8 wk. RESULTS: Twenty-eight subjects completed the study (n = 14 per group). The serum iron response to the test meal increased in the HP group at postintervention, resulting in a 41% increase in the area under the curve (AUC; P < 0.0001). However, no effect was observed in the LP group (21% decrease in AUC; P = 0.76). The postintervention serum iron response was lower (P < 0.0001) in the LP group than in the HP group after controlling for the baseline serum iron response and hepcidin concentration, reflecting in a 64% lower AUC. CONCLUSIONS: We found that habitual consumption of an HP diet can reduce the negative effect of phytate on nonheme-iron absorption among young women with suboptimal iron stores. Future studies are needed to explore possible mechanisms. This trial was registered at clinicaltrials.gov as NCT02370940. PMID- 26041678 TI - Dietary Fiber Intake Modifies the Positive Association between n-3 PUFA Intake and Colorectal Cancer Risk in a Caucasian Population. AB - BACKGROUND: The association between dietary fat intake and the risk of colorectal cancer (CRC) is still unclear. OBJECTIVES: We analyzed whether intakes of dietary polyunsaturated fatty acids (PUFAs) and saturated fatty acids (SFAs) were associated with CRC risk and whether these associations were modified by dietary fiber (DF) intake. METHODS: This study was embedded in the Rotterdam Study, a prospective cohort study among subjects aged >=55 y (n = 4967). At baseline, diet was measured by a food-frequency questionnaire. CRC events were diagnosed on the basis of pathology data and medical records. Multivariable adjusted HRs were calculated using Cox regression models. RESULTS: During a mean follow-up period of 14.6 y, we identified 222 incident cases of CRC. There was no association between total PUFA, n-6 (omega-6) PUFA, or SFA intake and CRC risk. n-3 PUFA intake was associated with an increased risk of CRC [tertile 3 vs. tertile 1: HR = 1.44 (95% CI: 1.02, 2.04), P-trend = 0.04]. When data were analyzed by food sources, only n-3 PUFAs from nonmarine sources were associated with an increased risk of CRC. A significant interaction between n-3 PUFA and DF intakes was found (P-interaction = 0.02). After stratification by median DF intake, an increased risk of CRC caused by n-3 PUFA intake was observed in participants with a DF intake less than the median [tertile 3 vs. tertile 1: HR = 1.96 (95% CI: 1.20, 3.19), P-trend = 0.01]. No association was observed in subjects with DF intake equal to or higher than the median. CONCLUSIONS: This study suggests that intake of n-3 PUFAs by adults is associated with an increased risk of CRC, which may be driven mainly by sources other than fish. Moreover, a complex interaction with DF intake may be present. PMID- 26041679 TI - Outcomes of 1503 cycles of modified natural cycle in vitro fertilization: a single-institution experience. AB - PURPOSE: A retrospective cohort study was conducted in a single academic center to determine if modified natural cycle in vitro fertilization (mnIVF) is an acceptable treatment for the infertile couple. METHODS: Cycles performed between July 2005 and December 2011 were included. In our center's mnIVF protocol, a GnRH antagonist, gonadotrophin, as well as Indocid are given on a daily basis from detection of a dominant follicle until ovulation induction. The primary outcomes were clinical pregnancy rates (CPR) per cycle started and per embryo transfer (ET). Outcomes were stratified by female patient age (<=35 years and >=36 years). They were further stratified in each age group by ovarian response status according to the 2011 Bologna criteria. RESULTS: A total of 1503 cycles of mnIVF, performed in 782 patients, were analyzed. CPRs were 13.7 % per started cycle and 32.5 % per ET. Stratification by ovarian response status (normal or poor) in each age group showed similar CPRs in patients <=35 years (p = 0.373), and divergent CPRs per ET in patients >=36 years old (26.26 vs 6.25 %). CONCLUSION: MnIVF is an acceptable treatment option for patients considering IVF, particularly for women <=35 years old and for women >=36 years old with normal ovarian response. PMID- 26041680 TI - What does a hospital mean? PMID- 26041681 TI - Health care policy and politics in Italy in hard times. PMID- 26041682 TI - Exposure to a patient-centered, Web-based intervention for managing cancer symptom and quality of life issues: impact on symptom distress. AB - BACKGROUND: Effective eHealth interventions can benefit a large number of patients with content intended to support self-care and management of both chronic and acute conditions. Even though usage statistics are easily logged in most eHealth interventions, usage or exposure has rarely been reported in trials, let alone studied in relationship to effectiveness. OBJECTIVE: The intent of the study was to evaluate use of a fully automated, Web-based program, the Electronic Self Report Assessment-Cancer (ESRA-C), and how delivery and total use of the intervention may have affected cancer symptom distress. METHODS: Patients at two cancer centers used ESRA-C to self-report symptom and quality of life (SxQOL) issues during therapy. Participants were randomized to ESRA-C assessment only (control) or the ESRA-C intervention delivered via the Internet to patients' homes or to a tablet at the clinic. The intervention enabled participants to self monitor SxQOL and receive self-care education and customized coaching on how to report concerns to clinicians. Overall and voluntary intervention use were defined as having >=2 exposures, and one non-prompted exposure to the intervention, respectively. Factors associated with intervention use were explored with Fisher's exact test. Propensity score matching was used to select a sample of control participants similar to intervention participants who used the intervention. Analysis of covariance (ANCOVA) was used to compare change in Symptom Distress Scale (SDS-15) scores from pre-treatment to end-of-study by groups in the matched sample. RESULTS: Radiation oncology participants used the intervention, overall and voluntarily, more than medical oncology and transplant participants. Participants who were working and had more than a high school education voluntarily used the intervention more. The SDS-15 score was reduced by an estimated 1.53 points (P=.01) in the intervention group users compared to the matched control group. CONCLUSIONS: The intended effects of a Web-based, patient centered intervention on cancer symptom distress were modified by intervention use frequency. Clinical and personal demographics influenced voluntary use. TRIAL REGISTRATION: Clinicaltrials.gov NCT00852852; http://clinicaltrials.gov/ct2/show/NCT00852852 (Archived by WebCite at http://www.webcitation.org/6YwAfwWl7). PMID- 26041684 TI - Cyclometalation and coupling of a rigid 4,5-bis(imino)acridanide pincer ligand on yttrium. AB - An extremely rigid NNN-donor proligand, 4,5-bis{(diphenylmethylene)amino}-2,7,9,9 tetramethylacridan, H[AIm2] was prepared in five steps starting from 5-methyl-2 aminobenzoic acid and 4-bromotoluene. Reaction of intensely orange H[AIm2] with LiCH2SiMe3 formed deep blue Li(x)[AIm2]x (x = 2 in the solid state), while reaction with [Y(CH2SiMe3)3(THF)2] (0.5 equiv.) afforded deep blue [Y(AIm2)(AIm)] (1; AIm = an AIm2 ligand cyclometalated at the ortho-position of one of the phenyl rings). Compound 1 slowly isomerizes to form green-brown 2, which contains a single trianionic, hexadentate ligand that features one amine, two imine, and three amido donors. The acridanide backbone and one imine group in each of the original AIm2 ligands is intact, but the two acridanide backbones are now linked by an isoindoline heterocycle. Yttrium in 2 is coordinated to six nitrogen donors and the ortho carbon of an isoindoline phenyl substituent. The intense colours of H[AIm2], Li(x)[AIm2]x and 1 were shown by TD-DFT calculations to arise from charge transfer transitions from the HOMO, which is localized on the acridanide ligand backbone, to the LUMO and LUMO+1, which are localized on the imine substituents. The conversion of 1 to 2 was studied by UV-Visible absorption spectroscopy and is first-order with a half-life of 7.8 hours at room temperature. PMID- 26041683 TI - Extended followup of a cohort of chromium production workers. AB - BACKGROUND: The current study evaluates the mortality of 2,354 workers first employed at a Baltimore chromate production plant between 1950 and 1974. METHODS: The National Death Index (NDI Plus) was used to determine vital status and cause of death. Cumulative chromium (VI) exposure and nasal and skin irritation were evaluated as risk factors for lung cancer mortality. RESULTS: There are 91,186 person-years of observation and 217 lung cancer deaths. Cumulative chromium (VI) exposure, nasal irritation, nasal perforation, nasal ulceration, and other forms of irritation (e.g., skin irritation) were associated with lung cancer mortality. CONCLUSION: Cumulative chromium (VI) exposure was a risk factor for lung cancer death. Cancer deaths, other than lung cancer, were not significantly elevated. Irritation may be a possible mechanism for chromium (VI)-induced lung cancer. PMID- 26041685 TI - [Not Available]. PMID- 26041686 TI - Aqueous dispersions of few-layer-thick chemically modified magnesium diboride nanosheets by ultrasonication assisted exfoliation. AB - The discovery of graphene has led to a rising interest in seeking quasi two dimensional allotropes of several elements and inorganic compounds. Boron, carbon's neighbour in the periodic table, presents a curious case in its ability to be structured as graphene. Although it cannot independently constitute a honeycomb planar structure, it forms a graphenic arrangement in association with electron-donor elements. This is exemplified in magnesium diboride (MgB2): an inorganic layered compound comprising boron honeycomb planes alternated by Mg atoms. Till date, MgB2 has been primarily researched for its superconducting properties; it hasn't been explored for the possibility of its exfoliation. Here we show that ultrasonication of MgB2 in water results in its exfoliation to yield few-layer-thick Mg-deficient hydroxyl-functionalized nanosheets. The hydroxyl groups enable an electrostatically stabilized aqueous dispersion and create a heterogeneity leading to an excitation wavelength dependent photoluminescence. These chemically modified MgB2 nanosheets exhibit an extremely small absorption coefficient of 2.9 ml mg(-1) cm(-1) compared to graphene and its analogs. This ability to exfoliate MgB2 to yield nanosheets with a chemically modified lattice and properties distinct from the parent material presents a fundamentally new perspective to the science of MgB2 and forms a first foundational step towards exfoliating metal borides. PMID- 26041688 TI - Effect of lymph node metastasis size on breast cancer-specific and overall survival in women with node-positive breast cancer. AB - We investigated whether increasing size of lymph nodes (LN) metastases is associated with lower breast cancer-specific survival (BCSS) and overall survival (OS) independent of the number of positive LNs. Using Surveillance, Epidemiology, and End Results registry data, we identified 8791 women diagnosed between 1990 and 2003 with node-positive, non-metastatic invasive breast cancer treated with surgery and axillary LN dissection. Size of the largest involved LN metastasis was categorized as <=2 mm, >2 mm to <2 cm, and >=2 cm. BCSS and OS were estimated using the Kaplan-Meier method and compared using log-rank statistics. Adjusted hazard ratios (HR) were calculated using Cox proportional hazards models. Median follow-up was 109 months. Largest LN size was <=2 mm, >2 mm to <2 cm, and >=2 cm in 2219 (25.2 %), 5047 (57.4 %), and 1525 (17.3 %) women, respectively. The 10 year BCSS for women with LNs <=2 mm, >2 mm to <2 cm, and >=2 cm was 82.9, 75.5, 64.8 %, respectively (p < 0.001). On multivariable analysis, large (>=2 cm) LN size was significantly associated with worsened BCSS (HR: 1.169; p = 0.026) and OS (HR: 1.169; p = 0.006) in addition to age, race, grade, PR status, adjuvant radiation, T-stage, and number of positive LNs. Large (>=2 cm) LNs metastases were associated with lower BCSS and OS after controlling for other known prognostic factors including number of positive LNs. LN size could be useful to risk-stratify patients for adjuvant therapy if these results are validated in future prospective studies. PMID- 26041687 TI - Quality assessment of estrogen receptor and progesterone receptor testing in breast cancer using a tissue microarray-based approach. AB - Assessing hormone receptor status is an essential part of the breast cancer diagnosis, as this biomarker greatly predicts response to hormonal treatment strategies. As such, hormone receptor testing laboratories are strongly encouraged to participate in external quality control schemes to achieve optimization of their immunohistochemical assays. Nine Dutch pathology departments provided tissue blocks containing invasive breast cancers which were all previously tested for estrogen receptor and/or progesterone receptor expression during routine practice. From these tissue blocks, tissue microarrays were constructed and tested for hormone receptor expression. When a discordant result was found between the local and TMA result, the original testing slide was revised and staining was repeated on a whole-tissue block. Sensitivity and specificity of individual laboratories for testing estrogen receptor expression were high, with an overall sensitivity and specificity [corrected] of 99.7 and 95.4%, respectively. Overall sensitivity and specificity of progesterone receptor testing were 94.8 and 92.6%, respectively. Out of 96 discordant cases, 36 cases would have been concordant if the recommended cut-off value of 1% instead of 10% was followed. Overall sensitivity and specificity of estrogen and progesterone receptor testing were high among participating laboratories. Continued enrollment of laboratories into quality control schemes is essential for achieving and maintaining the highest standard of care for breast cancer patients. PMID- 26041689 TI - Photoinduced reductive perfluoroalkylation of phosphine oxides: synthesis of P perfluoroalkylated phosphines using TMDPO and perfluoroalkyl iodides. AB - A photoinduced reaction between TMDPO (diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide) and perfluoroalkyl iodides successfully affords P (perfluoroalkyl)diphenylphosphines as promising ligands for recyclable catalysts. Interestingly, the perfluoroalkylation reaction involves the reduction of phosphorus(V) compounds to phosphorus(III) species. The advantages of the present reaction include the use of an air-stable phosphorus source and good yields of P perfluoroalkylphosphines in short reaction times. PMID- 26041690 TI - Fast wake-up time in obese patients: Which anesthetic is best? PMID- 26041691 TI - Microporous metal-organic framework with dual functionalities for highly efficient removal of acetylene from ethylene/acetylene mixtures. AB - The removal of acetylene from ethylene/acetylene mixtures containing 1% acetylene is a technologically very important, but highly challenging task. Current removal approaches include the partial hydrogenation over a noble metal catalyst and the solvent extraction of cracked olefins, both of which are cost and energy consumptive. Here we report a microporous metal-organic framework in which the suitable pore/cage spaces preferentially take up much more acetylene than ethylene while the functional amine groups on the pore/cage surfaces further enforce their interactions with acetylene molecules, leading to its superior performance for this separation. The single X-ray diffraction studies, temperature dependent gas sorption isotherms, simulated and experimental column breakthrough curves and molecular simulation studies collaboratively support the claim, underlying the potential of this material for the industrial usage of the removal of acetylene from ethylene/acetylene mixtures containing 1% acetylene at room temperature through the cost- and energy-efficient adsorption separation process. PMID- 26041693 TI - Older maternal age and child behavioral and cognitive outcomes: a review of the literature. AB - The trend toward delayed childbearing is widespread in industrialized nations. Although the physical consequences for offspring in utero and in the prenatal period are well known, the psychologic consequences of older motherhood for offspring have received less attention in the literature. In contrast to the heightened physical risks for offspring, the existing research suggests that children of older mothers are often at lower risk for problem behavioral and academic outcomes compared with offspring of mothers in their teens and twenties. Maternal age is inextricably linked with a complex web of psychosocial variables, and the challenge for future research is to better understand the relative influence of these variables on the relationship between maternal age and offspring outcomes. PMID- 26041694 TI - Animal Models for Progressive Multifocal Leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease of the CNS caused by the human polyomavirus JC (JCV). JCV replication occurs only in human cells and investigation of PML has been severely hampered by the lack of an animal model. The common feature of PML is impairment of the immune system. The key to understanding PML is working out the complex mechanisms that underlie viral entry and replication within the CNS and the immunosurveillance that suppresses the virus or allows it to reactivate. Early models involved the simple inoculation of JCV into animals such as monkeys, hamsters, and mice. More recently, mouse models transgenic for the gene encoding the JCV early protein, T-antigen, a protein thought to be involved in the disruption of myelin seen in PML, have been employed. These animal models resulted in tumorigenesis rather than demyelination. Another approach is to use animal polyomaviruses that are closely related to JCV but able to replicate in the animal such as mouse polyomavirus and SV40. More recently, novel models have been developed that involve the engraftment of human cells into the animal. Here, we review progress that has been made to establish an animal model for PML, the advances and limitations of different models and weigh future prospects. PMID- 26041695 TI - Dynamics of the sensory response to urethral flow over multiple time scales in rat. AB - KEY POINTS: Sensory information from the urethra is essential to maintain continence and to achieve efficient micturition and when compromised by disease or injury can lead to substantial loss of function. Despite the key role urethral sensory information plays in the lower urinary tract, the relationship between physiological urethral stimuli, such as fluid flow, and the neural sensory response is poorly understood. This work systematically quantifies pudendal afferent responses to a range of fluid flows in the urethra in vivo and describes a previously unknown long-term neural accommodation phenomenon in these afferents. We present a compact mechanistic mathematical model that reproduces the pudendal sensory activity in response to urethral flow. These results have implications for understanding urinary tract dysfunction caused by neuropathy or nerve damage, such as urinary retention or incontinence, as well as for the development of strategies to mitigate the symptoms of these conditions. The pudendal nerve carries sensory information from the urethra that controls spinal reflexes necessary to maintain continence and achieve efficient micturition. Despite the key role urethral sensory feedback plays in regulation of the lower urinary tract, there is little information about the characteristics of urethral sensory responses to physiological stimuli, and the quantitative relationship between physiological stimuli and the evoked sensory activation is unknown. Such a relation is critical to understanding the neural control of the lower urinary tract and how dysfunction arises in disease states. We systematically quantified pudendal afferent responses to fluid flow in the urethra in vivo in the rat. We characterized the sensory response across a range of stimuli, and describe a previously unreported long-term neural accommodation phenomenon. We developed and validated a compact mechanistic mathematical model capable of reproducing the pudendal sensory activity in response to arbitrary profiles of urethral flows. These results describe the properties and function of urethral afferents that are necessary to understand how sensory disruption manifests in lower urinary tract pathophysiology. PMID- 26041696 TI - Being overweight is associated with hippocampal atrophy: the PATH Through Life Study. AB - BACKGROUND: The prevalence of obesity has increased dramatically in the past two decades, with major implications for individual well-being, population health and the economy. Of particular concern is the risk obesity presents for brain health and its consequences in an ageing population. These associations and their time course are not well understood, particularly after middle age. The aim of this study was to investigate whether being overweight/obese or having an increasing body weight is associated with hippocampal atrophy in early old age. METHODS: Participants were 420 unimpaired (Mini-Mental State Examination >26) individuals aged 60-64 years, living in the community and taking part in a large prospective study of ageing over an 8 year follow-up. Magnetic resonance imaging scans were collected at three assessments and the hippocampus was manually traced by expert neuroscientists. Multi-level analyses assessing the relationship between body mass index (BMI) and hippocampal atrophy over 8 years while controlling for important covariates were conducted. RESULTS: Analyses showed that BMI was negatively associated with left (coefficient: -10.65 mm(3); s.e. 4.81; P=0.027) and right (coefficient: -8.18 mm(3); s.e. 4.91; P=0.097) hippocampal volume at the first assessment. Over the follow-up period, those with a higher BMI experienced greater hippocampal atrophy and more so in the left (P=0.001) than in the right (P=0.058) hippocampus. CONCLUSIONS: The findings from this study provide important evidence indicating that being overweight or obese is associated with poorer brain health. These results are consistent with those of previous animal and human studies and further stress the importance of reducing the rate of obesity through education, population health interventions and policy. PMID- 26041697 TI - Job strain and risk of obesity: systematic review and meta-analysis of cohort studies. AB - Job strain, the most widely used indicator of work stress, is a risk factor for obesity-related disorders such as cardiovascular disease and type 2 diabetes. However, the extent to which job strain is related to the development of obesity itself has not been systematically evaluated. We carried out a systematic review (PubMed and Embase until May 2014) and meta-analysis of cohort studies to address this issue. Eight studies that fulfilled inclusion criteria showed no overall association between job strain and the risk of weight gain (pooled odds ratio for job strain compared with no job strain 1.04, 95% confidence interval (CI) 0.99 1.09, NTotal=18 240) or becoming obese (1.00, 95% CI 0.89-1.13, NTotal=42 222). In addition, a reduction in job strain over time was not associated with lower obesity risk (1.13, 95% CI 0.90-1.41, NTotal=6507). These longitudinal findings do not support the hypothesis that job strain is an important risk factor for obesity or a promising target for obesity prevention. PMID- 26041699 TI - Six-year changes in body mass index and cardiorespiratory fitness of English schoolchildren from an affluent area. AB - We compared values of body mass index (BMI) and cardiorespiratory fitness (20 m shuttle-run test) of n=157 boys and n=150 girls aged 10-11 measured in 2014 with measures from 2008 and 1998. Boys' fitness was lower (d=0.68) in 2014 than 2008, despite a small (d=0.37) decline in BMI. Girl's BMI changed trivially (d=0.08) but cardiorespiratory fitness was lower (d=0.47) in 2014 than 2008. This study suggests fitness is declining at 0.95% per year, which exceeds the 0.8% rate of decline we reported between 1998 and 2008 and is double the global average of 0.43%. Declines in fitness were independent of changes in BMI suggesting continued reductions in English children's habitual physical activity levels. PMID- 26041700 TI - Radial force measurement of endovascular stents: Influence of stent design and diameter. AB - BACKGROUND AND PURPOSE: Angioplasty and endovascular stent placement is used in case to rescue the coverage of main branches to supply blood to brain from aortic arch in thoracic endovascular aortic repair. This study assessed mechanical properties, especially differences in radial force, of different endovascular and thoracic stents. MATERIAL AND METHODS: We analyzed the radial force of three stent models (Epic, E-Luminexx and SMART) stents using radial force-tester method in single or overlapping conditions. We also analyzed radial force in three thoracic stents using Mylar film testing method: conformable Gore-TAG, Relay, and Valiant Thoracic Stent Graft. RESULTS: Overlapping SMART stents had greater radial force than overlapping Epic or Luminexx stents (P < 0.01). The radial force of the thoracic stents was greater than that of all three endovascular stents (P < 0.01). CONCLUSIONS: Differences in radial force depend on types of stents, site of deployment, and layer characteristics. In clinical settings, an understanding of the mechanical characteristics, including radial force, is important in choosing a stent for each patient. PMID- 26041698 TI - Intermuscular and perimuscular fat expansion in obesity correlates with skeletal muscle T cell and macrophage infiltration and insulin resistance. AB - BACKGROUND/OBJECTIVES: Limited numbers of studies demonstrated obesity-induced macrophage infiltration in skeletal muscle (SM), but dynamics of immune cell accumulation and contribution of T cells to SM insulin resistance are understudied. SUBJECTS/METHODS: T cells and macrophage markers were examined in SM of obese humans by reverse transcription-PCR (RT-PCR). Mice were fed high-fat diet (HFD) for 2-24 weeks, and time course of macrophage and T-cell accumulation was assessed by flow cytometry and quantitative RT-PCR. Extramyocellular adipose tissue (EMAT) was quantified by high-resolution micro-computed tomography (CT), and correlation to T-cell number in SM was examined. CD11a-/- mice and C57BL/6 mice were treated with CD11a-neutralizing antibody to determine the role of CD11a in T-cell accumulation in SM. To investigate the involvement of Janus kinase/signal transducer and activator of transcription (JAK/STAT), the major pathway for T helper I (TH1) cytokine interferon-gamma, in SM and adipose tissue inflammation and insulin resistance, mice were treated with a JAK1/JAK2 inhibitor, baricitinib. RESULTS: Macrophage and T-cell markers were upregulated in SM of obese compared with lean humans. SM of obese mice had higher expression of inflammatory cytokines, with macrophages increasing by 2 weeks on HFD and T cells increasing by 8 weeks. The immune cells were localized in EMAT. Micro-CT revealed that EMAT expansion in obese mice correlated with T-cell infiltration and insulin resistance. Deficiency or neutralization of CD11a reduced T-cell accumulation in SM of obese mice. T cells polarized into a proinflammatory TH1 phenotype, with increased STAT1 phosphorylation in SM of obese mice. In vivo inhibition of JAK/STAT pathway with baricitinib reduced T-cell numbers and activation markers in SM and adipose tissue and improved insulin resistance in obese mice. CONCLUSIONS: Obesity-induced expansion of EMAT in SM was associated with accumulation and proinflammatory polarization of T cells, which may regulate SM metabolic functions through paracrine mechanisms. Obesity-associated SM 'adiposopathy' may thus have an important role in the development of insulin resistance and inflammation. PMID- 26041701 TI - Superior electro-optic response in multiferroic bismuth ferrite nanoparticle doped nematic liquid crystal device. AB - A superior electro-optic (E-O) response has been achieved when multiferroic bismuth ferrite (BiFeO3/BFO) nanoparticles (NPs) were doped in nematic liquid crystal (NLC) host E7 and the LC device was addressed in the large signal regime by an amplitude modulated square wave signal at the frequency of 100 Hz. The optimized concentration of BFO is 0.15 wt%, and the corresponding total optical response time (rise time + decay time) for a 5 MUm-thick cell is 2.5 ms for ~7 V(rms). This might be exploited for the construction of adaptive lenses, modulators, displays, and other E-O devices. The possible reason behind the fast response time could be the visco-elastic constant and restoring force imparted by the locally ordered LCs induced by the multiferroic nanoparticles (MNPs). Polarized optical microscopic textural observation shows that the macroscopic dislocation-free excellent contrast have significant impact on improving the image quality and performance of the devices. PMID- 26041703 TI - Nano-antidotes for drug overdose and poisoning. AB - The number of intoxications from xenobiotics--natural or synthetic foreign chemicals, or substances given in higher doses than typically present in humans- has risen tremendously in the last decade, placing poisoning as the leading external cause of death in the United States. This epidemic has fostered the development of antidotal nanomedicines, which we call "nano-antidotes," capable of efficiently neutralizing offending compounds in situ. Although prototype nano antidotes have shown efficacy in proof-of-concept studies, the gap to clinical translation can only be filled if issues such as the clinical relevance of intoxication models and the safety profile of nano-antidotes are properly addressed. As the unmet medical needs in resuscitative care call for better treatments, this Perspective critically reviews the recent progress in antidotal medicine and emerging nanotechnologies. PMID- 26041702 TI - Global implementation of genomic medicine: We are not alone. AB - Around the world, innovative genomic-medicine programs capitalize on singular capabilities arising from local health care systems, cultural or political milieus, and unusual selected risk alleles or disease burdens. Such individual efforts might benefit from the sharing of approaches and lessons learned in other locales. The U.S. National Human Genome Research Institute and the National Academy of Medicine recently brought together 25 of these groups to compare projects, to examine the current state of implementation and desired near-term capabilities, and to identify opportunities for collaboration that promote the responsible practice of genomic medicine. Efforts to coalesce these groups around concrete but compelling signature projects should accelerate the responsible implementation of genomic medicine in efforts to improve clinical care worldwide. PMID- 26041704 TI - Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. AB - In animals, immunomodulatory dendritic cells (DCs) exposed to autoantigen can suppress experimental arthritis in an antigen-specific manner. In rheumatoid arthritis (RA), disease-specific anti-citrullinated peptide autoantibodies (ACPA or anti-CCP) are found in the serum of about 70% of RA patients and are strongly associated with HLA-DRB1 risk alleles. This study aimed to explore the safety and biological and clinical effects of autologous DCs modified with a nuclear factor kappaB (NF-kappaB) inhibitor exposed to four citrullinated peptide antigens, designated "Rheumavax," in a single-center, open-labeled, first-in-human phase 1 trial. Rheumavax was administered once intradermally at two progressive dose levels to 18 human leukocyte antigen (HLA) risk genotype-positive RA patients with citrullinated peptide-specific autoimmunity. Sixteen RA patients served as controls. Rheumavax was well tolerated: adverse events were grade 1 (of 4) severity. At 1 month after treatment, we observed a reduction in effector T cells and an increased ratio of regulatory to effector T cells; a reduction in serum interleukin-15 (IL-15), IL-29, CX3CL1, and CXCL11; and reduced T cell IL-6 responses to vimentin(447-455)-Cit450 relative to controls. Rheumavax did not induce disease flares in patients recruited with minimal disease activity, and DAS28 decreased within 1 month in Rheumavax-treated patients with active disease. This exploratory study demonstrates safety and biological activity of a single intradermal injection of autologous modified DCs exposed to citrullinated peptides, and provides rationale for further studies to assess clinical efficacy and antigen-specific effects of autoantigen immunomodulatory therapy in RA. PMID- 26041705 TI - Regulator of G protein signaling 5 is a determinant of gestational hypertension and preeclampsia. AB - Preeclampsia is a systemic vascular disorder of pregnancy and is associated with increased sensitivity to angiotensin II (AngII) and hypertension. The cause of preeclampsia remains unknown. We identified the role of regulator of G protein (heterotrimeric guanine nucleotide-binding protein) signaling 5 (RGS5) in blood pressure regulation during pregnancy and preeclampsia. RGS5 expression in human myometrial vessels is markedly suppressed in gestational hypertension and/or preeclampsia. In pregnant RGS5-deficient mice, reduced vascular RGS5 expression causes gestational hypertension by enhancing vascular sensitivity to AngII. Further challenge by increasing AngII results in preeclampsia-like symptoms, namely, more severe hypertension, proteinuria, placental pathology, and reduced birth weight. In pregnant heterozygote null mice, treatment with peroxisome proliferator-activated receptor (PPAR) agonists normalizes vascular function and blood pressure through effects on RGS5. These findings highlight a key role of RGS5 at the interface between AngII and PPAR signaling. Because preeclampsia is refractory to current standard therapies, our study opens an unrecognized and urgently needed opportunity for treatment of gestational hypertension and preeclampsia. PMID- 26041706 TI - A screen of approved drugs and molecular probes identifies therapeutics with anti Ebola virus activity. AB - Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration-approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections. PMID- 26041707 TI - A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates. AB - Currently, there are no commercially available human vaccines against leishmaniasis. In rodents, cellular immunity to salivary proteins of sand fly vectors is associated to protection against leishmaniasis, making them worthy targets for further exploration as vaccines. We demonstrate that nonhuman primates (NHP) exposed to Phlebotomus duboscqi uninfected sand fly bites or immunized with salivary protein PdSP15 are protected against cutaneous leishmaniasis initiated by infected bites. Uninfected sand fly-exposed and 7 of 10 PdSP15-immunized rhesus macaques displayed a significant reduction in disease and parasite burden compared to controls. Protection correlated to the early appearance of Leishmania-specific CD4(+)IFN-gamma(+) lymphocytes, suggesting that immunity to saliva or PdSP15 augments the host immune response to the parasites while maintaining minimal pathology. Notably, the 30% unprotected PdSP15 immunized NHP developed neither immunity to PdSP15 nor an accelerated Leishmania specific immunity. Sera and peripheral blood mononuclear cells from individuals naturally exposed to P. duboscqi bites recognized PdSP15, demonstrating its immunogenicity in humans. PdSP15 sequence and structure show no homology to mammalian proteins, further demonstrating its potential as a component of a vaccine for human leishmaniasis. PMID- 26041708 TI - alpha-Enolase-binding peptide enhances drug delivery efficiency and therapeutic efficacy against colorectal cancer. AB - Colorectal cancer is one of the most commonly diagnosed cancers and a leading cause of cancer mortality worldwide. Current treatment for colorectal cancer results in only limited success, and more effective therapeutic approaches are thus urgently needed. The development of new methods for early detection and effective treatments for cancer is contingent on the identification of biomarkers on the surface of cancer cells, as well as isolation of tumor-specific ligands with high binding affinity to such biomarkers. In vitro biopanning of a phage displayed peptide library was used to identify specific peptides binding to human colorectal carcinoma cells. The targeting peptide pHCT74 showed the greatest potential for drug delivery in both in vitro and in vivo studies. The use of biotinylated peptides combined with an affinity trapping method and liquid chromatography-tandem mass spectrometry identified the target protein for the pHCT74 peptide as alpha-enolase. In animal model studies, combined pHCT74 conjugated liposomal doxorubicin (pHCT74-LD) and pHCT74-conjugated liposomal vinorelbine (pHCT74-sLV) therapy exhibited an enhanced antitumor effect and markedly extended the survival of mice with human colorectal cancer in subcutaneous and orthotopic models. Our findings indicate that alpha-enolase targeted lipid nanoparticles have great potential for application in targeted drug delivery systems for colorectal cancer therapy. PMID- 26041710 TI - COPING IN YOUNG PEOPLE WITH CHRONIC KIDNEY DISEASE (CKD). AB - BACKGROUND: Chronic kidney disease (CKD) is an irreversible disease with physiological, psychological and psychosocial challenges, especially for young people. OBJECTIVES: The objective of this phenomenological study was to identify coping strategies in two groups of young people aged 12-18 years. In one group, the young people were healthy and in the other group, the young people had stage 4-5 CKD. DESIGN: Young people with CKD (stages 4-5) (n = 7) (mean age = 11.5 yrs.) and young healthy people (n = 7) (mean age = 14 yrs.) were recruited from a Children's Hospital and Youth Club respectively, and were invited to take part in one face-to-face, semi-structured interview. FINDINGS: Data analysis showed 11 different coping themes. CONCLUSION: It can be concluded from the interviews that young healthy people and those with CKD alike, utilise a range of coping strategies. The themes derived can prompt researchers to potentially develop a coping measure for a young CKD population. However, a longitudinal study would help to recognise coping strategies young people adopt over time and provide a pathway for the development of a formal coping framework. PMID- 26041709 TI - Drug-induced regeneration in adult mice. AB - Whereas amphibians regenerate lost appendages spontaneously, mammals generally form scars over the injury site through the process of wound repair. The MRL mouse strain is an exception among mammals because it shows a spontaneous regenerative healing trait and so can be used to investigate proregenerative interventions in mammals. We report that hypoxia-inducible factor 1alpha (HIF 1alpha) is a central molecule in the process of regeneration in adult MRL mice. The degradation of HIF-1alpha protein, which occurs under normoxic conditions, is mediated by prolyl hydroxylases (PHDs). We used the drug 1,4-dihydrophenonthrolin 4-one-3-carboxylic acid (1,4-DPCA), a PHD inhibitor, to stabilize constitutive expression of HIF-1alpha protein. A locally injectable hydrogel containing 1,4 DPCA was designed to achieve controlled delivery of the drug over 4 to 10 days. Subcutaneous injection of the 1,4-DPCA/hydrogel into Swiss Webster mice that do not show a regenerative phenotype increased stable expression of HIF-1alpha protein over 5 days, providing a functional measure of drug release in vivo. Multiple peripheral subcutaneous injections of the 1,4-DPCA/hydrogel over a 10 day period led to regenerative wound healing in Swiss Webster mice after ear hole punch injury. Increased expression of the HIF-1alpha protein may provide a starting point for future studies on regeneration in mammals. PMID- 26041713 TI - Robert Gunter Spiro. PMID- 26041711 TI - Geographic Variation of Amyotrophic Lateral Sclerosis Incidence in New Jersey, 2009-2011. AB - Few analyses in the United States have examined geographic variation and socioeconomic disparities in amyotrophic lateral sclerosis (ALS) incidence, because of lack of population-based incidence data. In this analysis, we used population-based ALS data to identify whether ALS incidence clusters geographically and to determine whether ALS risk varies by area-based socioeconomic status (SES). This study included 493 incident ALS cases diagnosed (via El Escorial criteria) in New Jersey between 2009 and 2011. Geographic variation and clustering of ALS incidence was assessed using a spatial scan statistic and Bayesian geoadditive models. Poisson regression was used to estimate the associations between ALS risk and SES based on census-tract median income while controlling for age, sex, and race. ALS incidence varied across and within counties, but there were no statistically significant geographic clusters. SES was associated with ALS incidence. After adjustment for age, sex, and race, the relative risk of ALS was significantly higher (relative risk (RR) = 1.37, 95% confidence interval (CI): 1.02, 1.82) in the highest income quartile than in the lowest. The relative risk of ALS was significantly lower among blacks (RR = 0.57, 95% CI: 0.39, 0.83) and Asians (RR = 0.63, 95% CI: 0.41, 0.97) than among whites. Our findings suggest that ALS incidence in New Jersey appears to be associated with SES and race. PMID- 26041715 TI - Combined Spectroscopic and Electrochemical Detection of a Ni(I) ???H-N Bonding Interaction with Relevance to Electrocatalytic H2 Production. AB - The [Ni(P(R) 2 N(R') 2 )2 ](2+) family of complexes are exceptionally active catalysts for proton reduction to H2 . In this manuscript, we explore the first protonation step of the proposed catalytic cycle by using a catalytically inactive Ni(I) complex possessing a sterically demanding variation of the ligand. Due to the paramagnetic nature of the Ni(I) oxidation state, the protonated Ni(I) intermediate has been characterized through a combination of cyclic voltammetry, electron nuclear double resonance (ENDOR) spectroscopy, and hyperfine sublevel correlation (HYSCORE) spectroscopy. Both the electrochemical and spectroscopic studies indicate that the Ni(I) complex is protonated at a pendant amine that is endo to Ni, which suggests the presence of an intramolecular Ni(I) ???HN bonding interaction. Using density functional theory, the hydrogen bond was found to involve three doubly-occupied, localized molecular orbitals: the 3dxz , 3d z 2, and 3dyz orbitals of nickel. These studies provide the first direct experimental evidence for this critical catalytic intermediate, and implications for catalytic H2 production are discussed. PMID- 26041714 TI - Neuroendocrine neoplasms of the sinonasal region. AB - Neuroendocrine neoplasms of the sinonasal region, which are relatively uncommon but clinically very important, are reviewed here in the light of current knowledge. Using a definition for neuroendocrine based on phenotypic, histologic, immunohistochemical, and electron microscopic features rather than histogenetic criteria, sinonasal neuroendocrine carcinomas are examined with a particular emphasis on the small-cell and large-cell subtypes. This is followed by revisiting olfactory neuroblastoma because it is also a tumor that shows a neuroendocrine phenotype. Kadish clinical and Hyams histologic grading systems as prognosticators of olfactory neuroblastoma are also considered in detail. Finally, controversies regarding sinonasal undifferentiated carcinoma as a neuroendocrine tumor are discussed and a possible relationship with high-grade olfactory neuroblastoma is explored. Genetic events and current management of these tumors are also outlined. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E2259-E2266, 2016. PMID- 26041716 TI - Haemostatic efficacy of fibrinogen concentrate: is it the threshold or the timing of therapy? PMID- 26041717 TI - Pitfalls in reporting sample size calculation in randomized controlled trials published in leading anaesthesia journals: a systematic review. AB - We have evaluated the pitfalls in reporting sample size calculation in randomized controlled trials (RCTs) published in the 10 highest impact factor anaesthesia journals.Superiority RCTs published in 2013 were identified and checked for the basic components required for sample size calculation and replication. The difference between the reported and replicated sample size was estimated. The sources used for estimating the expected effect size (Delta) were identified, and the difference between the expected and observed effect sizes (Delta gap) was estimated.We enrolled 194 RCTs. Sample size calculation was reported in 91.7% of studies. Replication of sample size calculation was possible in 80.3% of studies. The original and replicated sample sizes were identical in 67.8% of studies. The difference between the replicated and reported sample sizes exceeded 10% in 28.7% of studies. The expected and observed effect sizes were comparable in RCTs with positive outcomes (P=0.1). Studies with negative outcome tended to overestimate the effect size (Delta gap 42%, 95% confidence interval 32-51%), P<0.001. Post hoc power of negative studies was 20.2% (95% confidence interval 13.4-27.1%). Studies using data derived from pilot studies for sample size calculation were associated with the smallest Delta gaps (P=0.008).Sample size calculation is frequently reported in anaesthesia journals, but the details of basic elements for calculation are not consistently provided. In almost one-third of RCTs, the reported and replicated sample sizes were not identical and the assumptions for the expected effect size and variance were not supported by relevant literature or pilot studies. PMID- 26041718 TI - Right Ventricular Wall Dissection With Ventricular Septal Rupture Following Myocardial Infarction Visualized on 3-Dimensional Transthoracic Echocardiography. PMID- 26041719 TI - Is Circulating Fibroblast Growth Factor 23 a Surrogate Marker or Active Mediator for the Construction of Atrial Fibrillation Substrate? PMID- 26041720 TI - Fountain of Youth in the Aorta. PMID- 26041721 TI - Exon 19 deletion was associated with better survival outcomes in advanced lung adenocarcinoma with mutant EGFR treated with EGFR-TKIs as second-line therapy after first-line chemotherapy: a retrospective analysis of 128 patients. AB - OBJECTIVE: To determine whether the specific genotype of exon 19 deletion has a better survival outcome than that of exon 21 substitution in advanced lung adenocarcinoma with EGFR mutant patients that were treated with EGFR-TKIs as second-line therapy after first-line chemotherapy. METHODS: Between April 1, 2010 and December 31, 2012, the detailed clinical information of 128 patients was screened from the hospital information database of the First Affiliated Hospital and the Third Affiliated Hospital of Kunming Medical University by inclusion/exclusion criteria. Then, a telephone follow-up and a review of all patients' image data were done to obtain the survival information of all patients. After that, all patients' data were processed by IBM((r)) SPSS((r)) version 19.0. RESULTS: There were correlations between EGFR mutation status, gross tumor type and PFS or OS according to the Kaplan-Meier survival analyses and log-rank tests. The exon 19 deletions had significantly better survival outcomes in comparison to exon 21 substitutions (median PFS: 8.1 vs. 6.8 months, P = 0.002; median OS: 17.6 vs. 12.5 months, P = 0.000). Stratification analyses of PFS and OS revealed that exon 19 deletions had a survival superior to exon 21 substitutions. CONCLUSION: Compared with L858R mutation, the genotype of exon 19 deletion had a better survival outcome in terms of PFS and OS in patients with advanced lung adenocarcinoma treated with EGFR-TKIs as second-line therapy after first-line chemotherapy. PMID- 26041722 TI - Locoregional recurrence after curative intent resection for intrahepatic cholangiocarcinoma: implications for adjuvant radiotherapy. AB - BACKGROUNDS: As for intrahepatic cholangiocarcinoma, the most frequent site of failure after curative intent resection is the liver. We identified the risk factors for locoregional recurrence after curative intent resection for intrahepatic cholangiocarcinoma. METHODS: Medical records of 115 patients treated with surgical resection alone for intrahepatic cholangiocarcinoma from November 2000 to December 2010 were retrospectively reviewed. Locoregional failure was defined as recurrence within 20 mm from resection margin or regional lymph node. Overall survival and locoregional recurrence rates were analyzed using Kaplan Meier methods, and the prognostic factors were analyzed using Cox proportional hazards model. RESULTS: Median follow-up duration of surviving patients was 61 months (range 8-139). Sixty-six patients had recurrence, and 45 of 66 patients (68 %) had locoregional recurrence. The 5-year overall survival and locoregional control rates were 49.1 and 51.6 %, respectively. >= T2b disease and R1 resection were associated with locoregional recurrence in multivariate analysis. Patients were divided into two groups whether these risk factors exist or not. The 5-year locoregional control rates of low (no risk factor n = 64) and high (1 or 2 risk factors n = 51) risk groups were 62.5 and 34.7 %, respectively (P = 0.001). CONCLUSIONS: After curative intent resection, locoregional control and survival of patients with intrahepatic cholangiocarcinoma were far from satisfactory. Further studies are needed to evaluate the potential benefit of adjuvant locoregional treatment such as radiotherapy for patients with high-risk factors (>= T2b disease or R1 resection). PMID- 26041723 TI - Sonographic features of primary tumor as independent predictive factors for lymph node metastasis in papillary thyroid carcinoma. AB - PURPOSE: The aim of this research was to find the sonographic features of primary tumor as independent predictive factors for lymph node metastasis in papillary thyroid carcinoma. METHODS/PATIENTS: To facilitate the research, 514 patients with papillary thyroid carcinoma were divided into solitary and multifocal groups. In solitary group, thyroid lesions were divided into several subgroups by size, border, margin, echogenicity, echohomogeneity, calcification, vascularization, location, stiffness and Hashimoto's thyroiditis (HT) conditions. Then, univariable and multivariable analyses were performed to find the sonographic features of primary tumor as independent predictive factors for lymph node metastasis in papillary thyroid carcinoma. RESULTS: A significant difference of lymph node metastasis rate was found between multifocal and solitary groups (P < 0.05). In univariable analysis, size, vascularization and coexistence of HT were found to be statistically significant factors (P = 0.004, 0.118, 0.016). Multivariable analysis revealed that lymph node metastasis rate was mainly associated with size [odds ratio (OR) = 1.690, 95 % confidence interval (CI) 1.157-2.469] and coexistence of HT (OR = 0.441, 95 % CI 0.219-0.888). CONCLUSION: Preoperative sonographic features of primary tumor including the number, size and coexistence of HT were independent predictive factors for the state of cervical lymph node metastasis in patients with papillary thyroid carcinoma. PMID- 26041724 TI - Long-term morbidity after multivisceral resection for retroperitoneal sarcoma. AB - BACKGROUND: More than 60 per cent of patients treated surgically for primary retroperitoneal sarcoma survive for at least 5 years. Extended surgical resection has been proposed for primary disease, but long-term morbidity data are lacking. A cross-sectional study was conducted to assess the long-term morbidity of patients undergoing surgery for retroperitoneal sarcoma. METHODS: Patients operated on between January 2002 and December 2011 were eligible for the study. Long-term morbidity was evaluated based on a semistructured clinical interview. Lower limb function was assessed by means of the Lower Extremity Functional Scale (LEFS), a self-report questionnaire with a total score ranging from 0 (low functioning) to 80 (high functioning). Pain was investigated by means of the Brief Pain Inventory--Short Form, with pain intensity scores reported on a scale from 0 (no pain) to 10 (worst pain). RESULTS: Some 243 patients underwent surgery, and 101 of 160 patients who were alive at the time of the investigation responded to the study invitation letter. Finally, 95 patients were enrolled in the study. Sensory impairment of the limbs was reported in 72 patients (76 per cent). The median LEFS score was 60 (i.q.r. 43-73). Mean scores for the pain intensity items varied from 1.23 to 2.68. In multivariable analysis, there was no difference in median levels of creatinine at survey between patients who did or did not undergo nephrectomy (difference between median values 13 (95 per cent c.i. -4 to 30) umol/l; P = 0.170). CONCLUSION: Severe chronic pain and lower limb motor impairment after multivisceral resection for retroperitoneal sarcomas are rare. Long-term renal function is not significantly impaired when nephrectomy is performed. PMID- 26041725 TI - Erratum to: Evolutionary trends of European bat lyssavirus type 2 including genetic characterization of Finnish strains of human and bat origin 24 years apart. PMID- 26041728 TI - Post-infection symptoms following two large waterborne outbreaks of Cryptosporidium hominis in Northern Sweden, 2010-2011. AB - BACKGROUND: In 2010-2011, two large waterborne outbreaks caused by Cryptosporidium hominis affected two cities in Sweden, Ostersund and Skelleftea. We investigated potential post-infection health consequences in people who had reported symptoms compatible with cryptosporidiosis during the outbreaks using questionnaires. METHODS: We compared cases linked to these outbreaks with non cases in terms of symptoms present up to eleven months after the initial infection. We examined if cases were more likely to report a list of symptoms at follow-up than non-cases, calculating odds ratios (OR) and 95 % confidence intervals (CI) obtained through logistic regression. RESULTS: A total of 872 (310 cases) and 743 (149 cases) individuals responded to the follow-up questionnaires in Ostersund and Skelleftea respectively. Outbreak cases were more likely to report diarrhea (Ostersund OR: 3.3, CI: 2.0-5.3. Skelleftea OR: 3.6, CI: 2.0 6.6), watery diarrhea (Ostersund OR: 3.4, CI: 1.9-6.3. Skelleftea OR: 2.8, CI: 1.5-5.1) abdominal pain (Ostersund OR: 2.1, CI: 1.4-3.3, Skelleftea OR: 2.7, CI: 1.5-4.6) and joint pain (Ostersund OR: 2.0, CI: 1.2-3.3, Skelleftea OR: 2.0, CI: 1.1-3.6) at follow-up compared to non-cases. CONCLUSIONS: Our findings suggest that gastrointestinal- and joint symptoms can persist several months after the initial infection with Cryptosporidium and should be regarded as a potential cause of unexplained symptoms in people who have suffered from the infection. PMID- 26041729 TI - Reconstruction of recurrent synaptic connectivity of thousands of neurons from simulated spiking activity. AB - Dynamics and function of neuronal networks are determined by their synaptic connectivity. Current experimental methods to analyze synaptic network structure on the cellular level, however, cover only small fractions of functional neuronal circuits, typically without a simultaneous record of neuronal spiking activity. Here we present a method for the reconstruction of large recurrent neuronal networks from thousands of parallel spike train recordings. We employ maximum likelihood estimation of a generalized linear model of the spiking activity in continuous time. For this model the point process likelihood is concave, such that a global optimum of the parameters can be obtained by gradient ascent. Previous methods, including those of the same class, did not allow recurrent networks of that order of magnitude to be reconstructed due to prohibitive computational cost and numerical instabilities. We describe a minimal model that is optimized for large networks and an efficient scheme for its parallelized numerical optimization on generic computing clusters. For a simulated balanced random network of 1000 neurons, synaptic connectivity is recovered with a misclassification error rate of less than 1 % under ideal conditions. We show that the error rate remains low in a series of example cases under progressively less ideal conditions. Finally, we successfully reconstruct the connectivity of a hidden synfire chain that is embedded in a random network, which requires clustering of the network connectivity to reveal the synfire groups. Our results demonstrate how synaptic connectivity could potentially be inferred from large scale parallel spike train recordings. PMID- 26041730 TI - Can standards and regulations keep up with health technology? AB - Technology is changing at a rapid rate, opening up new possibilities within the health care domain. Advances such as open source hardware, personal medical devices, and mobile phone apps are creating opportunities for custom-made medical devices and personalized care. However, they also introduce new challenges in balancing the need for regulation (ensuring safety and performance) with the need to innovate flexibly and efficiently. Compared with the emergence of new technologies, health technology design standards and regulations evolve slowly, and therefore, it can be difficult to apply these standards to the latest developments. For example, current regulations may not be suitable for approaches involving open source hardware, an increasingly popular way to create medical devices in the maker community. Medical device standards may not be flexible enough when evaluating the usability of mobile medical devices that can be used in a multitude of different ways, outside of clinical settings. Similarly, while regulatory guidance has been updated to address the proliferation of health related mobile phone apps, it can be hard to know if and when these regulations apply. In this viewpoint, we present three examples of novel medical technologies to illustrate the types of regulatory issues that arise in the current environment. We also suggest opportunities for support, such as advances in the way we review and monitor medical technologies. PMID- 26041731 TI - Tobacco plain packaging: Evidence based policy or public health advocacy? AB - In December 2012, Australia became the first country to require all tobacco products be sold solely in standardised or 'plain' packaging, bereft of the manufacturers' trademarked branding and colours, although retaining large graphic and text health warnings. Following the publication of Sir Cyril Chantler's review of the evidence on the effects of plain tobacco packaging, the Ministers of the United Kingdom Parliament voted in March 2015 to implement similar legislation. Support for plain packaging derives from the belief that tobacco products sold in plain packs have reduced appeal and so are more likely to deter young people and non-smokers from starting tobacco use, and more likely to motivate smokers to quit and stay quit. This article considers why support for the plain packaging policy has grown among tobacco control researchers, public health advocates and government ministers, and reviews Australian survey data that speak to the possible introductory effect of plain packaging on smoking prevalence within Australia. The article concludes by emphasising the need for more detailed research to be undertaken before judging the capacity of the plain packaging policy to deliver the multitude of positive effects that have been claimed by its most ardent supporters. PMID- 26041732 TI - Over-expression of Trxo1 increases the viability of tobacco BY-2 cells under H2O2 treatment. AB - BACKGROUND AND AIMS: Reactive oxygen species (ROS), especially hydrogen peroxide, play a critical role in the regulation of plant development and in the induction of plant defence responses during stress adaptation, as well as in plant cell death. The antioxidant system is responsible for controlling ROS levels in these processes but redox homeostasis is also a key factor in plant cell metabolism under normal and stress situations. Thioredoxins (Trxs) are ubiquitous small proteins found in different cell compartments, including mitochondria and nuclei (Trxo1), and are involved in the regulation of target proteins through reduction of disulphide bonds, although their role under oxidative stress has been less well studied. This study describes over-expression of a Trxo1 for the first time, using a cell-culture model subjected to an oxidative treatment provoked by H2O2. METHODS: Control and over-expressing PsTrxo1 tobacco (Nicotiana tabacum) BY-2 cells were treated with 35 mm H2O2 and the effects were analysed by studying the growth dynamics of the cultures together with oxidative stress parameters, as well as several components of the antioxidant systems involved in the metabolism of H2O2. Analysis of different hallmarks of programmed cell death was also carried out. KEY RESULTS: Over-expression of PsTrxo1 caused significant differences in the response of TBY-2 cells to high concentrations of H2O2, namely higher and maintained viability in over-expressing cells, whilst the control line presented a severe decrease in viability and marked indications of oxidative stress, with generalized cell death after 3 d of treatment. In over-expressing cells, an increase in catalase activity, decreases in H2O2 and nitric oxide contents and maintenance of the glutathione redox state were observed. CONCLUSIONS: A decreased content of endogenous H2O2 may be responsible in part for the delayed cell death found in over-expressing cells, in which changes in oxidative parameters and antioxidants were less extended after the oxidative treatment. It is concluded that PsTrxo1 transformation protects TBY-2 cells from exogenous H2O2, thus increasing their viability via a process in which not only antioxidants but also Trxo1 seem to be involved. PMID- 26041734 TI - Underrecognized Peripheral Arterial Disease in Patients With Diabetes Mellitus in Thailand: We Must Consider Neuroischemic Foot Ulcers From This Fallout. AB - A range of prevalence of peripheral artery disease in diabetic patients has been estimated using the measurement of ankle brachial pressure index and clinical features in Asian countries. These data may be underestimates and hence underrecognized, raising questions about the numbers of patients with neuroischemic feet who are also at risk of diabetic foot ulcers. Underrecognition of these lesions may well increase the high levels of chronic wound burden resulting from peripheral artery disease as well as neuroischemic foot lesions. Improved education and training of clinical staff (nurses and family physicians) is required to combat these serious issues. PMID- 26041733 TI - Polyphenol oxidase-mediated protection against oxidative stress is not associated with enhanced photosynthetic efficiency. AB - BACKGROUND AND AIMS: Polyphenol oxidases (PPOs) catalyse the oxidation of monophenols and/or o-diphenols to highly reactive o-quinones, which in turn interact with oxygen and proteins to form reactive oxygen species (ROS) and typical brown-pigmented complexes. Hence PPOs can affect local levels of oxygen and ROS. Although the currently known substrates are located in the vacuole, the enzyme is targeted to the thylakoid lumen, suggesting a role for PPOs in photosynthesis. The current study was designed to investigate the potential involvement of PPOs in the photosynthetic response to oxidative stress. METHODS: Photosynthesis (A, Fv/Fm, PhiPSII, qN, qP, NPQ) was measured in leaves of a wild type and a low-PPO mutant of red clover (Trifolium pratense 'Milvus') under control conditions and under a stress treatment designed to induce photooxidative stress: cold/high light (2 degrees C/580 umol m(2 )s(-1)) or 0-10 um methyl viologen. Foliar protein content and oxidation state were also determined. KEY RESULTS: Photosynthetic performance, and chlorophyll and protein content during 4 d of cold/high light stress and 3 d of subsequent recovery under control growth conditions showed similar susceptibility to stress in both lines. However, more extensive oxidative damage to protein in mutants than wild-types was observed after treatment of attached leaves with methyl viologen. In addition, PPO activity could be associated with an increased capacity to dissipate excess energy, but only at relatively low methyl viologen doses. CONCLUSIONS: The presence of PPO activity in leaves did not correspond to a direct role for the enzyme in the regulation or protection of photosynthesis under cold stress. However, an indication that PPO could be involved in cellular protection against low-level oxidative stress requires further investigation. PMID- 26041735 TI - PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope Modified DNA Vaccine Immunization. AB - DNA vaccines have demonstrated antitumor efficacy in multiple preclinical models, but low immunogenicity has been observed in several human clinical trials. This has led to many approaches seeking to improve the immunogenicity of DNA vaccines. We previously reported that a DNA vaccine encoding the cancer-testis antigen SSX2, modified to encode altered epitopes with increased MHC class I affinity, elicited a greater frequency of cytolytic, multifunctional CD8(+) T cells in non tumor-bearing mice. We sought to test whether this optimized vaccine resulted in increased antitumor activity in mice bearing an HLA-A2-expressing tumor engineered to express SSX2. We found that immunization of tumor-bearing mice with the optimized vaccine elicited a surprisingly inferior antitumor effect relative to the native vaccine. Both native and optimized vaccines led to increased expression of PD-L1 on tumor cells, but antigen-specific CD8(+) T cells from mice immunized with the optimized construct expressed higher PD-1. Splenocytes from immunized animals induced PD-L1 expression on tumor cells in vitro. Antitumor activity of the optimized vaccine could be increased when combined with antibodies blocking PD-1 or PD-L1, or by targeting a tumor line not expressing PD L1. These findings suggest that vaccines aimed at eliciting effector CD8(+) T cells, and DNA vaccines in particular, might best be combined with PD-1 pathway inhibitors in clinical trials. This strategy may be particularly advantageous for vaccines targeting prostate cancer, a disease for which antitumor vaccines have demonstrated clinical benefit and yet PD-1 pathway inhibitors alone have shown little efficacy to date. PMID- 26041736 TI - Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy. AB - The beta-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the beta-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti CTLA-4 antibody therapy. Finally, our data suggest that beta-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node-derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt-beta-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy. PMID- 26041737 TI - First-in-Human Case Study: Multipotent Adult Progenitor Cells for Immunomodulation After Liver Transplantation. AB - Mesenchymal stem cells and multipotent adult progenitor cells (MAPCs) have been proposed as novel therapeutics for solid organ transplant recipients with the aim of reducing exposure to pharmacological immunosuppression and its side effects. In the present study, we describe the clinical course of the first patient of the phase I, dose-escalation safety and feasibility study, MiSOT-I (Mesenchymal Stem Cells in Solid Organ Transplantation Phase I). After receiving a living-related liver graft, the patient was given one intraportal injection and one intravenous infusion of third-party MAPC in a low-dose pharmacological immunosuppressive background. Cell administration was found to be technically feasible; importantly, we found no evidence of acute toxicity associated with MAPC infusions. PMID- 26041738 TI - Identification of Neurexophilin 3 as a Novel Supportive Factor for Survival of Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors. AB - Successful cell transplantation for Parkinson's disease (PD) depends on both an optimal host brain environment and ideal donor cells. We report that a secreted peptide, neurexophilin 3 (NXPH3), supports the survival of mouse induced pluripotent stem cell-derived (iPSC-derived) dopaminergic (DA) neurons in vitro and in vivo. We compared the gene expression profiles in the mouse striatum from two different environments: a supportive environment, which we defined as 1 week after acute administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and a nonsupportive environment, defined as 8 weeks after chronic administration of MPTP. NXPH3 expression was higher in the former condition and lower in the latter compared with untreated controls. When we injected mouse iPSC derived neural cells along with NXPH3 into the mouse striatum, the ratio of tyrosine hydroxylase-positive DA neurons per graft volume was higher at 8 weeks compared with cell injections that excluded NXPH3. In addition, quantitative polymerase chain reaction analyses of the postmortem putamen revealed that the expression level of NXPH3 was lower in PD patients compared with normal controls. These findings will contribute to optimizing the host brain environment and patient recruitment in cell therapy for PD. PMID- 26041740 TI - Isolated Gallbladder Intramucosal Metastatic Melanoma With Features Mimicking Lymphoepithelial Carcinoma. AB - Malignant melanoma has a variety of morphologic patterns and can metastasize and mimic any type of neoplastic process creating significant diagnostic difficulty. When metastasis to the gastrointestinal system is identified, it is most commonly associated with widely metastatic disease. We report a rare case of isolated gallbladder intramucosal metastatic melanoma with features mimicking lymphoepithelial carcinoma in an adult patient who presented with cholecystitis. Additionally, we report the imaging and morphologic features and discuss the importance of these findings along with a clear clinical history and immunohistochemical profile to make a definitive diagnosis. PMID- 26041739 TI - Low Molecular Weight Fraction of Commercial Human Serum Albumin Induces Morphologic and Transcriptional Changes of Bone Marrow-Derived Mesenchymal Stem Cells. AB - Osteoarthritis (OA) is the most common chronic disease of the joint; however, the therapeutic options for severe OA are limited. The low molecular weight fraction of commercial 5% human serum albumin (LMWF5A) has been shown to have anti inflammatory properties that are mediated, in part, by a diketopiperazine that is present in the albumin preparation and that was demonstrated to be safe and effective in reducing pain and improving function when administered intra articularly in a phase III clinical trial. In the present study, bone marrow derived mesenchymal stem cells (BMMSCs) exposed to LMWF5A exhibited an elongated phenotype with diffuse intracellular F-actin, pronounced migratory leading edges, and filopodia-like projections. In addition, LMWF5A promoted chondrogenic condensation in "micromass" culture, concurrent with the upregulation of collagen 2alpha1 mRNA. Furthermore, the transcription of the CXCR4-CXCL12 axis was significantly regulated in a manner conducive to migration and homing. Several transcription factors involved in stem cell differentiation were also found to bind oligonucleotide response element probes following exposure to LMWF5A. Finally, a rapid increase in PRAS40 phosphorylation was observed following treatment, potentially resulting in the activation mTORC1. Proteomic analysis of synovial fluid taken from a preliminary set of patients indicated that at 12 weeks following administration of LMWF5A, a microenvironment exists in the knee conducive to stem cell infiltration, self-renewal, and differentiation, in addition to indications of remodeling with a reduction in inflammation. Taken together, these findings imply that LMWF5A treatment may prime stem cells for both mobilization and chondrogenic differentiation, potentially explaining some of the beneficial effects achieved in clinical trials. PMID- 26041741 TI - Eradication of B-ALL using chimeric antigen receptor-expressing T cells targeting the TSLPR oncoprotein. AB - Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting the CD19 B cell-associated protein have demonstrated potent activity against relapsed/refractory B-lineage acute lymphoblastic leukemia (B-ALL). Not all patients respond, and CD19-negative relapses have been observed. Overexpression of the thymic stromal lymphopoietin receptor (TSLPR; encoded by CRLF2) occurs in a subset of adults and children with B-ALL and confers a high risk of relapse. Recent data suggest the TSLPR signaling axis is functionally important, suggesting that TSLPR would be an ideal immunotherapeutic target. We constructed short and long CARs targeting TSLPR and tested efficacy against CRLF2-overexpressing B-ALL. Both CARs demonstrated activity in vitro, but only short TSLPR CAR T cells mediated leukemia regression. In vivo activity of the short CAR was also associated with long-term persistence of CAR-expressing T cells. Short TSLPR CAR treatment of mice engrafted with a TSLPR-expressing ALL cell line induced leukemia cytotoxicity with efficacy comparable with that of CD19 CAR T cells. Short TSLPR CAR T cells also eradicated leukemia in 4 xenograft models of human CRLF2-overexpressing ALL. Finally, TSLPR has limited surface expression on normal tissues. TSLPR-targeted CAR T cells thus represent a potent oncoprotein-targeted immunotherapy for high-risk ALL. PMID- 26041742 TI - Microenvironmental interleukin-6 suppresses toll-like receptor signaling in human leukemia cells through miR-17/19A. AB - The regulation of toll-like receptor (TLR) signaling in a tumor microenvironment is poorly understood despite its importance in cancer biology. To address this problem, TLR7-responses of chronic lymphocytic leukemia (CLL) cells were studied in the presence and absence of a human stromal cell-line derived from a leukemic spleen. CLL cells alone produced high levels of tumor necrosis factor (TNF)-alpha and proliferated in response to TLR7-agonists. A signal transducer and activator of transcription 3 -activating stromal factor, identified as interleukin (IL)-6, was found to upregulate microRNA (miR)-17 and miR-19a, target TLR7 and TNFA messenger RNA, and induce a state of tolerance to TLR7-agonists in CLL cells. Overexpression of the miR-17-92 cluster tolerized CLL cells directly and miR-17 and miR-19a antagomiRs restored TLR7-signaling. Inhibition of IL-6 signaling with antibodies or small-molecule Janus kinase inhibitors reversed tolerization and increased TLR7-stimulated CLL cell numbers in vitro and in NOD-SCIDgammac (null) mice. These results suggest IL-6 can act as tumor suppressor in CLL by inhibiting TLR-signaling. PMID- 26041744 TI - APNA's Suicide Competencies for Inpatient Psychiatric Nurses: "Saving Lives . . . One at a Time". PMID- 26041743 TI - Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial. AB - Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, to whose pathogenesis neoplastic and immune-mediated mechanisms contribute. Mammalian target of rapamycin (mTOR)-inhibitors have antiproliferative and immunosuppressive properties. We tested in this study, the efficacy and safety of the mTOR-inhibitor sirolimus (SRL) plus prednisone (PDN) in patients with ECD. PDN was given initially at 0.75 mg/kg per day, tapered to 5 to 2.5 mg per day by month 6. Target SRL blood levels were 8 to 12 ng/mL. Treatment was continued for at least 24 months in patients who showed disease stabilization or improvement. Ten patients were enrolled; 8 achieved stable disease or objective responses, whereas 2 had disease progression. Responses were mainly observed at the following sites: retroperitoneum in 5/8 patients (62.5%), cardiovascular in 3/4 (75%), bone in 3/9 (33.3%), and central nervous system (CNS) in 1/3 (33.3%). The median follow-up was 29 months (interquartile range, 16.5-74.5); 2 patients died of progressive CNS disease and small-cell lung cancer, respectively. Treatment related toxicity was mild. Using immunohistochemistry and immunofluorescence on ECD biopsies, we detected expression in foamy histiocytes of the phosphorylated forms of mTOR and of its downstream kinase p70S6K, which indicated mTOR pathway activation. In conclusion, SRL and PDN often induce objective responses or disease stabilization and may represent a valid treatment of ECD. The trial is registered at the Australia-New Zealand Clinical Trial Registry as #ACTRN12613001321730. PMID- 26041745 TI - Patients with Slowly Proliferative Early Breast Cancer Have Low Five-Year Recurrence Rates in a Phase III Adjuvant Trial of Capecitabine. AB - PURPOSE: We conducted a randomized phase III study to determine whether patients with early breast cancer would benefit from the addition of capecitabine (X) to a standard regimen of doxorubicin (A) plus cyclophosphamide (C) followed by docetaxel (T). EXPERIMENTAL DESIGN: Treatment comprised eight cycles of AC->T (T dose: 100 mg/m(2) on day 1) or AC->XT (X dose: 825 mg/m(2) twice daily, days 1 14; T dose: 75 mg/m(2) on day 1). The primary endpoint was 5-year disease-free survival (DFS). RESULTS: Of 2,611 women, 1,304 were randomly assigned to receive AC->T and 1,307 to receive AC->XT. After a median follow-up of 5 years, the study failed to meet its primary endpoint [HR, 0.84; 95% confidence interval (CI), 0.67 1.05; P = 0.125]. A significant improvement in overall survival, a secondary endpoint, was seen with AC->XT versus AC->T (HR, 0.68; 95% CI, 0.51-0.92; P = 0.011). There were no unexpected adverse events. Of patients with estrogen receptor (ER)-positive/HER2-negative disease, 70% of whom were node-positive, 26% and 59% had tumors with a centrally assessed Ki-67 score of <10% or <20%, respectively, and only 17 (2%) and 53 (6%) DFS events, respectively, occurred in these groups at 7 years. CONCLUSIONS: The very low event rate in patients with ER positive, low Ki-67 cancers, regardless of nodal status, strongly suggests that these patients should not be enrolled in adjuvant trials that assess 5-year DFS rates and that central Ki-67 analyses can identify these patients. PMID- 26041747 TI - Corrigendum. PMID- 26041746 TI - Tissue Transglutaminase Mediated Tumor-Stroma Interaction Promotes Pancreatic Cancer Progression. AB - PURPOSE: Aggressive pancreatic cancer is commonly associated with a dense desmoplastic stroma, which forms a protective niche for cancer cells. The objective of the study was to determine the functions of tissue transglutaminase (TG2), a Ca(2+)-dependent enzyme that cross-links proteins through transamidation and is abundantly expressed by pancreatic cancer cells in the pancreatic stroma. EXPERIMENTAL DESIGN: Orthotopic pancreatic xenografts and coculture systems tested the mechanisms by which the enzyme modulates tumor-stroma interactions. RESULTS: We show that TG2 secreted by cancer cells effectively molds the stroma by cross-linking collagen, which, in turn, activates fibroblasts and stimulates their proliferation. The stiff fibrotic stromal reaction conveys mechanical cues to cancer cells, leading to activation of the YAP/TAZ transcription factors, promoting cell proliferation and tumor growth. Stable knockdown of TG2 in pancreatic cancer cells leads to decreased size of pancreatic xenografts. CONCLUSIONS: Taken together, our results demonstrate that TG2 secreted in the tumor microenvironment orchestrates the cross-talk between cancer cells and stroma fundamentally affecting tumor growth. Our study supports TG2 inhibition in the pancreatic stroma as a novel strategy to block pancreatic cancer progression. PMID- 26041748 TI - EUS-guided gall bladder drainage with a lumen-apposing metal stent: a prospective long-term evaluation. PMID- 26041749 TI - Emerging role of microRNAs to tackle drug resistance in pancreatic cancer. PMID- 26041750 TI - Faecal immunochemical tests versus guaiac faecal occult blood tests: what clinicians and colorectal cancer screening programme organisers need to know. AB - Although colorectal cancer (CRC) is a common cause of cancer-related death, it is fortunately amenable to screening with faecal tests for occult blood and endoscopic tests. Despite the evidence for the efficacy of guaiac-based faecal occult blood tests (gFOBT), they have not been popular with primary care providers in many jurisdictions, in part because of poor sensitivity for advanced colorectal neoplasms (advanced adenomas and CRC). In order to address this issue, high sensitivity gFOBT have been recommended, however, these tests are limited by a reduction in specificity compared with the traditional gFOBT. Where colonoscopy is available, some providers have opted to recommend screening colonoscopy to their patients instead of faecal testing, as they believe it to be a better test. Newer methods for detecting occult human blood in faeces have been developed. These tests, called faecal immunochemical tests (FIT), are immunoassays specific for human haemoglobin. FIT hold considerable promise over the traditional guaiac methods including improved analytical and clinical sensitivity for CRC, better detection of advanced adenomas, and greater screenee participation. In addition, the quantitative FIT are more flexible than gFOBT as a numerical result is reported, allowing customisation of the positivity threshold. When compared with endoscopy, FIT are less sensitive for the detection of advanced colorectal neoplasms when only one time testing is applied to a screening population; however, this is offset by improved participation in a programme of annual or biennial screens and a better safety profile. This review will describe how gFOBT and FIT work and will present the evidence that supports the use of FIT over gFOBT, including the cost-effectiveness of FIT relative to gFOBT. Finally, specific issues related to FIT implementation will be discussed, particularly with respect to organised CRC screening programmes. PMID- 26041751 TI - Serum macrophage inflammatory protein 3alpha levels predict the severity of HBV related acute-on-chronic liver failure. PMID- 26041752 TI - Colorectal cancer screening: a global overview of existing programmes. AB - Colorectal cancer (CRC) ranks third among the most commonly diagnosed cancers worldwide, with wide geographical variation in incidence and mortality across the world. Despite proof that screening can decrease CRC incidence and mortality, CRC screening is only offered to a small proportion of the target population worldwide. Throughout the world there are widespread differences in CRC screening implementation status and strategy. Differences can be attributed to geographical variation in CRC incidence, economic resources, healthcare structure and infrastructure to support screening such as the ability to identify the target population at risk and cancer registry availability. This review highlights issues to consider when implementing a CRC screening programme and gives a worldwide overview of CRC burden and the current status of screening programmes, with focus on international differences. PMID- 26041753 TI - Management of acute-on-chronic liver failure: rotational thromboelastometry may reduce substitution of coagulation factors in liver cirrhosis. PMID- 26041754 TI - The knowledge system underpinning healthcare is not fit for purpose and must change. PMID- 26041755 TI - Reconstructing spinal dura-like tissue using electrospun poly(lactide-co glycolide) membranes and dermal fibroblasts to seamlessly repair spinal dural defects in goats. AB - Many neuro- and spinal surgeries involving access to the underlying nervous tissue will cause defect of spinal dural mater, further resulting in cerebrospinal fluid leakage. The current work was thus aimed to develop a package which included two layers of novel electrospun membranes, dermal fibroblasts and mussel adhesive protein for repairing spinal dural defect. The inner layer is electrospun fibrous poly(lactide-co-glycolide) membrane with oriented microstructure (O-poly(lactide-co-glycolide)), which was used as a substrate to anchor dermal fibroblasts as seed cells to reconstitute dura-like tissue via tissue engineering technique. The outer layer is chitosan-coated electrospun nonwoven poly(lactide-co-glycolide) membrane (poly(lactide-co-glycolide) chitosan). During surgery, the inner reconstituted tissue layer was first used to directly cover dura defects, while the outer layer was placed onwards with its marginal area tightly immobilized to the surrounding normal spinal dura aided by mussel adhesive protein. Efficacy of the current design was verified in goats with spinal dural defects (0.6 cm * 0.5 cm) in lumbar. It was shown that seamless and quick sealing of the defect area with the implants was realized by mussel adhesive protein. Guided tissue growth and regeneration in the defects of goats were observed when they were repaired by the current package. Effective cerebrospinal fluid containment and anti-adhesion of the regenerated tissue to the surrounding tissue could be achieved in the current animal model. Hence, it could be ascertained that the current package could be a favorite choice for surgeries involving spinal dural defects. PMID- 26041756 TI - Percutaneous coronary intervention in the UK: recommendations for good practice 2015. AB - Over the last 35 years, there has been dramatic progress in the technology and applicability of percutaneous techniques to treat obstructive coronary heart disease. Percutaneous coronary intervention (PCI) has a considerable evidence base and it is firmly established as the most common procedure used in the invasive treatment of patients with coronary heart disease in the UK. This set of guidelines aims to address specifically issues relating to PCI and not the growing subspecialty of structural heart disease intervention. It is not intended to provide a review of the entire evidence base for coronary intervention. The evidence base relating to PCI is extensively reviewed in international guidelines and the British Cardiovascular Intervention society endorses these guidelines and their updates. The guidelines presented here focus on issues pertinent to practice within the UK and set out a recommended template to ensure optimal delivery of patient care. PMID- 26041757 TI - Antidepressants in late pregnancy are linked to respiratory disorder in newborns, study finds. PMID- 26041758 TI - Prenatal genomic microarray and sequencing in Canadian medical practice: towards consensus. PMID- 26041759 TI - The BRCA2 polymorphic stop codon: stuff or nonsense? AB - BACKGROUND: Despite classification of the BRCA2c.9976A>T, p.(Lys3326Ter) variant as a polymorphism, it has been associated with increased risks of pancreatic, lung, oesophageal and breast cancer. METHODS: We have noticed multiple co occurrences of the BRCA2 c.9976A>T variant with the pathogenic BRCA2c.6275_6276delTT frameshift mutation p.(Leu2092ProfsTer7) and using a cohort study have assessed if this might account for these tumour risk associations. RESULTS: We identified 52 families with BRCA2c.6275_6276delTT, all of which occur in cis with the BRCA2c.9976A>T variant allele as demonstrated by co-segregation in all family members tested. Of 3245 breast/ovarian cancer samples sequenced for BRCA2, only 43/3245 (1.3%) carried BRCA2 c.9976A>T alone, after excluding individuals with BRCA2c.6275_6276delTT (n=22) or other BRCA1 (n=3) or BRCA2 (n=2) pathogenic mutations. The resultant frequency (1.3%) after removal of co occurring mutations is lower than the 1.7% and 1.67% frequencies from two control populations for BRCA2 c.9976A>T, but similar to the 1.39% seen in the Exome Aggregation Consortium database. We did not identify increased frequencies of oesophageal, pancreatic or lung cancer in families with just BRCA2 c.9976A>T using person-years at risk analysis. CONCLUSIONS: It is likely that the previous associations of increased cancer risks due to BRCA2c.9976A>T represent reporting bias and are contributed to because the variant is in LD with BRCA2c.6275_6276delTT. PMID- 26041760 TI - Streamlining review of research involving humans: Canadian models. PMID- 26041761 TI - Constitutional or biallelic? Settling on a name for a recessively inherited cancer susceptibility syndrome. PMID- 26041762 TI - Mutations in SLC1A4, encoding the brain serine transporter, are associated with developmental delay, microcephaly and hypomyelination. AB - BACKGROUND: L-serine plays an essential role in neuronal development and function. Although a non-essential amino acid, L-serine must be synthesised within the brain because of its poor permeability by the blood-brain barrier. Within the brain, its synthesis is confined to astrocytes, and its shuttle to neuronal cells is performed by a dedicated neutral amino acid transporter, ASCT1. METHODS AND RESULTS: Using exome analysis we identified the recessive mutations, p.E256K, p.L315fs, and p.R457W, in SLC1A4, the gene encoding ASCT1, in patients with developmental delay, microcephaly and hypomyelination; seizure disorder was variably present. When expressed in a heterologous system, the mutations did not affect the protein level at the plasma membrane but abolished or markedly reduced L-serine transport for p.R457W and p.E256K mutations, respectively. Interestingly, p.E256K mutation displayed a lower L-serine and alanine affinity but the same substrate selectivity as wild-type ASCT1. CONCLUSIONS: The clinical phenotype of ASCT1 deficiency is reminiscent of defects in L-serine biosynthesis. The data underscore that ASCT1 is essential in brain serine transport. The SLC1A4 p.E256K mutation has a carrier frequency of 0.7% in the Ashkenazi-Jewish population and should be added to the carrier screening panel in this community. PMID- 26041763 TI - Aplidin in patients with advanced dedifferentiated liposarcomas: a French Sarcoma Group Single-Arm Phase II study. AB - BACKGROUND: Preclinical data have suggested a therapeutic role of JUN pathway activation in dedifferentiated liposarcoma (DDLPS) tumorigenesis. Aplidin is a drug inducing apoptosis through a strong, sustained activation of c-Jun NH2 terminal kinase. METHODS: This phase II trial included patients with progressive advanced DDLPS. They received Aplidin 5 mg/m(2) days 1-15, 28-day cycle until disease progression or unacceptable toxicity. The primary end point was the 3 month nonprogression rate (PFS3) defined as the proportion of patients with nonprogressive disease at 3 months. A PFS3 of 40% considered as a reasonable objective to claim drug efficacy. RESULTS: Between August 2012 and May 2013, 24 patients were included. Sixteen had received prior chemotherapy. Twenty-two were assessable for efficacy. The PFS3 was 9.1% [95% confidence interval (CI) 1.1 29.2]. Median progression-free and overall survivals were 1.6 months (95% CI 1.4 2.6) and 9.2 months (95% CI 6.6-). The most frequent adverse events of any grade were nausea, fatigue, anorexia, vomiting and diarrhea. CONCLUSION: Aplidin did not meet the primary end point of this trial and do not deserve further investigation in DDLPS. CLINICALTRIALSGOV IDENTIFIER: NCT01876043. PMID- 26041766 TI - Hbp1 regulates the timing of neuronal differentiation during cortical development by controlling cell cycle progression. AB - In the developing mammalian brain, neural stem cells (NSCs) initially expand the progenitor pool by symmetric divisions. NSCs then shift from symmetric to asymmetric division and commence neurogenesis. Although the precise mechanisms regulating the developmental timing of this transition have not been fully elucidated, gradual elongation in the length of the cell cycle and coinciding accumulation of determinants that promote neuronal differentiation might function as a biological clock that regulates the onset of asymmetric division and neurogenesis. We conducted gene expression profiling of embryonic NSCs in the cortical regions and found that expression of high mobility group box transcription factor 1 (Hbp1) was upregulated during neurogenic stages. Induced conditional knockout mice of Hbp1, generated by crossing with Nestin-CreER(T2) mice, exhibited a remarkable dilatation of the telencephalic vesicles with a tangentially expanded ventricular zone and a thinner cortical plate containing reduced numbers of neurons. In these Hbp1-deficient mouse embryos, neural stem/progenitor cells continued to divide with a shorter cell cycle length. Moreover, downstream target genes of the Wnt signaling, such as cyclin D1 (Ccnd1) and c-jun (Jun), were upregulated in the germinal zone of the cortical regions. These results indicate that Hbp1 plays a crucial role in regulating the timing of cortical neurogenesis by elongating the cell cycle and that it is essential for normal cortical development. PMID- 26041767 TI - Bag of Marbles controls the size and organization of the Drosophila hematopoietic niche through interactions with the Insulin-like growth factor pathway and Retinoblastoma-family protein. AB - Bag of Marbles (Bam) is known to function as a positive regulator of hematopoietic progenitor maintenance in the lymph gland blood cell-forming organ during Drosophila hematopoiesis. Here, we demonstrate a key function for Bam in cells of the lymph gland posterior signaling center (PSC), a cellular domain proven to function as a hematopoietic niche. Bam is expressed in PSC cells, and gene loss-of-function results in PSC overgrowth and disorganization, indicating that Bam plays a crucial role in controlling the proper development of the niche. It was previously shown that Insulin receptor (InR) pathway signaling is essential for proper PSC cell proliferation. We analyzed PSC cell number in lymph glands double-mutant for bam and InR pathway genes, and observed that bam genetically interacts with pathway members in the formation of a normal PSC. The elF4A protein is a translation factor downstream of InR pathway signaling, and functional knockdown of this crucial regulator rescued the bam PSC overgrowth phenotype, further supporting the cooperative function of Bam with InR pathway members. Additionally, we documented that the Retinoblastoma-family protein (Rbf), a proven regulator of cell proliferation, was present in cells of the PSC, with a bam function-dependent expression. By contrast, perturbation of Decapentaplegic or Wingless signaling failed to affect Rbf niche cell expression. Together, these findings indicate that InR pathway-Bam-Rbf functional interactions represent a newly identified means to regulate the correct size and organization of the PSC hematopoietic niche. PMID- 26041768 TI - Prevalence of dynamic magnetic resonance imaging-identified pelvic organ prolapse in pre- and postmenopausal women without clinically evident pelvic organ descent. AB - Background Dynamic magnetic resonance imaging (dMRI) is an imaging tool that can be used to evaluate and stage pelvic organ prolapse (POP). Greater understanding of the incidental detection of POP in asymptomatic patients is needed. Purpose To evaluate the prevalence of dMRI-detected POP in pre-and postmenopausal women who were imaged for reasons unrelated to pelvic floor dysfunction. Material and Methods A total of 227 women who had diagnoses that did not include POP underwent abdominal/pelvic dMRI. Patients with a positive gynecological examination for or a clinical history of POP ( n = 11), hysterectomy ( n = 4), or gynecologic oncology surgery ( n = 2) were excluded, as well as patients who were unable to strain during MRI ( n = 11). A total of 199 patients without visible prolapse were enrolled in the study. An H-line, M-line, pubococcygeal line (PCL), and mid pubic line (MPL) were used to detect and grade prolapse. Results The prevalence of dMRI-identified POP was higher in postmenopausal subjects. The PCL led to a greater frequency of prolapse detection than the MPL. The frequency of middle compartment descent was similar regardless of whether the PCL or MPL was used as a reference line. There was a higher incidence of prolapse in the posterior compartment. Using an H-line and PCL as references, the anterior and posterior compartments were found to significantly differ between pre- and postmenopausal subjects. The MRI parameters that were used to define POP were not correlated with parity, vaginal birth, BMI, or fetal birth weight. With respect to the MPL, age was correlated with both the presence of an elongated H-line and with descent. Conclusion Dynamic MRI identified incidental pelvic organ prolapse in asymptomatic patients. The prevalence of dMRI-detected POP was higher in postmenopausal women without visible prolapse. These findings suggest the need for further studies to identify how to modify the currently used dMRI thresholds for postmenopausal women. PMID- 26041765 TI - Differences in attitudes and beliefs toward end-of-life care between hematologic and solid tumor oncology specialists. AB - BACKGROUND: Patients with hematologic malignancies often receive aggressive care at the end-of-life. To better understand the end-of-life decision-making process among oncology specialists, we compared the cancer treatment recommendations, and attitudes and beliefs toward palliative care between hematologic and solid tumor specialists. PATIENTS AND METHODS: We randomly surveyed 120 hematologic and 120 solid tumor oncology specialists at our institution. Respondents completed a survey examining various aspects of end-of-life care, including palliative systemic therapy using standardized case vignettes and palliative care proficiency. RESULTS: Of 240 clinicians, 182 (76%) clinicians responded. Compared with solid tumor specialists, hematologic specialists were more likely to favor prescribing systemic therapy with moderate toxicity and no survival benefit for patients with Eastern Cooperative Oncology Group (ECOG) performance status 4 and an expected survival of 1 month (median preference 4 versus 1, in which 1 = strong against treatment and 7 = strongly recommend treatment, P < 0.0001). This decision was highly polarized. Hematologic specialists felt less comfortable discussing death and dying (72% versus 88%, P = 0.007) and hospice referrals (81% versus 93%, P = 0.02), and were more likely to feel a sense of failure with disease progression (46% versus 31%, P = 0.04). On multivariate analysis, hematologic specialty [odds ratio (OR) 2.77, P = 0.002] and comfort level with prescribing treatment to ECOG 4 patients (OR 3.79, P = 0.02) were associated with the decision to treat in the last month of life. CONCLUSIONS: We found significant differences in attitudes and beliefs toward end-of-life care between hematologic and solid tumor specialists, and identified opportunities to standardize end-of-life care. PMID- 26041769 TI - The big, the bad and the ugly: Extreme animals as inspiration for biomedical research. PMID- 26041764 TI - Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. AB - The first St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) Expert Panel identified and reviewed the available evidence for the ten most important areas of controversy in advanced prostate cancer (APC) management. The successful registration of several drugs for castration-resistant prostate cancer and the recent studies of chemo-hormonal therapy in men with castration-naive prostate cancer have led to considerable uncertainty as to the best treatment choices, sequence of treatment options and appropriate patient selection. Management recommendations based on expert opinion, and not based on a critical review of the available evidence, are presented. The various recommendations carried differing degrees of support, as reflected in the wording of the article text and in the detailed voting results recorded in supplementary Material, available at Annals of Oncology online. Detailed decisions on treatment as always will involve consideration of disease extent and location, prior treatments, host factors, patient preferences as well as logistical and economic constraints. Inclusion of men with APC in clinical trials should be encouraged. PMID- 26041771 TI - Cardiovascular mortality in the UK: good news if you live in the South. PMID- 26041770 TI - The epidemiology of cardiovascular disease in the UK 2014. AB - Cardiovascular disease (CVD) presents a significant burden to the UK. This review presents data from nationally representative datasets to provide up-to-date statistics on mortality, prevalence, treatment and costs. Data focus on CVD as a whole, coronary heart disease (International Classification of Diseases (ICD):I20 25) and cerebrovascular disease (ICD:I60-69); however, where available, other cardiovascular conditions are also presented. In 2012, CVD was the most common cause of death in the UK for women (28% of all female deaths), but not for men, where cancer is now the most common cause of death (32% of all male deaths). Mortality from CVD varies widely throughout the UK, with the highest age standardised CVD death rates in Scotland (347/100 000) and the North of England (320/100 000 in the North West). Prevalence of coronary heart disease is also highest in the North of England (4.5% in the North East) and Scotland (4.3%). Overall, around three times as many men have had a myocardial infarction compared with women. Treatment for CVD is increasing over time, with prescriptions and operations for CVD having substantially increased over the last two decades. The National Health Service in England spent around L6.8 billion on CVD in 2012/2013, the majority of which came from spending on secondary care. Despite significant declines in mortality in the UK, CVD remains a considerable burden, both in terms of health and costs. Both primary and secondary prevention measures are necessary to reduce both the burden of CVD and inequalities in CVD mortality and prevalence. PMID- 26041772 TI - A Novel and Likely Inherited Lymphoproliferative Disease in British Shorthair Kittens. AB - An unusual lymphoproliferative disease was identified in multiple closely related British Shorthair (BSH) kittens, suggesting an inherited predisposition to disease. Affected kittens typically developed rapidly progressive and marked generalized lymphadenopathy, moderate splenomegaly, and regenerative and likely hemolytic anemia from 6 weeks of age. Microscopic findings were suggestive of multicentric T-cell lymphoma, but additional testing revealed a polyclonal population of CD3+/CD4-/CD8- "double negative" T cells (DNT cells). This is a novel disease presentation with similarities to the human disorder autoimmune lymphoproliferative syndrome (ALPS), a rare inherited disease causing lymphoproliferation and variable manifestations of autoimmunity. The human disease is most commonly due to the presence of Fas gene mutations causing defective lymphocyte apoptosis, and further investigations of both the mode of inheritance and genetic basis for disease in affected cats are currently in progress. PMID- 26041773 TI - Sequence-based Network Completion Reveals the Integrality of Missing Reactions in Metabolic Networks. AB - Genome-scale metabolic models are central in connecting genotypes to metabolic phenotypes. However, even for well studied organisms, such as Escherichia coli, draft networks do not contain a complete biochemical network. Missing reactions are referred to as gaps. These gaps need to be filled to enable functional analysis, and gap-filling choices influence model predictions. To investigate whether functional networks existed where all gap-filling reactions were supported by sequence similarity to annotated enzymes, four draft networks were supplemented with all reactions from the Model SEED database for which minimal sequence similarity was found in their genomes. Quadratic programming revealed that the number of reactions that could partake in a gap-filling solution was vast: 3,270 in the case of E. coli, where 72% of the metabolites in the draft network could connect a gap-filling solution. Nonetheless, no network could be completed without the inclusion of orphaned enzymes, suggesting that parts of the biochemistry integral to biomass precursor formation are uncharacterized. However, many gap-filling reactions were well determined, and the resulting networks showed improved prediction of gene essentiality compared with networks generated through canonical gap filling. In addition, gene essentiality predictions that were sensitive to poorly determined gap-filling reactions were of poor quality, suggesting that damage to the network structure resulting from the inclusion of erroneous gap-filling reactions may be predictable. PMID- 26041774 TI - Vibrio vulnificus Secretes an Insulin-degrading Enzyme That Promotes Bacterial Proliferation in Vivo. AB - We describe a novel insulin-degrading enzyme, SidC, that contributes to the proliferation of the human bacterial pathogen Vibrio vulnificus in a mouse model. SidC is phylogenetically distinct from other known insulin-degrading enzymes and is expressed and secreted specifically during host infection. Purified SidC causes a significant decrease in serum insulin levels and an increase in blood glucose levels in mice. A comparison of mice infected with wild type V. vulnificus or an isogenic sidC-deletion strain showed that wild type bacteria proliferated to higher levels. Additionally, hyperglycemia leads to increased proliferation of V. vulnificus in diabetic mice. Consistent with these observations, the sid operon was up-regulated in response to low glucose levels through binding of the cAMP-receptor protein (CRP) complex to a region upstream of the operon. We conclude that glucose levels are important for the survival of V. vulnificus in the host, and that this pathogen uses SidC to actively manipulate host endocrine signals, making the host environment more favorable for bacterial survival and growth. PMID- 26041775 TI - Leptin Elongates Hypothalamic Neuronal Cilia via Transcriptional Regulation and Actin Destabilization. AB - Terminally differentiated neurons have a single, primary cilium. The primary cilia of hypothalamic neurons play a critical role in sensing metabolic signals. We recently showed that mice with leptin deficiency or resistance have shorter cilia in the hypothalamic neurons, and leptin treatment elongates cilia in hypothalamic neurons. Here, we investigated the molecular mechanisms by which leptin controls ciliary length in hypothalamic neurons. In N1 hypothalamic neuronal cells, leptin treatment increased the expression of intraflagellar transport proteins. These effects occurred via phosphatase and tensin homolog/glycogen synthase kinase-3beta-mediated inhibition of the transcriptional factor RFX1. Actin filament dynamics were also involved in leptin-promoted ciliary elongation. Both leptin and cytochalasin-D treatment induced F-actin disruption and cilium elongation in hypothalamic neurons that was completely abrogated by co-treatment with the F-actin polymerizer phalloidin. Our findings suggest that leptin elongates hypothalamic neuronal cilia by stimulating the production of intraflagellar transport proteins and destabilizing actin filaments. PMID- 26041776 TI - Crystal Structure and Substrate Recognition of Cellobionic Acid Phosphorylase, Which Plays a Key Role in Oxidative Cellulose Degradation by Microbes. AB - The microbial oxidative cellulose degradation system is attracting significant research attention after the recent discovery of lytic polysaccharide mono oxygenases. A primary product of the oxidative and hydrolytic cellulose degradation system is cellobionic acid (CbA), the aldonic acid form of cellobiose. We previously demonstrated that the intracellular enzyme belonging to glycoside hydrolase family 94 from cellulolytic fungus and bacterium is cellobionic acid phosphorylase (CBAP), which catalyzes reversible phosphorolysis of CbA into glucose 1-phosphate and gluconic acid (GlcA). In this report, we describe the biochemical characterization and the three-dimensional structure of CBAP from the marine cellulolytic bacterium Saccharophagus degradans. Structures of ligand-free and complex forms with CbA, GlcA, and a synthetic disaccharide product from glucuronic acid were determined at resolutions of up to 1.6 A. The active site is located near the dimer interface. At subsite +1, the carboxylate group of GlcA and CbA is recognized by Arg-609 and Lys-613. Additionally, one residue from the neighboring protomer (Gln-190) is involved in the carboxylate recognition of GlcA. A mutational analysis indicated that these residues are critical for the binding and catalysis of the aldonic and uronic acid acceptors GlcA and glucuronic acid. Structural and sequence comparisons with other glycoside hydrolase family 94 phosphorylases revealed that CBAPs have a unique subsite +1 with a distinct amino acid residue conservation pattern at this site. This study provides molecular insight into the energetically efficient metabolic pathway of oxidized sugars that links the oxidative cellulolytic pathway to the glycolytic and pentose phosphate pathways in cellulolytic microbes. PMID- 26041777 TI - Folding and Intramembraneous BRICHOS Binding of the Prosurfactant Protein C Transmembrane Segment. AB - Surfactant protein C (SP-C) is a novel amyloid protein found in the lung tissue of patients suffering from interstitial lung disease (ILD) due to mutations in the gene of the precursor protein pro-SP-C. SP-C is a small alpha-helical hydrophobic protein with an unusually high content of valine residues. SP-C is prone to convert into beta-sheet aggregates, forming amyloid fibrils. Nature's way of solving this folding problem is to include a BRICHOS domain in pro-SP-C, which functions as a chaperone for SP-C during biosynthesis. Mutations in the pro SP-C BRICHOS domain or linker region lead to amyloid formation of the SP-C protein and ILD. In this study, we used an in vitro transcription/translation system to study translocon-mediated folding of the WT pro-SP-C poly-Val and a designed poly-Leu transmembrane (TM) segment in the endoplasmic reticulum (ER) membrane. Furthermore, to understand how the pro-SP-C BRICHOS domain present in the ER lumen can interact with the TM segment of pro-SP-C, we studied the membrane insertion properties of the recombinant form of the pro-SP-C BRICHOS domain and two ILD-associated mutants. The results show that the co-translational folding of the WT pro-SP-C TM segment is inefficient, that the BRICHOS domain inserts into superficial parts of fluid membranes, and that BRICHOS membrane insertion is promoted by poly-Val peptides present in the membrane. In contrast, one BRICHOS and one non-BRICHOS ILD-associated mutant could not insert into membranes. These findings support a chaperone function of the BRICHOS domain, possibly together with the linker region, during pro-SP-C biosynthesis in the ER. PMID- 26041778 TI - Intracellular Zinc Modulates Cardiac Ryanodine Receptor-mediated Calcium Release. AB - Aberrant Zn(2+) homeostasis is a hallmark of certain cardiomyopathies associated with altered contractile force. In this study, we addressed whether Zn(2+) modulates cardiac ryanodine receptor gating and Ca(2+) dynamics in isolated cardiomyocytes. We reveal that Zn(2+) is a high affinity regulator of RyR2 displaying three modes of operation. Picomolar free Zn(2+) concentrations potentiate RyR2 responses, but channel activation is still dependent on the presence of cytosolic Ca(2+). At concentrations of free Zn(2+) >1 nm, Zn(2+) is the main activating ligand, and the dependence on Ca(2+) is removed. Zn(2+) is therefore a higher affinity activator of RyR2 than Ca(2+). Millimolar levels of free Zn(2+) were found to inhibit channel openings. In cardiomyocytes, consistent with our single channel results, we show that Zn(2+) modulates both the frequency and amplitude of Ca(2+) waves in a concentration-dependent manner and that physiological levels of Zn(2+) elicit Ca(2+) release in the absence of activating levels of cytosolic Ca(2+). This highlights a new role for intracellular Zn(2+) in shaping Ca(2+) dynamics in cardiomyocytes through modulation of RyR2 gating. PMID- 26041779 TI - Coordinated Regulation of the Neutral Amino Acid Transporter SNAT2 and the Protein Phosphatase Subunit GADD34 Promotes Adaptation to Increased Extracellular Osmolarity. AB - Cells respond to shrinkage induced by increased extracellular osmolarity via programmed changes in gene transcription and mRNA translation. The immediate response to this stress includes the induction of expression of the neutral amino acid transporter SNAT2. Increased SNAT2-mediated uptake of neutral amino acids is an essential adaptive mechanism for restoring cell volume. In contrast, stress induced phosphorylation of the alpha subunit of the translation initiation factor eIF2 (eIF2alpha) can promote apoptosis. Here we show that the response to mild hyperosmotic stress involves regulation of the phosphorylation of eIF2alpha by increased levels of GADD34, a regulatory subunit of protein phosphatase 1 (PP1). The induction of GADD34 was dependent on transcriptional control by the c-Jun binding cAMP response element in the GADD34 gene promoter and posttranscriptional stabilization of its mRNA. This mechanism differs from the regulation of GADD34 expression by other stresses that involve activating transcription factor 4 (ATF4). ATF4 was not translated during hyperosmotic stress despite an increase in eIF2alpha phosphorylation. The SNAT2-mediated increase in amino acid uptake was enhanced by increased GADD34 levels in a manner involving decreased eIF2alpha phosphorylation. It is proposed that the induction of the SNAT2/GADD34 axis enhances cell survival by promoting the immediate adaptive response to stress. PMID- 26041781 TI - The Multicenter Aerobic Iron Respiratory Chain of Acidithiobacillus ferrooxidans Functions as an Ensemble with a Single Macroscopic Rate Constant. AB - Electron transfer reactions among three prominent colored proteins in intact cells of Acidithiobacillus ferrooxidans were monitored using an integrating cavity absorption meter that permitted the acquisition of accurate absorbance data in suspensions of cells that scattered light. The concentrations of proteins in the periplasmic space were estimated to be 350 and 25 mg/ml for rusticyanin and cytochrome c, respectively; cytochrome a was present as one molecule for every 91 nm(2) in the cytoplasmic membrane. All three proteins were rapidly reduced to the same relative extent when suspensions of live bacteria were mixed with different concentrations of ferrous ions at pH 1.5. The subsequent molecular oxygen-dependent oxidation of the multicenter respiratory chain occurred with a single macroscopic rate constant, regardless of the proteins' in vitro redox potentials or their putative positions in the aerobic iron respiratory chain. The crowded electron transport proteins in the periplasm of the organism constituted an electron conductive medium where the network of protein interactions functioned in a concerted fashion as a single ensemble with a standard reduction potential of 650 mV. The appearance of product ferric ions was correlated with the reduction levels of the periplasmic electron transfer proteins; the limiting first-order catalytic rate constant for aerobic respiration on iron was 7,400 s( 1). The ability to conduct direct spectrophotometric studies under noninvasive physiological conditions represents a new and powerful approach to examine the extent and rates of biological events in situ without disrupting the complexity of the live cellular environment. PMID- 26041780 TI - 1,25-Dihydroxyvitamin D3 Controls a Cohort of Vitamin D Receptor Target Genes in the Proximal Intestine That Is Enriched for Calcium-regulating Components. AB - 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) plays an integral role in calcium homeostasis in higher organisms through its actions in the intestine, kidney, and skeleton. Interestingly, although several intestinal genes are known to play a contributory role in calcium homeostasis, the entire caste of key components remains to be identified. To examine this issue, Cyp27b1 null mice on either a normal or a high calcium/phosphate-containing rescue diet were treated with vehicle or 1,25(OH)2D3 and evaluated 6 h later. RNA samples from the duodena were then subjected to RNA sequence analysis, and the data were analyzed bioinformatically. 1,25(OH)2D3 altered expression of large collections of genes in animals under either dietary condition. 45 genes were found common to both 1,25(OH)2D3-treated groups and were composed of genes previously linked to intestinal calcium uptake, including S100g, Trpv6, Atp2b1, and Cldn2 as well as others. An additional distinct network of 56 genes was regulated exclusively by diet. We then conducted a ChIP sequence analysis of binding sites for the vitamin D receptor (VDR) across the proximal intestine in vitamin D-sufficient normal mice treated with vehicle or 1,25(OH)2D3. The residual VDR cistrome was composed of 4617 sites, which was increased almost 4-fold following hormone treatment. Interestingly, the majority of the genes regulated by 1,25(OH)2D3 in each diet group as well as those found in common in both groups contained frequent VDR sites that likely regulated their expression. This study revealed a global network of genes in the intestine that both represent direct targets of vitamin D action in mice and are involved in calcium absorption. PMID- 26041782 TI - Endemic shrubs in temperate arid and semiarid regions of northern China and their potentials for rangeland restoration. AB - Some endemic shrubs in arid and semiarid ecosystems are in danger of extinction, and yet they can play useful roles in maintaining or restoring these ecosystems, thus practical efforts are needed to conserve them. The shrubs Amygdalus pedunculata Pall., Amygdalus mongolica (Maxim.) Ricker and Ammopiptanthus mongolicus (Maxim. ex Kom.) Cheng f. are endemic species in arid and semiarid regions of northern China, where rangeland desertification is pronounced due to chronic overgrazing. In this study, we tested the hypothesis that these endemic shrubs have developed adaptations to arid and semiarid environments and could play critical roles as nurse species to initiate the process of rangeland recovery. Based on careful vegetation surveys, we analysed the niches of these species in relation to precipitation, temperature and habitats. All sampling plots were categorized by these endemics and sorted by the non-metric multidimensional scaling method. Species ratios of each life form and species co occurrence rates with the endemics were also evaluated. Annual average temperature and annual precipitation were found to be the key factors determining vegetation diversity and distributions. Amygdalus pedunculata prefers low hills and sandy land in temperate semiarid regions. Amygdalus mongolica prefers gravel deserts of temperate semiarid regions. Ammopiptanthus mongolicus prefers sandy land of temperate arid regions. Communities of A. pedunculata have the highest diversity and the largest ratios of long-lived grass species, whereas those of A. mongolicus have the lowest diversity but the largest ratios of shrub species. Communities of A. mongolica are a transition between the first two community types. These findings demonstrate that our focal endemic shrubs have evolved adaptations to arid and semiarid conditions, thus they can be nurse plants to stabilize sand ground for vegetation restoration. We suggest that land managers begin using these shrub species to restore degraded rangelands as part of a general conservation effort. PMID- 26041784 TI - Comment on "patient-reported reasons for emergency department visits in the urban Medicaid population". PMID- 26041783 TI - Indole and Tryptophan Metabolism: Endogenous and Dietary Routes to Ah Receptor Activation. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor recognized for its role in xenobiotic metabolism. The physiologic function of AHR has expanded to include roles in immune regulation, organogenesis, mucosal barrier function, and the cell cycle. These functions are likely dependent upon ligand-mediated activation of the receptor. High-affinity ligands of AHR have been classically defined as xenobiotics, such as polychlorinated biphenyls and dioxins. Identification of endogenous AHR ligands is key to understanding the physiologic functions of this enigmatic receptor. Metabolic pathways targeting the amino acid tryptophan and indole can lead to a myriad of metabolites, some of which are AHR ligands. Many of these ligands exhibit species selective preferential binding to AHR. The discovery of specific tryptophan metabolites as AHR ligands may provide insight concerning where AHR is activated in an organism, such as at the site of inflammation and within the intestinal tract. PMID- 26041785 TI - Normalizing Rejection. AB - Getting turned down for grant funding or having a manuscript rejected is an uncomfortable but not unusual occurrence during the course of a nurse researcher's professional life. Rejection can evoke an emotional response akin to the grieving process that can slow or even undermine productivity. Only by "normalizing" rejection, that is, by accepting it as an integral part of the scientific process, can researchers more quickly overcome negative emotions and instead use rejection to refine and advance their scientific programs. This article provides practical advice for coming to emotional terms with rejection and delineates methods for working constructively to address reviewer comments. PMID- 26041788 TI - Histoid leprosy. PMID- 26041786 TI - Revealing protein-lncRNA interaction. AB - Long non-coding RNAs (lncRNAs) are associated to a plethora of cellular functions, most of which require the interaction with one or more RNA-binding proteins (RBPs); similarly, RBPs are often able to bind a large number of different RNAs. The currently available knowledge is already drawing an intricate network of interactions, whose deregulation is frequently associated to pathological states. Several different techniques were developed in the past years to obtain protein-RNA binding data in a high-throughput fashion. In parallel, in silico inference methods were developed for the accurate computational prediction of the interaction of RBP-lncRNA pairs. The field is growing rapidly, and it is foreseeable that in the near future, the protein lncRNA interaction network will rise, offering essential clues for a better understanding of lncRNA cellular mechanisms and their disease-associated perturbations. PMID- 26041789 TI - Olfactory and gustatory dysfunction in depression: Could it be a marker of folate deficiency? PMID- 26041787 TI - Ethylene-Mediated Regulation of A2-Type CYCLINs Modulates Hyponastic Growth in Arabidopsis. AB - Upward leaf movement (hyponastic growth) is frequently observed in response to changing environmental conditions and can be induced by the phytohormone ethylene. Hyponasty results from differential growth (i.e. enhanced cell elongation at the proximal abaxial side of the petiole relative to the adaxial side). Here, we characterize Enhanced Hyponasty-d, an activation-tagged Arabidopsis (Arabidopsis thaliana) line with exaggerated hyponasty. This phenotype is associated with overexpression of the mitotic cyclin CYCLINA2;1 (CYCA2;1), which hints at a role for cell divisions in regulating hyponasty. Indeed, mathematical analysis suggested that the observed changes in abaxial cell elongation rates during ethylene treatment should result in a larger hyponastic amplitude than observed, unless a decrease in cell proliferation rate at the proximal abaxial side of the petiole relative to the adaxial side was implemented. Our model predicts that when this differential proliferation mechanism is disrupted by either ectopic overexpression or mutation of CYCA2;1, the hyponastic growth response becomes exaggerated. This is in accordance with experimental observations on CYCA2;1 overexpression lines and cyca2;1 knockouts. We therefore propose a bipartite mechanism controlling leaf movement: ethylene induces longitudinal cell expansion in the abaxial petiole epidermis to induce hyponasty and simultaneously affects its amplitude by controlling cell proliferation through CYCA2;1. Further corroborating the model, we found that ethylene treatment results in transcriptional down-regulation of A2-type CYCLINs and propose that this, and possibly other regulatory mechanisms affecting CYCA2;1, may contribute to this attenuation of hyponastic growth. PMID- 26041790 TI - The impact of the Canterbury earthquakes on prescribing for mental health. AB - OBJECTIVE: The aim of this study is to evaluate the impact of the Canterbury earthquakes on the mental health of the local population by examining prescribing patterns of psychotropic medication. METHOD: Dispensing data from community pharmacies for antidepressants, antipsychotics, anxiolytics and sedatives/hypnotics are routinely recorded in a national database. The close relationship between prescribing and dispensing provides the opportunity to assess prescribing trends for Canterbury compared to national data and therefore examines the longitudinal impact of the earthquakes on prescribing patterns. RESULTS: Short-term increases in the use of anxiolytics and sedatives/hypnotics were observed after the most devastating February 2011 earthquake, but this effect was not sustained. There were no observable effects of the earthquakes on antidepressant or antipsychotic dispensing. CONCLUSION: Short-term increases in dispensing were only observed for the classes of anxiolytics and sedatives/hypnotics. No sustained changes in dispensing occurred. These findings suggest that long-term detrimental effects on the mental health of the Canterbury population were either not present or have not resulted in increased prescribing of psychotropic medication. PMID- 26041791 TI - Integrating physical activity as medicine in the care of people with severe mental illness. PMID- 26041792 TI - Why have Australian suicide rates decreased? PMID- 26041793 TI - Delivering a decision support intervention about PSA screening to patients outside of clinical encounters is ineffective in promoting informed decision making. PMID- 26041794 TI - High-sensitivity cardiac troponin T in isolation has limited diagnostic utility in identifying cardiac causes of syncope. PMID- 26041796 TI - Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study. PMID- 26041795 TI - Fingolimod effects on left ventricular function in multiple sclerosis. AB - BACKGROUND: Cardiovascular side effects such as bradycardia and atrioventricular block were observed during the early clinical trials of fingolimod in multiple sclerosis, and one cardiovascular- linked death has been reported in the post marketing period. OBJECTIVE: To investigate the medium-term effects of fingolimod on heart function in order to obtain further insights into its cardiac safety profile. METHODS: The study involved 53 patients starting treatment with fingolimod 0.5 mg daily and 25 patients treated with natalizumab 300 mg monthly. Cardiac function was assessed by means of echocardiography at baseline (T0), and after one (T1), six (T6), and (in the case of the fingolimod group) 12 months (T12). RESULTS: Mean left ventricular ejection fraction significantly decreased and end-systolic volume increased from T0 to T1 (p=0.005) and T6 (p=0.0001) in the fingolimod but not the natalizumab group, although a slight increase was observed at T12. A similar decrease in ejection fraction was also observed after six months in nine patients switched from natalizumab to fingolimod. CONCLUSION: Fingolimod significantly reduces left ventricular systolic function in MS patients. This effect has no clinical consequences in subjects without previous cardiac disorders, but suggests that more caution is required in patients with current or previous heart failure. PMID- 26041797 TI - Intrathecal CD8 T-cells of multiple sclerosis patients recognize lytic Epstein Barr virus proteins. AB - BACKGROUND: The association between Epstein-Barr virus (EBV) and multiple sclerosis (MS) may involve intrathecal EBV-specific T-cell responses targeting the virus or indirectly, autoantigens. OBJECTIVE: Compare the prevalence and fine specificity of EBV-specific T-cells in the cerebrospinal fluid (CSF) of patients with MS (n = 12), clinically-isolated syndrome (CIS) (n = 17) and other neurological diseases (OND) (n = 13). METHODS: Intrathecal EBV-specific T-cell reactivity was assayed using CSF-derived T-cell lines (CSF-TCL) and autologous EBV-transformed B-cells (autoBLCL) as antigen-presenting cells (APC). EBV proteins recognized by autoBLCL-specific CD8 T-cells were identified using human leukocyte antigen class I (HLA-I)-negative monkey cells as artificial APC, co transfected with 59 different EBV genes and the corresponding patient's HLA-I alleles that were involved in autoBLCL T-cell reactivity. Reactivity towards the MS-associated autoantigen alphaB-crystallin (CRYAB) was determined analogously. RESULTS: CSF-TCL from CIS and MS patients had significantly higher frequencies of autoBLCL-reactive CD4 T-cells, compared to the OND patients. CIS patients also had significantly higher autoBLCL-reactive CD8 T cells, which correlated with reactive CD4 T-cell frequencies. AutoBLCL-specific CD8 T-cell responses of four CSF-TCL analyzed in detail were oligoclonal and directed to lytic EBV proteins, but not CRYAB endogenously expressed by autoBLCL. CONCLUSIONS: Enhanced intrathecal autoBLCL-specific T-cell reactivity, selectively directed towards lytic EBV proteins in two CSF-TCL, suggested a localized T-cell response to EBV in patients with MS. Our data warrant further characterization of the magnitude and breadth of intrathecal EBV-specific T-cell responses in larger patient cohorts. PMID- 26041798 TI - In multiple sclerosis anxiety, not depression, is related to gender. AB - BACKGROUND: There is a high prevalence of depressive and anxiety disorders in multiple sclerosis (MS), a disease 2.5 times more frequent in females. Contrary to the general population, in whom studies have demonstrated higher rates of depression and anxiety in females, little is known about the impact of gender on psychiatric sequelae in MS patients. OBJECTIVES: We conducted a retrospective study to try to clarify this uncertainty. METHODS: Demographic, illness-related and behavioral variables were obtained from a neuropsychiatric database of 896 patients with a confirmed diagnosis of MS. Symptoms of depression and anxiety were obtained with the Hospital Anxiety and Depression Scale (HADS). Gender comparisons were undertaken and predictors of depression and anxiety sought with a linear regression analysis. RESULTS: HADS data were available for 711 of 896 (79.35%) patients. Notable gender differences included a higher frequency of primary progressive MS in males (p = 0.002), higher HADS anxiety scores in females (p < 0.001), but no differences in HADS depression scores. CONCLUSION: In MS, gender influences the frequency of anxiety only. This suggests that the etiological factors underpinning anxiety and depression in MS are not only different from one another, but also in the case of depression, different from those observed in general population samples. PMID- 26041799 TI - Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing-remitting multiple sclerosis. AB - BACKGROUND AND OBJECTIVE: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor imaging, and clinical impairments. METHODS: Thirty relapsing remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons. RESULTS: Patients showed decreased functional connectivity in 5 of 11 resting state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. CONCLUSIONS: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities. PMID- 26041800 TI - Erratum. AB - : In the article The use of gaming technology for rehabilitation in people with multiple sclerosis, DOI: 10.1177/1352458514563593, published in Multiple Sclerosis Volume 21 Issue 4, Table 1 was printed incorrectly. The corrected Table 1 is below:spmsj;22/12/NP9/TABLE11352458515585718T1table1-1352458515585718Table 1.Exergaming studies.Ref.PlatformParticipants and interventionOutcomesPlow and Finlayson31WiiPre-test vs. post-test repeated measures home-based Wii training. PARTICIPANTS: N=30, age 43.2 +/- 9.3 years, 9 +/- 6.8 years since diagnosis. INTERVENTION: 3 x per week programme consisting of yoga, balance, strength, and aerobic training in each session. Wii playing minutes ranged from 10-30 minutes based on participants' RPE when playing the "Basic Run" game. No therapist monitored training in the home. Participants were telephoned every other week (a total of four times) for the first seven weeks after receiving Wii-Fit to monitor adverse events and to encourage increases in the duration or frequency of using Wii-Fit. By the end of the seven weeks, all participants were encouraged to play Wii-Fit three to five times a week for 20 to 30 mins.TUG/TUG dual task; Maximum number of push-ups; timed number of sit-ups in 60s; Maximum number of steps in three mins onto a six-inch platform; Single/double leg balance with eyes open/closed on a soft/firm surface; Physical Activity and Disability Survey; SF 36; MFIS; The barrier self-efficacy scale.Improvements pre- vs. post-test: Number of steps and push-ups; Eyes/open closed, single leg balance on firm surface.Post test vs. follow-up (14 weeks): measures returned to baseline.Kalron et al.29WiiPilot intervention. No control group. PARTICIPANTS: N=32, age 43.6 +/- 1.9 years, 6.9 +/- 0.8 years since diagnosis, EDSS 3.1 +/- 0.2. INTERVENTION: Wii Tennis played for one session of 30 mins (3x10 mins).FRT and FSST taken pre- and post-intervention. FRT and FSST both significantly improved by 9.1% and 17.5% respectively.Prosperini et al.28WiiRandomized Crossover Trial - Home-Based. PARTICIPANTS: N=36, age 36.2 +/- 8.6 years, 10.7 +/- 5.8 years since diagnosis, and median EDSS of 3.5 (1.5-5.0). Wii group - 12-week duration, daily sessions (with the exception of the weekend) of home-based training with the Wii Balance Board, each lasting 30 mins. No intervention group - 12 weeks of no intervention. They then swapped to the Wii group after 12 weeks and the Wii group had no intervention for 12 weeks. Contact with physiotherapists every four weeks and phone contact once per week.CoP path, Four Square Step, 25-FWT, MSIS-29. Significant improvements for time * treatment interaction for all measures.Plow and Finlayson35WiiA repeated measures longitudinal design with a baseline control period. PARTICIPANTS: See Plow and Finlayson31 Intervention: All participants were prescribed a three-times-a-week exercise programme - see Plow and Finalyson.31Semi-structured interviews conducted over the phone before and after the 14-week Wii-Fit programme. Examined the usability of Nintendo Wii-Fit and identified reasons for using or not using Wii-Fit on; a regular basis.Nilsagard et al.25WiiA multicentre RCT with random (1:1) allocation to exercise group or non-exercise group. Wii group: participants N=42, age 50.0 +/- 11.5 years, 12.5 +/- 8.0 years since. Individual physiotherapist-supervised sessions of 30 mins of balance exercise using Wii-Fit Plus twice a week for six to seven weeks, a total of 12 sessions. Non-exercise group: participants N=42, age 49.4 +/- 11.1 years, 12.2 +/- 9.2 years since diagnosis. This group was invited to start exercising using Wii-Fit Plus after the second data collection.TUG; TUG dual task; Four Square Step; Timed Chair Stands; 25-FWT; Dynamic Gait Index; ABC; MSWS-12. Improvements in Wii Group pre- vs. post-test: TUG dual task, Four Square Step, Timed Chair Stands, Dynamic Gait Index.Improvements in Non-exercise group pre- vs. post-test: Dynamic Gait Index.Wii vs. non-exercise at follow-up: No significant difference.Guidi et al.27WiiSingle-blind, RCT. PARTICIPANTS: Aged between 25-65 years, at least three years since diagnosis, EDSS score 0-3.5. Wii group (N=9) played Physiofun Balance Training - Physio Mode. Sessions 10x45-mins, twice a week for five weeks. Non-exercise group (N=8) received advice about strategies for behaviour and environment aimed at reducing falls.BBS significantly improved for Wii Group vs. Non-exercise group.Brichetto et al.26WiiRCT: Wii vs. traditional rehabilitation strategies. Twelve sessions (three 60-minute sessions/week) of intervention. Wii group: participants N=18, age 40.7 +/- 11.5 years, years since diagnosis 11.2 +/- 6.4 years, mean EDSS 3.9 +/- 1.6. One hour of supervised Wii Balance Board sessions. CONTROL GROUP: participants N=18, age 43.2 +/- 10.6 years, years since diagnosis 12.3 +/- 7.2 years, mean EDSS 4.3 +/- 1.6. Exercises consisted of static and dynamic exercises in both single leg and double leg stance, with or without an equilibrium board and half-kneeling exercises of increasing difficulty.BBS and MFIS. Postural assessment was quantified with a stabilometric platform (quiet standing, barefoot with open/closed eyes). No significant differences between the groups at baseline. Significant improvements in outcomes for both modes at post-test. A significant group * time interaction, revealing a more marked improvement for BBS score, open/closed-eye stabilometry in the Wii group compared to the control group.Ortiz-Gutierrez, et al.32KinectXbox-group: participants N=24, age 39.7 +/- 8.1 years, years since diagnosis 9.7 +/- 6.8. 40 sessions - four sessions per week (20 mins per session) for 10 weeks. Individual Tele-Rehabilitation treatments using commercial games. Sessions were monitored via videoconference. CONTROL GROUP: participants N=23, age 42.8 +/- 7.4 years, years since diagnosis 10.9 +/- 5.4. Physiotherapy treatment twice a week (40 mins per session) at a clinic for 10 weeks. Low-load strength exercises, proprioception exercises on unstable surfaces, gait facilitation exercises, and muscle-tendon stretching.Computerized dynamic posturography and SOT. Improvement of general balance in both groups. Visual preference and the contribution of vestibular information, via SOT, yielded significant differences in the exercise group.Kramer et al.34WiiMatched controlled trial (3 groups). Three weeks, nine supervised training sessions lasting 30 mins each. PARTICIPANTS: N=23, age 42.8 +/- 7.4 years, years since diagnosis 10.9 +/- 5.4. Conventional balance training (control) group: Consisted of various exercises on the floor. Exergame training (playing exergames on an unstable platform) group: Wii Sports/Sports Resort/Fit games that require arm movements (tennis, table tennis, boxing, archery, and sword fight) or displacements of the whole body to control the game avatar (ski slalom, balance bubble, penguin picnic, soccer heading, tilt city, and perfect ten). Table tennis, tennis, and tilt city were the preferred games. Single task (ST) exercises on the unstable platform group.Pre- and post-testing. Combination of single and dual tasks. Six static balance tests: four balance tests on an unstable surface, and two gait analyses (normal and dual task). All groups significantly improved balance and gait measures. The exergame training group showed significantly higher improvements in the gait dual task condition compared to the single task condition. Adherence to home-based balance training was highest in the exergame group.Goble et al.24WiiCase study. N=1, 28 year old Male. Relapsing-remitting MS since age 11. EDSS 5.0. INTERVENTION: Six-week balance training, 3x30 mins per week. Wii-Fit games (yoga, table-tilt, penguin slide, ski jump and bubble balance).20s double leg standing. CoP path length (body sway). Participant relapsed after five weeks training. Follow-up measure taken post relapse (two months). Over first two weeks 12% decrease in body sway from baseline. 22% increase in body sway over the next two weeks despite training. Relapse occurred week five. Balance impairment remained upon remittance (follow up) when compared to week two.Forsberg et al.33WiiParticipants: N=15, median age 55 years, median time since diagnosis 13 years. INTERVENTION: See Nilsagard et al.25Qualitative research approach. Interviewed (15-45 mins) within two weeks after the end of the intervention period. Interview covered reflections on using Wii-Fit for exercising. Patients considered Wii-Fit exercises to be fun, challenging, and self-motivating.*Thomas et al.24WiiPublished trial methodology multicentre definitive RCT to assess the clinical and cost-effectiveness of a home-based physiotherapist-supported Wii intervention. Immediate arm (N=15): Wii training for 12 months. Delayed arm (N=15): Wii training after six months. Comparison between first six months of immediate arm vs. six months of no training in delayed group, and then 12 months of Wii training in immediate group vs. six months Wii training in delayed group.Balance, gait and mobility: Two minute walk test, Step test, Steady stance test, Instrumented TUG, Gait stride time rhythmicity, Static posturography.Physical activity: GLTEQ, ActivPAL.Hand dexterity/coordination: Nine-hole peg test.Self-efficacy: SCI-ESES, MSSE.Psychological well-being and QoL: HADS, EQ-5D-5L, MSIS-29, FSI, SF-36v2. Adherence to training.*published trial methodology25-FWT: 25 Foot Walk Time; ABC: Activities-specific Balance Confidence; AI: Ambulation Index; BBS: Berg Balance Score; CoP: Centre of Pressure; EDSS: Expanded Disability Status Scale; EQ-5D-5L: EuroQual 5 Dimensions-5 Levels; FRT: Functional Reach Test; FSI: Fatigue Symptom Inventory; FSST: Four Square Step Test; GLTEQ: Godin Leisure-Time Exercise Questionnaire; HADS: Hospital Anxiety and Depression Scale; MFIS: Modified Fatigue Impact Scale; MMSE: Mini-Mental State Examination; MS: Multiple Sclerosis; MSIS-29: Multiple Sclerosis Impact Scale; MSSE: Multiple Sclerosis Self-Efficacy Scale; MSWS-12: MS Walking Scale; QoL: Quality of Life; RCT: Randomized Control Trial; RPE: Ratings of Perceived Exertion; SCI-ESES: Spinal Cord Injury Exercise Self-Efficacy Scale; SF-36: Short-Form Health Survey; SOT: Sensory Organization Test; TUG: Timed-Up-and-Go. PMID- 26041802 TI - Cognitive and patient-reported outcomes in adults with pediatric-onset multiple sclerosis. AB - BACKGROUND: Little is known about long-term cognitive and patient-reported outcomes of pediatric-onset multiple sclerosis (POMS). OBJECTIVE: The objective of this paper is to compare cognitive and patient-reported outcomes in adults with POMS vs. adult-onset MS (AOMS). METHODS: We compared standardized patient reported measures MSQOL54, MFIS, CES-D and SDMT in adult patients with MS onset prior to and after age 18, using data gathered in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study. RESULTS: Fifty-one POMS and 550 AOMS patients were compared. SDMT scores were significantly lower in POMS after adjusting for age (-7.57 (-11.72, -3.43; p < 0.001), but not after adjusting for disease duration. Estimated group difference demonstrated lower normative z scores in POMS vs. AOMS in unadjusted analysis ( 0.74 (95% CI: -1.18, -0.30; p = 0.0009) and after adjusting for disease duration (-0.60; 95%CI: -1.05, -0.15; p = 0.0097). Findings were unchanged in a subset of POMS diagnosed prior to age 18. In unadjusted and adjusted analyses, no significant differences were observed in health-related quality-of-life, fatigue, depression or social support between POMS and AOMS. CONCLUSIONS: Younger age of onset was associated with more impairment in information-processing speed in adults with POMS compared to AOMS, and remained significant when controlling for disease duration in age-normed analysis. The two groups were similar in terms of patient-reported outcomes, suggesting similar qualitative experiences of MS. PMID- 26041801 TI - Clinical and MRI phenotype of children with MOG antibodies. AB - OBJECTIVE: To investigate the clinical and magnetic resonance imaging (MRI) features of anti-myelin oligodendrocyte glycoprotein (MOG) antibody-seropositive pediatric demyelinating syndromes. METHODS: Serum samples collected from 74 children with suspected demyelinating disorders whom were being followed at Massachusetts General Hospital were incubated with control green fluorescent protein (GFP)- and MOG-GFP-transfected Jurkat cell clones. The binding ratios were calculated using flow cytometry. Using statistical analyses, we compared the demographic, clinical and radiological features in our seropositive and seronegative patients. RESULTS: We found that 13 out of 74 (17.5%) patients were seropositive for MOG. The MOG-seropositive patients were younger than the seronegative patients (p = 0.049). No single disease category predominated among the seropositive patients, nor was one group more likely to have a polyphasic course. There were two out of four neuromyelitis optica (NMO) patients who had MOG antibodies; both were seronegative for aquaporin -4 (AQP4) antibodies. One had monophasic disease and the other had frequent relapses. There was a bimodal distribution of the MOG-seropositive patients by age at onset, with a distinct younger group (4-8 years) having a high prevalence of encephalopathy and an older group (13-18 years), whom presented almost exclusively with optic neuritis. MRI analysis demonstrated the absence of corpus callosum lesions in the seropositive patients (p = 0.012). The annualized relapse rate (ARR) and the Expanded Disability Status Scale (EDSS) results at 2 years did not differ between the seropositive and seronegative patients. CONCLUSION: MOG antibodies are found across a variety of pediatric demyelinating syndromes having some distinct clinical and MRI features. PMID- 26041803 TI - Psychiatric co-morbidity in multiple sclerosis: The risk of depression and anxiety before and after MS diagnosis. AB - BACKGROUND: Studies of depression and anxiety in multiple sclerosis (MS) patients have reported higher rates in MS patients than the general population. OBJECTIVE: To estimate the risk of depression and anxiety and the use of tricyclic antidepressant and selective serotonin reuptake inhibitors (SSRI) prescriptions, in the pre-diagnostic and the post-diagnostic period of MS compared to the background population. METHODS: A cohort of 5084 MS patients was included and matched with a control population of 24,771 persons linked to nationwide registers. Logistic regression analyses were performed estimating odds ratios (OR). RESULTS: In the pre-diagnostic period, the OR for having a diagnosis of depression and anxiety is 1.4 (95% confidence interval (CI) =1.05-1.88), and the OR of redemption prescriptions of TCAs is 1.90 (CI=1.54-2.34) and OR is 1.34 (CI= 1.20-1.51) for SSRI. In the post-diagnostic period the OR is 1.23 (CI= 0.92-1.64) for depression and anxiety diagnosis. The OR is 6.70 (CI=5.81-7.72) for TCA and OR is 2.46 (CI= 2.25-2.69) for SSRI. CONCLUSION: During both the pre- diagnostic and post-diagnostic period, MS patient have increased risk of depression and anxiety diagnoses and redemption of antidepressant and anxiolytic prescriptions, compared to the background population. PMID- 26041804 TI - Comparative analysis of treatment outcomes in patients with neuromyelitis optica spectrum disorder using multifaceted endpoints. AB - BACKGROUND: There is still an unmet need for comparative analyses of available treatment options for neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: We aimed to compare the efficacies of the immunosuppressants most commonly prescribed for patients with NMOSD using multifaceted endpoints. METHODS: We conducted a retrospective analysis of treatment outcomes in 138 NMOSD patients treated with azathioprine, mycophenolate mofetil (MMF), or rituximab. The primary outcome measures were the annualized relapse rate (ARR), annualized severe relapse rate, time to first relapse, and time to first severe relapse. RESULTS: A comparison of any relapse among the groups revealed that the azathioprine had a significantly higher risk of relapse relative to the rituximab (hazard ratio: 1.82; 95% CI: 1.1-3.1; p=0.03). A comparison of severe relapse among the groups revealed that the hazard ratios of severe relapse for the azathioprine and MMF relative to the rituximab were 11.66 (95% CI: 2.6-52.3; p=0.001) and 5.96 (95% CI: 1.0-35.1; p=0.048), respectively. The times to first relapse and first severe relapse were also significantly different among the treatment groups CONCLUSIONS: The present study showed that reductions in the risks of relapse and severe relapse differed among patients who were initially treated with azathioprine, MMF, and rituximab. PMID- 26041805 TI - Type IV pili mechanochemically regulate virulence factors in Pseudomonas aeruginosa. AB - Bacteria have evolved a wide range of sensing systems to appropriately respond to environmental signals. Here we demonstrate that the opportunistic pathogen Pseudomonas aeruginosa detects contact with surfaces on short timescales using the mechanical activity of its type IV pili, a major surface adhesin. This signal transduction mechanism requires attachment of type IV pili to a solid surface, followed by pilus retraction and signal transduction through the Chp chemosensory system, a chemotaxis-like sensory system that regulates cAMP production and transcription of hundreds of genes, including key virulence factors. Like other chemotaxis pathways, pili-mediated surface sensing results in a transient response amplified by a positive feedback that increases type IV pili activity, thereby promoting long-term surface attachment that can stimulate additional virulence and biofilm-inducing pathways. The methyl-accepting chemotaxis protein like chemosensor PilJ directly interacts with the major pilin subunit PilA. Our results thus support a mechanochemical model where a chemosensory system measures the mechanically induced conformational changes in stretched type IV pili. These findings demonstrate that P. aeruginosa not only uses type IV pili for surface specific twitching motility, but also as a sensor regulating surface-induced gene expression and pathogenicity. PMID- 26041806 TI - Integrated 3D view of postmating responses by the Drosophila melanogaster female reproductive tract, obtained by micro-computed tomography scanning. AB - Physiological changes in females during and after mating are triggered by seminal fluid components in conjunction with female-derived molecules. In insects, these changes include increased egg production, storage of sperm, and changes in muscle contraction within the reproductive tract (RT). Such postmating changes have been studied in dissected RT tissues, but understanding their coordination in vivo requires a holistic view of the tissues and their interrelationships. Here, we used high-resolution, multiscale micro-computed tomography (CT) scans to visualize and measure postmating changes in situ in the Drosophila female RT before, during, and after mating. These studies reveal previously unidentified dynamic changes in the conformation of the female RT that occur after mating. Our results also reveal how the reproductive organs temporally shift in concert within the confines of the abdomen. For example, we observed chiral loops in the uterus and in the upper common oviduct that relax and constrict throughout sperm storage and egg movement. We found that specific seminal fluid proteins or female secretions mediate some of the postmating changes in morphology. The morphological movements, in turn, can cause further changes due to the connections among organs. In addition, we observed apparent copulatory damage to the female intima, suggesting a mechanism for entry of seminal proteins, or other exogenous components, into the female's circulatory system. The 3D reconstructions provided by high-resolution micro-CT scans reveal how male and female molecules and anatomy interface to carry out and coordinate mating dependent changes in the female's reproductive physiology. PMID- 26041807 TI - Evolutionary signals of symbiotic persistence in the legume-rhizobia mutualism. AB - Understanding the origins and evolutionary trajectories of symbiotic partnerships remains a major challenge. Why are some symbioses lost over evolutionary time whereas others become crucial for survival? Here, we use a quantitative trait reconstruction method to characterize different evolutionary stages in the ancient symbiosis between legumes (Fabaceae) and nitrogen-fixing bacteria, asking how labile is symbiosis across different host clades. We find that more than half of the 1,195 extant nodulating legumes analyzed have a high likelihood (>95%) of being in a state of high symbiotic persistence, meaning that they show a continued capacity to form the symbiosis over evolutionary time, even though the partnership has remained facultative and is not obligate. To explore patterns associated with the likelihood of loss and retention of the N2-fixing symbiosis, we tested for correlations between symbiotic persistence and legume distribution, climate, soil and trait data. We found a strong latitudinal effect and demonstrated that low mean annual temperatures are associated with high symbiotic persistence in legumes. Although no significant correlations between soil variables and symbiotic persistence were found, nitrogen and phosphorus leaf contents were positively correlated with legumes in a state of high symbiotic persistence. This pattern suggests that highly demanding nutrient lifestyles are associated with more stable partnerships, potentially because they "lock" the hosts into symbiotic dependency. Quantitative reconstruction methods are emerging as a powerful comparative tool to study broad patterns of symbiont loss and retention across diverse partnerships. PMID- 26041809 TI - Patterns of Pharmacological Treatment for Osteoporosis Among Patients Qualified for Pharmacotherapy According to the National Osteoporosis Foundation Guidelines. AB - BACKGROUND: Whereas the National Osteoporosis Foundation (NOF) guidelines suggest pharmacological treatment for patients at high risk of fractures, little is known about the prevalence of osteoporosis treatment among those who met the NOF criteria for pharmacotherapy. OBJECTIVE: To evaluate the prevalence of osteoporosis treatment among patients who met the NOF criteria and to assess factors associated with pharmacological treatment. METHODS: The 2005-2010 National Health and Nutrition Examination Survey served as the data source. Using the Fracture Risk Assessment Tool, the study included postmenopausal women and men 50 years or older who met the NOF treatment criteria. Andersen's Behavioral Model was used to select predisposing, enabling, and need factors that might predict osteoporosis treatment. A logistic regression was used to assess factors associated with osteoporosis treatment. RESULTS: An estimated 16 million individuals qualified for osteoporosis treatment according to the NOF guidelines. Only 24% of them received pharmacological treatment, and 89% of the patients receiving treatment were women. Only 6% to 12% of men who were at high risk of osteoporosis or fracture received pharmacotherapy. Older age, long-term corticosteroid use, history of fractures, and T-score <=-2.5 were associated with increased odds of osteoporosis treatment, whereas male gender and lack of a usual source of health care were associated with decreased odds of osteoporosis treatment. CONCLUSIONS: Less than one-fourth of the population who should be considered for pharmacotherapy received osteoporosis treatment. Clinicians should be more aware of the unmet need for medication treatment for osteoporosis. PMID- 26041810 TI - Anti-CD30 antibody-induced radiation recall reaction: a collateral target for activated lymphocytes. PMID- 26041808 TI - NKG2D Receptor and Its Ligands in Host Defense. AB - NKG2D is an activating receptor expressed on the surface of natural killer (NK) cells, CD8(+) T cells, and subsets of CD4(+) T cells, invariant NKT cells (iNKT), and gammadelta T cells. In humans, NKG2D transmits signals by its association with the DAP10 adapter subunit, and in mice alternatively spliced isoforms transmit signals either using DAP10 or DAP12 adapter subunits. Although NKG2D is encoded by a highly conserved gene (KLRK1) with limited polymorphism, the receptor recognizes an extensive repertoire of ligands, encoded by at least eight genes in humans (MICA, MICB, RAET1E, RAET1G, RAET1H, RAET1I, RAET1L, and RAET1N), some with extensive allelic polymorphism. Expression of the NKG2D ligands is tightly regulated at the level of transcription, translation, and posttranslation. In general, healthy adult tissues do not express NKG2D glycoproteins on the cell surface, but these ligands can be induced by hyperproliferation and transformation, as well as when cells are infected by pathogens. Thus, the NKG2D pathway serves as a mechanism for the immune system to detect and eliminate cells that have undergone "stress." Viruses and tumor cells have devised numerous strategies to evade detection by the NKG2D surveillance system, and diversification of the NKG2D ligand genes likely has been driven by selective pressures imposed by pathogens. NKG2D provides an attractive target for therapeutics in the treatment of infectious diseases, cancer, and autoimmune diseases. PMID- 26041811 TI - Blinatumomab: A First-in-Class Bispecific T-Cell Engager for Precursor B-Cell Acute Lymphoblastic Leukemia. AB - OBJECTIVE: To review the clinical pharmacology, efficacy, and safety of blinatumomab for the treatment of pediatric and adult precursor B-cell acute lymphoblastic leukemia (B-ALL). DATA SOURCES: A literature search of EMBASE (1947 to April 2015), Medline (1946 to April 2015), PubMed (1996 to April 2015), the U.S. National Institutes of Health Clinicaltrials.gov, the Food and Drug Administration, and relevant meeting abstracts was conducted using the terms blinatumomab, BiTE, bispecific T-cell engager, MT103, MEDI-538, and Blincyto. STUDY SELECTION/DATA EXTRACTION: Human and animal studies describing the pharmacology, pharmacokinetics and pharmacodynamics, efficacy, and safety of blinatumomab for precursor B-ALL were identified. DATA SYNTHESIS: Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) antibody derived from a B lineage specific antitumor mouse monoclonal antibody that binds to both CD19 of B cells and CD3 of T-cells. A pivotal phase II trial demonstrated that response rates were high in a refractory or relapsed patient population, with 43% achieving complete remission (CR). Median relapse-free survival was 5.9 months for those with CR or CR with incomplete hematological recovery. Median overall survival was 6.1 months, and 60% of patients achieved minimal residual disease (MRD) negativity. The most common adverse events included pyrexia, neurological events, headache, febrile neutropenia, peripheral edema, nausea, hypokalemia, constipation, and anemia. CONCLUSIONS: Blinatumomab is a novel BiTE therapeutic monoclonal antibody that has shown promising results in patients with relapsed or refractory ALL or those achieving a CR with persistent MRD. Phase III clinical trials should define the optimal place in therapy of blinatumomab. PMID- 26041812 TI - Lack of standardisation between specialties for human factors content in postgraduate training: an analysis of specialty curricula in the UK. PMID- 26041813 TI - Associations between safety culture and employee engagement over time: a retrospective analysis. AB - With the growth of the patient safety movement and development of methods to measure workforce health and success have come multiple modes of assessing healthcare worker opinions and attitudes about work and the workplace. Safety culture, a group-level measure of patient safety-related norms and behaviours, has been proposed to influence a variety of patient safety outcomes. Employee engagement, conceptualised as a positive, work-related mindset including feelings of vigour, dedication and absorption in one's work, has also demonstrated an association with a number of important worker outcomes in healthcare. To date, the relationship between responses to these two commonly used measures has been poorly characterised. Our study used secondary data analysis to assess the relationship between safety culture and employee engagement over time in a sample of >50 inpatient hospital units in a large US academic health system. With >2000 respondents in each of three time periods assessed, we found moderate to strong positive correlations (r=0.43-0.69) between employee engagement and four Safety Attitudes Questionnaire domains. Independent collection of these two assessments may have limited our analysis in that minimally different inclusion criteria resulted in some differences in the total respondents to the two instruments. Our findings, nevertheless, suggest a key area in which healthcare quality improvement efforts might be streamlined. PMID- 26041814 TI - The association between health information attitudes and skills in patients with chronic disease in China. AB - OBJECTIVES: To assess and explore the relationship between the health information (HI)-related attitudes and skills of patients with chronic disease in China. METHODS: A questionnaire was developed to measure the participants' HI-related attitudes and skills. The study included all participants (N = 1671) undergoing routine physical examinations at the Health Management Centre, Third Xiangya Hospital of Central South University, Changsha, Hunan province, from September to November 2013. The Kruskal-Wallis test was used to assess the impacts of social demographic factors and chronic disease conditions on the patients' HI-related attitudes and skills. Multiple linear regression and bivariate correlation analyses were adopted to explain the relationship between attitudes and skills. RESULTS: The chronic disease patients clearly know that HI was valuable for their health, but their general HI-related skills were inadequate, particularly for elderly and undereducated patients. Additionally, the participants' HI attitudes positively correlated with their HI-related skills (r = 0.47, p < 0.001). Because the attitudes ascended by grade (i.e. negative, moderate, and active), the HI related evaluation, expression and comprehension, and seeking skills categories increased by 11%, 5.3%, and 8.4%, respectively. CONCLUSIONS: Although the chronic disease patients held explicit and active attitudes towards HI, their skills were unsatisfactory. Attitudes and skills, however, present a positive relationship. These results suggest that training in HI-related skills should be the main goal of health literacy promotion in patients who suffer from long-term chronic diseases, particularly elderly and undereducated patients. However, cultivating an active attitude towards HI is important to improve HI-related skills. PMID- 26041815 TI - DICER/AGO-dependent epigenetic silencing of D4Z4 repeats enhanced by exogenous siRNA suggests mechanisms and therapies for FSHD. AB - Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the DUX4 transcription factor in skeletal muscle. The DUX4 retrogene is encoded in the D4Z4 macrosatellite repeat array, and smaller array size or a mutation in the SMCHD1 gene results in inefficient epigenetic repression of DUX4 in skeletal muscle, causing FSHD1 and FSHD2, respectively. Previously we showed that the entire D4Z4 repeat is bi-directionally transcribed with the generation of small si- or miRNA-like fragments and suggested that these might suppress DUX4 expression through the endogenous RNAi pathway. Here we show that exogenous siRNA targeting the region upstream of the DUX4 transcription start site suppressed DUX4 mRNA expression and increased both H3K9 methylation and AGO2 recruitment. In contrast, similarly targeted MOE-gapmer antisense oligonucleotides that degrade RNA but do not engage the RNAi pathway did not repress DUX4 expression. In addition, knockdown of DICER or AGO2 using either siRNA or MOE-gapmer chemistries resulted in the induction of DUX4 expression in control muscle cells that normally do not express DUX4, indicating that the endogenous RNAi pathway is necessary to maintain repression of DUX4 in control muscle cells. Together these data demonstrate a role of the endogenous RNAi pathway in repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat, and show that enhancing the activity of this pathway by supplying exogenous siRNA oligonucleotides represents a potential therapeutic approach to silencing DUX4 in FSHD. PMID- 26041816 TI - Tissue-specific epigenetics in gene neighborhoods: myogenic transcription factor genes. AB - Myogenic regulatory factor (MRF) genes, MYOD1, MYOG, MYF6 and MYF5, are critical for the skeletal muscle lineage. Here, we used various epigenome profiles from human myoblasts (Mb), myotubes (Mt), muscle and diverse non-muscle samples to elucidate the involvement of multigene neighborhoods in the regulation of MRF genes. We found more far-distal enhancer chromatin associated with MRF genes in Mb and Mt than previously reported from studies in mice. For the MYF5/MYF6 gene pair, regions of Mb-associated enhancer chromatin were located throughout the adjacent 236-kb PTPRQ gene even though Mb expressed negligible amounts of PTPRQ mRNA. Some enhancer chromatin regions inside PTPRQ in Mb were also seen in PTPRQ mRNA-expressing non-myogenic cells. This suggests dual-purpose PTPRQ enhancers that upregulate expression of PTPRQ in non-myogenic cells and MYF5/MYF6 in myogenic cells. In contrast, the myogenic enhancer chromatin regions distal to MYOD1 were intergenic and up to 19 kb long. Two of them contain small, known MYOD1 enhancers, and one displayed an unusually high level of 5 hydroxymethylcytosine in a quantitative DNA hydroxymethylation assay. Unexpectedly, three regions of MYOD1-distal enhancer chromatin in Mb and Mt overlapped enhancer chromatin in umbilical vein endothelial cells, which might upregulate a distant gene (PIK3C2A). Lastly, genes surrounding MYOG were preferentially transcribed in Mt, like MYOG itself, and exhibited nearby myogenic enhancer chromatin. These neighboring chromatin regions may be enhancers acting in concert to regulate myogenic expression of multiple adjacent genes. Our findings reveal the very different and complex organization of gene neighborhoods containing closely related transcription factor genes. PMID- 26041817 TI - Oxidative metabolism in YAC128 mouse model of Huntington's disease. AB - Alterations in oxidative metabolism are considered to be one of the major contributors to Huntington's disease (HD) pathogenesis. However, existing data about oxidative metabolism in HD are contradictory. Here, we investigated the effect of mutant huntingtin (mHtt) on oxidative metabolism in YAC128 mice. Both mHtt and wild-type huntingtin (Htt) were associated with mitochondria and the amount of bound Htt was four-times higher than the amount of bound mHtt. Percoll gradient-purified brain synaptic and non-synaptic mitochondria as well as unpurified brain, liver and heart mitochondria, isolated from 2- and 10-month-old YAC128 mice and age-matched WT littermates had similar respiratory rates. There was no difference in mitochondrial membrane potential or ADP and ATP levels. Expression of selected nuclear-encoded mitochondrial proteins in 2- and 10-month old YAC128 and WT mice was similar. Cultured striatal and cortical neurons from YAC128 and WT mice had similar respiratory and glycolytic activities as measured with Seahorse XF24 analyzer in medium containing 10 mm glucose and 15 mm pyruvate. In the medium with 2.5 mm glucose, YAC128 striatal neurons had similar respiration, but slightly lower glycolytic activity. Striatal neurons had lower maximal respiration compared with cortical neurons. In vivo experiments with YAC128 and WT mice showed similar O2 consumption, CO2 release, physical activity, food consumption and fasted blood glucose. However, YAC128 mice were heavier and had more body fat compared with WT mice. Overall, our data argue against respiratory deficiency in YAC128 mice and, consequently, suggest that mitochondrial respiratory dysfunction is not essential for HD pathogenesis. PMID- 26041818 TI - A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius. AB - Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures, we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD (aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P < 5 * 10(-6) for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 * 10(-11), beta =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 * 10(-8), beta = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex. PMID- 26041819 TI - Inhibiting cytosolic translation and autophagy improves health in mitochondrial disease. AB - Mitochondrial respiratory chain (RC) disease therapies directed at intra mitochondrial pathology are largely ineffective. Recognizing that RC dysfunction invokes pronounced extra-mitochondrial transcriptional adaptations, particularly involving dysregulated translation, we hypothesized that translational dysregulation is itself contributing to the pathophysiology of RC disease. Here, we investigated the activities, and effects from direct inhibition, of a central translational regulator (mTORC1) and its downstream biological processes in diverse genetic and pharmacological models of RC disease. Our data identify novel mechanisms underlying the cellular pathogenesis of RC dysfunction, including the combined induction of proteotoxic stress, the ER stress response and autophagy. mTORC1 inhibition with rapamycin partially ameliorated renal disease in B6.Pdss2(kd/kd) mice with complexes I-III/II-III deficiencies, improved viability and mitochondrial physiology in gas-1(fc21) nematodes with complex I deficiency, and rescued viability across a variety of RC-inhibited human cells. Even more effective was probucol, a PPAR-activating anti-lipid drug that we show also inhibits mTORC1. However, directly inhibiting mTORC1-regulated downstream activities yielded the most pronounced and sustained benefit. Partial inhibition of translation by cycloheximide, or of autophagy by lithium chloride, rescued viability, preserved cellular respiratory capacity and induced mitochondrial translation and biogenesis. Cycloheximide also ameliorated proteotoxic stress via a uniquely selective reduction of cytosolic protein translation. RNAseq-based transcriptome profiling of treatment effects in gas-1(fc21) mutants provide further evidence that these therapies effectively restored altered translation and autophagy pathways toward that of wild-type animals. Overall, partially inhibiting cytosolic translation and autophagy offer novel treatment strategies to improve health across the diverse array of human diseases whose pathogenesis involves RC dysfunction. PMID- 26041821 TI - Phytonadione Content in Branded Intravenous Fat Emulsions. AB - BACKGROUND: Intravenous fat emulsions (IVFE) with different fatty acid compositions contain vitamin E as a by-product of vegetable and animal oil during the refining processes. Likewise, other lipid-soluble vitamins may be present in IVFE. No data, however, exist about phytonadione (vitamin K1) concentration in IVFE information leaflets. Therefore, our aim was to evaluate the phytonadione content in different IVFE. MATERIALS AND METHODS: Analyses were carried out in triplicate on 6 branded IVFE as follows: 30% soybean oil (100%), 20% olive soybean oil (80%-20%), 20% soybean-medium-chain triglycerides (MCT) coconut oil (50%-50%), 20% soybean-olive-MCT-fish oil (30%-25%-30%-15%), 20% soybean-MCT-fish oil (40%-50%-10%), and 10% pure fish oil (100%). Phytonadione was analyzed and quantified by a quali-quantitative liquid chromatography-mass spectrometry (LC MS) method after its extraction from the IVFE by an isopropyl alcohol-hexane mixture, reverse phase-liquid chromatography, and specific multiple-reaction monitoring for phytonadione and vitamin d3 (as internal standard). This method was validated through specificity, linearity, and accuracy. RESULTS: Average vitamin K1 content was 500, 100, 90, 100, 95, and 70 ug/L in soybean oil, olive soybean oil, soybean-MCT coconut oil, soybean-olive-MCT-fish oil, soybean-MCT fish oil, and pure fish oil intravenous lipid emulsions (ILEs), respectively. The analytical LC-MS method was extremely effective in terms of specificity, linearity ( r = 0.99), and accuracy (coefficient of variation <5%). CONCLUSIONS: Phytonadione is present in IVFE, and its intake varies according to IVFE type and the volume administered. It can contribute to daily requirements and become clinically relevant when simultaneously infused with multivitamins during long term parenteral nutrition. LC-MS seems adequate in assessing vitamin K1 intake in IVFE. PMID- 26041820 TI - PML/RARalpha-Regulated miR-181a/b Cluster Targets the Tumor Suppressor RASSF1A in Acute Promyelocytic Leukemia. AB - In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) treatment induces granulocytic maturation and complete remission of leukemia. microRNAs are known to be critical players in the formation of the leukemic phenotype. In this study, we report downregulation of the miR-181a/b gene cluster in APL blasts and NB4 leukemia cells upon ATRA treatment as a key event in the drug response. We found that miR-181a/b expression was activated by the PML/RARalpha oncogene in cells and transgenic knock-in mice, an observation confirmed and extended by evidence of enhanced expression of miR-181a/b in APL patient specimens. RNA interference (RNAi)-mediated attenuation of miR-181a/b expression in NB4 cells was sufficient to reduce colony-forming capacity, proliferation, and survival. Mechanistic investigations revealed that miR-181a/b targets the ATRA-regulated tumor suppressor gene RASSF1A by direct binding to its 3'-untranslated region. Enforced expression of miR-181a/b or RNAi-mediated attenuation of RASSF1A inhibited ATRA-induced granulocytic differentiation via regulation of the cell cycle regulator cyclin D1. Conversely, RASSF1A overexpression enhanced apoptosis. Finally, RASSF1A levels were reduced in PML/RARalpha knock-in mice and APL patient samples. Taken together, our results define miR-181a and miR-181b as oncomiRs in PML/RARalpha-associated APL, and they reveal RASSF1A as a pivotal element in the granulocytic differentiation program induced by ATRA in APL. PMID- 26041822 TI - Reduced GABAergic inhibition and abnormal sensory symptoms in children with Tourette syndrome. AB - Tourette Syndrome (TS) is characterized by the presence of chronic tics. Individuals with TS often report difficulty with ignoring (habituating to) tactile sensations, and some patients perceive that this contributes to a "premonitory urge" to tic. While common, the physiological basis of impaired tactile processing in TS, and indeed tics themselves, remain poorly understood. It has been well established that GABAergic processing plays an important role in shaping the neurophysiological response to tactile stimulation. Furthermore, there are multiple lines of evidence suggesting that a deficit in GABAergic transmission may contribute to symptoms found in TS. In this study, GABA-edited magnetic resonance spectroscopy (MRS) was combined with a battery of vibrotactile tasks to investigate the role of GABA and atypical sensory processing in children with TS. Our results show reduced primary sensorimotor cortex (SM1) GABA concentration in children with TS compared with healthy control subjects (HC), as well as patterns of impaired performance on tactile detection and adaptation tasks, consistent with altered GABAergic function. Moreover, in children with TS SM1 GABA concentration correlated with motor tic severity, linking the core feature of TS directly to in vivo brain neurochemistry. There was an absence of the typical correlation between GABA and frequency discrimination performance in TS as was seen in HC. These data show that reduced GABA concentration in TS may contribute to both motor tics and sensory impairments in children with TS. Understanding the mechanisms of altered sensory processing in TS may provide a foundation for novel interventions to alleviate these symptoms. PMID- 26041823 TI - Quantification of bursting and synchrony in cultured hippocampal neurons. AB - It is widely appreciated that neuronal networks exhibit patterns of bursting and synchrony that are not captured by simple measures such as average spike rate. These patterns can encode information or represent pathological behavior such as seizures. However, methods for quantifying bursting and synchrony are not agreed upon and can be confounded with spike rate measures. Previous validation has largely relied on in silico networks and single experimental conditions. How published measures of bursting and synchrony perform when applied to biological networks of varied average spike rate and subjected to varied experimental challenges is unclear. In multielectrode array recordings of network activity, we found that two mechanistically distinct drugs, cyclothiazide and bicuculline, produced equivalent increases in average spike rate but differed in bursting and synchrony. We applied several measures of bursting to the recordings (2 threshold interval methods and a surprise-based method) and found that a measure based on an average critical interval, adjusted for the array-wide spike rate, performed best in quantifying differential drug effects. To quantify synchrony, we compared a coefficient of variation-based measure, the recently proposed spike time tiling coefficient, the SPIKE-distance measure, and a global synchrony index. The spike time tiling coefficient, the SPIKE-distance measure, and the global synchrony index all captured a difference between drugs with the best performance exhibited by the global synchrony index. In summary, our exploration should aid other investigators by highlighting strengths and limitations of current methods. PMID- 26041824 TI - Comparison of contractile responses of single human motor units in the toe extensors during unloaded and loaded isotonic and isometric conditions. AB - Much of the repertoire of muscle function performed in everyday life involves isotonic dynamic movements, either with or without an additional load, yet most studies of single motor units measure isometric forces. To assess the effects of muscle load on the contractile response, we measured the contractile properties of single motor units supplying the toe extensors, assessed by intraneural microstimulation of single human motor axons, in isotonic, loaded isotonic, and isometric conditions. Tungsten microelectrodes were inserted into the common peroneal nerve, and single motor axons (n = 10) supplying the long toe extensors were electrically stimulated through the microelectrode. Displacement was measured from the distal phalanx of the toe with either an angular displacement transducer for the unloaded (i.e., no additional load) and loaded (addition of a 4-g mass) isotonic conditions or a force transducer for the isometric conditions. Mean twitch profiles were measured at 1 Hz for all conditions: rise time, fall time, and duration were shortest for the unloaded isotonic conditions and longest for the isometric conditions. Peak displacements were lower in the loaded than unloaded isotonic conditions, and the half-maximal response in the loaded condition was achieved at lower frequencies than in the unloaded isotonic condition. We have shown that the contractile responses of single motor units supplying the human toe extensors are influenced by how they are measured: twitches are much slower when measured in loaded than unloaded isotonic conditions and slowest when measured in isometric conditions. PMID- 26041825 TI - Spatial precision of population activity in primate area MT. AB - The middle temporal (MT) area is a cortical area integral to the "where" pathway of primate visual processing, signaling the movement and position of objects in the visual world. The receptive field of a single MT neuron is sensitive to the direction of object motion but is too large to signal precise spatial position. Here, we asked if the activity of MT neurons could be combined to support the high spatial precision required in the where pathway. With the use of multielectrode arrays, we recorded simultaneously neural activity at 24-65 sites in area MT of anesthetized marmoset monkeys. We found that although individual receptive fields span more than 5 degrees of the visual field, the combined population response can support fine spatial discriminations (<0.2 degrees ). This is because receptive fields at neighboring sites overlapped substantially, and changes in spatial position are therefore projected onto neural activity in a large ensemble of neurons. This fine spatial discrimination is supported primarily by neurons with receptive fields flanking the target locations. Population performance is degraded (by 13-22%) when correlations in neural activity are ignored, further reflecting the contribution of population neural interactions. Our results show that population signals can provide high spatial precision despite large receptive fields, allowing area MT to represent both the motion and the position of objects in the visual world. PMID- 26041826 TI - Different dynamic resting state fMRI patterns are linked to different frequencies of neural activity. AB - Resting state functional magnetic resonance imaging (rsfMRI) results have indicated that network mapping can contribute to understanding behavior and disease, but it has been difficult to translate the maps created with rsfMRI to neuroelectrical states in the brain. Recently, dynamic analyses have revealed multiple patterns in the rsfMRI signal that are strongly associated with particular bands of neural activity. To further investigate these findings, simultaneously recorded invasive electrophysiology and rsfMRI from rats were used to examine two types of electrical activity (directly measured low frequency/infraslow activity and band-limited power of higher frequencies) and two types of dynamic rsfMRI (quasi-periodic patterns or QPP, and sliding window correlation or SWC). The relationship between neural activity and dynamic rsfMRI was tested under three anesthetic states in rats: dexmedetomidine and high and low doses of isoflurane. Under dexmedetomidine, the lightest anesthetic, infraslow electrophysiology correlated with QPP but not SWC, whereas band-limited power in higher frequencies correlated with SWC but not QPP. Results were similar under isoflurane; however, the QPP was also correlated to band-limited power, possibly due to the burst-suppression state induced by the anesthetic agent. The results provide additional support for the hypothesis that the two types of dynamic rsfMRI are linked to different frequencies of neural activity, but isoflurane anesthesia may make this relationship more complicated. Understanding which neural frequency bands appear as particular dynamic patterns in rsfMRI may ultimately help isolate components of the rsfMRI signal that are of interest to disorders such as schizophrenia and attention deficit disorder. PMID- 26041827 TI - Stopping is not an option: the evolution of unstoppable motion elements (primitives). AB - Stopping performance is known to depend on low-level motion features, such as movement velocity. It is not known, however, whether it is also subject to high level motion constraints. Here, we report results of 15 subjects instructed to connect four target points depicted on a digitizing tablet and stop "as rapidly as possible" upon hearing a "stop" cue (tone). Four subjects connected target points with straight paths, whereas 11 subjects generated movements corresponding to coarticulation between adjacent movement components. For the noncoarticulating and coarticulating subjects, stopping performance was not correlated or only weakly correlated with motion velocity, respectively. The generation of a straight, point-to-point movement or a smooth, curved trajectory was not disturbed by the occurrence of a stop cue. Overall, the results indicate that stopping performance is subject to high-level motion constraints, such as the completion of a geometrical plan, and that globally planned movements, once started, must run to completion, providing evidence for the definition of a motion primitive as an unstoppable motion element. PMID- 26041828 TI - Distinct interneuronal networks influence excitability of the surround during movement initiation. AB - Surround inhibition (SI) is a feature of motor control in which activation of task-related muscles is associated with inhibition of neighboring, nonprotagonist muscles, allowing selective motor control. The physiological basis for SI still remains unknown. In all previous studies, SI in the motor system was measured during movement initiation by using transcranial magnetic stimulation (TMS) to deliver a posteroanterior current at a single suprathreshold intensity. To expand our understanding of SI, we explored this phenomenon at a wide range of intensities and by stimulating motor cortex with currents along anteroposterior and lateromedial directions. Fifteen healthy volunteers performed a brief isometric index finger flexion on hearing a tone. Electromyography was recorded from the synergist and surround finger muscles. Single-pulse TMS was applied to stimulate the surround muscle at different intensities at rest or movement initiation. The motor evoked potential (MEP) amplitudes were then plotted against stimulation intensities to obtain the MEP recruitment curves for the rest and movement initiation conditions and for the three current directions for every subject. From the recruitment curves, we found that surround inhibition could be elicited only by the posteroanterior current. Hence, we postulate that surround inhibition is mediated by intracortical circuits in the motor cortex. Also, for the first time, we observed surround facilitation when the motor cortex was stimulated with anteroposterior current. Further studies are needed to investigate the mechanisms underlying both these phenomena individually in healthy subjects and patients with dystonia and other movement disorders. PMID- 26041829 TI - Structural and functional characterization of dendritic arbors and GABAergic synaptic inputs on interneurons and principal cells in the rat basolateral amygdala. AB - The basolateral amygdala (BLA) is a complex brain region associated with processing emotional states, such as fear, anxiety, and stress. Some aspects of these emotional states are driven by the network activity of synaptic connections, derived from both local circuitry and projections to the BLA from other regions. Although the synaptic physiology and general morphological characteristics are known for many individual cell types within the BLA, the combination of morphological, electrophysiological, and distribution of neurochemical GABAergic synapses in a three-dimensional neuronal arbor has not been reported for single neurons from this region. The aim of this study was to assess differences in morphological characteristics of BLA principal cells and interneurons, quantify the distribution of GABAergic neurochemical synapses within the entire neuronal arbor of each cell type, and determine whether GABAergic synaptic density correlates with electrophysiological recordings of inhibitory postsynaptic currents. We show that BLA principal neurons form complex dendritic arborizations, with proximal dendrites having fewer spines but higher densities of neurochemical GABAergic synapses compared with distal dendrites. Furthermore, we found that BLA interneurons exhibited reduced dendritic arbor lengths and spine densities but had significantly higher densities of putative GABAergic synapses compared with principal cells, which was correlated with an increased frequency of spontaneous inhibitory postsynaptic currents. The quantification of GABAergic connectivity, in combination with morphological and electrophysiological measurements of the BLA cell types, is the first step toward a greater understanding of how fear and stress lead to changes in morphology, local connectivity, and/or synaptic reorganization of the BLA. PMID- 26041830 TI - Activity in the human superior colliculus relating to endogenous saccade preparation and execution. AB - In recent years a small number of studies have applied functional imaging techniques to investigate visual responses in the human superior colliculus (SC), but few have investigated its oculomotor functions. Here, in two experiments, we examined activity associated with endogenous saccade preparation. We used 3-T fMRI to record the hemodynamic activity in the SC while participants were either preparing or executing saccadic eye movements. Our results showed that not only executing a saccade (as previously shown) but also preparing a saccade produced an increase in the SC hemodynamic activity. The saccade-related activity was observed in the contralateral and to a lesser extent the ipsilateral SC. A second experiment further examined the contralateral mapping of saccade-related activity with a larger range of saccade amplitudes. Increased activity was again observed in both the contralateral and ipsilateral SC that was evident for large as well as small saccades. This suggests that the ipsilateral component of the increase in BOLD is not due simply to small-amplitude saccades producing bilateral activity in the foveal fixation zone. These studies provide the first evidence of presaccadic preparatory activity in the human SC and reveal that fMRI can detect activity consistent with that of buildup neurons found in the deeper layers of the SC in studies of nonhuman primates. PMID- 26041831 TI - Novel description of ionic currents recorded with the action potential clamp technique: application to excitatory currents in suprachiasmatic nucleus neurons. AB - The traditional method of recording ionic currents in neurons has been with voltage-clamp steps. Other waveforms such as action potentials (APs) can be used. The AP clamp method reveals contributions of ionic currents that underlie excitability during an AP (Bean BP. Nat Rev Neurosci 8: 451-465, 2007). A novel usage of the method is described in this report. An experimental recording of an AP from the literature is digitized and applied computationally to models of ionic currents. These results are compared with experimental AP-clamp recordings for model verification or, if need be, alterations to the model. The method is applied to the tetrodotoxin-sensitive sodium ion current, INa, and the calcium ion current, ICa, from suprachiasmatic nucleus (SCN) neurons (Jackson AC, Yao GL, Bean BP. J Neurosci 24: 7985-7998, 2004). The latter group reported voltage-step and AP-clamp results for both components. A model of INa is constructed from their voltage-step results. The AP clamp computational methodology applied to that model compares favorably with experiment, other than a modest discrepancy close to the peak of the AP that has not yet been resolved. A model of ICa was constructed from both voltage-step and AP-clamp results of this component. The model employs the Goldman-Hodgkin-Katz equation for the current-voltage relation rather than the traditional linear dependence of this aspect of the model on the Ca(2+) driving force. The long-term goal of this work is a mathematical model of the SCN AP. The method is general. It can be applied to any excitable cell. PMID- 26041832 TI - Coding of odor stimulus features among secondary olfactory structures. AB - Sensory systems must represent stimuli in manners dependent upon a wealth of factors, including stimulus intensity and duration. One way the brain might handle these complex functions is to assign the tasks throughout distributed nodes, each contributing to information processing. We sought to explore this important aspect of sensory network function in the mammalian olfactory system, wherein the intensity and duration of odor exposure are critical contributors to odor perception. This is a quintessential model for exploring processing schemes given the distribution of odor information by olfactory bulb mitral and tufted cells into several anatomically distinct secondary processing stages, including the piriform cortex (PCX) and olfactory tubercle (OT), whose unique contributions to odor coding are unresolved. We explored the coding of PCX and OT neuron responses to odor intensity and duration. We found that both structures similarly partake in representing descending intensities of odors by reduced recruitment and modulation of neurons. Additionally, while neurons in the OT adapt to odor exposure, they display reduced capacity to adapt to either repeated presentations of odor or a single prolonged odor presentation compared with neurons in the PCX. These results provide insights into manners whereby secondary olfactory structures may, at least in some cases, uniquely represent stimulus features. PMID- 26041834 TI - Clinical and Economic Burden of Visual Impairment in an Aging Society of South Korea. AB - Whereas the incidence of visual impairment and blindness (VI&B) is decreasing, the total number of VI&B is increasing due to the growth of elderly population. To compare the clinical and economic outcomes of patients with and without VI&B (ie, cases and controls) in Korea, a case-control study was performed using the Health Insurance Review and Assessment Service-National Patients Sample data. Cases had higher prevalence for all of the Charlson Comorbidity Index components, depression, fracture, and injury as well as eye diseases compared to age- and sex matched controls. In regression after adjustment of concomitant diseases, cases had 2.7 times (95% confidence interval = 2.3-3.2) higher medical expenditure than controls. The results of this study confirm that patients with VI&B have significantly higher direct medical expenditures and concomitant diseases than those without VI&B and highlight the need for a public health strategy to reduce potentially avoidable costs attributed to VI&B. PMID- 26041833 TI - A temperature rise reduces trial-to-trial variability of locust auditory neuron responses. AB - The neurophysiology of ectothermic animals, such as insects, is affected by environmental temperature, as their body temperature fluctuates with ambient conditions. Changes in temperature alter properties of neurons and, consequently, have an impact on the processing of information. Nevertheless, nervous system function is often maintained over a broad temperature range, exhibiting a surprising robustness to variations in temperature. A special problem arises for acoustically communicating insects, as in these animals mate recognition and mate localization typically rely on the decoding of fast amplitude modulations in calling and courtship songs. In the auditory periphery, however, temporal resolution is constrained by intrinsic neuronal noise. Such noise predominantly arises from the stochasticity of ion channel gating and potentially impairs the processing of sensory signals. On the basis of intracellular recordings of locust auditory neurons, we show that intrinsic neuronal variability on the level of spikes is reduced with increasing temperature. We use a detailed mathematical model including stochastic ion channel gating to shed light on the underlying biophysical mechanisms in auditory receptor neurons: because of a redistribution of channel-induced current noise toward higher frequencies and specifics of the temperature dependence of the membrane impedance, membrane potential noise is indeed reduced at higher temperatures. This finding holds under generic conditions and physiologically plausible assumptions on the temperature dependence of the channels' kinetics and peak conductances. We demonstrate that the identified mechanism also can explain the experimentally observed reduction of spike timing variability at higher temperatures. PMID- 26041835 TI - Return for Postpartum Oral Glucose Tolerance Test Following Gestational Diabetes Mellitus. AB - A cross-sectional study was conducted to assess the prevalence and characteristics of women who received a postpartum oral glucose tolerance test and to examine barriers as reported by women who failed to return for the test. Data were collected using a mobile phone-based short messaging service. Only 352 (81.9%) women returned for the test. Women who failed to return for the test were younger (30.1 vs 32.1, P = .003) and did not have a previous history of gestational diabetes (93.6% vs 84.9%, P = .043) compared to women who returned for the test. The commonest reasons given for not returning for the test was "Still waiting for the appointment date for the test" (37.2%), "had family/health problems" (11.5%), and "busy/no time" (10.3%). Flexible time for the test, active involvement from health care staff, and strengthening continuous care system were among the interventions needed to improve the return rate for this screening test. PMID- 26041836 TI - Incorporation of Estimated Community Viral Load Before HIV Diagnosis for Enhancing Epidemiologic Investigations: A Comparison Between Men Who Have Sex With Men and Heterosexual Men in Hong Kong. AB - Currently, no studies have specifically incorporated population-level viral load measures for analyzing temporal trends of HIV infection in the Asia Pacific. With the use of longitudinal data from 950 HIV-infected heterosexual male and 1331 men who have sex with men managed at a major HIV clinic in Hong Kong between 1985 and 2012, viral load changes at population levels were compared. We back-calculated seroconversion year of each diagnosed patient and estimated the population-level viral load under the framework recommended by the Centers for Disease Control and Prevention. Full community viral load, a newly designed measure incorporating diagnosed and undiagnosed HIV-infected patients, was 3 to 8 times higher than community viral load derived from diagnosed patients only. The growth curve of full community viral load was 5 years ahead of other viral load measures, the shape of which lent support to the phenomenon of local transmission of men who have sex with men but not among heterosexual male in the predominantly Chinese HIV community in Hong Kong. PMID- 26041838 TI - Correction for Patro et al., Shift in Monocyte Apoptosis with Increasing Viral Load and Change in Apoptosis-Related ISG/Bcl2 Family Gene Expression in Chronically HIV-1-Infected Subjects. PMID- 26041837 TI - Diagnosis of Basal-Like Breast Cancer Using a FOXC1-Based Assay. AB - BACKGROUND: Diagnosis of basal-like breast cancer (BLBC) remains a bottleneck to conducting effective clinical trials for this aggressive subtype. We postulated that elevated expression of Forkhead Box transcription factor C1 (FOXC1) is a simple and accurate diagnostic biomarker for BLBC. METHODS: Accuracy of FOXC1 expression in identifying BLBC was compared with the PAM50 gene expression panel in gene expression microarray (GEM) (n = 1992) and quantitative real-time polymerase chain reaction (qRT-PCR) (n = 349) datasets. A FOXC1-based immunohistochemical (IHC) assay was developed and assessed in 96 archival formalin-fixed, paraffin-embedded (FFPE) breast cancer samples that also underwent PAM50 profiling. All statistical tests were two-sided. RESULTS: A FOXC1 based two-tier assay (IHC +/- qRT-PCR) accurately identified BLBC (AUC = 0.88) in an independent cohort of FFPE samples, validating the accuracy of FOXC1-defined BLBC in GEM (AUC = 0.90) and qRT-PCR (AUC = 0.88) studies, when compared with platform-specific PAM50-defined BLBC. The hazard ratio (HR) for disease-specific survival in patients having FOXC1-defined BLBC was 1.71 (95% CI = 1.31 to 2.23, P < .001), comparable to PAM50 assay-defined BLBC (HR = 1.74, 95% CI = 1.40 to 2.17, P < .001). FOXC1 expression also predicted the development of brain metastasis. Importantly, unlike triple-negative or Core Basal IHC definitions, a FOXC1-based definition is able to identify BLBC in both ER+ and HER2+ patients. CONCLUSION: A FOXC1-based two-tier assay, by virtue of being rapid, simple, accurate, and cost-effective may emerge as the diagnostic assay of choice for BLBC. Such a test could substantially improve clinical trial enrichment of BLBC patients and accelerate the identification of effective chemotherapeutic options for this aggressive disease. PMID- 26041839 TI - Correction for Hwang et al., Polyomavirus small T antigen interacts with yes associated protein to regulate cell survival and differentiation. PMID- 26041842 TI - One hundred years of lessons about the impact of war on mental health; two steps forward, one step back. AB - OBJECTIVE: This paper outlines the substantial stigmatization of soldiers who suffered psychiatric disorders during World War I, and how there was little acceptance of the enduring impact of prolonged combat exposure once the war ended. CONCLUSION: Recent decades of research highlight the delayed impact of combat exposure and its long-term neurobiological consequences. PMID- 26041841 TI - IL-6 Trans-Signaling Drives Murine Crescentic GN. AB - The role of IL-6 signaling in renal diseases remains controversial, with data describing both anti-inflammatory and proinflammatory effects. IL-6 can act via classic signaling, engaging its two membrane receptors gp130 and IL-6 receptor (IL-6R). Alternatively, IL-6 trans-signaling requires soluble IL-6R (sIL-6R) to act on IL-6R-negative cells that express gp130. Here, we characterize the role of both pathways in crescentic nephritis. Patients with crescentic nephritis had significantly elevated levels of IL-6 in both serum and urine. Similarly, nephrotoxic serum-induced nephritis (NTN) in BALB/c mice was associated with elevated serum IL-6 levels. Levels of serum sIL-6R and renal downstream signals of IL-6 (phosphorylated signal transducer and activator of transcription 3, suppressor of cytokine signaling 3) increased over time in this model. Simultaneous inhibition of both IL-6 signaling pathways using anti-IL-6 antibody did not have a significant impact on NTN severity. In contrast, specific inhibition of trans-signaling using recombinant sgp130Fc resulted in milder disease. Vice versa, specific activation of trans-signaling using a recombinant IL-6-sIL-6R fusion molecule (Hyper-IL-6) significantly aggravated NTN and led to increased systolic BP in NTN mice. This correlated with increased renal mRNA synthesis of the Th17 cell cytokine IL-17A and decreased synthesis of resistin like alpha (RELMalpha)-encoding mRNA, a surrogate marker of lesion-mitigating M2 macrophage subtypes. Collectively, our data suggest a central role for IL-6 trans signaling in crescentic nephritis and offer options for more effective and specific therapeutic interventions in the IL-6 system. PMID- 26041843 TI - Australasian contributions to the "shell shock" literature of World War I. AB - OBJECTIVE: Australasians contributed to the medical literature on shell shock during and after World War I. CONCLUSIONS: AW Campbell, Elliot Smith, Carmalt Jones and AG Butler made significant contributions, and several 'frontline doctors' recorded astute observations. PMID- 26041844 TI - Latest guidelines for the management of the anxiety disorders - a report from The International Anxiety Disorders Society Conference, Melbourne 2014. AB - OBJECTIVE: The International Anxiety Disorders Society Conference, held in Melbourne in November 2014, enabled key researchers from Australia and internationally to interact with mental health practitioners with an interest in clinical anxiety disorders. The proceedings of previous conferences in 2006 and 2011 formed the basis of two well-received textbooks on anxiety disorders; this time we have taken up the invitation to publish the proceedings as articles in this issue of Australasian Psychiatry. At the end of the first day of the conference a lecture and linked international expert panel explored the topic of guidelines for the management of the anxiety disorders in conjunction with an engaged audience for 90 minutes - key elements of this discussion are presented here. CONCLUSIONS: Guidelines for anxiety disorder management should be applied with caution in clinical practice settings. PMID- 26041845 TI - On Credibility, Clarity, and Compliance. PMID- 26041846 TI - Proteotranscriptomic Profiling of 231-BR Breast Cancer Cells: Identification of Potential Biomarkers and Therapeutic Targets for Brain Metastasis. AB - Brain metastases are a devastating consequence of cancer and currently there are no specific biomarkers or therapeutic targets for risk prediction, diagnosis, and treatment. Here the proteome of the brain metastatic breast cancer cell line 231 BR has been compared with that of the parental cell line MDA-MB-231, which is also metastatic but has no organ selectivity. Using SILAC and nanoLC-MS/MS, 1957 proteins were identified in reciprocal labeling experiments and 1584 were quantified in the two cell lines. A total of 152 proteins were confidently determined to be up- or down-regulated by more than twofold in 231-BR. Of note, 112/152 proteins were decreased as compared with only 40/152 that were increased, suggesting that down-regulation of specific proteins is an important part of the mechanism underlying the ability of breast cancer cells to metastasize to the brain. When matched against transcriptomic data, 43% of individual protein changes were associated with corresponding changes in mRNA, indicating that the transcript level is a limited predictor of protein level. In addition, differential miRNA analyses showed that most miRNA changes in 231-BR were up- (36/45) as compared with down-regulations (9/45). Pathway analysis revealed that proteome changes were mostly related to cell signaling and cell cycle, metabolism and extracellular matrix remodeling. The major protein changes in 231-BR were confirmed by parallel reaction monitoring mass spectrometry and consisted in increases (by more than fivefold) in the matrix metalloproteinase-1, ephrin-B1, stomatin, myc target-1, and decreases (by more than 10-fold) in transglutaminase 2, the S100 calcium-binding protein A4, and l-plastin. The clinicopathological significance of these major proteomic changes to predict the occurrence of brain metastases, and their potential value as therapeutic targets, warrants further investigation. PMID- 26041848 TI - An intra-articular, extended-release formulation of triamcinolone acetonide prolongs and amplifies analgesic effect in patients with osteoarthritis of the knee: a randomized clinical trial. AB - BACKGROUND: Intra-articular corticosteroids are a mainstay in the treatment of knee osteoarthritis, and in clinical trials, they demonstrate a large initial analgesic effect that wanes over one to four weeks with the rapid efflux of drug from the joint. The present study was undertaken to determine if FX006, an extended-release formulation of triamcinolone acetonide, can provide pain relief that is superior to the current standard of care, immediate-release triamcinolone acetonide. METHODS: In this Phase-2, double-blind, multicenter study, 228 patients with moderate to severe knee osteoarthritis pain were randomized to a single intra-articular injection of FX006 (containing 10, 40, or 60 mg of triamcinolone acetonide) or 40 mg of immediate-release triamcinolone acetonide. Data on the mean daily pain on the 11-point Numeric Rating Scale were collected over twelve weeks; the primary efficacy end point was the change from baseline to each of eight, ten, and twelve weeks in the weekly mean of the mean daily pain intensity scores analyzed with a longitudinal mixed-effects model. RESULTS: The 10-mg dose of FX006 produced pain relief that was improved relative to immediate release triamcinolone acetonide at two through twelve weeks, although the difference in pain relief was not significant (p >= 0.05). The 40-mg dose of FX006 produced pain relief that was improved at two through twelve weeks and was significantly superior to immediate-release triamcinolone acetonide at five to ten weeks (p < 0.05 at each time point). At the 40-mg dose of FX006, prespecified secondary analyses, including responder analyses and all Western Ontario and McMaster Universities subscales, were significantly superior (p < 0.05) to immediate-release triamcinolone acetonide at eight weeks, and the time-weighted mean pain relief (assessed with mean daily pain intensity scores) was significantly superior to immediate-release triamcinolone acetonide over one to twelve weeks (p = 0.04). The 60-mg dose did not provide additional improvement relative to the 40-mg dose. Adverse events were generally mild and similar across all treatments. CONCLUSIONS: Intra-articular injection of FX006, an extended release formulation of triamcinolone acetonide, provided a clinically relevant improvement in pain relief in patients with knee osteoarthritis relative to immediate-release triamcinolone acetonide, the current standard of care. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041849 TI - A prospective randomized study to compare systemic emboli using the computer assisted and conventional techniques of total knee arthroplasty. AB - BACKGROUND: Conventional total knee arthroplasty is performed with use of an intramedullary alignment guide, which produces elevated intramedullary pressure that can create fat emboli. Total knee arthroplasty performed via computer assisted surgery does not require an intramedullary femoral rod, raising the question of whether computer-assisted surgery generates less embolic material than conventional total knee arthroplasty. The purpose of this study was to compare the emboli produced in the two techniques. METHODS: Fifty-seven patients were randomized into two groups: the computer-assisted surgery group (n = 29) and the conventional total knee arthroplasty group (n = 28). An intramedullary femoral alignment jig was used in the conventional total knee arthroplasty group but not in the computer-assisted surgery group. Intraoperative invasive monitoring was performed with use of transesophageal echocardiography and a pulmonary artery catheter. RESULTS: The mean embolic score was 6.21 points for the conventional technique group and 5.48 points for the computer-assisted surgery group (p = 0.0161). After tourniquet deflation, fat emboli were observed in the blood of five patients in the conventional surgery group and one patient in the computer-assisted surgery group. CONCLUSIONS: The patients in the computer assisted surgery group had lower embolic loads compared with the patients in the conventional total knee arthroplasty group. In patients with an uncompromised cardiopulmonary system, the embolic load difference between the techniques was not clinically relevant. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041847 TI - Tripeptidyl Peptidase II Mediates Levels of Nuclear Phosphorylated ERK1 and ERK2. AB - Tripeptidyl peptidase II (TPP2) is a serine peptidase involved in various biological processes, including antigen processing, cell growth, DNA repair, and neuropeptide mediated signaling. The underlying mechanisms of how a peptidase can influence this multitude of processes still remain unknown. We identified rapid proteomic changes in neuroblastoma cells following selective TPP2 inhibition using the known reversible inhibitor butabindide, as well as a new, more potent, and irreversible peptide phosphonate inhibitor. Our data show that TPP2 inhibition indirectly but rapidly decreases the levels of active, di phosphorylated extracellular signal-regulated kinase 1 (ERK1) and ERK2 in the nucleus, thereby down-regulating signal transduction downstream of growth factors and mitogenic stimuli. We conclude that TPP2 mediates many important cellular functions by controlling ERK1 and ERK2 phosphorylation. For instance, we show that TPP2 inhibition of neurons in the hippocampus leads to an excessive strengthening of synapses, indicating that TPP2 activity is crucial for normal brain function. PMID- 26041850 TI - Intermediate to Long-Term Outcomes of Total Ankle Replacement with the Scandinavian Total Ankle Replacement (STAR). AB - BACKGROUND: The Scandinavian Total Ankle Replacement (STAR) prosthesis has been in clinical use since 1981, with investigational use in the U.S. since 1998. Few studies of the North American version of the STAR are available. This prospective cohort study analyzed intermediate to long-term outcomes of total ankle arthroplasty with use of the STAR prosthesis at two Canadian centers. METHODS: Consecutive patients who received the STAR prosthesis between 2001 and 2005 were enrolled at two large, urban teaching hospitals. Patients were annually evaluated clinically, and the Ankle Osteoarthritis Scale (AOS) and the Short Form (SF)-36 were administered. RESULTS: One hundred and eleven ankles underwent arthroplasty with the STAR prosthesis. One-half of the patients were male; the mean age was 61.9 +/- 11.7 years. Sixty-eight of the ankles underwent a total of 121 additional procedures during ankle arthroplasty, including gastrocnemius release, subtalar arthrodesis, triple arthrodesis, tendoachilles lengthening, and removal of hardware. The mean duration of follow-up for all living patients without revision (seventy-three ankles) was 9.0 +/- 1.0 years. Thirteen (12%) of the ankles required metal component revision at a mean of 4.3 +/- 3.0 years (range, 0.6 to 10.2 years). Twenty (18%) of the prostheses underwent polyethylene bearing exchange, mostly due to fracture, at a mean of 5.2 +/- 2.1 years (range, 1.5 to 9.3 years). Most (97%) of the revisions and exchanges occurred in patients with a diagnosis of primary, secondary, or posttraumatic osteoarthritis (p = 0.0003). The mean change from baseline to final follow-up was -36.5 +/- 23.3 points for AOS pain, -38.6 +/- 26.8 points for AOS disability, and 9.6 +/- 10.3 points for the SF-36 physical component summary score. The SF-36 mental component summary score was unchanged. CONCLUSIONS: Intermediate patient-reported outcomes were good after ankle arthroplasty with the STAR prosthesis performed by experienced surgeons, and long-term outcomes demonstrated a 12% rate of metal component revision and 18% rate of polyethylene bearing failure. The revision rate was substantially higher among the first twenty ankles than among subsequent ankles, but the early ankles had nearly two years' longer follow-up than subsequent ankles. Additional study to elucidate possible reasons for polyethylene bearing failure is warranted. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041851 TI - The impact of obesity on the outcome of total ankle replacement. AB - BACKGROUND: Obese patients have a slightly higher proportion of revision and infection following knee or hip replacement, but functional improvement is equivalent to that of normal-weight patients. We compared outcomes of total ankle replacement for end-stage ankle arthritis in obese and normal-weight patients. METHODS: This retrospective cohort study compared thirty-nine obese patients (those with a body mass index of >=30 kg/m(2)) at a mean follow-up time of 3.76 years and forty-eight non-obese patients (those with a body mass index of <30 kg/m(2)) at a mean follow-up time of 3.92 years after total ankle replacement. Outcome measure scores (Ankle Osteoarthritis Scale [AOS] and Short-Form 36 [SF 36]) were collected preoperatively and at least two years postoperatively. Complication and revision data were collected by manual chart audits. Statistical analyses were performed with use of t tests, Wilcoxon signed-rank tests, and Mann Whitney U tests. Survival analysis was conducted with use of the Kaplan-Meier method. RESULTS: The two cohorts had similar demographic characteristics. Ten (26%) of thirty-nine patients in the obese group were morbidly obese (having a body mass index of >40 kg/m(2)). There were thirty-nine patients in the obese group and forty-eight patients in the non-obese group. The mean body mass index (and standard deviation) was 36.28 +/- 5.43 kg/m(2) for the obese group and 25.84 +/- 3.00 kg/m(2) for the non-obese group. The obese group had significantly worse preoperative SF-36 Physical Component Summary scores (p = 0.01) than the non obese group. Preoperatively to postoperatively, both obese and non-obese patients demonstrated significant improvements (p < 0.001) in AOS pain, AOS disability, and SF-36 Physical Component Summary scores, and the changes in these scores were similar for both groups. The SF-36 Mental Component Summary scores did not change significantly (p = 0.30) in either group. There was no significant difference (p = 0.48) in the proportion of complications or revisions between the groups. CONCLUSIONS: Although obese patients had increased disability and worse function preoperatively, total ankle replacement significantly and similarly improved pain and disability scores in both obese and non-obese patients, with no significant difference in the proportion of complications. We therefore maintain that total ankle replacement is a reliable treatment option for patients with end-stage ankle arthritis, including those who are obese. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041852 TI - Weight changes after total hip or knee arthroplasty: prevalence, predictors, and effects on outcomes. AB - BACKGROUND: Conflicting evidence exists with regard to weight loss after total hip arthroplasty or total knee arthroplasty. The purposes of this study were to determine whether patients lose weight after total hip arthroplasty or total knee arthroplasty, whether there are predictors of weight change after total hip arthroplasty or total knee arthroplasty, and whether weight changes after total hip arthroplasty or total knee arthroplasty affect patient-reported outcomes. METHODS: Using our institutional registry, we evaluated the two-year change in self-reported body mass indices for all patients who underwent elective, unilateral total hip arthroplasty or total knee arthroplasty for osteoarthritis. A 5% change in body mass index was considered clinically meaningful. Patient reported outcomes were compared between patients who underwent total hip arthroplasty and those who underwent total knee arthroplasty and between obesity classes, on the basis of whether patients gained, lost, or maintained weight. RESULTS: We reviewed 3893 total hip arthroplasties and 3036 total knee arthroplasties. Of the patients who underwent total joint arthroplasty, 73% (2850 patients) in the total hip arthroplasty group and 69% (2090 patients) in the total knee arthroplasty group demonstrated no change in body mass index. Patients who underwent total knee arthroplasty were more likely to lose weight than patients who underwent total hip arthroplasty. Increasing preoperative obesity correlated with a greater likelihood of weight loss. Patients who underwent total knee arthroplasty and lost weight demonstrated better clinical outcome scores, but weight gain in general was associated with inferior clinical outcomes. Greater body mass index, total knee arthroplasty, and female sex were significant predictors of weight loss (p < 0.05). Better preoperative functional status was significantly associated with a lower likelihood of weight gain (p < 0.05). CONCLUSIONS: Most patients maintained their body mass index after total hip arthroplasty or total knee arthroplasty. Female patients, patients with higher preoperative body mass index, and those who underwent total knee arthroplasty were more likely to lose weight after surgery. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041853 TI - Long-Term Outcomes of Liner Cementation into a Stable Retained Shell: A Concise Follow-up of a Previous Report. AB - Liner cementation into a preexisting stable socket may reduce the morbidity of revision hip arthroplasty and preserve acetabular bone. However, the long-term outcomes of this technique remain unknown. The purpose of this report was to analyze the long-term results of a previously reported cohort of patients. Cementation of thirty-two liners (seventeen polyethylene and fifteen metal liners) into preexisting sockets was performed during revision hip arthroplasty, and the patients were followed for a minimum of two years. A retrospective chart review was performed to investigate the complications and survivorship. The mean duration of follow-up was 12.7 years (range, 2.1 to 19.1 years), with ten hips requiring rerevision at a mean of 6.4 years (range, 1.0 to 15.5 years). Nine patients experienced posterior dislocations, and two hips required rerevision for instability. Liner dissociation from the shell occurred in two patients. Survivorship analysis, with rerevision as the end point, demonstrated ten and fifteen-year survivorship of 77.3% and 68.8%, respectively. Dissociation of the cemented liner from the acetabular shell was an infrequent cause of failure despite long-term follow-up. Given the high rate of dislocations in this study, careful patient selection and surgical technique should be considered. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041854 TI - Chondroblastoma of bone in the extremities: a multicenter retrospective study. AB - BACKGROUND: Chondroblastoma is a rare benign cartilage tumor that commonly occurs in children and adolescents. This study was designed to review the epidemiologic characteristics and outcomes of surgical management in a large series of patients with extremity chondroblastoma. METHODS: We performed a multicenter retrospective analysis of 199 patients with extremity chondroblastoma. Clinical data, radiographic images, histological findings, treatment, and outcome were analyzed. RESULTS: There were 145 male patients and fifty-four female patients with a mean age of 18.0 years. The most commonly involved bone was the proximal part of the tibia (fifty-five patients [27.6%]), followed by the proximal part of the femur (fifty-two patients [26.1%]) and the distal part of the femur (thirty-eight patients [19.1%]). Prior to presentation, 73.4% (146 of 199 patients) experienced pain. The mean duration of pain and other symptoms was 8.7 months. The physis was open in 25.7%, it was closing in 22.2%, and it was closed in 52.1% of the patients at the time of presentation. One hundred and twenty-six patients had at least twenty-four months of follow-up; their mean follow-up duration was 62.1 months (range, twenty-four to 190 months). Initial treatment was curettage for 119 patients (94.4%) and en bloc resection for seven patients (5.6%). The local recurrence rate was 5.0% after curettage and 0% after resection. The only significant factor related to recurrence was the location of the lesion in the proximal part of the humerus (p = 0.001). CONCLUSIONS: Chondroblastoma occurs most frequently in the proximal part of the tibia and the proximal part of the femur with significant male predilection. In this series, recurrence was most frequent in the proximal part of the humerus. Our results suggest that curettage and bone-grafting provide favorable local control and satisfactory functional outcome for patients with this disease. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041855 TI - The prevalence of sacroiliac joint degeneration in asymptomatic adults. AB - BACKGROUND: Degenerative changes of the sacroiliac joint have been implicated as a cause of lower back pain in adults. The purpose of this study was to determine the prevalence of sacroiliac joint degeneration in asymptomatic patients. METHODS: Five hundred consecutive pelvic computed tomography (CT) scans, made at a tertiary-care medical center, of patients with no history of pain in the lower back or pelvic girdle were retrospectively reviewed and analyzed for degenerative changes of the sacroiliac joint. After exclusion criteria were applied, 373 CT scans (746 sacroiliac joints) were evaluated for degenerative changes. Regression analysis was used to determine the association between age and the degree of sacroiliac joint degeneration. RESULTS: The prevalence of sacroiliac joint degeneration was 65.1%, with substantial degeneration occurring in 30.5% of asymptomatic subjects. The prevalence steadily increased with age, with 91% of subjects in the ninth decade of life displaying degenerative changes. CONCLUSIONS: Radiographic evidence of sacroiliac joint degeneration is highly prevalent in the asymptomatic population and is associated with age. Caution must be exercised when attributing lower back or pelvic girdle pain to sacroiliac joint degeneration seen on imaging. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 26041856 TI - Management of the pulseless pediatric supracondylar humeral fracture. AB - A pediatric supracondylar humeral fracture with a pulseless, poorly perfused hand requires emergency operative reduction. If the limb remains pulseless and poorly perfused after fracture fixation, vascular exploration and possible reconstruction is necessary. A pediatric supracondylar humeral fracture with a pulseless, well-perfused hand should be treated urgently with operative fixation of the fracture and subsequent reassessment of the vascular status. Controversy exists regarding the optimal management of pediatric supracondylar humeral fractures with a pulseless, well-perfused hand following anatomic reduction and fixation. Options include immediate vascular exploration or twenty-four to forty eight hours of inpatient observation. If perfusion is compromised during this period of observation, an emergency return to the operating room for vascular exploration and possible reconstruction is indicated. PMID- 26041857 TI - Sustainability assessment of a short-term international medical mission. AB - BACKGROUND: Few studies have analyzed the tangible impact of global, philanthropic medical missions. We used qualitative methods to analyze the work of one such mission, Operation Walk Boston, which has made yearly trips to a Dominican Republic hospital since 2008. METHODS: We interviewed twenty-one American and Dominican participants of the Operation Walk Boston team to investigate how the program led to changes at the host Dominican hospital and how the experience caused both mission protocols and U.S. practices to change. Transcripts were analyzed with the use of content analysis. RESULTS: Participants noted that Operation Walk Boston's technical knowledge transfer and managerial examples led to sustainable changes at the Dominican hospital. Additionally, participants observed an evolution in nursing culture, as the program inspired greater independence in decision-making. Participants also identified barriers such as language and organizational hierarchy that may limit bidirectional knowledge transfer. U.S. participants noted that their practices at home changed as a result of better appreciation for different providers' roles and for managing cost in a resource-constrained environment. CONCLUSIONS: Operation Walk Boston catalyzed sustainable changes in the Dominican hospital. Cultural norms and organizational structure are important determinants of program sustainability. PMID- 26041858 TI - Effectiveness of a microvascular surgery training curriculum for orthopaedic surgery residents. AB - BACKGROUND: The safe and effective acquisition of microvascular surgical skills is a challenge for any residency program. Variable clinical exposure to microsurgery, premiums on operating room efficiency, and a steep learning curve make these skills difficult to acquire through clinical experience alone. The purpose of this study was to determine the effectiveness of a training curriculum on the development of microvascular surgical skills in our orthopaedic residents. METHODS: A microvascular training curriculum was completed during each third-year resident's rotation on the hand and upper-extremity service. The training cycle began with learning the basics of microvascular surgery on nonliving models and progressed to performing end-to-end arterial anastomoses on a live rat femoral artery in the second session. Outcome evaluations consisted of the Global Rating Scale score, achievement of patency, and time to completion. T test analyses of Global Rating Scale scores, achievement of patency, and time to completion were conducted to determine significance (p < 0.05). RESULTS: All residents significantly improved (p < 0.005) on Global Rating Scale scores from a mean score (and standard deviation) of 15 +/- 4 points for the initial score to 20 +/- 3 points for the post-test score. Of the twelve residents, patency was achieved by eleven at the final evaluation, compared with six before training. Time to completion of the anastomosis also significantly improved (p < 0.005), from a mean of 37:17 +/- 8:41 minutes for the initial time to 24:46 +/- 5:32 minutes for the final time. CONCLUSIONS: In an effort to improve the microvascular surgical skills of orthopaedic residents at our institution, a microvascular training curriculum was developed and was implemented. This curriculum was effective at improving resident microvascular surgical skills at the completion of an eight week course. PMID- 26041859 TI - The Surgeon's Dilemma: Cement or Revise? Commentary on an article by Timothy L. Tan, MD, et al.: "Long-Term Outcomes of Liner Cementation into a Stable Retained Shell. A Concise Follow-up of a Previous Report". PMID- 26041860 TI - Sacroiliac Joint Degeneration: Forgiving, But Not to Be Forgotten: Commentary on an article by Jonathan-James T. Eno, MD, et al.: "The Prevalence of Sacroiliac Joint Degeneration in Asymptomatic Adults". PMID- 26041861 TI - First do no harm: intentionally shortening lives of patients without their explicit request in Belgium. AB - The aim of this article is to provide a critical review of one of the most worrying aspects of the euthanasia policy and practice in Belgium--the deliberate shortening of lives of some patients without their explicit voluntary request. Some suggestions designed to improve the situation and prevent abuse are offered. PMID- 26041862 TI - Exploiting altered patterns of choline kinase-alpha expression on human prostate tissue to prognosticate prostate cancer. AB - AIMS: Malignant transformation results in overexpression of choline-kinase (CHK) and altered choline metabolism, which is potentially detectable by immunohistochemistry (IHC). We investigated the utility of CHK-alpha (CHKA) IHC as a complement to current diagnostic investigation of prostate cancer by analysing expression patterns in normal (no evidence of malignancy) and malignant human prostate tissue samples. METHODS: As an initial validation, paraffin embedded prostatectomy specimen blocks with both normal and malignant prostate tissue were analysed for CHKA protein and mRNA expression by western blot and quantitative reverse transcriptase PCR (qRT-PCR), respectively. Subsequently, 100 paraffin-embedded malignant prostate tumour and 25 normal prostate cores were stained for both Ki67 (labelling-index: LI) and CHKA expression. RESULTS: The validity of CHKA-antibody was verified using CHKA-transfected cells and siRNA knockdown. Immunoblotting of tissues showed good resolution of CHKA protein in malignant prostate, verifying use of the antibody for IHC. There was minimal qRT PCR detectable CHKA mRNA in normal tissue, and conversely high expression in malignant prostate tissues. IHC of normal prostate cores showed mild (intensity) CHKA expression in only 28% (7/25) of samples with no Ki67 expression. In contrast, CHKA was expressed in all malignant prostate cores along with characteristically low proliferation (median 2% Ki67-LI; range 1-17%). Stratification of survival according to CHK intensity showed a trend towards lower progression-free survival with CHK score of 3. CONCLUSIONS: Increased expression of CHKA, detectable by IHC, is seen in malignant lesions. This relatively simple cost-effective technique (IHC) could complement current diagnostic procedures for prostate cancer and, therefore, warrants further investigation. PMID- 26041863 TI - Allometric variation in the antlers of cervids: a comment on Lemaitre et al. PMID- 26041864 TI - Response to Packard: make sure we do not throw out the biological baby with the statistical bath water when performing allometric analyses. PMID- 26041865 TI - Evolution of dinosaur epidermal structures. AB - Spectacularly preserved non-avian dinosaurs with integumentary filaments/feathers have revolutionized dinosaur studies and fostered the suggestion that the dinosaur common ancestor possessed complex integumentary structures homologous to feathers. This hypothesis has major implications for interpreting dinosaur biology, but has not been tested rigorously. Using a comprehensive database of dinosaur skin traces, we apply maximum-likelihood methods to reconstruct the phylogenetic distribution of epidermal structures and interpret their evolutionary history. Most of these analyses find no compelling evidence for the appearance of protofeathers in the dinosaur common ancestor and scales are usually recovered as the plesiomorphic state, but results are sensitive to the outgroup condition in pterosaurs. Rare occurrences of ornithischian filamentous integument might represent independent acquisitions of novel epidermal structures that are not homologous with theropod feathers. PMID- 26041866 TI - A sex allocation cost to polyandry in a parasitoid wasp. AB - The costs and benefits of polyandry are central to understanding the near ubiquity of female multiple mating. Here, we present evidence of a novel cost of polyandry: disrupted sex allocation. In Nasonia vitripennis, a species that is monandrous in the wild but engages in polyandry under laboratory culture conditions, sexual harassment during oviposition results in increased production of sons under conditions that favour female-biased sex ratios. In addition, females more likely to re-mate under harassment produce the least female-biased sex ratios, and these females are unable to mitigate this cost by increasing offspring production. Our results therefore argue that polyandry does not serve to mitigate the costs of harassment (convenience polyandry) in Nasonia. Furthermore, because males benefit from female-biased offspring sex ratios, harassment of ovipositing females also creates a novel cost of that harassment for males. PMID- 26041867 TI - Varroa destructor changes its cuticular hydrocarbons to mimic new hosts. AB - Varroa destructor (Vd) is a honeybee ectoparasite. Its original host is the Asian honeybee, Apis cerana, but it has also become a severe, global threat to the European honeybee, Apis mellifera. Previous studies have shown that Varroa can mimic a host's cuticular hydrocarbons (HC), enabling the parasite to escape the hygienic behaviour of the host honeybees. By transferring mites between the two honeybee species, we further demonstrate that Vd is able to mimic the cuticular HC of a novel host species when artificially transferred to this new host. Mites originally from A. cerana are more efficient than mites from A. mellifera in mimicking HC of both A. cerana and A. mellifera. This remarkable adaptability may explain their relatively recent host-shift from A. cerana to A. mellifera. PMID- 26041868 TI - The evolutionary ecology of decorating behaviour. AB - Many animals decorate themselves through the accumulation of environmental material on their exterior. Decoration has been studied across a range of different taxa, but there are substantial limits to current understanding. Decoration in non-humans appears to function predominantly in defence against predators and parasites, although an adaptive function is often assumed rather than comprehensively demonstrated. It seems predominantly an aquatic phenomenon presumably because buoyancy helps reduce energetic costs associated with carrying the decorative material. In terrestrial examples, decorating is relatively common in the larval stages of insects. Insects are small and thus able to generate the power to carry a greater mass of material relative to their own body weight. In adult forms, the need to be lightweight for flight probably rules out decoration. We emphasize that both benefits and costs to decoration are rarely quantified, and that costs should include those associated with collecting as well as carrying the material. PMID- 26041869 TI - The joint interagency task force and the global steering committee for the quality assurance of health products: two new and proactive approaches promoting access to safe and effective medicines. PMID- 26041870 TI - Radiotherapy in patients with pacemakers and implantable cardioverter defibrillators: a literature review. AB - An increasing number of patients with implantable cardiac rhythm devices undergo radiotherapy (RT) for cancer and are thereby exposed to the risk of device failure. Current safety recommendations seem to have limitations by not accounting for the risk of pacemakers and implantable cardioverter defibrillators malfunctioning at low radiation doses. Besides scant knowledge about optimal safety measures, only little is known about the exact prevalence of patients with devices undergoing RT. In this review, we provide a short overview of the principles of RT and present the current evidence on the predictors and mechanisms of device malfunctions during RT. We also summarize practical recommendations from recent publications and from the industry. Strongly associated with beam energy of photon RT, device malfunctions occur at ~3% of RT courses, posing a substantial issue in clinical practice. Malfunctions described in the literature typically consist of transient software disturbances and only seldom manifest as a permanent damage of the device. Through close cooperation between cardiologists and oncologists, a tailored individualized approach might be necessary in this patient group in waiting time for updated international guidelines in the field. PMID- 26041871 TI - Towards durable pulmonary vein isolation: we are closing the gap. PMID- 26041872 TI - EFFICAS II: optimization of catheter contact force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation. AB - AIMS: A challenge of pulmonary vein isolation (PVI) in catheter ablation for paroxysmal atrial fibrillation (PAF) is electrical reconnection of the PV. EFFICAS I showed correlation between contact force (CF) parameters and PV durable isolation but no prospective evaluation was made. EFFICAS II was a multicentre study to prospectively assess the impact of CF guidance for an effective reduction of PVI gaps. METHODS AND RESULTS: Pulmonary vein isolation using a radiofrequency (RF) ablation catheter with an integrated force sensor (TactiCathTM) was performed in patients with PAF. Operators were provided EFFICAS I-based CF guidelines [target 20 g, range 10-30 g, minimum 400 g s force-time integral (FTI)]. Conduction gaps were assessed by remapping of PVs after 3 months, and gap rate was compared with EFFICAS I outcome. At follow up, 24 patients had 85% of PVs remaining isolated, compared with 72% in EFFICAS I (P = 0.037) in which CF guidelines were not used. The remaining 15% of gaps correlated to the number of catheter moves at creating the PVI line, quantified as Continuity Index. For PV lines with contiguous lesions and low catheter moves, durable isolation was 81% in EFFICAS I and 98% in EFFICAS II (P = 0.005). At index procedure, the number of lesions was reduced by 15% in EFFICAS II vs. EFFICAS I. CONCLUSION: The use of CF with the above guidelines and contiguous deployment of RF lesions in EFFICAS II study resulted in more durable PVI in catheter ablation of PAF. PMID- 26041873 TI - Down-modulation of primate lentiviral receptors by Nef proteins of simian immunodeficiency virus (SIV) of chimpanzees (SIVcpz) and related SIVs: implication for the evolutionary event at the emergence of SIVcpz. AB - It has been estimated that human immunodeficiency virus type 1 originated from the zoonotic transmission of simian immunodeficiency virus (SIV) of chimpanzees, SIVcpz, and that SIVcpz emerged by the recombination of two lineages of SIVs in Old World monkeys (SIVgsn/mon/mus in guenons and SIVrcm in red-capped mangabeys) and SIVcpz Nef is most closely related to SIVrcm Nef. These observations suggest that SIVrcm Nef had an advantage over SIVgsn/mon/mus during the evolution of SIVcpz in chimpanzees, although this advantage remains uncertain. Nef is a multifunctional protein which downregulates CD4 and coreceptor proteins from the surface of infected cells, presumably to limit superinfection. To assess the possibility that SIVrcm Nef was selected by its superior ability to downregulate viral entry receptors in chimpanzees, we compared its ability to down-modulate viral receptor proteins from humans, chimpanzees and red-capped mangabeys with Nef proteins from eight other different strains of SIVs. Surprisingly, the ability of SIVrcm Nef to downregulate CCR5, CCR2B and CXCR6 was comparable to or lower than SIVgsn/mon/mus Nef, indicating that ability to down-modulate chemokine receptors was not the selective pressure. However, SIVrcm Nef significantly downregulates chimpanzee CD4 over SIVgsn/mon/mus Nefs. Our findings suggest the possibility that the selection of SIVrcm Nef by ancestral SIVcpz is due to its superior capacity to down-modulate chimpanzees CD4 rather than coreceptor proteins. PMID- 26041874 TI - Arterivirus nsp12 versus the coronavirus nsp16 2'-O-methyltransferase: comparison of the C-terminal cleavage products of two nidovirus pp1ab polyproteins. AB - The 3'-terminal domain of the most conserved ORF1b in three of the four families of the order Nidovirales (except for the family Arteriviridae) encodes a (putative) 2'-O-methyltransferase (2'-O-MTase), known as non structural protein (nsp) 16 in the family Coronaviridae and implicated in methylation of the 5' cap structure of nidoviral mRNAs. As with coronavirus transcripts, arterivirus mRNAs are assumed to possess a 5' cap although no candidate MTases have been identified thus far. To address this knowledge gap, we analysed the uncharacterized nsp12 of arteriviruses, which occupies the ORF1b position equivalent to that of the nidovirus 2'-O-MTase (coronavirus nsp16). In our in-depth bioinformatics analysis of nsp12, the protein was confirmed to be family specific whilst having diverged much further than other nidovirus ORF1b-encoded proteins, including those of the family Coronaviridae. Only one invariant and several partially conserved, predominantly aromatic residues were identified in nsp12, which may adopt a structure with alternating alpha-helices and beta-strands, an organization also found in known MTases. However, no statistically significant similarity was found between nsp12 and the twofold larger coronavirus nsp16, nor could we detect MTase activity in biochemical assays using recombinant equine arteritis virus (EAV) nsp12. Our further analysis established that this subunit is essential for replication of this prototypic arterivirus. Using reverse genetics, we assessed the impact of 25 substitutions at 14 positions, yielding virus phenotypes ranging from WT-like to non-viable. Notably, replacement of the invariant phenylalanine 109 with tyrosine was lethal. We concluded that nsp12 plays an essential role during EAV replication, possibly by acting as a co-factor for another enzyme. PMID- 26041875 TI - Assessment of cross-species transmission of hepatitis C virus-related non-primate hepacivirus in a population of humans at high risk of exposure. AB - The recent discovery of hepatitis C virus (HCV)-related viruses in different animal species has raised new speculations regarding the origin of HCV and the possibility of a zoonotic source responsible for the endemic HCV transmission. As a consequence, these new findings prompt questions regarding the potential for cross-species transmissions of hepaciviruses. The closest relatives to HCV discovered to date are the non-primate hepaciviruses (NPHVs), which have been described to infect horses. To evaluate the risk of a potential zoonotic transmission, we analysed NPHV RNA and antibodies in humans with occupational exposure to horses in comparison with a low-risk group. Both groups were negative for NPHV RNA, even though low seroreactivities against various NPHV antigens could be detected irrespective of the group. In conclusion, we did not observe evidence of NPHV transmission between horses and humans. PMID- 26041876 TI - European views on patients directly obtaining their laboratory test results. AB - BACKGROUND: Medicine is a highly professionalized endeavour, by tradition centred on the authority of physicians. Better education and the advent of the information age cater for increased demands on society in general and on health care in particular to enable people to make informed decisions regarding themselves. Participation in medical decisions requires informed knowledge which is hard to obtain without substantial and time consuming professional help. METHODS: We performed a survey amongst the member organizations of European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) in order to investigate the recognition and preparedness of providing help to patients in interpreting their laboratory results. RESULTS: Out of 40 EFLM Member Societies, 27 sent their responses to the survey. In most cases the first line delivery of laboratory results to physicians is by computer link (63%). Patients receive their laboratory results on demand from their physician in 60% of cases. However, 34% of laboratory specialists showed a negative attitude for delivering laboratory results to patients. Yet, in 48% of countries 1-5 patients per day ask a laboratory specialist about the significance of laboratory results outside the reference range. When patients are informed about the purpose of laboratory testing, they seek information primarily from their physician, followed by the internet and the Specialist in Laboratory Medicine. CONCLUSIONS: Changing practices increasingly enabling patient access to their records are on the increase facilitated by recent innovations in information technologies. Successful transfer of some of the responsibilities of physicians, demands a mutual triangular dialogue between the patient, their physician and laboratory medicine. PMID- 26041877 TI - Gene expression patterns through oral squamous cell carcinoma development: PD-L1 expression in primary tumor and circulating tumor cells. AB - Oral squamous cell carcinoma (OSCC) is the most common tumor of the oral cavity and has been associated with poor prognosis. Scarce prognostic markers are available for guiding treatment and/or sub-classifying patients. This study aims to identify biomarkers by searching for genes whose expression is increased or decreased during tumor progression (through T1 to T4 stages). Thirty-six samples from all tumor size stages (from T1 to T4) were analyzed using cDNA microarrays. Selected targets were analyzed by immunohistochemistry and in circulating tumor cells by immunofluorescence and Nanostring. Correlation was shown between PD-L1 and tumor size and lymph node metastasis, HOXB9 and tumor size, BLNK and perineural invasion, and between ZNF813 and perineural invasion. PD-L1 positivity was an independent prognostic factor in this cohort (p = 0.044, HH = 0.426). In CTCs from patients with locally advanced OSCC, we found a strong cytoplasmatic expression of PD-L1. PD-L1 is a ligand of PD-1 and is believed to limit T cell activity in inflammatory responses and limit autoimmune diseases. We demonstrated an important role for PD-L1 in primary tumors according to tumor size, and in disease specific survival. Therefore, we could further determine individuals with PD-L1+ CTCs, and possibly follow treatment using CTCs. PMID- 26041878 TI - Patient-derived bladder cancer xenografts in the preclinical development of novel targeted therapies. AB - Optimal animal models of muscle invasive bladder cancer (MIBC) are necessary to overcome the current lack of novel targeted therapies for this malignancy. Here we report on the establishment and characterization of patient-derived primary xenografts (PDX). Patient tumors were grafted under the renal capsule of mice and subsequently transplanted over multiple generations. Patient tumor and PDX were processed for analysis of copy number variations by aCGH, gene expression by microarray, and expression of target pathways by immunohistochemistry (IHC). One PDX harbouring an FGFR3 mutation was treated with an inhibitory monoclonal antibody targeting FGFR3. Five PDX were successfully established. Tumor doubling time ranged from 5 to 11 days. Array CGH revealed shared chromosomal aberrations in the patient tumors and PDX. Gene expression microarray and IHC confirmed that PDXs maintain similar patterns to the parental tumors. Tumor growth in the PDX with an FGFR3 mutation was inhibited by the FGFR3 inhibitor. PDXs recapitulate the tumor biology of the patients' primary tumors from which they are derived. Investigations related to tumor biology and drug testing in these models are therefore more likely to be relevant to the disease state in patients. They represent a valuable tool for developing precision therapy in MIBC. PMID- 26041879 TI - Sp1-driven up-regulation of miR-19a decreases RHOB and promotes pancreatic cancer. AB - Cancer treatment alters microRNA (miRNA) expression, revealing potential therapeutic targets (oncotarget). Here we treated pancreatic cancer (ASPC-1) cells with either recombinant human endostatin (rh-endostatin) or gemcitabine. Then high-throughput sequencing assay was performed to screen for altered miRNAs. Both treatments decreased levels of MiR-19a. We found that miR-19a stimulated cell proliferation, migration, invasion in vitro and tumor growth in vivo. High levels of miR-19a correlated with poor prognosis in patients. Ras homolog family member B (RHOB) was identified as a direct target of miR-19a. Furthermore, RHOB was down-regulated in human pancreatic cancer samples. Restoration of RHOB induced apoptosis, inhibited proliferation and migration of ASPC-1 cells. SP-1 was identified as an upstream transcription factor of miR-19a gene, promoting miR 19a transcription. Rh-endostatin decreased miR-19a expression by down-regulating SP-1. These findings suggest that miR-19a is a potential therapeutic target in pancreatic cancer. PMID- 26041880 TI - MET expression and copy number heterogeneity in nonsquamous non-small cell lung cancer (nsNSCLC). AB - OBJECTIVE: We aimed to assess MET intratumoral heterogeneity and its potential impact on biomarker-based patient selection as well as potential surrogate biomarkers of MET activation. METHODS: Our study included 120 patients with non squamous Non-small-cell Lung Cancer (nsNSCLC), of which 47 were incorporated in tissue microarrays (TMA). Four morphologically distinct tumor areas were selected to assess MET heterogeneity. MET positivity by immunohistochemistry (IHC) was defined as an above-median H-score and by +2/+3 staining intensity in >50% of tumor cells (Metmab criteria). MET FISH positivity was defined by MET/CEP7 ratio >= 2.0 and/or MET >= 5.0. MET staining pattern (cytoplasmic vs. membranous) and mesenchymal markers were investigated as surrogates of MET activation. RESULTS: Median MET H-score was 140 (range 0-400) and 47.8% of patients were MET positive by Metmab criteria. Eight cases (6.8%) were MET FISH positive and showed higher H scores (p = 0.021). MET positivity by IHC changed in up to 40% of cases among different tumor areas, and MET amplification in 25-50%. Cytoplasmic MET staining and positivity for vimentin predicted poor survival (p = 0.042 and 0.047, respectively). CONCLUSIONS: MET status is highly heterogeneous among different nsNSCLC tumor areas, hindering adequate patient selection for MET-targeted therapies. MET cytoplasmic staining and vimentin might represent surrogate markers for MET activation. PMID- 26041881 TI - The reciprocal regulation loop of Notch2 pathway and miR-23b in controlling gastric carcinogenesis. AB - Gastric carcinoma is one of the most common malignancies and the third highest cause of global cancer-related death. Notch2 receptor intracellular domain (N2IC), the activated form of Notch2 receptor, enhances gastric carcinogenesis. MicroRNAs (miRNAs) act as either oncogenes or tumor suppressors in tumorigenesis and cross-talk with Notch pathways. Herein, microRNA-23b (miR-23b) was identified as a Notch2 receptor-related miRNA and its role in gastric carcinogenesis was investigated. Levels of miR-23b in stomach adenocarcinoma samples were down regulated, whereas those of Notch2 receptor, v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets1), and E2F1 transcripts were up-regulated. Results also showed that N2IC down-regulated miR-23b expression in gastric cancer cells through up-regulating E2F1. The miR-23b inhibited gastric tumorigenesis including growth, viability, epithelial-mesenchymal transition, and abilities of colony formation, migration, invasion, and tumorsphere formation. Mechanistically, miR 23b suppressed tumor progression and pluripotency gene expression and affected tumorsphere ultra-structure in gastric cancer cells via targeting Notch2 receptor or Ets1. Furthermore, miR-23b diminished the xenografted tumor growth and lung metastasis of SC-M1 gastric cancer cells through Notch2 pathway. Our results suggest that Notch2 pathway and miR-23b interplay in a reciprocal regulation loop in gastric cancer cells and this axis plays an important role in gastric carcinogenesis. PMID- 26041882 TI - Chronic chemotherapeutic stress promotes evolution of stemness and WNT/beta catenin signaling in colorectal cancer cells: implications for clinical use of WNT-signaling inhibitors. AB - Most solid tumors contain a subfraction of cells with stem/progenitor cell features. Stem cells are naturally chemoresistant suggesting that chronic chemotherapeutic stress may select for cells with increased "stemness". We carried out a comprehensive molecular and functional analysis of six independently selected colorectal cancer (CRC) cell lines with acquired resistance to three different chemotherapeutic agents derived from two distinct parental cell lines. Chronic drug exposure resulted in complex alterations of stem cell markers that could be classified into three categories: 1) one cell line, HT-29/5-FU, showed increased "stemness" and WNT-signaling, 2) three cell lines showed decreased expression of stem cell markers, decreased aldehyde dehydrogenase activity, attenuated WNT-signaling and lost the capacity to form colonospheres and 3) two cell lines displayed prominent expression of ABC transporters with a heterogeneous response for stem cell markers. While WNT signaling could be attenuated in the HT-29/5-FU cells by the WNT-signaling inhibitors ICG-001 and PKF-118, this was not accompanied by any selective growth inhibitory effect suggesting that the cytotoxic activity of these compounds is not directly linked to WNT-signaling inhibition. We conclude that classical WNT signaling inhibitors have toxic off-target activities that need to be addressed for clinical development. PMID- 26041883 TI - Thyroid hormone and anti-apoptosis in tumor cells. AB - The principal secretory product of the thyroid gland, L-thyroxine (T4), is anti apoptotic at physiological concentrations in a number of cancer cell lines. Among the mechanisms of anti-apoptosis activated by the hormone are interference with the Ser-15 phosphorylation (activation) of p53 and with TNFalpha/Fas-induced apoptosis. The hormone also decreases cellular abundance and activation of proteolytic caspases and of BAX and causes increased expression of X-linked inhibitor of apoptosis (XIAP). The anti-apoptotic effects of thyroid hormone largely are initiated at a cell surface thyroid hormone receptor on the extracellular domain of integrin alphavbeta3 that is amply expressed and activated in cancer cells. Tetraiodothyroacetic acid (tetrac) is a T4 derivative that, in a model of resveratrol-induced p53-dependent apoptosis in glioma cells, blocks the anti-apoptotic action of thyroid hormone, permitting specific serine phosphorylation of p53 and apoptosis to proceed. In a nanoparticulate formulation limiting its action to alphavbeta3, tetrac modulates integrin-dependent effects on gene expression in human cancer cell lines that include increased expression of a panel of pro-apoptotic genes and decreased transcription of defensive anti apoptotic XIAP and MCL1 genes. By a variety of mechanisms, thyroid hormone (T4) is an endogenous anti-apoptotic factor that may oppose chemotherapy-induced apoptosis in alphavbeta3-expressing cancer cells. It is possible to decrease this anti-apoptotic activity pharmacologically by reducing circulating levels of T4 or by blocking effects of T4 that are initiated at alphavbeta3. PMID- 26041884 TI - Notch signaling sustains the expression of Mcl-1 and the activity of eIF4E to promote cell survival in CLL. AB - In chronic lymphocytic leukemia (CLL), Notch1 and Notch2 signaling is constitutively activated and contributes to apoptosis resistance. We show that genetic inhibition of either Notch1 or Notch2, through small-interfering RNA, increases apoptosis of CLL cells and is associated with decreased levels of the anti-apoptotic protein Mcl-1. Thus, Notch signaling promotes CLL cell survival at least in part by sustaining Mcl-1 expression. In CLL cells, an enhanced Notch activation also contributes to the increase in Mcl-1 expression and cell survival induced by IL-4.Mcl-1 downregulation by Notch targeting is not due to reduced transcription or degradation by caspases, but in part, to increased degradation by the proteasome. Mcl-1 downregulation by Notch targeting is also accompanied by reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), suggesting that this protein is another target of Notch signaling in CLL cells.Overall, we show that Notch signaling sustains CLL cell survival by promoting Mcl-1 expression and eIF4E activity, and given the oncogenic role of these factors, we underscore the therapeutic potential of Notch inhibition in CLL. PMID- 26041886 TI - Targeting Bcl-2 stability to sensitize cells harboring oncogenic ras. AB - The pro-survival factor Bcl-2 and its family members are critical determinants of the threshold of the susceptibility of cells to apoptosis. Studies are shown that cells harboring an oncogenic ras were extremely sensitive to the inhibition of protein kinase C (PKC) and Bcl-2 could antagonize this apoptotic process. However, it remains unrevealed how Bcl-2 is being regulated in this apoptotic process. In this study, we investigate the role of Bcl-2 stability in sensitizing the cells harboring oncogenic K-ras to apoptosis triggered by PKC inhibitor GO6976. We demonstrated that Bcl-2 in Swiss3T3 cells ectopically expressing or murine lung cancer LKR cells harboring K-ras rapidly underwent ubiquitin dependent proteasome pathway after the treatment of GO6976, accompanied with induction of apoptosis. In this process, Bcl-2 formed the complex with Keap-1 and Cul3. The mutation of serine-17 and deletion of BH-2 or 4 was required for Bcl-2 ubiquitination and degradation, which elevate the signal threshold for the induction of apoptosis in the cells following PKC inhibition. Thus, Bcl-2 appears an attractive target for the induction of apoptosis by PKC inhibition in cancer cells expressing oncogenic K-ras. PMID- 26041885 TI - Dynamic self-guiding analysis of Alzheimer's disease. AB - We applied a self-guiding evolutionary algorithm to initiate the synthesis of the Alzheimer's disease-related data and literature. A protein interaction network associated with amyloid-beta precursor protein (APP) and a seed model that treats Alzheimer's disease as progressive dysregulation of APP-associated signaling were used as dynamic "guides" and structural "filters" in the recursive search, analysis, and assimilation of data to drive the evolution of the seed model in size, detail, and complexity. Analysis of data and literature across sub disciplines and system-scale discovery platforms suggests a key role of dynamic cytoskeletal connectivity in the stability, plasticity, and performance of multicellular networks and architectures. Chronic impairment and/or dysregulation of cell adhesions/synapses, cytoskeletal networks, and/or reversible epithelial to-mesenchymal-like transitions, which enable and mediate the stable and coherent yet dynamic and reconfigurable multicellular architectures, may lead to the emergence and persistence of the disordered, wound-like pockets/microenvironments of chronically disconnected cells. Such wound-like microenvironments support and are supported by pro-inflammatory, pro-secretion, de-differentiated cellular phenotypes with altered metabolism and signaling. The co-evolution of wound-like microenvironments and their inhabitants may lead to the selection and stabilization of degenerated cellular phenotypes, via acquisition of epigenetic modifications and mutations, which eventually result in degenerative disorders such as cancer and Alzheimer's disease. PMID- 26041887 TI - EphA6 promotes angiogenesis and prostate cancer metastasis and is associated with human prostate cancer progression. AB - Metastasis is the primary cause of prostate cancer (CaP)-related death. We investigate the molecular, pathologic and clinical outcome associations of EphA6 expression and CaP metastasis. The expression profiling of Eph receptors (Ephs) and their ephrin ligands was performed in parental and metastatic CaP cell lines. Among Ephs and ephrins, only EphA6 is consistently overexpressed in metastatic CaP cells. Metastatic potential of EphA6 is assessed by RNAi in a CaP spontaneous metastasis mouse model. EphA6 knock-down in human PC-3M cells causes decreased invasion in vitro and reduced lung and lymph node metastasis in vivo. In addition, knock-down of EphA6 decreases tube formation in vitro and angiogenesis in vivo. EphA6 mRNA expression is higher in 112 CaP tumor samples compared with benign tissues from 58 benign prostate hyperplasia patients. Positive correlation was identified between EphA6 expression and vascular invasion, neural invasion, PSA level, and TNM staging in CaP cases. Further, genome-wide gene expression analysis in EphA6 knock-down cells identified a panel of differentially regulated genes including PIK3IPA, AKT1, and EIF5A2, which could contribute to EphA6 regulated cancer progression. These findings identify EphA6 as a potentially novel metastasis gene which positively correlates with CaP progression. EphA6 may be a therapeutic target in metastatic CaP. PMID- 26041888 TI - Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action. AB - The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention. PMID- 26041889 TI - C/D-box snoRNA-derived RNA production is associated with malignant transformation and metastatic progression in prostate cancer. AB - Small nucleolar RNAs (snoRNAs) are dynamically regulated in different tissues and affected in disease. SnoRNAs are processed further to stable smaller RNAs. We sequenced the small RNA transcriptome of prostate cancer (PCa) at different PCa stages and generated a quantified catalogue of 3927 small non-coding RNAs (sncRNAs) detected in normal and malignant prostate tissue. From these, only 1524 are microRNAs. The remaining 2401 sncRNAs represent stable sncRNAs species that originate from snoRNA, tRNA and other sncRNAs. We show that snoRNA-derived RNAs (sdRNAs) display stronger differential expression than microRNAs and are massively upregulated in PCa. SdRNAs account for at least one third of all small RNAs with expression changes in tumor compared to normal adjacent tissue. Multiple sdRNAs can be produced from one snoRNA in a manner related to the conservation of structural snoRNA motifs. Q-PCR analysis in an independent patient cohort (n=106) confirmed the processing patterns of selected snoRNAs (SNORD44, SNORD78, SNORD74 and SNORD81) and the cancer-associated up-regulation of their sdRNAs observed in sequencing data. Importantly, expression of SNORD78 and its sdRNA is significantly higher in a subset of patients that developed metastatic disease demonstrating that snoRNA and sdRNAs may present as novel diagnostic and/or prognostic biomarkers for PCa. PMID- 26041890 TI - Morphological and immunohistochemical identification of epithelial-to-mesenchymal transition in clinical prostate cancer. AB - Epithelial-to-mesenchymal transition (EMT) is a process known to be associated with aggressive tumor behavior, metastasis and treatment resistance. It is characterized by coincidental upregulation of mesenchymal markers such as vimentin, fibronectin and N-cadherin concurrent with E-cadherin downregulation. Studies on EMT are generally performed in cell lines and mouse models, while the histopathological and phenotypical properties in clinical prostate cancer (PCa) are still unclear. The objective of this study was to identify EMT in PCa patients. We demonstrated that N-cadherin, vimentin and fibronectin were generally not co-expressed in corresponding tumor regions. Immunofluorescent double stainings confirmed that co-expression of mesenchymal markers was uncommon, as we found no prostate cancer cells that co-expressed N-cadherin with fibronectin and only rare (<1%) cells that co-expressed N-cadherin with vimentin. Downregulation of E-cadherin was demonstrated in all N-cadherin positive tumor cells, but not in vimentin or fibronectin positive tumor cells. We further analyzed N-cadherin expression in morphologically distinct PCa growth patterns in a radical prostatectomy cohort (n = 77) and found that N-cadherin is preferentially expressed in ill-defined Gleason grade 4 PCa. In conclusion, we demonstrate that N-cadherin is the most reliable marker for EMT in clinical PCa and is preferentially expressed in ill-defined Gleason grade 4 growth pattern. PMID- 26041891 TI - Performance of a Noninvasive Test for Detecting Mycobacterium bovis Shedding in European Badger (Meles meles) Populations. AB - The incidence of Mycobacterium bovis, the causative agent of bovine tuberculosis, in cattle herds in the United Kingdom is increasing, resulting in substantial economic losses. The European badger (Meles meles) is implicated as a wildlife reservoir and is the subject of control measures aimed at reducing the incidence of infection in cattle populations. Understanding the epidemiology of M. bovis in badger populations is essential for directing control interventions and understanding disease spread; however, accurate diagnosis in live animals is challenging and currently uses invasive methods. Here we present a noninvasive diagnostic procedure and sampling regimen using field sampling of latrines and detection of M. bovis with quantitative PCR tests, the results of which strongly correlate with the results of immunoassays in the field at the social group level. This method allows M. bovis infections in badger populations to be monitored without trapping and provides additional information on the quantities of bacterial DNA shed. Therefore, our approach may provide valuable insights into the epidemiology of bovine tuberculosis in badger populations and inform disease control interventions. PMID- 26041892 TI - A Novel Quantitative Sampling Technique for Detection and Monitoring of Clostridium difficile Contamination in the Clinical Environment. AB - The horizontal transmission of Clostridium difficile in the hospital environment is difficult to establish. Current methods to detect C. difficile spores on surfaces are not quantitative, lack sensitivity, and are protracted. We propose a novel rapid method to detect and quantify C. difficile contamination on surfaces. Sponge swabbing was compared to contact plate sampling to assess the in vitro recovery of C. difficile ribotype 027 contamination (~10(0), 10(1), or 10(2) CFU of spores) from test surfaces (a bed rail, a stainless steel sheet, or a polypropylene work surface). Sponge swab contents were concentrated by vacuum filtration, and the filter membrane was plated onto selective agar. The efficacy of each technique for the recovery of C. difficile from sites in the clinical environment that are touched at a high frequency was evaluated. Contact plates recovered 19 to 32% of the total contamination on test surfaces, whereas sponge swabs recovered 76 to 94% of the total contamination, and contact plates failed to detect C. difficile contamination below a detection limit of 10 CFU/25 cm(2) (0.4 CFU/cm(2)). In use, contact plates failed to detect C. difficile contamination (0/96 contact plates; 4 case wards), while sponge swabs recovered C. difficile from 29% (87/301) of the surfaces tested in the clinical environment. Approximately 74% (36/49) of the area in the vicinity of the patient was contaminated (~1.34 +/- 6.88 CFU/cm(2) C. difficile spores). Reservoirs of C. difficile extended to beyond the areas near the patient: a dirty utility room sink (2.26 +/- 5.90 CFU/cm(2)), toilet floor (1.87 +/- 2.40 CFU/cm(2)), and chair arm (1.33 +/- 4.69 CFU/cm(2)). C. difficile was present on floors in ~90% of case wards. This study highlights that sampling with a contact plate may fail to detect C. difficile contamination and result in false-negative reporting. Our sponge sampling technique permitted the rapid and quantitative measurement of C. difficile contamination on surfaces with a sensitivity (limit, 0 CFU) greater than that which is otherwise possible. This technique could be implemented for routine surface hygiene monitoring for targeted cleaning interventions and as a tool to investigate routes of patient-patient transmission in the clinical environment. PMID- 26041895 TI - Biographical Feature: James Jorgensen, Ph.D. PMID- 26041894 TI - Clostridium difficile PCR Ribotype 018, a Successful Epidemic Genotype. AB - Clostridium difficile infection (CDI) became a public health problem for the global spreading of the so-called hypervirulent PCR ribotypes (RTs) 027 and 078, associated with increases in the transmission and severity of the disease. However, especially in Europe, several RTs are prevalent, and the concept of hypervirulence is currently debated. We investigated the toxin and resistance profiles and the genetic relatedness of 312 C. difficile strains isolated in a large Italian teaching hospital during a 5-year period. We evaluated the role of CDI-related antibiotic consumption and infection control practices on the RT predominance in association with their molecular features and transmission capacity. Excluding secondary cases due to nosocomial transmission, RT018 was the predominant genotype (42.4%) followed by RT078 (13.6%), while RT027 accounted for 0.8% of the strains. RT078 was most frequently isolated from patients in intensive care units. Its prevalence significantly increased over time, but its transmission capacity was very low. In contrast, RT018 was highly transmissible and accounted for 95.7% of the secondary cases. Patients with the RT018 genotype were significantly older than those with RT078 and other RTs, indicating an association between epidemic RT and age. We provide here the first epidemiological evidence to consider RT018 as a successful epidemic genotype that deserves more attention in clinical practice. PMID- 26041893 TI - Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering. AB - The goal of the study was to improve the methodology of HIV genotyping for analysis of HIV drug resistance and HIV clustering. Using the protocol of Gall et al. (A. Gall, B. Ferns, C. Morris, S. Watson, M. Cotten, M. Robinson, N. Berry, D. Pillay, and P. Kellam, J Clin Microbiol 50:3838-3844, 2012, doi:10.1128/JCM.01516-12), we developed a robust methodology for amplification of two large fragments of viral genome covering about 80% of the unique HIV-1 genome sequence. Importantly, this method can be applied to both viral RNA and proviral DNA amplification templates, allowing genotyping in HIV-infected subjects with suppressed viral loads (e.g., subjects on antiretroviral therapy [ART]). The two amplicons cover critical regions across the HIV-1 genome (including pol and env), allowing analysis of mutations associated with resistance to protease inhibitors, reverse transcriptase inhibitors (nucleoside reverse transcriptase inhibitors [NRTIs] and nonnucleoside reverse transcriptase inhibitors [NNRTIs]), integrase strand transfer inhibitors, and virus entry inhibitors. The two amplicons generated span 7,124 bp, providing substantial sequence length and numbers of informative sites for comprehensive phylogenic analysis and greater refinement of viral linkage analyses in HIV prevention studies. The long-range HIV genotyping from proviral DNA was successful in about 90% of 212 targeted blood specimens collected in a cohort where the majority of patients had suppressed viral loads, including 65% of patients with undetectable levels of HIV-1 RNA loads. The generated amplicons could be sequenced by different methods, such as population Sanger sequencing, single-genome sequencing, or next-generation ultradeep sequencing. The developed method is cost-effective-the cost of the long-range HIV genotyping is under $140 per subject (by Sanger sequencing)-and has the potential to enable the scale up of public health HIV prevention interventions. PMID- 26041896 TI - beta-D-Glucan Screening for Detection of Invasive Fungal Disease in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation. AB - While the assessment of beta-D-glucan (BDG) levels in adults improves the early diagnosis of invasive fungal disease (IFD), data on BDG levels in children are limited. We therefore assessed in a prospective cohort study the value of serial BDG screening for early detection of IFD in children undergoing allogeneic hematopoietic stem cell transplantation (HSCT). IFD was defined according to the revised European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) criteria, with the necessary modification that BDG was not included as a microbiological criterion. For the analysis, a total of 702 serum samples were obtained in 34 pediatric HSCT recipients. Proven IFD occurred in two patients (fusariosis and Candida sepsis, respectively), and probable invasive aspergillosis was diagnosed in four patients. Analyses including different cutoff values for BDG levels and different definitions of the onset of IFD demonstrated that the BDG assay has a relatively high sensitivity and good negative predictive value, whereas the positive predictive value has major limitations (<30%). Receiver operating characteristic analyses suggested an optimal cutoff between 60 and 70 pg/ml for different definitions of the onset of IFD. Our data show that BDG screening in pediatric HSCT recipients has a low positive predictive value and is therefore of limited usefulness. PMID- 26041897 TI - A Novel Solid Medium for Culturing Mycobacterium tuberculosis Isolates from Clinical Specimens. AB - The laboratory diagnosis of tuberculosis usually relies on culture-based isolation of the causative Mycobacterium tuberculosis bacteria. We developed and evaluated the performance of MOD9, a new blood-free derivative of the MOD4 solid medium on which we previously reported for the isolation and culture of mycobacteria. First, inoculation of Lowenstein-Jensen medium with 21 M. tuberculosis isolates at 10(5), 10(3), and 10 CFU yielded colonies in 5.7 +/- 1.5 days, 7.6 +/- 0.8 days, and 10.8 +/- 1.7 days versus 1.5 +/- 0.4 days, 3.5 +/- 0.6 days, and 4.9 +/- 1 days in MOD9 (P < 0.05, Student's t test). Further, the time to detectable growth of M. tuberculosis was measured on MOD9 and Lowenstein Jensen media after duplicate inoculation of 250 clinical specimens decontaminated with 0.7% chlorhexidine. The contamination rate was 1.6% (4/250) on MOD9 versus 4.4% (11/250) on Lowenstein-Jensen medium (P = 0.11, Fisher's exact test). Chlorhexidine-MOD9 yielded 38/250 (15.2%) isolates versus 32/250 (12.8%) isolates for the chlorhexidine-LJ (P = 0.5195, Fisher's exact test). All together, eight M. tuberculosis isolates were cultured solely from chlorhexidine-MOD9, and two M. tuberculosis isolates were cultured solely from chlorhexidine-LJ. The time to detection was 9.8 +/- 3.9 (range, 5 to 18) days for chlorhexidine-MOD9 versus 17.4 +/- 5.9 (range, 10 to 35) days for chlorhexidine-LJ (P < 0.05, Student's t test). These data indicate the superiority of the MOD9 medium over the standard LJ medium following chlorhexidine decontamination for the recovery of M. tuberculosis. PMID- 26041898 TI - Potential Pathogenetic Role of Bovine Herpesvirus 4 in Two Dairy Cows with Dermatitis-Pyrexia-Hemorrhagic Syndrome. AB - Dermatitis, pyrexia, and hemorrhagic syndrome (DPHS) is a rare bovine syndrome of unclear etiology. We describe two DPHS cases, the first to occur in Italy, with clinicopathological findings suggesting a potential pathogenetic role of bovine herpesvirus-4 (BoHV-4). PMID- 26041899 TI - Does the Presence of Scrapie Affect the Ability of Current Statutory Discriminatory Tests To Detect the Presence of Bovine Spongiform Encephalopathy? AB - Current European Commission (EC) surveillance regulations require discriminatory testing of all transmissible spongiform encephalopathy (TSE)-positive small ruminant (SR) samples in order to classify them as bovine spongiform encephalopathy (BSE) or non-BSE. This requires a range of tests, including characterization by bioassay in mouse models. Since 2005, naturally occurring BSE has been identified in two goats. It has also been demonstrated that more than one distinct TSE strain can coinfect a single animal in natural field situations. This study assesses the ability of the statutory methods as listed in the regulation to identify BSE in a blinded series of brain samples, in which ovine BSE and distinct isolates of scrapie are mixed at various ratios ranging from 99% to 1%. Additionally, these current statutory tests were compared with a new in vitro discriminatory method, which uses serial protein misfolding cyclic amplification (sPMCA). Western blotting consistently detected 50% BSE within a mixture, but at higher dilutions it had variable success. The enzyme-linked immunosorbent assay (ELISA) method consistently detected BSE only when it was present as 99% of the mixture, with variable success at higher dilutions. Bioassay and sPMCA reported BSE in all samples where it was present, down to 1%. sPMCA also consistently detected the presence of BSE in mixtures at 0.1%. While bioassay is the only validated method that allows comprehensive phenotypic characterization of an unknown TSE isolate, the sPMCA assay appears to offer a fast and cost-effective alternative for the screening of unknown isolates when the purpose of the investigation was solely to determine the presence or absence of BSE. PMID- 26041900 TI - Nocardia Septic Arthritis Complicating an Anterior Cruciate Ligament Repair. AB - Nocardia infection following anterior cruciate ligament (ACL) allograft reconstruction is a rare occurrence. We report a case of Nocardia infection of an allograft ACL reconstruction and septic arthritis of the knee joint due to an organism most similar to the novel Nocardia species Nocardia aobensis. PMID- 26041901 TI - Assessment of African Swine Fever Diagnostic Techniques as a Response to the Epidemic Outbreaks in Eastern European Union Countries: How To Improve Surveillance and Control Programs. AB - This study represents a complete comparative analysis of the most widely used African swine fever (ASF) diagnostic techniques in the European Union (EU) using field and experimental samples from animals infected with genotype II ASF virus (ASFV) isolates circulating in Europe. To detect ASFV, three different PCRs were evaluated in parallel using 785 field and experimental samples. The results showed almost perfect agreement between the Universal ProbeLibrary (UPL-PCR) and the real-time (kappa = 0.94 [95% confidence interval {CI}, 0.91 to 0.97]) and conventional (kappa = 0.88 [95% CI, 0.83 to 0.92]) World Organisation for Animal Health (OIE)-prescribed PCRs. The UPL-PCR had greater diagnostic sensitivity for detecting survivors and allows earlier detection of the disease. Compared to the commercial antigen enzyme-linked immunosorbent assay (ELISA), good-to-moderate agreement (kappa = 0.67 [95% CI, 0.58 to 0.76]) was obtained, with a sensitivity of 77.2% in the commercial test. For ASF antibody detection, five serological methods were tested, including three commercial ELISAs, the OIE-ELISA, and the confirmatory immunoperoxidase test (IPT). Greater sensitivity was obtained with the IPT than with the ELISAs, since the IPT was able to detect ASF antibodies at an earlier point in the serological response, when few antibodies are present. The analysis of the exudate tissues from dead wild boars showed that IPT might be a useful serological tool for determining whether or not animals had been exposed to virus infection, regardless of whether antibodies were present. In conclusion, the UPL-PCR in combination with the IPT was the most trustworthy method for detecting ASF during the epidemic outbreaks affecting EU countries in 2014. The use of the most appropriate diagnostic tools is critical when implementing effective control programs. PMID- 26041902 TI - High-Resolution Analysis by Whole-Genome Sequencing of an International Lineage (Sequence Type 111) of Pseudomonas aeruginosa Associated with Metallo Carbapenemases in the United Kingdom. AB - Whole-genome sequencing (WGS) was carried out on 87 isolates of sequence type 111 (ST-111) of Pseudomonas aeruginosa collected between 2005 and 2014 from 65 patients and 12 environmental isolates from 24 hospital laboratories across the United Kingdom on an Illumina HiSeq instrument. Most isolates (73) carried VIM-2, but others carried IMP-1 or IMP-13 (5) or NDM-1 (1); one isolate had VIM-2 and IMP-18, and 7 carried no metallo-beta-lactamase (MBL) gene. Single nucleotide polymorphism analysis divided the isolates into distinct clusters; the NDM-1 isolate was an outlier, and the IMP isolates and 6/7 MBL-negative isolates clustered separately from the main set of 73 VIM-2 isolates. Within the VIM-2 set, there were at least 3 distinct clusters, including a tightly clustered set of isolates from 3 hospital laboratories consistent with an outbreak from a single introduction that was quickly brought under control and a much broader set dominated by isolates from a long-running outbreak in a London hospital likely seeded from an environmental source, requiring different control measures; isolates from 7 other hospital laboratories in London and southeast England were also included. Bayesian evolutionary analysis indicated that all the isolates shared a common ancestor dating back ~50 years (1960s), with the main VIM-2 set separating approximately 20 to 30 years ago. Accessory gene profiling revealed blocks of genes associated with particular clusters, with some having high similarity (>=95%) to bacteriophage genes. WGS of widely found international lineages such as ST-111 provides the necessary resolution to inform epidemiological investigations and intervention policies. PMID- 26041904 TI - A systematic review of measurement tools of health and well-being for evaluating community-based interventions. AB - BACKGROUND: Those interested in evaluating the effectiveness of community interventions on health and well-being need information about what tools are available and best suited to measure improvements that could be attributed to the intervention.This study evaluated published measurement tools of health and well being that have the potential to be used before and after an intervention. METHODS: A literature search of health and sociological databases was undertaken for articles that utilised measurement tools in community settings to measure overall health, well-being or quality of life. Articles were considered potentially relevant because they included use of measurement tools related to general health or well-being. These tools were evaluated by further searching of the literature to assess each tool's properties including: reliability; validity; responsiveness; length; use in cross-cultural settings; global health or well being assessment; use of subjective measures; clarity and cost. A composite score was made based on the average rating of all fields. RESULTS: Of 958 abstracts that were screened, 123 articles were extracted for review. From those articles, 27 measurement tools were selected and assessed. Based on the composite score assessing across all domains, five tools were rated as excellent. CONCLUSIONS: While tools may need to be selected for particular aims and interventions, a range of potential well-described tools already exist and should be considered for use in preference to ad hoc or bespoke tools. Any of the five tools rated as excellent are recommended to assess the impact of a community intervention. PMID- 26041903 TI - Creation of an In-House Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry Corynebacterineae Database Overcomes Difficulties in Identification of Nocardia farcinica Clinical Isolates. AB - Nocardiosis is a rare disease that is caused by Gram-positive actinobacteria of the Nocardia genus and affects predominantly immunocompromised patients. In its disseminated form, it has a predilection for the central nervous system and is associated with high mortality rates. Therefore, prompt identification of the pathogen is critical. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry is a relatively novel technique used for identification of microorganisms. In this work, an upgraded MALDI-TOF Biotyper database containing Corynebacterineae representatives of strains deposited in the Polish Collection of Microorganisms was created and used for identification of the strain isolated from a nocardial brain abscess, mimicking a brain tumor, in an immunocompetent patient. Testing with the API Coryne system initially incorrectly identified Rhodococcus sp., while chemotaxonomic tests, especially mycolic acid analysis, enabled correct Nocardia identification only at the genus level. Subsequent sequence analysis of 16S rRNA and secA1 genes confirmed the identification. To improve the accuracy of the results, an in-house database was constructed using optimized parameters; with the use of the database, the strain was eventually identified as Nocardia farcinica. Clinical laboratories processing various clinical strains can upgrade a commercial database to improve and to accelerate the results obtained. This is especially important in the case of Nocardia, for which valid microbial diagnosis remains challenging; reference laboratories are often required to identify and to survey these rare actinobacteria. PMID- 26041905 TI - Current goals and prospects of the global polio eradication initiative. PMID- 26041906 TI - From Notes to Vowels: Neural Correlations between Musical Training and Speech Processing. PMID- 26041907 TI - Cognitive and action-based aspects of developing decisions in parietal cortex. PMID- 26041908 TI - Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons. AB - Dendrite development of newborn granule cells (GCs) in the dentate gyrus of adult hippocampus is critical for their incorporation into existing hippocampal circuits, but the cellular mechanisms regulating their dendrite development remains largely unclear. In this study, we examined the function of brain-derived neurotrophic factor (BDNF), which is expressed in adult-born GCs, in regulating their dendrite morphogenesis. Using retrovirus-mediated gene transfection, we found that deletion and overexpression of BDNF in adult-born GCs resulted in the reduction and elevation of dendrite growth, respectively. This effect was mainly due to the autocrine rather than paracrine action of BDNF, because deletion of BDNF only in the newborn GCs resulted in dendrite abnormality of these neurons to a similar extent as that observed in conditional knockout (cKO) mice with BDNF deleted in the entire forebrain. Furthermore, selective expression of BDNF in adult-born GCs in BDNF cKO mice fully restored normal dendrite development. The BDNF autocrine action was also required for the development of normal density of spines and normal percentage of spines containing the postsynaptic marker PSD-95, suggesting autocrine BDNF regulation of synaptogenesis. Furthermore, increased dendrite growth of adult-born GCs caused by voluntary exercise was abolished by BDNF deletion specifically in these neurons and elevated dendrite growth due to BDNF overexpression in these neurons was prevented by reducing neuronal activity with coexpression of inward rectifier potassium channels, consistent with activity-dependent autocrine BDNF secretion. Therefore, BDNF expressed in adult born GCs plays a critical role in dendrite development by acting as an autocrine factor. PMID- 26041909 TI - Synergy of direct and indirect cholinergic septo-hippocampal pathways coordinates firing in hippocampal networks. AB - The medial septum/diagonal band of Broca complex (MSDB) is a key structure that modulates hippocampal rhythmogenesis. Cholinergic neurons of the MSDB play a central role in generating and pacing theta-band oscillations in the hippocampal formation during exploration, novelty detection, and memory encoding. How precisely cholinergic neurons affect hippocampal network dynamics in vivo, however, has remained elusive. In this study, we show that stimulation of cholinergic MSDB neurons in urethane-anesthetized mice acts on hippocampal networks via two distinct pathways. A direct septo-hippocampal cholinergic projection causes increased firing of hippocampal inhibitory interneurons with concomitantly decreased firing of principal cells. In addition, cholinergic neurons recruit noncholinergic neurons within the MSDB. This indirect pathway is required for hippocampal theta synchronization. Activation of both pathways causes a reduction in pyramidal neuron firing and a more precise coupling to the theta oscillatory phase. These two anatomically and functionally distinct pathways are likely relevant for cholinergic control of encoding versus retrieval modes in the hippocampus. PMID- 26041910 TI - Astrocytes Are Primed by Chronic Neurodegeneration to Produce Exaggerated Chemokine and Cell Infiltration Responses to Acute Stimulation with the Cytokines IL-1beta and TNF-alpha. AB - Microgliosis and astrogliosis are standard pathological features of neurodegenerative disease. Microglia are primed by chronic neurodegeneration such that toll-like receptor agonists, such as LPS, drive exaggerated cytokine responses on this background. However, sterile inflammatory insults are more common than direct CNS infection in the degenerating brain and these insults drive robust IL-1beta and TNF-alpha responses. It is unclear whether these pro inflammatory cytokines can directly induce exaggerated responses in the degenerating brain. We hypothesized that glial cells in the hippocampus of animals with chronic neurodegenerative disease (ME7 prion disease) would display exaggerated responses to central cytokine challenges. TNF-alpha or IL-1beta were administered intrahippocampally to ME7-inoculated mice and normal brain homogenate-injected (NBH) controls. Both IL-1beta and TNF-alpha produced much more robust IL-1beta synthesis in ME7 than in NBH animals and this occurred exclusively in microglia. However, there was strong nuclear localization of the NFkappaB subunit p65 in the astrocyte population, associated with marked astrocytic synthesis of the chemokines CXCL1 and CCL2 in response to both cytokine challenges in ME7 animals. Conversely, very limited expression of these chemokines was apparent in NBH animals similarly challenged. Thus, astrocytes are primed in the degenerating brain to produce exaggerated chemokine responses to acute stimulation with pro-inflammatory cytokines. Furthermore, this results in markedly increased neutrophil, T-cell, and monocyte infiltration in the diseased brain. These data have significant implications for acute sterile inflammatory insults such as stroke and traumatic brain injury occurring on a background of aging or neurodegeneration. PMID- 26041911 TI - Trafficking of Na+/Ca2+ exchanger to the site of persistent inflammation in nociceptive afferents. AB - Persistent inflammation results in an increase in the amplitude and duration of depolarization-evoked Ca(2+) transients in putative nociceptive afferents. Previous data indicated that these changes were the result of neither increased neuronal excitability nor an increase in the amplitude of depolarization. Subsequent data also ruled out an increase in voltage-gated Ca(2+) currents and recruitment of Ca(2+)-induced Ca(2+) release. Parametric studies indicated that the inflammation-induced increase in the duration of the evoked Ca(2+) transient required a relatively large and long-lasting increase in the concentration of intracellular Ca(2+) implicating the Na(+)/Ca(2+) exchanger (NCX), a major Ca(2+) extrusion mechanism activated with high intracellular Ca(2+) loads. The contribution of NCX to the inflammation-induced increase in the evoked Ca(2+) transient in rat sensory neurons was tested using fura-2 AM imaging and electrophysiological recordings. Changes in NCX expression and protein were assessed with real-time PCR and Western blot analysis, respectively. An inflammation-induced decrease in NCX activity was observed in a subpopulation of putative nociceptive neurons innervating the site of inflammation. The time course of the decrease in NCX activity paralleled that of the inflammation induced changes in nociceptive behavior. The change in NCX3 in the cell body was associated with a decrease in NCX3 protein in the ganglia, an increase in the peripheral nerve (sciatic) yet no change in the central root. This single response to inflammation is associated with changes in at least three different segments of the primary afferent, all of which are likely to contribute to the dynamic response to persistent inflammation. PMID- 26041912 TI - Subcortical glutamate mediates the reduction of short-range functional connectivity with age in a developmental cohort. AB - Marked changes in brain physiology and structure take place between childhood and adulthood, including changes in functional connectivity and changes in the balance between main excitatory and inhibitory neurotransmitters glutamate (Glu) and GABA. The balance of these neurotransmitters is thought to underlie neural activity in general and functional connectivity networks in particular, but so far no studies have investigated the relationship between human development related differences in these neurotransmitters and concomitant changes in functional connectivity. GABA+/H2O and Glu/H2O levels were acquired in a group of healthy children, adolescents, and adults in a subcortical (basal ganglia) region, as well as in a frontal region in adolescents and adults. Our results showed higher GABA+/Glu with age in both the subcortical and the frontal voxel, which were differentially associated with significantly lower Glu/H2O with age in the subcortical voxel and by significantly higher GABA+/H2O with age in the frontal voxel. Using a seed-to-voxel analysis, we were further able to show that functional connectivity between the putamen (seed) and other subcortical structures was lower with age. Lower subcortical Glu/H2O with age mediated the lower connectivity in the dorsal putamen. Based on these results, and the potential role of Glu in synaptic pruning, we suggest that lower Glu mediates a reduction of local connectivity during human development. PMID- 26041913 TI - Microglia disrupt mesolimbic reward circuitry in chronic pain. AB - Chronic pain attenuates midbrain dopamine (DA) transmission, as evidenced by a decrease in opioid-evoked DA release in the ventral striatum, suggesting that the occurrence of chronic pain impairs reward-related behaviors. However, mechanisms by which pain modifies DA transmission remain elusive. Using in vivo microdialysis and microinjection of drugs into the mesolimbic DA system, we demonstrate in mice and rats that microglial activation in the VTA compromises not only opioid-evoked release of DA, but also other DA-stimulating drugs, such as cocaine. Our data show that loss of stimulated extracellular DA is due to impaired chloride homeostasis in midbrain GABAergic interneurons. Treatment with minocycline or interfering with BDNF signaling restored chloride transport within these neurons and recovered DA-dependent reward behavior. Our findings demonstrate that a peripheral nerve injury causes activated microglia within reward circuitry that result in disruption of dopaminergic signaling and reward behavior. These results have broad implications that are not restricted to the problem of pain, but are also relevant to affective disorders associated with disruption of reward circuitry. Because chronic pain causes glial activation in areas of the CNS important for mood and affect, our findings may translate to other disorders, including anxiety and depression, that demonstrate high comorbidity with chronic pain. PMID- 26041914 TI - Modulation of the Intracortical LFP during Action Execution and Observation. AB - The activity of mirror neurons in macaque ventral premotor cortex (PMv) and primary motor cortex (M1) is modulated by the observation of another's movements. This modulation could underpin well documented changes in EEG/MEG activity indicating the existence of a mirror neuron system in humans. Because the local field potential (LFP) represents an important link between macaque single neuron and human noninvasive studies, we focused on mirror properties of intracortical LFPs recorded in the PMv and M1 hand regions in two macaques while they reached, grasped and held different objects, or observed the same actions performed by an experimenter. Upper limb EMGs were recorded to control for covert muscle activity during observation.The movement-related potential (MRP), investigated as intracortical low-frequency LFP activity (<9 Hz), was modulated in both M1 and PMv, not only during action execution but also during action observation. Moreover, the temporal LFP modulations during execution and observation were highly correlated in both cortical areas. Beta power in both PMv and M1 was clearly modulated in both conditions. Although the MRP was detected only during dynamic periods of the task (reach/grasp/release), beta decreased during dynamic and increased during static periods (hold).Comparison of LFPs for different grasps provided evidence for partially nonoverlapping networks being active during execution and observation, which might be related to different inputs to motor areas during these conditions. We found substantial information about grasp in the MRP corroborating its suitability for brain-machine interfaces, although information about grasp was generally low during action observation. PMID- 26041915 TI - GluN2B-Containing NMDA Receptors Regulate AMPA Receptor Traffic through Anchoring of the Synaptic Proteasome. AB - NMDA receptors play a central role in shaping the strength of synaptic connections throughout development and in mediating synaptic plasticity mechanisms that underlie some forms of learning and memory formation in the CNS. In the hippocampus and the neocortex, GluN1 is combined primarily with GluN2A and GluN2B, which are differentially expressed during development and confer distinct molecular and physiological properties to NMDA receptors. The contribution of each subunit to the synaptic traffic of NMDA receptors and therefore to their role during development and in synaptic plasticity is still controversial. We report a critical role for the GluN2B subunit in regulating NMDA receptor synaptic targeting. In the absence of GluN2B, the synaptic levels of AMPA receptors are increased and accompanied by decreased constitutive endocytosis of GluA1-AMPA receptor. We used quantitative proteomic analysis to identify changes in the composition of postsynaptic densities from GluN2B(-/-) mouse primary neuronal cultures and found altered levels of several ubiquitin proteasome system components, in particular decreased levels of proteasome subunits. Enhancing the proteasome activity with a novel proteasome activator restored the synaptic levels of AMPA receptors in GluN2B(-/-) neurons and their endocytosis, revealing that GluN2B-mediated anchoring of the synaptic proteasome is responsible for fine tuning AMPA receptor synaptic levels under basal conditions. PMID- 26041916 TI - Sloppiness in spontaneously active neuronal networks. AB - Various plasticity mechanisms, including experience-dependent, spontaneous, as well as homeostatic ones, continuously remodel neural circuits. Yet, despite fluctuations in the properties of single neurons and synapses, the behavior and function of neuronal assemblies are generally found to be very stable over time. This raises the important question of how plasticity is coordinated across the network. To address this, we investigated the stability of network activity in cultured rat hippocampal neurons recorded with high-density multielectrode arrays over several days. We used parametric models to characterize multineuron activity patterns and analyzed their sensitivity to changes. We found that the models exhibited sloppiness, a property where the model behavior is insensitive to changes in many parameter combinations, but very sensitive to a few. The activity of neurons with sloppy parameters showed faster and larger fluctuations than the activity of a small subset of neurons associated with sensitive parameters. Furthermore, parameter sensitivity was highly correlated with firing rates. Finally, we tested our observations from cell cultures on an in vivo recording from monkey visual cortex and we confirm that spontaneous cortical activity also shows hallmarks of sloppy behavior and firing rate dependence. Our findings suggest that a small subnetwork of highly active and stable neurons supports group stability, and that this endows neuronal networks with the flexibility to continuously remodel without compromising stability and function. PMID- 26041917 TI - The Chromatin Remodeling Protein Bptf Promotes Posterior Neuroectodermal Fate by Enhancing Smad2-Activated wnt8a Expression. AB - During vertebrate embryogenesis, the neuroectoderm is induced from dorsal ectoderm and then partitioned into anterior and posterior neuroectodermal domains by posteriorizing signals, such as Wnt and fibroblast growth factor. However, little is known about epigenetic regulation of posteriorizing gene expression. Here, we report a requirement of the chromatin remodeling protein Bptf for neuroectodermal posteriorization in zebrafish embryos. Knockdown of bptf leads to an expansion of the anterior neuroectoderm at the expense of the posterior ectoderm. Bptf functionally and physically interacts with p-Smad2, which is activated by non-Nodal TGF-beta signaling, to promote the expression of wnt8a, a critical gene for neural posteriorization. Bptf and Smad2 directly bind to and activate the wnt8a promoter through recruiting NURF remodeling complex. When bptf function or TGF-beta signal transduction is inhibited, the nucleosome density on the wnt8a promoter is increased. We propose that Bptf and TGF-beta/Smad2 mediate nucleosome remodeling to regulate wnt8a expression and hence neural posteriorization. PMID- 26041918 TI - Lateral orbitofrontal cortex links social impressions to political choices. AB - Recent studies of political behavior suggest that voting decisions can be influenced substantially by "first-impression" social attributions based on physical appearance. Separate lines of research have implicated the orbitofrontal cortex (OFC) in the judgment of social traits on the one hand and economic decision-making on the other, making this region a plausible candidate for linking social attributions to voting decisions. Here, we asked whether OFC lesions in humans disrupted the ability to judge traits of political candidates or affected how these judgments influenced voting decisions. Seven patients with lateral OFC damage, 18 patients with frontal damage sparing the lateral OFC, and 53 matched healthy participants took part in a simulated election paradigm, in which they voted for real-life (but unknown) candidates based only on photographs of their faces. Consistent with previous work, attributions of "competence" and "attractiveness" based on candidate appearance predicted voting behavior in the healthy control group. Frontal damage did not affect substantially the ability to make competence or attractiveness judgments, but patients with damage to the lateral OFC differed from other groups in how they applied this information when voting. Only attractiveness ratings had any predictive power for voting choices after lateral OFC damage, whereas other frontal patients and healthy controls relied on information about both competence and attractiveness in making their choice. An intact lateral OFC may not be necessary for judgment of social traits based on physical appearance, but it seems to be crucial in applying this information in political decision-making. PMID- 26041920 TI - Goal-Directed Modulation of Neural Memory Patterns: Implications for fMRI-Based Memory Detection. AB - Remembering a past event elicits distributed neural patterns that can be distinguished from patterns elicited when encountering novel information. These differing patterns can be decoded with relatively high diagnostic accuracy for individual memories using multivoxel pattern analysis (MVPA) of fMRI data. Brain based memory detection--if valid and reliable--would have clear utility beyond the domain of cognitive neuroscience, in the realm of law, marketing, and beyond. However, a significant boundary condition on memory decoding validity may be the deployment of "countermeasures": strategies used to mask memory signals. Here we tested the vulnerability of fMRI-based memory detection to countermeasures, using a paradigm that bears resemblance to eyewitness identification. Participants were scanned while performing two tasks on previously studied and novel faces: (1) a standard recognition memory task; and (2) a task wherein they attempted to conceal their true memory state. Univariate analyses revealed that participants were able to strategically modulate neural responses, averaged across trials, in regions implicated in memory retrieval, including the hippocampus and angular gyrus. Moreover, regions associated with goal-directed shifts of attention and thought substitution supported memory concealment, and those associated with memory generation supported novelty concealment. Critically, whereas MVPA enabled reliable classification of memory states when participants reported memory truthfully, the ability to decode memory on individual trials was compromised, even reversing, during attempts to conceal memory. Together, these findings demonstrate that strategic goal states can be deployed to mask memory-related neural patterns and foil memory decoding technology, placing a significant boundary condition on their real-world utility. PMID- 26041919 TI - Shared sensory estimates for human motion perception and pursuit eye movements. AB - Are sensory estimates formed centrally in the brain and then shared between perceptual and motor pathways or is centrally represented sensory activity decoded independently to drive awareness and action? Questions about the brain's information flow pose a challenge because systems-level estimates of environmental signals are only accessible indirectly as behavior. Assessing whether sensory estimates are shared between perceptual and motor circuits requires comparing perceptual reports with motor behavior arising from the same sensory activity. Extrastriate visual cortex both mediates the perception of visual motion and provides the visual inputs for behaviors such as smooth pursuit eye movements. Pursuit has been a valuable testing ground for theories of sensory information processing because the neural circuits and physiological response properties of motion-responsive cortical areas are well studied, sensory estimates of visual motion signals are formed quickly, and the initiation of pursuit is closely coupled to sensory estimates of target motion. Here, we analyzed variability in visually driven smooth pursuit and perceptual reports of target direction and speed in human subjects while we manipulated the signal-to noise level of motion estimates. Comparable levels of variability throughout viewing time and across conditions provide evidence for shared noise sources in the perception and action pathways arising from a common sensory estimate. We found that conditions that create poor, low-gain pursuit create a discrepancy between the precision of perception and that of pursuit. Differences in pursuit gain arising from differences in optic flow strength in the stimulus reconcile much of the controversy on this topic. PMID- 26041921 TI - Neuro-oscillatory phase alignment drives speeded multisensory response times: an electro-corticographic investigation. AB - Even simple tasks rely on information exchange between functionally distinct and often relatively distant neuronal ensembles. Considerable work indicates oscillatory synchronization through phase alignment is a major agent of inter regional communication. In the brain, different oscillatory phases correspond to low- and high-excitability states. Optimally aligned phases (or high-excitability states) promote inter-regional communication. Studies have also shown that sensory stimulation can modulate or reset the phase of ongoing cortical oscillations. For example, auditory stimuli can reset the phase of oscillations in visual cortex, influencing processing of a simultaneous visual stimulus. Such cross-regional phase reset represents a candidate mechanism for aligning oscillatory phase for inter-regional communication. Here, we explored the role of local and inter-regional phase alignment in driving a well established behavioral correlate of multisensory integration: the redundant target effect (RTE), which refers to the fact that responses to multisensory inputs are substantially faster than to unisensory stimuli. In a speeded detection task, human epileptic patients (N = 3) responded to unisensory (auditory or visual) and multisensory (audiovisual) stimuli with a button press, while electrocorticography was recorded over auditory and motor regions. Visual stimulation significantly modulated auditory activity via phase reset in the delta and theta bands. During the period between stimulation and subsequent motor response, transient synchronization between auditory and motor regions was observed. Phase synchrony to multisensory inputs was faster than to unisensory stimulation. This sensorimotor phase alignment correlated with behavior such that stronger synchrony was associated with faster responses, linking the commonly observed RTE with phase alignment across a sensorimotor network. PMID- 26041922 TI - Developmental changes in synaptic distribution in arcuate nucleus neurons. AB - Neurons coexpressing neuropeptide Y, agouti-related peptide, and GABA (NAG) play an important role in ingestive behavior and are located in the arcuate nucleus of the hypothalamus. NAG neurons receive both GABAergic and glutamatergic synaptic inputs, however, the developmental time course of synaptic input organization of NAG neurons in mice is unknown. In this study, we show that these neurons have low numbers of GABAergic synapses and that GABA is inhibitory to NAG neurons during early postnatal period. In contrast, glutamatergic inputs onto NAG neurons are relatively abundant by P13 and are comparatively similar to the levels observed in the adult. As mice reach adulthood (9-10 weeks), GABAergic tone onto NAG neurons increases. At this age, NAG neurons received similar numbers of inhibitory and EPSCs. To further differentiate age-associated changes in synaptic distribution, 17- to 18-week-old lean and diet-induced obesity (DIO) mice were studied. Surprisingly, NAG neurons from lean adult mice exhibit a reduction in the GABAergic synapses compared with younger adults. Conversely, DIO mice display reductions in the number of GABAergic and glutamatergic inputs onto NAG neurons. Based on these experiments, we propose that synaptic distribution in NAG neurons is continuously restructuring throughout development to accommodate the animals' energy requirements. PMID- 26041924 TI - Inhibition shapes acoustic responsiveness in spherical bushy cells. AB - Signal processing in the auditory brainstem is based on an interaction of neuronal excitation and inhibition. To date, we have incomplete knowledge of how the dynamic interplay of both contributes to the processing power and temporal characteristics of signal coding. The spherical bushy cells (SBCs) of the anteroventral cochlear nucleus (AVCN) receive their primary excitatory input through auditory nerve fibers via large, axosomatic synaptic terminals called the endbulbs of Held and by additional, acoustically driven inhibitory inputs. SBCs provide the input to downstream nuclei of the brainstem sound source localization circuitry, such as the medial and lateral superior olive, which rely on temporal precise inputs. In this study, we used juxtacellular recordings in anesthetized Mongolian gerbils to assess the effect of acoustically evoked inhibition on the SBCs input-output function and on temporal precision of SBC spiking. Acoustically evoked inhibition proved to be strong enough to suppress action potentials (APs) of SBCs in a stimulus-dependent manner. Inhibition shows slow onset and offset dynamics and increasing strength at higher sound intensities. In addition, inhibition decreases the rising slope of the EPSP and prolongs the EPSP-to-AP transition time. Both effects can be mimicked by iontophoretic application of glycine. Inhibition also improves phase locking of SBC APs to low-frequency tones by acting as a gain control to suppress poorly timed EPSPs from generating postsynaptic APs to maintain precise SBC spiking across sound intensities. The present data suggest that inhibition substantially contributes to the processing power of second-order neurons in the ascending auditory system. PMID- 26041923 TI - Functional Upregulation of alpha4* Nicotinic Acetylcholine Receptors in VTA GABAergic Neurons Increases Sensitivity to Nicotine Reward. AB - Chronic nicotine exposure increases sensitivity to nicotine reward during a withdrawal period, which may facilitate relapse in abstinent smokers, yet the molecular neuroadaptation(s) that contribute to this phenomenon are unknown. Interestingly, chronic nicotine use induces functional upregulation of nicotinic acetylcholine receptors (nAChRs) in the mesocorticolimbic reward pathway potentially linking upregulation to increased drug sensitivity. In the ventral tegmental area (VTA), functional upregulation of nAChRs containing the alpha4 subunit (alpha4* nAChRs) is restricted to GABAergic neurons. To test the hypothesis that increased functional expression of alpha4* nAChRs in these neurons modulates nicotine reward behaviors, we engineered a Cre recombinase dependent gene expression system to selectively express alpha4 nAChR subunits harboring a "gain-of-function" mutation [a leucine mutated to a serine residue at the 9' position (Leu9'Ser)] in VTA GABAergic neurons of adult mice. In mice expressing Leu9'Ser alpha4 nAChR subunits in VTA GABAergic neurons (Gad2(VTA):Leu9'Ser mice), subreward threshold doses of nicotine were sufficient to selectively activate VTA GABAergic neurons and elicit acute hypolocomotion, with subsequent nicotine exposures eliciting tolerance to this effect, compared to control animals. In the conditioned place preference procedure, nicotine was sufficient to condition a significant place preference in Gad2(VTA):Leu9'Ser mice at low nicotine doses that failed to condition control animals. Together, these data indicate that functional upregulation of alpha4* nAChRs in VTA GABAergic neurons confers increased sensitivity to nicotine reward and points to nAChR subtypes specifically expressed in GABAergic VTA neurons as molecular targets for smoking cessation therapeutics. PMID- 26041925 TI - Persistent Nociception Triggered by Nerve Growth Factor (NGF) Is Mediated by TRPV1 and Oxidative Mechanisms. AB - Nerve growth factor (NGF) is elevated in certain chronic pain conditions and is a sufficient stimulus to cause lasting pain in humans, but the actual mechanisms underlying the persistent effects of NGF remain incompletely understood. We developed a rat model of NGF-induced persistent thermal hyperalgesia and mechanical allodynia to determine the role of transient receptor potential vanilloid 1 (TRPV1) and oxidative mechanisms in the persistent effects of NGF. Persistent thermal hypersensitivity and mechanical allodynia require de novo protein translation and are mediated by TRPV1 and oxidative mechanisms. By comparing effects after systemic (subcutaneous), spinal (intrathecal) or hindpaw (intraplantar) injections of test compounds, we determined that TRPV1 and oxidation mediate persistent thermal hypersensitivity via peripheral and spinal sites of action and mechanical allodynia via only a spinal site of action. Therefore, NGF-evoked thermal and mechanical allodynia are mediated by spatially distinct mechanisms. NGF treatment evoked sustained increases in peripheral and central TRPV1 activity, as demonstrated by increased capsaicin-evoked nocifensive responses, increased calcitonin gene-related peptide release from hindpaw skin biopsies, and increased capsaicin-evoked inward current and membrane expression of TRPV1 protein in dorsal root ganglia neurons. Finally, we showed that NGF treatment increased concentrations of linoleic and arachidonic-acid-derived oxidized TRPV1 agonists in spinal cord and skin biopsies. Furthermore, increases in oxidized TRPV1-active lipids were reduced by peripheral and spinal injections of compounds that completely blocked persistent nociception. Collectively, these data indicate that NGF evokes a persistent nociceptive state mediated by increased TRPV1 activity and oxidative mechanisms, including increased production of oxidized lipid TRPV1 agonists. PMID- 26041927 TI - Role of input correlations in shaping the variability and noise correlations of evoked activity in the neocortex. AB - Recent analysis of evoked activity recorded across different brain regions and tasks revealed a marked decrease in noise correlations and trial-by-trial variability. Given the importance of correlations and variability for information processing within the rate coding paradigm, several mechanisms have been proposed to explain the reduction in these quantities despite an increase in firing rates. These models suggest that anatomical clusters and/or tightly balanced excitation inhibition can generate intrinsic network dynamics that may exhibit a reduction in noise correlations and trial-by-trial variability when perturbed by an external input. Such mechanisms based on the recurrent feedback crucially ignore the contribution of feedforward input to the statistics of the evoked activity. Therefore, we investigated how statistical properties of the feedforward input shape the statistics of the evoked activity. Specifically, we focused on the effect of input correlation structure on the noise correlations and trial-by trial variability. We show that the ability of neurons to transfer the input firing rate, correlation, and variability to the output depends on the correlations within the presynaptic pool of a neuron, and that an input with even weak within-correlations can be sufficient to reduce noise correlations and trial by-trial variability, without requiring any specific recurrent connectivity structure. In general, depending on the ongoing activity state, feedforward input could either increase or decrease noise correlation and trial-by-trial variability. Thus, we propose that evoked activity statistics are jointly determined by the feedforward and feedback inputs. PMID- 26041926 TI - Experience with the "good" limb induces aberrant synaptic plasticity in the perilesion cortex after stroke. AB - Following unilateral stroke, the contralateral (paretic) body side is often severely impaired, and individuals naturally learn to rely more on the nonparetic body side, which involves learning new skills with it. Such compensatory hyper reliance on the "good" body side, however, can limit functional improvements of the paretic side. In rats, motor skill training with the nonparetic forelimb (NPT) following a unilateral infarct lessens the efficacy of rehabilitative training, and reduces neuronal activation in perilesion motor cortex. However, the underlying mechanisms remain unclear. In the present study, we investigated how forelimb movement representations and synaptic restructuring in perilesion motor cortex respond to NPT and their relationship with behavioral outcomes. Forelimb representations were diminished as a result of NPT, as revealed with intracortical microstimulation mapping. Using transmission electron microscopy and stereological analyses, we found that densities of axodendritic synapses, especially axo-spinous synapses, as well as multiple synaptic boutons were increased in the perilesion cortex by NPT. The synaptic density was negatively correlated with the functional outcome of the paretic limb, as revealed in reaching performance. Furthermore, in animals with NPT, there was dissociation between astrocytic morphological features and axo-spinous synaptic density in perilesion motor cortex, compared with controls. These findings demonstrate that skill learning with the nonparetic limb following unilateral brain damage results in aberrant synaptogenesis, potentially of transcallosal projections, and this seems to hamper the functionality of the perilesion motor cortex and the paretic forelimb. PMID- 26041928 TI - Transfer of myelin-reactive th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice. AB - Multiple sclerosis (MS) is a demyelinating disease of the CNS characterized by inflammation and neurodegeneration. Animal models that enable the study of remyelination in the context of ongoing inflammation are greatly needed for the development of novel therapies that target the pathological inhibitory cues inherent to the MS plaque microenvironment. We report the development of an innovative animal model combining cuprizone-mediated demyelination with transfer of myelin-reactive CD4(+) T cells. Characterization of this model reveals both Th1 and Th17 CD4(+) T cells infiltrate the CNS of cuprizone-fed mice, with infiltration of Th17 cells being more efficient. Infiltration correlates with impaired spontaneous remyelination as evidenced by myelin protein expression, immunostaining, and ultrastructural analysis. Electron microscopic analysis further reveals that demyelinated axons are preserved but reduced in caliber. Examination of the immune response contributing to impaired remyelination highlights a role for peripheral monocytes with an M1 phenotype. This study demonstrates the development of a novel animal model that recapitulates elements of the microenvironment of the MS plaque and reveals an important role for T cells and peripheral monocytes in impairing endogenous remyelination in vivo. This model could be useful for testing putative MS therapies designed to enhance remyelination in the setting of active inflammation, and may also facilitate modeling the pathophysiology of denuded axons, which has been a challenge in rodents because they typically remyelinate very quickly. PMID- 26041930 TI - Robust neuroprosthetic control from the stroke perilesional cortex. AB - Intracortical brain-machine interfaces (BMIs) may eventually restore function in those with motor disability after stroke. However, current research into the development of intracortical BMIs has focused on subjects with largely intact cortical structures, such as those with spinal cord injury. Although the stroke perilesional cortex (PLC) has been hypothesized as a potential site for a BMI, it remains unclear whether the injured motor cortical network can support neuroprosthetic control directly. Using chronic electrophysiological recordings in a rat stroke model, we demonstrate here the PLC's capacity for neuroprosthetic control and physiological plasticity. We initially found that the perilesional network demonstrated abnormally increased slow oscillations that also modulated neural firing. Despite these striking abnormalities, neurons in the perilesional network could be modulated volitionally to learn neuroprosthetic control. The rate of learning was surprisingly similar regardless of the electrode distance from the stroke site and was not significantly different from intact animals. Moreover, neurons achieved similar task-related modulation and, as an ensemble, formed cell assemblies with learning. Such control was even achieved in animals with poor motor recovery, suggesting that neuroprosthetic control is possible even in the absence of motor recovery. Interestingly, achieving successful control also reduced locking to abnormal oscillations significantly. Our results thus suggest that, despite the disrupted connectivity in the PLC, it may serve as an effective target for neuroprosthetic control in those with poor motor recovery after stroke. PMID- 26041929 TI - Regulation of Peripheral Nerve Myelin Maintenance by Gene Repression through Polycomb Repressive Complex 2. AB - Myelination of peripheral nerves by Schwann cells requires coordinate regulation of gene repression as well as gene activation. Several chromatin remodeling pathways critical for peripheral nerve myelination have been identified, but the functions of histone methylation in the peripheral nerve have not been elucidated. To determine the role of histone H3 Lys27 methylation, we have generated mice with a Schwann cell-specific knock-out of Eed, which is an essential subunit of the polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3 Lys27. Analysis of this mutant revealed no significant effects on early postnatal development of myelin. However, its loss eventually causes progressive hypermyelination of small-diameter axons and apparent fragmentation of Remak bundles. These data identify the PRC2 complex as an epigenomic modulator of mature myelin thickness, which is associated with changes in Akt phosphorylation. Interestingly, we found that Eed inactivation causes derepression of several genes, e.g., Sonic hedgehog (Shh) and Insulin-like growth factor-binding protein 2 (Igfbp2), that become activated after nerve injury, but without activation of a primary regulator of the injury program, c-Jun. Analysis of the activated genes in cultured Schwann cells showed that Igfbp2 regulates Akt activation. Our results identify an epigenomic pathway required for establishing thickness of mature myelin and repressing genes that respond to nerve injury. PMID- 26041931 TI - Circadian Activators Are Expressed Days before They Initiate Clock Function in Late Pacemaker Neurons from Drosophila. AB - Circadian pacemaker neurons in the Drosophila brain control daily rhythms in locomotor activity. These pacemaker neurons can be subdivided into early or late groups depending on whether rhythms in period (per) and timeless (tim) expression are initiated at the first instar (L1) larval stage or during metamorphosis, respectively. Because CLOCK-CYCLE (CLK-CYC) heterodimers initiate circadian oscillator function by activating per and tim transcription, a Clk-GFP transgene was used to mark when late pacemaker neurons begin to develop. We were surprised to see that CLK-GFP was already expressed in four of five clusters of late pacemaker neurons during the third instar (L3) larval stage. CLK-GFP is only detected in postmitotic neurons from L3 larvae, suggesting that these four late pacemaker neuron clusters are formed before the L3 larval stage. A GFP-cyc transgene was used to show that CYC, like CLK, is also expressed exclusively in pacemaker neurons from L3 larval brains, demonstrating that CLK-CYC is not sufficient to activate per and tim in late pacemaker neurons at the L3 larval stage. These results suggest that most late pacemaker neurons develop days before novel factors activate circadian oscillator function during metamorphosis. PMID- 26041934 TI - Erratum. AB - HOSOYA, T., HANAFUSA, Y., KUDO, T., TAMUKAI, K. AND UNE, Y. First Report of Veronaea Botryosa as a Causal Agent of Chromomycosis in Frogs. Medical Mycology 53(4). 2015: 369-377. DOI: 10.1093/mmy/myu094. An error occurred in the printed version of this article. The corresponding author was incorrectly denoted as Tsuyoshi Hosoya. The correct corresponding author for this article is Yasuko Hanafusa (hana@affrc.go.jp). PMID- 26041932 TI - Coupled changes in brain white matter microstructure and fluid intelligence in later life. AB - Understanding aging-related cognitive decline is of growing importance in aging societies, but relatively little is known about its neural substrates. Measures of white matter microstructure are known to correlate cross-sectionally with cognitive ability measures, but only a few small studies have tested for longitudinal relations among these variables. We tested whether there were coupled changes in brain white matter microstructure indexed by fractional anisotropy (FA) and three broad cognitive domains (fluid intelligence, processing speed, and memory) in a large cohort of human participants with longitudinal diffusion tensor MRI and detailed cognitive data taken at ages 73 years (n = 731) and 76 years (n = 488). Longitudinal changes in white matter microstructure were coupled with changes in fluid intelligence, but not with processing speed or memory. Individuals with higher baseline white matter FA showed less subsequent decline in processing speed. Our results provide evidence for a longitudinal link between changes in white matter microstructure and aging-related cognitive decline during the eighth decade of life. They are consistent with theoretical perspectives positing that a corticocortical "disconnection" partly explains cognitive aging. PMID- 26041935 TI - Nuclear pore complex integrity requires Lnp1, a regulator of cortical endoplasmic reticulum. AB - The nuclear envelope (NE) and endoplasmic reticulum (ER) are components of the same contiguous membrane system and yet have distinct cellular functions. Mounting evidence suggests roles for some ER proteins in the NE for proper nuclear pore complex (NPC) structure and function. In this study, we identify a NE role in Saccharomyces cerevisiae for Lnp1 and Sey1, proteins required for proper cortical ER formation. Both lnp1Delta and sey1Delta mutants exhibit synthetic genetic interactions with mutants in genes encoding key NPC structural components. Both Lnp1 and Sey1 physically associate with other ER components that have established NPC roles, including Rtn1, Yop1, Pom33, and Per33. Of interest, lnp1Delta rtn1Delta mutants but not rtn1Delta sey1Delta mutants exhibit defects in NPC distribution. Furthermore, the essential NPC assembly factor Ndc1 has altered interactions in the absence of Sey1. Lnp1 dimerizes in vitro via its C terminal zinc finger motif, a property that is required for proper ER structure but not NPC integrity. These findings suggest that Lnp1's role in NPC integrity is separable from functions in the ER and is linked to Ndc1 and Rtn1 interactions. PMID- 26041936 TI - Myristoylated CIL-7 regulates ciliary extracellular vesicle biogenesis. AB - The cilium both releases and binds to extracellular vesicles (EVs). EVs may be used by cells as a form of intercellular communication and mediate a broad range of physiological and pathological processes. The mammalian polycystins (PCs) localize to cilia, as well as to urinary EVs released from renal epithelial cells. PC ciliary trafficking defects may be an underlying cause of autosomal dominant polycystic kidney disease (PKD), and ciliary-EV interactions have been proposed to play a central role in the biology of PKD. In Caenorhabditis elegans and mammals, PC1 and PC2 act in the same genetic pathway, act in a sensory capacity, localize to cilia, and are contained in secreted EVs, suggesting ancient conservation. However, the relationship between cilia and EVs and the mechanisms generating PC-containing EVs remain an enigma. In a forward genetic screen for regulators of C. elegans PKD-2 ciliary localization, we identified CIL 7, a myristoylated protein that regulates EV biogenesis. Loss of CIL-7 results in male mating behavioral defects, excessive accumulation of EVs in the lumen of the cephalic sensory organ, and failure to release PKD-2::GFP-containing EVs to the environment. Fatty acylation, such as myristoylation and palmitoylation, targets proteins to cilia and flagella. The CIL-7 myristoylation motif is essential for CIL-7 function and for targeting CIL-7 to EVs. C. elegans is a powerful model with which to study ciliary EV biogenesis in vivo and identify cis-targeting motifs such as myristoylation that are necessary for EV-cargo association and function. PMID- 26041933 TI - Oomycete interactions with plants: infection strategies and resistance principles. AB - The Oomycota include many economically significant microbial pathogens of crop species. Understanding the mechanisms by which oomycetes infect plants and identifying methods to provide durable resistance are major research goals. Over the last few years, many elicitors that trigger plant immunity have been identified, as well as host genes that mediate susceptibility to oomycete pathogens. The mechanisms behind these processes have subsequently been investigated and many new discoveries made, marking a period of exciting research in the oomycete pathology field. This review provides an introduction to our current knowledge of the pathogenic mechanisms used by oomycetes, including elicitors and effectors, plus an overview of the major principles of host resistance: the established R gene hypothesis and the more recently defined susceptibility (S) gene model. Future directions for development of oomycete resistant plants are discussed, along with ways that recent discoveries in the field of oomycete-plant interactions are generating novel means of studying how pathogen and symbiont colonizations overlap. PMID- 26041937 TI - Molecular Mechanisms and Evolutionary Processes Contributing to Accelerated Divergence of Gene Expression on the Drosophila X Chromosome. AB - In species with a heterogametic sex, population genetics theory predicts that DNA sequences on the X chromosome can evolve faster than comparable sequences on autosomes. Both neutral and nonneutral evolutionary processes can generate this pattern. Complex traits like gene expression are not predicted to have accelerated evolution by these theories, yet a "faster-X" pattern of gene expression divergence has recently been reported for both Drosophila and mammals. Here, we test the hypothesis that accelerated adaptive evolution of cis regulatory sequences on the X chromosome is responsible for this pattern by comparing the relative contributions of cis- and trans-regulatory changes to patterns of faster-X expression divergence observed between strains and species of Drosophila with a range of divergence times. We find support for this hypothesis, especially among male-biased genes, when comparing different species. However, we also find evidence that trans-regulatory differences contribute to a faster-X pattern of expression divergence both within and between species. This contribution is surprising because trans-acting regulators of X-linked genes are generally assumed to be randomly distributed throughout the genome. We found, however, that X-linked transcription factors appear to preferentially regulate expression of X-linked genes, providing a potential mechanistic explanation for this result. The contribution of trans-regulatory variation to faster-X expression divergence was larger within than between species, suggesting that it is more likely to result from neutral processes than positive selection. These data show how accelerated evolution of both coding and noncoding sequences on the X chromosome can lead to accelerated expression divergence on the X chromosome relative to autosomes. PMID- 26041938 TI - VEGFR-1 Pseudogene Expression and Regulatory Function in Human Colorectal Cancer Cells. AB - A large number of pseudogenes have been found to be transcribed in human cancers. However, only a few pseudogenes are functionally characterized. Here, we identified a transcribed pseudogene of VEGFR1, or fms-related tyrosine kinase 1 (FLT1), in human colorectal cancer cells. Interestingly, this pseudogene (designated as FLT1P1) was found to be transcribed bidirectionally and functionally modulated cognate VEGFR1 protein expression in the cells. Mechanistically, expression of FLT1P1 antisense transcript not only inhibited the VEGFR1 expression, but also inhibited non-cognate VEGF-A expression through interaction with miR-520a. Perturbation of FLT1P1 expression by RNA interference (RNAi) markedly inhibited tumor cell proliferation and xenograft tumor growth. This study identifies FLT1P1 antisense as a critical regulator of VEGFR1 and VEGF A expression in colorectal cancer cells, and highlights its role in regulation of the pathogenesis of colorectal cancer. IMPLICATIONS: The VEGFR1 pseudogene, FLT1P1, is a novel and functional regulator of VEGF signaling and its targeting could be an alternative strategy to modulate its cognate/target gene expression and downstream activity in cancer. PMID- 26041939 TI - Ca2+-Activated IK K+ Channel Blockade Radiosensitizes Glioblastoma Cells. AB - Ca(2+)-activated K(+) channels, such as BK and IK channels, have been proposed to fulfill pivotal functions in neoplastic transformation, malignant progression, and brain infiltration of glioblastoma cells. Here, the ionizing radiation (IR) effect of IK K(+) channel targeting was tested in human glioblastoma cells. IK channels were inhibited pharmacologically by TRAM-34 or genetically by knockdown, cells were irradiated with 6 MV photons and IK channel activity, Ca(2+) signaling, cell cycling, residual double-strand breaks, and clonogenic survival were determined. In addition, the radiosensitizing effect of TRAM-34 was analyzed in vivo in ectopic tumors. Moreover, The Cancer Genome Atlas (TCGA) was queried to expose the dependence of IK mRNA abundance on overall survival (OS) of patients with glioma. Results indicate that radiation increased the activity of IK channels, modified Ca(2+) signaling, and induced a G2-M cell-cycle arrest. TRAM-34 decreased the IR-induced accumulation in G2-M arrest and increased the number of gammaH2AX foci post-IR, suggesting that TRAM-34 mediated an increase of residual DNA double-strand breaks. Mechanistically, IK knockdown abolished the TRAM-34 effects indicating the IK specificity of TRAM-34. Finally, TRAM-34 radiosensitized ectopic glioblastoma in vivo and high IK mRNA abundance associated with shorter patient OS in low-grade glioma and glioblastoma. IMPLICATIONS: Together, these data support a cell-cycle regulatory function for IK K(+) channels, and combined therapy using IK channel targeting and radiation is a new strategy for anti-glioblastoma therapy. PMID- 26041940 TI - Born-Jordan Quantization and the Equivalence of the Schrodinger and Heisenberg Pictures. AB - The aim of the famous Born and Jordan 1925 paper was to put Heisenberg's matrix mechanics on a firm mathematical basis. Born and Jordan showed that if one wants to ensure energy conservation in Heisenberg's theory it is necessary and sufficient to quantize observables following a certain ordering rule. One apparently unnoticed consequence of this fact is that Schrodinger's wave mechanics cannot be equivalent to Heisenberg's more physically motivated matrix mechanics unless its observables are quantized using this rule, and not the more symmetric prescription proposed by Weyl in 1926, which has become the standard procedure in quantum mechanics. This observation confirms the superiority of Born Jordan quantization, as already suggested by Kauffmann. We also show how to explicitly determine the Born-Jordan quantization of arbitrary classical variables, and discuss the conceptual advantages in using this quantization scheme. We finally suggest that it might be possible to determine the correct quantization scheme by using the results of weak measurement experiments. PMID- 26041941 TI - Cinchonidinium acetate as a convenient catalyst for the asymmetric synthesis of cis-stilbenediamines. AB - Inexpensive and readily available cinchonidinium acetate is an effective catalyst for the syn-selective aza-Henry reaction of arylnitromethanes and aryl imines. The resulting masked cis-stilbenediamine products are produced in excellent diastereoselectivity and good enantioselectivity, and enantiopure material can be achieved via recrystallization. The features of the cinchona catalyst needed for selectivity are discussed, with specific emphasis on formation of a kinetically controlled syn-product without epimerization of the highly acidic alpha-nitro stereocenter. PMID- 26041942 TI - Stereoselective Syntheses of alpha,beta-Unsaturated gamma-Amino Esters Through Phosphine-Catalyzed gamma-Umpolung Additions of Sulfonamides to gamma-Substituted Allenoates. AB - alpha,beta-Unsaturated gamma-amino esters can be synthesized efficiently and stereoselectively through phosphine-catalyzed gamma-umpolung additions of sulfonamides to gamma-substituted allenoates. The structures of the sulfonamide and gamma-substituted allenoate partners can be varied to achieve a range of alpha,beta-unsaturated gamma-amino esters with potentially interesting chemical and biological properties. PMID- 26041943 TI - Anatomical curve identification. AB - Methods for capturing images in three dimensions are now widely available, with stereo-photogrammetry and laser scanning being two common approaches. In anatomical studies, a number of landmarks are usually identified manually from each of these images and these form the basis of subsequent statistical analysis. However, landmarks express only a very small proportion of the information available from the images. Anatomically defined curves have the advantage of providing a much richer expression of shape. This is explored in the context of identifying the boundary of breasts from an image of the female torso and the boundary of the lips from a facial image. The curves of interest are characterised by ridges or valleys. Key issues in estimation are the ability to navigate across the anatomical surface in three-dimensions, the ability to recognise the relevant boundary and the need to assess the evidence for the presence of the surface feature of interest. The first issue is addressed by the use of principal curves, as an extension of principal components, the second by suitable assessment of curvature and the third by change-point detection. P spline smoothing is used as an integral part of the methods but adaptations are made to the specific anatomical features of interest. After estimation of the boundary curves, the intermediate surfaces of the anatomical feature of interest can be characterised by surface interpolation. This allows shape variation to be explored using standard methods such as principal components. These tools are applied to a collection of images of women where one breast has been reconstructed after mastectomy and where interest lies in shape differences between the reconstructed and unreconstructed breasts. They are also applied to a collection of lip images where possible differences in shape between males and females are of interest. PMID- 26041944 TI - Law in everyday life and death: a socio-legal study of chronic disorders of consciousness. AB - This paper addresses, from a socio-legal perspective, the question of the significance of law for the treatment, care and the end-of-life decision making for patients with chronic disorders of consciousness. We use the phrase 'chronic disorders of consciousness' as an umbrella term to refer to severely brain injured patients in prolonged comas, vegetative or minimally conscious states. Based on an analysis of interviews with family members of patients with chronic disorders of consciousness, we explore the images of law that were drawn upon and invoked by these family members when negotiating the situation of their relatives, including, in some cases, the ending of their lives. By examining 'legal consciousness' in this way (an admittedly confusing term in the context of this study,) we offer a distinctly sociological contribution to the question of how law matters in this particular domain of social life. PMID- 26041945 TI - Automatic Identification of Cochlear Implant Electrode Arrays for Post-Operative Assessment. AB - Cochlear implantation is a procedure performed to treat profound hearing loss. Accurately determining the postoperative position of the implant in vivo would permit studying the correlations between implant position and hearing restoration. To solve this problem, we present an approach based on parametric Gradient Vector Flow snakes to segment the electrode array in post-operative CT. By combining this with existing methods for localizing intra-cochlear anatomy, we have developed a system that permits accurate assessment of the implant position in vivo. The system is validated using a set of seven temporal bone specimens. The algorithms were run on pre- and post-operative CTs of the specimens, and the results were compared to histological images. It was found that the position of the arrays observed in the histological images is in excellent agreement with the position of their automatically generated 3D reconstructions in the CT scans. PMID- 26041946 TI - FEM-BEM coupling for the large-body limit in micromagnetics. AB - We present and analyze a coupled finite element-boundary element method for a model in stationary micromagnetics. The finite element part is based on mixed conforming elements. For two- and three-dimensional settings, we show well posedness of the discrete problem and present an a priori error analysis for the case of lowest order elements. PMID- 26041947 TI - Behavioral observations on the White-breasted Thrasher (Ramphocinclus brachyurus brachyurus): conservation implications. AB - The White-breasted Thrasher (Ramphocinclus brachyurus brachyurus) is surviving at the tip of the Caravelle peninsula in Martinique, on a 5 km2 territory. Once widespread throughout the island, this passerine was on the verge of extinction in the 1950s but managed to recover. The creation of the Caravelle Nature Reserve in 1976 contributed to the protection of its habitat, but little is known about the factors behind the slow population growth registered in the past decades. A year-long ethological study was launched by the Regional Natural Park of Martinique (PNRM) in order to understand the status of this endangered species. In spite of some limitations, original observations shed new light on the behavior of this endemic species. New calls and a song were identified for the White-breasted Thrasher. The study highlights seasonal variations in the bird's feeding behaviors and some behavioral plasticity in its reproductive strategies. Individuals appear to be exposed to strong predation pressure, especially during the breeding season. The confirmation of the modus operandi of rats against White breasted Thrashers' nests should help improve the conservation policy of this bird. PMID- 26041948 TI - Convergence Analysis of Triangular MAC Schemes for Two Dimensional Stokes Equations. AB - In this paper, we consider the use of H(div) elements in the velocity-pressure formulation to discretize Stokes equations in two dimensions. We address the error estimate of the element pair RT0-P0, which is known to be suboptimal, and render the error estimate optimal by the symmetry of the grids and by the superconvergence result of Lagrange inter-polant. By enlarging RT0 such that it becomes a modified BDM-type element, we develop a new discretization [Formula: see text]. We, therefore, generalize the classical MAC scheme on rectangular grids to triangular grids and retain all the desirable properties of the MAC scheme: exact divergence-free, solver-friendly, and local conservation of physical quantities. Further, we prove that the proposed discretization [Formula: see text] achieves the optimal convergence rate for both velocity and pressure on general quasi-uniform grids, and one and half order convergence rate for the vorticity and a recovered pressure. We demonstrate the validity of theories developed here by numerical experiments. PMID- 26041949 TI - Hepatic encephalopathy. PMID- 26041950 TI - Management in acute liver failure. AB - Acute liver failure (ALF) is a rare, potentially fatal complication of severe hepatic illness resulting from various causes. In a clinical setting, severe hepatic injury is usually recognised by the appearance of jaundice, encephalopathy and coagulopathy. The central and most important clinical event in ALF is occurrence of hepatic encephalopathy (HE) and cerebral edema which is responsible for most of the fatalities in this serious clinical syndrome. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a central role in the pathogenesis. The role of newer ammonia lowering agents is still evolving. Liver transplant is the only effective therapy that has been identified to be of promise in those with poor prognostic factors, whereas in the others, aggressive intensive medical management has been documented to salvage a substantial proportion of patients. A small fraction of patients undergo liver transplant and the remaining are usually treated with medical therapy. Therefore, identification of the complications and causes of death in such patients, and use of appropriate prognostic models to identify those who need liver transplant and those who can be managed with medical treatment is a vital component of therapeutic strategy. In this review, we discuss the various pathogenetic mechanisms and treatment options available. PMID- 26041951 TI - Approach to clinical syndrome of jaundice and encephalopathy in tropics. AB - A large number of patients present with jaundice and encephalopathy in tropical country like India and acute liver failure is the usual cause. Clinical presentation like ALF is also a complication of many tropical infections, and these conditions may mimic ALF but may have subtle differences from ALF. Moreover, what hepatologists see as acute liver failure in tropics is different from what is commonly described in Western Textbooks. Paracetamol overdose, which is possibly the commonest cause of ALF in UK and USA, is hardly ever seen in India. Most common etiology here is viral hepatitis (hepatitis E > hepatitis B> hepatitis A). Apart from ALF, one may also come across subacute hepatic failure (SAHF) as well as acute-on-chronic liver failure (ACLF) due to viral hepatitis. Interestingly, a host of other conditions can mimic ALF because clinical presentation in these conditions can be dominated by jaundice and encephalopathy. Malarial hepatopathy is possibly the best-known condition out of these and is not an uncommon manifestation of severe malaria. A similar presentation can also be seen in other common infections in tropics such as dengue fever, typhoid fever, leptospirosis, scrub typhus, amoebic liver abscesses, tuberculosis and other bacterial and fungal infections with or without human immunodeficiency virus (HIV) related disease. In many of these conditions, liver failure may not be underlying pathophysiology. Some pregnancy related liver diseases could also present with jaundice and encephalopathy. This review summarizes the commonly seen presentations in tropical country like India, where jaundice and encephalopathy dominate the clinical picture. PMID- 26041952 TI - Reprint of: Nutrition in the Management of Cirrhosis and its Neurological Complications. AB - Malnutrition is a common feature of chronic liver diseases that is often associated with a poor prognosis including worsening of clinical outcome, neuropsychiatric complications as well as outcome following liver transplantation. Nutritional assessment in patients with cirrhosis is challenging owing to confounding factors related to liver failure. The objectives of nutritional intervention in cirrhotic patients are the support of liver regeneration, the prevention or correction of specific nutritional deficiencies and the prevention and/or treatment of the complications of liver disease per se and of liver transplantation. Nutritional recommendations target the optimal supply of adequate substrates related to requirements linked to energy, protein, carbohydrates, lipids, vitamins and minerals. Some issues relating to malnutrition in chronic liver disease remain to be addressed including the development of an appropriate well-validated nutritional assessment tool, the identification of mechanistic targets or therapy for sarcopenia, the development of nutritional recommendations for obese cirrhotic patients and liver-transplant recipients and the elucidation of the roles of vitamin A hepatotoxicity, as well as the impact of deficiencies in riboflavin and zinc on clinical outcomes. Early identification and treatment of malnutrition in chronic liver disease has the potential to lead to better disease outcome as well as prevention of the complications of chronic liver disease and improved transplant outcomes. PMID- 26041953 TI - Neuroinflammation in hepatic encephalopathy: mechanistic aspects. AB - Hepatic encephalopathy (HE) is a major neurological complication of severe liver disease that presents in acute and chronic forms. While elevated brain ammonia level is known to be a major etiological factor in this disorder, recent studies have shown a significant role of neuroinflammation in the pathogenesis of both acute and chronic HE. This review summarizes the involvement of ammonia in the activation of microglia, as well as the means by which ammonia triggers inflammatory responses in these cells. Additionally, the role of ammonia in stimulating inflammatory events in brain endothelial cells (ECs), likely through the activation of the toll-like receptor-4 and the associated production of cytokines, as well as the stimulation of various inflammatory factors in ECs and in astrocytes, are discussed. This review also summarizes the inflammatory mechanisms by which activation of ECs and microglia impact on astrocytes leading to their dysfunction, ultimately contributing to astrocyte swelling/brain edema in acute HE. The role of microglial activation and its contribution to the progression of neurobehavioral abnormalities in chronic HE are also briefly presented. We posit that a better understanding of the inflammatory events associated with acute and chronic HE will uncover novel therapeutic targets useful in the treatment of patients afflicted with HE. PMID- 26041955 TI - Definition and nomenclature of hepatic encephalopathy. AB - Hepatic encephalopathy (HE) can manifest with a broad range of neuropsychiatric abnormalities of varying severity, acuity and time course with significant clinical implications. Lack of precise nomenclature and classification had hampered research in this complex clinical problem. A multiaxial classification system based on underlying etiology, clinical severity, time course and presence or absence of precipitating factors has been developed over the recent years and has been fully incorporated in the newly published AASLD-EASL guidelines on HE management. This multiaxial classification is expected to bring uniformity in describing and categorizing of HE across centers and nations, foster clinical research and improve patient care and outcome. PMID- 26041954 TI - Gut microbiota: its role in hepatic encephalopathy. AB - Ammonia, a key factor in the pathogenesis of hepatic encephalopathy (HE), is predominantly derived from urea breakdown by urease producing large intestinal bacteria and from small intestine and kidneys, where the enzyme glutaminases releases ammonia from circulating glutamine. Non-culture techniques like pyrosequencing of bacterial 16S ribosomal ribonucleic acid are used to characterize fecal microbiota. Fecal microbiota in patients with cirrhosis have been shown to alter with increasing Child-Turcotte-Pugh (CTP) and Model for End stage Liver Disease (MELD) scores, and with development of covert or overt HE. Cirrhosis dysbiosis ratio (CDR), the ratio of autochthonous/good bacteria (e.g. Lachnospiraceae, Ruminococcaceae and Clostridiales) to non autochthonous/pathogenic bacteria (e.g. Enterobacteriaceae and Streptococcaceae), is significantly higher in controls and patients with compensated cirrhosis than patients with decompensated cirrhosis. Although their stool microbiota do not differ, sigmoid colonic mucosal microbiota in liver cirrhosis patients with and without HE, are different. Linkage of pathogenic colonic mucosal bacteria with poor cognition and inflammation suggests that important processes at the mucosal interface, such as bacterial translocation and immune dysfunction, are involved in the pathogenesis of HE. Fecal microbiome composition does not change significantly when HE is treated with lactulose or when HE recurs after lactulose withdrawal. Despite improving cognition and endotoxemia as well as shifting positive correlation of pathogenic bacteria with metabolites, linked to ammonia, aromatic amino acids and oxidative stress, to a negative correlation, rifaximin changes gut microbiome composition only modestly. These observations suggest that the beneficial effects of lactulose and rifaximin could be associated with a change in microbial metabolic function as well as an improvement in dysbiosis. PMID- 26041956 TI - Hepatic encephalopathy: historical remarks. AB - The history of hepatic encephalopathy (HE) is briefly reviewed since the beginning of western medicine by Hippocrates. For about 2000 years the main evidence was the mere association between jaundice, fever and delirium. A clear link between delirium and cirrhosis was proven in the 17th century by Morgagni. In subsequent times the focus was manly the descriptions of symptoms and the only pathophysiological improvement was the evidence that jaundice, per se, does not alter brain function. Only at the end of the 19th century Hann et al proved the role of portal-systemic shunt and pf nitrogenous derivates in the pathophysiology of the syndrome. A terrific development of knowledge occurred in the last 60 years, after the works of Sherlock in London. Nowadays some consensus about HE was reached, so that new developments will likely occur. PMID- 26041957 TI - Minimal hepatic encephalopathy impairs quality of life. AB - Minimal hepatic encephalopathy (MHE) is the mildest form of the spectrum of neurocognitive impairment in cirrhosis. It is a frequent occurrence in patients of cirrhosis and is detectable only by specialized neurocognitive testing. MHE is a clinically significant disorder which impairs daily functioning, driving performance, work capability and learning ability. It also predisposes to the development of overt hepatic encephalopathy, increased falls and increased mortality. This results in impaired quality of life for the patient as well as significant social and economic burden for health providers and care givers. Early detection and treatment of MHE with ammonia lowering therapy can reverse MHE and improve quality of life. PMID- 26041958 TI - Hepatic encephalopathy and sleepiness: an interesting connection? AB - Sleep-wake abnormalities in patients with cirrhosis have been traditionally associated with hepatic encephalopathy (HE). In recent years, a certain amount of work has been devoted to the study of this relationship. This has lead to a modified picture, with weakening of the association between HE and poor night sleep, and the emergence of stronger links between HE and excessive daytime sleepiness. This brief review focuses on the evidence in favor of the interpretation of HE as a sleepiness syndrome, and on the diagnostic, therapeutic and social implications of such an interpretation. PMID- 26041959 TI - Diagnosis of minimal hepatic encephalopathy. AB - Minimal hepatic encephalopathy (mHE) has significant impact upon a liver patient's daily living and health related quality of life. Therefore a majority of clinicians agree that mHE should be diagnosed and treated. The optimal means for diagnosing mHE, however, is controversial. This paper describes the currently most frequently used methods-EEG, critical flicker frequency, Continuous Reaction time Test, Inhibitory Control Test, computerized test batteries such as the Cognitive Drug Research test battery, the psychometric hepatic encephalopathy score (PHES) and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)-and their pros and cons. PMID- 26041960 TI - Clinical neurophysiology of hepatic encephalopathy. AB - BACKGROUND/OBJECTIVES: Hepatic encephalopathy (HE) has relevant impact on the quality of life of patients and their caregivers and causes relevant costs because of hospitalizations and work days lost. Its quantification is important to perform adequate clinical trials on this relevant complication of cirrhosis and portal-systemic shunting. Clinical neurophysiology, which detects functional alterations of the nervous system, has been applied to the study of HE for over 60 years. This review aims at summarizing and clarifying the role of neurophysiologic techniques in the study of HE. METHODS: A narrative review was performed aiming at interpreting the cited papers and the techniques on the basis of their physiological and pathophysiological meaning. RESULTS: The potential role of EEG, quantified EEG, evoked potentials-both exogenous, endogenous and motor-have been clarified to the reader that may be unfamiliar with neurophysiology. CONCLUSIONS: The EEG, reflecting the oscillatory changes of neural network is the preferable tool to detect and monitor HE, with the exception of its most severe stage, when EEG flattens. SSEP and MEP have indication to detect and monitor transmission alterations that are likely related to myelin changes and microedema. PMID- 26041961 TI - Magnetic resonance imaging and spectroscopy in hepatic encephalopathy. AB - Hepatic encephalopathy is a brain alteration associated to liver failure that produces cognitive impairments at long term. Neuroimaging are non-invasive methods for the study of the brain by means of spectroscopy and imaging techniques. These technologies give huge information about cerebral metabolism and water distribution to explore brain pathways involved in the pathogenesis of hepatic encephalopathy. Furthermore, new magnetic resonance implementations such as voxel-based morphometry or resting-state functional magnetic resonance imaging allow studying brain atrophy and neuronal connectivity of the cerebral network involved in the neurocognitive impairments observed in the patients. The development of magnetic resonance technology will generate handy tools for the brain study of liver failure to elucidate the time-course of the pathology and thus to obtain an early diagnosis of cerebral complications. PMID- 26041962 TI - Pathogenesis of hepatic encephalopathy: role of ammonia and systemic inflammation. AB - The syndrome we refer to as Hepatic Encephalopathy (HE) was first characterized by a team of Nobel Prize winning physiologists led by Pavlov and Nencki at the Imperial Institute of Experimental Medicine in Russia in the 1890's. This focused upon the key observation that performing a portocaval shunt, which bypassed nitrogen-rich blood away from the liver, induced elevated blood and brain ammonia concentrations in association with profound neurobehavioral changes. There exists however a spectrum of metabolic encephalopathies attributable to a variety (or even absence) of liver hepatocellular dysfunctions and it is this spectrum rather than a single disease entity that has come to be defined as HE. Differences in the underlying pathophysiology, treatment responses and outcomes can therefore be highly variable between acute and chronic HE. The term also fails to articulate quite how systemic the syndrome of HE can be and how it can be influenced by the gastrointestinal, renal, nervous, or immune systems without any change in background liver function. The pathogenesis of HE therefore encapsulates a complex network of interdependent organ systems which as yet remain poorly characterized. There is nonetheless a growing recognition that there is a complex but influential synergistic relationship between ammonia, inflammation (sterile and non-sterile) and oxidative stress in the pathogenesis HE which develops in an environment of functional immunoparesis in patients with liver dysfunction. Therapeutic strategies are thus moving further away from the traditional specialty of hepatology and more towards novel immune and inflammatory targets which will be discussed in this review. PMID- 26041963 TI - Management of covert hepatic encephalopathy. AB - Hepatic encephalopathy is a reversible progressive neuropsychiatric disorder that encompasses a wide clinical spectrum. Covert hepatic encephalopathy is defined as patients with minimal hepatic encephalopathy and Grade I encephalopathy by West Haven Criteria. Terminology such as "sub-clinical", "latent", and "minimal" appear to trivialize the disease and have been replaced by the term covert. The lack of clinical signs means that covert hepatic encephalopathy is rarely recognized or treated outside of clinical trials with options for therapy based on patients with episodic hepatic encephalopathy. This review discusses the current available options for therapy in covert hepatic encephalopathy and focuses on non-absorbable disacharides (lactulose or lactitol), antibiotics (rifaximin), probiotics/synbiotics and l-ornithine-l-aspartate. PMID- 26041964 TI - Management of overt hepatic encephalopathy. AB - Hepatic encephalopathy (HE) is an important complication of cirrhosis with significant morbidity and mortality. Management of HE primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as non-absorbable disaccharides, antimicrobial agents like rifaximin and l-ornithine l-aspartate. The non-absorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and in primary and secondary prophylaxis of HE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Rifaximin is effective in treatment of HE and recent systemic reviews found it comparable to disaccharides and is effective in secondary prophylaxis of HE. Many agents like l-ornithine l-aspartate, probiotics, zinc, sodium benzoate have been tried either alone or in combination with lactulose for the treatment of HE. Combination therapy of disaccharides either with rifaximin, l-ornithine l aspartate, probiotics for the treatment of HE needs further validation in large studies. PMID- 26041965 TI - Encephalopathy in Wilson disease: copper toxicity or liver failure? AB - Hepatic encephalopathy (HE) is a complex syndrome of neurological and psychiatric signs and symptoms that is caused by portosystemic venous shunting with or without liver disease irrespective of its etiology. The most common presentation of Wilson disease (WD) is liver disease and is frequently associated with a wide spectrum of neurological and psychiatric symptoms. The genetic defect in WD leads to copper accumulation in the liver and later in other organs including the brain. In a patient presenting with Wilsonian cirrhosis neuropsychiatric symptoms may be caused either by the metabolic consequences of liver failure or by copper toxicity. Thus, in clinical practice a precise diagnosis is a great challenge. Contrary to HE in neurological WD consciousness, is very rarely disturbed and pyramidal signs, myoclonus dominate. Asterixis and many other clinical symptoms may be present in both disease conditions and are quite similar. However details of neurological assessment as well as additional examinations could help in differential diagnosis. PMID- 26041967 TI - Chimeric peptides as implant functionalization agents for titanium alloy implants with antimicrobial properties. AB - Implant-associated infections can have severe effects on the longevity of implant devices and they also represent a major cause of implant failures. Treating these infections associated with implants by antibiotics is not always an effective strategy due to poor penetration rates of antibiotics into biofilms. Additionally, emerging antibiotic resistance poses serious concerns. There is an urge to develop effective antibacterial surfaces that prevent bacterial adhesion and proliferation. A novel class of bacterial therapeutic agents, known as antimicrobial peptides (AMP's), are receiving increasing attention as an unconventional option to treat septic infection, partly due to their capacity to stimulate innate immune responses and for the difficulty of microorganisms to develop resistance towards them. While host- and bacterial- cells compete in determining the ultimate fate of the implant, functionalization of implant surfaces with antimicrobial peptides can shift the balance and prevent implant infections. In the present study, we developed a novel chimeric peptide to functionalize the implant material surface. The chimeric peptide simultaneously presents two functionalities, with one domain binding to a titanium alloy implant surface through a titanium-binding domain while the other domain displays an antimicrobial property. This approach gains strength through control over the bio material interfaces, a property built upon molecular recognition and self assembly through a titanium alloy binding domain in the chimeric peptide. The efficiency of chimeric peptide both in-solution and absorbed onto titanium alloy surface was evaluated in vitro against three common human host infectious bacteria, S. mutans, S. epidermidis, and E. coli. In biological interactions such as occurs on implants, it is the surface and the interface that dictate the ultimate outcome. Controlling the implant surface by creating an interface composed chimeric peptides may therefore open up new possibilities to cover the implant site and tailor it to a desirable bioactivity. PMID- 26041966 TI - Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure. AB - Neuropathologic investigations in acute liver failure (ALF) reveal significant alterations to neuroglia consisting of swelling of astrocytes leading to cytotoxic brain edema and intracranial hypertension as well as activation of microglia indicative of a central neuroinflammatory response. Increased arterial ammonia concentrations in patients with ALF are predictors of patients at risk for the development of brain herniation. Molecular and spectroscopic techniques in ALF reveal alterations in expression of an array of genes coding for neuroglial proteins involved in cell volume regulation and mitochondrial function as well as in the transport of neurotransmitter amino acids and in the synthesis of pro-inflammatory cytokines. Liver-brain pro-inflammatory signaling mechanisms involving transduction of systemically-derived cytokines, ammonia neurotoxicity and exposure to increased brain lactate have been proposed. Mild hypothermia and N-Acetyl cysteine have both hepato-protective and neuro-protective properties in ALF. Potentially effective anti-inflammatory agents aimed at control of encephalopathy and brain edema in ALF include etanercept and the antibiotic minocycline, a potent inhibitor of microglial activation. Translation of these potentially-interesting findings to the clinic is anxiously awaited. PMID- 26041968 TI - Integrative analyses of cancer data: a review from a statistical perspective. AB - It has become increasingly common for large-scale public data repositories and clinical settings to have multiple types of data, including high-dimensional genomics, epigenomics, and proteomics data as well as survival data, measured simultaneously for the same group of biological samples, which provides unprecedented opportunities to understand cancer mechanisms from a more comprehensive scope and to develop new cancer therapies. Nevertheless, how to interpret a wealth of data into biologically and clinically meaningful information remains very challenging. In this paper, I review recent development in statistics for integrative analyses of cancer data. Topics will cover meta analysis of homogeneous type of data across multiple studies, integrating multiple heterogeneous genomic data types, survival analysis with high-or ultrahigh-dimensional genomic profiles, and cross-data-type prediction where both predictors and responses are high-or ultrahigh-dimensional vectors. I compare existing statistical methods and comment on potential future research problems. PMID- 26041969 TI - Improved electro-mechanical performance of gold films on polyimide without adhesion layers. AB - Thin metal films on polymer substrates are of interest for flexible electronic applications and often utilize a thin interlayer to improve adhesion of metal films on flexible substrates. This work investigates the effect of a 10 nm Cr interlayer on the electro-mechanical properties of 50 nm Au films on polyimide substrates. Ex situ and in situ fragmentation experiments reveal the Cr interlayer causes brittle electro-mechanical behaviour, and thin Au films without an interlayer can support strains up to 15% without significantly degrading electrical conductivity. PMID- 26041970 TI - Quasi-likelihood for Spatial Point Processes. AB - Fitting regression models for intensity functions of spatial point processes is of great interest in ecological and epidemiological studies of association between spatially referenced events and geographical or environmental covariates. When Cox or cluster process models are used to accommodate clustering not accounted for by the available covariates, likelihood based inference becomes computationally cumbersome due to the complicated nature of the likelihood function and the associated score function. It is therefore of interest to consider alternative more easily computable estimating functions. We derive the optimal estimating function in a class of first-order estimating functions. The optimal estimating function depends on the solution of a certain Fredholm integral equation which in practise is solved numerically. The derivation of the optimal estimating function has close similarities to the derivation of quasi likelihood for standard data sets. The approximate solution is further equivalent to a quasi-likelihood score for binary spatial data. We therefore use the term quasi-likelihood for our optimal estimating function approach. We demonstrate in a simulation study and a data example that our quasi-likelihood method for spatial point processes is both statistically and computationally efficient. PMID- 26041971 TI - Growth rate in the dynamical dark energy models. AB - Dark energy models with a slowly rolling cosmological scalar field provide a popular alternative to the standard, time-independent cosmological constant model. We study the simultaneous evolution of background expansion and growth in the scalar field model with the Ratra-Peebles self-interaction potential. We use recent measurements of the linear growth rate and the baryon acoustic oscillation peak positions to constrain the model parameter [Formula: see text] that describes the steepness of the scalar field potential. PMID- 26041972 TI - Dispersive analysis of the pion transition form factor. AB - We analyze the pion transition form factor using dispersion theory. We calculate the singly-virtual form factor in the time-like region based on data for the [Formula: see text] cross section, generalizing previous studies on [Formula: see text] decays and [Formula: see text] scattering, and verify our result by comparing to [Formula: see text] data. We perform the analytic continuation to the space-like region, predicting the poorly-constrained space-like transition form factor below [Formula: see text], and extract the slope of the form factor at vanishing momentum transfer [Formula: see text]. We derive the dispersive formalism necessary for the extension of these results to the doubly-virtual case, as required for the pion-pole contribution to hadronic light-by-light scattering in the anomalous magnetic moment of the muon. PMID- 26041979 TI - MicroR-545 enhanced radiosensitivity via suppressing Ku70 expression in Lewis lung carcinoma xenograft model. AB - OBJECTIVE: Radiotherapy is an important therapeutic method for lung cancer. However, in clinical situations, cellular resistance to radiotherapy is a significant component of tumor treatment failure. Thus, clarification in cellular mechanism underlying radiosensitivity of cancer cell is urgently needed. In this study, we established a radiation model of Lewis lung carcinoma in C57BL/6 mice and investigated the possible signaling molecule involved in this process. METHODS: C57BL/6 mice were subcutaneously transplanted with Lewis lung carcinoma cells and locally irradiated followed by measurement in tumor volume. Levels of miR-545 and Ku70 mRNA expression were determined by using Quantitative Real-Time PCR. Expression of Ku70 was determined by using western blot assay. Cell viability was analyzed by MTT assay. Cell apoptosis was examined by using TUNEL assay. RESULTS: In mice bearing Lewis lung carcinoma tumor, local radiotherapy suppressed tumor growth as well as enhanced expression of miR-545 and downregulated Ku70 level. Inhibition of miR-545 expression reduced radiosensitivity of Lewis tumor. In vitro Lewis lung carcinoma cells experiment, we observed that miR-545 regulated Ku70 expression by targeting Ku70 3'UTR and this process was involved in radiotherapy. This was demonstrated by result of cell proliferation assay in which irradiation reduced apoptosis of cells was mediated by miR-545 inactivation which was reversed by Ku70 silence. CONCLUSION: miR-545 increased radiosensitivity of Lewis lung carcinoma via inhibiting Ku70 expression. PMID- 26041980 TI - Anatomical pathways for auditory memory II: information from rostral superior temporal gyrus to dorsolateral temporal pole and medial temporal cortex. AB - Auditory recognition memory in non-human primates differs from recognition memory in other sensory systems. Monkeys learn the rule for visual and tactile delayed matching-to-sample within a few sessions, and then show one-trial recognition memory lasting 10-20 min. In contrast, monkeys require hundreds of sessions to master the rule for auditory recognition, and then show retention lasting no longer than 30-40 s. Moreover, unlike the severe effects of rhinal lesions on visual memory, such lesions have no effect on the monkeys' auditory memory performance. The anatomical pathways for auditory memory may differ from those in vision. Long-term visual recognition memory requires anatomical connections from the visual association area TE with areas 35 and 36 of the perirhinal cortex (PRC). We examined whether there is a similar anatomical route for auditory processing, or that poor auditory recognition memory may reflect the lack of such a pathway. Our hypothesis is that an auditory pathway for recognition memory originates in the higher order processing areas of the rostral superior temporal gyrus (rSTG), and then connects via the dorsolateral temporal pole to access the rhinal cortex of the medial temporal lobe. To test this, we placed retrograde (3% FB and 2% DY) and anterograde (10% BDA 10,000 mW) tracer injections in rSTG and the dorsolateral area 38 DL of the temporal pole. Results showed that area 38DL receives dense projections from auditory association areas Ts1, TAa, TPO of the rSTG, from the rostral parabelt and, to a lesser extent, from areas Ts2-3 and PGa. In turn, area 38DL projects densely to area 35 of PRC, entorhinal cortex (EC), and to areas TH/TF of the posterior parahippocampal cortex. Significantly, this projection avoids most of area 36r/c of PRC. This anatomical arrangement may contribute to our understanding of the poor auditory memory of rhesus monkeys. PMID- 26041982 TI - Polarity-specific transcranial direct current stimulation disrupts auditory pitch learning. AB - Transcranial direct current stimulation (tDCS) is attracting increasing interest because of its potential for therapeutic use. While its effects have been investigated mainly with motor and visual tasks, less is known in the auditory domain. Past tDCS studies with auditory tasks demonstrated various behavioral outcomes, possibly due to differences in stimulation parameters, task-induced brain activity, or task measurements used in each study. Further research, using well-validated tasks is therefore required for clarification of behavioral effects of tDCS on the auditory system. Here, we took advantage of findings from a prior functional magnetic resonance imaging study, which demonstrated that the right auditory cortex is modulated during fine-grained pitch learning of microtonal melodic patterns. Targeting the right auditory cortex with tDCS using this same task thus allowed us to test the hypothesis that this region is causally involved in pitch learning. Participants in the current study were trained for 3 days while we measured pitch discrimination thresholds using microtonal melodies on each day using a psychophysical staircase procedure. We administered anodal, cathodal, or sham tDCS to three groups of participants over the right auditory cortex on the second day of training during performance of the task. Both the sham and the cathodal groups showed the expected significant learning effect (decreased pitch threshold) over the 3 days of training; in contrast we observed a blocking effect of anodal tDCS on auditory pitch learning, such that this group showed no significant change in thresholds over the 3 days. The results support a causal role for the right auditory cortex in pitch discrimination learning. PMID- 26041984 TI - Epigenetic modulation of brain gene networks for cocaine and alcohol abuse. AB - Cocaine and alcohol are two substances of abuse that prominently affect the central nervous system (CNS). Repeated exposure to cocaine and alcohol leads to longstanding changes in gene expression, and subsequent functional CNS plasticity, throughout multiple brain regions. Epigenetic modifications of histones are one proposed mechanism guiding these enduring changes to the transcriptome. Characterizing the large number of available biological relationships as network models can reveal unexpected biochemical relationships. Clustering analysis of variation from whole-genome sequencing of gene expression (RNA-Seq) and histone H3 lysine 4 trimethylation (H3K4me3) events (ChIP-Seq) revealed the underlying structure of the transcriptional and epigenomic landscape within hippocampal postmortem brain tissue of drug abusers and control cases. Distinct sets of interrelated networks for cocaine and alcohol abuse were determined for each abusive substance. The network approach identified subsets of functionally related genes that are regulated in agreement with H3K4me3 changes, suggesting cause and effect relationships between this epigenetic mark and gene expression. Gene expression networks consisted of recognized substrates for addiction, such as the dopamine- and cAMP-regulated neuronal phosphoprotein PPP1R1B/DARPP-32 and the vesicular glutamate transporter SLC17A7/VGLUT1 as well as potentially novel molecular targets for substance abuse. Through a systems biology based approach our results illustrate the utility of integrating epigenetic and transcript expression to establish relevant biological networks in the human brain for addiction. Future work with laboratory models may clarify the functional relevance of these gene networks for cocaine and alcohol, and provide a framework for the development of medications for the treatment of addiction. PMID- 26041985 TI - A neuromorphic implementation of multiple spike-timing synaptic plasticity rules for large-scale neural networks. AB - We present a neuromorphic implementation of multiple synaptic plasticity learning rules, which include both Spike Timing Dependent Plasticity (STDP) and Spike Timing Dependent Delay Plasticity (STDDP). We present a fully digital implementation as well as a mixed-signal implementation, both of which use a novel dynamic-assignment time-multiplexing approach and support up to 2(26) (64M) synaptic plasticity elements. Rather than implementing dedicated synapses for particular types of synaptic plasticity, we implemented a more generic synaptic plasticity adaptor array that is separate from the neurons in the neural network. Each adaptor performs synaptic plasticity according to the arrival times of the pre- and post-synaptic spikes assigned to it, and sends out a weighted or delayed pre-synaptic spike to the post-synaptic neuron in the neural network. This strategy provides great flexibility for building complex large-scale neural networks, as a neural network can be configured for multiple synaptic plasticity rules without changing its structure. We validate the proposed neuromorphic implementations with measurement results and illustrate that the circuits are capable of performing both STDP and STDDP. We argue that it is practical to scale the work presented here up to 2(36) (64G) synaptic adaptors on a current high-end FPGA platform. PMID- 26041983 TI - Identification, functional characterization, and pharmacological profile of a serotonin type-2b receptor in the medically important insect, Rhodnius prolixus. AB - In the Chagas disease vector, Rhodnius prolixus, two diuretic hormones act synergistically to dramatically increase fluid secretion by the Malpighian tubules (MTs) during the rapid diuresis that is initiated upon engorgement of vertebrate blood. One of these diuretic hormones is the biogenic amine, serotonin (5-hydroxytryptamine, 5-HT), which controls a variety of additional activities including cuticle plasticization, salivary gland secretion, anterior midgut absorption, cardioacceleratory activity, and myotropic activities on a number of visceral tissues. To better understand the regulatory mechanisms linked to these various physiological actions of serotonin, we have isolated and characterized a serotonin type 2b receptor in R. prolixus, Rhopr5HTR2b, which shares sequence similarity to the vertebrate serotonin type 2 receptors. Rhopr5HTR2b transcript is enriched in well-recognized physiological targets of serotonin, including the MTs, salivary glands and dorsal vessel (i.e., insect heart). Notably, Rhopr5HTR2b was not enriched in the anterior midgut where serotonin stimulates absorption and elicits myotropic control. Using a heterologous functional receptor assay, we examined Rhopr5HTR2b activation characteristics and its sensitivity to potential agonists, antagonists, and other biogenic amines. Rhopr5HTR2b is dose-dependently activated by serotonin with an EC50 in the nanomolar range. Rhopr5HTR2b is sensitive to alpha-methyl serotonin and is inhibited by a variety of serotonin receptor antagonists, including propranolol, spiperone, ketanserin, mianserin, and cyproheptadine. In contrast, the cardioacceleratory activity of serotonin revealed a unique pharmacological profile, with no significant response induced by alpha-methyl serotonin and insensitivity to ketanserin and mianserin. This distinct agonist/antagonist profile indicates that a separate serotonin receptor type may mediate cardiomodulatory effects controlled by serotonin in R. prolixus. PMID- 26041986 TI - Therapeutic benefits of nanoparticles in stroke. AB - Stroke represents one of the major causes of death and disability worldwide, for which no effective treatments are available. The thrombolytic drug alteplase (tissue plasminogen activator or tPA) is the only treatment for acute ischemic stroke but its use is limited by several factors including short therapeutic window, selective efficacy, and subsequent haemorrhagic complications. Numerous preclinical studies have reported very promising results using neuroprotective agents but they have failed at clinical trials because of either safety issues or lack of efficacy. The delivery of many potentially therapeutic neuroprotectants and diagnostic compounds to the brain is restricted by the blood-brain barrier (BBB). Nanoparticles (NPs), which can readily cross the BBB without compromising its integrity, have immense applications in the treatment of ischemic stroke. In this review, potential uses of NPs will be summarized for the treatment of ischemic stroke. Additionally, an overview of targeted NPs will be provided, which could be used in the diagnosis of stroke. Finally, the potential limitations of using NPs in medical applications will be mentioned. Since the use of NPs in stroke therapy is now emerging and is still in development, this review is far from comprehensive or conclusive. Instead, examples of NPs and their current use will be provided, as well as the potentials of NPs in an effort to meet the high demand of new therapies in stroke. PMID- 26041981 TI - Integrative neurobiology of metabolic diseases, neuroinflammation, and neurodegeneration. AB - Alzheimer's disease (AD) is a complex, multifactorial disease with a number of leading mechanisms, including neuroinflammation, processing of amyloid precursor protein (APP) to amyloid beta peptide, tau protein hyperphosphorylation, relocalization, and deposition. These mechanisms are propagated by obesity, the metabolic syndrome and type-2 diabetes mellitus. Stress, sedentariness, dietary overconsumption of saturated fat and refined sugars, and circadian derangements/disturbed sleep contribute to obesity and related metabolic diseases, but also accelerate age-related damage and senescence that all feed the risk of developing AD too. The complex and interacting mechanisms are not yet completely understood and will require further analysis. Instead of investigating AD as a mono- or oligocausal disease we should address the disease by understanding the multiple underlying mechanisms and how these interact. Future research therefore might concentrate on integrating these by "systems biology" approaches, but also to regard them from an evolutionary medicine point of view. The current review addresses several of these interacting mechanisms in animal models and compares them with clinical data giving an overview about our current knowledge and puts them into an integrated framework. PMID- 26041988 TI - Alteration of somatosensory response in adulthood by early life stress. AB - Early life stress is well-known as a critical risk factor for mental and cognitive disorders in adulthood. Such disorders are accompanied by altered neuro (synapto-) genesis and gene expression. Because psychosomatic disorders induced by early life stress (e.g., physical and/or sexual abuse, and neglect) have become a socio-economic problem, it is very important to clarify the mechanisms underlying these changes. However, despite of intensive clinical and animal studies, such mechanisms have not yet been clarified. Although the disturbance of glucocorticoid and glutamate homeostasis by stress has been well-documented, it has not yet been clarified whether such disturbance by early life stress persists for life. Furthermore, since previous studies have focused on the detection of changes in specific brain regions, such as the hippocampus and prefrontal cortex, it has not been clarified whether early life stress induced changes in the sensory/motor system. Thus, in this review, we introduce recent studies on functional/structural changes in the somatosensory cortex induced by early life stress. We believe that this review provides new insights into the functional alteration of the somatosensory system induced by early life stress. Such information may have clinical relevance in terms of providing effective therapeutic interventions to early life stressed individuals. PMID- 26041987 TI - Lentiviral vectors as tools to understand central nervous system biology in mammalian model organisms. AB - Lentiviruses have been extensively used as gene delivery vectors since the mid 1990s. Usually derived from the human immunodeficiency virus genome, they mediate efficient gene transfer to non-dividing cells, including neurons and glia in the adult mammalian brain. In addition, integration of the recombinant lentiviral construct into the host genome provides permanent expression, including the progeny of dividing neural precursors. In this review, we describe targeted vectors with modified envelope glycoproteins and expression of transgenes under the regulation of cell-selective and inducible promoters. This technology has broad utility to address fundamental questions in neuroscience and we outline how this has been used in rodents and primates. Combining viral tract tracing with immunohistochemistry and confocal or electron microscopy, lentiviral vectors provide a tool to selectively label and trace specific neuronal populations at gross or ultrastructural levels. Additionally, new generation optogenetic technologies can be readily utilized to analyze neuronal circuit and gene functions in the mature mammalian brain. Examples of these applications, limitations of current systems and prospects for future developments to enhance neuroscience knowledge will be reviewed. Finally, we will discuss how these vectors may be translated from gene therapy trials into the clinical setting. PMID- 26041989 TI - Erratum on: Highly efficient method for gene delivery into mouse dorsal root ganglia neurons. AB - [This corrects the article on p. 2 in vol. 8, PMID: 25698920.]. PMID- 26041990 TI - Evaluation of inflammation-related genes polymorphisms in Mexican with Alzheimer's disease: a pilot study. AB - Amyloid peptide is able to promote the activation of microglia and astrocytes in Alzheimer's disease (AD), and this stimulates the production of pro-inflammatory cytokines. Inflammation contributes to the process of neurodegeneration and therefore is a key factor in the development of AD. Some of the most important proteins involved in AD inflammation are: clusterin (CLU), complement receptor 1 (CR1), C reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), the interleukins 1alpha (IL-1alpha), 6 (IL-6), 10 (IL-10) and cyclooxygenase 2 (COX 2). In particular, COX-2 is encoded by the prostaglandin-endoperoxide synthase 2 gene (PTGS2). Since variations in the genes that encode these proteins may modify gene expression or function, it is important to investigate whether these variations may change the developing AD. The aim of this study was to determine whether the presence of polymorphisms in the genes encoding the aforementioned proteins is associated in Mexican patients with AD. Fourteen polymorphisms were genotyped in 96 subjects with AD and 100 controls; the differences in allele, genotype and haplotype frequencies were analyzed. Additionally, an ancestry analysis was conducted to exclude differences in genetic ancestry among groups as a confounding factor in the study. Significant differences in frequencies between AD and controls were found for the single-nucleotide polymorphism (SNP) rs20417 within the PTGS2 gene. Ancestry analysis revealed no significant differences in the ancestry of the compared groups, and the association was significant even after adjustment for ancestry and correction for multiple testing, which strengthens the validity of the results. We conclude that this polymorphism plays an important role in the development of the AD pathology and further studies are required, including their proteins. PMID- 26041991 TI - Activation of the endoplasmic reticulum stress response in skeletal muscle of G93A*SOD1 amyotrophic lateral sclerosis mice. AB - Mutations in Cu/Zn superoxide dismutase (SOD1) are one of the genetic causes of Amyotrophic Lateral Sclerosis (ALS). Although the primary symptom of ALS is muscle weakness, the link between SOD1 mutations, cellular dysfunction and muscle atrophy and weakness is not well understood. The purpose of this study was to characterize cellular markers of ER stress in skeletal muscle across the lifespan of G93A*SOD1 (ALS-Tg) mice. Muscles were obtained from ALS-Tg and age-matched wild type (WT) mice at 70d (pre-symptomatic), 90d and 120-140d (symptomatic) and analyzed for ER stress markers. In white gastrocnemius (WG) muscle, ER stress sensors PERK and IRE1alpha were upregulated ~2-fold at 70d and remained (PERK) or increased further (IRE1alpha) at 120-140d. Phospho-eIF2alpha, a downstream target of PERK and an inhibitor of protein translation, was increased by 70d and increased further to 12.9-fold at 120-140d. IRE1alpha upregulation leads to increased splicing of X-box binding protein 1 (XBP-1) to the XBP-1s isoform. XBP 1s transcript was increased at 90d and 120-140d indicating activation of IRE1alpha signaling. The ER chaperone/heat shock protein Grp78/BiP was upregulated 2-fold at 70d and 90d and increased to 6.1-fold by 120-140d. The ER stress-specific apoptotic signaling protein CHOP was upregulated 2-fold at 70d and 90d and increased to 13.3-fold at 120-140d indicating progressive activation of an apoptotic signal in muscle. There was a greater increase in Grp78/BiP and CHOP in WG vs. the more oxidative red gastrocnemius (RG) ALS-Tg at 120-140d indicating greater ER stress and apoptosis in fast glycolytic muscle. These data show that the ER stress response is activated in skeletal muscle of ALS-Tg mice by an early pre-symptomatic age and increases with disease progression. These data suggest a mechanism by which myocellular ER stress leads to reduced protein translation and contributes to muscle atrophy and weakness in ALS. PMID- 26041992 TI - Alternative kynurenic acid synthesis routes studied in the rat cerebellum. AB - Kynurenic acid (KYNA), an astrocyte-derived, endogenous antagonist of alpha7 nicotinic acetylcholine and excitatory amino acid receptors, regulates glutamatergic, GABAergic, cholinergic and dopaminergic neurotransmission in several regions of the rodent brain. Synthesis of KYNA in the brain and elsewhere is generally attributed to the enzymatic conversion of L-kynurenine (L-KYN) by kynurenine aminotransferases (KATs). However, alternative routes, including KYNA formation from D-kynurenine (D-KYN) by D-amino acid oxidase (DAAO) and the direct transformation of kynurenine to KYNA by reactive oxygen species (ROS), have been demonstrated in the rat brain. Using the rat cerebellum, a region of low KAT activity and high DAAO activity, the present experiments were designed to examine KYNA production from L-KYN or D-KYN by KAT and DAAO, respectively, and to investigate the effect of ROS on KYNA synthesis. In chemical combinatorial systems, both L-KYN and D-KYN interacted directly with peroxynitrite (ONOO(-)) and hydroxyl radicals (OH*), resulting in the formation of KYNA. In tissue homogenates, the non-specific KAT inhibitor aminooxyacetic acid (AOAA; 1 mM) reduced KYNA production from L-KYN and D-KYN by 85.1 +/- 1.7% and 27.1 +/- 4.5%, respectively. Addition of DAAO inhibitors (benzoic acid, kojic acid or 3 methylpyrazole-5-carboxylic acid; 5 MUM each) attenuated KYNA formation from L KYN and D-KYN by ~35% and ~66%, respectively. ONOO(-) (25 MUM) potentiated KYNA production from both L-KYN and D-KYN, and these effects were reduced by DAAO inhibition. AOAA attenuated KYNA production from L-KYN + ONOO(-) but not from D KYN + ONOO(-). In vivo, extracellular KYNA levels increased rapidly after perfusion of ONOO(-) and, more prominently, after subsequent perfusion with L-KYN or D-KYN (100 MUM). Taken together, these results suggest that different mechanisms are involved in KYNA production in the rat cerebellum, and that, specifically, DAAO and ROS can function as alternative routes for KYNA production. PMID- 26041975 TI - Measurement of pion, kaon and proton production in proton-proton collisions at [Formula: see text] TeV. AB - The measurement of primary [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] production at mid-rapidity ([Formula: see text] 0.5) in proton-proton collisions at [Formula: see text][Formula: see text] 7 TeV performed with a large ion collider experiment at the large hadron collider (LHC) is reported. Particle identification is performed using the specific ionisation energy-loss and time-of-flight information, the ring-imaging Cherenkov technique and the kink-topology identification of weak decays of charged kaons. Transverse momentum spectra are measured from 0.1 up to 3 GeV/[Formula: see text] for pions, from 0.2 up to 6 GeV/[Formula: see text] for kaons and from 0.3 up to 6 GeV/[Formula: see text] for protons. The measured spectra and particle ratios are compared with quantum chromodynamics-inspired models, tuned to reproduce also the earlier measurements performed at the LHC. Furthermore, the integrated particle yields and ratios as well as the average transverse momenta are compared with results at lower collision energies. PMID- 26041993 TI - Microglia are crucial regulators of neuro-immunity during central nervous system tuberculosis. AB - Mycobacterium tuberculosis (M. tuberculosis) infection of the central nervous system (CNS) is the most devastating manifestation of tuberculosis (TB), with both high mortality and morbidity. Although research has been fueled by the potential therapeutic target microglia offer against neurodegenerative inflammation, their part in TB infection of the CNS has not been fully evaluated nor elucidated. Yet, as both the preferential targets of M. tuberculosis and the immune-effector cells of the CNS, microglia are likely to be key determinants of disease severity and clinical outcomes. Following pathogen recognition, bacilli are internalized and capable of replicating within microglia. Cellular activation ensues, utilizing signaling molecules that may be neurotoxic. Central to initiating, orchestrating and modulating the tuberculous immune response is microglial secretion of cytokines and chemokines. However, the neurological environment is unique in that inflammatory signals, which appear to be damaging in the periphery, could be beneficial by governing neuronal survival, regeneration and differentiation. Furthermore, microglia are important in the recruitment of peripheral immune cells and central to defining the pro inflammatory milieu of which neurotoxicity may result from many of the participating local or recruited cell types. Microglia are capable of both presenting antigen to infiltrating CD4(+) T-lymphocytes and inducing their differentiation-a possible correlate of protection against M. tuberculosis infection. Clarifying the nature of the immune effector molecules secreted by microglia, and the means by which other CNS-specific cell types govern microglial activation or modulate their responses is critical if improved diagnostic and therapeutic strategies are to be attained. Therefore, this review evaluates the diverse roles microglia play in the neuro-immunity to M. tuberculosis infection of the CNS. PMID- 26041994 TI - Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA. AB - GABAA receptors mediate fast inhibitory neurotransmission in the brain. Dysfunction of these receptors is associated with various psychiatric/neurological disorders and drugs targeting this receptor are widely used therapeutic agents. Both the efficacy and plasticity of GABAA receptor mediated neurotransmission depends on the number of surface GABAA receptors. An understudied aspect of receptor cell surface expression is the post-translational regulation of receptor biogenesis within the endoplasmic reticulum (ER). We have previously shown that exogenous GABA can act as a ligand chaperone of recombinant GABAA receptors in the early secretory pathway leading us to now investigate whether endogenous GABA facilitates the biogenesis of GABAA receptors in primary cerebral cortical cultures. In immunofluorescence labeling experiments, we have determined that neurons expressing surface GABAA receptors contain both GABA and its degradative enzyme GABA transaminase (GABA-T). Treatment of neurons with GABA T inhibitors, a treatment known to increase intracellular GABA levels, decreases the interaction of the receptor with the ER quality control protein calnexin, concomittantly increasing receptor forward-trafficking and plasma membrane insertion. The effect of GABA-T inhibition on the receptor/calnexin interaction is not due to the activation of surface GABAA or GABAB receptors. Consistent with our hypothesis that GABA acts as a cognate ligand chaperone in the ER, immunogold labeling of rodent brain slices reveals the presence of GABA within the rough ER. The density of this labeling is similar to that present in mitochondria, the organelle in which GABA is degraded. Lastly, the effect of GABA-T inhibition on the receptor/calnexin interaction was prevented by pretreatment with a GABA transporter inhibitor. Together, these data indicate that endogenous GABA acts in the rough ER as a cognate ligand chaperone to facilitate the biogenesis of neuronal GABAA receptors. PMID- 26041996 TI - Ontogeny of kainate-induced gamma oscillations in the rat CA3 hippocampus in vitro. AB - GABAergic inhibition, which is instrumental in the generation of hippocampal gamma oscillations, undergoes significant changes during development. However, the development of hippocampal gamma oscillations remains largely unknown. Here, we explored the developmental features of kainate-induced oscillations (KA-Os) in CA3 region of rat hippocampal slices. Up to postnatal day P5, the bath application of kainate failed to evoke any detectable oscillations. KA-Os emerged by the end of the first postnatal week; these were initially weak, slow (20-25 Hz, beta range) and were poorly synchronized with CA3 units and synaptic currents. Local field potential (LFP) power, synchronization of units and frequency of KA-Os increased during the second postnatal week to attain gamma (30 40 Hz) frequency by P15-21. Both beta and gamma KA-Os are characterized by alternating sinks and sources in the pyramidal cell layer, likely generated by summation of the action potential-associated currents and GABAergic synaptic currents, respectively. Blockade of GABA(A) receptors with gabazine completely suppressed KA-Os at all ages indicating that GABAergic mechanisms are instrumental in their generation. Bumetanide, a NKCC1 chloride co-transporter antagonist which renders GABAergic responses inhibitory in the immature hippocampal neurons, failed to induce KA-Os at P2-4 indicating that the absence of KA-Os in neonates is not due to depolarizing actions of GABA. The linear developmental profile, electrographic features and pharmacological properties indicate that CA3 hippocampal beta and gamma KA-Os are fundamentally similar in their generative mechanisms and their delayed onset and developmental changes likely reflect the development of perisomatic GABAergic inhibition. PMID- 26041995 TI - An updated role of microRNA-124 in central nervous system disorders: a review. AB - MicroRNA-124 (miR-124) is the most abundant miRNA in the brain. Biogenesis of miR 124 displays specific temporal and spatial profiles in various cell and tissue types and affects a broad spectrum of biological functions in the central nervous system (CNS). Recently, the link between dysregulation of miR-124 and CNS disorders, such as neurodegeneration, CNS stress, neuroimmune disorders, stroke, and brain tumors, has become evident. Here, we provide an overview of the specific molecular function of miR-124 in the CNS and a revealing insight for the therapeutic potential of miR-124 in the treatment of human CNS diseases. PMID- 26041997 TI - ASK1 modulates the expression of microRNA Let7A in microglia under high glucose in vitro condition. AB - Hyperglycemia results in oxidative stress and leads to neuronal apoptosis in the brain. Diabetes studies show that microglia participate in the progression of neuropathogenesis through their involvement in inflammation in vivo and in vitro. In high-glucose-induced inflammation, apoptosis signal regulating kinase 1 (ASK1) triggers the release of apoptosis cytokines and apoptotic gene expression. MicroRNA-Let7A (miR-Let7A) is reported to be a regulator of inflammation. In the present study, we investigated whether miR-Let7A regulates the function of microglia by controlling ASK1 in response to high-glucose-induced oxidative stress. We performed reverse transcription (RT) polymerase chain reaction, Taqman assay, real-time polymerase chain reaction, and immunocytochemistry to confirm the alteration of microglia function. Our results show that miR-Let7A is associated with the activation of ASK1 and the expression of anti-inflammatory cytokine (interleukin (IL)-10) and Mycs (c-Myc and N-Myc). Thus, the relationship between Let-7A and ASK1 could be a novel target for enhancing the beneficial function of microglia in central nervous system (CNS) disorders. PMID- 26041998 TI - Activity-dependent plasticity of mouse hippocampal assemblies in vitro. AB - Memory formation is associated with the generation of transiently stable neuronal assemblies. In hippocampal networks, such groups of functionally coupled neurons express highly ordered spatiotemporal activity patterns which are coordinated by local network oscillations. One of these patterns, sharp wave-ripple complexes (SPW-R), repetitively activates previously established groups of memory-encoding neurons, thereby supporting memory consolidation. This function implies that repetition of specific SPW-R induces plastic changes which render the underlying neuronal assemblies more stable. We modeled this repetitive activation in an in vitro model of SPW-R in mouse hippocampal slices. Weak electrical stimulation upstream of the CA3-CA1 networks reliably induced SPW-R of stereotypic waveform, thus representing re-activation of similar neuronal activity patterns. Frequent repetition of these patterns (100 times) reduced the variance of both, evoked and spontaneous SPW-R waveforms, indicating stabilization of pre-existing assemblies. These effects were most pronounced in the CA1 subfield and depended on the timing of stimulation relative to spontaneous SPW-R. Additionally, plasticity of SPW-R was blocked by application of a NMDA receptor antagonist, suggesting a role for associative synaptic plasticity in this process. Thus, repetitive activation of specific patterns of SPW-R causes stabilization of memory-related networks. PMID- 26041999 TI - Neural discriminability in rat lateral extrastriate cortex and deep but not superficial primary visual cortex correlates with shape discriminability. AB - Recent studies have revealed a surprising degree of functional specialization in rodent visual cortex. It is unknown to what degree this functional organization is related to the well-known hierarchical organization of the visual system in primates. We designed a study in rats that targets one of the hallmarks of the hierarchical object vision pathway in primates: selectivity for behaviorally relevant dimensions. We compared behavioral performance in a visual water maze with neural discriminability in five visual cortical areas. We tested behavioral discrimination in two independent batches of six rats using six pairs of shapes used previously to probe shape selectivity in monkey cortex (Lehky and Sereno, 2007). The relative difficulty (error rate) of shape pairs was strongly correlated between the two batches, indicating that some shape pairs were more difficult to discriminate than others. Then, we recorded in naive rats from five visual areas from primary visual cortex (V1) over areas LM, LI, LL, up to lateral occipito-temporal cortex (TO). Shape selectivity in the upper layers of V1, where the information enters cortex, correlated mostly with physical stimulus dissimilarity and not with behavioral performance. In contrast, neural discriminability in lower layers of all areas was strongly correlated with behavioral performance. These findings, in combination with the results from Vermaercke et al. (2014b), suggest that the functional specialization in rodent lateral visual cortex reflects a processing hierarchy resulting in the emergence of complex selectivity that is related to behaviorally relevant stimulus differences. PMID- 26042001 TI - About connections. AB - Despite the attention attracted by "connectomics", one can lose sight of the very real questions concerning "What are connections?" In the neuroimaging community, "structural" connectivity is ground truth and underlying constraint on "functional" or "effective" connectivity. It is referenced to underlying anatomy; but, as increasingly remarked, there is a large gap between the wealth of human brain mapping and the relatively scant data on actual anatomical connectivity. Moreover, connections have typically been discussed as "pairwise", point x projecting to point y (or: to points y and z), or more recently, in graph theoretical terms, as "nodes" or regions and the interconnecting "edges". This is a convenient shorthand, but tends not to capture the richness and nuance of basic anatomical properties as identified in the classic tradition of tracer studies. The present short review accordingly revisits connectional weights, heterogeneity, reciprocity, topography, and hierarchical organization, drawing on concrete examples. The emphasis is on presynaptic long-distance connections, motivated by the intention to probe current assumptions and promote discussions about further progress and synthesis. PMID- 26042000 TI - Long-range projection neurons of the mouse ventral tegmental area: a single-cell axon tracing analysis. AB - Pathways arising from the ventral tegmental area (VTA) release dopamine and other neurotransmitters during the expectation and achievement of reward, and are regarded as central links of the brain networks that create drive, pleasure, and addiction. While the global pattern of VTA projections is well-known, the actual axonal wiring of individual VTA neurons had never been investigated. Here, we labeled and analyzed the axons of 30 VTA single neurons by means of single-cell transfection with the Sindbis-pal-eGFP vector in mice. These observations were complemented with those obtained by labeling the axons of small populations of VTA cells with iontophoretic microdeposits of biotinylated dextran amine. In the single-cell labeling experiments, each entire axonal tree was reconstructed from serial sections, the length of terminal axonal arbors was estimated by stereology, and the dopaminergic phenotype was tested by double-labeling for tyrosine hydroxylase immunofluorescence. We observed two main, markedly different VTA cell morphologies: neurons with a single main axon targeting only forebrain structures (FPN cells), and neurons with multibranched axons targeting both the forebrain and the brainstem (F + BSPN cells). Dopaminergic phenotype was observed in FPN cells. Moreover, four "subtypes" could be distinguished among the FPN cells based on their projection targets: (1) "Mesocorticolimbic" FPN projecting to both neocortex and basal forebrain; (2) "Mesocortical" FPN innervating the neocortex almost exclusively; (3) "Mesolimbic" FPN projecting to the basal forebrain, accumbens and caudateputamen; and (4) "Mesostriatal" FPN targeting only the caudateputamen. While the F + BSPN cells were scattered within VTA, the mesolimbic neurons were abundant in the paranigral nucleus. The observed diversity in wiring architectures is consistent with the notion that different VTA cell subpopulations modulate the activity of specific sets of prosencephalic and brainstem structures. PMID- 26042003 TI - Future think: cautiously optimistic about brain augmentation using tissue engineering and machine interface. PMID- 26042002 TI - Optimal feedback control successfully explains changes in neural modulations during experiments with brain-machine interfaces. AB - Recent experiments with brain-machine-interfaces (BMIs) indicate that the extent of neural modulations increased abruptly upon starting to operate the interface, and especially after the monkey stopped moving its hand. In contrast, neural modulations that are correlated with the kinematics of the movement remained relatively unchanged. Here we demonstrate that similar changes are produced by simulated neurons that encode the relevant signals generated by an optimal feedback controller during simulated BMI experiments. The optimal feedback controller relies on state estimation that integrates both visual and proprioceptive feedback with prior estimations from an internal model. The processing required for optimal state estimation and control were conducted in the state-space, and neural recording was simulated by modeling two populations of neurons that encode either only the estimated state or also the control signal. Spike counts were generated as realizations of doubly stochastic Poisson processes with linear tuning curves. The model successfully reconstructs the main features of the kinematics and neural activity during regular reaching movements. Most importantly, the activity of the simulated neurons successfully reproduces the observed changes in neural modulations upon switching to brain control. Further theoretical analysis and simulations indicate that increasing the process noise during normal reaching movement results in similar changes in neural modulations. Thus, we conclude that the observed changes in neural modulations during BMI experiments can be attributed to increasing process noise associated with the imperfect BMI filter, and, more directly, to the resulting increase in the variance of the encoded signals associated with state estimation and the required control signal. PMID- 26042004 TI - Motor imagery: lessons learned in movement science might be applicable for spaceflight. AB - Before participating in a space mission, astronauts undergo parabolic-flight and underwater training to facilitate their subsequent adaptation to weightlessness. Unfortunately, similar training methods can't be used to prepare re-adaptation to planetary gravity. Here, we propose a quick, simple and inexpensive approach that could be used to prepare astronauts both for the absence and for the renewed presence of gravity. This approach is based on motor imagery (MI), a process in which actions are produced in working memory without any overt output. Training protocols based on MI have repeatedly been shown to modify brain circuitry and to improve motor performance in healthy young adults, healthy seniors and stroke victims, and are routinely used to optimize performance of elite athletes. We propose to use similar protocols preflight, to prepare for weightlessness, and late inflight, to prepare for landing. PMID- 26042005 TI - The topology of connections between rat prefrontal and temporal cortices. AB - Understanding the structural organization of the prefrontal cortex (PFC) is an important step toward determining its functional organization. Here we investigated the organization of PFC using different neuronal tracers. We injected retrograde (Fluoro-Gold, 100 nl) and anterograde [Biotinylated dextran amine (BDA) or Fluoro-Ruby, 100 nl] tracers into sites within PFC subdivisions (prelimbic, ventral orbital, ventrolateral orbital, dorsolateral orbital) along a coronal axis within PFC. At each injection site one injection was made of the anterograde tracer and one injection was made of the retrograde tracer. The projection locations of retrogradely labeled neurons and anterogradely labeled axon terminals were then analyzed in the temporal cortex: area Te, entorhinal and perirhinal cortex. We found evidence for an ordering of both the anterograde (anterior-posterior, dorsal-ventral, and medial-lateral axes: p < 0.001) and retrograde (anterior-posterior, dorsal-ventral, and medial-lateral axes: p < 0.001) connections of PFC. We observed that anterograde and retrograde labeling in ipsilateral temporal cortex (i.e., PFC inputs and outputs) often occurred reciprocally (i.e., the same brain region, such as area 35d in perirhinal cortex, contained anterograde and retrograde labeling). However, often the same specific columnar temporal cortex regions contained only either labeling of retrograde or anterograde tracer, indicating that PFC inputs and outputs are frequently non matched. PMID- 26042006 TI - What makes a frontal area of primate brain the frontal eye field? AB - The frontal eye field region (FEF) of the oculomotor pathways has been intensely studied. The primary goal of this review is to illustrate the phylogenetic displacement of the FEF locus in primate species. The locus is arrayed along the arcuate sulcus in monkeys and abuts into the primary motor strip region in humans. The strengths and limitations of the various functional, anatomical and histological methodologies used to identify such regions are also discussed. PMID- 26042007 TI - Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis. AB - Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism of the N methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioral changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse (PP) facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus prefrontal cortex circuitry. PMID- 26042008 TI - Retrieval cues that trigger reconsolidation of associative fear memory are not necessarily an exact replica of the original learning experience. AB - Disrupting the process of memory reconsolidation may point to a novel therapeutic strategy for the permanent reduction of fear in patients suffering from anxiety disorders. However both in animal and human studies the retrieval cue typically involves a re-exposure to the original fear-conditioned stimulus (CS). A relevant question is whether abstract cues not directly associated with the threat event also trigger reconsolidation, given that anxiety disorders often result from vicarious or unobtrusive learning for which no explicit memory exists. Insofar as the fear memory involves a flexible representation of the original learning experience, we hypothesized that the process of memory reconsolidation may also be triggered by abstract cues. We addressed this hypothesis by using a differential human fear-conditioning procedure in two distinct fear-learning groups. We predicted that if fear learning involves discrimination on basis of perceptual cues within one semantic category (i.e., the perceptual-learning group, n = 15), the subsequent ambiguity of the abstract retrieval cue would not trigger memory reconsolidation. In contrast, if fear learning involves discriminating between two semantic categories (i.e., categorical-learning group, n = 15), an abstract retrieval cue would unequivocally reactivate the fear memory and might subsequently trigger memory reconsolidation. Here we show that memory reconsolidation may indeed be triggered by another cue than the one that was present during the original learning occasion, but this effect depends on the learning history. Evidence for fear memory reconsolidation was inferred from the fear-erasing effect of one pill of propranolol (40 mg) systemically administered upon exposure to the abstract retrieval cue. Our finding that reconsolidation of a specific fear association does not require exposure to the original retrieval cue supports the feasibility of reconsolidation-based interventions for emotional disorders. PMID- 26042009 TI - What does spatial alternation tell us about retrosplenial cortex function? AB - The retrosplenial cortex supports navigation, but there are good reasons to suppose that the retrosplenial cortex has a very different role in spatial memory from that of the hippocampus and anterior thalamic nuclei. For example, retrosplenial lesions appear to have little or no effect on standard tests of spatial alternation. To examine these differences, the current study sought to determine whether the retrosplenial cortex is important for just one spatial cue type (e.g., allocentric, directional or intra-maze cues) or whether the retrosplenial cortex helps the animal switch between competing spatial strategies or competing cue types. Using T-maze alternation, retrosplenial lesion rats were challenged with situations in which the available spatial information between the sample and test phases was changed, so taxing the interaction between different cue types. Clear lesion deficits emerged when intra- and extra-maze cues were placed in conflict (by rotating the maze between the sample and choice phases), or when the animals were tested in the dark in a double-maze. Finally, temporary inactivation of the retrosplenial cortex by muscimol infusions resulted in a striking deficit on standard T-maze alternation, indicating that, over time, other sites may be able to compensate for the loss of the retrosplenial cortex. This pattern of results is consistent with the impoverished use of both allocentric and directional information, exacerbated by an impaired ability to switch between different cue types. PMID- 26042010 TI - Both the COMT Val158Met single-nucleotide polymorphism and sex-dependent differences influence response inhibition. AB - Reactive and proactive controls of actions are cognitive abilities that allow one to deal with a continuously changing environment by adjusting already programmed actions. They also set forthcoming actions by evaluating the outcome of the previous ones. Earlier studies highlighted sex-related differences in the strategies and in the pattern of brain activation during cognitive tasks involving reactive and proactive control. To further identify sex-dependent characteristics in the cognitive control of actions, in this study, we have assessed whether/how differences in performance are modulated by the COMT Val158Met single-nucleotide polymorphism (SNP), a genetic factor known to influence the functionality of the dopaminergic system-in particular, at the level of the prefrontal cortex. Two groups of male and female participants were sorted according to their genotype (Val/Val, Val/Met, and Met/Met) and tested in a stop signal task, a consolidated tool for measuring executive control in experimental and clinical settings. In each group of participants, we estimated both a measure of the capacity to react to unexpected events and the ability to monitor their performance. The between-group comparison of these measures indicated a poorer ability of male individuals and Val/Val subjects in error monitoring. These observations suggest that sex differences in inhibitory control could be influenced by the efficiency of COMT and that other sex-specific factors have to be considered. Understanding the inter-group variability of behavioral and physiological correlates of cognitive control could provide more accurate diagnostic tools for predicting the incidence and/or the development of pathologies, like ADHD, or deviant behaviors, such as drug or alcohol abuse. PMID- 26042011 TI - Appetitive vs. Aversive conditioning in humans. AB - In classical conditioning, an initially neutral stimulus (conditioned stimulus, CS) becomes associated with a biologically salient event (unconditioned stimulus, US), which might be pain (aversive conditioning) or food (appetitive conditioning). After a few associations, the CS is able to initiate either defensive or consummatory responses, respectively. Contrary to aversive conditioning, appetitive conditioning is rarely investigated in humans, although its importance for normal and pathological behaviors (e.g., obesity, addiction) is undeniable. The present study intents to translate animal findings on appetitive conditioning to humans using food as an US. Thirty-three participants were investigated between 8 and 10 am without breakfast in order to assure that they felt hungry. During two acquisition phases, one geometrical shape (avCS+) predicted an aversive US (painful electric shock), another shape (appCS+) predicted an appetitive US (chocolate or salty pretzel according to the participants' preference), and a third shape (CS-) predicted neither US. In a extinction phase, these three shapes plus a novel shape (NEW) were presented again without US delivery. Valence and arousal ratings as well as startle and skin conductance (SCR) responses were collected as learning indices. We found successful aversive and appetitive conditioning. On the one hand, the avCS+ was rated as more negative and more arousing than the CS- and induced startle potentiation and enhanced SCR. On the other hand, the appCS+ was rated more positive than the CS- and induced startle attenuation and larger SCR. In summary, we successfully confirmed animal findings in (hungry) humans by demonstrating appetitive learning and normal aversive learning. PMID- 26042012 TI - Numerical processing efficiency improved in children using mental abacus: ERP evidence utilizing a numerical Stroop task. AB - This study examined whether long-term abacus-based mental calculation (AMC) training improved numerical processing efficiency and at what stage of information processing the effect appeard. Thirty-three children participated in the study and were randomly assigned to two groups at primary school entry, matched for age, gender and IQ. All children went through the same curriculum except that the abacus group received a 2-h/per week AMC training, while the control group did traditional numerical practice for a similar amount of time. After a 2-year training, they were tested with a numerical Stroop task. Electroencephalographic (EEG) and event related potential (ERP) recording techniques were used to monitor the temporal dynamics during the task. Children were required to determine the numerical magnitude (NC) (NC task) or the physical size (PC task) of two numbers presented simultaneously. In the NC task, the AMC group showed faster response times but similar accuracy compared to the control group. In the PC task, the two groups exhibited the same speed and accuracy. The saliency of numerical information relative to physical information was greater in AMC group. With regards to ERP results, the AMC group displayed congruity effects both in the earlier (N1) and later (N2 and LPC (late positive component) time domain, while the control group only displayed congruity effects for LPC. In the left parietal region, LPC amplitudes were larger for the AMC than the control group. Individual differences for LPC amplitudes over left parietal area showed a positive correlation with RTs in the NC task in both congruent and neutral conditions. After controlling for the N2 amplitude, this correlation also became significant in the incongruent condition. Our results suggest that AMC training can strengthen the relationship between symbolic representation and numerical magnitude so that numerical information processing becomes quicker and automatic in AMC children. PMID- 26042014 TI - Editorial: "The cognitive, emotional and neural correlates of creativity". PMID- 26042013 TI - Advantages in functional imaging of the brain. AB - As neuronal pathologies cause only minor morphological alterations, molecular imaging techniques are a prerequisite for the study of diseases of the brain. The development of molecular probes that specifically bind biochemical markers and the advances of instrumentation have revolutionized the possibilities to gain insight into the human brain organization and beyond this-visualize structure function and brain-behavior relationships. The review describes the development and current applications of functional brain imaging techniques with a focus on applications in psychiatry. A historical overview of the development of functional imaging is followed by the portrayal of the principles and applications of positron emission tomography (PET) and functional magnetic resonance imaging (fMRI), two key molecular imaging techniques that have revolutionized the ability to image molecular processes in the brain. We conclude that the juxtaposition of PET and fMRI in hybrid PET/MRI scanners enhances the significance of both modalities for research in neurology and psychiatry and might pave the way for a new area of personalized medicine. PMID- 26042016 TI - Quantitative evaluation of fMRI retinotopic maps, from V1 to V4, for cognitive experiments. AB - FMRI retinotopic mapping is a non-invasive technique for the delineation of low level visual areas in individual subjects. It generally relies upon the analysis of functional responses to periodic visual stimuli that encode eccentricity or polar angle in the visual field. This technique is used in vision research when the precise assignation of brain activation to retinotopic areas is an issue. It involves processing steps computed with different algorithms and embedded in various software suites. Manual intervention may be needed for some steps. Although the diversity of the available processing suites and manual interventions may potentially introduce some differences in the final delineation of visual areas, no documented comparison between maps obtained with different procedures has been reported in the literature. To explore the effect of the processing steps on the quality of the maps obtained, we used two tools, BALC, which relies on a fully automated procedure, and BrainVoyager, where areas are delineated "by hand" on the brain surface. To focus on the mapping procedures specifically, we used the same SPM pipeline for pretreatment and the same tissue segmentation tool. We document the consistency and differences of the fMRI retinotopic maps obtained from "routine retinotopy" experiments on 10 subjects. The maps obtained by skilled users are never fully identical. However, the agreement between the maps, around 80% for low-level areas, is probably sufficient for most applications. Our results also indicate that assigning cognitive activations, following a specific experiment (here, color perception), to individual retinotopic maps is not free of errors. We provide measurements of this error, that may help for the cautious interpretation of cognitive activation projection onto fMRI retinotopic maps. On average, the magnitude of the error is about 20%, with much larger differences in a few subjects. More variability may even be expected with less trained users or using different acquisition parameters and preprocessing chains. PMID- 26042015 TI - Intracortical inhibition is modulated by phase of prosthetic rehabilitation in transtibial amputees. AB - Reorganization of primary motor cortex (M1) is well-described in long-term lower limb amputees. In contrast cortical reorganization during the rehabilitation period after amputation is poorly understood. Thirteen transtibial amputees and 13 gender matched control participants of similar age were recruited. Transcranial magnetic stimulation was used to assess corticomotor and intracortical excitability of M1 bilaterally. Neurophysiological assessments were conducted at admission, prosthetic casting, first walk and discharge. Gait variability at discharge was assessed as a functional measure. Compared to controls, amputees had reduced short-latency intracortical inhibition (SICI) for the ipsilateral M1 at admission (p = 0.01). Analysis across rehabilitation revealed SICI was reduced for the contralateral M1 at first walk compared to discharge (p = 0.003). For the ipsilateral M1 both short and long-latency intracortical inhibition were reduced at admission (p < 0.05) and prosthetic casting (p < 0.02). Analysis of the neurophysiology and gait function revealed several interesting relationships. For the contralateral M1, reduced inhibition at admission (p = 0.04) and first walk (p = 0.05) was associated with better gait function. For the ipsilateral M1, reduced inhibition at discharge (p = 0.05) was associated with poor gait function. This study characterized intracortical excitability in rehabilitating amputees. A dichotomous relationship between reduced intracortical inhibition for each M1 and gait function was observed at different times. Intracortical inhibition may be an appropriate cortical biomarker of gait function in lower limb amputees during rehabilitation, but requires further investigation. Understanding M1 intracortical excitability of amputees undertaking prosthetic rehabilitation provides insight into brain reorganization in the sub-acute post-amputation period and may guide future studies seeking to improve rehabilitation outcomes. PMID- 26042017 TI - Toward an understanding of motivational influences on prospective memory using value-added intentions. AB - This study examined value-added intentions by manipulating the cognitive frame associated with monetary contingencies for detecting prospective memory (PM) cues. We associated a loss-frame with a monetary punishment for failing to respond to cues and a gain-frame with a monetary reward for remembering to respond to cues and compared those frames to a no-frame control condition with no contingency linked to performance. Across two experiments, we find increased PM performance for participants in the loss-frame (Experiments 1 and 2) and in the gain-frame (Experiment 2) conditions relative to the no-frame condition. This value-related improvement in PM was not accompanied by a significant increase in cue monitoring as measured by intention-induced interference to an ongoing task and recognition memory for ongoing-task items. The few previous studies investigating motivational PM showed mixed results regarding whether PM improves due to incentives or not. Our results provide further evidence that, under some experimental conditions, PM improves with rewards and that the benefit generalizes to penalizing performance. The results have both practical implications and theoretical implications for motivation models of PM. PMID- 26042018 TI - Spatial stimulus-response compatibility and affordance effects are not ruled by the same mechanisms. AB - Stimulus position is coded even if it is task-irrelevant, leading to faster response times when the stimulus and the response locations are compatible (spatial Stimulus-Response Compatibility-spatial SRC). Faster responses are also found when the handle of a visual object and the response hand are located on the same side; this is known as affordance effect (AE). Two contrasting accounts for AE have been classically proposed. One is focused on the recruitment of appropriate grasping actions on the object handle, and the other on the asymmetry in the object shape, which in turn would cause a handle-hand correspondence effect (CE). In order to disentangle these two accounts, we investigated the possible transfer of practice in a spatial SRC task executed with a S-R incompatible mapping to a subsequent affordance task in which objects with either their intact handle or a broken one were used. The idea was that using objects with broken handles should prevent the recruitment of motor information relative to object grasping, whereas practice transfer should prevent object asymmetry in driving handle-hand CE. A total of three experiments were carried out. In Experiment 1 participants underwent an affordance task in which common graspable objects with their intact or broken handle were used. In Experiments 2 and 3, the affordance task was preceded by a spatial SRC task in which an incompatible S-R mapping was used. Inter-task delays of 5 or 30 min were employed to assess the duration of transfer effect. In Experiment 2 objects with their intact handle were presented, whereas in Experiment 3 the same objects had their handle broken. Although objects with intact and broken handles elicited a handle-hand CE in Experiment 1, practice transfer from an incompatible spatial SRC to the affordance task was found in Experiment 3 (broken-handle objects), but not in Experiment 2 (intact-handle objects). Overall, this pattern of results indicate that both object asymmetry and the activation of motor information contribute to the generation of the handle-hand CE effect, and that the handle AE cannot be reduced to a SRC effect. PMID- 26042019 TI - Anodal transcranial direct current stimulation to the cerebellum improves handwriting and cyclic drawing kinematics in focal hand dystonia. AB - There is increasing evidence that the cerebellum has a role in the pathophysiology of primary focal hand dystonia and might provide an intervention target for non-invasive brain stimulation to improve function of the affected hand. The primary objective of this study was to determine if cerebellar transcranial direct current stimulation (tDCS) improves handwriting and cyclic drawing kinematics in people with hand dystonia, by reducing cerebellar-brain inhibition (CBI) evoked by transcranial magnetic stimulation (TMS). Eight people with dystonia (5 writer's dystonia, 3 musician's dystonia) and eight age-matched controls completed the study and underwent cerebellar anodal, cathodal and sham tDCS in separate sessions. Dystonia severity was assessed using the Writer's Cramp Rating Scale (WRCS) and the Arm Dystonia Disability Scale (ADDS). The kinematic measures that differentiated the groups were; mean stroke frequency during handwriting and fast cyclic drawing and average pen pressure during light cyclic drawing. TMS measures of cortical excitability were no different between people with FHD and controls. There was a moderate, negative relationship between TMS-evoked CBI at baseline and the WRCS in dystonia. Anodal cerebellar tDCS reduced handwriting mean stroke frequency and average pen pressure, and increased speed and reduced pen pressure during fast cyclic drawing. Kinematic measures were not associated with a decrease in CBI within an individual. In conclusion, cerebellar anodal tDCS appeared to improve kinematics of handwriting and circle drawing tasks; but the underlying neurophysiological mechanism remains uncertain. A study in a larger homogeneous population is needed to further investigate the possible therapeutic benefit of cerebellar tDCS in dystonia. PMID- 26042021 TI - Measuring executive function in control subjects and TBI patients with question completion time (QCT). AB - Questionnaire completion is a complex task that places demands on cognitive functions subserving reading, introspective memory, decision-making, and motor control. Although computerized questionnaires and surveys are used with increasing frequency in clinical practice, few studies have examined question completion time (QCT), the time required to complete each question. Here, we analyzed QCTs in 172 control subjects and 31 patients with traumatic brain injury (TBI) who completed two computerized questionnaires, the 17-question Post Traumatic Stress Disorder (PTSD) Checklist (PCL) and the 25-question Cognitive Failures Questionnaire (CFQ). In control subjects, robust correlations were found between self-paced QCTs on the PCL and CFQ (r = 0.82). QCTs on individual questions correlated strongly with the number of words in the question, indicating the critical role of reading speed. QCTs increased significantly with age, and were reduced in females and in subjects with increased education and computer experience. QCT z-scores, corrected for age, education, computer use, and sex, correlated more strongly with each other than with the results of other cognitive tests. Patients with a history of severe TBI showed significantly delayed QCTs, but QCTs fell within the normal range in patients with a history of mild TBI. When questionnaires are used to gather relevant patient information, simultaneous QCT measures provide reliable and clinically sensitive measures of processing speed and executive function. PMID- 26042022 TI - Society, organizations and the brain: building toward a unified cognitive neuroscience perspective. PMID- 26042020 TI - A predictive nature for tactile awareness? Insights from damaged and intact central-nervous-system functioning. AB - In the present paper, we will attempt to gain hints regarding the nature of tactile awareness in humans. At first, we will review some recent literature showing that an actual tactile experience can emerge in absence of any tactile stimulus (e.g., tactile hallucinations, tactile illusions). According to the current model of tactile awareness, we will subsequently argue that such (false) tactile perceptions are subserved by the same anatomo-functional mechanisms known to underpin actual perception. On these bases, we will discuss the hypothesis that tactile awareness is strongly linked to expected rather than actual stimuli. Indeed, this hypothesis is in line with the notion that the human brain has a strong predictive, rather than reactive, nature. PMID- 26042023 TI - From beauty to knowledge: a new frame for the neuropsychological approach to aesthetics. PMID- 26042025 TI - Estimation of the synaptic input firing rates and characterization of the stimulation effects in an auditory neuron. AB - To understand information processing in neuronal circuits, it is important to infer how a sensory stimulus impacts on the synaptic input to a neuron. An increase in neuronal firing during the stimulation results from pure excitation or from a combination of excitation and inhibition. Here, we develop a method for estimating the rates of the excitatory and inhibitory synaptic inputs from a membrane voltage trace of a neuron. The method is based on a modified Ornstein Uhlenbeck neuronal model, which aims to describe the stimulation effects on the synaptic input. The method is tested using a single-compartment neuron model with a realistic description of synaptic inputs, and it is applied to an intracellular voltage trace recorded from an auditory neuron in vivo. We find that the excitatory and inhibitory inputs increase during stimulation, suggesting that the acoustic stimuli are encoded by a combination of excitation and inhibition. PMID- 26042024 TI - Triplet correlations among similarly tuned cells impact population coding. AB - Which statistical features of spiking activity matter for how stimuli are encoded in neural populations? A vast body of work has explored how firing rates in individual cells and correlations in the spikes of cell pairs impact coding. Recent experiments have shown evidence for the existence of higher-order spiking correlations, which describe simultaneous firing in triplets and larger ensembles of cells; however, little is known about their impact on encoded stimulus information. Here, we take a first step toward closing this gap. We vary triplet correlations in small (approximately 10 cell) neural populations while keeping single cell and pairwise statistics fixed at typically reported values. This connection with empirically observed lower-order statistics is important, as it places strong constraints on the level of triplet correlations that can occur. For each value of triplet correlations, we estimate the performance of the neural population on a two-stimulus discrimination task. We find that the allowed changes in the level of triplet correlations can significantly enhance coding, in particular if triplet correlations differ for the two stimuli. In this scenario, triplet correlations must be included in order to accurately quantify the functionality of neural populations. When both stimuli elicit similar triplet correlations, however, pairwise models provide relatively accurate descriptions of coding accuracy. We explain our findings geometrically via the skew that triplet correlations induce in population-wide distributions of neural responses. Finally, we calculate how many samples are necessary to accurately measure spiking correlations of this type, providing an estimate of the necessary recording times in future experiments. PMID- 26042026 TI - Pulvinar thalamic nucleus allows for asynchronous spike propagation through the cortex. AB - We create two multilayered feedforward networks composed of excitatory and inhibitory integrate-and-fire neurons in the balanced state to investigate the role of cortico-pulvino-cortical connections. The first network consists of ten feedforward levels where a Poisson spike train with varying firing rate is applied as an input in layer one. Although the balanced state partially avoids spike synchronization during the transmission, the average firing-rate in the last layer either decays or saturates depending on the feedforward pathway gain. The last layer activity is almost independent of the input even for a carefully chosen intermediate gain. Adding connections to the feedforward pathway by a nine areas Pulvinar structure improves the firing-rate propagation to become almost linear among layers. Incoming strong pulvinar spikes balance the low feedforward gain to have a unit input-output relation in the last layer. Pulvinar neurons evoke a bimodal activity depending on the magnitude input: synchronized spike bursts between 20 and 80 Hz and an asynchronous activity for very both low and high frequency inputs. In the first regime, spikes of last feedforward layer neurons are asynchronous with weak, low frequency, oscillations in the rate. Here, the uncorrelated incoming feedforward pathway washes out the synchronized thalamic bursts. In the second regime, spikes in the whole network are asynchronous. As the number of cortical layers increases, long-range pulvinar connections can link directly two or more cortical stages avoiding their either saturation or gradual activity falling. The Pulvinar acts as a shortcut that supplies the input-output firing-rate relationship of two separated cortical areas without changing the strength of connections in the feedforward pathway. PMID- 26042027 TI - Different AMPA receptor subtypes mediate the distinct kinetic components of a biphasic EPSC in hippocampal interneurons. AB - CA1 hippocampal interneurons at the border between stratum radiatum (SR) and stratum lacunosum-moleculare (SLM) have AMPA receptor (AMPAR)-mediated excitatory postsynaptic currents (EPSCs) that consist of two distinct phases: a typical fast component (FC), and a highly unusual slow component (SC) that persists for hundreds of milliseconds. To determine whether these kinetically distinct components of the EPSC are mediated by distinct AMPAR subpopulations, we examined the relative contributions of GluA2-containing and-lacking AMPARs to the SC. GluA2-containing AMPARs mediated the majority of the FC whereas GluA2-lacking AMPARs preferentially generated the SC. When glutamate uptake through the glial glutamate transporter excitatory amino acid transporter (EAAT1) was inhibited, spill over-mediated AMPAR activation recruited an even slower third kinetic component that persisted for several seconds; however, this spillover-mediated current was mediated predominantly by GluA2-containing AMPARs and therefore was clearly distinct from the SC when uptake is intact. Thus, different AMPAR subpopulations that vary in GluA2 content mediate the distinct components of the AMPAR EPSC. The SC is developmentally downregulated in mice, declining after the second postnatal week. This downregulation affects both GluA2-containing and GluA2-lacking AMPARs mediating the SC, and is not accompanied by developmental changes in the GluA2 content of AMPARs underlying the FC. Thus, the downregulation of the SC appears to be independent of synaptic GluA2 expression, suggesting the involvement of another AMPAR subunit or an auxiliary protein. Our results therefore identify GluA2-dependent and GluA2-independent determinants of the SC: GluA2-lacking AMPARs preferentially contribute to the SC, while the developmental downregulation of the SC is independent of GluA2 content. PMID- 26042029 TI - Nanoparticle mediated drug delivery of rolipram to tyrosine kinase B positive cells in the inner ear with targeting peptides and agonistic antibodies. AB - AIM: Systemic pharmacotherapies have limitation due to blood-labyrinth barrier, so local delivery via the round window membrane opens a path for effective treatment. Multifunctional nanoparticle (NP)-mediated cell specific drug delivery may enhance efficacy and reduce side effects. Different NPs with ligands to target TrkB receptor were tested. Distribution, uptake mechanisms, trafficking, and bioefficacy of drug release of rolipram loaded NPs were evaluated. METHODS: We tested lipid based nanocapsules (LNCs), Quantum Dot, silica NPs with surface modification by peptides mimicking TrkB or TrkB activating antibodies. Bioefficacy of drug release was tested with rolipram loaded LNCs to prevent cisplatin-induced apoptosis. We established different cell culture models with SH SY-5Y and inner ear derived cell lines and used neonatal and adult mouse explants. Uptake and trafficking was evaluated with FACS and confocal as well as transmission electron microscopy. RESULTS: Plain NPs show some selectivity in uptake related to the in vitro system properties, carrier material, and NP size. Some peptide ligands provide enhanced targeted uptake to neuronal cells but failed to show this in cell cultures. Agonistic antibodies linked to silica NPs showed TrkB activation and enhanced binding to inner ear derived cells. Rolipram loaded LNCs proved as effective carriers to prevent cisplatin-induced apoptosis. DISCUSSION: Most NPs with targeting ligands showed limited effects to enhance uptake. NP aggregation and unspecific binding may change uptake mechanisms and impair endocytosis by an overload of NPs. This may affect survival signaling. NPs with antibodies activate survival signaling and show effective binding to TrkB positive cells but needs further optimization for specific internalization. Bioefficiacy of rolipram release confirms LNCs as encouraging vectors for drug delivery of lipophilic agents to the inner ear with ideal release characteristics independent of endocytosis. PMID- 26042028 TI - The emergence of Pax7-expressing muscle stem cells during vertebrate head muscle development. AB - Pax7 expressing muscle stem cells accompany all skeletal muscles in the body and in healthy individuals, efficiently repair muscle after injury. Currently, the in vitro manipulation and culture of these cells is still in its infancy, yet muscle stem cells may be the most promising route toward the therapy of muscle diseases such as muscular dystrophies. It is often overlooked that muscular dystrophies affect head and body skeletal muscle differently. Moreover, these muscles develop differently. Specifically, head muscle and its stem cells develop from the non somitic head mesoderm which also has cardiac competence. To which extent head muscle stem cells retain properties of the early head mesoderm and might even be able to switch between a skeletal muscle and cardiac fate is not known. This is due to the fact that the timing and mechanisms underlying head muscle stem cell development are still obscure. Consequently, it is not clear at which time point one should compare the properties of head mesodermal cells and head muscle stem cells. To shed light on this, we traced the emergence of head muscle stem cells in the key vertebrate models for myogenesis, chicken, mouse, frog and zebrafish, using Pax7 as key marker. Our study reveals a common theme of head muscle stem cell development that is quite different from the trunk. Unlike trunk muscle stem cells, head muscle stem cells do not have a previous history of Pax7 expression, instead Pax7 expression emerges de-novo. The cells develop late, and well after the head mesoderm has committed to myogenesis. We propose that this unique mechanism of muscle stem cell development is a legacy of the evolutionary history of the chordate head mesoderm. PMID- 26042030 TI - Effects of age on a real-world What-Where-When memory task. AB - Many cognitive abilities decline with aging, making it difficult to detect pathological changes against a background of natural changes in cognition. Most of the tests to assess cognitive decline are artificial tasks that have little resemblance to the problems faced by people in everyday life. This means both that people may have little practice doing such tasks (potentially contributing to the decline in performance) and that the tasks may not be good predictors of real-world cognitive problems. In this study, we test the performance of young people (18-25 years) and older people (60+-year-olds) on a novel, more ecologically valid test of episodic memory: the real-world What-Where-When (WWW) memory test. We also compare them on a battery of other cognitive tests, including working memory, psychomotor speed, executive function, and episodic memory. Older people show the expected age-related declines on the test battery. In the WWW memory task, older people were more likely to fail to remember any WWW combination than younger people were, although they did not significantly differ in their overall WWW score due to some older people performing as well as or better than most younger people. WWW memory performance was significantly predicted by other measures of episodic memory, such as the single-trial learning and long-term retention in the Rey Auditory Verbal Learning task and Combined Object Location Memory in the Object Relocation task. Self-reported memory complaints also predicted performance on the WWW task. These findings confirm that our real-world WWW memory task is a valid measure of episodic memory, with high ecological validity, which may be useful as a predictor of everyday memory abilities. The task will require a bit more development to improve its sensitivity to cognitive declines in aging and to potentially distinguish between mentally healthy older adults and those with early signs of cognitive pathologies. PMID- 26042031 TI - Efficacy of auditory training in elderly subjects. AB - Auditory training (AT) has been used for auditory rehabilitation in elderly individuals and is an effective tool for optimizing speech processing in this population. However, it is necessary to distinguish training-related improvements from placebo and test-retest effects. Thus, we investigated the efficacy of short term AT [acoustically controlled auditory training (ACAT)] in elderly subjects through behavioral measures and P300. Sixteen elderly individuals with auditory processing disorder (APD) received an initial evaluation (evaluation 1 - E1) consisting of behavioral and electrophysiological tests (P300 evoked by tone burst and speech sounds) to evaluate their auditory processing. The individuals were divided into two groups. The Active Control Group (n = 8) underwent placebo training. The Passive Control Group (n = 8) did not receive any intervention. After 12 weeks, the subjects were revaluated (evaluation 2 - E2). Then, all of the subjects underwent ACAT. Following another 12 weeks (eight training sessions), they underwent the final evaluation (evaluation 3 - E3). There was no significant difference between E1 and E2 in the behavioral test [F(9.6) = 0.06, p = 0.92, lambda de Wilks = 0.65)] or P300 [F(8.7) = 2.11, p = 0.17, lambda de Wilks = 0.29] (discarding the presence of placebo effects and test-retest). A significant improvement was observed between the pre- and post-ACAT conditions (E2 and E3) for all auditory skills according to the behavioral methods [F(4.27) = 0.18, p = 0.94, lambda de Wilks = 0.97]. However, the same result was not observed for P300 in any condition. There was no significant difference between P300 stimuli. The ACAT improved the behavioral performance of the elderly for all auditory skills and was an effective method for hearing rehabilitation. PMID- 26042032 TI - Corrigendum: Brain training with non-action video games enhances aspects of cognition in older adults: a randomized controlled trial. AB - [This corrects the article on p. 277 in vol. 6, PMID: 25352805.]. PMID- 26042033 TI - Comparative analysis of autophagy and tauopathy related markers in cerebral ischemia and Alzheimer's disease animal models. AB - Alzheimer's disease (AD) and cerebral ischemia (CI) are neuropathologies that are characterized by aggregates of tau protein, a hallmark of cognitive disorder and dementia. Protein accumulation can be induced by autophagic failure. Autophagy is a metabolic pathway involved in the homeostatic recycling of cellular components. However, the role of autophagy in those tauopathies remains unclear. In this study, we performed a comparative analysis to identify autophagy related markers in tauopathy generated by AD and CI during short-term, intermediate, and long term progression using the 3xTg-AD mouse model (aged 6,12, and 18 months) and the global CI 2-VO (2-Vessel Occlusion) rat model (1,15, and 30 days post-ischemia). Our findings confirmed neuronal loss and hyperphosphorylated tau aggregation in the somatosensory cortex (SS-Cx) of the 3xTg-AD mice in the late stage (aged 18 months), which was supported by a failure in autophagy. These results were in contrast to those obtained in the SS-Cx of the CI rats, in which we detected neuronal loss and tauopathy at 1 and 15 days post-ischemia, and this phenomenon was reversed at 30 days. We proposed that this phenomenon was associated with autophagy induction in the late stage, since the data showed a decrease in p-mTOR activity, an association of Beclin-1 and Vps34, a progressive reduction in PHF-1, an increase in LC3B puncta and autophago-lysosomes formation were observed. Furthermore, the survival pathways remained unaffected. Together, our comparative study suggest that autophagy could ameliorates tauopathy in CI but not in AD, suggesting a differential temporal approach to the induction of neuroprotection and the prevention of neurodegeneration. PMID- 26042034 TI - Detecting early egocentric and allocentric impairments deficits in Alzheimer's disease: an experimental study with virtual reality. AB - Several studies have pointed out that egocentric and allocentric spatial impairments are one of the earliest manifestations of Alzheimer's Disease (AD). It is less clear how a break in the continuous interaction between these two representations may be a crucial marker to detect patients who are at risk to develop dementia. The main objective of this study is to compare the performances of participants suffering from amnestic mild cognitive impairment (aMCI group), patients with AD (AD group) and a control group (CG), using a virtual reality (VR)-based procedure for assessing the abilities in encoding, storing and syncing different spatial representations. In the first task, participants were required to indicate on a real map the position of the object they had memorized, while in the second task they were invited to retrieve its position from an empty version of the same virtual room, starting from a different position. The entire procedure was repeated across three different trials, depending on the object location in the encoding phase. Our finding showed that aMCI patients performed significantly more poorly in the third trial of the first task, showing a deficit in the ability to encode and store an allocentric viewpoint independent representation. On the other hand, AD patients performed significantly more poorly when compared to the CG in the second task, indicating a specific impairment in storing an allocentric viewpoint independent representation and then syncing it with the allocentric viewpoint dependent representation. Furthermore, data suggested that these impairments are not a product of generalized cognitive decline or of general decay in spatial abilities, but instead may reflect a selective deficit in the spatial organization Overall, these findings provide an initial insight into the cognitive underpinnings of amnestic impairment in aMCI and AD patient exploiting the potentiality of VR. PMID- 26042035 TI - Uncertainties in pentose-phosphate pathway flux assessment underestimate its contribution to neuronal glucose consumption: relevance for neurodegeneration and aging. PMID- 26042036 TI - Brain metabolic stress and neuroinflammation at the basis of cognitive impairment in Alzheimer's disease. AB - Brain metabolic dysfunction is known to influence brain activity in several neurological disorders, including Alzheimer's disease (AD). In fact, deregulation of neuronal metabolism has been postulated to play a key role leading to the clinical outcomes observed in AD. Besides deficits in glucose utilization in AD patients, recent evidence has implicated neuroinflammation and endoplasmic reticulum (ER) stress as components of a novel form of brain metabolic stress that develop in AD and other neurological disorders. Here we review findings supporting this novel paradigm and further discuss how these mechanisms seem to participate in synapse and cognitive impairments that are germane to AD. These deleterious processes resemble pathways that act in peripheral tissues leading to insulin resistance and glucose intolerance, in an intriguing molecular connection linking AD to diabetes. The discovery of detailed mechanisms leading to neuronal metabolic stress may be a key step that will allow the understanding how cognitive impairment develops in AD, thereby offering new avenues for effective disease prevention and therapeutic targeting. PMID- 26042037 TI - The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: a randomized, controlled trial. AB - Cocoa supplementation has been associated with benefits to cardiovascular health. However, cocoa's effects on cognition are less clear. A randomized, placebo controlled, double-blind clinical trial (n = 40, age M = 24.13 years, SD = 4.47 years) was conducted to investigate the effects of both acute (same-day) and sub chronic (daily for four-weeks) 250 mg cocoa supplementation on mood and mental fatigue, cognitive performance and cardiovascular functioning in young, healthy adults. Assessment involved repeated 10-min cycles of the Cognitive Demand Battery (CDB) encompassing two serial subtraction tasks (Serial Threes and Sevens), a Rapid Visual Information Processing task, and a mental fatigue scale over the course of half an hour. The Swinburne University Computerized Cognitive Assessment Battery (SUCCAB) was also completed to evaluate cognition. Cardiovascular function included measuring both peripheral and central blood pressure and cerebral blood flow. At the acute time point, consumption of cocoa significantly improved self-reported mental fatigue and performance on the Serial Sevens task in cycle one of the CDB. No other significant effects were found. This trial was registered with the Australian and New Zealand Clinical Trial Registry (Trial ID: ACTRN12613000626763). Accessible via http://www.anzctr.org.au/TrialSearch.aspx?searchTxt=ACTRN12613000626763&ddlSearch Registered. PMID- 26041973 TI - Measurements of differential and double-differential Drell-Yan cross sections in proton-proton collisions at [Formula: see text][Formula: see text]. AB - Measurements of the differential and double-differential Drell-Yan cross sections in the dielectron and dimuon channels are presented. They are based on proton proton collision data at [Formula: see text] recorded with the CMS detector at the LHC and corresponding to an integrated luminosity of 19.7[Formula: see text]. The measured inclusive cross section in the [Formula: see text] peak region (60 120[Formula: see text]), obtained from the combination of the dielectron and dimuon channels, is [Formula: see text], where the statistical uncertainty is negligible. The differential cross section [Formula: see text] in the dilepton mass range 15-2000[Formula: see text] is measured and corrected to the full phase space. The double-differential cross section [Formula: see text] is also measured over the mass range 20 to 1500[Formula: see text] and absolute dilepton rapidity from 0 to 2.4. In addition, the ratios of the normalized differential cross sections measured at [Formula: see text] and 8[Formula: see text] are presented. These measurements are compared to the predictions of perturbative QCD at next-to leading and next-to-next-to-leading (NNLO) orders using various sets of parton distribution functions (PDFs). The results agree with the NNLO theoretical predictions computed with fewz 3.1 using the CT10 NNLO and NNPDF2.1 NNLO PDFs. The measured double-differential cross section and ratio of normalized differential cross sections are sufficiently precise to constrain the proton PDFs. PMID- 26042038 TI - Health economic modeling to assess short-term costs of maternal overweight, gestational diabetes, and related macrosomia - a pilot evaluation. AB - BACKGROUND: Despite the interest in the impact of overweight and obesity on public health, little is known about the social and economic impact of being born large for gestational age or macrosomic. Both conditions are related to maternal obesity and/or gestational diabetes mellitus (GDM) and associated with increased morbidity for mother and child in the perinatal period. Poorly controlled diabetes during pregnancy, pre- pregnancy maternal obesity and/or excessive maternal weight gain during pregnancy are associated with intermittent periods of fetal exposure to hyperglycemia and subsequent hyperinsulinemia, leading to increased birth weight (e.g., macrosomia), body adiposity, and glycogen storage in the liver. Macrosomia is associated with an increased risk of developing obesity and type 2 diabetes mellitus later in life. OBJECTIVE: Provide insight in the short-term health-economic impact of maternal overweight, GDM, and related macrosomia. To this end, a health economic framework was designed. This pilot study also aims to encourage further health technology assessments, based on country- and population-specific data. RESULTS: The estimation of the direct health-economic burden of maternal overweight, GDM and related macrosomia indicates that associated healthcare expenditures are substantial. The calculation of a budget impact of GDM, based on a conservative approach of our model, using USA costing data, indicates an annual cost of more than $1,8 billion without taking into account long-term consequences. CONCLUSION: Although overweight and obesity are a recognized concern worldwide, less attention has been given to the health economic consequences of these conditions in women of child-bearing age and their offspring. The presented outcomes underline the need for preventive management strategies and public health interventions on life style, diet and physical activity. Also, the predisposition in people of Asian ethnicity to develop diabetes emphasizes the urgent need to collect more country specific data on the incidence of macrosomic births and health outcomes. In addition, it would be of interest to further explore the long-term health economic consequences of macrosomia and related risk factors. PMID- 26042039 TI - On the multiple roles of the voltage gated sodium channel beta1 subunit in genetic diseases. AB - Voltage-gated sodium channels are intrinsic plasma membrane proteins that initiate the action potential in electrically excitable cells. They are composed of a pore-forming alpha-subunit and associated beta-subunits. The beta1-subunit was the first accessory subunit to be cloned. It can be important for controlling cell excitability and modulating multiple aspects of sodium channel physiology. Mutations of beta1 are implicated in a wide variety of inherited pathologies, including epilepsy and cardiac conduction diseases. This review summarizes beta1 subunit related channelopathies pointing out the current knowledge concerning their genetic background and their underlying molecular mechanisms. PMID- 26042043 TI - The role of markup for enabling interoperability in health informatics. AB - Interoperability is the faculty of making information systems work together. In this paper we will distinguish a number of different forms that interoperability can take and show how they are realized on a variety of physiological and health care use cases. The last 15 years has seen the rise of very cheap digital storage both on and off site. With the advent of the Internet of Things people's expectations are for greater interconnectivity and seamless interoperability. The potential impact these technologies have on healthcare are dramatic: from improved diagnoses through immediate access to a patient's electronic health record, to in silico modeling of organs and early stage drug trials, to predictive medicine based on top-down modeling of disease progression and treatment. We will begin by looking at the underlying technology, classify the various kinds of interoperability that exist in the field, and discuss how they are realized. We conclude with a discussion on future possibilities that big data and further standardizations will enable. PMID- 26042045 TI - Hepatocellular carcinoma: from hepatocyte to liver cancer stem cell. PMID- 26042041 TI - Flow cytometry and K-mer analysis estimates of the genome sizes of Bemisia tabaci B and Q (Hemiptera: Aleyrodidae). AB - The genome sizes of the B- and Q-types of the whitefly Bemisia tabaci (Gennnadius) were estimated using flow cytometry (Drosophila melanogaster as the DNA reference standard and propidium iodide (PI) as the fluorochrome) and k-mer analysis. For flow cytometry, the mean nuclear DNA content was 0.686 pg for B type males, 1.392 pg for B-type females, 0.680 pg for Q-type males, and 1.306 pg for Q-type females. Based on the relationship between DNA content and genome size (1 pg DNA = 980 Mbp), the haploid genome size of B. tabaci ranged from 640 to 682 Mbp. For k-mer analysis, genome size of B-type by two methods were consistent highly, but the k-mer depth distribution graph of Q-type was not enough perfect and the genome size was estimated about 60 M larger than its flow cytometry result. These results corroborate previous reports of genome size based on karyotype analysis and chromosome counting. However, these estimates differ from previous flow cytometry estimates, probably because of differences in the DNA reference standard and dyeing time, which were superior in the current study. For Q-type genome size difference by two method, some discussion were also stated, and all these results represent a useful foundation for B. tabaci genomics research. PMID- 26042044 TI - Selectivity filters and cysteine-rich extracellular loops in voltage-gated sodium, calcium, and NALCN channels. AB - How nature discriminates sodium from calcium ions in eukaryotic channels has been difficult to resolve because they contain four homologous, but markedly different repeat domains. We glean clues from analyzing the changing pore region in sodium, calcium and NALCN channels, from single-cell eukaryotes to mammals. Alternative splicing in invertebrate homologs provides insights into different structural features underlying calcium and sodium selectivity. NALCN generates alternative ion selectivity with splicing that changes the high field strength (HFS) site at the narrowest level of the hourglass shaped pore where the selectivity filter is located. Alternative splicing creates NALCN isoforms, in which the HFS site has a ring of glutamates contributed by all four repeat domains (EEEE), or three glutamates and a lysine residue in the third (EEKE) or second (EKEE) position. Alternative splicing provides sodium and/or calcium selectivity in T-type channels with extracellular loops between S5 and P-helices (S5P) of different lengths that contain three or five cysteines. All eukaryotic channels have a set of eight core cysteines in extracellular regions, but the T-type channels have an infusion of 4-12 extra cysteines in extracellular regions. The pattern of conservation suggests a possible pairing of long loops in Domains I and III, which are bridged with core cysteines in NALCN, Cav, and Nav channels, and pairing of shorter loops in Domains II and IV in T-type channel through disulfide bonds involving T-type specific cysteines. Extracellular turrets of increasing lengths in potassium channels (Kir2.2, hERG, and K2P1) contribute to a changing landscape above the pore selectivity filter that can limit drug access and serve as an ion pre-filter before ions reach the pore selectivity filter below. Pairing of extended loops likely contributes to the large extracellular appendage as seen in single particle electron cryo-microscopy images of the eel Nav1 channel. PMID- 26042046 TI - Bacterial symbionts, Buchnera, and starvation on wing dimorphism in English grain aphid, Sitobion avenae (F.) (Homoptera: Aphididae). AB - Wing dimorphism in aphids can be affected by multiple cues, including both biotic (nutrition, crowding, interspecific interactions, the presence of natural enemies, maternal and transgenerational effects, and alarm pheromone) and abiotic factors (temperature, humidity, and photoperiod). The majority of the phloem feeding aphids carry Buchnera, an obligate symbiotic proteobacteria. Buchnera has a highly reduced genome size, but encode key enzymes in the tryptophan biosynthetic pathway and is crucial for nutritional balance, development and reproduction in aphids. In this study, we investigated the impact of two nutritional-based biotic factors, symbionts and starvation, on the wing dimorphism in the English grain aphid, Sitobion avenae, a devastating insect pest of cereal crops (e.g., wheat) worldwide. Elimination of Buchnera using the antibiotic rifampicin significantly reduced the formation of winged morphs, body mass, and fecundity in S. avenae. Furthermore, the absence of this primary endosymbiont may disrupt the nutrient acquisition in aphids and alter transgenerational phenotypic expression. Similarly, both survival rate and the formation of winged morphs were substantially reduced after neonatal (<24 h old) offspring were starved for a period of time. The combined results shed light on the impact of two nutritional-based biotic factors on the phenotypic plasticity in aphids. A better understanding of the wing dimorphism in aphids will provide the theoretical basis for the prediction and integrated management of these phloem-feeding insect pests. PMID- 26042042 TI - Abnormalities associated with progressive aortic vascular dysfunction in chronic kidney disease. AB - Increased stiffness of large arteries in chronic kidney disease (CKD) has significant clinical implications. This study investigates the temporal development of thoracic aortic dysfunction in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Animals aged 12 and 18 weeks were studied alongside age-matched Lewis controls (total n = 94). LPK rodents had elevated systolic blood pressure, left ventricular hypertrophy and progressively higher plasma creatinine and urea. Relative to Lewis controls, LPK exhibited reduced maximum aortic vasoconstriction (Rmax) to noradrenaline at 12 and 18 weeks, and to K(+) (12 weeks). Sensitivity to noradrenaline was greater in 18-week-old LPK vs. age matched Lewis (effective concentration 50%: 24 * 10(-9) +/- 78 * 10(-10) vs. 19 * 10(-8) +/- 49 * 10(-9), P < 0.05). Endothelium-dependent (acetylcholine) and independent (sodium nitroprusside) relaxation was diminished in LPK, declining with age (12 vs. 18 weeks Rmax: 80 +/- 8% vs. 57 +/- 9% and 92 +/- 6% vs. 70 +/- 9%, P < 0.05, respectively) in parallel with the decline in renal function. L Arginine restored endothelial function in LPK, and L-NAME blunted acetylcholine relaxation in all groups. Impaired nitric oxide synthase (NOS) activity was recovered with L-Arginine plus L-NAME in 12, but not 18-week-old LPK. Aortic calcification was increased in LPK rats, as was collagen I/III, fibronectin and NADPH-oxidase subunit p47 (phox) mRNAs. Overall, our observations indicate that the vascular abnormalities associated with CKD are progressive in nature, being characterized by impaired vascular contraction and relaxation responses, concurrent with the development of endothelial dysfunction, which is likely driven by evolving deficits in NO signaling. PMID- 26042040 TI - Novel perspectives on the PHD-HIF oxygen sensing pathway in cardioprotection mediated by IPC and RIPC. AB - Reperfusion of ischemic cardiac tissue is the standard treatment for improving clinical outcome following myocardial infarction but is inevitably associated with ischemia-reperfusion injury (IRI). Ischemic myocardial injury can be alleviated by exposing the heart to brief episodes of sublethal ischemia reperfusion prior to the ischemic insult, a phenomenon that has been termed ischemic preconditioning (IPC). Similarly, remote IPC (RIPC) is defined as transient episodes of ischemia at a distant site before a subsequent prolonged injury of the target organ. In this setting, adaptive responses to hypoxia/ischemia in peripheral tissues include the release of soluble factors that have the potential to protect cardiomyocytes remotely. Oxygen fluctuations is a hallmark of insufficient tissue perfusion and ischemic episodes. Emerging evidence indicates that prolyl hydroxylase oxygen sensors (PHDs) and hypoxia inducible transcription factors (HIFs) are critical regulators of IPC and RIPC. In this review, we discuss recent findings concerning the role of the PHD-HIF axis in IPC and RIPC-mediated cardioprotection and examine molecular pathways and cell types that might be involved. We also appraise the therapeutic value of targeting the PHD-HIF axis to enhance cardiac tolerance against IRI. PMID- 26042047 TI - Muscular contraction mode differently affects autonomic control during heart rate matched exercise. AB - The precise contributions of afferent feedback to cardiovascular and respiratory responses to exercise are still unclear. The aim of this crossover study was to assess whether and how autonomic cardiovascular and respiratory control differed in response to dynamic (DYN) and isometric contractions (ISO) at a similar, low heart rate (HR) level. Therefore, 22 healthy males (26.7 +/- 3.6 yrs) performed two kinds of voluntary exercises at similar HR: ISO and DYN of the right quadriceps femoris muscle. Although HR was eqivalent (82 +/- 8 bpm for DYN and ISO, respectively), rating of exertion, blood pressures, and rate pressure product were higher, whereas breathing frequency, minute ventilation, oxygen uptake and carbon dioxide output were significantly lower during ISO. Tidal volume, end-tidal partial pressures of O2 and CO2, respiratory exchange ratio and capillary blood lactate concentration were comparable between both contraction modes. Heart rate variability (HRV) indicators, SDNN, HF-Power and LF-Power, representing both vagal and sympathetic influences, were significantly higher during ISO. Sample entropy, a non-linear measure of HRV was also significantly affected by contraction mode. It can be concluded that, despite the same net effect on HR, the quality of cardiovascular control during low intensity exercise is significantly different between DYN and ISO. HRV analysis indicated a sympatho vagal coactivation during ISO. Whether mechanoreceptor feedback alone, a change in central command, or the interaction of both mechanisms is the main contributor of the distinct autonomic responses to the different exercise modes remains to be elucidated. PMID- 26042048 TI - Mutations associated with Dent's disease affect gating and voltage dependence of the human anion/proton exchanger ClC-5. AB - Dent's disease is associated with impaired renal endocytosis and endosomal acidification. It is linked to mutations in the membrane chloride/proton exchanger ClC-5; however, a direct link between localization in the protein and functional phenotype of the mutants has not been established until now. Here, two Dent's disease mutations, G212A and E267A, were investigated using heterologous expression in HEK293T cells, patch-clamp measurements and confocal imaging. WT and mutant ClC-5 exhibited mixed cell membrane and vesicular distribution. Reduced ion currents were measured for both mutants and both exhibited reduced capability to support endosomal acidification. Functionally, mutation G212A was capable of mediating anion/proton antiport but dramatically shifted the activation of ClC-5 toward more depolarized potentials. The shift can be explained by impeded movements of the neighboring gating glutamate Gluext, a residue that confers major part of the voltage dependence of ClC-5 and serves as a gate at the extracellular entrance of the anion transport pathway. Cell surface abundance of E267A was reduced by ~50% but also dramatically increased gating currents were detected for this mutant and accordingly reduced probability to undergoing cycles associated with electrogenic ion transport. Structurally, the gating alternations correlate to the proximity of E267A to the proton glutamate Gluin that serves as intracellular gate in the proton transport pathway and regulates the open probability of ClC-5. Remarkably, two other mammalian isoforms, ClC-3 and ClC-4, also differ from ClC-5 in gating characteristics affected by the here investigated disease-causing mutations. This evolutionary specialization, together with the functional defects arising from mutations G212A and E267A, demonstrate that the complex gating behavior exhibited by most of the mammalian CLC transporters is an important determinant of their cellular function. PMID- 26042049 TI - The lowering effect of Gum Arabic on hyperlipidemia in Sudanese patients. AB - Hyperlipidemia especially low density lipoprotein cholesterol (LDL-C) is a major risk factor for developing ischemic heart disease. Soluble dietary fiber has lipid lowering characteristics. Gum Arabic (GA) is 95% soluble fiber calculated on dry bases. The beneficial effect of GA on lipid profile needs further verification. A case-control study was conducted at Omdurman Hospital, Sudan to assess the effect of G A on serum lipids in patients with hyperlipidemia. Cases received a 20 mg tablet of atorvastatin /day plus 30 mg of GA for 4 weeks while the controls received atorvastatin only. Levels of lipids in serum were assessed according to conventional methods before and 1 month after the trial. There is no significant difference in the basic characteristics between the study and the control groups (55 patients in each arm of the study). While there was no significant difference in the levels of HDL, there was a significant reduction of the total cholesterol (25.9 vs. 7.8%, P < 0.001), triglyceride (38.2 vs. 2.9%, P < 0.001), and LDL (30.8 vs. 8.1%, P < 0.001) before and after the intervention in the study compared to the controls groups. PMID- 26042050 TI - Muscle cell derived angiopoietin-1 contributes to both myogenesis and angiogenesis in the ischemic environment. AB - Recent strategies to treat peripheral arterial disease (PAD) have focused on stem cell based therapies, which are believed to result in local secretion of vascular growth factors. Little is known, however, about the role of ischemic endogenous cells in this context. We hypothesized that ischemic muscle cells (MC) are capable of secreting growth factors that act as potent effectors of the local cellular regenerative environment. Both muscle and endothelial cells (ECs) were subjected to experimental ischemia, and conditioned medium (CM) from each was collected and analyzed to assess myogenic and/or angiogenic potential. In muscle progenitors, mRNA expression of VEGF and its cognate receptors (Nrp1, Flt, Flk) was present and decreased during myotube formation in vitro, and EC CM or VEGF increased myoblast proliferation. Angiopoietin-1 (Ang-1), Tie1, and Tie2 mRNA increased during MC differentiation in vitro. Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. Myotube formation was enhanced by MC CM and inhibited by EC CM. Ang-1 protein was present in CM from MCs isolated from both the genetically ischemia-susceptible BALB/c and ischemia-resistant C57BL/6 mouse strains, and chimeric Tie2 receptor trapping in situ ablated Ang-1's myogenic effects in vitro. Ang-1 or MC CM enhanced myotube formation in a mixed isolate of muscle progenitors as well as a myoblast co-culture with pluripotent mesenchymal cells (10T1/2) and this effect was abrogated by viral expression of the extracellular domain of Tie2 (AdsTie2). Furthermore, mesh/tube formation by HUVECs was enhanced by Ang-1 or MC CM and abrogated by Tie2 chimeric receptor trapping. Our results demonstrate the ability of muscle and endothelial cell-derived vascular growth factors, particularly Ang-1, to serve as multi-functional stimuli regulating crosstalk between blood vessels and muscle cells during regeneration from ischemic myopathy. PMID- 26042051 TI - Air pollution and adverse cardiac remodeling: clinical effects and basic mechanisms. AB - Exposure to air pollution has long been known to trigger cardiovascular events, primarily through activation of local and systemic inflammatory pathways that affect the vasculature. Detrimental effects of air pollution exposure on heart failure and cardiac remodeling have also been described in human populations. Recent studies in both human subjects and animal models have provided insights into the basic physiological, cellular and molecular mechanisms that play a role in adverse cardiac remodeling. This review will give a brief overview of the relationship between air pollution and cardiovascular disease, describe the clinical effects of air pollution exposure on cardiac remodeling, describe the basic mechanisms that affect remodeling as described in human and animal systems and will discuss future areas of investigation. PMID- 26042053 TI - Project Stakeholder Management in the Clinical Research Environment: How to Do it Right. AB - This review introduces a conceptual framework for understanding stakeholder management (ShM) in the clinical and community-based research environment. In recent years, an evolution in practice has occurred in many applicants for public and non-governmental funding of public health research in hospital settings. Community health research projects are inherently complex, have sought to involve patients and other stakeholders in the center of the research process. Substantial evidence has now been provided that stakeholder involvement is essential for management effectiveness in clinical research. Feedback from stakeholders has critical value for research managers inasmuch as it alerts them to the social, environmental, and ethical implications of research activities. Additionally, those who are directly affected by program development and clinical research, the patients, their families, and others, almost universally have a strong motivation to be involved in the planning and execution of new program changes. The current overview introduces a conceptual framework for ShM in the clinical research environment and offers practical suggestions for fostering meaningful stakeholder engagement. The fifth edition of PMBOK((r)) of the Project Management Institute, has served as basis for many of the suggested guidelines that are put forward in this article. PMID- 26042052 TI - Arterial dilator function in athletes: present and future perspectives. PMID- 26042054 TI - Brain connectivity and prediction of relapse after cognitive-behavioral therapy in obsessive-compulsive disorder. AB - BACKGROUND: Intensive cognitive-behavioral therapy (CBT) can effectively reduce symptoms in obsessive-compulsive disorder (OCD). However, many relapse after treatment. Few studies have investigated biological markers predictive of follow up clinical status. The objective was to determine if brain network connectivity patterns prior to intensive CBT predict worsening of clinical symptoms during follow-up. METHODS: We acquired resting-state functional magnetic resonance imaging data from 17 adults with OCD prior to and following 4 weeks of intensive CBT. Functional connectivity data were analyzed to yield graph-theory metrics. We examined the relationship between pre-treatment connectome properties and OCD clinical symptoms before and after treatment and during a 12-month follow-up period. RESULTS: Mean OCD symptom decrease was 40.4 +/- 16.4% pre- to post treatment (64.7% responded; 58.8% remitted), but 35.3% experienced clinically significant worsening during follow-up. From pre- to post-treatment, small worldness and clustering coefficient significantly increased. Decreases in modularity correlated with decreases in OCD symptoms. Higher pre-treatment small world connectivity was significantly associated with worsening of OCD symptoms during the follow-up period. Psychometric and neurocognitive measures pre- and post-treatment were not significant predictors. CONCLUSION: This is the first graph-theory connectivity study of the effects of CBT in OCD, and the first to test associations with follow-up clinical status. Results show functional network efficiency as a biomarker of CBT response and relapse in OCD. CBT increases network efficiency as it alleviates symptoms in most patients, but those entering therapy with already high network efficiency are at greater risk of relapse. Results have potential clinical implications for treatment selection. PMID- 26042056 TI - Shape and spatial working memory capacities are mostly independent. AB - Whether visual working memory (WM) consists of a common storage resource or of multiple subsystems has been a controversial issue. Logie (1995) suggested that it can be divided into visual (for color, shape, objects, etc.) and spatial WM (for location). However, a recent study reported evidence against this hypothesis. Using a dual task paradigm, Wood (2011) showed interference between shape and spatial WM capacities, suggesting that they share a common resource limitation. We re-examined this finding controlling possible confounding factors, including the way to present spatial location cues, task order, and type of WM load to be manipulated. The same pattern of results was successfully reproduced, but only in a highly powered experiment (N = 90), and therefore the size of interference was estimated to be quite small (d = 0.24). Thus, these data offer a way to reconcile seemingly contradicting previous findings. On the one hand, some part of the storage system is genuinely shared by shape and spatial WM systems, confirming the report of Wood (2011). On the other hand, the amount of the overlap is only minimal, and therefore the two systems should be regarded as mostly independent from each other, supporting the classical visuo-spatial separation hypothesis. PMID- 26042055 TI - Perception of visual apparent motion is modulated by a gap within concurrent auditory glides, even when it is illusory. AB - Auditory and visual events often happen concurrently, and how they group together can have a strong effect on what is perceived. We investigated whether/how intra- or cross-modal temporal grouping influenced the perceptual decision of otherwise ambiguous visual apparent motion. To achieve this, we juxtaposed auditory gap transfer illusion with visual Ternus display. The Ternus display involves a multi element stimulus that can induce either of two different percepts of apparent motion: 'element motion' (EM) or 'group motion' (GM). In "EM," the endmost disk is seen as moving back and forth while the middle disk at the central position remains stationary; while in "GM," both disks appear to move laterally as a whole. The gap transfer illusion refers to the illusory subjective transfer of a short gap (around 100 ms) from the long glide to the short continuous glide when the two glides intercede at the temporal middle point. In our experiments, observers were required to make a perceptual discrimination of Ternus motion in the presence of concurrent auditory glides (with or without a gap inside). Results showed that a gap within a short glide imposed a remarkable effect on separating visual events, and led to a dominant perception of GM as well. The auditory configuration with gap transfer illusion triggered the same auditory capture effect. Further investigations showed that visual interval which coincided with the gap interval (50-230 ms) in the long glide was perceived to be shorter than that within both the short glide and the 'gap-transfer' auditory configurations in the same physical intervals (gaps). The results indicated that auditory temporal perceptual grouping takes priority over the cross-modal interaction in determining the final readout of the visual perception, and the mechanism of selective attention on auditory events also plays a role. PMID- 26042058 TI - Pseudoinefficacy: negative feelings from children who cannot be helped reduce warm glow for children who can be helped. AB - In a great many situations where we are asked to aid persons whose lives are endangered, we are not able to help everyone. What are the emotional and motivational consequences of "not helping all"? In a series of experiments, we demonstrate that negative affect arising from children that could not be helped decreases the warm glow of positive feeling associated with aiding the children who can be helped. This demotivation from the children outside of our reach may be a form of "pseudoinefficacy" that is non-rational. We should not be deterred from helping whomever we can because there are others we are not able to help. PMID- 26042057 TI - Effects of affective arousal on choice behavior, reward prediction errors, and feedback-related negativities in human reward-based decision making. AB - Emotional experience has a pervasive impact on choice behavior, yet the underlying mechanism remains unclear. Introducing facial-expression primes into a probabilistic learning task, we investigated how affective arousal regulates reward-related choice based on behavioral, model fitting, and feedback-related negativity (FRN) data. Sixty-six paid subjects were randomly assigned to the Neutral-Neutral (NN), Angry-Neutral (AN), and Happy-Neutral (HN) groups. A total of 960 trials were conducted. Subjects in each group were randomly exposed to half trials of the pre-determined emotional faces and another half of the neutral faces before choosing between two cards drawn from two decks with different assigned reward probabilities. Trial-by-trial data were fit with a standard reinforcement learning model using the Bayesian estimation approach. The temporal dynamics of brain activity were simultaneously recorded and analyzed using event related potentials. Our analyses revealed that subjects in the NN group gained more reward values than those in the other two groups; they also exhibited comparatively differential estimated model-parameter values for reward prediction errors. Computing the difference wave of FRNs in reward vs. non-reward trials, we found that, compared to the NN group, subjects in the AN and HN groups had larger "General" FRNs (i.e., FRNs in no-reward trials minus FRNs in reward trials) and "Expected" FRNs (i.e., FRNs in expected reward-omission trials minus FRNs in expected reward-delivery trials), indicating an interruption in predicting reward. Further, both AN and HN groups appeared to be more sensitive to negative outcomes than the NN group. Collectively, our study suggests that affective arousal negatively regulates reward-related choice, probably through overweighting with negative feedback. PMID- 26042059 TI - Is ambiguity tolerance malleable? Experimental evidence with potential implications for future research. AB - We conducted two research studies to address the malleability of tolerance of ambiguity (TA) by manipulating situational ambiguity. Students participated in a semester-end assessment of their management skills (n = 306). In Study 1, students in low and moderate ambiguity conditions had significantly higher post experiment TA, more positive change in self-efficacy, and marginally higher faculty ratings. In Study 2, a control group (n = 103) did not participate in the assessment and was established for comparison to the first study results. The Study 2 students reported TA significantly lower than Study 1 students in the low and moderate ambiguity conditions. The control group TA was not significantly different from that of the Study 1 high ambiguity condition. This further suggested TA's situational malleability, as those who had controlled access to structured information appeared to have increased their TA over that observed in the other two groups. These results suggest that TA may be malleable. We review the relevant literature, offer hypotheses, report our analyses and findings, and then propose future research, and potential prescriptive applications in such areas as management development, assessment, and decision-making. PMID- 26042060 TI - Flexible color perception depending on the shape and positioning of achromatic contours. AB - In this study, we present several demonstrations of color averaging between luminance boundaries. In each of the demonstrations, different black outlines are superimposed on one and the same colored surface. Whereas perception without these outlines comprises a blurry colored gradient, superimposing the outlines leads to a much clearer binary color percept, with different colors perceived on each side of the boundary. These demonstrations show that the color of the perceived surfaces is flexible, depending on the exact shape of the outlines that define the surface, and that different positioning of the outlines can lead to different, distinct color percepts. We argue that the principle of color averaging described here is crucial for the brain in building a useful model of the distal world, in which differences within object surfaces are perceptually minimized, while differences between surfaces are perceptually enhanced. PMID- 26042061 TI - Replication, falsification, and the crisis of confidence in social psychology. AB - The (latest) crisis in confidence in social psychology has generated much heated discussion about the importance of replication, including how it should be carried out as well as interpreted by scholars in the field. For example, what does it mean if a replication attempt "fails"-does it mean that the original results, or the theory that predicted them, have been falsified? And how should "failed" replications affect our belief in the validity of the original research? In this paper, we consider the replication debate from a historical and philosophical perspective, and provide a conceptual analysis of both replication and falsification as they pertain to this important discussion. Along the way, we highlight the importance of auxiliary assumptions (for both testing theories and attempting replications), and introduce a Bayesian framework for assessing "failed" replications in terms of how they should affect our confidence in original findings. PMID- 26042062 TI - The inability to self-evaluate smell performance. How the vividness of mental images outweighs awareness of olfactory performance. AB - To rate one's individual olfactory performance is difficult and in many cases differs clearly from validated objective olfactory performance measures. This study aimed to investigate the basis for this measurement drift between objective and subjective olfactory performance evaluation. In absence of an actual odor, one may imagine an olfactory stimulus to evaluate his subjective olfactory performance. Therefore, the impact of the vividness of mental images on self evaluation of smell performance in patients with mild to severe olfactory dysfunction and healthy controls was investigated. Fifty-nine patients with peripheral olfactory dysfunction ranging from reduced olfactory function (hyposmia) to complete loss of olfactory perception (anosmia) and 16 healthy controls were included. Olfactory performance was assessed using the Sniffin' Sticks battery, the vividness of olfactory mental images was evaluated using the vividness of olfactory imagery questionnaire (VOIQ). Decreased vividness of odor images was obtained for anosmic patients, and a trend of poorer odor imagery was determined in hyposmic patients. Multiple regression analyses revealed the VOIQ score as significant predictor for olfactory self-evaluation for hyposmic patients and healthy controls. In contrast, for anosmic patients, the only significant predictor for self-rating of olfactory performance was the threshold detection-identification (TDI) score, measuring overall olfactory performance. The results of this study indicate that sensory perception and mental images are closely related to each other. Furthermore, subjects who were able to perceive odors, even to a smaller extent, rely on the vividness of their mental odor images to evaluate their olfactory performance. In contrast, anosmic patients rather trust in their knowledge that they are not able to perceive odors. We are therefore able to subjectively rate our olfactory performance levels, if we are not able to perceive odors, but not if we are able to perceive olfactory input. PMID- 26042063 TI - Feeling right is feeling good: psychological well-being and emotional fit with culture in autonomy- versus relatedness-promoting situations. AB - The current research tested the idea that it is the cultural fit of emotions, rather than certain emotions per se, that predicts psychological well-being. We reasoned that emotional fit in the domains of life that afford the realization of central cultural mandates would be particularly important to psychological well being. We tested this hypothesis with samples from three cultural contexts that are known to differ with respect to their main cultural mandates: a European American (N = 30), a Korean (N = 80), and a Belgian sample (N = 266). Cultural fit was measured by comparing an individual's patterns of emotions to the average cultural pattern for the same type of situation on the Emotional Patterns Questionnaire (De Leersnyder et al., 2011). Consistent with our hypothesis, we found evidence for "universality without uniformity": in each sample, psychological well-being was associated with emotional fit in the domain that was key to the cultural mandate. However, cultures varied with regard to the particular domain involved. Psychological well-being was predicted by emotional fit (a) in autonomy-promoting situations at work in the U.S., (b) in relatedness promoting situations at home in Korea, and (c) in both autonomy-promoting and relatedness-promoting situations in Belgium. These findings show that the experience of culturally appropriate patterns of emotions contributes to psychological well-being. One interpretation is that experiencing appropriate emotions is itself a realization of the cultural mandates. PMID- 26042064 TI - Older adults report moderately more detailed autobiographical memories. AB - Autobiographical memory (AM) is an essential component of the human mind. Although the([A-z]+) amount and types of subjective detail (content) that compose AMs constitute important dimensions of recall, age-related changes in memory content are not well characterized. Previously, we introduced the Cue-Recalled Autobiographical Memory test (CRAM; see http://cramtest.info), an instrument that collects subjective reports of AM content, and applied it to college-aged subjects. CRAM elicits AMs using naturalistic word-cues. Subsequently, subjects date each cued AM to a life period and count the number of remembered details from specified categories (features), e.g., temporal detail, spatial detail, persons, objects, and emotions. The current work applies CRAM to a broad range of individuals (18-78 years old) to quantify the effects of age on AM content. Subject age showed a moderately positive effect on AM content: older compared with younger adults reported ~16% more details (~25 vs. ~21 in typical AMs). This age-related increase in memory content was similarly observed for remote and recent AMs, although content declined with the age of the event among all subjects. In general, the distribution of details across features was largely consistent among younger and older adults. However, certain types of details, i.e., those related to objects and sequences of events, contributed more to the age effect on content. Altogether, this work identifies a moderate age-related feature-specific alteration in the way life events are subjectively recalled, among an otherwise stable retrieval profile. PMID- 26042065 TI - Legitimate vs. illegitimate restrictions - a motivational and physiological approach investigating reactance processes. AB - Threats to our freedom are part of our daily social interactions. They are accompanied by an aversive state of motivational arousal, called reactance, which leads people to strive to reestablish their threatened freedom. This is especially the case if the threat seems to be illegitimate in nature. However, reactance theory suggests that reactance should also be aroused when people are exposed to legitimate freedom threats. In this article we first aim to show that both illegitimate and legitimate freedom threats evoke reactance. Second, we aim to extend past work on reactance by exploring the underlying process of experiencing a legitimate vs. an illegitimate restriction. In the current study (N= 57) participants were restricted in an illegitimate (unexpected and inappropriate) or legitimate (unexpected but appropriate) way, or were not restricted at all. We assessed participants' experience of reactance, their behavioral intentions to restore their freedom, their approach motivational states, as well as their physiological arousal (heart rate). Results indicated that when restricted in an illegitimate or a legitimate way, participants indicated the same amount of reactance as well as anger. However, when looking at people's physiological reactions, important differences between illegitimate and legitimate restrictions become apparent. Illegitimate restrictions led to an immediate arousal, whereas legitimate restrictions led to a time delayed arousal. This suggests that illegitimate restrictions lead to a sudden increase in aversive arousal. Legitimate restrictions, however, seem to be associated with a more cognitive process in which people first need to structure their thoughts and reflect upon the situation before getting into the feeling of reactance in a physiologically arousing sense. Moreover a mediation analysis could show that behavioral intentions to regain one's freedom result in positive and negative approach motivation. In sum we propose a combined dual-process and intertwined process model explaining people's reactions to legitimate vs. illegitimate restrictions. PMID- 26042066 TI - A truly human interface: interacting face-to-face with someone whose words are determined by a computer program. AB - We use speech shadowing to create situations wherein people converse in person with a human whose words are determined by a conversational agent computer program. Speech shadowing involves a person (the shadower) repeating vocal stimuli originating from a separate communication source in real-time. Humans shadowing for conversational agent sources (e.g., chat bots) become hybrid agents ("echoborgs") capable of face-to-face interlocution. We report three studies that investigated people's experiences interacting with echoborgs and the extent to which echoborgs pass as autonomous humans. First, participants in a Turing Test spoke with a chat bot via either a text interface or an echoborg. Human shadowing did not improve the chat bot's chance of passing but did increase interrogators' ratings of how human-like the chat bot seemed. In our second study, participants had to decide whether their interlocutor produced words generated by a chat bot or simply pretended to be one. Compared to those who engaged a text interface, participants who engaged an echoborg were more likely to perceive their interlocutor as pretending to be a chat bot. In our third study, participants were naive to the fact that their interlocutor produced words generated by a chat bot. Unlike those who engaged a text interface, the vast majority of participants who engaged an echoborg did not sense a robotic interaction. These findings have implications for android science, the Turing Test paradigm, and human-computer interaction. The human body, as the delivery mechanism of communication, fundamentally alters the social psychological dynamics of interactions with machine intelligence. PMID- 26042067 TI - Antecedents of teachers' emotions in the classroom: an intraindividual approach. AB - Using a preexisting, but as yet empirically untested theoretical model, the present study investigated antecedents of teachers' emotions in the classroom. More specifically, the relationships between students' motivation and discipline and teachers' enjoyment and anger were explored, as well as if these relationships are mediated by teachers' subjective appraisals (goal conduciveness and coping potential). The study employed an intraindividual approach by collecting data through a diary. The sample consisted of 39 teachers who each participated with one of their 9th or 10th grade mathematics classes (N = 758 students). Both teachers and students filled out diaries for 2-3 weeks pertaining to 8.10 lessons on average (N = 316 lessons). Multilevel structural equation modeling revealed that students' motivation and discipline explained 24% of variance in teachers' enjoyment and 26% of variance in teachers' anger. In line with theoretical assumptions, after introducing teachers' subjective appraisals as a mediating mechanism into the model, the explained variance systematically increased to 65 and 61%, for teachers' enjoyment and anger respectively. The effects of students' motivation and discipline level on teachers' emotions were partially mediated by teachers' appraisals of goal conduciveness and coping potential. The findings imply that since teachers' emotions depend to a large extent on subjective evaluations of a situation, teachers should be able to directly modify their emotional experiences during a lesson through cognitive reappraisals. PMID- 26042068 TI - A critical review and meta-analysis of the unconscious thought effect in medical decision making. AB - Based on research on the increasingly popular unconscious thought effect (UTE), it has been suggested that physicians might make better diagnostic decisions after a period of distraction than after an equivalent amount of time of conscious deliberation. However, published attempts to demonstrate the UTE in medical decision making have yielded inconsistent results. In the present study, we report the results of a meta-analysis of all the available evidence on the UTE in medical decisions made by expert and novice clinicians. The meta-analysis failed to find a significant contribution of unconscious thought (UT) to the accuracy of medical decisions. This result cannot be easily attributed to any of the potential moderators of the UTE that have been discussed in the literature. Furthermore, a Bayes factor analysis shows that most experimental conditions provide positive support for the null hypothesis, suggesting that these null results do not reflect a simple lack of statistical power. We suggest ways in which new studies could usefully provide further evidence on the UTE. Unless future research shows otherwise, the recommendation of using UT to improve medical decisions lacks empirical support. PMID- 26042069 TI - The wheelchair as a full-body tool extending the peripersonal space. AB - Dedicated multisensory mechanisms in the brain represent peripersonal space (PPS), a limited portion of space immediately surrounding the body. Previous studies have illustrated the malleability of PPS representation through hand object interaction, showing that tool use extends the limits of the hand-centered PPS. In the present study we investigated the effects of a special tool, the wheelchair, in extending the action possibilities of the whole body. We used a behavioral measure to quantify the extension of the PPS around the body before and after Active (Experiment 1) and Passive (Experiment 2) training with a wheelchair and when participants were blindfolded (Experiment 3). Results suggest that a wheelchair-mediated passive exploration of far space extended PPS representation. This effect was specifically related to the possibility of receiving information from the environment through vision, since no extension effect was found when participants were blindfolded. Surprisingly, the active motor training did not induce any modification in PPS representation, probably because the wheelchair maneuver was demanding for non-expert users and thus they may have prioritized processing of information from close to the wheelchair rather than at far spatial locations. Our results suggest that plasticity in PPS representation after tool use seems not to strictly depend on active use of the tool itself, but is triggered by simultaneous processing of information from the body and the space where the body acts in the environment, which is more extended in the case of wheelchair use. These results contribute to our understanding of the mechanisms underlying body-environment interaction for developing and improving applications of assistive technological devices in different clinical populations. PMID- 26042071 TI - Assessment of a model for achieving competency in administration and scoring of the WAIS-IV in post-graduate psychology students. AB - There is a need for an evidence-based approach to training professional psychologists in the administration and scoring of standardized tests such as the Wechsler Adult Intelligence Scale (WAIS) due to substantial evidence that these tasks are associated with numerous errors that have the potential to significantly impact clients' lives. Twenty three post-graduate psychology students underwent training in using the WAIS-IV according to a best-practice teaching model that involved didactic teaching, independent study of the test manual, and in-class practice with teacher supervision and feedback. Video recordings and test protocols from a role-played test administration were analyzed for errors according to a comprehensive checklist with self, peer, and faculty member reviews. 91.3% of students were rated as having demonstrated competency in administration and scoring. All students were found to make errors, with substantially more errors being detected by the faculty member than by self or peers. Across all subtests, the most frequent errors related to failure to deliver standardized instructions verbatim from the manual. The failure of peer and self-reviews to detect the majority of the errors suggests that novice feedback (self or peers) may be ineffective to eliminate errors and the use of more senior peers may be preferable. It is suggested that involving senior trainees, recent graduates and/or experienced practitioners in the training of post-graduate students may have benefits for both parties, promoting a peer learning and continuous professional development approach to the development and maintenance of skills in psychological assessment. PMID- 26042072 TI - Young children's learning of relational categories: multiple comparisons and their cognitive constraints. AB - Relational categories are notoriously difficult to learn because they are not defined by intrinsic stable properties. We studied the impact of comparisons on relational concept learning with a novel word learning task in 42-month-old children. Capitalizing on Gentner et al. (2011), two, three or four pairs of stimuli were introduced with a novel relational word. In a given trial, the set of pairs was composed of either close or far pairs (e.g., close pair: knife1 watermelon, knife2-orange, knife3-slice of bread and knife4-meat; far pair: ax evergreen tree, saw-log, cutter-cardboard, and knife-slice of bread, for the "cutter for" relation). Close pairs (2 vs. 3 vs. 4 pairs) led to random generalizations whereas comparisons with far pairs gave the expected relational generalization. The 3 pair case gave the best results. It is argued that far pairs promote deeper comparisons than close pairs. As shown by a control experiment, this was the case only when far pairs display well known associations. PMID- 26042070 TI - Effective connectivity of visual word recognition and homophone orthographic errors. AB - The study of orthographic errors in a transparent language like Spanish is an important topic in relation to writing acquisition. The development of neuroimaging techniques, particularly functional magnetic resonance imaging (fMRI), has enabled the study of such relationships between brain areas. The main objective of the present study was to explore the patterns of effective connectivity by processing pseudohomophone orthographic errors among subjects with high and low spelling skills. Two groups of 12 Mexican subjects each, matched by age, were formed based on their results in a series of ad hoc spelling related out-scanner tests: a high spelling skills (HSSs) group and a low spelling skills (LSSs) group. During the f MRI session, two experimental tasks were applied (spelling recognition task and visuoperceptual recognition task). Regions of Interest and their signal values were obtained for both tasks. Based on these values, structural equation models (SEMs) were obtained for each group of spelling competence (HSS and LSS) and task through maximum likelihood estimation, and the model with the best fit was chosen in each case. Likewise, dynamic causal models (DCMs) were estimated for all the conditions across tasks and groups. The HSS group's SEM results suggest that, in the spelling recognition task, the right middle temporal gyrus, and, to a lesser extent, the left parahippocampal gyrus receive most of the significant effects, whereas the DCM results in the visuoperceptual recognition task show less complex effects, but still congruent with the previous results, with an important role in several areas. In general, these results are consistent with the major findings in partial studies about linguistic activities but they are the first analyses of statistical effective brain connectivity in transparent languages. PMID- 26042073 TI - Video stimuli reduce object-directed imitation accuracy: a novel two-person motion-tracking approach. AB - Imitation is an important form of social behavior, and research has aimed to discover and explain the neural and kinematic aspects of imitation. However, much of this research has featured single participants imitating in response to pre recorded video stimuli. This is in spite of findings that show reduced neural activation to video vs. real life movement stimuli, particularly in the motor cortex. We investigated the degree to which video stimuli may affect the imitation process using a novel motion tracking paradigm with high spatial and temporal resolution. We recorded 14 positions on the hands, arms, and heads of two individuals in an imitation experiment. One individual freely moved within given parameters (moving balls across a series of pegs) and a second participant imitated. This task was performed with either simple (one ball) or complex (three balls) movement difficulty, and either face-to-face or via a live video projection. After an exploratory analysis, three dependent variables were chosen for examination: 3D grip position, joint angles in the arm, and grip aperture. A cross-correlation and multivariate analysis revealed that object-directed imitation task accuracy (as represented by grip position) was reduced in video compared to face-to-face feedback, and in complex compared to simple difficulty. This was most prevalent in the left-right and forward-back motions, relevant to the imitator sitting face-to-face with the actor or with a live projected video of the same actor. The results suggest that for tasks which require object directed imitation, video stimuli may not be an ecologically valid way to present task materials. However, no similar effects were found in the joint angle and grip aperture variables, suggesting that there are limits to the influence of video stimuli on imitation. The implications of these results are discussed with regards to previous findings, and with suggestions for future experimentation. PMID- 26042075 TI - Shared vision promotes family firm performance. AB - A clear picture of the influential drivers of private family firm performance has proven to be an elusive target. The unique characteristics of private family owned firms necessitate a broader, non-financial approach to reveal firm performance drivers. This research study sought to specify and evaluate the themes that distinguish successful family firms from less successful family firms. In addition, this study explored the possibility that these themes collectively form an effective organizational culture that improves longer-term firm performance. At an organizational level of analysis, research findings identified four significant variables: Shared Vision (PNS), Role Clarity (RCL), Confidence in Management (CON), and Professional Networking (OLN) that positively impacted family firm financial performance. Shared Vision exhibited the strongest positive influence among the significant factors. In addition, Family Functionality (APGAR), the functional integrity of the family itself, exhibited a significant supporting role. Taken together, the variables collectively represent an effective family business culture (EFBC) that positively impacted the long term financial sustainability of family owned firms. The index of effective family business culture also exhibited potential as a predictive non-financial model of family firm performance. PMID- 26042074 TI - Reconsidering the role of orthographic redundancy in visual word recognition. AB - Humans are known to continuously extract regularities from the flow of stimulation. This occurs in many facets of behavior, including reading. In spite of the ubiquitous evidence that readers become sensitive to orthographic regularities after very little exposure to print, the role of orthographic regularities receives at best a peripheral status in current theories of orthographic processing. In the present article, after the presentation of previous evidence on orthographic redundancy, the hypothesis that orthographic regularities may play a prominent role in word perception is developed. PMID- 26042076 TI - Motivational and evolutionary aspects of a physical exercise training program: a longitudinal study. AB - Several studies have indicated that motivational level and prior expectations influence one's commitment to physical activity. Moreover, these aspects are not properly described in terms of proximal (SDT, Self Determination Theory) and distal (evolutionary) explanations in the literature. This paper aims to verify if level of motivation (BREQ-2, Behavioral Regulation in Exercise Questionnaire 2) and expectations regarding regular physical exercise (IMPRAF-54) before starting a 1-year exercise program could determine likelihood of completion. Ninety-four volunteers (53 women) included a completed protocol group (CPG; n = 21) and drop-out group (n = 73). The IMPRAF-54 scale was used to assess six different expectations associated with physical activity, and the BREQ-2 inventory was used to assess the level of motivation in five steps (from amotivation to intrinsic motivation). Both questionnaires were assessed before starting a regular exercise program. The CPG group presented higher sociability and lower pleasure scores according to IMPRAF-54 domains. A logistic regression analysis showed that a one-point increment on sociability score increased the chance of completing the program by 10%, and the same one-point increment on pleasure score reduced the chance of completing the protocol by 16%. ROC curves were also calculated to establish IMPRAF-54 cutoffs for adherence (Sociability - 18.5 points - 81% sensibility/50% specificity) and dropout (Pleasure - 25.5 points - 86% sensibility/20% specificity) of the exercise protocol. Our results indicate that an expectation of social interaction was a positive factor in predicting adherence to exercise. Grounded in SDT and its innate needs (competence, autonomy, relatedness), physical exercise is not an end; it is a means to achieve autonomy and self-cohesion. The association of physical activity with social practices, as occurs in hunter-gathering groups, can engage people to be physically active and can provide better results in adherence exercise programs for the general population. PMID- 26042077 TI - Constructing the context through goals and schemata: top-down processes in comprehension and beyond. AB - My main purpose here is to provide an account of context selection in utterance understanding in terms of the role played by schemata and goals in top-down processing. The general idea is that information is organized hierarchically, with items iteratively organized in chunks-here called "schemata"-at multiple levels, so that the activation of any items spreads to schemata that are the most accessible due to previous experience. The activation of a schema, in turn, activates its other components, so as to predict a likely context for the original item. Since each input activates its own schemata, conflicting schemata compete with (and inhibit) each other, while multiple activations of a schema raise its likelihood to win the competition. There is therefore a double movement with bottom-up activation of schemata enabling top-down prediction of other contextual components-triggered by multiple sources. Another claim of the paper is that goals are represented by schemata placed at the highest-levels of the executive hierarchy, in accordance with Fuster's model of the brain as a hierarchically organized perception-action cycle. This account can be considered, in part at least, a development of ideas contained in Relevance Theory, though it may imply that some other claims of the theory are in need of revision. Therefore, a secondary purpose of the paper is a contribution to the analysis of that theory. PMID- 26042078 TI - An fMRI study dissociating distance measures computed by Broca's area in movement processing: clause boundary vs. identity. AB - Behavioral studies of sentence comprehension suggest that processing long distance dependencies is subject to interference effects when Noun Phrases (NP) similar to the dependency head intervene in the dependency. Neuroimaging studies converge in localizing such effects to Broca's area, showing that activity in Broca's area increases with the number of NP interveners crossed by a moved NP of the same type. To test if NP interference effects are modulated by adding an intervening clause boundary, which should by hypothesis increase the number of successive-cyclic movements, we conducted an fMRI study contrasting NP interveners with clausal (CP) interveners. Our design thus had two components: (I) the number of NP interveners crossed by movement was parametrically modulated; (II) CP-intervention was contrasted with NP-intervention. The number of NP interveners parametrically modulated a cluster straddling left BA44/45 of Broca's area, replicating earlier studies. Adding an intervening clause boundary did not significantly modulate the size of the NP interference effect in Broca's area. Yet, such an interaction effect was observed in the Superior Frontal Gyrus (SFG). Therefore, the involvement of Broca's area in processing syntactic movement is best captured by memory mechanisms affected by a grammatically instantiated type-identity (i.e., NP) intervention. PMID- 26042080 TI - Editorial: The long and short of mental time travel-self-projection over time scales large and small. PMID- 26042079 TI - The multisensory body revealed through its cast shadows. AB - One key issue when conceiving the body as a multisensory object is how the cognitive system integrates visible instances of the self and other bodies with one's own somatosensory processing, to achieve self-recognition and body ownership. Recent research has strongly suggested that shadows cast by our own body have a special status for cognitive processing, directing attention to the body in a fast and highly specific manner. The aim of the present article is to review the most recent scientific contributions addressing how body shadows affect both sensory/perceptual and attentional processes. The review examines three main points: (1) body shadows as a special window to investigate the construction of multisensory body perception; (2) experimental paradigms and related findings; (3) open questions and future trajectories. The reviewed literature suggests that shadows cast by one's own body promote binding between personal and extrapersonal space and elicit automatic orienting of attention toward the body-part casting the shadow. Future research should address whether the effects exerted by body shadows are similar to those observed when observers are exposed to other visual instances of their body. The results will further clarify the processes underlying the merging of vision and somatosensation when creating body representations. PMID- 26042081 TI - Probability judgments under ambiguity and conflict. AB - Whether conflict and ambiguity are distinct kinds of uncertainty remains an open question, as does their joint impact on judgments of overall uncertainty. This paper reviews recent advances in our understanding of human judgment and decision making when both ambiguity and conflict are present, and presents two types of testable models of judgments under conflict and ambiguity. The first type concerns estimate-pooling to arrive at "best" probability estimates. The second type is models of subjective assessments of conflict and ambiguity. These models are developed for dealing with both described and experienced information. A framework for testing these models in the described-information setting is presented, including a reanalysis of a multi-nation data-set to test best estimate models, and a study of participants' assessments of conflict, ambiguity, and overall uncertainty reported by Smithson (2013). A framework for research in the experienced-information setting is then developed, that differs substantially from extant paradigms in the literature. This framework yields new models of "best" estimates and perceived conflict. The paper concludes with specific suggestions for future research on judgment and decision making under conflict and ambiguity. PMID- 26042082 TI - Conscious intention: a challenge for AIR theory. PMID- 26042083 TI - NF-kappaB in Innate Neuroprotection and Age-Related Neurodegenerative Diseases. AB - NF-kappaB factors are cardinal transcriptional regulators of inflammation and apoptosis, involved in the brain programing of systemic aging and in brain damage. The composition of NF-kappaB active dimers and epigenetic mechanisms modulating histone acetylation, finely condition neuronal resilience to brain insults. In stroke models, the activation of NF-kappaB/c-Rel promotes neuroprotective effects by transcription of specific anti-apoptotic genes. Conversely, aberrant activation of NF-kappaB/RelA showing reduced level of total acetylation, but site-specific acetylation on lysine 310, triggers the expression of pro-apoptotic genes. Constitutive knockout of c-Rel shatters the resilience of substantia nigra (SN) dopaminergic (DA) neurons to aging and induces a parkinsonian like pathology in mice. c-rel(-/-) mice show increased level of aberrantly acetylated RelA in the basal ganglia, neuroinflammation, accumulation of alpha-synuclein, and iron. Moreover, they develop motor deficits responsive to l-DOPA treatment and associated with loss of DA neurons in the SN. Here, we discuss the effect of unbalanced activation of RelA and c-Rel during aging and propose novel challenges for the development of therapeutic strategies in neurodegenerative diseases. PMID- 26042084 TI - Poorer Cognitive Performance in Patients with Essential Tremor-Parkinson's Disease vs. Patients with Parkinson's Disease. AB - BACKGROUND: Patients with essential tremor (ET) seem to be at increased risk of developing Parkinson's disease (PD). Surprisingly, little has been written about this clinical entity, ET-PD. Cognitive dysfunction is a well-known feature of PD, and can also be an issue in patients with ET. Whether the presence of the combined diagnosis, ET-PD, is associated with additive cognitive effects as compared with PD has not been studied. METHODS: Thirty ET-PD patients and 53 age matched PD patients were enrolled in a clinical-epidemiological study. Two cognitive screens, the Telephone Interview for Cognitive Status (TICS, score = 0 41) and Folstein Mini-Mental State Examination (MMSE; range 0-30), were administered. RESULTS: The MMSE score was lower in ET-PD than PD [26.5 +/- 3.1 (median 28.0) vs. 28.4 +/- 2.2 (median 29.0), p = 0.001]. The TICS score was lower in ET-PD than PD [31.7 +/- 3.9 (32.0) vs. 35.0 +/- 2.0 (35.0), p < 0.001]. Subscores of these tests that related to orientation (p < 0.001), language (p < 0.001), and working memory (p = 0.001) were lower in ET-PD than PD, whereas the delayed memory subscore was only marginally lower in ET-PD than PD (p = 0.06), and the two groups did not differ with respect to the motor/construction subscore (p = 0.22). Both global cognitive scores were inversely correlated with disease duration (for MMSE score, Spearman's r = -0.46, p < 0.001; for TICS score, Spearman's r = -0.53, p < 0.001). CONCLUSION: The combined diagnosis, ET-PD, seemed to be associated with additive cognitive effects as compared with PD alone. PMID- 26042086 TI - Chemical Communication between Heart Cells is Disrupted by Intracellular Renin and Angiotensin II: Implications for Heart Development and Disease. AB - HighlightsIntracellular renin and angiotensin disrupts chemical communication in heart.Epigenetic modification of renin angiotensin aldosterone system (RAAS) and heart disease.Intracrine renin angiotensin and metabolic cooperation.Gap junction, intracellular renin and angiotensin, cellular patterns, and heart development. The finding that intracellular renin and angiotensin II (Ang II) disrupts chemical communication and impairs metabolic cooperation between cardiomyocytes induced by aldosterone, hyperglycemia, and pathological conditions like myocardial ischemia is discussed. The hypothesis is presented that epigenetic changes of the renin angiotensin aldosterone system (RAAS) are responsible for cardiovascular abnormalities, including the expression of RAAS components inside cardiac myocytes (intracrine RAAS) with serious consequences including inhibition of electrical and chemical communication in the heart, resulting in metabolic disarrangement and cardiac arrhythmias. Moreover, the inhibition of gap junctional communication induced by intracellular Ang II or renin can contribute to the selection of cellular patterns during heart development. PMID- 26042088 TI - The "love hormone" oxytocin regulates the loss and gain of the fat-bone relationship. AB - The involvement of oxytocin (OT) in bone metabolism is an interesting area of research that recently achieved remarkable results. Moreover, several lines of evidence have largely demonstrated that OT also participates in the regulation of energy metabolism. Hence, it has recently been determined that the posterior pituitary hormone OT directly regulates bone mass: mice lacking OT or OT receptor display severe osteopenia, caused by impaired bone formation. OT administration normalizes ovariectomy-induced osteopenia, bone marrow adiposity, body weight, and intra-abdominal fat depots in mice. This effect is mediated through inhibition of adipocyte precursor differentiation and reduction of adipocyte size. The exquisite role of OT in regulating the bone-fat connection adds another milestone to the biological evidence supporting the existence of a tight relationship between the adipose tissue and the skeleton. PMID- 26042089 TI - Using Micro-CT Derived Bone Microarchitecture to Analyze Bone Stiffness - A Case Study on Osteoporosis Rat Bone. AB - Micro-computed tomography (Micro-CT) images can be used to quantitatively represent bone geometry through a range of computed attenuation-based parameters. Nonetheless, those parameters remain indirect indices of bone microarchitectural strength and require further computational tools to interpret bone structural stiffness and potential for mechanical failure. Finite element analysis (FEA) can be applied to measure trabecular bone stiffness and potentially predict the location of structural failure in preclinical animal models of osteoporosis, although that procedure from image segmentation of Micro-CT derived bone geometry to FEA is often challenging and computationally expensive, resulting in failure of the model to build. Notably, the selection of resolution and threshold for bone segmentation are key steps that greatly affect computational complexity and validity. In the following study, we evaluated an approach whereby Micro-CT derived grayscale attenuation and segmentation data guided the selection of trabecular bone for analysis by FEA. We further correlated those FEA results to both two- and three-dimensional bone microarchitecture from sham and ovariectomized (OVX) rats (n = 10/group). A virtual cylinder of vertebral trabecular bone 40% in length from the caudal side was selected for FEA, because Micro-CT based image analysis indicated the largest differences in microarchitecture between the two groups resided there. Bone stiffness was calculated using FEA and statistically correlated with the three-dimensional values of bone volume/tissue volume, bone mineral density, fractal dimension, trabecular separation, and trabecular bone pattern factor. Our method simplified the process for the assessment of trabecular bone stiffness by FEA from Micro-CT images and highlighted the importance of bone microarchitecture in conferring significantly increased bone quality capable of resisting failure due to increased mechanical loading. PMID- 26042087 TI - Oxytocin during Development: Possible Organizational Effects on Behavior. AB - Oxytocin (Oxt) is a neurohormone known for its physiological roles associated with lactation and parturition in mammals. Oxt can also profoundly influence mammalian social behaviors such as affiliative, parental, and aggressive behaviors. While the acute effects of Oxt signaling on adult behavior have been heavily researched in many species, including humans, the developmental effects of Oxt on the brain and behavior are just beginning to be explored. There is evidence that Oxt in early postnatal and peripubertal development, and perhaps during prenatal life, affects adult behavior by altering neural structure and function. However, the specific mechanisms by which this occurs remain unknown. Thus, this review will detail what is known about how developmental Oxt impacts behavior as well as explore the specific neurochemicals and neural substrates that are important to these behaviors. PMID- 26042090 TI - Oxytocin reverses osteoporosis in a sex-dependent manner. AB - The increase of life expectancy has led to the increase of age-related diseases such as osteoporosis. Osteoporosis is characterized by bone weakening promoting the occurrence of fractures with defective bone regeneration. Men aged over 50 have a prevalence for osteoporosis of 20%, which is related to a decline in sex hormones occurring during andropause or surgical orchidectomy. As we previously demonstrated in a mouse model for menopause in women that treatment with the neurohypophyseal peptide hormone oxytocin (OT) normalizes body weight and prevents the development of osteoporosis, herein we addressed the effects of OT in male osteoporosis. Thus, we treated orchidectomized mice, an animal model suitable for the study of male osteoporosis, for 8 weeks with OT and then analyzed trabecular and cortical bone parameters as well as fat mass using micro computed tomography. Orchidectomized mice displayed severe bone loss, muscle atrophy accompanied by fat mass gain as expected in andropause. Interestingly, OT treatment in male mice normalized fat mass as it did in female mice. However, although OT treatment led to a normalization of bone parameters in ovariectomized mice, this did not happen in orchidectomized mice. Moreover, loss of muscle mass was not reversed in orchidectomized mice upon OT treatment. All of these observations indicate that OT acts on fat physiology in both sexes, but in a sex specific manner with regard to bone physiology. PMID- 26042085 TI - The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients. AB - Extensive studies were performed to decipher the mechanisms regulating feeding due to the worldwide obesity pandemy and its complications. The data obtained might be adapted to another disorder related to alteration of food intake, the restrictive anorexia nervosa. This multifactorial disease with a complex and unknown etiology is considered as an awful eating disorder since the chronic refusal to eat leads to severe, and sometimes, irreversible complications for the whole organism, until death. There is an urgent need to better understand the different aspects of the disease to develop novel approaches complementary to the usual psychological therapies. For this purpose, the use of pertinent animal models becomes a necessity. We present here the various rodent models described in the literature that might be used to dissect central and peripheral mechanisms involved in the adaptation to deficient energy supplies and/or the maintenance of physiological alterations on the long term. Data obtained from the spontaneous or engineered genetic models permit to better apprehend the implication of one signaling system (hormone, neuropeptide, neurotransmitter) in the development of several symptoms observed in anorexia nervosa. As example, mutations in the ghrelin, serotonin, dopamine pathways lead to alterations that mimic the phenotype, but compensatory mechanisms often occur rendering necessary the use of more selective gene strategies. Until now, environmental animal models based on one or several inducing factors like diet restriction, stress, or physical activity mimicked more extensively central and peripheral alterations decribed in anorexia nervosa. They bring significant data on feeding behavior, energy expenditure, and central circuit alterations. Animal models are described and criticized on the basis of the criteria of validity for anorexia nervosa. PMID- 26042092 TI - Microbial metabolism of transparent exopolymer particles during the summer months along a eutrophic estuary system. AB - This study explores the role of transparent exopolymer particles (TEP) as an additional carbon source for heterotrophic microbial activity in the eutrophic Qishon estuary. From the coastal station and upstream the estuary; TEP concentrations, beta-glucosidase activity, bacterial production and abundance have gradually increased. TEP were often found as bio-aggregates, scaffolding algae, detritus matter and bacteria that likely formed "hotspots" for enhance microbial activity. To further demonstrate the link between TEP and heterotrophic bacterial activity, confined incubations with ambient and polysaccharide-enriched estuary water were carried out. Following polysaccharide addition, elevated (~50%) beta-glucosidase activity rates were observed, leading to TEP hydrolysis. This newly formed bioavailable carbon resulted in significantly higher growth rates, with up to a 5-fold increase in heterotrophic bacterial biomass, comprising mostly high nucleic acid content bacteria. Taking together the findings from this research, we conclude that even in highly eutrophic environments heterotrophic bacteria may still be carbon limited. Further, TEP as a polysaccharide matrix can act as a metabolic surrogate, adding fresh bioavailable carbon through tight associations with bacteria in eutrophic ecosystems such as the Qishon estuary. PMID- 26042091 TI - Enterobacter aerogenes and Enterobacter cloacae; versatile bacterial pathogens confronting antibiotic treatment. AB - Enterobacter aerogenes and E. cloacae have been reported as important opportunistic and multiresistant bacterial pathogens for humans during the last three decades in hospital wards. These Gram-negative bacteria have been largely described during several outbreaks of hospital-acquired infections in Europe and particularly in France. The dissemination of Enterobacter sp. is associated with the presence of redundant regulatory cascades that efficiently control the membrane permeability ensuring the bacterial protection and the expression of detoxifying enzymes involved in antibiotic degradation/inactivation. In addition, these bacterial species are able to acquire numerous genetic mobile elements that strongly contribute to antibiotic resistance. Moreover, this particular fitness help them to colonize several environments and hosts and rapidly and efficiently adapt their metabolism and physiology to external conditions and environmental stresses. Enterobacter is a versatile bacterium able to promptly respond to the antibiotic treatment in the colonized patient. The balance of the prevalence, E. aerogenes versus E. cloacae, in the reported hospital infections during the last period, questions about the horizontal transmission of mobile elements containing antibiotic resistance genes, e.g., the efficacy of the exchange of resistance genes Klebsiella pneumoniae to Enterobacter sp. It is also important to mention the possible role of antibiotic use in the treatment of bacterial infectious diseases in this E. aerogenes/E. cloacae evolution. PMID- 26042093 TI - Welcome to pandoraviruses at the 'Fourth TRUC' club. AB - Nucleocytoplasmic large DNA viruses, or representatives of the proposed order Megavirales, belong to families of giant viruses that infect a broad range of eukaryotic hosts. Megaviruses have been previously described to comprise a fourth monophylogenetic TRUC (things resisting uncompleted classification) together with cellular domains in the universal tree of life. Recently described pandoraviruses have large (1.9-2.5 MB) and highly divergent genomes. In the present study, we updated the classification of pandoraviruses and other reported giant viruses. Phylogenetic trees were constructed based on six informational genes. Hierarchical clustering was performed based on a set of informational genes from Megavirales members and cellular organisms. Homologous sequences were selected from cellular organisms using TimeTree software, comprising comprehensive, and representative sets of members from Bacteria, Archaea, and Eukarya. Phylogenetic analyses based on three conserved core genes clustered pandoraviruses with phycodnaviruses, exhibiting their close relatedness. Additionally, hierarchical clustering analyses based on informational genes grouped pandoraviruses with Megavirales members as a super group distinct from cellular organisms. Thus, the analyses based on core conserved genes revealed that pandoraviruses are new genuine members of the 'Fourth TRUC' club, encompassing distinct life forms compared with cellular organisms. PMID- 26042094 TI - Dynamic transition of chemolithotrophic sulfur-oxidizing bacteria in response to amendment with nitrate in deposited marine sediments. AB - Although environmental stimuli are known to affect the structure and function of microbial communities, their impact on the metabolic network of microorganisms has not been well investigated. Here, geochemical analyses, high-throughput sequencing of 16S rRNA genes and transcripts, and isolation of potentially relevant bacteria were carried out to elucidate the anaerobic respiration processes stimulated by nitrate (20 mM) amendment of marine sediments. Marine sediments deposited by the Great East Japan Earthquake in 2011 were incubated anaerobically in the dark at 25?C for 5 days. Nitrate in slurry water decreased gradually for 2 days, then more rapidly until its complete depletion at day 5; production of N2O followed the same pattern. From day 2 to 5, the sulfate concentration significantly increased and the sulfur content in solid-phase sediments significantly decreased. These results indicated that denitrification and sulfur oxidation occurred simultaneously. Illumina sequencing revealed the proliferation of known sulfur oxidizers, i.e., Sulfurimonas sp. and Chromatiales bacteria, which accounted for approximately 43.5% and 14.8% of the total population at day 5, respectively. These oxidizers also expressed 16S rRNA to a considerable extent, whereas the other microorganisms, e.g., iron(III) reducers and methanogens, became metabolically active at the end of the incubation. Extinction dilution culture in a basal-salts medium supplemented with sulfur compounds and nitrate successfully isolated the predominant sulfur oxidizers: Sulfurimonas sp. strain HDS01 and Thioalkalispira sp. strain HDS22. Their 16S rRNA genes showed 95.2-96.7% sequence similarity to the closest cultured relatives and they grew chemolithotrophically on nitrate and sulfur. Novel sulfur oxidizing bacteria were thus directly involved in carbon fixation under nitrate reducing conditions, activating anaerobic respiration processes and the reorganization of microbial communities in the deposited marine sediments. PMID- 26042095 TI - Seasonal variation of bacterial endophytes in urban trees. AB - Bacterial endophytes, non-pathogenic bacteria residing within plants, contribute to the growth and development of plants and their ability to adapt to adverse conditions. In order to fully exploit the capabilities of these bacteria, it is necessary to understand the extent to which endophytic communities vary between species and over time. The endophytes of Acer negundo, Ulmus pumila, and Ulmus parvifolia were sampled over three seasons and analyzed using culture dependent and independent methods (culture on two media, terminal restriction fragment length polymorphism, and tagged pyrosequencing of 16S ribosomal amplicons). The majority of culturable endophytes isolated were Actinobacteria, and all the samples harbored Bacillus, Curtobacterium, Frigoribacterium, Methylobacterium, Paenibacilllus, and Sphingomonas species. Regardless of culture medium used, only the culturable communities obtained in the winter for A. negundo could be distinguished from those of Ulmus spp. In contrast, the nonculturable communities were dominated by Proteobacteria and Actinobacteria, particularly Erwinia, Ralstonia, and Sanguibacter spp. The presence and abundance of various bacterial classes and phyla changed with the changing seasons. Multivariate analysis on the culture independent data revealed significant community differences between the endophytic communities of A. negundo and Ulmus spp., but overall season was the main determinant of endophytic community structure. This study suggests studies on endophytic populations of urban trees should expect to find significant seasonal and species-specific community differences and sampling should proceed accordingly. PMID- 26042096 TI - Increased seawater temperature increases the abundance and alters the structure of natural Vibrio populations associated with the coral Pocillopora damicornis. AB - Rising seawater temperature associated with global climate change is a significant threat to coral health and is linked to increasing coral disease and pathogen-related bleaching events. We performed heat stress experiments with the coral Pocillopora damicornis, where temperature was increased to 31 degrees C, consistent with the 2-3 degrees C predicted increase in summer sea surface maxima. 16S rRNA amplicon sequencing revealed a large shift in the composition of the bacterial community at 31 degrees C, with a notable increase in Vibrio, including known coral pathogens. To investigate the dynamics of the naturally occurring Vibrio community, we performed quantitative PCR targeting (i) the whole Vibrio community and (ii) the coral pathogen Vibrio coralliilyticus. At 31 degrees C, Vibrio abundance increased by 2-3 orders of magnitude and V. coralliilyticus abundance increased by four orders of magnitude. Using a Vibrio specific amplicon sequencing assay, we further demonstrated that the community composition shifted dramatically as a consequence of heat stress, with significant increases in the relative abundance of known coral pathogens. Our findings provide quantitative evidence that the abundance of potential coral pathogens increases within natural communities of coral-associated microbes as a consequence of rising seawater temperature and highlight the potential negative impacts of anthropogenic climate change on coral reef ecosystems. PMID- 26042097 TI - Commentary: Probiotic and technological properties of Lactobacillus spp. strains from the human stomach in the search for potential candidates against gastric microbial dysbiosis. PMID- 26042098 TI - Involvement of aph(3')-IIa in the formation of mosaic aminoglycoside resistance genes in natural environments. AB - Intragenic recombination leading to mosaic gene formation is known to alter resistance profiles for particular genes and bacterial species. Few studies have examined to what extent aminoglycoside resistance genes undergo intragenic recombination. We screened the GenBank database for mosaic gene formation in homologs of the aph(3')-IIa (nptII) gene. APH(3')-IIa inactivates important aminoglycoside antibiotics. The gene is widely used as a selectable marker in biotechnology and enters the environment via laboratory discharges and the release of transgenic organisms. Such releases may provide opportunities for recombination in competent environmental bacteria. The retrieved GenBank sequences were grouped in three datasets comprising river water samples, duck pathogens and full-length variants from various bacterial genomes and plasmids. Analysis for recombination in these datasets was performed with the Recombination Detection Program (RDP4), and the Genetic Algorithm for Recombination Detection (GARD). From a total of 89 homologous sequences, 83% showed 99-100% sequence identity with aph(3')-IIa originally described as part of transposon Tn5. Fifty one were unique sequence variants eligible for recombination analysis. Only a single recombination event was identified with high confidence and indicated the involvement of aph(3')-IIa in the formation of a mosaic gene located on a plasmid of environmental origin in the multi-resistant isolate Pseudomonas aeruginosa PA96. The available data suggest that aph(3')-IIa is not an archetypical mosaic gene as the divergence between the described sequence variants and the number of detectable recombination events is low. This is in contrast to the numerous mosaic alleles reported for certain penicillin or tetracycline resistance determinants. PMID- 26042099 TI - Phyllostomid bat microbiome composition is associated to host phylogeny and feeding strategies. AB - The members of the Phyllostomidae, the New-World leaf-nosed family of bats, show a remarkable evolutionary diversification of dietary strategies including insectivory, as the ancestral trait, followed by appearance of carnivory and plant-based diets such as nectarivory and frugivory. Here we explore the microbiome composition of different feeding specialists: insectivore Macrotus waterhousii, sanguivore Desmodus rotundus, nectarivores Leptonycteris yerbabuenae and Glossophaga soricina, and frugivores Carollia perspicillata and Artibeus jamaicensis. The V4 region of the 16S rRNA gene from three intestinal regions of three individuals per species was amplified and community composition and structure was analyzed with alpha and beta diversity metrics. Bats with plant based diets had low diversity microbiomes, whereas the sanguivore D. rotundus and insectivore M. waterhousii had the most diverse microbiomes. There were no significant differences in microbiome composition between different intestine regions within each individual. Plant-based feeders showed less specificity in their microbiome compositions, whereas animal-based specialists, although more diverse overall, showed a more clustered arrangement of their intestinal bacterial components. The main characteristics defining microbiome composition in phyllostomids were species and feeding strategy. This study shows how differences in feeding strategies contributed to the development of different intestinal microbiomes in Phyllostomidae. PMID- 26042100 TI - Qualitative and quantitative proteomic analysis of Vitamin C induced changes in Mycobacterium smegmatis. AB - Vitamin C is a critical dietary nutrient in human which has a wide range of regulatory effects on gene expression and physiology of Mycobacterium tuberculosis that leads to a dormant drug-tolerant phenotype. In the presence of iron, vitamin C shows a high bactericidal activity even in the drug resistant phenotype of M. tuberculosis. The regulatory mechanisms underlying vitamin C induced adaptations are largely unknown due to lack of functional genomics data in this field. In this study, we attempt to characterize the direct effect of vitamin C treatment on the physiology of actively growing Mycobacterium smegmatis. The study chose M. smegmatis as it is a fast-growing bacterium and a non-pathogenic model system which shares many physiological features with the pathogenic M. tuberculosis including dormancy and its regulation. The proteomic adaptation of M. smegmatis on vitamin C treatment demonstrates the important changes in cellular and metabolic process such as reversal of tricarboxylic acid cycle, decrease in ATP synthesis, decrease in iron acquisition and storage, and induction of dormancy regulators WhiB3, PhoP, and Lsr2. PMID- 26042101 TI - Transcriptomic analysis of Campylobacter jejuni NCTC 11168 in response to epinephrine and norepinephrine. AB - Upon colonization in the host gastrointestinal tract, the enteric bacterial pathogen Campylobacter jejuni is exposed to a variety of signaling molecules including the catecholamine hormones epinephrine (Epi) and norepinephrine (NE). NE has been observed to stimulate the growth and potentially enhance the pathogenicity of C. jejuni. However, the underlying mechanisms are still largely unknown. In this study, both Epi and NE were also observed to promote C. jejuni growth in MEMalpha-based iron-restricted medium. Adhesion and invasion of Caco-2 cells by C. jejuni were also enhanced upon exposure to Epi or NE. To further examine the effect of Epi or NE on the pathobiology of C. jejuni, transcriptomic profiles were conducted for C. jejuni NCTC 11168 that was cultured in iron restricted medium supplemented with Epi or NE. Compared to the genes expressed in the absence of the catecholamine hormones, 183 and 156 genes were differentially expressed in C. jejuni NCTC 11168 that was grown in the presence of Epi and NE, respectively. Of these differentially expressed genes, 102 genes were common for both Epi and NE treatments. The genes differentially expressed by Epi or NE are involved in diverse cellular functions including iron uptake, motility, virulence, oxidative stress response, nitrosative stress tolerance, enzyme metabolism, DNA repair and metabolism and ribosomal protein biosynthesis. The transcriptome analysis indicated that Epi and NE have similar effects on the gene expression of C. jejuni, and provided insights into the delicate interaction between C. jejuni and intestinal stress hormones in the host. PMID- 26042102 TI - Stream microbial diversity in response to environmental changes: review and synthesis of existing research. AB - The importance of microbial activity to ecosystem function in aquatic ecosystems is well established, but microbial diversity has been less frequently addressed. This review and synthesis of 100s of published studies on stream microbial diversity shows that factors known to drive ecosystem processes, such as nutrient availability, hydrology, metal contamination, contrasting land-use and temperature, also cause heterogeneity in bacterial diversity. Temporal heterogeneity in stream bacterial diversity was frequently observed, reflecting the dynamic nature of both stream ecosystems and microbial community composition. However, within-stream spatial differences in stream bacterial diversity were more commonly observed, driven specifically by different organic matter (OM) compartments. Bacterial phyla showed similar patterns in relative abundance with regard to compartment type across different streams. For example, surface water contained the highest relative abundance of Actinobacteria, while epilithon contained the highest relative abundance of Cyanobacteria and Bacteroidetes. This suggests that contrasting physical and/or nutritional habitats characterized by different stream OM compartment types may select for certain bacterial lineages. When comparing the prevalence of physicochemical effects on stream bacterial diversity, effects of changing metal concentrations were most, while effects of differences in nutrient concentrations were least frequently observed. This may indicate that although changing nutrient concentrations do tend to affect microbial diversity, other environmental factors are more likely to alter stream microbial diversity and function. The common observation of connections between ecosystem process drivers and microbial diversity suggests that microbial taxonomic turnover could mediate ecosystem-scale responses to changing environmental conditions, including both microbial habitat distribution and physicochemical factors. PMID- 26042103 TI - Heterologous expression of the Monilinia fructicola CYP51 (MfCYP51) gene in Pichia pastoris confirms the mode of action of the novel fungicide, SYP-Z048. AB - The novel agricultural fungicide 3-[5-(4-chlorophenyl)-2,3-dimethyl-3 isoxazolidinyl] pyridine (SYP-Z048) developed by China Shenyang Research Institute of Chemical Industry has been confirmed to be an ergosterol biosynthesis inhibitor (EBI). Previous studies have shown that EBIs target the proteins from a range of genes, including CYP51, ERG2 and/or ERG24, and ERG27, which are involved in the ergosterol biosynthesis pathway. In the current study the ERG2, ERG24, and ERG27 genes were cloned from wild type and resistant mutants of Monilinia fructicola in an attempt to clarify the target site of SYP-Z048. Comparative analysis of the deduced aa sequence of these genes, as well as CYP51, revealed several point mutations that resulted in amino acid variation among the sensitive and resistant isolates. However, sensitivity assays indicated that only one, the substitution of phenylalanine (F) for the tyrosine (Y) at 136 in CYP51, was correlated with reduced sensitivity to SYP-Z048. Heterologous expression of MfCYP51-136Y (MfCYP136Y) and MfCYP51-136F (MfCYP136F) in Pichia pastoris revealed that MfCYP136F significantly reduced sensitivity to SYP-Z048, increasing the average EC50 of the transformants 11-fold relative to those carrying MfCYP136Y. However, neither the additional copy of MfCYP136Y nor multiple copies of MfCYP136F were found to reduce sensitivity relative to the empty vector control or single copy transformants, respectively. Molecular docking experiments using SYP-Z048 with HsCYP145Y and the mutated version HsCYP145F as substitutes for MfCYP136Y and MfCYP136F, respectively, indicated that the reduced affinity of HsCYP145F for SYP-Z048 resulted from the loss of a hydrogen bond between the fungicide and the active site. Taken together these results indicate that MfCYP51 is the major target site of SYP-Z048 in M. fructicola, which has important implications for the resistance management of this fungicide in the field. PMID- 26042104 TI - Soil microbial community structure is unaltered by plant invasion, vegetation clipping, and nitrogen fertilization in experimental semi-arid grasslands. AB - Global and regional environmental changes often co-occur, creating complex gradients of disturbance on the landscape. Soil microbial communities are an important component of ecosystem response to environmental change, yet little is known about how microbial structure and function respond to multiple disturbances, or whether multiple environmental changes lead to unanticipated interactive effects. Our study used experimental semi-arid grassland plots in a Mediterranean-climate to determine how soil microbial communities in a seasonally variable ecosystem respond to one, two, or three simultaneous environmental changes: exotic plant invasion, plant invasion + vegetation clipping (to simulate common management practices like mowing or livestock grazing), plant invasion + nitrogen (N) fertilization, and plant invasion + clipping + N fertilization. We examined microbial community structure 5-6 years after plot establishment via sequencing of >1 million 16S rRNA genes. Abiotic soil properties (soil moisture, temperature, pH, and inorganic N) and microbial functioning (nitrification and denitrification potentials) were also measured and showed treatment-induced shifts, including altered NO(-) 3 availability, temperature, and nitrification potential. Despite these changes, bacterial and archaeal communities showed little variation in composition and diversity across treatments. Even communities in plots exposed to three interacting environmental changes were similar to those in restored native grassland plots. Historical exposure to large seasonal and inter-annual variations in key soil properties, in addition to prior site cultivation, may select for a functionally plastic or largely dormant microbial community, resulting in a microbial community that is structurally robust to single and multiple environmental changes. PMID- 26042106 TI - Editorial: Viruses threatening stable production of cereal crops. PMID- 26042107 TI - Editorial: Biogenic amines in foods. PMID- 26042105 TI - Microbial community structure and function on sinking particles in the North Pacific Subtropical Gyre. AB - Sinking particles mediate the transport of carbon and energy to the deep-sea, yet the specific microbes associated with sedimenting particles in the ocean's interior remain largely uncharacterized. In this study, we used particle interceptor traps (PITs) to assess the nature of particle-associated microbial communities collected at a variety of depths in the North Pacific Subtropical Gyre. Comparative metagenomics was used to assess differences in microbial taxa and functional gene repertoires in PITs containing a preservative (poisoned traps) compared to preservative-free traps where growth was allowed to continue in situ (live traps). Live trap microbial communities shared taxonomic and functional similarities with bacteria previously reported to be enriched in dissolved organic matter (DOM) microcosms (e.g., Alteromonas and Methylophaga), in addition to other particle and eukaryote-associated bacteria (e.g., Flavobacteriales and Pseudoalteromonas). Poisoned trap microbial assemblages were enriched in Vibrio and Campylobacterales likely associated with eukaryotic surfaces and intestinal tracts as symbionts, pathogens, or saprophytes. The functional gene content of microbial assemblages in poisoned traps included a variety of genes involved in virulence, anaerobic metabolism, attachment to chitinaceaous surfaces, and chitin degradation. The presence of chitinaceaous surfaces was also accompanied by the co-existence of bacteria which encoded the capacity to attach to, transport and metabolize chitin and its derivatives. Distinctly different microbial assemblages predominated in live traps, which were largely represented by copiotrophs and eukaryote-associated bacterial communities. Predominant sediment trap-assocaited eukaryotic phyla included Dinoflagellata, Metazoa (mostly copepods), Protalveolata, Retaria, and Stramenopiles. These data indicate the central role of eukaryotic taxa in structuring sinking particle microbial assemblages, as well as the rapid responses of indigenous microbial species in the degradation of marine particulate organic matter (POM) in situ in the ocean's interior. PMID- 26042108 TI - Cylindrospermopsis raciborskii: review of the distribution, phylogeography, and ecophysiology of a global invasive species. AB - Cylindrospermopsis raciborskii is a cyanobacterial species extensively studied for its toxicity, bloom formation and invasiveness potential, which have consequences to public and environmental health. Its current geographical distribution, spanning different climates, suggests that C. raciborskii has acquired the status of a cosmopolitan species. From phylogeography studies, a tropical origin for this species seems convincing, with different conjectural routes of expansion toward temperate climates. This expansion may be a result of the species physiological plasticity, or of the existence of different ecotypes with distinct environmental requirements. In particular, C. raciborskii is known to tolerate wide temperature and light regimes and presents diverse nutritional strategies. This cyanobacterium is also thought to have benefited from climate change conditions, regarding its invasiveness into temperate climates. Other factors, recently put forward, such as allelopathy, may also be important to its expansion. The effect of C. raciborskii in the invaded communities is still mostly unknown but may strongly disturb species diversity at different trophic levels. In this review we present an up-to-date account of the distribution, phylogeography, ecophysiology, as well some preliminary reports of the impact of C. raciborskii in different organisms. PMID- 26042109 TI - Effects of marine actinomycete on the removal of a toxicity alga Phaeocystis globose in eutrophication waters. AB - Phaeocystis globosa blooms in eutrophication waters can cause severely damage in marine ecosystem and consequently influence human activities. This study investigated the effect and role of an algicidal actinomycete (Streptomyces sp. JS01) on the elimination process of P. globosa. JS01 supernatant could alter algal cell membrane permeability in 4 h when analyzed with flow cytometry. Reactive oxygen species (ROS) levels were 7.2 times higher than that at 0 h following exposure to JS01 supernatant for 8 h, which indicated that algal cells suffered from oxidative damage. The Fv/Fm value which could reflect photosystem II (PS II) electron flow status also decreased. Real-time PCR showed that the expression of the photosynthesis related genes psbA and rbcS were suppressed by JS01 supernatant, which might induce damage to PS II. Our results demonstrated that JS01 supernatant can change algal membrane permeability in a short time and then affect photosynthesis process, which might block the PS II electron transport chain to produce excessive ROS. This experiment demonstrated that Streptomyces sp. JS01 could eliminate harmful algae in marine waters efficiently and may be function as a harmful algal bloom controller material. PMID- 26042110 TI - A modular method for the extraction of DNA and RNA, and the separation of DNA pools from diverse environmental sample types. AB - A method for the extraction of nucleic acids from a wide range of environmental samples was developed. This method consists of several modules, which can be individually modified to maximize yields in extractions of DNA and RNA or separations of DNA pools. Modules were designed based on elaborate tests, in which permutations of all nucleic acid extraction steps were compared. The final modular protocol is suitable for extractions from igneous rock, air, water, and sediments. Sediments range from high-biomass, organic rich coastal samples to samples from the most oligotrophic region of the world's oceans and the deepest borehole ever studied by scientific ocean drilling. Extraction yields of DNA and RNA are higher than with widely used commercial kits, indicating an advantage to optimizing extraction procedures to match specific sample characteristics. The ability to separate soluble extracellular DNA pools without cell lysis from intracellular and particle-complexed DNA pools may enable new insights into the cycling and preservation of DNA in environmental samples in the future. A general protocol is outlined, along with recommendations for optimizing this general protocol for specific sample types and research goals. PMID- 26042111 TI - Antibacterial effects of Traditional Chinese Medicine monomers against Streptococcus pneumoniae via inhibiting pneumococcal histidine kinase (VicK). AB - Two-component systems (TCSs) have the potential to be an effective target of the antimicrobials, and thus received much attention in recent years. VicK/VicR is one of TCSs in Streptococcus pneumoniae (S. pneumoniae), which is essential for pneumococcal survival. We have previously obtained several Traditional Chinese Medicine monomers using a computer-based screening. In this study, either alone or in combination with penicillin, their antimicrobial activities were evaluated based on in vivo and in vitro assays. The results showed that the MICs of 5' (Methylthio)-5'-deoxyadenosine, octanal 2, 4-dinitrophenylhydrazone, deoxyshikonin, kavahin, and dodecyl gallate against S. pneumoniae were 37.1, 38.5, 17, 68.5, and 21 MUg/mL, respectively. Time-killing assays showed that these compounds elicited bactericidal effects against S. pneumoniae D39 strain, which led to a 6-log reduction in CFU after exposure to compounds at four times of the MIC for 24 h. The five compounds inhibited the growth of Streptococcus pyogenes, Streptococcus mitis, Streptococcus mutans or Streptococcus pseudopneumoniae, meanwhile, deoxyshikonin and dodecyl gallate displayed strong inhibitory activities against Staphylococcus aureus. These compounds showed no obvious cytotoxicity effects on Vero cells. Survival time of the mice infected by S. pneumoniae strains was prolonged by the treatment with the compounds. Importantly, all of the five compounds exerted antimicrobial effects against multidrug-resistant clinical strains of S. pneumoniae. Moreover, even at sub-MIC concentration, they inhibited cell division and biofilm formation. The five compounds all have enhancement effect on penicillin. Deoxyshikonin and dodecyl gallate showed significantly synergic antimicrobial activity with penicillin in vivo and in vitro, and effectively reduced nasopharyngeal and lung colonization caused by different penicillin-resistant pneumococcal serotypes. In addition, the two compounds also showed synergic antimicrobial activity with erythromycin and tetracycline. Taken together, our results suggest that these novel VicK inhibitors may be promising compounds against the pneumococcus, including penicillin-resistant strains. PMID- 26041974 TI - Measurement of the top-quark mass in the fully hadronic decay channel from ATLAS data at [Formula: see text]. AB - The mass of the top quark is measured in a data set corresponding to 4.6 [Formula: see text] of proton-proton collisions with centre-of-mass energy [Formula: see text] TeV collected by the ATLAS detector at the LHC. Events consistent with hadronic decays of top-antitop quark pairs with at least six jets in the final state are selected. The substantial background from multijet production is modelled with data-driven methods that utilise the number of identified [Formula: see text]-quark jets and the transverse momentum of the sixth leading jet, which have minimal correlation. The top-quark mass is obtained from template fits to the ratio of three-jet to dijet mass. The three-jet mass is calculated from the three jets produced in a top-quark decay. Using these three jets the dijet mass is obtained from the two jets produced in the [Formula: see text] boson decay. The top-quark mass obtained from this fit is thus less sensitive to the uncertainty in the energy measurement of the jets. A binned likelihood fit yields a top-quark mass of [Formula: see text]. PMID- 26042113 TI - Unsuitability of MALDI-TOF MS to discriminate Acinetobacter baumannii clones under routine experimental conditions. AB - MALDI-TOF MS (matrix-assisted laser desorption/ionization time-of-flight mass spectrometry) is now in the forefront for routine bacterial species identification methodologies, being its value for clonality assessment controversial. In this work we evaluated the potential of MALDI-TOF MS for assisting infection control by depicting Acinetobacter baumannii clones. Mass spectra of 58 A. baumannii clinical isolates belonging to the worldwide spread lineages (ST98, ST103, ST208, and ST218) isolated in our country, were obtained and analyzed with several chemometric tools (pseudo gel views, peakfind function, and partial least squares discriminant analysis). The clonal lineages were obtained using the "Oxford" scheme, belonging ST98, ST208, and ST218 to the international clone II and ST103 to an epidemic clonal lineage (SG5). Additionally, mass spectra of a highly diverse international collection of 38 isolates belonging to 22 sequence types (STs) were obtained for further comparisons. Pseudo gel views and direct peak pattern analysis did not allow the discrimination of A. baumannii isolates belonging to ST98, ST103, ST208, or ST218. Moreover, a partial least square discriminant analysis of the mass spectra considering two spectral ranges (2-20 kDa and 4-10 kDa) revealed a poor degree of discrimination with only 64.6 and 65.8% of correct ST assignments, respectively. Also, mass spectra of the international isolates (n = 38, 22STs) revealed a very congruent peak pattern among them as well as among the four lineages included in this work. Despite the increasing interest of MALDI-TOF MS for bacterial typing at different taxonomical levels, we demonstrated, using routine experimental conditions, the unsuitability of this methodology for A. baumannii clonal discrimination. PMID- 26042114 TI - Microbial communities of the Lemon Creek Glacier show subtle structural variation yet stable phylogenetic composition over space and time. AB - Glaciers are geologically important yet transient ecosystems that support diverse, biogeochemically significant microbial communities. During the melt season glaciers undergo dramatic physical, geochemical, and biological changes that exert great influence on downstream biogeochemical cycles. Thus, we sought to understand the temporal melt-season dynamics of microbial communities and associated geochemistry at the terminus of Lemon Creek Glacier (LCG) in coastal southern Alaska. Due to late season snowfall, sampling of LCG occurred in three interconnected areas: proglacial Lake Thomas, the lower glacial outflow stream, and the glacier's terminus. LCG associated microbial communities were phylogenetically diverse and varied by sampling location. However, Betaproteobacteria, Alphaproteobacteria, and Bacteroidetes dominated communities at all sampling locations. Strict anaerobic groups such as methanogens, SR1, and OP11 were also recovered from glacier outflows, indicating anoxic conditions in at least some portions of the LCG subglacial environment. Microbial community structure was significantly correlated with sampling location and sodium concentrations. Microbial communities sampled from terminus outflow waters exhibited day-to-day fluctuation in taxonomy and phylogenetic similarity. However, these communities were not significantly different from randomly constructed communities from all three sites. These results indicate that glacial outflows share a large proportion of phylogenetic overlap with downstream environments and that the observed significant shifts in community structure are driven by changes in relative abundance of different taxa, and not complete restructuring of communities. We conclude that LCG glacial discharge hosts a diverse and relatively stable microbiome that shifts at fine taxonomic scales in response to geochemistry and likely water residence time. PMID- 26042112 TI - Two decades of warming increases diversity of a potentially lignolytic bacterial community. AB - As Earth's climate warms, the massive stores of carbon found in soil are predicted to become depleted, and leave behind a smaller carbon pool that is less accessible to microbes. At a long-term forest soil-warming experiment in central Massachusetts, soil respiration and bacterial diversity have increased, while fungal biomass and microbially-accessible soil carbon have decreased. Here, we evaluate how warming has affected the microbial community's capability to degrade chemically-complex soil carbon using lignin-amended BioSep beads. We profiled the bacterial and fungal communities using PCR-based methods and completed extracellular enzyme assays as a proxy for potential community function. We found that lignin-amended beads selected for a distinct community containing bacterial taxa closely related to known lignin degraders, as well as members of many genera not previously noted as capable of degrading lignin. Warming tended to drive bacterial community structure more strongly in the lignin beads, while the effect on the fungal community was limited to unamended beads. Of those bacterial operational taxonomic units (OTUs) enriched by the warming treatment, many were enriched uniquely on lignin-amended beads. These taxa may be contributing to enhanced soil respiration under warming despite reduced readily available C availability. In aggregate, these results suggest that there is genetic potential for chemically complex soil carbon degradation that may lead to extended elevated soil respiration with long-term warming. PMID- 26042115 TI - Clicking on trans-translation drug targets. PMID- 26042118 TI - Phylogenetic relationship of some "accessory" helicases of plant positive stranded RNA viruses: toward understanding the evolution of triple gene block. AB - Recently, we hypothesized that silencing suppression activity gained by a viral replicative helicase led to the emergence of the second helicase possessing activity of the viral silencing suppressor and/or movement protein (MP). Our hypothesis accounted for the evolutionary origin of the specialized 'triple gene block' (TGB) in plant virus genomes encoding the MPs TGB1, TGB2, and TGB3 required for viral cell-to-cell transport through plasmodesmata. Here, we used public transcriptome databases to identify previously unrecognized viruses. The analysis of novel viral genomes further supported the previously proposed scenario of TGB origin and evolution, which included the following steps. First, the accessory helicase gene could have been acquired by horizontal gene transfer (HGT) presumably occured independently in different virus groups. Second, the TGB2 gene evolved by HGT or autonomization of the C-terminal transmembrane domain found in at least one TGB1 helicase. Third, the TGB3 gene has most likely emerged in the genomic block consisting of the TGB1 and TGB2 genes. PMID- 26042117 TI - Influence of dimethyl dicarbonate on the resistance of Escherichia coli to a combined UV-Heat treatment in apple juice. AB - Commercial apple juice inoculated with Escherichia coli was treated with UV-C, heat (55 degrees C) and dimethyl dicarbonate - DMDC (25, 50, and 75 mg/L)-, applied separately and in combination, in order to investigate the possibility of synergistic lethal effects. The inactivation levels resulting from each treatment applied individually for a maximum treatment time of 3.58 min were limited, reaching 1.2, 2.9, and 0.06 log10 reductions for UV, heat, and DMDC (75 mg/L), respectively. However, all the investigated combinations resulted in a synergistic lethal effect, reducing the total treatment time and UV dose, with the synergistic lethal effect being higher when larger concentrations of DMDC were added to the apple juice. The addition of 75 mg/L of DMDC prior to the combined UV-C light treatment at 55 degrees C resulted in 5 log10 reductions after only 1.8 min, reducing the treatment time and UV dose of the combined UV Heat treatment by 44%. PMID- 26042116 TI - Thymineless death, at the origin. AB - Thymineless death (TLD) in bacteria has been a focus of research for decades. Nevertheless, the advances in the last 5 years, with Escherichia coli as the model organism, have been outstanding. Independent research groups have presented compelling results that establish that the initiation of chromosome replication under thymine starvation is a key element in the scenario of TLD. Here we review the experimental results linking the initiation of replication to the lethality under thymine starvation and the proposed mechanisms by which TLD occurs. The concept of this relationship was 'in the air,' but approaches were not sufficiently developed to demonstrate the crucial role of DNA initiation in TLD. Genome-wide marker frequency analysis and Two Dimensional agarose gel electrophoresis have been critical methods employed to reveal that initiation events and the degradation of the oriC region occur during thymine starvation. The relationships between these events and TLD have established them to be the main underlying causes of the lethality under thymine starvation. Furthermore, we summarize additional important findings from the study of different mutant strains, which support the idea that the initiation of chromosomal replication and TLD are connected. PMID- 26041976 TI - Measurement of three-jet production cross-sections in [Formula: see text] collisions at 7 [Formula: see text] centre-of-mass energy using the ATLAS detector. AB - Double-differential three-jet production cross-sections are measured in proton proton collisions at a centre-of-mass energy of [Formula: see text] using the ATLAS detector at the large hadron collider. The measurements are presented as a function of the three-jet mass [Formula: see text], in bins of the sum of the absolute rapidity separations between the three leading jets [Formula: see text]. Invariant masses extending up to 5 TeV are reached for [Formula: see text]. These measurements use a sample of data recorded using the ATLAS detector in 2011, which corresponds to an integrated luminosity of [Formula: see text]. Jets are identified using the anti-[Formula: see text] algorithm with two different jet radius parameters, [Formula: see text] and [Formula: see text]. The dominant uncertainty in these measurements comes from the jet energy scale. Next-to leading-order QCD calculations corrected to account for non-perturbative effects are compared to the measurements. Good agreement is found between the data and the theoretical predictions based on most of the available sets of parton distribution functions, over the full kinematic range, covering almost seven orders of magnitude in the measured cross-section values. PMID- 26042119 TI - P2X7 on Mouse T Cells: One Channel, Many Functions. AB - The P2X7 receptor is an adenosine triphosphate (ATP)-gated cation channel that is expressed by several cells of the immune system. P2X7 is best known for its proinflammatory role in promoting inflammasome formation and release of mature interleukin (IL)-1beta by innate immune cells. Mounting evidence indicates that P2X7 is also an important regulatory receptor of murine and human T cell functions. Murine T cells express a sensitive splice variant of P2X7 that can be activated either by non-covalent binding of ATP or, in the presence of nicotinamide adenine dinucleotide, by its covalent ADP-ribosylation catalyzed by the ecto-ADP-ribosyltransferase ARTC2.2. Prolonged activation of P2X7 by either one of these pathways triggers the induction of T cell death. Conversely, lower concentrations of ATP can activate P2X7 to enhance T cell proliferation and production of IL-2. In this review, we will highlight the molecular and cellular consequences of P2X7 activation on mouse T cells and its versatile role in T cell homeostasis and activation. Further, we will discuss important differences in the function of P2X7 on human and murine T cells. PMID- 26042120 TI - Revisiting mouse peritoneal macrophages: heterogeneity, development, and function. AB - Tissue macrophages play a crucial role in the maintenance of tissue homeostasis and also contribute to inflammatory and reparatory responses during pathogenic infection and tissue injury. The high heterogeneity of these macrophages is consistent with their adaptation to distinct tissue environments and specialization to develop niche-specific functions. Although peritoneal macrophages are one of the best-studied macrophage populations, recently it was demonstrated the co-existence of two subsets in mouse peritoneal cavity (PerC), which exhibit distinct phenotypes, functions, and origins. These macrophage subsets have been classified, according to their morphology, as large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs). LPMs, the most abundant subset under steady state conditions, express high levels of F4/80 and low levels of class II molecules of the major histocompatibility complex (MHC). LPMs appear to be originated from embryogenic precursors, and their maintenance in PerC is regulated by expression of specific transcription factors and tissue derived signals. Conversely, SPMs, a minor subset in unstimulated PerC, have a F4/80(low)MHC-II(high) phenotype and are generated from bone-marrow-derived myeloid precursors. In response to infectious or inflammatory stimuli, the cellular composition of PerC is dramatically altered, where LPMs disappear and SPMs become the prevalent population together with their precursor, the inflammatory monocyte. SPMs appear to be the major source of inflammatory mediators in PerC during infection, whereas LPMs contribute for gut-associated lymphoid tissue-independent and retinoic acid-dependent IgA production by peritoneal B-1 cells. In the previous years, considerable efforts have been made to broaden our understanding of LPM and SPM origin, transcriptional regulation, and functional profile. This review addresses these issues, focusing on the impact of tissue-derived signals and external stimulation in the complex dynamics of peritoneal macrophage populations. PMID- 26042121 TI - Mast cells and influenza a virus: association with allergic responses and beyond. AB - Influenza A virus (IAV) is a widespread infectious agent commonly found in mammalian and avian species. In humans, IAV is a respiratory pathogen that causes seasonal infections associated with significant morbidity in young and elderly populations, and has a large economic impact. Moreover, IAV has the potential to cause both zoonotic spillover infection and global pandemics, which have significantly greater morbidity and mortality across all ages. The pathology associated with these pandemic and spillover infections appear to be the result of an excessive inflammatory response leading to severe lung damage, which likely predisposes the lungs for secondary bacterial infections. The lung is protected from pathogens by alveolar epithelial cells, endothelial cells, tissue resident alveolar macrophages, dendritic cells, and mast cells. The importance of mast cells during bacterial and parasitic infections has been extensively studied; yet, the role of these hematopoietic cells during viral infections is only beginning to emerge. Recently, it has been shown that mast cells can be directly activated in response to IAV, releasing mediators such histamine, proteases, leukotrienes, inflammatory cytokines, and antiviral chemokines, which participate in the excessive inflammatory and pathological response observed during IAV infections. In this review, we will examine the relationship between mast cells and IAV, and discuss the role of mast cells as a potential drug target during highly pathological IAV infections. Finally, we proposed an emerging role for mast cells in other viral infections associated with significant host pathology. PMID- 26042122 TI - Accelerated apoptosis of neutrophils in familial mediterranean Fever. AB - The causative mutations for familial Mediterranean fever (FMF) are located in the MEFV gene, which encodes pyrin. Pyrin modulates the susceptibility to apoptosis via its PYD domain, but how the mutated versions of pyrin affect apoptotic processes are poorly understood. Spontaneous and induced rates of systemic neutrophil apoptosis as well as the levels of proteins involved in apoptosis were investigated ex vivo in patients with FMF using flow cytometry and RT-qPCR. The freshly collected neutrophils from the patients in FMF remission displayed a significantly larger number of cells spontaneously entering apoptosis compared to control (6.27 +/- 2.14 vs. 1.69 +/- 0.18%). This elevated ratio was retained after 24 h incubation of neutrophils in the growth medium (32.4 +/- 7.41 vs. 7.65 +/- 1.32%). Correspondingly, the mRNA level for caspase-3 was also significantly increased under these conditions. In response to the inducing agents, the neutrophils from FMF patients also displayed significantly elevated apoptotic rates compared to control. The elevated rates, however, can be largely explained by the higher basal ratio of apoptotic cells in the former group. Monitoring of several proteins involved in apoptosis has not revealed any conventional mechanisms contributing to the enhanced apoptotic rate of neutrophils in FMF. Although the exact molecular mechanisms of accelerated neutrophil apoptosis in FMF remain unknown, it may provide a protection against excessive inflammation and tissue damage due to a massive infiltration of neutrophils in the acute period of the disease. PMID- 26042124 TI - B cells and progressive multifocal leukoencephalopathy: search for the missing link. AB - Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinating disease due to JC virus (JCV) replication in the brain. PML classically occurs in patients with severe immunodepression, and cases have recently been linked to therapeutic monoclonal antibodies such as natalizumab and also rituximab, which depletes B cells. B cells appear to play a complex role in the pathogenesis of PML. They may act as a viral reservoir and as a vector for viral dissemination in the central nervous system. Anti-JCV antibody responses appear to have a limited effect on JCV replication in the brain. However, accumulating evidence suggests that B cells may considerably influence T cell responses through their cytokine secretion. This immunomodulatory function of B cells may play an important role in the control of JCV infection and in the pathogenesis of PML, including rituximab-induced PML. PMID- 26042123 TI - Intravital imaging - dynamic insights into natural killer T cell biology. AB - Natural killer T (NKT) cells were first recognized more than two decades ago as a separate and distinct lymphocyte lineage that modulates an expansive range of immune responses. As innate immune cells, NKT cells are activated early during inflammation and infection, and can subsequently stimulate or suppress the ensuing immune response. As a result, researchers hope to harness the immunomodulatory properties of NKT cells to treat a variety of diseases. However, many questions still remain unanswered regarding the biology of NKT cells, including how these cells traffic from the thymus to peripheral organs and how they play such contrasting roles in different immune responses and diseases. In this new era of intravital fluorescence microscopy, we are now able to employ this powerful tool to provide quantitative and dynamic insights into NKT cell biology including cellular dynamics, patrolling, and immunoregulatory functions with exquisite resolution. This review will highlight and discuss recent studies that use intravital imaging to understand the spectrum of NKT cell behavior in a variety of animal models. PMID- 26042125 TI - Differential sensitivity of regulatory and effector T cells to cell death: a prerequisite for transplant tolerance. AB - Despite significant progress achieved in transplantation, immunosuppressive therapies currently used to prevent graft rejection are still endowed with severe side effects impairing their efficiency over the long term. Thus, the development of graft-specific, non-toxic innovative therapeutic strategies has become a major challenge, the goal being to selectively target alloreactive effector T cells while sparing CD4(+)Foxp3(+) regulatory T cells (Tregs) to promote operational tolerance. Various approaches, notably the one based on monoclonal antibodies or fusion proteins directed against the TCR/CD3 complex, TCR coreceptors, or costimulatory molecules, have been proposed to reduce the alloreactive T cell pool, which is an essential prerequisite to create a therapeutic window allowing Tregs to induce and maintain allograft tolerance. In this mini review, we focus on the differential sensitivity of Tregs and effector T cells to the depleting and inhibitory effect of these immunotherapies, with a particular emphasis on CD3 specific antibodies that beyond their immunosuppressive effect, also express potent tolerogenic capacities. PMID- 26042128 TI - A decision support system (GesCoN) for managing fertigation in open field vegetable crops. Part I-methodological approach and description of the software. AB - Reduced water availability and environmental pollution caused by nitrogen (N) losses have increased the need for rational management of irrigation and N fertilization in horticultural systems. Decision support systems (DSS) could be powerful tools to assist farmers to improve irrigation and N fertilization efficiency. Currently, fertilization by drip irrigation system (fertigation) is used for many vegetable crops around the world. The paper illustrates the theoretical basis, the methodological approach and the structure of a DSS called GesCoN for fertigation management in open field vegetable crops. The DSS is based on daily water and N balance, considering the water lost by evapotranspiration (ET) and the N content in the aerial part of the crop (N uptake) as subtraction and the availability of water and N in the wet soil volume most effected by roots as the positive part. For the water balance, reference ET can be estimated using the Penman-Monteith (PM) or the Priestley-Taylor and Hargreaves models, specifically calibrated under local conditions. Both single or dual Kc approach can be used to calculate crop ET. Rain runoff and deep percolation are considered to calculate the effective rainfall. The soil volume most affected by the roots, the wet soil under emitters and their interactions are modeled. Crop growth is modeled by a non-linear logistic function on the basis of thermal time, but the model takes into account thermal and water stresses and allows an in-season calibration through a dynamic adaptation of the growth rate to the specific genetic and environmental conditions. N crop demand is related to DM accumulation by the N critical curve. N mineralization from soil organic matter is daily estimated. The DSS helps users to evaluate the daily amount of water and N fertilizer that has to be applied in order to fulfill the water and N-crop requirements to achieve the maximum potential yield, while reducing the risk of nitrate outflows. PMID- 26042129 TI - Dimerization and thiol sensitivity of the salicylic acid binding thimet oligopeptidases TOP1 and TOP2 define their functions in redox-sensitive cellular pathways. AB - A long-term goal in plant research is to understand how plants integrate signals from multiple environmental stressors. The importance of salicylic acid (SA) in plant response to biotic and abiotic stress is known, yet the molecular details of the SA-mediated pathways are insufficiently understood. Our recent work identified the peptidases TOP1 and TOP2 as critical components in plant response to pathogens and programmed cell death (PCD). In this study, we investigated the characteristics of TOPs related to the regulation of their enzymatic activity and function in oxidative stress response. We determined that TOP1 and TOP2 interact with themselves and each other and their ability to associate in dimers is influenced by SA and the thiol-based reductant DTT. Biochemical characterization of TOP1 and TOP2 indicated distinct sensitivities to DTT and similarly robust activity under a range of pH values. Treatments of top mutants with Methyl Viologen (MV) revealed TOP1 and TOP2 as a modulators of the plant tolerance to MV, and that exogenous SA alleviates the toxicity of MV in top background. Finally, we generated a TOP-centered computational model of a plant cell whose simulation outputs replicate experimental findings and predict novel functions of TOP1 and TOP2. Altogether, our work indicates that TOP1 and TOP2 mediate plant responses to oxidative stress through spatially separated pathways and positions proteolysis in a network for plant response to diverse stressors. PMID- 26042130 TI - Water consumption and biomass production of protoplast fusion lines of poplar hybrids under drought stress. AB - Woody crops such as poplars (Populus) can contribute to meet the increasing energy demand of a growing human population and can therefore enhance the security of energy supply. Using energy from biomass increases ecological sustainability as biomass is considered to play a pivotal role in abating climate change. Because areas for establishing poplar plantations are often confined to marginal sites drought tolerance is one important trait for poplar genotypes cultivated in short rotation coppice. We tested 9-month-old plants of four tetraploid Populus tremula (L.) * P. tremuloides (Michx.) lines that were generated by protoplast fusion and their diploid counterpart for water consumption and drought stress responses in a greenhouse experiment. The fusion lines showed equivalent or decreased height growth, stem biomass and total leaf area compared to the diploid line. The relative height increment of the fusion lines was not reduced compared to the diploid line when the plants were exposed to drought. The fusion lines were distinguished from the diploid counterpart by stomatal characteristics such as increased size and lower density. The changes in the stomatal apparatus did not affect the stomatal conductance. When exposed to drought the carbohydrate concentrations increased more strongly in the fusion lines than in the diploid line. Two fusion lines consumed significantly less water with regard to height growth, producing equivalent or increased relative stem biomass under drought compared to their diploid relative. Therefore, these tetraploid fusion lines are interesting candidates for short rotation biomass plantation on dry sites. PMID- 26042127 TI - Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target. AB - Autophagy, a constitutive intracellular degradation pathway, displays essential role in the homeostasis of immune cells, antigen processing and presentation, and many other immune processes. Perturbation of autophagy has been shown to be related to several autoimmune syndromes, including systemic lupus erythematosus. Therefore, modulating autophagy processes appears most promising for therapy of such autoimmune diseases. Autophagy can be said non-selective or selective; it is classified into three main forms, namely macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), the former process being by far the most intensively investigated. The role of CMA remains largely underappreciated in autoimmune diseases, even though CMA has been claimed to play pivotal functions into major histocompatibility complex class II-mediated antigen processing and presentation. Therefore, hereby, we give a special focus on CMA as a therapeutic target in autoimmune diseases, based in particular on our most recent experimental results where a phosphopeptide modulates lupus disease by interacting with CMA regulators. We propose that specifically targeting lysosomes and lysosomal pathways, which are central in autophagy processes and seem to be altered in certain autoimmune diseases such as lupus, could be an innovative approach of efficient and personalized treatment. PMID- 26042126 TI - Dendritic cell-based vaccination in cancer: therapeutic implications emerging from murine models. AB - Dendritic cells (DCs) play a pivotal role in the orchestration of immune responses, and are thus key targets in cancer vaccine design. Since the 2010 FDA approval of the first cancer DC-based vaccine (Sipuleucel-T), there has been a surge of interest in exploiting these cells as a therapeutic option for the treatment of tumors of diverse origin. In spite of the encouraging results obtained in the clinic, many elements of DC-based vaccination strategies need to be optimized. In this context, the use of experimental cancer models can help direct efforts toward an effective vaccine design. This paper reviews recent findings in murine models regarding the antitumoral mechanisms of DC-based vaccination, covering issues related to antigen sources, the use of adjuvants and maturing agents, and the role of DC subsets and their interaction in the initiation of antitumoral immune responses. The summary of such diverse aspects will highlight advantages and drawbacks in the use of murine models, and contribute to the design of successful DC-based translational approaches for cancer treatment. PMID- 26042132 TI - Salicylic acid modulates arsenic toxicity by reducing its root to shoot translocation in rice (Oryza sativa L.). AB - Arsenic (As) is posing serious health concerns in South East Asia where rice, an efficient accumulator of As, is prominent crop. Salicylic acid (SA) is an important signaling molecule and plays a crucial role in resistance against biotic and abiotic stress in plants. In present study, ameliorative effect of SA against arsenate (As(V)) toxicity has been investigated in rice (Oryza sativa L.). Arsenate stress hampered the plant growth in terms of root, shoots length, and biomass as well as it enhanced the level of H2O2 and MDA in dose dependent manner in shoot. Exogenous application of SA, reverted the growth, and oxidative stress caused by As(V) and significantly decreased As translocation to the shoots. Level of As in shoot was positively correlated with the expression of OsLsi2, efflux transporter responsible for root to shoot translocation of As in the form of arsenite (As(III)). SA also overcame As(V) induced oxidative stress and modulated the activities of antioxidant enzymes in a differential manner in shoots. As treatment hampered the translocation of Fe in the shoot which was compensated by the SA treatment. The level of Fe in root and shoot was positively correlated with the transcript level of transporters responsible for the accumulation of Fe, OsNRAMP5, and OsFRDL1, in the root and shoot, respectively. Co-application of SA was more effective than pre-treatment for reducing As accumulation as well as imposed toxicity. PMID- 26042131 TI - The guard cell metabolome: functions in stomatal movement and global food security. AB - Guard cells represent a unique single cell-type system for the study of cellular responses to abiotic and biotic perturbations that affect stomatal movement. Decades of effort through both classical physiological and functional genomics approaches have generated an enormous amount of information on the roles of individual metabolites in stomatal guard cell function and physiology. Recent application of metabolomics methods has produced a substantial amount of new information on metabolome control of stomatal movement. In conjunction with other "omics" approaches, the knowledge-base is growing to reach a systems-level description of this single cell-type. Here we summarize current knowledge of the guard cell metabolome and highlight critical metabolites that bear significant impact on future engineering and breeding efforts to generate plants/crops that are resistant to environmental challenges and produce high yield and quality products for food and energy security. PMID- 26042133 TI - The maize (Zea mays ssp. mays var. B73) genome encodes 33 members of the purple acid phosphatase family. AB - Purple acid phosphatases (PAPs) play an important role in plant phosphorus nutrition, both by liberating phosphorus from organic sources in the soil and by modulating distribution within the plant throughout growth and development. Furthermore, members of the PAP protein family have been implicated in a broader role in plant mineral homeostasis, stress responses and development. We have identified 33 candidate PAP encoding gene models in the maize (Zea mays ssp. mays var. B73) reference genome. The maize Pap family includes a clear single-copy ortholog of the Arabidopsis gene AtPAP26, shown previously to encode both major intracellular and secreted acid phosphatase activities. Certain groups of PAPs present in Arabidopsis, however, are absent in maize, while the maize family contains a number of expansions, including a distinct radiation not present in Arabidopsis. Analysis of RNA-sequencing based transcriptome data revealed accumulation of maize Pap transcripts in multiple plant tissues at multiple stages of development, and increased accumulation of specific transcripts under low phosphorus availability. These data suggest the maize PAP family as a whole to have broad significance throughout the plant life cycle, while highlighting potential functional specialization of individual family members. PMID- 26042134 TI - Variations in foliar monoterpenes across the range of jack pine reveal three widespread chemotypes: implications to host expansion of invasive mountain pine beetle. AB - The secondary compounds of pines (Pinus) can strongly affect the physiology, ecology and behaviors of the bark beetles (Coleoptera: Curculionidae, Scolytinae) that feed on sub-cortical tissues of hosts. Jack pine (Pinus banksiana) has a wide natural distribution range in North America (Canada and USA) and thus variations in its secondary compounds, particularly monoterpenes, could affect the host expansion of invasive mountain pine beetle (Dendroctonus ponderosae), which has recently expanded its range into the novel jack pine boreal forest. We investigated monoterpene composition of 601 jack pine trees from natural and provenance forest stands representing 63 populations from Alberta to the Atlantic coast. Throughout its range, jack pine exhibited three chemotypes characterized by high proportions of alpha-pinene, beta-pinene, or limonene. The frequency with which the alpha-pinene and beta-pinene chemotypes occurred at individual sites was correlated to climatic variables, such as continentality and mean annual precipitation, as were the individual alpha-pinene and beta-pinene concentrations. However, other monoterpenes were generally not correlated to climatic variables or geographic distribution. Finally, while the enantiomeric ratios of beta-pinene and limonene remained constant across jack pine's distribution, (-):(+)-alpha-pinene exhibited two separate trends, thereby delineating two alpha-pinene phenotypes, both of which occurred across jack pine's range. These significant variations in jack pine monoterpene composition may have cascading effects on the continued eastward spread and success of D. ponderosae in the Canadian boreal forest. PMID- 26042136 TI - A commentary on "Eucalyptus obliqua seedling growth in organic vs. mineral soil horizons". PMID- 26042135 TI - Metabolic responses of willow (Salix purpurea L.) leaves to mycorrhization as revealed by mass spectrometry and (1)H NMR spectroscopy metabolite profiling. AB - The root system of most terrestrial plants form symbiotic interfaces with arbuscular mycorrhizal fungi (AMF), which are important for nutrient cycling and ecosystem sustainability. The elucidation of the undergoing changes in plants' metabolism during symbiosis is essential for understanding nutrient acquisition and for alleviation of soil stresses caused by environmental cues. Within this context, we have undertaken the task of recording the fluctuation of willow (Salix purpurea L.) leaf metabolome in response to AMF inoculation. The development of an advanced metabolomics/bioinformatics protocol employing mass spectrometry (MS) and (1)H NMR analyzers combined with the in-house-built metabolite library for willow (http://willowmetabolib. RESEARCH: mcgill.ca/index.html) are key components of the research. Analyses revealed that AMF inoculation of willow causes up-regulation of various biosynthetic pathways, among others, those of flavonoid, isoflavonoid, phenylpropanoid, and the chlorophyll and porphyrin pathways, which have well-established roles in plant physiology and are related to resistance against environmental stresses. The recorded fluctuation in the willow leaf metabolism is very likely to provide AMF inoculated willows with a significant advantage compared to non-inoculated ones when they are exposed to stresses such as, high levels of soil pollutants. The discovered biomarkers of willow response to AMF inoculation and corresponding pathways could be exploited in biomarker-assisted selection of willow cultivars with superior phytoremediation capacity or genetic engineering programs. PMID- 26042137 TI - Salt tolerance research in date palm tree (Phoenix dactylifera L.), past, present, and future perspectives. AB - The date palm can adapt to extreme drought, to heat, and to relatively high levels of soil salinity. However, excessive amounts of salt due to irrigation with brackish water lead to a significant reduction in the productivity of the fruits as well as marked decrease in the viable numbers of the date palm trees. It is imperative that the nature of the existing salt-adaptation mechanism be understood in order to develop future date palm varieties that can tolerate excessive soil salinity. In this perspective article, several research strategies, obstacles, and precautions are discussed in light of recent advancements accomplished in this field and the properties of this species. In addition to a physiological characterization, we propose the use of a full range of OMICS technologies, coupled with reverse genetics approaches, aimed toward understanding the salt-adaption mechanism in the date palm. Information generated by these analyses should highlight transcriptional and posttranscriptional modifications controlling the salt-adaptation mechanisms. As an extremophile with a natural tolerance for a wide range of abiotic stresses, the date palm may represent a treasure trove of novel genetic resources for salinity tolerance. PMID- 26041978 TI - Determination of spin and parity of the Higgs boson in the [Formula: see text] decay channel with the ATLAS detector. AB - Studies of the spin and parity quantum numbers of the Higgs boson in the [Formula: see text] final state are presented, based on proton-proton collision data collected by the ATLAS detector at the Large Hadron Collider, corresponding to an integrated luminosity of 20.3 fb[Formula: see text] at a centre-of-mass energy of [Formula: see text] TeV. The Standard Model spin-parity [Formula: see text] hypothesis is compared with alternative hypotheses for both spin and CP. The case where the observed resonance is a mixture of the Standard-Model-like Higgs boson and CP-even ([Formula: see text]) or CP-odd ([Formula: see text]) Higgs boson in scenarios beyond the Standard Model is also studied. The data are found to be consistent with the Standard Model prediction and limits are placed on alternative spin and CP hypotheses, including CP mixing in different scenarios. PMID- 26042138 TI - Microbial effectors target multiple steps in the salicylic acid production and signaling pathway. AB - Microbes attempting to colonize plants are recognized through the plant immune surveillance system. This leads to a complex array of global as well as specific defense responses, which are often associated with plant cell death and subsequent arrest of the invader. The responses also entail complex changes in phytohormone signaling pathways. Among these, salicylic acid (SA) signaling is an important pathway because of its ability to trigger plant cell death. As biotrophic and hemibiotrophic pathogens need to invade living plant tissue to cause disease, they have evolved efficient strategies to downregulate SA signaling by virulence effectors, which can be proteins or secondary metabolites. Here we review the strategies prokaryotic pathogens have developed to target SA biosynthesis and signaling, and contrast this with recent insights into how plant pathogenic eukaryotic fungi and oomycetes accomplish the same goal. PMID- 26042139 TI - Sesquiterpene volatile organic compounds (VOCs) are markers of elicitation by sulfated laminarine in grapevine. AB - Inducing resistance in plants by the application of elicitors of defense reactions is an attractive plant protection strategy, particularly for grapevine (Vitis vinifera), which is susceptible to severe fungal diseases. Although induced resistance (IR) can be successful under controlled conditions, in most cases, IR is not sufficiently effective for practical disease control under outdoor conditions. Progress in the application of IR requires a better understanding of grapevine defense mechanisms and the ability to monitor defense markers to identify factors, such as physiological and environmental factors, that can impact IR in the vineyard. Volatile organic compounds (VOCs) are well known plant defense compounds that have received little or no attention to date in the case of grape-pathogen interactions. This prompted us to investigate whether an elicitor, the sulfated laminarin (PS3), actually induces the production of VOCs in grapevine. An online analysis (proton-transfer-reaction quadrupole mass spectrometry) of VOC emissions in dynamic cuvettes and passive sampling in gas-tight bags with solid-phase microextraction-GC-MS under greenhouse conditions showed that PS3 elicited the emission of VOCs. Some of them, such as (E,E)-alpha-farnesene, may be good candidates as biomarkers of elicitor-IR, whereas methyl salicylate appears to be a biomarker of downy mildew infection. A negative correlation between VOC emission and disease severity suggests a positive role of VOCs in grape defense against diseases. PMID- 26041977 TI - Observation and measurements of the production of prompt and non-prompt [Formula: see text] mesons in association with a [Formula: see text] boson in [Formula: see text] collisions at [Formula: see text] with the ATLAS detector. AB - The production of a [Formula: see text] boson in association with a [Formula: see text] meson in proton-proton collisions probes the production mechanisms of quarkonium and heavy flavour in association with vector bosons, and allows studies of multiple parton scattering. Using [Formula: see text] of data collected with the ATLAS experiment at the LHC in [Formula: see text] collisions at [Formula: see text], the first measurement of associated [Formula: see text] production is presented for both prompt and non-prompt [Formula: see text] production, with both signatures having a significance in excess of [Formula: see text]. The inclusive production cross-sections for [Formula: see text] boson production (analysed in [Formula: see text] or [Formula: see text] decay modes) in association with prompt and non-prompt [Formula: see text] are measured relative to the inclusive production rate of [Formula: see text] bosons in the same fiducial volume to be [Formula: see text] and [Formula: see text] respectively. Normalised differential production cross-section ratios are also determined as a function of the [Formula: see text] transverse momentum. The fraction of signal events arising from single and double parton scattering is estimated, and a lower limit of [Formula: see text] at [Formula: see text] confidence level is placed on the effective cross-section regulating double parton interactions. PMID- 26042141 TI - Will selenium increase lentil (Lens culinaris Medik) yield and seed quality? AB - Lentil (Lens culinaris Medik), a nutritious traditional pulse crop, has been experiencing a declining area of production in South East Asia, due to lower yields, and marginal soils. The objective of this study was to determine whether selenium (Se) fertilization can increase lentil yield, productivity, and seed quality (both seed Se concentration and speciation). Selenium was provided to five lentil accessions as selenate or selenite by foliar or soil application at rates of 0, 10, 20, or 30 kg Se/ha and the resulting lentil biomass, grain yield, seed Se concentration, and Se speciation was determined. Seed Se concentration was measured using inductively coupled plasma optical emission spectrometry (ICP OES) after acid digestion. Seed Se speciation was measured using ICP-mass spectrometry with a high performance liquid chromatography (ICP-MS-LC) system. Foliar application of Se significantly increased lentil biomass (5586 vs. 7361 kg/ha), grain yield (1732 vs. 2468 kg /ha), and seed Se concentrations (0.8 vs. 2.4 MUg/g) compared to soil application. In general, both application methods and both forms of Se increased concentrations of organic Se forms (selenocysteine and selenomethionine) in lentil seeds. Not surprisingly, the high yielding CDC Redberry had the highest levels of biomass and grain yield of all varieties evaluated. Eston, ILL505, and CDC Robin had the greatest responses to Se fertilization with respect to both grain yield, seed Se concentration and speciation; thus, use of these varieties in areas with low-Se soils might require Se fertilization to reach yield potentials. PMID- 26042140 TI - Quantitative testing of the methodology for genome size estimation in plants using flow cytometry: a case study of the Primulina genus. AB - Flow cytometry (FCM) is a commonly used method for estimating genome size in many organisms. The use of FCM in plants is influenced by endogenous fluorescence inhibitors and may cause an inaccurate estimation of genome size; thus, falsifying the relationship between genome size and phenotypic traits/ecological performance. Quantitative optimization of FCM methodology minimizes such errors, yet there are few studies detailing this methodology. We selected the genus Primulina, one of the most representative and diverse genera of the Old World Gesneriaceae, to evaluate the methodology effect on determining genome size. Our results showed that buffer choice significantly affected genome size estimation in six out of the eight species examined and altered the 2C-value (DNA content) by as much as 21.4%. The staining duration and propidium iodide (PI) concentration slightly affected the 2C-value. Our experiments showed better histogram quality when the samples were stained for 40 min at a PI concentration of 100 MUg ml(-1). The quality of the estimates was not improved by 1-day incubation in the dark at 4 degrees C or by centrifugation. Thus, our study determined an optimum protocol for genome size measurement in Primulina: LB01 buffer supplemented with 100 MUg ml(-1) PI and stained for 40 min. This protocol also demonstrated a high universality in other Gesneriaceae genera. We report the genome size of nine Gesneriaceae species for the first time. The results showed substantial genome size variation both within and among the species, with the 2C value ranging between 1.62 and 2.71 pg. Our study highlights the necessity of optimizing the FCM methodology prior to obtaining reliable genome size estimates in a given taxon. PMID- 26042142 TI - Growth and lipid accumulation of microalgae from fluctuating brackish and sea water locations in South East Queensland-Australia. AB - One challenge constraining the use of microalgae in the food and biofuels industry is growth and lipid accumulation. Microalgae with high growth characteristics are more likely to originate from the local environment. However, to be commercially effective, in addition to high growth microalgae must also have high lipid productivities and contain the desired fatty acids for their intended use. We isolated microalgae from intertidal locations in South East Queensland, Australia with adverse or fluctuating conditions, as these may harbor more opportunistic strains with high lipid accumulation potential. Screening was based on a standard protocol using growth rate and lipid accumulation as well as prioritizing fatty acid profiles suitable for biodiesel or nutraceuticals. Using these criteria, an initial selection of over 50 local microalgae strains from brackish and sea water was reduced to 16 strains considered suitable for further investigation. Among these 16 strains, the ones most likely to be effective for biodiesel feedstock were Nitzschia sp. CP3a, Tetraselmis sp. M8, Cymbella sp. CP2b, and Cylindrotheca closterium SI1c, reaching growth rates of up to 0.53 day( 1) and lipid productivities of 5.62 MUg mL(-1)day(-1). Omega-3 fatty acids were found in some strains such as Nitzschia sp. CP2a, Nitzschia sp. CP3a and Cylindrotheca closterium SI1c. These strains have potential for further research as commercial food supplements. PMID- 26042144 TI - Allyl isothiocyanate affects the cell cycle of Arabidopsis thaliana. AB - Isothiocyanates (ITCs) are degradation products of glucosinolates present in members of the Brassicaceae family acting as herbivore repellents and antimicrobial compounds. Recent results indicate that allyl ITC (AITC) has a role in defense responses such as glutathione depletion, ROS generation and stomatal closure. In this study we show that exposure to non-lethal concentrations of AITC causes a shift in the cell cycle distribution of Arabidopsis thaliana leading to accumulation of cells in S-phases and a reduced number of cells in non replicating phases. Furthermore, transcriptional analysis revealed an AITC induced up-regulation of the gene encoding cyclin-dependent kinase A while several genes encoding mitotic proteins were down-regulated, suggesting an inhibition of mitotic processes. Interestingly, visualization of DNA synthesis indicated that exposure to AITC reduced the rate of DNA replication. Taken together, these results indicate that non-lethal concentrations of AITC induce cells of A. thaliana to enter the cell cycle and accumulate in S-phases, presumably as a part of a defensive response. Thus, this study suggests that AITC has several roles in plant defense and add evidence to the growing data supporting a multifunctional role of glucosinolates and their degradation products in plants. PMID- 26042148 TI - Variable mating behaviors and the maintenance of tropical biodiversity. AB - Current theoretical studies on mechanisms promoting species co-existence in diverse communities assume that species are fixed in their mating behavior. Each species is a discrete evolutionary unit, even though most empirical evidence indicates that inter-specific gene flow occurs in plant and animal groups. Here, in a data-driven meta-community model of species co-existence, we allow mating behavior to respond to local species composition and abundance. While individuals primarily out-cross, species maintain a diminished capacity for selfing and hybridization. Mate choice is treated as a variable behavior, which responds to intrinsic traits determining mate choice and the density and availability of sympatric inter-fertile individuals. When mate choice is strongly limited, even low survivorship of selfed offspring can prevent extinction of rare species. With increasing mate choice, low hybridization success rates maintain community level diversity for extended periods of time. In high diversity tropical tree communities, competition among sympatric congeneric species is negligible, because direct spatial proximity with close relatives is infrequent. Therefore, the genomic donorship presents little cost. By incorporating variable mating behavior into evolutionary models of diversification, we also discuss how participation in a syngameon may be selectively advantageous. We view this behavior as a genomic mutualism, where maintenance of genomic structure and diminished inter-fertility, allows each species in the syngameon to benefit from a greater effective population size during episodes of selective disadvantage. Rare species would play a particularly important role in these syngameons as they are more likely to produce heterospecific crosses and transgressive phenotypes. We propose that inter-specific gene flow can play a critical role by allowing genomic mutualists to avoid extinction and gain local adaptations. PMID- 26042143 TI - System approaches to study root hairs as a single cell plant model: current status and future perspectives. AB - Our current understanding of plant functional genomics derives primarily from measurements of gene, protein and/or metabolite levels averaged over the whole plant or multicellular tissues. These approaches risk diluting the response of specific cells that might respond strongly to the treatment but whose signal is diluted by the larger proportion of non-responding cells. For example, if a gene is expressed at a low level, does this mean that it is indeed lowly expressed or is it highly expressed, but only in a few cells? In order to avoid these issues, we adopted the soybean root hair cell, derived from a single, differentiated root epidermal cell, as a single-cell model for functional genomics. Root hair cells are intrinsically interesting since they are major conduits for root water and nutrient uptake and are also the preferred site of infection by nitrogen-fixing rhizobium bacteria. Although a variety of other approaches have been used to study single plant cells or single cell types, the root hair system is perhaps unique in allowing application of the full repertoire of functional genomic and biochemical approaches. In this mini review, we summarize our published work and place this within the broader context of root biology, with a significant focus on understanding the initial events in the soybean-rhizobium interaction. PMID- 26042145 TI - FAST: FAST Analysis of Sequences Toolbox. AB - FAST (FAST Analysis of Sequences Toolbox) provides simple, powerful open source command-line tools to filter, transform, annotate and analyze biological sequence data. Modeled after the GNU (GNU's Not Unix) Textutils such as grep, cut, and tr, FAST tools such as fasgrep, fascut, and fastr make it easy to rapidly prototype expressive bioinformatic workflows in a compact and generic command vocabulary. Compact combinatorial encoding of data workflows with FAST commands can simplify the documentation and reproducibility of bioinformatic protocols, supporting better transparency in biological data science. Interface self-consistency and conformity with conventions of GNU, Matlab, Perl, BioPerl, R, and GenBank help make FAST easy and rewarding to learn. FAST automates numerical, taxonomic, and text-based sorting, selection and transformation of sequence records and alignment sites based on content, index ranges, descriptive tags, annotated features, and in-line calculated analytics, including composition and codon usage. Automated content- and feature-based extraction of sites and support for molecular population genetic statistics make FAST useful for molecular evolutionary analysis. FAST is portable, easy to install and secure thanks to the relative maturity of its Perl and BioPerl foundations, with stable releases posted to CPAN. Development as well as a publicly accessible Cookbook and Wiki are available on the FAST GitHub repository at https://github.com/tlawrence3/FAST. The default data exchange format in FAST is Multi-FastA (specifically, a restriction of BioPerl FastA format). Sanger and Illumina 1.8+ FastQ formatted files are also supported. FAST makes it easier for non-programmer biologists to interactively investigate and control biological data at the speed of thought. PMID- 26042147 TI - DNA methylation results depend on DNA integrity-role of post mortem interval. AB - Major questions of neurological and psychiatric mechanisms involve the brain functions on a molecular level and cannot be easily addressed due to limitations in access to tissue samples. Post mortem studies are able to partly bridge the gap between brain tissue research retrieved from animal trials and the information derived from peripheral analysis (e.g., measurements in blood cells) in patients. Here, we wanted to know how fast DNA degradation is progressing under controlled conditions in order to define thresholds for tissue quality to be used in respective trials. Our focus was on the applicability of partly degraded samples for bisulfite sequencing and the determination of simple means to define cut-off values. After opening the brain cavity, we kept two consecutive pig skulls at ambient temperature (19-21 degrees C) and removed cortex tissue up to a post mortem interval (PMI) of 120 h. We calculated the percentage of degradation on DNA gel electrophoresis of brain DNA to estimate quality and relate this estimation spectrum to the quality of human post mortem control samples. Functional DNA quality was investigated by bisulfite sequencing of two functionally relevant genes for either the serotonin receptor 5 (SLC6A4) or aldehyde dehydrogenase 2 (ALDH2). Testing our approach in a heterogeneous collective of human blood and brain samples, we demonstrate integrity of measurement quality below the threshold of 72 h PMI. While sequencing technically worked for all timepoints irrespective of conceivable DNA degradation, there is a good correlation between variance of methylation to degradation levels documented in the gel (R (2) = 0.4311, p = 0.0392) for advancing post mortem intervals (PMI). This otherwise elusive phenomenon is an important prerequisite for the interpretation and evaluation of samples prior to in-depth processing via an affordable and easy assay to estimate identical sample quality and thereby comparable methylation measurements. PMID- 26042149 TI - The Red Queen in mitochondria: cyto-nuclear co-evolution, hybrid breakdown and human disease. AB - Cyto-nuclear incompatibility, a specific form of Dobzhansky-Muller incompatibility caused by incompatible alleles between mitochondrial and nuclear genomes, has been suggested to play a critical role during speciation. Several features of the mitochondrial genome (mtDNA), including high mutation rate, dynamic genomic structure, and uniparental inheritance, make mtDNA more likely to accumulate mutations in the population. Once mtDNA has changed, the nuclear genome needs to play catch-up due to the intimate interactions between these two genomes. In two populations, if cyto-nuclear co-evolution is driven in different directions, it may eventually lead to hybrid incompatibility. Although cyto nuclear incompatibility has been observed in a wide range of organisms, it remains unclear what type of mutations drives the co-evolution. Currently, evidence supporting adaptive mutations in mtDNA remains limited. On the other hand, it has been known that some mutations allow mtDNA to propagate more efficiently but compromise the host fitness (described as selfish mtDNA). Arms races between such selfish mtDNA and host nuclear genomes can accelerate cyto nuclear co-evolution and lead to a phenomenon called the Red Queen Effect. Here, we discuss how the Red Queen Effect may contribute to the frequent observation of cyto-nuclear incompatibility and be the underlying driving force of some human mitochondrial diseases. PMID- 26042146 TI - The differential view of genotype-phenotype relationships. AB - An integrative view of diversity and singularity in the living world requires a better understanding of the intricate link between genotypes and phenotypes. Here we re-emphasize the old standpoint that the genotype-phenotype (GP) relationship is best viewed as a connection between two differences, one at the genetic level and one at the phenotypic level. As of today, predominant thinking in biology research is that multiple genes interact with multiple environmental variables (such as abiotic factors, culture, or symbionts) to produce the phenotype. Often, the problem of linking genotypes and phenotypes is framed in terms of genotype and phenotype maps, and such graphical representations implicitly bring us away from the differential view of GP relationships. Here we show that the differential view of GP relationships is a useful explanatory framework in the context of pervasive pleiotropy, epistasis, and environmental effects. In such cases, it is relevant to view GP relationships as differences embedded into differences. Thinking in terms of differences clarifies the comparison between environmental and genetic effects on phenotypes and helps to further understand the connection between genotypes and phenotypes. PMID- 26042150 TI - Emerging applications of read profiles towards the functional annotation of the genome. AB - Functional annotation of the genome is important to understand the phenotypic complexity of various species. The road toward functional annotation involves several challenges ranging from experiments on individual molecules to large scale analysis of high-throughput sequencing (HTS) data. HTS data is typically a result of the protocol designed to address specific research questions. The sequencing results in reads, which when mapped to a reference genome often leads to the formation of distinct patterns (read profiles). Interpretation of these read profiles is essential for their analysis in relation to the research question addressed. Several strategies have been employed at varying levels of abstraction ranging from a somewhat ad hoc to a more systematic analysis of read profiles. These include methods which can compare read profiles, e.g., from direct (non-sequence based) alignments to classification of patterns into functional groups. In this review, we highlight the emerging applications of read profiles for the annotation of non-coding RNA and cis-regulatory elements (CREs) such as enhancers and promoters. We also discuss the biological rationale behind their formation. PMID- 26042152 TI - Epidemiology of envenomations by terrestrial venomous animals in Brazil based on case reporting: from obvious facts to contingencies. AB - BACKGROUND: Envenomation remains a neglected public health issue in most tropical countries. A better understanding of the epidemiology of bites and stings by venomous animals should facilitate their prevention and management. This study aimed to explore the benefits that could be derived from the compulsory notification of cases as it is now routinely practiced in Brazil. METHODS: The Brazilian Notifiable Diseases Information System (SINAN) was consulted online for the 2001-2012 period on all envenomations by venomous terrestrial animals. We studied the incidence, severity, number of deaths, gender, season of accident and time between the accident and hospital consultation. RESULTS: In total, 1,192,667 accidents and 2,664 deaths from terrestrial venomous animals (snakes, scorpions, spiders, bees and caterpillars) were reported in Brazil during these 12 years, the circumstances of which are detailed in this study. Most envenomations and deaths were caused by snakebites and scorpion stings. However, incidence and mortality showed high regional variations. During this period, the steady and parallel increase of the cases from all the species resulted from several factors including the human population increase, gradual improvement of data collection system and, probably, environmental and socioeconomic factors affecting in a different way the incidence of envenomation by each zoological group and by region. CONCLUSION: Mandatory reporting of cases appears to be a useful tool to improve the management of envenomations. However, local studies should be continued to account for the variability of accident circumstances and refine measures necessary for their management. PMID- 26042151 TI - Genome-wide analyses of small non-coding RNAs in streptococci. AB - Streptococci represent a diverse group of Gram-positive bacteria, which colonize a wide range of hosts among animals and humans. Streptococcal species occur as commensal as well as pathogenic organisms. Many of the pathogenic species can cause severe, invasive infections in their hosts leading to a high morbidity and mortality. The consequence is a tremendous suffering on the part of men and livestock besides the significant financial burden in the agricultural and healthcare sectors. An environmentally stimulated and tightly controlled expression of virulence factor genes is of fundamental importance for streptococcal pathogenicity. Bacterial small non-coding RNAs (sRNAs) modulate the expression of genes involved in stress response, sugar metabolism, surface composition, and other properties that are related to bacterial virulence. Even though the regulatory character is shared by this class of RNAs, variation on the molecular level results in a high diversity of functional mechanisms. The knowledge about the role of sRNAs in streptococci is still limited, but in recent years, genome-wide screens for sRNAs have been conducted in an increasing number of species. Bioinformatics prediction approaches have been employed as well as expression analyses by classical array techniques or next generation sequencing. This review will give an overview of whole genome screens for sRNAs in streptococci with a focus on describing the different methods and comparing their outcome considering sRNA conservation among species, functional similarities, and relevance for streptococcal infection. PMID- 26042153 TI - Antibacterial potential of a basic phospholipase A2 (VRV-PL-VIIIa) from Daboia russelii pulchella (Russell's viper) venom. AB - BACKGROUND: Microbial/bacterial resistance against antibiotics poses a serious threat to public health. Furthermore, the side effects of these antibiotics have stimulated tremendous interest in developing new molecules from diverse organisms as therapeutic agents. This study evaluates the antibacterial potential of a basic protein, Vipera russellii venom phospholipase A2 fraction VIIIa (VRV-PL VIIIa), from Daboia russelii pulchella venom against gram-positive and gram negative bacteria. METHODS: The antibacterial potential of VRV-PL-VIIIa in the presence and absence of an inhibitor (p-bromophenacyl bromide) was tested against gram-positive and gram-negative bacteria and the minimum inhibitory concentration was determined by microdilution tests. RESULTS: VRV-PL-VIIIa demonstrated potent antibacterial activities against all the human pathogenic strains tested. It more effectively inhibited such gram-positive bacteria as Staphylococcus aureus and Bacillus subtilis, when compared to the gram-negative bacteria Escherichia coli, Vibrio cholerae, Klebsiella pneumoniae and Salmonella paratyphi. It inhibited bacterial growth at minimum inhibitory concentration values ranging from 11.1 to 19.2 MUg/mL. The anti-bacterial potential of VRV-PL-VIIIa was comparable to the standards gentamycin, chlorophenicol and streptomycin. The PLA2's hemolytic and antibacterial activities were strongly correlated. Furthermore, even in the presence of p-bromophenacyl bromide, intense antibacterial activity was observed, suggesting a dissociation or partial overlapping of the bactericidal/antimicrobial domains. CONCLUSION: VRV-PL-VIIIa demonstrated potent antibacterial activities against all the human pathogenic strains tested. The study shows that despite a strong correlation between enzymatic and antimicrobial activities of VRV-PL-VIIIa, it may possess additional properties that mimic the bactericidal/membrane permeability-increasing protein. This study encourages further in-depth studies on the molecular mechanisms of antibacterial properties of VRV-PL-VIIIa, which would thereby facilitate development of this protein into a possible therapeutic lead molecule for treating bacterial infections. PMID- 26042154 TI - GAML: genome assembly by maximum likelihood. AB - BACKGROUND: Resolution of repeats and scaffolding of shorter contigs are critical parts of genome assembly. Modern assemblers usually perform such steps by heuristics, often tailored to a particular technology for producing paired or long reads. RESULTS: We propose a new framework that allows systematic combination of diverse sequencing datasets into a single assembly. We achieve this by searching for an assembly with the maximum likelihood in a probabilistic model capturing error rate, insert lengths, and other characteristics of the sequencing technology used to produce each dataset. We have implemented a prototype genome assembler GAML that can use any combination of insert sizes with Illumina or 454 reads, as well as PacBio reads. Our experiments show that we can assemble short genomes with N50 sizes and error rates comparable to ALLPATHS-LG or Cerulean. While ALLPATHS-LG and Cerulean require each a specific combination of datasets, GAML works on any combination. CONCLUSIONS: We have introduced a new probabilistic approach to genome assembly and demonstrated that this approach can lead to superior results when used to combine diverse set of datasets from different sequencing technologies. Data and software is available at http://compbio.fmph.uniba.sk/gaml. PMID- 26042155 TI - Protease-inhibiting, molecular modeling and antimicrobial activities of extracts and constituents from Helichrysum foetidum and Helichrysum mechowianum (compositae). AB - BACKGROUND: Helichrysum species are used extensively for stress-related ailments and as dressings for wounds normally encountered in circumcision rites, bruises, cuts and sores. It has been reported that Helichysum species are used to relief abdominal pain, heart burn, cough, cold, wounds, female sterility, menstrual pain. RESULTS: From the extracts of Helichrysum foetidum (L.) Moench, six known compounds were isolated and identified. They were 7, 4'-dihydroxy-5-methoxy flavanone (1), 6'-methoxy-2',4, 4'-trihydroxychalcone (2), 6'-methoxy-2',4 dihydroxychalcone -4'-O-beta-D-glucoside (3), apigenin (4), apigenin-7-O-beta-D glucoside (5), kaur-16-en-18-oic acid (6) while two known compounds 3,5,7 trihydroxy-8-methoxyflavone (12), 4,5-dicaffeoyl quinic acid (13) together with a mixture of phytosterol were isolated from the methanol extract of Helichrysum mechowianum Klatt. All the compounds were characterized by spectroscopic and mass spectrometric methods, and by comparison with literature data. Both extracts and all the isolates were screened for the protease inhibition, antibacterial and antifungal activities. In addition, the phytochemical profiles of both species were investigated by ESI-MS experiments. CONCLUSIONS: These results showed that the protease inhibition assay of H. foetidum could be mainly attributed to the constituents of flavonoids glycosides (3, 5) while the compound (13) from H. mechowianum contributes to the stomach protecting effects. In addition, among the antibacterial and antifungal activities of all the isolates, compound (6) was found to possess a potent inhibitor effect against the tested microorganisms. The heterogeneity of the genus is also reflected in its phytochemical diversity. The differential bioactivities and determined constituents support the traditional use of the species. Molecular modelling was carried out by computing selected descriptors related to drug absorption, distribution, metabolism, excretion and toxicity (ADMET). Graphical abstractCompounds isolated from Helichrysum species (Compositae). PMID- 26042157 TI - The extraordinary potential of primary care to improve mental health. PMID- 26042156 TI - Azoospermia and trisomy 18p syndrome: a fortuitous association? A patient report and a review of the literature. AB - Complete, isolated trisomy of the short arm of chromosome 18 is very rare. To date, only 24 cases of trisomy 18p have been reported in the literature, making it difficult to define a potentially associated phenotype. However, the available evidence suggests that few clinical features are shared by these patients: only variable intellectual disability, variable facial dysmorphism and epilepsy are reported in a few patients. Although three inherited cases of trisomy 18p have already been reported, all were of maternal origin. We report on a patient carrying an isolated complete trisomy 18p translocated to the short arm of chromosome 14 and presenting with facial dysmorphism, mild intellectual disability and non-obstructive azoospermia. Chromosomal abnormalities are more frequent in infertile men with poor sperm quality than the general population. Both numerical and structural chromosomal aberrations have been already reported within the context of azoospermia. To our knowledge, this is the first patient with trisomy 18p to present a fertility impairment due to totally altered spermatogenesis and azoospermia. Although fertility disorders were not mentioned in the four previous reports of men with trisomy 18p, none of the latter had children. We suggest that azoospermia is a previously uncharacterized feature of trisomy 18p syndrome. We further hypothesize that two mechanisms could be responsible of the fertility impairment: a meiotic synapsis defect due to the additional 18p arm that blocks meiosis, and/or overexpression of a gene located on the 18p chromosome involved in the normal testicular development. PMID- 26042158 TI - Is there a place for mental health research in general practice? PMID- 26042159 TI - Royal college of general practitioners position statement: mental health and primary care. PMID- 26042160 TI - Managing depression in childhood and adolescence. AB - This paper describes depression (a syndrome of low mood/irritability/lack of pleasure with associated physical and cognitive symptoms) in children and adolescents. It aims to help GPs to recognise more cases of it. It discusses why some young people do become depressed and will describe the treatments which are available, and how treatment may be implemented in the primary care setting. Current UK NICE guidelines recommend that: (i) psychological treatments should be offered as first-line treatment for moderate to severe depression and persistent mild depression; (ii) if this is not effective after four to six sessions, co existing factors such as social stresses and family discord should be considered and addressed; (iii) an antidepressant (fluoxetine) should only be considered after four to six sessions; (iv) antidepressants should only be offered in conjunction with psychological treatment. These guidelines are not in full agreement with large randomised controlled trials that demonstrate that fluoxetine is more effective than CBT; and that show equivocal benefit of combined fluoxetine and CBT over fluoxetine alone. Part of the reason for the predominance of psychological treatments in these guidelines is the small but significant risk of suicidality with fluoxetine. PMID- 26042161 TI - Managing depression in adults. AB - Depression is one of the leading causes of disability worldwide. The majority of patients suffering from depressive disorder are diagnosed and managed in primary care. Optimal management reduces the risk of relapse and improves the quality of life. The main treatment modalities are antidepressants and psychological therapies. Lifestyle changes, exercise and psychoeducation also play an important role in management. PMID- 26042162 TI - Depression: beyond the disease era. PMID- 26042163 TI - Maternal alcohol consumption. AB - Background Despite decades of research, the aetiology of attention deficit disorder with hyperactivity (ADHD) remains largely unknown. Next to a strong genetic component, increasing evidence suggests additional adverse impact of environmental factors, two of which have, although controversially, withstood meta-analysis: gestational exposure to smoking (OR 2.39) and low birth weight (OR 2.64). Several studies have investigated a possible association between prenatal exposure to alcohol and ADHD, although the matter is complicated due to foetal alcohol syndrome disorders (FASD) with ADHD-like symptoms. Questions Can an estimate of the effect of gestational exposure to alcohol for ADHD be determined? What is the relevance of primary care services in screening and intervention in mild to moderate drinking in pregnant women? Method MEDLINE, Cinahl, PsychInfo, EMBASE (1995-2008) were searched for articles in English, supplemented by a manual search. Out of 23 reviewed studies, three were included in the metaanalysis; one further study was added to undertake a sub-analysis comparing severe versus mild alcohol consumption. Summary odds ratios (OR) were extracted and fixed/random-effects meta-analysis were used for combining the OR's. Heterogeneity across the studies was formally assessed using Cochran's Q. Results An OR of 2.33 (95% CI, 1.18-4.61), (z = 2.43, p = 0.02) suggests that exposed children are 2.33 times more likely to have ADHD than non exposed children. Discussion Our meta-analysis suggests that children exposed to alcohol during pregnancy are at risk for ADHD. However, evidence is sparse and it remains uncertain whether a causal association exists. Further research is needed into dose-response relationship, timing of exposure, influence of genetic factors involved in maternal alcohol abuse and the role of FASD in ADHD-like symptoms. If a detrimental effect of mild to moderate drinking on the offspring is supported by stronger evidence, primary care services could have a major role in prevention and early intervention. This would be in addition to their already established role in helping heavy drinking mothers. PMID- 26042164 TI - Low recognition of post-traumatic stress disorder in primary care. AB - Post-traumatic stress disorder (PTSD) is a common and disabling disorder that develops as a consequence of traumatic events and is characterised by distressing re-experiencing of parts of the trauma, avoidance of reminders, emotional numbing and hyperarousal. The NICE guidelines for PTSD (2005) recommend trauma-focused psychological therapy as the first-line treatment. A survey of 129 GPs in south London investigated the recognition and treatment of PTSD in primary care. The majority of GPs underestimated the prevalence of PTSD. Most PTSD patients seen in GP surgeries currently do not receive or are not referred for NICE recommended psychological treatments. Medications, especially SSRIs, appear to be more commonly prescribed than recommended by NICE. Efforts to disseminate information about PTSD and effective treatments to both patients and GPs are needed to increase recognition rates and prompter access to treatment. The Improving Access to Psychological Therapies (IAPT) programme will make the NICE recommended treatments more widely available and will allow self-referral by adults with PTSD to trauma-focused psychological therapy. PMID- 26042166 TI - The Lord Layard interview. PMID- 26042165 TI - What information do general practitioners expect in letters from mental health services? AB - Background Psychiatrists and General Practitioners (GPs) communicate mainly by letters which often do not cover the necessary information. Setting Barnet PCT Question To identify what GPs regard as important and necessary information in psychiatric follow up letters. Method A postal questionnaire was sent to all GPs in the Borough of Barnet to determine their view on this matter. Results Out of 187 GPs, 129 responded to the questionnaire (69%). A mismatch was found between what psychiatrists write in their follow up letters and what GPs expect. Medication details, diagnosis, name of care coordinator and changes in mental state were considered very important to GPs. Conclusions Conveying information that GPs actually consider important may improve their ability to share care of mental health patients. This may be achievable by introducing standardised format letters. PMID- 26042167 TI - Improving access to psychological therapies: the intention. PMID- 26042168 TI - IAPT: help or hindrance to general practice? AB - KEY MESSAGES: IAPT needs to improve how it expresses itself to the outside world.Commissioning should be concerned with activities that develop and sustain trusting and therapeutic relationships as well as treat illnesses.Polyclinics should enable local people to collaborate and themselves improve their collective mental health.IAPT should enhance and not destabilise existing good practice. WHY THIS MATTERS TO ME: For years I have been working to improve mental health provision in primary care. IAPT is potentially a powerful device to make a quantum leap forward, leaving behind poor primary care practice that medicalises appropriate distress and responses to life, and building from the best. PMID- 26042169 TI - Setting up an IAPT site: the Ealing Mental Health & Well-Being Service. AB - KEY MESSAGE: IAPT will succeed or fail on the extent to which it enables partnerships. WHY THIS MATTERS TO ME: For years I have been working to integrate mental health services in Ealing. Improving Access to Psychological Therapies (IAPT) offers the best chance I have ever known to achieve this, and to make a coordinated impact on the health of the people of Ealing. IAPT is an exciting opportunity for us in Ealing and we have grabbed it with both hands. We are incorporating it into our beliefs, values and passion to produce a service that will reflect our vision for holistic primary care services. A service which is financially sound. A service which does not believe that there is one answer to everyone's mild to moderate mental health problems. A service which recognises that working in silos is detrimental to our patients' health. A service which is constantly striving to improve relationships with our partners. A service which is mindful about the people we see, and the staff who see them. PMID- 26042170 TI - Using guided self-help to treat common mental health problems: The Westminster Primary Care Psychology Service. AB - We describe a new service offering cognitive behavioural therapy in the form of guided self-help to patients experiencing mild mental health problems. The referral pathway is outlined and the various treatment options are illustrated with case descriptions of depression and panic disorder. Patients' responses to this new service are reported and discussed. PMID- 26042171 TI - Fever in returning travellers: a case of paratyphoid. PMID- 26042172 TI - APMS tenders and the future of general practice. PMID- 26042173 TI - Banding in F2 general practice posts. AB - There are educational benefits in Foundation Year 2 general practice postsJunior doctors experienced financial difficulties from the lack of banding payments in these postsLow payment is a disincentive for doctors when choosing their rotationsChanges made to the working hours and the antisocial nature of the posts may qualify doctors for higher banding. PMID- 26042174 TI - Life in the GP Vocational Training Scheme. PMID- 26042175 TI - An account of my life. AB - This is the third instalment of the autobiography of John Horder. He intended it to be read solely by family and friends. However LJPC persuaded him to serialise it for a wider readership. The autobiography as a whole is an important piece of history. It is remarkable for its humanity, perception and humility - much like the man himself. John is a founding father of modern general practice. He was doing his medical finals when the NHS was founded in 1948 and has been an active advocate of whole person, family and community-oriented general practice ever since. He became active in the College of General Practitioners shortly after its formation in 1952 and before it gained its Royal Charter in 1967. He was one of the two founders of the Leeuwenhorst European Study Group that defined the job description of a general practitioner in 1974. He was President of the RCGP between 1979 and 1982. He assisted the setting up of general practice educational bodies in several Western European countries, especially Yugoslavia and Portugal. He has been a tireless supporter of inter-disciplinary learning and founded the Centre for the Advancement of Inter-professional Education (CAIPE) in 1987. He lives in Primrose Hill with his wife Elizabeth June, who was also his partner in general practice. Abridged by Layla Stock (Ealing PCT). PMID- 26042176 TI - Bacon - psychoanalyst for human solitude. PMID- 26042177 TI - Football and alcohol: a short diary of a long and complex relationship. AB - KEY MESSAGES: Football is a high profile sport with a close relationship with alcohol, and many elite players have had problems with addiction. This can help raise public awareness of problem drinking. WHY THIS MATTERS TO US: We encounter alcohol problems daily in our different perspectives as a GP and an Accident and Emergency Consultant. Both of us are avid football fans. PMID- 26042179 TI - Dementia. PMID- 26042178 TI - WHO/WONCA report - Integrating Mental Health in Primary Care: A Global Perspective. PMID- 26042180 TI - Improving patients' lives: Disability Living Allowance (DLA). PMID- 26042181 TI - Triangulation. PMID- 26042182 TI - Draft genomes of Shigella strains used by the STOPENTERICS consortium. AB - BACKGROUND: Despite a significant global burden of disease, there is still no vaccine against shigellosis widely available. One aim of the European Union funded STOPENTERICS consortium is to develop vaccine candidates against Shigella. Given the importance of translational vaccine coverage, here we aimed to characterise the Shigella strains being used by the consortium by whole genome sequencing, and report on the stability of strains cultured in different laboratories or through serial passage. METHODS: We sequenced, de novo assembled and annotated 20 Shigella strains being used by the consortium. These comprised 16 different isolates belonging to 7 serotypes, and 4 derivative strains. Derivative strains from common isolates were manipulated in different laboratories or had undergone multiple passages in the same laboratory. Strains were mapped against reference genomes to detect SNP variation and phylogenetic analysis was performed. RESULTS: The genomes assembled into similar total lengths (range 4.14-4.83 Mbp) and had similar numbers of predicted coding sequences (average of 4,400). Mapping analysis showed the genetic stability of strains through serial passages and culturing in different laboratories, as well as varying levels of similarity to published reference genomes. Phylogenetic analysis revealed the presence of three main clades among the strains and published references, one containing the Shigella flexneri serotype 6 strains, a second containing the remaining S. flexneri serotypes and a third comprised of Shigella sonnei strains. CONCLUSIONS: This work increases the number of the publically available Shigella genomes available and specifically provides information on strains being used for vaccine development by STOPENTERICS. It also provides information on the variability among strains maintained in different laboratories and through serial passage. This work will guide the selection of strains for further vaccine development. PMID- 26042183 TI - Erratum: Parental phonological memory contributes to prediction of outcome of late talkers from 20 months to 4 years: a longitudinal study of precursors of specific language impairment. AB - [This corrects the article DOI: 10.1186/1866-1955-4-3.]. PMID- 26042184 TI - Two-stage hybrid feature selection algorithms for diagnosing erythemato-squamous diseases. AB - This paper proposes two-stage hybrid feature selection algorithms to build the stable and efficient diagnostic models where a new accuracy measure is introduced to assess the models. The two-stage hybrid algorithms adopt Support Vector Machines (SVM) as a classification tool, and the extended Sequential Forward Search (SFS), Sequential Forward Floating Search (SFFS), and Sequential Backward Floating Search (SBFS), respectively, as search strategies, and the generalized F score (GF) to evaluate the importance of each feature. The new accuracy measure is used as the criterion to evaluated the performance of a temporary SVM to direct the feature selection algorithms. These hybrid methods combine the advantages of filters and wrappers to select the optimal feature subset from the original feature set to build the stable and efficient classifiers. To get the stable, statistical and optimal classifiers, we conduct 10-fold cross validation experiments in the first stage; then we merge the 10 selected feature subsets of the 10-cross validation experiments, respectively, as the new full feature set to do feature selection in the second stage for each algorithm. We repeat the each hybrid feature selection algorithm in the second stage on the one fold that has got the best result in the first stage. Experimental results show that our proposed two-stage hybrid feature selection algorithms can construct efficient diagnostic models which have got better accuracy than that built by the corresponding hybrid feature selection algorithms without the second stage feature selection procedures. Furthermore our methods have got better classification accuracy when compared with the available algorithms for diagnosing erythemato-squamous diseases. PMID- 26042185 TI - Analysis of anastomotic leakage after rectal surgery: A case-control study. AB - BACKGROUND: The incidence of anastomotic leakage in rectal surgery is around 10 percent. Poor blood supply to the anastomosis, high anastomotic pressure and tension, increased operative blood loss, long operative time, and male sex are risk factors of anastomotic leakage. In the present study, we examined anastomotic leakage cases in rectal surgery at our institute and tried to ascertain the risk factors. METHODS: Three hundred fifty-seven consecutive patients who underwent rectal resection with anastomosis between January 2008 and October 2013 were included in the study. Patients were divided into two groups according to the existence of anastomotic leakage. Clinicopathological features, operative procedures, and intraoperative outcomes were compared between the two groups. Regarding intraoperative procedure, we focused on the ligation level of the inferior mesenteric artery, installing a transanal drainage tube in the rectum, and constructing a diverting stoma. RESULTS: Anastomotic leakage occurred in eight patients. All of them were male (p = 0.0284). There were no statistical differences in other characteristics of the patients or tumors, in operative procedures, or in intraoperative outcomes. CONCLUSIONS: In the present study, no statistically significant risk factors for anastomotic leakage in rectal surgery were detected, except for male sex. However, the rate of anastomotic leakage at our institute was revealed to be rather low. Our exertion to preserve good blood flow and to prevent high tension and pressure on the anastomosis in operation may have led to this result. PMID- 26042186 TI - Duodenal ulcer promoting gene 1 (dupA1) is associated with A2147G clarithromycin resistance mutation but not interleukin-8 secretion from gastric mucosa in Iraqi patients. AB - Helicobacter pylori causes peptic ulceration and gastric adenocarcinoma. The aims were to study the influence of dupA1 positivity upon interleukin-8 (IL-8) secretion from gastric mucosa and determine the prevalence of mutations responsible for clarithromycin and fluoroquinolone resistance. DNA was extracted from 74 biopsies and the virulence factors were studied. Levels of IL-8 in gastric mucosa were measured using ELISA and the mutations responsible for clarithromycin and fluoroquinolone resistance were determined using a GenoType HelicoDR assay. The prevalence of cagA in strains isolated from gastric ulcer (GU) and duodenal ulcer (DU) was significantly higher than those isolated from non-ulcer disease (NUD) (90% and 57.9% versus 33.3%; p 0.01). The vacA s1m1 genotype was more prevalent in patients with DU (73.7%) and GU (70%) than in those with NUD (13.3%) (p 0.01). The prevalence of dupA1 was higher in DU patients (36.8%) than those with GU (10%) and NUD (8.9%) (p 0.01). Multivariate analysis showed that a cagA+/vacA s1i1m2 virulence gene combination was independently associated with the developing peptic ulcer disease (PUD) with increased odds of developing PUD (p 0.03; OR = 2.1). We found no significant difference in the levels of IL-8 secretion in gastric mucosa infected with H. pylori dupA-negative and H. pylori dupA1-positive strains (dupA-negative: mean +/ median: 28 +/- 26 versus 30 +/- 27.1 for dupA1; p 0.6). While 12 strains were clarithromycin resistant, only three isolates were levofloxacin resistant. A significant association was found between dupA1 genotype and A2147G clarithromycin resistance mutation (p <0.01). Further study is needed to explore the relationship between virulence factors and disease process and treatment failure. PMID- 26042187 TI - First data on Pneumocystis jirovecii colonization in patients with respiratory diseases in North Lebanon. AB - Pneumocystis colonization may play a role in transmission and local inflammatory response. It was explored in patients with respiratory diseases in North Lebanon. Overall prevalence reached only 5.2% (95% CI 2.13-10.47) but it was higher (17.3%) in the subpopulation of patients with chronic obstructive pulmonary disease (COPD). COPD was the only factor associated with a significantly increased risk of colonization. mtLSU genotyping revealed predominance of genotype 2, identified in five patients (71.4%), including one patient who had co infection with genotype 3. These first data in North Lebanon confirm Pneumocystis circulation among patients with respiratory diseases and the potential for transmission to immunocompromised patients. PMID- 26042188 TI - Factors associated with methicillin-resistant coagulase-negative staphylococci as causing organisms in deep sternal wound infections after cardiac surgery. AB - Established preoperative antibiotic prophylaxis in cardiac surgery is ineffective against methicillin-resistant coagulase-negative staphylococci (CoNS). This case control study aimed to determine factors predicting deep sternal wound infections due to methicillin-resistant CoNS. All cardiac surgery patients undergoing sternotomy between June 2009 and March 2013 prospectively documented in a Swiss tertiary care center were included. Among 1999 patients, 82 (4.1%) developed deep sternal wound infection. CoNS were causal in 36 (44%) patients, with 25/36 (69%) being methicillin resistant. Early reintervention for noninfectious causes (odds ratio (OR) 4.3; 95% confidence interval (CI) 1.9-9.5) was associated with methicillin-resistant CoNS deep sternal wound infection. Among CoNS deep sternal wound infection, perioperative antimicrobial therapy (p 0.002), early reintervention for noninfectious causes (OR 7.9; 95% CI 0.9-71.1) and time between surgery and diagnosis of infection over 21 days (OR 10.8; 95% CI 1.2 97.8) were associated with methicillin resistance. These findings may help to better tailor preoperative antimicrobial prophylaxis. PMID- 26042189 TI - Nutritional Vulnerability in Older Adults: A Continuum of Concerns. AB - A nutritionally vulnerable older adult has a reduced physical reserve that limits the ability to mount a vigorous recovery in the face of an acute health threat or stressor. Often this vulnerability contributes to more medical complications, longer hospital stays, and increased likelihood of nursing home admission. We have characterized in this review the etiology of nutritional vulnerability across the continuum of the community, hospital, and long term care settings. Frail older adults may become less vulnerable with strong, consistent, and individualized nutritional care. Interventions for the vulnerable older adult must take their nutritional needs into account to optimize resiliency in the face of the acute and/or chronic health challenges they will surely face in their life course. PMID- 26042190 TI - Attendance and Utilization of Antenatal Care (ANC) Services: Multi-Center Study in Upcountry Areas of Uganda. AB - INTRODUCTION: Globally every year 529,000 maternal deaths occur, 99% of this in developing countries. Uganda has high maternal and neonatal morbidity and mortality ratios, typical of many countries in sub-Saharan Africa. Recent findings reveal maternal mortality ratio of 435:100,000 live births and neonatal mortality rate of 29 deaths per 1000 live births in Uganda; these still remain a challenge. Women in rural areas of Uganda are two times less likely to attend ANC than the urban women. Most women in Uganda have registered late ANC attendance, averagely at 5.5 months of pregnancy and do not complete the required four visits. The inadequate utilization of ANC is greatly contributing to persisting high rates of maternal and neonatal mortality in Uganda. This study was set to identify the factors associated with late booking and inadequate utilization of Antenatal Care services in upcountry areas of Uganda. METHOD: Cross-sectional study design with mixed methods of interviewer administered questionnaires, focus group discussions and key informant interviews. Data was entered using Epidata and analyzed using Stata into frequency tables using actual tallies and percentages. Ethical approval was sought from SOM-REC MakCHS under approval number "#REC REF 2012-117" before conducting the study. RESULTS: A total of four hundred one were enrolled with the majority being in the age group 20 - 24 years (mean age, 25.87 +/- 6.26). Health workers played a great role (72.04%), followed by the media (15.46%) and friends (12.50%) in creating awareness about ANC. A significant number of respondents went to TBAs with reasons such as "near and accessible", "my husband decided", and "they are the only people I know". 37.63% of the respondents considered getting an antenatal Card as an importance of ANC. 71 (19.67%) respondents gave a wrong opinion (late) on booking time with reasons like demands at work, no problems during pregnancy, advised by friends, just to get a card, long distance and others didn't know. Almost half of the respondents never knew the recommended number of visits. Religion, occupation, level of education, and parity were found to influence place of ANC attendance, number of ANC visits and booking time. Husbands were necessary to provide financial support, accompany their wives ANC clinic, and ensure that they complete the visits. But their response was poor due to: fear of routine investigations and constrained economically. CONCLUSION: The study findings show the actual rural setting of ANC services attendance and utilization. Much sensitization has to be done specifically in these rural areas to empower pregnant women and their husbands as to improve ANC attendance and utilization. PMID- 26042191 TI - ABCs of Evidence-based Anterior Cruciate Ligament Injury Prevention Strategies in Female Athletes. AB - Anterior cruciate ligament (ACL) injury is a major concern in physically active females. Although ACL reconstruction techniques have seen significant advances in recent years, risk associated with re-injury and future osteoarthritis remains a major concern. Thus, prevention of ACL injury is a logical step to protect and preserve healthy knee joints in young athletes. The current report aims to summarize a list of evidence-based prevention strategies to reduce ACL injury in female athletes. A list of six critical principles, which come from documented, large scale clinical trial studies and further analyses, were presented with ABC format including age, biomechanics, compliance, dosage, exercise, and feedback. Also, a grade for evidence and implications of future research is noted. Finally, in the conclusion section, importance of collaborative efforts from healthcare practitioners, researchers, and personnel associated with athletics is addressed. PMID- 26042192 TI - Estimating daily climatologies for climate indices derived from climate model data and observations. AB - : Climate indices help to describe the past, present, and the future climate. They are usually closer related to possible impacts and are therefore more illustrative to users than simple climate means. Indices are often based on daily data series and thresholds. It is shown that the percentile-based thresholds are sensitive to the method of computation, and so are the climatological daily mean and the daily standard deviation, which are used for bias corrections of daily climate model data. Sample size issues of either the observed reference period or the model data lead to uncertainties in these estimations. A large number of past ensemble seasonal forecasts, called hindcasts, is used to explore these sampling uncertainties and to compare two different approaches. Based on a perfect model approach it is shown that a fitting approach can improve substantially the estimates of daily climatologies of percentile-based thresholds over land areas, as well as the mean and the variability. These improvements are relevant for bias removal in long-range forecasts or predictions of climate indices based on percentile thresholds. But also for climate change studies, the method shows potential for use. KEY POINTS: More robust estimates of daily climate characteristicsStatistical fitting approachBased on a perfect model approach. PMID- 26042193 TI - Targeted Temperature Management in Pediatric Central Nervous System Disease. AB - Acute central nervous system conditions due to hypoxic-ischemic encephalopathy, traumatic brain injury (TBI), status epilepticus, and central nervous system infection/inflammation, are a leading cause of death and disability in childhood. There is a critical need for effective neuroprotective therapies to improve outcome targeting distinct disease pathology. Fever, defined as patient temperature > 38 degrees C, has been clearly shown to exacerbate brain injury. Therapeutic hypothermia (HT) is an intervention using targeted temperature management that has multiple mechanisms of action and robust evidence of efficacy in multiple experimental models of brain injury. Prospective clinical evidence for its neuroprotective efficacy exists in narrowly-defined populations with hypoxic-ischemic injury outside of the pediatric age range while trials comparing hypothermia to normothermia after TBI have failed to demonstrate a benefit on outcome but consistently demonstrate potential use in decreasing refractory intracranial pressure. Data in children from prospective, randomized controlled trials using different strategies of targeted temperature management for various outcomes are few but a large study examining HT versus controlled normothermia to improve neurological outcome in cardiac arrest is underway. PMID- 26042194 TI - Epigenetic Regulation by Sulforaphane: Opportunities for Breast and Prostate Cancer Chemoprevention. AB - Sulforaphane (SFN) is a phytochemical derived from cruciferous vegetables that has multiple molecular targets and anti-cancer properties. Researchers have demonstrated several chemopreventive benefits of SFN consumption, such as reductions in tumor growth, increases in cancer cell apoptosis, and disruption of signaling within tumor microenvironments both in vitro and in vivo. Emerging evidence indicates that SFN exerts several of its chemopreventive effects by altering epigenetic mechanisms. This review summarizes evidence of the impact of SFN on epigenetic events and how they relate to the chemopreventive effects of SFN observed in preclinical and clinical studies of breast and prostate cancers. Specific areas of focus include the role of SFN in the regulation of cell cycle, apoptosis, inflammation, antioxidant defense, and cancer cell signaling and their relationships to epigenetic mechanisms. Finally, remaining challenges and research needs for translating mechanistic work with SFN into human studies and clinical intervention trials are discussed. PMID- 26042195 TI - In vitro and in vivo assessment of the effect of antiprotozoal compounds isolated from Psoralea corylifolia against Ichthyophthirius multifiliis in fish. AB - Ichthyophthirius multifiliis, an external fish parasite, often causes significant economic damage to the aquaculture industry. Since the use of malachite green was banned, the search of alternative substance to control I. multifiliis infections becomes stringent. In present study, in vitro and in vivo anti-ich efficacies of isopsoralen and psoralidin, two active compounds isolated from methanol extract of Psoralea corylifolia by bioassay-guided fractionation based on the efficacy of anti-ich encysted tomonts, were evaluated. In vitro antiprotozoal efficacy of psoralidin is much better than that of isopsoralen. Psoralidin can kill all theronts at concentrations of 0.8 mg/L or more during 4 h exposure; and terminate reproduction of I. multifiliis post 6 h exposure of protomonts to 0.9 mg/L and encysted tomonts to 1.2 mg/L. In vivo trials showed that 5 h exposure of infected fish to 2.5 mg/L of psoralidin significantly reduced the number of theronts released from tomonts. Furthermore, we observed that a part of protomonts, collected from infected fish post treatment, presented characteristic morphological changes of apoptosis after staining with Annexin V-EGFP/propidium iodide, indicating the possible mechanism of psoralidin against I. multifiliis trophont in situ. On the basis of these results, psoralidin can be used as a potential lead compound for the development of commercial drug against I. multifiliis. PMID- 26042196 TI - Chimerization at the AQP2-AQP3 locus is the genetic basis of melarsoprol pentamidine cross-resistance in clinical Trypanosoma brucei gambiense isolates. AB - Aquaglyceroporin-2 is a known determinant of melarsoprol-pentamidine cross resistance in Trypanosoma brucei brucei laboratory strains. Recently, chimerization at the AQP2-AQP3 tandem locus was described from melarsoprol pentamidine cross-resistant Trypanosoma brucei gambiense isolates from sleeping sickness patients in the Democratic Republic of the Congo. Here, we demonstrate that reintroduction of wild-type AQP2 into one of these isolates fully restores drug susceptibility while expression of the chimeric AQP2/3 gene in aqp2-aqp3 null T. b. brucei does not. This proves that AQP2-AQP3 chimerization is the cause of melarsoprol-pentamidine cross-resistance in the T. b. gambiense isolates. PMID- 26042197 TI - Selection and characterisation of monepantel resistance in Teladorsagia circumcincta isolates. AB - Monepantel (MPTL) is one of two new anthelmintic compounds introduced onto the sheep market to control gastro-intestinal nematodes. Resistance to this compound is rare but has been reported. In order to preserve the efficacy of this and other anthelmintics, it is essential to understand both (a) the mechanisms involved in the selection of resistance and (b) how the parasites evolve to deal with these compounds. To address these questions three MPTL-resistant Teladorsagia circumcincta isolates (MTci2-11, MTci5-13 and MTci7-12) have been artificially selected in vivo from phenotypically characterised parent isolates (MTci2, MTci5, MTci7 respectively). The selection process involved collecting and culturing eggs from surviving worms from sheep administered sub-optimal dosages of MPTL (Zolvix(r)) to provide infective larvae to infect further sheep until resistant isolates were generated (between 9 and 13 rounds of selection). A controlled efficacy test was conducted using the original parental isolates and the newly generated MPTL resistant isolates (n = 5 per group). Selected isolates were assessed both under anthelmintic stress (Zolvix(r), 2.5 mg/kg bodyweight; MTci-MPTL) and at rest (untreated, MTci-CON). A number of life-history traits were assessed, namely, worm establishment rates, time to patency, faecal egg output, body length of adults and eggs in utero. The estimated resistance status of the selected isolates was confirmed with 48%, 28% and 9% reductions in worm burden at 7-days post Zolvix(r) administration for MTci2-11-MPTL, MTci5-13-MPTL and MTci7-12-MPTL, respectively, compared with untreated controls. One of the selected isolates MTci7-12-CON showed significantly greater total worm burden (p = 0.025), greater establishment rate (p = 0.033), decreased time to patency (p = 0.048), higher cumulative egg outputs (p = 0.002) compared with its parental derivative MTci7. The trial results suggest that anthelmintic selection in T. circumcincta, albeit under experimental conditions, can select for more prolific/fecund and quicker maturing populations. These data provide an insight into how parasites evolve in response to anthelmintic pressure. PMID- 26042198 TI - Crystal structure of human nicotinic acid phosphoribosyltransferase. AB - Nicotinic acid phosphoribosyltransferase (EC 2.4.2.11) (NaPRTase) is the rate limiting enzyme in the three-step Preiss-Handler pathway for the biosynthesis of NAD. The enzyme catalyzes the conversion of nicotinic acid (Na) and 5 phosphoribosyl-1-pyrophosphate (PRPP) to nicotinic acid mononucleotide (NaMN) and pyrophosphate (PPi). Several studies have underlined the importance of NaPRTase for NAD homeostasis in mammals, but no crystallographic data are available for this enzyme from higher eukaryotes. Here, we report the crystal structure of human NaPRTase that was solved by molecular replacement at a resolution of 2.9 A in its ligand-free form. Our structural data allow the assignment of human NaPRTase to the type II phosphoribosyltransferase subfamily and reveal that the enzyme consists of two domains and functions as a dimer with the active site located at the interface of the monomers. The substrate-binding mode was analyzed by molecular docking simulation and provides hints into the catalytic mechanism. Moreover, structural comparison of human NaPRTase with the other two human type II phosphoribosyltransferases involved in NAD biosynthesis, quinolinate phosphoribosyltransferase and nicotinamide phosphoribosyltransferase, reveals that while the three enzymes share a conserved overall structure, a few distinctive structural traits can be identified. In particular, we show that NaPRTase lacks a tunnel that, in nicotinamide phosphoribosiltransferase, represents the binding site of its potent and selective inhibitor FK866, currently used in clinical trials as an antitumoral agent. PMID- 26042200 TI - Integration of body temperature into the analysis of energy expenditure in the mouse. AB - OBJECTIVES: We quantified the effect of environmental temperature on mouse energy homeostasis and body temperature. METHODS: The effect of environmental temperature (4-33 degrees C) on body temperature, energy expenditure, physical activity, and food intake in various mice (chow diet, high-fat diet, Brs3 (-/y) , lipodystrophic) was measured using continuous monitoring. RESULTS: Body temperature depended most on circadian phase and physical activity, but also on environmental temperature. The amounts of energy expenditure due to basal metabolic rate (calculated via a novel method), thermic effect of food, physical activity, and cold-induced thermogenesis were determined as a function of environmental temperature. The measured resting defended body temperature matched that calculated from the energy expenditure using Fourier's law of heat conduction. Mice defended a higher body temperature during physical activity. The cost of the warmer body temperature during the active phase is 4-16% of total daily energy expenditure. Parameters measured in diet-induced obese and Brs3 ( /y) mice were similar to controls. The high post-mortem heat conductance demonstrates that most insulation in mice is via physiological mechanisms. CONCLUSIONS: At 22 degrees C, cold-induced thermogenesis is ~120% of basal metabolic rate. The higher body temperature during physical activity is due to a higher set point, not simply increased heat generation during exercise. Most insulation in mice is via physiological mechanisms, with little from fur or fat. Our analysis suggests that the definition of the upper limit of the thermoneutral zone should be re-considered. Measuring body temperature informs interpretation of energy expenditure data and improves the predictiveness and utility of the mouse to model human energy homeostasis. PMID- 26042201 TI - Brain-derived neurotrophic factor is required for axonal growth of selective groups of neurons in the arcuate nucleus. AB - OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal development, and the Bdnf gene produces two populations of transcripts with either a short or long 3' untranslated region (3' UTR). Deficiencies in BDNF signaling have been shown to cause severe obesity in humans; however, it remains unknown how BDNF signaling impacts the organization of neuronal circuits that control energy balance. METHODS: We examined the role of BDNF on survival, axonal projections, and synaptic inputs of neurons in the arcuate nucleus (ARH), a structure critical for the control of energy balance, using Bdnf (klox/klox) mice, which lack long 3' UTR Bdnf mRNA and develop severe hyperphagic obesity. RESULTS: We found that a small fraction of neurons that express the receptor for BDNF, TrkB, also expressed proopiomelanocortin (POMC) or neuropeptide Y (NPY)/agouti-related protein (AgRP) in the ARH. Bdnf(klox/klox) mice had normal numbers of POMC, NPY, and TrkB neurons in the ARH; however, retrograde labeling revealed a drastic reduction in the number of ARH axons that project to the paraventricular hypothalamus (PVH) in these mice. In addition, fewer POMC and AgRP axons were found in the dorsomedial hypothalamic nucleus (DMH) and the lateral part of PVH, respectively, in Bdnf (klox/klox) mice. Using immunohistochemistry, we examined the impact of BDNF deficiency on inputs to ARH neurons. We found that excitatory inputs onto POMC and NPY neurons were increased and decreased, respectively, in Bdnf (klox/klox) mice, likely due to a compensatory response to marked hyperphagia displayed by the mutant mice. CONCLUSION: This study shows that the majority of TrkB neurons in the ARH are distinct from known neuronal populations and that BDNF plays a critical role in directing projections from these neurons to the DMH and PVH. We propose that hyperphagic obesity due to BDNF deficiency is in part attributable to impaired axonal growth of TrkB-expressing ARH neurons. PMID- 26042202 TI - Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism. AB - OBJECTIVE: Brown adipose tissue (BAT) thermogenesis is critical in maintaining body temperature. The dorsomedial hypothalamus (DMH) integrates cutaneous thermosensory signals and regulates adaptive thermogenesis. Here, we study the function and synaptic connectivity of input from DMH cholinergic neurons to sympathetic premotor neurons in the raphe pallidus (Rpa). METHODS: In order to selectively manipulate DMH cholinergic neuron activity, we generated transgenic mice expressing channelrhodopsin fused to yellow fluorescent protein (YFP) in cholinergic neurons (choline acetyltransferase (ChAT)-Cre::ChR2-YFP) with the Cre LoxP technique. In addition, we used an adeno-associated virus carrying the Cre recombinase gene to delete the floxed Chat gene in the DMH. Physiological studies in response to optogenetic stimulation of DMH cholinergic neurons were combined with gene expression and immunocytochemical analyses. RESULTS: A subset of DMH neurons are ChAT-immunopositive neurons. The activity of these neurons is elevated by warm ambient temperature. A phenotype-specific neuronal tracing shows that DMH cholinergic neurons directly project to serotonergic neurons in the Rpa. Optical stimulation of DMH cholinergic neurons decreases BAT activity, which is associated with reduced body core temperature. Furthermore, elevated DMH cholinergic neuron activity decreases the expression of BAT uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (Pgc1alpha) mRNAs, markers of BAT activity. Injection of M2-selective muscarinic receptor antagonists into the 4th ventricle abolishes the effect of optical stimulation. Single cell qRT-PCR analysis of retrogradely identified BAT projecting neurons in the Rpa shows that all M2 receptor-expressing neurons contain tryptophan hydroxylase 2. In animals lacking the Chat gene in the DMH, exposure to warm temperature reduces neither BAT Ucp1 nor Pgc1alpha mRNA expression. CONCLUSION: DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMH(ACh)-Rpa(5-HT) pathway may mediate physiological heat defense responses to elevated environmental temperature. PMID- 26042205 TI - Genetic model selection for a case-control study and a meta-analysis. AB - A case-control study often compares the prevalence of a specific disease among persons with normal alleles and persons with variant alleles, which generates an odds ratio (OR). The most common type of allele variation, single-nucleotide polymorphism, consists of a major allele (M) and a minor allele (m). Thus, the genotype can be a major allele homozygote (MM), a heterozygote (Mm) or a minor allele homozygote (mm). Odds are given for each genotype, and a pair of odds generates an OR. Summarizing data using two-by-two contingency is the simplest method of estimating an OR. Thus, dominant, multiplicative, recessive, and over dominant models are often used. Traditionally, researchers used to calculate ORs using many models and then select the best model from among these calculated ORs. This may cause problems due to multiple comparisons. Therefore, we should choose the best model before calculating the OR for each model. In this article, we will discuss how to choose the best model among many subject-level models when evaluating the impact of the MM/Mm/mm genotype on the disease prevalence. PMID- 26042204 TI - The occurrence of taeniids of wolves in Liguria (northern Italy). AB - Canids are definitive hosts of Taenia and Echinococcus species, which infect a variety of mammals as intermediate or accidental hosts including humans. Parasite transmission is based on domestic, semi-domestic and wildlife cycles; however, little is known of the epidemiological significance of wild large definitive hosts such as the wolf. In this study, 179 scats of wolves (Canis lupus italicus) collected throughout the Italian region of Liguria were analyzed for the detection of taeniid infection. Taeniid egg isolation was performed using a sieving/flotation technique, and the species level was identified by PCR (gene target: 12S rRNA and nad 1) followed by sequence analyses. Based on sequence homologies of >=99%, Taenia hydatigena was identified in 19.6%, Taenia krabbei in 4.5%, Taenia ovis in 2.2%, Taenia crassiceps in 0.6%, Hydatigera taeniaeformis in 0.6% and Echinococcus granulosus in 5.6% of the samples. According to these results, Canis lupus italicus can be considered as involved in the wild (including cervids and rodents) and semi-domestic cycles (including sheep and goats) of taeniids in this area. PMID- 26042206 TI - Gene-gene and gene-environment interactions in the etiology of type 2 diabetes mellitus in the population of Hyderabad, India. AB - Fifteen SNPs from nine different genes were genotyped on 1379 individuals, 758 T2DM patients and 621 controls, from the city of Hyderabad, India, using Sequenom Massarray platform. These data were analyzed to examine the role of gene-gene and gene-environment interactions in the manifestation of T2DM. The multivariate analysis suggests that TCF7L2, CDKAL1, IGF2BP2, HHEX and PPARG genes are significantly associated with T2DM, albeit only the first two of the above 5 were associated in the univariate analysis. Significant gene-gene and gene-environment interactions were also observed with reference to TCF7L2, CAPN10 and CDKAL1 genes, highlighting their importance in the pathophysiology of T2DM. In the analysis for cumulative effect of risk alleles, SLC30A8 steps in as significant contributor to the disease by its presence in all combinations of risk alleles. A striking difference between risk allele categories, 1-4 and 5-6, was evident in showing protective and susceptible roles, respectively, while the latter was characterized by the presence of TCF7L2 and CDKAL1 variants. Overall, these two genes TCF7L2 and CDKAL1 showed strong association with T2DM, either individually or in interaction with the other genes. However, we need further studies on gene gene and gene-environment interactions among heterogeneous Indian populations to obtain unequivocal conclusions that are applicable for the Indian population as a whole. PMID- 26042207 TI - Association between interleukin-18 gene promoter (- 607C/A and - 137G/C) polymorphisms and chronic hepatitis C virus infections: A meta-analysis. AB - OBJECTIVE: HCV infection has a chronicity rate of about 70%, several studies have shown that interleukin-18 (IL-18) was associated with etiology and progression of hepatitis C virus (HCV) infections. However, the association between single nucleotide polymorphisms - 607C/A (rs1946518) and - 137G/C (rs187238) located in the IL-18 gene promoter and chronic hepatitis C virus infections was still controversial and ambiguous. To derive a more precise effect on the association between these polymorphisms and chronic hepatitis C virus infections, we performed this first meta-analysis based on the currently available evidence of the literature. METHODS: A total of 4 studies with 1222 cases and 1115 controls for - 607C/A polymorphism and 3 studies with 959 cases and 987 controls for - 137G/C polymorphism were identified to perform a meta-analysis. Summary ORs and corresponding 95% CIs for IL-18 polymorphisms and chronic hepatitis C virus infections were estimated using fixed- and random-effects models when appropriate. Heterogeneity, sensitivity analysis, and publication bias were evaluated. RESULTS: We found a significant association between - 137G/C polymorphism and chronic hepatitis C virus infections (CG + CC versus GG: OR = 2.157, 95% CI [1.822, 2.553]; CC versus CG + GG: OR = 2.007, 95% CI [1.441, 2.797]). However, no significant association was observed between - 607C/A polymorphism and chronic hepatitis C virus infections under different contrast models. CONCLUSIONS: The present meta-analysis suggested that IL-18 - 137G/C polymorphism in promoter region was associated with chronic hepatitis C virus infections, but no evidence indicate association between - 607C/A polymorphism and chronic hepatitis C virus infections. High-quality studies with larger sample size and larger number are warranted. PMID- 26042203 TI - Obesity in a model of gpx4 haploinsufficiency uncovers a causal role for lipid derived aldehydes in human metabolic disease and cardiomyopathy. AB - OBJECTIVE: Lipid peroxides and their reactive aldehyde derivatives (LPPs) have been linked to obesity-related pathologies, but whether they have a causal role has remained unclear. Glutathione peroxidase 4 (GPx4) is a selenoenzyme that selectively neutralizes lipid hydroperoxides, and human gpx4 gene variants have been associated with obesity and cardiovascular disease in epidemiological studies. This study tested the hypothesis that LPPs underlie cardio-metabolic derangements in obesity using a high fat, high sucrose (HFHS) diet in gpx4 haploinsufficient mice (GPx4(+/-)) and in samples of human myocardium. METHODS: Wild-type (WT) and GPx4(+/-) mice were fed either a standard chow (CNTL) or HFHS diet for 24 weeks, with metabolic and cardiovascular parameters measured throughout. Biochemical and immuno-histological analysis was performed in heart and liver at termination of study, and mitochondrial function was analyzed in heart. Biochemical analysis was also performed on samples of human atrial myocardium from a cohort of 103 patients undergoing elective heart surgery. RESULTS: Following HFHS diet, WT mice displayed moderate increases in 4 hydroxynonenal (HNE)-adducts and carbonyl stress, and a 1.5-fold increase in GPx4 enzyme in both liver and heart, while gpx4 haploinsufficient (GPx4(+/-)) mice had marked carbonyl stress in these organs accompanied by exacerbated glucose intolerance, dyslipidemia, and liver steatosis. Although normotensive, cardiac hypertrophy was evident with obesity, and cardiac fibrosis more pronounced in obese GPx4(+/-) mice. Mitochondrial dysfunction manifesting as decreased fat oxidation capacity and increased reactive oxygen species was also present in obese GPx4(+/-) but not WT hearts, along with up-regulation of pro-inflammatory and pro-fibrotic genes. Patients with diabetes and hyperglycemia exhibited significantly less GPx4 enzyme and greater HNE-adducts in their hearts, compared with age-matched non-diabetic patients. CONCLUSION: These findings suggest LPPs are key factors underlying cardio-metabolic derangements that occur with obesity and that GPx4 serves a critical role as an adaptive countermeasure. PMID- 26042199 TI - Ghrelin. AB - BACKGROUND: The gastrointestinal peptide hormone ghrelin was discovered in 1999 as the endogenous ligand of the growth hormone secretagogue receptor. Increasing evidence supports more complicated and nuanced roles for the hormone, which go beyond the regulation of systemic energy metabolism. SCOPE OF REVIEW: In this review, we discuss the diverse biological functions of ghrelin, the regulation of its secretion, and address questions that still remain 15 years after its discovery. MAJOR CONCLUSIONS: In recent years, ghrelin has been found to have a plethora of central and peripheral actions in distinct areas including learning and memory, gut motility and gastric acid secretion, sleep/wake rhythm, reward seeking behavior, taste sensation and glucose metabolism. PMID- 26042208 TI - Circulating levels of fibroblast growth factor-21 increase with age independently of body composition indices among healthy individuals. AB - BACKGROUND: Circulating FGF21 levels are commonly elevated in disease states. There is limited information regarding concentrations of circulating FGF21 in the absence of disease, as well as age-related differences in body composition that may contribute to FGF21 regulation across groups. OBJECTIVE: The objectives of this study were to assess FGF21 levels across age groups (childhood to elder adulthood), and investigate whether body composition indices are associated with age-related differences in circulating FGF21. MATERIALS AND METHODS: We cross sectionally analyzed serum concentrations of FGF21 in 184 healthy subjects aged 5 80y (45% male). Multiple linear regression was performed to assess the independent association of categorical age (children: 5-12y, young adults: 20 29y, adults: 30-50y, older adults: 55-64y, elder adults: 65-80y) with FGF21 concentration taking into account DXA-measured body composition indices [bone mineral density (BMD) and percent lean, trunk, and fat mass]. We also stratified analysis by tertile of FGF21. RESULTS: Incremental increases in FGF21 levels were observed across age groups (youngest to highest). Age group was positively associated with FGF21 level independent of body composition indices (age group variable: beta=0.25, 0.24, 0.24, 0.23, all P<0.0001, controlling for percent lean, BMD, percent fat, and percent trunk fat, respectively). By FGF21 tertile, age group was associated with FGF21 in the lowest tertile only (beta=13.1, 0.19, 0.18, all P<=0.01, accounting for percent lean, fat and trunk fat, respectively), but not when accounting for BMD. CONCLUSIONS: Our findings in a healthy population display an age-related increase in serum FGF21, highlighting a potential age effect in response to metabolic demand over the lifecourse. FGF21 levels increase with age independently of body composition. At lower levels of FGF21, BMD, but not other body composition parameters, attenuates the association between FGF21 level and age, suggesting the metabolic demand of the skeleton may provide a link between FGF21 and energy metabolism. PMID- 26042209 TI - Phosphatidylcholine-Mediated Aqueous Diffusion of Cellular Cholesterol Down Regulates the ABCA1 Transporter in Human Skin Fibroblasts. AB - : ATP-binding cassette protein A1 (ABCA1) is a cholesterol transporter that contributes to the active transport/removal of excess cellular cholesterol. ABCA1 expression is up-regulated when cells accumulate cholesterol. AIMS: The purpose of this study was to determine any correlation between extracellular phospholipid levels and ABCA1 expression and function. METHODOLOGY: Human foreskin fibroblasts were incubated with cholesterol alone or cholesterol and phosphatidylcholine. Total RNA was isolated and subjected to end-point RT-PCR to compare ABCA1 transcript levels. Cell lysates were subjected to Western blot analysis to compare ABCA1 protein levels. Cells were loaded with radiolabeled cholesterol and cellular cholesterol efflux was measured in the presence and absence of apoE, a cholesterol acceptor. ApoE-dependent efflux was calculated as a measure of ABCA1 mediated efflux. RESULTS: Here we show that incubation of cholesterol-loaded human skin fibroblasts with L-alpha-phosphatidylcholine (PC) decreases ABCA1 mRNA and protein levels by 93% and 57%, respectively, compared to cells loaded with cholesterol alone. Similarly, PC treatment results in a 25% reduction in ABCG1 mRNA levels compared to cells treated with cholesterol alone, but there is no change in SR-BI transcript levels. Subsequent incubation of phospholipid-treated cells with a cholesterol acceptor such as apoE for 24 hours shows a 65% reduction in ABCA1-mediated cholesterol efflux compared to efflux in cells not treated with PC. During the lipid treatment itself, there is a 2.7-fold greater loss of cholesterol from PC treated cells compared to cells treated with cholesterol alone. Measurement of cholesterol in cellular lipid extracts reveals that cells incubated in the presence of phosphatidylcholine are significantly depleted of cholesterol having only 20% of the cholesterol compared to cells loaded with cholesterol alone. CONCLUSION: Thus, phosphatidylcholine facilitates removal of cellular cholesterol, thereby negating the cholesterol-dependent induction of ABCA1 message, protein and function. PMID- 26042210 TI - Editorial: glycan diversity in fungi, bacteria, and sea organisms. PMID- 26042212 TI - Electronic medication monitoring-informed counseling to improve adherence to combination anti-retroviral therapy and virologic treatment outcomes: a meta analysis. AB - BACKGROUND: Adherence to combination anti-retroviral therapy for HIV infection is a primary determinant of treatment success, but is often suboptimal. Previous studies have suggested that electronic medication monitoring-informed counseling is among the most effective adherence intervention components. Our objective was to review available evidence about the effectiveness of monitoring-informed counseling and to aggregate findings into quantitative estimates of the effect of such intervention on medication adherence and virologic treatment outcomes. METHODS: We searched PubMed for papers reporting on randomized controlled trials comparing intervention groups receiving monitoring-informed counseling as one of the intervention components versus control groups not receiving such counseling for their effect on medication adherence and viral load concentrations. The standardized mean difference (SMD) in adherence and the odds ratio (OR) of undetectable HIV RNA in intervention versus control groups were the common effect sizes. Random-effect models with inverse variance weights were used to aggregate findings into pooled effect estimates with 95% confidence limits (CI). RESULTS: A total of 13 studies were included. Adherence was significantly higher in intervention groups than in control groups (SMD 0.51, 95% CI 0.31-0.71). Patients in intervention groups were significantly more likely to have undetectable HIV RNA concentrations than patients in control groups (OR 1.35, 95% CI 1.12-1.63). However, in studies in which monitoring-informed counseling was the only intervention component, the difference in adherence and virologic response between intervention and control groups was not statistically significant. CONCLUSION: Electronic monitoring-informed counseling improved adherence and virologic response compared with control groups not receiving such counseling in studies in which it was one out of multiple intervention components, but not in studies where it was the only intervention component. PMID- 26042211 TI - Intermittent hypoxia in childhood: the harmful consequences versus potential benefits of therapeutic uses. AB - Intermittent hypoxia (IH) often occurs in early infancy in both preterm and term infants and especially at 36-44 weeks postmenstrual age. These episodes of IH could result from sleep-disordered breathing or may be temporally unrelated to apnea or bradycardia events. There are numerous reports indicating adverse effects of IH on development, behavior, academic achievement, and cognition in children with sleep apnea syndrome. It remains uncertain about the exact causative relationship between the neurocognitive and behavioral morbidities and IH and/or its associated sleep fragmentation. On the other hand, well-controlled and moderate IH conditioning/training has been used in sick children for treating their various forms of bronchial asthma, allergic dermatoses, autoimmune thyroiditis, cerebral palsy, and obesity. This review article provides an updated and impartial analysis on the currently available evidence in supporting either side of the seemingly contradictory scenarios. We wish to stimulate a comprehensive understanding of such a complex physiological phenomenon as intermittent hypoxia, which may be accompanied by other confounding factors (e.g., hypercapnia, polycythemia), in order to prevent or reduce its harmful consequences, while maximizing its potential utility as an effective therapeutic tool in pediatric patients. PMID- 26042213 TI - The effect of using different competence frameworks to audit the content of a masters program in public health. AB - OBJECTIVES: (1) To quantify the effect of using different public health competence frameworks to audit the curriculum of an online distance learning MPH program, and (2) to measure variation in the outcomes of the audit depending on which competence framework is used. STUDY DESIGN: Retrospective audit. METHODS: We compared the teaching content of an online distance learning MPH program against each competence listed in different public health competence frameworks relevant to an MPH. We then compared the number of competences covered in each module in the program's teaching curriculum and in the program overall, for each of the competence frameworks used in this audit. RESULTS: A comprehensive search of the literature identified two competence frameworks specific to MPH programs and two for public health professional/specialty training. The number of individual competences in each framework were 32 for the taught aspects of the UK Faculty of Public Health Specialist Training Program, 117 for the American Association of Public Health, 282 for the exam curriculum of the UK Faculty of Public Health Part A exam, and 393 for the European Core Competencies for MPH Education. This gave a total of 824 competences included in the audit. Overall, the online MPH program covered 88-96% of the competences depending on the specific framework used. This fell when the audit focused on just the three mandatory modules in the program, and the variation between the different competence frameworks was much larger. CONCLUSION: Using different competence frameworks to audit the curriculum of an MPH program can give different indications of its quality, especially as it fails to capture teaching considered to be relevant, yet not included in an existing competence framework. The strengths and weaknesses of using competence frameworks to audit the content of an MPH program have largely been ignored. These debates are vital given that external organizations responsible for accreditation specify a particular competence framework to be used. Our study found that each of four different competence frameworks suggested different levels of quality in our teaching program, at least in terms of the competences included in the curriculum. Relying on just one established framework missed some aspects of the curriculum included in other frameworks used in this study. Conversely, each framework included items not covered by the others. Thus, levels of agreement with the content of our MPH and established areas of competence were, in part, dependent on the competence framework used to compare its' content. While not entirely a surprising finding, this study makes an important point and makes explicit the challenges of selecting an appropriate competence framework to inform MPH programs, and especially one which recruits students from around the world. PMID- 26042214 TI - Time to ban lead in industrial paints and coatings. PMID- 26042215 TI - High protein- and high lipid-producing microalgae from northern australia as potential feedstock for animal feed and biodiesel. AB - Microalgal biomass can be used for biodiesel, feed, and food production. Collection and identification of local microalgal strains in the Northern Territory, Australia was conducted to identify strains with high protein and lipid contents as potential feedstock for animal feed and biodiesel production, respectively. A total of 36 strains were isolated from 13 samples collected from a variety of freshwater locations, such as dams, ponds, and streams and subsequently classified by 18S rDNA sequencing. All of the strains were green microalgae and predominantly belong to Chlorella sp., Scenedesmus sp., Desmodesmus sp., Chlamydomonas sp., Pseudomuriella sp., Tetraedron caudatum, Graesiella emersonii, and Mychonastes timauensis. Among the fastest growing strains, Scenedesmus sp. NT1d possessed the highest content of protein; reaching up to 33% of its dry weight. In terms of lipid production, Chlorella sp. NT8a and Scenedesmus dimorphus NT8e produced the highest triglyceride contents of 116.9 and 99.13 MUg mL(-1) culture, respectively, as measured by gas chromatography mass spectroscopy of fatty acid methyl esters. These strains may present suitable candidates for biodiesel production after further optimization of culturing conditions, while their protein-rich biomass could be used for animal feed. PMID- 26042216 TI - Size-Dictionary Interpolation for Robot's Adjustment. AB - This paper describes the classification and size-dictionary interpolation of the three-dimensional data obtained by a laser scanner to be used in a realistic virtual fitting room, where automatic activation of the chosen mannequin robot, while several mannequin robots of different genders and sizes are simultaneously connected to the same computer, is also considered to make it mimic the body shapes and sizes instantly. The classification process consists of two layers, dealing, respectively, with gender and size. The interpolation procedure tries to find out which set of the positions of the biologically inspired actuators for activation of the mannequin robots could lead to the closest possible resemblance of the shape of the body of the person having been scanned, through linearly mapping the distances between the subsequent size-templates and the corresponding position set of the bioengineered actuators, and subsequently, calculating the control measures that could maintain the same distance proportions, where minimizing the Euclidean distance between the size-dictionary template vectors and that of the desired body sizes determines the mathematical description. In this research work, the experimental results of the implementation of the proposed method on Fits.me's mannequin robots are visually illustrated, and explanation of the remaining steps toward completion of the whole realistic online fitting package is provided. PMID- 26042217 TI - Influence of handrim wheelchair propulsion training in adolescent wheelchair users, a pilot study. AB - Ten full-time adolescent wheelchair users (ages 13-18) completed a total of three propulsion trials on carpet and tile surfaces, at a self-selected velocity, and on a concrete surface, at a controlled velocity. All trials were performed in their personal wheelchair with force and moment sensing wheels attached bilaterally. The first two trials on each surface were used as pre-intervention control trials. The third trial was performed after receiving training on proper propulsion technique. Peak resultant force, contact angle, stroke frequency, and velocity were recorded during all trials for primary analysis. Carpet and tile trials resulted in significant increases in contact angle and peak total force with decreased stroke frequency after training. During the velocity controlled trials on concrete, significant increases in contact angle occurred, as well as decreases in stroke frequency after training. Overall, the use of a training video and verbal feedback may help to improve short-term propulsion technique in adolescent wheelchair users and decrease the risk of developing upper limb pain and injury. PMID- 26042218 TI - PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors. AB - Cyclic-AMP (cAMP)-dependent protein kinase (PKA) is the main effector of cAMP signaling in all tissues. Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS) from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH). More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Calpha), were also identified in the pathogenesis of adrenocortical tumors. PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C) recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS. In vitro analysis demonstrated that this mutation led to constitutive Calpha activity, unregulated by its main partners, the PKA regulatory subunits. In this review, we summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of PKA's role in adrenocortical lesions. We also discuss potential therapeutic advances that can be made through targeting of PRKACA and the PKA pathway. PMID- 26042219 TI - Views of general practitioners on indoor environmental health risks in the perinatal period. AB - BACKGROUND: Home is generally perceived as a safety place, whereas the concentration of pollutants, influenced not only by external pollution but also by human activities, the presence of domestic animals, construction and furniture materials, are sometimes greater than outside. OBJECTIVES: The aim of this study is to determine the general practitioners' (GPs) views on indoor environmental health risks in the perinatal period. METHODS: Four semi-structured focus group with 31 GPs were conducted in two French departments in November 2009, February, March, and April 2010. The focus group meetings were analyzed using a general thematic analysis. RESULTS: Perinatal care is a special health issue and a time of privileged sensitization. The attitude of health risks are well known in the case of "traditionally" toxic substances. In the case of "emerging" environmental exposure, these attitudes depend on the knowledge, beliefs, and experience specific to each practitioner. GPs are acquiring a new role in the field of environmental health, while at the same time coming to grips with its own strengths and limitations. The implementation of prevention depends on factors, which are not only specific to the practitioner but also related to the parents and the organization of the medical practice. CONCLUSION: The sensitization of GPs to environmental medicine, promotion of eco-citizen education, development of research, and the distribution of information are some of the means which need to be implemented to prevent harmful exposure of the infant. PMID- 26042220 TI - Outcomes of the treatment of head and neck sarcomas in a tertiary referral center. AB - Head and neck sarcomas are a rare and heterogeneous group of tumors that pose management challenges. We report our experience with these tumors. Forty consecutive patients treated for 44 head and neck sarcomas between 1997 and 2014 were culled from our prospectively maintained head and neck database. Five patients were excluded. The adult cohort consisted 29 (83%) patients of a mean age of 57.7 years, with 33 sarcomas. The most common diagnoses were undifferentiated pleomorphic sarcoma (27%) and chondroblastic osteosarcoma (21%). Clear surgical margins were achieved in 24/33 (73%) lesions. Twenty-two patients received radiotherapy and/or chemotherapy. Fourteen patients developed local (n = 6), regional (n = 1) and distant (n = 7) recurrence. The overall 5-year survival was 66% with a mean survival interval of 66.5 months. Recurrent sarcoma, close (<1 mm) or involved surgical margins and advanced age were associated with statistically significantly reduced survival. The pediatric cohort consisted 6 (17%) patients, with a mean age of 9 years. Five patients had primary embryonal rhabdomyosarcomas and one had chondroblastic osteosarcoma. Clear surgical margins were achieved in five (83%) patients. All patients received adjuvant radiotherapy and/or chemotherapy. Mean survival interval was 102 months. Three patients developed local (n = 1) or distant (n = 2) recurrence. Twenty-three free and 8 pedicled flaps were performed in 25 patients. Eleven out of thirty-nine (28%) lesions in 11 patients developed a complication. In conclusion, head and neck sarcomas are best managed by a multidisciplinary team at a tertiary head and neck referral center and resection with clear margins is vital for disease control. PMID- 26042221 TI - Exploring intrinsically disordered proteins using site-directed spin labeling electron paramagnetic resonance spectroscopy. AB - Proteins are highly variable biological systems, not only in their structures but also in their dynamics. The most extreme example of dynamics is encountered within the family of Intrinsically Disordered Proteins (IDPs), which are proteins lacking a well-defined 3D structure under physiological conditions. Among the biophysical techniques well-suited to study such highly flexible proteins, Site Directed Spin Labeling combined with EPR spectroscopy (SDSL-EPR) is one of the most powerful, being able to reveal, at the residue level, structural transitions such as folding events. SDSL-EPR is based on selective grafting of a paramagnetic label on the protein under study and is limited neither by the size nor by the complexity of the system. The objective of this mini-review is to describe the basic strategy of SDSL-EPR and to illustrate how it can be successfully applied to characterize the structural behavior of IDPs. Recent developments aimed at enlarging the panoply of SDSL-EPR approaches are presented in particular newly synthesized spin labels that allow the limitations of the classical ones to be overcome. The potentialities of these new spin labels will be demonstrated on different examples of IDPs. PMID- 26042222 TI - Cooperation of Hsp70 and Hsp100 chaperone machines in protein disaggregation. AB - Unicellular and sessile organisms are particularly exposed to environmental stress such as heat shock causing accumulation and aggregation of misfolded protein species. To counteract protein aggregation, bacteria, fungi, and plants encode a bi-chaperone system composed of ATP-dependent Hsp70 and hexameric Hsp100 (ClpB/Hsp104) chaperones, which rescue aggregated proteins and provide thermotolerance to cells. The partners act in a hierarchic manner with Hsp70 chaperones coating first the surface of protein aggregates and next recruiting Hsp100 through direct physical interaction. Hsp100 proteins bind to the ATPase domain of Hsp70 via their unique M-domain. This extra domain functions as a molecular toggle allosterically controlling ATPase and threading activities of Hsp100. Interactions between neighboring M-domains and the ATPase ring keep Hsp100 in a repressed state exhibiting low ATP turnover. Breakage of intermolecular M-domain interactions and dissociation of M-domains from the ATPase ring relieves repression and allows for Hsp70 interaction. Hsp70 binding in turn stabilizes Hsp100 in the activated state and primes Hsp100 ATPase domains for high activity upon substrate interaction. Hsp70 thereby couples Hsp100 substrate binding and motor activation. Hsp100 activation presumably relies on increased subunit cooperation leading to high ATP turnover and threading power. This Hsp70-mediated activity control of Hsp100 is crucial for cell viability as permanently activated Hsp100 variants are toxic. Hsp100 activation requires simultaneous binding of multiple Hsp70 partners, restricting high Hsp100 activity to the surface of protein aggregates and ensuring Hsp100 substrate specificity. PMID- 26042224 TI - Neudesin as a unique secreted protein with multi-functional roles in neural functions, energy metabolism, and tumorigenesis. AB - Neudesin was originally identified as a secreted protein with neurotrophic activity, and, thereafter, was also termed neuron-derived neurotrophic factor (NENF) or the candidate oncogene GIG47. Neudesin with a conserved cytochrome 5 like heme/steroid-binding domain activates intracellular signaling pathways possibly through the activation of G protein-coupled receptors. In the brain, hypothalamic Neudesin decreases food intake. Neudesin knockout (KO) mice also exhibit anxiety-like behavior, indicating its roles in the hippocampal anxiety circuitry. Neudesin is also expressed in various peripheral tissues. Neudesin KO mice are strongly resistant to high-fat diet (HFD)-induced obesity due to elevated systemic sympathetic activity, heat production, and adipocytic lipolysis. Neudesin, which is over-expressed or induced by DNA hypomethylation in multiple human cancers, also stimulates tumorigenesis. These findings indicate that Neudesin plays roles in neural functions, energy metabolism, and tumorigenesis and is expected to be a novel target for obesity and anti-cancer treatments. PMID- 26042226 TI - Distinct Coping Combinations are Associated with Depression and Support Service Utilization in Men who have Sex with Men Living with HIV. AB - Stigma and stress may place HIV-positive men who have sex with men (HIV+ MSM) at risk for depression. Additionally, HIV+ MSM might utilize multiple HIV-related services as a way to gain support for, and more effectively manage, HIV-related stressors. Although prior research has demonstrated that depression severity and utilizing support services are associated with functional or dysfunctional coping strategies, researchers have not investigated the impact of different coping combinations-specifically, the concurrent use of functional and dysfunctional strategies-in this population. Thus, we explored (1) how items on one measure of coping, the Brief COPE, capture HIV-related coping of HIV+ MSM using Principal Components Analysis, (2) how HIV+ MSM's coping groups into unique combinations, and (3) how these coping combinations relate to depression and the scope of HIV related support service utilization. Our sample consisted of 170 HIV+ MSM engaged with medical care. Results indicated the use of both functional and dysfunctional coping strategies. Unique combinations of functional and dysfunctional strategies showed differential associations with depression and the extent of HIV-related support service utilization. Specifically, individuals who engaged in low levels of both functional and dysfunctional coping, compared to individuals who more frequently engaged in functional coping strategies, were significantly less likely to utilize a range of critical HIV-related services. Individuals who reported frequent use of dysfunctional coping strategies, regardless of functional coping strategy use, reported higher levels of depression. Therefore, providers should continue to focus more closely on identifying functional coping strategies and reducing dysfunctional coping when working with HIV+ MSM. PMID- 26042227 TI - Cross-Phosphorylation and Interaction between Src/FAK and MAPKAP5/PRAK in Early Focal Adhesions Controls Cell Motility. AB - P38-regulated and activated kinase (PRAK/MAPKAPK5) is a serine/threonine kinase which lies downstream of the p38 and ERK3/4 MAP kinase pathways. PRAK plays diverse roles in the processes of cell growth, nutrient starvation response, programmed cell death, senescence and motility. PRAK has been shown to both promote and inhibit cell motility in different contexts. The pro-motility functions of PRAK are attributed mainly to cytoskeletal rearrangement occurring downstream of its phosphorylated substrate HSP27; however, it was recently shown that PRAK is required for motility in endothelial cells upstream of Focal adhesion kinase (FAK). Along with Src, FAK functions as a mediator of motility signaling through the phosphorylation of substrates in focal adhesions. Here, we show that PRAK, initially identified as a FAK substrate in an in situ/ kinase overlay assay, is a Src substrate, the phosphorylation of which directs PRAK to focal adhesions. Focal adhesion localization of PRAK was not found to affect cell motility, however transient over expression of PRAK inhibited motility in HeLa cells. This effect requires PRAK kinase activity and proceeds through an impairment of FAK activation via phosphorylation on Y861. Our studies demonstrate for the first time that PRAK is regulated by tyrosine phosphorylation, localizes to focal adhesions, and interacts physically with and can phosphorylate FAK/Src. Further we provide a novel mechanism for the inhibition of motility downstream of PRAK. PMID- 26042225 TI - The role of molecular chaperones in clathrin mediated vesicular trafficking. AB - The discovery that the 70 kD "uncoating ATPase," which removes clathrin coats from vesicles after endocytosis, is the constitutively expressed Hsc70 chaperone was a surprise. Subsequent work, however, revealed that uncoating is an archetypal Hsp70 reaction: the cochaperone auxilin, which contains a clathrin binding domain and an Hsc70 binding J domain, recruits Hsc70(*)ATP to the coat and, concomitant with ATP hydrolysis, transfers it to a hydrophobic Hsc70-binding element found on a flexible tail at the C-terminus of the clathrin heavy chain. Release of clathrin in association with Hsc70(*)ADP follows, and the subsequent, persistent association of clathrin with Hsc70 is important to prevent aberrant clathrin polymerization. Thus, the two canonical functions of Hsp70-dissociation of existing protein complexes or aggregates, and binding to a protein to inhibit its inappropriate aggregation-are recapitulated in uncoating. Association of clathrin with Hsc70 in vivo is regulated by Hsp110, an Hsp70 NEF that is itself a member of the Hsp70 family. How Hsp110 activity is itself regulated to make Hsc70 free clathrin available for endocytosis is unclear, though at synapses it's possible that the influx of calcium that accompanies depolarization activates the Ca(++)/calmodulin dependent calcineurin phosphatase which then dephosphorylates and activates Hsp110 to stimulate ADP/ATP exchange and release clathrin from Hsc70(*)ADP:clathrin complexes. PMID- 26042228 TI - Progressive Myopia and Lid Suture Myopia are Explained by the Same Feedback Process: a Mathematical Model of Myopia. AB - OBJECTIVE: Progressive myopia in humans and lid-sutured myopia in primates have been considered to be different processes. This report seeks to establish the connection between progressive myopia in humans and lid suture myopia in macaque monkeys. METHODS: We followed the axial length of 4 lid-sutured macaque monkeys over an 18 month period. Their axial length is directly related to myopia. We also studied the myopia progression in corrected human subjects. Macaques and humans exhibit a linear time course of myopia progression when lid-sutured or corrected with lenses, respectively. RESULTS: A linear progression is observed in lid-sutured eyes of four macaques, r = 0.94, p < 0.05. Human progressive myopia and lid-suture myopia can be modeled by the same feedback process. In both cases the functional equivalent is the opening of the feedback loop. CONCLUSIONS: The open loop feedback process predicts a linear progression of myopia. This prediction was confirmed in human subjects and it is now confirmed in our macaque subjects. This process also explains the very rapid rate of myopia progression of lid sutured eyes. PMID- 26042223 TI - Fairy "tails": flexibility and function of intrinsically disordered extensions in the photosynthetic world. AB - Intrinsically Disordered Proteins (IDPs), or protein fragments also called Intrinsically Disordered Regions (IDRs), display high flexibility as the result of their amino acid composition. They can adopt multiple roles. In globular proteins, IDRs are usually found as loops and linkers between secondary structure elements. However, not all disordered fragments are loops: some proteins bear an intrinsically disordered extension at their C- or N-terminus, and this flexibility can affect the protein as a whole. In this review, we focus on the disordered N- and C-terminal extensions of globular proteins from photosynthetic organisms. Using the examples of the A2B2-GAPDH and the alpha Rubisco activase isoform, we show that intrinsically disordered extensions can help regulate their "host" protein in response to changes in light, thereby participating in photosynthesis regulation. As IDPs are famous for their large number of protein partners, we used the examples of the NAC, bZIP, TCP, and GRAS transcription factor families to illustrate the fact that intrinsically disordered extremities can allow a protein to have an increased number of partners, which directly affects its regulation. Finally, for proteins from the cryptochrome light receptor family, we describe how a new role for the photolyase proteins may emerge by the addition of an intrinsically disordered extension, while still allowing the protein to absorb blue light. This review has highlighted the diverse repercussions of the disordered extension on the regulation and function of their host protein and outlined possible future research avenues. PMID- 26042229 TI - Exploring the structure and formation mechanism of amyloid fibrils by Raman spectroscopy: a review. AB - Amyloid fibrils are beta-sheet rich protein aggregates that are strongly associated with various neurodegenerative diseases. Raman spectroscopy has been broadly utilized to investigate protein aggregation and amyloid fibril formation and has been shown to be capable of revealing changes in secondary and tertiary structures at all stages of fibrillation. When coupled with atomic force (AFM) and scanning electron (SEM) microscopies, Raman spectroscopy becomes a powerful spectroscopic approach that can investigate the structural organization of amyloid fibril polymorphs. In this review, we discuss the applications of Raman spectroscopy, a unique, label-free and non-destructive technique for the structural characterization of amyloidogenic proteins, prefibrilar oligomers, and mature fibrils. PMID- 26042230 TI - Dogs, humans and lymphoma therapy. PMID- 26042231 TI - [Letter to the editor re.: "Not celiac disease, non-wheat allergy, wheat sensitivity"]. PMID- 26042233 TI - [Importance of inflammation in the pathogenesis of osteoarthritis]. PMID- 26042232 TI - [Comment]. PMID- 26042235 TI - [Joint space measurement as a predictor for joint replacement after hip arthroscopy ]. PMID- 26042234 TI - [Falls/fractures dependent on pain management]. PMID- 26042236 TI - Guest editorial: introduction to the special issue on the 10th International Symposium on Bioinformatics Research and Applications (ISBRA 2014). PMID- 26042237 TI - Immunotherapy: The path to win the war on cancer? PMID- 26042238 TI - Ronald J. Konopka (1947-2015). PMID- 26042239 TI - Samuel Wesley ("Sam") Thompson II (1925-2014). PMID- 26042240 TI - Professor Jan Feijen: a pioneer in biomedical polymers and controlled drug release. PMID- 26042241 TI - In vitro work. PMID- 26042242 TI - Reflections on the field of metabolism. PMID- 26042243 TI - [Abstracts of the Dermatology Days, June 19-21, 2014, Paris, France ]. PMID- 26042244 TI - Molecular mechanisms for mediating light-dependent nucleo/cytoplasmic partitioning of phytochrome photoreceptors. AB - The photoreceptors phytochromes monitor the red/far-red part of the spectrum, exist in the biologically active Pfr (far-red absorbing) or inactive Pr (red absorbing) forms, and function as red/far-red light-regulated molecular switches to modulate plant development and growth. Phytochromes are synthesized in the cytoplasm, and light induces translocation of the Pfr conformer into the nucleus. Nuclear import of phytochromes is a highly regulated process and is fine-tuned by the quality and quantity of light. It appears that phytochrome A (phyA) and phytochrome B (phyB) do not possess active endogenous nuclear import signals (NLSs), thus light-induced translocation of these photoreceptors into the nucleus requires direct protein-protein interactions with their NLS-containing signaling partners. Sub-cellular partitioning of the various phytochrome species is mediated by different molecular machineries. Translocation of phyA into the nucleus is promoted by FAR-RED ELONGATED HYPOCOTYL 1 (FHY1) and FHY1-LIKE (FHL), but the identity of nuclear transport facilitators mediating the import of phyB-E into the nucleus remains elusive. Phytochromes localized in the nucleus are associated with specific protein complexes, termed photobodies. The size and distribution of these structures are regulated by the intensity and duration of irradiation, and circumstantial evidence indicates that they are involved in fine tuning phytochrome signaling. PMID- 26042245 TI - Home health care nurse interactions with homebound geriatric patients with depression and disability. AB - Building therapeutic nurse-patient relationships is pivotal to the provision of optimum nurse care management for geriatric home health care (HHC) patients. However, little is known about which strategies most effectively treat older adult HHC patients with concomitant depression and disability. This qualitative descriptive study was conducted in two parts to explore the issue further. The first part involved interviews regarding HHC nurse perceptions of geriatric depression and disability care management. The second part, which is the focus of the current analysis, describes HHC nurses' use of care management and therapeutic during home visits. Observation of nurse-patient interactions involved 25 nurses home visits to HHC patients 60 and older who had depression and disability. Drawing on clinical knowledge and interpersonal skills, nurses built relationships and fostered trust. However, despite their disabilities to make these connections, multiple missed opportunities occurred for nurses to engage in more productive interactions. Four training components to support improvement of nurse-patient therapeutic relationships are described and recommended. PMID- 26042247 TI - Abstracts of the 74th Scientific Sessions of the American Diabetes Association, June 13-17, 2014, San Francisco, California. PMID- 26042246 TI - When the lights go out: the evolutionary fate of free-living colorless green algae. AB - The endosymbiotic origin of plastids was a launching point for eukaryotic evolution. The autotrophic abilities bestowed by plastids are responsible for much of the eukaryotic diversity we observe today. But despite its many advantages, photosynthesis has been lost numerous times and in disparate lineages throughout eukaryote evolution. For example, among green algae, several groups have lost photosynthesis independently and in response to different selective pressures; these include the parasitic/pathogenic trebouxiophyte genera Helicosporidium and Prototheca, and the free-living chlamydomonadalean genera Polytomella and Polytoma. Here, we examine the published data on colorless green algae and argue that investigations into the different evolutionary routes leading to their current nonphotosynthetic lifestyles provide exceptional opportunities to understand the ecological and genomic factors involved in the loss of photosynthesis. PMID- 26042248 TI - [Abstracts of the 32nd Annual Congress of Dermatologic Research, June 2014, Brest, France]. PMID- 26042249 TI - The use of manual restraint in the emergency department, do we really know what's going on? PMID- 26042250 TI - Making the link and spreading the word - the Emergency Nursing Interest Group. PMID- 26042251 TI - Letter to the editor: Metabolic disorders due to methanol intoxication. PMID- 26042252 TI - Reply to the letter to editor. PMID- 26042253 TI - Journal roundup: Ebola, antibiotic use and abuse, and the usual suspects. PMID- 26042254 TI - [Bisphosphonates as new anticancer agents?]. PMID- 26042255 TI - [Doubling time of progression-free survival by palbociclib in metastatic breast cancer]. PMID- 26042256 TI - Making us fat (and sick). PMID- 26042257 TI - Insulin receptor substrate-1 Gly972Arg variant and type 2 diabetes mellitus. PMID- 26042258 TI - HIV research for prevention--huge potential but no 'magic bullet'. PMID- 26042259 TI - Using basic technology--and corporate social responsibility--to save lives. PMID- 26042260 TI - Health minister's ex-legal advisor slams Certificate of Need law. PMID- 26042261 TI - New HASA board: the right mix at the right time. PMID- 26042262 TI - Obituary. Lorna Macdougall, 1924 - 2014. PMID- 26042263 TI - Recommendations for amniocentesis in HIV-positive women. AB - There is limited literature on the known risk of HIV transmission during amniocentesis. Before the introduction of highly active antiretroviral therapy (HAART), amniocentesis was avoided owing to the increased risk of HIV transmission. Recent literature suggests that it is safe to perform amniocentesis in women on HAART with undetectable viral loads. In South Africa (SA), many women access antenatal care late in pregnancy and there is often insufficient time to attain undetectable viral loads within a pre-viability period. Guidelines and recommendations for invasive testing in HIV-positive women in the SA setting are lacking. This article provides recommendations to healthcare practitioners who are faced with an HIV-positive patient requiring amniocentesis. PMID- 26042264 TI - Newborns should be receiving premedication before elective intubation. AB - BACKGROUND: Intubation is a common neonatal procedure. Premedication is accepted as a standard of care, but its use is not universal and wide variations exist in practice. OBJECTIVE: To evaluate current practices for premedication use prior to elective neonatal intubation in South Africa (SA). METHOD: We invited 481 clinicians to participate in a cross-sectional web-based survey. RESULTS: We received responses from 28.3% of the clinicians surveyed; 54.1% were from the private sector and 45.9% from the state sector. Most respondents worked in medium sized neonatal units with six to ten beds. Most paediatricians (76.0%) worked in the private sector, and 78.6% of neonatologists in the state sector. Premedication was practised by 71.9% of the respondents, but only 38.5% of neonatal units had a written policy. Sedatives were used for premedication by 63.2% of the respondents. Midazolam (41.5%), morphine (34.0%) and ketamine (20.8%) were most commonly used. Muscle relaxants and atropine were not routinely administered. Suxamethonium was the muscle relaxant of choice. Varied combinations of agents or single agents were used. Midazolam used alone was the preferred option. CONCLUSION: This first survey of premedication for neonatal intubation in SA revealed variations in practice, with a minority of clinicians following a written policy. The findings can be used to benchmark practice and inform the design of local collaborative trials aimed at determining optimal premedication prior to neonatal intubation. The survey demonstrates clinicians' reluctance to participate in surveys, suggesting a need for a national collaborative network to obtain representative data. PMID- 26042265 TI - The structured communication tool SBAR (Situation, Background, Assessment and Recommendation) improves communication in neonatology. AB - BACKGROUND: Effective communication, co-operation and teamwork have been identified as key determinants of patient safety. SBAR (Situation, Background, Assessment and Recommendation) is a communication tool recommended by the World Health Organization and the UK National Health Service. SBAR is a structured method for communicating critical information that requires immediate attention and action, contributing to effective escalation of management and increased patient safety. To our knowledge, this is the first study showing use of SBAR in South Africa (SA). OBJECTIVE: To determine the effectiveness of adopting the SBAR communication tool in an acute clinical setting in SA. METHODS: In the first phase of this study, neonatal nurses and doctors at Groote Schuur Hospital, Cape Town, were gathered in a focus group and given a questionnaire asking about communication in the neonatal department. Neonatal nurses and doctors were then trained to use SBAR. RESULTS: A telephone audit demonstrated an increase in SBAR use by registrars from 29% to 70% when calling consultants for help. After training, the majority of staff agreed that SBAR had helped with communication, confidence, and quality of patient care. There was qualitative evidence that SBAR led to greater promptness in care of acutely ill patients. CONCLUSIONS: Adopting SBAR was associated with perceived improvement in communication between professionals and in the quality and safety of patient care. It is suggested that this simple tool be introduced to many other hospitals in SA. PMID- 26042266 TI - Tricuspid valve endocarditis associated with intravenous nyoape use: a report of 3 cases. AB - We report three cases of tricuspid valve infective endocarditis associated with intravenous nyoape use. Nyoape is a variable drug combination of an antiretroviral (efavirenz or ritonavir), heroin, metamphetamines and cannabis. Its use is becoming increasingly common among poor communities in South Africa. All our patients were young HIV-positive men from disadvantaged backgrounds. They all presented with tricuspid regurgitation and septic pulmonary emboli. They were treated with prolonged intravenous antibiotic courses, and one required referral for surgery. PMID- 26042267 TI - Towards early detection of retinoblastoma. PMID- 26042268 TI - Why aren't women getting safe abortions? PMID- 26042269 TI - Retinoblastoma outcome at a single institution in South Africa. AB - INTRODUCTION: Retinoblastoma (RB) is the most common eye cancer in children. Early detection is necessary for cure. OBJECTIVE: To compare stage and outcome of children with RB treated at Kalafong Hospital, Pretoria, South Africa (SA), during two time periods (1993 - 2000 and 2001 - 2008, after outreach interventions in 2000 and introduction of compulsory community service for doctors in 1998). METHODS: Data collected included demography (age, gender, date of birth), stage and treatment received. The main outcome measure was disease free survival and the study end-point was 60 months after diagnosis. RESULTS: There were 51 patients during the time period 1993 - 2000 (group 1) and 73 during 2001 - 2008 (group 2), with median ages of 32 and 26 months, respectively (marginally significantly younger in group 2; p = 0.046). In group 1, the majority (57%) presented with advanced disease (stages III and IV), with a decline in this proportion in group 2 (40%) indicating a downward but not significant trend (p = 0.075). Bilateral disease was diagnosed in 22% of patients in group 1 and 33% in group 2. Overall survival was 33% and 43% for groups 1 and 2, respectively. Excluding absconding patients, event-free survival was 50% in group 1, improving to 68% in group 2 (not statistically significant; p = 0.18). Fewer patients needed radiotherapy during the second period (statistically significant; p = 0.04), probably because of less advanced disease. CONCLUSION: Poor outcome is probably a result of late diagnosis. It is important to implement a strategy that will ensure early diagnosis and optimal management of RB in SA. PMID- 26042270 TI - Unwanted pregnancies in Gauteng and Mpumalanga provinces, South Africa: examining mortality data on dumped aborted fetuses and babies. AB - BACKGROUND: Across the world, millions of women unintentionally become pregnant and decide to terminate the pregnancy. Despite progressive abortion laws in South Africa (SA), evidence suggests that many women of all ages still resort to unsafe terminations outside legal, designated facilities. Media reports alert the public to an increase in the illegal dumping of fetuses and abandoned babies, suggesting an increase in unsafe termination practices as well as concealed births. OBJECTIVE: To examine mortality data to identify trends in the dumping of aborted fetuses and abandoned babies in SA. METHOD: This study utilised data from the National Injury Mortality Surveillance System in two provinces, namely Gauteng and Mpumalanga. A total sample of mortality data was used to analyse trends associated with this phenomenon from 2009 to 2011. Descriptive, exploratory statistics were used and included the calculation of crude population incidence rates for abortions and abandoned babies as well as figures (n) and percentages (%) for each category under investigation. RESULTS: An increase in the rate of discovery of non-viable fetuses was noted for both provinces over the 3-year period, while there was a significant decrease in the discovery of deceased abandoned babies in Gauteng only. CONCLUSION: The illegal dumping of fetuses and babies is a very real public health concern in both Gauteng and Mpumalanga. Information is insufficient for adequate surveillance, and improved data collection systems should be prioritised. PMID- 26042271 TI - Adolescent and young pregnant women at increased risk of mother-to-child transmission of HIV and poorer maternal and infant health outcomes: A cohort study at public facilities in the Nelson Mandela Bay Metropolitan district, Eastern Cape, South Africa. AB - BACKGROUND: South Africa (SA) has the highest burden of childhood HIV infection globally, and has high rates of adolescent and youth pregnancy. OBJECTIVE: To explore risks associated with pregnancy in young HIV-infected women, we compared mother-to-child transmission (MTCT) of HIV and maternal and infant health outcomes according to maternal age categories. METHODS: A cohort of HIV-positive pregnant women and their infants were followed up at three sentinel surveillance facilities in the Nelson Mandela Bay Metropolitan (NMBM) district, Eastern Cape Province, SA. Young women were defined as 24 years old and adolescents as 19 years. The effect of younger maternal age categories on MTCT and maternal and child health outcomes was assessed using log-binomial and Cox regression controlling for confounding, using women aged > 24 years as the comparison group. RESULTS: Of 956 mothers, 312 (32.6%) were young women; of these, 65 (20.8%) were adolescents. The proportion of young pregnant women increased by 24% between 2009/10 and 2011/12 (from 28.3% to 35.1%). Young women had an increased risk of being unaware of their HIV status when booking (adjusted risk ratio (aRR) 1.37; 95% confidence interval (CI) 1.21 - 1.54), a reduced rate of antenatal antiretroviral therapy (ART) uptake (adjusted hazard ratio 0.46; 95% CI 0.31 - 0.67), reduced early infant HIV diagnosis (aRR 0.94; 95% CI 0.94 - 0.94), and increased MTCT (aRR 3.07; 95% CI 1.18 - 7.96; adjusted for ART use). Of all vertical transmissions, 56% occurred among young women. Additionally, adolescents had increased risks of first presentation during labour (aRR 3.78; 95% CI 1.06 - 13.4); maternal mortality (aRR 35.1; 95% CI 2.89 - 426) and stillbirth (aRR 3.33; 95% CI 1.53 - 7.25). CONCLUSION: An increasing proportion of pregnant HIV positive women in NMBM were young, and they had increased MTCT and poorer maternal and infant outcomes than older women. Interventions targeting young women are increasingly needed to reduce pregnancy, HIV infection and MTCT and improve maternal and infant outcomes if SA is to attain its Millennium Development Goals. PMID- 26042272 TI - Management challenges in tuberculosis and HIV. PMID- 26042273 TI - The diagnosis, management and prevention of HIV-associated tuberculosis. AB - Tuberculosis (TB) and its strong association with HIV infection are the most important causes of the high rates of infectious morbidity and mortality in South African adults. The interaction between HIV and TB leads to more frequent smear negative and extrapulmonary disease, resulting in atypical clinical presentations and altered performance characteristics of diagnostic tests. New and emerging diagnostics are being used to support earlier initiation of therapy and detection of drug resistance, although these have inherent limitations and empirical therapy is often still required. The management of HIV-associated TB is complicated by rapid clinical progression of disease, immune reconstitution inflammatory syndrome, drug-drug interactions and shared toxicities. A strong evidence base now provides guidance on the timing of initiation of antiretroviral therapy, the use of corticosteroids in TB and the use of isoniazid preventive therapy. This article provides a clinically oriented overview of the diagnosis, management and prevention of HIV-associated TB, with a focus on recent evidence in the field. PMID- 26042274 TI - Restoring respect and stability to nursing and midwifery. PMID- 26042275 TI - PII and exemption for intrapartum care extended to end of 2015. PMID- 26042276 TI - Midwifery Group Practices on the increase in Queensland. PMID- 26042277 TI - Reflective exercise: issues for nurses highlighted at the inquest into infection deaths. PMID- 26042278 TI - New government means new opportunity to balance HHSs. PMID- 26042279 TI - New smoking laws require careful management. PMID- 26042280 TI - 66,000 domestic violence incidents in Queensland last year. PMID- 26042281 TI - Keeping the heart of both professions. PMID- 26042282 TI - A revision of the Palaearctic species of Reikosiella (Hirticauda) (Hymenoptera, Eupelmidae). AB - The Palaearctic species of Reikosiella Yoshimoto, subgenus R. (Hirticauda Boucek), are revised. Illustrated keys are given to identify females of the ten recognized species and all known males. In addition to R. (Hirticauda) hungarica (Erd6s), previously the only formally recognized Palaearctic species, two species are newly transferred to the genus and subgenus, R. (Hirticauda) bolivari (Kalina) comb. nov. and R. (Hirticauda) rostrata (Ruschka) comb. nov., both from Eupelmus Dalman. Seven species are described as new: R. (Hirticauda) andriescui sp. nov. from Canary Islands, R. (Hirticauda) gordoni sp. nov. and R. (Hirticauda) graeca sp. nov. from Greece, R. (Hirticauda) vanharteni sp. nov. from United Arab Emirates, and R. (Hirticauda) cornuta sp. nov., R. (Hirticauda) koreana sp. nov., and R. (Hirticauda) tripotinorum. sp. nov. from Korea. A lectotype is designated for Eupelmus rostratus Ruschka. Host records are critically discussed for several species in the light of their new generic placement. PMID- 26042283 TI - The genus Pustulatirus Vermeij and Snyder, 2006 (Gastropoda: Fasciolariidae: Peristerniinae) in the western Atlantic, with descriptions of three new species. AB - Western Atlantic species of the New World genus Pustulatirus Vermeij and Snyder, 2006 are revised. Types of previously named taxa are figured. Species recognized as valid include P. attenuata (Reeve, 1847), range uncertain; P. eppi (Melvill, 1891), Curagao; P. ogum (Petuch, 1979), northeastern Brazil; and P. virginensis (Abbott, 1958), Bahama Islands and eastern Caribbean Sea to Aruba. Latirus karinae Nowell-Usticke, 1969 is confirmed as ajunior subjective synonym of P. virginensis. Syrinx annulata Roding, 1798, treated as a Caribbean Pustulatirus by Vermeij and Snyder (2006), and Latirus annulatus Melvill, 1891 are regarded as species inquirenda. Three new species are described: P biocellatus, northeastern Brazil; P. utilaensis, Bay Islands, Honduras and northwestern Panama; and P. watermanorum, Honduras continental shelf and offshore Colombian banks. Most western Atlantic Pustulatirus shells exhibit little intraspecific variability in morphology or color and occur within rather precise, well-defined ranges; an exception is P. virginensis, whose shells exhibit much variability in size, morphology and color. PMID- 26042284 TI - A revision of the genus Pinthaeus (Hemiptera: Heteroptera: Pentatomidae). AB - The genus Pinthaeus Stal, 1868 (Hemiptera: Heteroptera: Pentatomidae: Asopinae) is revised, a single species is recog nized, redescribed, and illustrated. The following new synonymy is proposed: Pinthaeus sanguinipes (Fabricius, 1781): P. hunieralis Horvath, 1911, syn. nov. A lectotype is designated for P. sanguinipes. The geographic distribution and un usual intraspecific variability of P. sanguinipes is discussed. PMID- 26042285 TI - A new red-eyed treefrog of Agalychnis (Anura: Hylidae: Phyllomedusinae) from middle Magdalena River valley of Colombia with comments on its phylogenetic position. AB - We describe a new species of the charismatic red-eyed treefrogs (genus Agalychnis) from middle Magdalena River valley of Colombia (05 degrees 50'8.04"N, 74 degrees 50'16.55"W, 380 m a.s.l.). The new species is readily distinguished from all species members of the group by having orange flanks with small white warts. Phylogenetic analysis of DNA sequences of 16S rRNA gene recovered the new species as a member of the Agalychnis callidryas group. The presence of a red hue in the iris and a golden reticulated palpebral membrane, putative synapomorphies of the clade, support this hypothesis. Our analysis suggests that Agalychnis terranova sp. nov is closely related to A. callidryas from Central America and is proposed as its sister species with an uncorrected genetic distance of 5.69% between these taxa. The phylogenetic position and the geographic distribution of the new taxon add new lights to the presence of a biogeographic disjunction between Middle America lowlands, the Pacific region and Magdalena River valley of Colombia. PMID- 26042286 TI - Some scleractinian corals (Scleractinia: Anthozoa) of Larak Island, Persian Gulf. AB - There is a shortage of knowledge about taxonomy and distribution of coral reef communities in the Persian Gulf. One of the main steps in the conservation and evaluation of such an environment is to locate and identify the communities and their inhabited fauna and flora. In the present study scleractinian corals were collected from depths of 3 to 9 meter around Larak Island, Persian Gulf. Underwater photographs of the sampled specimens were obtained in the natural habitat before sampling. 37 species have been identified via morphological characteristics of exoskeletons. The following study provided a pictorial reference to enhance the basic knowledge about coral reef communities in the Persian Gulf. PMID- 26042287 TI - A new species of Diadema (Echinodermata: Echinoidea: Diadematidae) from the eastern Atlantic Ocean and a neotype designation of Diadema antillarum (Philippi, 1845). AB - Diadenia africanum sp. nov. Rodriguez et al. 2013 occurs in the eastern Atlantic Ocean at depths of 1-80 meters off Ma- deira Islands, Salvage Islands, Canary Islands, Cape Verde Islands, Sao Tome Islands and at the continental coast off Sen- egal and Ghana. This species was previously considered an eastern Atlantic population of D. antillarum. Genetic distances between the holotype of D. africanum and the neotype of D. antillarun herein designated, measured 3.34% in Cytochrome oxidase I, 3.80% in ATPase-8 and 2.31% in ATPase-6. Such divergence is similar to that already highlighted between other accepted species of Diadena. Morphometric analysis of test, spine and pedicellarial characters also separated D. africanum from D. antillartn and reveals that this new species is morphologically similar to D. antillarum ascensionis from the mid Atlantic. The tridentate pedicellariae, which have been shown to have diagnostic characters which discriminate among species of Diadema, occur as both broad and narrow valved forms in D. antillarumn from the western Atlantic. In D. africanum the tridentate pedicellariae occur only as a single form which is characterized by moderately broad and curved valves, with an expanded distal gripping region. This form of tridentate pedicellaria is very similar to that of D. antillarum ascensionis from the central Atlantic, with only slight variations in valve serration and valve curvature differ- entiating the two forms. PMID- 26042288 TI - A new species of African mole-rat (Fukomys, Bathyergidae, Rodentia) from the Zaire-Zambezi watershed. AB - A new species of bathyergid mole-rat, Fukomys vandewoestijneae, is described from an area on the Zaire-Zambezi watershed, centred on the Ikelenge pedicle in the North-Western province of Zambia. It is diagnosed by a unique combination of morphological (size, lack of clear headmarks), chromosomal (2n= 44) and DNA sequence characteristics. This medium-sized species belongs to the Giant mole-rat "F. mechowii" clade, which was hitherto considered monotypic. Its known distribution is limited to the Ikelenge pedicle of Zambia and adjacent areas in the Democratic Republic of Congo (DRC) and presumably Angola. Colonies of this social mole-rat were observed in the chanas (dambos), degraded miombo woodland and in villages. Although presumably sympatric in historical times with F. inechowii, no overlap in the species current distribution could be established. This local endemic species adds further evidence to the conservation importance of the two-pedicle region (Ikelenge pedicle (Zambia-Katanga pedicle (DRC)). PMID- 26042289 TI - A new species of the subgenus Stigmatochirus of Plastus Bernhauer (Coleoptera: Staphylinidae: Osoriinae) from Yunnan, China. AB - Plastus (Stigmatochirus) menglaius sp. nov. is described from Yunnan, China. Color images of the habitus and aedeagu of the new species are included. A key to the subgenus Stigmatochirus of World species is provided. PMID- 26042290 TI - Sychentia hainanensis sp. n., the first record of the genus from China, with notes on the morphology and biogeography (Hemiptera: Cicadellidae). AB - Sychentia hainanensis sp. n. is described and illustrated from Hainan Island, representing the first record of the genus from China and the second known species of the genus. The morphology and biogeography of the genus Sychentia Wei & Webb and related genera are discussed. PMID- 26042291 TI - To name or not to name: Criteria to promote economy of change in Linnaean classification schemes. AB - The Linnaean classification system provides the universal reference system for communicating about the diversity of life and its hierarchic history. Several limitations that challenge the stability of this system have been identified and, as a result, alternative systems have been proposed since its early inception. The revolution caused by molecular phylogenetics has, more than ever, exemplified that Linnaean classification schemes are subject to a degree of instability that may hamper their significance and communication power. Our analysis of recent changes in the classification of several groups of organisms, with a focus on amphibians and reptiles, reveals two main sources of instability: (i) revisionary, objective (empirical) changes based on the discovery of unambiguous instances of non-monophyly and on progress in the Globe's species inventory, and (ii) subjective changes based on author preferences or on a poor analysis of the advantages and limitations of new classification schemes. To avoid subjective taxonomic instability, we review and elaborate proposals for the assignment of Linnaean rank to clades, and thereby for the naming of these clades as Linnaean taxa (Taxon Naming Criteria: TNCs). These are drafted from the perspective of practicing taxonomists and can help choosing among alternative monophyly-based classifications under a premise of economy of change. We provide a rationale for each TNC along with real and theoretical examples to illustrate their practical advantages and disadvantages. We conclude that not all TNCs lead to equally informative and stable taxonomies. Therefore, we order the various TNCs by the generality of their implications and provide a workflow scheme to guide the procedure of taxonomic decisions concerning the creation or modification of supraspecific classifications. The following criteria are considered primary when naming taxa: (i) Mono phyly of the taxon in an inferred species tree; (ii) Clade Stability, i.e., the monophyly of a clade to be named as taxon should be as strongly supported as possible by various methods of tree inference, tests of clade robustness, and different data sets; and (iii) Phenotypic Diagnosability, i.e., ranked supraspecific taxa should be those that are phenotypically most conspicuous although in phenotypically cryptic groups of organisms it can be warranted to name taxa based on molecular differences alone. We consider various other criteria as secondary (i.e., the Time Banding, Biogeography, Adaptive Zone, and Hybrid Viability TNCs) and refute using them as sole arguments for the modification of established classifications or proposal of new ones. Taxonomists are encouraged to be explicit and consistent when applying TNCs for creating or modifying classifications. We emphasize that, except for monophyly, the priority TNCs are not proposed as mandatory requisites of a Linnaean taxon but as yardsticks to allow for an informed choice among various clades in a tree that could alternatively be named as Linnaean taxa. Despite a need for plurality, classifications should avoid deliberately violating any of the three primary TNCs because taxa of unstable monophyly or poor diagnosability reduce the information content and hence the utility of the Linnaean system. PMID- 26042292 TI - Revision of the Neotropical genus Eoneria Aczel (Diptera: Neriidae) with description of a new species from Colombia. AB - Here we revise Eoneria Aczdl, 1951, a small genus of flies in the Neriidae, previously known from two species from Argentina. We describe a new species, E. aczeli Sepulveda & Carvalho from Colombia, provide new records from Brazil, a distribution extension from Argentina and a new genus diagnosis, as well as an identification key based on adult morphology. PMID- 26042293 TI - Taxonomic review of the tree frog genus Rhacophorus from the Western Ghats, India (Anura: Rhacophoridae), with description of ontogenetic colour changes and reproductive behavior. AB - A taxonomic revision of the Western Ghats species from the genus Rhacophorus is presented. Based on museum studies and new collections from localities spanning the known range of Western Ghats Rhacophorus, we review the four known species of this genus, their type specimens, current taxonomic status and their geographic distribution on the basis of morphological and molecular data. The holotypes of Rhacophorus calcadensis, R. lateralis and R. nialabaricus are redescribed. The previously unidentified holotype of Rhacophorus inalabaricus is herein fixed. Descriptions of ontogenetic colour change (OCC) in the Western Ghats Rhacophorus are provided and we conjecture the taxonomic utility of OCC. Additionally we provide observations on nesting behaviour of each species, and report multiple male participation during amplexus, oviposition and foam nest construction in R. lateralis and R. malabaricus. PMID- 26042294 TI - A taxonomic contribution to the genus Pseudovelia Hoberlandt, 1951 (Hemiptera: Veliidae) from China, with descriptions of ten new species. AB - Thirteen species of the genus Pseudovelia Hoberlandt are now known from China. Of these, Plongitarsa Andersen, 1983 is the only member of the genus previously recorded from China. P. pusilla Hecher, 1997 and P. tibialis tibialis Esaki & Miyamoto, 1955 are previously described species newly recorded from China. In addition, 10 new species are described as follows: P. anthracina sp. n., P. contorta sp. n., P. extensa sp. n., P. fulva sp. n., P. globosa sp. n., P. hsiaoi sp. n., P. longiseta sp. n., P. piliformis sp. n., P. taiwanensis sp. n., P. vittiformis sp. n. Photographs of the male dorsal habitus, male forelegs, male middle legs, male hind legs, male hind tarsal details and male genitalic structures are provided, accompanied by line drawings of male genitalic structures and a distribution map for all Chinese Pseudovelia species. A key to the males of all 13 Chinese Pseudovelia species is also provided to assist in future identification. PMID- 26042295 TI - The first Aleyrodidae from the Lowermost Eocene Oise amber (Hemiptera: Sternorrhyncha). AB - The first records are provided of the family Aleyrodidae in the Lowermost Eocene amber of Oise, France. The following new taxa in the subfamily Aleurodicinae are described, figured and discussed, together with an identification key: Oisedicus maginus gen. et sp. n., Clodionusfizoli gen. et sp. n., Lukotekia menae gen. et sp. n. and Isaraselis cladiva gen. et sp. n. Unplaced species of Lukotekia are briefly described, and the diversity of the whiteflies from Oise amber is discussed. The importance of fossils for palaeoecological and palaeoclimatological reconstruction is briefly considered. PMID- 26042296 TI - A new species of Pseudopaludicola (Anura, Leiuperidae) from western Piaui State, Northeast Brazil. AB - A new species of Pseudopaludicola from western Piauf State, Brazil, in the Cerrado domain is described. Pseudopaludicola parnaiba sp. nov. is a member of the genus Pseudopaludicola, on the basis of the presence of one hypertrophied antebrachial tubercle, posterolateral process of the hyoid outlined and epicoracoid cartilages slightly overlapped. The new species is characterized by an advertisement call composed of 6-46 non-pulsed notes per call and dominant frequency of 4794 +/- 296 Hz, which supports an independent lineage. Additionally, the small size, body slender, toe tips knobbed with central groove, abdominal fold complete, tibio-tarsal articulation reaching the posterior border of the eye, and prepollex and prehallux composed of base and one element are character states that distinguish P. parnaiba from all the members of Pseudopaludicola. We provide its formal description with regard to external morphology, osteological characters and advertisement call. PMID- 26042297 TI - Three new species of triplefin blennies of the genus Enneanectes (Teleostei, Tripterygiidae) from the tropical eastern Pacific with a key to Pacific species of Enneanectes. AB - Three new species of the triplefin blenny genus Enneanectes found in the Pacific Ocean off southern Mexico are described. Two, Enneanectes glendae and Enneanectes macrops, are mainland species, while the third, Enneanectes exsul, is endemic to the Islas Revillagigedo. A key to the five species of Enneanectes known from the tropical eastern Pacific is provided. PMID- 26042298 TI - A new species of ocellated Xanthias Rathbun, 1897 (Crustacea: Decapoda: Brachyura: Xanthidae) from the Bohol Sea, Philippines. AB - A new species of xanthid crab (Brachyura: Xanthidae) is described from the Bohol Sea in the central Philippines. Xanthias joanneae sp. nov. is most similar in morphology to X. maculatus Sakai, 1961 (type locality: Sagami Bay, Japan), particularly in the presence of distinctive ocelli on the carapace and pereopods. It can be separated from this species by the greater number of ocelli on the dorsal surface of the carapace, wider teeth separated by narrow notches on the carapace anterolateral margin, absence of longitudinal ridges on the external surface of the chelar palm, shorter and stouter ambulatory legs, narrower male anterior thoracic sternum, and stouter G 1. PMID- 26042299 TI - The Decapoda described by Henri Filhol: checklist and dates of publication (Crustacea: Anomura, Brachyura, Caridea). AB - Henri Filhol authored thirteen publications that established new names for decapod crustaceans in 1884 and 1885. The accurate dates of these publications are determined utilising notices of Filhol's publications in contemporary journals and library date-stamps. A checklist of the names for the Decapoda established by Filhol and their current identities is presented. Labophrys Filhol, 1885, and not Lobophrys, is shown to be the correct spelling for the junior objective synonym of Parainithrax H. Milne Edwards, 1834 (type species Pisa barbicornis Latreille, in Latreille, Le Peletier, Serville & Guerin, 1825) (Brachyura: Majidae Samouelle, 1819). PMID- 26042300 TI - Three new species of Anchylorhynchus Schoenherr, 1836 from Colombia (Coleoptera: Curculionidae; Curculioninae; Acalyptini). AB - Three new species of the genus Anchylorhynchus from Colombia, are described: Anchylorhynchus pinocchio sp. nov., A. centrosquainatus sp. nov. and A. luteobrunneus sp. nov.. A morphological description, including the male genitalia, is provided for each species as well as a comparison with similar species within the genus. All three species are found in inflorescences of species of Syagrus Mart. (Arecaceae). The adults are pollinators and the larvae develop inside fruits and feed on the endosperm, interrupting seed formation and causing fruit abortion. PMID- 26042301 TI - A new species of Bachia Gray, 1845 (Squamata: Gymnophthalmidae) from the western Brazilian Amazonia. AB - A new species of Bachia of the B. dorbignyi group, Bachia scaea sp. nov., is described from the left bank of the upper Madeira River, at Rondonia state, at the western Brazilian Amazonia. The new species resembles morphologically B. dorbignyi and B. peruana, and seems to be related with the former species based on molecular data (16S and c-mos sequences). Nonetheless the presence of a first temporal separating parietal and supralabial scales and the absence of clawed fingers in the new species, can promptly distinguish it from their close relatives. This description ends with several-decades of stasis in the taxonomy of the Bachia dorbignyi group from Amazonian lowlands, and also presents new evidence that supports the Madeira River as a vicariant barrier. PMID- 26042302 TI - A new species of porcupine, genus Coendou (Rodentia: Erethizontidae) from the Atlantic forest of northeastern Brazil. AB - We report the discovery of a new species of Coendou (Rodentia, Erethizontidae), here designated Coendou speratus sp. nov. This small porcupine, locally known as coandumirim, is found in the Pernambuco Endemism Centre in the Atlantic coast of northeastern Brazil north of the Sao Francisco river, one of the most important known biodiversity hotspots. The geographic range of C. speratus overlaps with that of the larger, widespread C. prehensilis, but not with that of C. insidiosus from the southeastern Atlantic forest, nor with that of C. nycthemera, an eastern Amazonian species. Coendou speratus is a small-bodied, long-tailed species that appears to be completely spiny because it lacks long dorsal fur. The dorsal quills have conspicuously brownish red tips that contrast with the blackish dorsal background color. The new species is overall similar to C. nycthemera, but the dorsal body quills are typically tricolored in the former and bicolored in the latter. The new species is externally very distinct from C. insidiosus, especially because the latter has bicolored dorsal quills that are almost completely hidden beneath longer and homogeneous pale or dark hairs. PMID- 26042303 TI - Family placement of the enigmatic Otagia neozelanica (Chilton, 1897) Haustorioidea: Otagiidae fam. nov. (Amphipoda: Crustacea). AB - A neotype is designated for Otagia neozelanica (Chilton, 1897) and the new family Otagiidae is established for the monotypic genus Otagia. An assessment of the relationship of Otagiidae fam. nov. with the Haustorioidea families is provided. The Otagiidae fam. nov. share a close relationship with seven other haustorioid families Cheidae, Condukiidae, Ipanemidae, Platyischnopidae, Phoxocephalopsidae, Sinurothoidae and Zobrachoidae. PMID- 26042304 TI - Description of immatures and natural history of the weevil Loncophorus pustulatus (Champion, 1903) (Coleoptera: Curculionidae: Curculioninae) associated with flowers of Ceiba speciosa (A. St.-Hil.) Ravenna (Bombacoidea: Malvaceae) in southeast Brazil. AB - Larva and pupa of Loncophorus pustulatus (Champion, 1903) (Curculionidae: Curculioninae: Anthonomini) are described, illustrated and compared with descriptions of immatures of two other species of Loncophorus. Weevil larvae were found inside aborted flowers on the ground under Ceiba speciosa (A. St.-Hil.) Ravenna (Malvaceae), in the city of Sgo Paulo, State of S5o Paulo, and reared to adults in laboratory. Data obtained in the field and under laboratory conditions are presented. Parasitoidism of weevil larvae by wasps of the genus Catolaccus (Hymenoptera: Pteromalidae) is reported. PMID- 26042305 TI - A new species of Bolitoglossa (Caudata, Plethodontidae) from the continental divide of western Panama. AB - We describe the new salamander species Bolitoglossa jugivagans from the Atlantic slopes of the Fortuna depression in western Panama on the basis of morphological and molecular data. Based on mtDNA data, the new species seems to be closely related to B. aureogularis and B. robinsoni, with which it forms a subclade within the subgenus Eladinea. PMID- 26042306 TI - Review of the genus Camptochaeta Hippa & Vilkamaa (Diptera, Sciaridae), with the description of nine new species. AB - The following new species of the genus Camptochaeta Hippa & Vilkamaa, 1994 are described and illustrated: Camptochaeta anceps, C. fihfera, C. formosa, C. kajsae, C. inixta, C. orthochaeta, C. spatula, C. truncata, and C. winchesteri. For some previously described species, morphological characters are redefined. Camptochaeta pentacantha Komarova, Hippa & Vilkamaa, 2007 is regarded as a junior synonym of C. subcamptochaeta (Mohrig, 1992). PMID- 26042307 TI - Family Panorpodidae (Insecta, Mecoptera) from Baltic amber (upper Eocene): new species, redescription and palaeogeographic remarks of relict scorpionflies. AB - The history of the species-poor family Panorpodidae is very interesting due to its uneven present distribution. The only fossils of the genus Panorpodes are two species known from Baltic amber, described in 1856 and 1954. A third species, Panorpodes weitschati sp. nov., is herein described. New diagnoses and descriptions as well as new drawings of all fossil species of Panorpodes are provided, including the first illustration of the wing of P. hageni. Fossil Panorpodes display three diametrically opposed patterns of wings markings, from the highly transparent wings of P. brevicauda, through transparent wings with dark bands and spots of P. weitschati sp. nov., to the dark wings with only narrow transparent bands of P. hageni. The fossil specimens are characterized by a great variability in wing venation, even in a single specimen, similar to that of living species. PMID- 26042308 TI - On three new species of Cypretta Vavra, 1895 (Crustacea: Ostracoda) from the Yucatan Peninsula, Mexico. AB - Three new species of the genus Cypretta Vivra, 1985 are described from Southern Mexico, representing the first record of the genus in the country. Cypretta campechensis n. sp. is closely related to Florida and North Carolina species such as C. nigra Furtos, 1936, C. brevisaepta Furtos, 1934 and C. bilicis Furtos, 1936. Cypretta spinosa n. sp. is related to the North and South American species C. intonsa Furtos, 1936 and C. vivacis Wurdig & Pinto, 1993, but also to some Australian and South-East Asian Islands ones, such as C. obfuscata Victor & Fernando, 1981 and C. raciborskii (Grochmalicki, 1915). The last species described herein, Cypretta maya n. sp., is closely related to the South-East Asia islands, Australian and north Indian species, in particular to C. hirsuta Henry, 1923, C. longidactyla Victor & Fernando, 1981, and C. patialensis Battish, 1982. PMID- 26042309 TI - New Nipponentomon species from northern Asia (Protura: Acerentomata, Nipponentomidae). AB - Nipponentomnon imadatei sp. nov. from Northeast China and Nippon entomon taiga sp. nov. from Siberia, Russia are described. Nipponentornon heterothrixi Yin & Xie is redescribed based on type materials and lectotype and paralectotypes are designed for the species. Nipponentonon bidentatumn and N. nippon are reported for the first time from China. Nipponentornon imnadatei sp. nov. is characterized by a short labrum, absence of seta Pla on tergite VII and presence of three A setae on sternites IV-VI. It is similar to N. jaceki from the Russian Far East, but differs in the shape of the comb, shape of setabeta1 on the foretarsus, length of sensillum e on the foretarsus, and in chaetotaxy on tergite I and sternites IV-VI. Nipponentomnon taiga sp. nov. is characterized by a short labrum, presence of seta P2a' on nota, seta P0a on tergite I, seta Pla on tergites I-VII, and absence of seta P3a on tergites II-VII. It is similar to N. heterothrixi, but differs in absence of seta d6 on the head, shape of accessory setae on tergites VI and VII, long and setiform setabeta1, and shorter sensilla c, e, g, a' and c' on the foretarsus than in sensilla in N. heterothrixi and in the porotaxy. A key for the world species of the genus is provided and the porotaxy of five species is reported in detail. PMID- 26042310 TI - Phylogenetic relationships of the South American ground beetle subgenus Chilioperyphus Jeannel (Coleoptera: Carabidae: Trechinae: Bembidiini: Bembidion Latreille). AB - The boundaries and relationships of the ground beetle group Chilioperyphus Jeannel (a subgenus of the cosmopolitan genus Bembidion Latreille) are examined using DNA and morphological data. DNA sequence data from seven genes (six nuclear and one mitochondrial) indicates that Chiliopeiyphus (as newly defined) is monophyletic, and is related to the subgenera Antipetyphanes Jeannel and Plocanoperyphus Jeannel, within the South American Antiperyphanes Complex. Chilioperyphus includes two described species, B. iendocinum Jensen-Haarup and B. orregoi Germain. Beinbidion cassinense Roig-Junent and Gianuca as well as Bembidion cuyanum Roig-Junent and Scheibler, formerly placed in subgenus Chilioperyphus, are transferred to subgenus Antipetyphanes. Bembidion cuyanum is considered a junior synonym of B. hirtipes Jeannel. The male genitalia of Chilioperyphus is unique in having a very long flagellum that is folded twice, allowing it to fit much of its length within the walls of the median lobe. However, the brush sclerite and basal part of the flagellum are not contained within the median lobe, as they extend anterior to its base. PMID- 26042311 TI - Two new species of Xiphocentronidae (Trichoptera) and their bionomics in Central Amazonia, Brazil. AB - Two new Xiphocentronidae species are described, Machairocentron falciforme sp. nov. and Xiphocentron (Antillotrichia) sclerothrix sp. nov. Illustrations of the males, females and pupae are presented. Adults were obtained through the emergence of pupae in the laboratory and from collections in traps suspended 1 m above the water in four streams in Presidente Figueiredo, Manaus and Barcelos municipalities in Amazonas state, and Oiapoque municipality in Amapd state, Brazil. Larvae inhabiting submerged substrates and on stream banks were collected in order to determine the feeding habits by examining gut contents. Larvae of both species are practically indistinguishable; the list of material observed in the gut content therefore refers to both species. Larvae of analyzed species have scraper feeding habits. PMID- 26042312 TI - A new Stumpffia (Amphibia: Anura: Microhylidae) from the Ranomafana region, south eastern Madagascar. AB - We describe a new species of small-sized frogs from degraded rainforest patches in the southern central east of Madagascar. Stumpffia miery sp. nov. has a snout vent length of 13-15 mm and can be distinguished from all other nominal species of Stumpffia by its body size and absence of toe reduction combined with length reduction of fingers I, II and IV in external view. The advertisement call is a single tonal chirping note that ranges in duration between 51-88 ms and is emitted after relatively regular inter-note intervals (duration of 2679-4247 ms, call repetition rate 0.3/sec, frequency range 7700-8300 Hz, dominant frequency 7751-8225 Hz). Its type locality is the Ambolo forest fragment close to Ranomafana village in southeastern Madagascar. Molecular data from DNA sequences of one mitochondrial and one nuclear gene indicate a high divergence from all nominal species of Stumpffia, suggesting that it represents a strongly differentiated independent evolutionary unit. Stumnpffia miery sp. nov. is apparently able to tolerate some degree of habitat degradation and therefore is probably not threatened with extinction. PMID- 26042313 TI - A new apterous species of Platypalpus Macquart (Diptera: Hybotidae, Tachydromiinae) from Ecuador. AB - Tachydromiinae is a very diverse subfamily of Hybotidae that comprises quite small predaceous flies. It is clearly monophyletic and its species are distinguished from other subfamilies by the apomorphic loss of vein M2 and cell dm, neither pterostigma nor pseudotracheae, phallus with the apex not articulated and ejaculatory apodeme not fused to the base of phallus (Sinclair & Cumming 2006). Platypalpus Macquart belongs to the tribe Tachydromiini and it is defined by the following characters: eyes bare, separated in both sexes, postpronotal lobe differentiated, scutum longer than broad (except in P brevicornis species group), mid leg raptorial, mid femur thickened and armed with rows of spine-like ventral setae, mid tibia usually with a somewhat prominent apical projection, wing with veins A1 and CuA2 present (cell cup present) (Grootaert & Shamshev 2012). The genus is the most diverse of those in the Tachydromiinae, with approximately 550 species found almost worldwide, but preferentially inhabiting cold and temperate regions in the Nearctic and Palaearctic; it is particularly diverse in the latter region with 295 described species, whereas only 22 species are known from the Neotropics (Yang et al. 2007). In the tropics it is more diverse at higher altitudes and in cold regions, with few species known at lower altitudes and in tropical areas, where they likely compete with species of Elaphropeza Macquart that occupy similar habits and niches (Grootaert & Shamshev 2012). This apparent competitive exclusion is the probable reason the genus is not very diverse in tropical regions (op. cit.). This paper describes a very curious new wingless species of Platypalpus from the Parque Nacional Cajas, Ecuador. It is the first wingless species described in the genus and is the 23rd species known from the Neotropical Region. PMID- 26042314 TI - East African odontopygid millipedes 2: A new, geographically disjunct species of Chaleponcus (Attems 1914) from the Pare Mts., Tanzania (Diplopoda, Spirostreptida, Odontopygidae). AB - Chaleponcus parensis n. sp., found in the North Pare Mountains, Tanzania, is described. The find is remarkable due to its geographically disjunct location, being at least 1500 km as the crow flies to the nearest valid record in Zimbabwe of a Chaleponcus. PMID- 26042333 TI - Evaluation of the effect of nurse education on patient-reported foot checks and foot care behaviour of people with diabetes receiving haemodialysis. AB - AIMS: To assess whether a programme of nurse education increased the frequency with which nurses conducted foot checks on people with diabetes undergoing haemodialysis and to evaluate whether this influenced self-reported foot care behaviour. METHODS: A non-randomized stepped-wedge design was used to evaluate a nurse education programme implemented in four UK National Health Service dialysis units. People with diabetes undergoing haemodialysis were invited to complete a questionnaire on the frequency of foot examination by health professionals, on the presence of foot problems and on their own foot care behaviour, using the Nottingham Assessment of Functional Foot-care (NAFF). An education session for nurses, including procedures for foot examination, was conducted sequentially in each of four haemodialysis units. The questionnaire was repeated at 2-monthly intervals. RESULTS: The education session resulted in a significant increase in the reported number of foot examinations by nurses (P = 0.007). There was also a significant improvement in reported foot care behaviour (P < 0.001), but this occurred between the first and second 2-monthly assessments and was unrelated to the timing of the intervention. CONCLUSIONS: A single education session can improve the routine checking of the feet of people with diabetes undergoing haemodialysis. The administration of the Nottingham Assessment of Functional Foot care questionnaire was associated with improved self-reported foot care behaviour, reflecting greater awareness of risk in this population. PMID- 26042334 TI - Colorimetric and Fluorescent Dual Mode Sensing of Alcoholic Strength in Spirit Samples with Stimuli-Responsive Infinite Coordination Polymers. AB - This study demonstrates a new strategy for colorimetric and fluorescent dual mode sensing of alcoholic strength (AS) in spirit samples based on stimuli-responsive infinite coordination polymers (ICPs). The ICP supramolecular network is prepared with 1,4-bis(imidazol-1-ylmethyl)benzene (bix) as the ligand and Zn(2+) as the central metal ion in ethanol, in which rhodamine B (RhB) is encapsulated through self-adaptive chemistry. In pure ethanol solvent, the as-formed RhB/Zn(bix) is well dispersed and quite stable. However, the addition of water into the ethanol dispersion of RhB/Zn(bix) destroys Zn(bix) network structure, resulting in the release of RhB from ICP into the solvent. As a consequence, the solvent displays the color of released RhB and, at the meantime, turns on the fluorescence of RhB, which constitutes a new mechanism for colorimetric and fluorescent dual mode sensing of AS in commercial spirit samples. With the method developed here, we could distinguish the AS of different commercial spirit samples by the naked eye within a wide linear range from 20 to 100% vol and by monitoring the increase of fluorescent intensity of the released RhB. This study not only offers a new method for on-spot visible detection of AS in commercial spirit samples, but also provides a strategy for designing dual mode sensing mechanisms for different analytical purposes based on novel stimuli-responsive materials. PMID- 26042335 TI - Fabrication of Self-Cleaning, Reusable Titania Templates for Nanometer and Micrometer Scale Protein Patterning. AB - The photocatalytic self-cleaning characteristics of titania facilitate the fabrication of reuseable templates for protein nanopatterning. Titania nanostructures were fabricated over square centimeter areas by interferometric lithography (IL) and nanoimprint lithography (NIL). With the use of a Lloyd's mirror two-beam interferometer, self-assembled monolayers of alkylphosphonates adsorbed on the native oxide of a Ti film were patterned by photocatalytic nanolithography. In regions exposed to a maximum in the interferogram, the monolayer was removed by photocatalytic oxidation. In regions exposed to an intensity minimum, the monolayer remained intact. After exposure, the sample was etched in piranha solution to yield Ti nanostructures with widths as small as 30 nm. NIL was performed by using a silicon stamp to imprint a spin-cast film of titanium dioxide resin; after calcination and reactive ion etching, TiO2 nanopillars were formed. For both fabrication techniques, subsequent adsorption of an oligo(ethylene glycol) functionalized trichlorosilane yielded an entirely passive, protein-resistant surface. Near-UV exposure caused removal of this protein-resistant film from the titania regions by photocatalytic degradation, leaving the passivating silane film intact on the silicon dioxide regions. Proteins labeled with fluorescent dyes were adsorbed to the titanium dioxide regions, yielding nanopatterns with bright fluorescence. Subsequent near-UV irradiation of the samples removed the protein from the titanium dioxide nanostructures by photocatalytic degradation facilitating the adsorption of a different protein. The process was repeated multiple times. These simple methods appear to yield durable, reuseable samples that may be of value to laboratories that require nanostructured biological interfaces but do not have access to the infrastructure required for nanofabrication. PMID- 26042336 TI - Short-stay transurethral prostate surgery: A randomized controlled trial comparing transurethral resection in saline bipolar transurethral vaporization of the prostate with monopolar transurethral resection. AB - OBJECTIVES: The aim of the present study was to establish the safety and efficacy profile of transurethral resection in saline (TURis) bipolar vaporization of the prostate relative to monopolar transurethral resection of prostate (TURP) and to test the hospital stay efficiency after TURis vaporization. MATERIALS AND METHODS: in this multicenter, double-blinded, prospective, randomized controlled trial, men aged 50-75 years old were randomized into two arms: TURis bipolar vaporization and monopolar TURP. Intraoperative details, perioperative parameters, and postoperative functional outcomes were assessed after intervention. Follow-up with symptom score assessment, prostate volume measurement, and uroflowmetry were performed at 3 and 6 months. RESULTS: Eighty four patients (mean age, 65.0 +/- 5.6 years) were randomized into each study arm. TURis bipolar vaporization had a longer operative time than monopolar TURP (51.6 +/- 24.5 vs 38.5 +/- 20.3 min, P < 0.001). Postoperatively, the TURis group had a shorter catheter time (33.6 +/- 23.7 vs 40.8 +/- 29.4 h, P = 0.013) and a shorter length of hospital stay (43.14 +/- 18.79 vs 52.33 +/- 30.58 h, P = 0.013). The postoperative dysuria score was higher in the TURis vaporization arm. There was no statistically significant difference between the two arms in terms of hemoglobin change and postoperative complication. No significant difference was observed in quality of life score at 3 and 6 months. CONCLUSIONS: TURis bipolar vaporization of the prostate is a safe and comparable alternative to monopolar TURP. It leads to a reduction in both catheter time and length of hospital stay. PMID- 26042337 TI - Shikonin inhibits TNF-alpha-induced growth and invasion of rat aortic vascular smooth muscle cells. AB - Shikonin is a naphthoquinone compound extracted from the Chinese herb purple gromwell. Shikonin has broad antibacterial, anti-inflammatory, and antitumor activities. The tumor necrosis factor-alpha (TNF-alpha)-induced proliferation and invasion of vascular smooth muscle cells (VSMCs) is an important factor that contributes to atherosclerosis. The effects of shikonin on the proliferation and apoptosis of VSMCs have been reported; however, the function of shikonin on TNF alpha-mediated growth and invasion of VSMCs during atherosclerosis remains unclear. In this study, we used Western blot, flow cytometry, real-time quantitative PCR, and enzyme-linked immunosorbent assay to investigate the effect of shikonin on the TNF-alpha-induced growth and invasion of VSMCs and to determine the underlying mechanism. Our results showed that shikonin inhibits the TNF-alpha-mediated growth and invasion. Further study revealed that shikonin regulates the activation of nuclear factor kappa B and phosphatidyl inositol 3 kinase signaling pathways; modulates the expression of cyclin D1, cyclin E, B cell lymphoma 2, and Bax; activates caspase-3 and caspase-9; induces cell cycle arrest; and promotes the apoptosis of VSMCs. Together, our results indicate that shikonin may become a promising agent for the treatment of atherosclerosis and they also establish foundation for the development of anti-atherosclerosis drugs. PMID- 26042338 TI - An Integrated View of the Influence of Temperature, Pressure, and Humidity on the Stability of Trimorphic Cysteamine Hydrochloride. AB - Understanding the phase behavior of pharmaceuticals is important for dosage form development and regulatory requirements, in particular after the incident with ritonavir. In the present paper, a comprehensive study of the solid-state phase behavior of cysteamine hydrochloride used in the treatment of nephropathic cystinosis and recently granted orphan designation by the European Commission is presented employing (high-pressure) calorimetry, water vapor sorption, and X-ray diffraction as a function of temperature. A new crystal form (I2/a, form III) has been discovered, and its structure has been solved by X-ray powder diffraction, while two other crystalline forms are already known. The relative thermodynamic stabilities of the commercial form I and of the newly discovered form III have been established; they possess an overall enantiotropic phase relationship, with form I stable at room temperature and form III stable above 37 degrees C. Its melting temperature was found at 67.3 +/- 0.5 degrees C. Cysteamine hydrochloride is hygroscopic and immediately forms a concentrated saturated solution in water with a surprisingly high concentration of 47.5 mol % above a relative humidity of 35%. No hydrate has been observed. A temperature-composition phase diagram is presented that has been obtained with the unary pressure temperature phase diagram, measurements, and calculations. For development, form I would be the best form to use in any solid dosage form, which should be thoroughly protected against humidity. PMID- 26042340 TI - Development of novel CXC chemokine receptor 7 (CXCR7) ligands: selectivity switch from CXCR4 antagonists with a cyclic pentapeptide scaffold. AB - The CXC chemokine receptor 7 (CXCR7)/ACKR3 is a chemokine receptor that recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and interferon-inducible T-cell alpha chemoattractant (I-TAC)/CXCL11. Here, we report the development of novel CXCR7-selective ligands with a cyclic pentapeptide scaffold through an SAR study of CXC chemokine receptor 4 (CXCR4) selective antagonist FC131 [cyclo(-d Tyr-l-Arg-l-Arg-l-Nal-Gly-), Nal = 3-(2-naphthyl)alanine]. Substitution of Gly with l-Pro switched the receptor preference of the peptides from CXCR4 to CXCR7. The SAR study led to the identification of a potent CXCR7 ligand, FC313 [cyclo(-d Tyr-l-Arg-l-MeArg-l-Nal-l-Pro-)], which recruits beta-arrestin to CXCR7. Investigations via receptor mutagenesis and molecular modeling experiments suggest a possible binding mode of the cyclic pentapeptide CXCR7 agonist. PMID- 26042341 TI - Effect of donor age and parent-to-child transplant on living-related donor kidney transplantation: a single center's experience of 236 cases. AB - To study the impact of parent-to-child transplant and older donor age on recipients' post-transplant creatinine levels, a total of 236 patients who received living donor kidney transplantation were evaluated for kidney viability based on creatinine (Cr) level. Of the 236 pairings, 113 (48%) were parent-to child followed by sibling transplants (66, 30%). Recipient Cr levels were significantly higher at 6 months and 3 years post-transplant in the parent-to child transplants compared to other donor-recipient relationships. In addition, donor age (average age: 44.1 +/- 11.5; range: 19-66) contributed to higher recipient post-transplant Cr levels (p < 0.01). Pre-transplant donor and recipient Cr levels tended to result in higher post-transplant Cr levels in recipients (p < 0.05). Multivariate logistic regression analysis revealed that the presence of both parent-to-child transplant and older donor significantly increased the risk of elevated post-transplant Cr levels in recipients with an estimated odds ratios ranging from 3.46 (95% CI: 1.71-6.98) at 6 months to 8.04 (3.14-20.56) at 3 years post-transplant. Donor age significantly affected transplant survival as measured by higher recipient post-transplant Cr levels. In addition, parent-to-child transplant pairings, along with older donor age, significantly increased the risk of elevated post-transplant Cr levels in recipients. PMID- 26042342 TI - Undiagnosed hypertension in a rural community in Sudan and association with some features of the metabolic syndrome: how serious is the situation? AB - BACKGROUND: Hypertension is the leading risk factor for death and disability globally. Its prevalence is increasing worldwide especially in low and middle income countries. It is considered a silent killer because it has no specific symptoms and thus can go unnoticed for many years, only presenting for the first time with serious complications. The situation of undiagnosed hypertension in Sudan has not been fully investigated before. OBJECTIVE: To determine the prevalence of undiagnosed hypertension in the rural communities of River Nile State (RNS), Sudan and to assess the associated risk factors. METHODS: A cross sectional community-based study, in which 1099 volunteer adult participants from the rural communities in RNS, not known to be hypertensive, were included. Blood pressure was measured as well as anthropometric measurements. The WHO stepwise approach for non-communicable diseases surveillance was used for data collection. A p value below 0.05 was considered statistically significant. RESULTS: There were 461 males (41.9%) and 683 females (58.1%). The male to female ratio was 1:1.4. The age range was 18-90 years, with a mean age of 39.6 (STD +/- 15.9). The prevalence of undiagnosed hypertension was 38.2%, with a prevalence of 36.7% among males and 39.3% among females. There were significant associations between undiagnosed hypertension and increasing age, obesity, illiteracy and diabetes mellitus (p < 0.05). CONCLUSION: This study uncovers a hidden epidemic of a silent killer in the rural communities of RNS. Urgent interventions are required to address this serious health epidemic. PMID- 26042343 TI - The changing trends of peritoneal dialysis related peritonitis and novel risk factors. AB - AIM: Continuous ambulatory peritoneal dialysis (PD) has become a treatment modality for end stage renal disease with a peak of its use in 1990 s. The aim of this study was to examine the peritonitis rates, causative organisms and the risk factors of peritonitis in a large group of patients in our center. METHODS: The study was conducted in the Nephrology Department of a University Hospital in Turkey. Patients in the PD programme between January 2000 and January 2006 were included. Cohort-specific and subject specific peritonitis incidence, and peritonitis-free survival were calculated. Causative organisms and risk factors were evaluated. RESULTS: Totally 620 episodes of peritonitis occurred in 440 patients over the six years period. Peritonitis rates showed a decreasing trend through the years (0.79 episodes/patient-year 2000-2003 and 0.46 episodes/patient year 2003-2006). Cohort-specific peritonitis incidence was 0.62 episodes/patient years and median subject-specific peritonitis incidence was 0.44 episodes/patient years. The median peritonitis-free survival was 15.25 months (%95 CI, 9.45-21.06 months). The proportion of gram-negative organisms has increased from 9.8% to 17.3%. There was a significant difference in the percentage of culture negative peritonitis between the first three and the last three years (53.1% vs. 43.2%, respectively). Peritonitis incidence was higher in patients who had been transferred from HD, who had catheter related infection and who had HCV infection without cirrhosis. CONCLUSIONS: Our study showed significant trends in the peritonitis rates, causative organisms and antibiotic resistance. Prior HD therapy, catheter related infections and HCV infection were found to be risk factors for peritonitis. PMID- 26042345 TI - Transgenic animals: more than "commercial opportunities". PMID- 26042344 TI - High Prevalence of Porocephalus crotali Infection on a Barrier Island (Cumberland Island) off the Coast of Georgia, with Identification of Novel Intermediate Hosts. AB - Porocephalus crotali is a pentastomid parasite that uses crotaline snakes as definitive hosts and a variety of rodents as intermediate hosts. A study of definitive and intermediate pentastome hosts on Cumberland Island, Georgia, revealed high prevalence of P. crotali infection in crotalid snakes as well as several mammalian species. Despite the presence of numerous nymphs in some animals, clinical signs of disease were not observed. In intermediate hosts, the liver, mesentery, and reproductive organs were most commonly infected. No gross evidence of tissue damage was noted in association with the numerous encysted nymphal pentastomes, and histopathology demonstrated minimal reaction to the encysted nymphs. Partial 18S rRNA gene sequences confirmed the parasites were P. crotali. In contrast to many previous reports in rodents, the prevalence on this barrier island was high, and this is the first report of Virginia opossums (Didelphis virginiana) and any insectivore species as intermediate hosts. Although generally not considered pathogenic, the long-term consequences of high nymph intensities on individuals deserve attention. PMID- 26042346 TI - Reducing the use of laboratory animals in biomedical research: problems and possible solutions. PMID- 26042347 TI - A Comparison of the Acute and Chronic Effects of Antidepressants in Cultured C6 and 1321N1 Cells. PMID- 26042348 TI - Direct Determination of Glutathione S-transferase and Glucose-6-phosphate Dehydrogenase Activities in Cells Cultured in Microtitre Plates as Biomarkers for Oxidative Stress. PMID- 26042349 TI - Toxicity and Cell Density Monitoring in Monolayer and Three-dimensional Cultures with the XTT Assay. PMID- 26042350 TI - Magnetic resonance imaging of the common marmoset head. PMID- 26042351 TI - Molecular farming on rescue of pharma industry for next generations. AB - Recombinant proteins expressed in plants have been emerged as a novel branch of the biopharmaceutical industry, offering practical and safety advantages over traditional approaches. Cultivable in various platforms (i.e. open field, greenhouses or bioreactors), plants hold great potential to produce different types of therapeutic proteins with reduced risks of contamination with human and animal pathogens. To maximize the yield and quality of plant-made pharmaceuticals, crucial factors should be taken into account, including host plants, expression cassettes, subcellular localization, post-translational modifications, and protein extraction and purification methods. DNA technology and genetic transformation methods have also contributed to great parts with substantial improvements. To play their proper function and stability, proteins require multiple post-translational modifications such as glycosylation. Intensive glycoengineering research has been performed to reduce the immunogenicity of recombinant proteins produced in plants. Important strategies have also been developed to minimize the proteolysis effects and enhance protein accumulation. With growing human population and new epidemic threats, the need for new medications will be paramount so that the traditional pharmaceutical industry will not be alone to answer medication demands for upcoming generations. Here, we review several aspects of plant molecular pharming and outline some important challenges that hamper these ambitious biotechnological developments. PMID- 26042352 TI - Lutein and cataract: from bench to bedside. AB - Cataract is one of the most important leading causes of blindness in the world. Extensive research showed that oxidative stress may play an important role in the initiation and progression of a cataract and other age-related eye diseases. Extra-generation of reactive oxygen and nitrogen species in the eye tissue has been shown as one of the most important risk factors for cataracts and other age related eye diseases. With respect to this, it can be hypothesized that dietary antioxidants may be useful in the prevention and/or mitigation of cataract. Lutein is an important xanthophyll which is widely found in different vegetables such as spinach, kale and carrots as well as some other foods such as eggs. Lutein is concentrated in the macula and suppresses the oxidative stress in the eye tissues. A plethora of literature has shown that increased lutein consumption has a close correlation with reduction in the incidence of cataract. Despite this general information, there is a negligible number of review articles considering the beneficial effects of lutein on cataracts and age-related eye diseases. The present review is aimed at discussing the role of oxidative stress in the initiation and progression of a cataract and the possible beneficial effects of lutein in maintaining retinal health and fighting cataract. We also provide a perspective on the chemistry, sources, bioavailability and safety of lutein. PMID- 26042353 TI - Application of bacteriophages in post-harvest control of human pathogenic and food spoiling bacteria. AB - Bacteriophages have attracted great attention for application in food biopreservation. Lytic bacteriophages specific for human pathogenic bacteria can be isolated from natural sources such as animal feces or industrial wastes where the target bacteria inhabit. Lytic bacteriophages have been tested in different food systems for inactivation of main food-borne pathogens including Listeria monocytogenes, Staphylococcus aureus, Escherichia coli O157:H7, Salmonella enterica, Shigella spp., Campylobacter jejuni and Cronobacter sakazkii, and also for control of spoilage bacteria. Application of lytic bacteriophages could selectively control host populations of concern without interfering with the remaining food microbiota. Bacteriophages could also be applied for inactivation of bacteria attached to food contact surfaces or grown as biofilms. Bacteriophages may receive a generally recognized as safe status based on their lack of toxicity and other detrimental effects to human health. Phage preparations specific for L. monocytogenes, E. coli O157:H7 and S. enterica serotypes have been commercialized and approved for application in foods or as part of surface decontamination protocols. Phage endolysins have a broader host specificity compared to lytic bacteriophages. Cloned endolysins could be used as natural preservatives, singly or in combination with other antimicrobials such as bacteriocins. PMID- 26042354 TI - The complete mitochondrial genome of the Pacific needlefish Strongylura anastomella (Belonidae, Beloniformes) from Korea. AB - Belonidae is a good model for investigating speciation and biogeography. To obtain basic information on the phylogeny of Belonidae, we determined the complete mitogenome of Strongylura anastomella using next-generation sequencing. The complete mitogenome is 16,534 bp in length and consists of 2 rRNAs, 22 tRNAs, 13 protein-coding genes and a control region. The nucleotide composition is 31.1% A, 29.8% T, 14.5% G and 24.6% C, with an AT bias (60.9%). The gene direction and position were similar to those of other Beloniformes. Belonidae and Scomberesocidae were separated in the phylogenetic tree based on complete mitogenomes. Further study is required to clarify the phylogenetic relationships among Belonidae and families within Beloniformes. PMID- 26042355 TI - Mechanism of Copper-Catalyzed Hydroalkylation of Alkynes: An Unexpected Role of Dinuclear Copper Complexes. AB - This article describes a mechanistic study of copper-catalyzed hydroalkylation of terminal alkynes. Relying on the established chemistry of N-heterocyclic carbene copper hydride (NHCCuH) complexes, we previously proposed that the hydroalkylation reaction proceeds by hydrocupration of an alkyne by NHCCuH followed by alkylation of the resulting alkenylcopper intermediate by an alkyl triflate. NHCCuH is regenerated from NHCCuOTf through substitution with CsF followed by transmetalation with silane. According to this proposal, NHCCuH must react with an alkyne faster than with an alkyl triflate to avoid reduction of the alkyl triflate. However, we have determined that NHCCuH reacts with alkyl triflates significantly faster than with terminal alkynes, strongly suggesting that the previously proposed mechanism is incorrect. Additionally, we have found that NHCCuOTf rapidly traps NHCCuX (X = F, H, alkenyl) complexes to produce (NHCCu)2(MU-X)(OTf) (X = F, H, alkenyl) complexes. In this article, we propose a new mechanism for hydroalkylation of alkynes that features dinuclear (NHCCu)2(MU H)(OTf) (X = F, H, alkenyl) complexes as key catalytic intermediates. The results of our study establish feasible pathways for the formation of these intermediates, their ability to participate in the elementary steps of the proposed catalytic cycle, and their ability to serve as competent catalysts in the hydroalkylation reaction. We also provide evidence that the unusual reactivity of the dinuclear complexes is responsible for efficient hydroalkylation of alkynes without concomitant side reactions of the highly reactive alkyl triflates. PMID- 26042356 TI - Controlling the Electrical Transport Properties of Nanocontacts to Nanowires. AB - The ability to control the properties of electrical contacts to nanostructures is essential to realize operational nanodevices. Here, we show that the electrical behavior of the nanocontacts between free-standing ZnO nanowires and the catalytic Au particle used for their growth can switch from Schottky to Ohmic depending on the size of the Au particles in relation to the cross-sectional width of the ZnO nanowires. We observe a distinct Schottky to Ohmic transition in transport behavior at an Au to nanowire diameter ratio of 0.6. The current voltage electrical measurements performed with a multiprobe instrument are explained using 3-D self-consistent electrostatic and transport simulations revealing that tunneling at the contact edge is the dominant carrier transport mechanism for these nanoscale contacts. The results are applicable to other nanowire materials such as Si, GaAs, and InAs when the effects of surface charge and contact size are considered. PMID- 26042357 TI - A fusion protein derived from Moraxella catarrhalis and Neisseria meningitidis aimed for immune modulation of human B cells. AB - Moraxella IgD-binding protein (MID) is a well characterized trimeric autotransporter that specifically targets the IgD of B cells. We fused the membrane anchor of the meningococcal autotransporter NhhA with the IgD-binding region of MID (aa 962-1200) to create a chimeric protein designated as NID. The aim was to use this specific targeting to provide a better vaccine candidate against meningococci, in particular serogroup B by enhancing the immunogenicity of NhhA. NID was thereafter recombinantly expressed in E. coli. The NID expressing E. coli bound to peripheral B lymphocytes that resulted in cellular activation. Furthermore, we also successfully expressed NID on outer membrane vesicles, nanoparticles that are commonly used in meningococcal vaccines. This study thus highlights the applicability of the menigococcal-Moraxella fusion protein NID to be used for specific targeting of vaccine components to the IgD B cell receptor. PMID- 26042359 TI - Flat Panel Light Source with Lateral Gate Structure Based on SiC Nanowire Field Emitters. AB - A field-emission light source with high luminance, excellent luminance uniformity, and tunable luminance characteristics with a novel lateral-gate structure is demonstrated. The lateral-gate triode structure comprises SiC nanowire emitters on a Ag cathode electrode and a pair of Ag gate electrodes placed laterally on both sides of the cathode. The simple and cost-effective screen printing technique is employed to pattern the lateral-gates and cathode structure on soda lime glass. The area coverage of the screen-printed cathode and gates on the glass substrate (area: 6 * 8 cm(2)) is in the range of 2.04% - 4.74% depending on the set of cathode-gate electrodes on the substrate. The lateral gate structure with its small area coverage exhibits a two-dimensional luminance pattern with high brightness and good luminance uniformity. A maximum luminance of 10,952 cd/cm(2) and a luminance uniformity of >90% can be achieved with a gate voltage of 500 V and an anode voltage of 4000 V, with an anode current of 1.44 mA and current leakage to the gate from the cathode of about 10%. PMID- 26042358 TI - Are Executive Functioning Deficits Concurrently and Predictively Associated with Depressive and Anxiety Symptoms in Adolescents? AB - The central objective of the current study was to evaluate how executive functions (EF), and specifically cognitive flexibility, were concurrently and predictively associated with anxiety and depressive symptoms in adolescence. Adolescents (N = 220) and their parents participated in this longitudinal investigation. Adolescents' EF was assessed by the Wisconsin Card Sorting Test (WCST) during the initial assessment, and symptoms of depressive and anxiety disorders were reported by mothers and youths concurrently and 2 years later. Correlational analyses suggested that youths who made more total errors (TE), including both perseverative errors (PE) and nonperseverative errors (NPE), concurrently exhibited significantly more depressive symptoms. Adolescents who made more TE and those who made more NPE tended to have more anxiety symptoms 2 years later. Structural equation modeling analyses accounting for key explanatory variables (e.g., IQ, disruptive behavior disorders, and attention deficit hyperactive disorder) showed that TE was concurrently associated with parent reports of adolescent depressive symptoms. The results suggest internalizing psychopathology is associated with global (TE) and nonspecific (NPE) EF difficulties but not robustly associated with cognitive inflexibility (PE). Future research with the WCST should consider different sources of errors that are posited to reflect divergent underlying neural mechanisms, conferring differential vulnerability for emerging mental health problems. PMID- 26042360 TI - Alternating Current Dielectrophoresis Optimization of Pt-Decorated Graphene Oxide Nanostructures for Proficient Hydrogen Gas Sensor. AB - Alternating current dielectrophoresis (DEP) is an excellent technique to assemble nanoscale materials. For efficient DEP, the optimization of the key parameters like peak-to-peak voltage, applied frequency, and processing time is required for good device. In this work, we have assembled graphene oxide (GO) nanostructures mixed with platinum (Pt) nanoparticles between the micro gap electrodes for a proficient hydrogen gas sensors. The Pt-decorated GO nanostructures were well located between a pair of prepatterned Ti/Au electrodes by controlling the DEP technique with the optimized parameters and subsequently thermally reduced before sensing. The device fabricated using the DEP technique with the optimized parameters showed relatively high sensitivity (~10%) to 200 ppm hydrogen gas at room temperature. The results indicates that the device could be used in several industry applications, such as gas storage and leak detection. PMID- 26042362 TI - CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo controlled Phase 2b study. AB - BACKGROUND: New treatment options are required for patients with asthma not sufficiently controlled with inhaled therapies. In a Phase 2a trial, CYT003, a Toll-like receptor-9 agonist immunomodulator, improved asthma control during inhaled glucocorticosteroid reduction in patients with allergic asthma. This double-blind Phase 2b study assessed the efficacy and safety of CYT003 in patients with persistent moderate-to-severe allergic asthma not sufficiently controlled on standard inhaled glucocorticosteroid therapy with/without long acting beta-agonists (LABAs). METHODS: Overall, 365 patients received seven doses of subcutaneous CYT003 (0.3, 1, or 2 mg) or placebo as add-on therapy to conventional controller medication. Change from baseline in Asthma Control Questionnaire (ACQ) score was the primary outcome; secondary outcomes included change in forced expiratory volume, Mini Asthma Quality of Life Questionnaire, and safety. RESULTS: All groups, including placebo, showed a clinically important improvement in ACQ score; however, there was no significant difference between the CYT003 and placebo groups at week 12 (least-squares mean difference 0.3 mg: 0.027 [95% confidence interval -0.259 to 0.204]; 1 mg: 0.097 [-0.131 to 0.325]; 2 mg: 0.081 [-0.148 to 0.315]). No significant differences were seen in secondary outcomes. CYT003 was well tolerated; the most common treatment-emergent adverse events were injection site reactions. Due to lack of efficacy, the study was prematurely terminated at the end of the treatment phase with no further follow up. CONCLUSIONS: Toll-like receptor-9 agonism with CYT003 showed no additional benefit in patients with insufficiently controlled moderate-to-severe allergic asthma receiving standard inhaled glucocorticosteroid therapy with or without LABAs. PMID- 26042363 TI - A novel solid-state fractionation of naphthenic acid fraction components from oil sands process-affected water. AB - Various sorbent materials were evaluated for the fractionation of naphthenic acid fraction components (NAFCs) from oil sand process-affected water (OSPW). The solid phase materials include activated carbon (AC), cellulose, iron oxides (magnetite and goethite), polyaniline (PANI) and three types of biochar derived from biomass (BC-1; rice husks, BC-2; acacia low temperature and BC-3; acacia high temperature). NAFCs were semi-quantified using electrospray ionization high resolution Orbitrap mass spectrometry (ESI-MS) and the metals were assessed by inductively coupled plasma optical emission spectrometry (ICP-OES). The average removal efficacy of NAFCs by AC was 95%. The removal efficacy decreased in the following order: AC, BC-1>BC-2, BC-3, goethite>PANI>cellulose, magnetite. The removal of metals did not follow a clear trend; however, there was notable leaching of potassium by AC and biochar samples. The bound NAFCs by AC were desorbed efficiently with methanol. Methanol regeneration and recycling of AC revealed 88% removal on the fourth cycle; a 4.4% decrease from the first cycle. This fractionation method represents a rapid, cost-effective, efficient, and green strategy for NAFCs from OSPW, as compared with conventional solvent extraction. PMID- 26042364 TI - What is the optimal management of early-stage low-grade follicular lymphoma in the modern era? AB - BACKGROUND: Despite international practice guidelines endorsing radiotherapy (RT) as the preferred initial therapy, treatment approaches vary for patients with early-stage follicular lymphoma. The authors engaged the National Cancer Data Base to analyze patterns of care and survival outcomes for patients with early stage follicular lymphoma in the era of modern therapy. METHODS: A National Cancer Data Base retrospective cohort study was conducted of 35,961 patients with lymph node and extranodal, American Joint Committee on Cancer stage I to II, WHO grade 1 to 2 follicular lymphoma who were diagnosed between 1998 and 2012. Univariate and multivariable analyses were performed to identify sociodemographic, treatment, and tumor characteristics that were predictive of overall survival (OS) and treatment use. Propensity score-adjusted Cox proportional hazards ratios for survival in patients treated for follicular lymphoma were used. RESULTS: Of the 35,961 patients with follicular lymphoma included in the current study, 63% had stage I disease, 79% were without extranodal disease, and 61% were aged >60 years. RT use decreased from 37% in 1999 to 24% in 2012 (P<.0001), with corresponding significant increases in observation and single-agent chemotherapy. Patients who received RT had 5-year and 10-year OS rates of 86% and 68%, respectively, compared with 74% and 54%, respectively, for those who did not receive RT (P<.0001). On multivariable survival analysis, including a propensity score to account for potential uncaptured confounding variables due to a lack of randomization, upfront RT remained independently associated with improved OS (hazard ratio of death, 0.54; 95% confidence interval, 0.47-0.63 [P<.0001]). CONCLUSIONS: RT is an increasingly underused treatment approach in the era of modern therapy for patients with early stage follicular lymphoma. The use of RT appears to improve OS and should remain standard practice as encouraged by clinical practice guidelines. PMID- 26042365 TI - Class 1 Integrons and the Antiseptic Resistance Gene (qacEDelta1) in Municipal and Swine Slaughterhouse Wastewater Treatment Plants and Wastewater-Associated Methicillin-Resistant Staphylococcus aureus. AB - Class 1 integrons are mobile gene elements (MGEs) containing qacEDelta1 that are resistant to quaternary ammonium compound (QAC) disinfectants. This study compared the abundances of class 1 integrons and antiseptic resistance genes in municipal (M) and swine slaughterhouse (S) wastewater treatment plants (WWTPs) and investigated the presence of class 1 integrons and antiseptic resistance genes in methicillin-resistant Staphylococcus aureus (MRSA) isolated from wastewater samples. The abundances of intI1 and qacEDelta1 genes in 96 wastewater samples were quantified using real-time quantitative polymerase chain reaction (real-time qPCR), and 113 MRSA isolates recovered from the wastewater samples were detected class 1 integrons and linked antiseptic resistance genes (qacEDelta1), and minimum inhibitory concentrations (MICs) for QAC antiseptics. The intI1 and qacEDelta1 genes were detected in all the wastewater samples, and they were more abundant in S-WWTP samples than in M-WWTP samples. A higher percentage of MRSA isolates carried qacEDelta1 in MRSA from swine wastewater samples (62.8%) than in municipal MRSA (3.7%). All the MRSA isolates showed high MICs for antiseptic agents. This study provides important evidence regarding the abundances of intI1 and qacEDelta1 genes in municipal and swine slaughterhouse wastewater, and antiseptic-resistant MRSA strains were detected in swine slaughterhouse wastewater. PMID- 26042366 TI - An iPad-Based Tool for Improving the Skills of Children with Attention Deficit Disorder. AB - Attention Deficit Hyperactivity Disorder (ADHD), with a worldwide prevalence of 5.29%-7.1%, is one of the most common neurodevelopmental disorders among children and adolescents. Apart from typical symptoms like inattention, hyperactivity and impulsiveness, patients also evidence attention deficit problems with reading comprehension. This in turn causes poor school performance and widens the gap with peers without ADHD. This paper presents a novel and interactive tool based on Serious Games for Health, whose aim is not only to improve comprehension, but also hold the user's attention. This tool is geared towards assessing reading quality and is intended for iPad devices. Preliminary results obtained from the experiment performed to evaluate the game are included in this report. A group of six typically developing children from Colegio Vizcaya aged between 8 and 12 took part in the evaluation of motivation, satisfaction and usability of the same therapy in the new media. Results obtained by participants playing the game were analysed together with questionnaires concerning the usability of the system. Game evaluation resulted in relatively good statistics-average score was 3 points out of 4 and average time for completing the exercise was 59 seconds. A SUS questionnaire with an average score of 92.75 out of 100 indicates that the game presented is user-friendly and an effective tool. Moreover, based on the feedback obtained from participants, the game had been improved and additional functionality introduced. Older participants completed the first game faster than the younger ones, but age was not influential in subsequent games. PMID- 26042367 TI - Relationship between Urinary Pesticide Residue Levels and Neurotoxic Symptoms among Women on Farms in the Western Cape, South Africa. AB - BACKGROUND: This cross-sectional study aimed to investigate the relationship between urinary pesticide residue levels and neurotoxic symptoms amongst women working on Western Cape farms in South Africa. METHOD: A total of 211 women were recruited from farms (n=121) and neighbouring towns (n=90). Participant assessment was via a Q16 questionnaire, reporting on pesticide exposures and measurement of urinary OP metabolite concentrations of dialkyl phosphates (DAP) and chlorpyriphos, 3,5,6-trichloropyridinol (TCPY) and of pyrethroid (PYR) metabolite concentrations (3- phenoxybenzoic acid (3PBA), 4-fluoro-3 phenoxybenzoic acid (4F3PBA), cis-2,2-dibromovinyl-2,2-dimethylcyclopropane-1 carboxylic acid (DBCA), and the cis- and trans isomers of 2,2-dichlorovinyl-2,2 dimethylcyclopropane-1-carboxylic acid. RESULTS: Median urinary pesticide metabolites were slightly (6%-49%) elevated in the farm group compared to the town group, with 2 metabolites significantly higher and some lower in the farm group. The prevalence of all Q16 symptoms was higher amongst farm women compared to town women. Three Q16 symptoms (problems with buttoning, reading and notes) were significantly positively associated with three pyrethroid metabolites (cis- and trans-DCCA and DBCA), although associations may due to chance as multiple comparisons were made. The strongest association for a pyrethroid metabolite was between problems with buttoning and DBCA (odds ratio (OR)=8.93, 95% confidence interval (CI):1.71-46.5. There was no association between Q16 symptoms and OP metabolites. CONCLUSIONS: Women farm residents and rural women from neighbouring towns in the Western Cape are exposed to OP and PYR pesticides. The study did not provide strong evidence that pesticides are associated with neurotoxic symptoms but associations found could be explored further. PMID- 26042368 TI - Toxic releases and risk disparity: a spatiotemporal model of industrial ecology and social empowerment. AB - Information-based regulations (IBRs) are founded on the theoretical premise that public participation in accomplishing policy goals is empowered by open access to information. Since its inception in 1988, the Toxics Release Inventory (TRI) has provided the framework and regulatory impetus for the compilation and distribution of data on toxic releases associated with industrial development, following the tenets of IBR. As TRI emissions are reputed to disproportionately affect low-income communities, we investigated how demographic characteristics are related to change in TRI emissions and toxicity risks between 1989 and 2002, and we sought to identify factors that predict these changes. We used local indicators of spatial association (LISA) maps and spatial regression techniques to study risk disparity in the Los Angeles urban area. We also surveyed 203 individuals in eight communities in the same region to measure the levels of awareness of TRI, attitudes towards air pollution, and general environmental risk. We discovered, through spatial lag models, that changes in gross and toxic emissions are related to community ethnic composition, poverty level, home ownership, and base 1989 emissions (R-square=0.034-0.083). We generated a structural equation model to explain the determinants of social empowerment to act on the basis of environmental information. Hierarchical confirmatory factor analysis (HCFA) supports the theoretical model that individual empowerment is predicted by risk perception, worry, and awareness (Chi-square=63.315, p=0.022, df=42). This study provides strong evidence that spatiotemporal changes in regional-scale environmental risks are influenced by individual-scale empowerment mediated by IBRs. PMID- 26042369 TI - An evaluation of antifungal agents for the treatment of fungal contamination in indoor air environments. AB - Fungal contamination in indoor environments has been associated with adverse health effects for the inhabitants. Remediation of fungal contamination requires removal of the fungi present and modifying the indoor environment to become less favourable to growth. This may include treatment of indoor environments with an antifungal agent to prevent future growth. However there are limited published data or advice on chemical agents suitable for indoor fungal remediation. The aim of this study was to assess the relative efficacies of five commercially available cleaning agents with published or anecdotal use for indoor fungal remediation. The five agents included two common multi-purpose industrial disinfectants (Cavicide(r) and Virkon(r)), 70% ethanol, vinegar (4.0%-4.2% acetic acid), and a plant-derived compound (tea tree (Melaleuca alternifolia) oil) tested in both a liquid and vapour form. Tea tree oil has recently generated interest for its antimicrobial efficacy in clinical settings, but has not been widely employed for fungal remediation. Each antifungal agent was assessed for fungal growth inhibition using a disc diffusion method against a representative species from two common fungal genera, (Aspergillus fumigatus and Penicillium chrysogenum), which were isolated from air samples and are commonly found in indoor air. Tea tree oil demonstrated the greatest inhibitory effect on the growth of both fungi, applied in either a liquid or vapour form. Cavicide(r) and Virkon(r) demonstrated similar, although less, growth inhibition of both genera. Vinegar (4.0%-4.2% acetic acid) was found to only inhibit the growth of P. chrysogenum, while 70% ethanol was found to have no inhibitory effect on the growth of either fungi. There was a notable inhibition in sporulation, distinct from growth inhibition after exposure to tea tree oil, Virkon(r), Cavicide(r) and vinegar. Results demonstrate that common cleaning and antifungal agents differ in their capacity to inhibit the growth of fungal genera found in the indoor air environment. The results indicate that tea tree oil was the most effective antifungal agent tested, and may have industrial application for the remediation of fungal contamination in residential and occupational buildings. PMID- 26042370 TI - Prototype early warning systems for vector-borne diseases in Europe. AB - Globalization and environmental change, social and demographic determinants and health system capacity are significant drivers of infectious diseases which can also act as epidemic precursors. Thus, monitoring changes in these drivers can help anticipate, or even forecast, an upsurge of infectious diseases. The European Environment and Epidemiology (E3) Network has been built for this purpose and applied to three early warning case studies: (1) The environmental suitability of malaria transmission in Greece was mapped in order to target epidemiological and entomological surveillance and vector control activities. Malaria transmission in these areas was interrupted in 2013 through such integrated preparedness and response activities. (2) Since 2010, recurrent West Nile fever outbreaks have ensued in South/eastern Europe. Temperature deviations from a thirty year average proved to be associated with the 2010 outbreak. Drivers of subsequent outbreaks were computed through multivariate logistic regression models and included monthly temperature anomalies for July and a normalized water index. (3) Dengue is a tropical disease but sustained transmission has recently emerged in Madeira. Autochthonous transmission has also occurred repeatedly in France and in Croatia mainly due to travel importation. The risk of dengue importation into Europe in 2010 was computed with the volume of international travelers from dengue affected areas worldwide.These prototype early warning systems indicate that monitoring drivers of infectious diseases can help predict vector-borne disease threats. PMID- 26042372 TI - Enhancing the care transitions intervention protocol to better address the needs of family caregivers. AB - BACKGROUND: Family caregivers play a central role in ensuring the execution of the discharge care plan. OBJECTIVE: To enhance an evidence-based model-the Care Transitions Intervention (CTI)-and to make it more responsive to the needs of family caregivers and determine its impact on a measure of activation. METHODS: Prospective cohort of 83 patient-family caregiver partnerships discharged from hospital. The domains of the CTI were modified to incorporate those areas that family caregivers identified as wanting to feel better prepared and more confident. RESULTS: Family caregivers experienced a mean improvement in activation of 6 points on a 0-10 scale (p < .0001). Sixty-four percent (95% confidence interval [CI], 52-75%) of family caregivers met or exceeded self identified goals. Transitions Coaches identified 71% (95% CI, 60-80%) of patients as having medication discrepancies or errors after hospital discharge and coached family caregivers on how to respond. The mean 3-item Care Transitions Measure score on a 0-100 scale was 80.89 (95% CI, 76.62-85.16). Almost all (99%) (95% CI, 92-100%) participants would recommend the model to a friend of family member. DISCUSSION: The enhanced family caregiver CTI significantly improved activation, quality, goal achievement, satisfaction, and medication safety. The enhanced family caregiver CTI may have application in improving the hospital discharge experience. PMID- 26042373 TI - Family caregivers' experiences during transitions out of hospital. AB - BACKGROUND: Family caregivers play a central yet under recognized role in ensuring quality and safety during a loved one's transition out of the hospital. OBJECTIVE: To explore facilitators and challenges family caregivers face in assuming postdischarge family caregiving roles and completing complex care tasks. METHODS: A qualitative study recruited 32 participants from 4 sites. Participants were unpaid family caregivers whose loved one was recently discharged from an acute care hospital. A modified Grounded Theory approach was used. RESULTS: Five central themes emerged from the analysis: (1) family caregivers' contributions to the care of their loved one unfold along on a spectrum where the readiness, willingness, and ability of both parties are often dynamic; (2) family caregivers have unique and potentially incongruent goals from those of the patient; (3) family caregivers feel unprepared for postdischarge medication management; (4) family caregivers encouragement to assert an identity; (5) family caregivers often assume the responsibility for the sequencing of posthospital care plan tasks and anticipating next steps. CONCLUSION: Family caregivers provided valuable insights into the challenges they face facilitating their loved ones' transitions. These findings may directly inform the design and testing of an evidence-based intervention to enhance their roles. PMID- 26042374 TI - A standard handoff improves cardiac surgical patient transfer: operating room to intensive care unit. AB - BACKGROUND: Patient handoffs are high-risk times associated with sentinel events. Effective handoff processes may enhance patient safety and team member communication. This study assesses the impact of a standardized protocol for handoffs from the cardiac surgery operating room to intensive care unit (ICU). METHODS: Using a prospective pre-post study design, a formalized handoff process was developed including critical handoff elements and a standardized handoff procedure, script, and checklist. Data were collected from 60 handoff observations (30 pre and 30 post), evaluating 52 unique parameters, and survey of providers on perspectives of the handoff process. Results were compared by chi square test, two sample t-test, or nonparametric Mann-Whitney test. Statistical significance was defined as P <= .05. RESULTS: Provider's perspectives showed improved satisfaction with the standardized handoff process through improved responses in 19 of 22 survey items (P < .001). Median time until ventilator connection, ICU monitor transfer, first cardiac index, and chest radiograph were reduced after implementation. Completion of handoff process components also improved after implementation for 36 of 47 nontime parameters. CONCLUSIONS: A standard checklist-driven handoff process can dramatically improve key data transmission and reduce time of critical patient care steps during the high-risk period of patient handoff in a cardiac surgical ICU. PMID- 26042375 TI - Association of provider communication and discharge instructions on lower readmissions. AB - Since the implementation of Value-Based Purchasing, hospital readmissions now effect Medicare reimbursement. This creation of a financial incentive, along with the inherent medical incentives to reduce those readmissions forces hospitals to examine their practices on the subject. Using the Donabedian model for healthcare quality, this study examined the relationship between discharge instructions and nurse/doctor communication with the patient and lower readmissions. The readmissions variable (30-day medical) along with the discharge instruction, nurse communication, and doctor communication variables came from the Centers for Medicare and Medicaid Service's Hospital Compare dataset. Zip code-level contextual variables (aggregated to the hospital service area) were used as control variables. Results suggest that while each of the independent variables of nurse communication, doctor communication, and discharge instructions were significant in predicting lower readmissions, the strongest association came from discharge instructions, while controlling for other hospital-level and contextual factors. These results call for an increased focus on patient-centeredness by making sure that the patient understands the scope and content of their discharge instructions. PMID- 26042376 TI - A framework to guide implementation research for care transitions interventions. AB - Evaluating implementation of complex interventions to improve care transitions and comparison across studies is challenging due to issues such as variation in methods and lack of reporting key evaluation elements. This article describes a framework for evaluating implementation of hospital to ambulatory care transitions interventions and application to a case study. We searched published and gray literature for relevant frameworks. We adapted the general Consolidated Framework for Implementation Research, adding elements relevant to other complex interventions. We refined these adaptations through structured expert input and application to case studies. Key adaptations included conceptualization around organizations, not just settings, and around patient- and caregiver-centeredness. Although these interventions are often oriented toward institutional outcomes such as readmissions, tailoring interventions to specific patient needs strengthens effectiveness. Coordination and communication are important between organizations and providers and with patients and caregivers. Roles of those involved in the intervention--providers, administrators, and facilitators from different organizations--are also key constructs. Finally, as these interventions often are tailored to specific settings and adapt over time, assessing intervention design--which components are implemented as part of the bundle, how they are actually implemented, and their differential impact on effectiveness--is critical. PMID- 26042377 TI - Safety of Rural Nursing Home-to-Emergency Department Transfers: Improving Communication and Patient Information Sharing Across Settings. AB - The "siloed" approach to healthcare delivery contributes to communication challenges and to potential patient harm when patients transfer between settings. This article reports on the evaluation of a demonstration in 10 rural communities to improve the safety of nursing facility (NF) transfers to hospital emergency departments by forming interprofessional teams of hospital, emergency medical service, and NF staff to develop and implement tools and protocols for standardizing critical interfacility communication pathways and information sharing. We worked with each of the 10 teams to document current communication processes and information sharing tools and to design, implement, and evaluate strategies/tools to increase effective communication and sharing of patient information across settings. A mixed methods approach was used to evaluate changes from baseline in documentation of patient information shared across settings during the transfer process. Study findings showed significant improvement in key areas across the three settings, including infection status and baseline mental functioning. Improvement strategies and performance varied across settings; however, accurate and consistent information sharing of advance directives and medication lists remains a challenge. Study results demonstrate that with neutral facilitation and technical support, collaborative interfacility teams can assess and effectively address communication and information sharing problems that threaten patient safety. PMID- 26042378 TI - Using a Small Workgroup to Jump-start a Community-Wide Coalition to Reduce Preventable Hospital Readmissions. AB - Unplanned hospital readmissions are common and often preventable. A review of Medicare discharge data identified a geographical area with higher than expected readmission rates. The state Medicare quality improvement organization (QIO) used community organizing techniques to assess provider engagement and hypothesized that a small workgroup of high impact providers could address some root causes for preventable readmissions, achieve quick wins, and reinvigorate the broader community-wide coalition. Seven of the eight facilities targeted by the QIO actively engaged and began rapid cycle initiatives to improve the patient transfer process between providers. Monthly, 2-hr structured meetings were supplemented by additional ad hoc meetings convened by participants. Effectiveness of the intervention was measured by workgroup functioning, the implementation of multiple initiatives spread from the small workgroup to the broader provider coalition, and reductions in readmissions to the anchor hospital system from the participating skilled nursing facilities. The community impact of the workgroup initiative is shown by a decline in community readmission rates for Medicare beneficiaries. PMID- 26042379 TI - Resident handoff training: initial evaluation of a novel method. AB - INTRODUCTION: Residencies are required to have a standardized process for transitioning patient care. This study was designed to assess a novel method of training and evaluating handoffs using both a lecture format and standardized patient (SP) interactions. METHODS: Matched group design was used to randomly assign interns to trained versus control groups, with the trained group receiving formal handoff training before SP encounters. The residents evaluated three ER SPs and read four written scenarios and then transitioned patients to an SP acting as a resident. All handoffs were videotaped and scored by two blind raters using a rating scale developed based on specialist's interviews. RESULTS: Thirty two interns were included in the study. The trained interns performed significantly better with lower scores on patient handoffs (mean = 10.08, SD = 2.46) than the untrained interns (mean = 16.56, SD = 2.79). There was also a significant effect for case, with the ER SP cases (mean = 12.23, SD = 14.41) resulting in better performance than the written cases in both surgery and pediatrics (mean = 14.41, SD = 4.29). CONCLUSIONS: A protocol was designed and implemented for training residents to perform handoffs, with initial results showing that the curriculum is effective. PMID- 26042380 TI - Impact of an integrated transition management program in primary care on hospital readmissions. AB - Poorly executed transitions in care from hospital to home are associated with increased vulnerability to adverse medication events and hospital readmissions, and also excess healthcare costs. Efforts to improve care coordination on hospital discharge have been shown to reduce hospital readmission rates but often rely on interventions that are not fully integrated within the primary care setting. The Patient Centered Medical Home (PCMH) model, whose core principles include care coordination in the posthospital setting, is an approach that addresses transitions in care in a more integrated fashion. We examined the impact of multicomponent transition management (TM) services on hospital readmission rates and time to hospital readmission among 118 patients enrolled in a TM program that is part of Care By Design, the University of Utah Community Clinics' version of the PCMH. We conducted a retrospective analysis comparing outcomes for patients before receiving TM services with outcomes for the same patients after receiving TM services. The all-cause 30-day hospital readmission rate decreased from 17.9% to 8.0%, and the mean time to hospital readmission within 180 days was delayed from 95 to 115 days. These findings support the effectiveness of TM activities integrated within the primary care setting. PMID- 26042381 TI - What does the facial dot-probe task tell us about attentional processes in social anxiety? A systematic review. AB - BACKGROUND/OBJECTIVES: Current models of SAD assume that attentional processes play a pivotal role in the etiology and maintenance of social anxiety disorder. Social anxiety is supposedly associated with an attentional bias towards disorder related stimuli such as threatening faces. Using the facial dot probe task in socially anxious individuals has, however, revealed inconsistent findings. METHODS: The current systematic review aims at disentangling the heterogeneous findings using effect sizes across results by systematically taking into account potential moderating variables (stimulus type, stimulus duration, situational anxiety, disorder severity). RESULTS: Results provide some evidence that socially anxious individuals preferentially allocate their attention towards threat faces compared to non-anxious controls. This bias seems to depend on the type of reference stimulus, stimulus duration and clinical level of social anxiety. Avoidance of threat was neither found at early, nor at later stages of attentional processing. LIMITATIONS: Importantly, the results have to be considered in the light of the only few studies available. Given the heterogeneity of results and some methodological restrictions of the studies included, the picture of attentional bias seems to be much less clear than suggested in the recent social anxiety literature. CONCLUSIONS: Methodologically, combined measures of dot-probe and eye movement measures might be beneficial to detect overt attentional biases. Importantly, our results show that preferential processing of threat cues might guide early attentional processes in social anxiety, depending however on several contextual and situational factors. Clinically, patients with greater severity of SAD may be more prone to such an attentional bias, thus therapists should take this into account when planning behavioral experiments and exposure therapy. PMID- 26042382 TI - Label-free and depth resolved optical sectioning of iron-complex deposits in sickle cell disease splenic tissue by multiphoton microscopy. AB - Multiphoton microscopy (MPM) imaging of intrinsic two-photon excited fluorescence (TPEF) is performed on humanized sickle cell disease (SCD) mouse model splenic tissue. Distinct morphological and spectral features associated with SCD are identified and discussed in terms of diagnostic relevance. Specifically, spectrally unique splenic iron-complex deposits are identified by MPM; this finding is supported by TPEF spectroscopy and object size to standard histopathological methods. Further, iron deposits are found at higher concentrations in diseased tissue than in healthy tissue by all imaging methods employed here including MPM, and therefore, may provide a useful biomarker related to the disease state. These newly characterized biomarkers allow for further investigations of SCD in live animals as a means to gain insight into the mechanisms impacting immune dysregulation and organ malfunction, which are currently not well understood. PMID- 26042383 TI - US Food and Drug Administration regulatory oversight of laboratory-developed tests: Commentary on the draft guidance. PMID- 26042385 TI - Reprogramming fibroblasts toward cardiomyocytes, neural stem cells and hepatocytes by cell activation and signaling-directed lineage conversion. AB - Induction of tissue-specific cell types via a conventional transdifferentiation strategy typically uses overexpression of the corresponding lineage-specific transcription factors. Alternatively, somatic cells can be temporarily activated via a common set of reprogramming factors into a transition state, which can then be directed into various cell types via soluble lineage-specific signals, without establishing a pluripotent state. Here, we provide protocols for the generation of cardiomyocytes, neural stem cells and hepatocytes from fibroblasts with such a cell activation (CA) and signaling-directed (SD; CASD) strategy. In these protocols, beating cardiomyocytes can be induced from mouse fibroblasts in 2-5 weeks; expandable neural stem cells and definitive endoderm progenitors can be obtained from human fibroblasts as early as 2.5 weeks; and human definitive endoderm progenitors can be differentiated into functional hepatocytes in 2 weeks. Through further developments, the CASD strategy can serve as a unique avenue for generating diverse functional cell types for biomedical research and therapeutic applications. PMID- 26042386 TI - Single prokaryotic cell isolation and total transcript amplification protocol for transcriptomic analysis. AB - Until recently, transcriptome analyses of single cells have been confined to eukaryotes. The information obtained from single-cell transcripts can provide detailed insight into spatiotemporal gene expression, and it could be even more valuable if expanded to prokaryotic cells. Transcriptome analysis of single prokaryotic cells is a recently developed and powerful tool. Here we describe a procedure that allows amplification of the total transcript of a single prokaryotic cell for in-depth analysis. This is performed by using a laser capture microdissection instrument for single-cell isolation, followed by reverse transcription via Moloney murine leukemia virus, degradation of chromosomal DNA with McrBC and DpnI restriction enzymes, single-stranded cDNA (ss-cDNA) ligation using T4 polynucleotide kinase and CircLigase, and polymerization of ss-cDNA to double-stranded cDNA (ds-cDNA) by Phi29 polymerase. This procedure takes ~5 d, and sufficient amounts of ds-cDNA can be obtained from single-cell RNA template for further microarray analysis. PMID- 26042387 TI - Rebuttal from Drs Schroder-Back and Martakis. PMID- 26042384 TI - Efficient derivation and inducible differentiation of expandable skeletal myogenic cells from human ES and patient-specific iPS cells. AB - Skeletal muscle is the most abundant human tissue; therefore, an unlimited availability of myogenic cells has applications in regenerative medicine and drug development. Here we detail a protocol to derive myogenic cells from human embryonic stem (ES) and induced pluripotent stem (iPS) cells, and we also provide evidence for its extension to human iPS cells cultured without feeder cells. The procedure, which does not require the generation of embryoid bodies or prospective cell isolation, entails four stages with different culture densities, media and surface coating. Pluripotent stem cells are disaggregated to single cells and then differentiated into expandable cells resembling human mesoangioblasts. Subsequently, transient Myod1 induction efficiently drives myogenic differentiation into multinucleated myotubes. Cells derived from patients with muscular dystrophy and differentiated using this protocol have been genetically corrected, and they were proven to have therapeutic potential in dystrophic mice. Thus, this platform has been demonstrated to be amenable to gene and cell therapy, and it could be extended to muscle tissue engineering and disease modeling. PMID- 26042388 TI - Phase stability frustration on ultra-nanosized anatase TiO2. AB - This work sheds light on the exceptional robustness of anatase TiO2 when it is downsized to an extreme value of 4 nm. Since at this size the surface contribution to the volume becomes predominant, it turns out that the material becomes significantly resistant against particles coarsening with temperature, entailing a significant delay in the anatase to rutile phase transition, prolonging up to 1000 degrees C in air. A noticeable alteration of the phase stability diagram with lithium insertion is also experienced. Lithium insertion in such nanocrystalline anatase TiO2 converts into a complete solid solution until almost Li1TiO2, a composition at which the tetragonal to orthorhombic transition takes place without the formation of the emblematic and unwished rock salt Li1TiO2 phase. Consequently, excellent reversibility in the electrochemical process is experienced in the whole portion of lithium content. PMID- 26042389 TI - Antimicrobial interactions: mechanisms and implications for drug discovery and resistance evolution. AB - Combining antibiotics is a promising strategy for increasing treatment efficacy and for controlling resistance evolution. When drugs are combined, their effects on cells may be amplified or weakened, that is the drugs may show synergistic or antagonistic interactions. Recent work revealed the underlying mechanisms of such drug interactions by elucidating the drugs' joint effects on cell physiology. Moreover, new treatment strategies that use drug combinations to exploit evolutionary tradeoffs were shown to affect the rate of resistance evolution in predictable ways. High throughput studies have further identified drug candidates based on their interactions with established antibiotics and general principles that enable the prediction of drug interactions were suggested. Overall, the conceptual and technical foundation for the rational design of potent drug combinations is rapidly developing. PMID- 26042390 TI - Mononuclear Polypyridylruthenium(II) Complexes with High Membrane Permeability in Gram-Negative Bacteria-in particular Pseudomonas aeruginosa. AB - Ruthenium(II) complexes containing the tetradentate ligand bis[4(4'-methyl-2,2' bipyridyl)]-1,n-alkane ("bbn "; n=10 and 12) have been synthesised and their geometric isomers separated. All [Ru(phen)(bbn )](2+) (phen=1,10-phenanthroline) complexes exhibited excellent activity against Gram-positive bacteria, but only the cis-alpha-[Ru(phen)(bb12 )](2+) species showed good activity against Gram negative species. In particular, the cis-alpha-[Ru(phen)(bb12 )](2+) complex was two to four times more active than the cis-beta-[Ru(phen)(bb12 )](2+) complex against the Gram-negative strains. The cis-alpha- and cis-beta-[Ru(phen)(bb12 )](2+) complexes readily accumulated in the bacteria but, significantly, showed the highest level of uptake in Pseudomonas aeruginosa. Furthermore, the accumulation of the cis-alpha- and cis-beta-[Ru(phen)(bb12 )](2+) complexes in P. aeruginosa was considerably greater than in Escherichia coli. The uptake of the cis-alpha-[Ru(phen)(bb12 )](2+) complex into live P. aeruginosa was confirmed by using fluorescence microscopy. The water/octanol partition coefficients (log P) were determined to gain understanding of the relative cellular uptake. The cis alpha- and cis-beta-[Ru(phen)(bbn )](2+) complexes exhibited relatively strong binding to DNA (Kb ~10(6) M(-1) ), but no significant difference between the geometric isomers was observed. PMID- 26042391 TI - Large Single-Crystal Hexagonal Boron Nitride Monolayer Domains with Controlled Morphology and Straight Merging Boundaries. PMID- 26042392 TI - Assessing the need for psychooncological support: screening instruments in combination with patients' subjective evaluation may define psychooncological pathways. AB - BACKGROUND: Cancer patients suffer from severe distress. About one third show mental comorbidities. Nevertheless, there is no common agreement on how to measure distress or identify patients in need for psychooncological services using screening questionnaires. PATIENTS AND METHODS: A sample of N = 206 patients with confirmed breast cancer, being inpatient for surgical treatment, filled in distress assessment instruments: Distress Thermometer, Hospital Anxiety and Depression Scale, Patient Health Questionnaire 2, Hornheider Screening Instrument and parts of the EORTC-QLQ-C30. Additionally, they were asked for their subjective need for psychooncological counselling. RESULTS: The correlation between the assessment instruments is low to medium. The number of patients above the cut-off criteria varies quite a lot according to the instrument (10% to 66%). Therefore, the congruence between the instruments' indications is quite low. Patients with and without subjective need do not differ in personal data but in distress scores. CONCLUSIONS: Recommended instruments for distress assessment in psychooncology measure different areas of distress. They do not sufficiently agree in indicating a patient's need for psychooncological treatment. Hence, one should neither compare results of studies using different assessment instruments nor implement a screening without reflecting the used instrument's characteristics compared to the others. The subjective need seems to provide additional information to the assessment. At present, the combination of an assessment instrument and patients' subjective need is seen as a best practice for identifying patients in need of psychooncological treatment. PMID- 26042393 TI - Cost-Related Medication Nonadherence and Cost-Saving Behaviors Among Patients With Glaucoma Before and After the Implementation of Medicare Part D. AB - IMPORTANCE: Understanding factors that lead to nonadherence to glaucoma treatment is important to diminish glaucoma-related disability. OBJECTIVES: To determine whether the implementation of the Medicare Part D prescription drug benefit affected rates of cost-related nonadherence and cost-reduction strategies in Medicare beneficiaries with and without glaucoma and to evaluate associated risk factors for such nonadherence. DESIGN, SETTING, AND PARTICIPANTS: Serial cross sectional study using 2004 to 2009 Medicare Current Beneficiary Survey data linked with Medicare claims. Coding to extract data started in January 2014 and analyses were performed between September and November of 2014. Participants were all Medicare beneficiaries, including those with a glaucoma-related diagnosis in the year prior to the collection of the survey data, those with a nonglaucomatous ophthalmic diagnosis in the year prior to the collection of the survey data, and those without a recent eye care professional claim. INTERVENTION: Effect of the implementation of the Medicare Part D drug benefit. MAIN OUTCOMES AND MEASURES: The change in cost-related nonadherence and the change in cost-reduction strategies. RESULTS: Between 2004 and 2009, the number of Medicare beneficiaries with glaucoma who reported taking smaller doses and skipping doses owing to cost dropped from 9.4% and 8.2% to 2.7% (P < .001) and 2.8%, respectively (P = .001). However, reports of failure to obtain prescriptions owing to cost did not improve in the same period (3.4% in 2004 and 2.1% in 2009; P = .12). After Part D, patients with glaucoma had a decrease in several cost-reduction strategies, namely price shopping (26.2%-15.2%; P < .001), purchasing outside the United States (6.9%-1.3%; P < .001), and spending less money to save for medications (8.0% to 3.5%; P < .001). Using a multivariate analysis, the main independent risk factors common to all cost-related nonadherence measures were female sex, younger age, lower income (<$30 000), self-reported visual disability, and a smaller Lawton index. CONCLUSIONS AND RELEVANCE: After the implementation of Part D, there was a decrease in the rate that beneficiaries with glaucoma reported engaging in cost-saving measures. Although there was a decline in the rate of several cost-related nonadherence behaviors, patients reporting failure to fill prescriptions owing to cost remained stable. This suggests that efforts to improve cost-related nonadherence should focus both on financial hardship and medical therapy prioritization, particularly in certain high-risk sociodemographic groups. PMID- 26042394 TI - Functional status of thyroid and cognitive functions after menopause. AB - BACKGROUND: Thyroid activity plays a role in cognition. However, the relation between the functional state of thyroid and neuropsychiatric changes proceeding with age among people without clinical symptoms of thyroid dysfunction is still unknown. The aim of this study was analysis of cognitive function levels in reference to thyroid examination: thyroid-stimulating hormone (TSH), total thyroxin (TT4), triiodothyronine (TT3), free thyroxin (FT4), free triiodothyronine (FT3), thyroperoxidase antibodies (TPO-AB), and thyroglobulin antibodies (Tg-AB), TSH receptor antibodies (AB-TSHR) in women after menopause. MATERIAL AND METHODS: A group of 383 women was recruited for the study. The inclusion criteria were: minimum two years after the last menstruation and no dementia signs on Montreal Cognitive Assessment (MoCA). Computerized battery of Central Nervous System Vital Signs (CNS VS) test was used to diagnostic cognitive functions. The blood plasma values were determined: TSH, FT3, FT4, TT3, TT4, TPO AB, Tg-AB, and AB-TSHR. Statistical analysis was performed using Pearson's correlation coefficient and analysis of variance in STATISTICA software. RESULTS: In women after menopause, TSH was negatively correlated with NCI results, executive functions, complex attention, and cognitive flexibility. FT4 was positively correlated with results of psychomotor speed. TT3 and TT4 were negatively correlated with results of memory and verbal memory. Furthermore, TT4 was negatively correlated with NCI, executive functions, and cognitive flexibility. TPO-AB was negatively correlated with results of memory, verbal memory, and psychomotor speed. Tg-AB was positively correlated with results of reaction time. AB-TSHR was negatively correlated with NCI results, memory, executive functions, psychomotor speed, complex attention, and cognitive flexibility. CONCLUSIONS: Our study supports the importance of thyroid functionality in cognitive functioning in a group of women after menopause. The values of TSH, TT3, TT4, TPO-AB, and AB-TSHR were higher and FT4 was lower in examined women. The results were poorer in examination of cognitive functions measured with a battery of CNS-VS tests. PMID- 26042395 TI - Inferring the connectivity of coupled oscillators from time-series statistical similarity analysis. AB - A system composed by interacting dynamical elements can be represented by a network, where the nodes represent the elements that constitute the system, and the links account for their interactions, which arise due to a variety of mechanisms, and which are often unknown. A popular method for inferring the system connectivity (i.e., the set of links among pairs of nodes) is by performing a statistical similarity analysis of the time-series collected from the dynamics of the nodes. Here, by considering two systems of coupled oscillators (Kuramoto phase oscillators and Rossler chaotic electronic oscillators) with known and controllable coupling conditions, we aim at testing the performance of this inference method, by using linear and non linear statistical similarity measures. We find that, under adequate conditions, the network links can be perfectly inferred, i.e., no mistakes are made regarding the presence or absence of links. These conditions for perfect inference require: i) an appropriated choice of the observed variable to be analysed, ii) an appropriated interaction strength, and iii) an adequate thresholding of the similarity matrix. For the dynamical units considered here we find that the linear statistical similarity measure performs, in general, better than the non linear ones. PMID- 26042396 TI - Glucose-lowering medicines for type 2 diabetes. AB - BACKGROUND: There is an increasing array of medicines available to improve blood glucose control in type 2 diabetes. Finding the best combination for an individual patient requires an assessment of the patient's characteristics and understanding the mechanism of action for each drug. OBJECTIVE: The aim of this article is to provide a rational approach for choosing between the various blood glucose-lowering medicines available for treatment of patients with type 2 diabetes mellitus. DISCUSSION: Metformin is the first choice of glucose-lowering medicines for most patients with type 2 diabetes. Sulphonylureas have proven benefits in long-term trials. Insulin is required in patients with symptoms of insulin deficiency. Glucagon-like peptide 1 agonists and sodium-glucose co transporter 2 inhibitors provide some assistance in weight loss as well as improving blood glucose control. Dipeptidyl peptidase 4 inhibitors provide an alternative to metformin and sulphonylureas, especially when side effects of those drugs limit their use. Re-assessing blood glucose control after an appropriate trial period before deciding on continuing use is appropriate. PMID- 26042397 TI - Diet and diabetes. AB - BACKGROUND: Guidelines for the prevention and management of type 2 diabetes mellitus (T2DM) reinforce lifestyle management, yet advice to guide general practitioners on principles around dietary choices is needed. OBJECTIVE: This article provides current evidence regarding the differing diets in diabetes prevention and management once T2DM arises, including the role in management of complications such as hypoglycaemia. DISCUSSION: Diets should incorporate weight maintenance or loss, while complementing changes in physical activity to optimise the metabolic effects of dietary advice. Using a structured, team-care approach supports pragmatic and sustainable individualised plans, while incorporating current evidence-based dietary approaches. PMID- 26042398 TI - Type 2 diabetes and obesity in young adults. PMID- 26042400 TI - Continuous glucose monitoring and pumps. AB - BACKGROUND: While multiple daily insulin injections remains the state-of-the-art treatment for type 1 diabetes, continuous subcutaneous insulin infusion (CSII) has become increasingly popular in recent years. Up to 40% of people with type 1 diabetes in younger age groups are now using CSII. Very recently, continuous glucose monitoring (CGM) has been developed. This technology now has proven benefits in HbA1c and hypoglycaemia reduction. OBJECTIVE: This article reviews the use of insulin pumps and CGM in the treatment of diabetes mellitus. DISCUSSION: The combination of CSII and CGM has added benefits and we are heading rapidly towards a closed-loop system, or artificial pancreas. Patients likely to benefit from these technologies include those with frequent severe hypoglycaemia or poor glycaemic control despite good compliance and education. Given the rapid rise in the development of these technologies, it is important that primary care clinicians are aware and able to discuss these technologies with potential candidates. PMID- 26042399 TI - The introduction of insulin in type 2 diabetes mellitus. AB - BACKGROUND: Conservatively, over 1 million people have been diagnosed with diabetes mellitus in Australia, the majority with type 2 diabetes mellitus (T2DM). Until the progressive decline in pancreatic beta cell function, which characterises T2DM, can be meaningfully halted, most of these patients will require insulin therapy to maintain optimal glycaemic control over time. OBJECTIVE: The aim of this article is to provide a pragmatic overview of when and how to initiate insulin therapy for T2DM in a primary care setting. DISCUSSION: Current Australian guidelines recommend initiating insulin therapy as once daily basal therapy or as premixed insulin. Commencement and titration of either insulin in T2DM can be conducted safely in an ambulatory care setting and it is ideal that general practitioners become familiar with this, particularly in the context of the number of people affected. PMID- 26042401 TI - New-onset ptosis initially diagnosed as conjunctivitis. PMID- 26042402 TI - Management of castration-resistant (advanced) prostate cancer (CRPC): rationale, progress and future directions. AB - BACKGROUND: Prostate cancer is the most common solid organ cancer and the second most common cause of cancer-related deaths in Australian men. OBJECTIVE: The aim of our review is to provide general practitioners with up-to-date information about castration resistance and hormonal dependence in prostate cancer. We summarise the current ongoing and completed clinical trials targeting hormonal pathways in metastatic prostate cancer. DISCUSSION: The treatment paradigm of metastatic castration-resistant prostate cancer has changed markedly in the past decade and new agents targeting androgen receptor pathways have been introduced. However, the biggest challenge for clinicians is to develop guidelines to integrate these agents into clinical practice. PMID- 26042403 TI - Dementia, decision aids and general practice. AB - BACKGROUND: As our population ages, the prevalence of dementia is rising. Given the complex care needs that accompany dementia, general practitioners (GPs) will be increasingly called upon to address a range of challenging clinical issues. OBJECTIVE: This article offers an introduction to the use of decision aids by GPs when caring for patients with dementia (or their carers). In addition, obstacles that can arise during the development of dementia-related decision aids are explored. DISCUSSION: A person-centred approach to people with dementia is a worthy goal. Decision aids are evidence-based tools that help patients (and carers) participate in choosing among healthcare options. Several existing high quality, dementia-related decision aids are of relevance to the primary care setting. However, there is a need for additional research to develop decision aids which address a broader range of issues pertinent to dementia. PMID- 26042404 TI - The 2013 Australian dietary guidelines and recommendations for older Australians. AB - BACKGROUND: Dietary guidelines are designed to assist people to make appropriate food choices to reduce their risk of diet-related diseases. In 2013, the Australian Dietary Guidelines were updated and now includes food group recommendations for two groups of older Australians (51-70 years and 70+ years), where previously only one older age group existed (60+ years). OBJECTIVE: The aim of this article is to raise awareness among general practitioners (GPs) about the latest Australian Dietary Guidelines and to identify relevant resources that will help GPs provide up-to-date dietary advice for older patients. DISCUSSION: The 2013 Australian Guide to Healthy Eating visually represents the proportions of the five food groups recommended for daily consumption. The Recommended Dietary Intake for some nutrients is higher for older people, compared with the general adult population. Older people often turn to their GP for nutritional advice. PMID- 26042405 TI - Review of patient satisfaction with services provided by general practitioners in an antenatal shared care program. AB - BACKGROUND: Antenatal shared care (ANSC) is a model of care in Australia whereby pregnant women are managed by their general practitioner (GP) and an obstetrician at a public antenatal clinic throughout the pregnancy. The aim of this study was to assess pregnant women's satisfaction with the ANSC program and the adequacy of advice provided to pregnant women. METHODS: Women participating in ANSC in the Illawarra region of NSW were invited to complete a satisfaction survey, which included questions on relevant topics discussed with their GP. RESULTS: Most women reported being highly satisfied with the ANSC service. Over half of the women had not received any information about breastfeeding and nutritional supplementation of iodine. PMID- 26042407 TI - Residential aged care facility residents: training issues for Australian general practitioners. PMID- 26042406 TI - Reducing risk in general practice. AB - BACKGROUND: Healthcare services are complex and prone to accidents. Most medical incidents are the result of human error. Examination of these incidents can reveal contributing factors that can be addressed to prevent recurrence. OBJECTIVE: The aim of this paper is to describe the development and institution of an incident review committee (IRC) in the setting of a large general practice. DISCUSSION: Two hundred incident reports were reviewed, resulting in meaningful clinical and business alterations to the practice. The design and running of the committee was open and collaborative. A satisfaction survey showed high acceptance among staff. The instigation of an IRC in general practice is new and unique, and this paper offers a template for other general practices to replicate. PMID- 26042408 TI - Secondary siRNAs from Medicago NB-LRRs modulated via miRNA-target interactions and their abundances. AB - Small RNAs are a class of non-coding RNAs that are of great importance in gene expression regulatory networks. Different families of small RNAs are generated via distinct biogenesis pathways. One such family specific to plants is that of phased, secondary siRNAs (phasiRNAs); these require RDR6, DCL4, and (typically) a microRNA (miRNA) trigger for their biogenesis. Protein-encoding genes are an important source of phasi-RNAs. The model legume Medicago truncatula generates phasiRNAs from many PHAS loci, and we aimed to investigate their biogenesis and mechanism by which miRNAs trigger these molecules. We modulated miRNA abundances in transgenic tissues showing that the abundance of phasiRNAs correlates with the levels of both miRNA triggers and the target, precursor transcripts. We identified sets of phasiRNAs or PHAS loci that predominantly and substantially increase in response to miRNA overexpression. In the process of validating targets from miRNA overexpression tissues, we found that in the miRNA-mRNA target pairing, the 3' terminal nucleotide (the 22nd position), but not the 10th position, is important for phasiRNA production. Mutating the single 3' terminal nucleotide dramatically diminishes phasiRNA production. Ectopic expression of Medicago NB-LRR-targeting miRNAs in Arabidopsis showed that only a few NB-LRRs are capable of phasiRNA production; our data indicate that this might be due to target inaccessibility determined by sequences flanking target sites. Our results suggest that target accessibility is an important component in miRNA-target interactions that could be utilized in target prediction, and the evolution of mRNA sequences flanking miRNA-target sites may be impacted. PMID- 26042409 TI - Studies of OC-STAMP in Osteoclast Fusion: A New Knockout Mouse Model, Rescue of Cell Fusion, and Transmembrane Topology. AB - The fusion of monocyte/macrophage lineage cells into fully active, multinucleated, bone resorbing osteoclasts is a complex cell biological phenomenon that utilizes specialized proteins. OC-STAMP, a multi-pass transmembrane protein, has been shown to be required for pre-osteoclast fusion and for optimal bone resorption activity. A previously reported knockout mouse model had only mononuclear osteoclasts with markedly reduced resorption activity in vitro, but with paradoxically normal skeletal micro-CT parameters. To further explore this and related questions, we used mouse ES cells carrying a gene trap allele to generate a second OC-STAMP null mouse strain. Bone histology showed overall normal bone form with large numbers of TRAP-positive, mononuclear osteoclasts. Micro-CT parameters were not significantly different between knockout and wild type mice at 2 or 6 weeks old. At 6 weeks, metaphyseal TRAP positive areas were lower and mean size of the areas were smaller in knockout femora, but bone turnover markers in serum were normal. Bone marrow mononuclear cells became TRAP-positive when cultured with CSF-1 and RANKL, but they did not fuse. Expression levels of other osteoclast markers, such as cathepsin K, carbonic anhydrase II, and NFATc1, were not significantly different compared to wild type. Actin rings were present, but small, and pit assays showed a 3.5-fold decrease in area resorbed. Restoring OC-STAMP in knockout cells by lentiviral transduction rescued fusion and resorption. N- and C-termini of OC-STAMP were intracellular, and a predicted glycosylation site was shown to be utilized and to lie on an extracellular loop. The site is conserved in all terrestrial vertebrates and appears to be required for protein stability, but not for fusion. Based on this and other results, we present a topological model of OC-STAMP as a 6-transmembrane domain protein. We also contrast the osteoclast-specific roles of OC- and DC-STAMP with more generalized cell fusion mechanisms. PMID- 26042410 TI - Potential conflicts of interest of editorial board members from five leading spine journals. AB - Conflicts of interest arising from ties between pharmaceutical industry and physicians are common and may bias research. The extent to which these ties exist among editorial board members of medical journals is not known. This study aims to determine the prevalence and financial magnitude of potential conflicts of interest among editorial board members of five leading spine journals. The editorial boards of: The Spine Journal; Spine; European Spine Journal; Journal of Neurosurgery: Spine; and Journal of Spinal Disorders & Techniques were extracted on January 2013 from the journals' websites. Disclosure statements were retrieved from the 2013 disclosure index of the North American Spine Society; the program of the 20th International Meeting on Advanced Spine Techniques; the program of the 48th Annual Meeting of the Scoliosis Research Society; the program of the AOSpine global spine congress; the presentations of the 2013 Annual Eurospine meeting; and the disclosure index of the American Academy of Orthopaedic Surgeons. Names of the editorial board members were compared with the individuals who completed a disclosure for one of these indexes. Disclosures were extracted when full names matched. Two hundred and ten (29%) of the 716 identified editorial board members reported a potential conflict of interest and 154 (22%) reported nothing to disclose. The remaining 352 (49%) editorial board members had no disclosure statement listed for one of the indexes. Eighty-nine (42%) of the 210 editorial board members with a potential conflict of interest reported a financial relationship of more than $10,000 during the prior year. This finding confirms that potential conflicts of interest exist in editorial boards which might influence the peer review process and can result in bias. Academia and medical journals in particular should be aware of this and strive to improve transparency of the review process. We emphasize recommendations that contribute to achieving this goal. PMID- 26042411 TI - Hyponatremia: incidence, risk factors, and consequences in the elderly in a home based primary care program. AB - AIMS: To determine the incidence, risk factors, etiology, and associations of hyponatremia in community-dwelling elderly with geriatric morbidity and mortality. MATERIALS: Elderly participants of a single center home-based primary care program were included. METHOD: Retrospective chart review was conducted on demographic and clinical variables, comorbid diseases, frailty by Fried criteria and biochemical tests over a 1-year period. Primary outcome measure was a composite of falls, fractures due to falls, and hospitalization witnessed within the first year of enrollment into the program. Secondary outcome was all-cause mortality. RESULTS: The study population (n = 608) had a mean age of 84.3 +/- 9.3 years and was largely female (77.1%) and African-American (89.5%). Mean follow-up was 41.5 months. Frailty was seen in 44.4%. Incidence of allcause mortality was 26.9%. Initial hyponatremia occurred in 8.71% (n = 53), and persistent hyponatremia (> 6 months of low serum sodium) in 4.1% (n = 25) of the study population. The major causes of hyponatremia included multiple potential causes, idiopathic syndrome of inappropriate antidiuretic hormone (SIADH) and medications (thiazides and selective serotonin reuptake inhibitor (SSRI)). Primary outcome was independently associated with frailty (Odds ratio (OR) of 2.33) and persistent but not initial hyponatremia (OR 3.52). Secondary outcome was independently associated with age > 75 years (OR 2.88) and Afro-American race (OR 2.09) only but not to frailty or hyponatremia. CONCLUSIONS: Hyponatremia is common in home-bound elderly patients and its persistence independently contributes to falls, fractures, and hospitalization but not mortality. Our study highlights a new association of hyponatremia with frailty and underscores the need to study time-dependent association of hyponatremia with epidemiological outcomes. PMID- 26042412 TI - Keeping an eye on dialysis: the association of hemodialysis with intraocular hypertension. AB - Intraocular hypertension is common during hemodialysis. Dialysis disequilibrium syndrome and intraocular hypertension occur via similar pathophysiologic mechanisms. These mechanisms may contribute to the development of glaucoma and cataracts in a patient population already at high risk for ocular abnormalities, given the common risk factors for chronic kidney disease and impaired aqueous humor outflow. We describe a patient with complicated diabetes mellitus, end stage renal disease, and recent cataract surgery who developed severe intraocular hypertension during hemodialysis. We recommend increased awareness of the symptoms of intraocular hypertension and subsequent ophthalmologic surveillance in order to prevent long-term visual complications. PMID- 26042413 TI - Glycopeptide-specific drug-membrane interaction in continuous venovenous hemofiltration: an in vitro screening test. PMID- 26042414 TI - Rupture of an infectious pseudoaneurysm of the aortic arch in an end-stage renal failure patient with chronic hemodialysis. AB - In hemodialysis patients, vascular access infection remains a significant cause of morbidity and mortality. It has various complications, including bacterial endocarditis, spinal epidural abscess, osteomyelitis, septic arthritis, and septic pulmonary emboli. However, aortitis with infected pseudoaneurysm formation is very rare. Here, we report a case of necrotizing aortitis in a hemodialysis patient with an arteriovenous graft infection. PMID- 26042415 TI - Association of carotid intima-media thickness with cardiovascular risk factors and patient outcomes in advanced chronic kidney disease: the RRI-CKD study. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with accelerated atherosclerosis and an increased risk of adverse cardiovascular disease (CVD) outcomes. The relationships of intima-media thickness (IMT), a measure of subclinical atherosclerosis, with traditional and nontraditional risk factors and with adverse outcomes in CKD patients are not wellestablished. METHODS: IMT, clinical characteristics, cardiovascular risk factors, and clinical outcomes were measured in 198 subjects from the Renal Research Institute (RRI) CKD study, a four-center prospective cohort of patients with estimated glomerular filtration rate (eGFR)<=50 mL/min/1.73 m2 not requiring renal replacement therapy. RESULTS: The patients averaged 61+/-14 years of age; the mean eGFR was 29+/-12 mL/min/1.73 m2. Maximum IMT was more closely associated with traditional cardiovascular risk factors, including age, diabetes, dyslipidemia, and systolic blood pressure, than with nontraditional risk factors or with eGFR. Higher values of maximum IMT were also independently associated with clinical CVD and with other markers of subclinical CVD. Maximum IMT>=2.6 mm was predictive of the composite endpoint of CVD events and death (hazard ratio (HR): 5.47 (95% confidence interval (CI): 2.97 10.07, p<0.0001)) but was not related to progression to end-stage renal disease (HR: 1.67 (95% CI: 0.74-3.76, p=0.21)). CONCLUSION: In patients with advanced pre dialysis CKD, higher maximum IMT was associated with traditional cardiovascular risk factors, CVD, and other markers of subclinical CVD and as an independent predictor of cardiovascular events and death. Additional research is needed to examine the clinical utility of IMT in the risk stratification and clinical management of patients with CKD. PMID- 26042416 TI - Expected and Unexpected Features of the Newly Discovered Bat Influenza A-like Viruses. PMID- 26042417 TI - A legume genetic framework controls infection of nodules by symbiotic and endophytic bacteria. AB - Legumes have an intrinsic capacity to accommodate both symbiotic and endophytic bacteria within root nodules. For the symbionts, a complex genetic mechanism that allows mutual recognition and plant infection has emerged from genetic studies under axenic conditions. In contrast, little is known about the mechanisms controlling the endophytic infection. Here we investigate the contribution of both the host and the symbiotic microbe to endophyte infection and development of mixed colonised nodules in Lotus japonicus. We found that infection threads initiated by Mesorhizobium loti, the natural symbiont of Lotus, can selectively guide endophytic bacteria towards nodule primordia, where competent strains multiply and colonise the nodule together with the nitrogen-fixing symbiotic partner. Further co-inoculation studies with the competent coloniser, Rhizobium mesosinicum strain KAW12, show that endophytic nodule infection depends on functional and efficient M. loti-driven Nod factor signalling. KAW12 exopolysaccharide (EPS) enabled endophyte nodule infection whilst compatible M. loti EPS restricted it. Analysis of plant mutants that control different stages of the symbiotic infection showed that both symbiont and endophyte accommodation within nodules is under host genetic control. This demonstrates that when legume plants are exposed to complex communities they selectively regulate access and accommodation of bacteria occupying this specialized environmental niche, the root nodule. PMID- 26042418 TI - Eukaryote-Made Thermostable DNA Polymerase Enables Rapid PCR-Based Detection of Mycoplasma, Ureaplasma and Other Bacteria in the Amniotic Fluid of Preterm Labor Cases. AB - BACKGROUND: Intra-amniotic infection has long been recognized as the leading cause of preterm delivery. Microbial culture is the gold standard for the detection of intra-amniotic infection, but several days are required, and many bacterial species in the amniotic fluid are difficult to cultivate. METHODS: We developed a novel nested-PCR-based assay for detecting Mycoplasma, Ureaplasma, other bacteria and fungi in amniotic fluid samples within three hours of sample collection. To detect prokaryotes, eukaryote-made thermostable DNA polymerase, which is free from bacterial DNA contamination, is used in combination with bacterial universal primers. In contrast, to detect eukaryotes, conventional bacterially-made thermostable DNA polymerase is used in combination with fungal universal primers. To assess the validity of the PCR assay, we compared the PCR and conventional culture results using 300 amniotic fluid samples. RESULTS: Based on the detection level (positive and negative), 93.3% (280/300) of Mycoplasma, 94.3% (283/300) of Ureaplasma, 89.3% (268/300) of other bacteria and 99.7% (299/300) of fungi matched the culture results. Meanwhile, concerning the detection of bacteria other than Mycoplasma and Ureaplasma, 228 samples were negative according to the PCR method, 98.2% (224/228) of which were also negative based on the culture method. Employing the devised primer sets, mixed amniotic fluid infections of Mycoplasma, Ureaplasma and/or other bacteria could be clearly distinguished. In addition, we also attempted to compare the relative abundance in 28 amniotic fluid samples with mixed infection, and judged dominance by comparing the Ct values of quantitative real-time PCR. CONCLUSIONS: We developed a novel PCR assay for the rapid detection of Mycoplasma, Ureaplasma, other bacteria and fungi in amniotic fluid samples. This assay can also be applied to accurately diagnose the absence of bacteria in samples. We believe that this assay will positively contribute to the treatment of intra-amniotic infection and the prevention of preterm delivery. PMID- 26042419 TI - Biomathematical description of synthetic peptide libraries. AB - Libraries of randomised peptides displayed on phages or viral particles are essential tools in a wide spectrum of applications. However, there is only limited understanding of a library's fundamental dynamics and the influences of encoding schemes and sizes on their quality. Numeric properties of libraries, such as the expected number of different peptides and the library's coverage, have long been in use as measures of a library's quality. Here, we present a graphical framework of these measures together with a library's relative efficiency to help to describe libraries in enough detail for researchers to plan new experiments in a more informed manner. In particular, these values allow us to answer-in a probabilistic fashion-the question of whether a specific library does indeed contain one of the "best" possible peptides. The framework is implemented in a web-interface based on two packages, discreteRV and peptider, to the statistical software environment R. We further provide a user-friendly web interface called PeLiCa (Peptide Library Calculator, http://www.pelica.org), allowing scientists to plan and analyse their peptide libraries. PMID- 26042420 TI - Linkage Analysis in Autoimmune Addison's Disease: NFATC1 as a Potential Novel Susceptibility Locus. AB - BACKGROUND: Autoimmune Addison's disease (AAD) is a rare, highly heritable autoimmune endocrinopathy. It is possible that there may be some highly penetrant variants which confer disease susceptibility that have yet to be discovered. METHODS: DNA samples from 23 multiplex AAD pedigrees from the UK and Norway (50 cases, 67 controls) were genotyped on the Affymetrix SNP 6.0 array. Linkage analysis was performed using Merlin. EMMAX was used to carry out a genome-wide association analysis comparing the familial AAD cases to 2706 UK WTCCC controls. To explore some of the linkage findings further, a replication study was performed by genotyping 64 SNPs in two of the four linked regions (chromosomes 7 and 18), on the Sequenom iPlex platform in three European AAD case-control cohorts (1097 cases, 1117 controls). The data were analysed using a meta-analysis approach. RESULTS: In a parametric analysis, applying a rare dominant model, loci on chromosomes 7, 9 and 18 had LOD scores >2.8. In a non-parametric analysis, a locus corresponding to the HLA region on chromosome 6, known to be associated with AAD, had a LOD score >3.0. In the genome-wide association analysis, a SNP cluster on chromosome 2 and a pair of SNPs on chromosome 6 were associated with AAD (P <5x10-7). A meta-analysis of the replication study data demonstrated that three chromosome 18 SNPs were associated with AAD, including a non-synonymous variant in the NFATC1 gene. CONCLUSION: This linkage study has implicated a number of novel chromosomal regions in the pathogenesis of AAD in multiplex AAD families and adds further support to the role of HLA in AAD. The genome-wide association analysis has also identified a region of interest on chromosome 2. A replication study has demonstrated that the NFATC1 gene is worthy of future investigation, however each of the regions identified require further, systematic analysis. PMID- 26042421 TI - Occupational Hearing Loss among Chinese Municipal Solid Waste Landfill Workers: A Cross-Sectional Study. AB - BACKGROUND: Occupational hearing loss is an increasingly prevalent occupational condition worldwide, and has been reported to occur in a wide range of workplaces; however, its prevalence among workers from municipal solid waste landfills (MSWLs) remains less clear. This study aimed to investigate the occupational hearing loss among Chinese MSWL workers. METHODS: A cross-sectional study of 247 workers from 4 Chinese MSWLs was conducted. Noise and total volatile organic compounds (TVOCs) levels at worksites were determined. We conducted hearing examinations to determine hearing thresholds. A worker was identified as having hearing loss if the mean threshold at 2000, 3000 and 4000 Hz in either ear was equal to or greater than 25 dB. Prevalence of occupational hearing loss was then evaluated. Using unconditional Logistic regression models, we estimated the odds ratios (ORs) of MSWL work associated with hearing loss. RESULTS: According to the job title for each worker, the study subjects were divided into 3 groups, including group 1 of 63 workers without MSWL occupational hazards exposure (control group), group 2 of 84 workers with a few or short-period MSWL occupational hazards exposure, and group 3 of 100 workers with continuous MSWL occupational hazards exposure. Both noise and TVOCs levels were significantly higher at worksites for group 3. Significantly poorer hearing thresholds at frequencies of 2000, 3000 and 4000 Hz were found in group 3, compared with that in group 1 and group 2. The overall prevalence rate of hearing loss was 23.5%, with the highest in group 3 (36.0%). The OR of MSWL work associated with hearing loss was 3.39 (95% confidence interval [CI]: 1.28-8.96). CONCLUSION: The results of this study suggest significantly higher prevalence of hearing loss among MSWL workers. Further studies are needed to explore possible exposure-response relationship between MSWL occupational hazards exposure and hearing loss. PMID- 26042422 TI - Radiation induced chromatin conformation changes analysed by fluorescent localization microscopy, statistical physics, and graph theory. AB - It has been well established that the architecture of chromatin in cell nuclei is not random but functionally correlated. Chromatin damage caused by ionizing radiation raises complex repair machineries. This is accompanied by local chromatin rearrangements and structural changes which may for instance improve the accessibility of damaged sites for repair protein complexes. Using stably transfected HeLa cells expressing either green fluorescent protein (GFP) labelled histone H2B or yellow fluorescent protein (YFP) labelled histone H2A, we investigated the positioning of individual histone proteins in cell nuclei by means of high resolution localization microscopy (Spectral Position Determination Microscopy = SPDM). The cells were exposed to ionizing radiation of different doses and aliquots were fixed after different repair times for SPDM imaging. In addition to the repair dependent histone protein pattern, the positioning of antibodies specific for heterochromatin and euchromatin was separately recorded by SPDM. The present paper aims to provide a quantitative description of structural changes of chromatin after irradiation and during repair. It introduces a novel approach to analyse SPDM images by means of statistical physics and graph theory. The method is based on the calculation of the radial distribution functions as well as edge length distributions for graphs defined by a triangulation of the marker positions. The obtained results show that through the cell nucleus the different chromatin re-arrangements as detected by the fluorescent nucleosomal pattern average themselves. In contrast heterochromatic regions alone indicate a relaxation after radiation exposure and re-condensation during repair whereas euchromatin seemed to be unaffected or behave contrarily. SPDM in combination with the analysis techniques applied allows the systematic elucidation of chromatin re-arrangements after irradiation and during repair, if selected sub-regions of nuclei are investigated. PMID- 26042423 TI - Differential Epigenetic Effects of Atmospheric Cold Plasma on MCF-7 and MDA-MB 231 Breast Cancer Cells. AB - Cold atmospheric plasma (plasma) has emerged as a novel tool for a cancer treatment option, having been successfully applied to a few types of cancer cells, as well as tissues. However, to date, no studies have been performed to examine the effect of plasma on epigenetic alterations, including CpG methylation. In this study, the effects of plasma on DNA methylation changes in breast cancer cells were examined by treating cultured MCF-7 and MDA-MB-231 cells, representing estrogen-positive and estrogen-negative cancer cells, respectively, with plasma. A pyrosequencing analysis of Alu indicated that a specific CpG site was induced to be hypomethylated from 23.4 to 20.3% (p < 0.05) by plasma treatment in the estrogen-negative MDA-MB-231 cells only. A genome-wide methylation analysis identified "cellular movement, connective tissue development and function, tissue development" and "cell-to-cell signaling and interaction, cell death and survival, cellular development" as the top networks. Of the two cell types, the MDA-MB-231 cells underwent a higher rate of apoptosis and a decreased proliferation rate upon plasma treatment. Taken together, these results indicate that plasma induces epigenetic and cellular changes in a cell type specific manner, suggesting that a careful screening of target cells and tissues is necessary for the potential application of plasma as a cancer treatment option. PMID- 26042424 TI - The VEGF-Receptor Inhibitor Axitinib Impairs Dendritic Cell Phenotype and Function. AB - Inhibitors of VEGF receptor (VEGFR) signaling such as sorafenib and sunitinib that are currently used in the treatment of malignant diseases have been shown to affect immunological responses by inhibition of the function of antigen presenting cells and T lymphocytes. The VEGFR-inhibitor axitinib has recently been approved for second line therapy of metastatic renal cell carcinoma. While there is some evidence that axitinib might interfere with the activation of T cells, not much is known about the effects of axitinib on dendritic cell (DC) phenotype and function. We here show that the addition of axitinib during the final Toll-like receptor-4-induced maturation step of monocyte-derived human DCs results in a reduced DC activation characterized by impaired expression of activation markers and co-stimulatory molecules such as CD80, CD83 and CD86. We further found a decreased secretion of interleukin-12 which was accompanied by reduced nuclear expression of the transcription factor cRel. In addition, we found a dose-dependent reduced activation of p38 and STAT3 in axitinib-exposed DCs, whereas the expression was not affected. The dysfunction of axitinib-exposed DCs was further underlined by their impaired induction of allogeneic T cell proliferation in a mixed lymphocyte reaction assay and inhibition of DC migration. Our results demonstrate that axitinib significantly affects DC differentiation and function primarily via the inhibition of the nuclear factor kappa B signaling pathway leading to impaired T cell activation. This will be of importance for the design of future vaccination protocols and therapeutic approaches aiming at combining different treatment strategies, eg such as programmed death-1 inhibitors with axitinib. PMID- 26042425 TI - Projections of the current and future disease burden of hepatitis C virus infection in Malaysia. AB - BACKGROUND: The prevalence of hepatitis C virus (HCV) infection in Malaysia has been estimated at 2.5% of the adult population. Our objective, satisfying one of the directives of the WHO Framework for Global Action on Viral Hepatitis, was to forecast the HCV disease burden in Malaysia using modelling methods. METHODS: An age-structured multi-state Markov model was developed to simulate the natural history of HCV infection. We tested three historical incidence scenarios that would give rise to the estimated prevalence in 2009, and calculated the incidence of cirrhosis, end-stage liver disease, and death, and disability-adjusted life years (DALYs) under each scenario, to the year 2039. In the baseline scenario, current antiviral treatment levels were extended from 2014 to the end of the simulation period. To estimate the disease burden averted under current sustained virological response rates and treatment levels, the baseline scenario was compared to a counterfactual scenario in which no past or future treatment is assumed. RESULTS: In the baseline scenario, the projected disease burden for the year 2039 is 94,900 DALYs/year (95% credible interval (CrI): 77,100 to 124,500), with 2,002 (95% CrI: 1340 to 3040) and 540 (95% CrI: 251 to 1,030) individuals predicted to develop decompensated cirrhosis and hepatocellular carcinoma, respectively, in that year. Although current treatment practice is estimated to avert a cumulative total of 2,200 deaths from DC or HCC, a cumulative total of 63,900 HCV-related deaths is projected by 2039. CONCLUSIONS: The HCV-related disease burden is already high and is forecast to rise steeply over the coming decades under current levels of antiviral treatment. Increased governmental resources to improve HCV screening and treatment rates and to reduce transmission are essential to address the high projected HCV disease burden in Malaysia. PMID- 26042427 TI - The FRAME Reduction Initiative. PMID- 26042428 TI - Responses of Glutathione S-transferase and Glutathione Peroxidases to Feeding Rate of a Wolf Spider Pardosa prativaga. PMID- 26042426 TI - Mortality Rate for Children under 5 Years of Age in Zhejiang Province, China from 1997 to 2012. AB - OBJECTIVES: This is a population based descriptive study that examined the trends in childhood mortality among under five children and the major causes under five mortality in Zhejiang Province, China. METHODS: A population-based survey was conducted through a province-level surveillance network. The mortality rate and leading causes of death for children under 5 years of age were analyzed. The trend in the mortality rate for children under five and cause-specific mortality rates were analyzed by chi-square with SPSS 13.0 software. RESULTS: In Zhejiang Province, during 1997-2012, mortality rates in neonates, postneonatal infants, and children under 5 years were reduced by 64.2% (from 7.85 to 2.81 per 1000 livebirths), 66.7% (from 12.73 to 4.24 per 1000 livebirths), and 63% (from 15.76 to 5.85 per 1000 livebirths), respectively. The mortality rates in children under 5 years of age decreased by 59.5% (from 11.09 to 4.49 per 1000 livebirths) and 65.8% (from 19.30 to 6.61 per 1000 livebirths) in urban and rural areas, respectively. Prematurity/low birth weight and congenital heart disease were in the top five causes of death in children under 5 years of age during 1997-2012. CONCLUSIONS: Zhejiang province has achieved great progress in the reduction of mortality rates in children under five-years-old during the past two decades. The future tasks on reduction of mortality rate still rely on how to improve the management of premature birth/low birth weight, reduce birth defects and prevent accidental deaths in Zhejiang Province. PMID- 26042429 TI - Effects of Inducers of Drug Metabolism on Cytosolic Glutathione S-transferase Activity in Rat Hepatoma-derived Fa32 Cells. PMID- 26042430 TI - Monitoring Method as a Basis for Need-based Control of Varroa Mites ( Varroa jacobsoni) Infesting Honey Bee (Apis mellifera) Colonies. PMID- 26042431 TI - The use of biomarkers as alternatives to current animal tests on food chemicals. AB - Recent developments in biomarkers relating to the interrelationship of diet, disease and health were surveyed. Most emphasis was placed on biomarkers of deleterious effects, since these are of greatest relevance to the subject of this review. The area of greatest activity was found to be that relating to biomarkers of mutagenic, genotoxic and carcinogenic effects. This is also one of the major areas of concern in considerations of the beneficial and deleterious effects of dietary components, and also the area in which regulatory testing requires studies of the longest duration. A degree of progress has also been made in the identification and development of biomarkers relating to certain classes of target organ toxicity. Biomarkers for other types of toxicity, such as immunotoxicity, neurotoxicity, reproductive toxicity and developmental toxicity, are less developed, and further investigation in these areas is required before a comprehensive biomarker strategy can be established. A criticism that recurs constantly in the biomarker literature is the lack of standardisation in the methods used, and the lack of reference standards for the purposes of validation and quality control. It is encouraging to note the growing acknowledgement of the need for validation of biomarkers and biomarker assays. Some validation studies have already been initiated. This review puts forward proposals for criteria to be used in biomarker validation. More discussion on this subject is required. It is concluded that the use of biomarkers can, in some cases, facilitate the implementation of the Three Rs with respect to the testing of food chemicals and studies on the effects of diet on health. The greatest potential is seen to be in the refinement of animal testing, in which biomarkers could serve as early and sensitive endpoints, in order to reduce the duration of the studies and also reduce the number of animals required. Biomarkers could also contribute to establishing a mechanistic basis for in vitro test systems and to facilitating their validation and acceptance. Finally, the increased information that could result from the incorporation of biomarker determinations into population studies could reduce the need for supplementary animal studies. This review makes a number of recommendations concerning the prioritisation of future activities on dietary biomarkers in relation to the Three Rs. It is emphasised, however, that further discussions will be required among toxicologists, epidemiologists and others researching the relationship between diet and health. PMID- 26042432 TI - In vitro models for studying renal stone formation: a clear alternative. AB - This paper discusses the limitations of using laboratory animals for direct in vivo observation of the development of renal stones. In fact, the majority of hypotheses related to mechanisms of stone formation have been based on the results of in vitro experiments. The relevance of in vitro experiments that allow the study of urolithiasis depends upon the degree of correspondence between the experimental conditions and those prevailing in the stone-forming kidney in vivo. For this reason, several in vitro experimental systems that attempt to reproduce the conditions found in vivo have been developed in order to study renal stone formation, which have been classified into two main groups: a) models to study papillary stone formation; and b) models to study "sedimentary" stone formation. These models are briefly described in this paper, and the information obtained was compared with that resulting from a study of the fine structure of real human renal calculi, in order to prove the validity of the models. It was concluded that the experimental in vitro models can closely reproduce the renal conditions under which human calculi are developed. This allows important data to be obtained about the aetiology of renal lithiasis, which is of great relevance to the development of effective treatments for this disease. Therefore, experimental in vitro models constitute a clear alternative to the use of laboratory animals. PMID- 26042433 TI - The use of simultaneous fluorescence and differential phase confocal microscopy to study alamar blueTM reduction in an epithelial cell line. AB - The Alamar BlueTM reduction assay is used as an indicator of cellular viability in in vitro tests for the prediction of ocular irritancy. Alamar Blue itself has a low cytotoxicity, so repeat exposure and recovery studies can be performed on the same cells. This paper contains the results of a preliminary investigation of interactions between the Alamar Blue dye and a confluent monolayer of epithelial Madin-Darby canine kidney cells. This was performed by using an experimental fluorescence microscope and differential phase confocal microscope designed for studying live samples in vitro. The initiation of Alamar Blue reduction to its fluorescent product did not occur at the same time in all cells, but started in a small number and spread progressively through their immediate neighbours. There was clear localisation of the reduced (fluorescent) Alamar Blue within the nuclei and other organelles. PMID- 26042434 TI - A call for a European prohibition of monoclonal antibody production by the ascites procedure in laboratory animals. AB - Monoclonal antibodies (mAbs) are particularly valuable in therapeutics and research. Unfortunately, one of the most familiar methods of producing mAbs, the ascites induction method, causes pain and distress to the animals used. In most cases, non-animal or in vitro alternatives can be employed to reduce or eliminate the use of animals for mAb production. Prohibition of the use of animals in the production of mAbs is recommended, except when the replacement in vitro methods prove to be insufficient, and in a limited number of other well-documented cases, such as an exceptional need for an emergency therapeutic application. A total ban on the use of animals for mAb production is impractical and it is imperative that an appeals process should accompany the prohibition. The need for the establishment of core facilities for in vitro mAb production is emphasised. PMID- 26042435 TI - Influence of Slice Thickness and Culture Conditions on the Metabolism of 7 Ethoxycoumarin in Precision-cut Rat Liver Slices. PMID- 26042436 TI - Comments on appendix C of the national institutes of health response to the petition of the american anti-vivisection society to prohibit the use of animals in the production of monoclonal antibodies. PMID- 26042437 TI - Illustration and analysis of a coordinated approach to an effective forensic trace evidence capability. AB - An effective trace evidence capability is defined as one that exploits all useful particle types, chooses appropriate technologies to do so, and directly integrates the findings with case-specific problems. Limitations of current approaches inhibit the attainment of an effective capability and it has been strongly argued that a new approach to trace evidence analysis is essential. A hypothetical case example is presented to illustrate and analyze how forensic particle analysis can be used as a powerful practical tool in forensic investigations. The specifics in this example, including the casework investigation, laboratory analyses, and close professional interactions, provide focal points for subsequent analysis of how this outcome can be achieved. This leads to the specification of five key elements that are deemed necessary and sufficient for effective forensic particle analysis: (1) a dynamic forensic analytical approach, (2) concise and efficient protocols addressing particle combinations, (3) multidisciplinary capabilities of analysis and interpretation, (4) readily accessible external specialist resources, and (5) information integration and communication. A coordinating role, absent in current approaches to trace evidence analysis, is essential to achieving these elements. However, the level of expertise required for the coordinating role is readily attainable. Some additional laboratory protocols are also essential. However, none of these has greater staffing requirements than those routinely met by existing forensic trace evidence practitioners. The major challenges that remain are organizational acceptance, planning and implementation. PMID- 26042438 TI - Application of imaging ellipsometry to the detection of latent fingermarks. AB - Imaging ellipsometry (IE) is applied to visualize latent fingermarks on specular surfaces. Instead of a real image, IE provides images related to the polarization states, which are changed by the imprinted layer on a surface. Fingermarks formed on the surfaces of various materials are investigated, including a shiny metal and a black-colored plastic. Relatively clear IE images are obtained from most surfaces on which the optical properties are distinguishable from those of the fingermarks. Also, it is shown that discernible IE images can be obtained even after a fingermark is vigorously rubbed with lab tissues. PMID- 26042439 TI - Classification of Brazilian and foreign gasolines adulterated with alcohol using infrared spectroscopy. AB - The smuggling of products across the border regions of many countries is a practice to be fought. Brazilian authorities are increasingly worried about the illicit trade of fuels along the frontiers of the country. In order to confirm this as a crime, the Federal Police must have a means of identifying the origin of the fuel. This work describes the development of a rapid and nondestructive methodology to classify gasoline as to its origin (Brazil, Venezuela and Peru), using infrared spectroscopy and multivariate classification. Partial Least Squares Discriminant Analysis (PLS-DA) and Soft Independent Modeling Class Analogy (SIMCA) models were built. Direct standardization (DS) was employed aiming to standardize the spectra obtained in different laboratories of the border units of the Federal Police. Two approaches were considered in this work: (1) local and (2) global classification models. When using Approach 1, the PLS-DA achieved 100% correct classification, and the deviation of the predicted values for the secondary instrument considerably decreased after performing DS. In this case, SIMCA models were not efficient in the classification, even after standardization. Using a global model (Approach 2), both PLS-DA and SIMCA techniques were effective after performing DS. Considering that real situations may involve questioned samples from other nations (such as Peru), the SIMCA method developed according to Approach 2 is a more adequate, since the sample will be classified neither as Brazil nor Venezuelan. This methodology could be applied to other forensic problems involving the chemical classification of a product, provided that a specific modeling is performed. PMID- 26042440 TI - Children and guns: The detection of recent contact with firearms on children's hands by the PDT reagent. AB - Throughout the world, young children are worryingly found to be involved in both unintentional and intentional gun violence, rendering the forensic investigation of gun handling by children a highly important matter. The effectiveness of the PDT reaction for mapping iron traces on hands of children has been tested and compared to its application on adults. Counter-intuitively, children were found to produce considerably more intense PDT impressions than adults. A plausible explanation which is based on physiological differences between children and adolescents is suggested. PMID- 26042441 TI - [Andrological aspects of men's health in Kazakhstan]. AB - To study the prevalence of male sexual disorders in the Republic of Kazakhstan, the survey by the urologist and endocrinologist with the use of self-reported questionnaires (IIEF and AMS) was conducted in 2007. 2203 of 2676 men (70,4% - urban, 29,6% - rural residents) aged 18-74 years completed the survey. The prevalence rates for erectile dysfunction were 50,8% (1,3%) for 18- to 74-year olds which numbered 1550 urban residents and 55,6% (1,9%) for 18- to 74-year olds with a number of 653 rural residents; symptoms of androgen deficiency were defined at 29,3% (1,2%) (454/1550) of men and 30,3% (1,8%) (198/653) of men respectively. The scale devised by Prins was used for the survey in order to be considered a valid epidemiological study. PMID- 26042442 TI - [Comparative analysis of two main prognostic classifications for predicting the locally advanced prostate cancer after radical prostatectomy]. AB - OBJECTIVE: comparison of two main clinical classifications D'Amico and NCCN for predicting the locally advanced prostate cancer. In this study we evaluated the preoperative data of 150 patients who underwent the radical prostatectomy. All patients were divided in prognostic groups according to NCCN and D'Amico classification criteria based on preoperative PSA level, digital rectal examination (DRE) and Gleason score. For comparative analysis of two main models statistical calculation was performed. Clinical application of magnetic resonance tomography is mandatory for evaluation of local extension for patients with intermediate and high risk. Comparative analysis of two main methods revealed the superiority of NCCN over D'Amico classification (p=0,0032) in predicting locally advanced prostate cancer. PMID- 26042443 TI - [Benchmarking study of effectiveness of simultaneous and isolated surgeries]. AB - Benchmarking study was conducted on effectiveness of simultaneous and isolated surgeries in practice of obstetrics and gynecology. In terms of the work, data were analyzed on the isolated and simultaneous surgeries with the patients with combined gynecological and surgical pathologies, requiring operative treatment. Man group included 254 patients with combined abnormalities, who underwent simultaneous surgeries; control group included 122 patients who underwent surgical treatment for combined diseases consecutively in two stages, in different times. Periodicity of complications in early and late post-surgical periods was evaluated, as well as risk ratio (RR) and attributable risk (AR). Simultaneous surgery is safe method of treatment of combined gynecological and surgical abnormalities. Notwithstanding extension of duration of pre-surgical examinations and post- surgical hospital stay, simultaneous operations are considered to be opportunity for being cured from several combined abnormalities within one hospitalization and anesthesia, creating positive moral and psychological background for the patients and making additional argument in favor of their conducting. PMID- 26042444 TI - Imaging guided mediastinal percutaneal core biopsy--technique and complications. AB - 165 percutaneous biopsies of anterior, middle and posterior mediastinum lesions were performed to 156 patients. Procedure was guided by US in 40 cases, by CT - in 125 cases. Hydrodissection was used in 5 cases, artificial pneumothorax - in 3 cases in order to avoid transpulmonary needle pass. Post-biopsy CT scan was performed and patients observed for any complications. Adequate tissue for histological diagnosis was obtained in 156 (94.5%) cases at the first attempt; in 9 (5.5%) cases the repeated procedure was needed. No major complications were detected after biopsy procedures; minor complications (pneumothorax, hemothorax and hemophtysis) were detected in 23 (13.9%) cases. No complications were detected after US guided procedures; In 17 (10.3% of all complications) cases pneumothorax, in 4 (2.4%) cases - hemothorax and in 2 (1.2%) cases hemophtisis was detected on CT guided procedures. All hemothorax and hemophtisis and 10 pneumothorax cases happened to be self-limited; in 3 pneumothorax cases aspiration and in 4 cases - pleural drainage was needed. Percutaneous image guided core biopsy of mediastinal lesions is an accurate and safe procedure, which enables to get the tissue material from all mediastinum compartments. Ultrasound is the most efficient for biopsy guidance, if the target is adequately imaged by it; the advantages of US guidance are: a) possibility of real-time needle movement control b) possibility of real-time blood flow imaging b) noninvasiveness c) cost-effectiveness d) possibility to perform the biopsy at the bedside, in a semiupright position; so, ultrasound is a "Gold Standard" for procedure guidance if the 'target" can be adequately imaged by this technique. If US guidance is impossible biopsy should be performed under CT guidance. Hydrodissection and artificial pneumothorax enables to avoid the lung tissue penetration related complications. Pneumothorax was associated with multiple Needle passes and larger diameter needle use. The safety and biopsy procedure success high rate proves the use of IGMPCB as a first choice procedure when the mediastinal mass morphology is needed. PMID- 26042445 TI - [Dysbiosis and its consequences on oral cavity in children and adolescents]. AB - Gastrointestinal tract (GIT) diseases in children are often accompanied by changes in oral cavity, which is caused by common function of GIT and oral cavity organs. During last years, the number of dysbiosis of various severities has dramatically increased, which directly affects the oral cavity - dental hard tissue mineralization, especially in children and adolescents. The aim of our study was to identify the frequency of dysbiosis in children and adolescents and its influence on dental and general health. 279 patients aged 1 - 17 years were examined. Examinations have shown, that in patients with I-II degree dysbiosis spread and intensity (DMF index) of dental caries is significantly lower - 58,2% and 2,7 intensity, compared to III-IV degree dysbiosis, where 71,8% have caries with 4,2 intensity. According to this, dental and general health status in children and adolescents is highly dependent on severity of GI tract pathologies, particularly on qualitative and/or quantitative content of microbyotes of GI tract. PMID- 26042446 TI - [Evolution of oxidant-antioxidant homeostasis in patients with eczema treated using different methods]. AB - OBJECTIVE: to study the evolution of the oxidant-antioxidant homeostasis indices in patients with eczema using various methods of treating dermatosis. The study involved 63 patients with eczema (34 - males, 28 - females), aged 18-67 years, who were determined indices of pro- and antioxidant systems of blood. Patients with eczema were divided into 3 groups that were prescribed different treatments: the first comparative group (21 patients) - received a standard therapy; the second comparative group (20 patients) - had a standard therapy and additionally an antioxidant preparation "Mexidol", the third (basic group) - 22 patients, who were prescribed a complex therapy with a combination of two drugs with antioxidant effect: "Mexidol" and "Galavit." It was established that multimodality therapy for eczema while using two drugs with antioxidant action ("Mexidol", "Galavit") contributes to the most significant positive dynamics and normalization of the studied parameters of oxidant-antioxidant homeostasis of patients compared to a standard therapy of dermatosis or its combination with antioxidant preparation "Mexidol". PMID- 26042447 TI - Budget impact of rare diseases: proposal for a theoretical framework based on evidence from Bulgaria. AB - This study aimed to estimate the impact of rare disease (RD) drugs on Bulgaria's National Health Insurance Fund's (NHIF) total drug budget for 2011-2014. While standard budget impact analysis is usually used in a prospective way, assessing the impact of new health technologies on the health system's sustainability, we adopted a retrospective approach instead. Budget impact was quantified from a NHIF perspective. Descriptive statistics was used to analyse cost details, while dynamics was studied, using chain-linked growth rates (every period preceding the accounting period serves as a base). NHIF costs for RD therapies were expected to increase up to 74.5 million BGN in 2014 (7.8% of NHIF's total pharmaceutical expenditure). Greatest increase in cost per patient and number of patients treated was observed in conditions, for which there were newly approved for funding therapies. While simple cost drivers are well known - number of patients treated and mean cost per patient - in real-world settings these two factors are likely to depend on the availability and accessibility of effective innovative therapies. As RD were historically underdiagnosed, undertreated and underfunded in Bulgaria, improved access to RD drugs will inevitably lead to increasing budget burden for payers. Based on the evidence from this study, we propose a theoretical framework of a budget impact study for RD. First, a retrospective analysis could provide essential health policy insights in terms of impact on accessibility and population health, which are significant benchmarks in shaping funding decisions in healthcare. We suggest an interaction between the classical prospective BIA with the retrospective analysis in order to optimise health policy decision-making. Second, we recommend budget impact studies to focus on RD rather than orphan drugs (OD). In policy context, RD are the public health priority. OD are just one of the tools to address the complex issues of RD. Moreover, OD is a dynamic characteristic and compromises the consistency and comparability of the calculated budget indicators. PMID- 26042448 TI - The monthly variations in mortality from the cardiovascular diseases in Tbilisi. AB - Results of the detailed statistical analysis of the monthly average decade mortality on the reasons for cardiovascular diseases in Tbilisi into 1980-1992 and 2012-2013 are represented. Variable +background and random component of time series of mortality are determined. A share of the mean values of the component of variable +background from the mean value of real data of mortality constitute 68,4 % in 1980-1992 and 73,4 % in 2012-2013. Variations of the random component and their contribution to the real values of mortality (31,6 % in 1980-1992 and 26,6 % in 2012-2013) besides the air temperature can depend on many others meteorological, geophysical, social and so forth of factors. The scale of the six levels of cardiovascular mortality is proposed. In different months of year the indicated levels of mortality are various. PMID- 26042449 TI - [Study of bioavailability of paclitaxel after sublingual administration]. AB - The bioavailability of sublingual form of paclitaxel, developed in the pharmacology laboratory of pharmaceutical company - Legion "Provisus" is studied. Sublingual form of paclitaxel is an alcoholic solution of paclitaxel (1 mg/ml) with penetrator - dimethyl sulfoxide (DMSO) addition. Experiments were performed on 180 white mongrel male mice each of 25-30 g. The animals were divided into three groups. The first group served for control. 10 mg/kg of taxol was injected (once) in the lateral tail vein of the first group animals. A solution was prepared by diluting taxol with physiological sodium chloride solution until to a final concentration of paclitaxel to 1 mg/ml. The dose of 10 mg/kg (single dose) was applied under the tongue of the second group animals. Paclitaxel (substance) was extracted with dichloromethane - Taxol (by liquid-liquid extraction) for the manufacturing of a sublingual form. Unlike the second group, the third group animals took the same dose of sublingual form of paclitaxel orally (by gavage). The concentration of paclitaxel in plasma was studied by reversed-phase HPLC with spectrophotometric detection at lambda = 227 nm by Woo JS et al. (2003) method. Bioavailability was determined by comparing the concentration of paclitaxel in blood after sublingual and intravenous use of Taxol (as an area under the curve of concentration versus time). It is established that the bioavailability of sublingual forms of paclitaxel was 42.4%, Cmax = 615 +/- 73 ng * ml(-1) and tmax = 30-35 min. The value of the initial volume of distribution of paclitaxel (Vd = 3,14 +/- 0,85 l * kg(-1)) also shows its intensive penetration to the organs and tissues. The half-life of the drug on the terminal segment of concentration-time curve was averaged 1,06 +/- 0,21 h. The results create the preconditions for further preclinical study of sublingual form of paclitaxel, as the bioavailability of paclitaxel after sublingual application allows to have a systemic effect on the tumor process. PMID- 26042450 TI - [Morphological characteristic dysplastic features on colonic adenomas]. AB - Morphological changes of tubular adenomas with severe dysplasia are charachterized by low level of cytodifferentiation, epithelial cells intensive proliferation, detected by 3N-Thymidine and markedly reduction of goblet cells. Functional activity of tumor parenchyma decreases with change in ATP-ase activity. The quantity of young form fibroblasts is markedly increased in adenomous stroma, which caused a disturbance of fibrillogenesis. The local immunologic response was suppressed, the activity of T-suppressors was increased. The morphology of endotheliocytes and vascular network was changed. It is concluded that, adenomas with severe dysplasia are the risk factors for the carcinoma "in situ" development; microadenomas and adenomas are the essence of a single pathological process based on dysplastic changes. It is suggested that colonic microadenomas, are the causes the rudiments of forthcoming adenoma, and in some cases may lead to malignization. PMID- 26042451 TI - [Simvastatin's effect on insulin resistance in rats with diabetes mellitus]. AB - The aim of this experimental study was to estimate the effect of Simvastatin on glycemic variability-related insulin resistance in the course of diabetes mellitus (DM) in rats. Fifty seven male Wistar rats were divided into four groups: I - rats with diabetes mellitus and glycemic variability treated with Simvastatin (20 mg/kg body weight, intragastral during 8 weeks); II - placebo treated rats with DM and glycemic variability; III - placebo treated rats with DM and IV - nondiabetic control rats. DM was induced by feeding rats with high-fat diet (61%) during five weeks and low-dose of Streptozotocin (30 mg/kg, intraperitoneally). Daily glucose excursions were stimulated by feeding animals twice a day. We measured fasting blood glucose, glycated hemoglobin (HbA1c), insulin and HOMAIR was calculated. Higher insulin resistance in diabetic rats is related to greater daily glycemic variability. In our study was installed significant increasing HOMAIR in diabetics rats with glycemic excursions comparison with the control. Our results showed that the simvastatin-treatment decreases the indices glycemic variability and HOMA in diabetic rats with glycemic excursions. PMID- 26042452 TI - Prediction of soil and ground water contamination with fungicides of different classes according to soil and climate conditions in Ukrain and other European countries. AB - It was established that most of tested pesticides are moderately and low persistent in soil and climatic conditions of Ukraine, but more stable in Western and Northern Europe countries due to peculiarities of their climate type and soil characteristics. In addition, it was determined that all studied fungicides pertain to non- and low mobile compound (except moderately mobile pyrimethanil). Recommendations on application of studied fungicides in soil and climatic conditions of Ukraine and other European countries were given. PMID- 26042453 TI - The amount of polyphenols and antioxidant activity of fruits of different varieties of apple tree--Malus domectica L. AB - This article presents data on the content of phenolic compounds and antioxidant activity of the juice and residue, after squeezing the juice in the fruit of different varieties of Apple tree-Malus domestica L. The high content of phenolic compounds and antioxidant activity is characterized by endemic grade Kekhura, compared with introduced varieties. Found that in the fruit all varieties of apples mainly there is a correlation between the content of phenolic compounds and antioxidant activity, except for fruit varieties of Golden, in which the average measurement of polyphenols fixed high antioxidant activity. Shows that in residue, after squeezing the juice content of high content of phenolic compounds and antioxidant activity, which implies its use as biologically active additives for prevention and treatment of chronic diseases. PMID- 26042454 TI - Modulation of aryl hydrocarbon receptor regulated genes by acute administration of trimethylarsine oxide in the lung, kidney and heart of C57BL/6 mice. AB - 1. Arsenite alters the expression of aryl hydrocarbon receptor (AhR)-regulated genes in extrahepatic tissues; yet, the effect of organic arsenicals still unknown. Therefore, C57BL/6 mice received trimethylarsine oxide (TMAO; 13 mg/kg i.p.) with or without 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 15 MUg/kg), and euthanized at 6 or 24 h. 2. Our results demonstrated that TMAO increased Cyp1a1 and Cyp1b1 mRNA, protein and activity in the lung. TMAO potentiated the TCDD mediated induction of Cyp1a1 and Cyp1a2 mRNA, protein and activity in the lung. In the kidney, TMAO increased Cyp1b1 mRNA and protein. TMAO potentiated the TCDD mediated induction of Cyp1a1 and Cyp1b1 mRNA, protein and activity. In the heart, TMAO potentiated the TCDD-mediated induction of Cyp1a1 and Cyp1b1 mRNA. 3. Moreover, TMAO induced Nqo1 mRNA in the lung, kidney and heart, with subsequent increase in Nqo1 protein and activity in the lung. TMAO increased Gsta mRNA in the heart; and increased Gsta protein and activity in the lung and kidney. TMAO increased Nqo1 mRNA as compared to TCDD in the kidney and heart, and potentiated the TCDD-mediated induction of Gsta protein and activity in the kidney. 4. In conclusion, TMAO modulates AhR-regulated genes in a tissue- and enzyme-specific manner. PMID- 26042455 TI - Effect of glycyrrhizic acid on rhein renal penetration: a microdialysis study in rats. AB - 1. Rhein (RH), a primary active component isolated from rhubarb, is effective in protecting against the progression of diabetic nephropathy (DN) progression. Glycyrrhizic acid (GA), an active constituent of liquorice, is also considered to be a protective agent against DN. Here, we evaluated the effect of GA on the renal penetration of RH in rats. 2. Plasma and renal pharmacokinetics were profiled to estimate kidney penetration. After rats were anesthetized, the carotid artery was used for blood collection and a microdialysis probe was inserted into the kidney cortex to collect dialysate samples. 3. When co administered with GA, the Vss and CL values of RH in plasma increased by 25% and 34%, respectively. The Cmax in kidney dialysates significantly increased 1.3-fold (p<0.05). There was no change in AUC0-infinity in kidney dialysates, but a significant decrease (2*fold) in the plasma was observed. The AUC0 infinitykidney/AUC0-infinityplasma ratio of RH, representing kidney penetration, increased by 1.4-fold in the group pre-treated with GA compared to the RH alone group. 4. These results demonstrate that GA increases the renal penetration of RH efficiently and may exert a synergistic effect, although the molecular mechanism of interaction requires further investigation. PMID- 26042456 TI - Predicting Nurses' Turnover: The Aversive Effects of Decreased Identity, Poor Interpersonal Communication, and Learned Helplessness. AB - Through a social identity theoretical lens, this study examines how nurses' identification with their working small group, unit, or floor, nursing role (e.g., staff ER nurse, nurse practitioner), and nursing profession relate to nurses' interaction involvement, willingness to confront conflict, feelings of learned helplessness, and tenure (employment turnover) intentions. A cross sectional survey (N = 466) was conducted at a large, quaternary care hospital system. Structural equation modeling uncovered direct and indirect effects between the five primary variables. Findings demonstrate direct relationships between nurse identity (as a latent variable) and interaction involvement, willingness to confront conflict, and tenure intentions. Feelings of learned helplessness are attenuated by increased nurse identity through interaction involvement and willingness to confront conflict. In addition, willingness to confront conflict and learned helplessness mediate the relationship between interaction involvement and nurses' tenure intentions. Theoretical extensions include indirect links between nurse identity and learned helplessness via interaction involvement and willingness to confront conflict. Implications for interpersonal communication theory development, health communication, and the nursing profession are discussed. PMID- 26042457 TI - Frontoparietal and Cingulo-opercular Networks Play Dissociable Roles in Control of Working Memory. AB - We used magnetoencephalography to characterize the spatiotemporal dynamics of cortical activity during top-down control of working memory (WM). fMRI studies have previously implicated both the frontoparietal and cingulo-opercular networks in control over WM, but their respective contributions are unclear. In our task, spatial cues indicating the relevant item in a WM array occurred either before the memory array or during the maintenance period, providing a direct comparison between prospective and retrospective control of WM. We found that in both cases a frontoparietal network activated following the cue, but following retrocues this activation was transient and was succeeded by a cingulo-opercular network activation. We also characterized the time course of top-down modulation of alpha activity in visual/parietal cortex. This modulation was transient following retrocues, occurring in parallel with the frontoparietal network activation. We suggest that the frontoparietal network is responsible for top-down modulation of activity in sensory cortex during both preparatory attention and orienting within memory. In contrast, the cingulo-opercular network plays a more downstream role in cognitive control, perhaps associated with output gating of memory. PMID- 26042458 TI - Identification of ALK5 inhibitor via structure-based virtual screening and ADMET prediction. AB - TGF-beta plays a critical role in the initiation and progression of fibrosis in various organ systems such as kidney, heart, lung and liver. TGF-beta and its receptors (ALK5 and TbetaR II) are able to control the cellular growth and promote several biological responses. To date, many pharmaceutical companies have employed virtual screening to identify potent inhibitors against ALK5. Nevertheless, none of these studies had involved the in silico ADMET evaluation and Raccoon filtering. In our experiment, all 57423 molecules were downloaded from TCM database and were filtered and converted to PDBQT formats by Raccoon software. Then 24 189 structures were run through AutoDock Vina in PyRx 0.8, 164 molecules were selected and further evaluated by ADMET Predictor 6.5, and 56 structures were selected and docked by Glide 6.2. Finally, the top 10 hits were identified as promising oral ALK5 inhibitors according to their Glide scores. The Glide scores of the best two compounds, 40686 and 33534, were -10.75 and -10.30 kcal/mol, respectively. This research provides a set of combined and detailed virtual screening protocol and is helpful for explaining the mechanism of receptor-ligand interactions. PMID- 26042459 TI - Increased SIRT3 Expression and Antioxidant Defense under Hyperglycemic Conditions in HepG2 Cells. AB - BACKGROUND: Hyperglycemia exacerbates the production of mitochondrial reactive oxygen species and this contributes to a variety of pathological conditions. Sirtuin 3 (SIRT3) has been shown to play a role in decreasing oxidative stress and improving disease outcomes by regulating antioxidant defense. Our understanding of molecular events during oxidative stress under chronic hyperglycemia in the liver is limited. We postulated that SIRT3 may play a role in antioxidant defense under hyperglycemic conditions in HepG2 cells. METHODS: Cell viability was determined in HepG2 and human embryonic kidney (HEK) 293 cells cultured in the presence of 5.5 mM glucose (control), 19.9 mM mannitol (osmotic control), 10 mM glucose and 30 mM glucose (hyperglycemic), and nicotinamide (NAM) (10 mM) at 24-hr and 72-hr time points. SIRT3, peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), and cyclic adenosoine monophosphate (cAMP) response element binding protein (pCREB) protein expression were measured via western blotting. Mitochondrial antioxidant enzymes glutathione peroxidase 1 (GPx1), superoxide dismutase 2 (SOD2), and uncoupling protein 2 (UCP2) and mitochondrial DNA (mtDNA) repair enzyme 8-oxoguanine glycosylase (OGG1) were evaluated via quantitative PCR (qPCR). RESULTS: Increased cell viability and protein expression of SIRT3, pCREB, and PGC-1alpha were observed under hyperglycemic conditions at 24 hr. These were further elevated at the 72-hr time point. We also observed higher fold changes of SIRT3, GPx1, SOD2, UCP2, and OGG1 in the treated groups. Treatment with NAM decreased protein and gene expression of SIRT3, pCREB, PGC-1alpha, GPx1, SOD2, UCP2, and OGG1 at both time points in the hyperglycemic groups. CONCLUSIONS: Our data may allude to the relationship that has been established between SIRT3 and PGC-1alpha with regard to increased antioxidant defense during oxidative stress. This suggests that SIRT3 may play a role in increasing antioxidant defense and conferring resistance to oxidative stress-induced damage under hyperglycemic conditions in the human hepatoma cell line. PMID- 26042460 TI - Anger and effortful control moderate aggressogenic thought-behaviour associations. AB - The effects of anger and effortful control on aggressogenic thought-behaviour associations were investigated among a total of 311 Finnish fifth and sixth graders (mean age = 11.9 years). Self-reported aggressive cognitions (i.e., normative- and self-efficacy beliefs about aggression) were expected to be associated with higher peer-reported aggressive behaviour. Teacher reported anger and effortful control were hypothesised, and found, to moderate the effects of aggressive cognitions on aggression, such that the effects were strongest for children who were high in anger and low in effortful control, as compared to other conditions. Furthermore, under the conditions of high anger and high effortful control, self-efficacy was negatively related to aggression. Thus, aggression is a result of a complex, hierarchically organised motivational system, being jointly influenced by aggressive cognitions, anger and effortful control. The findings support the importance of examining cognitive and emotional structures jointly when predicting children's aggressive behaviour. PMID- 26042461 TI - Therapeutic Alliance With Depressed Adolescents: Predictor or Outcome? Disentangling Temporal Confounds to Understand Early Improvement. AB - Psychotherapy research reveals consistent associations between therapeutic alliance and treatment outcomes in the youth literature; however, past research frequently suffered measurement issues that obscured temporal relationships between alliance and symptomatology by measuring variables later in therapy, thereby precluding examination of important early changes. The current study aimed to explore the directions of effect between alliance and outcome early in therapy with adolescents by examining associations between first- and fourth session therapeutic alliance and symptomatology. Thirty-four adolescents (~63% female, 38% ethnic/racial minority) participated in a school-based cognitive behavioral therapy for adolescents with depression. Participants completed the Beck Depression Inventory at baseline and Session 4, and therapeutic alliance was coded from audiotapes of Sessions 1 and 4 by objective coders using the Alliance Observation Coding System. Autoregressive path analyses determined that first session therapeutic alliance was a strong significant predictor of Session 4 depression symptoms, but pretreatment depression scores were not significantly predictive of subsequent therapeutic alliance. Adding reciprocal effects between alliance and depression scores did not adversely affect model fit, suggesting that reciprocal effects may exist. Early therapeutic alliance with adolescents is critical to fostering early gains in depressive symptomatology. Knowing alliance's subsequent effect on youth outcomes, clinicians should increase effort to foster a strong relationship in early sessions and additional research should be conducted on the reciprocal effects of therapeutic alliance and treatment outcome in adolescence. PMID- 26042463 TI - Induction of Oxidative Stress and Antioxidative Mechanisms in Arabidopsis thaliana after Uranium Exposure at pH 7.5. AB - To evaluate the environmental impact of uranium (U) contamination, it is important to investigate the effects of U at ecologically relevant conditions. Since U speciation, and hence its toxicity, strongly depends on environmental pH, the present study aimed to investigate dose-dependent effects of U at pH 7.5. Arabidopsis thaliana plants (Mouse-ear Cress) were exposed for three days to different U concentrations at pH 7.5. In the roots, the increased capacities of ascorbate peroxidase and glutathione reductase indicate an important role for the ascorbate-glutathione cycle during U-induced stress. However, a significant decrease in the ascorbate redox state was observed after exposure to 75 and 100 uM U, indicating that those roots are severely stressed. In accordance with the roots, the ascorbate-glutathione cycle plays an important role in the antioxidative defence systems in A. thaliana leaves exposed to U at pH 7.5 as the ascorbate and glutathione biosynthesis were upregulated. In addition, small inductions of enzymes of the antioxidative defence system were observed at lower U concentrations to counteract the U-induced stress. However, at higher U concentrations it seems that the antioxidative defence system of the leaves collapses as reductions in enzyme activities and gene expression levels were observed. PMID- 26042462 TI - Technical guidelines for the application of seasonal influenza vaccine in China (2014-2015). AB - Influenza, caused by the influenza virus, is a respiratory infectious disease that can severely affect human health. Influenza viruses undergo frequent antigenic changes, thus could spread quickly. Influenza causes seasonal epidemics and outbreaks in public gatherings such as schools, kindergartens, and nursing homes. Certain populations are at risk for severe illness from influenza, including pregnant women, young children, the elderly, and people in any ages with certain chronic diseases. PMID- 26042464 TI - Induction of Apoptosis in Endometrial Cancer (Ishikawa) Cells by Pogostemon cablin Aqueous Extract (PCAE). AB - Pogostemon cablin (PC) is a traditional herbal medicine used in the treatment of the common cold, nausea, diarrhea, and even for headaches and fever. However, the mechanisms underlying the anti-proliferative activity of PC in endometrial cancer (EC) cells have yet to be fully elucidated. This study investigated the anticancer effects of an aqueous extract of Pogostemon cablin (PCAE), specifically induced apoptosis in EC (Ishikawa) cells. Proliferation of EC cells following exposure to PCAE was assessed by an MTT assay. DNA content and the induction of cell cycle apoptosis were analyzed by flow cytometry (FACS Calibur). Protein caspase-3 and, -9 as well as AIF were investigated using Western blot. Our results demonstrate growth inhibition of Ishikawa cells by PCAE. Furthermore, caspase-3 activity caused PCAE-treated cell lines to accumulate in apoptosis. Gene expression profiling (GEP) results further suggest that, in addition to its known effects with regard to EC prevention, PCAE may also exert antitumor activity on established EC cells. Many previous studies have identified the chemo preventive effects of natural plant materials and the potential role of these materials in chemotherapy. This current study used human EC Ishikawa cells to investigate the anti-tumor effects of PCAE in EC cells. Our results demonstrate that PCAE inhibits the growth of cancer cells and induces apoptosis, which suggests the potential applicability of PCAE as an antitumor agent. PMID- 26042465 TI - Circulating Levels of sFlt1 Splice Variants as Predictive Markers for the Development of Preeclampsia. AB - Angiogenic biomarkers, including soluble fms-like tyrosine kinase 1 (sFlt1), are thought to be predictors of preeclampsia onset; however, improvement is needed before a widespread diagnostic test can be utilized. Here we describe the development and use of diagnostic monoclonal antibodies specific to the two main splice variants of sFlt1, sFlt1-1 and sFlt1-14. These antibodies were selected for their sensitivity and specificity to their respective sFlt1 isoform in a capture ELISA format. Data from this pilot study suggest that sFlt1-1 may be more predictive of preeclampsia than total sFlt1. It may be possible to improve current diagnostic platforms if more specific antibodies are utilized. PMID- 26042466 TI - The Anti-Inflammatory Effects of the Methanolic Extract and Fractions from Davilla elliptica St. Hil. (Dilleniaceae) on Bothrops jararaca Envenomation. AB - Inflammation and haemorrhage are the main characteristics of tissue injury in botropic envenomation. Although some studies have shown that anti-venom prevents systemic reactions, it is not efficient in preventing tissue injury at the site of the bite. Therefore, this work was undertaken to investigate the anti inflammatory effects of the methanolic extract and fractions from D. elliptica and to evaluate the role of matrix metalloproteinases (MMPs) in this process. Effects of the extract and fractions from D. elliptica were evaluated using a carrageenan-induced paw oedema model in rats, and leukocyte rolling was visualized by intravital. The quantification of MMPs activities (MMP-2 and MMP-9) extracted from the dermis of mice treated with extract and fractions alone or incubated with venom was determined by zymographic analyses. Our results show that intraperitoneal (i.p.) injection of fractions significantly reduced paw oedema after the carrageenan challenge. Treatment with the tannins fraction also resulted in considerable inhibition of the rolling of leukocytes and this fraction was able to decrease the activation of MMP-9. These results confirmed the anti-inflammatory activity of the methanolic extract and tannins fraction of D. elliptica and showed that the dermonecrosis properties of B. jararaca venom might be mediated through the inhibition of MMP-9 activity. PMID- 26042467 TI - Phytochemical Characterization of Chinese Bayberry (Myrica rubra Sieb. et Zucc.) of 17 Cultivars and Their Antioxidant Properties. AB - In order to fully understand the variations of fruit quality-related phytochemical composition in Chinese bayberry (Myrica rubra Sieb. et Zucc.), mature fruit of 17 cultivars from Zhejiang and Jiangsu provinces was used for the investigation of fruit quality attributes, including fruit color, soluble sugars, organic acids, total phenolics, flavonoids, antioxidant capacity, etc. Sucrose was the main soluble sugar, while citric acid was the main organic acid in bayberry fruit. The content of total phenolics and total flavonoids were positively correlated with 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) antioxidant activity and 2,2'-azino-bis(3 ethylbenzothiazoline- 6-sulphonic acid) (ABTS) radical scavenging activity. Five anthocyanidins, i.e., delphinidin-hexoside (Dp-Hex), cyanidin-3-O-galactoside (C 3-Gal), cyanidin-3-O-glucoside (C-3-Glu), pelargonidin-3-O-glucoside (Pg-3-Glu) and peonidin-3-O-glucoside (Pn-3-Glu), and seven flavonols compounds, i.e., myricetin-3-O-rhamnoside (M-3-Rha), myricetin deoxyhexoside-gallate (M-DH-G), quercetin-3-O-galactoside (Q-3-Gal), quercetin-3- O-glucoside (Q-3-Glu), quercetin-3-O-rhamnoside (Q-3-Rha), kaempferol-3-O-galactoside (K-3-Gal) and kaempferol-3-O-glucoside (K-3-Glu), were identified and characterized among the cultivars. The significant differences in phytochemical compositions among cultivars reflect the diversity in bayberry germplasm, and cultivars of good flavor and/or rich in various health-promoting phytochemicals are good candidates for future genetic breeding of bayberry fruit of high quality. In conclusion, our results may provide important information for further breeding or industrial utilization of different bayberry resources. PMID- 26042468 TI - Colloidal Nanoparticles for Intermediate Band Solar Cells. AB - The Intermediate Band (IB) solar cell concept is a promising idea to transcend the Shockley-Queisser limit. Using the results of first-principles calculations, we propose that colloidal nanoparticles (CNPs) are a viable and efficient platform for the implementation of the IB solar cell concept. We focused on CdSe CNPs and we showed that intragap states present in the isolated CNPs with reconstructed surfaces combine to form an IB in arrays of CNPs, which is well separated from the valence and conduction band edges. We demonstrated that optical transitions to and from the IB are active. We also showed that the IB can be electron doped in a solution, e.g., by decamethylcobaltocene, thus activating an IB-induced absorption process. Our results, together with the recent report of a nearly 10% efficient CNP solar cell, indicate that colloidal nanoparticle intermediate band solar cells are a promising platform to overcome the Shockley Queisser limit. PMID- 26042469 TI - Effect of Natural Polyphenols on CYP Metabolism: Implications for Diseases. AB - Cytochromes P450 (CYPs) are a large group of hemeproteins located on mitochondrial membranes or the endoplasmic reticulum. They play a crucial role in the metabolism of endogenous and exogenous molecules. The activity of CYP is associated with a number of factors including redox potential, protein conformation, the accessibility of the active site by substrates, and others. This activity may be potentially modulated by a variety of small molecules. Extensive experimental data collected over the past decade point at the active role of natural polyphenols in modulating the catalytic activity of CYP. Polyphenols are widespread micronutrients present in human diets of plant origin and in medicinal herbs. These compounds may alter the activity of CYP either via direct interactions with the enzymes or by affecting CYP gene expression. The polyphenol-CYP interactions may significantly alter the pharmacokinetics of drugs and thus influence the effectiveness of chemical therapies used in the treatment of different types of cancers, diabetes, obesity, and cardiovascular diseases (CVD). CYPs are involved in the oxidation and activation of external carcinogenic agents, in which case the inhibition of the CYP activity is beneficial for health. CYPs also support detoxification processes. In this case, it is the upregulation of CYP genes that would be favorable for the organism. A CYP enzyme aromatase catalyzes the formation of estrone and estradiol from their precursors. CYPs also catalyze multiple reactions leading to the oxidation of estrogen. Estrogen signaling and oxidative metabolism of estrogen are associated with the development of cancer. Thus, polyphenol-mediated modulation of the CYP's activity also plays a vital role in estrogen carcinogenesis. The aim of the present review is to summarize the data collected over the last five to six years on the following topics: (1) the mechanisms of the interactions of CYP with food constituents that occur via the direct binding of polyphenols to the enzymes and (2) the mechanisms of the regulation of CYP gene expression mediated by polyphenols. The structure-activity relationship relevant to the ability of polyphenols to affect the activity of CYP is analyzed. The application of polyphenol-CYP interactions to diseases is discussed. PMID- 26042470 TI - Antimalarial 5,6-Dihydro-alpha-pyrones from Cryptocarya rigidifolia: Related Bicyclic Tetrahydro-alpha-Pyrones Are Artifacts1. AB - Antimalarial bioassay-guided fractionation of an EtOH extract of the root wood of Cryptocarya rigidifolia (Lauraceae) led to the isolation of the five new 5,6 dihydro-alpha-pyrones cryptorigidifoliols A-E (1-5) and the six bicyclic tetrahydro-alpha-pyrone derivatives cryptorigidifoliols F-K (6-11). The structure elucidations of all compounds were made on the basis of the interpretation of spectroscopic data and chemical derivatization, and the relative and absolute configurations were determined by NOESY, electronic circular dichroism (ECD), and (1)H NMR analysis of alpha-methoxyphenylacetyl (MPA) derivatives. The bicyclic tetrahydro-alpha-pyrone derivatives were identified as products of acid-catalyzed intramolecular Michael addition of the 5,6-dihydro-alpha-pyrones in the presence of silica gel. A structure-activity relationship study suggested that the presence of an alpha,beta-unsaturated carbonyl moiety is not essential for potent antimalarial activity. PMID- 26042471 TI - Structural Basis for Enhancement of Carbapenemase Activity in the OXA-51 Family of Class D beta-Lactamases. AB - Class D beta-lactamases of Acinetobacter baumannii are enzymes of the utmost clinical importance, producing resistance to last resort carbapenem antibiotics. Although the OXA-51-like enzymes constitute the largest family of class D beta lactamases, they are poorly studied and their importance in conferring carbapenem resistance is controversial. We present the detailed microbiological, kinetic, and structural characterization of the eponymous OXA-51 beta-lactamase. Kinetic studies show that OXA-51 has low catalytic efficiency for carbapenems, primarily due to the low affinity of the enzyme for these substrates. Structural studies demonstrate that this low affinity results from the obstruction of the enzyme active site by the side chain of Trp222, which presents a transient steric barrier to an incoming carbapenem substrate. The Trp222Met substitution relieves this steric hindrance and elevates the affinity of the mutant enzyme for carbapenems by 10-fold, significantly increasing the levels of resistance to these antibiotics. The ability of OXA-51 to evolve into a robust carbapenemase as the result of a single amino acid substitution may, in the near future, elevate the ubiquitous enzymes of the OXA-51 family to the status of the most deleterious A. baumannii carbapenemases, with dire clinical consequences. PMID- 26042472 TI - 3D Printed Programmable Release Capsules. AB - The development of methods for achieving precise spatiotemporal control over chemical and biomolecular gradients could enable significant advances in areas such as synthetic tissue engineering, biotic-abiotic interfaces, and bionanotechnology. Living organisms guide tissue development through highly orchestrated gradients of biomolecules that direct cell growth, migration, and differentiation. While numerous methods have been developed to manipulate and implement biomolecular gradients, integrating gradients into multiplexed, three dimensional (3D) matrices remains a critical challenge. Here we present a method to 3D print stimuli-responsive core/shell capsules for programmable release of multiplexed gradients within hydrogel matrices. These capsules are composed of an aqueous core, which can be formulated to maintain the activity of payload biomolecules, and a poly(lactic-co-glycolic) acid (PLGA, an FDA approved polymer) shell. Importantly, the shell can be loaded with plasmonic gold nanorods (AuNRs), which permits selective rupturing of the capsule when irradiated with a laser wavelength specifically determined by the lengths of the nanorods. This precise control over space, time, and selectivity allows for the ability to pattern 2D and 3D multiplexed arrays of enzyme-loaded capsules along with tunable laser triggered rupture and release of active enzymes into a hydrogel ambient. The advantages of this 3D printing-based method include (1) highly monodisperse capsules, (2) efficient encapsulation of biomolecular payloads, (3) precise spatial patterning of capsule arrays, (4) "on the fly" programmable reconfiguration of gradients, and (5) versatility for incorporation in hierarchical architectures. Indeed, 3D printing of programmable release capsules may represent a powerful new tool to enable spatiotemporal control over biomolecular gradients. PMID- 26042475 TI - Current status of randomized controlled trials for laparoscopic gastric surgery for gastric cancer in China. AB - China alone accounts for nearly 42% of all new gastric cancer cases worldwide, and gastric cancer is the third leading cause of cancer deaths in China nowadays. Without mass screening programs, unfortunately over 80% of all Chinese patients have been diagnosed as advanced diseases. As in other Asian countries, especially Japan and Korea, laparoscopic gastrectomy for the treatment of gastric cancer has gained increasingly popularity in China during the past decade. Whether laparoscopic surgery can be safely and effectively performed in the treatment of gastric cancer remains controversial, particularly with regard to curative intent in advanced diseases. Given the high incidence of these cancers, and their advanced stage at diagnosis, China has a significant interest in determining the safety and effectiveness of laparoscopic gastrectomy. A well-designed randomized controlled trial (RCT) is considered the only feasible way to provide conclusive evidence. To date, China has not played a significant role in terms of conducting RCT concerning laparoscopic surgery for gastric cancer. However, an effort has been made by the Chinese researchers, with the great help from our colleagues in neighboring countries such as Korea and Japan, through the establishment of the Chinese Laparoscopic Gastrointestinal Surgery Study Group. In this review, we present the current status of RCT for laparoscopic gastric surgery for gastric cancer in China, including published and ongoing registered RCT. PMID- 26042474 TI - The genetic influences on oxycodone response characteristics in human experimental pain. AB - Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone. PMID- 26042473 TI - Kinase-Independent Small-Molecule Inhibition of JAK-STAT Signaling. AB - Phenotypic cell-based screening is a powerful approach to small-molecule discovery, but a major challenge of this strategy lies in determining the intracellular target and mechanism of action (MoA) for validated hits. Here, we show that the small-molecule BRD0476, a novel suppressor of pancreatic beta-cell apoptosis, inhibits interferon-gamma (IFN-gamma)-induced Janus kinase 2 (JAK2) and signal transducer and activation of transcription 1 (STAT1) signaling to promote beta-cell survival. However, unlike common JAK-STAT pathway inhibitors, BRD0476 inhibits JAK-STAT signaling without suppressing the kinase activity of any JAK. Rather, we identified the deubiquitinase ubiquitin-specific peptidase 9X (USP9X) as an intracellular target, using a quantitative proteomic analysis in rat beta cells. RNAi-mediated and CRISPR/Cas9 knockdown mimicked the effects of BRD0476, and reverse chemical genetics using a known inhibitor of USP9X blocked JAK-STAT signaling without suppressing JAK activity. Site-directed mutagenesis of a putative ubiquitination site on JAK2 mitigated BRD0476 activity, suggesting a competition between phosphorylation and ubiquitination to explain small-molecule MoA. These results demonstrate that phenotypic screening, followed by comprehensive MoA efforts, can provide novel mechanistic insights into ostensibly well-understood cell signaling pathways. Furthermore, these results uncover USP9X as a potential target for regulating JAK2 activity in cellular inflammation. PMID- 26042476 TI - The intra-aortic balloon pump: an early chapter in translational medicine. PMID- 26042478 TI - Association of alpha-ADD1 Gene and Hypertension Risk: A Meta-Analysis. AB - BACKGROUND: Results regarding the association between a-adducin (ADD1) gene and essential hypertension (EH) risk remain inconsistent. Therefore, we performed this meta-analysis to investigate this association. MATERIAL AND METHODS: We comprehensively searched published literature from PubMed and Embase. All studies analyzing the association between ADD1 Gly460Trp polymorphism and EH risk were included. Fixed- or random-effects model was used to calculate pooled odds ratio (OR) with 95% confidence interval (CI). RESULTS: Data synthesis showed an increased risk of EH in T allele variant carriers with Asian descent, for GG vs. TT (OR=0.750, 95%CI: 0.585-0.960; P=0.022), recessive model (OR=1.196, 95%CI: 1.009-1.418; P=0.039), dominant model (OR=0.826, 95%CI: 0.693-0.985; P=0.033), and allelic model (OR=0.859, 95%CI: 0.756-0.964; P=0.01), respectively. However, no statistical differences were observed in Blacks and Caucasians. CONCLUSIONS: The findings showed the association of the T allele in ADD1 gene with EH susceptibility in Asians. However, well-designed studies involving gene-gene and gene-environment interactions should be considered in future. PMID- 26042479 TI - Consequences of a demographic bottleneck on genetic structure and variation in the Scandinavian brown bear. AB - The Scandinavian brown bear went through a major decline in population size approximately 100 years ago, due to intense hunting. After being protected, the population subsequently recovered and today numbers in the thousands. The genetic diversity in the contemporary population has been investigated in considerable detail, and it has been shown that the population consists of several subpopulations that display relatively high levels of genetic variation. However, previous studies have been unable to resolve the degree to which the demographic bottleneck impacted the contemporary genetic structure and diversity. In this study, we used mitochondrial and microsatellite DNA markers from pre- and postbottleneck Scandinavian brown bear samples to investigate the effect of the bottleneck. Simulation and multivariate analysis suggested the same genetic structure for the historical and modern samples, which are clustered into three subpopulations in southern, central and northern Scandinavia. However, the southern subpopulation appears to have gone through a marked change in allele frequencies. When comparing the mitochondrial DNA diversity in the whole population, we found a major decline in haplotype numbers across the bottleneck. However, the loss of autosomal genetic diversity was less pronounced, although a significant decline in allelic richness was observed in the southern subpopulation. Approximate Bayesian computations provided clear support for a decline in effective population size during the bottleneck, in both the southern and northern subpopulations. These results have implications for the future management of the Scandinavian brown bear because they indicate a recent loss in genetic diversity and also that the current genetic structure may have been caused by historical ecological processes rather than recent anthropogenic persecution. PMID- 26042481 TI - Pharmacological evaluation of nasal delivery of selegiline hydrochloride-loaded thiolated chitosan nanoparticles for the treatment of depression. AB - The aim of the present study was to investigate the propensity of thiolated chitosan nanoparticles (TCNs) to enhance the nasal delivery of selegiline hydrochloride. TCNs were synthesized by the ionic gelation method. The particle size distribution (PDI), entrapment efficiency (EE), and zeta potential of modified chitosan (CS) nanoparticles were found to be 215 +/- 34.71 nm, 70 +/- 2.71%, and + 17.06 mV, respectively. The forced swim and the tail suspension tests were used to evaluate the anti-depressant activity, in which elevated immobility time was found to reduce on treatment. TCNs seem to be promising candidates for nose-to-brain delivery in the evaluation of antidepressant activity. PMID- 26042482 TI - The potential of nanofibers in tissue engineering and stem cell therapy. AB - Electrospinning is a technique in which materials in solution are shaped into continuous nano- and micro-sized fibers. Combining stem cells with biomaterial scaffolds and nanofibers affords a favorable approach for bone tissue engineering, stem cell growth and transfer, ocular surface reconstruction, and treatment of congenital corneal diseases. This review seeks to describe the current examples of the use of scaffolds in stem cell therapy. Stem cells are classified as adult or embryonic stem (ES) cells, and the advantages and drawbacks of each group are detailed. The nanofibers and scaffolds are further classified in Tables I and II , which describe specific examples from the literature. Finally, the current applications of biomaterial scaffolds containing stem cells for tissue engineering applications are presented. Overall, this review seeks to give an overview of the biomaterials available for use in combination with stem cells, and the application of nanofibers in stem cell therapy. PMID- 26042483 TI - Key immune cell cytokines have a significant role in the expansion of CD26 population of cord blood mononuclear cells. AB - BACKGROUND: Umbilical cord blood expresses cluster of differentiation (CD) 26, a fraction of CD34 + cells, negatively regulating in vivo homing and engraftment of hematopoietic stem cells. CD26 is highly expressed in various cells such as HSCs, immune cells, fibroblasts, and epithelial cells. It has been shown that inhibition of the CD26 on CD34 + cells improve the efficiency of transplantation of hematopoietic stem and progenitor cells. This study aimed to investigate the effect of key immune cell cytokines on CD26 expansion. MATERIAL AND METHODS: Cord blood mononuclear cells were cultured for 21 days using the stem cell factor, fetal liver tyrosine kinase 3 (Flt3) ligand (FL), interleukin (IL) 2, IL7, and IL15. Harvested cells were analyzed by flow cytometry at distinct time points. RESULTS: Our results showed that utilization of IL7 significantly improved the expression of total CD26 + cells (8.6-fold higher). When either IL2 or IL15 were added to the culture, the expression also improved 2.5-fold. The IL2 and IL7 showed significant effect on the expansion of both the CD26 + and CD26 fractions of the CD34 + cells. However, the effects of IL15 on CD26 + and CD26 -expansion were similar. CONCLUSION: Taken together, our data suggested that using IL7 causes higher proliferation of CD26 cells in comparison to that seen under other culture conditions. PMID- 26042484 TI - Motorcycle safety among motorcycle taxi drivers and nonoccupational motorcyclists in developing countries: A case study of Maoming, South China. AB - OBJECTIVE: An increasing number of motorcycle taxis have been involved in traffic crashes in many developing countries. This study examines the characteristics of both motorcycle taxi drivers and nonoccupational motorcyclists, investigates the risks they pose to road safety, and provides recommendations to minimize their risks. METHODS: Based on the data collected from a questionnaire survey of 867 motorcycle taxi drivers and 2,029 nonoccupational motorcyclists in Maoming, South China, comparisons were made to analyze differences of personal attributes, attitudes toward road safety, and self-reported behavior of the 2 groups. RESULTS: Results of the chi-square tests show that not only motorcycle taxi drivers but also nonoccupational motorcyclists in Maoming held poor attitudes toward road safety and both groups reported unsafe driving behavior. There is much room for improving local road safety education among all motorcyclists in Maoming. Yet, motorcycle taxi drivers were more likely to pose road safety risks than nonoccupational motorcyclists under some circumstances, such as speeding late at night or early in the morning, not requiring passengers to wear helmets, and running a red light. The results of the binary logistic regression model show that possessing a vehicle license for a motorcycle or not was the common significant predictor for unsafe driving behavior of motorcycle taxi drivers and nonoccupational motorcyclists. Therefore, enforcement against all motorcyclists not showing vehicle licenses for their motorcycles should be stepped up. CONCLUSION: Motorcycle safety is largely poor in Maoming. Therefore, efforts to improve motorcycle safety should be strengthened by targeting not only motorcycle taxi drivers but also nonoccupational motorcyclists. PMID- 26042485 TI - Bioequivalence of budesonide plus formoterol (BF) Spiromax(r) and BF Turbohaler(r) (with and without charcoal block) in healthy volunteers. AB - OBJECTIVE: Budesonide formoterol (BF) Spiromax(r) is a breath-actuated dry-powder inhaler designed to deliver similar combinations of budesonide and formoterol as Symbicort(r) Turbohaler(r). We performed two studies to demonstrate pharmacokinetic (PK) equivalence of BF Spiromax with BF Turbohaler. MATERIALS AND METHODS: Two single-center, open-label, randomized, 5-period crossover studies were performed. The first study compared BF Spiromax 160/4.5 MUg with BF Turbohaler 200/6 MUg, while the second study compared BF Spiromax 320/9 MUg with BF Turbohaler 400/12 MUg. All treatments were administered with and without charcoal. PK parameters were calculated by measuring plasma drug concentrations from blood samples taken pre-dose and up to 24 hours post-dose. RESULTS: In each study, 90 healthy volunteers were randomized. Bioequivalence of BF Spiromax with BF Turbohaler was demonstrated for budesonide and formoterol (AUC0-t and Cmax (90% confidence intervals of the geometric mean between-device ratios for both parameters were within the predefined range of 0.80-1.25 in both studies)). Equivalence was observed without use of charcoal (overall absorption post inhalation) and with charcoal (pulmonary absorption). There were no major differences between treatments in tmax for either budesonide or formoterol. All study treatments were well tolerated (one treatment-emergent adverse event (TEAE) in the medium-dose study and four TEAEs in the high-dose study). CONCLUSIONS: These studies indicate that BF Spiromax (+/-charcoal block) is bioequivalent to BF Turbohaler with respect to the PK parameters assessed. Single doses of BF Spiromax were well tolerated; the overall safety profile of BF Spiromax and BF Turbohaler was similar. PMID- 26042487 TI - Biopharmaceuticals - from animals or plants? PMID- 26042486 TI - Pharmacokinetics and safety of intravenous oseltamivir in infants and children in open-label studies. AB - OBJECTIVE: Critically ill children with influenza may be unable to swallow or absorb oral drugs. An intravenous (IV) formulation of the antiviral oseltamivir was evaluated in two prospective open-label studies. METHODS: Hospitalized children aged <1 year (NCT01053663) or 1-12 years (NCT01033734) with clinical or laboratory-confirmed influenza, normal renal function, and who are unable to tolerate and/or absorb oral medication were enrolled. Patients received oseltamivir 2-3 mg/kg (age<1 year) or 2.5-3 mg/kg (max. 100 mg; age 1-12 years) by slow IV infusion twice daily for up to 6 days. Blood samples were taken for pharmacokinetics and nasal swabs taken to monitor viral shedding and resistance (by reverse transcriptase polymerase chain reaction (RTPCR) and culture). Adverse events (AEs) were monitored for 30 days from treatment initiation. RESULTS: 17 children were enrolled (9 aged<1 year; 8 aged 1-12 years). On day 1, 11 patients had laboratory-confirmed influenza. Seven patients switched from IV to oral dosing before the 10th dose. Individual plasma oseltamivir carboxylate exposures (AUClast) ranged from 1,700 to 11,500 h x ng/mL. 23 AEs were reported in 10 patients; 2 were considered treatment-related (rash, infusion site erythema). Eight serious AEs (SAEs) were reported in 7 patients, including 3 deaths in patients aged <1 year; none were considered treatment-related. Two SAEs caused treatment withdrawal. Six patients had influenza detected on or after day 11 of treatment. The oseltamivir resistance mutation H275Y was detected in three samples from 1 patient with H1N1pdm09 infection. CONCLUSIONS: IV oseltamivir was well tolerated in this sample of seriously ill children. The small patient numbers precluded any formal analysis by age group or dose. PMID- 26042488 TI - Non-animal Tests for Evaluating the Toxicity of Solid Xenobiotics. PMID- 26042489 TI - Progress in toxicological testing: reduction and refinement issues. PMID- 26042490 TI - Comparative evaluation of in vitro and in vivo assays for the detection of avian infectious bronchitis virus as a contaminant of live poultry vaccines. AB - A reverse transcriptase polymerase chain reaction (RT-PCR( assay specific for identifying avian infectious bronchitis virus (IBV) in poultry vaccines, and the serological response to IBV induced by the inoculation of chicks with a Newcastle disease vaccine spiked with the Massachusetts strain of IBV, were compared for their ability to detect IBV as a contaminant of avian vaccines. The sensitivity of the IBV-RT-PCR assay provided results which were at least equivalent to the biological effect produced by the inoculation of chicks, allowing this assay to be considered a valid alternative to animal testing in the quality control of avian immunologicals. This procedure can easily be adapted to detect a number of contaminants for which the in vivo test still represents the only available method of detection. PMID- 26042491 TI - A germination bioassay as a toxicological screening system for studying the effects of potential prodrugs of naproxen. AB - A germination bioassay with radish (Raphanus sativus L.) seeds was developed as a toxicological screening system for assessing the effects of new potential prodrugs of naproxen, as an alternative to animals and animal cell toxicity screens. Both enantiomers of naproxen (6-methoxy-alpha-methyl-2-naphthaleneacetic acid) and naproxol (6-methoxy-beta-2-naphthaleneethanol), and their racemic mixtures, inhibited the radicle growth of R. sativus at a concentration of 1mM, while only (R)-(+ )-naproxol and racemic naproxol inhibited the hypocotyl growth of R. sativus at the same concentration. Four novel combinatorial esters, naproxen naproxyl esters (6-methoxy-beta-methyl-2-naphthaleneethyl 6-methoxy alpha-methyl-2-naphthaleneacetate), resulting from the combinatorial chemistry of the esterification reaction between naproxen and naproxol, were synthesised and then tested in the germination bioassay, at a concentration of 0.5mM. It was found that they did not inhibit either the radicle or the hypocotyl growth of R. sativus. PMID- 26042492 TI - Alternative Approaches and Tests in Ecotoxicology: A Review of the Present Position and the Prospects for Change, Taking into Account ECVAM's Duties, Topic Selection and Test Criteria. AB - The objectives of this review are to summarise the present position concerning the use of vertebrates in ecotoxicity testing, giving particular attention to tests that cause suffering, and to discuss in some detail, alternatives to them, and the prospects for change. The report has been written with the objectives of the European Centre for the Validation of Alternative Methods (ECVAM) in mind, and some recommendations for action have been made at the end of the discussion section. The first section of the review describes the present requirements within the European Union for the ecotoxicity testing of industrial chemicals in general, and for pesticides in particular, and the very limited documentation of the tests that are actually carried out. The next four sections describe the many different assays and systems used to evaluate the harmful effects of chemicals on free-living organisms and natural populations, and the extent to which they might be suitable alternatives to vertebrate toxicity tests that cause suffering. Attention is drawn to certain assays and strategies that can already be used as satisfactory alternatives, and thus provide the basis for short-term change. Included here are non-destructive assays on vertebrates which are available for certain types of chemicals, and which provide a direct and relatively uncomplicated approach to the problem. Other approaches are described which still require development, but hold considerable promise in the longer term. The growth of knowledge in the broad field of biochemical toxicology and the development of related technologies should lead to the development of better and more sophisticated alternatives in the future. In vitro assays employing vertebrate cell systems are of particular interest here. The last section of the review deals with conclusions and recommendations. The recommendations are made with a view to the activities and responsibilities of ECVAM. PMID- 26042493 TI - A Study on UV Filter Chemicals from Annex VII of European Union Directive 76/768/EEC, in the In Vitro 3T3 NRU Phototoxicity Test. AB - In 1996, the Scientific Committee on Cosmetology of DGXXIV of the European Commission asked the European Centre for the Validation of Alternative Methods to test eight UV filter chemicals from the 1995 edition of Annex VII of Directive 76/768/EEC in a blind trial in the in vitro 3T3 cell neutral red uptake phototoxicity (3T3 NRU PT) test, which had been scientifically validated between 1992 and 1996. Since all the UV filter chemicals on the positive list of EU Directive 76/768/EEC have been shown not to be phototoxic in vivo in humans under use conditions, only negative effects would be expected in the 3T3 NRU PT test. To balance the number of positive and negative chemicals, ten phototoxic and ten non-phototoxic chemicals were tested under blind conditions in four laboratories. Moreover, to assess the optimum concentration range for testing, information was provided on appropriate solvents and on the solubility of the coded chemicals. In this study, the phototoxic potential of test chemicals was evaluated in a prediction model in which either the Photoirritation Factor (PIF) or the Mean Photo Effect (MPE) were determined. The results obtained with both PIF and MPE were highly reproducible in the four laboratories, and the correlation between in vitro and in vivo data was almost perfect. All the phototoxic test chemicals provided a positive result at concentrations of 1MU/ml, while nine of the ten non phototoxic chemicals gave clear negative results, even at the highest test concentrations. One of the UV filter chemicals gave positive results in three of the four laboratories only at concentrations greater than 100MU/ml; the other laboratory correctly identified all 20 of the test chemicals. An analysis of the impact that exposure concentrations had on the performance of the test revealed that the optimum concentration range in the 3T3 NRU PT test for determining the phototoxic potential of chemicals is between 0.1MUg/ml and 10MUg/ml, and that false positive results can be obtained at concentrations greater than 100MUg/ml. Therefore, the positive results obtained with some of the UV filter chemicals only at concentrations greater than 100MUg/ml do not indicate a phototoxic potential in vivo. When this information was taken into account during calculation of the overall predictivity of the 3T3 NRU PT test in the present study, an almost perfect correlation of in vitro versus in vivo results was obtained (between 95% and 100%), when either PIF or MPE were used to predict the phototoxic potential. The management team and participants therefore conclude that the 3T3 NRU PT test is a valid test for correctly assessing the phototoxic potential of UV filter chemicals, if the defined concentration limits are taken into account. PMID- 26042494 TI - An evaluation of the proposed OECD testing strategy for skin corrosion. AB - The use of testing strategies which incorporate a range of alternative methods and which use animals only as a last resort is widely considered to provide a reliable way of predicting chemical toxicity while minimising animal testing. The widespread concern over the severity of the Draize rabbit test for assessing skin irritation and corrosion led to the proposal of a stepwise testing strategy at an OECD workshop in January 1996. Subsequently, the proposed testing strategy was adopted, with minor modifications, by the OECD Advisory Group on Harmonization of Classification and Labelling. This article reports an evaluation of the proposed OECD testing strategy as it relates to the classification of skin corrosives. By using a set of 60 chemicals, an assessment was made of the effect of applying three steps in the strategy, taken both individually and in sequence. The results indicate that chemicals can be classified as corrosive (C) or non-corrosive (NC) with sufficient reliability by the sequential application of three alternative methods, i.e., structure-activity relationships (where available), pH measurements, and a single in vitro method (either the rat skin transcutaneous electrical resistance (TER) assay or the EPISKINTM assay). It is concluded that the proposed OECD strategy for skin corrosion can be simplified without compromising its predictivity. For example, it does not appear necessary to measure acid/alkali reserve (buffering capacity) in addition to pH for the classification of pure chemicals. PMID- 26042495 TI - Hepatic decompensation with sofosbuvir plus simeprevir in a patient with Child Pugh B compensated cirrhosis. AB - A 75-year-old male with compensated Child-Pugh B cirrhosis initiated sofosbuvir plus simeprevir, and developed hepatic decompensation and died a few days thereafter. High exposure to simeprevir leading to hepatotoxicity most likely explained this fatal outcome. This observation, along with similar cases recently reported in the literature, should raise awareness of the potential for decompensation in patients with advanced cirrhosis treated with simeprevir. PMID- 26042496 TI - Barriers to Clinical Trial Participation: Comparing Perceptions and Knowledge of African American and White South Carolinians. AB - Analyzing data from a survey of African American and White residents in South Carolina, this study attempts to understand how to better promote clinical trial participation specifically within the African American population. To explore why participation is lower in the African American population, the authors examined two sets of potential barriers: structural/procedural (limited accessibility, lack of awareness, doctors not discussing clinical trial options, lack of health insurance) and cognitive/psychological (lack of subjective and factual knowledge, misperceptions, distrust, fear, perceived risk). Findings revealed that African Americans were significantly less willing than Whites to participate in a clinical trial. African Americans also had lower subjective and factual knowledge about clinical trials and perceived greater risk involved in participating in a clinical trial. The authors found that lack of subjective knowledge and perceived risk were significant predictors of African Americans' willingness to participate in a clinical trial. Implications of the findings are discussed in detail. PMID- 26042497 TI - Development of an efficient soymilk cream production method by papain digestion, heat treatment, and low-speed centrifugation. AB - We developed the simple method of soymilk cream production from the high-fat soymilk, which was prepared by papain digestion and heat treatment. As a result of the treatment, high-fat soymilk was aggregated and it became possible to separate soymilk cream as the surface fraction by low-speed centrifugation (6000 * g, 10 min). PMID- 26042498 TI - Frequency-based Segregation of Syntactic and Semantic Unification during Online Sentence Level Language Comprehension. AB - During sentence level language comprehension, semantic and syntactic unification are functionally distinct operations. Nevertheless, both recruit roughly the same brain areas (spatially overlapping networks in the left frontotemporal cortex) and happen at the same time (in the first few hundred milliseconds after word onset). We tested the hypothesis that semantic and syntactic unification are segregated by means of neuronal synchronization of the functionally relevant networks in different frequency ranges: gamma (40 Hz and up) for semantic unification and lower beta (10-20 Hz) for syntactic unification. EEG power changes were quantified as participants read either correct sentences, syntactically correct though meaningless sentences (syntactic prose), or sentences that did not contain any syntactic structure (random word lists). Other sentences contained either a semantic anomaly or a syntactic violation at a critical word in the sentence. Larger EEG gamma-band power was observed for semantically coherent than for semantically anomalous sentences. Similarly, beta band power was larger for syntactically correct sentences than for incorrect ones. These results confirm the existence of a functional dissociation in EEG oscillatory dynamics during sentence level language comprehension that is compatible with the notion of a frequency-based segregation of syntactic and semantic unification. PMID- 26042499 TI - A Model of Emergent Category-specific Activation in the Posterior Fusiform Gyrus of Sighted and Congenitally Blind Populations. AB - Theories about the neural bases of semantic knowledge tend between two poles, one proposing that distinct brain regions are innately dedicated to different conceptual domains and the other suggesting that all concepts are encoded within a single network. Category-sensitive functional activations in the fusiform cortex of the congenitally blind have been taken to support the former view but also raise several puzzles. We use neural network models to assess a hypothesis that spans the two poles: The interesting functional activation patterns reflect the base connectivity of a domain-general semantic network. Both similarities and differences between sighted and congenitally blind groups can emerge through learning in a neural network, but only in architectures adopting real anatomical constraints. Surprisingly, the same constraints suggest a novel account of a quite different phenomenon: the dyspraxia observed in patients with semantic impairments from anterior temporal pathology. From this work, we suggest that the cortical semantic network is wired not to encode knowledge of distinct conceptual domains but to promote learning about both conceptual and affordance structure in the environment. PMID- 26042500 TI - Experience-based Auditory Predictions Modulate Brain Activity to Silence as do Real Sounds. AB - Interactions between stimuli's acoustic features and experience-based internal models of the environment enable listeners to compensate for the disruptions in auditory streams that are regularly encountered in noisy environments. However, whether auditory gaps are filled in predictively or restored a posteriori remains unclear. The current lack of positive statistical evidence that internal models can actually shape brain activity as would real sounds precludes accepting predictive accounts of filling-in phenomenon. We investigated the neurophysiological effects of internal models by testing whether single-trial electrophysiological responses to omitted sounds in a rule-based sequence of tones with varying pitch could be decoded from the responses to real sounds and by analyzing the ERPs to the omissions with data-driven electrical neuroimaging methods. The decoding of the brain responses to different expected, but omitted, tones in both passive and active listening conditions was above chance based on the responses to the real sound in active listening conditions. Topographic ERP analyses and electrical source estimations revealed that, in the absence of any stimulation, experience-based internal models elicit an electrophysiological activity different from noise and that the temporal dynamics of this activity depend on attention. We further found that the expected change in pitch direction of omitted tones modulated the activity of left posterior temporal areas 140-200 msec after the onset of omissions. Collectively, our results indicate that, even in the absence of any stimulation, internal models modulate brain activity as do real sounds, indicating that auditory filling in can be accounted for by predictive activity. PMID- 26042502 TI - Early and Late Electrophysiological Effects of Distractor Frequency in Picture Naming: Reconciling Input and Output Accounts. AB - The "distractor-frequency effect" refers to the finding that high-frequency (HF) distractor words slow picture naming less than low-frequency distractors in the picture-word interference paradigm. Rival input and output accounts of this effect have been proposed. The former attributes the effect to attentional selection mechanisms operating during distractor recognition, whereas the latter attributes it to monitoring/decision mechanisms operating on distractor and target responses in an articulatory buffer. Using high-density (128-channel) EEG, we tested hypotheses from these rival accounts. In addition to conducting stimulus- and response-locked whole-brain corrected analyses, we investigated the correct-related negativity, an ERP observed on correct trials at fronto-central electrodes proposed to reflect the involvement of domain general monitoring. The whole-brain ERP analysis revealed a significant effect of distractor frequency at inferior right frontal and temporal sites between 100 and 300-msec post-stimulus onset, during which lexical access is thought to occur. Response-locked, region of interest (ROI) analyses of fronto-central electrodes revealed a correct related negativity starting 121 msec before and peaking 125 msec after vocal onset on the grand averages. Slope analysis of this component revealed a significant difference between HF and low-frequency distractor words, with the former associated with a steeper slope on the time window spanning from 100 msec before to 100 msec after vocal onset. The finding of ERP effects in time windows and components corresponding to both lexical processing and monitoring suggests the distractor frequency effect is most likely associated with more than one physiological mechanism. PMID- 26042501 TI - Medial Prefrontal Cortex: Adding Value to Imagined Scenarios. AB - The medial prefrontal cortex (mPFC) is consistently implicated in the network supporting autobiographical memory. Whereas more posterior regions in this network have been related to specific processes, such as the generation of visuospatial imagery or the association of items and contexts, the functional contribution of the mPFC remains unclear. However, the involvement of mPFC in estimation of value during decision-making suggests that it might play a similar role in memory. We investigated whether mPFC activity reflects the subjective value of elements in imagined scenarios. Participants in an MRI scanner imagined scenarios comprising a spatial context, a physiological state of need (e.g., thirst), and two items that could be congruent (e.g., drink) or incongruent (e.g., food) with the state of need. Memory for the scenarios was tested outside the scanner. Our manipulation of subjective value by imagined need was verified by increased subjective ratings of value for congruent items and improved subsequent memory for them. Consistent with our hypothesis, fMRI signal in mPFC reflected the modulation of an item's subjective value by the imagined physiological state, suggesting the mPFC selectively tracked subjective value within our imagination paradigm. Further analyses showed uncorrected effects in non-mPFC regions, including increased activity in the insula when imagining states of need, the caudate nucleus when imagining congruent items, and the anterior hippocampus/amygdala when imagining subsequently remembered items. We therefore provide evidence that the mPFC plays a role in constructing the subjective value of the components of imagined scenarios and thus potentially in reconstructing the value of components of autobiographical recollection. PMID- 26042503 TI - Choosing to Stop: Responses Evoked by Externally Triggered and Internally Generated Inhibition Identify a Neural Mechanism of Will. AB - Inhibiting inappropriate action is key to human behavioral control. Studies of action inhibition largely investigated external stop signals, yet these are rare in everyday life. Instead healthy adults exert "self-control," implying an ability to decide internally to stop actions. We added "choose for yourself" stimuli to a conventional go/no-go task to compare reactive versus intentional action and inhibition. No-go reactions showed the N2 EEG potential characteristic of inhibiting prepotent motor responses, whereas go reactions did not. Interestingly, the N2 component was present for intentional choices both to act and also to inhibit. Thus, free choices involved a first step of intentionally inhibiting prepotent responses before generating or withholding an action. Intentional inhibition has a crucial role breaking the flow of stimulus-driven responding, allowing expression of volitional decisions. Even decisions to initiate self-generated actions require this prior negative form of volition, ensuring the "freedom from immediacy" characteristic of human behavior. PMID- 26042504 TI - Transferability of Training Benefits Differs across Neural Events: Evidence from ERPs. AB - Humans can show striking capacity limitations in sensorimotor processing. Fortunately, these limitations can be attenuated with training. However, less fortunately, training benefits often remain limited to trained tasks. Recent behavioral observations suggest that the extent to which training transfers may depend on the specific stage of information processing that is being executed. Training benefits for a task that taps the consolidation of sensory information (sensory encoding) transfer to new stimulus-response mappings, whereas benefits for selecting an appropriate action (decision-making/response selection) remain specific to the trained mappings. Therefore, training may have dissociable influences on the neural events underlying subsequent sensorimotor processing stages. Here, we used EEG to investigate this possibility. In a pretraining baseline session, participants completed two four-alternative-choice response time tasks, presented both as a single task and as part of a dual task (with another task). The training group completed a further 3,000 training trials on one of the four-alternative-choice tasks. Hence, one task became trained, whereas the other remained untrained. At test, a negative-going component that is sensitive to sensory-encoding demands (N2) showed increased amplitudes and reduced latencies for trained and untrained mappings relative to a no-train control group. In contrast, the onset of the stimulus-locked lateralized readiness potential, a component that reflects the activation of motor plans, was reduced only for tasks that employed trained stimulus-response mappings, relative to untrained stimulus-response mappings and controls. Collectively, these results show that training benefits are dissociable for the brain events that reflect distinct sensorimotor processing stages. PMID- 26042505 TI - Visual Causality Judgments Correlate with the Phase of Alpha Oscillations. AB - The detection of causality is essential for our understanding of whether distinct events relate. A central requirement for the sensation of causality is temporal contiguity: As the interval between events increases, causality ratings decrease; for intervals longer than approximately 100 msec, the events start to appear independent. It has been suggested that this effect might be due to perception relying on discrete processing. According to this view, two events may be judged as sequential or simultaneous depending on their temporal relationship within a discrete neuronal process. To assess if alpha oscillations underlie this discrete neuronal process, we investigated how these oscillations modulate the judgment of causality. We used the classic launching effect with concurrent recording of EEG signal. In each trial, a disk moved horizontally toward a second disk at the center of the screen and stopped when they touched each other. After a delay that varied between 0 and 400 msec after contact, the right disk began to move. Participants were instructed to judge whether or not they had a feeling that the first disk caused the movement of the second disk. We found that frontocentral alpha phase significantly biased causality estimates. Moreover, we found that alpha phase was concentrated around different angles for trials in which participants judged events as causally related versus not causally related. We conclude that alpha phase plays a key role in biasing causality judgments. PMID- 26042506 TI - Prostate cancer stroma: an important factor in cancer growth and progression. AB - Reactive stromal changes that occur in different human cancers might play a role in local tumor spreading and progression. Studies done on various human cancers have shown activated stromal cell phenotypes, modified extracellular matrix (ECM) composition, and increased microvessel density. Furthermore, they exhibit biological markers consistent with stroma at the site of wound repair. In prostate cancer, stroma is composed of fibroblasts, myofibroblasts, endothelial cells and immune cells. Predominant cells in the tumorous stroma are, however, fibroblasts/ myofibroblasts. They are responsible for the synthesis, deposition and remodeling of the ECM. Epithelial tumorous cells, in interaction with stromal cells and with the help of various molecules of ECM, create a microenvironment suitable for cancer cell proliferation, movement, and differentiation. In this review, we discussed the role of different stromal components in prostate cancer as well as their potential prognostic and therapeutic significance. PMID- 26042507 TI - Anticoagulant activity of some Artemisia dracunculus leaf extracts. AB - Platelet hyperactivity and platelet interaction with endothelial cells contribute to the development and progression of many cardiovascular diseases such as atherosclerosis and thrombosis. The impact of platelet activity with different pharmacological agents, such as acetylsalicylic acid and coumarin derivatives, has been shown to be effective in the prevention of cardiovascular disease. Artemisia dracunculus, L. Asteraceae (Tarragon) is used for centuries in the daily diet in many Middle Eastern countries, and it is well known for its anticoagulant activity. The present study investigates the presence of coumarins in tarragon leaves and subsequently determines the extract with a major amount of coumarin derivatives. The solvents of different polarities and different pH values were used for the purpose of purifying the primary extract in order to obtain fractions with the highest coumarin content. Those extracts and fractions were investigated for their anticoagulant activity by determining prothrombin time (PT) and the international normalized ratio (INR), expressed in relation to the coagulation time of the healthy person. Purified extracts and fractions obtained from plant residue after essential oil distillation, concentrated in coumarin derivatives, showed the best anticoagulant activity, using samples of human blood. INR maximum value (2.34) and consequently the best anticoagulant activity showed the methanol extract at concentration of 5%. The INR value of normal plasma in testing this extract was 1.05. PMID- 26042508 TI - Immunization with 3-oxododecanoyl-L-homoserine lactone-r-PcrV conjugate enhances survival of mice against lethal burn infections caused by Pseudomonas aeruginosa. AB - Quorum Sensing and type III secretion system play an important role in the virulence of Pseudomonas (P.) aeruginosa in burn wound infections. We aimed to explore the feasibility of using 3-oxo-C12-HSL-r-PcrV conjugate as a candidate vaccine against P. aeruginosa caused infections. 3-oxo-C12-HSL-r-PcrV conjugate was prepared and used for immunization of mice (10 MUg, subcutaneous, three times, at 2-week intervals). Mice were divided into five groups: I: PcrV; II: 3 oxo-C12-HSL-r-PcrV (10 MUg); III: 3-oxo-C12-HSL-r-PcrV (20 MUg); IV: 3-oxo-C12 HSL; and V: PBS receiving groups. After each shot of immunization, total and isotype antibody responses against corresponding antigen were measured to determine the immunization efficacy. One month after the last immunization, all groups were burned and challenged subeschar with P. aeruginosa PAO1. Survival rate and bacterial quantity in the skin and internal organs (liver and spleen) were evaluated 25-hr after burn infection. Immunization with 3-oxo-C12-HSL-r-PcrV significantly increased total IgG and specific subclass antibodies (IgG1, IgG2a, IgG2b, and IgM) in the serum of the groups II and III compared to the control group (p<0.001). While all the control mice (PBS injected group) died within 2 days after bacterial challenge, 64% of the group I, 78% of group II, and 86% of group III, survived within 14 days after challenge. Interestingly, bacterial burden in the liver and spleen of 3-oxo-C12-HSL-r-PcrV injected group (III) was significantly lower than the control group (p<0.001). The present study proposed two-component vaccine to inhibit Pseudomonas infections in burned mouse. PMID- 26042509 TI - Wound-healing potential of the fruit extract of Phaleria macrocarpa. AB - The wound-healing potential of Phaleria macrocarpa was evaluated by monitoring the levels of inflammatory mediators, collagen, and antioxidant enzymes. Experimentally, two-centimeter-wide full-thickness-deep skin excision wounds were created on the posterior neck area of the rats. The wounds were topically treated with gum acacia as a vehicle in the control group, intrasite gel in the reference group, and 100 and 200 mg/mL P. macrocarpa fruit extract in the treatment group. Granulation tissues were excised on the 15th day and were further processed for histological and biochemical analyzes. Wound healing was evaluated by measuring the contractions and protein contents of the wounds. Cellular redistribution and collagen deposition were assessed morphologically using Masson's trichrome stain. Superoxide dismutase (SOD) and catalase (CAT) activities, along with malondialdehyde (MDA) level were determined in skin tissue homogenates of the dermal wounds. Serum levels of transforming growth factor beta 1 (TGF-beta1) and tumor necrosis factor alpha (TNF-alpha) were evaluated in all the animals. A significant decrease in wound area was caused by a significant increase in TGF beta1 level in the treated groups. Decrease in TNF-alpha level and increase in the collagen formation were also observed in the treated groups. Topical treatment with P. macrocarpa fruit extract increased the SOD and CAT activities in the healing wounds, thereby significantly increasing MDA level. The topical treatment with P. macrocarpa fruit extract showed significant healing effect on excision wounds and demonstrated an important role in the inflammation process by increasing antioxidant enzyme activities, thereby accelerating the wound healing process and reducing tissue injury. PMID- 26042510 TI - Association between Opioid Receptor mu 1 (OPRM1) Gene Polymorphisms and Tobacco and Alcohol Consumption in a Spanish Population. AB - Evidence gained from animals and humans suggests that the encephalic opioid system might be involved in the development of drug addiction through its role in reward. Our aim is to assess the influence of genetic variations in the opioid receptor mu 1 on alcohol and tobacco consumption in a Spanish population. 763 unrelated individuals (465 women, 298 men) aged 18-85 years were recruited between October 2011 and April 2012. Participants were requested to answer a 35 item questionnaire on tobacco and alcohol consumption, as well as to complete the AUDIT and Fagerstrom tests. Individuals were genotyped for three polymorphisms in the opioid receptor mu 1 (OPRM1) gene, using a TaqMan protocol. In males, the rs10485057 polymorphism was associated with total pure ethanol intake and with the risk of being an alcohol consumer. Also, this polymorphism was significantly associated with higher Fagerstrom scores. Rs1799971 had a different influence on adaptive and maladaptive patterns of alcohol use. Despite the limited sample size, our study might enrich current knowledge on patterns of alcohol use, because it encompasses both extreme and adaptive phenotypes, providing thus a wider perspective on this subject. PMID- 26042511 TI - Genetic polymorphisms of ADH1B, ADH1C and ALDH2 in Turkish alcoholics: lack of association with alcoholism and alcoholic cirrhosis. AB - No data exists regarding the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) gene polymorphisms in Turkish alcoholic cirrhotics. We studied the polymorphisms of ADH1B, ADH1C and ALDH2 genes in alcoholic cirrhotics and compared the results with non-cirrhotic alcoholics and healthy volunteers. Overall, 237 subjects were included for the study: 156 alcoholic patients (78 cirrhotics, 78 non-cirrhotic alcoholics) and 81 healthy volunteers. Three different single-nucleotide-polymorphism genotyping methods were used. ADH1C genotyping was performed using a polymerase chain reaction-restriction fragment length polymorphism method. The identified ADH1C genotypes were named according to the presence or absence of the enzyme restriction sites. ADH1B (Arg47Hys) genotyping was performed using the allele specific primer extension method, and ALDH2 (Glu487Lys) genotyping was performed by a multiplex polymerase chain reaction using two allele-specific primer pairs. For ADH1B, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 97.4%, 94.9% and 99.4%, respectively. For ADH1C, the frequency of allele *1 in the cirrhotics, non-cirrhotic alcoholics and healthy volunteers was 47%, 36.3% and 45%, respectively. There was no statistical difference between the groups for ADH1B and ADH1C (p>0.05). All alcoholic and non-alcoholic subjects (100%) had the allele *1 for ALDH2. The obtained results for ADH1B, ADH1C, and ALDH gene polymorphisms in the present study are similar to the results of Caucasian studies. ADH1B and ADH1C genetic variations are not related to the development of alcoholism or susceptibility to alcoholic cirrhosis. ALDH2 gene has no genetic variation in the Turkish population. PMID- 26042512 TI - Dystrophin hydrophobic regions in the pathogenesis of Duchenne and Becker muscular dystrophies. AB - The aim of our study was to determine the role of dystrophin hydrophobic regions in the pathogenesis of Duchenne (DMD) and Becker (BMD) muscular dystrophies, by the Kyte-Doolittle scale mean hydrophobicity profile and 3D molecular models. A total of 1038 cases diagnosed with DMD or BMD with the in-frame mutation were collected in our hospital and the Leiden DMD information database in the period 2002-2013. Correlation between clinical types and genotypes were determined on the basis of these two sources. In addition, the Kyte-Doolittle scale mean hydrophobicity of dystrophin was analyzed using BioEdit software and the models of the hydrophobic domains of dystrophin were constructed. The presence of four hydrophobic regions is confirmed. They include the calponin homology CH2 domain on the actin-binding domain (ABD), spectrin-type repeat 16, hinge III and the EF Hand domain. The severe symptoms of DMD usually develop as a result of the mutational disruption in the hydrophobic regions I, II and IV of dystrophin - those that bind associated proteins of the dystrophin-glycoprotein complex (DGC). On the other hand, when the hydrophobic region III is deleted, the connection of the ordered repeat domains of the central rod domain remains intact, resulting in the less severe clinical presentation. We conclude that mutational changes in the structure of hydrophobic regions of dystrophin play an important role in the pathogenesis of DMD. PMID- 26042513 TI - The role of lipid dysregulation and vascular risk factors in glaucomatous retrobulbar circulation. AB - The aim of this study was to evaluate selected lipid-related and vascular factors and their effect on retrobulbar hemodynamics in glaucoma. Fifty-six patients with primary open angle glaucoma (POAG) [POAG group; mean age 68.32 years (SD+/-0.21)] and 54 patients in control group [CG, mean age 68.1 years (SD+/-5.34)] were examined. Peak systolic velocity, end-diastolic velocity, mean velocity, pulsatility index, and resistive index of the ophthalmic artery, the central retinal artery and the posterior ciliary arteries were measured by Color Doppler Imaging. Selected lipid-related, systemic and local vascular parameters were evaluated. Statistical methods included Shapiro-Wilk, Student-t and Mann-Whitney U tests, and Spearman rank correlations. In POAG group systolic arterial blood pressure, diastolic arterial blood pressure, total cholesterol, low density lipoprotein cholesterol (LDL-ch), and intraocular pressure were significantly higher; while ocular perfusion pressure, high density lipoprotein cholesterol (HDL-ch) and diastolic ocular perfusion pressure were significantly lower (p<=0.05). Color Doppler Imaging confirmed blood flow abnormalities in all investigated arteries. In addition, significant correlations of HDL-ch, LDL-ch and triglycerides (TG) with peak systolic velocity, end-diastolic velocity and mean velocity were found in individual arteries (p<=0.05). Also, significant associations of systolic arterial blood pressure, ocular perfusion pressure, systolic oclular perfusion pressure and diastolic ocular perfusion pressure with peak systolic velocity, end-diastolic velocity, mean velocity and resistive index were revealed in the posterior ciliary arteries (p<=0.05). Dysregulation of lipid related and vascular factors, as well as statistical correlation between the above and retrobulbar blood flow indices, might imply their role in vasoconstrictive processes during glaucomatous endotheliopathy. PMID- 26042514 TI - The comparison of the efficacy of radiofrequency nucleoplasty and targeted disc decompression in lumbar radiculopathy. AB - Chronic low back pain is a common clinical condition causing medical, socioeconomic, and treatment difficulties. In our study, we aimed to compare early and long-term efficacy of lumbar radiofrequency thermocoagulation (RFTC) nucleoplasty and targeted disc decompression (TDD) in patients with lumbar radiculopathy in whom previous conventional therapy had failed. The medical records of 37 patients undergoing TDD and 36 patients undergoing lumbar RFTC nucleoplasty were retrospectively examined and assigned to the Group D and Group N, respectively. In all patients Visual Analogue Scale (VAS) and Functional Rating Index (FRI) were recorded before treatment and after one, six and twelve months after the procedure. The North American Spine Society Satisfaction Scale (NASSSS) was also recoreded twelve months after the therapeutic procedure. Statistically significant postprocedural improvement in VAS and FRI was evident in both groups. VAS scores after one, six, and twelve month were slightly higher in Group N, compared to Group D. The overall procedure-related patient satisfaction ratio was 67.5% in the Group D, compared to 75% in the Group N. Regardless of the different mechanism of action, both methods are effective therapies for lumbar radiculopathy, with TDD showing long-term lower pain scores. PMID- 26042515 TI - The relationship between vitamin D status, physical activity and insulin resistance in overweight and obese subjects. AB - Type 2 diabetes mellitus (T2DM) incidence has been increasing worldwide along with the rise of obesity and sedantery lifestyle. Decreased physical activity (PA) and obesity have also been associated with the low vitamin D levels. We aimed to determine the association between PA, vitamin D status and insulin resistance in overweight and obese subjects. A total of 294 (186 female, 108 male) overweight or obese subjects were included in this cross-sectional study. 25-hydroxy vitamin D (25(OH)D), insulin, fasting plasma glucose (FPG) and HbA1c levels were measured in blood samples. Body mass index (BMI), HOMA-index and total score of International Physical Activity Questionnaire-long form (IPAQ) were calculated. Insulin resistant subjects were compared with the non-resistant group. The mean age of the participants was 45 +/- 12.25 and 41.39 +/- 10.32; 25(OH)D levels were 8.91 +/- 4.30 and 17.62 +/- 10.47 ng/dL; BMIs were 31.29 +/- 4.48 and 28.2 +/- 3.16 kg/m2, IPAQ total scores were 548.71 +/- 382.81 and 998 +/ 486.21 in the insulin resistant and nonresistant subjects, respectively. There was a statistically significant difference in terms of 25(OH)D, FPG, insulin levels, IPAQ total score and BMI between the two groups (p = 0.001, p = 0.001, p = 0.001, p = 0.001, p = 0.001).Significantly low 25(OH)D levels, high BMI and low PA in insulin resistant subjects confirm the importance of active lifestyle and the maintenance of normal vitamin D levels in overweight and obese subjects in prevention of T2DM. PMID- 26042516 TI - NOD2/CARD15 mutations in Polish and Bosnian populations with and without Crohn's disease: prevalence and genotype-phenotype analysis. AB - Data on prevalence and phenotypic consequences of nucleotide-binding oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) variants in Crohn's disease (CD) population in Poland and Bosnia and Herzegovina (B&H) are nonexistent. We aimed to determine the prevalence of NOD2/CARD15 mutations and their association with disease phenotype in Polish and Bosnian patients with CD and in healthy controls. We prospectively recruited 86 CD patients and 83 controls in Poland and 30 CD patients and 30 controls in B&H, 229 in total. We determined the prevalence of NOD2/CARD15 mutations and their association with the disease phenotype according to Montreal classification. Participants were genotyped for Leu1007fsinsC and Gly908Arg mutations. At least one CD-associated allele was found in 29/86 (33.7%) of Polish CD patients and in 9/83 (10.8%) of healthy controls (p<0.001). In both CD patients and controls in Bosnian sample, at least one NOD2 mutation was found in equal number of patients (3/30; 10%) with all of the NOD2 mutation positive CD patients being homozygous, while controls being heterozygous. In Polish sample, perianal disease was less frequent in CD patients with any NOD2 mutation (1/21; 4.8%) compared to those without (11/41; 26.8%; p=0.046). Higher percentage of patients with NOD2 mutations had history of CD related surgery when compared with those without mutations (66.7% vs. 43.3%; p=0.05). The risk for CD is increased in patients with NOD2 mutations (Poland) and especially in the presence of homozygous NOD2 mutations (Poland and Bosnia). The presence of variant NOD2 alleles is associated with increased need for surgery and reduced occurrence of perianal disease. PMID- 26042517 TI - Fractalkine receptor polymorphism may not be associated with the development and clinical course of ulcerative colitis. AB - Fractalkine (CX3C), a chemokine expressed by epithelial cells within normal and inflamed colorectal mucosa, induces leukocyte adhesion and migration via fractalkine receptor. The aim of this study was to investigate two single nucleotide polymorphisms of the fractalkine receptor gene as a risk factor both for the development and clinical findings of ulcerative colitis. In this study, 51 patients with ulcerative colitis (UC) and 80 controls were recruited. Genotypes of fractalkine receptorc.745G>A (V249I) and c.839C>T (T280M) polymorphisms were identified by restriction fragment length polymorphism analyses after polymerase chain reaction.Genotype distribution and allele frequencies of V249I and T280M were not statistically significantly different between UC and control groups (p>0.05). No statistically significant relationship was found between fractalkine receptor polymorphisms and clinical findings of UC. We observed no significant difference in fractalkine receptor polymorphism between patients and control group and no genotype-phenotype relation. Therefore, we concluded that fractalkine receptor polymorphisms may not contribute to the molecular pathogenesis of UC. PMID- 26042518 TI - Nonalcoholic Fatty Liver: The Association with Metabolic Abnormalities, Body Mass Index and Central Obesity--A Population-Based Study. AB - BACKGROUND: To assess the prevalence of nonalcoholic fatty liver (NAFL) in Iran and to evaluate correlates of NAFL in categories of body mass index (BMI). METHODS: Using a cluster random sampling approach, 7723 subjects over 18 years of age underwent abdominal ultrasonography, laboratory evaluations, blood pressure, and anthropometric measurements and were interviewed to obtain baseline characteristics. Prevalence of NAFL according to BMI and waist to hip ratio and its association with metabolic abnormalities in categories of BMI were assessed in multivariate analysis. RESULTS: The overall prevalence of NAFL was 35.2% [95% confidence interval (CI) 34.1-36.3]. A significant number of subjects with BMI < 30 had NAFL [22.1% (CI 21.0-23.2)]. Waist to hip ratio for 38.2% (CI 35.6-40.8) of the subjects with NAFL, and BMI < 30 was higher than normal values. The odds ratio for association of NAFL and dyslipidemias were higher in subjects with BMI < 30 versus those with BMI >= 30: (1) hypertriglyceridemia: 2.21 vs. 1.57, P = 0.006; (2) lower high-density lipoprotein: 1.29 versus 0.98, P = 0.046. Higher low-density lipoprotein also revealed greater association with NAFL in subjects with BMI < 25 than those with BMI >= 25 (odds ratio 1.84 vs. 1.1, P = 0.015). CONCLUSIONS: NAFL shows stronger association with central obesity compared to high BMI. NAFL has stronger association with dyslipidemias in subjects with low compared with high BMI. PMID- 26042519 TI - Hydrazine solution processed Sb2S3, Sb2Se3 and Sb2(S(1-x)Se(x))3 film: molecular precursor identification, film fabrication and band gap tuning. AB - Sb2(S(1-x)Se(x))3 (0 <= x <= 1) compounds have been proposed as promising light absorbing materials for photovoltaic device applications. However, no systematic study on the synthesis and characterization of polycrystalline Sb2(S(1-x)Se(x))3 thin films has been reported. Here, using a hydrazine based solution process, single-phase Sb2(S(1-x)Se(x))3 films were successfully obtained. Through Raman spectroscopy, we have investigated the dissolution mechanism of Sb in hydrazine: 1) the reaction between Sb and S/Se yields [Sb4S7](2-)/[Sb4Se7](2-) ions within their respective solutions; 2) in the Sb-S-Se precursor solutions, Sb, S, and Se were mixed on a molecular level, facilitating the formation of highly uniform polycrystalline Sb2(S(1-x)Se(x))3 thin films at a relatively low temperature. UV vis-NIR transmission spectroscopy revealed that the band gap of Sb2(S(1-x)Se(x))3 alloy films had a quadratical relationship with the Se concentration x and it followed the equation Eg(x) = 0.118x(2) - 0.662x + 1.621eV, where the bowing parameter was 0.118 eV. Our study provides a valuable guidance for the adjustment and optimization of the band gap in hydrazine solution processed Sb2(S(1 x)Se(x))3 alloy films for the future fabrication of improved photovoltaic devices. PMID- 26042520 TI - CdS quantum dots modified CuO inverse opal electrodes for ultrasensitive electrochemical and photoelectrochemical biosensor. AB - The CuO inverse opal photonic crystals (IOPCs) were synthesized by the sol-gel method and modified with CdS quantum dots by successive ionic layer adsorption and reaction (SILAR). CdS QDs modified CuO IOPCs FTO electrodes of different SILAR cycles were fabricated and their electrochemical properties were studied by cyclic voltammetry (CV) and chronoamperometry (I-t). Structure and morphology of the samples were characterized by transmission electron microscopy (TEM), scanning electron microscopy (SEM), high-resolution TEM (HRTEM), Energy dispersive X-ray analysis (EDX) and X-ray diffraction pattern (XRD). The result indicated that the structure of IOPCs and loading of CdS QDs could greatly improve the electrochemical properties. Three SILAR cycles of CdS QDs sensitization was the optimum condition for preparing electrodes, it exhibited a sensitivity of 4345 MUA mM(-1) cm(-2) to glucose with a 0.15 MUM detection limit (S/N= 3) and a linear range from 0.15 MUM to 0.5 mM under a working potential of +0.7 V. It also showed strong stability, good reproducibility, excellent selectivity and fast amperometric response. This work provides a promising approach for realizing excellent photoelectrochemical nonenzymatic glucose biosensor of similar composite structure. PMID- 26042521 TI - Intrinsic cardiomyopathy in Marfan syndrome: results from in-vivo and ex-vivo studies of the Fbn1C1039G/+ model and longitudinal findings in humans. AB - BACKGROUND: Mild intrinsic cardiomyopathy in patients with Marfan syndrome (MFS) has consistently been evidenced by independent research groups. So far, little is known about the long-term evolution and pathophysiology of this finding. METHODS: To gain more insights into the pathophysiology of MFS-related cardiomyopathy, we performed in-vivo and ex-vivo studies of 11 Fbn1(C1039G/+) mice and 9 wild-type (WT) littermates. Serial ultrasound findings obtained in mice were correlated to the human phenotype. We therefore reassessed left ventricular (LV) function parameters over a 6-y follow-up period in 19 previously reported MFS patients, in whom we documented mild LV dysfunction. RESULTS: Fbn1(C1039G/+) mice demonstrated LV contractile dysfunction. Subsequent ex-vivo studies of the myocardium of adult mutant mice revealed upregulation of TGFbeta-related pathways and consistent abnormalities of the microfibrillar network, implicating a role for microfibrils in the mechanical properties of the myocardium. Echocardiographic parameters did not indicate clinical significant deterioration of LV function during follow-up in our patient cohort. CONCLUSION: In analogy with what is observed in the majority of MFS patients, the Fbn1(C1039G/+) mouse model demonstrates mild intrinsic LV dysfunction. Both extracellular matrix and molecular alterations are implicated in MFS-related cardiomyopathy. This model may now enable us to study therapeutic interventions on the myocardium in MFS. PMID- 26042522 TI - Augmentation of transgene-encoded protein after neonatal injection of adeno associated virus improves hepatic copy number without immune responses. AB - BACKGROUND: Achieving persistent expression is a prerequisite for genetic therapies for inherited metabolic enzymopathies. Such disorders potentially could be treated with gene therapy shortly after birth to prevent pathology. However, rapid cell turnover leads to hepatic episomal vector loss, which diminishes effectiveness. The current studies assessed whether tolerance to transgene proteins expressed in the neonatal period is durable and if the expression may be augmented with subsequent adeno-associated virus (AAV) administration. METHODS: AAV was administered to mice on day 2 with reinjection at 14 or at 14 and 42 d with examination of changes in hepatic copies and B and T cell-mediated immune responses. RESULTS: Immune responses to the transgene protein and AAV were absent after neonatal administration. Reinjection at 14 or at 14 and 42 d resulted in augmented expression with greater hepatic genome copies. Unlike controls, immune responses to transgene proteins were not detected in animals injected as neonates and subsequently. However, while no immune response developed after neonatal administration, anticapsid immune responses developed with further injections suggesting immunological ignorance was the initial mechanism of unresponsiveness. CONCLUSIONS: Persistence of transgene protein allows for tolerance induction permitting readministration of AAV to re-establish protein levels that decline with growth. PMID- 26042523 TI - TonEBP suppresses adipogenesis and insulin sensitivity by blocking epigenetic transition of PPARgamma2. AB - TonEBP is a key transcription factor in cellular adaptation to hypertonic stress, and also in macrophage activation. Since TonEBP is involved in inflammatory diseases such as rheumatoid arthritis and atherosclerosis, we asked whether TonEBP played a role in adipogenesis and insulin resistance. Here we report that TonEBP suppresses adipogenesis and insulin signaling by inhibiting expression of the key transcription factor PPARgamma2. TonEBP binds to the PPARgamma2 promoter and blocks the epigenetic transition of the locus which is required for the activation of the promoter. When TonEBP expression is reduced, the epigenetic transition and PPARgamma2 expression are markedly increased leading to enhanced adipogenesis and insulin response while inflammation is reduced. Thus, TonEBP is an independent determinant of adipose insulin sensitivity and inflammation. TonEBP is an attractive therapeutic target for insulin resistance in lieu of PPARgamma agonists. PMID- 26042524 TI - Parenting Stress as a Mediator Between Childhood ADHD and Early Adult Female Outcomes. AB - The purpose of this study is to examine the mediating role of parenting stress (both parental distress and stress due to dysfunctional interactions in the mother-daughter relationship [PSDI]) in the link between childhood attention deficit/hyperactivity disorder (ADHD) status and several important young adult outcomes. The diverse sample comprised 140 girls with ADHD and 88 age- and ethnicity-matched comparisons, evaluated at ages 6-12 years and followed prospectively for five years (M age = 14.2) and 10 years (M age = 19.6). The PSDI experienced by a mother during her daughter's adolescence mediated the link between her daughter's childhood ADHD status and adult externalizing and internalizing symptoms. PSDI also mediated the link between ADHD status and young adult nonsuicidal self-injury and had an indirect effect in the relation between childhood ADHD and young adult depressive symptoms. The mediating role of PSDI with respect to internalizing symptoms and depressive symptoms remained in place even when covarying adolescent internalizing/depressive symptoms. Parenting stress, particularly related to maternal perceptions of dysfunctional interactions with adolescent daughters, serves as a key mediator in the association between childhood ADHD status and important domains of young adult functioning. Minimizing parenting stress and dysfunctional mother-daughter interactions during adolescence might reduce the risk of adverse adult outcomes for girls with ADHD. PMID- 26042525 TI - Whole Exome Sequencing Reveals CLCNKB Mutations in a Case of Sudden Unexpected Infant Death. PMID- 26042526 TI - A manual curation strategy to improve genome annotation: application to a set of haloarchael genomes. AB - Genome annotation errors are a persistent problem that impede research in the biosciences. A manual curation effort is described that attempts to produce high quality genome annotations for a set of haloarchaeal genomes (Halobacterium salinarum and Hbt. hubeiense, Haloferax volcanii and Hfx. mediterranei, Natronomonas pharaonis and Nmn. moolapensis, Haloquadratum walsbyi strains HBSQ001 and C23, Natrialba magadii, Haloarcula marismortui and Har. hispanica, and Halohasta litchfieldiae). Genomes are checked for missing genes, start codon misassignments, and disrupted genes. Assignments of a specific function are preferably based on experimentally characterized homologs (Gold Standard Proteins). To avoid overannotation, which is a major source of database errors, we restrict annotation to only general function assignments when support for a specific substrate assignment is insufficient. This strategy results in annotations that are resistant to the plethora of errors that compromise public databases. Annotation consistency is rigorously validated for ortholog pairs from the genomes surveyed. The annotation is regularly crosschecked against the UniProt database to further improve annotations and increase the level of standardization. Enhanced genome annotations are submitted to public databases (EMBL/GenBank, UniProt), to the benefit of the scientific community. The enhanced annotations are also publically available via HaloLex. PMID- 26042528 TI - Controllable release from high-transition temperature magnetoliposomes by low level magnetic stimulation. AB - High-transition temperature liposomes with embedded coated magnetite nanoparticles were prepared using the thin lipid film hydration method in order to obtain magnetoliposomes not sensitive to temperature increase (at least up to 50 degrees C). Accordingly, drug can be released from such magnetoliposomes using a low-level electromagnetic field as triggering agent, while no delivery would be obtained with temperature increase within the physiological acceptable range. The hypothesized release mechanism involves mechanical stress of the liposome membrane due to nanoparticles oscillations and it is investigated by means of a numerical model evaluated using multiphysics simulations. The carrier content was repetitively released by switching on and off a 20kHz, 60A/m magnetic field. The results indicated high reproducibility of cycle-to-cycle release induced by the magnetic-impelled motions driving to the destabilization of the bilayer rather than the liposome phase transition or the destruction of the liposome structure. PMID- 26042529 TI - Development of novel adenosine receptor ligands based on the 3-amidocoumarin scaffold. AB - With the aim of finding new adenosine receptor (AR) ligands presenting the 3 amidocoumarin scaffold, a study focusing on the discovery of new chemical entities was carried out. The synthesized compounds 1-8 were evaluated in radioligand binding (A1, A2A and A3) and adenylyl cyclase activity (A2B) assays in order to determine their affinity for human AR subtypes. The 3-benzamide derivative 4 showed the highest affinity of the whole series and was more than 30 fold selective for the A3 AR (Ki=3.24 MUM). The current study supported that small structural changes in this scaffold allowed modulating the affinity resulting in novel promising classes of A1, A2A, and/or A3 AR ligands. We also performed docking calculations in hA2A and hA3 to identify the hypothetical binding mode for the most active compounds. In addition, some ADME properties were calculated in order to better understand the potential of these compounds as drug candidates. PMID- 26042527 TI - The catalytic A1 domains of cholera toxin and heat-labile enterotoxin are potent DNA adjuvants that evoke mixed Th1/Th17 cellular immune responses. AB - DNA encoded adjuvants are well known for increasing the magnitude of cellular and/or humoral immune responses directed against vaccine antigens. DNA adjuvants can also tune immune responses directed against vaccine antigens to better protect against infection of the target organism. Two potent DNA adjuvants that have unique abilities to tune immune responses are the catalytic A1 domains of Cholera Toxin (CTA1) and Heat-Labile Enterotoxin (LTA1). Here, we have characterized the adjuvant activities of CTA1 and LTA1 using HIV and SIV genes as model antigens. Both of these adjuvants enhanced the magnitude of antigen specific cellular immune responses on par with those induced by the well characterized cytokine adjuvants IL-12 and GM-CSF. CTA1 and LTA1 preferentially enhanced cellular responses to the intracellular antigen SIVmac239-gag over those for the secreted HIVBaL-gp120 antigen. IL-12, GM-CSF and electroporation did the opposite suggesting differences in the mechanisms of actions of these diverse adjuvants. Combinations of CTA1 or LTA1 with IL-12 or GM-CSF generated additive and better balanced cellular responses to both of these antigens. Consistent with observations made with the holotoxin and the CTA1-DD adjuvant, CTA1 and LTA1 evoked mixed Th1/Th17 cellular immune responses. Together, these results show that CTA1 and LTA1 are potent DNA vaccine adjuvants that favor the intracellular antigen gag over the secreted antigen gp120 and evoke mixed Th1/Th17 responses against both of these antigens. The results also indicate that achieving a balanced immune response to multiple intracellular and extracellular antigens delivered via DNA vaccination may require combining adjuvants that have different and complementary mechanisms of action. PMID- 26042530 TI - Discovery of isoalloxazine derivatives as a new class of potential anti-Alzheimer agents and their synthesis. AB - This article describes discovery of a novel and new class of cholinesterase inhibitors as potential therapeutics for Alzheimer's disease. A series of novel isoalloxazine derivatives were synthesized and biologically evaluated for their potential inhibitory outcome for both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds exhibited high activity against both the enzymes AChE as well as BuChE. Of the synthesized compounds, the most potent isoalloxazine derivatives (7m and 7q) showed IC50 values of 4.72 MUM and 5.22 MUM respectively against AChE; and, 6.98 MUM and 5.29 MUM respectively against BuChE. These two compounds were further evaluated for their anti aggregatory activity for beta-amyloid (Abeta) in presence and absence of AChE by performing Thioflavin-T (ThT) assay and Congo red (CR) binding assay. In order to evaluate cytotoxic profile of these two potential compounds, cell viability assay of SH-SY5Y human neuroblastoma cells was performed. Further, to understand the binding behavior of these two compounds with AChE and BuChE enzymes, docking studies have been reported. PMID- 26042531 TI - Growth and nutritional status of children from dysfunctional families with alcohol addicted parents in Poland. AB - The study was aimed at assessment of impact of parents' alcohol addiction on growth and prevalence of underweight and overweight in their children. Two groups of subjects were compared: 80 children of alcohol addicted parents (ChAAP) aged from 7 to 14 years and reference group (RG) of 1000 children selected in terms of age and place of residence. Differences in z scores for height and Body Mass Index (BMI), prevalence of underweight and overweight were assessed. Families of ChAAP were characterized by: lower parents' education, higher unemployment rate, a greater number of children than in RG. The differences between ChAAP and RG in z scores for height (z scores: -0.54 vs. 0.45, t = -7.01, p < 0.001) and BMI (z scores: -0.61 vs. 0.29, t = -6.28, p < 0.001) remained significant when impact of the parents' employment (for height: F = 8.88, p = 0.003; for BMI: F = 21.90, p < 0.001) and the number of children (for height: F = 30.89, p < 0.001; for BMI: F = 21.89, p < 0.001) were controlled. Children raised in families with alcohol addicted parents were shorter and had lower BMI than children of the reference group. Underweight was more frequent in that group, and overweight and obesity were more rare. The observed differences seem to result from other factors than bad living conditions, e.g.: chronic post-natal stress, or adverse events during fetal development. PMID- 26042532 TI - The effect of electrolytes on the aggregation kinetics of three different ZnO nanoparticles in water. AB - Nanoscale ZnO particles are receiving increasing attention because they are widely used in commercial products, but they do have potentially hazardous effects. The aggregation behavior of ZnO nanoparticles (NPs) in the environment contributes to the real risk assessment of nano-toxicity, and the real size of the nano-aggregates should be investigated. In this study, the influences of electrolytes on the stabilities of three ZnO NPs were compared: the commercial powder (NP1), the lab synthesized suspension (NP2) and the commercial suspension (NP3). The initial particle size of NP2 and NP3 in water was at a nanoscale whilst NP1 tended to form microscale aggregates. The capping reagents helped to retain their suspension. The stability of ZnO NPs depends on their zeta potential under specific pH value, ionic types and ionic strength. In general, neutralization plays a major role in aggregation. The effect of divalent counter ions on ZnO NP aggregation was more than that of monovalent ones. The stabilities of NP2 and NP3 were confirmed by the large critical coagulation concentration (CCC) values of these particles. The experimental results also fit the Derjaguin Landau-Verwey-Overbeek (DLVO) theory. The aggregation of different ZnO NPs is relevant to their basic properties and is influenced by electrolytes, which decreases the possibility of the penetration of NPs into cells to cause toxicity in the environment. An understanding of the basic properties of NPs is crucial for assessing their fate in the environment as well as for setting up usage regulation and treatment strategy. PMID- 26042533 TI - The oxidized state of the nanocomposite Carbo-Iron(r) causes no adverse effects on growth, survival and differential gene expression in zebrafish. AB - For degradation of halogenated chemicals in groundwater Carbo-Iron(r), a composite of activated carbon and nano-sized Fe(0), was developed (Mackenzie et al., 2012). Potential effects of this nanocomposite on fish were assessed. Beyond the contaminated zone Fe(0) can be expected to have oxidized and Carbo-Iron was used in its oxidized form in ecotoxicological tests. Potential effects of Carbo Iron in zebrafish (Danio rerio) were investigated using a 48 h embryo toxicity test under static conditions, a 96 h acute test with adult fish under semi-static conditions and a 34 d fish early life stage test (FELST) in a flow-through system. Particle diameters in test suspensions were determined via dynamic light scattering (DLS) and ranged from 266 to 497 nm. Particle concentrations were measured weekly in samples from the FELST using a method based on the count rate in DLS. Additionally, uptake of particles into test organisms was investigated using microscopic methods. Furthermore, effects of Carbo-Iron on gene expression were investigated by microarray analysis in zebrafish embryos. In all tests performed, no significant lethal effects were observed. Furthermore, Carbo-Iron had no significant influence on weight and length of fish as determined in the FELST. In the embryo test and the early life stage test, growth of fungi on the chorion was observed at Carbo-Iron concentrations between 6.3 and 25mg/L. Fungal growth did not affect survival, hatching success and growth. In the embryo test, no passage of Carbo-Iron particles into the perivitelline space or the embryo was observed. In juvenile and adult fish, Carbo-Iron was detected in the gut at the end of exposure. In juvenile fish exposed to Carbo-Iron for 29 d and subsequently kept for 5d in control water, Carbo-Iron was no longer detectable in the gut. Global gene expression in zebrafish embryos was not significantly influenced by Carbo-Iron. PMID- 26042534 TI - Negative pressure wound therapy for treating surgical wounds healing by secondary intention. AB - BACKGROUND: Following surgery, incisions are usually closed by fixing the edges together with sutures (stitches), staples, adhesive glue or clips. This process helps the cut edges heal together and is called 'healing by primary intention'. However, not all incised wounds are closed in this way: where there is high risk of infection, or when there has been significant tissue loss, wounds may be left open to heal from the 'bottom up'. This delayed healing is known as 'healing by secondary intention'. Negative pressure wound therapy (NPWT) is one treatment option for surgical wounds that are healing by secondary intention. OBJECTIVES: To assess the effects of negative pressure wound therapy (NPWT) on the healing of surgical wounds healing by secondary intention (SWHSI) in any care setting. SEARCH METHODS: For this review, in May 2015 we searched the following databases: the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations; Ovid EMBASE; and EBSCO CINAHL. There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of NPWT with alternative treatments or different types of NPWT in the treatment of SWHSI. We excluded open abdominal wounds from this review as they are the subject of a separate Cochrane review that is in draft. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We located two studies (69 participants) for inclusion in this review. One study compared NPWT with an alginate dressing in the treatment of open, infected groin wounds. and one study compared NPWT with a silicone dressing in the treatment of excised pilonidal sinus. The trials reported limited outcome data on healing, adverse events and resource use. AUTHORS' CONCLUSIONS: There is currently no rigorous RCT evidence available regarding the clinical effectiveness of NPWT in the treatment of surgical wounds healing by secondary intention as defined in this review. The potential benefits and harms of using this treatment for this wound type remain largely uncertain. PMID- 26042535 TI - Amphiphilic Macromolecule Self-Assembled Monolayers Suppress Smooth Muscle Cell Proliferation. AB - A significant limitation of cardiovascular stents is restenosis, where excessive smooth muscle cell (SMC) proliferation following stent implantation causes blood vessel reocclusion. While drug-eluting stents minimize SMC proliferation through releasing cytotoxic or immunosuppressive drugs from polymer carriers, significant issues remain with delayed healing, inflammation, and hypersensitivity reactions associated with drug and polymer coatings. Amphiphilic macromolecules (AMs) comprising a sugar-based hydrophobic domain and a hydrophilic poly(ethylene glycol) tail are noncytotoxic and recently demonstrated a concentration-dependent ability to suppress SMC proliferation. In this study, we designed a series of AMs and studied their coating properties (chemical composition, thickness, grafting density, and coating uniformity) to determine the effect of headgroup chemistry on bioactive AM grafting and release properties from stainless steel substrates. One carboxyl-terminated AM (1cM) and two phosphonate- (Me-1pM and Pr-1pM) terminated AMs, with varying linker lengths preceding the hydrophobic domain, were grafted to stainless steel substrates using the tethering by aggregation and growth (T-BAG) approach. The AMs formed headgroup-dependent, yet uniform, biocompatible adlayers. Pr-1pM and 1cM demonstrated higher grafting density and an extended release from the substrate over 21 days compared to Me-1pM, which exhibited lower grafting density and complete release within 7 days. Coinciding with their release profiles, Me-1pM and 1cM coatings initially suppressed SMC proliferation in vitro, but their efficacy decreased within 7 and 14 days, respectively, while Pr-1pM coatings suppressed SMC proliferation over 21 days. Thus, AMs with phosphonate headgroups and propyl linkers are capable of sustained release from the substrate and have the ability to suppress SMC proliferation during the restenosis that occurs in the 3-4 weeks after stent implantation, demonstrating the potential for AM coatings to provide sustained delivery via desorption from coated coronary stents and other metal-based implants. PMID- 26042536 TI - Why the DNA self-depurination mechanism operates in HB-beta but not in beta globin paralogs HB-delta, HB-E1, HB-gamma1 and HB-gamma2. AB - The human beta-globin, delta-globin and E-globin genes contain almost identical coding strand sequences centered about codon 6 having potential to form a stem loop with a 5'GAGG loop. Provided with a sufficiently stable stem, such a structure can self-catalyze depurination of the loop 5'G residue, leading to a potential mutation hotspot. Previously, we showed that such a hotspot exists about codon 6 of beta-globin, with by far the highest incidence of mutations across the gene, including those responsible for 6 anemias (notably Sickle Cell Anemia) and beta-thalassemias. In contrast, we show here that despite identical loop sequences, there is no mutational hotspot in the delta- or E1-globin potential self-depurination sites, which differ by only one or two base pairs in the stem region from that of the beta-globin gene. These differences result in either one or two additional mismatches in the potential 7-base pair-forming stem region, thereby weakening its stability, so that either DNA cruciform extrusion from the duplex is rendered ineffective or the lifetime of the stem-loop becomes too short to permit self-catalysis to occur. Having that same loop sequence, paralogs HB-gamma1 and HB-gamma2 totally lack stem-forming potential. Hence the absence in delta- and E1-globin genes of a mutational hotspot in what must now be viewed as non-functional homologs of the self-depurination site in beta-globin. Such stem-destabilizing variants appeared early among vertebrates and remained conserved among mammals and primates. Thus, this study has revealed conserved sequence determinants of self-catalytic DNA depurination associated with variability of mutation incidence among human beta-globin paralogs. PMID- 26042537 TI - Plant developmental transitions: the role of microRNAs and sugars. AB - What determines the rate at which a multicellular organism ages is a mystery in biology. In plants the changes in morphological and physiological traits serve as markers for the developmental transitions. Mutant characterizations and genetic analyses in Arabidopsis thaliana delineate an evolutionarily conserved, microRNA156 (miR156)-guided timing mechanism that temporally regulates many aspects of biological processes during development. Recent studies now reveal that sugar metabolites, the products of photosynthesis, feed into this developmental timer by regulating miR156 levels, thereby ensuring that each developmental transition occurs under favorable conditions. PMID- 26042538 TI - Stress-induced structural changes in plant chromatin. AB - Stress defense in plants is elaborated at the level of protection and adaptation. Dynamic changes in sophisticated chromatin substructures and concomitant transcriptional changes play an important role in response to stress, as illustrated by the transient rearrangement of compact heterochromatin structures or the modulation of chromatin composition and modification upon stress exposure. To connect cytological, developmental, and molecular data around stress and chromatin is currently an interesting, multifaceted, and sometimes controversial field of research. This review highlights some of the most recent findings on nuclear reorganization, histone variants, histone chaperones, DNA- and histone modifications, and somatic and meiotic heritability in connection with stress. PMID- 26042539 TI - Laryngeal Swelling. PMID- 26042540 TI - The normalisation of CAPN gene expression in M. pectoralis superficialis in broiler lines differing in growth rate and their relationship to breast muscle tenderness. AB - The aim of this study was to assess mRNA abundance of calpain 1 (CAPN1) and calpain 3 (CAPN3) in breast muscle of 80 fast-growing (FG) and slow-growing broilers (SG) and relate gene expression in relation to growth and Warner Bratzler (WB) shear force of breast muscle. The expression of CAPN1 and CAPN3 genes was higher in the FG compared to the SG line, but significant results were obtained only for CAPN1. The CAPN1 mRNA level was strongly dependent on line and gender interaction. Lower values of shear force were observed in the FG line, where a higher level of calpain expression was shown. A new panel of housekeeping genes (RPL4 and SDHA) for normalisation of gene expression in muscle tissues could be used in other studies of gene expression in chicken. PMID- 26042541 TI - Chronic care coordination. AB - Chronic care management describes the services provided to patients with two or more chronic conditions that pose risks of exacerbation, clinical deterioration, or death. These services extend beyond the typical face-to-face office visit and require coordination and oversight by a physician or other qualified health-care professional to maintain and modify as necessary a comprehensive and multidisciplinary plan of care. New codes for 2015 describe chronic care management services per calendar month. While the new services acknowledge the role and importance of coordination by primary care providers, they are also appropriate for specialists who oversee the management of all of the chronic conditions of a patient and provide access, education, care coordination, communication, and health information exchange with other providers. PMID- 26042542 TI - Cellular trafficking, accumulation and DNA platination of a series of cisplatin based dicarboxylato Pt(IV) prodrugs. AB - A series of Pt(IV) anticancer prodrug candidates, having the equatorial arrangement of cisplatin and bearing two aliphatic carboxylato axial ligands, has been investigated to prove the relationship between lipophilicity, cellular accumulation, DNA platination and antiproliferative activity on the cisplatin sensitive A2780 ovarian cancer cell line. Unlike cisplatin, no facilitated influx/efflux mechanism appears to operate in the case of the Pt(IV) complexes under investigation, thus indicating that they enter by passive diffusion. While Pt(IV) complexes having lipophilicity comparable to that of cisplatin (negative values of log Po/w) exhibit a cellular accumulation similar to that of cisplatin, the most lipophilic complexes of the series show much higher cellular accumulation (stemming from enhanced passive diffusion), accompanied by greater DNA platination and cell growth inhibition. Even if the Pt(IV) complexes are removed from the culture medium in the recovery process, the level of DNA platination remains very high and persistent in time, indicating efficient storing of the complexes and poor detoxification efficiency. PMID- 26042543 TI - Non-two-state thermal denaturation of ferricytochrome c at neutral and slightly acidic pH values. AB - Thermal denaturation of ferricytochrome c (cyt c) has been methodically studied by absorbance, fluorescence, circular dichroism spectroscopy, viscosimetry and differential scanning calorimetry in pH range from pH 3.5 to 7.5. Thermal transitions have been monitored by intrinsic local probes of heme region such as absorbance at Soret, 620nm and 695nm bands and circular dichroism signals at 417nm. Global conformational changes were analyzed by circular dichroism signal at 222nm, fluorescence of the single tryptophan, reduced viscosity and differential scanning calorimetry. We show that cyt c thermal denaturation above pH ~5 can be described by an apparent two-step transition in which the heme iron stays in a low-spin state. The thermal denaturations of cyt c below pH ~5 proceed in one step to an unfolded highly compact form with a high-spin state of the heme iron. Cyt c conformational plasticity is discussed in regard to its physiological functions. PMID- 26042544 TI - Size dependence of gold nanoparticle interactions with a supported lipid bilayer: A QCM-D study. AB - Knowledge of nanoparticle (NP)-membrane interactions is important to advances in nanomedicine as well as for determining the safety of NPs to humans and the ecosystem. This study focuses on a unique mechanism of cytotoxicity, cell membrane destabilization, which is principally dependent on the nanoparticle nature of the material rather than on its molecular properties. We investigated the interactions of 2, 5, 10, and 40nm gold NPs with supported lipid bilayer (SLB) of L-alpha-phosphatidylcholine using quartz crystal microbalance with dissipation monitoring (QCM-D). Gold NPs were tested both in the absence of and in the presence of polymethacrylic acid (PMAA), used to simulate the natural organic matter (NOM) in the environment. In the absence of PMAA, for all NP sizes, we observed only small mass losses (1 to 6ng) from the membrane. This small lipid removal may be a free energy lowering mechanism to relieve stresses induced by the adsorption of NPs, with the changes too small to affect the membrane integrity. In the presence of PMAA, we observed a net mass increase in the case of smaller NPs. We suggest that the increased adhesion between the NP and the bilayer, promoted by PMAA, causes sufficient NP adsorption on the bilayer to overcompensate for any loss of lipid. The most remarkable observation is the significant mass loss (60ng) for the case of 40nm NPs. We attribute this to the lipid bilayer engulfing the NP and leaving the crystal surface. We propose a simple phenomenological model to describe the competition between the particle bilayer adhesion energy, the bilayer bending energy, and the interfacial energy at bilayer defect edges. The model shows that the larger NPs, which become more adhesive because of the polymer adsorption, are engulfed by the bilayer and leave the crystal surface, causing large mass loss and membrane disruption. The QCM-D measurements thus offer direct evidence that even if NPs are intrinsically not cytotoxic, they can become cytotoxic in the presence of environmental organic matter which modulates the adhesive interactions between the nanoparticle and the membrane. PMID- 26042545 TI - Dual-Phase Lithium Metal Anode Containing a Polysulfide-Induced Solid Electrolyte Interphase and Nanostructured Graphene Framework for Lithium-Sulfur Batteries. AB - Lithium-sulfur (Li-S) batteries, with a theoretical energy density of 2600 Wh kg( 1), are a promising platform for high-energy and cost-effective electrochemical energy storage. However, great challenges such as fast capacity degradation and safety concerns prevent it from widespread application. With the adoption of Li metal as the anode, dendritic and mossy metal depositing on the negative electrode during repeated cycles leads to serious safety concerns and low Coulombic efficiency. Herein, we report a distinctive graphene framework structure coated by an in situ formed solid electrolyte interphase (SEI) with Li depositing in the pores as the anode of Li-S batteries. The graphene-based metal anode demonstated a superior dendrite-inhibition behavior in 70 h of lithiation, while the cell with a Cu foil based metal anode was short-circuited after only 4 h of lithiation at 0.5 mA cm(-2). The graphene-modified Li anode with SEI induced by the polysulfide-containing electrolyte improved the Coulombic efficiency to ~97% for more than 100 cycles, while the control sample with Cu foil as the current collector exhibited huge fluctuations in Coulombic efficiency. The unblocked ion pathways and high electron conductivities of frameworks in the modified metal anode led to the rapid transfer of Li ions through the SEI and endowed the anode framework with an ion conductivity of 7.81 * 10(-2) mS cm(-1), nearly quintuple that of the Cu foil based Li metal anode. Besides, the polarization in the charge-discharge process was halved to 30 mV. The stable and efficient Li deposition was maintained after 2000 cycles. Our results indicated that nanoscale interfacial electrode engineering could be a promising strategy to tackle the intrinsic problems of lithium metal anodes, thus improving the safety of Li-S cells. PMID- 26042546 TI - In silico analysis and expression profiling of miRNAs targeting genes of steviol glycosides biosynthetic pathway and their relationship with steviol glycosides content in different tissues of Stevia rebaudiana. AB - miRNAs are emerging as potential regulators of the gene expression. Their proven promising role in regulating biosynthetic pathways related gene networks may hold the key to understand the genetic regulation of these pathways which may assist in selection and manipulation to get high performing plant genotypes with better secondary metabolites yields and increased biomass. miRNAs associated with genes of steviol glycosides biosynthetic pathway, however, have not been identified so far. In this study miRNAs targeting genes of steviol glycosides biosynthetic pathway were identified for the first time whose precursors were potentially generated from ESTs and nucleotide sequences of Stevia rebaudiana. Thereafter, stem-loop coupled real time PCR based expressions of these miRNAs in different tissues of Stevia rebaudiana were investigated and their relationship pattern was analysed with the expression levels of their target mRNAs as well as steviol glycoside contents. All the miRNAs investigated showed differential expressions in all the three tissues studied, viz. leaves, flowers and stems. Out of the eleven miRNAs validated, the expression levels of nine miRNAs (miR319a, miR319b, miR319c, miR319d, miR319e, miR319f, miR319h, miRstv_7, miRstv_9) were found to be inversely related, while expression levels of the two, i.e. miR319g and miRstv_11 on the contrary, showed direct relation with the expression levels of their target mRNAs and steviol glycoside contents in the leaves, flowers and stems. This study provides a platform for better understanding of the steviol glycosides biosynthetic pathway and these miRNAs can further be employed to manipulate the biosynthesis of these metabolites to enhance their contents and yield in S. rebaudiana. PMID- 26042547 TI - Analysis of Arabidopsis thaliana atfer4-1, atfh and atfer4-1/atfh mutants uncovers frataxin and ferritin contributions to leaf ionome homeostasis. AB - Ferritins are iron-storage proteins involved in the environmental and developmental control of the free iron pool within cells. Plant ferritins are targeted to mitochondria as well as to chloroplasts. AtFer4 is the Arabidopsis thaliana ferritin isoform that can be also targeted to mitochondria. Frataxin is a mitochondrial protein whose role is essential for plants; lack of AtFH frataxin causes early embryo-lethality in Arabidopsis. Because of that, the Arabidopsis atfh KO mutant is propagated in heterozygosis. For exploring the functional interaction between frataxin and ferritin, Arabidopsis double mutant atfer4 1/atfh was isolated and its physiological parameters were measured, as well as its ionome profile, together with those of both atfer4 and atfh single mutants, in different conditions of Fe supply. Impairment of both ferritin and frataxin did not lead to any effect on mitochondrial respiration. However, ionomics revealed that the content of macro- and microelements, occurring when the nutritional Fe supply changes, were altered in the mutants analysed. These results suggest that both ferritin and frataxin can contribute to the composition of the leaf ionome and also confirm ionomics as an excellent tool for detecting alterations in the plant's physiology. PMID- 26042548 TI - Triphenylphosphonium Cations of the Diterpenoid Isosteviol: Synthesis and Antimitotic Activity in a Sea Urchin Embryo Model. AB - A series of novel triphenylphosphonium (TPP) cations of the diterpenoid isosteviol (1, 16-oxo-ent-beyeran-19-oic acid) have been synthesized and evaluated in an in vivo phenotypic sea urchin embryo assay for antimitotic activity. The TPP moiety was applied as a carrier to provide selective accumulation of a connected compound into mitochondria. When applied to fertilized eggs, the targeted isosteviol TPP conjugates induced mitotic arrest with the formation of aberrant multipolar mitotic spindles, whereas both isosteviol and the methyltriphenylphosphonium cation were inactive. The structure activity relationship study revealed the essential role of the TPP group for the realization of the isosteviol effect, while the chemical structure and the length of the linker only slightly influenced the antimitotic potency. The results obtained using the sea urchin embryo model suggested that TPP conjugates of isosteviol induced mitotic spindle defects and mitotic arrest presumably by affecting mitochondrial DNA. Since targeting mitochondria is considered as an encouraging strategy for cancer therapy, TPP-isosteviol conjugates may represent promising candidates for further design as anticancer agents. PMID- 26042549 TI - Implementation science: describing implementation methods used by pediatric intensive care units in a national collaborative. AB - BACKGROUND: In 2001, the Committee on Quality in Health Care in America found it took 17 years for evidence from randomized controlled trials to be applied to practice, with little improvement over the last decade. Even abbreviated and summarized evidence fails to be consistently implemented at the bedside. More emphasis needs to be placed on understanding which Implementation Methods are most effective in successfully implementing evidence-based practice at the bedside. PURPOSE: The purpose of the study was to explore the use of 20 Implementation Methods by 57 Pediatric Intensive Care Units (PICUs) participating in the National Association of Children's Hospitals and Related Institutions (NACHRI, 2011) collaborative to eliminate central line associated blood stream infections (CLABSI) in critically ill children. METHODS: This descriptive research study was conducted using a Likert survey to determine the intensity of use of 20 Implementation Methods by PICUs. PICUs were also asked to identify any additional Implementation Methods that were used, but not included in the survey. RESULTS: Most Implementation Methods had high or very high use across the 57 PICUs. CONCLUSIONS: The 20 Implementation Methods identified as part of this study, represented the vast majority of Implementation Methods used by PICUs. PMID- 26042552 TI - Legal guardians understand how children with the human immunodeficiency virus perceive quality of life and stigma. AB - AIM: This aim of this study was to describe how legal guardians assessed health related quality of life and HIV-related stigma in children with the human immunodeficiency virus (HIV) compared to the children's own ratings. METHODS: A cross-sectional nationwide study was performed to compare how 37 children aged from eight to 16 years of age with perinatal HIV, and their legal guardians, assessed the children's health-related quality of life and HIV-related stigma. Data were collected using the 37-item DISABKIDS Chronic Generic Module and a short eight-item version of the HIV stigma scale. RESULTS: Intraclass correlations indicated concordance between the legal guardians' ratings and the children's own ratings of the child's health-related quality of life and HIV related stigma. There were no statistically significant differences between the ratings of the two groups and gender did not have any impact on the results. Both groups indicated that the children had concerns about being open about their HIV status. CONCLUSION: The results of this study indicated that legal guardians understood how their children perceived their health-related quality of life and HIV-related stigma. The results also indicated the need for interventions to support both the children and legal guardians when it came to disclosing the child's HIV status. PMID- 26042554 TI - Prevention of transient liver damage after laparoscopic gastrectomy via modification of the liver retraction technique using the Nathanson liver retractor. AB - INTRODUCTION: Although laparoscopic radical gastrectomy has several advantages over conventional surgery, postoperative liver dysfunction is an unwanted complication. The major cause is considered to be use of mechanical liver retraction. To prevent liver damage after laparoscopic gastrectomy, we modified the liver retraction method: the retractor was used only after lymph node dissection along the greater curvature had been completed, and it was released before reconstruction and intermittent repositioning to avoid discoloration of the liver parenchyma. This study sought to determine whether postoperative liver dysfunction could be prevented by making these simple modifications. METHODS: In this retrospective study involving 114 laparoscopic gastrectomy patients, postoperative serum aspartate aminotransferase, alanine aminotransferase (ALT), and total bilirubin levels were compared between laparoscopic gastrectomy patients who had undergone the modified procedure and those who had not. Discoloration of the liver was classified into three groups just before the retractor was released at the end of surgery. RESULTS: Aspartate aminotransferase and ALT levels on postoperative days 1 and 2 and the proportion of patients with elevated aspartate aminotransferase or ALT levels on postoperative day 1 were significantly lower after the modifications. ALT level on postoperative day 1 was significantly higher in the subgroup with broad liver discoloration. CONCLUSIONS: Reducing the duration of liver retraction and moving the position of the retractor or releasing it intermittently before discoloration of the liver parenchyma may be effective for preventing postoperative liver damage. PMID- 26042553 TI - Self-Assembly into Nanoparticles Is Essential for Receptor Mediated Uptake of Therapeutic Antisense Oligonucleotides. AB - Antisense oligonucleotides (ASOs) have the potential to revolutionize medicine due to their ability to manipulate gene function for therapeutic purposes. ASOs are chemically modified and/or incorporated within nanoparticles to enhance their stability and cellular uptake, however, a major challenge is the poor understanding of their uptake mechanisms, which would facilitate improved ASO designs with enhanced activity and reduced toxicity. Here, we study the uptake mechanism of three therapeutically relevant ASOs (peptide-conjugated phosphorodiamidate morpholino (PPMO), 2'Omethyl phosphorothioate (2'OMe), and phosphorothioated tricyclo DNA (tcDNA) that have been optimized to induce exon skipping in models of Duchenne muscular dystrophy (DMD). We show that PPMO and tcDNA have high propensity to spontaneously self-assemble into nanoparticles. PPMO forms micelles of defined size and their net charge (zeta potential) is dependent on the medium and concentration. In biomimetic conditions and at low concentrations, PPMO obtains net negative charge and its uptake is mediated by class A scavenger receptor subtypes (SCARAs) as shown by competitive inhibition and RNAi silencing experiments in vitro. In vivo, the activity of PPMO was significantly decreased in SCARA1 knockout mice compared to wild-type animals. Additionally, we show that SCARA1 is involved in the uptake of tcDNA and 2'OMe as shown by competitive inhibition and colocalization experiments. Surface plasmon resonance binding analysis to SCARA1 demonstrated that PPMO and tcDNA have higher binding profiles to the receptor compared to 2'OMe. These results demonstrate receptor-mediated uptake for a range of therapeutic ASO chemistries, a mechanism that is dependent on their self-assembly into nanoparticles. PMID- 26042555 TI - Protein Termini and Their Modifications Revealed by Positional Proteomics. AB - A myriad of co- and post-translational modifications occur at protein N- and C termini, resulting in an extra layer of proteome complexity and an additional source of protein regulation. Here, we review N- and C-terminal modifications and the contemporary positional proteomics techniques used to isolate protein terminal peptides from complex protein mixtures and characterize their diversity and occurrence in biological systems. Furthermore, these degradomics strategies- often referred to as N- and C-terminomics--represent dedicated high-throughput techniques to study proteolysis in dynamic living systems. Over the past decade, terminomics studies have provided indispensable information on the functional states of individual proteins, cell types, tissues, and biological processes and delivered fundamental new data for the Human Proteome Project, including high confidence identifications of many so-called "missing proteins", which had not been identified by traditional proteomics analyses. PMID- 26042556 TI - Motor and cognitive function analysis for home discharge using the Functional Independence Measure in patients undergoing cardiac rehabilitation at a long-term acute-care hospital. AB - BACKGROUND: Although numerous studies on Functional Independence Measure (FIM) analysis in stroke, orthopedic disease, and spinal cord injury patients have been conducted, it has rarely been done in patients undergoing cardiac rehabilitation (CR). AIM: To verify whether the Functional Independence Measure (FIM) score, and its subscale motor FIM and cognitive FIM, during inpatient CR can be a predictor of a patient's readiness for home discharge by establishing an FIM cutoff value. DESIGN: A retrospective, observational cohort study SETTING: This study was conducted at a long-term acute-care hospital. POPULATION: Participants were in hospital patients undergoing CR (N.=949). METHODS: Measurements included motor FIM, cognitive FIM, CR period, FIM gain per week, and discharge disposition. The strongest predictor for home discharge was analyzed by using multiple logistic regression analysis, and the cutoff value of the FIM score for home discharge was determined by using receiver operating characteristic (ROC) curves. RESULTS: Discharge to home was possible in 723 patients (76.2%), whereas 226 patients (23.8%) had other outcomes. In univariate analysis, a motor FIM gain per week of five points was achieved in the home discharge group. Multiple logistic regression analysis revealed that Body Mass Index, number of comorbidities, motor FIM at discharge, cognitive FIM gain, and CR period were predictive factors with 89.6% predictive ability. ROC curve analysis showed that the cutoff value was a discharge motor FIM score of 63/64 points with 0.912 areas under the curve. CONCLUSION: Discharge motor FIM and cognitive FIM gain were predictive factors for home discharge. A motor FIM gain per week of five points and discharge motor FIM score of 64 points at the end of inpatient CR may be important predictors of a patient's readiness for discharge to home. CLINICAL REHABILITATION IMPACT: The findings of this study indicate an alternative goal to the activities of daily living in inpatients with cardiovascular disease. PMID- 26042557 TI - Incorporation of Pendant Bases into Rh(diphosphine)2 Complexes: Synthesis, Thermodynamic Studies, And Catalytic CO2 Hydrogenation Activity of [Rh(P2N2)2](+) Complexes. AB - A series of five [Rh(P2N2)2](+) complexes (P2N2 = 1,5-diaza-3,7 diphosphacyclooctane) have been synthesized and characterized: [Rh(P(Ph)2N(Ph)2)2](+) (1), [Rh(P(Ph)2N(Bn)2)2](+) (2), [Rh(P(Ph)2N(PhOMe)2)2](+) (3), [Rh(P(Cy)2N(Ph)2)2](+) (4), and [Rh(P(Cy)2N(PhOMe)2)2](+) (5). Complexes 1-5 have been structurally characterized as square planar rhodium bis-diphosphine complexes with slight tetrahedral distortions. The corresponding hydride complexes 6-10 have also been synthesized and characterized, and X-ray diffraction studies of HRh(P(Ph)2N(Bn)2)2 (7), HRh(P(Ph)2N(PhOMe)2)2 (8) and HRh(P(Cy)2N(Ph)2)2 (9) show that the hydrides have distorted trigonal bipyramidal geometries. Equilibration of complexes 2-5 with H2 in the presence of 2,8,9 triisopropyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (Verkade's base) enabled the determination of the hydricities and estimated pKa's of the Rh(I) hydride complexes using the appropriate thermodynamic cycles. Complexes 1-5 were active for CO2 hydrogenation under mild conditions, and their relative rates were compared to that of [Rh(depe)2](+), a nonpendant-amine-containing complex with a similar hydricity to the [Rh(P2N2)2](+) complexes. It was determined that the added steric bulk of the amine groups on the P2N2 ligands hinders catalysis and that [Rh(depe)2](+) was the most active catalyst for hydrogenation of CO2 to formate. PMID- 26042558 TI - Building the connections between science, practice and policy: Griffith Edwards and the UK National Addiction Centre. PMID- 26042559 TI - Ahead of its time: 40 years after the advice versus treatment family study. AB - Griffith Edwards' proposal for the alcohol 'treatment versus advice' study--also known as 'the family study'--illustrates how ahead of his time he was. The sample consisted of 100 married men who attended with their wives for a comprehensive assessment. Those randomized to 'advice' were told that the responsibility for attaining the goal of abstinence lay in the patient's hands, supported by his wife, that no further intervention was indicated, but that the research social worker would 'keep a watching brief' by visiting the home every 4 weeks for 12 months. Across multiple outcome measures there was no evidence that 'treatment'- considerable in amount by modern standards--was better than advice. Conversely, marital variables such as wives' alcohol-related hardship were significantly predictive of the outcome of the drinking problem. The study was arguably one of the principal sources of the whole 'brief treatments'/'brief interventions' movement which gathered momentum from then on and which, arguably, has itself become the conventional wisdom. The findings questioned the very nature of the addiction change process, suggesting that non-specific factors might be the more important, an issue that still remains unresolved. It is less clear that the study has left such a mark in terms of the development of a family and social model of addiction treatment and change. For example, it continues to be a struggle to help treatment organizations to become more family-inclusive. PMID- 26042560 TI - The alcohol dependence syndrome: a legacy of continuing clinical and scientific importance. AB - This paper offers some reflections on Griffith Edwards' continuing legacy with particular reference to his and Milton Gross's formulation of alcohol dependence as a 'provisional' clinical syndrome. The ideas and language from this seminal paper have heavily influenced international diagnostic classification systems. However, it is observed that there has also been significant (and increasing) divergence-in particular around the original proposal that dependence and negative alcohol-related consequences are independent, if inevitably inter related dimensions. This is most apparent in the conflation of alcohol-related problems and dependence phenomena implicit in DSM-V. It is also argued that the alcohol dependence syndrome (ADS) has substantial continuing influence and relevance to current clinical practice. The hypothesis that degree of alcohol dependence is a useful indicator of the possibility of a return to controlled drinking continues to receive support, and underpins the widespread implementation of brief interventions for 'early stage' problem drinkers. It is suggested that the kind of careful clinical observations that underpinned the original concept of alcohol dependence have continuing relevance to the formulation of improved understanding, measurement instruments, diagnostic systems and clinical responses. PMID- 26042561 TI - Griffith Edwards' work on the life course of alcohol dependence. AB - In 1976 Edwards & Gross proposed the concept of the alcohol dependence syndrome, based on the clinical observation that heavy drinkers manifested an inter-related clustering of signs and symptoms. That this modest 'provisional description' turned out to be so significant and influential is perhaps unsurprising when the context in which it was made is appreciated. Griffith Edwards and his colleagues at the Maudsley Hospital had undergone a rigorous 3-year training in clinical psychiatry, during which they had been taught to think critically and were grounded in the art of clinical observation. As he assessed patients for various alcohol research studies he realized that there was a clustering of certain elements. Thus clinical observation and an appreciation of the patient's drinking history contributed to the genesis of the concept. This paper reflects on the integration of his rigorous training at the Maudsley, his enquiring mind and encyclopaedic knowledge of the historical and research literature which enabled him to formulate a testable hypothesis about the alcohol dependence syndrome. PMID- 26042562 TI - Griffith Edwards' rigorous sympathy with Alcoholics Anonymous. AB - Griffith Edwards made empirical contributions early in his career to the literature on Alcoholics Anonymous (AA), but the attitude he adopted towards AA and other peer-led mutual help initiatives constitutes an even more important legacy. Unlike many treatment professionals who dismissed the value of AA or were threatened by its non-professional approach, Edwards was consistently respectful of the organization. However, he never became an uncritical booster of AA or overgeneralized what could be learnt from it. Future scholarly and clinical endeavors concerning addiction-related mutual help initiatives will benefit by continuing Edwards' tradition of 'rigorous sympathy'. PMID- 26042563 TI - The development and testing of new nicotine replacement treatments: from 'nicotine replacement' to 'smoking replacement'. AB - Griffith Edwards, unusually in the 1970s, saw tobacco use as falling within the remit of addiction research, and brought Michael Russell to the Addiction Research Unit [ARU] to initiate research into smoking. The work of the tobacco section of ARU paved the way to a better understanding of tobacco dependence and to developing nicotine replacement treatments. Michael Russell pioneered the idea of attractive nicotine replacement products with an acceptable safety profile replacing cigarettes on the open market and ending the tobacco epidemic, envisaging a transition from medicinal and temporary 'nicotine replacement' to recreational and potentially permanent 'smoking replacement'. Mike's prediction that the pharmaceutical industry would develop such devices did not materialize. Instead, two such products were generated by the tobacco industry (snus) and independent developers (electronic cigarettes). Another of Mike's hopes was that regulators would adopt rational policies, and that tobacco control activists would become supportive of smoking replacement once they thought through the implications. Until now, the 'smoking replacement' idea has been met with vigorous opposition from some tobacco control activists. The voices of researchers with historical links to ARU are prominent in arguing in favour of harm reduction and e-cigarettes. The most important debate ever to occur in tobacco control is under way and it carries the signature of Griffith Edwards' ARU. PMID- 26042564 TI - History and its contribution to understanding addiction and society. AB - This paper provides a personal memoir of historical work at the Addiction Research Unit, in particular the genesis of the book Opium and the People. This topic had policy significance for US drug policy and a competing US study was funded. The development of the substance use history field is surveyed, and its expansion in recent times through a focused professional association and a critical mass of researchers in the area, covering a wide range of topics. The politics of using history in this area can be problematic. History now sits at the policy table more easily, but there is still a tendency for professionals in the field to use (and misuse) it, rather than calling on the interpretive and challenging approach they would obtain from professional historians. The paper calls for historians and others to move beyond a substance specific focus and to avoid the tendency for 'naive history' implicit in using only digitized industry archives as the sole source. PMID- 26042565 TI - Death matters: understanding heroin/opiate overdose risk and testing potential to prevent deaths. AB - AIMS: To describe work undertaken over a 20-year period, investigating overdose characteristics among survivors, effects of acute heroin administration, clustering of risk of overdose fatality and potential interventions to reduce this fatal outcome. METHODS: Privileged-access interviewers obtained data from non-treatment as well as treatment samples; experimental study of drop in oxygen saturation following heroin/opiate injection; investigation of clusterings of death following prison release and treatment termination; and study of target populations as intervention work-force, including family as well as peers, and action research built into pilot implementation. RESULTS: Overdose has been experienced by about half of heroin/opiate misusers, with even higher proportions having witnessed an overdose, and with high levels of willingness to intervene. Heroin/opiates are associated with the majority of drug-related deaths, despite relative scarcity of use. Heroin injection causes a rapid drop in oxygen saturation, recovering only slowly over the next half hour. Deaths from drug overdose are greatly more likely on prison release and post-discharge from detoxification and other in-patient or residential settings. High levels of declared willingness to intervene are matched by active interventions. Both drug using peers and family members show ability to improve knowledge and gain confidence from training. Audit study of take-home schemes finds approximately 10% of dispensed naloxone is used in real-life emergency situations. CONCLUSIONS: Overdose is experienced by most users, with heroin/opiates contributing disproportionately to drug overdose deaths. High-risk times (e.g. after prison release) are now clearly identified. Peers and family are a willing potential intervention work-force, but are rarely trained or given pre-supply of naloxone. Large-scale naloxone provision (e.g. national across Scotland and Wales) is now being delivered, while large-scale randomized trials (e.g. N-ALIVE prison-release trial) are finally under way. Better naloxone products and better-organized provision are needed. The area does not need more debate; it now needs proper implementation alongside good scientific study. PMID- 26042566 TI - Getting to grips with the cannabis problem: the evolving contributions and impact of Griffith Edwards. AB - Griffith Edwards played an important role in cannabis policy debates within government advisory committees in the United Kingdom from the early 1970s until the early 1980s. This has largely been hidden from public knowledge by the confidentiality of these committee discussions. The purpose of this paper is to use Griffith's writings and the results of recent historical scholarship to outline the views he expressed, the reasons he gave for them, and to provide a brief assessment of his contribution to the development of British cannabis policy. PMID- 26042567 TI - Linking science to policy: the role of international collaboration and problem focused integrative reviews. AB - This paper traces the modern history of alcohol and drug policy research through a series of four monographs that were written collaboratively by international groups of career scientists. The books promoted the view, supported by a considerable amount of evidence, that alcohol and drug problems can be reduced, if not prevented, through organized policy action by governments and public health organizations. The books used a problem-focused integrative approach to align research more effectively with public policy. A common thread that runs throughout the monographs is the influence of Professor Griffith Edwards. PMID- 26042568 TI - Empowerment through education and science: three intersecting strands in the career of Griffith Edwards. AB - This paper describes three important strands in the career of Griffith Edwards that define him as a leader and an innovator. Believing that education and science were critical for the development of addiction as a profession and as a field of inquiry, his approach was multi-faceted: educating all doctors to appreciate the fundamental issues in addiction; training psychiatrists in the complexity of 'dual diagnosis' and specific specialist intervention; and teaching that addiction could be a chronic condition which required care management over the life course. These three inter-related areas are directly related to the need for a range of practitioners to have an understanding of addiction so that patients can be properly managed. The greater our understanding of the nature of addiction behaviour, the more likely the potential to optimize treatment and train practitioners from different professional disciplines. PMID- 26042569 TI - The National Treatment Outcomes Research Study (NTORS) and its influence on addiction treatment policy in the United Kingdom. AB - This paper describes the political origins of the National Treatment Outcomes Research Study (NTORS) and the outputs and impacts of the study. NTORS was designed to meet the request of the Health Secretary and of a Government Task Force for evidence about the effectiveness of the national addiction treatment services. NTORS was a prospective cohort study which investigated outcomes over a 5-year period of drug users admitted to four major treatment modalities: in patient treatment, residential rehabilitation, methadone reduction and methadone maintenance programmes. The study investigated treatments delivered under day-to day operating conditions. Outcomes showed substantial reductions in illicit drug use and reduced injecting risk behaviours. These changes were accompanied by improved psychological and physical health and by reductions in criminal behaviour. However, not all outcomes were so positive. There was a continuing mortality rate in the cohort of about 1% per year, and many clients continued to drink heavily throughout the 5-year follow-up. NTORS findings informed and influenced UK addiction treatment policy both at the time and subsequently. The findings were influential in supporting an immediate increase in funding for treatment, and Government Ministers have repeatedly cited NTORS as evidence of the effectiveness of addiction treatment. One finding that received political attention was that of the cost savings provided by treatment through reductions in crime. This important finding led to an unanticipated consequence of NTORS; namely, the greater focus on crime reduction that has increasingly been promoted as a political and social priority for drug misuse treatment. PMID- 26042570 TI - Griffith Edwards, the Addiction Research Unit and research on the criminal justice system. AB - BACKGROUND: This paper reviews the early work of Griffith Edwards and his colleagues on alcohol in the criminal justice system and outlines the direction of research in this area in the Addiction Research Unit in the 1960s and 1970s. The paper outlines the link between that work and work undertaken in the more recent past in this area. METHODS: The key papers of the authors are reviewed and the impact of this work on policy and practice is discussed. CONCLUSIONS: There is a rich seam of work on deprived and incarcerated populations that has been under way at the Addiction Research Unit and subsequently the National Addiction Centre, Institute of Psychiatry, London. Griffith Edwards initiated this work that explores the risks and problems experienced by people moving between the health and criminal justice system, and demonstrated the need for better care and continuity across this system. PMID- 26042571 TI - Combining Bottom-Up Self-Assembly with Top-Down Microfabrication to Create Hierarchical Inverse Opals with High Structural Order. AB - Colloidal particles can assemble into ordered crystals, creating periodically structured materials at the nanoscale without relying on expensive equipment. The combination of small size and high order leads to strong interaction with visible light, which induces macroscopic, iridescent structural coloration. To increase the complexity and functionality, it is important to control the organization of such materials in hierarchical structures with high degrees of order spanning multiple length scales. Here, a bottom-up assembly of polystyrene particles in the presence of a silica sol-gel precursor material (tetraethylorthosilicate, TEOS), which creates crack-free inverse opal films with high positional order and uniform crystal alignment along the (110) crystal plane, is combined with top down microfabrication techniques. Micrometer scale hierarchical superstructures having a highly regular internal nanostructure with precisely controlled crystal orientation and wall profiles are produced. The ability to combine structural order at the nano- and microscale enables the fabrication of materials with complex optical properties resulting from light-matter interactions at different length scales. As an example, a hierarchical diffraction grating, which combines Bragg reflection arising from the nanoscale periodicity of the inverse opal crystal with grating diffraction resulting from a micrometer scale periodicity, is demonstrated. PMID- 26042573 TI - Reliability of digital orthodontic setups. AB - OBJECTIVE: To evaluate the reliability of digital orthodontic setup technology by comparing it with manual setups and models cast at the end of orthodontic treatment. MATERIALS AND METHODS: Initial models, manual setups, and final models of 20 patients were used. The initial and final models, as well as the manual setups, were scanned using a 3Shape R-700 scanner, while the digital setups were fabricated based on the initial models using 3Shape OrthoAnalyzer software. Evaluation of the models based on the manual setup, digital setup, and final models of each patient was performed using the following linear measurements: intercanine widths, intermolar widths, and length of the upper and lower dental arches. RESULTS: The results disclosed that none of the measures assessed through the manual setup, digital setup, and final models showed statistically significant differences (P > .05). CONCLUSIONS: Based on these findings, it can be inferred that digital setups are as effective and accurate as manual setups and constitute a tool for diagnosing and treatment planning that can be reliably reproduced in orthodontic treatments. PMID- 26042574 TI - Measuring a veteran's quality of healthcare managed by a nurse practitioner in a VA facility using professional practice evaluation and core performance measures. AB - PURPOSE: Quality of care provided by nurse practitioners (NPs) has been measured for the last 40 years; however, no known program measuring quality of care in an NP practice on an ongoing basis was found in the published literature. The purpose of this article is to describe the implementation of an ongoing professional practice evaluation (OPPE) program at a Veterans Health Administration facility. DATA SOURCES: An evidence-based review was conducted to assess, evaluate, and report findings from outcomes research, systematic reviews, and meta-analyses, and interventions regarding standards and oversight of NP practice in the following databases: PubMed, Google(r), Cumulative Index of Nursing and Allied Health, Agency for Healthcare Research and Quality, Institute of Medicine, and ".gov" websites. CONCLUSIONS: NPs have established a reputation in the delivery of efficient, accessible, effective, and high-quality care. Researchers suggest episodic measurement of care. For NPs, an OPPE program provides oversight of quality of care, surveillance, education, and feedback while evaluating and validating an NP's quality of care on an ongoing basis. IMPLICATIONS FOR PRACTICE: The OPPE program provides a prototype for measuring and improving NP practice nationally. In providing validation and transparency, it reassures administrators and the public that NP practice meets strenuous national standards. PMID- 26042575 TI - Evaluation of developmental metrics for utilization in a pediatric advanced automatic crash notification algorithm. AB - OBJECTIVE: Appropriate treatment at designated trauma centers (TCs) improves outcomes among injured children after motor vehicle crashes (MVCs). Advanced Automatic Crash Notification (AACN) has shown promise in improving triage to appropriate TCs. Pediatric-specific AACN algorithms have not yet been created. To create such an algorithm, it will be necessary to include some metric of development (age, height, or weight) as a covariate in the injury risk algorithm. This study sought to determine which marker of development should serve as a covariate in such an algorithm and to quantify injury risk at different levels of this metric. METHODS: A retrospective review of occupants age < 19 years within the MVC data set NASS-CDS 2000-2011 was performed. R(2) values of logistic regression models using age, height, or weight to predict 18 key injury types were compared to determine which metric should be used as a covariate in a pediatric AACN algorithm. Clinical judgment, literature review, and chi-square analysis were used to create groupings of the chosen metric that would discriminate injury patterns. Adjusted odds of particular injury types at the different levels of this metric were calculated from logistic regression while controlling for gender, vehicle velocity change (delta V), belted status (optimal, suboptimal, or unrestrained), and crash mode (rollover, rear, frontal, near-side, or far-side). RESULTS: NASS-CDS analysis produced 11,541 occupants age < 19 years with nonmissing data. Age, height, and weight were correlated with one another and with injury patterns. Age demonstrated the best predictive power in injury patterns and was categorized into bins of 0-4 years, 5-9 years, 10-14 years, and 15-18 years. Age was a significant predictor of all 18 injury types evaluated even when controlling for all other confounders and when controlling for age- and gender-specific body mass index (BMI) classifications. Adjusted odds of key injury types with respect to these age categorizations revealed that younger children were at increased odds of sustaining Abbreviated Injury Scale (AIS) 2+ and 3+ head injuries and AIS 3+ spinal injuries, whereas older children were at increased odds of sustaining thoracic fractures, AIS 3+ abdominal injuries, and AIS 2+ upper and lower extremity injuries. CONCLUSIONS: The injury patterns observed across developmental metrics in this study mirror those previously described among children with blunt trauma. This study identifies age as the metric best suited for use in a pediatric AACN algorithm and utilizes 12 years of data to provide quantifiable risks of particular injuries at different levels of this metric. This risk quantification will have important predictive purposes in a pediatric-specific AACN algorithm. PMID- 26042576 TI - Elimination of cost-sharing and receipt of screening for colorectal and breast cancer. AB - BACKGROUND: The aim of the cost-sharing provision of the Patient Protection and Affordable Care Act (ACA) was to reduce financial barriers for preventive services, including screening for colorectal cancer (CRC) and breast cancer (BC) among privately and Medicare-insured individuals. Whether the provision has affected CRC and BC screening prevalence is unknown. The current study investigated whether CRC and BC screening prevalence among privately and Medicare insured adults by socioeconomic status (SES) changed before and after the ACA. METHODS: Data obtained from the National Health Interview Survey pertaining to privately and Medicare-insured adults from 2008 (before the ACA) and 2013 (after the ACA) were used. There were 15,786 adults aged 50 to 75 years in the CRC screening analysis and 14,530 women aged >=40 years in the BC screening analysis. Changes in guideline-recommended screening between 2008 and 2013 by SES were expressed as the prevalence difference (PD) and 95% confidence interval (95% CI) adjusted for demographics, insurance, income, education, body mass index, and having a usual provider. RESULTS: Overall, CRC screening prevalence increased from 57.3% to 61.2% between 2008 and 2013 (P<.001). Adjusted CRC screening prevalence during the corresponding period increased in low-income (PD, 5.9; 95% CI, 1.8 to 10.2), least-educated (PD, 7.2; 95% CI, 0.9 to 13.5), and Medicare insured (PD, 6.2; 95% CI, 1.7 to 10.7) individuals, but not in high-income, most educated, and privately insured respondents. BC screening remained unchanged overall (70.5% in 2008 vs 70.2% in 2013) and in the low SES groups. CONCLUSIONS: Increases in CRC screening prevalence between 2008 and 2013 were confined to respondents with low SES. These findings may in part reflect the ACA's removal of financial barriers. PMID- 26042577 TI - Chiral N,O-Ligand/[Cu(OAc)2 ]-Catalyzed Asymmetric Construction of 4 Aminopyrrolidine Derivatives by 1,3-Dipolar Cycloaddition of Azomethine Ylides with alpha-Phthalimidoacrylates. AB - A protocol to access useful 4-aminopyrrolidine-2,4-dicarboxylate derivatives has been developed. A variety of chiral N,O-ligands derived from 2,3 dihydroimidazo[1,2-a]pyridine motifs have been evaluated in the asymmetric 1,3 dipolar cycloaddition of azomethine ylides to alpha-phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7-Cl-DHIPOH provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction. The reaction tolerates both beta-substituted and beta-unsubstituted alpha phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4 aminopyrrolidine cycloadducts with excellent diastereo- (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH4 reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized. PMID- 26042578 TI - Responses of Hyalella azteca to acute and chronic microplastic exposures. AB - Limited information is available on the presence of microplastics in freshwater systems, and even less is known about the toxicological implications of the exposure of aquatic organisms to plastic particles. The present study was conducted to evaluate the effects of microplastic ingestion on the freshwater amphipod, Hyalella azteca. Hyalella azteca was exposed to fluorescent polyethylene microplastic particles and polypropylene microplastic fibers in individual 250-mL chambers to determine 10-d mortality. In acute bioassays, polypropylene microplastic fibers were significantly more toxic than polyethylene microplastic particles; 10-d lethal concentration 50% values for polyethylene microplastic particles and polypropylene microplastic fibers were 4.64 * 10(4) microplastics/mL and 71.43 microplastics/mL, respectively. A 42-d chronic bioassay using polyethylene microplastic particles was conducted to quantify effects on reproduction, growth, and egestion. Chronic exposure to polyethylene microplastic particles significantly decreased growth and reproduction at the low and intermediate exposure concentrations. During acute exposures to polyethylene microplastic particles, the egestion times did not significantly differ from the egestion of normal food materials in the control; egestion times for polypropylene microplastic fibers were significantly slower than the egestion of food materials in the control. Amphipods exposed to polypropylene microplastic fibers also had significantly less growth. The greater toxicity of microplastic fibers than microplastic particles corresponded with longer residence times for the fibers in the gut. The difference in residence time might have affected the ability to process food, resulting in an energetic effect reflected in sublethal endpoints. PMID- 26042580 TI - Screening for endocrine disruptors - time for more science and less politics. PMID- 26042579 TI - Does time heal all wounds? A longitudinal study of the development of posttraumatic stress symptoms in parents of survivors of childhood cancer and bereaved parents. AB - BACKGROUND: A lack of longitudinal studies has hampered the understanding of the development of posttraumatic stress symptoms (PTSS) in parents of children diagnosed with cancer. This study examines level of PTSS and prevalence of posttraumatic stress disorder (PTSD) from shortly after diagnosis up to 5 years after end of treatment or child's death, in mothers and fathers. METHODS: A design with seven assessments (T1-T7) was used. T1-T3 were administered during treatment and T4-T7 after end of treatment or child's death. Parents (N = 259 at T1; n = 169 at T7) completed the PTSD Checklist Civilian Version. Latent growth curve modeling was used to analyze the development of PTSS. RESULTS: A consistent decline in PTSS occurred during the first months after diagnosis; thereafter the decline abated, and from 3 months after end of treatment only minimal decline occurred. Five years after end of treatment, 19% of mothers and 8% of fathers of survivors reported partial PTSD. Among bereaved parents, corresponding figures were 20% for mothers and 35% for fathers, 5 years after the child's death. CONCLUSIONS: From 3 months after end of treatment the level of PTSS is stable. Mothers and bereaved parents are at particular risk for PTSD. The results are the first to describe the development of PTSS in parents of children diagnosed with cancer, illustrate that end of treatment is a period of vulnerability, and that a subgroup reports PTSD 5 years after end of treatment or child's death. PMID- 26042581 TI - Validation of alternative methods for the potency testing of vaccines. PMID- 26042582 TI - The Development and Characterisation of a Structure-activity Relationship Model of the Draize Eye Irritation Test. AB - A structure-activity relationship (SAR) model based on the results of 297 chemicals tested in the Draize eye irritation assay was developed. The SAR model displayed a predictivity of 74% for chemicals not included in the model. The SAR analysis indicated that chemical reactivity was not a requirement for eye irritation. The major structural determinants included hydrophilicity, alkalinity (i.e. primary, secondary and tertiary amines), acidity (for example, the carboxylic acid moiety), and putative lipophobic 4.5-5.4A receptor-binding ligands. The analysis revealed that, while there were significant structural overlaps between the SAR models of ocular irritation, allergic contact dermatitis and respiratory hypersensitivity, there was much less overlap between ocular irritation and cell toxicity. This decreased overlap must be considered in developing strategies to replace the Draize test with in vitro cellular toxicity assays. PMID- 26042583 TI - Report on the COLIPA Workshop on Mechanisms of Eye Irritation. AB - This report summarises the discussions of a workshop sponsored by the European Cosmetics, Toiletries and Perfumery Association (COLIPA). The workshop discussed the state-of-the-art of eye irritancy testing, and made recommendations as to the best ways in which to validate alternatives to the Draize eye irritation test. The importance of understanding the mechanisms of eye irritation, particularly when attempting to improve in vitro prediction of in vivo eye irritancy, was also emphasised. PMID- 26042584 TI - In vitro models of the blood-brain barrier. AB - In this literature review on in vitro models of the blood-brain barrier (BBB), it is concluded that there is a need to identify a unified in vitro model for the BBB. The best evaluated model at present is based on the use of primary cultures of bovine brain endothelial cells. Primary cell cultures are usually shown to retain several BBB characteristics, but are time-consuming and difficult to establish. To make a unified in vitro model for the BBB more generally available, it is strongly suggested that such a model should be based on the use of an established cell line. To identify the best in vitro model, an evaluation of the most promising immortalised BBB-derived endothelial cell lines, as well as other established cell lines presently used as BBB models, is highly recommended. An evaluation of possible species variation is also important, in order to establish the most relevant species to be used. Furthermore, it is also suggested that the specific properties of in vitro BBB models, as compared to models for the "intestinal barrier", for example, should be evaluated. Finally, it is recommended that an evaluation of available computer models is performed, to further improve early predictions for drug candidates with regard to BBB permeability. PMID- 26042585 TI - Co-occurring Words: Finding Information About Alternatives to Animal Testing. AB - A collection of co-occurring words has been gathered from a small database of abstracts about alternatives to skin irritation testing by using Boolean logic. Words were selected according to a strategy based on methodology. Such words and their co-occurrences may be considered an archival code by which data that describe alternatives to skin irritation testing can be more readily recognised. As such, they can be used to enhance the efficiency with which information about this area of alternatives to animal testing is found in journal articles, databases and Web sites. PMID- 26042586 TI - Hypersensitivity reaction caused by folinic acid administration: a case report and literature review. AB - 5-Fluorouracil (5-FU) is combined with folinic acid (FA) for enhancing its cytotoxic effects in the colon cancer chemotherapy treatment. Folinic acid has rarely been involved in hypersensitivity reactions. Here, we report a case of FA hypersensitivity in an adult patient initially attributed to oxaliplatin administered concurrently. A 56-year-old male patient diagnosed with colon cancer received twelve cycles of FOLFOX4, one cycle of FOLFIRI plus cetuximab and nine cycles of FOLFOX6 uneventful. At the tenth cycle of FOLFOX6 chemotherapy, after 15 minutes of starting the infusion of oxaliplatin and FA, the patient reported flushing, pruritus and abdominal pain and erythema and oedema developed over the face and thorax. After progression, FOLFIRI plus aflibercept was scheduled and another reaction occurred. At this time, FA was discontinued and the patient received another cycle consisted on irinotecan plus 5-FU without incidences. This episode of hypersensitivity reaction following FA infusion with no oxaliplatin empirically confirmed that the hypersensitivity reaction was secondary to FA. Clinicians should be aware of hypersensitivity reaction with FA, especially when FA is administered concomitantly with oxaliplatin, despite its lower risk to cause hypersensitivity reactions. Furthermore, the similar signs and symptoms associated to the hypersensitivity reactions of each agent, highlight the importance of having a specialised allergist team for to make a prompt diagnose of the causative agent in order to prevent patient harm and proceed properly without unnecessary delays in the scheduled chemotherapy treatments. PMID- 26042587 TI - Anxiety at 13 and its effect on pain, pain-related anxiety, and pain-related disability at 17: An ALSPAC cohort longitudinal analysis. AB - The aim of the present study was to investigate the influence of anxiety at 13 years of age on the presence of chronic pain, pain-related anxiety, and pain related disability at 17 years of age in a large longitudinal cohort. We hypothesized that mother-reported anxiety at 13 would be associated with the presence of chronic pain at 17 and an increase in pain-related anxiety using all available data from the longitudinal cohort. Further, we hypothesized that anxiety at 13 would predict pain-related disability in adolescents who reported chronic pain at 17 years of age. Participants were recruited from the Avon Longitudinal Study of Parents and Children based in the UK who attended a university research clinic at 17. Child anxiety (reported by the mother) was extracted at child age 13, and self-report of the presence of chronic pain, pain related anxiety, and pain-related disability at 17. Analyses revealed that child anxiety at 13 was not significantly associated with the presence of chronic pain at 17 (n = 842). However, anxiety at 13 was significantly associated with pain related anxiety at 17 (n = 1831). For the subsample of adolescents who reported chronic pain, anxiety at 13 was associated with pain-related disability at 17 (n = 393). Further analyses revealed that pain-related anxiety at 17 mediated the association between anxiety at 13 and pain-related disability at 17, suggesting that pain-related anxiety should be a target for treatment in adolescents with chronic pain, to reduce the impact of pain in later adolescence. General anxiety at 13 was unrelated to the presence of chronic pain at 17, but should be considered a risk factor for later pain-related anxiety and disability in a subset of adolescents who develop chronic pain. PMID- 26042588 TI - Is Online Health Activity Alive and Well or Flatlining? Findings From 10 Years of the Health Information National Trends Survey. AB - The Internet increasingly enables diverse health communication activities, from information seeking to social media interaction. Up-to-date reporting is needed to document the national prevalence, trends, and user profiles of online health activities so that these technologies can be best used in health communication efforts. This study identifies prevalence, trend, and factors associated with seeking health information, e-mailing health care providers, and using social media for health purposes. Four iterations of HINTS survey data, collected in 2003, 2005, 2008, and 2012, were analyzed to assess population-level trends over the last decade, and current prevalence of Internet-based health communication activities. Sociodemographic and health correlates were explored through weighted logistic regression modeling. Findings demonstrated that Internet use has steadily increased, with 78% of U.S. adults online in 2012; however several digital divide factors--among them education, age, and race/ethnicity--still predict access. Once online, 70% of adults use the Internet as their first source for health information, and while 19% have e-mailed health care providers, engagement in health communication on social media is still relatively low. Distinct user profiles characterize each type of communication, with age, population density, and gender emerging as important predictors across online health activities. These findings have important implications for health communication research and practice. PMID- 26042590 TI - Marked preservation of the visual and olfactory pathways in ALS patients in a totally locked-in state. AB - MATERIALS AND METHODS: The present paper examines the brains and spinal cords in 7 patients with amyotrophic lateral sclerosis (ALS) receiving artificial respirator support in a totally locked-in state (TLS) neuropathologically in order to clarify whether any anatomical structures in the central nervous system are preserved. RESULTS AND CONCLUSION: We found that the visual and olfactory pathways, hypothalamus, nucleus basalis of Meynert, and commissura anterior were remarkably well preserved, whereas the somatosensory, auditory, and gustatory pathways in the brain stem and/or spinal cord showed severe deterioration. PMID- 26042589 TI - Tildrakizumab (MK-3222), an anti-interleukin-23p19 monoclonal antibody, improves psoriasis in a phase IIb randomized placebo-controlled trial. AB - BACKGROUND: Tildrakizumab is a high-affinity, humanized, IgG1/kappa, anti interleukin (IL)-23p19 monoclonal antibody that does not bind human IL-12 or p40 is being developed for the treatment of chronic plaque psoriasis. OBJECTIVES: To evaluate the safety and efficacy of subcutaneous tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis. METHODS: A three-part, randomized, double-blind, phase IIb trial was conducted in 355 adults with chronic plaque psoriasis. Participants were randomized to receive subcutaneous tildrakizumab (5, 25, 100, 200 mg) or placebo at weeks 0 and 4 (part I) and every 12 weeks thereafter until week 52 (part II). Study drug was discontinued at week 52 and participants were followed through week 72 (part III). Primary efficacy end point was Psoriasis Area and Severity Index (PASI) 75 response at week 16. Adverse events (AEs) and vital signs were monitored throughout the study. RESULTS: At week 16, PASI 75 responses were 33.3% (n = 14), 64.4% (n = 58), 66.3% (n = 59), 74.4% (n = 64) and 4.4% (n = 2) in the 5-, 25-, 100- and 200-mg tildrakizumab and placebo groups, respectively (P <= 0.001 for each tildrakizumab dose vs. placebo). PASI 75 response was generally maintained through week 52; only eight of 222 participants who achieved PASI 75 response at week 52 and continued to part III relapsed following discontinuation up to week 72. Possible drug-related serious AEs included bacterial arthritis and lymphoedema (part I), and melanoma, stroke, epiglottitis and knee infection (part II). CONCLUSIONS: Tildrakizumab had treatment effects that were superior to placebo, maintained for 52 weeks of treatment, and persisted for 20 weeks after cessation. Tildrakizumab was generally safe and well tolerated. These results suggest that IL-23p19 is a key target for suppressing psoriasis. PMID- 26042591 TI - Consequences of low dose ionizing radiation exposure on the hippocampal microenvironment. AB - The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (>= 45 Gy), few studies have been conducted at much lower doses (<= 2 Gy), where the response of the CNS (like many other tissues) may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT) animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios. PMID- 26042592 TI - What factors might have led to the emergence of Ebola in West Africa? AB - An Ebola outbreak of unprecedented scope emerged in West Africa in December 2013 and presently continues unabated in the countries of Guinea, Sierra Leone, and Liberia. Ebola is not new to Africa, and outbreaks have been confirmed as far back as 1976. The current West African Ebola outbreak is the largest ever recorded and differs dramatically from prior outbreaks in its duration, number of people affected, and geographic extent. The emergence of this deadly disease in West Africa invites many questions, foremost among these: why now, and why in West Africa? Here, we review the sociological, ecological, and environmental drivers that might have influenced the emergence of Ebola in this region of Africa and its spread throughout the region. Containment of the West African Ebola outbreak is the most pressing, immediate need. A comprehensive assessment of the drivers of Ebola emergence and sustained human-to-human transmission is also needed in order to prepare other countries for importation or emergence of this disease. Such assessment includes identification of country-level protocols and interagency policies for outbreak detection and rapid response, increased understanding of cultural and traditional risk factors within and between nations, delivery of culturally embedded public health education, and regional coordination and collaboration, particularly with governments and health ministries throughout Africa. Public health education is also urgently needed in countries outside of Africa in order to ensure that risk is properly understood and public concerns do not escalate unnecessarily. To prevent future outbreaks, coordinated, multiscale, early warning systems should be developed that make full use of these integrated assessments, partner with local communities in high-risk areas, and provide clearly defined response recommendations specific to the needs of each community. PMID- 26042593 TI - MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis. AB - BACKGROUND & AIM: MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis. METHODS: Wild type (WT) and miR-155 deficient (KO) mice were fed methionine-choline-deficient (MCD) or -supplemented (MCS) control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed. RESULTS: MCD diet resulted in steatohepatitis and increased miR-155 expression in total liver, hepatocytes and Kupffer cells. Steatosis and expression of genes involved in fatty acid metabolism were attenuated in miR-155 KO mice after MCD feeding. In contrast, miR-155 deficiency failed to attenuate inflammatory cell infiltration, nuclear factor kappa beta (NF kappaB) activation and enhanced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and monocyte chemoattractant protein-1 (MCP1) in MCD diet-fed mice. We found a significant attenuation of apoptosis (cleaved caspase-3) and reduction in collagen and alpha smooth muscle actin (alphaSMA) levels in miR-155 KO mice compared to WTs on MCD diet. In addition, we found attenuation of platelet derived growth factor (PDGF), a pro-fibrotic cytokine; SMAD family member 3 (Smad3), a protein involved in transforming growth factor-beta (TGFbeta) signal transduction and vimentin, a mesenchymal marker and indirect indicator of epithelial-to-mesenchymal transition (EMT) in miR-155 KO mice. Nuclear binding of CCAAT enhancer binding protein beta (C/EBPbeta) a miR 155 target involved in EMT was significantly increased in miR-155 KO compared to WT mice. CONCLUSIONS: Our novel data demonstrate that miR-155 deficiency can reduce steatosis and fibrosis without decreasing inflammation in steatohepatitis. PMID- 26042594 TI - Relationship of urinary phthalate metabolites with serum thyroid hormones in pregnant women and their newborns: a prospective birth cohort in Taiwan. AB - BACKGROUND: The purpose of this study was to examine the relationship of phthalates exposure with thyroid function in pregnant women and their newborns. METHODS: One hundred and forty-eight Taiwanese maternal and infant pairs were recruited from E-Da hospital in southern Taiwan between 2009 and 2010 for analysis. One-spot urine samples and blood samples in the third trimester of pregnant women and their cord blood samples at delivery were collected. Nine phthalate metabolites in urine were determined by triple quadrupole liquid chromatography tandem mass spectrometry, whereas serum from pregnant women and their cord blood were used to measure thyroid profiles (thyroid-stimulating hormone [TSH], thyroxine, free thyroxine, and triiodothyronine) by radioimmunoassay. RESULTS: Median levels of urinary mono-n-butyl phthalate, mono ethyl phthalate, and mono-(2-ethyl-5-oxohexyl) phthalate (MUg/g creatinine) were the three highest phthalate metabolites, which were 37.81, 34.51, and 21.73, respectively. Using Bonferroni correction at a significance of < 0.006, we found that urinary mono-benzyl phthalate (MBzP) levels were significantly and negatively associated with serum TSH in cord blood (beta = -2.644, p = 0.003). CONCLUSIONS: Maternal urinary MBzP, of which the parental compound is butylbenzyl phthalate, may affect TSH activity in newborns. The alteration of thyroid homeostasis by certain phthalates in the early life, a critical period for neurodevelopment, is an urgent concern. PMID- 26042595 TI - De novo Assembly, Characterization of Immature Seed Transcriptome and Development of Genic-SSR Markers in Black Gram [Vigna mungo (L.) Hepper]. AB - Black gram [V. mungo (L.) Hepper] is an important legume crop extensively grown in south and south-east Asia, where it is a major source of dietary protein for its predominantly vegetarian population. However, lack of genomic information and markers has become a limitation for genetic improvement of this crop. Here, we report the transcriptome sequencing of the immature seeds of black gram cv. TU94 2, by Illumina paired end sequencing technology to generate transcriptome sequences for gene discovery and genic-SSR marker development. A total of 17.2 million paired-end reads were generated and 48,291 transcript contigs (TCS) were assembled with an average length of 443 bp. Based on sequence similarity search, 33,766 TCS showed significant similarity to known proteins. Among these, only 29,564 TCS were annotated with gene ontology (GO) functional categories. A total number of 138 unique KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were identified, of which majority of TCS are grouped into purine metabolism (678) followed by pyrimidine metabolism (263). A total of 48,291 TCS were searched for SSRs and 1,840 SSRs were identified in 1,572 TCS with an average frequency of one SSR per 11.9 kb. The tri-nucleotide repeats were most abundant (35%) followed by di-nucleotide repeats (32%). PCR primer pairs were successfully designed for 933 SSR loci. Sequences analyses indicate that about 64.4% and 35.6% of the SSR motifs were present in the coding sequences (CDS) and untranslated regions (UTRs) respectively. Tri-nucleotide repeats (57.3%) were preferentially present in the CDS. The rate of successful amplification and polymorphism were investigated using selected primers among 18 black gram accessions. Genic-SSR markers developed from the Illumina paired end sequencing of black gram immature seed transcriptome will provide a valuable resource for genetic diversity, evolution, linkage mapping, comparative genomics and marker-assisted selection in black gram. PMID- 26042596 TI - Association of adiponectin gene polymorphism with nonalcoholic fatty liver disease in Taiwanese patients with type 2 diabetes. AB - OBJECTIVE: Patients with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD) have a higher prevalence of cardiovascular diseases. In this study we investigated the frequency of single nucleotide polymorphisms (SNPs) of several candidate genes associated with NAFLD in Taiwanese patients with type 2 diabetes mellitus (DM) and NAFLD and in those with DM but without fatty liver disease. METHODS: We enrolled 350 patients with type 2 DM and NAFLD and 209 patients with DM but without NAFLD. Body mass index (BMI), % body fat (% BF), glycated hemoglobin (HbA1c), high molecular weight (HMW) isoform of adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels were measured. Thirteen SNPs in 5 genes (adiponectin, leptin, peroxisome proliferator-activated receptor alpha, adiponutrin/patatin-like phospholipase domain-containing protein 3 and peroxisome proliferator-activated receptor gamma co-activator 1alpha ) were measured. RESULTS: Only adiponectin rs266729 polymorphism was associated with susceptibility to NAFLD (p = 0.001). Subgroup analysis revealed that the proportion of subjects with homozygous genotype GG was higher in patients with NAFLD (31%) than in controls (11%) and that the proportions of heterozygous CG and homozygous CC were higher in controls (37% and 52%, respectively) than in patients with NAFLD (33% and 36%, respectively). Patients with NAFLD carrying the GG genotype of rs266729 showed significantly lower serum HMW adiponectin levels than patients carrying the GC or CC genotype (3.75+/-0.37 vs. 3.99+/-0.66 vs. 4.79+/-0.58 MUg/ml, p< 0.001). Body fat and serum HMW adiponectin levels were the strongest predictors of developing NAFLD (p < 0.001 and 0.004, respectively). CONCLUSIONS: In patients with type 2 diabetes gene polymorphism of adiponectin rs266729 is associated with risk of NAFLD. G allele of rs266729 is associated with hypoadiponectinemia. Low serum adiponectin level may precipitate liver steatosis in patients with type 2 diabetes. PMID- 26042598 TI - A less saline Baltic Sea promotes cyanobacterial growth, hampers intracellular microcystin production, and leads to strain-specific differences in allelopathy. AB - Salinity is one of the main factors that explain the distribution of species in the Baltic Sea. Increased precipitation and consequent increase in freshwater inflow is predicted to decrease salinity in some areas of the Baltic Sea. Clearly such changes may have profound effects on the organisms living there. Here we investigate the response of the commonly occurring cyanobacterium Dolichospermum spp. to three salinities, 0, 3 and 6. For the three strains tested we recorded growth, intracellular toxicity (microcystin) and allelopathic properties. We show that Dolichospermum can grow in all the three salinities tested with highest growth rates in the lowest salinity. All strains showed allelopathic potential and it differed significantly between strains and salinities, but was highest in the intermediate salinity and lowest in freshwater. Intracellular toxin concentration was highest in salinity 6. In addition, based on monitoring data from the northern Baltic Proper and the Gulf of Finland, we show that salinity has decreased, while Dolichospermum spp. biomass has increased between 1979 and 2013. Thus, based on our experimental findings it is evident that salinity plays a large role in Dolichospermum growth, allelopathic properties and toxicity. In combination with our long-term data analyses, we conclude that decreasing salinity is likely to result in a more favourable environment for Dolichospermum spp. in some areas of the Baltic Sea. PMID- 26042597 TI - Characterization of cereulide synthetase, a toxin-producing macromolecular machine. AB - Cereulide synthetase is a two-protein nonribosomal peptide synthetase system that produces a potent emetic toxin in virulent strains of Bacillus cereus. The toxin cereulide is a depsipeptide, as it consists of alternating aminoacyl and hydroxyacyl residues. The hydroxyacyl residues are derived from keto acid substrates, which cereulide synthetase selects and stereospecifically reduces with imbedded ketoreductase domains before incorporating them into the growing depsipeptide chain. We present an in vitro biochemical characterization of cereulide synthetase. We investigate the kinetics and side chain specificity of alpha-keto acid selection, evaluate the requirement of an MbtH-like protein for adenylation domain activity, assay the effectiveness of vinylsulfonamide inhibitors on ester-adding modules, perform NADPH turnover experiments and evaluate in vitro depsipeptide biosynthesis. This work also provides biochemical insight into depsipeptide-synthesizing nonribosomal peptide synthetases responsible for other bioactive molecules such as valinomycin, antimycin and kutzneride. PMID- 26042599 TI - Adenovirus tales: from the cell surface to the nuclear pore complex. PMID- 26042600 TI - Selection for growth performance in broiler chickens associates with less diet flexibility. AB - Global competition for high standard feed-food resources between man and livestock, such as industrial broilers, is a concerning problem. In addition, the low productivity of scavenger chickens in developing countries leaves much to be desired. Changing the ingredients, and therefore, the nutrient composition of feed intake by commercial fed as well as scavenger chickens seems like an obvious solution. In this study, the ability of four broiler chicken breeds to perform on a commercial versus a scavenger diet was tested. The four broiler breeds differed genetically in growth potential. A significant (P < 0.01) negative effect of the scavenger diet on the bodyweight of the fast growing breeds was found and this effect decreased with decreasing growth rate in the other breeds. These differences in bodyweight gain could not be explained by differences in nutrient digestibility but were caused by the lack of ability of the fast growing breeds to increase their feed intake sufficiently. PMID- 26042601 TI - Giant seismites and megablock uplift in the East African Rift: evidence for Late Pleistocene large magnitude earthquakes. AB - In lieu of comprehensive instrumental seismic monitoring, short historical records, and limited fault trench investigations for many seismically active areas, the sedimentary record provides important archives of seismicity in the form of preserved horizons of soft-sediment deformation features, termed seismites. Here we report on extensive seismites in the Late Quaternary-Recent (<= ~ 28,000 years BP) alluvial and lacustrine strata of the Rukwa Rift Basin, a segment of the Western Branch of the East African Rift System. We document examples of the most highly deformed sediments in shallow, subsurface strata close to the regional capital of Mbeya, Tanzania. This includes a remarkable, clastic 'megablock complex' that preserves remobilized sediment below vertically displaced blocks of intact strata (megablocks), some in excess of 20 m-wide. Documentation of these seismites expands the database of seismogenic sedimentary structures, and attests to large magnitude, Late Pleistocene-Recent earthquakes along the Western Branch of the East African Rift System. Understanding how seismicity deforms near-surface sediments is critical for predicting and preparing for modern seismic hazards, especially along the East African Rift and other tectonically active, developing regions. PMID- 26042602 TI - Effect of Polypurine Reverse Hoogsteen Hairpins on Relevant Cancer Target Genes in Different Human Cell Lines. AB - We studied the ability of polypurine reverse Hoogsteen hairpins (PPRHs) to silence a variety of relevant cancer-related genes in several human cell lines. PPRHs are hairpins formed by two antiparallel polypurine strands bound by intramolecular Hoogsteen bonds linked by a pentathymidine loop. These hairpins are able to bind to their target DNA sequence through Watson-Crick bonds producing specific silencing of gene expression. We designed PPRHs against the following genes: BCL2, TOP1, mTOR, MDM2, and MYC and tested them for mRNA levels, cytotoxicity, and apoptosis in prostate, pancreas, colon, and breast cancer cell lines. Even though all PPRHs were effective, the most remarkable results were obtained with those against BCL2 and mammalian target of rapamycin (mTOR) in decreasing cell survival and mRNA levels and increasing apoptosis in prostate, colon, and pancreatic cancer cells. In the case of TOP1, MDM2, and MYC, their corresponding PPRHs produced a strong effect in decreasing cell viability and mRNA levels and increasing apoptosis in breast cancer cells. Thus, we confirm that the PPRH technology is broadly useful to silence the expression of cancer related genes as demonstrated using target genes involved in metabolism (DHFR), proliferation (mTOR), DNA topology (TOP1), lifespan and senescence (telomerase), apoptosis (survivin, BCL2), transcription factors (MYC), and proto-oncogenes (MDM2). PMID- 26042603 TI - Correction: Channel properties of Nax expressed in neurons. PMID- 26042604 TI - Pathway-based gene signatures predicting clinical outcome of lung adenocarcinoma. AB - Lung adenocarcinoma is often diagnosed at an advanced stage with poor prognosis. Patients with different clinical outcomes may have similar clinico-pathological characteristics. The results of previous studies for biomarkers for lung adenocarcinoma have generally been inconsistent and limited in clinical application. In this study, we used inverse-variance weighting to combine the hazard ratios for the four datasets and performed pathway analysis to identify prognosis-associated gene signatures. A total of 2,418 genes were found to be significantly associated with overall survival. Of these, a 21-gene signature in the HMGB1/RAGE signalling pathway and a 31-gene signature in the clathrin-coated vesicle cycle pathway were significantly associated with prognosis of lung adenocarcinoma across all four datasets (all p-values < 0.05, log-rank test). We combined the scores for the three pathways to derive a combined pathway-based risk (CPBR) score. Three pathway-based signatures and CPBR score also had more predictive power than single genes. Finally, the CPBR score was validated in two independent cohorts (GSE14814 and GSE13213 in the GEO database) and had significant adjusted hazard ratios 2.72 (p-value < 0.0001) and 1.71 (p-value < 0.0001), respectively. These results could provide a more complete picture of the lung cancer pathogenesis. PMID- 26042605 TI - Serum-induced keratinization processes in an immortalized human meibomian gland epithelial cell line. AB - PURPOSE: The aim of this study was to evaluate a human meibomian gland epithelial cell line (HMGEC) as a model for meibomian gland (patho)physiology in vitro. METHODS: HMGEC were cultured in the absence or presence of serum. Sudan III lipid staining, ultrastructural analysis and lipidomic analyses were performed. Impedance sensing, desmoplakin 1/2 mRNA and cytokeratin (CK) 1, 5, 6, 14 levels were evaluated. Serum containing medium supplemented with higher serum, glucose, an omega-3 lipid cocktail, eicosapentaenoic acid or sebomed medium were investigated for lipid accumulation and ultrastructural morphology. RESULTS: Lipid droplet accumulation in HMGEC was induced by serum containing media after 1 day, but decreased over time. Cultivation in serum induced desmosome and cytokeratin filament formation. Desmoplakin 1/2 gene levels were significantly upregulated after 1d of serum treatment. Furthermore, the normalized impedance increased significantly. Lipidome analysis revealed high levels of phospholipids (over 50%), but very low levels of wax ester and cholesteryl esters (under 1%). Stimulation with eicosapentaenoic acid increased lipid accumulation after one day. CONCLUSION: Serum treatment of HMGEC caused lipid droplet formation to some extent but also induced keratinization. The cells did not produce typical meibum lipids under these growth conditions. HMGEC are well suited to study (hyper)keratinization processes of meibomian gland epithelial cells in vitro. PMID- 26042606 TI - Pattern formation in multiplex networks. AB - The advances in understanding complex networks have generated increasing interest in dynamical processes occurring on them. Pattern formation in activator inhibitor systems has been studied in networks, revealing differences from the classical continuous media. Here we study pattern formation in a new framework, namely multiplex networks. These are systems where activator and inhibitor species occupy separate nodes in different layers. Species react across layers but diffuse only within their own layer of distinct network topology. This multiplicity generates heterogeneous patterns with significant differences from those observed in single-layer networks. Remarkably, diffusion-induced instability can occur even if the two species have the same mobility rates; condition which can never destabilize single-layer networks. The instability condition is revealed using perturbation theory and expressed by a combination of degrees in the different layers. Our theory demonstrates that the existence of such topology-driven instabilities is generic in multiplex networks, providing a new mechanism of pattern formation. PMID- 26042607 TI - Electrochemical nanoparticle-enzyme sensors for screening bacterial contamination in drinking water. AB - Traditional plating and culturing methods used to quantify bacteria commonly require hours to days from sampling to results. We present here a simple, sensitive and rapid electrochemical method for bacterial detection in drinking water based on gold nanoparticle-enzyme complexes. The gold nanoparticles were functionalized with positively charged quaternary amine headgroups that could bind to enzymes through electrostatic interactions, resulting in inhibition of enzymatic activity. In the presence of bacteria, the nanoparticles were released from the enzymes and preferentially bound to the bacteria, resulting in an increase in enzyme activity, releasing a redox-active phenol from the substrate. We employed this strategy for the electrochemical sensing of Escherichia coli and Staphylococcus aureus, resulting in a rapid detection (<1 h) with high sensitivity (10(2) CFU mL(-1)). PMID- 26042608 TI - Recent developments in capabilities for analysing chlorinated paraffins in environmental matrices: A review. AB - Concerns about the high production volumes, persistency, bioaccumulation potential and toxicity of chlorinated paraffin (CP) mixtures, especially short chain CPs (SCCPs), are rising. However, information on their levels and fate in the environment is still insufficient, impeding international classifications and regulations. This knowledge gap is mainly due to the difficulties that arise with CP analysis, in particular the chromatographic separation within CPs and between CPs and other compounds. No fully validated routine analytical method is available yet and only semi-quantitative analysis is possible, although the number of studies reporting new and improved methods have rapidly increased since 2010. Better cleanup procedures that remove interfering compounds, and new instrumental techniques, which distinguish between medium-chain CPs (MCCPs) and SCCPs, have been developed. While gas chromatography coupled to an electron capture negative ionisation mass spectrometry (GC/ECNI-MS) remains the most commonly applied technique, novel and promising use of high resolution time of flight MS (TOF-MS) has also been reported. We expect that recent developments in high resolution TOF-MS and Orbitrap technologies will further improve the detection of CPs, including long-chain CPs (LCCPs), and the group separation and quantification of CP homologues. Also, new CP quantification methods have emerged, including the use of mathematical algorithms, multiple linear regression and principal component analysis. These quantification advancements are also reflected in considerably improved interlaboratory agreements since 2010. Analysis of lower chlorinated paraffins (=45); olanzapine alone was weakly effective (NNT=11.3), and all but lurasidone (NNH=20.2) were not well tolerated (NNH<=4.18). Lithium appeared to be poorly effective but well tolerated in only one trial. CONCLUSIONS: Some anticonvulsants and antipsychotics seemed effective for acute bipolar depression, but most antipsychotics were not well tolerated. Antidepressants were effective and well-tolerated; lithium remains inadequately tested. LIMITATIONS: There are remarkably few short-term treatment trials (2.75/12 treatments), and fewer long-term trials for bipolar depression, possibly arising from exaggerated concerns about inducing mania. PMID- 26042635 TI - What do pathogens teach us about the immune system? PMID- 26042636 TI - Effect of cyanuric acid on the inactivation of Cryptosporidium parvum under hyperchlorination conditions. AB - Cyanuric acid (CYA) is a chlorine stabilizer used in swimming pools to limit UV degradation of chlorine, thus reducing chlorine use and cost. However, CYA has been shown to decrease the efficacy of chlorine disinfection. In the event of a diarrheal incident, CDC recommends implementing 3-log10 inactivation conditions for Cryptosporidium (CT value = 15 300 mg.min/L) to remediate pools. Currently, CYA's impact on Cryptosporidium inactivation is not fully determined. We investigated the impact of multiple concentrations of CYA on C. parvum inactivation (at 20 and 40 mg/L free chlorine; average pH 7.6; 25 degrees C). At 20 mg/L free chlorine, average estimated 3-log10 CT values were 17 800 and 31 500 mg.min/L with 8 and 16 mg/L CYA, respectively, and the average estimated 1-log10 CT value was 76 500 mg.min/L with 48 mg/L CYA. At 40 mg/L free chlorine, 3-log10 CT values were lower than those at 20 mg/L, but still higher than those of free chlorine-only controls. In the presence of ~100 mg/L CYA, average 0.8- and 1.4 log10 reductions were achieved by 72 h at 20 and 40 mg/L free chlorine, respectively. This study demonstrates CYA significantly delays chlorine inactivation of Cryptosporidium oocysts, emphasizing the need for additional pool remediation options following fecal incidents. PMID- 26042637 TI - Manganese Catalyzed C-H Halogenation. AB - The remarkable aliphatic C-H hydroxylations catalyzed by the heme-containing enzyme, cytochrome P450, have attracted sustained attention for more than four decades. The effectiveness of P450 enzymes as highly selective biocatalysts for a wide range of oxygenation reactions of complex substrates has driven chemists to develop synthetic metalloporphyrin model compounds that mimic P450 reactivity. Among various known metalloporphyrins, manganese derivatives have received considerable attention since they have been shown to be versatile and powerful mediators for alkane hydroxylation and olefin epoxidation. Mechanistic studies have shown that the key intermediates of the manganese porphyrin-catalyzed oxygenation reactions include oxo- and dioxomanganese(V) species that transfer an oxygen atom to the substrate through a hydrogen abstraction/oxygen recombination pathway known as the oxygen rebound mechanism. Application of manganese porphyrins has been largely restricted to catalysis of oxygenation reactions until recently, however, due to ultrafast oxygen transfer rates. In this Account, we discuss recently developed carbon-halogen bond formation, including fluorination reactions catalyzed by manganese porphyrins and related salen species. We found that biphasic sodium hypochlorite/manganese porphyrin systems can efficiently and selectively convert even unactivated aliphatic C-H bonds to C Cl bonds. An understanding of this novel reactivity derived from results obtained for the oxidation of the mechanistically diagnostic substrate and radical clock, norcarane. Significantly, the oxygen rebound rate in Mn-mediated hydroxylation is highly correlated with the nature of the trans-axial ligands bound to the manganese center (L-Mn(V)?O). Based on the ability of fluoride ion to decelerate the oxygen rebound step, we envisaged that a relatively long-lived substrate radical could be trapped by a Mn-F fluorine source, effecting carbon-fluorine bond formation. Indeed, this idea led to the discovery of the first Mn-catalyzed direct aliphatic C-H fluorination reactions utilizing simple, nucleophilic fluoride salts. Mechanistic studies and DFT calculations have revealed a trans difluoromanganese(IV) species as the key fluorine transfer intermediate. In addition to catalyzing normal (19)F-fluorination reactions, manganese salen complexes were found to enable the incorporation of radioactive (18)F fluorine via C-H activation. This advance represented the first direct Csp(3)-H bond (18)F labeling with no-carrier-added [(18)F]fluoride and facilitated the late-stage labeling of drug molecules for PET imaging. Given the high reactivity and enzymatic-like selectively of metalloporphyrins, we envision that this new Heteroatom-Rebound Catalysis (HRC) strategy will find widespread application in the C-H functionalization arena and serve as an effective tool for forming new carbon-heteroatom bonds at otherwise inaccessible sites in target molecules. PMID- 26042638 TI - Impact of Random Dopant Fluctuations on the Electronic Properties of In(x)Ga(1 x)N/GaN Axial Nanowire Heterostructures. AB - We study the electronic properties of axial In(x)Ga(1-x)N/GaN nanowire heterostructures with randomly placed ionized donors. Our simulations are based on an eight-band k.p model and indicate large variations of both the ground state transition energy and the spatial distribution of the electron and hole charge density. We show that these variations are intrinsic to nanostructures containing ionized donors and that the presence of donors has important consequences for all nanowire-based light-emitting devices including single-photon emitters required for quantum computing and quantum cryptography. PMID- 26042639 TI - The Cephalostatins. 24. Isolation, Structure, and Cancer Cell Growth Inhibition of Cephalostatin 20. AB - For the purpose of advancing knowledge of the structural variations available in the natural cephalostatins contained in the marine worm Cephalodiscus gilchristi, the isolation and structure of the 20th member (1) has been accomplished (10(-7) % yield). In turn cephalostatin 20 (1) proved to be enough for an initial SAR study comprising six important human cancer cell lines. A parallel objective was aimed at the possible discovery of a natural cephalostatin with a more accessible structure for total synthesis and/or synthetic modifications, but with powerful cancer cell growth inhibition. PMID- 26042640 TI - A quick rhizobacterial selection tests for the remediation of copper contaminated soils. AB - AIMS: The main objective of the study is to develop and improve quick bacterial tests to select the best candidates for the bioaugmentation of metal-contaminated soil, coupled with phytoextraction. METHODS AND RESULTS: Bacteria isolates (181) were selected from a collection originated from a Cu-contaminated sediment, on the basis of several miniaturized biochemical tests adapted to the copper contamination. Amongst them, we used a growth soil based-medium to select metal tolerant bacteria, and their ability to grow and mobilize metals by mean of metabolites (siderophores, organic acids) was also assessed. CONCLUSION: The result of the bacterial selection tests showed differences in presence or absence of copper, especially for phosphate-solubilizing strains which ability decreased by 53% in the presence of copper hydroxide phosphate as compared to the standard tricalcium phosphate test. A promising Pseudomonas putida was selected from the collection. SIGNIFICANCE AND IMPACT OF THE STUDY: The study underlined the importance of choosing significant selection tests regarding the nature of the metal occurring in the soil to be cleaned-up to assess the real potential of each bacterial strain for subsequent soil bioaugmentation purposes. PMID- 26042641 TI - Learning the ABC of oral fungal drug resistance. AB - ATP-binding cassette (ABC) proteins are ubiquitous in prokaryotes and eukaryotes. They are involved in energy-dependent transport of molecules across membranes. ABC proteins are often promiscuous transporters that can translocate a variety of substrates. In oral fungi, especially in Candida species, they have been implicated as major contributors to the high-level azole resistance of clinical isolates from infections that do not respond to drug therapy. Although this is predominantly due to efflux of azoles from the cells, ABC proteins can contribute to fungal drug resistance in other ways as well. Cells in biofilms are notoriously resistant to antifungal agents. ABC proteins can contribute to this resistance through the efflux of drugs. Biofilms are complex communities of myriad microorganisms which, to survive in such a milieu, need to communicate with, and respond to, other microorganisms and their products. ABC proteins are involved in the secretion of fungal mating factors and quorum sensing molecules. These molecules affect biofilm structure and behavior that can result in increased drug resistance. Hence, ABC proteins make multiple contributions to oral fungal drug resistance through a variety of responses to environmental signals. PMID- 26042642 TI - Association between histopathological features of dysplasia in oral leukoplakia and loss of heterozygosity. AB - AIMS: Oral leukoplakia (OL) dysplasia is graded on the basis of architectural and cytological features, and grade does not correlate well with malignant transformation. Loss of heterozygosity (LOH) profiles have been validated as risk predictors of OL malignant transformation. We aimed to assess whether the histological parameters used to grade dysplasia show different LOH profiles. METHODS AND RESULTS: Areas of epithelial dysplasia of 29 OL samples were microdissected, and LOH was assessed by use of a panel of 11 microsatellite markers located on chromosomes 3, 9, 11, and 17. Dysplasia was graded, and the cytological and architectural parameters were scored. Dysplasia was graded as mild in 18 samples, moderate in nine, and severe in two. The moderate/severe dysplasias and the mild dysplasias did not show different frequencies of allelic loss. Irregular epithelial stratification was associated with LOH at marker D3S1234 (3p14.2). In addition, the presence of drop-shaped rete ridges and premature keratinization in single cells showed associations with LOH at D9S162 (9p22) and P53 (17p13.1), respectively. CONCLUSIONS: We provide evidence that architectural and cellular changes in OL have different LOH patterns. PMID- 26042643 TI - Reference Materials: Significance, General Requirements, and Demand. AB - Reference materials play an important part in the quality control of measurements. Rapid development of such new scientific disciplines as proteomics, metabolomics, and genomics also necessitates development of new reference materials. This is a great challenge due to the complexity of the production of new reference materials and difficulties associated with achieving their homogeneity and stability. CRMs of tissue are of particular importance. They can be counted among the matrices that are most complex and time consuming in preparation. Tissue is the place of transformation and accumulation of many substances (e.g., metabolites, which are intermediate or end products resulting from metabolic processes). Trace amounts of many substances in tissues must be determined with adequate precision and accuracy. To meet the needs stemming from research and from problems and challenges faced by chemists, analysts, and toxicologists, the number of certified reference materials should be continuously increased. PMID- 26042644 TI - Nurse practitioners' role perception, stress, satisfaction, and intent to stay at a Midwestern academic medical center. AB - PURPOSE: There is a growing demand for nurse practitioners (NPs) within academic medical centers (AMCs) because of physician shortages and increased need for access to care. In order to retain these NPs, it is important to assess their role perception and satisfaction. The purpose of this study was to evaluate these concepts and their relationships to stress and intent to stay. DATA SOURCES: A 90 item descriptive survey, including a new role perception scale and the Misener Nurse Practitioner Job Satisfaction Scale, was administered to all NPs at a Midwestern AMC. CONCLUSIONS: The response rate was 62.4% (n = 181). Overall, the NPs had moderate role perception (M = 4.30, SD = 1.23) and were somewhat satisfied (M = 4.23, SD = 0.74). Over a third (39.4%) reported they were unsure about staying or did not intend to stay in their position. Intent to stay and stress were moderately correlated with overall satisfaction and weakly correlated with role perception. There were significant differences in the intrapractice and professional aspects of job satisfaction based on their supervisor. IMPLICATIONS FOR PRACTICE: With increased NP needs, it is crucial for AMCs and NP supervisors to assess role perception, satisfaction, and stress among NPs in order to ensure a stable, satisfied, and productive workforce. PMID- 26042645 TI - Serious road injuries in The Netherlands dissected. AB - OBJECTIVE: This article discusses the characteristics and injury patterns of serious road injuries (Maximum Abbreviated Injury Scale [MAIS] 2+ inpatients) in The Netherlands. METHODS: In The Netherlands, the actual number of serious injuries is estimated by linking police data to hospital data. The distribution of serious road injuries over (1) travel mode and gender and (2) crash type and age are compared for the years 2000 and 2011. Moreover, the distribution of the injuries over the body regions is illustrated using colored injury body profiles. RESULTS: The number of serious injuries is higher for men than for women and increased from 16,500 in 2000 to 19,700 in 2011. In 2011, about half (51%) of the serious road injuries were due to a bicycle crash not involving a motor vehicle. The share of casualties aged 60 years and older is relatively high (43% in 2011) in these crashes. The injury body profiles show that head injuries (31%) and injuries to the lower extremities (37%) are most prevalent. Compared to other travel modes, pedestrians and riders of powered 2-wheelers relatively often sustain lower-leg injuries compared to other travel modes. Head injuries are most prevalent in cyclists who are injured in a crash with a motorized vehicle. Cyclists who are injured in a crash not involving a motor vehicle and casualties of 60 years and older relatively often include hip or upper-leg injuries. CONCLUSION: The characteristics of serious road injuries differ from those of fatalities and the distribution of injuries over the body differs by travel mode, gender, and age. PMID- 26042646 TI - Prevalence of sexual violence against children and use of social services - seven countries, 2007-2013. AB - Sexual violence against children erodes the strong foundation that children require for leading healthy and productive lives. Globally, studies show that exposure to violence during childhood can increase vulnerability to a broad range of mental and physical health problems, ranging from depression and unwanted pregnancy to cardiovascular disease, diabetes, and sexually transmitted diseases, including human immunodeficiency virus (HIV). Despite this, in many countries, the extent of sexual violence against children is unknown; estimates are needed to stimulate prevention and response efforts and to monitor progress. Consequently, CDC, as a member of the global public-private partnership known as Together for Girls, collaborated with Cambodia, Haiti, Kenya, Malawi, Swaziland, Tanzania, and Zimbabwe to conduct national household surveys of children and youth aged 13-24 years to measure the extent of violence against children. The lifetime prevalence of experiencing any form of sexual violence in childhood ranged from 4.4% among females in Cambodia to 37.6% among females in Swaziland, with prevalence in most countries greater than 25.0%. In most countries surveyed, the proportion of victims that received services, including health and child protective services, was <=10.0%. Both prevention and response strategies for sexual violence are needed. PMID- 26042647 TI - Hepatitis B screening and prevalence among resettled refugees - United States, 2006-2011. AB - Globally, more than two billion persons have been infected at some time with the hepatitis B virus (HBV), and approximately 3.5 million refugees have chronic HBV infection. The endemicity of HBV varies by region. Because chronic hepatitis B is infectious and persons with chronic infection benefit from treatment, CDC recommends screening for HBV among all refugees who originate in countries where the prevalence of hepatitis B surface antigen (HBsAg; a marker for acute or chronic infection) is >=2% or who are at risk for HBV because of personal characteristics such as injection drug use or household contact with an individual with HBV infection. Currently, almost all refugees are routinely screened for hepatitis B. However, prevalence rates of HBV infection in refugee populations recently resettled in the United States have not been determined. A multisite, retrospective study was performed to evaluate the prevalence of past HBV infection, current infection, and immunity among refugees resettled in the United States; to better characterize the burden of hepatitis B in this population; and to inform screening recommendations. The study incorporated surveillance data from a large state refugee health program and chart reviews from three U.S. sites that conduct medical screenings of refugees. The prevalence of HBV infection (current or past as determined by available titer levels) varied among refugees originating in different countries and was higher among Burmese refugees than among refugees from Bhutan or Iraq. Current or past HBV infection was also higher among adults (aged >18 years) and male refugees. These data might help inform planning by states and resettlement agencies, as well as screening decisions by health care providers. PMID- 26042648 TI - Rapid large-scale deployment of tuberculosis testing in a high school - Riverside County, California, 2013-2014. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), can spread from person to person through the air, which can make contact investigations particularly complex in heavily populated settings such as schools. In November 2013, a student (the index patient) at a southern California high school with approximately 2,000 students and staff members was diagnosed with active pulmonary TB. Because of an unexpectedly high number of positive tuberculin skin test results in the initial contact investigation, testing was extended to the entire school population, which had to be completed before the end of the school term. A total of 1,806 persons were tested in 24 hours. The rapid testing of the entire population of a high school is unusual and led to widespread media attention and community concern, requiring close coordination among branches of the County of Riverside Department of Public Health, local governments, and the school district. The testing resulted in identification of two additional cases of TB; in addition, 72 persons underwent treatment for latent TB infection (LTBI). This incident demonstrates the importance of a coordinated emergency response in a large-scale deployment of rapid testing, including efficiently focused resources, organized testing operations, and effective media relations. PMID- 26042649 TI - Impact of arthritis and multiple chronic conditions on selected life domains - United States, 2013. AB - About half of U.S. adults have at least one chronic health condition, and the prevalence of multiple (two or more) chronic conditions increased from 21.8% in 2001 to 25.5% in 2012. Chronic conditions profoundly affect quality of life, are leading causes of death and disability, and account for 86% of total health care spending. Arthritis is a common cause of disability, one of the most common chronic conditions, and is included in prevalent combinations of multiple chronic conditions. To determine the impact of having arthritis alone or as one of multiple chronic conditions on selected important life domains, CDC analyzed data from the 2013 National Health Interview Survey (NHIS). Having one or more chronic conditions was associated with significant and progressively higher prevalences of social participation restriction, serious psychological distress, and work limitations. Adults with arthritis as one of their multiple chronic conditions had higher prevalences of adverse outcomes on all three life domains compared with those with multiple chronic conditions but without arthritis. The high prevalence of arthritis, its common co-occurrence with other chronic conditions, and its significant adverse effect on life domains suggest the importance of considering arthritis in discussions addressing the effect of multiple chronic conditions and interventions needed to reduce that impact among researchers, health care providers, and policy makers. PMID- 26042650 TI - Influenza activity - United States, 2014-15 season and composition of the 2015-16 influenza vaccine. AB - During the 2014-15 influenza season in the United States, influenza activity increased through late November and December before peaking in late December. Influenza A (H3N2) viruses predominated, and the prevalence of influenza B viruses increased late in the season. This influenza season, similar to previous influenza A (H3N2)-predominant seasons, was moderately severe with overall high levels of outpatient illness and influenza-associated hospitalization, especially for adults aged >=65 years. The majority of circulating influenza A (H3N2) viruses were different from the influenza A (H3N2) component of the 2014-15 Northern Hemisphere seasonal vaccines, and the predominance of these drifted viruses resulted in reduced vaccine effectiveness. This report summarizes influenza activity in the United States during the 2014-15 influenza season (September 28, 2014-May 23, 2015) and reports the recommendations for the components of the 2015-16 Northern Hemisphere influenza vaccine. PMID- 26042651 TI - Vital signs: melanoma incidence and mortality trends and projections - United States, 1982-2030. AB - BACKGROUND: Melanoma incidence rates have continued to increase in the United States, and risk behaviors remain high. Melanoma is responsible for the most skin cancer deaths, with about 9,000 persons dying from it each year. METHODS: CDC analyzed current (2011) melanoma incidence and mortality data, and projected melanoma incidence, mortality, and the cost of treating newly diagnosed melanomas through 2030. Finally, CDC estimated the potential melanoma cases and costs averted through 2030 if a comprehensive skin cancer prevention program was implemented in the United States. RESULTS: In 2011, the melanoma incidence rate was 19.7 per 100,000, and the death rate was 2.7 per 100,000. Incidence rates are projected to increase for white males and females through 2019. Death rates are projected to remain stable. The annual cost of treating newly diagnosed melanomas was estimated to increase from $457 million in 2011 to $1.6 billion in 2030. Implementation of a comprehensive skin cancer prevention program was estimated to avert 230,000 melanoma cases and $2.7 billion in initial year treatment costs from 2020 through 2030. CONCLUSIONS: If additional prevention efforts are not undertaken, the number of melanoma cases is projected to increase over the next 15 years, with accompanying increases in health care costs. Much of this morbidity, mortality, and health care cost can be prevented. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Substantial reductions in melanoma incidence, mortality, and cost can be achieved if evidence-based comprehensive interventions that reduce ultraviolet (UV) radiation exposure and increase sun protection are fully implemented and sustained. PMID- 26042652 TI - Notes from the Field: Outbreaks of Shigella sonnei Infection with Decreased Susceptibility to Azithromycin Among Men Who Have Sex with Men - Chicago and Metropolitan Minneapolis-St. Paul, 2014. AB - Increasing rates of shigellosis among adult males, particularly men who have sex with men (MSM), have been documented in the United States, Canada, and Europe, and MSM appear to be at greater risk for infection with shigellae that are not susceptible to ciprofloxacin or azithromycin. Azithromycin is the first-line empiric antimicrobial treatment for shigellosis among children and is a second line treatment among adults. Isolates collected in 2014 in two U.S. cities from outbreaks of shigellosis displayed highly similar pulsed-field gel electrophoresis (PFGE) patterns and decreased susceptibility to azithromycin (DSA). This report summarizes and compares the findings from investigations of the two outbreaks, which occurred among MSM in metropolitan Minneapolis-St. Paul, Minnesota, and Chicago, Illinois. PMID- 26042654 TI - A Series of Lanthanide Metal-Organic Frameworks with Interesting Adjustable Photoluminescence Constructed by Helical Chains. AB - Based on the isonicotinic acid (HIN=pyridine-4-carboxylic acid), seven lanthanide metal-organic frameworks (MOFs) with the formula [Ln(IN)2 L] (Ln=Eu (1), Tb (2), Er (3), Dy (4), Ho (5), Gd (6), La (7), L=OCH2 CH2 OH) have been synthesized by mixing Ln2 O3 with HIN under solvothermal conditions, and characterized by single crystal X-ray diffraction, powder X-ray diffraction, infrared spectroscopy, and fluorescence spectroscopy. Crystal structural analysis shows that compounds 1-6 are isostructural, crystallize in a chiral space group P21 21 21 , whereas compound 7 crystallizes in space group C2/c. Nevertheless, they all consist of new intertwined chains. Simultaneously, on the basis of the above-mentioned compounds, we have realized a rational design strategy to form the doped Ln MOFs [(Eux Tb1-x )(IN)2 L] (x=0.35 (8), x=0.19 (9), x=0.06 (10)) by utilizing Tb(III) as the second "rare-earth metal". Interestingly, the photoluminescence of [(Eux Tb1-x )(IN)2 L] are not only adjustable by the ratios of Eu/Tb, but also temperature or excitation wavelength. PMID- 26042653 TI - The lasting impact of the therapeutic alliance: Patient-oncologist alliance as a predictor of caregiver bereavement adjustment. AB - BACKGROUND: Caregivers of patients with advanced cancer provide extensive care and experience high levels of psychosocial distress. The patient-oncologist therapeutic alliance may be a modifiable factor that can prevent or reduce negative caregiver outcomes. METHODS: Coping with Cancer (CwC) was a prospective, longitudinal, multisite cohort study of terminally ill cancer patients (life expectancy <=6 months) and their informal caregivers, who were followed into bereavement (n = 68). Trained raters interviewed patients and caregivers upon study entry and also interviewed caregivers 6 months after the patient's death. Patients answered quantitative questions assessing their perception of the patient-oncologist therapeutic alliance (The Human Connection scale), and caregivers completed a measure of health-related quality of life (Medical Outcomes Study Short Form-36). Interviewers rated caregivers' level of emotional well being. Associations between therapeutic alliance and caregiver outcomes were analyzed using univariate analysis of variance and logistic regression analyses, controlling for baseline caregiver measures and confounding sample characteristics. RESULTS: A strong patient-oncologist therapeutic alliance was bivariately associated with caregiver self-report of less role limitation because of emotional problems, better social function and mental and general health related quality of life, and better interviewer-rated emotional well being after the patient's death. After controlling for baseline measures and confounding sample characteristics, the correlation between patient-perceived therapeutic alliance and bereaved caregivers' mental health and interviewer ratings of bereaved caregivers' emotional well being remained significant. CONCLUSIONS: The influence of the patient-oncologist alliance may generalize beyond the patient to positively impact the caregiver. By developing a strong relationship with the patient, the oncologist may benefit the caregiver and the patient. This caregiver benefit may extend into bereavement. PMID- 26042655 TI - Quantification of adverse effects of regular use of triazolam on clinical outcomes for older people with insomnia: a retrospective cohort study. AB - OBJECTIVE: Older people are more likely to have insomnia. One of the most prescribed hypnotics in Japan is triazolam. Although some studies showed the possibility of adverse effects of triazolam in older people, there have been few studies investigating these effects in a clinical setting. The aim of this study was to determine whether patients who used triazolam regularly had increased risks of pneumonia, trauma, and pressure ulcers. METHODS: The research design was a retrospective cohort study using claim data. The subjects of the study were patients who were insured by Fukuoka Late Stage Elderly Healthcare Insurance. We defined patients who had received triazolam for 180 days or longer during fiscal year 2011 as the triazolam group, and those who had not received any hypnotics during the period as the non-triazolam group. Each patient in the triazolam group was then matched with a unique control from the non-triazolam group according to propensity score. Multivariate conditional logistic regression analyses were used to obtain adjusted odds ratios for pneumonia, trauma, and pressure ulcer in the triazolam group compared with the non-triazolam group. RESULTS: The number of patients in the triazolam and non-triazolam groups in the unmatched cohort was 13,015 and 411,610, respectively. Adjusted odds ratios show that the risks for pneumonia, trauma, and pressure ulcer in the matched cohort increased by approximately 40%, 30%, and slightly less than 30%, respectively (all statistically significant). CONCLUSIONS: Regular use of triazolam is a risk factor for pneumonia, trauma, and pressure ulcer in older people. PMID- 26042656 TI - Psychosocial determinants of Chinese parental HPV vaccination intention for adolescent girls: preventing cervical cancer. AB - BACKGROUND: Intention is an important precursor of decisions to undergo vaccination. Using an extensively modified theory of planned behaviour, we explored psychosocial determinants of vaccination intention against human papillomavirus (HPV) among Hong Kong Chinese parents. METHODS: A random sample of 368 (response rate 54.6%) Chinese parents who had at least one daughter aged 12 17 years, had heard of HPV vaccine before but had not vaccinated daughters against HPV and had completed telephone interviews between February and April 2014. Hierarchical multiple regression analysis examined the additive effect of theoretical constructs. Stepwise multiple regression analysis determined which variables contributed the most to the prediction of vaccination intention. RESULTS: Principal determinants of parental HPV vaccination intention were anticipated worry if not vaccinated (beta = 0.23, p = 0.001), anticipated anxiety reduction after HPV vaccination (beta = 0.19, p = 0.005), proneness to peer influence (beta = 0.17, p = 0.002), private health insurance for children (beta = 0.14, p = 0.009), perceiving daughter's susceptibility to cervical cancer (beta = 0.17, p = 0.003), number of daughters (beta = -0.13, p = 0.011), descriptive norms of HPV vaccination (beta = 0.13, p = 0.021), perceiving cervical cancer as behaviour-preventable disease (beta = -0.11, p = 0.031) and anticipated regret if not vaccinated (beta = 0.14, p = 0.046). Cervical cancer-related worry/anxiety explained 32.8% of the variance in parental HPV vaccination intention. CONCLUSIONS: Results suggest that cervical cancer-related worry/anxiety is the most important predictor of parental HPV vaccination intention in Hong Kong Chinese and possibly other populations. Social influences also play an important role affecting parental vaccination intention, particularly peer influence and descriptive norm beliefs. Implications of these results are discussed in terms of future HPV vaccination promotion and cervical cancer prevention programme. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26042657 TI - Optimizing preoperative expectations in cardiac surgery patients is moderated by level of disability: the successful development of a brief psychological intervention. AB - Patients' expectations have shown to be a major psychological predictor of health outcome in cardiac surgery patients. However, it is unclear whether patients' expectations can be optimized prior to surgery. This study evaluates the development of a brief psychological intervention focusing on the optimization of expectations and its effect on change in patients' expectations prior to cardiac surgery. Ninety patients scheduled for coronary artery bypass graft were randomly assigned to (1) standard medical care, (2) additional expectation manipulation intervention (EMI), and (3) additional attention control group. Therapists' fidelity to intervention manuals and patients satisfaction with the intervention were assessed for both active intervention conditions. Patients' expectations about post-surgical disability, treatment control, personal control, and disease duration were assessed before and after the psychological intervention. Demographical, medical, and psychosocial characteristics and disability were assessed at baseline. Treatment fidelity and patient satisfaction was very high in both intervention conditions. Only patients receiving EMI developed higher personal control expectations and longer (more realistic) expectations of disease duration. The effect of intervention group on patients' disability expectations and patients' personal control expectations was moderated by patient's level of disability. EMI patients with low to moderate disability developed positive expectations whereas patients with high disability did not. This study shows the successful development of a short psychological intervention that was able to modify patients' expectations, especially in those with low to moderate disability. Given the robust association of expectations and surgery outcome, such an intervention might offer the opportunity to enhance patients' health following cardiac surgery. PMID- 26042658 TI - A rare bullous variant of dermatitis herpetiformis. PMID- 26042659 TI - Free-cholesterol-mediated autophagy of ORMDL1 stimulates sphingomyelin biosynthesis. AB - Cholesterol confers unique biophysical properties to the plasma membrane bilayer that are essential for maintaining optimal membrane fluidity, which in turn regulate multiple physiological functions required to promote cellular integrity and viability. Conversely, excessive cholesterol causes pathological conditions such as atherosclerosis that can lead to heart attacks. Human atheroma macrophages carry a large burden of free cholesterol (FC) in addition to cholesterol esters. It is recognized that sterols can modulate the levels of other lipids to attain lipid homeostasis; thus, excess FC may play a role in modulating compensatory sphingolipid pathways. Recent studies have shown that excess lipids can cause ER stress and apoptosis. In contrast, autophagy may play a protective role by clearing excess lipids from macrophage foam cell lipid droplets. Interestingly, a macrophage study using a TLR4-specifc agonist showed that de novo sphingolipid biosynthesis is essential for autophagy induction, suggesting links between sphingolipid biosynthesis and autophagy. While the role of autophagy in removing excess lipids has been the focus of many studies, its role in fine-tuning cellular lipid homeostasis remains largely unexplored. PMID- 26042660 TI - Unmet Need: Improving mHealth Evaluation Rigor to Build the Evidence Base. AB - mHealth-the use of mobile technologies for health-is a growing element of health system activity globally, but evaluation of those activities remains quite scant, and remains an important knowledge gap for advancing mHealth activities. In 2010, the World Health Organization and Columbia University implemented a small-scale survey to generate preliminary data on evaluation activities used by mHealth initiatives. The authors describe self-reported data from 69 projects in 29 countries. The majority (74%) reported some sort of evaluation activity, primarily nonexperimental in design (62%). The authors developed a 6-point scale of evaluation rigor comprising information on use of comparison groups, sample size calculation, data collection timing, and randomization. The mean score was low (2.4); half (47%) were conducting evaluations with a minimum threshold (4+) of rigor, indicating use of a comparison group, while less than 20% had randomized the mHealth intervention. The authors were unable to assess whether the rigor score was appropriate for the type of mHealth activity being evaluated. What was clear was that although most data came from mHealth projects pilots aimed for scale-up, few had designed evaluations that would support crucial decisions on whether to scale up and how. Whether the mHealth activity is a strategy to improve health or a tool for achieving intermediate outcomes that should lead to better health, mHealth evaluations must be improved to generate robust evidence for cost-effectiveness assessment and to allow for accurate identification of the contribution of mHealth initiatives to health systems strengthening and the impact on actual health outcomes. PMID- 26042661 TI - Quick note on tissue engineering-based surgical measures to treat patients with neurogenic bladder-due detrusor/sphincter dyssynergia. AB - To treat the neurogenic bladder-due detrusor/urethral rhabdosphincter dyssynergia, early combined clean intermittent catheterization/ pharmacotherapy (anticholinergic-, beta3-adrenoceptor agonist drugs) management may be at times crowned with success of preserving an adequate bladder compliance and renal safe conditions.The persistence, instead, of elevated bladder filling pressure levels with high voiding pressure/uroflow values, together with aberrant urethral rhabdosphincter electromyographic findings, make necessary the resort to surgery strategies, among which - a part from rhabdosphincterotomy or alternatively intrasphincteric botulinum A toxin injection or urethral stent insertion - the bladder augmentation cystoplasty, with either reconfigurated bowel- or gastric segment, is today the most efficacious surgical measure to increase the bladder urinary storage meanwhile lowering bladder filling pressure. Given the enterocistoplasty-dependent both potential systemic metabolic imbalances - such as hyperchloremic acidosis/hypokaliemia, hyperoxaluria, bone demineralization, chologenic diarrhoea/steatorrhoea, vit B12 deficiency - together with bowel prosthetic mucus overproduction-due recurrent stone formation, and, sometimes, malignant complications particularly at the intestinal-urinary tract suture line, tissue engineering techniques have been taken into consideration, more than twenty years ago, as alternative measure for bladder augmentation cystoplasty, until to reach successful clinical validation just in patients suffering from either congenital dysraphism- or acquired spinal cord injury-dependent neurogenic bladder. Nevertheless, also the tissue engineering-made augmentation cistoplasty, as well as that bowel-based one, unfortunately remains influenced by spinal cord neuropathydue dysfunctional effects, hence the tissue engineering research could be today directed to suitably overcome such disadvantageous conditions. PMID- 26042662 TI - MEIC Evaluation of Acute Systemic Toxicity: Part V. Rodent and Human Toxicity Data for the 50 Reference Chemicals. PMID- 26042663 TI - MEIC Evaluation of Acute Systemic Toxicity: Part VI. The Prediction of Human Toxicity by Rodent LD50 Values and Results From 61 In Vitro Methods. PMID- 26042664 TI - Enhanced functional recovery from sciatic nerve crush injury through a combined treatment of cold-water swimming and mesenchymal stem cell transplantation. AB - OBJECTIVE: Although regimens of stem cell implantation can elicit functional recovery following peripheral nerve injury, the degree of outcome is still limited. This study evaluated the synergistic effects of cold-water swimming (CWS) and mesenchymal stem cell (MSC) transplantation on functional recovery of crushed sciatic nerve in rats. METHOD: Forty Sprague-Dawley rats that had their sciatic nerve crushed during surgery were randomly divided into four groups: MSCCWS group, treated with combination of MSC and CWS; MSC group, treated with MSC alone; CWS group, treated with CWS alone; and non-treated group, without any treatments. The sciatic function index (SFI), vertical activity (VA), ankle activity (AA) and electrophysiological study were examined before, immediately after surgery, after the treatment and after 4 weeks from treatment. Morphological and S100 immunohistochemical studies were also performed. RESULTS: The MSCCWS group showed a greater improvement in SFI, VA, AA, peak amplitudes and onset latencies of compound muscle action potential (CMAP) in sciatic nerve and infiltration of immune cells with significant difference from the MSC, CWS and non-treated groups (P < 0.05). CONCLUSIONS: MSC transplantation combined with CWS could achieve better results in functional recovery than a single treatment of MSC alone or CWS alone in nerve crush injury. PMID- 26042665 TI - Alterations in DNA methylation may be the key to early detection and treatment of schistosomal bladder cancer. PMID- 26042666 TI - Putative regulatory factors associated with intramuscular fat content. AB - Intramuscular fat (IMF) content is related to insulin resistance, which is an important prediction factor for disorders, such as cardiovascular disease, obesity and type 2 diabetes in human. At the same time, it is an economically important trait, which influences the sensorial and nutritional value of meat. The deposition of IMF is influenced by many factors such as sex, age, nutrition, and genetics. In this study Nellore steers (Bos taurus indicus subspecies) were used to better understand the molecular mechanisms involved in IMF content. This was accomplished by identifying differentially expressed genes (DEG), biological pathways and putative regulatory factors. Animals included in this study had extreme genomic estimated breeding value (GEBV) for IMF. RNA-seq analysis, gene set enrichment analysis (GSEA) and co-expression network methods, such as partial correlation coefficient with information theory (PCIT), regulatory impact factor (RIF) and phenotypic impact factor (PIF) were utilized to better understand intramuscular adipogenesis. A total of 16,101 genes were analyzed in both groups (high (H) and low (L) GEBV) and 77 DEG (FDR 10%) were identified between the two groups. Pathway Studio software identified 13 significantly over-represented pathways, functional classes and small molecule signaling pathways within the DEG list. PCIT analyses identified genes with a difference in the number of gene-gene correlations between H and L group and detected putative regulatory factors involved in IMF content. Candidate genes identified by PCIT include: ANKRD26, HOXC5 and PPAPDC2. RIF and PIF analyses identified several candidate genes: GLI2 and IGF2 (RIF1), MPC1 and UBL5 (RIF2) and a host of small RNAs, including miR 1281 (PIF). These findings contribute to a better understanding of the molecular mechanisms that underlie fat content and energy balance in muscle and provide important information for the production of healthier beef for human consumption. PMID- 26042667 TI - Distinct patterns of desynchronized limb regression in malagasy scincine lizards (squamata, scincidae). AB - Scincine lizards in Madagascar form an endemic clade of about 60 species exhibiting a variety of ecomorphological adaptations. Several subclades have adapted to burrowing and convergently regressed their limbs and eyes, resulting in a variety of partial and completely limbless morphologies among extant taxa. However, patterns of limb regression in these taxa have not been studied in detail. Here we fill this gap in knowledge by providing a phylogenetic analysis of DNA sequences of three mitochondrial and four nuclear gene fragments in an extended sampling of Malagasy skinks, and microtomographic analyses of osteology of various burrowing taxa adapted to sand substrate. Based on our data we propose to (i) consider Sirenoscincus Sakata & Hikida, 2003, as junior synonym of Voeltzkowia Boettger, 1893; (ii) resurrect the genus name Grandidierina Mocquard, 1894, for four species previously included in Voeltzkowia; and (iii) consider Androngo Brygoo, 1982, as junior synonym of Pygomeles Grandidier, 1867. By supporting the clade consisting of the limbless Voeltzkowia mira and the forelimb only taxa V. mobydick and V. yamagishii, our data indicate that full regression of limbs and eyes occurred in parallel twice in the genus Voeltzkowia (as hitherto defined) that we consider as a sand-swimming ecomorph: in the Voeltzkowia clade sensu stricto the regression first affected the hindlimbs and subsequently the forelimbs, whereas the Grandidierina clade first regressed the forelimbs and subsequently the hindlimbs following the pattern prevalent in squamates. Timetree reconstructions for the Malagasy Scincidae contain a substantial amount of uncertainty due to the absence of suitable primary fossil calibrations. However, our preliminary reconstructions suggest rapid limb regression in Malagasy scincids with an estimated maximal duration of 6 MYr for a complete regression in Paracontias, and 4 and 8 MYr respectively for complete regression of forelimbs in Grandidierina and hindlimbs in Voeltzkowia. PMID- 26042668 TI - Mefunidone attenuates tubulointerstitial fibrosis in a rat model of unilateral ureteral obstruction. AB - BACKGROUND: Inflammation has a crucial role in renal interstitial fibrosis, which is the common pathway of chronic kidney diseases. Mefunidone (MFD) is a new compound which could effectively inhibit the proliferation of renal fibroblasts in vitro. However, the overall effect of Mefunidone in renal fibrosis remains unknown. METHODS: Sprague-Dawley rats were randomly divided intro 6 groups: sham operation, unilateral ureteral obstruction (UUO), UUO/Mefunidone (25, 50, 100mg/kg/day) and UUO/PFD (500mg/kg/day). The rats were sacrificed respectively on days 3, 7, and 14 after the operation. Tubulointerstitial injury index, interstitial collagen deposition, expression of fibronectin (FN), alpha-smooth muscle actin (alpha-SMA), type I and III collagen and the number of CD3+ and CD68+ cells were determined. The expressions of proinflammatory cytokines, p-ERK, p-IkappaB, and p-STAT3 were measured in human renal proximal tubular epithelial cells of HK-2 or macrophages. RESULTS: Mefunidone treatment significantly attenuated tubulointerstitial injury, interstitial collagen deposition, expression of FN, alpha-SMA, type I and III collagen in the obstructive kidneys, which correlated with significantly reduced the number of T cells and macrophages in the obstructive kidneys. Mechanistically, Mefunidone significantly inhibited tumor necrosis factor-alpha (TNF-alpha-) or lipopolysaccharide (LPS)-induced production of proinflammatory cytokines. This effect is possibly due to the inhibition of phosphorylation of ERK, IkappaB, and STAT3. CONCLUSION: Mefunidone treatment attenuated tubulointerstitial fibrosis in a rat model of UUO, at least in part, through inhibition of inflammation. PMID- 26042669 TI - Long- and short-term health effects of pesticide exposure: a cohort study from China. AB - Pesticides are extensively used by farmers in China. However, the effects of pesticides on farmers' health have not yet been systematically studied. This study evaluated the effects of pesticides exposure on hematological and neurological indicators over 3 years and 10 days respectively. A cohort of 246 farmers was randomly selected from 3 provinces (Guangdong, Jiangxi, and Hebei) in China. Two rounds of health investigations, including blood tests and neurological examinations, were conducted by medical doctors before and after the crop season in 2012. The data on pesticide use in 2009-2011 were collected retrospectively via face-to-face interviews and the 2012 data were collected from personal records maintained by participants prospectively. Ordinary least square (OLS), Probit, and fixed effect models were used to evaluate the relationship between pesticides exposure frequency and the health indicators. Long-term pesticide exposure was found to be associated with increased abnormality of nerve conductions, especially in sensory nerves. It also affected a wide spectrum of health indicators based on blood tests and decreased the tibial nerve compound muscle action potential amplitudes. Short-term health effects included alterations in complete blood count, hepatic and renal functions, and nerve conduction velocities and amplitudes. However, these effects could not be detected after 3 days following pesticide exposure. Overall, our results demonstrate that pesticide exposure adversely affects blood cells, the liver, and the peripheral nervous system. Future studies are needed to elucidate the specific effects of each pesticide and the mechanisms of these effects. PMID- 26042671 TI - Comparison of Retinal Thickness Measurements between the Topcon Algorithm and a Graph-Based Algorithm in Normal and Glaucoma Eyes. AB - PURPOSE: To assess the correlation and agreement between the Topcon built-in algorithm and our graph-based algorithm in measuring the total and regional macular thickness for normal and glaucoma subjects. METHODS: A total of 228 normal eyes and 93 glaucomatous eyes were enrolled in our study. All patients underwent comprehensive ophthalmic examination and Topcon 3D-OCT 2000 scan. One eye was randomly selected for each subject. The thickness of each layer and the total and regional macular thickness on an Early Treatment of Diabetic Retinopathy Study (ETDRS) chart were measured using the Topcon algorithm and our three-dimensional graph-based algorithm. Correlation and agreement analyses between these two algorithms were performed. RESULTS: Our graph search algorithm exhibited a strong correlation with Topcon algorithm. The macular GCC thickness values for normal and glaucoma subjects ranged from 0.86 to 0.91 and from 0.78 to 0.90, and the regional macular thickness values ranged from 0.79 to 0.96 and 0.70 to 0.95, respectively. Small differences were observed between the Topcon algorithm and our graph-based algorithm. The span of 95% limits of agreement of macular GCC thickness was less than 28 MUm in both normal and glaucoma subjects, respectively. These limits of total and regional macular thickness were 15.5 MUm and 23.1 MUm for normal subjects and 29.1 MUm and 46.4 MUm for glaucoma subjects, respectively. CONCLUSION: Our graph-based algorithm exhibited a high degree of agreement with the Topcon algorithm with respect to thickness measurements in normal and glaucoma subjects. Moreover, our graph-based algorithm can segment the retina into more layers than the Topcon algorithm does. PMID- 26042670 TI - SUMOylation of xeroderma pigmentosum group C protein regulates DNA damage recognition during nucleotide excision repair. AB - The xeroderma pigmentosum group C (XPC) protein complex is a key factor that detects DNA damage and initiates nucleotide excision repair (NER) in mammalian cells. Although biochemical and structural studies have elucidated the interaction of XPC with damaged DNA, the mechanism of its regulation in vivo remains to be understood in more details. Here, we show that the XPC protein undergoes modification by small ubiquitin-related modifier (SUMO) proteins and the lack of this modification compromises the repair of UV-induced DNA photolesions. In the absence of SUMOylation, XPC is normally recruited to the sites with photolesions, but then immobilized profoundly by the UV-damaged DNA binding protein (UV-DDB) complex. Since the absence of UV-DDB alleviates the NER defect caused by impaired SUMOylation of XPC, we propose that this modification is critical for functional interactions of XPC with UV-DDB, which facilitate the efficient damage handover between the two damage recognition factors and subsequent initiation of NER. PMID- 26042672 TI - Integrative approach to analyze biodiversity and anti-inflammatory bioactivity of Wedelia medicinal plants. AB - For the development of "medical foods" and/or botanical drugs as defined USA FDA, clear and systemic characterizations of the taxonomy, index phytochemical components, and the functional or medicinal bioactivities of the reputed or candidate medicinal plant are needed. In this study, we used an integrative approach, including macroscopic and microscopic examination, marker gene analysis, and chemical fingerprinting, to authenticate and validate various species/varieties of Wedelia, a reputed medicinal plant that grows naturally and commonly used in Asian countries. The anti-inflammatory bioactivities of Wedelia extracts were then evaluated in a DSS-induced murine colitis model. Different species/varieties of Wedelia exhibited distinguishable morphology and histological structures. Analysis of the ribosomal DNA internal transcribed spacer (ITS) region revealed significant differences among these plants. Chemical profiling of test Wedelia species demonstrated candidate index compounds and distinguishable secondary metabolites, such as caffeic acid derivatives, which may serve as phytochemical markers or index for quality control and identification of specific Wedelia species. In assessing their effect on treating DSS induced-murine colitis, we observed that only the phytoextract from W. chinensis species exhibited significant anti-inflammatory bioactivity on DSS induced murine colitis among the various Wedelia species commonly found in Taiwan. Our results provide a translational research approach that may serve as a useful reference platform for biotechnological applications of traditional phytomedicines. Our findings indicate that specific Wedelia species warrant further investigation for potential treatment of human inflammatory bowel disease. PMID- 26042673 TI - A 21st century perspective of poliovirus replication. PMID- 26042674 TI - Modulation of human valve interstitial cell phenotype and function using a fibroblast growth factor 2 formulation. AB - Valve interstitial cells (VICs) are fibroblastic in nature however in culture it is widely accepted that they differentiate into a myofibroblastic phenotype. This study assessed a fibroblast culture media formulation for its ability to maintain the phenotype and function of VICs as in the intact healthy valve. Normal human VICs were cultured separately in standard DMEM and in fibroblast media consisting of FGF2 (10 ng/ml), insulin (50 ng/ml) and 2% FCS for at least a week. Cell morphology, aspect ratio, size, levels and distribution of protein expression, proliferation, cell cycle, contraction and migration were assessed. Some VICs and some valve endothelial cells expressed FGF2 in valve tissue and this expression was increased in calcified valves. VICs in DMEM exhibited large, spread cells whereas VICs in fibroblast media were smaller, elongated and spindly. Aspect ratio and size were both significantly higher in DMEM (p<0.01). The level of expression of alpha-SMA was significantly reduced in fibroblast media at day 2 after isolation (p<0.01) and the expression of alpha-SMA, SM22 and EDA fibronectin was significantly reduced in fibroblast media at days 7 and 12 post isolation (p<0.01). Expression of cytoskeletal proteins, bone marker proteins and extracellular matrix proteins was reduced in fibroblast media. Proliferation of VICs in fibroblast media was significantly reduced at weeks 1 (p<0.05) and 2 (p<0.01). Collagen gel contraction was significantly reduced in fibroblast media (p<0.05). VICs were found to have significantly fewer and smaller focal adhesions in fibroblast media (p<0.01) with significantly fewer supermature focal adhesions in fibroblast media (p<0.001). Ultrastructurally, VICs in fibroblast media resembled native VICs from intact valves. VICs in fibroblast media demonstrated a slower migratory ability after wounding at 72 hours (p<0.01). Treatment of human VICs with this fibroblast media formulation has the ability to maintain and to dedifferentiate the VICs back to a fibroblastic phenotype with phenotypic and functional characteristics ascribed to cells in the intact valve. This methodology is fundamental in the study of normal valve biology, pathology and in the field of tissue engineering. PMID- 26042676 TI - Transcriptome Characterization of Cymbidium sinense 'Dharma' Using 454 Pyrosequencing and Its Application in the Identification of Genes Associated with Leaf Color Variation. AB - The highly variable leaf color of Cymbidium sinense significantly improves its horticultural and economic value, and makes it highly desirable in the flower markets in China and Southeast Asia. However, little is understood about the molecular mechanism underlying leaf-color variations. In this study, we found the content of photosynthetic pigments, especially chlorophyll degradation metabolite in the leaf-color mutants is distinguished significantly from that in the wild type of Cymbidium sinense 'Dharma'. To further determine the candidate genes controlling leaf-color variations, we first sequenced the global transcriptome using 454 pyrosequencing. More than 0.7 million expressed sequence tags (ESTs) with an average read length of 445.9 bp were generated and assembled into 103,295 isotigs representing 68,460 genes. Of these isotigs, 43,433 were significantly aligned to known proteins in the public database, of which 29,299 could be categorized into 42 functional groups in the gene ontology system, 10,079 classified into 23 functional classifications in the clusters of orthologous groups system, and 23,092 assigned to 139 clusters of specific metabolic pathways in the Kyoto Encyclopedia of Genes and Genomes. Among these annotations, 95 isotigs were designated as involved in chlorophyll metabolism. On this basis, we identified 16 key enzyme-encoding genes in the chlorophyll metabolism pathway, the full length cDNAs and expressions of which were further confirmed. Expression pattern indicated that the key enzyme-encoding genes for chlorophyll degradation were more highly expressed in the leaf color mutants, as was consistent with their lower chlorophyll contents. This study is the first to supply an informative 454 EST dataset for Cymbidium sinense 'Dharma' and to identify original leaf color-associated genes, which provide important resources to facilitate gene discovery for molecular breeding, marketable trait discovery, and investigating various biological process in this species. PMID- 26042677 TI - Correction: Correction: Mitotic-Chromosome-Based Physical Mapping of the Culex quinquefasciatus Genome. PMID- 26042675 TI - Identifying the Basal Ganglia network model markers for medication-induced impulsivity in Parkinson's disease patients. AB - Impulsivity, i.e. irresistibility in the execution of actions, may be prominent in Parkinson's disease (PD) patients who are treated with dopamine precursors or dopamine receptor agonists. In this study, we combine clinical investigations with computational modeling to explore whether impulsivity in PD patients on medication may arise as a result of abnormalities in risk, reward and punishment learning. In order to empirically assess learning outcomes involving risk, reward and punishment, four subject groups were examined: healthy controls, ON medication PD patients with impulse control disorder (PD-ON ICD) or without ICD (PD-ON non-ICD), and OFF medication PD patients (PD-OFF). A neural network model of the Basal Ganglia (BG) that has the capacity to predict the dysfunction of both the dopaminergic (DA) and the serotonergic (5HT) neuromodulator systems was developed and used to facilitate the interpretation of experimental results. In the model, the BG action selection dynamics were mimicked using a utility function based decision making framework, with DA controlling reward prediction and 5HT controlling punishment and risk predictions. The striatal model included three pools of Medium Spiny Neurons (MSNs), with D1 receptor (R) alone, D2R alone and co-expressing D1R-D2R. Empirical studies showed that reward optimality was increased in PD-ON ICD patients while punishment optimality was increased in PD OFF patients. Empirical studies also revealed that PD-ON ICD subjects had lower reaction times (RT) compared to that of the PD-ON non-ICD patients. Computational modeling suggested that PD-OFF patients have higher punishment sensitivity, while healthy controls showed comparatively higher risk sensitivity. A significant decrease in sensitivity to punishment and risk was crucial for explaining behavioral changes observed in PD-ON ICD patients. Our results highlight the power of computational modelling for identifying neuronal circuitry implicated in learning, and its impairment in PD. The results presented here not only show that computational modelling can be used as a valuable tool for understanding and interpreting clinical data, but they also show that computational modeling has the potential to become an invaluable tool to predict the onset of behavioral changes during disease progression. PMID- 26042678 TI - Detection of autonomic dysfunction in hemodialysis patients using the exercise treadmill test: the role of the chronotropic index, heart rate recovery, and R-R variability. AB - OBJECTIVE: To evaluate the ability of different parameters of exercise treadmill test to detect autonomic dysfunction in hemodialysis patients. METHODS: Cross sectional study involving hemodialysis patients and a control group. Clinical examination, blood sampling, echocardiogram, 24-hour Holter, and exercise treadmill test were performed. A ramp treadmill protocol symptom-limited with active recovery was employed. RESULTS: Forty-one hemodialysis patients and 41 controls concluded the study. There was significant difference between hemodialysis patients and controls in autonomic function parameters in 24h-Holter and exercise treadmill test. Probability of having autonomic dysfunction in hemodialysis patients compared to controls was 29.7 at the exercise treadmill test and 13.0 in the 24-hour Holter. Chronotropic index, heart rate recovery at the 1st min, and SDNN at exercise were used to develop an autonomic dysfunction score to grade autonomic dysfunction, in which, 83% of hemodialysis patients reached a scoring >=2 in contrast to 20% of controls. Hemodialysis was independently associated with either altered chronotropic index or autonomic dysfunction scoring >=2 in every tested model (OR=50.1, P=0.003; and OR=270.9, P=0.002, respectively, model 5). CONCLUSION: The exercise treadmill test was feasible and useful to diagnose of the autonomic dysfunction in hemodialysis patients. Chronotropic index and autonomic dysfunction scoring >=2 were the most effective parameters to differentiate between hemodialysis patients and controls suggesting that these variables portrays the best ability to detect autonomic dysfunction in this setting. PMID- 26042679 TI - Mechanical writing of n-type conductive layers on the SrTiO3 surface in nanoscale. AB - The fabrication and control of the conductive surface and interface on insulating SrTiO3 bulk provide a pathway for oxide electronics. The controllable manipulation of local doping concentration in semiconductors is an important step for nano-electronics. Here we show that conductive patterns can be written on bare SrTiO3 surface by controllable doping in nanoscale using the mechanical interactions of atomic force microscopy tip without applying external electric field. The conductivity of the layer is n-type, oxygen sensitive, and can be effectively tuned by the gate voltage. Hence, our findings have potential applications in oxide nano-circuits and oxygen sensors. PMID- 26042680 TI - Lifting baselines to address the consequences of conservation success. AB - Biologists and policymakers are accustomed to managing species in decline, but for the first time in generations they are also encountering recovering populations of ocean predators. Many citizens perceive these species as invaders and conflicts are increasing. It is time to celebrate these hard-earned successes and lift baselines for recovering species. PMID- 26042681 TI - Signaling dynamics and peroxisomes. AB - Peroxisomes are remarkably responsive organelles. Their composition, abundance and even their mechanism of biogenesis are influenced strongly by cell type and the environment. This plasticity underlies peroxisomal functions in metabolism and the detoxification of dangerous reactive oxygen species. However, peroxisomes are integrated into the cellular system as a whole such that they communicate intimately with other organelles, control signaling dynamics as in the case of innate immune responses to infectious disease, and contribute to processes as fundamental as longevity. The increasing evidence for peroxisomes having roles in various cellular and organismal functions, combined with their malleability, suggests complex mechanisms operate to control cellular dynamics and the specificity of cellular responses and functions extending well beyond the peroxisome itself. A deeper understanding of the functions of peroxisomes and the mechanisms that control their plasticity could offer opportunities for exploiting changes in peroxisome abundance to control cellular function. PMID- 26042683 TI - Antioxidant activities of nano-bubble hydrogen-dissolved water assessed by ESR and 2,2'-bipyridyl methods. AB - We prepared nano-bubble hydrogen-dissolved water (nano-H water) which contained hydrogen nano-bubbles of <717-nm diameter for 54% of total bubbles. In the DMPO spin trap electron spin resonance (ESR) method, the DMPO-OH:MnO ratio, being attributed to amounts of hydroxyl radicals (OH), was 2.78 for pure water (dissolved hydrogen [DH]<=0.01 ppm, oxidation-reduction potential [ORP]=+324 mV), 2.73 for tap water (0.01 ppm, +286 mV), 2.93 for commercially available hydrogen water (0.075 ppm, +49 mV), and 2.66 for manufactured hydrogen water (0.788 ppm, 614 mV), whereas the nano-H water (0.678 ppm, -644 mV) exhibited 2.05, showing the superiority of nano-H water to other types of hydrogen water in terms of OH scavenging activity. Then, the reduction activity of nano-H water was assessed spectrophotometrically by the 2,2'-bipyridyl method. Differential absorbance at 530 nm was in the order: 0.018 for pure water, 0.055 for tap water, 0.079 for nano-H water, 0.085 for commercially available hydrogen water, and 0.090 for manufactured hydrogen water, indicating a prominent reduction activity of hydrogen water and nano-H water against oxidation in ascorbate-coupled ferric ion bipyridyl reaction. Thus, nano-H water has an improved antioxidant activity as compared to hydrogen water of similar DH-level, indicating the more marked importance of nano-bubbles rather than the concentration of hydrogen in terms of OH-scavenging. PMID- 26042682 TI - The effect of synthesis parameters on the geometry and dimensions of mesoporous hydroxyapatite nanoparticles in the presence of 1-dodecanethiol as a pore expander. AB - Mesoporous hydroxyapatite with different pore diameters and pore volumes were synthesized by the self-assembly method using Cetyltrimethylammonium bromide (CTAB) as the cationic surfactant and 1-dodecanethiol as the pore expander at different micellization pHs, solvent types and surfactant concentrations. Results of field emission scanning electron microscopy (FESEM) showed a decrease in length/diameter ratio of rod-like particles by an increase in micellization pH and also a sphere to rod transition in morphology by an increase in CTAB concentration. Brunauer-Emmett-Teller (BET) surface area and Low angle X-ray diffraction analysis revealed that the optimized mesoporous hydroxyapatite with controlled pore structure can be obtained under basic micellization pH (about 12, pH of complete ionization of 1-dodecanethiol) by using water as the solvent and a high content of cationic surfactant. The results also show that micellization pH has a strong effect on pore structure and changing the pH can shift the mesostructure to a macroporous structure with morphological changes. PMID- 26042684 TI - Spectral imaging method for studying Physarum polycephalum growth on polyaniline surface. AB - The features of spectrophotometric scanner, generally exploited in the artwork field, are here considered in a non-conventional context to characterize the networks created by Physarum polycephalum slime mold during its motion on glass substrates covered with polyaniline: a polymer that varies its color and conductive properties according to the redox state. The used technique allowed the investigation of the effects coming out from the interaction between P. polycephalum and polyaniline. Thus, the contactless method of the analysis of polyaniline conductivity state resulted from the slime mold metabolism was suggested. Indeed, it is here demonstrated that P. polycephalum can modify properties of polyaniline due to its internal activity in contact zones. PMID- 26042685 TI - Influence of ceria nanoparticles on chemical structure and properties of segmented polyesters. AB - In this work, we present new nanocomposite materials derived from segmented copolyesters, comprising ethylene terephthalate (PET) segments and dimerized linoleic acid (DLA), and nanometric cerium oxide particles (CeO2). Nanoparticles were incorporated in situ during polycondensation in various concentrations, from 0.1 up to 0.6 wt.%. It was found that preparation of nanocomposites in situ, during polycondensation, had no significant influence on changes in segmental composition as determined from (1)H and (13)C, as well as 2D NMR. Thermal analysis and calculated degree of crystallinity showed that increasing concentration of ceria nanoparticles lead to an increase in mass content of PET crystallites in hard segments. The XRD investigations also showed an increased intensity of characteristic signals with increasing ceria concentration. Simultaneously, the incorporation of CeO2 led to an increase in tensile strength and elongation at break, indicating a reinforcing and plasticizing effect of ceria nanoparticles. However, the modulus at 10% strain decreased with increasing amount of nanoparticles. The in vitro culture of human cardiac progenitor cells (hCPCs) on the new materials indicated a homogenous cell displacement across the samples after 5 days with no signs of cytotoxicity, indicating good biocompatibility in vitro of CeO2-based nanocomposites and a potential for biomedical applications. PMID- 26042686 TI - Inhibiting the oxidation of diamond during preparing the vitrified dental grinding tools by depositing a ZnO coating using direct urea precipitation method. AB - Oxidation of diamond during the manufacturing of vitrified dental grinding tools would reduce the strength and sharpness of tools. Zinc oxide (ZnO) coating was deposited on diamond particles by urea precipitation method to protect diamond in borosilicate glass. The FESEM results showed that the ZnO coating was formed by plate-shaped particles. According to the TG results, the onset oxidation temperature of the ZnO-coated diamond was about 70 degrees C higher than the pristine diamond. The EDS results showed that ZnO diffused into the borosilicate glass during sintering. As the result, the bending strength of the composites containing ZnO-coated diamond was increased by 24% compared to that of the composites containing pristine diamond. PMID- 26042687 TI - Synthesis, characterization and in vitro study of magnetic biphasic calcium sulfate-bioactive glass. AB - Calcium sulfate-bioactive glass (CSBG) composites doped with 5, 10 and 20 mol% Fe were synthesized using quick alkali sol-gel method. X-ray diffraction (XRD) data of samples heated at 700 degrees C revealed the presence of anhydrite, while field emission scanning electron microscopy (FESEM) and energy dispersive X-ray (EDX) characterization confirmed the formation of nano-sized CSBGs. The UV-vis studies confirmed that the main iron species in 5% Fe and 10% Fe doped CSBGs were tetrahedral Fe(III) whereas that in 20% Fe doped CSBG were extra-framework FeOx oligomers or iron oxide phases. Measurement of magnetic properties of the samples by vibrating sample magnetometer (VSM) showed very narrow hysteresis loop with zero coercivity and remanence for 10% Fe and 20% Fe doped CSBG, indicating that they are superparamagnetic in nature. All samples induced the formation of apatite layer with Ca/P ratio close to the stoichiometric HA in simulated body fluid (SBF) assessment. PMID- 26042688 TI - Simultaneous determination of naphthol isomers at poly(3-methylthiophene)-nano-Au modified electrode with the enhancement of surfactant. AB - A polymer film incorporated gold nanoparticle modified electrode was fabricated. The fabricated process involved eletrodeposition of gold nanoparticles and electropolymerization of the 3-methylthiophene (abbreviated 3MT) onto the glassy carbon electrode (GCE). The resulting electrode (P3MT-nano-Au/GCE) was characterized by scanning electron microscopy (SEM), and a simultaneous determination of naphthol isomers at P3MT-nano-Au/GCE was studied using semi derivative voltammetry. Because of the synergistic effect of gold nanoparticles and poly(3MT), the sensitivity and distinguishability in the simultaneous determination of naphthol isomers were greatly increased. Besides, a further increase in the detecting sensitivity of naphthol isomers could be obtained in the presence of surfactant, cetyl trimethyl ammonium bromide (CTAB). Also, the role of different kinds of surfactants was texted and the action mechanism was discussed in detail. Under the optimal conditions, the linear calibration ranges of the determination of naphthols were 7.0*10(-7) to 1.5*10(-4) mol/L for 1 naphthol and 1.0*10(-6) to 1.5*10(-4) mol/L for 2-naphthol with detection limits of 1.0*10(-7) and 3.0*10(-7) mol/L (S/N=3), respectively. PMID- 26042689 TI - A novel nitrite biosensor based on the direct electron transfer hemoglobin immobilized in the WO3 nanowires with high length-diameter ratio. AB - WO3 nanowires (WO3NWs) with high length-diameter ratio have been synthesized through a simple synthetic route without any additive and then used to immobilize hemoglobin (Hb) to fabricate a mediator-free biosensor. The morphology and structure of WO3NWs were characterized by scanning electron microscopy, transmission electronic microscopy and X-ray diffraction. Spectroscopic and electrochemical results revealed that WO3NWs are an excellent immobilization matrix with biocompatibility for redox protein, affording good protein bioactivity and stability. Meanwhile, due to unique morphology and property of the WO3 nanowires, the direct electron transfer of Hb is facilitated and the prepared biosensors displayed good performance for the detection of nitrite with a wide linear range of 1 to 4200 MUM, as well as an extremely low detection limit of 0.28 MUM. The WO3 nanowires with high length-diameter ratio could be a promising matrix for the fabrication of mediator-free biosensors, and may find wide potential applications in environmental analysis and biomedical detection. PMID- 26042690 TI - Porous niobium coatings fabricated with selective laser melting on titanium substrates: Preparation, characterization, and cell behavior. AB - Nb, an expensive and refractory element with good wear resistance and biocompatibility, is gaining more attention as a new metallic biomaterial. However, the high price of the raw material, as well as the high manufacturing costs because of Nb's strong oxygen affinity and high melting point have limited the widespread use of Nb and its compounds. To overcome these disadvantages, porous Nb coatings of various thicknesses were fabricated on Ti substrate via selective laser melting (SLM), which is a 3D printing technique that uses computer-controlled high-power laser to melt the metal. The morphology and microstructure of the porous Nb coatings, which had pores ranging from 15 to 50 MUm in size, were characterized with scanning electron microscopy (SEM). The average hardness of the coating, which was measured with the linear intercept method, was 392+/-37 HV. In vitro tests of the porous Nb coating which was monitored with SEM, immunofluorescence, and CCK-8 counts of cells, exhibited excellent cell morphology, attachment, and growth. The simulated body fluid test also proved the bioactivity of the Nb coating. Therefore, these new porous Nb coatings could potentially be used for enhanced early biological fixation to bone tissue. In addition, this study has shown that SLM technique could be used to fabricate coatings with individually tailored shapes and/or porosities from group IVB and VB biomedical metals and their alloys on stainless steel, Co-Cr, and other traditional biomedical materials without wasting raw materials. PMID- 26042691 TI - Effect of a carbonated HAP/beta-glucan composite bone substitute on healing of drilled bone voids in the proximal tibial metaphysis of rabbits. AB - A novel elastic hydroxyapatite-based composite of high surgical handiness has been developed. Its potential application in orthopedics as a filler of bone defects has been studied. The biomaterial was composed of carbonated hydroxyapatite (CHAP) granules and polysaccharide polymer (beta-1,3-glucan). Cylinders of 4mm in diameter and 6mm in length were implanted into bone cavities created in the proximal metaphysis of tibiae of 24 New Zealand white rabbits. 18 sham-operated animals were used as controls. After 1, 3 or 6 months, the rabbits were euthanized, the bones were harvested and subjected to analysis. Radiological images and histological sections revealed integration of implants with bone tissue with no signs of graft rejection. Peripheral quantitative computed tomography (pQCT) indicated the stimulating effect of the biomaterial on bone formation and mineralization. Densitometry (DXA) analysis suggested that biomineralization of bones was preceded by bioresorption and gradual disappearance of porous ceramic granules. The findings suggest that the CHAP glucan composite material enables regeneration of bone tissue and could serve as a bone defect filler. PMID- 26042692 TI - Anti-tumor activity of folate targeted biodegradable polymer-paclitaxel conjugate micelles on EMT-6 breast cancer model. AB - BACKGROUND: Paclitaxel (PTX) is a first line chemotherapy drug for breast cancer. There have been few studies reported concerning the therapeutic efficacy of paclitaxel-conjugated polymeric micelles in breast cancer in vivo. METHODS: Two kinds of PTX conjugate micelles, one of which (M(PTX)) contained 25 wt.% of PTX and the other (M(FA/PTX)) contained 22.5 wt.% of PTX and 1.4 wt.% of folate (FA), were prepared for cell apoptosis and anti-tumor activity evaluation on EMT-6 mice breast cancer models in comparison with 0.9 wt.% saline (control) and equivalent PTX. Cell apoptosis was analyzed by flow cytometry. Breast tumors were examined histologically with H&E staining and immunohistochemically by examining Bax and Bcl-2 expression. The survival status of tumor-bearing mice with different treatments was also examined. RESULTS: On day 5 of the drug administration, the average tumor masses were 0.49, 0.33, 0.22, and 0.18 g for the control, PTX, M(PTX) and M(FA/PTX) groups, respectively. The inhibition rates of tumor growth calculated for the three drug groups were 32.6%, 51.6% and 62.3%, respectively. The percentage of cell apoptosis based on flow cytometry was 1.0%, 36.6%, 55.9% and 66.1%, respectively, which showed statistically significant differences (p<0.05) between three drug groups and the control group. Bcl-2 expression of PTX and M(FA/PTX) groups was lower than control group (p<0.05). Bax expression of drug groups was higher than control group (p<0.05). At an equivalent paclitaxel dose of 26.7 mg/kg, the average survival time was 33 days, 31 days, 34 days and 42 days, respectively (p<0.05). CONCLUSION: The M(FA/PTX) have better anti-tumor activity and are promising in treatment of human breast cancers. PMID- 26042693 TI - A new approach to fabricate bioactive silica binary and ternary hybrid microspheres. AB - Bioactive microspheres represent an extremely developing field in biomedical applications, such as bone tissue engineering and bone pathologies (metabolic bone disease, trauma or bone cancer). Their innate osteogenic properties have turned them to biomaterials with improved added value. The aim of this study was to prepare binary and ternary hybrid silica microspheres with enhanced bioactive properties according to our previous synthetic procedure. In brief, the synthetic approach based on the emulsifier free-emulsion polymerization method, by which polystyrene (PS) microspheres were produced and used as core template for the sol gel coating method. During the coating reaction an inorganic shell was fabricated by silane and phosphate precursors (tetraethoxysilane, trimethylphosphate). The final microspheres were treated by different catalyst concentrations, during the coating process, which resulted in the formation of diffused voids (a porous-like structure). The in vitro bioactivity of the resultant microspheres was studied by treatment in simulated body fluids (SBF). The bioassay evaluation indicates the deposition of a bone-like apatite layer on microspheres' surface with enhanced bioresorbability, which verifies their bioactivity and permits their application in the treatment of bone pathologies. PMID- 26042694 TI - Local administration of stromal cell-derived factor-1 promotes stem cell recruitment and bone regeneration in a rat periodontal bone defect model. AB - Stromal cell-derived factor-1 (SDF-1) recruits adult stem/progenitor cells via its specific receptor, C-X-C motif receptor 4 (CXCR4), to promote heart, kidney and tendon regeneration, but little is known about the effects of SDF-1 on bone regeneration in periodontal diseases. The objective of this study was to investigate whether local administration of SDF-1 in a collagen membrane scaffold enhanced the recruitment of host stem cells and improved periodontal bone defect repair. To this end, bone defects were established on the buccal side of bilateral mandibles in Wistar rats. After application of collagen membranes loaded with SDF-1 or phosphate-buffered saline (PBS) to the defects, the effects of SDF-1 on stem cell recruitment, inflammatory cell responses, angiogenesis, osteoclastogenesis, scaffold degradation, and bone regeneration were evaluated. It showed that SDF-1 recruited host-derived mesenchymal stem cells and hematopoietic stem cells to the wound area and significantly reduced the CD11b+ inflammatory cell response. Moreover, SDF-1 increased vascular formation, induced early bone osteoclastogenesis, accelerated scaffold degradation, and promoted the quality and quantity of regenerated bone. Our results suggest that this cell-free approach by local administration of SDF-1 may be an effective strategy for development as a simple and safe technique for periodontal bone regeneration. PMID- 26042695 TI - Composite bone cements loaded with a bioactive and ferrimagnetic glass-ceramic: Leaching, bioactivity and cytocompatibility. AB - In this work, composite bone cements, based on a commercial polymethylmethacrylate matrix (Palamed(r)) loaded with ferrimagnetic bioactive glass-ceramic particles (SC45), were produced and characterized in vitro. The ferrimagnetic bioactive glass-ceramic belongs to the system SiO2-Na2O-CaO-P2O5 FeO-Fe2O3 and contains magnetite (Fe3O4) crystals into a residual amorphous bioactive phase. Three different formulations (containing 10, 15 and 20 wt.% of glass-ceramic particles respectively) have been investigated. These materials are intended to be applied as bone fillers for the hyperthermic treatment of bone tumors. The morphological, compositional, calorimetric and mechanical properties of each formulation have been already discussed in a previous paper. The in vitro properties of the composite bone cements described in the present paper are related to iron ion leaching test (by graphite furnace atomic absorption spectrometer), bioactivity (i.e. the ability to stimulate the formation of a hydroxyapatite - HAp - layer on their surface after soaking in simulated body fluid SBF) and cytocompatibility toward human osteosarcoma cells (ATCC CRL-1427, Mg63). Morphological and chemical characterizations by scanning electron microscopy and energy dispersion spectrometry have been performed on the composite samples after each test. The iron release was negligible and all the tested samples showed the growth of HAp on their surface after 28 days of immersion in a simulated body fluid (SBF). Cells showed good viability, morphology, adhesion, density and the ability to develop bridge-like structures on all investigated samples. A synergistic effect between bioactivity and cell mineralization was also evidenced. PMID- 26042696 TI - Y-doped zinc oxide (YZO) nanoflowers, microstructural analysis and test their antibacterial activity. AB - Self-assembled 3D flower-like yttrium-doped zinc oxide (YZO) microstructures composed of nanorods were prepared by hydrothermal-precipitation, and tested their antibacterial activity. The morphological, structural, and compositional properties of YZO nanoflowers were characterized by various techniques, which confirmed a well-crystallized wurtzite hexagonal phase. X-ray photoelectron spectroscopy (XPS) of YZO nanopowder showed the 3d core level spectra of yttrium (Y), which formed by two components at about 158.2 eV (3d5/2) and 160.4 eV (3d3/2). The antibacterial activity of YZO nanoflowers were investigated using both gram-positive and gram-negative microorganisms. Enhancement in antibacterial activity was observed by the incorporation of yttrium (Y: 2 at.%) of nanorod based-flowers because of increased surface area. The prepared YZO nanocomposite showed potential as an antibacterial agent with applications in controlling the spread of infections and also the ability of fast antibacterial activity which can hinder the re-emergence of infection. PMID- 26042697 TI - Synthesis and characterization of Ag-containing calcium phosphates with various Ca/P ratios. AB - Ag-containing calcium phosphate (CaP) powders were synthesized by a precipitation method using aqueous solutions of calcium nitrate, silver nitrate, and ammonium phosphate. The powders were sintered at temperatures ranging from 1173 to 1473 K. The charged atomic ratios of (Ca+Ag)/P and Ag/(Ca+Ag) in solution were varied from 1.33 to 1.67 and from 0 to 0.30, respectively. The Ag content in the as precipitated CaP powders increased with the charged Ag/(Ca+Ag) atomic ratio in solution and was lower than the charged Ag/(Ca+Ag) value. The as-precipitated CaP powders consisted of hydroxyapatite (HA) as the main phase. Ag nanoparticles were observed on the as-precipitated HA particles under all conditions of Ag addition. After the sintering, HA, beta-TCP (tricalcium phosphate), alpha-TCP, and beta-CPP (calcium pyrophosphate) were mainly detected as CaPs on the basis of the Ca/P atomic ratio of the as-precipitated powders. The addition of Ag stabilized the beta-TCP phase, and the distribution of Ag in beta-TCP was homogeneous. A metallic Ag phase coexisted with HA. The solubility of Ag in HA was estimated to be 0.0019-0.0061 (Ag/(Ca+Ag)) atomic ratio, which was lower than that in beta-TCP (higher than 0.0536) and higher than that of beta-CPP (below the detection limit of analyses). PMID- 26042698 TI - Bio-synthesis of silver nanoparticles using Potentilla fulgens Wall. ex Hook. and its therapeutic evaluation as anticancer and antimicrobial agent. AB - The present study aims to develop an easy and eco-friendly method for the synthesis of silver nanoparticles using extracts from the medicinal plant, Potentilla fulgens and evaluation of its anticancer and antimicrobial properties. The various parts of P. fulgens were screened and the root extract was found to have the highest potential for the synthesis of nanoparticles. The root extracts were able to quickly reduce Ag(+) to Ag(0) and stabilized the nanoparticles. The synthesis of nanoparticles was confirmed by UV-Visible spectrophotometry and further characterized using Zeta sizer, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). Electron microscopic study showed that the size of the nanoparticle was in the range of 10 to 15 nm and spherical in shape. The studies of phytochemical analysis of nanoparticles indicated that the adsorbed components on the surface of nanoparticles were mainly flavonoid in nature. Furthermore, nanoparticles were evaluated as cytotoxic against various cancer cell lines and 0.2 to 12 MUg/mL nanoparticles showed good toxicity. The IC50 value of nanoparticles was found to be 4.91 and 8.23 MUg/mL against MCF-7 and U-87 cell lines, respectively. Additionally, the apoptotic effect of synthesized nanoparticles on normal and cancer cells was studied using trypan blue assay and flow-cytometric analysis. The results indicate the synthesized nanoparticle ability to kill cancer cells compared to normal cells. The nanoparticles also exhibited comparable antimicrobial activity against both Gram positive and Gram-negative bacteria. PMID- 26042699 TI - The red-eared slider turtle carapace under fatigue loading: The effect of rib suture arrangement. AB - Biological structures consisting of strong boney elements interconnected by compliant but tough collagenous sutures are abundantly found in skulls and shells of, among others, armadillos, alligators, turtles and more. In the turtle shell, a unique arrangement of alternating rigid (rib) and flexible (suture) elements gives rise to superior mechanical performance when subjected to low and high strain-rate loadings. However, the resistance to repeated load cycling - fatigue of the turtle shell has yet to be examined. Such repeated loading could approximately simulate the consecutive high-stress bending loads exerted during (a predator) biting or clawing. In the present study flexural high-stress cyclic loads were applied to rib and suture specimens, taken from the top dorsal part of the red-eared slider turtle shell, termed carapace. Subsequently, to obtain a more complete and integrated fatigue behavior of the carapace, specimens containing a complex alternating rib-suture-rib-suture-rib configuration were tested as well. Although the sutures were found to be the least resistant to repeated loads, a synergistic effect was observed for the complex specimens, displaying improved fatigue durability compared to the individual (suture or even rib) constituents. This study may assist in the design of future high-stress fatigue-resistant materials incorporating complex assemblies of rigid and flexible elements. PMID- 26042700 TI - Modification of glassy carbon electrode with a bilayer of multiwalled carbon nanotube/tiron-doped polypyrrole: Application to sensitive voltammetric determination of acyclovir. AB - A novel voltammetric sensor based on glassy carbon electrode (GCE) modified with a thin film of multi-walled carbon nanotubes (MWCNTs) coated with an electropolymerized layer of tiron-doped polypyrrole was developed and the resulting electrode was applied for the determination of acyclovir (ACV). The surface morphology and property of the modified electrode were characterized by field emission scanning electron microscopy and electrochemical impedance spectroscopy techniques. The electrochemical performance of the modified electrode was investigated by means of linear sweep voltammetry (LSV). The effect of several experimental variables, such as pH of the supporting electrolyte, drop size of the cast MWCNTssuspension, number of electropolymerization cycles and accumulation time was optimized by monitoring the LSV response of the modified electrode toward ACV. The best response was observed at pH7.0 after accumulation at open circuit for 160 s. Under the optimized conditions, a significant electrochemical improvement was observed toward the electrooxidation of ACV on the modified electrode surface relative to the bare GCE, resulting in a wide linear dynamic range (0.03-10.0MU M) and a low detection limit (10.0 nM) for ACV. Besides high sensitivity, the sensor represented high stability and good reproducibility for ACV analysis, and provided satisfactory results for the determination of this compound in pharmaceutical and clinical preparations. PMID- 26042701 TI - Effect of size of bioactive glass nanoparticles on mesenchymal stem cell proliferation for dental and orthopedic applications. AB - Bioactive glass nanoparticles (nanostructured bioglass ceramics or nBGs) have been widely employed as a filler material for bone tissue regeneration. The physical properties of nBG particles govern their biological actions. In this study, the impact of the size of nBG particles on mouse mesenchymal stem cell (mMSC) proliferation was investigated. Three different sizes of nBG particles were prepared via the sol-gel method with varying concentrations of the surfactant and polyethylene glycol (PEG), and the particles were characterized. Increased concentrations of PEG decreased the size of nBG particles (nBG-1: 74.7+/-0.62 nm, nBG-2: 43.25+/-1.5 nm, and nBG-3: 37.6+/-0.81 nm). All three nBGs were non-toxic at a concentration of 20mg/mL. Increased proliferation was observed in mMSCs treated with smaller nBG particles. Differential mRNA expression of cyclin A2, B2, D1, and E1 genes induced by nBG particles was noticed in the mMSCs. nBG-1 and nBG-3 particles promoted cells in the G0/G1 phase to enter the S and G2/M phases. nBG particles activated ERK, but prolonged activation was achieved with nBG-3 particles. Among the prepared nBG particles, nBG-3 particles showed enhanced mMSC proliferation via the sustained activation of ERKs, upregulation of cyclin gene(s) expression, and promotion of cell transition from the G0/G1 phase to the S and G2/M phases. Thus, this study indicates that small nBG particles have clinical applications in dental and bone treatments as fillers or bone-tissue bond forming materials. PMID- 26042702 TI - Effect of hydroxyapatite whisker surface graft polymerization on water sorption, solubility and bioactivity of the dental resin composite. AB - The aim of this study was to investigate the effect of poly bisphenol A glycidyl methacrylate (poly(Bis-GMA)) grafted hydroxyapatite whisker (PGHW) on water sorption, solubility and bioactivity of the dental resin composite. PGHW with different graft ratios was synthesized, by controlling grafting time, and filled into a dental resin matrix respectively. Fracture surface of the resin composites showed that PGHW-matrix interfacial compatibility and bonding were enhanced, and lower amounts of poly(Bis-GMA) on PGHW-1h (graft ratio: 8.5 wt.%) could facilitate the dispersion of PGHW-1 h in the composite. The PGHW-1h filled resin composite absorbed the lowest amount of water (27.16 MUg/mm(3), 7 d), whereas the untreated hydroxyapatite whisker (HW) filled resin composite absorbed the highest. PGHW with higher graft ratios induced the decrease of the monomer conversion in the resulting composite, therefore, the PGHW-18 h (graft ratio: 32.8 wt.%) filled resin composite had the highest solubility. In vitro bioactivity of the studied resin composites in simulated body fluid (SBF) showed that a dense and continuous apatite layer was formed on the surface of the resin composite, and the surface graft polymerization on the whisker did not significantly affect the apatite forming ability of the resin composite. It was revealed that graft polymerization of an appropriate amount of Bis-GMA onto HW could be an effective method to improve the interfacial properties and stability in water of the dental resin composite without compromising the bioactivity. PMID- 26042704 TI - Synthesis, recognition characteristics and properties of l-3-n-butylphthalide molecularly imprinted polymers as sorbent for solid-phase extraction through precipitation polymerization. AB - L-3-n-butylphthalide molecularly imprinted polymers (MIPs) were synthesized using l-3-n-butylphthalide as template molecule, acrylamide as functional monomer, ethylene glycol dimethacrylate as cross-linking agent, and acetone as the porogenic solvent through precipitation polymerization. The non-imprinted polymers (NIPs) were prepared with the same procedure, but with the absence of template molecule. The optimum preparation conditions of the MIPs such as the functional monomer, the porogenic solvent, the molar ratio of the template to the functional monomer and the molar ratio of the template to the cross-linker were investigated in detail. Prior to the polymerization, the molecular simulation with the computer-aided design was used to help choose a suitable polymerization porogen for the molecularly imprinted pre-assembled system and study the interactions between l-NBP and the functional monomers. The synthesized polymers were characterized with FTIR and SEM to observe their structures as well as the morphologies, and their adsorption properties were respectively evaluated by static and dynamic adsorption as well as selectivity experiments. Scatchard analyses revealed that there were high and low affinity sites formed in the MIPs, which elucidated good affinity to l-NBP in the ethanol system. The adsorption capacity of the MIPs for l-NBP was 3.561 mg g(-1), with an imprinting factor (alpha) of 2.321 when compared with that of the NIPs. Scatchard analysis illustrated that the binding sites with affinity for l-3-n-butylphthalide molecules were formed in the prepared MIPs. PMID- 26042703 TI - Exploring the affinity binding of alkylmaltoside surfactants to bovine serum albumin and their effect on the protein stability: A spectroscopic approach. AB - Steady-state and time-resolved fluorescence together with circular dichroism (CD) spectroscopic studies was performed to examine the interactions between bovine serum albumin (BSA) and two alkylmaltoside surfactants, i.e. n-decyl-beta-D maltoside (beta-C10G2) and n-dodecyl-beta-D-maltoside (beta-C12G2), having identical structures but different tail lengths. Changes in the intrinsic fluorescence of BSA from static as well as dynamic measurements revealed a weak protein-surfactant interaction and gave the corresponding binding curves, suggesting that the binding mechanism of surfactants to protein is essentially cooperative in nature. The behavior of both surfactants is similar, so that the differences detected were attributed to the more hydrophobic nature of beta C12G2, which favors the adsorption of micelle-like aggregates onto the protein surface. These observations were substantially demonstrated by data derived from synchronous, three-dimensional and anisotropy fluorescence experiments. Changes in the secondary structure of the protein induced by the interaction with surfactants were analyzed by CD to determine the contents of alpha-helix and beta strand. It was noted that whereas the addition of beta-C10G2 appears to stabilize the secondary structure of the protein, beta-C12G2 causes a marginal denaturation of BSA for a protein:surfactant molar ratio as high as 1 to 100. PMID- 26042705 TI - Bioactive glass reinforced elastomer composites for skeletal regeneration: A review. AB - Biodegradable elastomers have clinical applicability due to their biocompatibility, tunable degradation and elasticity. The addition of bioactive glasses to these elastomers can impart mechanical properties sufficient for hard tissue replacement. Hence, a composite with a biodegradable polymer matrix and a bioglass filler can offer a method of augmenting existing tissue. This article reviews the applications of such composites for skeletal augmentation. PMID- 26042706 TI - Analysis of mercerization process based on the intensity change of deconvoluted resonances of (13)C CP/MAS NMR: Cellulose mercerized under cooling and non cooling conditions. AB - The area intensity change of C1, C4, and C6 in spectrum obtained by (13)C CP/MAS NMR and the mutual relationship between their changes were examined for cellulose samples treated with various concentrations of aqueous NaOH solutions under non cooling and cooling conditions. The area intensity of C1-up and C6-down changed cooperatively with that of C4-down which corresponds to the crystallinity of samples: "-up" and "-down" are the up- and down- field component in a splitting peak of NMR spectrum, respectively. The intensity change of C1-up starts to decrease with decreasing in that of C4-down after that of C6-down is almost complete. These changes were more clearly observed for samples treated under cooling condition. It can be suggested that their characteristic change relates closely to the change in conformation of cellulose chains by induced decrystallization and the subsequent crystallization of cellulose II, and presumed that their changes at microscopic level relate to the macroscopic morphological changes such as contraction along the length of cellulose chains and recovery along the length. PMID- 26042707 TI - Self-assembly and cytotoxicity study of PEG-modified ursolic acid liposomes. AB - While ursolic acid (UA), one of the most broadly known triterpene compounds, has proved to be effective in cancer therapy, the applications of UA is limited due to its poor aqueous solubility and low bioavailability. The aim of our study was to prolong circulation time and enhance uptake of liposomes in tumor tissues through the modification of UA liposomes via water-soluble polyethylene glycol (PEG). In addition, this research also focuses on physicochemical properties of the liposome formulations, including encapsulation efficiency, particle morphology, size, stability, release rate in vitro and cytotoxicity test. The obtained liposomes were spherical particles with mean particle diameters around 100-200 nm. And the Fourier transform infrared spectroscopy (FTIR) indicated that PEG had been anchored successfully to the liposomes. Based on our experimental data achieved, PEG-modified UA liposomes possessed higher stability than conventional liposomes, and the release rate of UA from PEG-modified liposomes was slower when compared with those of UA solution and conventional liposomes. Meanwhile, the liposomal UA showed relatively low cytotoxic effect than UA conventional liposomes within 24h, which was consistent with their release rates. PMID- 26042708 TI - Influence of ethanol content in the precipitation medium on the composition, structure and reactivity of magnesium-calcium phosphate. AB - Biocompatible amorphous magnesium calcium phosphate (AMCP) particles were synthesized using ethanol in precipitation medium from moderately supersaturated solution at pH10. Some synthesis parameters such as, (Mg+Ca):P, Mg:Ca ratio and different drying methods on the structure and stability of as-produced powder was studied and characterized using SEM, XRD and cell cytocompatibility. The results showed that depending on the Mg(2+) concentration, nano crystalline Struvite (MgNH4PO4.6H2O) can also be alternatively formed. However, the as-formed AMCP preserved its amorphous structure after 7 days of incubation in SBF for tested phosphate concentration, and equally ionic concentration of magnesium and calcium. PMID- 26042709 TI - Hybrid collagen-based hydrogels with embedded montmorillonite nanoparticles. AB - Montmorillonite nanoparticles have been physically incorporated within a crosslinked collagen/poly(N-isopropyl acrylamide) network in order to adjust the properties of the stimuli-responsive hybrid systems. The research underlines both the influence of hydrogel composition and nanoparticle type on hybrid hydrogel properties. The dispersion of the montmorillonite nanoparticles in polymeric matrix have been visualized by SEM, TEM and AFM techniques and quantitatively and qualitatively estimated using near infrared chemical imaging. The electrical charge of the nanoparticles influenced the polymeric chain arrangement and the pore size. The morphologies of the nanoparticulated layers are partially exfoliated or intercalated and uniformly dispersed through the polymeric semi interpenetrated network based on collagen and poly(N-isopropyl acrylamide). The hybrid hydrogels exhibit pseudoplastic behavior and the addition of nanoparticles has resulted in the increase of the complex viscosity. The adhesion capacity was affected mainly by the presence of organically modified montmorillonites. PMID- 26042710 TI - Electrodeposition of chitosan/gelatin/nanosilver: A new method for constructing biopolymer/nanoparticle composite films with conductivity and antibacterial activity. AB - Electrodeposition of chitosan provides a controllable means to simultaneously assemble biological materials and nanoparticles for various applications. Here, we present a new method to construct biopolymer/nanoparticle composite films with conductivity and antibacterial activity by electrodeposition of chitosan/gelatin/nanosilver. Besides, this method can be employed to build biopolymer/nanoparticle composite hydrogels or coatings on various electrodes or conductive substrates. We initially use a simple approach to prepare the aqueous nanosilver that can be well-dispersed in water. Then, the codeposition mixture containing chitosan, gelatin and nanosilver is prepared, and it can be electrodeposited onto different electrodes or conductive substrates in response to imposed electrical signals. After electrodeposition, it is found that the deposited hydrogels and their dried films are smooth and homogeneous due to the elimination of H2 bubbles by addition of H2O2 in electrodeposition process. Importantly, the composite films are strong enough to completely and readily peel from the electrodes after they reacted with 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDC), which can build a type of biopolymer/nanoparticle film for further applications. Furthermore, the electrodeposition technique is able to offer controllable and convenient method to construct the composite films with diverse shapes. The composite films display improved conductivity and in vitro antibacterial activity against Escherichia coli and Staphylococcus aureus, which may provide attractive applications in biomedical fields such as artificial muscles, skin biomaterials and neuroprosthetic implants. PMID- 26042711 TI - Ball-milled solid dispersions of BCS Class IV drugs: Impact on the dissolution rate and intestinal permeability of acyclovir. AB - Acyclovir, an analog of 2'-deoxyguanosine, is one of the most important drugs in the current approved antiviral treatment. However, it's biopharmaceutical properties, contribute to acyclovir's poor oral bioavailability, which restricts the clinical use of the drug. In this view, the aim of this work was to improve the dissolution rate and intestinal permeability of acyclovir through the development of ball milling solid dispersions with the hydrophilic carriers Pluronic F68(r), hydroxypropylmethyl cellulose K100M(r) and chitosan. Solid dispersions were obtained and completely characterized through different solid state techniques. The solid state data demonstrated a decrease in the crystallinity (amorphous phase and defects) and the presence of hydrogen bonds for SD HPMC and SD CTS. The enhancement of dissolution rates was observed for all SDs developed. In addition, no detrimental effects over the in vitro antiviral activity were detected. The solid dispersions with Pluronic F68(r) significantly improved the intestinal permeability of acyclovir across Caco-2 cells. In summary, the SDs developed in this study could be considered as potential systems for solid dosage forms containing acyclovir with superior biopharmaceutical properties. PMID- 26042712 TI - DNA, the biopolymer as a target material for metalloinsertors: From chemistry to preclinical implications. AB - The coordination of therapeutically interesting designed complexes of stoichiometry [ML(Met)Cl2] [where M=Cu(II), Co(II), Ni(II), Mn(II) and Zn(II), L=benzylidene-4-aminoantipyrine and Met=methionine] has been ascertained on the basis of physicochemical techniques. Their interaction with CT DNA reveals that they are good intercalators. The anticancer mechanism of our complexes is documented from their enhanced DNA splitting personalities under physiological conditions. To reveal the chemotherapeutic action of these complexes, we explored the inflammatory response, analgesic and antioxidant activities. Moreover, all the complexes show good antimicrobial activity against few bacterial and fungal strains. Our study has identified the mechanism of action of these complexes on inhibiting tumor cells and suggested that they have great potential as novel anticancer agents. PMID- 26042713 TI - Influence of ZnO/MgO substitution on sintering, crystallisation, and bio-activity of alkali-free glass-ceramics. AB - The present study reports on the influence of partial replacement of MgO by ZnO on the structure, crystallisation behaviour and bioactivity of alkali-free bioactive glass-ceramics (GCs). A series of glass compositions (mol%): 36.07 CaO (19.24-x) MgO-x ZnO-5.61 P2O5-38.49 SiO2-0.59 CaF2 (x=2-10) have been synthesised by melt-quench technique. The structural changes were investigated by solid-state magic angle spinning nuclear magnetic resonance (MAS-NMR), X-ray diffraction and differential thermal analysis. The sintering and crystallisation behaviours of glass powders were studied by hot-stage microscopy and differential thermal analysis, respectively. All the glass compositions exhibited good densification ability resulting in well sintered and mechanically strong GCs. The crystallisation and mechanical behaviour were studied under non-isothermal heating conditions at 850 degrees C for 1h. Diopside was the primary crystalline phase in all the GCs followed by fluorapatite and rankinite as secondary phases. Another phase named petedunnite was identified in GCs with ZnO content >4 mol. The proliferation of mesenchymal stem cells (MSCs) and their alkaline phosphatase activity (ALP) on GCs was revealed to be Zn-dose dependent with the highest performance being observed for 4 mol% ZnO. PMID- 26042714 TI - Preparation, in vitro mineralization and osteoblast cell response of electrospun 13-93 bioactive glass nanofibers. AB - In this study, silicate based 13-93 bioactive glass fibers were prepared through sol-gel processing and electrospinning technique. A precursor solution containing poly (vinyl alcohol) and bioactive glass sol was used to produce fibers. The mixture was electrospun at a voltage of 20 kV by maintaining tip to a collector distance of 10 cm. The amorphous glass fibers with an average diameter of 464+/ 95 nm were successfully obtained after calcination at 625 degrees C. Hydroxyapatite formation on calcined 13-93 fibers was investigated in simulated body fluid (SBF) using two different fiber concentrations (0.5 and 1 mg/ml) at 37 degrees C. When immersed in SBF, conversion to a calcium phosphate material showed a strong dependence on the fiber concentration. At 1mg/ml, the surface of the fibers converted to the hydroxyapatite-like material in SBF only after 30 days. At lower solid concentrations (0.5 mg/ml), an amorphous calcium phosphate layer formation was observed followed by the conversion to hydroxyapatite phase after 7 days of immersion. The XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H Tetrazolium-5-Carboxanilide) assay was conducted to evaluate the osteoblast cell response to the bioactive glass fibers. PMID- 26042715 TI - Guided proliferation and bone-forming functionality on highly ordered large diameter TiO2 nanotube arrays. AB - The significantly enhanced osteoblast adhesion, proliferation and alkaline phosphatase (ALP) activity were observed on TiO2 nanotube surface in recent studies in which the scale of nanotube diameter was restricted under 100 nm. In this paper, a series of highly ordered TiO2 nanotube arrays with larger diameters ranging from 150 nm to 470 nm were fabricated via high voltage anodization. The behaviors of MC3T3-E1 cells in response to the diameter-controlled TiO2 nanotubes were investigated. A contrast between the trend of proliferation and the trend of cell elongation was observed. The highest cell elongation (nearly 10:1) and the lowest cell number were observed on the TiO2 nanotube arrays with 150 nm diameter. While, the lowest cell elongation and highest cell number were achieved on the TiO2 nanotube arrays with 470 nm diameter. Furthermore, the ALP activity peaked on the 150 nm diameter TiO2 nanotube arrays and decreased dramatically with the increase of nanotube diameter. Thus a narrow range of diameter (100-200 nm) that could induce the greatest bone-forming activity is determined. It is expected that more delicate design of orthopedic implant with regional abduction of cell proliferation or bone forming could be achieved by controlling the diameter of TiO2 nanotubes. PMID- 26042716 TI - Morphology impact on oxygen sensing ability of Ru(dpp)3Cl2 containing biocompatible polymers. AB - Especially for tissue engineering applications, the diffusion of oxygen is a critical factor affecting spatial distribution and migration of cells. The cellular oxygen demand also fluctuates depending on tissue type and growth phase. Sensors that determine dissolved oxygen levels under biological conditions provide critical metabolic information about the growing cells as well as the state of the tissue culture within the tissue scaffold. This work focused on the effect of the scaffold morphology on the oxygen sensing response time. It was found that electrospun scaffolds had a faster oxygen-sensing response time than their bulk film counterparts. Tris-(4,7-diphenyl-1,10-phenanthroline) ruthenium (II) dichloride doped electrospun fiber mats of polycaprolactone (PCL) were found to be the most responsive to the presence of oxygen, followed by polyethylene (PEO) glycol mats. Systems containing poly vinyl alcohol were found to be the least responsive. This would suggest that, out of all the polymers tested, PCL and PEO are the most suitable biomaterials for oxygen-sensing applications. PMID- 26042717 TI - Antibacterial activity of magnetic iron oxide nanoparticles synthesized by laser ablation in liquid. AB - In this study, (50-110 nm) magnetic iron oxide (alpha-Fe2O3) nanoparticles were synthesized by pulsed laser ablation of iron target in dimethylformamide (DMF) and sodium dodecyl sulfate (SDS) solutions. The structural properties of the synthesized nanoparticles were investigated by using Fourier Transform Infrared (FT-IR) spectroscopy, UV-VIS absorption, scanning electron microscopy (SEM), atomic force microscopy (AFM), and X-ray diffraction (XRD). The effect of laser fluence on the characteristics of these nanoparticles was studied. Antibacterial activities of iron oxide nanoparticles were tested against Gram-positive; Staphylococcus aureus and Gram-negative; Escherichia coli, Pseudomonas aeruginosa and Serratia marcescens. The results showed a noteworthy inhibition on both bacterial strains. The preparation conditions were found to affect significantly the antibacterial activity of these nanoparticles. The synthesized magnetic nanoparticles were used to capture rapidly S. aureus bacteria under the magnetic field effect. PMID- 26042718 TI - Green synthesis, characterization of gold and silver nanoparticles and their potential application for cancer therapeutics. AB - In the present article, we demonstrate the delivery of anti-cancer drug to the cancer cells using biosynthesized gold and silver nanoparticles (b-AuNP & b AgNP). The nanoparticles synthesized by using Butea monosperma (BM) leaf extract are thoroughly characterized by various analytical techniques. Both b-AuNP and b AgNP are stable in biological buffers and biocompatible towards normal endothelial cells (HUVEC, ECV-304) as well as cancer cell lines (B16F10, MCF-7, HNGC2 & A549). Administration of nanoparticle based drug delivery systems (DDSs) using doxorubicin (DOX) [b-Au-500-DOX and b-Ag-750-DOX] shows significant inhibition of cancer cell proliferation (B16F10, MCF-7) compared to pristine drug. Therefore, we strongly believe that biosynthesized nanoparticles will be useful for the development of cancer therapy using nanomedicine approach in near future. PMID- 26042719 TI - Thrombogenicity and biocompatibility studies of reduced graphene oxide modified acellular pulmonary valve tissue. AB - Current strategies in tissue engineering seek to obtain a functional tissue analogue by either seeding acellular scaffolds with cells ex vivo or repopulating them with cells in vivo, after implantation in patients. To function properly, the scaffold should be non-thrombogenic and biocompatible. Especially for the case of in vivo cell repopulation, the scaffold should be prepared in a manner that protects the tissue against platelet activation and adhesion. Anti thrombogenicity can be achieved by chemical or physical surface modification. The aim of our study was to evaluate the platelet activation and thrombogenic properties of an acellular tissue scaffold that was surface modified with reduced graphene oxide (rGO). Graphene oxide was prepared by a modified Hummers method. For the study, an acellular pulmonary valve conduit modified with rGO was used. The rGO modified tissue samples were subjected to in vitro testing through interaction with whole blood under simulated laminar flow conditions. The following cellular receptors were then analysed: CD42a, CD42b, CD41a, CD40, CD65P and PAC-1. In parallel, the adhesion of platelets (CD62P positive), leukocytes (CD45 positive) and platelet-leukocyte aggregates (CD62P/CD45 positive) on the modified surface was evaluated. As a reference, non-coated acellular tissue, Poly l lysine and fibronectin coated tissue were also tested. The rGO surface was also analysed for biocompatibility by performing a cytotoxicity test, TUNEL assay and Cell Cycle analysis. There was no significant difference in platelet activation and adhesion between the study groups. The only significant difference was observed for the PAC-1 receptor between Poly-l lysine group and rGO and the percentage of PAC-1 positive cells was 6% and 18% respectively. The average number of activated platelets (CD62P) in the field of view was 1, while the average number of leukocytes in the field of view was 3. No adherent platelet leukocyte aggregates were observed. There were no significant differences in the DNA fragmentation. No significant effect of rGO on the amount of cells in different phases of the cell cycle was observed. Cytotoxicity indicates that the rGO can damage cells in direct contact but have no effect on the viability of fibroblasts in indirect contact. PMID- 26042720 TI - The influence of Sr content in calcium phosphate coatings. AB - In this study calcium phosphate coatings with different amounts of strontium (Sr) were prepared using a biomineralization method. The incorporation of Sr changed the composition and morphology of coatings from plate-like to sphere-like morphology. Dissolution testing indicated that the solubility of the coatings increased with increased Sr concentration. Evaluation of extracts (with Sr concentrations ranging from 0 to 2.37 MUg/mL) from the HA, 0.06Sr, 0.6Sr, and 1.2Sr coatings during in vitro cell cultures showed that Sr incorporation into coatings significantly enhanced the ALP activity in comparison to cells treated with control and HA eluted media. These findings show that calcium phosphate coatings could promote osteogenic differentiation even in a low amount of strontium. PMID- 26042721 TI - Self-assembled micro-structured sensors for food safety in paper based food packaging. AB - Natural self-assembled microstructured particles (diatomaceous earth) were used to develop a gas sensor paper with detection mechanism based on visible and distinct color changes of the sensor paper when exposed to volatile basic nitrogen compounds. The coating formulation for paper was prepared by applying diatomites, polyvinyl alcohol (PVOH), and pH sensitive dyes on acidic paper substrate. The surface coating was designed to allow a maximum gas flow through the diatomite sensors. The produced sensor paper was tested for sensitivity using different ammonia concentrations and we observed a sensitivity lower limit at 63 ppm. As a comparison, the results show comparable sensitivity levels to carbon nanotube based sensor technologies reported in literature. PMID- 26042722 TI - Cell Penetrating Peptide Adsorption on Magnetite and Silica Surfaces: A Computational Investigation. AB - Magnetic nanoparticles (MNPs) represent one of the most promising materials as they can act as a versatile platform in the field of bionanotechnology for enhanced imaging, diagnosis, and treatment of various diseases. Silica is the most common compound for preparing coated iron oxide NPs since it improves colloidal stability and the binding affinity for various organic molecules. Biomolecules such as cell penetrating peptides (CPPs) might be employed to decorate MNPs, combining their promising physicochemical properties with a cell penetrating ability. In this work, a computational investigation on adsorption of Antennapedia homeodomain-derived penetrating peptide (pAntp) on silica and magnetite (MAG) surfaces is presented. By employing umbrella sampling molecular dynamics, we provided a quantitative estimation of the pAntp-surface adsorption free energy to highlight the influence of surface hydroxylation state on the adsorption mechanism. The interaction between peptide and surface has shown to be mainly driven by electrostatics. In case of MAG surface, also an important contribution of van der Waals (VdW) attraction was observed. Our data suggest that a competitive mechanism between MNPs and cell membrane might partially inhibit the CPP to carry out its membrane penetrating function. PMID- 26042724 TI - Tungsten Doped TiO2 with Enhanced Photocatalytic and Optoelectrical Properties via Aerosol Assisted Chemical Vapor Deposition. AB - Tungsten doped titanium dioxide films with both transparent conducting oxide (TCO) and photocatalytic properties were produced via aerosol-assisted chemical vapor deposition of titanium ethoxide and dopant concentrations of tungsten ethoxide at 500 degrees C from a toluene solution. The films were anatase TiO2, with good n-type electrical conductivities as determined via Hall effect measurements. The film doped with 2.25 at.% W showed the lowest resistivity at 0.034 Omega.cm and respectable charge carrier mobility (14.9 cm(3)/V.s) and concentration (*10(19) cm(-3)). XPS indicated the presence of both W(6+) and W(4+) in the TiO2 matrix, with the substitutional doping of W(4+) inducing an expansion of the anatase unit cell as determined by XRD. The films also showed good photocatalytic activity under UV-light illumination, with degradation of resazurin redox dye at a higher rate than with undoped TiO2. PMID- 26042723 TI - Metabolism at evolutionary optimal States. AB - Metabolism is generally required for cellular maintenance and for the generation of offspring under conditions that support growth. The rates, yields (efficiencies), adaptation time and robustness of metabolism are therefore key determinants of cellular fitness. For biotechnological applications and our understanding of the evolution of metabolism, it is necessary to figure out how the functional system properties of metabolism can be optimized, via adjustments of the kinetics and expression of enzymes, and by rewiring metabolism. The trade offs that can occur during such optimizations then indicate fundamental limits to evolutionary innovations and bioengineering. In this paper, we review several theoretical and experimental findings about mechanisms for metabolic optimization. PMID- 26042725 TI - Impact of a fast-track surgery programme for pancreaticoduodenectomy. AB - BACKGROUND: Fast-track (FT) programmes are multimodal, evidence-based approaches to optimize patient outcome after surgery. The aim of this study was to evaluate the safety, clinical outcome and patients' experience of a FT programme after pancreaticoduodenectomy (PD) in a high-volume institution in Sweden. METHODS: Consecutive patients undergoing PD were studied before and after implementation of the FT programme. FT changes included earlier mobilization, standardized removal of the nasogastric tube and drain, and earlier start of oral intake. Patient experience was evaluated with European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PAN26 questionnaires 2 weeks before and 4 weeks after surgery. RESULTS: Between 2011 and 2014, 100 consecutive patients undergoing PD were studied, of whom 50 received standard care (controls), followed by 50 patients treated after implementation of the FT programme. The nasogastric tube was removed significantly earlier in the FT group, and these patients were able fully to tolerate fluids and solid food sooner after PD. Delayed gastric emptying was significantly reduced in the FT group (26 versus 48 per cent; P = 0.030). Overall morbidity remained unchanged and there were no deaths in either group. Postoperative length of hospital stay was reduced from 14 to 10 days and hospital costs were decreased significantly. Health-related quality-of-life questionnaires showed similar patterns of change, with no significant difference between groups before or after surgery. CONCLUSION: The FT programme after PD was safe. Delayed gastric emptying, hospital stay and hospital costs were all reduced significantly. Although patients were discharged 4 days earlier in the FT group, this did not influence health-related quality of life compared with standard care. PMID- 26042726 TI - Platelet function testing in transient ischaemic attack and ischaemic stroke: A comprehensive systematic review of the literature. AB - The majority of patients with ischaemic cerebrovascular disease (CVD) are not protected from further vascular events with antiplatelet therapy. Measurement of inhibition of platelet function ex vivo on antiplatelet therapy, using laboratory tests that correlate with the clinical effectiveness of these agents, would potentially enable physicians to tailor antiplatelet therapy to suit individuals. A systematic review of the literature was performed to collate all available data on ex vivo platelet function/reactivity in CVD patients, especially those treated with aspirin, dipyridamole or clopidogrel. Particular emphasis was paid to information from commonly available whole blood platelet function analysers (PFA 100(r), VerifyNow(r) and Multiplate(r)). Data on pharmacogenetic mechanisms potentially influencing high on-treatment platelet reactivity (HTPR) on antiplatelet therapy in CVD were reviewed. Two-hundred forty-nine potentially relevant articles were identified; 93 manuscripts met criteria for inclusion. The prevalence of ex vivo HTPR in CVD varies between 3-62% with aspirin monotherapy, 8-61% with clopidogrel monotherapy and 56-59% when dipyridamole is added to aspirin in the early, subacute or late phases after TIA/stroke onset. The prevalence of HTPR on aspirin was higher on the PFA-100 than on the VerifyNow in one study (p < 0.001). Furthermore, the prevalence of HTPR on aspirin was lower when one used 'novel longitudinal' rather than 'cross-sectional, case-control' definitions of HTPR on the PFA early after TIA or stroke (p = 0.003; 1 study). Studies assessing the influence of genetic polymorphisms on HTPR in CVD patients are limited, and need validation in large multicentre studies. Available data illustrate that an important proportion of CVD patients have ex vivo HTPR on their prescribed antiplatelet regimen, and that the prevalence varies depending on the definition and assay used. Large, adequately-sized, prospective multicentre collaborative studies are urgently needed to determine whether comprehensive assessment of HTPR at high and low shear stress with a range of user-friendly whole blood platelet function testing platforms, in conjunction with pharmacogenetic data, improves our ability to predict the risk of recurrent vascular events in CVD patients, and thus enhance secondary prevention following TIA or ischaemic stroke. PMID- 26042727 TI - Cortical microtubule patterning in roots of Arabidopsis thaliana primary cell wall mutants reveals the bidirectional interplay with cell expansion. AB - Cell elongation requires directional deposition of cellulose microfibrils regulated by transverse cortical microtubules. Microtubules respond differentially to suppression of cell elongation along the developmental zones of Arabidopsis thaliana root apex. Cortical microtubule orientation is particularly affected in the fast elongation zone but not in the meristematic or transition zones of thanatos and pom2-4 cellulose-deficient mutants of Arabidopsis thaliana. Here, we report that a uniform phenotype is established among the primary cell wall mutants, as cortical microtubules of root epidermal cells of rsw1 and prc1 mutants exhibit the same pattern described in thanatos and pom2-4. Whether cortical microtubules assume transverse orientation or not is determined by the demand for cellulose synthesis, according to each root zone's expansion rate. It is suggested that cessation of cell expansion may provide a biophysical signal resulting in microtubule reorientation. PMID- 26042728 TI - Abnormal amygdala function in Parkinson's disease patients and its relationship to depression. AB - Depression is a common occurrence in patients with Parkinson's disease (PD). Thus, there may be a common neural mechanism underlying the two diseases. Lewy body accumulation in specific brain areas of PD patients may damage emotion related functions, leading to depression. Among these areas, the amygdala may present with the earliest to be damaged in PD. However, it is still unclear whether amygdala structural and functional changes are related to depression in PD. We enrolled 19 depressed PD patients, 19 non-depressed PD patients, and 28 normal control subjects. Clinical assessment, including the Unified Parkinson's Disease Rating Scale, the Hamilton Rating Scale for Depression, and the Mini Mental State Examination, was carried out on all the patients. Structural and resting-state functional brain images were also acquired to assess volumetric and functional changes of the amygdala in the patients. Results showed that although there is no significant volume change, left amygdala activity increased in the PD group compared with the normal control group, and it correlated with Hamilton Rating Scale for Depression scores. Furthermore, functional connectivity between the right amygdala and fronto-parietal areas was found to be decreased in the depressed PD patients compared with non-depressed PD patients. These results suggest that abnormal amygdala function may underlie the occurrence of depression in PD. PMID- 26042729 TI - Radio-frequency capacitance spectroscopy of metallic nanoparticles. AB - Recent years have seen great progress in our understanding of the electronic properties of nanomaterials in which at least one dimension measures less than 100 nm. However, contacting true nanometer scale materials such as individual molecules or nanoparticles remains a challenge as even state-of-the-art nanofabrication techniques such as electron-beam lithography have a resolution of a few nm at best. Here we present a fabrication and measurement technique that allows high sensitivity and high bandwidth readout of discrete quantum states of metallic nanoparticles which does not require nm resolution or precision. This is achieved by coupling the nanoparticles to resonant electrical circuits and measurement of the phase of a reflected radio-frequency signal. This requires only a single tunnel contact to the nanoparticles thus simplifying device fabrication and improving yield and reliability. The technique is demonstrated by measurements on 2.7 nm thiol coated gold nanoparticles which are shown to be in excellent quantitative agreement with theory. PMID- 26042730 TI - Target Product Profile (TPP) for Chagas Disease Point-of-Care Diagnosis and Assessment of Response to Treatment. PMID- 26042731 TI - Estimating the development assistance for health provided to faith-based organizations, 1990-2013. AB - BACKGROUND: Faith-based organizations (FBOs) have been active in the health sector for decades. Recently, the role of FBOs in global health has been of increased interest. However, little is known about the magnitude and trends in development assistance for health (DAH) channeled through these organizations. MATERIAL AND METHODS: Data were collected from the 21 most recent editions of the Report of Voluntary Agencies. These reports provide information on the revenue and expenditure of organizations. Project-level data were also collected and reviewed from the Bill & Melinda Gates Foundation and the Global Fund to Fight AIDS, Tuberculosis and Malaria. More than 1,900 non-governmental organizations received funds from at least one of these three organizations. Background information on these organizations was examined by two independent reviewers to identify the amount of funding channeled through FBOs. RESULTS: In 2013, total spending by the FBOs identified in the VolAg amounted to US$1.53 billion. In 1990, FB0s spent 34.1% of total DAH provided by private voluntary organizations reported in the VolAg. In 2013, FBOs expended 31.0%. Funds provided by the Global Fund to FBOs have grown since 2002, amounting to $80.9 million in 2011, or 16.7% of the Global Fund's contributions to NGOs. In 2011, the Gates Foundation's contributions to FBOs amounted to $7.1 million, or 1.1% of the total provided to NGOs. CONCLUSION: Development assistance partners exhibit a range of preferences with respect to the amount of funds provided to FBOs. Overall, estimates show that FBOS have maintained a substantial and consistent share over time, in line with overall spending in global health on NGOs. These estimates provide the foundation for further research on the spending trends and effectiveness of FBOs in global health. PMID- 26042732 TI - Retinal Vessel Oxygen Saturation during 100% Oxygen Breathing in Healthy Individuals. AB - PURPOSE: To detect how systemic hyperoxia affects oxygen saturation in retinal arterioles and venules in healthy individuals. METHODS: Retinal vessel oxygen saturation was measured in 30 healthy individuals with a spectrophotometric retinal oximeter (Oxymap T1). Oximetry was performed during breathing of room air, 100% oxygen (10 minutes, 6L/min) and then again room air (10 minutes recovery). RESULTS: Mean oxygen saturation rises modestly in retinal arterioles during 100% oxygen breathing (94.5%+/-3.8 vs. 92.0%+/-3.7% at baseline, p<0.0001) and dramatically in retinal venules (76.2%+/-8.0% vs. 51.3%+/-5.6%, p<0.0001). The arteriovenous difference decreased during 100% oxygen breathing (18.3%+/-9.0% vs. 40.7%+/-5.7%, p<0.0001). The mean diameter of arterioles decreased during 100% oxygen breathing compared to baseline (9.7+/-1.4 pixels vs. 10.3+/-1.3 pixels, p<0.0001) and the same applies to the mean venular diameter (11.4+/-1.2 pixels vs. 13.3+/-1.5 pixels, p<0.0001). CONCLUSIONS: Breathing 100% oxygen increases oxygen saturation in retinal arterioles and more so in venules and constricts them compared to baseline levels. The dramatic increase in oxygen saturation in venules reflects oxygen flow from the choroid and the unusual vascular anatomy and oxygen physiology of the eye. PMID- 26042733 TI - The Na+/H+ Exchanger-3 (NHE3) Activity Requires Ezrin Binding to Phosphoinositide and Its Phosphorylation. AB - Na+/H+ exchanger-3 (NHE3) plays an essential role in maintaining sodium and fluid homeostasis in the intestine and kidney epithelium. Thus, NHE3 is highly regulated and its function depends on binding to multiple regulatory proteins. Ezrin complexed with NHE3 affects its activity via not well-defined mechanisms. This study investigates mechanisms by which ezrin regulates NHE3 activity in epithelial Opossum Kidney cells. Ezrin is activated sequentially by phosphatidylinositol-4,5-bisphosphate (PIP2) binding and phosphorylation of threonine 567. Expression of ezrin lacking PIP2 binding sites inhibited NHE3 activity (-40%) indicating that ezrin binding to PIP2 is required for preserving NHE3 activity. Expression of a phosphomimetic ezrin mutated at the PIP2 binding region was sufficient not only to reverse NHE3 activity to control levels but also to increase its activity (+80%) similar to that of the expression of ezrin carrying the phosphomimetic mutation alone. Calcineurin Homologous Protein-1 (CHP1) is part, with ezrin, of the NHE3 regulatory complex. CHP1-mediated activation of NHE3 activity was blocked by expression of an ezrin variant that could not be phosphorylated but not by an ezrin variant unable to bind PIP2. Thus, for NHE3 activity under baseline conditions not only ezrin phosphorylation, but also ezrin spatial-temporal targeting on the plasma membrane via PIP2 binding is required; however, phosphorylation of ezrin appears to overcome the control of NHE3 transport. CHP1 action on NHE3 activity is not contingent on ezrin binding to PIP2 but rather on ezrin phosphorylation. These findings are important in understanding the interrelation and dynamics of a CHP1-ezrin-NHE3 regulatory complex. PMID- 26042735 TI - Stimulation of Proliferation and Migration of Mouse Macrophages by Type B CpG ODNs Is F-Spondin and IL-1Ra Dependent. AB - Macrophage proliferation and migration are important for many facets of immune response. Here we showed that stimulation of macrophages with type B CpG oligodeoxynucleotides (CpG-B ODNs) such as CpG-ODN 1668 increased the production of anti-inflammatory cytokine interleukin 1 receptor antagonist (IL-1Ra) in a TLR9- and MyD88-dependent manner. The CpG-B ODNs-induced IL-1Ra increased macrophage migration and promoted macrophage proliferation by down-regulating the expression of a cell cycle negative regulator, p27 to increase cell population in the S phase. The induction of IL-1Ra by CpG-B ODNs was F-spondin dependent. Knockdown of F-spondin and IL-1Ra decreased CpG-B ODNs-induced macrophage migration whereas overexpression of IL-1Ra increased migration of those cells. These findings demonstrated novel roles for F-spondin and IL-1Ra in CpG-B ODNs mediated cell proliferation and migration of macrophages. PMID- 26042734 TI - Host reticulocytes provide metabolic reservoirs that can be exploited by malaria parasites. AB - Human malaria parasites proliferate in different erythroid cell types during infection. Whilst Plasmodium vivax exhibits a strong preference for immature reticulocytes, the more pathogenic P. falciparum primarily infects mature erythrocytes. In order to assess if these two cell types offer different growth conditions and relate them to parasite preference, we compared the metabolomes of human and rodent reticulocytes with those of their mature erythrocyte counterparts. Reticulocytes were found to have a more complex, enriched metabolic profile than mature erythrocytes and a higher level of metabolic overlap between reticulocyte resident parasite stages and their host cell. This redundancy was assessed by generating a panel of mutants of the rodent malaria parasite P. berghei with defects in intermediary carbon metabolism (ICM) and pyrimidine biosynthesis known to be important for P. falciparum growth and survival in vitro in mature erythrocytes. P. berghei ICM mutants (pbpepc-, phosphoenolpyruvate carboxylase and pbmdh-, malate dehydrogenase) multiplied in reticulocytes and committed to sexual development like wild type parasites. However, P. berghei pyrimidine biosynthesis mutants (pboprt-, orotate phosphoribosyltransferase and pbompdc-, orotidine 5'-monophosphate decarboxylase) were restricted to growth in the youngest forms of reticulocytes and had a severe slow growth phenotype in part resulting from reduced merozoite production. The pbpepc-, pboprt- and pbompdc- mutants retained virulence in mice implying that malaria parasites can partially salvage pyrimidines but failed to complete differentiation to various stages in mosquitoes. These findings suggest that species-specific differences in Plasmodium host cell tropism result in marked differences in the necessity for parasite intrinsic metabolism. These data have implications for drug design when targeting mature erythrocyte or reticulocyte resident parasites. PMID- 26042736 TI - Open access target validation is a more efficient way to accelerate drug discovery. AB - There is a scarcity of novel treatments to address many unmet medical needs. Industry and academia are finally coming to terms with the fact that the prevalent models and incentives for innovation in early stage drug discovery are failing to promote progress quickly enough. Here we will examine how an open model of precompetitive public-private research partnership is enabling efficient derisking and acceleration in the early stages of drug discovery, whilst also widening the range of communities participating in the process, such as patient and disease foundations. PMID- 26042737 TI - The effect of pleural abrasion on the treatment of primary spontaneous pneumothorax: a systematic review of randomized controlled trials. AB - BACKGROUND: Pleural abrasion has been widely used to control the recurrence of primary spontaneous pneumothorax (PSP). However, controversy still exists regarding the advantages and disadvantages of pleural abrasion compared with other interventions in preventing the recurrence of PSP. METHODS: The PubMed, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to December 15, 2014 to identify randomized controlled trials (RCTs) that compared the effects of pleural abrasion with those of other interventions in the treatment of PSP. The study outcomes included the PSP recurrence rate and the occurrence rate of adverse effects. RESULTS: Mechanical pleural abrasion and apical pleurectomy after thoracoscopic stapled bullectomy exhibited similarly persistent postoperative air leak occurrence rates (p = 0.978) and 1-year PSP recurrence rates (p = 0.821), whereas pleural abrasion led to reduced residual chest pain and discomfort (p = 0.001) and a smaller rate of hemothorax (p = 0.036) than did apical pleurectomy. However, the addition of minocycline pleurodesis to pleural abrasion did not reduce the pneumothorax recurrence rate compared with apical pleurectomy (3.8% for both procedures) but was associated with fewer complications. There was no statistical difference in the pneumothorax recurrence rate between mechanical pleural abrasion and chemical pleurodesis with minocycline on either an intention-to-treat basis (4 of 42 versus 0 of 42, p = 0.12; Fisher exact test) or after exclusions (2 of 40 versus 0 of 42, p = 0.24; Fisher exact test). Pleural abrasion plus minocycline pleurodesis also did not reduce the pneumothorax recurrence rate compared with pleural abrasion alone (p = 0.055). Moreover, pleural abrasion plus minocycline pleurodesis was associated with more intense acute chest pain. The postoperative overall recurrence rate in patients who underwent staple line coverage with absorbable cellulose mesh and fibrin glue was similar to that with mechanical abrasion after thoracoscopic bullectomy (13.8% vs. 14.2%, respectively; p = 0.555), but staple line coverage resulted in less postoperative residual pain than mechanical abrasion (0.4% vs.3.2%; p<0.0001). Pleural abrasion after thoracoscopic wedge resection did not decrease the recurrence of pneumothorax compared with wedge resection alone (p = 0.791), but the intraoperative bleeding and postoperative pleural drainage rates were higher when pleural abrasion was performed. CONCLUSIONS: In addition to resulting in the same pneumothorax recurrence rate, thoracoscopic pleural abrasion with or without minocycline pleurodesis is safer than apical pleurectomy in the treatment of PSP. However, minocycline pleurodesis with or without pleural abrasion is not any more effective than pleural abrasion alone. Moreover, additional mechanical abrasion is not safer than additional staple line coverage with absorbable cellulose mesh and fibrin glue after thoracoscopic bullectomy because of increased postoperative pain. Additionally, pleural abrasion after thoracoscopic wedge resection should not be recommended for routine application due to the greater incidence of adverse effects than wedge resection alone. However, further large-scale, well-designed RCTs are needed to confirm the best procedure. PMID- 26042738 TI - Neural correlates of emotional interference in social anxiety disorder. AB - Disorder-relevant but task-unrelated stimuli impair cognitive performance in social anxiety disorder (SAD); however, time course and neural correlates of emotional interference are unknown. The present study investigated time course and neural basis of emotional interference in SAD using event-related functional magnetic resonance imaging (fMRI). Patients with SAD and healthy controls performed an emotional stroop task which allowed examining interference effects on the current and the succeeding trial. Reaction time data showed an emotional interference effect in the current trial, but not the succeeding trial, specifically in SAD. FMRI data showed greater activation in the left amygdala, bilateral insula, medial prefrontal cortex (mPFC), dorsal anterior cingulate cortex (ACC), and left opercular part of the inferior frontal gyrus during emotional interference of the current trial in SAD patients. Furthermore, we found a positive correlation between patients' interference scores and activation in the mPFC, dorsal ACC and left angular/supramarginal gyrus. Taken together, results indicate a network of brain regions comprising amygdala, insula, mPFC, ACC, and areas strongly involved in language processing during the processing of task-unrelated threat in SAD. However, specifically the activation in mPFC, dorsal ACC, and left angular/supramarginal gyrus is associated with the strength of the interference effect, suggesting a cognitive network model of attentional bias in SAD. This probably comprises exceeded allocation of attentional resources to disorder-related information of the presented stimuli and increased self referential and semantic processing of threat words in SAD. PMID- 26042739 TI - Regulation of NF-kappaB Oscillation by Nuclear Transport: Mechanisms Determining the Persistency and Frequency of Oscillation. AB - The activated transcription factor NF-kappaB shuttles between the cytoplasm and the nucleus resulting in the oscillation of nuclear NF-kappaB (NF-kappaBn). The oscillation pattern of NF-kappaBn is implicated in the regulation of gene expression profiles. Using computational models, we previously reported that spatial parameters, such as the diffusion coefficient, nuclear to cytoplasmic volume ratio, transport through the nuclear envelope, and the loci of translation of IkappaB protein, modified the oscillation pattern of NF-kappaBn. In a subsequent report, we elucidated the importance of the "reset" of NF-kappaBn (returning of NF-kappaB to the original level) and of a "reservoir" of IkappaB in the cytoplasm. When the diffusion coefficient of IkappaB was large, IkappaB stored at a distant location from the nucleus diffused back to the nucleus and "reset" NF-kappaBn. Herein, we report mechanisms that regulate the persistency and frequency of NF-kappaBn oscillation by nuclear transport. Among the four parameters of nuclear transport tested in our spatio-temporal computational model, the export of IkappaB mRNA from the nucleus regulated the persistency of oscillation. The import of IkappaB to the nucleus regulated the frequency of oscillation. The remaining two parameters, import and export of NF-kappaB to and from the nucleus, had virtually no effect on the persistency or frequency. Our analyses revealed that lesser export of IkappaB mRNA allowed NF-kappaBn to transcript greater amounts of IkappaB mRNA, which was retained in the nucleus, and was subsequently exported to the cytoplasm, where large amounts of IkappaB were synthesized to "reset" NF-kappaBn and drove the persistent oscillation. On the other hand, import of greater amounts of IkappaB led to an increase in the influx and the efflux of NF-kappaB to and from the nucleus, resulting in an increase in the oscillation frequency. Our study revealed the importance of nuclear transport in regulating the oscillation pattern of NF-kappaBn. PMID- 26042740 TI - Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. AB - BACKGROUND: Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to investigate first is important. AIM: Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis. PATIENTS AND METHODS: Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality. RESULTS: Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 [26-125], 104 [58-208] and 1807 [494-3,716] MUg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p<0.0001 (AUROC 0.957). Other attractive biomarkers for ATN diagnosis were IL-18, albumin, trefoil-factor-3 (TFF-3) and glutathione-S-transferase-pi (GST-pi) Biomarkers with less accuracy for ATN AUCROC<0.8 were beta2-microglobulin, calbindin, cystatin-C, clusterin and KIM-1 (kidney injury molecule-1). For ACLF, the biomarker with the best accuracy was NGAL (ACLF vs. No-ACLF: 165 [67-676] and 32 [19-40] MUg/g creatinine; respectively; p<0.0001; AUROC 0.878). Interestingly, other biomarkers with high accuracy for ACLF were osteopontin, albumin, and TFF 3. Biomarkers with best accuracy for prognosis were those associated with ACLF. CONCLUSIONS: A number of biomarkers appear promising for differential diagnosis between ATN and other types of AKI. The most interesting biomarkers for ACLF and prognosis are NGAL, osteopontin, albumin, and TFF-3. These results support the role of major inflammatory reaction in the pathogenesis of ACLF. PMID- 26042741 TI - Laryngeal Reinnervation Using a Split-Hypoglossal Nerve Graft in a Canine Model. AB - IMPORTANCE: Vocal fold immobility following injury to the recurrent laryngeal nerve (RLN) may lead to substantial morbidity. A reinnervation treatment strategy offers several theoretical benefits over static treatment options. This study evaluates the robustness of reinnervation of the larynx using a split-hypoglossal nerve graft in an animal model, with outcomes assessed by independent blinded review. OBJECTIVES: To assess whether a full-hypoglossal nerve graft to the RLN after RLN section can provide return of dynamic vocal fold motion in a canine model, and to validate that a split-hypoglossal nerve graft to the RLN may also provide dynamic vocal fold motion to rehabilitate laryngeal function in a canine model. DESIGN, SETTING, AND SUBJECTS: A pilot animal study to assess the feasibility and morbidity of laryngeal reinnervation following RLN injury with an end-to-end full-hypoglossal or split-hypoglossal nerve graft was performed at an animal care and research facility in 10 adult female dogs. The study dates were January to July 2013. INTERVENTIONS: We performed full-hypoglossal (full XII group [n = 5]) and split-hypoglossal (split XII group [n = 5]) nerve grafts to the RLN in a canine model following RLN section. MAIN OUTCOMES AND MEASURES: Morbidity was evaluated through scored feeding observation. Laryngeal function was assessed by video laryngoscopy and evoked laryngeal electromyography was performed at baseline and 6 months after surgery. Video laryngoscopy was graded by independent reviewers blinded to study intervention. RESULTS: No clinically significant morbidity was identified after surgery. On review of video laryngoscopy, all 5 animals in the full XII group and all 5 animals in the split XII group demonstrated vocal fold motion by at least 1 independent reviewer. All 3 reviewers agreed on motion in 1 of 5 animals in the full XII group and in 1 of 5 animals in the split XII group. Stimulation of the hypoglossal nerve demonstrated neural connection on evoked laryngeal electromyography in all animals at 6 months. CONCLUSIONS AND RELEVANCE: This study confirms that a full hypoglossal or split-hypoglossal nerve graft may restore vocal fold motion, without significant functional morbidity, following RLN section in a canine model. PMID- 26042742 TI - Patient Factors Predictive of Hospital Readmissions Within 30 Days. AB - BACKGROUND: Under the Affordable Care Act, the Congress has mandated that the Centers for Medicare and Medicaid Services reduce payments to hospitals subject to their Inpatient Prospective Payment System that exhibits excess readmissions. Using hospital-coded discharge abstracts, we constructed a readmission measure that accounts for cross-hospital variation that enables hospitals to monitor their entire inpatient populations and evaluate their readmission rates relative to national benchmarks. METHODS: Multivariate logistic regressions are applied to determine which patient factors increase the odds of a readmission within 30 days and by how much. This study uses deidentified discharge abstract data from a database of approximately 15 million inpatient discharges representing 611 acute care hospitals from Premier healthcare alliance over a 2-year period (2008q4 2010q3). The hospitals are geographically diverse and represent large urban academic centers and small rural community hospitals. RESULTS: This study demonstrates that meaningful risk-adjusted readmission rates can be tracked in a dynamic database. The clinical conditions responsible for the index admission were the strongest predictive factor of readmissions, but factors such as age and accompanying comorbid conditions were also important. Socioeconomic factors, such as race, income, and payer status, also showed strong statistical significance in predicting readmissions. CONCLUSIONS: Payment models that are based on stratified comparisons might result in a more equitable payment system while at the same time providing transparency regarding disparities based on these factors. No model, yet available, discriminates potentially modifiable readmissions from those not subject to intervention highlighting the fact that the optimum readmission rate for any given condition is yet to be identified. PMID- 26042743 TI - How Hospitals Reengineer Their Discharge Processes to Reduce Readmissions. AB - BACKGROUND: The Re-Engineered Discharge (RED) program is a hospital-based initiative shown to decrease hospital reutilization. We implemented the RED in 10 hospitals to study the implementation process. DESIGN: We recruited 10 hospitals from different regions of the United States to implement the RED and provided training for participating hospital leaders and implementation staff using the RED Toolkit as the basis of the curriculum followed by monthly telephone-based technical assistance for up to 1 year. METHODS: Two team members interviewed key informants from each hospital before RED implementation and then 1 year later. Interview data were analyzed according to common and comparative themes identified across institutions. Readmission outcomes were collected on participating hospitals and compared pre- versus post-RED implementation. RESULTS: Key findings included (1) wide variability in the fidelity of the RED intervention; (2) engaged leadership and multidisciplinary implementation teams were keys to success; (3) common challenges included obtaining timely follow-up appointments, transmitting discharge summaries to outpatient clinicians, and leveraging information technology. Eight out of 10 hospitals reported improvement in 30-day readmission rates after RED implementation. CONCLUSIONS: A supportive hospital culture is essential for successful RED implementation. A flexible implementation strategy can be used to implement RED and reduce readmissions. PMID- 26042744 TI - Clostridium difficile Infection in Inflammatory Bowel Disease: A Nursing-Based Quality Improvement Strategy. AB - OBJECTIVES: Patients with inflammatory bowel disease (IBD) have a higher prevalence of Clostridium difficile infection (CDI) and worse outcomes. Research has highlighted the inconsistent care that is provided to patients with IBD, and at our institution, the CDI testing rate was 41%. The present quality improvement intervention sought to increase CDI testing for inpatients with IBD with a flare. METHODS: Eighty-nine patients admitted to our gastrointestinal unit over a 9 month period with IBD flare were eligible for the study. If a patient did not have a test for CDI ordered, the floor nurse collected stool and alerted the provider to order the test. The primary outcome was percent of eligible patients receiving a test. Secondary outcomes included rate of CDI, length of hospital stay, and readmission rate within 6 months. RESULTS: There was a significant increase in testing for CDI to 75% (p = .0151). Patients who received a test were more likely to have CDI (p = .0316), shorter hospital stays (p = .0095), and fewer readmissions (p = .0366). CONCLUSION: This study used the nursing admission workflow to increase the rate of CDI testing. Future studies should further characterize inconsistencies in IBD care and implement quality improvements. PMID- 26042745 TI - Prevalence and Data Transparency of National Clinical Registries in the United States. AB - OBJECTIVE: To determine the prevalence and characteristics of national clinical registries. METHODS: Review of clinical registries through the following: (1) PubMed search using MeSH term "registries," (2) clinical trials database search using the term "registry," (3) review of the American Medical Association (AMA) recognized specialty societies for registry affiliation, and (4) consultation with a panel representing the American Board of Medical Specialties (ABMS). MAIN OUTCOME MEASURES: Outcomes that characterize registries (type, participants, specialty affiliation, funding), reflect data quality (risk adjustment, auditing practices), and indicate transparency (public reporting). RESULTS: We identified 153 clinical registries of which 47.7% (73) were health services registries, 43.1% (66) were disease registries, and 9.2% (14) were combination registries. The mean number of hospitals per registry was 1,693 (interquartile range [IQR] = 45-230), and the mean number of patients per registry was 1,160,492 (IQR = 2,150 10,045). Among the 117 AMA specialty societies, 16.2% (19) were affiliated with a registry. Government funding was associated with 26.1% (40/153) of registries. Of the 153 registries, 23.5% (36) risk adjusted outcomes and 18.3% (23) audited data. Mandatory public reporting of hospital outcomes for all participating hospitals was associated with 2.0% (3/153) of registries. CONCLUSION: There is substantial opportunity to develop more specialty-specific clinical registries with publicly available data. PMID- 26042747 TI - Validation of a Predictive Model to Identify Patients at High Risk for Hospital Readmission. AB - BACKGROUND: Hospital readmission is an adverse patient outcome that is serious, common, and costly. For hospitals, identifying patients at risk for hospital readmission is a priority to reduce costs and improve care. PURPOSE: The purposes were to validate a predictive algorithm to identify patients at a high risk for preventable hospital readmission within 30 days after discharge and determine if additional risk factors enhance readmission predictability. METHODS: A retrospective study was conducted on a randomized sample of 598 patients discharged from a Southeast community hospital. Data were collected from the organization's database and manually abstracted from the electronic medical record using a structured tool. Two separate logistic regression models were fit for the probability of readmission within 30 days after discharge. The first model used the LACE index as the predictor variable, and the second model used the LACE index with additional risk factors. The two models were compared to determine if additional risk factors increased the model's predictive ability. RESULTS: The results indicate both models have reasonable prognostic capability. The LACE index with additional risk factors did little to improve prognostication, while adding to the model's complexity. CONCLUSION: Findings support the use of the LACE index as a practical tool to identify patients at risk for readmission. PMID- 26042748 TI - Geographic Localization of Housestaff Inpatients Improves Patient-Provider Communication, Satisfaction, and Culture of Safety. AB - This study assesses whether geographic localization of housestaff patients contributes to improved patient knowledge of diagnosis, patient satisfaction, provider satisfaction, and workplace culture of safety. Due to national changes to graduate medical education, housestaff patients were localized to a single general medicine ward. Ninety-three patients prelocalization, 64 patients postlocalization, 26 localized physicians, and 10 localized nurses were surveyed. Validated questionnaires assessed patients' experiences during hospitalization, and physician and nurse job satisfaction. Fifty-seven percent of patients knew their diagnosis prior to localization, compared to 80% postlocalization (p < .0001). Prior to localization, 39% of patients who reported experiencing anxieties or fears during hospitalization felt physicians frequently discussed these emotions with them compared to 85% after localization (p < .0001). Before localization, 51% of patients stated that doctors spent 4 min or more daily with them discussing care, compared to 91% after localization (p < .0001). Both physician and nurse opinion significantly improved regarding some but not all aspects of collaboration, teamwork, patient safety, appropriate handling of errors, and culture of safety. The average length of stay was unchanged and the change in 30-day readmission rate was not statistically significant. Localization of patients to a single inpatient ward improved patient knowledge and satisfaction, and some aspects of interprofessional communication and workplace culture of safety. PMID- 26042749 TI - Ohio Children's Hospitals' Solutions for Patient Safety: A Framework for Pediatric Patient Safety Improvement. AB - OBJECTIVES: Building upon their previous collective success and a clinical imperative for rapid improvement, the eight tertiary pediatric referral centers in Ohio sought to dramatically decrease the most serious types of harm that occur to hospitalized children by collectively employing high reliability methods focused on safety culture. METHODS: With the support of the hospitals' executives, the Ohio collaborative obtained legal protection and built will by clearly identifying types and frequency of harm events that occur in each participating hospital and across the state. The improvement efforts were divided among task forces designed to incorporate the principles of high reliability organizations into the work of all employees, focusing primarily on the consistent application of error prevention behaviors. RESULTS: Between January 2010 and October 2012, the serious safety event rate among the participating hospitals decreased by 55%, equating to 70 fewer children per year who experienced this most severe type of event in the participating hospitals. Between January 2011 and October 2012, all events of serious harm were decreased by 40%, meaning 18 fewer children per month suffered serious harm. CONCLUSION: Rapid and significant improvement in pediatric patient safety is possible through collaboration of children's hospitals dedicated to the application of high reliability principles and the noncompetitive sharing of outcomes and best practices. PMID- 26042750 TI - Transitional Care in the Patient-Centered Medical Home: Lessons in Adaptation. AB - Older adults with multiple chronic conditions (MCCs) typically have risk factors (e.g., functional deficits, social barriers) that complicate the management of their healthcare, often with devastating human and economic consequences. Finding new ways to provide patient-centered care to community-based older adults with MCCs is essential. Two current models of care, the Patient-Centered Medical Home (PCMH) and the Transitional Care Model (TCM), have demonstrated improvements in the outcomes of high-risk older adults at different points on the chronic illness trajectory. However, neither care management approach has optimally engaged vulnerable patients to address needs throughout both acute and more stable transitions in health. In this article, we summarize the development of the PCMH plus TCM (hereafter, PCMH + TCM), an innovative approach to care, and the experience of the providers involved in testing the feasibility of implementing the PCMH + TCM. Using content analyses to code open-ended survey responses from transitional care nurses and PCMH clinical leaders', two major themes, collaboration and communication, emerged as critical to the process of implementing the PCMH + TCM. Barriers and facilitators to implementing the PCMH + TCM are presented. Findings support that the TCM can be adapted and integrated into the PCMH with meticulous planning and implementation. PMID- 26042751 TI - Is Access to and Use of Primary Care Practices that Patients Perceive as Having Essential Qualities of a Patient-Centered Medical Home Associated With Positive Patient Experience? Empirical Evidence From a U.S. Nationally Representative Sample. AB - OBJECTIVE: The patient-centered medical home (PCMH) has emerged as an innovative healthcare delivery model that holds the conceptual promise to improve healthcare quality and patient experience. This study examined how patient perceived PCMH is related to patient satisfaction and experience nationwide. This study advances academic discussion in that it is among the first to examine empirical evidence using a U.S. nationally representative sample. METHODS: This retrospective cohort study used data from the 2010 to 2011 Medical Expenditure Panel Survey. This study focused on insured individuals aged 18 and older. We measured and identified cohorts for a "full PCMH," a "partial PCMH" (i.e., with a usual source of care but not a PCMH), and an "unknown PCMH," with the reference group being the "no regular provider" group and the partial PCMH group, respectively. Using logit models, we assessed patient experiences of the PCMH use controlling for covariates in 2010. Given the nature of the complex survey design, the weights and variance were adjusted using the survey procedures to yield nationally representative results. RESULTS: The final study sample consisted of 7,743 individuals, representing 191 million individuals in the weighted population. After controlling for covariates in 2010, the full PCMH group was consistently observed to have higher odds of positive patient experience than individuals with no usual source of care: odds ratio (OR) = 1.89 (p = .003) for providers "listened carefully to you"; OR = 1.81 (p = .001) for providers "spent enough time with you"; OR = 1.85 (p = .007) for providers "showed respect for what you had to say"; and OR = 1.89 (p < .001) for the composite patient experience. Similarly, compared with the partial PCMH group, consistently higher odds of patient satisfaction among all patient experience measures were observed for the full medical home group: OR = 1.45 (p = .070, significant at alpha = 0.1 level) for providers "explained things so you understood"; OR = 1.69 (p = .002) for providers "listened carefully to you"; OR = 1.57 (p = .003) for providers "spent enough time with you"; OR = 1.48 (p = .039) for providers "showed respect for what you had to say"; and OR = 1.56 (p = .001) for the composite patient experience. CONCLUSIONS: Overall, the PCMH model was associated with improved patient satisfaction nationwide. Findings from this study have shed light on strategies of innovative healthcare delivery models in improving patient experience, which in turn, may translate to patients' compliance to treatment regimen and improved health outcomes. PMID- 26042752 TI - Is It Feasible to Use Electronic Health Records for Quality Measurement of Adolescent Care? AB - OBJECTIVE: To determine the extent to which it is feasible to implement quality measures on electronic health records (EHRs) as currently implemented in pediatric health centers. METHODS: A survey of information technology professionals at 10 institutions that provide primary care services to adolescents. The survey asked whether data about care was being captured electronically across the nine domains relevant to adolescent well care: Screening, Health Risks, Sexual Health, Diagnosis and History, Laboratory Results, Prescriptions, Referrals, Forms Management, and Patient Demographics. For each domain, we developed a scale of the extent to which the EHR makes quality measurement feasible. RESULTS: Overall feasibility scores varied across centers from 34% to 85% and from 53% to 80% across care domains. One centre reported 100% feasibility for 8 of 10 care domains. CONCLUSIONS: Electronic health records can facilitate quality improvement, but the feasibility of such use depends on the presence, validity, and accessibility of the quality data in the EHR. Even among the largest and most sophisticated pediatric EHR systems, quality of care measurement is not possible yet for all aspects of adolescent well care without manual effort to review and code data. Nevertheless, almost all quality measures were reported to be feasible in some systems. PMID- 26042753 TI - Electronic Healthcare's Relationship With Patient Satisfaction and Communication. AB - Healthcare information technology (HIT) has been examined and shown to be a tool to improve patient healthcare quality. This study seeks to define the relationship between HIT applications such as computerized physician order entry, clinical decision support systems, and handheld device use and select Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) measures (doctor and nurse communication, discharge instructions, and whether the patient would highly recommend the hospital). Several control variables were used that represent the hospital level and contextual hospital service area level. The analysis had mixed results: the aforementioned HIT applications may add and support certain HCAHPS measures (Always Given Discharge Information), whereas there were no significant findings for the more interpersonal quality measures (nurse and doctor communication, recommendation). These results show that although patients may not score doctors and nurses significantly higher for their communication in hospitals that use HIT, they did receive discharge instructions significantly at a higher rate than the non-HIT hospitals. PMID- 26042754 TI - Lessons From a Care Management Pilot Program for People With Acquired Brain Injury. AB - PROBLEM: From November 2010 to August 2013, 161 adults with acquired brain injury in Massachusetts transitioned from long-term care settings to the community through a Medicaid-funded waiver. Most participants transitioned with minimal risk; for some, the transition resulted in an increase in risk incidents above the rest. Specifically, despite risk mitigation efforts, 11% of the participants accounted for more than 75% of the reported first year incidents. SOLUTION: A registered nurse Care Manager was engaged in a pilot program to address the needs of participants at the highest risk. Based on incidents or potential for incidents, 30 participants were enrolled in care management (CM). METHODS: Secondary data analysis, interviews, and surveys assessed whether CM was associated with a decrease in incidents and to what extent participants and providers were satisfied with CM. RESULTS: Care management was significantly associated with a decrease in incidents including hospitalizations and emergency room visits. Participants, Case Managers, and service providers were highly satisfied with the Care Manager. CONCLUSIONS: Focusing on a specific population with increased risk, clearly explaining the purpose of CM, and remaining flexible when addressing the complex and individual nature of risk management are important strategies to ensure an effective CM program. PMID- 26042755 TI - Quality of Interhospital Transfer Communication Practices and Association With Adverse Events on an Internal Medicine Hospitalist Service. AB - Communication practices around interhospital transfer have not been rigorously assessed in adult medicine patients. Furthermore, the clinical implications of such practices have not been reported. This case-control study was designed to assess the quality of communication between clinicians during interhospital transfer and to determine if posttransfer adverse events (PTAEs) are associated with suboptimal communication. Cases included patients transferred to a Medicine Hospitalist Service from an outside hospital who subsequently experienced a PTAE, defined as unplanned transfer to an intensive care unit or death within 24 hours of transfer. Control patients also underwent interhospital transfer but did not experience a PTAE. A blinded investigator retrospectively reviewed the recorded pretransfer phone conversations between sending and receiving clinicians for adherence to a set of 13 empiric best practice communication elements. The primary outcome was the mean communication score, on a scale of 0-13. Mean scores between PTAE (8.3; 95% confidence interval [CI], 7.6-8.9) and control groups (7.9; 95% CI, 7.1-8.8) did not differ significantly (p = .50), although suboptimal communication on a subset of these elements was associated with increased PTAEs. Communication around interhospital transfer appears suboptimal compared with an empiric set of standard communication elements. Posttransfer adverse events were not associated with aggregate adherence to these standards. PMID- 26042756 TI - Improving Accuracy and Relevance of Race/Ethnicity Data: Results of a Statewide Collaboration in Hawaii. AB - Current race/ethnicity categories established by the U.S. Office of Management and Budget are neither reliable nor valid for understanding health disparities or for tracking improvements in this area. In Hawaii, statewide hospitals have collaborated to collect race/ethnicity data using a standardized method consistent with recommended practices that overcome the problems with the federal categories. The purpose of this observational study was to determine the impact of this collaboration on key measures of race/ethnicity documentation. After this collaborative effort, the number of standardized categories available across hospitals increased from 6 to 34, and the percent of inpatients with documented race/ethnicity increased from 88 to 96%. This improved standardized methodology is now the foundation for tracking population health indicators statewide and focusing quality improvement efforts. The approach used in Hawaii can serve as a model for other states and regions. Ultimately, the ability to standardize data collection methodology across states and regions will be needed to track improvements nationally. PMID- 26042757 TI - Cross-Site Scheduling of Endoscopic Procedures Improves Efficiency While Maintaining Patient Safety. AB - BACKGROUND AND AIM: Accuracy in scheduling complex procedures is improved through technology to aid nonmedically trained allied health professionals. We used a new computer technology to assess whether a single coordinator could schedule endoscopic procedures across sites of a multisite academic medical institution, thus improving efficiency within the clinic overall. METHODS: A multidisciplinary team designed a cross-site scheduling model. The first phase involved accurately identifying those procedures that were appropriate for nontrained coordinators to schedule. A pilot study with gastroenterology staff was implemented and evaluated and then rolled out to non-gastroenterology staff. RESULTS: A significant decrease in call volumes occurred which in turn led to a decrease from >100 to 38 seconds in average speed to answer (ASA). A total of 115 hours of manpower was saved with the efficiency of being able to schedule without the need for a second coordinator. CONCLUSIONS: Efficiencies in call volume and ASA led to substantial time and money savings. Because of the continued involvement of multiple work groups, changes were seen as favorable rather than burdensome. Such technology could be used across other disciplines where routine procedures or tests require specific scheduling knowledge. PMID- 26042758 TI - Using Lean to Advance Quality Improvement Research. AB - INTRODUCTION: Quality improvement research skills are not commonplace among quality improvement practitioners, and research on the effectiveness of quality improvement has not always kept pace with improvement innovation. However, the Lean tools applied to quality improvement should be equally relevant to the advancement of quality improvement research. METHODS: We applied the Lean methods to develop a simplified quality improvement publication pathway enabling a small research methodology group to increase quality improvement research throughout the institution. The key innovations of the pathway are horizontal integration of the quality improvement research methods group across the institution, implementation of a Lean quality improvement research pathway, and application of a just-in-time quality improvement research toolkit. RESULTS: This work provides a road map and tools for the acceleration of quality improvement research. At our institution, the Lean quality improvement research approach was associated with statistically significant increases in the number (annual mean increase from 3.0 to 8.5, p = .03) and breadth of published quality improvement research articles, and in the number of quality improvement research projects currently in process. DISCUSSION: Application of Lean methods to the quality improvement research process can aid in increasing publication of quality improvement articles from across the institution. PMID- 26042759 TI - Discharge Delays for Patients Requiring In-Hospital Guardianship: A Cohort Analysis. AB - OBJECTIVE: To assess nonclinical factors delaying hospital discharge of guardianship patients. DATA: Utilization review data over 3 years. DESIGN: Retrospective cohort study. ANALYSIS: Mann-Whitney test was used to compare patients' medically unnecessary days (MUD) of hospitalization with additional subcategories of delays-defined as beyond clinicians' control. FINDINGS: Overall median number of MUD was 19.5; 14 of 48 patients were additionally delayed while awaiting long-term care Medicaid approval (N = 7, 50%), pending insurance (N = 3, 21%), social or transportation difficulties (N = 3, 21%), or preadmission review (N = 1, 7%). The median number of MUD for the 14 delayed patients was 63, a difference of 53 days compared with the routine guardianship cohort (P < .0001) and $5.5M in net revenue opportunity. CONCLUSIONS: Nonclinical discharge delays for guardianship patients are costly and potentially unavoidable. Further exploration into policy change is therefore recommended. PMID- 26042760 TI - Strange Bedfellows: A Local Insurer/Physician Practice Partnership to Fund Innovation. AB - Despite an unprecedented urgency to control healthcare costs while simultaneously improving quality, there are many barriers to investing in quality improvement. Traditional fee-for-service reimbursement models fail to reward providers whose improved processes lead to decreases in billable clinical activity. In addition, providers may lack the necessary skills for improvement, or the organizational infrastructure to conduct these activities. Insurance firms lack incentives to invest in healthcare delivery system improvements that lead to benefits for all patients, even those covered by competitors. In this article, we describe a novel program in its sixth year of existence that funds ambulatory care improvements through a collaborative partnership between a local academic healthcare delivery system and an insurance firm. The program is designed as a competitive grant program and the payer and healthcare organization jointly benefit from completed improvement projects. Factors contributing to the ongoing success of the program and lessons learned are discussed in order to inform the potential development of similar programs in other markets. PMID- 26042761 TI - Preventable Readmission Risk Factors for Patients With Chronic Conditions. AB - Evidence indicates that the largest volume of hospital readmissions occurs among patients with preexisting chronic conditions. Identifying these patients can improve the way hospital care is delivered and prioritize the allocation of interventions. In this retrospective study, we identify factors associated with readmission within 30 days based on claims and administrative data of nine hospitals from 2005 to 2012. We present a data inclusion and exclusion criteria to identify potentially preventable readmissions. Multivariate logistic regression models and a Cox proportional hazards extension are used to estimate the readmission risk for 4 chronic conditions (congestive heart failure [CHF], chronic obstructive pulmonary disease [COPD], acute myocardial infarction, and type 2 diabetes) and pneumonia, known to be related to high readmission rates. Accumulated number of admissions and discharge disposition were identified to be significant factors across most disease groups. Larger odds of readmission were associated with higher severity index for CHF and COPD patients. Different chronic conditions are associated with different patient and case severity factors, suggesting that further studies in readmission should consider studying conditions separately. PMID- 26042762 TI - Routinization of HIV Testing in an Inpatient Setting: A Systematic Process for Organizational Change. AB - In 2006, the U.S. Centers for Disease Control and Prevention released revised recommendations for routinization of HIV testing in healthcare settings. Health professionals have been challenged to incorporate these guidelines. In March 2013, a routine HIV testing initiative was launched at a large urban academic medical center in a high prevalence region. The goal was to routinize HIV testing by achieving a 75% offer and 75% acceptance rate and promoting linkage to care in the inpatient setting. A systematic six-step organizational change process included stakeholder buy-in, identification of an interdisciplinary leadership team, infrastructure development, staff education, implementation, and continuous quality improvement. Success was measured by monitoring the percentage of offered and accepted HIV tests from March to December 2013. The targeted offer rate was exceeded consistently once nurses became part of the consent process (September 2013). Fifteen persons were newly diagnosed with HIV. Seventy-eight persons were identified as previously diagnosed with HIV, but not engaged in care. Through this process, patients who may have remained undiagnosed or out-of-care were identified and linked to care. The authors propose that this process can be replicated in other settings. Increasing identification and treatment will improve the individual patient's health and reduce community disease burden. PMID- 26042764 TI - Self-Assembled Three-Dimensional Graphene Macrostructures: Synthesis and Applications in Supercapacitors. AB - Graphene and its derivatives are versatile building blocks for bottom-up assembly of advanced functional materials. In particular, with exceptionally large specific surface area, excellent electrical conductivity, and superior chemical/electrochemical stability, graphene represents the ideal material for various electrochemical energy storage devices including supercapacitors. However, due to the strong pi-pi interaction between graphene sheets, the graphene flakes tend to restack to form graphite-like powders when they are processed into practical electrode materials, which can greatly reduce the specific surface area and lead to inefficient utilization of the graphene layers for electrochemical energy storage. The self-assembly of two-dimensional graphene sheets into three-dimensional (3D) framework structures can largely retain the unique properties of individual graphene sheets and has recently garnered intense interest for fundamental investigations and potential applications in diverse technologies. In this Account, we review the recent advances in preparing 3D graphene macrostructures and exploring them as a unique platform for supercapacitor applications. We first describe the synthetic strategies, in which reduction of a graphene oxide dispersion above a certain critical concentration can induce the reduced graphene oxide sheets to cross-link with each other via partial pi-pi stacking interactions to form a 3D interconnected porous macrostructure. Multiple reduction strategies, including hydrothermal/solvothermal reduction, chemical reduction, and electrochemical reduction, have been developed for the preparation of 3D graphene macrostructures. The versatile synthetic strategies allow for easy incorporation of heteroatoms, carbon nanomaterials, functional polymers, and inorganic nanostructures into the macrostructures to yield diverse composites with tailored structures and properties. We then summarize the applications of the 3D graphene macrostructures for high-performance supercapacitors. With a unique framework structure in which the graphene sheets are interlocked in 3D space to prevent their restacking, the graphene macrostructures feature very high specific surface areas, rapid electron and ion transport, and superior mechanical strength. They can thus be directly used as supercapacitor electrodes with excellent specific capacitances, rate capabilities, and cycling stabilities. We finally discuss the current challenges and future opportunities in this research field. By regarding the graphene as both a single-atom-thick carbon sheet and a conjugated macromolecule, our work opens a new avenue to bottom-up self-assembly of graphene macromolecule sheets into functional 3D graphene macrostructures with remarkable electrochemical performances. We hope that this Account will promote further efforts toward fundamental investigation of graphene self-assembly and the development of advanced 3D graphene materials for their real-world applications in electrochemical energy storage devices and beyond. PMID- 26042765 TI - Influence of fluoride content and pH on corrosion and tribocorrosion behaviour of Ti13Nb13Zr alloy in oral environment. AB - CpTi and Ti6Al4V alloy are the most widely used materials for implant application, but the release of toxic elements (e.g. Al and V) and the so-called stress-shielding effect are still a concern. In recent years, beta and near-beta titanium alloys have been developed, which overcome these issues with reduced modulus of elasticity and biocompatible alloying elements. However, literature is scarce studying the tribocorrosion behaviour of these alloys for dental implantology. The present work studies the tribocorrosion behaviour of the near beta Ti13Nb13Zr alloy in oral environment, using CpTi4 for comparison purposes. To that end, the influence of the pH and fluoride concentration in artificial saliva was analysed. Reciprocating sliding corrosion tests were carried out under open circuit potential and potentiostatic conditions. Results reveal a negative influence of the increase of fluoride concentration and the acidified artificial saliva on the material degradation. Moreover, some light has been shed on the different tribocorrosion mechanisms of Ti13Nb13Zr and CpTi4 in simulated oral environment. PMID- 26042766 TI - A mechanistic insight into the mechanical role of the stratum corneum during stretching and compression of the skin. AB - The study of skin biophysics has largely been driven by consumer goods, biomedical and cosmetic industries which aim to design products that efficiently interact with the skin and/or modify its biophysical properties for health or cosmetic benefits. The skin is a hierarchical biological structure featuring several layers with their own distinct geometry and mechanical properties. Up to now, no computational models of the skin have simultaneously accounted for these geometrical and material characteristics to study their complex biomechanical interactions under particular macroscopic deformation modes. The goal of this study was, therefore, to develop a robust methodology combining histological sections of human skin, image-processing and finite element techniques to address fundamental questions about skin mechanics and, more particularly, about how macroscopic strains are transmitted and modulated through the epidermis and dermis. The work hypothesis was that, as skin deforms under macroscopic loads, the stratum corneum does not experience significant strains but rather folds/unfolds during skin extension/compression. A sample of fresh human mid-back skin was processed for wax histology. Sections were stained and photographed by optical microscopy. The multiple images were stitched together to produce a larger region of interest and segmented to extract the geometry of the stratum corneum, viable epidermis and dermis. From the segmented structures a 2D finite element mesh of the skin composite model was created and geometrically non-linear plane-strain finite element analyses were conducted to study the sensitivity of the model to variations in mechanical properties. The hybrid experimental computational methodology has offered valuable insights into the simulated mechanics of the skin, and that of the stratum corneum in particular, by providing qualitative and quantitative information on strain magnitude and distribution. Through a complex non-linear interplay, the geometry and mechanical characteristics of the skin layers (and their relative balance), play a critical role in conditioning the skin mechanical response to macroscopic in-plane compression and extension. Topographical features of the skin surface such as furrows were shown to act as an efficient means to deflect, convert and redistribute strain-and so stress-within the stratum corneum, viable epidermis and dermis. Strain reduction and amplification phenomena were also observed and quantified. Despite the small thickness of the stratum corneum, its Young's modulus has a significant effect not only on the strain magnitude and directions within the stratum corneum layer but also on those of the underlying layers. This effect is reflected in the deformed shape of the skin surface in simulated compression and extension and is intrinsically linked to the rather complex geometrical characteristics of each skin layer. Moreover, if the Young's modulus of the viable epidermis is assumed to be reduced by a factor 12, the area of skin folding is likely to increase under skin compression. These results should be considered in the light of published computational models of the skin which, up to now, have ignored these characteristics. PMID- 26042767 TI - Biomaterial characteristics and application of silicone rubber and PVA hydrogels mimicked in organ groups for prostate brachytherapy. AB - It is definite that transparent material with similar structural characteristics and mechanical properties to human tissue is favorable for experimental study of prostate brachytherapy. In this paper, a kind of transparent polyvinyl alcohol (PVA) hydrogel and silicone rubber are developed as suitable substitutions for human soft tissue. Segmentation and 3D reconstruction of medical image are performed to manufacture the mould of organ groups through rapid prototyping technology. Micro-structure observation, force test and CCD deformation test have been conducted to investigate the structure and mechanical properties of PVA hydrogel used in organ group mockup. Scanning electron microscope (SEM) image comparison results show that PVA hydrogel consisting of 3 g PVA, 17 g de-ionized water, 80 g dimethyl-sulfoxide (DMSO), 4 g NaCl, 1.5 g NaOH, 3 g epichlorohydrin (ECH) and 7 freeze/thaw cycles reveals similar micro-structure to human prostate tissue. Through the insertion force comparison between organ group mockup and clinical prostate brachytherapy, PVA hydrogel and silicone rubber are found to have the same mechanical properties as prostate tissue and muscle. CCD deformation test results show that insertion force suffers a sharp decrease and a relaxation of tissue deformation appears when needle punctures the capsule of prostate model. The results exhibit that organ group mockup consisting of PVA hydrogel, silicone rubber, membrane and agarose satisfies the needs of prostate brachytherapy simulation in general and can be used to mimic the soft tissues in pelvic structure. PMID- 26042768 TI - Effect of normal compression on the shear modulus of soft tissue in rheological measurements. AB - While the effect of normal compression on the measured shear material properties of viscoelastic solids has been already acknowledged in rheological studies in the literature, to our knowledge, no systematic study has been conducted to investigate this effect in detail to date. In this study, we perform two sets of experiments to investigate the effect of normal strain and strain rate on the dynamic shear moduli of bovine liver. First, we apply normal compressive strain to the cylindrical bovine samples up to 20% at loading rates of v=0.000625, 0.00625, 0.0625, 0.315, 0.625 mm/s. Second, we perform torsional shear loading experiments, in the frequency range of omega=0.1-10 Hz, under varying amounts of compressive pre-strain (epsilon=1%, 2.5%, 5%, 7.5%, 10%, 12.5%, 15%, 17.5% and 20%) applied at the quasi-static loading rate of v=0.000625 mm/s. The results of the experiments show that the shear moduli of bovine liver increase with compressive pre-strain. A hyper-viscoelastic constitutive model is developed and fit to the experimental data to estimate the true shear moduli of bovine liver for zero pre-compression. With respect to this reference value, the mean relative error in the measurement of shear moduli of bovine liver varies between 0.2% and 243.1% for the compressive pre-strain varying from epsilon=1% to 20%. The dynamic shear modulus of bovine liver for compressive pre-strain values higher than epsilon>2.5% are found to be statistically different than the true shear moduli estimated for zero compressive strain (p<0.05). PMID- 26042769 TI - Effect of glucose on the biomechanical function of arterial elastin. AB - Elastin is essential to provide elastic support for blood vessels. As a remarkably long-lived protein, elastin can suffer from cumulative effects of exposure to biochemical damages, which can greatly compromise its biomechanical properties. Non-enzymatic glycation is one of the main mechanisms of aging and its effect is magnified in diabetic patients. The purpose of this study is to investigate the effects of glucose on mechanical properties of isolated porcine aortic elastin. Elastin samples were incubated in 2 M glucose solution and were allowed to equilibrate for 4, 7, 14, 21 or 28 days at 37 degrees C. Equibiaxial tensile tests were performed to study the changes of elastic properties of elastin due to glycation. Significant decreases in tissue dimension were observed after 7 days glucose incubation. Elastin samples treated for 14, 21 or 28 days demonstrate a significant increase in hysteresis in the stress-stretch curves, indicating a greater energy loss due to glucose treatment. Both the longitudinal and the circumferential directions show significant increases in tangent modulus with glucose treatment, however only significant increases are observed after 7 days for the circumferential direction. An eight-chain statistical mechanics based microstructural model was used to study the hyperelastic and orthotropic behavior of the glucose-treated elastin and the material parameters were estimated using a nonlinear least squares method. Material parameters in the model were related to elastin density and fiber orientation, and, hence, the possible microstructural changes in glucose-treated elastin. Estimated material parameters show a general increasing trend in elastin density per unit volume with glucose incubation. The simulation results also indicate that more elastic fibers are aligned in the longitudinal and circumferential directions, rather than in the radial direction. PMID- 26042771 TI - Optimal central obesity measurement site for assessing cardiometabolic and type 2 diabetes risk in middle-aged adults. AB - OBJECTIVES: Despite recommendations that central obesity assessment should be employed as a marker of cardiometabolic health, no consensus exists regarding measurement protocol. This study examined a range of anthropometric variables and their relationships with cardiometabolic features and type 2 diabetes in order to ascertain whether measurement site influences discriminatory accuracy. In particular, we compared waist circumference (WC) measured at two sites: (1) immediately below the lowest rib (WC rib) and (2) between the lowest rib and iliac crest (WC midway), which has been recommended by the World Health Organisation and International Diabetes Federation. MATERIALS AND METHODS: This was a cross-sectional study involving a random sample of 2,002 men and women aged 46-73 years. Metabolic profiles and WC, hip circumference, pelvic width and body mass index (BMI) were determined. Correlation, logistic regression and area under the receiver operating characteristic curve analyses were used to evaluate obesity measurement relationships with metabolic risk phenotypes and type 2 diabetes. RESULTS: WC rib measures displayed the strongest associations with non optimal lipid and lipoprotein levels, high blood pressure, insulin resistance, impaired fasting glucose, a clustering of metabolic risk features and type 2 diabetes, in both genders. Rib-derived indices improved discrimination of type 2 diabetes by 3-7% compared to BMI and 2-6% compared to WC midway (in men) and 5-7% compared to BMI and 4-6% compared to WC midway (in women). A prediction model including BMI and central obesity displayed a significantly higher area under the curve for WC rib (0.78, P=0.003), Rib/height ratio (0.80, P<0.001), Rib/pelvis ratio (0.79, P<0.001), but not for WC midway (0.75, P=0.127), when compared to one with BMI alone (0.74). CONCLUSIONS: WC rib is easier to assess and our data suggest that it is a better method for determining obesity-related cardiometabolic risk than WC midway. The clinical utility of rib-derived indices, or alternative WC measurements, deserves further investigation. PMID- 26042770 TI - mTORC1 Down-Regulates Cyclin-Dependent Kinase 8 (CDK8) and Cyclin C (CycC). AB - In non-alcoholic fatty liver disease (NAFLD) and insulin resistance, hepatic de novo lipogenesis is often elevated, but the underlying mechanisms remain poorly understood. Recently, we show that CDK8 functions to suppress de novo lipogenesis. Here, we identify the mammalian target of rapamycin complex 1 (mTORC1) as a critical regulator of CDK8 and its activating partner CycC. Using pharmacologic and genetic approaches, we show that increased mTORC1 activation causes the reduction of the CDK8-CycC complex in vitro and in mouse liver in vivo. In addition, mTORC1 is more active in three mouse models of NAFLD, correlated with the lower abundance of the CDK8-CycC complex. Consistent with the inhibitory role of CDK8 on de novo lipogenesis, nuclear SREBP-1c proteins and lipogenic enzymes are accumulated in NAFLD models. Thus, our results suggest that mTORC1 activation in NAFLD and insulin resistance results in down-regulation of the CDK8-CycC complex and elevation of lipogenic protein expression. PMID- 26042772 TI - Trypanothione reductase: a target protein for a combined in vitro and in silico screening approach. AB - With the goal to identify novel trypanothione reductase (TR) inhibitors, we performed a combination of in vitro and in silico screening approaches. Starting from a highly diverse compound set of 2,816 compounds, 21 novel TR inhibiting compounds could be identified in the initial in vitro screening campaign against T. cruzi TR. All 21 in vitro hits were used in a subsequent similarity search based in silico screening on a database containing 200,000 physically available compounds. The similarity search resulted in a data set containing 1,204 potential TR inhibitors, which was subjected to a second in vitro screening campaign leading to 61 additional active compounds. This corresponds to an approximately 10-fold enrichment compared to the initial pure in vitro screening. In total, 82 novel TR inhibitors with activities down to the nM range could be identified proving the validity of our combined in vitro/in silico approach. Moreover, the four most active compounds, showing IC50 values of <1 MUM, were selected for determining the inhibitor constant. In first on parasites assays, three compounds inhibited the proliferation of bloodstream T. brucei cell line 449 with EC50 values down to 2 MUM. PMID- 26042773 TI - Dietary supplement enriched in antioxidants and omega-3 protects from progressive light-induced retinal degeneration. AB - In the present study, we have evaluated one of the dietary supplements enriched with antioxidants and fish oil used in clinical care for patient with age-related macular degeneration. Rats were orally fed by a gastric canula daily with 0.2 ml of water or dietary supplement until they were sacrificed. After one week of treatment, animals were either sacrificed for lipid analysis in plasma and retina, or used for evaluation of rod-response recovery by electroretinography (ERG) followed by their sacrifice to measure rhodopsin content, or used for progressive light-induced retinal degeneration (PLIRD). For PLIRD, animals were transferred to bright cyclic light for one week. Retinal damage was quantified by ERG, histology and detection of apoptotic nuclei. Animals kept in dim-cyclic light were processed in parallel. PLIRD induced a thinning of the outer nuclear layer and a reduction of the b-wave amplitude of the ERG in the water group. Retinal structure and function were preserved in supplemented animals. Supplement induced a significant increase in omega-3 fatty acids in plasma by 168% for eicosapentaenoic acid (EPA), 142% for docosapentaenoic acid (DPA) and 19% for docosahexaenoic acid (DHA) and a decrease in the omega-6 fatty acids, DPA by 28%. In the retina, supplement induced significant reduction of linolenic acid by 67% and an increase in EPA and DPA by 80% and 72%, respectively, associated with significant decrease in omega-6 DPA by 42%. Supplement did not affect rhodopsin content or rod-response recovery. The present data indicate that supplement rapidly modified the fatty acid content and induced an accumulation of EPA in the retina without affecting rhodopsin content or recovery. In addition, it protected the retina from oxidative stress induced by light. Therefore, this supplement might be beneficial to slow down progression of certain retinal degeneration. PMID- 26042775 TI - Integration of acoustic radiation force and optical imaging for blood plasma clot stiffness measurement. AB - Despite the life-preserving function blood clotting serves in the body, inadequate or excessive blood clot stiffness has been associated with life threatening diseases such as stroke, hemorrhage, and heart attack. The relationship between blood clot stiffness and vascular diseases underscores the importance of quantifying the magnitude and kinetics of blood's transformation from a fluid to a viscoelastic solid. To measure blood plasma clot stiffness, we have developed a method that uses ultrasound acoustic radiation force (ARF) to induce micron-scaled displacements (1-500 MUm) on microbeads suspended in blood plasma. The displacements were detected by optical microscopy and took place within a micro-liter sized clot region formed within a larger volume (2 mL sample) to minimize container surface effects. Modulation of the ultrasound generated acoustic radiation force allowed stiffness measurements to be made in blood plasma from before its gel point to the stage where it was a fully developed viscoelastic solid. A 0.5 wt % agarose hydrogel was 9.8-fold stiffer than the plasma (platelet-rich) clot at 1 h post-kaolin stimulus. The acoustic radiation force microbead method was sensitive to the presence of platelets and strength of coagulation stimulus. Platelet depletion reduced clot stiffness 6.9 fold relative to platelet rich plasma. The sensitivity of acoustic radiation force based stiffness assessment may allow for studying platelet regulation of both incipient and mature clot mechanical properties. PMID- 26042774 TI - The Proteome of the Isolated Chlamydia trachomatis Containing Vacuole Reveals a Complex Trafficking Platform Enriched for Retromer Components. AB - Chlamydia trachomatis is an important human pathogen that replicates inside the infected host cell in a unique vacuole, the inclusion. The formation of this intracellular bacterial niche is essential for productive Chlamydia infections. Despite its importance for Chlamydia biology, a holistic view on the protein composition of the inclusion, including its membrane, is currently missing. Here we describe the host cell-derived proteome of isolated C. trachomatis inclusions by quantitative proteomics. Computational analysis indicated that the inclusion is a complex intracellular trafficking platform that interacts with host cells' antero- and retrograde trafficking pathways. Furthermore, the inclusion is highly enriched for sorting nexins of the SNX-BAR retromer, a complex essential for retrograde trafficking. Functional studies showed that in particular, SNX5 controls the C. trachomatis infection and that retrograde trafficking is essential for infectious progeny formation. In summary, these findings suggest that C. trachomatis hijacks retrograde pathways for effective infection. PMID- 26042776 TI - Antitumor Activity of a 5-Hydroxy-1H-Pyrrol-2-(5H)-One-Based Synthetic Small Molecule In Vitro and In Vivo. AB - Alternative chemo-reagents are in great demand because chemotherapy resistance is one of the major challenges in current cancer treatment. 5-hydoxy-1H-pyrrol-2 (5H)-one is an important N-heterocyclic scaffold that is present in natural products and medicinal chemistry. However, its antitumor activity has not been systematically explored. In this study, we screened a panel of 5-hydoxy-1H-pyrrol 2-(5H)-one derivatives and identified compound 1d as possessing strong anti proliferative activity in multiple cancer cell lines. Cell cycle analysis revealed that 1d can induce S-phase cell cycle arrest and that HCT116 was sensitive to 1d-induced apoptosis. Further analysis indicated that 1d preferentially induced DNA damage and p53 activation in HCT116 cells and that 1d induced apoptosis is partly dependent on p53. Furthermore, we showed that 1d significantly suppressed tumor growth in xenograft tumor models in vivo. Taken together, our results suggest that 5-hydoxy-1H-pyrrol-2-(5H)-one derivatives bear potential antitumor activity and that 1d is an effective agent for cancer treatment. PMID- 26042777 TI - Characterizing problematic hypoglycaemia: iterative design and preliminary psychometric validation of the Hypoglycaemia Awareness Questionnaire (HypoA-Q). AB - AIMS: To design and conduct preliminary validation of a measure of hypoglycaemia awareness and problematic hypoglycaemia, the Hypoglycaemia Awareness Questionnaire. METHODS: Exploratory and cognitive debriefing interviews were conducted with 17 adults (nine of whom were women) with Type 1 diabetes (mean +/- sd age 48 +/- 10 years). Questionnaire items were modified in consultation with diabetologists/psychologists. Psychometric validation was undertaken using data from 120 adults (53 women) with Type 1 diabetes (mean +/- sd age 44 +/- 16 years; 50% with clinically diagnosed impaired awareness of hypoglycaemia), who completed the following questionnaires: the Hypoglycaemia Awareness Questionnaire, the Gold score, the Clarke questionnaire and the Problem Areas in Diabetes questionnaire. RESULTS: Iterative design resulted in 33 items eliciting responses about awareness of hypoglycaemia when awake/asleep and hypoglycaemia frequency, severity and impact (healthcare utilization). Psychometric analysis identified three subscales reflecting 'impaired awareness', 'symptom level' and 'symptom frequency'. Convergent validity was indicated by strong correlations between the 'impaired awareness' subscale and existing measures of awareness: (Gold: rs =0.75, P < 0.01; Clarke: rs =0.76, P < 0.01). Divergent validity was indicated by weaker correlations with diabetes-related distress (Problem Areas in Diabetes: rs =0.25, P < 0.01) and HbA1c (rs =-0.05, non-significant). The 'impaired awareness' subscale and other items discriminated between those with impaired and intact awareness (Gold score). The 'impaired awareness' subscale and other items contributed significantly to models explaining the occurrence of severe hypoglycaemia and hypoglycaemia when asleep. CONCLUSIONS: This preliminary validation shows the Hypoglycaemia Awareness Questionnaire has robust face and content validity; satisfactory structure; internal reliability; convergent, divergent and known groups validity. The impaired awareness subscale and other items contribute significantly to models explaining recall of severe and nocturnal hypoglycaemia. Prospective validation, including determination of a threshold to identify impaired awareness, is now warranted. PMID- 26042778 TI - [Prevention of acute pancreatitis following endoscopic retrograde cholangiopancreatography]. AB - Over 14,000 endoscopic retrograde cholangiopancreatographies are performed in Hungary annually, and approximately 1400 patients are calculated to develop pancreatititis including 10 cases with fatal outcome. This article reviews the recent and relevant literature and presents a practical guide based on the authors' own experience for the prevention of pancreatitis following endoscopic retrograde cholangiopancreatography. The authors emphasize the importance of careful consideration of indications, analysis of risk factors, avoiding unnecessary diagnostic intervention, a decrease of the attempts for cannulation, early precut, implantation of pancreatic stent in high risk patients, administration of rectal indomethacin or diclofenac, and adequate intravenous fluid replacement. PMID- 26042779 TI - [Comprehensive evaluation of drug interaction screening programs: discrepancies and concordances]. AB - INTRODUCTION: Recognition of potentially harmful drug interactions is one of the duties of healthcare. However, solutions involving databases are fraught with contradictions due to the lack of standardized principles and data. AIM: The aims of the authors were to perform a comparative evaluation of Hungarian and international databases and to explore ambiguities and contradictions in order to develop more standardized criteria for screening interactions. METHOD: Four Hungarian and two English-language websites and software, and the summaries of product characteristics were compared. The authors analyzed 40 drug-drug and 8 drug-supplement interactions and looked at 8 cases, which represent 28 pairs of interacting substances. RESULTS: The databases warn about most interactions, but these warnings were rarely helpful in preventing undesired consequences. The authors found discrepancies between the databases in 70% of interactions. When looking at different products with the same active ingredients, discrepancies cropped up in 0-66.7% of the cases. Up to 80% of searches for supplementary product interactions did not produce satisfactory results. CONCLUSIONS: In the present situation mapping these ambiguities and creating a standardized classification system would be advantageous. PMID- 26042780 TI - [Study on religious addiction as a potential novel type of behavioral addiction in an adolescent population]. AB - INTRODUCTION: Religious addiction is a new behavioral addiction, featured with pathologic religious activity. AIM: The authors examined whether this new phenomenon appears in adolescence, and whether it correlates with substance use and mental health variables. METHOD: The General Addiction Screening Tool was used to investigate the presence of religious addiction among youth (N = 656; mean age, 16.5 years; 49.2% females). Besides monthly and lifetime prevalence of substance use, variables of psychological well-being (e.g., depression, aggression, optimism) were also detected. RESULTS: Religiosity was relatively low among adolescents. Nearly 1% of the sample might be characterized as being addicted to religion, 16.2% belonged to the symptomatic group, while 83% of them were asymptomatic. Religious addicts were more likely to be more religious and the role of religion in one's life was more important. Also, they tended to pray more and attend church more frequently. It was also found that amphetamine use was more frequent among the addicts. In terms of mental health level, aggression scored lower and spiritual well-being reached higher level. CONCLUSIONS: Religiosity is a vague phenomenon, and further investigation is needed to detect when healthy enthusiastic religiosity turns into religious addiction. PMID- 26042781 TI - [Differential diagnostic and therapeutic aspects of Q-fever in a male prisoner. Case report]. AB - The authors describe the case of a 46-year-old man, who developed atypical pneumonia caused by Coxiella burnetii. Chest X-ray revealed interstitial pneumonia. Western blot and ELISA test were positive for Coxiella burnetii antibody. After treatment with doxycyclin and amoxicillin supplemented with vitamin B6 for 10 days, the patient displayed a clinical improvement. The authors conclude that in cases with atypical pneumonia, Coxiella burnetii antibody as well as other bacterial or viral antibodies should be determined. PMID- 26042782 TI - [Comtemporary press on the disease and death of Semmelweis]. PMID- 26042783 TI - [Data and reflections on the energetic, chemical and biological processes of our Earth]. PMID- 26042784 TI - Correction: Changes in the pulmonary function test after radioactive iodine treatment in patients with pulmonary metastases of differentiated thyroid cancer. PMID- 26042785 TI - Risk Factors and Disability Associated with Low Back Pain in Older Adults in Low- and Middle-Income Countries. Results from the WHO Study on Global AGEing and Adult Health (SAGE). AB - BACKGROUND: Back pain is a common disabling chronic condition that burdens individuals, families and societies. Epidemiological evidence, mainly from high income countries, shows positive association between back pain prevalence and older age. There is an urgent need for accurate epidemiological data on back pain in adult populations in low- and middle-income countries (LMICs) where populations are ageing rapidly. The objectives of this study are to: measure the prevalence of back pain; identify risk factors and determinants associated with back pain, and describe association between back pain and disability in adults aged 50 years and older, in six LMICs from different regions of the world. The findings provide insights into country-level differences in self-reported back pain and disability in a group of socially, culturally, economically and geographically diverse LMICs. METHODS: Standardized national survey data collected from adults (50 years and older) participating in the World Health Organization (WHO) Study on global AGEing and adult health (SAGE) were analysed. The weighted sample (n = 30, 146) comprised respondents in China, Ghana, India, Mexico, South Africa and the Russian Federation. Multivariable regressions describe factors associated with back pain prevalence and intensity, and back pain as a determinant of disability. RESULTS: Prevalence was highest in the Russian Federation (56%) and lowest in China (22%). In the pooled multi-country analyses, female sex, lower education, lower wealth and multiple chronic morbidities were significant in association with past-month back pain (p<0.01). About 8% of respondents reported that they experienced intense back pain in the previous month. CONCLUSIONS: Evidence on back pain and its impact on disability is needed in developing countries so that governments can invest in cost effective education and rehabilitation to reduce the growing social and economic burden imposed by this disabling condition. PMID- 26042787 TI - The Complete Mitochondrial Genome of the Foodborne Parasitic Pathogen Cyclospora cayetanensis. AB - Cyclospora cayetanensis is a human-specific coccidian parasite responsible for several food and water-related outbreaks around the world, including the most recent ones involving over 900 persons in 2013 and 2014 outbreaks in the USA. Multicopy organellar DNA such as mitochondrion genomes have been particularly informative for detection and genetic traceback analysis in other parasites. We sequenced the C. cayetanensis genomic DNA obtained from stool samples from patients infected with Cyclospora in Nepal using the Illumina MiSeq platform. By bioinformatically filtering out the metagenomic reads of non-coccidian origin sequences and concentrating the reads by targeted alignment, we were able to obtain contigs containing Eimeria-like mitochondrial, apicoplastic and some chromosomal genomic fragments. A mitochondrial genomic sequence was assembled and confirmed by cloning and sequencing targeted PCR products amplified from Cyclospora DNA using primers based on our draft assembly sequence. The results show that the C. cayetanensis mitochondrion genome is 6274 bp in length, with 33% GC content, and likely exists in concatemeric arrays as in Eimeria mitochondrial genomes. Phylogenetic analysis of the C. cayetanensis mitochondrial genome places this organism in a tight cluster with Eimeria species. The mitochondrial genome of C. cayetanensis contains three protein coding genes, cytochrome (cytb), cytochrome C oxidase subunit 1 (cox1), and cytochrome C oxidase subunit 3 (cox3), in addition to 14 large subunit (LSU) and nine small subunit (SSU) fragmented rRNA genes. PMID- 26042786 TI - Host-Pathogen Coevolution: The Selective Advantage of Bacillus thuringiensis Virulence and Its Cry Toxin Genes. AB - Reciprocal coevolution between host and pathogen is widely seen as a major driver of evolution and biological innovation. Yet, to date, the underlying genetic mechanisms and associated trait functions that are unique to rapid coevolutionary change are generally unknown. We here combined experimental evolution of the bacterial biocontrol agent Bacillus thuringiensis and its nematode host Caenorhabditis elegans with large-scale phenotyping, whole genome analysis, and functional genetics to demonstrate the selective benefit of pathogen virulence and the underlying toxin genes during the adaptation process. We show that: (i) high virulence was specifically favoured during pathogen-host coevolution rather than pathogen one-sided adaptation to a nonchanging host or to an environment without host; (ii) the pathogen genotype BT-679 with known nematocidal toxin genes and high virulence specifically swept to fixation in all of the independent replicate populations under coevolution but only some under one-sided adaptation; (iii) high virulence in the BT-679-dominated populations correlated with elevated copy numbers of the plasmid containing the nematocidal toxin genes; (iv) loss of virulence in a toxin-plasmid lacking BT-679 isolate was reconstituted by genetic reintroduction or external addition of the toxins. We conclude that sustained coevolution is distinct from unidirectional selection in shaping the pathogen's genome and life history characteristics. To our knowledge, this study is the first to characterize the pathogen genes involved in coevolutionary adaptation in an animal host-pathogen interaction system. PMID- 26042788 TI - Bumblebee pupae contain high levels of aluminium. AB - The causes of declines in bees and other pollinators remains an on-going debate. While recent attention has focussed upon pesticides, other environmental pollutants have largely been ignored. Aluminium is the most significant environmental contaminant of recent times and we speculated that it could be a factor in pollinator decline. Herein we have measured the content of aluminium in bumblebee pupae taken from naturally foraging colonies in the UK. Individual pupae were acid-digested in a microwave oven and their aluminium content determined using transversely heated graphite furnace atomic absorption spectrometry. Pupae were heavily contaminated with aluminium giving values between 13.4 and 193.4 MUg/g dry wt. and a mean (SD) value of 51.0 (33.0) MUg/g dry wt. for the 72 pupae tested. Mean aluminium content was shown to be a significant negative predictor of average pupal weight in colonies. While no other statistically significant relationships were found relating aluminium to bee or colony health, the actual content of aluminium in pupae are extremely high and demonstrate significant exposure to aluminium. Bees rely heavily on cognitive function and aluminium is a known neurotoxin with links, for example, to Alzheimer's disease in humans. The significant contamination of bumblebee pupae by aluminium raises the intriguing spectre of cognitive dysfunction playing a role in their population decline. PMID- 26042789 TI - A recombinant fungal lectin for labeling truncated glycans on human cancer cells. AB - Cell surface glycoconjugates present alterations of their structures in chronic diseases and distinct oligosaccharide epitopes have been associated with cancer. Among them, truncated glycans present terminal non-reducing beta-N acetylglucosamine (GlcNAc) residues that are rare on healthy tissues. Lectins from unconventional sources such as fungi or algi provide novel markers that bind specifically to such epitopes, but their availability may be challenging. A GlcNAc-binding lectin from the fruiting body of the fungus Psathyrella velutina (PVL) has been produced in good yield in bacterial culture. A strong specificity for terminal GlcNAc residues was evidenced by glycan array. Affinity values obtained by microcalorimetry and surface plasmon resonance demonstrated a micromolar affinity for GlcNAcbeta1-3Gal epitopes and for biantennary N-glycans with GlcNAcbeta1-2Man capped branches. Crystal structure of PVL complexed with GlcNAcbeta1-3Gal established the structural basis of the specificity. Labeling of several types of cancer cells and use of inhibitors of glycan metabolism indicated that rPVL binds to terminal GlcNAc but also to sialic acid (Neu5Ac). Analysis of glycosyltransferase expression confirmed the higher amount of GlcNAc present on cancer cells. rPVL binding is specific to cancer tissue and weak or no labeling is observed for healthy ones, except for stomach glands that present unique alphaGlcNAc-presenting mucins. In lung, breast and colon carcinomas, a clear delineation could be observed between cancer regions and surrounding healthy tissues. PVL is therefore a useful tool for labeling agalacto-glycans in cancer or other diseases. PMID- 26042790 TI - Stages of Change Profiles among Adults Experiencing Hearing Difficulties Who Have Not Taken Any Action: A Cross-Sectional Study. AB - The aim of the current study was to test the hypothesis that adults experiencing hearing difficulties who are aware of their difficulties but have not taken any action would fall under contemplation and preparation stages based on the transtheoretical stages-of-change model. The study employed a cross-sectional design. The study was conducted in United Kingdom and 90 participants completed University of Rhode Island Change Assessment (URICA) scale as well as measures of self-reported hearing disability, self-reported anxiety and depression, self reported hearing disability acceptance, and provided additional demographic details online. As predicted, the results indicate that a high percentage of participants (over 90%) were in the contemplation and preparation stages. No statistically significant differences were observed among groups of stage with highest URICA scores and factors such as: years since hearing disability, self reported hearing disability, self-reported anxiety and depression, and self reported hearing disability acceptance. Cluster analysis identified three stages of-change clusters, which were named as: decision making (53% of sample), participation (28% of sample), and disinterest (19% of sample). Study results support the stages-of-change model. In addition, implications of the current study and areas for future research are discussed. PMID- 26042791 TI - Correlation of retinal nerve fibre layer thickness and spontaneous retinal venous pulsations in glaucoma and normal controls. AB - PURPOSE: To study the relationship between amplitude of spontaneous retinal venous pulsatility (SRVP) and retinal nerve fibre layer (RNFL) thickness in glaucomatous eyes, and to determine if this parameter may be a potential marker for glaucoma severity. METHOD: 85 subjects including 50 glaucoma (21 males, 67+/ 10 yrs) and 35 normals (16 males, 62+/-11 yrs) were studied. SRVP amplitude was measured using the Dynamic Vessel Analyser (DVA, Imedos, Germany) at four regions of the retina simultaneously within one disc diameter from the optic disc- temporal-superior (TS), nasal-superior (NS), temporal-inferior (TI) and nasal inferior (NI)). This was followed by RNFL thickness measurement using spectral domain optical coherence tomography (Spectralis OCT). The correlation between SRVP amplitude and corresponding sectoral RNFL thickness was assessed by means of non-linear regression (i.e. logarithmic). Linear regression was also applied and slopes were compared using analysis of covariance (ANCOVA). RESULTS: Greater SRVP amplitude was associated with thicker RNFL. Global SRVP amplitude was significantly lower in glaucoma eyes compared with normals (p<0.0001). The correlation coefficient of the linear regression between RNFL and SRVP at TS, NS, TI and NI quadrants in the glaucoma group were r = 0.5, 0.5, 0.48, 0.62. Mean SRVP amplitude and RNFL thickness for TS, NS, TI and NI quadrants were 4.3+/-1.5, 3.5+/-1.3, 4.7+/-1.6, 3.1+/-1 MUm and 96+/-30, 75+/-22, 89+/-35 and 88+/-30 MUm, respectively. The ANCOVA test showed that the slope of linear regression between the four quadrants was not significant (p>0.05). Since the slopes are not significantly different, it is possible to calculate one slope for all the data. The pooled slope equals 10.8 (i.e. RNFL = 10.8SRVP+41). CONCLUSION: While SRVP was present and measurable in all individuals, the amplitude of SRVP is reduced in glaucoma with increasing RNFL loss. Our findings suggest the degree of SRVP may be an additional marker for glaucoma severity. Further studies are needed to determine the mechanism of reduction in SRVP, and whether changes can predict increased risk of progression. PMID- 26042792 TI - Efficacy of Rifampin Plus Clofazimine in a Murine Model of Mycobacterium ulcerans Disease. AB - Treatment of Buruli ulcer, or Mycobacterium ulcerans disease, has shifted from surgical excision and skin grafting to antibiotic therapy usually with 8 weeks of daily rifampin (RIF) and streptomycin (STR). Although the results have been highly favorable, administration of STR requires intramuscular injection and carries the risk of side effects, such as hearing loss. Therefore, an all-oral, potentially less toxic, treatment regimen has been sought and encouraged by the World Health Organization. A combination of RIF plus clarithromycin (CLR) has been successful in patients first administered RIF+STR for 2 or 4 weeks. Based on evidence of efficacy of clofazimine (CFZ) in humans and mice with tuberculosis, we hypothesized that the combination of RIF+CFZ would be effective against M. ulcerans in the mouse footpad model of M. ulcerans disease because CFZ has similar MIC against M. tuberculosis and M. ulcerans. For comparison, mice were also treated with the gold standard of RIF+STR, the proposed RIF+CLR alternative regimen, or CFZ alone. Treatment was initiated after development of footpad swelling, when the bacterial burden was 4.64+/-0.14log10 CFU. At week 2 of treatment, the CFU counts had increased in untreated mice, remained essentially unchanged in mice treated with CFZ alone, decreased modestly with either RIF+CLR or RIF+CFZ, and decreased substantially with RIF+STR. At week 4, on the basis of footpad CFU counts, the combination regimens were ranked as follows: RIF+STR>RIF+CLR>RIF+CFZ. At weeks 6 and 8, none of the mice treated with these regimens had detectable CFU. Footpad swelling declined comparably with all of the combination regimens, as did the levels of detectable mycolactone A/B. In mice treated for only 6 weeks and followed up for 24 weeks, there were no relapses in RIF+STR treated mice, one (5%) relapse in RIF+CFZ-treated mice, but >50% in RIF+CLR treated mice. On the basis of these results, RIF+CFZ has potential as a continuation phase regimen for treatment of M. ulcerans disease. PMID- 26042794 TI - Mimicking the niche of lung epithelial stem cells and characterization of several effectors of their in vitro behavior. AB - The niche surrounding stem cells regulate their fate during homeostasis and after injury or infection. The 3D organoid assay has been widely used to study stem cells behavior based on its capacity to evaluate self-renewal, differentiation and the effect of various medium supplements, drugs and co-culture with supportive cells. We established an assay to study both lung and trachea stem cells in vitro. We characterized their proliferation and differentiation spectrum at baseline then evaluated the effect of co-culturing with fibroblasts and endothelial cells and/or treating with several biologically relevant substances as possible contributors to their niche. We found that lung epithelial (but not tracheal basal) stem cells require co-culture with stromal cells to undergo clonal proliferation and differentiation. Fibroblasts were more efficient than endothelial cells in offering this support and the pattern of support varied based on the tissue origin of the stromal cells. Treating distal lung epithelial or basal stem cells with FGF2, FGF9, FGF10, LIF as well as ALK5 and ROCK inhibitors increased their colony formation efficiency and resulted in variable effects on colonies number, size and differentiation spectrum. This model and findings pave the way for better understanding of lung stem cell niche components and factors that can manipulate lung stem cell behavior. PMID- 26042793 TI - The effect of low-frequency electromagnetic field on human bone marrow stem/progenitor cell differentiation. AB - Human bone marrow stromal cells (hBMSCs, also known as bone marrow-derived mesenchymal stem cells) are a population of progenitor cells that contain a subset of skeletal stem cells (hSSCs), able to recreate cartilage, bone, stroma that supports hematopoiesis and marrow adipocytes. As such, they have become an important resource in developing strategies for regenerative medicine and tissue engineering due to their self-renewal and differentiation capabilities. The differentiation of SSCs/BMSCs is dependent on exposure to biophysical and biochemical stimuli that favor early and rapid activation of the in vivo tissue repair process. Exposure to exogenous stimuli such as an electromagnetic field (EMF) can promote differentiation of SSCs/BMSCs via ion dynamics and small signaling molecules. The plasma membrane is often considered to be the main target for EMF signals and most results point to an effect on the rate of ion or ligand binding due to a receptor site acting as a modulator of signaling cascades. Ion fluxes are closely involved in differentiation control as stem cells move and grow in specific directions to form tissues and organs. EMF affects numerous biological functions such as gene expression, cell fate, and cell differentiation, but will only induce these effects within a certain range of low frequencies as well as low amplitudes. EMF has been reported to be effective in the enhancement of osteogenesis and chondrogenesis of hSSCs/BMSCs with no documented negative effects. Studies show specific EMF frequencies enhance hSSC/BMSC adherence, proliferation, differentiation, and viability, all of which play a key role in the use of hSSCs/BMSCs for tissue engineering. While many EMF studies report significant enhancement of the differentiation process, results differ depending on the experimental and environmental conditions. Here we review how specific EMF parameters (frequency, intensity, and time of exposure) significantly regulate hSSC/BMSC differentiation in vitro. We discuss optimal conditions and parameters for effective hSSC/BMSC differentiation using EMF treatment in an in vivo setting, and how these can be translated to clinical trials. PMID- 26042796 TI - Phase-Engineered Synthesis of Centimeter-Scale 1T'- and 2H-Molybdenum Ditelluride Thin Films. AB - We report the synthesis of centimeter-scale, uniform 1T'- and 2H-MoTe2 thin films via the tellurization of Mo thin films. 1T'-MoTe2 was initially grown and converted gradually to 2H-MoTe2 over a prolonged growth time under a Te atmosphere. Maintaining excessive Te was essential for obtaining the stable stoichiometric 2H-MoTe2 phase. Further annealing under a lower partial pressure of Te at the same temperature, followed by a rapid quenching, led to the reverse phase transition from 2H-MoTe2 to 1T'-MoTe2. The orientation of the 2H-MoTe2 film was determined by the tellurization rate. Slow tellurization was the key for obtaining a highly oriented 2H-MoTe2 film over the entire area, while fast tellurization led to a 2H-MoTe2 film with a randomly oriented c-axis. PMID- 26042795 TI - Chemically-defined albumin-free differentiation of human pluripotent stem cells to endothelial progenitor cells. AB - Human pluripotent stem cell (hPSC)-derived endothelial cells and their progenitors are important for vascular research and therapeutic revascularization. Here, we report a completely defined endothelial progenitor differentiation platform that uses a minimalistic medium consisting of Dulbecco's modified eagle medium and ascorbic acid, lacking of albumin and growth factors. Following hPSC treatment with a GSK-3beta inhibitor and culture in this medium, this protocol generates more than 30% multipotent CD34+ CD31+ endothelial progenitors that can be purified to >95% CD34+ cells via magnetic activated cell sorting (MACS). These CD34+ progenitors are capable of differentiating into endothelial cells in serum-free inductive media. These hPSC-derived endothelial cells express key endothelial markers including CD31, VE-cadherin, and von Willebrand factor (vWF), exhibit endothelial-specific phenotypes and functions including tube formation and acetylated low-density lipoprotein (Ac-LDL) uptake. This fully defined platform should facilitate production of proliferative, xeno free endothelial progenitor cells for both research and clinical applications. PMID- 26042798 TI - Correction: Local Difference Measures between Complex Networks for Dynamical System Model Evaluation. PMID- 26042797 TI - Acknowledging How Older Australian Women Experience Life After Stroke: How Does the WHO 18-Item Brief ICF Core Set for Stroke Compare? AB - We examined older women's qualitative experiences of stroke with the World Health Organization's 18-item Brief International Classification of Functioning, Disability and Health Core Set for Stroke. Women were participants of the Australian Longitudinal Study on Women's Health, born between 1921 and 1926, who had experienced a stroke in the previous 3 years. An inductive thematic analysis was conducted of women's qualitative experiences of stroke, which were then examined with the 18-item Brief Core Set for Stroke for congruency. Our analysis showed that for older Australian women, their concerns of poststroke living were not adequately classified, potentially impeding a full recovery. PMID- 26042799 TI - Objective assessment of reasons for needle change during endoscopic ultrasound guided fine-needle aspiration. PMID- 26042800 TI - Multifocal epithelioid hemangioma of the penis: a diagnostic and therapeutic challenge. PMID- 26042803 TI - Correction: Interspecific and geographic variation in the diets of sympatric carnivores: dingoes/wild dogs and red foxes in south-eastern Australia. PMID- 26042802 TI - Cooking and season as risk factors for acute lower respiratory infections in African children: a cross-sectional multi-country analysis. AB - BACKGROUND: Acute lower respiratory infections (ALRI) are a leading cause of death among African children under five. A significant proportion of these are attributable to household air pollution from solid fuel use. METHODS: We assessed the relationship between cooking practices and ALRI in pooled datasets of Demographic and Health Surveys conducted between 2000 and 2011 in countries of sub-Saharan Africa. The impacts of main cooking fuel, cooking location and stove ventilation were examined in 18 (n = 56,437), 9 (n = 23,139) and 6 countries (n = 14,561) respectively. We used a causal diagram and multivariable logistic mixed models to assess the influence of covariates at individual, regional and national levels. RESULTS: Main cooking fuel had a statistically significant impact on ALRI risk (p<0.0001), with season acting as an effect modifier (p = 0.034). During the rainy season, relative to clean fuels, the odds of suffering from ALRI were raised for kerosene (OR 1.64; CI: 0.99, 2.71), coal and charcoal (OR 1.54; CI: 1.21, 1.97), wood (OR 1.20; CI: 0.95, 1.51) and lower-grade biomass fuels (OR 1.49; CI: 0.93, 2.35). In contrast, during the dry season the corresponding odds were reduced for kerosene (OR 1.23; CI: 0.77, 1.95), coal and charcoal (OR 1.35; CI: 1.06, 1.72) and lower-grade biomass fuels (OR 1.07; CI: 0.69, 1.66) but increased for wood (OR 1.32; CI: 1.04, 1.66). Cooking location also emerged as a season-dependent statistically significant (p = 0.0070) determinant of ALRI, in particular cooking indoors without a separate kitchen during the rainy season (OR 1.80; CI: 1.30, 2.50). Due to infrequent use in Africa we could, however, not demonstrate an effect of stove ventilation. CONCLUSIONS: We found differential and season-dependent risks for different types of solid fuels and kerosene as well as cooking location on child ALRI. Future household air pollution studies should consider potential effect modification of cooking fuel by season. PMID- 26042805 TI - Real-time human action classification using a dynamic neural model. AB - The multiple timescale recurrent neural network (MTRNN) model is a useful tool for recording and regenerating a continuous signal for dynamic tasks. However, our research shows that the MTRNN model is difficult to use for the classification of multiple types of motion when observing a human action. Therefore, in this paper, we propose a new supervised MTRNN model for handling the issue of action classification. Instead of setting the initial states, we define a group of slow context nodes as "classification nodes." The supervised MTRNN model provides both prediction and classification outputs simultaneously during testing. Our experiment results show that the supervised MTRNN model inherits the basic function of an MTRNN and can be used to generate action signals. In addition, the results show that the robustness of the supervised MTRNN model is better than that of the MTRNN model when generating both action sequences and action classification tasks. PMID- 26042804 TI - Ongoing HIV Transmission and the HIV Care Continuum in North Carolina. AB - OBJECTIVE: HIV transmission is influenced by status awareness and receipt of care and treatment. We analyzed these attributes of named partners of persons with acute HIV infection (index AHI cases) to characterize the transmission landscape in North Carolina (NC). DESIGN: Secondary analysis of programmatic data. METHODS: We used data from the NC Screening and Tracing of Active Transmission Program (2002-2013) to determine HIV status (uninfected, AHI, or chronic HIV infection [CHI]), diagnosis status (new or previously-diagnosed), and care and treatment status (not in care, in care and not on treatment, in care and on treatment) of index AHI cases' named partners. We developed an algorithm identifying the most likely transmission source among known HIV-infected partners to estimate the proportion of transmissions arising from contact with persons at different HIV continuum stages. We conducted a complementary analysis among a subset of index AHI cases and partners with phylogenetically-linked viruses. RESULTS: Overall, 358 index AHI cases named 932 partners, of which 218 were found to be HIV infected (162 (74.3%) previously-diagnosed, 11 (5.0%) new AHI, 45 (20.6%) new CHI). Most transmission events appeared attributable to previously-diagnosed partners (77.4%, 95% confidence interval 69.4-85.3%). Among these previously diagnosed partners, 23.2% (14.0-32.3%) were reported as in care and on treatment near the index AHI case diagnosis date. In the subset study of 33 phylogenetically-linked cases and partners, 60.6% of partners were previously diagnosed (43.9-77.3%). CONCLUSIONS: A substantial proportion of HIV transmission in this setting appears attributable to contact with previously-diagnosed partners, reinforcing the need for improved engagement in care after diagnosis. PMID- 26042807 TI - Preparation and Surface Property of Fluoroalkyl End-Capped Vinyltrimethoxysilane Oligomer/Talc Composite-Encapsulated Organic Compounds: Application for the Separation of Oil and Water. AB - Fluoroalkyl end-capped vinyltrimethoxysilane oligomer [R(F)-(CH2-CHSi(OMe)3)n R(F); n = 2, 3; R(F) = CF(CF3)OC3F7 (R(F)-VM oligomer)] can undergo the sol-gel reaction in the presence of talc particles under alkaline conditions at room temperature to provide the corresponding fluorinated oligomeric silica/talc nanocomposites (RF-VM-SiO2/Talc). A variety of guest molecules such as 2-hydroxy 4-methoxybenzophenone (HMB), bisphenol A (BPA), bisphenol AF, 3-(hydroxysilyl)-1 propanesulfonic acid (THSP), and perfluoro-2-methyl-3-oxahexanoic acid (R(F) COOH) are effectively encapsulated into the R(F)-VM-SiO2/Talc composite cores to afford the corresponding fluorinated nanocomposites-encapsulated these guest molecules. The R(F)-VM-SiO2/Talc composites encapsulated low molecular weight aromatic compounds such as HMB and BPA can exhibit a superoleophilic superhydrophobic characteristic on the surfaces; however, the R(F)-VM-SiO2/Talc composite-encapsulated THSP and R(F)-COOH exhibit a superoleophobic superhydrophilic characteristic on the modified surfaces. In these nanocomposites, the R(F)-VM-SiO2/Talc/THSP composites are applicable to the surface modification of polyester fabric, and the modified polyester fabric possessing a superoleophobic-superhydrophilic characteristic on the surface can be used for the membrane for oil (dodecane)/water separation. In addition, the R(F)-VM-SiO2/Talc composites-encapsulated micrometer-size controlled cross-linked polystyrene particles can be also prepared under similar conditions, and the obtained composite white-colored particle powders are applied to the packing material for the column chromatography to separate water-in-oil (W/O) emulsion. PMID- 26042806 TI - De novo Transcriptome Analysis of Portunus trituberculatus Ovary and Testis by RNA-Seq: Identification of Genes Involved in Gonadal Development. AB - The swimming crab Portunus trituberculatus is a commercially important crab species in East Asia countries. Gonadal development is a physiological process of great significance to the reproduction as well as commercial seed production for P. trituberculatus. However, little is currently known about the molecular mechanisms governing the developmental processes of gonads in this species. To open avenues of molecular research on P. trituberculatus gonadal development, Illumina paired-end sequencing technology was employed to develop deep-coverage transcriptome sequencing data for its gonads. Illumina sequencing generated 58,429,148 and 70,474,978 high-quality reads from the ovary and testis cDNA library, respectively. All these reads were assembled into 54,960 unigenes with an average sequence length of 879 bp, of which 12,340 unigenes (22.45% of the total) matched sequences in GenBank non-redundant database. Based on our transcriptome analysis as well as published literature, a number of candidate genes potentially involved in the regulation of gonadal development of P. trituberculatus were identified, such as FAOMeT, mPRgamma, PGMRC1, PGDS, PGER4, 3beta-HSD and 17beta-HSDs. Differential expression analysis generated 5,919 differentially expressed genes between ovary and testis, among which many genes related to gametogenesis and several genes previously reported to be critical in differentiation and development of gonads were found, including Foxl2, Wnt4, Fst, Fem-1 and Sox9. Furthermore, 28,534 SSRs and 111,646 high-quality SNPs were identified in this transcriptome dataset. This work represents the first transcriptome analysis of P. trituberculatus gonads using the next generation sequencing technology and provides a valuable dataset for understanding molecular mechanisms controlling development of gonads and facilitating future investigation of reproductive biology in this species. The molecular markers obtained in this study will provide a fundamental basis for population genetics and functional genomics in P. trituberculatus and other closely related species. PMID- 26042808 TI - A Novel 1,4-Dihydropyridine Derivative Improves Spatial Learning and Memory and Modifies Brain Protein Expression in Wild Type and Transgenic APPSweDI Mice. AB - Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer's disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4 dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer's disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability of AP-12 to cross the BBB, improve spatial learning and memory in both mice strains, induce anxiolytic action in transgenic mice, and increase expression of hippocampal and cortical proteins (GAD67, Homer-1) related to synaptic plasticity. The compound AP-12 can be seen as a prototype molecule for use in the design of novel drugs useful to halt progression of clinical symptoms (more specifically, anxiety and decline in memory) of neurodegenerative diseases, particularly Alzheimer's disease. PMID- 26042809 TI - Association between the TERT Genetic Polymorphism rs2853676 and Cancer Risk: Meta Analysis of 76,108 Cases and 134,215 Controls. AB - BACKGROUND: Several recent studies have identified that the TERT genetic polymorphism rs2853676 is associated with cancer risk, but presented inconsistent results. We investigated these inconclusive results by performing a meta-analysis to systematically evaluate the association. METHODS: We conducted a search in PubMed, Google Scholar and ISI Web of Science to select studies on the association between TERT rs2853676 and cancer risk. We conducted a stratified analysis using cancer type, ethnicity and source of controls. We calculated the odds ratios (OR) and 95% confidence intervals (CI). Article quality, heterogeneity, sensitivity, publication bias and statistical power were also assessed. RESULTS: 26 articles covering 76,108 cases and 134,215 controls met our inclusion criteria. A significant association between TERT rs2853676 allele A and cancer susceptibility was demonstrated under a per-allele risk analysis (OR = 1.08, 95% CI = 1.04-1.13). Stratification analysis revealed an increased cancer risk in subgroups of glioma, lung cancer and ovarian cancer. No significant increase was found in melanoma, breast cancer, pancreatic cancer and colorectal cancer. In a subgroup analysis of lung cancer, a statistically significant increase was only observed in adenocarcinoma. Moreover, a stratified analysis performed for ethnic groups revealed that the significant increase was only observed in Caucasians, whereas a non-significant increase was found in Asians. CONCLUSIONS: This meta-analysis suggests that the TERT genetic polymorphism rs2853676 is associated with increased risk of glioma, lung adenocarcinoma and ovarian cancer among Caucasians. Further functional studies are warranted to validate this association and investigate further. PMID- 26042810 TI - Inferring regulatory networks from experimental morphological phenotypes: a computational method reverse-engineers planarian regeneration. AB - Transformative applications in biomedicine require the discovery of complex regulatory networks that explain the development and regeneration of anatomical structures, and reveal what external signals will trigger desired changes of large-scale pattern. Despite recent advances in bioinformatics, extracting mechanistic pathway models from experimental morphological data is a key open challenge that has resisted automation. The fundamental difficulty of manually predicting emergent behavior of even simple networks has limited the models invented by human scientists to pathway diagrams that show necessary subunit interactions but do not reveal the dynamics that are sufficient for complex, self regulating pattern to emerge. To finally bridge the gap between high-resolution genetic data and the ability to understand and control patterning, it is critical to develop computational tools to efficiently extract regulatory pathways from the resultant experimental shape phenotypes. For example, planarian regeneration has been studied for over a century, but despite increasing insight into the pathways that control its stem cells, no constructive, mechanistic model has yet been found by human scientists that explains more than one or two key features of its remarkable ability to regenerate its correct anatomical pattern after drastic perturbations. We present a method to infer the molecular products, topology, and spatial and temporal non-linear dynamics of regulatory networks recapitulating in silico the rich dataset of morphological phenotypes resulting from genetic, surgical, and pharmacological experiments. We demonstrated our approach by inferring complete regulatory networks explaining the outcomes of the main functional regeneration experiments in the planarian literature; By analyzing all the datasets together, our system inferred the first systems-biology comprehensive dynamical model explaining patterning in planarian regeneration. This method provides an automated, highly generalizable framework for identifying the underlying control mechanisms responsible for the dynamic regulation of growth and form. PMID- 26042812 TI - Median nail damage in nail-patella syndrome associated with triangular lunulae. PMID- 26042811 TI - Combinations of Kinase Inhibitors Protecting Myoblasts against Hypoxia. AB - Cell-based therapies to treat skeletal muscle disease are limited by the poor survival of donor myoblasts, due in part to acute hypoxic stress. After confirming that the microenvironment of transplanted myoblasts is hypoxic, we screened a kinase inhibitor library in vitro and identified five kinase inhibitors that protected myoblasts from cell death or growth arrest in hypoxic conditions. A systematic, combinatorial study of these compounds further improved myoblast viability, showing both synergistic and additive effects. Pathway and target analysis revealed CDK5, CDK2, CDC2, WEE1, and GSK3beta as the main target kinases. In particular, CDK5 was the center of the target kinase network. Using our recently developed statistical method based on elastic net regression we computationally validated the key role of CDK5 in cell protection against hypoxia. This method provided a list of potential kinase targets with a quantitative measure of their optimal amount of relative inhibition. A modified version of the method was also able to predict the effect of combinations using single-drug response data. This work is the first step towards a broadly applicable system-level strategy for the pharmacology of hypoxic damage. PMID- 26042813 TI - Distinct Clinicopathological Patterns of Mismatch Repair Status in Colorectal Cancer Stratified by KRAS Mutations. AB - In sporadic colorectal cancer (CRC), the BRAFV600E mutation is associated with deficient mismatch repair (MMR) status and inversely associated with to KRAS mutations. In contrast to deficient MMR (dMMR) CRC, data on the presence of KRAS oncogenic mutations in proficient MMR (pMMR) CRC and their relationship with tumor progression are scarce. We therefore examined the MMR status in combination with KRAS mutations in 913 Chinese patients and correlated the findings obtained with clinical and pathological features. The MMR status was determined based on detection of MLH1, MSH2, MSH6 and PMS2 expression. KRAS mutation and dMMR status were detected in 36.9% and 7.5% of cases, respectively. Four subtypes were determined by MMR and KRAS mutation status: KRAS (+)/pMMR (34.0%), KRAS (+)/dMMR (2.9%), KRAS (-)/pMMR (58.5%) and KRAS (-)/dMMR (4.6%). A higher percentage of pMMR tumors with KRAS mutation were most likely to be female (49.0%), proximal located (45.5%), a mucinous histology (38.4%), and to have increased lymph node metastasis (60.3%), compared with pMMR tumors without BRAFV600E and KRAS mutations (36.0%, 29.3%, 29.4% and 50.7%, respectively; all P < 0.01). To the contrary, compared with those with KRAS(-)/dMMR tumors, patients with KRAS(+)/dMMR tumors demonstrated no statistically significant differences in gender, tumor location, pT depth of invasion, lymph node metastasis, pTNM stage, and histologic grade. This study revealed that specific epidemiologic and clinicopathologic characteristics are associated with MMR status stratified by KRAS mutation. Knowledge of MMR and KRAS mutation status may enhance molecular pathologic staging of CRC patients and metastatic progression in CRC can be estimated based on the combination of these biomarkers. PMID- 26042814 TI - An in vitro model of latency and reactivation of varicella zoster virus in human stem cell-derived neurons. AB - Varicella zoster virus (VZV) latency in sensory and autonomic neurons has remained enigmatic and difficult to study, and experimental reactivation has not yet been achieved. We have previously shown that human embryonic stem cell (hESC) derived neurons are permissive to a productive and spreading VZV infection. We now demonstrate that hESC-derived neurons can also host a persistent non productive infection lasting for weeks which can subsequently be reactivated by multiple experimental stimuli. Quiescent infections were established by exposing neurons to low titer cell-free VZV either by using acyclovir or by infection of axons in compartmented microfluidic chambers without acyclovir. VZV DNA and low levels of viral transcription were detectable by qPCR for up to seven weeks. Quiescently-infected human neuronal cultures were induced to undergo renewed viral gene and protein expression by growth factor removal or by inhibition of PI3-Kinase activity. Strikingly, incubation of cultures induced to reactivate at a lower temperature (34 degrees C) resulted in enhanced VZV reactivation, resulting in spreading, productive infections. Comparison of VZV genome transcription in quiescently-infected to productively-infected neurons using RNASeq revealed preferential transcription from specific genome regions, especially the duplicated regions. These experiments establish a powerful new system for modeling the VZV latent state, and reveal a potential role for temperature in VZV reactivation and disease. PMID- 26042817 TI - Group 9 Metal Complexes of meso-Aryl-Substituted Rubyrin. AB - Invited for the cover of this issue are Takanori Soya and Atsuhiro Osuka at Kyoto University. The image depicts Group 9 metal (Co, Rh, and Ir) complexes of meso aryl-substituted rubyrin and a meteorite approaching to the atmosphere. A large amount of Iridium is often contained in meteorites. Read the full text of the article at 10.1002/chem.201501080. PMID- 26042816 TI - Towards a psychological construct of being moved. AB - The emotional state of being moved, though frequently referred to in both classical rhetoric and current language use, is far from established as a well defined psychological construct. In a series of three studies, we investigated eliciting scenarios, emotional ingredients, appraisal patterns, feeling qualities, and the affective signature of being moved and related emotional states. The great majority of the eliciting scenarios can be assigned to significant relationship and critical life events (especially death, birth, marriage, separation, and reunion). Sadness and joy turned out to be the two preeminent emotions involved in episodes of being moved. Both the sad and the joyful variants of being moved showed a coactivation of positive and negative affect and can thus be ranked among the mixed emotions. Moreover, being moved, while featuring only low-to-mid arousal levels, was experienced as an emotional state of high intensity; this applied to responses to fictional artworks no less than to own-life and other real, but media-represented, events. The most distinctive findings regarding cognitive appraisal dimensions were very low ratings for causation of the event by oneself and for having the power to change its outcome, along with very high ratings for appraisals of compatibility with social norms and self-ideals. Putting together the characteristics identified and discussed throughout the three studies, the paper ends with a sketch of a psychological construct of being moved. PMID- 26042818 TI - State all-driver distracted driving laws and high school students' texting while driving behavior. AB - OBJECTIVE: Texting while driving is highly prevalent among adolescents and young adults in the United States. Texting while driving can significantly increase the risk of road crashes and is associated with other risky driving behaviors. Most states have enacted distracted driving laws to prohibit texting while driving. This study examines effects of different all-driver distracted driving laws on texting while driving among high school students. METHODS: High school student data were extracted from the 2013 National Youth Risk Behavior Survey. Distracted driving law information was collected from the National Conference of State Legislatures. The final sample included 6,168 high school students above the restricted driving age in their states and with access to a vehicle. Logistic regression was applied to estimate odds ratios of laws on texting while driving. RESULTS: All-driver text messaging bans with primary enforcement were associated with a significant reduction in odds of texting while driving among high school students (odds ratio = 0.703; 95% confidence interval, 0.513-0.964), whereas all driver phone use bans with primary enforcement did not have a significant association with texting while driving (odds ratio = 0.846; 95% confidence interval, 0.501-1.429). CONCLUSIONS: The findings indicate that all-driver distracted driving laws that specifically target texting while driving as opposed to all types of phone use are effective in reducing the behavior among high school students. PMID- 26042819 TI - Structural ensembles reveal intrinsic disorder for the multi-stimuli responsive bio-mimetic protein Rec1-resilin. AB - Rec1-resilin is the first recombinant resilin-mimetic protein polymer, synthesized from exon-1 of the Drosophila melanogaster gene CG15920 that has demonstrated unusual multi-stimuli responsiveness in aqueous solution. Crosslinked hydrogels of Rec1-resilin have also displayed remarkable mechanical properties including near-perfect rubber-like elasticity. The structural basis of these extraordinary properties is not clearly understood. Here we combine a computational and experimental investigation to examine structural ensembles of Rec1-resilin in aqueous solution. The structure of Rec1-resilin in aqueous solutions is investigated experimentally using circular dichroism (CD) spectroscopy and small angle X-ray scattering (SAXS). Both bench-top and synchrotron SAXS are employed to extract structural data sets of Rec1-resilin and to confirm their validity. Computational approaches have been applied to these experimental data sets in order to extract quantitative information about structural ensembles including radius of gyration, pair-distance distribution function, and the fractal dimension. The present work confirms that Rec1-resilin is an intrinsically disordered protein (IDP) that displays equilibrium structural qualities between those of a structured globular protein and a denatured protein. The ensemble optimization method (EOM) analysis reveals a single conformational population with partial compactness. This work provides new insight into the structural ensembles of Rec1-resilin in solution. PMID- 26042820 TI - The Anti-Apoptotic Role of Berberine in Preimplantation Embryo In Vitro Development through Regulation of miRNA-21. AB - Traditional Chinese medicinal herbs containing berberine have been historically used to prevent miscarriage. Here, we investigated whether the anti-apoptotic effects of berberine on pre-implantation embryonic development are regulated by miRNA-21. Mouse pronuclear embryos were cultured in medium with or without berberine, and some were then microinjected with a miRNA-21 inhibitor. The in vitro developmental rates of 2- and 4-cell embryos and blastocysts, blastocyst cell numbers, apoptotic rates, and apoptotic cell numbers were measured in each group. Furthermore, we examined the transcription levels of miRNA-21 and its target genes (caspase-3, PTEN, and Bcl-2) and their translation levels. Comparisons were made with in vivo-developed and untreated embryos. We found that berberine significantly increased the developmental rates and cell numbers of mouse blastocysts and decreased apoptotic cell rates in vitro. Berberine also significantly increased miRNA-21 and Bcl-2 transcription levels and significantly decreased caspase-3 and PTEN transcription levels. In embryos treated with a miRNA-21 inhibitor, the results followed the opposite trend; PTEN and caspase-3 transcription levels increased significantly, while the transcription level of Bcl-2 decreased significantly. Additionally, berberine treatment significantly increased the Bcl-2 protein level and significantly decreased the caspase-3 and PTEN protein levels in blastocysts, but there were no significant differences observed in the levels of these proteins in 2- and 4-cell embryos. This study revealed that miRNA-21 is important for pre-implantation embryonic development, especially blastocyst development in vitro. Berberine elevates miRNA-21 expression, decreases PTEN and caspase-3 levels, increases Bcl-2 levels, and exerts anti-apoptotic and pro-growth effects. PMID- 26042821 TI - The relationship between high-sensitivity C-reactive protein at admission and post stroke depression: a 6-month follow-up study. AB - OBJECTIVE: A large body of evidence suggests that stroke and depression are accompanied by activation of inflammatory pathways. Thus, the primary purpose of this study was to assess the high-sensitivity C-reactive protein (Hs-CRP) to the presence of post stroke depression (PSD). METHODS: Two hundred and twenty-six ischemic stroke patients admitted to the hospital within the first 24 hours after stroke onset were consecutively recruited and followed up for 6 months. Clinical information was collected. Serum Hs-CRP levels were measured at baseline. Based on the symptoms, diagnoses of depression were made in accordance with DSM-IV criteria for depression at 6-month after stroke. RESULTS: At 6-month, ninety-five patients (42.0%) showed depression at 6 months after admission and in 69 patients (30.5%) this depression was classified as major. In the 69 patients with major depression, our results showed significantly higher Hs-CRP levels (1.54[IQR, 0.79 2.27]mg/dL vs. 0.43[IQR, 0.31-1.27]mg/dL, P<0.0001) at admission than patients without major depression. After adjusting for NIHSS on admission and all other recorded confounders, Hs-CRP still was an independent predicator of PSD with an adjusted OR of 1.339 (95% CI, 1.231-1.456; P<0.001). Further, in our study, we found that an increased risk of PSD was associated with serum Hs-CRP levels >=0.85mg/dL (adjusted OR 7.830, 95% CI: 4.193-14.620) after adjusting for above recorded confounders. CONCLUSION: Elevated Hs-CRP serum levels at admission was found to be associated with depression 6-month after stroke, suggesting that these alterations might participate in the pathophysiology of depression symptoms in stroke patients. PMID- 26042822 TI - The ULTRAPETALA1 trxG factor contributes to patterning the Arabidopsis adaxial abaxial leaf polarity axis. AB - The SAND domain protein ULTRAPETALA1 (ULT1) functions as a trithorax group factor that regulates a variety of developmental processes in Arabidopsis. We have recently shown that ULT1 regulates developmental patterning in the gynoecia and leaves. ULT1 acts together with the KANADI1 (KAN1) transcription factor to pattern the apical-basal axis during gynoecium formation, whereas the 2 genes act antagonistically to pattern the adaxial-abaxial axis during both gynoecium and leaf formation. In particular, our data showed that ULT1 is necessary for the kan1 adaxialized organ phenotype. Here, we observe the internal structure of ult1, kan1 and ult1 kan1 rosette leaves to better understand the suppression of the kan1 adaxialized leaf polarity defect by ult1 mutations. Our results indicate that ULT1 and KAN1 act antagonistically to pattern the adaxial-abaxial axis in leaves by establishing the asymmetry of the internal cell layers. PMID- 26042823 TI - Aerobic Biotransformation of Fluorotelomer Thioether Amido Sulfonate (Lodyne) in AFFF-Amended Microcosms. AB - The aerobic biotransformation pathways of 4:2, 6:2, and 8:2 fluorotelomer thioether amido sulfonate (FtTAoS) were characterized by determining the fate of the compounds in soil and medium microcosms amended with an aqueous film-forming foam (AFFF) solution. The biotransformation of FtTAoS occurred in live microcosms over approximately 40 days and produced 4:2, 6:2, and 8:2 fluorotelomer sulfonate (FtS), 6:2 fluorotelomer unsaturated carboxylic acid (FtUCA), 5:3 fluorotelomer carboxylic acid (FtCA), and C4 to C8 perfluorinated carboxylic acids (PFCAs). Two biotransformation products corresponding to singly and doubly oxygenated forms of 6:2 FtTAoS were also identified through high resolution mass spectrometry (MS) analysis and liquid chromatography tandem-MS. An oxidative assay was used to indirectly quantify the total concentration of polyfluorinated compounds and check the mass balance. The assay produced near complete mass recovery of FtTAoS after biotransformation, with 10% (mol/mol) of the amended FtTAoS accounted for in FtS, FtCA, and PFCA products. The transformation rates of identified products appear to be slow relative to FtTAoS, indicating that some intermediates may persist in the environment. This study confirms some of the sources of FtS and PFCAs in groundwater and soil at AFFF-impacted sites and suggests that fluorinated intermediates that are not routinely measured during the biotransformation of PFASs may accumulate. PMID- 26042824 TI - Cardiorespiratory Information Dynamics during Mental Arithmetic and Sustained Attention. AB - An analysis of cardiorespiratory dynamics during mental arithmetic, which induces stress, and sustained attention was conducted using information theory. The information storage and internal information of heart rate variability (HRV) were determined respectively as the self-entropy of the tachogram, and the self entropy of the tachogram conditioned to the knowledge of respiration. The information transfer and cross information from respiration to HRV were assessed as the transfer and cross-entropy, both measures of cardiorespiratory coupling. These information-theoretic measures identified significant nonlinearities in the cardiorespiratory time series. Additionally, it was shown that, although mental stress is related to a reduction in vagal activity, no difference in cardiorespiratory coupling was found when several mental states (rest, mental stress, sustained attention) are compared. However, the self-entropy of HRV conditioned to respiration was very informative to study the predictability of RR interval series during mental tasks, and showed higher predictability during mental arithmetic compared to sustained attention or rest. PMID- 26042825 TI - Stereospecific, High-Yielding, and Green Synthesis of beta-Glycosyl Esters. AB - A new method of synthesizing beta-glycosyl esters stereospecifically has been developed by treating O-benzyl-protected glycosyl chlorides with Cs2CO3, tetrabutylammomium bromide (TBAB), a carboxylic acid, water, and granular polytetrafluoroethylene (PTFE) at 80 degrees C under mechanical agitation. D Glucosyl, D-xylosyl, and D-galactosyl chlorides and 20 carboxylic acids were used to demonstrate the scope of the reaction. Control experiments showed that the water and granular PTFE had indispensable roles. Water-soluble TBAB has been found to be as efficient as N-methyl-N,N,N-trioctyloctan-1-ammonium chloride (Aliquat 336) in the reactions. After scaling up to 5-12 g, all of the products were obtained quantitatively via simple filtration and no organic solvents or chromatography was needed for the entire process. PMID- 26042826 TI - Dominant Red Coat Color in Holstein Cattle Is Associated with a Missense Mutation in the Coatomer Protein Complex, Subunit Alpha (COPA) Gene. AB - Coat color in Holstein dairy cattle is primarily controlled by the melanocortin 1 receptor (MC1R) gene, a central determinant of black (eumelanin) vs. red/brown pheomelanin synthesis across animal species. The major MC1R alleles in Holsteins are Dominant Black (MC1RD) and Recessive Red (MC1Re). A novel form of dominant red coat color was first observed in an animal born in 1980. The mutation underlying this phenotype was named Dominant Red and is epistatic to the constitutively activated MC1RD. Here we show that a missense mutation in the coatomer protein complex, subunit alpha (COPA), a gene with previously no known role in pigmentation synthesis, is completely associated with Dominant Red in Holstein dairy cattle. The mutation results in an arginine to cysteine substitution at an amino acid residue completely conserved across eukaryotes. Despite this high level of conservation we show that both heterozygotes and homozygotes are healthy and viable. Analysis of hair pigment composition shows that the Dominant Red phenotype is similar to the MC1R Recessive Red phenotype, although less effective at reducing eumelanin synthesis. RNA-seq data similarly show that Dominant Red animals achieve predominantly pheomelanin synthesis by downregulating genes normally required for eumelanin synthesis. COPA is a component of the coat protein I seven subunit complex that is involved with retrograde and cis-Golgi intracellular coated vesicle transport of both protein and RNA cargo. This suggests that Dominant Red may be caused by aberrant MC1R protein or mRNA trafficking within the highly compartmentalized melanocyte, mimicking the effect of the Recessive Red loss of function MC1R allele. PMID- 26042827 TI - Coverage of community-based management of severe acute malnutrition programmes in twenty-one countries, 2012-2013. AB - OBJECTIVE: This paper reviews coverage data from programmes treating severe acute malnutrition (SAM) collected between July 2012 and June 2013. DESIGN: This is a descriptive study of coverage levels and barriers to coverage collected by coverage assessments of community-based SAM treatment programmes in 21 countries that were supported by the Coverage Monitoring Network. Data from 44 coverage assessments are reviewed. SETTING: These assessments analyse malnourished populations from 6 to 59 months old to understand the accessibility and coverage of services for treatment of acute malnutrition. The majority of assessments are from sub-Saharan Africa. RESULTS: Most of the programmes (33 of 44) failed to meet context-specific internationally agreed minimum standards for coverage. The mean level of estimated coverage achieved by the programmes in this analysis was 38.3%. The most frequently reported barriers to access were lack of awareness of malnutrition, lack of awareness of the programme, high opportunity costs, inter programme interface problems, and previous rejection. CONCLUSIONS: This study shows that coverage of CMAM is lower than previous analyses of early CTC programmes; therefore reducing programme impact. Barriers to access need to be addressed in order to start improving coverage by paying greater attention to certain activities such as community sensitisation. As barriers are interconnected focusing on specific activities, such as decentralising services to satellite sites, is likely to increase significantly utilisation of nutrition services. Programmes need to ensure that barriers are continuously monitored to ensure timely removal and increased coverage. PMID- 26042828 TI - Elevated sodium and dehydration stimulate inflammatory signaling in endothelial cells and promote atherosclerosis. AB - Cardiovascular diseases (CVDs) are a leading health problem worldwide. Epidemiologic studies link high salt intake and conditions predisposing to dehydration such as low water intake, diabetes and old age to increased risk of CVD. Previously, we demonstrated that elevation of extracellular sodium, which is a common consequence of these conditions, stimulates production by endothelial cells of clotting initiator, von Willebrand Factor, increases its level in blood and promotes thrombogenesis. In present study, by PCR array, using human umbilical vein endothelial cells (HUVECs), we analyzed the effect of high NaCl on 84 genes related to endothelial cell biology. The analysis showed that the affected genes regulate many aspects of endothelial cell biology including cell adhesion, proliferation, leukocyte and lymphocyte activation, coagulation, angiogenesis and inflammatory response. The genes whose expression increased the most were adhesion molecules VCAM1 and E-selectin and the chemoattractant MCP-1. These are key participants in the leukocyte adhesion and transmigration that play a major role in the inflammation and pathophysiology of CVD, including atherosclerosis. Indeed, high NaCl increased adhesion of mononuclear cells and their transmigration through HUVECs monolayers. In mice, mild water restriction that elevates serum sodium by 5 mmol/l, increased VCAM1, E-selectin and MCP-1 expression in mouse tissues, accelerated atherosclerotic plaque formation in aortic root and caused thickening or walls of coronary arteries. Multivariable linear regression analysis of clinical data from the Atherosclerosis Risk in Communities Study (n=12779) demonstrated that serum sodium is a significant predictor of 10 Years Risk of coronary heart disease. These findings indicate that elevation of extracellular sodium within the physiological range is accompanied by vascular changes that facilitate development of CVD. The findings bring attention to serum sodium as a risk factor for CVDs and give additional support to recommendations for dietary salt restriction and adequate water intake as preventives of CVD. PMID- 26042830 TI - A Process-Based Model of TCA Cycle Functioning to Analyze Citrate Accumulation in Pre- and Post-Harvest Fruits. AB - Citrate is one of the most important organic acids in many fruits and its concentration plays a critical role in organoleptic properties. The regulation of citrate accumulation throughout fruit development, and the origins of the phenotypic variability of the citrate concentration within fruit species remain to be clarified. In the present study, we developed a process-based model of citrate accumulation based on a simplified representation of the TCA cycle to predict citrate concentration in fruit pulp during the pre- and post-harvest stages. Banana fruit was taken as a reference because it has the particularity of having post-harvest ripening, during which citrate concentration undergoes substantial changes. The model was calibrated and validated on the two stages, using data sets from three contrasting cultivars in terms of citrate accumulation, and incorporated different fruit load, potassium supply, and harvest dates. The model predicted the pre and post-harvest dynamics of citrate concentration with fairly good accuracy for the three cultivars. The model suggested major differences in TCA cycle functioning among cultivars during post harvest ripening of banana, and pointed to a potential role for NAD-malic enzyme and mitochondrial malate carriers in the genotypic variability of citrate concentration. The sensitivity of citrate accumulation to growth parameters and temperature differed among cultivars during post-harvest ripening. Finally, the model can be used as a conceptual basis to study citrate accumulation in fleshy fruits and may be a powerful tool to improve our understanding of fruit acidity. PMID- 26042832 TI - The Unique Practice Needs of Academic Facial Plastic and Reconstructive Surgeons. PMID- 26042831 TI - Multiple In Vivo Biological Processes Are Mediated by Functionally Redundant Activities of Drosophila mir-279 and mir-996. AB - While most miRNA knockouts exhibit only subtle defects, a handful of miRNAs are profoundly required for development or physiology. A particularly compelling locus is Drosophila mir-279, which was reported as essential to restrict the emergence of CO2-sensing neurons, to maintain circadian rhythm, and to regulate ovarian border cells. The mir-996 locus is located near mir-279 and bears a similar seed, but they otherwise have distinct, conserved, non-seed sequences, suggesting their evolutionary maintenance for separate functions. We generated single and double deletion mutants of the mir-279 and mir-996 hairpins, and cursory analysis suggested that miR-996 was dispensable. However, discrepancies in the strength of individual mir-279 deletion alleles led us to uncover that all extant mir-279 mutants are deficient for mature miR-996, even though they retain its genomic locus. We therefore engineered a panel of genomic rescue transgenes into the double deletion background, allowing a pure assessment of miR-279 and miR-996 requirements. Surprisingly, detailed analyses of viability, olfactory neuron specification, and circadian rhythm indicate that miR-279 is completely dispensable. Instead, an endogenous supply of either mir-279 or mir-996 suffices for normal development and behavior. Sensor tests of nine key miR-279/996 targets showed their similar regulatory capacities, although transgenic gain-of-function experiments indicate partially distinct activities of these miRNAs that may underlie that co-maintenance in genomes. Altogether, we elucidate the unexpected genetics of this critical miRNA operon, and provide a foundation for their further study. More importantly, these studies demonstrate that multiple, vital, loss-of-function phenotypes can be rescued by endogenous expression of divergent seed family members, highlighting the importance of this miRNA region for in vivo function. PMID- 26042833 TI - Improved predictive mapping of indoor radon concentrations using ensemble regression trees based on automatic clustering of geological units. AB - PURPOSE: According to estimations around 230 people die as a result of radon exposure in Switzerland. This public health concern makes reliable indoor radon prediction and mapping methods necessary in order to improve risk communication to the public. The aim of this study was to develop an automated method to classify lithological units according to their radon characteristics and to develop mapping and predictive tools in order to improve local radon prediction. METHOD: About 240 000 indoor radon concentration (IRC) measurements in about 150 000 buildings were available for our analysis. The automated classification of lithological units was based on k-medoids clustering via pair-wise Kolmogorov distances between IRC distributions of lithological units. For IRC mapping and prediction we used random forests and Bayesian additive regression trees (BART). RESULTS: The automated classification groups lithological units well in terms of their IRC characteristics. Especially the IRC differences in metamorphic rocks like gneiss are well revealed by this method. The maps produced by random forests soundly represent the regional difference of IRCs in Switzerland and improve the spatial detail compared to existing approaches. We could explain 33% of the variations in IRC data with random forests. Additionally, the influence of a variable evaluated by random forests shows that building characteristics are less important predictors for IRCs than spatial/geological influences. BART could explain 29% of IRC variability and produced maps that indicate the prediction uncertainty. CONCLUSION: Ensemble regression trees are a powerful tool to model and understand the multidimensional influences on IRCs. Automatic clustering of lithological units complements this method by facilitating the interpretation of radon properties of rock types. This study provides an important element for radon risk communication. Future approaches should consider taking into account further variables like soil gas radon measurements as well as more detailed geological information. PMID- 26042834 TI - Chemical mediation of coral larval settlement by crustose coralline algae. AB - The majority of marine invertebrates produce dispersive larvae which, in order to complete their life cycles, must attach and metamorphose into benthic forms. This process, collectively referred to as settlement, is often guided by habitat specific cues. While the sources of such cues are well known, the links between their biological activity, chemical identity, presence and quantification in situ are largely missing. Previous work on coral larval settlement in vitro has shown widespread induction by crustose coralline algae (CCA) and in particular their associated bacteria. However, we found that bacterial biofilms on CCA did not initiate ecologically realistic settlement responses in larvae of 11 hard coral species from Australia, Guam, Singapore and Japan. We instead found that algal chemical cues induce identical behavioral responses of larvae as per live CCA. We identified two classes of CCA cell wall-associated compounds--glycoglycerolipids and polysaccharides--as the main constituents of settlement inducing fractions. These algae-derived fractions induce settlement and metamorphosis at equivalent concentrations as present in CCA, both in small scale laboratory assays and under flow-through conditions, suggesting their ability to act in an ecologically relevant fashion to steer larval settlement of corals. Both compound classes were readily detected in natural samples. PMID- 26042835 TI - Effective Electro-Optical Modulation with High Extinction Ratio by a Graphene Silicon Microring Resonator. AB - Graphene opens up for novel optoelectronic applications thanks to its high carrier mobility, ultralarge absorption bandwidth, and extremely fast material response. In particular, the opportunity to control optoelectronic properties through tuning of the Fermi level enables electro-optical modulation, optical optical switching, and other optoelectronics applications. However, achieving a high modulation depth remains a challenge because of the modest graphene-light interaction in the graphene-silicon devices, typically, utilizing only a monolayer or few layers of graphene. Here, we comprehensively study the interaction between graphene and a microring resonator, and its influence on the optical modulation depth. We demonstrate graphene-silicon microring devices showing a high modulation depth of 12.5 dB with a relatively low bias voltage of 8.8 V. On-off electro-optical switching with an extinction ratio of 3.8 dB is successfully demonstrated by applying a square-waveform with a 4 V peak-to-peak voltage. PMID- 26042837 TI - Iron- and Cobalt-Catalyzed Alkene Hydrogenation: Catalysis with Both Redox-Active and Strong Field Ligands. AB - The hydrogenation of alkenes is one of the most impactful reactions catalyzed by homogeneous transition metal complexes finding application in the pharmaceutical, agrochemical, and commodity chemical industries. For decades, catalyst technology has relied on precious metal catalysts supported by strong field ligands to enable highly predictable two-electron redox chemistry that constitutes key bond breaking and forming steps during turnover. Alternative catalysts based on earth abundant transition metals such as iron and cobalt not only offer potential environmental and economic advantages but also provide an opportunity to explore catalysis in a new chemical space. The kinetically and thermodynamically accessible oxidation and spin states may enable new mechanistic pathways, unique substrate scope, or altogether new reactivity. This Account describes my group's efforts over the past decade to develop iron and cobalt catalysts for alkene hydrogenation. Particular emphasis is devoted to the interplay of the electronic structure of the base metal compounds and their catalytic performance. First generation, aryl-substituted pyridine(diimine) iron dinitrogen catalysts exhibited high turnover frequencies at low catalyst loadings and hydrogen pressures for the hydrogenation of unactivated terminal and disubstituted alkenes. Exploration of structure-reactivity relationships established smaller aryl substituents and more electron donating ligands resulted in improved performance. Second generation iron and cobalt catalysts where the imine donors were replaced by N-heterocyclic carbenes resulted in dramatically improved activity and enabled hydrogenation of more challenging unactivated, tri- and tetrasubstituted alkenes. Optimized cobalt catalysts have been discovered that are among the most active homogeneous hydrogenation catalysts known. Synthesis of enantiopure, C1 symmetric pyridine(diimine) cobalt complexes have enabled rare examples of highly enantioselective hydrogenation of a family of substituted styrene derivatives. Because improved hydrogenation performance was observed with more electron rich supporting ligands, phosphine cobalt(II) dialkyl complexes were synthesized and found to be active for the diastereoselective hydrogenation of various substituted alkenes. Notably, this class of catalysts was activated by hydroxyl functionality, representing a significant advance in the functional group tolerance of base metal hydrogenation catalysts. Through collaboration with Merck, enantioselective variants of these catalysts were discovered by high throughput experimentation. Catalysts for the hydrogenation of functionalized and essentially unfunctionalized alkenes have been discovered using this approach. Development of reliable, readily accessible cobalt precursors facilitated catalyst discovery and may, along with lessons learned from electronic structure studies, provide fundamental design principles for catalysis with earth abundant transition metals beyond alkene hydrogenation. PMID- 26042836 TI - Elevated Serum Level of IL-35 Associated with the Maintenance of Maternal-Fetal Immune Tolerance in Normal Pregnancy. AB - OBJECTIVES: IL-35 is a novel inhibitory cytokine. In this study, we investigate the serum levels of inhibitory cytokines IL-35, IL-10 and TGF-beta in both normal pregnancies and non-pregnant females, and whether IL-35 is associated with the pathogenesis of recurrent spontaneous abortion. We also try to elucidate the relationships of IL-35 with estrogen and alpha-fetoprotein (AFP). METHODS: The levels of IL-35, IL-10, TGF-beta, estradiol (E2), unconjugated estriol (uE3) and AFP were analyzed in 120 normal pregnancies, 40 women suffering recurrent spontaneous abortion, 40 postpartum healthy women and 40 non-pregnant women by enzyme-linked immunosorbent assay (ELISA). The correlations between inhibitory cytokines, estrogen and AFP were assessed with the Spearman rank correlation coefficient. RESULTS: Data are expressed as median and percentiles (Q1, Q3).The level of serum IL-35 in normal pregnancies was significantly higher than that in non-pregnant women [333.6 (59.32, 1391) pg/mL vs. 123.9 (8.763, 471.7) pg/mL; P < 0.001]. A significantly higher level of TGF-beta was observed in the first trimester only as compared to non-pregnant women [473.4 (398.0, 580.5) pg/mL vs. 379.7 (311.0, 441.3) pg/mL, P < 0.01]. The difference in serum IL-10 level between pregnant women and non-pregnant women was not significant [8.602 (5.854, 12.89) pg/mL vs. 9.339 (5.691, 12.07) pg/mL; P > 0.05]. The level of serum IL-35 in recurrent spontaneous abortion was significantly lower than that in normal early pregnancy [220.4 (4.951, 702.0) pg/mL vs. 386.5 (64.37, 1355) pg/mL; P < 0.05]. The higher IL-35 level in first trimester pregnant women correlated with E2 (r = 0.3062, P < 0.01) and AFP (r = 0.3179, P < 0.01). CONCLUSION: Serum levels of IL-35 increased in normal pregnancy and decreased in recurrent spontaneous abortion. Increased IL-35 correlated with estrogen and AFP levels in early pregnancy. IL-35 is becoming recognized as an active player in the maintenance of a successful pregnancy, but this is not the case for IL-10 or TGF beta. PMID- 26042815 TI - Sexually transmitted diseases treatment guidelines, 2015. AB - These guidelines for the treatment of persons who have or are at risk for sexually transmitted diseases (STDs) were updated by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta on April 30-May 2, 2013. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2010 (MMWR Recomm Rep 2010;59 [No. RR 12]). These updated guidelines discuss 1) alternative treatment regimens for Neisseria gonorrhoeae; 2) the use of nucleic acid amplification tests for the diagnosis of trichomoniasis; 3) alternative treatment options for genital warts; 4) the role of Mycoplasma genitalium in urethritis/cervicitis and treatment related implications; 5) updated HPV vaccine recommendations and counseling messages; 6) the management of persons who are transgender; 7) annual testing for hepatitis C in persons with HIV infection; 8) updated recommendations for diagnostic evaluation of urethritis; and 9) retesting to detect repeat infection. Physicians and other health-care providers can use these guidelines to assist in the prevention and treatment of STDs. PMID- 26042838 TI - Transcriptional profile of glucose-shocked and acid-adapted strains of Streptococcus mutans. AB - The aciduricity of Streptococcus mutans is an important virulence factor of the organism, required to both out-compete commensal oral microorganisms and cause dental caries. In this study, we monitored transcriptional changes that occurred as a continuous culture of either an acid-tolerant strain (UA159) or an acid sensitive strain (fabM::Erm) moved from steady-state growth at neutral pH, experienced glucose-shock and acidification of the culture, and transitioned to steady-state growth at low pH. Hence, the timing of elements of the acid tolerance response (ATR) could be observed and categorized as acute vs. adaptive ATR mechanisms. Modulation of branched chain amino acid biosynthesis, DNA/protein repair mechanisms, reactive oxygen species metabolizers and phosphoenolpyruvate:phosphotransferase systems occurred in the initial acute phase, immediately following glucose-shock, while upregulation of F1 F0 -ATPase did not occur until the adaptive phase, after steady-state growth had been re established. In addition to the archetypal ATR pathways mentioned above, glucose shock led to differential expression of genes suggesting a re-routing of resources away from the synthesis of fatty acids and proteins, and towards synthesis of purines, pyrimidines and amino acids. These adjustments were largely transient, as upon establishment of steady-state growth at acidic pH, transcripts returned to basal expression levels. During growth at steady-state pH 7, fabM::Erm had a transcriptional profile analogous to that of UA159 during glucose shock, indicating that even during growth in rich media at neutral pH, the cells were stressed. These results, coupled with a recently established collection of deletion strains, provide a starting point for elucidation of the acid tolerance response in S. mutans. PMID- 26042840 TI - Survival, growth and condition of freshwater mussels: effects of municipal wastewater effluent. AB - Freshwater mussels (Family Unionidae) are among the most imperiled group of organisms in the world, with nearly 65% of North American species considered endangered. Anthropogenic disturbances, including altered flow regimes, habitat alteration, and pollution, are the major driver of this group's decline. We investigated the effects of tertiary treated municipal wastewater effluent on survivorship, growth, and condition of freshwater mussels in experimental cages in a small Central Texas stream. We tested the effluent effects by measuring basic physical parameters of native three ridge mussels (Amblema plicata) and of non-native Asian clams (Corbicula fluminea), before and after 72-day exposure at four sites above and below a municipal wastewater treatment plant outfall. Survivorship and growth of the non-native Asian clams and growth and condition indices of the native three ridge mussels were significantly higher at the reference site above the outfall than in downstream sites. We attribute this reduction in fitness below the outfall to elevated nutrient and heavy metal concentrations, and the potential presence of other untested-for compounds commonly found in municipal effluent. These results, along with an absence of native mussels below the discharge, indicate a significant negative impact of wastewater effluent on both native and non-native mussels in the stream. PMID- 26042841 TI - Correction: A Geospatial Comparison of Distributed Solar Heat and Power in Europe and the US. PMID- 26042839 TI - Human Immunodeficiency Virus, Antiretroviral Therapy and Markers of Lymphatic Filariasis Infection: A Cross-sectional Study in Rural Northern Malawi. AB - BACKGROUND: Lymphatic filariasis (LF) and human immunodeficiency virus (HIV) are major public health problems. Individuals may be co-infected, raising the possibility of important interactions between these two pathogens with consequences for LF elimination through annual mass drug administration (MDA). METHODOLOGY AND PRINCIPAL FINDINGS: We analysed circulating filarial antigenaemia (CFA) by HIV infection status among adults in two sites in northern Malawi, a region endemic for both LF and HIV. Stored blood samples and data from two geographically separate studies were used: one a recruitment phase of a clinical trial of anti-filarial agent dosing regimens, and the other a whole population annual HIV sero-survey. In study one, 1,851 consecutive adult volunteers were screened for HIV and LF infection. CFA prevalence was 25.4% (43/169) in HIV positive and 23.6% (351/1487) in HIV-negative participants (p=0.57). Geometric mean CFA concentrations were 859 and 1660 antigen units per ml of blood (Ag/ml) respectively, geometric mean ratio (GMR) 0.85, 95%CI 0.49-1.50. In 7,863 adults in study two, CFA prevalence was 20.9% (86/411) in HIV-positive and 24.0% (1789/7452) in HIV-negative participants (p=0.15). Geometric mean CFA concentrations were 630 and 839 Ag/ml respectively (GMR 0.75, 95%CI 0.60-0.94). In the HIV-positive group, antiretroviral therapy (ART) use was associated with a lower CFA prevalence, 12.7% (18/142) vs. 25.3% (67/265), (OR 0.43, 95%CI 0.24 0.76). Prevalence of CFA decreased with duration of ART use, 15.2% 0-1 year (n=59), 13.6% >1-2 years (n=44), 10.0% >2-3 years (n=30) and 0% >3-4 years treatment (n=9), p<0.01 chi2 for linear trend. CONCLUSIONS/SIGNIFICANCE: In this large cross-sectional study of two distinct LF-exposed populations, there is no evidence that HIV infection has an impact on LF epidemiology that will interfere with LF control measures. A significant association of ART use with lower CFA prevalence merits further investigation to understand this apparent beneficial impact of ART. PMID- 26042842 TI - Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. AB - BACKGROUND: Proton-pump inhibitors (PPIs) are among the most frequently prescribed medications. Community-acquired pneumonia (CAP) is a common cause of morbidity, mortality and healthcare spending. Some studies suggest an increased risk of CAP among PPI users. We conducted a systematic review and meta-analysis to determine the association between outpatient PPI therapy and risk of CAP in adults. METHODS: We conducted systematic searches of MEDLINE, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Scopus and Web of Science on February 3, 2014. Case-control studies, case-crossover, cohort studies and randomized controlled trials reporting outpatient PPI exposure and CAP diagnosis for patients >=18 years old were eligible. Our primary outcome was the association between CAP and PPI therapy. A secondary outcome examined the risk of hospitalization for CAP and subgroup analyses evaluated the association between PPI use and CAP among patients of different age groups, by different PPI doses, and by different durations of PPI therapy. RESULTS: Systematic review of 33 studies was performed, of which 26 studies were included in the meta-analysis. These 26 studies included 226,769 cases of CAP among 6,351,656 participants. We observed a pooled risk of CAP with ambulatory PPI therapy of 1.49 (95% CI 1.16, 1.92; I2 99.2%). This risk was increased during the first month of therapy (OR 2.10; 95% CI 1.39, 3.16), regardless of PPI dose or patient age. PPI therapy also increased risk for hospitalization for CAP (OR 1.61; 95% CI: 1.12, 2.31). DISCUSSION: Outpatient PPI use is associated with a 1.5-fold increased risk of CAP, with the highest risk within the first 30 days after initiation of therapy. Providers should be aware of this risk when considering PPI use, especially in cases where alternative regimens may be available or the benefits of PPI use are uncertain. PMID- 26042844 TI - Fluorescent and Luminescent Probes for Monitoring Hydroxyl Radical under Biological Conditions. AB - Detection and quantitative determination in biological media of the hydroxyl radical are of great importance due to the role this radical plays in many physiological and pathological processes. This review focuses on the progress that has been made in recent years in the development of fluorescent and luminescent probes employed to monitor hydroxyl radical concentrations under biological conditions. PMID- 26042843 TI - Own-race faces capture attention faster than other-race faces: evidence from response time and the N2pc. AB - Studies have shown that people are better at recognizing human faces from their own-race than from other-races, an effect often termed the Own-Race Advantage. The current study investigates whether there is an Own-Race Advantage in attention and its neural correlates. Participants were asked to search for a human face among animal faces. Experiment 1 showed a classic Own-Race Advantage in response time both for Chinese and Black South African participants. Using event-related potentials (ERPs), Experiment 2 showed a similar Own-Race Advantage in response time for both upright faces and inverted faces. Moreover, the latency of N2pc for own-race faces was earlier than that for other-race faces. These results suggested that own-race faces capture attention more efficiently than other-race faces. PMID- 26042845 TI - Become acquainted with APIC's Roadmap for the Novice Infection Preventionist. PMID- 26042846 TI - What can we learn about the Ebola outbreak from tweets? AB - BACKGROUND: Twitter can address the challenges of the current Ebola outbreak surveillance. The aims of this study are to demonstrate the use of Twitter as a real-time method of Ebola outbreak surveillance to monitor information spread, capture early epidemic detection, and examine content of public knowledge and attitudes. METHODS: We collected tweets mentioning Ebola in English during the early stage of the current Ebola outbreak from July 24-August 1, 2014. Our analysis for this observational study includes time series analysis with geologic visualization to observe information dissemination and content analysis using natural language processing to examine public knowledge and attitudes. RESULTS: A total of 42,236 tweets (16,499 unique and 25,737 retweets) mentioning Ebola were posted and disseminated to 9,362,267,048 people, 63 times higher than the initial number. Tweets started to rise in Nigeria 3-7 days prior to the official announcement of the first probable Ebola case. The topics discussed in tweets include risk factors, prevention education, disease trends, and compassion. CONCLUSION: Because of the analysis of a unique Twitter dataset captured in the early stage of the current Ebola outbreak, our results provide insight into the intersection of social media and public health outbreak surveillance. Findings demonstrate the usefulness of Twitter mining to inform public health education. PMID- 26042847 TI - Studies on nurse staffing and health care-associated infection: methodologic challenges and potential solutions. AB - BACKGROUND: Researchers have been studying hospital nurse staffing in relation to health care-associated infections (HAIs) for >2 decades, and the results have been mixed. We summarized published research examining these issues, critically analyzed the commonly used approaches, identified methodologic challenges, proposed potential solutions, and suggested the possible benefits of applying an electronic health record (EHR) system. METHODS: A scoping review was conducted using MEDLINE and CINAHL from 1990 onward. Original research studies examining relationships between nurse staffing and HAIs in the hospital setting and published in peer-reviewed English-language journals were selected. RESULTS: A total of 125 articles and abstracts were identified, and 45 met inclusion criteria. Findings from these studies were mixed. The methodologic challenges identified included database selection, variable measurement, methods to link the nurse staffing and HAI data, and temporality. Administrative staffing data were often not precise or specific. The most common method to link staffing and HAI data did not assess the temporal relationship. We proposed using daily staffing information 2-4 days prior to HAI onset linked to individual patient HAI data. CONCLUSION: To assess the relationships between nurse staffing and HAIs, methodologic decisions are necessary based on what data are available and feasible to obtain. National efforts to promote an EHR may offer solutions for future studies by providing more comprehensive data on HAIs and nurse staffing. PMID- 26042848 TI - Data elements and validation methods used for electronic surveillance of health care-associated infections: a systematic review. AB - BACKGROUND: We describe the primary data sources, data elements, and validation methods currently used in electronic surveillance systems (ESS) for identification and surveillance of health care-associated infections (HAIs), and compares these data elements and validation methods with recommended standards. METHODS: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a PubMed and manual search was conducted to identify research articles describing ESS for identification and surveillance of HAIs published January 1, 2009-August 31, 2014. Selected articles were evaluated to determine what data elements and validation methods were included. RESULTS: Among the 509 articles identified in the original literature search, 30 met the inclusion criteria. Whereas the majority of studies (83%) used recommended data sources and validated the numerator (80%), only 10% of studies performed external and internal validation. In addition, there was variation in the ESS data formats used. CONCLUSIONS: Our findings suggest that the majority of ESS for HAI surveillance use standard definitions, but the lack of widespread internal data, denominator, and external validation in these systems reduces the reliability of their findings. Additionally, advanced programming skills are required to create, implement, and maintain these systems and to reduce the variability in data formats. PMID- 26042849 TI - Spread of infectious microbes during emergency medical response. AB - BACKGROUND: To our knowledge, no studies to date demonstrate potential spread of microbes during actual emergency medical service (EMS) activities. Our study introduces a novel approach to identification of contributors to EMS environment contamination and development of infection control strategies, using a bacteriophage surrogate for pathogenic organisms. METHODS: Bacteriophage PhiX174 was used to trace cross-contamination and evaluate current disinfection practices and a hydrogen peroxide (H2O2) wipe intervention within emergency response vehicles. Prior to EMS calls, 2 surfaces were seeded with PhiX174. On call completion, EMS vehicle and equipment surfaces were sampled before decontamination, after decontamination per current practices, and after implementation of the intervention. RESULTS: Current decontamination practices did not significantly reduce viral loads on surfaces (P = .3113), but H2O2 wipe intervention did (P = .0065). Bacteriophage spread to 56% (27/48) of sites and was reduced to 54% (26/48) and 40% (19/48) with current decontamination practices and intervention practices, respectively. CONCLUSION: Results suggest firefighters' hands were the main vehicles of microbial transfer. Current practices were not consistently applied or standardized and minimally reduced prevalence and quantity of microbial contamination on EMS surfaces. Although use of a consistent protocol of H2O2 wipes significantly reduced percent prevalence and concentration of viruses, training and promotion of surface disinfection should be provided. PMID- 26042850 TI - Lung cancer new leading cause of death for women in developed countries: Data reflects increased rates of smoking. PMID- 26042851 TI - Colorectal cancer incidence increasing in young adults. PMID- 26042852 TI - Georgia State University to expand China's tobacco control efforts. PMID- 26042853 TI - Coffee may lower risk of malignant melanoma. PMID- 26042855 TI - The crystal structure and magnetic properties of 3-pyridinecarboxylate-bridged Re(II)M(II) complexes (M = Cu, Ni, Co and Mn). AB - The novel Re(II) complex NBu4[Re(NO)Br4(Hnic)] (1) and the heterodinuclear compounds [Re(NO)Br4(MU-nic)Ni(dmphen)2].1/2CH3CN (2), [Re(NO)Br4(MU nic)Co(dmphen)2].1/2MeOH (3), [Re(NO)Br4(MU-nic)Mn(dmphen)(H2O)2].dmphen (4), [Re(NO)Br4(MU-nic)Cu(bipy)2] (5) [Re(NO)Br4(MU-nic)Cu(dmphen)2] (5') (NBu4(+) = tetra-n-butylammonium cation, Hnic = 3-pyridinecarboxylic acid, dmphen = 2,9 dimethyl-1,10-phenanthroline, bipy = 2,2'-bipyridine) have been prepared and the structures of 1-5 determined using single crystal X-ray diffraction. The structure of 1 consists of [Re(NO)Br4(Hnic)](-) anions and NBu4(+) cations. Each Re(II) is six-coordinate with four bromide ligands, a linear nitrosyl group and a nitrogen atom from the Hnic molecule, in a distorted octahedral surrounding. The structures of 2-5 are made up of discrete heterodinuclear Re(II)M(II) units where the fully deprotonated [Re(NO)Br4(nic)](2-) entity acts as a didentate ligand through the carboxylate group towards the [Ni(dmphen)2](2+) (2), [Co(dmphen)2](2+) (3), [Mn(dmphen)(H2O)2](2+) (4) and [Cu(bipy)2](2+) (5) fragments, the Re-M separation across the nic bridge being 7.8736(8) (2), 7.9632(10) (3), 7.7600(6) (4) and 8.2148(7) A (5). The environment of the Re(II) ion in 2-5 is the same as 1 that in and all M(II) are six-coordinate in highly distorted octahedral surroundings, the main source of the distortion being due to the reduced bite of the chelating carboxylate. The magnetic properties of 1-5' were investigated in the temperature range 1.9-300 K. 1 behaves as a quasi magnetically isolated spin doublet with very weak antiferromagnetic interactions through space Br...Br contacts. Its magnetic susceptibility data were successfully modeled through a deep analysis of the influence of the ligand field, spin-orbit coupling, tetragonal distortion and covalence effects as variable parameters. Compounds 2-5' exhibit weak antiferromagnetic interactions. The intramolecular exchange pathway in this family being discarded because of the symmetry of magnetic orbitals of the Re(II) ion (d(xy)) precludes any spin delocalization on the bridging nic orbitals, the observed magnetic interactions are most likely mediated by pi-pi type interactions between the peripheral ligands which occur in them. Only in the case of 4, short through space Br...Br contacts of ca. 4.03 A (values larger than 5.5 A in 2, 3 and 5) could be involved in the exchange coupling. PMID- 26042856 TI - Solving molecular docking problems with multi-objective metaheuristics. AB - Molecular docking is a hard optimization problem that has been tackled in the past with metaheuristics, demonstrating new and challenging results when looking for one objective: the minimum binding energy. However, only a few papers can be found in the literature that deal with this problem by means of a multi-objective approach, and no experimental comparisons have been made in order to clarify which of them has the best overall performance. In this paper, we use and compare, for the first time, a set of representative multi-objective optimization algorithms applied to solve complex molecular docking problems. The approach followed is focused on optimizing the intermolecular and intramolecular energies as two main objectives to minimize. Specifically, these algorithms are: two variants of the non-dominated sorting genetic algorithm II (NSGA-II), speed modulation multi-objective particle swarm optimization (SMPSO), third evolution step of generalized differential evolution (GDE3), multi-objective evolutionary algorithm based on decomposition (MOEA/D) and S-metric evolutionary multi objective optimization (SMS-EMOA). We assess the performance of the algorithms by applying quality indicators intended to measure convergence and the diversity of the generated Pareto front approximations. We carry out a comparison with another reference mono-objective algorithm in the problem domain (Lamarckian genetic algorithm (LGA) provided by the AutoDock tool). Furthermore, the ligand binding site and molecular interactions of computed solutions are analyzed, showing promising results for the multi-objective approaches. In addition, a case study of application for aeroplysinin-1 is performed, showing the effectiveness of our multi-objective approach in drug discovery. PMID- 26042857 TI - A new and efficient synthesis of 6-O-methylscutellarein, the major metabolite of the natural medicine scutellarin. AB - In this paper, a new and efficient synthesis of 6-O-methylscutellarein (3), the major metabolite of the natural medicine scutellarin, is reported. Two hydroxyl groups at C-4' and C-7 in 2 were selectively protected by chloromethyl methyl ether after the reaction conditions were optimized, then 6-O-methyl-scutellarein (3) was produced in high yield after methylation of the hydroxyl group at C-6 and subsequent deprotection of the two methyl ether groups. PMID- 26042858 TI - Antimicrobial resistance is a global health emergency. PMID- 26042859 TI - Public funding of clinical-stage antibiotic development in the United States and European Union. AB - The health and national security challenge of antibiotic resistance has led governments to adopt policies to stimulate new antibiotic R&D. Government programs that directly fund late-stage clinical development of antibiotics have emerged, including the Broad Spectrum Antimicrobial Program of the Biomedical Advanced Research and Development Authority in the United States, and the New Drugs for Bad Bugs program of the Innovative Medicines Initiative in the European Union. These efforts are collectively investing nearly $1 billion and are supporting nearly 20% of the global antibiotic pipeline. This article describes these programs, including the antibiotics and their targeted pathogens and clinical indications, as well as program mechanisms for project eligibility, selection, governance, funding, and IP management. Preliminary assessment of the impact of these mechanisms on the success of the programs is provided. PMID- 26042860 TI - Antimicrobial stewardship in outpatient settings: leveraging innovative physician pharmacist collaborations to reduce antibiotic resistance. AB - Antibiotic resistance is one of the world's most pressing public health problems. Historically, most drug-resistant bacteria have emerged in hospital settings, yet the vast majority of antimicrobials used in humans in the United States are administered in outpatient settings. Strong collaboration between physicians and pharmacists in the development of antimicrobial stewardship programs in outpatient settings is thus a critical strategy for curtailing antibiotic resistance. Recently, pilot projects have been launched in 3 states that pair physicians and community pharmacists under a Collaborative Practice Agreement (CPA) to treat patients with influenza and group A Streptococcus (GAS) pharyngitis. Under this model, community pharmacists use rapid point-of-care tests to guide clinical decision making and initiate treatment as appropriate under a physician-led, evidence-based protocol. Experience with this research initiative has suggested this model can lead to more judicious use of antibiotics and antivirals, improve public health, and provide safe and convenient care for patients. PMID- 26042861 TI - A plausible worst-case scenario of increasing multidrug resistance as a tool for assessing societal risks and capabilities in Sweden. AB - A "plausible worst-case scenario" of a gradually increasing level of multidrug resistant bacteria (carbapenem-resistant E. coli) in the human population was developed and used to study how Swedish authorities would manage this situation and to identify preventive measures that could be taken. Key findings include: (1) a scenario in which 5% of the population in southern Sweden become carriers of carbapenem-resistant E. coli is possible or even likely in 10 to 15 years; (2) it is not clear when and how the increase of E. coli resistant to carbapenems as in the scenario would be detected in the general human population; (3) identified negative consequences of the scenario on society were primarily due to increased demands on the healthcare system and potential consequences for food-producing animals, food safety, and environmental health; and (4) a number of preventive and mitigation measures were suggested, including initiating long-term screening programs for public and animal health as well as for food and water production to monitor increasing levels of carbapenem resistance. Strategies and plans to prevent and handle future increasing prevalence of multidrug-resistant bacteria need to be developed. PMID- 26042862 TI - Time for a professional association for healthcare emergency preparedness. PMID- 26042863 TI - Federal Funding for Health Security in FY2016. AB - This article assesses US government funding in 5 domains critical to strengthening health security: biodefense programs, radiological and nuclear programs, chemical programs, pandemic influenza and emerging infectious disease programs, and multiple-hazard and preparedness programs. This year's article also highlights the emergency funding appropriated in FY2015 to enable the international and domestic response to the Ebola outbreak in West Africa. PMID- 26042864 TI - Information security for compliance with select agent regulations. AB - The past decade has seen a significant rise in research on high-consequence human and animal pathogens, many now known as "select agents." While physical security around these agents is tightly regulated, information security standards are still lagging. The understanding of the threats unique to the academic and research environment is still evolving, in part due to poor communication between the various stakeholders. Perhaps as a result, information security guidelines published by select agent regulators lack the critical details and directives needed to achieve even the lowest security level of the Federal Information Security Management Act (FISMA). While only government agencies are currently required to abide by the provisions of FISMA (unless specified as preconditions for obtaining government grants or contracts--still a relatively rare or narrowly scoped occurrence), the same strategies were recently recommended by executive order for others. We propose that information security guidelines for select agent research be updated to promulgate and detail FISMA standards and processes and that the latter be ultimately incorporated into select agent regulations. We also suggest that information security in academic and research institutions would greatly benefit from active efforts to improve communication among the biosecurity, security, and information technology communities, and from a secure venue for exchange of timely information on emerging threats and solutions in the research environment. PMID- 26042865 TI - Autophagic adaptations in diabetic cardiomyopathy differ between type 1 and type 2 diabetes. AB - Little is known about the association between autophagy and diabetic cardiomyopathy. Also unknown are possible distinguishing features of cardiac autophagy in type 1 and type 2 diabetes. In hearts from streptozotocin-induced type 1 diabetic mice, diastolic function was impaired, though autophagic activity was significantly increased, as evidenced by increases in microtubule-associated protein 1 light chain 3/LC3 and LC3-II/-I ratios, SQSTM1/p62 (sequestosome 1) and CTSD (cathepsin D), and by the abundance of autophagic vacuoles and lysosomes detected electron-microscopically. AMP-activated protein kinase (AMPK) was activated and ATP content was reduced in type 1 diabetic hearts. Treatment with chloroquine, an autophagy inhibitor, worsened cardiac performance in type 1 diabetes. In addition, hearts from db/db type 2 diabetic model mice exhibited poorer diastolic function than control hearts from db/+ mice. However, levels of LC3-II, SQSTM1 and phosphorylated MTOR (mechanistic target of rapamycin) were increased, but CTSD was decreased and very few lysosomes were detected ultrastructurally, despite the abundance of autophagic vacuoles. AMPK activity was suppressed and ATP content was reduced in type 2 diabetic hearts. These findings suggest the autophagic process is suppressed at the final digestion step in type 2 diabetic hearts. Resveratrol, an autophagy enhancer, mitigated diastolic dysfunction, while chloroquine had the opposite effects in type 2 diabetic hearts. Autophagy in the heart is enhanced in type 1 diabetes, but is suppressed in type 2 diabetes. This difference provides important insight into the pathophysiology of diabetic cardiomyopathy, which is essential for the development of new treatment strategies. PMID- 26042866 TI - Putative bacterial volatile-mediated growth in soybean (Glycine max L. Merrill) and expression of induced proteins under salt stress. AB - AIMS: Plant root-associated rhizobacteria elicit plant immunity referred to as induced systemic tolerance (IST) against multiple abiotic stresses. Among multibacterial determinants involved in IST, the induction of IST and promotion of growth by putative bacterial volatile compounds (VOCs) is reported in the present study. METHODS AND RESULTS: To characterize plant proteins induced by putative bacterial VOCs, proteomic analysis was performed by MALDI-MS/MS after exposure of soybean seedlings to a new strain of plant growth promoting rhizobacteria (PGPR) Pseudomonas simiae strain AU. Furthermore, expression analysis by Western blotting confirmed that the vegetative storage protein (VSP), gamma-glutamyl hydrolase (GGH) and RuBisCo large chain proteins were significantly up-regulated by the exposure to AU strain and played a major role in IST. VSP has preponderant roles in N accumulation and mobilization, acid phosphatase activity and Na(+) homeostasis to sustain plant growth under stress condition. More interestingly, plant exposure to the bacterial strain significantly reduced Na(+) and enhanced K(+) and P content in root of soybean seedlings under salt stress. In addition, high accumulation of proline and chlorophyll content also provided evidence of protection against osmotic stress during the elicitation of IST by bacterial exposure. CONCLUSIONS: The present study reported for the first time that Ps. simiae produces a putative volatile blend that can enhance soybean seedling growth and elicit IST against 100 mmol l( 1) NaCl stress condition. SIGNIFICANCE AND IMPACT OF THE STUDY: The identification of such differentially expressed proteins provide new targets for future studies that will allow assessment of their physiological roles and significance in the response of glycophytes to stresses. Further work should uncover more about the chemical side of VOC compounds and a detailed study about their molecular mechanism responsible for plant growth. PMID- 26042867 TI - How Does Guanine-Cytosine Base Pair Affect Excess-Electron Transfer in DNA? AB - Charge transfer and proton transfer in DNA have attracted wide attention due to their relevance in biological processes and so on. Especially, excess-electron transfer (EET) in DNA has strong relation to DNA repair. However, our understanding on EET in DNA still remains limited. Herein, by using a strongly electron-donating photosensitizer, trimer of 3,4-ethylenedioxythiophene (3E), and an electron acceptor, diphenylacetylene (DPA), two series of functionalized DNA oligomers were synthesized for investigation of EET dynamics in DNA. The transient absorption measurements during femtosecond laser flash photolysis showed that guanine:cytosine (G:C) base pair affects EET dynamics in DNA by two possible mechanisms: the excess-electron quenching by proton transfer with the complementary G after formation of C(*-) and the EET hindrance by inserting a G:C base pair as a potential barrier in consecutive thymines (T's). In the present paper, we provided useful information based on the direct kinetic measurements, which allowed us to discuss EET through oligonucleotides for the investigation of DNA damage/repair. PMID- 26042868 TI - Joint impact of clinical and behavioral variables on the risk of unplanned readmission and death after a heart failure hospitalization. AB - Most current methods for modeling rehospitalization events in heart failure patients make use of only clinical and medications data that is available in the electronic health records. However, information about patient-reported functional limitations, behavioral variables and socio-economic background of patients may also play an important role in predicting the risk of readmission in heart failure patients. We developed methods for predicting the risk of rehospitalization in heart failure patients using models that integrate clinical characteristics with patient-reported functional limitations, behavioral and socio-economic characteristics. Our goal was to estimate the predictive accuracy of the joint model and compare it with models that make use of clinical data alone or behavioral and socio-economic characteristics alone, using real patient data. We collected data about the occurrence of hospital readmissions from a cohort of 789 heart failure patients for whom a range of clinical and behavioral characteristics data is also available. We applied the Cox model, four different variants of the Cox proportional hazards framework as well as an alternative non parametric approach and determined the predictive accuracy for different categories of variables. The concordance index obtained from the joint prediction model including all types of variables was significantly higher than the accuracy obtained from using only clinical factors or using only behavioral, socioeconomic background and functional limitations in patients as predictors. Collecting information on behavior, patient-reported estimates of physical limitations and frailty and socio-economic data has significant value in the predicting the risk of readmissions with regards to heart failure events and can lead to substantially more accurate events prediction models. PMID- 26042869 TI - Pleuritis caused by Acremonium strictum in a patient with metastatic testicular teratocarcinoma. PMID- 26042870 TI - Evolutionary food web model based on body masses gives realistic networks with permanent species turnover. AB - The networks of predator-prey interactions in ecological systems are remarkably complex, but nevertheless surprisingly stable in terms of long term persistence of the system as a whole. In order to understand the mechanism driving the complexity and stability of such food webs, we developed an eco-evolutionary model in which new species emerge as modifications of existing ones and dynamic ecological interactions determine which species are viable. The food-web structure thereby emerges from the dynamical interplay between speciation and trophic interactions. The proposed model is less abstract than earlier evolutionary food web models in the sense that all three evolving traits have a clear biological meaning, namely the average body mass of the individuals, the preferred prey body mass, and the width of their potential prey body mass spectrum. We observed networks with a wide range of sizes and structures and high similarity to natural food webs. The model networks exhibit a continuous species turnover, but massive extinction waves that affect more than 50% of the network are not observed. PMID- 26042872 TI - Electrochemiluminescent DNA sensing using carbon nitride nanosheets as emitter for loading of hemin labeled single-stranded DNA. AB - Carbon nitride nanosheets (CNNS) have been reported as a cathodic electrochemiluminescence (ECL) emitter in the presence of dissolved oxygen to produce an endogenous coreactant H2O2 on electrode surface. This work uses this emitter to construct an ECL sensing platform for sensitive DNA detection through its adsorption ability toward single-stranded DNA (ssDNA). The adsorption of hemin-labeled ssDNA on CNNS leads to in situ consumption of dissolved oxygen via hemin-mediated electrocatalytic reduction, thus decreases the formation of coreactant and quenches the ECL emission of CNNS. The ECL sensing platform is designed using hemin-labeled ssDNA to recognize the target DNA, which results in the departure of hemin-labeled hybridization product from the CNNS modified electrode, thus inhibits the annihilation of coreactant and recovers the ECL emission. Under optimized conditions, the proposed sensing strategy shows a wide detection range over 6 orders of magnitude and wondrously high sensitivity with a detection limit down to 2.0 fM. Moreover, the ECL sensor exhibits good performance with excellent selectivity, high reliability, and acceptable fabrication reproducibility. The sensitive sensing strategy provides a new paradigm for the design of ultrasensitive detection method. PMID- 26042871 TI - Highly sensitive and specific colorimetric detection of cancer cells via dual aptamer target binding strategy. AB - Simple, rapid, sensitive and specific detection of cancer cells is of great importance for early and accurate cancer diagnostics and therapy. By coupling nanotechnology and dual-aptamer target binding strategies, we developed a colorimetric assay for visually detecting cancer cells with high sensitivity and specificity. The nanotechnology including high catalytic activity of PtAuNP and magnetic separation & concentration plays a vital role on the signal amplification and improvement of detection sensitivity. The color change caused by small amount of target cancer cells (10 cells/mL) can be clearly distinguished by naked eyes. The dual-aptamer target binding strategy guarantees the detection specificity that large amount of non-cancer cells and different cancer cells (10(4) cells/mL) cannot cause obvious color change. A detection limit as low as 10 cells/mL with detection linear range from 10 to 10(5) cells/mL was reached according to the experimental detections in phosphate buffer solution as well as serum sample. The developed enzyme-free and cost effective colorimetric assay is simple and no need of instrument while still provides excellent sensitivity, specificity and repeatability, having potential application on point-of-care cancer diagnosis. PMID- 26042873 TI - Timing readout in paper device for quantitative point-of-use hemin/G-quadruplex DNAzyme-based bioassays. AB - This work describes a quantitative point-of-use hemin/G-quadruplex DNAzyme-based assay that integrates a simple timing detection motif with low-cost, portable microfluidic paper-based analytical devices (MUPADs). The timing readout is based on the selective DNAzyme-mediated wettability change of paper from hydrophilicity to hydrophobicity. Its utility is well demonstrated with sensitive, specific detection of K(+) ion as a model analyte in artificial samples as well as real human serum samples. This new method only requires a ubiquitous cheap timer (or a cell phone with a timing function) to provide quantitative results. It could offer new opportunities for the development of more peroxidase-mimicking DNAzyme based bioassays that are simple, affordable, portable, and operable by minimally trained users for broad point-of-use applications especially in resource-poor settings. PMID- 26042874 TI - Cascade DNA nanomachine and exponential amplification biosensing. AB - DNA is a versatile scaffold for the assembly of multifunctional nanostructures, and potential applications of various DNA nanodevices have been recently demonstrated for disease diagnosis and treatment. In the current study, a powerful cascade DNA nanomachine was developed that can execute the exponential amplification of p53 tumor suppressor gene. During the operation of the newly proposed DNA nanomachine, dual-cyclical nucleic acid strand-displacement polymerization (dual-CNDP) was ingeniously introduced, where the target trigger is repeatedly used as the fuel molecule and the nicked fragments are dramatically accumulated. Moreover, each displaced nicked fragment is able to activate the another type of cyclical strand-displacement amplification, increasing exponentially the value of fluorescence intensity. Essentially, one target binding event can induce considerable number of subsequent reactions, and the nanodevice was called cascade DNA nanomachine. It can implement several functions, including recognition element, signaling probe, polymerization primer and template. Using the developed autonomous operation of DNA nanomachine, the p53 gene can be quantified in the wide concentration range from 0.05 to 150 nM with the detection limit of 50 pM. If taking into account the final volume of mixture, the detection limit is calculated as lower as 6.2 pM, achieving an desirable assay ability. More strikingly, the mutant gene can be easily distinguished from the wild-type one. The proof-of-concept demonstrations reported herein is expected to promote the development and application of DNA nanomachine, showing great potential value in basic biology and medical diagnosis. PMID- 26042875 TI - High-sensitivity detection of ATP using a localized surface plasmon resonance (LSPR) sensor and split aptamers. AB - A highly sensitive localized surface plasmon resonance (LSPR) aptasensor for detection of adenosine triphosphate (ATP) has been developed. The sensor utilizes two split ATP aptamers, one (receptor fragment) being covalently attached to the surface of a gold nanorod (GNR) and the other labeled with a random DNA sequence and TAMRA dye (probe fragment). In the presence of both ATP and the probe fragment, a significant shift takes place in the wavelength of the LSPR band. This phenomenon is a consequence of the fact that the split fragments assemble into an intact folded structure in the presence of ATP, which brings about a decrease in the distance between the GNR surface and TAMRA dye and an associated LSPR wavelength. By using this sensor system, concentrations of ATP in the range of 10 pM-10 MUM can be determined. In addition, by taking advantage of its denaturation properties, the LSPR aptasensor can be reused by simply subjecting it to quadruple salt-addition/2M NaCl washing steps. That the new method is applicable to biological systems was demonstrated by its use to measure ATP concentrations in E. coli and, thus to determine cell concentrations as low as 1.0*10(3) CFU. PMID- 26042876 TI - Factors affecting conviction rates of intoxicated driver patients in two large trauma centers. AB - OBJECTIVE: Outcomes from previous studies report the driving under the influence (DUI) conviction rates for trauma patients in several cities within Canada and the United States over the last 2 decades. This study reports charge, conviction, and prosecution rates for trauma patients at 2 level I trauma centers servicing a large metropolitan city. METHODS: A retrospective review of the trauma databases was completed to identify patients meeting inclusion criteria. Four hundred sixty patients were identified and their records were compared with the district attorney's records for DUI charges and convictions. RESULTS: The conviction rate for this study was 8.7%, demonstrating continued low rates of conviction despite growing interest and public awareness of drinking and driving. CONCLUSIONS: We discuss legal considerations that providers should consider when treating patients who have been drinking and driving. PMID- 26042877 TI - Syncope due to Autonomic Dysfunction: Diagnosis and Management. AB - Syncope is one of several disorders that cause transient loss of consciousness. Cerebral hypoperfusion is the proximate cause of syncope. Transient or fixed autonomic nervous system dysfunction is a major contributor in many causes. A structured approach to the evaluation of syncope allows for more effective therapy. PMID- 26042878 TI - Cardiovascular disease risk assessment and prevention: current guidelines and limitations. AB - Even after decades of progress in understanding atherosclerotic cardiovascular disease (ASCVD) and improved cardiovascular event prevention, the incidence, consequences and cost of cardiovascular disease (CVD) remain a significant public health issue. Observational studies have identified major ASCVD risk factors and lead to the development of a number of risk assessment systems/scores now in use. However many patients who will develop clinically important CVD are not identified by current systems or approaches and significant numbers of recurrent cardiovascular events continue to occur even after aggressive secondary prevention treatment strategies are utilized. Some now term this residual risk. The statin era revolutionized clinical practice with effective outcome-driven risk reduction. As a result there are now numerous clinical recommendations or guidelines for ASCVD risk stratification and treatment. Further disease and event prevention may rely on improved patient-centered risk stratification using novel biomarkers, imaging techniques, and new treatment approaches including emerging pharmacologic therapies. PMID- 26042880 TI - How to follow patients with mitral and aortic valve disease. AB - Valvular heart diseases (VHDs) place a hemodynamic load on the left and/or right ventricle that, if severe, prolonged, and untreated, damages the myocardium, leading to heart failure and death. Because all VHDs are mechanical problems, definitive therapy usually requires valve repair or replacement. In most valve disease the onset of symptoms marks a change in disease prognosis and is usually an indication for prompt surgical correction. Echocardiography is an indispensable modality for assessing lesion severity, its effect on cardiac function, and the proper timing for lesion correction. Intervention enhanced with percutaneous options now allows patients to benefit from mechanical correction. PMID- 26042879 TI - 2014 Guideline for the Management of High Blood Pressure (Eighth Joint National Committee): Take-Home Messages. AB - The JNC 8 guidelines focus on 3 highest-ranked clinical questions that include BP thresholds for starting therapy, specific BP goals, and risks and benefits of specific antihypertensive drugs. Only randomized controlled trial data were used and JNC 8 panel did not include observational studies, systematic reviews, or meta-analyses. The investigators also suggested that benefit of lowering BP to less than 140/90 is not clear. Lifestyle modifications were considered very important for all patients with hypertension. These recommendations are not alternatives for clinical judgment, and decisions about medical care must be individualized to each patient. PMID- 26042881 TI - New oral anticoagulants: their role in stroke prevention in high-risk patients with atrial fibrillation. AB - Based on efficacy, safety, and ease of use, novel oral anticoagulants will likely replace VKAs for many if not most patients with atrial fibrillation. Novel anticoagulants have a lower rate of intracranial hemorrhage compared with vitamin K antagonists. The incidence of other life-threatening bleeds is similar if not lower. Dose adjustments need to be made based on renal function and advanced age. There is at present a need for an antidote for these new drugs. PMID- 26042882 TI - Management of atrial fibrillation. AB - Atrial fibrillation is a very common clinical problem with a high prevalence that is expected to rise over time because of increasing risk factors (eg, age, obesity, hypertension). This high prevalence is also associated with high cost, because atrial fibrillation represents about 1% of overall health care spending. The management of atrial fibrillation involves multiple facets: (1) management of underlying disease if present and the management of atrial fibrillation risk factors, (2) prevention of thromboembolism, (3) control of the ventricular rate during atrial fibrillation, and (4) restoration and maintenance of normal sinus rhythm. PMID- 26042883 TI - Indications for pacemakers, implantable cardioverter-defibrillator and cardiac resynchronization devices. AB - Implantable cardiac devices are important management tools for patients with heart rhythm disorders and heart failure. In this article, the current implantable cardiac rhythm devices are described in their evolution. The current indications and contraindications for these cardiac rhythm devices are reviewed. PMID- 26042884 TI - Current status of transcatheter aortic valve replacement. AB - The advent of transcatheter aortic valve replacement (TAVR) has modified the treatment of severe aortic stenosis (AS). Large randomized trials and multicenter registries have endorsed the efficacy of TAVR in improving outcomes in patients with severe AS who are inoperable or high surgical risk. There has been a noticeable shift in using TAVR in patients with AS who are not at a high surgical risk. Appropriate diagnosis, patient selection, and referral remain cornerstones to achieving optimal outcomes after TAVR or SAVR (surgical aortic valve replacement). PMID- 26042885 TI - Chest pain evaluation in the emergency department. AB - Chest pain is a common complaint in the emergency department. Recognition of chest pain symptoms and electrocardiographic changes consistent with acute coronary syndrome (ACS) can lead to prompt initiation of goal-directed therapy. Cardiac troponin testing confirms the diagnosis of acute myocardial infarction, but does not reveal the mechanism of injury. When patients with chest pain rule out for ACS the use of advanced, noninvasive testing has not been found to be associated with better patient outcomes. PMID- 26042886 TI - Cardiac MRI: A General Overview with Emphasis on Current Use and Indications. AB - Cardiac magnetic resonance is well-established as a robust modality of cardiovascular imaging, providing superior resolution, infinite imaging planes, and the ability to obtain multiple types of information without ionizing radiation. Limitations imposed by availability, cost effectiveness, and safety prevent universal application. Many general and specialty practitioners do not have routine exposure to Cardiac MRI (CMR). Guidelines for the use of CMR exist, but continue to adapt to advances in techniques and ongoing research. Understanding the basics of CMR acquisition techniques, categories of appropriate use, and pertinent safety information will assist with selecting the best clinical scenarios to consider CMR. PMID- 26042887 TI - Current Management of Heart Failure: When to Refer to Heart Failure Specialist and When Hospice is the Best Option. AB - Heart failure is a common syndrome caused by different abnormalities of the cardiovascular system that result in impairment of the ventricles in filling or ejecting blood. It is one of the most common causes of hospitalization in the United States, with a very high cost to the health care system. This article focuses on the causes of left ventricle dysfunction and the presentation and management of heart failure, both acute and chronic. PMID- 26042888 TI - Emerging role of digital technology and remote monitoring in the care of cardiac patients. AB - Current available mobile health technologies make possible earlier diagnosis and long-term monitoring of patients with cardiovascular diseases. Remote monitoring of patients with implantable devices and chronic diseases has resulted in better outcomes reducing health care costs and hospital admissions. New care models, which shift point of care to the outpatient setting and the patient's home, necessitate innovations in technology. PMID- 26042889 TI - Management of cardiovascular disease. PMID- 26042890 TI - Medical Clinics of North America. Management of Cardiovascular Disease. Preface. PMID- 26042891 TI - ABO Blood Group and Dementia Risk--A Scandinavian Record-Linkage Study. AB - BACKGROUND: Dementia includes a group of neuro-degenerative disorders characterized by varying degrees of cognitive impairment. Recent data indicates that blood group AB is associated with impaired cognition in elderly patients. To date there are no large-scale studies that have examined the relationship between ABO blood group and dementia-related disorders in detail. METHODS: We used data from the SCANDAT2 database that contains information on over 1.6 million blood donors from 1968 in Sweden and 1981 from Denmark. The database was linked with health outcomes data from nationwide patient and cause of death registers to investigate the relationship between blood groups and risk of different types of dementia. The incident rate ratios were estimated using log-linear Poisson regression models. RESULTS: Among 1,598,294 donors followed over 24 million person-years of observation we ascertained 3,615 cases of Alzheimer's disease, 1,842 cases of vascular dementia, and 9,091 cases of unspecified dementia. Overall, our study showed no association between ABO blood group and risk of Alzheimer's disease, vascular dementia or unspecified dementia. This was also true when analyses were restricted to donors aged 70 years or older except for a slight, but significantly decreased risk of all dementia combined in subjects with blood group A (IRR, 0.93; 95% confidence interval [CI], 0.88-0.98), compared to those with blood group O. CONCLUSIONS: Our results provide no evidence that ABO blood group influences the risk of dementia. PMID- 26042892 TI - Family caregiver communication in oncology: advancing a typology. AB - OBJECTIVES: The quality of communication between the patient and family caregiver impacts quality of life and well-being for the two; however, providers have few tools to understand communication patterns and assess the communication needs and preferences of caregivers. The aims of this study were to examine family communication patterns among oncology patients and their caregivers and to identify common characteristics among four different types of family caregivers. METHODS: Nurses recruited oncology patient-caregiver dyads through a large cancer treatment center in the Southeast. Patients and caregivers were separated from one another and interviewed during chemotherapeutic infusions. Interviews were recorded, transcribed, coded, and thematized. RESULTS: A sample of 24 patients and their caregivers (n = 48) were interviewed. The majority of dyads (21, 88%) shared the same family communication pattern. Common caregiver communication features support previous work identifying four caregiver communication types: Manager, Carrier, Partner, and Lone caregivers. Manager caregivers lead patients by utilizing extensive medical knowledge, whereas Carrier caregivers were led by patients and described tireless acts to maintain the family and avoid difficult conversations. Partner caregivers facilitated family involvement and open communication on a variety of topics, while Lone caregivers focused solely on biomedical matters and a hope for cure. CONCLUSIONS: Caregiver communication types were corroborated by patient-caregiver descriptions of caregiving. However, more information is needed to ascertain the variables associated with each caregiver type. Future work to improve identification of caregiver types and create targeted caregiver care plans will require further study of health literacy levels and tested communication interventions per type. PMID- 26042893 TI - Assessing burden of disease as disability adjusted life years in life cycle assessment. AB - Disability adjusted life years (DALYs) have been used to quantify endpoint indicators of the human burden of disease in life cycle assessment (LCA). The purpose of this paper was to examine the current use of DALYs in LCA, and also to consider whether DALYs as used in LCA have the potential to be compatible with DALYs as used in quantitative risk assessment (QRA) to facilitate direct comparison of the results of the two approaches. A literature review of current usage of DALYs in LCA was undertaken. Two prominent methods were identified: ReCiPe 2008 and LIME2. The methods and assumptions used in their calculations were then critically reviewed. The assumptions used for the derivation of characterization factors in DALYs were found to be considerably different between LCA methods. In many cases, transparency of these calculations and assumptions is lacking. Furthermore, global average DALY values are often used in these calculations, but may not be applicable for impact categories where the local factors play a significant role. The concept of DALYs seems beneficial since it enables direct comparison and aggregation of different health impacts. However, given the different assumptions used in each LCA method, it is important that LCA practitioners are aware of the differences and select the appropriate method for the focus of their study. When applying DALYs as a common metric between LCA and QRA, understanding the background information on how DALYs were derived is crucial to ensure the consistency of DALYs used in LCA and QRA for resulting DALYs to be comparable and to minimize any double counting of effects. PMID- 26042894 TI - Dissipation, metabolism and sorption of pesticides used in fruit-packaging plants: Towards an optimized depuration of their pesticide-contaminated agro industrial effluents. AB - Wastewaters from the fruit-packaging industry constitute a serious point source contamination with pesticides. In the absence of effective depuration methods, they are discharged in municipal wastewater treatment plants or spread to land. Modified biobeds could be an applicable solution for their treatment. We studied the dissipation of thiabendazole (TBZ), imazalil (IMZ), ortho-phenylphenol (OPP), diphenylamine (DPA) and ethoxyquin (EQ), used by the fruit-packaging industry, in anaerobically digested sewage sludge, liquid aerobic sewage sludge and in various organic substrates (biobeds packing materials) composed of soil, straw and spend mushroom substrate (SMS) in various volumetric ratios. Pesticide sorption was also determined. TBZ and IMZ showed higher persistence especially in the anaerobically digested sewage sludge (DT50=32.3-257.6d), in contrast to OPP and DPA which were rapidly dissipated especially in liquid aerobic sewage sludge (DT50=1.3-9.3d). EQ was rapidly oxidized mainly to quinone imine (QI) which did not persist and dimethyl ethoxyquinoline (EQNL, minor metabolite) which persisted for longer. Sterilization of liquid aerobic sewage sludge inhibited pesticide decay verifying the microbial nature of pesticide dissipation. Organic substrates rich in SMS showed the highest dissipation capacity with TBZ and IMZ DT50s of ca. 28 d compared to DT50s of >50 d in the other substrates. TBZ and IMZ showed the highest sorption affinity, whereas OPP and DPA were weakly sorbed. Our findings suggest that current disposal practices could not guarantee an efficient depuration of effluents from the fruit-packaging industry, whereas SMS-rich biobed organic substrates show efficient depuration of effluents from the fruit packaging industry via accelerated dissipation even of recalcitrant fungicides. PMID- 26042895 TI - Occurrence of (fluoro)quinolones and (fluoro)quinolone resistance in soil receiving swine manure for 11 years. AB - Because of the widespread use of antibiotics in animal breeding, the agricultural application of animal manure can lead to the introduction of antibiotics, antibiotic-resistant bacteria and antibiotic resistance genes to the soil and surrounding environment, which may pose a threat to public health. In this study, we investigated the status of (fluoro)quinolone (FQ) residues and FQ resistance levels in soil with and without receiving long-term swine manure. Six FQs (pipemidic acid, lomefloxacin, enrofloxacin, norfloxacin, ciprofloxacin, and ofloxacin) were only detected in manured soil, with individual concentrations ranging from below the detection limit to 27.2 MUg kg(-1) and increasing with the increase in swine manure application rates. Higher load rates of swine manure yielded a higher number of ciprofloxacin-resistant (CIPr) bacteria after spreading. A total of 24 CIPr bacterial isolates were obtained from the tested soil, which belonged to four phyla (Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes) or were related to nine different genera. Only 18 isolates from manured soil were positive for five plasmid-mediated quinolone resistance (PMQR) genes (aac(6')-Ib-cr, qnrD, qepA, oqxA, and oqxB). To our knowledge, this study is the first to examine the occurrence of PMQR genes in FQ-resistant bacteria from the soil environment. A similar result was observed for the total DNA from soil, with the exception of aac(6')-Ib being detected in the control sample. The absolute and relative abundances of total PMQR genes also increased with fertilization quantity. Significant correlations were observed between FQ resistance levels and FQ concentrations. These results indicated that the agricultural application of swine manure led to FQ residues and enhanced FQ resistance. This investigation provides baseline data on FQ resistance profiles in soils receiving long-term swine manure. PMID- 26042896 TI - Maternal transfer of emerging brominated and chlorinated flame retardants in European eels. AB - The European eel (Anguilla anguilla) is regarded as a critically endangered species. Scientists are in agreement that the "quality of spawners" is a vital factor for the survival of the species. This quality can be impaired by parasites, disease and pollution. Especially endocrine disrupting organic chemicals pose a potential threat to reproduction and development of offspring. To our knowledge, the findings in this publication for the first time describe maternal transfer of contaminants in eels. We analysed the concentrations of in total 53 polybrominated diphenyl ethers (PBDEs) and their halogenated substitutes in muscle, gonads and eggs of artificially matured European eels and in muscle and gonads of untreated European eels that were used for comparison. We found evidence that persistent organic pollutants such as PBDEs, as well as their brominated and chlorinated substitutes are redistributed from muscle tissue to gonads and eggs. Concentrations ranged from 0.001 ng g(-1)ww for sum Dechlorane metabolites (DPMA, aCL10DP, aCl11DP) to 2.1 ng g(-1)ww for TBA in eggs, 0.001 ng g(-1)ww for Dechlorane metabolites to 9.4 ng g(-1)ww for TBA in gonads and 0.002 ng g(-1)ww for Dechlorane metabolites to 54 ng g(-1)ww for TBA in muscle tissue. Average egg muscle ratios (EMRs) for compounds detectable in artificially matured eels from both Schlei Fjord and Ems River ranged from 0.01 for Dechlorane 602 (DDC-DBF) to 10.4 for PBEB. Strong correlations were found between flame retardant concentrations and lipid content in the analysed tissue types, as well as transfer rates and octanol-water partitioning coefficient, indicating that these parameters were the driving factors for the observed maternal transfer. Furthermore, indications were found, that TBP-DBPE, TBP-AE, BATE and TBA have a significant uptake from the surrounding water, rather than just food and might additionally be formed by metabolism or biotransformation processes. Dechloranes seem to be of increasing relevance as contaminants in eels and are transferred to eggs. A change of the isomer pattern in comparison to the technical product of Dechlorane Plus (DP) was observed indicating a redistribution of DP from muscle tissue to gonads during silvering with a preference of the syn-isomer. The highly bioaccumulative DDC-DBF was the most abundant Dechlorane in all fish of the comparison group even though it is not produced or imported in the EU. The aldrin related "experimental flame retardant" dibromoaldrin (DBALD) was detected for the first time in the environment in similar or higher concentrations than DP. PMID- 26042897 TI - Soluble HLA-G in pregnancies complicated by autoimmune rheumatic diseases. AB - Autoimmune rheumatic diseases in pregnancies are associated with increased adverse obstetric outcomes. We compared maternal soluble human leucocyte antigen G (sHLA-G) blood levels in subjects with a rheumatic disease preexisting pregnancy and unaffected controls. Third-trimester blood maternal sHLA-G concentrations were significantly higher in subjects with rheumatic diseases than in controls (mean 93.1ng/ml [SD 42.1] vs 58.1ng/ml [SD 96.3], p=0.003). Cord blood sHLA-G concentrations were significantly higher in rheumatic disease than in those born to control mothers (median 41.2ng/ml [IQR: 3.3-44.0] vs 17.9ng/ml [IQR: 17.2-88.1], p=0.007). A strict positive correlation (r=0.88, p<0.001) was found between the maternal and fetal titers of ANA autoantibodies as well as between maternal and fetal sHLAG circulating levels (r=0.58 and r=0.67, respectively, for controls and cases, p<0.001). Maternal s-HLA-G blood concentrations were significantly higher in subjects with rheumatic disease DEL/DEL homozygous for a polymorphism of the 3' untranslated regulatory region of HLA-G (HLA-G 14bp) than in the corresponding healthy controls (mean values 141.5ng/ml [SD: 166] vs 54.2ng/ml [SD: 35], p=0.009). Increasing maternal and cord blood levels of s-HLA-G concentrations among pregnant subjects with rheumatic diseases compared with controls suggest that autoimmune diseases prompt a maternal and fetal immune response that favors pregnancy immune tolerance. PMID- 26042898 TI - The Complete Mitochondrial Genome of Corizus tetraspilus (Hemiptera: Rhopalidae) and Phylogenetic Analysis of Pentatomomorpha. AB - Insect mitochondrial genome (mitogenome) are the most extensively used genetic information for molecular evolution, phylogenetics and population genetics. Pentatomomorpha (>14,000 species) is the second largest infraorder of Heteroptera and of great economic importance. To better understand the diversity and phylogeny within Pentatomomorpha, we sequenced and annotated the complete mitogenome of Corizus tetraspilus (Hemiptera: Rhopalidae), an important pest of alfalfa in China. We analyzed the main features of the C. tetraspilus mitogenome, and provided a comparative analysis with four other Coreoidea species. Our results reveal that gene content, gene arrangement, nucleotide composition, codon usage, rRNA structures and sequences of mitochondrial transcription termination factor are conserved in Coreoidea. Comparative analysis shows that different protein-coding genes have been subject to different evolutionary rates correlated with the G+C content. All the transfer RNA genes found in Coreoidea have the typical clover leaf secondary structure, except for trnS1 (AGN) which lacks the dihydrouridine (DHU) arm and possesses a unusual anticodon stem (9 bp vs. the normal 5 bp). The control regions (CRs) among Coreoidea are highly variable in size, of which the CR of C. tetraspilus is the smallest (440 bp), making the C. tetraspilus mitogenome the smallest (14,989 bp) within all completely sequenced Coreoidea mitogenomes. No conserved motifs are found in the CRs of Coreoidea. In addition, the A+T content (60.68%) of the CR of C. tetraspilus is much lower than that of the entire mitogenome (74.88%), and is lowest among Coreoidea. Phylogenetic analyses based on mitogenomic data support the monophyly of each superfamily within Pentatomomorpha, and recognize a phylogenetic relationship of (Aradoidea + (Pentatomoidea + (Lygaeoidea + (Pyrrhocoroidea + Coreoidea)))). PMID- 26042899 TI - The reproductive outcome of women with hypogonadotropic hypogonadism undergoing in vitro fertilization. AB - The aim of this study was to evaluate the reproductive outcome and assisted reproductive technology (ART) outcomes of patients with hypogonadotropic hypogonadism (HH) and to compare the results with male factor (MF) infertility patients. The reproductive outcome of 33 HH patients was evaluated retrospectively and compared with results of 47 patients with mild male factor infertility. For ovulation induction, human menopausal gonadotropin (hMG) was used in HH patients and recFSH was used in MF infertility patients. HH patients were divided into subgroups according to retrieved oocyte numbers and the groups were compared with each other. The main outcome measures were total gonadotropin dose used, duration of stimulation, human chorionic gonadotropin (hCG) day estradiol level and endometrial thickness, oocyte number retrieved, and rate of clinical pregnancy. ART outcomes and cycle characteristics of 33 HH patients were compared with 47 MF infertility patients. There was no difference in age and body mass index (BMI) between the groups, but mean follicle stimulating hormone FSH and luteinizing hormone LH levels were significantly lower in the HH group (p < 0.001). Duration of stimulation was 12.5 +/- 2.06 days in the HH patients and 10.08 +/- 1.62 days in the MF infertility patients and the difference was significant (p < 0.001). Total gonadotropin dose used was higher in the HH group than the MF infertility group (p < 0.001). However, there were no differences in hCG day estradiol levels, endometrial thickness on hCG day, total oocyte number retrieved, MII oocyte number, and pregnancy rate. In the HH subgroups, patient ages were significantly lower in the >15 oocyte retrieved group. Although patients with HH have a long-term estrogen deficiency, their response to controlled ovarian hyperstimulation treatment is similar to normal women. However, the HH group is heterogeneous and estimating the ovarian reserve before treatment is not always possible in this group. PMID- 26042901 TI - Gamut of genetic testing for neonatal care. AB - The field of clinical genetics has advanced at an unprecedented pace. Today, with the aid of several high-resolution and high-precision technologies, physicians are able to make molecular genetic diagnoses for many infants affected with genetic disease. It is imperative, however, that perinatologists and neonatologists understand the strengths and limitations of genetic testing. This article discusses the different genetic testing options available for perinatal and neonatal diagnostics, along with their clinical utilities and indications. From variant-specific testing to whole-exome and genome sequencing, the article covers the whole gamut of genetic testing, with some thoughts on the changing paradigm of medical genetics. PMID- 26042900 TI - Ligand Recognition of the Major Birch Pollen Allergen Bet v 1 is Isoform Dependent. AB - Each spring millions of patients suffer from allergies when birch pollen is released into the air. In most cases, the major pollen allergen Bet v 1 is the elicitor of the allergy symptoms. Bet v 1 comes in a variety of isoforms that share virtually identical conformations, but their relative concentrations are plant-specific. Glycosylated flavonoids, such as quercetin-3-O-sophoroside, are the physiological ligands of Bet v 1, and here we found that three isoforms differing in their allergenic potential also show an individual, highly specific binding behaviour for the different ligands. This specificity is driven by the sugar moieties of the ligands rather than the flavonols. While the influence of the ligands on the allergenicity of the Bet v 1 isoforms may be limited, the isoform and ligand mixtures add up to a complex and thus individual fingerprint of the pollen. We suggest that this mixture is not only acting as an effective chemical sunscreen for pollen DNA, but may also play an important role in recognition processes during pollination. PMID- 26042902 TI - Copy number variants, aneuploidies, and human disease. AB - In the perinatal setting, chromosome imbalances cause a range of clinically significant disorders and increase the risk for other particular phenotypes. As technologies have improved to detect increasingly smaller deletions and duplications, collectively referred to as copy number variants (CNVs), clinicians are learning the significant role that these types of genomic variants play in human disease and their high frequency in ~ 1% of all pregnancies. This article highlights key aspects of CNV detection and interpretation used during the course of clinical care in the prenatal and neonatal periods. Early diagnosis and accurate interpretation are important for targeted clinical management. PMID- 26042904 TI - Recognizable syndromes in the newborn period. AB - Making the diagnosis of genetic syndromes in the neonatal period can be challenging, as limited information concerning growth and development is available. The pattern of dysmorphic features and malformations is, therefore, correspondingly more important in syndrome recognition. The authors provide specific examples of the differences in the presentation for selected syndromes between the newborn period and later childhood. The purpose is to describe the variation in presentation that can occur with chronologic age and to aid in the early diagnosis of these conditions. PMID- 26042903 TI - Evaluation and diagnosis of the dysmorphic infant. AB - Neonatologists have a unique opportunity to be the first to identify abnormalities in a neonate. In this review, multiple anomalies and physical features are discussed along with the potential associated genetic syndromes. The anomalies and physical features that are discussed include birth parameters, aplasia cutis congenita, holoprosencephaly, asymmetric crying facies, preauricular ear tags and pits, cleft lip with or without cleft palate, esophageal atresia/tracheoesophageal fistula, congenital heart defects, ventral wall defects, and polydactyly. PMID- 26042905 TI - Congenital limb deficiency disorders. AB - Congenital limb deficiency disorders (LDDs) are birth defects characterized by the aplasia or hypoplasia of bones of the limbs. Limb deficiencies are classified as transverse, those due to intrauterine disruptions of previously normal limbs, or longitudinal, those that are isolated or associated with certain syndromes as well as chromosomal anomalies. Consultation with a medical geneticist is advisable. Long-term care should occur in a specialized limb deficiency center with expertise in orthopedics, prosthetics, and occupational and physical therapy and provide emotional support and contact with other families. With appropriate care, most children with LDDs can lead productive lives. PMID- 26042907 TI - Newborn craniofacial malformations: orofacial clefting and craniosynostosis. AB - Craniofacial malformations are among the most common birth defects. Although most cases of orofacial clefting and craniosynostosis are isolated and sporadic, these abnormalities are associated with a wide range of genetic syndromes, and making the appropriate diagnosis can guide management and counseling. Patients with craniofacial malformation are best cared for in a multidisciplinary clinic that can coordinate the care delivered by a diverse team of providers. PMID- 26042906 TI - Skeletal dysplasias. AB - The skeletal dysplasias are a group of more than 450 heritable disorders of bone. They frequently present in the newborn period with disproportion, radiographic abnormalities, and occasionally other organ system abnormalities. For improved clinical care, it is important to determine a precise diagnosis to aid in management, familial recurrence, and identify those disorders highly associated with mortality. Long-term management of these disorders is predicated on an understanding of the associated skeletal system abnormalities, and these children are best served by a team approach to health care surveillance. PMID- 26042908 TI - Structural brain defects. AB - Up to 14% of patients with congenital metabolic disease may show structural brain abnormalities from perturbation of cell proliferation, migration, and/or organization. Most inborn errors of metabolism have a postnatal onset. Abnormalities from genetic disease processes have a prenatal onset. Energy impairment, substrate insufficiency, cell membrane receptor and cell signaling abnormalities, and toxic byproduct accumulation are associations between genetic disorders and structural brain anomalies. Collective imaging patterns of brain abnormalities can provide clues to the underlying etiology. We review selected metabolic diseases associated with brain malformations and highlight characteristic clinical and imaging manifestations that help narrow the differential diagnosis. PMID- 26042909 TI - Neonatal hypotonia. AB - Neonatal hypotonia is a common problem in the neonatal intensive care unit. The genetic differential diagnosis is broad, encompassing primary muscular dystrophies, chromosome abnormalities, neuropathies, and inborn errors of metabolism. Recognition of hypotonia is relatively straightforward, but determining the cause can be challenging. It is important for the neonatologist to have an organized approach to the assessment of neonatal hypotonia. Physical examination and history alongside basic laboratory testing and imaging aid in the differential diagnosis. Identification of the cause is essential for determining prognosis, associated morbidities, and recurrence risk. The prevailing therapeutic modality is physical, occupational, speech/feeding, and respiratory therapy. PMID- 26042910 TI - Genetics and genetic testing in congenital heart disease. AB - Congenital heart defects (CHDs) are structural abnormalities of the heart and great vessels that are present from birth. The presence or absence of extracardiac anomalies has historically been used to identify patients with possible monogenic, chromosomal, or teratogenic CHD causes. These distinctions remain clinically relevant, but it is increasingly clear that nonsyndromic CHDs can also be genetic. This article discusses key morphologic, molecular, and signaling mechanisms relevant to heart development, summarizes overall progress in molecular genetic analyses of CHDs, and provides current recommendations for clinical application of genetic testing. PMID- 26042911 TI - Disorders of sexual development. AB - Disorders of sexual development (DSDs) are a group of disorders in which there is discordance between anatomic or hormonal sex and sex chromosome complement. These disorders present with ambiguity in the newborn period and require prompt evaluation to determine the underlying cause for treatment and appropriate sex assignment of the infant. Neonatologists should confer with a multidisciplinary team for the diagnostic evaluation and management of patients with DSDs. This article provides a review of normal sexual development, algorithms used for evaluating infants with ambiguous genitalia, and conditions that can present with ambiguous genitalia in the newborn period. PMID- 26042912 TI - Inborn errors of metabolism. AB - Inborn errors of metabolism (IEM) are individually rare but collectively common. Approximately 25% of IEMs can have manifestations in the neonatal period. Neonates with IEM are usually healthy at birth; however, in hours to days after birth they can develop nonspecific signs that are common to several other neonatal conditions. Therefore, maintaining a high index of suspicion is extremely important for early diagnosis and the institution of appropriate therapy, which are mandatory to prevent death and ameliorate complications from many IEMs. PMID- 26042913 TI - Newborn screening. AB - Newborn screening is a major aspect of public health success. Babies in every state are tested for a recommended uniform screening panel of conditions not otherwise immediately evident in the first days of life. With the goal of reducing morbidity and mortality, conditions should be added to newborn screening panels using a scientific, evidence-based process. Newborn screening is a system involving partners at many levels; neonatologists have a special role in ensuring that their vulnerable patients also receive this life-saving test. Careful attention to the social, legal, and ethical aspects will help increase the scope of newborn screening. PMID- 26042914 TI - The future of personalized and precision perinatal medicine. Foreword. PMID- 26042915 TI - Genetics in the twenty-first century. Preface. PMID- 26042916 TI - A Multiplexed, Two-Electrode Platform for Biosensing Based on DNA-Mediated Charge Transport. AB - We have developed a thin layer, multiplexed biosensing platform that features two working-electrode arrays for detecting small molecules, nucleic acid sequences, and DNA-binding proteins. DNA duplexes are patterned onto the primary electrode array, while a secondary electrode array is used both to initiate DNA monolayer formation and for electrochemical readout via DNA-mediated charge transport (DNA CT) chemistry. Electrochemical reduction of Cu(phendione)2(2+) (phendione is 1,10 phenanthroline-5,6-dione) at the secondary electrodes induces covalent attachment via click chemistry of ethynyl-labeled DNA probe duplexes onto the primary electrodes that have been treated with azide-terminated alkylthiols. Electrochemical impedance spectroscopy and cyclic voltammetry confirm that catalyst activation at the secondary electrode is essential to maintain the integrity of the DNA monolayer. Electrochemical readout of DNA CT processes that occur at the primary electrode is accomplished also at the secondary electrode. The two-electrode system enables the platform to function as a collector generator using either ferrocyanide or ferricyanide as mediators with methylene blue and DNA charge transport. Electrochemical measurements at the secondary electrode eliminate the need for large background corrections. The resulting sensitivity of this platform enables the reliable and simultaneous detection of femtomoles of the transcription factors TATA-binding protein and CopG on a single multiplexed device. PMID- 26042917 TI - Analysis of Cocoa Proanthocyanidins Using Reversed Phase High-Performance Liquid Chromatography and Electrochemical Detection: Application to Studies on the Effect of Alkaline Processing. AB - Flavan-3-ols and proanthocyanidins play a key role in the health beneficial effects of cocoa. Here, we developed a new reversed phased high-performance liquid chromatography-electrochemical detection (HPLC-ECD) method for the analysis of flavan-3-ols and proanthocyanidins of degree of polymerization (DP) 2 7. We used this method to examine the effect of alkalization on polyphenol composition of cocoa powder. Treatment of cocoa powder with NaOH (final pH 8.0) at 92 degrees C for up to 1 h increased catechin content by 40%, but reduced epicatechin and proanthocyanidins by 23-66%. Proanthocyanidin loss could be modeled using a two-phase exponential decay model (R(2) > 0.7 for epicatchin and proanthocyanidins of odd DP). Alkalization resulted in a significant color change and 20% loss of total polyphenols. The present work demonstrates the first use of HPLC-ECD for the detection of proanthocyanidins up to DP 7 and provides an initial predictive model for the effect of alkali treatment on cocoa polyphenols. PMID- 26042918 TI - Further statistical and clinical validity for the Weight Efficacy Lifestyle Questionnaire-Short Form. AB - Identifying barriers to long-term adherence to reduced energy intake and increased physical activity level is critically important for obese patients seeking weight loss treatment. Previous research has identified that one such barrier is low eating self-efficacy or poor confidence in one's ability to control eating behavior in the presence of challenging situations. Accordingly, a valid, brief measure of eating self-efficacy for longitudinal assessment of weight loss and regain is needed. The purpose of this study was to test the internal consistency and clinical validity of the Weight Efficacy Lifestyle Questionnaire-Short Form (WEL-SF). Participants were 1740 consecutive obese patients who presented for a psychological evaluation in consideration for bariatric surgery. Median BMI was 44.9 (range: 35.0-111.9), age 48.7years (range: 18.9-77.3years), and patients were predominantly female (71.1%) and Caucasian (90.8%). The median WEL-SF total score was 56 (range: 0-80) and Cronbach's alpha measuring internal consistency was 0.92 with a one-factor structure. In terms of clinical validation, lower WEL-SF total scores were significantly associated with higher rates of binge eating episodes (P<0.0001), food addiction severity and dependence (P<0.0001), night eating syndrome (P<0.0001), depression (P<0.0001), and anxiety (P<0.0001). In contrast, higher WEL-SF total scores were associated with higher weight management self-efficacy (P<0.0001) and motivation to make positive lifestyle changes (P<0.0001). Taken together, these findings suggest that the WEL-SF is a psychometrically valid clinically meaningful measure of eating self-efficacy. PMID- 26042919 TI - Gender differences in the relationship between impulsivity and disordered eating behaviors and attitudes. AB - OBJECTIVE: We investigated relationships among gender, impulsivity and disordered eating in healthy college students. METHOD: Participants (N=1223) were healthy, undergraduate men (28.5%) and women (71.5%), who completed the Barratt Impulsiveness Scale - Version 11 (BIS-11) and a four-factor version of the Eating Attitudes Test (EAT-16). RESULTS: As predicted, mean scores on all four EAT-16 factors were significantly higher for women than for men. Attentional impulsivity was related to poorer self-perception of body shape, more dieting, and a greater preoccupation with food for the sample as a whole. Moreover, motor impulsivity was related to poorer self-perceptions of body shape and a greater preoccupation with food. However, no gender differences emerged in the relationship between impulsivity and disordered eating attitudes. DISCUSSION: This study elucidates the role of impulsivity in disordered eating behaviors among non-clinical college students. For both women and men, attentional and motor impulsivity were related to disordered eating attitudes and behaviors. Overall, these findings suggest that different facets of impulsivity are related to disordered eating attitudes and behaviors in a non-clinical college population. PMID- 26042920 TI - Is level of intuitive eating associated with plate size effects? AB - OBJECTIVE: Intuitive eating is an eating approach that emphasizes increased focus on internal hunger and fullness cues to regulate eating behavior; thus, successful intuitive eating should curb the influence of environmental factors such as plate and portion size on consumption. The current study examined whether self-reported levels of intuitive eating moderated the influence of portion size on college students' food consumption during an afternoon meal of pasta and tomato sauce. METHOD: Participants (N=137, 63.5% female) were randomly assigned to either a large plate (12-inch) or small plate (8-inch) external cue condition. All participants fasted for four daytime hours, completed the Intuitive Eating Scale, and then were asked to rate a meal of pasta and tomato sauce on different dimensions of taste. Participants were told that they could eat as much pasta as they would like. RESULTS: Higher levels of intuitive eating were associated with greater food consumption. At the mean level of intuitive eating, participants ate more pasta in the large plate condition. Furthermore, the influence of plate size on food consumption increased as levels of intuitive eating increased. DISCUSSION: Individuals who report high levels of intuitive eating may be more likely to eat an objectively larger amount of food in a permissive food environment, and may have implications for eating approaches that promote eating in response to internal hunger and fullness cues. PMID- 26042921 TI - Physicochemical properties of foal meat as affected by cooking methods. AB - The present study deals with the effect of four different cooking techniques (roasting, grilling, microwave baking and frying with olive oil) on physicochemical parameters (cooking loss, WHC, texture and colour) and lipid oxidation (by TBARS measurement) of foal meat. Thermal treatments induced water loss (P<0.001), being lower in foal steaks cooked in the grill (25.8%) and higher in foal samples cooked in the microwave (39.5%). As it was expected, all the cooking methods increased TBARS index, since high temperature during cooking seems to cause an increase of the lipid oxidation in foal steaks. Statistical analysis displayed that WHC was affected (P<0.001) by thermal treatment, since the smallest WHC values were observed in samples from microwave treatment. Thermal treatment also caused a significant (P<0.001) increase in the force needed to cut the foal steaks. Regarding colour parameter, cooking led to an increase of L*-value (lightness) and b*-value (yellowness), while a*-value (redness) markedly decreased in all samples. PMID- 26042922 TI - The future of P2Y12 receptor antagonists. AB - Platelet P2Y12 inhibitors have become a central component of the treatment strategy for patients with atherothrombosis due to the importance of platelet P2Y12 receptors in arterial thrombosis. P2Y12 inhibitors effectively reduce the risk of adverse cardiovascular events in patients with acute coronary syndromes (ACS) and patients undergoing percutaneous coronary intervention (PCI). However, despite this, patients with ACS continue to suffer from recurrent atherothrombosis and an increased risk of mortality. In addition, P2Y12 inhibitors increase the risk of bleeding, thereby limiting their clinical benefit. It is therefore clear that further optimizations are needed in the pharmacology and treatment strategies of P2Y12 inhibitors. The objective of these optimizations is to maximize cardiovascular benefit whilst minimizing adverse effects on haemostasis. This review article summarizes the most successful recent strategies in P2Y12 inhibition in order to identify the optimizations and developments that are most likely to be successful in the future. PMID- 26042923 TI - Proton pump inhibitor-responsive oesophageal eosinophilia (PPI-REE): characteristics of a Spanish population in central Spain. PMID- 26042924 TI - Anticoagulant therapy and its impact on dental patients: a review. AB - Several new oral anticoagulants have been studied in the past decade, and have now started to enter the market. These drugs are reported to be as effective as, or more effective than, warfarin. In Australia, the Therapeutic Goods Administration has approved dabigatran, rivaroxaban and apixaban. The use of these newer anticoagulants is likely to increase in time, and it is important for dentists to have a sound understanding of the mechanisms of action, reversal strategies, and management guidelines for patients taking oral anticoagulants. This article discusses the process of coagulation, available anticoagulants and their monitoring and reversal, and provides clinical advice on the management of patients on anticoagulants who require dental treatment. PMID- 26042925 TI - Determinants of Medicare Costs for Elderly Patients With Oral Cavity and Pharyngeal Cancers. AB - IMPORTANCE: In the United States, nearly 8400 patients die each year from oral cavity and pharynx cancers, most of whom are 65 years and older; however, the costs attributable to these cancers are not well described. OBJECTIVE: To identify the primary determinants of cost in patients with oral and pharyngeal cancer. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort analysis of data from Medicare and Surveillance, Epidemiology, and End Results hospitals (January 1, 1995, through December 31, 2005), we studied patients 66 years and older with newly diagnosed oral cavity (n = 6724) and pharyngeal (n = 3987) cancers. MAIN OUTCOMES AND MEASURES: Five-year cumulative costs, defined as Medicare Parts A and B payments, were estimated using inverse probability weighting. Linear regression analysis with inverse probability weighting was used in multivariate analyses of costs to estimate the effects of covariates on cumulative costs. RESULTS: In multivariate analyses, costs were significantly increased by demographics, comorbidities, and treatment selection. Compared with white patients, African Americans accumulated $11,450 (95% CI, $1320-$22,299) and $25,093 (95% CI, $14,917-$34,985) more in costs for oral cavity and pharyngeal cancers, respectively. The presence of 1 or 2 comorbidities increased the mean 5 year cumulative costs by $13,342 (95% CI, $6248-$19,186) and $14,139 (95% CI, $6009-$22,217) for patients with oral cavity and pharyngeal cancers, respectively. For 3 or more comorbidities, the mean 5-year cumulative costs increased by $22,196 (95% CI, $15,319-$28,614) and $27,799 (95% CI, $19,139 $36,702) for patients with oral cavity and pharyngeal cancers, respectively. Patients who received chemotherapy accumulated a mean of $26,919 (95% CI, $18,309 $35,056) and $37,407 (95% CI, $29,971-$44,644) more in costs by 5 years for oral cavity and pharyngeal cancers, respectively. CONCLUSIONS AND RELEVANCE: Oral and pharyngeal cancer is burdensome to elderly patients from a Medicare cost perspective. Several factors were associated with 5-year costs, including some modifiable factors that may be potential targets for interventions to reduce overall costs. PMID- 26042926 TI - Routine use of continuous glucose monitoring in 10 501 people with diabetes mellitus. AB - AIMS: To analyse blood glucose control according to continuous glucose monitoring use in data from the CareLink database, and to identify factors associated with continuation of sensor use during sensor-augmented pump therapy. METHODS: The analysis used data from 10 501 people with Type 1 and 2 diabetes mellitus, of whom 7916 (61.7%) had used glucose sensors for >= 15 days during any 6-month period over a 2-year observation period. Data were analysed according to the extent of sensor use ( < 25%, 25-49%, 50-74% and >= 75% of the time). Time to discontinuation of sensor use was also analysed in new users of glucose sensors. RESULTS: Compared with patients in the lowest sensor usage group and non-users, the highest glucose sensor usage group had significantly (P < 0.0001) lower mean blood glucose and blood glucose sd, were more likely to achieve a mean blood glucose concentration < 8.6 mmol/l, (odds ratio 1.5, 95% CI 1.3-1.7; P < 0.0001), and had 50% fewer hypoglycaemic (blood glucose concentration < 2.8 mmol/l) episodes. Among new users, sensor use during the first month of therapy was an important predictor of subsequent discontinuation. Lack of full reimbursement was also significantly associated with early discontinuation, whereas measures of glycaemic control were predictive of discontinuation during long-term treatment. CONCLUSIONS: The use of continuous glucose monitoring was significantly associated with reductions in hypoglycaemia and improved metabolic control during insulin pump therapy. Sensor use during the first month was strongly associated with long-term adherence; patient education and training may be helpful in achieving this. PMID- 26042927 TI - The enduring effects of psychodynamic treatments vis-a-vis alternative treatments: A multilevel longitudinal meta-analysis. AB - Although evidence suggests that the benefits of psychodynamic treatments are sustained over time, presently it is unclear whether these sustained benefits are superior to non-psychodynamic treatments. Additionally, the extant literature comparing the sustained benefits of psychodynamic treatments compared to alternative treatments is limited with methodological shortcomings. The purpose of the current study was to conduct a rigorous test of the growth of the benefits of psychodynamic treatments relative to alternative treatments across distinct domains of change (i.e., all outcome measures, targeted outcome measures, non targeted outcome measures, and personality outcome measures). To do so, the study employed strict inclusion criteria to identify randomized clinical trials that directly compared at least one bona fide psychodynamic treatment and one bona fide non-psychodynamic treatment. Hierarchical linear modeling (Raudenbush, Bryk, Cheong, Congdon, & du Toit, 2011) was used to longitudinally model the impact of psychodynamic treatments compared to non-psychodynamic treatments at post treatment and to compare the growth (i.e., slope) of effects beyond treatment completion. Findings from the present meta-analysis indicated that psychodynamic treatments and non-psychodynamic treatments were equally efficacious at post treatment and at follow-up for combined outcomes (k=20), targeted outcomes (k=19), non-targeted outcomes (k=17), and personality outcomes (k=6). Clinical implications, directions for future research, and limitations are discussed. PMID- 26042928 TI - Caruncular Leishmaniasis--An Unusual Case. AB - CASE: A 50-year-old patient presented with a left eye caruncular mass of 5-year duration. Examination revealed a fleshy mass originating from the left nasal upper and the lower lid, involving the nasal conjunctiva and the whole of the cornea. The mass was excised and histopathological examination revealed the presence of LD bodies, the hallmark feature of leishmaniasis. CONCLUSION: Ocular leishmaniasis is a potentially blinding disease and delay in diagnosis and treatment can cause irreversible damage to the eye and adnexae. Due to the uncommon occurrence of this disease, its diagnosis and treatment remains a challenge. PMID- 26042929 TI - Ethiopian population dermatoglyphic study reveals linguistic stratification of diversity. AB - The manifestation of ethnic, blood type, & gender-wise population variations regarding Dermatoglyphic manifestations are of interest to assess intra-group diversity and differentiation. The present study reports on the analysis of qualitaive and quantitative finger Dermatoglyphic traits of 382 individuals cross sectionally sampled from an administrative region of Ethiopia, consisting of five ethnic cohorts from the Afro-Asiatic & Nilo-Saharan affiliations. These Dermatoglyphic parameters were then applied in the assessment of diversity & differentiation, including Heterozygosity, Fixation, Panmixia, Wahlund's variance, Nei's measure of genetic diversity, and thumb & finger pattern genotypes, which were inturn used in homology inferences as summarized by a Neighbour-Joining tree constructed from Nei's standard genetic distance. Results revealed significant correlation between Dermatoglyphics & population parameters that were further found to be in concordance with the historical accounts of the ethnic groups. Such inductions as the ancient north-eastern presence and subsequent admixure events of the Oromos (PII= 15.01), the high diversity of the Amharas (H= 0.1978, F= 0.6453, and P= 0.4144), and the Nilo-Saharan origin of the Berta group (PII= 10.66) are evidences to this. The study has further tested the possibility of applying Dermatoglyphics in population genetic & anthropologic research, highlighting on the prospect of developing a method to trace back population origins & ancient movement patterns. Additionally, linguistic clustering was deemed significant for the Ethiopian population, coinciding with recent genome wide studies that have ascertained that linguistic clustering as to being more crucial than the geographical patterning in the Ethiopian context. Finally, Dermatoglyphic markers have been proven to be endowed with a strong potential as non-invasive preliminary tools applicable prior to genetic studies to analyze ethnically sub-divided populations and also to reveal the stratification mechanism in play. PMID- 26042930 TI - Neuropsychological investigation in Chinese patients with progressive muscular atrophy. AB - BACKGROUND: Progressive muscular atrophy (PMA) is a rare type of degenerative motor neuron disease (MND) of which the onset happens in adult period. Despite its well-defined clinical characteristics, its neuropsychological profile has remained poorly understood, considering the consensus of cognitive and behavioral impairment reached in amyotrophic lateral sclerosis (ALS). METHODS: We conducted a cross-sectional evaluation of Chinese PMA patients with a series of comprehensive batteries emphasizing the executive and attention function, and covering other domains of memory, language, visuospatial function, calculation and behavior as well. Their performances were compared with those of age- and education-matched ALS and healthy controls (HC). RESULTS: 21 patients newly diagnosed with PMA were consecutively enrolled into our ALS and other MND registry platform, accounting for 14.7% of all the incident MND cases registered during the same period. 20 patients who completed the neuropsychological batteries were included into analysis. Compared with HC, PMA performed significantly worse in maintenance function of attention, while they exhibited quantitative similarity to ALS in all behavioral inventories and neuropsychological tests except the time for Stroop interference effect. CONCLUSION: PMA could display mild cognitive dysfunction in the same frontal mediated territory of ALS but in a lesser degree, whereas they did not differ from ALS behaviorally. PMID- 26042931 TI - The Role of piRNA-Mediated Epigenetic Silencing in the Population Dynamics of Transposable Elements in Drosophila melanogaster. AB - The piwi-interacting RNAs (piRNA) are small RNAs that target selfish transposable elements (TEs) in many animal genomes. Until now, piRNAs' role in TE population dynamics has only been discussed in the context of their suppression of TE transposition, which alone is not sufficient to account for the skewed frequency spectrum and stable containment of TEs. On the other hand, euchromatic TEs can be epigenetically silenced via piRNA-dependent heterochromatin formation and, similar to the widely known "Position-effect variegation", heterochromatin induced by TEs can "spread" into nearby genes. We hypothesized that the piRNA mediated spread of heterochromatin from TEs into adjacent genes has deleterious functional effects and leads to selection against individual TEs. Unlike previously identified deleterious effects of TEs due to the physical disruption of DNA, the functional effect we investigated here is mediated through the epigenetic influences of TEs. We found that the repressive chromatin mark, H3K9me, is elevated in sequences adjacent to euchromatic TEs at multiple developmental stages in Drosophila melanogaster. Furthermore, the heterochromatic states of genes depend not only on the number of and distance from adjacent TEs, but also on the likelihood that their nearest TEs are targeted by piRNAs. These variations in chromatin status probably have functional consequences, causing genes near TEs to have lower expression. Importantly, we found stronger selection against TEs that lead to higher H3K9me enrichment of adjacent genes, demonstrating the pervasive evolutionary consequences of TE-induced epigenetic silencing. Because of the intrinsic biological mechanism of piRNA amplification, spread of TE heterochromatin could result in the theoretically required synergistic deleterious effects of TE insertions for stable containment of TE copy number. The indirect deleterious impact of piRNA-mediated epigenetic silencing of TEs is a previously unexplored, yet important, element for the evolutionary dynamics of TEs. PMID- 26042932 TI - Increasing incidence of base of tongue cancers from 2000 to 2010 due to HPV: the largest demographic study of 210 Danish patients. AB - BACKGROUND: We assessed the development in the number of new base of tongue squamous-cell carcinoma (BSCC) cases per year in eastern Denmark from 2000 to 2010 and whether HPV may explain any observable increased incidence. METHODS: We performed HPV DNA PCR and p16 immunohistochemistry analysis for all (n=210) BSCCs registered in the Danish Head and Neck Cancer Group (DAHANCA) and the Danish Pathology Data Bank, and genotyped all HPV-positive specimens with amplicon-based next-generation sequencing. RESULTS: The overall crude incidence of BSCCs increased significantly (5.4% per year) during the study period. This was explained by a significant increase in the number of HPV-positive BSCCs (8.1% per year), whereas the number of HPV-negative BSCCs did not increase significantly. The overall HPV prevalence was 51%, with HPV16 as the predominant HPV type. CONCLUSIONS: The increased number of HPV-positive BSCCs may explain the increasing incidence of BSCCs in eastern Denmark, 2000-2010. PMID- 26042933 TI - Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial. AB - BACKGROUND: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. METHODS: In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. RESULTS: The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CONCLUSION: CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent. PMID- 26042934 TI - Oncogenic CXCL10 signalling drives metastasis development and poor clinical outcome. AB - BACKGROUND: The CXCL10/CXCR3 signalling mediates paracrine interactions between tumour and stromal cells that govern leukocyte trafficking and angiogenesis. Emerging data implicate noncanonical CXCL10/CXCR3 signalling in tumourigenesis and metastasis. However, little is known regarding the role for autocrine CXCL10/CXCR3 signalling in regulating the metastatic potential of individual tumour clones. METHODS: We performed transcriptomic and cytokine profiling to characterise the functions of CXCL10 and CXCR3 in tumour cells with different metastatic abilities. We modulated the expression of the CXCL10/CXCR3 pathway using shRNA-mediated silencing in both in vitro and in vivo models of B16F1 melanoma. In addition, we examined the expression of CXCL10 and CXCR3 and their associations with clinical outcomes in clinical data sets derived from over 670 patients with melanoma and colon and renal cell carcinomas. RESULTS: We identified a critical role for autocrine CXCL10/CXCR3 signalling in promoting tumour cell growth, motility and metastasis. Analysis of publicly available clinical data sets demonstrated that coexpression of CXCL10 and CXCR3 predicted an increased metastatic potential and was associated with early metastatic disease progression and poor overall survival. CONCLUSION: These findings support the potential for CXCL10/CXCR3 coexpression as a predictor of metastatic recurrence and point towards a role for targeting of this oncogenic axis in the treatment of metastatic disease. PMID- 26042936 TI - Zwitterionic N2O2-Type Protonated Dipyrrin Bearing a Phosphate Anionic Moiety as a pH-Responsive Fluorescence Indicator. AB - Zwitterionic protonated-dipyrrin 1 bearing a phosphate unit was synthesized from the N2O2-type tetradentate dipyrrin ligand. Compound 1 is in equilibrium with the deprotonated form 1' with a pKa value of 5.8. Compound 1 exhibited a pH responsive fluorescence under physiological conditions; the fluorescence intensity increased in aqueous media as the pH increased. In living cells, 1 also exhibited emission responsive to pH. Thus, 1 should be applicable as a pH probe for detecting tumor cells. PMID- 26042937 TI - Progress with molecular electronic junctions: meeting experimental challenges in design and fabrication. AB - Molecular electronics seeks to incorporate molecular components as functional elements in electronic devices. There are numerous strategies reported to date for the fabrication, design, and characterization of such devices, but a broadly accepted example showing structure-dependent conductance behavior has not yet emerged. This progress report focuses on experimental methods for making both single-molecule and ensemble molecular junctions, and highlights key results from these efforts. Based on some general objectives of the field, particular experiments are presented to show progress in several important areas, and also to define those areas that still need attention. Some of the variable behavior of ostensibly similar junctions reported in the literature is attributable to differences in the way the junctions are fabricated. These differences are due, in part, to the multitude of methods for supporting the molecular layer on the substrate, including methods that utilize physical adsorption and covalent bonds, and to the numerous strategies for making top contacts. After discussing recent experimental progress in molecular electronics, an assessment of the current state of the field is presented, along with a proposed road map that can be used to assess progress in the future. PMID- 26042935 TI - The prioritisation of paediatrics and palliative care in cancer control plans in Africa. AB - BACKGROUND: Given the burden of childhood cancer and palliative care need in Africa, this paper investigated the paediatric and palliative care elements in cancer control plans. METHODS: We conducted a comparative content analysis of accessible national cancer control plans in Africa, using a health systems perspective attentive to context, development, scope, and monitoring/evaluation. Burden estimates were derived from World Bank, World Health Organisation, and Worldwide Palliative Care Alliance. RESULTS: Eighteen national plans and one Africa-wide plan (10 English, 9 French) were accessible, representing 9 low-, 4 lower-middle-, and 5 upper-middle-income settings. Ten plans discussed cancer control in the context of noncommunicable diseases. Paediatric cancer was mentioned in 7 national plans, representing 5127 children, or 13% of the estimated continental burden for children aged 0-14 years. Palliative care needs were recognised in 11 national plans, representing 157 490 children, or 24% of the estimated Africa-wide burden for children aged 0-14 years; four plans specified paediatric palliative needs. Palliative care was itemised in four budgets. Sample indicators and equity measures were identified, including those highlighting contextual needs for treatment access and completion. CONCLUSIONS: Recognising explicit strategies and funding for paediatric and palliative services may guide prioritised cancer control efforts in resource-limited settings. PMID- 26042938 TI - The Quest for Nanoscale Magnets: The example of [Mn12] Single Molecule Magnets. AB - Recent advances on the organization and characterization of [Mn12] single molecule magnets (SMMs) on a surface or in 3D are reviewed. By using nonconventional techniques such as X-ray magnetic circular dichroism (XMCD) and scanning tunneling microscopy (STM), it is shown that [Mn12]-based SMMs deposited on a surface lose their SMM behavior, even though the molecules seem to be structurally undamaged. A new approach is reported to get high-density information-storage devices, based on the 3D assembling of SMMs in a liquid crystalline phase. The 3D nanostructure exhibits the anisotropic character of the SMMs, thus opening the way to address micrometric volumes by two photon absorption using the pump-probe technique. We present recent developments such as u-SQUID, magneto-optical Kerr effect (MOKE), or magneto-optical circular dichroism (MOCD), which enable the characterization of SMM nanostructures with exceptional sensitivity. Further, the spin-polarized version of the STM under ultrahigh vacuum is shown to be the key tool for addressing not only single molecule magnets, but also magnetic nano-objects. PMID- 26042939 TI - One-Step Direct-Patterning Template Utilizing Self-Assembly of POSS-Containing Block Copolymers. AB - We report the self-assembly of organic-inorganic block copolymers (BCP) in thin films by simple solvent annealing on unmodified substrates. The resulting vertically oriented lamellae and cylinders are converted to a hard silica mask by a single step highly selective oxygen plasma etching. The size of the resulting nanostructures in the case of cylinders is less than 10 nm. PMID- 26042940 TI - Smart drug-loaded polymer gold nanoshells for systemic and localized therapy of human epithelial cancer. AB - Near-infrared-light-sensitive multifunctional smart drug-loaded polymer gold nanoshells are fabricated as advanced prototypes, composed of chemotherapeutic agents (therapeutic antibody and anticancer drug-loaded polymeric nanoparticles) for systemic chemotherapy of human epithelial cancer and a polymer-based gold nanoshell for localized photothermal treatment by NIR light. PMID- 26042941 TI - Thin-film fabrication method for organic light-emitting diodes using electrospray deposition. AB - A new method for fabricating micropatterns of MEH-PPV thin films with surface roughnesses below 1nm is proposed, using electrospray deposition and a dual solvent technique. The basic concept is that nanoparticles are deposited on the target substrate just before they become completely dry, by adding a solvent that has an evaporation speed relatively lower than that of the original solution. PMID- 26042942 TI - Click-engineered, bioresponsive, drug-loaded PEG spheres. AB - A click-chemistry approach to synthesize bioresponsive poly(ethylene glycol acrylate) particles is described. The particles are loaded with a model anticancer drug (doxorubicin, DOX), and undergo simultaneous particle deconstruction and DOX release upon specific activation by the simulated environment of the cellular cytoplasm. PMID- 26042943 TI - Shielding nanowires and nanotubes with imogolite: a route to nanocables. AB - The use of an imogolite (aluminosilicate) sheath to protect a conducting core consisting of a carbon nanotube (CNT) or nanowire from mechanical and chemical attacks is proposed. The cross-sectional structure of such a nanocable is shown in the figure. The most stable CNT@ imogolite nanocable is calculated to have a tube-tube distance of 2.8 A and an insertion energy of ca. 60 meV per carbon atom. PMID- 26042944 TI - Macroscopic single-walled-carbon-nanotube fiber self-assembled by dip-coating method. AB - Pure macroscopic single-walled-carbon-nanotube (SWNT) fibers are fabricated by using a dip-coating method without any additive or additional electrical equipment or complex apparatus. The present method only utilizes microfluidics, which includes capillary condensation, capillary flow, and surface tension, and results in the self-assembly and self-alignment of SWNT colloids. PMID- 26042945 TI - Fabrication of reactivated biointerface for dual-controlled reversible immobilization of cytochrome C. AB - A light or pH dual-responsive reactivated biointerface is fabricated using of photocontrolled reversible inclusion and exclusion reactions between photoresponsive azobenzene-containing self-assembled monolayer and pH-responsive poly(acrylic acid) polymer grafted with cyclodextrins. The dual-controlled reactivated biointerface can be employed for reversible immobilization of redox protein-Cytochrome c, triggered by dual external stimuli-light and pH. PMID- 26042946 TI - Photoinduced electron transfer in zinc phthalocyanine loaded on single-walled carbon nanohorns in aqueous solution. AB - Notable electronic communication within ZnPc-SWNHox nanoensembles, where ZnPc is zinc phthalocyanine and SWNHox is an oxidized single-walled nanohorn, in both the ground and excited states is revealed by steady-state absorption and fluorescence spectroscopy measurements. The details of electron transfer reported here with time-resolved absorption and fluorescence measurements may broaden the use of SWNHox nanoensembles in photochemistry and photobiology. PMID- 26042947 TI - Chemical-to-Electrical-Signal Transduction Synchronized with Smart Gel Volume Phase Transition. AB - A stimulus-responsive polymer gel designed on a field-effect transistor gate undergoes a reversible volume phase transition in response to a specific biomolecule. An abrupt permittivity change at the gel/gate interface during the transition gives rise to a chemical to electrical signal conversion; the signal is thus detectable via a transistor without the limit of the Debye length. PMID- 26042948 TI - Active control of epithelial cell-density gradients grown along the channel of an organic electrochemical transistor. AB - Complex patterning of the extracellular matrix, cells, and tissues under in situ electronic control is the aim of the technique presented here. The distribution of epithelial cells along the channel of an organic electrochemical transistor is shown to be actively controlled by the gate and drain voltages, as electrochemical gradients are formed along the transistor channel when the device is biased.. PMID- 26042949 TI - One-step exfoliation synthesis of easily soluble graphite and transparent conducting graphene sheets. AB - Easily soluble expanded graphite is synthesized in a one-step exfoliation process that can be used for the lowcost mass production of graphene for various applications because of the simplicity and speed of the process. The graphene obtained is sufficiently expanded to be dispersed in aqueous solutions with an ordinary surfactant and in organic solvents. PMID- 26042950 TI - Free-Standing Biodegradable Poly(lactic acid) Nanosheet for Sealing Operations in Surgery. AB - A free-standing biodegradable nanosheet composed of poly(L-lactic acid) (PLLA) was shown to have excellent sealing efficacy for a gastric incision as a novel wound dressing material that did not require adhesive agents, and the PLLA nanosheet-induced wound repair showed neither scars nor tissue adhesion. This material may, therefore, be an ideal alternative to conventional tissue repairing procedures using suture/ligation in surgery. PMID- 26042951 TI - A conducting-polymer platform with biodegradable fibers for stimulation and guidance of axonal growth. AB - A biosynthetic platform composed of a conducting polypyrrole sheet embedded with unidirectional biodegradable polymer fibers is described (see image; scale bar = 50 um). Such hybrid systems can promote rapid directional nerve growth for neuro regenerative scaffolds and act as interfaces between the electronic circuitry of medical bionic devices and the nervous system. PMID- 26042952 TI - Device Performance of APFO-3/PCBM Solar Cells with Controlled Morphology. AB - Polymer/fullerene solar cells with three different device structures: A) diffuse bilayer, B) spontaneously formed multilayer, and C) vertically homogenous thin films, are fabricated. The photocurrent/voltage performance is compared and it is found that the self-stratified structure (B) yields the highest energy conversion efficiency. PMID- 26042953 TI - Localized attachment of carbon nanotubes in microelectronic structures. AB - Carbon Nanotubes (CNTs) are covalently modified by the monodiadozium salt of ethylene dianiline; further diazotation of the free amino group permits the selective attachment of these CNTs to the Si or Ti bottom of SiO2 trenches. The symmetrical electrografting of the bottom of the trenches, followed by the attachment of pristine CNTs, is also described. PMID- 26042954 TI - Nerve repair: a conducting-polymer platform with biodegradable fibers for stimulation and guidance of axonal growth (adv. Mater. 43/2009). AB - Effective functional innervation of medical bionic devices, as well as re innervation of target tissue in nerve and spinal cord injuries, requires a platform that can stimulate and orientate neural growth. Gordon Wallace and co workers report on p. 4393 that conducting and nonconducting biodegradable polymers show excellent potential as suitable hybrid substrata for neural regeneration and may form the basis of electrically active conduits designed to accelerate nerve repair. PMID- 26042955 TI - New kinds of injustice for women? PMID- 26042956 TI - Neoadjuvant chemotherapy vs primary debulking surgery for advanced ovarian cancer. What is the debate regarding the ideal treatment: approach? age? or cost? PMID- 26042958 TI - Isotopic Fingerprint for Phosphorus in Drinking Water Supplies. AB - Phosphate dosing of drinking water supplies, coupled with leakage from distribution networks, represents a significant input of phosphorus to the environment. The oxygen isotope composition of phosphate (delta(18)OPO4), a novel stable isotope tracer for phosphorus, offers new opportunities to understand the importance of phosphorus derived from sources such as drinking water. We report the first assessment of delta(18)OPO4 within drinking water supplies. A total of 40 samples from phosphate-dosed distribution networks were analyzed from across England and Wales. In addition, samples of the source orthophosphoric acid used for dosing were also analyzed. Two distinct isotopic signatures for drinking water were identified (average = +13.2 or +19.70/00), primarily determined by delta(18)OPO4 of the source acid (average = +12.4 or +19.70/00). Dependent upon the source acid used, drinking water delta(18)OPO4 appears isotopically distinct from a number of other phosphorus sources. Isotopic offsets from the source acid ranging from -0.9 to +2.80/00 were observed. There was little evidence that equilibrium isotope fractionation dominated within the networks, with offsets from temperature-dependent equilibrium ranging from -4.8 to +4.20/00. While partial equilibrium fractionation may have occurred, kinetic effects associated with microbial uptake of phosphorus or abiotic sorption and dissolution reactions may also contribute to delta(18)OPO4 within drinking water supplies. PMID- 26042957 TI - Unexpected complications of low-risk pregnancies in the United States. AB - OBJECTIVE: Determining appropriate sites of care for any type of medical issue assumes successful matching of patient risks to facility capabilities and resources. In obstetrics, predicting patients who will have a need for additional resources beyond routine obstetric and neonatal care is difficult. Women without prenatal risk factors and their newborns may experience unexpected complications during delivery or postpartum. In this study, we report the risk of unexpected maternal and newborn complications among pregnancies without identified prenatal risk factors. STUDY DESIGN: We conducted a cross-sectional investigation utilizing US natality data to analyze 10 million birth certificate records from 2011 through 2013. We categorized pregnancies as low risk (no prenatal risk factors) or high risk (at least 1 prenatal risk factor) according to 19 demographic, medical, and pregnancy characteristics. We evaluated 21 individual unexpected or adverse intrapartum and postpartum outcomes in addition to a composite indicator of any adverse outcome. RESULTS: Among 10,458,616 pregnancies, 38% were identified as low risk and 62% were identified as high risk for unexpected complications. At least 1 unexpected complication was indicated on the birth certificate for 46% of all pregnancies, 29% of low-risk pregnancies, and 57% of high-risk pregnancies. While the risk for unexpected or adverse outcomes was greatly reduced for the low-risk group compared to the high-risk group overall and for several of the individual outcomes, low-risk pregnancies had higher risks of vacuum delivery, forceps delivery, meconium staining, and chorioamnionitis compared to high-risk pregnancies. CONCLUSION: Of births, 29% identified to be low risk had an unexpected complication that would require nonroutine obstetric or neonatal care. Additionally, for select outcomes, risks were higher in the low-risk group compared to the group with identified risk factors. This information is important for planning location of birth and evaluating birthing centers and hospitals for necessary resources to ensure quality care and patient safety. PMID- 26042959 TI - Access to Contraceptives in Countries With Restrictive Abortion Laws: The Case of Brazil. AB - We aimed to determine whether current contraceptive use is affected by a history of abortion for women from a country with abortion-restricted laws. This is an analysis of 2006 Brazil Demographic and Health Survey. Nonpregnant women whose first pregnancy occurred in the previous 5 years were selected for this study (n = 2,181). We used propensity score matching to compare current contraceptive use among women with induced or spontaneous abortion and women with no abortion. We found differences in the use, but women with a history of abortion did not report more effective contraceptive than women with no abortion, as we expected. PMID- 26042960 TI - A Contemporary Approach to Facial Reanimation. AB - The management of acute facial nerve insult may entail medical therapy, surgical exploration, decompression, or repair depending on the etiology. When recovery is not complete, facial mimetic function lies on a spectrum ranging from flaccid paralysis to hyperkinesis resulting in facial immobility. Through systematic assessment of the face at rest and with movement, one may tailor the management to the particular pattern of dysfunction. Interventions for long-standing facial palsy include physical therapy, injectables, and surgical reanimation procedures. The goal of the management is to restore facial balance and movement. This article summarizes a contemporary approach to the management of facial nerve insults. PMID- 26042962 TI - Tuning the Friction Characteristics of Gecko-Inspired Polydimethylsiloxane Micropillar Arrays by Embedding Fe3O4 and SiO2 Particles. AB - In order to improve stiffness of polydimethylsiloxane (PDMS) pillars while maintaining high friction, the effects of embedding Fe3O4 and SiO2 particles on the friction behavior of PDMS micropillars are studied. Both types of added particles increase the stiffness of the PDMS composite, but affect the friction behavior differently. The frictional force of the fibrillar array fabricated with Fe3O4/PDMS composite decreases initially, then increases as the particle content increases. For silica/PDMS composite pillars, the frictional force is independent of the particle density. Characterization by scanning electron microscopy shows that Fe3O4 particles are distributed uniformly in the PDMS matrix at low concentration, but heterogeneous distribution is observed at high particle loading, with particles being hindered from penetrating into the pillars. For silica/PDMS composite pillars, the particles distribute homogeneously inside the pillars, which is attributed to the formation of hydrogen bonding between silica particles and PDMS. The difference in particle distribution behavior is used to explain the observed difference in the friction response of these two composite systems. PMID- 26042961 TI - Correlations between the Electronic Properties of Shewanella oneidensis Cytochrome c Nitrite Reductase (ccNiR) and Its Structure: Effects of Heme Oxidation State and Active Site Ligation. AB - The electrochemical properties of Shewanella oneidensis cytochrome c nitrite reductase (ccNiR), a homodimer that contains five hemes per protomer, were investigated by UV-visible and electron paramagnetic resonance (EPR) spectropotentiometries. Global analysis of the UV-vis spectropotentiometric results yielded highly reproducible values for the heme midpoint potentials. These midpoint potential values were then assigned to specific hemes in each protomer (as defined in previous X-ray diffraction studies) by comparing the EPR and UV-vis spectropotentiometric results, taking advantage of the high sensitivity of EPR spectra to the structural microenvironment of paramagnetic centers. Addition of the strong-field ligand cyanide led to a 70 mV positive shift of the active site's midpoint potential, as the cyanide bound to the initially five-coordinate high-spin heme and triggered a high-spin to low-spin transition. With cyanide present, three of the remaining hemes gave rise to distinctive and readily assignable EPR spectral changes upon reduction, while a fourth was EPR-silent. At high applied potentials, interpretation of the EPR spectra in the absence of cyanide was complicated by a magnetic interaction that appears to involve three of five hemes in each protomer. At lower applied potentials, the spectra recorded in the presence and absence of cyanide were similar, which aided global assignment of the signals. The midpoint potential of the EPR-silent heme could be assigned by default, but the assignment was also confirmed by UV-vis spectropotentiometric analysis of the H268M mutant of ccNiR, in which one of the EPR-silent heme's histidine axial ligands was replaced with a methionine. PMID- 26042963 TI - Impact of cemeteries on groundwater contamination by bacteria and viruses - a review. AB - In the process of decomposition of a human body, 0.4-0.6 litres of leachate is produced per 1 kg of body weight. The leachate contains pathogenic bacteria and viruses that may contaminate the groundwater and cause disease when it is used for drinking. So far, this topic has been investigated in several regions of the world (mainly Brazil, Australia, the Republic of South Africa, Portugal, the United Kingdom and Poland). However, recently more and more attention has been focused on this issue. This study reviews the results of investigations related to the impact of cemeteries on groundwater bacteriology and virology. This topic was mainly discussed in the context of the quantities and qualities of changes in types of microorganisms causing groundwater contamination. In some cases, these changes were related to the environmental setting of a place, where a cemetery was located. The review is completed by a list of recommendations. Their implementation aims to protect the local environment, employees of funeral homes and the residents living in the vicinity of cemeteries. In this form, this review aims to familiarize the reader with the results of this topic, and provide practical guidance for decision-makers in the context of expansion and management of cemeteries, as well as the location of new ones. PMID- 26042964 TI - Sensitivity of Vermamoeba (Hartmannella) vermiformis cysts to conventional disinfectants and protease. AB - Vermamoeba vermiformis is a free-living amoeba (FLA) widely distributed in the environment, known to colonize hot water networks and to be the reservoir of pathogenic bacteria such as Legionella pneumophila. FLA are partly resistant to biocides, especially in their cyst form. The control of V. vermiformis in hot water networks represents an important health issue, but there are very few data on their resistance to disinfection treatments. The sensitivity of cysts of two strains of V. vermiformis to three disinfectants frequently used in hot water networks (chlorine, heat shock, peracetic acid (PAA) mixed with hydrogen peroxide (H2O2)) was investigated. In vitro, several concentrations of biocides, temperatures and exposure times according to the French regulation were tested. Cysts were fully inactivated by the following conditions: 15 mg/L of chlorine for 10 min; 60 degrees C for 30 min; and 0.5 g/L equivalent H2O2 of PAA mixed with H2O2 for 30 min. For the first time, the strong efficacy of subtilisin (0.625 U/mL for 24 h), a protease, to inactivate the V. vermiformis cysts has been demonstrated. It suggests that novel approaches may be efficient for disinfection processes. Finally, V. vermifomis cysts were sensitive to all the tested treatments and appeared to be more sensitive than Acanthamoeba cysts. PMID- 26042965 TI - Virulence and plasmidic resistance determinants of Escherichia coli isolated from municipal and hospital wastewater treatment plants. AB - Escherichia coli is simultaneously an indicator of water contamination and a human pathogen. This study aimed to characterize the virulence and resistance of E. coli from municipal and hospital wastewater treatment plants (WWTPs) in central Portugal. From a total of 193 isolates showing reduced susceptibility to cefotaxime and/or nalidixic acid, 20 E. coli with genetically distinct fingerprint profiles were selected and characterized. Resistance to antimicrobials was determined using the disc diffusion method. Extended spectrum beta-lactamase and plasmid-mediated quinolone resistance genes, phylogroups, pathogenicity islands (PAIs) and virulence genes were screened by polymerase chain reaction (PCR). CTX-M producers were typed by multilocus sequence typing. Resistance to beta-lactams was associated with the presence of bla(TEM), bla(SHV), bla(CTX-M-15) and bla(CTX-M-32). Plasmid-mediated quinolone resistance was associated with qnrA, qnrS and aac(6')-Ib-cr. Aminoglycoside resistance and multidrug-resistant phenotypes were also detected. PAI IV(536), PAI II(CFT073), PAI II(536) and PAI I(CFT073), and uropathogenic genes iutA, papAH and sfa/foc were detected. With regard to the clinical ST131 clone, it carried bla(CTX-M-15), blaTEM-type, qnrS and aac(6')-lb-cr; IncF and IncP plasmids, and virulence factors PAI IV(536), PAI I(CFT073), PAI II(CFT073), iutA, sfa/foc and papAH were identified in the effluent of a hospital plant. WWTPs contribute to the dissemination of virulent and resistant bacteria in water ecosystems, constituting an environmental and public health risk. PMID- 26042966 TI - Microbial indicators, pathogens and methods for their monitoring in water environment. AB - Water is critical for life, but many people do not have access to clean and safe drinking water and die because of waterborne diseases. The analysis of drinking water for the presence of indicator microorganisms is key to determining microbiological quality and public health safety. However, drinking water-related illness outbreaks are still occurring worldwide. Moreover, different indicator microorganisms are being used in different countries as a tool for the microbiological examination of drinking water. Therefore, it becomes very important to understand the potentials and limitations of indicator microorganisms before implementing the guidelines and regulations designed by various regulatory agencies. This review provides updated information on traditional and alternative indicator microorganisms with merits and demerits in view of their role in managing the waterborne health risks as well as conventional and molecular methods proposed for monitoring of indicator and pathogenic microorganisms in the water environment. Further, the World Health Organization (WHO) water safety plan is emphasized in order to develop the better approaches designed to meet the requirements of safe drinking water supply for all mankind, which is one of the major challenges of the 21st century. PMID- 26042968 TI - Bacterial growth and biofilm formation in household-stored groundwater collected from public wells. AB - The research was aimed at assessing changes in the number of bacteria and evaluating biofilm formation in groundwater collected from public wells, both aspects directly related to the methods of household storage. In the research, water collected from Cretaceous aquifer wells in Torun (Poland) was stored in a refrigerator and at room temperature. Microbiological parameters of the water were measured immediately after the water collection, and then after 3 and 7 days of storage under specified conditions. The microbiological examination involved determining the number of heterotrophic bacteria capable of growth at 22 and 37 degrees C, the number of spore-forming bacteria, and the total number of bacteria on membrane filters. The storage may affect water quality to such an extent that the water, which initially met the microbiological criteria for water intended for human consumption, may pose a health risk. The repeated use of the same containers for water storage results in biofilm formation containing live and metabolically active bacterial cells. PMID- 26042967 TI - Comparison of four beta-glucuronidase and beta-galactosidase-based commercial culture methods used to detect Escherichia coli and total coliforms in water. AB - The MI agar, Colilert((r)), Chromocult coliform((r)) agar, and DC with BCIG agar chromogenic culture-based methods used to assess microbiological quality of drinking water were compared in terms of their ubiquity, sensitivity, ease of use, growth of atypical colonies and affordability. For ubiquity, 129 total coliform (representing 76 species) and 19 Escherichia coli strains were tested. Then, 635 1-L well water samples were divided into 100 mL subsamples for testing by all four methods. Test results showed that 70.5, 52.7, 36.4, and 23.3% of the non-E. coli total coliform strains and 94.7, 94.7, 89.5, and 89.5% of the 19 E. coli strains yielded a positive signal with the four methods, respectively. They also yielded a total coliform positive signal for 66.5, 51.7, 64.9, and 55.0% and an E. coli positive signal for 16.1, 14.8, 17.3, and 13.4% of the 635 well water samples tested, respectively. Results showed that Colilert((r)) is the most expensive method tested in terms of reactants, yet it is the easiest to use. Large numbers of atypical colonies were also often observed on Chromocult coliform((r)) and DC with BCIG, thereby challenging the target microorganism count. Thus, the MI agar method seems to be the best option for the assessment of drinking water quality. PMID- 26042969 TI - Assessment of a membrane drinking water filter in an emergency setting. AB - The performance and acceptability of the Nerox(TM) membrane drinking water filter were evaluated among an internally displaced population in Pakistan. The membrane filter and a control ceramic candle filter were distributed to over 3,000 households. Following a 6-month period, 230 households were visited and filter performance and use were assessed. Only 6% of the visited households still had a functioning filter, and the removal performance ranged from 80 to 93%. High turbidity in source water (irrigation canals), together with high temperatures and large family size were likely to have contributed to poor performance and uptake of the filters. PMID- 26042970 TI - Virus removal vs. subsurface water velocity during slow sand filtration. AB - In an attempt to obtain a conservative estimate of virus removal during slow sand and river bank filtration, a somatic phage was isolated with slow decay and poor adsorption to coarse sand. We continuously fed a phage suspension to a 7-m infiltration path and measured the phage removal. In a second set of experiments, we fed the phage suspension to 1-m long columns run at different pore water velocities. Using the data obtained, a mathematical model was constructed describing removal vs. pore water velocity (PWV), assuming different statistical distributions of the adsorption coefficient lambda. The bimodal distribution best fit the results for PWVs higher than 1 m/d. It predicted a removal of approximately 4 log10 after 50 days infiltration at 1 m/d. At PWVs below 1 m/d the model underestimated removal. Sand-bound phages dissociated slowly into the liquid phase, with a detachment constant kdet of 2.6 * 10-5. This low kdet suggests that river bank filtration plants should be intermittently operated when viral overload is suspected, e.g. during flooding events or at high water-marks in rivers, in order for viruses to become soil-associated during the periods of standstill. Resuming filtration will allow only a very slow virus release from the soil. PMID- 26042971 TI - Removal of trace mercury (II) from aqueous solution by in situ MnO(x) combined with poly-aluminum chloride. AB - Removal of trace mercury from aqueous solution by Mn (hydr)oxides formed in situ during coagulation with poly-aluminum chloride (PAC) (in situ MnO(x) combined with PAC) was investigated. The efficiency of trace mercury removal was evaluated under the experimental conditions of reaction time, Mn dosage, pH, and temperature. In addition, the ionic strength and the initial mercury concentration were examined to evaluate trace mercury removal for different water qualities. The results clearly demonstrated that in situ MnO(x) combined with PAC was effective for trace mercury removal from aqueous solution. A mercury removal ratio of 9.7 MUg Hg/mg Mn was obtained at pH 3. Furthermore, at an initial mercury concentration of 30 MUg/L and pH levels of both 3 and 5, a Mn dosage of 4 mg/L was able to lower the mercury concentration to meet the standards for drinking water quality at less than 1 MUg/L. Analysis by Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy suggests that the hydroxyls on the surface of Mn (hydr)oxides are the active sites for adsorption of trace mercury from aqueous solution. PMID- 26042972 TI - Removal of natural organic matter (NOM) from an aqueous solution by NaCl and surfactant-modified clinoptilolite. AB - Zeolitic tuffs are found in different parts of the world. Iranian zeolite is a low-cost material that can be frequently found in nature. Surfactant-modified zeolite (SMZ) can be used for the adsorption of natural organic matter (NOM) from aqueous solutions. The adsorption study was conducted to evaluate the adsorption capacity of SMZ; furthermore, the effects of contact time, initial pH, and the initial adsorbent dose on the adsorption process were investigated in a batch system. The kinetic studies showed that the adsorption of NOM on SMZ was a gradual process. The optimum initial pH values for the adsorption of NOM on SMZ were in the acidic ranges. The batch kinetic experiments showed that the adsorption followed the pseudo-second-order kinetic model with good correlation coefficients. The equilibrium data were well described by the Langmuir isotherm model. The results show that the natural zeolite being modified with NaCl and hexadecyltrimethylammonium bromide as a cationic surfactant was an appropriate adsorbent for the removal of NOM. PMID- 26042973 TI - A pulsed light system for the disinfection of flow through water in the presence of inorganic contaminants. AB - The use of ultraviolet (UV) light for water disinfection has become increasingly popular due to on-going issues with drinking water and public health. Pulsed UV light has proved to be an effective form of inactivating a range of pathogens including parasite species. However, there are limited data available on the use of pulsed UV light for the disinfection of flowing water in the absence or presence of inorganic contaminants commonly found in water sources. Here, we report on the inactivation of test species including Bacillus endospores following pulsed UV treatment as a flow through system. Significant levels of inactivation were obtained for both retention times tested. The presence of inorganic contaminants iron and/or manganese did affect the rate of disinfection, predominantly resulting in an increase in the levels of inactivation at certain UV doses. The findings of this study suggest that pulsed UV light may provide a method of water disinfection as it successfully inactivated bacterial cells and bacterial endospores in the absence and presence of inorganic contaminants. PMID- 26042974 TI - Evolution of regulatory targets for drinking water quality. AB - The last century has been marked by major advances in the understanding of microbial disease risks from water supplies and significant changes in expectations of drinking water safety. The focus of drinking water quality regulation has moved progressively from simple prevention of detectable waterborne outbreaks towards adoption of health-based targets that aim to reduce infection and disease to a level well below detection limits at the community level. This review outlines the changes in understanding of community disease and waterborne risks that prompted development of these targets, and also describes their underlying assumptions and current context. Issues regarding the appropriateness of selected target values, and how continuing changes in knowledge and practice may influence their evolution, are also discussed. PMID- 26042975 TI - Evaluation of an MPN test for the rapid enumeration of Pseudomonas aeruginosa in hospital waters. AB - In this study, the performance of a new most probable number (MPN) test (Pseudalert((r))/Quanti-Tray((r))) for the enumeration of Pseudomonas aeruginosa from hospital waters was compared with both international and national membrane filtration-based culture methods for P. aeruginosa: ISO 16266:2006 and UK The Microbiology of Drinking Water - Part 8 (MoDW Part 8), which both use Pseudomonas CN agar. The comparison based on the calculation of mean relative differences between the two methods was conducted according to ISO 17994:2014. Using both routine hospital water samples (80 from six laboratories) and artificially contaminated samples (192 from five laboratories), paired counts from each sample and the enumeration method were analysed. For routine samples, there were insufficient data for a conclusive assessment, but the data do indicate at least equivalent performance of Pseudalert((r))/Quanti-Tray((r)). For the artificially contaminated samples, the data revealed higher counts of P. aeruginosa being recorded by Pseudalert((r))/Quanti-Tray((r)). The Pseudalert((r))/Quanti Tray((r)) method does not require confirmation testing for atypical strains of P. aeruginosa, saving up to 6 days of additional analysis, and has the added advantage of providing confirmed counts within 24-28 hours incubation compared to 40-48 hours or longer for the ISO 16266 and MoDW Part 8 methods. PMID- 26042976 TI - Potential health impacts of consuming desalinated bottled water. AB - This study compared physicochemical properties, anion and carbon content and major and trace elements in desalinated and non-desalinated bottled water available in Qatar, and assessed the potential health risks associated with prolonged consumption of desalinated water. Results indicate that Qatar's population is not at elevated risk of dietary exposure to As (mean = 666 ng/L), Ba (48.0 MUg/L), Be (9.27 ng/L), Cd (20.1 ng/L), Cr (874 ng/L), Pb (258 ng/L), Sb (475 ng/L) and U (533 ng/L) from consumption of both desalinated and non desalinated bottled water types available in the country. Consumers who primarily consume desalinated water brands further minimize risk of exposure to heavy metals as levels were significantly lower than in non-desalinated bottled water. Desalinated bottled water was not a significant contributor to recommended daily intakes for Ca, Mg and F(-) for adults and children and may increase risk of deficiencies. Desalinated bottled water accounted for only 3% of the Institute of Medicine (IOM) adequate intake (AI) for Ca, 5-6% of the recommended daily allowance for Mg and 4% of the AI for F among adults. For children desalinated water contributed 2-3% of the IOM AICa, 3-10% of the RDA(Mg) and 3-9% of the AIF. PMID- 26042977 TI - Performance of three pilot-scale hybrid constructed wetlands for total coliforms and Escherichia coli removal from primary effluent - a 2-year study in a subtropical climate. AB - Three pilot-scale two-stage hybrid constructed wetlands were evaluated in order to compare their efficiency for total coliforms (TCol) and Escherichia coli removal and to analyze their performances in two 1-year periods of experimentation. System I consisted of a horizontal flow (HF) constructed wetland (CW) followed by a stabilization pond. System II was also configured with a HF CW as a first stage which was then followed by a vertical flow (VF) CW as a second stage. System III was configured with a VF CW followed by a HF CW. In the first year of evaluation, the HF-VF system was the most effective for TCol removal (p < 0.05) and achieved a reduction of 2.2 log units. With regard to E. coli removal, the HF-VF and VF-HF systems were the most effective (p < 0.05) with average reductions of 3.2 and 3.8 log units, respectively. In the second year, the most effective were those with a VF component for both TCol and E. coli which underwent average reductions of 2.34-2.44 and 3.44-3.74 log units, respectively. The reduction achieved in E. coli densities, in both years, satisfy the World Health Organization guidelines that require a 3-4 log unit pathogen reduction in wastewater treatment systems. PMID- 26042978 TI - Factors affecting decay of Salmonella Birkenhead and coliphage MS2 during mesophilic anaerobic digestion and air drying of sewage sludge. AB - Factors affecting the decay of Salmonella Birkenhead and coliphage, as representatives of bacterial and viral pathogens, respectively, during mesophilic anaerobic digestion (MAD) and air drying treatment of anaerobically digested sewage sludge were investigated. Controlled concentrations of S. Birkenhead were inoculated into non-sterile, autoclaved, gamma-irradiated and nutrient supplemented sludge and cultures were incubated at 37 degrees C (MAD sludge treatment temperature) or 20 degrees C (summer air drying sludge treatment temperature). Nutrient limitation caused by microbial competition was the principal mechanism responsible for the decay of S. Birkenhead by MAD and during air drying of digested sludge. The effects of protease activity in sludge on MS2 coliphage decay in digested and air dried sludge were also investigated. MS2 coliphage showed a 3.0-3.5 log10 reduction during incubation with sludge-protease extracts at 37 degrees C for 25 h. Proteases produced by indigenous microbes in sludge potentially increase coliphage inactivation and may therefore have a significant role in the decay of enteric viruses in sewage sludge. The results help to explain the loss of viability of enteric bacteria and viral pathogens with treatment process time and contribute to fundamental understanding of the various biotic inactivation mechanisms operating in sludge treatment processes at mesophilic and ambient temperatures. PMID- 26042979 TI - Assessment of source tracking methods for application in spring water. AB - For discriminating between human and animal faecal contamination in water, microbial source tracking (MST) approaches using different indicators have been employed. In the current study, a range of 10 such MST indicators described in the scientific literature were comparatively assessed. Bacteriophages infecting host strains of Bacteroides (GA-17, GB-124 and ARABA 84) as well as sorbitol fermenting bifidobacteria proved useful for indicating human faecal contamination while Rhodococcus coprophilus was associated with animal-derived faecal contamination. These potential source indicators were present in samples of faecal origin, i.e. either in human wastewater or animal waste, from many different regions in Switzerland and therefore showed a geographic stability. In addition, the MST indicators were abundant in surface water and were even sensitive enough to detect faecal contamination in spring water from two study areas in Switzerland. This is the first study that has compared and successfully applied MST methods in spring water. PMID- 26042980 TI - Extraction, characterization and application of malva nut gum in water treatment. AB - In view of green developments in water treatment, plant-based flocculants have become the focus due to their safety, degradation and renewable properties. In addition, cost and energy-saving processes are preferable. In this study, malva nut gum (MNG), a new plant-based flocculant, and its composite with Fe in water treatment using single mode mixing are demonstrated. The result presents a simplified extraction of the MNG process. MNG has a high molecular weight of 2.3 * 105 kDa and a high negative charge of -58.7 mV. From the results, it is a strong anionic flocculant. Moreover, it is observed to have a branch-like surface structure. Therefore, it conforms to the surface of particles well and exhibits good performance in water treatment. In water treatment, the Fe-MNG composite treats water at pH 3.01 and requires a low concentration of Fe and MNG of 0.08 and 0.06 mg/L, respectively, when added to the system. It is concluded that for a single-stage flocculation process, physico-chemical properties such as molecular weight, charge of polymer, surface morphology, pH, concentration of cation and concentration of biopolymeric flocculant affect the flocculating performance. PMID- 26042981 TI - Socio-economic factors influencing the spread of drinking water diseases in rural Africa: case study of Bondo sub-county, Kenya. AB - Socio-economic and medical information on Bondo sub-county community was studied to help establish the relationship between the water quality challenges, community health and water rights conditions. Health challenges have been linked to water quality and household income. A total of 1,510 households/respondents were studied by means of a questionnaire. About 69% of the households have no access to treated water. Although 92% of the respondents appear to be aware that treatment of water prevents waterborne diseases, the lowest income group and children share a high burden of waterborne diseases requiring hospitalization and causing mortality. Open defecation (12.3%) in these study areas contributes to a high incidence of waterborne diseases. The community's constitutional rights to quality water in adequate quantities are greatly infringed. The source of low quality water is not a significant determinant of waterborne disease. The differences in poverty level in the sub-county are statistically insignificant and contribute less than other factors. Increased investment in water provision across regions, improved sanitation and availability of affordable point-of-use water purification systems will have major positive impacts on the health and economic well-being of the community. PMID- 26042982 TI - Risk assessment and water safety plan: case study in Beijing, China. AB - Two typical rural water utilities in Beijing, China were chosen to describe the principles and applications of water safety plans (WSP), to provide a methodological guide for the actual application and improve the quality of rural drinking water quality, and to establish an appropriate method for WSP applied in rural water supply. Hazards and hazardous events were identified and risk assessment was conducted for rural water supply systems. A total of 13 and 12 operational limits were defined for two utilities, respectively. The main risk factors that affect the water safety were identified in water sources, water processes, water disinfection systems and water utility management. The main control measures were strengthening the water source protection, monitoring the water treatment processes, establishing emergency mechanisms, improving chemical input and operating system management. WSP can be feasibly applied to the management of a rural water supply. PMID- 26042983 TI - Determination of total vanadium and vanadium(V) in groundwater from Mt. Etna and estimate of daily intake of vanadium(V) through drinking water. AB - Vanadium(V) can be found in natural waters in the form of V(IV) and V(V) species, which have different biological properties and toxicity. The purpose of this study was to determine the concentrations of total V and V(V) in groundwater from the area of Mt. Etna and to assess the estimated daily intake (EDI) of V(V) of adults and children through drinking water. Water was sampled monthly at 21 sites in 2011. Total vanadium was determined by inductively coupled plasma-mass spectrometry (ICP-MS) and speciation by ion chromatography-ICP-MS (IC-ICP-MS). The concentration of V(V) species ranged from 62.8 to 98.9% of total V, with significantly higher concentrations in samples from the S/SW slope of Mt. Etna. The annual mean concentrations of total V exceeded the Italian legal limit of 140 MUg/L at four sites on the S/SW slope. In the absence of thresholds for V(V) intake, only the Environmental Protection Agency (EPA) has calculated a reference dose. Children's EDI of V(V) at the sites with the higher V concentrations exceeded EPA thresholds (9 MUg/kg/day). In particular, we found in Camporotondo, Mascalucia, Ragalna and San Pietro Clarenza sites children's EDIs of 11, 9.3, 11 and 9.9, respectively. The EDI of V(V) was significantly higher than the literature range (0.09-0.34 MUg/kg/day). PMID- 26042984 TI - Swimming in the USA: beachgoer characteristics and health outcomes at US marine and freshwater beaches. AB - Swimming in lakes and oceans is popular, but little is known about the demographic characteristics, behaviors, and health risks of beachgoers on a national level. Data from a prospective cohort study of beachgoers at multiple marine and freshwater beaches in the USA were used to describe beachgoer characteristics and health outcomes for swimmers and non-swimmers. This analysis included 54,250 participants. Most (73.2%) entered the water; of those, 65.1% put their head under water, 41.3% got water in their mouth and 18.5% swallowed water. Overall, 16.3% of beachgoers reported any new health problem. Among swimmers, 6.6% reported gastrointestinal (GI) illness compared with 5.5% of non-swimmers (unadjusted chi2 p < 0.001); 6.0% of swimmers and 4.9% of non-swimmers reported respiratory illness (p < 0.001); 1.8% of swimmers and 1.0% of non-swimmers reported ear problems (p < 0.001); and 3.9% of swimmers and 2.4% of non-swimmers experienced a rash (p < 0.001). Overall, swimmers reported a higher unadjusted incidence of GI illness and earaches than non-swimmers. Current surveillance systems might not detect individual cases and outbreaks of illness associated with swimming in natural water. Better knowledge of beachgoer characteristics, activities, and health risks associated with swimming in natural water can improve disease surveillance and prioritize limited resources. PMID- 26042985 TI - Point-of-use chlorination of turbid water: results from a field study in Tanzania. AB - Household-based chlorine disinfection is widely effective against waterborne bacteria and viruses, and may be among the most inexpensive and accessible options for household water treatment. The microbiological effectiveness of chlorine is limited, however, by turbidity. In Tanzania, there are no guidelines on water chlorination at household level, and limited data on whether dosing guidelines for higher turbidity waters are sufficient to produce potable water. This study was designed to assess the effectiveness of chlorination across a range of turbidities found in rural water sources, following local dosing guidelines that recommend a 'double dose' for water that is visibly turbid. We chlorinated water from 43 sources representing a range of turbidities using two locally available chlorine-based disinfectants: WaterGuard and Aquatabs. We determined free available chlorine at 30 min and 24 h contact time. Our data suggest that water chlorination with WaterGuard or Aquatabs can be effective using both single and double doses up to 20 nephelometric turbidity units (NTU), or using a double dose of Aquatabs up to 100 NTU, but neither was effective at turbidities greater than 100 NTU. PMID- 26042986 TI - The presence of opportunistic pathogens, Legionella spp., L. pneumophila and Mycobacterium avium complex, in South Australian reuse water distribution pipelines. AB - Water reuse has become increasingly important for sustainable water management. Currently, its application is primarily constrained by the potential health risks. Presently there is limited knowledge regarding the presence and fate of opportunistic pathogens along reuse water distribution pipelines. In this study opportunistic human pathogens Legionella spp., L. pneumophila and Mycobacterium avium complex were detected using real-time polymerase chain reaction along two South Australian reuse water distribution pipelines at maximum concentrations of 105, 103 and 105 copies/mL, respectively. During the summer period of sampling the concentration of all three organisms significantly increased (P < 0.05) along the pipeline, suggesting multiplication and hence viability. No seasonality in the decrease in chlorine residual along the pipelines was observed. This suggests that the combination of reduced chlorine residual and increased water temperature promoted the presence of these opportunistic pathogens. PMID- 26042987 TI - Water-related factors and childhood diarrhoea in African informal settlements. A cross-sectional study in Ouagadougou (Burkina Faso). AB - Improved access to water is a key factor in reducing diarrhoeal diseases, a leading cause of death among children in sub-Saharan Africa. In terms of water access, sub-Saharan African cities are some of the worst off in the world, with 20% of populations supplied by an unimproved water source. This situation is even worse in informal settlement areas. Using cross-sectional data on access to water from a survey implemented in three informal neighbourhoods of the Ouagadougou Health and Demographic Surveillance System, logistic regressions are modelled to test the effect of different modalities of access to water on childhood diarrhoea. Our results show that the prevalence of diarrhoea in children is high: one-third of households with a child under 10 experienced an episode of childhood diarrhoea during the 2 weeks preceding the survey, even though 91% of the households surveyed have access to an improved water source. The results show that efforts to reduce childhood morbidity would be greatly enhanced by strengthening piped water access in informal settlement areas in Africa. In addition, this study confirms that, beyond the single measure of the main access to water, accurate variables that assess the accessibility to water are needed. PMID- 26042988 TI - Elevated levels of iron in groundwater in Prey Veng province in Cambodia: a possible factor contributing to high iron stores in women. AB - Iron is a natural element found in food, water and soil and is essential for human health. Our aim was to determine the levels of iron and 25 other metals and trace elements in groundwater from 22 households in Prey Veng, Cambodia. Water analyses were conducted using inductively coupled plasma-mass spectrometry and optical emission spectrometry. Compared to the 2011 World Health Organization guidelines for drinking water quality, aluminum, iron and manganese exceeded maximum levels (in 4.5, 72.7 and 40.9% of samples, respectively). Compared to the 2004 Cambodian drinking water quality standards, iron and manganese exceeded maximum levels (in 59.1 and 36.4% of samples, respectively). We found no evidence of arsenic contamination. Guidelines for iron were established primarily for esthetic reasons (e.g. taste), whereas other metals and elements have adverse effects associated with toxicity. Iron in groundwater ranged from 134 to 5,200 MUg/L (mean ~1,422 MUg/L). Based on a daily consumption of 3 L groundwater, this equates to ~0.4-15.6 mg iron (mean ~4.3 mg/day), which may be contributing to high iron stores and the low prevalence of iron deficiency anemia in Prey Veng women. Elevated levels of manganese in groundwater are a concern and warrant further investigation. PMID- 26042989 TI - Critical parameters in the production of ceramic pot filters for household water treatment in developing countries. AB - The need to improve the access to safe water is generally recognized for the benefit of public health in developing countries. This study's objective was to identify critical parameters which are essential for improving the performance of ceramic pot filters (CPFs) as a point-of-use water treatment system. Defining critical production parameters was also relevant to confirm that CPFs with high flow rates may have the same disinfection capacity as pots with normal flow rates. A pilot unit was built in Cambodia to produce CPFs under controlled and constant conditions. Pots were manufactured from a mixture of clay, laterite and rice husk in a small-scale, gas-fired, temperature-controlled kiln and tested for flow rate, removal efficiency of bacteria and material strength. Flow rate can be increased by increasing pore sizes and by increasing porosity. Pore sizes were increased by using larger rice husk particles and porosity was increased with larger proportions of rice husk in the clay mixture. The main conclusions: larger pore size decreases the removal efficiency of bacteria; higher porosity does not affect the removal efficiency of bacteria, but does influence the strength of pots; flow rates of CPFs can be raised to 10-20 L/hour without a significant decrease in bacterial removal efficiency. PMID- 26042990 TI - Cryptosporidium genotypes and subtypes distribution in river water in Iran. AB - Little is known about the diversity and public health significance of Cryptosporidium species in river waters in Iran. In the present study, we determined the genotype and subtype distribution of Cryptosporidium spp. in river water samples in Iran. A total of 49 surface water samples were collected from rivers and surface water in Guilan and Tehran provinces during 2009-2010. Water samples were filtrated through a 1.2-MUm pore size membrane filter or by Filta Max filter followed by immunomagnetic separation or sucrose purification methods. Genotype and subtype of Cryptosporidium were identified by sequence analysis of the 18S rRNA and 60 kDa glycoprotein (gp60) genes, respectively. A total of 24 (48.97%) water samples were positive for Cryptosporidium species by the 18sRNA based polymerase chain reaction (PCR)-sequencing technique. DNA sequencing revealed the presence of five species of Cryptosporidium (C. parvum, C. hominis, C. muris, C. andersoni, and C. canis) in the water samples of the study area and, to our knowledge, the first report of C. muris in Iran. The results of GP60 gene analysis showed that all C. parvum and C. hominis isolates belonged to the IId and Id subtype families, respectively. The investigated river water supplies were heavily contaminated by pathogenic species of Cryptosporidium from humans and livestock. There is potential risk of waterborne cryptosporidiosis in humans and animals. PMID- 26042991 TI - Microbial quality of improved drinking water sources: evidence from western Kenya and southern Vietnam. AB - In recent decades, more than 2 billion people have gained access to improved drinking water sources thanks to extensive effort from governments, and public and private sector entities. Despite this progress, many water sector development interventions do not provide access to safe water or fail to be sustained for long-term use. The authors examined drinking water quality of previously implemented water improvement projects in three communities in western Kenya and three communities in southern Vietnam. The cross-sectional study of 219 households included measurements of viable Escherichia coli. High rates of E. coli prevalence in these improved water sources were found in many of the samples. These findings suggest that measures above and beyond the traditional 'improved source' definition may be necessary to ensure truly safe water throughout these regions. PMID- 26042992 TI - Occurrence of bacteriophages infecting Aeromonas, Enterobacter, and Klebsiella in water and association with contamination sources in Thailand. AB - The co-residence of bacteriophages and their bacterial hosts in humans, animals, and environmental sources directed the use of bacteriophages to track the origins of the pathogenic bacteria that can be found in contaminated water. The objective of this study was to enumerate bacteriophages of Aeromonas caviae (AecaKS148), Enterobacter sp. (EnspKS513), and Klebsiella pneumoniae (KlpnKS648) in water and evaluate their association with contamination sources (human vs. animals). Bacterial host strains were isolated from untreated wastewater in Bangkok, Thailand. A double-layer agar technique was used to detect bacteriophages. All three bacteriophages were detected in polluted canal samples, with likely contamination from human wastewater, whereas none was found in non-polluted river samples. AecaKS148 was found to be associated with human fecal sources, while EnspKS513 and KlpnKS648 seemed to be equally prevalent in both human and animal fecal sources. Both bacteriophages were also present in polluted canals that could receive contamination from other fecal sources or the environment. In conclusion, all three bacteriophages were successfully monitored in Bangkok, Thailand. This study provided an example of bacteriophages for potential use as source identifiers of pathogen contamination. The results from this study will assist in controlling sources of pathogen contamination, especially in developing countries. PMID- 26042993 TI - Biomarkers of insulin sensitivity and insulin resistance: Past, present and future. AB - Insulin resistance in insulin target tissues including liver, skeletal muscle and adipose tissue is an early step in the progression towards type 2 diabetes. Accurate diagnostic parameters reflective of insulin resistance are essential. Longstanding tests for fasting blood glucose and HbA1c are useful and although the hyperinsulinemic euglycemic clamp remains a "gold standard" for accurately determining insulin resistance, it cannot be implemented on a routine basis. The study of adipokines, and more recently myokines and hepatokines, as potential biomarkers for insulin sensitivity is now an attractive and relatively straightforward approach. This review discusses potential biomarkers including adiponectin, RBP4, chemerin, A-FABP, FGF21, fetuin-A, myostatin, IL-6, and irisin, all of which may play significant roles in determining insulin sensitivity. We also review potential future directions of new biological markers for measuring insulin resistance, including metabolomics and gut microbiome. Collectively, these approaches will provide clinicians with the tools for more accurate, and perhaps personalized, diagnosis of insulin resistance. PMID- 26042994 TI - Networks: On the relation of bi- and multivariate measures. AB - A reliable inference of networks from observations of the nodes' dynamics is a major challenge in physics. Interdependence measures such as a the correlation coefficient or more advanced methods based on, e.g., analytic phases of signals are employed. For several of these interdependence measures, multivariate counterparts exist that promise to enable distinguishing direct and indirect connections. Here, we demonstrate analytically how bivariate measures relate to the respective multivariate ones; this knowledge will in turn be used to demonstrate the implications of thresholded bivariate measures for network inference. Particularly, we show, that random networks are falsely identified as small-world networks if observations thereof are treated by bivariate methods. We will employ the correlation coefficient as an example for such an interdependence measure. The results can be readily transferred to all interdependence measures partializing for information of thirds in their multivariate counterparts. PMID- 26042995 TI - Meiosis completion and various sperm responses lead to unisexual and sexual reproduction modes in one clone of polyploid Carassius gibelio. AB - Unisexual polyploid vertebrates are commonly known to reproduce by gynogenesis, parthenogenesis, or hybridogenesis. One clone of polyploid Carassius gibelio has been revealed to possess multiple modes of unisexual gynogenesis and sexual reproduction, but the cytological and developmental mechanisms have remained unknown. In this study, normal meiosis completion was firstly confirmed by spindle co-localization of beta-tubulin and Spindlin. Moreover, three types of various nuclear events and development behaviors were revealed by DAPI staining and BrdU-incorporated immunofluorescence detection during the first mitosis in the fertilized eggs by three kinds of different sperms. They include normal sexual reproduction in response to sperm from the same clone male, typical unisexual gynogenesis in response to sperm from the male of another species Cyprinus carpio, and an unusual hybrid-similar development mode in response to sperm from another different clone male. Based on these findings, we have discussed cytological and developmental mechanisms on multiple reproduction modes in the polyploid fish, and highlighted evolutionary significance of meiosis completion and evolutionary consequences of reproduction mode diversity in polyploid vertebrates. PMID- 26042998 TI - Resampling method for applying density-dependent habitat selection theory to wildlife surveys. AB - Isodar theory can be used to evaluate fitness consequences of density-dependent habitat selection by animals. A typical habitat isodar is a regression curve plotting competitor densities in two adjacent habitats when individual fitness is equal. Despite the increasing use of habitat isodars, their application remains largely limited to areas composed of pairs of adjacent habitats that are defined a priori. We developed a resampling method that uses data from wildlife surveys to build isodars in heterogeneous landscapes without having to predefine habitat types. The method consists in randomly placing blocks over the survey area and dividing those blocks in two adjacent sub-blocks of the same size. Animal abundance is then estimated within the two sub-blocks. This process is done 100 times. Different functional forms of isodars can be investigated by relating animal abundance and differences in habitat features between sub-blocks. We applied this method to abundance data of raccoons and striped skunks, two of the main hosts of rabies virus in North America. Habitat selection by raccoons and striped skunks depended on both conspecific abundance and the difference in landscape composition and structure between sub-blocks. When conspecific abundance was low, raccoons and striped skunks favored areas with relatively high proportions of forests and anthropogenic features, respectively. Under high conspecific abundance, however, both species preferred areas with rather large corn-forest edge densities and corn field proportions. Based on random sampling techniques, we provide a robust method that is applicable to a broad range of species, including medium- to large-sized mammals with high mobility. The method is sufficiently flexible to incorporate multiple environmental covariates that can reflect key requirements of the focal species. We thus illustrate how isodar theory can be used with wildlife surveys to assess density-dependent habitat selection over large geographic extents. PMID- 26043000 TI - Updated global burden of cholera in endemic countries. AB - BACKGROUND: The global burden of cholera is largely unknown because the majority of cases are not reported. The low reporting can be attributed to limited capacity of epidemiological surveillance and laboratories, as well as social, political, and economic disincentives for reporting. We previously estimated 2.8 million cases and 91,000 deaths annually due to cholera in 51 endemic countries. A major limitation in our previous estimate was that the endemic and non-endemic countries were defined based on the countries' reported cholera cases. We overcame the limitation with the use of a spatial modelling technique in defining endemic countries, and accordingly updated the estimates of the global burden of cholera. METHODS/PRINCIPAL FINDINGS: Countries were classified as cholera endemic, cholera non-endemic, or cholera-free based on whether a spatial regression model predicted an incidence rate over a certain threshold in at least three of five years (2008-2012). The at-risk populations were calculated for each country based on the percent of the country without sustainable access to improved sanitation facilities. Incidence rates from population-based published studies were used to calculate the estimated annual number of cases in endemic countries. The number of annual cholera deaths was calculated using inverse variance-weighted average case-fatality rate (CFRs) from literature-based CFR estimates. We found that approximately 1.3 billion people are at risk for cholera in endemic countries. An estimated 2.86 million cholera cases (uncertainty range: 1.3m-4.0m) occur annually in endemic countries. Among these cases, there are an estimated 95,000 deaths (uncertainty range: 21,000-143,000). CONCLUSION/SIGNIFICANCE: The global burden of cholera remains high. Sub-Saharan Africa accounts for the majority of this burden. Our findings can inform programmatic decision-making for cholera control. PMID- 26042999 TI - Transcriptional landscape of trans-kingdom communication between Candida albicans and Streptococcus gordonii. AB - Recent studies have shown that the transcriptional landscape of the pleiomorphic fungus Candida albicans is highly dependent upon growth conditions. Here using a dual RNA-seq approach we identified 299 C. albicans and 72 Streptococcus gordonii genes that were either upregulated or downregulated specifically as a result of co-culturing these human oral cavity microorganisms. Seventy-five C. albicans genes involved in responses to chemical stimuli, regulation, homeostasis, protein modification and cell cycle were significantly (P <= 0.05) upregulated, whereas 36 genes mainly involved in transport and translation were downregulated. Upregulation of filamentation-associated TEC1 and FGR42 genes, and of ALS1 adhesin gene, concurred with previous evidence that the C. albicans yeast to hypha transition is promoted by S. gordonii. Increased expression of genes required for arginine biosynthesis in C. albicans was potentially indicative of a novel oxidative stress response. The transcriptional response of S. gordonii to C. albicans was less dramatic, with only eight S. gordonii genes significantly (P <= 0.05) upregulated at least two-fold (glpK, rplO, celB, rplN, rplB, rpsE, ciaR and gat). The expression patterns suggest that signals from S. gordonii cause a positive filamentation response in C. albicans, whereas S. gordonii appears to be transcriptionally less influenced by C. albicans. PMID- 26043002 TI - The Clinical Course of Intermittent Exotropia With Small Initial Deviation. AB - PURPOSE: To address the clinical course of patients who initially presented with small exodeviation (>= 10 and <= 18 prism diopters [PD]) and to investigate the risk factors associated with progression. METHODS: The clinical records of patients who were first diagnosed as having intermittent exotropia of small initial deviation from August 2008 to March 2011 and were followed up for 2 or more years were reviewed retrospectively. The initial clinical features associated with the risk of disease progression and surgical intervention were analyzed. RESULTS: Among 86 patients who met the inclusion criteria, 37 reached a distance deviation of 20 PD or greater and 51 underwent surgical correction for exodeviation during the follow-up. Cumulative percentages of patients whose distance deviation reached 20 PD or greater and who underwent surgery at 24 months were 47.5% and 47.7%, respectively. Mean initial stereoacuity was significantly worse in patients whose final exodeviation progressed to 20 PD or greater. The cumulative probability of surgery was significantly higher in patients who showed constant deviation at the initial examination. CONCLUSIONS: Nearly half of patients with small exodeviation are expected to reach a final distance deviation of 20 PD or greater or to undergo surgery after 2 years of follow-up. Initial constant deviation was associated with increased cumulative probability of surgical intervention. PMID- 26043003 TI - Trends in Pediatric Versus Adult Ophthalmology Publications Over 15 Years. AB - PURPOSE: To evaluate and compare trends in different categories of pediatric and adult ophthalmology publications. METHODS: Publications in ophthalmology between January 1, 1998, and December 31, 2012, were retrieved from PubMed. An age filter separated pediatric from adult articles. RESULTS: There was a significant linear increase in the number of publications in both pediatric and adult publications. There was an increase over time in pediatric and adult clinical trials, letters to the editor, meta-analyses, and systematic reviews. There was a significant increase in adult randomized controlled trials only. No meaningful statistical analyses could be conducted for practice guidelines. CONCLUSIONS: Pediatric and adult ophthalmology have demonstrated a significant increase in annual published articles. Practicing ophthalmologists have an increasing number of articles to read and might become more and more dependent on search engines and reviews to remain informed, emphasizing the need for official practice guidelines that are, unfortunately, seldom published. PMID- 26043001 TI - Genome-Wide Collation of the Plasmodium falciparum WDR Protein Superfamily Reveals Malarial Parasite-Specific Features. AB - Despite a significant drop in malaria deaths during the past decade, malaria continues to be one of the biggest health problems around the globe. WD40 repeats (WDRs) containing proteins comprise one of the largest and functionally diverse protein superfamily in eukaryotes, acting as scaffolds for assembling large protein complexes. In the present study, we report an extensive in silico analysis of the WDR gene family in human malaria parasite Plasmodium falciparum. Our genome-wide identification has revealed 80 putative WDR genes in P. falciparum (PfWDRs). Five distinct domain compositions were discovered in Plasmodium as compared to the human host. Notably, 31 PfWDRs were annotated/re annotated on the basis of their orthologs in other species. Interestingly, most PfWDRs were larger as compared to their human homologs highlighting the presence of parasite-specific insertions. Fifteen PfWDRs appeared specific to the Plasmodium with no assigned orthologs. Expression profiling of PfWDRs revealed a mixture of linear and nonlinear relationships between transcriptome and proteome, and only nine PfWDRs were found to be stage-specific. Homology modeling identified conservation of major binding sites in PfCAF-1 and PfRACK. Protein protein interaction network analyses suggested that PfWDRs are highly connected proteins with ~1928 potential interactions, supporting their role as hubs in cellular networks. The present study highlights the roles and relevance of the WDR family in P. falciparum, and identifies unique features that lay a foundation for further experimental dissection of PfWDRs. PMID- 26043004 TI - The Optical Performance of Spherical and Aspheric Intraocular Lenses in Pediatric Eyes: A Comparative Study. AB - PURPOSE: To compare the optical performance of aspheric intraocular lenses (IOLs) designed to correct the corneal spherical aberration versus spherical IOLs in pediatric eyes after cataract surgery. METHODS: In this prospective study, 40 eyes of patients 6 to 16 years old with developmental cataract were randomly assigned to receive a spherical IOL or an aspheric IOL after pediatric cataract surgery. At 3 months postoperatively, the outcomes compared between the two groups were best-corrected visual acuity, contrast sensitivity, and wavefront aberrometry. RESULTS: The mean best-corrected visual acuity was 0.32 +/- 0.19 logMAR in the spherical IOL group and 0.28 +/- 0.16 logMAR in the aspheric IOL group (P = .179). The aspheric IOL group showed better contrast sensitivity at 1.5, 3, and 6 cycles per degree than the spherical IOL group (P < .05). Total ocular aberrations, higher-order aberrations, and spherical aberrations were significantly lower in the aspheric IOL group (P < .05). CONCLUSIONS: The results suggest that aspheric IOLs compensate for the spherical aberration of pediatric eyes. In comparison to spherical IOLs, eyes with aspheric IOLs had decreased ocular aberrations, particularly spherical aberration, which contributed to better contrast sensitivity in these eyes. Further studies are required to evaluate the role of aspheric IOLs in children. PMID- 26043005 TI - Correction: Diurnal and seasonal variations in carbon dioxide exchange in ecosystems in the Zhangye Oasis area, northwest China. PMID- 26043008 TI - Ensuring good end-of-life care. PMID- 26043006 TI - Analgesic Effect of Electroacupuncture in a Mouse Fibromyalgia Model: Roles of TRPV1, TRPV4, and pERK. AB - Fibromyalgia (FM) is among the most common chronic pain syndromes encountered in clinical practice, but there is limited understanding of FM pathogenesis. We examined the contribution of transient receptor potential vanilloid 1 (TRPV1) and TRPV4 channels to chronic pain in the repeated acid injection mouse model of FM and the potential therapeutic efficacy of electroacupuncture. Electroacupuncture (EA) at the bilateral Zusanli (ST36) acupoint reduced the long-lasting mechanical hyperalgesia induced by repeated acid saline (pH 4) injection in mouse hindpaw. Isolated L5 dorsal root ganglion (DRG) neurons from FM model mice (FM group) were hyperexcitable, an effect reversed by EA pretreatment (FM + EA group). The increase in mechanical hyperalgesia was also accompanied by upregulation of TRPV1 expression and phosphoactivation of extracellular signal regulated kinase (pERK) in the DRG, whereas DRG expression levels of TRPV4, p-p38, and p-JNK were unaltered. Blockade of TRPV1, which was achieved using TRPV1 knockout mice or via antagonist injection, and pERK suppressed development of FM-like pain. Both TRPV1 and TRPV4 protein expression levels were increased in the spinal cord (SC) of model mice, and EA at the ST36 acupoint decreased overexpression. This study strongly suggests that DRG TRPV1 overexpression and pERK signaling, as well as SC TRPV1 and TRPV4 overexpression, mediate hyperalgesia in a mouse FM pain model. The therapeutic efficacy of EA may result from the reversal of these changes in pain transmission pathways. PMID- 26043007 TI - Energetic Calculations to Decipher pH-Dependent Oligomerization and Domain Swapping of Proteins. AB - Domain swapping mechanism is a specialised mode of oligomerization of proteins in which part of a protein is exchanged in a non-covalent manner between constituent subunits. This mechanism is highly affected by several physiological conditions. Here, we present a detailed analysis ofthe effect of pH on different regions of the domain swapped oligomer by considering examples which are known to be sensitive to pH in transiting from monomeric to domain-swapped dimeric form. The energetic calculations were performed using a specialized method which considers changes in pH and subsequent changes in the interactions between subunits. This analysis provides definitive hints about the pH-dependence switch from monomer to domain-swapped oligomer and the steps that may be involved in the swapping mechanism. PMID- 26043009 TI - Shaping future delivery of care: district nurses seizing the day! PMID- 26043010 TI - Assessing and treating urinary incontinence in men. PMID- 26043011 TI - Analysing the role played by district and community nurses in bereavement support. AB - This article explores bereavement support as one of the roles of the district nurse (DN) and community nurse (CN). Bereavement support is considered part of palliative care, which is a major role for all nurses. There is, however, a constant move to increase acute care in the home, questionably placing greater demand on DNs/CNs and primary care provision. Discussion in this article is framed around research into bereavement care in the community, existing guidelines, and policy drivers stressing its importance. Bereavement can result in depression, stress-related disorders, and high mortality; it is therefore imperative to understand the complexities, theoretical aspects, and implications of poor service provision. Palliative care is one of the primary roles of a DN, and it largely involves emotional support. It has been shown that DNs lack confidence and the skills to provide bereavement support to families and carers of palliative care patients. Education, training, and time management are the main determinants of effective bereavement support. The need is to develop a standard collaborative approach to bereavement support and incorporate it into the palliative care role of DNs. PMID- 26043012 TI - Working toward building carer-friendly communities. PMID- 26043013 TI - Informal carers' experiences of caring for older adults at home: a phenomenological study. AB - Informal carers provide vital input to maintain the health and social care needs of older adults. A more in-depth understanding of the experiences of informal carers, their value to society, and the support required to assist them is necessary to ensure the future care of older adults. The aim of this study is to explore the experiences of informal carers in Ireland and to identify the support required in caring for older adults at home. Informal carers' experiences are critically discussed under four main themes: time is not your own, duty of care, burden of caring, and support for informal carers. It is evident that informal carers of older adults provide the majority of care in the home with inconsistent or no support. Strategies to support carers have been identified but now require a uniform implementation that must be translated into practice. PMID- 26043014 TI - Managing lower limb oedema with compression therapy. PMID- 26043015 TI - Nurses' health behaviours and physical activity-related health-promotion practices. AB - Many registered nurses (RNs) are not achieving the recommended daily levels of physical activity. This study collected data from 623 RNs about their personal health behaviours and their professional, physical activity-related health promotion practices. The findings showed that 75% of the sample reported engaging in personal physical activity, 25% were at risk of hazardous drinking or active alcohol use disorders, 17% were past smokers and 11% were current smokers, 47% reported having a normal body weight-size, and 73% desired to be a normal body weight-size. Nearly half of the sample reported that they were promoting physical activity within their clinical practice. Personal physical activity behaviour, perceived health status, length of clinical practice, clinical specialty, and actual body weight-size were significantly related to the RNs' professional, physical activity-related practices. This study highlights a need for training on physical activity-related counselling, including awareness of the latest recommendations and strategies to promote physical activity. Health-care employers should also consider addressing nurses' barriers to the promotion of physical activity within their clinical practice so that all health-care contacts are able to maximise opportunities to promote active ageing. PMID- 26043016 TI - Nurse collaboration in community and psychiatric care: a Swedish study. AB - AIM: The aim of the study was to examine registered nurses' (RNs) experiences of collaboration in the community health care and psychiatric inpatient care systems. BACKGROUND: RNs in one area in the west of Sweden have indicated the need for collaborative routines between the community health care and psychiatric inpatient care systems. METHOD: Qualitative content analysis of focus group interviews. RESULTS: RNs felt the web-based health-care communication programme was a major obstacle to the development of a collaboration plan. The poor collaboration between RNs was due to the absence of knowledge about the duties of each nursing team. CONCLUSION: The findings contribute to the understanding of the barriers to collaboration between RNs in community health care and psychiatric inpatient care, and highlight the need for nurse managers to ensure well-functioning routines. PMID- 26043017 TI - Understanding the Code: scope of the duty of confidentiality. AB - In a series explaining the law underpinning the Nursing and Midwifery Council's revised Code (2015), this month's article considers the scope of a district nurse's duty of confidence. The article explains how three areas of law are drawn together to provide maximum protection against inappropriate disclosure of sensitive health information. PMID- 26043018 TI - Engaging in reminiscence with palliative care patients. PMID- 26043019 TI - Achieving effective dementia care in the community. PMID- 26043020 TI - Rising health-care costs within limited resources. PMID- 26043021 TI - Daily methotrexate can be lethal! PMID- 26043022 TI - Monosomal karyotype predicts inferior survival independently of a complex karyotype in patients with myelodysplastic syndromes. AB - BACKGROUND: Conflicting data exist about the impact of a monosomal karyotype (MK) on overall survival (OS) for patients with myelodysplastic syndromes (MDSs) and particularly for those with a complex karyotype (CK). This study was aimed at determining whether an MK is associated with OS independently of the number of cytogenetic abnormalities (CAs) in a population-based MDS cohort. METHODS: Cancer registry data on incident MDS cases were linked with cytogenetic data and hospital administrative data from 2000 to 2010 for the Australian state of Victoria. RESULTS: Between 2000 and 2010, 1404 incident MDS cases with cytogenetic results were identified. A CK, defined as 3 or more abnormalities, was present in 126 (9%). A very complex karyotype (vCK), defined as 5 or more abnormalities, was present in 95 (7%). An MK was associated with worse OS in the whole cohort (median 6 vs 39 months, P < 0.001) including those with a coexisting CK (6 vs 17 months, P < 0.001) or vCK (6 vs 9 months, P = 0.02). After adjustments for the number of CAs, an MK remained independently associated with OS, although its effect size decreased with increasing cytogenetic complexity (hazard ratio for an MK, 4.81; 95% confidence interval, 3.08-7.52; hazard ratio for the number of CAs, 1.22; 95% confidence interval, 1.15-1.30; and hazard ratio for the interaction between an MK and CAs, 0.83; 95% confidence interval, 0.77 0.89). CONCLUSIONS: These results support the clinical utility of an MK as an independent predictor of adverse outcomes for MDS patients, even among CK and vCK groups, although its prognostic effect decreases with increasing cytogenetic complexity. PMID- 26043023 TI - Correction: The Impact of Gender Norms on Condom Use among HIV-Positive Adults in KwaZulu-Natal, South Africa. PMID- 26043024 TI - A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells. AB - Multiple myeloma (MM) is the paradigmatic proteasome inhibitor (PI) responsive cancer, but many patients fail to respond. An attractive target to enhance sensitivity is (macro)autophagy, recently found essential to bone marrow plasma cells, the normal counterpart of MM. Here, integrating proteomics with hypothesis driven strategies, we identified the autophagic cargo receptor and adapter protein, SQSTM1/p62 as an essential component of an autophagic reserve that not only synergizes with the proteasome to maintain proteostasis, but also mediates a plastic adaptive response to PIs, and faithfully reports on inherent PI sensitivity. Lentiviral engineering revealed that SQSTM1 is essential for MM cell survival and affords specific PI protection. Under basal conditions, SQSTM1 dependent autophagy alleviates the degradative burden on the proteasome by constitutively disposing of substantial amounts of ubiquitinated proteins. Indeed, its inhibition or stimulation greatly sensitized to, or protected from, PI-induced protein aggregation and cell death. Moreover, under proteasome stress, myeloma cells selectively enhanced SQSTM1 de novo expression and reset its vast endogenous interactome, diverting SQSTM1 from signaling partners to maximize its association with ubiquitinated proteins. Saturation of such autophagic reserve, as indicated by intracellular accumulation of undigested SQSTM1-positive aggregates, specifically discriminated patient-derived myelomas inherently susceptible to PIs from primarily resistant ones. These aggregates correlated with accumulation of the endoplasmic reticulum, which comparative proteomics identified as the main cell compartment targeted by autophagy in MM. Altogether, the data integrate autophagy into our previously established proteasome load versus-capacity model, and reveal SQSTM1 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM. PMID- 26043026 TI - Hyperthermia effects on Hsp27 and Hsp72 associations with mismatch repair (MMR) proteins and cisplatin toxicity in MMR-deficient/proficient colon cancer cell lines. AB - PURPOSE: Hyperthermia is used in combination with conventional anticancer agents to potentiate their cytotoxicity. One of its key events is the synthesis of heat shock proteins (HSPs), which are able to associate with components from DNA repair mechanisms. However, little is known about their relationship with the mismatch repair system (MMR). Our aim was to study the effects of hyperthermia on cisplatin (cPt) sensitivity and to determine whether MLH1 and MSH2 associate with Hsp27 and Hsp72 in MMR-deficient(-)/-proficient(+) cells. MATERIALS AND METHODS: HCT116+ch2 (MMR-) and HCT116+ch3 (MMR+) cell lines were exposed to cPt with or without previous hyperthermia (42 degrees C, 1 h). Clonogenic survival assays, MTT, confocal immunofluorescence, immunoprecipitation, immunoblotting and flow cytometry were performed. RESULTS: Hyperthermia increased the cPt resistance in MMR- cells 1.42-fold. Immunofluorescence revealed that after cPt, Hsp27 and Hsp72 translocated to the nucleus and colocalisation coefficients between these proteins with MLH1 and MSH2 increased in MMR+ cells. Immunoprecipitation confirmed the interactions between HSPs and MMR proteins in control and treated cells. Hyperthermia pretreatment induced cell cycle arrest, increased p73 expression and potentiated cPt sensitivity in MMR+ cells. CONCLUSIONS: This is the first report showing in a MMR-/+ cellular model that MLH1 and MSH2 are client proteins of Hsp27 and Hsp72. Our study suggests that p73 might participate in the cellular response to hyperthermia and cPt in a MMR-dependent manner. Further functional studies will confirm whether HSPs cooperate with the MMR system in cPt induced DNA damage response or whether these protein interactions are only the result of their chaperone functions. PMID- 26043027 TI - Effects of psychological stress on hypertension in middle-aged Chinese: a cross sectional study. AB - We examined the effect and relative contributions of different types of stress on the risk of hypertension. Using cluster sampling, 5,976 community-dwelling individuals aged 40-60 were selected. Hypertension was defined according to the Seventh Report of the Joint National Committee, and general psychological stress was defined as experiencing stress at work or home. Information on known risk factors of hypertension (e.g., physical activity levels, food intake, smoking behavior) was collected from participants. Logistic regression analysis was used to determine the associations between psychological stress and hypertension, calculating population-attributable risks and 95% confidence intervals (CIs). General stress was significantly related to hypertension (odds ratio [OR] = 1.247, 95% CI [1.076, 1.446]). Additionally, after adjustment for all other risk factors, women showed a greater risk of hypertension if they had either stress at work or at home: OR = 1.285, 95% CI (1.027, 1.609) and OR = 1.231, 95% CI (1.001, 1.514), respectively. However, this increased risk for hypertension by stress was not found in men. General stress contributed approximately 9.1% (95% CI [3.1, 15.0]) to the risk for hypertension. Thus, psychological stress was associated with an increased risk for hypertension, although this increased risk was not consistent across gender. PMID- 26043028 TI - Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model. AB - Schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to both a broad range of symptoms and disease heterogeneity, current therapeutic approaches to treat schizophrenia fail to address all symptomatic manifestations of the disease. Therefore, disease models that reproduce core pathological features of schizophrenia are needed for the elucidation of pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatography-mass spectrometry proteomic (LC-MS(E)) and metabonomic (LC-MS) profiling analysis combined with the targeted proteomics (selected reaction monitoring and multiplex immunoassay) of serum and brain tissues to investigate a chronic phencyclidine (PCP) rat model in which glutamatergic hypofunction is induced through noncompetitive NMDAR-receptor antagonism. Using a multiplex immunoassay, we identified alterations in the levels of several cytokines (IL-5, IL-2, and IL-1beta) and fibroblast growth factor-2. Extensive proteomic and metabonomic brain tissue profiling revealed a more prominent effect of chronic PCP treatment on both the hippocampal proteome and metabonome compared to the effect on the frontal cortex. Bioinformatic pathway analysis confirmed prominent abnormalities in NMDA-receptor-associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA, and GABAergic signaling in the hippocampus and in proteins associated with neurodegeneration. We further identified abundance changes in the level of the superoxide dismutase enzyme (SODC) in both the frontal cortex and hippocampus, which indicates alterations in oxidative stress and substantiates the apoptotic pathway alterations. The present study could lead to an increased understanding of how perturbed glutamate receptor signaling affects other relevant biological pathways in schizophrenia and, therefore, support drug discovery efforts for the improved treatment of patients suffering from this debilitating psychiatric disorder. PMID- 26043025 TI - Simvastatin Suppresses Airway IL-17 and Upregulates IL-10 in Patients With Stable COPD. AB - BACKGROUND: Statins have immunomodulatory properties that may provide beneficial effects in the treatment of COPD. We investigated whether a statin improves the IL-17/IL-10 imbalance in patients with COPD, as has previously been demonstrated in patients with asthma. METHODS: Thirty patients with stable COPD were recruited to a double-blind, randomized, controlled, crossover trial comparing the effect of simvastatin, 20 mg po daily, with that of a matched placebo on sputum inflammatory markers and airway inflammation. Each treatment was administered for 4 weeks separated by a 4-week washout period. The primary outcome was the presence of T-helper 17 cytokines and indoleamine 2,3-dioxygenase (IDO) in induced sputum. Secondary outcomes included sputum inflammatory cells, FEV1, and symptoms using the COPD Assessment Test (CAT). RESULTS: At 4 weeks, there was a significant reduction in sputum IL-17A, IL-22, IL-6, and CXCL8 concentrations (mean difference, -16.4 pg/mL, P = .01; -48.6 pg/mL, P < .001; -45.3 pg/mL, P = .002; and -190.9 pg/mL, P = .007, respectively), whereas IL-10 concentrations, IDO messenger RNA expression (fold change), and IDO activity (kynurenine to tryptophan ratio) were markedly increased during simvastatin treatment compared with placebo treatment periods (mean difference, 24.7 pg/mL, P < .001; 1.02, P < .001; and 0.47, P < .001, respectively). The absolute sputum macrophage count, proportion of macrophages, and CAT score were reduced after simvastatin compared with placebo (mean difference, -0.16 * 106, P = .004; -14.1%, P < .001; and -3.2, P = .02, respectively). Values for other clinical outcomes were similar between the simvastatin and placebo treatments. CONCLUSIONS: Simvastatin reversed the IL 17A/IL-10 imbalance in the airways and reduced sputum macrophage but not neutrophil counts in patients with COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01944176; www.clinicaltrials.gov. PMID- 26043029 TI - Effect of milk fat content on the performance of ohmic heating for inactivation of Escherichia coli O157:H7, Salmonella enterica Serovar Typhimurium and Listeria monocytogenes. AB - AIMS: The effect of milk fat content on ohmic heating compared to conventional heating for inactivation of food-borne pathogens was investigated. METHODS AND RESULTS: Sterile cream was mixed with sterile buffered peptone water and adjusted to 0, 3, 7, 10% (w/v) milk fat content. These samples with varying fat content were subjected to ohmic and conventional heating. The effect of milk fat on temperature increase and electrical conductivity were investigated. Also, the protective effect of milk fat on the inactivation of foodborne pathogens was studied. For conventional heating, temperatures of samples increased with time and were not significantly (P > 0.05) different regardless of fat content. Although the inactivation rate of Escherichia coli O157:H7, Salmonella Typhimurium and L. monocytogens decreased in samples of 10% fat content, a protective effect was not observed for conventional heating. In contrast with conventional heating, ohmic heating was significantly affected by milk fat content. Temperature increased more rapidly with lower fat content for ohmic heating due to higher electrical conductivity. Nonuniform heat generation of nonhomogeneous fat-containing samples was verified using a thermal infrared camera. Also, the protective effect of milk fat on E. coli O157:H7 and Listeria monocytogenes was observed in samples subjected to ohmic heating. CONCLUSIONS: These results indicate that food-borne pathogens can survive in nonhomogeneous fat-containing foods subjected to ohmic heating. Therefore, more attention is needed regarding ohmic heating than conventional heating for pasteurizing fat containing foods. SIGNIFICANCE AND IMPACT OF THE STUDY: The importance of adequate pasteurization for high milk fat containing foods was identified. PMID- 26043030 TI - Zinc status affects glucose homeostasis and insulin secretion in patients with thalassemia. AB - Up to 20% of adult patients with Thalassemia major (Thal) live with diabetes, while 30% may be zinc deficient. The objective of this study was to explore the relationship between zinc status, impaired glucose tolerance and insulin sensitivity in Thal patients. Charts from thirty subjects (16 male, 27.8 +/- 9.1 years) with Thal were reviewed. Patients with low serum zinc had significantly lower fasting insulin, insulinogenic and oral disposition indexes (all p < 0.05) and elevated glucose response curve, following a standard 75 g oral load of glucose compared to those with normal serum zinc after controlling for baseline (group * time interaction p = 0.048). Longitudinal data in five patients with a decline in serum zinc over a two year follow up period (-19.0 +/- 9.6 MUg/dL), showed consistent increases in fasting glucose (3.6 +/- 3.2 mg/dL) and insulin to glucose ratios at 120 min post glucose dose (p = 0.05). Taken together, these data suggest that the frequently present zinc deficiency in Thal patients is associated with decreased insulin secretion and reduced glucose disposal. Future zinc trials will require modeling of oral glucose tolerance test data and not simply measurement of static indices in order to understand the complexities of pancreatic function in the Thal patient. PMID- 26043031 TI - A comparison of postoperative early enteral nutrition with delayed enteral nutrition in patients with esophageal cancer. AB - We examined esophageal cancer patients who received enteral nutrition (EN) to evaluate the validity of early EN compared to delayed EN, and to determine the appropriate time to start EN. A total of 208 esophagectomy patients who received EN postoperatively were divided into three groups (Group 1, 2 and 3) based on whether they received EN within 48 h, 48 h-72 h or more than 72 h, respectively. The postoperative complications, length of hospital stay (LOH), days for first fecal passage, cost of hospitalization, and the difference in serum albumin values between pre-operation and post-operation were all recorded. The statistical analyses were performed using the t-test, the Mann-Whitney U test and the chi square test. Statistical significance was defined as p < 0.05. Group 1 had the lowest thoracic drainage volume, the earliest first fecal passage, and the lowest LOH and hospitalization expenses of the three groups. The incidence of pneumonia was by far the highest in Group 3 (p = 0.019). Finally, all the postoperative outcomes of nutritional conditions were the worst by a significant margin in Group 3. It is therefore safe and valid to start early enteral nutrition within 48 h for postoperative esophageal cancer patients. PMID- 26043032 TI - Folate and nutrients involved in the 1-carbon cycle in the pretreatment of patients for colorectal cancer. AB - To assess the ingestion of folate and nutrients involved in the 1-carbon cycle in non-treated patients with colorectal adenocarcinoma in a reference center for oncology in southeastern Brazil. In total, 195 new cases with colorectal adenocarcinoma completed a clinical evaluation questionnaire and a Food Frequency Questionnaire (FFQ). Blood samples from 161 patients were drawn for the assessment of serum folate. A moderate correlation was found between serum concentrations of folate, folate intake and the dietary folate equivalent (DFE) of synthetic supplements. Mulatto or black male patients with a primary educational level had a higher intake of dietary folate. Of patients obtaining folate from the diet alone or from dietary supplements, 11.00% and 0.10%, respectively, had intake below the recommended level. Of the patients using dietary supplements, 35% to 50% showed high levels of folic acid intake. There was a prevalence of inadequacy for vitamins B2, B6 and B12, ranging from 12.10% to 20.18%, while 13.76% to 22.55% of patients were likely to have adequate choline intake. The considerable percentage of patients with folate intake above the recommended levels deserves attention because of the harmful effects that this nutrient may have in the presence of established neoplastic lesions. PMID- 26043033 TI - Lack of efficacy of a salience nudge for substituting selection of lower-calorie for higher-calorie milk in the work place. AB - Obesity is a major burden on healthcare systems. Simple, cost effective interventions that encourage healthier behaviours are required. The present study evaluated the efficacy of a salience nudge for promoting a change in milk selection from full-cream to low-fat (lower calorie) in the kitchen of a university-based research institute that provided full-cream and low-fat milk free of charge. Milk selection was recorded for 12 weeks (baseline). A sign with the message "Pick me! I am low calorie" was then placed on the low-fat milk and consumption was recorded for a further 12 weeks. During baseline, selection of low-fat milk was greater than selection of full-cream milk (p = 0.001) with no significant milk-type * time interaction (p = 0.12). During the intervention period overall milk selection was not different from baseline (p = 0.22), with low-fat milk consumption remaining greater than full-cream milk selection (p < 0.001) and no significant milk-type * time interaction (p = 0.41). However, sub analysis of the first two weeks of the intervention period indicated an increase in selection of both milk types (p = 0.03), but with a greater increase in low fat milk selection (p = 0.01, milk-type * time interaction). However, milk selection then returned towards baseline during the rest of the intervention period. Thus, in the present setting, salience nudging promoted a transient increase in low-fat milk consumption, but also increased selection of full-cream milk, indicating that nudging was not effective in promoting healthier milk choices. PMID- 26043034 TI - Profiling physical activity, diet, screen and sleep habits in Portuguese children. AB - Obesity in children is partly due to unhealthy lifestyle behaviours, e.g., sedentary activity and poor dietary choices. This trend has been seen globally. To determine the extent of these behaviours in a Portuguese population of children, 686 children 9.5 to 10.5 years of age were studied. Our aims were to: (1) describe profiles of children's lifestyle behaviours; (2) identify behaviour pattern classes; and (3) estimate combined effects of individual/ socio demographic characteristics in predicting class membership. Physical activity and sleep time were estimated by 24-h accelerometry. Nutritional habits, screen time and socio-demographics were obtained. Latent Class Analysis was used to determine unhealthy lifestyle behaviours. Logistic regression analysis predicted class membership. About 78% of children had three or more unhealthy lifestyle behaviours, while 0.2% presented no risk. Two classes were identified: Class 1 Sedentary, poorer diet quality; and Class 2-Insufficiently active, better diet quality, 35% and 65% of the population, respectively. More mature children (Odds Ratio (OR) = 6.75; 95%CI = 4.74-10.41), and boys (OR = 3.06; 95% CI = 1.98-4.72) were more likely to be overweight/obese. However, those belonging to Class 2 were less likely to be overweight/obese (OR = 0.60; 95% CI = 0.43-0.84). Maternal education level and household income did not significantly predict weight status (p >= 0.05). PMID- 26043035 TI - Do Overweight Adolescents Adhere to Dietary Intervention Messages? Twelve-Month Detailed Dietary Outcomes from Curtin University's Activity, Food and Attitudes Program. AB - Dietary components of adolescent obesity interventions are rarely evaluated with comprehensive reporting of dietary change. The objective was to assess dietary change in overweight adolescents, including adherence to dietary intervention. The dietary intervention was part of a multi-component intervention (CAFAP) targeting the physical activity, sedentary and healthy eating behaviors of overweight adolescents (n = 69). CAFAP was a staggered entry, within-subject, waitlist controlled clinical trial with 12 months of follow up. Diet was assessed using three-day food records and a brief eating behavior questionnaire. Changes in dietary outcomes were assessed using linear mixed models, adjusted for underreporting. Food record data suggested reduced adherence to dietary intervention messages over time following the intervention, despite conflicting information from the brief eating behavior questionnaire. During the intervention, energy intake was stable but favorable nutrient changes occurred. During the 12 month maintenance period; self-reported eating behaviors improved, energy intake remained stable but dietary fat and saturated fat intake gradually returned to baseline levels. Discrepancies between outcomes from brief dietary assessment methods and three-day food records show differences between perceived and actual intake, highlighting the need for detailed dietary reporting. Further, adherence to dietary intervention principles reduces over time, indicating a need for better maintenance support. PMID- 26043037 TI - Feasibility and Use of the Mobile Food Record for Capturing Eating Occasions among Children Ages 3-10 Years in Guam. AB - Children's readiness to use technology supports the idea of children using mobile applications for dietary assessment. Our goal was to determine if children 3-10 years could successfully use the mobile food record (mFR) to capture a usable image pair or pairs. Children in Sample 1 were tasked to use the mFR to capture an image pair of one eating occasion while attending summer camp. For Sample 2, children were tasked to record all eating occasions for two consecutive days at two time periods that were two to four weeks apart. Trained analysts evaluated images. In Sample 1, 90% (57/63) captured one usable image pair. All children (63/63) returned the mFR undamaged. Sixty-two children reported: The mFR was easy to use (89%); willingness to use the mFR again (87%); and the fiducial marker easy to manage (94%). Children in Sample 2 used the mFR at least one day at Time 1 (59/63, 94%); Time 2 (49/63, 78%); and at both times (47/63, 75%). This latter group captured 6.21 +/- 4.65 and 5.65 +/- 3.26 mean (+/- SD) image pairs for Time 1 and Time 2, respectively. Results support the potential for children to independently record dietary intakes using the mFR. PMID- 26043036 TI - Resveratrol Inhibits the Invasion of Glioblastoma-Initiating Cells via Down Regulation of the PI3K/Akt/NF-kappaB Signaling Pathway. AB - Invasion and metastasis of glioblastoma-initiating cells (GICs) are thought to be responsible for the progression and recurrence of glioblastoma multiforme (GBM). A safe drug that can be applied during the rest period of temozolomide (TMZ) maintenance cycles would greatly improve the prognosis of GBM patients by inhibiting GIC invasion. Resveratrol (RES) is a natural compound that exhibits anti-invasion properties in multiple tumor cell lines. The current study aimed to evaluate whether RES can inhibit GIC invasion in vitro and in vivo. GICs were identified using CD133 and Nestin immunofluorescence staining and tumorigenesis in non-obese diabetic severe combined immunodeficient (NOD/SCID) mice. Invasive behaviors, including the adhesion, invasion and migration of GICs, were determined by tumor invasive assays in vitro and in vivo. The activity of matrix metalloproteinases (MMPs) was measured by the gelatin zymography assay. Western blotting analysis and immunofluorescence staining were used to determine the expression of signaling effectors in GICs. We demonstrated that RES suppressed the adhesion, invasion and migration of GICs in vitro and in vivo. Moreover, we proved that RES inhibited the invasion of GICs via the inhibition of PI3K/Akt/NF kappaB signal transduction and the subsequent suppression of MMP-2 expression. PMID- 26043038 TI - Effect of dietary Fatty acids on human lipoprotein metabolism: a comprehensive update. AB - Dyslipidemia is a major risk factor for cardiovascular disease (CVD). Dietary fatty-acid composition regulates lipids and lipoprotein metabolism and may confer CVD benefit. This review updates understanding of the effect of dietary fatty acids on human lipoprotein metabolism. In elderly participants with hyperlipidemia, high n-3 polyunsaturated fatty-acids (PUFA) consumption diminished hepatic triglyceride-rich lipoprotein (TRL) secretion and enhanced TRL to low-density lipoprotein (LDL) conversion. n-3 PUFA also decreased TRL-apoB-48 concentration by decreasing TRL-apoB-48 secretion. High n-6 PUFA intake decreased very low-density lipoprotein (VLDL) cholesterol and triglyceride concentrations by up-regulating VLDL lipolysis and uptake. In a study of healthy subjects, the intake of saturated fatty-acids with increased palmitic acid at the sn-2 position was associated with decreased postprandial lipemia. Low medium-chain triglyceride may not appreciably alter TRL metabolism. Replacing carbohydrate with monounsaturated fatty-acids increased TRL catabolism. Trans-fatty-acid decreased LDL and enhanced high-density lipoprotein catabolism. Interactions between APOE genotype and n-3 PUFA in regulating lipid responses were also described. The major advances in understanding the effect of dietary fatty-acids on lipoprotein metabolism has centered on n-3 PUFA. This knowledge emphasizes the importance of regulating lipoprotein metabolism as a mode to improve plasma lipids and potentially CVD risk. Additional studies are required to better characterize the cardiometabolic effects of other dietary fatty-acids. PMID- 26043039 TI - Food Choice Architecture: An Intervention in a Secondary School and its Impact on Students' Plant-based Food Choices. AB - With growing evidence for the positive health outcomes associated with a plant based diet, the study's purpose was to examine the potential of shifting adolescents' food choices towards plant-based foods. Using a real world setting of a school canteen, a set of small changes to the choice architecture was designed and deployed in a secondary school in Yorkshire, England. Focussing on designated food items (whole fruit, fruit salad, vegetarian daily specials, and sandwiches containing salad) the changes were implemented for six weeks. Data collected on students' food choice (218,796 transactions) enabled students' (980 students) selections to be examined. Students' food choice was compared for three periods: baseline (29 weeks); intervention (six weeks); and post-intervention (three weeks). Selection of designated food items significantly increased during the intervention and post-intervention periods, compared to baseline (baseline, 1.4%; intervention 3.0%; post-intervention, 2.2%) chi(2)(2) = 68.1, p < 0.001. Logistic regression modelling also revealed the independent effect of the intervention, with students 2.5 times as likely (p < 0.001) to select the designated food items during the intervention period, compared to baseline. The study's results point to the influence of choice architecture within secondary school settings, and its potential role in improving adolescents' daily food choices. PMID- 26043041 TI - Foreword: We Will be What We Eat or What We Were Fed. PMID- 26043040 TI - The suppression of maternal-fetal leukemia inhibitory factor signal relay pathway by maternal immune activation impairs brain development in mice. AB - Recent studies in rodents suggest that maternal immune activation (MIA) by viral infection is associated with schizophrenia and autism in offspring. Although maternal IL-6 is though t to be a possible mediator relating MIA induced these neuropsychiatric disorders, the mechanism remains to be elucidated. Previously, we reported that the maternal leukemia inhibitory factor (LIF)-placental ACTH fetal LIF signaling relay pathway (maternal-fetal LIF signal relay) promotes neurogenesis of fetal cerebrum in rats. Here we report that the maternal-fetal LIF signal relay in mice is suppressed by injection of polyriboinosinic polyribocytidylic acid into dams, which induces MIA at 12.5 days post-coitum. Maternal IL-6 levels and gene expression of placental suppressor of cytokine signaling 3 (Socs3) increased according to the severity of MIA and gene expression of placental Socs3 correlated with maternal IL-6 levels. Furthermore, we show that MIA causes reduction of LIF level in the fetal cerebrospinal fluid, resulting in the decreased neurogenesis in the cerebrum. These findings suggest that maternal IL-6 interferes the maternal-fetal LIF signal relay by inducing SOCS3 in the placenta and leads to decreased neurogenesis. PMID- 26043042 TI - Early factors leading to later obesity: interactions of the microbiome, epigenome, and nutrition. AB - Obesity is a major public health problem in the United States and many other countries. Childhood obesity rates have risen extensively over the last several decades with the numbers continuing to rise. Obese and overweight children are at high risk of becoming overweight adolescents and adults. The causes are multifactorial and are affected by various genetic, behavioral, and environmental factors. This review aims to discuss a previously under-recognized antecedent of obesity and related chronic metabolic diseases such as heart disease and diabetes. Specifically, we highlight the relationship of the microbial ecology of the gastrointestinal tract during early development and the consequent effects on metabolism, epigenetics, and inflammatory responses that can subsequently result in metabolic syndrome. Although studies in this area are just beginning, this area of research is rapidly expanding and may lead to early life interventions that may have significant impacts in the prevention of obesity. PMID- 26043043 TI - Stable odor recognition by a neuro-adaptive electronic nose. AB - Sensitivity, selectivity and stability are decisive properties of sensors. In chemical gas sensors odor recognition can be severely compromised by poor signal stability, particularly in real life applications where the sensors are exposed to unpredictable sequences of odors under changing external conditions. Although olfactory receptor neurons in the nose face similar stimulus sequences under likewise changing conditions, odor recognition is very stable and odorants can be reliably identified independently from past odor perception. We postulate that appropriate pre-processing of the output signals of chemical sensors substantially contributes to the stability of odor recognition, in spite of marked sensor instabilities. To investigate this hypothesis, we use an adaptive, unsupervised neural network inspired by the glomerular input circuitry of the olfactory bulb. Essentially the model reduces the effect of the sensors' instabilities by utilizing them via an adaptive multicompartment feed-forward inhibition. We collected and analyzed responses of a 4 * 4 gas sensor array to a number of volatile compounds applied over a period of 18 months, whereby every sensor was sampled episodically. The network conferred excellent stability to the compounds' identification and was clearly superior over standard classifiers, even when one of the sensors exhibited random fluctuations or stopped working at all. PMID- 26043045 TI - Molecular Design for Dual Modulation Effect of Amyloid Protein Aggregation. AB - Modulation of protein self-assembly has been a powerful strategy for controlling and understanding amyloid protein aggregation. Most modulators of amyloid aggregation only involve simple inhibition or acceleration. Here we report a new multivalent molecular motif, the polyethylenimine-perphenazine (PEI-P) conjugate which has a dual "acceleration-inhibition" modulation effect on amyloid beta (Abeta) aggregation. Dose dependent results from Thioflavin T fluorescence assays, circular dichroism, and atomic force microscopy show that PEI-P conjugates accelerate formation of Abeta prefibrillar intermediates and then inhibit Abeta fibrillation. Furthermore, compared to perphenazine alone, PEI-P conjugates exhibit an enhanced inhibitory effect due to multivalency. Cell viability assays indicate that the PEI-P conjugates reduce the cytotoxicity of Abeta aggregates in a dose-dependent manner. This new modulation strategy may shed light on controlling amyloid aggregation, which offers a general concept for designing new modulators. PMID- 26043044 TI - GJB2 Mutation Spectrum and Genotype-Phenotype Correlation in 1067 Han Chinese Subjects with Non-Syndromic Hearing Loss. AB - Mutations in Gap Junction Beta 2 (GJB2) have been reported to be a major cause of non-syndromic hearing loss in many populations worldwide. The spectrums and frequencies of GJB2 variants vary substantially among different ethnic groups, and the genotypes among these populations remain poorly understood. In the present study, we carried out a systematic and extended mutational screening of GJB2 gene in 1067 Han Chinese subjects with non-syndromic hearing loss, and the resultant GJB2 variants were evaluated by phylogenetic, structural and bioinformatic analysis. A total of 25 (23 known and 2 novel) GJB2 variants were identified, including 6 frameshift mutations, 1 nonsense mutation, 16 missense mutations and 2 silent mutations. In this cohort, c.235delC is the most frequently observed pathogenic mutation. The phylogenetic, structural and bioinformatic analysis showed that 2 novel variants c.127G>T (p.V43L), c.293G>C (p.R98P) and 2 known variants c. 107T>C (p.L36P) and c.187G>T (p.V63L) are localized at highly conserved amino acids. In addition, these 4 mutations are absent in 203 healthy individuals, therefore, they are probably the most likely candidate pathogenic mutations. In addition, 66 (24 novel and 42 known) genotypes were identified, including 6 homozygotes, 20 compound heterozygotes, 18 single heterozygotes, 21 genotypes harboring only polymorphism(s) and the wild type genotype. Among these, 153 (14.34%) subjects were homozygous for pathogenic mutations, 63 (5.91%) were compound heterozygotes, and 157 (14.71%) carried single heterozygous mutation. Furthermore, 65.28% (141/216) of these cases with two pathogenic mutations exhibited profound hearing loss. These data suggested that mutations in GJB2 gene are responsible for approximately 34.96% of non syndromic hearing loss in Han Chinese population from Zhejiang Province in eastern China. In addition, our results also strongly supported the idea that other factors such as alterations in regulatory regions, additional genes, and environmental factors may contribute to the clinical manifestation of deafness. PMID- 26043046 TI - Durability of highly cross-linked polyethylene in total hip and total knee arthroplasty. AB - This article reviews the history of the development of highly cross-linked polyethylene and provides an in-depth review of the clinical results regarding the durability of highly cross-linked polyethylene (HXLPE) used in total hip arthroplasty (THA) and total knee arthroplasty (TKA). The use of polyethylene as a bearing surface has contributed to the success of THA and TKA; however, polyethylene wear and osteolysis can lead to failure. Ongoing clinical and retrieval studies are required to analyze outcomes at longer-term follow-up. PMID- 26043047 TI - Management of severe femoral bone loss in revision total hip arthroplasty. AB - Femoral bone loss is a complex problem in revision total hip arthroplasty. The Paprosky classification is used when determining the degree and location of bone loss. Meticulous operative planning is essential where severe bone loss is a concern. One must correctly identify the bone loss pattern, safely remove the existing components, and proceed with the proper reconstruction technique based on the pattern of bone loss. This article discusses the etiology and classification of bone loss, clinical and radiographic evaluation, components of effective preoperative planning, and clinical results of various treatment options with a focus on more severe bone loss patterns. PMID- 26043048 TI - Reducing blood loss in bilateral total knee arthroplasty with patient-specific instrumentation. AB - Patient-specific instrumentation (PSI) in total knee arthroplasty (TKA) has been introduced to obtain consistent alignment, prevent instrumentation of the medullary canal and improve operating room efficiency. This article compares simultaneous bilateral TKA performed with and without the use of PSI in terms of surgical time; blood loss and transfusion requirements; length-of-stay, early thromboembolic events and complication rates. There was a trend to reduced total blood loss (as measured by drop in hemoglobin values) and lower transfusion rate after surgery. Further research in the form of high quality randomized trials and cost-benefit analyses may help in further consolidation of these findings. PMID- 26043049 TI - Risk assessment tools used to predict outcomes of total hip and total knee arthroplasty. AB - This article reviews recently proposed clinical tools for predicting risks and outcomes in total hip arthroplasty and total knee arthroplasty patients. Additionally, we share the Massachusetts General Hospital experience with using the Risk Assessment and Prediction Tool to predict the need for an extended care facility after total joint arthroplasty. PMID- 26043050 TI - Definitive fixation of tibial plateau fractures. AB - Tibial plateau fractures present in a wide spectrum of injury severity and pattern, each requiring a different approach and strategy to achieve good clinical outcomes. Achieving those outcomes starts with a thorough evaluation and preoperative planning period, which leads to choosing the most appropriate surgical approach and fixation strategy. Through a case-based approach, this article presents the necessary pearls, techniques, and strategies to maximize outcomes and minimize complications for some of the more commonly presenting plateau fracture patterns. PMID- 26043051 TI - Orthopedic applications of acellular human dermal allograft for shoulder and elbow surgery. AB - Shoulder and elbow tendon injuries are some of the most challenging problems to treat surgically. Tendon repairs in the upper extremity can be complicated by poor tendon quality and, often times, poor healing. Extracellular matrices, such as human dermal allografts, have been used to augment tendon repairs in shoulder and elbow surgery. The indications and surgical techniques regarding the use of human dermal allograft continue to evolve. This article reviews the basic science, rationale for use, and surgical applications of human dermal allograft in shoulder and elbow tendon injuries. PMID- 26043052 TI - Glenoid bone loss in anatomic shoulder arthroplasty: literature review and surgical technique. AB - Despite major advances in total shoulder arthroplasty, management of severe posterior glenoid bone loss remains controversial. Several companies have provided alternative treatment options for type C glenoids associated with posterior subluxation of the humeral head. However, preoperative planning, proper selection of glenoid size, and recognition of the operative pitfalls are crucial for successful outcomes. A review of the literature and presentation of the surgical technique for the management of severe posterior glenoid bone loss are presented. PMID- 26043053 TI - Pain management strategies in hand surgery. AB - Modern anesthetic agents have allowed for the rapid expansion of ambulatory surgery, particularly in hand surgery. The choice between general anesthesia, peripheral regional blocks, regional intravenous anesthesia (Bier block), local block with sedation, and the recently popularized wide-awake hand surgery depends on several variables, including the type and duration of the procedure and patient characteristics, coexisting conditions, location, and expected length of the procedure. This article discusses the various perioperative and postoperative analgesic options to optimize the hand surgical patients' experience. PMID- 26043054 TI - PET Imaging in Sarcoma. AB - PET imaging has been evaluated in five areas of sarcoma diagnosis and treatment: biopsy guidance, therapeutic monitoring, tumor detection and grading, tumor staging, and prognostication. Current evidence does not include any cost-benefit analysis showing a decreased number of invasive procedures from false-positive results. There is overlap from more conventional imaging and PET imaging without obvious added benefit from information gained from PET/computed tomography scanning. Use as a routine test in patients with sarcoma cannot be recommended. Use in specific histologic subtypes with differing patterns of metastasis or in monitoring those cases undergoing neoadjuvant chemotherapy needs further study before PET/computed tomography becomes standard of care for patients with sarcoma. PMID- 26043055 TI - Soft tissue masses for the general orthopedic surgeon. AB - Soft tissue sarcomas are a rare, heterogeneous group of malignancies that should be included in the differential diagnosis for any patient presenting with a soft tissue mass. This article reviews strategies for differentiating between benign and malignant soft tissue masses. Epidemiology, appropriate workup, and treatment of soft tissue sarcomas are reviewed. PMID- 26043056 TI - Adult Reconstruction. Preface. PMID- 26043057 TI - Oncology. Preface. PMID- 26043058 TI - Trauma. Preface. PMID- 26043059 TI - Upper Extremity. Preface. PMID- 26043060 TI - Effects of thymoquinone on testicular structure and sperm production in male obese rats. AB - Thymoquinone (TQ) is a phytochemical compound found in the plant Nigella sativa. It has antioxidant and anti-cancer effects. This study investigated the effects of TQ on obesity and testicular structure of high-fat-diet (HFD) fed rats. Obese control (OC) and obese thymoquinone (OT) groups were fed a special diet containing 40% of total calories from fat. Non-obese control (NC) and non thymoquinone (NT) groups were fed a standard diet for nine weeks. Then, intraperitoneal TQ injections were carried out to the OT and NT groups for six weeks and testes were removed. Catalase and myeloperoxidase activity were determined in rat testis tissue. Stereological, histopathological, and immunohistochemical changes were evaluated in the testes of the rats. In stereological studies, mean volumes of testis and seminiferous tubules, the number of spermatogenic cells and also Leydig cells in the OC group were reduced, but these values significantly increased in the OT group. Apoptotic cells were observed in the OC group in comparison to the OT group. The number of healthy sperms were reduced in the OC group, whereas the majority showed anomalies in the head, neck, and tail. The number of healthy sperm was increased and the anomalies significantly reduced by using TQ in both the NT, and especially the OT group. TQ like antioxidants may improve fertility by means of increasing the healthy sperm number and preventing sperm anomalies. PMID- 26043061 TI - DiameterJ: A validated open source nanofiber diameter measurement tool. AB - Despite the growing use of nanofiber scaffolds for tissue engineering applications, there is not a validated, readily available, free solution for rapid, automated analysis of nanofiber diameter from scanning electron microscope (SEM) micrographs. Thus, the goal of this study was to create a user friendly ImageJ/FIJI plugin that would analyze SEM micrographs of nanofibers to determine nanofiber diameter on a desktop computer within 60 s. Additional design goals included 1) compatibility with a variety of existing segmentation algorithms, and 2) an open source code to enable further improvement of the plugin. Using existing algorithms for centerline determination, Euclidean distance transforms and a novel pixel transformation technique, a plugin called "DiameterJ" was created for ImageJ/FIJI. The plugin was validated using 1) digital synthetic images of white lines on a black background and 2) SEM images of nominally monodispersed steel wires of known diameters. DiameterJ analyzed SEM micrographs in 20 s, produced diameters not statistically different from known values, was over 10-times closer to known diameter values than other open source software, provided hundreds of times the sampling of manual measurement, and was hundreds of times faster than manual assessment of nanofiber diameter. DiameterJ enables users to rapidly and thoroughly determine the structural features of nanofiber scaffolds and could potentially allow new insights to be formed into fiber diameter distribution and cell response. PMID- 26043062 TI - Epicardial application of cardiac progenitor cells in a 3D-printed gelatin/hyaluronic acid patch preserves cardiac function after myocardial infarction. AB - Cardiac cell therapy suffers from limitations related to poor engraftment and significant cell death after transplantation. In this regard, ex vivo tissue engineering is a tool that has been demonstrated to increase cell retention and survival. The aim of our study was to evaluate the therapeutic potential of a 3D printed patch composed of human cardiac-derived progenitor cells (hCMPCs) in a hyaluronic acid/gelatin (HA/gel) based matrix. hCMPCs were printed in the HA/gel matrix (30 * 10(6) cells/ml) to form a biocomplex made of six perpendicularly printed layers with a surface of 2 * 2 cm and thickness of 400 MUm, in which they retained their viability, proliferation and differentiation capability. The printed biocomplex was transplanted in a mouse model of myocardial infarction (MI). The application of the patch led to a significant reduction in adverse remodeling and preservation of cardiac performance as was shown by both MRI and histology. Furthermore, the matrix supported the long-term in vivo survival and engraftment of hCMPCs, which exhibited a temporal increase in cardiac and vascular differentiation markers over the course of the 4 week follow-up period. Overall, we developed an effective and translational approach to enhance hCMPC delivery and action in the heart. PMID- 26043064 TI - Monte Carlo QSAR models for predicting organophosphate inhibition of acetycholinesterase. AB - A series of 278 organophosphate compounds acting as acetylcholinesterase inhibitors has been studied. The Monte Carlo method was used as a tool for building up one-variable quantitative structure-activity relationship (QSAR) models for acetylcholinesterase inhibition activity based on the principle that the target endpoint is treated as a random event. As an activity, bimolecular rate constants were used. The QSAR models were based on optimal descriptors obtained from Simplified Molecular Input-Line Entry System (SMILES) used for the representation of molecular structure. Two modelling approaches were examined: (1) 'classic' training-test system where the QSAR model was built with one random split into a training, test and validation set; and (2) the correlation balance based QSAR models were built with two random splits into a sub-training, calibration, test and validation set. The DModX method was used for defining the applicability domain. The obtained results suggest that studied activity can be determined with the application of QSAR models calculated with the Monte Carlo method since the statistical quality of all build models was very good. Finally, structural indicators for the increase and the decrease of the bimolecular rate constant are defined. The possibility of using these results for the computer aided design of new organophosphate compounds is presented. PMID- 26043063 TI - Incidence and risk factors for psychiatric comorbidity among people newly diagnosed with cancer based on Korean national registry data. AB - OBJECTIVE: The present study investigates the incidence of psychiatric disorders, related risk factors, and the use of mental health services among people newly diagnosed with one of five major cancers (stomach, liver, colorectal, lung, and breast cancer) based on national registry data from the National Health Insurance Service (NHIS) in the Korean population. METHODS: We collected data on people newly diagnosed with one of the five major cancers between 2005 and 2008 using the nationwide claims data and cancer registration files of the NHIS. We analyzed the data of those diagnosed with psychiatric disorders over a 5-year period, from 2004 to 2009. RESULTS: Among 302,844 people with newly diagnosed cancer, we identified 31,579 patients (10.43%) who were also newly diagnosed with psychiatric disorders after their cancer diagnosis. Among psychiatric diagnoses, anxiety disorders and depression showed the highest incidences of 18.13 and 13.16 per 1000 person-years, respectively. Among major cancers, patients with lung cancer showed the highest incidence of psychiatric disorders. Older age and female gender were shown to be risk factors associated with psychiatric comorbidity, and no significant differences were found for region of residence. CONCLUSION: The present study showed a low incidence of psychiatric comorbidity and suggests that psychiatric disorders in cancer patients tend to be underrecognized in actual clinical practice. Greater risk for psychiatric comorbidity was associated with lung cancer, older age, and female gender. The present findings provide important information for establishing national policies to detect and manage mental health problems during cancer care. PMID- 26043065 TI - Electrostatic Stabilized InP Colloidal Quantum Dots with High Photoluminescence Efficiency. AB - Electrostatically stabilized InP quantum dots (QDs) showing a high luminescence yield of 16% without any long alkyl chain coordinating ligands on their surface are demonstrated. This is achieved by UV-etching the QDs in the presence of fluoric and sulfuric acids. Fluoric acid plays a critical role in selectively etching nonradiative sites during the ligand-exchange process and in relieving the acidity of the solution to prevent destruction of the QDs. Given that the InP QDs show high luminescence without any electrical barriers, such as long alkyl ligands or inorganic shells, this method can be applied for QD treatment for application to highly efficient QD-based optoelectronic devices. PMID- 26043066 TI - Memory plasticity in older adults: Cognitive predictors of training response and maintenance following learning of number-consonant mnemonic. AB - The study investigated the relationship between cognitive factors and gains in number recall following training in a number-consonant mnemonic in a sample of 112 older adults (M = 70.9 years). The cognitive factors examined included baseline episodic memory, working memory, processing speed, and verbal knowledge. In addition, predictors of maintenance of gains to a follow-up assessment, eight months later, were examined. Whereas working memory was a prominent predictor of baseline recall, the magnitude of gains in recall from pre- to post-test assessments were predicted by baseline episodic memory, processing speed, and verbal knowledge. Verbal knowledge was the only significant predictor of maintenance. Collectively, the results indicate the need to consider multiple factors to account for individual differences in memory plasticity. The potential contribution of additional factors to individual differences in memory plasticity is discussed. PMID- 26043067 TI - An evolutionarily conserved gene, FUWA, plays a role in determining panicle architecture, grain shape and grain weight in rice. AB - Plant breeding relies on creation of novel allelic combinations for desired traits. Identification and utilization of beneficial alleles, rare alleles and evolutionarily conserved genes in the germplasm (referred to as 'hidden' genes) provide an effective approach to achieve this goal. Here we show that a chemically induced null mutation in an evolutionarily conserved gene, FUWA, alters multiple important agronomic traits in rice, including panicle architecture, grain shape and grain weight. FUWA encodes an NHL domain-containing protein, with preferential expression in the root meristem, shoot apical meristem and inflorescences, where it restricts excessive cell division. Sequence analysis revealed that FUWA has undergone a bottleneck effect, and become fixed in landraces and modern cultivars during domestication and breeding. We further confirm a highly conserved role of FUWA homologs in determining panicle architecture and grain development in rice, maize and sorghum through genetic transformation. Strikingly, knockdown of the FUWA transcription level by RNA interference results in an erect panicle and increased grain size in both indica and japonica genetic backgrounds. This study illustrates an approach to create new germplasm with improved agronomic traits for crop breeding by tapping into evolutionary conserved genes. PMID- 26043068 TI - A testis-specific gene, Ubqlnl, is dispensable for mouse embryonic development and spermatogenesis. PMID- 26043070 TI - Sodium Iodide Symporter Expression in Adenoid Cystic Carcinoma of the Head and Neck. AB - IMPORTANCE: Sodium iodide symporter (NIS) expression in adenoid cystic carcinoma (ACC) has not been fully elucidated in the literature, and it is unclear whether radioactive iodine may be a potential therapeutic modality. To our knowledge, the present study includes the largest ACC tumor sample size to evaluate for NIS expression. OBJECTIVE: To assess whether ACC of the head and neck expresses NIS by using immunohistochemical staining techniques, as well as assess whether the presence or intensity of staining correlates with tumor or patient variables. DESIGN, SETTING, AND PARTICIPANTS: Immunohistochemical analysis of NIS expression was performed on 20 ACC specimens from various head and neck subsites obtained from January 1, 1988, to May 6, 2013, at a single academic tertiary care medical center. Staining intensity was graded on a scale of 0 to 3+ (higher numbers indicate greater staining intensity) and was analyzed according to multiple patient and tumor variables. Tumors were eliminated from the study if the patient had undergone prior surgical resection, chemotherapy, or radiotherapy, or was receiving thyroid hormone supplementation at the time of the operation. MAIN OUTCOMES AND MEASURES: Presence or absence of staining was the primary outcome measured; secondary outcomes were the intensity and localization of staining. RESULTS: Sodium iodide symporter staining was positive in 15 of the 20 tumor specimens (75%). Staining was largely localized to the cytoplasm and was of low intensity. There was no significant association between the presence or intensity of staining and the tumor subtype, tumor location, or any of the patient variables assessed (P > .05). No association between staining intensity and tumor growth pattern was shown on chi2 analysis: 1+ (P = .53), 2+ (P = .14), or a combination of 1+ and 2+ staining (P = .64). Parotid control tissue demonstrated intense membranous staining of the striated parotid gland ducts. CONCLUSIONS AND RELEVANCE: Sodium iodide symporter was expressed in the cytoplasm with low intensity in most of the tumor specimens examined in this study. These staining characteristics are also commonly found in thyroid cancer cells. Further investigation is required to determine the significance of this finding. We are optimistic that future studies using endogenous NIS stimulation and identification of genes associated with NIS plasma membrane localization could be applied to the treatment of ACC with radioactive iodine techniques. PMID- 26043072 TI - A Modified One-Stage Early Correction of Blepharophimosis Syndrome Using Tutopatch Slings. AB - PURPOSE: To investigate the efficacy of a one-stage early correction of blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), using bovine pericardium derived membrane (TUTOPATCH((r))) for the frontalis suspension. METHODS: We prospectively studied 12 eyes from 6 patients (median age 14 months) affected by BPES with severe ptosis. All patients were submitted to a one-stage early correction of ptosis (frontalis suspension with TUTOPACH((r))) and telecanthus and epicanthus inversus. Upper margin reflex distance (MRD), nasal inner intercanthal distance (IICD), horizontal fissure length (HFL), and IICD/HFL ratio were evaluated using photographs. RESULTS: The Wilcoxon signed-rank test showed a statistically significant difference between pre- and post-operative MRD, IICD, HFL, and the IICD/HFL ratio. CONCLUSION: An early TUTOPATCH-assisted frontalis suspension, together with the correction of telecanthus and epicanthus inversus, is an effective procedure for BPES cases with severe ptosis. PMID- 26043071 TI - Elevated serum complement C3 levels are related to the development of prediabetes in an adult population: the Tianjin Chronic Low-Grade Systematic Inflammation and Health Cohort Study. AB - AIMS: To investigate whether serum complement C3 is related to the prevalence and incidence of prediabetes in an adult population. METHODS: A cross-sectional (n = 10 206) and prospective cohort study (n = 3333), with a mean (range; 95% CI) follow-up of 2.63 (1-6; 2.58-2.68) years, was conducted in people recruited from the Health Management Centre of Tianjin Medical University General Hospital in Tianjin, China. Measurement of serum C3 concentration, blood fasting glucose, oral glucose tolerance, HbA1c and other potential confounding factors was performed at baseline and each year during the follow-up. Prediabetes was defined according to the criteria of the American Diabetes Association. Adjusted logistic and Cox proportional hazards regression models were used to assess the relationships between C3 quintiles and prediabetes. RESULTS: The prevalence and incidence of prediabetes were 38.5% and 119 per 1000 person-years, respectively. In cross-sectional analysis, after adjustment for potential confounders, the odds ratios of prediabetes for increasing quintiles of C3 were 1.00 (reference), 1.32 (95% CI 1.14-1.53), 1.37 (95% CI 1.18-1.59), 1.75 (95% CI 1.51-2.03), 2.25 (95% CI 1.93-2.62; P for trend < 0.0001). In the cohort analysis, the multiple adjusted hazard ratio of prediabetes in the highest quintile of baseline C3 was 1.43 (95% CI 1.15, 1.78; P for trend < 0.001), when compared with the lowest quintile. CONCLUSIONS: These findings indicate that elevated serum C3 levels are significantly related to an increased risk of developing prediabetes in an adult population, suggesting that C3 can be used as a biomarker in high-risk individuals to improve primary prevention of prediabetes and diabetes. PMID- 26043073 TI - Conceptualizing the use of public involvement in health policy decision-making. AB - The concept of public involvement use is not well-defined in the literature. Previous research studies have provided brief accounts of how public involvement may influence health policy, but have not detailed the internal dynamics and process through which it is actually used in the policy process. The study objective is to examine and clarify the concept and process of public involvement use in health policy decision-making. Using qualitative concept analysis methods, we reviewed the literature on the use of public involvement and conducted semi structured interviews with key informants who have theoretical and/or practical insights on public involvement and its use in policy decision-making. Our findings are organized around interrelated questions that animate how the concept of use is understood, interpreted, and operationalized. In asking, "How is 'use' perceived in relation to health policy decision-making?" meanings are constructed for the concept by identifying differences and drawing connections between "use" and related terms. In asking "How would one know if public involvement was used in health policy decision-making?" our findings weigh in on the act of listening as a precursor to use, the ways in which use is mediated, and responses to the input obtained from public involvement processes as signals of use. These findings are a first step toward improving conceptual clarity about what public involvement use means, how it is understood and interpreted by relevant actors in the public involvement and public policy fields, and how it might be operationalized. We expect our findings to be particularly useful for public involvement practitioners who are often confronted with questions from public involvement participants regarding how their input will be used in health policy decision-making. PMID- 26043074 TI - Voltage-gated sodium channels. AB - Voltage-gated sodium channels play a key role in the transmission of sensory information about the status of organs in the periphery. Sensory fibers contain a heterogeneous yet specific distribution of voltage-gated sodium channel isoforms. Major efforts by industry and academic groups are underway to develop medicines that interrupt inappropriate signaling for a number of clinical indications by taking advantage of this specific distribution of channel isoforms. This review highlights recent advances in the study of human channelopathies, animal toxins and channel structure that may facilitate the development of selective voltage gated sodium channel blockers. PMID- 26043075 TI - Activation of transient receptor potential vanilloid 4 induces apoptosis in hippocampus through downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways. AB - Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable cation channel that is sensitive to cell swelling, arachidonic acid and its metabolites, epoxyeicosatrienoic acids, which are associated with cerebral ischemia. The activation of TRPV4 induces cytotoxicity in many types of cells, accompanied by an increase in the intracellular free calcium concentration. TRPV4 activation modulates the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3 kinase (PI3K)/ protein kinase B (Akt) signaling pathways that regulate cell death and survival. Herein, we examined TRPV4-induced neuronal apoptosis by intracerebroventricular (ICV) injection of a TRPV4 agonist (GSK1016790A) and assessed its involvement in cerebral ischemic injury. ICV injection of GSK1016790A dose-dependently induced apoptosis in the mouse hippocampi (GSK injected mice). The protein level of phosphorylated p38 MAPK (p-p38 MAPK) was markedly increased and that of phosphorylated c-Jun N-terminal protein kinase (p JNK) was virtually unchanged. TRPV4 activation also decreased Bcl-2/Bax protein ratio and increased the cleaved caspase-3 protein level, and these effects were blocked by a PI3K agonist and a p38 MAPK antagonist, but were unaffected by a JNK antagonist. ICV injection of the TRPV4 antagonist HC-067047 reduced brain infarction after reperfusion for 48 h in mice with middle cerebral artery occlusion (MCAO). In addition, HC-067047 treatment attenuated the decrease in the phosphorylated Akt protein level and the increase in p-p38 MAPK protein level at 48 h after MCAO, while the increase in p-JNK protein level remained unchanged. Finally, the decreased Bcl-2/Bax protein ratio and the increased cleaved caspase 3 protein level at 48 h after MCAO were markedly attenuated by HC-067047. We conclude that activation of TRPV4 induces apoptosis by downregulating PI3K/Akt and upregulating p38 MAPK signaling pathways, which is involved in cerebral ischemic injury. PMID- 26043076 TI - Chloride transporter KCC2-dependent neuroprotection depends on the N-terminal protein domain. AB - Neurodegeneration is a serious issue of neurodegenerative diseases including epilepsy. Downregulation of the chloride transporter KCC2 in the epileptic tissue may not only affect regulation of the polarity of GABAergic synaptic transmission but also neuronal survival. Here, we addressed the mechanisms of KCC2-dependent neuroprotection by assessing truncated and mutated KCC2 variants in different neurotoxicity models. The results identify a threonine- and tyrosine phosphorylation-resistant KCC2 variant with increased chloride transport activity, but they also identify the KCC2 N-terminal domain (NTD) as the relevant minimal KCC2 protein domain that is sufficient for neuroprotection. As ectopic expression of the KCC2-NTD works independently of full-length KCC2-dependent regulation of Cl(-) transport or structural KCC2 C-terminus-dependent regulation of synaptogenesis, our study may pave the way for a selective neuroprotective therapeutic strategy that will be applicable to a wide range of neurodegenerative diseases. PMID- 26043077 TI - Brain death and marginal grafts in liver transplantation. AB - It is well known that most organs for transplantation are currently procured from brain-dead donors; however, the presence of brain death is an important risk factor in liver transplantation. In addition, one of the mechanisms to avoid the shortage of liver grafts for transplant is the use of marginal livers, which may show higher risk of primary non-function or initial poor function. To our knowledge, very few reviews have focused in the field of liver transplantation using brain-dead donors; moreover, reviews that focused on both brain death and marginal grafts in liver transplantation, both being key risk factors in clinical practice, have not been published elsewhere. The present review aims to describe the recent findings and the state-of-the-art knowledge regarding the pathophysiological changes occurring during brain death, their effects on marginal liver grafts and summarize the more controversial topics of this pathology. We also review the therapeutic strategies designed to date to reduce the detrimental effects of brain death in both marginal and optimal livers, attempting to explain why such strategies have not solved the clinical problem of liver transplantation. PMID- 26043078 TI - Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation. AB - While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1 1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-xL leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1. PMID- 26043080 TI - Analysis of weight distribution strategies in unilateral transtibial amputees during the stand-to-sit activity. AB - Current methods of quantifying the stand-to-sit activity (StTS) are resource intensive and have not been applied to unilateral transtibial amputees (TTAs). The purpose of this study is to define five phases of arm-rest assisted and unassisted StTS using simple instrumentation and implement this method for assessing TTA movement patterns. Twelve TTAs and 12 age-matched non-amputees performed StTS with and without arm-rest support. Symmetry of weight distribution between lower limbs was calculated for five StTS phases: Descent Initiation; Descent Deceleration; Seat-Contact; Stabilisation and Sitting. TTAs demonstrated an asymmetrical weight distribution pattern and a tendency to transfer weight to the intact limb during the course of the activity. Non-amputees had relatively higher symmetry and did not exhibit substantial weight shifts during the activity. Symmetry indices were similar for assisted and unassisted sitting in both subject groups. These results highlight a need for therapeutic interventions in TTAs for reducing loading asymmetries and associated co-morbidities. PRACTITIONER SUMMARY: This study defines a novel method for quantifying stand-to sit movements using clinically friendly equipment and is the first to investigate the stand-to-sit activity of unilateral transtibial amputees. The observed differences in inter-limb weight distribution strategies between amputees and non amputees could provide insights for clinical assessment and intervention. PMID- 26043079 TI - Microglia-derived IL-1beta triggers p53-mediated cell cycle arrest and apoptosis in neural precursor cells. AB - Neurogenesis persists in the adult brain and can contribute to learning and memory processes and potentially to regeneration and repair of the affected nervous system. Deregulated neurogenesis has been observed in neuropathological conditions including neurodegenerative diseases, trauma and stroke. However, the survival of neural precursor cells (NPCs) and newly born neurons is adversely affected by the inflammatory environment that arises as a result of microglial activation associated with injury or disease processes. In the present study, we have investigated the mechanisms by which microglia affect NPC proliferation and survival. Importantly, we demonstrate that interleukin-1beta (IL-1beta) produced by lipopolysaccharide/interferon-gamma-activated microglia is necessary to induce cell cycle arrest and apoptosis in NPCs in vitro. Mechanistically, we show that IL-1beta activates the tumor suppressor p53 through an oxidative stress-dependent mechanism resulting in p53-mediated induction of the cyclin-dependent kinase inhibitor p21 and the proapoptotic Bcl-2 (B-cell lymphoma-2) family members Puma (p53-upregulated modulator of apoptosis) and Noxa. Furthermore, we demonstrate that cell cycle arrest and apoptosis induced by recombinant IL-1beta or activated microglia is attenuated in p53-deficient NPCs. Finally, we have determined that IL-1beta induces NPC death via the p53-dependent induction of Puma leading to the activation of a Bax (Bcl-2-associated X protein)-mediated mitochondrial apoptotic pathway. In summary, we have elucidated a novel role for p53 in the regulation of NPC proliferation and survival during neuroinflammatory conditions that could be targeted to promote neurogenesis and repair in a number of neurological conditions. PMID- 26043081 TI - Facile Synthesis of Spirocyclic Lactams from beta-Keto Carboxylic Acids. AB - A facile synthesis of spirocyclic lactams starting from beta-keto carboxylic acids via a one-pot cascade reaction involving a Curtius rearrangement and an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate is reported. The same conditions have also been used for the generation of fused cyclic lactams with similar good yields. The synthetic value of this method has been demonstrated by efficient synthesis of tetracyclic spirolactam 8 and pentacyclic spirolactam 9. PMID- 26043083 TI - Stimuli-Responsive Surfaces for Tunable and Reversible Control of Wettability. AB - Surfaces with controllable wettability can be fabricated by embedding superhydrophobic particles into stimuli-responsive hydrogels. When the hydrogel changes its size due to a specific stimulus, the wettability of the surface can be reversibly tuned from superhydrophobic to superhydrophilic. This general method is used to fabricate "smart" membranes for controlling the permeability of chemicals under the influence of multiple stimuli simultaneously. PMID- 26043082 TI - Brazilian pediatric reference data for quantitative ultrasound of phalanges according to gender, age, height and weight. AB - AIMS: To establish normative data for phalangeal quantitative ultrasound (QUS) measures in Brazilian students. METHODS: The sample was composed of 6870 students (3688 females and 3182 males), aged 6 to 17 years. The bone status parameter, Amplitude Dependent Speed of Sound (AD-SoS) was assessed by QUS of the phalanges using DBM Sonic BP (IGEA, Carpi, Italy) equipment. Skin color was obtained by self-evaluation. The LMS method was used to derive smoothed percentiles reference charts for AD-SoS according to sex, age, height and weight and to generate the L, M, and S parameters. RESULTS: Girls showed higher AD-SoS values than boys in the age groups 7-16 (p<0.001). There were no differences on AD-SoS Z-scores according to skin color. In both sexes, the obese group showed lower values of AD-SoS Z scores compared with subjects classified as thin or normal weight. Age (r2 = 0.48) and height (r2 = 0.35) were independent predictors of AD-SoS in females and males, respectively. CONCLUSION: AD-SoS values in Brazilian children and adolescents were influenced by sex, age and weight status, but not by skin color. Our normative data could be used for monitoring AD-SoS in children or adolescents aged 6-17 years. PMID- 26043084 TI - MiR-130a and MiR-374a Function as Novel Regulators of Cisplatin Resistance in Human Ovarian Cancer A2780 Cells. AB - Chemoresistance remains a major obstacle to effective treatment in patients with ovarian cancer, and recently increasing evidences suggest that miRNAs are involved in drug-resistance. In this study, we investigated the role of miRNAs in regulating cisplatin resistance in ovarian cancer cell line and analyzed their possible mechanisms. We profiled miRNAs differentially expressed in cisplatin resistant human ovarian cancer cell line A2780/DDP compared with parental A2780 cells using microarray. Four abnormally expressed miRNAs were selected (miR-146a, 130a, -374a and miR-182) for further studies. Their expression were verified by qRT-PCR. MiRNA mimics or inhibitor were transfected into A2780 and A2780/DDP cells and then drug sensitivity was analyzed by MTS array. RT-PCR and Western blot were carried out to examine the alteration of MDR1, PTEN gene expression. A total of 32 miRNAs were found to be differentially expressed in A2780/DDP cells. Among them, miR-146a was down-regulated and miR-130a,-374a,-182 were upregulated in A2780/DDP cells, which was verified by RT-PCR. MiR-130a and miR-374a mimics decreased the sensitivity of A2780 cells to cisplatin, reversely, their inhibitors could resensitize A2780/DDP cells. Furthermore, overexpression of miR 130a could increase the MDR1 mRNA and P-gp levels in A2780 and A2780/DDP cells, whereas knockdown of miR-130a could inhibit MDR1 gene expression and upregulate the PTEN protein expression .In a conclusion, the deregulation of miR-374a and miR-130a may be involved in the development and regulation of cisplatin resistance in ovarian cancer cells. This role of miR-130a may be achieved by regulating the MDR1 and PTEN gene expression. PMID- 26043086 TI - Characterisation and determination of fullerenes: A critical review. AB - A prominent sector of nanotechnology is occupied by a class of carbon-based nanoparticles known as fullerenes. Fullerene particle size and shape impact in how easily these particles are transported into and throughout the environment and living tissues. Currently, there is a lack of adequate methodology for their size and shape characterisation, identification and quantitative detection in environmental and biological samples. The most commonly used methods for their size measurements (aggregation, size distribution, shape, etc.), the effect of sampling and sample treatment on these characteristics and the analytical methods proposed for their determination in complex matrices are discussed in this review. For the characterisation and analysis of fullerenes in real samples, different analytical techniques including microscopy, spectroscopy, flow field flow fractionation, electrophoresis, light scattering, liquid chromatography and mass spectrometry have been reported. The existing limitations and knowledge gaps in the use of these techniques are discussed and the necessity to hyphenate complementary ones for the accurate characterisation, identification and quantitation of these nanoparticles is highlighted. PMID- 26043085 TI - Leveraging Identity-by-Descent for Accurate Genotype Inference in Family Sequencing Data. AB - Sequencing family DNA samples provides an attractive alternative to population based designs to identify rare variants associated with human disease due to the enrichment of causal variants in pedigrees. Previous studies showed that genotype calling accuracy can be improved by modeling family relatedness compared to standard calling algorithms. Current family-based variant calling methods use sequencing data on single variants and ignore the identity-by-descent (IBD) sharing along the genome. In this study we describe a new computational framework to accurately estimate the IBD sharing from the sequencing data, and to utilize the inferred IBD among family members to jointly call genotypes in pedigrees. Through simulations and application to real data, we showed that IBD can be reliably estimated across the genome, even at very low coverage (e.g. 2X), and genotype accuracy can be dramatically improved. Moreover, the improvement is more pronounced for variants with low frequencies, especially at low to intermediate coverage (e.g. 10X to 20X), making our approach effective in studying rare variants in cost-effective whole genome sequencing in pedigrees. We hope that our tool is useful to the research community for identifying rare variants for human disease through family-based sequencing. PMID- 26043087 TI - A label-free and self-assembled electrochemical biosensor for highly sensitive detection of cyclic diguanylate monophosphate (c-di-GMP) based on RNA riboswitch. AB - Cyclic diguanylate monophosphate (c-di-GMP) is an important second messenger that regulates a variety of complex physiological processes involved in motility, virulence, biofilm formation and cell cycle progression in several bacteria. Herein we report a simple label-free and self-assembled RNA riboswitch-based biosensor for sensitive and selective detection of c-di-GMP. The detectable concentration range of c-di-GMP is from 50 nM to 1 MUM with a detection limit of 50 nM. PMID- 26043088 TI - Sensitive detection of a serum biomarker based on peptide nucleic acid-coupled dual cycling reactions. AB - Serum level of disease markers may provide important guidance for diagnosis and prognosis. In this work, a sensitive and specific method suitable for direct serum detection of biomarkers is developed based on peptide nucleic acid (PNA) coupled DNA cycling reactions with dual amplification. In this method, PNA released from a target-triggered homogeneous DNA cycling is employed to initiate an interface DNA cycling, and both of the cycling reactions are based on polymerase-assisted strand displacement reaction. Consequently, two PNA-coupled DNA cycling steps can take place simultaneously in one-pot, leading to greatly enhanced limit of detection and simplified operation. This method has also been successfully applied for evaluating serum insulin in pregnant women as an indicator of gestational diabetes mellitus. So the application of this method in real bio-samples may allow it to hold considerable potential in clinical practice. In addition, since there is no requirement for specific sequence of aptamer, the strategy proposed can be extended for the detection of many other protein markers and peptide-hormones in the future. PMID- 26043089 TI - Label-free electrochemical aptasensor constructed by layer-by-layer technology for sensitive and selective detection of cancer cells. AB - Here, a cytosensor was constructed with ferrocene-appended poly(allylamine hydrochloride) (Fc-PAH) functionalized graphene (Fc-PAH-G), poly(sodium-p styrenesulfonate) (PSS) and aptamer (AS1411) by layer-by-layer assembly technology. The hybrid nanocomposite Fc-PAH-G not only brings probes on the electrode and also promotes electron transfer between the probes and the substrate electrode. Meanwhile, LBL technology provides more effective probes to enhance amplified signal for improving the sensitivity of the detection. While AS1411 forming G-quardruplex structure and binding cancer cells, the current response of the sensing electrode decreased due to the insulating properties of cellular membrane. Differential pulse voltammetry (DPV) was performed to investigate the electrochemical detection of HeLa cells attributing to its sensitivity of the current signal change. The as-prepared aptasensor showed a high sensitivity and good stability, a widely detection range from 10 to 10(6) cells/mL with a detection limit as low as 10 cells/mL for the detection of cancer cells. PMID- 26043090 TI - Quantitative analysis of low-abundance serological proteins with peptide affinity based enrichment and pseudo-multiple reaction monitoring by hybrid quadrupole time-of-flight mass spectrometry. AB - Multiple reaction monitoring (MRM) is commonly used for the quantitative analysis of proteins during mass pectrometry (MS), and has excellent specificity and sensitivity for an analyte in a complex sample. In this study, a pseudo-MRM method for the quantitative analysis of low-abundance serological proteins was developed using hybrid quadrupole time-of-flight (hybrid Q-TOF) MS and peptide affinity-based enrichment. First, a pseudo-MRM-based analysis using hybrid Q-TOF MS was performed for synthetic peptides selected as targets and spiked into tryptic digests of human serum. By integrating multiple transition signals corresponding to fragment ions in the full scan MS/MS spectrum of a precursor ion of the target peptide, a pseudo-MRM MS analysis of the target peptide showed an increased signal-to-noise (S/N) ratio and sensitivity, as well as an improved reproducibility. The pseudo-MRM method was then used for the quantitative analysis of the tryptic peptides of two low-abundance serological proteins, tissue inhibitor of metalloproteinase 1 (TIMP1) and tissue-type protein tyrosine phosphatase kappa (PTPkappa), which were prepared with peptide affinity-based enrichment from human serum. Finally, this method was used to detect femtomolar amounts of target peptides derived from TIMP1 and PTPkappa, with good coefficients of variation (CV 2.7% and 9.8%, respectively), using a few microliters of human serum from colorectal cancer patients. The results suggest that pseudo-MRM using hybrid Q-TOF MS, combined with peptide affinity-based enrichment, could become a promising alternative for the quantitative analysis of low-abundance target proteins of interest in complex serum samples that avoids protein depletion. PMID- 26043091 TI - Coumarins as new matrices for matrix-assisted laser-desorption/ionization Fourier transform ion cyclotron resonance mass spectrometric analysis of hydrophobic compounds. AB - Hydrophobic compounds with hydroxyl, aldehyde or ketone groups are generally difficult to detect using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), because these compounds have low proton affinity and are poorly ionized by MALDI. Herein, coumarins have been used as new matrices for MALDI-MS analysis of a variety of hydrophobic compounds with low ionization efficiency, including steroids, coenzyme Q10, a cyclic lipopeptide and cholesterol oleate. Five coumarins, including coumarin, umbelliferone, esculetin, 7-hydroxycoumarin-3-carboxylic acid (HCA) and 6,7-dihydroxycoumarin-3-carboxylic acid (DCA), were compared with the conventional matrices of 2,5-dihydroxybenzoic acid (DHB) and alpha-cyano-4-hydroxycinnamic acid (CHCA). Coumarins with hydroxyl or carboxylic acid groups enabled detection. Taking DCA as an example, this matrix proved to be superior to DHB or CHCA in detection sensitivity, stability, spot-to-spot and sample-to-sample reproducibility, and accuracy. DCA increased the stability of the target compounds and decreased the loss of water. The [M+Na](+) peaks were observed for all target compounds by adding NaCl as an additive, and the [M-H2O+H](+) and [M+H](+) peaks decreased. DCA was selected for the identification of sterols in yeast cells, and thirteen sterols were detected by Fourier transform ion cyclotron resonance (FT ICR) mass spectrometry. This work demonstrates the potential of DCA as a new matrix for detection of hydrophobic molecules by MALDI-MS and provides an alternative tool for screening sterols in antifungal research. PMID- 26043092 TI - A colorimetric sensor array for detection and discrimination of biothiols based on aggregation of gold nanoparticles. AB - Developments of sensitive, rapid, and cheap systems for identification of a wide range of biomolecules have been recognized as a critical need in the biology field. Here, we introduce a simple colorimetric sensor array for detection of biological thiols, based on aggregation of three types of surface engineered gold nanoparticles (AuNPs). The low-molecular-weight biological thiols show high affinity to the surface of AuNPs; this causes replacement of AuNPs' shells with thiol containing target molecules leading to the aggregation of the AuNPs through intermolecular electrostatic interaction or hydrogen-bonding. As a result of the predetermined aggregation, color and UV-vis spectra of AuNPs are changed. We employed the digital mapping approach to analyze the spectral variations with statistical and chemometric methods, including hierarchical cluster analysis (HCA) and principal component analysis (PCA). The proposed array could successfully differentiate biological molecules (e.g., cysteine, glutathione and glutathione disulfide) from other potential interferences such as amino acids in the concentration range of 10-800 MUmol L(-1). PMID- 26043093 TI - A highly selective turn-on fluorescent probe for hypochlorous acid based on hypochlorous acid-induced oxidative intramolecular cyclization of boron dipyrromethene-hydrazone. AB - A BODIPY-based fluorescent probe, HBP, was developed for the detection of hypochlorous acid based on the specific hypochlorous acid-promoted oxidative intramolecular cyclization of heterocyclic hydrazone in response to the amount of HOCl. The reaction is accompanied by a 41-fold increase in the fluorescent quantum yield (from 0.004 to 0.164). The fluorescence intensity of the reaction between HOCl and HBP is linear in the HOCl concentration range of 1-8 MUM with a detection limit of 2.4 nM (S/N=3). Confocal fluorescence microscopy imaging using RAW264.7 cells showed that the new probe HBP could be used as an effective fluorescent probe for detecting HOCl in living cells. PMID- 26043094 TI - A near-infrared emissive Al(3+) sensing platform for specific detection in solution, cells and probing DNase activity. AB - A new tricarbocyanine-based chemosensor exhibited a dramatic Al(3+)-specific fluorescence turn-on response in the near-infrared (NIR) region. The receptor was found to be highly selective towards Al(3+) over other metal ions in physiological condition. The sensor was non-toxic and could thus be employed as an imaging probe for detecting intracellular Al(3+) in live cells. Interestingly, upon interaction with DNA in solution, the L-Al(3+) ensemble rendered tracking of DNase activity in solution through a systematic reduction in the fluorescence emission intensity. PMID- 26043096 TI - Determination of carbohydrates in tobacco by pressurized liquid extraction combined with a novel ultrasound-assisted dispersive liquid-liquid microextraction method. AB - A novel derivatization-ultrasonic assisted-dispersive liquid-liquid microextraction (UA-DLLME) method for the simultaneous determination of 11 main carbohydrates in tobacco has been developed. The combined method involves pressurized liquid extraction (PLE), derivatization, and UA-DLLME, followed by the analysis of the main carbohydrates with a gas chromatography-flame ionization detector (GC-FID). First, the PLE conditions were optimized using a univariate approach. Then, the derivatization methods were properly compared and optimized. The aldononitrile acetate method combined with the O-methoxyoxime-trimethylsilyl method was used for derivatization. Finally, the critical variables affecting the UA-DLLME extraction efficiency were searched using fractional factorial design (FFD) and further optimized using Doehlert design (DD) of the response surface methodology. The optimum conditions were found to be 44 MUL for CHCl3, 2.3 mL for H2O, 11% w/v for NaCl, 5 min for the extraction time and 5 min for the centrifugation time. Under the optimized experimental conditions, the detection limit of the method (LODs) and linear correlation coefficient were found to be in the range of 0.06-0.90 MUg mL(-1) and 0.9987-0.9999. The proposed method was successfully employed to analyze three flue-cured tobacco cultivars, among which the main carbohydrate concentrations were found to be very different. PMID- 26043095 TI - Single-step, paper-based concentration and detection of a malaria biomarker. AB - The lateral-flow immunoassay (LFA) is an inexpensive and rapid paper-based assay that can potentially detect infectious disease biomarkers in resource-poor settings. Despite its many advantages that make it suitable for point-of-care diagnosis, LFA is limited by its inferior sensitivity relative to sophisticated laboratory-based assays. Our group previously introduced the use of a micellar aqueous two-phase system (ATPS), comprised of the nonionic Triton X-114 surfactant, to concentrate biomarkers in a sample and enhance their detection with LFA. However, achieving complete phase separation and target concentration using the Triton X-114 system required many hours, and the concentrated sample needed to be manually extracted and applied to LFA. Here, we successfully integrated the concentration and detection steps into a single step that occurs entirely within a portable paper-based diagnostic strip. In a novel approach, we applied the micellar ATPS to a 3-D paper design and effectively reduced the macroscopic phase separation time from 8 h to approximately 3 min. The 3-D design was integrated with LFA to simultaneously concentrate and detect Plasmodium lactate dehydrogenase (pLDH), a malaria biomarker, in both phosphate-buffered saline and fetal bovine serum within 20 min at room temperature. Compared to a conventional LFA setup with a pLDH detection limit of 10 ng MUL(-1), our single step diagnostic successfully detected pLDH at 1.0 ng MUL(-1), demonstrating a 10 fold detection limit improvement and resulting in a sensitive and user-friendly assay that can be used at the point-of-care. The integration of a micellar ATPS and LFA represents a new platform that can improve and promote the use of paper based diagnostic assays for malaria and other diseases within resource-poor settings. PMID- 26043097 TI - Advanced dress-up chiral columns: New removable chiral stationary phases for enantioseparation of chiral carboxylic acids. AB - This paper describes the preparation of new dress-up columns featuring reproducibly removable and replaceable chiral stationary phases. After synthesizing perfluroalkylated quinine and quinidine derivatives as chiral stationary phase compounds (F-CSPs), we adsorbed them reversibly onto a fluorous LC column through pumping of their solutions. Using this dress-up chiral column and fluorophobic elution of aqueous ammonium formate/MeOH mixtures, we could enantioseparate four racemic N-acetyl amino acids, dichlorprop, and sixteen fluorescent 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC)-derivatized amino acids. Dressing and undressing of the coated F-CSPs could be controlled by varying the fluorophilicity and fluorophobicity of the eluent. The relative standard deviations of the retention times, the retention factors, the number of theoretical plates, the enantioseparation factors, and the resolutions of each of four preparations of such dress-up columns were all less than or equal to 5.26% (from 20 repeated analyses); the reproducibilities from four different preparations were all less than or equal to 10.6%. These columns also facilitated highly sensitive and selective analyses of AQC-amino acids when detected using LC MS/MS. PMID- 26043098 TI - Determination of chiral pharmaceuticals and illicit drugs in wastewater and sludge using microwave assisted extraction, solid-phase extraction and chiral liquid chromatography coupled with tandem mass spectrometry. AB - This is the first study presenting a multi-residue method allowing for comprehensive analysis of several chiral pharmacologically active compounds (cPACs) including beta-blockers, antidepressants and amphetamines in wastewater and digested sludge at the enantiomeric level. Analysis of both the liquid and solid matrices within wastewater treatment is crucial to being able to carry out mass balance within these systems. The method developed comprises filtration, microwave assisted extraction and solid phase extraction followed by chiral liquid chromatography coupled with tandem mass spectrometry to analyse the enantiomers of 18 compounds within all three matrices. The method was successfully validated for 10 compounds within all three matrices (amphetamine, methamphetamine, MDMA, MDA, venlafaxine, desmethylvenlafaxine, citalopram, metoprolol, propranolol and sotalol), 7 compounds validated for the liquid matrices only (mirtazapine, salbutamol, fluoxetine, desmethylcitalopram, atenolol, ephedrine and pseudoephedrine) and 1 compound (alprenolol) passing the criteria for solid samples only. The method was then applied to wastewater samples; cPACs were found at concentration ranges in liquid matrices of: 1.7 ng L(-1) (metoprolol) - 1321 ng L(-1) (tramadol) in influent, 99.8%) without apparent defects or secondary phases. The EDX and HRTEM characterization confirm that the template layers act as an efficient diffusion barrier and form a sharp interface between the substrate and the PZT. The electrical measurements indicate a dielectric constant of ~650, low dielectric loss of ~0.02, coercive field of 70 kV/cm, remnant polarization of 25 MUC/cm(2), and large breakdown electric field of 1000 kV/cm. Finally, the effective electro-optic coefficients of the films are estimated with a spectroscopic ellipsometer measurement, considering the electric field induced variations in the phase reflectance ratio. The electro-optic measurements reveal excellent linear effective pockels coefficients of 110 to 240 pm/V, which makes the CSD deposited PZT thin film an ideal candidate for Si-based active integrated nanophotonic devices. PMID- 26043102 TI - Structural Abnormalities of the Inner Macula in Incontinentia Pigmenti. AB - IMPORTANCE: This report presents evidence from spectral-domain optical coherence tomography and fluorescein angiography of inner foveal structural abnormalities associated with vision loss in incontinentia pigmenti (IP). OBSERVATIONS: Two children had reduced visual behavior in association with abnormalities of the inner foveal layers on spectral-domain optical coherence tomography. Fluorescein angiography showed filling defects in retinal and choroidal circulations and irregularities of the foveal avascular zones. The foveal to parafoveal ratios were greater than 0.57 in 6 eyes of 3 patients who had extraretinal neovascularization and/or peripheral avascular retina on fluorescein angiography and were treated with laser. Of these, 3 eyes of 2 patients had irregularities in foveal avascular zones and poor vision. CONCLUSIONS AND RELEVANCE: Besides traction retinal detachment, vision loss in IP can occur with abnormalities of the inner foveal structure seen on spectral-domain optical coherence tomography, consistent with prior descriptions of foveal hypoplasia. The evolution of abnormalities in the neural and vascular retina suggests a vascular cause of the foveal structural changes. More study is needed to determine any potential benefit of the foveal to parafoveal ratio in children with IP. Even with marked foveal structural abnormalities, vision can be preserved in some patients with IP with vigilant surveillance in the early years of life. PMID- 26043104 TI - Structure and Mechanism of the Siderophore-Interacting Protein from the Fuscachelin Gene Cluster of Thermobifida fusca. AB - Microbial iron acquisition is a complex process and frequently a key and necessary step for survival. Among the several paths for iron assimilation, small molecule siderophore-mediated transport is a commonly employed strategy of many microorganisms. The chemistry and biology of the extraordinary tight and specific binding of siderophores to metal is also exploited in therapeutic treatments for microbial virulence and metal toxicity. The intracellular fate of iron acquired via the siderophore pathway is one of the least understood steps in the complex process at the molecular level. A common route to cellular incorporation is the single-electron reduction of ferric to ferrous iron catalyzed by specific and/or nonspecific reducing agents. The biosynthetic gene clusters for siderophores often contain representatives of one or two families of redox-active enzymes: the flavin-containing "siderophore-interacting protein" and iron-sulfur ferric siderophore reductases. Here we present the structure and characterization of the siderophore-interacting protein, FscN, from the fuscachelin siderophore gene cluster of Thermobifida fusca. The structure shows a flavoreductase fold with a noncovalently bound FAD cofactor along with an unexpected metal bound adjacent to the flavin site. We demonstrated that FscN is redox-active and measured the binding and reduction of ferric fuscachelin. This work provides a structural basis for the activity of a siderophore-interacting protein and further insight into the complex and important process of iron acquisition and utilization. PMID- 26043105 TI - On the use of randomization tests following adaptive designs. AB - Randomization tests (sometimes referred to as "re-randomization" tests) are used in clinical trials, either as an assumption-free confirmation of parametric analyses, or as an independent analysis based on the principle of randomization based inference. In the context of adaptive randomization, either restricted or response-adaptive procedures, it is unclear how accurate such Monte Carlo approximations are, or how many Monte Carlo sequences to generate. In this paper, we describe several randomization procedures for which there is a known exact or asymptotic distribution of the randomization test. For a special class of procedures, called [Formula: see text], and binary responses, the exact test statistic has a simple closed form. For the limited subset of existing procedures with known exact and asymptotic distributions, we can use these as a benchmark for the accuracy of Monte Carlo randomization techniques. We conclude that Monte Carlo tests are very accurate, and require minimal computation time. For simple tests with binary response in the class of [Formula: see text] procedures, the exact distribution provides the best test, but Monte Carlo approximations can be used when the exact distribution is difficult to compute. PMID- 26043106 TI - Novel epigenetic changes unveiled by monozygotic twins discordant for smoking habits. AB - Exposure to cigarette smoking affects the epigenome and could increase the risk of developing diseases such as cancer and cardiovascular disorders. Changes in DNA methylation associated with smoking may help to identify molecular pathways that contribute to disease etiology. Previous studies are not completely concordant in the identification of differentially methylated regions in the DNA of smokers. We performed an epigenome-wide DNA methylation study in a group of monozygotic (MZ) twins discordant for smoking habits to determine the effect of smoking on DNA methylation. As MZ twins are considered genetically identical, this model allowed us to identify smoking-related DNA methylation changes independent from genetic components. We investigated the whole blood genome-wide DNA methylation profiles in 20 MZ twin pairs discordant for smoking habits by using the Illumina HumanMethylation450 BeadChip. We identified 22 CpG sites that were differentially methylated between smoker and non-smoker MZ twins by intra pair analysis. We confirmed eight loci already described by other groups, located in AHRR, F2RL3, MYOG1 genes, at 2q37.1 and 6p21.33 regions, and also identified several new loci. Moreover, pathway analysis showed an enrichment of genes involved in GTPase regulatory activity. Our study confirmed the evidence of smoking-related DNA methylation changes, emphasizing that well-designed MZ twin models can aid the discovery of novel DNA methylation signals, even in a limited sample population. PMID- 26043107 TI - Towards a model of contemporary parenting: the parenting behaviours and dimensions questionnaire. AB - The assessment of parenting has been problematic due to theoretical disagreement, concerns over generalisability, and problems with the psychometric properties of current parenting measures. The aim of this study was to develop a comprehensive, psychometrically sound self-report parenting measure for use with parents of preadolescent children, and to use this empirical scale development process to identify the core dimensions of contemporary parenting behaviour. Following item generation and parent review, 846 parents completed an online survey comprising 116 parenting items. Exploratory and confirmatory factor analyses supported a six factor parenting model, comprising Emotional Warmth, Punitive Discipline, Anxious Intrusiveness, Autonomy Support, Permissive Discipline and Democratic Discipline. This measure will allow for the comprehensive and consistent assessment of parenting in future research and practice. PMID- 26043108 TI - The Ankyrin Repeat Domain 49 (ANKRD49) Augments Autophagy of Serum-Starved GC-1 Cells through the NF-kappaB Pathway. AB - The ankyrin repeat domain 49 (ANKRD49) is an evolutionarily conserved protein highly expressed in testes. However, the function of ANKRD49 in spermatogenesis is unknown. In this study, we found that ANKRD49 resides primarily in nucleus of spermatogonia, spermatocytes and round spermatids. ANKRD49 overexpression augments starvation-induced autophagy in male germ GC-1 cells whereas shRNA knockdown of ANKRD49 attenuates the autophagy. Inhibition of NF-kappaB pathway by its inhibitors or p65 siRNA prevents the ANKRD49-dependent autophagy augmentation, demonstrating that ANKRD49 enhances autophagy via NF-kappaB pathway. Our findings suggest that ANKRD49 plays an important role in spermatogenesis via promotion of autophagy-dependent survival. PMID- 26043109 TI - Ultrasensitive and highly selective graphene-based single yarn for use in wearable gas sensor. AB - Electric components based on fibers or textiles have been investigated owing to their potential applications in wearable devices. High performance on response to gas, drape-ability and washing durability are of important for gas sensors based on fiber substrates. In this report, we demonstrate the bendable and washable electronic textile (e-textile) gas sensors composed of reduced graphene oxides (RGOs) using commercially available yarn and molecular glue through an electrostatic self-assembly. The e-textile gas sensor possesses chemical durability to several detergent washing treatments and mechanical stability under 1,000 bending tests at an extreme bending radius of 1 mm as well as a high response to NO2 gas at room temperature with selectivity to other gases such as acetone, ethanol, ethylene, and CO2. PMID- 26043110 TI - Integrated copy number and expression analysis identifies profiles of whole-arm chromosomal alterations and subgroups with favorable outcome in ovarian clear cell carcinomas. AB - Ovarian clear cell carcinoma (CCC) is generally associated with chemoresistance and poor clinical outcome, even with early diagnosis; whereas high-grade serous carcinomas (SCs) and endometrioid carcinomas (ECs) are commonly chemosensitive at advanced stages. Although an integrated genomic analysis of SC has been performed, conclusive views on copy number and expression profiles for CCC are still limited. In this study, we performed single nucleotide polymorphism analysis with 57 epithelial ovarian cancers (31 CCCs, 14 SCs, and 12 ECs) and microarray expression analysis with 55 cancers (25 CCCs, 16 SCs, and 14 ECs). We then evaluated PIK3CA mutations and ARID1A expression in CCCs. SNP array analysis classified 13% of CCCs into a cluster with high frequency and focal range of copy number alterations (CNAs), significantly lower than for SCs (93%, P < 0.01) and ECs (50%, P = 0.017). The ratio of whole-arm to all CNAs was higher in CCCs (46.9%) than SCs (21.7%; P < 0.0001). SCs with loss of heterozygosity (LOH) of BRCA1 (85%) also had LOH of NF1 and TP53, and LOH of BRCA2 (62%) coexisted with LOH of RB1 and TP53. Microarray analysis classified CCCs into three clusters. One cluster (CCC-2, n = 10) showed more favorable prognosis than the CCC-1 and CCC-3 clusters (P = 0.041). Coexistent alterations of PIK3CA and ARID1A were more common in CCC-1 and CCC-3 (7/11, 64%) than in CCC-2 (0/10, 0%; P < 0.01). Being in cluster CCC-2 was an independent favorable prognostic factor in CCC. In conclusion, CCC was characterized by a high ratio of whole-arm CNAs; whereas CNAs in SC were mainly focal, but preferentially caused LOH of well-known tumor suppressor genes. As such, expression profiles might be useful for sub classification of CCC, and might provide useful information on prognosis. PMID- 26043111 TI - Extra and intracellular synthesis of nickel oxide nanoparticles mediated by dead fungal biomass. AB - The use of dead biomass of the fungus Hypocrea lixii as a biological system is a new, effective and environmentally friendly bioprocess for the production and uptake of nickel oxide nanoparticles (NPs), which has become a promising field in nanobiotechnology. Dead biomass of the fungus was successfully used to convert nickel ions into nickel oxide NPs in aqueous solution. These NPs accumulated intracellularly and extracellularly on the cell wall surface through biosorption. The average size, morphology and location of the NPs were characterized by transmission electron microscopy, high-resolution transmission electron microscopy, scanning electron microscopy, and energy dispersive X-ray spectroscopy. The NPs were mainly spherical and extra and intracellular NPs had an average size of 3.8 nm and 1.25 nm, respectively. X-ray photoelectron spectroscopy analysis confirmed the formation of nickel oxide NPs. Infrared spectroscopy detected the presence of functional amide groups, which are probable involved in particle binding to the biomass. The production of the NPs by dead biomass was analyzed by determining physicochemical parameters and equilibrium concentrations. The present study opens new perspectives for the biosynthesis of nanomaterials, which could become a potential biosorbent for the removal of toxic metals from polluted sites. PMID- 26043117 TI - Correction: Evidence for the Involvement of Loosely Bound Plastosemiquinones in Superoxide Anion Radical Production in Photosystem II. PMID- 26043112 TI - In silico Mechano-Chemical Model of Bone Healing for the Regeneration of Critical Defects: The Effect of BMP-2. AB - The healing of bone defects is a challenge for both tissue engineering and modern orthopaedics. This problem has been addressed through the study of scaffold constructs combined with mechanoregulatory theories, disregarding the influence of chemical factors and their respective delivery devices. Of the chemical factors involved in the bone healing process, bone morphogenetic protein-2 (BMP 2) has been identified as one of the most powerful osteoinductive proteins. The aim of this work is to develop and validate a mechano-chemical regulatory model to study the effect of BMP-2 on the healing of large bone defects in silico. We first collected a range of quantitative experimental data from the literature concerning the effects of BMP-2 on cellular activity, specifically proliferation, migration, differentiation, maturation and extracellular matrix production. These data were then used to define a model governed by mechano-chemical stimuli to simulate the healing of large bone defects under the following conditions: natural healing, an empty hydrogel implanted in the defect and a hydrogel soaked with BMP-2 implanted in the defect. For the latter condition, successful defect healing was predicted, in agreement with previous in vivo experiments. Further in vivo comparisons showed the potential of the model, which accurately predicted bone tissue formation during healing, bone tissue distribution across the defect and the quantity of bone inside the defect. The proposed mechano-chemical model also estimated the effect of BMP-2 on cells and the evolution of healing in large bone defects. This novel in silico tool provides valuable insight for bone tissue regeneration strategies. PMID- 26043118 TI - Long-acting reversible contraception: Findings from the Understanding Fertility Management in Contemporary Australia survey. AB - OBJECTIVES: The aim of this research was to investigate awareness, perceived reliability and consideration of use of long-acting reversible contraception (LARC) among Australians of reproductive age. METHODS: A sample of 18- to 50-year old women and men (N = 2235) was randomly recruited from the Australian electoral roll in 2013. Respondents completed a self-administered, anonymous questionnaire. Data were weighted to reduce non-response bias. Factors associated with perceived reliability and consideration of use of LARC were identified in multivariable analyses. RESULTS: Most respondents had heard of implants (76.5%) and intrauterine contraception (63.7%). However, most did not think implants (56.3%) or IUDs (63.9%) were reliable and would not consider using implants (71.6%) or IUDs (77.5%). Those significantly more likely to perceive LARC as reliable were younger, did not regard religion as important in fertility choices, had private health insurance, had been pregnant and had had an abortion; and women who had a partner. Those more likely to consider using LARC were younger and did not regard religion as important in fertility choices; women who had private health insurance, lived in an area of socioeconomic advantage and had had an abortion; and men without a partner, born in Australia and comfortable talking to a health care provider about contraceptive matters. CONCLUSIONS: Despite high awareness of LARC among Australian adults, its perceived reliability and willingness to use it remain low in certain groups. Targeted interventions that aim to increase knowledge of the benefits and reliability of LARC and allow informed use are recommended. PMID- 26043119 TI - Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. AB - BACKGROUND: Mesenchymal stem cells (MSCs) have been recently demonstrated as a promising stem cell type to rescue damaged myocardium after acute infarction. One of the most important mechanisms underlying their therapeutic effects is the secretion of paracrine factors. However, the expression profile of paracrine factors of MSCs in infarcted hearts, especially at single cell level, is poorly defined. METHODS AND RESULTS: We aimed to depict the transcriptional profile of paracrine factors secreted by MSCs in vivo, with particular interest in the comparison between normal and infarcted hearts. Bone marrow mesenchymal stem cells were isolated and injected into mice hearts immediately after infarction surgery. Bioluminescence imaging (BLI) indicated a proportion of cells still alive even up to 10 days post surgery. Paralleled with survived cells, cardiac function was significantly improved after MSC injection compared to that in PBS injected mice, indicated by MRI and histology. Despite increased number of vessels in MSC-injected hearts, endothelial cells and cardiomyocytes transdifferentiation were not observed in infarcted hearts 5 days after infarction. Furthermore, laser capture microdissection (LCM) followed by high through-put real time PCR was employed in our study, uncovering that the injected MSCs, compared to local cardiomyocytes, displayed elevated levels of secreted factors. To further investigate the regulation of those factors, we performed single cell analysis to dissect the gene expression profile of MSCs at single cell level in infarcted and normal hearts, respectively. Consistent with the in vivo observation, a similar regulation pattern of those factors was detected in cultured MSCs under hypoxia. CONCLUSIONS: Our study, for the first time, elucidated gene expression profiles, as well as regulation of paracrine factors, of MSCs at single cell level in vivo, indicating that paracrine factors from MSCs account for the improvement of cardiac function after infarction. PMID- 26043120 TI - Ten-Year Trends in Direct Costs of COPD: A Population-Based Study. AB - BACKGROUND: Up-to-date estimates of burden of diseases are required for evidence based decision-making. The objectives of this study were to determine the excess costs of COPD and its trend from 2001 to 2010 in British Columbia, Canada. METHODS: We used British Columbia's administrative health data to construct a cohort of patients with COPD and a matched comparison cohort of subjects without COPD. We followed each patient from the time of first COPD-related health-care event (or equivalent time for the comparison cohort). Direct medical costs (in 2010 Canadian dollars [$]) were calculated based on billing records pertaining to hospital admissions, outpatient services use, medication dispensations, and community care services. We determined the excess medical costs of COPD by calculating the difference in overall medical costs between the COPD and the comparison cohorts. RESULTS: The COPD and comparison cohorts comprised 153,570 and 246,801 people, respectively (for both cohorts, mean age at entry was 66.9 years; 47.2% female patients). The excess costs of COPD during the study period were $5,452 per patient-year. Inpatient, outpatient, medication, and community care costs were responsible for 57%, 16%, 22%, and 5% of the excess costs, respectively. Excess costs increased by $296/person-y (P < .01), with hospital costs demonstrating the largest increase over time ($258/person-y; P < .01). CONCLUSIONS: The direct economic burden of COPD is high and has increased significantly between 2001 and 2010 over and above the increase in the health care costs of the general population. Further investigation is required to elucidate the underlying reasons for the temporal increase in COPD direct costs. PMID- 26043122 TI - While new salaries grow, debt remains a drag: AVMA report is most thorough study of veterinary debt and income to date. PMID- 26043123 TI - More on pregnant sow housing and animal welfare. PMID- 26043124 TI - What is your diagnosis? Pyonephritis. PMID- 26043125 TI - What is your neurologic diagnosis? Aortic thromboembolic disease (ATE) and hind limb ischemia. PMID- 26043126 TI - Pathology in practice. Jejunal duplication cyst, with minimal segmental lymphoplasmacytic and eosinophilic jejunitis in a dog. PMID- 26043127 TI - Pathology in practice. Distomiasis (fascioliasis) in a New Mexico Dahl sheep. PMID- 26043128 TI - Lessons learned and knowledge gaps about the epidemiology and control of porcine reproductive and respiratory syndrome virus in North America. PMID- 26043130 TI - Correlation between glucose concentrations in serum, plasma, and whole blood measured by a point-of-care glucometer and serum glucose concentration measured by an automated biochemical analyzer for canine and feline blood samples. AB - OBJECTIVE: To investigate the correlation between glucose concentrations in serum, plasma, and whole blood measured by a point-of-care glucometer (POCG) and serum glucose concentration measured by a biochemical analyzer. DESIGN: Prospective clinical study. SAMPLES: 96 blood samples from 80 dogs and 90 blood samples from 65 cats. PROCEDURES: Serum, plasma, and whole blood were obtained from each blood sample. The glucose concentrations in serum, plasma, and whole blood measured by a POCG were compared with the serum glucose concentration measured by a biochemical analyzer by use of the Lin concordance correlation coefficient (rhoc) and Bland-Altman plots. RESULTS: For both canine and feline samples, glucose concentrations in serum and plasma measured by the POCG were more strongly correlated with the serum glucose concentration measured by the biochemical analyzer (rhoc, 0.98 for both canine serum and plasma; rhoc, 0.99 for both feline serum and plasma) than was that in whole blood (rhoc, 0.62 for canine samples; rhoc, 0.90 for feline samples). The mean difference between the glucose concentrations determined by the biochemical analyzer and the POCG in serum, plasma, and whole blood was 0.4, 0.3, and 31 mg/dL, respectively, for canine samples and 7, 6, and 32 mg/dL, respectively, for feline samples. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that use of a POCG to measure glucose concentrations in serum or plasma may increase the accuracy and reliability of diagnostic and treatment decisions associated with glucose homeostasis disorders in dogs and cats. PMID- 26043131 TI - Evaluation of marketing claims, ingredients, and nutrient profiles of over-the counter diets marketed for skin and coat health of dogs. AB - OBJECTIVE: To evaluate marketing claims, ingredients, and nutrient profiles of over-the-counter diets marketed for skin and coat health of dogs. DESIGN: Cross sectional study. SAMPLE: 24 over-the-counter dry and canned diets marketed for skin and coat health of dogs. PROCEDURES: Data on marketing claims and ingredients were collected from diet packaging and manufacturer websites. Concentrations of selected nutrients were obtained by contacting the manufacturers and were compared against minimum values for Association of American Feed Control Officials Dog Food Nutrient Profiles for adult dog maintenance based on calorie content. RESULTS: Most diets incorporated marketing terms such as digestive health, sensitive, or premium that are poorly defined and may have limited relevance to skin, coat, or general health. The types and numbers of major ingredients (ie, potential to contribute protein to the diet) differed. The total number of unique major ingredients in each diet ranged from 3 to 8 (median, 5.5), but the total number of unique ingredients in each diet ranged from 28 to 68 (median, 38). Concentrations of nutrients associated with skin and coat condition also differed widely. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that the large variation among over-the-counter diets marketed for skin and coat health may cause confusion for owners during diet selection. Owners of a dog with dermatologic problems should consult their veterinarian to select a good-quality diet that meets specific nutrient goals. PMID- 26043132 TI - Characteristics of bone fractures and usefulness of micro-computed tomography for fracture detection in rabbits: 210 cases (2007-2013). AB - OBJECTIVE: To characterize bone fractures and the usefulness of micro-CT for imaging fractures in pet rabbits. DESIGN: Retrospective case series. ANIMALS: 210 client-owned rabbits with bone fractures. PROCEDURES: Medical records of rabbits evaluated for bone fractures from 2007 through 2013 were examined. Information was collected on signalment and nature of fractures, and radiographic and micro CT images of fractures were reviewed. RESULTS: Almost half (n = 95 [47.7%]) of fractures were in rabbits < 3 years old. Accidental fall was the most common cause. Vertebral fracture was the most common type of fracture with a nonneoplastic cause (n = 46 [23.2%]) and was most common in the L4-L7 region. The tibia was the most common site for limb fracture among all fractures with a nonneoplastic cause (45 [22.7%]). Twelve (5.7%) fractures had a neoplastic cause, and 7 of these were associated with metastatic uterine adenocarcinoma. Females were significantly more likely to have a fracture caused by neoplasia than were males. Compared with radiography, micro-CT provided more detailed fracture information, particularly for complicated fractures or structures (eg, skull, pelvic, vertebral, and comminuted limb fractures). CONCLUSIONS AND CLINICAL RELEVANCE: Findings were useful for understanding the nature of fractures in pet rabbits and supported the use of micro-CT versus radiography for fracture detection and evaluation. PMID- 26043133 TI - A randomized controlled field trial of a novel trimethoprim-sulfadiazine oral suspension for treatment of Streptococcus equi subsp zooepidemicus infection of the lower respiratory tract in horses. AB - OBJECTIVE: To evaluate the effectiveness of a novel trimethoprim-sulfadiazine oral suspension for the treatment of naturally acquired Streptococcus equi subsp zooepidemicus infection in horses. DESIGN: Randomized, controlled field trial. ANIMALS: 180 horses with S equi subsp zooepidemicus infection. PROCEDURES: Horses with lower respiratory tract infections caused by S equi subsp zooepidemicus were treated with a new formulation of combined trimethoprim-sulfadiazine oral suspension at a dosage of 24 mg/kg (10.9 mg/lb) twice daily for 10 days (treatment group) or with an equivalent volume of saline (0.9% NaCl) solution (placebo group). Response to treatment, including clinical signs and fecal consistency scores, was assessed twice daily. Any adverse effects were recorded. The primary outcome variable was clinical response; the secondary outcome variable was eradication of S equi subsp zooepidemicus on study day 17 as determined by bacteriologic culture of repeated transtracheal-wash specimens. RESULTS: Of the 119 horses allocated to the treatment group, 69 (58%) had a positive clinical response. A significantly smaller proportion of horses in the placebo group (9/61 [15%]) had a positive clinical response. By day 5, 25 of 61 (41%) placebo horses had been withdrawn from the study because of negative clinical response, compared with only 10 of 119 (8.4%) treated horses. By day 10, 28 of 61 (46%) placebo horses had been withdrawn because of negative clinical response, compared with only 13 of 119 (11%) treated horses. There were few adverse events associated with the trimethoprim-sulfadiazine suspension. There were no significant differences in fecal consistency scores between treatment and placebo groups. CONCLUSIONS AND CLINICAL RELEVANCE: The new oral suspension administered at 24 mg/kg twice daily effectively treated the clinical signs of S equi subsp zooepidemicus lower respiratory infection in horses and eliminated the organism from the respiratory tract. Adverse effects were minimal. PMID- 26043134 TI - Cervical wedge resection for treatment of pyometra secondary to transluminal cervical adhesions in six mares. AB - CASE DESCRIPTION: 6 mares with pyometra secondary to transluminal cervical adhesions were examined. CLINICAL FINDINGS: Reasons for hospital admission included infertility (5 mares) and acute colic (1 mare). In the 6 mares, palpation per rectum of the reproductive tract revealed uterine distention, and transrectal ultrasonography confirmed the presence of echogenic fluid accumulation within the uterus. Cervical palpation during vaginal speculum examination indicated transluminal cervical adhesions. Three mares had severe distortion of the cervix as a result of diverticula and fibrosis. All 6 mares had a diagnosis of pyometra secondary to transluminal cervical adhesions. TREATMENT AND OUTCOME: Initially, the cervical adhesions were manually broken down to establish a patent cervical lumen to accommodate a uterine lavage catheter. A sample of the uterine content was obtained for bacteriologic culture and antimicrobial susceptibility testing, and the uterus was lavaged with 0.05% povidone-iodine solution to remove the mucopurulent exudate. Once the uterus was evacuated, cervical surgery was performed in standing mares following sedation and caudal epidural anesthesia. A full-thickness wedge-shaped defect was made in the dorsolateral aspect of the cervix that created a permanent opening to the uterus. Postoperative care included applying topical medication to the cervix to reduce the recurrence of adhesion formation. All 6 mares had patent cervices and resolution of pyometra following surgery. CONCLUSIONS AND CLINICAL RELEVANCE: Cervical wedge resection enabled treatment of pyometra in mares with transluminal cervical adhesions, without the need for ovariohysterectomy. PMID- 26043135 TI - Bovine viral diarrhea virus outbreak in a beef cow herd in South Dakota. AB - CASE DESCRIPTION: 136 pregnant beef cows were purchased in the fall of 2003. The following spring, 128 cows calved as expected; 8 cows were believed to have aborted with the fetuses unavailable for evaluation. Of the 128 calves born, 8 died within 2 weeks after birth and 9 were born with congenital abnormalities. CLINICAL FINDINGS: Cows and their calves were evaluated for bovine viral diarrhea virus (BVDV) infection. Forty-four of 120 calves, but 0 cows, tested positive for BVDV antigen by immunohistochemical staining of ear notch specimens. TREATMENT AND OUTCOME: Five BVDV test-positive calves died shortly after weaning, and the remaining 39 BVDV test-positive calves were moved to an isolated feedlot and retested for BVDV at 5 to 6 months of age; 36 had positive results, which indicated that they were persistently infected (PI) with BVDV, whereas 3 had negative results, which indicated that they were transiently infected with BVDV at the time of the first test. All PI calves were infected with the same BVDV type 2a strain. As yearlings, 17 of the 36 PI calves died peracutely with lesions consistent with mucosal disease, 6 died without gross lesions, and 2 were euthanized because of chronic ill thrift. The remaining 11 PI calves appeared healthy and were sold for slaughter. Screening of the following year's calf crop for BVDV by use of immunohistochemical staining of ear-notch specimens yielded negative results for all calves. CLINICAL RELEVANCE: Introduction of BVDV into a naive cow herd resulted in a loss of 44% of the calf crop subsequent to reproductive loss, poor thrift, and mucosal disease. PMID- 26043136 TI - The first outbreak of eastern equine encephalitis in Vermont: outbreak description and phylogenetic relationships of the virus isolate. AB - The first known outbreak of eastern equine encephalitis (EEE) in Vermont occurred on an emu farm in Rutland County in 2011. The first isolation of EEE virus (EEEV) in Vermont (VT11) was during this outbreak. Phylogenetic analysis revealed that VT11 was most closely related to FL01, a strain from Florida isolated in 2001, which is both geographically and temporally distinct from VT11. EEEV RNA was not detected in any of the 3,905 mosquito specimens tested, and the specific vectors associated with this outbreak are undetermined. PMID- 26043138 TI - Nonenriched PCR Versus Mutant-Enriched PCR in Detecting Selected Epidermal Growth Factor Receptor Gene Mutations Among Nonsmall-Cell Lung Cancer Patients. AB - BACKGROUND: Biopsies obtained from lung cancers contain a mixture of cancerous and healthy tissues. The mutant-enriched polymerase chain reaction (ME-PCR) identifies low-level somatic DNA mutations within an excess wild-type sample. AIMS: This study aimed at comparing nonenriched PCR (NE-PCR) versus ME-PCR for the detection of two epidermal growth factor receptor (EGFR) gene mutations among nonsmall cell lung cancer patients. METHODS: Fifty lung tissue biopsies were screened for inframe TTAA deletions in exon-19 and the L858R point mutation in exon-21, using ME-PCR and NE-PCR, followed by capillary electrophoresis. RESULTS: Only exon-19 deletions were detected in 22% and 18% of cases using ME-PCR and NE PCR, respectively. Diagnostic performance of the NE-PCR versus the ME-PCR serving as a "gold standard" revealed a sensitivity of 82%, and a specificity of 100%, with positive and negative predictive values of 100% and 95%, respectively, and an overall accuracy of 96%. Despite a strong agreement shown between the two assays (K=0.875), the NE-PCR showed an 18% false-negative rate in bronchoscopically obtained biopsies compared to ME-PCR. CONCLUSION: The false negativity encountered with NE-PCR in bronchoscopically obtained samples makes ME PCR the technique of choice in such situations. PMID- 26043137 TI - Vav1 Regulates T-Cell Activation through a Feedback Mechanism and Crosstalk between the T-Cell Receptor and CD28. AB - Vav1, a Rac/Rho guanine nucleotide exchange factor and a critical component of the T-cell receptor (TCR) signaling cascade is tyrosine phosphorylated rapidly in response to T-cell activation. Vav1 has established roles in proliferation, cytokine secretion, Ca(2+) responses, and actin cytoskeleton regulation; however, its function in the regulation of phosphorylation of TCR components, including the zeta chain, the CD3 delta, epsilon, gamma chains, and the associated kinases Lck and ZAP-70, is not well established. To obtain a more comprehensive picture of the role of Vav1 in receptor proximal signaling, we performed a wide-scale characterization of Vav1-dependent tyrosine phosphorylation events using quantitative phosphoproteomic analysis of Vav1-deficient T cells across a time course of TCR stimulation. Importantly, this study revealed a new function for Vav1 in the negative feedback regulation of the phosphorylation of immunoreceptor tyrosine-based activation motifs within the zeta chains, CD3 delta, epsilon, gamma chains, as well as activation sites on the critical T cell tyrosine kinases Itk, Lck, and ZAP-70. Our study also uncovered a previously unappreciated role for Vav1 in crosstalk between the CD28 and TCR signaling pathways. PMID- 26043140 TI - Serum IGF-BP2 strongly moderates age's effect on cognition: a MIMIC analysis. AB - We have used structural equation models to explicitly distinguish functional status and therefore "dementia-relevant" variance in cognitive task performance (i.e., "delta" for dementia). Our approach is modular and can be directed to other targets. In this analysis, we construct a delta ortholog representing the "cognitive correlates of age" (cAGE). cAGE largely mediates age's effects on dementia severity, as rated by the Clinical Dementia Rating Scale Sum of boxes and has an area under the receiver operating curve = 0.96 for the diagnosis of Alzheimer's Disease versus controls. We then test cAGE's association with serum insulin-like growth factor binding protein 2 (IGF-BP2), which has previously been associated with age-related cognitive changes in animals, and with cortical atrophy in older humans. IGF-BP2's adverse effects on cognition are largely mediated through cAGE, independent of education, ethnicity, gender, depression ratings, serum homocysteine levels, hemoglobin A1c, and apolipoprotein e4 status. This suggests that age-specific cognitive decline may be moderated by IGF-BP2 and that modulation of that protein's function(s) might ameliorate age-specific cognitive impairments. PMID- 26043139 TI - Altered resting state functional connectivity of anterior cingulate cortex in drug naive adolescents at the earliest stages of anorexia nervosa. AB - Previous Resting-State Functional Connectivity (RSFC) studies have shown several functional alterations in adults with or recovered from long Anorexia Nervosa (AN). The aim of this paper was to investigate whole brain RSFC in adolescents with AN in the earliest stages, less than 6 months, of the disorder. Sixteen drug naive outpatient female adolescents with AN-restrictive type (AN-r) (mean age: 15,8; SD 1,7) were compared to 16 age-matched healthy female (mean age: 16,3; SD 1,4). Relevant resting state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data; a dual regression technique was used to detect between-group differences in the RSNs. Between-group differences of the functional connectivity maps were found in the executive control network (ECN). Particularly, decreased temporal correlation was observed in AN-r patients relative to healthy controls between the ECN functional connectivity maps and the anterior cingulate cortex (p < 0.05 corrected). Our results in AN adolescents may represent an early trait-related biomarker of the disease. Considering that the above mentioned network and its area are mainly involved in cognitive control and emotional processing, our findings could explain the impaired cognitive flexibility in relation to body image and appetite in AN patients. PMID- 26043141 TI - Neurofibromatosis type 2. AB - Neurofibromatosis type 2 (NF2) is a rare syndrome characterized by bilateral vestibular schwannomas, multiple meningiomas, cranial nerve tumors, spinal tumors, and eye abnormalities. NF2 presents unique challenges to the otologist because hearing loss may be the presenting complaint leading to the diagnosis of the disorder. Care of patients with NF2 requires knowledge of all tumors and symptoms involved with the disorder. It is recommended that patients receive care in a center with expertise in NF2. The role of the neuro-otologist in this care is determined by the specialty center. PMID- 26043142 TI - Nonschwannoma tumors of the cerebellopontine angle. AB - Although the preponderance of cerebellopontine angle lesions are schwannomas, focused attention to patient clinical history, imaging studies, and tissue biopsies when indicated will aid in detection of less common lesions that might otherwise be misdiagnosed. This is most critical for pathologies that dictate different management paradigms be undertaken. PMID- 26043143 TI - Enhancement of the Carbon Nanowall Film Capacitance. Electron Transfer Kinetics on Functionalized Surfaces. AB - The effects of electrochemical oxidation and surfactant adsorption on behavior of vertically oriented carbon-nanowall (CNW)-based electrodes are studied. Electrochemical oxidation is carried out by the electrode polarization in aqueous solutions at high anodic potentials corresponding to water electrolysis, whereas the modification of surface by surfactants is accomplished by the adsorption of molecules characterized by the cage-like structure. Using the methods of cyclic voltammetry and impedancemetry, it is shown that a substantial increase in the capacitance of CNW-based electrodes is observed in both cases (30-50-fold and 3-5 fold, respectively). The as-grown and modified electrodes are characterized by scanning electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy. A substantial increase in a number of oxygen-containing functional groups is observed on the CNW surface after the electrode polarization at high anodic potentials. The kinetics of redox reactions on the CNW film surface is studied by comparing the behavior of systems [Ru(NH3)6](2+/3+), [Fe(CN)6](4-/3-), Fe(2+/3+), and VO3(-)/VO(2+). It is demonstrated that oxidation of nanowalls makes the electron transfer in the redox reaction VO3(-)/VO(2+) and the redox system Fe(2+/3+) considerably easier due to coordination of discharging ions of these systems with the functional groups; however, no such effect is observed for the redox-systems [Fe(CN)6](3-/4-) and [Ru(NH3)6](2+/3+). PMID- 26043144 TI - Expression of TaCYP78A3, a gene encoding cytochrome P450 CYP78A3 protein in wheat (Triticum aestivum L.), affects seed size. AB - Several studies have described quantitative trait loci (QTL) for seed size in wheat, but the relevant genes and molecular mechanisms remain largely unknown. Here we report the functional characterization of the wheat TaCYP78A3 gene and its effect on seed size. TaCYP78A3 encoded wheat cytochrome P450 CYP78A3, and was specifically expressed in wheat reproductive organs. TaCYP78A3 activity was positively correlated with the final seed size. Its silencing caused a reduction of cell number in the seed coat, resulting in an 11% decrease in wheat seed size, whereas TaCYP78A3 over-expression induced production of more cells in the seed coat, leading to an 11-48% increase in Arabidopsis seed size. In addition, the cell number in the final seed coat was determined by the TaCYP78A3 expression level, which affected the extent of integument cell proliferation in the developing ovule and seed. Unfortunately, TaCYP78A3 over-expression in Arabidopsis caused a reduced seed set due to an ovule developmental defect. Moreover, TaCYP78A3 over-expression affected embryo development by promoting embryo integument cell proliferation during seed development, which also ultimately affected the final seed size in Arabidopsis. In summary, our results indicated that TaCYP78A3 plays critical roles in influencing seed size by affecting the extent of integument cell proliferation. The present study provides direct evidence that TaCYP78A3 affects seed size in wheat, and contributes to an understanding of the cellular basis of the gene influencing seed development. PMID- 26043145 TI - Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival. AB - BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression free survival (PFS), and overall survival (OS) were analyzed using the Kaplan Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated. PMID- 26043146 TI - Psychological Issues in Infertility: from epidemiology to intervention. PMID- 26043147 TI - Molecular ion battery: a rechargeable system without using any elemental ions as a charge carrier. AB - Is it possible to exceed the lithium redox potential in electrochemical systems? It seems impossible to exceed the lithium potential because the redox potential of the elemental lithium is the lowest among all the elements, which contributes to the high voltage characteristics of the widely used lithium ion battery. However, it should be possible when we use a molecule-based ion which is not reduced even at the lithium potential in principle. Here we propose a new model system using a molecular electrolyte salt with polymer-based active materials in order to verify whether a molecular ion species serves as a charge carrier. Although the potential of the negative-electrode is not yet lower than that of lithium at present, this study reveals that a molecular ion can work as a charge carrier in a battery and the system is certainly a molecular ion-based "rocking chair" type battery. PMID- 26043148 TI - Iron deficiency: Prevalence and relation to cardiovascular biomarkers in heart failure outpatients. AB - BACKGROUND: Both iron deficiency (ID) and cardiovascular biomarkers are associated with a poor outcome in heart failure (HF). The relationship between different cardiovascular biomarkers and ID is unknown, and the true prevalence of ID in an outpatient HF clinic is probably overlooked. OBJECTIVES: To identify the prevalence of ID in a HF clinic and evaluate whether ID is associated with increased plasma concentrations of different cardiovascular biomarkers that carry a poor prognosis. METHODS: We prospectively included 149 patients with systolic HF referred to an outpatients HF clinic. ID was defined as ferritin<100 MUg/L or ferritin 100-300 MUg/L and Tranferin-saturation<0.20. Five different cardiovascular biomarkers were analyzed on frozen plasma. RESULTS: The patients had a median age of 70 (Interquartile range: 64-75) years, 25% were females, 29% were in functional class III-IV and LVEF was 32 (27-39) %. The prevalence of ID was 45% (95%-confidence interval (CI): 37-53%). In multivariate analyses, ID was not associated with plasma concentrations of troponin I, NT-proBNP, MR-proANP, chromogranin A or copeptin (P>0.05 for all) but with plasma concentrations of hs CRP (odds ratio: 2.03, 95%-CI: 1.02-4.02, P=0.043). CONCLUSION: ID is frequent in an outpatient HF clinic. ID is not associated with cardiovascular biomarkers after adjustment for traditional confounders. Inflammation, but not neurohormonal activation is associated with ID in systolic HF. Further studies are needed to understand iron metabolism in elderly HF patients. PMID- 26043149 TI - Cardiac complications during pregnancy are better predicted with the modified WHO risk score. AB - BACKGROUND/OBJECTIVE: Several risk scores (RSs) have been used to stratify risk of cardiac complications (CCs) in pregnant patients with heart disease. We aimed to compare and contrast the accuracy of several RSs for predicting CC in this population. METHODS: Prospective inclusion of all consecutive pregnant patients with heart disease, and follow-up until 6 months postpartum. CCs were defined as primary if admission was required due to heart failure, arrhythmia or thromboembolic events, and secondary if the decline in NYHA class compared with baseline was >2 or urgent invasive cardiac procedures were needed. The discriminatory power of each RS was assessed by the area-under-the receiver operating characteristic (ROC) curve (AUC). RESULTS: 179 patients, mean age: 32 years, accounted for 13.4% of CC (primary 11.7%, secondary 1.7%); the main diagnosis was congenital heart disease (CHD) in 68% followed by valvulopathies in 16%, arrhythmia in 7% and myocardiopathies in 5%. 22% (n=40) were classified as mWHO=1, 59% (n=105) mWHO=2 including subgroup 2-3, 14% (n=26) mWHO=3 and 4%(n=7) mWHO=4; 1 patient was unclassifiable. mWHO showed a better AUC (0.763) than CARPREG (0.67). For the CHD population, ZAHARA RS showed an AUC of 0.74, and Khairy an AUC of 0.632. CONCLUSIONS: mWHO was better at predicting CC than CARPREG; mWHO was also better at predicting CC than the specific CHD RS in the CHD subgroup. PRACTICE: There are an increasing number of pregnant women with HD. IMPLICATIONS: Improved prediction of CC risk during pregnancy can provide better preconception assessment in women with HD. PMID- 26043150 TI - The importance of national and international collaboration in adult congenital heart disease: A network analysis of research output. AB - BACKGROUND: The determinants of adult congenital heart disease (ACHD) research output are only partially understood. The heterogeneity of ACHD naturally calls for collaborative work; however, limited information exists on the impact of collaboration on academic performance. We aimed to examine the global topology of ACHD research, distribution of research collaboration and its association with cumulative research output. METHODS AND RESULTS: Based on publications presenting original research between 2005 and 2011, a network analysis was performed quantifying centrality measures and key players in the field of ACHD. In addition, network maps were produced to illustrate the global distribution and interconnected nature of ACHD research. The proportion of collaborative research was 35.6 % overall, with a wide variation between countries (7.1 to 62.8%). The degree of research collaboration, as well as measures of network centrality (betweenness and degree centrality), were statistically associated with cumulative research output independently of national wealth and available workforce. The global ACHD research network was found to be scale-free with a small number of central hubs and a relatively large number of peripheral nodes. In addition, we could identify potentially influential hubs based on cluster analysis and measures of centrality/key player analysis. CONCLUSIONS: Using network analysis methods the current study illustrates the complex and global structures of ACHD research. It suggests that collaboration between research institutions is associated with higher academic output. As a consequence national and international collaboration in ACHD research should be encouraged and the creation of an adequate supporting infrastructure should be further promoted. PMID- 26043151 TI - Early rule-out and rule-in of myocardial infarction using sensitive cardiac Troponin I. AB - BACKGROUND: It is currently unknown, whether and to what extent sensitive cardiac troponin (s-cTn) allows shortening of the time required for safe rule-out and rule-in of acute myocardial infarction (AMI). METHODS: We aimed to develop and validate early rule-out and rule-in algorithms for AMI using a thoroughly examined and commonly used s-cTnI assay in a prospective multicenter study including 2173 patients presenting to the emergency department with suspected AMI. S-cTnI was measured in a blinded fashion at 0 h, 1 h, and 2 h. The final diagnosis was centrally adjudicated by two independent cardiologists. In the derivation cohort (n = 1496), we developed 1h- and 2h-algorithms assigning patients to "rule-out", "rule-in", or "observe". The algorithms were then prospectively validated in the validation cohort (n = 677). RESULTS: AMI was the adjudicated diagnosis in 17% of patients. After applying the s-cTnI 1h-algorithm developed in the derivation cohort to the validation cohort, 65% of patients were classified as "rule-out", 12% as "rule-in", and 23% to "observe". The negative predictive value for AMI in the "rule-out" group was 98.6% (95% CI, 96.9-99.5), the positive predictive value for AMI in the "rule-in" group 76.3% (95% CI, 65.4 85.1). Overall, 30-day mortality was 0.2% in the "rule-out" group, 1.0% in the "observe" group, and 3.0% in the "rule-in" group. Similar results were obtained for the 2h-algorithm. CONCLUSION: When used in conjunction with other clinical information including the ECG, a simple algorithm incorporating s-cTnI values at presentation and after 1h (or 2h) will allow safe rule-out and accurate rule-in of AMI in the majority of patients. PMID- 26043152 TI - Transfemoral aortic valve implantation with the repositionable Lotus valve compared with the balloon-expandable Edwards Sapien 3 valve. AB - BACKGROUND: The rate of paravalvular aortic insufficiency (AI) with transcatheter aortic valve implantation (TAVI) with first generation devices was higher compared with surgical replacement. Residual AI after TAVI has been linked to an increased mortality rate. We compared two second generation TAVI devices - the repositionable Lotus valve with the balloon-expandable Edwards Sapien 3 valve - regarding procedural and 30 day outcome. METHODS AND RESULTS: In 78 patients with severe aortic stenosis undergoing transfemoral TAVI we evaluated post-procedural paravalvular AI, device success and early safety according to VARC criteria. Valve size was based on a 256-multislice computed tomography. Patients were followed for 30 days. The Lotus valve (N = 26) and the Edwards Sapien 3 valve (N = 52) were implanted under fluoroscopic guidance. Baseline characteristics were similar between groups. Perimeter derived annulus diameter did not differ with 25.7 +/- 1.6mm for Lotus and 25.2 +/- 2.1mm for Edwards Sapien 3 patients. After TAVI aortography and transthoracic echocardiography revealed no moderate or severe AI. The rate of mild AI was 12% for Lotus and 15% for Edwards Sapien 3 (p = 0.62). There were no deaths, stroke, annulus rupture or coronary obstruction. Device success was 96% and 98% (p = 0.61), early safety according to VARC 11.5% in both groups (p = 1.0) and the need for pacemaker implantation 27% and 4% (p < 0.003), respectively. CONCLUSIONS: TAVI with second-generation devices was associated with no moderate or severe AI and a low rate of mild AI. Device success was high for Lotus and Edwards Sapien 3 while the need for permanent pacemaker was significantly higher with the Lotus valve. PMID- 26043153 TI - The patient's selection of PARACHUTE(r) endoventricular partitioning device: The important role of detailed echocardiography. PMID- 26043154 TI - Quantitative analysis of myocardial 18F-fluorodeoxyglucose uptake by PET/CT for detection of cardiac sarcoidosis. AB - BACKGROUND: Imaging with fluorodeoxyglucose (FDG) PET/CT is used to diagnose patients with cardiac sarcoidosis (CS). However, its specificity is relatively low. We aimed to demonstrate that higher diagnostic specificity for CS can be obtained using quantitative methodology to analyze PET/CT. METHODS: A total of 125 consecutive patients with suspected CS were enrolled in the study. After clinical assessment and cardiac imaging studies, the patients underwent FDG PET/CT imaging after eating a low-carbohydrate diet followed by an overnight fast lasting >= 18 h. For visual analysis, fusion and maximum intensity projection images were reviewed. For quantitative analysis, the maximum standardized uptake value (SUV max) within the myocardium was obtained. RESULTS: Of the 92 patients who met study inclusion criteria, 37 were diagnosed with CS. Myocardial SUV max was significantly higher in patients with CS compared with non-CS patients (9.5 +/- 4.8 vs. 3.0 +/- 1.7, p < 0.0001). The area under the curve by receiver operating characteristic analysis was 0.960 for SUV max. Using a cut-off value of 4.0, the sensitivity was 97.3% and specificity was 83.6% for diagnosing CS, which is more accurate than visual analysis. Moreover, SUV max was the only significant predictor of CS among 10 clinical and imaging variables. In 18 patients who received steroid therapy with a mean follow-up duration of 6.4 +/- 5.2 months, SUV max significantly decreased from 9.8 +/- 4.2 to 5.5 +/- 3.5 (p = 0.003). CONCLUSION: When evaluated by quantification of myocardial SUV max, FDG PET/CT imaging provides high sensitivity and specificity for diagnosing CS. PMID- 26043155 TI - TNFAIP3 promotes survival of CD4 T cells by restricting MTOR and promoting autophagy. AB - Autophagy plays important roles in metabolism, differentiation, and survival in T cells. TNFAIP3/A20 is a ubiquitin-editing enzyme that is thought to be a negative regulator of autophagy in cell lines. However, the role of TNFAIP3 in autophagy remains unclear. To determine whether TNFAIP3 regulates autophagy in CD4 T cells, we first analyzed Tnfaip3-deficient naive CD4 T cells in vitro. We demonstrated that Tnfaip3-deficient CD4 T cells exhibited reduced MAP1LC3/LC3 (microtubule associated protein 1 light chain 3) puncta formation, increased mitochondrial content, and exaggerated reactive oxygen species (ROS) production. These results indicate that TNFAIP3 promotes autophagy after T cell receptor (TCR) stimulation in CD4 T cells. We then investigated the mechanism by which TNFAIP3 promotes autophagy signaling. We found that TNFAIP3 bound to the MTOR (mechanistic target of rapamycin) complex and that Tnfaip3-deficient cells displayed enhanced ubiquitination of the MTOR complex and MTOR activity. To confirm the effects of enhanced MTOR activity in Tnfaip3-deficient cells, we analyzed cell survival following treatment with Torin1, an MTOR inhibitor. Tnfaip3-deficient CD4 T cells exhibited fewer cell numbers than the control cells in vitro and in vivo. In addition, the impaired survival of Tnfaip3-deficient cells was ameliorated with Torin1 treatment in vitro and in vivo. The effect of Torin1 was abolished by Atg5 deficiency. Thus, enhanced MTOR activity regulates the survival of Tnfaip3 deficient CD4 T cells. Taken together, our findings illustrate that TNFAIP3 restricts MTOR signaling and promotes autophagy, providing new insight into the manner in which MTOR and autophagy regulate survival in CD4 T cells. PMID- 26043156 TI - Spatiotemporal oscillatory dynamics during the encoding and maintenance phases of a visual working memory task. AB - Many electrophysiology studies have examined neural oscillatory activity during the encoding, maintenance, and/or retrieval phases of various working memory tasks. Together, these studies have helped illuminate the underlying neural dynamics, although much remains to be discovered and some findings have not replicated in subsequent work. In this study, we examined the oscillatory dynamics that serve visual working memory operations using high-density magnetoencephalography (MEG) and advanced time-frequency and beamforming methodology. Specifically, we recorded healthy adults while they performed a high load, Sternberg-type working memory task, and focused on the encoding and maintenance phases. We found significant 9-16 Hz desynchronizations in the bilateral occipital cortices, left dorsolateral prefrontal cortex (DLPFC), and left superior temporal areas throughout the encoding phase. Our analysis of the dynamics showed that the left DLPFC and superior temporal desynchronization became stronger as a function of time during the encoding period, and was sustained throughout most of the maintenance phase until sharply decreasing in the milliseconds preceding retrieval. In contrast, desynchronization in occipital areas became weaker as a function of time during encoding and eventually evolved into a strong synchronization during the maintenance period, consistent with previous studies. These results provide clear evidence of dynamic network-level processes during the encoding and maintenance phases of working memory, and support the notion of a dynamic pattern of functionally-discrete subprocesses within each working memory phase. The presence of such dynamic oscillatory networks may be a potential source of inconsistent findings in this literature, as neural activity within these networks changes dramatically with time. PMID- 26043157 TI - Proton radiography and tomography with application to proton therapy. AB - Proton radiography and tomography have long promised benefit for proton therapy. Their first suggestion was in the early 1960s and the first published proton radiographs and CT images appeared in the late 1960s and 1970s, respectively. More than just providing anatomical images, proton transmission imaging provides the potential for the more accurate estimation of stopping-power ratio inside a patient and hence improved treatment planning and verification. With the recent explosion in growth of clinical proton therapy facilities, the time is perhaps ripe for the imaging modality to come to the fore. Yet many technical challenges remain to be solved before proton CT scanners become commonplace in the clinic. Research and development in this field is currently more active than at any time with several prototype designs emerging. This review introduces the principles of proton radiography and tomography, their historical developments, the raft of modern prototype systems and the primary design issues. PMID- 26043158 TI - Survey of volume CT dose index in Japan in 2014. AB - OBJECTIVE: The aims of this study are to propose a new set of Japanese diagnostic reference levels (DRLs) for 2014 and to study the impact of tube voltage and the type of reconstruction algorithm on patient doses. The volume CT dose index (CTDI(vol)) for adult and paediatric patients is assessed and compared with the results of a 2011 national survey and data from other countries. METHODS: Scanning procedures for the head (non-helical and helical), chest and upper abdomen were examined for adults and 5-year-old children. A questionnaire concerning the following items was sent to 3000 facilities: tube voltage, use of reconstruction algorithms and displayed CTDI(vol). RESULTS: The mean CTDI(vol) values for paediatric examinations using voltages ranging from 80 to 100 kV were significantly lower than those for paediatric examinations using 120 kV. For adult examinations, the use of iterative reconstruction algorithms significantly reduced the mean CTDI(vol) values compared with the use of filtered back projection. Paediatric chest and abdominal scans showed slightly higher mean CTDI(vol) values in 2014 than in 2011. The proposed DRLs for adult head and abdominal scans were higher than those reported in other countries. CONCLUSION: The results imply that further optimization of CT examination protocols is required for adult head and abdominal scans as well as paediatric chest and abdominal scans. ADVANCES IN KNOWLEDGE: Low-tube-voltage CT may be useful for reducing radiation doses in paediatric patients. The mean CTDI(vol) values for paediatric scans showed little difference that could be attributed to the choice of reconstruction algorithm. PMID- 26043159 TI - Biosynthetic Studies of Telomycin Reveal New Lipopeptides with Enhanced Activity. AB - Telomycin (TEM) is a cyclic depsipeptide antibiotic active against Gram-positive bacteria. In this study, five new natural telomycin analogues produced by Streptomyces canus ATCC 12646 were identified. To understand the biosynthetic machinery of telomycin and to generate more analogues by pathway engineering, the TEM biosynthesis gene cluster has been characterized from S. canus ATCC 12646: it spans approximately 80.5 kb and consists of 34 genes encoding fatty acid ligase, nonribosomal peptide synthetases (NRPSs), regulators, transporters, and tailoring enzymes. The gene cluster was heterologously expressed in Streptomyces albus J1074 setting the stage for convenient biosynthetic engineering, mutasynthesis, and production optimization. Moreover, in-frame deletions of one hydroxylase and two P450 monooxygenase genes resulted in the production of novel telomycin derivatives, revealing these genes to be responsible for the specific modification by hydroxylation of three amino acids found in the TEM backbone. Surprisingly, natural lipopeptide telomycin precursors were identified when characterizing an unusual precursor deacylation mechanism during telomycin maturation. By in vivo gene inactivation and in vitro biochemical characterization of the recombinant enzyme Tem25, the maturation process was shown to involve the cleavage of previously unknown telomycin precursor lipopeptides, to yield 6-methylheptanoic acid and telomycins. These lipopeptides were isolated from an inactivation mutant of tem25 encoding a (de)acylase, structurally elucidated, and then shown to be deacylated by recombinant Tem25. The TEM precursor and several semisynthetic lipopeptide TEM derivatives showed rapid bactericidal killing and were active against several multidrug-resistant (MDR) Gram-positive pathogens, opening the path to future chemical optimization of telomycin for pharmaceutical application. PMID- 26043160 TI - Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT(1A) activity. Part 5. AB - A series of novel 4-aryl-pyrido[1,2-c]pyrimidine derivatives containing a 1-(2 quinoline)piperazine moiety was synthesized. The chemical structure of new compounds was confirmed by FT-IR, (1)H NMR, (13)C NMR and HRMS spectra as well as elemental analysis. Affinity of the novel pyrido[1,2-c]pyrimidine derivatives for 5-HT1A, 5-HT2A receptors and serotonin transporter (SERT) was evaluated in an in vitro radioligand binding assay. Tested compounds showed moderate to high affinity for 5-HT1AR and SERT and low affinity for 5-HT2AR. Selected ligands were subjected to in vivo tests, such as induced hypothermia and the forced swimming test in mice, which determined presynaptic agonistic activity of the ligands 8d, 8e, 9d and 9e and presynaptic antagonistic activity of the ligands 8a, 8b, 9a, 9b. Additionally, metabolic stability evaluation was performed for selected ligands, proving that a para-substitution in the 4-aryl-pyrido[1,2-c]pyrimidine moiety leads to an increase in stability, whereas a substitution in the ortho position lowers the stability. PMID- 26043161 TI - Novel routes to either racemic or enantiopure alpha-amino-(4-hydroxy-pyrrolidin-3 yl)acetic acid derivatives and biological evaluation of a new promising pharmacological scaffold. AB - Cycloaddition between (+) or (-)-menthone-derived nitrones and N-benzyl-3 pyrroline afforded enantiopure spiro-fused heterocycles. The reaction occurred enantio- and diastereo-selectively on the less hindered side of the nitrone, the 3-pyrroline N-benzyl group being oriented outwards, thus controlling the configurations of three simultaneously created chiral centers. From either (+) or (-)-menthone, both enantiomeric cycloadducts were synthesized in excellent yield. Removing the chiral auxiliary and the N-benzyl group delivered a series of enantiopure 4-hydroxy-3-glycinyl-pyrrolidine derivatives in 3-5 steps and 36 to 81 overall yields. Using two other achiral nitrones, shorter routes to racemic analogues were developed. Two of the synthesized compounds markedly lowered extracellular glutamate level and modestly interacted with cannabinoid type-1 receptors. As these two neuroactive compounds were devoid of in vitro toxicity and did not cross the blood brain interface, they might represent potential pharmacological agents to target peripheral organs. PMID- 26043163 TI - Reliable change indices and standardized regression-based change score norms for evaluating neuropsychological change in children with epilepsy. AB - Reliable change indices (RCIs) and standardized regression-based (SRB) change score norms permit evaluation of meaningful changes in test scores following treatment interventions, like epilepsy surgery, while accounting for test-retest reliability, practice effects, score fluctuations due to error, and relevant clinical and demographic factors. Although these methods are frequently used to assess cognitive change after epilepsy surgery in adults, they have not been widely applied to examine cognitive change in children with epilepsy. The goal of the current study was to develop RCIs and SRB change score norms for use in children with epilepsy. Sixty-three children with epilepsy (age range: 6-16; M=10.19, SD=2.58) underwent comprehensive neuropsychological evaluations at two time points an average of 12 months apart. Practice effect-adjusted RCIs and SRB change score norms were calculated for all cognitive measures in the battery. Practice effects were quite variable across the neuropsychological measures, with the greatest differences observed among older children, particularly on the Children's Memory Scale and Wisconsin Card Sorting Test. There was also notable variability in test-retest reliabilities across measures in the battery, with coefficients ranging from 0.14 to 0.92. Reliable change indices and SRB change score norms for use in assessing meaningful cognitive change in children following epilepsy surgery are provided for measures with reliability coefficients above 0.50. This is the first study to provide RCIs and SRB change score norms for a comprehensive neuropsychological battery based on a large sample of children with epilepsy. Tables to aid in evaluating cognitive changes in children who have undergone epilepsy surgery are provided for clinical use. An Excel sheet to perform all relevant calculations is also available to interested clinicians or researchers. PMID- 26043164 TI - Long-term neurocognitive outcome and auditory event-related potentials after complex febrile seizures in children. AB - OBJECTIVES: Whether prolonged or complex febrile seizures (FS) produce long-term injury to the hippocampus is a critical question concerning the neurocognitive outcome of these seizures. Long-term event-related evoked potential (ERP) recording from the scalp is a noninvasive technique reflecting the sensory and cognitive processes associated with attention tasks. This study aimed to investigate the long-term outcome of neurocognitive and attention functions and evaluated auditory event-related potentials in children who have experienced complex FS in comparison with other types of FS. METHODS: One hundred and forty seven children aged more than 6 years who had experienced complex FS, simple single FS, simple recurrent FS, or afebrile seizures (AFS) after FS and age matched healthy controls were enrolled. Patients were evaluated with Wechsler Intelligence Scale for Children (WISC; Chinese WISC-IV) scores, behavior test scores (Chinese version of Conners' continuous performance test, CPT II V.5), and behavior rating scales. Auditory ERPs were recorded in each patient. RESULTS: Patients who had experienced complex FS exhibited significantly lower full-scale intelligence quotient (FSIQ), perceptual reasoning index, and working memory index scores than did the control group but did not show significant differences in CPT scores, behavior rating scales, or ERP latencies and amplitude compared with the other groups with FS. We found a significant decrease in the FSIQ and four indices of the WISC-IV, higher behavior rating scales, a trend of increased CPT II scores, and significantly delayed P300 latency and reduced P300 amplitude in the patients with AFS after FS. CONCLUSION: We conclude that there is an effect on cognitive function in children who have experienced complex FS and patients who developed AFS after FS. The results indicated that the WISC-IV is more sensitive in detecting cognitive abnormality than ERP. Cognition impairment, including perceptual reasoning and working memory defects, was identified in patients with prolonged, multiple, or focal FS. These results may have implications for the pathogenesis of complex FS. Further comprehensive psychological evaluation and educational programs are suggested. PMID- 26043166 TI - Brief report: Associations between in-person and electronic bullying victimization and missing school because of safety concerns among U.S. high school students. AB - Although associations between bullying and health risk behaviors are well documented, research on bullying and education-related outcomes, including school attendance, is limited. This study examines associations between bullying victimization (in-person and electronic) and missing school because of safety concerns among a nationally representative sample of U.S. high school students. We used logistic regression analyses to analyze data from the 2013 national Youth Risk Behavior Survey of students in grades 9-12. In-person and electronic victimization were each associated with increased odds of missing school due to safety concerns compared to no bullying victimization. Having been bullied both in-person and electronically was associated with greater odds of missing school compared to electronic bullying only for female students and in-person bullying only for male students. Collaborations between health professionals and educators to prevent bullying may improve school attendance. PMID- 26043165 TI - How predictable is the erectile function of patients with epilepsy? AB - INTRODUCTION: Erectile dysfunction (ED) is often reported by patients with epilepsy and may be related to endocrine system abnormalities, side effects of antiepileptic drugs, psychiatric comorbidities, and family or social difficulties. AIMS: This study aimed to identify independent predictor factors for ED in patients with epilepsy. MAIN OUTCOME MEASURES: the five-question form of the International Index of Erectile Function (IIEF-5). METHODS: Independent predictive factors for ED evaluated by the IIEF-5 questionnaire in 36 patients (mean age: 39 years) with focal epilepsy (mean: 6 seizures/month) were identified by multiple linear regression analysis. RESULTS: Eight (21.1%) patients were asymptomatic. Among the symptomatic patients, 11 (28.9%) had mild dysfunction, 10 (26.3%) had moderate dysfunction, and 9 (23.7%) showed severe ED. The multiple linear regression model including family income (B=0.005; p=0.05), education levels in years (B=0.54; p=0.03), depressive symptoms determined by HADS depression subscale (B=-0.49; p=0.03), and prolactin levels (B=-0.45; p=0.07) showed a moderate association (r=0.64) with the IIEF questionnaire and explained 41% (r(2)=0.41) of its variation. CONCLUSIONS: Erectile dysfunction is highly prevalent in patients with focal epilepsies. Education, depressive symptoms, and prolactin levels can predict erectile dysfunction in up to 41% of patients with epilepsy. This preliminary report justifies further efforts to make a large sample size study to identify independent biomarkers and therapeutic targets for ED treatment in patients with epilepsy. PMID- 26043167 TI - The audience effect in adolescence depends on who's looking over your shoulder. AB - Adolescents have been shown to be particularly sensitive to peer influence. However, the data supporting these findings have been mostly limited to the impact of peers on risk-taking behaviours. Here, we investigated the influence of peers on performance of a high-level cognitive task (relational reasoning) during adolescence. We further assessed whether this effect on performance was dependent on the identity of the audience, either a friend (peer) or the experimenter (non peer). We tested 24 younger adolescent (10.6-14.2 years), 20 older adolescent (14.9-17.8 years) and 20 adult (21.8-34.9 years) female participants. The presence of an audience affected adolescent, but not adult, relational reasoning performance. This audience effect on adolescent performance was influenced by the participants' age, task difficulty and the identity of the audience. These findings may have implications for education, where adolescents often do classwork or homework in the presence of others. PMID- 26043168 TI - Brief report: Bifactor modeling of general vs. specific factors of religiousness differentially predicting substance use risk in adolescence. AB - Religiousness is important to adolescents in the U.S., and the significant link between high religiousness and low substance use is well known. There is a debate between multidimensional and unidimensional perspectives of religiousness (Gorsuch, 1984); yet, no empirical study has tested this hierarchical model of religiousness related to adolescent health outcomes. The current study presents the first attempt to test a bifactor model of religiousness related to substance use among adolescents (N = 220, 45% female). Our bifactor model using structural equation modeling suggested the multidimensional nature of religiousness as well as the presence of a superordinate general religiousness factor directly explaining the covariation among the specific factors including organizational and personal religiousness and religious social support. The general religiousness factor was inversely related to substance use. After accounting for the contribution of the general religiousness factor, high organizational religiousness related to low substance use, whereas personal religiousness and religious support were positively related to substance use. The findings present the first evidence that supports hierarchical structures of adolescent religiousness that contribute differentially to adolescent substance use. PMID- 26043169 TI - How you look versus how you feel: Associations between BMI z-score, body dissatisfaction, peer victimization, and self-worth for African American and white adolescents. AB - Being overweight and having negative self-perceptions (body dissatisfaction) can have problematic consequences for adolescents physically, socially, and psychologically. Understanding associations between weight, self-perceptions, and peer experiences across ethnicities is particularly important given recent increases in obesity among ethnic minorities. The current study aimed to address these issues by examining Body Mass Index (BMI) z-scores and body dissatisfaction predicting change in general self-worth over time via peer victimization experiences in a diverse sample of 236 youth (ages 10-16 years). Body dissatisfaction predicted decreases in self-worth over time even after controlling for BMI z-score. BMI z-scores predicted decreases in self-worth over time only for white adolescents, whereas body dissatisfaction directly predicted decreases in self-worth for African American youth and indirectly via peer victimization for white youth. Associations were also considered by gender. Implications for intervention efforts for both white and African American adolescents are discussed. PMID- 26043170 TI - Differential transcriptomic and metabolic profiles of M. africanum- and M. tuberculosis-infected patients after, but not before, drug treatment. AB - The epidemiology of Mycobacterium tuberculosis (Mtb) and M. africanum (Maf) suggests differences in their virulence, but the host immune profile to better understand the pathogenesis of tuberculosis (TB) have not been studied. We compared the transcriptomic and metabolic profiles between Mtb- and Maf-infected TB cases to identify host biomarkers associated with lineages-specific pathogenesis and response to anti-TB chemotherapy. Venous blood samples from Mtb- and Maf-infected patients obtained before and after anti-TB treatment were analyzed for cell composition, gene expression and metabolic profiles. Prior to treatment, similar transcriptomic profiles were seen in Maf- and Mtb-infected patients. In contrast, post treatment, over 1600 genes related to immune responses and metabolic diseases were differentially expressed between the groups. Notably, the upstream regulator hepatocyte nuclear factor 4-alpha (HNF4alpha), which regulated 15% of these genes, was markedly enriched. Serum metabolic profiles were similar in both group pre-treatment, but the decline in pro-inflammatory metabolites post treatment were most pronounced in Mtb-infected patients. Together, the differences in both peripheral blood transcriptomic and serum metabolic profiles between Maf- and Mtb-infected patients observed over the treatment period, might be indicative of intrinsic host factors related to susceptibility to TB and/or differential efficacy of the standard anti-TB treatment on the two lineages. PMID- 26043171 TI - A conserved sugar bridge connected to the WSXWS motif has an important role for transport of IL-21R to the plasma membrane. AB - Interleukin-21 (IL-21) is a class I cytokine that belongs to the gammac-subfamily of cytokines and regulates immune responses. It signals through a heterodimeric receptor complex composed of the IL-21R1 and gammac-receptor chains. A characteristic feature of class I cytokine receptors is the presence of a consensus motif WSXWS (WS motif) in the membrane proximal fibronectin type III domain (FNIII) of these receptors. We recently described the structure of the IL 21R:IL-21 complex and showed that the first tryptophan of the WS motif of IL-21R is mannosylated and involved in formation of a sugar bridge that connects the two FNIII domains of the receptor. Furthermore, a mutation within the WS motif of IL 21R was recently shown to cause a novel kind of primary immunodeficiency syndrome (PID). Here, we report the structure of IL-21R alone, which shows that the sugar bridge forms independently of whether IL-21R binds IL-21 or not, and we furthermore investigate the role of this bridge in the export of IL-21R and gammaC to the plasma membrane. Thus, we provide a molecular explanation for how mutations in the WS motif may cause PIDs. PMID- 26043172 TI - Polymorphism of X-linked CD40 ligand gene associated with pulmonary tuberculosis in the Han Chinese population. AB - Among those developing tuberculosis (TB) after exposure to Mycobacterium tuberculosis, approximately 70% are males. Host genetic variation, particularly immune-related genes on the X chromosome, may contribute to sex-specific differences in TB incidences. To study whether X-linked gene variation is associated with sex-specific presentation of pulmonary TB (pTB), three single nucleotide polymorphisms (SNPs) of the TLR8, CD40LG and IRAK1 genes on the X chromosome were genotyped in 923 patients and 1033 healthy individuals of the Han Chinese population. Frequencies of the variants were analyzed independently as well as in their combinations. CD40LG rs3092923 and its combined effects with the other two SNPs were associated with an increased risk of pTB only in males. In males, the rs3092923 genotype C/(-) conferred relative protection (odds ratio (OR): 0.52, 95% confidence interval (CI): 0.35-0.78, Pcorr.=0.0045) and the combined effects of three SNPs increased gradually as the number of risk alleles increased (OR: 2.58, 2.83 and 2.96 for one, two and three risk alleles, respectively). For the remaining SNPs, significance was obtained only for the AA genotype of IRAK1 rs3027898 in the combined and female-only analysis. Our results indicate a role of a CD40LG variant and its combined effects with distinct TLR8 and IRAK1 variants in susceptibility to pTB in males. PMID- 26043174 TI - Longitudinal modes along thin piezoelectric waveguides for liquid sensing applications. AB - The propagation of longitudinally polarized acoustic modes along thin piezoelectric plates (BN, ZnO, InN, AlN and GaN) is theoretically studied, aiming at the design of high frequency electroacoustic devices suitable for work in liquid environments. The investigation of the acoustic field profile across the plate revealed the presence of longitudinally polarized Lamb modes, travelling at velocities close to that of the longitudinal bulk acoustic wave propagating in the same direction. Such waves are suitable for the implementation of high frequency, low-loss electroacoustic devices operating in liquid environments. The time-averaged power flow density, the phase velocity and the electroacoustic coupling coefficient K2 dispersion curves were studied, for the first (S0) and four higher order (S1, S2, S3, S4) symmetrical modes for different electrical boundary conditions. Two electroacoustic coupling configurations were investigated, based on interdigitated transducers, with or without a metal floating electrode at the opposite plate surface. Enhanced performances, such as a K2 as high as 8.5% and a phase velocity as high as 16,700 m/s, were demostrated for the ZnO- and BN-based waveguides, as an example. The relative velocity changes, and the inertial and viscous sensitivities of the first symmetric and anti-symmetric mode, S0 and A0, propagating along thin plates bordered by a viscous liquid were derived using the perturbation approach. The present study highlights the feasibility of the piezoelectric waveguides to the development of high-frequency, integrated-circuits compatible electroacoustic devices suitable for working in liquid environment. PMID- 26043175 TI - Novel method of detecting movement of the interference fringes using one dimensional PSD. AB - In this paper, a method of using a one-dimensional position-sensitive detector (PSD) by replacing charge-coupled device (CCD) to measure the movement of the interference fringes is presented first, and its feasibility is demonstrated through an experimental setup based on the principle of centroid detection. Firstly, the centroid position of the interference fringes in a fiber Mach Zehnder (M-Z) interferometer is solved in theory, showing it has a higher resolution and sensitivity. According to the physical characteristics and principles of PSD, a simulation of the interference fringe's phase difference in fiber M-Z interferometers and PSD output is carried out. Comparing the simulation results with the relationship between phase differences and centroid positions in fiber M-Z interferometers, the conclusion that the output of interference fringes by PSD is still the centroid position is obtained. Based on massive measurements, the best resolution of the system is achieved with 5.15, 625 MUm. Finally, the detection system is evaluated through setup error analysis and an ultra-narrow band filter structure. The filter structure is configured with a one-dimensional photonic crystal containing positive and negative refraction material, which can eliminate background light in the PSD detection experiment. This detection system has a simple structure, good stability, high precision and easily performs remote measurements, which makes it potentially useful in material small deformation tests, refractivity measurements of optical media and optical wave front detection. PMID- 26043173 TI - Functional analyses of polymorphic variants of human terminal deoxynucleotidyl transferase. AB - Human terminal deoxynucleotidyl transferase (hTdT) is a DNA polymerase that functions to generate diversity in the adaptive immune system. Here, we focus on the function of naturally occurring single-nucleotide polymorphisms (SNPs) of hTdT to evaluate their role in genetic-generated immune variation. The data demonstrate that the genetic variations generated by the hTdT SNPs will vary the human immune repertoire and thus its responses. Human TdT catalyzes template independent addition of nucleotides (N-additions) during coding joint formation in V(D)J recombination. Its activity is crucial to the diversity of the antigen receptors of B and T lymphocytes. We used in vitro polymerase assays and in vivo human cell V(D)J recombination assays to evaluate the activity and the N-addition levels of six natural (SNP) variants of hTdT. In vitro, the variants differed from wild-type hTdT in polymerization ability with four having significantly lower activity. In vivo, the presence of TdT varied both the efficiency of recombination and N-addition, with two variants generating coding joints with significantly fewer N-additions. Although likely heterozygous, individuals possessing these genetic changes may have less diverse B- and T-cell receptors that would particularly effect individuals prone to adaptive immune disorders, including autoimmunity. PMID- 26043176 TI - Quantum dot-based molecular beacon to monitor intracellular microRNAs. AB - Fluorescence monitoring of endogenous microRNA (miRNA or miR) activity related to neuronal development using nano-sized materials provides crucial information on miRNA expression patterns in a noninvasive manner. In this study, we report a new method to monitor intracellular miRNA124a using quantum dot-based molecular beacon (R9-QD-miR124a beacon). The R9-QD-miR124a beacon was constructed using QDs and two probes, miR124a-targeting oligomer and arginine rich cell-penetrating peptide (R9 peptide). The miR124a-targeting oligomer contains a miR124a binging sequence and a black hole quencher 1 (BHQ1). In the absence of target miR124a, the R9-QD-miR124a beacon forms a partial duplex beacon and remained in quenched state because the BHQ1 quenches the fluorescence signal of the R9-QD-miR124a beacon. The binding of miR124a to the miR124a binding sequence of the miR124a targeting oligomer triggered the separation of the BHQ1 quencher and subsequent signal-on of a red fluorescence signal. Moreover, enhanced cellular uptake was achieved by conjugation with the R9 peptide, which resulted in increased fluorescent signal of the R9-QD-miR124a beacons in P19 cells during neurogenesis due to the endogenous expression of miR124a. PMID- 26043177 TI - Research on the interaction of hydrogen-bond acidic polymer sensitive sensor materials with chemical warfare agents simulants by inverse gas chromatography. AB - Hydrogen-bond acidic polymers are important high affinity materials sensitive to organophosphates in the chemical warfare agent sensor detection process. Interactions between the sensor sensitive materials and chemical warfare agent simulants were studied by inverse gas chromatography. Hydrogen bonded acidic polymers, i.e., BSP3, were prepared for micro-packed columns to examine the interaction. DMMP (a nerve gas simulant) and 2-CEES (a blister agent simulant) were used as probes. Chemical and physical parameters such as heats of absorption and Henry constants of the polymers to DMMP and 2-CEES were determined by inverse gas chromatography. Details concerning absorption performance are also discussed in this paper. PMID- 26043178 TI - Comparison between low-cost marker-less and high-end marker-based motion capture systems for the computer-aided assessment of working ergonomics. AB - The paper deals with the comparison between a high-end marker-based acquisition system and a low-cost marker-less methodology for the assessment of the human posture during working tasks. The low-cost methodology is based on the use of a single Microsoft Kinect V1 device. The high-end acquisition system is the BTS SMART that requires the use of reflective markers to be placed on the subject's body. Three practical working activities involving object lifting and displacement have been investigated. The operational risk has been evaluated according to the lifting equation proposed by the American National Institute for Occupational Safety and Health. The results of the study show that the risk multipliers computed from the two acquisition methodologies are very close for all the analysed activities. In agreement to this outcome, the marker-less methodology based on the Microsoft Kinect V1 device seems very promising to promote the dissemination of computer-aided assessment of ergonomics while maintaining good accuracy and affordable costs. PRACTITIONER'S SUMMARY: The study is motivated by the increasing interest for on-site working ergonomics assessment. We compared a low-cost marker-less methodology with a high-end marker based system. We tested them on three different working tasks, assessing the working risk of lifting loads. The two methodologies showed comparable precision in all the investigations. PMID- 26043179 TI - A rare Robertsonian translocation rob(14;22) carrier with azoospermia, meiotic defects, and testicular sperm aneuploidy. AB - Male infertility is a serious problem in an increasing number of couples. We report an infertile man with non-obstructive azoospermia and karyotype 45,XY,rob(14;22). The immunofluorescence analysis of his testicular tissue using antibodies to SYCP1, SYCP3, HORMAD2, MLH1, and centromeres showed delayed synapsis of the chromosomes involved in the translocation, a varying extent of trivalent asynapsis and its association with sex chromosomes. The mean frequency of meiotic recombination per cell was within the range of normal values. Fluorescence in situ hybridization (FISH) with probes for chromosomes 14 and 22 revealed 5.83% of chromosomally abnormal testicular spermatozoa. FISH with probes for chromosomes X, Y, and 21 showed frequencies of disomic and diploid testicular spermatozoa increased when compared to ejaculated sperm of healthy donors, but comparable with published results for azoospermic patients. PGD by FISH for the translocation and aneuploidy of chromosomes X, Y, 13, 18, and 21 showed a normal chromosomal complement in one out of three analyzed embryos. A healthy carrier girl was born after the embryo transfer. This study shows the benefits of preimplantation genetic diagnosis in a case of a rare Robertsonian translocation carrier with azoospermia and a relatively low frequency of chromosomally unbalanced testicular spermatozoa. PMID- 26043180 TI - Acetyl CoA carboxylase inactivation and meiotic maturation in mouse oocytes. AB - In mouse oocytes, meiotic induction by pharmacological activation of PRKA (adenosine monophosphate-activated protein kinase; formerly known as AMPK) or by hormones depends on stimulation of fatty acid oxidation (FAO). PRKA stimulates FAO by phosphorylating and inactivating acetyl CoA carboxylase (ACAC; formerly ACC), leading to decreased malonyl CoA levels and augmenting fatty-acid transport into mitochondria. We investigated a role for ACAC inactivation in meiotic resumption by testing the effect of two ACAC inhibitors, CP-640186 and Soraphen A, on mouse oocytes maintained in meiotic arrest in vitro. These inhibitors significantly stimulated the resumption of meiosis in arrested cumulus cell enclosed oocytes, denuded oocytes, and follicle-enclosed oocytes. This stimulation was accompanied by an increase in FAO. Etomoxir, a malonyl CoA analogue, prevented meiotic resumption as well as the increase in FAO induced by ACAC inhibition. Citrate, an ACAC activator, and CBM-301106, an inhibitor of malonyl CoA decarboxylase, which converts malonyl CoA to acetyl CoA, suppressed both meiotic induction and FAO induced by follicle-stimulating hormone, presumably by maintaining elevated malonyl CoA levels. Mouse oocyte-cumulus cell complexes contain both isoforms of ACAC (ACACA and ACACB); when wild-type and Acacb(-/-) oocytes characteristics were compared, we found that these single knockout oocytes showed a significantly higher FAO level and a reduced ability to maintain meiotic arrest, resulting in higher rates of germinal vesicle breakdown. Collectively, these data support the model that ACAC inactivation contributes to the maturation-promoting activity of PRKA through stimulation of FAO. PMID- 26043181 TI - Diagnostic Pitfalls in "Low-Grade Lymphoma" of the Orbit and Lacrimal Gland. AB - AIMS: To investigate potential diagnostic pitfalls associated with the identification of low grade lymphoma in the orbit and lacrimal gland region. METHODS: To systemically review all cases diagnosed as low grade lymphoma of orbit and lacrimal gland within a 2 year period at a specialist ophthalmic centre. To ascertain the frequency of diagnostic errors in this group of cases, in particular to look for known pitfalls associated with follicular colonisation by marginal zone lymphoma and the recently identified atypical variant of follicular lymphoma (FL). A series of 21 cases were reviewed. RESULTS: We identified two diagnostic errors; one case of extra nodal marginal zone lymphoma (ENMZL) which showed follicular colonisation and was misinterpreted as a FL and a case of missed mantle cell lymphoma (MCL). We identified no cases of atypical FL. CONCLUSION: Within the orbit and lacrimal gland the term "low grade lymphoma" encompasses the following types of lymphoma: ENMZL, FL, MCL and chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). The typical and atypical immunophenotype of these entities is discussed. The diagnosis of ENMZL, by far the most common low grade lymphoma to occur in these areas, is to some extent a difficult diagnosis and is often one of exclusion. The pitfalls of follicular colonisation and the concept of atypical follicular lymphoma are discussed. PMID- 26043183 TI - alpha-Crotyl-alpha-difluoroboranyloxy-amides: Structure and Reactivity of Isolable Intermediates in Stereospecific alpha-Ketol Rearrangements. AB - The stereospecific BF3-mediated alpha-ketol rearrangement of beta-hydroxy-alpha ketoamides yields isolable 2-difluoroboranyloxy-3-keto-amides. X-ray and NMR analysis reveal a carbonyl coordination of the boron by the amide not the ketone. The boron complexes are air-stable solids, can be purified by silica gel chromatography, and exhibit novel reactivity in bromination and superior stereoselectivity in dipolar cycloaddition reactions. PMID- 26043182 TI - Poor association of allergen-specific antibody, T- and B-cell responses revealed with recombinant allergens and a CFSE dilution-based assay. AB - BACKGROUND: The adaptive immunity underlying allergy comprises two components, the allergen-specific antibody (i.e. IgE, IgG) and the T-cell response. These two components are responsible for different disease manifestations and can be targeted by different therapeutic approaches. Here, we investigated the association of allergen-specific antibody and T- as well as B-cell responses in pollen-allergic patients using recombinant (r) major birch pollen allergen rBet v 1 and major timothy grass pollen allergen rPhl p 5 as defined antigens. METHODS: Allergen-specific IgE and IgG antibody responses were determined by ELISA, and allergen-specific T- and B-cell responses were measured in peripheral blood mononuclear cells using a carboxyfluorescein-diacetate-succinimidylester (CFSE) dilution assay. RESULTS: CFSE staining in combination with T-cell- and B-cell specific gating allowed discriminating between allergen-specific T-cell and B cell responses. Interestingly, we identified patients where mainly T cells and others where mainly B cells proliferated in response to allergen stimulation. No association between the level of allergen-specific Ig responses and B- or T-cell proliferation was observed. CONCLUSION: Purified recombinant allergens in conjunction with CFSE staining allow the dissection of allergen-specific B- and T cell responses. The dissociation of allergen-specific antibody, and B- and T-cell responses may explain the occurrence of selective IgE- and T-cell-mediated manifestations of allergic inflammation and may be important for the development of diagnostic and therapeutic strategies selectively targeting B cells and T cells. PMID- 26043184 TI - Synthesis of a Cytotoxic Amanitin for Biorthogonal Conjugation. AB - Alpha-amanitin is an exceedingly toxic, naturally occurring, bicyclic octapeptide that inhibits RNA polymerase and results in cellular and organismal death. Here we report the straightforward synthesis of an amanitin analogue that exhibited near-native toxicity. A pendant alkyne was readily installed to enable copper catalyzed alkyne-azide cycloaddition (CuAAC) to azido-rhodamine and two azide bearing versions of the RGD peptide. The fluorescent toxin analogue entered cells and provoked morphological changes consistent with cell death. The latter two conjugates are as toxic as the parent alkyne precursor, which demonstrates that conjugation does not diminish toxicity. In addition, we showed that toxicity depends on a single diastereomer of the unnatural amino acid, dihydroxyisoleucine (DHIle), at position 3. The convenient synthesis of a heptapeptide precursor now provides access to bioactive amanitin analogues that may be readily conjugated to biomolecules of interest. PMID- 26043185 TI - Quality Indicators for Physical and Behavioral Health Care Integration. PMID- 26043187 TI - Synthesis and Reactions of 3d Metal Complexes with the Bulky Alkoxide Ligand [OC(t)Bu2Ph]. AB - Treatment of NiCl2(dme) and NiBr2(dme) (dme = dimethoxyethane) with 2 equiv of LiOR (OR = OC(t)Bu2Ph) forms the distorted trigonal planar complexes [NiLiX(OR)2(THF)2] (THF = tetrahydrofuran) 5 (X = Cl) and 6 (X = Br). The reaction of CuX2 (X = Cl, Br) with 2 equiv of LiOR affords the Cu(I) product Cu4(OR)4 (7). The same product can be obtained using the Cu(I) starting material CuCl. NMR studies indicated that the reduction of Cu(II) to Cu(I) is accompanied by the oxidation of the alkoxide RO(-) to form the alkoxy radical RO(*), which subsequently forms tert-butyl phenyl ketone by beta-scission. Treatment of compounds 1-4 ([M2Li2Cl2(OR)4], M = Cr-Co) with thallium hexafluorophosphate allowed the isolation of the distorted tetrahedral complexes of the form M(OR)2(THF)2 for M = Mn (8), Fe (9), and Co (10). Cyclic voltammetry performed on compounds 8-10 demonstrated irreversible oxidations for all complexes, with the iron complex 9 being the most reducing. Complex 9 shows a reactivity toward PhIO and Ph3SbS to form the corresponding dinuclear iron(III) complexes Fe2(O)(OR)4(THF)2 (11) and Fe2(S)(OR)4(THF)2 (12), respectively. X-ray structural studies were performed, showing that the Fe-O-Fe angle for complex 11 is 176.4(1) degrees and that the Fe-S-Fe angle for complex 12 is 164.83(3) degrees . PMID- 26043186 TI - Randomized controlled trial comparing impact on platelet reactivity of twice daily with once-daily aspirin in people with Type 2 diabetes. AB - AIMS: Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively. METHODS: Participants with Type 2 diabetes (n = 24) but without known cardiovascular disease were randomized in a three-way crossover design to 2-week treatment periods with aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily. The primary outcome was platelet reactivity, assessed using the VerifyNow(TM) ASA method. Relationships between platelet reactivity and aspirin dosing were examined using generalized linear mixed models with random subject effects. RESULTS: Platelet reactivity decreased from baseline with all doses of aspirin. Modelled platelet reactivity was more effectively reduced with aspirin 100 mg twice daily vs. 100 mg once daily, but not vs. 200 mg once daily. Aspirin 200 mg once daily did not differ from 100 mg once daily. Aspirin 100 mg twice daily was also more effective than once daily as measured by collagen/epinephrine-stimulated platelet aggregation and urinary thromboxane levels, with a similar trend measured by serum thromboxane levels. No episodes of bleeding occurred. CONCLUSIONS: In Type 2 diabetes, aspirin 100 mg twice daily reduced platelet reactivity more effectively than 100 mg once daily, and numerically more than 200 mg once daily. Clinical outcome trials evaluating primary cardiovascular disease prevention with aspirin in Type 2 diabetes may need to consider using a more frequent dosing schedule. PMID- 26043188 TI - Can Impacts of Climate Change and Agricultural Adaptation Strategies Be Accurately Quantified if Crop Models Are Annually Re-Initialized? AB - Estimates of climate change impacts on global food production are generally based on statistical or process-based models. Process-based models can provide robust predictions of agricultural yield responses to changing climate and management. However, applications of these models often suffer from bias due to the common practice of re-initializing soil conditions to the same state for each year of the forecast period. If simulations neglect to include year-to-year changes in initial soil conditions and water content related to agronomic management, adaptation and mitigation strategies designed to maintain stable yields under climate change cannot be properly evaluated. We apply a process-based crop system model that avoids re-initialization bias to demonstrate the importance of simulating both year-to-year and cumulative changes in pre-season soil carbon, nutrient, and water availability. Results are contrasted with simulations using annual re-initialization, and differences are striking. We then demonstrate the potential for the most likely adaptation strategy to offset climate change impacts on yields using continuous simulations through the end of the 21st century. Simulations that annually re-initialize pre-season soil carbon and water contents introduce an inappropriate yield bias that obscures the potential for agricultural management to ameliorate the deleterious effects of rising temperatures and greater rainfall variability. PMID- 26043189 TI - Genetic determinants of quantitative traits associated with cardiovascular disease risk. AB - Established risk factors for cardiovascular diseases (CVD) may be moderated by genetic variants. In 2403 unrelated individuals from general practice (mean age 40.5 years), we evaluated the influence of 15 variants in 12 candidate genes on quantitative traits (QT) associated with CVD (body mass index, abdominal obesity, glucose, serum lipids, and blood pressure). Prior to multiple testing correction, univariate analysis associated APOE rs429358, rs7412 and ATG16L1 rs2241880 variants with serum lipid levels, while LEPR rs1137100 and ATG16L1 rs2241880 variants were linked to obesity related QTs. After taking into account confounding factors and correcting for multiple comparisons only APOE rs429358 and rs7412 variants remained significantly associated with risk of dyslipidemia. APOE rs429358 variant almost tripled the risk in homozygous subjects (OR = 2.97; 95% CI 1.09-8.10, p < 0.03) and had a lesser but still highly significant association also in heterozygous individuals (OR = 1.67; 95% CI 1.24-2.10; p < 0.001). Associations with hypertension, diabetes mellitus, and metabolic syndrome were not significant after Bonferroni correction. The influence of genetic variation is more evident in dyslipidemia than in other analyzed QTs. These results may contribute to strategic research aimed at including genetic variation in the set of data required to identify subjects at high risk of CVD. PMID- 26043190 TI - Serological Prevalence of Schistosoma japonicum in Mobile Populations in Previously Endemic but Now Non-Endemic Regions of China: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Schistosomiasis japonica has been resurging in certain areas of China where its transmission was previously well controlled or interrupted. Several factors may be contributing to this, including mobile populations, which if infected, may spread the disease. A wide range of estimates have been published for S. japonicum infections in mobile populations, and a synthesis of these data will elucidate the relative risk presented from these groups. METHODS: A literature search for publications up to Oct 31, 2014 on S. japonicum infection in mobile populations in previously endemic but now non-endemic regions was conducted using four bibliographic databases: China National Knowledge Infrastructure, WanFang, VIP Chinese Journal Databases, and PubMed. A meta analysis was conducted by pooling one arm binary data with MetaAnalyst Beta 3.13. The protocol is available on PROSPERO (No. CRD42013005967). RESULTS: A total of 41 studies in Chinese met the inclusion criteria, covering seven provinces of China. The time of post-interruption surveillance ranged from the first year to the 31st year. After employing a random-effects model, from 1992 to 2013 the pooled seroprevalence ranged from 0.9% (95% CI: 0.5-1.6%) in 2003 to 2.3% (95% CI: 1.5-3.4) in 1995; from the first year after the disease had been interrupted to the 31st year, the pooled seroprevalence ranged from 0.6% (95% CI: 0.2-2.1%) in the 27th year to 4.0% (95%CI: 1.3-11.3%) in the second year. The pooled seroprevalence in mobile populations each year was significantly lower than among the residents of endemic regions, whilst four papers reported a lower level of infection in the mobile populations than in the local residents out of only 13 papers which included this data. CONCLUSIONS: The re-emergence of S. japonicum in areas which had previously interrupted transmission might be due to other factors, although risk from re-introduction from mobile populations could not be excluded. PMID- 26043191 TI - En Face Optical Coherence Tomography of Outer Retinal Discontinuity and Fan Shaped Serous Macular Detachment in Diabetic Macular Edema. PMID- 26043192 TI - Performance development in adolescent track and field athletes according to age, sex and sport discipline. AB - INTRODUCTION: Sex-specific differences that arise during puberty have a pronounced effect on the training process. However, the consequences this should have for goal-setting, planning and implementation of training for boys and girls of different ages remains poorly understood. The aim of this study was to quantify performance developments in athletic running and jumping disciplines in the age range 11-18 and identify progression differences as a function of age, discipline and sex. METHODS: The 100 all-time best Norwegian male and female 60 m, 800-m, long jump and high jump athletes in each age category from 11 to 18 years were analysed using mixed models with random intercept according to athlete. RESULTS: Male and female athletes perform almost equally in running and jumping events up to the age of 12. Beyond this age, males outperform females. Relative annual performance development in females gradually decreases throughout the analyzed age period. In males, annual relative performance development accelerates up to the age of 13 (for running events) or 14 (for jumping events) and then gradually declines when approaching 18 years of age. The relative improvement from age 11 to 18 was twice as high in jumping events compared to running events. For all of the analyzed disciplines, overall improvement rates were >50% higher for males than for females. The performance sex difference evolves from < 5% to 10-18% in all the analyzed disciplines from age 11 to 18 yr. CONCLUSION: To the authors' knowledge, this is the first study to present absolute and relative annual performance developments in running and jumping events for competitive athletes from early to late adolescence. These results allow coaches and athletes to set realistic goals and prescribe conditioning programs that take into account sex-specific differences in the rate of performance development at different stages of maturation. PMID- 26043193 TI - Popularity and Resource Control Goals as Predictors of Adolescent Indirect Aggression. AB - Resource Control Theory conceptualizes aggression as a behavior that allows access to, and control of, limited resources (P. H. Hawley, 1999 ). This study investigated the associations of adolescents' indirect aggression with their resource control goals, or goals related to controlling social resources such as dating opportunities and peer status, and with their levels of popularity and social intelligence. Participants were 109 seventh-graders (52% girls) who completed a resource control goals measure, the Tromso Social Intelligence Scale, and peer nominations of popularity and indirect aggression. Results indicated positive associations between resource control goals and peer-nominated indirect aggression, with popularity further moderating these associations. These findings suggest that the resource control goals of adolescents can be a motivating force to engage in hurtful behaviors. They provide a context from which peer relations researchers can improve their understanding and prevention of adolescents' indirect aggression. PMID- 26043194 TI - Long-term survival after traumatic brain injury part I: external validity of prognostic models. AB - OBJECTIVES: To develop prognostic models for long-term survival in adults with traumatic brain injury (TBI) and to assess their external validity in 2 independent populations. DESIGN: Survival analysis. SETTING: Post-discharge from rehabilitation units and long-term follow-up at regional centers. PARTICIPANTS: Two cohorts of long-term survivors of TBI (N=12,481): the Traumatic Brain Injury Model Systems (TBIMS) cohort comprised 7365 persons who were admitted to a TBIMS facility and were assessed at >=1 years postinjury, and the California Department of Developmental Services (CDDS) cohort comprised 5116 persons who sustained a TBI and received long-term services from the CDDS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Survival/mortality. RESULTS: Older age, male sex, and severity of disability in walking and feeding were significant predictors of increased long-term mortality rates (all P<.05, both databases). The CDDS model predicted 623 deaths for persons in the TBIMS cohort, with an observed-to expected ratio of .94 (95% confidence interval [CI], 0.87-1.02). The TBIMS model predicted a total of 525 deaths for persons in the CDDS cohort, with an observed to-expected ratio of 1.08 (95% CI, 0.99-1.17). Regression calibration statistics were satisfactory, and both models ranked survival times well from shortest to longest (TBIMS: C index, .78; 95% CI, .76-.80; CDDS: C index, .80; 95% CI, .78 .82). CONCLUSIONS: Long-term survival prognosis in TBI is related to age, sex, and severity of disability. When compared on the basis of these factors, the survival estimates derived from the TBIMS and CDDS cohorts are found to be similar. The close agreement between model predictions and actual mortality rates confirm the external validity of the prognostic models presented herein. PMID- 26043195 TI - Long-Term Survival After Traumatic Brain Injury Part II: Life Expectancy. AB - OBJECTIVES: To compute the life expectancy of persons with traumatic brain injury (TBI) based on validated prognostic models from 2 cohorts, to compare mortality and life expectancy of persons with TBI with those of the U.S. general population, and to investigate trends toward improved survival over the last 2 decades. DESIGN: Survival analysis. SETTING: Postdischarge from rehabilitation units and long-term follow-up at regional centers. PARTICIPANTS: Two cohorts of long-term survivors of TBI (N=12,481): the Traumatic Brain Injury Model Systems (TBIMS) cohort comprised 7365 persons who were admitted to a TBIMS facility with moderate to severe TBI and were assessed at >=1 years postinjury, and the California Department of Developmental Services (CDDS) cohort comprised 5116 persons who sustained a TBI and received long-term services from the CDDS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Life expectancy. RESULTS: The estimates of age-, sex-, and disability-specific life expectancy of persons with TBI derived from the CDDS and TBIMS were similar. The estimates of age- and sex-specific life expectancy were lower than those of the U.S. general population. Mortality rates of persons with TBI were higher than those of the U.S. general population. Mortality rates did not improve and the standardized mortality ratio increased over the study period from 1988 to 2010. CONCLUSIONS: Life expectancy of persons with TBI is lower than that of the general population and depends on age, sex, and severity of disability. When compared, the survival outcomes in the TBIMS and CDDS cohorts are remarkably similar. Because there have been no marked trends in the last 20 years, the life expectancies presented in this article may remain valid in the future. PMID- 26043196 TI - The authors respond. PMID- 26043197 TI - Prevalence and predictors of adolescent idiopathic scoliosis in adolescent ballet dancers. PMID- 26043198 TI - Sleep and traumatic brain injury. PMID- 26043199 TI - Alternating Stacked Graphene-Conducting Polymer Compact Films with Ultrahigh Areal and Volumetric Capacitances for High-Energy Micro-Supercapacitors. AB - Graphene-based compact nanohybrid films made by alternate deposition of electrochemically exfoliated graphene and mesoporous graphene-conducting polymer nanosheets are constructed for high-energy micro-supercapacitors. They are shown to have a landmark areal capacitance of 368 mF cm(-2) and volumetric capacitance of 736 F cm(-3) . PMID- 26043200 TI - Directional and Polarized Emission from Nanowire Arrays. AB - Lighting applications require directional and polarization control of the emitted light, which is currently achieved by bulky optical components such as lenses, parabolic mirrors, and polarizers. Ideally, this control would be achieved without any external optics, but at the nanoscale, during the generation of light. Semiconductor nanowires are promising candidates for lighting devices due to their efficient light outcoupling and synthesis flexibility. In this work, we demonstrate a precise control of both the directionality and the polarization of the nanowire array emission by changing the nanowire diameter. We change the angular emission pattern from a large-angle doughnut shape to a narrow-angle beaming along the nanowire axis. In addition, we tune the polarization from unpolarized to either p- or s-polarized. Both the far-field emission pattern and its polarization are controlled by the number and type of guided or leaky modes supported by the nanowire, which are determined by the nanowire diameter. PMID- 26043201 TI - A framework to assess the value of subgroup analyses when the overall treatment effect is significant. AB - Although subgroup analysis has been developed and widely used for many years, it is still not clear whether we should perform and how to perform such subgroup analyses when the overall treatment effect is significant. In this paper, we develop a framework to assess and compute the long-term impact of different strategies to perform subgroup analysis. We propose two performance measures: the average gain for patients in the future (E) and the probability of recommending a change to a worse treatment at individual patient level (P). Five families of decision rules are applied under different assumptions for the individual treatment effect (TE) variation. Three distributions reflecting optimistic, moderate, and pessimistic scenarios are assumed for true treatment effects across studies. This framework allows us to compare subgroup analyses decision rules, and we demonstrate through simulation studies that there are decision rules for subgroup analysis which can decrease P and increase E simultaneously compared to the situation of no subgroup analysis. These rules are much more liberal than the usual superiority testing. The latter typically implies a dramatic decrease in E. PMID- 26043205 TI - GRK3 suppresses L-DOPA-induced dyskinesia in the rat model of Parkinson's disease via its RGS homology domain. AB - Degeneration of dopaminergic neurons causes Parkinson's disease. Dopamine replacement therapy with L-DOPA is the best available treatment. However, patients develop L-DOPA-induced dyskinesia (LID). In the hemiparkinsonian rat, chronic L-DOPA increases rotations and abnormal involuntary movements modeling LID, via supersensitive dopamine receptors. Dopamine receptors are controlled by G protein-coupled receptor kinases (GRKs). Here we demonstrate that LID is attenuated by overexpression of GRK3 in the striatum, whereas knockdown of GRK3 by microRNA exacerbated it. Kinase-dead GRK3 and its separated RGS homology domain (RH) suppressed sensitization to L-DOPA, whereas GRK3 with disabled RH did not. RH alleviated LID without compromising anti-akinetic effect of L-DOPA. RH binds striatal Gq. GRK3, kinase-dead GRK3, and RH inhibited accumulation of ?FosB, a marker of LID. RH-dead mutant was ineffective, whereas GRK3 knockdown exacerbated ?FosB accumulation. Our findings reveal a novel mechanism of GRK3 control of the dopamine receptor signaling and the role of Gq in LID. PMID- 26043206 TI - Facile Routes To Improve Performance of Solution-Processed Amorphous Metal Oxide Thin Film Transistors by Water Vapor Annealing. AB - Here, we report on a simple and high-rate oxidization method for producing solution-based compound mixtures of indium zinc oxide (IZO) and indium gallium zinc oxide (IGZO) metal-oxide semiconductors (MOS) for thin-film transistor (TFT) applications. One of the issues for solution-based MOS fabrication is how to sufficiently oxidize the precursor in order to achieve high performance. As the oxidation rate of solution processing is lower than vacuum-based deposition such as sputtering, devices using solution-processed MOS exhibit relatively poorer performance. Therefore, we propose a method to prepare the metal-oxide precursor upon exposure to saturated water vapor in a closed volume for increasing the oxidization efficiency without requiring additional oxidizing agent. We found that the hydroxide rate of the MOS film exposed to water vapor is lower than when unexposed (<=18%). Hence, we successfully fabricated oxide TFTs with high electron mobility (27.9 cm(2)/V.s) and established a rapid process (annealing at 400 degrees C for 5 min) that is much shorter than the conventional as-deposited long-duration annealing (at 400 degrees C for 1 h) whose corresponding mobility is even lower (19.2 cm(2)/V.s). PMID- 26043208 TI - A high-level language for rule-based modelling. AB - Rule-based languages such as Kappa excel in their support for handling the combinatorial complexities prevalent in many biological systems, including signalling pathways. But Kappa provides little structure for organising rules, and large models can therefore be hard to read and maintain. This paper introduces a high-level, modular extension of Kappa called LBS-kappa. We demonstrate the constructs of the language through examples and three case studies: a chemotaxis switch ring, a MAPK cascade, and an insulin signalling pathway. We then provide a formal definition of LBS-kappa through an abstract syntax and a translation to plain Kappa. The translation is implemented in a compiler tool which is available as a web application. We finally demonstrate how to increase the expressivity of LBS-kappa through embedded scripts in a general purpose programming language, a technique which we view as generally applicable to other domain specific languages. PMID- 26043207 TI - Inter-Individual Differences in Neurobehavioural Impairment following Sleep Restriction Are Associated with Circadian Rhythm Phase. AB - Although sleep restriction is associated with decrements in daytime alertness and neurobehavioural performance, there are considerable inter-individual differences in the degree of impairment. This study examined the effects of short-term sleep restriction on neurobehavioural performance and sleepiness, and the associations between individual differences in impairments and circadian rhythm phase. Healthy adults (n = 43; 22 M) aged 22.5 +/- 3.1 (mean +/- SD) years maintained a regular 8:16 h sleep:wake routine for at least three weeks prior to laboratory admission. Sleep opportunity was restricted to 5 hours time-in-bed at home the night before admission and 3 hours time-in-bed in the laboratory, aligned by wake time. Hourly saliva samples were collected from 5.5 h before until 5 h after the pre laboratory scheduled bedtime to assess dim light melatonin onset (DLMO) as a marker of circadian phase. Participants completed a 10-min auditory Psychomotor Vigilance Task (PVT), the Karolinska Sleepiness Scale (KSS) and had slow eye movements (SEM) measured by electrooculography two hours after waking. We observed substantial inter-individual variability in neurobehavioural performance, particularly in the number of PVT lapses. Increased PVT lapses (r = 0.468, p < 0.01), greater sleepiness (r = 0.510, p < 0.0001), and more slow eye movements (r = 0.375, p = 0.022) were significantly associated with later DLMO, consistent with participants waking at an earlier circadian phase. When the difference between DLMO and sleep onset was less than 2 hours, individuals were significantly more likely to have at least three attentional lapses the following morning. This study demonstrates that the phase of an individual's circadian system is an important variable in predicting the degree of neurobehavioural performance impairment in the hours after waking following sleep restriction, and confirms that other factors influencing performance decrements require further investigation. PMID- 26043211 TI - Foreword. Cancer biomarkers. PMID- 26043212 TI - Identification of melanoma initiating cells: does CD271 have a future? PMID- 26043213 TI - Cellular prognostic markers in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the five big killers worldwide and is frequently associated with chronic hepatitis B and C virus (HBV and HCV) infections. Tumor microenvironment consists of a complex network of cells and factors that plays a key role in the tumor progression and prognosis. This is true also for HCC. Several studies have shown strikingly strong correlation between HCC clinical prognosis and intratumoral infiltration of cells affecting tumor growth, invasion, angiogenesis and metastasis. None of such cells is yet validated for routine diagnostic and prognostic assessment. The present review aims at providing a state-of-the-art of such studies. PMID- 26043214 TI - SUMO pathway components as possible cancer biomarkers. AB - SUMOylation is a key post-translational modification that regulates crucial cellular functions and pathological processes. Recently, Small Ubiquitin-related MOdifier (SUMO) modification has emerged as a fundamental route that may drive different steps of human tumorigenesis. Indeed, alteration in expression or activity of one of the different SUMO pathway components may completely subvert cellular properties through fine-tuning modulation of protein(s) involved in carcinogenic pathways, leading to altered cell proliferation, apoptosis resistance and metastatic potential. Here we describe some of the most interesting findings pointing to a clear link between SUMO pathway and human malignancies. Importantly, a putative role for SUMO enzymes to predict cancer behavior can be speculated, and thus the possible application of alterations in SUMO pathway components as tumor biomarkers is discussed. PMID- 26043215 TI - EGFR mutations in lung cancer: from tissue testing to liquid biopsy. AB - ABSTRACT The presence of EGFR mutations predicts the sensitivity to EGF receptor (EGFR)-tyrosine kinase inhibitors in a molecularly defined subset of non-small cell lung carcinoma (NSCLC) patients. For this reason, EGFR testing of NSCLC is required to provide personalized treatment options and better outcomes for NSCLC patients. As surgery specimens are not available in the majority of NSCLC, other currently available DNA sources are small biopsies and cytological samples, providing however limited and low-quality material. In order to address this issue, the use of surrogate sources of DNA, such as blood, serum and plasma samples, which often contains circulating free tumor DNA or circulating tumor cells, is emerging as a new strategy for tumor genotyping. PMID- 26043216 TI - An overview of new biomolecular pathways in pathogen-related cancers. AB - Cancer molecular pathways are combinations of metabolic processes deregulated in neoplastic cells. Besides pathways specific to tissues from which cancers originate, common neoplastic traits are present among most tumors. Hanahan and Weinberg have described the most critical 'hallmarks' shared by many cancer types. In recent years, cancer stem cell specific properties and pathways have also been identified. Other altered pathways are peculiar of cancer type and cancer stage, even in different cancer stem cell types. In pathogen-related tumors, the alteration of inflammatory and immunologic response along with impairment of cell cycle control represents key molecular events of tumor progression. This article summarizes the recent discoveries of new altered pathways in cancer and their importance in cancer diagnosis and tailored therapies. PMID- 26043217 TI - Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma. AB - The prognosis of patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) remains poor and current treatments are typically of limited benefit. Histone deacetylase (HDAC) inhibitors have proven effective for the treatment of relapsed/refractory PTCL. To date approved HDAC inhibitors for patients with T cell lymphoma are vorinostat, romidepsin and, recently, belinostat. Here we review the pharmacology and the clinical activity of belinostat. Belinostat is a well-tolerated HDAC inhibitor that has shown activity in heavily pretreated patients with relapsed/refractory PTCL. Several clinical trials are currently investigating the use of belinostat in different cancers and in combination with other chemotherapeutic agents. PMID- 26043219 TI - 3q26/EVI1 rearrangements in myeloid hemopathies: a cytogenetic review. AB - The EVI1 gene, located in chromosomal band 3q26, is a transcription factor that has stem cell-specific expression pattern and is essential for the regulation of self-renewal of hematopoietic stem cells. It is now recognized as one of the dominant oncogenes associated with myeloid leukemia. EVI1 overexpression is associated with minimal to no response to chemotherapy and poor clinical outcome. Several chromosomal rearrangements involving band 3q26 are known to induce EVI1 overexpression. They are mainly found in acute myeloid leukemia and blastic phase of Philadelphia chromosome-positive chronic myeloid leukemia, more rarely in myelodysplastic syndromes. They include inv(3)(q21q26), t(3;3)(q21;q26), t(3;21)(q26;q22), t(3;12)(q26;p13) and t(2;3)(p15-23;q26). However, many other chromosomal rearrangements involving 3q26/EVI1 have been identified. The precise molecular event has not been elucidated in the majority of these chromosomal abnormalities and most gene partners remain unknown. PMID- 26043218 TI - Chemotherapy-associated anemia in patients with lung cancer: an epidemiological, retrospective and multicenter study. AB - AIM: Providing epidemiological data and treatment of anemia in lung cancer patients undergoing first-line chemotherapy. METHODS: Epidemiological, observational, retrospective and multicenter study carried out at 30 sites throughout Spain. RESULTS: The prevalence of anemia (hemoglobin [Hb] level <12 g/dl) was 18.3% and the incidence 80.7%. Mean Hb levels were 13.4 g/dl (95% Cl: 13.2-13.6) and 11.5 g/dl (95% Cl: 11.3-11.7) at starting and at the end of chemotherapy, respectively. Of the 294 patients with anemia, 174 (59.2%) were treated. Erythropoiesis-stimulating agents were given to 90.2% patients, alone in 31.6% and combined iron in 39.7%, transfusion in 9.2% and iron and transfusion in 9.8%. CONCLUSION: These results suggest an appropriate and rational use of erythropoiesis-stimulating agents in the treatment of chemotherapy-associated anemia in lung cancer patients. [corrected]. PMID- 26043220 TI - Clinical efficacy of mTOR inhibitors in solid tumors: a systematic review. AB - The common dysregulation of the mTOR signaling pathway in tumor cells makes it a key target in oncotherapy. To better understand the effects of mTOR inhibitors, we analyzed 32 published clinical trials on solid tumors other than renal cell cancer, neuroendocrine tumors and metastatic breast cancer, for mTOR inhibitors are already approved by the US FDA to treat the three cancers. A lack of therapeutic effects was observed when mTOR inhibitors were used as a single agent. When combined with other agents, mTOR inhibitors still lacked sufficient clinical activity or just had minimal activity. More studies are required to better understand the clinically effects of mTOR inhibitors and the development of novel mTOR inhibitors is absolutely necessary. PMID- 26043221 TI - Corrigendum. PMID- 26043222 TI - Recovery kinetics of knee flexor and extensor strength after a football match. AB - We examined the temporal changes of isokinetic strength performance of knee flexor (KF) and extensor (KE) strength after a football match. Players were randomly assigned to a control (N = 14, participated only in measurements and practices) or an experimental group (N = 20, participated also in a football match). Participants trained daily during the two days after the match. Match and training overload was monitored with GPS devices. Venous blood was sampled and muscle damage was assessed pre-match, post-match and at 12 h, 36 h and 60 h post match. Isometric strength as well as eccentric and concentric peak torque of knee flexors and extensors in both limbs (dominant and non-dominant) were measured on an isokinetic dynamometer at baseline and at 12 h, 36 h and 60 h after the match. Functional (KFecc/KEcon) and conventional (KFcon/KEcon) ratios were then calculated. Only eccentric peak torque of knee flexors declined at 60 h after the match in the control group. In the experimental group: a) isometric strength of knee extensors and knee flexors declined (P<0.05) at 12 h (both limbs) and 36 h (dominant limb only), b) eccentric and concentric peak torque of knee extensors and flexors declined (P<0.05) in both limbs for 36 h at 60 degrees /s and for 60 h at 180 degrees /s with eccentric peak torque of knee flexors demonstrating a greater (P<0.05) reduction than concentric peak torque, c) strength deterioration was greater (P<0.05) at 180 degrees /s and in dominant limb, d) the functional ratio was more sensitive to match-induced fatigue demonstrating a more prolonged decline. Discriminant and regression analysis revealed that strength deterioration and recovery may be related to the amount of eccentric actions performed during the match and athletes' football-specific conditioning. Our data suggest that recovery kinetics of knee flexor and extensor strength after a football match demonstrate strength, limb and velocity specificity and may depend on match physical overload and players' physical conditioning level. PMID- 26043223 TI - Amyloid properties of the mouse egg zona pellucida. AB - The zona pellucida (ZP) surrounding the oocyte is an extracellular fibrillar matrix that plays critical roles during fertilization including species-specific gamete recognition and protection from polyspermy. The mouse ZP is composed of three proteins, ZP1, ZP2, and ZP3, all of which have a ZP polymerization domain that directs protein fibril formation and assembly into the three-dimensional ZP matrix. Egg coats surrounding oocytes in nonmammalian vertebrates and in invertebrates are also fibrillar matrices and are composed of ZP domain containing proteins suggesting the basic structure and function of the ZP/egg coat is highly conserved. However, sequence similarity between ZP domains is low across species and thus the mechanism for the conservation of ZP/egg coat structure and its function is not known. Using approaches classically used to identify amyloid including conformation-dependent antibodies and dyes, X-ray diffraction, and negative stain electron microscopy, our studies suggest the mouse ZP is a functional amyloid. Amyloids are cross-beta sheet fibrillar structures that, while typically associated with neurodegenerative and prion diseases in mammals, can also carry out functional roles in normal cells without resulting pathology. An analysis of the ZP domain from mouse ZP3 and ZP3 homologs from five additional taxa using the algorithm AmylPred 2 to identify amyloidogenic sites, revealed in all taxa a remarkable conservation of regions that were predicted to form amyloid. This included a conserved amyloidogenic region that localized to a stretch of hydrophobic amino acids previously shown in mouse ZP3 to be essential for fibril assembly. Similarly, a domain in the yeast protein alpha-agglutinin/Sag 1p, that possesses ZP domain-like features and which is essential for mating, also had sites that were predicted to be amyloidogenic including a hydrophobic stretch that appeared analogous to the critical site in mouse ZP3. Together, these studies suggest that amyloidogenesis may be a conserved mechanism for ZP structure and function across billions of years of evolution. PMID- 26043225 TI - Correction: Impact of Maternal HIV Seroconversion during Pregnancy on Early Mother to Child Transmission of HIV (MTCT) Measured at 4-8 Weeks Postpartum in South Africa 2011-2012: A National Population-Based Evaluation. PMID- 26043224 TI - Effect of chronic training on heart rate variability, salivary IgA and salivary alpha-amylase in elite swimmers with a disability. AB - The purpose of this study was to a) determine the heart rate variability (HRV) and saliva markers of immunity (salivary immunoglobulin A; sIgA) and stress (salivary alpha-amylase; sAA) responses to chronic training in elite swimmers with a disability; and b) identify the relationships between HRV, sIgA, sAA and training volume. Eight members of a high performance Paralympic swimming program were monitored for their weekly resting HRV, sIgA and sAA levels in the 14 weeks leading up to a major international competition. The 14 week training program included aerobic, anaerobic, power and speed, and taper training phases, while also incorporating two swimming step tests and two swimming competitions. Specific time (root mean square of the successive differences; RMSSD) and frequency (high frequency normalized units [HFnu]) domain measures, along with non-linear indices (standard deviation of instantaneous RR variability; SD1 and short term fractal scaling exponent; alpha1) of HRV were used for all analyses with effects examined using magnitude-based inferences. Relationships between HRV and saliva markers were identified by Spearman rank rho (rho) correlation coefficients. Compared with week 1, SD1 was very likely lower (96/4/0, ES = 2.21), while sAA was very likely elevated (100/0/0, ES = 2.32) at the beginning of week 7 for all athletes. The training program did not alter HRV or saliva whereas competition did. There were also no apparent differences observed for HRV, sIgA and sAA between each of the training phases during the 14 week swimming program. Correlations were observed between sAA and SD1 (rho = -0.212, p<0.05), along with sAA and mean HR (rho = 0.309, p<0.05). These results show that high level national competition influences depresses HRV (SD1) and increases saliva biomarkers of stress (sAA). It appears that a well-managed and periodised swimming program can maintain these indices within normal baseline levels. The study also highlighted the parasympathetic nervous system influence on sAA. PMID- 26043226 TI - Point: should childhood vaccination against measles be a mandatory requirement for attending school? Yes. PMID- 26043227 TI - Long-term asymmetric hearing affects cochlear implantation outcomes differently in adults with pre- and postlingual hearing loss. AB - In many countries, a single cochlear implant is offered as a treatment for a bilateral hearing loss. In cases where there is asymmetry in the amount of sound deprivation between the ears, there is a dilemma in choosing which ear should be implanted. In many clinics, the choice of ear has been guided by an assumption that the reorganisation of the auditory pathways caused by longer duration of deafness in one ear is associated with poorer implantation outcomes for that ear. This assumption, however, is mainly derived from studies of early childhood deafness. This study compared outcomes following implantation of the better or poorer ear in cases of long-term hearing asymmetries. Audiological records of 146 adults with bilateral hearing loss using a single hearing aid were reviewed. The unaided ear had 15 to 72 years of unaided severe to profound hearing loss before unilateral cochlear implantation. 98 received the implant in their long-term sound-deprived ear. A multiple regression analysis was conducted to assess the relative contribution of potential predictors to speech recognition performance after implantation. Duration of bilateral significant hearing loss and the presence of a prelingual hearing loss explained the majority of variance in speech recognition performance following cochlear implantation. For participants with postlingual hearing loss, similar outcomes were obtained by implanting either ear. With prelingual hearing loss, poorer outcomes were obtained when implanting the long-term sound-deprived ear, but the duration of the sound deprivation in the implanted ear did not reliably predict outcomes. Contrary to an apparent clinical consensus, duration of sound deprivation in one ear has limited value in predicting speech recognition outcomes of cochlear implantation in that ear. Outcomes of cochlear implantation are more closely related to the period of time for which the brain is deprived of auditory stimulation from both ears. PMID- 26043228 TI - GLP-1 Receptor Agonist Treatment Increases Bone Formation and Prevents Bone Loss in Weight-Reduced Obese Women. AB - CONTEXT: Recent studies indicate that glucagon-like peptide (GLP)-1 regulates bone turnover, but the effects of GLP-1 receptor agonists (GLP-1 RAs) on bone in obese weight-reduced individuals are unknown. OBJECTIVE: To investigate the role of GLP-1 RAs on bone formation and weight loss-induced bone mass reduction. DESIGN: Randomized control study. SETTING: Outpatient research hospital clinic. PARTICIPANTS: Thirty-seven healthy obese women with body mass index of 34 +/- 0.5 kg/m(2) and age 46 +/- 2 years. INTERVENTION: After a low-calorie-diet-induced 12% weight loss, participants were randomized to treatment with or without administration of the GLP-1 RA liraglutide (1.2 mg/d) for 52 weeks. In case of weight gain, up to two meals per day could be replaced with a low-calorie-diet product to maintain the weight loss. MAIN OUTCOME MEASURES: Total, pelvic, and arm-leg bone mineral content (BMC) and bone markers [C-terminal telopeptide of type 1 collagen (CTX-1) and N-terminal propeptide of type 1 procollagen (P1NP)] were investigated before and after weight loss and after 52-week weight maintenance. Primary endpoints were changes in BMC and bone markers after 52-week weight maintenance with or without GLP-1 RA treatment. RESULTS: Total, pelvic, and arm-leg BMC decreased during weight maintenance in the control group (P < .0001), but not significantly in the liraglutide group. Thus, total and arm-leg BMC loss was four times greater in the control group compared to the liraglutide group (estimated difference, 27 g; 95% confidence interval, 5-48; P = .01), although the 12% weight loss was maintained in both groups. In the liraglutide group, the bone formation marker P1NP increased by 16% (7 +/- 3 MUg/L) vs a 2% ( 1 +/- 4 MUg/L) decrease in the control group (P < .05). The bone resorption marker CTX-1 collagen did not change during the weight loss maintenance phase. CONCLUSIONS: Treatment with a long-acting GLP-1 RA increased bone formation by 16% and prevented bone loss after weight loss obtained through a low-calorie diet, supporting its role as a safe weight-lowering agent. PMID- 26043231 TI - Management strategies for the treatment of early osteoarthritis(OA) present the clinician with a conundrum. Introduction. PMID- 26043229 TI - Hepatic De Novo Lipogenesis in Obese Youth Is Modulated by a Common Variant in the GCKR Gene. AB - OBJECTIVE: This study's aim was to evaluate whether the GCKR rs1260326 variant increases hepatic de novo lipogenesis (DNL). SETTING AND DESIGN: To test this hypothesis, 14 adolescents, seven homozygous for the common allele (CC) and seven homozygous for the risk allele (TT), underwent measurement of hepatic DNL during the fasting state and after consumption of a carbohydrate (CHO) drink (75 g glucose and 25 g fructose). DNL was assessed through incorporation of deuterium in the palmitate contained in the very low-density lipoprotein. RESULTS: Subjects with TT demonstrated higher fasting fractional DNL (P = .036) and a lower increase in fractional DNL after the CHO challenge (P = .016). With regard to absolute lipogenesis, TT subjects had both higher fasting rates (P = .015) and 44% greater area under the curve of absolute lipogenesis during the study (P = .016), compared to CC subjects. Furthermore, subjects carrying the TT genotype showed higher basal rates of glucose oxidation (P = .0028) and a lower ability than CC subjects to increase the rates of glucose oxidation after the CHO load (P = .054). CONCLUSIONS: This study reports for the first time rates of DNL in obese adolescents and suggests that the GCKR rs1260326 gene variant, which is associated with greater glycolysis, increases hepatic DNL. These data highlight the role of glycolytic carbon flux in liver lipid synthesis and hypertriglyceridemia in these youngsters. PMID- 26043232 TI - BASK_questionnaire survey. PMID- 26043230 TI - Assessing Fit Between Evidence-Based Psychotherapies for Youth Depression and Real-Life Coping in Early Adolescence. AB - The modest efficacy of psychological interventions for youth depression, including evidence-based psychotherapies (EBPs), suggests a question: Do the therapy components match the coping strategies youths find helpful when dealing with depressed mood? Answering this question may help strengthen treatments. We asked 105 middle schoolers across a range of depression symptom levels to identify the coping strategies they used when they felt sad (habitual responses) and those that made them feel better (perceived-effective responses). Habitual and perceived-effective responses were coded for resemblance to EBPs, and each youth's habitual responses were coded for their match to the youth's perceived effective responses. Most perceived-effective responses (92.6%) matched EBP components (most frequent: Behavioral Activation); however, 65.0% of the EBP components did not match any youth's habitual or perceived-effective responses. Youths at higher depression symptom levels were significantly more likely than low-symptom youths to report (a) habitual responses that did not match EBP components, (b) habitual responses that did not match their own perceived effective responses, and (c) perceiving no effective response. The higher their depression symptom level, the less likely youths were to use strategies identified by researchers and perceived by themselves as effective, and the less likely they were to identify any perceived-effective coping strategy. The findings suggest a need to (a) determine which EBP components do in fact enhance youth coping, (b) design the most effective ways to help youths master those effective components, and PMID- 26043234 TI - Correction to Biaxially Stretchable, Integrated Array of High Performance Microsupercapacitors. PMID- 26043233 TI - Crystal structure of TRIM20 C-terminal coiled-coil/B30.2 fragment: implications for the recognition of higher order oligomers. AB - Many tripartite motif-containing (TRIM) proteins, comprising RING-finger, B-Box, and coiled-coil domains, carry additional B30.2 domains on the C-terminus of the TRIM motif and are considered to be pattern recognition receptors involved in the detection of higher order oligomers (e.g. viral capsid proteins). To investigate the spatial architecture of domains in TRIM proteins we determined the crystal structure of the TRIM20Delta413 fragment at 2.4 A resolution. This structure comprises the central helical scaffold (CHS) and C-terminal B30.2 domains and reveals an anti-parallel arrangement of CHS domains placing the B-box domains 170 A apart from each other. Small-angle X-ray scattering confirmed that the linker between CHS and B30.2 domains is flexible in solution. The crystal structure suggests an interaction between the B30.2 domain and an extended stretch in the CHS domain, which involves residues that are mutated in the inherited disease Familial Mediterranean Fever. Dimerization of B30.2 domains by means of the CHS domain is crucial for TRIM20 to bind pro-IL-1beta in vitro. To exemplify how TRIM proteins could be involved in binding higher order oligomers we discuss three possible models for the TRIM5alpha/HIV-1 capsid interaction assuming different conformations of B30.2 domains. PMID- 26043236 TI - Synthesis and Preclinical Evaluation of Three Novel Fluorine-18 Labeled Radiopharmaceuticals for P-Glycoprotein PET Imaging at the Blood-Brain Barrier. AB - P-Glycoprotein (P-gp), along with other transporter proteins at the blood-brain barrier (BBB), limits the entry of many pharmaceuticals into the brain. Altered P gp function has been found in several neurological diseases. To study the P-gp function, many positron emission tomography (PET) radiopharmaceuticals have been developed. Most P-gp radiopharmaceuticals are labeled with carbon-11, while labeling with fluorine-18 would increase their applicability due to longer half life. Here we present the synthesis and in vivo evaluation of three novel fluorine-18 labeled radiopharmaceuticals: 4-((6,7-dimethoxy-3,4 dihydroisoquinolin-2(1H)-yl)methyl)-2-(4-fluorophenyl)oxazole (1a), 2-biphenyl-4 yl-2-fluoroethoxy-6,7-dimethoxy-1,2,3,4-tetrahydro-isoquinoline (2), and 5-(1-(2 fluoroethoxy))-[3-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-propyl]-5,6,7,8 tetrahydronaphthalen (3). Compounds were characterized as P-gp substrates in vitro, and Mdr1a/b((-/-))Bcrp1((-/-)) and wild-type mice were used to assess the substrate potential in vivo. Comparison was made to (R)-[(11)C]verapamil, which is currently the most frequently used P-gp substrate. Compound [(18)F]3 was performing the best out of the new radiopharmaceuticals; it had 2-fold higher brain uptake in the Mdr1a/b((-/-))Bcrp1((-/-)) mice compared to wild-type and was metabolically quite stable. In the plasma, 69% of the parent compound was intact after 45 min and 96% in the brain. Selectivity of [(18)F]3 to P-gp was tested by comparing the uptake in Mdr1a/b((-/-)) mice to uptake in Mdr1a/b((-/-))Bcrp1((-/ )) mice, which was statistically not significantly different. Hence, [(18)F]3 was found to be selective for P-gp and is a promising new radiopharmaceutical for P gp PET imaging at the BBB. PMID- 26043235 TI - The mu opioid receptor: A new target for cancer therapy? AB - Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioid induced constipation, can be used to target the mu opioid receptor. PMID- 26043237 TI - Infection of host plants by Cucumber mosaic virus increases the susceptibility of Myzus persicae aphids to the parasitoid Aphidius colemani. AB - Plant viruses can profoundly alter the phenotypes of their host plants, with potentially far-reaching implications for ecology. Yet few studies have explored the indirect, host-mediated, effects of plant viruses on non-vector insects. We examined how infection of Cucurbita pepo plants by Cucumber mosaic virus (CMV) impacted the susceptibility of aphids (Myzus persicae) to attack by the parasitoid wasp Aphidius colemani. In semi-natural foraging assays, we observed higher rates of aphid parasitism on infected plants compared to healthy plants. Subsequent experiments revealed that this difference is not explained by different attack rates on plants differing in infection status, but rather by the fact that parasitoid larvae successfully complete their development more often when aphid hosts feed on infected plants. This suggests that the reduced nutritional quality of infected plants as host for aphids--documented in previous studies--compromises their ability to mount effective defenses against parasitism. Furthermore, our current findings indicate that the aphid diet during parasitoid development (rather than prior to wasp oviposition) is a key factor influencing resistance. These findings complement our previous work showing that CMV-induced changes in host plant chemistry alter patterns of aphid recruitment and dispersal in ways conducive to virus transmission. PMID- 26043238 TI - Activation of miR165b represses AtHB15 expression and induces pith secondary wall development in Arabidopsis. AB - Secondary cell-wall thickening takes place in sclerenchyma cells, but not in surrounding parenchyma cells. The molecular mechanism of switching on and off secondary wall synthesis in various cell types is still elusive. Here, we report the identification of a dominant mutant stp-2d showing secondary wall thickening in pith cells (STP). Immunohistochemistry assays confirmed accumulation of secondary cell walls in the pith cells of the stp-2d mutant. Activation of microRNA 165b (miR165b) expression is responsible for the STP phenotype, as demonstrated by transgenic over-expression experiments. The expression of three class III HD-ZIP transcription factor genes, including AtHB15, was repressed in the stp-2d mutant. Transgenic over-expression of a mutant form of AtHB15 that is resistant to miR165-mediated cleavage reversed the stp-2d mutant phenotype to wild-type, indicating that AtHB15 represses secondary wall development in pith. Characterization of two athb15 mutant alleles further confirmed that functional AtHB15 is necessary for retaining primary walls in parenchyma pith cells. Expression analyses of cell-wall synthetic genes and wall-related transcription factors indicated that a transcriptional pathway is involved in AtHB15 function. These results provide insight into the molecular mechanism of secondary cell-wall development. PMID- 26043239 TI - Subtalar anatomy and mechanics. AB - Understanding subtalar joint biomechanics and pathomechanics provides a framework for understanding both common pathologic hindfoot and forefoot conditions and surgical planning. It is important to identify mechanical impairment and to define what mechanical effect is needed to change a pathologic condition. It is also important to know what the initial problem is and what the consequences are in terms of soft tissue or bony stress leading to peritalar injury. Whenever possible, one should try to operate to change pathomechanics and facilitate spontaneous repair of stressed structures. PMID- 26043240 TI - Imaging of the subtalar joint. AB - Imaging of the subtalar joint can be challenging because of its complex planar anatomy. This article reviews the anatomy and common anatomic variants as seen with different imaging techniques. Although radiography remains the initial mode of imaging, computed tomography and MRI are frequently needed to better delineate the joint anatomy and improve the sensitivity and the specificity of detection of joint pathology. A short review of arthrographic techniques and various examples of imaging of common pathology involving this joint are also included. PMID- 26043241 TI - Subtalar instability. AB - Subtalar instability is a common clinical entity. Clinicians should have a high index of suspicion of this diagnosis in patients who have been diagnosed with chronic lateral ankle instability but have failed standard management and have continued pain in the sinus tarsi. As with ankle instability, nonoperative management is the initial mainstay of treatment. Operative management includes ligamentous reconstruction of key lateral stabilizers of the subtalar joint. Future research on this subject should be focused at improving diagnosis and recognition of this entity. PMID- 26043242 TI - Subtalar dislocations. AB - Subtalar dislocations make up 1-2% of all dislocations, about 75% of them being medial dislocations. Treatment consists of early reduction under adequate sedation. In cases of soft tissue interposition or locked dislocations, open reduction is warranted. More than 60% of subtalar dislocations are associated with additional fractures, therefore a postreduction CT is recommended. Complications include avascular necrosis of the talus, infection, posttraumatic arthritis, chronic subtalar instability, and complex regional pain syndrome with delayed reduction. The prognosis of purely ligamentous injuries is excellent after early reduction. Negative prognostic factors include lateral and open dislocations, total talar dislocations, and associated fractures. PMID- 26043243 TI - Subtalar coalition in pediatrics. AB - Subtalar tarsal coalition is an autosomal dominant developmental maldeformation that affects between 2% and 13% of the population. The most common locations are between the calcaneus and navicular and between the talus and calcaneus. If prolonged attempts at nonoperative management do not relieve the pain, surgery is indicated. The exact surgical technique(s) should be based on the location of the pain, the size and histology of the coalition, the health of the other joints and facets, the degree of foot deformity, and the excursion of the heel cord. PMID- 26043244 TI - Subtalar coalitions in the adult. AB - Tarsal coalitions, while relatively uncommon, are typically identified in adult patients during an evaluation for ankle instability, sinus tarsus pain, and/or pes planovalgus. The true incidence of tarsal coalition is unknown with estimates ranging from 1% to 12% of the overall population. The most common area of involvement of the subtalar joint is the middle facet, and heightened awareness should be present in adult patients with limited motion of the subtalar joint. Standard radiographic imaging, to include a Harris heel view, is recommended initially, although computerized tomography scan and MRI are often necessary to confirm the diagnosis. PMID- 26043245 TI - The spectrum of indications for subtalar joint arthrodesis. AB - The preferred surgical approaches to subtalar fusion are the sinus tarsi incision, the medial incision, and the extensile lateral approach. The choice of one over the other depends on the underlying pathology, previous surgeries, associated foot pathologies, soft tissue quality, and medical comorbidities. This article reports on several cases of subtalar joint fusion. PMID- 26043246 TI - Medial approach to the subtalar joint: anatomy, indications, technique tips. AB - The medial approach to the subtalar joint allows good visualization of the articular surfaces. Compared with the lateral approach, advantages are found particularly in flatfoot correction, in which the single-incision technique can be used for corrective fusions of rigid flatfoot deformity. Union rates are comparable with the traditional lateral approach; however, wound healing problems occur less frequently. Avascular necrosis of the talus is a rare but serious complication, although frequency seems to be independent of the approach chosen. Clinical studies showed no increased morbidity when comparing the medial to the lateral approach. PMID- 26043247 TI - Subtalar joint arthrodesis: open and arthroscopic indications and surgical techniques. AB - Arthrodesis of the subtalar joint can be performed via both open and arthroscopic techniques. Both groups of procedures have their own relative indications and contraindications, as well as complications. Good results have been reported for both general procedures, although some studies suggest superiority with arthroscopic subtalar arthrodesis. PMID- 26043248 TI - Distraction subtalar arthrodesis. AB - There is a high potential for disability following calcaneal fracture. This potential exists whether a patient is treated with conservative or operative management. Subfibular impingement and irritation of the peroneal tendon and sural nerve may also be present. Posttraumatic arthritis of the subtalar joint can occur. In patients with symptomatic calcaneal malunion, systematic evaluation is required to determine the source of pain. Nonsurgical treatment may be effective. One surgical treatment option is subtalar distraction arthrodesis. High rates of successful arthrodesis and patient satisfaction have been reported with this surgical option in correctly selected patients. PMID- 26043249 TI - The subtalar joint: it is more complicated than you think. Preface. PMID- 26043250 TI - [Analysis of patient flows: basis for regional control of antibiotic resistance]. AB - Antibiotic resistance is a worldwide threat to health care as it impairs the effective treatment of bacterial infections. Measures against the spread of resistance are mainly focused on individual health care institutions as these are viewed as the main source of resistance. However, health care institutions are not completely independent in their control of the prevalence of resistance, as movement of patients between hospitals and care institutions can induce movement of resistant micro-organisms. In other words, antibiotic resistance follows the flow of patients. Mapping this flow of patients results in a network that includes all health care institutions, and has a distinctive modular structure. Patients are moved primarily within regions, much less so between regions. We argue that the structure of this health care network should be used to design efficient and effective control strategies. To this end, we advocate (a) regional coordination of control measures, (b) differentiation of investment in infection prevention according to the network position of the institution, and PMID- 26043251 TI - [A man with multiple erythematous and hyperpigmented papules]. AB - A 25-year-old male patient developed multiple polycyclic papules after he had been involved in a bombardment in Syria and was hit by metal particles. We recognized the lesions as keloids, a fibroproliferative condition with abundant scar tissue. Our patient was treated with intralesional glucocorticoid injections and pressure therapy. PMID- 26043252 TI - [A man with a skin condition on his trunk and extremities]. AB - A 68-year-old man with a non-itching skin disease on his trunk and extremities was referred to the dermatologist. The patient had no medication changes, allergies or high-risk sexual contacts. The results of the laboratory tests revealed the diagnosis 'syphilis'. The patient was treated with benzylpenicillin. PMID- 26043253 TI - [A premature neonate with a right pre-auricular swelling]. AB - We present a 14-day-old premature born girl with a temperature of 37.8 degrees C and a swelling and redness of the right parotid gland. Laboratory tests revealed a CRP of 79 mg/l and ultrasound examination confirmed a parotitis. Treatment with augmentin i.v. resolved the condition. PMID- 26043254 TI - [18F-Fluorocholine PET-CT for localization of parathyroid adenomas]. AB - 18F-fluorocholine PET-CT is a new imaging modality for the localization of pathological parathyroid glands in patients with primary hyperparathyroidism. The PET-CT is a combination scan that uses both the physiological information from the PET and the anatomical information from the CT. Uptake of the radio-isotope 18F-fluorocholine is increased in pathological parathyroid glands. 18F fluorocholine PET-CT helps clinicians to localize the pathological parathyroid glands where conventional modalities fail to do so. This enables surgeons to carry out targeted minimal invasive surgery. It may also prevent the patient having to undergo a more extensive exploration, with its associated risks, and alleviate the necessity of taking medications with side effects. Although the literature on this subject is still scarce, preliminary results are promising. As any hospital with a PET-CT can perform the scan, we expect that its use in patients with hyperparathyroidism will increase over the next few years. PMID- 26043255 TI - [A woman with a blast injury]. AB - A 39-year-old woman presented with extensive soft tissue injury involving her upper legs and her left hand caused by the explosion of her cell phone. She suffered second and third-degree burns. She underwent surgery. She underwent surgical removal of metal slivers, wound debridement and repair of the soft tissue injury. PMID- 26043256 TI - [Estimating weight accurately for safe treatment: body weight estimation in patients with acute ischaemic stroke is frequently inaccurate]. AB - Patients with acute ischaemic stroke should receive intravenous thrombolysis with 0.9 mg/kg of recombinant tissue plasminogen activator as quickly as possible. In order to reduce the door-to-needle time, many physicians estimate the patient's body weight. However, these estimates are frequently inaccurate and inaccuracy can lead to dosage errors. According to a meta-analysis in a Cochrane study, the risk of developing intracranial haemorrhage is almost tripled for patients treated with higher thrombolytic doses, compared with patients receiving a dosage based on accurate weight measurements (odds ratio: 2.71). Only 28% of physicians estimate to within 5 kilograms of actual body weight. In order to reduce the risk of complications, patients arriving at the emergency room should be weighted with a scale. Alternatively, the body weight can be estimated using a validated nomogram. PMID- 26043257 TI - [Burnout among medical students: already being extinguished]. AB - In the Dutch Journal of Medicine, Conijn, Boersma and Van Rhenen present alarming statistics on the prevalence of burnout among medical students. Everyone in the field of medicine should take these findings seriously. Doctors who suffer from burnout early in their career are a hazard within the health care system. In order to tackle burnout among students it will not suffice to only focus on factors within the hospital. The societal context of the 'Achievement Generation' is of equal importance. PMID- 26043258 TI - [Dutch trial results drive a major change in stroke care]. AB - Recent randomised clinical trials have convincingly shown that endovascular therapy with the use of a retrievable stent considerably improves the chance of a good outcome in selected patients with acute ischaemic stroke and an occlusion of a proximal intracranial artery in the anterior circulation. The benefit of treatment strongly increases with shorter delays to reperfusion. This has major implications for the organisation of stroke care in the Netherlands. Agreements between all relevant parties are required in each region regarding the rapid referral of eligible patients to intervention centres. CT angiography must now become part of the standard evaluation of all patients with suspected ischaemic stroke presenting within six hours of symptom onset in order to achieve appropriate patient selection. Attention should be paid to workflow efficiencies to reduce delays. Since only a small proportion of stroke patients is eligible for endovascular therapy, the development of additional stroke therapies remains essential. PMID- 26043260 TI - Correction: Overexpression of periostin in stroma positively associated with aggressive prostate cancer. PMID- 26043259 TI - Expression of Selenoproteins Is Maintained in Mice Carrying Mutations in SECp43, the tRNA Selenocysteine 1 Associated Protein (Trnau1ap). AB - Selenocysteine tRNA 1 associated protein (Trnau1ap) has been characterized as a tRNA[Ser]Sec-binding protein of 43 kDa, hence initially named SECp43. Previous studies reported its presence in complexes containing tRNA[Ser]Sec implying a role of SECp43 as a co-factor in selenoprotein expression. We generated two conditionally mutant mouse models targeting exons 3+4 and exons 7+8 eliminating parts of the first RNA recognition motif or of the tyrosine-rich domain, respectively. Constitutive inactivation of exons 3+4 of SECp43 apparently did not affect the mice or selenoprotein expression in several organs. Constitutive deletion of exons 7+8 was embryonic lethal. We therefore generated hepatocyte specific Secp43 knockout mice and characterized selenoprotein expression in livers of mutant mice. We found no significant changes in the levels of 75Se labelled hepatic proteins, selenoprotein levels as determined by Western blot analysis, enzymatic activity or selenoprotein mRNA abundance. The methylation pattern of tRNA[Ser]Sec remained unchanged. Truncated Secp43 Delta7,8mRNA increased in Secp43-mutant livers suggesting auto-regulation of Secp43 mRNA abundance. We found no signs of liver damage in Secp433-mutant mice, but neuron specific deletion of exons 7+8 impaired motor performance, while not affecting cerebral selenoprotein expression or cerebellar development. These findings suggest that the targeted domains in the SECp43 protein are not essential for selenoprotein biosynthesis in hepatocytes and neurons. Whether the remaining second RNA recognition motif plays a role in selenoprotein biosynthesis and which other cellular process depends on SECp43 remains to be determined. PMID- 26043261 TI - Silver-based wound dressings reduce bacterial burden and promote wound healing. AB - Various types of wound dressings have been designed for different purposes and functions. Controlling bacterial burden in a wound during the early phase is important for successful wound repair. Once bacterial burden is under control, the active promotion of wound healing is another important factor for efficient wound healing. This study investigated the potential of three silver-containing dressings, namely KoCarbonAg((r)) , Aquacel((r)) Ag and Acticoat 7, in reducing bacterial survival and promoting wound healing. The ability of these dressings to block the entry of bacteria from external environment and retain intrinsic bacteria was studied in vitro. In addition, the study used a rat model to compare the healing efficiencies of the three dressings and investigate the quantity of collagen synthesis in vivo. In vitro results indicated that the silver-containing dressings prevented bacterial growth in wounds by blocking the entry of external bacteria and by retaining the bacteria in the dressing. In vivo study indicated that reduction in bacterial burden accelerated wound healing. Wounds treated by the silver-containing dressings showed better healing than those treated with gauze. Moreover, KoCarbonAg((r)) further accelerated wound healing by promoting collagen synthesis and arrangement. PMID- 26043262 TI - Determining Organ Doses from CT with Direct Measurements in Postmortem Subjects: Part 1--Methodology and Validation. AB - PURPOSE: To develop a methodology that allows direct measurement of organ doses from computed tomographic (CT) examinations of postmortem subjects. MATERIALS AND METHODS: In this institutional review board approved study, the x-ray linear attenuation coefficients of various tissues were calculated from the mean CT numbers of images that were obtained in eight embalmed adult female cadavers and compared with the corresponding linear attenuation coefficients calculated from CT images obtained in eight living patients that were body mass index (BMI) matched. Dosimetry was performed in three of the cadavers by accessing organs of interest and affixing partially sealed vinyl tubes inside them. Optically stimulated luminescent dosimeters (OSLDs) were inserted into the tubes and positioned within the organs of interest and on the skin. OSLDs were read with an InLight MicroStar (Landauer, Glenwood, Ill) reader, and readings were corrected for energy and scatter response. Fifteen tubes containing dosimeters were used, and imaging was repeated twice in each cadaver, for a total of five standard clinical protocols. Average dosimetry values were used for analysis. RESULTS: Differences in linear attenuation coefficients between living and embalmed cadaveric tissues were within 3% for the tissues investigated. Measured organ doses for a chest-abdomen-pelvis CT protocol were less than 32 mGy for all organs measured. Organs that were completely irradiated during a given examination received similar doses, whereas organs that were partially irradiated displayed a large variation in measured organ dose. CONCLUSION: The anatomic and radiation attenuation characteristics of cadavers are comparable to those of living human tissue. This methodology allows direct measurement of organ doses from clinical CT examinations. PMID- 26043263 TI - MR Imaging for Selection of Patients for Partial Breast Irradiation: A Systematic Review and Meta-Analysis. AB - PURPOSE: To systematically review articles that estimated the ineligibility for partial breast irradiation (PBI) after magnetic resonance (MR) imaging. MATERIALS AND METHODS: No ethics committee approval was needed. A systematic search was performed by using MEDLINE and EMBASE. The rate of patients eligible at standard assessment (ie, clinical examination, mammography, and/or ultrasonography) but ineligible after MR imaging was a study outcome. Odds ratios (ORs) were calculated to identify predictors. Quality was appraised by using the Strengthening Reporting of Observational Studies in Epidemiology checklist. RESULTS: Of 93 retrieved articles, six were included (total, 3136 patients). For PBI eligibility, all studies applied National Surgical Adjuvant Breast and Bowel Project B-39 criteria. Ineligibility at standard assessment varied from 21% to 80%; MR imaging prompted ineligibility for PBI in 6%-25% of patients who were initially deemed eligible or in 2%-20% if calculated on the overall number of patients initially screened. Meta-regression showed a negative correlation between ineligibility at standard assessment and ineligibility after MR imaging (P < .001). The pooled percentage of patients eligible at standard assessment but ineligible after MR imaging was 11% (95% confidence interval [CI]: 6%, 19%). Predictors for ineligibility after MR imaging were cancers stage pT2 or greater versus less than stage pT2 (OR, 8.8 [95% CI: 4.7, 16.7]; P < .001), invasive lobular histopathologic results versus invasive ductal pathologic results (OR, 3.0 [95% CI: 1.6, 6.6]; P = .007), pre- versus postmenopausal status (OR, 1.9 [95% CI: 1.3, 2.6]; P < .001), invasive cancer versus ductal carcinoma in situ (OR, 1.6 [95% CI: 1.0, 2.4]; P = .031). Study quality ranged from 17 to 20 (maximum quality, 22). The risk of publication bias was moderate. CONCLUSION: One of nine women (11%), who on the sole basis of standard assessment were candidates to undergo PBI, was found to be ineligible after undergoing MR imaging. Breast MR imaging should be used to select patients for PBI. PMID- 26043264 TI - Toward Simultaneous Real-Time Fluoroscopic and Nuclear Imaging in the Intervention Room. AB - PURPOSE: To investigate the technical feasibility of hybrid simultaneous fluoroscopic and nuclear imaging. MATERIALS AND METHODS: An x-ray tube, an x-ray detector, and a gamma camera were positioned in one line, enabling imaging of the same field of view. Since a straightforward combination of these elements would block the lines of view, a gamma camera setup was developed to be able to view around the x-ray tube. A prototype was built by using a mobile C-arm and a gamma camera with a four-pinhole collimator. By using the prototype, test images were acquired and sensitivity, resolution, and coregistration error were analyzed. RESULTS: Nuclear images (two frames per second) were acquired simultaneously with fluoroscopic images. Depending on the distance from point source to detector, the system resolution was 1.5-1.9-cm full width at half maximum, the sensitivity was (0.6-1.5) * 10(-5) counts per decay, and the coregistration error was -0.13 to 0.15 cm. With good spatial and temporal alignment of both modalities throughout the field of view, fluoroscopic images can be shown in grayscale and corresponding nuclear images in color overlay. CONCLUSION: Measurements obtained with the hybrid imaging prototype device that combines simultaneous fluoroscopic and nuclear imaging of the same field of view have demonstrated the feasibility of real-time simultaneous hybrid imaging in the intervention room. PMID- 26043265 TI - Multimodal Quantitative MR Imaging of the Thalamus in Multiple Sclerosis and Neuromyelitis Optica. AB - PURPOSE: To systematically investigate structural and functional alterations of the thalamus and its subregions through a multimodal magnetic resonance (MR) imaging technique and examine its clinical relevance in multiple sclerosis (MS) and neuromyelitis optica (NMO). MATERIALS AND METHODS: The institutional review board approved this study, and written informed consent was obtained from each participant. Thirty-seven patients with MS, 39 patients with NMO, and 40 healthy control subjects were recruited. Six MR imaging measurements were obtained for each participant and compared between groups in the thalamus and its seven subregions, including gray matter (GM) volume, fractional anisotropy, mean diffusivity, amplitude of low-frequency fluctuation, cross-correlation coefficient of spontaneous low frequency, and weighted functional connectivity strength. Partial correlation was used to estimate the MR imaging-clinical relationships. RESULTS: Both MS and NMO exhibited widespread GM atrophy (GM volume in MS, 0.244; NMO, 0.297; and control subjects, 0.329; P < .001) and diffusion abnormalities (fractional anisotropy in MS, 0.293; NMO, 0.323; and control subjects, 0.355; P < .001) in the whole thalamus and several subregions, while MS showed more severe changes than NMO. Decreased cross-correlation coefficient of spontaneous low-frequency and weighted functional connectivity strength was observed in several thalamus subregions in MS (P < .05), but no significant functional abnormalities were identified in NMO. GM volume, fractional anisotropy, and mean diffusivity, not functional changes of the thalamus and thalamic subregions, correlated with the patients' clinical variables and exhibited high discriminative power in distinguishing the three groups. CONCLUSION: Similar patterns of thalamic structural alteration were identified in MS and NMO, but MS showed more severe pathologic changes. The thalamus is a key node for functional disconnection in MS but not in NMO. PMID- 26043267 TI - Romantic Story or Raman Scattering? Rose Petals as Ecofriendly, Low-Cost Substrates for Ultrasensitive Surface-Enhanced Raman Scattering. AB - In this Article, we present a facile approach for the preparation of ecofriendly substrates, based on common rose petals, for ultrasensitive surface-enhanced Raman scattering (SERS). The hydrophobic concentrating effect of the rose petals allows us to concentrate metal nanoparticle (NP) aggregates and analytes onto their surfaces. From a systematic investigation of the SERS performance when using upper and lower epidermises as substrates, we find that the lower epidermis, with its quasi-three-dimensional (quasi-3D) nanofold structure, is the superior biotemplate for SERS applications. The metal NPs and analytes are both closely packed in the quasi-3D structure of the lower epidermis, thereby enhancing the Raman signals dramatically within the depth of focus (DOF) of the Raman optical system. We have also found the effect of the pigment of the petals on the SERS performance. With the novel petal-based substrate, the SERS measurements reveal a detection limit for rhodamine 6G below the femtomolar regime (10(-15) M), with high reproducibility. Moreover, when we employ an upside down drying process, the unique effect of the Wenzal state of the hydrophobic petal surface further concentrate the analytes and enhanced the SERS signals. Rose petals are green, natural materials that appear to have great potential for use in biosensors and biophotonics. PMID- 26043268 TI - Mutual perception of communication between general practitioners and hospital based specialists. AB - BACKGROUND: Communication between general practitioners (GPs) and specialists is an important aspect of qualitative care. Efficient communication exchange is essential and key in guaranteeing continuity of care. Inefficient communication is related to several negative outcomes, including patient harm. This study aimed to investigate the perception of GPs and hospital-based specialists in Belgium of the quality of their mutual communication. METHODS: A cross-sectional study was conducted among GPs and specialists. Participants were asked to complete a validated questionnaire on several aspects of their mutual communication. RESULTS: Response rates of 17.9% (343/1.912) for GPs and 17.3% (392/2.263) for specialists were obtained. Both specialists and GPs qualify their mutual telephone accessibility as suboptimal. Specialists think poorly of the GP referral letter, in contrast to GP perception. Eighty per cent of the GPs feel that specialists address their questions appropriately; specialists have a similar perception of their own performance. According to 16.7% of the specialists, GPs not always follow their recommendations. Contrarily, GPs rate their compliance much higher (90.7%). Less than half of the GPs feel that the specialists' letter arrives on time, whereas specialists have a different and a more positive perception. CONCLUSIONS: GPs and specialists disagree on several aspects of their mutual communication. These include the perception of accessibility, in both directions, and of the timeliness of written communication. Feedback is positively appreciated, again in both directions. Nevertheless, specialists feel that uptake of their recommendations is insufficient. Hence, there may remain significant room for improvement, which could contribute significantly to continuity of care and patient safety. PMID- 26043269 TI - Coordination of care in colon cancer. PMID- 26043270 TI - Biomechanical Properties of Human Ascending Thoracic Aortic Dissections. AB - Thoracic aortic dissections are associated with a significant risk of morbidity and mortality, and currently challenge our understanding of the biomechanical factors leading to their initiation and propagation. We quantified the biaxial mechanical properties of human type A dissections (n = 16) and modeled the stress strain data using a microstructurally motivated form of strain energy function. Our results show significantly higher stiffness for dissected tissues as compared to control aorta without arterial disease. Higher stiffness of dissected tissues did not, however, correlate with greater aortic diameter measured prior to surgery nor were there any age dependent differences in the tissue properties. PMID- 26043271 TI - Three stage cultivation process of facultative strain of Chlorella sorokiniana for treating dairy farm effluent and lipid enhancement. AB - Reserve lipids of microalgae are promising for biodiesel production. However, economically feasible and sustainable energy production from microalgae requires optimization of cultivation conditions for both biomass yield and lipid production of microalgae. Biomass yield and lipid production in microalgae are a contradictory problem because required conditions for both targets are different. Simultaneously, the mass cultivation of microalgae for biofuel production also depends extremely on the performance of the microalgae strains used. In this study a green unicellular microalgae Chlorella sorokiniana (DS6) isolated from the holding tanks of farm wastewater treatment plant using multi-step screening and acclimation procedures was found high-lipid producing facultative heterotrophic microalgae strain capable of growing on dairy farm effluent (DFE) for biodiesel feedstock and wastewater treatment. Morphological features and the phylogenetic analysis for the 18S rRNA identified the isolated strains. A novel three stage cultivation process of facultative strain of C. sorokiniana was examined for lipid production. PMID- 26043272 TI - Monoacylated Cellular Prion Proteins Reduce Amyloid-beta-Induced Activation of Cytoplasmic Phospholipase A2 and Synapse Damage. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of amyloid-beta (Abeta) and the loss of synapses. Aggregation of the cellular prion protein (PrPC) by Abeta oligomers induced synapse damage in cultured neurons. PrPC is attached to membranes via a glycosylphosphatidylinositol (GPI) anchor, the composition of which affects protein targeting and cell signaling. Monoacylated PrPC incorporated into neurons bound "natural Abeta", sequestering Abeta outside lipid rafts and preventing its accumulation at synapses. The presence of monoacylated PrPC reduced the Abeta induced activation of cytoplasmic phospholipase A2 (cPLA2) and Abeta-induced synapse damage. This protective effect was stimulus specific, as treated neurons remained sensitive to alpha-synuclein, a protein associated with synapse damage in Parkinson's disease. In synaptosomes, the aggregation of PrPC by Abeta oligomers triggered the formation of a signaling complex containing the cPLA2.a process, disrupted by monoacylated PrPC. We propose that monoacylated PrPC acts as a molecular sponge, binding Abeta oligomers at the neuronal perikarya without activating cPLA2 or triggering synapse damage. PMID- 26043273 TI - Orbital Branch of the Infraorbital Artery: Further Characterization of an Important Surgical Landmark. AB - The orbital branch of the infraorbital artery, a key vascular structure that is not universally noted in orbital textbooks and atlases, is clinically significant, since injury to it can result in perioperative hemorrhage. We conducted a cadaver dissection to document its presence, measure its location, and evaluate it histopathologically. It was present in 8 of 9 orbits and was a mean distance of 16.6 mm (range 10-23) from the inferior orbital rim. In half of the specimens, there were 2 separate structures seen. Histopathology confirmed these structures to be neurovascular bundles. PMID- 26043275 TI - Ergot alkaloids in feed for Pekin ducks: toxic effects, metabolism and carry over into edible tissues. AB - Hardened sclerotia (ergots) of Claviceps purpurea contaminate cereal grains and contain toxic ergot alkaloids (EA). Information on EA toxicity in ducks is scarce. Therefore, the aim of the growth experiment (Day 0-49, n = 54/group) was to titrate the lowest observed adverse effect level (LOAEL) for total ergot alkaloids (TEA). A control diet was prepared without ergots, and the diets designated Ergot 1 to 4 contained 1, 10, 15 and 20 g ergot per kg diet, respectively, corresponding to TEA contents of 0.0, 0.6, 7.0, 11.4 and 16.4 mg/kg. Sensitivity of ducks to EA was most pronounced at the beginning of the experiment when feed intake decreased significantly by 9%, 28%, 41% and 47% in groups Ergot 1 to 4, respectively, compared to the control group. The experiment was terminated after two weeks for ducks exposed to Ergot 3 and 4 due to significant growth retardation. Ergot alkaloid residues in edible tissues were lower than 5 ng/g. Bile was tested positive for ergonovine (=ergometrine = ergobasine) with a mean concentration of 40 ng/g. Overall, the LOAEL amounted to 0.6 mg TA/kg diet suggesting that ducks are not protected by current European Union legislation (1 g ergot/kg unground cereal grains). PMID- 26043274 TI - A novel Peptide-binding motifs inference approach to understand deoxynivalenol molecular toxicity. AB - Deoxynivalenol (DON) is a type B trichothecene mycotoxin that is commonly detected in cereals and grains world-wide. The low-tolerated levels of this mycotoxin, especially in mono-gastric animals, reflect its bio-potency. The toxicity of DON is conventionally attributed to its ability to inhibit ribosomal protein biosynthesis, but recent advances in molecular tools have elucidated novel mechanisms that further explain DON's toxicological profile, complementing the diverse symptoms associated with its exposure. This article summarizes the recent findings related to novel mechanisms of DON toxicity as well as how structural modifications to DON alter its potency. In addition, it explores feasible ways of expanding our understating of DON-cellular targets and their roles in DON toxicity, clearance, and detoxification through the utilization of computational biology approaches. PMID- 26043276 TI - Validation of reference materials for uranium radiochronometry in the frame of nuclear forensic investigations. AB - The results of a joint effort by expert nuclear forensic laboratories in the area of age dating of uranium, i.e. the elapsed time since the last chemical purification of the material are presented and discussed. Completely separated uranium materials of known production date were distributed among the laboratories, and the samples were dated according to routine laboratory procedures by the measurement of the (230)Th/(234)U ratio. The measurement results were in good agreement with the known production date showing that the concept for preparing uranium age dating reference material based on complete separation is valid. Detailed knowledge of the laboratory procedures used for uranium age dating allows the identification of possible improvements in the current protocols and the development of improved practice in the future. The availability of age dating reference materials as well as the evolvement of the age dating best-practice protocol will increase the relevance and applicability of age dating as part of the tool-kit available for nuclear forensic investigations. PMID- 26043277 TI - Foliar interception of radionuclides in dry conditions: a meta-analysis using a Bayesian modeling approach. AB - Uncertainty on the parameters that describe the transfer of radioactive materials into the (terrestrial) environment may be characterized thanks to datasets such as those compiled within International Atomic Energy Agency (IAEA) documents. Nevertheless, the information included in these documents is too poor to derive a relevant and informative uncertainty distribution regarding dry interception of radionuclides by the pasture grass and the leaves of vegetables. In this paper, 145 sets of dry interception measurements by the aboveground biomass of specific plants were collected from published scientific papers. A Bayesian meta-analysis was performed to derive the posterior probability distributions of the parameters that reflect their uncertainty given the collected data. Four competing models were compared in terms of both fitting performances and predictive abilities to reproduce plausible dry interception data. The asymptotic interception factor, applicable whatever the species and radionuclide to the highest aboveground biomass values (e.g. mature leafy vegetables), was estimated with the best model, to be 0.87 with a 95% credible interval (0.85, 0.89). PMID- 26043278 TI - Emerging fluorescent protein technologies. AB - Fluorescent proteins (FPs), such as the Aequorea jellyfish green FP (GFP), are firmly established as fundamental tools that enable a wide variety of biological studies. Specifically, FPs can serve as versatile genetically encoded markers for tracking proteins, organelles, or whole cells, and as the basis for construction of biosensors that can be used to visualize a growing array of biochemical events in cells and tissues. In this review we will focus on emerging applications of FPs that represent unprecedented new directions for the field. These emerging applications include new strategies for using FPs in biosensing applications, and innovative ways of using FPs to manipulate protein function or gene expression. PMID- 26043279 TI - Method for Measuring the Distribution of Adhesion Forces on Continuous Nanoscale Protrusions Using Carbon Nanofiber Tip on a Scanning Probe Microscope Cantilever. AB - The adhesion force on surfaces has received attention in numerous scientific and technological fields, including catalysis, thin-film growth, and tribology. Many applications require knowledge of the strength of these forces as a function of position in three dimensions, but until now such information has only been theoretically proposed. Here, we demonstrate an approach based on scanning probe microscopy that can obtain such data and be used to image the three-dimensional surface force field of continuous nanoscale protrusions. We present adhesion force maps with nanometer and nanonewton resolution that allow detailed characterization of the interaction between a surface and a thin carbon nanofiber (CNF) rod synthesized by plasma-enhanced chemical vapor deposition (PECVD) at the end of a tip on a scanning probe microscope cantilever in three dimensions. In these maps, the positions of all continuous nanoscale protrusions are identified and the differences in the adhesive forces among limited areas at inequivalent sites are quantified. PMID- 26043280 TI - Degradation of Li/S Battery Electrodes On 3D Current Collectors Studied Using X ray Phase Contrast Tomography. AB - Lithium/sulphur batteries are promising candidates for future energy storage systems, mainly due to their high potential capacity. However low sulphur utilization and capacity fading hinder practical realizations. In order to improve understanding of the system, we investigate Li/S electrode morphology changes for different ageing steps, using X-ray phase contrast tomography. Thereby we find a strong decrease of sulphur loading after the first cycle, and a constant loading of about 15% of the initial loading afterwards. While cycling, the mean sulphur particle diameters decrease in a qualitatively similar fashion as the discharge capacity fades. The particles spread, migrate into the current collector and accumulate in the upper part again. Simultaneously sulphur particles lose contact area with the conducting network but regain it after ten cycles because their decreasing size results in higher surface areas. Since the capacity still decreases, this regain could be associated with effects such as surface area passivation and increasing charge transfer resistance. PMID- 26043281 TI - Cooperative Self-Assembly of Gold Nanoparticles on the Hydrophobic Surface of Vesicles in Water. AB - Adsorption of gold nanoparticles (NPs) on a hydrophobic fullerene bilayer vesicle ca. 30 nm in diameter occurs through cooperation of vesicle/NP and NP/NP interactions to produce a NP-vesicle hybrid whose surface is uniformly covered with the NPs separated from each other by a few nm. The vesicle coverage by NPs makes the NP-vesicle hybrid unusually stable to withstand high temperature, chromatographic purification, and high salt concentration-conditions too harsh for ordinary self-assembled vesicles, such as lipid vesicles, to survive. The hybrid serves as a platform of chemical reactions; for example, gold-catalyzed reduction of an aromatic nitro group and deposition of gold atoms for in situ growth of the NPs from 3.5 to 7.2 nm in diameter. The robust vesicle structure can be destroyed by the heat produced in interparticle plasmon coupling absorption of a 532 nm laser irradiation. PMID- 26043282 TI - Issues relating to the release of proprietary information and data for use in the validation of alternative methods. PMID- 26043283 TI - A Quantitative Structure-toxicokinetic Relationship Model for Highly Metabolised Chemicals. PMID- 26043284 TI - The Neutral Red Uptake Assay: Comments on the Results of the Istituto Superiore di Sanita in the EC/HO Validation Study. PMID- 26043285 TI - C-Reactive protein and insulin growth factor 1 serum levels during the menstrual cycle in adolescents with Type 1 diabetes. AB - AIMS: To evaluate C-reactive protein, insulin growth factor 1 and lipid levels during the follicular and luteal phases in adolescents with Type 1 diabetes. METHODS: Adolescents with Type 1 diabetes (N = 40) and healthy controls (C; N = 43) were studied during the follicular and luteal phases of their menstrual cycles. C-Reactive protein, insulin growth factor 1 and lipid levels were measured. RESULTS: Adolescents with Type 1 diabetes exhibited higher C-reactive protein levels than the C group during the follicular (P < 0.0001) and luteal phases (P < 0.01). The elevation of C-reactive protein levels was more pronounced in overweight adolescents with Type 1 diabetes than in adolescents in the C group. More adolescents with Type 1 diabetes were classified as having an elevated risk of cardiovascular disease (C-reactive protein > 3 mg/l) in the luteal phase than in the follicular phase (37.5% and 17.5%, respectively); half of the overweight adolescents with Type 1 diabetes in the luteal phase reached this level. BMI was the only significant factor affecting follicular and luteal phase C-reactive protein levels in adolescents with Type 1 diabetes. Lower insulin growth factor 1 levels were observed during both phases of the menstrual cycle in adolescents with Type 1 diabetes compared with controls. An elevation in insulin growth factor 1 levels in the luteal phase relative to the follicular phase was observed in controls, but not in adolescents with Type 1 diabetes. Luteal insulin growth factor 1 and C-reactive protein exhibited an inverse correlation (r = -0.4, P = 0.01). CONCLUSIONS: Adolescents with Type 1 diabetes have higher C-reactive protein levels and lower insulin growth factor 1 levels relative to controls, especially during the luteal phase. Type 1 diabetes diminishes the natural elevation in insulin growth factor 1 levels observed during the luteal phase in controls. Excess weight exacerbates the subclinical inflammatory state observed during both phases of the menstrual cycle in adolescents with Type 1 diabetes. PMID- 26043286 TI - Review of experience with a collaborative eye care clinic in inpatient stroke rehabilitation. AB - BACKGROUND: Visual deficits following stroke are frequently subtle and are often overlooked. Even though these visual deficits may be less overt in nature, they are still debilitating to survivors. Visual deficits have been shown to negatively impact cognition, mobility, and activities of daily living (ADL). There is little consistency across healthcare facilities regarding protocol for assessing vision following stroke. OBJECTIVE: This research was designed to describe a profile for patients exhibiting visual deficits following stroke, examine the role of occupational therapists in vision assessment, and discuss a potential model to provide a protocol for collaboration with an eye care professional as part of the rehabilitation team. METHODS: The sample consisted of 131 patients in an inpatient rehabilitation (IPR) unit who were identified as having potential visual deficits. Occupational therapists on an IPR unit administered initial vision screenings and these patients were subsequently evaluated by the consulting optometrist. Frequencies were calculated for the appearance of functional symptoms, diagnoses, and recommendations. Correlations were also computed relating diagnoses and recommendations made. RESULTS: All patients referred by the occupational therapist for optometrist evaluation had at least one visual diagnosis. The most frequent visual diagnoses included: saccades (77.7%), pursuits (61.8%), and convergence (63.4%). There was also a positive correlation between number of functional symptoms seen by occupational therapists and visual diagnoses made by the optometrist (r = 0.209, P = 0.016). CONCLUSION: Results of this study support the need for vision assessment following stroke in IPR, confirm the role of occupational therapists in vision assessment, and support the need for an optometrist as a member of the rehabilitation team. PMID- 26043287 TI - All-nanophotonic NEMS biosensor on a chip. AB - Integrated chemical and biological sensors give advantages in cost, size and weight reduction and open new prospects for parallel monitoring and analysis. Biosensors based on nanoelectromechanical systems (NEMS) are the most attractive candidates for the integrated platform. However, actuation and transduction techniques (e.g. electrostatic, magnetomotive, thermal or piezoelectric) limit their operation to laboratory conditions. All-optical approach gives the possibility to overcome this problem, nevertheless, the existing schemes are either fundamentally macroscopic or excessively complicated and expensive in mass production. Here we propose a novel scheme of extremely compact NEMS biosensor monolithically integrated on a chip with all-nanophotonic transduction and actuation. It consists of the nanophotonic waveguide and the nanobeam cantilever placed above the waveguide, both fabricated in the same CMOS-compatible process. Being in the near field of the strongly confined photonic or plasmonic mode, cantilever is efficiently actuated and its response is directly read out using the same waveguide, which results in a very high sensitivity and capability of single-molecule detection even in atmosphere. PMID- 26043288 TI - Development of antiviral drugs for the treatment of hepatitis C at an accelerating pace. AB - Anno 2015, the race for developing the ideal therapy, or what is now called "cure," for hepatitis C virus infection has continued unabatedly. The targets (NS3/4A protease, NS5A protein, and NS5B polymerase) have remained the same, and the number of compounds [direct-acting antivirals (DAAs)] interacting with these targets has continued to increase. Whereas pan-genotypic activity has remained a mandatory requirement, the problem of virus drug resistance has become less crucial. The need for combining DAAs acting at different sites has remained compelling, with the drugs used for combinations emanating from the same pharmaceutical company, that is, Gilead (sofosbuvir and ledipasvir) (Gilead Sciences, Foster City, CA, USA) (AbbVie, North Chicago, IL, USA), AbbVie (ABT/r, ombitasvir, and dasabuvir), and BMS (Bristol-Myers Squibb), (New York City, NY, USA) (asunaprevir and daclatasvir) among the leading contenders. At stake is the definitive cure of HCV infection [as reflected by a sustained viral response (SVR) after 12 weeks of treatment]. This SVR is expected to reduce cirrhosis and hepatocellular carcinoma, two complications inherently linked to HCV infection. Unlike hepatitis B virus and human immunodeficiency virus, HCV infection can be definitely and permanently cured by antiviral therapy because HCV has no long term reservoir in the body. Peginterferon combined with ribavirin and even the first-wave protease inhibitors telaprevir and boceprevir now belong to the milestones that had an important, although historical, role in the final conquest of hepatitis C. PMID- 26043289 TI - Usefulness of indirect noninvasive methods in predicting progression to cirrhosis in chronic hepatitis C. AB - BACKGROUND AND AIMS: The ability of noninvasive methods to predict the development of cirrhosis has not been established. We evaluated the ability of three noninvasive methods [the Forns index, the aspartate aminotransferase-to platelet ratio index (APRI), and the Non-Invasive Hepatitis-C-related Cirrhosis Early Detection (NIHCED) score] to determine the risk of developing cirrhosis in chronic hepatitis C. METHODS: Consecutive patients with chronic hepatitis C who had undergone liver biopsy between 1998 and 2004 were eligible. We used the three methods to evaluate patients at baseline and at follow-up (4-10 years later). When these methods yielded discordant or indeterminate results, a second liver biopsy was performed. Logistic regression models were fitted for each method to predict whether cirrhosis would appear and to predict long-term mortality from cirrhosis. RESULTS: We included 289 patients in our study. The mean scores at baseline and at follow-up, respectively, were as follows: Forns, 5.47 +/- 1.95 and 6.56 +/- 2.02; APRI, 1.1 +/- 2.33 and 1.4 +/- 1.53; and NIHCED, 7.79 +/- 11.45 and 15.48 +/- 15.28. The area under the receiver operating characteristic curve for predicting cirrhosis was 0.83 for Forns, 0.79 for APRI, and 0.76 for NIHCED. The sensitivity and specificity for predicting cirrhosis, respectively, were 75 and 71% for Forns (cutoff 4.7), 86 and 42% for APRI (cutoff 0.48), and 41 and 82% for NIHCED (cutoff 0). The area under the receiver operating characteristic curve for predicting mortality was 0.86 for Forns, 0.79 for APRI, and 0.84 for NIHCED. CONCLUSION: Indirect noninvasive markers could help identify patients with chronic hepatitis C at risk of progression to cirrhosis. PMID- 26043290 TI - Efficacy of rifaximin on circulating endotoxins and cytokines in patients with nonalcoholic fatty liver disease. AB - OBJECTIVE: Recent studies have suggested that endotoxin-induced cytokines play an important role in nonalcoholic fatty liver disease (NAFLD). Rifaximin is a nonabsorbable antibiotic that might act on Gram-negative bacteria, thereby inhibiting endotoxin proinflammatory cytokine production in patients with NAFLD. Our aim was to investigate the efficacy of rifaximin on NAFLD. METHODS: Forty-two patients with biopsy-proven NAFLD [15 steatosis, 27 nonalcoholic steatohepatitis (NASH)] were included in this prospective, open-label, observational cohort study. BMI and serum aspartate aminotransferase, alanine aminotransferase (ALT), gamma glutamyl transferase, lipid profile, ferritin, C-reactive protein, glucose, insulin, homeostatic model assessment as well as endotoxin, serum Toll-like receptor 4 (TlR4), interleukin-1alpha (IL-1alpha), IL-6, IL-10, IL-12, and tumor necrosis factor-alpha (TNF-alpha) levels were measured before and after a 28-day administration of rifaximin (1200 mg/daily). Results were analyzed using nonparametric Wilcoxon signed-rank tests. RESULTS: A mild reduction in the mean BMI (32.3 +/- 6.9 vs. 31.9 +/- 6.8, P = 0.02) and a significant reduction in the endotoxin (0.9 +/- 0.34 vs. 0.8 +/- 0.13, P = 0.03) and IL-10 (4.08 +/- 0.9 vs. 3.73 +/- 0.7, P = 0.006) levels in the NASH group were noted. A significant reduction was observed in serum aspartate aminotransferase (50.4 +/- 39 vs. 33 +/ 14, P = 0.01), ALT (72 +/- 48 vs. 45.2 +/- 26.3, P = 0.0001), gamma glutamyl transferase (52 +/- 33 vs. 41.2 +/- 21.1, P = 0.02), LDL (137 +/- 34 vs. 127 +/- 27.5, P = 0.03), and ferritin (142 +/- 214 vs. 89.3 +/- 123, P = 0.0001) in the NASH group, but only in ALT (50.4 +/- 26 vs. 35.5 +/- 23.25, P = 0.01), and ferritin (73.6 +/- 83 vs. 55 +/- 76, P = 0.004) levels decreased significantly in the steatosis group. Treatment with rifaximin did not exert a significant effect on serum levels of TLR-4, IL-1, IL-6, IL-12, or TNF-alpha in either group. CONCLUSION: In NAFLD and especially in NASH, short-term administration of rifaximin appears to be safe and effective. PMID- 26043291 TI - State-offered ethnically targeted reproductive genetic testing. PMID- 26043292 TI - Bleeding complications in pregnancies with low-lying placenta. AB - OBJECTIVE: To evaluate pregnancy outcomes with low-lying placenta according to the distance from placenta to cervical os. METHODS: Retrospective cohort study of singleton pregnancies with low-lying placenta (placenta edge within 20 mm of internal os on transvaginal sonography) delivered at our hospital from 2002 to 2012, excluding suspected placenta accreta and vasa previa. Vaginal delivery was offered in the absence of another indication for cesarean. Outcomes were stratified according to placenta-os distance <=10 mm and 11-20 mm. RESULTS: Of 98 pregnancies with low-lying placenta, 41% had placenta-os distance <=10 mm and 59% placenta-os distance 11-20 mm. Fifty-four percent had a trial of labor. Six (15%) with placenta-os <=10 mm and 21 (36%) with placenta-os 11-20 mm delivered vaginally, p = 0.02. Bleeding necessitating cesarean occurred in 25%, and postpartum hemorrhage in 43%; neither complication associated with placenta-os distance. Third-trimester bleeding prior to delivery hospitalization was reported in 44% and associated with later bleeding requiring cesarean in 51% versus 4% of those without third-trimester bleeding, p < 0.001. CONCLUSION: Whereas low-lying placenta does not contraindicate labor, we found significant risk for bleeding complications, regardless of the planned mode of delivery. Placenta-os distance did not significantly affect outcomes in our series. PMID- 26043293 TI - The association between previous single first trimester abortion and pregnancy outcome in nulliparous women. AB - OBJECTIVE: To determine the association between single previous abortion and pregnancy outcome in nulliparous women. METHODS: A retrospective cohort study of all nulliparous women who delivered in a university-affiliated tertiary hospital (2009-2014). Pregnancy outcome of women with single previous first trimester abortion (study group) was compared to those of primigravida (control group). RESULTS: Of the 44 371 deliveries during the study period, 14 498 (32.6%) were of nulliparous women, of them 1501 (10.3%) had single previous abortion (<13 weeks). Except for a higher rate of diabetes mellitus in the study group (6.1 versus 4.4%, p = 0.003), no differences were found between the groups regarding pregnancy complications. In multivariate analysis, previous single abortion was independently associated with induction of labor (OR = 1.31, 95%C.I 1.04-1.63, p = 0.01), cesarean section (OR = 1.38, 95%C.I 1.18-1.60, p < 0.001) and retained placenta (OR = 1.29, 95%C.I 1.03-1.61, p = 0.02). Among nulliparous women with previous single abortion no difference in pregnancy outcome was observed between those with previous induced termination of pregnancy and spontaneous abortion, except for increased risk for retained placenta in those with previous spontaneous abortion. CONCLUSION: Single early previous abortion in nulliparous women was associated with higher rate of induction of labor, cesarean section and retained placenta compared to primigravida women. PMID- 26043294 TI - Do tall women beget larger babies? AB - OBJECTIVE: To evaluate the possible relationship between maternal height and fetal size. PATIENTS AND METHODS: We used a population-based cohort of apparently healthy mothers of singletons to evaluate quartiles of the maternal height distribution for parity, being overweight or obese, and for gestational age and birth weight parameters. We also generated birth weight by gestational age curves for each quartile. RESULTS: We analyzed data of 198,745 mothers. Mother from the four quartiles had similar parity, pre-gravid BMI, and gestational age at birth. Short mothers had a significantly higher rate of VLBW and LBW and 2501-4000 g infants, for an OR = 1.38 (95% CI: 1.17-1.62), OR = 2.2 (95% CI: 2.05-2.37) and OR = 1.82 (95% CI: 1.73-1.87) between the shortest and tallest mothers, respectively. By contrast, the opposite trend was noticed for birth weights >4000 g, for an OR = 2.77 (95% CI: 2.65-2.89) between the tallest and shortest mothers. A very similar "growth curve" was apparent until 33 weeks, when a slower growth velocity was observed for shorter compared with taller women. CONCLUSIONS: Maternal stature does not appear to be associated with gestational age but significantly influences birth weight. Height-related differences between mothers appears to begin after 33 weeks' gestation. PMID- 26043295 TI - The evaluation of Nesfatin-1 levels in patients with and without intrauterine growth restriction. AB - OBJECTIVE: To evaluate Nesfatin-1 levels in patients with and without intrauterine growth restriction and to analyze the correlation between Nesfatin-1 levels and fetal birth weights. METHODS: This study comprised a total of 81 cases; 41 patients with IUGR and 40 healthy cases. Demographic data, pregnancy weeks, fetal birth weights and Nesfatin-1 levels were all recorded. The Nesfatin 1 levels were compared between the groups and the correlation between fetal birth weights and Nesfatin-1 levels was analyzed. RESULTS: No statistical significant difference was determined between the groups in terms of demographic data (p > 0.05). Average birth weights were determined as 3420 +/- 259 g in the control group and 2041 +/- 350 g in the IUGR group, which was found to be statistically unequal (p = 0.001). The average Nesfatin levels in the control group were 0.069 +/- 0.011 and 0.094 +/- 0.042 in the IUGR group. This difference was statistically unequal (p = 0.001). While no correlation was determined between Nesfatin levels and fetal birthweights in the control group (r = -0.034 versus p = 0.836), in the IUGR group and when all the cases were evaluated together, a statistically moderately significant negative correlation was determined (r = 0.469, p = 0.002 and r = -0.251, p = 0.024, respectively). CONCLUSIONS: Although intrauterine growth is a multifactorial process, the effect mechanism has not yet been established. The results of this study offer some indications about the possible effect of Nesfatin 1 on fetal growth. PMID- 26043296 TI - Influence of medical nutrition therapy on borderline glucose intolerance in pregnant Taiwanese women. AB - OBJECTIVE: To investigate the influence of medical nutrition therapy (MNT) on borderline glucose intolerance (BGI) in pregnant Taiwanese women. METHODS: A total of 5194 singleton pregnant women were enrolled in this prospective, non randomized study. The participants were subjected to the 50 g 1-h glucose challenge test (GCT) and 100 g 3-h oral glucose tolerance test (OGTT) to screening gestational diabetes mellitus (GDM). BGI was defined as a positive GCT and normal OGTT results. GDM was defined as a positive GCT and abnormal OGTT results. The women were categorized into the following groups: (1) GCT-negative, n = 3881; (2) BGI with MNT, n = 273; (3) BGI without MNT, n = 712; and (4) GDM, n = 328. Multiple logistic analyses were used to estimate the risks of pregnancy outcomes. RESULTS: The odds ratios (95% confidence interval) for total cesareans, third- or fourth-degree perineal lacerations, gestational hypertension or preeclampsia and macrosomia were 1.24 (1.04-1.49), 1.55 (1.06-1.28), 1.78 (1.21 2.61) and 2.50 (1.28-4.91) in the BGI without MNT group compared to the GCT negative group. There was no difference between BGI with MNT and GCT-negative groups. CONCLUSIONS: Women with BGI who did not receive MNT had increased risks of adverse pregnancy outcomes, whereas who received MNT had no different risk with GCT-negative women. PMID- 26043297 TI - Prenatal risk stratification of severe small-for-gestational-age infants: a Japanese multicenter study. AB - OBJECTIVE: To establish a prenatal prognostic classification of severe small-for gestational-age (SGA) infants based on gestational age and fetal findings. METHODS: A retrospective cohort study of 366 singleton infants (birth weight <3rd percentile) delivered between 22 and 34 weeks' gestation at nine tertiary perinatal centers. A decision tree model was developed for the prediction of death or severe morbidity. RESULTS: There were 35 infants with poor outcome. Prematurity was the most powerful factor in those born before 27.9 weeks' gestation, while oligohydramnios was the most powerful factor in those born at 27.9 weeks or after. The rate of poor outcome in infants born before 25.1 weeks, between 25.1 and 27.9 weeks, at 27.9 weeks or after with oligohydramnios, at 27.9 weeks or after without oligohydramnios, was 53.9%, 18.2%, 13.6% and 3.2%, respectively. CONCLUSIONS: Risk stratification based on gestation of 25 weeks, 28 weeks and oligohydramnios may aid in prognosis of severe SGA infants. PMID- 26043298 TI - Placenta praevia: incidence, risk factors and outcome. AB - OBJECTIVE: Aim of this study was to evaluate the incidence, potential risk factors and the respective outcomes of pregnancies with placenta praevia. METHODS: Data were prospectively collected from women diagnosed with placenta praevia in 10 Austrian hospitals in in the province of Styria between 1993 and 2012. We analyzed the incidence, potential risk factors and the respective outcomes of pregnancies with placenta praevia. Differences between women with major placenta praevia (complete or partial placenta praevia) and minor placenta praevia (marginal placenta praevia or low-lying placenta) were evaluated. RESULTS: 328 patients with placenta praevia were identified. The province wide incidence of placenta praevia was 0.15%. Maternal morbidity was high (ante-partum bleeding [42.3%], post-partum hemorrhage [7.1%], maternal anemia [30%], comorbid adherent placentation [4%], and hysterectomy [5.2%]) and neonatal complications were frequent (preterm birth [54.9%], low birth weight <2500 g [35.6%], Apgar score after five minutes <7 [5.8%], and fetal mortality [1.5%]. Women with major placenta praevia had a significant higher incidence of preterm delivery, birthweight <2500 g and Apgar-score after five minutes <7. CONCLUSIONS: Placenta praevia was associated with adverse maternal (34.15%) and neonatal (60.06%) outcome. The extent of placenta praevia was not related with differences regarding risk factors and maternal outcome. PMID- 26043299 TI - PKC and AMPK regulation of Kv1.5 potassium channels. AB - The voltage-gated Kv1.5 potassium channel, conducting the ultra-rapid rectifier K(+) current (IKur), is regulated through several pathways. Here we investigate if Kv1.5 surface expression is controlled by the 2 kinases PKC and AMPK, using Xenopus oocytes, MDCK cells and atrial derived HL-1 cells. By confocal microscopy combined with electrophysiology we demonstrate that PKC activation reduces Kv1.5 current, through a decrease in membrane expressed channels. AMPK activation was found to decrease the membrane expression in MDCK cells, but not in HL-1 cells and was furthermore shown to be dependent on co-expression of Nedd4-2 in Xenopus oocytes. These results indicate that Kv1.5 channels are regulated by both kinases, although through different molecular mechanisms in different cell systems. PMID- 26043300 TI - Can the observed association between serum perfluoroalkyl substances and delayed menarche be explained on the basis of puberty-related changes in physiology and pharmacokinetics? AB - BACKGROUND: An association between serum levels of two perfluoroalkyl substances (PFAS) and delayed age at menarche was reported in a cross-sectional study of adolescents. Because perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have half-lives of years, growth dilution and the development of a new route of excretion (menstruation) could account for some or all of the reported association. OBJECTIVES: To assess how much of the epidemiologic association between PFAS and delayed menarche can be explained by the correlation of growth and maturation with PFAS body burden. METHODS: We developed a Monte Carlo (MC) physiologically-based pharmacokinetic (PBPK) model of PFAS to simulate plasma PFAS levels in a hypothetical female population aged 2 to 20years old. Realistic distributions of physiological parameters as well as timing of growth spurts and menarche were incorporated in the model. The association between PFAS level and delayed menarche in the simulated data was compared with the reported association. RESULTS: The prevalence of menarche, distributions of age-dependent physiological parameters, and quartiles of serum PFAS concentrations in the simulated subjects were comparable to those reported in the epidemiologic study. The delay of menarche in days per natural log increase in PFAS concentrations in the simulated data were about one third as large as the observed values. CONCLUSION: The reported relationship between PFAS and age at menarche appears to be at least partly explained by pharmacokinetics rather than a toxic effect of these substances. PMID- 26043301 TI - The Cleveland-Cuyahoga County Food Policy Coalition: "we have evolved". AB - Several pieces of legislation passed in Cleveland, Ohio, from 2007 to 2011, focused on improving the city's food environment through urban agriculture initiatives. We used qualitative, case study methods, including interviews with 7 key informants, to examine the policy development process and investigate the role of the Cleveland-Cuyahoga County Food Policy Coalition in developing and implementing 4 pieces of legislation. In this article, we focus on 2 pieces of legislation: zoning designation of an urban garden and allowance of small farm animals and bees on residential property. Five key themes emerged: impetus for policy came from community needs; education and raising awareness helped mitigate barriers; a cultural shift took place among policy makers; social connections and individual champions were needed; and concerns over food access and health influenced policy decisions. Legislative actions are important tools to influence the nutrition environment, as long as they are based on local needs and context. PMID- 26043302 TI - Spending at mobile fruit and vegetable carts and using SNAP benefits to pay, Bronx, New York, 2013 and 2014. AB - This study examines purchases at fruit and vegetable carts and evaluates the potential benefits of expanding the availability of electronic benefit transfer machines at Green Carts. Customers at 4 Green Carts in the Bronx, New York, were surveyed in 3 waves from June 2013 through July 2014. Customers who used Supplemental Nutrition Assistance Program benefits spent on average $3.86 more than customers who paid with cash. This finding suggests that there may be benefits to increasing the availability of electronic benefit transfer machines at Green Carts. PMID- 26043303 TI - An assessment of nutrition practices and attitudes in family child-care homes: implications for policy implementation. AB - INTRODUCTION: Family child-care homes (FCCHs) provide care and nutrition for millions of US children, including 28% in Rhode Island. New proposed regulations for FCCHs in Rhode Island require competencies and knowledge in nutrition. We explored nutrition-related practices and attitudes of FCCH providers in Rhode Island and assessed whether these differed by provider ethnicity or socioeconomic status of the enrolled children. METHODS: Of 536 licensed FCCHs in Rhode Island, 105 randomly selected FCCH providers completed a survey about provider nutrition attitudes and practices, demographics of providers, and characteristics of the FCCH, including participation in the federal Child and Adult Care Food Program (CACFP). No differences between CACFP and non-CACFP participants were found; responses were compared by provider ethnicity using chi(2) tests and multivariate models. RESULTS: Nearly 70% of FCCHs reported receiving nutrition training only 0 to 3 times during the past 3 years; however, more than 60% found these trainings to be very helpful. More Hispanic than non-Hispanic providers strongly agreed to sitting with children during meals, encouraging children to finish their plate, and being involved with parents on the topics of healthy eating and weight. These differences persisted in multivariate models. DISCUSSION: Although some positive practices are in place in Rhode Island FCCHs, there is room for improvement. State licensing requirements provide a foundation for achieving better nutrition environments in FCCHs, but successful implementation is key to translating policies into real changes. FCCH providers need culturally and linguistically appropriate nutrition-related training. PMID- 26043305 TI - Acquired Combined Hamartoma of the Retina and Retinal Pigment Epithelium. PMID- 26043304 TI - Drinking water in California child care sites before and after 2011-2012 beverage policy. AB - INTRODUCTION: Drinking water is promoted to improve beverage nutrition and reduce the prevalence of obesity. The aims of this study were to identify how water was provided to young children in child care and to determine the extent to which water access changed after a federal and state child care beverage policy was instituted in 2011 and 2012 in California. METHODS: Two independent cross sectional samples of licensed child care providers completed a self-administered survey in 2008 (n = 429) and 2012 (n = 435). Logistic regression was used to analyze data for differences between 2008 and 2012 survey responses, after adjustment for correlations among the measurements in each of 6 child care categories sampled. RESULTS: A significantly larger percentage of sites in 2012 than in 2008 always served water at the table with meals or snacks (47.0% vs 28.0%, P = .001). A significantly larger percentage of child care sites in 2012 than in 2008 made water easily and visibly available for children to self-serve both indoors (77.9% vs 69.0%, P = .02) and outside (78.0% vs 69.0%, P = .03). Sites that participated in the federal Child and Adult Care Food Program had greater access to water indoors and outside than sites not in the program. In 2012 most (76.1%) child care providers reported no barriers to serving water to children. Factors most frequently cited to facilitate serving water were information for families (39.0% of sites), beverage policy (37.0%), and lessons for children (37.9%). CONCLUSION: Water provision in California child care improved significantly between samples of sites studied in 2008 and 2012, but room for improvement remains after policy implementation. Additional training for child care providers and parents should be considered. PMID- 26043306 TI - Towards a blocking-free electrochemical immunosensing strategy for anti transglutaminase antibodies using screen-printed electrodes. PMID- 26043307 TI - Development of loop-mediated isothermal amplification to detect Streptococcus suis and its application to retail pork meat in Japan. AB - We here developed a novel loop-mediated isothermal amplification (LAMP) method to detect Streptococcus suis in raw pork meat. This method, designated LAMPSS, targeted the recombination/repair protein (recN) gene of S. suis and detected all serotypes of S. suis, except those taxonomically removed from authentic S. suis, i.e., serotypes 20, 22, 26, 32, 33, and 34. The specificity of LAMPSS was confirmed and its detection limit was 5.4cfu/reaction. Among the 966 raw pork meat samples examined, including sliced pork, minced pork, and the liver, tongue, heart, and small intestine, 255 samples tested positive with LAMPSS. The rate of contamination was higher in the organs than in pork. No significant difference was observed in the total bacterial count between LAMPSS-positive and -negative samples. The number of shops that provided LAMPSS-positive pork was slightly higher in those that sold swine organs and pork than in those that sold only pork, suggesting that cross contamination occurred from the organs to pork. Among the 255 which tested positive for LAMPSS, only 47 samples tested positive for the previously described LAMP specific for S. suis serotype 2. Two isolates of S. suis serotype 2, belonging to sequence type 28, which is potentially hazardous to humans, as well as those of some other serotypes were obtained from 19 out of 47 samples by combining LAMP with a replica plating method. These results suggest that LAMPSS will be a useful tool for the surveillance of raw pork meat in the retail market. PMID- 26043309 TI - Beyond clinical trials in advanced soft tissue sarcoma: what to expect from trabectedin treatment? Foreword. PMID- 26043308 TI - Microglia Determine Brain Region-Specific Neurotoxic Responses to Chemically Functionalized Carbon Nanotubes. AB - Surface tunability and their ability to translocate plasma membranes make chemically functionalized carbon nanotubes (f-CNTs) promising intracellular delivery systems for therapeutic or diagnostic purposes in the central nervous system (CNS). The present study aimed to determine the biological impact of different types of multiwalled CNTs (MWNTs) on primary neuronal and glial cell populations isolated from fetal rat frontal cortex (FCO) and striatum (ST). Neurons from both brain regions were generally not affected by exposure to MWNTs as determined by a modified LDH assay. In contrast, the viability of mixed glia was reduced in ST-derived mixed glial cultures, but not in FCO-derived ones. Cytotoxicity was independent of MWNT type or dose, suggesting an inherent sensitivity to CNTs. Characterization of the cell populations in mixed glial cultures prior to nanotube exposure showed higher number of CD11b/c positive cells in the ST-derived mixed glial cultures. After exposure to MWNTs, CNT were uptaken more effectively by CD11b/c positive cells (microglia), compared to GFAP positive cells (astrocytes). When exposed to conditioned media from microglia enriched cultures exposed to MWNTs, ST-derived glial cultures secreted more NO than FCO-derived cells. These results suggested that the more significant cytotoxic response obtained from ST-derived mixed glia cultures was related to the higher number of microglial cells in this brain region. Our findings emphasize the role that resident macrophages of the CNS play in response to nanomaterials and the need to thoroughly investigate the brain region-specific effects toward designing implantable devices or delivery systems to the CNS. PMID- 26043310 TI - Optimizing the use of trabectedin for advanced soft tissue sarcoma in daily clinical practice. AB - Compared with conventional chemotherapy for advanced soft tissue sarcoma, trabectedin has several distinguishing characteristics which, when optimized, may maximize clinical benefits for patients. In this review, evidence is examined with the aim of answering some vital questions about the use of trabectedin in clinical practice. Who should be treated? When should patients be treated? For how long should patients be treated? What is the safety profile of trabectedin? How should trabectedin be administered? In brief, trabectedin has shown activity and clinical benefit in nearly all subtypes of soft tissue sarcoma. Improved efficacy outcomes are observed when trabectedin is administered as second-line therapy compared with later-line use. In line with this observation, the European Society for Medical Oncology clinical practice guidelines for soft tissue sarcoma recommend use of trabectedin in the second-line setting. Trabectedin has a role for treatment of elderly patients in whom alternatives are lacking, and can be administered for prolonged periods without cumulative toxicity. A statistically significant improvement in median progression-free survival has been observed when trabectedin is administered uninterrupted until disease progression. The flexibility of trabectedin administration in terms of dose, interval and duration allows for patient-tailored treatment optimization. PMID- 26043311 TI - Trabectedin clinical cases: use according to indication in diverse clinical scenarios. AB - BACKGROUND: Key distinguishing characteristics of trabectedin in the treatment of advanced soft tissue sarcoma are its prolonged tumor control activity in multiple histological subtypes, positive outcomes in translocation-related sarcomas, maintenance of response, option to rechallenge after treatment interruption and lack of cumulative toxicity. Trabectedin is indicated for use in advanced soft tissue sarcoma after failure of anthracyclines and ifosfamide, or as front-line treatment in patients unsuited to receive these agents. METHODS: In this review, cases studies are presented in which trabectedin was used according to its indication but in diverse clinical settings. RESULTS: As second-line treatment of uterine leiomyosarcoma, trabectedin produced prolonged tumor control with good quality of life. In treatment of recurrent synovial sarcoma, the best objective response (partial response) and longest disease control (37 months) was achieved under treatment with trabectedin. As neoadjuvant treatment of undifferentiated pleomorphic sarcoma in a patient unsuited to receive doxorubicin-based chemotherapy, trabectedin induced a pathological response with 85% of necrosis. CONCLUSION: These cases illustrate the broad range of indications for trabectedin in advanced soft tissue sarcoma and highlight how its unique characteristics can be optimized to achieve maximum clinical benefit. PMID- 26043312 TI - Counterpoint: should childhood vaccination against measles be a mandatory requirement for attending school? No. PMID- 26043313 TI - High sensitivity automated multiplexed immunoassays using photonic crystal enhanced fluorescence microfluidic system. AB - We demonstrate a platform that integrates photonic crystal enhanced fluorescence (PCEF) detection of a surface-based microspot fluorescent assay with a microfluidic cartridge to achieve simultaneous goals of high analytic sensitivity (single digit pg/mL), high selectivity, low sample volume, and assay automation. The PC surface, designed to provide optical resonances for the excitation wavelength and emission wavelength of Cyanines 5 (Cy5), was used to amplify the fluorescence signal intensity measured from a multiplexed biomarker microarray. The assay system is comprised of a plastic microfluidic cartridge for holding the PC and an assay automation system that provides a leak-free fluid interface during introduction of a sequence of fluids under computer control. Through the use of the assay automation system and the PC embedded within the microfluidic cartridge, we demonstrate pg/mL-level limits of detection by performing representative biomarker assays for interleukin 3 (IL3) and Tumor Necrosis Factor (TNF-alpha). The results are consistent with limits of detection achieved without the use of the microfluidic device with the exception that coefficients of variability from spot-to-spot are substantially lower than those obtained by performing assays with manual manipulation of assay liquids. The system's capabilities are compatible with the goal of diagnostic instruments for point-of care settings. PMID- 26043315 TI - Nanoparticle-based lateral flow biosensors. AB - Lateral flow biosensors (LFBs) are paper-based devices which permit the performance of low-cost and fast diagnostics with good robustness, specificity, sensitivity and low limits of detection. The use of nanoparticles (NPs) as labels play an important role in the design and fabrication of a lateral flow strip (LFS). The choice of NPs and the corresponding detection method directly affect the performance of these devices. This review discusses aspects related to the application of different nanomaterials (e.g. gold nanoparticles, carbon nanotubes, quantum dots, up-converting phosphor technologies, and latex beads, between others) in LFBs. Moreover, different detection methods (colorimetric, fluorescent, electrochemical, magnetic, etc.) and signal enhancement strategies (affording secondary reactions or modifying the architecture of the LFS) as well as the use of devices such as smartphones to mediate the response of LFSs will be analyzed. PMID- 26043314 TI - Amplified electrochemical hydrogen peroxide reduction based on hemin/G-quadruplex DNAzyme as electrocatalyst at gold particles modified heated copper disk electrode. AB - A new gold particles modified heated copper disk electrode (Au-HCuDE) with direct current was fabricated. The hemin/G-quadruplex horseradish peroxidase-mimicking DNAzyme (HRP-DNAzyme) was self-assembled on the heated electrode and resulted in a new biosensor denoted as HRP-DNAzyme/Au-HCuDE. By controlling the temperature of the surface of the electrode, the dramatic temperature effect on the electrocatalytic reduction of H2O2 at HRP-DNAzyme/Au-HCuDE sensing platform was demonstrated. This electrocatalytic activity of HRP-DNAzyme was enhanced with electrode temperature elevated. This method was thus preliminarily used to develop an electrochemical biosensor for highly sensitive detection of H2O2. A detection limit of 1.6*10(-7) M could be obtained (S/N=3) with an electrode temperature of 50 degrees C, which was more than one magnitude lower than that at electrode temperature of 0 degrees C. This heated electrochemical biosensor shows many merits such as easy fabrication and simple heating equipment, low cost, high thermal stability, and high sensitivity and good reproducibility. PMID- 26043317 TI - Psychoeducation as a Mediator of Treatment Approach on Parent Engagement in Child Psychotherapy for Disruptive Behavior. AB - Parent engagement in treatment for child disruptive behavior has been associated with improved child outcomes in care. However, many families who enter care do not receive an adequate dose of treatment, and parents are often not involved. We examined therapists' use of psychoeducation, a therapeutic practice used to present factual information about target problems and treatments, and its association with parent engagement in child psychotherapy. Participants were drawn from the Child System and Treatment Enhancement Projects' multisite trial contrasting standard evidence-based treatments, modular treatment, or usual care. We included an ethnically diverse sample of 46 youth (ages 7-13) who received treatment for disruptive behavior in modular treatment or usual care. A reliable observational coding system was developed to assess therapists' in-session use of psychoeducation strategies (e.g., discussing causes of misbehavior, describing and providing rationale for treatment, etc.), as well as other engagement strategies (e.g., collaborative goal setting, managing expectations, etc.), in the early phase of treatment. Findings revealed that modular treatment therapists provided more psychoeducation and other engagement strategies compared with usual care therapists. Furthermore, psychoeducation strategies employed by therapists early on uniquely predicted subsequent parent involvement in treatment, over and above the use of other engagement strategies. Finally, therapists' use of the psychoeducation strategy of discussing causes of child's misbehavior mediated the effect of treatment condition on parent involvement in their child's therapy. These findings suggest that the implementation of psychoeducation strategies upon entry into care promotes parent involvement in child psychotherapy for disruptive behavior. PMID- 26043316 TI - Modified primers for rapid and direct electrochemical analysis of coeliac disease associated HLA alleles. AB - Direct detection of PCR product via hybridisation assay, would facilitate the development of rapid tools for genetic analysis. Here, a PCR primer designed to generate a PCR amplicon tagged with single stranded DNA tails at each end of the duplex, which can be used for direct hybridisation with a surface immobilised probe and an enzyme labelled reporter probe is presented. Four modified sequence specific primers (SSP) pairs were designed for the selective amplification of coeliac disease associated alleles (DQA1*05, DQB1*02, DQB1*03:02 alleles), and human growth hormone (positive control). Multiplex PCR products were electrochemically detected in less than 5 min at 37 degrees C via direct hybridisation to short probes immobilised on individual electrodes of a genosensor array, and subsequent hybridisation to an enzyme labelled reporter probe. The developed electrochemical genosensor array exploiting the modified primers for the direct detection of PCR products was applied to the genotyping of real patient samples. PMID- 26043319 TI - Prospects and problems for a phenomenological approach to delusions. PMID- 26043318 TI - Thalidomide embryopathy: Follow-up of cases born between 1959 and 2010. AB - BACKGROUND: Thalidomide is a known teratogen and it is estimated that more than ten thousand babies were affected by thalidomide embryopathy (TE), which is characterized mainly by limb defects, but can involve many organs and systems. Most people with TE were only evaluated at birth and it is not well established if thalidomide exposure during embryonic development leads to later effects. We analyzed the clinical history of adults with TE to better understand this gap in the clinical findings of TE. METHODS: Brazilian individuals with TE were invited to answer a clinical questionnaire which considered family history, social information, medical history, and current clinical and psychological health status. A clinical examination was also performed, including on the infant subjects to evaluate congenital anomalies. The characterization of the features was analyzed using descriptive statistics and Chi-square or Fisher's exact test. RESULTS: The congenital anomalies caused by thalidomide were reviewed in 28 Brazilian individuals, and the questionnaire was applied to the 23 adult subjects with TE (aged 19 to 55). Progressive deafness and dental loss were reported. From the comparison of TE individuals with the general Brazilian population, the early onset of cardiovascular diseases (p = 0.009) and a higher frequency of psychological disorders (p = 0.011) were observed. CONCLUSION: Although there is no sufficient evidence that thalidomide exposure caused or worsened the described events, this approach helps to better understand the TE phenotype, improves the clinical diagnosis, and can lead to adequate health support for these individuals. PMID- 26043320 TI - Neural dynamics in mental disorders. PMID- 26043323 TI - The NIMH experimental medicine initiative. PMID- 26043324 TI - The human connectome in health and psychopathology. PMID- 26043322 TI - The effectiveness of psychodynamic psychotherapies: An update. AB - This paper provides a comprehensive review of outcome studies and meta-analyses of effectiveness studies of psychodynamic therapy (PDT) for the major categories of mental disorders. Comparisons with inactive controls (waitlist, treatment as usual and placebo) generally but by no means invariably show PDT to be effective for depression, some anxiety disorders, eating disorders and somatic disorders. There is little evidence to support its implementation for post-traumatic stress disorder, obsessive-compulsive disorder, bulimia nervosa, cocaine dependence or psychosis. The strongest current evidence base supports relatively long-term psychodynamic treatment of some personality disorders, particularly borderline personality disorder. Comparisons with active treatments rarely identify PDT as superior to control interventions and studies are generally not appropriately designed to provide tests of statistical equivalence. Studies that demonstrate inferiority of PDT to alternatives exist, but are small in number and often questionable in design. Reviews of the field appear to be subject to allegiance effects. The present review recommends abandoning the inherently conservative strategy of comparing heterogeneous "families" of therapies for heterogeneous diagnostic groups. Instead, it advocates using the opportunities provided by bioscience and computational psychiatry to creatively explore and assess the value of protocol-directed combinations of specific treatment components to address the key problems of individual patients. PMID- 26043325 TI - What has serotonin to do with depression? PMID- 26043321 TI - Effects of antipsychotics, antidepressants and mood stabilizers on risk for physical diseases in people with schizophrenia, depression and bipolar disorder. AB - People with severe mental illness have a considerably shorter lifespan than the general population. This excess mortality is mainly due to physical illness. Next to mental illness-related factors, unhealthy lifestyle, and disparities in health care access and utilization, psychotropic medications can contribute to the risk of physical morbidity and mortality. We systematically reviewed the effects of antipsychotics, antidepressants and mood stabilizers on physical health outcomes in people with schizophrenia, depression and bipolar disorder. Updating and expanding our prior systematic review published in this journal, we searched MEDLINE (November 2009 - November 2014), combining the MeSH terms of major physical disease categories (and/or relevant diseases within these categories) with schizophrenia, major depressive disorder and bipolar disorder, and the three major psychotropic classes which received regulatory approval for these disorders, i.e., antipsychotics, antidepressants and mood stabilizers. We gave precedence to results from (systematic) reviews and meta-analyses wherever possible. Antipsychotics, and to a more restricted degree antidepressants and mood stabilizers, are associated with an increased risk for several physical diseases, including obesity, dyslipidemia, diabetes mellitus, thyroid disorders, hyponatremia; cardiovascular, respiratory tract, gastrointestinal, haematological, musculoskeletal and renal diseases, as well as movement and seizure disorders. Higher dosages, polypharmacy, and treatment of vulnerable (e.g., old or young) individuals are associated with greater absolute (elderly) and relative (youth) risk for most of these physical diseases. To what degree medication-specific and patient-specific risk factors interact, and how adverse outcomes can be minimized, allowing patients to derive maximum benefits from these medications, requires adequate clinical attention and further research. PMID- 26043326 TI - The interaction between stress and genetic factors in the etiopathogenesis of depression. PMID- 26043328 TI - Delusions, epistemology and phenophobia. PMID- 26043327 TI - Phenomenological and neurocognitive perspectives on delusions: A critical overview. AB - There is considerable overlap between phenomenological and neurocognitive perspectives on delusions. In this paper, we first review major phenomenological accounts of delusions, beginning with Jaspers' ideas regarding incomprehensibility, delusional mood, and disturbed "cogito" (basic, minimal, or core self-experience) in what he termed "delusion proper" in schizophrenia. Then we discuss later studies of decontextualization and delusional mood by Matussek, changes in self and world in delusion formation according to Conrad's notions of "apophany" and "anastrophe", and the implications of ontological transformations in the felt sense of reality in some delusions. Next we consider consistencies between: a) phenomenological models stressing minimal-self (ipseity) disturbance and hyperreflexivity in schizophrenia, and b) recent neurocognitive models of delusions emphasizing salience dysregulation and prediction error. We voice reservations about homogenizing tendencies in neurocognitive explanations of delusions (the "paranoia paradigm"), given experiential variations in states of delusion. In particular we consider shortcomings of assuming that delusions necessarily or always involve "mistaken beliefs" concerning objective facts about the world. Finally, we offer some suggestions regarding possible neurocognitive factors. Current models that stress hypersalience (banal stimuli experienced as strange) might benefit from considering the potential role of hyposalience in delusion formation. Hyposalience - associated with experiencing the strange as if it were banal, and perhaps with activation of the default mode network - may underlie a kind of delusional derealization and an "anything goes" attitude. Such an attitude would be conducive to delusion formation, yet differs significantly from the hypersalience emphasized in current neurocognitive theories. PMID- 26043329 TI - Phenomenological models of delusions: concerns regarding the neglect of the role of emotional pain and intersubjectivity. PMID- 26043330 TI - The interpersonal world of psychosis. PMID- 26043331 TI - The intersubjectivity of delusions. PMID- 26043332 TI - Therapeutic advances for people with delusions will come from greater specification and empirical investigation. PMID- 26043333 TI - Answering some phenomenal challenges to the prediction error model of delusions. PMID- 26043334 TI - Are the neurocognitive correlates of subtle subjective symptoms the way forward in psychiatry? PMID- 26043335 TI - Phenomenology is Bayesian in its application to delusions. PMID- 26043336 TI - Phenomenological and neurocognitive perspectives on polythematic and monothematic delusions. PMID- 26043337 TI - Age matters in the prevalence and clinical significance of ultra-high-risk for psychosis symptoms and criteria in the general population: Findings from the BEAR and BEARS-kid studies. AB - Early detection of psychosis is an important topic in psychiatry. Yet, there is limited information on the prevalence and clinical significance of high-risk symptoms in children and adolescents as compared to adults. We examined ultra high-risk (UHR) symptoms and criteria in a sample of individuals aged 8-40 years from the general population of Canton Bern, Switzerland, enrolled from June 2011 to May 2014. The current presence of attenuated psychotic symptoms (APS) and brief intermittent psychotic symptoms (BLIPS) and the fulfillment of onset/worsening and frequency requirements for these symptoms in UHR criteria were assessed using the Structured Interview for Psychosis Risk Syndromes. Additionally, perceptive and non-perceptive APS were differentiated. Psychosocial functioning and current non-psychotic DSM-IV axis I disorders were also surveyed. Well-trained psychologists performed assessments. Altogether, 9.9% of subjects reported APS and none BLIPS, and 1.3% met all the UHR requirements for APS. APS were related to more current axis I disorders and impaired psychosocial functioning, indicating some clinical significance. A strong age effect was detected around age 16: compared to older individuals, 8-15-year olds reported more perceptive APS, that is, unusual perceptual experiences and attenuated hallucinations. Perceptive APS were generally less related to functional impairment, regardless of age. Conversely, non-perceptive APS were related to low functioning, although this relationship was weaker in those below age 16. Future studies should address the differential effects of perceptive and non-perceptive APS, and their interaction with age, also in terms of conversion to psychosis. PMID- 26043338 TI - 5-HTTLPR genotype potentiates the effects of war zone stressors on the emergence of PTSD, depressive and anxiety symptoms in soldiers deployed to iraq. AB - Exposure to war zone stressors is common, yet only a minority of soldiers experience clinically meaningful disturbance in psychological function. Identification of biomarkers that predict vulnerability to war zone stressors is critical for developing more effective treatment and prevention strategies not only in soldiers but also in civilians who are exposed to trauma. We investigated the role of the serotonin transporter linked polymorphic region (5-HTTLPR) genotype in predicting the emergence of post-traumatic stress disorder (PTSD), depressive and anxiety symptoms as a function of war zone stressors. A prospective cohort of 133 U.S. Army soldiers with no prior history of deployment to a war zone, who were scheduled to deploy to Iraq, was recruited. Multilevel regression models were used to investigate associations between 5-HTTLPR genotype, level of war zone stressors, and reported symptoms of PTSD, depression and anxiety while deployed to Iraq. Level of war zone stressors was associated with symptoms of PTSD, depression and anxiety. Consistent with its effects on stress responsiveness, 5-HTTLPR genotype moderated the relationship between level of war zone stressors and symptoms of emotional disturbance. Specifically, soldiers carrying one or two low functioning alleles (S or LG ) reported heightened symptoms of PTSD, depression and anxiety in response to increased levels of exposure to war zone stressors, relative to soldiers homozygous for the high functioning allele (LA ). These data suggest that 5-HTTLPR genotype moderates individual sensitivity to war zone stressors and the expression of emotional disturbance including PTSD symptoms. Replication of this association along with identification of other genetic moderators of risk can inform the development of biomarkers that can predict relative resilience vs. vulnerability to stress. PMID- 26043339 TI - Comparative efficacy and acceptability of psychotherapies for depression in children and adolescents: A systematic review and network meta-analysis. AB - Previous meta-analyses of psychotherapies for child and adolescent depression were limited because of the small number of trials with direct comparisons between two treatments. A network meta-analysis, a novel approach that integrates direct and indirect evidence from randomized controlled studies, was undertaken to investigate the comparative efficacy and acceptability of psychotherapies for depression in children and adolescents. Systematic searches resulted in 52 studies (total N=3805) of nine psychotherapies and four control conditions. We assessed the efficacy at post-treatment and at follow-up, as well as the acceptability (all-cause discontinuation) of psychotherapies and control conditions. At post-treatment, only interpersonal therapy (IPT) and cognitive behavioral therapy (CBT) were significantly more effective than most control conditions (standardized mean differences, SMDs ranged from -0.47 to -0.96). Also, IPT and CBT were more beneficial than play therapy. Only psychodynamic therapy and play therapy were not significantly superior to waitlist. At follow up, IPT and CBT were significantly more effective than most control conditions (SMDs ranged from -0.26 to -1.05), although only IPT retained this superiority at both short-term and long-term follow-up. In addition, IPT and CBT were more beneficial than problem-solving therapy. Waitlist was significantly inferior to other control conditions. With regard to acceptability, IPT and problem-solving therapy had significantly fewer all-cause discontinuations than cognitive therapy and CBT (ORs ranged from 0.06 to 0.33). These data suggest that IPT and CBT should be considered as the best available psychotherapies for depression in children and adolescents. However, several alternative psychotherapies are understudied in this age group. Waitlist may inflate the effect of psychotherapies, so that psychological placebo or treatment-as-usual may be preferable as a control condition in psychotherapy trials. PMID- 26043340 TI - Telemental health: A status update. AB - A rather large body of literature now exists on the use of telemental health services in the diagnosis and management of various psychiatric conditions. This review aims to provide an up-to-date assessment of telemental health, focusing on four main areas: computerized CBT (cCBT), Internet-based CBT (iCBT), virtual reality exposure therapy (VRET), and mobile therapy (mTherapy). Four scientific databases were searched and, where possible, larger, better-designed meta analyses and controlled trials were highlighted. Taken together, published studies support an expanded role for telepsychiatry tools, with advantages that include increased care access, enhanced efficiency, reduced stigma associated with visiting mental health clinics, and the ability to bypass diagnosis-specific obstacles to treatment, such as when social anxiety prevents a patient from leaving the house. Of technology-mediated therapies, cCBT and iCBT possess the most efficacy evidence, with VRET and mTherapy representing promising but less researched options that have grown in parallel with virtual reality and mobile technology advances. Nonetheless, telepsychiatry remains challenging because of the need for specific computer skills, the difficulty in providing patients with a deep understanding or support, concerns about the "therapeutic alliance", privacy fears, and the well documented problem of patient attrition. Future studies should further test the efficacy, advantages and limitations of technology-enabled CBT, as well as explore the online delivery of other psychotherapeutic and psychopharmacological modalities. PMID- 26043341 TI - Toward a new definition of mental health. PMID- 26043342 TI - The alternative DSM-5 model for personality disorders. PMID- 26043343 TI - The psychodynamic diagnostic manual - 2nd edition (PDM-2). PMID- 26043344 TI - The critical ingredients of assertive community treatment. PMID- 26043345 TI - Need for a realistic appraisal of benzodiazepines. PMID- 26043346 TI - Psychotropic drugs and homicide: A prospective cohort study from Finland. PMID- 26043347 TI - Designer benzodiazepines: A new challenge. PMID- 26043348 TI - When local poverty is more important than your income: Mental health in minorities in inner cities. PMID- 26043349 TI - Urbanization and the prevalence of schizophrenia in China between 1990 and 2010. PMID- 26043350 TI - Obituary: juan jose lopez-ibor (1941-2015). PMID- 26043351 TI - WPA - social justice for the mentally ill. PMID- 26043352 TI - An update on the activities of WPA scientific sections. PMID- 26043353 TI - Among antithrombotic agents, prasugrel, but not ticagrelor, is associated with reduced 30 day mortality in patients with ST-elevated myocardial infarction. AB - BACKGROUND: ST-elevated myocardial infarction (STEMI) holds the highest early mortality among patients with acute coronary syndromes. Despite numerous claims of clinical benefits and superiority over clopidogrel, there are no head-to-head outcome randomized clinical trials (RCTs) directly comparing novel antithrombotic agents in STEMI. Moreover, since most regulatory approvals are based on a single RCT's results, their meta-analyses are rare to compare death rates. We analyzed the 30-day mortality in STEMI patients who underwent percutaneous coronary intervention (PCI) and were treated with antithrombotic agents compared to clopidogrel as a reference. METHODS AND RESULTS: Altogether, 10 RCT's and 1 retrospective study with a total number of 26,658 STEMI patients were included. Random-effects model with Mantel-Heanszel weighting was used to pool outcomes into a meta-analysis. Therapy with clopidogrel was associated with 2.76% 30-day STEMI mortality which was similar to that of ticagrelor (2.6%; OR=0.9395 [CI=0.76 to 1.17; p=0.58]), and for bivalirudin (2.8%; OR=1.02 [CI=0.82 to 1.27; p=0.86]), but was slightly higher for heparin (3.0%; OR=1.08 [CI=0.86 to 1.35; p=0.52]). There was a trend towards lower mortality after tirofiban (2.1%; OR=0.77 [CI=0.52 to 1.13; p=0.20]), and cangrelor (1.7%; OR=0.59 [CI=0.29 to 1.20; p=0.19]), although the sample size for both agents was woefully small. The only agent which offers a significant 30-day mortality benefit in STEMI was prasugrel with significant lowest 1.75% death rate (OR=0.63 [CI=0.46 to 0.86; p=0.03]). CONCLUSIONS: Among antithrombotic agents, prasugrel, but not ticagrelor, offers significant 30-day mortality benefit over clopidogrel in PCI-treated STEMI patients justifying short-term use in such a high-risk population. PMID- 26043354 TI - Prospective evaluation of where reperfusion ventricular arrhythmia "bursts" fit into optimal reperfusion in STEMI. AB - BACKGROUND: Early reperfusion of ischemic myocytes is essential for optimal salvage in acute myocardial infarction. VA (ventricular arrhythmia) bursts after recanalization of the culprit vessel have been found to be related to larger infarct size (IS), using SPECT. OBJECTIVE: The hypothesis was tested that this finding could be confirmed in an independent cohort using a more accurate technique, i.e. delayed-enhancement cardiovascular magnetic resonance imaging (DE CMR). METHODS: All 196 patients from the PREPARE and MAST studies who had 24 hour, continuous, 12-lead Holter, started before primary percutaneous coronary intervention resulting in brisk TIMI (thrombolysis in myocardial infarction) 3 flow and stable ST-recovery were included. VA bursts were identified against subject-specific background VA rates using a previously published statistical outlier method. IS was assessed using DE-CMR. Angiography, Holter and DE-CMR results were assessed in core laboratories, blinded to all other data. RESULTS: VA bursts were present in 154/196 (79%) of patients. Baseline characteristics between the groups with and without bursts were similar. VA burst was associated with significantly larger infarct size in the population as a whole (median 11.3% vs 5.3%; p=0.001) and also when divided in non-anterior (median 9.9% vs 4.9%; p=0.003) and anterior myocardial infarction (median 21.4% vs 12.0%; p=0.48), the latter not reaching statistical significance due to the small subset of patients. CONCLUSION: Beyond the classical markers of "optimal" reperfusion such as TIMI 3 flow and stable ST-segment recovery, VA bursts occurring during the reperfusion phase are an early electrobiomarker of larger IS. CLINICAL TRIAL REGISTRATION: PREPARE: ISRCTN71104460 http://www.controlled-trials.com/ISRCTN71104460. PMID- 26043356 TI - A comparative study on splitting criteria of a survival tree based on the Cox proportional model. AB - We treat the situations that the effect of covariates on hazard is differed in subgroups of patients. To handle this situation, we can consider the hybrid model of the Cox model and tree-structured model. Through simulation studies, we compared several splitting criteria for constructing this hybrid model. As a result, the criterion using the degree of the improvement in the negative maximum partial log-likelihood obtained by splitting showed a good performance for many situations. We also present the results obtained by applying this tree model in an actual medical research study to show its utility. PMID- 26043355 TI - Selective Tumor Targeting of Desacetyl Vinblastine Hydrazide and Tubulysin B via Conjugation to a Cholecystokinin 2 Receptor (CCK2R) Ligand. AB - As the delivery of selectively targeted cytotoxic agents via antibodies or small molecule ligands to malignancies has begun to show promise in the clinic, the need to identify and validate additional cellular targets for specific therapeutic delivery is critical. Although a multitude of cancers have been targeted using the folate receptor, PSMA, bombesin receptor, somatostatin receptor, LHRH, and alphavbeta3, there is a notable lack of specific small molecule ligand/receptor pairs to cellular targets found within cancers of the GI tract. Because of the selective GI tract expression of the cholecystokinin 2 receptor (CCK2R), we undertook the creation of conjugates that would deliver microtubule-disrupting drugs to malignancies through the specific targeting of CCK2R via a high affinity small molecule ligand. The cytotoxic activity of these conjugates were shown to be receptor mediated in vitro and in vivo with xenograft mouse models exhibiting delayed growth or regression of tumors that expressed CCK2R. Overall, this work demonstrates that ligands to CCK2R can be used to create selectively targeted therapeutic conjugates. PMID- 26043357 TI - An unusual xylan in Arabidopsis primary cell walls is synthesised by GUX3, IRX9L, IRX10L and IRX14. AB - Xylan is a crucial component of many plant primary and secondary cell walls. However, the structure and function of xylan in the dicotyledon primary cell wall is not well understood. Here, we characterized a xylan that is specific to tissues enriched in Arabidopsis primary cell walls. Unlike previously described xylans, this xylan carries a pentose linked 1-2 to the alpha-1,2-d-glucuronic acid (GlcA) side chains on the beta-1,4-Xyl backbone. The frequent and precisely regular spacing of GlcA substitutions every six xylosyl residues along the backbone is also unlike that previously observed in secondary cell wall xylan. Molecular genetics, in vitro assays, and expression data suggest that IRX9L, IRX10L and IRX14 are required for xylan backbone synthesis in primary cell wall synthesising tissues. IRX9 and IRX10 are not involved in the primary cell wall xylan synthesis but are functionally exchangeable with IRX9L and IRX10L. GUX3 is the only glucuronyltransferase required for the addition of the GlcA decorations on the xylan. The differences in xylan structure in primary versus secondary cell walls might reflect the different roles in cross-linking and interaction with other cell wall components. PMID- 26043359 TI - Editorial note. PMID- 26043358 TI - Exploring RNA polymerase regulation by NMR spectroscopy. AB - RNA synthesis is a central process in all organisms, with RNA polymerase (RNAP) as the key enzyme. Multisubunit RNAPs are evolutionary related and are tightly regulated by a multitude of transcription factors. Although Escherichia coli RNAP has been studied extensively, only little information is available about its dynamics and transient interactions. This information, however, are crucial for the complete understanding of transcription regulation in atomic detail. To study RNAP by NMR spectroscopy we developed a highly efficient procedure for the assembly of active RNAP from separately expressed subunits that allows specific labeling of the individual constituents. We recorded [(1)H,(13)C] correlation spectra of isoleucine, leucine, and valine methyl groups of complete RNAP and the separately labeled beta' subunit within reconstituted RNAP. We further produced all RNAP subunits individually, established experiments to determine which RNAP subunit a certain regulator binds to, and identified the beta subunit to bind NusE. PMID- 26043360 TI - Basophils exhibit antibacterial activity through extracellular trap formation. AB - Basophils are primarily associated with immunomodulatory functions in allergic diseases and parasitic infections. Recently, it has been demonstrated that both activated human and mouse basophils can form extracellular DNA traps (BETs) containing mitochondrial DNA and granule proteins. In this report, we provide evidence that, in spite of an apparent lack of phagocytic activity, basophils can kill bacteria through BET formation. PMID- 26043361 TI - Synthesis of Dibenzofurans via C-H Activation of o-Iodo Diaryl Ethers. AB - An efficient method for the synthesis of dibenzofuran from o-iododiaryl ether using reusable Pd/C under ligand-free conditions has been developed. Synthesis of o-iododiaryl ether was achieved in one pot through sequential iodination and O arylation of phenol under mild reaction conditions. PMID- 26043362 TI - Vapor Phase Synthesis of Organometal Halide Perovskite Nanowires for Tunable Room Temperature Nanolasers. AB - Semiconductor nanowires have received considerable attention in the past decade driven by both unprecedented physics derived from the quantum size effect and strong isotropy and advanced applications as potential building blocks for nanoscale electronics and optoelectronic devices. Recently, organic-inorganic hybrid perovskites have been shown to exhibit high optical absorption coefficient, optimal direct band gap, and long electron/hole diffusion lengths, leading to high-performance photovoltaic devices. Herein, we present the vapor phase synthesis free-standing CH3NH3PbI3, CH3NH3PbBr3, and CH3NH3PbIxCl3(-x) perovskite nanowires with high crystallinity. These rectangular cross-sectional perovskite nanowires have good optical properties and long electron hole diffusion length, which ensure adequate gain and efficient optical feedback. Indeed, we have demonstrated optical-pumped room-temperature CH3NH3PbI3 nanowire lasers with near-infrared wavelength of 777 nm, low threshold of 11 MUJ/cm(2), and a quality factor as high as 405. Our research advocates the promise of optoelectronic devices based on organic-inorganic perovskite nanowires. PMID- 26043363 TI - Comparative study of 2-D and bichanneled 3-D laparoscopic images: Is there a difference? AB - INTRODUCTION: Lack of depth perception and spatial orientation are drawbacks of laparoscopic surgery. The advent of the 3-D camera system enables surgeons to regain binocular vision. The aim of this study was to gain subjective and objective data to determine whether 3-D systems are superior to 2-D systems. MATERIALS AND METHODS: Our study consisted of two parts: a laparoscopic training model and an actual operation assessment. In the first part, we compared two groups of surgeon (specialists and trainees) performing a laparoscopic task using a 2-D and a 3-D camera system. In the second part, surgeons were assessed on their performance of standard laparoscopic cholecystectomies using the two different camera systems. At the end of each assessment, participants were required to complete a questionnaire on their impressions of the comparative ease of operation tasks under 2-D and 3-D vision. RESULT: In the laboratory training model, trainees' performance time was shorter with the 3-D camera system than with the 2-D camera, but no difference was observed in the specialists group. In the surgical (cholecystectomy) assessment, no significant difference was observed between the 2-D and 3-D camera systems in terms of operative time and precision. The questionnaire indicated that all participants did not significantly favor the 3-D system. CONCLUSION: We believe that the 3-D camera system can allow young surgeons to perform standard laparoscopic tasks safely and quickly, so as to accelerate the learning curve. However, new-generation 3-D systems will be essential to overcome surgeons' discomfort. PMID- 26043364 TI - Associations between plasma total homocysteine, blood pressure stages and pulse wave velocity in Chinese rural community population. AB - The aim of the study was to examine the associations among plasma total homocysteine (tHcy) and blood pressure (BP) stages and brachial-ankle pulse wave velocity (ba-PWV) in a Chinese rural community population. In this cross sectional study, 2148 rural community subjects with normotension and mild hypertension (HTN) were classified into four groups according to ba-PWV level. Multivariate regression showed that ba-PWV was significantly and independently correlated with tHcy (beta = 5.32, p < 0.001) in the entire study population. Moreover, ba-PWV showed a significant increase with increasing plasma tHcy level in subjects with both high normal BP and grade 1 HTN (p < 0.05). Compared with optimal BP stage, ba-PWV was significantly associated with high normal BP stage (beta = 193, p < 0.001) and grade 1 HTN (beta = 413, p < 0.001).There was a statistical interaction effect between high normal BP stage and optimal BP stage (p = 0.045). The similar result was found between subjects with optimal BP and those with grade 1 HTN (p = 0.037). In conclusion, tHcy was independently correlated with ba-PWV in subjects with high normal BP and grade 1 HTN. High normal BP and grade 1 HTN may worsen the impact of tHcy on arterial stiffness in a Chinese rural community population. PMID- 26043365 TI - Fragment-Based Design of Selective Nanomolar Ligands of the CREBBP Bromodomain. AB - Novel ligands of the CREBBP bromodomain were identified by fragment-based docking. The in silico discovered hits have been optimized by chemical synthesis into selective nanomolar compounds, thereby preserving the ligand efficiency. The selectivity for the CREBBP bromodomain over other human bromodomain subfamilies has achieved by a benzoate moiety which was predicted by docking to be involved in favorable electrostatic interactions with the Arg1173 side chain, a prediction that could be verified a posteriori by the high-resolution crystal structure of the CREBBP bromodomain in complex with ligand 6 and also by MD simulations (see Xu, M.; Unzue, A.; Dong, J.; Spiliotopoulos, D.; Nevado, C.; Caflisch, A. Discovery of CREBBP bromodomain inhibitors by high-throughput docking and hit optimization guided by molecular dynamics. J. Med. Chem. 2015, DOI: 10.1021/acs.jmedchem.5b00171). PMID- 26043366 TI - An Equilibrium Constitutive Model of Anisotropic Cartilage Damage to Elucidate Mechanisms of Damage Initiation and Progression. AB - Traumatic injuries and gradual wear-and-tear of articular cartilage (AC) that can lead to osteoarthritis (OA) have been hypothesized to result from tissue damage to AC. In this study, a previous equilibrium constitutive model of AC was extended to a constitutive damage articular cartilage (CDAC) model. In particular, anisotropic collagen (COL) fibril damage and isotropic glycosaminoglycan (GAG) damage were considered in a 3D formulation. In the CDAC model, time-dependent effects, such as viscoelasticity and poroelasticity, were neglected, and thus all results represent the equilibrium response after all time dependent effects have dissipated. The resulting CDAC model was implemented in two different finite-element models. The first simulated uniaxial tensile loading to failure, while the second simulated spherical indentation with a rigid indenter displaced into a bilayer AC sample. Uniaxial tension to failure simulations were performed for three COL fibril Lagrangian failure strain (i.e., the maximum elastic COL fibril strain) values of 15%, 30%, and 45%, while spherical indentation simulations were performed with a COL fibril Lagrangian failure strain of 15%. GAG damage parameters were held constant for all simulations. Our results indicated that the equilibrium postyield tensile response of AC and the macroscopic tissue failure strain are highly dependent on COL fibril Lagrangian failure strain. The uniaxial tensile response consisted of an initial nonlinear ramp region due to the recruitment of intact fibrils followed by a rapid decrease in tissue stress at initial COL fibril failure, as a result of COL fibril damage which continued until ultimate tissue failure. In the spherical indentation simulation, damage to both the COL fibril and GAG constituents was located only in the superficial zone (SZ) and near the articular surface with tissue thickening following unloading. Spherical indentation simulation results are in agreement with published experimental observations. Our results indicate that the proposed CDAC model is capable of simulating both initial small magnitude damage as well as complete failure of AC tissue. The results of this study may help to elucidate the mechanisms of AC tissue damage, which initiate and propagate OA. PMID- 26043367 TI - Decreasing the Limits of Detection and Analysis Time of Ion Current Rectification Biosensing Measurements via a Mechanically Applied Pressure Differential. AB - Improving on the analytical capabilities of a measurement is a fundamental challenge with all assays, particularly decreasing the limit of detection while maintaining a practical associated analysis time. Of late, ion current rectification (ICR) biosensing measurements have received a great deal of attention as an analyte-specific, label-free assay. In ICR biosensing, a nanopore coated with an analyte specific binding molecule (e.g., an antibody, an aptamer, etc.) is used to detect a target analyte based on the ability of the target analyte to alter the ICR response of the nanopore upon it binding to the aperture interior. This binding changes the local surface charge and/or size of the nanopore aperture, thus altering its ICR response in a time dependent manner. Here, we report the ability to enhance the transport of a target analyte molecule to and through the aperture of an antibody modified glass nanopore membrane (AMGNM) with the application of a mechanically applied pressure differential. We demonstrate that there is an optimal pressure that balances the flux of the target analyte through the AMGNM aperture with its ability to be bound and detected. Applying the optimal pressure differential allows for picomolar concentrations of the cleaved form of synaptosomal-associated protein 25 (cSNAP 25) to be detected within the same analysis time as micromolar concentrations detected without the use of the pressure differential. The methodology presented here significantly expands the utility of ICR biosensing measurements for detecting low-abundance biomolecules by lowering the limit of detection and reducing the associated analysis time. PMID- 26043369 TI - The impact of posttraumatic stress disorder on cannabis quit success. AB - BACKGROUND: Though a growing number of US Veterans are being diagnosed with cannabis use disorders, with posttraumatic stress disorder (PTSD) observed as the most frequently co-occurring psychiatric disorder among this population, no research has investigated the impact of PTSD diagnosis on cannabis quit success. OBJECTIVES: The present study sought to determine the impact of PTSD on cannabis use following a self-guided quit attempt. METHODS: Participants included 104, primarily male, cannabis-dependent US Veterans (Mage = 50.90 years, SDage = 9.90). The study design was prospective and included an assessment immediately prior to the quit attempt, and assessments weekly for the first 4 weeks post quit, and then monthly through 6 months post-quit. RESULTS: Results indicated that PTSD diagnosis was not associated with time to first lapse or relapse. However, individuals with PTSD used more cannabis at baseline and evidenced a slower initial decline in cannabis use immediately following the quit attempt. All findings were significant after accounting for alcohol and tobacco use across the cessation period, as well as co-occurring mood and anxiety disorder diagnoses. CONCLUSION: Findings highlight the potential utility of interventions for individuals with cannabis use disorder and co-occurring PTSD, particularly early in a cessation attempt. PMID- 26043368 TI - Fragmentation in specialist care and stage III colon cancer. AB - BACKGROUND: Patients with cancer frequently transition between different types of specialists and across care settings. This study explored how frequently the surgical and medical oncology care of stage III colon cancer patients occurred across more than 1 hospital and whether this was associated with mortality and costs. METHODS: This was a retrospective Surveillance, Epidemiology, and End Results-Medicare cohort study of 9075 stage III colon cancer patients diagnosed between 2000 and 2009 who had received both surgical and medical oncology care within 1 year of their diagnosis. Patients were assigned to the hospital at which they had undergone their cancer surgery and to their oncologist's primary hospital, and then they were characterized according to whether these hospitals were the same or different. Outcomes included all-cause mortality, subhazards for colon cancer-specific mortality, and costs of care at 12 months. RESULTS: Thirty seven percent of the patients received their surgical and medical oncology care from different hospitals. Rural patients were less likely than urban patients to receive medical oncology care from the same hospital (odds ratio, 0.62; 95% confidence interval, 0.43-0.90). Care from the same hospital was not associated with reduced all-cause or colon cancer-specific mortality but resulted in lower costs (8% of the median cost) at 12 months (dollars saved, $5493; 95% confidence interval, $1799-$9525). CONCLUSIONS: The delivery of surgical and medical oncology care at the same hospital was associated with lower costs; however, reforms seeking to improve outcomes and lower costs through the integration of complex care will need to address the significant proportion of patients receiving care at more than 1 hospital. PMID- 26043370 TI - Effects of calcium on the chromophores of dissolved organic matter and their interactions with copper. AB - The binding of Ca(2+) and Cu(2+) by dissolved organic matter (DOM) exemplified by Suwannee River Humic Acid (SRHA) was examined in this study. Metal-DOM interactions were quantified using linear and log-transformed DOM absorbance spectra acquired at varying pHs and total Ca(2+) and Cu(2+) concentrations. The binding of Cu(2+) by DOM was examined in the presence of three different Ca(2+) concentrations. Interactions of Ca(2+) with DOM chromophores were accompanied by the emergence of features in the differential spectra that were dissimilar from those characteristic for the binding of Cu(2+). The amount of Ca(2+) and Cu(2+) bound by DOM was ascertained using changes of the slopes of log-transformed absorbance spectra in the range of wavelength 350-400 nm (denoted as S350-400) and comparing the data with model predictions. The observed effects indicated the occurrence of the replacement of a characteristic number of protons by the bound Ca(2+) and Cu(2+) ions. PMID- 26043371 TI - Water reclamation from emulsified oily wastewater via effective forward osmosis hollow fiber membranes under the PRO mode. AB - By using a novel hydrophilic cellulose acetate butyrate (CAB) as the membrane material for the hollow fiber substrate and modifying its outer surface by polydopamine (PDA) coating and inner surface by interfacial polymerization, we have demonstrated that the thin-film composite (TFC) membranes can be effectively used for sustainable water reclamation from emulsified oil/water streams via forward osmosis (FO) under the pressure retarded osmosis (PRO) mode. The newly developed TFC-FO hollow fiber membrane shows characteristics of high water flux, outstanding salt and oil rejection, and low fouling propensity. Under the PRO mode, the newly developed TFC-FO membrane exhibits a water flux of 37.1 L m(-2) h(-1) with an oil rejection of 99.9% using a 2000 ppm soybean oil/water emulsion as the feed and 1 M NaCl as the draw solution. Remarkable anti-fouling behaviors have also been observed. Under the PRO mode, the water flux decline is only 10% of the initial value even after a 12 h test for oil/water separation. The water flux of the fouled membrane can be effectively restored to 97% of the original value by water rinses on the fiber outer surface without using any chemicals. Furthermore, the flux declines are only 25% and 52% when the water recovery of a 2000 ppm soybean oil/water emulsion and a 2000 ppm petroleum oil/water emulsion containing 0.04 M NaCl reaches 82%, respectively. This study may not only provide insightful guidelines for the fabrication of effective TFC-FO membranes with high performance and low fouling behaviors for oily wastewater under the PRO mode but also add an alternative perspective to the design of new materials for water purification purposes. PMID- 26043372 TI - Surrogates for herbicide removal in stormwater biofilters. AB - Real time monitoring of suitable surrogate parameters are critical to the validation of any water treatment processes, and is of particularly high importance for validation of natural stormwater treatment systems. In this study, potential surrogates for herbicide removal in stormwater biofilters (also known as stormwater bio-retention or rain-gardens) were assessed using field challenge tests and matched laboratory column experiments. Differential UV absorbance at 254mn (DeltaUVA254), total phosphorus (DeltaTP), dissolved phosphorus (DeltaDP), total nitrogen (DeltaTN), ammonia (DeltaNH3), nitrate and nitrite (DeltaNO3+NO2), dissolved organic carbon (DeltaDOC) and total suspended solids (DeltaTSS) were compared with glyphosate, atrazine, simazine and prometryn removal rates. The influence of different challenge conditions on the performance of each surrogate was studied. Differential TP was significantly and linearly related to glyphosate reduction (R(2) = 0.75-0.98, P < 0.01), while DeltaTP and DeltaUVA254 were linearly correlated (R(2) = 0.44-0.84, P < 0.05) to the reduction of triazines (atrazine, simazine and prometryn) in both field and laboratory tests. The performance of DeltaTP and DeltaUVA254 as surrogates for herbicides were reliable under normal and challenge dry conditions, but weaker correlations were observed under challenge wet conditions. Of those tested, DeltaTP is the most promising surrogate for glyphosate removal and DeltaUVA254 is a suitable surrogate for triazines removal in stormwater biofilters. PMID- 26043373 TI - Stimulation of oxygen to bioanode for energy recovery from recalcitrant organic matter aniline in microbial fuel cells (MFCs). AB - The challenge of energy generation from biodegradation of recalcitrant organics in microbial fuel cells (MFCs) is mainly attributed to their persistence to degradation under anaerobic condition in anode chamber of MFCs. In this work, we demonstrated that electricity generation from aniline, a typical recalcitrant organic matter under anaerobic condition was remarkably facilitated by employing oxygen into bioanode of MFCs. By exposing bioanode to air, electrons of 47.2 +/- 6.9 C were recovered with aniline removal efficiency of 91.2 +/- 2.2% in 144 h. Limited oxygen supply (the anodic headspace was initially filled with air and then closed) resulted in the decrease of electrons recovery and aniline removal efficiency by 52.5 +/- 9.4% and 74.2 +/- 2.1%, respectively, and further decline by respective 64.3 +/- 4.5% and 82.7 +/- 1.0% occurred under anaerobic condition. Community analysis showed that anode biofilm was predominated by several aerobic aniline degrading bacteria (AADB) and anode-respiration bacteria (ARB), which likely cooperated with each other and finally featured the energy recovery from aniline. Cyclic voltammetry indicated that anodic bacteria transferred electrons to anode mainly through electron shuttle. This study provided a new sight to acquaint us with the positive role of oxygen in biodegradation of recalcitrant organics on anode as well as electricity generation. PMID- 26043374 TI - Impact of fluctuations in gaseous H2S concentrations on sulfide uptake by sewer concrete: The effect of high H2S loads. AB - The acid production from the oxidation of hydrogen sulfide (H2S) in sewer air results in serious corrosion of exposed concrete surfaces in sewers. Large fluctuations of gaseous H2S concentrations occur in sewers due to the diurnal profiles of sewage flow and retention times and the necessity of intermittent pumping of sewage from pressure pipes into gravity pipes. How the high concentrations of H2S due to these events may affect H2S uptake and subsequent corrosion by concrete sewers is largely unknown. This study determined the effect of short- and long-term increases in H2S levels on the sulfide uptake rate (SUR) of concrete surfaces with an active corrosion layer. The results showed that during the high load situation the SUR increased significantly but then decreased (compared to the baseline SUR) by about 7-14% and 41-50% immediately after short- and long-term H2S high-load periods, respectively. For both exposure conditions, the SUR gradually (over several hours) recovered to approximately 90% of the baseline SUR. Further tests suggest multiple factors may contribute to the observed decrease of SUR directly after the high H2S load. This includes the temporary storage of elemental sulfur in the corrosion layer and inhibition of sulfide oxidizing bacteria (SOB) due to high H2S level and temporary acid surge. Additionally, the delay of the corrosion layer to fully recover the SUR after the high H2S load suggests that there is a longer-term inhibitive effect of the high H2S levels on the activity of the SOB in the corrosion layer. Due to the observed activity reductions, concrete exposed to occasional short-term high H2S load periods had an overall lower H2S uptake compared to concrete exposed to constant H2S levels at the same average concentration. To accurately predict H2S uptake by sewer concrete and hence the likely maximum corrosion rates, a correction factor should be adopted for the H2S fluctuations when average H2S levels are used in the prediction. PMID- 26043375 TI - Comparing different reactor configurations for Partial Nitritation/Anammox at low temperatures. AB - Partial Nitritation/Anammox (PN/A) is a well-established technology for side stream nitrogen removal from highly concentrated, warm wastewaters. The focus has now shifted to weakly concentrated municipal wastewaters with much lower concentrations and temperatures. The major challenge is the temperature, which ranges from moderate 20 degrees C in summer to cold 10 degrees C in winter. For this study, the most frequently used configurations for side-stream applications were exposed to a slow temperature reduction from 20 degrees C to 10 degrees C to simulate a realistic temperature gradient. To evaluate the behavior of the different biomasses based on their properties, four lab reactors were operated in two different configurations. Synthetic wastewater was used to avoid side effects of heterotrophic growth. Differences in the response of the different reactor systems to this temperature gradient clearly indicated, that the geometry of the biomass has a major impact on the overall PN/A performance at low temperatures: While anammox activity in suspended biomass suffered already at 15 degrees C, it persevered in granular biomass as well as in biofilms on carriers for temperatures down to <13 degrees C. Further, anammox activity in thicker biofilms was less affected than in thinner biofilms and even adaption to low temperatures was observed. PMID- 26043376 TI - Process simulation and dynamic control for marine oily wastewater treatment using UV irradiation. AB - UV irradiation and advanced oxidation processes have been recently regarded as promising solutions in removing polycyclic aromatic hydrocarbons (PAHs) from marine oily wastewater. However, such treatment methods are generally not sufficiently understood in terms of reaction mechanisms, process simulation and process control. These deficiencies can drastically hinder their application in shipping and offshore petroleum industries which produce bilge/ballast water and produced water as the main streams of marine oily wastewater. In this study, the factorial design of experiment was carried out to investigate the degradation mechanism of a typical PAH, namely naphthalene, under UV irradiation in seawater. Based on the experimental results, a three-layer feed-forward artificial neural network simulation model was developed to simulate the treatment process and to forecast the removal performance. A simulation-based dynamic mixed integer nonlinear programming (SDMINP) approach was then proposed to intelligently control the treatment process by integrating the developed simulation model, genetic algorithm and multi-stage programming. The applicability and effectiveness of the developed approach were further tested though a case study. The experimental results showed that the influences of fluence rate and temperature on the removal of naphthalene were greater than those of salinity and initial concentration. The developed simulation model could well predict the UV induced removal process under varying conditions. The case study suggested that the SDMINP approach, with the aid of the multi-stage control strategy, was able to significantly reduce treatment cost when comparing to the traditional single stage process optimization. The developed approach and its concept/framework have high potential of applicability in other environmental fields where a treatment process is involved and experimentation and modeling are used for process simulation and control. PMID- 26043377 TI - [Fertility preservation in oncology: updates in 2015]. PMID- 26043378 TI - Rapid Onset of Eyebrow Pilomatrixoma After Blunt Trauma. PMID- 26043379 TI - Anti-Inflammatory Activity of Haskap Cultivars is Polyphenols-Dependent. AB - Haskap (Lonicera caerulea L.) berries have long been used for their health promoting properties against chronic conditions. The current study investigated the effect of Canadian haskap berry extracts on pro-inflammatory cytokines using a human monocytic cell line THP-1 derived macrophages stimulated by lipopolysaccharide. Methanol extracts of haskap from different growing locations in Canada were prepared and characterized for their total phenolic profile using colorimetric assays and liquid chromatography-Mass spectrometry (UPLC-MS/MS). Human THP-1 monocytes were seeded in 24-well plates (5 * 105/well) and treated with phorbol 12-myristate 13-acetate (PMA, 0.1 MUg/mL) for 48 h to induce macrophage differentiation. After 48 h, the differentiated macrophages were washed with Hank's buffer and treated with various concentrations of test compounds for 4 h, followed by the lipopolysaccharide (LPS)-stimulation (18 h). Borealis cultivar showed the highest phenolic content, flavonoid content and anthocyanin content (p < 0.05). A negative correlation existed between the polyphenol concentration of the extracts and pro-inflammatory cytokines: Interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), prostaglandin (PGE2), and cyclooxygenase-2 (COX-2) enzyme. Borealis exhibited comparable anti inflammatory effects to COX inhibitory drug, diclofenac. The results showed that haskap berry polyphenols has the potential to act as an effective inflammation inhibitor. PMID- 26043380 TI - The Molecular Switch of Telomere Phages: High Binding Specificity of the PY54 Cro Lytic Repressor to a Single Operator Site. AB - Temperate bacteriophages possess a molecular switch, which regulates the lytic and lysogenic growth. The genomes of the temperate telomere phages N15, PY54 and phiKO2 harbor a primary immunity region (immB) comprising genes for the prophage repressor, the lytic repressor and a putative antiterminator. The roles of these products are thought to be similar to those of the lambda proteins CI, Cro and Q, respectively. Moreover, the gene order and the location of several operator sites in the prototype telomere phage N15 and in phiKO2 are also reminiscent of lambda like phages. By contrast, in silico analyses revealed the presence of only one operator (O?(_{?rm{R}}?)3) in PY54. The purified PY54 Cro protein was used for EMSA studies demonstrating that it exclusively binds to a 16-bp palindromic site (O?(_{?rm{R}}?)3) upstream of the prophage repressor gene. The O?(_{?rm{R}}?)3 operator sequences of PY54 and phiKO2/N15 only differ by their peripheral base pairs, which are responsible for Cro specificity. PY54 cI and cro transcription is regulated by highly active promoters initiating the synthesis of a homogenious species of leaderless mRNA. The location of the PY54 Cro binding site and of the identified promoters suggests that the lytic repressor suppresses cI transcription but not its own synthesis. The results indicate an unexpected diversity of the growth regulation mechanisms in lambda-related phages. PMID- 26043383 TI - Hemolysis from ABO Incompatibility. AB - ABO incompatibility of red blood cells leads to brisk complement-mediated lysis, particularly in the setting of red cell transfusion. The ABO blood group is the most clinically significant blood group because of preformed immunoglobulin M (IgM) and IgG antibodies to ABO blood group antigens (isohemagglutinins) in everyone except group AB individuals. In addition to transfusion, ABO incompatibility can cause hemolysis in hematopoietic and solid organ transplantation, hemolytic disease of the newborn, and intravenous immunoglobulin infusion. It is important to prevent ABO incompatibility when possible and to anticipate complications when ABO incompatibility is unavoidable. PMID- 26043381 TI - Dynamics of virus-receptor interactions in virus binding, signaling, and endocytosis. AB - During viral infection the first challenge that viruses have to overcome is gaining access to the intracellular compartment. The infection process starts when the virus contacts the surface of the host cell. A complex series of events ensues, including diffusion at the host cell membrane surface, binding to receptors, signaling, internalization, and delivery of the genetic information. The focus of this review is on the very initial steps of virus entry, from receptor binding to particle uptake into the host cell. We will discuss how viruses find their receptor, move to sub-membranous regions permissive for entry, and how they hijack the receptor-mediated signaling pathway to promote their internalization. PMID- 26043384 TI - Warm autoimmune hemolytic anemia. AB - Warm autoimmune hemolytic anemia (AIHA) is defined as the destruction of circulating red blood cells (RBCs) in the setting of anti-RBC autoantibodies that optimally react at 37 degrees C. The pathophysiology of disease involves phagocytosis of autoantibody-coated RBCs in the spleen and complement-mediated hemolysis. Thus far, treatment is aimed at decreasing autoantibody production with immunosuppression or reducing phagocytosis of affected cells in the spleen. The role of complement inhibitors in warm AIHA has not been explored. This article addresses the diagnosis, etiology, and treatment of warm AIHA and highlights the role of complement in disease pathology. PMID- 26043382 TI - Complement: an overview for the clinician. AB - The complement system is an essential component of the immune system. It is a highly integrative system and has a number of functions, including host defense, removal of injured cells and debris, modulation of metabolic and regenerative processes, and regulation of adaptive immunity. Complement is activated via different pathways and it is regulated tightly by several mechanisms to prevent host injury. Imbalance between complement activation and regulation can manifest in disease and injury to self. This article provides an outline of complement activation pathways, regulatory mechanisms, and normal physiologic functions of the system. PMID- 26043385 TI - Cold agglutinin-mediated autoimmune hemolytic anemia. AB - Cold antibody types account for about 25% of autoimmune hemolytic anemias. Primary chronic cold agglutinin disease (CAD) is characterized by a clonal lymphoproliferative disorder. Secondary cold agglutinin syndrome (CAS) complicates specific infections and malignancies. Hemolysis in CAD and CAS is mediated by the classical complement pathway and is predominantly extravascular. Not all patients require treatment. Successful CAD therapy targets the pathogenic B-cell clone. Complement modulation seems promising in both CAD and CAS. Further development and documentation are necessary before clinical use. We review options for possible complement-directed therapy. PMID- 26043386 TI - Paroxysmal cold hemoglobinuria. AB - Paroxysmal cold hemoglobinuria is a rare cause of autoimmune hemolytic anemia predominantly seen as an acute form in young children after viral illnesses and in a chronic form in some hematological malignancies and tertiary syphilis. It is a complement mediated intravascular hemolytic anemia associated with a biphasic antibody against the P antigen on red cells. The antibody attaches to red cells at colder temperatures and causes red cell lysis when blood recirculates to warmer parts of the body. Treatment is mainly supportive and with red cell transfusion, but immunosuppressive therapy may be effective in severe cases. PMID- 26043388 TI - Congenital CD59 Deficiency. AB - The severe clinical symptoms of inherited CD59 deficiency confirm the importance of CD59 as essential complement regulatory protein for protection of cells against complement attack, in particular protection of hematopoietic cells and human neuronal tissue. Targeted complement inhibition might become a treatment option as suggested by a case report. The easy diagnostic approach by flow cytometry and the advent of a new treatment option should increase the awareness of this rare differential diagnosis and lead to further studies on their pathophysiology. PMID- 26043387 TI - Paroxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia. AB - Paroxysmal nocturnal hemoglobinuria is manifests with a chronic hemolytic anemia from uncontrolled complement activation, a propensity for thrombosis and marrow failure. The hemolysis is largely mediated by the alternative pathway of complement. Clinical manifestations result from the lack of specific cell surface proteins, CD55 and CD59, on PNH cells. Complement inhibition by eculizumab leads to dramatic clinical improvement. While this therapeutic approach is effective, there is residual complement activity resulting from specific clinical scenarios as well as from upstream complement components that can account for suboptimal responses in some patients. Complement inhibition strategies are an area of active research. PMID- 26043390 TI - Shiga toxin associated hemolytic uremic syndrome. AB - Shiga toxin associated hemolytic uremic syndrome (Stx HUS), a thrombotic microangiopathy, is the most common cause of pediatric acute kidney injury but has no direct treatment. A better understanding of disease pathogenesis may help identify new therapeutic targets. For this reason, the role of complement is being actively studied while eculizumab, the C5 monoclonal antibody, is being used to treat Stx HUS but with conflicting results. A randomized controlled trial would help properly evaluate its use in Stx HUS while more research is required to fully evaluate the role complement plays in the disease pathogenesis. PMID- 26043389 TI - Ultralarge von Willebrand factor-induced platelet clumping and activation of the alternative complement pathway in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndromes. AB - The molecular linkage between ultralarge (UL) von Willebrand factor (VWF) multimers and the alternative complement pathway (AP) has recently been described. Endothelial cell (EC)-secreted and anchored ULVWF multimers (in long stringlike structures) function as both hyperadhesive sites that initiate platelet adhesion and aggregation and activating surfaces for the AP. In vitro, the active form of C3, C3b binds to the EC-anchored ULVWF multimeric strings and initiates the assembly on the strings of C3 convertase (C3bBb) and C5 convertase (C3bBbC3b). In vivo, activation of the AP via this mechanism proceeds all the way to generation of terminal complement complexes (C5b-9). PMID- 26043391 TI - Thrombotic microangiopathy: focus on atypical hemolytic uremic syndrome. AB - Thrombotic microangiopathies (TMA) such as atypical hemolytic uremic syndrome (aHUS) have evolved from rare, fulminant childhood afflictions to uncommon diseases with acute and chronic phases involving both children and adults. Breakthroughs in complement and coagulation regulation have allowed redefinition of specific entities despite substantial phenotypic mimicry. Reconciliation of phenotypes and delivery of life saving therapies require a multidisciplinary team of experts. The purpose of this review is to describe advances in the molecular pathophysiology of aHUS and to share the 2014 experience of the multidisciplinary Johns Hopkins TMA Registry in applying diagnostic assays, reporting disease associations, and genetic testing. PMID- 26043392 TI - Current and future pharmacologic complement inhibitors. AB - The availability of anticomplement therapies has been a major achievement for medicine in the last decade. Indeed, eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome and promises to do the same in several other human complement-mediated diseases. Nowadays, a 10-year experience has also taught us that there are some pitfalls that represent a challenge to improve the current anticomplement treatment. Most of these observations come from paroxysmal nocturnal hemoglobinuria, where unmet clinical needs are emerging, triggering the attention of several investigators and pharmaceutical companies. PMID- 26043393 TI - Complement in health and disease. PMID- 26043394 TI - Emotion generation and regulation in anorexia nervosa: a systematic review and meta-analysis of self-report data. AB - This systematic review sought to examine the generation and regulation of emotion in people with Anorexia Nervosa (AN). Key databases (Medline, Embase, PsychINFO and Web of Science) were searched for peer-reviewed articles published by March 2015 yielding 131 studies relevant to emotion generation and emotion regulation (ER) processes as defined by Gross (1998). Meta-analyses determined pooled group differences between AN and healthy control (HC) groups. More maladaptive schemata were reported by people with AN than HCs, with largest pooled effects for defectiveness/shame (d=2.81), subjugation (d=1.59) and social isolation (d=1.66). Poorer awareness of and clarity over emotion generated and some elevated emotionality (disgust and shame) were reported. A greater use of 'maladaptive' ER strategies was reported by people with AN than HCs, alongside less use of 'adaptive' strategies. Pooled differences of particularly large effect were observed for: experiential avoidance (d=1.00), negative problem-solving style (d=1.06), external/social comparison (d=1.25), submissiveness (d=1.16), attention concentration (worry/rumination; d=1.44) and emotion suppression (d=1.15), particularly to avoid conflict (d=1.54). These data support the notion that emotion regulation difficulties are a factor in AN and support use of associated cognitive-affective models. The implications of these findings for further understanding AN, and developing models and related psychological interventions are discussed. PMID- 26043395 TI - Mixed Phytochemicals Mediated Synthesis of Multifunctional Ag-Au-Pd Nanoparticles for Glucose Oxidation and Antimicrobial Applications. AB - The growing awareness toward the environment is increasing commercial demand for nanoparticles by green route syntheses. In this study, alloy-like Ag-Au-Pd trimetallic nanoparticles have been prepared by two plants extracts Aegle marmelos leaf (LE) and Syzygium aromaticum bud extracts (CE). Compositionally different Ag-Au-Pd nanoparticles with an atomic ratio of 5.26:2.16:1.0 (by LE) and 11.36:13.14:1.0 (by LE + CE) of Ag:Au:Pd were easily synthesized within 10 min at ambient conditions by changing the composition of phytochemicals. The average diameters of the nanoparticles by LE and LE + CE are ~8 and ~11 nm. The catalytic activity of the trimetallic nanoparticles was studied, and they were found to be efficient catalysts for the glucose oxidation process. The prepared nanoparticles also exhibited efficient antibacterial activity against a model Gram-negative bacteria Escherichia coli. The catalytic and antimicrobial properties of these readymade trimetallic nanoparticles have high possibility to be utilized in diverse fields of applications such as health care to environmental. PMID- 26043397 TI - Reducing the use of laboratory animals: time for strategic actions and the setting of realistic targets. PMID- 26043396 TI - Non-contact intracellular binding of chloroplasts in vivo. AB - Non-contact intracellular binding and controllable manipulation of chloroplasts in vivo was demonstrated using an optical fiber probe. Launching a 980-nm laser beam into a fiber, which was placed about 3 MUm above the surface of a living plant (Hydrilla verticillata) leaf, enabled stable binding of different numbers of chloroplasts, as well as their arrangement into one-dimensional chains and two dimensional arrays inside the leaf without damaging the chloroplasts. Additionally, the formed chloroplast chains were controllably transported inside the living cells. The optical force exerted on the chloroplasts was calculated to explain the experimental results. This method provides a flexible method for studying intracellular organelle interaction with highly organized organelle organelle contact in vivo in a non-contact manner. PMID- 26043398 TI - Alternative methods for skin irritation testing: the current status. PMID- 26043399 TI - The coumarin 7-hydroxylation microassay in living hepatic cells in culture. PMID- 26043401 TI - The validation of computational prediction techniques. PMID- 26043400 TI - In Vitro Studies on the Metabolism and Toxicity of Aflatoxin B1 in Primary Cultures of Black Catfish (Ictalurus melas) Hepatocytes. PMID- 26043402 TI - Anti-ageing Efficacy Screening. PMID- 26043404 TI - Multiresidue determination of pyrethroid pesticide residues in pepper through a modified QuEChERS method and gas chromatography with electron capture detection. AB - This study developed and used a modified quick, easy, cheap, efficient, rugged and safe (QuEChERS) method coupled with gas chromatography with electron capture detection to determine eight pyrethroid pesticide residues in green, red and dehydrated red peppers. Pyrethroids were extracted with acetonitrile, partitioned with sodium chloride and purified with primary secondary amino and graphitized carbon black in hexane. The QuEChERS extraction conditions were optimized, and the matrix effects that might influence recoveries were evaluated and minimized using matrix-matched calibration curves. Under the optimized conditions, the calibration curves for pyrethroid pesticides showed good linearities in the concentration range of 0.05-20 ug/mL with determination coefficients (R(2) ) >0.997. The limits of quantification of eight pyrethroids were 0.004-0.04 mg/kg for green and red pepper and 0.04-0.5 mg/kg for dehydrated red pepper. These values are below the suggested regulatory maximum residue limits. The mean recoveries ranged between 79.0 and 104%, and the relative standard deviations were <11%. The developed method was successfully applied to commercial samples. Some samples were found to contain pyrethroid pesticides with levels below the legal limits. PMID- 26043403 TI - A Simple RNA-DNA Scaffold Templates the Assembly of Monofunctional Virus-Like Particles. AB - Using the components of a particularly well-studied plant virus, cowpea chlorotic mottle virus (CCMV), we demonstrate the synthesis of virus-like particles (VLPs) with one end of the packaged RNA extending out of the capsid and into the surrounding solution. This construct breaks the otherwise perfect symmetry of the capsid and provides a straightforward route for monofunctionalizing VLPs using the principles of DNA nanotechnology. It also allows physical manipulation of the packaged RNA, a previously inaccessible part of the viral architecture. Our synthesis does not involve covalent chemistry of any kind; rather, we trigger capsid assembly on a scaffold of viral RNA that is hybridized at one end to a complementary DNA strand. Interaction of CCMV capsid protein with this RNA-DNA template leads to selective packaging of the RNA portion into a well-formed capsid but leaves the hybridized portion poking out of the capsid through a small hole. We show that the nucleic acid protruding from the capsid is capable of binding free DNA strands and DNA-functionalized colloidal particles. Separately, we show that the RNA-DNA scaffold can be used to nucleate virus formation on a DNA-functionalized surface. We believe this self-assembly strategy can be adapted to viruses other than CCMV. PMID- 26043405 TI - GCK monogenic diabetes and gestational diabetes: possible diagnosis on clinical grounds. AB - AIM: To determine if the previously published clinical criteria for identifying glucokinase monogenic diabetes [GCK gene mutation in maturity-onset diabetes of the young (GCK-MODY)], an elevated antenatal fasting blood glucose of 5.5-8.0 mmol/l, an increment of < 4.6 mmol/l at 2 h in an oral glucose tolerance test and slim are applicable in a large multi-ethnic cohort of women with gestational diabetes. METHODS: We analysed de-identified data from all women with gestational diabetes, diagnosed using the Australasian Diabetes in Pregnancy Society (1998) Australian criteria at our institution between 1993 and 2013, making comparisons among those with complete antenatal data including: diagnostic oral glucose tolerance test results meeting the above criteria; pregestational BMI; birth outcomes; and postpartum oral glucose tolerance test data. We categorized these women into two groups: Group A1 had a BMI <= 21 kg/m(2) and Group A2 had a BMI > 21 kg/m(2) and < 25 kg/m(2). RESULTS: Of the 302 women meeting the study entry criteria, we had complete data including a postpartum oral glucose tolerance test result for 171 women: 54 in Group A1 and 117 in Group A2. Ethnicity was significantly different between the groups. The oral glucose tolerance test and postpartum HbA1c results identified few women ( < 14%) in Group A1 and Group A2 who still had 'possible GCK-MODY'. CONCLUSIONS: Our findings indicate that previously recommended clinical criteria for the identification of women likely to have GCK-MODY lack specificity in a cohort of women with multi-ethnic backgrounds. Using these criteria to select women for testing for GCK-MODY in pregnancy would therefore be costly and is likely to yield few women positive for this condition. PMID- 26043406 TI - Emerging roles of hypoxia-inducible factors and reactive oxygen species in cancer and pluripotent stem cells. AB - Eukaryotic organisms require oxygen homeostasis to maintain proper cellular function for survival. During conditions of low oxygen tension (hypoxia), cells activate the transcription of genes that induce an adaptive response, which supplies oxygen to tissues. Hypoxia and hypoxia-inducible factors (HIFs) may contribute to the maintenance of putative cancer stem cells, which can continue self-renewal indefinitely and express stemness genes in hypoxic stress environments (stem cell niches). Reactive oxygen species (ROS) have long been recognized as toxic by-products of aerobic metabolism that are harmful to living cells, leading to DNA damage, senescence, or cell death. HIFs may promote a cancer stem cell state, whereas the loss of HIFs induces the production of cellular ROS and activation of proteins p53 and p16(Ink4a), which lead to tumor cell death and senescence. ROS seem to inhibit HIF regulation in cancer cells. By contrast, controversial data have suggested that hypoxia increases the generation of ROS, which prevents hydroxylation of HIF proteins by inducing their transcription as negative feedback. Moreover, hypoxic conditions enhance the generation of induced pluripotent stem cells (iPSCs). During reprogramming of somatic cells into a PSC state, cells attain a metabolic state typically observed in embryonic stem cells (ESCs). ESCs and iPSCs share similar bioenergetic metabolisms, including decreased mitochondrial number and activity, and induced anaerobic glycolysis. This review discusses the current knowledge regarding the emerging roles of ROS homeostasis in cellular reprogramming and the implications of hypoxic regulation in cancer development. PMID- 26043407 TI - The effects of electromagnetic fields on the number of ovarian primordial follicles: An experimental study. AB - The aim of this study was to evaluate the effect of an electromagnetic field (EMF), generated close to the ovaries, on primordial follicles. A total of 16 rats were used in this study. The study group consisted of rats exposed to an EMF in the abdominal region for 15 min/d for 15 days. Both the study and control group were composed of eight rats. After the treatment period of 15 days, the ovaries of the rats were extracted, and sections of ovarian tissue were taken for histological evaluation. The independent samples t test was used to compare the two groups. In the study group, the means of the right and left ovarian follicle numbers were 34.00 +/- 10.20 and 36.00 +/- 10.53, respectively. The average total ovarian follicle number was 70.00 +/- 19.03. In the control group, the means of the right and left ovarian follicle numbers were 78.50 +/- 25.98 and 71.75 +/- 29.66, respectively, and the average total ovarian follicle number was 150.25 +/- 49.53. The comparisons of the means of the right and left ovarian follicle numbers and the means of the total ovarian follicle numbers between the study and control groups indicated that the study group had significantly fewer follicles (p < 0.001, p = 0.011, and p = 0.002, respectively). This study found a significant decrease in the number of ovarian follicles in rats exposed to an EMF. Further clinical studies are needed to reveal the effects of EMFs on ovarian reserve and infertility. PMID- 26043408 TI - Yakammaoto inhibits enterovirus 71 infection by reducing viral attachment, internalization, replication, and translation. AB - Enterovirus 71 (EV71) can cause central nervous system infections with mortality and neurologic sequelae. At present, there is no effective therapeutic modality for EV71 infection. The infection is more common in families with poor socioeconomic status. Therefore, finding a readily available, cost-effective therapeutic modality would be very helpful to these socioeconomically disadvantaged families. Yakammaoto is a cheap and readily available traditional prescription that is proven to have antiviral activity against coxsackievirus B4 (CVB4). CVB4 and EV71 are enteroviruses. In this study, we evaluated the antiviral activity of hot water extract of yakammaoto against EV71. The results of plaque reduction assay and flow cytometry demonstrated that yakammaoto dose dependently inhibited EV71 infection. In addition, reverse transcription polymerase chain reaction (RT-PCR) and quantitative RT-PCR results showed that yakammaoto reduced viral replication. Western blotting analysis showed that yakammaoto can inhibit viral protein production. Thus, our results suggest that yakammaoto should be considered to manage EV71 infection in the future. PMID- 26043409 TI - Anti-inflammatory effects of bamboo salt and sodium fluoride in human gingival fibroblasts--An in vitro study. AB - Dental caries preventive agents, such as sodium fluoride (NaF) and bamboo salt (BS), are known to cause cellular growth that is characterized by morphological and gene expression changes. This study was designed to investigate the dual effect of NaF and BS on interleukin (IL)-1beta-induced gingival inflammation. Under in vitro experimental conditions, exposure to a subcytotoxic dose of IL 1beta enhanced human gingival fibroblast inflammation, as characterized by increased levels of inflammation-associated proteins. A combination of NaF and BS significantly protected fibroblasts from IL-1beta-induced cellular deterioration. Exposure to NaF and BS induced the cell growth and no changes in viability were found with the Lactate Dehydrogenase Assay (LDH) assay at the NaF and BS concentration analyzed. Molecular analysis demonstrated that NaF and BS increased resistance to inflammation by reduction of IL-1beta, IL-8, and tumor necrosis factor (TNF)-alpha production. In addition, NaF and BS decreased the expression of IL-1beta, IL-8, and TNF-alpha mRNA in IL-1beta-induced human gingival fibroblast cells. The study identifies a new role for NaF and BS in the IL-1beta induced inflammation of gingival fibroblasts and provides a potential target for gingival protection. PMID- 26043410 TI - The gene mutation in a Taiwanese family with X-linked retinoschisis. AB - X-linked retinoschisis (XLRS) is one of the leading causes of macular degeneration in male children. The purpose of this study is to describe the clinical characteristics of a Taiwanese family with X-linked retinoschisis (XLRS) and to investigate the genetic mutation in the retinoschisin 1 (RS1) gene. A total of four participants in this XLRS family were analyzed. Complete ophthalmic examinations were performed, including best corrected visual acuity, optical coherence tomography (OCT), and electroretinogram (ERG). Direct DNA sequence of the RS1 gene identified one affected male and one female carrier. The affected male, had a cartwheel-like macular appearance and abnormal retinal pigment epithelium pigmentation in his bilateral eyes. The mixed scotopic ERG b-wave was more reduced than a-wave. OCT revealed typical macular microcystic schisis cavities. Direct DNA sequence analysis revealed a single base pair substitution in Exon 4, 304C > T, resulting in Arg102Trp. Our results show a RS1 (304C > T) mutation in a Taiwanese family with XLRS. This finding expands the clinical profiles of RS1 mutation and may help to further understand its pathogenesis. PMID- 26043411 TI - Percentage of free prostate-specific antigen (PSA) is a useful method in deciding to perform prostate biopsy with higher core numbers in patients with low PSA cut off values. AB - The aim of this study was to evaluate the predictive role of percentage of free prostate-specific antigen (%fPSA) cut-points in prostate cancer (PCa) detection in patients with total PSA (tPSA) levels between 2.5 ng/mL and 10.0 ng/mL. In total, 1321 consecutive initial transrectal ultrasound (TRUS)-guided 12-core biopsies performed between 2005 and 2011 were evaluated retrospectively. Benign pathologies, high-grade prostatic intraepithelial neoplasia, and atypical small acinary proliferations were categorized as noncancerous (benign), and prostate adenocarcinomas were categorized as cancerous (malignant). The patients were categorized according to: Catalona's published %fPSA categories (<10%, 10-15%, 15 20%, 20-25%, or > 25%); digital rectal examination (DRE) results [benign (negative) or suspicious of malignancy (positive)]. There was a significant relationship between the %fPSA cut-points and detection of PCa in DRE-negative patients. The presence of a 10% cut-point increased the probability of PCa threefold. The %fPSA was significantly more related to PCa than the tPSA value in receiver operating characteristic (ROC) curve analyses (p = 0.001). Based on our findings, a lower %fPSA, especially <10%, is an important parameter when deciding whether to perform a biopsy on patients with a tPSA between 2.5 ng/mL and 10 ng/mL. PMID- 26043412 TI - Different risk factors between reflux symptoms and mucosal injury in gastroesophageal reflux disease. AB - Gastroesophageal reflux disease (GERD) is diagnosed based on typical symptoms in clinical practice. It can be divided into two groups using endoscopy: erosive and nonerosive reflux disease (NERD). This study aims to determine the risk factors of reflux symptoms and mucosal injury. This was a two-step case-control study derived from a cohort of 998 individuals having the data of reflux disease questionnaire (RDQ) and endoscopic findings. Those with minor reflux symptoms were excluded. The first step compared symptomatic GERD patients with healthy controls. The 2(nd) step compared patients with erosive esophagitis with healthy controls. In this study, the prevalence of symptomatic GERD and erosive esophagitis were 163 (16.3%) and 166 (16.6%), respectively. A total of 507 asymptomatic individuals without mucosal injury of the esophagus on endoscopy were selected as healthy controls. Compared with healthy controls, multivariate analyses showed that symptomatic GERD patients had a higher prevalence of hypertriglyceridemia [odds ratio (OR), 1.83; 95% confidence interval (CI) 1.13 2.96] and obesity (OR, 1.85; 95% CI 1.08-3.02). By contrast, male sex (OR, 2.24; 95% CI 1.42-3.52), positive Campylo-like organism (CLO) test (OR, 0.56; 95% CI 0.37-0.84), and hiatus hernia (OR, 14.36; 95% CI 3.05-67.6) were associated with erosive esophagitis. In conclusion, obesity and hypertriglyceridemia were associated with reflux symptoms. By contrast, male sex, negative infection of Helicobacter pylori, and hiatus hernia were associated with mucosal injury. Our results suggested that risk factors of reflux symptoms or mucosal injury might be different in GERD patients. The underlying mechanism awaits further studies to clarify. PMID- 26043413 TI - Risks of nonadherence to hormone therapy in Asian women with breast cancer. AB - The aim of this study was to quantify the hormone therapy (HT) nonadherence patterns and to assess the associated risk factors in Asian women with breast cancer. This retrospective cohort study used the Taiwan Health Insurance Research Database from 2003 to 2011. Data from women with newly diagnosed primary breast cancer were identified, and persistence (without HT prescribing gap >= 180 days) to HT was defined through records of dispensing prescriptions. Study cohorts were further classified as adjuvant and primary HT groups. Each individual's HT utilization patterns and the medication possession ratio at overall HT course were measured. The odds ratios (ORs) of nonadherence (medication possession ratio, <80%) in adjuvant and primary HT patients were estimated using logistic regressions with adjustment of potential confounding variables. These patients had 15.6% and 23.4% nonadherence rates to HT in adjuvant and primary HT groups, respectively. In the adjuvant HT group, older age groups (>=50 years) and taking aromatase inhibitors were less likely to show nonadherence (p < 0.05). In the primary HT group, women older than 70 years were significantly less likely to exhibit nonadherence (OR = 0.53; 95% confidence interval, 0.28-0.99); however, women with presence of HT-related adverse events had significantly increased risk (OR = 1.44; 95% confidence interval, 1.02-2.03). Young age and experience of musculoskeletal and joint symptoms were identified as risk factors for nonadherence. PMID- 26043414 TI - Chronic mucocutaneous herpes simplex virus. PMID- 26043416 TI - Triimidosulfonates as Acute Bite-Angle Chelates: Slow Relaxation of the Magnetization in Zero Field and Hysteresis Loop of a Co(II) Complex. AB - Starting from a polyimido sulfonate the four-coordinate, N,N'-chelated Co(II) complex [Co{(NtBu)3 SMe}2 ] (1) was synthesized, and its molecular structure was elucidated by single-crystal X-ray structural analysis. The acute N-Co-N bite angle imposed by the N,N'-chelating ligand (NtBu)3 SMe(-) leads to pronounced C2v distortion of the tetrahedral coordination environment and thus to high anisotropy of the Co(II) ion (D~-58 cm(-1) ), favorable for single-molecule magnet (SMM) properties. Magnetic measurements revealed a high barrier to spin reversal (Ueff =75 cm(-1) ) that gives rise to the observation of slow relaxation of the magnetization in zero field and a hysteresis loop at 2 K for this unique complex. PMID- 26043415 TI - Understanding the association of Escherichia coli with diverse macroalgae in the lagoon of Venice. AB - Recent studies provided evidence that the macroalga Cladopohora in lakes hosts associated Escherichia coli, with consequences on the environmental and human health. We expanded these investigations to other macroalgae (Ulva spp., Sargassum muticum and Undaria pinnatifida) widespread in the lagoon of Venice (Italy). Attached E. coli were abundant, accounting up to 3,250 CFU gram(-1) of alga. Macroalgal-associated isolates belonged to all E. coli phylogroups, including pathogenic ones, and to Escherichia cryptic clades. Attached E. coli showed potential to grow even at in situ temperature on macroalgal extracts as only source of carbon and nutrients, and ability to produce biofilm in vitro. The genotypic diversity of the attached isolates was high, with significant differences between algae and the overlying water. Our evidences suggest that attached populations consist of both resident and transient strains, likely resulting from the heterogeneous input of fecal bacteria from the city. We report that cosmopolitan and invasive macroalgae may serve as source of E. coli, including pathogenic genotypes, and that this habitat can potentially support their growth. Considering the global diffusion of the macroalgae here studied, this phenomenon is likely occurring in other coastal cities worldwide and deserves further investigations from either the sanitary and ecological perspectives. PMID- 26043417 TI - Neonatal nasal intermittent positive pressure ventilation efficacy and lung pressure transmission. AB - OBJECTIVE: The objective of this study was to evaluate carbon dioxide (CO2) clearance, delivered pressures and tidal volume (VT) during neonatal nasal intermittent positive pressure ventilation (NIPPV) with two commonly used interfaces. STUDY DESIGN: A neonatal lung model, with either short binasal prongs (SBP) or a small caliber nasal cannula (RAM) interface, was tested over a range of clinically relevant settings. A fixed amount of CO2 was infused and the fraction remaining in the lung 100 s postinfusion was measured. Pressure transmission to the lung and VT was measured at the level of the trachea. RESULT: CO2 elimination was directly proportional to the inspiratory pressure during NIPPV. At peak pressures of 22 to 34 cm H2O, CO2 clearance was greater (P<0.001) with SBP as compared with RAM. Relative to the set ventilator parameters, a substantial pressure dampening effect was documented at the lung level, which was significantly lower with RAM when compared with SBP (2.8% (0.2) versus 11.9% (1.5), P<0.0001). CO2 elimination was dependent on VT and effective despite only a small fraction of physiological VT (maximum delivered VT%: SBP 15.5 (0.7) versus RAM 6.1 (1.4), P<0.0001). CONCLUSION: NIPPV promotes CO2 elimination even at low transmitted airway pressures, but less effective with RAM as compared with SBP. CO2 elimination despite small VT suggests that NIPPV may depend on a non conventional gas-exchange mechanism. PMID- 26043418 TI - Weight-related risk perception among healthy and overweight pregnant women: a cross-sectional study. AB - OBJECTIVE: The objective of this study was to evaluate weight-related risk perception in early pregnancy and to compare this perception between women commencing pregnancy healthy weight and overweight. STUDY DESIGN: Pregnant women (n=664) aged 29+/-5 (mean+/-s.d.) years were recruited from a metropolitan teaching hospital in Australia. A self-administered questionnaire was completed at around 16 weeks of gestation. Height measured at baseline and self-reported pre-pregnancy weight were used to calculate body mass index. Cross-sectional analysis was conducted.Differences between groups were assessed using chi-squared tests for categorical variables and t-tests or Mann-Whitney U tests for continuous variables depending on distribution. RESULT: Excess gestational weight gain (GWG) during pregnancy was more important in leading to health problems for women or their child compared with pre-pregnancy weight. Personal risk perception for complications was low for all women, although overweight women had slightly higher scores than healthy-weight women (2.4+/-1.0 vs 2.9+/-1.0; P<0.001). All women perceived their risk for complications to be below that of an average pregnant woman. CONCLUSION: Women should be informed of the risk associated with their pre-pregnancy weight (in the case of maternal overweight) and excess GWG. If efforts to raise risk awareness are to result in preventative action, this information needs to be accompanied by advice and appropriate support on how to reduce risk. PMID- 26043419 TI - Facial Ulcers and Restrictive Strabismus From Delayed Periorbital Granuloma After Poly-L-Lactic Acid Injection. PMID- 26043421 TI - The prevalence of amblyopia in Germany: data from the prospective, population based Gutenberg Health Study. AB - BACKGROUND: Amblyopia is due to insufficient development of the visual system in early childhood and is a major source of lifelong impairment of visual acuity. Too little is known about the prevalence of amblyopia in Germany and the frequency of its various causes. METHODS: The Gutenberg Health Study of the University of Mainz Faculty of Medicine is an ongoing population-based, prospective, monocentric cohort study with 15 010 participants aged 35 to 74. All participants are examined for the presence of ocular, cardiovascular, neoplastic, metabolic, immunologic, and mental diseases. 3227 participants aged 35 to 44 underwent ophthalmological examination from 2007 to 2012. Amblyopia was defined as impaired visual acuity in the absence of any organic pathology capable of explaining the condition, and in the presence of a known risk factor for amblyopia. RESULTS: Amblyopia, when defined as a visual acuity less than or equal to 0.63, was present in 182 participants (5.6%, 95% confidence interval [CI] 4.9 6.5%), 120 of whom had a visual acuity less than or equal to 0.5 (3.7%, 95% CI 3.3-5.2%). A narrower definition of amblyopia requiring, in addition, an interocular difference in acuity of at least two lines yielded slightly lower prevalence figures: 5.0% (95% CI 4.2-5.8%) and 3.7% (95% CI 3.1-4.4%), respectively. The causes of amblyopia (visual acuity <= 0.63) were anisometropia (different refractive strengths of the two eyes) in 49% of participants, strabismus (a squint) in 23%, both of these factors in 17%, and visual deprivation in 2%. 3 patients (2%) had relative amblyopia due to a traumatic cataract sustained in early childhood. 7% of the participants with amblyopia had binocular amblyopia. CONCLUSION: This study yielded a prevalence figure of 5.6% for amblyopia in Germany-a higher figure than in other, comparable population based studies, which have generally yielded figures of ca. 3% for visual acuity <= 0.63. The distribution of the causes of amblyopia is similar across studies. PMID- 26043422 TI - Epidemiology of clostridium difficile infection. PMID- 26043420 TI - Hoarseness-causes and treatments. AB - BACKGROUND: Hoarseness (dysphonia) is the reason for about 1% of all consultations in primary care. It has many causes, ranging from self-limited laryngitis to malignant tumors of the vocal cords. METHODS: This review is based on literature retrieved by a selective search in PubMed employing the terms "hoarseness," "hoarse voice," and "dysphonia," on the relevant guideline of the American Academy of Otolaryngology -Head and Neck Surgery, and on Cochrane reviews. RESULTS: Hoarseness can be caused by acute (42.1%) and chronic laryngitis (9.7%), functional vocal disturbances (30%), and benign (10.7-31%) and malignant tumors (2.2-3%), as well as by neurogenic disturbances such as vocal cord paresis (2.8-8%), physiologic aging of the voice (2%), and psychogenic factors (2-2.2 %). Hoarseness is very rarely a manifestation of internal medical illness. The treatment of hoarseness has been studied in only a few randomized controlled trials, all of which were on a small scale. Voice therapy is often successful in the treatment of functional and organic vocal disturbances (level 1a evidence). Surgery on the vocal cords is indicated to treat tumors and inadequate vocal cord closure. The only entity causing hoarseness that can be treated pharmacologically is chronic laryngitis associated with gastro-esophageal reflux, which responds to treatment of the reflux disorder. The empirical treatment of hoarseness with antibiotics or corticosteroids is not recommended. CONCLUSION: Voice therapy, vocal cord surgery, and drug therapy for appropriate groups of patients with hoarseness are well documented as effective by the available evidence. In patients with risk factors, especially smokers, hoarseness should be immediately evaluated by laryngos - copy. PMID- 26043423 TI - Duodenal application is the method of choice. PMID- 26043424 TI - In reply. PMID- 26043425 TI - Characterization of DNA substrate specificities of apurinic/apyrimidinic endonucleases from Mycobacterium tuberculosis. AB - Apurinic/apyrimidinic (AP) endonucleases are key enzymes involved in the repair of abasic sites and DNA strand breaks. Pathogenic bacteria Mycobacterium tuberculosis contains two AP endonucleases: MtbXthA and MtbNfo members of the exonuclease III and endonuclease IV families, which are exemplified by Escherichia coli Xth and Nfo, respectively. It has been shown that both MtbXthA and MtbNfo contain AP endonuclease and 3'->5' exonuclease activities. However, it remains unclear whether these enzymes hold 3'-repair phosphodiesterase and nucleotide incision repair (NIR) activities. Here, we report that both mycobacterial enzymes have 3'-repair phosphodiesterase and 3'-phosphatase, and MtbNfo contains in addition a very weak NIR activity. Interestingly, depending on pH, both enzymes require different concentrations of divalent cations: 0.5mM MnCl2 at pH 7.6 and 10 mM at pH 6.5. MtbXthA requires a low ionic strength and 37 degrees C, while MtbNfo requires high ionic strength (200 mM KCl) and has a temperature optimum at 60 degrees C. Point mutation analysis showed that D180 and N182 in MtbXthA and H206 and E129 in MtbNfo are critical for enzymes activities. The steady-state kinetic parameters indicate that MtbXthA removes 3' blocking sugar-phosphate and 3'-phosphate moieties at DNA strand breaks with an extremely high efficiency (kcat/KM=440 and 1280 MUM(-1)?min(-1), respectively), while MtbNfo exhibits much lower 3'-repair activities (kcat/KM=0.26 and 0.65 MUM( 1)?min(-1), respectively). Surprisingly, both MtbXthA and MtbNfo exhibited very weak AP site cleavage activities, with kinetic parameters 100- and 300-fold lower, respectively, as compared with the results reported previously. Expression of MtbXthA and MtbNfo reduced the sensitivity of AP endonuclease-deficient E. coli xth nfo strain to methylmethanesulfonate and H2O2 to various degrees. Taken together, these data establish the DNA substrate specificity of M. tuberculosis AP endonucleases and suggest their possible role in the repair of oxidative DNA damage generated by endogenous and host- imposed factors. PMID- 26043426 TI - Rebuttal from Prof Silverman and Dr Hendrix. PMID- 26043427 TI - Association between polymorphisms at the GREM1 locus and the risk of nonsyndromic cleft lip with or without cleft palate in the Polish population. AB - BACKGROUND: The locus on chromosome 15q13.3 containing GREM1 is correlated with the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P). The aim of the present study was to find the GREM1 functional variants implicated in the aetiology of this common developmental anomaly in the Polish population. METHODS: Eight polymorphisms were genotyped in 334 NSCL/P patients and 955 controls. In addition, the GREM1 protein-coding region was sequenced in 96 NSCL/P patients. RESULTS: Significant association with a risk of oral clefts was found for 5 tested polymorphisms. The lowest p(trend) values were identified for rs16969681, rs16969816, and rs1258763 (p(trend) 4.09E-05, 3.35E-05, and 0.0002, respectively). The putative functional variant rs16969681, located in a region that has enhancer activity, was associated with a 2.6-fold lower risk for NSCL/P (odds ratio [OR] = 0.38; 95% confidence interval [CI], 0.24-0.61, p = 2.37E-05). The previously reported association of rs1258763 with NSCL/P was replicated (OR = 0.57; 95% CI, 0.44-0.73; p = 1.10E-05). For all tested GREM1 variants, no significant sex-by-genotype interaction effects were observed. The sequencing analysis did not detect any rare variants implicated in the development of oral clefts. CONCLUSION: Our results might suggest that variants influencing GREM1 expression levels, rather than variants affecting the function of the encoded protein, are significant factors in NSCL/P etiology. PMID- 26043428 TI - Solvent-Free Synthesis of Zeolite Crystals Encapsulating Gold-Palladium Nanoparticles for the Selective Oxidation of Bioethanol. AB - The conversion of bioethanol into valuable products is an important area in the conversion of biomass. We demonstrate the successful synthesis of bimetallic gold palladium (Au-Pd) nanoparticles encapsulated within S-1 zeolite crystals (AuPd@S 1) by a solvent-free strategy. This strategy allows highly efficient use of the noble metals, with more than 96 % of the gold and palladium being loaded into the final samples. Electron microscopy characterization and investigations with probe molecules confirm that the Au-Pd nanoparticles are encapsulated inside the S-1 crystals. The AuPd@S-1 catalyst is very active for the aerobic oxidation of bioethanol, giving 100 % conversion and 99 % selectivity to acetic acid. Even in the presence of 90 % water, the catalyst still gives a conversion higher than 80 % and a selectivity of 95 %. More importantly, the AuPd@S-1 catalyst exhibits excellent stability in the oxidation of bioethanol. These features are important for future practical applications of the AuPd@S-1 catalyst. PMID- 26043429 TI - Driver education and teen crashes and traffic violations in the first two years of driving in a graduated licensing system. AB - Our primary research question was whether teens obtaining their intermediate level provisional operators permit (POP) in a graduated driver licensing (GDL) environment through driver education differed in crashes and traffic violations from teens who obtained their POP by completing a supervised driving certification log without taking driver education. A descriptive epidemiological study examining a census of all teen drivers in Nebraska (151,880 teens, 48.6% girls, 51.4% boys) during an eight year period from 2003 to 2010 was conducted. The driver education cohort had significantly fewer crashes, injury or fatal crashes, violations, and alcohol-related violations than the certification log cohort in both years one and two of driving following receipt of the POP. Hierarchical logistic regression was conducted, controlling for gender, race/ethnicity, median household income, urban-rural residence, and age receiving the POP. In both year one and two of driving, teens in the certification log cohort had higher odds of a crash, injury or fatal crash, violation, or alcohol related violation. Findings support that relative to a supervised driving certification log approach, teens taking driver education are less likely to be involved in crashes or to receive a traffic violation during their first two years of driving in an intermediate stage in a graduated driver licensing system. Because teen crash and fatality rates are highest at ages 16-18, these reductions are especially meaningful. Driver education appears to make a difference in teen traffic outcomes at a time when risk is highest. PMID- 26043430 TI - Programming cancer through phase-functionalized silicon based biomaterials. AB - Applications of biomaterials in cancer therapy has been limited to drug delivery systems and markers in radiation therapy. In this article, we introduce the concept of phase-functionalization of silicon to preferentially select cancer cell populations for survival in a catalyst and additive free approach. Silicon is phase-functionalized by the interaction of ultrafast laser pulses, resulting in the formation of rare phases of SiO2 in conjunction with differing silicon crystal lattices. The degree of phase-functionalization is programmed to dictate the degree of repulsion of cancer cells. Unstable phases of silicon oxides are synthesized during phase-functionalization and remain stable at ambient conditions. This change in phase of silicon as well as formation of oxides contributes to changes in surface chemistry as well as surface energy. These material properties elicit in precise control of migration, cytoskeleton shape, direction and population. To the best of our knowledge, phase-functionalized silicon without any changes in topology or additive layers and its applications in cancer therapy has not been reported before. This unique programmable phase functionalized silicon has the potential to change current trends in cancer research and generate focus on biomaterials as cancer repelling or potentially cancer killing surfaces. PMID- 26043431 TI - The Effect of Size and Location of Tears in the Supraspinatus Tendon on Potential Tear Propagation. AB - Rotator cuff tears are a common problem in patients over the age of 50 yr. Tear propagation is a potential contributing factor to the failure of physical therapy for treating rotator cuff tears, thus requiring surgical intervention. However, the evolution of tears within the rotator cuff is not well understood yet. The objective of this study is to establish a computational model to quantify initiation of tear propagation in the supraspinatus tendon and examine the effect of tear size and location. A 3D finite element (FE) model of the supraspinatus tendon was constructed from images of a healthy cadaveric tendon. A tear of varying length was placed at six different locations within the tendon. A fiber reinforced Mooney-Rivlin material model with spatial variation in material properties along the anterior-posterior (AP) axis was utilized to obtain the stress state of the computational model under uniaxial stretch. Material parameters were calibrated by comparing computational and experimental stress strain response and used to validate the computational model. The stress state of the computational model was contrasted against the spatially varying material strength to predict the critical applied stretch at which a tear starts propagating further. It was found that maximum principal stress (as well as the strain) was localized at the tips of the tear. The computed critical stretch was significantly lower for the posterior tip of the tear than for the anterior tip suggesting a propensity to propagate posteriorly. Onset of tear propagation was strongly correlated with local material strength and stiffness in the vicinity of the tear tip. Further, presence of a stress-shielded zone along the edges of the tear was observed. This study illustrates the complex interplay between geometry and material properties of tendon up to the initiation of tear propagation. Future work will examine the evolution of tears during the propagation process as well as under more complex loading scenarios. PMID- 26043432 TI - Breath ammonia and ethanol increase in response to a high protein challenge. AB - Quantifying changes in ammonia and ethanol in blood and body fluid assays in response to food is cumbersome. We used breath analysis of ammonia, ethanol, hydrogen (an accepted standard of gut transit) and acetone to investigate gastrointestinal physiology. In 30 healthy participants, we measured each metabolite serially over 6 h in control and high protein trials. Two-way repeated measures ANOVA compared treatment (control versus intervention), change from baseline to maximum and interaction of treatment and time change. Interaction was significant for ammonia (p < 0.0001) and hydrogen (p < 0.0001). We describe the dynamic measurement of multiple metabolites in response to an oral challenge. PMID- 26043433 TI - Association of proximity and density of parks and objectively measured physical activity in the United States: A systematic review. AB - One strategy for increasing physical activity is to create and enhance access to park space. We assessed the literature on the relationship of parks and objectively measured physical activity in population-based studies in the United States (US) and identified limitations in current built environment and physical activity measurement and reporting. Five English-language scholarly databases were queried using standardized search terms. Abstracts were screened for the following inclusion criteria: 1) published between January 1990 and June 2013; 2) US-based with a sample size greater than 100 individuals; 3) included built environment measures related to parks or trails; and 4) included objectively measured physical activity as an outcome. Following initial screening for inclusion by two independent raters, articles were abstracted into a database. Of 10,949 abstracts screened, 20 articles met the inclusion criteria. Five articles reported a significant positive association between parks and physical activity. Nine studies found no association, and six studies had mixed findings. Our review found that even among studies with objectively measured physical activity, the association between access to parks and physical activity varied between studies, possibly due to heterogeneity of exposure measurement. Self-reported (vs. independently-measured) neighborhood park environment characteristics and smaller (vs. larger) buffer sizes were more predictive of physical activity. We recommend strategies for further research, employing standardized reporting and innovative study designs to better understand the relationship of parks and physical activity. PMID- 26043434 TI - Are public subsidies effective to reduce emergency care? Evidence from the PLASA study. AB - Elderly people facing dependence are exposed to the financial risk of long lasting care expenditures. This risk is high for people facing cognitive, functional and behavioral problems. In the short-term, dependent elderly people face increased non-medical care expenditures. In the long-term, they face increased medical care expenditures, which are driven by emergency care events such as: emergency hospitalization, emergency medical visits, and emergency institutionalizations. In France, providing public financial assistance has been shown to improve dependent people's access to non-medical care services. However, the impact of public financial assistance on emergency care use has not been explored yet. Our study aims at determining whether financial assistance on non medical care provision decreases the probability of emergency care rates using data of 1131 French patients diagnosed with Alzheimer's disease, collected between 2003 and 2007. Using instrumental variables to deal with the presence of a potential endogeneity bias, we find that beneficiaries of long-term care subsidies have a significantly lower rate of emergency care than non beneficiaries. Failing to control for endogeneity problems would lead to misestimate the impact of long-term care subsidies on emergency care rates. Finding that home care subsidies has a protective effect for emergency care confirmed the efficacy of this public policy tool. PMID- 26043435 TI - Recent developments in arbuscular mycorrhizal signaling. AB - Plants can establish root endosymbioses with both arbuscular mycorrhizal fungi and rhizobial bacteria to improve their nutrition. Our understanding of the molecular events underlying the establishment of these symbioses has significantly advanced in the last few years. Here I highlight major recent findings in the field of endosymbiosis signaling. Despite the identification of new signaling components and the definition, or in some cases better re definition of the molecular functions of previously known players, major questions still remain that need to be addressed. Most notably the mechanisms defining signaling specificities within either symbiosis remain unclear. PMID- 26043436 TI - Regulation of appressorium development in pathogenic fungi. AB - Many plant pathogenic fungi have the capacity to breach the intact cuticles of their plant hosts using specialised infection cells called appressoria. These cells exert physical force to rupture the plant surface, or deploy enzymes in a focused way to digest the cuticle and plant cell wall. They also provide the means by which focal secretion of effectors occurs at the point of plant infection. Development of appressoria is linked to re-modelling of the actin cytoskeleton, mediated by septin GTPases, and rapid cell wall differentiation. These processes are regulated by perception of plant cell surface components, and starvation stress, but also linked to cell cycle checkpoints that control the overall progression of infection-related development. PMID- 26043437 TI - Quantifying the complexity of human colonic pressure signals using an entropy measure. AB - Studying the complexity of human colonic pressure signals is important in understanding this intricate, evolved, dynamic system. This article presents a method for quantifying the complexity of colonic pressure signals using an entropy measure. As a self-adaptive non-stationary signal analysis algorithm, empirical mode decomposition can decompose a complex pressure signal into a set of intrinsic mode functions (IMFs). Considering that IMF2, IMF3, and IMF4 represent crucial characteristics of colonic motility, a new signal was reconstructed with these three signals. Then, the time entropy (TE), power spectral entropy (PSE), and approximate entropy (AE) of the reconstructed signal were calculated. For subjects with constipation and healthy individuals, experimental results showed that the entropies of reconstructed signals between these two classes were distinguishable. Moreover, the TE, PSE, and AE can be extracted as features for further subject classification. PMID- 26043438 TI - Antihistamine from Tragia involucrata L. leaves. AB - BACKGROUND: Synthetic antihistamine drugs cause various adverse effects to overcome these problems with natural phytomedicine or phytoconstituents. METHODS: Tragia involucrata leaves were extracted with soxhlet apparatus and fractionated with column chromatography the homogenized fractions were monitored with thin layer chromatography (TLC) and characterized by using UV-visible, FT-IR, 1H NMR, 13C NMR and MS spectral studies. Isolated compounds were screened their antihistamine activity on ileum preparation, bronchoconstriction and triple response on histamine-induced guinea pig. RESULTS: Antihistamine 5-hydroxy-1 methylpiperidin-2-one has been isolated and characterized from the leaves of Tragia involucrata L. A promising muscle relaxant, bronchorelaxant and anti allergic effect of 5-hydroxy-1-methylpiperidin-2-one was observed in histamine induced guinea pig and found to be 55.54+/-2.78% protection at the dose level of 12.5 mg/kg in bronchoconstriction effect and 49.05+/-2.45% protection in triple response. These findings were confirmed by in silico molecular docking also against histamine H1 receptor compared with chlorpheniramine maleate and mepyramine. This shows that the 5-hydroxy-1-methylpiperidine-2-one possess good inhibitory effect on histamine-induced guinea pig. The muscle relaxant, bronchodilating and anti-allergic potency of 5-hydroxy-1-methylpiperidin-2-one has been discussed in context with its probable profile as an anti-asthmatic agent from T. involucrata L. leaves. CONCLUSIONS: We can conclude that isolated 5 hydroxy-1-methylpiperidin-2-one from T. involucrata L. has potent antihistamine agent on histamine-induced guinea pig. PMID- 26043439 TI - The balance of clinician and patient input into treatment decision-making in older women with operable breast cancer. AB - OBJECTIVE: Primary endocrine therapy (PET) is an alternative to surgery for oestrogen receptor positive operable breast cancer in some older women. However the decision to offer PET involves complex trade-offs and is influenced by both patient choice and healthcare professional (HCP) preference. This study aimed to compare the views of patients and HCPs about this decision and explore decision making (DM) preferences and whether these are taken into account during consultations. METHODS: This multicentre, UK, mixed methods study had three components: (a) questionnaires to older women undergoing counseling about breast cancer treatment options which assessed their DM preferences and realities; (b) qualitative interviews with older women with operable breast cancer offered a choice of either surgery or PET and (c) qualitative interviews with HCPs (both of which focused on DM preferences in this setting). RESULTS: Thirty-three patients and 34 HCPs were interviewed. A range of opinions about patient involvement in DM were identified. Patients indicated varying preferences for DM involvement which were variably taken into account by HCPs. These qualitative findings were broadly supported by the questionnaire results. Most patients (536/729; 73.5%) achieved their preferred DM style; however, the remainder felt that their DM preferences had not been taken into consideration. CONCLUSIONS: These results suggest that whilst many older women achieve their desired level of DM engagement, some do not, raising the possibility that they may be making choices which are not concordant with their treatment preferences. PMID- 26043440 TI - Structure Modification Function of g-C3 N4 for Al2 O3 in the In Situ Hydrothermal Process for Enhanced Photocatalytic Activity. AB - Heterojunctions of g-C3 N4 /Al2 O3 (g-C3 N4 =graphitic carbon nitride) are constructed by an in situ one-pot hydrothermal route based on the development of photoactive gamma-Al2 O3 semiconductor with a mesoporous structure and a high surface area (188 m(2) g(-1) ) acting as electron acceptor. A structure modification function of g-C3 N4 for Al2 O3 in the hydrothermal process is found, which can be attributed to the coordination between unoccupied orbitals of the Al ions and lone-pair electrons of the N atoms. The as-synthesized heterojunctions exhibit much higher photocatalytic activity than pure g-C3 N4 . The hydrogen generation rate and the reaction rate constant for the degradation of methyl orange over 50 % g-C3 N4 /Al2 O3 under visible-light irradiation (lambda>420 nm) are 2.5 and 7.3 times, respectively, higher than those over pristine g-C3 N4 . The enhanced activity of the heterojunctions is attributed to their large specific surface areas, their close contact, and the high interfacial areas between the components as well as their excellent adsorption performance, and efficient charge transfer ability. PMID- 26043441 TI - Prevalence, Risk Factors, and Visual Features of Undiagnosed Glaucoma: The Singapore Epidemiology of Eye Diseases Study. AB - IMPORTANCE: Glaucoma can remain asymptomatic until a severe stage, resulting in a high prevalence of undiagnosed glaucoma worldwide. Asia accounts for 60% of the world's total glaucoma cases. To our knowledge, no epidemiological studies have assessed ethnic differences in undiagnosed glaucoma among various Asian subgroups. OBJECTIVE: To determine the prevalence of, risk factors for, and visual features of undiagnosed primary glaucoma in a multiethnic Asian population. DESIGN, SETTING, AND PARTICIPANTS: The Singapore Epidemiology of Eye Diseases Study is a population-based trial in which 3353 Chinese (2009-2011), 3280 Malays (2004-2006), and 3400 Indians (2007-2009) aged 40 to 80 years were invited for an eye examination, including visual field assessment, to establish glaucoma diagnosis. Participants with undiagnosed glaucoma (ie, answering no to whether they previously had been told by a physician that they had glaucoma, not using glaucoma medication, or not having undergone glaucoma surgery) were identified. MAIN OUTCOMES AND MEASURES: Prevalence of, risk factors for, and visual features of undiagnosed glaucoma. RESULTS: Of 272 participants with primary glaucoma, 196 (72.1%) were previously undiagnosed. The overall prevalence of undiagnosed primary glaucoma was highest among Malays (2.65%; 95% CI, 2.10% 3.31%), followed by Chinese (1.51%; 95% CI, 1.13%-2.01%) and Indians (0.97%; 95% CI, 0.64%-1.43%). In multivariable analysis, variables associated with higher risk of undiagnosed glaucoma were younger age (odds ratio [OR], 1.04; 95% CI, 1.00-1.09; P = .04), Malay ethnicity (OR, 3.65; 95% CI, 1.31-10.13; P = .01), presence of primary open-angle glaucoma (OR, 3.82; 95% CI, 1.60-9.14; P = .003), absence of yearly eyeglass checks (OR, 9.29; 95% CI, 3.43-25.21; P < .001), and lack of cataract surgery (OR, 4.19; 95% CI, 1.68-10.48; P < .001). No patients were blind in both eyes. A mean (SD) of 4.1% (2.8%) (n = 8) of the newly diagnosed patients were blind in 1 eye, and a mean (SD) of 56.0% (7.2%) (n = 102) had noteworthy visual field damage (mean deviation worse than -6 dB) in at least 1 eye. CONCLUSIONS AND RELEVANCE: The prevalence of undiagnosed primary glaucoma varied among ethnic populations in whom a mean (SD) of 49.0% (14.0%) (n = 24) of affected individuals 50 to 59 years old already had clinically significant visual field loss. Such data may assist policymakers in implementing cost-effective public health interventions to reduce the effect of blindness associated with undiagnosed glaucoma. PMID- 26043442 TI - In reference to "Redesigning an inpatient pediatric service using lean to improve throughput efficiency". PMID- 26043443 TI - C-N and N-H Bond Metathesis Reactions Mediated by Carbon Dioxide. AB - Herein, we report CO2 -mediated metathesis reactions between amines and DMF to synthesize formamides. More than 20 amines, including primary, secondary, aromatic, and heterocyclic amines, diamines, and amino acids, are converted to the corresponding formamides with good-to-excellent conversions and selectivities under mild conditions. This strategy employs CO2 as a mediator to activate the amine under metal-free conditions. The experimental data and in situ NMR and attenuated total reflectance IR spectroscopy measurements support the formation of the N-carbamic acid as an intermediate through the weak acid-base interaction between CO2 and the amine. The metathesis reaction is driven by the formation of a stable carbamate, and a reaction mechanism is proposed. PMID- 26043444 TI - Effect of Capparis spinosa extract on sutural ossification: A stereological study. AB - OBJECTIVE: To investigate the effects of systemically administered Capparis spinosa extract (CSE) on expanded sutures in rats via three dimensionally morphometric method (stereological method). MATERIALS AND METHODS: Thirty-two Wistar rats were used. Subjects were divided into four groups, each with eight rats. Orthopaedic expansion force was applied for 5 days to maxillary incisors by attaching springs. Control-1 and CSE-1 waited 1 week for consolidation, and Control-2 and CSE-2 waited 2 weeks for consolidation. After the consolidation period, the subjects were sacrificed. Stereological examination was performed to determine the volume and area of new bone, connective tissue, and capillaries. RESULTS: New bone area, new bone volume, connective tissue space, and connective tissue volume were statistically different in CSE-1 compared to Control-1. But there were no statistically difference between CSE-2 and Control_2. In terms of the volume of blood vessels and vascular area, there were no statistically significant differences when comparing Groups CSE-1 and Control-1 or CSE-2 and Control-2. CONCLUSION: Systemic use of CSE accelerated fastened osteoblastic activity in the early period. PMID- 26043445 TI - Porphyromonas gingivalis promotes the cell cycle and inflammatory cytokine production in periodontal ligament fibroblasts. AB - OBJECTIVE: The infection of Porphyromonas gingivalis (P. gingivalis) modulates host immune-inflammatory responses and destructs homeostasis of normal cell cycle, thereby leading to periodontal tissue destruction. Human periodontal ligament fibroblasts (PDLFs) are key players in the host immune responses and periodontal tissue regeneration. The aim of the present study was to discover the effects of P. gingivalis infection on the cell cycle and inflammatory cytokine production in PDLFs. DESIGN: P. gingivalis infection model into PDLFs was established. The effect of P. gingivalis on the cell proliferation and cell cycle were detected by MTT and flow cytometry. The p21, cyclin D1 and cyclin E mRNA expression, p21 protein expression, as well as IL-6 and IL-8 protein levels were analyzed by RT-qPCR, Western blot and ELISA, respectively. RESULTS: P. gingivalis promoted proliferation and G1 phase of PDLFs. G1 phase promotion was associated with the decreased level of p21 and the up-regulation of cyclin D1 at 6h, and with the increased level of cyclin E at 12h. Simultaneously, the immune inflammatory response of PDLFs was initiated by P. gingivalis during the initial stage of infection, including the increased expressions of IL-6 and IL-8. CONCLUSION: We confirmed that the infection of P. gingivalis could modulate the expression of PDLF genes, which control cell cycle and inflammatory cytokine production. Thus, P. gingivalis may contribute to the proliferation and inflammation of periodontal tissue. PMID- 26043447 TI - Resident rounds part III: case report: a papulo- nodular eruption with systemic signs and symptoms. AB - This is a typical presentation of erythema nodosum leprosum in a patient with lepromatous leprosy who recently migrated from Micronesia. The clinical presentation, pathology findings, pathogenesis, and therapeutic options are reviewed here. PMID- 26043446 TI - Salivary amylase - The enzyme of unspecialized euryphagous animals. AB - INTRODUCTION: Alpha-amylase (EC 3.2.1.1) is the most abundant enzyme in the saliva of man and of several vertebrates. In humans, salivary amylase is mainly formed in the parotid gland; its activity is of high inter-individual and intra individual variability. The physiological functions of alpha-amylase have not yet been explored completely. It is well known that the enzyme cleaves the alpha (1,4)-glycosidic bonds of polysaccharides. Furthermore it plays an important role in initial bioadhesion in man, facilitating carbohydrate metabolism and bacterial adherence at the tooth surface and therewith caries initiation. Nevertheless, it is still a matter of interest why humans have such high amounts of salivary amylase. OBJECTIVE: The review presents an evolutionary approach by considering salivary amylase in the animal kingdom with special focus on mammalians divided into the three main nutritional types carnivores, herbivores, and omnivores; it was postulated that for most mammalian animals salivary alpha-amylase is essential. RESULTS: The enzyme has been detected in saliva of some herbivores and many omnivorous animals, but not in pure carnivores. Focusing on ruminants, negligible levels or an absence of alpha-amylase was determined. Presence and activity probably differ depending on the species-specific diet. Animals feeding on unripe fruits, seeds, roots and bulbs exhibit higher activity of salivary alpha-amylase than species consuming ripe fruits, insects, and vertebrates. CONCLUSION: In contrast to carnivores and most herbivores, omnivores have considerable amounts of amylase in their saliva. Though, the starch-digesting enzyme has been investigated well, the physiological function of amylase in saliva has not yet been explored completely. It can be hypothesized that nutritional habits affect expression of enzymes in the saliva of animals. It has to be verified, whether alpha-amylase is genetically or epigenetically determined. As a consequence of the development of agriculture, and following dietary changes, amylase can be recognized as a nutritional and evolutionary marker. Interdisciplinary evolutionary research might offer new perspectives for preventive dentistry. PMID- 26043449 TI - Hull House: a safe haven. PMID- 26043451 TI - The Jonathan E. Rhoads Lecture. Books and men, redux. PMID- 26043450 TI - Philosophy and dietetics in the Hippocratic on Regimen. A delicate balance of health. PMID- 26043452 TI - Normative consistency. PMID- 26043453 TI - Happiness and meaning: a plurality of values rather than a conflict of norms. PMID- 26043454 TI - Conflict of values: a decision view. PMID- 26043455 TI - Lou Pollak: The road to Brown v. Board of Education and beyond. PMID- 26043456 TI - Evelyn Byrd Harrison: 5 June 1920 - 3 November 2012. PMID- 26043457 TI - Sir Andrew Fielding Huxley: 22 November 1917 - 30 May 2012. PMID- 26043458 TI - Louis H. Pollak: 7 December 1922 - 8 May 2012. PMID- 26043459 TI - Robin M. Williams, Jr.: 11 October 1914 - 3 June 2006. PMID- 26043460 TI - [The Library of the Franciscan pharmacy in Jerusalem]. AB - The inventory of the pharmacy of Franciscan monks in Jerusalem contained the description of the eighty books they kept in their Library. Most of them could be identified. A great number were of Italian origin, 45 were redacted in Latin, and 32 in an Italian language. 27 dealt with pharmacy, 18 with medicine and 17 were encyclopaedias or hygiene books. PMID- 26043461 TI - [A series of radio broadcasts of the French School Radio devoted to Pharmacy in 1966]. AB - In December 1966, the French School Radio devoted three of its emissions to Pharmacy. Found in the archives of the National Center for Educational Documentation (CNDP), those short programs resumed life. PMID- 26043462 TI - [The engraving of pharmacopoeia between XVIth-XVIIIth Century]. AB - The pharmacopea is mainly known like a book containing descriptions of drugs and preparations of medicines. During the XVIth-XVIIIth centuries, some of these books were illustrated with engraving frontispieces. This study shows the meaning of these pictures, the composition and the artists and the messages which are incorporated. PMID- 26043463 TI - [Remy Willemet (1735-1807), naturalist, professor of natural history and chairman of the botanical garden of Nancy]. AB - Remy Willemet is above all a local botanist whose first work was selected by the academy of Nancy in 1766. His notoriety began when another work with Jean Francois Coste was chosen by the academy of Lyon ten years later. He published then in many papers and was elected in numerous academies and scientific societies. During the Revolution, he was a professor of the Ecole centrale de la Meurthe and of the Societe de sante, and he became the chairman of the botanical garden. Willemet wrote some botanical books. Today, what is the memory of his researchs and papers? Fairly few things because he never undertook botanical travels in order to discover and compare pharmaceutical plants. However, Willemetia was the name used to denominate some species and honour his family. His name was also engraved on the wall of some university buidings and it was chosen some years ago to entitle a botanical paper in Lorraine. PMID- 26043464 TI - [Louis-Marie Rousseau and the "Chocolat rationnel des pharmaciens francais" (Rational Chocolate of French pharmacists)]. AB - In 1883, the chemist Louis-Marie Rousseau (1849-1930) creats the "Compagnie hygienique francaise" (French Hygienic Company). The company manufactures and sells the "Poudre de viande Rousseau" (Rousseau meat powder) and the "Chocolat Rousseau" (Rousseau Chocolate) by methods developed and patented by the pharmacist. Ten years after a successful collaboration, L.-M. Rousseau separates from his associates and founds the "Chocolaterie speciale d'Ermont" (Special Chocolate factory of Ermont) in the village of Ermont near Paris. Here is manufactured the "Chocolat Rationnel des pharmaciens francais" (Rational Chocolate of French pharmacists), hygienic chocolate sold only in pharmacies. The factory is also a pharmaceutical laboratory where is extracted theobromine from waste vegetable substances of cocoa. It then produces the "Theobromine Rousseau cristallisee" (crystallized Rousseau's Theobromine) sold as tablets, then the "Theosol" that will be commercialized until the middle of 1930s. PMID- 26043465 TI - [Theophile-Jules Pelouze (1807-1867) was one of the French pharmacists who has the most contributed to the evolution of the organic chemisty in the first half of the 19th century]. AB - Through some examples of his works, realized between 1833 and 1845 (studies on the tannin, the reaction of etherification, and on the nature of the chemical function of the glycerin), this article tries to bring to light his scientific approach. This one is not only based on the immediate analysis and the elementary analysis, but also on the study of characteristic chemical reactions, which are going to give him information onto the chemical nature and the constitution of the molecules which he studies. This approach will lead him finally to use these reactions not only in an analytical purpose but also in a purpose of synthesis. PMID- 26043466 TI - [The professor Jacques Etienne Berard (1789-1869)]. AB - In the Languedoc region, chemist J.E. Berard was a key character XVIIIth century. First Professor of toxicology in Montpellier, pioneer in the fields of chemical and pharmaceutical engineering in France, he became Managing Director of la Paille, a manufacturing site founded by J.A. Chaptal in 1782. He was among youngest members of the Arcueil Society, chaired by the famous scholar, Berthollet. PMID- 26043467 TI - [Louis Vialleton (1859-1929) was the first Professor of Histology in the Faculty of medicine of Montpellier]. AB - Dean for few years, he mainly focused his research on a precise criticism of transformism, which began to represent the common explanation of the emergence of life and species. For him, no classical argument in favour of this theory could be retained when considering Morphology as a complete association of structure and function in the whole animal. Beyond some aspects of this criticism related to his time, Vialleton transcends them by his conception of Morphology as an incarnated "platonician idea", that inserts him in the fliation of Montpellier vitalism. PMID- 26043468 TI - Good ideas sorely needed on OSHA's PELs. PMID- 26043469 TI - Professional trust should be earned. PMID- 26043470 TI - Key considerations for emergency equipment. PMID- 26043471 TI - Working with a hazardous substance: one industry's workplace safety success. PMID- 26043472 TI - How technology megatrends are shaping the future of safety, health, and environmental monitoring. AB - The Safety, Health and Environmental professional will soon be able to choose from a wider number of solutions that incorporate the latest developments in electronics, cellular and wireless communication, sensors, and software, all of which are driven by and are essential components of three "megatrends"--IoT, Big Data, and Social Networking. This will fundamentally alter the way in which we go about collecting information for risk assessment, exposure assessment, and thus how we implement better and more cost-effective solutions for protecting workers' lives and well-being. The more we become aware of these trends and developments, the better we will be able to integrate them into our sampling strategies and analysis methods, which creates greater value from our daily work as safety and health professionals. PMID- 26043473 TI - Combustible dust vacuums save lives and property. PMID- 26043474 TI - Be prepared for disasters. PMID- 26043475 TI - The role of training in your disaster preparedness plan. PMID- 26043476 TI - Engage employees in dusting off safety plans and procedures. PMID- 26043477 TI - Common MSDS-to-SDS conversion questions. PMID- 26043478 TI - How portable are your safety efforts? PMID- 26043479 TI - Four-dimensional leadership. PMID- 26043480 TI - Bored? Not with our parallel universes. PMID- 26043481 TI - Giving back. Student who conquered obstacles shares her benefactor's commitment. PMID- 26043482 TI - This surgeon was 'born to be on the stage'. PMID- 26043483 TI - Milestone. 50 years Alaska Regional Hospital. PMID- 26043484 TI - 5 ways physicians inadvertently violate HIPAA. PMID- 26043485 TI - Alaska unit assists wounded, ill, injured soldiers with difficult adjustments after life's 'curveballs'. PMID- 26043486 TI - Congenital toxoplasmosis presenting with fetal atrial flutter after maternal ingestion of infected moose meat. AB - Consumption of undercooked game meat during pregnancy is considered a risk factor for congenital toxoplasmosis, but cases definitively linking ingestion of infected meat to clinical disease are lacking. We report a confirmed case of congenital toxoplasmosis identified because of atrial flutter in the fetus and linked to maternal consumption of Toxoplasma gondii PCR-positive moose meat. PMID- 26043487 TI - Rabies post-exposure management. Current issues for Alaskan travelers to Asia. PMID- 26043488 TI - Of rock docs, frequent fliers and marijuana. PMID- 26043489 TI - Pot or not? PMID- 26043490 TI - Upbeat for 'down there' awareness. PMID- 26043491 TI - A wing & a care. Flying and doctoring: a blissful marriage for Kenai pediatrician. PMID- 26043492 TI - UAA lab is 'Amazon of influenza data'. PMID- 26043493 TI - Avoid the social networks. A mobile communication platform should provide a secure, efficient workflow. PMID- 26043494 TI - Current & future medical costs of childhood obesity in Alaska. AB - This study examines the medical costs of childhood obesity in Alaska, today and in the future. We estimate that 15.2 percent of those ages 2 to 19 in Alaska are obese. Using parameters from published reports and studies, we estimate that the total excess medical costs due to obesity for both adults and children in Alaska in 2012 were $226 million, with medical costs of obese children and adolescents accounting for about $7 million of that total. And those medical costs will get much higher over time, as today's children transition into adulthood. Aside from the 15.2 percent currently obese, another estimated 20 percent of children who aren't currently obese will become obese as adults, if current national patterns continue. We estimate that the 20-year medical costs--discounted to present value -of obesity among the current cohort of Alaska children and adolescents will be $624 million in today's dollars. But those future costs could be decreased if Alaskans found ways to reduce obesity. We consider how reducing obesity in several ways could reduce future medical costs: reducing current rates of childhood obesity, rates of obese children who become obese adults, or rates of non-obese children and adolescents who become obese adults. We undertake modest reductions to showcase the potential cost savings associated with each of these channels. Clearly the financial savings are a direct function of the obesity reductions and therefore the magnitude of the realized savings will vary accordingly. Also keep in mind that these figures are only for the current cohort of children and adolescents; over time more generations of Alaskans will grow from children into adults, repeating the same cycle unless rates of obesity decline. And finally, remember that medical costs are only part of the broader range of social and economic costs obesity creates. PMID- 26043495 TI - Considering collection actions under new IRS regulations. PMID- 26043496 TI - Hiring revenue cycle staff with a service mind-set. PMID- 26043497 TI - The top 20 coding changes for ICD-10. Prepare now for the upcoming ICD-10 coding conversion. PMID- 26043498 TI - PrEP works. PMID- 26043499 TI - The trimer transformed. PMID- 26043500 TI - Opening the envelope. PMID- 26043501 TI - Neuroimaging and clinical characterization of Sotos syndrome. AB - Sotos syndrome is a well-known overgrowth syndrome characterized by excessive growth during childhood, macrocephaly, distinctive facial appearance and learning disability. This disorder is caused by mutations or deletions in NSD1 gene. The aim of this study is to examine the relationship between the neuroimaging and clinical features of children with Sotos syndrome. Six Turkish children with Sotos syndrome were followed up about 3-7 years. The diagnosis was confirmed with molecular genetic analysis. We identified the pathogenic NSD1 mutation including three novel in all patients. All the patients had a characteristic facial gestalt of Sotos syndrome consisting of triangular face with prominent forehead, frontoparietal sparseness of hair and small nose. However, the degree of psychomotor and intellectual development was variable. Severe learning defect and speech delay were remarkable in two patients. The neuroimaging analysis showed abnormalities in four of six patients including bilateral large ventricles, thinning of the corpus callosum and persistent cavum septum pellucidum et vergae. Typical craniofacial appearance is the primary finding for the diagnosis of the disease even in the infantile period. However, the degree of psychomotor and intellectual development is very variable and does not correlate with the neuroimaging findings. PMID- 26043502 TI - Micronucleus assay as a biomarker for chromosome malsegregation in young mothers with Down syndrome children. AB - The aim of the present study is to test the susceptibility of chromosome 21 malsegregation in young mothers of Down syndrome children using combined micronucleus (MN) assay and FISH analysis. The present study included 62 Egyptian young mothers (age < 30 y) who were divided into 22 mothers of DS offspring and 40 age matched controls. All subjects were subjected to chromosomal analysis, micronucleus assay, and FISH analysis. High statistical significant difference was found between mothers of Down syndrome (MDS) and the controls in the MN percentage (P=0.034). Also there was high statistical significant difference between MDS and the controls in the percentage of positive malsegregation (P =0.0001). The specificity of combined MN% with FISH was 90%, while the sensitivity was 63.6%. Combined MN-FISH test is highly specific but moderately sensitive in assessing the risk of having children with DS in young mothers. PMID- 26043503 TI - A novel mutation in the FRAS1 gene in a patient with Fraser syndrome. AB - Fraser Syndrome (FS) is a rare disease with autosomal recessive inheritance characterized by cryptophthalmus, cutaneous syndactyly, laryngeal and urogenital anomalies. Mutations in the genes FRAS1 and FREM2 encoding components of a protein complex of the extracellular matrix, and recently also mutations in GRIP1 have been found to be causative for FS. We present here molecular and clinical findings of a patient with FS who was found to have a novel homozygous frameshift mutation c.9739delA, p.(T3247Pfs*44) in exon 63 of FRAS1 gene. Further testing confirmed the heterozygous carrier status of parents. PMID- 26043504 TI - A fertile patient with 45X/47XXX mosaicism. AB - Turner syndrome (TS) is a sex chromosome abnormality with a frequency of 1/2,000 3,000 among female live births. Characteristic findings are short stature and gonadal dysgenesis. Short and webbed neck, low posterior hairline, broad chest, widespread nipples, cubitus valgus, short 4th and 5th metacarpals, multiple pigmented nevi, primary amenorrhea, lack of secondary sexual characteristics, cardiovascular and renal anomalies are the most common presentations. Most of the cases are infertile. Spontaneous pregnancy is unusual and the risk for congenital anomaly, spontaneous abortion, stillbirth and aneuploidy is increased. Fifty percent of the patients have classical monosomy X (45,X). However mosaicism of 45,X/47,XXX is rare and accounts for 1.7% of the TS cases. Some cases may not reflect the characteristic phenotype. Some cases with normal height, normal menstrual cyclus and fertility have been defined before. The case we present herein is a 26 years old woman who was admitted to our clinic due to recurrent pregnancy loss. In her medical history she had type 1 diabetes mellitus and endometrium cancer, in her family history her mother had recurrent pregnancy loss. The patient's first, third, fourth, fifth and sixth pregnancies had resulted in spontaneous abortions in the first trimester. She had a healthy daughter with 46,XX karyotype from her second pregnancy. A 45,X[8]/47,XXX[12] karyotype was detected by conventional cytogenetic analysis of the patient who did not have dysmorphic findings. The mosaicism was confirmed by FISH analysis with CEP X probe. Of the 100 cells evaluated, 65 of them had 3 signals of X chromosome while 35 had 1 signal. We present the case because of its scarcity in the literature. PMID- 26043505 TI - Optic disc drusen mimicking papilledema in an infant with Joubert syndrome. AB - Joubert Syndrome is a rare autosomal recessive disorder characterized by absence or underdevelopment of the cerebellar vermis. Various ocular and oculomotor findings are frequently seen in cases with Joubert Syndrome. However, only three adolescent patients with Joubert Syndrome were diagnosed with optic disc drusen. Here we present an infant case of Joubert Syndrome referred with papilledema and diagnosed with optic disc drusen. PMID- 26043506 TI - A rare mutation in EIF2B4 gene in an epileptic child with vanishing white matter disease: a case report. AB - A 12-month old boy presented with intractable seizures present since 3-month of age. He had, previously, been admitted numerous times to the pediatric emergency room for intractable and prolonged seizures during the course of his disease. Differential diagnosis was made to exclude several inborn metabolic disorders, including vitamin B6 deficiency, biotinidase deficiency and nonketotic hyperglycinemia. Although the initial brain MRI revealed a mild cerebral and cerebellar white matter involvement, follow-up images showed diffuse cerebral and cerebellar white matter dysmyelination, progressive rarefaction and cystic degeneration. A genetic analysis was performed for vanishing white matter (VWM) disease and a homozygote c. 1091G>A mutation was detected at the EIF2B4 gene. This case emphasizes the fact that VWM disease may present with refractory seizures since early infancy. PMID- 26043507 TI - A familial case of Coffin-Lowry syndrome caused by RPS6KA3 C.898C>T mutation associated with multiple abnormal brain imaging findings. AB - Coffin-Lowry syndrome (CLS) is a rare X linked mental retardation syndrome characterised by severe psychomotor and growth retardation, distinct facial phenotype, and progressive skeletal malformations. It is caused by mutations in the RPS6KA3 gene located at Xp22.2. In this report we describe a family with CLS consists of three affected males, and two affected females, arising from c.898C>T mutation in RPS6KA3 gene. A 6 year-old, and a 3 year-old boy both had distinct clinical features of Coffin-Lowry syndrome; severe mental and motor retardation, microcephaly, prominent forehead, hypertelorism, large mouth, large ears, large soft hands, puffy tapered fingers, and pectus carinatum. In addition, they had multiple abnormal brain MRI findings. Other siblings presented with a mild and variable phenotype. PMID- 26043508 TI - The deletion 22q13 syndrome: a new case. AB - The deletion 22q13.3 syndrome (Phelan-McDermid syndrome) is a chromosome microdeletion syndrome characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Behavior is autisticlike with decreased perception of pain and habitual chewing or mouthing. The loss of 22q13.3 can result from simple deletion, translocation, ring chromosome formation and less common structural changes affecting the long arm of chromosome 22, specifically the region containing the SHANK3 gene. The present case was referred at the age of 8 months because of delayed psychomotor development, hypotonia and autistic features. Clinical examination showed a small forehead, long eyelashes, epicanthal folds and lowset ears, large and broad hands and feet with short terminal phalanges. He had no eye contact and could not sit without support. PMID- 26043509 TI - Thanatophoric dysplasia type 1 with cloverleaf skull in a dichorionic twin. AB - Here is reported for the first time, a case of thanatophoric dysplasia type 1 with cloverleaf skull in a (Mexican) dichorionic female twin. The patient's main clinical and radiographic findings included severe limb shortening, narrow thorax shape; short ribs, marked platyspondyly, curved short femurs, and a cloverleaf skull. The female twin sib had normal growth parameters and phenotypic appearance. According to the literature, cloverleaf skull in thanatophoric dysplasia type 1 is rare, even more so in dichorionic twins. Moreover, the present observation confirms that thanatophoric dysplasia type 1 patients may show phenotypic heterogeneity related to cloverleaf skull and other congenital anomalies. Therefore, a careful family history along with clinical, radiological, and molecular investigations is suggested, in order to achieve an accurate parental counseling for thanatophoric dysplasia. PMID- 26043510 TI - 22q11.2 syndrome due to maternal translocation t(18;22) (pl1.2;q11.2). AB - 22q11.2 deletion syndrome is a pattern of malformations resulting from abnormalities during cephalic neural crest migration and during the development of the third and fourth branchial arch. It is also known as DiGeorge syndrome, as it is most often associated with a de novo 3 Mb hemizygous 22q11.2 deletion. The recognition of similarities and phenotypic overlap between DiGeorge syndrome and other disorders associated with genetic defects in 22q11 has led to an expanded description of the phenotypic features of this syndrome. Indeed, the extent of this phenotypic variability can often make it difficult to accurately diagnose DiGeorge syndrome. Tertiary monosomy resulting from the 3:1 segregation of the respective chromosomal segments of the chromosomes involved in a balanced translocation in meiosis is rarely reported in the literature. In this report, we present a female infant with dysmorphic facial features, microcephaly, a cleft palate, unilateral membranous choanal atresia, convulsions, hypocalcemia, semilobar holoporencephaly and echocardiographic abnormalities. To the best of our knowledge, this is the first description of a newborn displaying both DiGeorge syndrome and deletion 18p syndromes. PMID- 26043511 TI - Concomitant omphalocele, anencephaly and arthrogryposis associated with trisomy 18. PMID- 26043512 TI - Iniencephaly: a case with survival of after neonatal period. PMID- 26043513 TI - Bardet-Biedl syndrome in a preterm newborn. PMID- 26043514 TI - A case with rare type of congenital disorder of glycosylation: PGM1-CDG. PMID- 26043515 TI - Mutational analysis of the galactose-1-phosphate uridyltransferase (GALT) gene in southeast part of Turkey: a regional report. PMID- 26043516 TI - Neonatal Marfan syndrome with angle-closure glaucoma, tricuspid and mitral insufficiency. PMID- 26043517 TI - The academic health center in a disrupted world. PMID- 26043518 TI - The $6 million physician. A history of robotics making surgeons better, stronger, faster. PMID- 26043519 TI - 23andWe. How can doctors decode direct-to-consumer genetic testing? PMID- 26043520 TI - Claude Bernard. A failed playwright. PMID- 26043521 TI - Breaking the silence. PMID- 26043522 TI - Cowboy. PMID- 26043523 TI - The Doctor Jim health plan. PMID- 26043525 TI - Re "How postoperative respiratory distress conspired with friendly fire to kill 'Stonewall' Jackson". PMID- 26043526 TI - [Diagnosing frailty to delay onset of dependency ]. PMID- 26043527 TI - [Public Health Administration's preliminary report on elderly's clinical paths]. PMID- 26043528 TI - [To coordinate medical and non-medical time spent with hospitalized patients]. PMID- 26043529 TI - [State of the art in health professions]. PMID- 26043530 TI - [End-of-Life legislation modification expected on December]. PMID- 26043531 TI - [Developing a culture of health and prevention for adolescents]. PMID- 26043532 TI - [Open letter for nursing profession maintenance]. PMID- 26043533 TI - [Analyzing end of life conditions for hospital-based home cared patients]. PMID- 26043534 TI - [Improving wound management with telemedicine]. PMID- 26043535 TI - [Getting familiarized with advance directives]. PMID- 26043536 TI - [New tools to screen and improve COPD management]. PMID- 26043537 TI - [Social factors reinforce obesity risks]. PMID- 26043538 TI - [Health promotion in public politics]. PMID- 26043539 TI - [Family carers, invisible players]. AB - The term "carer" is becoming increasingly familiar in the sectors of assistance and nursing care. Referring to the people who look after a sick, disabled or dependent family member, it started to be used by the public authorities in the 2000s and today is particularly pertinent in the light of the bill relating to the adaptation of society to ageing. However, it is ultimately a phenomenon which has always existed in all societies: solidarity between family members. PMID- 26043540 TI - [Coordination for a successful return home]. AB - The organisation of the return home of a dependent person is an important stage in their care. Good coordination between the different healthcare and social professionals enable their needs to be assessed in order for adapted solutions to be offered. In this global approach, the teams take into account not only the patient in their living environment but also their family carer. PMID- 26043541 TI - [The triangulation of help relationships, decryption and challenges]. AB - Situations involving people struggling with their day-to-day living activities, family carers, professionals and many other players are complex. Each is singular, evolves, and is sometimes difficult to decipher. While supporting a family member can be a wonderful human adventure, some situations generate extreme suffering. PMID- 26043542 TI - [Identifying and assessing the family carer's support needs]. AB - Taking the example of a nursing situation, a nurse shares with us the clinical approach taken by the nursing teams caring for a dependent person helped by a family member. While the patient is at the centre of the approach, the family carer also benefits from the attention of the nurses. The Zarit Burden Interview is an effective toolfor identifying and assessing the carer's needs. PMID- 26043543 TI - [Respite solutions for family carers]. AB - The platforms for respite care and support for carers are recent developments. They enable support to be extended to the family members and not just the patients themselves. These services are provided by daycare centres which, through their missions, already offer a form of respite care to families supporting an elderly person at home in the process of losing their autonomy, often as a consequence of a form of dementia such as Alzheimer's. PMID- 26043544 TI - [Support and assistance from the social and associative sectors]. AB - Patient associations are very active in the support and defence of the rights of patients and their families. They offer training to support them and long respite breaks during which patients and carers can recharge their batteries. Digital technologies open up new approaches in the support provided. PMID- 26043545 TI - ["Supporting a person with Alzheimer's, this mystery incarnate"]. AB - This personal account describes the pas de deux performed for four years by a couple living with Alzheimer's. Therese, a former nurse, is suffering from the disease. Her husband, Rene is also a former caregiver who has taken on the mantle of his wife's carer to accompany Therese on her one-way journey to an unknown land. A journey scattered with obstacles during which the need for assistance, support and love is highlighted. PMID- 26043546 TI - [Nurse hygienist, a role in everyone's interest]. AB - Pascale Auguste has been working as a nurse hygienist for four years. Her managerial and pedagogical skills, specialised and up-to-date knowledge and human qualities enable her to work efficiently with the nursing teams. The diversity of the missions which she carries out makes her practice in hospital hygiene, not only complex but also very interesting. PMID- 26043547 TI - [Physiological ageing is not a disease]. AB - Physiological ageing is a slow process which brings about natural changes in the functioning of the organism. These changes are to be distinguished from the effects of diseases. Nurses, who care for more and more elderly people due to the ageing of the population, must be able to distinguish between these changes to adjust their practice. PMID- 26043548 TI - [Army nurse in French Guiana, nursing practice in exceptional circumstances]. AB - French Guiana is the site of intensive and illegal gold mining which French military forces from the Harpie mission are engaged in combating. This gold washing is particularly harmful to the fauna and flora in the tropical rainforest. The army nurse provides the healthcare support for this mission, which is carried out in the rainforest, in an isolated location and with restricted resources. PMID- 26043549 TI - [When hand hygiene takes to the dance floor!]. AB - Since 2009, the Minister for Health has supported the World Health Organisation's "Clean Care is Safer Care" initiative. To this effect, a national Clean Hands Mission day is organised every year on 5th May. The French South West Centrefor the Coordination and Fight against Nosocomial Infections (CClin) marks the day by holding the "hydroalcoholic solution dance". An original approach to improve practices. PMID- 26043550 TI - [Insulin therapy in diabetes treatment]. PMID- 26043551 TI - [The nurse facing an unconscious patient]. PMID- 26043552 TI - Sophie and Pierre take part in a drug education programme in Costa Rica. PMID- 26043553 TI - [Health promotion program for high school students]. PMID- 26043554 TI - [Standard Swan-Ganz pulmonary artery catheterization with thermodilution]. PMID- 26043555 TI - [Flipped classroom as a strategy to enhance active learning]. AB - This paper reviews the introduction of a flipped class for fourth grade dentistry students, and analyzes the characteristics of the learning method. In fiscal 2013 and 2014, a series of ten three-hour units for removable partial prosthodontics were completed with the flipped class method; a lecture video of approximately 60 minutes was made by the teacher (author) and uploaded to the university's e learning website one week before each class. Students were instructed to prepare for the class by watching the streaming video on their PC, tablet, or smartphone. In the flipped class, students were not given a lecture, but were asked to solve short questions displayed on screen, to make a short presentation about a part of the video lecture, and to discuss a critical question related to the main subject of the day. An additional team-based learning (TBL) session with individual and group answers was implemented. The average individual scores were considerably higher in the last two years, when the flipped method was implemented, than in the three previous years when conventional lectures were used. The following learning concepts were discussed: the role of the flipped method as an active learning strategy, the efficacy of lecture videos and short questions, students' participation in the class discussion, present-day value of the method, cooperation with TBL, the significance of active learning in relation with the students' learning ability, and the potential increase in the preparation time and workload for students. PMID- 26043556 TI - [GLP-1 receptor expression in rat major salivary glands and the effects of bilateral maxillary molar extraction on its expression]. AB - Glucagon-like peptide 1 (GLP-1) is the gastrointestinal hormone released from L cells of the small intestine and promotes insulin secretion by acting on the pancreas islet. GLP-1 receptor (GLP-1R) expression has been detected in many organs that are involved in carbohydrate metabolism, however its expression in the salivary glands, which participate in the first carbohydrate metabolism, has not been clarified yet. Furthermore, it is known that occlusion affects both the morphology and function of the salivary glands. Thus in this study, we focused on the expression of GLP-1R in the major salivary glands, and analyzed the changes of GLP-1R expression under the occlusal changes. Twenty-four male Wistar rats were used in this study. In the experimental group, all maxillary molars were extracted at 7 weeks old. The rats without molar extraction were used as the control group. The rats were sacrificed at 8 and 11 weeks old, then the parotid gland (PG), submandibular gland (SMG), and sublingual gland (SLG) were analyzed immunohistochemically for the presence of GLP-1R. Immunohistochemical staining showed GLP-1R to be localized in the ductal cells of PG, SMG, and SLG. In SLG, there were no differences in the intensity of GLP-1R staining in both the control and experimental groups at 8 and 11 weeks old. In PG and SMG, the intensity of GLP-1R staining in the experimental group was significantly weaker than in the control group at 11 weeks old, otherwise there were no differences at 8 weeks old. In conclusion, GLP-1R is expressed in rat PG, SMG, and SLG, and its expression can be influenced by molar extraction. PMID- 26043558 TI - [WANG Yong-jun - an successor and innovator of integrative medical traumatology]. PMID- 26043557 TI - [Summary of the 7th National Member Congress of Chinese Association of Integrative Medicine]. PMID- 26043559 TI - [Clinical practice of integrative medicine in the United States and its development in primary care]. AB - The field of integrative medicine (IM) has grown tremendously in the United States over last two decades, in terms of clinical practice, research, and education. Its growing popularity among patients has led to increased need for physicians with appropriate counseling skills and a knowledge base of the efficacy and safety of complementary and alternative medicine (CAM) therapies. Family medicine is the first specialty as a whole to embrace IM, which encounters similar ailing conditions and emphasizes similar core values-person centered, evidence based, proactive, and continuous in nature. As integrative family medicine emerges, family medicine educators have developed suggested curriculum guidelines and approved measurable competencies to implement the best of evidence based CAM and principles of IM. There are currently over 40 family medicine residencies that officially advertise CAM/IM in their programs. Meanwhile, IM centers have also been developing their own primary care programs based on their unique characteristics. This physician-led IM workforce is similar to that of China's IM in the early 1960s. As the Chinese government embarks on repeating its efforts to educate more Western medicine trained physicians in Chinese medicine in primary care training programs, the process and insights related to implementation of their practice in the United States would provide useful food for thought. PMID- 26043560 TI - [Treating non-alcoholic fatty liver disease patients of Gan stagnation Pi deficiency syndrome by tiaogan lidi recipe: a randomized controlled clinical trial]. AB - OBJECTIVE: To evaluate the efficacy and safety of tiaogan Lipi Recipe (TLR) in treating non-alcoholic fatty liver disease (NAFLD) patients of Gan stagnation Pi deficiency syndrome (GSP-DS). METHODS: A randomized, double blind, placebo controlled clinical trial was performed. Totally 99 NAFLD patients of GSPDS were randomly allocated into two groups, 66 patients in the treatment group (treated with-TLR, one dose per day) and 33 patients in the control group (treated with placebos, one dose per day). The therapeutic course for all was 12 weeks. All patients received lifestyle interventions including moderate aerobic exercise, moderate caloric restriction, and dietary changes. Clinical symptoms, CT indices, liver functions and blood lipids were observed before and after treatment. RESULTS: After 12 weeks of treatment, the total score of clinical symptoms decreased in the two groups (P <0. 01), and it was lower in the treatment group than in the control group (P <0. 05). Liver/spleen CT ratio increased in the treatment group (P <0. 01), and it was higher in the treatment group than in the control group (P <0. 01). After treatment levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) all decreased in the treatment group (P <0. 05, P <0. 01), while levels of ALT decreased in the control group (P <0. 05). Besides, all the 3 levels mentioned above were lower in the treatment group than in the control group (P <0. 05). Levels of total cholesterol (CHO) and triglyceride (TG) decreased in the two groups (P <0. 05), and they were lower in the treatment group (P <0. 05). Total effective rates of TCM syndrome, abdominal CT, liver functions, and blood lipids were 79. 69% (51/64 cases), 54. 69% (35/64 cases), 67. 65% (23/34 cases), and 67. 39% (31/46 cases) in the treatment group, while they were 56. 25% (18/32 cases), 25. 00% (8/32 cases), 33. 33% (6/18 cases), and 55. 56% (10/18 cases) in the control group. All were superior in the treatment group (P <0.05, P <0.01, respectively). CONCLUSION: TLR combined with lifestyle intervention could safely and effectively improve clinical symptoms of NAFLD patients of GSPDS, elevate liver/spleen CT ratios, and play a role in liver protection, anti-inflammation, and lowering blood lipids. PMID- 26043561 TI - [Observation on clinical therapeutic effect of acupuncture treatment on functional dyspepsia based on syndrome differentiation]. AB - OBJECTIVE: To observe the clinical efficacy difference in treatment of functional dyspepsia (FD) between syndrome differentiation based acupuncture and ordinary acupuncture. METHODS: Seventy FD patients were assigned to a syndrome differentiation based acupuncture group (Group A) and an ordinary acupuncture group (Group B) by Excel Software randomization. Zhongwan (RN12 ), Tianshu (ST25), and Zusanli (ST36) were needled as main points for patients in Group A. Meanwhile, different combined acupoints were needled according to syndrome differentiation. Only the same main points were needled for patients in Group B. All patients were needled once per day, 30 min each time, 6 days as one treatment cycle, 2 treatment cycles in total. Fasting serum levels of gastrin (GAS) and motilin (MTL) were determined before treatment and after 2 treatment cycles. 36 item Short-form Heath Survey (SF-36) and Nepean Dyspepsia Index [NDI, including Nepean Dyspepsia Symptom Index (NDSI) and Nepean Dyspepsia Life Quality Index (NDLQI)] were assessed before treatment, after 2 treatment cycles, and one month after treatment. RESULTS: Compared with before treatment in the same group, serum levels of GAS and MLT increased in the two groups after 2 treatment cycles (P <0. 05), but changes were more obvious in Group A (P <0. 05). Compared with before treatment in the same group, SF-36 and NDLQI score increased, and NDSI score decreased in the two groups after 2 treatment cycles and 1 month after treatment (all P <0. 05). Compared with Group B, SF-36 and NDLQI score increased in Group A after 2 treatment cycles and 1 month after treatment (P <0. 05, P <0. 01). But NDSI score at 1 month after treatment was lower in Group A than in Group B (P <0.01). CONCLUSION: Syndrome differentiation based acupuncture could evidently improve dyspeptic symptoms of FD patients, and significantly improve their quality of life with remarkable curative effect. PMID- 26043562 TI - [Treating irritable bowel syndrome by wuling capsule combined pinaverium bromide: a clinical research]. AB - OBJECTIVE: To evaluate the efficacy and safety of wuling Capsule combined with Pinaverium Bromide in treatment of irritable bowel syndrome (IBS). METHODS: Sixty four IBS patients were randomized into two groups, the treatment group and the control group, 32 in each group. Patients in the treatment group took wuling Capsule (0. 33 g/capsule, 3 times per day) and Pinaverium Bromide (50 mg/tablet, one tablet each time, 3 times per day) , while those in the control group only took Pinaverium Bromide (50 mg/tablet, one tablet each time, 3 times per day). The therapeutic course for all was 6 weeks. IBS symptom score questionnaire, IBS Quality of Life (IBS-QOL) , Self-Rating Depression Scale (SDS) , and Self-Rating Anxiety Scale (SAS) were assessed before and after treatment. Adverse reactions were also observed. RESULTS: The improvement of abdominal pain, stool frequency, and stool properties, as well as changing rates of integrals were significantly higher in the treatment group than in the control group (P <0. 05). The improvement of dysphoria, body image, concerns for health, and dietary restriction of IBS-QOL, as well as changing rates of integrals were significantly higher in the treatment group than in the control group (P <0. 05). The improvement of SDS and SAS, as well as changing rates of integrals were significantly higher in the treatment group than in the control group (P <0. 05). No severe adverse reaction occurred in either group. CONCLUSION: Combination therapy of wuling Capsule and Pinaverium Bromide could improve abdominal pain and defecation, attenuate depression and anxiety of IBS patients with higher safety. PMID- 26043563 TI - [Effect of baicalin on signal transduction and activating transcription factor expression in ulcerative colitis patients]. AB - OBJECTIVE: To explore the intervention of baicalin on signal transduction and activating transcription factor expression of ulcerative colitis (UC) patients. METHODS: Recruited were UC patients at Outpatient Department of Digestive Disease, Inpatient Department of Digestive Disease, Center for Digestive Endoscopy of College City Branch, Guangdong Provincial Hospital of Traditional Chinese Medicine, and Southern Hospital affiliated to Southern Medical University from June 2010 to January 2011. They were assigned to the UC group (33 cases) and the diarrhea-predominant irritable bowel syndrome (IBS-D) group (30 cases). Another 30 healthy subjects were recruited as a healthy control group. Peripheral blood mononuclear cells (PBMCs) in vitro intervened by different concentrations baicalin were taken from UC patients. IL23R gene expressions in vitro intervened by different concentrations baicalin were detected using Q-PCR. Expressions of signal transducer and activator of transcription 4 (STAT4) , STAT6, phosphorylated-STAT4 (p-STAT4), and p-STAT6 were detected using Western blot. Serum levels of IFN-gamma, IL-4, IL-6, and IL-10 were measured by ELISA. Effects of different concentrations baicalin on expressions of PBMCs, and levels of IFN gamma, IL-4, IL-10 of UC patients were also detected. RESULTS: Compared with the negative control group, 40 umol baicalin obviously decreased IL23R gene expression of UC patients (P <0. 01). Compared with the healthy control group and the IBS-D group, p-STAT4/STAT4 ratios increased, p-STAT6/STAT6 ratios decreased, levels of IFN-gamma, IL-4, IL-10 all increased in the US group (all P <0. 05). Compared with the negative control, 5 and 10 umol baicalin groups, 20 and 40 moL baicalin obviously decreased p-STAT4/STAT4 ratios (all P <0. 05); 20 and 40 umoL baicalin obviously increased p-STAT6/STAT6 ratios (all P <0. 05); 20 and 40 umoL baicalin obviously lowered levels of IFN-gamma and IL-4, and elevated IL-10 levels (all P <0. 05). CONCLUSION: 40 umoL baicalin could in vitro inhibit p STAT4/STAT4 ratios, adjust p-STAT6/STAT6 ratios and related cytokines, thereby balancing the immunity and relieving inflammatory reactions of UC. PMID- 26043565 TI - [External therapy of plasma cell mastitis by jiuyi powder using partial least squares discriminant analysis: a safety analysis]. AB - OBJECTIVE: To evaluate the safety and the clinical value of external use of jiuyi Powder (JP) in treating plasma cell mastitis using partial least-squares discriminant analysis (PLSDA). METHODS: Totally 50 patients with plasma cell mastitis treated by external use of JP were observed and biochemical examinations of blood and urine detected before application, at day 4 after application, at day 1 and 14 after discontinuation. Blood mercury and urinary mercury were detected before application, at day 1, 4, and 7 after application, at day 1 and 14 after discontinuation. Urinary mercury was also detected at 28 after discontinuation and 3 months after discontinuation. The information of wound, days of external application and the total dosage of external application were recorded before application, at day 1, 4, and 7 after application, as well as at day 1 after discontinuation. Then a discriminant model covering potential safety factors was set up by PLSDA after screening safety indices with important effects. The applicability of the model was assessed using area under ROC curve. Potential safety factors were assessed using variable importance in the projection (VIP). RESULTS: Urinary beta2-microglobulin (beta2-MG), urinary N acetyl-beta-D-glucosaminidase (NAG), 24 h urinary protein, and urinary alpha1 microglobulin (alpha1-MG) were greatly affected by external use of JP in treating plasma cell mastitis. The accuracy rate of PLSDA discriminate model was 74. 00%. The sensitivity, specificity, and the area under ROC curve was 0. 7826, 0. 7037, and 0. 8084, respectively. Three factors with greater effect on the potential safety were screened as follows: pre-application volume of the sore cavity, days of external application, and the total dosage of external application. CONCLUSIONS: PLSDA method could be used in analyzing bioinformation of clinical Chinese medicine. Urinary beta2-MG and urinary NAG were two main safety monitoring indices. Days of external application and the total dosage of external application were main factors influencing blood mercury and urine mercury. A safety classification simulation model of treating plasma cell mastitis by external therapy of JP was established by the two factors, which could be used to assess the safety of external application of JP to some extent. PMID- 26043564 TI - [Relief of urinary retention after radical hysterectomy for cervical cancer patients by acupressure: a randomized controlled trial]. AB - OBJECTIVE: To study whether acupressure could relieve urinary retention after radical hysterectomy in cervical cancer patients. METHODS: A randomized controlled prospective double-blinded trial was carried out in 107 urinary retention patients undergoing grade III radical hysterectomy. They were assigned to Group A (positive acupoints, 40 cases), Group B (negative acupoints, 32 cases) , and Group C (with no acupoints, 35 cases). All patients received protective 115 000 potassium permanganate sitz bath, 15 - 20 min each time, 3 times per day. Patients in Group A received acupressure at positive points [liniao point and Qihai (RN6)] combined points by syndrome typing [Guanyuan (RN4) , Zhongji (RN3) , Shenshu (BL23) , Zusanli (ST36), Sanyinjiao (SP6), and Taixi (K13)]. Patients in Group B received negative acupressure at sham-acupoints (for adjusting gastrointestinal functions). Patients in Group C only received conventional sitz bath. All medication was performed 3 times per day, 7 days as one therapeutic course, 21 days in total. The residual urine volume was detected. The recovery time for bladder function was recorded. The average residual urine volume was also recorded at day 7, 14, and 21. RESULTS: Compared with Group B and C, the time for ureter retention was shortened for mild and severe CKD patients in Group A (P <0. 01). The residual urine volume was also lessened for mild and severe CKD patients in Group A at day 7, 14, and 21 (P <0.01). CONCLUSION: Cervical cancer patients could relieve urinary retention by self-acupressure after radical hysterectomy. PMID- 26043566 TI - [Effect of various ambient temperatures on activities of mitochondrial complex II in patients of deficiency-cold syndrome and deficiency-heat syndrome]. AB - OBJECTIVE: To explore activity laws of mitochondrial complex II in patients of deficiency-cold syndrome (DCS) and deficiency-heat syndrome (DHS) under various ambient temperatures. METHODS: Subjects were recruited by questionnaire and expert diagnosis from grade 1 - 3 undergraduates at Henan College of Traditional Chinese Medicine in November 2012, and assigned to a normal control group, the DCS group, and the DHS group, 20 in each group. Their venous blood samples were collected at two different temperature conditions. Activities of mitochondrial complex II were measured by spectrophotometry. RESULTS: (1) Comparison of mitochondrial complex It under various ambient temperatures: Compared with room temperature in the same group, activity values were all increased in the normal control group at cold temperature with significant difference (P <0.05), but there was no significant difference in the DCS group and the DHS group (P >0. 05). Compared with the normal control group, activity values of complex H were reduced in the DCS group at cold and room temperatures with significant difference (P <0.05). Compared with the DCS group, activity values of complex It were increased in the DHS group with significant difference (P <0. 05). (2) Changes of adjustment rates: Compared with room temperature, the adjustment rate all rose at cold temperature in the normal control group and the DHS group with significant difference (P <0.05), but with no significant difference found in the DCS group (P >0. 05). Compared with the normal control group at the same temperature, the adjustment rate in the DHS group and the DCS group was all reduced at cold and room temperatures with significant difference (P <0. 05). There were no significant difference in the adjustment rate between the DHS group and the DCS group (P > 0. 05). CONCLUSIONS: Environment temperature can affect the activity of mitochondrial complex II with different influence degrees on different syndrome types of people, but its change trend are basically identical. PMID- 26043567 TI - [Effect of qidong huoxue decoction on inflammatory factors and TLR4 mRNA Expression in acute lung injury rats]. AB - OBJECTIVE: To explore the effect of qidong huoxue decoction (QHD) on inflammatory factors and Toll-like receptor (TLR4) mRNA expressions in acute lung injury (ALI) rats. METHODS: Totally 50 healthy male SD rats were randomly divided into the blank control group, the lipopolysaccharide (LPS) model group, low, middle, high dose QHD groups according to body weight, 10 rats in each group. Rats in low, middle, high dose QHD groups were intragastrically administered with QHD at 4, 8, and 16 mL/kg 24, 12 h before modeling and 12 h after modeling, respectively. Normal saline was intragastrically administered to rats in the blank control group and the LPS model group. An ALI rat model was established using intratracheal instillation of LPS. Rats were killed after 24-h modeling. Then the bronchoalveolar lavage fluid was prepared. Contents of TNF-alpha, IL-1beta, and L 10 were detected using ELISA. TLR4 mRNA expressions were determined byreal time PCR. RESULTS: Compared with the blank control group, contents of TNF-alpha, IL 1beta , and IL-10 increased (P <0. 01), TLR4 mRNA expressions also increased in the LPS model group (all P <0. 01). Compared with the LPS model group, contents of TNF-alpha and IL-1beta decreased (P <0. 05, P <0. 01), IL-10 levels increased (P <0. 01) , TLR4 mRNA expressions were also reduced (P <0. 01), in high and middle dose QHD groups. Compared with the high dose QHD group, con- tents of TNF alpha and IL-1beta increased in middle and low dose QHD groups (P <0. 05); IL-10 levels decreased (P <0. 05) in the low dose QHD group(P <0. 05), TLR4 mRNA expressions also increased in the low dose QHD group (P <0. 05). Compared with the middle dose QHD group, IL-10 levels was reduced, but TLR4 mRNA expressions increased in the low dose QHD group (P <0. 05). CONCLUSIONS: QHD had the protective effect on LPS induced ALI rats. Its mechanism might be associated with inhibiting TLR4 mRNA expressions, leading to decreased pro-inflammatory cytokines such as TNF-alpha and IL-beta, elevated anti-inflammatory cytokine IL-10, and thereby, correcting unbalanced inflammation. PMID- 26043568 TI - [Effect of Cordyceps sinensis powder on renal oxidative stress and mitochondria functions in 5/6 nephrectomized rats]. AB - OBJECTIVE: To observe the effect of Cordyceps sinensis (CS) powder on renal oxidative stress and mitochondria functions in 5/6 nephrectomized rats, and to primarily explore its possible mechanisms. METHODS: Totally 30 male Sprague Dawley rats were divided into the sham-operation group, the model group, and the treatment group by random digit table, 10 in each group. A chronic kidney disease (CKD) rat model was prepared by one step 5/6 nephrectomy. Rats in the treatment group were intragastrically administered with CS powder solution at the daily dose of 2 g/kg, once per day. Equal volume of double distilled water was intragastrically administered to rats in the sham-operation group and the model group. All medication lasted for 12 weeks. The general condition of rats, their body weight, blood pressure, 24 h proteinuria, urinary N-acetyl-beta-D glucosaminidase (NAG), serum creatinine (SCr) , and blood urea nitrogen (BUN) were assessed before surgery, at week 2, 4, 6, 8, 10, and 10 after surgery. Pathological changes of renal tissues were observed under light microscope. Morphological changes of mitochondria in renal tubular epithelial cells were observed under transmission electron microscope. Activities of antioxidant enzymes including reduced glutathione (GSH), manganese superoxide dismutase (MnSOD), and malondialdehyde (MDA) in fresh renal tissue homogenate were detected. Mitochondria of renal tissues were extracted to detect levels of mitochondrial membrane potential and changes of reactive oxygen species (ROS). And expressions of cytochrome-C (Cyto-C) and prohibitin in both mitochondria and cytoplasm of the renal cortex were also measured by Western blot. RESULTS: (1) Compared with the sham-operation group, body weight was significantly decreased at week 2 (P <0. 01), but blood pressure increased at week 4 (P <0. 05) in the model group. Compared with the model group, body weight was significantly increased at week 12 (P <0. 01), but blood pressure decreased at week 8 (P < 0. 01) in the treatment group. (2) Compared with the sham-operation group, 24 h proteinuria, urinary NAG, blood SCr and BUN significantly increased in the model group (all P <0. 01). Compared with the model group, blood and urinary biochemical indices all significantly decreased in the treatment group (all P <0. 01). (3) Results of pathological renal scoring: Glomerular sclerosis index, scoring for tubulointerstitial fibrosis, degree of tubulointerstitial inflammatory infiltration were all obviously higher in the model group than in the sham-operation group (all P <0. 01). All the aforesaid indices were more obviously improved in the treatment group than in the model group (all P <0. 01). (4) Compared with the sham-operation group, activities of MnSOD and GSH-Px were significantly reduced, but MDA contents obviously increased in the renal cortex of the model group (all P <0. 01). Compared with the model group, activities of MnSOD and GSH-Px obviously increased (P <0. 05, P <0. 01), but MDA contents obviously decreased in the renal cortex of the treatment group (P <0. 01). (5) Compared with the sham-operation group, the mitochondrial membrane potential significantly decreased, but ROS levels significantly increased in the model group (all P <0.01). Compared with the model group, mitochondrial transmembrane potential increased in the treatment group, thereby inhibiting the tendency of increased production of ROS (both P < 0. 01). (6) Results of Western blot showed that, compared with the sham-operation group, expression levels of mitochondrial Cyto-C and Prohibitin were significantly reduced in the renal cortex (P <0. 01), but significantly elevated in the cytoplasm of the model group (P <0. 01). Compared with the model group, each index was obviously improved in the treatment group with statistical difference (P <0. 05, P <0. 01). CONCLUSION: CS powder had renal protection, and its mechanism might partially depend on in- hibition of oxidative stress and protection for mitochondria. PMID- 26043570 TI - [Effect of Shen warming Pi strengthening method on the expression of serum T cell subsets in IBS-D rats]. AB - OBJECTIVE: To observe the effect of Shen warming Pi strengthening method on expressions of serum T cell subsets (C045+%, C03+%, and C04 +/COB+) in diarrhea predominant irritable bowel syndrome (IBS-0) rats. Methods An IBS-0 rat model was established referring to AL-Chaer's modeling method combined with tail clamp and intragastric administration of sanna leaf. After modeling 30 SO rats were randomly divided into 6 groups according to random digit table, i.e., the model group, the high, middle, low dose Wenshen Jianpi Recipe (WJR) groups, and the Sishen Pill control group, 6 in each group. A normal control group consisting of 6 SO rats were also set up. Rats in high, middle, low dose WJ R groups were administered by gastrogavage with boil-free WJ R at the daily dose of 3. 100, 1. 550, 0. 775 g/kg, respectively. Rats in the Sis hen Pill control group were administered by gastrogavage with boil-free Sis hen Pill at the daily dose of 0. 736 g/kg. Equal volume of normal saline was given by gastrogavage to rats in the model group and the normal control group. All medication lasted for 2 successive weeks. Rats' general state, expressions of T cell subsets (CD45+%, CD3+%, and CD4+ /CDB+) changes were observed. RESULTS: Compared with the normal control group, expressions of CD45+% and CD3+% increased, but CD4+ /CDB+ decreased with statistical difference (P < 0. 05). Compared with the model group, expressions of CD45+% and CD3+% decreased, but CD4+ ICDB+ increased with statistical difference in high, middle, low dose WJR groups, and the Sis hen Pill control group (P <0. 05). Compared with the Sis hen Pill control group, there was statistical difference in all indices except CD45+ value in the low dose SWPSM group (P <0. 05). Compared with the low dose WJ R group, the expression of CD3+% decreased in high and middle dose WJR groups, and the Sis hen Pill control group; CD4+ /CD8+ increased in the Sishen Pill control group and the high dose SWPSM group (all P < 0. 05). CONCLUSIONS: WJR showed better treatment effect. The mechanism of Shen warming Pi strengthening method might be achieved by regulating expressions of CD45+% and CD3+%, and CD4+ /CD8+ ratios. PMID- 26043569 TI - [Effect of ultrafiltration-membrane extracts of Radix Rehmanniae Praeparata on proliferation and genetic stability of bone marrow-derived mesenchymal stem cells induced by cadmium chloride]. AB - OBJECTIVE: To study the effect of ultrafiltration-membrane extracts of Radix Rehmanniae Praeparata (UMERRP) on theproliferation and genetic stability of bone marrow-derived mesenchymal stem cells (BMSCs) induced by cadmium chloride (CdCl2). METHODS: Protective effects on the proliferation, micronuclear rates, chromosome aberration rates, and apoptosis rates were observed by micronuclei test, karyotype analysis, and flow cytometry. RESULTS: Compared with the CdCl2 group, UMERRP with different molecular weights at 0. 8 g/L could obviously promote the proliferation (P <0. 05). Compared with the control group, micronuclear rates, chromosome aberration rates, and apoptosis rates were obviously enhanced in the CdCl2 group (P <0. 05). Compared with the CdCl2 group, UMERRP with different molecular weights could obviously decreased CdCl2 induced micronuclear rates, chromosome aberration rates, and apoptosis rates (P <0. 05). Of them, BMSC micronuclear rates and chromosome aberration rates decreased most obvious in UMERRP groups with molecular weight below 10 000 (P <0. 05). The apoptosis rate decreased most obviously in UMERRP groups with molecular weight ranging 100 000 and 200 000 (P <0. 05). CONCLUSION: UMERRP could reduce CdCl2 induced micronuclear rates, chromosome aberration rates, and apoptosis rates. PMID- 26043571 TI - [Study on analgesia of oxymatrine and its relation to calcium channels]. AB - OBJECTIVE: To study whether the analgesis of oxymatrine (OMT) affects N-type voltage-gated calcium channels (VGCCs). METHODS: Totally 45 mice were randomly divided into the sham-operation group, the model group [established by partial sciatic nerve ligation (PSNL)] , and the OMT treatment group according to random digit table, 15 in each group. The dorsal root ganglions (DRG) were separated in PSNL pain model mice. Intracellular calcium concentration ([Ca2+]i) was determined with Fluo-3 AM immunofluorescent probe in cultured DRG neurons. Different protein expression levels of N-type (Cav2. 2) and L-type ( Cav1. 3) among VGCCs from brain and DRG tissues were detected with Western blot. RESULTS: Compared with the sham-operation group, [Ca2+]i, increased in cultured DRG neurons (P <0. 05) , protein expression levels of Cav2. 2 in the brain tissue increased (P <0. 05), protein expression levels of Cav2. 2 in DRG tissues decreased in the model group (P <0. 01). Compared with the model group, [Ca2+]i, decreased in cultured DRG neurons (P < 0. 05), protein expression levels of Cav2. 2 in the brain tissue decreased (P <0. 01), protein expression levels of Cav2. 2 in DRG tissues increased in the OMT treatment group (P <0. 01). There was no statistical difference in Cav1. 3 expressions in cultured DRG neurons and the brain (P >0. 05). CONCLUSION: Analgesic effect of OMT might be related to Cav2. 2 channel mediated calcium ion flux. PMID- 26043572 TI - [Effect of jiedu quyu zishen recipe on TLR9 signal pathway of murine macrophage cells]. AB - OBJECTIVE: To explore efficacy enhancing and detoxification roles of Jiedu Quyu Zishen Recipe (JQZR) in treating systemic lupus erythematosus (SLE) by studying its effect on Toll like receptor 9 (TLR9) signal pathway of murine macrophage cells after JQZR stimulated CpG oligodeoxynucletide (CpG ODN). METHODS: Murine macrophage cells in vitro cultured were randomly divided into 4 groups, i.e., the blank serum group, the CpG ODN stimulus group, the CpG ODN + dexamethasone group, the CpG ODN + medicated serum group. Murine macrophage cells were collected after 24-h intervention. The expression of TLR9, myeloid differentiation factor 88 (MyD88), NF-KB, IFN-alpha mRNA were analyzed by RT-PCR. The expression of TLR9 and NF-kappaB protein were analyzed by Western blot. Changes of the NF-KB transcriptional activity were assayed by Dual-Luciferase reporter assay system. RESULTS: mRNA expressions of TLR9, MyD88, NF-kappaB, and IFN-alpha, protein expressions of TLR9 and NF-kappaB, and NF-kappaB transcriptional activities were enhanced, showing statistical difference when compared with those of the blank serum group (P <0. 05, P <0. 01). Compared with the CpG ODN stimulus group, mRNA expressions of MyD88, NF-kappaB, and IFN-alpha, the protein expression of NF kappaB and the NF-kappaB transcriptional activities decreased in the CpG ODN + dexamethasone group with statistical difference (P <0. 01). Compared with the CpG ODN stimulus group, mRNA expressions of TLR9, MyD88, NF-kappaB, and IFN-alpha, protein expressions of TLR9 and NF-kappaB, and NF-kappaB transcriptional activities were decreased in CpG ODN+ medicated serum group with statistical difference (P <0. 01). CONCLUSION: Efficacy enhancing and detoxification roles of JQZR in treatment of SLE might be realized through regulating TLR9 signal pathways. PMID- 26043574 TI - [Effect of acupuncture at different acupoints on electric activities of rat cerebellar fastigial nuclear]. AB - OJECTIVE: To explore whether different acupuncture signals were afferent to the cerebellar fastigial nucleus (FN) neuron and to find out their corresponding effect features through observing the effect of spontaneous discharge of cerebellar FN neuron by needling at different acupoints. METHODS: Totally 120 male SD rats were anesthetized by 20% urethane and their right cerebellar FN were positioned (AP 11. 6 mm, RL 1. 0 mm, H 5. 6 mm). Extracelluar discharge was recorded by glass microelectrode (AP: -11. 6 mm, R: 1. 0 mm, H: 5.7 -7. 0 mm), using extracellular microelectrode recording method, recording the spontaneous discharge of cerebellar FN neurons as a baseline. Random order of needling at zusanli (ST36), quchi (Lil1), weishu (BL21), and zhongwan (CV12) were compared with the baseline before each acupuncture. Their effects on the discharge of cerebellar FN neurons were observed and compared with baselines. RESULTS: The frequency of FN neuronal discharge could be elevated by needling at zusanli (ST36), quchi (LiI), weishu (BL21), and zhongwan (CV12) (P <0. 01, P <0. 05). The response rate of needling at Zhongwan (CV12, 56. 00%) was higher than that of needling at Zusanli (ST36), Quchi (Ll1), and Weishu (BL21) (35. 00%, 34. 62%, 36. 63%, respectively) with statistical difference (P <0. 05). The response rate of needling at zhongwan (CV12) was obviously higher than that of needing at other points (F = 2. 101, P < 0. 05). CONCLUSIONS: Needling at zusanli (ST36 ), quchi (Lil), weishu (BL21), and zhongwan (CV12) could elevate the spontaneous discharge frequency of cerebellar FN neurons. Needling at Zhongwan (CV12) had advantageous roles in regulating cerebellar FN. PMID- 26043573 TI - [Curcumin inhibited rat colorectal carcinogenesis by activating PPAR-gamma: an experimental study]. AB - OBJECTIVE: To explore the chemopreventive effect of curcumin on DMH induced colorectal carcinogenesis and the underlining mechanism. METHODS: Totally 40 Wistar rats were divided into the model group and the curcumin group by random digit table, 20 in each group. Meanwhile, a normal control group was set up (n =10). A colorectal cancer model was induced by subcutaneously injecting 20 mg/kg DMH. The tumor incidence and the inhibition rate were calculated. The effect of curcumin on the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in rat colon mucosal tissues was observed using immunohistochemistry and Western blot. HT 29 cell line were cultured and divided into a control group, the curcumin + GW9662 (2-chloro-5-nitro-N-4-phenylbenzamide) intervention group, and the curcumin group. The inhibition of different concentrations curcumin on HT29 cell line was detected using MTT. The expression of curcumin on PPARy was also detected using Western blot. RESULTS: The tumor incidence was 80. 00% (12/15 cases) in the model group, obviously higher than that of the curcumin group (58. 82%, 10/17 cases, P <0. 05). The inhibition rate of curcumin on DMH induced colorected carcinoma reached 26. 46%. Compared with the normal control group, the expression of PPARgamma protein was significantly increased in the curcumin group and the model group (P <0. 01). Compared with the model group at the same time point, the expression of PPARy protein was significantly enhanced in the curcumin group (P <0. 05). MTT analysis showed that curcumin could inhibit the proliferation of in vitro HT 29 cells in dose and time dependent manners. The expression of PPARy protein was significantly increased in the GW9662 group and the curcumin group, showing statistical difference when compared with the normal control group (P <0. 01). Compared with the GW9662 group, the expression of PPARgamma protein was significantly increased in the curcumin group (P <0. 01). CONCLUSION: Curcumin could inhibit DMH-induced rat colorectal carcinogenesis and the growth of in vitro cultured HT 29 cell line, which might be achieved by activating PPARy signal transduction pathway. PMID- 26043575 TI - [Effect of tianma gouteng decoction on the endothelial function and the renal protein expression in spontaneously hypertensive rats]. AB - OJECTIVE: To observe the effect of tianma gouteng decoction (TGD) on the endothelial function and the renal protein expression of spontaneously hypertensive rats, and to analyze its possible mechanism. METHODS: Totally 18 6 week-old SHR were randomly divided into 3 groups according to randomized block design, the SHR control group, the TGD group, and the captopril group, 6 in each group. Meanwhile, Wistar Kyoto (WKY) rats of the same age were recruited as a WKY control group. Rats in the TGD group were administered with TGD at the daily dose of 10. 260 g/kg. Rats in the captopril group were administered with captopril at the daily dose of 3. 375 g/kg. 2 mL/100 g distilled water was administered to rats in the SHR control group and the WKY control group. All medication was performed by gastrogavage once per day till rats were 24 weeks old. Changes of blood pressure were measured once per two weeks. The relaxation of the thoracic aorta and the superior mesenteric artery was determined by vascular ring in vitro to reflect the endothelial function. The total renal protein was separated by two dimensional electrophoresis (2-DE). The significantly deviated protein was verified by Western blot. RESULTS: (1) Compared with the SHR control group, blood pressure was significantly lowered in rats (10 - 24 weeks old) of the captopril group (P <0.01, P <0.05). The hypotensive effect of TGD was obvious at the beginning of hypertension (10 -12 weeks) (P <0. 01). But along with the progression of hypertension, its hypotensive effect was not obvious (P>0. 05). (2) Compared with the SHR control group, the relaxation of the superior mesenteric artery was obviously improved in the TGD group (P <0. 05); the relaxation of the thoracic aorta and the superior mesenteric artery was obviously superior in the WKY control group (P <0. 01, P <0. 05). But there was no statistical difference in each relaxation index between the captopril group and the SHR control group (P >0. 05).(3) RESULTS: of 2-DE found 16 significantly differential renal protein, mainly involved nitric oxide (NO) system, oxidative stress, and cytoskeleton-related proteins. Results of Western blot showed that TGD could significantly improve expressions of Cu-Zn superoxide dismutase (SOD), N(G, N(G)-dimethylarginine dimethylaminohydrolase 2 (DDAH2), and pterin-4-alpha carbinolamine dehydratase 1 (PCBD1) (P <0. 05). CONCLUSION: GTD could protect the endothelial function of the superior mesenteric artery in SHR, and its intervention mechanism of hypertension induced early renal injury might be relevant to regulating the NO system and antioxidative stress. PMID- 26043576 TI - [Beneficial pharmacodynamic interaction between Chinese medicine and Western medicine]. AB - Useful pharmacodynamic changes occur when some Chinese medicine are used together with some Western medicine, namely enhanced curative effect, lowered adverse reactions, reduced dosages, shortened treatment courses, enlarged indications scope, improved compliance of treatment and rational medication, which could be explored to provide scientific bases for further improving diagnosis and treatment levels and rational use of drugs. PMID- 26043577 TI - [Application of qualitative interviews in inheritance research of famous old traditional Chinese medicine doctors: ideas and experience]. AB - The inheritance of famous old traditional Chinese medicine (TCM) doctors plays an essential role in the fields of TCM research. Qualitative interviews allow for subjectivity and individuality within clinical experience as well as academic ideas of doctors, making it a potential appropriate research method for inheritance of famous old TCM doctors. We summarized current situations of inheritance research on famous old TCM doctors, and then discussed the feasibility of applying qualitative interviews in inheritance of famous old TCM doctors. By combining our experience in research on inheritance of famous old TCM doctors, we gave some advice on study design, interview implementation, data transcription and analyses , and report writing, providing a reference for further relevant research. PMID- 26043578 TI - [Diagnosis and treatment strategies for chronic constipation by integrative medicine]. PMID- 26043579 TI - [Experience and understanding in rectal touch in syndrome typing and disease identification of constipation]. PMID- 26043580 TI - [Progress in diagnosis methods for chronic constipation]. PMID- 26043582 TI - Domestic medical journals in the Web of Science--the main route to inclusion of Serbian medicine in the world scientific streams. PMID- 26043581 TI - [Research progress of cytoskeleton and endothelial ageing relation]. PMID- 26043583 TI - Anismus as a cause of functional constipation--experience from Serbia. AB - BACKROUND/AIM: Anismus is paradoxal pressure increase or pressure decrease less than 20% of external anal sphincter during defecation straining. This study analyzed the presence of anismus as within a group of patients with the positive Rome III criteria for functional constipation. We used anorectal manometry as the determination method for anismus. METHODS: We used anorectal water-perfused manometry in 60 patients with obstructive defecation defined by the Rome III criteria for functional constipation. We also analyzed anorectal function in 30 healthy subjects. RESULTS: The presence of anismus is more frequent in the group of patients with obstructive defecation compared to the control group (a highly statistically significant difference, p < 0.01). Furthermore, we found that the Rome III criteria for functional constipation showed 90% accuracy in predicting obstructive defecation. We analyzed the correlation of anismus with the presence of weak external anal sphincter, rectal sensibility disorders, enlarged piles, diverticular disease and anatomic variations of colon. We found no correlation between them in any of these cases. CONCLUSION: There is a significant correlation between anismus and positive Rome III criteria for functional constipation. Anorectal manometry should be performed in all patients with the positive Rome III criteria for functional constipation. PMID- 26043584 TI - Index of orthodontic treatment need in children from the Nis region. AB - BACKGROUND/AIM: The Index of Orthodontic Treatment Need (IOTN) is a scoring system for malocclusion that con- sists of the two independent components: Denal Health Component (DHC) and Aesthetic-Component (AC). IOTNs are usually used in the countries with dental healthcare financed by the government through the national healthcare system or healthcare insurance. The aim of the study was to determine IOTN in primary school children from the town of Nis and to asses percent of children with any kind of orthodontic treatment. METHODS: The study involved 301 school children, 11-14 (12.4 +/- 1.1) years old. The IOTN was used by the two examiners in order to evaluate the treatment need. RESULTS: The results of the study showed that 111 (37%) out of 301 examined children had orthodonic treat- ment (33.33% boys and 66.67% girls) and they were excluded from the study. Out of final sample of 190 school children, considering DHC of the IOTN, 27.4% of the children showed great (grades 4-5), 41.0% moderate (grade 3) and 31.6% slight or no treatment need (grade 1-2). Considering IOTN AC, 15.3% of the children showed great (grade 8-10), 24.3 % moderate (grade 5-7) and 60.4% slight or no treatment need (grade 1-4). CONCLUSION: The need for ortho- dontic treatment in school children in the town of Nis, Serbia, is similar to the need in most European countries, despite the fact that the number of children orthodontically treated is much higher compared to most of European countries. PMID- 26043586 TI - Influence of disease activity on functional capacity in patients with rheumatoid arthritis. AB - BACKGROUND/AIM: Progressive erosive changes in cartilage and bone in rheumatoid arthritis (RA) ultimately lead to joint deformities and disability which may be early, severe and permanent. Consequently, there is the reduction of functional ability and changes in the quality of life. The aim of this study was to estimate the impact of disease activity on functional status of patients with RA. METHODS: A prospective investigation included 74 patients with RA who were treated in the Rheumatology Clinic of the "Niska Banja" Institute. Assessment of functional status (capacity) was measured by the Health Assessment Questionnaire (HAQ) with the values from 0 to 3 that patients fill out on their own. The patients were then divided into three groups: the group I with the HAQ values from 0.125 to 1.000, the group II with the values from 1.125 to 2.000 and the group III with the values from 2.125 to 3.000. Disease activity was measured by Disease Activity Score (DAS28). The assessment also included sedimentation rate (SE) influence, IgM rheumatoid factor (RF) and C-reactive protein (CRP) positivity, age, and disease duration. RESULTS: The patients with the most severe functional damage estimated by the HAQ--the group III, had the highest values of DAS28 SE (7.4 +/- 0.8) compared to the group II (6.5 +/- 1.2) and the group I (3.4 +/- 1.2). The group III also showed the highest values of DAS28 CRP (7.1 +/- 0.8) compared to the group II (6.7 +/- 0.8) and the group I (3.6 +/- 0.4). Compared with the patients with small and moderate functional damage, the patients in the group III had positive IgM RF and CRP as well as higher SE values more frequently and the difference was statistically significant. In the univariate logistic model, the tested parameters of DAS28 SE, DAS 28 CRP, SE, RF and CRP represent significant predictors of functional disability. The most significant factors that increase the odds of patient having the most severe functional damage include DAS28 SE which increases the odds by 5.5 times (OR = 5.450, 95% CI = 3.211-7.690, p = 0.001), DAS28 CRP by 5.1 times (OR = 5.111, 95% CI = 2.123-10.636, p < 0.01), and the presence of increased CRP (OR = 5.219, 95% CI = 1.305-18.231, p = 0.019) by 5.2 times. CONCLUSION: Functional status evaluated by the HAQ is a standard for as- sessment of RA due to its convenience and good correlation with parameters of disease activity. The most significant factors that increase the odds that the patient has the greatest functional damage are DAS28 SE, DAS28 CRP and the pres- ence of CRP. PMID- 26043585 TI - Effect of diode laser cyclophotocoagulation in treatment of patients with refractory glaucoma. AB - BACKGROUND/AIM: Refractory glaucoma is glaucoma resistant to conventional management (maximally tolerated medical therapy, one or more glaucoma surgeries) and glaucoma in cases of neovascularisation after panretinal photocoagulation or cryoablation. The aim of the study was to determine the intraocular pressure (IOP) lowering efficacy of transscleral diode laser cyclophotocoagulation (DCPC) treatment in the management of pain and IOP in patients with refractory glaucoma. METHODS: This nonrandomized, retrospective study, included 95 patients (95 eyes) with refractory glaucoma treated at the University Eye Clinic, Clinical Center of Vojvodina, Novi Sad, Serbia, between November 2007 and November 2012 in accordance with the established protocols (16-18 spots, 270 degrees , up to 5J of energy). All the eyes were treated with transscleral DCPC (Iris Medical OcuLight SLx, Iridex Co, Mountain View, USA). Patient's symptoms, bests corrected visual acuity and IOP were recorded 7 days, and 1, 3 and 6 months after the DCPC treatment. RESULTS: Out of 95 patients (95 eyes) enrolled in this study 24 (25.2%) were with primary (the group I), and 71 (74.5%) with secondary (the group II) glaucoma. The mean baseline IOP in these two groups was similar: 36.08 +/- 8.39 mmHg for the first group and 37.36 +/- 8.19 mmHg in the second group. Measurement of the mean IOP in the group I showed the following results: on the day 7 it was 13.96 +/- 8.30 mmHg (62.1% decrease of the baseline value), on the day 30 it was 18.44 +/- 8.85 mmHg (48.9% decrease regarding the baseline value), after 3 months it was 22.44 +/- 7.36 mmHg (37.8% decrease regarding the baseline value), and after 6 months it was 25.92 +/- 7.65 mmHg (28.2% decrease regarding the baseline value). Measurement of IOP in the group II showed the following results: on the day 7 it was 15.77 +/- 9.73 mmHg (57.8% decrease of the baseline value), on the day 30 it was 20.14 +/- 10.20 mmHg (46.1% decrease regarding the baseline value), after 3 months it was 23.46 +/- 9.83 mmHg (37.2% decrease regarding the baseline value) and after 6 months it was 27.23 +/- 9.87 mmHg (27.2% decrease regarding the baseline value). Pain was the main symptom in 70 (73.6%) patients before the treatment and it persisted in only 4 (4.2%) of our patients. Other complaints (burning, stinging, foreign body sensation) were experienced by 39 (41%) of the patients, postoperatively. A total of 52 (54.7%) patients had no com- plaints after the treatment. CONCLUSION: Our study confirmed that transscleral DCPC is a useful, effective and safe procedure with predictable amount of IOP decrease, which makes it the treatment of choice for refractory glaucoma. PMID- 26043587 TI - Follicular lymphoma patients with a high FLIPI score and a high tumor burden: a risk stratification model. AB - BACKGROUND/AIM: The widely accepted Follicular Lymphoma International Prognostic Index (FLIPI) divides patients into three risk groups based on the score of adverse prognostic factors. The estimated 5-year survival in patients with a high FLIPI score is around 50%. The aim of this study was to analyse the prognostic value of clinical and laboratory parameters that are not included in the FLIPI and the New Prognostic Index for Follicular Lymphoma developed by the International Follicular Lymphoma Prognostic Factor Project (FLIPI2) indices, in follicular lymphoma (FL) patients with a high FLIPI score and high tumor burden. METHODS: The retrospective analysis included 57 newly diagnosed patients with FL, a high FLIPI score and a high tumor burden. All the pa- tients were diagnosed and treated between April 2000 and June 2007 at the Clinic for Hematology, Clinical Center of Serbia, Belgrade. RESULTS: The patients with a histological grade > 1, erythrocyte sedimentation rate (ESR) 45 mm/h and hypoalbuminemia had a significantly worse overall survival (P = 0.015; p = 0.001; p = 0.008, respectively), while there was a tendency toward worse overall survival in the patients with an Eastern Cooperative Oncology Group (ECOG) > 1 (p = 0.075). Multivariate Cox regression analysis identified a histological grade > 1, ESR 45 mm/h and hypoalbuminemia as independent risk factors for a poor outcome. Based on a cumulative score of unfavourable prognostic factors, patients who had 0 or 1 unfavourable factors had a significantly better 5-year overall survival compared to patients with 2 or 3 risk factors (75% vs 24.1%, p = 0.000). CONCLUSION: The obtained results suggest that from the examined prognostic parameters histological grade > 1, ESR 45 mm/h and hypoalbuminemia can contribute in defining patients who need more aggressive initial treatment approach, if two or three of these parameters are present on presentation. PMID- 26043588 TI - Social functioning of elderly persons with malignant diseases. AB - BACKGROUND/AIM: Malignant disease, its treatment and consequences of treatment can often lead to social marginalization and reduced quality of life. The aim of this research was to determine how elderly patients with malignant diseases function in their social environment. METHODS: Sociodemographic questionnaire and interview were used to investigate a group of 49 elderly persons undergoing adjuvant chemotherapy treatment against early carcinomas (P1), and a group of 51 elderly persons with advanced stages of cancer undergoing systemic chemotherapy (P2). There were two cycles of assessment: one just before the beginning of the first cycle of adjuvant or systemic chemotherapy, and the other three months later. The research paradigm was based on the relation between individual treatment and the impact of the malignant disease on functional and social incompetence. The obtained findings were compared with the group of 50 healthy elderly people (K) who share the same relevant features but do not suffer from malignant diseases. RESULTS: It was found that most healthy older people live in share house, whereas those who suffer from malignant diseases mostly live in separate households. In both groups of patients and healthy group older people are mostly taken care of by their children. Individuals in both groups of patients have been frequently visited by their relatives during initial stages of treatment, unlike the elderly people in the control group. However, the difference did not reach a statistical significance. Three months after the beginning of chemotherapy, there was a statistically relevant difference in favor of the group undergoing adjuvant treatment. Home visits eventually become less frequent, whereas communication by telephone becomes more frequent. It was also found that visits by friends and neighbors are statistically more frequent among subjects who undergo adjuvant treatment, both before the treatment began and three months later when compared to other groups. CONCLUSION: Our research shows that elderly people are subject to social exclusion, especially those with malignant diseases. Special care should be dedicated to monitoring of social functioning during treatment of patients with malignant disease considering the detected trend of deterioration and significance for further recover and cure. PMID- 26043589 TI - Long term complications of ventilation tube insertion in children with otitis media with effusion. AB - BACKGROUND/AIM: Otitis media with effusion (OME) is characterized by the prolonged presence of fluid (longer than 12 weeks) of different viscosity in the middle ear, without perforation of the eardrum or signs of acute inflammation. The conservative treatment does not always provide satisfactory recovery, so surgical treatment may be unavoidable. The aim of the study was to determine the incidence, type and frequency of complications caused by ventilation tube insertion as a part of treatment for OME in children, and specifically, to evaluate the evolution of these changes over the extended period of time. METHODS: During a 5-year period (1986-1991), 84 children with chronic bilateral OME, aged from 6 months to 12 years, were enrolled in the study and treated with ventilation tube insertion. All the patients were periodically checked every 6 months over a 3-8 year period following the intervention (otomicroscopic examination, audiometry, tympanometry), and reexamined in 2013 (22-27 years after the primary surgical intervention). RESULTS: The complications observed in this study (51%) were atrophic scarring of the tympanic membrane, myringo- and tympanosclerosis, retraction of the eardrum, persistent perforations, granulation tissue formations, development of chronic otitis and sensorineural hearing loss. CONCLUSION: The incidence of complications after ventilation tube insertion was 51% in this study. Atrophic scars and myringosclerosis were the most prominent complications. Despite high complications rate ventilation tube insertion still remains the treatment of choice in children with otitis media with effusion. PMID- 26043590 TI - Disease relapses in multiple sclerosis can be influenced by air pollution and climate seasonal conditions. AB - BACKGROUND/AIM: Environmental factors may influence the disease activity in patients with relapsing-remitting multiple sclerosis (MS). The aim of this study was to evaluate the in- fluence of air pollution and seasonal climate factors of any on number of relapses in MS patients during a consecutive 5 years of observation. METHODS: We retrospectively analyzed data of MS patients from the town of Nis, hospitalized at the Clinic of Neurology, Clinical Center Nis, Serbia, from 2005 to 2009. Climate data: mean daily sun shining; mean monthly sun shining, mean whole daily cloudiness, daily cloudiness at 7 a.m, 2 p.m. and 9 p.m. and air pollution expressed by NSR (New Source Review) were obtained from the Meteorology Observatory Nis. RESULTS: During a 5-year of observation there were 260 relapses in 101 MS patients. The number of relapses showed a significantly negative correlation with the number of days with NSR < 2 (p = 0.31; p < 0.01) and a positive correlation with the mean whole daily cloudiness (p < 0.05), mean daily cloudiness at 7 a.m. (p < 0.05) and 2 p.m. (p < 0.01). We found a significantlly positive correlation (p < 0.05) between the reduced number of relapses during the period of high vitamin D season, i.e. July-October. There was a statistically significant increase (p < 0.01) of the number of relapses during spring (x = 6.53; SD = 3.98) compared to the other three seasons. The joint presence of lower number of days with NSR < 2 during low vitamin D season (January- April) correlated with a statistically significant increase of the number of relapses in MS patients (F = 5.06, p < 0.01). CON- CLUSION: The obtained results confirmed the influence of air pollution and climate seasonal conditions on disease relapses in MS patients based on a long-term observation. Lower numbers of days with low air pollution during the periods with low vitamin D (January-April), especially with increased cloudiness at 2 p.m, induce a higher risk of MS relapses in southern continental parts of Europe. PMID- 26043592 TI - Small bowel incarceration as a complication of port site drainage following laparoscopic hysterectomy. AB - INTRODUCTION: Indication for surgical drainage may be prophylactic or therapeutic. However, surgical drains may cause complications. These complications can arise either following laparoscopic or open surgery. One of the rare complications resulting from drainage includes herniation of abdominal viscera at the drain site. The most common herniated abdominal organ is the small bowel. CASE REPORT: A 75-year-old woman underwent laparoscopic hysterectomy for atypical endometrial hyperplasia. After the operation, she developed small bowel herniation in the abdominal wall at the drain site, which was confirmed by multislice computed tomography. The patient underwent emergency relaparotomy that identified drain site incarceration of an ileal loop. Following resection of the incarcerated bowel, her postoperative recovery was uneventful. CONCLUSION: This case presents rare causative mechanism of intestinal obstruction. The possible occurrence of hernias following surgical drainage must be kept in mind. PMID- 26043591 TI - Quality of analgesia after lower third molar surgery: A randomised, double-blind study of levobupivacaine, bupivacaine and lidocaine with epinephrine. AB - BACKGROUND/AIM: Surgical extraction of lower third molars is followed by mild or severe postoperative pain which peaks at maximal intensity in the first 12 hours and has a significant impact on a patient's postoperative quality of life. The use of long-acting local anaesthetics is a promising strategy to improve postoperative analgesia. The aim of the present study was to investigate analgesic parameters and patient satisfaction after using 0.5% levobupivacaine (Lbup), 0.5% bupivacaine (Bup) and 2% lidocaine with epinephrine 1:80,000 (Lid + Epi) for an inferior alveolar nerve block following lower third molar surgery. METHODS: A total of 102 patients (ASA I) were divided into three groups, each of which received either 3 mL of Lbup, Bup or Lid + Epi. The intensity of postoperative analgesia was measured using a verbal rating scale (VRS). The total amounts of rescue analgesics were recorded on the first and during seven postoperative days. Patients satisfaction was noted using a modified verbal scales. RESULTS: A significantly higher level of postoperative pain was recorded in Lid + Epi group compared to Bup and Lbup groups. No significant differences were seen between Bup and Lbup, but a significant reduction in the need for rescue analgesics was seen postoperatively in both Lbup and Bup (50%) in comparison with Lid + Epi (80%) in the first 24 hours. The same significant trend in rescue analgesic consumption was recorded for seven postoperative days. Patients' overall satisfaction was significantly lower for Lid + Epi (10%) than for Lbup (56%) and Bup (52%). CONCLUSION: The use of a new and long-acting local anaesthetic 0.5% levobupivacaine is clinically relevant and effective for an inferior alveolar nerve block and postoperative pain control after third molar surgery. In our study Lbup and Bup controled postoperative pain more efficiently after lower third molar surgery compared to Lid + Epi. PMID- 26043593 TI - Penile fracture: a rare case of simultaneous rupture of the one corpus cavernosum and complete urethral rupture. AB - INTRODUCTION: Penile fracture is a traumatic rupture of tunica albuginea and the tumescent corpora cavernosa due to the nonphysiological bending of the penile shaft, presenting with or without rupture of corpus pongiosum and urethra. The incidence of concomitant injury of the urethra is 0-38%. Complete urethral rupture is rare, but it is almost always associated with bilateral corporeal injury. CASE REPORT: We presented a patient with complete urethral rupture, and rupture of the right cavernous body. According to the available literature, this case is extremely rare. CONCLUSION: Fracture of the penis is relatively uncommon and is considered a urologic emergency. Prompt surgical explo- ration and repair can preserve erectile and voiding function. PMID- 26043594 TI - Specificities of transplantation of kidneys procured from donors with situs inversus totalis--a case report and review of the literature. AB - INTRODUCTION: Situs inversus totalis (SIT) represents a total vertical transposition of the thoracic and abdominal organs which are arranged in a mirror image reversal of the normal positioning. We presented a successful pre-dialysis kidney transplantation from a living sibling donor with SIT and the longest donor follow-up period, along with analysis of the reviewed literature. CASE REPORT: The pair for pre-dialysis kidney transplantation included a 68-year-old mother and 34-year-old daughter at low immunological risk. Comorbid- ities evidenced in kidney donors with previously diagnosed SIT, included moderate arterial hypertension and borderline blood glucose level. Explantation of the left donor kidney and its placement into the right iliac fossa of the recipient were performed in the course of the surgical procedure. A month after nephrectomy, second degree renal failure was noticed in the donor. A 20-month follow-up of the donor's kidney and graft in the recipient proved that their functions were excellent. CONCLUSION: In donors with previously di- agnosed SIT the multidisciplinary approach, preoperative evaluation of the patient and detection of possible vascular anomalies are required to provide maximum safety for the donor. PMID- 26043595 TI - Challenges in treatment of postinfarction ventricular septal defect and heart failure. AB - INTRODUCTION: Acquired ventricular septal defect (VSD) is uncommon, but serious mechanical complication of acute myocardial infarction with poor outcome and high mortality rate in surgically or medically treated patients. CASE REPORT: We report a 58-year-old male patient admitted to our hospital six days following acute inferior myocardial infarction complicated by ventricular septal rupture with signs of heart failure. Coronary angiography revealed 3-vessel disease, with proximally occluded dominant right coronary artery. Transthoracic echo exam revealed aneurysm of a very thin inferior septum and the basal portion of the inferior left ventricular wall, with septal wall rupture. One of the VSD dimensions was 15 mm and left- to right shunt was calculated 2:1. Since the patient was at too high risk for surgical closure, transcatheter closure of VSD was chosen as a better option. Under short intravenous sedation, 24 mm Am- platzer device was implanted percutaneously with transesophageal echo guidance. The post-procedural result revealed a small residual shunt, but it was followed by significant improvement of the patient's clinical status. A 24h Holter ECG monitoring did not show cardiac rhythm or conduction disturbances. Coronary angiography was repeated ten days following the procedure, after hemodynamic stabilization of the patient, with direct stenting of the circumflex artery and the intermediate artery. Ostial left descending artery lesion was left for further functional significance assessment. CONCLUSION: Percutaneous closure with a septal occluder device can be definitive primary treatment for anatomically suitable patients or it can serve as a bridge to surgical treatment. PMID- 26043596 TI - Osteoporosis reversibility in a patient with celiac disease and primary autoimmune hypothyroidism on gluten free diet--a case report. AB - INTRODUCTION: Secondary osteoporosis occurs in many diseases. Celiac disease induced osteoporosis is the consequence of secondary hyperparathyroidism. Biochemical bone markers show predominance of bone resorption, thus making the bisphosphonates the first line therapy option. Intestinal mucosal changes are reversible on gluten-free diet. Osteoporosis reversibility is also possible, provided postmenopausal osteoporosis risk factors independent from celiac disease are not present. CASE REPORT: We presented a postmenopausal woman with at least a 10-year history of celiac disease prior to diagnosis, which had overt secondary hyperparathyroidism with insufficient status of vitamin D and a significant bone mass reduction. At the time of diagnosis of celiac disease the patient was receiving 250 MUg of levothyroxine daily without achieving optimal substitution. Three years after the initiation of gluten-free diet the patient was without any signs and symptoms of the disease. All laboratory findings were within normal range. It was decided to treat the underlying disease and to supplement calcium and vitamin D without the initiation of bisphosponate therapy. CONCLUSION: Osteoporosis regression justified this therapeutic approach. The presence of primary autoimmune hypothyroidism makes this case specific, since the inability for optimal substitution therapy with a high daily dose of levothyroxine provoked the suspicion of celiac disease. PMID- 26043597 TI - Moral responsibility of healthcare personnel. PMID- 26043598 TI - [Professional liability insurance of physicians and other medical workers]. PMID- 26043599 TI - Mobile integrated healthcare and community paramedicine (MIH-CP): a national survey. PMID- 26043608 TI - Tri-county health care EMS. Rural, hospital-based ambulance provider takes referrals from physicians to reduce readmissions, improve access to care. PMID- 26043609 TI - Regulatory barriers pose challenges. PMID- 26043610 TI - Limited funding, reimbursement for MIH-CP makes long-term outlook cloudy. PMID- 26043611 TI - Acadian Ambulance. Private ambulance company partners with Medicaid managed care organization to improve pediatric asthma care. PMID- 26043612 TI - Measuring outcomes and patient satisfaction to show value. PMID- 26043613 TI - Colorado Springs Fire Department. Partnering with hospitals, Medicaid care coordination organization to reduce 911 calls. PMID- 26043615 TI - Conclusion: what will it take for MIH-CP to become a success? PMID- 26043614 TI - Lessons learned--tips from the experts. PMID- 26043616 TI - [Humor, a dimension of nursing?]. PMID- 26043617 TI - [What are the new euthanasia laws?]. PMID- 26043618 TI - [Is outpatient surgery the future of the French health system?]. PMID- 26043619 TI - [Patient safety and nurse classifications]. PMID- 26043620 TI - [Public health law, an opportunity for the evolution of nursing practice]. PMID- 26043621 TI - [The state of health of the French population, continuing health status inequalities]. PMID- 26043622 TI - [A video campaign for the development of telemedicine]. PMID- 26043623 TI - [A study on the organization of acute care hospitals]. PMID- 26043624 TI - [A welcome guide for nursing students]. PMID- 26043625 TI - [Which solutions for various wounds?]. PMID- 26043626 TI - [An assessment scale for the prevention of pressure sores in children]. AB - Pressure sores in children are rare. However, when they do occur they can have significant consequences. Professionals in paediatric units realised the importance of assessing the risk of pressure sores and developed a pressure sore assessment scale specific to children. This project, carried out through a hospital-training school partnership, emphasises the importance of clinical reasoning in nursing practices. PMID- 26043627 TI - [Is nursing care an intrusion?]. PMID- 26043628 TI - [Defining and questioning intrusion in care situations]. AB - Most care procedures require the patient to give personal information and to reveal their body in order to enable a clinical examination or a care procedure to be carried out, which can leave them feeling embarrassed. Considering as a team what causes the feeling of intrusion in a care procedure enables nursing strategies to be adopted which can help the patient overcome their modesty and feel secure, becoming a partner in a care procedure for which they understand the clinical need and underlying intentionality. Testimonies. PMID- 26043629 TI - [Intrusive care and the nursing approach]. AB - All caregivers who listen to patients will hear them tell their experience of the intrusive nature of care, whether it be basic, technical, educational or relational. The relational approach implemented by nurses enables them to identify organisational and behavioural methods which favour the establishment of a climate of trust. It helps them appropriate this interdisciplinary approach to caregiving, limiting as much as possible the intrusion felt by the patient during their hospital stay. PMID- 26043630 TI - [Proximity, intimacy and promiscuity in care]. AB - Lying at the heart of the intimacy of the other person, the nature of care supposes that the caregiver identifies the components resulting from the proximity and the invasion of the patient's personal space, where perceptions and representations give rise to reactive emotions and behaviour. Between modesty and nudity, proximity and promiscuity, caregivers have to adjust their approach of proper care, limiting the risks of intrusion. PMID- 26043631 TI - [Fitting a male sheath urinal while respecting the patient's intimacy]. AB - The fitting of a male sheath urinal directly concerns the patient's area of sexual intimacy. The modesty of the patient and caregiver as they interact is tested, leading to discomfort or clumsiness which can provoke a feeling of intrusion. Preparing this care procedure favours the adherence of both parties. PMID- 26043632 TI - [Home care, when the visiting nurse becomes an intruder]. AB - The home, a living space and a place of privacy, is also a place of care where caregivers are invited to enter. However, do professional standards not sometimes risk altering the patients'environment? Do the high numbers of caregivers who come and go and the information they exchange not reduce the patients' area of freedom? In this context, reflecting upon what can sometimes lead the caregiver to become an intruder helps to prevent undue risks. PMID- 26043633 TI - [The caregiver's intrusion in psychiatry, interaction or interference?]. AB - The intrusive nature of care can be examined using a clinical situation experienced bya nurse from a medical-psychological unit caring for a psychotic patient at home. It is then possible to consider the link between illness, commensurate care and nursing interference. An analysis of the nurse's practice can be a way of helping to limit intrusion. PMID- 26043634 TI - [Identifying and preventing pain linked to an invasive care procedure]. AB - Preventing pain linked to the invasive nature of a care procedure is a shared inter-disciplinary responsibility where the doctor and nurse play a central role. It is necessary to identify the foreseeable circumstances for its occurrence and to find operational implementation strategies. The attention given to the nurse patient relationship, to the methods of pain relief, to the organisation before, during and after the care procedure, as well as the assessment of practices, are integral parts of the approach. PMID- 26043635 TI - [The removal of organs and intrusion]. AB - Approaching the family of a brain dead patient to enquire about the deceased's wishes with regard to the donation of their organs is a delicate matter. It is also a difficult time for the medical and paramedical teams, in intensive care as well as the operating theatre. Describing the phenomena of potential intrusions and the methods of guidance and support can help those involved adjust their practice to the specific situation of the families and professionals concerned. PMID- 26043636 TI - [Approaching intrusive care in nursing education]. AB - The initial representations of the profession and of proper care of student nurses beginning their training, will, throughout their course, come up against the reality of nursing practice. At the heart of the complexity of potentially intrusive care procedures and the relational approach in which they are players or witnesses, their practical work experience becomes a modelling tool for their career. This is facilitated when the teaching team structures the reflexive analysis through pedagogical approaches favouring expression and objectivity between peers. PMID- 26043637 TI - [Intrusion in nursing care]. PMID- 26043638 TI - [Bibliography. Intrusion in nursing care]. PMID- 26043639 TI - [SIGAPS, a tool for the analysis of scientific publications]. AB - The System for the Identification, Management and Analysis of Scientific Publications (SIGAPS) is essential for the funding of teaching hospitals on the basis of scientific publications. It is based on the analysis of articles indexed in Medline and is calculated by taking into account the place of the author and the ranking of the journal according to the disciplinary field. It also offers tools for the bibliometric analysis of scientific production. PMID- 26043640 TI - [Obtaining support for a protocol]. PMID- 26043641 TI - The impact of assisted reproductive technology and chorionicity in twin pregnancies complicated by obstetric cholestasis. AB - OBJECTIVE: To assess in a cohort of twin pregnancies the prevalence of obstetric cholestasis (OC) and its correlation with the type of conception and chorionicity. METHODS: A retrospective cohort study including all the twin pregnancies delivered between 2005 and 2013 at our University Hospital was carried out. In the study population, the prevalence of OC was investigated in relationship to the impact of assisted reproductive technology (ART) and of chorionicity. RESULTS: Overall, 569 twin pregnancies were included in the study population. Among those complicated by OC, the rate of ART was 3-fold higher (OR 3.4, 95% CI 1.2-9.5, p = 0.02), whereas the rate of dichorionicity did not differ significantly (OR 1.6, 95% CI 0.3-7.9, p = 0.53). CONCLUSION: The risk of developing OC seems to be significantly higher among twin pregnancies obtained after ART in comparison with those conceived spontaneously. PMID- 26043642 TI - A pharmacological approach to panic disorder during pregnancy. AB - Anxiety disorders and pregnancy may occur concurrently in some women. Although, several epidemiological or clinical studies about anxiety disorders in pregnancy exist, data on their treatment are very limited. Similar to other anxiety disorders, specific pharmacological treatment approaches in pregnant women with panic disorder (PD) have not been discussed in the literature. An important issue in the treatment of pregnant women with any psychiatric diagnosis is the risk benefit profile of pharmacotherapy. Therefore, the treatment should be individualized. Untreated PD seems to be associated with several negative outcomes in the pregnancy. When the results of current study regarding the safety of pharmacological agents on the fetus and their efficacy in PD were gathered, sertraline, citalopram, imipramine and clomipramine at low doses for pure PD, and venlafaxine appeared to be more favorable than the other potential drugs. However, controlled studies examining optimum dosing, efficacy of antipanic medications and risk-benefit profile of intrauterine exposure to treated or untreated PD are urgently needed. PMID- 26043644 TI - Pregnancy outcome and placental pathology differences in term gestational diabetes with and without hypertensive disorders. AB - OBJECTIVE: To compare pregnancy outcome and placental pathology in pregnancies complicated by gestational diabetes mellitus (GDM A1 and A2), with and without hypertensive disorders. METHODS: Pregnancy outcome and placental pathology from term deliveries of women complicated with GDM with (GDM + H) and without (GDM - H) hypertensive disorders were compared. Results of the GDM + H group were compared also with the non-diabetic patients but with hypertensive disorders (non GDM + H). Composite neonatal outcome was defined as one or more of early complications: respiratory distress or need of ventilation support, sepsis, phototherapy, transfusion, seizure, hypoxic-ischemic encephalopathy. Placental lesions were categorized to lesions related to maternal and fetal vascular supply abnormalities, and maternal and fetal inflammatory responses. RESULTS: Of the 192 women with GDM, the GDM + H group (n = 41) were more obese, p < 0.001, with higher rate of placental maternal and fetal vascular supply lesions, p = 0.008, p = 0.03, respectively, but similar neonatal outcome, compared to the GDM - H (n = 151) group. Compared to the non-GDM + H group (n = 41), the GDM + H group had higher birth weights, similar neonatal outcome and similar rate of placental vascular lesions. CONCLUSIONS: Higher rate of placental maternal and fetal vascular supply lesions express underlying placental pathology in women with diabetes and hypertensive disorders, similar to women without DM and with hypertensive complications. PMID- 26043643 TI - Gestational age-specific neonatal morbidity among pregnancies complicated by advanced maternal age: a population-based retrospective cohort study. AB - OBJECTIVE: Compare significant neonatal morbidity frequency differences in advanced maternal age (AMA) versus non-AMA pregnancies, assessing which gestational week is associated with the lowest morbidity risk. METHODS: Population-based retrospective cohort study. Adverse neonatal outcome frequency differences were stratified by each week of gestation. Multivariate logistic regression estimated the relative risk (RR) of composite neonatal morbidity for women aged 35-39, 40-44, 45-49 and 50-55 versus 18-34 years, adjusted sequentially for relevant risk factors. RESULTS: Neonatal morbidity decreased with each advancing week of term gestation, lowest at 39 weeks for all the groups. Adverse neonatal outcome risk for births to AMA women increased at 40 weeks: 35-39 years adjRR 1.12 [1.01-1.24] and >=40 years 1.24 [1.01-1.52]. Each older maternal age category had increased risk for overall neonatal morbidity: 35 39 years adjRR 1.11 [95% CI 1.08-1.15], 40-44 years 1.21 [95% CI 1.14-1.29] and 45-49 years 1.34 [95% CI 1.05-1.69]. CONCLUSIONS: Lowest neonatal morbidity risk is at 39-week gestation with a significantly increased risk observed thereafter, especially in women >=40 years. PMID- 26043645 TI - A standardized approach for the assessment of the lower uterine segment at first trimester by transvaginal ultrasound: a flash study. AB - OBJECTIVES: To evaluate the reproducibility of a standardized approach to lower uterine segment (LUS) imaging by transvaginal ultrasound at 11-14 weeks. METHODS: This was a "flash" study lasting for 1 month. Obstetrician-sonographers performing more than 50 first trimester ultrasounds per year participated. All consecutive women attending for their 11-14 weeks scan were included. A standardized, transvaginal approach to the imaging of LUS was defined. The sonographers recorded one or two images of the LUS. The quality of the images was assessed by sonographers and reviewed by an independent fetal medicine specialist using the same scoring system. Inter and intra-reviewer variability was assessed. RESULTS: Seventy-one sonographers and 851 pregnant women participated. The mean (+/-SD) and medium (IQR) scores attributed by sonographer versus reviewer were 5.01 (+/-0.92) and 5 [4-6] versus 4.68 (+/-1.14) and 5 [4-5.24], p = 0.08. The mean [95% CI] difference of -0.33 [-2.6;2] was recorded. There was good, moderate and poor agreement in 74.4%, 16.7% and 8.9% cases, respectively. Variability in inter-reviewer and intra-reviewer was low with the mean [95% CI] difference of 0.1 [-1.6;1.4] and -0.1 [-1.4;1.2] respectively. CONCLUSIONS: A standardized approach to LUS imaging at 11-14 weeks is feasible and highly reproducible in a large population. PMID- 26043646 TI - Performance of a dosage individualization table for extended interval gentamicin in neonates beyond the first week of life. AB - OBJECTIVE: To assess the performance of a gentamicin dosing table for the individualization of extended-interval dosing (EID) in a neonatal population >7 days old. METHODS: A prospective observational study was carried out on gentamicin concentrations achieved using a dosing table in neonates >7 days old. Neonates were given 5 mg/kg IV gentamicin; then a table using 22 h post-first dose gentamicin concentrations was used to individualize dosing intervals. Pre- and post-serum gentamicin concentrations were measured and used to calculate the true peak and trough concentrations achieved. RESULTS: Use of the table resulted in dosing intervals that provided appropriate peak (mean 9.8 +/- 1.8 mg/L) and trough (mean 0.6 +/- 0.3 mg/L) concentrations in all neonates (n = 38). All trough concentrations were <2 mg/L, 83% were <1 mg/L. The majority of peak concentrations were in the usual target range (87%, 5-12 mg/L), with a few being in a higher, although likely safe range (13%, 12.1-15.7 mg/L). CONCLUSIONS: Use of this dosing table to individualize extended-interval gentamicin dosages in neonates >7 days old resulted in appropriate peak and trough concentrations in all neonates studied. This allows appropriate extended-interval aminoglycoside dosages in neonates early in treatment. PMID- 26043647 TI - Evaluation of neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and red blood cell distribution width-platelet ratio as early predictor of acute pancreatitis in pregnancy. AB - OBJECTIVE: Acute pancreatitis (AP) is a state of inflammation. It has been widely known that neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and red blood cell distribution width (RDW) to platelet ratio (RPR) reflect systemic inflammation. The aim of this study is to investigate whether these inflammatory markers could be used as reliable markers in early prediction of AP in pregnancy and if there is a relationship between disease severity and these markers. METHODS: The study group consisted of 14 patients, who developed AP in ongoing pregnancy, and the control group consisted of 30 healthy pregnant women. NLR, PLR and RPR were calculated for both the groups. RESULTS: NLR was significantly elevated in the AP group when compared with the controls (p = 0.00), but there was no statistically significant difference in terms of PLR and RPR (p > 0.05). ROC curve analysis results for NLR showed that there was a significant prediction power of NLR for AP (R(2) = 0.842; p < 0.001). For NLR parameter, if cut-off value is chosen to be 4.1030, then sensitivity is 71.4% and specificity is 100.0%. There was statistically significant and positive correlation between C-reactive protein (CRP) and glucose with NLR (p = 0.001, p = 0.043). It was seen that Ranson was close to be significant (p = 0.051). CONCLUSION: NLR might be used as an early marker of AP and may have a role in prediction of disease severity. PMID- 26043648 TI - Evaluation of risk factors in women with puerperal genital hematomas. AB - AIM: Our aim was to assess the incidence and risk factors of the puerperal genital hematomas (PGH). METHODS: We retrospectively reviewed recorded cases of PGH at Zekai Tahir Burak Research and Training Hospital, Ankara, Turkey, between January 2010 and 2014. Next three patients were chosen as control group. RESULTS: There were 47 cases of PGH with an incidence of 1 in 762 deliveries. Patients with PGH were younger, more likely to be nulliparous and had a greater weight gain during pregnancy than the control group. Patients with PGH had a longer first and second stage of labor than the control group. Mediolateral episiotomy and operative delivery were more frequently performed in patients with PGH than the control group. Neonates born to mothers with PGH were heavier than the control group (3525 +/- 428 versus 3325 +/- 579; p = 0.031). In the logistic regression model, nulliparity (OR: 8.68, 95% CI = 2.96-25.3), instrumental delivery (OR: 7.96, 95% CI = 1.37-49.0) and mediolateral episiotomy (OR: 6.67, 95% CI = 2.61-17.1) were factors which had an independent impact on risk of PGH. CONCLUSIONS: Nulliparity, instrumental delivery and mediolateral episiotomy are the main risk factors for hematomas. PMID- 26043649 TI - Work-to-family conflict as a mediator of the relationship between job satisfaction and turnover intention. AB - AIMS: To investigate the mediating effect of work-to-family conflict on the relationship between job satisfaction and turnover intention among licensed nurses in long-term care settings. BACKGROUND: The considerable research on turnover in long-term care has primarily focused on the impact of job satisfaction on turnover intention. Given the well-documented high turnover rate in nursing home staffing, dissatisfaction is expected to continue. Alternatives (e.g. reduction in work-to-family conflict) for reducing turnover under the circumstance of job dissatisfaction have not been investigated extensively. DESIGN: A cross-sectional mailed survey. METHODS: A convenience sample comprising 200 nurses from 25 private nursing homes in Central Taiwan was created. Data were collected from nurses about their level of turnover intention, job satisfaction and work-to-family conflict in 2012. A composite indicator structural equation model was used to examine the mediation model of this study. RESULTS: Overall, 186 nurses (93%) returned the completed questionnaires. Consistent with published research from other countries, turnover intention in our study was significantly and negatively associated with job satisfaction and significantly and positively associated with work-to-family conflict. In addition, job dissatisfaction indirectly influenced turnover intention through high work-to-family conflict. CONCLUSION: Findings from this study indicate the importance of work-to-family conflict to nurse turnover. While work setting has a strong, well-documented influence on job satisfaction, limiting job satisfaction efforts to work setting improvements may not yield the hoped-for results unless work-to-family conflict is also considered and addressed. PMID- 26043650 TI - Barrels XXVII meeting report: Barrels in the monument city. AB - The 27th annual Barrels meeting highlighted the latest advances in this rapidly growing field. The Barrels meeting annually focuses on the role of the posterior medial thalamus in somatosensation, dendritic processing, and the cortical dynamics involved during touch perception. Speakers utilized diverse molecular, physiological, computational techniques to understand the development, sensory processing, and motor commands that are involved with the rodent mystacial vibrissae. The meeting was held Thursday, 13 November through Friday, 14 November 2014 on the Homewood campus of Johns Hopkins University, Baltimore, MD. PMID- 26043651 TI - The Effect of Insertion Torque on the Clinical Outcome of Single Implants: A Randomized Clinical Trial. AB - BACKGROUND: The insertion torque value has been extensively used as an indicator for implant primary stability, which is considered a determining parameter for the implants success. PURPOSE: The primary goal of the present randomized clinical trial was to evaluate and compare the clinical outcome for implants placed with high insertion torque (between 50 Ncm and 100 Ncm) and regular insertion torque (within 50 Ncm) in healed ridges. MATERIALS AND METHODS: Partially edentulous patients, missing one or more mandibular or maxillary teeth, having an adequate amount of bone, requiring implant placement, were randomized to receive Blossom CT implants with regular insertion torque (<50 Ncm) or CT implants with high insertion torque (>=50 Ncm). Implants were left to heal submerged for 3 months. Implants were restored with individualized abutments and cemented metal-ceramic crowns. Acquired measurements were: insertion torque values (IT), thickness of buccal bone plate after implant osteotomy preparation (BBT), marginal bone level (MBL), and facial soft tissue level (FST). All patients were followed 12 months after implant placement. RESULTS: One hundred sixteen implants were placed in one hundred sixteen patients and enrolled for the study. Fifty-eight implants were randomly allocated in regular-IT and high-IT groups with a mean insertion torque ranging from 20 Ncm to 50 Ncm and from 50 Ncm to 100 Ncm, respectively. Three implants failed, and another five implants showed at the 12-month evaluation a marginal bone loss (DeltaMBL) greater than 1.5 mm, being considered unsuccessful. CONCLUSIONS: The findings suggested that implants inserted with high-IT (>=50 Ncm) in healed bone ridges showed more peri-implant bone remodeling and buccal soft tissue recession than implants inserted with a regular-IT (<50 Ncm). Moreover, sites with a thick buccal bone wall (>=1 mm) - after implant osteotomy site preparation - seemed to be less prone to buccal soft tissue recession after 12 months than sites with a thin buccal bone wall (<1 mm). PMID- 26043652 TI - Relating hepatocellular carcinoma tumor samples and cell lines using gene expression data in translational research. AB - Cancer cell lines are used extensively to study cancer biology and to test hypotheses in translational research. The relevance of cell lines is dependent on how closely they resemble the tumors being studied. Relating tumors and cell lines, and recognizing their similarities and differences are thus very important for translational research. Rapid advances in genomics have led to the generation of large volumes of genomic and transcriptomic data for a diverse set of primary cancer samples, normal tissue samples and cancer cell lines. Hepatocellular Carcinoma (HCC) is one of the most common tumors worldwide, with high occurrence in Asia and sub-Saharan regions. The current effective treatments of HCC remain limited. In this work, we compared the gene expression measurements of 200 HCC tumor samples from The Cancer Genome Atlas and over 1000 cancer cell lines including 25 HCC cancer cell lines from Cancer Cell Line Encyclopedia. We showed that the HCC tumor samples correlate closely with HCC cell lines in comparison to cell lines derived from other tumor types. We further demonstrated that the most commonly used HCC cell lines resemble HCC tumors, while we identified nearly half of the cell lines that do not resemble primary tumors. Interestingly, a substantial number of genes that are critical for disease development or drug response are either expressed at low levels or absent among highly correlated cell lines; additional attention should be paid to these genes in translational research. Our study will be used to guide the selection of HCC cell lines and pinpoint the specific genes that are differentially expressed in either tumors or cell lines. PMID- 26043653 TI - Contrast-enhanced ultrasound for the differentiation of small atypical hepatocellular carcinomas from dysplastic nodules in cirrhosis. AB - BACKGROUND: Contrast-enhanced ultrasound is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to evaluate the usefulness of contrast-enhanced ultrasound for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules showing atypical or not coincidental typical vascular pattern on two dynamic imaging techniques (computed tomography and magnetic resonance imaging). METHODS: A total of 46 patients with cirrhosis and a liver nodule smaller than 3cm showing an atypical or non-coincident typical vascular pattern on two dynamic imaging techniques, who underwent liver contrast-enhanced ultrasound and ultrasound-guided liver biopsy, were retrospectively reviewed. Contrast-enhanced ultrasound findings were compared with histopathological and clinical data, and with the two dynamic imaging findings. RESULTS: Significantly different contrast-enhanced ultrasound enhancement patterns were observed among dysplastic nodules, Edmondson grade I and grade II-III hepatocellular carcinomas. Ten out of 11 (90.9%) non-hypervascular hepatocellular carcinomas on two dynamic imaging techniques showed a hypervascular pattern on contrast-enhanced ultrasound, and these made it possible to distinguish hepatocellular carcinomas from dysplastic nodules. CONCLUSION: Contrast-enhanced ultrasound is useful for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules. PMID- 26043654 TI - Solid-state stability studies of crystal form of tebipenem. AB - The aim of this study was to determine the kinetic and thermodynamic parameters of tebipenem degradation in the solid state. The process was analyzed based on the results obtained by a high performance liquid chromatography (HPLC) method using ultraviolet diode-array detector (DAD)/electrospray ionization tandem mass spectrometry (Q-TOF-MS/MS), Fourier transform infrared spectroscopy (FT-IR) and Raman spectroscopic (RS) studies. In dry air, the degradation of tebipenem was a first-order reaction depending on the substrate concentration while at an increased relative air humidity tebipenem was degraded according to the kinetic model of autocatalysis. The thermodynamic parameters: energy of activation (Ea), enthalpy (DeltaH(?a)) and entropy (DeltaS(?a)) of tebipenem degradation were calculated. Following a spectroscopic analysis of degraded samples of tebipenem, a cleavage of the beta-lactam bond was proposed as the main degradation pathway, next confirmation using HPLC-Q-TOF-MS/MS method. PMID- 26043655 TI - Nursing students' knowledge and practices of standard precautions: A Jordanian web-based survey. AB - BACKGROUND: The main purpose of this web-based survey was to evaluate Jordanian nursing students' knowledge and practice of standard precautions. METHODS: A cross-sectional, descriptive design was used. Six public and four private Jordanian universities were invited to participate in the study. Approximately, seventeen hundred nursing students in the participating universities were invited via the students' portal on the university electronic system. For schools without an electronic system, students received invitations sent to their personal commercial email. RESULTS: The final sample size was 594 students; 65.3% were female with mean age of 21.2 years (SD=2.6). The majority of the sample was 3rd year students (42.8%) who had no previous experience working as nurses (66.8%). The mean total knowledge score was 13.8 (SD=3.3) out of 18. On average, 79.9% of the knowledge questions were answered correctly. The mean total practice score was 67.4 (SD=9.9) out of 80. There was no significant statistical relationship between students' total knowledge and total practice scores (r=0.09, p=0.032). CONCLUSION: Jordanian nursing educators are challenged to introduce different teaching modalities to effectively translate theoretical infection control knowledge into safe practices. PMID- 26043656 TI - The value of using test response data for content validity: An application of the bifactor-MIRT to a nursing knowledge test. AB - AIM: This paper aimed 1) to argue for the value of using test response data for content validation, and b) to demonstrate this practice using bifactor multidimensional item response theory (bifactor-MIRT) for nurse education. METHOD: The Nursing Knowledge Test (NKT) response data by 1491 nurse students from China were used for demonstration. Based on the content structure assumed by subject-matter experts (SME), a bifactor-MIRT model was constructed and tested. This involved five steps: dimensionality assessment, local dependence detection, model specification, calibrating and unit weighting. RESULTS: Dimensionality assessment results confirmed the content structure assumed by SME. Through local dependence detection and calibrating (i.e., item parameter check), items suspected of contaminating content were detected and those producing substantive harm were removed or constrained. Finally, content contributions by items to the overall scale and to their subscales were obtained through unit weighting. CONCLUSION: Deficiencies residing in SME for content validation must raise attention. The study suggests the value of modeling test response data to compensate these deficiencies. The theoretical implication is discussed. PMID- 26043657 TI - Interprofessional education in primary health care for entry level students--A systematic literature review. AB - OBJECTIVE: This systematic review investigated student learning and patient outcomes associated with interprofessional education in outpatient, primary care clinics. DESIGN: Medline, Cinahl and Embase databases were searched to March 2014. A mixed method evaluation framework was applied to investigate the participants, interventions and effects on student learning and patient outcomes. RESULTS: 26 studies met the inclusion criteria; 13 were quantitative, predominately pre-post-survey design, 6 qualitative and 7 mixed methods design. Studies most commonly investigated student volunteers from medicine, nursing and allied health working in interprofessional clinics that were established to address gaps in community health care. Students appeared to learn teamwork skills and increase their knowledge of the roles of other disciplines. We found no convincing evidence that participation results in changes in attitudes towards other disciplines compared to single discipline education. We also found insufficient evidence to estimate the effectiveness of patient care delivered by interprofessional student teams in this setting compared to single discipline or no care. CONCLUSIONS: Given the logistical challenges associated with coordinating clinic attendance for interprofessional teams, high quality studies are needed to assess the effects of clinics on student learning and patient health outcomes. PMID- 26043658 TI - Measuring nursing assistants' knowledge, skills and attitudes in a palliative approach: A literature review. AB - BACKGROUND: Nursing assistants are the largest aged care workforce providing care to older people in residential aged care facilities. Although studies have focused on their training and development needs when providing a palliative approach, a valid and reliable instrument to evaluate their knowledge, skills and attitudes is required. AIMS: To examine what instruments have been used to evaluate nursing assistants' knowledge of, skills in and attitudes towards a palliative approach in residential aged care facilities, critically evaluate development processes, and discuss the strengths and limitations of existing instruments for this population. METHODS: CINAHL, the Cochrane Library, ERIC, MEDLINE, PubMed, Scopus and Web of Science were searched using key words. Selected articles were published in English in the period 2004-2014 and included instruments which evaluated nursing assistants and a palliative approach. RESULTS: Ten studies using seven instruments met the inclusion criteria. One of these instruments measured nursing assistants' level of comfort in providing end of-life care. The six remaining instruments measured palliative care knowledge, palliative care practice, self-efficacy, knowledge and attitudes towards people with advanced dementia, beliefs and attitudes to death, dying, palliative and interdisciplinary care across the aged care workforce. CONCLUSION: Seven instruments have been used to evaluate nursing assistants' knowledge, skills and attitudes in a palliative approach. Instrument design and recommended psychometric processes for development limit specificity and usefulness of these instruments for nursing assistants' scope of practice. Adhering to recommended psychometric processes will increase the validity and reliability of an instrument tailored to this population and a palliative approach. PMID- 26043659 TI - In vitro effects of tamoxifen on adipose-derived stem cells. AB - In breast reconstructive procedures, adipose-derived stem cells (ASCs) that are present in clinical fat grafting isolates are considered to play the main role in improving wound healing. In patients following chemotherapy for breast cancer, poor soft tissue wound healing is a major problem. However, it is unclear if tamoxifen (TAM) as the most widely used hormonal therapeutic agent for breast cancer treatment, affects the ASCs and ultimately wound healing. This study evaluated whether TAM exposure to in vitro human ASCs modulate cellular functions. Human ASCs were isolated and treated with TAM at various concentrations. The effects of TAM on cell cycle, cell viability and proliferation rates of ASCs were examined by growth curves, MTT assay and BrdU incorporation, respectively. Annexin V and JC-1 Mitochondrial Membrane Potential assays were used to analyze ASC apoptosis rates. ASCs were cultured in derivative specific differentiation media with or without TAM (5 uM) for 3 weeks. Adipogenic and osteogenic differentiation levels were measured by quantitative RT-PCR and histological staining. TAM has cytotoxic effects on human ASCs through apoptosis and inhibition of proliferation in dose- and time-dependent manners. TAM treatment significantly down-regulates the capacity of ASCs for adipogenic and osteogenic differentiation (p<0.05 vs. control), and inhibit the ability of the ASCs to subsequently formed cords in Matrigel. This study is the first findings to our knowledge that demonstrated that TAM inhibited ASC proliferation and multi lineage ASC differentiation rates. These results may provide insight into the role of TAM with associated poor soft tissue wound healing and decreased fat graft survival in cancer patients receiving TAM. PMID- 26043660 TI - Layered SiC sheets: A promising metal-free catalyst for NO reduction. AB - Recently, the catalytic reduction is shown to be an effective method to remove the harmful NO. In terms of the high cost and limited supply of the traditional transition metal-based catalysts, the novel metal-free catalyst is highly desirable for NO reduction. Here, density functional theory (DFT) computations were performed to explore the potentials of layered SiC sheets as a metal-free catalyst for NO reduction. From our DFT results, it can be predicted that layered SiC sheets exhibit superior catalytic activity toward NO reduction. In particular, a dimer mechanism is shown to be more favorable than the direct dissociation one for NO reduction on this metal-free catalyst and a three-step mechanism is involved in this process: (1) the formation of a (NO)2 dimer on layered SiC sheet, followed by (2) its dissociation into N2O+Oad, and (3) the recovery of catalyst by subsequent NO. The trans-(NO)2 dimer might be a necessary intermediate, in which the calculated barrier for the rate-determining step along the energetically most favorable pathway is 0.722 eV. The high reactivity of layered SiC sheets may be attributed to the certain amount of charge transfer from the catalyst to (NO)2 dimer, which shortens the NN bonding and thus stabilizes these systems due to the extra electrons on the dimers. This excellent catalytic activity provides a useful guidance to design the next generation catalysts for NO reduction with lower cost and higher activity. PMID- 26043661 TI - Structure-based virtual screening as a tool for the identification of novel inhibitors against Mycobacterium tuberculosis 3-dehydroquinate dehydratase. AB - 3-Dehydroquinate dehydratase (DHQase), the third enzyme of the shikimate pathway, catalyzes the reversible reaction of 3-dehydroquinate into 3-dehydroshikimate. The aim of the present study was to identify new drug-like molecules as inhibitors for Mycobacterium tuberculosis DHQase employing structure-based pharmacophore modeling technique using an in house database consisting of about 2500 small molecules. Further the pharmacophore models were validated using enrichment calculations, and finally three models were employed for high throughput virtual screening and docking to identify novel small molecules as DHQase inhibitors. Five compounds were identified, out of which, one molecule (Lead 1) showed 58% inhibition at 50MU M concentration in the Mtb DHQase assay. Chemical derivatives of the Lead 1 when tested evolved top two hits with IC50s of 17.1 and 31.5 MUM as well as MIC values of 25 and 6.25 MUg/mL respectively and no cytotoxicity up to 100 MUM concentration. PMID- 26043662 TI - Effective virtual screening strategy focusing on the identification of novel Bruton's tyrosine kinase inhibitors. AB - Dysregulation of the B-cell receptor (BCR) signaling pathway plays a vital role in the pathogenesis and development of B-cell malignancies. Bruton's tyrosine kinase (BTK), a key component in the BCR signaling, has been validated as a valuable target for the treatment of B-cell malignancies. In an attempt to find novel and potent BTK inhibitors, both ligand- and structure-based pharmacophore models were generated using Discovery Studio 2.5 and Ligandscout 3.11 with the aim of screening the ChemBridge database. The resulting hits were then subjected to sequential docking experiments using two independent docking programs, CDOCKER and Glide. Molecules displaying high glide scores and H-bond interactions with the key residue Met477 in both of the docking programs were retained. Drug-like criteria including Lipinski's rule of five and ADMET properties filters were employed for further refinement of the retrieved hits. By clustering, eight promising compounds with novel chemical scaffolds were finally selected and the top two ranking compounds were evaluated by molecular dynamics simulation. We believe that these compounds are of great potential in BTK inhibition and will be used for further investigation. PMID- 26043663 TI - Four new sesquiterpenes from the rhizomes of Curcuma phaeocaulis and their iNOS inhibitory activities. AB - Three new guaiane-type sesquiterpenes named phaeocaulisins K-M (1-3), and one germacrane-type sesquiterpenoid with new ring system of 1,5- and 1,8-ether groups named phagermadiol (4), were isolated from rhizomes of Curcuma phaeocaulis. Their structures were established based on extensive spectroscopic analysis. Compound 1, the first example of norsesquiterpene with tropone backbone, and compound 3 with a novel 1,2-dioxolane sesquiterpene alcohol were isolated from the genus Curcuma. All of the isolated compounds were tested for inhibitory activity against lipopolysaccharide-induced nitric oxide (NO) production in RAW 264.7 macrophages. Compound 3 inhibited NO production with IC50 value of 6.05 +/- 0.43 MUM. The plausible biosynthetic pathway for compounds 3 and 4 in C. phaeocaulis was also discussed. PMID- 26043664 TI - Statin therapy and the risk of intracerebral haemorrhage: a nationwide observational study. AB - BACKGROUND: The association between statin therapy and intracerebral haemorrhage is still unclear. The aim was to investigate whether prior use of statin was associated with risk of intracerebral haemorrhage. METHODS: Between 2006 and 2009, we identified 7696 cases of intracerebral haemorrhage that were first-ever strokes in the Swedish Stroke Register and 14 670 stroke-free controls that were matched on age and gender in the Population Register. Drug therapy at the time of intracerebral haemorrhage was extracted from the Drug Prescription Register. The risk of intracerebral haemorrhage with statins was estimated by conditional logistic regression. RESULTS: In cases and controls, the median age was 73 years and 53% were men. Intracerebral haemorrhage cases had higher prevalence of antithrombotic therapy, hypertension, and diabetes than controls. Statins were used by 1276 (16.6%) of the intracerebral haemorrhage cases and by 2552 (17.4%) of the controls. The crude odds ratios of intracerebral haemorrhage did not differ significantly between patients with and without statins, but after adjustment for antithrombotic therapy, hypertension, and diabetes, patients with statins had a decreased risk of intracerebral haemorrhage (odds ratio = 0.68, 95% confidence interval, 0.63-0.74). The highest proportion (>20%) of antecedent statins was seen in the 70-84 age group, for both cases and controls. CONCLUSIONS: In this matched case-controlled study, statin therapy was associated with a decreased risk of incident intracerebral haemorrhage. Future studies on risk of stroke with statin therapy after intracerebral haemorrhage are needed. PMID- 26043665 TI - Novel approaches to improving the chemical safety of the meat chain towards toxicants. AB - In addition to microbiological issues, meat chemical safety is a growing concern for the public authorities, chain stakeholders and consumers. Meat may be contaminated by various chemical toxicants originating from the environment, treatments of agricultural production or food processing. Generally found at trace levels in meat, these toxicants may harm human health during chronic exposure. This paper overviews the key issues to be considered to ensure better control of their occurrence in meat and assessment of the related health risk. We first describe potential contaminants of meat products. Strategies to move towards a more efficient and systematic control of meat chemical safety are then presented in a second part, with a focus on emerging approaches based on toxicogenomics. The third part presents mitigation strategies to limit the impact of process-induced toxicants in meat. Finally, the last part introduces methodological advances to refine chemical risk assessment related to the occurrence of toxicants in meat by quantifying the influence of digestion on the fraction of food contaminants that may be assimilated by the human body. PMID- 26043666 TI - Research gaps in evaluating the relationship of meat and health. AB - Humans evolved as omnivores and it has been proposed that cooking meat allowed for evolution of larger brains that has led to our success as a species. Meat is one of the most nutrient dense foods, providing high-quality protein, heme iron, zinc, and vitamins B6 and B12. Despite these advantages, epidemiologic studies have linked consumption of red or processed meat with obesity, type 2 diabetes, cardiovascular diseases, and cancers of multiple organs. Most observational studies report small, increased relative risks. However, there are many limitations of such studies including inability to accurately estimate intake, lack of prespecified hypotheses, multiple comparisons, and confounding from many factors - including body weight, fruit/vegetable intake, physical activity, smoking, and alcohol - that correlate significantly either positively or negatively with meat intake and limit the reliability of conclusions from these studies. The observational studies are heterogeneous and do not fulfill many of the points proposed by AB Hill in 1965 for inferring causality; his most important factor was strength of the association which in dietary studies is usually <1.5 but is not considered adequate in virtually all other areas of epidemiology outside nutrition. Accepting small, statistically significant risks as "real" from observational associations, the field of nutrition has a long list of failures including beta-carotene and lung cancer, low-fat diets and breast cancer or heart disease that have not been confirmed in randomized trials. Moderate intake of a variety of foods that are enjoyed by people remains the best dietary advice. PMID- 26043667 TI - Correction for faking in self-report personality tests. AB - Faking is a common problem in testing with self-report personality tests, especially in high-stakes situations. A possible way to correct for it is statistical control on the basis of social desirability scales. Two such scales were developed and applied in the present paper. It was stressed that the statistical models of faking need to be adapted to different properties of the personality scales, since such scales correlate with faking to different extents. In four empirical studies of self-report personality tests, correction for faking was investigated. One of the studies was experimental, and asked participants to fake or to be honest. In the other studies, job or school applicants were investigated. It was found that the approach to correct for effects of faking in self-report personality tests advocated in the paper removed a large share of the effects, about 90%. It was found in one study that faking varied as a function of degree of how important the consequences of test results could be expected to be, more high-stakes situations being associated with more faking. The latter finding is incompatible with the claim that social desirability scales measure a general personality trait. It is concluded that faking can be measured and that correction for faking, based on such measures, can be expected to remove about 90% of its effects. PMID- 26043668 TI - Imidazolium salts with antifungal potential against multidrug-resistant dermatophytes. AB - AIMS: To investigate the antidermatophytic action of a complementary set imidazolium salts (IMS), determining structure-activity relationships and characterizing the IMS toxicological profiles. METHODS AND RESULTS: The susceptibility evaluation of 45 dermatophytic clinical isolates, treated in vitro with eleven different IMS (ionic compounds) and commercial antifungals (nonionic compounds), was performed by broth microdilution, following the standard norm of CLSI M38-A2. All dermatophytes were inhibited by IMS, where the lowest minimum inhibitory concentration (MIC) values were observed for salts with n-hexadecyl segment in the cation side chain, containing either the chloride or methanesulfonate anion. 1-n-Hexadecyl-3-methylimidazolium chloride (C16 MImCl) and 1-n-hexadecyl-3-methylimidazolium methanesulfonate (C16 MImMeS) acted as fungicides, even in extremely low concentrations, wherein C16 MImMeS exerted this effect on 100% of the tested dermatophytes. Some of these IMS provoked evident alterations on the fungi cell morphology, causing a total cell damage of >= 70%. Importantly, none of the screened IMS were cytotoxic, mutagenic or genotoxic to human leucocyte cells. CONCLUSIONS: This report demonstrates for the first time the strong antifungal potential of IMS against multidrug-resistant dermatophytes, without presenting toxicity to human leucocyte cells at MIC. SIGNIFICANCE AND IMPACT OF THE STUDY: The expressive antifungal activity of IMS, combined with the in vitro nontoxicity, makes them promising compounds for the safe and effective treatment of dermatophytoses, mainly when this skin mycosis is unresponsive to conventional drugs. PMID- 26043669 TI - Age-related differences in inter-joint coordination during stair walking transitions. AB - Stair negotiation is one of the most difficult and hazardous locomotor tasks for older adults with fall-related accidences reported frequently. Since knowledge about inter-joint coordination during stair walking provides insights to age related changes in neuromuscular control of gait that can inform prevention or intervention strategies, the current study investigated the effect of age on the pattern and variability of inter-joint coordination during stair-floor transitions during gait. Gait and motion analyses of the lower extremities of 20 young and 20 older adults during floor to stair (F-S) and stair to floor (S-F) walking transitions provided continuous measures of relative phase (CRP) that assessed inter-joint coordination of the hip, knee, and angle joints. The mean absolute relative phase (MARP) and deviation phase (DP) provided descriptive metrics for CRP pattern and variability respectively. For hip-knee CRP pattern, older adults demonstrated significantly smaller MARP than young adults in stance and most swing phases during F-S and S-F. For knee-ankle, older adults showed a significant smaller MARP of the trailing limb during S-F than young adults. In most stance and swing phases, the hip-knee DP values of older adults were significantly lower than that of young adults. Significant lower knee-ankle DP values of older adults were only detected in swing phase during S-F. The findings suggest that normal aging adults have less independent control of adjacent joints compared to younger adults suggesting they have less flexibility to modulate inter-joints coordination appropriately during stair walking transitions. PMID- 26043670 TI - Gait Deviation Index, Gait Profile Score and Gait Variable Score in children with spastic cerebral palsy: Intra-rater reliability and agreement across two repeated sessions. AB - The Gait Deviation Index (GDI) and Gait Profile Score (GPS) are the most used summary measures of gait in children with cerebral palsy (CP). However, the reliability and agreement of these indices have not been investigated, limiting their clinimetric quality for research and clinical practice. The aim of this study was to investigate the intra-rater reliability and agreement of summary measures of gait (GDI; GPS; and the Gait Variable Score (GVS) derived from the GPS). The intra-rater reliability and agreement were investigated across two repeated sessions in 18 children aged 5-12 years diagnosed with spastic CP. No systematic bias was observed between the sessions and no heteroscedasticity was observed in Bland-Altman plots. For the GDI and GPS, excellent reliability with intraclass correlation coefficient (ICC) values of 0.8-0.9 was found, while the GVS was found to have fair to good reliability with ICCs of 0.4-0.7. The agreement for the GDI and the logarithmically transformed GPS, in terms of the standard error of measurement as a percentage of the grand mean (SEM%) varied from 4.1 to 6.7%, whilst the smallest detectable change in percent (SDC%) ranged from 11.3 to 18.5%. For the logarithmically transformed GVS, we found a fair to large variation in SEM% from 7 to 29% and in SDC% from 18 to 81%. The GDI and GPS demonstrated excellent reliability and acceptable agreement proving that they can both be used in research and clinical practice. However, the observed large variability for some of the GVS requires cautious consideration when selecting outcome measures. PMID- 26043671 TI - Injury narrative text classification using factorization model. AB - Narrative text is a useful way of identifying injury circumstances from the routine emergency department data collections. Automatically classifying narratives based on machine learning techniques is a promising technique, which can consequently reduce the tedious manual classification process. Existing works focus on using Naive Bayes which does not always offer the best performance. This paper proposes the Matrix Factorization approaches along with a learning enhancement process for this task. The results are compared with the performance of various other classification approaches. The impact on the classification results from the parameters setting during the classification of a medical text dataset is discussed. With the selection of right dimension k, Non Negative Matrix Factorization-model method achieves 10 CV accuracy of 0.93. PMID- 26043673 TI - Intradural migration of cervical posterior fixation rods. AB - BACKGROUND: Instrumented spinal fixations are an important tool in the management of traumatic conditions and delayed complications are rare. CASE REPORT: We present a case of open reduction and fixation of traumatic C5/6 facet fracture dislocation with late complication in the form of intradural hardware migration. CONCLUSION: To our knowledge, this is the first report of an intradural rod migration distant to the initial surgery in a patient without posterior decompression. This highlights the need for long-term follow-up of patients with spinal instrumentation. PMID- 26043672 TI - Modeling Pathologies of Diastolic and Systolic Heart Failure. AB - Chronic heart failure is a medical condition that involves structural and functional changes of the heart and a progressive reduction in cardiac output. Heart failure is classified into two categories: diastolic heart failure, a thickening of the ventricular wall associated with impaired filling; and systolic heart failure, a dilation of the ventricles associated with reduced pump function. In theory, the pathophysiology of heart failure is well understood. In practice, however, heart failure is highly sensitive to cardiac microstructure, geometry, and loading. This makes it virtually impossible to predict the time line of heart failure for a diseased individual. Here we show that computational modeling allows us to integrate knowledge from different scales to create an individualized model for cardiac growth and remodeling during chronic heart failure. Our model naturally connects molecular events of parallel and serial sarcomere deposition with cellular phenomena of myofibrillogenesis and sarcomerogenesis to whole organ function. Our simulations predict chronic alterations in wall thickness, chamber size, and cardiac geometry, which agree favorably with the clinical observations in patients with diastolic and systolic heart failure. In contrast to existing single- or bi-ventricular models, our new four-chamber model can also predict characteristic secondary effects including papillary muscle dislocation, annular dilation, regurgitant flow, and outflow obstruction. Our prototype study suggests that computational modeling provides a patient-specific window into the progression of heart failure with a view towards personalized treatment planning. PMID- 26043674 TI - Liposomal delivery of lipoarabinomannan triggers Mycobacterium tuberculosis specific T-cells. AB - Lipoarabinomannan (LAM) is a major cell wall component of Mycobacterium tuberculosis (Mtb). LAM specific human T-lymphocytes release interferon-gamma (IFNgamma) and have antimicrobial activity against intracellular Mtb suggesting that they contribute to protection. Therefore the induction of LAM-specific memory T-cells is an attractive approach for the design of a new vaccine against tuberculosis. A prerequisite for the activation of LAM-specific T-cells is the efficient uptake and transport of the glycolipid antigen to the CD1 antigen presenting machinery. Based on the hydrophobicity of LAM we hypothesized that packaging of LAM into liposomes will support the activation of T-lymphocytes. We prepared liposomes containing phosphatidylcholine, cholesterol, stearylated octaarginine and LAM via thin layer hydration method (LIPLAM). Flow cytometry analysis using fluorescently labelled LIPLAM showed an efficient uptake by antigen presenting cells. LAM delivered via liposomes was biologically active as demonstrated by the down-regulation of peroxisome proliferator activated receptor gamma (PPARgamma) protein expression. Importantly, LIPLAM induced higher IFNgamma production by primary human T-lymphocytes than purified LAM (2-16 times) or empty liposomes. These results suggest that the delivery of mycobacterial glycolipids via liposomes is a promising approach to promote the induction of M. tuberculosis specific T-cell responses. PMID- 26043675 TI - Expression of aryl hydrocarbon receptor 1 (AHR1), AHR1 nuclear translocator 1 (ARNT1) and CYP1 family monooxygenase mRNAs and their activity in chicken ovarian follicles following in vitro exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). AB - The aim of this in vitro study was to determine the effect of TCDD and luteinizing hormone (LH) on mRNA expression of aryl hydrocarbon receptor 1 (AHR1), AHR1 nuclear translocator 1 (ARNT1), and the CYP1 family monooxygenases (CYP1A4, CYP1A5, CYP1B1), and to assess the basal and TCDD-induced activity of these enzymes in chicken ovarian follicles. White (WF) and yellowish (YF) prehierarchical follicles and fragments of the theca (TL) and granulosa (GL) layers of the 3 largest preovulatory follicles (F3-F1) were exposed to TCDD (10nM), ovine LH (oLH; 10ng/mL) or a combination of TCDD (10nM) and oLH (10ng/mL), and increasing doses of TCDD (0.01-100nM). AHR1 and ARNT1 mRNA transcripts were found in all examined follicles. The effect of TCDD and oLH on AHR1 and ARNT1 mRNA expression depended on the maturational state of the follicle. CYP1A4 was predominantly expressed in the GL of the F3-F1 follicles; in comparison with the WF, a higher level of CYP1A5 mRNA was found both in the GL and TL of F3-F1 follicles. Alternatively, the highest level of CYP1B1 mRNA was noticed in the WF follicles. In different developmental stages of the follicle TCDD and oLH induced a different CYP1 isoform. TCDD increased EROD and MROD activities in all the investigated ovarian follicles. In conclusion, AHR1 and ARNT1 mRNA expression indicate that the chicken ovary is a target tissue for dioxin and dioxin-like compounds. The expression of CYP1-family genes and TCDD inducible EROD and MROD activities in ovarian follicles suggest the possibility of xenobiotic detoxification in the chicken ovary. PMID- 26043676 TI - Expression of BMI1 and ZEB1 in epithelial-mesenchymal transition of tongue squamous cell carcinoma. AB - Epithelial-mesenchymal transition (EMT) is a crucial event required for the invasion and progression of carcinogenesis, inducing stem-like properties in epithelial cells. In the present study, the expression of BMI1, which controls self-renewal in stem cells, as well as that of ZEB1, a transcription factor that regulates EMT, was evaluated for its role in EMT and the carcinogenic processes of tongue squamous cell carcinoma (TSCC). Collagen invasion assays using two TSCC cells and 64 tongue specimens (32 carcinomas and 32 dysplasias) were employed and analyzed in the present study. We assessed the protein and mRNA expression levels of BMI1, ZEB1, vimentin and E-cadherin in the two cell lines and tumor tissues. The protein and mRNA expression of BMI1 and ZEB1 occurred at the invasion of TSCC. The elevated levels of BMI1 and ZEB1 were accompanied by the downregulation of E-cadherin and upregulation of vimentin at the invasive front, indicative of EMT in vitro and in vivo. The results showed that BMI1 and ZEB1 are important factors in association with the promotion of EMT and invasion of TSCC. PMID- 26043679 TI - Cutaneous Fistulization of an Ovarian Mature Cystic Teratoma: An Unusual Occurrence. AB - A bilobulated mature cystic teratoma (MCT) at the left ovary measuring 6 cm in diameter fistulized to the left lower quadrant of the anterior abdominal wall, contralateral to McBurney's point. This is the first reported case of a MCT fistulized to the skin. Symptoms, if present, usually depend on the size of the teratoma. However, most patients with a MCT are asymptomatic. Complications such as rupture of the cyst capsule are quite rare. Moreover, complication of fistulization is highly infrequent. PMID- 26043678 TI - Effect of aflibercept in patients with age-related macular degeneration. AB - The purpose of this study was to evaluate the efficacy of standard induction therapy with intravitreal aflibercept (IVA) in patients with exudative age related macular degeneration (AMD) at 6 months after completion of induction therapy. Eleven eyes with typical AMD (tAMD) and 13 eyes with polypoidal choroidal vasculopathy (PCV) received three monthly doses of IVA (2 mg/0.05 ml in weeks 0, 4, and 8) for treatment of exudative AMD. Best-corrected visual acuity (BCVA) was measured, and optical coherence tomography was performed at baseline and at each monthly visit until 6 months after IVA. Treatment failure was defined as persistent or recurrent AMD that presented with cystoid macular edema, serous retinal detachment, and pigment epithelium detachment. Mean logMAR BCVA was improved from 0.62 +/- 0.46 at baseline to 0.54 +/- 0.43 at 6 months after IVA (p < 0.05). The success rate was 95.8 % at 3 months and 75.0 % at 6 months after IVA. Failure of IVA was positively associated with the absence of PVD before treatment (r = 0.35) and with the AMD type (tAMD, r = 0.43) by univariate analysis. Cox proportional hazards analysis demonstrated that the absence of PVD before treatment was associated with an increased risk of failure of IVA (OR = 33.17, p = 0.0219). Three months of induction IVA achieved a high success rate in patients with AMD monitored for up to 6 months. Factors associated with failure of IVA were the absence of PVD and the presence of tAMD. Accordingly, continuation of IVA following induction therapy may be beneficial to manage AMD in patients with tAMD or those without PVD. PMID- 26043677 TI - A comprehensive review of diagnostic imaging technologies to evaluate the retina and the optic disk. AB - Ophthalmic imaging has undergone a revolution over the past 20 years with increasingly efficient and high-definition modalities now available. The use of wide-field retinal angiography, fundus autofluorescence, state-of-the-art spectral domain, and enhanced depth imaging optical coherence tomography has proven to be effective in this field. This comprehensive review is devoted to retinal and optic disk imaging modalities and their clinical implications. It is based on the published literature in the field of ophthalmic imaging with a focus on recent advances. Ophthalmic imaging plays a crucial role in the management of patients with both isolated retinal disease and systemic diseases with ocular manifestations. Evolving technology enables imaging of ocular disease in vivo, facilitating objective assessment of disease progression and response to treatment. These latest technical improvements in ophthalmic imaging are now a part of standard ophthalmic assessment in academic centers and most private practices. In the coming years, further advances may improve diagnostic sensitivity and enable cost-effective screening of large populations. PMID- 26043680 TI - Effects of expiring reimbursability of pentaerythrityl tetranitrate (PETN, pentalong(r)) on anti-anginal therapy: an observational study. AB - PURPOSE: Pentaerythrityl tetranitrate (PETN) was the most commonly prescribed long-acting nitrate in Germany. We aimed to assess whether the discontinuation of PETN reimbursability in 2011 resulted in alternative prescriptions of anti anginal medications or in a discontinuation of anti-anginal therapy. METHODS: This is an observational study using health claims data from one German federal state analysing all patients discontinuing a PETN treatment. Patients starting a new alternative anti-anginal treatment (long-acting nitrates, molsidome, ivabradine and ranolazine) were compared with patients without a new anti-anginal treatment with respect to use of short-acting nitrates, beta blockers (BBs) and calcium channel blockers (CCBs). RESULTS: Out of 12,909 patients, 12,763 (99%) discontinued PETN until 12/2012. Of these, 52% started an alternative anti anginal treatment, 43% did not receive any alternative treatment and 5% were excluded from analysis. Before termination of PETN reimbursability, 65% of patients received BBs, 29% CCBs and 10% short-acting nitrates. In patients started on alternative anti-anginal treatment, prescription rates for short acting nitrates, BBs and CCBs remained constant after discontinuing PETN. In patients without any alternative anti-anginal treatment, prescription rates for BBs and CCBs did not change meaningfully (<3%), and prescription rates for short acting nitrates decreased from 9% to 6%. CONCLUSIONS: Half of the patients discontinued PETN without alternative. This did not lead to increased prescription rates of standard IHD medications or total medication number indicating that there might still be a high percentage of ischaemic heart disease patients treated unnecessarily with long-acting nitrates. The undertreatment with prognostically relevant first-line medications indicates a need for better guideline implementation activities. PMID- 26043682 TI - The lifetime of the actomyosin complex in vitro under load corresponding to stretch of contracting muscle. AB - During eccentric contraction, muscle is lengthening so that the actin-myosin cross-bridges bear a load that exceeds the force they generate during isometric contraction. Using the optical trap technique, we simulated eccentric contraction at the single molecule level and investigated the effect of load on the skeletal actomyosin lifetime at different ATP concentrations. The range of the loads was up to 17 pN above the isometric level. We found that the frequency distribution of the lifetime of the actin-bound state of the myosin molecule was biphasic: it quickly rose and then decreased slowly. The rate of the slow phase of this distribution increased with both the load and the ATP concentration. The fast phase accelerated sharply with the load, but it was independent of ATP concentration. The presence of the fast phase demonstrates that some transition(s) in the actomyosin complex occur before the myosin head becomes able to bind ATP and detach from actin. Its high sensitivity to the load indicates that the transition is load-dependent. PMID- 26043681 TI - A novel and highly specific phage endolysin cell wall binding domain for detection of Bacillus cereus. AB - Rapid, specific and sensitive detection of pathogenic bacteria is crucial for public health and safety. Bacillus cereus is harmful as it causes foodborne illness and a number of systemic and local infections. We report a novel phage endolysin cell wall-binding domain (CBD) for B. cereus and the development of a highly specific and sensitive surface plasmon resonance (SPR)-based B. cereus detection method using the CBD. The newly discovered CBD from endolysin of PBC1, a B. cereus-specific bacteriophage, provides high specificity and binding capacity to B. cereus. By using the CBD-modified SPR chips, B. cereus can be detected at the range of 10(5)-10(8) CFU/ml. More importantly, the detection limit can be improved to 10(2) CFU/ml by using a subtractive inhibition assay based on the pre-incubation of B. cereus and CBDs, removal of CBD-bound B. cereus, and SPR detection of the unbound CBDs. The present study suggests that the small and genetically engineered CBDs can be promising biological probes for B. cereus. We anticipate that the CBD-based SPR-sensing methods will be useful for the sensitive, selective, and rapid detection of B. cereus. PMID- 26043683 TI - Ameliorative effect of methylthiouracil on TGFBIp-induced septic responses. AB - The screening of bioactive compound libraries can be an effective approach for repositioning FDA-approved drugs or discovering new treatments for human diseases. Transforming growth factor beta-induced protein (TGFBIp) is an extracellular matrix protein whose expression in several cell types is greatly increased by TGF-beta. TGFBIp is released by human umbilical vein endothelial cells (HUVECs), and functions as a mediator of experimental sepsis. Here, we investigated the anti-septic effects and underlying mechanisms of methylthiouracil (MTU), used as antithyroid drug, against TGFBIp-mediated septic responses in HUVECs and mice. The anti-inflammatory activities of MTU were determined by measuring permeability, human neutrophils adhesion and migration, and activation of pro-inflammatory proteins in TGFBIp-activated HUVECs and mice. According to the results, MTU effectively inhibited lipopolysaccharide-induced release of TGFBIp, and suppressed TGFBIp-mediated septic responses, such as hyperpermeability, adhesion and migration of leukocytes, and expression of cell adhesion molecules. In addition, MTU suppressed CLP-induced sepsis lethality and pulmonary injury. Collectively, these results indicate that MTU could be a potential therapeutic agent for treatment of various severe vascular inflammatory diseases via inhibition of the TGFBIp signaling pathway. PMID- 26043684 TI - Mitogen activated protein kinase pathway-dependent effects of platelet-derived growth factor on migration of trophectoderm cells. AB - Successful development of the conceptus and implantation requires an intimate trophic connection between maternal uterus and conceptus mediated by local regulators including growth factors. Platelet-derived growth factor (PDGF) acts as a chemotactic factor for a variety of cell types. Current studies have determined that PDGF participates in rapid growth and development of cleavage stage embryos, but PDGF-induced effects on the growth and development of peri implantation conceptus remains unknown. In the present study, PDGF induced phosphorylation of ERK1/2, AKT and RPS6 proteins in porcine trophectoderm (pTr) cells in a dose- and time-dependent manner. Addition of U0126 (an inhibitor of ERK1/2) or LY294002 (a PI3K inhibitor) blocked PDGF-induced effects on phosphorylation of signaling proteins. Combinations of PDGF and U0126 decreased PDGF-induced p-ERK1/2 and p-AKT1, but combinations of PDGF and LY294002 blocked only PDGF-induced AKT phosphorylation. Furthermore, PDGF significantly induced pTr cell migration and these stimulatory effects were blocked by U0126 and LY294002. Immunoreactive p-ERK1/2 and p-RPS6 proteins were abundant in pTr cells treated with PDGF, but U0126 reduced PDGF-induced p-ERK1/2 and p-RPS6 levels to basal amounts. Present study suggests that PDGF secreted into the maternal conceptus microenvironment stimulates pTr cell migration through signal transduction cascades mediated by the ERK1/2 MAPK and AKT1 pathways. PMID- 26043685 TI - TRIM26 functions as a novel tumor suppressor of hepatocellular carcinoma and its downregulation contributes to worse prognosis. AB - Hepatocellular carcinoma (HCC) is the one of the most common malignancies worldwide and its prognosis is extremely poor. Tripartite motif (TRIM) proteins play crucial roles in cancer cell biology but the function of tripartite motif 26 (TRIM26) has not been investigated. We demonstrated that low expression level of TRIM26 in tumor samples was significantly correlated with worse prognosis in HCC patients. We also demonstrated its expression level was associated with several clinicopathologic features such as AFP level and T stage of HCC patients. Furthermore, we validated that TRIM26 was significantly downregulated in HCC tissue compared with normal liver tissue. To further clarify the functional role of TRIM26 in HCC, We confirmed that TRIM26 silencing can promote cancer cell proliferation, colony forming, migration and invasion in vitro with HCC cell lines HepG2 and Bel-7402. Then we utilized bioinformatic tool to predict gene influenced by TRIM26, showing TRIM26 could modulate gene sets about cancer cell metabolism. In conclusion, we proved that TRIM26 is a novel tumor suppressor modulating multiple metabolism-related pathways in HCC. To our best knowledge, this is the first study to investigate the function of TRIM26 in cancer biology. Our findings provide useful insight into the mechanism of HCC origin and progression. Moreover, TRIM26 may represent a novel therapeutic target for HCC. PMID- 26043686 TI - Up-regulation of fatty acid synthase induced by EGFR/ERK activation promotes tumor growth in pancreatic cancer. AB - Lipid metabolism is dysregulated in many human diseases including atherosclerosis, type 2 diabetes and cancers. Fatty acid synthase (FASN), a key lipogenic enzyme involved in de novo lipid biosynthesis, is significantly upregulated in multiple types of human cancers and associates with tumor progression. However, limited data is available to understand underlying biological functions and clinical significance of overexpressed FASN in pancreatic ductal adenocarcinoma (PDAC). Here, upregulated FASN was more frequently observed in PDAC tissues compared with normal pancreas in a tissue microarray. Kaplan-Meier survival analysis revealed that high expression level of FASN resulted in a significantly poor prognosis of PDAC patients. Knockdown or inhibition of endogenous FASN decreased cell proliferation and increased cell apoptosis in HPAC and AsPC-1 cells. Furthermore, we demonstrated that EGFR/ERK signaling accounts for elevated FASN expression in PDAC as ascertained by performing siRNA assays and using specific pharmacological inhibitors. Collectively, our results indicate that FASN exhibits important roles in tumor growth and EGFR/ERK pathway is responsible for upregulated expression of FASN in PDAC. PMID- 26043687 TI - DNA methyltransferases have an essential role in female fecundity in brown planthopper, Nilaparvata lugens. AB - DNA methylation is an ancient epigenetic modification present in all three domains of life. However, the understanding of DNA methylation in insects is limited. Here, we amplified the full-length transcripts of the DNA methyltransferases Nlu-Dnmt1 and Nlu-Dnmt3, indicating that a complete DNA methylation toolkit exists in the brown planthopper, Nilaparvata lugens, a destructive pest in rice production. Nlu-DNMT1 and Nlu-DNMT3 had the conserved motifs and domains of the DNA methyltransferase family. Nlu-Dnmt1 and Nlu-Dnmt3 were highly expressed in the mated and gravid female adults but weakly expressed in larvae, male adults, and virgin female adults. Silencing Nlu-Dnmt1 and Nlu Dnmt3 in gravid brachypterous female adults led to fewer offspring, suggesting that DNA methylation regulates female fecundity in insects. PMID- 26043688 TI - Identification and characterization of the linear region of ATG3 that interacts with ATG7 in higher eukaryotes. AB - Transfer of GABARAP thioester from the E1 ATG7 to the E2 ATG3 requires the interaction between the N-terminal domain of ATG7 and the flexible region (FR) of ATG3. This interaction has been visualized in the yeast Atg7-Atg3 complex crystal structure, but remains to be defined in higher eukaryotes. Here, our NMR data precisely define the region of the FR of human ATG3 that interacts with ATG7 (RIA7) and demonstrate RIA7 partially overlaps with the E3-interacting region, explaining how the E1-E2 and E2-E3 interactions are mutually exclusive. Mutational analyses identify critical residues of the RIA7 for the E1 interaction and GABARAP transfer, advancing our understanding of a molecular mechanism of the autophagic conjugation cascade in higher eukaryotes. PMID- 26043689 TI - Evaluation of drug toxicity profiles based on the phenotypes of ascidian Ciona intestinalis. AB - In vivo toxicity evaluation using model organisms is an important step for the development of new drugs. Here, we report that Ciona intestinalis, a chordate invertebrate, is beneficial to drug toxicity evaluation for the following reasons: rapid embryonic and larval development, resemblance to vertebrates, ease of management, low cost, transparent body, and low risk of ethical issues. The dynamic phenotypic change of Ciona larvae during metamorphosis prompted us to examine the effect of cytotoxic drugs on its development by quantifying six toxicity endpoints: degenerated tail size, ampulla length, rotation of body axis, stomach size, heart rate, and body size. As a result, mitochondrial respiratory inhibitors, tubulin polymerization/depolymerization inhibitors, or DNA/RNA synthesis inhibitors showed distinct toxicity profiles against these six endpoints, but drugs with the same targets showed a similar toxicity profile in Ciona. Our results suggest Ciona is an effective animal model for profiling drug toxicity and exploring the mechanisms of drugs with unknown targets. PMID- 26043690 TI - Tetramethylpyrazine inhibits neutrophil activation following permanent cerebral ischemia in rats. AB - Experimental studies have demonstrated the beneficial effects of tetramethylpyrazine (TMP) against ischemic stroke and highlighted its crucial role in anti-inflammatory activity. This study provides evidence of an alternative target for TMP and sheds light on the mechanism of its anti inflammatory action against ischemic brain injury. We report a global inhibitory effect of TMP on inflammatory cell intracerebral activation and infiltration in a rat model of permanent cerebral ischemia. The results of immunohistochemistry, enzymatic assay, flow cytometric analysis, and cytological analysis revealed that intraperitoneal TMP administration reduced neuronal loss, macrophage/microglia activation, brain parenchyma infiltrative neutrophils, and circulating neutrophils after cerebral ischemia. Biochemical studies of cultured neutrophils further demonstrated that TMP attenuated neutrophil migration, endothelium adhesion, spontaneous nitric oxide (NO) production, and stimuli-activated NO production after cerebral ischemia. In parallel with these anti-neutrophil phenomena, TMP also attenuated the activities of ischemia-induced inflammation associated signaling molecules, including plasma high-mobility group box-1 protein (HMGB1) and neutrophil toll-like receptor-4 (TLR4), Akt, extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase. Another finding in this study was that the anti-neutrophil effect of TMP was accompanied by a further elevated expression of NF-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in neutrophils after cerebral ischemia. Taken together, our results suggest that both the promotion of endogenous anti-inflammatory defense capacity and the attenuation of pro-inflammatory responses via targeting of circulating neutrophils by elevating Nrf2/HO-1 expression and inhibiting HMGB1/TLR4, Akt, and ERK signaling might actively contribute to TMP-mediated neuroprotection against cerebral ischemia. PMID- 26043691 TI - Src tyrosyl phosphorylates cortactin in response to prolactin. AB - The hormone/cytokine prolactin (PRL) is implicated in breast cancer cell invasion and metastasis. PRL-induced pathways are mediated by two non-receptor tyrosine kinases, JAK2 and Src. We previously demonstrated that prolactin stimulates invasion of breast cancer cells TMX2-28 through JAK2 and its target serine/threonine kinase PAK1. We hypothesize herein that the actin-binding protein cortactin, a protein involved in invadopodia formation and cell invasion, is activated by PRL. We demonstrate that TMX2-28 cells are more invasive than T47D breast cancer cells in response to PRL. We determine that cortactin is tyrosyl phosphorylated in response to PRL in a time and dose-dependent manner in TMX2-28 cells, but not in T47D cells. Furthermore, we show that PRL mediates cortactin tyrosyl phosphorylation via Src, but not JAK2. Finally, we demonstrate that maximal PRL-mediated TMX2-28 cell invasion requires both Src and JAK2 kinase activity, while T47D cell invasion is JAK2- but not Src-dependent. Thus PRL may induce cell invasion via two pathways: through a JAK2/PAK1 mediated pathway that we have previously demonstrated, and Src-dependent activation and tyrosyl phosphorylation of cortactin. PMID- 26043692 TI - Long none coding RNA HOTTIP/HOXA13 act as synergistic role by decreasing cell migration and proliferation in Hirschsprung disease. AB - Long noncoding RNAs (lncRNAs) have been confirmed to be associated with various human diseases. However, whether they are associated with Hirschsprung disease (HSCR) progression remains unclear. In this study, we designed the experiment to explore the relationship between lncRNA HOTTIP and HOXA13, and their pathogenicity to HSCR. Quantitative real-time PCR and Western blot were performed to detect the levels of lncRNA, mRNAs, and proteins in colon tissues from 79 patients with HSCR and 79 controls. Small RNA interference transfection was used to study the function experiments in human 293T and SK-N-BE cell lines. The cell viability and activities were detected by the transwell assays, CCK8 assay, and flow cytometry, respectively. LncRNA HOTTIP and HOXA13 were significantly down regulated in HSCR compared to the controls. Meanwhile, the declined extent of their expression levels makes sense between two main phenotype of HSCR. SiRNA mediated knock-down of HOTTIP or HOXA13 correlated with decreased levels of each other and both reduced the cell migration and proliferation without affecting cell apoptosis or cell cycle. Our study demonstrates that aberrant reduction of HOTTIP and HOXA13, which have a bidirectional regulatory loop, may play an important role in the pathogenesis of HSCR. PMID- 26043693 TI - Neuregulin 1 as an endogenous regulator of nicotinic acetylcholine receptors in adult major pelvic ganglion neurons. AB - We investigated whether endogenous neuregulin 1 (NRG1) is released in a soluble form (called sNRG1) and upregulates expression of nicotinic acetylcholine receptor (nAChR) in autonomic major pelvic ganglion (MPG) neurons of adult rats. To elicit the release of sNRG1, either the hypogastric nerve or the pelvic nerve was electrically stimulated. Then, the MPG-conditioned medium (CM) was subjected to western blotting using an antibody directed against the N-terminal ectodomain of NRG1. Both sympathetic and parasympathetic nerve activation elicited the release of sNRG1 from MPG neurons in a frequency-dependent manner. The sNRG1 release was also induced by treatment of MPG neurons with either high KCl or neurotrophic factors. The biological activity of the released sNRG1 was detected by tyrosine phosphorylation (p185) of the ErbB2 receptors in MPG neurons. When MPG neurons were incubated for 6 h in the CM, the protein level of the nAChR alpha3 subunit and ACh-induced current (IACh) density were significantly increased. The CM-induced changes in IACh was abolished by a selective ErbB2 tyrosine kinase inhibitor. Taken together, these data suggest that NRG1 functions as an endogenous regulator of nAChR expression in adult MPG neurons. PMID- 26043694 TI - Sgk1 regulates desmoglein 1 expression levels in oligodendrocytes in the mouse corpus callosum after chronic stress exposure. AB - Major depression, one of the most prevalent mental illnesses, is thought to be a multifactorial disease related to both genetic and environmental factors. However, the genes responsible for and the pathogenesis of major depression at the molecular level remain unclear. Recently, we reported that stressed mice with elevated plasma corticosterone levels show upregulation and activation of serum glucocorticoid-regulated kinase (Sgk1) in oligodendrocytes. Active Sgk1 causes phosphorylation of N-myc downstream-regulated gene 1 (Ndrg1), and phospho-Ndrg1 increases the expression of N-cadherin, alpha-catenin, and beta-catenin in oligodendrocytes. This activation of the Sgk1 cascade results in morphological changes in the oligodendrocytes of nerve fiber bundles, such as those present in the corpus callosum. However, little is known about the molecular functions of the traditional and/or desmosomal cadherin superfamily in oligodendrocytes. Therefore, in this study, we aimed to elucidate the functions of the desmosomal cadherin superfamily in oligodendrocytes. Desmoglein (Dsg) 1, Dsg2, and desmocollin 1 (Dsc1) were found to be expressed in the corpus callosum of mouse brain, and the expression of a subtype of Dsg1, Dsg1c, was upregulated in oligodendrocytes after chronic stress exposure. Furthermore, Dsg1 proteins were localized around the plasma membrane regions of oligodendrocytes. A study in primary oligodendrocyte cultures also revealed that chronic upregulation of Sgk1 by dexamethasone administration is involved in upregulation of Dsg1c mRNA. These results may indicate that chronic stress induced Sgk1 activation in oligodendrocytes, which increases Dsg1 expression near the plasma membrane. Thus, Dsg1 upregulation may be implicated in the molecular mechanisms underlying the morphological changes in oligodendrocytes in response to chronic stress exposure. PMID- 26043695 TI - Knockdown of ERp44 leads to apoptosis via activation of ER stress in HeLa cells. AB - ERp44, an endoplasmic reticulum (ER) resident protein, regulates intracellular Ca(2+) release and involves in the maturation of many proteins in mammalian cells. In this study, we investigated the effects and mechanism of ERp44 on cell apoptosis by using ERp44 knockdown stable HeLa cell lines. We found that ERp44 knockdown resulted in increases in cell apoptosis rate more than one fold higher than that of control; using serum starvation, caspase-3 protein level was significantly up-regulated in ERp44 knockdown cells compared to the control cells. Furthermore, we demonstrated that in response to serum starvation, the protein levels of CHOP and GRP78 were also largely raised in ERp44 knockdown cells. Moreover, caspase-12 was activated, which suggested cell apoptosis was induced by ER stress. Taken together, our results indicate that knockdown of ERp44 leads to cell apoptosis through the activation of ER stress. PMID- 26043696 TI - Valosin-containing protein (VCP/p97) is capable of unfolding polyubiquitinated proteins through its ATPase domains. AB - Valosin-containing protein (VCP or p97) is required for the proteasomal degradation of polyubiquitinated proteins. However, the molecular mechanism for VCP to process the polyubiquitinated proteins remains unclear. Here, we show that VCP can unfold polyubiquitinated proteins. It preferably unfolds the pentaubiquitin-over monoubiquin-conjugated dihydrofolate reductase (Ub5-DHFR or Ub-DHFR) in a dose dependent manner. In addition, the unfolding activity of VCP does not depend on its ATPase activity, on the contrary, ATP and its non hydrolysable analogs suppress the unfolding of Ub5-DHFR. The structural and functional analysis showed that either D1 or D2 domain of VCP is sufficient to carry out this unfolding activity. The structure of the substrates also affects its unfolding by VCP. VCP is unable to unfold Ub5-DHFR in a tight structure when it binds with methotrexate, a folate analog with high affinity to DHFR. Thus, these results support that VCP is capable of unfolding polyubiquitinated proteins and suggest that VCP may facilitate the proteasomal degradation of polyubiquitinated proteins through its unfolding activity. PMID- 26043698 TI - TAZ promotes temozolomide resistance by upregulating MCL-1 in human glioma cells. AB - Temozolomide is a novel cytotoxic agent currently used as first-line chemotherapy for glioblastoma multiforme (GBM). However, intrinsic or acquired chemoresistance to temozolomide remains the greatest obstacle to the successful treatment of human GBM. The principal mechanism responsible for this resistance is largely unknown. In the present study, we showed that expression of transcriptional co activator with PDZ-binding motif (TAZ) in glioma cells correlated with temozolomide chemoresistance in human glioma cells. Overexpression of TAZ promoted temozolomide resistance in U-87MG cells, whereas knockdown of TAZ expression sensitized temozolomide-resistant U-251MG cells to temozolomide. Further, TAZ inhibits temozolomide induced apoptosis via upregulation of MCL-1 (myeloid cell leukemia 1) and high expression of TAZ predicts a poor prognosis for GBM patients. In conclusion, our results suggest that TAZ had a critical role in the resistance to temozolomide in glioma cells, and it may provide a promising target for improving the therapeutic outcome of temozolomide-resistant gliomas. PMID- 26043697 TI - Long non-coding RNA APTR promotes the activation of hepatic stellate cells and the progression of liver fibrosis. AB - In this study, we aimed at assessing a role of Alu-mediated p21 transcriptional regulator (APTR) in hepatofibrogenesis. APTR was upregulated in fibrotic liver samples and activated hepatic stellate cells (HSCs). Knockdown of APTR inhibited the activation of HSCs in vitro and mitigated the accumulation of collagen in vivo. Importantly, APTR silencing could abrogate TGF-beta1-induced upregulation of alpha-SMA in HSCs. In addition, inhibition of cell cycle and cell proliferation by APTR knockdown was attenuated by p21 siRNA1 in primary HSCs. Finally, serum APTR levels were increased in patients with liver cirrhosis, indicating a potential biomarker for liver cirrhosis. Collectively, evidence is proposed for a new biological role of APTR in hepatofibrogenesis. PMID- 26043699 TI - SHC1 sensitizes cancer cells to the 8-Cl-cAMP treatment. AB - 8-Chloro-cyclic AMP (8-Cl-cAMP) is a cyclic AMP analog that induces growth inhibition and apoptosis in a broad spectrum of cancer cells. Previously, we found that 8-Cl-cAMP-induced growth inhibition is mediated by AMP-activated protein kinase (AMPK) as well as p38 mitogen-activated protein kinase (p38 MAPK). To identify downstream mediators of the 8-Cl-cAMP signaling, we performed co immunoprecipitation combined with mass spectrometry using the anti-AMPK or p38 MAPK antibodies. Through this approach, SHC1 was identified as one of the binding partners of p38 MAPK. SHC1 phosphorylation was suppressed by 8-Cl-cAMP in HeLa and MCF7 cancer cells, which was mediated by its metabolites, 8-Cl-adenosine and 8-Cl-ATP; however, 8-Cl-cAMP showed no effect on SHC1 phosphorylation in normal human fibroblasts. SHC1 siRNA induced AMPK and p38 MAPK phosphorylation and growth inhibition in cancer cells, and SHC1 overexpression re-sensitized human foreskin fibroblasts to the 8-Cl-cAMP treatment. SHC1 phosphorylation was unaffected by Compound C (an AMPK inhibitor) and SB203580 (a p38 MAPK inhibitor), which suggests that SHC1 is upstream of AMPK and p38 MAPK in the 8-Cl-cAMP stimulated signaling cascade. On the basis of these findings, we conclude that SHC1 functions as a sensor during the 8-Cl-cAMP-induced growth inhibition in SHC1 overexpressing cancer cells. PMID- 26043700 TI - Pretransplant management of basilar artery aneurysm and moyamoya disease in a child with Alagille syndrome. PMID- 26043702 TI - Direct ophthalmoscopy should be taught to undergraduate medical students-yes. PMID- 26043701 TI - Toll-like receptor 7/8 agonist, R848, exhibits antitumoral effects in a breast cancer model. AB - Toll-like receptors have been utilized in cancer therapeutic strategies in recent years. To the best of our knowledge, the systemic use of the toll-like receptor 7/8 (TLR7/8) agonist has not been investigated in a breast cancer model. In the current study, tumor growth following drug therapy was examined. Immunofluorescence and TUNEL staining were performed in order to examine the tumor vasculature and apoptosis, respectively. In addition, immunohistochemistry was used to assess HMGB1 in tumor tissues. Activated CD4+ T cells in the peripheral blood were examined by flow cytometry. In the present study, it was identified that the TLR7/8 agonist, R848, exhibited a robust antitumoral effect. R848 reduced tumor vasculature and induced tumor cell apoptosis. In addition, R848 increased high mobility group box 1 expression in tumor tissues and activated CD4+ T cells in the peripheral blood. A synergistic antitumoral effect of R848 and the anti-angiogenic agent, sunitinib, was observed. The present findings suggest that the TLR7/8 agonist may be a potential adjuvant to potentiate the effect of anti-angiogenic therapy. PMID- 26043703 TI - Performance of a computerised visual acuity measurement device in subjects with age-related macular degeneration: comparison with gold standard ETDRS chart measurements. AB - PURPOSE: The aim of the study was to compare the performance of two different COMPlog computerised, single letter scoring, visual acuity (VA) measurements against gold standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart measurements in patients with age-related macular degeneration (AMD). One computerised algorithm presented five and the other presented three letters per line; both computerised algorithms utilised half, rather than the full-letter width spacing standard on ETDRS charts that might induce crowding, fixation problems, increased test-retest variability (TRV), and bias. METHODS: Fifty patients with AMD (mean age 83 years) underwent timed test and retest VA measurements using ETDRS charts and COMPlog five (C5) and three (C3) letters per line computerised VA measurement algorithms. All tests utilised single-letter scoring methodology. Bland and Altman methods were employed. Performance was measured in terms of bias, TRV, and test time. RESULTS: The C5 and C3 scores showed no bias compared with the ETDRS chart measurements. C5 measurements had equal TRV to the ETDRS chart (+/-0.13 logMAR) with similar median test times (105 and 96 s, respectively). C3 measurements were slightly more variable (TRV +/-0.17 logMAR), but 30 s quicker than ETDRS chart measurements. CONCLUSIONS: The closer letter spacing employed in COMPlog testing algorithms appears to have no adverse effect on VA measurements compared with the gold standard ETDRS chart in patients with AMD. The three letter per line testing algorithm facilitates faster testing but with a two letter increase in TRV. PMID- 26043705 TI - A 10-year review of orbital biopsy: the Newcastle Eye Centre Study. AB - PURPOSE: To review the histopathological diagnoses, visual outcome, and complication rate of orbital biopsy in a UK tertiary referral centre. METHODS: This was a retrospective, clinical-pathological, interventional, consecutive case series. All orbital biopsies performed between July 2004 and June 2014 in Newcastle Eye Centre (Newcastle upon Tyne, UK) were included in this study. All relevant data collected from the local electronic database and medical records were analysed. RESULTS: A total of 166 orbital biopsies were identified during the study period: 86 patients (53.1%) were female and the mean age was 53.7 +/- 19.7 years. Of all the cases, orbital biopsies were performed unilaterally in 158 (97.5%) patients and bilaterally in 4 (2.5%) patients. The mean follow-up period was 2.2 +/- 2.3 years. The two most common histopathological diagnoses were non specific inflammatory disease (62, 38.3%) and lymphoproliferative disease (40, 24.7%). None of the patients experienced >= 2-Snellen line visual loss. There were 7 (4.2%) postoperative complications noted: 1 (0.6%) orbital haemorrhage with no loss of vision, 4 (2.4%) diplopia, 1 (0.6%) short-term symblepharon, and 1 (0.6%) conjunctival granuloma. Postoperative diplopia was associated with lateral orbitotomy (P = 0.044) and excisional biopsy (P = 0.015). CONCLUSIONS: Orbital biopsy serves as a safe diagnostic tool in managing orbital diseases. Patient should be made aware of the risk of postoperative diplopia. Our data provides useful guidance to clinicians when counselling patients for orbital biopsy. PMID- 26043704 TI - Retinal pigment epithelium transplantation: concepts, challenges, and future prospects. AB - The retinal pigment epithelium (RPE) is a single layer of cells that supports the light-sensitive photoreceptor cells that are essential for retinal function. Age related macular degeneration (AMD) is a leading cause of visual impairment, and the primary pathogenic mechanism is thought to arise in the RPE layer. RPE cell structure and function are well understood, the cells are readily sustainable in laboratory culture and, unlike other cell types within the retina, RPE cells do not require synaptic connections to perform their role. These factors, together with the relative ease of outer retinal imaging, make RPE cells an attractive target for cell transplantation compared with other cell types in the retina or central nervous system. Seminal experiments in rats with an inherited RPE dystrophy have demonstrated that RPE transplantation can prevent photoreceptor loss and maintain visual function. This review provides an update on the progress made so far on RPE transplantation in human eyes, outlines potential sources of donor cells, and describes the technical and surgical challenges faced by the transplanting surgeon. Recent advances in the understanding of pluripotent stem cells, combined with novel surgical instrumentation, hold considerable promise, and support the concept of RPE transplantation as a regenerative strategy in AMD. PMID- 26043706 TI - Long-term visual outcomes of intravitreal ranibizumab treatment for wet age related macular degeneration and effect on blindness rates in south-east Scotland. AB - AIMS: To evaluate patient visual acuity outcomes and blindness rates attributable to wet AMD with a potential 5-year follow-up from intravitreal ranibizumab treatment (IVTR) in south-east Scotland. METHODS: Data was analysed from 104 eyes of 96 patients who initiated treatment prior to September 2008. The main outcome measures were LogMAR visual acuity, number of clinic visits and the number of injections. Annual blind registration data in south-east Scotland were analysed using blind certifications recorded by the Royal National Institute of Blind People. RESULTS: Patients had a mean clinical follow-up of 4 years and 1 month and a mean loss of 5.5 letters over the study period. Of the treated eyes 9.6% gained >= 15 letters whilst 24.0% lost >= 15 letters during this period. An average of 9.56 injections were administered per patient. The age-sex standardised incidence of legal blindness attributable to wet AMD in south-east Scotland peaked at 9.1 cases per 100,000 of the population in 2006 in either eye. Following the introduction of IVTR there were annual decreases in the incidence of blindness attributable to AMD falling to a trough of 4.8 cases per 100,000 of the population in 2011. CONCLUSIONS: This study demonstrates that the majority of patients in a south-east Scotland maintain their vision following IVTR in wet AMD in the real-world setting. Our study also suggests that the introduction of IVTR has had population wide benefits in reducing the blindness attributable to wet AMD in the south-east Scotland population. PMID- 26043707 TI - MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity. AB - A new class of chemotherapeutic agents, MEK inhibitors, has recently been developed and is proving to be an effective treatment for a number of cancers. A pattern of ocular adverse events has followed these drugs through clinical trials and their association with retinopathy is only just beginning to be recognized. We present two cases of MEK inhibitor-associated retinopathy followed by a review of the current literature on ocular toxicity associated with MEK inhibitors. Patients undergoing treatment with MEK inhibitors appear to have high rates of multifocal serous retinal detachments as well as retinal vein occlusions. We present the first report of cystoid macular edema associated with MEK inhibitor use. The mechanism of these adverse events is still unclear though they seem to be related to oxidative stress and blood retinal barrier breakdown. Management of the ocular toxicity can range from observation to topical treatments or intravitreal injections. Fortunately most ocular adverse events appear to be self limited and do not require discontinuing the MEK inhibitor. Discontinuation or decreased dosing of MEK inhibitors may be reserved for cases of severe sight threatening ocular toxicity. PMID- 26043708 TI - Direct ophthalmoscopy should be taught to undergraduate medical students--No. PMID- 26043710 TI - Vaccines for preventing invasive salmonella infections in people with sickle cell disease. AB - BACKGROUND: Salmonella infections are a common bacterial cause of invasive disease in people with sickle cell disease especially children, and are associated with high morbidity and mortality rates. Although available in some centres, people with sickle cell anaemia are not routinely immunized with salmonella vaccines. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine whether routine administration of salmonella vaccines to people with sickle cell disease reduces the morbidity and mortality associated with infection. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.We also conducted a search of the LILACS database.Date of most recent searches: 05 May 2015. SELECTION CRITERIA: We planned to select all randomized controlled trials that compared the use of either the inactivated vaccine or an oral attenuated vaccine with a placebo among people with sickle cell disease. Equally, studies that compared the efficacy of one vaccine type over another were to be selected for the review. DATA COLLECTION AND ANALYSIS: No trials of salmonella vaccines in people with sickle cell disease were found. MAIN RESULTS: There is an absence of randomized controlled trial evidence relating to the scope of this review. AUTHORS' CONCLUSIONS: It is expected that salmonella vaccines may be useful in people with sickle cell disease, especially in resource-poor settings where the majority of those who suffer from the condition are found. Unfortunately, there are no randomized controlled trials on the efficacy and safety of the different types of salmonella vaccines in people with sickle cell disease. We conclude that there is a need for a well-designed, adequately-powered, randomized controlled trial to assess the benefits and risks of the different types of salmonella vaccines as a means of improving survival and decreasing mortality from salmonella infections in people with sickle cell disease. PMID- 26043709 TI - The invisible work of personal health information management among people with multiple chronic conditions: qualitative interview study among patients and providers. AB - BACKGROUND: A critical problem for patients with chronic conditions who see multiple health care providers is incomplete or inaccurate information, which can contribute to lack of care coordination, low quality of care, and medical errors. OBJECTIVE: As part of a larger project on applications of consumer health information technology (HIT) and barriers to its use, we conducted a semistructured interview study with patients with multiple chronic conditions (MCC) with the objective of exploring their role in managing their personal health information. METHODS: Semistructured interviews were conducted with patients and providers. Patients were eligible if they had multiple chronic conditions and were in regular care with one of two medical organizations in New York City; health care providers were eligible if they had experience caring for patients with multiple chronic conditions. Analysis was conducted from a grounded theory perspective, and recruitment was concluded when saturation was achieved. RESULTS: A total of 22 patients and 7 providers were interviewed; patients had an average of 3.5 (SD 1.5) chronic conditions and reported having regular relationships with an average of 5 providers. Four major themes arose: (1) Responsibility for managing medical information: some patients perceived information management and sharing as the responsibility of health care providers; others-particularly those who had had bad experiences in the past-took primary responsibility for information sharing; (2) What information should be shared: although privacy concerns did influence some patients' perceptions of sharing of medical data, decisions about what to share were also heavily influenced by their understanding of health and disease and by the degree to which they understood the health care system; (3) Methods and tools varied: those patients who did take an active role in managing their records used a variety of electronic tools, paper tools, and memory; and (4) Information management as invisible work: managing transfers of medical information to solve problems was a tremendous amount of work that was largely unrecognized by the medical establishment. CONCLUSIONS: We conclude that personal health information management should be recognized as an additional burden that MCC places upon patients. Effective structural solutions for information sharing, whether institutional ones such as care management or technological ones such as electronic health information exchange, are likely not only to improve the quality of information shared but reduce the burden on patients already weighed down by MCC. PMID- 26043711 TI - Torticollis in children: an alert symptom not to be turned away. AB - PURPOSE: The aim of this study is to investigate the spectrum of underlying disease in children with torticollis. METHODS: We investigated the spectrum of underlying disease and to evaluate the clinical features of the children presented with torticollis in the last 2 years. RESULTS: Of the 20 children (13 girls and 7 boys with the mean age of 8 years, ranging 2 months-12 years), eight of them have craniospinal pathologies (cerebellar tumors in three, exophytic brain stem glioma, eosinophilic granuloma of C2 vertebra, neuroenteric cyst of the spinal cord, Chiari type 3 malformation, arachnoid cysts causing brainstem compression, and cerebellar empyema), followed by osseous origin in five (congenital vertebral anomalies including hemivertebrae, blocked vertebra, and segmentation anomalies), two muscular torticollis (soft tissue inflammation due to subclavian artery catheterization, myositis ossificans with sternocleidomastoid muscle atrophy), and ocular (congenital cataract and microphthalmia), Sandifer syndrome, paroxysmal torticollis, retropharyngeal abscess each in one patients were detected. Ten patients underwent surgery; two patients received medical therapy for reflux and benign paroxysmal torticollis; and one patient with torticollis due to muscle spasm and soft tissue inflammation was treated with physiotherapy. CONCLUSIONS: Various underlying disorders from relatively benign to life-threatening conditions may present with torticollis. The first step should be always a careful and complete physical examination, which must include all systems. Imaging must be performed for ruling out underlying life-threatening diseases in children with torticollis, particularly, if acquired neurological symptoms exist. Besides craniospinal tumors, ophthalmological problems and central nervous system infections should also be kept in mind. Moreover, early diagnosis of these disorders will reduce mortality and morbidity. Therefore, alertness of clinicians in pediatric and pediatric neurosurgery practice must be increased about this alert symptom. PMID- 26043713 TI - Joint Meeting of the European Society for Microcirculation (ESM) European Vascular Biology Organisation (EVBO). Pisa, Italy, June 3-6, 2015: Abstracts. PMID- 26043712 TI - Metabolomic analysis of serum from obese adults with hyperlipemia by UHPLC-Q-TOF MS/MS. AB - The prevalence of obesity has dramatically increased and poses a major threat to human health. Obesity often accompanies hyperlipemia, which is strongly related to the occurrence and development of obesity-related chronic diseases. Differences in metabolomic profiling of serum between obese (with hyperlipemia) and normal-weight men (n = 30 in each group) were investigated using ultrahigh pressure liquid chromatography-quadrupole-time of flight mass spectrometry (UHPLC Q-TOF MS/MS) and partial least-squares-discriminant analysis (PLS-DA). Obese men showed higher levels of weight, body mass index, fat mass, systolic blood pressure, fasting plasma glucose, triglyeride, total cholesterol, insulin, HOMA IR and high-sensitivity CRP. Obese and normal-weight groups were clearly discriminated from each other on a PLS-DA score plot and nine major metabolites contributing to the discrimination were assigned, including increased 2 octenoylcarnitine, eicosadienoic acid, 12-hydroperoxyeicosatetraenoic acid, 4 hydroxyestrone sulfate, lysoPE[18:1(11Z)/0:0], thromboxane B2 and pyridinoline and decreased vitamin D3 glucosiduronate and 9,10-DHOME. These metabolites were associated with lipid metabolism and obesity-related diseases, and reflected the metabolic differences between normal and obese men, which may be important for future clinical diagnosis, treatment and assessment of the therapeutic effect on obesity-related chronic disease. PMID- 26043714 TI - CORR(r) Curriculum--Orthopaedic Education: The Evolution of Orthopaedic Surgery Education in Germany. PMID- 26043715 TI - Not the Last Word: Codman Was Right--Spread The Word. PMID- 26043716 TI - CORR Insights: Low Albumin Levels, More Than Morbid Obesity, Are Associated With Complications After TKA. PMID- 26043717 TI - Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression. AB - Radiotherapy is common in the treatment of brain tumors in children but often causes deleterious, late-appearing sequelae, including cognitive decline. This is thought to be caused, at least partly, by the suppression of hippocampal neurogenesis. However, the changes in neuronal network properties in the dentate gyrus (DG) following the irradiation of the young, growing brain are still poorly understood. We characterized the long-lasting effects of irradiation on the electrophysiological properties of the DG after a single dose of 6-Gy whole-brain irradiation on postnatal day 11 in male Wistar rats. The assessment of the basal excitatory transmission in the medial perforant pathway (MPP) by an examination of the field excitatory postsynaptic potential/volley ratio showed an increase of the synaptic efficacy per axon in irradiated animals compared to sham controls. The paired-pulse ratio at the MPP granule cell synapses was not affected by irradiation, suggesting that the release probability of neurotransmitters was not altered. Surprisingly, the induction of long-term synaptic plasticity in the DG by applying 4 trains of high-frequency stimulation provoked a shift from long term potentiation (LTP) to long-term depression (LTD) in irradiated animals compared to sham controls. The morphological changes consisted in a virtually complete ablation of neurogenesis following irradiation, as judged by doublecortin immunostaining, while the inhibitory network of parvalbumin interneurons was intact. These data suggest that the irradiation of the juvenile brain caused permanent changes in synaptic plasticity that would seem consistent with an impairment of declarative learning. Unlike in our previous study in mice, lithium treatment did unfortunately not ameliorate any of the studied parameters. For the first time, we show that the effects of cranial irradiation on long-term synaptic plasticity is different in the juvenile compared with the adult brain, such that while irradiation of the adult brain will only cause a reduction in LTP, irradiation of the juvenile brain goes further and causes LTD. Although the mechanisms underlying the synaptic alterations need to be elucidated, these findings provide a better understanding of the effects of irradiation in the developing brain and the cognitive deficits observed in young patients who have been subjected to cranial radiotherapy. (c) 2015 S. Karger AG, Basel. PMID- 26043718 TI - Ipilimumab for Previously Untreated Unresectable Malignant Melanoma: A Critique of the Evidence. AB - The National Institute for Health and Care Excellence (NICE) invited the manufacturer of ipilimumab (Bristol-Myers Squibb Pharmaceuticals Limited) to submit clinical and cost-effectiveness evidence for previously untreated advanced (unresectable or metastatic) melanoma as part of the Institute's Single Technology Appraisal process. The Centre for Reviews and Dissemination and Centre for Health Economics at the University of York were commissioned to act as the independent Evidence Review Group (ERG). This article presents a summary of the manufacturer's submission of ipilimumab, the ERG review and the resulting NICE guidance TA319, issued in July 2014. Ipilimumab at a recommended dose of 3 mg/kg monotherapy was previously granted marketing authorisation by the European Medicines Agency in adult patients who had received prior therapy and was recommended by NICE in guidance TA268. In October 2013, the EMA approved the extension of this indication to previously untreated advanced melanoma patients. NICE decisions are bound by the marketing authorisation; therefore, the decision problem faced by the NICE Appraisal Committee was whether ipilimumab at a recommended dose of 3 mg/kg monotherapy was effective and cost effective compared with first-line standard of care involving dacarbazine (DTIC) and vemurafenib (for BRAF V600 mutation-positive patients). The CA184-024 trial was the primary source of clinical evidence for ipilimumab. However, this was based on a dose of 10 mg/kg with concomitant DTIC. The results over a 5-year period indicated that ipilimumab 10 mg/kg plus DTIC demonstrated a significant increase in median overall survival (OS) of 2.1 months compared with DTIC plus placebo (11.2 vs. 9.1 months). The BRIM-3 trial, which was an open-label randomised controlled trial (RCT) in BRAF V600 mutation-positive patients, was the primary source of evidence for an indirect comparison with vemurafenib. The results showed that vemurafenib increased median OS by 3.6 months compared with DTIC (13.2 vs. 9.6 months). The economic evaluation compared the costs and outcomes of ipilimumab by assuming that the 3 mg/kg dosing regimen was clinically equivalent in efficacy to an ipilimumab 10 mg/kg dosing regimen plus DTIC and by using a treatment sequencing approach that incorporated second-line active therapy and third-line best supportive care (BSC). In the first appraisal meeting, the committee recommended ipilimumab only in the context of research as part of a clinical study. This was primarily based on the lack of robust evidence to support the assumption of clinical equivalence between dosages and the absence of evidence available to inform the sequential use of treatments. Following the consultation, the manufacturer submitted additional analyses and evidence to support the cost effectiveness of ipilimumab at first line. The manufacturer's response was based on concerns relating to uncertainty surrounding the relative efficacy of ipilimumab 3 mg/kg monotherapy compared with DTIC and vemurafenib, comparability of the patient populations at first and second line, and the effects of concomitant DTIC. These additional analyses indicated that the incremental cost effectiveness ratio (ICER) was L 47,900 per quality-adjusted life-year (QALY) gained for ipilimumab compared with DTIC and L 28,600 per QALY gained for ipilimumab compared with vemurafenib. Following consideration of the additional evidence and the responses from a large number of consultees and commentators, the committee recommended ipilimumab as an option for adults with previously untreated advanced melanoma. PMID- 26043719 TI - Temperature-driven growth of antiferromagnetic domains in thin-film FeRh. AB - The evolution of the antiferromagnetic phase across the temperature-driven ferromagnetic (FM) to antiferromagnetic (AF) phase transition in epitaxial FeRh thin films was studied by x-ray magnetic linear and circular dichroism (XMLD and XMCD) and photoemission electron microscopy. By comparing XMLD and XMCD images recorded at the same temperature, the AF phase was identified, its structure directly imaged, and its evolution studied across the transition. A quantitative analysis of the correlation length of the images shows differences between the characteristic length scale of the two phases with the AF phase having a finer feature size. The asymmetry of the transition from FM to AF upon cooling and AF FM upon heating is evidenced: upon cooling the formation of AF phase is dominated by nucleation at defects, with little subsequent growth, resulting in a small and non-random final AF domain structure, while upon heating, heterogeneous nucleation at different sites followed by significant domain size growth of the FM phase is observed, resulting in a non-reproducible final FM large domain structure. PMID- 26043720 TI - Defective pollen wall contributes to male sterility in the male sterile line 1355A of cotton. AB - To understand the mechanisms of male sterility in cotton (Gossypium spp.), combined histological, biochemical and transcription analysis using RNA-Seq was carried out in the anther of the single-gene recessive genic male sterility system of male sterile line 1355A and male fertile line 1355B, which are near isogenic lines (NILs) differing only in the fertility trait. A total of 2,446 differentially expressed genes were identified between the anthers of 1355AB lines, at three different stages of development. Cluster analysis and functional assignment of differentially expressed genes revealed differences in transcription associated with pollen wall and anther development, including the metabolism of fatty acids, glucose, pectin and cellulose. Histological and biochemical analysis revealed that a major cellular defect in the 1355A was a thicker nexine, consistent with the RNA-seq data, and further gene expression studies implicated differences in fatty acids synthesis and metabolism. This study provides insight into the phenotypic characteristics and gene regulatory network of the genic male sterile line 1355A in upland cotton. PMID- 26043721 TI - Delays in Manual Reaching Are Associated with Impaired Functional Abilities in Early Dementia Patients. AB - BACKGROUND/AIMS: Recent evidence shows that early dementia patients have deficits in manual reaching tasks. It is important to understand the impact of these functional disabilities on their quality of life. The aim of this study was to investigate if there is an association between manual reaching and measures of (instrumental) activities of daily living (IADL) in a group of patients with cognitive complaints. METHODS: The manual reaching performance of 27 patients was assessed in detail with eye and hand tracking devices. Patients were divided into three groups based on self-reported loss of IADL function. Parameters describing hand response and movement times were compared between groups. RESULTS: Patients with loss of IADL function in >=1 domain had delayed hand response and hand movement times towards visible targets compared to patients with no loss of IADL function. CONCLUSION: Delays in manual reaching movements are related to the degree of loss of IADL function in early dementia patients. PMID- 26043722 TI - Rapid and reliable preimplantation genetic diagnosis of common hemoglobin Bart's hydrops fetalis syndrome and hemoglobin H disease determinants using an enhanced single-tube decaplex polymerase chain reaction assay. PMID- 26043723 TI - Outcomes of Systemic Therapy for Patients with Metastatic Angiosarcoma. AB - BACKGROUND: Angiosarcomas (AS) are rare tumors of vascular origin with a variable behavior and overall poor prognosis. We sought to assess the outcomes of patients treated for metastatic disease. METHODS: We performed a retrospective analysis of 119 patients treated for metastatic AS. Outcomes and efficacy measurements of the first and subsequent lines of treatment were analyzed. RESULTS: Median age was 61 years, and the most frequent primary sites were chest wall/breast (31%), viscera (22%) and head/neck (20%). Seventy-three (61%) and 46 (39%) patients received >= 2 and >= 3 lines of therapy, respectively. The most commonly used agents included taxanes and anthracyclines. Median overall survival was 12.1 months. Median times to tumor progression were 3.5 months for first line, 3.7 months for second line and 2.7 months for third line. Among 48 patients evaluable per RECIST, the overall response rate to first line was 30% and <10% in subsequent lines. Doxorubicin, liposomal doxorubicin and taxanes resulted in similar response rates and survival, and there was no apparent benefit for combination chemotherapy. CONCLUSION: Despite reasonable response rates in the first-line setting, benefit from systemic therapy is short-lived in metastatic AS, and outcomes are poor. Doxorubicin, liposomal doxorubicin and taxanes are reasonable and appropriate choices for monotherapy. PMID- 26043724 TI - Feasibility of Computed Tomography in a Multicenter COPD Trial: A Study of the Effect of AZD9668 on Structural Airway Changes. AB - INTRODUCTION: The aim of this study was to establish the feasibility of using computed tomography (CT) in a multicenter setting to assess structural airway changes. METHODS: This was a 12-week, randomized, double-blind, placebo controlled, Phase IIb trial using CT to investigate the effect of a novel, oral, reversible neutrophil elastase inhibitor, AZD9668 60 mg twice daily (BID), on structural airway changes in patients aged 50-80 years with chronic obstructive pulmonary disease (COPD) (ex-smokers). PRIMARY OUTCOME VARIABLE: airway wall thickness at an extrapolated interior perimeter of 10 mm (AWT-Pi10). Secondary outcome variables: fifth-generation wall area %; air trapping index; pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1); morning and evening peak expiratory flow and FEV1; body plethysmography; EXAcerbations of Chronic pulmonary disease Tool (EXACT); Breathlessness, Cough, and Sputum Scale (BCSS); St George's Respiratory Questionnaire for COPD; and proportion of reliever medication-free trial days. Safety variables were also assessed. RESULTS: There was no difference between placebo (n = 19) and AZD9668 (n = 17) for AWT-Pi10 at treatment end. This was consistent with results for most secondary variables. However, patients randomized to AZD9668 experienced an improvement versus placebo for morning and evening FEV1, and EXACT and BCSS cough and sputum scores. AZD9668 60 mg BID was well tolerated and no new safety concerns were identified. CONCLUSIONS: This study confirmed the feasibility of using CT to assess structural airway changes in COPD. However, there was no evidence of improvements in CT structural measures following 12 weeks' treatment with AZD9668 60 mg BID. FUNDING: AstraZeneca. PMID- 26043725 TI - Acetylcarnitine potentiates the anticarcinogenic effects of butyrate on SW480 colon cancer cells. AB - Butyrate is a potent anticarcinogenic compound against colon cancer cells in vitro. However, its rapid metabolism is hypothesized to limit its anticancer benefits in colonic epithelial cells. Carnitine, a potent antioxidant, is essential to fatty acid oxidation. The aims of this study were to identify a colon cancer cell line capable of transporting carnitine. We evaluated the effect of carnitine and acetylcarnitine (ALCAR) on the response of colon carcinoma cells to butyrate. We explored the mechanisms underlying the anticarcinogenic benefit. SW480 cells were incubated with butyrate +/- carnitine or ALCAR. Carnitine uptake was assessed using [3H]-carnitine. Apoptosis and cell viability were assessed using an ELISA kit and flow cytometry, respectively. Modulation of proteins implicated in carnitine transport, cell death and proliferation were assessed by western blotting. SW480 cells were found to transport carnitine primarily via the OCTN2 transporter. Butyrate induced SW480 cell death occurred at concentrations of 2 mM and higher. Cells treated with the combination of butyrate (3 mM) with ALCAR exhibited increased mortality. The addition of carnitine or ALCAR also increased butyrate-induced apoptosis. Butyrate increased levels of cyclin D1, p21 and PARP p86, but decreased Bcl-XL and survivin levels. Butyrate also downregulated dephospho-beta-catenin and increased acetylated histone H4 levels. Butyrate and carnitine decreased survivin levels by >=25%. ALCAR independently induced a 20% decrease in p21. These results demonstrate that butyrate and ALCAR are potentially beneficial anticarcinogenic nutrients that inhibit colon cancer cell survival in vitro. The combination of both agents may have superior anticarcinogenic properties than butyrate alone. PMID- 26043726 TI - Regulatory Roles of Endogenous Mitogen-Activated Protein Kinases and Tyrosine Kinases in the Pacemaker Activity of Colonic Interstitial Cells of Cajal. AB - BACKGROUND AND PURPOSE: Mitogen-activated protein (MAP) and tyrosine kinases play an important role in regulating smooth muscle contraction of the gastrointestinal (GI) tract. Interstitial cells of Cajal (ICCs) are pacemaker cells that regulate GI smooth muscle activity. Thus, the role of MAP and tyrosine kinases on the pacemaker potentials of colonic ICCs was investigated. METHODS: Cultured ICCs were prepared from mice colons, and their pacemaker potentials were recorded using whole-cell patch clamping. RESULTS: In current-clamping mode, colonic ICCs displayed spontaneous pacemaker potentials. SB203580 (a p38 MAP kinase inhibitor), SP600125 (a c-jun NH2-terminal kinase (JNK) inhibitor), genistein and herbimycin A (tyrosine kinase inhibitors) blocked the generation of pacemaker potentials. However, PD98059 (a p42/44 MAP kinase inhibitor) had no effects on pacemaker potentials. LY-294002 (phosphoinositide 3-kinase inhibitor) also reduced the pacemaker potential frequency but calphostin C and chelerythrine (protein kinase C inhibitors) had no effects. However, PD98059, SB203589, SP600125, genistein, herbimycin A, LY-294002, and calphostin C had no effect on normal pacemaker activity in small intestinal ICCs. CONCLUSIONS: Endogenous p38 MAP kinases, JNKs, tyrosine kinases, and PI3-kinases participate in the generation of pacemaker potentials in colonic ICCs but not in ICCs of the small intestine. PMID- 26043727 TI - Towards meso-Ester BODIPYs with Aggregation-Induced Emission Properties: The Effect of Substitution Positions. AB - Three meso-ester boron dipyrromethene (BODIPY) dyes have been synthesized and functionalized with aggregation-induced emission (AIE)-active tetraphenylethene or triphenylethene moieties. It was found that functionalizing at the different positions of the BODIPY core resulted in the final dye having different emission properties in response to aggregation: from aggregation-induced quenching (ACQ) to being AIE active. X-ray crystallographic analysis was thus performed to provide an explanation for these differences. PMID- 26043728 TI - Malaria elimination in Haiti by the year 2020: an achievable goal? AB - Haiti and the Dominican Republic, which share the island of Hispaniola, are the last locations in the Caribbean where malaria still persists. Malaria is an important public health concern in Haiti with 17,094 reported cases in 2014. Further, on January 12, 2010, a record earthquake devastated densely populated areas in Haiti including many healthcare and laboratory facilities. Weakened infrastructure provided fertile reservoirs for uncontrolled transmission of infectious pathogens. This situation results in unique challenges for malaria epidemiology and elimination efforts. To help Haiti achieve its malaria elimination goals by year 2020, the Laboratoire National de Sante Publique and Henry Ford Health System, in close collaboration with the Direction d'Epidemiologie, de Laboratoire et de Recherches and the Programme National de Controle de la Malaria, hosted a scientific meeting on "Elimination Strategies for Malaria in Haiti" on January 29-30, 2015 at the National Laboratory in Port au-Prince, Haiti. The meeting brought together laboratory personnel, researchers, clinicians, academics, public health professionals, and other stakeholders to discuss main stakes and perspectives on malaria elimination. Several themes and recommendations emerged during discussions at this meeting. First, more information and research on malaria transmission in Haiti are needed including information from active surveillance of cases and vectors. Second, many healthcare personnel need additional training and critical resources on how to properly identify malaria cases so as to improve accurate and timely case reporting. Third, it is necessary to continue studies genotyping strains of Plasmodium falciparum in different sites with active transmission to evaluate for drug resistance and impacts on health. Fourth, elimination strategies outlined in this report will continue to incorporate use of primaquine in addition to chloroquine and active surveillance of cases. Elimination of malaria in Haiti will require collaborative multidisciplinary approaches, sound strategic planning, and strong ownership of strategies by the Haiti Ministere de la Sante Publique et de la Population. PMID- 26043730 TI - PAK1 regulates cortical development via promoting neuronal migration and progenitor cell proliferation. AB - BACKGROUND: p21-activated kinase 1 (PAK1) is a serine/threonine kinase known to be activated by the Rho family small GTPases and to play a key role in cytoskeletal reorganization, spine morphology and synaptic plasticity. PAK1 is also implicated in a number of neurodevelopmental and neurodegenerative diseases, including autism, intellectual disability and Alzheimer's disease. However, the role of PAK1 in early brain development remains unknown. RESULTS: In this study, we employed genetic manipulations to investigate the role of PAK1 in the cerebral cortical development in mice. We showed that compared to the wild type littermates, PAK1 knockout mice have a reduction in the number of pyramidal neurons in several layers of the cerebral cortex, which is associated with a smaller pool of neural progenitor cells and impaired neuronal migration. CONCLUSION: These results suggest that PAK1 regulates cortical development by promoting the proliferation of neural progenitor cells and facilitating the migration of these neurons to specific regions of the cortex. PMID- 26043732 TI - Variation in lung cancer resources and workload: results from the first national lung cancer organisational audit. AB - We report the findings of the first national lung cancer organisational audit. The results demonstrate marked variation in service provision and workload of some lung cancer specialists. For example, over half of the clinical nurse specialists report case volumes over recommended numbers. Some trusts have no access to key treatments such as video assisted thoracoscopy (VAT) lobectomy and stereotactic radiotherapy. Multivariate regression analysis demonstrated an association between higher surgical resection rates and the on-site availability of advanced staging and therapeutic modalities, for example, PET scan and VAT lobectomy. We conclude by making a number of recommendations to address the variation in lung cancer care. PMID- 26043731 TI - Designing faculty development to support the evaluation of resident competency in the intrinsic CanMEDS roles: practical outcomes of an assessment of program director needs. AB - BACKGROUND: The Royal College of Physicians and Surgeons of Canada and the College of Family Physicians of Canada mandate that faculty members demonstrate they are evaluating residents on all CanMEDS (Canadian Medical Education Directions for Specialists) roles as part of the accreditation process. Postgraduate Medical Education at the University of Ottawa initiated a 5-year project to develop and implement a comprehensive system to assess the full spectrum of CanMEDS roles. This paper presents the findings from a needs assessment with Program Directors, in order to determine how postgraduate medical faculty can be motivated and supported to evaluate residents on the intrinsic CanMEDS roles. METHODS: Semi-structured individual interviews were conducted with 60 Postgraduate Program Directors in the Faculty of Medicine. Transcribed interviews were analyzed using qualitative analysis. Once the researchers were satisfied the identified themes reflected the views of the participants, the data was assigned to categories to provide rich, detailed, and comprehensive information that would indicate what faculty need in order to effectively evaluate their residents on the intrinsic roles. RESULTS: Findings indicated faculty members need faculty development and shared point of care resources to support them with how to not only evaluate, but also teach, the intrinsic roles. Program Directors expressed the need to collaborate and share resources across departments and national specialty programs. Based on our findings, we designed and delivered workshops with companion eBooks to teach and evaluate residents at the point of care (Developing the Professional, Health Advocate and Scholar). CONCLUSIONS: Identifying stakeholder needs is essential for designing effective faculty development. By sharing resources, faculties can prevent 'reinventing the wheel' and collaborate to meet the Colleges' accreditation requirements more efficiently. PMID- 26043733 TI - Emerging Nanonisation Technologies: Tailoring Crystalline Versus Amorphous Nanomaterials. AB - The overall pharmaceutical market is changing. A more personalised medicine approach is replacing the concept of blockbuster drugs and the "one size fits all" model. The two main forces that fuel the growth of nano-enabled drug technologies are the low aqueous solubility of new chemical entities and the pharmaceutical market itself, as the development of novel drug delivery systems can extend the drug patent lifetime. Classical solubilisation techniques, such as salt formation and the use of cyclodextrins can only be applied to drugs with ionisable groups or specific molecular weight ranges in order to fit in the cavity of the cyclodextrin. However, drug nanonisation, or particle size reduction into the nanosize range, is a versatile technique that can be applied to a wide range of pharmaceutical compounds. Nano-drugs exhibit higher surface area per unit of volume, which leads to faster dissolution kinetics and hence potentially improved bioavailability. Marketed nano-drugs are mostly crystalline due to the improved physical stability afforded by the crystalline state whereas amorphous nano-drugs have been largely neglected in spite of generating higher saturation solubility compared to their crystalline counterparts. Due to the vast potential in the global pharmaceutical market, many technologies have been licensed to produce nano-drugs. Among them, the most successful by far is Nanocrystal((r)); Technology based on wet milling methods. In this review, the main methods to generate and characterise nano-drugs are covered and also, the biopharmaceutical characteristics of the marketed nano-drugs are discussed. PMID- 26043734 TI - Peptide Self-Assemblies for Drug Delivery. AB - Peptide amphiphiles (PAs) are novel engineered biomaterials able to self-assemble into supramolecular systems that have shown significant promise in drug delivery across the cell membane and across challenging biological barriers showing promise in the field of brain diseases, regenerative medicine and cancer. PAs are amino-acid block co-polymers, with a peptide backbone composed usually of 8-30 amino acids, a hydrophilic block formed by polar amino acids, a hydrophobic block which usually entails either non-polar or aromatic amino acids and alkyl, acyl or aryl lipidic tails and in some cases a spacer or a conjugated targeting moiety. Finely tuning the balance between the hydrophilic and hydrophobic blocks results in a range of supramolecular structures that are usually stabilised by hydrophobic, electrostatic, beta-sheet hydrogen bonds and pi-pi stacking interactions. In an aqueous environment, the final size, shape and interfacial curvature of the PA is a result of the complex interplay of all these interactions. Lanreotide is the first PA to be licensed for the treatment of acromegaly and neuroendocrine tumours as a hydrogel administered subcutaneously, while a number of other PAs are undergoing preclinical development. This review discusses PAs architecture fundamentals that govern their self-assembly into supramolecular systems for applications in drug delivery. PMID- 26043735 TI - Comparison of Various Types of Ligand Decorated Nanoliposomes for their Ability to Inhibit Amyloid Aggregation and to Reverse Amyloid Cytotoxicity. AB - Three different amyloid targeting ligands, previously shown to exhibit amyloid specific properties, have been used to develop amyloid -targeted nanoliposomes (AT-NLs. For this a MAb against Abeta-peptides (Abeta-MAb (immobilized on NLs at 0.015 and 0.05 mol %, and two different curcumin-lipid derivatives were attached to the surface of preformed NLs or incorporated in NL membranes during their formation. Following physicochemical characterization, these AT-NLs were studied for their ability to inhibit or delay amyloid peptide aggregation -using the thioflavin-T assay, and for their potential to reverse amyloid-induced (and Zn, or, amyloid + Zn cytotoxicity, on wild type (N2aWT and transformed (N2aAPP neuroblastoma cells, applying the MTT assay. Experimental results reveal that all formulations were found to strongly delay amyloid peptide aggregation (with no significant differences between the different AT-NL types. However, although Abeta-MAb-NLs significantly reversed amyloid-induced cytotoxicity in all cases, both curcumin-NL types did not reverse Zn-induced, nor Zn+Abeta-induced cytotoxicity in N2aWT cells, suggesting lower activity against synthetic-Abeta peptides (compared to endogenous Abeta peptides; perhaps due to different affinity towards different (aggregation stages of peptide species (monomers, oligomers, fibrils, etc. Taken into account that the aggregation stage of amyloid species is an important determinant of their toxicity, the importance of the affinity of each AT-NL type towards specific species, is highlighted. PMID- 26043736 TI - Multiscale Inorganic Hierarchically Materials: Towards an Improved Orthopaedic Regenerative Medicine. AB - Bone is a biologically and structurally sophisticated multifunctional tissue. It dynamically responds to biochemical, mechanical and electrical clues by remodelling itself and accordingly the maximum strength and toughness are along the lines of the greatest applied stress. The challenge is to develop an orthopaedic biomaterial that imitates the micro- and nano-structural elements and compositions of bone to locally match the properties of the host tissue resulting in a biologically fixed implant. Looking for the ideal implant, the convergence of life and materials sciences occurs. Researchers in many different fields apply their expertise to improve implantable devices and regenerative medicine. Materials of all kinds, but especially hierarchical nano-materials, are being exploited. The application of nano-materials with hierarchical design to calcified tissue reconstructive medicine involve intricate systems including scaffolds with multifaceted shapes that provides temporary mechanical function; materials with nano-topography modifications that guarantee their integration to tissues and that possesses functionalized surfaces to transport biologic factors to stimulate tissue growth in a controlled, safe, and rapid manner. Furthermore materials that should degrade on a timeline coordinated to the time that takes the tissues regrow, are prepared. These implantable devices are multifunctional and for its construction they involve the use of precise strategically techniques together with specific material manufacturing processes that can be integrated to achieve in the design, the required multifunctionality. For such reasons, even though the idea of displacement from synthetic implants and tissue grafts to regenerative-medicine-based tissue reconstruction has been guaranteed for well over a decade, the reality has yet to emerge. In this paper, we examine the recent approaches to create enhanced bioactive materials. Their design and manufacturing procedures as well as the experiments to integrate them into engineer hierarchical inorganic materials for their practical application in calcified tissue reparation are evaluated. PMID- 26043737 TI - Electrohydrodynamic Preparation of Nanomedicines. AB - The preparation of nanomedicines can be achived using a host of methods ranging from wet-chemical approaches to more engineering related techniques. As a maturing branch of nanotechnology, nanomedcines are being tailored to serve multiple pharmaceutic and biomedical related funcitons (e.g. targeted delivery, imaging, healing, sensing which may require the utilisaiton of one or more actives or excipients. In some instances, handling of materials (such as sensitive biomolecules or active pharmaceutical ingredient) becomes a limiting factor along with issues related to fabrication steps (loss or degradation of active components and functional materials, deposition location & procedure (removal of formed structures, process environment sensitivity and scale-up potential. This short review focuses on the electrohydrodynamic preparation of emerging nanomedicines that have potential to serve as therapeutic platforms. An insight into the underpinning process (jet-formation, related paramerts (material and process and strucutral outcomes (particles and fibres is given in relation to highlighted research. The ambient temperature processing, user friendly preparation and present industrial scale up potential (now in kg/hr make such processes valuable in the preparation of future nano-scaled and sensitive dosage forms. PMID- 26043738 TI - Thinking Outside the 'Block': Alternative Polymer Compositions for Micellar Drug Delivery. AB - With a number of formulations currently in clinical trials, the interest in polymer micelles as drug carriers in unlikely to subside. Historically, linear diblock copolymers have been used as the building blocks for micelle preparation. Yet, recent advances in polymer chemistry have meant that a wider variety of polymer architectures and compositions have become available and been trialed for pharmaceutical applications. This mini-review aims to provide an overview of recent, exciting developments in triblock, graft and hyperbranched polymer chemistries that may change the way polymeric micelles drug formulations are prepared. PMID- 26043739 TI - Smart Mesoporous Silica Nanocarriers for Antitumoral Therapy. AB - The development of nanocarriers able transport and release therapeutic agents in a controlled manner has provided a promising alternative in the oncology field due to the lack of selectivity of the conventional treatments. The encapsulation of cytotoxic compounds within nanoparticles improves the pharmacokinetic profile of the trapped drugs and allows their selective accumulation into the tumoral tissue owing to the enhance permeation and retention effect (EPR. In addition, the selectivity of the nanocarrier can be enhanced attaching targeting agents on their surface able to be specifically recognized by cancer cells or by the tumor microenvironment. Among the different materials which can be employed, mesoporous silica nanoparticles (MCM-41 type constitutes a promising candidate due to their very interesting properties such as tuneable size, shape and porosity, high loading capacity, low toxicity, robustness and easiness fabrication and functionalization. This material presents a unique pore architecture which allows the synthesis of stimuliresponsive devices able to release the trapped drugs only in the presence of certain stimuli achieving a precise control on the drug dosage. This review presents some of the recent advances in the development of mesoporous silica nanocarriers for antitumoral therapy paying special attention on the stimuli-responsive systems able to release their load in response to external (light, magnetic field, temperature or ultrasounds or internal stimulus (enzymes, pH, redox, among others. PMID- 26043740 TI - Engineering Nanomedicines into Safe and Effective Therapeutics. PMID- 26043741 TI - Why don't people exercise, even a little? PMID- 26043742 TI - Impact of laws aimed at healthcare-associated infection reduction: a qualitative study. AB - BACKGROUND: Healthcare-associated infections (HAIs) are preventable. Globally, laws aimed at reducing HAIs have been implemented. In the USA, these laws are at the federal and state levels. It is not known whether the state interventions are more effective than the federal incentives alone. OBJECTIVE: The aims of this study were to explore the impact federal and state HAI laws have on state departments of health and hospital stakeholders in the USA and to explore similarities and differences in perceptions across states. METHODS: A qualitative study was conducted. In 2012, we conducted semistructured interviews with key stakeholders from states with and without state-level laws to gain multiple perspectives. Interviews were transcribed and open coding was conducted. Data were analysed using content analysis and collected until theoretical saturation was achieved. RESULTS: Ninety interviews were conducted with stakeholders from 12 states (6 states with laws and 6 states without laws). We found an increase in state-level collaboration. The publicly reported data helped hospitals benchmark and focus leaders on HAI prevention. There were concerns about the publicly reported data (eg, lack of validation and timeliness). Resource needs were also identified. No major differences were expressed by interviewees from states with and without laws. CONCLUSIONS: While we could not tease out the impact of specific interventions, increased collaboration between departments of health and their partners is occurring. Harmonisation of HAI definitions and reporting between state and federal laws would minimise reporting burden. Continued monitoring of the progress of HAI prevention is needed. PMID- 26043743 TI - Is There Evidence to Support Brand to Generic Interchange of the Mycophenolic Acid Products? AB - The uptake of generic immunosuppressants lags comparatively to other drug classes, despite that the Food and Drug Administration (FDA) uses identical bioequivalence standards for all drugs. Transplant societies acknowledge the cost savings associated with generic immunosuppressants and support their use following heart, lung, kidney, or bone marrow transplantation. Seven studies of the pharmacokinetics or clinical efficacy of generic mycophenolate mofetil compared to the innovator product are published; all studies and products were ex United States. Three studies did not demonstrate any pharmacokinetic differences between generic and innovator products in healthy subjects, achieving FDA bioequivalence requirements. Two studies in renal allograft recipients demonstrated no difference in area under the curves between generic and innovator products, and in one, the maximum concentration (Cmax) fell outside the FDA regulatory range. Two studies revealed no difference in acute organ rejection or graft function in renal allograft recipients. Patient surveys indicate that cost is a barrier to immunosuppressant adherence. Generics present a viable method to reduce costs to payers, patients, and health care systems. Adherence to immunosuppressants is crucial to prevent graft failure. An affordable regimen potentially confers greater adherence. Concerns regarding the presumed inferiority of generic immunosuppressants should be assuaged by regulatory requirements for bioequivalency testing, transplant society position statements, and pharmacokinetic and clinical studies. PMID- 26043744 TI - Arthroscopic Evaluation of Syndesmotic Instability in a Cadaveric Model. AB - BACKGROUND: Ankle fractures are among the most common lower extremity injuries. Proper care requires evaluation for syndesmotic ligament disruption. Ankle arthroscopy has been proposed as an intraoperative tool that can evaluate stability. Our focus was to evaluate the amount of displacement produced in the coronal, sagittal, and transverse planes visualized through ankle arthroscopy in a cadaveric model. METHODS: Seven below-knee specimens were mounted in a traction tower. Four groups were evaluated: no ligamentous disruption; anterior inferior tibiofibular ligament and interosseous ligament disruption; above plus anterior talofibular ligament and calcaneofibular ligament disruption; and posterior inferior tibiofibular ligament and transverse ligament disruption. Force was applied and measured using a digital scale. The amount of displacement of the fibula in relation to the center of the incisura was measured under arthroscopic evaluation using a calibrated probe. RESULTS: An intact syndesmosis and lateral ankle ligaments provided multiplanar stability. In group 2, syndesmosis diastasis was appreciated in the transverse-external rotation plane with as little as 6 lb of force. In group 3, a greater amount of displacement was appreciated with less force. Multiplane instability was visible in every specimen with as little as 2 lb of force. Group 4 specimens were completely disrupted and so grossly unstable that testing was impossible. CONCLUSION: Ankle arthroscopy has the potential to evaluate even partial disruption of the syndesmotic ligament complex. Instability in the sagittal and transverse planes was encountered early in the spectrum of disruption. Traditional evaluation methods have poor sensitivity for instability in these planes. CLINICAL RELEVANCE: Arthroscopic evaluation of subtle displacement in multiple planes may assist the surgeon in understanding the extent of the syndesmotic injury. Further studies are necessary to determine to what extent instability requires fixation as well as the role for arthroscopy in assessing anatomic reduction of the syndesmosis after fixation is performed. PMID- 26043745 TI - Flow sorting of C-genome chromosomes from wild relatives of wheat Aegilops markgrafii, Ae. triuncialis and Ae. cylindrica, and their molecular organization. AB - BACKGROUND AND AIMS: Aegilops markgrafii (CC) and its natural hybrids Ae. triuncialis (U(t)U(t)C(t)C(t)) and Ae. cylindrica (D(c)D(c)C(c)C(c)) represent a rich reservoir of useful genes for improvement of bread wheat (Triticum aestivum), but the limited information available on their genome structure and the shortage of molecular (cyto-) genetic tools hamper the utilization of the extant genetic diversity. This study provides the complete karyotypes in the three species obtained after fluorescent in situ hybridization (FISH) with repetitive DNA probes, and evaluates the potential of flow cytometric chromosome sorting. METHODS: The flow karyotypes obtained after the analysis of 4',6 diamidino-2-phenylindole (DAPI)-stained chromosomes were characterized and the chromosome content of the peaks on the flow karyotypes was determined by FISH. Twenty-nine conserved orthologous set (COS) markers covering all seven wheat homoeologous chromosome groups were used for PCR with DNA amplified from flow sorted chromosomes and genomic DNA. KEY RESULTS: FISH with repetitive DNA probes revealed that chromosomes 4C, 5C, 7C(t), T6U(t)S.6U(t)L-5C(t)L, 1C(c) and 5D(c) could be sorted with purities ranging from 66 to 91 %, while the remaining chromosomes could be sorted in groups of 2-5. This identified a partial wheat-C genome homology for group 4 and 5 chromosomes. In addition, 1C chromosomes were homologous with group 1 of wheat; a small segment from group 2 indicated 1C-2C rearrangement. An extensively rearranged structure of chromosome 7C relative to wheat was also detected. CONCLUSIONS: The possibility of purifying Aegilops chromosomes provides an attractive opportunity to investigate the structure and evolution of the Aegilops C genome and to develop molecular tools to facilitate the identification of alien chromatin and support alien introgression breeding in bread wheat. PMID- 26043746 TI - Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis. AB - BACKGROUND: Statins lower low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD), but they may be ineffective or not tolerated. Bile acid sequestrants (BAS) reduce LDL-C, yet their clinical efficacy on CAD remains controversial. METHODS AND RESULTS: We conducted a systematic review and meta analysis of randomized controlled trials to assess the effect of cholestyramine and colesevelam. We then used Mendelian randomization to estimate the effect of BAS on reducing the risk of CAD. First, we quantified the effect of rs4299376 (ABCG5/ABCG8), which affects the intestinal cholesterol absorption pathway targeted by BAS and then we used these estimates to predict the effect of BAS on CAD. Nineteen randomized controlled trials with a total of 7021 study participants were included. Cholestyramine 24 g/d was associated with a reduction in LDL-C of 23.5 mg/dL (95% confidence interval [CI] -26.8,-20.2; N=3806) and a trend toward reduced risk of CAD (odds ratio 0.81, 95% CI 0.70-1.02; P=0.07; N=3806), whereas colesevelam 3.75 g/d was associated with a reduction in LDL-C of 22.7 mg/dL (95% CI -28.3, -17.2; N=759). Based on the findings that rs4299376 was associated with a 2.75 mg/dL decrease in LDL-C and a 5% decrease in risk of CAD outcomes, we estimated that cholestyramine was associated with an odds ratio for CAD of 0.63 (95% CI 0.52-0.77; P=6.3*10(-6)) and colesevelam with an odds ratio of 0.64 (95% CI 0.52-0.79, P=4.3*10(-5)), which were not statistically different from BAS clinical trials (P>0.05). CONCLUSIONS: The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD. PMID- 26043747 TI - Identification of genomic features in the classification of loss- and gain-of function mutation. AB - BACKGROUND: Alterations of a genome can lead to changes in protein functions. Through these genetic mutations, a protein can lose its native function (loss-of function, LoF), or it can confer a new function (gain-of-function, GoF). However, when a mutation occurs, it is difficult to determine whether it will result in a LoF or a GoF. Therefore, in this paper, we propose a study that analyzes the genomic features of LoF and GoF instances to find features that can be used to classify LoF and GoF mutations. METHODS: In order to collect experimentally verified LoF and GoF mutational information, we obtained 816 LoF mutations and 474 GoF mutations from a literature text-mining process. Next, with data preprocessing steps, 258 LoF and 129 GoF mutations remained for a further analysis. We analyzed the properties of these LoF and GoF mutations. Among the properties, we selected features which show different tendencies between the two groups and implemented classifications using support vector machine, random forest, and linear logistic regression methods to confirm whether or not these features can identify LoF and GoF mutations. RESULTS: We analyzed the properties of the LoF and GoF mutations and identified six features which have discriminative power between LoF and GoF conditions: the reference allele, the substituted allele, mutation type, mutation impact, subcellular location, and protein domain. When using the six selected features with the random forest, support vector machine, and linear logistic regression classifiers, the result showed accuracy levels of 72.23%, 71.28%, and 70.19%, respectively. CONCLUSIONS: We analyzed LoF and GoF mutations and selected several properties which were different between the two classes. By implementing classifications with the selected features, it is demonstrated that the selected features have good discriminative power. PMID- 26043749 TI - Arterial hypoxaemia and its impact on coagulation: significance of altered redox homeostasis. AB - AIMS: Arterial hypoxaemia stimulates free radical formation. Cellular studies suggest this may be implicated in coagulation activation though human evidence is lacking. To examine this, an observational study was designed to explore relationships between systemic oxidative stress and haemostatic responses in healthy participants exposed to inspiratory hypoxia. RESULTS: Activated partial thromboplastin time and international normalised ratio were measured as routine clinical biomarkers of coagulation and ascorbate free radical (A(*-)) as a direct global biomarker of free radical flux. Six hours of hypoxia activated coagulation, and increased formation of A(*-), with inverse correlations observed against oxyhaemoglobin saturation. CONCLUSIONS: This is the first study to address the link between free radical formation and coagulation in vivo. This 'proof-of-concept' study demonstrated functional associations between hypoxaemia and coagulation that may be subject to redox activation of the intrinsic pathway. Further studies are required to identify precisely which intrinsic factors are subject to redox activation. PMID- 26043748 TI - Relationship between expression of IGFBP7 and clinicopathological variables in gastric cancer. AB - AIMS: Insulin-like growth factor binding protein 7 (IGFBP7) is reported to have tumour suppressor function through an IGF-dependent pathway in various malignant tumours. However, the expression of IGFBP7 in adenocarcinoma and its relationship with tumour progression and survival differs among studies. Our aims were to investigate the relationship between the expression of IGFBP7 and clinicopathological variables and outcomes of patients with gastric cancer. METHODS: Tumour samples were obtained from 219 patients with gastric cancer who underwent gastrectomy. The expression of IGFBP7 protein was examined by immunohistochemical staining. IGFBP7 mRNA levels were analysed using real-time quantitative reverse-transcriptase PCR in 24 of the gastric cancer tumours and in adjacent non-tumour tissues. Correlation of IGFBP7 expression with clinicopathological features was analysed. RESULTS: The protein expression of IGFBP7 was positively correlated with depth of invasion, lymph node metastasis, distant metastasis or recurrence and pathological stage. High expression of IGFBP7 protein was associated with a significantly worse disease-specific survival (p<0.001) and was an independent prognostic factor in multivariable analysis (HR, 4.8; 95% CI 2.1 to 10.6; p<0.001). The IGFBP7 mRNA level was significantly higher in advanced gastric cancer than in early gastric cancer, in tumours with lymph node metastasis than in tumours without lymph node metastasis, and in tumours with distant metastasis or recurrence than in tumours without distant metastasis or recurrence. CONCLUSIONS: Overexpression of IGFBP7 was associated with tumour progression and poor survival in gastric cancer. IGFBP7 may play a role in tumour progression in gastric cancer. PMID- 26043750 TI - Evaluation of the structured bowel management program in inpatient rehabilitation: a prospective study. AB - PURPOSE: The purpose of this study is to evaluate the impact of the structured bowel management program (SBMP) in an inpatient rehabilitation service. METHOD: Prospective recruitment of consecutive patients admitted to the rehabilitation unit (n = 100). Each patient was assessed for bowel dysfunction on admission and an individualised SBMP was instituted based on the clinical needs. The assessments were at baseline (T1), and discharge from ward (T2) using validated questionnaires. Program evaluation was at 3-month (T3) post-discharge. RESULTS: Participants were predominantly female (52%), mean age 68 +/- 13 years. Almost one-half (43%) had neurological conditions and 41% musculoskeletal problems. At admission, 62% self-reported bowel dysfunction, mainly constipation (82%) and faecal incontinence (FI) (11%). At T2, participants showed significant improvement in bowel habit and stool consistency (Bristol stool chart, p < 0.001); severity of bowel symptoms such as FI (Wexner FI score, p < 0.05); and impact on quality of life (FI Quality of Life (QoL) subscales: "life style" and "coping/behavior", p < 0.05 for both). All functional independent measure "motor" and "cognition" subscales improved significantly (p < 0.01 for all), with moderate to large effect sizes (r = 0.5-0.7). No adverse effects were reported. CONCLUSIONS: Bowel management should be a priority within rehabilitative services. Evidence-based SBMP can improve bowel symptoms and enhance overall QoL in patients admitted to rehabilitation settings. IMPLICATIONS FOR REHABILITATION: Bowel dysfunction is common in inpatient rehabilitation settings. A structured bowel management program can improve bowel symptoms and enhance overall QoL in patient. Bowel management should be a priority for patients admitted to rehabilitation settings. PMID- 26043751 TI - Enhancing social participation in young people with communication disabilities living in rural Australia: outcomes of a home-based intervention for using social media. AB - PURPOSE: The purpose of this study is to investigate the effectiveness of a home based intervention using social media to enhance social networks of young people with disabilities and communication difficulties. METHOD: Eight young people (M(age) = 15.4 years) with communication disabilities participated from two rural Australian towns. The intervention provided assistive technology and training to learn social media use. A mixed-method design combined pre- and post-assessments measuring changes in performance, satisfaction with performance, attainment on social media goals, and social network extension, and interviews investigated the way in which the intervention influenced social participation. RESULTS: Participants showed an increase in performance, and satisfaction with performance, on the Canadian Occupational Performance Measure; paired t-tests showed statistical significance at p <0.01. Wilcoxon Signed Ranks revealed a significant increase in the number of online communication partners, p <0.05. The interviews highlighted participants' and parents' perceptions of increased social connections, improved communication frequency and nature, and speech intelligibility and literacy as a result of the intervention. CONCLUSIONS: The findings suggest that learning to use social media leads to increase in social participation among rural-based young people with communication disabilities. In order to benefit from advantages of learning to use social media in rural areas, parents and service providers need knowledge and skills to integrate assistive technology with the Internet needs of this group. PMID- 26043752 TI - Using different methods to communicate: how adults with severe acquired communication difficulties make decisions about the communication methods they use and how they experience them. AB - PURPOSE: This study aimed to explore how adults with severe acquired communication difficulties experience and make decisions about the communication methods they use. The primary objectives were to explore their perceptions of different communication methods, how they choose communication methods to use in different situations and with different communication partners, and what facilitates their decision-making. METHOD: A qualitative phenomenological approach was used. Data collection methods were face-to-face video-recorded interviews using each participant's choice of communication method and e-mail interviews. The methodological challenges of involving participants with severe acquired communication disorders in research were addressed in the study design. Seven participants, all men, were recruited from a long-term care setting in a rehabilitation hospital. The data analysis process was guided by Colaizzi's (1978) analytic framework. RESULTS: Four main themes were identified: communicating in the digital age - e-mail and social media, encountering frustrations in using communication technologies, role and identity changes and the influences of communication technology and seeking a functional interaction using communication technologies. CONCLUSION: Adults with acquired communication difficulties find digital communication, such as e-mail and social media, and mainstream technologies, such as iPads, beneficial in communicating with others. Current communication technologies present a number of challenges for adults with disabilities and are limited in their communicative functions to support desired interactions. The implications for AAC technology development and speech and language therapy service delivery are addressed. PMID- 26043753 TI - Lentiviral vector-mediated survivin shRNA delivery in gastric cancer cell lines significantly inhibits cell proliferation and tumor growth. AB - It has been well documented that survivin has multiple functions including cytoprotection, inhibition of cell death, and cell cycle regulation, particularly at the mitotic stage of the cell cycle, all of which favor cancer survival. Its expression in normal tissue is developmentally regulated, and any type of deregulation in survivin expression favors cancer survival. Gastric cancer is one of the most common malignancies and the second most common cause of cancer related mortality worldwide. The molecular mechanisms involved in the transformation and progression of gastric cancer remain unclear. In the present study, we investigated the effect of lentiviral vector-mediated survivin shRNA delivery in gastric cancer cell lines. Lentiviral-mediated survivin shRNA was used to knock down survivin expression in gastric cancer cell lines SGC-7901, MGC 803 and MKN-28. The Tauranswell chemotaxis and the CCK-8 assays were used to assess the migration and proliferation of the tumor cells, respectively. TUNEL assay was used to detect apoptosis. Quantitative real-time PCR and western blot analysis were used to quantify mRNA and protein levels, respectively. Our results demonstrated that lentiviral-mediated RNAi markedly suppressed the survivin expression in all three gastric cancer cell lines. Significant decrease in survivin mRNA and protein expression were detected in the gastric cancer cell lines stably transfected with the lentiviral survivin shRNA vector, and knockdown of survivin also significantly inhibited the proliferation and migration in the gastric cancer cells and tumorigenicity in a xenograft animal model. Our results indicated that aberrant high cytoplasmic survivin expression in gastric cancer cells is associated with increased proliferation index and tumor growth. In conclusion, our results suggest that lentiviral-mediated gene therapy has the potential to be developed into a novel therapeutic strategy for the treatment of gastric cancer. PMID- 26043754 TI - Bioactive prenylated xanthones from the stems of Cratoxylum cochinchinense. AB - Cochinchinones M-U (1-9), together with 12 known compounds (10-21), were isolated from the stems of Cratoxylum cochinchinense (Lour.) Blume. Their structures were determined on the basis of extensive spectroscopic data analyses. In addition, their retinoid X receptor-alpha transcriptional activities were evaluated using an in vitro assay. PMID- 26043755 TI - Intracellular calcium signaling regulates autophagy via calcineurin-mediated TFEB dephosphorylation. AB - The transcription-regulating activity of TFEB is dependent on its phosphorylation modification, but the phosphatase(s) involved in TFEB dephosphorylation have remained elusive. It has now become clear that lysosomal calcium signaling activates calcineurin, an endogenous serine/threonine phosphatase, which dephosphorylate TFEB leading to upregulation of autophagy. PMID- 26043756 TI - Silence of MACC1 expression by RNA interference inhibits proliferation, invasion and metastasis, and promotes apoptosis in U251 human malignant glioma cells. AB - The overexpression of metastasis-associated in colon cancer 1 (MACC1) has been demonstrated not only in colon cancer, but also in various other types of cancer. Gliomas are the most common type of intracranial tumors, and recent studies have reported MACC1 to be involved in human glioma progression. The present study aimed to investigate the effects of MACC1 expression silencing in glioma cells using RNA interference, in order to determine the underlying biological mechanisms of glioma progression, including proliferation, apoptosis, invasion and metastasis. The expression levels of MACC1 were determined in various types of U251 glioma cells using western blot analyses. MACC1-specific short hairpin RNA (shRNA) was used to silence the expression of MACC1 in the U251 cells. The results obtained following MACC1 silencing demonstrated a significant inhibition of cell proliferation, invasion and migration, as well as a marked enhancement of apoptosis. MACC1 shRNA-induced inhibition of cell proliferation was observed by colony forming and MTT assays, and cell apoptosis was measured using flow cytometry and Hoechst staining. In addition, inhibition of cell invasion and migration was assessed using wound healing and transwell assays. Western blotting and fluorescence-activated cell sorting (FACS) revealed a G0/G1 phase cell cycle arrest regulated by cyclins D1 and E; cell apoptosis regulated by caspase-3; and cell invasion and migration regulated by matrix metalloproteinases 2 and 9, respectively. The present study demonstrated that the expression levels of MACC1 were significantly correlated with the biological processes underlying glioma cell proliferation, invasion and metastasis. Therefore, MACC1 may serve as a promising novel therapeutic target in human glioma. Notably, the inhibition of MACC1 expression by shRNA may prove to be an effective genetic therapeutic strategy for glioma treatment. PMID- 26043757 TI - Molecular perception of interactions between bis(7)tacrine and cystamine-tacrine dimer with cholinesterases as the promising proposed agents for the treatment of Alzheimer's disease. AB - The infamous chronic neurodegenerative disease, Alzheimer's, that starts with short-term memory loss and eventually leads to gradual bodily function decline which has been attributed to the deficiency in brain neurotransmitters, acetylcholine, and butylcholine. As a matter of fact, design of compounds that can inhibit cholinesterases activities (acetylcholinesterase and butylcholinesterase) has been introduced as an efficient method to treat Alzheimer's. Among proposed compounds, bis(7)tacrine (B7T) is recognized as a noteworthy suppressor for Alzheimer's disease. Recently a new analog of B7T, cystamine-tacrine dimer is offered as an agent to detain Alzheimer's complications, even better than the parent compound. In this study, classical molecular dynamic simulations have been employed to take a closer look into the modes of interactions between the mentioned ligands and both cholinesterase enzymes. According to our obtained results, the structural differences in the target enzymes active sites result in different modes of interactions and inhibition potencies of the ligands against both enzymes. The obtained information can help to investigate those favorable fragments in the studied ligands skeletons that have raised the potency of the analog in comparison with the parent compound to design more potent multi target ligands to heal Alzheimer's disease. PMID- 26043758 TI - Identification of epigenetic modifications that contribute to pathogenesis in therapy-related AML: Effective integration of genome-wide histone modification with transcriptional profiles. AB - BACKGROUND: Therapy-related, secondary acute myeloid leukemia (t-AML) is an increasingly frequent complication of intensive chemotherapy. This malignancy is often characterized by abnormalities of chromosome 7, including large deletions or chromosomal loss. A variety of studies suggest that decreased expression of the EZH2 gene located at 7q36.1 is critical in disease pathogenesis. This histone methyltransferase has been implicated in transcriptional repression through modifying histone H3 on lysine 27 (H3k27). However, the critical target genes of EZH2 and their regulatory roles remain unclear. METHOD: To characterize the subset of EZH2 target genes that might contribute to t-AML pathogenesis, we developed a novel computational analysis to integrate tissue-specific histone modifications and genome-wide transcriptional regulation. Initial integrative analysis utilized a novel "seq2gene" strategy to explore largely the target genes of chromatin immuneprecipitation sequencing (ChIP-seq) enriched regions. By combining seq2gene with our Phenotype-Genotype-Network (PGNet) algorithm, we enriched genes with similar expression profiles and genomic or functional characteristics into "biomodules". RESULTS: Initial studies identified SEMA3A (semaphoring 3A) as a novel oncogenic candidate that is regulated by EZH2 silencing, using data derived from both normal and leukemic cell lines as well as murine cells deficient in EZH2. A microsatellite marker at the SEMA3A promoter has been associated with chemosensitivity and radiosensitivity. Notably, our subsequent studies in primary t-AML demonstrate an expected up-regulation of SEMA3A that is EZH2-modulated. Furthermore, we have identified three biomodules that are co-expressed with SEMA3A and up-regulated in t-AML, one of which consists of previously characterized EZH2-repressed gene targets. The other two biomodules include MAPK8 and TATA box targets. Together, our studies suggest an important role for EZH2 targets in t-AML pathogenesis that warrants further study. CONCLUSION: These developed computational algorithms and systems biology strategies will enhance the knowledge discovery and hypothesis-driven analysis of multiple next generation sequencing data, for t-AML and other complex diseases. PMID- 26043759 TI - Proper muscle layer damage affects ulcer healing after gastric endoscopic submucosal dissection. AB - BACKGROUND AND AIM: Endoscopic submucosal dissection (ESD) is the established therapy for superficial gastrointestinal neoplasms. However, management of the artificial ulcers associated with ESD has become important and the relationship between ulcer healing factors and treatment is still unclear. We aimed to evaluate ESD-related artificial ulcer reduction ratio at 4 weeks to assess factors associating with ulcer healing after ESD that may lead to optimal treatment. METHODS: Between January 2009 and December 2013, a total of 375 lesions fulfilled the expanded criteria for ESD. We defined ulcer reduction rate <90% as (A) poor-healing group; and rate >=90% as (B) well-healing group. After exclusion, 328 lesions were divided into two groups and analyzed. These two groups were compared based on clinicopathological/endoscopic features, concomitant drugs, and treatment. RESULTS: Ulcer reduction rate was significantly correlated with factors related to the ESD procedure (i.e. procedure time, submucosal fibrosis, and injury of the proper muscle layer, in univariate analysis. Multivariate logistic regression analysis showed that submucosal fibrosis (F2) (P = 0.03; OR, 16.46; 95% CI, 1.31-206.73) and injury of the proper muscle layer (P = 0.01; OR, 4.27; 95% CI, 2.04-8.92) were statistically significant predictors of delayed healing. CONCLUSION: This single-center retrospective study indicated that ESD-induced artificial ulcer healing was affected by submucosal fibrosis and injury of the proper muscle layer, which induced damage to the muscle layer. Therefore, the preferable pharmacotherapy can be determined on completion of the ESD procedure. PMID- 26043760 TI - Concentration Dependent Dimensionality of Resonance Energy Transfer in a Postsynthetically Doped Morphologically Homologous Analogue of UiO-67 MOF with a Ruthenium(II) Polypyridyl Complex. AB - A method is described here by which to dope ruthenium(II) bis(2,2'-bipyridine) (2,2'-bipyridyl-5,5'-dicarboxylic acid), RuDCBPY, into a UiO-67 metal-organic framework (MOF) derivative in which 2,2'-bipyridyl-5,5'-dicarboxylic acid, UiO-67 DCBPY, is used in place of 4,4'-biphenyldicarboxylic acid. Emission lifetime measurements of the RuDCBPY triplet metal-to-ligand charge transfer, (3)MLCT, excited state as a function of RuDCBPY doping concentration in UiO-67-DCBPY are discussed in light of previous results for RuDCBPY-UiO-67 doped powders in which quenching of the (3)MLCT was said to be due to dipole-dipole homogeneous resonance energy transfer, RET. The bulk distribution of RuDCBPY centers within MOF crystallites are also estimated with the use of confocal fluorescence microscopy. In the present case, it is assumed that the rate of RET between RuDCBPY centers has an r(-6) separation distance dependence characteristic of Forster RET. The results suggest (1) the dimensionality in which RET occurs is dependent on the RuDCBPY concentration ranging from one-dimensional at very low concentrations up to three-dimensional at high concentration, (2) the occupancy of RuDCBPY within UiO-67-DCBPY is not uniform throughout the crystallites such that RuDCBPY densely populates the outer layers of the MOF at low concentrations, and (3) the average separation distance between RuDCBPY centers is ~21 A. PMID- 26043761 TI - Feature Statistics Modulate the Activation of Meaning During Spoken Word Processing. AB - Understanding spoken words involves a rapid mapping from speech to conceptual representations. One distributed feature-based conceptual account assumes that the statistical characteristics of concepts' features--the number of concepts they occur in (distinctiveness/sharedness) and likelihood of co-occurrence (correlational strength)--determine conceptual activation. To test these claims, we investigated the role of distinctiveness/sharedness and correlational strength in speech-to-meaning mapping, using a lexical decision task and computational simulations. Responses were faster for concepts with higher sharedness, suggesting that shared features are facilitatory in tasks like lexical decision that require access to them. Correlational strength facilitated responses for slower participants, suggesting a time-sensitive co-occurrence-driven settling mechanism. The computational simulation showed similar effects, with early effects of shared features and later effects of correlational strength. These results support a general-to-specific account of conceptual processing, whereby early activation of shared features is followed by the gradual emergence of a specific target representation. PMID- 26043762 TI - Fluorescence in situ hybridization identifies high risk Barrett's patients likely to develop esophageal adenocarcinoma. AB - Barrett's esophagus (BE) with high-grade dysplasia (HGD) defines a group of individuals at high risk of progression to esophageal adenocarcinoma (EA). Fluorescence in situ hybridization (FISH) has been shown to be useful for the detection of dysplasia and EA in endoscopic brushing specimens from BE patients. The aim of this study was to determine whether FISH in combination with histological findings would further identify more rapid progressors to EA. This is a retrospective cohort study of high-risk patients, having a history of biopsy confirmed HGD without EA, with an endoscopic brushing specimen analyzed by FISH while undergoing endoscopic surveillance and treatment between April 2003 and October 2010. Brushing specimens were assessed by FISH probes targeting 8q24 (MYC), 9p21 (CDKN2A), 17q12 (ERBB2), and 20q13 (ZNF217) and evaluated for the presence of polysomy, defined as multiple chromosomal gains (displaying >= 3 signals for >= 2 probes). Specimens containing >= 4 cells exhibiting polysomy were considered polysomic. HGD was confirmed by at least two experienced gastrointestinal pathologists. Of 245 patients in this study, 93 (38.0%) had a polysomic FISH result and 152 (62.0%) had a non-polysomic FISH result. Median follow-up was 3.6 years (interquartile range [IQR] 2-5 years). Patients with a polysomic FISH result had a significantly higher risk of developing EA within 2 years (14.2%) compared with patients with a non-polysomic FISH result (1.4%, P < 0.001). These findings suggest that a polysomic FISH result in BE patients with simultaneous HGD identifies patients at a higher risk for developing EA compared with those with non-polysomy. PMID- 26043763 TI - Small cortical infarcts: prevalence, determinants, and cognitive correlates in the general population. AB - BACKGROUND: Cortical brain infarcts are defined as infarcts involving cortical gray matter, but may differ considerably in size. It is unknown whether small cortical infarcts have a similar clinical phenotype as larger counterparts. We investigated prevalence, determinants, and cognitive correlates of small cortical infarcts in the general population and compared these with large cortical infarcts and lacunar infarcts. METHODS: Four thousand nine hundred five nondemented individuals (age 63.95 +/- 10.99) from a population-based study were included. Infarcts were rated on magnetic resonance imaging and participants were classified according to mean infarct diameter into small (<=15 mm in largest diameter) or large (>15 mm) cortical infarcts, lacunar infarcts, or a combination of subtypes. Spatial distribution maps were created for manually labeled small and large infarcts. Participants underwent cognitive testing. Analyses were performed using multinomial regression and analysis of covariance. RESULTS: Three hundred eighty-one (7.8%) persons had any infarct on magnetic resonance imaging, among whom 54 with small (1.1%) and 77 (1.6%) with large cortical infarcts. Small cortical infarcts were mainly localized in external watershed areas, whereas large cortical infarcts were localized primarily in large arterial territories. Age (odds ratio = 1.06; 95% confidence interval = 1.02, 1.09), male gender (1.98; 1.01, 3.92), and smoking (2.55; 1.06, 6.14) were determinants of small cortical infarcts. Participants with these infarcts had worse scores in delayed memory, processing speed, and attention tests than persons without infarcts, even after adjustment for cardiovascular risk factors. CONCLUSIONS: In the elderly, small cortical infarcts appear as frequent as large infarcts but in different localization. Our results suggest that small cortical infarcts share cardiovascular risk factors and cognitive correlates with large cortical, but also with lacunar infarcts. PMID- 26043764 TI - Study of the negative magneto-resistance of single proton-implanted lithium-doped ZnO microwires. AB - The magneto-transport properties of single proton-implanted ZnO and of Li(7%) doped ZnO microwires have been studied. The as-grown microwires were highly insulating and not magnetic. After proton implantation the Li(7%) doped ZnO microwires showed a non-monotonous behavior of the negative magneto-resistance (MR) at temperature above 150 K. This is in contrast to the monotonous NMR observed below 50 K for proton-implanted ZnO. The observed difference in the transport properties of the wires is related to the amount of stable Zn vacancies created at the near surface region by the proton implantation and Li doping. The magnetic field dependence of the resistance might be explained by the formation of a magnetic/non-magnetic heterostructure in the wire after proton implantation. PMID- 26043765 TI - Risk factors associated with intraoperatively acquired pressure ulcers in the park-bench position: a retrospective study. AB - Patients undergoing surgery in the park-bench position are at high risk of developing intraoperatively acquired pressure ulcers (IAPUs). The purpose was to examine retrospectively risk factors associated with IAPUs in the park-bench position. This study was conducted at a general hospital during the period of September 2010 to September 2012. Twenty-one potential risk factors were evaluated using data obtained from the hospital database. IAPUs developed in 30 of 277 patients (11%). Perspiration was statistically found to be independently associated with IAPUs [OR 3.09, 95% confidence interval (Cl) 1.07-8.58, P = 0.037]. A length of surgery of more than 6 hours was identified to be likely associated with IAPUs (OR 2.64, 95% Cl 0.84-9.08, P = 0.095) compared with less than 6 hours. Furthermore, there was an interaction between the length of surgery and the core temperature; that is, when the length of surgery was more than 6 hours, a core temperature of more than 38.1 degrees C at the end of surgery had a higher odds ratio (8.45, 95% Cl 3.04-27.46, P < 0.001) than that at a lower core temperature (3.20, 95% Cl 1.23-8.78, P = 0.017). These results suggest that perspiration and core temperature are preventable causative factors of pressure ulcers, even under conditions of prolonged surgery in the park-bench position. PMID- 26043766 TI - Cartographic Analysis of Antennas and Towers: A Novel Approach to Improving the Implementation and Data Transmission of mHealth Tools on Mobile Networks. AB - BACKGROUND: Most mHealth tools such as short message service (SMS), mobile apps, wireless pill counters, and ingestible wireless monitors use mobile antennas to communicate. Limited signal availability, often due to poor antenna infrastructure, negatively impacts the implementation of mHealth tools and remote data collection. Assessing the antenna infrastructure prior to starting a study can help mitigate this problem. Currently, there are no studies that detail whether and how the antenna infrastructure of a study site or area is assessed. OBJECTIVE: To address this literature gap, we analyze and discuss the use of a cartographic analysis of antennas and towers (CAAT) for mobile communications for geographically assessing mobile antenna and tower infrastructure and identifying signal availability for mobile devices prior to the implementation of an SMS based mHealth pilot study. METHODS: An alpha test of the SMS system was performed using 11 site staff. A CAAT for the study area's mobile network was performed after the alpha test and pre-implementation of the pilot study. The pilot study used a convenience sample of 11 high-risk men who have sex with men who were given human immunodeficiency virus test kits for testing nonmonogamous sexual partners before intercourse. Product use and sexual behavior were tracked through SMS. Message frequency analyses were performed on the SMS text messages, and SMS sent/received frequencies of 11 staff and 11 pilot study participants were compared. RESULTS: The CAAT helped us to successfully identify strengths and weaknesses in mobile service capacity within a 3-mile radius from the epicenters of four New York City boroughs. During the alpha test, before CAAT, 1176/1202 (97.84%) text messages were sent to staff, of which 26/1176 (2.21%) failed. After the CAAT, 2934 messages were sent to pilot study participants and none failed. CONCLUSIONS: The CAAT effectively illustrated the research area's mobile infrastructure and signal availability, which allowed us to improve study setup and sent message success rates. The SMS messages were sent and received with a lower fail rate than those reported in previous studies. PMID- 26043767 TI - Estrogen-dependent expression and subcellular localization of the tight junction protein claudin-4 in HEC-1A endometrial cancer cells. AB - Endometrial cancer is the most common female reproductive cancer in the United States and is associated with deregulated tight junction protein expression. Given the highly estrogen-responsive nature of this tissue, we investigated the effects of estrogen and its agonist, 4-OH TAM, on the expression and subcellular localization of the tight junction protein claudin-4 (CLDN-4), in HEC-1A endometrial cancer cells. In untreated HEC-1A cells, we observed dramatic overexpression of claudin-4 protein. In addition, differential detergent extraction analysis indicated that claudin-4 was localized primarily in the membrane but also found in the cytosolic, nuclear and cytoskeletal fractions. Upon exposure of HEC-1A to estradiol (E2), we observed a biphasic effect both on the overall expression of claudin-4 protein and on its cytosolic and cytoskeletal presence as demonstrated by immunoblot analysis. Immunofluorescence analysis also revealed a biphasic effect of E2 on claudin-4 expression. In contrast, we observed no changes in expression levels nor in the subcellular distribution patterns of claudin-4 in HEC-1A cells treated with different concentrations of 4 OH TAM. The intracellular presence of CLDN-4 coupled with the biphasic effects of E2 on CLDN-4 expression in the cytoskeleton suggest that this protein may be involved in cell signaling to and from TJs. PMID- 26043768 TI - Investigation of spatio-temporal cancer clusters using residential histories in a case-control study of non-Hodgkin lymphoma in the United States. AB - BACKGROUND: Non-Hodgkin lymphoma (NHL) is an enigmatic disease with few known risk factors. Spatio-temporal epidemiologic analyses have the potential to reveal patterns that may give clues to new risk factors worthy of investigation. We sought to investigate clusters of NHL through space and time based on life course residential histories. METHODS: We used residential histories from a population based NHL case-control study of 1300 cases and 1044 controls with recruitment centers in Iowa, Detroit, Seattle, and Los Angeles, and diagnosed in 1998-2000. Novel methods for cluster detection allowing for residential mobility, called Q statistics, were used to quantify nearest neighbor relationships through space and time over the life course to identify cancer clusters. Analyses were performed on all cases together and on two subgroups of NHL: Diffuse large B-cell lymphoma and follicular lymphoma. These more homogenous subgroups of cases might have a more common etiology that could potentially be detected in cluster analysis. Based on simulation studies designed to help account for multiple testing across space and through time, we required at least four significant cases nearby one another to declare a region a potential cluster, along with confirmatory analyses using spatial-only scanning windows (SaTScan). RESULTS: Evidence of a small cluster in southeastern Oakland County, MI was suggested using residences 10-18 years prior to diagnosis, and confirmed by SaTScan in a time-slice analysis 20 years prior to diagnosis, when all cases were included in the analysis. Consistent evidence of clusters was not seen in the two histologic subgroups. CONCLUSIONS: Suggestive evidence of a small space-time cluster in southeastern Oakland County, MI was detected in this NHL case-control study in the USA. PMID- 26043771 TI - Infection and exposure to vector-borne pathogens in rural dogs and their ticks, Uganda. AB - BACKGROUND: In rural parts of Africa, dogs live in close association with humans and livestock, roam freely, and usually do not receive prophylactic measures. Thus, they are a source of infectious disease for humans and for wildlife such as protected carnivores. In 2011, an epidemiological study was carried out around three conservation areas in Uganda to detect the presence and determine the prevalence of vector-borne pathogens in rural dogs and associated ticks to evaluate the risk that these pathogens pose to humans and wildlife. METHODS: Serum samples (n = 105), blood smears (n = 43) and blood preserved on FTA cards (n = 38) and ticks (58 monospecific pools of Haemaphysalis leachi and Rhipicephalus praetextatus including 312 ticks from 52 dogs) were collected from dogs. Dog sera were tested by indirect immunofluorescence to detect the presence of antibodies against Rickettsia conorii and Ehrlichia canis. Antibodies against R. conorii were also examined by indirect enzyme immunoassay. Real time PCR for the detection of Rickettsia spp., Anaplasmataceae, Bartonella spp. and Babesia spp. was performed in DNA extracted from FTA cards and ticks. RESULTS: 99% of the dogs were seropositive to Rickettsia spp. and 29.5% to Ehrlichia spp. Molecular analyses revealed that 7.8% of the blood samples were infected with Babesia rossi, and all were negative for Rickettsia spp. and Ehrlichia spp. Ticks were infected with Rickettsia sp. (18.9%), including R. conorii and R. massiliae; Ehrlichia sp. (18.9%), including E. chaffeensis and Anaplasma platys; and B. rossi (1.7%). Bartonella spp. was not detected in any of the blood or tick samples. CONCLUSIONS: This study confirms the presence of previously undetected vector-borne pathogens of humans and animals in East Africa. We recommend that dog owners in rural Uganda be advised to protect their animals against ectoparasites to prevent the transmission of pathogens to humans and wildlife. PMID- 26043770 TI - Appearance of fast astrocytic component in voltage-sensitive dye imaging of neural activity. AB - BACKGROUND: Voltage-sensitive dye (VSD) imaging and intrinsic optical signals (IOS) are widely used methods for monitoring spatiotemporal neural activity in extensive networks. In spite of that, identification of their major cellular and molecular components has not been concluded so far. RESULTS: We addressed these issues by imaging spatiotemporal spreading of IOS and VSD transients initiated by Schaffer collateral stimulation in rat hippocampal slices with temporal resolution comparable to standard field potential recordings using a 464-element photodiode array. By exploring the potential neuronal and astroglial molecular players in VSD and IOS generation, we identified multiple astrocytic mechanisms that significantly contribute to the VSD signal, in addition to the expected neuronal targets. Glutamate clearance through the astroglial glutamate transporter EAAT2 has been shown to be a significant player in VSD generation within a very short (<5 ms) time-scale, indicating that astrocytes do contribute to the development of spatiotemporal VSD transients previously thought to be essentially neuronal. In addition, non-specific anion channels, astroglial K(+) clearance through Kir4.1 channel and astroglial Na(+)/K(+) ATPase also contribute to IOS and VSD transients. CONCLUSION: VSD imaging cannot be considered as a spatially extended field potential measurement with predominantly neuronal origin, instead it also reflects a fast communication between neurons and astrocytes. PMID- 26043772 TI - Why medical students do not choose a career in geriatrics: a systematic review. AB - BACKGROUND: While the demand for doctors specialised in the medical care of elderly patients is increasing, the interest among medical students for a career in geriatrics is lagging behind. METHODS: To get an overview of the different factors reported in the literature that affect the (low) interest among medical students for a career in geriatrics, a systematic literature search was conducted using PubMed, Embase, PsycINFO, and ERIC. Quality assessment criteria were applied. RESULTS: Twenty studies met the criteria and were included in the review. In relation to the nature of the work, the preference of medical students is young patients, and acute somatic diseases that can be cured. The complexity of the geriatric patient deters students from choosing this specialty. Exposure by means of pre-clinical and particularly clinical education increases interest. The lack of status and the financial aspects have a negative influence on interest. CONCLUSION: Exposure to geriatrics by means of education is necessary. The challenge in geriatric education is to show the rewarding aspects of the specialty. PMID- 26043773 TI - Development of a method to rate the primary safety of vehicles using linked New Zealand crash and vehicle licensing data. AB - OBJECTIVE: Vehicle safety rating systems aim firstly to inform consumers about safe vehicle choices and, secondly, to encourage vehicle manufacturers to aspire to safer levels of vehicle performance. Primary rating systems (that measure the ability of a vehicle to assist the driver in avoiding crashes) have not been developed for a variety of reasons, mainly associated with the difficult task of disassociating driver behavior and vehicle exposure characteristics from the estimation of crash involvement risk specific to a given vehicle. The aim of the current study was to explore different approaches to primary safety estimation, identifying which approaches (if any) may be most valid and most practical, given typical data that may be available for producing ratings. METHODS: Data analyzed consisted of crash data and motor vehicle registration data for the period 2003 to 2012: 21,643,864 observations (representing vehicle-years) and 135,578 crashed vehicles. Various logistic models were tested as a means to estimate primary safety: Conditional models (conditioning on the vehicle owner over all vehicles owned); full models not conditioned on the owner, with all available owner and vehicle data; reduced models with few variables; induced exposure models; and models that synthesised elements from the latter two models. RESULTS: It was found that excluding young drivers (aged 25 and under) from all primary safety estimates attenuated some high risks estimated for make/model combinations favored by young people. The conditional model had clear biases that made it unsuitable. Estimates from a reduced model based just on crash rates per year (but including an owner location variable) produced estimates that were generally similar to the full model, although there was more spread in the estimates. The best replication of the full model estimates was generated by a synthesis of the reduced model and an induced exposure model. CONCLUSIONS: This study compared approaches to estimating primary safety that could mimic an analysis based on a very rich data set, using variables that are commonly available when registered fleet data are linked to crash data. This exploratory study has highlighted promising avenues for developing primary safety rating systems for vehicle makes and models. PMID- 26043774 TI - Prediction of Significant Prostate Cancer at Prostate Biopsy and Per Core Detection Rate of Targeted and Systematic Biopsies Using Real-Time Shear Wave Elastography. AB - INTRODUCTION: Prostate cancer (PCa) detection is accompanied by overdiagnosis and mischaracterization of PCa. Therefore, new imaging modalities like shear wave elastography (SWE) are required. AIM: The aim of this study was to evaluate per core detection rates (DRs) of targeted biopsies and systematic biopsies and to test if SWE findings can predict presence of clinically significant PCa (csPCa) at biopsy. PATIENTS AND METHODS: Overall, 95 patients scheduled for prostate biopsy in our center underwent SWE. SWE findings were classified into suspicious or normal. Targeted biopsies were taken in up to 3 SWE-suspicious areas. csPCa was defined as the presence of Gleason pattern >=4, level of prostate-specific antigen >=10 ng/ml or >2 positive cores. RESULTS: Overall DR for csPCa in our study cohort was 40%. Per-core DR for exclusively SWE-targeted cores versus systematic samples cores was 10.5 vs. 8.6% (p = 0.3). In the logistic regression models, individuals with suspicious SWE findings are at 6.4-fold higher risk of harboring csPCa (p = 0.03). Gain in predictive accuracy was 2.3% (0.82 vs. 0.84, p = 0.01). CONCLUSIONS: Presence of suspicious SWE findings is an independent predictor of csPCa. Therefore, SWE may be helpful in selecting patients for biopsy. Nonetheless, per-core DR for SWE-targeted cores was not statistically significant higher than DR of systematic sampled cores. Therefore, additional systematic biopsy is mandatory. PMID- 26043775 TI - Identification of key genes and pathways in renal cell carcinoma through expression profiling data. AB - BACKGROUND/AIMS: To isolate key genes and pathways in renal cell carcinoma (RCC), which might reveal more evidences on the regulation network and contribute to pathogenic mechanisms of RCC. METHODS: Microarray data of GSE34676, GSE23926 and GSE48008 were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) and differentially expressed miRNAs were respectively screened using Limma package, followed by the selection of CNV associated genes and miRNAs. A multi-molecular regulation interaction network was constructed, and significant modules were subsequently isolated from the network by Molecular Complex Detection (Mcode) of Cytoscape. Finally, GO terms and KEGG pathways of these genes and miRNAs in significant modules were enriched using DAVID. RESULTS: Total 403 DEGs and 231 differentially expressed miRNAs were screened in RCC samples and normal group. Moreover, 1369 genes and 68 miRNAs were isolated by CNV analysis. Besides, a total of 59 miRNAs and 209 genes that related to 340 interaction pairs were analyzed and used to construct the network and 2 significant modules were identified. In the modules, CAV1 and CAV2 were shown to correlate with RCC. GNAI1, GPSM2 and GNAO1 were likely involved in the regulation of RCC through G protein signal transduction. Besides, G-protein coupled receptor protein signaling pathway, focal adhesion, MAPK signaling pathway and neuroactive ligand receptor interaction were enriched. CONCLUSION: Our study suggests that several crucial genes including CAV1,CAV2, GNAI1, GPSM2, and GNAO1 and pathways may play key roles in RCC progression. PMID- 26043776 TI - The Core Outcomes in Women's Health (CROWN) Initiative: Journal Editors Invite Researchers to Develop Core Outcomes in Women's Health. PMID- 26043777 TI - Ofatumumab in the treatment of non-Hodgkin's lymphomas. AB - INTRODUCTION: Ofatumumab is a second-generation humanized monoclonal antibody targeting CD20 registered for the treatment of patients with relapsing/refractory chronic lymphocytic leukemia. This review will describe the activity of ofatumumab in patients with CD20 B-cell lymphomas. AREAS COVERED: A review of all manuscript published on ofatumumab activity in B-cell lymphomas is presented with conclusions on the future use of this antibody in these patients. EXPERT OPINION: Ofatumumab activity is low in indolent or aggressive B-cell lymphomas. The future of this drug is challenged by new monoclonal antibodies and new targeted drugs. PMID- 26043778 TI - Adrenomedullin promotes intrahepatic cholangiocellular carcinoma metastasis and invasion by inducing epithelial-mesenchymal transition. AB - Intrahepatic cholangiocellular carcinoma (ICC) is the second most common type of primary liver cancer. However, its etiology and molecular pathogenesis remain largely unknown. The present study aimed to investigate the association between adrenomedullin (ADM) and epithelial-mesenchymal transition (EMT) in ICC and to elucidate the underlying signaling pathway. We evaluated the clinical significance of ADM in 133 ICC patients using tissue microarray analysis of ICC tissues. We also investigated the mechanisms of ADM in ICC EMT-mediated metastasis in cholangiocarcinoma cell lines in vitro. The results revealed that ADM was upregulated in human ICC tissues (73/133) compared with that in healthy controls. ADM expression was positively correlated with shorter overall survival (P<0.01). The characteristics of EMT were induced in vitro by adenoviral transduction of ADM into HuCCT1 cells, resulting in the downregulation of E cadherin and ZO-1, and the concomitant upregulation of N-cadherin and vimentin. Knockdown of ADM by short hairpin RNA in HUH28 cells expressing high levels of ADM was associated with the reversal of EMT. Functional studies revealed that ADM regulated the activation of ZEB1, which subsequently mediated EMT. The results of the present study suggest that ADM plays an important role in ICC metastasis, and that ADM signaling of EMT may represent a valuable therapeutic target in cancer patients. PMID- 26043779 TI - Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data. AB - BACKGROUND: It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. RESULTS: In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. CONCLUSIONS: This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation. PMID- 26043780 TI - Development of the Cognitive Test for Severe Dementia. AB - BACKGROUND/AIMS: Existing cognitive measures for moderate-to-severe dementia have shown floor effects and an inability to assess the remaining cognitive function, especially for profound dementia. METHODS: We constructed the Cognitive Test for Severe Dementia (CTSD), which consists of 13 items covering 7 cognitive domains, and examined its reliability and validity. RESULTS: Cronbach's alpha in severe dementia participants was 0.896. Interrater and test-retest reliability were 0.961 and 0.969, respectively. The CTSD showed a significant correlation with 3 other measures of cognitive function (Mini-Mental State Examination, Severe Cognitive Impairment Rating Scale, and Hasegawa Dementia Scale-Revised: r values = 0.870-0.922, p values <0.001). While the other measures showed floor effects, the CTSD did not. CONCLUSION: The CTSD was able to sensitively capture the remaining cognitive function in severe dementia patients when compared with other cognitive tests. PMID- 26043781 TI - Molecular dynamics studies on the buffalo prion protein. AB - It was reported that buffalo is a low susceptibility species resisting to transmissible spongiform encephalopathies (TSEs) (same as rabbits, horses, and dogs). TSEs, also called prion diseases, are invariably fatal and highly infectious neurodegenerative diseases that affect a wide variety of species (except for rabbits, dogs, horses, and buffalo), manifesting as scrapie in sheep and goats; bovine spongiform encephalopathy (BSE or "mad-cow" disease) in cattle; chronic wasting disease in deer and elk; and Creutzfeldt-Jakob diseases, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and Kulu in humans etc. In molecular structures, these neurodegenerative diseases are caused by the conversion from a soluble normal cellular prion protein (PrP(C)), predominantly with alpha-helices, into insoluble abnormally folded infectious prions (PrP(Sc)), rich in beta-sheets. In this article, we studied the molecular structure and structural dynamics of buffalo PrP(C) (BufPrP(C)), in order to understand the reason why buffalo is resistant to prion diseases. We first did molecular modeling of a homology structure constructed by one mutation at residue 143 from the NMR structure of bovine and cattle PrP(124-227); immediately we found that for BufPrP(C)(124-227), there are five hydrogen bonds (HBs) at Asn143, but at this position, bovine/cattle do not have such HBs. Same as that of rabbits, dogs, or horses, our molecular dynamics studies also revealed there is a strong salt bridge (SB) ASP178-ARG164 (O-N) keeping the beta2-alpha2 loop linked in buffalo. We also found there is a very strong HB SER170-TYR218 linking this loop with the C-terminal end of alpha-helix H3. Other information, such as (i) there is a very strong SB HIS187-ARG156 (N-O) linking alpha-helices H2 and H1 (if mutation H187R is made at position 187, then the hydrophobic core of PrP(C) will be exposed (L.H. Zhong (2010). Exposure of hydrophobic core in human prion protein pathogenic mutant H187R. Journal of Biomolecular Structure and Dynamics 28(3), 355-361)), (ii) at D178, there is a HB Y169-D178 and a polar contact R164 D178 for BufPrP(C) instead of a polar contact Q168-D178 for bovine PrP(C) (C.J. Cheng, & V. Daggett. (2014). Molecular dynamics simulations capture the misfolding of the bovine prion protein at acidic pH. Biomolecules 4(1), 181-201), (iii) BufPrP(C) owns three 310 helices at 125-127, 152-156, and in the beta2 alpha2 loop, respectively, and (iv) in the beta2-alpha2 loop, there is a strong pi-pi stacking and a strong pi-cation F175-Y169-R164.(N)NH2, has been discovered. PMID- 26043782 TI - Ginsenoside Rb2 Attenuates UV-B Radiation-Induced Reactive Oxygen Species and Matrix Metalloproteinase-2 through Upregulation of Antioxidant Components in Human Dermal Fibroblasts. AB - AIMS: The antiphotoaging activities of ginsenoside Rb2 on the skin, one of the predominant protopanaxadiol-type ginsenosides, were evaluated in cultured human dermal fibroblasts. METHODS: The antiphotoaging activity was examined by analyzing the levels of reactive oxygen species (ROS), matrix metalloproteinase-2 (MMP-2), total glutathione (GSH) and superoxide dismutase (SOD) activity as well as cell viability for fibroblasts under UV-B irradiation. RESULTS: When cultured fibroblasts were exposed to Rb2 prior to UV-B irradiation, Rb2 displayed suppressive activities on UV-B-induced ROS elevation and MMP-2 on both activity and protein levels, while it exhibited an enhancing activity on total GSH level and SOD activity diminished by UV-B irradiation. However, Rb2 could not interfere with cell viabilities in UV-B-irradiated fibroblasts. CONCLUSION: Ginsenoside Rb2 plays a photoprotective role against UV-B-induced oxidative stress in human dermal fibroblasts, which implies its skin antiphotoaging potential. PMID- 26043783 TI - Adrenomedullin improves intestinal epithelial barrier function by downregulating myosin light chain phosphorylation in ulcerative colitis rats. AB - Adrenomedullin (AM) is a pivotal endogenous vasoactive peptide, which can maintain epithelial barrier function in inflammatory bowel disease. Myosin light chain kinase (MLCK)-dependent phosphorylated myosin light chain kinase (p-MLC) is a key regulator of intestinal barrier function. The aim of the present study was to investigate the effect and mechanism of AM on the intestinal epithelial barrier in a rat model of ulcerative colitis (UC) induced by 2,4,6-trinitro benzene-sulfonic acid (TNBS). A total of 21 male Sprague-Dawley rats were randomly divided into the following three groups and administered different agents for 7 days: The normal group (water and saline), model group (TNBS and saline) and the AM group (TNBS and AM; 1.0 ug). The weight of rats was recorded every day. Serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels were detected using ELISA kits. Colon tissue was collected for the assessment of histological alterations. The protein expression of MLCK, p-MLC and zonula occludens-1 (ZO-1) was examined by western blot analysis. Intestinal epithelial tight junctions were examined using transmission electron microscopy. The results demonstrated that in colitis model rats, the expression of TNF-alpha, IL-6, MLCK and p-MLC significantly increased compared with normal rats. In addition, the expression of ZO-1 decreased (P<0.05) and intestinal epithelial cell permeability increased. Following AM administration, TNF-alpha, IL-6, MLCK and p-MLC expression significantly decreased compared with the model rats, the expression of ZO-1 increased (P<0.05) and intestinal epithelial cell permeability reduced. These data indicate a protective effect of AM on intestinal epithelial barrier dysfunction via suppression of inflammatory cytokines and downregulation of MLCK-p-MLC in TNBS-induced UC. In conclusion, AM/MLCK-p-MLC may be an important signaling pathway in the occurrence and development of UC. PMID- 26043784 TI - Complications after esophagectomy: it is time to speak the same language. PMID- 26043785 TI - Health care in your pocket: an e-induction manual. PMID- 26043786 TI - Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension. AB - BACKGROUND: Antiproliferative strategies have emerged as a potential therapeutic option for pulmonary arterial hypertension (PAH). OBJECTIVE: To evaluate the long term efficacy and safety of imatinib. METHODS: This is an observational study of 15 patients with idiopathic PAH (n = 13) or PAH associated with connective tissue disease (n = 2) treated off-label with imatinib 400 mg daily. Pulmonary hypertension-specific therapy was established in all patients (triple therapy in 10, dual therapy in 3, and monotherapy in 2 patients). RESULTS: After 6 months, improvement in hemodynamics (p < 0.01), functional class (p = 0.035), and quality of life (p = 0.005) was observed. After a median follow-up of 37 months, there was a sustained improvement in functional class (p = 0.032), quality of life (p = 0.019), and echocardiographic parameters of right ventricular function (p < 0.05). Three patients (20%) presented with completely normal echocardiography, absent tricuspid regurgitation, and normal pro-brain natriuretic peptide levels, indicative of 'hemodynamic remission'. Of note, however, only 1 case was assessed by invasive hemodynamics. The overall 1- and 3-year survival was 100 and 90%, respectively. Two patients experienced a subdural hematoma (SDH), which in both cases resolved without sequelae. After careful consultation of the potential risks and benefits, all patients as well as a safety cohort of 9 subsequent cases decided to continue the imatinib therapy. After adjusting the target international normalized ratio (INR) to around 2.0, no further cases of SDH occurred during 50 patient-years. CONCLUSIONS: Long-term treatment with imatinib may improve the functional class and quality of life. Single cases might even attain hemodynamic remission. The occurrence of 5% SDH per patient-years is concerning. However, adjusting the INR to around 2.0 might obviate this complication. PMID- 26043788 TI - Nonvisualization of the Fetal Gallbladder: Can Levels of Gamma-Glutamyl Transpeptidase in Amniotic Fluid Predict Fetal Prognosis? AB - OBJECTIVE: In cases of nonvisualization of the fetal gallbladder (NVFGB), we investigated whether amniotic fluid levels of gamma-Glutamyl transpeptidase (GGTP) can distinguish normal development or benign gallbladder agenesis from severe anomaly such as biliary atresia. METHODS: This is a retrospective cohort study of pregnancies in which the gallbladder was not visualized in the second trimester fetal anatomy scan. Levels of GGTP in amniotic fluid were analyzed prior to 22 weeks of gestation by amniocentesis. Data were collected regarding other fetal malformations, fetal karyotype, and screening results for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. RESULTS: Of 32 cases of NVFGB, 27 (84%) had normal GGTP levels and a normal CFTR gene screening, and 1 of them had an abnormal karyotype. Three of the 5 cases with low GGTP were diagnosed with extrahepatic biliary atresia, proven by histopathological examination following termination of pregnancy. The fourth case had hepatic vasculature abnormality and the fifth isolated gallbladder agenesis. In 22 of 32 cases (68.7%), the gallbladder was detected either later in pregnancy or after delivery. CONCLUSION: The findings support low levels of GGTP in amniotic fluid, combined with NVFGB, as a sign of severe disease, mainly biliary atresia. Normal GGTP levels, concomitant with isolated NVFGB, carry a good prognosis. PMID- 26043787 TI - Detection and analysis of disease-associated single nucleotide polymorphism influencing post-translational modification. AB - Post-translational modification (PTM) plays a crucial role in biological functions and corresponding disease developments. Discovering disease-associated non-synonymous SNPs (nsSNPs) altering PTM sites can help to estimate the various PTM candidates involved in diseases, therefore, an integrated analysis between SNPs, PTMs and diseases is necessary. However, only a few types of PTMs affected by nsSNPs have been studied without considering disease-association until now. In this study, we developed a new database called PTM-SNP which contains a comprehensive collection of human nsSNPs that affect PTM sites, together with disease information. Total 179,325 PTM-SNPs were collected by aligning missense SNPs and stop-gain SNPs on PTM sites (position 0) or their flanking region (position -7 to 7). Disease-associated SNPs from GWAS catalogs were also matched with detected PTM-SNP to find disease associated PTM-SNPs. Our result shows PTM SNPs are highly associated with diseases, compared with other nsSNP sites and functional classes including near gene, intron and so on. PTM-SNP can provide an insight about discovering important PTMs involved in the diseases easily through the web site. PTM-SNP is freely available at http://gcode.kaist.ac.kr/ptmsnp. PMID- 26043789 TI - Nano-cartography: knowing where to look. PMID- 26043793 TI - Feasibility of a dynamic web guidance approach for personalized physical activity prescription based on daily information from wearable technology. AB - BACKGROUND: Computer tailored, Web-based interventions have emerged as an effective approach to promote physical activity. Existing programs, however, do not adjust activities according to the participant's compliance or physiologic adaptations, which may increase risk of injury and program attrition in sedentary adults. To address this limitation, objective activity monitor (AM) and heart rate data could be used to guide personalization of physical activity, but improved Web-based frameworks are needed to test such interventions. OBJECTIVE: The objective of this study is to (1) develop a personalized physical activity prescription (PPAP) app that combines dynamic Web-based guidance with multi sensor AM data to promote physical activity and (2) to assess the feasibility of using this system in the field. METHODS: The PPAP app was constructed using an open-source software platform and a custom, multi-sensor AM capable of accurately measuring heart rate and physical activity. A novel algorithm was written to use a participant's compliance and physiologic response to aerobic training (ie, changes in daily resting heart rate) recorded by the AM to create daily, personalized physical activity prescriptions. In addition, the PPAP app was designed to (1) manage the transfer of files from the AM to data processing software and a relational database, (2) provide interactive visualization features such as calendars and training tables to encourage physical activity, and (3) enable remote administrative monitoring of data quality and participant compliance. A 12-week feasibility study was performed to assess the utility and limitations of the PPAP app used by sedentary adults in the field. Changes in physical activity level and resting heart rate were monitored throughout the intervention. RESULTS: The PPAP app successfully created daily, personalized physical activity prescriptions and an interactive Web environment to guide and promote physical activity by the participants. The varied compliance of the participants enabled evaluation of administrative features of the app including the generation of automated email reminders, participation surveys, and daily AM file upload logs. CONCLUSIONS: This study describes the development of the PPAP app, a closed-loop technology framework that enables personalized physical activity prescription and remote monitoring of an individual's compliance and health response to the intervention. Data obtained during a 12-week feasibility study demonstrated the ability of the PPAP app to use objective AM data to create daily, personalized physical activity guidance, provide interactive feedback to users, and enable remote administrative monitoring of data quality and subject compliance. Using this approach, public health professionals, clinicians, and researchers can adapt the PPAP app to facilitate a range of personalized physical activity interventions to improve health outcomes, assess injury risk, and achieve fitness performance goals in diverse populations. PMID- 26043794 TI - Role of the tumor necrosis factor family member LIGHT in the pathogenesis of atopic dermatitis. AB - BACKGROUND: LIGHT (the name of which is derived from "homologous to lymphotoxins, exhibits inducible expression, competes with herpes simplex virus glycoprotein D for herpes simplex virus entry mediator, and expressed by T lymphocytes"), is a member of the tumor necrosis factor superfamily that is involved in various inflammatory diseases. OBJECTIVES: To assess serum LIGHT levels in patients with atopic dermatitis (AD) before and after treatment and compare it with controls. To correlate serum LIGHT with the severity scoring of AD (SCORAD) index. Another objective is to compare LIGHT levels between lesional skin in patients with AD and controls. METHODS: Twenty patients with AD and 20 healthy controls were enrolled in the study. Serum LIGHT levels were examined using an enzyme immunoassay technique. Serum total IgE levels, absolute eosinophil count, and eosinophil percentage were also done for both patients and controls. The SCORAD index was done for every patient before and after treatment. Skin LIGHT levels were analyzed using enzyme-linked immunosorbent assay kit and compared with control skin. RESULTS: Serum LIGHT levels in patients with AD were significantly higher than that of healthy controls and correlated positively with SCORAD index. LIGHT concentrations decreased as the symptoms were improved by treatment. A significant correlation was found on comparing the LIGHT serum levels and other established markers of disease severity. LIGHT levels in lesional skin in these patients were markedly higher than LIGHT levels in normal skin. CONCLUSION: LIGHT may play an important role in the pathogenesis of AD. This may presumably have possible future implications on the treatment of this chronic disease. PMID- 26043790 TI - Cocaine-mediated microglial activation involves the ER stress-autophagy axis. AB - Cocaine abuse leads to neuroinflammation, which, in turn, contributes to the pathogenesis of neurodegeneration associated with advanced HIV-1 infection. Autophagy plays important roles in both innate and adaptive immune responses. However, the possible functional link between cocaine and autophagy has not been explored before. Herein, we demonstrate that cocaine exposure induced autophagy in both BV-2 and primary rat microglial cells as demonstrated by a dose- and time dependent induction of autophagy-signature proteins such as BECN1/Beclin 1, ATG5, and MAP1LC3B. These findings were validated wherein cocaine treatment of BV-2 cells resulted in increased formation of puncta in cells expressing either endogenous MAP1LC3B or overexpressing GFP-MAP1LC3B. Specificity of cocaine induced autophagy was confirmed by treating cells with inhibitors of autophagy (3 MA and wortmannin). Intriguingly, cocaine-mediated induction of autophagy involved upstream activation of 2 ER stress pathways (EIF2AK3- and ERN1 dependent), as evidenced by the ability of the ER stress inhibitor salubrinal to ameliorate cocaine-induced autophagy. In vivo validation of these findings demonstrated increased expression of BECN1, ATG5, and MAP1LC3B-II proteins in cocaine-treated mouse brains compared to untreated animals. Increased autophagy contributes to cocaine-mediated activation of microglia since pretreatment of cells with wortmannin resulted in decreased expression and release of inflammatory factors (TNF, IL1B, IL6, and CCL2) in microglial cells. Taken together, our findings suggest that cocaine exposure results in induction of autophagy that is closely linked with neuroinflammation. Targeting autophagic proteins could thus be considered as a therapeutic strategy for the treatment of cocaine-related neuroinflammation diseases. PMID- 26043795 TI - Prevalence and cognitive impact of medial temporal atrophy in a hospital stroke service: retrospective cohort study. AB - BACKGROUND: Cerebrovascular disease and neurodegeneration cause cognitive impairment and frequently coexist. AIMS: Our objectives were to investigate the prevalence and cognitive impact of medial temporal lobe atrophy - a radiological marker often associated with Alzheimer's disease - in a hospital stroke service. METHODS: Retrospective cohort study of patients from a hospital stroke service. Patients assessed for suspected ischemic stroke or transient ischemic attack, irrespective of final diagnosis, underwent neuropsychological testing and magnetic resonance imaging. medial temporal lobe atrophy, white matter hyperintensities, lacunes, and cerebral microbleeds were rated using established criteria and validated scales. The associations between medial temporal lobe atrophy and cognition were tested using multivariable logistic regression analyses, adjusted for age and imaging markers of cerebrovascular disease. RESULTS: Three hundred and ninety-three patients were included, of whom 169 (43%; 95% confidence interval: 38.1-48.1%) had medial temporal lobe atrophy; in 38 patients (9.7%), medial temporal lobe atrophy was severe (mean score >=2). In unadjusted logistic regression analyses in the whole cohort, mean medial temporal lobe atrophy score was associated with verbal memory, nominal and perceptual skills, executive function, and speed and attention. After adjustment for age, white matter hyperintensities, number of lacunes, presence of cerebral microbleeds, previous ischemic stroke or transient ischemic attack, and premorbid intelligence quotient, mean medial temporal lobe atrophy score remained associated with impairment in verbal memory (odds ratio: 1.64; 95% confidence interval 1.04-2.58) and nominal skills (odds ratio: 1.61; 95% confidence interval 1.04-2.48). CONCLUSIONS: Medial temporal lobe atrophy is common and has an independent impact on cognitive function in a stroke service population, independent of confounding factors including age and magnetic resonance imaging markers of cerebrovascular disease. Medial temporal lobe atrophy is independently related to verbal memory and nominal skills, while small vessel pathology also contributes to speed and attention, and executive and perceptual functions. PMID- 26043796 TI - Systematic Review of Phosphodiesterase-5 Inhibitor Use in Right Ventricular Failure Following Left Ventricular Assist Device Implantation. AB - Our aim was to identify relevant literature supporting the use of phosphodiesterase-5 (PDE5) inhibitors in patients with persistent pulmonary hypertension with signs of postprocedural right ventricular (RV) dysfunction following left ventricular assist device (LVAD) implantation. We searched MEDLINE, SCOPUS, and Web of Science from inception through November 27, 2014 for citations evaluating patients with end-stage heart failure necessitating LVAD, continuous and pulsatile, who received a PDE5 inhibitor to prevent RV failure. Outcomes of interest included changes in mean pulmonary artery pressure, pulmonary vascular resistance, central venous pressure, cardiac index, and mean arterial pressure. Results are presented qualitatively. Four citations (n = 83 patients) were included. These included a single case report, two retrospective case series, and a prospective open-label study with a historical control. All four studies utilized the PDE5 inhibitor sildenafil with various doses for up to 3 months. Sildenafil routinely reduced mean pulmonary artery pressures as soon as 90 min after administration. Reductions in pulmonary vascular resistance were also seen shortly after the procedure and maintained through 12-15 weeks. While one study saw improvements in postoperative central venous pressures, another did not. Evidence supporting PDE5 inhibitor use to attenuate RV failure in patients requiring an LVAD is weak. PMID- 26043797 TI - MHY218-induced apoptotic cell death is enhanced by the inhibition of autophagy in AGS human gastric cancer cells. AB - We previously reported the anticancer effects of MHY218, which is a hydroxamic acid derivative, in HCT116 human colon cancer cells. In the present study, the involvement of autophagy in the MHY218-induced apoptotic cell death of AGS human gastric cancer cells was investigated. MHY218 treatment induced growth inhibition and apoptotic cell death in a concentration- and time-dependent manner. The induction of apoptosis was confirmed by observations of decreased viability, DNA fragmentation, and an increase in late apoptosis and sub-G1 DNA, which were detected with a flow cytometric analysis. Western blot analyses showed that MHY218 treatment resulted in decreased protein levels of procaspase-8, -9, and 3; cleavage of poly(ADP-ribose) polymerase (PARP); and alterations in the ratio of Bax/Bcl-2 protein expression. Apoptosis induced by MHY218 was involved in the activation of caspase-8, -9, and -3, and it was blocked by the addition of Z-VAD FMK, a pan-caspase inhibitor. In addition, autophagy-inducing effects of MHY218 were indicated by cytoplasmic vacuolation, the accumulation of acidic vesicular organelles, the appearance of green fluorescent protein-light-chain 3 (LC3) punctate dots, and increased levels of Beclin-1 and LC3-II protein expression. Pretreatment with the autophagy inhibitors LY294002, 3-methyladenine, chloroquine, and bafilomycin A1 enhanced the induction of apoptosis by MHY218, and this was accompanied by an increase in PARP cleavage. Taken together, these results provide new insights into the role of MHY218 as a potential antitumor agent. The combination of MHY218 with an autophagy inhibitor might be a useful candidate for the chemoprevention and/or treatment of gastric cancer. PMID- 26043798 TI - Molecular characterization of BrMYB28 and BrMYB29 paralogous transcription factors involved in the regulation of aliphatic glucosinolate profiles in Brassica rapa ssp. pekinensis. AB - Glucosinolates (GSL) are one of the major secondary metabolites of the Brassicaceae family. In the present study, we aim at characterizing the multiple paralogs of aliphatic GSL regulators, such as BrMYB28 and BrMYB29 genes in Brassica rapa ssp. pekinensis, by quantitative real-time PCR (qRT-PCR) analysis in different tissues and at various developmental stages. An overlapping gene expression pattern between the BrMYBs as well as their downstream genes (DSGs) was found at different developmental stages. Among the BrMYB28 and BrMYB29 paralogous genes, the BrMYB28.3 and BrMYB29.1 genes were dominantly expressed in most of the developmental stages, compared to the other paralogs of the BrMYB genes. Furthermore, the differential expression pattern of the BrMYBs was observed under various stress treatments. Interestingly, BrMYB28.2 showed the least expression in most developmental stages, while its expression was remarkably high in different stress conditions. More specifically, the BrMYB28.2, BrMYB28.3, and BrMYB29.1 genes were highly responsive to various abiotic and biotic stresses, further indicating their possible role in stress tolerance. Moreover, the in silico cis motif analysis in the upstream regulatory regions of BrMYBs showed the presence of various putative stress-specific motifs, which further indicated their responsiveness to biotic and abiotic stresses. These observations suggest that the dominantly expressed BrMYBs, both in different developmental stages and under various stress treatments (BrMYB28.3 and BrMYB29.1), may be potential candidate genes for altering the GSL level through genetic modification studies in B. rapa ssp. pekinensis. PMID- 26043799 TI - The roles of Dmrt (Double sex/Male-abnormal-3 Related Transcription factor) genes in sex determination and differentiation mechanisms: Ubiquity and diversity across the animal kingdom. AB - The Dmrt (Double sex/Male-abnormal-3 Related Transcription factor) genes have been intensively studied because they represent major transcription factors in the pathways governing sex determination and differentiation. These genes have been identified in animal groups ranging from cnidarians to mammals, and some of the genes functionally studied. Here, we propose to analyze (i) the presence/absence of various Dmrt gene groups in the different taxa across the animal kingdom; (ii) the relative expression levels of the Dmrt genes in each sex; (iii) the specific spatial (by organ) and temporal (by developmental stage) variations in gene expression. This review considers non-mammalian animals at all levels of study (i.e. no particular importance is given to animal models), and using all types of sexual strategy (hermaphroditic or gonochoric) and means of sex determination (i.e. genetic or environmental). To conclude this global comparison, we offer an analysis of the DM domains conserved among the different DMRT proteins, and propose a general sex-specific pattern for each member of the Dmrt gene family. PMID- 26043800 TI - Invertebrate diversity in relation to chemical pollution in an Umbrian stream system (Italy). AB - We used self-organizing maps (SOM, neural network) to bring out patterns of benthic macroinvertebrate diversity in relation to river pollution. Fourteen stations were sampled over various seasons in the Nestore drainage basin (Central Italy) and characterized for macroinvertebrate communities, nutrient and heavy metal concentrations. Physicochemical variables were introduced into a SOM previously trained with macroinvertebrate data. Patterns of communities matched spatial and seasonal changes in environmental conditions, including water chemistry related to economic activities in the catchment. Although our analyses did not allow us to establish the specific effect of any given environmental parameter upon macroinvertebrate community composition based on the field study, they enabled us to map the ecological health of river ecosystems in a readily interpretable manner. PMID- 26043801 TI - Missed Pathologic Fracture From Multiple Myeloma. PMID- 26043802 TI - Physical Examination of the Wrist: Useful Provocative Maneuvers. AB - Chronic wrist pain resulting from partial interosseous ligament injury remains a diagnostic dilemma for many hand and orthopedic surgeons. Overuse of costly diagnostic studies including magnetic resonance imaging, computed tomography scans, and bone scans can be further frustrating to the clinician because of their inconsistent specificity and reliability in these cases. Physical diagnosis is an effective (and underused) means of establishing a working diagnosis of partial ligament injury to the wrist. Carefully performed provocative maneuvers can be used by the clinician to reproduce the precise character of a patient's problem, reliably establish a working diagnosis, and initiate a plan of treatment. Using precise physical examination techniques, the examiner introduces energy into the wrist in a manner that puts load on specific support ligaments of the carpus, leading to an accurate diagnosis. This article provides a broad spectrum of physical diagnostic tools to help the surgeon develop a working diagnosis of partial wrist ligament injuries in the face of chronic wrist pain and normal x-rays. PMID- 26043803 TI - Management of the Acutely Burned Hand. AB - Despite contributing a small percentage to the total body surface area, hands are the most commonly burned body part and are involved in over 90% of severe burns. Although the mortality of isolated hand burns is negligible, morbidity can be substantial given our need for functioning hands when performing activities of daily living. The greatest challenges of treating hand burns are 2-fold. First, determining the depth of injury can be difficult even for the most experienced surgeon, but despite many diagnostic options, clinical examination remains the gold standard. Second, appropriate postoperative hand therapy is crucial and requires a multidisciplinary approach with an experienced burn surgeon, hand surgeon, and hand therapist. Ultimately, the goals of treatment should include preservation of function and aesthetics. In this review, we present an approach to the management of the acutely burned hand with discussion of both conservative and surgical options. Regardless of the initial treatment decision, subsequent care for this subset of patients should be aimed at preventing debilitating postburn scar contractures that can severely limit hand function and ultimately require reconstructive surgery. PMID- 26043804 TI - Neurohypophyseal Neuregulin 1 Is Derived from the Hypothalamus as a Potential Prolactin Modulator. AB - Although neuregulin 1 (Nrg1) has been identified in the rat hypothalamus, the localisation of Nrg1 in the hypothalamus-hypophyseal structure and its functions remain unclear and require further elucidation. In this study, we identified the existence of Nrg1beta types I-III in the rat hypothalamus. We demonstrated that Nrg1 was partially localised in somatostatin-positive cells in the periventricular nucleus. It was also co-localised with arginine vasopressin in the supraoptic nucleus, median eminence and pituitary stalk. Nrg1 was also extensively distributed in the posterior pituitary (PP), including the projected neuronal fibres that surround the vascular structure and Herring bodies. Western blotting confirmed that these signals were primarily produced by soluble Nrg1 derived from a 45-kDa Nrg1 precursor mainly identified in the hypothalamus. Similar to Nrg1alpha, Nrg1beta increased the prolactin (PRL) expression in rat pituitary RC-4B/C cells, which can be inhibited by an Akt inhibitor. In addition, Nrg1beta had no apparent effect on growth hormone expression at the mRNA or protein levels. Collectively, we conclude that hypothalamic Nrg1 may be transported to the PP as the beta form. We further hypothesise that Nrg1beta may function via the regulation of PRL expression through a paracrine mechanism. PMID- 26043805 TI - Conditional sentences create a blind spot in theory of mind during narrative comprehension. AB - We identify a blind spot in the early Theory of Mind processing of conditional sentences that describe a protagonist's potential action, and its predictable consequences. We propose that such sentences create expectations through two independent channels. A decision theoretic channel creates an expectation that the action will be taken (viz., not taken) if it has desirable (viz., undesirable) consequences, but a structural channel acts in parallel to create an expectation that the action will be taken, irrespective of desirability. Accordingly, reading should be disrupted when a protagonist avoids an action with desirable consequences, but reading should not be disrupted when a protagonist takes an action with undesirable consequences. This prediction was supported by the eye movements of participants reading systematically varied vignettes. Reading was always disrupted when the protagonist avoided an action with desirable consequences, but disruptions were either delayed (Experiment 1) or recovered from faster (Experiment 2) when the protagonist took an action with undesirable consequences. PMID- 26043806 TI - A qualitative study of college students' perceptions of risky driving and social influences. AB - OBJECTIVES: Young adults and teens are documented as the riskiest drivers on the road, and newer issues such as texting and driving are a growing concern. This study sought to determine the risk perceptions of young adults regarding various driving behaviors, their past experiences, how their social circles are structured, and how this might affect their driving. METHODS: This study conducted qualitative research with 25 college undergraduate students to determine their peer and social influences regarding distracted driving. Data were analyzed and related to the health belief model and past research on social influence. RESULTS: Though most participants felt that their behaviors were set after learning to drive, they were, in fact, quite susceptible to the influence of those in their social circles (e.g., fear of judgment and accountability) and, more broadly, to social norms. Texting and driving was the largest and most topical distracted driving issue and was also identified as very difficult to stop due to perceived barriers and the idea that intervening is rude. Participants identified low perceived susceptibility and severity (perceived threat) for a number of risky driving behaviors, including texting and driving. CONCLUSIONS: Training is needed to encourage people to intervene and speak up regarding behaviors other than drinking and driving, and cues to action and campaigns should target intervention to increase self-efficacy, as well as norms, susceptibility, and common rationalizations for risky behavior. PMID- 26043807 TI - Insight of patients and their parents into schizophrenia: Exploring agreement and the influence of parental factors. AB - Poor insight is found in up to 80% of schizophrenia patients and has been associated with multiple factors of which cognitive functioning, social and environmental factors. Few studies have explored associations between patient insight and that of their biological parents', and the influence of parental factors. Insight was assessed in 41 patients and their biological parents with Amador's Scale for the assessment of Unawareness of Mental Disorder (SUMD). Parents' knowledge about schizophrenia and critical attitudes were assessed with validated self-report questionnaires. Both groups underwent cognitive assessments for working memory and executive functioning. Insight in patients and their parents was not associated for any of the SUMD dimensions but a significant correlation was found between patient and parent awareness of treatment effect for patient-parent dyads with frequent daily contact. Low parental critical attitude was associated with higher patient awareness of symptoms and a high parental memory task score with high patient insight. Our study is the first to suggest a possible influence of parental factors such as critical attitudes and cognitive performance on patient insight. PMID- 26043808 TI - Adsorption and Desorption of Hydrogen by Gas-Phase Palladium Clusters Revealed by In Situ Thermal Desorption Spectroscopy. AB - Adsorption and desorption of hydrogen by gas-phase Pd clusters, Pdn(+), were investigated by thermal desorption spectroscopy (TDS) experiments and density functional theory (DFT) calculations. The desorption processes were examined by heating the clusters that had adsorbed hydrogen at room temperature. The clusters remaining after heating were monitored by mass spectrometry as a function of temperature up to 1000 K, and the temperature-programmed desorption (TPD) curve was obtained for each Pdn(+). It was found that hydrogen molecules were released from the clusters into the gas phase with increasing temperature until bare Pdn(+) was formed. The threshold energy for desorption, estimated from the TPD curve, was compared to the desorption energy calculated by using DFT, indicating that smaller Pdn(+) clusters (n <= 6) tended to have weakly adsorbed hydrogen molecules, whereas larger Pdn(+) clusters (n >= 7) had dissociatively adsorbed hydrogen atoms on the surface. Highly likely, the nonmetallic nature of the small Pd clusters prevents hydrogen molecule from adsorbing dissociatively on the surface. PMID- 26043809 TI - Supramolecular Cross-Links in Poly(alkyl methacrylate) Copolymers and Their Impact on the Mechanical and Reversible Adhesive Properties. AB - Hydrogen-bonded, side-chain-functionalized supramolecular poly(alkyl methacrylate)s were investigated as light- and temperature-responsive reversible adhesives that are useful for bonding and debonding on demand applications. Here, 2-hydroxyethyl methacrylate (HEMA) was functionalized with 2-ureido 4[1H]pyrimidinone (UPy) via a hexamethylenediisocyanate (HMDI) linker, to create a monomer (UPy-HMDI-HEMA) that serves to form supramolecular cross-links by way of forming quadruple hydrogen bonded dimers. UPy-HMDI-HEMA was copolymerized with either hexyl methacrylate or butyl methacrylate to create copolymers comprising 2.5, 5, or 10 mol % of the cross-linker. The mechanical properties of all (co)polymers were investigated with stress-strain experiments and dynamic mechanical analysis. Furthermore, the adhesive properties were studied at temperatures between 20 and 60 degrees C by testing single lap joints formed with stainless steel substrates. It was found that increasing the concentration of the UPy-HMDI-HEMA cross-linker leads to improved mechanical and adhesive properties at elevated temperatures. Concurrently, the reversibility of the bond formation remained unaffected, where rebonded samples displayed the same adhesive strength as regularly bonded samples. Debonding on demand abilities were also tested exemplarily for one copolymer, which for light-induced debonding experiments was blended with a UV-absorber that served as light-heat converter. Single lap joints were subjected to a constant force and heated or irradiated with UV light until debonding occurred. The necessary debonding temperature was comparable for direct heating and UV irradiation and varied between 28 and 82 degrees C, depending on the applied force. The latter also influenced the debonding time, which under the chosen conditions ranged from 30 s to 12 min. PMID- 26043812 TI - Evaluation of store lesion in platelet obtained by apheresis compared to platelet derived from whole blood and its impact on the in vitro functionality. AB - Platelet units for transfusion purposes are obtained manually from whole blood or by apheresis, in an automated process. In both methods, platelets during storage present a characteristics grouped under the name "storage lesion" that are associated with adverse effects on platelet units. Oxidative stress has been claimed to be one of major causes, leading to activation and apoptosis processes affecting their post transfusion functionality. In this work, we observed an association between apheresis and a reduced presence of oxidative stress and better results in functional markers in stored platelets, compared to manually obtained platelets. Then, apheresis which would ensure a greater number of functional platelets during the 5 days of storage, compared to concentrates obtained from whole blood. PMID- 26043810 TI - Long-term velaglucerase alfa treatment in children with Gaucher disease type 1 naive to enzyme replacement therapy or previously treated with imiglucerase. AB - BACKGROUND: Gaucher Disease type 1 (GD1) often manifests in childhood. Early treatment with enzyme replacement therapy (ERT) may prevent disease complications. We report the assessment of velaglucerase alfa ERT in pediatric GD1 patients who participated in a long-term extension study (HGT-GCB-044, ClinicalTrials.gov Identifier NCT00635427). METHODS: Safety and efficacy were evaluated in pediatric patients receiving velaglucerase alfa 30-60U/kg by intravenous infusion every other week. In addition to key hematological and visceral efficacy assessments, exploratory assessments conducted specifically in pediatric patients included evaluation of height, bone age, bone marrow burden, and Tanner stage of puberty. RESULTS: The study included 24 pediatric patients. Fifteen patients were naive to ERT on entry into the preceding trials TKT032 (12 month trial) or HGT-GCB-039 (9-month trial): in the preceding trials, ten of these 15 patients received velaglucerase alfa and five patients received imiglucerase ERT. Nine patients in the study were previously treated with imiglucerase for >30months and were switched to velaglucerase alfa in the preceding trial TKT034 (12-month trial). Cumulative ERT exposure in the clinical studies ranged from 2.0 to 5.8years. Three serious adverse events, including a fatal convulsion, were reported; none were deemed related to velaglucerase alfa. One patient tested positive for anti-velaglucerase alfa antibodies. An efficacy assessment at 24months showed that velaglucerase alfa had positive effects on primary hematological and visceral parameters in treatment-naive patients, which were maintained with longer-term treatment. Disease parameters were stable in patients switched from long-term imiglucerase ERT. Exploratory results may suggest benefits of early treatment to enable normal growth in pediatric patients. CONCLUSION: The safety profile and clinical response seen in pediatric patients are consistent with results reported in adults. PMID- 26043813 TI - Peripheral blood stem cell mobilization from healthy donors. AB - Most frequently used graft of hematopoietic stem cells (HSCs) for allogeneic transplantation is peripheral blood stem cells (PBSCs) that are collected after mobilization with frequently granulocyte colony-stimulating factor (G-CSF). Administration of the optimal dose of G-CSF while preserving the donor health is one of the most important points for sufficient PBSC mobilization and harvest. We hereby tried to summarize characteristic features, potential side effects and main topics in peripheral blood stem cell mobilization from healthy donors. PMID- 26043814 TI - Early peritonitis is an independent risk factor for mortality in elderly peritoneal dialysis patients. AB - BACKGROUND/AIMS: The impact of early peritonitis on the outcome of elderly peritoneal dialysis (PD) patients has not been studied. We aimed to research the influence of early peritonitis on patient outcomes in elderly PD patients. METHODS: This study involved elderly PD patients (age >=65) who underwent PD between Jan 1, 2004 and Jul 31, 2013. Patient characteristics were collected in our database. Early peritonitis was defined as peritonitis within 6 months after the initiation of PD. Patient survival and technique were compared among the non peritonitis, early peritonitis and late peritonitis groups using Cox regression analysis. RESULTS: There were 155 subjects involved in this study. The patients were divided among a non-peritonitis group (n=78), early peritonitis group (n=32) and late peritonitis group (n=45). The organisms causing first peritonitis in the two groups did not differ significantly. After adjustment for age, diabetes, serum albumin and residual renal function, multivariable Cox regression model revealed that compared with the early peritonitis group, both the non-peritonitis group (HR 0.57, RI 0.32-0.99, p=0.046) and the late peritonitis group (HR 0.37, RI 0.16-0.75, p=0.004) exhibited a lower patient mortality rate. CONCLUSIONS: Early peritonitis is an independent risk factor for mortality in elderly peritoneal dialysis patients. PMID- 26043816 TI - Abecedarium: Who am I? X'.... PMID- 26043815 TI - Lipoic acid and N-acetylcysteine prevent ammonia-induced inflammatory response in C6 astroglial cells: The putative role of ERK and HO1 signaling pathways. AB - Hyperammonemia induces significant changes in the central nervous system (CNS) in direct association with astroglial functions, such as oxidative damage, glutamatergic excitotoxicity, and impaired glutamine synthetase (GS) activity and pro-inflammatory cytokine release. Classically, lipoic acid (LA) and N acetylcysteine (NAC) exhibit antioxidant and anti-inflammatory activities by increasing glutathione (GSH) biosynthesis and decreasing pro-inflammatory mediator levels in glial cells. Thus, we evaluated the protective effects of LA and NAC against ammonia cytotoxicity in C6 astroglial cells. Ammonia decreased GSH levels and increased cytokine release and NFkappaB transcriptional activation. LA and NAC prevented these effects by the modulation of ERK and HO1 pathways. Taken together, these observations show that LA and NAC prevent the ammonia-induced inflammatory response. PMID- 26043817 TI - Patient information: Law, ethics and reality. PMID- 26043818 TI - Epstein-Barr virus-associated lymphoepithelial carcinoma of the larynx. AB - INTRODUCTION: Lymphoepithelial carcinoma is a rare tumour, named after its histological resemblance to undifferentiated nasopharyngeal carcinoma. The pathogenesis of lymphoepithelial carcinoma remains unknown. This tumour has been described in several organs, but the larynx remains an exceptional site. CASE REPORT: The authors report the case of a 73-year-old man who consulted for longstanding dysphonia and rapidly deteriorating dyspnoea requiring emergency tracheotomy. Endoscopic examination demonstrated a tumour of the left hemilarynx with fixed vocal cords. Histological examination and immunohistochemistry demonstrated lymphoepithelial carcinoma of the larynx. Screening for Epstein-Barr Virus (EBV) by immunohistochemistry and in situ hybridization was positive. Treatment consisting of neoadjuvant chemotherapy followed by surgical resection and then external beam radiotherapy achieved cure with a follow-up of 18months since completion of treatment. DISCUSSION: Lymphoepithelial carcinoma of the larynx is rare. Immunohistochemical examination is essential for the positive diagnosis. Epstein-Barr virus-associated lymphoepithelial carcinoma has been exceptionally reported. The radiosensitivity of this tumour allows conservative first-line treatment. PMID- 26043819 TI - An Unusual Foreign Body Ingestion: To Scope or Not to Scope. PMID- 26043820 TI - Enigma of HIV-1 latent infection in astrocytes: an in-vitro study using protein kinase C agonist as a latency reversing agent. AB - Purging HIV-1 to cure the infection in patients undergoing suppressive antiretroviral therapy requires targeting all possible viral reservoirs. Other than the memory CD4(+) T cells, several other HIV-1 reservoirs have been identified. HIV-1 infection in the brain as a reservoir is well documented, but not fully characterized. There, microglia, perivascular macrophages, and astrocytes can be infected by HIV-1. HIV-1 infection in astrocytes has been described as a nonproductive and primarily a latent infection. Using primary human astrocytes, we investigated latent HIV-1 infection and tested phorbol 12 myristate 13-acetate (PMA), a protein kinase C agonist, as an HIV-1-latency- reversing agent in infected astrocytes. Chloroquine (CQ) was used to facilitate initial HIV-1 escape from endosomes in astrocytes. CQ significantly increased HIV 1 infection. But treatment with PMA or viral Tat protein was similar to untreated HIV-1-infected astrocytes. Long-term follow-up of VSV-envelope-pseudotyped HIV-1 infected astrocytes showed persistent infection for 110 days, indicating the active state of the virus. PMID- 26043821 TI - Mycobacterium avium MAV_2941 mimics phosphoinositol-3-kinase to interfere with macrophage phagosome maturation. AB - Mycobacterium avium subsp hominissuis (M. avium) is a pathogen that infects and survives in macrophages. Previously, we have identified the M. avium MAV_2941 gene encoding a 73 amino acid protein exported by the oligopeptide transporter OppA to the macrophage cytoplasm. Mutations in MAV_2941 were associated with significant impairment of M. avium growth in THP-1 macrophages. In this study, we investigated the molecular mechanism of MAV_2941 action and demonstrated that MAV_2941 interacts with the vesicle trafficking proteins syntaxin-8 (STX8), adaptor-related protein complex 3 (AP-3) complex subunit beta-1 (AP3B1) and Archain 1 (ARCN1) in mononuclear phagocytic cells. Sequencing analysis revealed that the binding site of MAV_2941 is structurally homologous to the human phosphatidylinositol 3-kinase (PI3K) chiefly in the region recognized by vesicle trafficking proteins. The beta3A subunit of AP-3, encoded by AP3B1, is essential for trafficking cargo proteins, including lysosomal-associated membrane protein 1 (LAMP-1), to the phagosome and lysosome-related organelles. Here, we show that while the heat-killed M. avium when ingested by macrophages co-localizes with LAMP-1 protein, transfection of MAV_2941 in macrophages results in significant decrease of LAMP-1 co-localization with the heat-killed M. avium phagosomes. Mutated MAV_2941, where the amino acids homologous to the binding region of PI3K were changed, failed to interact with trafficking proteins. Inactivation of the AP3B1 gene led to alteration in the trafficking of LAMP-1. These results suggest that M. avium MAV_2941 interferes with the protein trafficking within macrophages altering the maturation of phagosome. PMID- 26043822 TI - Development and in vitro evaluation of lipid nanoparticle-based dressings for topical treatment of chronic wounds. AB - This research addresses the development and in vitro evaluation of lipid nanoparticle (NP)-based dressings to optimize the delivery of human recombinant epidermal growth factor (rhEGF) for the topical treatment of chronic wounds. The systems investigated were rhEGF-loaded solid lipid nanoparticles (rhEGF-SLN) and rhEGF-loaded nanostructured lipid carriers (rhEGF-NLC) formulated in wound dressings comprising either semi-solid hydrogels or fibrin-based solid scaffolds. Following detailed characterisation of the NP, in vitro diffusion cell experiments (coupled with dermatopharmacokinetic measurements), together with confocal microscopic imaging, conducted on both intact skin samples, and those from which the barrier (the stratum corneum) had been removed, revealed that (a) the particles remained essentially superficially located for at least up to 48h post-application, (b) rhEGF released on the surface of intact skin was unable to penetrate to the deeper, viable layers, and (c) sustained release of growth factor from the NP "drug reservoirs" into barrier-compromised skin was observed. There were no significant differences between the in vitro performance of rhEGF SLN and rhEGF-NLC, irrespective of the formulation employed. It is concluded that, because of their potentially longer-term stability, the fibrin-based scaffolds may be the most suitable approach to formulate rhEGF-loaded lipid nanoparticles. PMID- 26043823 TI - Effect of inhalation profile and throat geometry on predicted lung deposition of budesonide and formoterol (BF) in COPD: An in-vitro comparison of Spiromax with Turbuhaler. AB - Successful delivery of inhalation medication to the lungs can be affected by the inhalation manoeuvre used. Conventional in-vitro testing of the emitted dose from a dry powder inhaler (DPI) uses a vacuum pump to simulate an inhalation. We have adapted this method by replacing the pump with patient inhalation profiles and an anatomical throat. Three anatomical throat sizes and three inhalation profiles were used. The profiles represented the 10th, 50th and 90th percentiles of peak inhalation flow and acceleration of flow from a population of 50 COPD patients inhaling through empty Spiromax and Turbuhaler devices. Combining the dose emission results for the three throat sizes, the mean (SD) budesonide fine particle dose (FPD) from budesonide-formoterol Spiromax 320/9 MUg was 78.91 (20.18), 79.91 (15.36) and 75.10 (19.91)MUg and the total emitted dose (TED) of budesonide was 263.69 (40.74), 261.20 (21.65) and 261.61 (45.65)MUg. Similarly, the FPD from 320/9 MUg Turbuhaler was 22.45 (3.24), 52.20 (12.57) and 69.11 (75.10)MUg with a TED of 143.80 (14.90), 149.50 (26.61) and 158.61 (43.04)MUg. Spiromax showed greater consistency than Turbuhaler over a range of inspiratory flow profiles. The results demonstrate the value of this new method to assess the doses that patients receive during real-life use of their DPI. PMID- 26043824 TI - A combined experimental and numerical approach to explore tribocharging of pharmaceutical excipients in a hopper chute assembly. AB - Electrostatic charging via contact electrification or tribocharging refers to the process of charge transfer between two solid surfaces when they are brought into contact with each other and separated. Charging of continuous particulate flows on solid surfaces is poorly understood and has often been empirical. This study aims toward understanding the tribocharging of pharmaceutical excipients using a simplified geometry of unidirectional flow in a hopper-chute assembly. Assuming electron transfer to be the dominant mechanism of electrification, a triboelectric series was generated using work functions estimated from quantum chemical calculations. A 3D-DEM model has been developed employing charge transfer and electrostatic forces. Using numerical simulations, the charge accumulation for an assemblage of particles during flow was determined under different conditions. To theoretically analyze the process of charging, parametric studies affecting powder flow have been investigated. A higher specific charge was observed at larger friction coefficients and lower restitution coefficients. The results obtained from the simulation model reinforce the collisional nature of triboelectrification. The simulation results revealed similar trends to experimental observations. However, to enable a priori prediction the model needs to be tested for additional materials or extended to other process operations. PMID- 26043825 TI - Predictive model for tensile strength of pharmaceutical tablets based on local hardness measurements. AB - In the pharmaceutical field, tablets are the most common dosage forms for oral administration. During the manufacture of tablets, measures are taken to assure that they possess a suitable mechanical strength to avoid crumbling or breaking when handling while ensuring disintegration after administration. Accordingly, the tensile strength is an essential parameter to consider. In the present study, microscopic hardness and macroscopic tensile strength of binary tablets made from microcrystalline cellulose and caffeine in various proportions were measured. A relationship between these two mechanical properties was found for binary mixture. The proposed model was based on two physical measurements easily reachable: hardness and tablet density. Constants were determined from the two extreme compositions of this given system. This model was validated with experimental results, and a comparison was made with the one developed by Wu et al. (2005). Both models are relevant for this studied system. Nonetheless, with this model, the tablet tensile strength can be connected with a tablet characteristic at microscopic scale in which porosity is not needed. PMID- 26043826 TI - In vitro disposition profiling of heterocyclic compounds. AB - Compound libraries that are screened for biological activity commonly contain heterocycles. Besides potency, drug-like properties need to be evaluated to ensure in vivo efficacy of test compounds. In this context, we determined hepatic and intestinal disposition profiles for 17 heterocyclic compounds. All studied compounds showed rapid uptake in suspended rat hepatocytes, whereas metabolism was poor and the rate-limiting step in hepatic elimination. In vitro assays demonstrated a relatively low solubility and high intestinal permeability. Based on these in vitro data, heterocycles were categorized in the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS) to predict disposition characteristics before clinical data are available. Our findings emphasized the importance to use hepatocytes in addition to microsomes to study metabolism, since the latter lack non-microsomal enzymes and cellular context. Moreover, intracellular exposure should be considered to gain insight in the relevant fraction of the compound available at the enzymatic site. Finally, the study reveals discrepancies associated with the classification of heterocycles in BCS versus BDDCS. These probably originate from the binary character of both systems. PMID- 26043827 TI - Electrospun medicated shellac nanofibers for colon-targeted drug delivery. AB - Medicated shellac nanofibers providing colon-specific sustained release were fabricated using coaxial electrospinning. A solution of 7.5 g shellac and 1.5 g of ferulic acid (FA) in 10 mL ethanol was used as the core fluid, and a mixture of ethanol and N,N-dimethylformamide (8/10 v/v) as the shell. The presence of the shell fluid was required to prevent frequent clogging of the spinneret. The diameters of the fibers (D) can be manipulated by varying the ratio of shell to core flow rates (F), according to the equation D=0.52 F(-0.19). Scanning electron microscopy images revealed that fibers prepared with F values of 0.1 and 0.25 had linear morphologies with smooth surfaces, but when the shell fluid flow rate was increased to 0.5 the fiber integrity was compromised. FA was found to be amorphously distributed in the fibers on the basis of X-ray diffraction and differential scanning calorimetry results. This can be attributed to good compatibility between the drug and carrier: IR spectra indicated the presence of hydrogen bonds between the two. In vitro dissolution tests demonstrated that there was minimal FA release at pH 2.0, and sustained release in a neutral dissolution medium. The latter occurred through an erosion mechanism. During the dissolution processes, the shellac fibers were gradually converted into nanoparticles as the FA was freed into solution, and ultimately completely dissolved. PMID- 26043828 TI - The Health Care Provider's Experience With Fathers of Overweight and Obese Children: A Qualitative Analysis. AB - PURPOSE: The purpose of this study was to explore the experience of health care providers (HCPs) in the outpatient setting as they work with fathers of children who are overweight and obese. METHOD: Interpretative phenomenological analysis was used for data collection and analysis. Seven HCPs were interviewed about their experiences. RESULTS: Two major themes emerged from the experiences of these HCPs: "dad in the back seat" and "paternal resistance." DISCUSSION: The theme of "dad in the back seat" captured the HCPs' experiences and perceptions of parental roles and related stereotypes with respect to fathers' lack of presence in the health-care setting, family roles that relegate fathers to the back seat in dealing with this issue, and the tendency of fathers to take a passive role and defer to mothers in the management of their child's weight. "Paternal resistance" reflected the perceived tendency of the father to resist the acceptance of his child's weight as a problem and to resist change and even undermine family efforts to make healthier choices. CONCLUSION: HCPs' experiences of fathers as having a minimal role in the management of their child's overweight and obesity may lead them to neglect fathers as agents of change with regard to this important issue. PMID- 26043829 TI - Confocal microscopy reveals uniform male reproductive anatomy in eriophyoid mites (Acariformes, Eriophyoidea) including spermatophore pump and paired vasa deferentia. AB - Male internal genitalia of eriophyoid mites comprise cuticle lined (anterior genital apodeme, genital chamber and ductus ejculatorius) and soft (paired vasa deferentia and single testis) organs. Three-dimensional reconstructions based on autofluorescence show that a thin-walled genital chamber is usually situated in a transverse plane and precisely copies the shape of the spermatophore. A thin vertical longitudinal plate (homologous to female longitudinal bridge) joins the genital chamber and ventral genital cuticle. The anterior genital apodeme is a separate vertical plate situated ahead of the genital chamber and provides a rigid support for it. The brightly autofluorescent ductus ejaculatorius starts from the posterior extremity of the genital chamber and goes backward. Proximally, the ductus ejaculatorius is tube-like, whereas distally, it is expanded into a sac. Confocal laser scanning microscopy observations on males, stained with phalloidin, indicate that the proximal ductus ejaculatorius is devoid of muscles whereas the distal ductus ejaculatorius possesses well developed musculature (the "spermatophore pump"), appearing in 3D reconstructions as a hollow sphere with three apertures: one anterior and two posterior. Two thin walled sausage-like vasa deferentia join the distal ductus ejaculatorius with a large single testis, each junction is encircled by a strong, ring-shaped muscle (musculus sphincter testiculodeferentis). Thin muscular fibers of the wall of the testis form a net-like pattern consisting of distinct polygonal cells. The topography of the male internal genitalia and musculature suggests that, contrary to previous observations, the spermatophore head might be extruded first and then the spermatophore stalk appears. The possible role of visceral and skeletal musculature, in the process of the expulsion of a spermatophore, is discussed. PMID- 26043830 TI - Functional elements of the gastric inhibitory polypeptide receptor: Comparison between secretin- and rhodopsin-like G protein-coupled receptors. AB - Innovative crystallographic techniques have resulted in an exponential growth in the number of solved G-protein coupled receptor (GPCR) structures and a better understanding of the mechanisms of class A receptor activation and G protein binding. The recent release of the type 1 receptor for the corticotropin releasing factor and the glucagon receptor structures, two members of the secretin-like family, gives the opportunity to understand these mechanisms of activation in this family of GPCRs. Here, we addressed the comparison of the functional elements of class A and secretin-like GPCRs, using the glucose dependent insulinotropic polypeptide receptor (GIPR) as a model receptor. Inactive and active models of GIPR permitted to select, by structural homology with class A GPCRs, several residues that may form key interactions presumably involved in receptor activation and Gs coupling, for pharmacological evaluation. Mutants on these amino acids were expressed in HEKT 293 cells and characterized in terms of GIP-induced cAMP production. We identified various functional domains spanning from the peptide-binding to the G protein pockets: including: a network linking the extracellular part of transmembrane (TM) 6 with TMs 2 and 7; a polar lock that resembles the ionic-lock in class A GPCRs; an interaction between TMs 3 and 7 that favors activation; and two clusters of polar/charged and of hydrophobic residues that interact with the C-terminus of the Galpha. The results show that despite the low degree of sequence similarity between rhodopsin- and secretin-like GPCRs, the two families share conserved elements in their mechanisms of activation and G protein binding. PMID- 26043831 TI - Associations Between PADI4 Gene Polymorphisms and Rheumatoid Arthritis: An Updated Meta-analysis. AB - BACKGROUND AND AIMS: Studies investigating the association between the peptidylarginine deiminase 4 (PADI4) gene polymorphisms and rheumatoid arthritis (RA) reported conflicting results. The aim of this meta-analysis was to assess the association between PADI4 gene polymorphisms and RA. METHODS: A systematic literature search was conducted to identify relevant studies. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of the association. RESULTS: A total of 34 studies from 28 articles involving 19859 patients with RA and 25771 healthy controls were included. Significant association of PADI4-94G/A polymorphism and RA was observed (OR = 0.891, 95% CI = 0.833-0.954, p = 0.001) in the overall study population and in the Asian populations (OR = 0.824, 95% CI = 0.759-0.894, p = 0.000) respectively. For the 92C/G polymorphism, a significant association was observed (OR = 1.481, 95% CI = 1.166-1.882, p = 0.001) in Africans. For the -90C/T polymorphism, a significant association was observed (OR = 0.576, 95% CI = 0.381-0.872, p = 0.009) in the Latin American population. The pooled estimates for the other polymorphisms were not statistically significantly associated with RA (PADI4-104C/T, -89A/G, 96T/C). CONCLUSIONS: This meta-analysis demonstrates that PADI4-94G/A polymorphism is associated with susceptibility to RA in the overall population and in the Asian population. The PADI4 -92C/G polymorphism confers susceptibility to RA in Africans and the PADI4-90C/T polymorphism was associated with RA in the Latin American population. PMID- 26043832 TI - Serenoa repens as an Endocrine Disruptor in a 10-Year-Old Young Girl: A New Case Report. AB - Serenoa repens, commonly known as saw palmetto, is the sole species currently classified in the genus Serenoa. The plant is a low shrubby palm that is native of West Indies, and it grows in the coastal lands of North America and other European mediterranean countries. Its fruits contain high concentrations of fatty acids and phytosterols. S. repens extracts have been studied for the symptomatic treatment of benign prostatic hyperplasia. Recently, they have been proposed to treat androgenic alopecia and other hair disorders. We report a new case of hot flashes in a 10-year-old girl using a food supplement containing the extract of S. repens for the treatment of hirsutism. When the girl discontinued the treatment, the hot flashes stopped. A 'rechallenge' of the supplement was tried and symptoms reappeared. About 4 months after starting therapy, the girl experienced menarche. Exposure to the plant-derived product could be responsible for the appearance of menarche. In our opinion, use of phytotherapeutic agents in pediatric patients should be associated to a better evaluation of benefit/risk profile taking in account the physiological changes that occurs at different ages in this subgroup of population. PMID- 26043833 TI - Erratum to: Genetic link of type 1 diabetes susceptibility loci with rheumatoid arthritis in Pakistani patients. PMID- 26043834 TI - Erratum. PMID- 26043835 TI - Rearrangement of chromosome bands 12q14~15 causing HMGA2-SOX5 gene fusion and HMGA2 expression in extraskeletal osteochondroma. AB - We describe two cases of extraskeletal osteochondroma in which chromosome bands 12q14~15 were visibly rearranged through a pericentric inv(12). Molecular analysis of the first tumor showed that both transcript 1 (NM_003483) and transcript 2 (NM_003484) of HMGA2 were expressed. In the second tumor, the inv(12) detected by karyotyping had resulted in an HMGA2-SOX5 fusion transcript in which exons 1-3 of HMGA2 were fused with a sequence from intron 1 of SOX5. The observed pattern is similar to rearrangements of HMGA2 found in several other benign mesenchymal tumors, i.e., disruption of the HMGA2 locus leaves intact exons 1-3 which encode the AT-hook domains and separates them from the 3' terminal part of the gene. Our data therefore show that a subset of soft tissue osteochondromas shares pathogenetic involvement of HMGA2 with lipomas, leiomyomas and other benign connective tissue neoplasms. PMID- 26043836 TI - Overexpression of miR-199b-5p inhibits Ewing's sarcoma cell lines by targeting CCNL1. AB - MicroRNAs (miRNAs) are known to regulate the expression of a variety of genes, which are important in the development of several types of tumor, including Ewing's sarcoma (ES), at the post-transcriptional level. Although previous studies have identified that the expression of miRNA-199b-5p was downregulated in various types of tumor, the expression levels of miR-199b-5p in ES cells remain to be elucidated. The mechanism underlying ES via the miRNA pathway remains to be elucidated. The present study demonstrated that miR-199b-5p was an important regulator in ES cells and its expression was downregulated in ES originated A673/TC252 cells. The ES cell lines, A673 and TC252, were transfected with an miR 199b-5p mimic to overexpress the levels of this miRNA. This forced expression of miR-199b-5p suppressed the cell proliferation and invasion, arrested cell cycle progression, and promoted cell apoptosis. Furthermore, CCNL1 was identified by bioinformatic software as a potential target gene of miR-199b-5p. Following this, the present study identified CCNL1 as a direct target of miR-199b-5p in ES cells. Taken together, the present study established a functional link between ES, miR 199b-5p and CCNL1, and suggested that miR-199b-5p acts as a tumor suppressor and may be of diagnostic and therapeutic importance for human ES. PMID- 26043837 TI - Preoperative carboplatin and paclitaxel-based chemoradiotherapy for esophageal carcinoma: results of a modified CROSS regimen utilizing radiation doses greater than 41.4 Gy. AB - Trimodality therapy for resectable esophageal and gastroesophageal junction cancers utilizing preoperative radiotherapy with concurrent carboplatin and paclitaxel-based chemotherapy is being increasingly utilized secondary to the results of the phase III CROSS trial. However, there is a paucity of reports of this regimen as a component of chemoradiotherapy in North America. We aim to report on our clinical experience using a modified CROSS regimen with higher radiotherapy doses. Patients with advanced (cT2-cT4 or node positive) esophageal or gastroesophageal junction carcinoma who received preoperative carboplatin/paclitaxel-based chemoradiotherapy with radiation doses of greater than 41.4 Gray (Gy) followed by esophagectomy were identified from an institutional database. Patient, imaging, treatment, and tumor response characteristics were analyzed. Twenty-four patients were analyzed. All but one tumor had adenocarcinoma histology. The median radiation dose was 50.4 Gy. Pathologic complete response was achieved in 29% of patients, with all receiving 50.4 Gy. Three early postoperative deaths were seen, due in part to acute respiratory distress syndrome and all three patients received 50-50.4 Gy. With a median follow-up of 9.4 months (23 days-2 years), median survival was 24 months. Trimodality therapy utilizing concurrent carboplatin/paclitaxel with North American radiotherapy doses appeared to have similar pathologic complete response rates compared with the CROSS trial, but may be associated with higher toxicity. Although the sample size is small and further follow-up is necessary, radiation doses greater than 41.4 Gy may not be warranted secondary to a potentially increased risk of severe radiation-induced acute lung injury. PMID- 26043838 TI - Monitoring biothreat agents (Francisella tularensis, Bacillus anthracis and Yersinia pestis) with a portable real-time PCR instrument. AB - In the event of suspected releases or natural outbreaks of contagious pathogens, rapid identification of the infectious agent is essential for appropriate medical intervention and disease containment. The purpose of this study was to compare the performance of a novel portable real-time PCR thermocycler, PikoRealTM, to the standard real-time PCR thermocycler, Applied Biosystems(r) 7300 (ABI 7300), for the detection of three high-risk biothreat bacterial pathogens: Francisella tularensis, Bacillus anthracis and Yersinia pestis. In addition, a novel confirmatory real-time PCR assay for the detection of F. tularensis is presented and validated. The results show that sensitivity of the assays, based on a dilution series, for the three infectious agents ranged from 1 to 100 fg of target DNA with both instruments. No cross-reactivity was revealed in specificity testing. Duration of the assays with the PikoReal and ABI 7300 systems were 50 and 100 min, respectively. In field testing for F. tularensis, results were obtained with the PikoReal system in 95 min, as the pre-PCR preparation, including DNA extraction, required an additional 45 min. We conclude that the PikoReal system enables highly sensitive and rapid on-site detection of biothreat agents under field conditions, and may be a more efficient alternative to conventional diagnostic methods. PMID- 26043839 TI - A formal concept analysis and semantic query expansion cooperation to refine health outcomes of interest. AB - BACKGROUND: Electronic Health Records (EHRs) are frequently used by clinicians and researchers to search for, extract, and analyze groups of patients by defining Health Outcome of Interests (HOI). The definition of an HOI is generally considered a complex and time consuming task for health care professionals. METHODS: In our clinical note-based pharmacovigilance research, we often operate upon potentially hundreds of ontologies at once, expand query inputs, and we also increase the search space over clinical text as well as structured data. Such a method implies to specify an initial set of seed concepts, which are based on concept unique identifiers. This paper presents a novel method based on Formal Concept Analysis (FCA) and Semantic Query Expansion (SQE) to assist the end-user in defining their seed queries and in refining the expanded search space that it encompasses. RESULTS: We evaluate our method over a gold-standard corpus from the 2008 i2b2 Obesity Challenge. This experimentation emphasizes positive results for sensitivity and specificity measures. Our new approach provides better recall with high precision of the obtained results. The most promising aspect of this approach consists in the discovery of positive results not present our Obesity NLP reference set. CONCLUSIONS: Together with a Web graphical user interface, our FCA and SQE cooperation end up being an efficient approach for refining health outcome of interest using plain terms. We consider that this approach can be extended to support other domains such as cohort building tools. PMID- 26043840 TI - Partial repair of salinity-induced damage to sprouting sugarcane buds by proline and glycinebetaine pretreatment. AB - Sugarcane shows reduced crop stand under relatively suboptimal conditions; the main reason for this is its sensitivity to ionic stress in the soil solution. This research was performed to explore some physiological and developmental changes in the immature sugarcane buds submitted to salt stress and possible role of glycinebetaine (GB) and proline (Pro) in mitigating the ion toxicity in a time course manner. Salinity stress reduced fresh and dry weight, induced the generation of hydrogen peroxide, increased tissue levels of Na(+) sand Cl(-), reduced K(+) and Ca(2+), and K(+):Na(+) and Ca(2+):Na(+) ratios, while increasing the osmolyte synthesis in expanding sugarcane buds. Salinity stress reduced and delayed the formation of new bud leaves and their expansion, which was mainly because of reduction in the number and area of mesophyll cells and poor development of vascular bundles. The pretreatment of bud chips with 20 mM each of GB and Pro decreased tissue levels of Na(+) and Cl(-), reduced the generation of H2O2, improved K(+) and Ca(2+), K(+):Na(+) and Ca(2+):Na(+) ratios, and further increased the levels of GB, free proline (FP), and soluble sugars in the buds. The pretreatment increased mesophyll cell number and expansion of bud leaves and formation of elaborated vascular tissues, which apparently enabled the sprouting buds to adapt to salinity stress. Of the two osmolytes, GB was a relatively better inducer of salinity tolerance than Pro. In short, salinity-induced oxidative stress was the main cause for altered tissue development, the production of which was offset by pretreatment of bud tissues with Pro and GB. PMID- 26043841 TI - Is pornography consumption associated with condom use and intoxication during hookups? AB - In order to examine whether pornography consumption is associated with risky sexual behaviour among emerging adults, we examined two large samples of those who reported hooking up in the past 12 months (combined n = 1216). Pornography use was associated with a higher likelihood of having a penetrative hookup; a higher incidence of intoxication during hookups for men (but a lower incidence of intoxication during hookups for women); increasing levels of intoxication during hookups for men but decreasing levels of intoxication for women; and a higher likelihood of being in the riskiest category of having a penetrative hookup, without a condom, while intoxicated. For each of these outcomes, our point estimates for Study 2 fell within the 95% confidence intervals from Study 1. Controlling for trait self-control, binge drinking frequency, broader problematic patterns of alcohol use, openness to experience, and attitudes toward casual sex did not change the pattern of results. Implications for interventions to reduce sexual risk are discussed. PMID- 26043842 TI - Lithium nephrotoxicity. AB - Reports of toxic effects on the kidney of lithium treatment emerged very soon after lithium therapy was introduced. Lithium-induced nephrogenic diabetes insipidus is usually self-limiting or not clinically dangerous. Some reports of irreversible chronic kidney disease and renal failure were difficult to attribute to lithium treatment since chronic kidney disease and renal failure exist in the population at large. In recent years, large-scale epidemiological studies have convincingly shown that lithium treatment elevates the risk of chronic kidney disease and renal failure. Most patients do not experience renal side effects. The most common side effect of polyuria only weakly predicts increasing creatinine or reduced kidney function. Among those patients who do experience decrease in creatinine clearance, some may require continuation of lithium treatment even as their creatinine increases. Other patients may be able to switch to a different mood stabilizer medication, but kidney function may continue to deteriorate even after lithium cessation. Most, but not all, evidence today recommends using a lower lithium plasma level target for long-term maintenance and thereby reducing risks of severe nephrotoxicity. PMID- 26043843 TI - Prescribing preferences in rapid tranquillisation: a survey in Belgian psychiatrists and emergency physicians. AB - BACKGROUND: The pharmacotherapeutic management of agitation is a common clinical challenge. Pharmacotherapy is frequently used, the use of published guidelines is not known. The purpose of this study was twofold; to describe the prescribing patterns of psychiatrists and emergency physicians and to evaluate to which extent guidelines are used. METHODS: A cross-sectional survey in the Dutch speaking part of Belgium is carried out in 39 psychiatric hospitals, 11 psychiatric wards of a general hospital and 61 emergency departments. All physicians are asked for demographic information, their prescribing preferences, their use of guidelines and the type of monitoring (effectiveness, safety). For the basic demographic data and prescription preferences descriptive statistics are given. For comparing prescribing preferences of the drug between groups Chi square tests (or in case of low numbers Fisher's exact test) were performed. Mc Nemar test for binomial proportions for matched-pair data was performed to see if the prescription preferences of the participants differ between secluded and non secluded patients. RESULTS: 550 psychiatrist and emergency physicians were invited. The overall response rate was 20% (n = 108). The number 1 preferred medication classes were antipsychotics (59.3%) and benzodiazepines (40.7%). In non-secluded patients, olanzapine (22.2%), lorazepam (21.3%) and clotiapine (19.4%) were most frequently picked as number 1 choice drug. In secluded patients, clotiapine (21.3%), olanzapine (21.3%) and droperidol (14.8%) were the three most frequently chosen number 1 preferred drugs. Between-group comparisons show that emergency physicians prefer benzodiazepines significantly more than psychiatrists do. Zuclopenthixol and olanzapine show a particular profile in both groups of physicians. Polypharmacy is more frequently used in secluded patients. Published guidelines and safety or outcome monitoring are rarely used. CONCLUSIONS: Our results show that prescription practice in Flanders (Belgium) in acute agitation shows a complex relationship with published guidelines. Prescription preferences differ accordingly to medical specialty. These findings should be taken into account in future research. PMID- 26043844 TI - Comparative analysis of Rb1, P16 and ER as diagnostic, prognostic and potential targets for therapeutic agents in ovarian epithelial tumors: an immunohistochemical study of 130 ovarian carcinomas. AB - BACKGROUND: Deregulation of CDK4/6, cyclin D/P16 and retinoblastoma (Rb) are known aberrations in certain malignancies. There has been a recent interest in exploring the combination of letrozole and CDK4/6 inhibitors in recurrent ER+ ovarian cancers. METHODS: This study aimed to determine the frequency of expression of Rb1, P16 and ER in ovarian epithelial tumors by immunohistochemistry. RESULTS: Co-expression of all 3 markers studied was seen in 10% of high grade serous carcinoma (HGSC) and low grade serous carcinoma (LGSC). Coordinate expression of Rb1+ and ER+ in HGSC and LGSC was seen in 67% of grade 1/2 vs. 44 % of grade three tumors (p < 0.05). The reverse was true with positive P16 staining in 73% of grade three vs. 32% of grade 1/2 tumors (p < 0.001). CONCLUSIONS: Coordinate pattern of Rb1+ and ER+ in HGSC and LGSC is 19 and 50%, respectively. Rb1 and P16 show inverse expression pattern according to tumor grade with more frequent Rb1 in low grade vs. more frequent P16 in grade 3 tumors. These data provide a rational basis for clinical trials that aim to target these proteins. PMID- 26043845 TI - Corpus callosum area and brain volume in autism spectrum disorder: quantitative analysis of structural MRI from the ABIDE database. AB - Reduced corpus callosum area and increased brain volume are two commonly reported findings in autism spectrum disorder (ASD). We investigated these two correlates in ASD and healthy controls using T1-weighted MRI scans from the Autism Brain Imaging Data Exchange (ABIDE). Automated methods were used to segment the corpus callosum and intracranial region. No difference in the corpus callosum area was found between ASD participants and healthy controls (ASD 598.53 +/- 109 mm(2); control 596.82 +/- 102 mm(2); p = 0.76). The ASD participants had increased intracranial volume (ASD 1,508,596 +/- 170,505 mm(3); control 1,482,732 +/- 150,873.5 mm(3); p = 0.042). No evidence was found for overall ASD differences in the corpus callosum subregions. PMID- 26043846 TI - Stop and change: inhibition and flexibility skills are related to repetitive behavior in children and young adults with autism spectrum disorders. AB - Cognitive control dysfunctions, like inhibitory and attentional flexibility deficits are assumed to underlie repetitive behavior in individuals with autism spectrum disorders (ASD). In the present study, prepotent response inhibition and attentional flexibility were examined in 64 high-functioning individuals with ASD and 53 control participants. Performance under different task conditions were tested both in response to visual and auditory information, and requiring a motor or verbal response. Individuals with ASD showed significant more control dysfunctions than typically developing participants on the auditory computer task. Inhibitory control and attentional flexibility predicted RRB in everyday life. Specifically, response inhibition in reaction to visual information and task switching in reaction to auditory information predicted motor and sensory stereotyped behavior. PMID- 26043847 TI - Brief report: the impact of changing from DSM-IV 'Asperger's' to DSM-5 'autistic spectrum disorder' diagnostic labels on stigma and treatment attitudes. AB - In the DSM-5, 'Asperger's Disorder' was incorporated into 'Autistic Spectrum Disorder' (ASD). One key concern in this change has been that the ASD label will increase negative attitudes relative to the Asperger's label. To test this, we asked 465 American adults to read a vignette describing a child with autistic symptoms that included an ASD label, an Asperger's label, or no label, and rate their stigma and treatment attitudes (help-seeking and perceived effectiveness). Contrary to predictions, label did not impact stigma. Label did impact treatment attitudes, with greater help-seeking and perceived treatment effectiveness for both Asperger's and ASD labels. In sum, concern that the ASD label will increase negative perceptions, at least amongst the general public, is not supported. PMID- 26043851 TI - Immunodiagnostic Properties of Wucheraria bancrofti SXP-1, a Potential Filarial Diagnostic Candidate Expressed in Tobacco Plant, Nicotiana tabacum. AB - Transgenic tobacco plants were developed expressing WbSXP-1, a diagnostic antigen isolated from the cDNA library of L3 stage larvae of Wucheraria bancrofti. This antigen produced by recombinant Escherichia coli has been demonstrated by to be successful as potential diagnostic candidate against lymphatic filariasis. A rapid format simple and qualitative flow through immune-filtration diagnostic kit has been developed for the identification of IgG antibodies to the recombinant WbSXP-1 and is being marketed by M/S Span Diagnostics Ltd in India and Africa. Here, we present the results of experiments on the transformation and expression of the same filarial antigen, WbSXP-1, in tobacco plant, Nicotiana tabacum, to produce plant-based diagnostic antigen. It was possible to successfully transform the tobacco plant with WbSXP-1, the integration of the parasite-specific gene in plants was confirmed by PCR amplification and the expression of the filarial protein by Western blotting. The immunoreactivity of the plant-produced WbSXP-1 was assessed based on its reaction with the monoclonal antibodies developed against the E. coli-produced protein. Immunological screening using clinical sera from patients indicates that the plant-produced protein is comparable to E. coli produced diagnostic antigen. The result demonstrated that plants can be used as suitable expression systems for the production of diagnostic proteins against lymphatic filariasis, a neglected tropical infectious disease which has a negative impact on socioeconomic development. This is the first report of the integration, expression and efficacy of a diagnostic candidate of lymphatic filariasis in plants.Key MessageTransgenic tobacco plants with WbSXP-1, a filarial diagnostic candidate, were developed. The plant-produced protein showed immunoreactivity on par with the E. coli product. PMID- 26043850 TI - Vitamin D Status and Adiposity in Pediatric Malabsorption Syndromes. AB - BACKGROUND: The combined effects of nutrient malabsorption and adiposity on vitamin D status are unclear in pediatric malabsorption syndromes. AIM: To determine the relationship between adiposity and serum 25-hydroxyvitamin D (25(OH)D) in malabsorption disorders. METHODS: Prepubertal children of ages 3-12 with either lactose intolerance (LI) (n = 38, age 8.61 +/- 3.08, male/female 19/19), or celiac disease (CD) (n = 24) were compared to healthy controls (n = 49, age 7.95 +/- 2.64, male/female 28/21). A separate cohort of combined prepubertal and pubertal subjects with inflammatory bowel disease (IBD) (n = 59, age 16.4 +/- 2.2, male/female 31/27) were also compared to healthy controls (n = 116, male/female 49/67, age 14.6 +/- 4.4). Vitamin D deficiency was defined as 25(OH)D of <50 nmol/l, overweight as body mass index (BMI) of >= 85th but <95th percentile, and obesity as BMI >= 95th percentile. RESULTS: Among the controls, 25(OH)D was significantly higher in the normal-weight prepubertal controls vs. the overweight/obese controls (p = 0.001), and similarly so for the combined cohort of prepubertal and pubertal controls (p = 0.031). In contrast, there was no significant difference in 25(OH)D concentration between the normal-weight vs. overweight/obese patients with LI (p = 0.335), CD (p = 0.387), and IBD (p = 0.883). CONCLUSION: There is no association between adiposity and serum 25(OH)D in pediatric malabsorption syndromes. PMID- 26043848 TI - The effect of visual perceptual load on auditory awareness in autism spectrum disorder. AB - Recent work on visual selective attention has shown that individuals with Autism Spectrum Disorder (ASD) demonstrate an increased perceptual capacity. The current study examined whether increasing visual perceptual load also has less of an effect on auditory awareness in children with ASD. Participants performed either a high- or low load version of a line discrimination task. On a critical trial, an unexpected, task-irrelevant auditory stimulus was played concurrently with the visual stimulus. In contrast to typically developing (TD) children, children with ASD demonstrated similar detection rates across perceptual load conditions, and reported greater awareness than TD children in the high perceptual load condition. These findings suggest an increased perceptual capacity in children with ASD that operates across sensory modalities. PMID- 26043853 TI - Enhanced Xylitol Production by Mutant Kluyveromyces marxianus 36907-FMEL1 Due to Improved Xylose Reductase Activity. AB - A directed evolution and random mutagenesis were carried out with thermotolerant yeast Kluyveromyces marxianus ATCC 36907 for efficient xylitol production. The final selected strain, K. marxianus 36907-FMEL1, exhibited 120 and 39 % improvements of xylitol concentration and xylitol yield, respectively, as compared to the parental strain, K. marxianus ATCC 36907. According to enzymatic assays for xylose reductase (XR) activities, XR activity from K. marxianus 36907 FMEL1 was around twofold higher than that from the parental strain. Interestingly, the ratios of NADH-linked and NADPH-linked XR activities were highly changed from 1.92 to 1.30 when K. marxianus ATCC 36907 and K. marxianus 36907-FMEL1 were compared. As results of KmXYL1 genes sequencing, it was found that cysteine was substituted to tyrosine at position 36 after strain development which might cause enhanced XR activity from K. marxianus 36907-FMEL1. PMID- 26043852 TI - Biological Properties and Characterization of ASL50 Protein from Aged Allium sativum Bulbs. AB - Allium sativum is well known for its medicinal properties. The A. sativum lectin 50 (ASL50, 50 kDa) was isolated from aged A. sativum bulbs and purified by gel filtration chromatography on Sephacryl S-200 column. Agar well diffusion assay were used to evaluate the antimicrobial activity of ASL50 against Candida species and bacteria then minimal inhibitory concentration (MIC) was determined. The lipid A binding to ASL50 was determined by surface plasmon resonance (SPR) technology with varying concentrations. Electron microscopic studies were done to see the mode of action of ASL50 on microbes. It exerted antimicrobial activity against clinical Candida isolates with a MIC of 10-40 MUg/ml and clinical Pseudomonas aeruginosa isolates with a MIC of 10-80 MUg/ml. The electron microscopic study illustrates that it disrupts the cell membrane of the bacteria and cell wall of fungi. It exhibited antiproliferative activity on oral carcinoma KB cells with an IC50 of 36 MUg/ml after treatment for 48 h and induces the apoptosis of cancer cells by inducing 2.5-fold higher caspase enzyme activity than untreated cells. However, it has no cytotoxic effects towards HEK 293 cells as well as human erythrocytes even at higher concentration of ASL50. Biological properties of ASL50 may have its therapeutic significance in aiding infection and cancer treatments. PMID- 26043854 TI - Uniparental Disomy in Somatic Mosaicism 45,X/46,XY/46,XX Associated with Ambiguous Genitalia. AB - Disorders of sex development (DSD) affect the development of chromosomal, gonadal and/or anatomical sex. We analyzed a patient with ambiguous genitalia aiming to correlate the genetic findings with the phenotype. Blood and tissue samples from a male patient with penoscrotal hypospadias were analyzed by immunohistochemistry, karyotyping and FISH. DNA was sequenced for the AR, SRY and DHH genes, and further 26 loci in different sex chromosomes were analyzed by MLPA. The gonosomal origin was evaluated by simple tandem repeat (STR) analysis and SNP array. Histopathology revealed a streak gonad, a fallopian tube and a rudimentary uterus, positive for placental alkaline phosphatase, cytokeratin-7 and c-kit, and negative for estrogen, androgen and progesterone receptors, alpha inhibin, alpha-1-fetoprotein, beta-hCG, and oct-4. Karyotyping showed a 45,X/46,XY mosaicism, yet FISH showed both 46,XX/46,XY mosaicism (gonad and urethral plate), 46,XX (uterus and tube) and 46,XY karyotypes (rudimentary testicular tissue). DNA sequencing revealed intact sequences in SOX9, WNT4, NR0B1, NR5A1, CYP21A2, SRY, AR, and DHH. STR analysis showed only one maternal allele for all X chromosome markers (uniparental isodisomy, UPD), with a weaker SRY signal and a 4:1 ratio in the X:Y signal. Our findings suggest that the observed complex DSD phenotype is the result of somatic gonosomal mosaicism and UPD despite a normal blood karyotype. The presence of UPD warrants adequate genetic counseling for the family and frequent, lifelong, preventive follow-up controls in the patient. PMID- 26043855 TI - Efficacy and Safety of Tacrolimus versus Pimecrolimus for the Treatment of Atopic Dermatitis in Children: A Network Meta-Analysis. AB - OBJECTIVE: Using a network meta-analysis, we aimed to compare the efficacy and safety of tacrolimus and pimecrolimus as treatment options for children with atopic dermatitis (AD). METHODS: Randomized controlled studies with a modified Jadad score >3 using tacrolimus or pimecrolimus in pediatric patients with AD were studied. RESULTS: Out of 163 articles, 19 studies enrolling a total of 6,413 pediatric patients were selected. Pooled analysis revealed that tacrolimus 0.03% or 0.1% and pimecrolimus 1% were better at reducing eczema compared with vehicles. No significance was found between tacrolimus and pimecrolimus in improving the severity of eczema. More patients tended to withdraw in the vehicle groups compared to the tacrolimus and pimecrolimus groups. No significant difference existed between total adverse events and withdrawals in the tacrolimus and pimecrolimus groups. CONCLUSIONS: Pimecrolimus was similar to tacrolimus in both efficacy and safety for AD in children, but both were better than vehicles. PMID- 26043856 TI - Monitoring Effects of Excipients, Formulation Parameters and Mutations on the High Order Structure of Filgrastim by NMR. AB - PURPOSE: Filgrastim is the generic name for recombinant methionyl human granulocyte colony-stimulating factor (r-metHuG-CSF). It is marketed under the brand name Neupogen(r) by Amgen. Since this product has lost patent protection, many biosimilar versions have been approved or are in the process of filing for market authorization throughout the world. Here we show that NMR spectroscopy can be used to assess the three-dimensional structure of the active ingredient in the formulated approved product Neupogen(r). METHODS: Recombinant metHuG-CSF was prepared in E. coli and isotopically enriched with (13)C and (15) N isotopes. NMR spectroscopy was used to study the effects of excipients on the conformation. RESULTS: The effects of pH variation on the amide chemical shifts suggest the presence of cation-pi interactions between His-79 and Trp-118, and His-156-Trp-58 His-52 that stabilizes the conformation at low pH. This may be associated with a small local conformational change. The NMR data showed that polysorbate does not interact significantly with filgrastim thus allowing the collection of spectra in the presence of 20 times the formulation concentration in the sample. However, at higher detergent concentrations a reduction of signal intensity is observed. Conclusions The NMR fingerprint assay applied to filgrastim (Neupogen(r) and a CRS from the European Pharmacopeia (EP)) provided residue specific information of the structure of the drug substance. In addition to current methods, the ability to assess the conformation with a high degree of resolution can greatly facilitate comparability exercises. PMID- 26043857 TI - Factors associated with cesarean delivery in public and private hospitals in a city of northeastern Brazil: a cross-sectional study. AB - BACKGROUND: To evaluate the prevalence and factors associated with cesarean delivery according to whether care was provided in public or private hospitals in Brazil. METHODS: This was a cross-sectional study based on a cohort of live births between April 2004 and March 2005. A total of 1,344 mother-child pairs were followed up during the first month of life. The variables analyzed were the socioeconomic and demographic characteristics of the mother and newborn, as well as the healthcare provided during pregnancy and childbirth. Hierarchical analysis was carried out for both prediction models, i.e. healthcare provision either within the Brazilian National Health System (public service) or within the private network. Prevalence and association measurement calculations were carried out. Values were considered significant when pless than or equal to 5.0 %. RESULTS: A total of 1,019 (75,8 %) gave birth in public hospital. The prevalences of cesarean delivery were 29.9 % and 86.2 % in the public and private sectors, respectively. Through hierarchical logistic regression, the risk factors for cesarean delivery presented in the public hospital were maternal age greater than or equal to 20 years (p = 0.003), primiparity (p = 0.004), twinning (p = 0.039), prenatal care provided in the private network (p = 0.004), delivery in hospitals providing high complexity medical care (p = 0.000) and prenatal care with greater than or equal to 6 consultations (p = 0.035). In the private sector, no association was observed between the variables studied and cesarean delivery. CONCLUSIONS: The cesarean delivery rates were high in both sectors, although in the private network the rate was almost triple that of the public service. The absence of determinant factors of birth in the private sector drew attention. In planning measures against the growing cesarean rates, it is necessary to take into consideration the environmental determinants as primiparity, twinning and greater maternal age, frequent indications of primary cesarean delivery, as well as to implement actions that might improve the quality of prenatal and delivery care. PMID- 26043858 TI - RCARE: RNA Sequence Comparison and Annotation for RNA Editing. AB - The post-transcriptional sequence modification of transcripts through RNA editing is an important mechanism for regulating protein function and is associated with human disease phenotypes. The identification of RNA editing or RNA-DNA difference (RDD) sites is a fundamental step in the study of RNA editing. However, a substantial number of false-positive RDD sites have been identified recently. A major challenge in identifying RDD sites is to distinguish between the true RNA editing sites and the false positives. Furthermore, determining the location of condition-specific RDD sites and elucidating their functional roles will help toward understanding various biological phenomena that are mediated by RNA editing. The present study developed RNA-sequence comparison and annotation for RNA editing (RCARE) for searching, annotating, and visualizing RDD sites using thousands of previously known editing sites, which can be used for comparative analyses between multiple samples. RCARE also provides evidence for improving the reliability of identified RDD sites. RCARE is a web-based comparison, annotation, and visualization tool, which provides rich biological annotations and useful summary plots. The developers of previous tools that identify or annotate RNA editing sites seldom mention the reliability of their respective tools. In order to address the issue, RCARE utilizes a number of scientific publications and databases to find specific documentations respective to a particular RNA-editing site, which generates evidence levels to convey the reliability of RCARE. Sequence-based alignment files can be converted into VCF files using a Python script and uploaded to the RCARE server for further analysis. RCARE is available for free at http://www.snubi.org/software/rcare/. PMID- 26043859 TI - Interprofessional learning on a stroke unit. AB - BACKGROUND: The importance of a collaborative approach to patient care in improving safety and outcomes has been highlighted by medical regulatory organisations. The World Health Organization has advocated that future health care professionals should be 'collaborative practice ready', and there is a global drive to incorporate interprofessional learning into health education. Interprofessional learning promotes the development of effective teamworking skills and improves the understanding of roles in the multidisciplinary team. This article outlines the development of a practice-based interprofessional learning initiative on a stroke unit. The World Health Organization has advocated that future health care professionals should be 'collaborative practice ready' METHODS: A half-day seminar was developed by King's College London in conjunction with an interprofessional clinical team from the Stroke Unit at St Thomas' Hospital. Students were assigned discipline-specific supervisors who allocated them to care for a patient within the confines of their usual professional role. They were asked to present the patient to a mixed-discipline group of students within the seminar from the perspective of their individual disciplines. This was followed by supervisor-led group discussions concerning the care of the patient and interprofessional working. RESULTS: Sixty-seven students from different disciplines participated in nine seminars over a 2-year period. Thematic analysis of participants' comments revealed an improvement in the students' awareness of: the varying roles and responsibilities of professionals; how differing disciplines share functions; and the importance of effective communication. All students stated that they would recommend the seminar to other students. DISCUSSION: Effective interprofessional learning programmes are imperative to promote collaborative practice amongst health care professionals. Stroke units are ideal learning environments for practice-based interprofessional education. PMID- 26043860 TI - Changes in macronutrient, micronutrient, and food group intakes throughout the menstrual cycle in healthy, premenopausal women. AB - PURPOSE: It is thought that total energy intake in women is increased during the luteal versus follicular phase of the menstrual cycle; however, less is understood regarding changes in diet composition (i.e., macro- and micronutrient intakes) across the cycle. The aim of this study was to investigate changes in macronutrient, micronutrient, and food group intakes across phases of the menstrual cycle among healthy women, and to assess whether these patterns differ by ovulatory status. METHODS: The BioCycle study (2005-2007) was a prospective cohort study of 259 healthy regularly menstruating women age 18-44 who were followed for up to two menstrual cycles. Dietary intake was measured using 24-h dietary recalls, and food cravings were assessed via questionnaire, up to four times per cycle, corresponding to menses, mid-follicular, expected ovulation, and luteal phases. Linear mixed models adjusting for total energy intake were used to evaluate changes across the cycle. RESULTS: Total protein (P = 0.03), animal protein (P = 0.05), and percent of caloric intake from protein (P = 0.02) were highest during the mid-luteal phase compared to the peri-ovulatory phase. There were also significant increases in appetite, craving for chocolate, craving for sweets in general, craving for salty flavor, and total craving score during the late luteal phase compared to the menstrual, follicular, and ovulatory phases (P < 0.001). CONCLUSIONS: Our findings suggest an increased intake of protein, and specifically animal protein, as well as an increase in reported food cravings, during the luteal phase of the menstrual cycle independent of ovulatory status. These results highlight a plausible link between macronutrient intake and menstrual cycle phase. PMID- 26043862 TI - Type B Lactic Acidosis in a Patient with Gastric Adenocarcinoma and Extensive Hepatic Metastases. AB - OBJECTIVE: We report the second case of gastric adenocarcinoma associated with type B lactic acidosis. CLINICAL PRESENTATION AND INTERVENTION: An 81-year-old man presenting with upper gastrointestinal bleeding was found to have an advanced gastric adenocarcinoma. He had persistently elevated serum lactate attributed to malignancy-associated type B lactic acidosis as a diagnosis of exclusion. As he remained clinically stable with a near-normal pH, his elevated lactate was not specifically treated. CONCLUSION: This patient had an unusual type B lactic acidosis associated with gastric cancer. In the absence of signs and symptoms of other etiologies of lactic acidosis, physicians should consider malignancy associated type B lactic acidosis. PMID- 26043861 TI - Comparison of plasma alkylresorcinols (AR) and urinary AR metabolites as biomarkers of compliance in a short-term, whole-grain intervention study. AB - PURPOSE: Alkylresorcinols (AR) are phenolic lipids present in the bran of wheat and rye. Plasma AR and their urinary metabolites may be suitable biomarkers of whole-grain (WG) wheat and rye consumption. The objective of this study was to examine plasma AR and urinary AR metabolites in response to WG wheat consumption. METHODS: In a randomized crossover study, 19 subjects (10 males, 9 females; BMI 22.0 kg/m(2); age 26 years) incorporated either 3 servings (48 g) or 6 servings (96 g) of WG wheat daily into their regular diet for 1 week. Subjects completed a 2-week washout period, abstaining from all WG consumption, before each intervention. Fasting blood and 24-h urine were collected before and after each intervention. Plasma AR homologues (C19:0, C21:0, C23:0) were quantified by GC-MS after diethyl ether and solid phase extraction and derivatization. Urinary AR metabolites [3,5-dihydroxybenzoic acid and 3-(3,5-dihydroxyphenyl)-propanoic acid] were determined using HPLC with electrochemical detection after enzymatic deconjugation and ethyl acetate extraction. RESULTS: Urinary total AR metabolites were significantly higher after 6 compared with 3 servings of WG wheat (56 vs. 32 MUmol/day, P < 0.001). This dose-response relationship was independent of age, sex, energy intake, and baseline urinary AR metabolite concentration. Plasma total AR tended to be higher after 6 compared with 3 servings of WG wheat (103.0 vs. 86.9 nmol/L), but this difference was not significant (P = 0.42). CONCLUSION: The results suggest that urinary AR metabolites from 24-h urine collections may be useful as biomarkers of compliance in intervention studies of WG wheat. PMID- 26043863 TI - Impact of Cell-free Supernatant of Lactic Acid Bacteria on Putrescine and Other Polyamine Formation by Foodborne Pathogens in Ornithine Decarboxylase Broth. AB - Conversion of ornithine to putrescine by Salmonella Paratyphi A, Listeria monocytogenes, Staphylococcus aureus, and Escherichia coli was investigated in ornithine decarboxylase broth (ODB) using cell-free supernatants (CFSs) obtained from Leuconostoc mesenterodies subsp. cremoris, Pediococcus acidilactici, Lactococcus lactis subsp. lactis, Streptococcus thermophilus. Two groups of cell free supernatants (25 or 50%) and control (only ODB) were prepared to investigate putrescine (PUT) and other polyamine formation by foodborne pathogens (FBPs). Significant differences (p < 0.05) were observed among the species for each amine. All of the CFSs reduced the formation of PUT by >=65%. The production of cadaverine (CAD) was scarcely affected by the presence of CFSs, with the exception of the samples inoculated with L. monocytogenes. The variation in polyamine was found with respect to the control samples. Spermidine (SPD) was produced in lower amount in many samples, especially in Gram-negative FBPs, whereas spermine (SPN) increased drastically in the major part of the samples concerning the control. Histamine (HIS) was characterized by a marked concentration decrease in all of the samples, and tyramine (TYR) was accumulated in very low concentrations in the controls. Therefore, the ability of bacteria to produce certain biogenic amines such as HIS, TYR, PUT, and CAD has been studied to assess their risk and prevent their formation in food products. The results obtained from this study concluded that the lactic acid bacteria (LAB) strains with non-decarboxylase activity are capable of avoiding or limiting biogenic amine formation by FBP. PMID- 26043864 TI - Risk factors for inadequate bone marrow biopsies in children. PMID- 26043867 TI - WITHDRAWN: Anticholinergics for urinary symptoms in multiple sclerosis. PMID- 26043866 TI - Bevacizumab loaded solid lipid nanoparticles prepared by the coacervation technique: preliminary in vitro studies. AB - Glioblastoma, the most common primary brain tumor in adults, has an inauspicious prognosis, given that overcoming the blood-brain barrier is the major obstacle to the pharmacological treatment of brain tumors. As neoangiogenesis plays a key role in glioblastoma growth, the US Food and Drug Administration approved bevacizumab (BVZ), an antivascular endothelial growth factor antibody for the treatment of recurrent glioblastoma in patients whose the initial therapy has failed. In this experimental work, BVZ was entrapped in solid lipid nanoparticles (SLNs) prepared by the fatty-acid coacervation technique, thanks to the formation of a hydrophobic ion pair. BVZ activity, which was evaluated by means of four different in vitro tests on HUVEC cells, increased by 100- to 200-fold when delivered in SLNs. Moreover, SLNs can enhance the permeation of fluorescently labelled BVZ through an hCMEC/D3 cell monolayer-an in vitro model of the blood brain barrier. These results are promising, even if further in vivo studies are required to evaluate the effective potential of BVZ-loaded SLNs in glioblastoma treatment. PMID- 26043868 TI - Realization of large-area wrinkle-free monolayer graphene films transferred to functional substrates. AB - Structural inhomogeneities, such as the wrinkles and ripples within a graphene film after transferring the free-standing graphene layer to a functional substrate, degrade the physical and electrical properties of the corresponding electronic devices. Here, we introduced titanium as a superior adhesion layer for fabricating wrinkle-free graphene films that is highly applicable to flexible and transparent electronic devices. The Ti layer does not influence the electronic performance of the functional substrates. Experimental and theoretical investigations confirm that the strong chemical interactions between Ti and any oxygen atoms unintentionally introduced on/within the graphene are responsible for forming the clean, defect-free graphene layer. Our results accelerate the practical application of graphene-related electronic devices with enhanced functionality. The large-area monolayer graphenes were prepared by a simple attachment of the Ti layer with the multi-layer wrinkle-free graphene films. For the first time, the graphene films were addressed for applications of superior bottom electrode for flexible capacitors instead of the novel metals. PMID- 26043869 TI - Postmortem diffusion MRI of the human brainstem and thalamus for deep brain stimulator electrode localization. AB - Deep brain stimulation (DBS) is an established surgical therapy for medically refractory tremor disorders including essential tremor (ET) and is currently under investigation for use in a variety of other neurologic and psychiatric disorders. There is growing evidence that the anti-tremor effects of DBS for ET are directly related to modulation of the dentatorubrothalamic tract (DRT), a white matter pathway that connects the cerebellum, red nucleus, and ventral intermediate nucleus of the thalamus. Emerging white matter targets for DBS, like the DRT, will require improved three-dimensional (3D) reference maps of deep brain anatomy and structural connectivity for accurate electrode targeting. High resolution diffusion MRI of postmortem brain specimens can provide detailed volumetric images of important deep brain nuclei and 3D reconstructions of white matter pathways with probabilistic tractography techniques. We present a high spatial and angular resolution diffusion MRI template of the postmortem human brainstem and thalamus with 3D reconstructions of the nuclei and white matter tracts involved in ET circuitry. We demonstrate registration of these data to in vivo, clinical images from patients receiving DBS therapy, and correlate electrode proximity to tractography of the DRT with improvement of ET symptoms. PMID- 26043870 TI - Vaccination-Related Side Effects, Humoral Immunity, and Adverse Events during the Civilian Smallpox Vaccination Campaign, Arkansas, 2003. AB - OBJECTIVE: Smallpox vaccination has been associated with notable side effects and adverse events. This study assessed the frequency of each among public health workers immunized during the 2003 Arkansas civilian smallpox vaccination campaign to allow individuals and policymakers to make informed decisions whether repeat vaccination, as recommended in 10-year intervals, should be considered. DESIGN AND SAMPLE: This descriptive study summarizes postvaccination surveillance data for all civilians receiving smallpox vaccine (Dryvax) in Arkansas in 2003. MEASURES: Rates of side effects and adverse events were determined. Vaccinia specific antibody titers among a subset of public health response team members were also assessed. RESULTS: Of the 1,124 vaccine recipients, 87% had a major take response. Substantial symptomatology, a 2% adverse event rate, a 0.5% hospitalization rate, and zero inadvertent transmission following vaccination were observed. Vaccinia-specific antibody titers increased on average 9-fold from 2.21*10(2) to 2.16*10(3) one month after vaccination. We found no association of age, sex, or racial subgroups with adverse events, hospitalizations, a lower take response rate, or lower postvaccination antibody titers. CONCLUSIONS: Prominent side effect profiles and adverse events among study participants seem to support individual and institutional reluctance to vaccinate civilians in the absence of smallpox reemergence. PMID- 26043871 TI - Neural crest derivatives in ocular development: discerning the eye of the storm. AB - Neural crest cells (NCCs) are vertebrate-specific transient, multipotent, migratory stem cells that play a crucial role in many aspects of embryonic development. These cells emerge from the dorsal neural tube and subsequently migrate to different regions of the body, contributing to the formation of diverse cell lineages and structures, including much of the peripheral nervous system, craniofacial skeleton, smooth muscle, skin pigmentation, and multiple ocular and periocular structures. Indeed, abnormalities in neural crest development cause craniofacial defects and ocular anomalies, such as Axenfeld Rieger syndrome and primary congenital glaucoma. Thus, understanding the molecular regulation of neural crest development is important to enhance our knowledge of the basis for congenital eye diseases, reflecting the contributions of these progenitors to multiple cell lineages. Particularly, understanding the underpinnings of neural crest formation will help to discern the complexities of eye development, as these NCCs are involved in every aspect of this process. In this review, we summarize the role of ocular NCCs in eye development, particularly focusing on congenital eye diseases associated with anterior segment defects and the interplay between three prominent molecules, PITX2, CYP1B1, and retinoic acid, which act in concert to specify a population of neural crest derived mesenchymal progenitors for migration and differentiation, to give rise to distinct anterior segment tissues. We also describe recent findings implicating this stem cell population in ocular coloboma formation, and introduce recent evidence suggesting the involvement of NCCs in optic fissure closure and vascular development. PMID- 26043872 TI - CRISPR-Cas9-mediated gene knockout in primary human airway epithelial cells reveals a proinflammatory role for MUC18. AB - Targeted knockout of genes in primary human cells using CRISPR-Cas9-mediated genome-editing represents a powerful approach to study gene function and to discern molecular mechanisms underlying complex human diseases. We used lentiviral delivery of CRISPR-Cas9 machinery and conditional reprogramming culture methods to knockout the MUC18 gene in human primary nasal airway epithelial cells (AECs). Massively parallel sequencing technology was used to confirm that the genome of essentially all cells in the edited AEC populations contained coding region insertions and deletions (indels). Correspondingly, we found mRNA expression of MUC18 was greatly reduced and protein expression was absent. Characterization of MUC18 knockout cell populations stimulated with TLR2, 3 and 4 agonists revealed that IL-8 (a proinflammatory chemokine) responses of AECs were greatly reduced in the absence of functional MUC18 protein. Our results show the feasibility of CRISPR-Cas9-mediated gene knockouts in AEC culture (both submerged and polarized), and suggest a proinflammatory role for MUC18 in airway epithelial response to bacterial and viral stimuli. PMID- 26043873 TI - Hepatocyte-specific Hmgb1 Deletion. AB - High mobility group box 1 (HMGB1) plays a key role in human health and disease. Currently, three different labs in the USA use Cre-lox technology to create mice with a hepatocyte-specific Hmgb1 deletion (HMGB1-HC-KO mice) by backcrossing Hmgb1 (flox)/(flox) mice to Alb-Cre mice. This mouse strain has a different phenotype following exposure to several stressors. PMID- 26043874 TI - Surgical guide for symmetrical aesthetic surgery in unilateral fibrous dysplasia. PMID- 26043875 TI - Inactivation of BLU is associated with methylation of Sp1-binding site of BLU promoter in gastric cancer. AB - BLU is a candidate tumor suppressor gene, which is epigenetically inactivated in many human malignancies. However, the expression and biological functions of BLU in gastric cancer has not yet been reported. In the present study, we identified a functional BLU promoter which was regulated by the transcription activator Sp1. Bisulfite sequencing and qRT-PCR assays indicated that the silence of BLU expression in gastric cancer was significantly associated with DNA hypermethylation of BLU promoter including -39 CpG site located in the Sp1 transcription element. The expression of BLU was notably restored in AGS and SGC7901 cells following the demethylation-treatment with 5'-Aza-2'-deoxycytidine. Moreover, the results from ChIP, EMSA and luciferase reporter gene showed that 39 CpG methylation could prevent Sp1 from binding to the promoter of BLU and decreased transcription activity of the BLU gene by ~70%. In addition, knockdown of BLU significantly promoted cellular proliferation and colony formation in gastric cancer cells. In conclusion, we identified a novel functional BLU promoter and proved that BLU promoter activity was regulated by Sp1. Furthermore, we found that hypermethylated -39 CpG in BLU proximal promoter directly reduced its binding with Sp1, which may be one of the mechanisms accounting for the inactivation of BLU in gastric cancer. PMID- 26043876 TI - Factors in Early-Life Programming of Reproductive Fitness. AB - Fertility rates have been declining worldwide, with a growing number of young women suffering from infertility. Infectious and inflammatory diseases are important causes of infertility, and recent evidence points to the critical role of the early-life microbial environment in developmental programming of adult reproductive fitness. Our laboratory and others have demonstrated that acute exposure to an immunological challenge early in life has a profound and prolonged impact on male and female reproductive development. This review presents evidence that perinatal exposure to immunological challenge by a bacterial endotoxin, lipopolysaccharide, acts at all levels of the hypothalamic-pituitary-gonadal axis, resulting in long-lasting changes in reproductive function, suggesting that disposition to infertility may begin early in life. PMID- 26043877 TI - Advantages and challenges of the spray-drying technology for the production of pure drug particles and drug-loaded polymeric carriers. AB - Spray-drying is a rapid, continuous, cost-effective, reproducible and scalable process for the production of dry powders from a fluid material by atomization through an atomizer into a hot drying gas medium, usually air. Often spray-drying is considered only a dehydration process, though it also can be used for the encapsulation of hydrophilic and hydrophobic active compounds within different carriers without substantial thermal degradation, even of heat-sensitive substances due to fast drying (seconds or milliseconds) and relatively short exposure time to heat. The solid particles obtained present relatively narrow size distribution at the submicron-to-micron scale. Generally, the yield% of spray-drying at laboratory scale with conventional spray-dryers is not optimal (20-70%) due to the loss of product in the walls of the drying chamber and the low capacity of the cyclone to separate fine particles (<2 MUm). Aiming to overcome this crucial drawback in early development stages, new devices that enable the production of submicron particles with high yield, even for small sample amounts, have been introduced into the market. This review describes the most outstanding advantages and challenges of the spray-drying method for the production of pure drug particles and drug-loaded polymeric particles and discusses the potential of this technique and the more advanced equipment to pave the way toward reproducible and scalable processes that are critical to the bench to-bedside translation of innovative pharmaceutical products. PMID- 26043878 TI - Effects of digital countdown timer on intersection safety and efficiency: A systematic review. AB - OBJECTIVE: To investigate the available evidence referring to the effectiveness of digital countdown timers (DCTs) in improving the safety and operational efficiency of signalized intersection. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA) statement guidelines. Relevant literature was searched from electronic databases using key terms. Based on study selection and methodological quality assessment, 14 studies were included in the review. Findings of the studies were synthesized in a narrative analysis. RESULTS: Three types of DCT had different effects on intersection safety and operational efficiency. Green signal countdown timers (GSCTs) reduced red light violations, type I dilemma zone distributions, and rear-end collision likelihood but increased crossing after yellow onset and had mixed impacts on type II dilemma zone distributions and intersection capacity. In contrast, red signal countdown timers (RSCTs) increased intersection capacity, although their effectiveness in reducing red light violations dissipated over time. Likewise, continuous countdown timers (CCTs) significantly enhanced intersection capacity but had mixed influences on red light violations and crossing after yellow onset. CONCLUSIONS: Due to the limited and inconsistent evidence regarding DCTs' effects on intersection safety and efficiency, it is not sufficient to recommend any type of DCT to be installed at signalized intersections to improve safety and operational efficiency. Nevertheless, it is apparent that both RSCTs and CCTs enhance intersection capacity, though their impacts on intersection safety are unclear. Future studies need to further verify those anticipated safe and operational benefits of DCTs with enriched field observation data. PMID- 26043879 TI - Measuring tibial component rotation of TKA in MRI: What is reproducible? AB - PURPOSE: Correct rotational alignment of components is crucial for the success of total knee arthroplasty (TKA). Defining landmarks on the tibia that allow for reproducible measurement of component rotation seems to be more challenging than on the femoral side. This study compares the reproducibility of three different measurement techniques. SCOPE: A magnetic resonance imaging (MRI) analysis of 55 patients following TKA was conducted. The rotation of the tibial components was determined using three different reference lines: a tangent to the posterior tibial margin, the tibial epicondylar axis, and the tibial tubercle. Data were analyzed for intra- and inter-observer reliability using intra-class correlation coefficients (ICCs), and a variance comparison between measurement techniques via F-test. RESULTS: Highest reliability and lowest variances for measurement of tibial component rotation were achieved by relation to the tibial epicondylar axis and posterior tibial margin. The tibial tubercle proved to be less reliable (ICC 0.632 (interobserver) and 0.526 (intraobserver)), and variances were significantly higher in comparison with the other two techniques. CONCLUSION: Based on the presented MRI data, measurements of the tibial component rotation are done best using the posterior tibial margin and the tibial epicondylar axis. The tibial tubercle measurement proved to be less reliable for this purpose. We suggest that all three reference lines will be used for assessment of a painful knee following TKA to allow for informed decision making and for choice of best treatment options for the patient. PMID- 26043880 TI - Toward a mechanistic understanding of interindividual differences in cognitive changes after stress: reply to van den Bos. PMID- 26043881 TI - Medical physics aspects of the synchrotron radiation therapies: Microbeam radiation therapy (MRT) and synchrotron stereotactic radiotherapy (SSRT). AB - Stereotactic Synchrotron Radiotherapy (SSRT) and Microbeam Radiation Therapy (MRT) are both novel approaches to treat brain tumor and potentially other tumors using synchrotron radiation. Although the techniques differ by their principles, SSRT and MRT share certain common aspects with the possibility of combining their advantages in the future. For MRT, the technique uses highly collimated, quasi parallel arrays of X-ray microbeams between 50 and 600 keV. Important features of highly brilliant Synchrotron sources are a very small beam divergence and an extremely high dose rate. The minimal beam divergence allows the insertion of so called Multi Slit Collimators (MSC) to produce spatially fractionated beams of typically ~25-75 micron-wide microplanar beams separated by wider (100-400 microns center-to-center(ctc)) spaces with a very sharp penumbra. Peak entrance doses of several hundreds of Gy are extremely well tolerated by normal tissues and at the same time provide a higher therapeutic index for various tumor models in rodents. The hypothesis of a selective radio-vulnerability of the tumor vasculature versus normal blood vessels by MRT was recently more solidified. SSRT (Synchrotron Stereotactic Radiotherapy) is based on a local drug uptake of high-Z elements in tumors followed by stereotactic irradiation with 80 keV photons to enhance the dose deposition only within the tumor. With SSRT already in its clinical trial stage at the ESRF, most medical physics problems are already solved and the implemented solutions are briefly described, while the medical physics aspects in MRT will be discussed in more detail in this paper. PMID- 26043882 TI - Loganin and secologanin derived tryptamine-iridoid alkaloids from Palicourea crocea and Palicourea padifolia (Rubiaceae). AB - During comparative analysis on Palicourea species from Costa Rica, two unusual loganin derived tryptamine-iridoid alkaloids were isolated from an accession of Palicourea crocea. Besides the already known brachycerine (2), palicroceaine (1) features a novel hexacyclic backbone. A second provenance, however, yielded strictosidinic acid (3), belonging to the more common secologanin derived tryptamine-iridoid alkaloids, such as those found in Palicourea padifolia. From this species, strictosidine (4), lyaloside (5) and its derivative (E)-O-(6')-(4" hydroxy-3",5"-dimethoxy)-cinnamoyl lyaloside (6) could be isolated. A herbarium specimen-based screening was performed, indicating some degree of regional differentiation in alkaloid content and biosynthetic pathways within the widespread and variable Pal. crocea. It further shows its differentiation from the related strictosidine containing Palicourea croceoides. The occurrence of loganin derived tryptamine-iridoid alkaloids in Pal. crocea, Psychotria brachyceras and Psychotria brachypoda, all putatively unrelated members of the Palicourea s.l. clade, is a noteworthy exception within the genus, otherwise largely characterized by secologanin-derived tryptamine-iridoid alkaloids. PMID- 26043883 TI - The downside of success: confirmation of HIV infection in early treated children. PMID- 26043885 TI - Report calls for co-location of primary care with A&E. PMID- 26043884 TI - Reactivity of routine HIV antibody tests in children who initiated antiretroviral therapy in early infancy as part of the Children with HIV Early Antiretroviral Therapy (CHER) trial: a retrospective analysis. AB - BACKGROUND: Early antiretroviral therapy (ART) and virological suppression can affect evolving antibody responses to HIV infection. We aimed to assess frequency and predictors of seronegativity in infants starting early ART. METHODS: We compared HIV antibody results between two of three treatment groups of the Children with HIV Early Antiretroviral Therapy (CHER) trial, done from July, 2005, until July, 2011, in which infants with HIV infection aged 5.7-12.0 weeks with a percentage of CD4-positive T lymphocytes of at least 25% were randomly assigned to immediate ART for 96 weeks (ART-96W) or deferred ART until clinical or immunological progression (ART-Def). We measured antibody from all available stored samples for ART-96W and ART-Def at trial week 84 using three assays: fourth-generation enzyme immunoassay HIV antigen-antibody combination, HIV-1 and HIV-2 rapid antibody test, and quantitative anti-gp120 IgG ELISA. We also assessed odds of seropositivity with respect to age of ART initiation and cumulative viral load. The CHER trial was registered with ClinicalTrials.gov, number NCT00102960. FINDINGS: The median age of the infants from when samples were taken (184 samples from 268 infants) was 92 weeks (IQR 90.6-93.4). More specimens from the ART-96W group were seronegative than from the ART-Def group by enzyme immunoassay (ART-96W 49 [46%] of 107 vs ART-Def eight [11%] of 75; p<0.0001) and rapid antibody test (54 [53%] of 101 vs eight [11%] of 74; p<0.0001). Median anti-gp120 IgG concentration was lower in the ART-96W group (230 MUg/MUL [IQR 133-13 129]) than in the ART-Def group (6870 MUg/MUL [1706-53 645]; p<0.0001). If ART was started between 12 and 24 weeks of age, odds of seropositivity were increased 13.7 times (95% CI 3.1-60.2; p=0.001) compared with starting it between 0 and 12 weeks. All children starting ART aged older than 24 weeks were seropositive. Cumulative viral load to week 84 correlated with anti gp120 IgG concentrations (coefficient 0.54; p<0.0001) and increased odds of seropositivity (odds ratio 1.59 [95% CI 1.1-2.3]) adjusted for ART initiation age. INTERPRETATION: About half of children starting ART before 12 weeks of age were HIV seronegative by almost 2 years of age. HIV antibody tests cannot be used to reconfirm HIV diagnosis in children starting early ART. Long-term effects of seronegativity need further study. Clear guidelines are needed for retesting alongside improved diagnostic tests. FUNDING: Wellcome Trust, Medical Research Council, and National Institutes of Health. PMID- 26043886 TI - Subcutaneous administration of monosodium glutamate to pregnant mice reduces weight gain in pups during lactation. AB - Administering monosodium glutamate (MSG) to neonatal rodents induces obesity and type 2 diabetes. In addition, several studies have shown that MSG administered to pregnant animals can cross the placenta and reach the foetus. The present study was performed to investigate the effects of administering MSG to pregnant ICR mice on dam and neonatal growth. Pregnant mice were treated with 60 or 120 mg MSG once daily from day 5 of pregnancy to one day before parturition by subcutaneous injection. In addition, the body weights of the neonates were determined until nine weeks of age. The birth weights of neonates were not different between the control and MSG-treated groups. However, MSG treatment resulted in a lower body weight gain of neonates during lactation. In addition, this underweight of the MSG-treated group at weaning returned to normal compared with the control group at five weeks of age. Cross-fostering experiments indicated that the lower body weight gain of neonates in the MSG-treated group during lactation was due to its effects on the dam. Serum prolactin levels and mammary gland development of the mice were examined next to determine the reasons for this lactation problem. Although there were no differences in prolactin levels, morphological analyses of the mammary glands revealed apparent differences, including low numbers and altered phenotype of alveoli, between the control and MSG-treated groups. Taken together, our results show that treating pregnant mice with excess MSG induced lower neonate body weight gain during lactation. PMID- 26043887 TI - The missing link - likely pathogenetic role of GM3 and other gangliosides in the development of diabetic nephropathy. AB - Despite scientific advances, diabetic nephropathy remains both a therapeutical challenge, and one of the major diabetic complications. Chemical structure of gangliosides, the most complex of glycosphingolipids, is characterised by one or more sialic acids and carbohydrate groups linked to a ceramide structure. Their potential pathogenetic role in a number of disorders linked to diabetes mellitus has recently been conjectured, due to evidence of their negative modulation of the insulin-mediated signaling and general effects on key cell functions like proliferation, differentiation, apoptosis, cellular signaling and adhesion. Elevated levels of advanced glycation products (AGE) usually found in diabetic conditions seem to be responsible for increased concentration of a-series gangliosides in tissues, most notably GM3. GM3 was shown to compromise the renal pericyte and mesangial cell regeneration via the inactivation of VEGF receptor and the receptor-associated Akt signaling pathway. Likewise, the lipid raft theory opened a new research area for GM3 influence, since in the glycosynapse model glycosphingolipids have a key cell-to-cell communication unit with modulating capabilities on signaling receptors. The goal of this review is to provide insight into currently available theories on proposed mechanisms that mark the GM3 as a pathophysiological mediator in the development of diabetic nephropathy. PMID- 26043888 TI - Long term clinical outcome of dental implants placed in a patient with Singleton Merten syndrome. AB - PATIENTS: Singleton-Merten syndrome is an extremely rare autosomal dominant condition with less than 10 reported cases in the literature. It is characterized by abnormal aortic calcifications and dental abnormalities. The goal of this case report is to discuss the abnormal oral clinical features and the modified treatment protocol that was used in order to achieve osseointegration of dental implants in a patient having abnormal bone density and bone turnover associated with Singleton-Merten Syndrome. DISCUSSION: Following extraction of the remaining teeth, titanium implants (Friadent GmbH, Mannheim, Germany and Straumann((r)), Basel, Switzerland) were placed in the upper and lower jaw of the patient. The upper jaw which was treated with dental implants, received a bar supported implant retained prosthesis and the lower jaw an implant retained telescopic prosthesis. The patient was regularly followed up for the past 13 years during which, clinical and radiological evaluation of osseointegration was undertaken. All the loaded implants showed clinical and radiographic evidence of osseointegration. With a follow up of 13 years after insertion of the first implant, the patient reported functioning well with no complications. CONCLUSION: The treatment with dental implants in the extremely rare Singleton-Merten syndrome patients is a reasonable treatment option to rehabilitate maxillofacial aesthetics and establish normal function of the jaws. PMID- 26043889 TI - Structural equation modeling for alteration of occlusal plane inclination. AB - PURPOSE: Occlusal plane inclination is important to maintain a normal opening closing/biting function. However, there can be several causes that lead to alterations of the occlusal plane. The purpose of this study was to observe variations of occlusal plane inclination in adult patients, and to uncover the factors affecting changes in occlusal plane inclination with aging. METHODS: Subjects were 143 patients. A cephalometric image was taken of these patients. In this study, our inquiry points were age, 3 variables on intra-oral findings, and 7 variables on cephalometric analysis. To evaluate the possible causes that affect occlusal plane inclination, factor analysis was carried out, and each component was treated as factors, which were then statistically applied to a structural equation model. Statistical analysis was carried out through the SPSS 20.0 (SPSS Inc., Chicago, USA). RESULTS: In all patients, Camper-occlusal plane angle (COA) ranged from -25.7 to -4.9 degrees (Mean+/-SD: -6.4+/-5.36). In the 60 patients who had no missing teeth, COA ranged from -11.6 to -4.9 degrees (Mean+/-SD: -3.3+/-3.31). From the results of the structural analysis, it was suggested that the occlusal plane changes to counter-clockwise (on the right lateral cephalograms) with aging. CONCLUSION: In this study, variations of occlusal plane inclination in adult patients were observed, and the factors affecting changes in occlusal plane inclination with aging were investigated via factor analysis. From our results, it was suggested that the mandibular morphology change and loss of teeth with aging influence occlusal plane inclination. PMID- 26043890 TI - Modification of existed prosthesis into a flexible wall hollow bulb obturator by permanent silicone soft liner for a hemimaxillectomy patient with restricted mouth opening. AB - PATIENT: A patient of hemimaxillectomy with restricted mouth opening, wearing a hard acrylic bulb obturator encountered difficulty in insertion and removal of the prosthesis. The prosthesis was converted into a open hollow bulb obturator with flexible walls with permanent silicone soft liner for easy insertion and removal. DISCUSSION: Patients having acquired maxillary defects due to surgical resection of the maxilla often suffer with difficulty in mastication, swallowing, nasal regurgitation, speech disturbances and poor esthetics. Different types of obturator with various bulb designs most commonly fabricated from acrylic resins together with "acrylic resin plate and/or" metal framework are used to improve the quality of life of these patients by restoring the function. But restricted mouth opening in some of these patients makes it difficult to place and remove the prosthesis with hard acrylic bulb. Fabrication of flexible open hollow bulb and relining of remaining obturator with resilient permanent silicone soft liner makes easy insertion and removal of the prosthesis and also improve the retention by intimate contact of soft liner with the tissues. CONCLUSION: Permanent silicone soft liner open hollow bulb obturator is a novel way for the functional rehabilitation of a hemimaxillectomy patient suffering with restricted mouth opening. PMID- 26043891 TI - Epigenetic mechanisms: An emerging role in pathogenesis and its therapeutic potential in systemic sclerosis. AB - Systemic sclerosis (SSc) is a heterogeneous and life-threatening autoimmune disease characterized by damage to small blood vessels, interruption of immune homeostasis and ultimately, fibrosis. Currently, the mechanisms involved in SSc pathogenesis remain unknown. An increasing amount of data shows that, via certain signaling pathways, epigenetic mechanisms, including DNA methylation, histone modification, and miRNAs, are closely related to the three primary processes that characterize SSc: vascular abnormalities, activation of immune system, and excessive extracellular matrix deposition. In the clinical setting, identification of molecules and biomarkers for determining disease severity, predicting disease progression and assessing response to treatment remains challenging. In this review, we aim to summarize the key epigenetic mechanisms involved in the pathogenesis of SSc. Certain cytokines or molecules, such as CD40, CD70, and Fli-1, are expressed at varying rates in SSc due to epigenetic modification and play important roles in SSc. It is therefore likely that these molecules may be biomarkers for SSc. In addition, epigenetic changes of certain genes, including Fli-1, BMPRII, CD11a, Foxp3, and eNOS, influence the expression of these genes to ultimately result in an anti-fibrotic effect. The influence that epigenetics has on SSc pathogenesis suggests that epigenetics-targeting drugs may have potential therapeutic effects against SSc. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 26043893 TI - PUMA-mediated mitochondrial apoptotic disruption by hypoxic postconditioning. AB - Postconditioning can reduce ischemia-reperfusion (I/R)-induced cardiomyocyte apoptosis by targeting mitochondria. p53 upregulated modulator of apoptosis (PUMA) is involved in lethal I/R injury. Here, we hypothesized that postconditioning might inhibit mitochondrial pathway-mediated cardiomyocyte apoptosis by controlling PUMA expression. The cultured neonatal rat cardiomyocytes underwent 3 h of hypoxia and 3 h of reoxygenation. Postconditioning consisted of three cycles of 5 min reoxygenation and 5 min hypoxia after prolonged hypoxia. Hypoxic postconditioning reduced the levels of PUMA mRNA and protein. Concomitantly, the loss of mitochondrial membrane potential, cytochrome c release and caspase-3 activation were decreased significantly by postconditioning. Overexpression of PUMA increased greatly not only the number of apoptotic cardiomyocytes, but also the collapse of mitochondrial membrane potential, cytochrome c release and caspase-3 activation under postconditioning condition. The data suggest that reduction of PUMA expression mediates the endogenous cardioprotective mechanisms of postconditioning by disrupting mitochondrial apoptotic pathway. PMID- 26043892 TI - GMP synthase is essential for viability and infectivity of Trypanosoma brucei despite a redundant purine salvage pathway. AB - The causative agent of human African trypanosomiasis, Trypanosoma brucei, lacks de novo purine biosynthesis and depends on purine salvage from the host. The purine salvage pathway is redundant and contains two routes to guanosine-5' monophosphate (GMP) formation: conversion from xanthosine-5'-monophosphate (XMP) by GMP synthase (GMPS) or direct salvage of guanine by hypoxanthine-guanine phosphoribosyltransferase (HGPRT). We show recombinant T. brucei GMPS efficiently catalyzes GMP formation. Genetic knockout of GMPS in bloodstream parasites led to depletion of guanine nucleotide pools and was lethal. Growth of gmps null cells was only rescued by supraphysiological guanine concentrations (100 MUM) or by expression of an extrachromosomal copy of GMPS. Hypoxanthine was a competitive inhibitor of guanine rescue, consistent with a common uptake/metabolic conversion mechanism. In mice, gmps null parasites were unable to establish an infection demonstrating that GMPS is essential for virulence and that plasma guanine is insufficient to support parasite purine requirements. These data validate GMPS as a potential therapeutic target for treatment of human African trypanosomiasis. The ability to strategically inhibit key metabolic enzymes in the purine pathway unexpectedly bypasses its functional redundancy by exploiting both the nature of pathway flux and the limited nutrient environment of the parasite's extracellular niche. PMID- 26043894 TI - Proven efficacy, equitable access, and adjusted pricing of anti-cancer therapies: no 'sweetheart' solution. PMID- 26043896 TI - Transcatheter aortic valve replacement and stroke. PMID- 26043895 TI - Clinical outcomes according to diabetic status in patients treated with biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus eluting stents: prespecified subgroup analysis of the BIOSCIENCE trial. AB - BACKGROUND: Ultrathin strut biodegradable polymer sirolimus-eluting stents (BP SES) proved noninferior to durable polymer everolimus-eluting stents (DP-EES) for a composite clinical end point in a population with minimal exclusion criteria. We performed a prespecified subgroup analysis of the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Stent Versus Durable Polymer Everolimus Eluting Stent for Percutaneous Coronary Revascularisation (BIOSCIENCE) trial to compare the performance of BP-SES and DP-EES in patients with diabetes mellitus. METHODS AND RESULTS: BIOSCIENCE trial was an investigator-initiated, single blind, multicentre, randomized, noninferiority trial comparing BP-SES versus DP EES. The primary end point, target lesion failure, was a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target lesion revascularization within 12 months. Among a total of 2119 patients enrolled between February 2012 and May 2013, 486 (22.9%) had diabetes mellitus. Overall diabetic patients experienced a significantly higher risk of target lesion failure compared with patients without diabetes mellitus (10.1% versus 5.7%; hazard ratio [HR], 1.80; 95% confidence interval [CI], 1.27-2.56; P=0.001). At 1 year, there were no differences between BP-SES versus DP-EES in terms of the primary end point in both diabetic (10.9% versus 9.3%; HR, 1.19; 95% CI, 0.67 2.10; P=0.56) and nondiabetic patients (5.3% versus 6.0%; HR, 0.88; 95% CI, 0.58 1.33; P=0.55). Similarly, no significant differences in the risk of definite or probable stent thrombosis were recorded according to treatment arm in both study groups (4.0% versus 3.1%; HR, 1.30; 95% CI, 0.49-3.41; P=0.60 for diabetic patients and 2.4% versus 3.4%; HR, 0.70; 95% CI, 0.39-1.25; P=0.23, in nondiabetics). CONCLUSIONS: In the prespecified subgroup analysis of the BIOSCIENCE trial, clinical outcomes among diabetic patients treated with BP-SES or DP-EES were comparable at 1 year. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01443104. PMID- 26043897 TI - Employment situation and risk of death among middle-aged Japanese women. AB - BACKGROUND: Few studies have examined the health effects of employment situation among women, taking social and economic conditions into consideration. The objective of this research was to investigate the association of employment situation (full-time or part-time employee and self-employed) with mortality risk in women over a 20-year follow-up period. Additionally, we examined whether the association between employment situation and mortality in women differed by education level and marital status. METHODS: We investigated the association of employment situation with mortality among 16,692 women aged 40-59 years enrolled in the Japan Collaborative Cohort Study. Multivariate HRs and 95% CIs for total deaths by employment situation were calculated after adjustment for age, disease history, residential area, education level, marital status and number of children. We also conducted subgroup analysis by education level and marital status. RESULTS: Multivariate HRs for mortality of part-time employees and self employed workers were 1.48 (95% CI, 1.25 to 1.75) and 1.44 (95% CI, 1.21 to 1.72), respectively, with reference to women working full-time. Subgroup analysis by education level indicated that health effects in women according to employment situation were likely to be more evident in the low education-level group. Subgroup analysis by marital status indicated that this factor also affected the association between employment situation and risk of death. CONCLUSIONS: Among middle-aged Japanese women, employment situation was associated with mortality risk. Health effects were likely to differ by household structure and socioeconomic conditions. PMID- 26043899 TI - Circulating tumour cells in patients with lung cancer undergoing endobronchial cryotherapy. AB - Early diagnosis of lung cancer still poses a major issue, with a large proportion of patients diagnosed at late stages. Therapeutic options and treatment remain limited in these patients. In most cases only palliative therapies are available to alleviate any severe symptoms. Endobronchial cryotherapy (EC) is one form of palliative treatment offered to patients with obstructive airway tumours. Although successful, the impact on circulating tumour cell (CTCs) spread has not been investigated in detail. This study recruited 20 patients awaiting EC treatment. Baseline and post EC blood samples were analysed for presence of CTCs. Results showed an increase in CTCs following EC in 75% of patients. Significant increases were noticeable in some cases. Although EC is a well-accepted modality of treatment to alleviate symptoms, it may lead to an increase in CTCs, which in turn may have implications for tumour dissemination and metastatic spread. PMID- 26043898 TI - The impact of neighbourhood violence and social cohesion on smoking behaviours among a cohort of smokers in Mexico. AB - BACKGROUND: Recent increases in violent crime may impact a variety of health outcomes in Mexico. We examined relationships between neighbourhood-level violence and smoking behaviours in a cohort of Mexican smokers from 2011 to 2012, and whether neighbourhood-level social cohesion modified these relationships. METHODS: Data were analysed from adult smokers and recent ex-smokers who participated in waves 5 and 6 of the International Tobacco Control Mexico survey. Self-reported neighbourhood violence and social cohesion were asked of wave 6 survey participants (n=2129 current and former smokers, n=150 neighbourhoods). Neighbourhood-level averages for violence and social cohesion (ranges 4-14 and 10 25, respectively) were assigned to individuals. We used generalised estimating equations to determine associations between neighbourhood indicators and individual-level smoking intensity, quit behaviours and relapse. RESULTS: Higher neighbourhood violence was associated with higher smoking intensity (risk ratio (RR)=1.17, 95% CI 1.02 to 1.33), and fewer quit attempts (RR=0.72, 95% CI 0.61 to 0.85). Neighbourhood violence was not associated with successful quitting or relapse. Higher neighbourhood social cohesion was associated with more quit attempts and more successful quitting. Neighbourhood social cohesion modified the association between neighbourhood violence and smoking intensity: in neighbourhoods with higher social cohesion, as violence increased, smoking intensity decreased and in neighbourhoods with lower social cohesion, as violence increased, so did smoking intensity. CONCLUSIONS: In the context of recent increased violence in Mexico, smokers living in neighbourhoods with more violence may smoke more cigarettes per day and make fewer quit attempts than their counterparts in less violent neighbourhoods. Neighbourhood social cohesion may buffer the impact of violence on smoking intensity. PMID- 26043900 TI - Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C. AB - INTRODUCTION: The approval of sofosbuvir (SOF), a nucleotide analogue NS5B polymerase inhibitor, and ledipasvir (LDV), a NS5A inhibitor, marked a new chapter in IFN and ribavirin-free treatment of hepatitis C virus (HCV). This drug reduces adverse events associated with IFN therapy. AREAS COVERED: The purpose of this paper is to evaluate the safety and efficacy of LDV/SOF. Clinical trials illustrating safety and efficacy of LDV/SOF are reviewed and compared to other IFN and ribavirin-free treatment options available. EXPERT OPINION: In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug-drug interactions must be carefully evaluated, as demonstrated by recent post marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug-drug interactions. PMID- 26043901 TI - Protection of photoreceptors by intravitreal injection of the Y-27632 Rho associated protein kinase inhibitor in Royal College of Surgeons rats. AB - Retinitis pigmentosa (RP) is an inherited retinal disease, which is characteristic by degeneration of the rod and cone photoreceptors. The present study aimed to assess the protective effects on photoreceptors of intravitreal injection of Y-27632, a specific inhibitor of Rho-associated protein kinase (ROCK), in a Royal College of Surgeons (RCS) rat model. Different concentrations of Y-27632 (1-50 mM) were administered by intravitreal injection into the RCS rats. The effects of Y-27632 were recorded using electroretinography (ERG), measuring the thicknesses of the retinal outer nuclear layer (ONL) and examination of apoptotic markers using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and western blot analysis. Treatment of the eyes with Y27632 at 10 or 50 mM, led to a 30% increase in a- and b-wave amplitudes in ERG, and an increase in ONL thickness by 10%, compared with the 1 mM Y-27632-treated and vehicle (phosphate-buffered saline; PBS)-treated groups. In addition, eyes treated with 10 mM Y27632 exhibited a 90% decrease in TUNEL positive cells, accompanied by decreased protein expression levels of active caspase 3 and Bax by 50%, and a 90% increase in the ratio of Bcl-2/Bax, compared with the PBS-treated groups. These data suggested that Y-27632 protected retinal function by inhibiting the apoptosis of photoreceptor cells in the RCS rat model. The present study demonstrated for the first time, to the best of our knowledge, to report the use of Y-27632 for protection against RP in an RCS rat model. Y 27632 may be a potential candidate for the treatment of human RP. PMID- 26043902 TI - Epigenetically silenced microRNAs in gastric cancer: Functional analysis and identification of their target genes. AB - microRNAs (miRNAs), which are small non-coding RNA molecules, can participate in diverse biological functions and act as oncogenes or tumor suppressors by inhibiting target gene expression. The alteration of miRNA expression is observed in many types of human cancers and has been implicated in carcinogenesis. Since miRNAs have been known to be downregulated in most cancer types, there is growing evidence that several miRNAs are downregulated by DNA hypermethylation. Here, we determined that MIR219.2, MIR663b and MIR1237 were transcriptionally silenced by DNA hypermethylation in human gastric cancer cell lines. Moreover, we demonstrated the functional roles of these epigenetically silenced miRNAs by ectopically expressing them in gastric cancer cells, which caused the suppression of growth and proliferation. In addition, wound closure, cell migration, and invasion were significantly reduced in AGS cells following transfection with MIR219.2, MIR663b or MIR1237 mimics. Notably, epithelial-to-mesenchymal transition (EMT)-associated proteins were decreased in response to ectopic expression of these miRNAs, supporting the notion that these miRNAs have a tumor suppressive effect in gastric cancer. We finally predicted the targets of these miRNAs and identified several candidate genes, the expression levels of which were significantly downregulated by ectopic expression of MIR219.2, MIR663b or MIR1237 mimics in the gastric cancer cell lines. Our study provides strong evidence that these miRNAs are transcriptionally regulated by DNA methylation in gastric cancer and have tumor-suppressive roles by decreasing the mesenchymal traits in cancer as well as by targeting cancer-associated genes. PMID- 26043903 TI - Sequence-structure relationship study in all-alpha transmembrane proteins using an unsupervised learning approach. AB - Transmembrane proteins (TMPs) are major drug targets, but the knowledge of their precise topology structure remains highly limited compared with globular proteins. In spite of the difficulties in obtaining their structures, an important effort has been made these last years to increase their number from an experimental and computational point of view. In view of this emerging challenge, the development of computational methods to extract knowledge from these data is crucial for the better understanding of their functions and in improving the quality of structural models. Here, we revisit an efficient unsupervised learning procedure, called Hybrid Protein Model (HPM), which is applied to the analysis of transmembrane proteins belonging to the all-alpha structural class. HPM method is an original classification procedure that efficiently combines sequence and structure learning. The procedure was initially applied to the analysis of globular proteins. In the present case, HPM classifies a set of overlapping protein fragments, extracted from a non-redundant databank of TMP 3D structure. After fine-tuning of the learning parameters, the optimal classification results in 65 clusters. They represent at best similar relationships between sequence and local structure properties of TMPs. Interestingly, HPM distinguishes among the resulting clusters two helical regions with distinct hydrophobic patterns. This underlines the complexity of the topology of these proteins. The HPM classification enlightens unusual relationship between amino acids in TMP fragments, which can be useful to elaborate new amino acids substitution matrices. Finally, two challenging applications are described: the first one aims at annotating protein functions (channel or not), the second one intends to assess the quality of the structures (X-ray or models) via a new scoring function deduced from the HPM classification. PMID- 26043904 TI - Topical hemostatic powder promotes reepithelialization and reduces scar formation after extensive esophageal mucosal resection. AB - The development of techniques for endoscopic resection has provided new strategies for radical conservative treatment of superficial esophageal neoplasms, even those that are circumferential, such as Barrett's neoplasia. However, it is necessary to prevent the formation of scar tissue that can be responsible for esophageal strictures following circumferential resection. Preliminary data have suggested the possible efficacy of a hemostatic powder in the promotion of wound healing. The study aims to assess the effectiveness of Hemospray (Cook Medical) in a swine model of post-endoscopic esophageal stricture. Our prospective controlled study included 21 pigs. A 6-cm circumferential submucosal dissection of the esophagus (CESD) was performed in each pig. Group 1 (n = 11) only underwent CESD and Group 2 (n = 10) had repeated Hemospray applications after CESD. Clinical, endoscopic, and radiological monitoring were performed, blood levels of four inflammatory or pro-fibrotic cytokines were assessed, and histological analysis was performed. Median esophageal diameter was greater in the group treated with Hemospray (2 mm [1-3] vs. 3 mm [2-4], P = 0.01), and the rate of symptomatic esophageal stricture was 100% and 60% in Groups 1 and 2, respectively (P = 0.09). The thicknesses of esophageal fibrosis and inflammatory cell infiltrate were significantly lower in Group 2 than in Group 1 (P = 0.002 and 0.0003, respectively). The length of the neoepithelium was greater in Group 2 than in Group 1 (P = 0.0004). Transforming growth factor-beta levels were significantly lower in Group 2 than in Group 1 (P = 0.01). The application of Hemospray after esophageal CESD reduces scar tissue formation and promotes reepithelialization, and therefore is a promising therapeutic approach in the prevention of post-endoscopic esophageal stricture. PMID- 26043905 TI - Comparison of mammalian and bacterial expression library screening to detect recombinant alpha-1 proteinase inhibitor variants with enhanced thrombin inhibitory capacity. AB - Serpins are a widely distributed family of serine proteases. A key determinant of their specificity is the reactive centre loop (RCL), a surface motif of ~20 amino acids in length. Expression libraries of variant serpins could be rapidly probed with proteases to develop novel inhibitors if optimal systems were available. The serpin variant alpha-1 proteinase inhibitor M358R (API M358R) inhibits the coagulation protease thrombin, but at sub-maximal rates compared to other serpins. Here we compared two approaches to isolate functional API variants from serpin expression libraries, using the same small library of API randomized at residue 358 (M358X): flow cytometry of transfected HEK 293 cells expressing membrane-displayed API; and a thrombin capture assay (TCA) performed on pools of bacterial lysates expressing soluble API. No enrichment for specific P1 residues was observed when the RCL codons of the 1% of sorted transfected 293 cells with the highest fluorescent thrombin-binding signals were subcloned and sequenced. In contrast, screening of 16 pools of bacterial API-expressing transformants led to the facile identification of API M358R and M358K as functional variants. Kinetic characterization showed that API M358R inhibited thrombin 17-fold more rapidly than API M358K. Reducing the incubation time with immobilized thrombin improved the sensitivity of TCA to detect supra-active API M358R variants and was used to screen a hypervariable library of API variants expressing 16 different amino acids at residues 352-357. The most active variant isolated, with TLSATP substituted for FLEAI, inhibited thrombin 2.9-fold more rapidly than API M358R. Our results indicate that flow cytometric approaches used in protein engineering of antibodies are not appropriate for serpins, and highlight the utility of the optimized TCA for serpin protein engineering. PMID- 26043906 TI - Late-in-life childbearing (korei shussan) in contemporary Japan. AB - This paper draws on interviews with a group of 27 Japanese women who were classified as late-in-life-childbearing mothers, or korei shussan--women who had had their first delivery at 35 years of age or over. In making sense of the significance, symbolism and consequences of late-life motherhood, the paper utilises a symbolic interactionist perspective to shed light on the cultural, structural, interpersonal and intrapsychic dimensions underpinning the experiences of this group of mothers. The paper highlights the relevance of social interaction and everyday life that make pregnancy an 'obligation' for these women. Grounded in the Foucauldian notion of normalisation, the analysis suggests that the experience of late-in-life childbearing can be understood as the result of three forms of pressure: biological, homosocial and work. The late in-life-childbearing mother largely stems from governmental economic neoliberalism imbued with traditional conservatism and the pervasive influence of the Assisted Reproduction Treatments industry. PMID- 26043907 TI - Developing a hybrid dictionary-based bio-entity recognition technique. AB - BACKGROUND: Bio-entity extraction is a pivotal component for information extraction from biomedical literature. The dictionary-based bio-entity extraction is the first generation of Named Entity Recognition (NER) techniques. METHODS: This paper presents a hybrid dictionary-based bio-entity extraction technique. The approach expands the bio-entity dictionary by combining different data sources and improves the recall rate through the shortest path edit distance algorithm. In addition, the proposed technique adopts text mining techniques in the merging stage of similar entities such as Part of Speech (POS) expansion, stemming, and the exploitation of the contextual cues to further improve the performance. RESULTS: The experimental results show that the proposed technique achieves the best or at least equivalent performance among compared techniques, GENIA, MESH, UMLS, and combinations of these three resources in F-measure. CONCLUSIONS: The results imply that the performance of dictionary-based extraction techniques is largely influenced by information resources used to build the dictionary. In addition, the edit distance algorithm shows steady performance with three different dictionaries in precision whereas the context only technique achieves a high-end performance with three difference dictionaries in recall. PMID- 26043908 TI - Therapeutic hypothermia for acute brain injuries. AB - Therapeutic hypothermia, recently termed target temperature management (TTM), is the cornerstone of neuroprotective strategy. Dating to the pioneer works of Fay, nearly 75 years of basic and clinical evidence support its therapeutic value. Although hypothermia decreases the metabolic rate to restore the supply and demand of O2, it has other tissue-specific effects, such as decreasing excitotoxicity, limiting inflammation, preventing ATP depletion, reducing free radical production and also intracellular calcium overload to avoid apoptosis. Currently, mild hypothermia (33 degrees C) has become a standard in post resuscitative care and perinatal asphyxia. However, evidence indicates that hypothermia could be useful in neurologic injuries, such as stroke, subarachnoid hemorrhage and traumatic brain injury. In this review, we discuss the basic and clinical evidence supporting the use of TTM in critical care for acute brain injury that extends beyond care after cardiac arrest, such as for ischemic and hemorrhagic strokes, subarachnoid hemorrhage, and traumatic brain injury. We review the historical perspectives of TTM, provide an overview of the techniques and protocols and the pathophysiologic consequences of hypothermia. In addition, we include our experience of managing patients with acute brain injuries treated using endovascular hypothermia. PMID- 26043909 TI - A phase II trial of erlotinib monotherapy for pretreated elderly patients with advanced EGFR wild-type non-small cell lung cancer. AB - BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, which is an effective treatment for patients with non-small cell lung cancer (NSCLC), especially those harboring activating EGFR mutations. A previous phase III trial suggested that patients with EGFR wild-type (EGFR-wt) NSCLC or elderly patients with disease progression after cytotoxic chemotherapy might benefit from erlotinib monotherapy. However, few studies have prospectively evaluated the efficacy and safety of second- or third-line erlotinib monotherapy for elderly patients with EGFR-wt advanced or recurrent NSCLC. METHODS: Pretreated patients aged >=70 years with EGFR-wt stage IIIB/IV NSCLC or those with postoperative recurrence were enrolled and received oral erlotinib at a dose of 150 mg/day until disease progression. Primary outcome was the objective response rate (ORR). Secondary end points included the disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: This study was terminated early because of the results from a Japanese phase III trial (DELTA trial). Sixteen patients were enrolled between April 2010 and May 2013. The median age was 78 years (range 70-84 years). Six patients were female. Five patients had an Eastern Cooperative Oncology Group performance status of 0. Eleven (69%) patients had adenocarcinoma. Fifteen (94%) patients were treated with erlotinib as a second-line therapy. The ORR was 0% [95% confidence interval (CI) 0-17.1]. DCR was 56.3% (95% CI 33.2-76.9). The median PFS and OS were 1.7 months (95% CI 1.3-2.2) and 7.2 months (95% CI 5.6 8.7), respectively. The most commonly occurring adverse events included acneiform eruption (31.3%) and skin rash (25.0%). One patient developed grade 3 interstitial lung disease, which improved following steroid therapy. CONCLUSIONS: In pretreated elderly patients with advanced or recurrent EGFR-wt NSCLC, daily oral erlotinib was well tolerated; however, administration of the drug should not be considered as a second line therapy. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry UMIN000004561 (Date of registration: November 15th, 2010). PMID- 26043911 TI - An externally validated age-related model of mean follicle density in the cortex of the human ovary. AB - PURPOSE: The ability to accurately estimate a woman's ovarian reserve by non invasive means is the goal of ovarian reserve prediction. It is not known whether a correlation exists between model-predicted estimates of ovarian reserve and data generated by direct histological analysis of ovarian tissue. The aim of this study was to compare mean non-growing follicle density values obtained from analysis of ovarian cortical tissue samples against ovarian volume models. METHODS: Non-growing follicle density values were obtained from 13 ovarian cortical biopsies (16-37 years). A mean non-growing follicle density was calculated for each patient by counting all follicles in a given volume of biopsied ovarian cortex. These values were compared to age-matched model generated densities (adjusted to take into consideration the proportion of ovary that is cortex) and the correlation between data sets tested. RESULTS: Non growing density values obtained from fresh biopsied ovarian cortical samples closely matched model generated data with low mean difference, tight agreement limits and no proportional error between the observed and predicted results. CONCLUSION: These findings validate the use of the adjusted population and ovarian volume models, to accurately predict mean follicle density in the ovarian cortex of healthy adult women. PMID- 26043912 TI - Integrating a Web-Based Whole-Slide Imaging System and Online Questionnaires in a National Cytopathology Peer Comparison Educational Program in Taiwan. AB - OBJECTIVE: In a peer comparison educational program, transferring glass slides between laboratories and collecting responses are time- and cost-consuming. Integrating a web-based whole-slide imaging (WSI) system and online questionnaires may serve as a promising solution. STUDY DESIGN: Five gynecologic Papanicolaou-stained smears and 5 nongynecologic slides were selected. The 10 whole-slide images were acquired by a Leica SCN-400 system and released via an Aperio eSlide Manager. Online questionnaires generated by Google Forms with access to the 10 whole-slide images were released to all the practitioners in Taiwan by e-mail. After closing the program, an online posttest feedback survey was conducted. RESULTS: A total of 302 participants joined the gynecologic test, and 291 joined the nongynecologic test. The correct interpretation rates were 81.8-93.7% in the former and 28.5-93.1% in the latter. In the posttest feedback survey, there were 63.2% of the participants reporting first-time WSI experience, and 97.9% of them said they would like to participate in a similar program again. CONCLUSION: Integrating a web-based WSI system and online questionnaires is an easy method to access nationwide practitioners. Participants can make interpretations using WSI even without prior experience. The model is valuable for those who want to initiate a large-scale cytopathology peer comparison educational program. PMID- 26043913 TI - Low-Dose Intravaginal Estriol and Pelvic Floor Rehabilitation in Post-Menopausal Stress Urinary Incontinence. AB - INTRODUCTION: Pelvic floor muscle training (PFMT) and electrical stimulation (ES) are conservative models of therapy for treating female stress urinary incontinence (SUI). The presence of estradiol receptors in the lower urinary tract advances the case for estradiol therapy in SUI. The aim of our study was to investigate the effects of the combination of pelvic floor rehabilitation and intravaginal estriol (IE) on SUI treatment in postmenopausal women. MATERIAL AND METHODS: Sixty-two women with SUI were randomized to PFMT, ES and biofeedback (Group 1) or the same treatment plus 1 mg IE (Group 2) for 6 months. Patients were evaluated with medical history, pelvic examination, urodynamics, 24-hour pad test. Urinary incontinence was evaluated using the International Consultation on Incontinence questionnaire on urinary incontinence short form and quality of life using the Incontinence Impact Questionnaire-Short Form. RESULTS: Two patients were lost at follow-up and one discontinued the study. Mean urine leakage at the 24-hour pad test dropped from 42.3 +/- 20.2 g/die to 31.5 +/- 14.2 g/die in Group 1 and from 48.3 +/- 19.8 g/die to 22.3 +/- 10.1 g/die in Group 2. Symptoms scores and incontinence status were statistically significant better in Group 2 when compared to Group 1. CONCLUSION: IE added to PFMT, ES and BF is a safe and efficacious first-line therapy in postmenopausal women with SUI. PMID- 26043914 TI - Trace Element Concentrations in Human Tissues of Death Cases Associated With Secondary Infection and MOF After Severe Trauma. AB - Proper trace element level is crucial for the organs in maintaining normal physiological functions. Multiple organ failure (MOF) might be added to critically ill patients due to a lack of trace elements. Alterations of trace element levels in brain, heart, liver, and kidney after severe trauma, however, have been little studied so far. In this study, tissue samples of the frontal cortex of the brain, interventricular septum of the heart, right lobe of the liver, and upper pole of the kidney were obtained from forensic autopsies, of which 120 cases died during the 5th to 15th day of hospitalization, whereas the trauma death group and 43 cases immediately died due to severe craniocerebral trauma as the control group. Copper (Cu), iron (Fe), zinc (Zn), and selenium (Se) were quantified by inductively coupled plasma atomic emission spectrophotometry (ICP-AES). Cu, Fe, Zn, and Se concentrations in the brain, heart, liver, and kidney in the trauma group decreased dramatically (p<0.05) compared to the control group. The incidence of secondary infection and multiple organ failure (MOF) in the trauma death group were 78.33 and 29.17%, respectively. The concentrations of all elements exhibited a significant correlation with secondary infection and MOF (p<0.01). Our data suggest that low concentrations of Cu, Fe, Zn, and Se in pivotal organs may contribute to the incidence of secondary infection and MOF after severe trauma, which to some extent results in death. PMID- 26043915 TI - Activity of Selected Antioxidant Enzymes, Selenium Content and Fatty Acid Composition in the Liver of the Brown Hare (Lepus europaeus L.) in Relation to the Season of the Year. AB - The aim of the study was to evaluate the effect of low concentrations of selenium in the environment on the activity of selected antioxidant enzymes: Se-GSHPx, total GSHPx, SOD, CAT, and GST as well as fatty acid profile in the livers of brown hares during winter and spring. Liver tissues obtained from 20 brown hares collected in the north-eastern Poland in the winter and spring season were analyzed. In the tissue analyzed, a significantly lower level of selenium was noticeable in the spring compared to winter; however, values measured in both seasons indicated a deficiency of this element in the analyzed population of brown hares. There were no differences found that could indicate the influence of Se deficiency on the activity of antioxidant enzymes. The determined activity of antioxidant enzymes and fatty acid composition suggest a negligible impact of the low concentration of Se on the analyzed biochemical parameters of brown hare livers. PMID- 26043916 TI - Gestational form of Selenium in Free-Choice Mineral Mixes Affects Transcriptome Profiles of the Neonatal Calf Testis, Including those of Steroidogenic and Spermatogenic Pathways. AB - In areas where soils are deficient in Selenium (Se), dietary supplementation of this trace mineral directly to cattle is recommended. Because Se status affects testosterone synthesis and frequency of sperm abnormalities, and the form of Se supplemented to cows affects tissue-specific gene expression, the objective of this study was to determine whether the form of Se consumed by cows during gestation would affect the expression of mRNAs that regulate steroidogenesis and/or spermatogenesis in the neonatal calf testis. Twenty-four predominantly Angus cows were assigned randomly to have individual, ad libitum, access of a mineral mix containing 35 ppm of Se in free-choice vitamin-mineral mixes as either inorganic (ISe), organic (OSe), or a 50/50 mix of ISe and OSe (MIX), starting 4 months prior to breeding and continuing throughout gestation. Thirteen male calves were born over a 3-month period (ISe, n = 5; OSe, n = 4; MIX, n = 4), castrated within 2 days of birth, and extracted testis RNA subjected to transcriptomal analysis by microarray (Affymetrix Bovine 1.0 ST arrays) and targeted gene expression analysis by real-time reverse-transcription PCR (RT-PCR) of mRNAs encoding proteins known to affect steroidogenesis and/or spermatogenesis. The form of dam Se affected (P < 0.05) the expression of 853 annotated genes, including 17 mRNAs putatively regulating steroidogenesis and/or spermatogenesis. Targeted RT-PCR analysis indicated that the expression of mRNA encoding proteins CYP2S1 (cytochrome P450, family 2, subfamily S, polypeptide 1), HSD17B7 (hydroxysteroid (17beta) dehydrogenase 7), SULT1E1 (sulfotransferase family 1E, estrogen preferring, member 1), LDHA (lactate dehydrogenase A), CDK5R1 (cyclin-dependent kinase 5, regulatory subunit 1), and LEP (leptin) was affected (P < 0.05) by form of Se consumed by dams of developing bull calves, while AKR1C4 (aldo-keto reductase family 1, member C4) and CCND2 (cyclin D2) tended (P < 0.09) to be affected. Our results indicate that form of Se fed to dams during gestation affected the transcriptome of the neonatal calf testis. If these profiles are maintained throughout maturation, then the form of Se fed to dams may impact bull fertility and the development of Se form-dependent mineral mixes that target gestational development of the testis are warranted. PMID- 26043917 TI - Copper-Induced Inactivation of Camel Liver Glutathione S-Transferase. AB - Glutathione S-transferases (GSTs) are multifunctional enzymes and play an important role in detoxification of xenobiotics and protection against oxidative stress. Camel liver glutathione transferase (cGST) was recently isolated and characterized in our lab. In this study, we have evaluated the effect of monovalent, divalent, and trivalent cations on its activity and stability. Cu(++) was found to be the potent inhibitor of GST activity which loses complete activity at 0.5-mM concentration. Other metal ions did not inhibit GST even at higher concentration of 2 mM. GST incubated with Cu(++) (0.1 mM) resulted decrease in free sulfhydryl groups by 55%, whereas other metal ions did not show any effect on free thiol content. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed formation of GST aggregates instantly in the presence of Cu(++), which further increased in molecular size with increase in time of incubation. DTT treatment resulted in de-aggregation of GST oligomers to its monomeric form. However, the GST activity was not recovered completely after de-aggregation. Cu(++) was found to inhibit GST activity by accelerating the inter- and intra-disulfide bond formation. Far-UV circular dichroism (CD) results showed that Cu(++)-catalyzed air oxidation of sulfhydryl groups leads to minor conformational changes in the GST. PMID- 26043918 TI - Non-Celiac Gluten Sensitivity among Patients Perceiving Gluten-Related Symptoms. AB - BACKGROUND: Non-celiac gluten sensitivity (NCGS) is a recently recognized disorder, characterized by the occurrence of symptoms following gluten ingestion. It is often self-diagnosed by the patient, but should be confirmed by the response to a gluten-free diet, followed by a gluten challenge. Celiac disease (CD) and wheat allergy (WA) must first be ruled out. AIMS: (1) to determine the frequency of visits performed for symptoms self-perceived as gluten-related; (2) to assess in this cohort, the proportion of patients satisfying the diagnostic criteria for NCGS. METHODS: A two-year prospective study including all consecutive patients complaining of gluten-related symptoms. NCGS was diagnosed on the basis of the disappearance of the symptoms within 6 months of a gluten free diet, followed by their reappearance with the reintroduction of gluten in the diet for 1 month. RESULTS: Three hundred and ninety two patients complaining of gluten-related symptoms were enrolled; 26 of these (6.63%) were affected by CD, 2 (0.51%) by WA and 27 were diagnosed with NCGS (6.88%). The remaining 337 patients (85.96%) did not experience any change of symptoms with a gluten-free diet. The PPV of the gluten-related symptom was found to be 7%. CONCLUSION: Eighty six percent of patients reporting gluten-related symptoms have neither NCGS, nor CD, nor WA. Self-perceived gluten-related symptoms are rarely indicative of the presence of NCGS. PMID- 26043919 TI - GC-MS Method for the Quantitation of Carbohydrate Intermediates in Glycation Systems. AB - Glycation is a ubiquitous nonenzymatic reaction of carbonyl compounds with amino groups of peptides and proteins, resulting in the formation of advanced glycation end-products (AGEs) and thereby affecting the properties and quality of thermally processed foods. In this context, mechanisms of the Maillard reaction of proteins need to be understood; that is, glycation products and intermediates (alpha dicarbonyls and sugars) need to be characterized. Although the chemical analysis of proteins, peptides, and alpha-dicarbonyls is well established, sensitive and precise determination of multiple sugars in glycation mixtures is still challenging. This paper presents a gas chromatography-mass spectrometry (GC-MS) method for absolute quantitation of 22 carbohydrates in the model of phosphate buffered glycation systems. The approach relied on the removal of the phosphate component by polymer-based ion exchange solid phase extraction (SPE) followed by derivatization of carbohydrates and subsequent GC-MS analysis. Thereby, baseline separation for most of the analytes and detection limits of up to 10 fmol were achieved. The method was successfully applied to the analysis of in vitro glycation reactions. Thereby, at least seven sugar-related Maillard reaction intermediates could be identified and quantified. The most abundant reaction product was d-fructose, reaching 2.70 +/- 0.12 and 2.38 +/- 0.66 mmol/L after 120 min of incubation in the absence and presence of the model peptide, respectively. PMID- 26043920 TI - Network-based prediction and knowledge mining of disease genes. AB - BACKGROUND: In recent years, high-throughput protein interaction identification methods have generated a large amount of data. When combined with the results from other in vivo and in vitro experiments, a complex set of relationships between biological molecules emerges. The growing popularity of network analysis and data mining has allowed researchers to recognize indirect connections between these molecules. Due to the interdependent nature of network entities, evaluating proteins in this context can reveal relationships that may not otherwise be evident. METHODS: We examined the human protein interaction network as it relates to human illness using the Disease Ontology. After calculating several topological metrics, we trained an alternating decision tree (ADTree) classifier to identify disease-associated proteins. Using a bootstrapping method, we created a tree to highlight conserved characteristics shared by many of these proteins. Subsequently, we reviewed a set of non-disease-associated proteins that were misclassified by the algorithm with high confidence and searched for evidence of a disease relationship. RESULTS: Our classifier was able to predict disease related genes with 79% area under the receiver operating characteristic (ROC) curve (AUC), which indicates the tradeoff between sensitivity and specificity and is a good predictor of how a classifier will perform on future data sets. We found that a combination of several network characteristics including degree centrality, disease neighbor ratio, eccentricity, and neighborhood connectivity help to distinguish between disease- and non-disease-related proteins. Furthermore, the ADTree allowed us to understand which combinations of strongly predictive attributes contributed most to protein-disease classification. In our post-processing evaluation, we found several examples of potential novel disease related proteins and corresponding literature evidence. In addition, we showed that first- and second-order neighbors in the PPI network could be used to identify likely disease associations. CONCLUSIONS: We analyzed the human protein interaction network and its relationship to disease and found that both the number of interactions with other proteins and the disease relationship of neighboring proteins helped to determine whether a protein had a relationship to disease. Our classifier predicted many proteins with no annotated disease association to be disease-related, which indicated that these proteins have network characteristics that are similar to disease-related proteins and may therefore have disease associations not previously identified. By performing a post-processing step after the prediction, we were able to identify evidence in literature supporting this possibility. This method could provide a useful filter for experimentalists searching for new candidate protein targets for drug repositioning and could also be extended to include other network and data types in order to refine these predictions. PMID- 26043921 TI - Matrix metalloproteases as maestros for the dual role of LPS- and IL-10 stimulated macrophages in cancer cell behaviour. AB - BACKGROUND: The interactions established between macrophages and cancer cells are largely dependent on instructions from the tumour microenvironment. Macrophages may differentiate into populations with distinct inflammatory profiles, but knowledge on their role on cancer cell activities is still very scarce. In this work, we investigated the influence of pro-inflammatory (LPS-stimulated) and anti inflammatory (IL-10-stimulated) macrophages on gastric and colorectal cancer cell invasion, motility/migration, angiogenesis and proteolysis, and the associated molecular mechanisms. METHODS: Following exposure of gastric and colon cancer cell lines to LPS- and IL-10-stimulated human macrophages, either by indirect contact or conditioned media, we analyzed the effect of the different macrophage populations on cancer cell invasion, migration, motility and phosphorylation status of EGFR and several interacting partners. Cancer-cell induced angiogenesis upon the influence of conditioned media from both macrophage populations was assessed using the chick embryo chorioallantoic membrane assay. MMP activities were evaluated by gelatin zymograhy. RESULTS: Our results show that IL-10 stimulated macrophages are more efficient in promoting in vitro cancer cell invasion and migration. In addition, soluble factors produced by these macrophages enhanced in vivo cancer cell-induced angiogenesis, as opposed to their LPS-stimulated counterparts. We further demonstrate that differences in the ability of these macrophage populations to stimulate invasion or angiogenesis cannot be explained by the EGFR-mediated signalling, since both LPS- and IL-10 stimulated macrophages similarly induce the phosphorylation of cancer cell EGFR, c-Src, Akt, ERK1/2, and p38. Interestingly, both populations exert distinct proteolytic activities, being the IL-10-stimulated macrophages the most efficient in inducing matrix metalloprotease (MMP)-2 and MMP-9 activities. Using a broad spectrum MMP inhibitor, we demonstrated that proteolysis was essential for macrophage-mediated cancer cell invasion and angiogenesis. CONCLUSIONS: We propose that IL-10- and LPS-stimulated macrophages distinctly modulate gastric and colorectal cancer cell behaviour, as result of distinct proteolytic profiles that impact cell invasion and angiogenesis. PMID- 26043922 TI - The Ca(2+)-activated cation channel TRPM4 is a negative regulator of angiotensin II-induced cardiac hypertrophy. AB - Cardiac muscle adapts to hemodynamic stress by altering myocyte size and function, resulting in cardiac hypertrophy. Alteration in myocyte calcium homeostasis is known to be an initial signal in cardiac hypertrophy signaling. Transient receptor potential melastatin 4 protein (TRPM4) is a calcium-activated non-selective cation channel, which plays a role in regulating calcium influx and calcium-dependent cell functions in many cell types including cardiomyocytes. Selective deletion of TRPM4 from the heart muscle in mice resulted in an increased hypertrophic growth after chronic angiotensin (AngII) treatment, compared to WT mice. The enhanced hypertrophic response was also traceable by the increased expression of hypertrophy-related genes like Rcan1, ANP, and alpha Actin. Intracellular calcium measurements on isolated ventricular myocytes showed significantly increased store-operated calcium entry upon AngII treatment in myocytes lacking the TRPM4 channel. Elevated intracellular calcium is a key factor in the development of pathological cardiac hypertrophy, leading to the activation of intracellular signaling pathways. In agreement with this, we observed significantly higher Rcan1 mRNA level, calcineurin enzyme activity and protein level in lysates from TRPM4-deficient mice heart compared to WT after AngII treatment. Collectively, these observations are consistent with a model in which TRPM4 is a regulator of calcium homeostasis in cardiomyocytes after AngII stimulation. TRPM4 contributes to the regulation of driving force for store operated calcium entry and thereby the activation of the calcineurin-NFAT pathway and the development of pathological hypertrophy. PMID- 26043923 TI - How can we improve the recognition, reporting and resolution of medical device related incidents in hospitals? A qualitative study of physicians and registered nurses. AB - BACKGROUND: To explore factors that influence and to identify initiatives to improve the recognition, reporting and resolution of device-related incidents. METHODS: Semi-structured telephone interviews with 16 health professionals in two tertiary care hospitals were conducted. Purposive sampling was used to identify appropriate study participants. Transcribed interviews were read independently by one individual to identify, define and organize themes and verified by another reviewer. RESULTS: Themes related to incident recognition were the hospital staff's knowledge and professional experience, medical device performance and clinical manifestations of patients, while incident reporting was influenced by error severity, personal attitudes of clinicians, feedback received on the error reported. Physicians often discontinued using medical devices if they malfunctioned. Education and training and the implementation of registries were discussed as important initiatives to improve medical device surveillance in clinical practice. CONCLUSIONS: Results from the telephone interviews suggest that multiple factors that influence participation in medical device surveillance activities are consistent with results for medical errors as reported in previous studies. The study results helped to propose a conceptual framework for a medical device surveillance system in a hospital context that would enhance patient safety and health care delivery. PMID- 26043924 TI - Simulation of cardiac emergencies with real patients. AB - BACKGROUND: Simulation training with manikin simulators for medical emergencies is increasingly used in medical training. The assessment of a manikin, in particular history and examination, is very different to that of a real patient. We sought to combine aspects of traditional simulation training with the assessment of real hospital in-patients. STUDY DESIGN: In-patients who had recently experienced a cardiac emergency were asked to recall their symptoms as if they were still present. Medical students assessed these patients in the role of foundation year-1 (FY1) doctors, supervised by core medical trainee (CMT) doctors, and were encouraged to formulate a differential diagnosis and initial management plan. The students filled in a questionnaire prior to, immediately after and 1 week after each simulation session. This included a self-assessment of confidence in managing cardiac emergencies, as well as knowledge-based questions on aspects of assessment and management of cardiac emergencies. We sought to combine aspects of traditional simulation training with the assessment of real hospital in-patients RESULTS: Confidence in managing cardiac emergencies was initially low, but significantly increased after one simulation training session (p < 0.001). This increase was sustained on re-assessment 1 week after the training session (p < 0.001). In addition to the increase in confidence, a significant and sustained increase in knowledge score was also observed (p < 0.001). CONCLUSION: Simulation training with real patients led to an immediate and sustained increase in self-assessed confidence. There was also an increase in medical knowledge of the assessment and management of cardiac emergencies. This simulation technique is inexpensive, easily reproducible and can be used to complement learning from traditional simulation training with manikins. PMID- 26043925 TI - Giant intracardiac blood cyst: assessing the relationship between its formation and previous cardiac surgery. AB - This case report discusses a 23-year-old male patient who presented with shortness of breath during exercise. Echocardiography revealed an intracardiac mass located on the mitral valve. His medical history included surgical closure of an atrial septal defect type 2 at the age of 2 years. After being discussed within a multidisciplinary heart team, the intracardiac mass was surgically removed. Histopathological examination revealed a blood cyst. This case report emphasises that the presence of an acquired intracardiac cyst is a rare entity and that a pathophysiological association between the formation of a blood cyst and previous cardiac surgery has not been proven yet. PMID- 26043926 TI - Myocardial infarction, atrial fibrillation and mortality: timing is everything. PMID- 26043927 TI - Non-intubated recovery from refractory cardiogenic shock on percutaneous VA extracorporeal membrane oxygenation. AB - We report on the use of percutaneous femoral veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in a fully awake, non-intubated and spontaneously breathing patient suffering from acute, severe and refractory cardiogenic shock due to a (sub)acute anterior myocardial infarction. Intensified heart failure therapy was closely monitored with a pulmonary artery catheter and allowed gradual weaning off the ECMO support without additional invasive measures, notably without mechanical ventilation. Neurological assessment was possible at all times and complete physical mobilisation was straightforward directly after weaning from ECMO. This limited invasive approach may encourage a more widespread use of percutaneous VA-ECMO. PMID- 26043928 TI - A Study on the Specifications of Cold Pressed Colza Oil. AB - Cold pressed oil extraction is the preferred method for seeds with high contents of oil, such as colza. Generally speaking, expeller pressing is less complex, more cost efficient and safer than solvent extraction. Moreover, cold pressed oils retain their natural properties better. Cold pressed colza oil has been found to have numerous health benefits. This was an original and unique study conducted as part of the research for the international Codex standard for cold pressed fats and oils, and aims to examine the chemical properties of two varieties of Iranian colza seed, Hyola and Okapi. The studied factors included (a) chemical properties, and (b) physicochemical and quality characteristics. Based on our findings, both varieties of colza seeds in this study had satisfactory levels of oleic and linoleic acid, and no trans-fatty acids. Although both samples had good nutritional properties, the Hyola variety was higher in oleic acid, indicating better oxidative stability. Due to the considerable amounts of beta-sitosterol in both varieties, they may be effective in reducing cholesterol and preventing cancer. PMID- 26043929 TI - Multiple Sclerosis Presenting as a Delirium: A Case Report. AB - OBJECTIVE: To report a case of multiple sclerosis (MS) with delirium as the first presentation. CLINICAL PRESENTATION AND INTERVENTION: A 34-year-old female was referred to our department with an acute onset of drowsiness, withdrawal from routine activities and aggression, followed by neurologic deficits after a couple of days. Clinical and radiographic examinations were performed, leading to the initial diagnosis of MS. A vast range of differential diagnoses was excluded to confirm the diagnosis of MS. CONCLUSION: Neurological examination and appropriate imaging enabled the diagnosis of MS with delirium in this patient followed by the appropriate treatment. PMID- 26043930 TI - Authors' Response. PMID- 26043931 TI - Plasmon coupling in vertical split-ring resonator metamolecules. AB - The past decade has seen a number of interesting designs proposed and implemented to generate artificial magnetism at optical frequencies using plasmonic metamaterials, but owing to the planar configurations of typically fabricated metamolecules that make up the metamaterials, the magnetic response is mainly driven by the electric field of the incident electromagnetic wave. We recently fabricated vertical split-ring resonators (VSRRs) which behave as magnetic metamolecules sensitive to both incident electric and magnetic fields with stronger induced magnetic dipole moment upon excitation in comparison to planar SRRs. The fabrication technique enabled us to study the plasmon coupling between VSRRs that stand up side by side where the coupling strength can be precisely controlled by varying the gap in between. The resulting wide tuning range of these resonance modes offers the possibility of developing frequency selective functional devices such as sensors and filters based on plasmon coupling with high sensitivity. PMID- 26043932 TI - Development of a risk prediction model for incident hypertension in a working-age Japanese male population. PMID- 26043933 TI - Mapping the Interactions of I2 , I(.) , I(-) , and I(+) with Alkynes and Their Roles in Iodocyclizations. AB - A combination of experiment and theory has been used to explore the mechanisms by which molecular iodine (I2 ) and iodonium ions (I(+) ) activate alkynes towards iodocyclization. Also included in the analysis are the roles of atomic iodine (I(.) ) and iodide ion (I(-) ) in mediating the competing addition of I2 to the alkyne. These studies show that I2 forms a bridged I2 -alkyne complex, in which both alkyne carbons are activated towards nucleophilic attack, even for quite polarized alkynes. By contrast, I(+) gives unsymmetrical, open iodovinyl cations, in which only one carbon is activated toward nucleophilic attack, especially for polarized alkynes. Addition of I2 to alkynes competes with iodocyclization, but is reversible. This fact, together with the capacity of I2 to activate both alkyne carbons towards nucleophilic attack, makes I2 the reagent of choice (superior to iodonium reagents) for iodocyclizations of resistant substrates. The differences in the nature of the activated intermediate formed with I2 versus I(+) can also be exploited to accomplish reagent-controlled 5-exo/6-endo divergent iodocyclizations. PMID- 26043934 TI - Antifibrotic effect of rapamycin containing polyethylene glycol-coated alginate microcapsule in islet xenotransplantation. AB - Islet microencapsulation is an attractive strategy for the minimization or avoidance of life-long immunosuppression after transplantation. However, the clinical implementation of this technique is currently limited by incomplete biocompatibility. Thus, the aim of the present study was to demonstrate the improved biocompatibility of rapamycin-containing polyethylene glycol (Rapa-PEG) coating on alginate microcapsules containing xenogeneic islets. The Rapa-PEG coating on the alginate layer was observed using scanning electron microscopy (SEM) and the molecular cut-off weight of the microcapsules was approximately 70 kDa. The viabilities of the alginate-encapsulated and Rapa-PEG-coated alginate encapsulated islets were lower than the viability of the naked islets just after encapsulation, but these the differences diminished over time in culture dishes. Rapa-PEG-coating on the alginate capsules effectively decreased the proliferation of macrophage cells compared to the non-coating and alginate coating of xenogeneic pancreas tissues. Glucose-stimulated insulin secretion did not significantly differ among the groups prior to transplantation. The random blood glucose levels of diabetic mice significantly improved following the transplantation of alginate-encapsulated and Rapa-PEG-coated alginate encapsulated islets, but there were no significant differences between these two groups. However, there was a significant decrease in the number of microcapsules with fibrotic cell infiltration in the Rapa-PEG-coated alginate microcapsule group compared to the alginate microcapsule group. In conclusion, Rapa-PEG coating might be an effective technique with which to improve the biocompatibility of microcapsules containing xenogeneic islets. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26043935 TI - A new approach to prevent contralateral hip fracture: Evaluation of the effectiveness of a fracture preventing implant. AB - BACKGROUND: Among the millions of people suffering from a hip fracture each year, 20% may sustain a contralateral hip fracture within 5 years with an associated mortality risk increase reaching 64% in the 5 following years. In this context, we performed a biomechanical study to assess the performance of a hip fracture preventing implant. METHODS: The implant consists of two interlocking peek rods unified with surgical cement. Numerical and biomechanical tests were performed to simulate single stance load or lateral fall. Seven pairs of femurs were selected from elderly subjects suffering from osteoporosis or osteopenia, and tested ex vivo after implantation of the device on one side. FINDINGS: The best position for the implant was identified by numerical simulations. The loadings until failure showed that the insertion of the implant increased significantly (P<0.05) both fracture load (+18%) and energy to fracture (+32%) of the implanted femurs in comparison with the intraindividual controls. The instrumented femur resisted the implementation of the non-instrumented femur fracture load for 30 cycles and kept its performance at the end of the cyclic loading. INTERPRETATION: Implantation of the fracture preventing device improved both fracture load and energy to fracture when compared with intraindividual controls. This is consistent with previous biomechanical side-impact testing on pairs of femur using the same methodology. Implant insertion seems to be relevant to support multiple falls and thus, to prevent a second hip fracture in elderly patients. PMID- 26043936 TI - Biomechanical study of unilateral pedicle screw combined with contralateral translaminar facet screw in transforaminal lumbar interbody fusion. AB - BACKGROUND: The biomechanical stability of unilateral pedicle screw (UPS) combined with contralateral translaminar facet screw (TLFS), especially long-term stability, still needs to be compared to traditional UPS or bilateral pedicle screws (BPSs) in details. METHODS: Twenty-four porcine spines (L2-L5) were tested for flexibility with pure moments of 5Nm under intact status and transforaminal lumbar interbody fusion status using UPS+TLFS, UPS or BPS at L3-L4. After short term (3cycles) and long-term cyclic loading (18,000cycles), the range of motion was obtained and analyzed for single-level constructs in flexion/extension, lateral bending and axial rotation modes. In addition, the relative displacement of contralateral articular processes was recorded in a real time fashion. FINDINGS: The range of motion was significantly reduced in all instrumented constructs. In all movement directions, UPS+TLFS achieved similar range of motion to BPS after short and long-term loading, which were significantly lower than that in UPS. A significantly larger displacement of contralateral articular process was recorded in UPS than UPS+TLFS and BPS during extension/flexion, lateral bending and axial rotation, suggesting its compromised stability. INTERPRETATION: The hybrid construct of UPS+TLFS showed instant and long-term equivalent biomechanical ability to that of traditional BPS, making it an alternative option to BPS that could be less invasive while maintains a stable and effective instrumentation. PMID- 26043937 TI - Novel grafted agar disks for the covalent immobilization of beta-D-galactosidase. AB - Novel grafted agar disks were prepared for the covalent immobilization of beta-D galactosidase (beta-gal). The agar disks were activated through reacting with ethylenediamine or different molecular weights of Polyethyleneimine (PEI), followed by glutaraldehyde (GA). The modification of the agar gel and the binding of the enzyme were verified by Fourier Transform Infrared (FTIR) and elemental analysis. Moreover, the agar's activation process was optimized, and the amount of immobilized enzyme increased 3.44 folds, from 38.1 to 131.2 U/g gel, during the course of the optimization process. The immobilization of beta-gal onto the activated agar disks caused its optimum temperature to increase from 45 degrees C to 45-55 degrees C. The optimum pH of the enzyme was also shifted towards the acidic side (3.6-4.6) after its immobilization. Additionally, the Michaelis Menten constant (Km ) increased for the immobilized beta-gal as compared to its free counterpart whereas the maximum reaction rate (Vmax ) decreased. The immobilized enzyme was also shown to retain 92.99% of its initial activity after being used for 15 consecutive times. PMID- 26043940 TI - Placement of an eyelid weight as an upper lid spacer for lagophthalmos. PMID- 26043938 TI - Thalidomide-induced teratogenesis: history and mechanisms. AB - Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man-made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. PMID- 26043939 TI - Longitudinal reproducibility of automatically segmented hippocampal subfields: A multisite European 3T study on healthy elderly. AB - Recently, there has been an increased interest in the use of automatically segmented subfields of the human hippocampal formation derived from magnetic resonance imaging (MRI). However, little is known about the test-retest reproducibility of such measures, particularly in the context of multisite studies. Here, we report the reproducibility of automated Freesurfer hippocampal subfields segmentations in 65 healthy elderly enrolled in a consortium of 13 3T MRI sites (five subjects per site). Participants were scanned in two sessions (test and retest) at least one week apart. Each session included two anatomical 3D T1 MRI acquisitions harmonized in the consortium. We evaluated the test-retest reproducibility of subfields segmentation (i) to assess the effects of averaging two within-session T1 images and (ii) to compare subfields with whole hippocampus volume and spatial reliability. We found that within-session averaging of two T1 images significantly improved the reproducibility of all hippocampal subfields but not that of the whole hippocampus. Volumetric and spatial reproducibility across MRI sites were very good for the whole hippocampus, CA2-3, CA4-dentate gyrus (DG), subiculum (reproducibility error~2% and DICE > 0.90), good for CA1 and presubiculum (reproducibility error ~ 5% and DICE ~ 0.90), and poorer for fimbria and hippocampal fissure (reproducibility error ~ 15% and DICE < 0.80). Spearman's correlations confirmed that test-retest reproducibility improved with volume size. Despite considerable differences of MRI scanner configurations, we found consistent hippocampal subfields volumes estimation. CA2-3, CA4-DG, and sub CA1 (subiculum, presubiculum, and CA1 pooled together) gave test-retest reproducibility similar to the whole hippocampus. Our findings suggest that the larger hippocampal subfields volume may be reliable longitudinal markers in multisite studies. PMID- 26043941 TI - Systematic review: Body composition in children with inflammatory bowel disease. AB - BACKGROUND: Paediatric inflammatory bowel disease (IBD) is associated with weight loss, growth restriction and malnutrition. Bone mass deficits are well described, little is known about other body composition compartments. AIMS: To define the alterations in non-bone tissue compartments in children with IBD, and explore the effects of demographic and disease parameters. METHODS: A systematic search was carried out in the PubMed (www.ncbi.nlm.nih.gov/pubmed) and Web of Science databases in May 2014 (limitations age <17 years, and composition measurements compared with a defined control population). RESULTS: Twenty-one studies were included in this systematic review, reporting on a total of 1479 children with IBD [1123 Crohn's disease, 243 ulcerative colitis], pooled mean age 13.1 +/- 3.2 years, and 34.9% female. Data were highly heterogeneous, in terms of methodology and patients. Deficits in protein-related compartments were reported. Lean mass deficits were documented in 93.6% of Crohn's disease and 47.7% of ulcerative colitis patients when compared with healthy control populations. Lower lean mass was common to both sexes in Crohn's disease and ulcerative colitis, deficits in females with persisted for longer. Fat-related compartment findings were inconsistent, some studies report reductions in body fat in new diagnosis/active Crohn's disease. CONCLUSIONS: It is clear that almost all children with Crohn's disease and half with ulcerative colitis have reduced lean mass, however, body fat alterations are not well defined. To understand what impact this may have on health and disease in children with IBD, further studies are needed to identify in which tissues these deficits lie, and to quantify body fat and its distribution. PMID- 26043944 TI - Long-Term Outcomes of Surgical Management of Pancreatic Neuroendocrine Tumors with Synchronous Liver Metastases. AB - BACKGROUND: The value of surgical resection in the management of pancreatic neuroendocrine tumors (PNET) with liver metastases (LM) is still debated. The aim of this study was to evaluate the outcomes of surgery of PNET with LM. METHODS: Patients with PNET with synchronous LM between 2000 and 2011 from 4 high-volume institutions were included. The patients were divided into 3 groups: curative resection, palliative resection, and no resection. RESULTS: Overall, 166 patients were included. Eighteen patients (11%) underwent curative resection, 73 patients (43%) underwent palliative resection, and 75 patients (46%) underwent conservative treatment. The median overall survival (OS) from the time of diagnosis was 73 months. Patients who underwent curative resection had a significantly better median OS from the initial diagnosis compared with those who underwent palliative resection and those who were conservatively treated (97 vs. 89 vs. 36 months, p = 0.0001). The median OS from the time of diagnosis in those patients who underwent radical or palliative resection was 97 months, with a 5 year survival rate of 76%. On multivariate analysis, factors associated with OS from the time of diagnosis were the presence of bilobar metastases, tumor grading, and curative resection in a first model. On a second model, curative or palliative surgery was an independent predictor of OS. Among 91 patients who underwent surgery, the presence of pancreatic neuroendocrine carcinoma G3 was the only factor independently associated with a poorer survival after surgery (median OS: 35 vs. 97 months, p < 0.0001). CONCLUSIONS: Patients with LM from PNET benefit from surgical resection, although surgery should be reserved to well- or moderately differentiated forms. PMID- 26043945 TI - Room temperature direct imprinting of porous glass prepared from phase-separated glass. AB - This work describes a room-temperature imprinting of nanoporous glass prepared by selective chemical etching of phase-separated glass. A highly porous (58%) and highly transparent (>90%) porous glass layer can be formed on a transparent phase separated glass substrate. It is shown that the lateral resolution of the imprinting is a few tens of nanometers. As the porosity increases, the imprint depth increases and reaches up to 90% of the height of the mold pattern. The porous glass has a wider transmittance window (300-2700 nm) and a higher thermal durability (~500 degrees C) than other materials used for imprinting. The technique has various potential applications such as diffraction optical elements, waveguides, biosensors, and microfluidic devices. PMID- 26043943 TI - Capsid, membrane and NS3 are the major viral proteins involved in autophagy induced by Japanese encephalitis virus. AB - Japanese encephalitis virus (JEV) is an important zoonotic pathogen causing viral encephalitis in human and reproductive failure in pigs. In the present study, we first examined the autophagy induced by JEV infection in host cells, and then analyzed the JEV proteins involving in autophagy induction, and further investigated the relationship between viral protein and immunity-related GTPases M (IRGM). Our results showed that JEV infection could induce autophagy in host cells and autophagy promoted the replication of JEV in vitro; the cells transfected with individual plasmid that was expressing C, M and NS3 had a significantly higher conversion of LC3-I/II, and enhanced LC3 signals with the fluorescence punctuates accumulation which was completely co-localized with LC3 and increased number of autophagosomes-like vesicles, suggesting that C, M and NS3 are the major viral proteins involving in autophagy induction upon JEV infection; the virus titer in the cells treated by the siRNA specific for IRGM had a significant decrease, and the NS3 signals in the cells transfected with the plasmid that was expressing NS3 were completely co-localized with the IRGM signals, suggesting that the NS3 of JEV could target IRGM which may play a role in the replication of JEV. Our findings help to understand the role of autophagy in JEV and other flaviviruses infections. PMID- 26043942 TI - Disruption in the autophagic process underlies the sensory neuropathy in dystonia musculorum mice. AB - A homozygous mutation in the DST (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in dystonia musculorum (Dst(dt)) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the Dst(dt-Tg4) mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3 II, a marker of autophagosomes, were elevated. Consequently, Dst(dt-Tg4) sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described Dst(dt-Tg4) mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to Dst(dt-Tg4) mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in Dst(dt-Tg4) dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies Dst(dt) pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis. PMID- 26043946 TI - PABA/NO lead optimization: Improved targeting of cytotoxicity to glutathione S transferase P1-overexpressing cancer cells. AB - PABA/NO [O(2)-{2,4-dinitro-5-[4-(N-methylamino)benzoyloxy]phenyl} 1-(N,N dimethylamino) diazen-1-ium-1,2-diolate] is a nitric oxide (NO)-releasing arylating agent designed to be selectively activated by reaction with glutathione (GSH) on catalysis by glutathione S-transferase P1 (GSTP1), an enzyme frequently overexpressed in cancer cells. PABA/NO has proven active in several cancer models in vitro and in vivo, but its tendency to be metabolized via a variety of pathways, some that generate inactive metabolites and hydrolysis products, limits its potential as a drug. Here we show that a simple replacement of cyano for nitro at the 4 position to give compound 4b ('p-cyano-PABA/NO') has the dual effect of slowing the undesired side reactions while enhancing the proportion of NO release and arylating activity on catalysis by GSTP1. Compound 4b showed increased resistance to hydrolysis and uncatalyzed reaction with GSH, along with a more favorable product distribution in the presence of GSTP1. It also showed significant proapoptotic activity. The data suggest p-cyano-PABA/NO to be a more promising prodrug than PABA/NO, with better selectivity toward cancer cells. PMID- 26043947 TI - Double Sonogashira reactions on dihalogenated aminopyridines for the assembly of an array of 7-azaindoles bearing triazole and quinoxaline substituents at C-5: Inhibitory bioactivity against Giardia duodenalis trophozoites. AB - The synthesis of 2,3,5-trisubstituted 7-azaindoles as well as 2,5-disubstituted 7 azaindoles from 3,5-dihalogenated 2-aminopyridines is outlined. Using a double Sonogashira coupling reaction on 2-amino-3,5-diiodopyridine followed by the Cacchi reaction the synthesis of 2,3,5-trisubstituted 7-azaindoles was accomplished. In addition, using two sequential Sonogashira coupling reactions on 2-amino-5-bromo-3-iodopyridine and a potassium t-butoxide mediated ring closure reaction resulted in the assembly of 2,5-disubstituted 7-azaindoles. The 5 alkynyl substituent of the azaindole was easily converted into both quinoxaline and triazole substituents, the latter utilizing an alkyne-azide cycloaddition reaction. Some of these azaindole derivatives showed very promising biological activity against the gastrointestinal protozoal parasite Giardia duodenalis. PMID- 26043949 TI - Is There a New Era for Stroke Therapy? PMID- 26043948 TI - Synthesis and in vitro kinetic evaluation of N-thiazolylacetamido monoquaternary pyridinium oximes as reactivators of sarin, O-ethylsarin and VX inhibited human acetylcholinesterase (hAChE). AB - Presently available medications for treatment of organiphosphorus poisoning are not sufficiently effective due to various pharmacological and toxicological reasons. In this regard, herein we report the synthesis of a series of N thiazolylacetamide monoquaternary pyridinium oximes and its analogs (1a-1b to 6a 6b) with diversely substituted thiazole ring and evaluation of their in vitro reactivation efficacies against nerve agent (sarin, O-ethylsarin and VX) inhibited human erythrocyte acetylcholinesterase (hAChE). Reactivation kinetics was performed to determine dissociation constant (KD), reactivity rate constant (kr) and the second order rate constant (kr2) for all the compounds and compared their efficacies with commercial antidotes viz. 2-PAM and obidoxime. All the newly synthesized oximes were evaluated for their physicochemical parameters (pKa) and correlated with their respective reactivation efficacies to assess the capability of the oxime reactivator. Three of these novel compounds showed promising reactivation efficacies toward OP inhibited hAChE. Molecular docking studies were performed in order to correlate the reactivation efficacies with their interactions in the active site of the AChE. PMID- 26043951 TI - [Urine microbiota and urinary tract symptoms]. PMID- 26043950 TI - [Prostate cancer incidence and mortality trends in France from 1980 to 2011]. AB - The prostate cancer became for two decades the most frequent cancer in men. We describe the evolution of its incidence and mortality from 1980 to 2011 for France. METHODS: Incidence data were collected from registries and national incidence estimates were based on the use of mortality as a correlate of incidence. RESULTS: After a very strong increase of incidence between 1980 (24.8/100,000) and 2005 (124.5/100,000), we observe a net decline since (97.7/100,000, in 2011). The reduction began earlier for the old patients. The evolution of mortality is very different. We observe a regular reduction since the end of 1990s (from 18.0/100,000 in 1990 to 10.5/100,000 in 2011). The reduction began earlier for the young patients. CONCLUSION: This pattern of evolution is observed in all the countries where the use of the PSA had caused an important increase of the diagnosis of prostate cancer. LEVEL OF EVIDENCE: 3. PMID- 26043952 TI - Familial Hypercholesterolemia and the 2013 American College of Cardiology/American Heart Association Guidelines: Myths, Oversimplification, and Misinterpretation Versus Facts. AB - Familial hypercholesterolemia (FH) is a genetic condition resulting in severe, lifelong elevations in low-density lipoprotein cholesterol and a marked increased risk of early-onset coronary disease. FH is treatable when identified, yet is vastly under-recognized and undertreated. Although the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of cholesterol presented a paradigm shift, we believe that there have been serious oversimplifications, misinterpretations, and erroneous reporting about the current ACC/AHA cholesterol guidelines that have contributed to suboptimal care for these subjects. In summary, the ACC/AHA guidelines place tremendous emphasis on the identification of patients with FH, the initiation of high-intensity statin therapy, the need to obtain follow-up lipid values to assess the efficacy and compliance to lifestyle and medical therapy, and the role of nonstatin drugs when needed for optimal care of the individual patient. PMID- 26043953 TI - Enhanced short-term sensitization of facial compared with limb heat pain. AB - Habituation and sensitization are important features of individual sensitivity to repetitive noxious stimulation and have been investigated in numerous studies. However, it is unclear whether these phenomena vary depending on the site of stimulation. Here we compared short-term and long-term effects of painful heat stimulation on the forehead and limb using an established longitudinal heat pain paradigm performed over 8 consecutive days in 36 healthy volunteers. Participants were randomized into 2 groups; participants received repetitive heat pain stimulation either on the left volar forearm or on the left side of the forehead. Our data show a comparable degree of habituation over the course of 8 days in both groups. However, participants in the trigeminal stimulation group exhibited stronger within-session sensitization (indexed by a higher within-session increase in pain intensity ratings) than those who received the forearm stimulation. Furthermore, over the course of the experiment we found a correlation between habituation and anxiety, showing less habituation in participants with higher trait anxiety scores. Our findings are in line with somatotopic differences in response to painful stimulation and a higher proneness of trigeminal pain to sensitization processes, which might be explained by the biological relevance of the head and facial area for vital functions. The contribution of this sensitivity to the development and maintenance of clinical facial pain and headache disorders warrants further investigation. PERSPECTIVE: This study uses psychophysical methods to evaluate the differences in long-term habituation and short-term sensitization to heat pain between the trigeminal and spinal systems. We found stronger sensitization for trigeminal compared with nociceptive stimuli on the forearm. The contribution of this sensitivity to clinical pain states warrants further investigation. PMID- 26043954 TI - Lupus around the world. PMID- 26043955 TI - Haemostatic function and biomarkers of endothelial damage before and after platelet transfusion in patients with acute myeloid leukaemia. AB - OBJECTIVES: The beneficial effect of platelet transfusion on haemostasis is well established, but there is emerging evidence that platelet transfusion induces an inflammatory response in vascular endothelial cells. BACKGROUND: We investigated haemostatic function and endothelial biomarkers before and after platelet transfusion in patients with acute myeloid leukaemia. MATERIALS AND METHODS: Blood was sampled before, 1 and 24 h after platelet transfusion. Primary and secondary haemostasis was evaluated by whole blood aggregometry (Multiplate) and thromboelastography (TEG). Endothelial biomarkers (sICAM-1, syndecan-1, sThrombomodulin, sVE-Cadherin) and platelet activation biomarkers (sCD40L, TGF beta) were investigated along with haematology/biochemistry analyses. RESULTS: Twenty-two patients were included. Despite continued low platelet counts, platelet transfusion normalised the median values of most TEG parameters and slightly increased platelet aggregation (all P < 0.05). Endothelial biomarkers were not significantly affected by transfusion. The 1 h sCD40L level correlated positively with Syndecan-1 and soluble thrombomodulin delta values, biomarkers of endothelial damage (both P = 0.005). CONCLUSION: Platelet transfusion improved haemostasis, whereas post-transfusion increases in sCD40L were associated with endothelial damage, indicating that transfused platelets and platelet-derived pro inflammatory mediators may have opposite effects on the endothelium. PMID- 26043956 TI - Prediction of vehicle crashes by drivers' characteristics and past traffic violations in Korea using a zero-inflated negative binomial model. AB - AIMS: Traffic safety is a significant public health challenge, and vehicle crashes account for the majority of injuries. This study aims to identify whether drivers' characteristics and past traffic violations may predict vehicle crashes in Korea. METHODS: A total of 500,000 drivers were randomly selected from the 11.6 million driver records of the Ministry of Land, Transport and Maritime Affairs in Korea. Records of traffic crashes were obtained from the archives of the Korea Insurance Development Institute. After matching the past violation history for the period 2004-2005 with the number of crashes in year 2006, a total of 488,139 observations were used for the analysis. Zero-inflated negative binomial model was used to determine the incident risk ratio (IRR) of vehicle crashes by past violations of individual drivers. The included covariates were driver's age, gender, district of residence, vehicle choice, and driving experience. RESULTS: Drivers violating (1) a hit-and-run or drunk driving regulation at least once and (2) a signal, central line, or speed regulation more than once had a higher risk of a vehicle crash with respective IRRs of 1.06 and 1.15. Furthermore, female gender, a younger age, fewer years of driving experience, and middle-sized vehicles were all significantly associated with a higher likelihood of vehicle crashes. CONCLUSIONS: Drivers' demographic characteristics and past traffic violations could predict vehicle crashes in Korea. Greater resources should be assigned to the provision of traffic safety education programs for the high-risk driver groups. PMID- 26043958 TI - Pre- and perioperative predictors of changes in mobility and living arrangements after hip fracture--a population-based study. AB - PURPOSE OF THE RESEARCH: Examining pre- and perioperative predictors of changes in mobility and living arrangements after hip fracture. MATERIALS AND METHODS: Population-based prospective data were collected on 1027 hip fracture patients aged >=65. The outcomes were decreased vs. same or improved mobility level and need for more supported vs. same or less supported living arrangements 1 year after hip fracture. The independent variables were age, gender, body mass index, American Society of Anesthesiologists score, diagnosis of memory disorder, mobility level and living arrangements, fracture type, delay to surgery and urinary catheter removal during acute hospitalization. THE PRINCIPAL RESULTS: Multivariate logistic regression analysis revealed the prefracture mobility level of walking outdoors (OR=0.47, 95% CI 0.30-0.75) or indoors (OR=0.25, 95% CI 0.09 0.72) assisted to be associated with a smaller decrease in mobility level. Non independent mobility level (OR=2.74, 95% CI 1.70-4.41) was associated with the need of more supported living arrangements. Living in assisted living accommodations (OR=0.23, 95% CI 0.12-0.44) was associated with less need for more supported living arrangements. Removal of the urinary catheter showed a protective association on both decline in mobility level (OR=0.45; 95% CI 0.29 0.70) and moving to a more supported living arrangement(OR=0.49,95% CI 0.31-0.77. MAJOR CONCLUSIONS: Worsening of mobility was significant for independent mobilizers. Prefracture impaired mobility was associated with the need of more supported living arrangements. Living in an assisted living accommodation protected against institutionalization. The findings emphasize the importance of a prompt removal of the urinary catheter after hip fracture. PMID- 26043957 TI - Factors associated with self-reported ill health among older Ugandans: a cross sectional study. AB - INTRODUCTION: There is limited research on the prevalence and factors associated with self-reported ill health among older people in Uganda. OBJECTIVE: Therefore, the aim of this paper was to estimate the prevalence of self-reported ill health and to identify associated risk factors among older people (age 50+) in Uganda. MATERIALS AND METHODS: We conducted secondary analysis of a cross sectional survey data from a weighted sample of 2382 older persons from the 2010 Uganda National Household survey. We used frequency distributions for descriptive statistics, chi-square tests (significance set at 95%) to identify initial associations and multivariable logistic regressions reporting odds ratios to examine observed associations with self-reported ill health. RESULTS: Over half (62%) of the older people reported ill health in the 30 days preceding the survey. Self-reported ill health was positively associated with being a woman, being among the oldest old, living in the eastern region, being a household head, being Catholic, self-reported non-communicable diseases (NCDs) and being disabled. CONCLUSION: Gender differentials exist in self-reported ill health among older persons in Uganda. PMID- 26043960 TI - Speciation Analysis of (129)I and (127)I in Aerosols Using Sequential Extraction and Mass Spectrometry Detection. AB - A new analytical method has been developed for speciation analysis of (127)I and (129)I in aerosols collected on polypropylene (PP) filter paper. Iodide, iodate, NaOH soluble iodine, and insoluble iodine were separated from aerosols using sequential extraction, chromatography separation, and alkaline ashing and measured using inductive coupled plasma mass spectrometry (ICP-MS) for (127)I and accelerator mass spectrometry (AMS) for (129)I. Parameters affecting the leaching efficiency and stability of iodine species, such as leaching time and temperature, amount of alkaline reagent for ashing, ashing temperature and time, and iodine protective agent, were investigated and optimized. It was observed that long time water leaching would change inorganic iodine species due to photochemical oxidation of iodide on the PP filter surface. NaOH leaching can only extract less than 60% of iodine from the studied aerosol filters even under heating, implying that total (129)I in aerosol might be underestimated by NaOH leaching. The addition of a reductive agent significantly reduced the loss of iodine during alkaline ashing from more than 35% to 4%, efficiently improving the separation efficiency of iodine in aerosols. Speciation analysis of (129)I and (127)I in aerosol samples collected at Riso, Denmark using the developed method shows that the measured values of total (129)I and (127)I are in good agreement with the sum of all iodine species for each isotope, confirming the reliability of the proposed method. Similar distribution patterns between (129)I and (127)I species show that iodine is enriched in NaOH leachable and insoluble species and depleted in water-soluble species, as observed in all aerosol samples. PMID- 26043959 TI - Self-transcendence (ST) among very old people--its associations to social and medical factors and development over five years. AB - AIMS AND OBJECTIVES: The aims of this study were to describe the associations between ST and psychological and physical wellbeing among oldest old people and to test the influence of negative life events on ST, and the predictive value of the self-transcendence scale (STS) for mortality. BACKGROUND: ST has been identified as a valuable resource for transcending psychological and physical suffering and has been related to psychological wellbeing and higher quality of life. DESIGN: The study design was correlational, prospective, and longitudinal. SETTINGS: The participants were recruited from a medium-sized town and from an adjacent rural area in northern Sweden. METHOD: The sample consisted of 190 participants (123 women and 67 men) who completed the STS. At a 5-year follow-up, 55 people (29.5%) were alive and able to complete the assessments again. RESULTS: ST was positively associated with psychological wellbeing, self-rated health, having someone to talk with and being able to go outdoors independently. Diagnoses of depression, dementia disease, and osteoporosis were associated with lower STS scores as were living in a residential care facility, and feeling lonely. There was a significant relationship between the index of negative life events and ST between baseline and follow-up. More negative life events were associated with a larger decline in STS scores over five years. CONCLUSION: ST is an important source for wellbeing among the oldest old, and the accumulation of negative life events might threaten the ability to transcend setbacks. PMID- 26043961 TI - Comparison of codon usage bias across Leishmania and Trypanosomatids to understand mRNA secondary structure, relative protein abundance and pathway functions. AB - Understanding the variations in gene organization and its effect on the phenotype across different Leishmania species, and to study differential clinical manifestations of parasite within the host, we performed large scale analysis of codon usage patterns between Leishmania and other known Trypanosomatid species. We present the causes and consequences of codon usage bias in Leishmania genomes with respect to mutational pressure, translational selection and amino acid composition bias. We establish GC bias at wobble position that governs codon usage bias across Leishmania species, rather than amino acid composition bias. We found that, within Leishmania, homogenous codon context coding for less frequent amino acid pairs and codons avoiding formation of folding structures in mRNA are essentially chosen. We predicted putative differences in global expression between genes belonging to specific pathways across Leishmania. This explains the role of evolution in shaping the otherwise conserved genome to demonstrate species-specific function-level differences for efficient survival. PMID- 26043962 TI - The Global Network for Women's and Children's Health Research: A model of capacity-building research. AB - In response to the global effort to accelerate progress towards the Millennium Development Goals 4 and 5, a partnership was created between the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the Bill and Melinda Gates Foundation to establish the Global Network for Women's and Children's Health Research (Global Network) in 2000. The Global Network was developed with a goal of building local maternal and child health research capacity in resource-poor settings. The objective of the network was to conduct research focused on several high-need areas, such as preventing life-threatening obstetric complications, improving birth weight and infant growth, and improving childbirth practices in order to reduce mortality. Scientists from developing countries, together with peers in the USA, lead research teams that identify and address population needs through randomized clinical trials and other research studies. Global Network projects develop and test cost-effective, sustainable interventions for pregnant women and newborns and provide guidance for national policy and for the practice of evidence-based medicine. This article reviews the results of the Global Network's research, the impact on policy and practice, and highlights the capacity-building efforts and collaborations developed since its inception. PMID- 26043964 TI - Does debulking of enlarged positive lymph nodes improve survival in different gynaecological cancers? AB - Lymph-node-positive gynaecological cancers remain a pharmacotherapeutic challenge, and patients with lymph-node-positive gynaecological cancers have poor survival. The purpose of this review is to determine whether a survival advantage arises from surgical debulking of enlarged positive lymph nodes in different types of gynaecological cancers. Information from studies published on the survival benefits from debulking lymph nodes in gynaecological cancers was investigated. Pertaining to therapeutic lymphadenectomy, survival benefit can be analysed in two ways, direct survival benefit following therapeutic lymphadenectomy of bulky positive metastatic lymph nodes and indirect survival benefit, which results after a sequela of systematic lymphadenectomy, proper, accurate staging of disease and stage migration and tailor-made adjuvant treatment. The direct hypothesis of therapeutic lymphadenectomy and survival benefit has been prospected in cervical cancers and vulval cancers and in post chemotherapy residual paraarotic nodal mass in germ cell ovarian cancer. The indirect survival benefit of therapeutic paraarotic lymphadenectomy in high-risk endometrial cancers and advanced epithelial ovarian cancers needs to be tested in randomized controlled trials. More randomized controlled trials are required to investigate this research question. Further, indirect benefit due to tailor-made adjuvant treatment, secondary to accurate staging achieved as a sequela of systematic lymphadenectomy, needs to be analysed in future trials. PMID- 26043963 TI - Multisite extracoronary calcification indicates increased risk of coronary heart disease and all-cause mortality: The Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Cardiovascular calcification outside of the coronary tree, known as extracoronary calcification (ECC), is highly prevalent, often occurs concurrently in multiple sites, and yet its prognostic value is unclear. OBJECTIVE: To determine whether multisite ECC is associated with coronary heart disease (CHD) events, CHD mortality, and all-cause mortality. METHODS: We evaluated 5903 participants from the Multi-Ethnic Study of Atherosclerosis without diabetes who underwent CT imaging for calcification of the aortic valve, aortic root, mitral valve, and thoracic aorta. Participants were followed for 10.3 years. Multivariable adjusted hazard ratios estimated risk of outcomes for increasing numbers of ECC sites (0, 1, 2, 3, and 4), and receiver operator characteristic analysis assessed model discrimination. RESULTS: Prevalence of any ECC was 45%; median age was 62 years. Compared with those without ECC, those with ECC in 4 sites had increased hazards of 4.5, 7.1 and 2.3 for CHD events, CHD mortality, and all-cause mortality, respectively, independent of traditional risk factors (TRF; all P <= .05), and had >=2-fold increased hazards for outcomes independent of coronary artery calcification (CAC). Each additional site of ECC was positively associated with each outcome in a graded fashion. When added to TRF, ECC significantly increased the area under the receiver operator characteristic curve for all outcomes and modestly increased the area under the curve for mortality beyond TRF + CAC (0.799 to 0.802; P = .03). CONCLUSION: Increasing multisite ECC has a graded association with higher CHD and mortality risk, contributing information beyond TRF. Multisite ECC incidentally identified on imaging can be used to improve individualized risk prediction. PMID- 26043965 TI - Inhibitory effect of vitamin K1 on growth and polyamine biosynthesis of human gastric and colon carcinoma cell lines. AB - Gastric and colon cancers remain the leading cause of cancer mortality throughout the world. Since the gastrointestinal tract works in a constant link with the external environment, chemoprevention by dietary constituents could represent a possible approach to reduce cancer risk. Dietary vitamin K1 (VK1) has been shown to prevent the growth of many types of cancer cells. However, no data are available on possible different susceptibility to VK1 by gastric or colon neoplastic cell lines. Moreover, the exact mechanism of action of VK1 is still object of investigation, even if it has been reported that VK1 may induce cell cycle arrest and apoptosis. Therefore, molecules affecting cell growth such as the natural polyamines could be of interest in VK1 action. The aim of the present study was to investigate the effects of increasing concentrations of VK1 (from 10 to 200 uM) administered up to 72 h, on the cell proliferation and apoptosis of a gastric (HGC-27) and a colon (SW480) cancer cell line. Additionally, the polyamine biosynthesis and the MAPK pathway were also examined. VK1 treatments caused an inhibition of cell proliferation and an induction of apoptosis in both cell lines, with a concomitant significant decrease of the polyamine biosynthesis, increased phospho-ERK 1/2 expression was also observed. A different proliferative behavior and a different response to VK1 by gastric and colon cancer cells was evident, with colon cells showing a more pronounced susceptibility to VK1 action. VK1 is safe and without known toxicities in adult humans, consequently it could be effective in prevention and treatment of selected gastrointestinal neoplasms. Protocols based on the use of VK1, along with polyamine inhibitors and/or analogues, could represent a suitable alternative option for improving the efficacy of chemoprevention and treatment in future strategies for gastrointestinal cancer management. PMID- 26043966 TI - Association between breakfast intake with anthropometric measurements, blood pressure and food consumption behaviors among Iranian children and adolescents: the CASPIAN-IV study. AB - OBJECTIVE: The aim of this study is to assess the association between breakfast intake with anthropometric measurements and blood pressure among Iranian children and adolescents. The second goal is to investigate the correction of breakfast consumption with other food consumption behaviors. RESEARCH METHODS & PROCEDURES: In this national survey, 13,486 children and adolescents, aged 6-18 years, were selected by multistage, cluster sampling method from rural and urban areas of 31 provinces of Iran (2011-2012). Physical measurements included height, weight, waist circumference, and blood pressure. Food habits were assessed by self reported questionnaire. Breakfast frequency was defined as skippers (eating breakfast 0-2 days/week), semi-skippers (eating breakfast 3-4 days/week) and non skippers (eating breakfast 5-7 days/week). The data were analyzed by the STATA package. RESULTS: Of the participants, 18.9%, 13.2% and 67.9%, were breakfast skippers, semi-skippers and non-skippers respectively. The prevalence of overweight and obesity among breakfast skippers were higher than non-skippers counterparts (P-value < 0.001). The percentage rates of abdominal obesity among breakfast skippers and non-skippers group were 22.6% (CI 95%: 21-24.3) and 17.9% (CI 95%: 17-18.6), respectively. Blood pressure did not significantly differ between non-skippers students and breakfast skippers (P-value = 0.1). Non skipping adolescents ate more fresh fruits, dried fruits, vegetables and drank milk more frequently compared with breakfast skipper; while the skippers showed a higher intake of salty snack, soft drinks, packed fruit juice and fast foods (all P-value < 0.001). CONCLUSION: Regular breakfast consumption is significantly associated with lower body fatness and healthier dietary habits but that further study, using controlled intervention trials, is required to test whether this represents a causal relationship. PMID- 26043967 TI - Functional orthosis post pectoralis muscle rupture. AB - This author described her success at fabricating a chest compression orthosis for a patient who underwent repair of a pectoralis major muscle rupture. The repair occurred nine months prior to orthotic fabrication, but the patient continued to experience weakness and pain which limited motion. The design of the orthotic allowed him increased mobility and functional use. - Victoria Priganc, PhD, OTR, CHT, CLT, Practice Forum Editor. PMID- 26043968 TI - IL-1 receptor antagonist improves morphine and buprenorphine efficacy in a rat neuropathic pain model. AB - An interesting research and therapeutic problem is the reduced beneficial efficacy of opioids in the treatment of neuropathic pain. The present study sought to investigate the potential role of IL-1 family members in this phenomenon. We studied the time course of changes in IL-1alpha, IL-1beta, IL-1 receptor type I and IL-1 receptor antagonist mRNA and protein levels experienced by rats after chronic constriction injury (CCI) of the sciatic nerve using qRT PCR and Western blot analysis. In CCI-exposed rats, spinal levels of IL-1alpha mRNA were slightly downregulated on the 7th day, and protein levels were not changed on the 7th and 14th days. Levels of IL-1 receptor antagonist and IL-1 receptor type I were slightly upregulated in the ipsilateral part of the spinal cord on the 7th and 14th days; however, protein levels were not changed at those time points. Interestingly, we observed that IL-1beta mRNA and protein levels were strongly elevated in the ipsilateral part of the dorsal spinal cord on the 7th and 14th days following CCI. Moreover, in rats exposed to a single intrathecal administration of an IL-1 receptor antagonist (100 ng i.t.) on the 7th and 14th day following CCI, symptoms of neuropathic pain were attenuated, and the analgesic effects of morphine (2.5 ug i.t.) and buprenorphine (2.5 ug i.t.) were enhanced. In summary, restoration of the analgesic activity of morphine and buprenorphine by blockade of IL-1 signaling suggests that increased IL-1beta responses may account for the decreased analgesic efficacy of opioids observed in the treatment of neuropathy. PMID- 26043969 TI - Regulation analysis of AcMNPV-mediated expression of a Chinese scorpion neurotoxin under the IE1, P10 and PH promoter in vivo and its use as a potential bio-insecticide. AB - OBJECTIVE: To analyze the regulation mechanism of AcMNPV (Autographa californica multicapsid nucleopolyhedrovirus)-mediated expression of BmK IT under IE1, P10 and PH promoters in the larva of Heliothis armigera.. RESULTS: The transcription level of BmK IT gene in midgut and epidermal tissue was analyzed by quantitative PCR. The start time of transcription of recombinant BmK IT gene was early under the regulation of IE promoter, whereas transcription of BmK IT was high under the regulation of P10 promoter in the midgut tissue of infected larvae. TdT-UTP nick end labeling (TUNEL) assay showed the degree of apoptotic cell death in the midgut tissue of AcMNPV-BmK IT-transfected insect larvae was higher than that in the AcMNPV treatment group at 8 h post-infection. The time-effect relationship between the insect's humoral immunity and regulation of promoters was confirmed in the phenoloxidase activity assay. CONCLUSION: The anti-insect mechanism and regulation of different promoters in AcMNPV-BmK IT at molecular and cellular levels provide an experimental basis for the development of recombinant baculovirus biopesticides. PMID- 26043970 TI - Influenza vaccination in patients with end-stage renal disease. AB - INTRODUCTION: Patients with end-stage renal disease (ESRD) are considered at higher risk of influenza-related complications and are listed worldwide among the subjects for whom yearly influenza vaccination is strongly recommended. However, influenza vaccination coverage of patients with ESRD is significantly lower than desired. AREAS COVERED: This paper explores why compliance with official recommendations for influenza vaccination is poor in patients with ESRD and analyzes the true risk of infection as well as the immunogenicity, the effectiveness and the safety of influenza vaccination in these patients. EXPERT OPINION: Epidemiological and clinical data support the importance of influenza in conditioning clinical deterioration of patients with ESRD, particularly in relation to their level of immunosuppression. However, the variable levels of immunodeficiency detected in patients with ESRD may reduce the immune response to influenza vaccination, which appears to be lower than that usually found in healthy subjects. However, few studies are available, and they are difficult to compare for several reasons. Additionally, limited data have been collected on influenza vaccine effectiveness, although the available studies support positive results of vaccination on outcomes of severe disease. Despite such limitations, it is important to highlight that all the available studies have confirmed the good safety and tolerability of inactivated influenza vaccines. These findings, together with the risks associated with influenza in these patients, support annual influenza vaccination in patients with ESRD as well as vaccination of their close contacts and should be presented in educational programs organized for nephrologists and patient associations. PMID- 26043971 TI - Lactic acid production from xylose by engineered Saccharomyces cerevisiae without PDC or ADH deletion. AB - Production of lactic acid from renewable sugars has received growing attention as lactic acid can be used for making renewable and bio-based plastics. However, most prior studies have focused on production of lactic acid from glucose despite that cellulosic hydrolysates contain xylose as well as glucose. Microbial strains capable of fermenting both glucose and xylose into lactic acid are needed for sustainable and economic lactic acid production. In this study, we introduced a lactic acid-producing pathway into an engineered Saccharomyces cerevisiae capable of fermenting xylose. Specifically, ldhA from the fungi Rhizopus oryzae was overexpressed under the control of the PGK1 promoter through integration of the expression cassette in the chromosome. The resulting strain exhibited a high lactate dehydrogenase activity and produced lactic acid from glucose or xylose. Interestingly, we observed that the engineered strain exhibited substrate dependent product formation. When the engineered yeast was cultured on glucose, the major fermentation product was ethanol while lactic acid was a minor product. In contrast, the engineered yeast produced lactic acid almost exclusively when cultured on xylose under oxygen-limited conditions. The yields of ethanol and lactic acid from glucose were 0.31 g ethanol/g glucose and 0.22 g lactic acid/g glucose, respectively. On xylose, the yields of ethanol and lactic acid were <0.01 g ethanol/g xylose and 0.69 g lactic acid/g xylose, respectively. These results demonstrate that lactic acid can be produced from xylose with a high yield by S. cerevisiae without deleting pyruvate decarboxylase, and the formation patterns of fermentations can be altered by substrates. PMID- 26043974 TI - MicroRNA-522 reverses drug resistance of doxorubicin-induced HT29 colon cancer cell by targeting ABCB5. AB - MicroRNAs (miRNAs) are small non-coding RNAs, which are important in the development of multidrug resistance in cancer by regulating gene expression at the post-transcriptional level. The present study investigated the functional effects of miR-522 in chemoresistant colon cancer cells. The results demonstrated that miR-522 was significantly downregulated in doxorubicin (DOX) resistant colon cell line, HT29/DOX, compared with the parental HT29 colon cancer cell line. Overexpression of miR-522 in the HT29/DOX cells partially restored DOX sensitivity. miRNA target prediction algorithms suggested that ABCB5 was a target gene for miR-522. A fluorescent reporter assay confirmed that miR-522 was able to specifically bind to the predicted site of the ABCB5 mRNA 3'-untranslated region. When miR-522 was overexpressed in the HT29/DOX cells, the protein expression levels of ABCB5 were downregulated. Furthermore, knockdown of ABCB5 significantly increased the growth inhibition rate of the HT29/DOX cells, compared with the control group. These results suggested that miR-522 may affect the sensitivity of colon cancer cell lines to DOX treatment by targeting ABCB5. PMID- 26043975 TI - Listening to the voices of abused older people: should we classify system abuse? PMID- 26043972 TI - Bidirectional actin transport is influenced by microtubule and actin stability. AB - Local and long-distance transport of cytoskeletal proteins is vital to neuronal maintenance and growth. Though recent progress has provided insight into the movement of microtubules and neurofilaments, mechanisms underlying the movement of actin remain elusive, in large part due to rapid transitions between its filament states and its diverse cellular localization and function. In this work, we integrated live imaging of rat sensory neurons, image processing, multiple regression analysis, and mathematical modeling to perform the first quantitative, high-resolution investigation of GFP-actin identity and movement in individual axons. Our data revealed that filamentous actin densities arise along the length of the axon and move short but significant distances bidirectionally, with a net anterograde bias. We directly tested the role of actin and microtubules in this movement. We also confirmed a role for actin densities in extension of axonal filopodia, and demonstrated intermittent correlation of actin and mitochondrial movement. Our results support a novel mechanism underlying slow component axonal transport, in which the stability of both microtubule and actin cytoskeletal components influence the mobility of filamentous actin. PMID- 26043976 TI - Placentophagy: therapeutic miracle or myth? AB - Postpartum women are consuming their placentas encapsulated, cooked, and raw for the prevention of postpartum depression (PPD), pain relief, and other health benefits. Placentophagy is supported by health advocates who assert that the placenta retains hormones and nutrients that are beneficial to the mother. A computerized search was conducted using PubMed, Medline Ovid, and PsychINFO between January 1950 and January 2014. Keywords included placentophagy, placentophagia, maternal placentophagia, maternal placentophagy, human placentophagia, and human placentophagy. A total of 49 articles were identified. Empirical studies of human or animal consumption of human placentas were included. Editorial commentaries were excluded. Animal placentophagy studies were chosen based on their relevance to human practice. Ten articles (four human, six animal) were selected for inclusion. A minority of women in developed countries perceive placentophagy to reduce PPD risk and enhance recovery. Experimental animal research in support of pain reduction has not been applied in humans. Studies investigating placenta consumption for facilitating uterine contraction, resumption of normal cyclic estrogen cycle, and milk production are inconclusive. The health benefits and risks of placentophagy require further investigation of the retained contents of raw, cooked, and encapsulated placenta and its effects on the postpartum woman. PMID- 26043977 TI - Programmed death 1 and its ligands do not limit experimental foreign antigen induced immune complex glomerulonephritis. AB - AIM: Interactions between the co-stimulatory molecule programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, constrain T-cell responses and help maintain peripheral tolerance. Glomerulonephritis can result from a variety of antigens, both self and foreign, and from humoural and cellular effector responses. These studies aimed to define the role of PD1 and its ligands in circulating immune complex glomerulonephritis induced by immunity to a foreign antigen. METHODS: Immune complex glomerulonephritis was initiated by injecting BALB/c mice with horse spleen apoferritin intraperitoneally daily for 14 days. Inhibitory anti mouse PD-1, anti-PD-L1 or anti-PD-L2 antibodies were administered every other day. Renal disease and immune responses were studied. RESULTS: Daily injection of horse spleen apoferritin-induced proliferative immune complex glomerulonephritis in control antibody-treated mice, but inhibiting PD-1 did not augment renal injury. Specifically, blocking PD-1 did not increase serum antigen-specific antibodies or increase glomerular immunoglobulin G deposition, the hallmark of injury in this model. Furthermore, C3 deposition was unaffected and glomerular macrophages were reduced after anti-PD-1 antibodies. However, anti-PD-1 administration did increase splenocyte proliferation and cytokine production including interferon-gamma, interleukin (IL)-4, and IL-17, but not IL-10. Neutralizing either PD-L1 or PD-L2 alone did not result in major alterations in renal injury. CONCLUSION: The endogenous PD-1/PD-L pathway does not limit acute experimental foreign antigen-induced circulating immune complex glomerulonephritis. PMID- 26043978 TI - Bovine viral diarrhea virus type 2 in vivo infection modulates TLR4 responsiveness in differentiated myeloid cells which is associated with decreased MyD88 expression. AB - Symptoms of bovine viral diarrhea virus (BVDV) infection range from subclinical to severe, depending on strain virulence. Several in vitro studies showed BVDV infection impaired leukocyte function. Fewer studies have examined the effects of in vivo BVDV infection on monocyte/macrophage function, especially with strains of differing virulence. We characterized cytokine production by bovine myeloid cells isolated early or late in high (HV) or low virulence (LV) BVDV2 infection. Given BVDV infection may enhance susceptibility to secondary bacterial infection, LPS responses were examined as well. Monocytes from HV and LV infected calves produced higher levels of cytokines compared to cells from controls. In contrast, monocyte-derived macrophage cytokine levels were generally reduced. Modulated cytokine expression in HV BVDV2 macrophages was associated with decreased MyD88 expression, likely due to its interaction with viral NS5A. These data and those of others, suggest that certain Flaviviridae may have evolved strategies for subverting receptor signaling pathways involving MyD88. PMID- 26043973 TI - Repression of somatic cell fate in the germline. AB - Germ cells must transmit genetic information across generations, and produce gametes while also maintaining the potential to form all cell types after fertilization. Preventing the activation of somatic programs is, therefore, crucial to the maintenance of germ cell identity. Studies in Caenorhabditis elegans, Drosophila melanogaster, and mouse have revealed both similarities and differences in how somatic gene expression is repressed in germ cells, thereby preventing their conversion into somatic tissues. This review will focus on recent developments in our understanding of how global or gene-specific transcriptional repression, chromatin regulation, and translational repression operate in the germline to maintain germ cell identity and repress somatic differentiation programs. PMID- 26043979 TI - Effect of amino acids residues 323-433 and 628-747 in Nsp2 of representative porcine reproductive and respiratory syndrome virus strains on inflammatory response in vitro. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an important pathogen that is responsible for large economic losses in the swine industry worldwide. In PRRSV strains, many genetic variations occur in the central hypervariable region (HV2) of the Nsp2 gene, which encodes non-structural protein 2. For example, PRRSV strains VR2332, Em2007, MN184C, and TJM-F92 contained variations in the Nsp2 sequences and exhibited differing levels of virulence in adult pigs. However, the role of HV2 with respect to PRRSV immunity is unclear. In this study, four recombinant PRRSV strains (rBB/+30aa, rBB/Delta68aa, rBB/Delta111aa, and rBB/Delta120aa) were rescued using a highly pathogenic type 2 PRRSV cDNA clone (pBB). All rescued strains displayed similar growth characteristics to the parental rBB virus in pulmonary alveolar macrophages (PAMs). Expression levels of inflammatory cytokines IL-beta, IL-6, and TNF-alpha were significantly lower, at the mRNA and protein level, for groups infected with rBB/Delta111aa and rBB/Delta120aa than those in the rBB group. Levels of these inflammatory cytokines in the rBB/+30aa and rBB/Delta68aa groups were not significantly different with those in the rBB group. Phosphorylation levels of IkappaB were decreased to a greater extent in the rBB/Delta111aa and rBB/Delta120aa groups compared with those in the rBB/+30aa, rBB/Delta68aa, and rBB groups. Our results indicate that amino acids 323-433 and 628-747 of Nsp2 failed to exert significant effects on PRRSV replication in PAMs, but modulated the expression of inflammatory cytokines in vitro. PMID- 26043980 TI - Tolerance and immune response to the porcine endogenous retrovirus in German landrace pigs immunised with viral proteins. AB - Immunisation of goats, mice, rats, rabbits, guinea pigs, and hamsters with the recombinant ectodomain of the porcine endogenous retrovirus (PERV) transmembrane envelope (TM) protein (p15E) induced binding and neutralising immune antibodies in all animals. In contrast, no antibodies were induced when pigs were immunised with p15E, indicating that pigs are tolerant to their endogenous retroviruses, at least to the TM protein. To answer the question of whether pigs are tolerant to other structural proteins of PERV, we immunised German landrace pigs with p15E, this time in conjunction with the surface envelope proteins gp70 and the core capsid Gag protein p27CA. To ensure that the pigs were immunocompetent and that immunisation was successful, all animals also received an injection of an unrelated protein, keyhole limpet hemocyanin (KLH). Whereas all animals produced antibodies against KLH, no animals produced antibodies against the viral envelope proteins, thus confirming previous results for p15E and extending them to the other envelope protein, gp70. However, the pigs did produce antibodies against p27CA, indicating that there is no tolerance to the core capsid protein of PERV. PMID- 26043981 TI - Connecting the dots in translational bioinformatics: TBC 2014 collection. PMID- 26043982 TI - The early days of blotting. AB - The history of the development of DNA blotting is described in this chapter. DNA blotting, involving the transfer of electrophoretically separated DNA fragments to a membrane support through capillary action, is also known as Southern blotting. This procedure enables the detection of a specific DNA sequence by hybridization with probes. The term Southern blotting led to a "geographic" naming tradition, with RNA blotting bearing the name Northern blotting and protein transfer to membranes becoming known as Western blotting. PMID- 26043983 TI - Origins of protein blotting. AB - The development of protein blotting in its early days is recounted as arising from the need to tackle a specific analytical problem. Combining diverse elements of common methods and simple lab equipment resulted in a procedure of general utility. The expansion of the idea of carrying out immunoassays on membranes as predecessors of microarrays is briefly touched upon. PMID- 26043984 TI - Western blotting: remembrance of things past. AB - Western blotting sprung from the need to develop a sensitive visual assay for the antigen specificity of monoclonal antibodies. The technique employed SDS-PAGE of protein antigens, electrophoretic replica transfer of gel-resolved proteins to unmodified nitrocellulose sheets, probing the immobilized antigens with hybridomas, and detection of antibody-antigen complexes with radiolabeled staphylococcal protein A and autoradiography. The simplicity and relevance of the method have led to its expansive application as an immunodiagnostic and a ubiquitous research tool in biology and medicine. PMID- 26043985 TI - Simian virus 40 and protein transfer. AB - Protein transfer to solid supports after polyacrylamide gel electrophoresis, and subsequent probing with specific antibodies, is one of the most important tools in modern molecular and cellular biology. Since its development in 1979, the improvement of the technique has been impressive, from new apparatus to streamline the electrophoresis step to different modalities of the transfer step or solid supports for the transfer. Perhaps most impressive has been the explosion of the production and availability of antibodies. In this chapter, I describe the environment and conditions that led to the development of this technique in George Stark's laboratory. PMID- 26043986 TI - Western blotting: an introduction. AB - Western blotting is an important procedure for the immunodetection of proteins, particularly proteins that are of low abundance. This process involves the transfer of protein patterns from gel to microporous membrane. Electrophoretic as well as non-electrophoretic transfer of proteins to membranes was first described in 1979. Protein blotting has evolved greatly since the inception of this protocol, allowing protein transfer to be accomplished in a variety of ways. PMID- 26043987 TI - From little helpers to automation. AB - Western blot technology has continually evolved to enhance sensitivity, speed, and ease of operation. For enhancing awareness to these developments, this brief review outlines a representative selection of methods and devices, many of which are commercial products. In particular, the steps taken towards partial and full automation of western blotting are addressed. PMID- 26043988 TI - Spectrophotometric methods to determine protein concentration. AB - Measuring the concentration of proteins is an essential part of enzyme evaluations or to monitor protein yields during protein isolation procedures. Decisions on the usefulness of any isolation procedure depend on knowing the relative concentrations of a particular protein or enzyme in relation to the concentrations of all the proteins present. Protein concentration in solution is generally measured with spectrophotometry in the UV range or in the presence of dyes or copper interacting with the protein. This review describes protein determination methods for measuring protein concentration in solution. PMID- 26043989 TI - Solubilization of proteins: the importance of lysis buffer choice. AB - The efficient extraction of proteins of interest from cells and tissues is not always straightforward. Here we demonstrate the differences in extraction of the focal adhesion protein Kindlin-2 from choriocarcinoma cells using NP-40 and RIPA lysis buffer. Furthermore, we demonstrate the use of a more denaturing urea/thiourea lysis buffer for solubilization, by comparing its effectiveness for solubilization of small heat-shock proteins from smooth muscle with the often utilized RIPA lysis buffer. Overall, the results demonstrate the importance of establishing the optimal lysis buffer for specific protein solubilization within the experimental workflow. PMID- 26043990 TI - Simultaneous immunoblotting analysis with activity gel electrophoresis and 2-D gel electrophoresis. AB - Diffusion blotting method can couple immunoblotting analysis with another biochemical technique in a single polyacrylamide gel, however, with lower transfer efficiency as compared to the conventional electroblotting method. Thus, with diffusion blotting, protein blots can be obtained from an SDS polyacrylamide gel for zymography assay, from a native polyacrylamide gel for electrophoretic mobility shift assay (EMSA) or from a 2-D polyacrylamide gel for large-scale screening and identification of a protein marker. Thereafter, a particular signal in zymography, electrophoretic mobility shift assay, and 2-dimensional gel can be confirmed or identified by simultaneous immunoblotting analysis with a corresponding antiserum. These advantages make diffusion blotting desirable when partial loss of transfer efficiency can be tolerated or be compensated by a more sensitive immunodetection reaction using enhanced chemiluminescence detection. PMID- 26043991 TI - Diffusion blotting: a rapid and simple method for production of multiple blots from a single gel. AB - A very simple and fast method for diffusion blotting of proteins from precast SDS PAGE gels on a solid plastic support was developed. Diffusion blotting for 3 min gives a quantitative transfer of 10 % compared to 1-h electroblotting. For each subsequent blot from the same gel a doubling of transfer time is necessary to obtain the same amount of protein onto each blot. High- and low-molecular-weight components are transferred equally efficiently when compared to electroblotting. However, both methods do give a higher total transfer of the low-molecular-weight proteins compared to the large proteins. The greatest advantage of diffusion blotting is that several blots can be made from each lane, thus enabling testing of multiple antisera on virtually identical blots. The gel remains on the plastic support, which prevents it from stretching or shrinking. This ensures identical blots and facilitates more reliable molecular weight determination. Furthermore the proteins remaining in the gel can be stained with Coomassie Brilliant Blue or other methods for exact and easy comparison with the developed blots. These advantages make diffusion blotting the method of choice when quantitative protein transfer is not required. PMID- 26043992 TI - Multiple Immunoblots by Passive Diffusion of Proteins from a Single SDS-PAGE Gel. AB - Western blotting enables the detection and characterization of proteins of low abundance. Sodium dodecyl sulfate (SDS) polyacrylamide gel-separated proteins are normally transferred electrophoretically to nitrocellulose or polyvinylidene difluoride membranes. Here we describe the transfer proteins [Ro 60 (or SSA) autoantigen, 220 and 240 kDa spectrin antigens, and prestained molecular weight standards] by diffusion from SDS polyacrylamide gels at 37 degrees C. Up to 12 immunoblots can be obtained from a single gel by this method. PMID- 26043993 TI - Slice blotting. AB - Slice blotting is a technique for recording the spatial distribution of extracellular signaling molecules released from thin slices of living tissue. Slices are positioned on the surface of a membrane that can trap secreted substances diffusing from the tissue. The pattern of membrane-bound antigens is subsequently visualized by immunoblotting. PMID- 26043994 TI - Localizing proteins by tissue printing. AB - The simple technique of making tissue prints on appropriate substrate material has made possible the easy localization of proteins, nucleic acids, carbohydrates, and small molecules in a tissue-specific mode. Plant tissues can be used to produce prints revealing a remarkable amount of anatomical detail, even without staining, which might be used to record developmental changes over time. In this chapter we will focus on the protocols for the localization of proteins and glycans using antibodies or lectins, probably the most frequently used application, but the localization of other molecules is reported and the sources indicated. PMID- 26043995 TI - Dot-immunobinding assay (Dot-Iba). AB - Dot-immunobinding assay (Dot-Iba) is a simple and highly reproducible immunodiagnostic method. Antibody or antigen is dotted directly onto nitrocellulose membrane (NCM) discs. The diagnostic material to be checked can be incubated on this disc. Presence of antigen-antibody complex in NCM discs can be directly demonstrated with enzyme-conjugated antiglobulins and substrate. Development of a purple-pink colored, insoluble substrate product in the nitrocellulose membrane will be considered a positive result in the assay. This assay allows the processing of multiple specimens at a time and the entire operational procedures required only 4-6 h. Dot-IBA is rapid and the technical steps involved in the assay are much simpler than the other immunoassays such as enzyme-linked immunosorbent assay in detecting circulating antigen and antibody in clinical samples. The Dot-Iba showed an overall sensitivity of 60 % for tuberculous meningitis diagnosis and no false positive results were encountered. Hence this assay is highly specific for the diagnosis of paucibacillary diseases like extrapulmonary tuberculosis. Dot-Iba is best suited to laboratories in developing world where there are constraints in laboratory resources. PMID- 26043996 TI - Analysis of antibody clonotype by affinity immunoblotting. AB - A sensitive and specific method to analyze specific antibody clonotype changes in a lupus patient who developed autoantibodies to the Ro 60 autoantigen under observation is described. Patient sera, collected over several years, were separated by flatbed isoelectric focusing (IEF) and analyzed by affinity immunoblotting utilizing Ro 60-coated nitrocellulose membrane. When the Ro 60 coated nitrocellulose was laid over the surface of the IEF gel, the antibodies present on the surface of the acrylamide gel bound the Ro antigen on the nitrocellulose. Tween-20 was used to prevent nonspecific binding. The bound IgG clonotypes were detected using alkaline phosphatase conjugated anti-IgG. The patient's sera demonstrated an oligoclonal response to the Ro 60 autoantigen that increased in complexity and affinity over time. PMID- 26043997 TI - Glycosaminoglycan blotting and detection after electrophoresis separation. AB - Separation of glycosaminoglycans (GAGs) by electrophoresis and their characterization to the microgram level are integral parts of biochemical research. Their blotting on membranes after electrophoresis offers the advantage to perform further analysis on single separated species such as identification with antibodies and/or recovery of single band. A method for the blotting and immobilizing of several nonsulfated and sulfated complex GAGs on membranes made hydrophilic and positively charged by cationic detergent after their separation by conventional agarose-gel electrophoresis is illustrated. This approach to the study of these complex macromolecules utilizes the capacity of agarose-gel electrophoresis to separate single species of polysaccharides from mixtures and the membrane technology for further preparative and analytical uses. Nitrocellulose membranes are derivatized with the cationic detergent cetylpyridinium chloride (CPC) and mixtures of GAGs are capillary blotted after their separation in agarose-gel electrophoresis. Single purified species of variously sulfated polysaccharides are transferred on derivatized membranes with an efficiency of 100 % and stained with alcian blue (irreversible staining) and toluidine blue (reversible staining). This enables a lower amount limit of detection of 0.1 MUg. Nonsulfated polyanions, for example hyaluronic acid (HA), may also be transferred to membranes with a limit of detection of approximately 0.1-0.5 MUg after irreversible or reversible staining. The membranes may be stained with reversible staining and the same lanes used for immunological detection or other applications. PMID- 26043998 TI - A well-based reverse-phase protein array of formalin-fixed paraffin-embedded tissue. AB - Biomarkers from tissue-based proteomic studies directly contribute to defining disease states as well as promise to improve early detection or provide for further targeted therapeutics. In the clinical setting, tissue samples are preserved as formalin-fixed paraffin-embedded (FFPE) tissue blocks for histological examination. However, proteomic analysis of FFPE tissue is complicated due to the high level of covalently cross-linked proteins arising from formalin fixation. To address these challenges, we developed well-based reverse-phase protein array (RPPA). This approach is a robust protein isolation methodology (29.44 +/- 7.8 MUg per 1 mm(3) of FFPE tissue) paired with a novel on electrochemiluminescence detection system. Protein samples derived from FFPE tissue by means of laser capture dissection, with as few as 500 shots, demonstrate measurable signal differences for different proteins. The lysates coated to the array plate, dried up and vacuum-sealed, remain stable up to 2 months at room temperature. This methodology is directly applicable to FFPE tissue and presents the direct opportunity of addressing hypothesis within clinical trials and well-annotated clinical tissue repositories. PMID- 26043999 TI - Quantitative computerized western blotting in detail. AB - The analysis of antibody reactivity against multiple antigens separated according to their molecular weights is facilitated by western blotting. The distinction between immune dominant and recessive antigens is often difficult and carried out by qualitative or empirical means. Quantitative computerized western blotting (QCWB) analyzes reactivity to specific antigens by providing a statistically measurable value for each band allowing differentiation between immunodominant and immunorecessive determinants. QCWB is useful for both single time point analysis and longitudinal studies where multiple time points are evaluated and the relativities against individual bands compared. This technique can be employed to study humoral responses to complex antigenic mixtures such as allergens and infectious agents, or identify serologic markers for early diagnosis of cancer, autoimmune or infectious diseases, or to monitor patient's clinical status. PMID- 26044000 TI - Cationic electrophoresis and eastern blotting. AB - Denaturing, discontinuous electrophoresis in the presence of SDS has become a standard method for the protein scientist. However, there are situations where this method produces suboptimal results. In these cases electrophoresis in the presence of positively charged detergents like cetyltrimethylammonium bromide (CTAB) may work considerably better. Methods for electrophoresis, staining, and blotting of such gels are presented. PMID- 26044001 TI - A miniaturized blotting system for simultaneous detection of different autoantibodies. AB - Sera of tumor patients frequently contain autoantibodies to tumor associated antigens. Here we describe a miniaturized immunoblot platform allowing us to screen sera of patients for the presence of autoantibodies to ten autoantigens in parallel. PMID- 26044002 TI - Proteomic expressional profiling of a paraffin-embedded tissue by multiplex tissue immunoblotting. AB - In the functional proteome era, the proteomic profiling of clinicopathologic annotated tissues is an essential step for mining and evaluations of candidate biomarkers for disease. Previously, application of routine proteomic methodologies to clinical tissue specimens has provided unsatisfactory results. Multiplex tissue immunoblotting is a method of transferring proteins from a formalin-fixed, paraffin-embedded tissue section to a stack of membranes which can be applied to a conventional immunoblotting method. A single tissue section can be transferred to up to ten membranes, each of which is probed with antibodies and detected with fluorescent tags. By this approach, total protein and target signals can be simultaneously determined on each membrane; hence each antibody is internally normalized. Phosphorylation specific antibodies as well as antibodies that do not readily work well with paraffin-embedded tissue are applicable to the membranes, expanding the menu of antibodies that can be utilized with formalin-fixed tissue. This novel platform can provide quantitative detection retaining histomorphologic detail in clinical samples and has great potential to facilitate discovery and development of new diagnostic assays and therapeutic agents. PMID- 26044003 TI - Post-staining electroblotting for efficient and reliable peptide blotting. AB - Post-staining electroblotting has been previously described to transfer Coomassie blue-stained proteins from polyacrylamide gel onto polyvinylidene difluoride (PVDF) membranes. Actually, stained peptides can also be efficiently and reliably transferred. Because of selective staining procedures for peptides and increased retention of stained peptides on the membrane, even peptides with molecular masses less than 2 kDa such as bacitracin and granuliberin R are transferred with satisfactory results. For comparison, post-staining electroblotting is about 16 fold more sensitive than the conventional electroblotting for visualization of insulin on the membrane. Therefore, the peptide blots become practicable and more accessible to further applications, e.g., blot overlay detection or immunoblotting analysis. In addition, the efficiency of peptide transfer is favorable for N-terminal sequence analysis. With this method, peptide blotting can be normalized for further analysis such as blot overlay assay, immunoblotting, and N-terminal sequencing for identification of peptide in crude or partially purified samples. PMID- 26044004 TI - Multistrip Western blotting: a tool for comparative quantitative analysis of multiple proteins. AB - The qualitative and quantitative measurements of protein abundance and modification states are essential in understanding their functions in diverse cellular processes. Typical Western blotting, though sensitive, is prone to produce substantial errors and is not readily adapted to high-throughput technologies. Multistrip Western blotting is a modified immunoblotting procedure based on simultaneous electrophoretic transfer of proteins from multiple strips of polyacrylamide gels to a single membrane sheet. In comparison with the conventional technique, Multistrip Western blotting increases data output per single blotting cycle up to tenfold; allows concurrent measurement of up to nine different total and/or posttranslationally modified protein expression obtained from the same loading of the sample; and substantially improves the data accuracy by reducing immunoblotting-derived signal errors. This approach enables statistically reliable comparison of different or repeated sets of data and therefore is advantageous to apply in biomedical diagnostics, systems biology, and cell signaling research. PMID- 26044005 TI - Western Blotting Using PVDF Membranes and Its Downstream Applications. AB - Western blotting using polyvinylidene difluoride (PVDF) membranes is one of the most popular techniques for detection and characterization of proteins. If this technique is combined with immunodetection, the behavior of a particular protein can be clarified. On the other hand, if it is combined with Edman sequencing, the primary structure of the protein can be determined. A protein sample is transferred from an SDS-polyacrylamide gel electrophoresis (PAGE) gel onto a PVDF membrane by electroblotting. The membrane carrying the protein is either used for immunodetection or protein sequencing. SDS-PAGE followed by Western blotting combined with immunodetection using antibodies can easily detect protein behavior in crude protein mixtures. Furthermore, two-dimensional PAGE followed by Western blotting and Edman sequencing allows effective sequence determination of crude protein mixtures that may not be easily purified by conventional column chromatography. PMID- 26044006 TI - Blotting from PhastGel to Membranes by Ultrasound. AB - Ultrasound based approach for enhanced protein blotting is proposed. Three minutes of ultrasound exposure (1 MHz, 2.5 W/cm(2)) was sufficient for a clear transfer of proteins from a polyacrylamide gel (PhastGel) to nitrocellulose or Nylon 66 Biotrans membrane. The proteins evaluated were prestained sodium dodecyl sulfate-polyacrylamide standards (18,500-106,000 Da) and 14C-labeled Rainbow protein molecular weight markers (14,300-200,000 Da). PMID- 26044007 TI - Western blotting of high and low molecular weight proteins using heat. AB - A method for the electrophoretic transfer of high and low molecular weight proteins to nitrocellulose membranes following sodium dodecyl sulfate (SDS) polyacrylamide gel is described here. The transfer was performed with heated (70 75 degrees C) normal transfer buffer from which methanol had been omitted. Complete transfer of high and low molecular weight antigens (molecular weight protein standards, a purified protein, and proteins from a human tissue extract) could be carried out in 10 min for a 7 % (0.75 mm) SDS polyacrylamide gel. For 10 and 12.5 % gels (0.75 mm) the corresponding time was 15 min. A complete transfer could be carried out in 20 min for 7, 10, and 12.5 % gels (1.5 mm gels). The permeability of the gel is increased by heat, such that the proteins trapped in the polyacrylamide gel matrix can be easily transferred to the membrane. The heat mediated transfer method was compared with a conventional transfer protocol, under similar conditions. The conventional method transferred minimal low molecular weight proteins while retaining most of the high molecular weight proteins in the gel. In summary, this procedure is particularly useful for the transfer of high molecular weight proteins, very rapid, and avoids the use of methanol. PMID- 26044008 TI - Membrane strip affinity purification of autoantibodies. AB - A method for affinity purification of autoantibodies from a membrane strip using small volumes of human sera is described. The membrane strip is excised from a western blot containing a target antigen electrophoretically transferred from a sodium dodecyl sulfate (SDS) polyacrylamide gel. This method is a very useful alternative for affinity column chromatography, particularly when the antigen of interest is of low abundance in a HeLa cell extract. The protein mixture is resolved on a preparative SDS polyacrylamide gel and transferred to nitrocellulose membrane. A couple of strips are excised from either side of the blotted membrane and immunoblotted with specific antisera to identify the target band. Then the target band is excised horizontally and used for affinity purification. We have used this procedure to affinity purify antibodies to a 70,000 molecular weight protein derived from HeLa cell extract. A sham band, excised away from the target antigen, was used as a control for sham purification of autoantibodies. The autoantibodies purified in this manner reproduced the multiple nuclear dot anti-nuclear antibody pattern obtained using crude sera from 21 patients without primary biliary cirrhosis or anti-mitochondrial antibody. PMID- 26044009 TI - Strip immunoblotting of multiple antigenic peptides. AB - Sodium dodecyl sulfate (SDS) polyacrylamide gel electrophoresis can be employed to efficiently separate multiple antigenic peptides (MAPs). Moreover, the electrophoresed MAPs are amenable for transfer to nitrocellulose membrane for immunoblotting. MAPs involve a hepta lysine core with end groups for anchoring multiple copies of the same synthetic peptide. MAPs are amenable to staining with Coomassie and silver on SDS polyacrylamide gels as well as by Fast Green on a blotted nitrocellulose membrane. They lend themselves to analysis on an immunoblot as they behave like low molecular weight proteins. Affinity immunoblotting for analysis of antibody clonotype distribution has also been carried out using these peptides. PMID- 26044010 TI - Double-blotting: a solution to the problem of nonspecific binding of secondary antibodies in immunoblotting procedures. AB - Nonspecific interactions between blotted proteins and unrelated secondary antibodies generate false positives in immunoblotting techniques. Some procedures have been developed to reduce this adsorption, but they may work in specific applications and be ineffective in others. "Double-blotting" has been developed to overcome this problem. It consists of interpolating a second blotting step between the usual probings of the blot membrane with the primary antibody and the secondary antibodies. This step, by isolating the primary antibody from the interfering proteins, guarantees the specificity of the probing with the secondary antibody. This method has been developed for the study of erythropoietin in concentrated urine since a strong nonspecific binding of biotinylated secondary antibodies to some urinary proteins is observed using classical immunoblotting protocols. However, its concept makes it usable in other applications that come up against this kind of problem. This method is expected to be especially useful for investigating proteins that are present in minute amounts in complex biological media. PMID- 26044012 TI - Immunodetection of P-selectin using an antibody to its C-terminal tag. AB - P-selectin is a multi-domain glycoprotein expressed on activated endothelial cells and activated platelets. We previously expressed a recombinant form of P selectin containing only its N-terminal lectin and EGF domains in CHO-K1 cells and showed that these two domains are sufficient to mediate ligand binding. We have now expressed the same construct in CHO-Lec1 cells that make truncated glycans. The uniform glycosylation in these cells should make it easier to crystallize this protein. PMID- 26044011 TI - Method for resolution and western blotting of very large proteins using agarose electrophoresis. AB - Proteins larger than 200 kDa are difficult to separate electrophoretically using polyacrylamide gels, and their transfer during western blotting is typically incomplete. A vertical SDS agarose gel system was developed that has vastly improved resolving power for very large proteins. Complete transfer of proteins as large as titin (Mr 3,000-3,700 kDa) onto blots can be achieved. The addition of a sulfhydryl reducing agent in the upper reservoir buffer and transfer buffer markedly improves the blotting of large proteins. PMID- 26044013 TI - Improvements and Variants of the Multiple Antigen Blot Assay-MABA: An Immunoenzymatic Technique for Simultaneous Antigen and Antibody Screening. AB - This simple, versatile, reliable, reproducible, multipurpose, and inexpensive technique is based on the adhesion of different antigens to a single nitrocellulose strip using, as template, an acrylic device containing 28 parallel channels. The inclusion of channels containing normal human serum improves the quality control of this assay. Antigen-sensitized nitrocellulose strips are cut perpendicularly to the antigen-rows, exposed to immune sera followed by the appropriate conjugate. Positive signals are recorded using chemiluminescent or precipitable colorimetric substrates. This assay allows the simultaneous qualitative demonstration of antigenicity and immunogenicity of antigens obtained as synthetic peptides, recombinant molecules, or crude preparations, with high sensitivity and specificity. Its major value is based on the rapid and simultaneous comparative evaluation of various antigenic preparations allowing the diagnosis of a variety of infectious, allergic, and autoimmune diseases. It can in general be used to detect any type of antibody or circulating antigen. Some improvements and variants of the original technique are included. PMID- 26044014 TI - Blotting from Immobilized pH Gradient Gels: Application to Total Cell Lysates. AB - Isoelectric focusing as used in the first dimension of two-dimensional gel electrophoresis separates protein isoforms such as those due to phosphorylation and acetylation. The immunoblotting method described here reveals this diversity by a one-dimensional separation. Using commercially available immobilized pH gradient plates or strips, the resolved proteins are transferred to PVDF membranes by diffusion and are probed with protein-specific antibody. The system is useful for monitoring changes of banding patterns and permits parallel processing of samples. Since the effect of posttranslational modifications on the isoelectric point can be predicted, inferring the number and extent of modifications is possible. PMID- 26044015 TI - Immunoprecipitation: Western blot for proteins of low abundance. AB - Combining the procedures of immunoprecipitation and immunoblotting can help overcome some of the limitations of each separate procedure. Immunoblotting can identify immunoprecipitated proteins more specifically and with higher sensitivity than nonspecific protein stains or autoradiography. Immunoprecipitation can enrich proteins of interest to improve sensitivity for detection when compared with immunoblotting of whole cell extracts. Recently, immunoprecipitation-blotting helped us characterize a new autoantibody, anti p155, and to test for the presence of the autoantibody in patient sera to study its clinical associations. The procedure for immunoprecipitation-blotting, with specific reference to this autoantibody test ("reverse" immunoprecipitation blotting), is reported here in detail. PMID- 26044016 TI - Native Electrophoresis and Western Blot Analysis (NEWeB): Methods and Applications. AB - Native Electrophoresis and Western Blot Analysis (NEWeB) has been developed for the study of plant virus characteristics, among others, virus particle-protein interactions, electrophorotype formation, and strain separation. The method is based on the property of electrophoretic mobility of virus particles (VP) and proteins and combines the analytical capacity of electrophoresis with the specificity of western blot. One of its advantages is that it deals with entire VP that can be studied in cause and effect or in time-interval experiments. Some of the most interesting approaches include VP structural studies, VP interaction with host or viral proteins, and also the characterization of VP-protein complexes. In this protocol, NEWeB is used to demonstrate the interaction of Plum pox virus particles with the helper component, a virus encoded protein. It is expected that the method could be used in analogous studies of other viruses or large protein complexes, where similar principles apply. PMID- 26044017 TI - Shift-Western Blotting: Separate Analysis of Protein and DNA from Protein-DNA Complexes. AB - The electrophoretic mobility shift assay (EMSA) is the most frequently used experiment for studying protein-DNA interactions and to identify DNA-binding proteins. Protein-DNA complexes formed during EMSA experiments can be further analyzed by shift-western blotting, where the protein and DNA components contained in a polyacrylamide gel are transferred to stacked membranes: First a nitrocellulose membrane retains the proteins while double-stranded DNA passes through the nitrocellulose membrane and binds only to a charged membrane placed below. Immobilized proteins can then be stained with specific antibodies while the DNA can be detected by a radioactive label or a nonradioactive detection system. Shift-western blotting can overcome many limitations of supershift experiments and allows for the analysis of complex protein-DNA complexes containing multiple protein factors. Moreover, proteins and/or DNA may be recovered from membranes after the blotting step for further analysis by other means. PMID- 26044018 TI - Grid-immunoblotting. AB - Grid-immunoblotting is a fast, simple, and efficient method for simultaneously testing multiple allergens utilizing small amount of antibody. PMID- 26044019 TI - Detection and quantification of protein-protein interactions by far-western blotting. AB - Far-western blotting is a convenient method to characterize protein-protein interactions, in which protein samples of interest are immobilized on a membrane and then probed with a non-antibody protein. In contrast to western blotting, which uses specific antibodies to detect target proteins, far-western blotting detects proteins on the basis of the presence or absence of binding sites for the protein probe. When specific modular protein binding domains are used as probes, this approach allows characterization of protein-protein interactions involved in biological processes such as signal transduction, including interactions regulated by posttranslational modification. We here describe a rapid and simple protocol for far-western blotting, in which GST-tagged Src homology 2 (SH2) domains are used to probe cellular proteins in a phosphorylation-dependent manner. We also present a batch quantification method that allows for the direct comparison of probe binding patterns. PMID- 26044020 TI - Western blot analysis of adhesive interactions under fluid shear conditions: the blot rolling assay. AB - Western blotting has proven to be an important technique in the analysis of receptor-ligand interactions (i.e., by ligand blotting) and for identifying molecules mediating cell attachment (i.e., by cell blotting). Conventional ligand blotting and cell blotting methods employ non-dynamic (static) incubation conditions, whereby molecules or cells of interest are placed in suspension and overlaid on membranes. However, many cell-cell and cell-matrix adhesive interactions occur under fluid shear conditions, and shear stress itself mediates and/or facilitates the engagement of these physiologically appropriate receptors and ligands. Notably, shear forces critically influence the adhesion of circulating cells and platelets to vessel walls in physiologic cell migration and hemostasis, as well as in inflammatory and thrombotic disorders, cancer metastasis, and atherosclerosis. Use of non-dynamic blotting conditions to analyze such interactions can introduce bias, overtly missing relevant effectors and/or exaggerating the relative role(s) of non-physiologic adhesion molecules. To address this shortfall, we have developed a new technique for identifying binding interactions under fluid shear conditions, the "blot rolling assay." Using this method, molecules in a complex mixture are resolved by gel electrophoresis, transferred to a membrane that is rendered semitransparent, and the membrane is then incorporated into a parallel-plate flow chamber apparatus. Under controlled flow conditions, cells or particles bearing adhesion proteins of interest are then introduced into the chamber and interactions with individual immobilized molecules (bands) can be visualized in real time. The substrate molecule(s) supporting adhesion under fluid shear can then be identified by staining with specific antibodies or by excising the relevant band(s) and performing mass spectrometry or microsequencing of the isolated material. This method thus allows for the identification, within a complex mixture and without prior isolation or purification, of both known and previously uncharacterized adhesion molecules operational under dynamic conditions. PMID- 26044021 TI - Centrifuge blotting. AB - Centrifuge blotting is an efficient and convenient method for elution and transfer of proteins from a polyacrylamide gel onto a polyvinylidene difluoride (PVDF) membrane by centrifugation. PMID- 26044022 TI - Blotting of Coomassie Blue-Stained Proteins from PAGE Gels to Transparencies. AB - A simple, convenient, and inexpensive method for long-term non-photographic storage of information present in electrophoresis gel, based on protein blotting patterns, is presented here. PMID- 26044023 TI - B-Cell ELISPOT: For the Identification of Antigen-Specific Antibody-Secreting Cells. AB - The B-cell ELISPOT assay is a sensitive tool that can be utilized to measure total immunoglobulin (Ig) and antigen-specific antibody-secreting cells. Typically, membrane-bound antigen enables binding of antibody secreted by B cells. Bound antibody is then detected by using an anti-Ig antibody and a colorimetric substrate, resulting in colored spots on the membrane that can be easily enumerated. Here we have described a method to quantitate antigen-specific antibody-secreting cells from the spleen or bone marrow of a vaccinated mouse. PMID- 26044024 TI - T Cell ELISPOT: For the Identification of Specific Cytokine-Secreting T Cells. AB - The ELISPOT is a powerful functional assay used to detect biological activity and immunological secretions from immune cells. In this chapter, we specifically discuss T cell ELISPOT methods for the detection of secreted cytokines. A detailed protocol is given enabling the detection of interferon gamma-secreting CD8(+) T cells and/or peripheral blood mononuclear cells following their isolation and polyclonal activation. Included is a brief discussion on choosing the activation method for your T cell ELISPOT assay, as well as additional instructions for the adaptation of this protocol for the study of memory and antigen-specific T cell responses. PMID- 26044025 TI - Membrane Microplates for One- and Two-Color ELISPOT and FLUOROSPOT Assays. AB - Membranes are widely used as protein blotting matrices for a large variety of research applications including western blotting and enzyme-linked immunospot assay (ELISPOT). The largest advantage of using membranes versus solid plastic support is the porosity of membranes allowing for immobilization of high concentrations of proteins and antibodies which, in turn, increases the sensitivity of detection. Similar to plastic surfaces, polyvinylidene difluoride (PVDF) and nitrocellulose membranes create good microenvironment for live cells cultured in vitro and do not interfere with cellular physiology. It appears that PVDF-backed microplates are a golden standard for ELISPOT assays: such plates are inexpensive, easy to use and after assay development, membranes can be removed from the plates and archived. Given the convenience and reliability of membrane microplates, they are widely used in ELISPOT assays for basic research and clinical trials. The ELISPOT assay is an antibody "sandwich" technique aimed at trapping cell-secreted molecules between capture and detection antibodies, followed by either chromogenic enzymatic or fluorescence detection. This review covers the principles of the ELISPOT assay on membrane microplates including single-color and two-color detection techniques with the emphasis on assay design, choosing membrane microplates, and troubleshooting protocols. PMID- 26044026 TI - SDS-PAGE to Immunoblot in One Hour. AB - An ultra-rapid method for electrophoresing proteins on sodium dodecyl sulfate polyacrylamide gel electrophoresis, transfer of proteins to nitrocellulose membranes, and immunoblotting is described here. Electrophoresis of the autoantigens La and Ro60, as well as molecular weight standards on a 4-20 % gradient gel, was performed in about 10 min using heated (70-75 degrees C) normal Laemmli running buffer. Electrophoretic transfer of these proteins was achieved in 7 min using a semidry transfer method. Finally, immunoblotting of La and Ro60 was carried out in 30 min. Thus, the entire process of electrophoresis, electrotransfer, and immunoblotting could be carried out in 1 h. PMID- 26044027 TI - Single-cell western blotting. AB - Cell heterogeneity is a variation in cellular processes in functionally similar cells. Cells from the same tissue which are considered genetically identical may have difference in size, structure, and level of protein expression which can lead to major impact on the functions of cell leading to difference in physiological consequences. Single-cell proteome-wide studies are used to detect cell heterogeneity. Flow cytometry and immunocytochemistry do play an important role in evaluating cell heterogeneity. However, these methods are based on separation by antibodies with limited specificity. Cross-reactivity can occur leading to bias in result. Western blot is done to separate the proteins according to molecular weight. Therefore, off-target and on-target signals can be discriminated. Detection of protein expression from a tissue can be done with the help of western blot. However, it is unable to differentiate protein expression of individual cells. For detection of this cell-to-cell variation, a highly advanced technique termed "single-cell western blotting" is carried out. Single cell western blot has enabled us to detect protein expression at cellular level at a fairly advanced high resolution using a western blot designed to assess cell heterogeneity. PMID- 26044028 TI - Protein detection by Simple WesternTM analysis. AB - Protein Simple(c) has taken a well-known protein detection method, the western blot, and revolutionized it. The Simple WesternTM system uses capillary electrophoresis to identify and quantitate a protein of interest. Protein Simple(c) provides multiple detection apparatuses (Wes, Sally Sue, or Peggy Sue) that are suggested to save scientists valuable time by allowing the researcher to prepare the protein sample, load it along with necessary antibodies and substrates, and walk away. Within 3-5 h the protein will be separated by size, or charge, immuno-detection of target protein will be accurately quantitated, and results will be immediately made available. Using the Peggy Sue instrument, one study recently examined changes in MAPK signaling proteins in the sex-determining stage of gonadal development. Here the methodology is described. PMID- 26044029 TI - Western blotting using microfluidics. AB - Together with polyacrylamide gel electrophoresis, the western blot has been an invaluable research technique in biological sciences. It continues to serve as an important diagnostic tool in medical laboratories. The procedure, however, involves multiple steps that are often time and resource intensive in addition to being of low throughput. Using advances in microfluidics, Hughes and Herr et al. initially developed a microfluidic western blot approach that significantly optimizes resources and assay times. More recent developments have enabled multiplexing to facilitate probing of multiple proteins. PMID- 26044030 TI - Two-dimensional gel-based protein standardization verified by western blot analysis. AB - In data presentation of biochemical investigation the amount of a target protein is shown in the y-axis against the x-axis representing time, concentrations of various agents, or other parameters. Western blot is a versatile and convenient tool in such an analysis to quantify and display the amount of proteins. In western blot, so-called housekeeping gene product(s), or "housekeeping proteins," are widely used as internal standards. The rationale of using housekeeping proteins for standardization of western blot is based on the assumption that the expression of chosen housekeeping gene is always constant, which could be false under certain physiological or pathological conditions. We have devised a two dimensional gel-based standardization method in which the protein content of each sample is determined by scanning the total protein density of two-dimensional gels and the expression of each protein is quantified as the density ratio of each protein divided by the density of the total proteins on the two-dimensional gel. The advantage of this standardization method is that it is not based on any presumed "housekeeping proteins" that are supposed to be being expressed constantly under all physiological conditions. We will show that the total density of a two-dimensional gel can render a reliable protein standardization parameter by running western blot analysis on one of the proteins analyzed by two dimensional gels. PMID- 26044031 TI - Fingerprint deposition on nitrocellulose and polyvinylidene difluoride membranes using alkaline phosphatase. AB - Dactyloscopy or fingerprint identification is a vital part of forensic evidence. Identification with fingerprints has been known since the finding of finger impressions on the clay surface of Babylonian legal contracts almost 4,000 years ago. The skin on the fingers and palms appears as grooves and ridges when observed under a microscope. A unique fingerprint is produced by the patterns of these friction skin ridges. Visible fingerprints can be deposited on solid surfaces. Colored inks have been used to deposit fingermarks on documents. Herein, we show that alkaline phosphatase can be used to transfer prints from fingers or palm to nitrocellulose or polyvinylidene difluoride membranes. The prints can be detected by using the nitro blue tetrazolium/5-bromo-4-chloro-3 indolyl phosphate method of detection. PMID- 26044032 TI - Other notable protein blotting methods: a brief review. AB - Proteins have been transferred from the gel to the membrane by a variety of methods. These include vacuum blotting, centrifuge blotting, electroblotting of proteins to Teflon tape and membranes for N- and C-terminal sequence analysis, multiple tissue blotting, a two-step transfer of low- and high-molecular-weight proteins, acid electroblotting onto activated glass, membrane-array method for the detection of human intestinal bacteria in fecal samples, protein microarray using a new black cellulose nitrate support, electrotransfer using square wave alternating voltage for enhanced protein recovery, polyethylene glycol-mediated significant enhancement of the immunoblotting transfer, parallel protein chemical processing before and during western blot and the molecular scanner concept, electronic western blot of matrix-assisted laser desorption/ionization mass spectrometric-identified polypeptides from parallel processed gel-separated proteins, semidry electroblotting of peptides and proteins from acid-urea polyacrylamide gels, transfer of silver-stained proteins from polyacrylamide gels to polyvinylidene difluoride (PVDF) membranes, and the display of K(+) channel proteins on a solid nitrocellulose support for assaying toxin binding. The quantification of proteins bound to PVDF membranes by elution of CBB, clarification of immunoblots on PVDF for transmission densitometry, gold coating of nonconductive membranes before matrix-assisted laser desorption/ionization tandem mass spectrometric analysis to prevent charging effect for analysis of peptides from PVDF membranes, and a simple method for coating native polysaccharides onto nitrocellulose are some of the methods involving either the manipulation of membranes with transferred proteins or just a passive transfer of antigens to membranes. All these methods are briefly reviewed in this chapter. PMID- 26044034 TI - A Rare Malignant Fetal Brain Tumor. AB - A gravida 4, para 3 female at 37 weeks' gestation presented for a routine ultrasound. She had an otherwise uncomplicated low-risk pregnancy. The sonographic evaluation of the fetus revealed a macrocephaly and a deviation of the brain midline structures with a mass effect as well as a massively dilated left cerebral ventricular system with ill-defined echogenic ventricular delineation. Multiple free intracavitary echogenicities and disruptions of the brain mantle were visible. Our images were suggestive of either an intracranial bleed with the presence of an underlying tumor or a spontaneous bleed. A postnatal MRI was consistent with our prenatal findings of a possible tumor. The postnatal biopsy revealed an anaplastic astroblastoma within a hemorrhagic background. The infant received multiple courses of chemotherapy and further tumor debulking. At present, the infant is 18 months old. This is only the 4th case of an astrocytoma identified in the fetal period, and our case has the longest known survival yet. PMID- 26044036 TI - Intestinal Endometriosis: Mimicker of Inflammatory Bowel Disease? AB - BACKGROUND/AIMS: Endometriosis of the intestinal tract (IE) is thought to mimic inflammatory bowel disease (IBD) both clinically and pathologically but robust data on a large unselected series are missing. Diagnostic problems arise both at colonoscopy as well as on resection specimens for IE when IBD-like features are encountered. The aim was to establish the frequency of IBD-like histology in IE and which type of histological lesions are shared by these two entities. METHODS: One hundred consecutive, unselected cases of surgically resected IE were collected and clinical features and histopathology reviewed and reevaluated. RESULTS: Seventy-five surgical specimens showed no histological alterations except for endometriosis foci. Twenty-two cases showed focal architectural alterations in the absence of significant inflammation. Three cases showed marked inflammatory and architectural mucosal changes making a differential diagnosis with IBD particularly challenging. On follow-up, however, these patients remained symptom-free and with no need for anti-inflammatory therapy after surgical resection of IE. CONCLUSIONS: Diagnostic problems may arise in women who have IBD like symptoms and histology at colonoscopy but who lack a known diagnosis of endometriosis. Clinicians must be aware that the diagnosis of IBD in patients with IE should be reevaluated over time. PMID- 26044035 TI - Short Children with CHARGE Syndrome: Do They Benefit from Growth Hormone Therapy? AB - AIM: The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome. PATIENTS: We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 MUg/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years. RESULTS: Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged. CONCLUSIONS: Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues. PMID- 26044033 TI - Information content of long-range NMR data for the characterization of conformational heterogeneity. AB - Long-range NMR data, namely residual dipolar couplings (RDCs) from external alignment and paramagnetic data, are becoming increasingly popular for the characterization of conformational heterogeneity of multidomain biomacromolecules and protein complexes. The question addressed here is how much information is contained in these averaged data. We have analyzed and compared the information content of conformationally averaged RDCs caused by steric alignment and of both RDCs and pseudocontact shifts caused by paramagnetic alignment, and found that, despite the substantial differences, they contain a similar amount of information. Furthermore, using several synthetic tests we find that both sets of data are equally good towards recovering the major state(s) in conformational distributions. PMID- 26044037 TI - Identification of Black Bean (Phaseolus vulgaris L.) Polyphenols That Inhibit and Promote Iron Uptake by Caco-2 Cells. AB - In nutritional studies, polyphenolic compounds are considered to be inhibitors of Fe bioavailability. Because they are presumed to act in a similar manner, total polyphenols are commonly measured via the Folin-Ciocalteu colorimetric assay. This study measured the content of polyphenolic compounds in white and black beans and examined the effect of individual polyphenols on iron uptake by Caco-2 cells. Analysis of seed coat extracts by LC-MS revealed the presence of a range of polyphenols in black bean, but no detectable polyphenols in white bean. Extracts from black bean seed coats strongly inhibited iron uptake. Examination of the eight most abundant black bean seed coat, non-anthocyanin polyphenols via Caco-2 cell assays showed that four (catechin, 3,4-dihydroxybenzoic acid, kaempferol, and kaempferol 3-glucoside) clearly promoted iron uptake and four (myricetin, myricetin 3-glucoside, quercetin, and quercetin 3-glucoside) inhibited iron uptake. The four inhibitors were present in 3-fold higher total concentration than the promoters (143 +/- 7.2 vs 43.6 +/- 4.4 MUM), consistent with the net inhibitory effect observed for black bean seed coats. The ability of some polyphenols to promote iron uptake and the identification of specific polyphenols that inhibit Fe uptake suggest a potential for breeding bean lines with improved iron nutritional qualities. PMID- 26044038 TI - Correction for Ye et al., Nrf2- and ATF4-Dependent Upregulation of xCT Modulates the Sensitivity of T24 Bladder Carcinoma Cells to Proteasome Inhibition. PMID- 26044040 TI - Na+/K+-ATPase alpha1 mRNA expression in the gill and rectal gland of the Atlantic stingray, Dasyatis sabina, following acclimation to increased salinity. AB - BACKGROUND: The salt-secreting rectal gland plays a major role in elasmobranch osmoregulation, facilitating ion balance in hyperosmotic environments in a manner analogous to the teleost gill. Several studies have examined the central role of the sodium pump Na(+)/K(+)-ATPase in osmoregulatory tissues of euryhaline elasmobranch species, including regulation of Na(+)/K(+)-ATPase activity and abundance in response to salinity acclimation. However, while the transcriptional regulation of Na(+)/K(+)-ATPase in the teleost gill has been well documented the potential for mRNA regulation to facilitate rectal gland plasticity during salinity acclimation in elasmobranchs has not been examined. Therefore, in this study we acclimated Atlantic stingrays, Dasyatis sabina (Lesueur) from 11 to 34 ppt salinity over 3 days, and examined changes in plasma components as well as gill and rectal gland Na(+)/K(+)-ATPase alpha1 (atp1a1) mRNA expression. RESULTS: Acclimation to increased salinity did not affect hematocrit but resulted in significant increases in plasma osmolality, chloride and urea. Rectal gland atp1a1 mRNA expression was higher in 34 ppt-acclimated D. sabina vs. CONTROLS: There was no significant change in gill atp1a1 mRNA expression, however mRNA expression of this gene in the gill and rectal gland were negatively correlated. CONCLUSIONS: This study demonstrates regulation of atp1a1 in the elasmobranch salt-secreting gland in response to salinity acclimation and a negative relationship between rectal gland and gill atp1a1 expression. These results support the hypothesis that the gill and rectal gland play opposing roles in ion balance with the gill potentially facilitating ion uptake in hypoosmotic environments. Future studies should further examine this possibility as well as potential differences in the regulation of Na(+)/K(+)-ATPase gene expression between euryhaline and stenohaline elasmobranch species. PMID- 26044042 TI - Longer duration of B cell depletion is associated with better outcome. AB - OBJECTIVE: To report on the long-term follow-up, clinically and serologically, of 98 patients with SLE treated with B cell depletion (BCD) over a 12 year period, focusing on the duration of the depletion. METHODS: A retrospective review of clinical and serological features of all SLE patients treated with BCD from January 2000 until December 2012 in the Centre for Rheumatology, University College London Hospital. Clinical activity was assessed by the classic BILAG score at baseline and 6 and 12 months after the treatment. RESULTS: The period of depletion is extremely variable between patients and within the same patient on different occasions. The patients were divided into two groups according to the duration of depletion and a defined threshold of 12 months was utilized. The group with longer duration of depletion was associated with a better outcome, with a decrease in BILAG score at 6 and 12 months. This group was also associated with lymphopenia present at any time during the course of the patient's disease. No other clinical or serological feature was associated with longer duration of BCD. CONCLUSION: Cycles of BCD that induce longer duration of BCD are associated with better outcome. Lymphopenia may help to predict longer duration of the depletion and better outcome, although the mechanism is unclear. PMID- 26044043 TI - Comment on: Ultrasonography as a useful modality for documenting sacroiliitis in radiographically negative inflammatory back pain: a comparative evaluation with MRI: reply. PMID- 26044045 TI - [Purpose of medical education]. PMID- 26044046 TI - Medical students' agenda-setting abilities during medical interviews. AB - PURPOSE: Identifying patients' agendas is important; however, the extent of Korean medical students' agenda-setting abilities is unknown. The study aim was to investigate the patterns of Korean medical students' agenda solicitation. METHODS: A total of 94 third-year medical students participated. One scenario involving a female patient with abdominal pain was created. Students were video recorded as they interviewed the patient. To analyze whether students identify patients' reasons for visiting, a checklist was developed based on a modified version of the Calgary-Cambridge Guide to the Medical Interview: Communication Process checklist. The duration of the patient's initial statement of concerns was measured in seconds. The total number of patient concerns expressed before interruption and the types of interruption effected by the medical students were determined. RESULTS: The medical students did not explore the patients' concerns and did not negotiate an agenda. Interruption of the patient's opening statement occurred in 4.62+/-2.20 seconds. The most common type of initial interruption was a recompleter (79.8%). Closed-ended questions were the most common question type in the second and third interruptions. CONCLUSION: Agenda setting should be emphasized in the communication skills curriculum of medical students. The Korean Clinical Skills Exam must assess medical students' ability to set an agenda. PMID- 26044047 TI - [What is the current orientation of undergraduate medical education in Korea?]. AB - PURPOSE: The educational purpose of a medical school is important, because it guides educational decisions in an individual organization and projects the image of the doctors that we are generating. By analyzing the educational goals of entire medical schools, this study aimed to examine the current orientation and future direction of undergraduate medical education in Korea. METHODS: Educational goals were collected from the website of each medical school and subjected to inductive content analysis. After identifying categories and themes, we examined the differences between medical school subgroups and compared the categories with competencies that have been suggested by the "Korean Doctor's Role." RESULTS: Thirteen themes were identified: medical expertise, professionalism, contribution to various levels of society, self-management and development, basic educational ideology, research ability, cooperation, leadership, dealing with future change, respect for life, creativity, problem solving ability, and ability to educate. There was a significant difference in educational goals between medical schools when grouped by geographic location and affiliation of research-driven hospitals. Of the 16 competencies that are suggested by the Korean Doctor's Role, 12 had one or more corresponding categories. CONCLUSION: Per their current educational purposes, Korean medical schools pursue a broad variety of competencies that need cultivating during the course of undergraduate medical education. Further research is needed to determine how best to apply these educational purposes in actual institutions and ultimately lead them to become part of the competency of a graduate. PMID- 26044048 TI - [Two-and-a-half year follow-up study of strategy factors in successful learning to predict academic achievements in medical education]. AB - PURPOSE: We performed a two-and-a-half year follow-up study of strategy factors in successful learning to predict academic achievements in medical education. METHODS: Strategy factors in successful learning were identified using a content analysis of open-ended responses from 30 medical students who were ranked in the top 10 of their class. Core words were selected among their responses in each category and the frequency of the words were counted. Then, a factors survey was conducted among year 2 students, before the second semester. Finally, we performed an analysis to assess the association between the factors score and academic achievement for the same students 2.5 years later. RESULTS: The core words were "planning and execution," "daily reviews" in the study schedule category; "focusing in class" and "taking notes" among class-related category; and "lecture notes," "previous exams or papers," and "textbooks" in the primary self-learning resources category. There were associations between the factors scores for study planning and execution, focusing in class, and taking notes and academic achievement, representing the second year second semester credit score, third year written exam scores and fourth year written and skill exam scores. Study planning was only one independent variable to predict fourth year summative written exam scores. CONCLUSION: In a two-and-a-half year follow-up study, associations were founded between academic achievement and the factors scores for study planning and execution, focusing in class, and taking notes. Study planning as only one independent variable is useful for predicting fourth year summative written exam score. PMID- 26044049 TI - [A school-level longitudinal study of clinical performance examination scores]. AB - PURPOSE: This school-level longitudinal study examined 7 years of clinical performance data to determine differences (effects) in students and annual changes within a school and between schools; examine how much their predictors (characteristics) influenced the variation in student performance; and calculate estimates of the schools' initial status and growth. METHODS: A school-level longitudinal model was tested: level 1 (between students), level 2 (annual change within a school), and level 3 (between schools). The study sample comprised students who belonged to the CPX Consortium (n=5,283 for 2005~2008 and n=4,337 for 2009~2011). RESULTS: Despite a difference between evaluation domains, the performance outcomes were related to individual large-effect differences and small-effect school-level differences. Physical examination, clinical courtesy, and patient education were strongly influenced by the school effect, whereas patient-physician interaction was not affected much. CONCLUSION: Student scores are influenced by the school effect (differences), and the predictors explain the variation in differences, depending on the evaluation domain. PMID- 26044050 TI - [Students' perception of the educational environment of medical schools in Korea: findings from a nationwide survey]. AB - PURPOSE: The purpose of this study was to examine students' perception of the educational environment of medical schools in Korea. METHODS: A total of 9,096 of 12,035 students (75.6%) responded to our questionnaire. This study was conducted at the end of the 2013 academic year using the Dundee Ready Education Environment Measure (DREEM) at 40 medical schools in Korea. DREEM comprises five domains: students' perceptions of learning (SPL); students' perceptions of teachers (SPT); students' academic self-perceptions; students' perceptions of atmosphere; and students' social self-perception. The data were analyzed using descriptive statistics, independent t-test, and one-way analysis of variance. RESULTS: The overall mean DREEM score was 113.97 (of 200), and the scores for the 40 medical schools ranged from 100.24 to 134.32. The overall mean and domains scores of the DREEM differed significantly between educational systems, grades, genders, and academic achievement levels. Graduate-level medical students had higher scores for the DREEM and its five domains than undergraduate medical students. The scores were lowest in second-year students (mean, 111.80). Male students' perceptions were significantly higher than those of female students except for SPL and SPT. High academic achievers' perceptions were also greater versus low academic achievers. CONCLUSION: Students' perceptions of their educational environment are positive in Korea. The learning environment should be evaluated by curriculum planners and administrators of medical schools to improve its quality. PMID- 26044051 TI - [Learning objectives achievement in ethics education for medical school students]. AB - PURPOSE: This study aimed to examine the necessity for research ethics and learning objectives in ethics education at the undergraduate level. METHODS: A total of 393 fourth-year students, selected from nine medical schools, participated in a survey about learning achievement and the necessity for it. RESULTS: It was found that the students had very few chances to receive systematic education in research ethics and that they assumed that research ethics education was provided during graduate school or residency programs. Moreover, the students showed a relatively high learning performance in life ethics, while learning achievement was low in research ethics. CONCLUSION: Medical school students revealed low interest in and expectations of research ethics in general; therefore, it is necessary to develop guidelines for research ethics in the present situation, in which medical education mainly focuses on life ethics. PMID- 26044052 TI - ["The secret weapon of good teachers" series. The second secret weapon: "Good teachers are excellent classroom managers"]. PMID- 26044055 TI - Association of glutathione S-transferase pi (GSTP1) Ile105Val polymorphism with the risk of skin cancer: a meta-analysis. AB - Numerous epidemiological studies have evaluated the association of Glutathione S transferase P1 (GSTP1) Ile105Val polymorphism with the risk of skin cancer. However, the results remain inconclusive. To derive a more precise estimation of the association between the GSTP1 Ile105Val polymorphism and skin cancer risk, a meta-analysis was performed. A comprehensive search was conducted to identify the eligible studies. We used odds ratios (ORs) with 95 % confidence intervals (CIs) to assess the association of GSTP1 Ile105Val polymorphism with skin cancer risk. Thirteen case-control studies in nine articles, which included a total of 1504 cases and 2243 controls. Overall, we found that GSTP1 Ile105Val polymorphism was not associated with skin cancer risk. Furthermore, subgroup analysis by histological types showed that GSTP1 Ile105Val polymorphism was associated with risks of malignant melanoma under the dominant model (Val/Val + Val/Ile vs. Ile/Ile: OR 1.230, 95 % CI 1.017-1.488, P = 0.033). However, lack of association between GSTP1 Ile105Val polymorphism and BCC and SCC risk in all genetic models. Our meta-analysis suggested that the GSTP1 Ile105Val polymorphism might be associated with increased risk of malignant melanoma in Caucasian population. PMID- 26044056 TI - Scaling Up the Production of Recombinant Antimicrobial Plantaricin E from a Heterologous Host, Escherichia coli. AB - Enhanced production of heterologously expressed plantaricin (plnE) from Escherichia coli BL21 (DE3) was achieved from a small- to large-scale batch culture. Starting from a 15-ml shake-flask culture grown in Luria-Bertani (LB) broth, the protein expression could be scaled up using 50 ml, 100 ml, 1 l, and 2 l batch culture. Using similar condition, plantaricin E (PlnE) was successfully expressed in a 30-l stirred fermenter. The protein was expressed as TRX-(His)6 fusion protein and separated by Ni(2+) affinity chromatography. Growth in two complex media, LB and Terrific broth (TB), was optimized and compared for the production of PlnE, which was higher in LB in comparison with that of TB. In the fermenter, 140 and 180 mg of PlnE could be produced from 12 l of culture volume at 30 and 25 degrees C, respectively. The yield of heterologously purified PlnE was found to be 1.2-1.5%, which was much higher in comparison with the plantaricins produced from the native strain of Lactobacillus plantarum (0.3 0.7%). Overproduction of PlnE with the help of heterologous expression can overcome the constraint of the low yield from producer strain and provides an easy and low-cost strategy for large-scale production. PMID- 26044054 TI - A comprehensive evidence-based review on the role of topicals and dressings in the management of skin scarring. AB - Wound healing after dermal injury is an imperfect process, inevitably leading to scar formation as the skin re-establishes its integrity. The resulting scars have different characteristics to normal skin, ranging from fine-line asymptomatic scars to problematic scarring including hypertrophic and keloid scars. Scars appear as a different colour to the surrounding skin and can be flat, stretched, depressed or raised, manifesting a range of symptoms including inflammation, erythema, dryness and pruritus, which can result in significant psychosocial impact on patients and their quality of life. In this paper, a comprehensive literature review coupled with an analysis of levels of evidence (LOE) for each published treatment type was conducted. Topical treatments identified include imiquimod, mitomycin C and plant extracts such as onion extract, green tea, Aloe vera, vitamin E and D, applied to healing wounds, mature scar tissue or fibrotic scars following revision surgery, or in combination with other more established treatments such as steroid injections and silicone. In total, 39 articles were included, involving 1703 patients. There was limited clinical evidence to support their efficacy; the majority of articles (n = 23) were ranked as category 4 LOE, being of limited quality with individual flaws, including low patient numbers, poor randomisation, blinding, and short follow-up periods. As trials were performed in different settings, they were difficult to compare. In conclusion, there is an unmet clinical need for effective solutions to skin scarring, more robust long-term randomised trials and a consensus on a standardised treatment regime to address all aspects of scarring. PMID- 26044057 TI - Effective Treatment of Staphylococcal Scalded Skin Syndrome with Platelet Microbicidal Protein in CBRB-Rb(8.17)1Iem Mice Model. AB - Skin and soft-tissue infections are among the most common infections. Staphylococcus aureus may cause a number of toxin-mediated diseases, including staphylococcal scalded skin syndrome (SSSS). The therapeutic efficacy of some antimicrobial peptides was recently evaluated in a mouse model of SSSS. This study is the first in vivo demonstration of the use of PMP to improve outcome of SSSS. Twenty-four CBRB-Rb(8.17)1Iem female mice naturally infected by endogenous S. aureus with SSSS symptoms were used in this work and divided into two equal groups. From neck of each mouse was isolated and identified endogenous exfoliative producing strain of S. aureus. PMP was obtained from human platelets and tested against Bacillus subtilis ATCC 6633. PMP had bactericidal activity against B. subtilis ATTC 6633 and endogenous strain of S. aureus at 2.0 +/- 0.5 and 14.5 +/- 0.5 ug/ml, respectively. At 4 weeks, the mice of experimental group were treated subcutaneous near exfoliative zone with 0.2 ml of PMP in final concentration 10 ug/ml every day. Control mice was injected with 0.2 ml 0.9% NaCl. At 1 day of experiment maximal zone of alopecia was at PMP-treating group (380 +/- 20 mm(2)) in comparison with control group (167 +/- 10 mm(2), p < 0.01). At 50 day of observation (22nd day after the end of treatment), the square of alopecia in control group was 1220 +/- 40 mm(2) in comparison with 870 +/- 17 mm(2) in experimental group (p < 0.01). The antistaphylococcal in vivo activity of PMP demonstrated in present study makes these molecules potentially useful for treatment of SSSS. PMID- 26044058 TI - In vivo imaging of CREB phosphorylation in awake-mouse brain. AB - The cyclic adenosine monophosphate response element binding protein (CREB) is a phosphorylation-dependent transcription factor that plays important roles in memory consolidation and several neuropsychological disorders. Although analyzing the spatiotemporal pattern of CREB phosphorylation is required for elucidating the mechanism of memory consolidation, imaging of phosphorylation of a particular protein in the brain of live animals is impossible at present. Here, we developed a method for visualizing the CREB phosphorylation in the cerebral cortex of an awake mouse using a split luciferase technique. Using this technique, we demonstrated the correlation between the change in CREB phosphorylation at a particular region in the brain and behavioral consequences induced by the administration of reserpine, a psychotropic agent. PMID- 26044059 TI - Migraine headache in children. AB - INTRODUCTION: Diagnosis of migraine headache in children can be difficult as it depends on subjective symptoms; diagnostic criteria are broader than in adults. Migraine occurs in 3% to 10% of children and increases with age up to puberty. Migraine spontaneously remits after puberty in half of children, but if it begins during adolescence it may be more likely to persist throughout adulthood. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute attacks of migraine headache in children? What are the effects of pharmacological prophylaxis for migraine headache in children? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: Twenty-three studies were included. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions. For acute symptom relief: 5HT1 agonists [such as triptans], non-steroidal anti inflammatory drugs [NSAIDs], and paracetamol. And, for prophylaxis: beta blockers, flunarizine, pizotifen, and topiramate. PMID- 26044060 TI - Comment on "deferiprone versus deferoxamine in thalassemia intermedia: results from a 5-year long-term Italian multicenter randomized clinical trial". PMID- 26044061 TI - trans-Symmetric Dynamic Covalent Systems: Connected Transamination and Transimination Reactions. AB - The development of chemical transaminations as a new type of dynamic covalent reaction is described. The key 1,3-proton shift is under complete catalytic control and can be conducted orthogonally to, or simultaneous with, transimination in the presence of an amine to rapidly yield two-dimensional dynamic systems with a high degree of complexity evolution. The transamination transimination systems are proven to be fully reversible, stable over several days, compatible with a range of functional groups, and highly tunable. Kinetic studies show transamination to be the rate-limiting reaction in the network. Furthermore, it was discovered that readily available quinuclidine is a highly potent catalyst for aldimine transaminations. This study demonstrates how connected dynamic reactions give rise to significantly larger systems than the unconnected counterparts, and shows how reversible isomerizations can be utilized as an effective diversity-generating element. PMID- 26044062 TI - Student views of stressful simulated ward rounds. AB - BACKGROUND: Medical error is common, and frequently results from a failure in non technical skills. Simulated ward rounds are an innovative new trend in undergraduate medical education. They are increasingly used to recreate the challenges of the real clinical environment to foster appropriate non-technical skills. The objective of this study is to assess whether stressful simulated ward experiences that prepare students for practice are acceptable to undergraduate participants. The simulated ward round experience ... helped students to reflect on positive behavioural changes for safe future practice METHODS: A 30-minute simulated ward round experience with a focus on medical error and distraction was constructed and its pedagogical development described. Twenty-eight final-year medical students volunteered to take part in two simulated ward exercises, with a lag time of 1 month between each. Students were asked to complete an anonymised electronic questionnaire to evaluate their experiences. A thematic analysis of qualitative responses was undertaken. RESULTS: The response rate was 96.4 per cent, with 27 of 28 students completing the evaluation questionnaires. The simulated ward round experience, although acknowledged as being stressful, helped students to reflect on positive behavioural changes for safe future practice, built confidence and was deemed to be of high fidelity. All students felt that mandatory curricular integration was important. DISCUSSION: With growing evidence on acceptability, coupled with research showing simulated ward rounds to improve undergraduate patient safety behaviours, there is a compelling argument for curricular integration. Improving the cost-effectiveness of simulation is important in realising this aim. Solutions to potentiate feasibility that also address student critique are discussed. CONCLUSION: Simulated ward rounds offer medical schools an innovative and acceptable approach to meeting the World Health Organisation's Patient Safety Curriculum. PMID- 26044063 TI - Lung Ultrasonography and Vertical Artifacts: The Shape of Air. PMID- 26044064 TI - Systemic adalimumab induces peripheral corneal infiltrates: a case report. AB - BACKGROUND: Tumor necrosis factor-alpha inhibitors are widely used agents in the treatment of immune disorders such as rheumatoid arthritis and inflammatory bowel disease. Despite their anti-inflammatory action, paradoxical drug-induced inflammatory events have been occasionally associated with the use of infliximab, etanercept, and in a lesser extent adalimumab. However, eye involvement is uncommon and anterior uveitis is the only reported ocular adverse manifestation. It can be induced by etanercept, but has also been described during adalimumab therapy. We present here the first report of recurrent peripheral corneal infiltrates following subcutaneous injections of adalimumab. CASE PRESENTATION: A 34 year-old Caucasian woman with Crohn's disease presented to the emergency department with bilateral red eyes and discomfort 36 hours after she received her bimonthly dose of subcutaneous adalimumab. Examination revealed bilateral peripheral corneal infiltrates with characteristic features of immune infiltrates. Symptoms and infiltrates regressed after topical corticosteroid therapy, but recurred after each adalimumab injection over the following weeks. CONCLUSION: Paradoxical immune reactions associated with tumor necrosis factor alpha inhibitors may result either from hypersensitivity mechanisms, or from immune-complex deposition via anti-adalimumab antibodies. Both mechanisms could explain this newly described manifestation. Care should be taken to search for corneal infiltrates in the event of red eye symptoms during adalimumab therapy since they respond to topical corticosteroids and do not necessarily prompt the discontinuation of the immunosuppressive therapy. PMID- 26044066 TI - The influence of exercise and dehydration on the urine concentrations of salbutamol after inhaled administration of 1600 ug salbutamol as a single dose in relation to doping analysis. AB - The present study investigated the influence of exercise and dehydration on the urine concentrations of salbutamol after inhalation of that maximal permitted (1600 ug) on the 2015 World Anti-Doping Agency (WADA) prohibited list. Thirteen healthy males participated in the study. Urine concentrations of salbutamol were measured during three conditions: exercise (EX), exercise+dehydration (EXD), and rest (R). Exercise consisted of 75 min cycling at 60% of VO2max and a 20-km time trial. Fluid intake was 2300, 270, and 1100 mL during EX, EXD, and R, respectively. Urine samples of salbutamol were collected 0-24 h after drug administration. Adjustment of urine concentrations of salbutamol to a specific gravity (USG) of 1.020 g/mL was compared with no adjustment. The 2015 WADA decision limit (1200 ng/mL) for salbutamol was exceeded in 23, 31, and 10% of the urine samples during EX, EXD, and R, respectively, when unadjusted for USG. When adjusted for USG, the corresponding percentages fell to 21, 15, and 8%. During EXD, mean urine concentrations of salbutamol exceeded (1325+/-599 ng/mL) the decision limit 4 h after administration when unadjusted for USG. Serum salbutamol Cmax was lower (P<0.01) for R(3.0+/-0.7 ng/mL) than EX(3.8+/-0.8 ng/mL) and EXD(3.6+/-0.8 ng/mL). AUC was lower for R (14.1+/-2.8 ng/mL.?h) than EX (16.9+/ 2.9 ng/mL.?h)(P<0.01) and EXD (16.1+/-3.2 ng/mL.?h)(P<0.05). In conclusion, exercise and dehydration affect urine concentrations of salbutamol and increase the risk of Adverse Analytical Findings in samples collected after inhalation of that maximal permitted (1600 ug) for salbutamol. This should be taken into account when evaluating doping cases of salbutamol. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26044065 TI - Specific humoral response of hosts with variable schistosomiasis susceptibility. AB - The schistosome blood flukes are some of the largest global causes of parasitic morbidity. Further study of the specific antibody response during schistosomiasis may yield the vaccines and diagnostics needed to combat this disease. Therefore, for the purposes of antigen discovery, sera and antibody-secreting cell (ASC) probes from semi-permissive rats and sera from susceptible mice were used to screen a schistosome protein microarray. Following Schistosoma japonicum infection, rats had reduced pathology, increased antibody responses and broader antigen recognition profiles compared with mice. With successive infections, rat global serological reactivity and the number of recognized antigens increased. The local antibody response in rat skin and lung, measured with ASC probes, increased after parasite migration and contributed antigen-specific antibodies to the multivalent serological response. In addition, the temporal variation of anti parasite serum antibodies after infection and reinfection followed patterns that appear related to the antigen driving the response. Among the 29 antigens differentially recognized by the infected hosts were numerous known vaccine candidates, drug targets and several S. japonicum homologs of human schistosomiasis resistance markers-the tegument allergen-like proteins. From this set, we prioritized eight proteins that may prove to be novel schistosome vaccine and diagnostic antigens. PMID- 26044068 TI - Prevalence and clinical presentation of headache in a National Neurofibromatosis 1 Service and impact on quality of life. AB - In our clinical practice, we noticed a high frequency of headaches amongst NF1 patients. We sought to characterize the phenotype and prevalence of headache in our cohort of NF1 patients attending the London NF clinic and to determine the impact on quality of life. Participants over the age of 16 fulfilling diagnostic criteria for NF1 from the general NF1 outpatient clinics at Guy's and St. Thomas' NHS Foundation Trust and the nationally commissioned Complex NF1 service were asked to fill in a questionnaire during the clinic consultation. Data were recorded regarding the headache frequency, intensity, duration, and phenotype, and a validated quality of life questionnaire, HIT-6 was also completed by the participant. IHS (International Headache Society) criteria were used to diagnose migraine. One hundred fifteen patients (48 males, 67 females) completed the questionnaire. The age range of participants was 16-67 with a mean age of 36 years. Twenty-five reported no headaches. Seventy-five (65%) fulfilled IHS diagnostic criteria for migraine (15 with aura). The mean HIT-6 score was 56 (out of a maximum 78) implying a significant effect on quality of life. Migraine is common in our NF1 population and has a significant impact on quality of life. Patients may not volunteer information regarding headache and this should be actively sought during consultations and the headache phenotype should be carefully characterized. PMID- 26044069 TI - The Protective Roles of IL-6 Trans-Signaling Regulated by ADAM9 on the Liver in Carbon Tetrachloride-Induced Liver Injury in Mice. AB - Our study was undertaken to evaluate the important role that a disintegrin and metalloproteinase 9 (ADAM9) regulates IL-6 trans-signaling in carbon tetrachloride (CCl4)-induced liver injury in mice. Mice were divided into four groups. Each group respectively received mineral oil injection, CCl4 injection, anti-ADAM9 monoclonal antibody (mAb) pretreatment and CCl4 injection, anti-ADAM9 mAb and recombinant mouse ADAM9 molecules pretreatment with CCl4 injection. Our results showed that anti-ADAM9 mAb pretreatment significantly aggravated liver injury, inhibited IL-6 trans-signaling, which led to downregulation of proliferating cell nuclear antigen (PCNA), vascular endothelial growth factor (VEGF), upregulation of Caspase3, cytochrome P450 2E1 (CYP2E1), and hepatocytes apoptosis at 24 h after CCl4 injection. Recombinant ADAM9 molecules pretreatment reversed the impact of anti-ADAM9 mAb pretreatment in mice. In conclusion, our study suggested that ADAM9 could regulate the hepatocytes proliferation, apoptosis, angiogenesis, and CYP2E1 expression by activating IL-6 trans-signaling and play important protective roles during CCl4-induced liver injury in mice. PMID- 26044070 TI - Safety and pharmacokinetics of bapineuzumab in a single ascending-dose study in Japanese patients with mild to moderate Alzheimer's disease. AB - AIM: To evaluate the safety, tolerability and pharmacokinetic profile of bapineuzumab after a single intravenous injection in Japanese patients with mild to moderate Alzheimer's disease. METHODS: Participants received either a placebo (n = 8), or bapineuzumab 0.15 (n = 6), 0.5 (n = 6), 1.0 (n = 6) or 2.0 (n = 6) mg/kg. Serum concentrations of bapineuzumab, antibapineuzumab antibody and total plasma beta-amyloidx-40 were assayed. RESULTS: Adverse events for bapineuzumab and placebo groups were 71% and 88%, respectively. Treatment-emergent adverse events (cataract, injection site hemorrhage, nasopharyngitis, pneumonia and muscle twitching) reported for >=2 participants were mild or moderate in severity and unrelated to bapineuzumab dose. No deaths, serious adverse events or withdrawals were reported. Mean peak concentration for bapineuzumab increased with dose, from 3.3 +/- 0.9 MUg/mL with the 0.15 mg/kg dose to 61.0 +/- 32.8 MUg/mL with 2.0 mg/kg. Mean bapineuzumab exposure (area under the curve from time 0 to last measurable concentration; MUg.h/mL) increased in a linear manner with increasing dose (mean 1260 for 0.15 mg/kg, 4264 for 0.5 mg/kg, 7818 for 1.0 mg/kg, 15 313 for 2.0 mg/kg). Mean half-life ranged from 15 to 28 days, and clearance was similar across dose groups (range 0.12-0.17 mL/h/kg). CONCLUSIONS: Plasma beta-amyloidx-40 levels increased with increasing doses of bapineuzumab. Bapineuzumab was safe and well tolerated at all doses in Japanese patients with mild to moderate Alzheimer's disease. Geriatr Gerontol Int 2016; 16: 644-650. PMID- 26044071 TI - Gonadotropin-releasing hormone receptor mutations in ageing men. PMID- 26044067 TI - Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naive HIV-Infected Patients: Results of the ENCORE1 Study. AB - Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naive patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68 0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL >=200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration. PMID- 26044072 TI - Impact of Melatonin on Zeitgeber Time-Dependent Changes in Cell Proliferation and Apoptosis in the Adult Murine Hypothalamic-Hypophyseal System. AB - BACKGROUND/AIMS: Cell proliferation and apoptosis are known to adjust neuroendocrine circuits to the photoperiod. The latter is communicated by melatonin, the hormone secreted by the pineal organ. The present study investigated zeitgeber time (ZT)-dependent changes in cell proliferation and apoptosis in the adult murine neuroendocrine system and their regulation by melatonin. METHODS: Adult melatonin-proficient (C3H/HeN) and melatonin-deficient (C57Bl/6J) mice, as well as melatonin-proficient (C3H/HeN) mice with targeted deletion of both melatonin receptor types (MT1 and MT2) were adapted to a 12-hour light, 12-hour dark photoperiod and were sacrificed at ZT00, ZT06, ZT12, and ZT18. Immunohistochemistry for Ki67 and activated caspase-3 served to identify and quantify proliferating and apoptotic cells in the median eminence (ME), hypophyseal pars tuberalis, and pars distalis (PD). RESULTS: ZT-dependent changes in cell proliferation and apoptosis were found exclusively in melatonin proficient mice with functional MTs. Cell proliferation in the ME and PD showed ZT-dependent changes indicated by an increase at ZT12 (ME) and a decrease at ZT06 (PD). Apoptosis showed ZT-dependent changes in all regions analyzed, indicated by an increase at ZT06. Proliferating and apoptotic cells were found in nearly all cell types residing in the regions analyzed. CONCLUSIONS: Our results indicate that ZT-dependent changes in cell proliferation are counterbalanced by ZT dependent changes in apoptosis exclusively in melatonin-proficient mice with functional MTs. Melatonin signaling appears to be crucial in both the generation and timing of proliferation and apoptosis that serve the high rate of physiological cell turnover in the adult neuroendocrine system. PMID- 26044073 TI - Ageism and age discrimination in health care: Fact or fiction? A narrative review of the literature. AB - Ageism and age discrimination are terms used in best practice statements and in the literature to define negative attitudes towards older people and towards people because of their age (whether old or young). However, 'old age' is a nebulous concept with definitions ranging from the over 50s to the over 85s. In seeking to explore ageism and age discrimination within health care, this paper discusses the concept of 'old' and discusses the findings of a narrative review of the literature on these two concepts. Results show that negative attitudes have been perceived by users of health care services, but the reasons are not clear. Such attitudes are usually reported in acute health care settings, where targets and quick turnover are encouraged. Thus people, usually those with complex needs, who require longer periods of recuperation and rehabilitation following an episode of ill health, are troublesome to staff working in a system geared up for early discharges. This type of service user is usually over the age of 85. Recommendations from this paper include the need for acute frailty units, with well trained staff, where frail older people can be comprehensively assessed, receive timely and targeted care, followed by a supported discharge. PMID- 26044074 TI - Immunosenescence: Implications for response to infection and vaccination in older people. AB - People aged 60 and older represent over 11% of the world population and it is expected to rise 22% by 2050. Population aging is associated to an increased frequency of age-related diseases including higher susceptibility to infections, cancer, cardiovascular and neurodegenerative diseases. Immunosenescence refers to the decline of the immune system associated to aging. It affects both, innate and adaptive immunity limiting the response to pathogens and to vaccines. The analyses of the immune system in elderly individuals determined several immune signatures constituting an immune risk phenotype that predicts mortality. An inverse CD4/CD8 ratio, loss of naive T cells, increased numbers of terminally differentiated T cells and oligoclonal expansions of virus-specific T cells constitute hallmarks of immunosenescence. Natural killer (NK) cells are also found severely altered in the elderly. The contribution of latent cytomegalovirus infection to immunosenescence of T and NK cells has been shown. Considering the worldwide ageing of the population in the next decades, the impact of infections will be a real health problem for older individuals requiring preventive strategies. Thus, further studies are required to analyse the bases of immunosenescence and to establish protocols to overcome the age-associated alterations of the immune response in order to define effective vaccines against those pathogens, such as influenza, contributing to increased morbidity and mortality in the elderly. PMID- 26044076 TI - Comparative life histories of fishes in the subgenus Limia (Pisces: Poeciliidae). AB - This study presents life-history descriptions for 12 species in the subgenus Limia, which are endemic to the Greater Antilles. All species in this study lack evidence of superfoetation, producing a single brood of offspring before developing subsequent broods. Interbrood intervals (number of days between parturition events) are also consistent with intervals of species that lack superfoetation. Maternal provisioning, characterized by matrotrophy index, is <1.0 for all species of Limia. This is consistent with species that provide little or no maternal provisioning to developing embryos after ovum fertilization (lecithotrophic). Four species exhibit potentially bi-modal size distributions of mature males. Work on other poeciliids suggests that such bimodal distributions can be caused by genetic polymorphisms in some species. Principle component analyses revealed an axis of interspecific variation in life histories that separated species with small size at maturity and the production of many, small offspring from those with large size at maturity and that produce few, large offspring. This pattern of life-history diversity occurs in many other groups of organisms. PMID- 26044075 TI - Calcium and vitamin D supplementation do not influence menopause-related symptoms: Results of the Women's Health Initiative Trial. AB - BACKGROUND: It is unknown whether supplementation with calcium and vitamin D has an impact on menopause-related symptoms. METHODS: As part of the Women's Health Initiative Calcium/Vitamin D Supplementation Trial (CaD), women were randomized at 40 clinical sites to elemental calcium carbonate 1000 mg with vitamin D 400 IU daily or placebo. At the CaD baseline visit (year 1 or year 2) and during a mean follow-up of 5.7 years, participants provided data on menopause-related symptoms via questionnaires. Generalized linear mixed effects techniques were used to address research questions. RESULTS: After excluding participants with missing data (N=2125), we compared menopause-related symptoms at follow-up visits of 17,101 women randomized to CaD with those of 17,056 women given the placebo. Women in the CaD arm did not have a different number of symptoms at follow-up compared to women taking the placebo (p=0.702). Similarly, there was no difference between sleep disturbance, emotional well-being, or energy/fatigue at follow-up in those who were randomized to CaD supplementation compared to those taking the placebo. CONCLUSIONS: Our data suggest that supplementation with 1000 mg of calcium plus 400 IU of vitamin D does not influence menopause-related symptoms over an average of 5.7 years of follow-up among postmenopausal women with an average age of 64 at the WHI baseline visit. PMID- 26044077 TI - Silver catalyzed gallium phosphide nanowires integrated on silicon and in situ Ag alloying induced bandgap transition. AB - In this work, we demonstrate a silver catalyzed heteroepitaxial growth of gallium phosphide nanowires (GaP NWs) on silicon. The morphology and growth direction of GaP NWs on differently orientated Si substrates were investigated. From crystallographic analysis, we inferred that Ag from catalyst is incorporated into the GaP during the chemical beam epitaxy (CBE) process. Using the PL spectrum and time-resolved emission spectroscopy, the optical properties of Ag-catalyzed GaP NWs were greatly modified, with bandgap transitions in the blue range. The Raman characterizations further confirmed the Ag incorporation into GaP during the growth. From the bandgap calculations, it was deduced that Ag was substituted on the Ga site with bandgap broadening. The in situ Ag-alloying during the growth of Ag-catalyzed GaP NWs greatly modified the band structure of GaP, and could lead to further applications in optoelectronics for low-dimensional GaP-based nanomaterials. PMID- 26044078 TI - Horizontal gene transfer and genome evolution in Methanosarcina. AB - BACKGROUND: Genomes of Methanosarcina spp. are among the largest archaeal genomes. One suggested reason for that is massive horizontal gene transfer (HGT) from bacteria. Genes of bacterial origin may be involved in the central metabolism and solute transport, in particular sugar synthesis, sulfur metabolism, phosphate metabolism, DNA repair, transport of small molecules etc. Horizontally transferred (HT) genes are considered to play the key role in the ability of Methanosarcina spp. to inhabit diverse environments. At the moment, genomes of three Methanosarcina spp. have been sequenced, and while these genomes vary in length and number of protein-coding genes, they all have been shown to accumulate HT genes. However, previous estimates had been made when fewer archaeal genomes were known. Moreover, several Methanosarcinaceae genomes from other genera have been sequenced recently. Here, we revise the census of genes of bacterial origin in Methanosarcinaceae. RESULTS: About 5% of Methanosarcina genes have been shown to be horizontally transferred from various bacterial groups to the last common ancestor either of Methanosarcinaceae, or Methanosarcina, or later in the evolution. Simulation of the composition of the NCBI protein non redundant database for different years demonstrates that the estimates of the HGT rate have decreased drastically since 2002, the year of publication of the first Methanosarcina genome. The phylogenetic distribution of HT gene donors is non uniform. Most HT genes were transferred from Firmicutes and Proteobacteria, while no HGT events from Actinobacteria to the common ancestor of Methanosarcinaceae were found. About 50% of HT genes are involved in metabolism. Horizontal transfer of transcription factors is not common, while 46% of horizontally transferred genes have demonstrated differential expression in a variety of conditions. HGT of complete operons is relatively infrequent and half of HT genes do not belong to operons. CONCLUSIONS: While genes of bacterial origin are still more frequent in Methanosarcinaceae than in other Archaea, most HGT events described earlier as Methanosarcina-specific seem to have occurred before the divergence of Methanosarcinaceae. Genes horizontally transferred from bacteria to archaea neither tend to be transferred with their regulators, nor in long operons. PMID- 26044079 TI - A comparative cephalometric study for adult operated cleft palate and unoperated cleft palate patients. AB - OBJECTIVE: To determine the effects of a cleft deformity unilateral cleft lip and palate (UCLP) and the subsequent surgical interventions on maxillary growth. MATERIALS AND METHODS: This retrospective study evaluated the lateral cephalograms of 3 groups of individuals: 40 adult patients with ULCP who underwent surgery for both lip and palate; 40 adult patients with ULCP who underwent surgery for lip only; and 40 age- and gender-matched noncleft controls. Differences in jaw morphology among them were analyzed statistically. RESULTS: Adult UCLP patients in both groups showed maxillary hypoplasia in anteroposterior and vertical directions compared with noncleft control adults. Significant differences (p <= 0.01) in the ANB (subspinale-nasion-supramentale angle), NA-FH (the angle formed between Frankfort horizontal plane and the plane from nasion to subspinale), MP-FH (the angle formed between mandibular plane and Frankfort horizontal plane), and GoMe/SN (the ratio between length of mandibular body and length of anterior cranial base) were found between the two UCLP patient groups. Although maxillary growth in the two UCLP groups was less than that in the noncleft control group, the anteroposterior growth in the UCLP patients with palatoplasty was even less than that in the UCLP patients with unoperated palate. CONCLUSIONS: There may be an intrinsic deficiency of maxillary anteroposterior and vertical development in UCLP patients compared with the noncleft controls. Palatoplasty can further limit the anteroposterior growth of maxilla but has no detrimental effect on maxillary vertical development. The mandible is rotated clockwise after palatoplasty in UCLP patients. PMID- 26044080 TI - Lambl's Excrescences: Association with Cerebrovascular Disease and Pathogenesis. AB - BACKGROUND: Lambl's excrescences (LEx) are detected by transesophageal echocardiography (TEE) and are characterized as thin, elongated, and hypermobile structures located at the leaflets' coaptation point of the heart valves. The association of LEx with cerebrovascular disease (CVD) is still undefined and yet patients with LEx and suspected CVD receive unproven effective antiplatelet or anticoagulant therapy or even undergo valve surgery. Also, the association of LEx with aging and atherogenic, inflammatory, or thrombogenic parameters has not been reported. METHODS: Seventy-seven patients with systemic lupus erythematosus (SLE) (71 women, age 37 +/- 12 years) and 26 age- and sex-matched healthy controls (22 women, age 34 +/- 11 years) prospectively underwent routine history and physical exam, transcranial Doppler, brain MRI, TEE, carotid duplex, and clinical and laboratory evaluations of atherogenesis, inflammation, platelet activity, coagulation, and fibrinolysis. Subjects without stroke/TIA on enrollment (with and without LEx) had a median follow-up of 57 months. RESULTS: On enrollment, 33 (43%) of 77 patients had CVD manifested as acute stroke/TIA (23 patients), cerebromicroembolism by transcranial Doppler (17 patients), or cerebral infarcts by MRI (14 patients). Mitral or aortic valve LEx were equally frequent in healthy controls (46%) as in patients with and without any CVD (39 and 43%), stroke/TIA (35 and 43%), cerebromicroembolism (41 and 42%), or cerebral infarcts (36 and 43%) (all p >= 0.72). Also, other mechanisms for CVD other than LEx such as Libman-Sacks vegetations, patent foramen ovale or interatrial septal aneurysm, aortic or carotid atherosclerosis, or thrombogenesis were found in >=94% of patients with CVD. In addition, 36 subjects with and 44 without LEx had similar low incidence of stroke/TIA (1 (1.3%) and 2 (2.5%), respectively, p = 1.0) during follow-up. Finally, LEx were not associated with aging, atherogenic risk factors, atherosclerosis, inflammation, or thrombogenesis. CONCLUSIONS: In this study, LEx are similarly prevalent in healthy controls and SLE patients, are not associated with CVD, and are not associated with pathogenic risk factors. Therefore, the study findings suggest that LEx may not be cardioembolic substrates, may not represent pathologic valve structures, and may not require therapy. PMID- 26044081 TI - A comparison of models for predicting early hospital readmissions. AB - Risk sharing arrangements between hospitals and payers together with penalties imposed by the Centers for Medicare and Medicaid (CMS) are driving an interest in decreasing early readmissions. There are a number of published risk models predicting 30day readmissions for particular patient populations, however they often exhibit poor predictive performance and would be unsuitable for use in a clinical setting. In this work we describe and compare several predictive models, some of which have never been applied to this task and which outperform the regression methods that are typically applied in the healthcare literature. In addition, we apply methods from deep learning to the five conditions CMS is using to penalize hospitals, and offer a simple framework for determining which conditions are most cost effective to target. PMID- 26044082 TI - Characterization of HLA-G and Related Immunosuppressive Effects in Human Umbilical Cord Stroma-Derived Stem Cells. AB - Mesenchymal stem cells (MSCs) and especially those derived from fetal tissues exert a potent immunosuppressive effect that can be enhanced under inflammatory conditions. This study aimed to explore the immunosuppressive properties of human umbilical cord mesenchymal stem cells (HUCMSCs). We found that HLA-G, the nonclassical HLA allele with strong immune-inhibitory properties, was much more expressed on the HUCMSCs than on MSCs of other origins. Flow cytometry revealed that 90.8% of the HUCMSCs expressed HLA-G. RT-PCR revealed expression of HLA-G1, HLA-G5, and HLA-G7 in all of four HUCMSC lines. In a mixed lymphocyte reaction assay, the HUCMSCs inhibited the proliferation of lymphocytes by 35 +/- 3% and could be reversed by treatment with an HLA-G blocking antibody. Upon coculture with the HUCMSCs, peripheral blood mononuclear cells expressed lower levels of proinflammatory mediators such as IL-6, TNF-alpha, and VEGF-alpha. This immunosuppressive effect was enhanced when the HUCMSCs were pretreated with IFN gamma, such that the expression of HLA-G was highly activated and HLA-DR diminished. The same phenomenon was not observed in MSCs derived from bone marrow or the placenta. In a xenograft rejection assay, the HUCMSCs survived in immunocompetent mice, whereas primary fibroblasts did not survive. This study confirms the HLA-G-related immunosuppressive property of HUCMSCs, which is more potent than MSCs of other origin. A good tolerance of this mesenchymal stem cell in allogeneic transplantation can thus be anticipated. PMID- 26044083 TI - Development of a method to predict crash risk using trend analysis of driver behavior changes over time. AB - OBJECTIVE: This study aimed at identifying and predicting in advance the point in time with a high risk of a virtual accident before a virtual accident actually occurs using the change of behavioral measures and subjective rating on drowsiness over time and the trend analysis of each behavioral measure. METHODS: Behavioral measures such as neck bending angle and tracking error in steering maneuvering during the simulated driving task were recorded under the low arousal condition of all participants who stayed up all night without sleeping. The trend analysis of each evaluation measure was conducted using a single regression model where time and each measure of drowsiness corresponded to an independent variable and a dependent variable, respectively. Applying the trend analysis technique to the experimental data, we proposed a method to predict in advance the point in time with a high risk of a virtual accident (in a real-world driving environment, this corresponds to a crash) before the point in time when the participant would have encountered a crucial accident if he or she continued driving a vehicle (we call this the point in time of a virtual accident). RESULTS: On the basis of applying the proposed trend analysis method to behavioral measures, we found that the proposed approach could predict in advance the point in time with a high risk of a virtual accident before the point in time of a virtual accident. CONCLUSION: The proposed method is a promising technique for predicting in advance the time zone with potentially high risk (probability) of being involved in an accident due to drowsy driving and for warning drivers of such a drowsy and risky state. PMID- 26044084 TI - Eplerenone in chronic heart failure with depressed systolic function. AB - Eplerenone is a selective mineralocorticoid receptor antagonist that has been recently included in the treatment of patients with chronic heart failure (CHF) and reduced systolic function. This brief review aims to summarize current evidence on the role of eplerenone in the therapy of patients with CHF. In the EPHESUS trial, 6632 post-myocardial infarction patients with ejection fraction (EF) <40% and clinical HF signs were randomized to eplerenone or placebo added to standard therapy 3 to 14 days after the event. After a 16 month follow-up period, eplerenone given early (<7 days) reduced the primary endpoints of all-cause mortality by 15% and cardiovascular death or cardiovascular hospitalization by 13%. In the subsequent EMPHASIS-HF trial, the efficacy and tolerability of eplerenone were tested in patients with mild CHF (NYHA functional class II) and EF <= 30% or between 30 and 35% with QRS duration >130 ms. After a median follow up of 21 months eplerenone significantly reduced (by 37%) the primary composite outcome of risk of death from CV causes and first hospitalization for HF. Based on the above findings, the addition of eplerenone to standard therapy, at doses to be titrated from 25 to 50mg per day, is currently recommended in CHF patients with functional classes II to IV closely resembling those enrolled in these large clinical trials, with adequate monitoring for side effects (mainly hyperkalemia and renal failure). Whether the same beneficial effects of eplerenone extend to CHF patients with mild symptoms and no additional risk factors are unknown. PMID- 26044085 TI - DNA Nanostructure-Based Magnetic Beads for Potentiometric Aptasensing. AB - In this work, a simple, general, and sensitive potentiometric platform is presented, which allows potentiometric sensing to be applied to any class of molecule irrespective of the analyte charge. DNA nanostructures are self assembled on magnetic beads via the incorporation of an aptamer into a hybridization chain reaction. The aptamer-target binding event leads to the disassembly of the DNA nanostructures, which results in a dramatic change in the surface charge of the magnetic beads. Such a surface charge change can be sensitively detected by a polycation-sensitive membrane electrode using protamine as an indicator. With an endocrine disruptor bisphenol A as a model, the proposed potentiometric method shows a wide linear range from 0.1 to 100 nM with a low detection limit of 80 pM (3sigma). The proposed sensing strategy will lay a foundation for the development of potentiometric sensors for highly sensitive and selective detection of various targets. PMID- 26044087 TI - The immunoproteasome beta5i subunit is a key contributor to ictogenesis in a rat model of chronic epilepsy. AB - The proteasome is the core of the ubiquitin-proteasome system and is involved in synaptic protein metabolism. The incorporation of three inducible immuno-subunits into the proteasome results in the generation of the so-called immunoproteasome, which is endowed of pathophysiological functions related to immunity and inflammation. In healthy human brain, the expression of the key catalytic beta5i subunit of the immunoproteasome is almost absent, while it is induced in the epileptogenic foci surgically resected from patients with pharmaco-resistant seizures, including temporal lobe epilepsy. We show here that the beta5i immuno subunit is induced in experimental epilepsy, and its selective pharmacological inhibition significantly prevents, or delays, 4-aminopyridine-induced seizure like events in acute rat hippocampal/entorhinal cortex slices. These effects are stronger in slices from epileptic vs normal rats, likely due to the more prominent beta5i subunit expression in neurons and glia cells of diseased tissue. beta5i subunit is transcriptionally induced in epileptogenic tissue likely by Toll-like receptor 4 signaling activation, and independently on promoter methylation. The recent availability of selective beta5i subunit inhibitors opens up novel therapeutic opportunities for seizure inhibition in drug-resistant epilepsies. PMID- 26044088 TI - A systematic review on the sensory reinnervation of free flaps for tongue reconstruction: Does improved sensibility imply functional benefits? AB - BACKGROUND: Tongue reconstruction after (hemi)glossectomy including sensory recovery is challenging. Although sensory recovery could improve functional outcome, no consensus on the need for reinnervation of the neo-tongue exists. Therefore, a systematic review was performed to determine if sensory reinnervation of free flaps in tongue reconstruction is better than no sensory reinnervation. The secondary study aim was to assess the effect of sensory reinnervation on overall functional outcome, such as speech and deglutition. METHODS: Seven databases (Embase, Medline, Web of Science, Scopus, PubMed publisher, Cochrane, and Google Scholar) were searched. Studies that reported the effect of sensory reinnervation on overall functional outcome were identified. RESULTS: Fourteen articles were included in the systematic review, concerning a total of 271 tongue reconstructions. Free flaps that were used were the radial forearm (RF) flap (n = 137), the anterolateral thigh (ALT) flap (n = 65), the rectus abdominis (RA) flap (n = 20), and the tensor fascia latae (TFL) flap (n = 5). Seven out of seven articles directly comparing sensory reinnervation with no sensory reinnervation revealed superior sensibility in the reinnervated group. Moreover, the innervated RF and ALT flaps showed superior recovery of sensibility compared to other flaps used for the reconstruction of hemiglossectomy as well as total glossectomy defects. There are indications that sensory reinnervation may have a beneficial effect on overall tongue function. Age, smoking, and sex did not affect sensory recovery. Four out of five articles showed that postoperative radiotherapy does not have a long-term adverse effect on sensory recovery. CONCLUSIONS: Sensory reinnervation of free flaps in the reconstruction of (hemi)glossectomy defects improves sensory recovery; however, evidence for beneficial effects on function is poor. PMID- 26044086 TI - Depression as sickness behavior? A test of the host defense hypothesis in a high pathogen population. AB - Sadness is an emotion universally recognized across cultures, suggesting it plays an important functional role in regulating human behavior. Numerous adaptive explanations of persistent sadness interfering with daily functioning (hereafter "depression") have been proposed, but most do not explain frequent bidirectional associations between depression and greater immune activation. Here we test several predictions of the host defense hypothesis, which posits that depression is part of a broader coordinated evolved response to infection or tissue injury (i.e. "sickness behavior") that promotes energy conservation and reallocation to facilitate immune activation. In a high pathogen population of lean and relatively egalitarian Bolivian forager-horticulturalists, we test whether depression and its symptoms are associated with greater baseline concentration of immune biomarkers reliably associated with depression in Western populations (i.e. tumor necrosis factor alpha [TNF-alpha], interleukin-1 beta [IL-1beta], interleukin-6 [IL-6], and C-reactive protein [CRP]). We also test whether greater pro-inflammatory cytokine responses to ex vivo antigen stimulation are associated with depression and its symptoms, which is expected if depression facilitates immune activation. These predictions are largely supported in a sample of older adult Tsimane (mean+/-SD age=53.2+/-11.0, range=34-85, n=649) after adjusting for potential confounders. Emotional, cognitive and somatic symptoms of depression are each associated with greater immune activation, both at baseline and in response to ex vivo stimulation. The association between depression and greater immune activation is therefore not unique to Western populations. While our findings are not predicted by other adaptive hypotheses of depression, they are not incompatible with those hypotheses and future research is necessary to isolate and test competing predictions. PMID- 26044089 TI - Contribution of breast skin elastometry measurement in breast augmentation surgery: A pilot study evaluating the correlation between skin elasticity and nipple-to-inframammary fold distance. PMID- 26044090 TI - ABI1 regulates carbon/nitrogen-nutrient signal transduction independent of ABA biosynthesis and canonical ABA signalling pathways in Arabidopsis. PMID- 26044092 TI - Towards recommendations for metadata and data handling in plant phenotyping. AB - Recent methodological developments in plant phenotyping, as well as the growing importance of its applications in plant science and breeding, are resulting in a fast accumulation of multidimensional data. There is great potential for expediting both discovery and application if these data are made publicly available for analysis. However, collection and storage of phenotypic observations is not yet sufficiently governed by standards that would ensure interoperability among data providers and precisely link specific phenotypes and associated genomic sequence information. This lack of standards is mainly a result of a large variability of phenotyping protocols, the multitude of phenotypic traits that are measured, and the dependence of these traits on the environment. This paper discusses the current situation of standardization in the area of phenomics, points out the problems and shortages, and presents the areas that would benefit from improvement in this field. In addition, the foundations of the work that could revise the situation are proposed, and practical solutions developed by the authors are introduced. PMID- 26044091 TI - Functional analysis of the three HMA4 copies of the metal hyperaccumulator Arabidopsis halleri. AB - In Arabidopsis halleri, the HMA4 gene has an essential function in Zn/Cd hypertolerance and hyperaccumulation by mediating root-to-shoot translocation of metals. Constitutive high expression of AhHMA4 results from a tandem triplication and cis-activation of the promoter of all three copies. The three AhHMA4 copies possess divergent promoter sequences, but highly conserved coding sequences, and display identical expression profiles in the root and shoot vascular system. Here, an AhHMA4::GFP fusion was expressed under the control of each of the three A. halleri HMA4 promoters in a hma2hma4 double mutant of A. thaliana to individually examine the function of each AhHMA4 copy. The protein showed non polar localization at the plasma membrane of the root pericycle cells of both A. thaliana and A. halleri. The expression of each AhHMA4::GFP copy complemented the severe Zn-deficiency phenotype of the hma2hma4 mutant by restoring root-to-shoot translocation of Zn. However, each copy had a different impact on metal homeostasis in the A. thaliana genetic background: AhHMA4 copies 2 and 3 were more highly expressed and provided higher Zn tolerance in roots and accumulation in shoots than copy 1, and AhHMA4 copy 3 also increased Cd tolerance in roots. These data suggest a certain extent of functional differentiation among the three A. halleri HMA4 copies, stemming from differences in expression levels rather than in expression profile. HMA4 is a key node of the Zn homeostasis network and small changes in expression level can have a major impact on Zn allocation to root or shoot tissues. PMID- 26044093 TI - From lateral root density to nodule number, the strigolactone analogue GR24 shapes the root architecture of Medicago truncatula. PMID- 26044094 TI - De novo status epilepticus with isolated aphasia. AB - BACKGROUND: Sudden onset of aphasia is usually due to stroke. Rapid diagnostic workup is necessary if reperfusion therapy is considered. Ictal aphasia is a rare condition but has to be excluded. Perfusion imaging may differentiate acute ischemia from other causes. In dubious cases, EEG is required but is time consuming and laborious. We report a case where we considered de novo status epilepticus as a cause of aphasia without any lesion even at follow-up. A 62-year old right-handed woman presented to the emergency department after nurses found her aphasic. She had undergone operative treatment of varicosis 3 days earlier. Apart from hypertension and obesity, no cardiovascular risk factors and no intake of medication other than paracetamol were reported. Neurological examination revealed global aphasia and right pronation in the upper extremity position test. Computed tomography with angiography and perfusion showed no abnormalities. Electroencephalogram performed after the CT scan showed left-sided slowing with high-voltage rhythmic 2/s delta waves but no clear ictal pattern. Intravenous lorazepam did improve EEG slightly, while aphasia did not change. Lumbar puncture was performed which likely excluded encephalitis. Magnetic resonance imaging showed cortical pathological diffusion imaging (restriction) and cortical hyperperfusion in the left parietal region. Intravenous anticonvulsant therapy under continuous EEG resolved neurological symptoms. The patient was kept on anticonvulsant therapy. Magnetic resonance imaging after 6 months showed no abnormalities along with no clinical abnormalities. CONCLUSIONS: Magnetic resonance imaging findings were only subtle, and EEG was without clear ictal pattern, so the diagnosis of aphasic status remains with some uncertainty. However, status epilepticus can mimic stroke symptoms and has to be considered in patients with aphasia even when no previous stroke or structural lesions are detectable and EEG shows no epileptic discharges. Epileptic origin is favored when CT or MR imaging reveal no hypoperfusion. In this case, MRI was superior to CT in detecting hyperperfusion. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26044095 TI - SRF-miR-29b-MMP2 axis inhibits NSCLC invasion and metastasis. AB - MicroRNAs play key roles in tumour metastasis. miR-29b was previously reported to act as a tumour suppressor or an oncogene in diverse cancers. However, its accurate function and mechanism in metastasis of no-small cell lung cancer (NSCLC) are not well known. In this study, we describe the function of miR-29b in NSCLC metastasis and its regulatory mechanisms. We found that miR-29b is downregulated in high-metastatic NSCLC cells and low-expression of miR-29b in primary NSCLC tissue was correlated with lymph node metastasis. Both gain- and loss-of-function study indicated overexpression of miR-29b could suppress migration and invasion abilities of high-metastatic NSCLC cells, while downregulation of miR-29b expression promoted migration and invasion of low metastatic NSCLC cells in vitro. Moreover, introduction of miR-29b inhibited high metastatic NSCLC cells, in vivo, metastasis to liver and lungs. Mechanistically, miR-29b, induced by the transcription factor SRF, posttranscriptionally downregulates MMP2 expression by directly targeting its 3'-untranslated regions. These findings indicate a new regulatory mode, whereby miR-29b, which is inhibited by its upstream transcription factor SRF, was able to promote its direct target MMP2 leading to NSCLC invasion and metastasis. PMID- 26044096 TI - Changes in Doctors' Working Hours: A Longitudinal Analysis. AB - The study examined changes in doctors' working hours and satisfaction with working hours over five time points and explored the influence of personal characteristics on these outcomes. Latent growth curve modeling was applied to Medicine in Australia: Balancing Employment and Life data, collected from 2008 to 2012. Findings showed that working hours significantly declined over time, with a greater decrease among males, older doctors, and doctors with fewer children. Satisfaction increased faster over time among specialists, doctors with poorer health, those whose partners did not work full-time, and those with older children. The more hours the doctors worked initially, the lower satisfaction reported, and the greater the increase in satisfaction. Findings are consistent with a culture change in the medical profession, whereby long working hours are no longer seen as synonymous with professionalism. This is important to take into account in projecting future workforce supply. PMID- 26044097 TI - 30 years of surfactant research - from basic science to new clinical treatments for the preterm infant. PMID- 26044098 TI - Ethics of birth at the limits of viability: the risky business of prediction. AB - Infants born at the limits of viability present neonatologists in particular and society in general with difficult challenges. Ethical and legal considerations establish a framework for action, although this varies between countries, departments and individuals and shows dynamic changes over time. This brief review includes a vignette telling a familiar story. In this case, the parents ask searching questions and the caring, knowledgeable neonatologist uses up-to date information to offer empathic and thoughtful guidance - a challenge for all. PMID- 26044099 TI - A unique story in neonatal research: the development of a porcine surfactant. AB - Surfactant deficiency was identified as the cause of respiratory distress syndrome (RDS) as long ago as 1959. Trials of surfactant replacement in the 1960s were unsuccessful because the preparations used contained only phospholipids and they were administered inefficiently by nebulization. In the 1970s Bengt Robertson and Goran Enhorning showed that natural surfactant, containing both phospholipids and proteins, could ameliorate the signs of RDS in immature rabbits. In the 1980s Bengt Robertson and Tore Curstedt developed a porcine surfactant, Curosurf (named after their surnames), which was effective in immature animals and was used in a pilot clinical trial beginning in 1983. Subsequent randomized clinical trials were planned a year later by Bengt Robertson, Tore Curstedt and Henry Halliday, and the first trial was begun in 1985. This showed that Curosurf reduced pulmonary air leaks and neonatal mortality in preterm infants with severe RDS. A second trial, coordinated by Christian Speer, demonstrated that multiple doses of Curosurf were more effective than a single dose. Subsequent trials conducted by the Collaborative European Multicenter Study Group, which included among others Guilio Bevilacqua, Janna Koppe, Ola Saugstad, Nils Svenningsen and Jean-Pierre Relier, showed that early treatment was more effective than later administration and that infants treated at birth had similar neurodevelopmental status to untreated controls at a corrected age of 2 years. Members of the Collaborative European Multicenter Study Group in Denmark and Sweden performed studies to demonstrate the benefits of a combination of surfactant treatment and early continuous positive airway pressure. Curosurf has also been compared with several synthetic and natural surfactants, and at a dose of 200 mg/kg Curosurf has been shown to be superior to either Survanta or Curosurf used at a dose of 100 mg/kg. Recently, new-generation synthetic surfactants containing both phospholipids and proteins have been developed. After preclinical testing, CHF5633 (developed by Tore Curstedt and Jan Johansson in collaboration with Chiesi Farmaceutici) has undergone a preliminary first study in humans under the guidance of Christian Speer. If effective, this new surfactant preparation could revolutionize the treatment of preterm infants worldwide as it could be made consistently and safely in almost unlimited quantities. This story of a porcine surfactant preparation has been truly remarkable, and many thousands of preterm babies worldwide are now alive and well because of it. PMID- 26044100 TI - Surfactant and noninvasive ventilation. AB - There is mounting evidence that early continuous positive airway pressure (CPAP) from birth is feasible and safe even in very preterm infants. However, many infants will develop respiratory distress syndrome (RDS) and require surfactant treatment. Combining a noninvasive ventilation approach with a strategy for surfactant administration is important to ensure optimal outcome, but questions remain about the optimal timing, mode of delivery and value of predictive tests for surfactant deficiency. Key findings in this review include the following: (1) a noninvasive ventilation strategy with CPAP from birth has a similar outcome to routine intubation in the delivery room; (2) prophylactic surfactant treatment has no advantage over early CPAP with selective surfactant administration; (3) surfactant during CPAP can be safely administered by rapid intubation-extubation (the INSURE method or via tracheal placement of a thin catheter), and (4) predictive tests for surfactant deficiency are being developed and might in future aid in directing surfactant treatment to infants at risk of developing severe RDS. A strategy for surfactant administration should be part of a noninvasive ventilation approach for preterm infants at risk of developing significant RDS. The different methods for surfactant administration during CPAP are reviewed here. PMID- 26044101 TI - Lungs, microbes and the developing neonate. AB - Microbes are ubiquitous on the human body and comprise approximately 90% of the cells and 99% of the genes of the human supraorganism. High-throughput sequencing technology has permitted the development of culture-independent means to identify the microbiota that are unique to the various microenvironments of the body and probably contribute some function. Although the respiratory tract interfaces with the environment, the lungs were always thought to be a sterile environment - until recently, when these techniques were applied to healthy and disease states. Further, there appears to be a complex interplay between the development of the gastrointestinal and respiratory microbiota and the regulation of immune function. The contribution of this dynamic metabolic mass to respiratory disease in the newborn is unknown. This article will review emerging data from recent human and murine studies that suggest there is a microbial influence on the development of respiratory disease, but it will also highlight many of the gaps that remain in understanding the function of the respiratory microbiome. PMID- 26044103 TI - The Story of Antenatal Steroid Therapy before Preterm Birth. AB - Antenatal glucocorticoid has proven to be one of the most successful single therapeutic approaches for preventing serious consequences after preterm birth. The fetal compartment is protected against endogenous corticosteroid by the high endogenous 11beta-hydroxysteroid dehydrogenase type 2 that converts cortisol to cortisone and by the poor responsiveness of the fetal hypothalamus to corticotropin-releasing hormone. High corticosteroid activity acutely enhances the functional maturity of the fetus. Persistently high fetal glucocorticoid activity has adverse effects on the growth and differentiation of the fetal brain and other organs. Intrauterine growth restriction may be associated with high fetal glucocorticoid activity. Antenatal glucocorticoid therapy which is aimed to be given within 1-10 days before preterm birth is likely to increase the success of postnatal noninvasive treatments of very preterm infants. PMID- 26044104 TI - Inhalation or instillation of steroids for the prevention of bronchopulmonary dysplasia. AB - Survival of extremely preterm infants has increased over recent years, but bronchopulmonary dysplasia (BPD) remains a major cause of morbidity. In the USA, BPD is the most common chronic respiratory disorder of infancy and affects the pulmonary and overall health of 10,000 preterm infants annually. Preclinical and clinical studies suggest a crucial role for lung inflammation and host immune response in the pathogenesis of BPD. Inflammation may result from, amongst others, chorioamnionitis, postnatal infection, ventilation, and the administration of oxygen. Infants with BPD have worse long-term outcomes than those without chronic lung disease. They are more than twice as likely to be readmitted to hospital in their first year of life and, having survived their primary hospitalizations, they are more likely to die than very preterm infants without chronic lung disease. Survivors with BPD have an increased risk of neurodevelopmental impairment and their respiratory function remains compromised well into adolescence. As the first generations of extremely low birth weight (ELBW) survivors have not yet reached retirement age, there are currently no reliable data addressing the association between BPD and pulmonary diseases of the elderly such as chronic obstructive pulmonary disease. Although BPD is quite common in ELBW infants, there are infants who do not develop BPD, which supports the argument that BPD is a preventable disease, emphasizing the need for high quality safety and efficacy prevention studies. However, according to an Institute of Medicine statement regarding pediatric drug studies, the therapeutic area that has the fewest drugs indicated for neonates is BPD. As inflammation seems to be a primary mediator of injury in the pathogenesis of BPD, anti inflammatory agents such as steroids have long been the focus of preventive research activities. However, systemic steroids, although reducing BPD, have frequently been linked to adverse neurodevelopmental outcomes and these considerations may have contributed to the recently reported widespread use of inhaled corticosteroids in neonatal units in North America and Europe. Inhaled corticosteroids were prescribed to 25% of infants born at <29 weeks of gestation with birth weights <1,500 g in neonatal units of 35 children's hospitals in the USA. According to a survey across all neonatal units in Germany, 46% administered inhaled corticosteroids to preterm infants either as prophylaxis or treatment for BPD [10]. Pediatricians and neonatologists should ask themselves whether the off label use of inhaled corticosteroids in preterm infants is justifiable in view of the available evidence. The authors of the pertinent review from the Cochrane Collaboration, including 7 studies and 492 infants, conclude that there is currently no evidence to support the routine use of inhaled steroids for the prevention of BPD. Recently, the primary outcome results of the Neonatal European Study of Inhaled Steroids (NEUROSIS), including 863 very preterm infants (gestational age 23-27 weeks), have been presented at scientific conferences, but the full study report is not yet published. By contrast, intratracheal instillation of budesonide using surfactant as a vehicle has not yet become part of clinical practice. There are fewer studies addressing the risks and benefits of this mode of administration. In a randomized blinded pilot study in 116 very low birth weight infants who had severe radiographic respiratory distress syndrome and required mechanical ventilation shortly after birth, early intratracheal instillation of budesonide using surfactant as a vehicle resulted in significantly lower mean airway pressure on day 1 and day 3 and a significantly lower oxygen index and PCO2 during the first 3 days compared with infants in the control group who had received surfactant without corticosteroids. More infants were extubated in the treatment group than in the controls at 1 and 2 weeks and the combined outcome of death or chronic lung disease was significantly lower in the treatment group than in the control group (19 of 60 vs. 34 of 56). No clinically significant adverse effects were observed during the study and at the time of the follow-up assessment at 2-3 years of age. In the future, intratracheal instillation of budesonide using surfactant as a vehicle may play a role in the prevention of BPD in ELBW infants. However, before this therapy can be introduced into routine clinical care, remaining open questions need to be answered and appropriately powered studies need to be performed. PMID- 26044105 TI - Stem cells for the prevention of neonatal lung disease. AB - Preterm birth affects approximately 11% of all newborns worldwide and is a major risk factor for infant mortality and morbidity. A common complication of preterm birth is the chronic lung disease of prematurity called bronchopulmonary dysplasia (BPD). Due to the lack of a specific treatment for BPD, preterm infants surviving with BPD face a lifelong risk of poor lung health. The therapeutic potential of stem cells in regenerative medicine is being harnessed for many diseases, including BPD. Compelling preclinical data using stem cells to prevent/repair lung damage in animal models of experimental BPD has built the basis for its translation into the clinic in preterm infants. This review highlights the exciting translation from bench to bedside that will hopefully lead in the near future to improved pulmonary outcomes in preterm infants. PMID- 26044102 TI - Impaired pulmonary vascular development in bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD), the chronic lung disease associated with preterm birth, results from the disruption of normal pulmonary vascular and alveolar growth. Though BPD was once described as primarily due to postnatal injury from mechanical ventilation and oxygen therapy after preterm birth, it is increasingly appreciated that BPD results from antenatal and perinatal factors that interrupt lung development in infants born at the extremes of prematurity. The lung in BPD consists of a simplified parenchymal architecture that limits gas exchange and leads to increased cardiopulmonary morbidity and mortality. This review outlines recent advances in the understanding of pulmonary vascular development and describes how the disruption of these mechanisms results in BPD. We point to future therapies that may augment postnatal vascular growth to prevent and treat this severe chronic lung disease. PMID- 26044106 TI - Delivery room management of term and preterm newly born infants. AB - Delivery room management, especially in the first 'golden' minute, is of the utmost importance. An exact and universal definition of when a baby is born is needed to obtain agreement on what is meant by the first minute of life. Education of young girls is a basic requirement to optimize the health of the mother and baby. Interventions in pregnancy should as far as possible be evidence based. Antenatal care, the selection of birth mode and antenatal steroid therapy when indicated also contribute to obtaining the best outcome. Delayed cord clamping is recommended for both preterm and term infants. However, more data are needed regarding the most immature infants. Routine suctioning of the mouth and airways is not required. Thermal control is important - keep the temperature in the delivery room at 26 degrees C and wrap infants <28 weeks of gestation in plastic. However, this procedure does not reduce mortality. Since delayed cord clamping increases mean birth weight by approximately 30 g/kg, the present birth weight charts based on early clamping need to be corrected. Preterm infants in need of ventilatory support should start with CPAP from the first breath. A T piece device seems to have some advantages compared to self-inflating bags. Surfactant instillation is often not needed prophylactically provided the mother has received antenatal steroids. Less invasive methods for administering surfactant may be useful. If ventilatory support is needed, start with air in term and near-term infants. For babies of 29-33 weeks of gestation start with 21 30% oxygen and for infants <29 weeks start with 30% oxygen and adjust according to the response obtained. PMID- 26044108 TI - Re: Enhanced Recovery Protocol after Radical Cystectomy for Bladder Cancer: S. Daneshmand, H. Ahmadi, A. K. Schuckman, A. P. Mitra, J. Cai, G. Miranda and H. Djaladat J Urol 2014;192:50-56. PMID- 26044109 TI - Re: Subcentimeter Pulmonary Nodules are Not Associated with Disease Progression in Patients with Renal Cell Carcinoma: R. Mano, E. Vertosick, A. I. Sankin, M. S. Chevinsky, Y. Larish, C. D. Jakubowski, A. M. Hotker, A. A. Hakimi, D. D. Sjoberg, O. Akin and P. Russo J Urol 2015;193:776-782. PMID- 26044110 TI - Inequalities in the use of helmets by race and payer status among pediatric cyclists. AB - BACKGROUND: Despite nationwide campaigns to increase the use of helmets among pediatric cyclists, many children continue to be injured while riding without a helmet. To determine where programs and policies intended to promote helmet use should be directed, we surveyed a large national dataset to identify variables associated with helmet use. METHODS: The National Trauma Data Bank was queried during the years 2007, 2010, and 2011 for children younger than the age of 16 years who were involved in a bicycle accident. Children were grouped based on whether they had a helmet on during the accident. A multivariable logistic mixed effects model was utilized to determine factors associated with helmet use. RESULTS: Of the 7,678 children included in the analysis, 1,695 (22.1%) were wearing a helmet during their accident. On unadjusted analysis, nonhelmeted riders were more likely to be older (median age 11 years vs 10 years, P < .001), black (10.1% vs 3.7%, P < .001) or insured by Medicaid (32.8% vs 14.3%, P < .001). After adjustment, black children were still less likely to have had worn a helmet compared with white children (adjusted odds ratio 0.38, 95% confidence interval 0.28-0.50). Children on Medicaid were also less likely to have been wearing a helmet compared to children with private insurance (adjusted odds ratio 0.33, 95% confidence interval 0.28-0.39). CONCLUSION: Children who are black or who are on Medicaid are less likely to be wearing a helmet when involved in a bicycle accident than white children or children with private insurance, respectively. Future efforts to promote helmet use should be directed towards these groups. PMID- 26044111 TI - Cognitive remediation for adolescents with 22q11 deletion syndrome (22q11DS): a preliminary study examining effectiveness, feasibility, and fidelity of a hybrid strategy, remote and computer-based intervention. AB - BACKGROUND: 22q11DS is a multiple anomaly syndrome involving intellectual and behavioral deficits, and increased risk for schizophrenia. As cognitive remediation (CR) has recently been found to improve cognition in younger patients with schizophrenia, we investigated the efficacy, feasibility, and fidelity of a remote, hybrid strategy, computerized CR program in youth with 22q11DS. METHODS: A longitudinal design was implemented in which 21 participants served as their own controls. Following an eight month baseline period in which no interventions were provided, cognitive coaches met with participants remotely for CR via video conferencing three times a week over a targeted 8month timeframe and facilitated their progress through the intervention, offering task-specific strategies. A subset of strategies were examined for fidelity. Outcomes were evaluated using a neurocognitive test battery at baseline, pre-treatment and post-treatment. RESULTS: All participants adhered to the intervention. The mean length of the treatment phase was 7.96months. A moderately high correlation (intraclass correlation coefficient, 0.73) was found for amount and type of strategies offered by coaches. Participants exhibited significant improvements (ES=.36-.55, p<=.009) in working memory, shifting attention and cognitive flexibility. All significant models were driven by improvements in pre to post-treatment scores. CONCLUSIONS: Based on our preliminary investigation, a remote, hybrid strategy, computerized CR program can be implemented with 22q11DS youth despite geographic location, health, and cognitive deficits. It appears effective in enhancing cognitive skills during the developmental period of adolescence, making this type of CR delivery useful for youth with 22q11DS transitioning into post-school environments. PMID- 26044112 TI - The negative syndrome of schizophrenia: three -underlying components are better than two. AB - AIMS: To analyse the underlying structure of the negative syndrome of schizophrenia as it is represented in the Brief Negative Symptom Scale. METHODS: Cross-sectional, multicentre study, employing data from 190 evaluations. STATISTICS: Exploratory factor analysis using the principal component analysis method. RESULTS: The three-component solution explained 77.4% of the total variance. Pearson correlation coefficients between components were: 1-2=-0.494, 1 3=-0.117, and 2-3=0.179. CONCLUSION: Our solution favours a three-component structure of the negative syndrome, consisting of: external world (anhedonia and asociality), inner world (avolition and blunted affect), and alogia, with the latter only marginally related to the two former components. PMID- 26044113 TI - The relationship between Positive and Negative Syndrome Scale (PANSS) schizophrenia severity scores and risk for hospitalization: an analysis of the CATIE Schizophrenia Trial. AB - BACKGROUND: Little is known about the effect of treatment-related changes in Positive and Negative Syndrome Scale (PANSS) schizophrenia severity scores on the risk for subsequent hospitalization. METHODS: We used limited-access data from the Clinical Antipsychotic Trials of Intervention Effectiveness Project Schizophrenia Trial (CATIE Sz) to evaluate the relationship between baseline and changes in PANSS clinical symptom scores and risks for subsequent psychiatric hospitalization. RESULTS: Reductions in PANSS total scores during a three-month period were associated with a significantly lower risk for psychiatric hospitalization (OR, 0.78, 95% CI, 0.72 to 0.84, p<0.001 for 10 point reductions). Ten-point reductions in PANSS total score during three months reduced predicted number of psychiatric hospitalizations by 0.02 (95% CI, 0.012 to 0.027) and nights in the hospital by 0.24 (95% CI, 0.07 to 0.41). Maintenance of this reduction for a year is expected to reduce psychiatric hospitalizations by 0.10 (95% CI, 0.08 to 0.13) and nights hospitalized by 1.4 (95% CI, 0.9 to 1.9). A 10-point reduction in PANSS total score was associated with a savings in psychiatric hospitalization cost of $192 over three months and $1135 over a year. CONCLUSIONS: Reductions in PANSS total scores significantly reduced risks for psychiatric hospitalizations, total number of psychiatric hospitalizations, total nights for psychiatric admissions, and the costs of these hospitalizations. These data highlight the benefits of symptom control on the direct costs of care in schizophrenia. PMID- 26044114 TI - Effects of integrated supported employment plus cognitive remediation training for people with schizophrenia and schizoaffective disorders. AB - OBJECTIVES: The present study aims to investigate the synergistic effects of cognitive remediation training (CRT) on Integrated Supported Employment (ISE). ISE blends individual placement support service with work-related social skills training for Chinese people suffering from schizophrenia or schizoaffective disorder. METHOD: Ninety participants with schizophrenia or schizoaffective disorders were recruited from two psychiatric outpatient services in Hong Kong. They were randomly assigned into the ISE+CRT (n=45) and ISE (n=45) conditions. Blinded assessments on vocational, clinical, psychological, and neurocognitive outcomes were conducted by independent assessors. The two groups were followed up at 7 and 11months. RESULTS: Both groups yielded similar improvements across several outcome domains assessed immediately after the interventions and at 7 and 11month follow-ups, but no significant group differences were found. Significant positive trends over time in vocational, clinical and cognitive outcomes consistently favored the ISE+CRT condition. CONCLUSION: While both the ISE+CRT and ISE groups demonstrated improvement in vocational, clinical, psychological, and neurocognitive outcomes, there was no evidence to show that cognitive remediation facilitated further improvement in these domains beyond gains associated with ISE alone. Further investigation is needed to fully exploit the synergistic potential of ISE combined with CRT, and to better understand which individuals experience a maximal benefit from the specific rehabilitation program components. PMID- 26044115 TI - Results of screening for cervical cancer among pregnant and non-pregnant women in Brazil. AB - OBJECTIVE: To compare cervical cytology test results among pregnant and non pregnant women, and to assess associations with age, screening history, and onset of sexual intercourse. METHODS: A retrospective analysis was conducted of cervical smears obtained from women aged 18-34 years in the Campinas region of Brazil between January 2000 and December 2009. Eligible participants had not undergone cytological screening within the previous year and had no history of precursor lesions or cervical cancer. Multinomial logistic regression was performed for different age groups, with high-grade squamous intraepithelial lesions (HSILs) as the endpoint. RESULTS: Overall, 3072 (0.4%) of 861 353 non pregnant women and 135 (0.4%) of 37 568 pregnant women had HSILs. Odds of HSIL among pregnant and non-pregnant women did not differ in any age group. An increased age at first sexual intercourse among pregnant women reduced odds of HSILs in all age groups (odds ratio 0.9 [95% confidence interval 0.8-0.9] for all). Among women aged 21-24 years, 25-29 years, and 30-34 years, some associations were identified between an interval of less than 5 years since previous screening and reduced odds of HSILs. CONCLUSION: Mandatory cervical cytology screening does not seem to be necessary for pregnant women; protocols in place for non-pregnant women should be followed. PMID- 26044116 TI - Best practices for the use of itraconazole as a replacement for ketoconazole in drug-drug interaction studies. AB - Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug-drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Development's Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLG's recommendations are based on careful review of available literature and internal industry experiences. PMID- 26044117 TI - Hydrophobically-modified poly(vinyl pyrrolidone) as a physically-associative, shear-responsive ophthalmic hydrogel. AB - The potential of hydrophobically-modified poly(vinyl pyrrolidone) as a shear responsive, self-associative hydrogel for ophthalmic applications is demonstrated. Hydrophobic modification was achieved via random copolymerization of N-vinylpyrrolidone with N-vinylformamide, the latter of which can be hydrolyzed to expose a desired degree of reactive amine groups permitting grafting of alkyl chlorides of varying alkyl chain lengths. The resulting materials formed highly shear-responsive physical hydrogels, exhibiting tunable shear thinning over 4-5 decades of viscosity from infinite shear to zero shear conditions that facilitates lubrication upon blinking and/or facile injection or drop-based delivery to the anterior or posterior segments of the eye. Viscosity changes due to self-association over time can also be tuned by changing the length of the hydrophobe, with C18-grafted materials exhibiting prolonged thickening over several weeks to form extremely stiff hydrogels and shorter grafts equilibrating significantly faster but forming weaker gels. The hydrogels remained transparent even at very high polymer concentrations (20 wt%) and are demonstrated to facilitate controlled release of a model drug (doxorubicin). The polymers exhibit minimal cytotoxicity in vitro to human corneal epithelial cells and retinal pigment epithelial cells, particularly when lower molecular weight backbone polymers were used. In vivo assessments in rabbits indicated no significant conjunctival edema or redness, secretion, corneal opacity, or iris involvement upon anterior application. Following intravitreal injection in rat eyes, no opacification of the lens, cornea or vitreous, nor any morphological or functional change to the posterior segment was observed. Examination of wholemount tissues and histology demonstrated no adverse effect from the injection or deposition of material. As such, these shear-thinning materials offer potential for drug delivery in both the anterior and posterior segments or as a vitreal replacement that can be easily administered or removed. PMID- 26044118 TI - Identity of cofactor bound to mycothiol conjugate amidase (Mca) influenced by expression and purification conditions. AB - Mycothiol serves as the primary reducing agent in Mycobacterium species, and is also a cofactor for the detoxification of xenobiotics. Mycothiol conjugate amidase (Mca) is a metalloamidase that catalyzes the cleavage of MS-conjugates to form a mercapturic acid, which is excreted from the mycobacterium, and 1-D-myo inosityl-2-amino-2-deoxy-alpha-D-glucopyranoside. Herein we report on the metal cofactor preferences of Mca from Mycobacterium smegmatis and Mycobacterium tuberculosis. Importantly, results from homology models of Mca from M. smegmatis and M. tuberculosis suggest that the metal binding site of Mca is identical to that of the closely related protein N-acetyl-1-D-myo-inosityl-2-amino-2-deoxy alpha-D-glucopyranoside deacetylase (MshB). This finding is supported by results from zinc ion affinity measurements that indicate Mca and MshB have comparable K(D)(ZnII) values (~10-20 pM). Furthermore, results from pull-down experiments using Halo-Mca indicate that Mca purifies with (stoichiometric) Fe(2+) when purified under anaerobic conditions, and Zn(2+) when purified under aerobic conditions. Consequently, Mca is likely a Fe(2+)-dependent enzyme under physiological conditions; with Zn(2+)-Mca an experimental artifact that could become biologically relevant under oxidatively stressed conditions. Importantly, these findings suggest that efforts towards the design of Mca inhibitors should include targeting the Fe(2+) form of the enzyme. PMID- 26044119 TI - Role and mechanisms of resistance of epidermal growth factor receptor antagonists in the treatment of colorectal cancer. AB - INTRODUCTION: Although epidermal growth factor receptor (EGFR) inhibitors have progressively become a relevant therapeutic arm in the treatment of patients with advanced colorectal cancer, the responses achieved are not durable and resistance invariably occurs. The advances in sequencing technology have allowed not only a more profound molecular tumor characterization but also the identification of the different molecular pathways involved in drug resistance and disease progression. These biological improvements have encouraged researchers to design clinical studies testing novel target therapies. AREAS COVERED: After discussing the results of key Phase III randomized trials and providing commentary on the most promising novel agents (Sym004, MM-151, GA201 and MEHD7945A), the authors present the future steps ahead toward a real tailored treatment. EXPERT OPINION: EGFR inhibitors are highly effective in the advanced disease setting. Although the negative predictive role of RAS and possibly BRAF mutations has already been established, more comprehensive efforts are needed to optimize the use of these drugs. At the same time, understanding the underlying biology will help basic scientists to develop new compounds able to overcome both primary and acquired resistance and help clinical researchers to test novel drugs within adequately designed trials whose results eventually are expected to reshape the overall treatment strategy. PMID- 26044120 TI - Test-retest reproducibility of the metabotropic glutamate receptor 5 ligand [18F]FPEB with bolus plus constant infusion in humans. AB - PURPOSE: [(18)F]FPEB is a promising PET radioligand for the metabotropic glutamate receptor 5 (mGluR5), a potential target for the treatment of neuropsychiatric diseases. The purpose of this study was to evaluate the test retest reproducibility of [(18)F]FPEB in the human brain. METHODS: Seven healthy male subjects were scanned twice, 3 - 11 weeks apart. Dynamic data were acquired using bolus plus infusion of 162 +/- 32 MBq [(18)F]FPEB. Four methods were used to estimate volume of distribution (V T): equilibrium analysis (EQ) using arterial (EQA) or venous input data (EQV), MA1, and a two-tissue compartment model (2 T). Binding potential (BP ND) was also estimated using cerebellar white matter (CWM) or gray matter (CGM) as the reference region using EQ, 2 T and MA1. Absolute test-retest variability (aTRV) of V T and BP ND were calculated for each method. Venous blood measurements (C V) were compared with arterial input (C A) to examine their usability in EQ analysis. RESULTS: Regional V T estimated by the four methods displayed a high degree of agreement (r (2) ranging from 0.83 to 0.99 among the methods), although EQA and EQV overestimated V T by a mean of 9 % and 7 %, respectively, compared to 2 T. Mean values of aTRV of V T were 11 % by EQA, 12 % by EQV, 14 % by MA1 and 14 % by 2 T. Regional BP ND also agreed well among the methods and mean aTRV of BP ND was 8 - 12 % (CWM) and 7 - 9 % (CGM). Venous and arterial blood concentrations of [(18)F]FPEB were well matched during equilibrium (C V = 1.01 . C A, r (2) = 0.95). CONCLUSION: [(18)F]FPEB binding shows good TRV with minor differences among analysis methods. Venous blood can be used as an alternative for input function measurement instead of arterial blood in EQ analysis. Thus, [(18)F]FPEB is an excellent PET imaging tracer for mGluR5 in humans. PMID- 26044121 TI - Clinical value of SPECT/CT in the painful total knee arthroplasty (TKA): a prospective study in a consecutive series of 100 TKA. AB - PURPOSE: Bone single photon emission computed tomography (SPECT)/CT is considered as beneficial in unhappy patients with pain, stiffness or swelling after total knee arthroplasty (TKA). The purpose of this study was to identify typical patterns of bone tracer uptake (BTU), distribution and intensity values in patients after TKA. The above findings were correlated with the type and fixation of TKA, the time from TKA and intraoperative findings at revision surgery. METHODS: A total of 100 knees of 84 consecutive patients (mean age +/- SD 70 +/- 11 years) after TKA with persistent knee pain were prospectively included. All patients underwent clinical examination, standardized radiographs and (99m)Tc hydroxymethane diphosphonate (HDP) SPECT/CT as part of a routine diagnostic algorithm. The diagnosis before and after SPECT/CT and final treatment were recorded. TKA component position was determined on 3-D reconstructed images. Intensity and anatomical distribution of BTU was determined. Maximum intensity values were recorded as well as ratios in relation to the proximal midshaft of the femur. Univariate analyses (chi-square test, Pearson's correlation and t test for independent samples) were performed (p < 0.05). RESULTS: SPECT/CT changed the clinical diagnosis and final treatment in 85/100 (85 %) knees. Intraoperative findings confirmed the preoperative SPECT/CT diagnosis in 32/33 knees (97 %). TKA loosening as well as progression of patellofemoral osteoarthritis (OA) was correctly diagnosed in 100 % of knees. Typical patterns of BTU for specific pathologies were identified. Loose femoral TKA components significantly correlated with increased BTU at the lateral femoral regions (p < 0.05). Loose tibial TKA components significantly correlated with increased BTU at all tibial regions (p < 0.05) and around the tibial peg (p > 0.01). CONCLUSION: The diagnostic benefits of SPECT/CT in patients after TKA have been proven. Typical pathology-related BTU patterns were identified, which will improve reporting quality. Due to the benefits in establishing the correct diagnosis, SPECT/CT should be part of the routine diagnostic algorithm for patients with pain after TKA. PMID- 26044122 TI - High-resolution mapping of a major effect QTL from wild tomato Solanum habrochaites that influences water relations under root chilling. AB - QTL stm9 controlling rapid-onset water stress tolerance in S. habrochaites was high-resolution mapped to a chromosome 9 region that contains genes associated with abiotic stress tolerances. Wild tomato (Solanum habrochaites) exhibits tolerance to abiotic stresses, including drought and chilling. Root chilling (6 degrees C) induces rapid-onset water stress by impeding water movement from roots to shoots. S. habrochaites responds to such changes by closing stomata and maintaining shoot turgor, while cultivated tomato (S. lycopersicum) fails to close stomata and wilts. This response (shoot turgor maintenance under root chilling) is controlled by a major QTL (designated stm9) on chromosome 9, which was previously fine-mapped to a 2.7-cM region. Recombinant sub-near-isogenic lines for chromosome 9 were marker-selected, phenotyped for shoot turgor maintenance under root chilling in two sets of replicated experiments (Fall and Spring), and the data were used to high-resolution map QTL stm9 to a 0.32-cM region. QTL mapping revealed a single QTL that was coincident for both the Spring and Fall datasets, suggesting that the gene or genes contributing to shoot turgor maintenance under root chilling reside within the marker interval H9-T1673. In the S. lycopersicum reference genome sequence, this chromosome 9 region is gene rich and contains representatives of gene families that have been associated with abiotic stress tolerance. PMID- 26044123 TI - Effects of estrogen deficiency on microstructural changes in rat alveolar bone proper and periodontal ligament. AB - The present study aimed to analyze the effects of estrogen deficiency on buccal alveolar bone proper and the periodontal ligament in ovariectomized (OVX) rats, compared with rats that had been subjected to sham treatment. Morphological and histological changes in the periodontium were analyzed using micro-computed tomography and paraffin sectioning. Sections were stained using hematoxylin and eosin, and tartrate-resistant acid phosphatase. Expression of receptor activator of nuclear factor-kappaB ligand (RANKL), dentin matrix protein 1 C-terminal (DMP1 C) and osteopontin (OPN) were analyzed using immunohistochemistry. Histomorphometric analysis of buccal alveolar bone proper samples revealed porotic changes and disorganized bone structure in OVX rats. Furthermore, bone mineral density and pore spacing were significantly lower in OVX rats compared with sham rats. Porosity was significantly higher in OVX rats compared with sham rats (P<0.01). A greater number of osteoclasts were observed along the margins of the buccal alveolar bone proper samples from OVX rats compared with those from the sham rats. Expression of OPN and RANKL was significantly higher, and that of DMP1-C was significantly lower, in OVX rats compared with sham rats. Ovariectomy induced osteoporosis is capable of changing the structure of buccal alveolar bone proper and the periodontal ligament, which is likely to increase the risk of periodontal disease. PMID- 26044124 TI - Oxidized and reduced [2Fe-2S] clusters from an iron(I) synthon. AB - Synthetic [2Fe-2S] clusters are often used to elucidate ligand effects on the reduction potentials and spectroscopy of natural electron-transfer sites, which can have anionic Cys ligands or neutral His ligands. Current synthetic routes to [2Fe-2S] clusters are limited in their feasibility with a range of supporting ligands. Here, we report a new synthetic route to synthetic [2Fe-2S] clusters, through oxidation of an iron(I) source with elemental sulfur. This method yields a neutral diketiminate-supported [2Fe-2S] cluster in the diiron(III)-oxidized form. The oxidized [2Fe-2S] cluster can be reduced to a mixed valent iron(II) iron(III) compound. Both the diferric and reduced mixed valent clusters are characterized using X-ray crystallography, Mossbauer spectroscopy, EPR spectroscopy and cyclic voltammetry. The reduced compound is particularly interesting because its X-ray crystal structure shows a difference in Fe-S bond lengths to one of the iron atoms, consistent with valence localization. The valence localization is also evident from Mossbauer spectroscopy. PMID- 26044125 TI - A new horizon for liver support in acute liver failure. PMID- 26044128 TI - Corrigendum. PMID- 26044126 TI - Ursodeoxycholic acid inhibits hepatic cystogenesis in experimental models of polycystic liver disease. AB - BACKGROUND & AIMS: Polycystic liver diseases (PLDs) are genetic disorders characterized by progressive biliary cystogenesis. Current therapies show short term and/or modest beneficial effects. Cystic cholangiocytes hyperproliferate as a consequence of diminished intracellular calcium levels ([Ca(2+)]i). Here, the therapeutic value of ursodeoxycholic acid (UDCA) was investigated. METHODS: Effect of UDCA was examined in vitro and in polycystic (PCK) rats. Hepatic cystogenesis and fibrosis, and the bile acid (BA) content were evaluated from the liver, bile, serum, and kidneys by HPLC-MS/MS. RESULTS: Chronic treatment of PCK rats with UDCA inhibits hepatic cystogenesis and fibrosis, and improves their motor behaviour. As compared to wild-type animals, PCK rats show increased BA concentration ([BA]) in liver, similar hepatic Cyp7a1 mRNA levels, and diminished [BA] in bile. Likewise, [BA] is increased in cystic fluid of PLD patients compared to their matched serum levels. In PCK rats, UDCA decreases the intrahepatic accumulation of cytotoxic BA, normalizes their diminished [BA] in bile, increases the BA secretion in bile and diminishes the increased [BA] in kidneys. In vitro, UDCA inhibits the hyperproliferation of polycystic human cholangiocytes via a PI3K/AKT/MEK/ERK1/2-dependent mechanism without affecting apoptosis. Finally, the presence of glycodeoxycholic acid promotes the proliferation of polycystic human cholangiocytes, which is inhibited by both UDCA and tauro-UDCA. CONCLUSIONS: UDCA was able to halt the liver disease of a rat model of PLD through inhibiting cystic cholangiocyte hyperproliferation and decreasing the levels of cytotoxic BA species in the liver, which suggests the use of UDCA as a potential therapeutic tool for PLD patients. PMID- 26044127 TI - Urinary bladder urothelial carcinoma with concurrent plasmacytoid and micropapillary differentiations: A report of two cases with an emphasis on serum carbohydrate antigen 19-9. AB - We report two cases of urinary bladder urothelial carcinoma (UC). In both, histological examination of a transurethral resection specimen of the bladder tumor revealed UC with plasmacytoid and micropapillary differentiations. In Case 1, residual plasmacytoid UC deeply invaded the extravesical fat tissue of the radical cystectomy specimen, and metastatic carcinoma was found in almost all the dissected lymph nodes. Despite adjuvant chemotherapy and radiotherapy, the patient died 25 months postdiagnosis. Elevated serum carbohydrate antigen 19-9 (CA19-9) returned to near normal levels after radical cystectomy, but they increased shortly before death. In Case 2, no residual carcinoma was found in the radical cystectomy specimen or lymph nodes. Postoperative serum CA19-9 was maintained at normal levels, and the patient remains alive without recurrence or metastasis. Although plasmacytoid and micropapillary UC are known aggressive variants of UC, plasmacytoid UC may be more aggressive. Serum CA19-9 could serve as a useful biomarker to monitor progression of plasmacytoid UC. PMID- 26044129 TI - Novel therapeutics for coronary artery disease from genome-wide association study data. AB - BACKGROUND: Coronary artery disease (CAD), one of the leading causes of death globally, is influenced by both environmental and genetic risk factors. Gene centric genome-wide association studies (GWAS) involving cases and controls have been remarkably successful in identifying genetic loci contributing to CAD. Modern in silico platforms, such as candidate gene prediction tools, permit a systematic analysis of GWAS data to identify candidate genes for complex diseases like CAD. Subsequent integration of drug-target data from drug databases with the predicted candidate genes can potentially identify novel therapeutics suitable for repositioning towards treatment of CAD. METHODS: Previously, we were able to predict 264 candidate genes and 104 potential therapeutic targets for CAD using Gentrepid (http://www.gentrepid.org), a candidate gene prediction platform with two bioinformatic modules to reanalyze Wellcome Trust Case-Control Consortium GWAS data. In an expanded study, using five bioinformatic modules on the same data, Gentrepid predicted 647 candidate genes and successfully replicated 55% of the candidate genes identified by the more powerful CARDIoGRAMplusC4D consortium meta-analysis. Hence, Gentrepid was capable of enhancing lower quality genotype phenotype data, using an independent knowledgebase of existing biological data. Here, we used our methodology to integrate drug data from three drug databases: the Therapeutic Target Database, PharmGKB and Drug Bank, with the 647 candidate gene predictions from Gentrepid. We utilized known CAD targets, the scientific literature, existing drug data and the CARDIoGRAMplusC4D meta-analysis study as benchmarks to validate Gentrepid predictions for CAD. RESULTS: Our analysis identified a total of 184 predicted candidate genes as novel therapeutic targets for CAD, and 981 novel therapeutics feasible for repositioning in clinical trials towards treatment of CAD. The benchmarks based on known CAD targets and the scientific literature showed that our results were significant (p < 0.05). CONCLUSIONS: We have demonstrated that available drugs may potentially be repositioned as novel therapeutics for the treatment of CAD. Drug repositioning can save valuable time and money spent on preclinical and phase I clinical studies. PMID- 26044130 TI - The implant infection paradox: why do some succeed when others fail? Opinion and discussion paper. AB - Biomaterial-implants are frequently used to restore function and form of human anatomy. However, the presence of implanted biomaterials dramatically elevates infection risk. Paradoxically, dental-implants placed in a bacteria-laden milieu experience moderate failure-rates, due to infection (0.0-1.1%), similar to the ones of joint-arthroplasties placed in a near-sterile environment (0.1-1.3%). Transcutaneous bone-fixation pins breach the immune-barrier of the epidermis, exposing underlying sterile-tissue to an unsterile external environment. In contrast to dental-implants, also placed in a highly unsterile environment, these pins give rise to relatively high infection-associated failure-rates of up to 23.0%. Herein, we attempt to identify causes as to why dental-implants so often succeed, where others fail. The major part of all implants considered are metal made, with similar surface-finishes. Material choice was therefore discarded as underlying the paradox. Antimicrobial activity of saliva has also been suggested as a cause for the success of dental-implants, but was discarded because saliva is the implant-site-fluid from which viable bacteria adhere. Crevicular fluid was discarded as it is largely analogous to serum. Instead, we attribute the relative success of dental-implants to (1) ability of oral tissues to heal rapidly in the continuous presence of commensal bacteria and opportunistic pathogens, and (2) tolerance of the oral immune-system. Inability of local tissue to adhere, spread and grow in presence of bacteria and an intolerant immune-system are identified as the likely main causes explaining the susceptibility of other implants to infection-associated failure. In conclusion, it is the authors' belief that new anti-infection strategies for a wide range of biomaterial-implants may be derived from the relative success of dental-implants. PMID- 26044131 TI - Successful Pregnancy and Neobladder Subsequent to Muscle Invasive Bladder Cancer and Fertility Preserving Surgery: Case Report and Review of the Literature. AB - We report a successful pregnancy and birth subsequent to fertility-preserving cystectomy and neobladder formation in a muscle-invasive sarcomatoid urothelial carcinoma. PMID- 26044132 TI - Management of anaemia in chronic kidney disease: summary of updated NICE guidance. PMID- 26044133 TI - Do we prescribe medicines rationally? PMID- 26044134 TI - Exclusively breastfed overweight infants are at the same risk of childhood overweight as formula fed overweight infants. AB - BACKGROUND AND OBJECTIVE: Several early life determinants play a role in childhood obesity. Rapid weight gain and overweight in infancy increases the risk while breast feeding seems to protect against childhood overweight. However, should we worry about exclusively breastfed overweight infants? The aim of the study is to examine the association of feeding type (exclusive breast feeding (EBF), formula feeding or mixed feeding) and overweight at the age of 6 months with the risk of overweight at the age of 5-6 years. METHODS: The Amsterdam Born Children and their Development study is a large prospective population-based birth cohort study conducted in Amsterdam, the Netherlands. Children with complete information pertaining to feeding type and weight status at the age of 6 months and 5-6 years were included (N=3367). EBF was defined as receiving only breast feeding for at least 3 months. Overweight at the ages of 6 months and 5-6 years were defined by the WHO child growth standards and the International Obesity Task Force guidelines, respectively. The association of feeding type and overweight at 6 months with overweight at 5-6 years was assessed using logistic regression analyses. RESULTS: Overweight infants have a 4.10-fold (95% CI 2.91 to 5.78) higher odds of childhood overweight compared with those who were not overweight, independent of feeding type. EBF did not affect the association between infant overweight and childhood overweight. CONCLUSIONS: Overweight in infancy increases the odds of childhood overweight, equally for exclusively breastfed and formula fed infants. Overweight prevention should start before or at birth and applies to formula fed children as well as exclusively breastfed children. PMID- 26044135 TI - Hypokalaemia in children with asthma treated with nebulised salbutamol. PMID- 26044136 TI - The voices of children and young people in health: where are we now? PMID- 26044137 TI - Pattern of symptoms and signs of primary intracranial tumours in children and young adults: a record linkage study. AB - OBJECTIVE: To describe the age pattern and temporal evolution of symptoms and signs of intracranial tumours in children and young adults before diagnosis. DESIGN AND SETTING: A record linkage study using population-based data from the National Cancer Registry, linked to Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). PATIENT COHORT: Patients aged 0-24 years when diagnosed with a primary intracranial tumour between 1989 and 2006 in England. METHODS: Linked records of relevant symptoms and signs in primary care and hospitals were extracted from CPRD (1989-2006, 181 patients) and HES (1997 2006, 3959 patients). Temporal and age-specific changes in presentation rates before diagnosis of an intracranial tumour, for each of eight symptom groups, were estimated in generalised additive models. RESULTS: All symptoms presented with increasing frequency until eventual diagnosis. The frequency of presentation of raised intracranial pressure (ICP) to hospitals rose rapidly to 36.4 per 100 person-months (95% CI 34.6 to 38.4) in the final month before diagnosis in the entire cohort. Clinical features in primary care were less specific: the main features were visual disturbance (rate: 0.49 per 100 person-months; 95% CI 0.33 to 0.72) in newborns to 4-year-olds, headache in 5-year-olds to 11-year-olds (0.64; 0.47 to 0.88), 12-year-olds to 18-year-olds (1.59; 1.21 to 2.08) and 19 year-olds to 24-year-olds (2.44; 1.71 to 3.49). The predominant features at hospital admission were those of raised ICP: between 1.17 per 100 person-months (95% CI 1.08 to 1.26) in newborns to 4-year-olds and 0.77 (0.67 to 0.88) in 19 year-olds to 24-year-olds. CONCLUSIONS: Non-localising symptoms and signs were more than twice as common as focal neurological signs. An intracranial tumour should be considered in patients with relevant symptoms that do not resolve or that progress rapidly. PMID- 26044138 TI - Is there a greater maternal than paternal influence on offspring adiposity in India? AB - Previous research has provided conflicting evidence regarding fetal roots of adiposity in India. To compare the strength of association between maternal and paternal body mass indexes (BMIs) corrected for height with offspring BMI in India to examine the potential for intrauterine mechanisms to influence offspring adiposity in India, we analysed a sample of 16,528 mother-father-offspring trios from the 2005 to 2006 Indian National Family Health Survey. Children were aged 0 59 months with parents aged 15-49 years (mothers) and 15-54 years (fathers). Linear and logistic regression models, specified in multiple ways, were used to estimate associations between parental BMI* (BMI redefined by power term x (kg/m(x)) to be independent from height), and child BMI/top decile of child BMI. Higher values of maternal BMI and paternal BMI were associated with higher values of offspring BMI. In comparing the effects of maternal BMI and paternal BMI, however, no consistent differences were found in the strength of these parental influences on offspring BMI. In the fully adjusted linear model, the standardised coefficient was 0.131 (95% CI 0.110 to 0.154) for maternal BMI* and 0.079 (95% CI 0.056 to 0.103) for paternal BMI*; with evidence of heterogeneity between maternal-offspring and paternal-offspring associations (p=0.005). This was not robust in the unstandardised regression (beta=0.056, 95% CI 0.044 to 0.067 for maternal BMI and beta=0.039, 95% CI 0.025 to 0.053 for paternal BMI, p=0.093). Mixed results indicate that compared with paternal BMI, maternal BMI did not have a consistently stronger influence on offspring BMI in India. PMID- 26044140 TI - Patients with diabetes type 1 and thyroid autoimmunity have low prevalence of microangiopathic complications. PMID- 26044139 TI - Modulation of Clr Ligand Expression and NKR-P1 Receptor Function during Murine Cytomegalovirus Infection. AB - Viruses are known to induce pathological cellular states that render infected cells susceptible or resistant to immune recognition. Here, we characterize an MHC-I-independent natural killer (NK) cell recognition mechanism that involves modulation of inhibitory NKR-P1B:Clr-b receptor-ligand interactions in response to mouse cytomegalovirus (MCMV) infection. We demonstrate that mouse Clr-b expression on healthy cells is rapidly lost at the cell surface and transcript levels in a time- and dose-dependent manner upon MCMV infection. In addition, cross-species infections using rat cytomegalovirus (RCMV) infection of mouse fibroblasts and MCMV infection of rat fibroblasts suggest that this response is conserved during host-pathogen interactions. Active viral infection appears to be necessary for Clr-b loss, as cellular stimulation using UV-inactivated whole virus or agonists of many innate pattern recognition receptors failed to elicit efficient Clr-b downregulation. Notably, Clr-b loss could be partially blocked by titrated cycloheximide treatment, suggesting that early viral or nascent host proteins are required for Clr-b downregulation. Interestingly, reporter cell assays suggest that MCMV may encode a novel Clr-b-independent immunoevasin that functionally engages the NKR-P1B receptor. Together, these data suggest that Clr b modulation is a conserved innate host cell response to virus infection that is subverted by multiple CMV immune evasion strategies. PMID- 26044141 TI - 24 h nesfatin-1 treatment promotes apoptosis in cardiomyocytes. PMID- 26044142 TI - Ecophysiological and ultrastructural effects of dust pollution in lichens exposed around a cement plant (SW Slovakia). AB - The study investigated the ecophysiological and ultrastructural effects of dust pollution from a cement industry in the lichen species Evernia prunastri and Xanthoria parietina, which were exposed for 30, 90 and 180 days around a cement mill, two quarries, and inhabited and agricultural sites in SW Slovakia. The results showed that dust deposition from quarrying activities and cement works at the cement mill (mainly enriched in Ca, Fe and Ti) significantly affected the photosynthetic apparatus of E. prunastri (sensitive to dust and habitat eutrophication), while X. parietina (tolerant to dust and habitat eutrophication) adapted to the new environment. The length of the exposure strongly affected the vitality of the mycobiont (measured as dehydrogenase activity) in transplanted lichens. Dust deposition led to ultrastructural alterations, including lipid droplets increase, swelling of cellular components, thylakoid degeneration and sometimes plasmolysis, which, on the whole, gave the cells an aged appearance. Photosynthetic parameters deserve further attention as potential indicators for monitoring early biological symptoms of the air pollution caused during cement production. PMID- 26044143 TI - Monitoring of heavy metal burden in mute swan (Cygnus olor). AB - Concentrations of heavy metals (especially arsenic, cadmium, chromium, copper, mercury and lead) were measured in the contour (body) feathers of mute swans (Cygnus olor) and in its nutrients (fragile stonewort [Chara globularis], clasping leaf pondweed [Potamogeton perfoliatus], Eurasian watermilfoil [Myriophyllum spicatum], fennel pondweed [Potamogeton pectinatus]) to investigate the accumulation of metals during the food chain. The samples (17 feathers, 8 plants) were collected at Keszthely Bay of Lake Balaton, Hungary. Dry ashing procedure was used for preparing of sample and the heavy metal concentrations were analysed by inductively coupled plasma optical emission spectroscopy (ICP OES). Copper (10.24 +/- 2.25 mg/kg) and lead (1.11 +/- 1.23 mg/kg) were detected the highest level in feathers, generally, the other metals were mostly under the detection limit (0.5 mg/kg). However, the concentrations of the arsenic (3.17 +/- 1.87 mg/kg), cadmium (2.41 +/- 0.66 mg/kg) and lead (2.42 +/- 0.89 mg/kg) in the plants were low but the chromium (198.27 +/- 102.21 mg/kg) was detected in high concentration. PMID- 26044144 TI - Human health risk assessment of heavy metals in tropical fish and shellfish collected from the river Buriganga, Bangladesh. AB - Although fish, crustacean, and shellfish are significant sources of protein, they are currently affected by rapid industrialization, resulting in increased concentrations of heavy metals. Accumulation of heavy metals (V, Cr, Mn, Ni, Cu, Zn, As, Se, Mo, Ag, Cd, Sb, Ba, and Pb) and associated human health risk were investigated in three fish species, namely Ailia coila, Gagata youssoufi, and Mastacembelus pancalus; one crustacean (prawn), Macrobrachium rosenbergii; and one Gastropoda, Indoplanorbis exustus, collected from the Buriganga River, Bangladesh. Samples were collected from the professional fishermen. Cu was the most accumulated metal in M. rosenbergii. Ni, As, Ag, and Sb were in relatively lower concentrations, whereas relatively higher accumulation of Cr, Mn, Zn, and Se were recorded. Mn, Zn, and Pb were present in higher concentrations than the guidelines of various authorities. There were significant differences in metal accumulation among different fish, prawn, or shellfish species. Target hazard quotient (THQ) and target cancer risk (TR) were calculated to estimate the non carcinogenic and carcinogenic health risks, respectively. The THQ for individual heavy metals were below 1 suggesting no potential health risk. But combined impact, estimated by hazard index (HI), suggested health risk for M. pancalus consumption. Although consumption of fish at current accumulation level is safe but continuous and excess consumption for a life time of more than 70 years has probability of target cancer risk. PMID- 26044145 TI - Efficacy of Caraway Oil Poultices in Treating Irritable Bowel Syndrome--A Randomized Controlled Cross-Over Trial. AB - BACKGROUND/AIM: Irritable bowel syndrome (IBS) is a frequent gastrointestinal disorder, with only limited evidence regarding self-management approaches. This study tested the efficacy of caraway oil poultices (CarO) for treating IBS. METHODS: This randomized controlled open-label cross-over trial included three treatment periods with hot CarO and hot olive oil poultice (OlivH) or nonheated poultices (OlivC) with olive oil as control interventions. Patients applied each intervention daily for 3 weeks. The primary outcome was symptom severity (IBS SSS); secondary outcomes included responder rates (improvement >= 50 IBS-SSS), quality of life (EQ-5D, IBS-QOL), psychological distress (HADS), adequate relief, and safety. RESULTS: 48 patients with IBS were included (40 females, 53.9 +/- 14.4 years). A significant difference was found for symptom severity in favor of CarO compared to OlivC (difference -38.4, 95% CI -73.6, -3.1, p = 0.033), but not compared to OlivH (difference -24.3, 95% CI -56.5, 7.9, p = 0.139). Responder rates were highest for CarO compared to OlivH and OlivC (43.9, 20.0, 18.9%, respectively). Within the CarO, 51.8% reported adequate relief compared to 23.5% (OlivH) and 25.8% (OlivC). One adverse event (gastrointestinal infection) was reported during CarO. CONCLUSION: Hot caraway oil poultices appear effective and safe, although their effects may be a result of the heat application. Patients reported highest levels of subjective benefit from caraway oil poultices, making their use appropriate in the self-management of IBS. PMID- 26044146 TI - Motivation and satisfaction among community health workers in Morogoro Region, Tanzania: nuanced needs and varied ambitions. AB - BACKGROUND: In 2012, the Ministry of Health and Social Welfare (MOHSW), Tanzania, approved national guidelines and training materials for community health workers (CHWs) in integrated maternal, newborn and child health (Integrated MNCH), with CHWs trained and deployed across five districts of Morogoro Region soon after. To inform future scale up, this study assessed motivation and satisfaction among these CHWs. METHODS: A survey of all CHWs trained by the Integrated MNCH Programme was conducted in the last quarter of 2013. Motivation and satisfaction were assessed using a five-point Likert scale with 29 and 27 items based on a literature review and discussions with CHW programme stakeholders. Exploratory factor analysis was conducted to identify motivation and satisfaction determinants. RESULTS: Out of 238 eligible CHWs, 96 % were included in the study. Findings showed that respondents were motivated to become CHWs due to altruism (work on MNCH, desire to serve God, work hard) and intrinsic needs (help community, improve health, pride) than due to external stimuli (monetary incentives, skill utilization, community respect or hope for employment). CHWs were satisfied by relationships with health workers and communities, job aids and the capacity to provide services. CHWs were dissatisfied with the lack of transportation, communication devices and financial incentives for carrying out their tasks. Factors influencing motivation and satisfaction did not differ across CHW socio-demographic characteristics. Nonetheless, older and less educated CHWs were more likely to be motivated by altruism, intrinsic needs and skill utilization, community respect and hope for employment. Less educated CHWs were more satisfied with service and quality factors and more wealthy CHWs satisfied with job aids. CONCLUSION AND RECOMMENDATIONS: A combination of financial and non-financial incentives is required to support motivation and satisfaction among CHWs. Although CHWs joined mainly due to their altruistic nature, they became discontented with the lack of monetary compensation, transportation and communication support received. With the planned rollout of the national CHW cadre, improved understanding of CHWs as a heterogeneous group with nuanced needs and varied ambitions is vital for ensuring sustainability. PMID- 26044147 TI - Enzymatic Decoration of Prebiotic Galacto-oligosaccharides (Vivinal GOS) with Sialic Acid Using Trypanosoma cruzi trans-Sialidase and Two Bovine Sialoglycoconjugates as Donor Substrates. AB - Decoration of prebiotic galacto-oligosaccharides (GOS) with sialic acid yields mixtures of GOS and sialylated GOS (Sia-GOS), novel products that are expected to have both prebiotic and antiadhesive functionalities. The recombinantly produced trans-sialidase enzyme from Trypanosoma cruzi (TcTS), an enzyme with the ability to transfer (alpha2-3)-linked sialic acid from sialogalactoglycans to asialogalactoglycans, was employed to catalyze this sialylation. As sialic acid acceptor substrates, Vivinal GOS and derived fractions of specific degree of polymerization were taken. As sialic acid donor substrates, bovine kappa-casein derived glycomacropeptide [>99% N-acetylneuraminic acid (Neu5Ac); <1% N glycolylneuraminic acid (Neu5Gc)] and bovine blood plasma glycoprotein mixture (45% Neu5Ac; 55% Neu5Gc) were selected, yielding potential food and feed products, respectively. High-pH anion-exchange chromatography, matrix-assisted laser-desorption ionization time-of-flight mass spectrometry, and nuclear magnetic resonance spectroscopy were used for product analysis. PMID- 26044148 TI - Vaginal progesterone for prevention of preterm labor in asymptomatic twin pregnancies with sonographic short cervix: a randomized clinical trial of efficacy and safety. AB - PURPOSE: To evaluate the value of vaginal progesterone therapy for reduction of preterm labor in asymptomatic women with twin pregnancies and sonographic short cervix. METHODS: This randomized controlled study was conducted in Mansoura University Hospital and private practice settings in Mansoura, Egypt. Of 322 women with dichorionic twin pregnancy, 250 asymptomatic women with cervical length of 20-25 mm at 20-24 weeks of gestation were included in the study. All women were randomly divided into two groups; the study group (n = 125) received vaginal progesterone suppositories in a dose of 400 mg daily starting at 20-24 weeks of gestation while the control group (n = 125) received no treatment. The primary outcome measure was preterm labor before 34 weeks of gestation and the secondary outcome measures were neonatal respiratory distress syndrome (RDS) and early neonatal death (END). RESULTS: 224 women (116 in the study group and 108 in the control group) were subjected to final analysis. The duration of pregnancy was significantly longer in the study group and the incidence of preterm labor before 34 and 32 weeks of gestation was significantly lower in the study group. The neonatal morbidities and mortality were significantly lower in the study group as shown by lower incidence of very low (<1500 gm) birth weight, neonatal RDS, the need for mechanical ventilation and END. CONCLUSIONS: Vaginal progesterone administration in asymptomatic twin pregnancies with sonographic short cervix (20-25 mm) at 20-24 weeks of gestation is effective and safe treatment for reducing the incidence of preterm labor with subsequent reduction in the neonatal morbidities and mortality associated with preterm birth. PMID- 26044149 TI - Macrosomic and low birth weight neonates in Pacific Islanders from Samoa: a case control study. AB - BACKGROUND: To assess the perinatal morbidity and mortality of macrosomic (>4500 g) and low birth weight (LBW) (<2500 g) neonates in a Pacific Islander population (PIP) from Samoa compared to a Caucasian population (CP). METHODS: Case-control study. Clinical data were extracted by chart review. RESULTS: In 3166 (PIP) and 2101 (CP) deliveries, macrosomia was more prevalent and LBW less prevalent in the PIP [76/3166 (2.4 %) vs. 21/2101 (0.9 %); p < 0.0001 and 149/3166 (4.7 %) vs. 163/2101 (7.7 %); p < 0.0001, respectively]. Among macrosomic neonates, perinatal mortality and composite severe neonatal morbidity (CNM) were higher in the PIP compared to the CP [2/76 (3 %) vs. 0/21 (0 %) and 6/76 (7 %) vs. 1/21 (4 %), respectively]. Among LBW neonates, mortality, but not CNM, was significantly higher in the PIP [16/149 (7 %) vs. 2/163 (1 %), p < 0.0001 and 10/149 (6 %) vs. 5/163 (3 %), p = 0.2, respectively]. The proportion of macrosomic neonates transferred to the Neonatal Intensive Care Unit was significantly higher in the PIP [50/76 (65 %) vs. 0/21 (0 %), p < 0.0001]. Age, body mass index, and delivery mode did not independently predict CNM. CONCLUSION: Samoan women have higher rates of macrosomia and lower rates of LBW compared to Caucasians, suggesting an anthropomorphic basis of this phenomenon. PMID- 26044150 TI - Amniotic fluid CA-125 as a marker of intra-amniotic inflammation associated with preterm delivery: a preliminary single center study. AB - OBJECTIVE: The purpose of this study was to investigate whether amniotic fluid (AF) CA-125 in patients with preterm labor or preterm premature rupture of membranes can help predict intra-amniotic inflammation (IAI), microbial invasion of the amniotic cavity (MIAC) and imminent delivery. METHODS: We recruited 36 women who admitted with impending preterm delivery and suspicious AF infection. AF matrix metalloproteinase-8 (MMP-8), white blood cell (WBC) count, glucose levels, and CA-125 levels were measured, and the MMP-8 bedside rapid test was also performed. AF culture and PCR were subsequently performed to confirm MIAC. We compared AF CA-125 levels according to the presence of IAI or MIAC and assessed its predictive value for delivery within 7 days of admission. RESULTS: AF CA-125 levels were significantly higher in the IAI group than in the non-IAI group (mean +/- standard deviation: 5608 +/- 864 vs 904 +/- 84 IU/ml; p = 0.001). AF CA-125 levels showed a negative correlation with gestational age and a positive correlation with AF WBC counts and MMP-8 levels. AF CA-125 levels were higher in the MIAC group, though this difference was not statistically significant (p = 0.064). Delivery within 7 days of admission was significantly more common in patients with higher AF CA-125 levels (cut-off: 1650 IU/ml, sensitivity: 71.4 %, specificity: 86.4 %, p = 0.005). CONCLUSION: AF CA-125 levels are increased in patients with AF inflammation and can be a predictor of imminent preterm delivery. PMID- 26044151 TI - Novel use of photoplethysmographic technology (NexfinTM) for real-time assessment of cardiac output during endovascular stenting in a patient with chronic inferior vena cava occlusion. PMID- 26044154 TI - Use of real patients in teaching ENT diseases to undergraduate students and its effects on patient satisfaction: cross-sectional survey. AB - OBJECTIVES: To describe a method of using real patients in teaching ENT to undergraduates and to examine whether being a case patient affected patient satisfaction. METHODS: In a cross-sectional study, 68 teaching-involved patients (case patients) with a suspected common ENT illness and 68 matched (in terms of age, sex and region of complaint) control patients evaluated the health service and their encounter with the physician. The students saw the case patients first independently and then saw the patient with the teacher physician. The controls were treated in a normal way. RESULTS: Fifty-eight case patients (84 per cent) and 65 control patients (95 per cent) answered the questionnaire. The median duration of the visit was significantly longer for the case patients than the controls (115 vs 60 minutes). Almost all patients in both groups graded the overall quality of the health service, and the variables describing various aspects of the setting and the encounter with the physician, as either good or excellent. CONCLUSION: Patients who took part in the undergraduate teaching of ENT diseases were equally content with their primary visit as the control patients, even though their visit took a markedly longer time. PMID- 26044153 TI - Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying Golgi/post-Golgi compartments. AB - MUC16, precursor of the most widely used ovarian cancer biomarker CA125, is up regulated in multiple malignancies and is associated with poor prognosis. While the pro-tumorigenic and metastatic roles of MUC16 are ascribed to the cell associated carboxyl-terminal MUC16 (MUC16-Cter), the exact biochemical nature of MUC16 cleavage generating MUC16-Cter has remained unknown. Using different lengths of dual-epitope (N-terminal FLAG- and C-terminal HA-Tag) tagged C terminal MUC16 fragments, we demonstrate that MUC16 cleavage takes place in the juxta-membrane ectodomain stretch of twelve amino acids that generates a ~17 kDa cleaved product and is distinct from the predicted sites. This was further corroborated by domain swapping experiment. Further, the cleavage of MUC16 was found to take place in the Golgi/post-Golgi compartments and is dependent on the acidic pH in the secretory pathway. A similar pattern of ~17 kDa cleaved MUC16 was observed in multiple cell types eliminating the possibility of cell type specific phenomenon. MUC16-Cter translocates to the nucleus in a cleavage dependent manner and binds to the chromatin suggesting its involvement in regulation of gene expression. Taken together, we demonstrate for the first time the oft-predicted cleavage of MUC16 that is critical in designing successful therapeutic interventions based on MUC16. PMID- 26044155 TI - Pancreatic iron overload by T2* MRI in a large cohort of well treated thalassemia major patients: can it tell us heart iron distribution and function? PMID- 26044156 TI - Appendiceal Neuroendocrine, Goblet and Signet-Ring Cell Tumors: A Spectrum of Diseases with Different Patterns of Presentation and Outcome. AB - PURPOSE: Appendiceal tumors are a heterogeneous group of diseases that include typical neuroendocrine tumors (TNET), goblet cell carcinoids (GCC), and atypical GCC. Atypical GCC are classified into signet-ring cell cancers (SRCC) and poorly differentiated appendiceal adenocarcinoids. The prognosis and management of these diseases is unclear because there are no prospective studies. The aim of this study is to assess the characteristics and outcome of appendiceal TNET, GCC, and SRCC patients. MATERIALS AND METHODS: Appendiceal TNET, GCC, and SRCC patients diagnosed between 1973 and 2011 were identified in the Surveillance Epidemiology and End Results (SEER) database. Demographics, type of surgery, and clinicopathologic characteristics were collected. Survival functions were estimated by the Kaplan-Meier method, and log-rank test was used to assess the difference in overall survival (OS) among the three histologies. RESULTS: The SEER database yielded 1,021 TNET patients, 1,582 with GCC, and 534 SRCC patients. TNET presented at a younger age (p < 0.001). Patients with SRCC presented with advanced stage disease (p < 0.001). The median OS (mOS) for GCC and TNET patients was not reached; mOS for SRCC was 24 months. Multivariate analysis stratified for stage revealed significantly longer survival for TNET and GCC than SRCC (p < 0.001). CONCLUSION: This is the largest report to date for appendiceal neuroendocrine tumor patients, suggesting a spectrum of diseases with different characteristics and outcomes. In this report, we present a treatment approach for this complex spectrum of disease, based on the experience of Ohio State and Emory Universities investigators. PMID- 26044157 TI - Negative Public Attitudes Towards Cancer Survivors Returning to Work: A Nationwide Survey in Korea. AB - PURPOSE: Early diagnosis and an improved survival rate have emerged as important issues for cancer survivors returning to work during the prime of their working life. This study investigated the attitudes of the general public towards cancer survivors returning to work in Korea and attempted to identify the factors influencing this negative attitude. MATERIALS AND METHODS: A general public perception survey regarding cancer survivors returning to work, targeting 2,000 individuals between 40-70 years of age, was conducted as face-to-face home visit. RESULTS: The public expressed a negative attitude towards cancer survivors returning to work, in terms of both perception and acceptance. Negative perception was higher among those in metropolitan areas compared with urban/rural areas (odds ratio [OR], 1.71), with monthly incomes < $2,000 compared with > $4,000 (OR, 1.54), and with patient care experience compared with those without (OR, 1.41). Negative acceptance was higher among those with monthly incomes < $2,000 compared with > $4,000 (OR, 1.71) and those with patient care experience compared with those without (OR, 1.54). The common factors between acceptance and perception that influenced negative attitude included area of residence, patient care experience, and monthly income. CONCLUSION: This study identified negative attitudes towards cancer survivors returning to work in South Korea and the factors influencing the reintegration of cancer survivors into society. It is necessary to promote community awareness and intervention activities to enable access to community, social, and individual units for the social reintegration of cancer survivors. PMID- 26044158 TI - Oncologic and Functional Outcomes after Partial Nephrectomy Versus Radical Nephrectomy in T1b Renal Cell Carcinoma: A Multicenter, Matched Case-Control Study in Korean Patients. AB - PURPOSE: The study was to compare the oncologic and functional outcomes of partial nephrectomy (PN) and radical nephrectomy (RN) for pathologically proven T1b renal cell carcinoma using pair-matched groups. MATERIALS AND METHODS: We reviewed our prospectively maintained database for RN and PN in T1b renal tumors surgically treated between 1999 and 2011 at five institutions in Korea. Of 611 patients treated with PN or RN for a solitary and NX/N0 M0 renal mass (4-7 cm), 577 (PN, 100; RN, 477) patients with pathologically confirmed pT1b remained for analysis. Study subjects were grouped by PN or RN, then matched by age, sex, comorbidities, body mass index, tumor size and depth, histologic type, and preoperative estimated glomerular filtration rate (eGFR) using propensities score. To evaluate oncologic outcomes, overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were analyzed. The functional outcomes were evaluated by postoperative eGFR. RESULTS: The median follow-up in the RN group was 48.1 and 42.6 months in the PN group. The estimated 10-year CSS rate (PN 85.7% vs. RN 84.4%, p=0.52) and 5- and estimated 10-year PFS rates (PN: 86.4% and 79.2% vs. RN: 86.0% and 66.1%, p=0.66) did not differ significantly between groups. The estimated 10-year OS rate was significantly higher in the PN group (85.7%) compared to the RN group (73.3%) (p=0.003). PN was less likely to induce new-onset chronic kidney disease (CKD) and end-stage CKD compared with RN. CONCLUSION: Our study suggests that patients treated with PN demonstrate a superior OS rate and postoperative renal function with analogous CSS and PFS rates compared with pair-matched patients treated with RN. PMID- 26044159 TI - Validation of Prediction Models for Mismatch Repair Gene Mutations in Koreans. AB - PURPOSE: Lynch syndrome, the commonest hereditary colorectal cancer syndrome, is caused by germline mutations in mismatch repair (MMR) genes. Three recently developed prediction models for MMR gene mutations based on family history and clinical features (MMRPredict, PREMM(1,2,6), and MMRPro) have been validated only in Western countries. In this study, we propose validating these prediction models in the Korean population. MATERIALS AND METHODS: We collected MMR gene analysis data from 188 individuals in the Korean Hereditary Tumor Registry. The probability of gene mutation was calculated using three prediction models, and the overall diagnostic value of each model compared using receiver operator characteristic (ROC) curves and area under the ROC curve (AUC). Quantitative test characteristics were calculated at sensitivities of 90%, 95%, and 98%. RESULTS: Of the individuals analyzed, 101 satisfied Amsterdam criteria II, and 87 were suspected hereditary nonpolyposis colorectal cancer. MMR mutations were identified in 62 of the 188 subjects (33.0%). All three prediction models showed a poor predictive value of AUC (MMRPredict, 0.683; PREMM(1,2,6), 0.709; MMRPro, 0.590). Within the range of acceptable sensitivity (> 90%), PREMM(1,2,6) demonstrated higher specificity than the other models. CONCLUSION: In the Korean population, overall predictive values of the three models (MMRPredict, PREMM(1,2,6), MMRPro) for MMR gene mutations are poor, compared with their performance in Western populations. A new prediction model is therefore required for the Korean population to detect MMR mutation carriers, reflecting ethnic differences in genotype-phenotype associations. PMID- 26044160 TI - Effect of Time Interval between Breast-Conserving Surgery and Radiation Therapy on Outcomes of Node-Positive Breast Cancer Patients Treated with Adjuvant Doxorubicin/Cyclophosphamide Followed by Taxane. AB - PURPOSE: This study evaluated the effect of surgery-radiotherapy interval (SRI) on outcomes in patients treated with adjuvant radiotherapy (RT) after breast conserving surgery (BCS) and adjuvant four cycles of doxorubicin/cyclophosphamide (AC) followed by four cycles of taxane. MATERIALS AND METHODS: From 1999 to 2007, 397 eligible patients were diagnosed. The effect of SRI on outcomes was analyzed using a Cox proportional hazards model, and a maximal chi-square method was used to identify optimal cut-off value of SRI for each outcome. RESULTS: The median SRI was 6.7 months (range, 5.6 to 10.3 months). A SRI of 7 months was the significant cut-off value for distant metastasis-free survival (DMFS) and disease free survival (DFS) using a maximal chi-square method. For overall survival, a significant cut-off value was not found. The patients with SRI > 7 months had worse 6-year DMFS and DFS than those with SRI <= 7 months on univariate analysis (DMFS, 81% vs. 91%, p=0.003; DFS, 78% vs. 89%, p=0.002). On multivariate analysis, SRI > 7 months did not affect DMFS and DFS. CONCLUSION: RT delayed for more than 7 months after BCS and adjuvant four cycles of AC followed by four cycles of taxane did not compromise clinical outcomes. PMID- 26044162 TI - Public Perceptions on Cancer Incidence and Survival: A Nation-wide Survey in Korea. AB - PURPOSE: The aim of this study was to compare the public perceptions of the incidence rates and survival rates for common cancers with the actual rates from epidemiologic data. MATERIALS AND METHODS: We conducted a survey of Korean adults without history of cancer (n=2,000). The survey consisted of questions about their perceptions regarding lifetime incidence rates and 5-year survival rates for total cancer, as well as those of eight site-specific cancers. To investigate associated factors, we included questions about cancer worry (Lerman's Cancer Worry Scale) or cared for a family member or friend with cancer as a caregiver. RESULTS: Only 19% of Korean adults had an accurate perception of incidence rates compared with the epidemiologic data on total cancer. For specific cancers, most of the respondents overestimated the incidence rates and 10%-30% of men and 6% 18% of women had an accurate perception. A high score in "cancer worry" was associated with higher estimates of incidence rates in total and specific cancers. In cancers with high actual 5-year survival rates (e.g., breast and thyroid), the majority of respondents underestimated survival rates. However, about 50% of respondents overestimated survival rates in cancers with low actual survival rates (e.g., lung and liver). There was no factor consistently associated with perceived survival rates. CONCLUSION: Widespread discrepancies were observed between perceived probability and actual epidemiological data. In order to reduce cancer worry and to increase health literacy, communication and patient education on appropriate risk is needed. PMID- 26044161 TI - The Effect of Chemoradiotherapy with SRC Tyrosine Kinase Inhibitor, PP2 and Temozolomide on Malignant Glioma Cells In Vitro and In Vivo. AB - PURPOSE: We investigated the effect of chemoradiotherapy with PP2 and temozolomide (TMZ) on malignant glioma cells using clonogenic assays and in vivo brain tumor model. MATERIALS AND METHODS: The effect of PP2 on radiosensitivity of U251 and T98G cells was investigated using clonogenic assays. The expression of E-cadherin, matrix metalloproteinases 2 (MMP2), Ephrin type-A receptor 2 (EphA2), and vascular endothelial growth factor (VEGF) was measured by Western blotting and an accumulation of gammaH2AX foci 6 hours after radiotherapy was measured after PP2 treatment. The effect of PP2 on migration, invasion, and vasculogenic mimicry formation (VMF) of U251 cells was evaluated. In an orthotopical brain tumor model with U251 cells, PP2 was injected intraperitoneally with or without oral TMZ before, during and after whole brain radiotherapy. Bioluminescence images were taken to visualize in vivo tumors and immunohistochemical staining of VEGF, CD31, EphA2, and hypoxia-inducible factor 1a was performed. RESULTS: PP2 increased radiosensitivity of U251 and T98G cells without decreasing survival of normal human astrocytes. Chemoradiotherapy with PP2 and TMZ resulted in increased accumulation of gammaH2AX foci. PP2 induced overexpression of E-cadherin and suppression of MMP2, VEGF, and EphA2. PP2 also compromised invasion, migration, and VMF of U251 cells. In brain tumors, chemoradiotherapy with PP2 and TMZ decreased tumor volume best, but not statistically significantly compared with chemoradiotherapy with TMZ. The expression of VEGF and CD31 was suppressed in PP2-treated tumors. CONCLUSION: PP2 enhances radiosensitivity of malignant glioma cells and suppresses invasion and migration of U251 cells. Chemoradiotherapy with PP2 and TMZ resulted in non significant tumor volume decrease. PMID- 26044163 TI - Clinicopathological Features and Type of Surgery for Lynch Syndrome: Changes during the Past Two Decades. AB - PURPOSE: The Korean Hereditary Tumor Registry, the first and one of the largest registries of hereditary tumors in Korea, has registered about 500 families with hereditary cancer syndromes. This study evaluates the temporal changes in clinicopathologic features and surgical patterns of Lynch syndrome (LS) patients. MATERIALS AND METHODS: Data on 182 unrelated LS patients were collected retrospectively. The patients were divided into the period 1 group (registered in 1990-2004) and 2 (registered in 2005-2014). The clinical characteristics of the two groups were compared to identify changes over time. RESULTS: The period 1 group included 76 patients; the period 2 group, 106 patients. The mean ages at diagnosis were 45.1 years (range, 13 to 85 years) for group 1 and 49.7 years (range, 20 to 84 years) for group 2 (p=0.015). The TNM stage at diagnosis did not differ significantly-period 1 group: stage 0-I (n=18, 23.7%), II (n=37, 48.7%), III (n=19, 25.0%), and IV (n=2, 2.6%); period 2 group: stage 0-I (n=30, 28.3%), II (n=35, 33.0%), III (n=37, 34.9%), and IV (n=4, 3.8%). Extended resection was more frequently performed (55/76, 72.4%) in the period 1 group than period 2 (49/106, 46.2%) (p=0.001). CONCLUSION: Colorectal cancer in patients with LS registered at the Korean Hereditary Tumor Registry is still diagnosed at an advanced stage, more than two decades after registry's establishment. Segmental resection was more frequently performed in the past decade. A prompt nationwide effort to raise public awareness of hereditary colorectal cancer and to support hereditary cancer registries is required in Korea. PMID- 26044164 TI - A Phase II Study of Weekly Paclitaxel Plus Gemcitabine as a Second-Line Therapy in Patients with Metastatic or Recurrent Small Cell Lung Cancer. AB - PURPOSE: Paclitaxel (P) and gemcitabine (G) are clinically synergistic in small cell lung cancer (SCLC). We evaluated the efficacy of PG as a salvage treatment for SCLC patients whose disease progressed after a platinum-containing regimen. MATERIALS AND METHODS: Eligibility included histologically confirmed SCLC, one dimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and progressive disease after platinum-based chemotherapy. Treatment consisted of P (80 mg/m(2)) and G (1,000 mg/m(2)) on days 1 and 8 of each cycle of 21 days until disease progression. RESULTS: Thirty-three patients seen between December 2005 and February 2009 were selected into this study. Thirty patients (91%) had received irinotecan-platinum, and three had received etoposide platinum. Sixteen patients (49%) had a treatment-free interval of less than 3 months. The overall response rate was 30.3% (29.4% in sensitive relapse and 31.3% in refractory relapse). The median time to progression was 12.0 weeks and median overall survival (OS) 31.0 weeks, with a 1-year OS rate of 30.3%. Toxicities were moderate and manageable with 18.2% grade (G) 4 neutropenia, 24.2% G3 thrombocytopenia, 6.1% G3 sensory neuropathy, and 3% G3 asthenia. One patient developed febrile neutropenia. CONCLUSION: Second-line paclitaxel and gemcitabine were well-tolerated and moderately active in SCLC patients previously treated with platinum-based chemotherapy. PMID- 26044165 TI - Avoiding unnecessary blood transfusions in women with profound anaemia. AB - BACKGROUND: Blood transfusions may be associated with risks and the risk: benefit ratio is not always clear, even in the setting of haemorrhage. AIMS: To describe the management practices and outcomes in women with profound anaemia who refused blood transfusion. MATERIALS AND METHODS: Retrospective analysis over a 10-year time frame of severely anaemic women (Hb <50 g/L) with benign conditions who had requested not to receive a blood transfusion. Demographic data, clinical presentation, anaemia management practice and serious adverse events were collected from the medical record charts. Women were analysed in two groups: a gynaecologic (Gyn) and an obstetric (Ob) population. RESULTS: A total of 19 women (12 Gyn and 7 Ob) met the inclusion criteria with a mean age of 35.8 +/- 10.2 years. The lowest mean Hb concentration was 41.3 +/- 9.7 g/L (Gyn Group) and 36.0 +/- 8.9 g/L (Ob Group) which increased, to 67.3 +/- 14.3 g/L and 73.1 +/- 6.9 g/L, respectively, by the time of hospital discharge. Anaemia management initially addressed the underlying etiology and was followed by intravenous iron (all cases) plus erythropoiesis stimulating agents, haemocoagulase and/or fluids. The mean length of hospital stay was 10.5 +/- 4.4 and 13.7 +/- 4.1 days for the Gyn and Ob groups, respectively. No deaths or other serious complications occurred. CONCLUSION: These findings suggest that young and otherwise healthy women can tolerate profound anaemia (Hb <50 g/L) permitting corrective strategies to be successfully implemented without the need for blood transfusion. PMID- 26044166 TI - Conscientious objection and medical tribunals. PMID- 26044167 TI - Prospective Randomized Long-Term Study on the Efficacy and Safety of UV-Free Blue Light for Treating Mild Psoriasis Vulgaris. AB - BACKGROUND: Blue light irradiation reduces the proliferation of keratinocytes and modulates T-cell immune response in vitro and has been shown to reduce the severity of psoriasis vulgaris (Pv) in two clinical trials. OBJECTIVE: Evaluation of safety and efficacy of long-term UV-free blue light treatment at home for mild Pv. METHODS: Forty-seven patients with mild Pv were randomized for receiving high intensity blue light treatment (HI: 453 nm LED, 200 mW/cm(2), n = 24) and low intensity treatment (LI: 453 nm LED, 100 mW/cm(2), n = 23) of one Pv plaque for 12 weeks. A contralateral control plaque remained untreated. RESULTS: Patient compliance and satisfaction were high. The primary endpoint, change from baseline (CfB) of the Local Psoriasis Severity Index, revealed a significant improvement of the target compared to the control plaques (DeltaCfB for the HI group: -0.92 +/- 1.10, p = 0.0005; for the LI group: -0.74 +/- 1.18, p = 0.0064). CONCLUSION: UV-free blue light home treatment is safe and improves Pv plaques. PMID- 26044169 TI - Early clinical evaluation of the intranasal TLR7 agonist GSK2245035: Use of translational biomarkers to guide dosing and confirm target engagement. AB - Modulation of the airways' immune milieu is a key therapeutic goal for remission from respiratory allergies. To explore this hypothesis, GSK2245035, a selective Toll-like receptor 7 (TLR7) agonist with preferential Type-1 interferon (IFN) stimulating properties, was developed for intranasal application. Doses for clinical assessment were extrapolated from translational biomarker studies in primates. Randomized, double-blind, placebo-controlled trials in healthy volunteers and patients with allergic rhinitis demonstrated that intranasal GSK2245035 doses <100 ng were tolerated and did not cause nasal inflammation. Higher doses were not tested due to considerable cytokine release syndrome related symptoms observed at 100 ng. Clear target engagement, reflected by local and peripheral increase of IFN-gamma-inducible protein-10, was observed at 20 ng, indicating IFN-stimulated immune changes at tolerated doses. Repeat intranasal administration at weekly intervals did not tolerize or amplify the pharmacological response. Intranasal GSK2245035 has an acceptable safety profile at doses that induce local TLR7-mediated immune responses. PMID- 26044168 TI - Evaluation of sorafenib treatment and hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma: a comparative study using the propensity score matching method. AB - While sorafenib (SFN) is the established worldwide standard therapeutic agent for advanced hepatocellular carcinoma (HCC), hepatic arterial infusion chemotherapy (HAIC) is also considered a favorable treatment for some advanced HCCs. This study aimed to evaluate each treatment and provide an optimal therapeutic choice for advanced HCCs. We analyzed 72 patients treated with SFN and 128 patients receiving HAIC. Both treatment groups were analyzed for prognostic and disease progression factors, and matched pair analysis was performed using the propensity score matching method. The preferable status of intrahepatic lesions, that is, no lesions or only a single (< 3 cm) intrahepetic lesion, was positively associated with good prognosis and negatively associated with disease progression in the SFN group. Maximum tumor size (> 5 cm) and low albumin (<= 3.4 g/dL) were poor prognostic and disease progression factors in the HAIC group. Analysis of 53 patients selected from each of the SFN and HAIC groups based on the propensity score matching method showed no significant differences in survival or disease progression between the two matched subgroups. On the other hand, progression free survival (PFS) in the HAIC-matched subgroup was significantly longer than in the SFN-matched subgroup, particularly in patients with portal vein invasion (PVI) and/or without extrahepatic spread (EHS). The treatment efficacy of HAIC is similar to that of SFN regarding survival and disease progression. Longer PFS might be expected for HAIC compared with SFN, particularly in patients with PVI and/or without EHS. PMID- 26044170 TI - Delirium among elderly patients admitted to a post-acute care facility and 3 months outcome. AB - AIM: To investigate the prevalence and risk factors of delirium in an extended care unit, the persistence of delirium and 3-month outcome. METHOD: Patients aged >65 years were recruited. Basic demographic data, medical comorbidity using the Charlson Comorbidity Index, pre-existing cognitive impairment using the informant questionnaire on cognitive decline in the elderly, place of residence and physical function as measured by the modified Barthel Index were recorded. Delirium was assessed by the Confusion Assessment Method and Direct Observation Scale. Delirium status, physical function and placement were reassessed on discharge, and at 1 month and 3 months after discharge. RESULTS: A total of 261 patients were recruited with a mean age of 81.9 years. Delirium was present in 89 participants (34.1%). Of these, 70 patients continued to be delirious on discharge. A total of 76 patients had persistent delirium at 1 month, and 49 remained to be delirious at 3 months. Pre-existing cognitive impairment (OR 9.12), use of psychoactive drugs (OR 3.61), presence of metabolic disturbances (OR 3.53), acute infection (OR 3.49) and old age home residents (OR 3.04) were associated with delirium on admission. A smaller number of delirium patients can return home on discharge, and they have poorer functional status on admission, at discharge, and at 1 month and 3 months after discharge. Unplanned hospital admission was significantly higher among the delirium group (42.9% vs 24.1%, P < 0.001). CONCLUSION: Delirium in post-acute convalescence units is highly prevalent and persistent. It is associated with poor functional recovery, higher nursing home placement and unplanned hospital admission. These findings reinforce the necessity to implement a program to prevent, early detect and treat delirium in elderly patients admitted to post-acute care units. Geriatr Gerontol Int 2016; 16: 586-592. PMID- 26044171 TI - [The gingivo periosto plastic surgery with osseous substitute: Technique and first results]. AB - INTRODUCTION: Ortho dontico-surgical coverage of alveolar crack is essential in reason of its repercussions on facial growth and implementation of children's teeth set. We proposed to realize a premature gingivo periosto plastic surgery from 4 years old by osseous substitute to lower age of alveolar cracks closure and decrease the morbidity of patients. PATIENTS AND METHODS: We conducted a retrospective study over one year (January, 2012 to December, 2012), with six months postoperatively outcomes, on 23 cases of gingivo periosto plastic sugary with osseous substitute type glass by bone transplant at infantile plastic surgery service of Timone - Children teaching hospital of Marseille, France. RESULTS: We held 23 patients. Seventeen children, 12 boys and 5 girls presented unilateral cracks. Twenty patients required a quantity of glass bone under 1cc for the narrow cracks. Prevalence of the mucous cracks was low (4 cases on 23). Technique of gingivo periosto plastic surgery with osseous substitute is simple and our results are globally satisfactory. We observed less morbidity of the operating site. CONCLUSION: The first results of this study showed that gingivo periosto plastic surgery with osseous substitute glass bone is a simple, reliable and reproducible technique, with promising results. Reduction of site's morbidity by osseous transplant, accessibility of glass bone cost and simplicity of surgical gesture justified adoption of this technique. PMID- 26044172 TI - Inherited variation in immune response genes in follicular lymphoma and diffuse large B-cell lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) both depend on immune-mediated survival and proliferation signals from the tumor microenvironment. Inherited genetic variation influences this complex interaction. A total of 89 studies investigating immune-response genes in DLBCL and FL were critically reviewed. Relatively consistent association exists for variation in the tumor necrosis factor alpha (TNFA) and interleukin-10 loci and DLBCL risk; for DLBCL outcome association with the TNFA locus exists. Variations at chromosome 6p31-32 were associated with FL risk. Importantly, individual risk alleles have been shown to interact with each other. We suggest that the pathogenetic impact of polymorphic genes should include gene-gene interaction analysis and should be validated in preclinical model systems of normal B lymphopoiesis and B-cell malignancies. In the future, large cohort studies of interactions and genome-wide association studies are needed to extend the present findings and explore new risk alleles to be studied in preclinical models. PMID- 26044173 TI - A Novel Homozygous c.800C>G Substitution in GP1BA Exon 2 in a Kuwaiti Family with Bernard-Soulier Syndrome. AB - BACKGROUND: Bernard-Soulier syndrome (BSS) is a congenital bleeding disorder characterised by thrombocytopenia, giant platelets and decreased platelet adhesion resulting from genetic alterations of the glycoprotein (GP) Ib/IX/V complex. OBJECTIVES: Three sisters with a lifelong bleeding history and a provisional diagnosis of BSS were referred for further characterisation of their bleeding diathesis. The siblings' symptoms varied in severity from skin and gum bleeding to menorrhagia associated with iron-deficiency anaemia requiring regular transfusion of red cells and platelets. The parents were consanguineous but did not demonstrate any bleeding disorder. METHODS: The family were investigated using standard haematological techniques, platelet aggregometry, platelet membrane GP analysis and DNA sequencing of the genes encoding the GPIb/IX complex. RESULTS: All 3 sisters had thrombocytopenia and giant platelets. Platelet aggregation and flow cytometry studies confirmed the lack of aggregation with ristocetin and a markedly reduced GPIb/IX surface expression. Molecular analysis demonstrated a novel homozygous c.800C>G substitution in GP1BA exon 2 leading to a serine 267 Ter stop codon in all 3 siblings. CONCLUSIONS: A novel, nonsense mutation was identified as the cause of the bleeding disorder in this family. This is the first reported BSS mutation identified in a family from Kuwait. PMID- 26044174 TI - Biological characterization of the skin of shortfin mako shark Isurus oxyrinchus and preliminary study of the hydrodynamic behaviour through computational fluid dynamics. AB - This study characterized the morphology, density and orientation of the dermal denticles along the body of a shortfin mako shark Isurus oxyrinchus and identified the hydrodynamic parameters of its body through a computational fluid dynamics model. The study showed a great variability in the morphology, size, shape, orientation and density of dermal denticles along the body of I. oxyrinchus. There was a significant higher density in dorsal and ventral areas of the body and their highest angular deviations were found in the lower part of the mouth and in the areas between the pre-caudal pit and the second dorsal and pelvic fins. A detailed three-dimensional geometry from a scanned body of a shark was carried out to evaluate the hydrodynamic properties such as drag coefficient, lift coefficient and superficial (skin) friction coefficient of the skin together with flow velocity field, according to different roughness coefficients simulating the effect of the dermal denticles. This preliminary approach contributed to detailed information of the denticle interactions. As the height of the denticles was increased, flow velocity and the effect of lift decreased whereas drag increased. The highest peaks of skin friction coefficient were observed around the pectoral fins. PMID- 26044175 TI - Spatial mapping of focused surface acoustic waves in the investigation of high frequency strain induced changes. AB - The field of straintronics, in which strain is used to drive phase transitions, ordering and structural changes, has conventionally been limited to dc or low frequency strain. High frequency large strains, which have the potential to serve as a high frequency trigger of strain sensitive physical phenomena, can be generated using focused surface acoustic waves, which produce two dimensional standing strain waves with very high strain at the elliptical focus. Here, the strain standing wave pattern generated by a focused surface acoustic wave is mapped and quantified as a function of voltage and frequency with high spatial resolution. A knife-edge optical reflection method is used to map the strain standing wave pattern generated by a 87.95 MHz annular interdigital transducer on 128 degrees Y-Cut LiNbO3. Subsequent to strain mapping, ferromagnetic Co/Pt multilayers nanostructures are lithographically patterned within the high strain region for preliminary measurements of magnetization changes arising from high frequency fast strain. The knife edge technique is simple, results in excellent spatial resolution and is fully compatible with other optical measurements, such as focused magneto-optic Kerr measurements, while maintaining spatial information. This ability to accurately and reproducibly determine the position of maximum strain and to lock onto a specific strain region is an important step in the investigation of the effects of high frequency strain on thin film materials, which range from magnetic reorientations to strain induced phase transitions. PMID- 26044176 TI - Photoscopic characterization of green synthesized silver nanoparticles from Trichosanthes tricuspidata and its antibacterial potential. AB - The present study focused on the finding of reducing agents for the formation of silver nanoparticles (AgNPs) from the plant, Trichosanthes tricuspidata. The synthesized AgNPs were characterized using UV-Visible spectroscopy, particle size analyzer (PSA), X-ray diffraction (XRD), scanning electron microscopy (SEM) and atomic force microscopy (AFM) analyses. The UV-Visible spectrum resulted a sharp peak (at 430nm) represents the strong plasmon resonance of silver. The average size distributions of AgNPs were found to be 78.49nm, through (PSA), and the silver ion with its crystalline nature was confirmed using intensity (2theta) peak value of 38.22 degrees , 44.66 degrees , 64.61 degrees , and 77.49 degrees . The SEM micrograph revealed that the synthesized AgNPs have a spherical morphology with the size ranges from 20 to 28nm. AFM showed the presence of polydispersed AgNPs with its size (20 to 60nm in height). The gas chromatography mass spectroscopy (GC-MS) study analyzed the responsible compounds present in the methanolic extracts for the bio-reduction of AgNPs and their antibacterial effect was studied. AgNPs exhibited preponderant activity than the methanolic extracts on clinical pathogens. Thus, the synthesized AgNPs might act as an effective antibacterial agent. Further studies are required to isolate the specific compound responsible for the reduction capability and its their inhibitory mechanisms for target bacterial strains. PMID- 26044177 TI - Identification and Characterization of a Novel IL-4 Receptor alpha Chain (IL 4Ralpha) Antagonist to Inhibit IL-4 Signalling. AB - BACKGROUND/AIMS: In recent times, allergy has become a financial, physical and psychological burden to the society as a whole. In allergic cascades, cytokine IL 4 binds to IL-4 receptor (IL-4R), consequently producing allergen-specific IgE antibodies by B cells. In addition, among other functions, IL-4 is also responsible for B and T cell proliferation and differentiation. Hence, characterization of novel antagonists that inhibit IL-4 signalling forms the overall aim of this study. METHODS: Phage display was used to screen a random 12 mer synthetic peptide library with a human IL-4Ralpha to identify peptide candidates. Once identified, the peptides were commercially synthesized and used for in vitro immunoassays. RESULTS: We have successfully used phage display to identify M13 phage clones that demonstrated specific binding to IL-4Ralpha. The peptide N1 was synthesized for use in ELISA, demonstrating significant binding to IL-4Ralpha and inhibiting interaction with cytokine IL-4. Furthermore, the peptide was tested in a transfected HEK-Blue IL-4 reporter cell line model, which produces alkaline phosphatase (AP). QUANTI-Blue, a substrate, breaks down in the presence of AP producing a blue coloration. Using this colorimetric analysis, >50% inhibition of IL-4 signalling was achieved. CONCLUSION: We have successfully identified and characterised a synthetic peptide antagonist against IL-4Ralpha, which effectively inhibits IL-4 interaction with the IL-4Ralpha in vitro. Since IL-4 interaction with IL-4Ralpha is a common pathway for many allergies, a prophylactic treatment can be devised by inhibiting this interaction for future treatment of allergies. PMID- 26044178 TI - [Prophylactic axillary radiotherapy for breast cancer]. AB - Adjuvant radiotherapy, after breast conserving surgery or mastectomy for breast cancer, improves overall survival while decreasing the risk of recurrence. However, prophylactic postoperative radiotherapy of locoregional lymph nodes for breast cancer, particularly of the axillary region, is still controversial since the benefits and the risks due to axillary irradiation have not been well defined. To begin with, when performing conformal radiotherapy, volume definition is crucial for the analysis of the risk-benefit balance of any radiation treatment. Definition and contouring of the axillary lymph node region is discussed in this work, as per the recommendations of the European Society for Radiotherapy and Oncology (ESTRO). Axillary recurrences are rare, and the recent trend leads toward less aggressive surgery with regard to the axilla. In this literature review we present the data that lead us to avoid adjuvant axillary radiotherapy in pN0, pN0i+ and pN1mi patients even without axillary clearance and to perform it in some other situations. Finally, we propose an update about the potential toxicity of adjuvant axillary irradiation, which is essential for therapeutic decision-making based on current evidence, and to guide us in the evolution of our techniques and indications of axillary radiotherapy. PMID- 26044179 TI - Quality and improvement. PMID- 26044180 TI - Macro- and microvascular disease in systemic sclerosis. AB - Vasculopathy is common in patients with connective tissue disease and can be directly implicated in the pathogenesis of the disease. Systemic sclerosis is an auto-immune multiorgan connective tissue disorder characterized by fibrosis of the skin and visceral organs and vascular disease. Micro- and macro-vessels are a direct target of the disease. In this review, we present the various clinical manifestations of the vasculopathy that can be present in SSc patients, and then discuss the various aspects of the pathophysiology of the vascular disorders. PMID- 26044181 TI - Plasmonic gold nanoparticles possess the ability to open potassium channels in rat thoracic aorta smooth muscles in a remote control manner. AB - Colloidal gold nanoparticles (AuNPs) of ~5nm core size and Zeta-potential of 35mV, having absorption maximum and plasmon resonance in the range of 510-570nm, were studied as a potential K(+)-channel opener in vascular smooth muscle (SM) cells. Experimental design of the study comprised SM contractile recordings. When externally applied to the organ bath, AuNPs (10(-6)-3*10(-4)M) led to decrease in amplitude of norepinephrine-induced contractions in a concentration-dependent and endothelium-independent manner in SM thoracic aorta, with mean value of pD2 (-log EC50) 4.2+/-0.03, Emax=55+/-4%. Being added to the bath solution in concentration of 10(-4)M, AuNPs significantly increased whole cell peak outward current at +70mV from 32+/-2pA/pF to 59+/-5pA/pF (n=14, P<0.05). External irradiation using a 5mW/532nm green laser, to facilitate plasmon resonance, led to an increment in the AuNPs-induced macroscopic outward potassium current (IK) from 59+/-5pA/pF to 74+/-1pA/pF (n=10, P<0.05). Paxilline (500nM), when added to the external bathing solution, significantly decreased AuNPs-induced increment of IK in SM cells. Single channel recordings provided a direct confirmation of BKCa activation by AuNPs at the single-channel level. Application of AuNPs to the bath potentiated BKCa activity with a delay of 1-2min, as was seen initially by more frequent channel openings followed by the progressive appearance of additional open levels corresponding to multiple openings of channels with identical single-channel amplitudes. Eventually, after 10-15min in the presence of AuNPs and especially when combined with the green laser illumination, there was a massive increase in channel activity with >10 channels evident. When irradiated by laser, AuNPs significantly increased the amplitude of maximal AuNPs-induced relaxation from 55+/-5% to 85+/-5% (n=10, P<0.05) while the sensitivity of SM to AuNPs was without changes. In summary, plasmonic AuNPs possess the ability to activate BKCa channel opening in vascular SM. Laser irradiation facilitates this effect due to local plasmon resonance that, in turn, further increases BKCa channel activity causing SM relaxation. PMID- 26044182 TI - Arterial stiffness and sedentary lifestyle: Role of oxidative stress. AB - Sedentary lifestyle is a risk factor for the development of cardiovascular disease, and leads to a quantifiable impairment in vascular function and arterial wall stiffening. We tested the hypothesis of oxidative stress as a determinant of arterial stiffness (AS) in physically inactive subjects, and challenged the reversibility of these processes after the completion of an eight-week, high intensity exercise training (ET). AS was assessed before and after ET, measuring carotid to femoral pulse wave velocity (PWV) with a Vicorder device. At baseline and after ET, participants performed urine collection and underwent fasting blood sampling. Urinary 8-iso-PGF2alpha, an in vivo marker of lipid peroxidation, total, HDL and LDL cholesterol, and triglyceride concentrations were measured. ET was associated with significantly reduced urinary 8-iso-PGF2alpha(p<0.0001) levels. PWV was significantly reduced after ET completion (p<0.0001), and was directly related to urinary 8-iso-PGF2alpha(Rho=0.383, p=0.021). After ET, cardiovascular fitness improved [peak oxygen consumption (p<0.0001), peak heart rate (p<0.0001)]. However, no improvement in lipid profile was observed, apart from a significant reduction of triglycerides (p=0.022). PWV and triglycerides were significantly related (Rho=0.466, p=0.005) throughout the study period. PWV levels were also related to urinary 8-iso-PGF2alpha in our previously sedentary subjects. We conclude that regular physical exercise may be a natural antioxidant strategy, lowering oxidant stress and thereby the AS degree. PMID- 26044183 TI - Sodium nitrite causes relaxation of the isolated rat aorta: By stimulating both endothelial NO synthase and activating soluble guanylyl cyclase in vascular smooth muscle. AB - Ingestion of dietary nitrites lowers arterial blood pressure in experimental animals and in humans. However, the exact mechanism underlying the hypotensive effect of nitrite remains unclear. The present study compared nitrite-induced responses in rings (with or without endothelium) of aortae of 18-20weeks old Wistar-Kyoto Rats (WKY) and spontaneously hypertensive (SHR) rats and investigated the underlying mechanism. Relaxations of aortae from WKY and SHR to increasing concentrations (1nM-100MUM) of sodium nitrite (NaNO2) were determined during sustained contractions to phenylephrine, in the absence and presence of pharmacological agents. The nitrite-induced relaxations were concentration dependent and larger in SHR than in WKY aortic rings. Inhibition of endothelial nitric oxide synthase (eNOS) and the absence of endothelium decreased nitrite induced relaxations in both WKY and SHR aortae, indicating the role of endothelium-derived nitric oxide (NO) in the response. The involvement of eNOS was further confirmed by increases in phosphorylation of eNOS at ser1177 in HUVEC cells following treatment with sodium nitrite. The presence of NO scavengers decreased the relaxation to nitrite in both WKY and SHR preparations while inhibition of soluble guanylyl cyclase (sGC) abolished the response, indicating that besides producing NO, nitrite also induces relaxation by directly activating the enzyme. Thus, the present study demonstrates that the sensitivity to exogenous nitrite is increased in the aorta of the SHR compared to that of the WKY. The endothelium-dependent component of the relaxation to nitrite involves activation of eNOS with production of endothelium-derived NO, while the endothelium-independent component is due to stimulation of sGC. PMID- 26044185 TI - Androgen and oestrogen modulation by D-aspartate in rat epididymis. AB - Testosterone (T) synthesised in Leydig cells enters the epididymis and may there be converted into dihydrotestosterone (DHT) by 5alpha-reductase (5alpha-red) or into 17beta-oestradiol (E2) by P450 aromatase (P450-aro). D-aspartate (D-Asp) is known to induce T synthesis in the testis. In this study, we investigated the effects of in vivo D-Asp administration in two major regions of the rat epididymis (Region I: initial segment, caput, corpus; Region II: cauda). The results suggest that exogenous D-Asp was taken up by both regions of rat epididymis. D-Asp administration induced a rapid increase in T, followed by a more gradual decrease in the T:DHT ratio in Region I. In Region II, T levels rapidly decreased and the T:DHT ratio was consistently lower relative to the control. Expression of 5alpha-red and androgen receptor genes showed a good correlation with DHT levels in both regions. D-Asp treatment also induced an increase of both E2 levels and oestradiol receptor-alpha (ERalpha) expression in Region I, whereas neither E2 levels nor ERalpha expression were affected in Region II. The early increase of P450-aro expression in Region I and late increase in Region II suggests a direct involvement of D-Asp modulation in P450 aro gene expression. Our results suggest that D-Asp modulates androgen and oestrogen levels and expression of androgen and oestrogen receptors in the rat epididymis by acting on the expression of 5alpha-red and P450-aro genes. PMID- 26044184 TI - Nuclear myosin 1 contributes to a chromatin landscape compatible with RNA polymerase II transcription activation. AB - BACKGROUND: Nuclear myosin 1c (NM1) is emerging as a regulator of transcription and chromatin organization. RESULTS: Using chromatin immunoprecipitation and deep sequencing (ChIP-Seq) in combination with molecular analyses, we investigated the global association of NM1 with the mammalian genome. Analysis of the ChIP-Seq data demonstrates that NM1 binds across the entire mammalian genome with occupancy peaks correlating with distributions of RNA Polymerase II (Pol II) and active epigenetic marks at class II gene promoters. In mouse embryonic fibroblasts subjected to RNAi mediated NM1 gene silencing, we show that NM1 synergizes with polymerase-associated actin to maintain active Pol II at the promoter. NM1 also co-localizes with the nucleosome remodeler SNF2h at class II promoters where they assemble together with WSTF as part of the B-WICH complex. A high resolution micrococcal nuclease (MNase) assay and quantitative real time PCR shows that this mechanism is required for local chromatin remodeling. Following B WICH assembly, NM1 mediates physical recruitment of the histone acetyl transferase PCAF and the histone methyl transferase Set1/Ash2 to maintain and preserve H3K9acetylation and H3K4trimethylation for active transcription. CONCLUSIONS: We propose a novel genome-wide mechanism where myosin synergizes with Pol II-associated actin to link the polymerase machinery with permissive chromatin for transcription activation. PMID- 26044186 TI - Estimated trends and patterns of road traffic fatalities in China, 2002-2012. AB - OBJECTIVE: This study examined the time trends and age distribution patterns of estimated road traffic fatalities (RTFs) in China over the period 2002-2012. METHODS: Data on age-, sex-, and region-specific RTF rates were provided by the Chinese Ministry of Health. The crude rates were standardized and the Mann Kendall test was used to test the significance of time trends. Annual number of RTFs was calculated. To minimize the effect of yearly variations, magnitude of changes in and age distribution patterns of the RTFs were examined using mean values of 2 years. RESULTS: RTFs increased significantly in China during the study period. Several features were identified for the RTFs in China. First, RTF rates skyrocketed in rural areas including towns and counties. Second, a significant increase in RTFs was also observed in cities even though the change in RTF rates was not statistically significant there. Third, individuals aged 20 24, 40-49, and 55-64, especially in rural areas, were particularly at risk for RTFs in recent years. Finally, RTFs became more common among middle-aged and older adults than young Chinese, with roughly 57% of all RTFs occurring among individuals aged 45 and above during 2011-2012. CONCLUSIONS: RTFs increased dramatically in China during the past decade, especially in rural areas. Age distribution patterns of RTFs have changed there. Community-based public health education and intervention programs are warranted. PMID- 26044187 TI - Structure-Switching Aptamer Triggering Hybridization Chain Reaction on the Cell Surface for Activatable Theranostics. AB - The ability to probe low-abundance biomolecules or transport a high-load drug in target cells is essential for biology and theranostics. We develop a novel activatable theranostic approach by using a structure-switching aptamer triggered hybridization chain reaction (HCR) on the cell surface, which for the first time creates an aptamer platform enabling real-time activation and amplification for fluorescence imaging and targeting therapy. The aptamer probe is designed not to initiate HCR in its free state but trigger HCR on binding to the target cell via structure switching. The HCR not only amplifies fluorescence signals from a fluorescence-quenched probe for activatable tumor imaging but also accumulates high-load prodrugs from a drug-labeled probe and induces its uptake and conversion into cisplatin in cells for selective tumor therapy. An in vitro assay shows that this approach affords efficient signal amplification for fluorescence detection of target protein tyrosine kinase-7 (PTK7) with a detection limit of 1 pM. Live cell studies reveal that it provides high-contrast fluorescence imaging and highly sensitive detection of tumor cells, while renders high-efficiency drug delivery into tumor cells via an endocytosis pathway. The results imply the potential of the developed approach as a promising platform for early stage diagnosis and precise therapy of tumors. PMID- 26044188 TI - Accuracy of micro powder dosing via a vibratory sieve-chute system. AB - This paper describes a powder dosing system with a vibratory sieve mounted on a chute that doses particles into a capsule. Vertical vibration occurred with a broad range of frequencies and amplitudes. During dosing events, the fill weight was accurately recorded via a capacitance sensor, covering the capsules and making it possible to analyze filling characteristics, that is, the fill rates and their robustness. The range of frequencies and amplitudes was screened for settings that facilitated reasonable (no blocking, no spilling) fill rates for three lactose powders. The filling characteristics were studied within this operating space. The results reveal similar operating spaces for all investigated powders. The fill rate robustness varied distinctly in the operating space, which is of prime importance for selecting the settings for continuous feeding applications. In addition, we present accurate dosing studies utilizing the knowledge about the filling characteristics of each powder. PMID- 26044189 TI - Measurement of cardiac troponin I in healthy lactating dairy cows using a point of care analyzer (i-STAT-1). AB - BACKGROUND: Cardiac troponin I (cTnI) has been shown to be an accurate predictor of myocardial injury in cattle. The point-of-care i-STAT 1 immunoassay can be used to quantify blood cTnI in cattle. However, the cTnI reference interval in whole blood of healthy early lactating dairy cows remains unknown. OBJECTIVE: To determine a blood cTnI reference interval in healthy early lactating Holstein dairy cows using the analyzer i-STAT 1. METHODS: Forty healthy lactating dairy Holstein cows (0-60 days in milk) were conveniently selected from four commercial dairy farms. Each selected cow was examined by a veterinarian and transthoracic echocardiography was performed. A cow-side blood cTnI dosage was measured at the same time. A bootstrap statistical analysis method using unrestricted resampling was used to determine a reference interval for blood cTnI values. RESULTS: Forty healthy cows were recruited in the study. Median blood cTnI was 0.02 ng/mL (minimum: 0.00, maximum: 0.05). Based on the bootstrap analysis method with 40 cases, the 95th percentile of cTnI values in healthy cows was 0.036 ng/mL (90% CI: 0.02-0.05 ng/mL). CONCLUSIONS: A reference interval for blood cTnI values in healthy lactating cows was determined. Further research is needed to determine whether cTnI blood values could be used to diagnose and provide a prognosis for cardiac and noncardiac diseases in lactating dairy cows. PMID- 26044190 TI - Bacterial resistance, the medical challenge of the next 20 years. PMID- 26044192 TI - Different Techniques of Respiratory Support Do Not Significantly Affect Gas Exchange during Cardiopulmonary Resuscitation in a Newborn Piglet Model. AB - BACKGROUND: There are no evidence-based recommendations on the use of different techniques of respiratory support and chest compressions (CC) during neonatal cardiopulmonary resuscitation (CPR). OBJECTIVES: We studied the short-term effects of different ventilatory support strategies along with CC representing clinical practice on gas exchange [arterial oxygen saturation (SaO2), arterial partial pressure of oxygen (PaO2) and arterial partial pressure of carbon dioxide (PaCO2)], hemodynamics and cerebral oxygenation. We hypothesized that in newborn piglets with cardiac arrest, use of a T-piece resuscitator (TPR) providing positive end-expiratory pressure (PEEP) improves gas exchange as measured by SaO2 during CPR as compared to using a self-inflating bag (SIB) without PEEP. Furthermore, we explored the effects of a mechanical ventilator without synchrony to CC. METHODS: Thirty newborn piglets with asystole were randomized into three groups and resuscitated for 20 min [fraction of inspired oxygen (FiO2) = 0.21 for 10 min and 1.0 thereafter]. Group 1 received ventilation using a TPR [peak inspiratory pressure (PIP)/PEEP of 20/5 cm H2O, rate 30/min] with inflations interposed between CC (3:1 ratio). Group 2 received ventilation using a SIB (PIP of 20 cm H2O without PEEP, rate 30/min) with inflations interposed between CC (3:1 ratio). Group 3 received ventilation using a mechanical ventilator (PIP/PEEP of 20/5 cm H2O, rate 30/min). CC were applied with a rate of 120/min without synchrony to inflations. RESULTS: We found no significant differences in SaO2 between the three groups. However, there was a trend toward a higher SaO2 [TPR: 28.0% (22.3-40.0); SIB: 23.7% (13.4-52.3); ventilator: 44.1% (39.2-54.3); median (interquartile range)] and a lower PaCO2 [TPR: 95.6 mm Hg (82.1-113.6); SIB: 100.8 mm Hg (83.0-108.0); ventilator: 74.1 mm Hg (68.5-83.1); median (interquartile range)] in the mechanical ventilator group. CONCLUSIONS: We found no significant effect on gas exchange using different respiratory support strategies during CPR. PMID- 26044193 TI - Forced Phase Separation by Laser-Heated Gold Nanoparticles in Thermoresponsive Aqueous PNIPAM Polymer Solutions. AB - We have investigated the formation, growth, and dissolution dynamics of aggregates of the thermoresponsive polymer poly(N-isopropylacrylamide) (PNIPAM) that form around laser heated gold nanoparticles (GNPs). The aggregates show an initial rapid growth followed by a slow long-term tail that is caused by the temperature dependent induction time until phase separation sets in. The maximum aggregate radius is determined by the distance from the GNP where the temperature crosses the binodal. Melting and evaporation of the GNP can be identified as characteristic steps in the aggregate size as a function of the heating laser power. After prolonged exposure, the polymer concentration inside the aggregate increases considerably. GNPs get immobilized at the perimeter, and a stepwise increase of the laser power results in onionskin-like growth shells. After switching the laser off, the system returns to the homogeneous phase and the growth shells are radially repelled by the high osmotic pressure within the volume previously occupied by the aggregate. PMID- 26044191 TI - NVP-BKM120 potentiates apoptosis in tumor necrosis factor-related apoptosis inducing ligand-resistant glioma cell lines via upregulation of Noxa and death receptor 5. AB - We previously observed that glioma cells are differentially sensitive to TRAIL induced toxicity. Based on our observation that TRAIL-resistant glioma cell lines typically exhibited high levels of Akt activation, we hypothesized that inhibition of Akt signaling using the PI3 kinase inhibitor NVP-BKM120 could promote TRAIL-induced apoptosis in gliomas. We assessed this combination in established and primary cultured glioma cells. Combination treatment led to significant cellular death when compared to either drug alone, but had no effect in normal human astrocytes, and demonstrated activation of the caspase cascade. This enhanced apoptosis appears dependent upon the loss of mitochondrial membrane potential and the release of Smac/DIABLO, AIF and cytochrome c into the cytosol. The upregulation of Noxa and sequestration of Mcl-1 by Noxa were important factors for cell death. Knockdown of Noxa abrogated apoptosis and suggested dependency on Noxa in combination-induced apoptosis. BKM120 upregulated cell surface expression of death receptor 5 (DR5), but did not increase levels of the other major TRAIL receptor, death receptor 4 (DR4). This study demonstrates that antagonizing apoptosis-resistance pathways, such as the PI3/Akt pathway, in combination with death receptor activation, may induce cell death in TRAIL resistant glioma. PMID- 26044194 TI - Confocal Raman microscopy for investigating the penetration of various oils into the human skin in vivo. PMID- 26044195 TI - Critical evaluation of three hemodynamic models for the numerical simulation of intra-stent flows. AB - We evaluate here three hemodynamic models used for the numerical simulation of bare and stented artery flows. We focus on two flow features responsible for intra-stent restenosis: the wall shear stress and the re-circulation lengths around a stent. The studied models are the Poiseuille profile, the simplified pulsatile profile and the complete pulsatile profile based on the analysis of Womersley. The flow rate of blood in a human left coronary artery is considered to compute the velocity profiles. "Ansys Fluent 14.5" is used to solve the Navier Stokes and continuity equations. As expected our results show that the Poiseuille profile is questionable to simulate the complex flow dynamics involved in intra stent restenosis. Both pulsatile models give similar results close to the strut but diverge far from it. However, the computational time for the complete pulsatile model is five times that of the simplified pulsatile model. Considering the additional "cost" for the complete model, we recommend using the simplified pulsatile model for future intra-stent flow simulations. PMID- 26044196 TI - Nonlinear elastic wave tomography for the imaging of corrosion damage. AB - This paper presents a nonlinear elastic wave tomography method, based on ultrasonic guided waves, for the image of nonlinear signatures in the dynamic response of a damaged isotropic structure. The proposed technique relies on a combination of high order statistics and a radial basis function approach. The bicoherence of ultrasonic waveforms originated by a harmonic excitation was used to characterise the second order nonlinear signature contained in the measured signals due to the presence of surface corrosion. Then, a radial basis function interpolation was employed to achieve an effective visualisation of the damage over the panel using only a limited number of receiver sensors. The robustness of the proposed nonlinear imaging method was experimentally demonstrated on a damaged 2024 aluminium panel, and the nonlinear source location was detected with a high level of accuracy, even with few receiving elements. Compared to five standard ultrasonic imaging methods, this nonlinear tomography technique does not require any baseline with the undamaged structure for the evaluation of the corrosion damage, nor a priori knowledge of the mechanical properties of the specimen. PMID- 26044197 TI - Chondroitinase gene therapy improves upper limb function following cervical contusion injury. AB - Chondroitin sulphate proteoglycans (CSPGs) are known to be important contributors to the intensely inhibitory environment that prevents tissue repair and regeneration following spinal cord injury. The bacterial enzyme chondroitinase ABC (ChABC) degrades these inhibitory molecules and has repeatedly been shown to promote functional recovery in a number of spinal cord injury models. However, when used to treat more traumatic and clinically relevant spinal contusion injuries, findings with the ChABC enzyme have been inconsistent. We recently demonstrated that delivery of mammalian-compatible ChABC via gene therapy led to sustained and widespread digestion of CSPGs, resulting in significant functional repair of a moderate thoracic contusion injury in adult rats. Here we demonstrate that chondroitinase gene therapy significantly enhances upper limb function following cervical contusion injury, with improved forelimb ladder performance and grip strength as well as increased spinal conduction through the injury site and reduced lesion pathology. This is an important addition to our previous findings as improving upper limb function is a top priority for spinal injured patients. Additionally great importance is placed on replication in the spinal cord injury field. That chondroitinase gene therapy has now been shown to be efficacious in contusion models at either thoracic or cervical level is an important step in the further development of this promising therapeutic strategy towards the clinic. PMID- 26044198 TI - Genotyping of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) in a tertiary care centre in Mysore, South India: ST2371-SCCmec IV emerges as the major clone. AB - The burden of community-associated methicillin resistant Staphylococcus aureus (CA-MRSA) is on the rise in population and clinical settings on account of the adaptability and virulence traits of this pathogen. We characterized 45 non duplicate CA-MRSA strains implicated mainly in skin and soft tissue infections (SSTIs) in a tertiary care hospital in Mysore, South India. All the isolates were genotyped by staphylococcal cassette chromosome mec (SCCmec) typing, staphylococcal protein A (spa) typing, accessory gene regulator (agr) typing, and multi-locus sequence typing (MLST). Four sequence types (STs) belonging to three major clonal complexes (CCs) were identified among the isolates: CC22 (ST2371 and ST22), CC1 (ST772) and CC8 (ST8). The majority (53.3%) of the isolates was of the genotype ST2371-t852-SCCmec IV [sequence type-spa type-SCCmec type], followed by ST22-t852-SCCmec IV (22.2%), ST772-t657-SCCmec V (13.3%) and ST8-t008-SCCmec IV (11.1%). ST237I, a single locus variant of ST22 (EMRSA-15 clone), has not been reported previously from any of the Asian countries. Our study also documents for the first time, the appearance of ST8-SCCmec IV (USA300) strains in India. Representative strains of the STs were further analyzed by pulsed field gel electrophoresis (PFGE). agr typing detected type I or II alleles in the majority of the isolates. All the isolates were positive for the leukotoxin gene, pvl (Panton-Valentine leukocidin) and the staphylococcal enterotoxin gene cluster, egc. Interestingly, multidrug resistance (resistance to ?3 classes of non-beta lactam antibiotics) was observed in 77.8% (n=35) of the isolates. The highest (75.5%) resistance was recorded for ciprofloxacin, followed by erythromycin (53.3%), and quinupristin-dalfopristin (51.1%). Inducible clindamycin-resistance was identified in 37.7% of the isolates and it was attributed to the presence of erm(A), erm(C) and a combination of erm(A) and erm(C) genes. Isolates which showed a phenotypic pattern of M(R)/L(S) (macrolide-resistance/lincosamide sensitivity) harbored the msr(A) gene. In conclusion, we report a high rate of multidrug resistance among Indian strains of CA-MRSA and the emergence of the lineages ST2371 and ST8 in India. PMID- 26044199 TI - Molecular phylogeny and evolutionary dynamics of matrix gene of avian influenza viruses in China. AB - In China, several subtype avian influenza viruses consistently circulate in poultry. Numerous studies have focused on the evolution of the hemagglutinin gene; however, studies on the evolution of the matrix (M) gene are limited. In this study, a large-scale phylogenetic analysis of M gene sequences of avian influenza viruses isolated in China revealed that the M gene has evolved into six different lineages denoted as I-VI. The majority of lineages I and IV were isolated in terrestrial birds, while the majority of lineages II, III, V and VI were isolated in aquatic birds. Lineage I included 148 H9N2 subtype viruses (72.2%), lineage II comprised of 63 H6 subtype viruses (100%), and lineage IV included 157 H5 subtype viruses (97.5%). The mean substitution rates of different lineages ranged from 1.32*10(-3) (lineage III) to 3.64*10(-3) (lineage IV) substitutions per site per year. According to the most recent common ancestor of all lineages, lineage III was the oldest lineage, formed in 1981 or even earlier. And lineage V was the most recent, established around the year 2000. Selective pressure on M2 was stronger than that on M1. The strongest selection pressure was observed in lineage IV. In addition, site-by-site analyses of each lineage identified 8 positive selection sites, all in M2. Most of the sites (5 out of 8) were located in the extracellular domain, which is an antigen for vaccine development. The positive selection sites (amino acid positions 66, 82 and 97) are likely associated with virus budding. This study enhanced our knowledge of M gene evolution of avian influenza viruses, and is expected to improve the early detection of new viruses and lead to vaccine development. PMID- 26044201 TI - Testicular biodistribution of silica-gold nanoparticles after intramuscular injection in mice. AB - With the continuing development of nanomaterials, the assessment of their potential impact on human health, and especially human reproductive toxicity, is a major issue. The testicular biodistribution of nanoparticles remains poorly studied. This study investigated whether gold-silica nanoparticles could be detected in mouse testes after intramuscular injection, with a particular focus on their ability to cross the blood-testis barrier. To that purpose, well characterized 70-nm gold core-silica shell nanoparticles were used to ensure sensitive detection using high-resolution techniques. Testes were collected at different time points corresponding to spermatogenesis stages in mice. Transmission electron microscopy and confocal microscopy were used for nanoparticle detection, and nanoparticle quantification was performed by atomic emission spectroscopy. All these techniques showed that no particles were able to reach the testes. Results accorded with the normal histological appearance of testes even at 45 days post sacrifice. High-resolution techniques did not detect 70-nm silica-gold nanoparticles in mouse testes after intramuscular injection. These results are reassuring about the safety of nanoparticles with regard to male human reproduction, especially in the context of nanomedicine. PMID- 26044200 TI - PPARdelta preserves a high resistance to fatigue in the mouse medial gastrocnemius after spinal cord transection. AB - INTRODUCTION: Skeletal muscle oxidative capacity decreases and fatigability increases after spinal cord injury. Transcription factor peroxisome proliferator activated receptor delta (PPARdelta) promotes a more oxidative phenotype. METHODS: We asked whether PPARdelta overexpression could ameliorate these deficits in the medial gastrocnemius of spinal cord transected (ST) adult mice. RESULTS: Time-to-peak tension and half-relaxation times were longer in PPARdelta Con and PPARdelta-ST compared with littermate wild-type (WT) controls. Fatigue index was 50% higher in PPARdelta-Con than WT-Con and 70% higher in the PPARdelta ST than WT-ST. There was an overall higher percent of darkly stained fibers for succinate dehydrogenase in both PPARdelta groups. CONCLUSIONS: The results indicate a conversion toward slower, more oxidative, and less fatigable muscle properties with overexpression of PPARdelta. Importantly, the elevated fatigue resistance was maintained after ST, suggesting that enhanced PPARdelta expression, and possibly small molecule agonists, could ameliorate the increased fatigability routinely observed in chronically paralyzed muscles. PMID- 26044202 TI - The effect of AZD2171- or sTRAIL/Apo2L-loaded polylactic-co-glycolic acid microspheres on a subcutaneous glioblastoma model. AB - Studies with AZD2171-a new anti-angiogenic inhibitor of tyrosine kinases associated with VEGF signaling-have shown great promise for treating glioblastoma. Unfortunately, AZD2171 success is limited by low permeability through the blood-brain barrier. Due to AZD2171's short half-life and high toxicity, its local administration will require multiple intracranial procedures, making this approach clinically unfeasible. In this study, we investigated the potential of the highly hydrophobic AZD2171, released from modified polylactic-co glycolic acid microspheres (PLGA-MS), to treat glioblastoma. To further demonstrate the versatile loading capacity of this system, the same PLGA formulation, which was found optimal for the loading and release of AZD2171, was tested with sTRAIL/Apo2L-a biologic drug that is very different than AZD2171 in its molecular weight, solubility, and charge. AZD2171 released from PLGA-MS was at least effective as the free drug in inhibiting endothelial growth and proliferation (in vitro), and, surprisingly, had a profound cytotoxic effect also towards in vitro cultured glioblastoma cell-lines (U87 and A172). Complete tumor inhibition was achieved following a single treatment with AZD2171-loaded PLGA-MS (6 (mg)/kg) administered locally adjacent to human U87 glioma tumors inoculated subcutaneously in nude mice. This improved effect, compared to other therapeutic approaches involving AZD2171, was shown to affect both tumor vasculature and the glioma cells. sTRAIL-loaded microspheres, administered at very low doses (0.3 (mg)/kg), led to 35 % inhibition of tumor growth in 2 weeks. Collectively, our results provide pre-clinical evidence for the potential of PLGA formulations of AZD2171 and sTRAIL to serve as an effective treatment for glioblastoma. PMID- 26044203 TI - Pump-free gradient-based micro-device enables quantitative and high-throughput bacterial growth inhibition analysis. AB - Antibiotic susceptibility testing is very important in antibiotic therapy. Traditional methods to determine antibiotic susceptibility include disk diffusion and broth dilution. However, these tests are always labor intensive, time consuming, and need large amounts of reagents. In this paper, we demonstrated a novel pump-free micro-device that enables quantitative and high-throughput bacterial growth inhibition analysis. This device consists of a series of wells and diffusion-based antibiotic gradient channels. The wells serve as antibiotic sources and buffer sinks, and we could easily observe the bacterial growth in the gradient channels .The design of the multi-wells is adapted to the commercialized multi-channel pipette, which makes it very convenient for loading reagents into the wells. For each assay, only about 20 MUL antibiotic solution is needed. As a demonstration, we used both fluorescence images and dark-field images to quantify the bacterial growth inhibition effect under different antibiotics. The quantitative data of bacterial growth inhibition under different antibiotics can be obtained within 3 to 4 h. Considering the simple operation process and the high-throughput and quantitative result this device can offer, it has great potential to be widely used in clinics and may be useful for the study of the kinetics of bacterial growth. PMID- 26044204 TI - A bio-inspired attachment mechanism for long-term adhesion to the small intestine. AB - To achieve long-term attachment of capsule endoscopes (CEs) and miniature biosensors in the human gastrointestinal (GI) tract, a tissue attachment mechanism (TAM) was designed, optimized and tested for safety and adhesive capabilities on excised tissue in vitro and in vivo on a live pig model. Six TAMs were tested for their attachment strength in an in vitro attachment tensile experiment in which each TAM was tested on three different proximal intestine tissue samples. The maximum strength and average value are 8.09 N and 4.54 N respectively. The initial attachment damage was tested for 10 min using a sine wave pull force on the TAM with a 0.4 N peak value and 6 s period, which represents typical human intestinal traction force from peristalsis. The in vitro attachment tensile test verified that the tissue was not visually damaged nor perforated by the attachment process. In the in vivo experiment, four TAMs were placed in the intestine of a pig through individual longitudinal enterotomies. X ray images were taken each hour after the surgery and showed zero migration of the TAMs after 24 h of adhesion. X-ray images taken each day indicated the attachment duration of this mechanism lasted up to 6 days. Post experiment inspection confirmed the attachment did not cause visible damage to tissue. These results confirmed the reliability of the TAM in vivo and demonstrated preliminary feasibility of long-term sensor adhesion to the GI tract. PMID- 26044205 TI - Peripheral IL-6 signaling: a promising therapeutic target for depression? PMID- 26044206 TI - Effects of insulin degludec and insulin glargine on day-to-day fasting plasma glucose variability in individuals with type 1 diabetes: a multicentre, randomised, crossover study. AB - AIMS/HYPOTHESIS: We compared the effects of insulin degludec (IDeg; Des(B30)LysB29(gamma-Glu Nepsilon-hexadecandioyl) human insulin) and insulin glargine (IGlar; A21Gly,B31Arg,B32Arg human insulin) on the day-to-day variability of fasting plasma glucose (FPG) levels in individuals with type 1 diabetes treated with basal-bolus insulin injections. METHODS: The effects of basal-bolus insulin therapy for 4 weeks with either IDeg or IGlar as the basal insulin in adult C-peptide-negative outpatients with type 1 diabetes were investigated in an open-label, multicentre, randomised, crossover trial. Randomisation was conducted using a centralised allocation process. The primary endpoints were the SD and CV of FPG during the final week of each treatment period. Secondary endpoints included serum glycoalbumin level, daily dose of insulin, intraday glycaemic variability and frequency of severe hypoglycaemia. RESULTS: Thirty-six randomised participants (17 in the IDeg/IGlar and 19 in the IGlar/IDeg groups) were recruited, and data for 32 participants who completed the trial were analysed. The mean (7.74 +/- 1.76 vs 8.56 +/- 2.06 mmol/l; p = 0.04) and SD (2.60 +/- 0.97 vs 3.19 +/- 1.36 mmol/l; p = 0.03) of FPG were lower during IDeg treatment than during IGlar treatment, whereas the CV did not differ between the two treatments. The dose of IDeg was smaller than that of IGlar (11.0 +/- 5.2 vs 11.8 +/- 5.6 U/day; p < 0.01), but other secondary endpoints did not differ between the treatments. CONCLUSIONS/INTERPRETATION: IDeg yielded a lower FPG level and smaller day-to-day variability of FPG at a lower daily dose compared with IGlar in participants with type 1 diabetes. IDeg serves as a good option for basal insulin in the treatment of type 1 diabetes. TRIAL REGISTRATION: University Hospital Medical Information Network 000009965. FUNDING: This research recieved no specific grant from any funding agency in the public, commercial or not-for profit sectors. PMID- 26044207 TI - Increased aortic stiffness predicts future development and progression of peripheral neuropathy in patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study. AB - AIMS/HYPOTHESIS: Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication that is strongly associated with poor glycaemic control and also with a worse prognosis. We aimed to evaluate the predictors of the development and progression of DPN in a cohort of high-risk patients with type 2 diabetes. METHODS: In a prospective study, 477 patients with type 2 diabetes were clinically assessed for the presence of DPN at baseline and after a median follow up of 6.2 years (range 2-10 years). Clinical laboratory data were obtained at study entry and throughout the follow-up. Aortic stiffness was assessed by the carotid-femoral pulse wave velocity (cf-PWV) at baseline. Multivariate Poisson regression analysis was used to examine independent predictors of the development/progression of DPN. RESULTS: At baseline, 135 patients (28%) had DPN, and during follow-up 97 patients (20%) had either a new development or a worsening of DPN. Patients who showed a development or progression of DPN were taller and had a longer duration of diabetes, a greater prevalence of other microvascular complications and hypertension, greater aortic stiffness and poorer glycaemic control than patients who did not have new or progressive neuropathy. After adjustments for the baseline prevalence of DPN, the patient's age and sex, and the time interval between DPN assessments; an increased aortic stiffness (cf PWV >10 m/s) were predictive of new/progressive DPN (incidence rate ratio 2.04, 95% CI 1.28, 3.23; p = 0.002). Other independent predictors were the mean first year HbA1c level (p = 0.05), nephropathy (p = 0.006), arterial hypertension (p = 0.06) and height (p = 0.03). CONCLUSIONS/INTERPRETATION: Increased aortic stiffness at baseline predicts the future development or progression of peripheral neuropathy, independent of diabetic metabolic control, suggesting a physiopathological link between macrovascular and microvascular abnormalities in type 2 diabetes. PMID- 26044208 TI - Understanding the Harms and Benefits of Cancer Screening: A Model of Factors That Shape Informed Decision Making. AB - OBJECTIVE: Decisions about cancer screenings often involve the consideration of complex and counterintuitive evidence. We investigated psychological factors that promote the comprehension of benefits and harms associated with common cancer screenings and their influence on shared decision making. METHODS: In experiment 1, 256 men received information about PSA-based prostate cancer screening. In experiment 2, 355 women received information about mammography-based breast cancer screening. In both studies, information about potential screening outcomes was provided in 1 of 3 formats: text, a fact box, or a visual aid (e.g., mortality with and without screening and rate of overdiagnosis). We modeled the interplay of comprehension, perceived risks and benefits, intention to participate in screening, and desire for shared decision making. RESULTS: Generally, visual aids were the most effective format, increasing comprehension by up to 18%. Improved comprehension was associated with 1) superior decision making (e.g., fewer intentions to participate in screening when it offered no benefit) and 2) more desire to share in decision making. However, comprehension of the evidence had a limited effect on experienced emotions, risk perceptions, and decision making among those participants who felt that the consequences of cancer were extremely severe. CONCLUSIONS: Even when information is counterintuitive and requires the integration of complex harms and benefits, user friendly risk communications can facilitate comprehension, improve high-stakes decisions, and promote shared decision making. However, previous beliefs about the effectiveness of screening or strong fears about specific cancers may interfere with comprehension and informed decision making. PMID- 26044209 TI - Effects of astaxanthin on dinitrofluorobenzene-induced contact dermatitis in mice. AB - Astaxanthin (AST) is known to exhibit antioxidative and antitumor properties, therefore, the present study investigated its other potential medical applications. AST was observed to exhibit anti-allergic and anti-inflammatory effects in a dinitrofluorobenzene (DNFB)-induced contact dermatitis (CD) mouse model and RBL-2H3 cell lines. The topical application of AST effectively inhibited the enlargement of ear thickness and increase in weight, which occurred following repeated application of DNFB. Furthermore, topical application of different concentrations of AST inhibited inflammatory hyperplasia, edema, spongiosis, and the infiltration of mononuclear cells and mast cells in the ear tissue. In addition, the levels of TNF-alpha and IFN-gamma produced were decreased by application of AST in vivo, and treatment of RBL-2H3 cells with AST inhibited the release of histamine and beta-hexosaminidase in vitro. Taken together, these data suggested that AST may be used to treat patients with allergic skin diseases through a mechanism, which may be associated with that involved in anti-inflammatory or anti-allergic activities. PMID- 26044210 TI - Excess influx of Zn(2+) into dentate granule cells affects object recognition memory via attenuated LTP. AB - The influx of extracellular Zn(2+) into dentate granule cells is nonessential for dentate gyrus long-term potentiation (LTP) and the physiological significance of extracellular Zn(2+) dynamics is unknown in the dentate gyrus. Excess increase in extracellular Zn(2+) in the hippocampal CA1, which is induced with excitation of zincergic neurons, induces memory deficit via excess influx of Zn(2+) into CA1 pyramidal cells. In the present study, it was examined whether extracellular Zn(2+) induces object recognition memory deficit via excess influx of Zn(2+) into dentate granule cells. KCl (100 mM, 2 ul) was locally injected into the dentate gyrus. The increase in intracellular Zn(2+) in dentate granule cells induced with high K(+) was blocked by co-injection of CaEDTA and CNQX, an extracellular Zn(2+) chelator and an AMPA receptor antagonist, respectively, suggesting that high K(+) increases the influx of Zn(2+) into dentate granule cells via AMPA receptor activation. Dentate gyrus LTP induction was attenuated 1 h after KCl injection into the dentate gyrus and also attenuated when KCl was injected 5 min after the induction. Memory deficit was induced when training of object recognition test was performed 1 h after KCl injection into the dentate gyrus and also induced when KCl was injected 5 min after the training. High K(+)-induced impairments of LTP and memory were rescued by co-injection of CaEDTA. These results indicate that excess influx of Zn(2+) into dentate granule cells via AMPA receptor activation affects object recognition memory via attenuated LTP induction. Even in the dentate gyrus where is scarcely innervated by zincergic neurons, it is likely that extracellular Zn(2+) homeostasis is strictly regulated for cognition. PMID- 26044211 TI - Mass-forming primary angiitis of central nervous system with Rosai-Dorfmann disease-like massive histiocytosis with emperipolesis. AB - Primary angiitis of the central nervous system (PACNS) is a vasculitis restricted to the CNS without systemic involvement. We report a case of PACNS that was radiologically tumor-mimicking, and pathologically similar to the Rosai-Dorfmann disease. A 20-year-old woman presented with a focal facial motor seizure. Magnetic resonance image revealed heterogeneously enhanced well-demarcated solitary cerebral mass in the posterior frontal lobe. Histopathologically, the lesion showed lymphoplasmacytic vasculitis with massive parenchymal infiltration of large histiocytes with emperipolesis. Diffuse ischemic change, necrosis, hemorrhage of the brain parenchyma with neuronophagia, and extensive reactive gliosis by gemistocytic astrocytes were accompanying microscopic features. The patient was doing well for 3 years after complete resection of the lesion, except for occasional occurrence of alcohol- or sleep deprivation-associated seizure. We describe this unique case to provide evidence that mass formation can be developed in PACNS by accompanying parenchymal lymphohistiocytic infiltration, necrosis, and marked reactive gliosis. PMID- 26044212 TI - Combined analysis of gene regulatory network and SNV information enhances identification of potential gene markers in mouse knockout studies with small number of samples. AB - RNA-sequencing is widely used to measure gene expression level at the whole genome level. Comparing expression data from control and case studies provides good insight on potential gene markers for phenotypes. However, discovering gene markers that represent phenotypic differences in a small number of samples remains a challenging task, since finding gene markers using standard differential expressed gene methods produces too many candidate genes and the number of candidates varies at different threshold values. In addition, in a small number of samples, the statistical power is too low to discriminate whether gene expressions were altered by genetic differences or not. In this study, to address this challenge, we purpose a four-step filtering method that predicts gene markers from RNA-sequencing data of mouse knockout studies by utilizing a gene regulatory network constructed from omics data in the public domain, biological knowledge from curated pathways, and information of single-nucleotide variants. Our prediction method was not only able to reduce the number of candidate genes than the differentialy expressed gene-only filtered method, but also successfully predicted significant genes that were reported in research findings of the data contributors. PMID- 26044213 TI - The combination of hydralazine and isosorbide dinitrate: the only antioxidant treatment recommended in the guidelines. PMID- 26044214 TI - Important details while assessing leptin results. PMID- 26044215 TI - A complication of xanthogranulomatous cholecystitis with Mirizzi syndrome. AB - A patient had right upper quadrant pain with sclera was transferred from emergency room to the hospital, she was proposed to have acute cholecystitis, gallstones, obstructive jaundice, and a four-year history of gallbladder stones. The NMR results showed that the gallbladder was significantly enlarged and the gallbladder wall was thickening irregularly. The liver morphology was not abnormal except with extensive intrahepatic bile duct dilatation. The MRCP results demonstrated that the intrahepatic bile ducts were significant expanded. The ERCP results showed that duodenal stenosis and extra-hepatic bile duct stenosis. We placed a plastic stent of 8.5Fr and 12 cm in length in the hepatic duct, and after biliary plastic stent placement, jaundice was rapidly reduced and liver function was improved significantly. A surgery was performed and the final pathologic diagnosis is a complication of Xanthogranulomatous cholecystitis with Mirizzi syndrome. After the surgery of cholecystectomy and a bile duct repair were performed, the patient was recovered well. Conclusively, if a patient was diagnosed as biliary stricture, a biliary metal stent should not be placed until pathological diagnosis of malignancy. PMID- 26044216 TI - Variation of craniocervical junction volume as an effective parameter for basilar invagination treatment. AB - OBJECTIVE: The major pathological change in basilar invagination (BI) is represented in the decrease of craniocervical junction (CVJ) volume resulting from abnormal bone protrusion around the foramen magnum. The diagnosis and clinical evaluation of BI is mainly based on the clinical manifestations and radiographic measurements by means of calculation of the scan lines of CVJ in X ray, CT and MRI. With the transoral decompression atlantoaxial reduction plate (TARP III) system, the decompression, reduction and fixation can be achieved to decompress and stabilize medulla spinalis change the position of the dens in CVJ, thus expand the CVJ relative volume, relieve the compression on medulla spinalis and the nerve injury. However, the correlation between the dens position change and the variation of CVJ has not been established previously. This study focused on the clinical significance of the variation of craniocervical junction (CVJ) volume caused by the dens position change for the treatment of BI. PATIENTS AND METHODS: We've performed an analysis of data from 62 BI patients admitted from January 2008 to May 2013, who were treated by TARP III system. The data include preoperative, postoperative JOA scores (Japanese Orthopaedic Association scores, 17 points method), preoperative and postoperative X-ray, thin-slice CT scan with three-dimensional reconstruction and MRI scan to measure the cervicomedullary angle (CMA). We have analyzed the preoperative and postoperative three dimensional CT data by means of MIMICS 10.01 software system according to the Box volume (BV) method to determine the changes of CVJ volume resulting from preoperative and postoperative dens position change, assessed the correlation between the CVJ volume changes and the JOA scores with correlation between CMA change and the JOA scores. All data were analyzed by paired t-test and Pearson correlation analysis. RESULTS: In all 62 patients, JOA scores were recovered from preoperative 9.26 +/- 1.66 to postoperative 13.02 +/- 1.44, CMA change rate was 21%, and CVJ volume change rate was 36%. The CMA change rate and the JOA score recovery rat exhibited relevance, as Pearson's correlation coefficient was 0.46 (p < 0.005). The Pearson's correlation coefficient between CVJ volume change rate and JOA score recovery rate was 0.63 (p < 0.005), and the CVJ volume change rate was significantly different while compared with the correlation between CMA change rate and JOA score (p < 0.005). CONCLUSIONS: the CVJ volume change rate is a sensitive and reliable parameter for the evaluation of neurological function improvement in patients with BI. It can be used as a predictor to evaluate the postoperative neurological recovery. PMID- 26044217 TI - Serum paraoxonase and arylesterase values as antioxidants in healthy premature infants at fasting and posprandial times. AB - OBJECTIVE: Newborn infants, particularly preterm infants, are at greater risk of oxidative stress because of an imbalance between high oxidant loads and immature antioxidant defenses. In several studies, the activities of serum paraoxonase (PON) and arylesterase (ARE) have been found to decline in patients under increased oxidative stress. We investigated the relationships between PON-1 and ARE with fasting and postprandial in premature newborns in this study. PATIENTS AND METHODS: Serum paraoxonase-1 and arylesterase levels were investigated in premature infants less than 37 weeks, after birth while they were fasting and postprandial. RESULTS: The paraoxonase-1 and arylesterase values of infants in fasting were significantly lower than the values in postprandial (for paraoxonase 1, p = 0.034, 0.002, and 0.002, respectively; for arylesterase, p < 0.001, 0.002, and p < 0.001, respectively). CONCLUSIONS: In premature infants, paraoxonase-1 and arylesterase values are increased in postprandial and reduced in fasting, showing that these neonates are subjected to oxidative stress. Thus, starting feeding as soon as possible in premature newborns is vital to protect them from oxidative damage. PMID- 26044218 TI - Effect analysis of nasotracheal suction mechanical ventilation treatment of cerebral ischemic stroke induced by sleep apnea. AB - OBJECTIVE: To investigate the difference between the clinical effects of nasotracheal suction (NTS) mechanical ventilation and noninvasive positive pressure ventilation (CPAP) treatment of cerebral ischemic stroke (IS) induced by sleep apnea. PATIENTS AND METHODS: Fifty-three patients diagnosed with cerebral IS caused by sleep apnea from February 2013 to February 2014 were selected for this study from our hospital. After the approval of the hospital's Ethics Committee and patients' signed consent, the patients were randomly divided into a test group (n=29 cases) and a control group (n=24 cases). All patients were given conventional treatment for stroke. The control group received the noninvasive ventilator application with CPAP model. The test group was treated with nasal endotracheal suction of mechanical ventilation treatment. Using the NIHSS scale and Barthel index, we compared the status of the nervous system on admission and after seven days stroke recovery treatment of the two groups. Through the comparison of apnea-hypopnea index (AHI), oxygen desaturation index (ODI), LSaO2 and MSaO2 of the two groups on the seventh day, we compared the efficacy of the obstructive sleep apnea-hypopnea syndrome (OSAHS). RESULTS: The NIHSS score and Barthel index score of mild, moderate and severe were compared on the OSAHS patients at admission, and the difference was not statistically significant (p > 0.05). After treatment, all patients showed lower NIHSS score and increased Barthel scores, and the difference had statistical significance (p < 0.05). For the mild OSAHS patients, we compared the NIHSS score and Barthel index score of the test and control group, and the difference was not statistically significant (p > 0.05). For the moderate and severe OSAHS patients, the NIHSS score of the test group decreased significantly. However, the Barthel index scores increased significantly, and the difference had statistical significance (p > 0.05). The AHI, LSaO2, MSaO2, and ODI index of the two groups of patients were compared with the treatment, and the differences were not statistically significant (p > 0.05). After treatment, the AHI and the ODI index of the two groups decreased, LSaO2 and MSaO2 index increased, and AHI and ODI index of the test group decreased more than that of the control group. However, the LSaO2 and the MSaO2 index increased, and the difference had statistical significance (p > 0.05). The total effective rate of patients of the test group was higher than that of the control group, but no effectiveness and overall mortality was lower than the control group. The difference was statistically significant (p > 0.05). CONCLUSIONS: Compared with noninvasive ventilator therapy, nasotracheal suction mechanical ventilation and noninvasive positive pressure ventilation treatment of cerebral IS induced by sleep apnea can naturally improve the prognosis of nervous system recovery, and improve the respiratory ventilation function. This may be a better treatment option for moderate and severe sleep apnea patients that is worthy of clinical application. PMID- 26044219 TI - Sarcoidosis at onset of Psoriasis: a common immunopathogenesis. Review and case report. AB - Sarcoidosis is an inflammatory systemic disease that may present in many different ways. The pathophysiological mechanisms are not still well known, although sarcoidosis results from an exaggerated Th1 immune response. About 30% of sarcoidosis patients may suffer from skin lesions during the course of the disease and, occasionally, psoriasiform lesions have been observed. Sarcoidosis may present associated with other diseases and psoriasis is actually one of them, even though not particularly frequent. Few cases of patients who showed clinical and histological features compatible with both pulmonary sarcoidosis and psoriasis vulgaris have been reported. We report an interesting case of a patient affected by sarcoidosis at the onset of psoriasis and discuss immunopathogenetic mechanisms that can be associated with these conditions. Recent data confirm that sarcoidosis is a Th1/Th17 multisystem disorder. These clarifications may be helpful in the management of the diseases and in identifying patients at risk. PMID- 26044220 TI - Resistance training vs. aerobic training and role of other factors on the exercise effects on visceral fat. AB - In the last 25 years, obesity has reached epidemic levels of prevalence. It has even affected the children such that rates of severe childhood obesity that have almost tripled in numbers. These numbers are alarming because of the known fact that obesity is associated with an increased risk of several comorbidities as well as with an increased risk of premature death. Almost since the beginning, exercise has been known to play a key role in the prevention and treatment of overweight and the non-pharmacological treatment of dyslipidemia. However, the effects of exercise on obesity seems to be dynamic and influenced by several other factors. These factors can be related to exercise or to the associated comorbidities. In this review we will address following factors: (1) The type of exercise which could be either aerobic or resistance training (2) The volume or amount of training (3) Intensity of training and (4) The effect of comorbidity of diabetes mellitus. We will observe that all of these factors modify the effect of exercise on the visceral fat. PMID- 26044221 TI - A new protocol for separation of acid soluble and insoluble fractions from total glycogen and simultaneous measurements. AB - OBJECTIVE: The glycogen is extracted routinely from animal tissues with cold perchloric acid (PCA). Acid soluble glycogen (ASG) is extracted, while the insoluble fraction (AIG) is liberated using hot alkaline. The current study was performed to separate and measure ASG, AIG and total glycogen in the same sample simultaneously. MATERIALS AND METHODS: The protocol has the four phases of tissue digestion, extraction, separation of fractions and measurement. The liver tissue was weighed and digested with four volumes of 30% KOH and heated in boiling water bath for 10 min. Total glycogen was extracted with ethanol at a final concentration of 55%. The suspension of total glycogen was separated into the two fractions of acid soluble and insoluble by adding of 30 uL PCA (70%) followed by a short and mild centrifugation. Total glycogen, ASG and AIG have derived from the same sample and analyzed for glucose. RESULTS: Analysis of different weights of the liver tissue using the current procedure shows that the fractions of glycogen are measured accurately. The CV% was less than 5% for inter- and intra assays of total glycogen and ASG. The CV% was more than 5% for inter-assays of AIG, but it lessened in intra-assays. During 24 h starvation, total glycogen depleted completely (71.4 +/- 8.3 mg/g wet vs. 4.4 +/- 1.2, p <= 0.004) and the change occurred entirely in ASG (66.9 +/- 7.8 vs. 1.9 +/- 1.1, p <= 0.004), while AIG did not change significantly (4.4 +/- 1.3 vs. 2.2 +/- 0.9, p <= 0.08). CONCLUSIONS: The values of ASG, AIG and total glycogen obtained by the current protocol are the same as the classical homogenization method but the procedure is more easy and precise. ASG is the main and metabolically active portion of glycogen in rat liver. PMID- 26044222 TI - Effect of different concentrations of medroxy-progesterone acetate combined with 17beta-estradiol on endothelial progenitor cells. AB - OBJECTIVE: Endothelial progenitor cells (EPCs) have the ability to differentiate into mature endothelial cells. Inhibition of EPC proliferation and migration may be a new method for anti-tumor therapy. Medroxyprogesterone acetate (MPA) may act on tumor angiogenesis by impacting biological functions of EPCs. The aim of this work was to study the effect of different concentrations of MPA combined with 17beta-estradiol (17beta-E2) on proliferation, migration, and apoptosis of EPCs in vitro. MATERIALS AND METHODS: Proliferation tests (MTT analysis) and migration assay of EPCs, isolated from bone marrow of canine, were performed to detect their response to different concentrations of MPA combined with 17beta-E2 (1 * 10(-8) mol/L). The growth curves were drawn every 24 h for 7 consecutive days. The cell cycle and apoptosis of EPCs were analyzed by flow cytometry. RESULTS: 17beta-E2 (1 * 10(-8) mol/L) increased EPC proliferation, while lower concentration of MPA (<= 10(-5) mol/L) partially inhibited it. The higher concentration of MPA (>= 10(-4) mol/L) combined with 17beta-E2 had a significant inhibitory effect on EPC growth, arresting it in the S phase. It also increased the apoptosis rate and damaged the migration ability of EPCs. CONCLUSIONS: Low concentration of MPA partially inhibited the function of 17beta-E2 that promotes the proliferation of EPCs. However, high concentration of MPA combined with 17beta-E2 inhibited a variety of biological functions of EPCs. So, the MPA has a bidirectional effect combined with 17beta-E2 on the cell biology of EPCs. PMID- 26044223 TI - Facial osteomas: fourteen cases and a review of literature. AB - OBJECTIVE: Osteomas are benign tumors that frequently affect the cranio-facial region, especially the temporal bones, jaw and sinus. This lesion very rarely involves the maxillary bones. The aim of our study is to describe our surgical case series and to evaluate the diagnosis and management of peripheral craniofacial osteomas with a review of the literature. PATIENTS AND METHODS: We retrospectively analyzed a series of 14 patients that underwent surgery for the removal of a cranio-facial osteoma, 10 cases were peripheral osteoma of the lower jaw and 4 were peripheral osteomas of the upper jaw. The 14 patients included 8 females and 6 males, with a mean age of 42 years. The median follow up period was 48 months. RESULTS: All patients received a total surgical removal and we did not have any intraoperative complications with optimal cosmetic and functional results. Pain resolved in all cases and a single case postoperative dysesthesia occurred. NO recurrence has been detected at last follow-up visit. CONCLUSIONS: Osteomas must be well identified and differentiated from other solid diseases of the bone and should be treated if symptomatic. The elective treatment is surgical removal, resulting in a complete resolution of the pathology. PMID- 26044224 TI - Secreted protein acidic and rich in cysteine expression in human colorectal cancer predicts postoperative prognosis. AB - OBJECTIVE: Secreted protein acidic and rich in cysteine (SPARC) is an extracellular matrix glycoprotein involved in cell proliferation, migration and angiogenesis. The aim of this study was to assess its expression in colorectal cancer, see whether and how it correlates with clinicopathological features, and evaluate its potential prognostic significance. PATIENTS AND METHODS: SPARC expression was detected by microarrays containing 847 immunohistochemically stained specimens, and further correlated with the clinicopathological and prognostic data. The prognostic significance of its expression was assessed using Kaplan-Meier survival with log-rank tests. Multivariate regression utilizing Cox's proportional hazard model was used to evaluate prognostic factors. RESULTS: SPARC expression in the normal colorectal mucosa and colorectal cancer tissue was significantly different (p < 0.001). Low SPARC expression was found to be associated with poor prognosis, and it was unfavorably correlated with overall survival and disease-free survival in colorectal cancer patients. In addition, SPARC expression in surrounding mesenchymal and stromal cells, bowel wall invasion, lymph node metastasis, and distant metastasis were independent prognostic factors for overall survival and disease-free survival. CONCLUSIONS: Reduced expression of SPARC in colorectal cancer tissue is associated with poor prognosis and aggressive clinicopathological features. Therefore, SPARC expression could potentially be used as a prognostic predictor for colorectal cancer patients. PMID- 26044225 TI - A pilot study of conformal radiotherapy combined with erlotinib-based multimodality therapy in newly diagnosed metastatic non-small-cell lung cancer. AB - OBJECTIVE: Lung cancer is the leading cause of cancer-related death in the world, particularly in major cities in China. We aimed to determine the benefit of survival and toxicity of Conformal Radiotherapy (CRT) combined with erlotinib based multimodality therapy in newly diagnosed metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Newly diagnosed metastatic NSCLC patients were treated with CRT and erlotinib, with or without chemotherapy matched protocol. The patients received CRT with a dose of 30-66 Gy. Erlotinib was used at least one 28-day cycle. The primary end point was overall survival (OS). RESULTS: Thirty-two patients were analyzed. The median OS was 517 days. Patients with only one metastasis showed longer survival than patients with multi metastases (986 vs. 380 days, n = 8 vs. 24, p = .009). Patients with multiple metastases in brain conferred worse survival for patients without and with sole brain metastasis (321 vs. 700 days, n=11 vs 21, p = .006). There was no significant difference in median survival whether erlotinib was used as a first-, second- or third-line therapy (380 vs. 700 vs. 310 days, n = 10 vs. 15 vs 7, respectively. p = .179). Patients with TTCRT > 90 days had longer OS than patients with TTCRT <= 90 days (749 vs. 322 days, n = 11 vs. 21, p = .012). Patients tolerated treatment with limited Grade 1/2 toxicity. CONCLUSIONS: In this study, patients with newly diagnosed metastatic NSCLC had survival benefits when erlotinib was used combined with CRT. Further prospective trials are needed to derive maximal benefit from the drug treatment. PMID- 26044226 TI - Cancer stem cells: targeting tumors at the source. AB - The cancer stem cell hypothesis states that tumors rely exclusively on the continued proliferation of a subset of cancer cells that originated from normal adult stem cells. These cells have two key traits: multipotency, and self renewal. The prolonged lifespan of stem cells makes them perfect candidates for the accumulation of carcinogenic mutations that would convert them into cancer stem cells (CSCs) no longer responsive to the many regulatory pathways in place that are responsible for tight governance of proliferation and differentiation in normal stem cells. Comprehending what these regulatory pathways are, and how their derailment contributes to oncogenic transformation, can hold the key to finding new strategies to target CSCs in order to effectively treat cancer. Additionally, what environmental factors are involved in promoting or suppressing CSC tumorigenicity requires attention. The possibility that some cancers may have clonal origins in non-stem cell populations that were able to acquire stem cell like properties, and the lack of complete cell autonomy in carcinogenesis, suggests that the CSC hypothesis is continually evolving. Continued research in this field can shed light on how effective selective elimination of CSCs as opposed to generalized targeting of cancer cells will be in the treatment of cancer. PMID- 26044227 TI - Hematopoietic stem cells: cancer involvement and myeloid leukemia. AB - Hematopoietic stem cells (HSCs) are rare multipotent cells that possess ability to self-renew and differentiate to progenitor cells, which give rise to all blood cell lineages. The process involves specific regulation of gene transcription and its deregulation resulting in imbalance between self-renew and differentiation, can lead to cellular transformation and cancers. Substantial evidence indicates that accumulated mutations in HSCs contribute to the initiation and pathogenesis of at least some hematopoietic cancers. In particular, myeloid leukemias have been extensively characterized with regard to HSC and progenitor involvement. Thus, as a focal point for scientific and therapeutic endeavours, formation of cancer cells from HSCs represents a critical area of investigation. Consequently, understanding how HSCs function and how they undergo to transformation, is of fundamental importance to get insight in their contribution to the hematopoietic cancer development. PMID- 26044228 TI - Efficiency of ultrasound and water capsule-guided local injection of botulinum toxin type A treatment on patients with facial spasm. AB - OBJECTIVE: To study the efficacy of ultrasound and water capsule-guided local injection of botulinum toxin type A (BTX-A) treatment on patients with facial spasm. PATIENTS AND METHODS: One hundred and fifty-seven cases of facial spasm were randomly divided into oral drug treatment group (group A) (78 cases) and ultrasound and water capsule-guided local injection of botulinum toxin type A treatment group (group B) (79 cases). Cohen, Acbert spasm strength grade scores in each case with facial spasm were recorded. Therapeutic effect, duration, significant efficiency, and muscle spasm strength were compared before and three after treatment. RESULTS: The muscle spasm strength showed no significant change in group A after the treatment. However, the muscle spasm strength was decreased significantly in group B after treatment (p < 0.01). CONCLUSIONS: Ultrasound and water capsule-guided local injection of botulinum toxin type A treatment is a safe, effective, and simple treatment for patients with facial spasm. PMID- 26044229 TI - Acute encephalopathy associated with hemolytic uremic syndrome caused by Escherichia coli O157: H7 and rotavirus infection. AB - We reported a case of a 22-months child with hemolytic uremic syndrome associated with encephalopathy. As the cause of this case, the involvements of verotoxin 1 and 2 caused by O157: the H7 strain of the enterohemorrhagic Escherichia coli and rotavirus were presumed. We administered brain hypothermic therapy and steroid pulse therapy in the intensive care unit, but we were not able to save his life and the child died on the 6th day from the onset. PMID- 26044230 TI - A study on lesion pattern of bilateral cerebellar infarct. AB - OBJECTIVE: To explore the lesion patterns and stroke mechanism of the acute bilateral cerebellar infarct. PATIENTS AND METHODS: Patients admitted to Xiangyang Hospital with acute cerebellar infarcts, confirmed by diffusion weighted imaging (DWI), were investigated. Patients were divided into two groups by lesions: unilateral cerebellar infarct (UCI) and bilateral cerebellar infarct (BCI). The demographic features, involved territories and concomitant lesions outside the cerebellum (CLOC). The causes were analyzed. RESULTS: Amongst the 115 patients hospitalized with posterior circulation cerebral infarct due to acute stroke, 56 patients had cerebellar infarct. There were 36 (64.3%) cases of unilateral cerebellar infarct and 20 (35.7%) cases of the BCI. The baseline information shows that stroke history (p = 0.002), fibrinogen (p = 0.036) and admission NIHSS score (M) (p = 0.001) for the BCI group are higher than the unilateral cerebellar infarct group. The incidence rate of cerebellar infarct in a posterior inferior cerebellar artery (PICA) blood supplying territory is the highest by divisions of vascular distribution. Unilateral cerebellar infarct occurs more often (p = 0.006); BCI is more common in PICA+SCA blood supplying territory (p = 0.004). The incidence rate of BCI merged with CLOC is much higher than the unilateral cerebellar infarct (p = 0.002). Merged infratentorial lesions are more common (p = 0.022) than BCI with atherosclerosis (p = 0.041). Offending artery diseases are mainly in the V4 segment of the vertebral artery, and in the severe stenosis or occlusion of V4 and BA junction. CONCLUSIONS: BCI was frequently involved in the PICA + SCA territory. Our results support the fact that embolism resulted from large artery atherosclerosis is the important stroke mechanism in the BCI. PMID- 26044231 TI - Safety and effectiveness of intravenous thrombolysis with recombinant tissue plasminogen activator in eighty years and older acute ischemic stroke patients. AB - OBJECTIVE: To explore the safety and efficacy of intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) in elderly (>= 80 years old) acute ischemic stroke (AIS) patients. PATIENTS AND METHODS: The clinical data of patients who were treated in Tianjin Huanhu Hospital from June 2012 to November 2013 were retrospectively analyzed; amongst them 404 patients had received IVT with rt-PA and 200 patients had not received IVT. Among >= 80 years' old patients, 204 had received IVT and 200 had not. And, the 404 patients who had received IVT, they were divided into two subgroups: elderly (>= 80 years of age; n = 204) and controls (< 80 years old; n = 200). The incidence of intracranial hemorrhage (ICH) and symptomatic intracranial hemorrhage (sICH), case-fatality rate, and other prognostic indicators were compared. RESULTS: Among all >= 80 years' old patients, the IVT subgroup had significantly superior good outcome rates than the non-IVT subgroup at 24-h and 3-month, along with significantly lower case-fatality rate. But for the patients those who had received IVT, the incidence of ICH and the 7-day case-fatality rate were not significantly increased in both the elderly and control subgroups. The 24-h and 3-month good outcome rates were not significantly different between these two subgroups as well. CONCLUSIONS: IVT with rt-PA is a safe and effective treatment for >= 80 year's old AIS patients. PMID- 26044232 TI - The left ventricular assist effect and biocompatibility study of a novel para aortic counterpulsation device. AB - OBJECTIVE: To evaluate the hemodynamic characteristics and biocompatibility of a new para-aortic counterpulsation device in animal experiment studies. MATERIALS AND METHODS: Para-aortic counterpulsation device (PACD), a monoport device, consists of a blood chamber anastomosed to the descending aorta by means of a valveless graft and an air chamber connected to IABP machine. Hemodynamic parameters during the PACD-assisted beats were compared with those during the unassist beats. Acute heart failure was induced in all animals, and the hemodynamic effects of PACD were then reassessed. RESULTS: We successfully induced heart failure in all cases, in conditions of which cardiac output (CO) and MAP decreased 17.6% and 27.7% respectively, and PCWP increased 57.7%. Hemodynamic indexes, cerebral and heart perfusion improved significantly after PACD assisting. PACD activation increased significantly CO and MAP 6.29% and 2.04% respectively. Both of SAP and DAP decreased significantly from 85.00 to 81.88 mmHg and 59.63 to 54.63 respectively, at the same time, MADP increased 19.4%, after PACD assist. The value of MDLMF, LMF and CSF was increased by 14.0%, 13.8% and 11.6% respectively. LCAF increased by 11.23%, after PACD assist. The PFH increased significantly in the first six hours. There was no statistically significant difference in the last two hours. When the acute animal experiments were completed, there were no infarct ischemic, thrombosis change in organs by Gross and histologic observation. CONCLUSIONS: PACD with good biological compatibility significantly reduced the left ventricular afterload, increased diastolic arterial pressure and myocardial perfusion, improved heart function and cerebral perfusion. PMID- 26044233 TI - Use of the neutrophil to lymphocyte ratio for prediction of in-stent restenosis in bifurcation lesions. AB - OBJECTIVE: Percutaneous coronary interventions (PCI) are the preferred treatment for coronary artery disease, even though the development of in-stent restenosis (ISR) continues to be an important complication. Neutrophil to lymphocyte ratio (NLR) is indicative of the inflammatory process and can predict the short- and long-term prognosis of cardiovascular diseases. We investigated the relationship between ISR development and neutrophil-lymphocyte ratio (NLR) in bifurcation lesions in stable coronary artery disease (CAD) patients. PATIENTS AND METHODS: We analyzed the clinical and angiographic data of 181 consecutive stable CAD patients who had undergone successful PCI to the true bifurcation lesion from January 2010-December 2012. Patients were divided into two groups based on the development of ISR (group 1, ISR -; group 2, ISR +). RESULTS: NLR(after) (p < 0.001) and NLRDelta (p < 0.001) were significantly higher in group 2. NLRDelta was found to be significant independent predictor of ISR in the multivariate logistic regression analysis. A NLRDelta level > 0.58 mg/dL had 81.8% sensitivity and 93.5% specificity for the prediction of ISR, as identified by the ROC curve. A NLR(after) level > 3.43 predicted ISR with 45.5% sensitivity and 95.8% specificity. The comparison of ROC curve analysis demonstrated that NLRDelta was the strongest independent predictor of ISR (p = 0.001). CONCLUSIONS: As a result, although drug eluting stent implantation is known to be recommended in the bifurcation lesion PCI in worldwide, we want to emphasize the usage of the NLR values in the prediction of ISR. So, we think that NLRDelta levels may be a useful marker for the prediction of ISR in patients who undergo bifurcation PCI. PMID- 26044234 TI - Impact of stent over-expansion at distal edge: insights from a 12-month follow-up study. AB - OBJECTIVE: Although the use of drug-eluting stents has significantly reduced the incidence of restenosis and target lesion revascularization, in-stent and in segment restenosis remain clinically challenging problems, the underlying mechanisms of which remain unknown. This study aimed to explore the outcomes of different stenting strategies in target vessels with different proximal and distal reference diameters (?D >= 0.25 mm). PATIENTS AND METHODS: In this prospective clinical study, 167 patients undergoing percutaneous coronary intervention with ?D >= 0.25 mm according to QCA results were randomized into 2 groups. Group A (n = 85) was treated by a single stent with high-pressure balloon inflation. Group B (n = 82) was treated by a single stent, with high- and low pressure balloon inflation at the proximal and distal segment, respectively. The target vessel size and late lumen loss were determined by angiographic analysis. RESULTS: Compared with normal expansion, overexpansion increased the early minimum lumen diameter (A: 2.40 +/- 0.18 mm vs. 2.89 +/- 0.21 mm; B: 2.45 +/- 0.14 mm vs. 2.49 +/- 0.24 mm, p < 0.001), but also increased the percentage of late lumen loss (A: 18.22 +/- 0.56%; B: 5.63 +/- 0.41%, p < 0.001). Although the total restenosis ratio was similar in 2 groups, the incidence of late lumen loss of group A was higher than that of group B. CONCLUSIONS: Stent overexpansion increased the early minimum lumen diameter, but also increased the occurrence of late lumen loss at the distal edge of the stent. PMID- 26044235 TI - Relationship between neutrophil-to-lymphocyte ratio and impaired myocardial perfusion in cardiac syndrome X. AB - OBJECTIVE: Myocardial tissue perfusion is decreased in patients with cardiac syndrome X (CSX). Systemic inflammation appears to be an important contributor to the diseased microvascular network of these patients. The neutrophil-to lymphocyte ratio (NLR) is a surrogate marker of inflammation. Accordingly, we evaluated this biomarker concerning the microvascular circulation of CSX patients. PATIENTS AND METHODS: This study included 60 consecutive patients (54.1 +/- 7.8 years of age, 49 females) with CSX (typical chest pain, positive exercise stress test results, and normal coronary angiograms) and 60 consecutive age- and sex-matched control subjects. In all coronary territories, epicardial coronary flow was assessed by the Thrombolysis In Myocardial Infarction frame count (TFC) method, and myocardial tissue perfusion was assessed by the myocardial blush grade (MBG) method. Normal myocardial perfusion was accepted as an MBG score of 3 in all coronary territories. RESULTS: Patients with CSX had higher NLRs than those of control subjects (1.98 +/- 0.77 vs 1.72 +/- 0.55, respectively; p = 0.04). Among patients with CSX, those with impaired myocardial perfusion had higher NLRs than those with normal myocardial perfusion (2.13 +/- 0.82 vs 1.71 +/ 0.59, respectively; p = 0.028). There was a negative correlation between the NLR and total MBG score (p = 0.027, r = -0.29). Logistic regression analysis showed that the NLR was an independent and negative predictor of myocardial tissue perfusion (p = 0.027; Beta, -1.057; odds ratio, 2.878; 95% confidence interval, 1.129-7.335). CONCLUSIONS: Patients with CSX have high NLRs, and inflammation seems to be associated with distorted myocardial perfusion in these patients. PMID- 26044236 TI - Genotype-phenotype correlation in multiresistant Escherichia coli and Klebsiella pneumoniae strains isolated in Western Romania. AB - OBJECTIVE: Bacterial multidrug-resistance (MDR) to antimicrobials has become an important public health issue all over the world and it involves both hospital and community-acquired strains. MATERIALS AND METHODS: A number of 75 Escherichia coli and 77 Klebsiella pneumoniae (K.) strains identified in biological samples collected from community (CA) and hospital-acquired (HA) infections were found to be resistant to the third generation cephalosporins. Of these, 93 MDR strains were subjected to microarray analysis to detect the expression of 31 antimicrobial resistance genes. RESULTS: We found that all HA extended-spectrum beta-lactamase (ESBL) producing E. coli strains had at least one resistance gene to third generation cephalosporins, while in 54% of all CA strains genetic substrates justifying their antibiotic resistance were identified. Almost 81% of HA-ESBL (Extended-Spectrum beta Lactamase) K. pneumoniae strains had at least one resistance gene to third generation cephalosporins, while in only 6% of the CA strains a similar genotype was identified. In the HA group, the blaCTX-M-15 genotype proved to be most frequent in multidrug-resistant E. coli strains and second most frequent (after ampC) in K. pneumoniae, while in the CA group, this genotype was the fourth most frequent in ESBL E. coli (after ampC, sul1, tet(R)). CONCLUSIONS: Overall, in 67% of all ESBL producing Enterobacteriaceae strains a genetic substrate justifying the resistance to beta-lactam antibiotics was identified; most of the remaining 33.33% strains were CA with a predominance of K. pneumoniae, in which a different antibiotic resistance genetic substrate (outside the detection limit of the kit used in this study) might have been involved. PMID- 26044237 TI - Antibacterial activity of ovary extract from sea urchin Diadema setosum. AB - OBJECTIVE: Sea urchin gonad is considered as a highly prized delicacy in several countries. It is also rich in valuable bioactive compounds including polyunsaturated fatty acids (PUFAs) and beta-carotene. This study was undertaken to examine the antimicrobial properties of the ovary extract from sea urchin Diadema setosum against selected Gram-negative and Gram-positive bacteria. MATERIALS AND METHODS: The ovary extract was obtained using two different solvents such as methanol and chloroform. The obtained extract was used to examine its potential antimicrobial properties against the following 11 bacterial species using the disc diffusion method: Gram-negative bacteria (Salmonella typhi, Salmonella typhimurium, Shigella flexneri, Pseudomonas aeruginosa, Aeromonas hydrophila, Acinetobacter sp, Citrobacter freundii and Klebsiella pneumonia) and Gram-positive bacteria (Bacillus subtilis, Staphylococcus epidermidis and Staphylococcus aureus). The activity was measured in terms of zone of inhibition (mm). RESULTS: The methanol extract exhibited a higher zone of inhibition against all the bacteria taken for examination. Whereas, the ovary extract obtained by chloroform did not show any antimicrobial activity against S. typhi, S. epidermidis, C. freundii and K. pneumonia. The results indicated that the ovary extract obtained by methanol extracts are capable of inhibiting the growth of pathogenic microbes taken for analysis. Moreover, the result indicates the presence of antimicrobial agents in sea urchin ovary. CONCLUSIONS: The study suggests that the ovary extract of D. setosum may be a potential source of antimicrobial agent for pathogenic microorganisms. PMID- 26044238 TI - Comparison of angiogenic and proliferative effects of three commonly used agents for pulmonary artery hypertension (sildenafil, iloprost, bosentan): is angiogenesis always beneficial? AB - OBJECTIVE: Pulmonary artery hypertension (PAH) is devastating disease that has very serious outcomes. Dysregulated angiogenesis is one of the main responsible courses in pathophysiology of disease. Our experimental research intends to find out and compare the angiogenic effects of medications used sildenafil, iloprost, and bosentan in the treatment of PAH. MATERIALS AND METHODS: This study was performed in Department of Biochemistry and Cancer and Stem Cell Research Laboratory of our institutes between August and October 2014. Angiogenic activity of sildenafil, iloprost, and bosentan were examined in vivo in chick chorioallantoic membrane (CAM) model and in vitro tube formation assay of human umbilical vein endothelial cells (HUVECs). Proliferative activity of these three agents was also determined through 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay on HUVECs. RESULTS: In CAM assay, when compared to the control and drug groups, treatment with sildenafil solutions resulted in a significant dose-dependent increase (budding, sprouting, extravasation) on CAM vessel growth. While there was no significant proliferative effect with iloprost and bosentan, presence of sildenafil caused a statistically significant proliferation on HUVECs following 24 and 48 h incubation (p < 0.05) compared to the control group. Comparing the tube length/area ratio values, there was statistically significant increase in sildenafil group with respect to the other 2 groups (p < 0.05). Iloprost and bosentan did not show a significant effect. CONCLUSIONS: The results provide evidence that sildenafil but not iloprost and bosentan induces angiogenesis in vitro and in vivo. Dysregulated angiogenesis, as an important pathophysiological part in the progression of PAH, may be triggered by the chronic ingestion of sildenafil in the long treatment period and may cause negative effects. PMID- 26044239 TI - The effects of caffeic acid phenethyl ester (CAPE) on bacterial translocation and inflammatory response in an experimental intestinal obstruction model in rats. AB - OBJECTIVE: Intestinal obstruction (IO) is a disease which generates approximately 20% of emergency surgery and tends to with high mortality. Prevention of oxidative stress, bacterial translocation and tissue damage caused by IO is an important medical issue. Caffeic acid phenethyl ester (CAPE) is an anti inflammatory, antioxidant, anti-bacterial and immunomodulatory agent. In this experimental study, we aimed to investigate the effects of CAPE on bacterial translocation, inflammatory response, oxidative stress and tissue injury caused by intestinal obstruction in a rat model. MATERIALS AND METHODS: Breafly, thirty Wistar albino rats divided into three groups as Sham (n=10), IO (n=10) and IO + CAPE (10 umol/kg day, intraperitoneal) (n=10). The tissues from the study groups were examined biochemically, microbiologically and histopathologically. RESULTS: In CAPE treated group, decreased serum levels of proinflammatory cytokines (TNF alpha, IL-6, IL-1beta) and CRP (p < 0.05), additionally increased serum levels of antioxidant parameters (PONS, TAS) (p < 0.05), were observed after IO. Microbiologically, the rates of positive cultures of the lymph node, spleen, liver and blood were significantly decreased in CAPE treated group compared to the IO group. Also histopathological examination showed that the intestinal mucosal injury score and hepatic portal inflammation score were significantly decreased in the CAPE treated group (p < 0.05). CONCLUSIONS: It is suggested that intraperitoneal administration of CAPE might has potential antibacterial, anti inflammatory, antioxidant and immunomodulatory effects in IO. So, further studies on IO are needed to evaluate exact antibacterial, antiinflammatory, antioxidant and immunomodulatory effects of CAPE. PMID- 26044240 TI - The investigation of melatonin effect on liver antioxidant and oxidant levels in fructose-mediated metabolic syndrome model. AB - OBJECTIVE: Metabolic syndrome (MetS) can be induced by the oxidative stress conditions caused by ingestion of large amounts of fructose. We investigated the possible protective effects of melatonin administration on liver tissues in fructose-fed rats. MATERIALS AND METHODS: Thirty-two rats were randomly divided into four groups; control, fructose, melatonin, and fructose plus melatonin. MetS was induced by a fructose solution (20% in tap water) and melatonin (20 mg/kg daily) was administered by oral gavage. Systolic blood pressures (SBP) were measured. After the end of the 8-week experimental period, serum lipid profile, glucose and insulin levels, tissue total oxidant status (TOS) and activities of paraoxonase (PON), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) were measured. RESULTS: Fructose consumption significantly increased SBP, serum triglyceride and insulin levels and induced insulin resistance, confirming successful establishment of the MetS model. After fructose administration, the TOS levels and GSH-Px activities significantly increased in all groups compared to the control group. The PON activity in the fructose group significantly decreased compared to the control group. Melatonin supplementation, with or without fructose, increased PON activity. The SOD activity significantly increased in the fructose group compared to the control group, but significantly decreased in the melatonin group compared to the control and fructose groups. CAT activity was unchanged in all groups. CONCLUSIONS: GSH-PX and PON are important antioxidants for reducing oxidant stress. Melatonin might act as a prooxidant at the dose given in our experimental design when administered with fructose. PMID- 26044241 TI - The effects of alcohol on gastrointestinal tract, liver and pancreas: evidence based suggestions for clinical management. AB - Alcohol has a direct impact on the digestive system due to its contact with mucosal lining and interference with digestive functions. Various diseases of the gastrointestinal tract, including tumors, may be related to an excess of alcohol intake and the relationship between alcohol abuse and hepatic and pancreatic damage is well established. According to WHO, alcohol and alcohol-related diseases represent a major health problem and will probably continue to do so in the foreseeable future. In this review, we summarize the present knowledge on clinically relevant alcohol-related problems in order to provide practicing physicians with evidence-based general suggestions which might help in the management of alcohol-related gastrointestinal disorders. A thorough clinical history together with a number of questionnaires are essential for detecting alcohol dependence or abuse. Biochemical tests (nonspecific and specific) have been considered to be less sensitive than questionnaires in screening for alcohol abuse, but they may be useful in identifying relapses. Protracted behavior modification, cognitive behavioral therapy, psychological counseling, and mutual support groups have been considered the most effective long-term treatments. Several drugs have been developed that are able to interfere with the neurotransmitters involved in craving mechanisms, and we summarize the evidence of their efficacy to increase abstinence and to prevent relapse. PMID- 26044242 TI - A homozygous CARD9 mutation in a Brazilian patient with deep dermatophytosis. AB - Deep dermatophytosis has been described in HIV and immunosuppressed patients. Recently, CARD9 (caspase recruitment domain-containing protein 9) deficiency has been reported in individuals with deep dermatophytosis previously classified as "immunocompetent". We report a 24-year-old Brazilian male patient with deep dermatophytosis born to an apparently non-consanguineous family. The symptoms started with oral candidiasis when he was 3 years old, persistent although treated. At 11 years old, well delimited, desquamative and pruriginous skin lesions appeared in the mandibular area; ketoconazole and itraconazole were introduced and maintained for 5 years. At 12 years of age, the lesions, which initially affected the face, started to spread to thoracic and back of the body (15 cm of diameter) and became ulcerative, secretive and painful. Terbinafine was introduced without any improvement. Trichophyton mentagrophytes was isolated from the skin lesions. A novel homozygous mutation in CARD9 (R101L) was identified in the patient, resulting in impaired neutrophil fungal killing. Both parents, one brother (with persistent superficial but not deep dermatophytosis) and one sister were heterozygous for this mutation, while another brother was found to be homozygous for the CARD9 wild-type allele. This is the first report of CARD9 deficiency in Latin America. PMID- 26044243 TI - Older Adults' Reasons for Using Technology while Aging in Place. AB - BACKGROUND: Most older adults prefer to age in place, and supporting older adults to remain in their own homes and communities is also favored by policy makers. Technology can play a role in staying independent, active and healthy. However, the use of technology varies considerably among older adults. Previous research indicates that current models of technology acceptance are missing essential predictors specific to community-dwelling older adults. Furthermore, in situ research within the specific context of aging in place is scarce, while this type of research is needed to better understand how and why community-dwelling older adults are using technology. OBJECTIVE: To explore which factors influence the level of use of various types of technology by older adults who are aging in place and to describe these factors in a comprehensive model. METHODS: A qualitative explorative field study was set up, involving home visits to 53 community-dwelling older adults, aged 68-95, living in the Netherlands. Purposive sampling was used to include participants with different health statuses, living arrangements, and levels of technology experience. During each home visit: (1) background information on the participants' chronic conditions, major life events, frailty, cognitive functioning, subjective health, ownership and use of technology was gathered, and (2) a semistructured interview was conducted regarding reasons for the level of use of technology. The study was designed to include various types of technology that could support activities of daily living, personal health or safety, mobility, communication, physical activity, personal development, and leisure activities. Thematic analysis was employed to analyze interview transcripts. RESULTS: The level of technology use in the context of aging in place is influenced by six major themes: challenges in the domain of independent living; behavioral options; personal thoughts on technology use; influence of the social network; influence of organizations, and the role of the physical environment. CONCLUSION: Older adults' perceptions and use of technology are embedded in their personal, social, and physical context. Awareness of these psychological and contextual factors is needed in order to facilitate aging in place through the use of technology. A conceptual model covering these factors is presented. PMID- 26044244 TI - A Frameshift Mutation in PEN-2 Causes Familial Comedones Syndrome. AB - BACKGROUND: Familial comedones without dyskeratosis are a rare autosomal dominant skin disorder, characterized by the occurrence of comedones that are distributed all over the body with specific features. We have previously reported two Thai families with familial comedones with expanded phenotypic spectrum. However, its genetic defect and pathogenesis remain unknown. OBJECTIVE: To explore the molecular defect causing familial comedones. METHODS: Whole-genome linkage analysis and whole-exome sequencing in family I were performed. RESULTS: We identified a heterozygous one-base pair insertion, c.84_85insT (p. L28FfsX93) in PEN-2, located within the linked region on chromosome 19. PCR-Sanger sequencing confirmed the identified mutation. The mutation segregated with the disease phenotype in family I and was fully penetrant. This similar mutation was also present in the unrelated affected individual from family II. Quantitative PCR revealed increased mRNA expression of PEN-2 in leukocytes of affected individuals. CONCLUSION: We for the first time identify PEN-2 as the causative gene of familial comedones. PMID- 26044245 TI - Introduction to a compendium on sudden cardiac death: epidemiology, mechanisms, and management. PMID- 26044247 TI - Sudden cardiac death risk stratification. AB - Arrhythmic sudden cardiac death (SCD) may be caused by ventricular tachycardia/fibrillation or pulseless electric activity/asystole. Effective risk stratification to identify patients at risk of arrhythmic SCD is essential for targeting our healthcare and research resources to tackle this important public health issue. Although our understanding of SCD because of pulseless electric activity/asystole is growing, the overwhelming majority of research in risk stratification has focused on SCD-ventricular tachycardia/ventricular fibrillation. This review focuses on existing and novel risk stratification tools for SCD-ventricular tachycardia/ventricular fibrillation. For patients with left ventricular dysfunction or myocardial infarction, advances in imaging, measures of cardiac autonomic function, and measures of repolarization have shown considerable promise in refining risk. Yet the majority of SCD-ventricular tachycardia/ventricular fibrillation occurs in patients without known cardiac disease. Biomarkers and novel imaging techniques may provide further risk stratification in the general population beyond traditional risk stratification for coronary artery disease alone. Despite these advances, significant challenges in risk stratification remain that must be overcome before a meaningful impact on SCD can be realized. PMID- 26044248 TI - Genetics of sudden cardiac death. AB - Sudden cardiac death occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Genetic studies conducted during the past 20 years have markedly illuminated the genetic basis of the inherited cardiac disorders associated with sudden cardiac death. Here, we review the genetic basis of sudden cardiac death with a focus on the current knowledge on the genetics of the primary electric disorders caused primarily by mutations in genes encoding ion channels, and the cardiomyopathies, which have been attributed to mutations in genes encoding a broader category of proteins, including those of the sarcomere, the cytoskeleton, and desmosomes. We discuss the challenges currently faced in unraveling genetic factors that predispose to sudden cardiac death in the setting of sequela of coronary artery disease and present the genome-wide association studies conducted in recent years on electrocardiographic parameters, highlighting their potential in uncovering new biological insights into cardiac electric function. PMID- 26044246 TI - The spectrum of epidemiology underlying sudden cardiac death. AB - Sudden cardiac death (SCD) from cardiac arrest is a major international public health problem accounting for an estimated 15%-20% of all deaths. Although resuscitation rates are generally improving throughout the world, the majority of individuals who experience a sudden cardiac arrest will not survive. SCD most often develops in older adults with acquired structural heart disease, but it also rarely occurs in the young, where it is more commonly because of inherited disorders. Coronary heart disease is known to be the most common pathology underlying SCD, followed by cardiomyopathies, inherited arrhythmia syndromes, and valvular heart disease. During the past 3 decades, declines in SCD rates have not been as steep as for other causes of coronary heart disease deaths, and there is a growing fraction of SCDs not due to coronary heart disease and ventricular arrhythmias, particularly among certain subsets of the population. The growing heterogeneity of the pathologies and mechanisms underlying SCD present major challenges for SCD prevention, which are magnified further by a frequent lack of recognition of the underlying cardiac condition before death. Multifaceted preventative approaches, which address risk factors in seemingly low-risk and known high-risk populations, will be required to decrease the burden of SCD. In this Compendium, we review the wide-ranging spectrum of epidemiology underlying SCD within both the general population and in high-risk subsets with established cardiac disease placing an emphasis on recent global trends, remaining uncertainties, and potential targeted preventive strategies. PMID- 26044249 TI - Mechanisms of sudden cardiac death: oxidants and metabolism. AB - Ventricular arrhythmia is the leading cause of sudden cardiac death (SCD). Deranged cardiac metabolism and abnormal redox state during cardiac diseases foment arrhythmogenic substrates through direct or indirect modulation of cardiac ion channel/transporter function. This review presents current evidence on the mechanisms linking metabolic derangement and excessive oxidative stress to ion channel/transporter dysfunction that predisposes to ventricular arrhythmias and SCD. Because conventional antiarrhythmic agents aiming at ion channels have proven challenging to use, targeting arrhythmogenic metabolic changes and redox imbalance may provide novel therapeutics to treat or prevent life-threatening arrhythmias and SCD. PMID- 26044250 TI - Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death. AB - Despite improvements in the therapy of underlying heart disease, sudden cardiac death is a major cause of death worldwide. Disturbed Na and Ca handling is known to be a major predisposing factor for life-threatening tachyarrhythmias. In cardiomyocytes, many ion channels and transporters, including voltage-gated Na and Ca channels, cardiac ryanodine receptors, Na/Ca-exchanger, and SR Ca-ATPase are involved in this regulation. We have learned a lot about the pathophysiological relevance of disturbed ion channel function from monogenetic disorders. Changes in the gating of a single ion channel and the activity of an ion pump suffice to dramatically increase the propensity for arrhythmias even in structurally normal hearts. Nevertheless, patients with heart failure with acquired dysfunction in many ion channels and transporters exhibit profound dysregulation of Na and Ca handling and Ca/calmodulin-dependent protein kinase and are especially prone to arrhythmias. A deeper understanding of the underlying arrhythmic principles is mandatory if we are to improve their outcome. This review addresses basic tachyarrhythmic mechanisms, the underlying ionic mechanisms and the consequences for ion homeostasis, and the situation in complex diseases like heart failure. PMID- 26044251 TI - Ion channel macromolecular complexes in cardiomyocytes: roles in sudden cardiac death. AB - The movement of ions across specific channels embedded on the membrane of individual cardiomyocytes is crucial for the generation and propagation of the cardiac electric impulse. Emerging evidence over the past 20 years strongly suggests that the normal electric function of the heart is the result of dynamic interactions of membrane ion channels working in an orchestrated fashion as part of complex molecular networks. Such networks work together with exquisite temporal precision to generate each action potential and contraction. Macromolecular complexes play crucial roles in transcription, translation, oligomerization, trafficking, membrane retention, glycosylation, post translational modification, turnover, function, and degradation of all cardiac ion channels known to date. In addition, the accurate timing of each cardiac beat and contraction demands, a comparable precision on the assembly and organizations of sodium, calcium, and potassium channel complexes within specific subcellular microdomains, where physical proximity allows for prompt and efficient interaction. This review article, part of the Compendium on Sudden Cardiac Death, discusses the major issues related to the role of ion channel macromolecular assemblies in normal cardiac electric function and the mechanisms of arrhythmias leading to sudden cardiac death. It provides an idea of how these issues are being addressed in the laboratory and in the clinic, which important questions remain unanswered, and what future research will be needed to improve knowledge and advance therapy. PMID- 26044252 TI - Finding the rhythm of sudden cardiac death: new opportunities using induced pluripotent stem cell-derived cardiomyocytes. AB - Sudden cardiac death is a common cause of death in patients with structural heart disease, genetic mutations, or acquired disorders affecting cardiac ion channels. A wide range of platforms exist to model and study disorders associated with sudden cardiac death. Human clinical studies are cumbersome and are thwarted by the extent of investigation that can be performed on human subjects. Animal models are limited by their degree of homology to human cardiac electrophysiology, including ion channel expression. Most commonly used cellular models are cellular transfection models, which are able to mimic the expression of a single-ion channel offering incomplete insight into changes of the action potential profile. Induced pluripotent stem cell-derived cardiomyocytes resemble, but are not identical, adult human cardiomyocytes and provide a new platform for studying arrhythmic disorders leading to sudden cardiac death. A variety of platforms exist to phenotype cellular models, including conventional and automated patch clamp, multielectrode array, and computational modeling. Induced pluripotent stem cell-derived cardiomyocytes have been used to study long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, hypertrophic cardiomyopathy, and other hereditary cardiac disorders. Although induced pluripotent stem cell-derived cardiomyocytes are distinct from adult cardiomyocytes, they provide a robust platform to advance the science and clinical care of sudden cardiac death. PMID- 26044254 TI - Clinical management and prevention of sudden cardiac death. AB - Despite the revolutionary advancements in the past 3 decades in the treatment of ventricular tachyarrhythmias with device-based therapy, sudden cardiac death (SCD) remains an enormous public health burden. Survivors of SCD are generally at high risk for recurrent events. The clinical management of such patients requires a multidisciplinary approach from postresuscitative care to a thorough cardiovascular investigation in an attempt to identify the underlying substrate, with potential to eliminate or modify the triggers through catheter ablation and ultimately an implantable cardioverter-defibrillator (ICD) for prompt treatment of recurrences in those at risk. Early recognition of low left ventricular ejection fraction as a strong predictor of death and association of ventricular arrhythmias with sudden death led to significant investigation with antiarrhythmic drugs. The lack of efficacy and the proarrhythmic effects of drugs catalyzed the development and investigation of the ICD through several major clinical trials that proved the efficacy of ICD as a bedrock tool to detect and promptly treat life-threatening arrhythmias. The ICD therapy is routinely used for primary prevention of SCD in patients with cardiomyopathy and high risk inherited arrhythmic conditions and secondary prevention in survivors of sudden cardiac arrest. This compendium will review the clinical management of those surviving SCD and discuss landmark studies of antiarrhythmic drugs, ICD, and cardiac resynchronization therapy in the primary and secondary prevention of SCD. PMID- 26044253 TI - Cardiac innervation and sudden cardiac death. AB - Afferent and efferent cardiac neurotransmission via the cardiac nerves intricately modulates nearly all physiological functions of the heart (chronotropy, dromotropy, lusitropy, and inotropy). Afferent information from the heart is transmitted to higher levels of the nervous system for processing (intrinsic cardiac nervous system, extracardiac-intrathoracic ganglia, spinal cord, brain stem, and higher centers), which ultimately results in efferent cardiomotor neural impulses (via the sympathetic and parasympathetic nerves). This system forms interacting feedback loops that provide physiological stability for maintaining normal rhythm and life-sustaining circulation. This system also ensures that there is fine-tuned regulation of sympathetic-parasympathetic balance in the heart under normal and stressed states in the short (beat to beat), intermediate (minutes to hours), and long term (days to years). This important neurovisceral/autonomic nervous system also plays a major role in the pathophysiology and progression of heart disease, including heart failure and arrhythmias leading to sudden cardiac death. Transdifferentiation of neurons in heart failure, functional denervation, cardiac and extracardiac neural remodeling has also been identified and characterized during the progression of disease. Recent advances in understanding the cellular and molecular processes governing innervation and the functional control of the myocardium in health and disease provide a rational mechanistic basis for the development of neuraxial therapies for preventing sudden cardiac death and other arrhythmias. Advances in cellular, molecular, and bioengineering realms have underscored the emergence of this area as an important avenue of scientific inquiry and therapeutic intervention. PMID- 26044256 TI - Xanthogranulomatous Adrenalitis: A Case Report of a Diabetic, 55-Year-Old Male. AB - We report a rare case of xanthogranulomatous adrenalitis in a 55-year-old man. The patient presented to the hospital with fever, nausea, and right flank pain. His medical history was significant for diabetes and an adrenal mass that was detected 6 years prior to presentation during a computed tomography (CT) scan for trauma secondary to a motor vehicle collision. The mass was thought to be a myelolipoma. Magnetic resonance imaging (MRI) revealed a 12-cm right adrenal mass that was considered suspicious for carcinoma, which was surgically excised and cultured intraoperatively. The cultures subsequently grew methicillin-resistant Staphylococcus aureus (MRSA). Grossly, the adrenal mass was an encapsulated, necrotic lesion with surrounding areas of fat necrosis. On histologic examination, the tissue showed sheets of histiocytes, lymphocytes, and plasma cells diffusely involving the adrenal gland along with bright yellow lipofuscin crystals in a background of necrosis and fibrosis. PMID- 26044258 TI - Three-Year Course of Cannabis Dependence and Prediction of Persistence. AB - AIMS: To examine the course and the predictors of the persistence of cannabis dependence. METHODS: Through cannabis outlets and chain referral, a prospective enriched community cohort of 207 young adults (aged 18-30) with DSM-IV cannabis dependence at baseline (T0) was formed and followed-up after 1.5 (T1) and 3 (T2) years. The presence of cannabis dependence, cannabis-related problems, functional impairment and treatment was assessed using the Composite International Diagnostic Interview (CIDI 3.0) and the Sheehan Disability Scale (SDS). Predictors of persistence were lifetime cannabis abuse and dependence symptoms, cannabis use characteristics, distant vulnerability factors (e.g. childhood adversity, family history of psychological/substance use problems, impulsivity, mental disorders), and proximal stress factors (recent life events, social support). RESULTS: Four groups were distinguished: persistent dependent (DDD: 28.0%), stable non-persistent (DNN: 40.6%), late non-persistent (DDN: 17.9%) and recurrent dependent (DND: 13.5%). At T2, persisters (DDD) reported significantly more (heavy) cannabis use and cannabis problems than non-persisters (DNN/DDN/DND). Treatment seeking for cannabis-related problems was rare, even among persisters (15.5%). The number (OR = 1.23 (1.03-1.48)) and type ('role impairment' OR = 2.85 (1.11-7.31), 'use despite problems' OR = 2.34 (1.15-4.76)) of lifetime cannabis abuse/dependence symptoms were the only independent predictors of persistence with a total explained variance of 8.8%. CONCLUSIONS: Persistence of cannabis dependence in the community is low, difficult to predict, and associated with a negative outcome. The substantial proportion of stable non persisters suggests that screening and monitoring or low-threshold brief interventions may suffice for many non-treatment-seeking cannabis-dependent people. However, those with many lifetime abuse/dependence symptoms may benefit from more intensive interventions. PMID- 26044255 TI - Cardiac arrest: resuscitation and reperfusion. AB - The modern treatment of cardiac arrest is an increasingly complex medical procedure with a rapidly changing array of therapeutic approaches designed to restore life to victims of sudden death. The 2 primary goals of providing artificial circulation and defibrillation to halt ventricular fibrillation remain of paramount importance for saving lives. They have undergone significant improvements in technology and dissemination into the community subsequent to their establishment 60 years ago. The evolution of artificial circulation includes efforts to optimize manual cardiopulmonary resuscitation, external mechanical cardiopulmonary resuscitation devices designed to augment circulation, and may soon advance further into the rapid deployment of specially designed internal emergency cardiopulmonary bypass devices. The development of defibrillation technologies has progressed from bulky internal defibrillators paddles applied directly to the heart, to manually controlled external defibrillators, to automatic external defibrillators that can now be obtained over-the-counter for widespread use in the community or home. But the modern treatment of cardiac arrest now involves more than merely providing circulation and defibrillation. As suggested by a 3-phase model of treatment, newer approaches targeting patients who have had a more prolonged cardiac arrest include treatment of the metabolic phase of cardiac arrest with therapeutic hypothermia, agents to treat or prevent reperfusion injury, new strategies specifically focused on pulseless electric activity, which is the presenting rhythm in at least one third of cardiac arrests, and aggressive post resuscitation care. There are discoveries at the cellular and molecular level about ischemia and reperfusion pathobiology that may be translated into future new therapies. On the near horizon is the combination of advanced cardiopulmonary bypass plus a cocktail of multiple agents targeted at restoration of normal metabolism and prevention of reperfusion injury, as this holds the promise of restoring life to many patients for whom our current therapies fail. PMID- 26044260 TI - Regulators to take over running of three failing NHS areas in England. PMID- 26044257 TI - Effects of combined physical exercise training on DNA damage and repair capacity: role of oxidative stress changes. AB - Regular physical exercise has been shown to be one of the most important lifestyle influences on improving functional performance, decreasing morbidity and all causes of mortality among older people. However, it is known that acute physical exercise may induce an increase in oxidative stress and oxidative damage in several structures, including DNA. Considering this, the purpose of this study was to identify the effects of 16 weeks of combined physical exercise in DNA damage and repair capacity in lymphocytes. In addition, we aimed to investigate the role of oxidative stress involved in those changes. Fifty-seven healthy men (40 to 74 years) were enrolled in this study. The sample was divided into two groups: the experimental group (EG), composed of 31 individuals, submitted to 16 weeks of combined physical exercise training; and the control group (CG), composed of 26 individuals, who did not undergo any specifically orientated physical activity. We observed an improvement of overall physical performance in the EG, after the physical exercise training. A significant decrease in DNA strand breaks and FPG-sensitive sites was found after the physical exercise training, with no significant changes in 8-oxoguanine DNA glycosylase enzyme activity. An increase was observed in antioxidant activity, and a decrease was found in lipid peroxidation levels after physical exercise training. These results suggest that physical exercise training induces protective effects against DNA damage in lymphocytes possibly related to the increase in antioxidant capacity. PMID- 26044259 TI - Efficient in vitro generation of functional thymic epithelial progenitors from human embryonic stem cells. AB - Thymic epithelial cells (TECs) are the major components of the thymic microenvironment for T cell development. TECs are derived from thymic epithelial progenitors (TEPs). It has been reported that human ESCs (hESCs) can be directed to differentiate into TEPs in vitro. However, the efficiency for the differentiation is low. Furthermore, transplantation of hESC-TEPs in mice only resulted in a very low level of human T cell development from co-transplanted human hematopoietic precursors. We show here that we have developed a novel protocol to efficiently induce the differentiation of hESCs into TEPs in vitro. When transplanted into mice, hESC-TEPs develop into TECs and form a thymic architecture. Most importantly, the hESC-TECs support the long-term development of functional mouse T cells or a higher level of human T cell development from co transplanted human hematopoietic precursors. The hESC-TEPs may provide a new approach to prevent or treat patients with T cell immunodeficiency. PMID- 26044261 TI - Gray zone lymphoma with features intermediate between classical Hodgkin lymphoma and diffuse large B-cell lymphoma: characteristics, outcomes, and prognostication among a large multicenter cohort. AB - Gray zone lymphoma (GZL) with features between classical Hodgkin lymphoma and diffuse large B-cell lymphoma (DLBCL) is a recently recognized entity reported to present primarily with mediastinal disease (MGZL). We examined detailed clinical features, outcomes, and prognostic factors among 112 GZL patients recently treated across 19 North American centers. Forty-three percent of patients presented with MGZL, whereas 57% had non-MGZL (NMGZL). NMGZL patients were older (50 versus 37 years, P = 0.0001); more often had bone marrow involvement (19% versus 0%, P = 0.001); >1 extranodal site (27% versus 8%, P = 0.014); and advanced stage disease (81% versus 13%, P = 0.0001); but they had less bulk (8% versus 44%, P = 0.0001), compared with MGZL patients. Common frontline treatments were cyclophosphamide-doxorubicin-vincristine-prednisone +/- rituximab (CHOP+/-R) 46%, doxorubicin-bleomycin-vinblastine-dacarbazine +/- rituximab (ABVD+/-R) 30%, and dose-adjusted etoposide-doxorubicin-cyclophosphamide-vincristine-prednisone rituximab (DA-EPOCH-R) 10%. Overall and complete response rates for all patients were 71% and 59%, respectively; 33% had primary refractory disease. At 31-month median follow-up, 2-year progression-free survival (PFS) and overall survival rates were 40% and 88%, respectively. Interestingly, outcomes in MGZL patients seemed similar compared with that of NMGZL patients. On multivariable analyses, performance status and stage were highly prognostic for survival for all patients. Additionally, patients treated with ABVD+/-R had markedly inferior 2 year PFS (22% versus 52%, P = 0.03) compared with DLBCL-directed therapy (CHOP+/ R and DA-EPOCH-R), which persisted on Cox regression (hazard ratio, 1.88; 95% confidence interval, 1.03-3.83; P = 0.04). Furthermore, rituximab was associated with improved PFS on multivariable analyses (hazard ratio, 0.35; 95% confidence interval, 0.18-0.69; P = 0.002). Collectively, GZL is a heterogeneous and likely more common entity and often with nonmediastinal presentation, whereas outcomes seem superior when treated with a rituximab-based, DLBCL-specific regimen. PMID- 26044262 TI - Are income-related differences in active travel associated with physical environmental characteristics? A multi-level ecological approach. AB - BACKGROUND: Rates of active travel vary by socio-economic position, with higher rates generally observed among less affluent populations. Aspects of both social and built environments have been shown to affect active travel, but little research has explored the influence of physical environmental characteristics, and less has examined whether physical environment affects socio-economic inequality in active travel. This study explored income-related differences in active travel in relation to multiple physical environmental characteristics including air pollution, climate and levels of green space, in urban areas across England. We hypothesised that any gradient in the relationship between income and active travel would be least pronounced in the least physically environmentally deprived areas where higher income populations may be more likely to choose active transport as a means of travel. METHODS: Adults aged 16+ living in urban areas (n = 20,146) were selected from the 2002 and 2003 waves of the UK National Travel Survey. The mode of all short non-recreational trips undertaken by the sample was identified (n = 205,673). Three-level binary logistic regression models were used to explore how associations between the trip being active (by bike/walking) and three income groups, varied by level of multiple physical environmental deprivation. RESULTS: Likelihood of making an active trip among the lowest income group appeared unaffected by physical environmental deprivation; 15.4% of their non-recreational trips were active in both the least and most environmentally-deprived areas. The income-related gradient in making active trips remained steep in the least environmentally-deprived areas because those in the highest income groups were markedly less likely to choose active travel when physical environment was 'good', compared to those on the lowest incomes (OR = 0.44, 95% CI = 0.22 to 0.89). CONCLUSIONS: The socio-economic gradient in active travel seems independent of physical environmental characteristics. Whilst more affluent populations enjoy advantages on some health outcomes, they will still benefit from increasing their levels of physical activity through active travel. Benefits of active travel to the whole community would include reduced vehicle emissions, reduced carbon consumption, the preservation or enhancement of infrastructure and the presentation of a 'normalised' behaviour. PMID- 26044264 TI - Perineal management techniques among midwives at five hospitals in New South Wales - a cross-sectional survey. AB - BACKGROUND: Midwives are reported to have changed from 'hands on' to 'hands poised or off' approaches to birth at the same time as obstetric anal sphincter injuries (OASIs) are increasing. As perineal management details are not routinely collected, it is difficult to quantify practice. AIMS: To determine which perineal protections techniques midwives prefer for low-risk non-water births; whether preference is associated with technique taught or with other characteristics; and whether midwives change preference according to clinical scenario. MATERIALS AND METHODS: Midwives in Northern Sydney Local Health District (NSLHD) were surveyed during a 2-week period in 2014. Multiple-choice questions were used, with free text option. Descriptive analyses, chi-square and McNemar tests were undertaken. RESULTS: One hundred and eight midwives participated (response rate 76.7%). 'Hands poised or off' was preferred by 63.0% for a low-risk birth. Current practice was associated with technique taught (P < 0.01). For scenarios with increased OASI risk midwives reported switching to 'hands on', with 83.4% employing 'hands on' whether there was concern about an impending OASI. There has been a shift over time from teaching 'hands on' to 'hands poised or off'. CONCLUSION: The preferred technique for a low-risk birth appears to have changed from 'hands on' to 'hands poised or off', but most midwives adopt 'hands on' in situations of high risk for OASI. Further research is needed to establish whether there is an association with the rising OASI rate and the change in preferred perineal management technique for a low-risk birth. PMID- 26044265 TI - Characterization of a non-approved selective androgen receptor modulator drug candidate sold via the Internet and identification of in vitro generated phase-I metabolites for human sports drug testing. AB - RATIONALE: Potentially performance-enhancing agents, particularly anabolic agents, are advertised and distributed by Internet-based suppliers to a substantial extent. Among these anabolic agents, a substance referred to as LGD 4033 has been made available, comprising the core structure of a class of selective androgen receptor modulators (SARMs). METHODS: In order to provide comprehensive analytical data for doping controls, the substance was obtained and characterized by nuclear magnetic resonance spectroscopy (NMR) and liquid chromatography/electrospray ionization high resolution/high accuracy tandem mass spectrometry (LC/ESI-HRMS). Following the identification of 4-(2-(2,2,2-trifluoro 1-hydroxyethyl)pyrrolidin-1-yl)-2-(trifluoromethyl)benzonitrile, the substance was subjected to in vitro metabolism studies employing human liver microsomes and Cunninghamella elegans (C. elegans) preparations as well as electrochemical metabolism simulations. RESULTS: By means of LC/ESI-HRMS, five main phase-I metabolites were identified as products of liver microsomal preparations including three monohydroxylated and two bishydroxylated species. The two most abundant metabolites (one mono- and one bishydroxylated product) were structurally confirmed by LC/ESI-HRMS and NMR. Comparing the metabolic conversion of 4-(2-(2,2,2-trifluoro-1-hydroxyethyl)pyrrolidin-1-yl)-2 (trifluoromethyl)benzonitrile observed in human liver microsomes with C. elegans and electrochemically derived metabolites, one monohydroxylated product was found to be predominantly formed in all three methodologies. CONCLUSIONS: The implementation of the intact SARM-like compound and its presumed urinary phase-I metabolites into routine doping controls is suggested to expand and complement existing sports drug testing methods. PMID- 26044266 TI - Laser ablation generation of clusters from As-Te mixtures, As-Te glass nano layers and from Au-As-Te nano-composites. Quadrupole ion trap time-of-flight mass spectrometry. AB - RATIONALE: Arsenic tellurides have found important applications in various fields of science, but only a few gold-arsenic tellurides have been reported. Laser ablation synthesis (LAS), a suitable method for the generation of new compounds, has been used to generate clusters from As-Te mixtures, an As-Te glass and Au-As Te nano-composites. METHODS: Chalcogenide glass nano-layers prepared via Physical Vapour Deposition - thermal evaporation were characterized using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDX). LAS with laser desorption ionisation quadrupole ion trap time-of-flight mass spectrometry (LDI QIT TOFMS) was used for the generation and analysis of new AuxAsmTen clusters. The stoichiometry of the clusters was determined via isotopic envelope modelling. RESULTS: A simple procedure for the preparation of the Au-As Te nano-composite was developed. From As-Te mixtures only five binary AsmTen clusters were generated, while from a glass layer 10 binary AsmTen clusters were identified, because during the deposition of the glass the elements reacted with each other to form a complex three-dimensional (3D) structure. Using LAS on the Au-As-Te nano-composite leads to the formation of six unary Ten (n = 1-6), 16 binary (AsmTen and AuxTen), and 31 ternary AuxAsmTen clusters. CONCLUSIONS: LAS was demonstrated to be a useful technique for the generation of AuxAsmTen clusters in the gas phase. More AsmTen clusters were generated from the deposited glass layers than from As-Te mixtures. Most of the ternary AuxAsmTen clusters generated from the nano-composite are reported here for the first time. PMID- 26044267 TI - Absorption mode Fourier transform mass spectrometry with no baseline correction using a novel asymmetric apodization function. AB - RATIONALE: Absorption mode Fourier transform ion cyclotron resonance (FTICR) mass spectra offer significant benefits in terms of spectral resolution, signal-to noise (S/N) ratio and measured mass accuracy. However, to date, methods for producing absorption mode spectra have created an undesirable baseline deviation as a consequence of FFT artifacts, resulting in interference of the frequency side-lobes of intense peaks. Methods for fitting and removing this deviation have been developed, but these are computationally intensive, slow and can be unreliable in practice. METHODS: We have developed an approach for producing FTICR mass spectra which uses a new apodization approach to produce spectra which do not exhibit baseline deviation, whilst maintaining all the normal absorption mode benefits. This method involves the use of 'full' apodization function, replacing the more common Hann or half Hann functions, and where the user can control the position of the function maximum expressed as a fraction (F) of the transient length. RESULTS: Absorption mode spectra produced using the new apodization function we propose provide all the normal benefits but do not exhibit baseline deviation that must be corrected prior to spectral interpretation. Additionally, varying the value of the F parameter allows users additional control over the compromise between the spectral resolving power and the S/N ratio. This is particularly beneficial in spectra with pronounced amplitude changes during the recording of the transient (detection). CONCLUSIONS: The use of a 'full' apodization function, which may be asymmetric, prior to zero padding and Fourier transformation, allows the production of absorption mode spectra which do not suffer from baseline deviation. Hence, it is no longer necessary to apply a baseline deviation correction in post processing, providing a significant performance advantage. PMID- 26044268 TI - Resolution pattern for mass spectrometry imaging. AB - RATIONALE: Up to now, there is no 'gold standard' for determining the resolution of a mass spectrometry imaging (MSI) setup (comprising the instrument, the sample preparation, the sample and the instrument settings). A standard sample in combination with a standard protocol to define the MSI resolution would be desirable in order to compare the setups of different laboratories, and as a regular quality control/performance check. METHODS: Microstructured resolution patterns were fabricated that can be used to determine the spatial resolution in MSI experiments, down to the range of a few um. Two different strategies were employed, one where the resolution pattern is laser machined into a thin metal foil, which can be placed over a sample to be imaged, and a second one where hydrophilic grooves are machined into an omniphobic coating covering the surface of an indium tin oxide covered glass slide. When dragging a sample solution over the slide's surface, the sample is automatically retained in the hydrophilic grooves, but repelled by the omniphobic coating. RESULTS: The technology was tested on a commercial matrix-assisted laser desorption/ionization (MALDI) imaging instrument, and a spatial resolution in the vicinity of 50 um was determined. The finest features of the microstructured resolution patterns are compatible with the best spatial resolution of MALDI imaging systems available to date. CONCLUSIONS: The use of metal resolution grids or glass slides with hydrophilic/hydrophobic structures is suitable for the convenient determination of the resolution limit of the MALDI imaging instrument as determined by its hardware. These structures are straightforward both to produce and to use. PMID- 26044269 TI - MS(3)-based quantitative proteomics using pulsed-Q dissociation. AB - RATIONALE: Isobaric tagging reagents, such as tandem mass tags (TMT) and isobaric tags for relative and absolute quantitation (iTRAQ), are high-throughput methods that allow the analysis of multiple samples simultaneously, which reduces instrument time and error. Accuracy and precision of isobaric tags are limited, however, in tandem mass spectrometry (MS/MS) acquisition due to co-isolation and co-fragmentation of neighboring peptide peaks in precursor scans. Here we present a MS(3) method using pulsed-Q dissociation (PQD) in ion trap and Orbitrap instrumentation as a means to improve ratio distortion and maintain high numbers of identified and quantified proteins. METHODS: Mouse brain protein digests were labeled with TMT-128, 129, 130, 131 reagents, mixed in the following molar ratios 1:1:2:5, respectively, and analyzed using HCD-MS(3) and PQD-MS(3) methods. The most intense fragment ion (termed as HCD-MS(3)-top ion or PQD-MS(3)-top ion) or y1 ion (i.e., lysine-TMT tag ion; termed as HCD-MS(3)-y1 or PQD-MS(3)-y1) in collision-induced dissociation (CID) MS/MS was selected for MS(3). RESULTS: Calculated protein ratios obtained in HCD-MS(3)-top ion and PQD-MS(3)-top ion, HCD-MS(3)-y1, and PQD-MS(3)-y1 are accurate and PQD-MS(3) methods resulted in higher numbers of identified and quantified peptide spectral counts and proteins. CONCLUSIONS: PQD-MS(3) methods increase the amount of MS/MS spectra collected and number of quantified proteins and are accessible to those researchers with not only an orbitrap but also an ion trap mass spectrometer. PMID- 26044270 TI - The use of isoprene as a novel dopant in negative ion atmospheric pressure photoionization mass spectrometry coupled to high-performance liquid chromatography. AB - RATIONALE: As in the case with positive ion atmospheric pressure photoionization (PI-APPI), the addition of dopants significantly improves the sensitivity of negative ion APPI (NI-APPI). However, the research on dopant-assisted-NI-APPI has been quite limited compared to the studies on dopant-assisted PI-APPI. This work presents the potential of isoprene as a novel dopant for NI-APPI. METHODS: Thirteen compounds, possessing suitable gas-phase ion energetic properties in order to make stable negative ions, were selected. Dopants were continuously introduced into a tee junction prior to the ion source through a fused-silica capillary, while analytes were directly injected into the same tee. Then both were mixed with the continuous solvent from high-performance liquid chromatography (HPLC), nebulized, and entered the source. The nebulized stream was analyzed by APPI tandem quadrupole mass spectrometry in the negative ion mode. RESULTS: The results obtained using isoprene were compared with those obtained by using toluene as a dopant and dopant-free NI-APPI. Isoprene enhanced the ionization intensities of the studied compounds, which were found to be comparable and, in some cases, more effective than toluene. The mechanisms leading to the observed set of negative analyte ions were also discussed. Because in NI-APPI, thermal electrons, which are produced during the photoionization of a dopant, are considered the main reagent ions, both isoprene and toluene promoted the ionization of analytes through the same mechanisms, as expected. CONCLUSIONS: Isoprene was shown to perform well as a novel dopant for NI-APPI. Isoprene has a high photoabsorption cross section in the VUV region; therefore, its photoionization leads to a highly effective production of thermal electrons, which further promotes the ionization of analytes. In addition, isoprene is environmentally benign and less toxic compared to currently used dopants. PMID- 26044271 TI - Improved analysis of ultra-high molecular mass polystyrenes in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using DCTB matrix and caesium salts. AB - RATIONALE: The ionization of polystyrenes in matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) is typically achieved by the use of silver salts. Since silver salts can cause severe problems, such as cluster formation, fragmentation of polymer chains and end group cleavage, their substitution by alkali salts is highly desirable. METHODS: The influence of various cations (Ag(+), Cs(+) and Rb(+)) on the MALDI process of polystyrene (PS) mixtures and high mass polystyrenes was examined. The sample preparation was kept as straightforward as possible. Consequently, no recrystallization or other cleaning procedures were applied. RESULTS: The investigation of a polystyrene mixture showed that higher molecular polystyrenes could be more easily ionized using caesium, rather than rubidium or silver salts. In combination with the use of DCTB as matrix a high-mass polymer analysis could be achieved, which was demonstrated by the detection of a 1.1 MDa PS. CONCLUSIONS: A fast, simple and robust MALDI sample preparation method for the analysis of ultra-high molecular weight polystyrenes based on the use of DCTB and caesium salts has been presented. The suitability of the presented method has been validated by using different mass spectrometers and detectors. PMID- 26044272 TI - A protocol to correct for intra- and interspecific variation in tail hair growth to align isotope signatures of segmentally cut tail hair to a common time line. AB - RATIONALE: In recent years, segmental stable isotope analysis of hair has been a focus of research in animal dietary ecology and migration. To correctly assign tail hair segments to seasons or even Julian dates, information on tail hair growth rates is a key parameter, but is lacking for most species. METHODS: We (a) reviewed the literature on tail hair growth rates in mammals; b) made own measurements of three captive equid species; (c) measured delta(2)H, delta(13)C and delta(15)N values in sequentially cut tail hairs of three sympatric, free ranging equids from the Mongolian Gobi, using isotope ratio mass spectrometry (IRMS); and (d) collected environmental background data on seasonal variation by measuring delta(2)H values in precipitation by IRMS and by compiling pasture productivity measured by remote sensing via the normalized difference vegetation index (NDVI). RESULTS: Tail hair growth rates showed significant inter- and intra specific variation making temporal alignment problematic. In the Mongolian Gobi, high seasonal variation of delta(2)H values in precipitation results in winter lows and summer highs of delta(2)H values of available water sources. In water dependent equids, this seasonality is reflected in the isotope signatures of sequentially cut tails hairs. CONCLUSIONS: In regions which are subject to strong seasonal patterns we suggest identifying key isotopes which show strong seasonal variation in the environment and can be expected to be reflected in the animal tissue. The known interval between the maxima and minima of these isotope values can then be used to correctly temporally align the segmental stable isotope signature for each individual animal. PMID- 26044273 TI - Design and study of an atmospheric pressure ion funnel by computer simulations. AB - RATIONALE: An atmospheric pressure ion funnel (APIF) has been developed to transfer and focus ions at atmospheric pressure. This ion funnel can be used as an interface connecting the ion source and the mass spectrometer detector. METHODS: The APIF designs were studied mainly by using computer simulations. Different APIF configurations with various geometrical and electrical parameters were analyzed. Investigation of the electrical field and ion transmission characteristics of the APIF was carried out using SIMION 8.0. RESULTS: The APIF exhibits good ion-guiding performance with transmission efficiency of >90%. An approximate formula for determining the optimal parameters of the APIF has been derived by theoretical calculation. CONCLUSIONS: When both the geometrical and the electrical parameters are optimized, the APIF can provide high ion transmission efficiency. In addition, the proposed empirical formula is helpful in guiding the design of APIFs. PMID- 26044274 TI - Discrimination factors of carbon and nitrogen stable isotopes from diet to hair and scat in captive tigers (Panthera tigris) and snow leopards (Uncia uncia). AB - RATIONALE: In order to use stable isotope ratio values obtained from wild animal tissues, we must accurately calculate the differences in isotope ratios between diet and consumer (deltatissue - deltadiet). These values, called trophic discrimination factors (TDFs, denoted with ?), are necessary for stable isotope ecology studies and are best calculated in controlled environments. METHODS: Scat, hair, and diet samples were collected from captive tigers (n = 8) and snow leopards (n = 10) at the Bronx Zoo. The isotope ratios of carbon and nitrogen, the two most commonly used in ecological studies, of the samples were measured by continuous-flow isotope ratio mass spectrometry. The trophic discrimination factors were calculated for both carbon (delta(13)C values) and nitrogen (delta(15)N values). RESULTS: It was found that the only significant TDFs in this study were diet-hair, ?(13)CHair, for snow leopards (5.97 +/- 1.250/00) and tigers (6.45 +/- 0.540/00), and diet-scat, ?(15)NScat, in snow leopards (2.49 +/- 1.300/00). The other mean isotope ratios were not significantly different from that of the premixed feline diet. The ?(15)NHair values for both species were unusually low, potentially due to the protein content and quality of the feline diet. CONCLUSIONS: The discrimination factors of the stable isotopes of carbon and nitrogen calculated in this study can be applied to ecological studies of wild, non-captive terrestrial mammals. The effect of protein quality in isotope discrimination is also worthy of further investigation to better understand variation in TDFs. Carnivore scat is shown to be a valuable material for isotopic analysis. PMID- 26044275 TI - Direct detection and quantification of malondialdehyde vapour in humid air using selected ion flow tube mass spectrometry supported by gas chromatography/mass spectrometry. AB - RATIONALE: It has been proposed that malondialdehyde (MDA) reflects free oxygen radical lipid peroxidation and can be useful as a biomarker to track this process. For the analysis of MDA molecules in humid air by selected ion flow tube mass spectrometry (SIFT-MS), the rate coefficients and the ion product distributions for the reactions of the SIFT-MS reagent ions with volatile MDA in the presence of water vapour are required. METHODS: The SIFT technique has been used to determine the rate coefficients and ion product distributions for the reactions of H3O(+), NO(+) and O2 (+*) with gas-phase MDA. In support of the SIFT MS analysis of MDA, solid-phase microextraction, SPME, coupled with gas chromatography/mass spectrometry, GC/MS, has been used to confirm the identification of MDA. RESULTS: The primary product ions have been identified for the reactions of H3O(+), NO(+) and O2 (+*) with MDA and the formation of their hydrates formed in humid samples is described. The following combinations of reagent and the analyte ions (given as m/z values) have been adopted for SIFT-MS analyses of MDA in the gas phase: H3O(+): 109; NO(+): 89, 102; O2 (+*): 72, 90, 108, 126. The detection and quantification of MDA released by a cell culture by SIFT-MS are demonstrated. CONCLUSIONS: This detailed study has provided the kinetics data required for the SIFT-MS analysis of MDA in humid air, including exhaled breath and the headspace of liquid-phase biogenic media. The detection and quantification by SIFT-MS of MDA released by a cell culture are demonstrated. PMID- 26044276 TI - Interactions between nanoparticles and lung surfactant investigated by matrix assisted laser desorption/ionization time-of-flight mass spectrometry. AB - RATIONALE: Inhaled nanoparticles may cause adverse effects due to inactivation of lung surfactants. We have studied how three different nanoparticles interact with dipalmitoyl-phosphatidylcholine (DPPC), the main component in lung surfactant. METHODS: DPPC in solution was mixed with a suspension of nanoparticles, both in organic solvent, and allowed to interact for 40 min under conditions partly resembling the alveolar lining. Nanoparticles were isolated by centrifugation, washed, and re-suspended in ethanol/water 1:1 (v/v). The resulting solution was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) using dihydroxybenzoic acid as matrix. RESULTS: The developed methodology was successfully applied for quantitative detection of phospholipid lung surfactant bound to three different types of nanoparticles. Titanium dioxide nanoparticles had a strong affinity for binding of lipid lung surfactant in contrast to pristine and methylated silica nanoparticles. When the concentration of lipid surfactant was raised in the reaction mixture, the titanium dioxide nanoparticles showed an apparently non-linear binding process. CONCLUSIONS: This work demonstrates that MALDI-TOFMS can be used for direct determination of the binding of surfactant lipids to nanoparticles and represents an important initial step towards a simple and quantitative in vitro method for assessment of interactions of nanoparticles with lung surfactants. PMID- 26044277 TI - Producing absorption mode Fourier transform ion cyclotron resonance mass spectra with non-quadratic phase correction functions. AB - RATIONALE: Previously described methods for producing absorption mode Fourier transform ion cyclotron resonance (FTICR) mass spectra have all relied on the phase correction function being quadratic. This assumption has been found to be invalid for some instruments and spectra and so it has not been possible to produce absorption mode spectra for these cases. METHODS: The Autophaser algorithm has been adapted to allow nth order polynomial phase correction functions to be optimized. The data was collected on a modified Thermo LTQ FTICR mass spectrometer, using electrospray ionization and a novel ICR cell design (NADEL). Peak assignment and mass calibration were undertaken using the pyFTMS framework. RESULTS: An nth-order phase correction function has been used to produce an absorption mode mass spectrum of the maltene fraction of a crude oil sample which was not possible using the previous assumption that the phase correction function must be quadratic. Data processing for this spectrum in absorption mode has shown the expected benefits in terms of increasing the number of assigned peaks and also improving the mass accuracy (i.e. confidence) of the assignments. CONCLUSIONS: It is possible to phase-correct time-domain data in FTICRMS to yield absorption mode mass spectra representation even when the data does not correspond to the theoretical quadratic phase correction function predicted by previous studies. This will allow a larger proportion of spectra to be processed in absorption mode. PMID- 26044278 TI - Intakes of magnesium, potassium, and calcium and the risk of stroke among men. AB - BACKGROUND: Intakes of magnesium, potassium, and calcium have been inversely associated with the incidence of hypertension, a known risk factor for stroke. However, only a few studies have examined intakes of these cations in relation to risk of stroke. AIM: The aim of this study was to investigate whether high intake of magnesium, potassium, and calcium is associated with reduced stroke risk among men. METHODS: We prospectively examined the associations between intakes of magnesium, potassium, and calcium from diet and supplements, and the risk of incident stroke among 42 669 men in the Health Professionals Follow-up Study, aged 40 to 75 years and free of diagnosed cardiovascular disease and cancer at baseline in 1986. We calculated the hazard ratio of total, ischemic, and haemorrhagic strokes by quintiles of each cation intake, and of a combined dietary score of all three cations, using multivariate Cox proportional hazard models. RESULTS: During 24 years of follow-up, 1547 total stroke events were documented. In multivariate analyses, the relative risks and 95% confidence intervals of total stroke for men in the highest vs. lowest quintile were 0.87 (95% confidence interval, 0.74-1.02; P, trend = 0.04) for dietary magnesium, 0.89 (95% confidence interval, 0.76-1.05; P, trend = 0.10) for dietary potassium, and 0.89 (95% confidence interval, 0.75-1.04; P, trend = 0.25) for dietary calcium intake. The relative risk of total stroke for men in the highest vs. lowest quintile was 0.74 (95% confidence interval, 0.59-0.93; P, trend = 0.003) for supplemental magnesium, 0.66 (95% confidence interval, 0.50-0.86; P, trend = 0.002) for supplemental potassium, and 1.01 (95% confidence interval, 0.84-1.20; P, trend = 0.83) for supplemental calcium intake. For total intake (dietary and supplemental), the relative risk of total stroke for men in the highest vs. lowest quintile was 0.83 (95% confidence interval, 0.70-0.99; P, trend = 0.04) for magnesium, 0.88 (95% confidence interval, 0.75-4; P, trend = 6) for potassium, and 3 (95% confidence interval, 79-09; P, trend = 84) for calcium. Men in the highest quintile for a combined dietary score of all three cations had a multivariate relative risk of 0.79 (95% confidence interval, 0.67-0.92; P, trend = 0.008) for total stroke, compared with those in the lowest. CONCLUSIONS: A diet rich in magnesium, potassium, and calcium may contribute to reduced risk of stroke among men. Because of significant collinearity, the independent contribution of each cation is difficult to define. PMID- 26044279 TI - Risks of congenital malformations in offspring exposed to valproic acid in utero: A systematic review and cumulative meta-analysis. AB - Despite extensive research efforts over decades, the teratogenic profile of valproic acid (VPA) remains obscure. We performed cumulative and conventional meta-analyses of cohort studies to determine the time profiles of signal emergence of VPA-associated congenital malformations (CMs) and to define risk estimates of each of the CMs. Fifty-nine studies were identified and analyzed. We found that the significant risk signals began to emerge over the last 10-20 years even before large-scale studies were performed: neural tube defect (the significant risk signal emerged in 1992); genitourinary and musculoskeletal anomalies (2004); cleft lip and/or palate (2005); and congenital heart defects (2006). At present, the risks of VPA-associated CMs are 2-7-fold higher than other common antiepileptic drugs. VPA should not be used as a first-line therapy in women of childbearing age unless it is the only option for the patient. PMID- 26044280 TI - Distribution of the T2-MITE Family Transposons in the Xenopus (Silurana) tropicalis Genome. AB - The T2 family of miniature inverted-repeat transposable elements (T2-MITE) is a prevalent MITE family found in both Xenopus(Silurana) tropicalis and X. laevis. Some subfamilies, particularly T2-A1 and T2-C, may have originated prior to the diversification of the 2 Xenopus lineages and currently include active members in X. tropicalis, whereas another subfamily, T2-E, may have lost its transposition activity even earlier. The distribution of each T2-MITE subfamily in X. tropicalis was investigated and compared to evaluate the evolutionary dynamics of the T2-MITE subfamilies. The subfamilies showed differences in chromosomal distribution, uniformity of insertion density on scaffolds, ratios of upstream to downstream insertions with respect to genes, and their distance from genes. Among these, the T2-C subfamily was interesting because it was frequently inserted upstream and close to genes and because genes with close insertions of this subfamily showed high correlations in spatial expression patterns. This unique distribution and long-lived transposition activity may reflect a mutual relationship evolved between this subfamily and the host. PMID- 26044281 TI - Optimization of ultrasound parameters for microbubble-nanoliposome complex mediated delivery. AB - PURPOSE: The aim of this study was to identify the optimal ultrasound (US) parameters for gene and drug delivery. METHODS: In order to target SkBr3, which is a breast cancer cell overexpressing the Her2 receptor, trastuzumab (Herceptin) was used. Micobubble-nanoliposome complex (MLC) was mixed with trastuzumab and stored overnight. Finally, MLC was combined with Her2Ab. A US device equipped with a 1-MHz probe was used for delivery to the cell. Several parameters, including intensity (w/cm(2)), time (minutes), and duty cycle (%), were varied within a range from 1 w/cm(2), 1 minute, and 20% to 2 w/cm(2), 2 minutes, and 60%, respectively. A confocal laser scanning microscope (CLSM) was used to confirm the delivery of MLC to the cells after US treatment. RESULTS: MLC with fluorescent dyes and trastuzumab was synthesized successfully. By delivering MLC with Her2Ab to cells, the targeting effect of trastuzumab with MLC was confirmed by CLSM. The cell membranes showed green (fluorescein isothiocyanate) and red (Texas red) fluorescence but treatments with MLC without Her2Ab did not show any fluorescence. Optimal conditions for US-mediated delivery were 1 or 2 w/cm(2), 2 minutes, and 60% (uptake ratio, 95.9% for 1 w/cm(2) and 95.7% for 2 w/cm(2)) for hydrophobic materials and 2 w/cm(2), 2 minutes, and 60% (uptake ratio, 95.0%) for hydrophilic materials. CONCLUSION: The greater the strength, duty cycle, and period of US application within the tested range, the more efficiently the fluorescent contents were conveyed. PMID- 26044282 TI - Hepatocellular carcinoma surveillance in hepatitis B virus-infected individuals: Who and how? PMID- 26044283 TI - Caregiver daily impression could reflect illness latency and severity in frail elderly residents in long-term care facilities: A pilot study. AB - AIMS: To propose a caregiver daily impression (CDI) rating instrument for personal caregivers of residents living in long-term care facilities (LTCF) to comprehensively evaluate residents' daily health condition, and to investigate whether the CDI reflects illness latency and severity in residents transferred emergently. METHODS: We carried out a retrospective review of facility care records from 20 LTCF in Hyogo, Japan. The participants were 169 LTCF residents with episodes of transfer to emergency hospitalization facilities during a 3 month period. We determined specific CDI variables by interviewing experienced LTCF caregivers, and then carried out a principal component analysis to determine the major parameter set. The generated components were incorporated into a regression model to investigate the association with hospitalization. RESULTS: The mean age was 87.9 +/- 6.5 years, 68% were women and 28% of transfers resulted in hospitalization. The interview procedure identified 12 specific CDI variables, and the principal component analysis generated five distinct components: "change in feeding," "change in emotion," "disengaged or listless gaze," "decrease in eye reactivity" and "change in movement." By multivariate logistic regression, hospitalization was associated with "decrease in eye reactivity" (adjusted OR 1.78, 95% CI 1.07-2.97) and poor vital signs (adjusted OR 2.84, 95% CI 1.15 6.98), but not with body temperature (adjusted OR 1.29, 95% CI 0.52-3.21). CONCLUSIONS: The CDI might reflect underlying illness severity beyond quantitative physical findings. Once the CDI can be appropriately validated, quantified and linked to physical findings, it could be used by caregivers for daily resident assessments and as a practical triage tool in emergency situations. Geriatr Gerontol Int 2016; 16: 612-617. PMID- 26044284 TI - Deletion of Stat3 enhances myeloid cell expansion and increases the severity of myeloproliferative neoplasms in Jak2V617F knock-in mice. AB - The JAK2V617F mutation commonly found in myeloproliferative neoplasms (MPNs) induces constitutive phosphorylation/activation of the signal transducer and activator of transcription 3 (Stat3). However, the contribution of Stat3 in MPN evoked by JAK2V617F remains unknown. To determine the role of Stat3 in JAK2V617F induced MPN, we generated Stat3-deficient Jak2V617F-expressing mice. Whereas expression of Jak2V617F resulted in a polycythemia vera-like disease characterized by increased red blood cells (RBCs), hematocrit, neutrophils and platelets in the peripheral blood of Jak2V617F knock-in mice, deletion of Stat3 slightly reduced RBC and hematocrit parameters and modestly increased platelet numbers in Jak2V617F knock-in mice. Moreover, deletion of Stat3 significantly increased the neutrophil counts/percentages and markedly reduced the survival of mice expressing Jak2V617F. These phenotypic manifestations were reproduced upon bone marrow (BM) transplantation into wild-type animals. Flow cytometric analysis showed increased hematopoietic stem cell and granulocyte-macrophage progenitor populations in the BM and spleens of Stat3-deficient Jak2V617F mice. Stat3 deficiency also caused a marked expansion of Gr-1+/Mac-1+ myeloid cells in Jak2V617F knock-in mice. Histopathologic analysis revealed marked increase in granulocytes in the BM, spleens and livers of Stat3-deficient Jak2V617F expressing mice. Together, these results suggest that deletion of Stat3 increases the severity of MPN induced by Jak2V617F. PMID- 26044285 TI - Switchable Release of Entrapped Nanoparticles from Alginate Hydrogels. AB - Natural biological processes are intricately controlled by the timing and spatial distribution of various cues. To mimic this precise level of control, the physical sizes of gold nanoparticles are utilized to sterically entrap them in hydrogel materials, where they are subsequently released only in response to ultrasound. These nanoparticles can transport bioactive factors to cells and direct cell behavior on-demand. PMID- 26044286 TI - Anaemia in patients with aortic stenosis: influence on long-term prognosis. AB - AIMS: The prognostic implications of anaemia in patients with aortic stenosis (AS) remain unclear. Accordingly, the present study aimed to evaluate the prognostic implications of anaemia in AS patients before and after aortic valve replacement (AVR). METHODS AND RESULTS: A total of 856 AS patients (age 71 +/- 12 years, 60.2% male, 47.4% severe AS) were included. The mean haemoglobin (Hb) level was 13.2 +/- 1.8 g/dL, and the prevalence of anaemia (Hb <13.0 g/dL for men, <12.0 g/dL for women) was 32.0%. The prevalence of anaemia rose with increasing severity of AS (28.9% and 35.6% in moderate and severe AS, respectively, P = 0.048) and was independently associated with increased all cause mortality in severe AS patients whilst under medical therapy [hazard ratio (HR) 2.26, 95% confidence interval (CI) 1.29-3.97, P = 0.005). Similarly, each 1.0 g/dL decrease in Hb was independently associated with increased mortality risk at follow-up (HR 1.35, 95% CI 1.07-1.47, P = 0.006). However, after AVR surgery, severe AS patients who had anaemia had similar long-term survival as patients with normal Hb (log rank P = 0.19). When all AS patients were included and AVR surgery entered as a covariate, anaemia was still independently associated with increased all-cause mortality irrespective of the severity of AS. CONCLUSIONS: A high prevalence of anaemia in moderate and severe AS patients was observed, and its presence was independently associated with increased all-cause mortality. However, after AVR surgery, anaemic patients had similar survival rates as patients with normal Hb. PMID- 26044287 TI - PRAME Expression and Its Clinical Relevance in Hodgkin's Lymphoma. AB - OBJECTIVES: Although Hodgkin's lymphoma (HL) is one of the most curable cancers in adult patients, new targets have to be defined in cases resistant to traditional chemotherapy. The preferentially expressed antigen of melanoma (PRAME) is a cancer testis antigen and its expression is very scarce or absent in normal tissues. For this reason PRAME is a promising candidate for tumor immunotherapy. The aim of this study is to understand the correlation of PRAME expression with prognostic factors in HL, to determine the utility of PRAME as a targeted molecule for immunotherapy and to compare real-time polymerase chain reaction (real-time PCR) and immunohistochemistry (IHC) for the detection of PRAME. METHODS: In 82 patients, PRAME was studied using real-time PCR and IHC. Data analyses were performed using statistical methods such as t test, Mann Whitney U test, chi 2 test, Kaplan-Meier method, log-rank test and Cox regression analysis. RESULTS: PRAME was detected in 15 (18.3%) patients using IHC and in 8 (9.8%) patients using real-time PCR. A correlation was found between PRAME positivity and higher International Prognostic Score (p = 0.039). PRAME positivity detected using real-time PCR was found to be correlated with shorter disease-free survival (DFS) and overall survival (OS, p = 0.0005). DISCUSSION: The demonstration of PRAME especially in histiocytes and Reed-Sternberg cells may provide guidance for immunotherapy. Although PRAME positivity increases the risk for death (3.56), independent risk factors that affected DFS and OS occurred in advanced age and high-risk groups. CONCLUSION: Although real-time PCR is sensitive in the detection of PRAME, IHC can be another useful method. Despite the need for studies conducted on larger patient samples, PRAME expression is considered as a poor prognostic parameter in HL. PMID- 26044288 TI - Acute exacerbation of rheumatoid interstitial lung disease during the maintenance therapy with certolizumab pegol. AB - We report a case involving a 68-year-old woman with rheumatoid arthritis (RA) with acute exacerbated interstitial lung disease (ILD) during certolizumab pegol maintenance therapy. She recovered quickly with steroid pulse therapy and was discharged without deterioration of basal pulmonary function. Immunoblot analysis demonstrated the circulating cleaved interleukin-1beta at the phase of acute exacerbation of RA-associated ILD (RA-ILD) in this patient. The findings from this case suggested that the Nod-like receptor pyrin domain-containing protein 3 inflammasome is implicated in acute RA-ILD exacerbation. PMID- 26044290 TI - Opportunistic Infections and Mortality: Still Room for Improvement. PMID- 26044289 TI - Mortality Risk After AIDS-Defining Opportunistic Illness Among HIV-Infected Persons--San Francisco, 1981-2012. AB - OBJECTIVE: To examine whether improved human immunodeficiency virus (HIV) treatment was associated with better survival after diagnosis of AIDS-defining opportunistic illnesses (AIDS-OIs) and how survival differed by AIDS-OI. DESIGN: We used HIV surveillance data to conduct a survival analysis. METHODS: We estimated survival probabilities after first AIDS-OI diagnosis among adult patients with AIDS in San Francisco during 3 treatment eras: 1981-1986; 1987 1996; and 1997-2012. We used Cox proportional hazards models to determine adjusted mortality risk by AIDS-OI in the years 1997-2012. RESULTS: Among 20 858 patients with AIDS, the most frequently diagnosed AIDS-OIs were Pneumocystis pneumonia (39.1%) and Kaposi sarcoma (20.1%). Overall 5-year survival probability increased from 7% in 1981-1986 to 65% in 1997-2012. In 1997-2012, after adjustment for known confounders and using Pneumocystis pneumonia as the referent category, mortality rates after first AIDS-OI were highest for brain lymphoma (hazard ratio [HR], 5.14; 95% confidence interval [CI], 2.98-8.87) and progressive multifocal leukoencephalopathy (HR, 4.22; 95% CI, 2.49-7.17). CONCLUSIONS: Survival after first AIDS-OI diagnosis has improved markedly since 1981. Some AIDS-OIs remain associated with substantially higher mortality risk than others, even after adjustment for known confounders. Better prevention and treatment strategies are still needed for AIDS-OIs occurring in the current HIV treatment era. PMID- 26044291 TI - Oral and Vaginal Tenofovir for Genital Herpes Simplex Virus Type 2 Shedding in Immunocompetent Women: A Double-Blind, Randomized, Cross-over Trial. AB - BACKGROUND: Tenofovir is a potent anti-human immunodeficiency virus (HIV) agent that decreased risk of herpes simplex virus type 2 (HSV-2) acquisition in HIV pre exposure prophylaxis trials. Whether tenofovir has utility in established HSV-2 disease is unclear. METHODS: We randomized immunocompetent women with symptomatic HSV-2 infection to oral tenofovir disoproxil fumarate (TDF)/placebo vaginal gel, oral placebo/tenofovir (TFV) vaginal gel, or double placebo (ratio 2:2:1) in a one-way cross-over trial. Women collected genital swabs twice daily for HSV PCR during 4-week lead-in and 5-week treatment phases. The primary intent-to-treat end point was within-person comparison of genital HSV shedding and lesion rates. RESULTS: 64 women completed the lead-in phase and were randomized. Neither TDF nor TFV gel decreased overall shedding or lesion rate in the primary analysis; TFV gel decreased quantity of HSV DNA by -0.50 (-0.86-0.13) log10 copies/mL. In the per-protocol analysis, TDF reduced shedding (relative risk [RR] = 0.74, P = .006) and lesion rates (RR = 0.75, P = .032); quantity of virus shed decreased by 0.41 log10 copies/mL. CONCLUSIONS: Oral TDF modestly decreased HSV shedding and lesion rate, and quantity of virus shed when used consistently. Vaginal TFV gel decreased quantity of virus shed by 60%. In contrast to effects on HSV-2 acquisition, tenofovir is unlikely to provide clinically meaningful reductions in the frequency of HSV shedding or genital lesions. CLINICAL TRIALS REGISTRATION: NCT01448616. PMID- 26044292 TI - An Essential Role for Coagulase in Staphylococcus aureus Biofilm Development Reveals New Therapeutic Possibilities for Device-Related Infections. AB - High-level resistance to antimicrobial drugs is a major factor in the pathogenesis of chronic Staphylococcus aureus biofilm-associated, medical device related infections. Antimicrobial susceptibility analysis revealed that biofilms grown for <= 24 hours on biomaterials conditioned with human plasma under venous shear in iron-free cell culture medium were significantly more susceptible to antistaphylococcal antibiotics. Biofilms formed under these physiologically relevant conditions were regulated by SaeRS and dependent on coagulase-catalyzed conversion of fibrinogen into fibrin. In contrast, SarA-regulated biofilms formed on uncoated polystyrene in nutrient-rich bacteriological medium were mediated by the previously characterized biofilm factors poly-N-acetyl glucosamine, fibronectin-binding proteins, or autolytic activity and were antibiotic resistant. Coagulase-mediated biofilms exhibited increased antimicrobial resistance over time (>48 hours) but were always susceptible to dispersal by the fibrinolytic enzymes plasmin or nattokinase. Biofilms recovered from infected central venous catheters in a rat model of device-related infection were dispersed by nattokinase, supporting the important role of the biofilm phenotype and identifying a potentially new therapeutic approach with antimicrobials and fibrinolytic drugs, particularly during the early stages of device-related infection. PMID- 26044293 TI - Respiratory gated PET/CT of the liver: A novel method and its impact on the detection of colorectal liver metastases. AB - PURPOSE: To evaluate the diagnostic performance of a new method for respiratory gated positron emission tomography (rgPET/CT) for colorectal liver metastases (CRLM), secondly, to assess its additional value to standard PET/CT (PET/CT). MATERIALS AND METHODS: Forty-three patients scheduled for resection of suspected CRLM were prospectively included from September 2011 to January 2013. None of the patients had previously undergone treatment for their CRLM. All patients underwent PET/CT and rgPET/CT in the same session. For rgPET/CT an in-house developed electronic circuit was used which displayed a color-coded countdown for the patient. The patients held their breath according to the countdown and only the data from the inspiration breath-hold period was used for image reconstruction. Two independent and blinded readers evaluated both PET/CT and rgPET/CT separately. The reference standard was histopathological confirmation for 73 out of 131 CRLM and follow-up otherwise. RESULTS: Reference standard identified 131 CRLM in 39/43 patients. Nine patients accounted for 25 mucinous CRLM. The overall per-lesion sensitivity for detection of CRLM was for PET/CT 60.0%, for rgPET/CT 63.1%, and for standard+rgPET/CT 67.7%, respectively. Standard+rgPET/CT was overall significantly more sensitive for CRLM compared to PET/CT (p=0.002) and rgPET/CT (p=0.031). The overall positive predictive value (PPV) for detection of CRLM was for PET/CT 97.5%, for rgPET/CT 95.3%, and for standard+rgPET/CT 93.6%, respectively. CONCLUSION: Combination of PET/CT and rgPET/CT improved the sensitivity significantly for CRLM. However, high patient compliance is mandatory to achieve optimal performance and further improvements are needed to overcome these limitations. The diagnostic performance of the evaluated new method for rgPET/CT was comparable to earlier reported technically more complex and expensive methods. PMID- 26044294 TI - MRI detection of hypointense brain lesions in patients with multiple sclerosis: T1 spin-echo vs. gradient-echo. AB - OBJECTIVE: Compare T1 spin-echo (T1SE) and T1 gradient-echo (T1GE) sequences in detecting hypointense brain lesions in multiple sclerosis (MS). BACKGROUND: Chronic hypointense lesions on T1SE MRI scans are a surrogate of severe demyelination and axonal loss in MS. The role of T1GE images in the detection of such lesions has not been clarified. DESIGN/METHODS: In 45 patients with MS [Expanded Disability Status Scale (EDSS) score (mean+/-SD) 3.5+/-2.0; 37 relapsing-remitting (RR); 8 secondary progressive (SP)], cerebral T1SE, T1GE, and T2-weighted fluid-attenuated inversion-recovery (FLAIR) images were acquired on a 1.5T MRI scanner. Images were re-sampled to axial 5mm slices before directly comparing lesion detectability using Jim (v.7, Xinapse Systems). Statistical methods included Wilcoxon signed rank tests to compare sequences and Spearman correlations to test associations. RESULTS: Considering the entire cohort, T1GE detected a higher lesion volume (5.90+/-6.21 vs. 4.17+/-4.84ml, p<0.0001) and higher lesion number (27.82+/-20.66 vs. 25.20+/-20.43, p<0.05) than T1SE. Lesion volume differences persisted when considering RR and SP patients separately (both p<0.01). A higher lesion number by T1GE was seen only in the RR group (p<0.05). When comparing correlations between lesion volume and overall neurologic disability (EDSS score), T1SE correlated with EDSS (Spearman r=0.29, p<0.05) while T1GE (r=0.23, p=0.13) and FLAIR (r=0.24, p=0.12) did not. CONCLUSION: Our data suggest that hypointense lesions on T1SE and T1GE are not interchangeable in patients with MS. Based on these results, we hypothesize that T1GE shows more sensitivity to lesions at the expense of less pathologic specificity for tissue destruction than T1SE. PMID- 26044295 TI - Construction of pediatric homogeneous phantoms for optimization of chest and skull radiographs. AB - OBJECTIVES: To develop two pediatric patient-equivalent phantoms, the Pediatric Chest Equivalent Patient (PCEP) and the Pediatric Skull Equivalent Patient (PSEP) for children aged 1 to 5 years. We also used both phantoms for image quality evaluations in computed radiography systems to determine Gold Standard (GS) techniques for pediatric patients. METHODS: To determine the simulator materials thickness (Lucite and aluminum), we quantified biological tissues (lung, soft, and bone) using an automatic computational algorithm. To objectively establish image quality levels, two physical quantities were used: effective detective quantum efficiency and contrast-to-noise ratio. These quantities were associated to values obtained for standard patients from previous studies. RESULTS: For chest radiographies, the GS technique applied was 81kVp, associated to 2.0mAs and 83.6MUGy of entrance skin dose (ESD), while for skull radiographies, the GS technique was 70kVp, associated to 5mAs and 339MUGy of ESD. CONCLUSION: This procedure allowed us to choose optimized techniques for pediatric protocols, thus improving quality of diagnosis for pediatric population and reducing diagnostic costs to our institution. These results could also be easily applied to other services with different equipment technologies. PMID- 26044296 TI - (Ton)silly seasons? Do atmospheric conditions actually affect post-tonsillectomy secondary haemorrhage rates? AB - BACKGROUND: Tonsillectomy is a common procedure, with potentially life threatening complications. Previous investigations into post-tonsillectomy secondary haemorrhage rates suggest an influence of climactic and atmospheric conditions on haemorrhage rate, particularly temperature and water vapour pressure. With a single emergency department and a large variance in atmospheric conditions, Darwin, Australia, is ideal for investigating the effects of local climate on rates of post-operative haemorrhage. METHODS: A five-year retrospective review was conducted of all tonsillectomy procedures performed between 2008 and 2013. Effects of atmospheric variables were examined using Pearson's correlation coefficient and analysis of variance. RESULTS: A total of 941 patients underwent tonsillectomy in the study period. The bleeding rate was 7.7 per cent. No variation was found between wet and dry season tonsillectomies (p = 0.4). Temperature (p = 0.74), water vapour pressure (p = 0.94) and humidity (p = 0.66) had no effect on bleeding. CONCLUSION: The findings revealed no correlation between humidity, season, water vapour pressure and haemorrhage rates. Further research should use multi-site data to investigate the effect of air conditioning, humidification and climactic conditions between different regions in Australia. PMID- 26044297 TI - Inactivation of Listeria monocytogenes using Water Bath Heat Treatment in Vacuum Packed Ricotta Salata Cheese Wedges. AB - Ricotta salata cheese is frequently contaminated on the surface with Listeria monocytogenes. Water bath heat treatment in vacuum packed whole ricotta salata cheese wheels demonstrated to be effective in inactivating L. monocytogenes. However, the risk of cross-contamination in ricotta salata wedges is increased during cheese cutting. Therefore, the effectiveness of heat treatment in ricotta salata wedges has to be demonstrated conducting a new validation study. In this study, 9 different time temperature combinations, 75, 85, and 90 degrees C applied for 10, 20, and 30 min each, were tested on artificially contaminated ricotta salata cheese wedges. The extent of the lethal effect on L. monocytogenes was assessed 1 and 30 d after the application of the hot water bath treatment. Five of 9 combinations, 75 degrees C for 30 min, 85 degrees C for 20, and 30 min, and 90 degrees C for 20 and 30 min, demonstrated to meet the process criteria of at least 5 log reduction. Sensory analyses were also conducted in order to account for the potential impact on sensory features of ricotta salata wedges, which showed no significant differences between treatments. PRACTICAL APPLICATION: This study allowed to select water bath heat treatments of vacuum packed ricotta salata wedges effective to reduce L. monocytogenes contamination. Such treatments can be successfully applied by food business operator to meet compliance with microbiological criteria through the designated shelf-life. PMID- 26044298 TI - STRUCTURAL VIROLOGY. X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability. AB - The detailed molecular interactions between native HIV-1 capsid protein (CA) hexamers that shield the viral genome and proteins have been elusive. We report crystal structures describing interactions between CA monomers related by sixfold symmetry within hexamers (intrahexamer) and threefold and twofold symmetry between neighboring hexamers (interhexamer). The structures describe how CA builds hexagonal lattices, the foundation of mature capsids. Lattice structure depends on an adaptable hydration layer modulating interactions among CA molecules. Disruption of this layer alters interhexamer interfaces, highlighting an inherent structural variability. A CA-targeting antiviral affects capsid stability by binding across CA molecules and subtly altering interhexamer interfaces remote to the ligand-binding site. Inherent structural plasticity, hydration layer rearrangement, and effector binding affect capsid stability and have functional implications for the retroviral life cycle. PMID- 26044299 TI - STRUCTURAL VIROLOGY. Conformational plasticity of a native retroviral capsid revealed by x-ray crystallography. AB - Retroviruses depend on self-assembly of their capsid proteins (core particle) to yield infectious mature virions. Despite the essential role of the retroviral core, its high polymorphism has hindered high-resolution structural analyses. Here, we report the x-ray structure of the native capsid (CA) protein from bovine leukemia virus. CA is organized as hexamers that deviate substantially from sixfold symmetry, yet adjust to make two-dimensional pseudohexagonal arrays that mimic mature retroviral cores. Intra- and interhexameric quasi-equivalent contacts are uncovered, with flexible trimeric lateral contacts among hexamers, yet preserving very similar dimeric interfaces making the lattice. The conformation of each capsid subunit in the hexamer is therefore dictated by long range interactions, revealing how the hexamers can also assemble into closed core particles, a relevant feature of retrovirus biology. PMID- 26044301 TI - CLIMATE CHANGE. Possible artifacts of data biases in the recent global surface warming hiatus. AB - Much study has been devoted to the possible causes of an apparent decrease in the upward trend of global surface temperatures since 1998, a phenomenon that has been dubbed the global warming "hiatus." Here, we present an updated global surface temperature analysis that reveals that global trends are higher than those reported by the Intergovernmental Panel on Climate Change, especially in recent decades, and that the central estimate for the rate of warming during the first 15 years of the 21st century is at least as great as the last half of the 20th century. These results do not support the notion of a "slowdown" in the increase of global surface temperature. PMID- 26044300 TI - GENE REGULATION. Discrete functions of nuclear receptor Rev-erbalpha couple metabolism to the clock. AB - Circadian and metabolic physiology are intricately intertwined, as illustrated by Rev-erbalpha, a transcription factor (TF) that functions both as a core repressive component of the cell-autonomous clock and as a regulator of metabolic genes. Here, we show that Rev-erbalpha modulates the clock and metabolism by different genomic mechanisms. Clock control requires Rev-erbalpha to bind directly to the genome at its cognate sites, where it competes with activating ROR TFs. By contrast, Rev-erbalpha regulates metabolic genes primarily by recruiting the HDAC3 co-repressor to sites to which it is tethered by cell type specific transcription factors. Thus, direct competition between Rev-erbalpha and ROR TFs provides a universal mechanism for self-sustained control of the molecular clock across all tissues, whereas Rev-erbalpha uses lineage-determining factors to convey a tissue-specific epigenomic rhythm that regulates metabolism tailored to the specific need of that tissue. PMID- 26044302 TI - The prognostic role of bone turnover markers in multiple myeloma patients: The impact of their assay. A systematic review and meta-analysis. AB - BACKGROUND: Multiple myeloma (MM) is characterized by the progressive destruction of bone tissue due to the uncontrolled proliferation of the immunoglobulins. The detection of bone turnover markers (BTMs) may represent a non-invasive method to assess the bone involvement and to predict the risk of bone morbidity. This systematic review evaluates clinical utility of changes in BTMs levels in MM patients and their prognostic role. METHODS: We searched Medline, Embase, WOS and Scopus. All eligible articles were examined and the risk of bias was evaluated. Results about PICP, PINP, ICTP, OC, CTX, NTX, RANKL and OPG were extracted. Weighted mean difference, risk ratio and hazard ratio were pooled. RESULTS: Thirty studies and more than 2500 patients were included in this systematic review. The majority of them (50%) used ELISA to quantify BTMs, 10 of them used RIA and only 4 did not report the information regarding the type of immunoassays. In MM patients, the concentration of NTX and ICTP increased, instead the concentrations of BAP and OC lowered when compared to healthy subjects. High levels of ICTP were predictive of bone events (RR 1.18) and they were associated to poor survival (HR 1.08). Most of the included studies were considered at high risk of bias, in fact the reporting of the results was often incomplete. Between studies heterogeneity was high. CONCLUSIONS: BTMs measurement may be very useful in the management of MM patients, especially to evaluate the bone disease progression. They could help clinicians to identify patients at high risk of bone events and to opt for more appropriate therapy; nevertheless their high biological and analytical variability limit their implementation in clinical practice. PMID- 26044303 TI - Catheter-related blood stream infection caused by Dermacoccus barathri, representing the first case of Dermacoccus infection in humans. AB - A 7-year-old boy undergoing home parenteral nutrition with totally implantable central venous access device for chronic intestinal pseudo-obstruction experienced repeated episodes of fever with a temperature above 39.0 degrees C despite the antibiotic treatment. The fever was considered to be catheter-related blood stream infections, as no other etiology could be justified. Repeated blood culture tests revealed negative after 1-week incubation, whereas some samples of blood collected from the central venous catheter yielded positive and gram positive rods were detected. These bacteria were detected repeatedly, then the central venous access device was removed with consideration for the possibility of this bacteria being a pathogen. Thereafter, the fever did not recur and the blood culture tests were negative. The causative agent was identified as Dermacoccus barathri based on the 16S rRNA gene sequence and phylogenetic analysis of 6118-bp concatenated sequences of 4 housekeeping genes. Genus Dermacoccus are one form of Actinomycetes isolated from human skin and water, but human infection with Dermacoccus spp. has not been previously reported and the pathogenicity of the bacteria remains unclear. To our knowledge, this is the first reported case of Dermacoccus infection in humans. PMID- 26044304 TI - ["Heart, arteries and women" an innovative care pathway for women at high risk: First evaluation at one year]. AB - INTRODUCTION: Cardiovascular diseases remain the first cause of death in women. To improve women's health cardiologists and gynaecologists should work together on women's specific cardiovascular risk factor. METHOD: Our study evaluated a care pathway named "heart, arteries and women". One hundred and ninety-one women were included for vascular (n=55) or hypertensive (n=136) explorations from January the first to December the 31st of 2013. We studied their clinical presentation and medical management. RESULTS: All women were at high cardiovascular risk (38% of them at very high risk). The average age was 52 years old. A woman on three had experienced high blood pressure or diabetes during pregnancy. One on two was postmenopausal woman. We stopped twelve estrogen progesterone contraceptions; 60% didn't have gynaecological follow-up; 146 had high blood pressures (73% at night, 50% had no dipping blood pressure profile and 15 were newly diagnosed for hypertension). Sleep apnoea syndrome was suspected in half women. Medical therapies were optimized especially for women with atheroma in which 30 to 46% were properly treated (P=0.0005). Only 18% of the gynecologists received conclusive reports. CONCLUSION: At one year, our care pathway "heart, arteries and women" allowed to optimize medical therapy and clinical management. Everyone should be aware of this program. PMID- 26044305 TI - [The metabolic syndrome in hypertensive black population of South Algeria]. AB - INTRODUCTION: The metabolic syndrome is a risk factor for cardiovascular diseases. It exposes to two main complications: cardiovascular diseases and type II diabetes. This risk is higher among women. It causes a high cardiovascular mortality. OBJECTIVES: Assess the prevalence of the metabolic syndrome (MS) among our black hypertensive population. Study of the distribution of the different criteria in the cluster. Search cardiovascular complications. MATERIALS AND METHODS: This longitudinal study that was carried out included one thousand five hundred and fifty subjects of both sexes from black and white populations aged 40 and older, living in the Algerian Sahara and reviewed after six years of decline. The control consisted of filling a questionnaire oriented on civil status, in addition to a clinical examination, including morphometry, measurement of blood pressure performed with validated electronic device (OMRON 705 CP). Also, a biological check-up was done (glycemy, HDL, cholesterol). A univariate and multivariate analysis have been carried out. All calculations and statistical analyzes are processed by the SPSS 17.0 and Epi Info6 software. RESULTS: The MS frequency is 20.8%, more frequent among women than among men, with a significant difference (28.4% versus 15.1%, P<0.001). We found out a difference between black and white populations in terms of obesity (37.6% versus 31.1%), hypertension (60.6% versus 55.0%), diabetes (25.2% versus 19.2%) or other metabolic syndrome criteria. The most frequent complications according to decreasing frequency are: hospitalization for cardiovascular diseases 8.9%, stroke 6.3%, heart failure 5.8%, myocardial infarction 3.6%. The mortality rate is 14.7% among the blacks and 11.3% among the whites without difference. The survival rate of the population is influenced by the MS and by a non-checked blood pressure by an antihypertensive treatment. CONCLUSION: The MS is highly prevailing among hypertensive black population, and significantly higher among women. The ranking of the cluster elements frequency shows clearly the specifities of our population. It is necessary to elaborate an adequate strategy to prevent such cardiovascular morbidity and mortality. PMID- 26044306 TI - [Epidemiology of pre-eclampsia in Tizi-ouzou city (Algeria)]. AB - OBJECTIVES: The main objective was to estimate the prevalence of pre-eclampsia (PE) in pregnant women in Tizi-ouzou (Algeria). Secondary objectives were to estimate the frequency of PE risk factors, and the incidence of maternal and fetal complications. METHODS: Our study was observational, prospective and descriptive, including all pregnant women at the prenatal appointment in the 2 maternity units of Tizi-ouzou, between January 2012 and June 2013. PE was diagnosed if gestational hypertension was associated with proteinuria > 300 mg/24h, after 20 weeks of gestation. RESULTS: We had 252 cases of PE on 3225 pregnant women. The prevalence of PE was 7.8% (CI 95%: 6.9%-8.7%). The most frequent PE risk factors were nulliparity (56%), age >40 years (27%), obesity (26%) and PE in any previous pregnancy (21%). The incidence of maternal adverse events was 28.7% (CI 95%: 23.1%-34.3%), including 5 deaths. The rates of prematurity, small for gestational age infant and fetal death were 58.2%, 49.7% and 6.7%, respectively. CONCLUSION: The prevalence of PE in pregnant women in Tizi-ouzou is around 8%. The incidence of maternal and fetal adverse outcomes remains high. Only earlier diagnosis and closer monitoring could improve the prognosis of our patients, since the treatment of PE remains currently childbirth. PMID- 26044307 TI - [Diagnosis of essential thrombocythemia after myocardial infarction and cardiac arrest: A case report]. AB - Acute coronary syndrome is now a well-known disease, with codified treatments. The main presentation is chest pain, but more and more cases are revealed by cardiorespiratory arrest thanks to pre-hospital care. And, depending on the evolution in such situations, cardiocirculatory support techniques like extracorporeal membrane oxygenation (ECMO) can be implemented. If the more common cause of SCA is atherosclerosis, consequence of the combination of one or more cardiovascular risk factors, there are rare aetiologies, which include myeloproliferative syndromes, in particular essential thrombocythemia. We describe the case of a 34-year-old man presenting with anterior ST-elevation myocardial infarction complicated by an initial cardiac arrest, whose aetiology is unknown essential thrombocythemia, and its therapeutic management requiring circulatory support by ECMO and IMPELLA((r)) techniques. PMID- 26044308 TI - [Self-medication among black African hypertensive patients: Factors and consequences]. AB - INTRODUCTION: Self-medication practice is under-evaluated among black African hypertensive patients. AIM: To assess the level of self-medication among black African hypertensive patients and to determine the factors favoring this practice and their consequences. METHODS: Prospective study during a 3-month period including 612 hypertensive patients followed in Abidjan cardiology institute. RESULTS: Mean age was 55.1. The patients had a self-medication use in 60.1% of cases. Medicinal plants and derived products were commonly involved. Self medication use reasons were: influence of relatives (89.8%) and the fear of antihypertensive drugs adverses effects (54.9%). Multivariate analysis shows that factors of self-medication were age (56.6 years vs. 50.3 years, P<0.001), income less than 762 euros/month (88% vs. 75.4%; OR=2.73; 95% CI: 1.62-4.6; P<0,0001), obesity (70.4% vs. 35.6%; OR=1.24; 95% CI: 0.75-1.15; P=0.037), dyslipidemia (40.8% vs. 27.9%; OR=6.72; 95% CI: 0.57-2.13; P=0.043), antihypertensive association therapy (61.7% vs. 51.4%; OR=2.27; 95% CI: 0.25-0.97; P=0.037). Poor control of high blood pressure (HBP) was a consequence of self-medication (6.5% vs. 47.1%; OR=10.27; 95% CI: 4.65-56.4; P=0.034), repercussions of HBP on major organ (75% vs. 17.2%; OR=12.9; 95% CI: 8.5-19.6; P=0.0001). CONCLUSION: Self medication is a common practice in African hypertensive patients. It has many consequences. PMID- 26044309 TI - [Hypertension in the elderly in France: Characteristics of treatments and frequency of cognitive complaint according to the 2014 French League against Hypertension Survey]. AB - OBJECTIVE: Describe hypertensive patients treated in 2014 in France by age and estimate the degree of cognitive complaint among subjects aged 55 and over. METHOD: French League against Hypertension Survey (FLAHS) was conducted by mail in a representative sample of subjects aged 35 and over living in metropolitan France. Antihypertensive treatment data were obtained by self-administered questionnaire. Among the owners of a self-measurement device, blood pressure was considered to be controlled if the average of three measurements in the morning was below 135/85 mmHg. Cognitive complaint was detected by the cognitive complaint questionnaire (QPC) and analyzed by age and medical history of each subject. RESULTS: In 2014, 30% of the population aged 35 and over (11.6 million) was treated with antihypertensive drugs. The number of treated hypertensive was: 3.45 million in the 75 and older, 2.96 million in 65-74 years, 3.24 million in 55 64 years, 1.58 million in the 45-54 years and 0.441 million in 35-44. The mono/bi/tri/quad-therapy is used in 46%/35%/14%/5% of patients. This distribution varies with age with monotherapy used in 63% of subjects under 55 years but in 40% of subjects 75 years and over. A positive QPC was noted in 11% of 55-64 years, in 21% of 75 years and older (P<0.001), in 20% of uncontrolled hypertensive patients, and in 34% of subjects with a personal history of stroke. CONCLUSION: In France, hypertension is a disease that affects mainly the elderly. The modalities of treatment are different depending on age. Cognitive complaints are more common in uncontrolled hypertensive patients and in patients with a history of stroke. PMID- 26044310 TI - Cardiomyocyte-Specific Transgenic Expression of Prolyl-4-Hydroxylase Domain 3 Impairs the Myocardial Response to Ischemia. AB - AIMS: The prolyl-4-hydroxylase domain (PHD) enzymes are representing novel therapeutic targets for ischemic tissue protection. Whereas the consequences of a knock out of the PHDs have been analyzed in the context of cardioprotection, the implications of PHD overexpression is unknown so far. METHODS AND RESULTS: We generated cardiomyocyte-specific PHD3transgenic mice (cPhd3tg). Resting cPhd3tg mice did not show constitutive accumulation of HIF-1alpha or HIF-2alpha or changes in HIF target gene expression in the heart. Cardiac function was followed up for 14 months in these mice and found to be unchanged. After challenging the cPhd3tg mice with ligation of the left anterior descending artery, HIF-1alpha/ 2alpha accumulation in the left ventricles was blunted. This was associated with a significantly increased infarct size of the cPhd3tg compared to wild type mice. CONCLUSION: Whereas overexpression of PHD3 in the resting state does not significantly influence cardiac function, it is crucial for the cardiac response to ischemia by affecting HIFalpha accumulation in the ischemic tissue. PMID- 26044312 TI - Alcoholic Cirrhosis Increases Risk for Autoimmune Diseases: A Nationwide Registry Based Cohort Study. AB - BACKGROUND & AIMS: Alcoholic cirrhosis is associated with hyperactivation and dysregulation of the immune system. In addition to its ability to increase risk for infections, it also may increase the risk for autoimmune diseases. We studied the incidence of autoimmune diseases among patients with alcoholic cirrhosis vs controls in Denmark. METHODS: We collected data from nationwide health care registries to identify and follow up all citizens of Denmark diagnosed with alcoholic cirrhosis from 1977 through 2010. Each patient was matched with 5 random individuals from the population (controls) of the same sex and age. The incidence rates of various autoimmune diseases were compared between patients with cirrhosis and controls and adjusted for the number of hospitalizations in the previous year (a marker for the frequency of clinical examination). RESULTS: Of the 24,679 patients diagnosed with alcoholic cirrhosis, 532 developed an autoimmune disease, yielding an overall increased adjusted incidence rate ratio (aIRR) of 1.36 (95% confidence interval [CI], 1.24-1.50). The strongest associations were with Addison's disease (aIRR, 2.47; 95% CI, 1.04-5.85), inflammatory bowel disease (aIRR, 1.56; 95% CI, 1.26-1.92), celiac disease (aIRR, 5.12; 95% CI, 2.58-10.16), pernicious anemia (aIRR, 2.35; 95% CI, 1.50-3.68), and psoriasis (aIRR, 4.06; 95% CI, 3.32-4.97). There was no increase in the incidence rate for rheumatoid arthritis (aIRR, 0.89; 95% CI, 0.69-1.15); the incidence rate for polymyalgia rheumatica decreased in patients with alcoholic cirrhosis compared with controls (aIRR, 0.47; 95% CI, 0.33-0.67). CONCLUSIONS: Based on a nationwide cohort study of patients in Denmark, alcoholic cirrhosis is a risk factor for several autoimmune diseases. PMID- 26044311 TI - The role of curriculum dose for the promotion of fruit and vegetable intake among adolescents: results from the Boost intervention. AB - BACKGROUND: Multi-component interventions combining educational and environmental strategies have proved effective in increasing children and adolescents' fruit and vegetable intake. However such interventions are complex and difficult to implement and several studies report poor implementation. There is a need for knowledge on the role of dose for behaviour change and for assessment of intervention dose to avoid conclusions that intervention components which are not implemented are ineffective. This study aimed to examine 1) the association between dose of a class curriculum and adolescents' fruit and vegetable intake in a school-based multi-component intervention, 2) if gender and socioeconomic position modify this association. METHODS: We carried out secondary analysis of data from intervention schools in the cluster-randomized Boost study targeting 13 year-olds' fruit and vegetable intake. Teacher- and student data on curriculum dose delivered and received were aggregated to the school-level and class-level (only possible for student data). We analysed the association between curriculum dose and students' (n 995) self-reported fruit and vegetable intake (24-h recall questionnaire) after finalization of the intervention using multi-level analyses. Potential moderation was examined by analyses stratified by gender and socioeconomic position. RESULTS: Average dose received at class-level was significantly associated with students' fruit and vegetable intake (10 g (CI: 0.06, 20.33) per curricular activity received). In stratified analyses the association remained significant among boys only (14 g (CI: 2.84, 26.76) per curricular activity received). The average dose delivered and received at the school-level was not significantly associated with students' intake. CONCLUSIONS: We found a dose-response relationship between number of curricular activities received and adolescents' fruit and vegetable intake. The results indicate that curriculum dose received only mattered for promotion of fruit and vegetable intake among boys. Future studies should explore this gender difference in larger samples to guide the planning of school-based curricular interventions with regards to the optimal number of curricular activities required to promote behavioural change in subgroups with low fruit and vegetable intake at baseline. TRIAL REGISTRATION: Current Controlled Trials ISRCTN11666034. PMID- 26044313 TI - Esophageal Strictures: An Unusual Presentation of a Common Disorder. PMID- 26044314 TI - Prevalence of Anal Dysplasia in Patients With Inflammatory Bowel Disease. AB - BACKGROUND & AIMS: Although the prevalence of anal dysplasia is higher in some immunosuppressed populations, the prevalence in patients with inflammatory bowel disease (IBD) is unknown. We examined the prevalence of abnormal anal cytology among IBD patients, and its relation to the human papilloma virus (HPV). METHODS: Adults with IBD and age-matched healthy controls (HC) were recruited. IBD patients were categorized as nonimmunosuppressed (IBD-N) or immunosuppressed (IBD I). Anal Papanicolaou tests were performed for HPV testing and classification by a cytopathologist as follows: negative, atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, cancer, or unsatisfactory. RESULTS: A total of 270 subjects (100 IBD-I, 94 IBD-N, and 76 HC) were recruited. ASC-US were detected in 19 subjects, with a trend toward a higher prevalence among IBD subjects compared with HC (8.8% vs 2.6%; P = .10). The prevalence did not differ with respect to immunosuppression. Crohn's disease (CD) subjects had a higher prevalence of ASC-US compared with others with IBD (P = .02). Among those with CD, female sex and disease duration longer than 10 years were risk factors. There were no cases of low-grade squamous intraepithelial lesion, high-grade squamous intraepithelial lesion, or anal cancer in the cohort. HPV was present in 5.3% and 1.5% of subjects with and without ASC-US, respectively (P = .26). CONCLUSIONS: Although there was a trend toward abnormal anal Papanicolaou tests in IBD subjects compared with HC, there was no difference based on immunosuppression. The presence of HPV did not correlate with abnormal anal cytology. Risk factors associated with this increased trend include female CD subjects and those with a longer duration of CD. ClinicalTrials.gov number: NCT01860963; https://clinicaltrials.gov/ct2/show/NCT01860963. PMID- 26044315 TI - Weight Loss Is Truly Effective in Reducing Symptoms and Proton Pump Inhibitor Use in Patients With Gastroesophageal Reflux Disease. PMID- 26044316 TI - Long-term Outcomes of Patients Receiving a Magnetic Sphincter Augmentation Device for Gastroesophageal Reflux. AB - BACKGROUND & AIMS: Based on results from year 2 of a 5-year trial, in 2012 the US Food and Drug Administration approved the use of a magnetic device to augment lower esophageal sphincter function in patients with gastroesophageal reflux disease (GERD). We report the final results of 5 years of follow-up evaluation of patients who received this device. METHODS: We performed a prospective study of the safety and efficacy of a magnetic device in 100 adults with GERD for 6 months or more, who were partially responsive to daily proton pump inhibitors (PPIs) and had evidence of pathologic esophageal acid exposure, at 14 centers in the United States and The Netherlands. The magnetic device was placed using standard laparoscopic tools and techniques. Eighty-five subjects were followed up for 5 years to evaluate quality of life, reflux control, use of PPIs, and side effects. The GERD-health-related quality of life (GERD-HRQL) questionnaire was administered at baseline to patients on and off PPIs, and after placement of the device; patients served as their own controls. A partial response to PPIs was defined as a GERD-HRQL score of 10 or less on PPIs and a score of 15 or higher off PPIs, or a 6-point or more improvement when scores on vs off PPI were compared. RESULTS: Over the follow-up period, no device erosions, migrations, or malfunctions occurred. At baseline, the median GERD-HRQL scores were 27 in patients not taking PPIs and 11 in patients on PPIs; 5 years after device placement this score decreased to 4. All patients used PPIs at baseline; this value decreased to 15.3% at 5 years. Moderate or severe regurgitation occurred in 57% of subjects at baseline, but only 1.2% at 5 years. All patients reported the ability to belch and vomit if needed. Bothersome dysphagia was present in 5% at baseline and in 6% at 5 years. Bothersome gas-bloat was present in 52% at baseline and decreased to 8.3% at 5 years. CONCLUSIONS: Augmentation of the lower esophageal sphincter with a magnetic device provides significant and sustained control of reflux, with minimal side effects or complications. No new safety risks emerged over a 5-year follow-up period. These findings validate the long term safety and efficacy of the magnetic sphincter augmentation device for patients with GERD. ClinicalTrials.gov no: NCT00776997. PMID- 26044318 TI - Patients Receiving Prebiotics and Probiotics Before Liver Transplantation Develop Fewer Infections Than Controls: A Systematic Review and Meta-Analysis. AB - BACKGROUND & AIMS: Among patients who have received liver transplants, infections increase morbidity and mortality and prolong hospital stays. Administration of antibiotics and surgical trauma create intestinal barrier dysfunction and microbial imbalances that allow enteric bacteria to translocate to the blood. Probiotics are believed to prevent bacterial translocation by stabilizing the intestinal barrier and stimulating proliferation of the intestinal epithelium, mucus secretion, and motility. We performed a meta-analysis to determine the effects of probiotics on infections in patients receiving liver transplants. METHODS: We searched PubMed and EMBASE for controlled trials that evaluated the effects of prebiotics and probiotics on infections in patients who underwent liver transplantation. Heterogeneity was analyzed by the Cochran Q statistic. Pooled Mantel-Haenszel relative risks were calculated with a fixed-effects model. RESULTS: We identified 4 controlled studies, comprising 246 participants (123 received probiotics, 123 served as controls), for inclusion in the meta-analysis. In these studies, the intervention groups received enteric nutrition and fiber (prebiotics) with probiotics, and the control groups received only enteric nutrition and fiber without probiotics. The infection rate was 7% in groups that received probiotics vs 35% in control groups (relative risk [RR], 0.21; 95% confidence interval [CI], 0.11-0.41; P = .001). The number needed to treat to prevent 1 infection was 3.6. In subgroup analyses, only 2% of subjects in the probiotic groups developed urinary tract infections, compared with 16% of controls (RR, 0.14; 95% CI, 0.04-0.47; P < .001); only 2% of subjects in the probiotic groups developed intra-abdominal infections, compared with 11% of controls (RR, 0.27; 95% CI, 0.09-0.78; P = .02). Subjects receiving probiotics also had shorter stays in the hospital than controls (mean difference, 1.41 d; P < .001), as well as in the intensive care unit (mean difference, 1.41 d; P < .001), and duration of antibiotic use (mean difference, 3.89 d; P < .001). There was no difference in mortality between groups (RR, 0.97; 95% CI, 0.21-4.47). There was no significant heterogeneity among studies. CONCLUSIONS: Based on the meta-analysis, giving patients a combination of probiotics and prebiotics before, or on the day of, liver transplantation reduces the rate of infection after surgery. These agents also reduced the amount of time spent in the hospital or intensive care unit and the duration of antibiotic use. PMID- 26044317 TI - Efficacy of Sofosbuvir and Daclatasvir in Patients With Fibrosing Cholestatic Hepatitis C After Liver Transplantation. AB - BACKGROUND & AIMS: Fibrosing cholestatic hepatitis (FCH) is a life-threatening disorder that develops in patients with recurrent hepatitis C virus (HCV) infection after liver transplantation. Until recently, therapeutic options have been limited. We evaluated the efficacy and safety of sofosbuvir- and daclatasvir based regimens. METHODS: We analyzed data from 23 patients with FCH who participated in a prospective cohort study in France and Belgium of the effects of antiviral agents in patients with recurrence of HCV infection after liver transplantation, from October 2013 through April 2014. Most of the patients had genotype 1 infections that had not responded to previous treatment; 4 patients also were infected with human immunodeficiency virus. Eight patients (37%) had ascites and 15 patients (65%) had bilirubin levels greater than 100 mmol/L; their median serum level of HCV RNA was 7 log IU/mL. The median time between transplantation and treatment initiation was 5 months. Subjects were given either sofosbuvir and daclatasvir (n = 15) or sofosbuvir and ribavirin (n = 8) for 24 weeks. The primary outcome was complete clinical response (survival without re transplantation, bilirubin level <34 MUmol/L, and no ascites or hepatic encephalopathy 36 weeks after treatment began). RESULTS: All patients survived, without re-transplantation, until week 36. Rapid and dramatic improvements in clinical status were observed. The patients' median bilirubin concentration decreased from 122 MUmol/L at baseline to a normal value at week 12 of treatment. Twenty-two patients (96%) had a complete clinical response at week 36. Despite the low rate of rapid virologic response, 22 patients (96%) achieved a sustained virologic response at week 12. The only relapse of HCV infection occurred in a patient with human immunodeficiency virus infection who received sofosbuvir and ribavirin. Tolerance was satisfactory, with no grade 3 or 4 adverse events related to sofosbuvir or daclatasvir and no significant interactions among drugs. CONCLUSIONS: Sofosbuvir therapy with daclatasvir or ribavirin leads to major clinical improvement and high rates of sustained virologic response at week 12 in most patients with recurrence of HCV infection and FCH after liver transplantation. ClinicalTrial.gov no: NCT01944527. PMID- 26044320 TI - Structural comparison of group 7 tricarbonyl complexes of 2-{[2-(1H-imidazol-4 yl)ethyl]iminomethyl}-5-methylphenolate. AB - Two tricarbonyl complexes of rhenium(I) and manganese(I) coordinated by the ligand 2-{[2-(1H-imidazol-4-yl)ethyl]iminomethyl}-5-methylphenolate are reported, viz. fac-tricarbonyl(2-{[2-(1H-imidazol-4-yl-kappaN(3))ethyl]iminomethyl-kappaN} 5-methylphenolato-kappaO)rhenium(I) methanol monosolvate, [Re(C16H14N3O4)(CO)3].CH3OH, (I), and fac-tricarbonyl(2-{[2-(1H-imidazol-4-yl kappaN(3))ethyl]iminomethyl-kappaN}-5-methylphenolato-kappaO)manganese(I), fac [Mn(C16H14N3O4)(CO)3], (II), display facial coordination in a distorted octahedral environment. The crystal structure of (I) is stabilized by O-H...O, N H...O and C-H...O hydrogen-bond interactions, while that of (II) is stabilized by N-H...O hydrogen-bond interactions only. These interactions result in two dimensional networks and pi-pi stacking for both structures. PMID- 26044319 TI - Association Between Level of Hepatitis D Virus RNA at Week 24 of Pegylated Interferon Therapy and Outcome. AB - BACKGROUND & AIMS: Interferon is the only effective treatment for chronic hepatitis D virus (HDV) infection. No rules have been set for stopping treatment based on viral kinetics. We analyzed data from an international study of hepatitis D treatment to identify factors associated with outcomes of pegylated interferon treatment, with and without adefovir. METHODS: We analyzed data from the Hep-Net-International Delta Hepatitis Intervention Trial on 50 patients with compensated liver disease who tested positive for anti-HDV and HDV RNA. Subjects received pegylated interferon alpha 2a, with adefovir or placebo, or only adefovir, for 48 weeks. Twenty-four weeks after treatment ended, 41 patients were evaluated for levels of HDV RNA and DNA, liver enzymes, and hepatitis B surface antigen (HBsAg); liver biopsy specimens were analyzed for fibrosis. Response to therapy was defined as end-of-treatment response or post-treatment week 24 virologic response. In both cases virologic response was associated with undetectable HDV RNA levels. Patients with less than a 1 log decrease in HDV RNA at the end of treatment were considered null responders. RESULTS: Based on univariate and multivariate analysis, the level of HDV RNA at week 24 of treatment was associated more strongly with response to therapy than other factors analyzed. The level of HBsAg at week 24 of treatment was associated with a response to therapy only in univariate analysis. Lack of HDV RNA at week 24 of treatment, or end of treatment, identified responders with positive predicted values of 71% and 100%, respectively. At 24 weeks after treatment, a decrease in HDV RNA level of less than 1 log, combined with no decrease in HBsAg level, identified null responders with a positive predictive value of 83%. A decrease in HDV RNA level of more than 2 log at week 24 of treatment identified null responders with a negative predictive value of 95%. CONCLUSIONS: Based on an analysis of data from a large clinical trial, the level of HDV RNA at week 24 of treatment with pegylated interferon, with or without adefovir for 48 weeks, can identify patients who will test negative for HDV RNA 24 weeks after the end of treatment. This information can be used to help physicians manage patients receiving therapy for chronic hepatitis D. PMID- 26044321 TI - Partial conversion of thioamide into nitrile in a copper(II) complex of 2,6 diacetylpyridine bis(thiosemicarbazone), a drug prototype for Alzheimer's disease. AB - This work reports the crystal structure of [(Z)-2-((E)-1-{6-[1 ({[amino(sulfanidyl-kappaS)methylidene]amino}imino-kappaN)ethyl]pyridin-2-yl kappaN}ethylidene)-1-cyanohydrazinido-kappaN(1)]copper(II), [Cu(C11H11N7S)], the first description of a copper(II) complex of 2,6-diacetylpyridine bis(thiosemicarbazone) showing partial conversion of a thioamide group to a nitrile group. The asymmetric ligand coordinates to the metal centre in an N,N',N'',S-tetradentate manner via the pyridine N atom, an imine N atom, the hydrazinide N atom and the sulfanidyl S atom, displaying a square-planar geometry. Ligand coordination results in two five-membered chelate rings and one six-membered chelate ring, and in crystal packing based on N-H...N hydrogen bonds of the cyanohydrazinide and hydrazinecarbothioamidate arms of the ligand. The correlation between the partial conversion upon metal complexation, H2S release and possible effects on the activity of bis(thiosemicarbazone)s as drug prototypes for Alzheimer's disease is also discussed. PMID- 26044322 TI - The crystal structure, luminescence and nitrobenzene-sensing properties of a two dimensional Mn(II) coordination polymer based on 2,6-bis(imidazol-1-yl)pyridine. AB - A two-dimensional Mn(II) coordination polymer (CP), poly[bis[MU2-2,6-bis(imidazol 1-yl)pyridine-kappa(2)N(3):N(3')]bis(thiocyanato-kappaN)manganese] [Mn(NCS)2(C11H9N5)2]n, (I), has been obtained by the self-assembly reaction of Mn(ClO4)2.6H2O, NH4SCN and bent 2,6-bis(imidazol-1-yl)pyridine (2,6-bip). CP (I) was characterized by FT-IR spectroscopy, elemental analysis and single-crystal X ray diffraction. The crystal structure features a unique two-dimensional (4,4) network with one-dimensional channels. The luminescence and nitrobenzene-sensing properties were explored in a DMF suspension, revealing that CP (I) shows a strong luminescence emission and is highly sensitive for nitrobenzene detection. PMID- 26044323 TI - Polymorphism of NaVO2F2: a P21/c superstructure with pseudosymmetry of P21/m in the subcell. AB - The ADDSYM routine in the program PLATON [Spek (2015). Acta Cryst. C71, 9-18] has helped researchers to avoid structures of (metal-)organic compounds being reported in an unnecessarily low symmetry space group. However, determination of the correct space group may get more complicated in cases of pseudosymmetric inorganic compounds. One example is NaVO2F2, which was reported [Crosnier-Lopez et al. (1994). Eur. J. Solid State Inorg. Chem. 31, 957-965] in the acentric space group P21 based on properties but flagged by ADDSYM as (pseudo)centrosymmetric P21/m within default distance tolerances. Herein a systematic investigation reveals that NaVO2F2 exists in at least four polymorphs: P21, (I), P21/m, (II), P21/c, (III), and one or more low-temperature ones. The new centrosymmetric modification, (III), with the space group P21/c has a similar atomic packing geometry to phase (I), except for having a doubled c axis. The double-cell of phase (III) arises from atomic shifts from the glide plane c at (x, 1/4, z). With increasing temperature, the number of observed reflections decreases. The odd l reflections gradually become weaker and, correspondingly, all atoms shift towards the glide plane, resulting in a gradual second-order transformation of (III) into high-temperature phase (II) (P21/m) at below 493 K. At least one first-order enantiotropic phase transition was observed below 139 K from both the single-crystal X-ray diffraction and the differential scanning calorimetry analyses. Periodic first-principles calculations within density functional theory show that both P21/c superstructure (III) and P21 substructure (I) are more stable than P21/m structure (II), and that P21/c superstructure (III) is more stable that P21 substructure (I). PMID- 26044324 TI - The first example of a two-coordinated Au(I) atom bonded to an Fe(II) atom and an N-heterocyclic carbene (NHC) ligand. AB - The aurophilicity exhibited by Au(I) complexes depends strongly on the nature of the supporting ligands present and the length of the Au-element (Au-E) bond may be used as a measure of the donor-acceptor properties of the coordinated ligands. A binuclear iron-gold complex, [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 2kappaC(2)]dicarbonyl-1kappa(2)C-(1eta(5)-cyclopentadienyl)gold(I)iron(II)(Au-Fe) benzene trisolvate, [AuFe(C5H5)(C27H36N2)(CO)2].3C6H6, was prepared by reaction of K[CpFe(CO)2] (Cp is cyclopentadienyl) with (NHC)AuCl [NHC = 1,3-bis(2,6 diisopropylphenyl)imidazol-2-ylidene]. In addition to the binuclear complex, the asymmetric unit contains three benzene solvent molecules. This is the first example of a two-coordinated Au atom bonded to an Fe and a C atom of an N heterocyclic carbene. PMID- 26044325 TI - Synthesis of dithiafulvene-quinone donor-acceptor systems: isolation of a Michael adduct. AB - pi-Conjugated donor-acceptor systems based on dithiafulvene (DTF) donor units and various acceptor units have attracted attention for their linear and nonlinear optical properties. The reaction between p-benzoquinone and a 1,3-dithiole phosphonium salt, deprotonated by lithium hexamethyldisilazide (LiHMDS), gave a product mixture from which the Michael adduct [systematic name: dimethyl 2-(3 hydroxy-6-oxocyclohexa-2,4-dien-1-ylidene)-2H-1,3-dithiole-4,5-dicarboxylate], C13H10O6S2, was isolated. It is likely that one of the unidentified products obtained previously by others from related reactions could be a similar Michael adduct. PMID- 26044326 TI - The structure of the first stable monosubstituted sulfur diimide. AB - The title compound, 4-(4-methylphenyl)-1,3-diaza-2,4-dithiabuta-1,2-diene, C7H8N2S2, was the first example of a stable monosubstituted sulfur diimide to be documented [Jones (1988). PhD thesis, Imperial College, University of London, England]. Although a partial description of this structure was published previously, the full details are presented here. This allows a detailed comparison against the only other example of this system published to date, highlighting differences in bonding, conformation and packing. PMID- 26044327 TI - The exopolyhedral ligand orientation (ELO) in 3-(nitrato-kappaO)-3,3 bis(triphenylphosphane-kappaP)-3-rhoda-1,2-dicarba-closo-dodecaborane(11) dichloromethane 2.2-solvate. AB - In the title compound, [Rh(C2H11B9)(NO3)(C18H15P)2].2.2CH2Cl2, studied as a 2.2 solvate of what was assumed to be dichloromethane, the nitrate ligand lies cis with respect to both cage C atoms. Accordingly, the compound displays a pronounced preferred exopolyhedral ligand orientation (ELO) which is traced to both the greater trans influence of the cage B over the cage C atoms and the greater trans influence of the triphenylphosphane ligands over the nitrate ligand. The overall molecular architecture therefore agrees with that of a number of similar 3-L-3,3-L'2-3,1,2-closo-MC2B9H11 species in the literature. PMID- 26044328 TI - One-dimensional decavanadate chains in the crystal structure of Rb4[Na(H2O)6][HV10O28].4H2O. AB - New decavanadate minerals, the products of the leaching or metasomatic processes, are possible in nature via Na/Rb removal/inclusion reactions. As part of our search for novel vanadate phases with varying functionalities, a new phase, tetrarubidium hexaaquasodium hydrogen decavanadate tetrahydrate, Rb4[Na(H2O)6][HV10O28].4H2O, has been synthesized by the hydrothermal technique at 553 K. Ten shared edges of V-centred octahedra form monoprotonated decavanadate cages, which are joined together via hydrogen bonds into one dimensional chains parallel to the [101] direction. Within these chains, H atoms are sandwiched between neighbouring polyanions. Na and Rb atoms and H2O molecules occupy interstices flanked by the anionic chains providing additional crosslinking in the structure. This compound is the second decavanadate with P2/n symmetry. Structural relationships among protonated and deprotonated decavanadates with inorganic cations, including minerals of the pascoite group, are discussed. PMID- 26044329 TI - A two-dimensional layered Cd(II) coordination polymer with a three-dimensional supramolecular architecture incorporating mixed multidentate N- and O-donor ligands. AB - The combination of N-heterocyclic and multicarboxylate ligands is a good choice for the construction of metal-organic frameworks. In the title coordination polymer, poly[bis{MU2-1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole kappa(2)N(3):N(4)}(MU4-butanedioato-kappa(4)O(1):O(1'):O(4):O(4'))(MU2 butanedioato-kappa(2)O(1):O(4))dicadmium], [Cd(C4H4O4)(C9H8N6)]n, each Cd(II) ion exhibits an irregular octahedral CdO4N2 coordination geometry and is coordinated by four O atoms from three carboxylate groups of three succinate (butanedioate) ligands and two N atoms from two 1-[(1H-benzimidazol-2-yl)methyl]-1H-tetrazole (bimt) ligands. Cd(II) ions are connected by two kinds of crystallographically independent succinate ligands to generate a two-dimensional layered structure with bimt ligands located on each side of the layer. Adjacent layers are further connected by hydrogen bonding, leading to a three-dimensional supramolecular architecture in the solid state. Thermogravimetric analysis of the title polymer shows that it is stable up to 529 K and then loses weight from 529 to 918 K, corresponding to the decomposition of the bimt ligands and succinate groups. The polymer exhibits a strong fluorescence emission in the solid state at room temperature. PMID- 26044330 TI - A sterically congested cis-stilbene and its phosphonium salt precursor. AB - Triphenyl(2,4,5-trimethoxybenzyl)phosphonium chloride is formed in solvent-free form by the reaction under anhydrous conditions between triphenylphosphane and 2,4,5-trimethoxybenzyl chloride, but when it is crystallized from a mixture of ethyl acetate and chloroform in the presence of air it forms a stoichiometric monohydrate, C28H28O3P(+).Cl(-).H2O, (I). The reactions between the anhydrous phosphonium salt and alkoxy-substituted benzaldehydes, using Wittig reactions in the presence of potassium tert-butoxide, provide a series of multiply substituted stilbenes, most of which were assigned the Z configuration on the basis of their NMR spectra. However, no such deduction could be made for the symmetrically substituted (Z)-2,2',4,4',5,5'-hexamethoxystilbene, C20H24O6, (II). Compound (II) does in fact have the Z configuration and the molecular geometry provides evidence for steric congestion around the central double bond; in particular, the central alkene fragment is nonplanar, with a C-C=C-C torsion angle of 7.8 (4) degrees . In hydrated salt (I), the chloride anions and water molecules are linked by O-H...Cl hydrogen bonds to form C2(1)(4) chains; each cation is linked by C-H...O hydrogen bonds to two different chains, so forming a sheet structure. There are no direction-specific intermolecular interactions in the structure of (II). PMID- 26044331 TI - Synthesis, structure and properties of a new three-dimensional interpenetrated metal-organic framework with 3,3'-azodibenzoic acid (H2azdc) and 1,4-bis(1H imidazol-1-yl)butane (bimb): {[Cd(azdc)(bimb)2].H2O}n. AB - A new three-dimensional interpenetrated Cd(II)-organic framework based on 3,3' azodibenzoic acid [3,3'-(diazenediyl)dibenzoic acid, H2azdc] and the auxiliary flexible ligand 1,4-bis(1H-imidazol-1-yl)butane (bimb), namely poly[[bis[MU2-1,4 bis(1H-imidazol-1-yl)butane-kappa(2)N(3):N(3')][MU2-3,3'-(diazenediyl)dibenzoato kappa(2)O:O']cadmium(II)] monohydrate], {[Cd(C14H8N2O4)(C10H14N2)2].H2O}n, (1), was obtained by a typical solution reaction in mixed solvents (water and N,N' dimethylformamide). Each Cd(II) centre is six-coordinated by two O atoms of bis monodentate bridging carboxylate groups from two azdc(2-) ligands and by four N atoms from four bimb ligands, forming an octahedral coordination environment. The Cd(II) ions are connected by the bimb ligands, resulting in two-dimensional (4,4) layers, which are further pillared by the azdc(2-) ligands, affording a threefold interpenetrated three-dimensional alpha-Po topological framework with the Schlafli symbol 4(12)6(3). The thermal stability and solid-state fluorescence properties of (1) have been investigated. PMID- 26044332 TI - A structural study of (1RS,2SR,3RS,4SR,5RS)-2,4-dibenzoyl-1,3,5 triphenylcyclohexan-1-ol chloroform hemisolvate and (1RS,2SR,3RS,4SR,5RS)-2,4 dibenzoyl-1-phenyl-3,5-bis(2-methoxyphenyl)cyclohexan-1-ol. AB - (1RS,2SR,3RS,4SR,5RS)-2,4-Dibenzoyl-1,3,5-triphenylcyclohexan-1-ol or (4-hydroxy 2,4,6-triphenylcyclohexane-1,3-diyl)bis(phenylmethanone), C38H32O3, (1), is formed as a by-product in the NaOH-catalyzed synthesis of 1,3,5-triphenylpentane 1,5-dione from acetophenone and benzaldehyde. Single crystals of the chloroform hemisolvate, C38H32O3.0.5CHCl3, were grown from chloroform. The structure has triclinic (P1) symmetry. One diastereomer [as a pair of (1RS,2SR,3RS,4SR,5RS) enantiomers] of (1) has been found in the crystal structure and confirmed by NMR studies. The dichoromethane hemisolvate has been reported previously [Zhang et al. (2007). Acta Cryst. E63, o4652]. (1RS,2SR,3RS,4SR,5RS)-2,4-Dibenzoyl-3,5 bis(2-methoxyphenyl)-1-phenylcyclohexan-1-ol or [4-hydroxy-2,6-bis(2 methoxyphenyl)-4-phenylcyclohexane-1,3-diyl]bis(phenylmethanone), C40H36O5, (2), is also formed as a by-product, under the same conditions, from acetophenone and 2-methoxybenzaldehyde. Crystals of (2) have been grown from chloroform. The structure has orthorhombic (Pca21) symmetry. A diastereomer of (2) possesses the same configuration as (1). In both structures, the cyclohexane ring adopts a chair conformation with all bulky groups (benzoyl, phenyl and 2-methoxyphenyl) in equatorial positions. The molecules of (1) and (2) both display one intramolecular O-H...O hydrogen bond. PMID- 26044333 TI - The structures of the isomorphous potassium and rubidium salts of 4-nitrobenzoic acid and an overview of the metal complex stereochemistries of the alkali metal salt series with this ligand. AB - 4-Nitrobenzoic acid (PNBA) has proved to be a useful ligand for the preparation of metal complexes but the known structures of the alkali metal salts of PNBA do not include the rubidium salt. The structures of the isomorphous potassium and rubidium polymeric coordination complexes with PNBA, namely poly[MU2-aqua-aqua MU3-(4-nitrobenzoato)-potassium], [K(C7H4N2O2)(H2O)2]n, (I), and poly[MU3-aqua aqua-MU5-(4-nitrobenzoato)-rubidium], [Rb(C7H4N2O2)(H2O)2]n, (II), have been determined. In (I), the very distorted KO6 coordination sphere about the K(+) centres in the repeat unit comprise two bridging nitro O-atom donors, a single bridging carboxylate O-atom donor and two water molecules, one of which is bridging. In Rb complex (II), the same basic MO6 coordination is found in the repeat unit, but it is expanded to RbO9 through a slight increase in the accepted Rb-O bond-length range and includes an additional Rb-O(carboxylate) bond, completing a bidentate O,O'-chelate interaction, and additional bridging Rb O(nitro) and Rb-O(water) bonds. The comparative K-O and Rb-O bond-length ranges are 2.7352 (14)-3.0051 (14) and 2.884 (2)-3.182 (2) A, respectively. The structure of (II) is also isomorphous, as well as isostructural, with the known structure of the nine-coordinate caesium 4-nitrobenzoate analogue, (III), in which the Cs-O bond-length range is 3.047 (4)-3.338 (4) A. In all three complexes, common basic polymeric extensions are found, including two different centrosymmetric bridging interactions through both water and nitro groups, as well as extensions along c through the para-related carboxylate group, giving a two-dimensional structure in (I). In (II) and (III), three-dimensional structures are generated through additional bridges involving the nitro and water O atoms. In all three structures, the two water molecules are involved in similar intra polymer O-H...O hydrogen-bonding interactions to both carboxylate and water O atom acceptors. A comparison of the varied coordination behaviour of the full set of Li-Cs salts with 4-nitrobenzoic acid is also made. PMID- 26044334 TI - Grown from lithium flux, the ErCo5Si(3.17) silicide is a combination of disordered derivatives of the UCo5Si3 and Yb6Co30P19 structure types. AB - A ternary hexaerbium triacontacobalt enneakaidecasilicide, ErCo5Si(3.17), crystallizes as a combination of disordered variants of the hexagonal UCo5Si3 (P63/m) and Yb6Co30P19 (P6) structure types and is closely related to the Sc6Co30Si19 and Ce6Rh30Si19 types. The Er, Co and three of the Si atoms occupy sites of m.. symmetry and a fourth Si atom occupies a site of -6.. symmetry. The environment of the Er atom is a 21-vertex pseudo-Frank-Kasper polyhedron. Trigonal prismatic coordination is observed for the Si atoms. The Co atoms are enclosed in heavily deformed cuboctahedra and 11-vertex polyhedra. Crystallochemistry analysis and the data from electronic structure calculations (TB-LMTO-ASA) suggest that the Er atoms form positively charged cations which compensate the negative charge of the [Co12Si9](m-) polyanions. PMID- 26044335 TI - Two reversible enantiotropic phase transitions in a pentacoordinate silicon complex with an O,N,O'-tridentate valinate ligand. AB - Dimethyl[N-(4-oxidopent-3-en-2-ylidene)valinato-kappa(3)O,N,O']silicon(IV), C12H21NO3Si, (II), crystallizes in the orthorhombic space group P212121. The chiral compound undergoes two sharp enantiotropic phase transitions upon cooling. The first transformation occurs at 163 K to yield a unit cell with one axis having double length. This intermediate-temperature form has the monoclinic space group P21. The second transition takes place at 142 K and converts the single crystal into the low-temperature form in the orthorhombic space group P212121. This transition proceeds under tripling of the a axis of the high-temperature form. Both phase transitions are fully reversible and correspond to order disorder transitions of the isopropyl group of the valine unit in the ligand backbone. The phase transitions presented here raise questions, since they do not fit into the rules of group-subgroup relationships. PMID- 26044336 TI - Potential for international spread of wild poliovirus via travelers. AB - BACKGROUND: The endgame of polio eradication is hampered by the international spread of poliovirus via travelers. In response to ongoing importations of poliovirus into polio-free countries, on 5 May 2014, WHO's Director-General declared the international spread of wild poliovirus a public health emergency of international concern. Our objective was to develop a mathematical model to estimate the international spread of polio infections. METHODS: Our model took into account polio endemicity in polio-infected countries, population size, polio immunization coverage rates, infectious period, the asymptomatic-to-symptomatic ratio, and also the probability of a traveler being infectious at the time of travel. We applied our model to three scenarios: (1) number of exportations of both symptomatic and asymptomatic polio infections out of currently polio infected countries, (2) the risk of spread of poliovirus to Saudi Arabia via Hajj pilgrims, and (3) the importation risk of poliovirus into India. RESULTS: Our model estimated 665 polio exportations (>99 % of which were asymptomatic) from nine polio-infected countries in 2014, of which 78.3 % originated from Pakistan. Our model also estimated 21 importations of poliovirus into Saudi Arabia via Hajj pilgrims and 20 poliovirus infections imported to India in the same year. CONCLUSION: The extent of importations of asymptomatic and symptomatic polio infections is substantial. For countries that are vulnerable to polio outbreaks due to poor national polio immunization coverage rates, our newly developed model may help guide policy-makers to decide whether imposing an entry requirement in terms of proof of vaccination against polio would be justified. PMID- 26044337 TI - Selection of bioprotective cultures for preventing cold-smoked salmon spoilage. AB - Biopreservation is a natural technology of food preservation, which consists of inoculating food with microorganisms selected for their antibacterial properties. The objective of this study was to select lactic acid bacteria (LAB) to improve the quality of cold-smoked salmon (CSS). In this work, different strains representative of the 4 dominant species, identified in a previous study by pyrosequencing the 16S rRNA gene, were isolated and their spoiling potential in CSS blocks, sterilized by ionization, was assessed by twelve trained panelists along the vacuum storage at 8 degrees C. Photobacterium phosphoreum, Brochothrix thermosphacta and Serratia proteamaculans released strong off-odors whereas the spoiling potential of Carnobacterium divergens was weaker. The spoiling capacity of Lactococcus piscium EU2241, Leuconostoc gelidum EU2247, Lactobacillus sakei EU2885, Staphylococcus equorum S030674 and 4 commercial starters was tested by the same method and 2 strains were eliminated due to off-odor production. The effect of the 6 selected LAB against the 4 specific spoiling organisms (SSOs) selected was tested by challenge tests in sterile CSS blocks. The protective effect of the LAB differed from one SSO to another and no correlation could be established between the sensory improvement, SSO inhibition, and the implantation or acidification of protective cultures (PCs). All the PCs except L. piscium reduced the off-odors released by P. phosphoreum although some of them had no effect on its growth. S. equorum, which did not grow in CSS, favored the implantation of P. phosphoreum but prevented its off-odor formation. L. piscium was the only strain that prevented the spoilage of B. thermosphacta and S. proteamaculans although it did not grow very well and did not acidify the product. L. gelidum EU2247 inhibited the growth of these 2 SSOs and lowered the pH but had no effect on the sensory quality. Finally, L. piscium was tested in 2 naturally contaminated products, with a positive effect on 1 batch. This effect was not correlated with the microbial ecosystem as determined by acultural and cultural techniques. Based on these results, the selection strategy is discussed. PMID- 26044339 TI - Predators and hijackers in academic publishing. PMID- 26044342 TI - Mind, Mood, and Aesthetics. PMID- 26044343 TI - Catalytic C-C Bond Activations via Oxidative Addition to Transition Metals. PMID- 26044338 TI - The genome of Diuraphis noxia, a global aphid pest of small grains. AB - BACKGROUND: The Russian wheat aphid, Diuraphis noxia Kurdjumov, is one of the most important pests of small grains throughout the temperate regions of the world. This phytotoxic aphid causes severe systemic damage symptoms in wheat, barley, and other small grains as a direct result of the salivary proteins it injects into the plant while feeding. RESULTS: We sequenced and de novo assembled the genome of D. noxia Biotype 2, the strain most virulent to resistance genes in wheat. The assembled genomic scaffolds span 393 MB, equivalent to 93% of its 421 MB genome, and contains 19,097 genes. D. noxia has the most AT-rich insect genome sequenced to date (70.9%), with a bimodal CpG(O/E) distribution and a complete set of methylation related genes. The D. noxia genome displays a widespread, extensive reduction in the number of genes per ortholog group, including defensive, detoxification, chemosensory, and sugar transporter groups in comparison to the Acyrthosiphon pisum genome, including a 65% reduction in chemoreceptor genes. Thirty of 34 known D. noxia salivary genes were found in this assembly. These genes exhibited less homology with those salivary genes commonly expressed in insect saliva, such as glucose dehydrogenase and trehalase, yet greater conservation among genes that are expressed in D. noxia saliva but not detected in the saliva of other insects. Genes involved in insecticide activity and endosymbiont-derived genes were also found, as well as genes involved in virus transmission, although D. noxia is not a viral vector. CONCLUSIONS: This genome is the second sequenced aphid genome, and the first of a phytotoxic insect. D. noxia's reduced gene content of may reflect the influence of phytotoxic feeding in shaping the D. noxia genome, and in turn in broadening its host range. The presence of methylation-related genes, including cytosine methylation, is consistent with other parthenogenetic and polyphenic insects. The D. noxia genome will provide an important contrast to the A. pisum genome and advance functional and comparative genomics of insects and other organisms. PMID- 26044344 TI - Reduced expression of HSP27 following HAD-B treatment is associated with Her2 downregulation in NIH:OVCAR-3 human ovarian cancer cells. AB - The Korean traditional medicine, HangAmDan (HAD), was developed in 1996 for use as an antitumor agent, and has since been modified to HAD-B (an altered form of HAD), in order to potentiate its therapeutic effects. In the present study, the effect of HAD-B on the proliferation and invasion of NIH:OVCAR-3 and SKOV-3 human ovarian cancer cell lines was investigated. In addition, the expression of major signal transduction molecules and changes in the proteome in these cells were measured. HAD-B treatment effectively induced a reduction in the levels of cell proliferation in serum-free conditioned media. However, unaltered levels of PARP and caspase-3 indicated that HAD-B does not reduce proliferation by inducing apoptotic cell death. Fluorescence-activated cell sorting analysis revealed no significant change in apoptosis following HAD-B treatment. Invasion assay results indicated a reduced rate of invasion following HAD-B treatment. HAD-B also influenced the expression of major signal transduction molecules; the phosphorylation of mTOR and AKT was reduced, while that of ERK was increased. Alterations in the proteomes of the two cell lines were investigated following HAD-B treatment. Among the 9 proteins with differential expression, heat-shock protein beta-1 (HSP27) was downregulated in NIH:OVCAR-3 cells treated with HAD-B. The reduced expression of HSP27 was associated with human epidermal growth factor receptor 2 (Her2) downregulation in these cells. In conclusion, the results of the current proteome assessment suggest that HAD-B has the potential to suppress the proliferation and invasion of human ovarian cancer cells. HAD-B treatment of NIH:OVCAR-3 cells suppressed HSP27 expression and was also associated with Her2 downregulation. PMID- 26044345 TI - The Mini-Balance Evaluation Systems Test (Mini-BESTest). PMID- 26044346 TI - The Senior Fitness Test. PMID- 26044347 TI - Cathelicidin-BF suppresses intestinal inflammation by inhibiting the nuclear factor-kappaB signaling pathway and enhancing the phagocytosis of immune cells via STAT-1 in weanling piglets. AB - The severity of intestinal inflammation in mammals can be profoundly impacted by weaning stress. Cathelicidins protect intestinal homeostasis by not only directly killing bacteria but also immune regulators. Here, we investigated the effects of cathelicidin-BF (C-BF) derived from the snake venoms of Bungarus fasciatus on weaning stress and intestinal inflammation and examined the mechanisms by which C BF modulates intestinal immune responses in weanling piglets. We found that C-BF treatment significantly increased performance and reduced the diarrheal index in weanling piglets. Serum IL-6, IL-22 and TNF-alpha production was decreased by C BF treatment. We demonstrated that C-BF inhibited the expression of the inflammatory cytokines TNF-alpha, IL-6 and IL-8 but increased the expression of the anti-inflammatory cytokine IL-10 in the intestine. We also demonstrated that C-BF suppressed inflammation by down-regulating the nuclear factor-kappaB (NF kappaB) signaling pathway in the intestine and in LPS-induced macrophages in vitro. However, C-BF significantly induced the phosphorylation of signal transducer and activator of transcription 1 (STAT-1) to enhance the phagocytosis of macrophages when inflammation was suppressed. In summary, our study demonstrated that C-BF suppressed intestinal inflammation by down-regulating the NF-kappaB signaling pathway and enhancing the phagocytosis of immune cells by activating STAT-1 during weaning. PMID- 26044348 TI - Cholinergic urethral brush cells are widespread throughout placental mammals. AB - We previously identified a population of cholinergic epithelial cells in murine, human and rat urethrae that exhibits a structural marker of brush cells (villin) and expresses components of the canonical taste transduction signaling cascade (alpha-gustducin, phospholipase Cbeta2 (PLCbeta2), transient receptor potential cation channel melanostatin 5 (TRPM5)). These cells serve as sentinels, monitoring the chemical composition of the luminal content for potentially hazardous compounds such as bacteria, and initiate protective reflexes counteracting further ingression. In order to elucidate cross-species conservation of the urethral chemosensory pathway we investigated the occurrence and molecular make-up of urethral brush cells in placental mammals. We screened 11 additional species, at least one in each of the five mammalian taxonomic units primates, carnivora, perissodactyla, artiodactyla and rodentia, for immunohistochemical labeling of the acetylcholine synthesizing enzyme, choline acetyltransferase (ChAT), villin, and taste cascade components (alpha-gustducin, PLCbeta2, TRPM5). Corresponding to findings in previously investigated species, urethral epithelial cells with brush cell shape were immunolabeled in all 11 mammals. In 8 species, immunoreactivities against all marker proteins and ChAT were observed, and double-labeling immunofluorescence confirmed the cholinergic nature of villin-positive and chemosensory (TRPM5-positive) cells. In cat and horse, these cells were not labeled by the ChAT antiserum used in this study, and unspecific reactions of the secondary antiserum precluded conclusions about ChAT expression in the bovine epithelium. These data indicate that urethral brush cells are widespread throughout the mammalian kingdom and evolved not later than about 64.5millionyears ago. PMID- 26044349 TI - Resveratrol suppresses persistent airway inflammation and hyperresponsivess might partially via nerve growth factor in respiratory syncytial virus-infected mice. AB - Respiratory syncytial virus (RSV) infection is involved in persistent and recurrent wheezing. There are no effective and safe drugs for the sequelae of persistent wheezing after early bronchiolitis. In this study, we investigated the effect of resveratrol on persistent airway inflammation and airway hyperresponsiveness (AHR) induced by RSV infection. RSV-infected mice were sacrificed at serial time points after infection to collect samples and measure the number of inflammatory cells and levels of interferon-gamma (IFN-gamma), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF). Airway inflammation, AHR, and the levels of NGF and BDNF were detected after resveratrol administration. Furthermore, Ab-NGF was used to investigate the role of NGF in RSV-induced prolonged airway inflammation and AHR. We found that RSV RNA remained detectable in the lungs of RSV-infected mice on day 60, accompanying persistent airway inflammation and AHR for 60 days. IFN-gamma levels in BALF were increased on day 7 but reduced to normal levels by day 14 post-RSV infection, while NGF and BDNF levels gradually increased from day 14 to 60. Furthermore, after resveratrol treatment, the total number of cells in BALF was reduced; the number of inflammatory cells infiltrating the lungs was also lower. Resveratrol attenuated the airway response to methacholine and significantly decreased NGF levels in BALF without affecting BDNF levels. Moreover, airway inflammation and AHR associated with RSV persistence were attenuated after Ab-NGF administration. In all, resveratrol suppresses persistent airway inflammation and AHR might partially through reducing the levels of NGF after RSV infection. PMID- 26044350 TI - Natural helper cells contribute to pulmonary eosinophilia by producing IL-13 via IL-33/ST2 pathway in a murine model of respiratory syncytial virus infection. AB - It has been reported that natural helper cells, which are a non-T, non-B innate lymphoid cell type expressing c-Kit and ST2, mediate influenza-induced airway hyper-reactivity by producing substantial IL-13. However, little is known about natural helper cells for the development of RSV-induced airway inflammation, particularly eosinophilic infiltration. By using BALB/c mice that were infected intranasally with RSV, it became clear that infection with RSV can induce an increase in the absolute number of natural helper cells in the lungs of mice. It seems likely that these natural helper cells contribute to the massive eosinophilic infiltration in an IL-13-dependent manner. In fact, the number of IL 13-producing natural helper cells as well as the expression of IL-13 mRNA in natural helper cells was enhanced significantly during RSV infection, suggesting that natural helper cells might be cellular source of the Th2-type cytokine IL 13. Indeed, adoptive transfer of pulmonary natural helper cells augmented not only the production of IL-13 but also the infiltration of eosinophils in the lungs of transferred mice. Pulmonary natural helper cells can produce IL-13 following response to IL-33, which was increased markedly in the lungs of mice after intranasal RSV infection. The expression of IL-13 mRNA in pulmonary natural helper cells was up-regulated by in vitro IL-33 stimulation. Furthermore, blockade of IL-33 receptor subunit, ST2, diminished the frequency of IL-13 producing natural helper cells. Taken together, these results demonstrate that natural helper cells may play an important role in RSV-induced pulmonary eosinophilia by producing IL-13 via the IL-33/ST2 pathway. PMID- 26044352 TI - Landing mechanics during single hop for distance in females following anterior cruciate ligament reconstruction compared to healthy controls. AB - PURPOSE: To determine possible differences in single-hop kinematics and kinetics in females with anterior cruciate ligament reconstruction compared to healthy controls. A second purpose was to make comparisons between the healthy and reconstructed limbs. METHODS: Subjects were grouped based on surgical status (33 ACLR patients and 31 healthy controls). 3D motion capture synchronized with force plates was used to capture the landing phase of three successful trials of single hop for distance during a single data collection session. Peak values during the loading phase were analysed. Subjects additionally completed three successful trials of the triple hop for distance Tegner activity scale and International Knee Document Committee 2000 (IKDC). RESULTS: Controls demonstrated greater peak knee flexion and greater internal knee extension moment and hip extension moment than ACLR subjects. Within the ACLR group, the healthy limb exhibited greater peak knee flexion, hip flexion, hip extension moment, single hop and triple hops for distance and normalized quadriceps strength. CONCLUSION: Patients who undergo anterior cruciate ligament reconstruction land in a more extended posture when compared to healthy controls and compared to their healthy limb. LEVEL OF EVIDENCE: III. PMID- 26044353 TI - Randomized comparison of tape versus semi-rigid and versus lace-up ankle support in the treatment of acute lateral ankle ligament injury. AB - PURPOSE: Functional treatment is the optimal non-surgical treatment for acute lateral ankle ligament injury (ALALI) in favour of immobilization treatment. There is no single most effective functional treatment (tape, semi-rigid brace or lace-up brace) based on currently available randomized trials. METHODS: This study is designed as a randomized controlled trial to evaluate the difference in functional outcome after treatment with tape versus semi-rigid versus lace-up ankle support (brace) for grades II and III ALALIs. The Karlsson score and the FAOS were evaluated at 6-month follow-up. RESULTS: One hundred and ninety-three patients (52% males) were randomized, 66 patients were treated with tape, 58 patients with a semi-rigid brace and 62 patients with a lace-up brace. There were no significant differences in any baseline characteristics between the three groups. Mean age of the patients was 37.3 years (35.1-39.5; SD 15.3). Ninety-five males (49%) were included. One hundred and sixty-one (59 + 50 + 52) patients completed the study through final follow-up; 32% lost at follow-up. In two patients treated with tape support, the treatment was changed to a semi-rigid brace because of dermatomal blisters. Except for the difference in Foot and Ankle Outcome Score sport between the lace-up and the semi-rigid brace, there are no differences in any of the outcomes after 6-month follow-up. CONCLUSION: The most important finding of current study was that there is no difference in outcome 6 months after treatment with tape, semi-rigid brace and a lace-up brace. LEVEL OF EVIDENCE: I. PMID- 26044351 TI - Whole-Genome Resequencing of Experimental Populations Reveals Polygenic Basis of Egg-Size Variation in Drosophila melanogaster. AB - Complete genome resequencing of populations holds great promise in deconstructing complex polygenic traits to elucidate molecular and developmental mechanisms of adaptation. Egg size is a classic adaptive trait in insects, birds, and other taxa, but its highly polygenic architecture has prevented high-resolution genetic analysis. We used replicated experimental evolution in Drosophila melanogaster and whole-genome sequencing to identify consistent signatures of polygenic egg size adaptation. A generalized linear-mixed model revealed reproducible allele frequency differences between replicated experimental populations selected for large and small egg volumes at approximately 4,000 single nucleotide polymorphisms (SNPs). Several hundred distinct genomic regions contain clusters of these SNPs and have lower heterozygosity than the genomic background, consistent with selection acting on polymorphisms in these regions. These SNPs are also enriched among genes expressed in Drosophila ovaries and many of these genes have well-defined functions in Drosophila oogenesis. Additional genes regulating egg development, growth, and cell size show evidence of directional selection as genes regulating these biological processes are enriched for highly differentiated SNPs. Genetic crosses performed with a subset of candidate genes demonstrated that these genes influence egg size, at least in the large genetic background. These findings confirm the highly polygenic architecture of this adaptive trait, and suggest the involvement of many novel candidate genes in regulating egg size. PMID- 26044354 TI - Management of an engaging Hill-Sachs lesion: arthroscopic remplissage with Bankart repair versus Latarjet procedure. AB - PURPOSE: This study compared the clinical outcomes of arthroscopic remplissage with Bankart repair and Latarjet operation in patients with a large engaging Hill Sachs lesion. METHODS: Thirty-seven shoulders subjected to arthroscopic remplissage with a Bankart repair (group A) and 35 shoulders subjected to a Latarjet operation (group B), for a large engaging Hill-Sachs lesion without significant glenoid bone loss, were retrospectively evaluated. Each group was followed up for a mean more than 2-year period. RESULTS: At the last follow-up, postoperative pain, shoulder mobility, muscle strength, Rowe score, and UCLA score revealed no significant difference between the two groups. The postoperative mean deficit in external rotation at the side (ERs) was 8 degrees +/- 23 degrees in group A (P = 0.044). In group B, the mean deficits in ERs, external rotation at 90 degrees of abduction, and internal rotation to the posterior were 10 degrees +/- 20 degrees , 7 degrees +/- 16 degrees , and 1.9 degrees +/- 4 degrees , respectively (P = 0.004, 0.022, and 0.009, respectively). The recurrence rate was 5.4 % (two shoulders) in group A and 5.7 % (two shoulders) in group B (n.s.). The overall complication rate was significantly higher in group B (14.3 %) than in group A (0 %) (P = 0.017). CONCLUSIONS: For recurrent anterior shoulder instability with a large engaging Hill-Sachs lesion, both arthroscopic remplissage with Bankart repair and the Latarjet procedure were safe and reliable techniques with a low recurrence rate. However, the Latarjet group had a significantly higher postoperative complication rate than the remplissage group. LEVEL OF EVIDENCE: Case-control study, Level III. PMID- 26044355 TI - Effects of alpha,beta-unsaturated lactones on larval survival and gut trypsin as well as oviposition response of Aedes aegypti. AB - Lactones are organic cyclic esters that have been described as larvicides against Aedes aegypti and as components of oviposition pheromone of Culex quinquefasciatus. This work describes the effect of six alpha,beta-unsaturated lactones (5a-5f) on survival of A. aegypti fourth instar larvae (L4). It is also reported the effects of the lactones on L4 gut trypsin activity and oviposition behavior of A. aegypti females. Five lactones were able to kill L4 being the lactones 5a (LC50 of 39.05 ppm), 5e (LC50 of 36.30 ppm) and 5f (LC50 of 40.46 ppm) the most promising larvicides. Only the lactone 5a inhibited L4 gut trypsin activity, with an IC50 of 115.15 ug/mL. Lactones 5a, 5c, 5d and 5e did not exert deterrent or stimulatory effects on oviposition, whereas lactone 5b exhibited a strong deterrent oviposition activity. In conclusion, this work introduces new alpha,beta-unsaturated lactones as promising alternatives to control A. aegypti dissemination. The larvicidal mechanism of the lactone 5a can involve the disruption of proteolysis at larval gut. PMID- 26044356 TI - Natural products as inhibitors of recombinant cathepsin L of Leishmania mexicana. AB - Cysteine proteinases (cathepsins) from Leishmania spp. are promising molecular targets against leishmaniasis. Leishmania mexicana cathepsin L is essential in the parasite life cycle and a pivotal in virulence factor in mammals. Natural products that have been shown to display antileishmanial activity were screened as part of our ongoing efforts to design inhibitors against the L. mexicana cathepsin L-like rCPB2.8. Among them, agathisflavone (1), tetrahydrorobustaflavone (2), 3-oxo-urs-12-en-28-oic acid (3), and quercetin (4) showed significant inhibitory activity on rCPB2.8 with IC50 values ranging from 0.43 to 18.03 uM. The mechanisms of inhibition for compounds 1-3, which showed Ki values in the low micromolar range (Ki = 0.14-1.26 uM), were determined. The biflavone 1 and the triterpene 3 are partially noncompetitive inhibitors, whereas biflavanone 2 is an uncompetitive inhibitor. The mechanism of action established for these leishmanicidal natural products provides a new outlook in the search for drugs against Leishmania. PMID- 26044357 TI - Neuromuscular complications of hematopoietic stem cell transplantation. AB - Neuromuscular diseases such as polymyositis, dermatomyositis, peripheral neuropathy, and disorders of neuromuscular transmission are reported to be complications of hematopoietic stem cell transplantation (HSCT). Although cases have been reported with allogeneic HSCT in the setting of chronic graft versus host disease, they are also known to occur without evidence thereof and even occur in the setting of autologous HSCT. The 2005 National Institutes of Health Consensus Criteria classify polymyositis and dermatomyositis as "distinctive" features, and neuropathy and MG as "other" features. These neuromuscular complications present very similarly to the idiopathic autoimmune disorders and respond to similar treatment modalities. PMID- 26044358 TI - Molecular dynamics simulation study of chitosan and gemcitabine as a drug delivery system. AB - By using molecular dynamics (MD) simulation, biodegradable biopolymer chitosan as a carrier for the drug gemcitabine was investigated and the effect of three initial drug concentrations (10, 40, and 80%) on its loading efficiency was studied. Then water was added to the systems of drug and biopolymer and the effects of water on the interactions of drug and chitosan and on the drug loading efficiency were examined. From the results it was found that the maximum loading of the drug occurred at 40% of the drug concentration. The radial distribution function calculations indicated that in the absence of water molecules, the drug molecules were located at shorter distance from chitosan and the loading efficiency of the drug in these systems was higher. PMID- 26044359 TI - Characterization of interactions and pharmacophore development for DFG-out inhibitors to RET tyrosine kinase. AB - RET (rearranged during transfection) tyrosine kinase is a promising target for several human cancers. Abt-348, Birb-796, Motesanib and Sorafenib are DFG-out multi-kinase inhibitors that have been reported to inhibit RET activity with good IC50 values. Although the DFG-out conformation has attracted great interest in the design of type II inhibitors, the structural requirements for binding to the RET DFG-out conformation remains unclear. Herein, the DFG-out conformation of RET was determined by homology modelling, the four inhibitors were docked, and the binding modes investigated by molecular dynamics simulation. Binding free energies were calculated using the molecular mechanics/Poisson-Bolzmann surface area (MM/PBSA) method. The trends in predicted binding free affinities correlated well with experimental data and were used to explain the activity difference of the studied inhibitors. Per-residue energy decomposition analyses provided further information on specific interaction properties. Finally, we also conducted a detailed e-pharmacophore modelling of the different RET-inhibitor complexes, explaining the common and specific pharmacophore features of the different complexes. The results reported herein will be useful in future rational design of novel DFG-out RET inhibitors. PMID- 26044360 TI - Involvement of electron and hydrogen transfers through redox metabolism on activity and toxicity of the nimesulide. AB - An electronic study of nimesulide was performed by using density functional theory calculations. The activities of the six different derivatives were related with electron donating or accepting capacities. All compounds which had nitro moiety had low electron donating and high electron accepting capacities. However, the reduced derivative of nimesulide have more electron donating capacity than other compounds. The highest spin density contribution in nitro and lowest spin density contribution on phenoxyl moieties can be related with preferential metabolism by reduction when compared with the oxidation. The redox behavior between nitro and amino groups can be related with anti-inflammatory mechanism of nimesulide. These results explain the redox influence of nitro moiety on biological metabolism and mechanism of nimesulide. PMID- 26044361 TI - Breast Cancer Patients Undergoing Sentinel Node Biopsy: Additional Axillary Tumor Burden as a Function of the Total Number of Excised Sentinel Nodes-A Multicenter Study. AB - BACKGROUND: Recent studies have challenged the long-standing assumption that breast cancer prognosis is determined by lymph node regional status. We assessed locoregional relapse, distant metastases, and mortality alongside additional axillary disease in breast cancer patients undergoing sentinel node (SN) biopsy. PATIENTS AND METHODS: This prospective study assessed 1070 women with clinical T1 T2 invasive breast cancer with negative clinical/ultrasound axillae. RESULTS: A total of 25.1% of patients had positive SN biopsy findings, of whom 69.2% had only 1 involved SN. The rate of axillary recurrence was 0.7%, with no significant differences found between patients with positive or negative SN (0.6% vs. 1.1%). There were also no significant differences in the rate of distant metastases or breast cancer-specific mortality. If we had applied the Z0011 trial suggestions, residual axillary disease would have reached 16.2%: 13.5% in patients over 50% and 21.3% in patients under 50. The rate of residual axillary disease would have been 25.2% in patients with only 1 SN (20.2% in patients over 50% and 38.2% in patients under 50). In patients with 2 SN, residual disease would have ranged from 12.0% in patients over 50% to 19.0% in patients under 50. From 3 SN on, residual disease seems negligible. CONCLUSION: There were no significant differences in locoregional relapse, distant metastases, or mortality between patients with negative and positive SN. Patients with 3 or more SN have no additional axillary disease. In patients younger 50, one must be extremely cautious if the Z0011 suggestions are to be applied, especially if there is only 1 SN. PMID- 26044362 TI - Being Born Small for Gestational Age Influences Amplitude-Integrated Electroencephalography and Later Outcome in Preterm Infants. AB - BACKGROUND: The impact of growth restriction on perinatal morbidity is well known, but electroencephalographic (EEG) data on its influence are still scarce. OBJECTIVES: We aimed to analyze the influence of being born small for gestational age (SGA; defined as a birth weight <10th percentile) on the amplitude-integrated EEG (aEEG) score in the first 2 weeks of life in preterm infants born before 30 weeks of gestation, and its impact on later outcome. METHODS: aEEG data obtained within the first 2 weeks of life on preterm infants born SGA and before 30 weeks of gestational age (GA) were analyzed retrospectively using a combined score [including background activity, occurrence of sleep-wake cycles (SWC) and suspected seizure activity]. Neurodevelopmental outcome was evaluated at 24 months by means of the Bayley Scales of Infant Development II and a standardized neurological examination. RESULTS: One hundred and thirty-six patients were included (47 SGA and 89 controls). Infants with SGA had abnormal aEEG scores significantly more often (57 vs. 24%, p = 0.002) than infants born appropriate for gestational age (AGA). They also displayed SWC less frequently (65 vs. 96%, p = 0.001), were more likely to develop seizure activity (15 vs. 4%, p = 0.013) and had a normal neurodevelopmental outcome at the age of 2 years less frequently (36.2 vs. 59.6%, p = 0.02). CONCLUSION: Preterm infants born SGA and before 30 weeks of GA had less optimal scores on early aEEG and a poorer neurodevelopmental outcome at 24 months than the AGA controls. PMID- 26044363 TI - Improving Blood Plasma Glycoproteome Coverage by Coupling Ultracentrifugation Fractionation to Electrostatic Repulsion-Hydrophilic Interaction Chromatography Enrichment. AB - Blood plasma is considered to be an excellent source of disease biomarkers because it contains proteins, lipids, metabolites, cell, and cell-derived extracellular vesicles from different cellular origins including diseased tissues. Most secretory and membranous proteins that can be found in plasma are glycoproteins; therefore, the plasma glycoproteome is one of the major subproteomes that is highly enriched with disease biomarkers. As a result, the glycoproteome has attracted much attention in clinical proteomic research. The modification of proteins with glycans regulates a wide range of functions in biology, but profiling plasma glycoproteins on a global scale has been hampered by the presence of low stoichiometry of glycoproteins in a complex high abundance plasma proteome background and lack of effective analytical technique. This study aims to improve plasma glycoproteome coverage using pig plasma as a model sample with a two-step strategy. The first step involves fractionation of the plasma proteins using ultracentrifugation into supernatant and pellet that is believed to contain low abundant glycoproteins. In the second step, further enrichment of glycopeptides was achieved in both fractions by adopting electrostatic repulsion hydrophilic interaction chromatography (ERLIC) coupled to tandem mass spectrometry (LC-MS/MS) analysis. The coverage of enriched glycoproteins in supernatant, pellet, and whole plasma sample as control was compared. Using this simple sample fractionation approach by ultracentrifugation and further ERLIC enrichment technique, sample complexity was reduced and glycoproteome coverage was significantly enhanced in supernatant and pellet fractions (by >50%) compared with whole plasma sample. This study showed that when ultracentrifugation is coupled to ERLIC glycopeptides enrichment and glycoproteome identification are significantly improved. This study demonstrates the combination of ultracentrifugation and ERLIC as a useful method for discovering plasma glycoprotein disease biomarkers. PMID- 26044364 TI - Using combinatorial bioinformatics methods to analyze annual perspective changes of influenza viruses and to accelerate development of effective vaccines. AB - The standard World Health Organization procedure for vaccine development has provided a guideline for influenza viruses, but no systematic operational model. We recently designed a systemic analysis method to evaluate annual perspective sequence changes of influenza virus strains. We applied dnaml of PHYLIP 3.69, developed by Joseph Felsenstein of Washington University, and ClustalX2, developed by Larkin et al, for calculating, comparing, and localizing the most plausible vaccine epitopes. This study identified the changes in biological sequences and associated alignment alterations, which would ultimately affect epitope structures, as well as the plausible hidden features to search for the most conserved and effective epitopes for vaccine development. Addition our newly designed systemic analysis method to supplement the WHO guidelines could accelerate the development of urgently needed vaccines that might concurrently combat several strains of viruses within a shorter period. PMID- 26044365 TI - Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects. AB - In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by (1)H NMR, (13)CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4 methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4 bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2 acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1-S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1-S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with Kis in the range of 1.79 +/- 0.22-2.73 +/- 0.08 nM against hCA I and in the range of 1.72 +/ 0.58-11.64 +/- 5.21 nM against hCA II, respectively. PMID- 26044366 TI - Identifying network biomarkers based on protein-protein interactions and expression data. AB - Identifying effective biomarkers to battle complex diseases is an important but challenging task in biomedical research today. Molecular data of complex diseases is increasingly abundant due to the rapid advance of high throughput technologies. However, a great gap remains in identifying the massive molecular data to phenotypic changes, in particular, at a network level, i.e., a novel method for identifying network biomarkers is in pressing need to accurately classify and diagnose diseases from molecular data and shed light on the mechanisms of disease pathogenesis. Rather than seeking differential genes at an individual-molecule level, here we propose a novel method for identifying network biomarkers based on protein-protein interaction affinity (PPIA), which identify the differential interactions at a network level. Specifically, we firstly define PPIAs by estimating the concentrations of protein complexes based on the law of mass action upon gene expression data. Then we select a small and non-redundant group of protein-protein interactions and single proteins according to the PPIAs, that maximizes the discerning ability of cases from controls. This method is mathematically formulated as a linear programming, which can be efficiently solved and guarantees a globally optimal solution. Extensive results on experimental data in breast cancer demonstrate the effectiveness and efficiency of the proposed method for identifying network biomarkers, which not only can accurately distinguish the phenotypes but also provides significant biological insights at a network or pathway level. In addition, our method provides a new way to integrate static protein-protein interaction information with dynamical gene expression data. PMID- 26044367 TI - Analysis of EPA's endocrine screening battery and recommendations for further review. AB - EPA's Endocrine Disruptor Screening Program Tier 1 battery consists of eleven assays intended to identify the potential of a chemical to interact with the estrogen, androgen, thyroid, or steroidogenesis systems. We have collected control data from a subset of test order recipients from the first round of screening. The analysis undertaken herein demonstrates that the EPA should review all testing methods prior to issuing further test orders. Given the frequency with which certain performance criteria were violated, a primary focus of that review should consider adjustments to these standards to better reflect biological variability. A second focus should be to provide detailed, assay specific direction on when results should be discarded; no clear guidance exists on the degree to which assays need to be re-run for failing to meet performance criteria. A third focus should be to identify permissible differences in study design and execution that have a large influence on endpoint variance. Experimental guidelines could then be re-defined such that endpoint variances are reduced and performance criteria are violated less frequently. It must be emphasized that because we were restricted to a subset (approximately half) of the control data, our analyses serve only as examples to underscore the importance of a detailed, rigorous, and comprehensive evaluation of the performance of the battery. PMID- 26044368 TI - All for one and one for all: Regionalization of the Drosophila intestine. AB - Physiological responses are the ultimate outcomes of the functional interactions and proper organization of the different cell types that make up an organ. The digestive tract represents a good example where such structure/function correlation is manifested. To date, the molecular mechanisms that establish and/or maintain gut segmentation and functional specialization remain poorly understood. Recently, the use of model systems such as Drosophila has enriched our knowledge about the gut organization and physiology. Here, we review recent studies deciphering the morphological and functional properties of the Drosophila adult midgut compartments. Intestinal compartments are established through the differentiation of regionalized stem cell populations in concert with the joint activity of patterned transcription factors and locally produced morphogens. The maintenance of a compartmentalized gut structure is vital to the organism, allowing sequentially the ingestion and digestion of food, absorption of nutrients, and excretion of waste products in addition to the compartmentalization of immune and homeostatic functions. Further characterization of the gene regulatory networks underlying gut compartmentalization will pave the way for a better understanding of gastrointestinal function in insects and mammals, in both health and disease conditions. PMID- 26044369 TI - The proportion of postmenopausal breast cancer cases in the Netherlands attributable to lifestyle-related risk factors. AB - We aimed to estimate the proportion of Dutch postmenopausal breast cancer cases in 2010 that is attributable to lifestyle-related risk factors. We calculated population attributable fractions (PAFs) of potentially modifiable risk factors for postmenopausal breast cancer in Dutch women aged >50 in 2010. First, age specific PAFs were calculated for each risk factor, based on their relative risks for postmenopausal breast cancer (from meta-analyses) and age-specific prevalence in the population (from national surveys) around the year 2000, assuming a latency period of 10 years. To obtain the overall PAF, age-specific PAFs were summed in a weighted manner, using the age-specific breast cancer incidence rates (2010) as weights. 95 % confidence intervals for PAF estimates were derived by Monte Carlo simulations. Of Dutch women >40 years, in 2000, 51 % were overweight/obese, 55 % physically inactive (<5 days/week 30 min activity), 75 % regularly consumed alcohol, 42 % ever smoked cigarettes and 79 % had a low-fibre intake (<3.4 g/1000 kJ/day). These factors combined had a PAF of 25.7 % (95 % CI 24.2-27.2), corresponding to 2,665 Dutch postmenopausal breast cancer cases in 2010. PAFs were 8.8 % (95 % CI 6.3-11.3) for overweight/obesity, 6.6 % (95 % CI 5.2-8.0) for alcohol consumption, 5.5 % (95 % CI 4.0-7.0) for physical inactivity, 4.6 % (95 % CI 3.3-6.0) for smoking and 3.2 % (95 % CI 1.6-4.8) for low-fibre intake. Our findings imply that modifiable risk factors are jointly responsible for approximately one out of four Dutch postmenopausal breast cancer cases. This suggests that incidence rates can be lowered substantially by living a more healthy lifestyle. PMID- 26044370 TI - A network meta-analysis of everolimus plus exemestane versus chemotherapy in the first- and second-line treatment of estrogen receptor-positive metastatic breast cancer. AB - The goal of this study was to compare the efficacy and toxicity of chemotherapy to exemestane plus everolimus (EXE/EVE) through a network meta-analysis (NMA) of randomized controlled trials. NMA methods extend standard pairwise meta-analysis to allow simultaneous comparison of multiple treatments while maintaining randomization of individual studies. The method enables "direct" evidence (i.e., evidence from studies directly comparing two interventions) and "indirect" evidence (i.e., evidence from studies that do not compare the two interventions directly) to be pooled under the assumption of evidence consistency. We used NMA to evaluate progression-free survival (PFS) and time to progression (TTP) curves in 34 studies, and response rate (RR) and the hazard ratios (HRs) of the PFS/TTP in 36 studies. A number needed to treat (NNT) analysis was also performed as well as descriptive comparison of reported toxicities. The NMA for PFS/TTP curves and for HR shows EXE/EVE is more efficacious than capecitabine plus sunitinib, CMF, megestrol acetate and tamoxifen, with an average of related-PFS/TTP difference ranging from about 10 months for capecitabine plus sunitinib to more than 6 months for tamoxifen. The NMA for overall RR shows that EXE/EVE provides a better RR than bevacizumab plus capecitabine, capecitabine, capecitabine plus sorafenib, capecitabine plus sunitinib, CMF, gemcitabine plus epirubicin plus paclitaxel, EVE plus tamoxifen, EXE, FEC, megestrol acetate, mitoxantrone, and tamoxifen. Finally, the NMA for NNT shows that EXE/EVE is more beneficial as compared to BMF, capecitabine, capecitabine plus sunitinib, CMF, FEC, megestrol acetate, mitoxantrone, and tamoxifen. The combination of EXE/EVE as first- or second-line therapy for ER+ve/HER2-ve metastatic breast cancer is more efficacious than several chemotherapy regimens that were reported in the literature. Toxicities also favored EXE/EVE in most instances. PMID- 26044371 TI - Anti-inflammatory effects of Gualou Guizhi decoction in transient focal cerebral ischemic brains. [Corrected]. PMID- 26044372 TI - Cyclodialysis-enhanced trabeculectomy with triple Ologen implantation. AB - PURPOSE: To describe a novel technique of trabeculectomy combined with cyclodialysis and Ologen implantation at 3 sites in cases with high risk for failure of trabeculectomy. METHODS: Six eyes of 6 patients who had high risk for failure of trabeculectomy underwent cyclodialysis-augmented trabeculectomy with Ologen implantation at 3 sites using the described technique. RESULTS: All the eyes achieved target intraocular pressure, which was maintained until 1 year of follow-up. One eye required bleb needling at 6 weeks postoperative follow-up. None of the eyes had any other intraoperative or postoperative complications. CONCLUSIONS: This novel technique of combining trabeculectomy with cyclodialysis augmented by Ologen placement at 3 locations appears to have encouraging short term intraocular pressure control and may be adopted in eyes with risk factors for failure of conventional trabeculectomy. PMID- 26044373 TI - Variability of different reference bodies in normal, keratoconus, and collagen crosslinked corneas. AB - PURPOSE: To evaluate the reproducibility of different Scheimpflug imaging-derived reference bodies in normal, keratoconus (KC), and crosslinked (CXL) eyes. METHODS: In this prospective, observational study, 40 participants populated the control group (CG), while 33 and 34 patients formed the KC group and the CXL group, respectively. One eye was randomly selected when both were eligible. Elevation measurements were obtained using Scheimpflug camera, by applying the following reference bodies: the best fit sphere (BFS), the best fit toric ellipsoid (BFTE), the best fit toric ellipsoid with fixed eccentricity of 0.4 (BFTEF), the best fit ellipsoid (BFE), and the best fit torus, by 2 operators in 2 sessions. The variability of different reference bodies' parameters was assessed using intraclass correlation coefficient (ICC). RESULTS: Differences between operators were nonsignificant for all reference bodies' parameters in all study groups (p>0.1). Regarding CG, BFS for both operators and BFTE for operator 1 presented the best intrasession repeatability (majority of ICCs >0.90), while average interobserver reliability was recorded for the majority of reference bodies' parameters. Regarding KC and CXL groups, BFS, BFTEF, and BFE reference bodies demonstrated the best intrasession and interobserver reproducibility (majority of ICCs >0.90) for both groups. Steep and flat radius parameters presented the best overall reproducibility, with the majority of ICCs for all reference bodies ranging above 0.90, in all study groups. CONCLUSIONS: High variability was encountered for most reference surfaces. Ellipsotoric surfaces presented acceptable repeatability in KC and post-CXL corneas. PMID- 26044374 TI - Intravitreal autologous plasmin prepared by urokinase for vitreolysis: a pilot study. AB - PURPOSE: To evaluate the effects of intravitreal autologous plasmin injection (IVAP) on vitreoretinal diseases and vitreolysis. METHODS: In this interventional, prospective, case series pilot study, 8 eyes were assigned to IVAP. Plasminogen as centrifuged from the patients' plasma was converted to plasmin by adding urokinase. A total of 0.2 mL extracted plasmin was injected intravitreally. Posterior vitreous detachment (PVD) and potential injection related complications at week 4 were the primary outcome measures. Secondary outcomes included changes in best-corrected visual acuity (VA) (logMAR) and central macular thickness (CMT). RESULTS: Mean age of the patients was 54.35 years. Two patients had complete PVD and 3 patients had partial PVD. Four patients had decrease in CMT. The VA was not changed in 6 patients, improved in 1 patient, and decreased in 1 patient. No uveitis, endophthalmitis, or postinjection vitreous hemorrhage was observed. CONCLUSIONS: This pilot study demonstrated the efficacy of urokinase-prepared IVAP injection on releasing vitreomacular traction and inducing vitreolysis. PMID- 26044375 TI - Ranibizumab prefilled syringes: benefits of reduced syringe preparation times and less complex preparation procedures. AB - PURPOSE: A recently developed ranibizumab prefilled syringe (PFS) eliminates several preparatory steps versus the standard vial-based method, and is expected to reduce syringe preparation time (SPT) and enhance procedural simplicity for intravitreal injections. METHODS: Syringe preparation times for the ranibizumab PFS and vial were recorded during standard treatment sessions at 2 centers, without randomization. The duration of each step in preparing the syringe was recorded. At each center, total SPT (mean total duration of all syringe preparation steps) for each method was compared using a 2-tailed t test. RESULTS: In total, 97 SPTs were analyzed across both centers. Center 1 SPTs were 46 seconds (PFS) versus 75 seconds (vial; difference, 29 seconds; p<0.001). Center 2 SPTs were 46 seconds (PFS) versus 63 seconds (vial; difference, 17 seconds; p<0.001). This equates to a 27%-39% reduction in SPT when using the PFS rather than the vial, resulting mostly from the reduced number of syringe preparation steps associated with the PFS. CONCLUSIONS: Syringe preparation times for ranibizumab intravitreal injections are significantly shorter with the PFS than with the vial. The time saved by using the PFS may benefit physicians and nurses, and the simplicity of the injection preparation process with the PFS is advantageous. PMID- 26044376 TI - Foveal pit morphology evaluation during optical biometry measurements using a full-eye-length swept-source OCT scan biometer prototype. AB - PURPOSE: To assess the scan quality of foveal pit morphology (FPM) and to quantify central retinal thickness (CRT) during routine optical biometry measurements with a full-eye-length swept-source optical coherence tomography (SS OCT) scan biometer prototype (IOLMaster700) and to compare these results with standard examinations using spectral-domain optical coherence tomography (SD-OCT) technique (Cirrus4000 SD-OCT). METHODS: As part of a SS-OCT scan protocol to measure biometric parameters for intraocular lens power calculation, central horizontal 1 mm retinal B scans were taken from phakic (group I) and pseudophakic (group II) nonvitrectomized eyes. To evaluate FPM, macular scans of either examination technique were subjectively analyzed and compared. Repeated CRT measurements were performed to analyze repeatability and consistency of IOLMaster700 recordings. These results were compared with CRT evaluations using SD-OCT. RESULTS: Overall, 146 eyes of 146 patients were included in this series. The subjective assessments of FPM are illustrated. Repeated CRT measurements (repeatability) with the IOLMaster700 disclosed an overall intraclass correlation of 0.57 (group I: 0.48; group II: 0.89). Overall coefficient of variation (accuracy) was calculated to be 12.43% (group I: 14.21%; group II: 5.66%). The comparison of CRT measurements between both devices showed significant differences in group I (p = 0.006). CONCLUSIONS: Compared with SD-OCT, resolution of the 1 mm retinal B scan of SS-OCT scan biometry was lower. However, advanced pathologic characteristics were clearly discernible. Repeatability and accuracy of CRT measurements were acceptable though lower than with the standard SD-OCT technique. The CRT differed significantly in eyes of particular interest (group I) between both devices. The new scan could provide useful information for subsequent patient examination and further treatment planning for cataract surgery. PMID- 26044377 TI - Efficacy of adjunctive mitomycin C in transcanalicular diode laser dacryocystorhinostomy in different age groups. AB - PURPOSE: To evaluate the efficacy of adjunctive mitomycin C (MMC) in transcanalicular multidiode laser dacryocystorhinostomy (TCL-DCR) in different age groups. METHODS: Ninety-six eyes of 96 patients who underwent TCL-DCR for the treatment of nasolacrimal duct obstruction were included in this retrospective, comparative study. Patients were divided into 4 groups based on age and intraoperative use of MMC: group 1, TCL-DCR without MMC in the 20- to 44-year age group; group 2, TCL-DCR with MMC in the 20- to 44-year age group; group 3, TCL DCR without MMC in the 45- to 76-year age group; group 4, TCL-DCR with MMC in the 45- to 76-year age group. The postoperative evaluation consisted of calculating and comparing the success rates between groups. RESULTS: Success rates at the final visit were 50% for group 1, 66.66% for group 2, 79.16% for group 3, and 84.61% for group 4. The differences between group 1 and group 4, and group 1 and group 3, were significant (p = 0.01 and p = 0.038, respectively). Logistic regression showed that age group had significant effect on success rate (p = 0.013). However, use of MMC had no significant effect on success rate (p = 0.23). CONCLUSIONS: The success rates of the TCL-DCR with MMC application were found to be higher than those of TCL-DCR without MMC in different age groups. However, the differences did not reach statistical significance. In addition, our study demonstrated that age may be a significant factor influencing the surgical outcome of TCL-DCR. PMID- 26044378 TI - High-capacity magnetic hollow porous molecularly imprinted polymers for specific extraction of protocatechuic acid. AB - Magnetic hollow porous molecularly imprinted polymers (HPMIPs) with high binding capacity, fast mass transfer, and easy magnetic separation have been fabricated for the first time. In this method, HPMIPs was firstly synthesized using protocatechuic acid (PCA) as template, 4-vinylpyridine (4-VP) as functional monomer, glycidilmethacrylate (GMA) as co-monomer, and MCM-48 as sacrificial support. After that, epoxide ring of GMA was opened for chemisorbing Fe3O4 nanoparticles to prepare magnetic HPMIPs. The results of characterization indicated that magnetic HPMIPs exhibited large surface area (548m(2)/g) with hollow porous structure and magnetic sensitivity (magnetic saturation at 2.9emu/g). The following adsorption characteristics investigation exhibited surprisingly higher adsorption capacity (37.7mg/g), and faster kinetic binding (25min) than any previously reported PCA imprinted MIPs by traditional or surface imprinting technology. The equilibrium data fitted well to Langmuir equation and the adsorption process could be described by pseudo-second order model. The selective recognition experiments also demonstrated the high selectivity of magnetic HPMIPs towards PCA over analogues. The results of the real sample analysis confirmed the superiority of the proposed magnetic HPMIPs for selective and efficient enrichment of trace PCA from complex matrices. PMID- 26044379 TI - Effects of supercritical fluid chromatography conditions on enantioselectivity and performance of polyproline-derived chiral stationary phases. AB - The chromatographic behaviour and performance of four polyproline-derived chiral stationary phases (CSPs) were tested using supercritical fluid chromatography (SFC). A series of structurally related racemic compounds, whose enantioseparation was proved to be sensitive to the type of mobile phase used in NP-HPLC, were chosen to be tested in the SFC conditions. Good enantioselection ability was shown by the CSPs for the analytes tested in the new conditions. Resolution, efficiency and analysis time, were considerably improved with respect to NP-HPLC when CO2/alcohol mobile phases were used. Monolithic columns clearly show enhanced chromatographic parameters and improved performance respect to their bead-based counterparts. PMID- 26044380 TI - Hexafluoroisopropanol-modified cetyltrimethylammonium bromide/sodium dodecyl sulfate vesicles as a pseudostationary phase in electrokinetic chromatography. AB - A novel catanionic surfactant vesicle system, formulated from hexafluoroisopropanol (HFIP), cetyltrimethylammonium bromide (CTAB) and sodium dodecyl sulfate (SDS), was developed as pseudostationary phase (PSP) in electrokinetic chromatography (EKC). HFIP, as an organic modifier with the prominent properties of ionization, hydrogen bond donor and hydrophobicity, was used to effectively promote the spontaneous vesicle formation from CTAB/SDS mixed aqueous solutions, where precipitates are easy to occur due to long carbon chains, and adjust the performance of CTAB/SDS vesicles. The physical features (size and viscosity) and electrophoretic parameters (electroosmotic mobility, electrophoretic mobility and elution range) of HFIP-modified CTAB/SDS vesicles were characterized as HFIP volume content (0-4%, v/v), CTAB/SDS molar ratio (2:8 7:3mol/mol) and total surfactant concentration (10-50mM) varying, respectively. The 3% v/v HFIP-modified CTAB/SDS (3:7mol/mol, 50mM) vesicle system proves to have the largest mean diameter (288.20nm) and the widest elution range (12.41), which is also much wider than that of the corresponding other four PSP systems including trifluoroethanol (TFE)-modified CTAB/SDS vesicles (5.69), isopropanol modified CTAB/SDS micelles (2.03), HFIP-modified SDS micelles (4.86) and unmodified SDS micelles (3.12). The chromatographic performance of the HFIP modified vesicle system was evaluated by separating eight polycyclic aromatic hydrocarbons, nitrotoluene positional isomers, five positively charged and five negatively charged/neutral drugs, respectively. Baseline or near-baseline separation was achieved for each series of solutes. Compared with the TFE modified vesicle system, as well as the HFIP-modified and unmodified SDS micelle systems, the HFIP-modified vesicle system shows the best separation selectivity, the highest or comparable efficiency, and the lowest retention. PMID- 26044381 TI - On the inherent data fitting problems encountered in modeling retention behavior of analytes with dual retention mechanism. AB - Some valuable insights have been obtained in the inherent fitting problems when trying to predict the retention time of complex, multi-modal retention modes such as encountered in HILIC and SFC. In this study, we used mathematical models with known input parameters to generate different sets of numerical test curves representative for systems exhibiting a complex, non-LSS dual retention behavior. Subsequently, we tried to fit these data sets using some popular (non-linear) literature models. Even in cases where a physical fitting model exists (e.g., the mixed model in case of pure additive adsorptive and partitioning retention), the fitting quality can only be expected to be relatively good (prediction errors expressed in terms of a normalized resolution error ERs) when carefully selecting the scouting runs and the appropriate starting values for the fitting algorithm. The latter can best be done using a comprehensive grid search scanning a wide range of different starting values. This becomes even more important when no good physical model is available and one has to use a non-physical fitting model, such as the empirical Neue-model. The use of higher-order models is found to be quasi indispensable to keep the prediction errors on the order of some DeltaRs=0.05. Also, the choice of the scouting runs becomes even more important using these higher-order models. For highly retained compounds we recommend using scouting runs with long tG/t0-values or to include a run with a higher fraction of eluting solvent at the start of the gradient. When trying to predict gradient retention, errors with which the isocratic retention behavior is fitted are much less important for high retention factors k than errors made in the range of k near the one at the point of elution. The results obtained with a so-called segmented Neue-model (containing 7 parameters) were less good and thus practically not interesting (because of the high number of initial runs). PMID- 26044382 TI - Multi-residue pesticide analysis (gas chromatography-tandem mass spectrometry detection)-Improvement of the quick, easy, cheap, effective, rugged, and safe method for dried fruits and fat-rich cereals-Benefit and limit of a standardized apple puree calibration (screening). AB - Some steps of the QuEChERS method for the analysis of pesticides with GC-MS/MS in cereals and dried fruits were improved or simplified. For the latter, a mixing vessel with stator-rotor-system proved to be advantageous. The extraction procedure of dried fruits is much easier and safer than the Ultra Turrax and results in excellent validation data at a concentration level of 0.01mg/kg (116 of 118 analytes with recoveries in the range of 70-120%, 117 of 118 analytes with RSD <20%). After qualifying problematic lipophilic pesticides in fat-rich cereals (fat content >7%), predominantly organochlorines showed recoveries of <70% in quantification when the standard QuEChERS method with water was used. A second extraction was carried out analogous to the QuEChERS method, however, without the addition of water. With this simple modification, the problematic lipophilic pesticides, which had been strongly affected by the fat content of the commodities, could be determined with recoveries above 70% even at a concentration level of 0.01mg/kg. Moreover, a GC-MS/MS screening method for 120 pesticides at a concentration level of 0.01mg/kg was established by employing analyte protectants (ethylglycerol, gulonolactone, and sorbitol). The use of only one standardized calibration, made of an apple puree extract in combination with analyte protectants, allowed for a qualitative and quantitative analysis of 120 pesticides in different matrix extracts (tomato, red pepper, sour cherries, dried apples, black currant powder, raisins, wheat flour, rolled oats, wheat germ). The analyte protectants leveled the differences in the matrix-induced protection effect of the analyzed extracts over a wide range. The majority of the pesticides were analyzed with good analytical results (recoveries in the range of 70-120% and RSD <20%). PMID- 26044383 TI - Characterization of quinone derived protein adducts and their selective identification using redox cycling based chemiluminescence assay. AB - The cytotoxic mechanism of many quinones has been correlated to covalent modification of cellular proteins. However, the identification of relevant proteins targets is essential but challenging goals. To better understand the quinones cytotoxic mechanism, human serum albumin (HSA) was incubated in vitro with different concentration of menadione (MQ). In this respect, the initial nucleophilic addition of proteins to quinone converts the conjugates to redox cycling quinoproteins with altered conformation and secondary structure and extended life span than the short lived, free quinones. The conjugation of MQ with nucleophilic sites likewise, free cysteine as well as E-amino group of lysine residue of HSA has been found to be in concentration dependent manner. The conventional methods for modified proteins identification in complex mixtures are complicated and time consuming. Herein, we describe a highly selective, sensitive, simple, and fast strategy for quinoproteins identification. The suggested strategy exploited the unique redox-cycling capability of quinoproteins in presence of a reductant, dithiothreitol (DTT), to generate reactive oxygen species (ROS) that gave sufficient chemiluminescence (CL) when mixed with luminol. The CL approach is highly selective and sensitive to detect the quinoproteins in ten-fold molar excess of native proteins without adduct enrichment. The approach was also coupled with gel filtration chromatography (GFC) and used to identify adducts in complex mixture of proteins in vitro as well as in rat plasma after MQ administration. Albumin was identified as the main protein in human and rat plasma forming adduct with MQ. Overall, the identification of quinoproteins will encourage further studies of toxicological impact of quinones on human health. PMID- 26044384 TI - An analytic description of electrodynamic dispersion in free-flow zone electrophoresis. AB - The present work analyzes the electrodynamic dispersion of sample streams in a free-flow zone electrophoresis (FFZE) chamber resulting due to partial or complete blockage of electroosmotic flow (EOF) across the channel width by the sidewalls of the conduit. This blockage of EOF has been assumed to generate a pressure-driven backflow in the transverse direction for maintaining flow balance in the system. A parallel-plate based FFZE device with the analyte stream located far away from the channel side regions has been considered to simplify the current analysis. Applying a method-of-moments formulation, an analytic expression was derived for the variance of the sample zone at steady state as a function of its position in the separation chamber under these conditions. It has been shown that the increase in stream broadening due to the electrodynamic dispersion phenomenon is additive to the contributions from molecular diffusion and sample injection, and simply modifies the coefficient for the hydrodynamic dispersion term for a fixed lateral migration distance of the sample stream. Moreover, this dispersion mechanism can dominate the overall spatial variance of analyte zones when a significant fraction of the EOF is blocked by the channel sidewalls. The analysis also shows that analyte streams do not undergo any hydrodynamic broadening due to unwanted pressure-driven cross-flows in an FFZE chamber in the absence of a transverse electric field. The noted results have been validated using Monte Carlo simulations which further demonstrate that while the sample concentration profile at the channel outlet approaches a Gaussian distribution only in FFZE chambers substantially longer than the product of the axial pressure-driven velocity and the characteristic diffusion time in the system, the spatial variance of the exiting analyte stream is well described by the Taylor-Aris dispersion limit even in analysis ducts much shorter than this length scale. PMID- 26044385 TI - Liquid chromatography coupled to quadrupole-time of flight tandem mass spectrometry based quantitative structure-retention relationships of amino acid analogues derivatized via n-propyl chloroformate mediated reaction. AB - In the current study, quantitative structure-retention relationships (QSRR) were constructed based on data obtained by a LC-(ESI)-QTOF-MS/MS method for the determination of amino acid analogues, following their derivatization via chloroformate esters. Molecules were derivatized via n-propyl chloroformate/n propanol mediated reaction. Derivatives were acquired through a liquid-liquid extraction procedure. Chromatographic separation is based on gradient elution using methanol/water mixtures from a 70/30% composition to an 85/15% final one, maintaining a constant rate of change. The group of examined molecules was diverse, including mainly alpha-amino acids, yet also beta- and gamma-amino acids, gamma-amino acid analogues, decarboxylated and phosphorylated analogues and dipeptides. Projection to latent structures (PLS) method was selected for the formation of QSRRs, resulting in a total of three PLS models with high cross validated coefficients of determination Q(2)Y. For this reason, molecular structures were previously described through the use of descriptors. Through stratified random sampling procedures, 57 compounds were split to a training set and a test set. Model creation was based on multiple criteria including principal component significance and eigenvalue, variable importance, form of residuals, etc. Validation was based on statistical metrics Rpred(2),QextF2(2),QextF3(2) for the test set and Roy's metrics rm(Av)(2) and rm(delta)(2), assessing both predictive stability and internal validity. Based on aforementioned models, simplified equivalent were then created using a multi-linear regression (MLR) method. MLR models were also validated with the same metrics. The suggested models are considered useful for the estimation of retention times of amino acid analogues for a series of applications. PMID- 26044386 TI - Successful treatment by coil embolization for infantile hemangioma with Kasabach Meritt syndrome of newborn. AB - Infantile hemangioma (IH) is the most common tumor of infancy, and it sometimes associated with Kasabach-Meritt syndrome (KMS) characterized by anemia, intraperitoneal hemorrhage secondary to rupture, coagulopathy, jaundice, and vascular malformations involving the brain, skin, gut, and other organs. Here, we report two newborn patients having IH with KMS at birth. The first patient had a giant hemangioma in the liver, which was successfully treated with i.v. corticosteroid and coil embolization. The second patient had a large hemangioma of the right axillary region, which was also successfully treated with i.v. corticosteroid, beta-blocker, coil embolization and local irradiation. All symptoms were controlled without any side-effects in both patients. According to these findings, combination therapy including coil embolization and corticosteroid is effective for IH patients with KMS. The indications for and timing of coil embolization should be determined further cases have been accumulated. PMID- 26044387 TI - Fatal pneumoperitoneum following endoscopic retrograde cholangiopancreatography confirmed by post-mortem computed tomography. PMID- 26044388 TI - Potentially preventable infant and child deaths identified at autopsy; findings and implications. AB - PURPOSE: The purpose of the study was to determine the proportion of pediatric deaths investigated by HM Coronial autopsy which were potentially preventable deaths due to treatable natural disease, and what implications such findings may have for health policies to reduce their occurrence. METHODS: A retrospective study of 1779 autopsies of individuals between 7 days and 14 years of age requested by HM Coroner, taking place in one specialist pediatric autopsy center, was undertaken. Cases were included if they involved a definite natural disease process in which appropriate recognition and treatment was likely to have affected their outcome. Strict criteria were used and cases were excluded where the individual had any longstanding condition which might have predisposed them to, or altered the recognition of, acute illness, or its response to therapy. RESULTS: Almost 8% (134/1779) of the study group were potentially preventable deaths as a result of natural disease, the majority occurring in children younger than 2 years of age. Most individuals reported between 1 and 7 days of symptoms before their death, and the majority had sought medical advice during this period, including from general practitioners within working hours, and hospital emergency departments. Of those who had sought medical attention, around one third had done so more than once (28%, 15/53). Sepsis and pneumonia accounted for the majority of deaths (46 and 34% respectively), with all infections (sepsis, pneumonia and meningitis) accounting for 110/134 (82%). CONCLUSION: Around 10% of pediatric deaths referred to HM Coroner are potentially preventable, being the result of treatable natural acute illnesses. In many cases medical advice had been sought during the final illness. The results highlight how a review of autopsy data can identify significant findings with the potential to reduce mortality, and the importance of centralized investigation and reporting of pediatric deaths. PMID- 26044389 TI - Physical and chemical properties of biochars co-composted with biowastes and incubated with a chicken litter compost. AB - Two experiments were conducted where three biochars, made from macadamia nutshell (MS), hardwood shaving (WS) and chicken litter (CL), were co-composted with chicken manure and sawdust, and also incubated with a chicken litter based commercial compost. Biochars were added at the rates of 5% and 10% in the co composting and 10% and 20% in the incubation experiment. The rates of biochar had no consistent effect on the change in element contents of composted- or incubated biochars. The biochar C demonstrated recalcitrance in both composting and incubation systems. Composting increased the CEC of biochars probably due to thermophilic oxidation. The increases in CEC of WS and CL were 6.5 and 2.2 times, respectively, for composting. Translocation of elements, between biochar and compost medium, occurred in both directions. In most cases, biochars gained elements under the influence of positive difference of concentrations (i.e., when compost medium had higher concentration of elements than biochar), while in some cases they lost elements despite a positive difference. Biochar lost some elements (WS: B; CL: B, Mg and S) under the influence of negative difference of concentrations. Some biochars showed strong affinity for B, C, N and S: the concentration of these elements gained by biochars surpassed the concentration in the respective composting medium. The material difference in the biochars did not have influence on N retention: all three netbag-biochars increased their N content. The cost of production of biochar-compost will be lower in co-composting than incubation, which involves two separate processes, i.e., composting and subsequent incubation. PMID- 26044390 TI - Molecular Diversity of Compounds from Pygidial Gland Secretions of Cave-Dwelling Ground Beetles: The First Evidence. AB - Three adult cave-dwelling ground beetle species were induced to discharge secretions of their pygidial glands into vials. Dichloromethane extraction was used to obtain the secretions. In total, 42 compounds were identified by GC/MS analysis. Pheggomisetes ninae contained 32 glandular compounds, Laemostenus (Pristonychus) punctatus 13, whereas Duvalius (Paraduvalius) milutini had nine compounds. Caproic, oleic, palmitic, and stearic acids were present in the samples of all analyzed species. Undecane was predominant in the extract of L. punctatus. Palmitic acid was the major component in the secretion of D. milutini. Finally, the most abundant compounds in P. ninae secretion were heptacosene and nonacosadienes. Herein, we present the first data on the identification of pygidial gland secretion components in both troglophilous and troglobite cave dwelling ground beetles. Some compounds are reported for the first time in the secretions of ground beetles and other higher or lower taxa. The adaptation to underground life has not led to a reduction or changes in the chemical defense mechanism in the analyzed troglophilous and troglobitic Platyninae and Trechinae taxa. PMID- 26044392 TI - Platelet Preparations for Use in Facial Rejuvenation and Wound Healing: A Critical Review of Current Literature. AB - In facial plastic surgery, the potential for direct delivery of growth factors from platelet preparations has been of particular interest for use in facial rejuvenation, recovery after facial surgery, and wound healing. A literature search was conducted through PubMed for the terms PRP, PRFM, platelet-rich plasma, platelet-rich fibrin matrix, platelet preparations, platelet therapy, growth factors, platelet facial, platelet facial rejuvenation, platelet wound healing, platelet plastic surgery. Articles pertaining to the use of platelet preparations in facial surgery and wound healing in plastic surgery after 2001 were included. Thirteen in vitro studies showed use of platelet-rich plasma (PRP) and platelet-rich fibrin matrix (PRFM) had a significant effect on cellular activity. Twenty-four out of 28 animal studies exhibited favorable results with use of a platelet preparation, including five of six studies that showed enhanced fat graft survival with addition of a platelet preparation. Twenty-three case series and clinical trials were identified, only two of which showed no differences. Twenty-one reported favorable results with use of various platelet preparations. A total of 47 studies used PRP, four studies evaluated Leukocyte rich PRP, and fourteen studies used PRFM. The vast majority of studies examined show a significant and measurable effect on cellular changes, wound healing, and facial esthetic outcomes with use of platelet preparations, both topical and injectable. One must also consider possible publication bias against null results that may have had an influence on the data that were available for review. However, the preponderance of studies suggests that platelet preparations might represent an as-of-yet untapped adjunct in facial plastic surgery. PMID- 26044391 TI - A Prospective, Randomized, Multicenter Trial Assessing a Novel Lysine-Derived Urethane Adhesive in a Large Flap Surgical Procedure without Drains. AB - OBJECTIVE: To evaluate the safety and effectiveness of a lysine-derived urethane adhesive as a noninvasive alternative to closed suction drains in a commonly performed large flap surgical procedure. METHODS: One hundred thirty subjects undergoing abdominoplasty at five centers were prospectively randomized to standard flap closure with surgical drains (Control group) or a lysine-derived urethane adhesive (Treatment group) without drains. The primary outcome measured was the number of post-operative procedures, including drain removals (as the event marking the use of a surgical drain) and needle aspirations. Secondary endpoints included total wound drainage, cumulative days of treatment, and days to drain removal. A patient questionnaire evaluating quality of life measures was also administered. RESULTS: Subjects in the Treatment group required significantly fewer post-operative procedures compared to the Control group (1.8 +/- 3.8 vs. 2.4 +/- 1.2 procedures; p < 0.0001) and fewer cumulative days of treatment (1.6 +/- 0.4 vs. 7.3 +/- 3.3; p < 0.0001). A procedure to address fluid accumulation was required for only 27.3 % of the subjects in the Treatment group versus 100 % of Control group, which by study design required the use of drains. The mean duration of use of indwelling surgical drains for the Control group was 6.9 +/- 3.3 days. All fluid collections treated with percutaneous aspiration were resolved and there were no unanticipated adverse events. CONCLUSION: The results of the study support that the use of a lysine-derived urethane adhesive is a safe and effective alternative to drains in patients undergoing a common large flap surgical procedure. PMID- 26044393 TI - Allogeneic Adipose-Derived Stem Cells Protect Fat Grafts at the Early Stage and Improve Long-Term Retention in Immunocompetent Rats. AB - BACKGROUND: Syngeneic adipose-derived stem cells (ASCs) promote the survival of fat grafts. But it is unclear whether allogeneic ASCs have a similar protective effect. In this study, we investigated the protective effect of allogeneic ASCs in a fat graft model of immunocompetent rats. METHODS: Syngeneic and allogeneic ASCs were derived from Lewis (LEW) and Norway-Brown rats, respectively. Fifty four LEW rats were divided into three groups. Each LEW rat was injected subcutaneously at two paravertebral spots with adipose granules premixed with DMEM (AFT group), syngeneic ASCs (SYNG group), or allogeneic ASCs (ALLG group). Fat grafts were harvested at 7 and 14 days to examine apoptosis rates and immunochemistry staining was performed for Perilipin A and CD34. At 3 months, fat graft volume retentions were measured. The proportion of regulatory T (Treg) cells and the ratio of CD4/CD8 cells in blood were analyzed at 7 days. RESULTS: Expression of Perilipin A and CD34 was higher in the ALLG group than the AFT group at 14 days (P < 0.05). The apoptosis rate in the ALLG group decreased in comparison with the AFT group at 7 and 14 days (P < 0.05). At 3 months, allogeneic ASCs increased fat graft volume retentions (P < 0.05). No difference was found in the proportion of Treg cells and CD4/CD8 cells ratio between groups. There were no statistically significant difference between ALLG and SYNG groups at all time points (P > 0.05). CONCLUSIONS: Allogeneic ASCs protected fat grafts at the early stage and improved long-term volume retention in the fat graft model of immunocompetent rats with no or little obvious immune rejection. PMID- 26044394 TI - Fast and Painless Skin Tag Excision with Ethyl Chloride. AB - Skin tags (acrochordon) are skin colored or hyperpigmented, usually pedunculated benign skin lesions and often occur on the neck, axilla, and groin regions. It is difficult choice to excise these multiple, widespread, and pedinculated lesions with or without local anesthesia. One option is to infiltrate local anesthesia to every single skin tag, while cutting pedicle with single move is another option. However, both of these options are painful to some degree. We routinely use ethyl chloride spray anesthesia for skin tag excision with micro-scissor and micro forceps. We received positive feedback from patients, who underwent skin tag excision before with conventional techniques. They declare that ethyl chloride procedure is more comfortable and painless. PMID- 26044395 TI - Skin Sterility After Application of a Vapocoolant Spray Part 2. AB - INTRODUCTION: Refrigerant sprays have been used for pain relief at the time of minor office procedures. However, their sterility remains in question. This study investigates the microbiologic effect of this vapocoolant when sprayed after 70 % isopropyl alcohol skin preparation. MATERIALS AND METHODS: In 50 healthy volunteers, three skin culture samples were collected: Group 1 prior to alcohol application; Group 2 after preparation with alcohol, and Group 3 after preparation with alcohol followed with vapocoolant spray. Samples were cultured in a blinded fashion and analyzed after 5 days of incubation. Gram staining was performed when cultures were positive. RESULTS: Bacterial growth was found in 98 % of samples prior to any skin preparation. This was reduced to 54 % after alcohol use (Group 2). Spraying with the skin refrigerant further reduced bacterial growth to 46 % (Group 3). The results showed a significant reduction in the number of positive bacterial cultures following skin preparation with alcohol and when alcohol prep was followed by vapocoolant spray (p < 0.001) compared to initial cultures. No statistical difference was observed between Groups 2 and 3 (p = 0.74). CONCLUSIONS: The use of the vapocoolant spray does not compromise the sterility of the skin following alcohol prep. Both 70 % isopropyl alcohol antiseptic preparation and skin preparation followed by vapocoolant spray significantly reduce skin colonization when compared to unprepared skin (p < 0.001). PMID- 26044396 TI - An Experimental Study of Auricular Reconstruction Using a Thin Porous Silastic Frame Assisted by Tissue Expansion: An Animal Study. AB - BACKGROUND: In the 1960s, the silastic ear frame was used for auricular reconstruction. Most surgeons abandoned the use of the silastic ear frame in the 1980s because of the high incidence of exposure. In this study, we introduce the computer-aided design and manufacture of a thin, porous silastic auricle frame and investigate the possibility of auricular reconstruction using this frame assisted by tissue expansion. METHODS: An adult male with average sized, normal ears was selected. A spiral CT scan was performed to obtain primitive data on his external ear. Mimics-8.1 and Geomagic studio-12 were used for 3D reconstruction and image processing. A thin, porous silastic auricle frame 1.4 mm in thickness was manufactured. A 50 ml kidney-shaped tissue expander was implanted between the panniculus carnosus and the deep fascia through an incision on the back of each of 10 New Zealand white rabbits. Each week the expander was inflated with 10 ml saline to a total of 160 m1. Maintenance of the expansion lasted for a month. The expander was then removed, and the silastic auricle frame was inserted into the pocket. The reconstructed ears were observed for 6 months postoperatively. RESULTS: The reconstructed ears remained soft and flexible, with no deformation, contracture, or extrusion observed 6 months postoperatively. The scaphoid fossa, triangular fossa, cavum, helix, and antihelix remained defined. CONCLUSIONS: The silastic frame, 1.4 mm in thickness manufactured by computer-aided design, stood up to the contraction of the overlying expanded flap. It is possible to be used for auricular reconstruction assisted by tissue expansion. PMID- 26044397 TI - Use of Extended Lateral Upper Arm Free Flap for Tongue Reconstruction After Radical Glossectomy for Tongue Cancer. AB - BACKGROUND: This study evaluated the safety and effectiveness of the extended lateral arm free flap (ELAFF) for repair of partial tongue defects after radical resection of tongue cancer. METHODS: The study included nine consecutive patients who underwent repair of a partial tongue defect with an ELAFF after radical resection of tongue cancer from November 2010 to December 2013. Lesions were at the tip or margin of the tongue. Details of the reconstructive surgery, donor site and recipient-site morbidity, and functional and esthetic outcomes were evaluated during a minimum of 12 months follow-up. Patient-reported Visual Analog Scale (VAS) scores on a scale of 0 (minimum satisfaction) to 10 (maximum satisfaction) were used to evaluate esthetic outcomes. RESULTS: All patients were followed up for 12 months (median 24 months). The overall survival rate was 88 % (8/9). The donor site was closed primarily in all patients. The most frequent donor-site morbidity was a broad scar. Poor functional outcomes were associated with postoperative adjuvant radiotherapy. The shape and function of the reconstructed tongue were satisfactory. VAS scores (mean +/- SD) for patient satisfaction with recipient-site and donor-site esthetics were 6.92 +/- 1.70 and 7.33 +/- 2.01, respectively. CONCLUSION: The ELAFF is a safe and effective option for repair of partial tongue defects after radical resection of tongue cancer. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 26044398 TI - The Senile Lung as a Possible Source of Pitfalls on Chest Ultrasonography and Computed Tomography. AB - BACKGROUND: Age-associated changes in the pulmonary system could be detected with imaging techniques. Widespread use of lung ultrasonography (US) requires characterization of a normal pattern. OBJECTIVES: To compare US and computed tomography (CT) findings in healthy subjects undergoing both techniques (with CT as the gold standard). METHODS: We prospectively selected 59 subjects undergoing chest CT and US on the same day, without a history of smoking, respiratory symptoms, or known pulmonary pathologies. There were 44 patients in group 1 (age >=60 years - elderly) and 15 patients in group 2 (age <=50 years - young). Lung US was performed with a convex and a linear probe, and 10 chest areas per patient were analyzed. Convex and linear probe agreement was evaluated by means of the Cohen kappa statistic; Fisher's exact test was used to compare categorical variables between groups. RESULTS: Isolated B-lines were frequent in both group 1 (54.5%) and group 2 (40.0%); the number of chest areas positive for B-lines increased with age (16.1% in group 1 vs. 5.3% in group 2, p = 0.0028). In group 2, we found that 37.5% of subjects with B-lines had at least 1 chest area with multiple B-lines, but only 2 subjects had 2 or more. Moreover, in group 1 the chest CT documented a reticular pattern (2.3%), areas of increased density (9.1%), ground glass (6.8%), cysts (2.3%), bronchiectasis (22.7%), and bronchial thickening (6.8%); in group 2, only cysts (6.7%) and bronchiectasis (6.7%) were found. CONCLUSIONS: The senile lung is characterized by mild changes on CT and US. Chest areas positive for B-lines increase with age, and focal multiple B lines can be found. However, diffuse patterns, especially in symptomatic subjects, suggest a different diagnosis. PMID- 26044399 TI - Essential Tremor: A Common Disorder of Purkinje Neurons? AB - Essential tremor (ET) is one of the most common neurological diseases, with an estimated 7 million affected individuals in the United States. Postmortem studies in the past few years have resulted in new knowledge as well as a new formulation of disease pathophysiology. This new formulation centers on the notion that ET might be a disease of the cerebellum and, more specifically, the Purkinje cell (PC) population. Indeed, several investigators have proposed that ET may be a "Purkinjopathy." Supporting this formulation are data from controlled postmortem studies demonstrating (1) a range of morphological changes in the PC axon, (2) abnormalities in the position and orientation of PC bodies, (3) reduction in the number of PCs in some studies, (4) morphological changes in and pruning of the PC dendritic arbor with loss of dendritic spines, and (5) alterations in both the PC basket cell interface and the PC-climbing fiber interface in ET cases. This new formulation has engendered some controversy and raised additional questions. Whether the constellation of changes observed in ET differs from that seen in other degenerative disorders of the cerebellum remains to be determined, although initial studies suggest the likely presence of a distinct profile of changes in ET. PMID- 26044401 TI - Short- and Long-Term Stroke Risk after Urgent Management of Transient Ischaemic Attack: The Bologna TIA Clinical Pathway. AB - BACKGROUND: Rapid management can reduce the short stroke risk after transient ischaemic attack (TIA), but the long-term effect is still little known. We evaluated 3-year vascular outcomes in patients with TIA after urgent care. METHODS: We prospectively enrolled all consecutive patients with TIA diagnosed by a vascular neurologist and referred to our emergency department (ED). Expedited assessment and best secondary prevention was within 24 h. Endpoints were stroke within 90 days, and stroke, myocardial infarction, and vascular death at 12, 24 and 36 months. RESULTS: Between August 2010 and July 2013, we evaluated 686 patients with suspected TIA; 433 (63%) patients had confirmed TIA. Stroke at 90 days was 2.07% (95% confidence interval (CI), 1.1-3.9) compared with the ABCD2 predicted risk of 9.1%. The long-term stroke risk was 2.6% (95% CI, 1.1-4.2), 3.7% (95% CI, 1.6-5.9) and 4.4% (95% CI, 1.9-6.8) at 12, 24 and 36 months, respectively. The composite outcome of stroke, myocardial infarction, and vascular death was 3.5% (95% CI, 1.7-5.1), 4.9% (95% CI, 2.5-7.4), and 5.6% (95% CI, 2.8-8.3) at 12, 24, and 36 months, respectively. CONCLUSIONS: TIA expedited management driven by vascular neurologists was associated with a marked reduction in the expected early stroke risk and low long-term risk of stroke and other vascular events. PMID- 26044400 TI - Peer-assisted teaching of basic surgical skills. AB - BACKGROUND: Basic surgical skills training is rarely emphasised in undergraduate medical curricula. However, the provision of skills tutorials requires significant commitment from time-constrained surgical faculty. PURPOSE: We aimed to determine how a peer-assisted suturing workshop could enhance surgical skills competency among medical students and enthuse them towards a career in surgery. METHODS: Senior student tutors delivered two suturing workshops to second- and third- year medical students. Suturing performance was assessed before and after teaching in a 10-min suturing exercise (variables measured included number of sutures completed, suture tension, and inter-suture distance). Following the workshop, students completed a questionnaire assessing the effect of the workshop on their suturing technique and their intention to pursue a surgical career. RESULTS: Thirty-five students attended. Eighty-one percent believed their medical school course provided insufficient basic surgical skills training. The mean number of sutures completed post-teaching increased significantly (p < 0.001), and the standard deviation of mean inter-suture distance halved from +/- 4.7 mm pre-teaching, to +/- 2.6 mm post-teaching. All students found the teaching environment to be relaxed, and all felt the workshop helped to improve their suturing technique and confidence; 87% found the peer-taught workshop had increased their desire to undertake a career in surgery. DISCUSSION: Peer assisted learning suturing workshops can enhance medical students' competence with surgical skills and inspire them towards a career in surgery. With very little staff faculty contribution, it is a cheap and sustainable way to ensure ongoing undergraduate surgical skills exposure. PMID- 26044402 TI - A lipid pathway for heat adaptation. PMID- 26044403 TI - Long-term remission of locally recurrent oropharyngeal cancer after docetaxel based chemotherapy plus cetuximab. AB - BACKGROUND: In recurrent head and neck squamous cell carcinoma ineligible for resection or irradiation, treatment aims primarily at symptom control and quality of life enhancement with an expected outcome of 6-12 months. METHODS: In 2005, a male patient, born in 1944, with a second local recurrence of human papillomavirus negative tonsil cancer was enrolled in the EXTREME trial, and randomized to platinum/5-fluorouracil/cetuximab arm resulting in partial remission with progression-free survival of 12 months. The second-line systemic therapy comprised 5 cycles of 3-weekly docetaxel/cisplatin/5-fluorouracil regimen plus weekly cetuximab. RESULTS: As confirmed on imaging and repeated biopsies, complete response was achieved with disease-free survival of 8 years and follow up period of 12 years. Severe acute toxicities during the taxane-based chemotherapy plus cetuximab included grade 4 anorexia and grade 3 febrile neutropenia. CONCLUSIONS: Poor tumor differentiation, no weight loss, oropharyngeal location, white race, and particularly the induced complete response were most likely the key favorable prognostic factors in the reported patient. The possibility of a synergistic interaction between taxanes and cetuximab should be further explored. PMID- 26044404 TI - Risk factors for treatment failure in surgery for primary hyperparathyroidism: the impact of change in surgical strategy and training procedures. AB - Surgery for primary hyperparathyroidism (pHPT) has a high cure-rate and few complications. Preoperative localization procedures have permitted a dramatic shift from routine bilateral exploration to focused, minimally invasive procedures. At Odense University Hospital, Denmark, the introduction of focused surgery was combined with training of new surgeons. The objective of this study was to identify possible risk factors for treatment failure with special focus on surgical strategy and training of new surgeons. A 6-year prospective and consecutive series of 567 pHPT patients operated at Odense University hospital, Denmark, was analyzed. A shift in strategy was made in 2006 and at the same time new surgeons started training in parathyroid surgery. Biochemical-, clinical- and follow-up data were analyzed. Overall cure-rate was 90.7 %. Complication rates were 1.1 % for hemorrhage, 1.1 % for wound infection and 0.9 % for recurrent nerve paralysis. The only significant predictor of treatment failure at 6 months was histology of hyperplasia (OR 4.3). Neither the introduction of minimal invasive surgical strategy nor the training of new surgeons had a significant influence on the rate of treatment failures. Hyperplasia is a significant predictor of treatment failure in pHPT surgery. A shift towards systematic preoperative localization with focused surgery as well as training of new surgeons can be done without negative impact on treatment results. Identification of the hyperplasia and multigland patients in need of bilateral cervical exploration is crucial to avoid failures and raise cure rates. PMID- 26044405 TI - Pediatric middle ear cholesteatoma: the comparative study of congenital cholesteatoma and acquired cholesteatoma. AB - This study examined the differences between congenital cholesteatoma (CC) and acquired cholesteatomas (AC) in children by comparing clinical features and treatment courses. This was a retrospective study which retrospectively evaluated 127 children with middle ear cholesteatomas using medical records from January 1999 to December 2012 in the Department of Otolaryngology, Niigata University Hospital. The study comprised 69 and 58 cases of CC and AC, respectively. The main outcome measures include patient backgrounds, the opportunities for consultations, mastoid cell development, intraoperative finding of stapes, surgical procedure and number of surgeries. The average age at operation was 6.4 and 9.8 years in CC and AC, respectively. AC was more prevalent in boys. Mastoid development was better in CC than in AC. We adopted a two-stage operation in 17 cases (25 %) of CC and in 22 cases (38 %) of AC. The repeat surgery rate was 11.6 % in CC and 27.6 % in AC. Three times as many operations were required for three cases (4.3 %) of CC and 10 cases (17.2 %) of AC. The lesions in AC were more difficult to control. In the treatment of pediatric middle ear cholesteatoma, we had to keep the outcome in mind. PMID- 26044406 TI - Controllable Synthesis and Tunable Photocatalytic Properties of Ti(3+)-doped TiO2. AB - Photocatalysts show great potential in environmental remediation and water splitting using either artificial or natural light. Titanium dioxide (TiO2)-based photocatalysts are studied most frequently because they are stable, non-toxic, readily available, and highly efficient. However, the relatively wide band gap of TiO2 significantly limits its use under visible light or solar light. We herein report a facile route for controllable synthesis of Ti(3+)-doped TiO2 with tunable photocatalytic properties using a hydrothermal method with varying amounts of reductant, i.e., sodium borohydride (NaBH4). The resulting TiO2 showed color changes from light yellow, light grey, to dark grey with the increasing amount of NaBH4. The present method can controllably and effectively reduce Ti(4+) on the surface of TiO2 and induce partial transformation of anatase TiO2 to rutile TiO2, with the evolution of nanoparticles into hierarchical structures attributable to a high pressure and strong alkali environment in the synthesis atmosphere; in this way, the photocatalytic activity of Ti(3+)-doped TiO2 under visible-light can be tuned. The as-developed strategy may open up a new avenue for designing and functionalizing TiO2 materials for enhancing visible light absorption, narrowing band gap, and improving photocatalytic activity. PMID- 26044408 TI - Improving the Efficiency and Safety of Aspirin by Complexation with the Natural Polysaccharide Arabinogalactan. AB - BACKGROUND: The main undesirable side effect of the aspirin is the damage to the gastrointestinal mucosa, leading to the formation of erosions, peptic ulcers, and as a result, bleeding. To overcome this problem "host-guest" complexation with natural polysaccharide arabinogalactan could be applied. METHODS: The complex with a weight ratio of ASA:AG = 1:10 was prepared by solid phase method in a rotary mill. Complex was administered orally to mice or rats at doses of 250, 500 or 1000 mg/kg. The "acetic acid induced writhing" and "hot plate" tests were used as an in vivo pain models. The antiinflammatory activity was studied using "histamine swelling" test. Also, long-term (30 days) oral introduction of the complex to rats was performed and gastric mucosa damages were evaluated. In all experiments pure aspirin (ASA) was used as a control in appropriate doses. RESULTS: The minimal effective analgesic dose of the complex was 250 mg/kg, equivalent to 23 mg/kg of ASA, a dose in which aspirin itself was not active. The anti-inflammatory effect was found at relatively higher doses: 500 and 1000 mg/kg (46 and 92 mg/kg of ASA respectively) for the complex and only at 100 mg/kg for the ASA. Long-term introduction of the complex at doses of 250 and 500 mg/kg was safe for gastric mucosa, while ASA at the dose of 50 mg/kg showed a strong gastric mucosal damage. CONCLUSION: The effective analgesic and anti-inflammatory doses of 1:10 aspirin complex with arabinogalactan are twice less compared to pure aspirin and safer for the gastrointestinal mucosa. PMID- 26044410 TI - Usefulness of elastography in predicting the outcome of Foley catheter labour induction. AB - BACKGROUND: Incorrect selection of women for labour induction may increase the risk of caesarean section and other postpartum and neonatal complications. It has been recently shown that elastography of the uterine cervix holds the potential to predict the outcome of pharmacological labour induction. There are no data on the usefulness of elastography in predicting the outcome of mechanical induction of labour. AIM: To assess the usefulness of elastographic cervical assessment in predicting the success of Foley catheter labour induction. MATERIALS AND METHODS: This prospective observational study included 39 pregnant women at term with an unfavourable cervix (Bishop score <= 6) suitable for Foley catheter labour induction. Before labour induction the following data were recorded: Bishop score, cervical length (measured by ultrasound) and the stiffness of cervical internal os, canal and external os assessed by elastography (elastography index - EI). Statistical relationships between pre-interventional assessment of the cervix and outcome of Foley catheter labour induction (successful induction, time to delivery and route of delivery) were analysed. RESULTS: EI's of internal cervical os and cervical canal were significantly lower (softer) in women with successful labour induction and vaginal delivery, while EI's of the external cervical os, Bishop score and cervix length were not significantly different. Time to vaginal delivery was significantly correlated with the EI's of internal cervical os, cervical canal and Bishop score, but not with EI's of the external cervical os and cervix length. CONCLUSION: Elastography has the potential to predict the outcome of Foley catheter labour induction. PMID- 26044409 TI - Fertility in transfusion-dependent thalassemia men: effects of iron burden on the reproductive axis. PMID- 26044411 TI - Complete Genome Sequence of a Fish Nervous Necrosis Virus Isolated from Sea Perch (Lateolabrax japonicus) in China. AB - We sequenced and analyzed the complete genome of a fish nervous necrosis virus isolated from diseased sea perch (Lateolabrax japonicus) in Guangdong Province, China. The virus genome contains RNA1 (3,103 bp) and RNA2 (1,433 bp). Phylogenetic analysis shows that the virus belongs to the redspotted grouper nervous necrosis virus genotype of betanodavirus. PMID- 26044412 TI - Complete genome sequence of a classical Swine Fever virus isolate belonging to a new subgenotype, 2.1c, from guangxi province, china. AB - The complete genome sequence of a field isolate of classical swine fever strain (CSFV), GXF29/2013, was determined in this study. This strain was originally isolated from infected pigs in Guangxi Province, China. The most significant difference in the amino acid sequence of the polyprotein from subgenotypes 2.1a and 2.1b is an SPA->APV amino acid substitution at positions 88 and 90 in the E2 protein. PMID- 26044413 TI - Complete Genome Sequence of Rat Cytomegalovirus Strain ALL-03 (Malaysian Strain). AB - The complete genome sequence of the ALL-03 strain of rat cytomegalovirus (RCMV) has been determined. The RCMV genome has a length of 197,958 bp and is arranged as a single unique sequence flanked by 504-bp terminal direct repeats. This strain is closely related to the English strain of RCMV in terms of genetic arrangement but differs slightly in size. PMID- 26044414 TI - Draft Genome Sequence of Human-Pathogenic Lactococcus garvieae LG-ilsanpaik gs201105 That Caused Acute Acalculous Cholecystitis. AB - Lactococcus garvieae, which is generally known as a marine and freshwater fish pathogen, is now considered to be an emerging zoonotic pathogen in both human and veterinary medicine. In recent years, we have reported the infection of L. garvieae LG-ilsanpaik-gs201105 in the gallbladder of an old fisherman. In this study, we present the draft genome sequence of L. garvieae LG-ilsanpaik-gs201105, with a total genome size of 1,960,261 bp in 53 contigs and a 38.1% average G+C content. Interestingly, the capsule gene cluster, which was known as one of the crucial virulence factors in L. garvieae, was not detected in our isolate. This is the first genome sequence of human-pathogenic L. garvieae, which caused acute acalculous cholecystitis. PMID- 26044415 TI - Draft Genome Sequence of Erwinia tracheiphila, an Economically Important Bacterial Pathogen of Cucurbits. AB - Erwinia tracheiphila is one of the most economically important pathogens of cucumbers, melons, squashes, pumpkins, and gourds in the northeastern and midwestern United States, yet its molecular pathology remains uninvestigated. Here, we report the first draft genome sequence of an E. tracheiphila strain isolated from an infected wild gourd (Cucurbita pepo subsp. texana) plant. The genome assembly consists of 7 contigs and includes a putative plasmid and at least 20 phage and prophage elements. PMID- 26044416 TI - Draft Genome Sequence of the Biowarfare Simulant Bacillus atrophaeus Strain 930029. AB - We report here the draft genome sequence of Bacillus atrophaeus strain 930029. Strain 930029 shows evidence of drift, based on a comparison to the corresponding source strain publicly available today. PMID- 26044417 TI - Draft genomes of gammaproteobacterial methanotrophs isolated from terrestrial ecosystems. AB - Genome sequences of Methylobacter luteus, Methylobacter whittenburyi, Methylosarcina fibrata, Methylomicrobium agile, and Methylovulum miyakonense were generated. The strains represent aerobic methanotrophs typically isolated from various terrestrial ecosystems. PMID- 26044418 TI - Genome Sequence of Photobacterium halotolerans MELD1, with Mercury Reductase (merA), Isolated from Phragmites australis. AB - Here, we present the whole-genome sequence of Photobacterium halotolerans strain, MELD1, isolated from the roots of a terrestrial plant Phragmites australis grown in soil heavily contaminated with mercury and dioxin. The genome provides further insight into the adaptation of bacteria to the toxic environment from where it was isolated. PMID- 26044419 TI - Complete genome sequence of a porcine epidemic diarrhea s gene indel strain isolated in france in december 2014. AB - We report the first and only case of a porcine epidemic diarrhea (PED) outbreak occurring in December 2014 in northern France, and we show using the full-length genome sequence of the French PED virus (PEDV) isolate that it was a PEDV indel strain close to German PEDV strains recently isolated. PMID- 26044420 TI - Draft Genome Sequence of Pseudomonas syringae pv. persicae NCPPB 2254. AB - Pseudomonas syringae pv. persicae is a pathogen that causes bacterial decline of stone fruit. Here, we report the draft genome sequence for P. syringae pv. persicae, which was isolated from Prunus persica. PMID- 26044421 TI - Draft Genome Sequences of Pseudomonas aeruginosa Strain PS3 and Citrobacter freundii Strain SA79 Obtained from a Wound Dressing-Associated Biofilm. AB - Two isolates, one from the genus Pseudomonas and the second from Citrobacter, were isolated from a wound dressing-associated biofilm. Following whole-genome sequencing, the two isolates presented genes encoding for resistance to antibiotics and those involved in exopolysaccharide production. PMID- 26044422 TI - Draft Whole-Genome Sequences of 10 Enterotoxigenic Escherichia coli Serogroup O6 Strains. AB - Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in children under the age of 5 years and in adults living in developing countries, as well as in travelers to these countries. In this announcement, we release the draft whole-genome sequences of 10 ETEC serogroup O6 strains. PMID- 26044423 TI - Draft genome sequence of a halorubrum h3 strain isolated from the burlinskoye salt lake (altai krai, Russia). AB - A Halorubrum H3 strain was isolated from a water and silt sample from Burlinskoye Lake (Altai Krai, Russia, 53 degrees 8'19"N 78 degrees 24'27"E). According to 16S rRNA sequences, this strain is most closely related to Halorubrum saccharovorum. The completely sequenced and annotated genome is 3,282,373 bp and contains 3,237 genes. PMID- 26044424 TI - Draft Genome Sequence of the Toluene-Degrading Pseudomonas stutzeri Strain ST-9. AB - Strain ST-9 was isolated from toluene-contaminated soil (Samaria, Israel). The draft genome has an estimated size of 4.8 Mb, exhibits an average G+C content of 60.37%, and is predicted to encode 4,183 proteins, including a gene cluster for aromatic hydrocarbon degradation. It is assigned to genomovar 3 of Pseudomonas stutzeri. PMID- 26044425 TI - Complete Genome Sequence of Agrobacterium tumefaciens Ach5. AB - Agrobacterium tumefaciens is a phytopathogenic bacterium that causes crown gall disease. The strain Ach5 was isolated from yarrow (Achillea ptarmica L.) and is the wild-type progenitor of other derived strains widely used for plant transformation. Here, we report the complete genome sequence of this bacterium. PMID- 26044426 TI - Draft Genome Sequence of Mycobacterium tuberculosis Strain MT11, Which Represents a New Lineage. AB - We sequenced the genome of Mycobacterium tuberculosis strain MT11, which exhibits a specific 16S rRNA gene mutation found in 6% of French Polynesian M. tuberculosis isolates. It comprises a 4,110,293-bp chromosome with 65.15% G+C content, and it encodes 3,949 proteins and contains 85 predicted RNA genes. The TbD1 region is absent in strain MT11 as in modern M. tuberculosis strains. PMID- 26044427 TI - Draft Genome Sequence of Mycobacterium tuberculosis Strain MT43, a Representative of the Manu2 Genotype. AB - We announce the draft genome sequence of Mycobacterium tuberculosis strain MT43, isolated from a pulmonary form of tuberculosis in French Polynesia. Analyzing its 4,145,007-bp, 65.17% G+C chromosome confirmed a fully antibiotic-susceptible Manu2 spoligotype. PMID- 26044428 TI - Draft Genome Sequence of Staphylococcus gallinarum DSM 20610T, Originally Isolated from the Skin of a Chicken. AB - Staphylococcus gallinarum DSM 20610(T) is a rare pathogen in humans. The increasing relevance of human health prompted us to determine the genomic sequence of S. gallinarum. The complete genome sequence of S. gallinarum includes a genome of 3,171,720 bp (33.02% G+C content) without any plasmids. PMID- 26044429 TI - Genome Sequence of the Potato Plant Pathogen Dickeya dianthicola Strain RNS04.9. AB - Dickeya dianthicola is one of the causative agents of soft rot and blackleg diseases, which are currently identified in European countries in a wide range of crops. Here, we report the draft genome sequence of D. dianthicola strain RNS04.9, which was isolated from a potato plant with blackleg symptoms in 2004. PMID- 26044430 TI - Draft Genome Sequence of Thermoanaerobacter sp. Strain YS13, a Novel Thermophilic Bacterium. AB - Here, we report the draft genome sequence of Thermoanerobacter sp. YS13, isolated from a geothermal hot spring in Yellowstone National Park, which consists of 2,713,030 bp with a mean G+C content of 34.05%. A total of 2,779 genes, including 2,707 protein-coding genes, 12 rRNAs, and 59 tRNAs were identified. PMID- 26044431 TI - Draft genome sequences of two protease-producing strains of arsukibacterium, isolated from two cold and alkaline environments. AB - Arsukibacterium ikkense GCM72(T) and a close relative, Arsukibacterium sp. MJ3, were isolated from two cold and alkaline environments as producers of extracellular proteolytic enzymes active at high pH and low temperature. This report describes the two draft genome sequences, which may serve as sources of future industrial enzymes. PMID- 26044432 TI - Draft Genome Sequence of the Bacterium Lysobacter capsici X2-3, with a Broad Spectrum of Antimicrobial Activity against Multiple Plant-Pathogenic Microbes. AB - Lysobacter capsici strain X2-3 was isolated from the wheat rhizosphere in China and exhibits a remarkable capacity to inhibit the growth of multiple pathogens. Here, we report the draft genome sequence of L. capsici strain X2-3 in China. PMID- 26044433 TI - Draft Genome Sequence of Hydrocarbon-Degrading Pseudomonas putida Strain KG-4, Isolated from Soil Samples Collected from Krishna-Godavari Basin in India. AB - We report here the 5.58-Mb draft genome of Pseudomonas putida strain KG-4 obtained from the oil fields of the Krishna-Godavari basin, Andhra Pradesh, India. The genome sequence is expected to facilitate identification and understanding of genes associated with hydrocarbon metabolism, which can help in developing strategies for managing oil spills and bioremediation. PMID- 26044434 TI - Genome Sequence of Rhodococcus sp. 4J2A2, a Desiccation-Tolerant Bacterium Involved in Biodegradation of Aromatic Hydrocarbons. AB - The genome sequence for Rhodococcus sp. 4J2A2, a newly described desiccation tolerant strain that removes aromatic hydrocarbons, is reported here. The genome is estimated to be around 7.5 Mb in size, with an average G+C content of 60.77% and a predicted number of protein-coding sequences of 6,354. PMID- 26044435 TI - Draft Genome Sequence of Aliivibrio fischeri Strain 5LC, a Bacterium Retrieved from Gilthead Sea Bream (Sparus aurata) Larvae Reared in Aquaculture. AB - To shed light on the putative host-mediated lifestyle of the quintessential marine symbiont Aliivibrio fischeri, and on the symbiosis versus potentially pathogenic features of bacteria associated with farmed fish, we report the draft genome sequence of A. fischeri strain 5LC, a bacterium retrieved from gilthead sea bream (Sparus aurata) larvae. PMID- 26044436 TI - Draft Genome Sequence of Rice Endophyte-Associated Isolate Kosakonia oryzae KO348. AB - Kosakonia oryzae KO348 is an endophytic and plant growth-promoting strain isolated from the roots of rice in Italy. Here, we report the draft genome sequence of Kosakonia oryzae KO348. PMID- 26044437 TI - Draft Genome Sequence of Triclosan-Degrading Bacterium Sphingomonas sp. Strain YL JM2C, Isolated from a Wastewater Treatment Plant in China. AB - Sphingomonas sp. strain YL-JM2C was isolated from a wastewater treatment plant in Xiamen, China, by enrichment on triclosan. The bacterium is of special interest because of its ability to degrade triclosan. Here, we present a draft genome sequence of the microorganism and its functional annotation. To our best knowledge, this is the first report of a draft genome sequence of a triclosan degrading bacterium. PMID- 26044438 TI - Genome Sequence of Anoxybacillus flavithermus Strain AK1, a Thermophile Isolated from a Hot Spring in Saudi Arabia. AB - Anoxybacillus flavithermus strain AK1 was isolated from Al-Ain Alhara, a thermal hot spring located 50 km southeast of the city of Gazan, Saudi Arabia (16 degrees 56'N, 43 degrees 15'E). The sequenced and annotated genome is 2,630,664 bp and encodes 2,799 genes. PMID- 26044439 TI - Draft Genome Sequence of Burkholderia sp. MR1, a Methylarsenate-Reducing Bacterial Isolate from Florida Golf Course Soil. AB - To elucidate the environmental organoarsenical biocycle, we isolated a soil organism, Burkholderia sp. MR1, which reduces relatively nontoxic pentavalent methylarsenate to the more toxic trivalent methylarsenite, with the goal of identifying the gene for the reductase. Here, we report the draft genome sequence of Burkholderia sp. MR1. PMID- 26044440 TI - Correction for Bartoli et al., Whole-Genome Sequencing of 10 Pseudomonas syringae Strains Representing Different Host Range Spectra. PMID- 26044441 TI - Retraction for Abolnik, Complete Genome Sequence of Mycoplasma meleagridis, a Possible Emerging Pathogen in Chickens. PMID- 26044442 TI - Poor utility of grading scales in acute intracerebral hemorrhage: results from the INTERACT2 trial. AB - BACKGROUND: Several simple clinical grading scores have been developed for intracerebral hemorrhage, primarily to predict 30-day mortality. AIMS: We aimed to determine the accuracy of three popular scores (original intracerebral hemorrhage, modified intracerebral hemorrhage, and intracerebral hemorrhage grading scale) on 30-day mortality and 90-day death or major disability, and whether the magnitude of benefit varies according to prognosis graded by the three predictive scores. METHODS: Data from the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial which included 2839 intracerebral hemorrhage patients (<6 hours) and elevated systolic blood pressure (150-220 mmHg), randomized to intensive (target systolic blood pressure <140 mmHg) or guideline-based (<180 mmHg) blood pressure management. Discrimination of scales for predicting death and poor outcome (modified Rankin scale 3-6) was evaluated in area under receiver operator characteristic curves. RESULTS: Among 2556 (90%) participants with available data, the modified intracerebral hemorrhage had the highest discrimination (receiver operator characteristic 0.75) for 90-day poor outcome compared with the original intracerebral hemorrhage (receiver operator characteristic 0.68) and intracerebral hemorrhage grading scale (receiver operator characteristic 0.69). All scores had good positive predictive value (approximately 80-90%) for poor outcome but poor sensitivity and positive predictive value for death. The scores do not clearly discriminate a patient group most likely to benefit from blood pressure lowering. CONCLUSIONS: Intracerebral hemorrhage prognostic scores are not useful in defining patients at high probability of early death, but they are reliable for predicting poor outcome, defined by death or major disability. Potential benefits of early intensive blood pressure lowering are broadly applicable across grades of severity defined by such scores. PMID- 26044443 TI - Effects of Fixed and Removable Space Maintainers on Plaque Accumulation, Periodontal Health, Candidal and Enterococcus Faecalis Carriage. AB - OBJECTIVE: To evaluate the effects of space maintainers on plaque accumulation, periodontal health and oral microflora. SUBJECTS AND METHODS: The study participants comprised 38 patients aged 4-10 years requiring either fixed or removable space maintainers. Plaque index, gingival index, bleeding on probing index, candidal colonization and Enterococcus faecalis were recorded just before the application of space maintainers (T0) and during treatment at the 1st (T1), 3rd (T2) and 6th (T3) month. RESULTS: The gingival and bleeding on probing index scores increased significantly (gingival index from 0.20 +/- 0254 to 0.54 +/- 0417 and bleeding on probing index from 7.18 +/- 9.946 to 18.07 +/- 14.074) in the regions with fixed space maintainers at T3 (p < 0.01). The mean Candida counts also increased (for removable appliances from 1.90 +/- 3.638 to 1.98 +/- 3.318, p < 0.05, and for fixed appliances from 4.25 +/- 4.587 to 4.52 +/- 4.431, p < 0.001). The salivary E. faecalis counts at T3 also increased significantly with the use of fixed and removable appliances (for removable appliances from 5.93 +/- 2.65 to 85.53 +/- 34.1 and for fixed appliances from 4.95 +/- 2.94 to 123.59 +/- 29.51, p < 0.001). A positive correlation was found between the plaque (r = 0.67), gingival (r = 0.76) and bleeding on probing index scores (r = 0.76) and the candidal colonization for the fixed space maintainers (p < 0.01, p < 0.001). CONCLUSIONS: In this study, both fixed and removable space maintainers led to an increase in the number of microorganisms in the oral cavity as well as to increases in the periodontal index scores. Patients should be informed that space maintainers may serve as a source of infection and that special attention must be given to their oral hygiene. PMID- 26044444 TI - Identification of Candidate Biomarkers in Peripheral Blood for Cardiac Allograft Rejection based on Bioinformatics Analysis. AB - BACKGROUND: Cardiac allograft rejection (AR) can cause graft dysfunction and even mortality, and an early noninvasive diagnosis of cardiac AR is required. This study aims to identify candidate biomarkers in peripheral blood for cardiac AR, which might benefit early diagnosis. MATERIAL AND METHODS: Gene expression profile (ID: GSE5967) of peripheral blood from cardiac allograft recipients was achieved from the Gene Expression Omnibus database, including 7 chips in rejection group, 7 chips in post-rejection group, and 7 chips in control group. After data preprocessing, limma package was used to screen the differentially expressed genes (DEGs) between these groups (|log2 fold change| >=0.58, and p value <0.05). Then, online software DAVID was utilized to study the pathways and functions involving these DEGs (p-value <0.05). RESULTS: Totally, 21 up-regulated and 16 down-regulated DEGs were identified between rejection and control groups, and up-regulated DEGs were mainly enriched in bio-functions about translation and ribosome. Furthermore, 3 up-regulated and 14 down-regulated DEGs were identified between post-rejection and control groups. The down-regulated DEGs in 2 contrast groups were mainly enriched in bio-functions about lipid biosynthesis and membrane. CONCLUSIONS: RPL7, RPL11, RPS23, RPS25, SCD5, CSF3R, and FPR1 were predicted as candidate biomarkers in peripheral blood for monitoring cardiac AR. The up-regulation of RPL7, RPS25, RPS23, and RPL11 might promote the translation of AR-related cytokines, and the down-regulation of SCD5, CSF3R, and FPR1 might reduce the stability of cell membrane, mediating cytokines secretion and the phagocytosis of macrophages. However, further studies are required to validate these predictions. PMID- 26044445 TI - A novel, minimally invasive technique for management of peristomal varices. PMID- 26044446 TI - Multifunctional Architectures Constructing of PANI Nanoneedle Arrays on MoS2 Thin Nanosheets for High-Energy Supercapacitors. AB - Multifunctional MoS2 @PANI (polyaniline) pseudo-supercapacitor electrodes consisting of MoS2 thin nanosheets and PANI nanoarrays are fabricated via a large scale approach. The superior capacitance retention is retained up to 91% after 4000 cycles and a high energy density of 106 Wh kg(-1) is delivered at a power density of 106 kW kg(-1) . PMID- 26044447 TI - A web-based cognitive behaviour therapy for chronic fatigue in type 1 diabetes (Dia-Fit): study protocol for a randomised controlled trial. AB - BACKGROUND: Fatigue is frequently reported by patients with type 1 diabetes mellitus. A recent study showed that 40 % of patients experienced severe fatigue that lasted for more than six months and was accompanied by substantial impairments in daily functioning. Currently, there is no effective treatment available for chronic fatigue in patients with type 1 diabetes. Cognitive behaviour therapy aimed at cognitions and behaviours that perpetuate fatigue is effective in reducing fatigue in other chronic diseases. Recent research showed that these cognitions and behaviours are also potential determinants of fatigue in type 1 diabetes. We designed Dia-Fit, a web-based cognitive behaviour therapy for severe and chronic fatigue in patients with type 1 diabetes. This patient tailored intervention is aimed at reducing fatigue by changing cognitions and behaviours assumed to maintain fatigue. The efficacy of Dia-Fit will be investigated in this study. METHODS/DESIGN: A randomised controlled trial will be conducted in 120 patients with type 1 diabetes who are chronically and severely fatigued. Patients will be randomised to a treatment or waiting list group. The treatment group will receive Dia-Fit, a blended care therapy consisting of up to eight internet modules and face-to-face sessions with a therapist during a five month period. The treatment will be tailored to the fatigue-maintaining cognitions and behaviours that are relevant for the patient and are determined at baseline. The waiting list group will receive Dia-Fit after a waiting period of five months. The primary outcome measure is fatigue severity. Secondary outcome measures are functional impairment and glucose control determined by haemoglobin A1c and blood glucose variability. DISCUSSION: To our knowledge, this is the first study investigating the efficacy of a cognitive behavioural intervention for chronic fatigue in patients with type 1 diabetes. TRIAL REGISTRATION: Dutch trial register NTR4312 (10 December 2013). PMID- 26044448 TI - Management of degenerative meniscal tears and the role of surgery. PMID- 26044450 TI - Self-reported exhaustion associated with physical activity among older adults. AB - AIM: Self-reported exhaustion (SE) is a clinical complaint that is associated with a wide range of chronic diseases. However, the association of SE with physical activity, physical function or cognitive function among the older adult Japanese population is unclear. The present study aimed to determine the prevalence of SE, as well as whether physical function, cognitive function and physical activity were significant covariates. METHODS: A total of 4607 adults (mean age 71 years) were considered eligible for participation based on the study criteria. SE was evaluated using the Study of Osteoporotic Fracture Index. We also evaluated physical activity, physical function (grip strength, Timed Up & Go) and cognitive function (Mini-Mental State Examination, Trail Making Test part A and B, Symbol Digit Substitution Task). RESULTS: The prevalence of SE ranged from 40.9% to 55.0%, and significantly increased with age. The results of the multiple logistic regression analyses showed that in the adjusted model of the 65 69 years age group, physical activity, Timed Up & Go and Symbol Digit Substitution Task were independently associated with SE. In the 70-79 years age group, physical activity, Timed Up & Go, Trail Making Test part A and B and Symbol Digit Substitution Task were independently associated with exhaustion. Only physical activity was associated with exhaustion in the >=80 years age group. CONCLUSIONS: The prevalence of SE increased with age in the older adult Japanese population. Exhaustion was strongly associated with reduced daily physical activity, especially in those aged >=80 years. Further studies should be carried out to determine if physical activity causes SE. Geriatr Gerontol Int 2016; 16: 625-630. PMID- 26044454 TI - A salute to Dr. Ford on the 50th anniversary of nurse practitioners. PMID- 26044455 TI - Expanding the Imine Reductase Toolbox by Exploring the Bacterial Protein-Sequence Space. AB - Recent investigations on imine reductases (IREDs) have enriched the toolbox of potential catalysts for accessing chiral amines, which are important building blocks for the pharmaceutical industry. Herein, we describe the characterization of 20 new IREDs. A C-terminal domain clustering of the bacterial protein-sequence space was performed to identify the novel IRED candidates. Each of the identified enzymes was characterized against a set of nine cyclic imine model substrates. A refined clustering towards putative active-site residues was performed and was consistent both with our screening and previously reported results. Finally, preparative scale experiments on a 100 mg scale with two purified IREDs, IR_20 from Streptomyces tsukubaensis and IR_23 from Streptomyces vidiochromogenes, were carried out to provide (R)-2-methylpiperidine in 98% ee (71% yield) and (R)-1 methyl-1,2,3,4-tetrahydroisoquinoline in >98% ee (82% yield). PMID- 26044451 TI - Clinical significance of newly emerged isolated del(20q) in patients following cytotoxic therapies. AB - Deletion 20q is a common chromosomal abnormality in myeloid neoplasms. Detection of del(20q) in patients following cytotoxic therapies raises concerns for an emerging therapy-related myeloid neoplasm. In this study, we identified 92 patients who acquired isolated del(20q) in their bone marrow following cytotoxic therapies for malignant neoplasms. Seventy-six patients showed interstitial and sixteen patients showed terminal 20q deletion. The median interval from prior cytotoxic therapies to detection of del(20q) was 58 months (range, 5-213 months). With a median follow-up of 23 months (range, 1-183 months), 21 (23%) patients developed therapy-related myeloid neoplasm and 71 (77%) patients did not. In patients who developed therapy-related myeloid neoplasm, del(20q) presented in a higher percentage of metaphases (60 vs 25%, P<0.0001); persisted for a longer period of time (24 vs 10 months, P=0.0487); and was more often a terminal deletion (33 vs 13%, P=0.0006) compared with patients who did not develop therapy related myeloid neoplasm. Clonal evolution was only detected in patients with therapy-related myeloid neoplasm (4 patients, 19%). We conclude that del(20q) emerging after cytotoxic therapy represents an innocuous finding in more than two thirds of patients. In patients who develop a therapy-related myeloid neoplasm, del(20q) often involves a higher percentage of metaphases, persists longer and more frequently is a terminal rather than an interstitial deletion. PMID- 26044456 TI - Association of serum lipids with outcomes in Hispanic hemodialysis patients of the West versus East Coasts of the United States. AB - BACKGROUND: Paradoxical associations exist between serum lipid levels and mortality in patients on maintenance hemodialysis (MHD) including those of Hispanic origin. However, there are significant racial and ethnic variations in patients of 'Hispanic' background. We hypothesized that clinically meaningful differences existed in the association between lipids and survival in Hispanic MHD patients on the West versus East Coast. METHODS: We examined the survival impact of serum lipids in a 2-year cohort of 15,109 MHD patients of Hispanic origin being treated in California, Texas, representing the West versus New York, New Jersey and Florida representing the East Coast, using Cox models with various degrees of adjustments. RESULTS: The association of serum total and HDL cholesterol with mortality follows a U-shaped pattern in Hispanic patients residing in the West. This is in contrast to Hispanic patients in the East Coast whose survival seems to improve with increasing total and HDL cholesterol levels. Elevated serum LDL levels in Hispanic patients on the West Coast are associated with a significant increase in mortality, while this association is not observed in patients residing on the East Coast. CONCLUSIONS: Substantial differences exist in the association of serum lipids with mortality in MHD patients of Hispanic background depending on whether they reside on the West or East Coast of the United States. These geographical variances most likely reflect ethnic, racial and genetic distinctions, which are usually ignored. Future studies should take into account these critical variations in a population of patients who make up a significant portion of our society. PMID- 26044458 TI - Evidenced-based management of haemoptysis by otolaryngologists. AB - BACKGROUND: Haemoptysis is an uncommon presenting symptom to the ENT clinic and ward, but has potentially sinister aetiology. This article aims to provide a systematic and evidence-based method of managing patients with haemoptysis. METHODS: The data in this article are based on a literature search performed using PubMed in August 2013. The keywords used included 'haemoptysis' in combination with 'otolaryngology', 'ENT', 'head & neck', 'diagnosis', 'management', 'investigations' and 'treatment'. RESULTS: The majority of published literature on the subject is level IV evidence. However, this can guide ENT specialists in assessing, investigating and managing presentations of haemoptysis. CONCLUSION: Understanding the different causes of haemoptysis is important for the otolaryngologist. The main concern is the detection of a malignant lesion in the upper aerodigestive tract or tracheobronchial tree. A thorough history and systematic examination can aid diagnosis. PMID- 26044459 TI - The American College of Cardiology and Maintenance of Certification: The Path Forward. PMID- 26044457 TI - Diffuse large B-cell lymphoma presenting with central pontine myelinolysis: a case report. AB - INTRODUCTION: The most common cause of central pontine myelinolysis is an overly rapid correction of hyponatremia, although it can also occur in patients with any condition leading to nutritional or electrolyte stress. We report a case of diffuse large B-cell lymphoma with central pontine myelinolysis developing at the onset of disease. To the best of our knowledge, hematological malignancies presenting with central pontine myelinolysis have been rarely reported, especially in previously untreated patients, as in our case report. CASE PRESENTATION: A 78-year-old Japanese woman presented to a neighborhood clinic with persistent high fever, edema, and general weakness. Despite the absence of specific neurological findings, brain magnetic resonance imaging showed an abnormal lesion in the central pons area of her brain (hyperintense on T2 weighted and hypointense on T1-weighted sequences), compatible with central pontine myelinolysis. She was admitted to our emergency department in a state of shock one month later. The results of her blood tests showed greatly elevated C reactive protein and lactate dehydrogenase levels. She had severe hypoalbuminemia and mild hyponatremia, and showed signs of disseminated intravascular coagulation. Mild bilateral pleural effusion, prominent subcutaneous edema, and splenomegaly were detected on her systemic computed tomography scan. Her body fluid cultures did not show signs of infection and her spinal aspiration did not show pleocytosis or abnormal cells. A diagnosis of diffuse large B-cell lymphoma was made based on the results of her bone marrow examination. As she was critically ill before the diagnosis was made, she was treated with methylprednisolone pulse therapy, followed by systemic chemotherapy (rituximab with modified THP-COP regimen, including cyclophosphamide, pirarubicin, vindesine, and prednisolone), which resulted in complete remission and recovery without any neurological defects, and resolution of her abnormal findings on magnetic resonance imaging. CONCLUSIONS: Central pontine myelinolysis is a serious condition that may result in neuropathological sequelae and mortality, and clinicians should be aware of its potential presence in patients with malignancies. PMID- 26044460 TI - Theoretical model of ice nucleation induced by acoustic cavitation. Part 1: Pressure and temperature profiles around a single bubble. AB - This paper deals with the inertial cavitation of a single gas bubble in a liquid submitted to an ultrasonic wave. The aim was to calculate accurately the pressure and temperature at the bubble wall and in the liquid adjacent to the wall just before and just after the collapse. Two different approaches were proposed for modeling the heat transfer between the ambient liquid and the gas: the simplified approach (A) with liquid acting as perfect heat sink, the rigorous approach (B) with liquid acting as a normal heat conducting medium. The time profiles of the bubble radius, gas temperature, interface temperature and pressure corresponding to the above models were compared and important differences were observed excepted for the bubble size. The exact pressure and temperature distributions in the liquid corresponding to the second model (B) were also presented. These profiles are necessary for the prediction of any physical phenomena occurring around the cavitation bubble, with possible applications to sono-crystallization. PMID- 26044461 TI - Ultrasound Guided High Intensity Focused Ultrasound for malignant tumors: The Spanish experience of survival advantage in stage III and IV pancreatic cancer. AB - We described the experience of the HIFU Onco Unit of Hospital University Mutua Terrassa (Barcelona, Spain) treating malignant tumors, focusing on results of unresectable pancreatic tumors treated with Ultrasound Guided High Intensity Focused Ultrasound (USgHIFU) hyperthermia ablation in combination with adjuvant chemotherapy. MATERIALS AND METHODS: From February 2008 to December 2013, we treated 140 malignant cases. Of those, 48 cases of unresectable pancreatic tumors were treated from March 2010 to December 2013, and the first 43 were included in the analysis. All the 43 cases (29 cases of stage III and 14 cases of stage IV) were treated with systemic chemotherapy. Clinical responses (thermical ablation achieved) were measured by image techniques, and complications were also recorded and analyzed. RESULTS: The majority of the 140 cases treated at our HIFU center were pancreatic and liver tumors, among which 43 cases of pancreatic tumors were analyzed. Clinical responses (ablation obtained) were observed in 82% of the cases, and the responses lasted at 8 weeks post-procedure. We obtained 11 complete responses (25%) at the end of the combined treatment, nine from stage III patients and two from stage IV patients. Major complications included severe pancreatitis with GI bleeding (1), and skin burning of grade III that required plastic surgery (2). The median survival was 13 months (6 months-2.7 years). No deaths were registered during the course of the treatment. CONCLUSIONS: HIFU is a potentially effective and safe modality for the treatment of malignant tumors. HIFU proves to have a survival advantage in treating unresectable pancreatic cancer. PMID- 26044462 TI - Blinding in pharmaceutical clinical trials: An overview of points to consider. AB - Blinding is a corner-stone for the robustness of many clinical trials. Achieving a robust level of trial blinding involves close partnership across a number of trial disciplines, and numerous challenges can arise. This paper provides a wide ranging overview of issues to consider in managing blinding, including clinical and statistical considerations, supply planning and inventory management strategy, and the management and disclosure of unplanned unblinding events that arise during trial conduct. PMID- 26044464 TI - The Vitality, Independence, and Vigor in the Elderly 2 Study (VIVE2): Design and methods. AB - BACKGROUND: Nutritional supplementation may potentiate the increase in skeletal muscle protein synthesis following exercise in healthy older individuals. Whether exercise and nutrition act synergistically to produce sustained changes in physical functioning and body composition has not been well studied, particularly in mobility-limited older adults. METHODS: The VIVE2 study was a multi-center, randomized controlled trial, conducted in the United States and Sweden. This study was designed to compare the effects of a 6-month intervention with a once daily, experimental, 4 fl.oz. liquid nutritional supplement providing 150 kcal, whey protein (20 g), and vitamin D (800 IU) (Nestle Health Science, Vevey, Switzerland), to a low calorie placebo drink (30 kcal, non-nutritive; identical format) when combined with group-based exercise in 150 community-dwelling, mobility-limited older adults. All participants participated in a structured exercise program (3 sessions/week for 6 months), which included aerobic, strength, flexibility, and balance exercises. RESULTS: The primary outcome was 6 month change in 400 m walk performance (m/s) between supplement and placebo groups. Secondary outcomes included 6 month change in: body composition, muscle cross-sectional area, leg strength, grip strength, stair climb time, quality of life, physical performance, mood/depressive symptoms and nutritional status. These outcomes were selected based on their applicability to the health and well being of older adults. CONCLUSIONS: The results of this study will further define the role of nutritional supplementation on physical functioning and restoration of skeletal muscle mass in older adults. Additionally, these results will help refine the current physical activity and nutritional recommendations for mobility limited older adults. PMID- 26044463 TI - FAmily CEntered (FACE) advance care planning: Study design and methods for a patient-centered communication and decision-making intervention for patients with HIV/AIDS and their surrogate decision-makers. AB - Although the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has become a chronic illness, disease-specific advance care planning has not yet been evaluated for the palliative care needs of adults with HIV/AIDS. This prospective, longitudinal, randomized, two-arm controlled clinical trial aims to test the efficacy of FAmily CEntered advance care planning among adults living with AIDS and/or HIV with co-morbidities on congruence in treatment preferences, healthcare utilization, and quality of life. The FAmily CEntered intervention arm is two face-to-face sessions with a trained, certified facilitator: Session 1) Disease-Specific Advance Care Planning Respecting Choices Interview; Session 2) Completion of advance directive. The Healthy Living Control arm is: Session 1) Developmental/Relationship History; Session 2) Nutrition. Follow-up data will be collected at 3, 6, 12, and 18 months post-intervention. A total of 288 patient/surrogate dyads will be enrolled from five hospital-based, out-patient clinics in Washington, District of Columbia. Participants will be HIV positive and >= 21 years of age; surrogates will be >= 18 years of age. Exclusion criteria are homicidality, suicidality, psychosis, and impaired cognitive functioning. We hypothesize that this intervention will enhance patient-centered communication with a surrogate decision-maker about end of life treatment preferences over time, enhance patient quality of life and decrease health care utilization. We further hypothesize that this intervention will decrease health disparities for Blacks in completion of advance directives. If proposed aims are achieved, the benefits of palliative care, particularly increased treatment preferences about end-of-life care and enhanced quality of life, will be extended to people living with AIDS. PMID- 26044465 TI - Novel insights in SHBG regulation and clinical implications. AB - Sex hormone-binding globulin (SHBG) is produced and secreted by the liver into the bloodstream where it binds sex steroids and regulates their bioavailability. Traditionally, body mass index (BMI) was thought to be the major determinant of SHBG concentrations and hyperinsulinemia the main cause for low SHBG levels found in obesity. However, no mechanisms have ever been described. Emerging evidence now shows that liver fat content rather than BMI is a strong determinant of circulating SHBG. In this review we discuss evidence demonstrating that insulin might not regulate SHBG production, describe putative molecular mechanisms by which proinflammatory cytokines downregulate SHBG, and comment on recent findings suggesting dietary SHBG regulation. Finally, clinical implications of all of these findings and future perspectives are discussed. PMID- 26044466 TI - Plagiarism--one disease, many manifestations. PMID- 26044467 TI - Reproducibility of retinal nerve fiber layer measurements across the glaucoma spectrum using optical coherence tomography. AB - PURPOSE: The purpose was to determine intra-session and inter-session reproducibility of retinal nerve fiber layer (RNFL) thickness measurements with the spectral-domain Cirrus optical coherence tomography (OCT) (r) (SD-OCT) in normal and glaucomatous eyes, including a subset of advanced glaucoma. MATERIALS AND METHODS: RNFL measurements of 40 eyes of 40 normal subjects and 40 eyes of 40 glaucomatous patients including 14 with advanced glaucoma were obtained on the Cirrus OCT (r) (Carl Zeiss Meditec, Dublin, CA, USA) five times on 1-day (intra session) and on five separate days (inter-session). Intraclass correlation coefficient (ICC), coefficient of variation (COV), and test-retest variability (TRT) values were calculated for mean and quadrant RNFL in each group separately. Reproducibility values were correlated with age and stage of glaucoma. RESULTS: For intra-session reproducibility, the ICC, COV, and TRT values for mean RNFL thickness in normal eyes were 0.993, 1.96%, and 4.02 um, respectively, 0.996, 2.39%, and 3.84 um in glaucomatous eyes, and 0.996, 2.41%, and 3.70 um in advanced glaucoma. The corresponding inter-session values in normal eyes were 0.992, 2.16%, and 4.09 um, 0.995, 2.62%, and 3.98 um in glaucoma and 0.990, 2.70%, and 4.16 um in advanced glaucoma. The mean RNFL thickness measurements were the most reproducible while the temporal quadrant had the lowest reproducibility values in all groups. There was no correlation between reproducibility and age or mean deviation on visual fields. CONCLUSIONS: Peripapillary RNFL thickness measurements using Cirrus OCT (r) demonstrated excellent reproducibility in normal and glaucomatous eyes, including eyes with advanced glaucoma. Mean RNFL thickness measurements appear to be the most reproducible and probably represent the best parameter to use for longitudinal follow-up. PMID- 26044468 TI - Ophthalmic surgical training in Karnataka and Southern India: Present status and future interests from a survey of final-year residents. AB - SETTINGS AND DESIGN: This study documents a survey of final-year ophthalmology postgraduates on the subject of their surgical training and their future plans after residency. PURPOSE: This survey aimed to answer the question, "What is the present status of surgical training in ophthalmic training centers?" by obtaining information from students about (1) various methods used in surgical training (2) numbers and types of surgeries performed by them in the training centers (3) their plans after residency. MATERIALS AND METHODS: A questionnaire containing 21 questions was distributed to 155 students attending an intensive 4-day teaching program. The questions related to orientation training, wet lab training, facilities for training, free surgical camps and detailed information about numbers and types of surgeries observed and performed. Completed questionnaires were collected, and responses analyzed. RESULTS: One hundred and seven completed responses were analyzed. The majority had not received formal orientation training. More than half had undergone wet lab training. Most residents performed their first ophthalmic surgery during the 1 st year of residency and went to the operation theatre multiple times a week. Most of the students planned to undergo further training after residency. More than half of the students found their surgical training to be fair or satisfactory. CONCLUSIONS: The number and frequency of ophthalmic surgeries done by residents appear satisfactory, but further efforts from trainers on enhancing the quality and range of surgical training would benefit students and improve their satisfaction. PMID- 26044469 TI - Comparison of aqueous concentrations of angiogenic and inflammatory cytokines based on optical coherence tomography patterns of diabetic macular edema. AB - PURPOSE: The purpose was to compare aqueous inflammatory and angiogenic cytokine levels in diabetic macular edema (DME). MATERIALS AND METHODS: Aqueous samples were obtained from 50 eyes with DME and 12 normal eyes (control group). DME was classified according to the morphologic pattern based on optical coherence tomography: Diffuse retinal thickening (DRT; n = 19), cystoid macular edema (CME; n = 17), or serous retinal detachment (SRD; n = 14). Aqueous samples were collected just before intravitreal injection and at the beginning of cataract surgery in the control group. Interleukin (IL)-6, IL-8, interferon-induced protein (IP)-10, monocyte chemotactic protein (MCP)-1, platelet-derived growth factor (PDGF)-AA, and vascular endothelial growth factor (VEGF) levels were measured by multiplex bead assay. RESULTS: The IL-6, IL-8, IP-10, and PDGF-AA levels differed significantly among the three groups of DME (P = 0.014, P = 0.038, P = 0.021, and P = 0.041, respectively). However, there were no differences between groups in aqueous concentration levels of MCP-1 and VEGF (P = 0.205 and P = 0.062, respectively). IL-6 (P = 0.026) and IL-8 (P = 0.023) correlated positively with central foveal thickness (CFT) in the CME group. None of the cytokine levels correlated significantly with CFT in any of the DRT and SRD groups. CONCLUSIONS: Aqueous concentrations of cytokines varied according to the morphologic pattern of DME, which might explain the variable response to treatments such as intravitreal bevacizumab or triamcinolone injection. PMID- 26044470 TI - Pulse cyclophosphamide therapy in the management of patients with macular serpiginous choroidopathy. AB - PURPOSE: To evaluate safety and efficacy of intravenous pulse cyclophosphamide (CyP) in acute macular serpiginous choroiditis (SC). METHODS: Patients with acute macular SC with lesions threatening and/or involving fovea were enrolled. All patients received CyP (1 g/m2) for 3 days followed by high-dose oral steroids (1.5 mg/kg) tapered over 6 months and monitored for visual acuity, response to treatment and systemic side effects. RESULTS: Eight patients (seven unilateral and one bilateral) with median age of 27 years (range: 13-40 years) were recruited. Mean visual acuity at presentation was 0.71 +/- 0.35 logarithm of the minimum angle of resolution while postpulse visual acuity was 0.40 +/- 0.32. Final mean visual acuity at 1-year was 0.31 +/- 0.23 (P <= 0.05). Three eyes had recurrence and 3 patients developed transient hair loss with no other adverse effect. CONCLUSION: Intravenous CyP provides rapid resolution of lesion activity and thereby helps in maintaining good functional acuity. PMID- 26044472 TI - In vivo confocal microscopy of meibomian glands and palpebral conjunctiva in vernal keratoconjunctivitis. AB - PURPOSE: To investigate the correlations between conjunctival inflammatory status and meibomian gland (MG) morphology in vernal keratoconjunctivitis (VKC) patients by using in vivo confocal microscopy (CM). MATERIALS AND METHODS: Nineteen VKC patients (7 limbal, 7 tarsal, and 5 mixed forms) and 16 normal volunteers (controls) were enrolled. All subjects underwent CM scanning to obtain the images of upper palpebral conjunctiva and MGs. Inflammatory cell (IC) density in palpebral conjunctival epithelial and stromal layers, Langerhans cell (LC) density at lid margins and the stroma adjacent to the MG, and MG acinar unit density (MGAUD) were recorded. The longest and shortest diameters of MG acinar were measured. The Kruskal-Wallis test was used to compare the parameter differences whereas the Spearman's rank correlation analysis was applied to determine their correlations. RESULTS: Among all groups, no significant statistical differences were found in epithelial and stromal IC densities, mean values of MG acinar unit densities, or longest and shortest diameters. Both LC parameters in the tarsal-mixed groups were significantly higher than those in the limbal and control groups. All LC densities of VKC patients showed a positive correlation with MGAUD and shortest diameter. CONCLUSIONS: In VKC patients, the conjunctival inflammatory status could be associated with the MG status. In vivo CM is a noninvasive, efficient tool in the assessment of MG status and ocular surface. PMID- 26044471 TI - Comparison of intraocular pressure measurement with Scheimpflug-based noncontact tonometer with and without hydrogel contact lenses. AB - OBJECTIVES: The objective was to determine the repeatability of intraocular pressure (IOP) measurements made through a soft contact lens (CL) using the Scheimpflug noncontact tonometry in healthy subjects. METHODS: This prospective, randomized, single-center study included one eye of 88 subjects (40 male and 48 female). Only participants without glaucoma or any other ocular pathology were included in this study. Three consecutive IOP measurements by the Scheimpflug noncontact tonometry were performed with and without daily disposable hydrogel CLs (-0.50 DS) (Dailies-nelfilcon A, 69% water, 8.7 mm base curve, 14 mm diameter, center thickness 0.10 mm) by a single operator. To avoid any bias arising from diurnal variation, all measurements were made at a similar time of day (11 am +/- 1 h). The repeatability of IOP measurements using the Scheimpflug noncontact tonometry with and without CLs was evaluated using Pearson's correlation analysis. Bland-Altman plotting was used to assess the limits of agreement between the measurements with and without CLs. RESULTS: The mean (+/- standard deviation) IOPs with and without CL were 13.80 +/- 2.70 and 13.79 +/- 2.54 mm of Hg respectively. The mean difference was 0.01 +/- 0.16 (95% confidence interval, +1.97 to - 2.00) mm Hg. Statistical analysis via paired t-test showed no statistical difference between the two groups with (P = 0.15). A good correlation was found for IOP measurements with and without CL (r = 0.93, P < 0.001). Good test-retest reliability was found when IOP was measured with and without CL. CONCLUSION: There was no significant difference between IOP measured with and without CLs by Scheimpflug noncontact tonometry. PMID- 26044473 TI - Intra-arterial chemotherapy for retinoblastoma: First Indian report. AB - AIM: To describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC) for retinoblastoma (RB) in Indian eyes. MATERIALS AND METHODS: Single center, retrospective interventional case series of 6 eyes with RB who underwent IAC using Melphalan (3 mg/5 mg/7.5 mg) and topetecan (1 mg) (n = 4) or melphalan (3 mg/5 mg/7.5 mg) alone (n = 2) between December 2013 and June 2014. In all, 17 IAC procedures were performed using selective ophthalmic artery cannulation. Treatment outcomes were evaluated in terms of tumor control, vitreous and subretinal seeds control and globe salvage rates. RESULTS: IAC was employed as primary (n = 1) or secondary (n = 5) modality of treatment. Each eye received mean 3 IAC sessions (median: 3; range: 1-4 sessions). Eyes were classified according to international classification of RB as Group B (n = 1), C (n = 1), D (n = 2) and E (n = 2). Following IAC, complete regression of the main tumor was seen in 3 cases (50%), partial regression in 2 (33%), while 1 case (15%) showed no response. Of 4 eyes with subretinal seeds, 1 (25%) eye had complete regression while 3 (75%) eyes had partial regression. Of 5 eyes with vitreous seeds, 2 (40%) eyes had complete regression while 3 (60%) eyes had a partial response. Globe salvage was achieved in 5 of 6 eyes (83%). Diffuse choroidal atrophy and vitreous hemorrhage were observed in 1 (17%) eye, each. No hematologic toxicity or cerebro-vascular events were observed. Mean follow-up period was 5.5 months (median: 6 months, range: 1-6 months). CONCLUSION: IAC is an effective therapy for globe preservation in eyes with RB. Larger studies with longer follow-up are required to validate these results. PMID- 26044475 TI - Isolated superior oblique myositis causing acquired Brown's syndrome. PMID- 26044474 TI - Mitomycin-C in dacryocystorhinostomy: From experimentation to implementation and the road ahead: A review. AB - Dacryocystorhinostomy (DCR) is the procedure of choice in patients with epiphora due to primary acquired nasolacrimal duct obstruction. The evolution of surgical tools, fiber-optic endoscopes, effective anesthesia techniques, and the adjunct use of antimetabolites intraoperatively; namely mitomycin-C (MMC) have significantly contributed to the advancement of DCR surgery. MMC is a systemic chemotherapeutic agent derived from Streptomyces caespitosus that inhibits the synthesis of DNA, cellular RNA, and protein by inhibiting the synthesis of collagen by fibroblasts. Even the cellular changes in the human nasal mucosal fibroblasts induced by MMC at an ultrastructural level have been documented. There, however, seems to be a lack of consensus regarding MMC: The dosage, the route of delivery/application, the time of exposure and subsequently what role each of these variables plays in the final outcome of the surgery. In this review, an attempt is made to objectively examine all the evidence regarding the role of MMC in DCR. MMC appears to improve the success rate of DCR. PMID- 26044476 TI - Spectral domain optical coherence tomography in the diagnosis and monitoring of dengue maculopathy. PMID- 26044477 TI - A case of acute postoperative keratitis after deep anterior lamellar keratoplasty by multidrug resistant Klebsiella. AB - A healthy lady of 42 years underwent deep anterior lamellar keratoplasty for granular dystrophy. The very next day, it was complicated by development of infectious keratitis. The organism was identified as multidrug resistant Klebsiella pneumoniae. Donor corneal button may be implicated in the transmission of infection in an otherwise uneventful surgery and follow-up. Nosocomial infections are usually severe, rapidly progressive and difficult to treat. Finally, the lady had to undergo therapeutic penetrating keratoplasty for complete resolution of infection. PMID- 26044478 TI - Bilateral optic disc pit with maculopathy in a patient with cleft lip and cleft palate. AB - Optic disc pit (ODP) is small, gray-white, oval depression found at the optic nerve head. It is a congenital defect that occurs due to imperfect closure of superior edge of the embryonic fissure. Cleft lip and palate are also congenital midline abnormalities occurring due to defect in the fusion of frontonasal prominence, maxillary prominence and mandibular prominence. There is only one case report describing the occurrence of ODP in a young patient with cleft lip and palate who also had basal encephalocele. We describe a 52-year-old patient with congenital cleft lip and palate with bilateral ODP with maculopathy but without any other midline abnormality. PMID- 26044479 TI - Bilateral macular colobomata: Temporal dragging of optic disc. AB - A 13-year-old male presented with decreased vision and squint from childhood. He had bilateral large colobomata at the macula in each eye, the one on the right being larger than the left. The disc was dragged temporally with straightening of the temporal retinal vessels. This is a case report of bilateral large macular coloboma and serves to report its association with a temporally dragged disc and straightened temporal retinal vessels. A dragged disc if present with a colobomatous defect at the macula may strengthen the case for diagnosis of macular coloboma and help exclude other differentials. PMID- 26044480 TI - Ligneous conjunctivitis in a patient of juvenile colloid milia: A rare association. AB - We present to you, case of a 10-year-old female with h/o redness, watering since 8 months. Her vision was 20/30 in right eye and 20/70 in left eye. Conjunctiva had plenty of purulent discharge and palpebral conjunctiva was studded with membranous lesions. She was found to have multiple hyperpigmented papulopustular lesions over face, palms and legs. She was started with topical moxifloxacin and lubricating drops. Patient was followed-up after 15 days. At that time her conjunctiva had formation of a woody pseudomembrane. Excision of the lesions and skin biopsy was done and sent for hislopathological examination. Findings of histopathological examination were suggestive of ligneous conjunctivitis and juvenile colloid milia. We have started this patient with long-term cyclosporine drops and tear supplements. In next visit, the membrane was resolved. Hence, we continued with the same treatment, but again the woody membrane recurred. PMID- 26044481 TI - No evidence for a genetic blueprint: The case of the "complex" mammalian photoreceptor. AB - Despite the intensity of the search for genes causing inherited retinal degenerations over the past 3 decades, of the approximately 200 disease genes identified to date, all appear to be ordinary housekeeping genes specifying proteins playing basic structural and functional roles in the mature photoreceptor cells. No genes or genetic elements have been identified which can be construed as having a specific morphogenic role, directing the development of the cytoarchitecture of any particular retinal cell. The evidence suggests that the cytoarchitecture of the retinal photoreceptors, although enormously complex, arises from the self-organization of the cells constituents without any regulation or direction from an external genetic blueprint. PMID- 26044482 TI - Isolated clival metastasis as the cause of abducens nerve palsy in a patient of breast carcinoma: A rare case report. AB - Metastatic lesions to the clivus have been reported in various cancers including lung cancer, prostate carcinoma, skin melanoma, and hepatocellular carcinoma. There have been only a few reports of breast cancer presenting with isolated clival metastasis. We report a case of 35-year-old lady, who was known case of breast carcinoma presented with diplopia as the only sign of clival metastasis. The etiology was established by magnetic resonance imaging which showed an enhancing lesion in the clivus. The diagnosis of clival metastasis from breast cancer was confirmed by transsphenoidal biopsy. PMID- 26044483 TI - Considerations in the management of aphakia. PMID- 26044484 TI - Comment on: Augmented surgical amounts for intermittent exotropia to prevent recurrence. PMID- 26044485 TI - Etiology and clinical profile of childhood optic nerve atrophy at a tertiary eye care center in South India. PMID- 26044486 TI - Comparison of clinical outcomes, patient and surgeon satisfaction following topical versus peribulbar anesthesia for phacoemulsification: A randomized controlled trial. PMID- 26044487 TI - Full thickness macular hole following intravitreal ranibizumab injection for diabetic macular edema; a rare complication or coincidence? PMID- 26044488 TI - Author response: Repeat gas insufflation for successful closure of idiopathic macular hole following failed primary surgery. PMID- 26044489 TI - Bilateral optic neuropathy and intraretinal deposits after pars plana vitrectomy in amyloidosis: Erratum. PMID- 26044490 TI - Antagonism Between Saturated and Unsaturated Fatty Acids in ROS Mediated Lipotoxicity in Rat Insulin-Producing Cells. AB - BACKGROUND/AIMS: Elevated levels of non-esterified fatty acids (NEFAs) are under suspicion to mediate beta-cell dysfunction and beta-cell loss in type 2 diabetes, a phenomenon known as lipotoxicity. Whereas saturated fatty acids show a strong cytotoxic effect upon insulin-producing cells, unsaturated fatty acids are not toxic and can even prevent toxicity. Experimental evidence suggests that oxidative stress mediates lipotoxicity and there is evidence that the subcellular site of ROS formation is the peroxisome. However, the interaction between unsaturated and saturated NEFAs in this process is unclear. METHODS: Toxicity of rat insulin-producing cells after NEFA incubation was measured by MTT and caspase assays. NEFA induced H2O2 formation was quantified by organelle specific expression of the H2O2 specific fluorescence sensor protein HyPer. RESULTS: The saturated NEFA palmitic acid had a significant toxic effect on the viability of rat insulin-producing cells. Unsaturated NEFAs with carbon chain lengths >14 showed, irrespective of the number of double bonds, a pronounced protection against palmitic acid induced toxicity. Palmitic acid induced H2O2 formation in the peroxisomes of insulin-producing cells. Oleic acid incubation led to lipid droplet formation, but in contrast to palmitic acid induced neither an ER stress response nor peroxisomal H2O2 generation. Furthermore, oleic acid prevented palmitic acid induced H2O2 production in the peroxisomes. CONCLUSION: Thus unsaturated NEFAs prevent deleterious hydrogen peroxide generation during peroxisomal beta-oxidation of long-chain saturated NEFAs in rat insulin-producing cells. PMID- 26044491 TI - The antibody response to influenza vaccination is not impaired in type 2 diabetics. AB - BACKGROUND: Diabetics are considered to be at high risk for complications from influenza infection and type 2 diabetes is a significant comorbidity of obesity. Obesity is an independent risk factor for complications from infection with influenza. Annual vaccination is considered the best strategy for protecting against influenza infection and it's complications. Our previous study reported intact antibody responses 30 days post vaccination in an obese population. This study was designed to determine the antibody response to influenza vaccination in type 2 diabetics. METHODS: Subjects enrolled were 18 or older without immunosuppressive diseases or taking immunosuppressive medications. A pre vaccination blood draw was taken at time of enrollment, the subjects received the influenza vaccine and returned 28-32 days later for a post-vaccination blood draw. Height and weight were also obtained at the first visit and BMI was calculated. Antibody levels to the vaccine were determined by both ELISA and hemagglutination inhibition (HAI) assays. RESULTS: As reported in our previous work, obesity positively correlates with the influenza antibody response (p=0.02), while age was negatively correlated with antibody response (p<0.001). In both year 1 and year 2 of our study there was no significant difference in the percentage of the type 2 diabetic subjects classified as seroprotected or a responder to the influenza vaccine compared to the non-diabetic subjects. CONCLUSIONS: These data are important because they demonstrate that diabetics, considered a high risk group during influenza season, are able to mount an antibody response to influenza vaccination that may protect them from influenza infection. PMID- 26044492 TI - Reactogenicity of trivalent inactivated influenza vaccine in young children: Pronounced reactions by previous successive vaccinations. AB - In order to assess factors associated with reactogenicity of trivalent inactivated influenza vaccine (IIV3) among young children, data on 1538 vaccinees aged 0-5 years in a previous vaccine effectiveness study were analyzed. The most frequent reaction was redness (19%), followed by induration, swelling, itching, and pain (6-12%); there were no serious adverse events. For some local reactions, multivariate analyses indicated associations of younger age, preschool attendance, presence of siblings, and allergy with lower risk, and use of thinner needles with higher risk. Most notably, administration of one or more IIV3 vaccines during the previous 3 seasons was positively associated with each local reaction (adjusted odds ratios: 3.6-5.4). For subjects aged >=3 years, prior successive annual vaccinations were associated with substantially increased local reactions, with clear dose-response relationships (P for trend: <0.001 for each); for example, an 9.8-fold greater risk of swelling following three successive annual vaccinations before the study season. PMID- 26044493 TI - Cost-effectiveness of Haemophilus influenzae type b vaccine in Vietnam. AB - BACKGROUND: With GAVI support, Vietnam introduced Haemophilus influenzae type b (Hib) vaccine in 2010 without evidence on cost-effectiveness. We aimed to analyze the cost-effectiveness of Hib vaccine from societal and governmental perspectives. METHOD: We constructed a decision-tree cohort model to estimate the costs and effectiveness of Hib vaccine versus no Hib vaccine for the 2011 birth cohort. The disease burden was estimated from local epidemiologic data and literature. Vaccine delivery costs were calculated from governmental reports and 2013 vaccine prices. A prospective cost-of-illness study was conducted to estimate treatment costs. The human capital approach was employed to estimate productivity loss. The incremental costs of Hib vaccine were divided by cases, deaths, and disability-adjusted life years (DALY) averted. We used the WHO recommended cost-effectiveness thresholds of an intervention being highly cost effective if incremental costs per DALY were below GDP per capita. RESULT: From the societal perspective, incremental costs per discounted case, death and DALY averted were US$ 6252, US$ 26,476 and US$ 1231, respectively; the break-even vaccine price was US$ 0.69/dose. From the governmental perspective, the results were US$ 6954, US$ 29,449, and US$ 1373, respectively; the break-even vaccine price was US$ 0.48/dose. Vietnam's GDP per capita was US$ 1911 in 2013. In deterministic sensitivity analysis, morbidity and mortality parameters were among the most influential factors. In probabilistic sensitivity analysis, Hib vaccine had an 84% and 78% probability to be highly cost-effective from the societal and governmental perspectives, respectively. CONCLUSION: Hib vaccine was highly cost effective from both societal and governmental perspectives. However, with GAVI support ending in 2016, the government will face a six-fold increase in its vaccine budget at the 2013 vaccine price. The variability of vaccine market prices adds an element of uncertainty. Increased government commitment and improved resource allocation decision making will be necessary to retain Hib vaccine. PMID- 26044494 TI - Characteristics and health behaviors of diabetic patients receiving influenza vaccination. AB - OBJECTIVE: Epidemiological research has posited a 'healthy user' bias in patients receiving influenza vaccination; thus we sought to evaluate potential healthy user attributes and their associations with influenza vaccination. RESEARCH DESIGN & METHODS: Between 2011 and 2013, adults with type 2 diabetes were enrolled in a prospective cohort in Alberta, Canada. Information collected included sociodemographics, diabetes-related data (e.g., duration, complications), health behaviors (e.g., smoking status), functional health status, and satisfaction with healthcare. Data were collected by a mailed, self administered survey. Multivariable logistic regression analyses were used to identify potential healthy-user attributes independently associated with influenza vaccination. RESULTS: From a cohort of 2040 patients, 1287 (63%) reported receiving the influenza vaccine in the previous year. Average age of the cohort was 64 years (standard deviation 11) and 55% were male. In multivariable analysis, attributes independently associated with influenza vaccination included receiving preventive medications: aspirin (64% vs 44%; adjusted odds ratio, aOR 1.65, 95% CI 1.34-2.04); blood pressure medications (76% vs 56%; aOR 1.36, 95% CI 1.07-1.71); and cholesterol-lowering medications (74% vs 53%; aOR 1.50, 95% CI 1.19-1.89), as well as having a healthcare professional check feet for lesions (47% vs 31%; aOR 1.39, 95% CI 1.12-1.74). Additional covariates independently associated with influenza vaccination included: age over 65 years, respiratory disease, the number of additional comorbidities, and higher ratings of healthcare experience. CONCLUSION: Vaccinated diabetic patients exhibit many postulated attributes of 'healthy users', which has implications for the interpretation of epidemiological studies of influenza vaccine effectiveness, as well as targeting future vaccination campaigns. PMID- 26044495 TI - Improving influenza and Tdap vaccination during pregnancy: A cluster-randomized trial of a multi-component antenatal vaccine promotion package in late influenza season. AB - BACKGROUND: Evidence-based interventions to improve influenza vaccine coverage among pregnant women are needed, particularly among those who remain unvaccinated late into the influenza season. Improving rates of antenatal tetanus, diphtheria and acellular pertussis (Tdap) vaccination is also needed. PURPOSE: To test the effectiveness of a practice-, provider-, and patient-focused influenza and Tdap vaccine promotion package on improving antenatal influenza and Tdap vaccination in the obstetric setting. METHODS: A cluster-randomized trial among 11 obstetric practices in Georgia was conducted in 2012-2013. Intervention practices adopted the intervention package that included identification of a vaccine champion, provider-to-patient talking points, educational brochures, posters, lapel buttons, and iPads loaded with a patient-centered tutorial. Participants were recruited from December 2012-April 2013 and included 325 unvaccinated pregnant women in Georgia. Random effects regression models were used to evaluate primary and secondary outcomes. RESULTS: Data on antenatal influenza and Tdap vaccine receipt were obtained for 300 (92.3%) and 291 (89.5%) women, respectively. Although antenatal influenza and Tdap vaccination rates were higher in the intervention group than the control group, improvements were not significant (For influenza: risk difference (RD)=3.6%, 95% confidence interval (CI): -4.0%, 11.2%; for Tdap: RD=1.3%, 95% CI: -10.7%, 13.2%). While the majority of intervention package components were positively associated with antenatal vaccine receipt, a provider's recommendation was the factor most strongly associated with actual receipt, regardless of study group or vaccine. CONCLUSIONS: The intervention package did not significantly improve antenatal influenza or Tdap vaccine coverage. More research is needed to determine what motivates women remaining unvaccinated against influenza late into the influenza season to get vaccinated. Future research should quantify the extent to which clinical interventions can bolster a provider's recommendation for vaccination. This study is registered with clinicaltrials.gov, study ID NCT01761799. PMID- 26044497 TI - Prevalence and associated factors of seasonal influenza vaccination among 24- to 59-month-old children in Hong Kong. AB - BACKGROUND: Influenza results in severe complications among 24- to 59-month-old children, who are recommended by the WHO to take up influenza vaccination (IV) annually. Health promotion is warranted. Yet, there is a dearth of studies on IV prevalence and associated factors in this age group. METHODS: A random population based telephone survey interviewed 540 parents of Chinese children aged 24-59 months in Hong Kong during March through June, 2011. Constructs of the Health Belief Model (HBM) and subjective norm formed basis for assessing parental perceptions on influenza and IV. For data analysis, adjusted, and stepwise multiple logistic regression models were fit. RESULTS: The prevalence of having taken up at least one dose and two doses of IV among children aged 24-59 months was 58.9 and 42.4%, respectively. Significant associated factors included family members' IV experience (ORu=5.37, 95% CI: 3.48, 8.29), variables related to the HBM constructs (except perceived severity) [perceived susceptibility of seasonal influenza (ORu=2.03, 95% CI: 1.39, 2.95), perceived benefits of IV (ORu=3.11, 95% CI: 2.05, 4.71), perceived barriers (ORu=0.49, 95% CI: 0.25, 0.96) of IV, and cue to action (ORu=4.79, 95% CI: 2.87, 7.99)], supportive subjective norm (ORu=4.26, 95% CI: 2.91, 6.25), and level of fear felt during the H1N1 pandemic (ORu=1.97, 95% CI: 1.01, 3.87). Adjusted for the child's age, the same significant factors were found. Exposure to related media messages was statistically non-significant. CONCLUSION: The reported IV prevalence was higher than that of 24- to 59-month old children reported in other studies. There is room for improvement through health promotion, which should modify parental cognitions related to HBM (except perceived severity and self-efficacy) and involve family members to create subjective norm. Media campaigns may be inadequate for promotion of IV; use of the setting approach may be considered. PMID- 26044496 TI - Competitive detection of influenza neutralizing antibodies using a novel bivalent fluorescence-based microneutralization assay (BiFMA). AB - Avian-derived influenza A zoonoses are closely monitored and may be an indication of virus strains with pandemic potential. Both successful vaccination and convalescence of influenza A virus in humans typically results in the induction of antibodies that can neutralize viral infection. To improve long-standing and new-generation methodologies for detection of neutralizing antibodies, we have employed a novel reporter-based approach that allows for multiple antigenic testing within a single sample. Central to this approach is a single-cycle infectious influenza A virus (sciIAV), where a functional hemagglutinin (HA) gene was changed to encode either the green or the monomeric red fluorescent protein (GFP and mRFP, respectively) and HA is complemented in trans by stable HA expressing cell lines. By using fluorescent proteins with non-overlapping emission spectra, this novel bivalent fluorescence-based microneutralization assay (BiFMA) can be used to detect neutralizing antibodies against two distinct influenza isolates in a single reaction, doubling the speed of experimentation while halving the amount of sera required. Moreover, this approach can be used for the rapid identification of influenza broadly neutralizing antibodies. Importantly, this novel BiFMA can be used for any given influenza HA-pseudotyped virus under BSL-2 facilities, including highly pathogenic influenza HA isolates. PMID- 26044498 TI - Safety, tolerability, and immunogenicity of 7-valent pneumococcal conjugate vaccine in older infants and young children in China who are naive to pneumococcal vaccination: Results of a phase 4 open-label trial. AB - BACKGROUND: This postlicensure study was conducted to assess immunogenicity and safety of PCV7 catch-up regimens in previously unvaccinated older infants and young children in China. METHODS: Healthy children 121 days to <72 months were grouped by age and immunized with 1 of 4 PCV7 dosing regimens. Serotype-specific IgG geometric mean concentrations (GMCs) and percentage of subjects with IgG>=0.35MUg/mL were assessed before vaccination and 1 and 12 months postvaccination. The incidence of clinically important adverse events (AEs) and serious AEs (SAEs), AEs leading to study withdrawal, and protocol-related AEs were assessed throughout the study. RESULTS: Prevaccination serotype-specific GMCs were generally low in subjects <24 months; the majority of children 24 to <72 months had IgG concentrations >=0.35 MUg/mL. One month postvaccination, GMCs were similar across groups for the 7 PCV serotypes, ranging from 3.95 to 13.02 MUg/mL; the highest antibody levels were observed for serotype 14. Regardless of dosing regimen, >90% of subjects had IgG>=0.35 MUg/mL for each PCV serotype. At 12-month follow-up, IgG GMCs ranged from 0.65 to 5.19, and all remained above prevaccination IgG GMC; >70% of subjects had IgG>=0.35 MUg/mL. Older children generally had the most robust immune response both at 1 month postvaccination and during 12-month follow-up. PCV7 was well tolerated. Pyrexia, which was mild to moderate in severity, was the most common AE. Two subjects reported SAEs (n=4), and there was 1 study withdrawal; none of these were considered treatment related. CONCLUSION: In China, PCV7 catch-up vaccinations given to older infants and young children naive to pneumococcal vaccines resulted in a robust immune response to all serotypes; this response persisted after 1 year. PCV7 was well tolerated in Chinese infants and children. PMID- 26044499 TI - ["Placebo effect", from personal convictions to collective representations: A psychosocial reading of a pharmacodynamic phenomenon]. AB - After starting with a brief historical account of the placebo effect organized around the elaboration of clinical trials and around sham therapy as a method, we will offer a psychosocial point of view on the placebo phenomenon. The placebo effect is at the heart of medicine and particularly of therapeutic trials from theoretical research on a drug to its acceptance and its use in every-day clinical practice. The placebo effect intermingles biology, relationships and the context of therapeutic interactions. This type of phenomenon originates as much from biology as from human psychology. Our article puts more precisely into question the part that psychology has in the placebo phenomenon and suggests a chart to address it. This chart refers both to the pharmacodynamic effect given to drugs in a subjective way, and to the collective representations and social interactions depending on them. What can we say about the psychosociological dimensions of the placebo effect? How is it possible to organize the scope of these dimensions to base systematic studies on them in the field of clinical trials? We try to give elements of response to these questions by suggesting the study of the placebo effect as an original field of study by necessarily mobilizing both health sciences and the human and social sciences. PMID- 26044500 TI - Has the prevalence of stunting in South African children changed in 40 years? A systematic review. AB - BACKGROUND: In the last 20 years, South Africa has experienced political, economic, and demographic transitions accompanied by an epidemiological transition. Like several sub-Saharan countries, the South African population is facing both under-and over-nutrition, and nutrition and lifestyle related chronic disease while the burden of infectious disease remains high. It is critical to understand these trends overtime in order to highlights the pitfalls and successful measures initiatives taken in the efforts to tackle malnutrition. The objective of this systematic review is to investigate the changes in the prevalence of stunting, a chronic form of undernutrition, in South Africa over 40 years, and to derive lessons from the South African experience, a country in an advanced process of transition in sub-Saharan Africa. METHODS: We undertook a systematic review of publications selected from PubMed, Science Direct and Scopus. We included studies and surveys published between 1970 and 2013 if they reported the prevalence of stunting (low height-for-age) in children under-6 years of age living in South Africa. We excluded studies conducted in health facility outpatients or hospital wards, or children with known chronic and acute infectious diseases. We extracted Date of data collection, study setting, ethnicity, age, sex, sample size, growth references/standards, diagnostic criteria for stunting and prevalence of stunting from each study. RESULTS: Over the last decade, the national prevalence of stunting has decreased. However, between and within provincial, age and ethnic group disparities remain. Unlike other countries in sub-Saharan Africa, no sex or rural/urban differences were found in preschool children. However, the analysis of long-term trends and identification of vulnerable groups is complicated by the use of different growth references/standards and sampling methods. CONCLUSION: Despite economic growth, political and social transitions, and national nutritional programs, stunting remains stubbornly persistent and prevalent in South Africa. A multi-sectoral and public health approach is needed to: (i) better monitor stunting over time, (ii) combat malnutrition during the first thousand days of life through continued efforts to improve maternal nutrition during pregnancy and infant feeding practices. PMID- 26044504 TI - Impaired phenotype of circulating endothelial microparticles in chronic heart failure patients: Relevance to body mass index. AB - AIMS: The objective of the study was to investigate the relationship of circulating endothelial-derived microparticls (EMP) pattern with body mass index (BMI) in CHF patients. METHODS: The study retrospectively evolved 153 patients (86 males) who were underwent multispiral contrast-enhanced computed tomography angiography or conventional angiographic examination of coronary arteries. Flowcytometry analysis for quantifying the number of EMPs was used at baseline. RESULTS: Using C-statistics for models with CHF, BMI, and circulating biomarkers (NT-pro-BNP, OPG and adiponectin) as continuous variables we found that adding of BMI to the based model (NYHA class of CHF) improved the relative IDI by 12.5% for increased CD31+/annexin V+ EMPs to CD62E+ EMPs ratio. When we used other model constructed on entering variables IDI appears to be improved up to 5.8% for increased EMPs (available for NT-pro-BNP as continuous variable). Three biomarkers (NYHA class of CHF+NT-pro-BNP+OPG) and four biomarkers (NYHA class of CHF+NT-pro-BNP+OPG+adiponectin) could not significantly improve predictive model based on combination of BMI and NYHA class of CHF for increased CD31+/annexin V+ EMPs to CD62E+ EMPs ratio. CONCLUSION: We suggested that lower BMI is significant predictor for impaired phenotype of circulating EMPs in CHF patients. PMID- 26044503 TI - Obesity and male breast cancer: provocative parallels? AB - While rare compared to female breast cancer the incidence of male breast cancer (MBC) has increased in the last few decades. Without comprehensive epidemiological studies, the explanation for the increased incidence of MBC can only be speculated. Nevertheless, one of the most worrying global public health issues is the exponential rise in the number of overweight and obese people, especially in the developed world. Although obesity is not considered an established risk factor for MBC, studies have shown increased incidence among obese individuals. With this observation in mind, this article highlights the correlation between the increased incidence of MBC and the current trends in obesity as a growing problem in the 21(st) century, including how this may impact treatment. With MBC becoming more prominent we put forward the notion that, not only is obesity a risk factor for MBC, but that increasing obesity trends are a contributing factor to its increased incidence. PMID- 26044505 TI - Resveratrol amplifies BMP-4-stimulated osteoprotegerin synthesis via p38 MAP kinase in osteoblasts. AB - Resveratrol is a naturally occurring polyphenol that possesses health-related properties, and is predominantly found in grapes and berries. Bone morphogenetic protein-4 (BMP-4) stimulates osteocalcin synthesis via p38 mitogen-activated protein (MAP) kinase in osteoblast-like MC3T3-E1 cells. The present study aimed to investigate the effects of resveratrol on BMP-4-induced osteoprotegerin (OPG) synthesis in MC3T3-E1 cells. Resveratrol alone had no effect on OPG expression levels, but significantly enhanced BMP-4-induced OPG release. In addition, resveratrol markedly amplified the mRNA expression levels of BMP-4-induced OPG. SB203580 is an inhibitor of p38 MAP kinase, which was shown to suppress BMP-4 stimulated OPG release. BMP-4-induced phosphorylation of p38 MAP kinase was also enhanced by resveratrol. Furthermore, SB203580 significantly reduced the resveratrol-induced amplification of BMP-4-stimulated OPG release. These results suggested that resveratrol was able to upregulate BMP-4-stimulated OPG synthesis via the amplification of p38 MAP kinase activity in osteoblasts. PMID- 26044506 TI - Biochemical marker reference values across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. AB - BACKGROUND: Biological covariates such as age and sex can markedly influence biochemical marker reference values, but no comprehensive study has examined such changes across pediatric, adult, and geriatric ages. The Canadian Health Measures Survey (CHMS) collected comprehensive nationwide health information and blood samples from children and adults in the household population and, in collaboration with the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER), examined biological changes in biochemical markers from pediatric to geriatric age, establishing a comprehensive reference interval database for routine disease biomarkers. METHODS: The CHMS collected health information, physical measurements, and biosamples (blood and urine) from approximately 12 000 Canadians aged 3-79 years and measured 24 biochemical markers with the Ortho Vitros 5600 FS analyzer or a manual microplate. By use of CLSI C28-A3 guidelines, we determined age- and sex-specific reference intervals, including corresponding 90% CIs, on the basis of specific exclusion criteria. RESULTS: Biochemical marker reference values exhibited dynamic changes from pediatric to geriatric age. Most biochemical markers required some combination of age and/or sex partitioning. Two or more age partitions were required for all analytes except bicarbonate, which remained constant throughout life. Additional sex partitioning was required for most biomarkers, except bicarbonate, total cholesterol, total protein, urine iodine, and potassium. CONCLUSIONS: Understanding the fluctuations in biochemical markers over a wide age range provides important insight into biological processes and facilitates clinical application of biochemical markers to monitor manifestation of various disease states. The CHMS-CALIPER collaboration addresses this important evidence gap and allows the establishment of robust pediatric and adult reference intervals. PMID- 26044508 TI - Sequence Variant Interpretation 2.0: Perspective on New Guidelines for Sequence Variant Classification. PMID- 26044507 TI - Complex reference values for endocrine and special chemistry biomarkers across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. AB - BACKGROUND: Defining laboratory biomarker reference values in a healthy population and understanding the fluctuations in biomarker concentrations throughout life and between sexes are critical to clinical interpretation of laboratory test results in different disease states. The Canadian Health Measures Survey (CHMS) has collected blood samples and health information from the Canadian household population. In collaboration with the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER), the data have been analyzed to determine reference value distributions and reference intervals for several endocrine and special chemistry biomarkers in pediatric, adult, and geriatric age groups. METHODS: CHMS collected data and blood samples from thousands of community participants aged 3 to 79 years. We used serum samples to measure 13 immunoassay-based special chemistry and endocrine markers. We assessed reference value distributions and, after excluding outliers, calculated age- and sex-specific reference intervals, along with corresponding 90% CIs, according to CLSI C28-A3 guidelines. RESULTS: We observed fluctuations in biomarker reference values across the pediatric, adult, and geriatric age range, with stratification required on the basis of age for all analytes. Additional sex partitions were required for apolipoprotein AI, homocysteine, ferritin, and high sensitivity C reactive protein. CONCLUSIONS: The unique collaboration between CALIPER and CHMS has enabled, for the first time, a detailed examination of the changes in various immunochemical markers that occur in healthy individuals of different ages. The robust age- and sex-specific reference intervals established in this study provide insight into the complex biological changes that take place throughout development and aging and will contribute to improved clinical test interpretation. PMID- 26044509 TI - Complex biological profile of hematologic markers across pediatric, adult, and geriatric ages: establishment of robust pediatric and adult reference intervals on the basis of the Canadian Health Measures Survey. AB - BACKGROUND: In a collaboration between the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) and the Canadian Health Measures Survey (CHMS), we determined reference value distributions using an a priori approach and created a comprehensive database of age- and sex-stratified reference intervals for clinically relevant hematologic parameters in a large household population of children and adults. METHODS: The CHMS collected data and blood samples from 11 999 respondents aged 3-79 years. Hematology markers were measured with either the Beckman Coulter HmX or Siemens Sysmex CA-500 Series analyzers. After applying exclusion criteria and removing outliers, we determined statistically relevant age and sex partitions and calculated reference intervals, including 90% CIs, according to CSLI C28-A3 guidelines. RESULTS: Hematology marker values showed dynamic changes from childhood into adulthood as well as between sexes, necessitating distinct partitions throughout life. Most age partitions were necessary during childhood, reflecting the hematologic changes that occur during growth and development. Hemoglobin, red blood cell count, hematocrit, and indices (mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration) increased with age, but females had lower hemoglobin and hematocrit starting at puberty. Platelet count gradually decreased with age and required multiple sex partitions during adolescence and adulthood. White blood cell count remained relatively constant over life, whereas fibrinogen increased slightly, requiring distinct age and sex partitions. CONCLUSIONS: The robust dataset generated in this study has allowed observation of dynamic biological profiles of several hematology markers and the establishment of comprehensive age- and sex-specific reference intervals that may contribute to accurate monitoring of pediatric, adult, and geriatric patients. PMID- 26044510 TI - Extracellular matrix scaffold as a tubular graft for ascending aorta aneurysm repair. AB - BACKGROUND: Although extracellular xenograft repair has produced encouraging results when applied to cardiac, valvular, and specific aortic defects, its employment as a tube graft to replace the ascending aorta has not been reported. We describe a patient who underwent resection and replacement of an infected ascending aortic graft with an extracellular matrix conduit. The patient did well, but 14 months later developed a pseudoaneurysm from the staple line used to construct the extracellular matrix conduit. METHODS: The patient underwent a repeat sternotomy and removal of the graft. Because of the increased risk of graft failure, a homograft was felt to be more appropriate in this setting. Ultimately, we were unable to implant the homograft because it was too small for the aortic root; therefore we decided to construct a tubular graft from Cormatrix extracellular matrix (CorMatrix, Roswell, GA, USA). Fourteen months later, he presented with shortness of breath. Computed tomography scan revealed a 3.5 cm pseudoaneurysm of the ascending aorta. It appeared as if there was a disruption of the staple line in the extra cellular matrix graft. The plan was to replace it with a Dacron graft. RESULTS: The Cormatrix graft material was removed and sent for culture and histological analysis. A 28-mm Gel weave graft (Terumo Cardiovascular Systems, Ann Arbor, MI, USA) was implanted. The patient tolerated the procedure well with good hemodynamics. CONCLUSIONS: Our experience suggests that the superior strength, handling characteristics, and resistance to infection make extra cellular matrix scaffold a possible alternative conduit to cryopreserved homografts. Applicability as an aortic conduit merits further investigation to better understand behavior of extra cellular matrix in this situation. PMID- 26044512 TI - Potential drugs which activate nuclear factor E2-related factor 2 signaling to prevent diabetic cardiovascular complications: A focus on fumaric acid esters. AB - Diabetes and its cardiovascular complications have been a major public health issue. These complications are mainly attributable to a severe imbalance between free radical and reactive oxygen species production and the antioxidant defense systems. Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the basal and inducible expression of a battery of antioxidant enzyme genes and other cyto-protective phase II detoxifying enzymes. As a result, Nrf2 has gained great attention as a promising drug target for preventing diabetic cardiovascular complications. And while animal studies have shown that several Nrf2 activators manifest a potential to efficiently prevent the diabetic complications, their use in humans has not been approved due to the lack of substantial evidence regarding safety and efficacy of the Nrf2 activation. We provide here a brief review of a few clinically-used drugs that can up-regulate Nrf2 with the potential of extending their usage to diabetic patients for the prevention of cardiovascular complications and conclude with a closer inspection of dimethyl fumarate and its mimic members. PMID- 26044511 TI - Obstetric anal sphincter injuries: review of anatomical factors and modifiable second stage interventions. AB - INTRODUCTION AND HYPOTHESIS: Obstetric anal sphincter injuries (OASIs) are the leading cause of anal incontinence in women. Modification of various risk factors and anatomical considerations have been reported to reduce the rate of OASI. METHODS: A PubMed search (1989-2014) of studies and systematic reviews on risk factors for OASI. RESULTS: Perineal distension (stretching) of 170 % in the transverse direction and 40 % in the vertical direction occurs at crowning, leading to significant differences (15-30 degrees ) between episiotomy incision angles and suture angles. Episiotomies incised at 60 degrees achieve suture angles of 43-50 degrees ; those incised at 40 degrees result in a suture angle of 22 degrees . Episiotomies with suture angles too acute (<30 degrees ) and too lateral (>60 degrees ) are associated with an increased risk of OASI. Suture angles of 40-60 degrees are in the safe zone. Clinicians are poor at correctly estimating episiotomy angles on paper and in patients. Sutured episiotomies originating 10 mm away from the midline are associated with a lower rate of OASIs. Compared to spontaneous tears, episiotomies appear to be associated with a reduction in OASI risk by 40-50 %, whereas shorter perineal lengths, perineal oedema and instrumental deliveries are associated with a higher risk. Instrumental deliveries with mediolateral episiotomies are associated with a significantly lower OASI risk. Other preventative measures include warm perineal compresses and controlled delivery of the head. CONCLUSIONS: Relieving pressure on the central posterior perineum by an episiotomy and/or controlled delivery of the head should be important considerations in reducing the risk of OASI. Episiotomies should be performed 60 degrees from the midline. Prospective studies should evaluate elective episiotomies in women with a short perineal length and application of standardised digital perineal support. PMID- 26044514 TI - Asymmetric Synthesis with Hypervalent Iodine Reagents. AB - This chapter describes recent developments in stereoselective synthesis using hypervalent iodine reagents. PMID- 26044513 TI - Myotonic dystrophy health index: Correlations with clinical tests and patient function. AB - INTRODUCTION: The Myotonic Dystrophy Health Index (MDHI) is a disease-specific patient-reported outcome measure. Here, we examine the associations between the MDHI and other measures of disease burden in a cohort of individuals with myotonic dystrophy type-1 (DM1). METHODS: We conducted a cross-sectional study of 70 patients with DM1. We examined the associations between MDHI total and subscale scores and scores from other clinical tests. Participants completed assessments of strength, myotonia, motor and respiratory function, ambulation, and body composition. Participants also provided blood samples, underwent physician evaluations, and completed other patient-reported outcome measures. RESULTS: MDHI total and subscale scores were strongly associated with muscle strength, myotonia, motor function, and other clinical measures. CONCLUSIONS: Patient-reported health status, as measured by the MDHI, is associated with alternative measures of clinical health. These results support the use of the MDHI as a valid tool to measure disease burden in DM1 patients. PMID- 26044515 TI - Fetal Erythroblastosis May Be an Indicator of Neonatal Transient Hyperinsulinism. AB - BACKGROUND: Small for gestational age and birth asphyxia are associated with neonatal transient hyperinsulinism (THI). Some newborns with THI showed marked erythroblastosis on admission to our neonatal intensive care unit. OBJECTIVE: This study was designed to test our hypothesis that fetal erythroblastosis may be a risk factor for developing THI. METHODS: The records of all babies admitted to our neonatal intensive care unit within 24 h of birth between January 2010 and May 2014, and who were born after 34 weeks of gestation, were retrospectively reviewed. Hyperinsulinism was diagnosed as hypoglycemia concomitant with high serum insulin in babies requiring >6 mg/kg/min intravenous glucose and THI as hyperinsulinism without maternal diabetes or genetic disorders. The following three possible risk factors for THI were evaluated: (1) birth weight z-score, (2) 1-min Apgar score and (3) absolute nucleated red blood cell (aNRBC) count on admission. RESULTS: Of 705 infants, 8 were diagnosed with THI. Multivariate logistic regression analysis revealed that the aNRBC count was the most significant risk factor for THI. The median aNRBC count was 181/ul (interquartile range 0-538/ul), and 8 of 71 infants (11.3%) having an aNRBC count >1,413/ul (90th percentile in this study) had THI. The aNRBC counts in the 8 cases with THI were significantly higher than those in the 5 cases with hyperinsulinism caused by maternal diabetes or genetic disorders. CONCLUSIONS: This study showed that the aNRBC count was strongly associated with subsequent THI. Fetal erythroblastosis, characterized by chronic fetal hypoxia, may be an indicator of perinatal stress sufficient to cause THI. PMID- 26044516 TI - The triglyceride-lowering effect of supplementation with dual probiotic strains, Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032: Reduction of fasting plasma lysophosphatidylcholines in nondiabetic and hypertriglyceridemic subjects. AB - BACKGROUND AND AIMS: This study evaluated the triglyceride (TG)-lowering effects of consuming dual probiotic strains of Lactobacillus curvatus (L. curvatus) HY7601 and Lactobacillus plantarum (L. plantarum) KY1032 on the fasting plasma metabolome. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled study was conducted on 92 participants with hypertriglyceridemia but without diabetes. Over a 12-week testing period, the probiotic group consumed 2 g of powder containing 5 * 10(9) colony-forming units (cfu) of L. curvatus HY7601 and 5 * 10(9) cfu of L. plantarum KY1032 each day, whereas the placebo group consumed the same product without probiotics. Fasting plasma metabolomes were profiled using UPLC-LTQ-Orbitrap MS. After 12 weeks of treatment, the probiotic group displayed a 20% reduction (p = 0.001) in serum TGs and 25% increases (p=0.001) in apolipoprotein A-V (apoA-V). At the 12-week follow-up assessment, the following 11 plasma metabolites were significantly reduced in the probiotic group than the placebo group: palmitoleamide, palmitic amide, oleamide, and lysophosphatidyl choline (lysoPC) containing C14:0, C16:1, C16:0, C17:0, C18:3, C18:2, C18:1, and C20:3. In the probiotic group, changes (?) in TG were negatively correlated with ? apoA-V, which was positively correlated with ? FFA. In addition, ? FFA was strongly and positively correlated with ? lysoPCs in the probiotic group but not the placebo group. CONCLUSIONS: The triglyceride-lowering effects of probiotic supplementation, partly through elevated apoA-V, in borderline to moderate hypertriglyceridemic subjects showed reductions in plasma metabolites, fatty acid primary amides and lysoPCs (NCT02215694; http://www.clinicaltrials.gov). Clinical trials: NCT02215694; http://www.clinicaltrials.gov. PMID- 26044517 TI - Validation of diet and urinary excretion derived estimates of sodium excretion against 24-h urine excretion in a worksite sample. AB - BACKGROUND AND AIMS: To validate diet and urinary excretion derived estimates of sodium intake against those derived from 24-h urine collections in an Irish manufacturing workplace sample. METHODS AND RESULTS: We have compared daily sodium (Na) excretion from PABA validated 24-h urine collections with estimated daily sodium excretion derived from the following methods: a standard Food Frequency Questionnaire (FFQ), a modified 24-h dietary recall method, arithmetic extrapolations from morning and evening spot urine samples, predicted sodium excretion from morning and evening spot urine samples using Tanaka's, Kawasaki's and the INTERSALT formula. All were assessed using mean differences (SD), Bland Altman plots, correlation coefficients and ROC Area under the Curve (AUC) for a cut off of >=100 mmol of Na/day. The Food Choice at Work study recruited 802 participants aged 18-64 years, 50 of whom formed the validation sample. The mean measured 24-h urinary sodium (gold standard) was 138 mmol/day (8.1 g salt). At the group level, mean differences were small for both dietary methods and for the arithmetic extrapolations from morning urine samples. The Tanaka, Kawasaki and INTERSALT methods provided biased estimates of 24-h urinary sodium. R(2) values for all methods ranged from 0.1 to 0.48 and AUC findings from 0.57 to 0.76. CONCLUSION: Neither dietary nor spot urine sample methods provide adequate validity in the estimation of 24-h urinary sodium at the individual level. However, group mean errors from dietary methods are small and random and compare favourably with those from spot urine samples in this population. PMID- 26044519 TI - Expose sur les consequences ethiques des tests aleatoires de depistage des drogues en milieu de travail. AB - Le present article traite des repercussions scientifiques et ethiques des tests aleatoires de depistage des drogues en milieu de travail. Ces tests sont pratique courante, particulierement dans les secteurs constituant un risque pour la securite, mais s'appuient sur peu d'analyses critiques. J'en conclus que ces programmes s'associent a des defis ethiques importants. Les employeurs doivent s'assurer que chaque aspect de leurs politiques repose sur des donnees scientifiques, est lie rationnellement a l'objectif de la securite en milieu de travail et est justifie sur le plan ethique. PMID- 26044518 TI - Pharmacological treatment of binge eating disorder: update review and synthesis. AB - INTRODUCTION: Binge eating disorder (BED), a formal eating disorder diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), is characterized by recurrent binge eating, marked distress about binge eating, and the absence of extreme weight compensatory behaviors. BED is more prevalent than other eating disorders, with broader distribution across age, sex and ethnic/racial groups, and is associated strongly with obesity and heightened risk for psychiatric/medical comorbidities. AREAS COVERED: This article provides an overview of pharmacotherapy for BED with a focus on Phase III randomized controlled trials (RCTs). The search with minimal methodological inclusion requirements yielded 22 RCTs investigating several different medication classes; most were pharmacotherapy-only trials with 8 trials testing combination approaches with psychological-behavioral methods. EXPERT OPINION: The evidence base regarding pharmacotherapy for BED remains limited, although this year the FDA approved the first medication (i.e., lisdexamfetamine dimesylate; LDX) specifically for moderate-to-severe BED. Data from RCTs suggest certain medications are superior to placebos for reducing binge eating over the short term; almost no data exist regarding longer-term effects of pharmacotherapy for BED. Except for topiramate, which significantly reduces both binge eating and weight, tested medications yield minimal weight loss and LDX is not indicated for weight loss. Psychological-behavioral and combination approaches with certain medications yield superior outcomes to pharmacotherapy-only acutely and over longer-term follow-up. PMID- 26044520 TI - Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice. AB - Kainic acid (KA)-induced brain neuronal cell death (especially in the hippocampus) was shown to be mainly mediated by the intrinsic (mitochondrial) apoptotic pathway. This study investigated the regulation of the extrinsic apoptotic pathway mediated by Fas ligand/Fas receptor and components of the indispensable death-inducing signaling complex (DISC) in the hippocampus (marked changes) and cerebral cortex (modest changes) of KA-treated mice. KA (45mg/kg) induced a severe behavioral syndrome with recurrent motor seizures (scores; maximal at 60-90min; minimal at 72h) with activation of hippocampal pro-apoptotic JNK (+2.5 fold) and increased GFAP (+57%) and nuclear PARP-1 fragmentation (+114%) 72h post-treatment (delayed neurotoxicity). In the extrinsic apoptotic pathway (hippocampus), KA (72h) reduced Fas ligand (-92%) and Fas receptor aggregates (-24%). KA (72h) also altered the contents of major DISC components: decreased FADD adaptor (-44%), reduced activation of initiator caspase-8 (-47%) and increased survival FLIP-S (+220%). Notably, KA (72h) upregulated the content of anti-apoptotic p-Ser191 FADD (+41%) and consequently the expression of p FADD/FADD ratio (+1.9-fold), a neuroplastic index. Moreover, the p-FADD dependent transcription factor NF-kappaB was also increased (+61%) in the hippocampus after KA (72h). The convergent adaptation of the extrinsic apoptotic machinery 72h after KA in mice (with otherwise normal gross behavior) is a novel finding which suggests the induction of survival mechanisms to partly counteract the delayed neuronal death in the hippocampus. PMID- 26044521 TI - Arsenic trioxide inhibits accelerated allograft rejection mediated by alloreactive CD8(+) memory T cells and prolongs allograft survival time. AB - CD8(+) memory T (Tm) cells are a significant barrier to transplant tolerance induction in alloantigen-primed recipients, and are insensitive to existing clinical immunosuppressants. Here, we studied the inhibition of CD8(+) Tm cells by arsenic trioxide (As2O3) for the first time. Alloantigen-primed CD8(+) Tm cells were transferred to T cell immunodeficient nude mice. The mice were subjected to heart allotransplantation, and treated with As2O3. The transplant survival time was determined, and the inhibitory effects of As2O3 on CD8(+) Tm cell-mediated immune rejection were assessed through serological studies and inspection of the transplanted heart and lymphoid organs. We found that As2O3 treatment prolonged the mean survival time of the graft and reduced the number of CD8(+) Tm cells in the spleen and lymph nodes. The expression of the genes encoding interleukin (IL)-2, and IFN-gamma was reduced, while expression of IL-10 and transforming growth factor-beta was increased in the transplant. Our findings show that As2O3 treatment inhibits allograft rejection mediated by alloreactive CD8(+) Tm cells in the mouse heart transplantation model. PMID- 26044522 TI - Graph pyramids for protein function prediction. AB - BACKGROUND: Uncovering the hidden organizational characteristics and regularities among biological sequences is the key issue for detailed understanding of an underlying biological phenomenon. Thus pattern recognition from nucleic acid sequences is an important affair for protein function prediction. As proteins from the same family exhibit similar characteristics, homology based approaches predict protein functions via protein classification. But conventional classification approaches mostly rely on the global features by considering only strong protein similarity matches. This leads to significant loss of prediction accuracy. METHODS: Here we construct the Protein-Protein Similarity (PPS) network, which captures the subtle properties of protein families. The proposed method considers the local as well as the global features, by examining the interactions among 'weakly interacting proteins' in the PPS network and by using hierarchical graph analysis via the graph pyramid. Different underlying properties of the protein families are uncovered by operating the proposed graph based features at various pyramid levels. RESULTS: Experimental results on benchmark data sets show that the proposed hierarchical voting algorithm using graph pyramid helps to improve computational efficiency as well the protein classification accuracy. Quantitatively, among 14,086 test sequences, on an average the proposed method misclassified only 21.1 sequences whereas baseline BLAST score based global feature matching method misclassified 362.9 sequences. With each correctly classified test sequence, the fast incremental learning ability of the proposed method further enhances the training model. Thus it has achieved more than 96% protein classification accuracy using only 20% per class training data. PMID- 26044523 TI - miRNA-24-3p promotes cell proliferation and inhibits apoptosis in human breast cancer by targeting p27Kip1. AB - MicroRNAs (miRNAs) are often aberrantly expressed in breast cancer and are postulated to play a role in its initiation and progression. In the present study, we found that the expression level of miR-24-3p was upregulated in breast cancer in comparison with the level in adjacent normal tissues. Overexpression of miR-24-3p was able to promote cell proliferation and inhibit cell apoptosis in MDA-MB-435 and MDA-MB-468 cells. With the bioinformatic method, we further identified that p27Kip1 is a direct target of miR-24-3p, and its protein level was negatively regulated by miR-24-3p. Therefore, the data reported here demonstrate that miR-24-3p is an important regulator in breast cancer, and imply that the miR-24-3p/p27Kip1 axis has potential as a therapeutic target for breast cancer. PMID- 26044524 TI - Near-infrared spectroscopy combined with intravascular ultrasound in carotid arteries. AB - Limited insights into the pathophysiology of the atherosclerotic carotid stenosis are available in vivo. We conducted a prospective study to assess safety and feasibility of intravascular ultrasound (IVUS) combined with near-infrared spectroscopy (NIRS) in carotid arteries. In addition, we described the size and the distribution of lipid rich plaques in significant atherosclerotic carotid stenoses. In a prospective single centre study 45 consecutive patients (mean age 66 +/- 8 years) with symptomatic (>=50 %) or asymptomatic (>=70 %) stenosis of internal carotid artery (ICA) amendable to carotid stenting were enrolled. A 40 mm long NIRS-IVUS pullback through the stenosis was performed. IVUS and NIRS data were analyzed to assess minimal luminal area (MLA), plaque burden (PB), remodeling index (RI), calcifications, lipid core burden index (LCBI), maximal LCBI in any 4 mm segment of the artery (LCBImx) and LCBI in the 4 mm segment at the site of minimal luminal area (LCBImxMLA). NIRS-IVUS pullbacks were safely performed without overt clinical events. LCBImx was significantly higher than LCBImxMLA (369.1 +/- 221.1 vs. 215.7 +/- 2589; p = 0.004). Conversely, PB was significantly larger at the site of MLA (87.4 +/- 4.8 % vs. 58.3 +/- 18.2 %; p < 0001). Distance of the NIRS-IVUS frame with the highest LCBI from the site of MLA was 6.5 +/- 7.7 mm. Eighty percent of frames with maximal LCBI were localized within 10 mm from the site of MLA and 67 % proximally to or at the site of MLA. This study suggested safety and feasibility of the NIRS-IVUS imaging of the carotid stenosis and provided insights on the distribution of lipids in the carotid stenosis. Lipid rich plaques were more often located in the sites with a milder stenosis and smaller plaque burden than at the site of MLA. PMID- 26044526 TI - Pelvic discontinuity: modern techniques and outcomes for treating pelvic disassociation. AB - Pelvic discontinuity is an uncommon condition that usually presents in the revision total hip arthroplasty population. However, its incidence will most likely increase due to the increasing number of primary and revision total hip arthroplasties (THA) done in recent years. Pelvic discontinuity (acetabular disassociation) is perhaps one of the more challenging cases for the hip arthroplasty surgeon to manage. Historically, the management of pelvic discontinuity has been wrought with many challenges. What follows is a review of the current techniques and outcomes for acetabular reconstruction in patients with acetabular disassociation including: porous metal components, internal fixation with acetabular reconstruction, acetabular distraction with jumbo cups, cup and cage construct, and the use of custom triflange.The complexity of pelvic discontinuity and with the myriad of options available to the hip arthroplasty surgeon to address this particular issue, preoperative planning becomes all the more essential. PMID- 26044527 TI - Introductory editorial to 25th Anniversary edition. PMID- 26044525 TI - Global and regional myocardial deformation mechanics of microvascular obstruction in acute myocardial infarction: a three dimensional speckle-tracking imaging study. AB - Microvascular obstruction (MVO) and transmural infarct size are prognostic factors after acute myocardial infarction (AMI). We assessed the value of myocardial deformation patterns using 3D speckle tracking imaging (3DSTI) in detecting myocardial and microvascular damage after AMI. One hundred patients with first ST-segment elevation MI from the REMI Study were prospectively included. Transthoracic echocardiography with 3DSTI and CMR were performed within 72 h after revascularization therapy. Global (3DG) and segmental (3DS) values of LV longitudinal (LS), circumferential and radial area strain were obtained. Late gadolinium enhancement (LGE) and MVO was quantified as transmural (>50%) or non transmural (<50%). Predictive performance was assessed by area under the receiver operating curve characteristic (AUC). Mean LVEFCMR was 45.8 +/- 9.2 % with 22.2 +/- 12.7% transmural LGE. MVO was present in 55 patients (MVO transmural extent 11.4 +/- 11.8%). In global analysis, all 3DG strain values were correlated with LVEFCMR and infarct size, with the best correlation obtained for 3DGAS (r = 0.678; p < 0.0001). All 3DG strain values, with the exception of LS, were significantly different between patients with and without MVO. In segmental analysis, all 3DS strain values were significantly lower in transmurally infarcted segments than in non-infarcted segments, and all 3DS values except 3DSRS were significantly lower in non-transmural infarcted segments than in non infarcted segments. The best 3DS strain for detecting non-viable segments with MVO (MVO > 75%) was 3DSAS [AUC 0.867 (0.849-0.884), 78.0% sensitivity and 81.1% specificity for 3DSAS = -16.1%]. Importantly, 3DSRS and 3DSAS were associated with an increase in diagnostic accuracy of both transmural LGE and MVO over 3DSLS (all increase in AUC > 0.04, all p < 0.01). The newly developed 3DSTI, especially 3DSAS, is a sensitive and reproducible tool to predict and quantify the transmural extent of scar. This new early imaging strategy improve the prediction of MVO while enabling to assess the success of reperfusion and the risk of late systolic remodeling in STEMI. PMID- 26044528 TI - Patient-adapted treatment for prosthetic hip joint infection. AB - Hip joint replacement is 1 of the most successful surgical procedures of the last century and the number of replacements implanted is steadily growing. An infected hip arthroplasty is a disaster, it leads to patient suffering, surgeon's frustration and significant costs to the health system. The treatment of an infected hip replacement is challenging, healing rates can be low, functional results poor with decreased patient satisfaction. However, if a patient-adapted treatment of infected hip joints is used a success rate of above 90% can be obtained.Patient-adapted treatment is based on 5 important concepts: teamwork; understanding the biofilm; diagnostic accuracy; correct definition and classification of PJI; and patient-tailored treatment.This review presents a patient-adapted treatment strategy to prosthetic hip infection. It incorporates the best aspects of the single and staged surgical strategies and promotes the short interval philosophy for the 2-stage approach. PMID- 26044529 TI - The prevention and treatment of dislocation following total hip arthroplasty: efforts to date and future strategies. AB - Dislocation continues as one of the common complications following primary Total Hip Arthroplasty (THA). Considering revision THA, dislocation is also one of the leading causes of failure and the subsequent need for re-revision surgery. This article aims to highlight the efforts to date that surgeons have utilised together with the implants employed to both prevent and treat THA dislocation. A fundamental principal in the management of THA instability is identification of the risk factors for dislocation and these are considered in 5 subgroups; patient factors, surgeon factors, implant design, implant orientation and soft tissue factors. Risk stratification is proposed as a future method of deciding upon best treatment for those patients most at danger of THA dislocation and subsequent continued instability. PMID- 26044530 TI - Fixation of a fractured femoral head through a medial hip approach: an original approach to the femoral head. AB - The decision to treat a femoral head fracture conservatively or surgically is the subject of ongoing debate. Several surgical approaches have been proposed for the open reduction and internal fixation of femoral head fractures. To our knowledge, fixation through a minimally invasive medial approach has not been described until now. The novel medial hip approach passes between the adductor muscle bellies posteriorly and their aponeuroses anteriorly. It provides direct access to the fracture site and allows for fixation by compression, without needing to dislocate the hip or detach the muscles. Any loose bodies in the joint that cannot be fixed can also be removed during the procedure. These features make the medial hip approach a clinically-relevant treatment option for the surgical management of femoral head fractures. PMID- 26044531 TI - Diagnostic accuracy of bone turnover markers as a screening tool for aseptic loosening after total hip arthroplasty. AB - Aseptic loosening is the most common cause of prosthesis failure after total hip arthroplasty (THA). We measured serum cross-linked carboxyterminal telopeptide of type I collagen (ICTP), tartrate-resistant acid phosphatase 5b (TRAP5b), dickkopf 1 (dkk-1) and sclerostin; and urinary alpha isomer of C-terminal cross-linked telopeptide of type I collagen (alphaCTX-I) to investigate their potential diagnostic value detecting aseptic loosening after THA. Biomarkers were measured in 24 subjects with aseptic loosening of THA versus 26 control subjects without loosening after THA. Serum ICTP in the loose group (7.04 ng/mL) was higher than controls (5.15 ng/mL), (p = 0.0007). ROC analysis demonstrated that a serum ICTP >5.5 ng/L had a sensitivity of 91% and specificity of 69% for detecting aseptic loosening (area under ROC curve = 0.77, p = 0.0001), resulting in a positive predictive value (PPV) of 73% and a negative predictive value (NPV) of 90%. Serum TRAP5b in the aseptic loosening group (4.17U/L) was higher than controls (3.44 U/L), (p = 0.03). A serum TRAP5b >2.46 U/L had sensitivity of 100% and a specificity of 31% to detect aseptic loosening (AUC 0.67, p = 0.031), resulting in a PPV of 57% and a NPV of 100%. Serum dkk-1, serum sclerostin and urinary alphaCTX-I were not elevated in subjects with aseptic loosening (p>0.05). Serum ICTP and TRAP5b show potential utility as screening biomarkers for excluding aseptic loosening, because of their ability to discriminate individuals without disease. Our finding of elevated ICTP, generated by the action of matrix metalloproteinases, suggests a role for this group of endopeptidases in aseptic loosening. PMID- 26044532 TI - The seasonality of slipped upper femoral epiphysis--meta-analysis: a possible association with vitamin D. AB - We performed a meta-analysis of studies evaluating the seasonality of slipped upper femoral epiphysis (SUFE). In addition we compared the monthly incidences of SUFE at latitudes greater than 40 degrees with the established serum 25 hydroxyvitamin levels for children resident at a comparative latitude. In total 11 relevant studies were identified, involving 7451 cases of SUFE. There was significant variation in the month of onset of SUFE. The degree of variability increased with increasing latitude. The modal month of symptomatic onset was dependent upon latitude. At latitudes greater than 40 degrees , the most common month of onset was August. At latitudes between 20 degrees and 40 degrees , this was earlier in the calendar year, around April. The seasonal variability was statistically significant (p<0.0001 and p<0.005 for latitudes >40 degrees and 20 degrees -40 degrees respectively). The pattern of monthly fluctuation in onset of SUFE very closely mirrored the monthly pattern of variation for serum 25 hydroxyvitamin D3. There was a very strong positive correlation (Spearman rank rho = + 0.8, p = 0.001). There is a monthly variation in incidence of SUFE. The degree of variability increases with increasing latitude. There may be an association with vitamin D. We hypothesise that elevated serum 25-hydroxyvitamin D3 accelerates growth thus rendering the growth plate vulnerable to slippage in analogous manner to the pubertal growth spurt. PMID- 26044533 TI - The biological approach in acetabular revision surgery: impaction bone grafting and a cemented cup. AB - Acetabular impaction bone grafting (IBG) in combination with a cemented cup in revision total hip arthroplasty (THA) is a proven and well-recognised technique which has been used in clinical practice for more than 35 years. Nowadays, with cemented prostheses tending to lose a larger part of the THA market every year in primary and revision cases, and many young surgeons being only trained in implanting uncemented prostheses, this technique is considered by many as technically demanding and time consuming, making its use less appealing. Despite this image and many new innovative techniques using uncemented implants in acetabular revisions over the last 25 years, IBG with a cemented cup is still one of the few techniques that really can reconstitute bone and respects human biology. In this era of many biologically-based breakthroughs in medicine, it is hard to explain that the solution of most orthopaedic surgeons for the extensive bone defects as frequently seen during acetabular revision surgery, consists of implanting bigger and larger metal implants. This review aims to put the IBG method into a historical perspective, to describe the surgical technique and present the clinical results. PMID- 26044534 TI - Preoperative predictors of outcome in the arthroscopic treatment of femoroacetabular impingement. AB - AIMS: The aim of this study was to establish preoperative factors associated with a good outcome in the surgical treatment of femoroacetabular impingement. METHODS: A prospective study including 253 consecutive patients (280 hips) was carried out. We defined a "good" score as one which had either a 20 point improvement from preoperative to 12 months postoperative follow-up, or a score of over 80 points at 12-month follow-up in either the Non Arthritic Hip Score (NAHS) or Modified Harris Hip Score (MHHS). We analysed 9 potential predictors of 12 month postoperative outcome: patient age, gender, BMI, surgery type (primary/revision), preoperative anxiety level, preoperative labro-chondral damage, operative side, patients belonging to the armed forces and patients being treated under the workers compensation scheme. We used logistic regression (multivariable, adjusted) and, Fisher's exact test and student t test (bivariate, unadjusted) to analyse the data. RESULTS: A strong association between workers' compensation status and not achieving a good outcome following arthroscopic surgery for femoroacetabular impingement (odds ratio 3.84, 95% CI, 0.13-0.51, P<0.0001) was found. A negative effect on postoperative outcome was also observed with increased BMI, although this association was modest (odds ratio 1.06, 95% CI, 0.87-0.99 p = 0.03). Patients with a higher preoperative score did better at 12 months than the rest of the cohort. CONCLUSIONS: The data from this study may be useful for both patient and physician to consider when deciding on a suitable treatment in potential surgical candidates suffering from femoroacetabular impingement. PMID- 26044535 TI - The taper disaster--how could it happen? AB - Corrosion of metallic implants in contact with body fluids is unavoidable, especially at interfaces where movement occurs or in gaps. Corrosion became clinically relevant with the introduction of large modular metal-on-metal total hip joint articulations (MoM THA) early in the 21st century. This review attempts to summarise the scientific knowledge about taper problems available at the time of introduction of these bearings, why this "disaster" could happen. It is speculated that changes to the taper connection made in the 1990s to increase the range of motion with small heads (28 and 32 mm) reduced the mechanical strength of this connection, which did not matter for small heads. With the use of large and very large metal heads in MoM articulations, which have a larger lever arm and can generate high friction in unfavourable situations, suddenly the taper interface exhibited corrosion problems on a previously unknown scale. It is speculated that due to the higher mechanical loading with larger heads, the taper connection became less forgiving with respect to assembly conditions, contamination, manufacturing tolerances and other factors, which are yet not known. Since no major clinical problems had been reported before the introduction of these bearings and the pre-clinical testing was very successful, the disaster took its course. The patient-implant-surgeon system is a very complex intrinsically hazardous system. Pre-clinical testing addresses few and defined factors and such, good results cannot be directly transferred to the clinical reality. A controlled stepwise introduction of innovations is required. PMID- 26044536 TI - Hip arthroscopy: a focus on the future. AB - The indications for hip arthroscopy over the last decade have increased rapidly, driven by technical and technological advances aimed at hip joint preservation. This article reviews the current indications and supporting evidence for hip arthroscopy, explores some newer techniques/technologies and discusses the future directions in this rapidly evolving and expanding field. PMID- 26044537 TI - New cementless fixation in hip arthroplasty: a radiostereometric analysis. AB - INTRODUCTION: Scyon Orthopaedics AG developed a new mode of cementless fixation of the femoral component that provides immediate and permanent anchorage by monocortical locking screws. The aim of this study was to evaluate the stability of the Scyon total hip replacement (THR) stem in-vivo. METHODS: A total of 15 patients, with an average age of 50 years had surgery between 2008 and 2011. Each patient received a Scyon THR. Standard questionnaires were completed at each follow-up visit for evaluation of functional outcomes. RSA, patient reported outcomes, and plain radiographic follow-up were obtained at 6 months, 1 year, 2 years, and 5 years postoperatively. RESULTS: The median +/- standard error (SE) stem subsidence (negative y-translation) was 0.07 +/- 0.07 mm at 1 year, 0.05 +/- 0.04 mm at 2 years and 0.04 +/- 0.13 mm at 5 years. The median +/- SE stem rotation (y-rotation) was 0.1 +/- 0.21 degrees at 1 year, 0.51 +/- 0.31 degrees at 2 years and 0.60 +/- 0.37 degrees at 5 years. Plain radiographs showed bone on growth onto medial aspect of the stem. Median HHS improved from 55 preoperatively to 93 at 1 year and 97 at 5 years. The median UCLA Activity Score improved from 4 preoperatively to 6 at 1 year and 5 years. CONCLUSIONS: RSA results indicate that the Scyon stem with its 5 monocortical locking screws is stable at 5 years. Immediate surgical fixation of the stem and bony on-growth onto the femoral component may ultimately decrease the rate of aseptic stem loosening in these THR patients. PMID- 26044538 TI - Diagnosis of infected total hip arthroplasty. AB - Despite the battery of available tests, the diagnosis of periprosthetic joint infection (PJI) remains a challenge. A comprehensive medical history and physical examination with appropriate radiographs followed by erythrocyte sedimentation rate and serum C-reactive protein are the first-line screening test for patients with suspected hip PJI. The second line of investigation of patients with abnormal serology or a strong suspicion for PJI, is joint aspiration. Aspirates should be sent for assessment of white blood cell count, polymorphonuclear percentage, leukocyte esterase strip test, and microbiology. If the first attempt fails, the joint should be re-aspirated at a different time. The International Consensus recommends against infiltration of saline or other fluids into a "dry" joint. In patients not planned for surgery but need further evaluation for PJI, a nuclear imaging study may help. In others with a planned revision surgery, intraoperative samples for frozen section and culture study are the best measures available. Treatment strategies for PJI are well established in the literature. Poor surgical candidates receive oral suppressive antibiotic therapy alone. Acute PJI, presenting within 4 weeks of the index surgery, or as a result of bacteraemia, may be treated with irrigation and debridement and implant retention. Chronic PJI, occurring more than 4 weeks after initial surgery, is treated with 1-stage or 2-stage revision arthroplasty. In some persistent infections or patients who refuse to undergo revision surgery, salvage procedures may be needed. PMID- 26044539 TI - Endogenously and exogenously driven selective sustained attention: Contributions to learning in kindergarten children. AB - Selective sustained attention is vital for higher order cognition. Although endogenous and exogenous factors influence selective sustained attention, assessment of the degree to which these factors influence performance and learning is often challenging. We report findings from the Track-It task, a paradigm that aims to assess the contribution of endogenous and exogenous factors to selective sustained attention within the same task. Behavioral accuracy and eye-tracking data on the Track-It task were correlated with performance on an explicit learning task. Behavioral accuracy and fixations to distractors during the Track-It task did not predict learning when exogenous factors supported selective sustained attention. In contrast, when endogenous factors supported selective sustained attention, fixations to distractors were negatively correlated with learning. Similarly, when endogenous factors supported selective sustained attention, higher behavioral accuracy was correlated with greater learning. These findings suggest that endogenously and exogenously driven selective sustained attention, as measured through different conditions of the Track-It task, may support different kinds of learning. PMID- 26044540 TI - Interleukin-8-producing primary cardiac undifferentiated sarcoma in a child with sustained fever. AB - We report the case of a 12-year-old boy with primary undifferentiated sarcoma of the left atrium. He had sustained fever during the clinical course and multiple lung and brain metastases. Chemotherapy and irradiation were ineffective; he died 41 days after hospitalization. On retrospective analysis, interleukin-8 (IL-8) was elevated; this was supported by immunohistochemistry and gene expression analysis of tumor samples. IL-8 continued to increase with tumor progression accompanied by elevated neutrophil count and C-reactive protein. IL-8 is involved in malignant tumor proliferation, migration, and angiogenesis and may have been related to the clinical condition and prognosis in the present case. PMID- 26044541 TI - Intranasal immunization with an epitope-based vaccine results in earlier protection, but not better protective efficacy, against Helicobacter pylori compared to subcutaneous immunization. AB - The route of vaccination plays an important role in the generation of protective immunity against pathogens. In one of our previous studies, subcutaneous (SC) immunization with Epivac had been shown to induce a local and systemic Th1-biased response but failed to provide complete protection. In this study, we investigated whether intranasal (IN) immunization with Epivac could protect against Helicobacter pylori infection to a greater extent than SC immunization. Despite the generation of high serum IgG levels via the two routes of vaccination, the protective effect was independent of the humoral response level. At 2-week post-challenge, examination of the IgG subclass response showed that a dominant IgG2a response was generated after IN immunization, which coincided with elevated IFN-gamma production in both splenocytes and stomach homogenates, and a significant reduction in the H. pylori load was found. In contrast, a balanced Th1/Th2 response was induced by SC immunization at the same time point and no protective effect was observed. Two weeks later, the immune response in the SC vaccination groups shifted to Th1 and was equivalent in protection to the IN vaccination route. Our results showed that IN vaccination elicited earlier systemic and gastric Th1 response, which may contribute to the earlier protection compared to SC vaccination. PMID- 26044542 TI - Evaluation of Angiogenesis in Early Mycosis Fungoides Patients: Dermoscopic and Immunohistochemical Study. AB - BACKGROUND: Angiogenesis is the production of new blood vessels from an existing vascular network; it plays a critical role in solid tumor development and metastasis. OBJECTIVES: To assess angiogenesis in early cases of mycosis fungoides (MF) and to determine vascular patterns in MF dermoscopically. METHODS: 25 patients with MF and 20 healthy controls were included. The MF lesions were assessed dermoscopically. CD34 immunohistochemistry was performed to count dermal microvessel density (MVD). RESULTS: The total dermal MVD was significantly higher in MF patients (19.77 +/- 5.81) than in controls (4.44 +/- 3.16; p = 0.013). Among them, there were 10.8 +/- 4.1 sprouts of endothelial buds (clusters of cells per field) in patients and 2.4 +/- 2 in controls (p = 0.000). The dotted pattern of blood vessels was the most frequently encountered pattern in the MF lesions by dermoscopy. CONCLUSIONS: Our findings support that neoangiogenesis is significantly increased in early MF lesions and that the main dermoscopic feature of MF is dotted blood vessels. PMID- 26044544 TI - A Comparison of Telephone Genetic Counseling and In-Person Genetic Counseling from the Genetic Counselor's Perspective. AB - Growing demand for and limited geographic access to genetic counseling services is increasing the need for alternative service delivery models (SDM) like telephone genetic counseling (TGC). Little research has been done on genetic counselors' perspectives of the practice of TGC. We created an anonymous online survey to assess whether telephone genetic counselors believed the tasks identified in the ABGC (American Board of Genetic Counseling) Practice Analysis were performed similarly or differently in TGC compared to in person genetic counseling (IPGC). If there were differences noted, we sought to determine the nature of the differences and if additional training might be needed to address them. Eighty eight genetic counselors with experience in TGC completed some or all of the survey. Respondents identified differences in 13 (14.8%) of the 88 tasks studied. The tasks identified as most different in TGC were: "establishing rapport through verbal and nonverbal interactions" (60.2%; 50/83 respondents identified the task as different), "recognizing factors affecting the counseling interaction" (47.8%; 32/67), "assessing client/family emotions, support, etc." (40.1%; 27/66) and "educating clients about basic genetic concepts" (35.6%; 26/73). A slight majority (53.8%; 35/65) felt additional training was needed to communicate information without visual aids and more effectively perform psychosocial assessments. In summary, although a majority of genetic counseling tasks are performed similarly between TGC and IPGC, TGC counselors recognize that specific training in the TGC model may be needed to address the key differences. PMID- 26044543 TI - Evolutionary medicine and bone loss in chronic inflammatory diseases--A theory of inflammation-related osteopenia. AB - OBJECTIVE: Bone loss is typical in chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases, pemphigus vulgaris, and others. It is also typical in transplantation-related inflammation and during the process of aging. While we recognized that bone loss is tightly linked to immune system activation or inflamm-aging in the form of acute, chronic active, or chronic smoldering inflammation, bone loss is typically discussed to be an "accident of inflammation." METHODS: Extensive literature search in PubMed central. RESULTS: Using elements of evolutionary medicine, energy regulation, and neuroendocrine regulation of homeostasis and immune function, we work out that bone waste is an adaptive, evolutionarily positively selected program that is absolutely necessary during acute inflammation. However, when acute inflammation enters a chronic state due to the inability to terminate inflammation (e.g., in autoimmunity or in continuous immunity against microbes), the acute program of bone loss is a misguided adaptive program. CONCLUSIONS: The article highlights the complexity of interwoven pathways of osteopenia. PMID- 26044545 TI - Perspectives in Genetics and Sickle Cell Disease Prevention in Africa: Beyond the Preliminary Data from Cameroon. AB - Management of sickle cell disease (SCD) in Africa needs to be accompanied by various preventive strategies, including early detection via prenatal genetic diagnosis (PND). Contrary to Cameroonian doctors who considered termination of an affected pregnancy (TAP) for SCD in 36.1%, the majority of parents (62.5%) with affected children accepted TAP in principle. In practice, most women opted for TAP (90%), justified by a huge psycho-social burden. The ethical and legal challenges of PND prompted the need to explore the use of genetics for secondary prevention of SCD. In 610 Cameroonian SCD patients, the genomic variations in two principal foetal haemoglobin-promoting loci were significantly associated with foetal haemoglobin levels. In addition, the co-inheritance of a 3.7-kb alpha globin gene deletion and SCD was associated with a late disease onset and possibly improved survival: there was a much higher allele frequency of the 3.7 kb alpha-globin gene deletion in SCD patients (~ 40%) than in haemoglobin AA controls (~ 10%). The data indicate the urgent need to develop and implement policy actions in sub-Saharan Africa on at least four levels: (1) the implementation of SCD screening practices and early neonatal follow-up; (2) the development and incorporating of socio-economic support to alleviate the burden of SCD on affected families; (3) the exploration of the appropriateness of the medical abortion laws for SCD, and (4) the development of national plans for genetic medicine, including research on genomic variants that affect the phenotypes of SCD, in order to potentially use them for anticipatory guidance. PMID- 26044546 TI - Efficacy of Intravenous Lidocaine for Postoperative Analgesia Following Laparoscopic Surgery: A Meta-Analysis. AB - BACKGROUND: Intravenous (IV) lidocaine has analgesic and anti-inflammatory properties. This study aims to evaluate the efficacy of IV lidocaine in controlling postoperative pain following laparoscopic surgery. METHODS: A meta analysis of randomised controlled trials (RCTs) comparing IV lidocaine versus placebo/routine treatment for postoperative analgesia following laparoscopic surgery. The primary outcome was opiate requirement at 24 h. Secondary outcomes included cumulative opiate requirement, numerical pain scores (2, 12, 24, 48 h at rest and on movement), recovery indices (nausea and vomiting, length of stay, time until diet resumption, first flatus and bowel movement) and side effects (cardiac/neurological toxicity). Subgroup analyses were performed according to operation type and to compare IV lidocaine with intraperitoneal lidocaine. RESULTS: Fourteen RCTs with 742 patients were included. IV lidocaine was associated with a small but significant reduction in opiate requirement at 24 h compared with placebo/routine care. IV lidocaine was associated with reduced cumulative opiate requirement, reduced pain scores at rest at 2, 12 and 24 h, reduced nausea and vomiting and a shorter time until resumption of diet. The length of stay did not differ between groups. There was a low incidence of IV lidocaine-associated toxicity. In subgroup analyses, there was no difference between IV and intraperitoneal lidocaine in the measured outcomes. CONCLUSIONS: IV lidocaine has a multidimensional effect on the quality of recovery. IV lidocaine was associated with lower opiate requirements, reduced nausea and vomiting and a shorter time until resumption of diet. Whilst IV lidocaine appears safe, the optimal treatment regimen remains unknown. Statistical heterogeneity was high. PMID- 26044547 TI - Biased Agonism and Biased Allosteric Modulation at the CB1 Cannabinoid Receptor. AB - CB1 cannabinoid receptors (CB1Rs) are attractive therapeutic targets for numerous central nervous system disorders. However, clinical application of cannabinoid ligands has been hampered owing to their adverse on-target effects. Ligand-biased signaling from, and allosteric modulation of, CB1Rs offer pharmacological approaches that may enable the development of improved CB1R drugs, through modulation of only therapeutically desirable CB1R signaling pathways. There is growing evidence that CB1Rs are subject to ligand-biased signaling and allosterism. Therefore, in the present study, we quantified ligand-biased signaling and allosteric modulation at CB1Rs. Cannabinoid agonists displayed distinct biased signaling profiles at CB1Rs. For instance, whereas 2 arachidonylglycerol and WIN55,212-2 [(R)-(+)-[2,3-dihydro-5-methyl-3-(4 morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone] showed little preference for inhibition of cAMP and phosphorylation of extracellular signal-regulated kinase 1/2 (pERK1/2), N-arachidonoylethanolamine (anandamide), methanandamide, CP55940 [2-[(1R,2R,5R)-5-hydroxy-2-(3 hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol], and HU-210 [11-hydroxy Delta(8)-THC-dimethylheptyl] were biased toward cAMP inhibition. The small molecule allosteric modulator Org27569 [5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)ethyl]amide] displayed biased allosteric effects by blocking cAMP inhibition mediated by all cannabinoid ligands tested, at the same time having little or no effect on ERK1/2 phosphorylation mediated by a subset of these ligands. Org27569 also displayed negative binding cooperativity with [(3)H]SR141716A [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N (piperidin-1-yl)-1H-pyrazole-3-carboxamide]; however, it had minimal effects on binding of cannabinoid agonists. Furthermore, we highlight the need to validate the reported allosteric effects of the endogenous ligands lipoxin A4 and pregnenolone at CB1Rs. Pregnenolone but not lipoxin A4 displaced [(3)H]SR141716A, but there was no functional interaction between either of these ligands and cannabinoid agonists. This study demonstrates an approach to validating and quantifying ligand-biased signaling and allosteric modulation at CB1Rs, revealing ligand-biased "fingerprints" that may ultimately allow the development of improved CB1R-targeted therapies. PMID- 26044548 TI - Pharmacologic Inhibition of MNKs in Acute Myeloid Leukemia. AB - The Ras/Raf/MAPK and PI3K/Akt/mTOR pathways are key signaling cascades involved in the regulation of cell proliferation and survival, and have been implicated in the pathogenesis of several types of cancers, including acute myeloid leukemia (AML). The oncogenic activity of eIF4E driven by the Mnk kinases is a convergent determinant of the two cascades, suggesting that targeting the Mnk/eIF4E axis may provide therapeutic opportunity for the treatment of cancer. Herein, a potent and selective Mnk2 inhibitor (MNKI-85) and a dual-specific Mnk1 and Mnk2 inhibitor (MNKI-19), both derived from a thienopyrimidinyl chemotype, were selected to explore their antileukemic properties. MNKI-19 and MNKI-85 are effective in inhibiting the growth of AML cells that possess an M5 subtype with FLT3-internal tandem duplication mutation. Further mechanistic studies show that the downstream effects with respect to the selective Mnk1/2 kinase inhibition in AML cells causes G1 cell cycle arrest followed by induction of apoptosis. MNKI-19 and MNKI 85 demonstrate similar Mnk2 kinase activity and cellular antiproliferative activity but exhibit different time-dependent effects on cell cycle progression and apoptosis. Collectively, this study shows that pharmacologic inhibition of both Mnk1 and Mnk2 can result in a more pronounced cellular response than targeting Mnk2 alone. However, MNKI-85, a first-in-class inhibitor of Mnk2, can be used as a powerful pharmacologic tool in studying the Mnk2/eIF4E-mediated tumorigenic mechanism. In conclusion, this study provides a better understanding of the mechanism underlying the inhibition of AML cell growth by Mnk inhibitors and suggests their potential utility as a therapeutic agent for AML. PMID- 26044549 TI - Monoclonal antibody-conjugated superparamagnetic iron oxide nanoparticles for imaging of epidermal growth factor receptor-targeted cells and gliomas. AB - The objective of this study was to successfully synthesize epidermal growth factor receptor monoclonal antibody-conjugated superparamagnetic iron oxide nanoparticles (EGFRmAb-SPIONs) and explore their biocompatibility and potential applications as a targeted magnetic resonance imaging (MRI) contrast agent for the EGFR-specific detection of brain glioma in vivo. After conjugation of EGFRmAb with SPIONs, the magnetic characteristics of EGFRmAb-SPIONs were investigated. Thereafter, the targeting abilities of EGFRmAb-SPIONs with MRI were qualitatively and quantitatively assessed in EGFR-positive C6 glioma cells in vitro and in a Wistar rat model bearing C6 glioma in vivo. Furthermore, the preliminary biocompatibility and toxicity of EGFRmAb-SPIONs were evaluated in normal rats through hematology assays and histopathologic analyses. Statistical analysis was performed using one-way analysis of variance and Student t-test, with a significance level of p < .05. From the results of EGFRmAb-SPION characterizations, the average particle size was 10.21 nm and the hydrodynamic diameter was 161.5 +/- 2.12 nm. The saturation magnetization was 55 emu/g.Fe, and T2 relaxivity was 92.73 s-1mM-1 in distilled water. The preferential accumulation of the EGFRmAb-SPIONs within glioma and subsequent MRI contrast enhancement were demonstrated both in vitro in C6 cells and in vivo in rats bearing C6 glioma. After intravenous administration of EGFRmAb-SPIONs, T2-weighted MRI of the rat model with brain glioma exhibited an apparent hypointense region within glioma from 2 to 48 hours. The maximal image contrast was reached at 24 hours, where the signal intensity decreased and the R2 value increased by 30% compared to baseline. However, T2-weighted imaging of the rat model administered with SPIONs showed no visible signal changes within the tumor over the same time period. Moreover, no evident toxicities in vitro and in vivo with EGFRmAb-SPIONs were clearly identified based on the laboratory examinations. EGFRmAb-SPIONs could potentially be employed as a targeted contrast agent in the molecule-specific diagnosis of brain glioma in MRI. PMID- 26044550 TI - A Bayesian Partitioning Model for the Detection of Multilocus Effects in Case Control Studies. AB - BACKGROUND: Genome-wide association studies (GWASs) have identified hundreds of genetic variants associated with complex diseases, but these variants appear to explain very little of the disease heritability. The typical single-locus association analysis in a GWAS fails to detect variants with small effect sizes and to capture higher-order interaction among these variants. Multilocus association analysis provides a powerful alternative by jointly modeling the variants within a gene or a pathway and by reducing the burden of multiple hypothesis testing in a GWAS. METHODS: Here, we propose a powerful and flexible dimension reduction approach to model multilocus association. We use a Bayesian partitioning model which clusters SNPs according to their direction of association, models higher-order interactions using a flexible scoring scheme and uses posterior marginal probabilities to detect association between the SNP set and the disease. RESULTS: We illustrate our method using extensive simulation studies and applying it to detect multilocus interaction in Atherosclerosis Risk in Communities (ARIC) GWAS with type 2 diabetes. CONCLUSION: We demonstrate that our approach has better power to detect multilocus interactions than several existing approaches. When applied to the ARIC study dataset with 9,328 individuals to study gene-based associations for type 2 diabetes, our method identified some novel variants not detected by conventional single-locus association analyses. PMID- 26044551 TI - A mathematical method for quantifying in vivo mechanical behaviour of heel pad under dynamic load. AB - Mechanical behaviour of the heel pad, as a shock attenuating interface during a foot strike, determines the loading on the musculoskeletal system during walking. The mathematical models that describe the force deformation relationship of the heel pad structure can determine the mechanical behaviour of heel pad under load. Hence, the purpose of this study was to propose a method of quantifying the heel pad stress-strain relationship using force-deformation data from an indentation test. The energy input and energy returned densities were calculated by numerically integrating the area below the stress-strain curve during loading and unloading, respectively. Elastic energy and energy absorbed densities were calculated as the sum of and the difference between energy input and energy returned densities, respectively. By fitting the energy function, derived from a nonlinear viscoelastic model, to the energy density-strain data, the elastic and viscous model parameters were quantified. The viscous and elastic exponent model parameters were significantly correlated with maximum strain, indicating the need to perform indentation tests at realistic maximum strains relevant to walking. The proposed method showed to be able to differentiate between the elastic and viscous components of the heel pad response to loading and to allow quantifying the corresponding stress-strain model parameters. PMID- 26044552 TI - Determination of the unmetabolised (18)F-FDG fraction by using an extension of simplified kinetic analysis method: clinical evaluation in paragangliomas. AB - Tumours with high (18)F-FDG uptake values on static late PET images do not always exhibit high proliferation indices. These discrepancies might be related to high proportion of unmetabolised (18)F-FDG components in the tissues. We propose a method that enables to calculate different (18)F-FDG kinetic parameters based on a new mathematical approach that integrates a measurement error model. Six patients with diagnosed non-metastatic paragangliomas (PGLs) and six control patients with different types of lesions were investigated in this pilot study using (18)F-FDG PET/CT. In all cases, a whole-body acquisition was followed by four static acquisitions centred over the target lesions, associated with venous blood samplings. We used an extension of the Hunter's method to calculate the net influx rate constant (K H). The exact net influx rate constant and vascular volume fraction (K i and V, respectively) were subsequently obtained by the method of least squares. Next, we calculated the mean percentages of metabolised (PM) and unmetabolised (PUM) (18)F-FDG components, and the times required to reach 80 % of the amount of metabolised (18)F-FDG (T80%). A test-retest evaluation indicated that the repeatability of our approach was accurate; the coefficients of variation were below 2 % regardless of the kinetic parameters considered. We observed that the PGLs were characterised by high dispersions of the maximum standardised uptake value SUVmax (9.7 +/- 11, coefficient of variation CV = 114 %), K i (0.0137 +/- 0.0119, CV = 87 %), and V (0.292 +/- 0.306, CV = 105 %) values. The PGLs were associated with higher PUM (p = 0.02) and T80% (p = 0.02) values and lower k 3 (p = 0.02) values compared to the malignant lesions despite the similar SUVmax values (p = 0.55). The estimations of these new kinetic parameters are more accurate than SUVmax or K i for in vivo metabolic assessment of PGLs at the molecular level. PMID- 26044553 TI - Combined magnetic fields provide robust coverage for interbody and posterolateral lumbar spinal fusion sites. AB - Electromagnetic fields generated by spinal bone growth stimulation devices have been computationally modelled to determine coverage of the lumbar spinal vertebrae. The underlying assumption of these models was that the electric field, but not the magnetic field, was therapeutically relevant. However, there are no published studies examining the therapeutic coverage of spinal fusion sites by stimulators utilizing combined magnetic fields. To assess the coverage, an anatomical model of the vertebrae and discs of the lumbar spine was developed to represent interbody and posterolateral fusion sites. Computer simulations of the induced electromagnetic fields were analysed to determine coverage of the fusion sites. For both interbody and posterolateral fusion models, combined magnetic fields provided 100% coverage of the fusion sites for all intervertebral disc spaces and for all posterior planes from L1 to L5, respectively. Within the vertebral column, the magnitude of the electric field reached a maximum value of 3.6 * 10(-4) V/m, which is several orders of magnitude less than any reported study demonstrating a biological effect. Given its clinical efficacy, a bone growth stimulator utilizing combined magnetic fields must rely on the action of its magnetic field rather than its electric field for a therapeutic effect. PMID- 26044554 TI - Prediction of drug-induced eosinophilia adverse effect by using SVM and naive Bayesian approaches. AB - Drug-induced eosinophilia is a potentially life-threatening adverse effect; clinical manifestations, eosinophilia-myalgia syndrome, mainly include severe skin eruption, fever, hematologic abnormalities, and organ system dysfunction. Using experimental methods to evaluate drug-induced eosinophilia is very complicated, time-consuming, and costly in the early stage of drug development. Thus, in this investigation, we established computational prediction models of drug-induced eosinophilia using SVM and naive Bayesian approaches. For the SVM modeling, the overall prediction accuracy for the training set by means of fivefold cross-validation is 91.6 and for the external test set is 82.9 %. For the naive Bayesian modeling, the overall prediction accuracy for the training set is 92.5 and for the external test set is 85.4 %. Moreover, some molecular descriptors and substructures considered as important for drug-induced eosinophilia were identified. Thus, we hope the prediction models of drug-induced eosinophilia built in this work should be applied to filter early-stage molecules for potential eosinophilia adverse effect, and the selected molecular descriptors and substructures of toxic compounds should be taken into consideration in the design of new candidate drugs to help medicinal chemists rationally select the chemicals with the best prospects to be effective and safe. PMID- 26044555 TI - ASK1 is involved in cognitive impairment caused by long-term high-fat diet feeding in mice. AB - Although high-fat diet intake is known to cause obesity and diabetes, the effect of high-fat diet itself on cognitive function remains to be clarified. We have previously shown that apoptosis signal-regulating kinase 1 (ASK1) is responsible for cognitive impairment caused by chronic cerebral hypoperfusion. The present work, by using ASK1 deficient mice, was undertaken to explore the influence of chronic high-fat diet intake on cognitive function and the role of ASK1. Cognitive function in wild-type mice fed high-fat diet from 2 to 24 months of age was significantly impaired compared to those fed control diet, which was associated with the significant white matter lesions, reduction of hippocampal capillary density, and decrement of hippocampal neuronal cell. However, ASK1 deficiency abolished the development of cognitive impairment and cerebral injury caused by high-fat diet. Our results provided the evidence that high-fat diet itself causes cognitive impairment and ASK1 participates in such cognitive impairment. PMID- 26044556 TI - Efficacy and Safety of OM-85 in Patients with Chronic Bronchitis and/or Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: Recurrent acute exacerbations are generally associated with accelerated decline of lung function and characterized by reduced physical activity and worsening of clinical status in patients with chronic obstructive pulmonary disease (COPD). Effective practices and therapies aimed at preventing acute exacerbations are continuously under investigation by healthcare providers. This double-blind, placebo-control, randomized clinical trial sought to evaluate the preventive effect of a bacterial lysate (OM-85) on acute exacerbations in patients with COPD or chronic bronchitis in China. METHODS: A total of 428 patients were randomly assigned either to OM-85 treatment or to placebo. Patients received study drug or placebo for 10 days per month over 3 consecutive months, with a 10-week follow-up. Three hundred and eighty-four (384) patients completed the study (192 in the OM-85 group and 192 in the placebo group) and were included in the full analysis set (FAS). Thirty (30) patients, 21 in the OM-85 and 9 in the placebo groups, were excluded due to protocol violations and drop-outs, and the remaining 354 patients (171 in the OM-85 and 183 in the placebo groups) were included in the per protocol set (PPS). RESULTS: The proportion of patients with recurrent acute exacerbations in the OM-85 group was significantly lower than in the placebo group at the end of the treatment period, both, in the FAS (23.4 % vs. 33.3 %, p = 0.0311) and in the PPS (17.0 % vs. 31.2 %, p < 0.05). Throughout the entire 22-week study period, the proportion of patients with recurrent acute exacerbations in the OM-85 group was lower than in the placebo group in the FAS (32.8 % vs. 38.0 %, p = 0.277), while the difference is statistically significant in the PPS (26.3 % vs. 36.1 %, p < 0.05). CONCLUSION: OM-85 significantly reduced the proportion of patients with acute exacerbation after 12 weeks of therapy and the benefit appeared to be maintained up to 22 weeks, and showed a favorable tolerability profile. PMID- 26044557 TI - C9orf72 ablation in mice does not cause motor neuron degeneration or motor deficits. AB - OBJECTIVE: How hexanucleotide (GGGGCC) repeat expansions in C9ORF72 cause amyotrophic lateral sclerosis (ALS) remains poorly understood. Both gain- and loss-of-function mechanisms have been proposed. Evidence supporting these mechanisms in vivo is, however, incomplete. Here we determined the effect of C9orf72 loss-of-function in mice. METHODS: We generated and analyzed a conditional C9orf72 knockout mouse model. C9orf72(fl/fl) mice were crossed with Nestin-Cre mice to selectively remove C9orf72 from neurons and glial cells. Immunohistochemistry was performed to study motor neurons and neuromuscular integrity, as well as several pathological hallmarks of ALS, such as gliosis and TDP-43 mislocalization. In addition, motor function and survival were assessed. RESULTS: Neural-specific ablation of C9orf72 in conditional C9orf72 knockout mice resulted in significantly reduced body weight but did not induce motor neuron degeneration, defects in motor function, or altered survival. INTERPRETATION: Our data suggest that C9orf72 loss-of-function, by itself, is insufficient to cause motor neuron disease. These results may have important implications for the development of therapeutic strategies for C9orf72-associated ALS. PMID- 26044558 TI - Predictive value of vascular endothelial growth factor polymorphisms on the risk of renal cell carcinomas: a case-control study. AB - We conducted this case-control study to assess the role of vascular endothelial growth factor (VEGF) -2578C/A, +460T/C, +1612G/A, +936C/T, and -634G/C polymorphisms in the development of renal cell carcinoma (RCC), and analyzed the association of gene polymorphisms with demographic and clinical characteristics of RCC. This study included 412 consecutive primary RCC patients and 824 controls. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to detect VEGF -2578C/A, +460T/C, +1612G/A, +936C/T, and -634G/C polymorphisms. Compared with the control subjects, the RCC cancer cases were more likely to have a habit of cigarette smoking, and suffered from hypertension and diabetes. Conditional logistic regression analysis showed that individuals carrying the AA genotype of -2578C/A were more likely to greatly increase risk of RCC, and the CC genotype of +460T/C revealed a significant association with increased risk of RCC. The CA + AA genotype of -2578C/A had a significantly increased risk of RCC in ever cigarette smokers, and individuals who suffered from hypertension and diabetes. TC + CC genotype of +460T/C was significantly associated with the elevated risk of RCC in those suffered from hypertension and diabetes. Our study suggests that -2578C/A and +460T/C polymorphisms of VEGF modulate the risk of developing RCC in Chinese population. PMID- 26044559 TI - Clinicopathological significance and biological role of TCF21 mRNA in breast cancer. AB - TCF21 is known to function as a tumor suppressor and deregulated in several types of cancers; however, its role in breast cancer remains poorly understood. The aim of this study was to examine the expression of TCF21 messenger RNA (mRNA) in breast cancer and evaluate its clinical significance and biological role in tumor progression. TCF21 mRNA expression was analyzed in breast cancer cell lines and tissues by qRT-PCR. Overexpression approach was used to investigate the biological functions of TCF21 mRNA in breast cancer cell line (MDA-MB-231). A notably lower level of TCF21 mRNA expression was found in breast cancer cell lines and tissues. Furthermore, the low expression of TCF21 mRNA was associated with large tumor size and positive lymph node metastasis. Functional analysis showed that overexpression of TCF21 mRNA inhibited cell proliferation and epithelial-mesenchymal transition (EMT) of MDA-MB-231. In conclusion, our data provided the first evidence that TCF21 mRNA is significantly downregulated in breast cancer cell lines and tissues and regulates breast cancer cell proliferation and EMT. Thus, TCF21 may act as a potential therapeutic target for breast cancer intervention. PMID- 26044560 TI - Retinoic acid amide inhibits JAK/STAT pathway in lung cancer which leads to apoptosis. AB - Small cell lung cancer (SCLC) accounts for 12 to 16% of lung neoplasms and has a high rate of metastasis. The present study demonstrates the antiproliferative effect of retinoic acid amide in vitro and in vivo against human lung cancer cells. The results from MTT assay showed a significant growth inhibition of six tested lung cancer cell lines and inhibition of clonogenic growth at 30 MUM. Retinoic acid amide also leads to G2/M-phase cell cycle arrest and apoptosis of lung cancer cells. It caused inhibition of JAK2, STAT3, and STAT5, increased the level of p21WAF1, and decreased cyclin A, cyclin B1, and Bcl-XL expression. Retinoic acid amide exhibited a synergistic effect on antiproliferative effects of methotrexate in lung cancer cells. In lung tumor xenografts, the tumor volume was decreased by 82.4% compared to controls. The retinoic acid amide-treated tumors showed inhibition of JAK2/STAT3 activation and Bcl-XL expression. There was also increase in expression of caspase-3 and caspase-9 in tumors on treatment with retinoic acid amide. Thus, retinoic acid amide exhibits promising antiproliferative effects against human lung cancer cells in vitro and in vivo and enhances the antiproliferative effect of methotrexate. PMID- 26044561 TI - Application of chemokine receptor antagonist with stents reduces local inflammation and suppresses cancer growth. AB - Severe pain and obstructive jaundice resulting from invasive cholangiocarcinoma or pancreatic carcinoma can be alleviated by implantation of biliary and duodenal stents. However, stents may cause local inflammation to have an adverse effect on the patients' condition and survival. So far, no efficient approaches have been applied to prevent the occurrence of stents-related inflammation. Here, we reported significantly higher levels of serum stromal cell-derived factor 1 (SDF 1) in the patients that developed stents-associated inflammation. A higher number of inflammatory cells have been detected in the cancer close to stent in the patients with high serum SDF-1. Since chemokine plays a pivotal role in the development of inflammation, we implanted an Alzet osmotic pump with the stents to gradually release AMD3100, a specific inhibitor binding of SDF-1 and its receptor C-X-C chemokine receptor 4 (CXCR4), at the site of stents in mice that had developed pancreatic cancer. We found that AMD3100 significantly reduced local inflammation and significantly inhibited cancer cell growth, resulting in improved survival of the mice that bore cancer. Moreover, the suppression of cancer growth may be conducted through modulation of CyclinD1, p21, and p27 in the cancer cells. Together, these data suggest that inhibition of chemokine signaling at the site of stents may substantially improve survival through suppression of stent-related inflammation and tumor growth. PMID- 26044562 TI - Expression of cancer-associated fibroblast-related proteins in adipose stroma of breast cancer. AB - Cancer-associated fibroblasts (CAFs) play key roles in tumor microenvironment; they are thought to originate from adipocytes. This study aimed to evaluate CAF related protein expression and its implications in breast cancer. Of the 939 enrolled breast cancer patients, 642 had fibrous and 297 had adipose stroma. The status of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER-2), Ki-67, podoplanin, prolyl 4-hydroxylase, fibroblast activation protein alpha (FAPalpha), S100A4, platelet-derived growth factor receptor alpha (PDGFRalpha), PDGFRbeta, and chondroitin sulfate proteoglycan (NG2) was evaluated via tissue microarrays. Tumors were divided into luminal A, luminal B, HER-2, or triple-negative breast cancer subtypes according to their molecular status. Luminal A subtype was more prevalent in breast cancer of adipose stroma type, whereas other molecular subtypes were more common in fibrous stroma type (p < 0.001). Tumor cell expression of podoplanin and FAPalpha was higher in adipose stroma type, while higher expression of prolyl 4-hydroxylase and PDGFRalpha was observed in fibrous stroma type. Furthermore, adipose stroma type exhibited higher stromal expression of podoplanin, FAPalpha, PDGFRbeta, and NG2, whereas fibrous stroma type had higher prolyl 4-hydroxylase and S100A4 expression. In adipose stroma type, tumor positivity (p = 0.034) and stromal positivity (p = 0.005) of prolyl 4-hydroxylase were associated with shorter disease-free survival, and stromal prolyl 4-hydroxylase positivity was with shorter overall survival (p < 0.001). In conclusion, expression of CAF-related proteins was observed in breast cancer, with different profiles between adipose and fibrous stroma types. Prolyl 4-hydrolase status might be of prognostic value in adipose stroma type. PMID- 26044563 TI - Regulation of MET-mediated proliferation of thyroid carcinoma cells by miR-449b. AB - Thyroid carcinoma (TC) is a lethal cancer worldwide, whereas its carcinogenesis is not fully understood. Although growing evidence has demonstrated that dysregulation of microRNAs (miRNAs) contributes to the development of various cancers, the role of miRNAs in the pathogenesis of TC is poorly characterized. Here, we analyzed the levels of miR-449b in TC tissues and detected significantly lower miR-449b levels in TC tissues. Moreover, the low miR-449b levels were associated with poor survival. We then overexpressed miR-449b by miRNA mimic transfection and inhibited miR-449b by miRNA antisense transfection. Cell growth was analyzed by CCK-8 assay and MTT assay, and apoptosis and cell proliferation were analyzed by flow cytometry. Overexpression of miR-449b significantly inhibited cell growth, while depletion of miR-449b increased cell growth. Moreover, the effects of miR-449b on cell growth were through modulation of cell proliferation rather than through modulation of cell apoptosis. Targeted genes were predicted by a bioinformatics algorithm and confirmed by a dual luciferase reporter assay, showing that miR-449b binds to the 3'-UTR of MET (hepatocyte growth factor receptor) mRNA, to inhibit its expression in TC cells. MET levels were regulated by miR-449b in TT cells. Together, we show that reduced miR-449b levels in TT tissues may promote TC growth, through MET-mediated cell proliferation. PMID- 26044564 TI - Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway. AB - Rab31 belongs to the Ras superfamily of small GTP-binding proteins, which has been found to regulate the vesicle transport from the Golgi apparatus to early and late endosomes. The investigation here detected the expression of Rab31 in 96 patients with hepatocellular carcinoma (HCC) and tried to identify its significance on outcome of HCCs after liver resection. By immunohistochemistry staining, it was found that Rab31 expression in HCC tissues was remarkably higher than that in adjacent liver tissues. Aberrant Rab31 overexpression in HCC tissues was identified to be associated with worse prognosis after liver resection. Univariate analysis showed that advanced tumor-nodes-metastasis (TNM) staging of HCC, intrahepatic metastases, portal vein invasion, and higher Rab31 were the predictive factors of poor prognosis. Multivariate analysis demonstrated that intrahepatic metastases and higher Rab31 were the independent prognostic factors. Furthermore, forced expression of Rab31 in Huh7 cells was found to promote cell growth via upregulation of Bcl-2/BAX ratio induced by PI3K/AKT. Correspondingly, silencing Rab31 induced cell apoptosis and in turn suppressed the growth capacity of MHCC97 cells in vitro. Taken together, this study provides the evidence of Rab31 overexpression in HCC, and Rab31 is potentially used as a novel biomarker of poor prognosis in patients with HCC. PI3K/AKT/Bcl-2/BAX axis was involved in Rab31-promoting HCC progression. PMID- 26044565 TI - Risk of high-grade cervical dysplasia and gynaecological malignancies following the cytologic diagnosis of atypical endocervical cells of undetermined significance: a retrospective study of a state-wide screening population in Western Australia. AB - BACKGROUND: In 2006, Australia adopted a revised cervical cytology terminology system, known as the Australian Modified Bethesda System (AMBS). One substantial change in the AMBS was the introduction of the diagnostic category of atypical endocervical cells (AEC) of undetermined significance. AIM: The aim of this study was to investigate the incidence of histologically confirmed high-grade cervical dysplasia (cervical intra-epithelial neoplasia (CIN) grades 2 and 3 and adenocarcinoma in situ (ACIS)), cervical carcinoma and endometrial carcinoma in women presenting with AEC on cervical cytology. METHODS: A seven-year retrospective study examining clinical outcomes of women with AEC on a screening cervical smear. Cytology and histology results were extracted from the Western Australia Cervical Screening Registry, and time-to-event analysis was used to predict the odds of having or developing in situ and invasive neoplasia. RESULTS: AEC was reported in index smears from 0.093% (584/622754) women during the study period. No follow-up was available in 35 AEC cases. Sixty-five of the remaining 549 women (11.8%) had, or developed, high-grade cervical dysplasia within five years of their index AEC diagnosis. Endometrial cancer was diagnosed in 21 women and cervical cancer in four women during the follow-up period. CONCLUSION: Cytologic demonstration of AEC requires careful gynaecologic evaluation, particularly in younger women who may be found to have either high-grade squamous (CIN) or glandular (ACIS) lesions, while in older women, the possibility of endometrial neoplasia needs to be considered. PMID- 26044567 TI - Application of the Bethesda System for Reporting Thyroid Cytopathology in the Eastern Province of Saudi Arabia: A Follow-Up Study. AB - This is a follow-up study to our previous analysis of thyroid aspirates utilizing the Bethesda System for Reporting Thyroid Cytology (BSRTC). The same study design was utilized for 2 years comparing 2 periods. A total of 251 thyroid aspirates from 218 patients were reviewed and deemed comparable to the previous cohort. The variance and consequently the number of interpretations dropped from 26 to 11 with a statistically significant 58% reduction and more consistency. Our unsatisfactory rate dropped from 22 to 10% (reduction of 55%). The risk of malignancy in this follow-up study showed a similar trend: an increase in risk with each step up in the BSRTC categories starting from the 'nondiagnostic' and up to 'malignant'. Few of our benign cases ended up with resection. We noticed sensitivity to the word 'follicular' in this benign category; therefore we propose a modification of the current BSRTC system by omitting the word 'follicular' from the benign category. We strongly believe that this modification harbors no serious damage to the intentions of BSRTC. This follow-up study has shown that the previous awareness campaign about the implementation has worked and can be considered a valid performance improvement program. PMID- 26044568 TI - The Epidemiological, Mechanistic and Potential Clinical Role of Androgen Receptor (AR) in Urothelial Carcinoma. AB - The androgen receptor (AR) is a ligand-inducible transcription factor that regulates target gene expression. Androgen signaling has been considered a putative explanation for gender differences in urothelial carcinoma (UC) incidence. In the absence of established risk factors, men still experience a threefold risk of UC as compared to women. Multiple investigations to modulate the AR have been performed with in vitro and in vivo models of UC. Down regulation of the AR has been shown to inhibit UC growth through increased apoptosis, decreased cell proliferation, and decreased cell migration. AR activation up-regulates EGFR and HER2/neu expression contributing to UC progression. UC is more easily induced in male than female models and the incidence of chemically-induced UC is decreased by castration and the addition of estrogens; it is increased by testosterone. Epithelial to mesenchymal transition (EMT) has been postulated to be androgen-driven in UC and affects chemotherapy sensitivity. UC has not achieved the same therapeutic advances that have been seen in other tumor types in recent years. Androgen-driven events may account for some of the treatment resistance seen in this tumor type. Novel agents which disrupt androgen synthesis and/or AR signaling are in development and some (abiraterone, enzalutamide) are approved for advanced prostate cancer. Biomarker AR-driven clinical trials of highly effective anti-androgen therapy (HEAT) agents in UC present a promising picture. PMID- 26044566 TI - Rationale and design of the PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage (PICASSO) study: A randomized controlled trial. AB - RATIONALE: Prior intracerebral haemorrhage and cerebral microbleeds may increase the risk of haemorrhagic stroke. However, the optimal long-term antiplatelet therapy and lipid management in these patients remain unclear. AIM: PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage was designed to compare cilostazol and aspirin and to assess the effect of adding probucol, a lipid-lowering and anti-oxidative agent, in patients at high risk of haemorrhagic stroke. SAMPLE SIZE ESTIMATE: The projected sample size is 1600 patients with at least 12 months of follow-up. METHODS AND DESIGN: PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage is a randomized trial involving 67 institutes from 3 countries. Patients with non-cardioembolic ischemic stroke or transient ischemic attack within 180 days and with prior intracerebral haemorrhage or multiple cerebral microbleeds on gradient echo imaging are eligible. Enrolled patients are simultaneously randomized in a 2 * 2 factorial design: double-blind for cilostazol 200 mg/day vs. aspirin 100 mg/day, and an open-label, blind end-point evaluation for probucol 500 mg/day vs. non-probucol. STUDY OUTCOMES: The co primary end-points are the safety end-point of haemorrhagic stroke and the efficacy end-point of a composite of stroke, myocardial infarction, or vascular death. Time-to-event will be analyzed separately for each intervention: superiority testing for the safety of cilostazol over aspirin as well as the efficacy of probucol over non-probucol, and non-inferiority testing for the efficacy of cilostazol to aspirin. DISCUSSION: PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage is the largest secondary stroke prevention trial for informing antiplatelet therapy and lipid management in patients at high risk of haemorrhagic stroke. PMID- 26044569 TI - Carbohydrate-responsive element-binding protein, Sirtuin 1, and ethanol metabolism: a complicated network in alcohol-induced hepatic steatosis. PMID- 26044570 TI - All-trans retinoic Acid reduces joint adhesion formation: an experimental study in rats. AB - BACKGROUND: Intra-articular adhesion is a common complication in post-surgical knees. The formation of post-surgical joint adhesion could lead to serious conditions. All-trans retinoic acid (ATRA) is a physiological metabolite of vitamin A that has a wide range of biological activities. The aim of the study was to verify the effects of (ATRA) in preventing adhesions in the post-operative rat knee. MATERIAL AND METHODS: Eighty healthy adult male Wistar rats underwent femoral condyle-exposing surgery. After surgery, cotton pads soaked with the vehicle or various concentrations of ATRA (0.1%, 0.05%, 0.025%) were applied to the surgery site for 5 min. The post-surgical knee joints were fixed with micro Kirschner wires in a flexed position for 4 weeks. The rats were killed 4 weeks after surgery. The effect of ATRA on the prevention of intra-articular adhesion was evaluated using histological analyses, hydroxyproline content, visual score, and inflammatory factor activity evaluation. RESULTS: No obvious postoperative complications or signs of infection in the rats were observed. None of the rats died before the scheduled time. The rats in the 0.1% ATRA group showed better outcomes, as suggested by the visual scores, hydroxyproline contents, and inflammatory factors expressional levels, than the other 2 groups. The local application of 0.1% ATRA was able to suppress adhesions, collagen expression, and inflammatory activity in the post-surgical rat knees. CONCLUSIONS: In the rat knee surgery model, the application of intra-articular ATRA was able to decrease intra-articular scar adhesion formation, collagen expression, and inflammatory activities. ATRA was found to work in a dose-dependent manner, with 0.1% being possible optimal concentration. PMID- 26044571 TI - Associations between healthy lifestyles and health outcomes among older Koreans. AB - AIM: Healthy lifestyles have been found to be positively associated with physical and mental health outcomes in later life. Although multiple health behaviors have the potential to enhance health among older adults, little is known about a multiple behavior approach. Therefore, the purpose of the present study was to examine the relationship between multiple healthy lifestyles and health outcomes among Korean older adults. METHODS: The study sample consisted of 3844 Korean older adults aged 65 years and older from a cross-section sample being followed in the nationally representative dataset, the 2012 Korean Longitudinal Study of Ageing. Healthy lifestyles included non-smoking, normal drinking, physical activity and normal weight. Adjusting for covariates (age, sex, marital status, education, household income and having chronic condition), a multivariate logistic regression was carried out to examine self-rated health, disability, cognitive impairment and depression as four individual health outcomes. RESULTS: Compared with respondents with no healthy lifestyle factors, respondents with at least one healthy lifestyle factor had better self-rated health, respondents with at least two healthy lifestyle factors had reduced risk of disability, and respondents with at least three healthy lifestyle factors had reduced risk of cognitive impairment. Interestingly, having just two or three healthy lifestyle factor was associated with reduced risk of depression. CONCLUSIONS: These results suggest that older Koreans with more healthy lifestyles are healthier than those with less healthy lifestyles. Also, the association between multiple healthy lifestyle factors and health outcomes is different by specific health outcome, showing different mechanisms between multiple healthy lifestyle factors and each health outcome. Geriatr Gerontol Int 2015; ??: ??-??. PMID- 26044573 TI - Access to emergency room for hypoglycaemia in people with diabetes. AB - BACKGROUND: Hypoglycaemia is a major burden of the pharmacological therapy of diabetes and is associated with increased morbidity, mortality and treatment costs. METHODS: We screened all admissions to the emergency room of the Pisa University Hospital from 1 January 2009 to 31 December 2013, selecting individuals with a discharge diagnosis of hypoglycaemia. We retrieved 500 admissions involving adult diabetic patients: age 71 +/- 16 years; M/F 50.2/49.8%; 70.2% type 2 diabetes (T2DM). RESULTS: Among T2DM, 42.2% were on insulin, 10.8% on insulin plus oral anti-diabetes drugs and 38.2% on oral anti diabetes drugs alone (92% sulphonylureas/glinides +/- insulin-sensitizers). Glibenclamide was the most frequently used sulphonylurea (69%). Individuals treated with oral anti-diabetes drugs were older than those on insulin (79 +/- 11 versus 74 +/- 12 years; p < 0.0001). Among patients taking sulphonylurea, 47% had estimated glomerular filtration rate <60 mL/min/1.73 m(2) and 13.5% had <30 mL/min/1.73 m(2) . In-hospital admission occurred in 20% of cases. Hospitalized patients with T2DM were older than those discharged (80 +/- 10 versus 76 +/- 12 years, p < 0.01) and were on oral antidiabetic drugs in 54.8% of the cases, whereas 35.7% were on insulin (chi(2) , p < 0.0001) and 8.3% on combined therapy. Notably, 93.5% of those on oral anti-diabetic drugs were taking a secretagogue. Insulin-treated subjects were younger than those treated with oral anti-diabetic drugs alone (77 +/- 12 versus 82 +/- 7 years; p < 0.02). The mean in-hospital annual mortality rate was 85 deaths per 1000 patients-year. CONCLUSIONS: Our results support the recommendation that the risk associated with insulin and insulin-secretagogues should be carefully assessed, particularly when prescribed in vulnerable patients with T2DM. PMID- 26044574 TI - Treatment of severe renal disease in ANCA positive and negative small vessel vasculitis with rituximab. AB - BACKGROUND/AIMS: Rituximab and glucocorticoids are a non-inferior alternative to cyclophosphamide and glucocorticoid therapy for induction of remission in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) patients with moderate renal disease. The efficacy and safety of this approach in patients with severe renal impairment are unknown. We report the outcomes and safety profile of rituximab and glucocorticoid therapy for induction of remission in patients with AAV and ANCA-negative vasculitis presenting with severe renal disease. METHODS: A multicenter, retrospective, cohort study was conducted between 2005 and 2014. Patients with new or relapsing disease with an estimated glomerular filtration rate (eGFR) of <=20 ml/min/1.73 m(2) treated with rituximab and glucocorticoid induction with or without plasmapheresis were included. Fourteen patients met the inclusion criteria. The primary outcomes were rate of remission and dialysis independence at 6 months. The secondary outcomes were eGFR at 6 months, end-stage renal disease (ESRD), survival rates and adverse events. RESULTS: All patients were Caucasian, and 57% were male. The mean eGFR was 12 ml/min/1.73 m(2) at diagnosis. All patients achieved remission with a median time to remission of 55 days. Seven patients required dialysis at presentation of which 5 patients recovered renal function and discontinued dialysis by 6-month follow-up. The mean eGFR for the 11 patients without ESRD who completed 6-month follow-up was 33 ml/min/1.73 m(2). Four patients ultimately developed ESRD, and one died during the follow-up period. CONCLUSION: Patients with AAV and severe renal disease achieve high rates of remission and dialysis independence when treated with rituximab and glucocorticoids without cyclophosphamide. PMID- 26044575 TI - Stretchable and Tunable Microtectonic ZnO-Based Sensors and Photonics. AB - The concept of realizing electronic applications on elastically stretchable "skins" that conform to irregularly shaped surfaces is revolutionizing fundamental research into mechanics and materials that can enable high performance stretchable devices. The ability to operate electronic devices under various mechanically stressed states can provide a set of unique functionalities that are beyond the capabilities of conventional rigid electronics. Here, a distinctive microtectonic effect enabled oxygen-deficient, nanopatterned zinc oxide (ZnO) thin films on an elastomeric substrate are introduced to realize large area, stretchable, transparent, and ultraportable sensors. The unique surface structures are exploited to create stretchable gas and ultraviolet light sensors, where the functional oxide itself is stretchable, both of which outperform their rigid counterparts under room temperature conditions. Nanoscale ZnO features are embedded in an elastomeric matrix function as tunable diffraction gratings, capable of sensing displacements with nanometre accuracy. These devices and the microtectonic oxide thin film approach show promise in enabling functional, transparent, and wearable electronics. PMID- 26044578 TI - Dexmedetomidine improves the quality of the operative field for functional endoscopic sinus surgery: systematic review. AB - BACKGROUND: Intra-operative bleeding diminishes visualisation during functional endoscopic sinus surgery and can cause unfavourable outcomes. Dexmedetomidine is a potent alpha-2 agonist, with sympatholytic effects. This systematic review aimed to assess whether dexmedetomidine decreases intra-operative bleeding and improves operative field quality. METHODS: All randomised, controlled trials that assessed the ability of dexmedetomidine to provide good operative fields for functional endoscopic sinus surgery were identified from Medline and Embase. The outcomes of interest were: operative field quality, intra-operative bleeding, operative time and adverse events. RESULTS: Five studies (254 patients) met the inclusion criteria. When compared to saline, dexmedetomidine improved the quality of the operative field. The operative time was similar between groups. When compared to other drugs, dexmedetomidine was as effective as esmolol and remifentanil. There were no adverse incidents. CONCLUSION: Dexmedetomidine is beneficial in providing good visibility during functional endoscopic sinus surgery. Controlled hypotensive anaesthesia with this medicine decreases intra operative bleeding and enhances surgical field quality. PMID- 26044572 TI - TCTEX1D2 mutations underlie Jeune asphyxiating thoracic dystrophy with impaired retrograde intraflagellar transport. AB - The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retrograde intraflagellar transport (IFT) in humans and the protist Chlamydomonas, accompanied by destabilization of the retrograde IFT dynein motor. We thus define TCTEX1D2 as an integral component of the evolutionarily conserved retrograde IFT machinery. In complex with several IFT dynein light chains, it is required for correct vertebrate skeletal formation but may be functionally redundant under certain conditions. PMID- 26044576 TI - Development of an attention-touch control for manual cervical distraction: a pilot randomized clinical trial for patients with neck pain. AB - BACKGROUND: Manual cervical distraction (MCD) is a traction-based therapy performed with a manual contact over the cervical region producing repeating cycles while patients lie prone. This study evaluated a traction force-based minimal intervention for use as an attention-touch control in clinical trials of MCD for patients with chronic neck pain. METHODS: We conducted a mixed-methods, pilot randomized clinical trial in adults with chronic neck pain. Participants were allocated to three traction force ranges of MCD: low force/minimal intervention (0-20 N), medium force (21-50 N), or high force (51-100 N). Clinicians delivered five treatments over two weeks consisting of three sets of five cycles of MCD at the C5 vertebra and occiput. Traction forces were measured at each treatment. Patient-reported outcomes included a pain visual analogue scale (VAS), Neck Disability Index (NDI), Credibility and Expectancy Questionnaire (CEQ), and adverse effects. A qualitative interview evaluated treatment group allocation perceptions. RESULTS: We randomized 48 participants, allocating an average of five each month. Forty-five participants completed the trial with three participants lost to follow-up. Most participants were women (65%) and white (92%) with a mean (SD) age of 46.8 (12.5) years. Mean traction force values were within the prescribed force ranges for each group at the C5 and occiput levels. Neck pain VAS demonstrated a benefit for high traction force MCD compared to the low force group [adjusted mean difference 15.6; 95% confidence interval (CI) 1.6 to 29.7]. Participants in the medium traction force group demonstrated improvements in NDI compared to the low force group (adjusted mean difference 3.0; 95% CI 0.1 to 5.9), as did participants in the high traction force group (adjusted mean difference 2.7; 95% CI -0.1 to 5.6). CEQ favored the high force group. Most low force participants correctly identified their treatment allocation in the qualitative interview. No serious adverse events were documented. CONCLUSIONS: This pilot study demonstrated the feasibility of a clinical trial protocol and the utility of a traction-based, minimal intervention as an attention-touch control for future efficacy trials of MCD for patients with neck pain. TRIAL REGISTRATION: ClinicalTrials.gov NCT01765751 (Registration Date 30 May 2012). PMID- 26044579 TI - Population pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents. AB - AIM: In view of the increasing prevalence of obesity in adolescents, the aim of this study was to determine the pharmacokinetics of the CYP3A substrate midazolam and its metabolites in overweight and obese adolescents. METHODS: Overweight (BMI for age >= 85(th) percentile) and obese (BMI for age >= 95(th) percentile) adolescents undergoing surgery received 2 or 3 mg intravenous midazolam as a sedative drug pre-operatively. Blood samples were collected until 6 or 8 h post dose. Population pharmacokinetic modelling and systematic covariate analysis were performed using nonmem 7.2. RESULTS: Nineteen overweight and obese patients with a mean body weight of 102.7 kg (62-149.8 kg), a mean BMI of 36.1 kg m(-2) (24.8 55 kg m(-2)), and a mean age of 15.9 years (range 12.5-18.9 years) were included. In the model for midazolam and metabolites, total body weight was not of influence on clearance (0.66 l min(-1) (RSE 8.3%)), while peripheral volume of distribution of midazolam (154 l (11.2%)), increased substantially with total body weight (P < 0.001). The increase in peripheral volume could be explained by excess body weight (WTexcess ) instead of body weight related to growth (WTfor age and length ). CONCLUSIONS: The pharmacokinetics of midazolam and its metabolites in overweight and obese adolescents show a marked increase in peripheral volume of distribution and a lack of influence on clearance. The findings may imply a need for a higher initial infusion rate upon initiation of a continuous infusion in obese adolescents. PMID- 26044580 TI - G7 leaders are urged to commit to health emergency response. PMID- 26044581 TI - Associations of ApoAI and ApoB-containing lipoproteins with AngII-induced abdominal aortic aneurysms in mice. AB - OBJECTIVE: Dyslipidemia is implicated in abdominal aortic aneurysms (AAAs) in humans and angiotensin (Ang) II-infused mice. This study determined effects of major lipoprotein classes on AngII-induced AAAs using multiple mouse strains with dietary and pharmacological manipulations. APPROACH AND RESULTS: Western diet had minor effects on plasma cholesterol concentrations and the low incidence of AngII induced AAAs in C57BL/6J mice. Low incidence of AAAs in this strain was not attributed to protection from high-density lipoprotein, because apolipoprotein (apo) AI deficiency did not increase AngII-induced AAAs. ApoAI deletion also failed to alter AAA occurrence in hypercholesterolemic mice. Low-density lipoprotein receptor-/- mice fed normal diet had low incidence of AngII-induced AAAs. Western diet feeding of this strain provoked pronounced hypercholesterolemia because of increased apoB-containing lipoproteins with attendant increases of atherosclerosis in both sexes, but AAAs only in male mice. ApoE-deficient mice fed normal diet were modestly hypercholesterolemic, whereas this strain fed Western diet was severely hypercholesterolemic because of increased apoB-containing lipoprotein concentrations. The latter augmented atherosclerosis, but did not change the high incidence of AAAs in this strain. To determine whether reductions in apoB-containing lipoproteins influenced AngII induced AAAs, ezetimibe was administered at a dose that partially reduced plasma cholesterol concentrations to ApoE-deficient mice fed Western diet. This decreased atherosclerosis, but not AAAs. This ezetimibe dose in ApoE-deficient mice fed normal diet significantly decreased plasma apoB-containing lipoprotein concentrations and reduced AngII-induced AAAs. CONCLUSIONS: ApoB-containing lipoproteins contribute to augmentation of AngII-induced AAA in male mice. However, unlike atherosclerosis, AAA occurrence was not correlated with increases in plasma apoB-containing lipoprotein concentrations. PMID- 26044583 TI - Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. AB - OBJECTIVE: In addition to P2Y12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function. APPROACH AND RESULTS: Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks. (1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%+/-1.8%; P<0.001) and 30 mg/kg (21.4%+/-2.6%; P<0.001) versus control (45.3+/-1.7%), whereas clopidogrel had no effect (42.4%+/-2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%+/ 3.5%) versus sham (77.6%+/-0.9%). All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%+/-1.6%), chronic (69.2%+/-1.0%), and acute+chronic (76.3%+/-1.2%), whereas clopidogrel had no effect (37.4%+/-3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-alpha, interleukin-1beta, and interleukin-18, and increased anti-inflammatory 15-epi lipoxin-A4 levels. CONCLUSIONS: Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect. PMID- 26044582 TI - Inflammatory cell phenotypes in AAAs: their role and potential as targets for therapy. AB - Abdominal aortic aneurysms (AAAs) are characterized by chronic inflammatory cell infiltration. AAA is typically an asymptomatic disease and caused ~15 000 deaths annually in the United States. Previous studies have examined both human and murine aortic tissue for the presence of various inflammatory cell types. Studies show that in both human and experimental AAAs, prominent inflammatory cell infiltration, such as CD4(+) T cells and macrophages, occurs in the damaged aortic wall. These cells have the ability to undergo phenotypic modulation based on microenvironmental cues, potentially influencing disease progression. Proinflammatory CD4(+) T cells and classically activated macrophages dominate the landscape of aortic infiltrates. The skew to proinflammatory phenotypes alters disease progression and plays a role in causing chronic inflammation. The local cytokine production and presence of inflammatory mediators, such as extracellular matrix breakdown products, influence the uneven balance of the inflammatory infiltrate phenotypes. Understanding and developing new strategies that target the proinflammatory phenotype could provide useful therapeutic targets for a disease with no current pharmacological intervention. PMID- 26044584 TI - ABO Blood Group as a Model for Platelet Glycan Modification in Arterial Thrombosis. AB - ABO blood groups have long been associated with cardiovascular disease, thrombosis, and acute coronary syndromes. Many studies over the years have shown type O blood group to be associated with lower risk of cardiovascular disease than non-type O blood groups. However, the mechanisms underlying this association remain unclear. Although ABO blood group is associated with variations in concentrations of circulating von Willebrand Factor and other endothelial cell adhesion molecules, ABO antigens are also present on several platelet surface glycoproteins and glycosphingolipids. As we highlight in this platelet-centric review, these glycomic modifications may affect platelet function in arterial thrombosis. More broadly, improving our understanding of the role of platelet glycan modifications in acute coronary syndromes may inform future diagnostics and therapeutics for cardiovascular diseases. PMID- 26044585 TI - Chromatin Modifications Associated With Diabetes and Obesity. AB - The incidence of obesity across the globe has doubled over the past several decades, leading to escalating rates of diabetes mellitus, cardiovascular disease, and other complications. Given this dramatic rise in disease incidence, understanding the cause of these diseases is therefore of paramount importance. Metabolic diseases, such as obesity and diabetes mellitus, result from a multitude of genetic and environmental factors. Although the genetic basis of these diseases has been extensively studied, the molecular pathways whereby environmental factors influence disease progression are only beginning to be understood. One manner by which environmental factors can contribute to disease progression is through modifications to chromatin. The highly structured packaging of the genome into the nucleus through chromatin has been shown to be fundamental to tissue-specific gene regulation. Modifications to chromatin can regulate gene expression and are involved in a myriad of biological functions, and hence, disruption of these modifications is central to many human diseases. These modifications can furthermore be epigenetic in nature, thereby contributing to prolonged disease risk. Recent work has demonstrated that modifications to chromatin are associated with the progression of both diabetes mellitus and obesity, which is the subject of this review. PMID- 26044586 TI - Assessment of mental health literacy in patients with breast cancer. AB - INTRODUCTION: Psychosocial distress is often underdiagnosed and undertreated among breast cancer patients due to the poor recognition of the associated symptoms and inadequate knowledge of the treatments available. OBJECTIVE: To evaluate the mental health literacy of breast cancer patients by assessing (1) their ability to recognize the symptoms of anxiety, fatigue, depression, and cognitive disturbances, and (2) their knowledge of help-seeking options and professional treatments. METHODS: In this multi-center, cross-sectional study, early-stage breast cancer patients receiving chemotherapy underwent four assessments to measure their levels of anxiety, depression, fatigue, and cognitive disturbances. With the aid of cancer-specific vignettes, a questionnaire was administered to evaluate their mental health literacy. RESULTS: Fifty-four patients were recruited (77.7% Chinese, aged 52.7 +/- 8.5 years). Clinically significant anxiety (15.1%), fatigue (27.8%), and cognitive disturbances (25.9%) were more prevalent than depression (5.6%). Although the majority of the patients could recognize the symptoms of fatigue accurately (75.9%), less than half could identify those of anxiety (35.2%), depression (48.1%), and cognitive disturbances (48.1%). Patients were more receptive to help from their family members (score: 3.39 out of 4.00) and oncologists (score: 3.13) than from other mental health specialists, such as psychiatrists (score: 2.26) and psychologists (score: 2.19) in the management of their psychosocial distress. Approximately half of the patients indicated that embarrassment and fear were their main barriers to seeking professional treatment (55.6%). CONCLUSIONS: Our results suggest that the mental health literacy of breast cancer patients was inadequate. Intervention and management strategies could be implemented to teach these patients about evidence-based treatments and professional help that are specific to mental disorders. PMID- 26044587 TI - Fatal pulmonary toxicity due to carfilzomib (KyprolisTM). AB - INTRODUCTION: Carfilzomib (KyprolisTM) is a second-generation proteasome inhibitor for the treatment of relapsing multiple myeloma (MM). In 2012, carfilzomib was approved by Food and Drug Administration for the treatment of patients with relapsed MM who had received at least two prior therapies. We present a case of fatal pulmonary toxicity presumed secondary to carfilzomib. CLINICAL PRESENTATION: A 61-year-old male was initially diagnosed with MM in 2003 for which he received multiple treatments. In 2013, he was started on carfilzomib for relapsing MM. After 24 h, the patient developed an acute respiratory distress syndrome for which he needed mechanical ventilation. One week later, patient developed diffuse alveolar hemorrhage and despite aggressive supportive care, the patient died after three weeks. DISCUSSION: The temporal relationship between the first exposure to carfilzomib and development of symptoms, and the exclusion of other possible etiologies, leads us to believe that our patient's lung toxicity is a possible adverse reaction to carfilzomib. To the best of our knowledge, there are no previous reports of deaths due to carfilzomib-related pulmonary toxicity. PMID- 26044588 TI - Evidence-based practice in times of drug shortage. AB - Shortage of oncology drugs is a particularly complicated issue because there are usually limited therapeutic options. Moreover, oncology practice may employ medications for supportive indications which differ from their main usage. This means shortage of oncology drugs is not usually addressed by the major drug shortage guidelines. We have previously shown that, during a shortage crisis, it is possible to make a recommendation on the use of an expired drug supply based on a reasonable estimate of its safety and efficacy. Here, we would like to share further examples on how to deduce potential therapeutic alternatives based on pharmacokinetic and pharmacodynamic principles in the absence of direct clinical evidence in the literature. PMID- 26044589 TI - Fabrication of electrospun poly(D,L lactide-co-glycolide)80/20 scaffolds loaded with diclofenac sodium for tissue engineering. AB - BACKGROUND: Adaptation of nanotechnology into materials science has also advanced tissue engineering research. Tissues are basically composed of nanoscale structures hence making nanofibrous materials closely resemble natural fibers. Adding a drug release function to such material may further advance their use in tissue repair. METHODS: In the current study, bioabsorbable poly(D,L lactide-co glycolide)80/20 (PDLGA80/20) was dissolved in a mixture of acetone/dimethylformamide. Twenty percent of diclofenac sodium was added to the solution. Nanofibers were manufactured using electrospinning. The morphology of the obtained scaffolds was analyzed by scanning electron microscopy (SEM). The release of the diclofenac sodium was assessed by UV/Vis spectroscopy. Mouse fibroblasts (MC3T3) were seeded on the scaffolds, and the cell attachment was evaluated with fluorescent microscopy. RESULTS: The thickness of electrospun nanomats was about 1 mm. SEM analysis showed that polymeric nanofibers containing drug particles formed very interconnected porous nanostructures. The average diameter of the nanofibers was 500 nm. Drug release was measured by means of UV/Vis spectroscopy. After a high start peak, the release rate decreased considerably during 11 days and lasted about 60 days. During the evaluation of the release kinetics, a material degradation process was observed. MC3T3 cells attached to the diclofenac sodium-loaded scaffold. CONCLUSIONS: The nanofibrous porous structure made of PDLGA polymer loaded with diclofenac sodium is feasible to develop, and it may help to improve biomaterial properties for controlled tissue repair and regeneration. PMID- 26044590 TI - Quality Evaluation of Abstracts Presented at the Society of Gynecologic Surgeons Annual Scientific Meeting. AB - STUDY OBJECTIVE: To examine the rate of abstract publication from the Society of Gynecologic Surgeons Annual Scientific Meeting (SGSASM), 2004 to 2012. STUDY DESIGN: This is a retrospective study in which all abstracts presented at the SGSASM from 2004 to 2012 were reviewed. Information was collected on oral (O), oral poster (OP), and poster (P) presentations. To evaluate for publication, all abstracts were searched for in the US National Library of Medicine's PubMed database. Chi-square tests were used to evaluate whether there were differences in distribution of published studies by first author location and affiliation and number of abstract authors. DESIGN CLASSIFICATION: Canadian Task Force III. MEASUREMENTS AND MAIN RESULTS: In total, 867 abstracts were reviewed, including all O, OP, and P presentations. Video and tips and tricks presentations were excluded. Overall rate of publication for all abstracts from 2004 to 2012 was 55.7%, comprising 82.4% for O presentations, 60.9% for OP presentations, and 41.4% for P presentations. There was no significant difference in location for published abstracts (p = .878), although published abstracts had a significantly greater number of authors (p < .001). Abstracts presented by authors from university programs were more likely to be published (p < .001). For all presentation types, the mean number of citations for published abstracts was different for the 9-year period (O, OP, and P: p < .001), with an overall decline toward the end of the assessment period. CONCLUSION: Over a 9-year period (2004 2012), the rate of abstract publication at the SGSASM was 55.7%, which is similar to other academic meetings. The comparability of this publication rate shows that the abstract selection committee is able to select high-quality research with limited information provided in abstract submissions. PMID- 26044591 TI - Adnexal Incarceration in a Posterior Pelvic Peritoneal Defect Mimics Ovarian Torsion. AB - Surgery for suspected ovarian torsion sometimes reveals unexpected sources of pelvic pain, such as internal hernias, adhesions, or anatomic defects. A 23-year old nulligravida with Alagille syndrome was taken to the operating room with suspected ovarian torsion. Intraoperatively, the right adnexa bulged out of a right-sided, posterior peritoneal cleft that incarcerated most of the enlarged ovary. No ovarian torsion was identified. The left adnexa appeared to be normal; however, it dwelled within a left-sided posterior peritoneal cleft. The bilateral posterior peritoneal defects that housed the adnexa were likely of congenital etiology. Although adnexal incarceration is a rare finding at surgery for suspected ovarian torsion, it should be part of the differential diagnosis when evaluating acute pelvic pain. PMID- 26044592 TI - Reproducibility of Endometrial Pathologic Findings Obtained on Hysteroscopy, Transvaginal Sonography, and Gel Infusion Sonography in Women With Postmenopausal Bleeding. AB - STUDY OBJECTIVE: To evaluate and compare interobserver variation in endometrial pattern recognition with hysteroscopy (HY) and transvaginal sonography (TVS) and gel infusion sonography (GIS) with regard to the diagnosis of endometrial pathology. DESIGN: Prospective study (Canadian Task Force II-1). SETTING: University clinic. PATIENTS: One hundred twenty-two consecutive women with postmenopausal bleeding and an endometrium thickness >= 5 mm. INTERVENTION: Two observers using HY and 2 others using TVS and GIS evaluated the endometrial pattern in recorded video clips. Interobserver agreement regarding findings obtained with TVS, GIS, and HY for a diagnosis of cancer, hyperplasia, polyps, and no endometrial pathology was expressed by kappa coefficients and compared. MEASUREMENT AND MAIN RESULTS: Interobserver agreement (kappa) was as follows: identification of normal endometrium: HY (.74), TVS (.68), and GIS (.48); diagnosis of cancer: HY (.56), TVS (.59), and GIS (.34); classification in all categories of endometrial pathology: HY (.70), TVS (.47), and GIS (.41) (p < .05 HY vs GIS). The presence of additional endometrial polyps decreased agreement on HY in patients with hyperplasia or cancer. Observer agreement was poor regarding the diagnosis of hyperplasia by all techniques. CONCLUSION: Observer agreement regarding both HY and TVS was reliable for the diagnosis of a normal endometrium but poor with HY, TVS, and especially GIS for a diagnosis of cancer. In patients with hyperplasia or cancer, agreement between observers was especially low in the presence of additional polyps when HY was used. These findings call attention to the need for systematic methods to improve reliability in endometrial pattern recognition. PMID- 26044593 TI - Streamlined Genome Engineering with a Self-Excising Drug Selection Cassette. AB - A central goal in the development of genome engineering technology is to reduce the time and labor required to produce custom genome modifications. Here we describe a new selection strategy for producing fluorescent protein (FP) knock ins using CRISPR/Cas9-triggered homologous recombination. We have tested our approach in Caenorhabditis elegans. This approach has been designed to minimize hands-on labor at each step of the procedure. Central to our strategy is a newly developed self-excising cassette (SEC) for drug selection. SEC consists of three parts: a drug-resistance gene, a visible phenotypic marker, and an inducible Cre recombinase. SEC is flanked by LoxP sites and placed within a synthetic intron of a fluorescent protein tag, resulting in an FP-SEC module that can be inserted into any C. elegans gene. Upon heat shock, SEC excises itself from the genome, leaving no exogenous sequences outside the fluorescent protein tag. With our approach, one can generate knock-in alleles in any genetic background, with no PCR screening required and without the need for a second injection step to remove the selectable marker. Moreover, this strategy makes it possible to produce a fluorescent protein fusion, a transcriptional reporter and a strong loss-of function allele for any gene of interest in a single injection step. PMID- 26044595 TI - Adipokines influence the inflammatory balance in autoimmunity. AB - Over the past few decades, our understanding of the role of adipose tissue has changed dramatically. Far from simply being a site of energy storage or a modulator of the endocrine system, adipose tissue has emerged as an important regulator of multiple important processes including inflammation. Adipokines are a diverse family of soluble mediators with a range of specific actions on the immune response. Autoimmune diseases are perpetuated by chronic inflammatory responses but the exact etiology of these diseases remains elusive. While researchers continue to investigate these causes, millions of people continue to suffer from chronic diseases. To this end, an increased interest has developed in the connection between adipose tissue-secreted proteins that influence inflammation and the onset and perpetuation of autoimmunity. This review will focus on recent advances in adipokine research with specific attention on a subset of adipokines that have been associated with autoimmune diseases. PMID- 26044594 TI - Chaos of Rearrangements in the Mating-Type Chromosomes of the Anther-Smut Fungus Microbotryum lychnidis-dioicae. AB - Sex chromosomes in plants and animals and fungal mating-type chromosomes often show exceptional genome features, with extensive suppression of homologous recombination and cytological differentiation between members of the diploid chromosome pair. Despite strong interest in the genetics of these chromosomes, their large regions of suppressed recombination often are enriched in transposable elements and therefore can be challenging to assemble. Here we show that the latest improvements of the PacBio sequencing yield assembly of the whole genome of the anther-smut fungus, Microbotryum lychnidis-dioicae (the pathogenic fungus causing anther-smut disease of Silene latifolia), into finished chromosomes or chromosome arms, even for the repeat-rich mating-type chromosomes and centromeres. Suppressed recombination of the mating-type chromosomes is revealed to span nearly 90% of their lengths, with extreme levels of rearrangements, transposable element accumulation, and differentiation between the two mating types. We observed no correlation between allelic divergence and physical position in the nonrecombining regions of the mating-type chromosomes. This may result from gene conversion or from rearrangements of ancient evolutionary strata, i.e., successive steps of suppressed recombination. Centromeres were found to be composed mainly of copia-like transposable elements and to possess specific minisatellite repeats identical between the different chromosomes. We also identified subtelomeric motifs. In addition, extensive signs of degeneration were detected in the nonrecombining regions in the form of transposable element accumulation and of hundreds of gene losses on each mating type chromosome. Furthermore, our study highlights the potential of the latest breakthrough PacBio chemistry to resolve complex genome architectures. PMID- 26044596 TI - CrkL meditates CCL20/CCR6-induced EMT in gastric cancer. AB - BACKGROUND: In recent years, Crk-like adapter protein (CrkL) has been identified as a key regulator in the epithelial-to-mesenchymal transition (EMT). However, the molecular mechanisms underlying the CC chemokine receptor 6 (CCR6) and chemokine (C-C motif) ligand 20 (CCL20)-induced EMT in gastric cancer are still unclear. METHODS: We conducted the immunohistochemistry and immunoblotting to detect the expression of CCR6 and CrkL in 90 cases of gastric cancer tissues and five kinds of cell lines. And then, gastric cancer cells were subjected to small interfering RNA (siRNA) treatment and in vitro assay. RESULTS: Both CCR6 and CrkL were aberrantly expressed in gastric cancer specimens and closely correlated with differentiation of cell lines. The expression of CCR6 and CrkL was also significantly associated with metastasis, stage, and poor prognosis of gastric cancer. In addition, we validated CCL20 activated the expression of p-CrkL, p Erk1/2, p-Akt, vimentin, N-cadherin and MMP2 in MGC803 cells in a dose-dependent manner. However, si-CrkL abrogated the CCL20-induced p-Erk1/2, vimentin, N cadherin and MMP2 expression. Most importantly, the knockdown of CrkL decreased migration and invasion of MGC803 cells. CONCLUSIONS: CrkL mediates CCL20/CCR6 induced EMT via Akt pathway, instead of Erk1/2 pathway in development of gastric cancer, which indicated CCL20/CCR6-CrkL-Erk1/2-EMT pathway may be targeted to antagonize the progression of gastric cancer. PMID- 26044598 TI - Clinical Value of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Upper Tract Urothelial Carcinoma: Impact on Detection of Metastases and Patient Management. AB - OBJECTIVE: To determine the diagnostic accuracy of 18F-fluorodeoxyglucose (18F FDG) positron emission tomography/computed tomography (PET/CT) for detecting metastasis and its impact on patient management with upper tract urothelial carcinoma (UTUC). PATIENTS AND METHODS: Consecutive patients with UTUC underwent 18F-FDG PET/CT after CT for initial staging (n = 47) and for restaging at recurrence (n = 9). Diagnostic accuracy for detecting metastases with PET/CT and CT was compared statistically. The impact of PET/CT on patient management was assessed by comparing questionnaires that were completed by the attending physicians before and after PET/CT. RESULTS: In the lesion-based analysis, 142 lesions were diagnosed as metastases. The sensitivity of PET/CT was significantly better than that of CT (85 vs. 50%, p = 0.0001). In the patient-based analysis, 22 patients were diagnosed as having metastases. The sensitivity/specificity/accuracy of PET/CT tended to be superior to those of CT, but these values were not significantly different (95, 91, and 93% vs. 82, 85, and 84%; p = 0.25, 0.50, and 0.063, respectively). The clinicians changed their assessments of disease extent and management plans in 18 (32%) and 11 (20%) patients, respectively, based on the PET/CT results. CONCLUSIONS: The diagnostic accuracy of PET/CT for detecting metastasis was superior to that of CT. PET/CT provided additional information to the CT-based staging, which had an impact on patient management. PMID- 26044600 TI - Frontal Sinus Mucopyocele Presenting as a Subcutaneous Forehead Mass. AB - Mucoceles of the paranasal sinuses are benign, chronic, expanding lesions that characteristically develop because of obstruction of the sinus ostium. The frontal sinus is the most common sinus to be affected by a mucocele, which usually results from trauma or inflammatory processes. Patients with these lesions frequently present with visual complaints of decreased visual acuity, visual field abnormalities, proptosis, ptosis, displacement of the globe, or restricted ocular movements secondary to erosion through the thin bone of the superior orbit and compression on the globe. Often, intracranial extension of frontal sinus mucoceles is also present from erosion through the posterior table of the frontal sinus. Very rarely, they will present as a subcutaneous forehead mass or swelling. To the best of our knowledge, only 5 cases of a frontal sinus mucocele presenting as a forehead subcutaneous mass has been previously reported. We report the case of an 80-year-old woman with a history of remote forehead trauma who presented with a frontal sinus mucopyocele manifesting as a subcutaneous forehead mass eroding through the skin. PMID- 26044599 TI - Tauroursodeoxycholate Protects Rat Hepatocytes from Bile Acid-Induced Apoptosis via beta1-Integrin- and Protein Kinase A-Dependent Mechanisms. AB - BACKGROUND/AIMS: Ursodeoxycholic acid, which in vivo is rapidly converted into its taurine conjugate, is frequently used for the treatment of cholestatic liver disease. Apart from its choleretic effects, tauroursodeoxycholate (TUDC) can protect hepatocytes from bile acid-induced apoptosis, but the mechanisms underlying its anti-apoptotic effects are poorly understood. METHODS: These mechanisms were investigated in perfused rat liver and isolated rat hepatocytes. RESULTS: It was found that TUDC inhibited the glycochenodeoxycholate (GCDC) induced activation of the CD95 death receptor at the level of association between CD95 and the epidermal growth factor receptor. This was due to a rapid TUDC induced beta1-integrin-dependent cyclic AMP (cAMP) signal with induction of the dual specificity mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1), which prevented GCDC-induced phosphorylation of mitogen-activated protein kinase kinase 4 (MKK4) and c-jun-NH2-terminal kinase (JNK) activation. Furthermore, TUDC induced a protein kinase A (PKA)-mediated serine/threonine phosphorylation of the CD95, which was recently identified as an internalization signal for CD95. Furthermore, TUDC inhibited GCDC-induced CD95 targeting to the plasma membrane in a beta1-integrin-and PKA-dependent manner. In line with this, the beta1-integrin siRNA knockdown in sodium taurocholate cotransporting polypeptide (Ntcp) transfected HepG2 cells abolished the protective effect of TUDC against GCDC induced apoptosis. CONCLUSION: TUDC exerts its anti-apoptotic effect via a beta1 integrin-mediated formation of cAMP, which prevents CD95 activation by hydrophobic bile acids at the levels of JNK activation and CD95 serine/threonine phosphorylation. PMID- 26044601 TI - Significantly Decreased Recurrence Rates in Keratocystic Odontogenic Tumor With Simple Enucleation and Curettage Using Carnoy's Versus Modified Carnoy's Solution. AB - PURPOSE: A variety of modalities has been suggested for treatment of keratocystic odontogenic tumor (KOT), including Carnoy's solution (CS) and modified Carnoy's (without chloroform) solution (MC). The purpose of the present study was to investigate the effect of CS versus MC as it relates to the KOT recurrence rates when used in conjunction with simple enucleation and curettage (E&C) for treatment of KOT. MATERIALS AND METHODS: A retrospective cohort study of patients with a pathologic diagnosis of KOT treated with E&C and application of CS or MC by 3 surgeons at a single center from January 1996 to April 2014 was completed. The demographic, clinical, radiographic, and histologic data were collected for each patient. All disease recurrences were confirmed by biopsy. The primary outcome variable of the study was the interval to recurrence, with the predictor of CS versus MC. Other variables included in the analysis were gender, age, surgeon, and lesion location. Multivariate analysis, including the Wilcoxon test and chi(2) test of associations, was performed. RESULTS: A total of 210 patient medical records were reviewed, with 80 patients meeting the final study criteria. Of the 80 patients, 44 were in the CS arm and 36 in the MC arm. The median age was 47 years (range 10 to 89) in the CS group and 50 years (range 14 to 72) in the MC group (P = .70). Women accounted for 43% (19 of 44) and 44% (16 of 36) of the patients in the CS and MC treatment arms, respectively (P = .91). The lesions were found in the mandible in 26 of the 44 patients (59%) treated with CS and 22 of the 36 patients (61%) treated with MC (P = .85). Surgeon 1 treated 37 of the 44 patients (84%) and 21 of 36 patients (58%) in the CS and MC groups, respectively (P = .01). The recurrence rate was 10% for the CS arm and 35% for the MC arm (P = .027; hazard ratio 6.9). CONCLUSION: In the present retrospective study, the recurrence rate of KOTs treated by E&C with application of CS is significantly lower than that of MC. The data provided could be considered by the Food and Drug Administration for a clinical trial of CS in patients with KOT. PMID- 26044602 TI - Comparison of the Effects of Topical Ketamine and Tramadol on Postoperative Pain After Mandibular Molar Extraction. AB - PURPOSE: This study compared the analgesic efficacy of postoperative tramadol versus ketamine for preventing pain after mandibular molar extraction. PATIENTS AND METHODS: Ninety patients who had undergone molar extraction were randomly divided into 3 groups: group T (tramadol 1 mg/kg), group K (ketamine 0.5 mg/kg), and group P (saline 2 mL). The treatment was applied to the extraction sockets using resorbable gelatin sponges. Pain after extraction was evaluated using a visual analog scale (VAS) 0.5, 1, 2, 4, 6, 12, 24, and 48 hours postoperatively. RESULTS: The VAS scores after extraction were statistically higher in group P than in either treatment group. Group K had the lowest pain intensity. CONCLUSION: This study shows that topical tramadol and ketamine are effective alternatives for decreasing pain after molar extractions. PMID- 26044603 TI - Perceptions of Young Adults Having Undergone Combined Orthodontic and Orthognathic Surgical Treatment: A Grounded Theory Approach. AB - PURPOSE: The present qualitative study aimed to explore the subjective perceptions and values of young adults having undergone combined orthodontic and orthognathic surgical treatment to resolve their dentofacial deformity. MATERIALS AND METHODS: Ten participants (5 women and 5 men; 20 to 25 yr of age) whose combined orthodontic and orthognathic surgical treatment had been terminated 1 to 3 years before undertaking the present study were selected. Open in-depth interviews, of approximately 30 minutes' duration, were digitally recorded and transcribed verbatim. The interviews were analyzed using procedures inherent to the grounded theory approach, a qualitative approach to collecting and analyzing data that aims to develop a theoretical proposition grounded in real-world observations. RESULTS: A core category was identified describing the participants' satisfaction with treatment outcome despite the difficult experiences that they lived through during the orthodontic and orthognathic surgical treatment. In association to the core category, 6 other categories emerged: experiences shared by those already having undergone similar treatment; shock for family and close friends at the hospital; difficulty eating; pain caused by orthodontic treatment; fears caused by swelling and complications; and smiling with self-confidence. CONCLUSION: A better understanding of patients' views on combined orthodontic and orthognathic surgical treatment can assist health care professionals in properly counseling patients and their families and providing better patient-centered care. PMID- 26044597 TI - T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production. AB - Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these "type 2 immune response-related" cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naive CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. PMID- 26044604 TI - Autotransplantation of Immature Third Molars and Orthodontic Treatment After En Bloc Resection of Conventional Ameloblastoma. AB - Ameloblastoma treatment can lead to significant bone defects; consequently, oral rehabilitation can be challenging. We present the case of a 14-year-old girl diagnosed with a conventional ameloblastoma in the mandible who was treated using en bloc resection and rehabilitated with autotransplantation of the immature third molars and orthodontic treatment. The lesion was in the region of the lower left canine and premolars, and en bloc resection resulted in a significant alveolar bone defect. Autotransplantation of the lower third molars to the site of the lower left premolars was performed. After 2 years, the upper left third molar was transplanted to the site of the lower left canine. During the orthodontic treatment period, considerable alveolar bone formation was observed in the region of the transplanted teeth, and roots developed. To the best of our knowledge, this is the first reported case of alveolar bone formation induction caused by tooth transplantation after ameloblastoma treatment. PMID- 26044605 TI - Dynamic Analysis of New Bone Obtained by Nonvascular Transport Distraction Osteogenesis in Canines. AB - PURPOSE: The aim of the present study was to construct a nonvascular transport disc to repair the canine mandibular defects model and to perform a dynamic analysis of the new bone obtained by nonvascular transport distraction osteogenesis (NTDO) in canines. MATERIALS AND METHODS: Thirty adult dogs were randomly divided into 3 groups, with 10 dogs in each group. Canine mandibular defect models of NTDO were constructed. All the dogs were marked by tetracycline hydrochloride at a different distraction stage. The dogs were euthanized at 2, 4, and 12 weeks after distraction, and the quality ratio of calcium and phosphate for the new bone was measured using electron dispersive spectroscopy. RESULTS: The canine mandibular defects were successfully repaired. Using tetracycline hydrochloride, we successfully observed the quality and speed of new bone formation. The quality ratio of calcium and phosphate was similar between the new bone formation and the original bone. The time spent using a nonvascular transport disc to repair mandibular defects was consistent with using a vascularized transport disc, and the quality of the new bone and the original bone was exactly the same. CONCLUSION: When the bone mass is insufficient or the conditions are not suitable for a vascularized transport disc, the nonvascular transport disc can be used as an alternative. PMID- 26044606 TI - Does Self-Citation Influence Quantitative Measures of Research Productivity Among Academic Oral and Maxillofacial Surgeons? AB - PURPOSE: Quantitative measures of research productivity depend on the citation frequency of a publication. Citation-based metrics, such as the h-index (total number of publications h that have at least h citations), can be susceptible to self-citation, resulting in an inflated measure of research productivity. The purpose of the present study was to estimate the effect of self-citation on the h index among academic oral and maxillofacial surgeons (OMSs). MATERIALS AND METHODS: The present study was a cross-sectional study of full-time academic OMSs in the United States. The predictor variable was the frequency of self-citation. The primary outcome of interest was the h-index. Other study variables included demographic factors and citation metrics. Descriptive, bivariate, and regression statistics were computed. RESULTS: The study sample consisted of 325 full-time academic OMSs. Most surgeons were men (88.3%); approximately 40% had medical degrees. The study subjects had an average of 23.5 +/- 37.1 publications. The mean number of self-citations was 15 + 56. The sample's mean h-index was 6.6 +/- 7.6 and was associated with self-citation (r = 0.71, P < .001). Approximately 9% of subjects had a change in their h-index after removing self-citations. After adjusting for PhD degree, total number of publications, and academic rank, an increasing self-citation rate influenced the h-index (r = 0.006, P < .001). Surgeons with more than 14 self-citations were more likely to have their h-index influenced by self-citation. CONCLUSION: Self-citation among full-time academic OMSs does not substantially affect the h-index. Surgeons in the top quartile of self-citation rates are more likely to influence their h-index. PMID- 26044607 TI - Pectoralis Major Myocutaneous Flap in Primary and Salvage Head and Neck Cancer Surgery. AB - PURPOSE: To analyze the oncologic, functional, and esthetic results of using the pectoralis major myocutaneous flap (PMMF) from November 2001 to April 2012 at the Department of Otorhinolaryngology and Cervicofacial Surgery, University Medical Center Ljubljana (Ljubljana, Slovenia). PATIENTS AND METHODS: Patients with squamous cell carcinoma of the head and neck (SCCHN) who underwent tissue defect reconstruction with a PMMF were identified from a prospective database. Medical and surgical records were reviewed for information on clinical characteristics, treatment, and outcome and specifically for indications for the PMMF, wound healing, flap vitality, functional results, and esthetics. RESULTS: Forty PMMFs were used in 39 patients with SCCHN. With respect to previous therapy and prognosis, patients were sorted into a primary surgery group (19 patients) and a salvage surgery group (20 patients with recurrent disease). Statistically better locoregional control and disease-free survival were observed in the first group. Wound healing was completed in 32 patients (median time from surgery, 22 days). Three cases exhibited partial PMMF necrosis. Functional results, occlusion of pharyngocutaneous fistula, speech intelligibility, upper limb dysfunction, and esthetic outcome did not differ between the 2 groups. CONCLUSION: The PMMF is a reasonable choice for primary head and neck cancer surgery and in salvage procedures. Its use is characterized by vitality, a reasonably short recovery time, and a favorable esthetic outcome at the donor site in most patients. PMID- 26044608 TI - The Impact of Orthognathic Surgery on Facial Expressions. AB - PURPOSE: The aim of this study was to evaluate the impact of orthognathic surgical correction of facial asymmetry and maxillary hypoplasia on the magnitude and pattern of facial expressions. PATIENTS AND METHODS: This study was carried out on 2 cohorts of patients: in group 1, 10 patients had surgical correction of facial asymmetry; in group 2, 13 patients had Le Fort I osteotomy to correct maxillary hypoplasia. The patients were asked to perform 3 facial expressions (maximal smile, lip purse, and cheek puff) that were recorded using the Di4D image-capture system before and after surgery. The capture of each expression generated 180 3-dimensional (3D) facial images. Twenty-seven facial soft tissue landmarks were digitized on the first frame of the 3D image of each expression and a mathematical generic mesh was applied on the 3D model to clone each patient's face. The cloned mesh was superimposed automatically on each sequence of the 3D images to evaluate the pattern of facial expressions. The digitization of facial landmarks was satisfactorily accurate and reproducible. RESULTS: In group 1, the asymmetry of facial expressions was significantly decreased after surgical correction (P = .0458). In group 2, Le Fort I osteotomy decreased the magnitude of facial expressions (P = .0267). CONCLUSION: This study confirmed that orthognathic surgery affects the dynamics of facial expressions; this should be considered when planning the surgery and informing patients about the surgical correction of dentofacial deformities. PMID- 26044609 TI - Diabetes in Asian Indians-How much is preventable? Ten-year follow-up of the Chennai Urban Rural Epidemiology Study (CURES-142). AB - We sought to evaluate the contribution of various modifiable risk factors to the partial population attributable risk (PARp) for diabetes in an Asian Indian population. Of a cohort of 3589 individuals, representative of Chennai, India, followed up after a period of ten years, we analyzed data from 1376 individuals who were free of diabetes at baseline. A diet risk score was computed incorporating intake of refined cereals, fruits and vegetables, dairy products, and monounsaturated fatty acid. Abdominal obesity was found to contribute the most to incident diabetes [Relative Risk (RR) 1.63(95%CI 1.21-2.20)]; (PARp 41.1% (95%CI 28.1-52.6)]. The risk for diabetes increased with increasing quartiles of the diet risk score [highest quartile RR 2.14(95% CI 1.26-3.63)] and time spent viewing television [(RR 1.84(95%CI 1.36-2.49] and sitting [(RR 2.09(95%CI 1.42 3.05)]. The combination of five risk factors (obesity, physical inactivity, unfavorable diet risk score, hypertriglyceridemia and low HDL cholesterol) could explain 80.7% of all incident diabetes (95%CI 53.8-92.7). Modifying these easily identifiable risk factors could therefore prevent the majority of cases of incident diabetes in the Asian Indian population. Translation of these findings into public health practice will go a long way in arresting the progress of the diabetes epidemic in this region. PMID- 26044610 TI - Perceptions about professionally and non-professionally trained hypoglycemia detection dogs. AB - AIMS: Patients with diabetes increasingly have questions about diabetes alert dogs. This study evaluated perceptions about dogs trained professionally or otherwise to detect glucose levels. METHODS: A link to a survey about glucose detecting dogs was announced on diabetes websites. RESULTS: 135 persons responded, with 63 answering about their child with diabetes. Most respondents obtained their dog from a professional trainer (n = 54) or trained it themselves (n = 51). Owners of self- and professionally-trained dogs were very positive about dogs' abilities to alert them to low and high glucose levels, while owners of dogs that learned entirely on their own (n = 15) reported lower frequencies of alerts and more missed hypoglycemic episodes, p<.01. Regardless of how dogs learned, perceptions about managing diabetes were improved during periods of dog ownership relative to times without, p<.001. Self-reported rates of diabetes related hospitalizations, assistance from others for treating hypoglycemia, and accidents or near accidents while driving reduced during periods of dog ownership compared to periods without dogs, ps<.01. CONCLUSIONS: These data suggest potential effectiveness of and high satisfaction with glucose-detecting dogs. Clinicians can use these results to address pros and cons of dog ownership with patients who inquire about them. PMID- 26044611 TI - Trends in diabetes-related lower extremities amputations in Romania-A five year nationwide evaluation. AB - The aim of the study was to perform a nationwide evaluation of the frequency, incidence and trends of diabetes-related LEA (lower extremities amputations) in Romania. We have retrospectively analysed DRG data (ICD 10 AM codes) from all hospitals in the country, over a 5 year period (2006-2010). Knowing the shortcomings of this approach, we have assumed that our study can serve as a platform for future comparisons. The total number of non-traumatic diabetes related LEA procedures was 24,312, they were performed in 16,873 patients with diabetes, 22.55% with type 1 diabetes, 70.26 with type 2 diabetes and 7.19% with non-specified diabetes at discharge. The total number of hospital admissions for these patients was 46,985. During the five years of the study there was an increase in the absolute number of major amputations (above the ankle), as well as of minor amputations. The rate of amputations decreased in type 1 diabetes, from baseline (2006): -8.15% in 2007, -25.83% in 2008, -23.43% in 2009, -27.71% in 2010, whereas it increased in type 2 diabetes in the respective years: 16.96%, 60.75%, 66.91%, and 104.64%, due to an increase in minor amputations and mainly in elderly people. Male: female amputations rate was 2:1 in type 1 diabetes patients and 2.4:1 in type 2 diabetes patients. This study, the first of its kind in the Romanian population, offers a starting point for future comparisons and identifies a target for preventive measures. PMID- 26044612 TI - The effect of gliquidone on KATP channels in pancreatic beta-cells, cardiomyocytes, and vascular smooth muscle cells. AB - AIMS: Sulfonylurea drugs exert an insulinotropic effect through ATP-sensitive potassium (KATP) channel inhibition in pancreatic islet cells. These channels are also expressed in cardiomyocytes and vascular smooth muscle cells (VSMCs), suggesting potential for adverse cardiovascular effects. We evaluated the effects of Gliquidone (Glq) on sulfonylurea receptors in HIT-T15 cells (SUR1), cardiomyocytes (SUR2A), and VSMCs (SUR2B). METHODS: The concentration-dependent effects of Glq (0.001-500 MUM) on KATP channels were assessed using whole-cell patch clamp in HIT-T15 cells, rat cardiomyocytes, and VSMCs. Parallel studies using Glibenclamide (Glb) (0.001-10 MUM) and Gliclazide (Glc) (0.01-500 MUM)were conducted as controls. RESULTS: In HIT-T15 cells, Glb exhibited the lowest IC50 (0.03 MUM), as compared to Glq (0.45MUM) and Glc (1.21MUM). However, Glq had higher IC50 in cardiomyoctes and VSMCs, as compared to Glb (119.1 vs. 0.01 and 149.7 vs. 0.09 MUM, respectively), suggesting that Glq is more selective to beta cells than Glb. Thus, Glq may have fewer side effects in cardiomyoctes and VSMCs. CONCLUSIONS: Glq is a highly selective SUR secretagogue with moderate affinity to beta-cells, but low affinity to cardiomyocytes and VSMCs. Our data also reveal the non-selective nature of Glb, as evidenced by high binding affinity to KATP channels in all the three cell types examined. PMID- 26044613 TI - Aggressive nutritional strategy in morbid obesity in clinical practice: Safety, feasibility, and effects on metabolic and haemodynamic risk factors. AB - BACKGROUND: In morbid obesity, optimisation of nutritional strategies impacting cardiovascular and metabolic risk profile is a desirable target in clinical practice. OBJECTIVE: To assess in morbid obesity the feasibility, safety and efficacy of a nutritional cycle comprising a short-term carbohydrates-free diet delivered by nasogastric tube followed by an almost equivalent oral diet. DESIGN: In our clinical practice, adults with body mass index (BMI)>=45kg/m(2), otherwise clinically healthy, signed informed consent for a 14-day stint of continuous and controlled carbohydrates-free nutritional regiment delivered via 8-Fr nasogastric tube (enteral nutrition, EN), followed by a 14-day stint of almost comparable oral nutrition (ON). Body metrics, insulin resistance, blood pressure (BP) and heart rate (HR), as well as parameters for safety were monitored. RESULTS: In 112 patients, EN significantly reduced BMI and waist circumference (WC), BP, insulin resistance while it increased urine ketones and uric acid increased (all p<0.01 independent to confounders), but had no clinically significant impact on kidney and renal function, and coagulation parameters as well. With ON, findings were consistent. No major safety concerns were recorded during the nutritional treatment. In a subset of patients sharing clinical characteristics with the whole sample, the nutritional strategy reduced the mesenteric fat assessed by ultrasound. CONCLUSIONS: In morbid obesity, an aggressive nutritional cycle comprising a short-term ketogenic EN followed by an almost carbohydrates-free ON may be feasible, safe, and highly effective in reducing body weight, WC, BP and insulin resistance. PMID- 26044614 TI - Predicting dropout in dietary weight loss trials using demographic and early weight change characteristics: Implications for trial design. AB - Attrition causes analytical and efficacy issues in weight loss trials. Consistent predictors of attrition in weight loss trials have not been identified. Trial design could be improved if factors predicting attrition are accounted for. The aim of this study is to quantify the effect of easily measured pre study and early study variables to determine their relationship with attrition in dietary weight loss trials. METHODS: Data was pooled from four previous dietary weight loss trials. Mixed effects logistic regression, Receiver Operator Curves and decision trees (classification and regression trees) were used to determine which of the variables (percent weight loss at 1 month, age, gender and baseline BMI) predicted dropout and to determine cutoffs useful for future trial design. RESULTS: The sample included 289 subjects, 73% female, with a mean age of 46.68+/ 9.27years and average dropout of 25%. Percent weight loss at 1 month was the strongest predictor of dropout, those with a weight loss <=2% were 4.99 times (95% CI 2.71, 9.18) more likely to drop out than those with a weight loss >2% in the first month (P<0.001). When considering only data available at the beginning of a trial those <=50 years old were 2.07 times (95% CI 1.2, 3.5) more likely to drop out than those >50 (P=0.006). DISCUSSION: Early weight loss and age were identified as significant variables for predicting attrition in weight loss trials. Trial designs maybe improved by incorporating these variables and developing interventions targeting these factors may improve participant retention. PMID- 26044615 TI - Toxicity of nickel ions and comprehensive analysis of nickel ion-associated gene expression profiles in THP-1 cells. AB - The aim of the present study was to explore the toxic effects and underlying mechanisms of nickel ions during therapeutic nickel-based alloy-treatment in congenital heart disease by investigating the metal-induced cytotoxicity to the human monocyte-derived macrophage cell line THP-1. THP-1 cells were treated with NiCl2.6H2O (25, 50, 100, 200, 400 and 800 uM) for 24, 48 and 72 h, respectively. MTT was applied to detect THP-1 cell proliferation following NiCl2 treatment. Apoptosis of THP-1 cells was quantified using flow cytometry. Illumina sequencing was used for screening the associated genes, whose mRNA expression levels were further confirmed by quantitative real-time polymerase chain reaction. High concentrations of nickel ions had a significant suppressive effect on cell proliferation at the three concentrations investigated (200, 400 and 800 uM). Treatment with nickel ions (25-400 uM) for 48 h reduced cell viability in a dose dependent manner. The mRNA expression levels of RELB, FIGF, SPI-1, CXCL16 and CRLF2 were significantly increased following nickel treatment. The results of the present study suggested that nickel ions exert toxic effects on THP-1 cell growth, which may indicate toxicity of the nickel ion during treatment of congenital heart disease. The identification of genes modified by the toxic effects of nickel on THP-1 cells (EPOR, RELB, FIGF, SPI-1, TGF-beta1, CXCL16 and CRLF2) may aid in the development of interventional measures for the treatment/prevention of nickel ion-associated toxic effects during the treatment of congenital heart disease. PMID- 26044616 TI - Complete genome of Kangiella geojedonensis KCTC 23420(T), putative evidence for recent genome reduction in marine environments. AB - Kangiella geojedonensis KCTC 23420(T) is an aerobic, Gram-negative, non-motile, non-spore-forming, rod-shaped bacterium that was isolated from seawater off the southern coast of Korea. We here report the complete genome of K. geojedonensis KCTC 23420(T), which consists of 2,495,242 bp (G+C content of 43.78%) with 2,257 protein-coding genes, 41 tRNAs, 2 rRNA operons. The genome is smaller than the other closely related genomes, indicating that K. geojedonensis has recently experienced reductive evolution. PMID- 26044617 TI - De novo transcriptome of the European brittle star Amphiura filiformis pluteus larvae. AB - BACKGROUND: In non-classical model species, Next Generation Sequencing increases the ability to analyze the expression of transcripts/genes. In this study, paired end Illumina HiSeq sequencing technology has been employed to describe a larval transcriptome generated from 64 h post-fertilization pluteus larvae of the brittle star Amphiura filiformis. We focused our analysis on the detection of actors involved in the opsin based light perception, respectively the opsins and the phototransduction actors. METHODS & RESULTS: In this research, about 47 million high quality reads were generated and 86,572 total unigenes were predicted after de novo assembly. Of all the larval unigenes, 18% show significant matches with reference online databases. 46% of annotated larval unigenes were significantly similar to transcripts from the purple sea urchin. COG, GO and KEGG analyses were performed on predicted unigenes. Regarding the opsin-based photoreception process, even if possible actors of ciliary and rhabdomeric phototransduction cascades were detected, no ciliary or rhabdomeric opsin was identified in these larvae. Additionally, partial non-visual RGR (retinal G protein coupled receptor) opsin mRNAs were identified,possibly indicating the presence of visual cycle reaction in early pluteus larvae. The eye morphogene Pax 6 was also identified in the pluteus transcriptome. CONCLUSIONS: Contrary to sea-urchin larvae, brittle star larvae appear to be characterized by an absence of visual-like opsins. These RNA-seq data also provide a useful resource for the echinoderm research community and researchers with an interest in larval biology. PMID- 26044618 TI - Caste-based social inequalities and childhood anemia in India: results from the National Family Health Survey (NFHS) 2005-2006. AB - BACKGROUND: Caste is one of the traditional measures of social segregation in India and differs from other indicators as it is both, endogamous and hereditary. Evidence suggests that belonging to lower castes exposes one to social inequalities and affects health adversely. We examined the association of caste with childhood anemia in India and explored the effect modifying role of adult education and household wealth. METHODS: A cross-sectional analysis of National Family Health Survey (NFHS) data of 43,484 children aged 6-59 months was performed. Poisson regression analysis was conducted to study the association between caste and childhood anemia accounting for various maternal, child, and household related variables. Caste was categorized as "other caste" (least disadvantageous), "other backward caste", "scheduled tribe" and "scheduled caste" (most disadvantageous). Anemia was defined as mild (hemoglobin level 7-11 g/dL), moderate (hemoglobin level 5-7 g/dL) and severe (hemoglobin level <5 g/dL). RESULTS: We found that children in scheduled caste had higher risk of having anemia [mild anemia: RR = 1.10, 95% CI = 1.05-1.15; moderate anemia: RR = 1.19, 95% CI = 1.14-1.24; severe anemia: RR = 1.87, 95% CI = 1.51-2.31] after accounting for child, maternal and household covariates including adult education and household wealth. The interaction of caste with adult education and household wealth was not statistically significant for any level of anemia. Sensitivity analyses for children born to mothers of age >= 18 years at first child birth and body mass index (BMI) >= 18.5 kg/m(2), resulted in similar findings. CONCLUSION: Caste is an independent determinant of childhood anemia in India. The level of adult education and household wealth did not modify the association between caste and childhood anemia. The findings may be used for countering childhood anemia and it may be beneficial to target future public health actions towards disadvantageous castes in India. PMID- 26044621 TI - Koplik's Spots: The Harbinger of a Measles Epidemic. PMID- 26044619 TI - The group II metabotropic glutamate receptor agonist LY379268 reduces toluene induced enhancement of brain-stimulation reward and behavioral disturbances. AB - RATIONALE: Toluene, a widely abused solvent with demonstrated addictive potential in humans, hasbeen reported to negatively modulate N-methyl-D-aspartate receptors (NMDARs) and alter glutamatergicneurotransmission. The group II metabotropic glutamate receptor (mGluR) agonist LY379268 has beenshown to regulate glutamate release transmission and NMDAR function and block toluene-induced locomotorhyperactivity. However, remaining unknown is whether group II mGluRs are involved in the toluene-induced reward-facilitating effect and other behavioral manifestations. OBJECTIVES: The present study evaluated the effects of LY379268 on toluene-induced reward enhancement, motor incoordination, recognition memory impairment, and social interaction deficits. RESULTS: Our data demonstrated that LY379268 significantly reversed the toluene-induced lowering of intracranial self stimulation (ICSS) thresholds and impairments in novel object recognition, rotarod performance, and social interaction with different potencies. CONCLUSIONS: These results indicate a negative modulatory role of group II mGluRs in acute toluene-induced reward-facilitating and behavioral effects and suggest that group II mGluR agonists may have therapeutic potential for toluene addiction and the prevention of toluene intoxication caused by occupational or intentional exposure. PMID- 26044622 TI - Science, politics, and the end of the lifelong gay blood donor ban. PMID- 26044620 TI - Gene network analysis shows immune-signaling and ERK1/2 as novel genetic markers for multiple addiction phenotypes: alcohol, smoking and opioid addiction. AB - BACKGROUND: Addictions to alcohol and tobacco, known risk factors for cancer, are complex heritable disorders. Addictive behaviors have a bidirectional relationship with pain. We hypothesize that the associations between alcohol, smoking, and opioid addiction observed in cancer patients have a genetic basis. Therefore, using bioinformatics tools, we explored the underlying genetic basis and identified new candidate genes and common biological pathways for smoking, alcohol, and opioid addiction. RESULTS: Literature search showed 56 genes associated with alcohol, smoking and opioid addiction. Using Core Analysis function in Ingenuity Pathway Analysis software, we found that ERK1/2 was strongly interconnected across all three addiction networks. Genes involved in immune signaling pathways were shown across all three networks. Connect function from IPA My Pathway toolbox showed that DRD2 is the gene common to both the list of genetic variations associated with all three addiction phenotypes and the components of the brain neuronal signaling network involved in substance addiction. The top canonical pathways associated with the 56 genes were: 1) calcium signaling, 2) GPCR signaling, 3) cAMP-mediated signaling, 4) GABA receptor signaling, and 5) G-alpha i signaling. CONLUSIONS: Cancer patients are often prescribed opioids for cancer pain thus increasing their risk for opioid abuse and addiction. Our findings provide candidate genes and biological pathways underlying addiction phenotypes, which may be future targets for treatment of addiction. Further study of the variations of the candidate genes could allow physicians to make more informed decisions when treating cancer pain with opioid analgesics. PMID- 26044623 TI - Health Reform Redux: Where Might a Republican Congress Be Heading? PMID- 26044624 TI - Co-ops Discover the Challenges of Starting an Insurance Business. PMID- 26044625 TI - Why healthy behavior is the hard choice. PMID- 26044626 TI - Peer Review and the Public's Health. PMID- 26044627 TI - Electronic cigarettes: gateway to understanding the FDA? PMID- 26044628 TI - Improving Our Children's Health Is an Investment Priority. PMID- 26044629 TI - Criteria for Action in Population Health: The Hill Criteria a Half Century Later. PMID- 26044630 TI - Pursuing the Triple Aim: The First 7 Years. AB - POLICY POINTS: In 2008, researchers at the Institute for Healthcare Improvement (IHI) proposed the Triple Aim, strategic organizing principles for health care organizations and geographic communities that seek, simultaneously, to improve the individual experience of care and the health of populations and to reduce the per capita costs of care for populations. In 2010, the Triple Aim became part of the US national strategy for tackling health care issues, especially in the implementation of the Patient Protection and Affordable Care Act (ACA) of 2010. Since that time, IHI and others have worked together to determine how the implementation of the Triple Aim has progressed. Drawing on our 7 years of experience, we describe 3 major principles that guided the organizations and communities working on this endeavor: creating the right foundation for population management, managing services at scale for the population, and establishing a learning system to drive and sustain the work over time. CONTEXT: In 2008, researchers at the Institute for Healthcare Improvement (IHI) described the Triple Aim as simultaneously "improving the individual experience of care; improving the health of populations; and reducing the per capita costs of care for populations." IHI and its close colleagues had determined that both individual and societal changes were needed. METHODS: In 2007, IHI began recruiting organizations from around the world to participate in a collaborative to implement what became known as the Triple Aim. The 141 participating organizations included health care systems, hospitals, health care insurance companies, and others closely tied to health care. In addition, key groups outside the health care system were represented, such as public health agencies, social services groups, and community coalitions. This collaborative provided a structure for observational research. By noting the contrasts between the contexts and structures of those sites in the collaborative that progressed and those that did not, we were able to develop an ex post theory of what is needed for an organization or community to successfully pursue the Triple Aim. FINDINGS: Drawing on our 7 years of experience, we describe the 3 major principles that guided the organizations and communities working on the Triple Aim: creating the right foundation for population management, managing services at scale for the population, and establishing a learning system to drive and sustain the work over time. CONCLUSIONS: The concept of the Triple Aim is now widely used, because of IHI's work with many organizations and also because of the adoption of the Triple Aim as part of the national strategy for US health care, developed during the implementation of the Patient Protection and Affordable Care Act of 2010. Even those organizations working on the Triple Aim before IHI coined the term found our concept to be useful because it helped them think about all 3 dimensions at once and organize their work around them. PMID- 26044631 TI - Participatory workplace wellness programs: reward, penalty, and regulatory conflict. AB - POLICY POINTS: Workplace wellness programs that provide incentives for completing a health risk assessment are a form of participatory programs. There are legal and ethical concerns when employers assess penalties for not completing a health risk assessment, raising questions about the voluntariness of such a program. The Departments of Treasury, Labor, and Health and Human Services' 2013 regulations for participatory programs and employers' current practices conflict with the Equal Employment Opportunity Commission's prevailing interpretation of the Americans with Disabilities Act of 1990. CONTEXT: In keeping with the Patient Protection and Affordable Care Act, Congress revised the law related to workplace wellness programs. In June 2013, the Departments of Treasury, Labor, and Health and Human Services passed the final regulations, updating their 2006 regulatory framework. Participatory programs that reward the completion of a health risk assessment are now the most common type of wellness program in the United States. However, legal and ethical concerns emerge when employers utilize incentives that raise questions about the voluntariness of such programs. At issue is that under the Americans with Disabilities Act (ADA) of 1990, employers cannot require health-related inquiries and exams. METHODS: To analyze the current interpretation of the ADA, I conducted research on both LexisNexis and federal agency websites. The resulting article evaluates the differences in the language of Congress's enabling legislation and the federal departments' regulations and how they may conflict with the ADA. It also reviews the federal government's authority to address both the legal conflict and ethical concerns related to nonvoluntary participatory programs. FINDINGS: Employers' practices and the federal departments' regulations conflict with the current interpretation of the ADA by permitting employers to penalize employees who do not complete a health risk assessment. The departments' regulations may be interpreted as conflicting with Congress's legislation, which mentions penalties only for health-contingent wellness programs. Furthermore, the regulatory protections for employees applicable to health-contingent wellness programs do not apply to participatory programs. CONCLUSIONS: Either Congress or the federal agencies should address the conflict among employers' practices, the wellness regulations, and the ADA and also consider additional protections for employees. Employers can avoid ethical and legal complications by offering voluntary programs with positive incentives. PMID- 26044632 TI - Tobacco-control policies in tobacco-growing states: where tobacco was king. AB - POLICY POINTS: The tobacco companies prioritized blocking tobacco-control policies in tobacco-growing states and partnered with tobacco farmers to oppose tobacco-control policies. The 1998 Master Settlement Agreement, which settled state litigation against the cigarette companies, the 2004 tobacco-quota buyout, and the companies' increasing use of foreign tobacco led to a rift between the companies and tobacco farmers. In 2003, the first comprehensive smoke-free local law was passed in a major tobacco-growing state, and there has been steady progress in the region since then. Health advocates should educate the public and policymakers on the changing reality in tobacco-growing states, notably the major reduction in the volume of tobacco produced. CONTEXT: The 5 major tobacco-growing states (Kentucky, North Carolina, South Carolina, Tennessee, and Virginia) are disproportionately affected by the tobacco epidemic, with higher rates of smoking and smoking-induced disease. These states also have fewer smoke-free laws and lower tobacco taxes, 2 evidence-based policies that reduce tobacco use. Historically, the tobacco farmers and hospitality associations allied with the tobacco companies to oppose these policies. METHODS: This research is based on 5 detailed case studies of these states, which included key informant interviews, previously secret tobacco industry documents (available at http://legacy.library.ucsf.edu), and media articles. This was supplemented with additional tobacco document and media searches specifically for this article. FINDINGS: The tobacco companies were particularly concerned about blocking tobacco-control policies in the tobacco-growing states by promoting a pro-tobacco culture, beginning in the late 1960s. Nevertheless, since 2003, there has been rapid progress in the tobacco-growing states' passage of smoke-free laws. This progress came after the alliance between the tobacco companies and the tobacco farmers fractured and hospitality organizations stopped opposing smoke-free laws. In addition, infrastructure built by National Cancer Institute research projects (COMMIT and ASSIST) led to long-standing tobacco-control coalitions that capitalized on these changes. Although tobacco production has dramatically fallen in these states, pro-tobacco sentiment still hinders tobacco-control policies in the major tobacco-growing states. CONCLUSIONS: The environment has changed in the tobacco-growing states, following a fracture of the alliance between the tobacco companies and their former allies (tobacco growers and hospitality organizations). To continue this progress, health advocates should educate the public and policymakers on the changing reality in the tobacco-growing states, notably the great reduction in the number of tobacco farmers as well as in the volume of tobacco produced. PMID- 26044633 TI - Long-term care financing: lessons from France. AB - POLICY POINTS: France's model of third-party coverage for long-term services and supports (LTSS) combines a steeply income-adjusted universal public program for people 60 or older with voluntary supplemental private insurance. French and US policies differ: the former pay cash; premiums are lower; and take-up rates are higher, in part because employer sponsorship, with and without subsidization, is more common-but also because coverage targets higher levels of need and pays a smaller proportion of costs. Such inexpensive, bare-bones private coverage, especially if marketed as a supplement to a limited public benefit, would be more affordable to those Americans currently most at risk of "spending down" to Medicaid. CONTEXT: An aging population leads to a growing demand for long-term services and supports (LTSS). In 2002, France introduced universal, income adjusted, public long-term care coverage for adults 60 and older, whereas the United States funds means-tested benefits only. Both countries have private long term care insurance (LTCI) markets: American policies create alternatives to out of-pocket spending and protect purchasers from relying on Medicaid. Sales, however, have stagnated, and the market's viability is uncertain. In France, private LTCI supplements public coverage, and sales are growing, although its potential to alleviate the long-term care financing problem is unclear. We explore whether France's very different approach to structuring public and private financing for long-term care could inform the United States' long-term care financing reform efforts. METHODS: We consulted insurance experts and conducted a detailed review of public reports, academic studies, and other documents to understand the public and private LTCI systems in France, their advantages and disadvantages, and the factors affecting their development. FINDINGS: France provides universal public coverage for paid assistance with functional dependency for people 60 and older. Benefits are steeply income adjusted and amounts are low. Nevertheless, expenditures have exceeded projections, burdening local governments. Private supplemental insurance covers 11% of French, mostly middle-income adults (versus 3% of Americans 18 and older). Whether policyholders will maintain employer-sponsored coverage after retirement is not known. The government's interest in pursuing an explicit public/private partnership has waned under President Francois Hollande, a centrist socialist, in contrast to the previous center-right leader, President Nicolas Sarkozy, thereby reducing the prospects of a coordinated public/private strategy. CONCLUSIONS: American private insurers are showing increasing interest in long-term care financing approaches that combine public and private elements. The French example shows how a simple, cheap, cash-based product can gain traction among middle income individuals when offered by employers and combined with a steeply income adjusted universal public program. The adequacy of such coverage, however, is a concern. PMID- 26044634 TI - Advocacy for health equity: a synthesis review. AB - POLICY POINTS: Many barriers hamper advocacy for health equity, including the contemporary economic zeitgeist, the biomedical health perspective, and difficulties cooperating across policy sectors on the issue. Effective advocacy should include persistent efforts to raise awareness and understanding of the social determinants of health. Education on the social determinants as part of medical training should be encouraged, including professional training within disadvantaged communities. Advocacy organizations have a central role in advocating for health equity given the challenges bridging the worlds of civil society, research, and policy. CONTEXT: Health inequalities are systematic differences in health among social groups that are caused by unequal exposure to and distributions of-the social determinants of health (SDH). They are persistent between and within countries despite action to reduce them. Advocacy is a means of promoting policies that improve health equity, but the literature on how to do so effectively is dispersed. The aim of this review is to synthesize the evidence in the academic and gray literature and to provide a body of knowledge for advocates to draw on to inform their efforts. METHODS: This article is a systematic review of the academic literature and a fixed-length systematic search of the gray literature. After applying our inclusion criteria, we analyzed our findings according to our predefined dimensions of advocacy for health equity. Last, we synthesized our findings and made a critical appraisal of the literature. FINDINGS: The policy world is complex, and scientific evidence is unlikely to be conclusive in making decisions. Timely qualitative, interdisciplinary, and mixed-methods research may be valuable in advocacy efforts. The potential impact of evidence can be increased by "packaging" it as part of knowledge transfer and translation. Increased contact between researchers and policymakers could improve the uptake of research in policy processes. Researchers can play a role in advocacy efforts, although health professionals and disadvantaged people, who have direct contact with or experience of hardship, can be particularly persuasive in advocacy efforts. Different types of advocacy messages can accompany evidence, but messages should be tailored to advocacy target. Several barriers hamper advocacy efforts. The most frequently cited in the academic literature are the current political and economic zeitgeist and related public opinion, which tend to blame disadvantaged people for their ill health, even though biomedical approaches to health and political short-termism also act as barriers. These barriers could be tackled through long-term actions to raise public awareness and understanding of the SDH and through training of health professionals in advocacy. Advocates need to take advantage of "windows of opportunity," which open and close quickly, and demonstrate expertise and credibility. CONCLUSIONS: This article brings together for the first time evidence from the academic and the gray literature and provides a building block for efforts to advocate for health equity. Evidence regarding many of the dimensions is scant, and additional research is merited, particularly concerning the applicability of findings outside the English-speaking world. Advocacy organizations have a central role in advocating for health equity, given the challenges bridging the worlds of civil society, research, and policy. PMID- 26044636 TI - Adolescent social isolation increases anxiety-like behavior and ethanol intake and impairs fear extinction in adulthood: Possible role of disrupted noradrenergic signaling. AB - Alcohol use disorder, anxiety disorders, and post-traumatic stress disorder (PTSD) are highly comorbid, and exposure to chronic stress during adolescence may increase the incidence of these conditions in adulthood. Efforts to identify the common stress-related mechanisms driving these disorders have been hampered, in part, by a lack of reliable preclinical models that replicate their comorbid symptomatology. Prior work by us, and others, has shown that adolescent social isolation increases anxiety-like behaviors and voluntary ethanol consumption in adult male Long-Evans rats. Here we examined whether social isolation also produces deficiencies in extinction of conditioned fear, a hallmark symptom of PTSD. Additionally, as disrupted noradrenergic signaling may contribute to alcoholism, we examined the effect of anxiolytic medications that target noradrenergic signaling on ethanol intake following adolescent social isolation. Our results confirm and extend previous findings that adolescent social isolation increases anxiety-like behavior and enhances ethanol intake and preference in adulthood. Additionally, social isolation is associated with a significant deficit in the extinction of conditioned fear and a marked increase in the ability of noradrenergic therapeutics to decrease ethanol intake. These results suggest that adolescent social isolation not only leads to persistent increases in anxiety-like behaviors and ethanol consumption, but also disrupts fear extinction, and as such may be a useful preclinical model of stress-related psychopathology. Our data also suggest that disrupted noradrenergic signaling may contribute to escalated ethanol drinking following social isolation, thus further highlighting the potential utility of noradrenergic therapeutics in treating the deleterious behavioral sequelae associated with early life stress. PMID- 26044637 TI - Effects of orally-bioavailable short-acting kappa opioid receptor-selective antagonist LY2456302 on nicotine withdrawal in mice. AB - Kappa opioid receptor (KOR) signaling has been implicated in mediating behavioral and biochemical effects associated with drug dependence. The most commonly used KOR antagonists, norbinaltorphimine (norBNI) and (3R)-7-Hydroxy-N{(1S)-1 {[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl} 1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), have provided a wealth of information in this area; however, the delayed onset and long-lasting effects of these antagonists complicate experimental design and interpretation of results, and make them less than ideal for clinical studies. Initial studies with the recently developed KOR antagonist, LY2456302, show that the compound is a short acting, high-affinity, selective KOR antagonist with therapeutic potential for mood disorders and ethanol use in animal models, and is well tolerated in humans. The goal of the current study was to evaluate the effectiveness of LY2456302 in alleviating the nicotine withdrawal syndrome in mice. Mice were chronically treated with nicotine for 14 days and physical and affective nicotine withdrawal signs were measured using a spontaneous nicotine withdrawal model and conditioned place aversion (CPA) following pre-treatment with LY2456302, administered orally. Vehicle treated nicotine withdrawn mice displayed significant anxiety-related behavior, somatic signs, hyperalgesia, and CPA. Similar to previous studies with norBNI and JDTic, LY2456302 alleviated the nicotine withdrawal syndrome, as evidenced by decreased expression of nicotine withdrawal induced anxiety-related behavior, somatic signs, and CPA, and increased hotplate latency in nicotine withdrawn mice following pre-treatment. Given the current results, and with its favorable pharmacokinetic and pharmacodynamic profile, LY2456302 may be a useful therapeutic agent for treatment of multiple aspects of the nicotine withdrawal syndrome. PMID- 26044638 TI - The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents. AB - Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2 neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor. PMID- 26044639 TI - Regulation of neuronal high-voltage activated Ca(V)2 Ca(2+) channels by the small GTPase RhoA. AB - High-Voltage-Activated (HVA) Ca(2+) channels are known regulators of synapse formation and transmission and play fundamental roles in neuronal pathophysiology. Small GTPases of Rho and RGK families, via their action on both cytoskeleton and Ca(2+) channels are key molecules for these processes. While the effects of RGK GTPases on neuronal HVA Ca(2+) channels have been widely studied, the effects of RhoA on the HVA channels remains however elusive. Using heterologous expression in Xenopus laevis oocytes, we show that RhoA activity reduces Ba(2+) currents through CaV2.1, CaV2.2 and CaV2.3 Ca(2+) channels independently of CaVbeta subunit. This inhibition occurs independently of RGKs activity and without modification of biophysical properties and global level of expression of the channel subunit. Instead, we observed a marked decrease in the number of active channels at the plasma membrane. Pharmacological and expression studies suggest that channel expression at the plasma membrane is impaired via a ROCK-sensitive pathway. Expression of constitutively active RhoA in primary culture of spinal motoneurons also drastically reduced HVA Ca(2+) current amplitude. Altogether our data revealed that HVA Ca(2+) channels regulation by RhoA might govern synaptic transmission during development and potentially contribute to pathophysiological processes when axon regeneration and growth cone kinetics are impaired. PMID- 26044642 TI - Investigation into the Effect of Altitude on the Differential Hemocyte Count of Circulating Plasmatocytes and Granulocytes of Larval Stage of Antheraea assama (Lepidoptera: Saturniidae). AB - Differential hemocyte count of circulating plasmatocytes (PL) and granulocytes (GR) of fifth-instar larvae of Muga Silkworm Antheraea assama Westwood (Lepidoptera: Saturniidae) reared at four different sericulture farms situated at different altitudes, viz, Khanapara State Sericulture Farm, Assam, altitude 55.5 m above sea level (ASL); Nongpoh (Central Silk Board farm), Meghalaya, altitude 464 m ASL; Tura (Central Silk Board farm), West Garo Hills, Meghalaya, 657 m ASL; and Kalimpong (Central Silk Board farm), West Bengal, altitude 1,247 m ASL, were calculated and compared to investigate the effect of altitude on the number of PL and GR per mm(3) of larval hemolymph. The investigation showed that the mean circulating PL and GR were highest at Khanapara (55.5 m ASL) located at the lowest altitude, whereas their numbers gradually decreased with increase in altitude at Nongpoh (464 m ASL), Tura (657 m ASL), and Kalimpong (1,247 m ASL). This may be attributed to the average environmental temperatures observed at different altitudes, which may affect the overall hemocyte load of larval stages reared at those altitudes. PMID- 26044640 TI - Mu opioid receptor modulation in the nucleus accumbens lowers voluntary wheel running in rats bred for high running motivation. AB - The exact role of opioid receptor signaling in mediating voluntary wheel running is unclear. To provide additional understanding, female rats selectively bred for motivation of low (LVR) versus high voluntary running (HVR) behaviors were used. Aims of this study were 1) to identify intrinsic differences in nucleus accumbens (NAc) mRNA expression of opioid-related transcripts and 2) to determine if nightly wheel running is differently influenced by bilateral NAc injections of either the mu-opioid receptor agonist D-Ala2, NMe-Phe4, Glyo5-enkephalin (DAMGO) (0.25, 2.5 MUg/side), or its antagonist, naltrexone (5, 10, 20 MUg/side). In Experiment 1, intrinsic expression of Oprm1 and Pdyn mRNAs were higher in HVR compared to LVR. Thus, the data imply that line differences in opioidergic mRNA in the NAc could partially contribute to differences in wheel running behavior. In Experiment 2, a significant decrease in running distance was present in HVR rats treated with 2.5 MUg DAMGO, or with 10 MUg and 20 MUg naltrexone between hours 0-1 of the dark cycle. Neither DAMGO nor naltrexone had a significant effect on running distance in LVR rats. Taken together, the data suggest that the high nightly voluntary running distance expressed by HVR rats is mediated by increased endogenous mu-opioid receptor signaling in the NAc, that is disturbed by either agonism or antagonism. In summary, our findings on NAc opioidergic mRNA expression and mu-opioid receptor modulations suggest HVR rats, compared to LVR rats, express higher running levels mediated by an increase in motivation driven, in part, by elevated NAc opioidergic signaling. PMID- 26044643 TI - Millennial Mind-Set: Pursuing the Next Generation of Consumers. PMID- 26044641 TI - Oxaliplatin-induced neurotoxicity is mediated through gap junction channels and hemichannels and can be prevented by octanol. AB - Oxaliplatin-induced neurotoxicity (OIN) is a common complication of chemotherapy without effective treatment. In order to clarify the mechanisms of both acute and chronic OIN, we used an ex-vivo mouse sciatic nerve model. Exposure to 25 MUM oxaliplatin caused a marked prolongation in the duration of the nerve evoked compound action potential (CAP) by nearly 1200% within 300 min while amplitude remained constant for over 20 h. This oxaliplatin effect was almost completely reversed by the gap junction (GJ) inhibitor octanol in a concentration-dependent manner. Further GJ blockers showed similar effects although with a narrower therapeutic window. To clarify the target molecule we studied sciatic nerves from connexin32 (Cx32) and Cx29 knockout (KO) mice. The oxaliplatin effect and neuroprotection by octanol partially persisted in Cx29 better than in Cx32 KO nerves, suggesting that oxaliplatin affects both, but Cx32 GJ channels more than Cx29 hemichannels. Oxaliplatin also accelerated neurobiotin uptake in HeLa cells expressing the human ortholog of Cx29, Cx31.3, as well as dye transfer between cells expressing the human Cx32, and this effect was blocked by octanol. Oxaliplatin caused no morphological changes initially (up to 3 h of exposure), but prolonged nerve exposure caused juxtaparonodal axonal edema, which was prevented by octanol. Our study indicates that oxaliplatin causes forced opening of Cx32 channels and Cx29 hemichannels in peripheral myelinated fibers leading to disruption of axonal K(+) homeostasis. The GJ blocker octanol prevents OIN at very low concentrations and should be further studied as a neuroprotectant. PMID- 26044644 TI - Organizational behavior: a primer. PMID- 26044645 TI - Intraoperative radiography for evaluation of surgical miscounts. AB - PURPOSE: Retained surgical items result in substantial morbidity, health care related expense, and legal liability. This study determines the performance of a protocol for locating surgical items after a miscount, in which intraoperative radiography included a radiograph of the unaccounted for item. METHODS: Institutional review board approval was obtained. In 20,820 operations performed between January 1, 2011 and April 1, 2013, a total of 183 consecutive surgical miscounts occurred, involving 180 patients (97 male, 83 female; median age: 55 years). Departmental protocol mandated that a radiograph of an example of the potentially retained item be taken simultaneously with each patient intraoperative radiograph. Three board-certified radiologists retrospectively reviewed these radiographs and follow-up imaging, achieving consensus on interpretation. Adherence to institutional protocol was assessed. Demographic data, surgical documentation, and clinical follow-up data were recorded. RESULTS: The incidence of surgical miscounts was 0.9% (183 of 20,820). Only 9% (17 of 183) were resolved by discovery: outside the patient (8 cases); on intraoperative radiographs (5 cases); incidentally on follow-up radiographs (2 cases); and on retrospective review (2 cases). The false-negative rate was 44% (4 of 9). Neither of the 2 retained needles discovered postoperatively was removed. The procedures most prone to miscounts were: esophagogastrectomy (33%; 2 of 6); liver transplant (18%; 12 of 66); and Whipple procedure (16%; 7 of 44). Needles (65%) and sponges (9%) were the items that were overlooked most often. Adherence to the protocol of imaging an example of a potentially retained item was 91% (167 of 183). CONCLUSIONS: Despite good adherence to a protocol of imaging the potentially retained items, small needles often were not visualized on intraoperative radiographs and were not subsequently removed, without known adverse events. This finding suggests that intraoperative radiography for small needles may be unnecessary, but further study is required. PMID- 26044647 TI - Early integration processing between faces and vowel sounds in human brain: an MEG investigation. AB - OBJECTIVE: Unconscious fast integration of face and voice information is a crucial brain function necessary for communicating effectively with others. Here, we investigated for evidence of rapid face-voice integration in the auditory cortex. METHODS: Magnetic fields (P50m and N100m) evoked by visual stimuli (V), auditory stimuli (A) and audiovisual stimuli (VA), i.e. by face, vowel and simultaneous vowel-face stimuli, were recorded in 22 healthy subjects. Magnetoencephalographic data from 28 channels around bilateral auditory cortices were analyzed. RESULTS: In both hemispheres, AV - V showed significantly larger P50m amplitudes than A. Additionally, compared with A, the N100m amplitudes and dipole moments of AV - V were significantly smaller in the left hemisphere, but not in the right hemisphere. CONCLUSIONS: Differential changes in P50m (bilateral) and N100m (left hemisphere) that occur when V (faces) are associated with A (vowel sounds) indicate that AV (face-voice) integration occurs in early processing, likely enabling us to communicate effectively in our lives. PMID- 26044646 TI - Mechanical and photoelastic analysis of conventional screws and cannulated screws for sagittal split osteotomy fixation: a comparative study. AB - PURPOSE: The aim of the present study was to use mechanical and photoelastic tests to compare the performance of cannulated screws with solid-core screws in sagittal split osteotomy fixation. METHODS: Ten polyurethane mandibles, with a prefabricated sagittal split ramus osteotomy, were fixed with an L inverted technique and allocated to each group as follows: cannulated screw group (CSG), fixed with three 2.3-cannulated screws; and solid-core screw group (SCSG), fixed with three 2.3-solid-core screws. Vertical linear loading tests were performed. The differences between mean values were analyzed through T test for independent samples. The photoelastic test was carried out using a polariscope. RESULTS: The results revealed differences between the two groups only at 1 mm of displacement, in which the cannulated-screw revealed more resistance. Photoelastic test showed higher stress concentration close to mandibular branch in the solid-core group. CONCLUSIONS: Cannulated screws performed better than solid-core ones in a mechanical test at 1-mm displacement and photoelastic tests. PMID- 26044648 TI - Challenges in the treatment of hypertriglyceridemia: glass half empty or half full? AB - Fasting and postprandial hypertriglyceridemia appear to be causally related to atherosclerotic cardiovascular disease, and plasma triglyceride (TG) concentrations above 10 mmol/l increase susceptibility to acute pancreatitis. Exclusion of secondary causes of hypertriglyceridemia and implementation of lifestyle measures are the initial treatment in all types of hypertriglyceridemia. Current evidence regarding the benefit of adding non-statin agents, i.e. fibrates and n-3 polyunsaturated fatty acids, to statins in patients with hypertriglyceridemia (plasma 2.3 < TG <= 5.7 mmol/l) is insufficient. Therefore, the clinical use of non-statin agents in this context requires a careful trade-off between anticipated benefits and potential adverse events within the context of a clinical consultation. It is reasonable to consider adding fenofibrate to a maximally tolerated dose of a statin with or without ezetimibe in higher risk patients with metabolic syndrome or established atherosclerotic cardiovascular disease with persistent, residual elevation in TG > 2 mmol/l. Patients with very high fasting plasma TG levels (>10 mmol/l) need immediate expert review to offset pancreatitis and, along with strict dietary control and triglyceride-lowering pharmacotherapy, may need lipoprotein apheresis or plasma exchange. PMID- 26044649 TI - Integrated isolation and quantitative analysis of exosome shuttled proteins and nucleic acids using immunocapture approaches. AB - Clinical implementation of exosome based diagnostic and therapeutic applications is still limited by the lack of standardized technologies that integrate efficient isolation of exosomes with comprehensive detection of relevant biomarkers. Conventional methods for exosome isolation based on their physical properties such as size and density (filtration, ultracentrifugation or density gradient), or relying on their differential solubility (chemical precipitation) are established primarily for processing of cell supernatants and later adjusted to complex biological samples such as plasma. Though still representing gold standard in the field, these methods are clearly suboptimal for processing of routine clinical samples and have intrinsic limits that impair their use in biomarker discovery and development of novel diagnostics. Immunoisolation (IA) offers unique advantages for the recovery of exosomes from complex and viscous fluids, in terms of increased efficiency and specificity of exosome capture, integrity and selective origin of isolated vesicles. We have evaluated several commercially available solutions for immunoplate- and immunobead-based affinity isolation and have further optimized protocols to decrease non-specific binding due to exosomes complexity and matrix contaminants. In order to identify best molecular targets for total exosome capture from diverse biological sources, as well as for selective enrichment in populations of interest (e.g. tumor derived exosomes) several exosome displayed proteins and respective antibodies have been evaluated for plate and bead functionalisation. Moreover, we have optimized and directly implemented downstream steps allowing on-line quantification and characterization of bound exosome markers, namely proteins and RNAs. Thus assembled assays enabled rapid overall quantification and validation of specific exosome associated targets in/on plasma exosomes, with multifold increased yield and enrichment ratio over benchmarking technologies. Assays directly coupling selective immobilization of exosomes to a solid phase and their immune- and or molecular profiling through conventional ELISA and PCR analysis, resulted in easy to-elaborate, quantitative readouts, with high low-end sensitivity and dynamic range, low costs and hands-on time, minimal sample handling and downscaling of a working plasma volumes to as few as 100 MUl. PMID- 26044650 TI - An empirical energy function for structural assessment of protein transmembrane domains. AB - Knowing the structure of a protein is essential to characterize its function and mechanism at the molecular level. Despite major advances in solving structures experimentally, most membrane protein native conformations remain unknown. This lack of available structures, along with the physical constraints imposed by the lipid bilayer environment, constitutes a difficulty for the modeling of membrane protein structures. Assessing the quality of membrane protein models is therefore critical. Using a non-redundant set of 66 membrane protein structures (41 alpha and 25 beta), we have developed an empirical energy function for the structural assessment of alpha-helical and beta-sheet transmembrane domains. This statistical potential quantifies the interatomic distance between residues located in the lipid bilayer. To minimize the problem of insufficient sampling, we have used kernel density estimations of the distance distributions. Following a leave-one-out cross-validation procedure, we show that our method outperforms current statistical potentials in discriminating correct from incorrect membrane protein models. Furthermore, the comparison of our distance-dependent statistical potential with one optimized on globular proteins provides insights into the rules by which residues interact within the lipid bilayer. PMID- 26044651 TI - Growth inhibitory effect of adenovirus-mediated tissue-targeted expression of ribosomal protein L23 on human colorectal carcinoma cells. AB - A large body of evidence has established murine double minute 2 (MDM2) as a crucial negative regulator of p53 and the major suppressor of p53 function in tumors with wild-type (wt)-p53. Therefore, by inhibiting MDM2 one may reactivate p53 in tumor cells, leading to their demise. Previous studies revealed that ribosomal protein L23 (RPL23) inhibited MDM2-mediated p53 ubiquitination through direct binding to MDM2, and subsequently induced the p53 level as well as its activity, suggesting that it may be a candidate for use in tumor gene therapy. In the present study, we developed a recombinant adenoviral vector expressing the RPL23 gene under control of the carcinoembryonic antigen (CEA) promoter (rAd/CEA RPL23), and using an in vitro system with cultured human colorectal carcinoma LoVo cells harboring the wt-p53 gene, we proved that rAd/CEA-RPL23 infection could induce the accumulation of endogenous wt-p53 protein and thus lead to the inhibition of tumor cell growth via inducing cell cycle arrest and apoptosis. In vivo treatment of rAd/CEA-RPL23 also exhibited a significant inhibitory effect on tumor growth in nude mice bearing LoVo xenografts. Furthermore, we showed that rAd/CEA-RPL23 synergized with classic chemotherapeutic agent 5-fluorouracil (5 FU) and enhanced its activity against LoVo cells in vivo and in vitro. Taken together, the data presented here suggest that CEA promoter-targeted exogenous RPL23 expression could be of therapeutic value against human colorectal carcinoma that retains wt-p53. PMID- 26044652 TI - SeedsGraph: an efficient assembler for next-generation sequencing data. AB - DNA sequencing technology has been rapidly evolving, and produces a large number of short reads with a fast rising tendency. This has led to a resurgence of research in whole genome shotgun assembly algorithms. We start the assembly algorithm by clustering the short reads in a cloud computing framework, and the clustering process groups fragments according to their original consensus long sequence similarity. We condense each group of reads to a chain of seeds, which is a kind of substring with reads aligned, and then build a graph accordingly. Finally, we analyze the graph to find Euler paths, and assemble the reads related in the paths into contigs, and then lay out contigs with mate-pair information for scaffolds. The result shows that our algorithm is efficient and feasible for a large set of reads such as in next-generation sequencing technology. PMID- 26044653 TI - Coping Styles Among Individuals with Severe Mental Illness and Comorbid PTSD. AB - There is little known about coping styles used by individuals with severe mental illness (SMI) and even less known about the influence of a comorbid posttraumatic stress disorder (SMI-PTSD) diagnosis on coping. The current study examines differences in utilization of coping strategies, overall psychological distress, and exposure to traumatic events between SMI only and SMI-PTSD individuals seeking community mental health clinic services (N = 90). Results demonstrate that overall psychological distress and use of avoidance coping were significantly higher among the SMI-PTSD sample. Avoidance coping partially mediated the relationship between PTSD symptom severity and psychological distress. Findings suggest that the experience of PTSD for those with SMI is associated with increases in avoidance coping, a coping style that significantly contributes to psychological distress. Implications for further study and treatment within community mental health clinics are considered. PMID- 26044655 TI - Natremia, tonicity, and conductivity measurements in hemodialyzed patients. AB - PURPOSE: Natremia is usually considered to reflect tonicity in non-hemodialyzed patients. Some hemodialysis monitors provide an online value (NaCond) of natremia calculated from conductivity measurements. This study compared the relation between tonicity and natremia (NaLab) measured at laboratory with the relation between tonicity and NaCond in hemodialysis patients. METHODS: Fifty-five hemodialysis sessions performed with a Fresenius 5008 dialysis monitor (Fresenius Medical Care, Bad Homburg, Germany) providing a value of NaCond were analyzed. Tonicity (calculated as "osmolality - urea"), NaLab and NaCond were measured at the beginning and end of sessions. RESULTS: The r2 correlation-coefficient between tonicity and NaLab is 0.48 (n = 110). The correlation between tonicity and NaCond is stronger (r2 = 0.71). CONCLUSIONS: Conductivity measurements provide a natremia value (NaCond) that is a better surrogate for tonicity than natremia measured at laboratory. Because NaCond is not obtained from sodium measurement, dialysis monitors should display a value for plasma conductivity (mS/cm) instead for natremia (mmol/l). PMID- 26044656 TI - Extracorporeal membrane oxygenation and severe portopulmonary hypertension following liver transplantation: brief report. AB - BACKGROUND: Patients with severe portopulmonary hypertension (PoPH) responsive to medical therapy may be considered for liver transplantation. We present a case of extracorporeal membrane oxygenation (ECMO) resuscitation for PoPH crisis in a child following liver transplantation (LT), and review the literature on management of this challenging setting. CASE REPORT: A 7-year-old girl, with previous Kasai portoenterostomy and subsequent severe PoPH responsive to pulmonary vasodilator therapy, underwent orthotopic LT. Five days following surgery, she had an asystolic arrest with suprasystemic pulmonary hypertension, and was resuscitated with ECMO therapy. Multi-modal strategies included sildenafil, ambrisentan, nitric oxide, intravenous Epoprostenol infusion, levosimendan, and atrial septostomy. Ten days after her LT, exploration for bleeding was necessary following abdominal drain removal. By 10 days of ECMO support, she was reviewed and considered for lung transplantation. Unfortunately, she deteriorated precipitously with abdominal compartment syndrome and multi organ failure; sadly, life support was withdrawn 23 days after transplantation. DISCUSSION: Patients with severe PoPH may need combined thoracic organ and liver transplantation either at single or serial events. Case reports on ECMO use include resuscitation after massive pulmonary embolism during liver transplantation, bridge until the goal of vasodilatory therapy was reached in worsening PoPH following LT, and bridge to lung or repeat liver transplantation for severe pulmonary hypertension. CONCLUSIONS: ECMO resuscitation and support may be deployed as rescue therapy around the period of liver transplantation. We highlight the importance of patient selection and high risk of complications during ECMO therapy as a bridge to PoPH control. PMID- 26044654 TI - Reference genome of wild goat (capra aegagrus) and sequencing of goat breeds provide insight into genic basis of goat domestication. AB - BACKGROUND: Domestic goats (Capra hircus) have been selected to play an essential role in agricultural production systems, since being domesticated from their wild progenitor, bezoar (Capra aegagrus). A detailed understanding of the genetic consequences imparted by the domestication process remains a key goal of evolutionary genomics. RESULTS: We constructed the reference genome of bezoar and sequenced representative breeds of domestic goats to search for genomic changes that likely have accompanied goat domestication and breed formation. Thirteen copy number variation genes associated with coat color were identified in domestic goats, among which ASIP gene duplication contributes to the generation of light coat-color phenotype in domestic goats. Analysis of rapidly evolving genes identified genic changes underlying behavior-related traits, immune response and production-related traits. CONCLUSION: Based on the comparison studies of copy number variation genes and rapidly evolving genes between wild and domestic goat, our findings and methodology shed light on the genetic mechanism of animal domestication and will facilitate future goat breeding. PMID- 26044657 TI - A novel design of a polymeric aortic valve. AB - INTRODUCTION: In this paper we propose a novel method for developing a polymeric heart valve that could potentially offer an optimum solution for a heart valve substitute. The valve design proposed will provide superior hydrodynamic performance and excellent structural integrity. A full description of the design process is given together with an analysis of the hemodynamic performance using a 2-way strongly coupled Fluid Structure Interaction (FSI). METHOD: A polymeric tri leaflet heart valve is designed based on a patient's sinus of Valsalva (SOV) geometry. The design strategy aims to improve valve hemodynamic performance as well as valve durability by avoiding stress concentrations in the leaflets and reducing the maximum stress level. The valve dynamics and stress levels are also validated by comparing the predicted data to existing experimental and numerical data. RESULTS: The stress distribution in the valve structure is fully characterized throughout the simulation and Von Mises stress is found to be up to 5.32 Mpa during diastole. The results show that an effective orifice area (EOA) and a pressure drop of 3.22 cm^2, and 3.52 mmHg, respectively, can be achieved using the proposed design. CONCLUSIONS: The optimized valve demonstrates high hemodynamic performance with no sign of damaging stress concentration in the entire cardiac cycle. PMID- 26044658 TI - Synthesis and antibacterial evaluation of calcinated Ag-doped nano hydroxyapatite with dispersibility. AB - PURPOSE: Dispersible hydroxyapatite (HAp) nanoparticles are very useful for applying a monolayer to implantable medical devices using the nano-coating technique. To improve tolerance to infection on implanted medical devices, silver doped HAp (Ag-HAp) nanoparticles with dispersiblity and crystallinity were synthesized, avoiding calcination-induced sintering, and evaluated for antibacterial activity. METHODS: The Ca10-xAgx(PO4)6(OH)2 with x = 0 and 0.2 were prepared by wet chemical processing at 100 degrees C. Before calcination at 700 degrees C for 2 h, two kinds of anti-sintering agents, namely a Ca(NO3)2 (Ca salt) and a polyacrylic acid/Ca salt mixture (PAA-Ca), were used. Escherichia coli was used to evaluate the antibacterial activity of the nanopowder. RESULTS: When PAA-Ca was used as an anti-sintering agent in calcination to prepare the dispersible nanoparticles, strong metallic Ag peaks were observed at 38.1 degrees and 44.3 degrees (2theta) in the X-ray diffraction (XRD) profile. However, the Ag peak was barely observed when Ca salt was used alone as the anti-sintering agent. Thus, using Ca salt alone was more effective for preparation of dispersible Ag-HAp than PAA-Ca. The particle average size of Ag-HAp with 0.5 mol% of Ag content was found to be 325 +/- 70 nm when the formation of large particleaggregations was prevented, as determined by dynamic light scattering instrument. The antibacterial activity of the Ag-HAp nanoparticles possessing 0.5 mol% against E. coli was greater than 90.0%. CONCLUSIONS: Dispersible and crystalline nano Ag-HAp can be obtained by using Ca salt alone as an anti sintering agent. The nanoparticles showed antibacterial activity. PMID- 26044659 TI - 3D finite element modeling of epiretinal stimulation: Impact of prosthetic electrode size and distance from the retina. AB - PURPOSE: A novel 3-dimensional (3D) finite element model was established to systematically investigate the impact of the diameter (Phi) of disc electrodes and the electrode-to-retina distance on the effectiveness of stimulation. METHODS: The 3D finite element model was established based on a disc platinum stimulating electrode and a 6-layered retinal structure. The ground electrode was placed in the extraocular space in direct attachment with sclera and treated as a distant return electrode. An established criterion of electric-field strength of 1000 Vm-1 was adopted as the activation threshold for RGCs. RESULTS: The threshold current (TC) increased linearly with increasing Phi and electrode-to retina distance and remained almost unchanged with further increases in diameter. However, the threshold charge density (TCD) increased dramatically with decreasing electrode diameter. TCD exceeded the electrode safety limit for an electrode diameter of 50 um at an electrode-to-retina distance of 50 to 200 MUm. The electric field distributions illustrated that smaller electrode diameters and shorter electrode-to-retina distances were preferred due to more localized excitation of RGC area under stimulation of different threshold currents in terms of varied electrode size and electrode-to-retina distances. Under the condition of same-amplitude current stimulation, a large electrode exhibited an improved potential spatial selectivity at large electrode-to-retina distances. CONCLUSIONS: Modeling results were consistent with those reported in animal electrophysiological experiments and clinical trials, validating the 3D finite element model of epiretinal stimulation. The computational model proved to be useful in optimizing the design of an epiretinal stimulating electrode for prosthesis. PMID- 26044660 TI - An intradialytic increase in serum interleukin-6 levels is associated with an increased mortality in hemodialysis patients. AB - BACKGROUND: The inflammatory marker interleukin-6 (IL-6) increases early in the inflammatory cascade. The aim of this study was to evaluate whether an increase in serum IL-6 levels during a hemodialysis (HD) session is associated with mortality. METHODS: 57 adult patients treated with HD for more than 1 month were prospectively studied over a 3-year follow-up period. Demographic and clinical data were collected and blood samples were drawn before and after a midweek HD session. Events of death and censoring were recorded. RESULTS: During the 3-year follow-up, 50.8% of the patients died. In univariate Cox regression analysis, an increase in IL-6 levels during HD was associated with an increased mortality (HR 1.41 per pg/ml; 95% CI 1.06 to 1.88; P = .017). In multivariate Cox models, the only independent predictors of all-cause mortality were: an increase in IL-6 levels during dialysis (HR 1.46 per pg/ml; 95% CI 1.08 to 1.98; P = .014), higher baseline C-reactive protein (CRP) levels and older age. When predictors of an increase in serum IL-6 levels during HD were introduced into the model, mortality was still significantly associated with IL-6 elevation during dialysis (HR 1.47 per pg/ml, 95% CI 1.01 to 2.14; P = .045). CONCLUSIONS: A rise in serum IL-6 levels during a single HD session is associated with a higher mortality among HD patients, independent of predialysis CRP or IL-6 levels. The results may imply the presence of an intradialytic inflammatory response that affects survival in HD patients. PMID- 26044661 TI - Idiopathic disseminated bacillus Calmette-Guerin infection in three infants. AB - We describe the cases of three infants between 4 and 9 months of age with disseminated bacillus Calmette-Guerin (BCG) infection who developed persistent fever, skin rash, and multiple chest nodules visible on computed tomography 22-34 days after BCG vaccination. These infants were healthy before inoculation, and their detailed immunological profiles, including T cell and neutrophil levels, were within normal range. Most reported BCG cases involve impaired immunity, such as children with chronic granulomatous disease, severe combined immunodeficiency, or human immunodeficiency virus infections. Because of their immature immune systems, BCG vaccination can be hazardous even in early infants without immune abnormalities. Hence, we advise caution when administering BCG vaccines to early infants. PMID- 26044662 TI - Schwann cells induce Proliferation and Migration of Oligodendrocyte Precursor Cells Through Secretion of PDGF-AA and FGF-2. AB - Our previous study has showed that co-grafted Schwann cells (SCs) promote proliferation and migration of the grafted oligodendrocyte precursor cells (OPCs). However, how the co-grafted SCs affect OPCs has not been clarified. In the present study, we confirmed that SC-induced proliferation and migration of OPCs were mediated by SC-secreted factors using SC-conditioned medium (SCM). Then, we detected several candidate factors, PDGF-AA, FGF-2, and IGF-1, in SCs and SCM, and their receptors in OPCs. Finally, by using the selective inhibitors, the effects of these candidate factors on proliferation and migration of OPCs were examined. Our results showed that SCM-stimulated proliferation and migration of OPCs could be markedly decreased by both AG1295 (the inhibitor of PDGFR) and PD173074 (the inhibitor of FGFR). Together, our study suggests that SCs affect proliferation and migration of OPCs through secreting PDGF-AA and FGF-2. Identity of these molecules not only contributes to understand the mechanism of SC-induced proliferation and migration of OPCs but also provides possible target for treatment of CNS diseases. PMID- 26044664 TI - Mapping the Visual World of Fishes. PMID- 26044663 TI - Functions for the cAMP/Epac/Rap1 Signaling Pathway in Low-Dose Endothelial Monocyte-Activating Polypeptide-II-Induced Opening of Blood-Tumor Barrier. AB - Previous studies have demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) induces blood-tumor barrier (BTB) hyperpermeability via both paracellular and transcellular pathways. In a recent study, we revealed that cAMP/PKA-dependent and cAMP/PKA-independent signaling pathways are both involved in EMAP-II-induced BTB hyperpermeability. The present study further investigated the exact mechanisms through which the cAMP/PKA-independent signaling pathway affects EMAP-II-induced BTB hyperpermeability. In an in vitro BTB model, low-dose EMAP-II (0.05 nM) induced a significant decrease in Rap1 activity in RBMECs. Pretreatment with forskolin to elevate intracellular cAMP concentration completely blocked EMAP-II-induced Rap1 inactivation. Epac/Rap1 activation by 8 pCPT-2'-O-Me-cAMP significantly prevented EMAP-II-induced activation of RhoA/ROCK. Furthermore, 8-pCPT-2'-O-Me-cAMP pretreatment significantly inhibited EMAP-II-induced decreases in TEER and increases in HRP flux. Pretreatment also significantly prevented EMAP-II-induced changes in MLC phosphorylation, actin cytoskeleton arrangement, and expression and distribution of ZO-1 in RBMECs. This study demonstrates that the cAMP/Epac/Rap1 signaling cascade is a crucial pathway in EMAP-II-induced BTB hyperpermeability. PMID- 26044665 TI - Instability of the non-activated rotational thromboelastometry assay (NATEM) in citrate stored blood. AB - INTRODUCTION: The non-activated rotational thromboelastometric assay (NATEM) is increasingly used as sensitive test for the evaluation of the endogenous activation of haemostasis. The reproducibility of the test results in citrate stored blood has never been investigated. MATERIALS AND METHODS: The NATEM assay was performed in citrated blood samples stored for 0, 45 and 90minutes using ROTEM(r) (TEM International, Munich, Germany). Blood samples were drawn from healthy volunteers and a population of patients admitted to the intensive care (ICU). In 10 ICU patients, citrate concentrations were measured at baseline and after 90minutes of storage. RESULTS: The NATEM clotting time shortened in stored citrated blood from healthy volunteers (t=0 1226+/-160; t=45 986+/-171; t=90 903+/-177; p<0.001) and ICU patients (t=0 986+/-318; t=90 750+/-187; p<0.001). A similar decrease in clot formation time (CFT) was seen whereas the MCF remained unaffected. Citrate concentration did not change over time, baseline 13.3+/ 0.5mmol/l; after 90minutes 13.2+/-0.7mmol/l; n.s.. CONCLUSIONS: The non-activated rotational thromboelastometric assay test results change over time in citrate stored blood. The NATEM test should be initiated at a standardised time point, in order to prevent bias by different test initiation times, preferably directly after blood withdrawal. PMID- 26044666 TI - A microfluidic cell culture system for monitoring of sequential changes in endothelial cells after heat stress. AB - Endothelial damage induced by a highly elevated body temperature is crucial in some diseases including viral hemorrhagic fevers. Here, we report the heat induced sequential changes of endothelial cells under shear stress, which were determined with a microfluidic culture system. Although live cell imaging showed only minor changes in the appearance of heat-treated cells, Hsp70 mRNA expression analysis demonstrated that the endothelial cells in channels of the system responded well to heat treatment. F-actin staining also revealed clear changes in the bundles of actin filaments after heat treatment. Well-organized bundles of actin filaments in control cells disappeared in heat-treated cells cultured in the channel. Furthermore, the system enabled detection of sequential changes in plasminogen activator inhibitor-1 (PAI-1) secretion from endothelial cells. PAI-1 concentration in the effluent solution was significantly elevated for the first 15min after initiation of heat treatment, and then decreased subsequently. This study provides fundamental information on heat-induced endothelial changes under shear stress and introduces a potent tool for analyzing endothelial secretions. PMID- 26044667 TI - Social, Occupational, and Spatial Exposures and Mental Health Disparities of Working-Class Latinas in the US. AB - Grounded in ecosocial theory, this paper discusses the mental health disparities of working-class Latinas from multiple perspectives. An overview of working-class Latinas' prevalent mental health disorders, barriers to care and suggestions for interventions and future studies are provided. PMID- 26044668 TI - Comparison of Percutaneous Cementoplasty with and Without Interventional Internal Fixation for Impending Malignant Pathological Fracture of the Proximal Femur. AB - PURPOSE: To compare the efficacy of percutaneous cementoplasty (PCP) with and without interventional internal fixation (IIF) on malignant impending pathological fracture of proximal femur. METHODS: A total of 40 patients with malignant impending pathological fracture of proximal femur were selected for PCP and IIF (n = 19, group A) or PCP alone (n = 21, group B) in this non-randomized prospective study. Bone puncture needles were inserted into the proximal femur, followed by sequential installation of the modified trocar inner needles through the puncture needle sheath. Then, 15-45 ml cement was injected into the femur lesion. RESULTS: The overall excellent and good pain relief rate during follow ups were significantly higher in group A than that in group B (89 vs. 57 %, P = 0.034). The average change of VAS, ODI, KPS, and EFES in group A were significantly higher than those in group B at 1-, 3-, 6-month, 1-year (P < 0.05). Meanwhile, The stability of the treated femur was significantly higher in group A than that in group B (P < 0.05). CONCLUSION: PCP and IIF were not only a safe and effective procedure, but resulted in greater pain relief, bone consolidation, and also reduced the risk of fracture than the currently recommended approach of PCP done on malignant proximal femoral tumor. PMID- 26044669 TI - Radiosynthesis and Preliminary Biological Evaluation of [18F]VC701, a Radioligand for Translocator Protein. AB - Positron emission tomography (PET) can be used to monitor in vivo translocator protein (TSPO) expression by using specific radioligands. Recently, several [11C]PK11195 analogues have been synthesized to improve binding stability and brain availability. [18F]VC701 was synthesized and validated in CD healthy rats by biodistribution and inhibition analysis. Imaging studies were also conducted on animals injected unilaterally in the striatum with quinolinic acid (QA) to evaluate the TSPO ligand uptake in a neuroinflammation/neurodegenerative model. [18F]VC701 was synthesized with a good chemical and radiochemical purity and specific activity higher than 37 GBq/MUmol. Kinetic studies performed on healthy animals showed the highest tracer biodistribution in TSPO-rich organs, and preadministration of cold PK11195 caused an overall radioactivity reduction. Metabolism studies showed the absence of radiometabolites in the rat brain of QA lesioned rats, and biodistribution analysis revealed a progressive increase in radioactivity ratios (lesioned to nonlesioned striatum) during time, reaching an approximate value of 5 4 hours after tracer injection. These results encourage further evaluation of this TSPO radioligand in other models of central and peripheral diseases. PMID- 26044670 TI - Sampling Males Who Inject Drugs in Haiphong, Vietnam: Comparison of Time-Location and Respondent-Driven Sampling Methods. AB - Accurate measurements of HIV prevalence and associated risk factors among hidden and high-risk groups are vital for program planning and implementation. However, only two sampling methods are purported to provide representative estimates for populations without sampling frames: time-location sampling (TLS) and respondent driven sampling (RDS). Each method is subject to potential biases and questionable reliability. In this paper, we evaluate surveys designed to estimate HIV prevalence and associated risk factors among people who inject drugs (PWID) sampled through TLS versus RDS. In 2012, males aged >=16 years who reported injecting drugs in the previous month and living in Haiphong, Vietnam, were sampled using TLS or RDS. Data from each survey were analyzed to compare HIV prevalence, related risk factors, socio-demographic characteristics, refusal estimates, and time and expenditures for field implementation. TLS (n = 432) and RDS (n = 415) produced similarly high estimates for HIV prevalence. Significantly lower proportions of PWID sampled through RDS received methadone treatment or met an outreach worker. Refusal estimates were lower for TLS than for RDS. Total expenditures per sample collected and number of person-days of staff effort were higher for TLS than for RDS. Both survey methods were successful in recruiting a diverse sample of PWID in Haiphong. In Vietnam, surveys of PWID are conducted throughout the country; although the refusal estimate was calculated to be much higher for RDS than TLS, RDS in Haiphong appeared to sample PWID with less exposure to services and required fewer financial and staff resources compared with TLS. PMID- 26044671 TI - Return to work from long-term sick leave: a six-year prospective study of the importance of adjustment latitudes at work and home. AB - PURPOSE: The aim was to investigate the long-term importance of adjustment latitude for increased work ability and return to work among female human service workers on long-term sick leave. METHODS: A cohort of female human service workers on long-term sick leave (>60 days) was given a questionnaire four times (0, 6, 12, 60 months). Linear mixed models were used for longitudinal analysis of the repeated measurements of work ability and return to work. RESULTS: Having a higher level of adjustment latitude was associated with both increased work ability and return to work. Adjustments related to work pace were strongly associated with increased work ability, as were adjustments to the work place. Having individual opportunities for taking short breaks and a general acceptance of taking short breaks were associated with increased work ability. At home, a higher level of responsibility for household work was related to increased work ability and return to work. Individuals with possibilities for adjustment latitude, especially pace and place at work, and an acceptance of taking breaks had greater increased work ability over time and a greater work ability compared with individuals who did not have such opportunities. CONCLUSIONS: This study highlights the importance of opportunities for adjustment latitude at work to increase work ability and return to work among female human service workers who have been on long-term sick leave. The results support push and pull theories for individual decision-making on return to work. PMID- 26044672 TI - Microneedle-based drug and vaccine delivery via nanoporous microneedle arrays. AB - In the literature, several types of microneedles have been extensively described. However, porous microneedle arrays only received minimal attention. Hence, only little is known about drug delivery via these microneedles. However, porous microneedle arrays may have potential for future microneedle-based drug and vaccine delivery and could be a valuable addition to the other microneedle-based drug delivery approaches. To gain more insight into porous microneedle technologies, the scientific and patent literature is reviewed, and we focus on the possibilities and constraints of porous microneedle technologies for dermal drug delivery. Furthermore, we show preliminary data with commercially available porous microneedles and describe future directions in this field of research. PMID- 26044674 TI - The association between endometrial polyps and metabolic syndrome: a case-control study. AB - BACKGROUND: Endometrial polyps are common benign gynaecologic disorders. The etiopathogenesis of this condition remains unclear, however obesity is an important risk factor for the development of endometrial polyps. AIM: The aim of the study was to evaluate a possible association between endometrial polyps and clinical parameters of metabolic syndrome (MetS). MATERIALS AND METHODS: Forty five women with endometrial polyps (study group) and 45 without (control group) were included in this cross-sectional study. The main parameters evaluated between the groups were age, BMI (body mass index), waist circumference (WC), blood pressure, serum lipid profiles, fasting glucose levels and homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: There was a significant difference between the groups in terms of BMI, WC, insulin levels and HOMA-IR (P < 0.05). The MetS was present in 32 (71.1%) of women in the study group and in 6 (13.3%) in the control group (P < 0.001). Logistic regression demonstrated that MetS was a significant risk factor for endometrial polyps. ROC curve analysis also showed that MetS was the most significant discriminative risk factor in the study group with an AUC of 0.789 (0.691-0.887; CI 95%). CONCLUSION: Our study suggests that there may be a relationship between endometrial polyps, MetS and insulin resistance. Further studies are required to explain the role of this relationship in the pathogenesis of the disease. PMID- 26044673 TI - Enhanced renoprotective effect of HIF-1alpha modified human adipose-derived stem cells on cisplatin-induced acute kidney injury in vivo. AB - Current therapeutic options for acute kidney injury (AKI) are limited to the use of supportive measures and dialysis. A recent approach that has sparked great interest and gained enormous popularity is the implantation of stem cells to repair acutely damaged kidney organ. Hypoxia inducible factor-1alpha (HIF-1alpha) is effective in protecting the kidney from ischemia and nephrotoxicity. In this study, we investigated whether HIF-1alpha-modified adipose-derived stem cells (ASCs) had an enhanced protective effect on cisplatin-induced kidney injury in vivo. Cisplatin-induced AKI was established in nude mice. Our study demonstrated that HIF-1alpha-modified ASCs obviously promoted the recovery of renal function, ameliorated the extent of histologic injury and reduced renal apoptosis and inflammation, but HIF-1alpha-modified ASCs homed to kidney tissues at very low levels after transplantation. In addition, we also found that HIF-1alpha-modified ASCs significantly increased HO-1 expression in cisplatin-induced AKI in vivo. Thus, our study indicated HIF-1alpha-modified ASCs implantation could provide advanced benefits in the protection again AKI, which will contribute to developing a new therapeutic strategy for the treatment of AKI. PMID- 26044675 TI - SRUC seeks 'uniquely Scottish' solution to surveillance conundrum. PMID- 26044676 TI - Profession must broaden its employment horizons, says FVE. PMID- 26044677 TI - Use of controlled shooting in the pilot badger culls. PMID- 26044678 TI - Guidance to help pig producers cope with porcine epidemic diarrhoea. PMID- 26044679 TI - Updated assessment on African swine fever in eastern Europe. PMID- 26044680 TI - New name, new look for industry body. PMID- 26044681 TI - Insurer calls for clearer labelling of pet treats. PMID- 26044683 TI - RCVS governance: the case for reform. AB - On being appointed President of the RCVS in July last year, Stuart Reid set out three main ambitions for his term of office. One was to consult on whether veterinary surgeons should be allowed to use the title 'Doctor', and this already been realised. The second was to strengthen the College's European and international role, and a new international strategy is being considered by the RCVS Council this month. His third ambition was to continue the College's modernisation agenda and streamline the governance of the College itself. Here, he and Bradley Viner, the incoming President, briefly set out the case for reform. PMID- 26044684 TI - Next steps for the Practice Standards Scheme. PMID- 26044685 TI - Suspected Ragwort Poisoning among Suckler Cows in Aberdeen. PMID- 26044686 TI - Do genetics play a role in porcine periweaning failure-to-thrive syndrome? PMID- 26044687 TI - TB control strategy. PMID- 26044688 TI - Mental health and seeking help. PMID- 26044689 TI - Acute respiratory disease in Irish wolfhounds. PMID- 26044690 TI - Adverse event reports relating to Augmentin. PMID- 26044699 TI - Learning about equine biosecurity. AB - Equine consultant, Jane Nixon, attended the first equine biosecurity course at the British Racing School in November last year, organised by Whorl Publishing. Here, she reports on some of the issues covered. PMID- 26044700 TI - Ten-minute chat. AB - Fiona Thomson took time away from Pets'n'Vets, Blantyre, South Lanarkshire, to spend two weeks volunteering in Blantyre, Malawi, as part of Mission Rabies' first trip to Africa. She spoke to Vet Record Careers just before departing for Malawi on May 14. PMID- 26044701 TI - Intra-arterial bone marrow mononuclear cells (BM-MNCs) transplantation in acute ischemic stroke (IBIS trial): protocol of a phase II, randomized, dose-finding, controlled multicenter trial. AB - RATIONALE: No neuroprotective or neurorestorative therapies have been approved for ischemic stroke. Bone marrow mononuclear cell intra-arterial transplantation improves recovery in experimental models of ischemic stroke. AIMS: This trial aims to test safety and efficacy of intra-arterial injection of autologous bone marrow mononuclear cell in ischemic stroke patients. DESIGN: Multicenter, prospective, phase II, randomized, controlled (non-treated group as control), assessor-blinded clinical trial. Seventy-six stroke patients will be enrolled. Patients fulfilling clinical and radiological criteria (e.g. age between 18 and 80 years, middle cerebral artery ischemic stroke with a National Institutes of Health Stroke Scale score of 6-20 within one- to seven-days from stroke onset and no lacunar stroke) will be randomized to intervention or control group (1 : 1). Bone marrow harvest and intra-arterial injection of autologous bone marrow mononuclear cell will be done in the intervention group with two different doses (2 * 10(6) /kg or 5 * 10(6) /kg in 1 : 1 proportion). Patients will be stratified at randomization by National Institutes of Health Stroke Scale score. Patients will be followed up for two-years. STUDY OUTCOMES: The primary outcome is the proportion of patients with modified Rankin Scale scores of 0-2 at 180 days. Secondary outcomes include National Institutes of Health Stroke Scale and Barthel scores at six-months, infarct volume, mortality, and seizures. DISCUSSION: This is the first trial to explore efficacy of different doses of intra-arterial bone marrow mononuclear cell in moderate-to-severe acute ischemic stroke patients. The trial is registered as NCT02178657. PMID- 26044702 TI - Muscle velocity recovery cycles: Comparison between surface and needle recordings. AB - INTRODUCTION: Recording of muscle velocity recovery cycles (MVRCs) has been developed as a technique to investigate the pathophysiology of muscle diseases. MVRCs have been measured by direct muscle stimulation and concentric electromyographic needle recording. This study was undertaken to determine whether recordings can be made with surface electrodes. METHODS: MVRCs with 1 and 2 conditioning stimuli were recorded simultaneously with concentric needle and surface electrodes from the brachioradialis muscle in 12 healthy volunteers. Muscle relative refractory period, early and late supernormality, and extra-late supernormality were compared between the recording techniques. RESULTS: Surface recordings were possible in all subjects. The multifiber action potentials recorded with surface electrodes were smaller than those recorded with needles, but there was no significant difference between any of their MVRC properties. CONCLUSIONS: MVRCs can be recorded with surface electrodes in healthy subjects. The use of surface electrodes may facilitate the technique of recording MVRCs. PMID- 26044704 TI - Ergocalciferol versus Cholecalciferol for Nutritional Vitamin D Replacement in CKD. AB - BACKGROUND/AIMS: Is cholecalciferol (D3) superior to ergocalciferol (D2) in treating nutritional vitamin D deficiency in chronic kidney disease (CKD)? The answer to this question has not been fully explored. METHODS: A retrospective analysis of 57 patients with non-dialysis-requiring CKD was conducted to assess the relative effectiveness of D2 versus D3 replacement on circulating 25(OH)D levels. Levels of 25(OH) D were assessed at baseline, after attempted repletion with D2, and then after attempted repletion with D3. The relative paired differences of the drug treatment effects were tested using t-tests. Multiple regression modeling was used to determine the factors significantly associated with differential responsiveness to the drugs. RESULTS: The mean (SEM) age was 66.4 +/- 1.4 and mean eGFR was 40.5 +/- 2.2 ml/min/1.73 m(2). The baseline 25(OH)D level was 15.3 +/- 0.8 ng/ml. After standardizing to 100,000 units of drug, increases after cholecalciferol (2.7 +/- 0.3 ng/ml) were more than twice as great as those from ergocalciferol (1.1 +/- 0.3 ng/ml) (p < 0.0001). A sensitivity analysis, which pooled the results of an additional 109 individuals treated with ergocalciferol alone, revealed similar findings (standardized change 2.7 +/- 0.3 vs. 1.6 +/- 0.3 ng/ml, p = 0.0025). Factors associated with a superior response to cholecalciferol were lower baseline 25(OH) D level at the start of therapy (p = 0.015) and the interaction of sex and age (p = 0.0048), with younger females tending to benefit relatively more from cholecalciferol than older males did. CONCLUSION: Cholecalciferol may be superior to ergocalciferol in treating nutritional vitamin D deficiency in non-dialysis CKD. PMID- 26044703 TI - Absence of the intestinal microbiota exacerbates hepatobiliary disease in a murine model of primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, fibroinflammatory cholangiopathy. The role of the microbiota in PSC etiopathogenesis may be fundamentally important, yet remains obscure. We tested the hypothesis that germ free (GF) mutltidrug resistance 2 knockout (mdr2(-/-) ) mice develop a distinct PSC phenotype, compared to conventionally housed (CV) mdr2(-/-) mice. Mdr2(-/-) mice (n = 12) were rederived as GF by embryo transfer, maintained in isolators, and sacrificed at 60 days in parallel with age-matched CV mdr2(-/-) mice. Serum biochemistries, gallbladder bile acids, and liver sections were examined. Histological findings were validated morphometrically, biochemically, and by immunofluorescence microscopy (IFM). Cholangiocyte senescence was assessed by p16(INK4a) in situ hybridization in liver tissue and by senescence-associated beta-galactosidase staining in a culture-based model of insult-induced senescence. Serum biochemistries, including alkaline phosphatase, aspartate aminotransferase, and bilirubin, were significantly higher in GF mdr2(-/-) (P < 0.01). Primary bile acids were similar, whereas secondary bile acids were absent, in GF mdr2(-/-) mice. Fibrosis, ductular reaction, and ductopenia were significantly more severe histopathologically in GF mdr2(-/-) mice (P < 0.01) and were confirmed by hepatic morphometry, hydroxyproline assay, and IFM. Cholangiocyte senescence was significantly increased in GF mdr2(-/-) mice and abrogated in vitro by ursodeoxycholic acid (UDCA) treatment. CONCLUSIONS: GF mdr2(-/-) mice exhibit exacerbated biochemical and histological features of PSC and increased cholangiocyte senescence, a characteristic and potential mediator of progressive biliary disease. UDCA, a commensal microbial metabolite, abrogates senescence in vitro. These findings demonstrate the importance of the commensal microbiota and its metabolites in protecting against biliary injury and suggest avenues for future studies of biomarkers and therapeutic interventions in PSC. PMID- 26044705 TI - G protein-coupled odorant receptors: From sequence to structure. AB - Odorant receptors (ORs) are the largest subfamily within class A G protein coupled receptors (GPCRs). No experimental structural data of any OR is available to date and atomic-level insights are likely to be obtained by means of molecular modeling. In this article, we critically align sequences of ORs with those GPCRs for which a structure is available. Here, an alignment consistent with available site-directed mutagenesis data on various ORs is proposed. Using this alignment, the choice of the template is deemed rather minor for identifying residues that constitute the wall of the binding cavity or those involved in G protein recognition. PMID- 26044706 TI - CRISPR-Cas9 systems: versatile cancer modelling platforms and promising therapeutic strategies. AB - The RNA-guided nuclease CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9) and its variants such as nickase Cas9, dead Cas9, guide RNA scaffolds and RNA-targeting Cas9 are convenient and versatile platforms for site-specific genome editing and epigenome modulation. They are easy-to-use, simple-to-design and capable of targeting multiple loci simultaneously. Given that cancer develops from cumulative genetic and epigenetic alterations, CRISPR-Cas9 and its variants (hereafter referred to as CRISPR-Cas9 systems) hold extensive application potentials in cancer modeling and therapy. To date, they have already been applied to model oncogenic mutations in cell lines (e.g., Choi and Meyerson, Nat Commun 2014;5:3728) and in adult animals (e.g., Xue et al., Nature 2014;514:380-4), as well as to combat cancer by disabling oncogenic viruses (e.g., Hu et al., Biomed Res Int 2014;2014:612823) or by manipulating cancer genome (e.g., Liu et al., Nat Commun 2014;5:5393). Given the importance of epigenome and transcriptome in tumourigenesis, manipulation of cancer epigenome and transcriptome for cancer modeling and therapy is a promising area in the future. Whereas (epi)genetic modifications of cancer microenvironment with CRISPR-Cas9 systems for therapeutic purposes represent another promising area in cancer research. Herein, we introduce the functions and mechanisms of CRISPR-Cas9 systems in genome editing and epigenome modulation, retrospect their applications in cancer modelling and therapy, discuss limitations and possible solutions and propose future directions, in hope of providing concise and enlightening information for readers interested in this area. PMID- 26044707 TI - Quantitative ultrasound molecular imaging. AB - Ultrasound molecular imaging using targeting microbubbles is predominantly a semi quantitative tool, thus limiting its potential diagnostic power and clinical applications. In the work described here, we developed a novel method for acoustic quantification of molecular expression. E-Selectin expression in the mouse heart was induced by lipopolysaccharide. Real-time ultrasound imaging of E selectin expression in the heart was performed using E-selectin-targeting microbubbles and a clinical ultrasound scanner in contrast pulse sequencing mode at 14 MHz, with a mechanical index of 0.22-0.26. The level of E-selectin expression was quantified using a novel time-signal intensity curve analytical method based on bubble elimination, which consisted of curve-fitting the bi exponential equation [Formula: see text] to the elimination phase of the myocardial time-signal intensity curve. Ar and Af represent the maximum signal intensities of the retained and freely circulating bubbles in the myocardium, respectively; lambdar and lambdaf represent the elimination rate constants of the retained and freely circulating bubbles in the myocardium, respectively. Ar correlated strongly with the level of E-selectin expression (|r|>0.8), determined using reverse transcriptase real-time quantitative polymerase chain reaction, and the duration of post-lipopolysaccharide treatment-both linearly related to cell surface E-selectin protein (actual bubble target) concentration in the expression range imaged. Compared with a conventional acoustic quantification method (which used retained bubble signal intensity at 20 min post-bubble injection), this new approach exhibited greater dynamic range and sensitivity and was able to simultaneously quantify other useful characteristics (e.g., the microbubble half life). In conclusion, quantitative determination of the level of molecular expression is feasible acoustically using a time-signal intensity curve analytical method based on bubble elimination. PMID- 26044708 TI - Hemodialysis patients with hepatitis C infection are not receiving the new antiviral medications. PMID- 26044709 TI - Bone remodelling markers in hypertensive patients with and without diabetes mellitus: link between bone and glucose metabolism. AB - OBJECTIVE: Growing evidence suggests the presence of a complex interplay between hypertension as well as type 2 diabetes mellitus (DM) and osteoporosis. The present study was designed to investigate a possible effect of type 2 DM on bone remodelling markers such as osteoprotegerin and N-terminal propeptide of type 1 collagen (P1NP) in hypertensive patients. DESIGN AND METHODS: The 100 study participants were divided into three groups according to the presence of DM and hypertension: group one included diabetic hypertensive subjects, group 2 included hypertensive subjects without diabetes and group 3 included subjects without hypertension and without DM (controls). Blood sampling for metabolic parameters, including osteoprotegerin, P1NP, adiponectin, fasting glucose, HbA1c , CRP, homeostasis model assessment-insulin resistance, homeostasis model assessment beta function was performed. RESULTS: Circulating P1NP increased from group 1 to group 3 in a continuous fashion. P1NP was significantly lower in hypertensive subjects with DM (group 1), than in groups 2 and 3 (p < 0.0001). P1NP, was marginally lower in diabetic hypertensive subjects as compared with nondiabetic subjects with hypertension (p = 0.079). Circulating osteoprotegerin did not differ significantly between groups (p = 0.593). CONCLUSIONS: In the present study, bone formation marker, P1NP, was significantly lower in diabetic hypertensive subjects as compared with nondiabetic subjects with and without hypertension. P1NP was inversely associated with parameters of glucose homeostasis such as fasting glucose, HbA1c and positively with homeostasis model assessment-beta cell function. Type 2 DM was associated with an adverse effect on bone formation independently of age, sex and exposure to anti-diabetic drugs. PMID- 26044710 TI - A cis-encoded sRNA, Hfq and mRNA secondary structure act independently to suppress IS200 transposition. AB - IS200 is found throughout Enterobacteriaceae and transposes at a notoriously low frequency. In addition to the transposase protein (TnpA), IS200 encodes an uncharacterized Hfq-binding sRNA that is encoded opposite to the tnpA 5'UTR. In the current work we asked if this sRNA represses tnpA expression. We show here that the IS200 sRNA (named art200 for antisense regulator of transposase IS200) basepairs with tnpA to inhibit translation initiation. Unexpectedly, art200-tnpA pairing is limited to 40 bp, despite 90 nt of perfect complementarity. Additionally, we show that Hfq and RNA secondary structure in the tnpA 5'UTR each repress tnpA expression in an art200-independent manner. Finally, we show that disrupting translational control of tnpA expression leads to increased IS200 transposition in E. coli. The current work provides new mechanistic insight into why IS200 transposition is so strongly suppressed. The possibility of art200 acting in trans to regulate a yet-unidentified target is discussed as well as potential applications of the IS200 system for designing novel riboregulators. PMID- 26044711 TI - Surface plasmon resonance imaging reveals multiple binding modes of Agrobacterium transformation mediator VirE2 to ssDNA. AB - VirE2 is the major secreted protein of Agrobacterium tumefaciens in its genetic transformation of plant hosts. It is co-expressed with a small acidic chaperone VirE1, which prevents VirE2 oligomerization. After secretion into the host cell, VirE2 serves functions similar to a viral capsid in protecting the single stranded transferred DNA en route to the nucleus. Binding of VirE2 to ssDNA is strongly cooperative and depends moreover on protein-protein interactions. In order to isolate the protein-DNA interactions, imaging surface plasmon resonance (SPRi) studies were conducted using surface-immobilized DNA substrates of length comparable to the protein-binding footprint. Binding curves revealed an important influence of substrate rigidity with a notable preference for poly-T sequences and absence of binding to both poly-A and double-stranded DNA fragments. Dissociation at high salt concentration confirmed the electrostatic nature of the interaction. VirE1-VirE2 heterodimers also bound to ssDNA, though by a different mechanism that was insensitive to high salt. Neither VirE2 nor VirE1-VirE2 followed the Langmuir isotherm expected for reversible monomeric binding. The differences reflect the cooperative self-interactions of VirE2 that are suppressed by VirE1. PMID- 26044712 TI - CATNAP: a tool to compile, analyze and tally neutralizing antibody panels. AB - CATNAP (Compile, Analyze and Tally NAb Panels) is a new web server at Los Alamos HIV Database, created to respond to the newest advances in HIV neutralizing antibody research. It is a comprehensive platform focusing on neutralizing antibody potencies in conjunction with viral sequences. CATNAP integrates neutralization and sequence data from published studies, and allows users to analyze that data for each HIV Envelope protein sequence position and each antibody. The tool has multiple data retrieval and analysis options. As input, the user can pick specific antibodies and viruses, choose a panel from a published study, or supply their own data. The output superimposes neutralization panel data, virus epidemiological data, and viral protein sequence alignments on one page, and provides further information and analyses. The user can highlight alignment positions, or select antibody contact residues and view position specific information from the HIV databases. The tool calculates tallies of amino acids and N-linked glycosylation motifs, counts of antibody-sensitive and resistant viruses in conjunction with each amino acid or N-glycosylation motif, and performs Fisher's exact test to detect potential positive or negative amino acid associations for the selected antibody. Website name: CATNAP (Compile, Analyze and Tally NAb Panels). Website address: http://hiv.lanl.gov/catnap. PMID- 26044713 TI - Age and sex differences of risk factors of activity limitations in Japanese older adults. AB - AIM: The objective of the present study was to verify how socioeconomic and physical/mental health status would be associated with activity limitations by age and sex among older adults, using nationally representative cross-sectional data in Japan. METHODS: The present study focused on 8373 older adults aged 65 years or older extracted from the Comprehensive Survey of Living Conditions conducted in 2007 by the Japanese Ministry of Health, Labor and Welfare. Univariate and multiple logistic regression analyses and population-attributable risk were applied to validate the relationships of socioeconomic and physical/mental health status with activity limitations among the total population, and by age groups (young-old or old-old) and sex. RESULTS: Mental health showed the highest odds ratio and population-attributable risk in the total population. In addition, low back pain was associated with activity limitations regardless of age and sex. Other musculoskeletal diseases, such as arthropathy and osteoporosis, were related to activity limitations for women, regardless of age, whereas cardiovascular diseases, including angina pectoris/myocardial infarction and cerebral stroke, were associated with activity limitations for men in any age group. There were no statistically significant correlations between socioeconomic status and activity limitations in any groups. CONCLUSION: Mental health was the most important factor of activity limitations in Japanese older adults. Furthermore, low back pain regardless of age and sex, other musculoskeletal diseases only for women and cardiovascular diseases mainly for men could also be significant risk factors to activity limitations. Therefore, preventive approaches of activity limitations considering sex differences are important for older adults in Japan. Geriatr Gerontol Int 2015; ??: ??-??. PMID- 26044714 TI - Discrimination accuracy between real and sham press needles in the hands. AB - OBJECTIVES: To evaluate the blinding effectiveness of a modified blunt sham press needle on the basis of the ability of subjects to discriminate between real and sham acupuncture needles compared with their discrimination ability based on pure guessing, and to define differences between senses (touch and vision) in the rates of correctly identified needles. METHODS: Sixty-three healthy students and staff members were recruited through convenience sampling. First, real or sham acupuncture was randomly administered to the left LI4 point while subjects could not observe the needle tip. A real or sham needle tip was then shown to the subjects. Finally, a random combination of real or sham acupuncture needles were randomly administered to the left and right LI4 points, this time with the subjects observing the procedure. In all conditions the subjects gave their judgement as Yes or No in response to questions asking them to identify the needle type. The proportion of correct judgements (P(C)) was computed for the last part of the trial in left and right LI4 points, and the rates of correctly identified needles for each trial were obtained. RESULTS: The subjects' accuracy of discrimination between the real and sham acupuncture needles in left and right LI4 points was not significantly different from that based on pure guess (P(C)=0.50 (chance level)), which indicates complete inability to discriminate between needles. The rates of correctly identified needles using touch, vision and a combination of both senses were not significantly different (p=0.807). CONCLUSIONS: The findings from this study show that this sham acupuncture device successfully blinded subjects to real and sham press needles, suggesting that it is effective for subject blinding in studies on acupuncture using press needles, and facilitating evaluation of the effects of acupuncture in placebo-controlled trials using a rigorous scientific research methodology. PMID- 26044715 TI - Newborn Infection Control and Care Initiative for health facilities to accelerate reduction of newborn mortality (NICCI): study protocol for a randomized controlled trial. AB - BACKGROUND: Newborn health is a key issue in addressing the survival of children under five years old, particularly in low and middle income countries, and the evidence base for newborn health interventions continues to evolve. Over the last decade, maternal and under five-year-old mortality and morbidity rates have been successfully reduced in Cambodia, but newborn health has lagged behind. Evidence suggests that an important proportion of newborn mortality both globally and in Cambodia is attributable to infections and sepsis. While initiatives are being implemented to address some causes of newborn illness (related to pre-term birth and asphyxia), a country-level approach to reducing infections has not been formulated. The Newborn Infection Control and Care Initiative (NICCI) is a community and health facility linked intervention to improve health outcomes for newborns. METHODS/DESIGN: The present study applies a cluster randomized trial, using a stepped wedge design, to assess the impact of a package intervention on newborn health. The intervention components include addressing infection control in the perinatal period in health facilities, promoting infection prevention and control practices in health center and home environments, and improving the timeliness of referrals for newborns with suspected infections to appropriate health facilities, by linking families to the medical system through a network of community based volunteers who will make home visits to families in the first week of a newborn's life. DISCUSSION: The NICCI trial is designed to complement and enhance the Cambodian Ministry of Health strategies and objectives for maternal and newborn care. Results of the study will help to inform policy and the possible scale-up of newborn health interventions in the country. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov (identifier: NCT02271737) on 5 October 2014. PMID- 26044716 TI - Physical activity and negative emotion during peer-rejection: Evidence for emotion context sensitivity. AB - It is well-established that physical activity is beneficial to physical and psychological health. However, how physical activity contributes to psychological health is still unclear. In this investigation, we examined the association between physical activity and negative emotions assessed in real-time during simulated-peer-rejection. Moreover, we explored mediation of this association by higher-order neurocognitive functioning and cardiovascular flexibility. Although we found no evidence for mediation, we did find that greater physical activity predicted contextually responsive negative emotion. Specifically, greater physical activity predicted generation of negative emotions in response to peer rejection and flexible reduction of negative emotions in response to peer acceptance. PMID- 26044717 TI - Integrating tobacco treatment into thoracic oncology settings: Lessons learned. AB - Clinical practice guidelines recommend tobacco treatment for all cancer patients. However, little is known about how to integrate tobacco treatment into cancer care. The results of our pilot study of an evidence-based tobacco treatment integrated into a thoracic oncology clinic demonstrated good feasibility and efficacy, providing an opportunity to inform future tobacco treatment integration efforts. Here, we describe the process of intervention development, clinic integration, patient identification, and patient enrollment. We report on the intervention content and delivery, patterns of quitting for participants in the tobacco treatment group, and changes in smoking-related psychosocial variables. Clinical implications and suggestions for future research are discussed. PMID- 26044718 TI - Inflammatory bowel disease: The harmful mechanism of experiential avoidance for patients' quality of life. AB - This study aimed to test the effects of inflammatory bowel disease symptomatology and associated medical complications on physical and psychological quality of life and to explore whether these relationships are mediated by experiential avoidance. A total of 200 inflammatory bowel disease patients reported demographic and medical data and completed self-report instruments. Results revealed that the tested model presented an excellent fit, explaining 51 per cent of physical quality of life and 53 per cent of psychological quality of life. Inflammatory bowel disease-associated complications directly impacted on physical quality of life, and experiential avoidance significantly mediated the relationships between inflammatory bowel disease symptomatology and physical and psychological quality of life. These results highlight the importance of implementing psychological interventions for inflammatory bowel disease patients. PMID- 26044719 TI - I wonder if robots will take care of me when I am old: Positive aging representations of professionals working in health promotion services. AB - How the social and institutional context is structured and represented by its actors has an impact on positive aging representations. This qualitative study explores professionals' views on positive aging, how they promote positive aging in their practice and what disparities occur between their discourses and the actual practice of promoting positive aging. Interviews were conducted with professionals from different active aging promotion services and analyzed with thematic coding. Findings show professionals hold negative views on aging while trying to promote positive views in their work, illustrating an existing theory practice gap. Strategies used in practice can be integrated in existing agency models and inform interventions and active aging policies. PMID- 26044721 TI - Synthesis of Nanogels via Cell Membrane-Templated Polymerization. AB - The synthesis of biomimetic hydrogel nanoparticles coated with a natural cell membrane is described. Compared to the existing strategy of wrapping cell membranes onto pre-formed nanoparticle substrates, this new approach forms the cell membrane-derived vesicles first, followed by growing nanoparticle cores in situ. It adds significant controllability over the nanoparticle properties and opens unique opportunities for a broad range of biomedical applications. PMID- 26044722 TI - MicroRNA-18a Decreases Choroidal Endothelial Cell Proliferation and Migration by Inhibiting HIF1A Expression. AB - BACKGROUND: The aim of this study was to investigate the effect of hypoxia on the level of microRNA-18a (miR-18a) and hypoxia-inducible factor 1A (HIF1A) expressed by choroidal endothelial cells through cytological analysis. MATERIAL AND METHODS: After culturing choroidal endothelial cells (CECs) under normoxia or hypoxia, microRNAs, expressed in different ways, were screened by using GeneChip microRNA array, and the results were confirmed by real-time PCR. The bioinformatics approach was used to screen target genes of target miRNA. In addition, CECs were transfected with target miRNA mimic or inhibitor and then expression levels of targeted miRNA and genes were observed. RESULTS: The GeneChip microRNA Array detected 14 miRNAs that were expressed differently. Among these miRNAs, 12 miRNAs were identified as being upregulated and 2 miRNAs as being down-regulated. MiR-18a was most significantly down-regulated. Bioinformatics analysis showed that HIF1A was the target gene of miR-18a. In CECs transfected with miR-18a mimic, there was a remarkable decrease in gene expression level and protein level of HIF1A, and thereby, significant reduction in proliferation and migration of CECs. In CECs transfected with miR-18a inhibitor, there was a significant increase in gene and protein expression levels of HIF1A, and enhanced proliferation and migration of CECs. CONCLUSIONS: We conclude that miR-18a affects the function of CECs by inhibiting the expression of HIF1A. PMID- 26044723 TI - Phase stability and dynamics of entangled polymer-nanoparticle composites. AB - Nanoparticle-polymer composites, or polymer-nanoparticle composites (PNCs), exhibit unusual mechanical and dynamical features when the particle size approaches the random coil dimensions of the host polymer. Here, we harness favourable enthalpic interactions between particle-tethered and free, host polymer chains to create model PNCs, in which spherical nanoparticles are uniformly dispersed in high molecular weight entangled polymers. Investigation of the mechanical properties of these model PNCs reveals that the nanoparticles have profound effects on the host polymer motions on all timescales. On short timescales, nanoparticles slow-down local dynamics of the host polymer segments and lower the glass transition temperature. On intermediate timescales, where polymer chain motion is typically constrained by entanglements with surrounding molecules, nanoparticles provide additional constraints, which lead to an early onset of entangled polymer dynamics. Finally, on long timescales, nanoparticles produce an apparent speeding up of relaxation of their polymer host. PMID- 26044724 TI - Clinical impact of circulating miR-26a, miR-191, and miR-208b in plasma of patients with acute myocardial infarction. AB - BACKGROUND: Aberrant expression of several types of miRNAs has been reported in acute myocardial infarction (AMI). The objective of our study was to compare miRNA expression in AMI patients and normal healthy people and determine whether miR-26a, miR-191, and miR-208b could be measured in plasma as indicators for AMI. METHODS: Detection of AMI patients and normal persons by using miRNA microarray chip analysis and miR-26a, miR-191, and miR-208b was screened out. Eighty-seven AMI patients and eighty-seven homogeneous healthy individuals were recruited. Total mRNA including miRNA was isolated and miR-26a, miR-191, and miR-208b expression were determined by qRT-PCR. Receiver operating characteristic curve analysis was performed to evaluate the instructive power of miR-26a, miR-191, and miR-208b for AMI. Dual-luciferase reporter assays indicated p21 is a direct target of miR-208b. RESULTS: miR-26a and miR-191 were low expressed in AMI compared with normal healthy people, but miR-208b was expressed at a high level in AMI. miR-26a showed an area under the curve (AUC) of 0.745, with a sensitivity of 73.6 % and a specificity of 72.4 %.The AUC for miR-191 was 0.669, with a sensitivity of 62.1 % and a specificity of 69.0 %.The AUC for miR-208b was 0.674, with a sensitivity of 59.8 % and a specificity of 73.6 %. CONCLUSIONS: miR-208b was significantly increased in the AMI compared with healthy people, while miR 26a and miR-191 were decreased. miR-26a, miR-191, and miR-208b were potential indices of AMI, and miR-208b was more effective in patients with non-ST-elevation myocardial infarction. PMID- 26044725 TI - [Parvovirus B19 infection and pregnancy]. AB - "Small virus" contagious during spring, parvovirus B19 is responsible for fifth disease of children. The prevalence of infection is very high before 10 years old and children are especially responsible for transmission to pregnant women. Approximately 50% of women old enough to procreate have stigmas serologic of old infection. Acquired immunity is long hasting and solid. During pregnancy, this virus is responsible for abortion, fetal anemia. Severe anemia can cause hydrops fetalis or fetal mortality in utero or neurologic damage. We are going to start again point by point of the contage has the care the situations with which the doctor can be confronted during the pregnancy. PMID- 26044727 TI - The Troika of Aortopathy: Size, Function and Etiology. PMID- 26044728 TI - Kerinokeratosis Papulosa of Childhood. AB - BACKGROUND: Kerinokeratosis papulosa (KP) is considered an extremely rare genodermatosis presenting usually as waxy papules on the trunk in childhood. OBJECTIVE: To describe and analyze the clinical, histological and potential etiopathological aspects of KP. METHODS: The dermatoscopic features of a new case of KP of childhood are investigated. The presence of human papillomavirus (HPV) DNA in lesional skin was studied by polymerase chain reaction. Furthermore, all cases of KP of childhood reported so far were reviewed. RESULTS: As a diagnostic tool, we describe for the first time a dermatoscopic feature, namely a cribriform pattern of KP, in an 11-year-old boy. In addition, we detected HPV (type 57) in his KP lesions. CONCLUSIONS: Dermatoscopic examination might be a useful tool to distinguish KP from other skin lesions, e.g. common warts. The detection of HPV type 57 might hint to an etiological role of HPV for KP. PMID- 26044726 TI - Gestational tissue transcriptomics in term and preterm human pregnancies: a systematic review and meta-analysis. AB - BACKGROUND: Preterm birth (PTB), or birth before 37 weeks of gestation, is the leading cause of newborn death worldwide. PTB is a critical area of scientific study not only due to its worldwide toll on human lives and economies, but also due to our limited understanding of its pathogenesis and, therefore, its prevention. This systematic review and meta-analysis synthesizes the landscape of PTB transcriptomics research to further our understanding of the genes and pathways involved in PTB subtypes. METHODS: We evaluated published genome-wide pregnancy studies across gestational tissues and pathologies, including those that focus on PTB, by performing a targeted PubMed MeSH search and systematically reviewing all relevant studies. RESULTS: Our search yielded 2,361 studies on gestational tissues including placenta, decidua, myometrium, maternal blood, cervix, fetal membranes (chorion and amnion), umbilical cord, fetal blood, and basal plate. Selecting only those original research studies that measured transcription on a genome-wide scale and reported lists of expressed genetic elements identified 93 gene expression, 21 microRNA, and 20 methylation studies. Although 30 % of all PTB cases are due to medical indications, 76 % of the preterm studies focused on them. In contrast, only 18 % of the preterm studies focused on spontaneous onset of labor, which is responsible for 45 % of all PTB cases. Furthermore, only 23 of the 10,993 unique genetic elements reported to be transcriptionally active were recovered 10 or more times in these 134 studies. Meta-analysis of the 93 gene expression studies across 9 distinct gestational tissues and 29 clinical phenotypes showed limited overlap of genes identified as differentially expressed across studies. CONCLUSIONS: Overall, profiles of differentially expressed genes were highly heterogeneous both between as well as within clinical subtypes and tissues as well as between studies of the same clinical subtype and tissue. These results suggest that large gaps still exist in the transcriptomic study of specific clinical subtypes as well in the generation of the transcriptional profile of well-studied clinical subtypes; understanding the complex landscape of prematurity will require large-scale, systematic genome wide analyses of human gestational tissues on both understudied and well-studied subtypes alike. PMID- 26044729 TI - Health technology assessment of medical devices: a survey of non-European union agencies. AB - OBJECTIVES: The aim of this study was to review and compare current health technology assessment (HTA) activities for medical devices across non-European Union HTA agencies. METHODS: HTA activities for medical devices were evaluated from three perspectives: organizational structure, processes, and methods. Agencies were primarily selected upon membership of existing HTA networks. The data collection was performed in two stages: stage 1-agency Web-site assessment using a standardized questionnaire, followed by review and validation of the collected data by a representative of the agency; and stage 2-semi-structured telephone interviews with key informants of a sub-sample of agencies. RESULTS: In total, thirty-six HTA agencies across twenty non-EU countries assessing medical devices were included. Twenty-seven of thirty-six (75 percent) agencies were judged at stage 1 to have adopted HTA-specific approaches for medical devices (MD specific agencies) that were largely organizational or procedural. There appeared to be few differences in the organization, process and methods between MD specific and non-MD-specific agencies. Although the majority (69 percent) of both categories of agency had specific methods guidance or policy for evidence submission, only one MD-specific agency had developed methodological guidelines specific to medical devices. In stage 2, many MD-specific agencies cited insufficient resources (budget, skilled employees), lack of coordination (between regulator and reimbursement bodies), and the inability to generalize findings from evidence synthesis to be key challenges in the HTA of medical devices. CONCLUSIONS: The lack of evidence for differentiation in scientific methods for HTA of devices raises the question of whether HTA needs to develop new methods for medical devices but rather adapt existing methodological approaches. In contrast, organizational and/or procedural adaptation of existing HTA agency frameworks to accommodate medical devices appear relatively commonplace. PMID- 26044730 TI - CRISPR/Cas9 Genome Editing in Caenorhabditis elegans: Evaluation of Templates for Homology-Mediated Repair and Knock-Ins by Homology-Independent DNA Repair. AB - Precise genome editing by the Cas9 nuclease depends on exogenously provided templates for homologous recombination. Here, we compare oligonucleotides with short homology and circular DNA molecules with extensive homology to genomic targets as templates for homology-based repair of CRISPR/Cas9 induced double strand breaks. We find oligonucleotides to be templates of choice for introducing small sequence changes into the genome based on editing efficiency and ease of use. We show that polarity of oligonucleotide templates greatly affects repair efficiency: oligonucleotides in the sense orientation with respect to the target gene are better templates. In addition, combining a gene loss-of-function phenotype screen with detection of integrated fluorescent markers, we demonstrate that targeted knock-ins in Caenorhabditis elegans also can be achieved by homology-independent repair. PMID- 26044731 TI - Genome Assembly Improvement and Mapping Convergently Evolved Skeletal Traits in Sticklebacks with Genotyping-by-Sequencing. AB - Marine populations of the threespine stickleback (Gasterosteus aculeatus) have repeatedly colonized and rapidly adapted to freshwater habitats, providing a powerful system to map the genetic architecture of evolved traits. Here, we developed and applied a binned genotyping-by-sequencing (GBS) method to build dense genome-wide linkage maps of sticklebacks using two large marine by freshwater F2 crosses of more than 350 fish each. The resulting linkage maps significantly improve the genome assembly by anchoring 78 new scaffolds to chromosomes, reorienting 40 scaffolds, and rearranging scaffolds in 4 locations. In the revised genome assembly, 94.6% of the assembly was anchored to a chromosome. To assess linkage map quality, we mapped quantitative trait loci (QTL) controlling lateral plate number, which mapped as expected to a 200-kb genomic region containing Ectodysplasin, as well as a chromosome 7 QTL overlapping a previously identified modifier QTL. Finally, we mapped eight QTL controlling convergently evolved reductions in gill raker length in the two crosses, which revealed that this classic adaptive trait has a surprisingly modular and nonparallel genetic basis. PMID- 26044732 TI - Inhibitor of p53-p21 pathway induces the differentiation of human umbilical cord derived mesenchymal stem cells into cardiomyogenic cells. AB - P53 is shown recently to play an important role in the proliferation and differentiation of mesenchymal stem cells. In this study, human umbilical cord derived mesenchymal stem cells (hUCMSCs) were isolated and purified from the umbilical cords of normal or cesarean term deliveries, after treatment with 20 MUmol/L PFT-alpha for 24 h, hUCMSCs were continued to be cultured for 4 weeks, cardiac-specific protein expression of cTnI, Desmin and Nkx2.5 was determined using immunofluorescence assay and RT-PCR. The expression of p53 and p21 was detected by western blot. Results showed that no expression of cTnI, Desmin or Nkx2.5 was observed in the control and the PFT-alpha group at 1 week after induction. However, after 4 weeks, while control group still had little expression of cTnI, Desmin and Nkx2.5, the PFT-alpha group demonstrated strong expression of cTnI, Desmin and Nkx2.5 (P < 0.001). At 4 weeks after induction, differentiation rate of cardiomyogenic cells in the PFT-alpha group (36.98 %) was significantly higher than that in the control group (4.41 %) (P < 0.01). Western blot analysis show that downregulation of p53 and p21 was seen in the PFT-alpha group at 4 weeks. The difference compared with the control group was statistically significant (P < 0.01). In conclusion, PFT-alpha can promote the differentiation of hUCMSCs into cardiomyogenic cells by modulating the p53-p21 pathway. PMID- 26044733 TI - Osteoprotegerin exposure at different stages of osteoclastogenesis differentially affects osteoclast formation and function. AB - This study aimed to investigate the effects of osteoprotegerin (OPG), a decoy receptor for receptor activator for nuclear factor kappaB ligand (RANKL), during the various stages of osteoclast differentiation, and additionally investigate its effects on osteoclast adhesion and activity. RAW264.7 murine monocytic cells were incubated with macrophage colony-stimulating factor and RANKL for 1, 3, 5, or 7 days, followed by an additional 24-h incubation in the presence or absence of OPG (80 ng/mL). We examined osteoclast differentiation and adhesion capacity using the tartrate-resistant acid phosphatase (TRAP) assay and immunofluorescence microscopy, and additionally examined cell growth in real time using the xCELLigence system. Furthermore, the expression levels of TRAP, RANK, integrin beta3, matrix metalloproteinase 9, cathepsin K, carbonic anhydrase II, and vesicular-type H(+)-ATPase A1 were examined using western blotting. OPG exposure on day 1 enhanced the osteoclast growth curve as well as adhesion, and increased RANK and integrin beta3 expression. In contrast, exposure to OPG at later time points (days 3-7) inhibited osteoclast differentiation, adhesion structure formation, and protease expression. In conclusion, the biological effects of OPG exposure at the various stages of osteoclast differentiation were varied, and included the enhanced adhesion and survival of preosteoclasts, the block of differentiation from the early to the terminal stages of osteoclastogenesis, and suppression of mature osteoclast activation following OPG exposure during the terminal differentiation stage, suggesting that the effects of OPG exposure differ based on the stage of differentiation. PMID- 26044734 TI - Genetic architecture is more complex for resistance to Septoria tritici blotch than to Fusarium head blight in Central European winter wheat. AB - BACKGROUND: Fusarium head blight (FHB) and Septoria tritici blotch (STB) severely impair wheat production. With the aim to further elucidate the genetic architecture underlying FHB and STB resistance, we phenotyped 1604 European wheat hybrids and their 135 parental lines for FHB and STB disease severities and determined genotypes at 17,372 single-nucleotide polymorphic loci. RESULTS: Cross validated association mapping revealed the absence of large effect QTL for both traits. Genomic selection showed a three times higher prediction accuracy for FHB than STB disease severity for test sets largely unrelated to the training sets. CONCLUSIONS: Our findings suggest that the genetic architecture is less complex and, hence, can be more properly tackled to perform accurate prediction for FHB than STB disease severity. Consequently, FHB disease severity is an interesting model trait to fine-tune genomic selection models exploiting beyond relatedness also knowledge of the genetic architecture. PMID- 26044735 TI - Occurrence of the Codon 24 (A > T) Mutation in the Mauritanian Population. AB - Using direct DNA sequencing, we identified the codon 24 (A > T) (HBB: c.72T > A, p.Gly24Gly), mutation in two out of 15 Mauritanian beta-thalassemia (beta-thal) carriers. Both were of Black origin and had hematological indices compatible with mild beta-thal minor. Could this variant be more common than expected in the Black Mauritanian population? PMID- 26044736 TI - Aurora kinases are essential for PKC-induced invasion and matrix metalloproteinase-9 expression in MCF-7 breast cancer cells. AB - The Aurora kinase family of serine/threonine kinases are known to be crucial for cell cycle control. Aurora kinases are considered a target of anticancer drugs. However, few studies have assessed the effect of Aurora kinases in breast cancer. In the present study, to determine whether Aurora kinases play a role in oncogenic actions of protein kinase C (PKC), we investigated the effect of Aurora kinases on PKC-induced invasion and MMP-9 expression using breast cancer cells. Treatment of MCF-7 cells with 12-O-tetradecanoylphorbol-13-acetate (TPA) induced the upregulation and phosphorylation of Aurora kinases via the MAPK signaling pathway. Moreover, the inhibition of Aurora kinases by their siRNAs and inhibitors suppressed TPA-induced cell invasion and expression of MMP-9 by inhibiting the activation of NF-kappaB/AP-1, major transcription factors for MMP 9 expression in MCF-7 cells. These results suggested that Aurora kinases mediate PKC-MAPK signal to NF-kappaB/AP-1 with increasing MMP-9 expression and invasion of MCF-7 cells. To the best of our knowledge, this is the first study to show that Aurora kinases are key molecules in PKC-induced invasion in breast cancer cells. PMID- 26044737 TI - Silver-nanoparticle-based surface-enhanced Raman scattering wiper for the detection of dye adulteration of medicinal herbs. AB - By using a silver nanoparticle wiper as a surface-enhanced Raman scattering substrate, a highly sensitive, convenient, and rapid platform for detecting dye adulteration of medicinal herbs was obtained. Commercially available filter paper was functionalized with silver nanoparticles to transform it into the flexible wiper. This device was found to collect dye molecules with unprecedented ease. Experiments were performed to optimize various factors such as the type of wiper used, the wetting reagent, and the wetting/wiping mode and time. Excellent wiper performance was observed in the detection of the simulated adulteration of samples with dyes at various concentrations. The limits of detection for nine dyes, including 10(-6) g/mL for malachite green, 10(-7) g/mL for Rhodamine 6G, and 5 * 10(-8) g/mL for methylene blue, were discerned. The results of this investigation show that this proposed method is potentially highly advantageous for field-based applications. Graphical Abstract Schematic diagram illustrating the fabrication of the paper-based SERS substrate, sample collection process on a herb and SERS examination with the portable Raman spectrometer. PMID- 26044738 TI - Analysis of hydraulic fracturing additives by LC/Q-TOF-MS. AB - The chemical additives used in fracturing fluids can be used as tracers of water contamination caused by hydraulic fracturing operations. For this purpose, a complete chemical characterization is necessary using advanced analytical techniques. Liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (LC/Q-TOF-MS) was used to identify chemical additives present in flowback and produced waters. Accurate mass measurements of main ions and fragments were used to characterize the major components of fracking fluids. Sodium adducts turned out to be the main molecular adduct ions detected for some additives due to oxygen-rich structures. Among the classes of chemical components analyzed by mass spectrometry include gels (guar gum), biocides (glutaraldehyde and alkyl dimethyl benzyl ammonium chloride), and surfactants (cocamidopropyl dimethylamines, cocamidopropyl hydroxysultaines, and cocamidopropyl derivatives). The capabilities of accurate mass and MS-MS fragmentation are explored for the unequivocal identification of these compounds. A special emphasis is given to the mass spectrometry elucidation approaches used to identify a major class of hydraulic fracturing compounds, surfactants. PMID- 26044739 TI - Capillary electrophoresis with mass spectrometric detection for separation of S nitrosoglutathione and its decomposition products: a deeper insight into the decomposition pathways. AB - S-Nitrosoglutathione (GSNO) is a very important biomolecule that has crucial functions in many physiological and physiopathological processes. GSNO acts as NO donor and is a candidate for future medicines. This work describes, for the first time, the separation and the detection of GSNO and its decomposition products using capillary electrophoresis coupled to mass spectrometry (CE-MS). The separation was performed in slightly alkaline medium (pH 8.5) under positive ionization MS detection. The identification of three byproducts of GSNO was formally performed for the first time: oxidized glutathione (GSSG), glutathione sulfinic acid (GSO2H), and glutathione sulfonic acid (GSO3H). GSO2H and GSO3H are known to have important biological activity, including inhibition of the glutathione transferase family of enzymes which are responsible for the elimination of many mutagenic, carcinogenic, and pharmacologically active molecules. We observed, after the ageing of GSNO in the solid state, that the proportion of both GSSG and GSO3H increases whereas that of GSO2H decreases. These results enabled us to propose an oxidation scheme explaining the formation of such products. PMID- 26044740 TI - Chiral separation of D/L-aldoses by micellar electrokinetic chromatography using a chiral derivatization reagent and a phenylboronic acid complex. AB - A novel method was developed for D/L-isomeric separation of aldopentoses and aldohexoses as their (S)-(+)-4-(N,N-dimethylaminosulfonyl)-7-(3-aminopyrrolidin-1 yl)-2,1,3-benzoxadiazole derivatives using phenylboronate buffer containing sodium dodecyl sulfate as a background electrolyte. The combination of derivatization with a chiral labeling reagent and micellar electrokinetic chromatography with phenylboronate made possible the efficient separation of D/L isomers as well as epimeric isomers of aldopentoses and aldohexoses. Laser induced fluorescence detection permitted the micromolar-level determination of monosaccharide derivatives. The limit of detection was 105 amol (300 nM), and the repeatabilities of the migration times and peak area responses were 0.8 % and 7.9 % (relative standard deviation; n = 6), respectively. The method was applied to the determination of D/L- galactose in red seaweed. PMID- 26044741 TI - Auxin inhibits expansion rate independently of cortical microtubules. AB - A recent publication announces that auxin inhibits expansion by a mechanism based on the orientation of cortical microtubules. This is a textbook-revising claim, but as I argue here, a claim that is supported by neither the authors' data nor previous research, and is contradicted by a simple experiment. PMID- 26044742 TI - Precise protein post-translational modifications modulate ABI5 activity. AB - Abscisic acid-insensitive 5 (ABI5), a plant basic leucine zipper (bZIP) transcription factor, has been revealed to be the key regulator in the abscisic acid (ABA) signaling pathway controlling seed dormancy, germination, plant growth, and flowering time. Recently, new evidence has come to light that a combination of different post-translational modifications (PTMs) might together control the stability and activity of ABI5. In this review, we highlight three types of PTM (protein phosphorylation/dephosphorylation, ubiquitination, and sumoylation) and their interactions that precisely regulate ABI5 signaling. ABI5 is the best-studied key molecule in the ABA signaling pathway with respect to PTMs; therefore, this review could serve as a model to guide post-translational studies of important regulators in other plant hormone signaling pathways. PMID- 26044743 TI - Probiotics and prebiotics associated with aquaculture: A review. AB - There is a rapidly growing literature, indicating success of probiotics and prebiotics in immunomodulation, namely the stimulation of innate, cellular and humoral immune response. Probiotics are considered to be living microorganisms administered orally and lead to health benefits. These Probiotics are microorganisms in sufficient amount to alter the microflora (by implantation or colonization) in specific host's compartment exerting beneficial health effects at this host. Nevertheless, Prebiotics are indigestible fiber which enhances beneficial commensally gut bacteria resulting in improved health of the host. The beneficial effects of prebiotics are due to by-products derived from the fermentation of intestinal commensal bacteria. Among the many health benefits attributed to probiotics and prebiotics, the modulation of the immune system is one of the most anticipated benefits and their ability to stimulate systemic and local immunity, deserves attention. They directly enhance the innate immune response, including the activation of phagocytosis, activation of neutrophils, activation of the alternative complement system, an increase in lysozyme activity, and so on. Prebiotics acting as immunosaccharides directly impact on the innate immune system of fish and shellfish. Therefore, both probiotics and prebiotics influence the immunomodulatory activity boosting up the health benefits in aquatic animals. PMID- 26044744 TI - Expression of apolipoprotein A-I and A-II in rainbow trout reproductive tract and their possible role in antibacterial defence. AB - Antimicrobial proteins such as apolipoproteins A (ApoA-I and ApoA-II) play an important role in the primary defence barrier in vertebrates including fish. The aims of the present study were to isolate and characterise rainbow trout seminal plasma ApoA-I and ApoA-II, to examine the mRNA expression of each apolipoprotein in testis and spermatic ducts, and to test the antibacterial properties of the apolipoproteins. Using a three-step isolation procedure consisting of ion exchange chromatography, gel filtration and preparative SDS-PAGE, apolipoproteins were purified and identified as ApoA-I and ApoA-II. Both apolipoproteins were represented by several proteoforms. The expression of ApoA-I and ApoA-II mRNA in the reproductive tract and their antibacterial properties against Escherichia coli suggest that seminal apolipoproteins play an important role in innate immunity in the rainbow trout reproductive tract. The functions of seminal ApoA can be related to protection of sperm and reproductive tissue from microbial attack and to the maintenance of sperm membrane integrity. PMID- 26044745 TI - Resilience and organisational empowerment among long-term care nurses: effects on patient care and absenteeism. AB - AIM: To study resilience among long-term care (LTC) nurses and its relationship to organisational empowerment, self-reported quality of care, perceptions of resident personhood (i.e. viewing another person as a person, implying respect) and absenteeism. BACKGROUND: Although resilience has been examined among nurses, it has not been studied in LTC nurses where resident rates of dementia are high, and nurses may experience stress affecting care and the way residents are perceived. METHOD: A sample of one hundred and thirty LTC nurses from across North America completed a series of questionnaires. RESULTS: Resilient nurses were more likely to report higher quality of care and to view residents as having higher personhood status (despite deteriorating cognitive function). Resilience was not predictive of absenteeism. Organisational empowerment did not add to the predictive power of resilience. CONCLUSIONS: Resilience is of importance in LTC nursing research and future studies could examine this construct in relation to objectively measured resident outcomes. IMPLICATIONS FOR NURSING MANAGEMENT: Our findings suggest that interventions to improve LTC staff resilience would be important to pursue and that consideration should be given to resilience in optimizing the match between potential staff members and LTC positions. PMID- 26044746 TI - MicroRNAs and Stem Cells to the Rescue. PMID- 26044747 TI - Treatment of Incidental Prostate Cancer by Active Surveillance: Results of the HAROW Study. AB - OBJECTIVE: To report on a cohort of patients with incidental prostate cancer (IPC) that was treated by an active surveillance (AS) protocol in the HAROW study. MATERIALS AND METHODS: The HAROW study is an observational study on the management of localized prostate cancer in Germany. Treating urologists were reporting clinical parameters, information on therapy and clinical course of disease at 6-month intervals. RESULTS: In total, 3,169 patients were enrolled. In 224 patients were found an IPC and 104 (46%) of them were put on an AS protocol. The mean follow-up was 26.5 months. Tumor progression was noted in 16 patients. In 11 patients, AS was replaced by a definite intervention. In univariate and multivariate analyses, only PSA density correlated with progression. CONCLUSION: This is the first prospective description of an IPC patient cohort on AS as part of an outcomes research study. AS was selected as a therapeutic strategy in nearly half of the patients (46%). Only a minor proportion (16%) displayed progression. Of the clinical parameters, only PSA density correlated with progression. PMID- 26044749 TI - Response to: 'Occupational asthma contribution to phenotyping adult asthma by using age-of-asthma onset clustering'. PMID- 26044750 TI - Germ line transformation and in vivo labeling of nuclei in Diptera: report on Megaselia abdita (Phoridae) and Chironomus riparius (Chironomidae). AB - To understand how and when developmental traits of the fruit fly Drosophila melanogaster originated during the course of insect evolution, similar traits are functionally studied in variably related satellite species. The experimental toolkit available for relevant fly models typically comprises gene expression and loss as well as gain-of-function analyses. Here, we extend the set of available molecular tools to piggyBac-based germ line transformation in two satellite fly models, Megaselia abdita and Chironomus riparius. As proof-of-concept application, we used a Gateway variant of the piggyBac transposon vector pBac{3xP3-eGFPafm} to generate a transgenic line that expresses His2Av-mCherry as fluorescent nuclear reporter ubiquitously in the gastrulating embryo of M. abdita. Our results open two phylogenetically important nodes of the insect order Diptera for advanced developmental evolutionary genetics. PMID- 26044748 TI - Angiotensin-(1-7) is Reduced and Inversely Correlates with Tau Hyperphosphorylation in Animal Models of Alzheimer's Disease. AB - As a recently identified bioactive peptide of brain renin-angiotensin system (RAS), angiotensin-(1-7) [Ang-(1-7)] along with its metabolic enzyme angiotensin converting enzyme (ACE) 2 and its receptor Mas forms ACE2/Ang-(1-7)/Mas axis. Accumulating evidence suggests an essential role of ACE2/Ang-(1-7)/Mas axis in maintaining normal cognitive functions in both animals and human subjects, and dysregulation of this axis contributed to the pathogenesis of several neurodegenerative diseases such as hypertension-induced neurodegeneration and vascular dementia. To date, whether this axis was associated with the etiology and progression of Alzheimer's disease (AD), the most prevalent neurodegenerative disease in the elderly, remains unclear. In the current study, by using senescence-accelerated mouse prone 8 (SAMP8) mice, an animal model of sporadic AD, we showed for the first time that the level of Ang-(1-7) in the brain was significantly reduced during disease progression. More importantly, an inverse correlation was found between Ang-(1-7) level and tau hyperphosphorylation, a pathological hallmark of AD, in cerebral cortex and hippocampus of SAMP8 mice. Meanwhile, this has been further confirmed in P301S mice, an animal model of pure tauopathy. All these findings suggested that Ang-(1-7), the main effector of brain ACE2/Ang-(1-7)/Mas axis, might be implicated in the etiology and progression of AD, possibly via modulation of tau hyperphosphorylation. PMID- 26044751 TI - Serum oxytocin, posttraumatic coping and C-reactive protein in motor vehicle accident survivors by gender. AB - BACKGROUND: Previous studies indicate that oxytocin (OT) might play a major role in the prevention of posttraumatic stress disorder (PTSD) and that the effects of OT might differ by gender. This exploratory study aimed to clarify the relationships between the OT level and physical and psychosocial factors by gender in accident survivors. METHODS: Two hundred and thirty-five accident survivors offered blood samples at baseline, 155 of whom participated in follow up assessments 1 month later. Spearman's correlation coefficients were calculated between the serum OT levels and physical and psychosocial factors assessed at baseline by gender. Univariate and multivariate regression analyses were then used to examine the relationships between the serum OT levels and psychological variables by gender. RESULTS: In men, the OT levels were negatively associated with C-reactive protein at baseline and did not predict any psychological variables at the 1-month follow-up. On the other hand, in women, the OT levels were positively associated with cooperativeness at baseline and predicted seeking social support, positive reappraisal, accepting responsibility and planful problem solving at the 1-month follow-up. The OT levels were not associated with PTSD, depression, and anxiety symptoms. CONCLUSIONS: The findings suggest that the role of OT in posttraumatic coping and inflammation differs by gender in accident survivors. Gender differences in the effects and mechanism of OT might be a key consideration when developing interventions using OT. PMID- 26044752 TI - Students' prior emergency medicine experience impacts cognitive skills development. PMID- 26044753 TI - The relationship between age and outcome in out-of-hospital cardiac arrest patients. AB - AIM: To determine the association between age and outcome in a large multicenter cohort of out-of-hospital cardiac arrest patients. METHODS: Retrospective, observational, cohort study of out-of-hospital cardiac arrest from the CARES registry between 2006 and 2013. Age was categorized into 5-year intervals and the association between age group and outcomes (return of spontaneous circulation (ROSC), survival and good neurological outcome) was assessed in univariable and multivariable analysis. We performed a subgroup analysis in patients who had return of spontaneous circulation. RESULTS: A total of 101,968 people were included. The median age was 66 years (quartiles: 54, 78) and 39% were female. 31,236 (30.6%) of the included patients had sustained ROSC, 9761 (9.6%) survived to hospital discharge and 8058 (7.9%) survived with a good neurological outcome. The proportion of patients with ROSC was highest in those with age <20 years (34.1%) and lowest in those with age 95-99 years (23.5%). Patients with age <20 years had the highest proportion of survival (16.7%) and good neurological outcome (14.8%) whereas those with age 95-99 years had the lowest proportion of survival (1.7%) and good neurological outcome (1.2%). In the full cohort and in the patients with ROSC there appeared to be a progressive decline in survival and good neurological outcome after the age of approximately 45-64 years. Age alone was not a good predictor of outcome. CONCLUSIONS: Advanced age is associated with outcomes in out-of-hospital cardiac arrest. We did not identify a specific age threshold beyond which the chance of a meaningful recovery was excluded. PMID- 26044755 TI - Critical maternal health knowledge gaps in low- and middle-income countries for the post-2015 era. AB - Effective interventions to promote maternal health and address obstetric complications exist, however 800 women die every day during pregnancy and childbirth from largely preventable causes and more than 90% of these deaths occur in low and middle income countries (LMIC). In 2014, the Maternal Health Task Force consulted 26 global maternal health researchers to identify persistent and critical knowledge gaps to be filled to reduce maternal morbidity and mortality and improve maternal health. The vision of maternal health articulated was comprehensive and priorities for knowledge generation encompassed improving the availability, accessibility, acceptability, and quality of institutional labor and delivery services and other effective interventions, such as contraception and safe abortion services. Respondents emphasized the need for health systems research to identify models that can deliver what is known to be effective to prevent and treat the main causes of maternal death at scale in different contexts and to sustain coverage and quality over time. Researchers also emphasized the development of tools to measure quality of care and promote ongoing quality improvement at the facility, district, and national level. Knowledge generation to improve distribution and retention of healthcare workers, facilitate task shifting, develop and evaluate training models to improve "hands on" skills and promote evidence-based practice, and increase managerial capacity at different levels of the health system were also prioritized. Interviewees noted that attitudes, behavior, and power relationships between health professionals and within institutions must be transformed to achieve coverage of high-quality maternal health services in LMIC. The increasing burden of non communicable diseases, urbanization, and the persistence of social and economic inequality were identified as emerging challenges that require knowledge generation to improve health system responses and evaluate progress. Respondents emphasized evaluating effectiveness, feasibility, and equity impacts of health system interventions. A prominent role for implementation science, evidence for policy advocacy, and interdisciplinary collaboration were identified as critical areas for knowledge generation to improve maternal health in the post-2015 era. PMID- 26044754 TI - Pulmonary Hemodynamic Response to Exercise in Chronic Thromboembolic Pulmonary Hypertension before and after Pulmonary Endarterectomy. AB - BACKGROUND: Pulmonary endarterectomy (PEA) is the treatment of choice in surgically accessible chronic thromboembolic pulmonary hypertension (CTEPH). An important predictor of outcome is postsurgical residual pulmonary hypertension. OBJECTIVE: We aimed to use the hemodynamic response during exercise before PEA as a measurement for the hemodynamic outcome 1 year after PEA. METHODS: Between January 2011 and December 2013, 299 patients underwent PEA in our center. A total of 16 patients who were assessed by means of invasive hemodynamic measurements during exercise both at baseline and 1 year after PEA were retrospectively analyzed. RESULTS: Pre-PEA mean pulmonary arterial pressure (mPAP) increased during exercise from 35.8 +/- 7.6 to 53.8 +/- 5.1 mm Hg, diastolic pulmonary arterial pressure (dPAP) from 21.5 +/- 5.6 to 30.3 +/- 9.6 mm Hg, cardiac output (CO) from 4.4 +/- 0.8 to 6.5 +/- 1.9 l/min and diastolic pulmonary gradient (DPG) from 14.6 +/- 4.9 to 20.7 +/- 12.7 mm Hg. Post-PEA mPAP increased from 23.7 +/- 6.6 at rest to 43.2 +/- 7.1 mm Hg, while CO increased to a higher extent from 5.1 +/- 0.9 to 8.4 +/- 1.9 l/min. There were significant correlations between pre-PEA DPG/CO and dPAP/CO slopes with the pulmonary vascular resistance (Spearman r = 0.578, p = 0.019, and r = 0.547, p = 0.028) and mPAP at rest after PEA (Spearman r = 0.581, p = 0.018, and r = 0.546, p = 0.028). CONCLUSIONS: In CTEPH, the presurgical dynamic DPG/CO and dPAP/CO slopes during submaximal exercise are associated with the hemodynamic outcome 1 year after PEA. PMID- 26044756 TI - The effect of food environments on fruit and vegetable intake as modified by time spent at home: a cross-sectional study. AB - OBJECTIVE: There is a growing body of research that investigates how the residential neighbourhood context relates to individual diet. However, previous studies ignore participants' time spent in the residential environment and this may be a problem because time-use studies show that adults' time-use pattern can significantly vary. To better understand the role of exposure duration, we designed a study to examine 'time spent at home' as a moderator to the residential food environment-diet association. DESIGN: Cross-sectional observational study. SETTINGS: City of Toronto, Ontario, Canada. PARTICIPANTS: 2411 adults aged 25-65. PRIMARY OUTCOME MEASURE: Frequency of vegetable and fruit intake (VFI) per day. RESULTS: To examine how time spent at home may moderate the relationship between residential food environment and VFI, the full sample was split into three equal subgroups--short, medium and long duration spent at home. We detected significant associations between density of food stores in the residential food environment and VFI for subgroups that spend medium and long durations at home (ie, spending a mean of 8.0 and 12.3 h at home, respectively- not including sleep time), but no associations exist for people who spend the lowest amount of time at home (mean=4.7 h). Also, no associations were detected in analyses using the full sample. CONCLUSIONS: Our study is the first to demonstrate that time spent at home may be an important variable to identify hidden population patterns regarding VFI. Time spent at home can impact the association between the residential food environment and individual VFI. PMID- 26044757 TI - Tobacco addiction and smoking cessation in Austrian migrants: a cross-sectional study. AB - OBJECTIVE: Recent observations revealed substantial differences in smoking behaviour according to individuals' migration background. However, smoking cessation strategies are rarely tailored on the basis of a migration background. We aimed to determine whether smoking behaviour and preferences for smoking cessation programmes differ between Austrian migrant smokers and Austrian smokers without a migration background. STUDY DESIGN: Cross-sectional study. SETTING: Recruitment and interview were performed at public places in Vienna, Austria. PARTICIPANTS: The 420 smokers included: 140 Bosnian, 140 Turkish migrant smokers of the first or second generation, as well as 140 Austrian smokers without a migration background. METHODS: We cross-sectionally assessed determinants of smoking behaviour and smoking cessation of every participant with a standardised questionnaire. PRIMARY OUTCOME MEASURE: The Fagerstrom Test for Nicotine Dependence. SECONDARY OUTCOME MEASURES: Determinants of smoking behaviour, willingness to quit smoking and smoking cessation. RESULTS: Nicotine addiction expressed via the Fagerstrom score was significantly higher in smokers with a migration background versus those without (Bosnian migrant smokers 4.7 +/- 2.5, Turkish migrant smokers 4.0 +/- 2.0, Austrian smokers without a migration background 3.4 +/- 2.3, p<0.0001). Bosnian and Turkish migrant smokers described a greater willingness to quit, but have had more previous cessation trials than Austrian smokers without a migration background, indicating an increased demand for cessation strategies in these study groups. They also participated in counselling programmes less often than Austrian smokers without a migration background. Finally, we found significant differences in preferences regarding smoking cessation programmes (ie, preferred location, service offered in another language besides German, and group rather than single counselling). CONCLUSIONS: We found significant differences in addictive behaviour and cessation patterns between smokers with and without a migration background. Our results indicate a strong demand for adjusting cessation programmes to the cultural background. PMID- 26044758 TI - A pre-postintervention study to evaluate the impact of dose calculators on the accuracy of gentamicin and vancomycin initial doses. AB - OBJECTIVES: Gentamicin and vancomycin are narrow-therapeutic-index antibiotics with potential for high toxicity requiring dose individualisation and continuous monitoring. Clinical decision support (CDS) tools have been effective in reducing gentamicin and vancomycin dosing errors. Online dose calculators for these drugs were implemented in a London National Health Service hospital. This study aimed to evaluate the impact of these calculators on the accuracy of gentamicin and vancomycin initial doses. METHODS: The study used a pre-postintervention design. Data were collected using electronic patient records and paper notes. Random samples of gentamicin and vancomycin initial doses administered during the 8 months before implementation of the calculators were assessed retrospectively against hospital guidelines. Following implementation of the calculators, doses were assessed prospectively. Any gentamicin dose not within +/- 10% and any vancomycin dose not within +/- 20% of the guideline-recommended dose were considered incorrect. RESULTS: The intranet calculator pages were visited 721 times (gentamicin=333; vancomycin=388) during the 2-month period following the calculators' implementation. Gentamicin dose errors fell from 61.5% (120/195) to 44.2% (95/215), p<0.001. Incorrect vancomycin loading doses fell from 58.1% (90/155) to 32.4% (46/142), p<0.001. Incorrect vancomycin first maintenance doses fell from 55.5% (86/155) to 33.1% (47/142), p<0.001. Loading and first maintenance vancomycin doses were both incorrect in 37.4% (58/155) of patients before and 13.4% (19/142) after calculator implementation, p<0.001. CONCLUSIONS: This study suggests that gentamicin and vancomycin dose calculators significantly improved the prescribing of initial doses of these agents. Therefore, healthcare organisations should consider using such CDS tools to support the prescribing of these high-risk drugs. PMID- 26044759 TI - Association between body mass index and onset of hypertension in men and women with and without diabetes: a cross-sectional study using national health data from the State of Kuwait in the Arabian Peninsula. AB - OBJECTIVE: Obesity contributes directly to the risk of diabetes and hypertension. Effective management of diabetes is essential to prevent or delay the onset of comorbid hypertension. In this study, we delineate the association body mass index (BMI) has with risk and age at onset of hypertension and explore how this association is modulated by sex and the pre-existing condition of diabetes. DESIGN: Cross-sectional study using retrospective data. SETTING: Kuwait Health Network that integrates primary health and hospital laboratory data into a single system. PARTICIPANTS: We considered 3904 native Kuwaiti comorbid individuals who had the onset of type 2 diabetes prior to that of hypertension, and 1403 native Kuwaiti hypertensive individuals with no incidence of diabetes. These participants have been regularly monitored for BMI, glycated haemoglobin and blood pressure measurements. Mean variance in BMI per individual over the period from registration is seen to be low. MAIN OUTCOME MEASURES: Association between age at onset of hypertension and BMI (as measured at hypertension diagnosis); HRs for developing hypertension. RESULTS: Risk of hypertension increases with obesity levels, and is higher in patients with diabetes than in patients without diabetes but of similar obesity levels. Age at onset of hypertension is inversely related to BMI; this relationship is seen to be stronger in men compared to women (slope estimate in men, -0.62 years per unit increase in BMI; in women -0.18) and in individuals (particularly women) with diabetes compared to those without (slope estimate in women, -0.39 vs -0.18, p<0.001; in men -0.66 vs -0.62; p=0.66). CONCLUSIONS: The observation that the presence of diabetes doubles the slope of inverse relationship between hypertension onset age and BMI in women (while the slope is high in men irrespective of diabetes status) leads to a possible proposition that pre-existing diabetes narrows down sex-specific differences in the impact of obesity on blood pressure. PMID- 26044761 TI - Erratum to: Determination of Dicyandiamide in Powdered Milk Using Direct Analysis in Real Time Quadrupole Time-of-Flight Tandem Mass Spectrometry. PMID- 26044760 TI - Pivotal clinical trials of novel ophthalmic drugs and medical devices: retrospective observational study, 2002-2012. AB - OBJECTIVES: Novel therapeutics are an important part of ophthalmologists' armamentarium, and the risks and benefits of these therapies must be carefully evaluated. We sought to quantify the characteristics of the pivotal clinical trials supporting the regulatory approval of new ophthalmic drugs and medical devices. DESIGN: Retrospective observational study. SETTING AND DATA SOURCE: Medical review dossiers for new ophthalmic drug and high-risk device approvals released publicly by the US Food and Drug Administration (FDA). MAIN OUTCOME MEASURES: Proportion of pivotal trials with randomisation, masking, active or placebo controls and subgroup analyses; total and median number of trial enrollees; and the number of drugs and devices approved with required postapproval studies. RESULTS: From 2002 to 2012, the FDA approved 11 ophthalmic drugs and 25 devices. The pivotal trials underlying the approvals of ophthalmic drugs in our study cohort enrolled a median of 809 patients. Virtually all drug trials were randomised and masked (91%), of which 7 (70%) used a placebo control. Pivotal trials for ophthalmic devices enrolled 324 patients on average, and significantly fewer trials for ophthalmic devices versus drugs were randomised (16% vs 91%; p<0.001) or masked (12% vs 91%; p<0.001). 8 (32%) ophthalmic devices and 6 (55%) ophthalmic drugs were approved with required postapproval studies. CONCLUSIONS: Ophthalmic therapeutics were approved based on varying levels of evidence. Postapproval studies could be used to confirm or refute early indications of safety and effectiveness of these therapeutics, with the study results accessible to patients and clinicians who need to make informed treatment decisions. PMID- 26044762 TI - Cell therapy clinical trials in Germany--Critical aspects of quality data content: Summary of meeting presentation. AB - This article is summarizing a presentation given by the author at the International Alliance for Biological Standardization and Japan Science and Technology Agency (IABS-JST) Joint Workshop on "Challenges towards sound scientific regulation of cell therapy products" held at the Kyoto International Conference Center, Kyoto Japan on March 7-8, 2014. The main topics of the presentation were to give a short overview about the regulatory approval process for clinical trials in Germany and to summarize important manufacturing aspects of cell based medicinal products (CBMPs) which are intended to be studied in clinical trials in Germany. PMID- 26044763 TI - Who does not participate in telehealth trials and why? A cross-sectional survey. AB - BACKGROUND: Telehealth interventions use information and communication technology to provide clinical support. Some randomised controlled trials of telehealth report high patient decline rates. A large study was undertaken to determine which patients decline to participate in telehealth trials and their reasons for doing so. METHODS: Two linked randomised controlled trials were undertaken, one for patients with depression and one for patients with raised cardiovascular disease risk (the Healthlines Study). The trials compared usual care with additional support delivered by the telephone and internet. Patients were recruited via their general practice and could return a form about why they were not participating. RESULTS: Of the patients invited, 82.9% (20,021/24,152) did not accept the study invite, either by returning a decline form (n = 7134) or by not responding (n = 12,887). In both trials patients registered at deprived general practices were less likely to accept the study invite. Decline forms were received from 29.5% (7134/24,152) of patients invited. There were four frequently reported types of reasons for declining. The most common was telehealth-related: 54.7% (3889/,7115) of decliners said they did not have access or the skills to use the internet and/or computers. This was more prevalent amongst older patients and patients registered at deprived general practices. The second was health need related: 40.1% (n = 2852) of decliners reported that they did not need additional support for their health condition. The third was related to life circumstances: 27.2% (n = 1932) of decliners reported being too busy. The fourth was research related: 15.3% (n = 1092) of decliners were not interested in the research. CONCLUSIONS: A large proportion of patients declining participation in these telehealth trials did so because they were unable to engage with telehealth or did not perceive a need for it. This has implications for engagement with telehealth in routine practice, as well as for trials, with a need to offer technological support to increase patients' engagement with telehealth. More generally, triallists should assess why people decline to participate in their studies. TRIAL REGISTRATION: The Healthlines Study has the following trial registrations: depression trial: ISRCTN14172341 (registered 26 June 2012) and CVD risk trial: ISRCTN27508731 (registered 05 July 2012). PMID- 26044766 TI - Trajectories and Predictors of Health-Related Quality of Life during Childhood. AB - OBJECTIVE: To identify distinct trajectories of health-related quality of life (HRQOL) during childhood, along with their predictors. STUDY DESIGN: A nationally representative sample of 2700 children aged 4-5 years at baseline was followed up every 24 months through to age 12-13 years. Parents reported the children's HRQOL and data on potential predictors at each wave (5 in total) as part of the Longitudinal Study of Australian Children. RESULTS: Growth mixture modeling identified 5 distinct trajectories of HRQOL during childhood. Eighty-five percent of children had consistently high levels of HRQOL from age 4-5 years to 12-13 years (healthy); 8% of children had a significant and continuous decrease in HRQOL over time (high risk); and a further 5.3% of children had decreases in HRQOL from age 4-5 years to 8-9 years, followed by increases through to 12-13 years (rebound). Finally, a small percentage (1.6%) of children had extremely low levels of HRQOL at age 4-5 years that increased over time (recovery). Maternal smoking, lower household income, living in a non-English speaking household, and nonparticipation in organized sports were predictive of poorer HRQOL trajectories when compared with children in the healthy trajectory. CONCLUSION: There are distinct trajectories of HRQOL during childhood. Most children (85%) have a healthy, stable pattern, but the remaining children have trajectories indicative of poor HRQOL. Participation in sports, maternal smoking, lower family income, and language spoken at home distinguish among these trajectories. Of these, participation in organized sports has received relatively little attention as a preventative health priority. PMID- 26044764 TI - Gradual reduction in rRNA transcription triggers p53 acetylation and apoptosis via MYBBP1A. AB - The nucleolus, whose primary function is ribosome biogenesis, plays an essential role in p53 activation. Ribosome biogenesis is inhibited in response to cellular stress and several nucleolar proteins translocate from the nucleolus to the nucleoplasm, where they activate p53. In this study, we analysed precisely how impaired ribosome biogenesis regulates the activation of p53 by depleting nucleolar factors involved in rRNA transcription or rRNA processing. Nucleolar RNA content decreased when rRNA transcription was inhibited. In parallel with the reduced levels of nucleolar RNA content, the nucleolar protein Myb-binding protein 1 A (MYBBP1A) translocated to the nucleoplasm and increased p53 acetylation. The acetylated p53 enhanced p21 and BAX expression and induced apoptosis. In contrast, when rRNA processing was inhibited, MYBBP1A remained in the nucleolus and nonacetylated p53 accumulated, causing cell cycle arrest at the G1 phase by inducing p21 but not BAX. We propose that the nucleolus functions as a stress sensor to modulate p53 protein levels and its acetylation status, determining cell fate between cell cycle arrest and apoptosis by regulating MYBBP1A translocation. PMID- 26044767 TI - Complementary and Alternative Medicine Use Among Overweight and Obese Cancer Survivors in the United States. AB - PURPOSE: The purpose of the study was to determine the prevalence of complementary and alternative medicine (CAM) use among US cancer survivors; examine whether use varies by underweight/normal weight, overweight, and obese body mass index status; determine reasons for use; and document disclosure rates of CAM use to medical professionals. METHODS: Data for 1785 cancer survivors were obtained from the 2007 National Health Interview Survey and CAM supplement. The prevalence and associations of CAM use in the previous 12 months were compared among underweight/normal weight, overweight, and obese adult cancer survivors. RESULTS: Nearly 90% of cancer survivors used at least one type of CAM therapy in the 12 months preceding the survey. Those who were overweight, but not obese, were more likely to use a CAM modality compared to normal/underweight respondents. Over two thirds (71%) reported using CAM therapy for general health and wellness and 39.3% used CAM because a health care provider recommended it. Disclosure rates of CAM use to conventional medical professionals varied widely by CAM modality. CONCLUSIONS: An overwhelming majority of US cancer survivors use CAM for a variety of reasons. Overweight cancer survivors may be more likely to use CAM than those who are underweight, normal weight, or obese. Cancer survivors should be screened by medical providers for the use of CAM therapies; furthermore, prospective clinical research evaluating the efficacy and safety of biologically based CAM therapies, often used by cancer survivors, is important and necessary for the well-being of this population. PMID- 26044769 TI - Oral Absorption and Disposition of alpha-Linolenic, Rumenic and Vaccenic Acids After Administration as a Naturally Enriched Goat Dairy Fat to Rats. AB - Although there is extensive information describing the positive biological effects of conjugated linoleic acid and its main isomer rumenic acid (RA; C18:2 cis 9, trans 11), and alpha-linolenic acid (ALA) and vaccenic acid (TVA), data about their bioavailability are not available. In this work, we investigated the oral absorption and disposition of these fatty acids in Wistar rats. A naturally enriched goat dairy fat (EDF) was obtained by supplementing ruminant diets with oils or oilseeds rich in polyunsaturated fatty acids (PUFA). The EDF was administered orally (single dose of 3000 mg EDF/kg body weight equivalent to 153 mg TVA/kg body weight, 46 mg RA/kg body weight and 31 mg ALA/kg body weight), and serial blood and liver samples were collected and TVA, RA and ALA concentrations determined by GC/MS. The fatty acids TVA, RA and ALA were rapidly absorbed (t1/2a, 0.36, 0.66 and 0.76 h, respectively, for plasma) and slowly eliminated (t1/2beta, 17.04, 18.40 and 16.52 h, respectively, for plasma). The maximum concentration (C max) was detected in liver > plasma > erythrocyte. Our study shows that when orally administered EDF, its components TVA, RA and ALA were rapidly absorbed and distributed throughout the body by the blood circulation to exert systemic effects. PMID- 26044768 TI - A 3D-RISM/RISM study of the oseltamivir binding efficiency with the wild-type and resistance-associated mutant forms of the viral influenza B neuraminidase. AB - The binding affinity of oseltamivir to the influenza B neuraminidase and to its variants with three single substitutions, E119G, R152K, and D198N, is investigated by the MM/3D-RISM method. The binding affinity or the binding free energy of ligand to receptor was found to be determined by a subtle balance of two major contributions that largely cancel out each other: the ligand-receptor interactions and the dehydration free energy. The theoretical results of the binding affinity of the drug to the mutants reproduced the observed trend in the resistivity, measured by IC50 ; the high-level resistance of E119G and R152K, and the low-level resistance of D198N. For E119G and R152K, reduction of the direct drug-target interaction, especially at the mutated residue, is the main source of high-level oseltamivir resistance. This phenomenon, however, is not found in the D198N strain, which is located in the framework of the active-site. PMID- 26044770 TI - Health services received by individuals with duchenne/becker muscular dystrophy. AB - INTRODUCTION: Anecdotal reports from families and care providers suggest a wide variation in services received by individuals with Duchenne/Becker muscular dystrophy (DBMD). METHODS: We documented the type and frequency of health services received by individuals with DBMD using the Muscular Dystrophy Surveillance Tracking and Research Network (MD STARnet) interview data released in June 2012. Interviews with eligible caregivers from 5 sites (Arizona, Colorado, Georgia, Iowa, and western New York) were conducted from April 2007 to March 2012. RESULTS: Two hundred ninety-six caregivers (66% of those contactable) participated in the interview. There were significant differences among sites in the specialists seen and services received. Concurrence with cardiac recommendations was higher than that with respiratory recommendations. CONCLUSIONS: The results of this survey support and quantify the anecdotal reports from families and care providers regarding the disparities in services received by individuals with DBMD. It remains to be determined whether these differences affect outcomes. PMID- 26044771 TI - Body selectivity in occipitotemporal cortex: Causal evidence. AB - Perception of others' bodies provides information that is useful for a number of important social-cognitive processes. Evidence from neuroimaging methods has identified focal cortical regions that are highly selective for perceiving bodies and body parts, including the extrastriate body area (EBA) and fusiform body area (FBA). Our understanding of the functional properties of these regions, and their causal contributions to behavior, has benefitted from the study of neuropsychological patients and particularly from investigations using transcranial magnetic stimulation (TMS). We review this evidence, focusing on TMS studies that are revealing of how (and when) activity in EBA contributes to detecting people in natural scenes; to resolving their body shape, movements, actions, individual parts, and identities; and to guiding goal-directed behavior. These findings are considered in reference to a framework for body perception in which the patterns of neural activity in EBA and FBA jointly serve to make explicit the elements of the visual scene that correspond to the body and its parts. These representations are modulated by other sources of information such as prior knowledge, and are shared with wider brain networks involved in many aspects of social cognition. PMID- 26044772 TI - Infection with Rhinovirus Facilitates Allergen Penetration Across a Respiratory Epithelial Cell Layer. AB - BACKGROUND: Rhinovirus infections are a major risk factor for asthma exacerbations. We sought to investigate in an in vitro system whether infection with human rhinovirus reduces the integrity and barrier function of a respiratory epithelial cell layer and thus may influence allergen penetration. METHODS: We cultured the human bronchial epithelial cell line 16HBE14o- in a transwell culture system as a surrogate of respiratory epithelium. The cell monolayer was infected with human rhinovirus 14 at 2 different doses. The extent and effects of transepithelial allergen penetration were assessed using transepithelial resistance measurements and a panel of (125)I-labeled purified recombinant respiratory allergens (rBet v 1, rBet v 2, and rPhl p 5). RESULTS: Infection of respiratory cell monolayers with human rhinovirus decreased transepithelial resistance and induced a pronounced increase in allergen penetration. CONCLUSIONS: Our results indicate that infection with rhinovirus damages the respiratory epithelial barrier and allows allergens to penetrate more efficiently into the subepithelial tissues where they may cause increased allergic inflammation. PMID- 26044773 TI - PDEGEM: Modeling non-uniform read distribution in RNA-Seq data. AB - BACKGROUND: RNA-Seq is a powerful new technology to comprehensively analyze the transcriptome of any given cells. An important task in RNA-Seq data analysis is quantifying the expression levels of all transcripts. Although many methods have been introduced and much progress has been made, a satisfactory solution remains be elusive. RESULTS: In this article, we borrow the idea from the Positional Dependent Nearest Neighborhood (PDNN) model, originally developed for analyzing microarray data, to model the non-uniformity of read distribution in RNA-seq data. We propose a robust nonlinear regression model named PDEGEM, a Positional Dependent Energy Guided Expression Model to estimate the abundance of transcripts. Using real data, we find that the PDEGEM fits the data better than mseq in all three real datasets we tested. We also find that the expression measure obtained using PDEGEM showed higher correlation with that obtained from alterative assays for quantifying gene and isoform expressions. CONCLUSIONS: Based on these results, we believe that our PDEGEM can improve the accuracy in modeling and estimating the transcript abundance and isoform expression in RNA Seq data. Additionally, although the stacking energy and positional weight of the PDEGEM are relatively related to sequencing platforms and species, they share some common trends, which indicates that the PDEGEM could partly reflect the mechanism of DNA binding between the template strain and the new synthesized read. PMID- 26044774 TI - Impact of preanalytical factors on fecal immunochemical tests: need for new strategies in comparison of methods. AB - BACKGROUND: Harmonization of fecal immunochemical tests for hemoglobin (FIT-Hb) is crucial to compare clinical outcomes in screening programs. The lack of reference materials and standard procedures does not allow the use of usual protocols to compare methods. We propose 2 protocols, based on artificial biological samples (ABS), to discriminate preanalytical and analytical variation and investigate clinical performances. The protocols were used to compare 2 FIT systems available on European markets: the OC-Sensor Diana (Eiken, Tokyo, Japan) and HM-JACKarc (Kyowa-Medex, Tokyo, Japan). METHODS: ABS were obtained adding Hb to Hb-free feces. In the first procedure, 35 ABS were collected for each collection device and analyzed on both systems. In the second, 188 ABS (106 positive and 82 negative) were -collected and tested on the specific systems. Passing-Bablock (PB), Pearson's correlation coefficients (R) and Bland-Altman difference analysis were used to compare data. RESULTS: PB, R and mean standard errors for Bland-Altman analysis (Diana vs. Arc) results were 0.93x-0.56: R = 0.97 and 19%; and 1.09x + 5.60: R = 0.96 and -18%; for Diana and Arc devices, respectively. No correlations and no difference in positive/negative assessment were observed with the second protocol. CONCLUSIONS: A good correlation was observed in comparing data generated using collection devices on the 2 systems. Manufacturers have developed different sample collection procedures for feces: therefore, data from different systems cannot easily be compared. Adoption of protocols to discriminate preanalytical and analytical variation would be a significant contribution to harmonization of FIT, facilitating data comparison and information acquisition for sample collection strategy and effect of buffers on systems. PMID- 26044775 TI - Circulating tumor cells are predictive of poor response to chemotherapy in metastatic gastric cancer. AB - BACKGROUND: The aim of this study was to investigate the impact of number of circulating tumor cells (CTCs) on the treatment outcome for metastatic gastric cancer (GC) following palliative chemotherapy. METHODS: CTCs were isolated from 7.5 mL of whole blood from 100 patients with metastatic GC by anti-EpCAM antibody coated magnetic particles using the CTC-Profiler (Veridex). Correlations between CTC counts and clinicopathological variables, progression-free survival and overall survival were examined. RESULTS: Between January 2010 and August 2010, 100 metastatic GC patients were enlisted. Among 100 patients, 5 or more CTCs (CTC positive) were detected in 27 of 95 patients (28%). Even though the clinical characteristics of the CTC-positive and CTC-negative groups were not significantly different, the treatment response to cytotoxic chemotherapy in the CTC-positive group was significantly poorer (progressive disease: 23.4% vs. 60.0% in CTC-negative vs. CTC-positive group, respectively; p = 0.004). The median progression-free survival of the CTC-positive group was substantially shorter than that of the CTC-negative group (59 days vs. 141 days; p = 0.004). For overall survival, CTC-positive group had significantly shorter survival than CTC negative group (median OS, 120 days vs. 220 days; p = 0.030). A multivariate Cox proportional hazards regression model showed that CTC positivity was an independent adverse factor for progression-free survival and overall survival. CONCLUSIONS: This study suggests CTCs are associated with poor response to chemotherapy in metastatic GC-patients. PMID- 26044776 TI - Vulnerable plaque detection and quantification with gold particle-enhanced computed tomography in atherosclerotic mouse models. AB - Recently, an apolipoprotein E-deficient (ApoE-/-) mouse model with a mutation (C1039G+/-) in the fibrillin-1 (Fbn1) gene (ApoE-/-Fbn1C1039G+/- mouse model) was developed showing vulnerable atherosclerotic plaques, prone to rupture, in contrast to the ApoE-/- mouse model, where mainly stable plaques are present. One indicator of plaque vulnerability is the level of macrophage infiltration. Therefore, this study aimed to measure and quantify in vivo the macrophage infiltration related to plaque development and progression. For this purpose, 5 weekly consecutive gold nanoparticle-enhanced micro-computed tomography (microCT) scans were acquired. Histology confirmed that the presence of contrast agent coincided with the presence of macrophages. Based on the microCT scans, regions of the artery wall with contrast agent present were calculated and visualized in three dimensions. From this information, the contrast-enhanced area and contrast enhanced centerline length were calculated for the branches of the carotid bifurcation (common, external, and internal carotid arteries). Statistical analysis showed a more rapid development and a larger extent of plaques in the ApoE-/-Fbn1C1039G+/- compared to the ApoE-/- mice. Regional differences between the branches were also observable and quantifiable. We developed and applied a methodology based on gold particle-enhanced microCT to visualize the presence of macrophages in atherosclerotic plaques in vivo. PMID- 26044778 TI - Profiling circulating microRNAs in maternal serum and plasma. AB - Serum and plasma are two of the most commonly used materials in clinical diagnosis and investigations. Whether differential nucleic acids exist between the serum and plasma, and the way in which they may be selected in clinical diagnosis and applications remains to be elucidated. The present study sequenced microRNAs (miRNAs) in the serum and plasma of pregnant females using next generation sequencing technology. Several differentially expressed miRNAs were also verified by reverse transcription-quantitative polymerase chain reaction (RT qPCR). In total, 329 miRNAs and 193 miRNAs were detected in maternal serum and plasma. Differential expression and different types of miRNAs were found in the serum and plasma, among them, 19 were upregulated and 6 were downregulated in serum when compared with plasma with a fold change >2.0 (P<0.001). The results demonstrated that a number of miRNAs were differentially expressed in the serum and plasma, and several of the miRNAs expressed in the serum were absent in the plasma. The results obtained using RT-qPCR in the selected miRNAs were similar to these results, and indicated that the differential expression of miRNAs in the serum and plasma provide a guide for further investigation and clinical use. The results of the analysis also suggested that differentially expressed DNA and RNA in the serum and plasma of pregnant females may be a result of the differential expression of miRNAs. PMID- 26044777 TI - Arsenic-induced dyslipidemia in male albino rats: comparison between trivalent and pentavalent inorganic arsenic in drinking water. AB - BACKGROUND: Recent epidemiological evidences indicate close association between inorganic arsenic exposure via drinking water and cardiovascular diseases. However, the exact mechanism of this arsenic-mediated increase in cardiovascular risk factors remains enigmatic. METHODS: In order to investigate the effects of inorganic arsenic exposure on lipid metabolism, male albino rats were exposed to 50, 100 and 150 ppm arsenic as sodium arsenite and 100, 150 and 200 ppm arsenic as sodium arsenate respectively in their drinking water for 12 weeks. RESULTS: Dyslipidemia induced by the two arsenicals exhibited different patterns. Hypocholesterolemia characterised the effect of arsenite at all the doses, but arsenate induced hypercholesterolemia at the 150 ppm As dose. Hypertriglyceridemia was the hallmark of arsenate effect whereas plasma free fatty acids (FFAs) was increased by the two arsenicals. Reverse cholesterol transport was inhibited by the two arsenicals as evidenced by decreased HDL cholesterol concentrations whereas hepatic cholesterol was increased by arsenite (100 ppm As), but decreased by arsenite (150 ppm As) and arsenate (100 ppm As) respectively. Brain cholesterol and triglyceride were decreased by the two arsenicals; arsenate decreased the renal content of cholesterol, but increased renal content of triglyceride. Arsenite, on the other hand, increased the renal contents of the two lipids. The two arsenicals induced phospholipidosis in the spleen. Arsenite (150 ppm As) and arsenate (100 ppm As) inhibited hepatic HMG CoA reductase. At other doses of the two arsenicals, hepatic activity of the enzyme was up-regulated. The two arsenicals however up-regulated the activity of the brain enzyme. We observed positive associations between tissue arsenic levels and plasma FFA and negative associations between tissue arsenic levels and HDL cholesterol. CONCLUSION: Our findings indicate that even though sub-chronic exposure to arsenite and arsenate through drinking water produced different patterns of dyslipidemia, our study identified two common denominators of dyslipidemia namely: inhibition of reverse cholesterol transport and increase in plasma FFA. These two denominators (in addition to other individual perturbations of lipid metabolism induced by each arsenical), suggest that in contrast to strengthening a dose-dependent effect phenomenon, the two forms of inorganic arsenic induced lipotoxic and non-lipotoxic dyslipidemia at "low" or "medium" doses and these might be responsible for the cardiovascular and other disease endpoints of inorganic arsenic exposure through drinking water. PMID- 26044779 TI - Income inequalities and stroke mortality trends in Sao Paulo, Brazil, 1996-2011. AB - BACKGROUND: It is not clear the relationship between stroke mortality trends and socioeconomic inequalities in low- and middle-income countries. AIMS: We compared differences of trends in stroke mortality by socioeconomic status in the city of Sao Paulo, Brazil. METHODS: We analyzed the intra-urban distribution of stroke death rates from 1996 to 2011 for persons aged 35-74 years old according to income using joinpoint regression. RESULTS: We confirmed 77 848 stroke deaths in the period, 51.4% of them among persons aged 35-74 years old. For all areas, there was parallelism between genders, and the average annual percent changes combined was -5.2 (-5.7 to -4.6) from 1996 to 2005 and -3.0 (-4.3 to -1.7) from 2005 to 2011. The full period average annual percent changes of age-adjusted rates between persons living in the high- and low-income area were, respectively, -5.4 and -4.2 (P = 0.002) for men and -5.9 vs. -4.9 (P = 0.017) for women. Differences in the risk of stroke between the high- and low-income areas increased more than twofold in the period in both genders. CONCLUSIONS: The risk of stroke death is decreasing in all regions, but the faster decline in mortality rates in the wealthiest area contributes to further greater inequalities. PMID- 26044780 TI - Gait characteristics associated with the foot and ankle in inflammatory arthritis: a systematic review and meta-analysis. AB - BACKGROUND: Gait analysis is increasingly being used to characterise dysfunction of the lower limb and foot in people with inflammatory arthritis (IA). The aim of the systematic review was to evaluate the spatiotemporal, foot and ankle kinematic, kinetic, peak plantar pressure and muscle activity parameters between patients with inflammatory arthritis and healthy controls. METHODS: An electronic literature search was performed on Medline, CINAHL, SportsDiscus and The Cochrane Library. Methodological quality was assessed using a modified Quality Index. Effect sizes with 95% confidence intervals (CI) were calculated as the standardised mean difference (SMD). Meta-analysis was conducted if studies were homogenous. RESULTS: Thirty six studies with quality ranging from high to low met the inclusion criteria. The majority of studies reported gait parameters in Rheumatoid arthritis (RA). The gait pattern in RA was characterised by decreased walking speed (SMD 95% CI -1.57, -2.25 to -0.89), decreased cadence (SMD -0.97, 1.49 to -0.45), decreased stride length (SMD -1.66, -1.84 to -1.49), decreased ankle power (SMD -1.36, -1.70 to -1.02), increased double limb support time (SMD 1.03, 0.84 to 1.22), and peak plantar pressures at the forefoot (SMD 1.11, 0.76 to 1.45). Walking velocity was reduced in psoriatic arthritis and gout with no differences in ankylosing spondylitis. No studies have been conducted in polymyalgia rheumatica, systemic sclerosis or systemic lupus erythematosus. CONCLUSIONS: The review identified the majority of studies reporting gait adaptations in RA, but limited evidence relating to other IA conditions. Poor data reporting, small sample sizes and heterogeneity across IA conditions limit the interpretation of the findings. Future studies may consider a standardised analytical approach to gait analysis that will provide clinicians and researchers with objective evidence of foot function in people with IA. PMID- 26044781 TI - Implantation of left ventricular assist devices under extracorporeal life support in patients with heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) is a rare but life-threatening side effect of heparin therapy. It is a demanding therapeutic challenge in patients undergoing left ventricular assist device (LVAD) implantation. We present our experience with LVAD implantation under extracorporeal life support (ECLS) in patients suffering from HIT. Seven patients (mean age 54.0 +/- 16.7 years, 1 female, 6 male patients) suffering from acute heart failure were stabilized with ECLS. Under heparin therapy, they all showed a sudden decrease of mean platelet count (maximum 212.6 +/- 41.5 tsd/MUl; minimum 30.7 +/- 13.1 tsd/MUl). Due to the clinical suspicion of HIT anticoagulation was switched from heparin to argatroban (aPTT 70-80 s.). No improvement of cardiac function could be detected under ECLS, so LVAD implantation was indicated. We performed LVAD implantation under ECLS. During LVAD implantation under argatroban (aPTT of 50-60 s.) one patient developed massive intraventricular thrombus formations, so the device had to be removed. In 6 cases, we could successfully perform LVAD implantation under argatroban with a higher aPTT of 70-80 s and modified operative strategy. Four patients needed postoperative re-exploration because of bleeding complications. Perioperative management of LVAD patients under argatroban anticoagulation is very difficult. We were able to minimize the perioperative risk for thrombosis with a target aPTT of 70-80 s. To keep the phase of stasis within the device as short as possible we anastomosed the VAD outflow graft to the ascending aorta first before connecting the device to the apex. However, postoperative bleeding complications are frequent. PMID- 26044782 TI - The umbilicus: a reliable surface landmark for the aortic bifurcation? AB - PURPOSE: Anatomical surface landmarks are frequently used by clinicians to guide both diagnosis and treatment. Few studies have examined the reliability of vascular anatomical landmarks in living subjects. The umbilicus has traditionally been described as a surface landmark for the bifurcation of the abdominal aorta. This study examined the factors affecting the position of the umbilicus relative to that of the aortic bifurcation in 95 patients. METHODS: 106 consecutive abdominal CT scans were analysed by a surgeon and radiologist. Following exclusion of CT scans with relevant significant intra-abdominal pathology, 95 patients were included in the study. Measurements were taken of the craniocaudal distance between the aortic bifurcation and umbilicus, as well as maximum subcutaneous fat thickness at the level of the umbilicus. Patient age and gender were also documented. RESULTS: The umbilicus was found to lie -6.3 +/- 26.5 mm from the aortic bifurcation. Increasing subcutaneous fat thickness was associated with a more caudal position of the umbilicus relative to the aortic bifurcation. This result was highly statistically significant in males over 65 years old. CONCLUSIONS: This study suggests that the umbilicus is a reliable clinical surface landmark for the bifurcation of the abdominal aorta. Whilst some variation in craniocaudal distance exists between patients, in the majority of cases, the bifurcation of the abdominal aorta lies within a clinically narrow range of distances from the umbilicus. PMID- 26044783 TI - Lower pole anatomy and mid-renal-zone classification applied to flexible ureteroscopy: experimental study using human three-dimensional endocasts. AB - PURPUSE: The aim of this study was to analyze the anatomy of the inferior pole collecting system and the mid-renal-zone classification in human endocasts applied to flexible ureteroscopy. METHODS: 170 three-dimensional polyester resin endocasts of the kidney collecting system were obtained from 85 adult cadavers. We divided the endocasts into four groups: A1--kidney midzone (KM), drained by minor calices (mc) that are dependent on the superior or the inferior caliceal groups; A2--KM drained by crossed calices; B1--KM drained by a major caliceal group independent of both the superior and inferior groups; and B2--KM drained by mc entering directly into the renal pelvis. We studied the number of calices, the angle between the lower infundibulum and renal pelvis and the angle between the lower infundibulum and the inferior mc (LIICA). Means were statistically compared using ANOVA and the unpaired T test (p < 0.05). RESULTS: We found 57 (33.53 %) endocasts of group A1; 23 (13.53 %) of group A2; 59 (34.71 %) of group B1; and 31 (18.23 %) of group B2. The inferior pole was drained by four or more calices in 84 cases (49.41 %), distributed into groups as follows: A1 = 35 cases (41.67 %); A2 = 18 (21.43 %); B1 = 22 (26.19 %); and B2 = 9 (10.71 %). Perpendicular mc were observed in 15 cases (8.82 %). We did not observe statistical differences between the LIICA in the groups studied. CONCLUSIONS: Collector systems with kidney midzone drained by minor calices that are dependent on the superior or on the inferior caliceal groups presented at least two restrictive anatomical features. The mid-renal-zone classification was predictive of anatomical risk factors for lower pole ureteroscopy difficulties. PMID- 26044784 TI - New-onset refractory status epilepticus in an adult with an atypical presentation of cat-scratch disease: successful treatment with high-dose corticosteroids. AB - New-onset refractory status epilepticus (NORSE) is defined as a sudden onset of refractory status epilepticus in patients who do not have a history of epilepsy. It is a neurologic emergency, and determining the underlying etiology is an important factor for effectively managing and predicting the prognosis of NORSE. We describe the case of a 28-year-old woman who was hospitalized with NORSE secondary to an unknown etiology. She did not respond to traditional anticonvulsant therapy, including benzodiazepines, fosphenytoin, propofol, and levetiracetam. The patient was placed on continuous electroencephalography (EEG) monitoring and was treated further with multiple antiepileptics, which were titrated aggressively based on EEG readings and therapeutic drug levels; despite this treatment, EEG monitoring revealed continued seizures. Thus, high-dose corticosteroids were started for seizure control. Her workup included computed tomography and magnetic resonance imaging of the head, a lumbar puncture, toxicology screening, and extensive testing for multiple infectious and inflammatory etiologies. The patient's history revealed recent exposure to a new cat. Serologic results were positive for Bartonella henselae, and she was diagnosed with cat-scratch disease (CSD). She did not have the typical presentation of symptoms of lymphadenopathy, however, which is common in CSD. Doxycycline 100 mg and rifampin 300 mg twice daily were added to the patient's anticonvulsant and corticosteroid therapy. She was hospitalized for a total of 26 days and discharged with only minor neurologic impairment (short-term memory deficits and minor cognitive problems). The patient was discharged receiving antiepileptics, antibiotics, and a corticosteroid taper. To our knowledge, this is the first clinically known case of NORSE secondary to CSD without typical CSD symptoms in the adult population. The patient failed to respond to traditional anticonvulsant therapy alone. With the addition of high-dose corticosteroids to aggressive anticonvulsant therapy, seizure control was achieved. Further studies are needed to determine the effectiveness of high-dose corticosteroid and anticonvulsant therapy followed by antibiotics in patients with NORSE secondary to CSD. PMID- 26044785 TI - Postmarket Modifications of High-Risk Therapeutic Devices in Otolaryngology Cleared by the US Food and Drug Administration. AB - OBJECTIVE: The US Food and Drug Administration (FDA) grants initial marketing clearance for novel high-risk medical devices via the premarket approval (PMA) pathway, which requires clinical data demonstrating safety and effectiveness. Manufacturers may subsequently file supplemental PMA applications (supplements) to implement incremental device changes, usually without additional clinical data. Given the potentially significant clinical implications of using new device models, this study characterized the frequency and nature of changes to high-risk therapeutic otolaryngic devices cleared via the PMA pathway. STUDY DESIGN: Retrospective cohort study. SETTING: FDA PMA database. METHODS: Original high risk therapeutic otolaryngic devices and supplements were identified. Supplements were characterized by clearance date, change type, and review track, including real-time (design-minor) and 180-day (design-major) tracks. Median device lineage life span (postmarket period over which changes occurred) and median number of changes per original device were calculated. RESULTS: Through 2014, the FDA cleared 14 original high-risk therapeutic otolaryngic devices via the PMA pathway and 528 incremental changes via supplements. Devices were modified over a median 10.5-year life span (interquartile range, 4.4-15.8; range, 0.7-24.1), and they underwent a median 22 changes (interquartile range, 10-70; range, 2-108). Over half (272 of 528; 52%) altered device design, most of which were reviewed via the 180-day track (199 of 272; 73%) intended for major design changes. Few real-time design changes (11 of 73; 15%) were designated by the FDA as "minor." CONCLUSION: A substantial number of incremental changes have been made to high-risk therapeutic otolaryngic devices over time, including many major design changes without supporting clinical data. PMID- 26044786 TI - Optimal Management of Proliferative Verrucous Leukoplakia: A Systematic Review of the Literature. AB - OBJECTIVE: Proliferative verrucous leukoplakia (PVL) is a rare and recalcitrant form of leukoplakia. The purpose of this review is to further characterize the risk factors, clinical course, and optimal treatment for this highly aggressive, premalignant lesion. DATA SOURCES: Twenty-six articles on PVL with a total of 329 PVL cases. REVIEW METHODS: A systematic review of the literature using Ovid, PubMed, Cochrane Database, and gray literature was conducted of all PVL cases reported between 1985 and 2014. Inclusion criteria required reporting of patient follow-up and recurrence rates. Data were analyzed using descriptive statistics. Student t test and Fisher exact test were used to identify factors associated with malignant transformation. RESULTS: The mean patient age was 63.9 years. Most patients were female (66.9%) and nontobacco users (65.22%). Mean follow-up was 7.4 years, with an average of 9.0 biopsies per patient during this period. Proliferative verrucous leukoplakia exhibited histopathologic features along a progressive spectrum, evolving from leukoplakia to verrucous hyperplasia and ultimately invasive carcinoma. Surgery was the most common treatment implemented, but recurrence rates among 222 patients reached 71.2%. Subgroup analysis of 277 patients identified a 63.9% malignant transformation rate, and 39.6% of patients died of their disease. Age, sex, and tobacco use were not identified as risk factors associated with progression to cancer. CONCLUSIONS: Proliferative verrucous leukoplakia is a rare form of leukoplakia with a high rate of malignant transformation. It necessitates high clinical suspicion, to include a lifetime of close follow-up and repeat biopsies by a health care provider well versed in oral carcinoma. PMID- 26044787 TI - Accountable Care Organizations and Otolaryngology. AB - Accountable care organizations represent a shift in health care delivery while providing a significant potential for improved quality and coordination of care across multiple settings. Otolaryngologists have an opportunity to become leaders in this expanding arena. However, the field of otolaryngology-head and neck surgery currently lacks many of the tools necessary to implement value-based care, including performance measurement, electronic health infrastructure, and data management. These resources will become increasingly important for surgical specialists to be active participants in population health. This article reviews the fundamental issues that otolaryngologists should consider when pursuing new roles in accountable care organizations. PMID- 26044788 TI - Drug-Induced Sedation Endoscopy in the Evaluation of OSA Patients with Incomplete Oral Appliance Therapy Response. AB - OBJECTIVE: To use drug-induced sedation endoscopy (DISE) to identify locations and patterns of residual collapse in patients with obstructive sleep apnea (OSA) with incomplete response to oral appliance therapy (OAT). STUDY DESIGN: Case series with chart review. SETTING: Academic multidisciplinary sleep practice. SUBJECTS AND METHODS: Thirty-five consecutively screened adult patients with OSA with continuous positive airway pressure (CPAP) intolerance and incomplete response to OAT (apnea-hypopnea index [AHI] >15 or AHI >5 with persistent subjective symptoms) who underwent DISE with and without the oral appliance. Data collected included demographics, body mass index, polysomnography data, and management decisions after DISE. Each DISE video pair was retrospectively scored using the VOTE classification system by the same blinded reviewer (R.J.S.). RESULTS: All patients had multilevel airway collapse at baseline. The palate was the most common location of OAT failure. Fifteen (42.9%) had persistent collapse of the velum during DISE with OAT, and 7 (20%) had persistent collapse of the epiglottis. Twenty-three (65.7%) patients were offered targeted surgery based on DISE findings to augment OAT effectiveness. Twenty (57.1%) patients underwent additional medical therapy such as OAT adjustment or cervical positional therapy. Mean AHI was reduced from 37.4 at baseline, to 16.4 with OAT (P < .01), and to 10.7 after post-DISE intervention (P < .78). CONCLUSION: In patients with incomplete response to OAT, DISE with and without the appliance can identify residual anatomical locations of collapse, which may direct additional medical and surgical treatment options to augment OAT effectiveness. Further work is needed to determine if DISE affects outcomes. PMID- 26044789 TI - Effect of Adenotonsillectomy on Central and Obstructive Sleep Apnea in Children with Down Syndrome. AB - OBJECTIVES: To determine and quantify changes in both central and obstructive sleep apnea in patients with Down syndrome (DS) after adenotonsillectomy (AT). STUDY DESIGN: Case series with chart review. SETTING: Tertiary care children's hospital. SUBJECTS AND METHODS: The records of all patients with DS who underwent AT for sleep-disordered breathing between November 2008 and December 2014 were examined. In total, 113 patients were identified, and 36 of these patients had pre- and postoperative polysomnograms (PSGs) that were analyzed for obstructive and central components. Wilcoxon signed-rank test, paired t test, and McNemar test were used to examine pre- and postoperative PSG differences. Logistic regression and multivariate analysis of variance of patient characteristics (between subjects) and PSG results (within subjects) were conducted. RESULTS: The mean (SD) patient age was 5.5 (4.0) years (range, 0.9-15 years); 50.0% were male. After AT, significant reductions were identified in both obstructive apnea hypopnea index (AHI) (P < .001) and overall AHI (P < .001). Among the 15 patients with severe obstructive sleep apnea, 86.7% experienced a significant AHI reduction to moderate or mild disease (P < .001). In addition, of the 15 patients with central sleep apnea (central apnea index [CAI] >1), 66.7% had resolution of central sleep apnea postoperatively (P = .004). There was also a significant interaction identified between CAI reduction, preoperative CO2 retention, and adenoid size, F(2, 20) = 6.87, P = .05. CONCLUSION: Children with DS who underwent AT demonstrated significant reductions in both obstructive and central apneic indices on PSG. A significant number of patients with central sleep apnea demonstrated resolution postoperatively. Additional analysis demonstrated a significant interaction between CO2 retention, adenoid size, and postoperative CAI reduction. PMID- 26044790 TI - Craniofacial Resection for T4 Maxillary Sinus Carcinoma: Managing Cases with Involvement of the Skull Base. AB - OBJECTIVE: The objective of this study was to clarify the outcomes of craniofacial resection for locally advanced maxillary sinus carcinoma classified as T4 and to present methods for managing cases involving the skull base. STUDY DESIGN: Case series with chart review. SETTING: Tertiary university hospital. SUBJECTS AND METHODS: We performed anterolateral craniofacial resection in en bloc fashion for locally advanced maxillary sinus carcinoma at stage T4. Participants comprised 40 patients with T4 maxillary sinus carcinoma treated between 1992 and 2011. Surgical outcomes were analyzed retrospectively. RESULTS: Forty patients with stage T4a (n = 26) or stage T4b (n = 14) were included in this study. Five-year overall and disease-free survival rates for the 40 patients with T4 maxillary sinus carcinoma were 62.7% and 52.6%, respectively. Cavernous sinus involvement correlated significantly with worse prognosis (P = .012). In 35 cases without cavernous sinus involvement, previous treatment (P = .017) and positive margins (P = .019) correlated significantly with worse prognosis, and 5 year overall and disease-free survival rates were 72.4% and 55.3%, respectively. CONCLUSION: This study only included cases of locally advanced maxillary sinus carcinoma classified as T4. Considering the advanced stage, our study suggests relatively favorable outcomes and the importance of managing the cavernous sinus in en bloc resections of malignant skull base tumors. Craniofacial resection in en bloc fashion achieved good survival rates. PMID- 26044791 TI - Clinical outcomes of mesh exposure/extrusion: presentation, timing and management. AB - BACKGROUND: The Food and Drug Administration has recently highlighted an increase in reported complications associated with the use of transvaginal mesh. AIMS: To describe the clinical outcomes, presentation, timing and management of mesh exposure/extrusion MATERIALS AND METHODS: Retrospective study from December 2006 to March 2012. A total of 40 women had vaginal mesh exposure/extrusion secondary to prior transvaginal mesh (TVM) surgery. Descriptive statistics were used for demographics and pre-operative data. Paired-samples t-test was applied for comparison of pre- and postoperation. A P value of <0.05 was considered statistically significant. RESULTS: The mesh exposure/extrusion rate was noted to be 2.64% (17/642). Vaginal bleeding in 29 of 40 (72.5%) and hispareunia in 12 of 13 (92.3%) were identified as the most common symptoms for mesh exposure/extrusion. The onset of complications occurred in two peaks: between 3 and 4 months and after 1-year of follow-up. Initial conservative treatment was given for 12.5% (5/40) of women, while 87.5% (35/40) had undergone repair for mesh exposure/extrusion (21 outpatient and 14 inpatient cases). Among those who had conservative treatment, 80% (4/5) had persistent mesh exposure. CONCLUSION: Persistent or new-onset abnormal vaginal bleeding and hispareunia after TVM surgery should be considered as 'red flag' symptoms for mesh exposure/extrusion. Frequent follow-up from the first 3-4 months up to 1 year postoperative may identify complications. Utilisation of mesh excision or trimming as the initial means of treatment may yield a better outcome. PMID- 26044793 TI - A novel murine model for evaluating bovine papillomavirus prophylactics/therapeutics for equine sarcoid-like tumours. AB - Equine sarcoids are highly recurrent bovine papillomavirus (BPV)-induced fibroblastic neoplasms that are the most common skin tumours in horses. In order to facilitate the study of potential equine sarcoid prophylactics or therapeutics, which can be a slow and costly process in equines, a murine model for BPV-1 protein-expressing equine sarcoid-like tumours was developed in mice through stable transfection of BPV-1 E5 and E6 in a murine fibroblast tumour cell line (K-BALB). Like equine sarcoids, these murine tumour cells (BPV-KB) were of fibroblast origin, were tumorigenic and expressed BPV-1 proteins. As an initial investigation of the preclinical potential of this tumour model for equine sarcoids prophylactics, mice were immunized with BPV-1 E5E6 Venezuelan equine encephalitis virus replicon particles, prior to BPV-KB challenge, which resulted in an increased tumour-free period compared with controls, indicating that the BPV-KB murine model may be a valuable preclinical alternative to equine clinical trials. PMID- 26044792 TI - Exploring the virome of diseased horses. AB - Metagenomics was used to characterize viral genomes in clinical specimens of horses with various organ-specific diseases of unknown aetiology. A novel parvovirus as well as a previously described hepacivirus closely related to human hepatitis C virus and equid herpesvirus 2 were identified in the cerebrospinal fluid of horses with neurological signs. Four co-infecting picobirnaviruses, including an unusual genome with fused RNA segments, and a divergent anellovirus were found in the plasma of two febrile horses. A novel cyclovirus genome was characterized from the nasal secretion of another febrile animal. Lastly, a small circular DNA genome with a Rep gene, from a virus we called kirkovirus, was identified in the liver and spleen of a horse with fatal idiopathic hepatopathy. This study expands the number of viruses found in horses, and characterizes their genomes to assist future epidemiological studies of their transmission and potential association with various equine diseases. PMID- 26044794 TI - Identification of the functional domain of the porcine epidemic diarrhoea virus receptor. AB - Porcine aminopeptidase N (pAPN) is a functional receptor for porcine epidemic diarrhoea virus (PEDV). Although PEDV is known to use the pAPN as the major receptor for cell entry, the crucial domain of the pAPN that interacts with the PEDV is still unknown. In the present study, in order to determine the crucial domain of the pAPN, the extracellular domain of pAPN was divided into three subdomains named SPA, SPB and SPC, based on its secondary structure. Recombinant plasmid pcDNA3.1 expressing SPA, SPB and SPC was constructed and introduced into Madin-Darby canine kidney (MDCK) cells by transfection. Following the detection of PEDV infection in transfected MDCK cells after PEDV challenge, we clearly demonstrated that the SPC subdomain plays a key role in cell entry of PEDV and its expression permits PEDV growth in transfected MDCK cells, while virus propagation can be inhibited by anti-SPC serum, indicating that the SPC subdomain appears to be a crucial functional domain in contributing to efficient PEDV infection. PMID- 26044795 TI - Factors related to low serum vitamin B12 levels in elderly patients with non atrophic gastritis in contrast to patients with normal vitamin B12 levels. AB - AIM: Vitamin B12 deficiency is frequent in older patients, and the main reason is pernicious anemia. However, vitamin B12 deficiency can occur in patients who do not have atrophic gastritis. The aim of the present study was to investigate factors affecting serum vitamin B12 levels in older patients with non-atrophic gastritis. METHODS: A total of 1256 out of 1607 patients aged over 60 years who had undergone upper gastrointestinal endoscopy for various reasons, and who had serum vitamin B12 value and were diagnosed as having "non-atrophic gastritis" were analyzed by means of factors affecting low serum vitamin B12 levels. RESULTS: Non-atrophic gastritis patients were divided into two groups: patients with normal serum vitamin B12 (group I, n = 759) and patients with low serum vitamin B12 (group II, n = 497). The median serum vitamin B12 was 339 pg/mL (range 201-987 pg/mL) in group I and 180 pg/mL (range 50-200 pg/mL) in group II. Helicobacter pylori (n = 154 vs 325, P < 0.001), neutrophil activity (n = 176 vs 367, P < 0.001), intestinal metaplasia (n = 35 vs 14, P < 0.001) and inflammation (n = 230 vs 386, P < 0.001) were present significantly more often in group II compared with group I. A total of 785 patients were both negative for Helicobacter pylori and atrophy. Of these 785 patients, neutrophil activity (n = 56, [32.6%] vs 25, [4.4%], P < 0.001) and inflammation (n = 69, [40.1%] vs 82, [13.4%], P < 0.001) scores were present significantly more often in group II compared with group I. CONCLUSIONS: Helicobacter pylori was present significantly more often in older patients whose serum vitamin B12 levels were <=200 pg/mL, and Helicobacter pylori density was inversely correlated with serum B12 level. Upper gastrointestinal endoscopic examination should be suggested for elderly patients with serum vitamin B12 level <=200 pg/mL. Geriatr Gerontol Int 2015; ??: ??-??. PMID- 26044797 TI - Sol-gel preparation and luminescent properties of red-emitting phosphor Sr-Ba-Mo W-O-(Eu(3+),Sm(3+)). AB - Two series of red-emitting phosphors Sr-Ba-Mo-W-O:Eu,Sm and Sr-Ba-Mo-W-O:Eu have been synthesized by a sol-gel method. The effects of the chemical composition, concentrations of Sm(3+) and Eu(3+), the Sr(2+)/Ba(2+) ratio, and the W(6+)/Mo(6+) ratio on the luminescent properties were investigated. The as prepared phosphors were characterized by X-ray diffraction and Raman spectra. Results showed that single phases of the two series were prepared. The compositions of Sr0.6 Ba0.13Mo0.8 W0.2O4:Eu0.10Sm0.08 and Sr0.75Ba0.1Mo0.8 W0.2O4:Eu0.10 had the strongest luminescent intensity. The excitation spectra of Sm(3+), Eu(3+) co-doped phosphors were broader and the strongest peak moved to 404 nm when compared with that of Eu(3+) single-doped phosphors. The luminescent intensity of the Sr0.6Ba0.13Mo0.8W0.2O4:Eu0.10 Sm0.08 at 618 nm were 2.8 times greater than that of Sr0.75Ba0.1Mo0.8 W0.2O4:Eu0.10. The luminescent intensity of Sr0.6Ba0.13Mo0.8 W0.2 O4:Eu0.10Sm0.08 and Sr0.75Ba0.1Mo0.8W0.2O4:Eu0.10 at 150 degrees C decreased to 56.8% and 50.3% of the initial value at room temperature, respectively. PMID- 26044796 TI - Comparative proteomic analysis of drought tolerance in the two contrasting Tibetan wild genotypes and cultivated genotype. AB - BACKGROUND: Drought is one of major abiotic stresses constraining crop productivity worldwide. To adapt to drought stress, plants have evolved sophisticated defence mechanisms. Wild barley germplasm is a treasure trove of useful genes and offers rich sources of genetic variation for crop improvement. In this study, a proteome analysis was performed to identify the genetic resources and to understand the mechanisms of drought tolerance in plants that could result in high levels of tolerance to drought stress. RESULTS: A greenhouse pot experiment was performed to compare proteomic characteristics of two contrasting Tibetan wild barley genotypes (drought-tolerant XZ5 and drought sensitive XZ54) and cv. ZAU3, in response to drought stress at soil moisture content 10% (SMC10) and 4% (SMC4) and subsequently 2 days (R1) and 5 days (R2) of recovery. More than 1700 protein spots were identified that are involved in each gel, wherein 132, 92, 86, 242 spots in XZ5 and 261, 137, 156, 187 in XZ54 from SMC10, SMC4, R1 and R2 samples were differentially expressed by drought over the control, respectively. Thirty-eight drought-tolerance-associated proteins were identified using mass spectrometry and data bank analysis. These proteins were categorized mainly into photosynthesis, stress response, metabolic process, energy and amino-acid biosynthesis. Among them, 6 protein spots were exclusively expressed or up-regulated under drought stress in XZ5 but not in XZ54, including melanoma-associated antigen p97, type I chlorophyll a/b-binding protein b, glutathione S-transferase 1, ribulosebisphosphate carboxylase large chain. Moreover, type I chlorophyll a/b-binding protein b was specifically expressed in XZ5 (Spots A4, B1 and C3) but not in both of XZ54 and ZAU3. These proteins may play crucial roles in drought-tolerance in XZ5. Coding Sequences (CDS) of rbcL and Trx-M genes from XZ5, XZ54 and ZAU3 were cloned and sequenced. CDS length of rbcL and Trx-M was 1401 bp (the partial-length CDS region) and 528 bp (full length CDS region), respectively, encoding 467 and 176 amino acids. Comparison of gene sequences among XZ5, XZ54 and ZAU3 revealed 5 and 2 SNPs for rbcL and Trx-M, respectively, with two 2 SNPs of missense mutation in the both genes. CONCLUSIONS: Our findings highlight the significance of specific-proteins associated with drought tolerance, and verified the potential value of Tibetan wild barley in improving drought tolerance of barley as well as other cereal crops. PMID- 26044798 TI - Investigation of the protective properties of glycosylphosphatidylinositol-based vaccine candidates in a Toxoplasma gondii mouse challenge model. AB - Vaccination against the ubiquitous parasite Toxoplasma gondii would provide the most efficient prevention against toxoplasmosis-related congenital, brain and eye diseases in humans. We investigated the immune response elicited by pathogen specific glycosylphosphatidylinositol (GPI) glycoconjugates using carbohydrate microarrays in a BALB/c mouse model. We further examined the protective properties of the glycoconjugates in a lethal challenge model using the virulent T. gondii RH strain. Upon immunization, mice raised antibodies that bind to the respective GPIs on carbohydrate microarrays, but were mainly directed against an unspecific GPI epitope including the linker. The observed immune response, though robust, was unable to provide protection in mice when challenged with a lethal dose of viable tachyzoites. We demonstrate that anti-GPI antibodies raised against the here described semi-synthetic glycoconjugates do not confer protective immunity against T. gondii in BALB/c mice. PMID- 26044799 TI - Quality of Life in Dialysis Patients: A Retrospective Cohort Study. AB - BACKGROUND/AIM: Physical component summary (PCS) and mental component summary (MCS) scores are associated with hospitalization and mortality in patients with end-stage renal disease. Most studies in these patients are cross-sectional in nature. This study aimed to assess the dynamics of health-related quality of life (HRQOL) over time, as well as determinants of changes in HRQOL. Also, the relation between changes in HRQOL with respect to both hospitalization and mortality was assessed. METHODS: A cross-sectional analysis was performed in 77,848 hemodialysis (HD) patients whereas changes in HRQOL were assessed in 8,339 patients over a 1-year time period. HRQOL measurements were assessed with Kidney Disease Quality of Life-36 questionnaires. Also, relevant biomarkers (albumin, creatinine, hemoglobin, sodium) and equilibrated normalized protein catabolic rate (enPCR) were measured. RESULTS: HRQOL were found to be decreased in HD patients. Nutritional indices like creatinine (r = 0.23; p < 0.0001) and serum albumin (r = 0.21; p < 0.0001) positively correlated with PCS scores. An increase in levels of albumin, creatinine, hemoglobin, enPCR and serum sodium over time are significantly (p < 0.0001) associated with positive changes in PCS scores. Changes in PCS scores were found to be predictive for hospitalization and mortality. The correlates of predictors for MCS scores were less strong compared to that of PCS scores. The strongest positive predictors of MCS scores were age (r = 0.08; p < 0.0001), albumin (r = 0.05; p < 0.0001) and sodium (r = 0.05; p < 0.0001). CONCLUSIONS: Nutritional factors are strongly associated with changes in HRQOL, especially with regard to PCS scores (change over time in HRQOL was an independent predictor of hospitalization and mortality). Increased scores of HRQOL over time are positively associated with survival. PMID- 26044801 TI - Prevalence of Sleep-Disordered Breathing-Related Symptoms in Patients with Chronic Heart Failure and Reduced Ejection Fraction. AB - BACKGROUND: Sleep-disordered breathing (SDB) is highly prevalent in patients with chronic heart failure (CHF) and is associated with a poor prognosis. Data on SDB related symptoms and vigilance impairment in patients with CHF and SDB are rare. Thus, the objective of the present study was to assess a wide spectrum of SDB related symptoms and objective vigilance testing in patients with CHF with and without SDB. METHODS: Patients with CHF (n = 222; average age, 62 years; left ventricular ejection fraction [LVEF], 34%) underwent polysomnography regardless of the presence or absence of SDB-related symptoms. Patients were stratified into those with no SDB (apnea-hypopnea index [AHI] < 15 episodes/h), moderate SDB (AHI >= 15 to < 30 episodes/h), and severe SDB (AHI >= 30 episodes/h). A standardized institutional questionnaire assessing a wide spectrum of SDB-related symptoms was applied. A subset of patients underwent objective vigilance testing (Quatember Maly, 100 stimuli within 25 minutes). RESULTS: Daytime fatigue (no SDB, moderate SDB, and severe SDB: 53%, 69%, and 80%, respectively; P = 0.005), unintentional sleep (9%, 15%, and 32%, respectively; P = 0.004), and xerostomia (52%, 49%, and 70%, respectively; P = 0.018), as well as an impaired objective vigilance test result (mean reaction time, 0.516, 0.497, and 0.579 ms, respectively; P < 0.001) occurred more frequently with increasing severity of SDB. Seventy-eight percent of patients with CHF and SDB had at least 3 SDB-related symptoms. In a linear multivariable regression model, the frequency of daytime fatigue (P = 0.014), unintentional sleep (P = 0.001), xerostomia (P = 0.016), and mean reaction time (P = 0.001) were independently associated with increasing AHI independent of age, body mass index, New York Heart Association functional class, and LVEF. CONCLUSIONS: The majority of patients with CHF and SDB have several potential SDB related symptoms and objective impairment of vigilance as potential treatment targets. PMID- 26044800 TI - Future of Sleep-Disordered Breathing Therapy Using a Mechanistic Approach. AB - Sleep disordered breathing (SDB) is highly prevalent among patients with cardiovascular disease (CVD), and the relationship between SDB and CVD may be bidirectional. However, SDB remains underdiagnosed and undertreated. One of the major barriers identified by cardiologists is lack of satisfaction with SDB therapy. This situation could be the result of the discordance between treatment and the pathophysiological characteristics of SDB. This condition is caused by multiple pathophysiological mechanisms, which could be classified into upper airway anatomic compromise, pharyngeal dilator muscle dysfunction, and ventilatory control instability. However, the effective treatment of SDB remains limited, and positive airway pressure therapy is still the mainstay of the treatment. Therefore, we review the pathophysiological characteristics of SDB in this article, and we propose to provide individualized treatment of SDB based on the underlying mechanism. This approach requires further study but could potentially improve adherence and success of therapy. PMID- 26044803 TI - Precision medicine in oncology needs to integrate pharmacogenetic profiling. PMID- 26044802 TI - Comprehensive Characterization of the Perioperative Morbidity of Cytoreductive Nephrectomy. AB - BACKGROUND: Although cytoreductive nephrectomy (CN) has been associated with perioperative morbidity, data are lacking regarding the risk of prolonged length of stay (pLOS) and delay to receipt of systemic therapy (ST). OBJECTIVE: To evaluate the association of clinicopathologic features with postoperative complications, pLOS, and time to receipt of ST. DESIGN, SETTING, AND PARTICIPANTS: We evaluated 294 patients with M1 renal cell carcinoma treated between 1990 and 2009. INTERVENTIONS: CN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Logistic and Cox regressions were used to evaluate associations of clinicopathologic features with 30-d postoperative complications, pLOS (LOS >=75th percentile), and time to receipt of ST. RESULTS AND LIMITATIONS: Fifteen (5%) patients experienced at least one Clavien grade >=3 early complication. Among patients for whom postsurgical ST was recommended, 61% did not receive ST within 60 d, but the delay was surgery-related in only 11%. In multivariable models limited to preoperative features, liver metastases were associated with complications (odds ratio [OR] 3.73, p=0.004) and pLOS (OR 2.46, p=0.03), while a laparoscopic approach was associated with earlier administration of ST (hazard ratio [HR] 5.05, p<0.001). In multivariable models incorporating operative features, intraoperative transfusion was associated with complications (OR 1.14, p<0.001) and pLOS (OR 1.22, p<0.001), while pN1 disease was associated with pLOS (OR 2.12, p=0.049) and delay to ST (HR 0.38, p=0.004). Limitations include the retrospective design and surgical selection bias. CONCLUSIONS: Overall, 61% of CN patients did not receive timely ST, but only 5% of patients experienced Clavien grade >=3 complications and the delay to ST was surgery-related in 11%. Liver metastases, intraoperative transfusion, and pN1 disease were independently associated with perioperative morbidity. PATIENT SUMMARY: We evaluated the morbidity of cytoreductive nephrectomy and identified predictors of unfavorable perioperative outcomes. Although 61% of patients did not receive timely systemic therapy, the rates of complications and surgery-related delay to systemic therapy were low. PMID- 26044804 TI - Obesity--A Short Overview of Health Policies. PMID- 26044805 TI - Erratum: A Bayesian modelling framework for tornado occurrences in North America. PMID- 26044806 TI - Perfusion-diffusion Mismatch Predicts Early Neurological Deterioration in Anterior Circulation Infarction without Thrombolysis. AB - Perfusion-diffusion mismatch in magnetic resonance imaging (MRI) represents the non-core hypoperfused area in acute ischemic stroke. The mismatch has been used to predict clinical response after thrombolysis in acute ischemic stroke, but its role for predicting early neurological deterioration (END) in acute ischemic stroke without thrombolysis has not been clarified yet. In this study, we prospectively recruited 54 patients with acute non-lacunar ischemic stroke in anterior circulation without thrombolysis. All patients received the first perfusion MRI within 24 hours from stroke onset. Target mismatch profile was defined as a perfusion-diffusion mismatch ratio >= 1.2. END was defined as an increase of >= 4 points in the National Institute of Health Stroke Scale (NIHSS) score within 72 hours. There were 13 (24.1%) patients developing END, which was associated with larger infarct growth (p = 0.002), worse modified Rankin Scale (p = 0.001) and higher mortality rate at 3 months (p = 0.025). Target mismatch profiles measured by T(max) >= 4, 5 and 6 seconds were independent predictors for END after correcting initial NIHSS score. Among the 3 T(max) thresholds, target mismatch measured by T(max) >= 6 seconds had the highest odd's ratio in predicting END (p < 0.01, odd's ratio = 17), with an 80% sensitivity and a 79.5% specificity. In conclusion, perfusion-diffusion mismatch could identify the patients at high risk of early clinical worsening in acute ischemic stroke without thrombolysis. PMID- 26044807 TI - Interleukin-1beta Receptor Antagonism Prevents Cognitive Impairment Following Experimental Bacterial Meningitis. AB - Pneumococcal meningitis is characterized by high rates of mortality and long-term cognitive impairment. In this study, we evaluated the effects of interleukin (IL) 1beta receptor antagonist (IL-1Ra) on memory, cytokine, and brain-derived neurotrophic factor (BDNF) levels in hippocampus after experimental pneumococcal meningitis. In a first experiment the animals were divided into four groups: control/saline, control treated with IL-1Ra, meningitis/saline, and meningitis treated with IL-1Ra. In the meningitis/saline group IL-1beta and cytokine-induced neutrophil chemoattractant-1 (CINC-1) levels increased at 24 h post-infection; adjuvant treatment with IL-1Ra reversed the increased levels in the hippocampus. The levels of tumour necrosis factor-alpha (TNF-alpha), IL-4, IL-6, IL-10, and BDNF did not change in all groups at 24 h post-infection. In a second experiment, the animals were subjected to behavioural tasks (open field, step-down inhibitory avoidance task, and object recognition task), cytokine, and BDNF levels analysis 10 days after experimental meningitis induction. In the open-field task, the meningitis/saline group did not exhibit difference between the training and test sessions, in the motor and exploratory activity indicating memory injury. The meningitis/IL-1Ra group presented difference between training and test session indicating habituation memory. The meningitis/saline group showed impairment in long-term memory for novel object recognition and in aversive memory. The adjuvant treatment with IL-1Ra prevented memory impairment. After behavioural tasks the hippocampus was evaluated. The levels of IL-4, IL-6, IL-10, and BDNF were maintained elevated 10 days post-infection. CINC-1 levels were elevated only in meningitis/saline group and IL-1beta decreased in meningitis/IL-Ra group. The levels of TNF-alpha did not change at 10 days post-infection. These findings illustrate the anti-inflammatory activity of IL-1Ra inhibitor in the first hours after meningitis induction. Adjuvant treatment with IL-1beta receptor antagonist could be a new avenue as therapeutic target during bacterial meningitis. PMID- 26044808 TI - Combination of Local Transplantation of In Vitro Bone-marrow Stromal Cells and Pulsed Electromagnetic Fields Accelerate Functional Recovery of Transected Sciatic Nerve Regeneration: A Novel Approach in Transected Nerve Repair. AB - Effect of combination of undifferentiated bone marrow stromal cells (BMSCs) and pulsed electromagnetic fields (PEMF) on transected sciatic nerve regeneration was assessed in rats. A 10 mm nerve segment was excised and a vein graft was used to bridge the gap. Twenty microliter undifferentiated BMSCs (2* 107 cells /mL) were administered into the graft inBMSC group with no exposure to PEMF. In BMSC/PEMF group the whole body was exposed to PEMF (0.3 mT, 2Hz) for 4h/day within 1-5 days. In PEMF group the transected nerve was bridged and phosphate buffered saline was administered into the graft. In authograft group (AUTO), the transected nervesegments were reimplanted reversely and the whole body was exposed to PEMF. The regenerated nerve fibers were studied within 12 weeks after surgery. Behavioral, functional, electrophysiological, biomechanical, gastrocnemius muscle mass findings, morphometric indices and immuonohistochemical reactions confirmed faster recovery of regenerated axons in BMSC/PEMF group compared to those in the other groups (P<0.05). The use of undifferentiated BMSCs with whole body exposure to PEMF improved functional recovery. Combination of local transplantation of in vitro bone-marrow stromal cells and pulsed electromagnetic fields could be considered as an effective, safe and tolerable treatment for peripheral nerve repair in clinical practice. PMID- 26044809 TI - Differential Regulation of microRNAs in Patients with Ischemic Stroke. AB - MicroRNAs have been discovered as regulators of gene expression and thus their potential in clinical disease diagnostics, prognosis and therapy is being actively pursued. MicroRNAs play an important role in atherosclerosis-related diseases, such as cerebrovascular and cardiovascular disease. However, the effect of miR-185 and miR-146a on patients with ischemic stroke (IS) in the different phases has not been reported. In this study, we investigated the amounts of three miRNAs, miR-185, miR-146a, and miR-145 in blood circulation of IS patients. We enrolled 60 patients with IS in the acute or sub-acute phase and 30 healthy controls. We divided the patients into two groups, patients with ischemic stroke in the acute phase (ISA) and patients with ischemic stroke in the subacute phase (ISS). We measured circulating miRNAs expression by miRNA microarray and real time polymerase chain reaction (PCR) analysis. Testing by miRNA microarray and RT PCR analyses showed that miR-145 levels in healthy subjects were similar to patients with IS, whereas miR-146a and miR-185 were present with quite low abundance in ISA compared with healthy individuals; moreover, we found that miR 146a levels were downregulated in ISA but upregulated in ISS which may help provide new insights into the diagnosis and therapy of IS. PMID- 26044810 TI - Breakpoint mapping by whole genome sequencing identifies PTH2R gene disruption in a patient with midline craniosynostosis and a de novo balanced chromosomal rearrangement. AB - BACKGROUND: Craniosynostosis (CRS) is a premature closure of calvarial sutures caused by gene mutation or environmental factors or interaction between the two. Only a small proportion of non-syndromic CRS (NSC) patients have a known genetic cause, and thus, it would be meaningful to search for a causative gene disruption for the development NSC. We applied a whole genome sequencing approach on a 15 month-old boy with sagittal and metopic synostosis to identify a gene responsible for the development of the disease. METHODS AND RESULTS: Conventional chromosome study revealed a complex paracentric inversion involving 2q14.3 and 2q34. Array comparative genomic hybridisation did not show any copy number variation. Multicolour banding analysis was carried out and the breakpoints were refined to 2q14 and 2q34. An intronic break of the PTH2R gene was detected by whole genome sequencing and fluorescence in situ hybridisation analysis confirmed disruption of PTH2R. CONCLUSIONS: We report PTH2R as a gene that is disrupted in NSC. The disruption of the PTH2R gene may cause uncontrolled proliferation and differentiation of chondrocytes, which in turn results in premature closure of sutures. This addition of PTH2R to the list of genes associated with NSC expands our understanding of the development of NSC. PMID- 26044811 TI - Comorbidity between chronic obstructive pulmonary disease and type 2 diabetes: A nation-wide cohort twin study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality and is associated with several systemic diseases, such as type 2 diabetes. It has been suggested that comorbidity between COPD and type 2 diabetes is due to shared genetic factors. AIM: To examine the relationship between type 2 diabetes and chronic bronchitis and COPD in adult twins, and to examine to what extent comorbidity between these diseases is explained by shared genetic or environmental factors. METHODS: Questionnaire data on chronic bronchitis and hospital discharge data on diagnosed COPD in 13,649 twins, aged 50 71 years, from the Danish Twin Registry were cross-linked with hospital discharge diagnosis data on type 2 diabetes from the Danish National Patient Registry. RESULTS: The risk of type 2 diabetes was higher in persons with symptoms of chronic bronchitis than in those without symptoms (3.5 vs. 2.3%), OR = 1.57 (1.10 2.26), p = 0.014, and in individuals with diagnosed COPD than in those without the diagnosis (6.6 vs. 2.3%), OR = 2.62 (1.63-4.2), p < 0.001. The results were significant after adjusting for age, sex, smoking, and BMI. Correlations between genetic effects on chronic bronchitis and type 2 diabetes, and between genetic effects on diagnosed COPD and type 2 diabetes, respectively, were 0.33 (0.00 0.79), p = 0.103, and 0.43 (0.00-0.98), p = 0.154. Non-shared environmental correlations between chronic bronchitis and type 2 diabetes were -0.13 (-0.43 to 0), p = 0.498 and diagnosed COPD and type 2 diabetes -0.12 (-0.48 to 0), p = 0.665. CONCLUSIONS: Patients with chronic bronchitis or COPD have an increased risk of type 2 diabetes independent of sex, age, smoking and BMI. The genetic correlation between type 2 diabetes and chronic bronchitis was 33% and type 2 diabetes and COPD was 43%, however neither were statistically significant. The increased risk of type 2 diabetes should be accommodated in the management of patients with chronic bronchitis or COPD. PMID- 26044812 TI - Detecting laryngopharyngeal reflux in patients with upper airways symptoms: Symptoms, signs or salivary pepsin? AB - BACKGROUND: Laryngopharyngeal reflux (LPR) can induce laryngeal hyper responsiveness, a unifying feature underlying chronic cough and vocal cord dysfunction. The diagnosis of LPR currently relies on invasive oesophageal pH impedance testing. We compared symptoms, laryngeal signs and salivary pepsin as potential diagnostic methods for identifying LPR in patients with upper airway symptoms. METHODS: Symptoms were assessed using the Reflux Symptom Index (RSI) and signs of laryngeal inflammation quantified using the Reflux Finding Score (RFS) during laryngoscopy. Saliva samples were analysed for the presence of pepsin. A sub-group of patients with severe symptoms and signs of LPR were investigated with oesophageal pH monitoring and impedance study. RESULTS: Seventy eight patients with chronic cough and/or suspected vocal cord dysfunction were recruited, mean (SD) age, 54.6 (15.6) years. The majority (87%) had significant symptoms of reflux (RSI>13). There were clinical signs of LPR (RFS>7) in 51% of cases. Pepsin was detected in the saliva of 63% of subjects and 78% of those with a high RFS. Salivary pepsin had a sensitivity of 78% and specificity of 53% for predicting a high RFS. There was a correlation between the RSI and RFS (r = 0.51, p < 0.001) and between the severity of laryngeal inflammation and the concentration of pepsin (r = 0.28, p = 0.01). All cases investigated with pH impedance study had objective evidence of proximal reflux. CONCLUSION: Salivary pepsin may be used as a screening adjunct to supplement the RFS in the clinical workup of patients with extra-oesophageal symptoms and upper respiratory tract presentations of reflux. PMID- 26044813 TI - Hypothermic Machine Perfusion in DCD Kidney Transplantation: A Single Center Experience. AB - INTRODUCTION: Donation after cardiac death (DCD) began in 2011 after the program hosted by the First Affiliated Hospital of Sun Yat-sen University in China. The aim of this study is to report on our experience regarding the method of preserving donated kidneys for DCD kidney transplantation. MATERIAL AND METHODS: A total of 37 donors and 73 primary kidney transplant recipients during the period 2011-2014 in the Urology Center of the First Hospital of Jilin University were enrolled in the study. Recipients were assigned to traditional static cold storage (SCS) group and hypothermic machine perfusion (HMP) group based on the preservation environment of donated kidneys after organ harvest. Clinical data were collected for each group. RESULT: The HMP group had a lower rate of delayed graft function (DGF), better postoperative recovery and kidney function compared with that of SCS group. There is no significant difference in postoperative rejection incidence between the 2 groups. CONCLUSIONS: DCD kidneys stored by hypothermic machine contribute to a lower rate of DGF and promoted the rehabilitation progress. PMID- 26044815 TI - Ruthenium Complexes Stabilized by Bidentate Enamido-Phosphine Ligands: Aspects of Cooperative H2 Activation. AB - Four bidentate, hybrid ligands ((R)(NP)(R')H) featuring imine-nitrogen and alkyl phosphine donors linked by a cyclopentyl ring were synthesized. The ortho position of the aryl group attached to nitrogen is varied such that R is Me or Pr(i); additionally, the groups decorating phosphorus (R') are varied between Bu(t) or Pr(i). The addition of each ligand to RuHCl(PPr(i)3)2(CO) in the presence of KOBu(t) generates four enamido-phosphine complexes RuH{(R)(NP)(R')}(PPr(i)3)(CO) that were characterized by NMR spectroscopy, elemental analyses, and, in the case of R = Pr(i) and R' = Bu(t) or Pr(i), X-ray crystallography. Depending on R', the reaction of RuH{(R)(NP)(R')}(PPr(i)3)(CO) with H2 generates varying amounts of the imine-phosphine complex RuH2{(R)(NP)(R')H}(PPr(i)3)(CO). Insights into the mechanism of H2 activation by these enamido derivatives were explored using RuH{(Pr)(NP)(Pri)}(PPr(i)3)(CO), for which an intermediate was identified as the dihydrogen-dihydride complex, RuH2(H2){(Pri)(NP)(Pri)H}(PPr(i)3)(CO), on the basis of the T1,min value of 22 ms for the (1)H NMR resonance at delta -7.2 at 238 K (measured at 400 MHz). The N donor of the enamine tautomeric form of the ligand is protonated by H2 or D2 and dissociates from Ru. Tautomerization of the enamine to the imine form of the dissociated arm is involved in formation of the final product. PMID- 26044817 TI - How to introduce more (or better) ethical arguments in HTA? AB - All evaluation exercises involve ethical values, as they require some conception of the "good life." Evaluation of health technologies is no exception. Because there is no consensus about what is a good life, we have to devise decision making procedures in which citizens with different opinions are heard and treated fairly (1). The purpose of health technology assessment (HTA) is to offer useful input into this process so as to increase the quality of the deliberations and of the resulting decisions. How to bring ethical values into this process? PMID- 26044814 TI - Making randomised trials more efficient: report of the first meeting to discuss the Trial Forge platform. AB - Randomised trials are at the heart of evidence-based healthcare, but the methods and infrastructure for conducting these sometimes complex studies are largely evidence free. Trial Forge ( www.trialforge.org ) is an initiative that aims to increase the evidence base for trial decision making and, in doing so, to improve trial efficiency.This paper summarises a one-day workshop held in Edinburgh on 10 July 2014 to discuss Trial Forge and how to advance this initiative. We first outline the problem of inefficiency in randomised trials and go on to describe Trial Forge. We present participants' views on the processes in the life of a randomised trial that should be covered by Trial Forge.General support existed at the workshop for the Trial Forge approach to increase the evidence base for making randomised trial decisions and for improving trial efficiency. Agreed upon key processes included choosing the right research question; logistical planning for delivery, training of staff, recruitment, and retention; data management and dissemination; and close down. The process of linking to existing initiatives where possible was considered crucial. Trial Forge will not be a guideline or a checklist but a 'go to' website for research on randomised trials methods, with a linked programme of applied methodology research, coupled to an effective evidence-dissemination process. Moreover, it will support an informal network of interested trialists who meet virtually (online) and occasionally in person to build capacity and knowledge in the design and conduct of efficient randomised trials.Some of the resources invested in randomised trials are wasted because of limited evidence upon which to base many aspects of design, conduct, analysis, and reporting of clinical trials. Trial Forge will help to address this lack of evidence. PMID- 26044819 TI - Comparison of high versus low-medium prednisone doses for the treatment of systemic lupus erythematosus patients with high activity at diagnosis. AB - OBJECTIVE: To compare the efficacy and safety of high vs. low-moderate oral doses of prednisone to treat patients with highly active lupus at diagnosis. PATIENTS AND METHODS: Patients from the Lupus-Cruces cohort with an SLEDAI score >=6 at diagnosis and treated with regimes containing low-medium prednisone doses (<=30 mg/day) were identified (group M). They were matched by sex and SLEDAI score with historical patients treated with high doses (>30 mg/day) at diagnosis (group H). Patients with proliferative nephritis were excluded. The difference in SLEDAI scores between baseline (SLEDAI-0) and year one (SLEDAI-1) was the efficacy variable. Damage at 5 years was calculated using the SLICC damage index (SDI) and regarded as the safety variable. Glucocorticoid related damage was considered in the presence of cataracts, osteonecrosis, osteoporotic fractures and/or diabetes mellitus. RESULTS: 30 patients were included in each group. Patients in group H received 5-fold higher doses of prednisone, less hydroxychloroquine and less methyl-prednisolone pulses. SLEDAI improvement was similar in both groups. Patients in group H were more likely to accrue new damage (adjusted HR 3.85 (95% CI 1.03-14.2)). No patients in group M suffered glucocorticoid-related damage, vs. 5 patients in group H (p=0.02). The average daily prednisone dose during the first year predicted accrual of new damage (adjusted HR 1.03, 95% CI 1.0-1.07, p=0.056) and accrual of glucocorticoid-related damage (adjusted HR 1.06, 95% CI 1.01-1.13, p=0.03). Likewise, average doses of prednisone >7.5mg/day were an independent predictor of new damage (adjusted HR 4.8, 95% CI 1.2-19.1). CONCLUSION: Prednisone doses <=30 mg/day are similarly effective and safer than higher doses for treating active lupus. PMID- 26044818 TI - Relaxant effects of a hydroalcoholic extract of Ruta graveolens on isolated rat tracheal rings. AB - BACKGROUND: Ruta graveolens L. (R. graveolens) is a medicinal plant employed in non-traditional medicines that has various therapeutic properties, including anthelmintic, and vasodilatory actions, among others. We evaluated the trachea relaxant effects of hydroalcoholic extract of R. graveolens against potassium chloride (KCl)- and carbachol-induced contraction of rat tracheal rings in an isolated organ bath. RESULTS: The results showed that the airway smooth muscle contraction induced by the depolarizing agent (KCl) and cholinergic agonist (carbachol) was markedly reduced by R. graveolens in a concentration-dependent manner, with maximum values of 109 +/- 7.9 % and 118 +/- 2.6 %, respectively (changes in tension expressed as positive percentages of change in proportion to maximum contraction), at the concentration of 45 MUg/mL (half-maximal inhibitory concentration IC50: 35.5 MUg/mL and 27.8 MUg/mL for KCl- and carbachol-induced contraction, respectively). Additionally, the presence of R. graveolens produced rightward parallel displacement of carbachol dose-response curves and reduced over 35 % of the maximum smooth muscle contraction. CONCLUSIONS: The hydroalcoholic extract of R. graveolens exhibited relaxant activity on rat tracheal rings. The results suggest that the trachea-relaxant effect is mediated by a non-competitive antagonistic mechanism. More detailed studies are needed to identify the target of the inhibition, and to determine more precisely the pharmacological mechanisms involved in the observed biological effects. PMID- 26044821 TI - Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio. AB - PURPOSE: Age-related macular degeneration (AMD) is one of the leading causes of blindness. Degeneration of the retinal pigment epithelium (RPE) is pathognomonic for the disease, and oxidative stress plays an important role in the pathogenesis of this disease. This study investigates potential antiapoptotic and cytoprotective effects of idebenone on cultured RPE cells (ARPE-19) under conditions of oxidative stress. METHODS: ARPE-19 cells were treated with 1-100 uM idebenone. Cell viability (MTT assay), induction of intracellular reactive oxygen species (ROS) and histone-associated DNA fragments in mono- and oligonucleosomes, expression of proapoptotic BAX and antiapoptotic Bcl-2 as well as senescence-associated beta-galactosidase (SA-beta-Gal) activity were investigated under exposure to hydrogen peroxide (H2O2). RESULTS: Idebenone concentrations from 1 to 20 uM showed no toxic effects on ARPE 19 cells. When cells were treated with H2O2, pretreatment with 5, 7.5, 10, and 20 uM idebenone led to a significant increase in the viability of ARPE-19 cells. In addition, idebenone pretreatment significantly attenuated the induction of SA-beta-Gal and intracellular ROS as well as the amount of histone associated DNA fragments after treatment with H2O2. The reduction of proapoptotic BAX and the elevation of antiapoptotic Bcl-2 under idebenone show that this process is rather mediated by inhibiting H2O2-induced apoptosis, not necrosis. CONCLUSION: In this study, idebenone increased survival of ARPE-19 cells and reduced cell death, senescence, and oxidative stress by stabilizing the BAX/Bcl-2 ratio. PMID- 26044822 TI - Comment on: Long-term outcomes and experience of laparoscopic adjustable gastric banding: one center's results in China. PMID- 26044820 TI - Teriparatide use during an economic crisis: baseline data from the Greek cohort of the Extended Forsteo Observational Study (ExFOS). AB - BACKGROUND: The Extended Forsteo Observational Study (ExFOS) is a multinational, non-interventional, prospective, observational study that aims to provide real life data on patients with osteoporosis treated with teriparatide for up to 24 months. It includes the new indications of osteoporosis in men and glucocorticoid induced osteoporosis (GIOP). We describe the Greek subpopulation enrolled in this study and compare it with a similar cohort from the previous European Forsteo Observational Study (EFOS). METHODS: Baseline data were collected from the Greek cohort of ExFOS. Data included demographic characteristics, medical and osteoporosis history, disease status, prior use of medications, back pain and quality of life. RESULTS: Baseline data for 439 patients, enrolled at 31 sites, indicated the majority of patients were females (92.3%), elderly [mean (standard deviation; SD) age 70.1 (9.8) years] and slightly overweight [mean (SD) body mass index 26.7 (4.3) kg/m(2)], with very low bone mineral density (mean T-score <-3 in lumbar spine or total hip) and at least one previous fracture (55.1% of patients). Of the 439 patients, 19.8% were osteoporosis treatment naive, 88.4% had experienced back pain during the previous 12 months, 68.1% had experienced back pain at least fairly often during the previous month and 50.9% reported moderate to severe limitation of activities due to back pain, with a mean (SD) of 4.2 (7.7) days spent in bed because of back pain during the previous month. Most baseline characteristics were numerically similar between the female ExFOS and EFOS cohorts; however, the rate of enrolment was faster in ExFOS (by approximately 45%) and a history of fracture was recorded in 53.8% of female patients in ExFOS versus 74.5% in EFOS. CONCLUSIONS: Greek patients prescribed teriparatide in ExFOS had severe osteoporosis with a high risk of fractures and back pain. Female patients shared similarities with EFOS counterparts, reflecting a constant prescribing profile for use of teriparatide, although a noticeable difference in fracture history between the two study cohorts may indicate a change towards prescribing in less severely affected patients. The economic crisis in Greece did not appear to affect patient enrolment. Data are interpreted in the context of an observational setting. PMID- 26044823 TI - Cinderella in Pathology. PMID- 26044824 TI - A Pilot Study Evaluating Fine-Needle Aspiration Cytology of Clear-Cell Renal Cell Carcinoma: Comparison of Ancillary Immunocytochemistry and Cytomorphological Characteristics of SurePathTM Liquid-Based Preparations with Conventional Smears. AB - OBJECTIVE: Fine-needle aspiration cytology (FNAC) based on a liquid-based preparation is a safe and valuable diagnostic tool. However, due to unfamiliarity with this method and the considerably altered morphology that is associated with it, diagnosing renal cell carcinoma (RCC) from this type of preparation remains a challenge for cytopathologists. The aim of this study was to evaluate the cytomorphological characteristics of SurePathTM (SP)-based preparations compared with conventional smear (CS), and also the role of SP-based FNAC in the diagnosis of clear-cell RCC (CRCC), the most common primary renal malignancy. STUDY DESIGN: Ex vivo FNAC of both tumors and normal renal parenchyma was prepared from 73 cases. Comparative cytomorphological analysis between liquid-based cytology (LBC) and CS as well as Fuhrman nuclear grading (FNG) was carried out. Immunocytochemistry was performed from normal and CRCC cytology specimens. RESULTS: Normal renal cytology (NRC) showed no significant morphological differences between LBC and CS. For CRCC, LBC showed small, fragmented cell clusters, a 3-dimensional configuration, distinct cytoplasmic vacuoles, and irregular nuclear contours when compared with CS. FNG was overgraded with LBC compared to with CS. AMACR was the most valuable immunocytochemical marker for distinguishing CRCC from NRC. CONCLUSION: Once cytopathologists become familiar with the altered cytomorphological features of CRCC, FNAC, along with immunocytochemistry, may prove helpful for diagnosis. PMID- 26044825 TI - Perceptual choice boosts network stability: effect of neuromodulation? AB - A recent paper demonstrates that conscious perceptual decisions are characterized by a hallmark of attractor states in recurrent cortical networks: increased stability of cortex-wide activity patterns. We propose that this global cortical state change may be caused by a transient gain modulation through ascending brainstem systems. PMID- 26044826 TI - Effect of S100A6 over-expression on beta-catenin in endometriosis. AB - AIM: S100A6 is over-expressed in several human tumors, including pancreatic carcinoma, malignant fibrous histiocytoma, breast, colon, and gastric carcinoma, but little is known about the role of S100A6 in endometriosis. The aim of the present study was to investigate the effect of S100A6 over-expression on beta catenin in endometrial stromal cells. METHODS: Endometrial stromal cells were transfected with an hS100A6-expressing recombinant lentivirus construct. The expression of beta-catenin was assessed using western blot and reverse transcription-polymerase chain reaction. RESULTS: S100A6 over-expression promoted beta-catenin expression at the RNA and protein levels, in endometrial stromal cells. CONCLUSIONS: S100A6 induces expression of beta-catenin in endometrial stromal cells. PMID- 26044827 TI - The inflammation, vascular repair and injury responses to exercise in fit males with and without Type 1 diabetes: an observational study. AB - BACKGROUND: Type 1 diabetes is associated with raised inflammation, impaired endothelial progenitor cell mobilisation and increased markers of vascular injury. Both acute and chronic exercise is known to influence these markers in non-diabetic controls, but limited data exists in Type 1 diabetes. We assessed inflammation, vascular repair and injury at rest and after exercise in physically fit males with and without Type 1 diabetes. METHODS: Ten well-controlled type 1 diabetes (27 +/- 2 years; BMI 24 +/- 0.7 kg.m(2); HbA1c 53.3 +/- 2.4 mmol/mol) and nine non-diabetic control males (27 +/- 1 years; BMI 23 +/- 0.8 kg.m(2)) matched for age, BMI and fitness completed 45-min of running. Venous blood samples were collected 60-min before and 60-min after exercise, and again on the following morning. Blood samples were processed for TNF-alpha using ELISA, and circulating endothelial progenitor cells (cEPCs; CD45(dim)CD34(+)VEGFR2(+)) and endothelial cells (cECs; CD45(dim)CD133(-)CD34(+)CD144(+)) counts using flow cytometry. RESULTS: TNF-alpha concentrations were 4-fold higher at all-time points in Type 1 diabetes, when compared with control (P < 0.001). Resting cEPCs were similar between groups; after exercise there was a significant increase in controls (P = 0.016), but not in Type 1 diabetes (P = 0.202). CEPCs peaked the morning after exercise, with a greater change in controls vs. Type 1 diabetes (+139 % vs. 27 %; P = 0.01). CECs did not change with exercise and were similar between groups at all points (P > 0.05). Within the Type 1 diabetes group, the delta change in cEPCS from rest to the following morning was related to HbA1c (r = -0.65, P = 0.021) and TNF-alpha (r = -0.766, P = 0.005). CONCLUSIONS: Resting cEPCs and cECs in Type 1 diabetes patients with excellent HbA1c and high physical fitness are comparable to healthy controls, despite eliciting 4-fold greater TNF alpha. Furthermore, Type 1 diabetes patients appear to have a blunted post exercise cEPCs response (vascular repair), whilst a biomarker of vascular injury (cECs) remained comparable to healthy controls. PMID- 26044829 TI - Effects of intranasal oxytocin on steroid hormones in men and women. AB - BACKGROUND: Recent interest in the social and cognitive effects of intranasal oxytocin prompts a need for understanding its physiological effects in humans. Few studies have examined the effects of intranasal oxytocin on steroid hormones. Filling this gap is especially important given the evidence that steroid hormones participate in some of the same behavioral functions as oxytocin, e.g. in stress, processing of emotional stimuli, aggression, trust, empathy, and parental care. METHODS: In randomized, double-blind experiments, we administered oxytocin (24 IU) or saline placebo to 97 healthy participants. Saliva samples were collected before and at several time points after the oxytocin/placebo administration to assess the levels of cortisol, progesterone, and testosterone. RESULTS: Oxytocin had no effects on testosterone, progesterone, or cortisol in women or men. CONCLUSION: Acute intranasal oxytocin does not affect the levels of cortisol, testosterone or progesterone in humans, at least in the absence of a stressful context. These data suggest that acute oxytocin does not have a direct impact on the human hypothalamic-pituitary-adrenal or hypothalamic-pituitary-gonadal axes under nonstressful circumstances. This knowledge helps rule out potential mechanisms for some of the effects of oxytocin in humans and adds to the generally limited body of knowledge on the basic physiological or psychological effects of intranasal oxytocin in human beings. PMID- 26044828 TI - Heterologous expression and transcript analysis of gibberellin biosynthetic genes of grasses reveals novel functionality in the GA3ox family. AB - BACKGROUND: The gibberellin (GA) pathway plays a central role in the regulation of plant development, with the 2-oxoglutarate-dependent dioxygenases (2-ODDs: GA20ox, GA3ox, GA2ox) that catalyse the later steps in the biosynthetic pathway of particularly importance in regulating bioactive GA levels. Although GA has important impacts on crop yield and quality, our understanding of the regulation of GA biosynthesis during wheat and barley development remains limited. In this study we identified or assembled genes encoding the GA 2-ODDs of wheat, barley and Brachypodium distachyon and characterised the wheat genes by heterologous expression and transcript analysis. RESULTS: The wheat, barley and Brachypodium genomes each contain orthologous copies of the GA20ox, GA3ox and GA2ox genes identified in rice, with the exception of OsGA3ox1 and OsGA2ox5 which are absent in these species. Some additional paralogs of 2-ODD genes were identified: notably, a novel gene in the wheat B genome related to GA3ox2 was shown to encode a GA 1-oxidase, named as TaGA1ox-B1. This enzyme is likely to be responsible for the abundant 1beta-hydroxylated GAs present in developing wheat grains. We also identified a related gene in barley, located in a syntenic position to TaGA1ox B1, that encodes a GA 3,18-dihydroxylase which similarly accounts for the accumulation of unusual GAs in barley grains. Transcript analysis showed that some paralogs of the different classes of 2-ODD were expressed mainly in a single tissue or at specific developmental stages. In particular, TaGA20ox3, TaGA1ox1, TaGA3ox3 and TaGA2ox7 were predominantly expressed in developing grain. More detailed analysis of grain-specific gene expression showed that while the transcripts of biosynthetic genes were most abundant in the endosperm, genes encoding inactivation and signalling components were more highly expressed in the seed coat and pericarp. CONCLUSIONS: The comprehensive expression and functional characterisation of the multigene families encoding the 2-ODD enzymes of the GA pathway in wheat and barley will provide the basis for a better understanding of GA-regulated development in these species. This analysis revealed the existence of a novel, endosperm-specific GA 1-oxidase in wheat and a related GA 3,18 dihydroxylase enzyme in barley that may play important roles during grain expansion and development. PMID- 26044830 TI - Infliximab Dose Escalation as an Effective Strategy for Managing Secondary Loss of Response in Ulcerative Colitis. AB - BACKGROUND: The outcomes of infliximab dose escalation in ulcerative colitis (UC) have not been well evaluated. AIMS: To assess the short- and long-term outcomes of infliximab dose escalation in a cohort of patients with UC. METHODS: This was a multicenter, retrospective, cohort study. All consecutive UC patients who had lost response to infliximab maintenance infusions and who underwent infliximab dose escalation were included. Post-escalation short-term clinical response and remission were evaluated. In the long term, the cumulative probabilities of infliximab failure-free survival and colectomy-free survival were calculated. Predictors of short-term response and event-free survival were estimated using logistic regression analysis and Cox proportional hazard regression analysis. RESULTS: Seventy-nine patients were included. Fifty-four patients (68.4%) achieved short-term clinical response and 41 patients (51.9%) entered in clinical remission. After a median follow-up of 15 months [interquartile range (IQR) 8 26], 33 patients (41.8%) had infliximab failure. Patients with short-term response had a significantly lower adjusted rate of infliximab failure [hazard ratio (HR) 0.24, 95% confidence interval (CI) 0.12-0.49; p < 0.001]. During a median follow-up of 24 months (IQR 13-34), 9 patients (11.4%) needed colectomy. Short-term response was identified as a predictor of colectomy avoidance (HR 0.14; 95% CI 0.03-0.69; p < 0.007). CONCLUSIONS: In UC patients who lost response to infliximab during maintenance, infliximab dose escalation enabled recovery of short-term response in nearly 70% of patients. In the long term, 58% of patients maintained sustained clinical benefit, and 9 of 10 avoided colectomy. Short-term response was associated with an 86% reduction in the relative risk of colectomy. PMID- 26044831 TI - Clinical factors prolonging the operative time of flexible ureteroscopy for renal stones: a single-center analysis. AB - The objective of the study was to evaluate the clinical factors affecting the operative time of flexible ureteroscopy (fURS). We retrospectively evaluated 233 patients with renal stones who had been treated successfully and had stone-free status 3 months after fURS and holmium laser lithotripsy between December 2009 and December 2013 at a single institute. Operative time was divided into three periods (total, before fragmentation, and after starting fragmentation), and associations between possible factors and these periods were analyzed by a multivariate logistic regression model with backward selection. The mean total operative time was 74.0 +/- 32.0 min. There were significant differences in the following clinical factors: sex, body height, stone volume, maximum and mean Hounsfield units (HUs), diameter of the ureteral access sheath, and experience of the surgeon, between patients who underwent procedures with a total operative time of less or more than 90 min. A multivariate assessment revealed four independent factors influencing total operative time (P < 0.05): stone volume (P < 0.001), experience of the surgeon (P < 0.001), maximum HUs (P = 0.014), and lack of preoperative stenting (P = 0.027). Larger stone volume, lower experience level of the surgeon, higher HUs, and the absence of preoperative stenting were identified as parameters prolonging the total operative time of fURS and, in particular, the operative time after starting fragmentation. On the other hand, operative time before starting fragmentation, which represented the time required to identify the stone by ureteroscopy and insert the access sheath, was more difficult to predict preoperatively. PMID- 26044833 TI - A path of hope for organ transplantation in China? PMID- 26044832 TI - Outcomes of integrated home dialysis care: a multi-centre, multi-national registry study. AB - BACKGROUND: The 'integrated home dialysis' model involving initiation of peritoneal dialysis (PD) first followed by home haemodialysis (HHD) has previously been proposed as an optimal form of dialysis that maximizes the advantages of both modalities. While this model has great potential, its clinical outcomes, especially compared with direct HHD initiation, remain uncertain. METHODS: All incident home dialysis patients from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry between 2000 and 2012 were included. Propensity score matching was performed to evaluate patients initially treated with PD followed by HHD ('PD + HHD'), PD without subsequent transition to HHD ('PD only') and HHD without subsequent transition to PD ('HHD only'). The composite primary outcome was death and home dialysis technique failure (defined as transfer to facility haemodialysis for 90 days). Groups were compared using a Cox proportional hazards model. RESULTS: The 2:1 matched cohort included 84 patients in the 'PD + HHD' group, 168 patients in the 'HHD only' group and 168 patients in the 'PD only' group. Compared with the 'PD + HHD' group, death and home dialysis technique failure was similar for patients treated with 'HHD only' [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.52-1.62; P = 0.77] and higher for those treated with 'PD only' (HR 3.22, 95% CI 1.97-5.25; P < 0.001). CONCLUSION: Patients treated with PD first followed by HHD had a risk of death and home dialysis technique failure that was comparable to those treated with HHD as the only home dialysis modality and inferior to those treated with PD as the only home dialysis modality. These results support the 'integrated home dialysis model' in patients who initiate dialysis with PD. PMID- 26044834 TI - Volume regression of native polycystic kidneys after renal transplantation. AB - BACKGROUND: The natural course of native kidneys after renal transplantation (RT) or dialysis in patients with autosomal dominant polycystic kidney disease (ADPKD) remains poorly understood. METHODS: We measured the total volumes of native kidneys and liver in 78 and 68 ADPKD patients, respectively, who had pre transplant (within 2 years) and at least one post-transplant computed tomography (CT)/magnetic resonance imaging (MRI); in 40 patients with at least two post transplant but no pre-transplant CT/MRIs; in 9 patients on chronic hemodialysis with at least one CT/MRI before and after beginning dialysis; and in 5 patients who had no image before and more than one image after dialysis. The last imaging was used in patients with multiple studies. RESULTS: Mean total kidney volume (TKV) ( +/- SD) prior to transplantation was 3187 +/- 1779 mL in the 78 patients who had imaging before and after transplantation and decreased by 20.2, 28.6, 38.3 and 45.8% after 0.5-1 (mean 0.7), 1-3 (1.8), 3-10 (5.7) and >10 (12.6) years, respectively. In the multivariable analysis, time on dialysis prior to RT and time from baseline to transplantation were negatively associated with reduction in TKV, whereas estimated glomerular filtration rate (eGFR) after transplantation and time from transplantation were positively associated with percent reduction in TKV. In the 40 patients with imaging only after transplantation, TKV decreased by 3.2 +/- 16.3% between 7.2 +/- 6.0 and 11.2 +/- 6.8 years after transplantation (P < 0.001). TKV was 11.2 +/- 35.6% higher (P = NS) after a follow-up of 3.4 +/- 2.0 years in the 9 patients with imaging before and after initiation of hemodialysis and 3.4 +/- 40.2% lower (P = NS) in the 5 patients with imaging between 2.0 +/- 2.1 and 3.5 +/- 3.6 years after initiation of hemodialysis. In the 68 patients with liver measurements, volume increased by 5.8 +/- 17.9% between baseline and follow-up at 3.7 +/- 3.8 years after transplantation (P = 0.009). CONCLUSIONS: TKV of native polycystic kidneys decreases substantially after RT. The reduction occurs mainly during the early post-transplantation period and more slowly thereafter. PMID- 26044835 TI - Cell-cycle arrest and acute kidney injury: the light and the dark sides. AB - Acute kidney injury (AKI) is a common consequence of systemic illness or injury and it complicates several forms of major surgery. Two major difficulties have hampered progress in AKI research and clinical management. AKI is difficult to detect early and its pathogenesis is still poorly understood. We recently reported results from multi-center studies where two urinary markers of cell cycle arrest, tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) were validated for development of AKI well ahead of clinical manifestations--azotemia and oliguria. Cell-cycle arrest is known to be involved in the pathogenesis of AKI and this 'dark side' may also involve progression to chronic kidney disease. However, cell-cycle arrest has a 'light side' as well, since this mechanism can protect cells from the disastrous consequences of entering cell division with damaged DNA or insufficient bioenergetic resources during injury or stress. Whether we can use the light side to help prevent AKI remains to be seen, but there is already evidence that cell cycle arrest biomarkers are indicators of both sides of this complex physiology. PMID- 26044836 TI - Iohexol plasma clearance measurement in older adults with chronic kidney disease sampling time matters. AB - BACKGROUND: Accurate and precise measurement of GFR is important for patients with chronic kidney disease (CKD). Sampling time of exogenous filtration markers may have great impact on measured GFR (mGFR) results, but there is still uncertainty about optimal timing of plasma clearance measurement in patients with advanced CKD, for whom 24-h measurement is recommended. This satellite project of the Berlin Initiative Study evaluates whether 24-h iohexol plasma clearance reveals a clinically relevant difference compared with 5-h measurement in older adults. METHODS: In 104 participants with a mean age of 79 years and diagnosed CKD, we performed standard GFR measurement over 5 h (mGFR300) using iohexol plasma concentrations at 120, 180, 240 and 300 min after injection. With an additional sample at 1440 min, we assessed 24-h GFR measurement (mGFR1440). Study design was cross-sectional. Calculation of mGFR was conducted with a one compartment model using the Brochner-Mortensen equation to calculate the fast component. mGFR values were compared with estimated GFR values (MDRD, CKD-EPI, BIS1, Revised Lund-Malmo and Cockcroft-Gault). RESULTS: In all 104 subjects, mGFR1440 was lower than mGFR300 (23 +/- 8 versus 29 +/- 9 mL/min/1.73 m(2), mean +/- SD; P < 0.001). mGFR1440 was highly correlated with mGFR300 (r = 0.9). The mean absolute difference mGFR300 - mGFR1440 was 5.9 mL/min/1.73 m(2) corresponding to a mean percentage difference of 29%. In individuals with eGFRCKD EPI <= 30 mL/min/1.73 m(2), percentage difference of mGFR300 and mGFR1440 was even higher (35%). To predict mGFR1440 from mGFR300, we developed the correction formula: mGFR1440 = -2.175 + 0.871 * mGFR300 (1-fold standard error of estimate: +/-2.3 mL/min/1.73 m(2)). The GFR estimating equation with the best accuracy and precision compared with mGFR300 and mGFR1440 was the Revised Lund Malmo. CONCLUSIONS: In elderly CKD patients, measurement of iohexol clearance up to 5 h leads to a clinically relevant overestimation of GFR compared with 24-h measurement. In clinical care, this effect should be bore in mind especially for patients with considerably reduced GFR levels. A new correction formula has been developed to predict mGFR1440 from mGFR300. For accurate GFR estimates in elderly CKD patients, we recommend the Revised Lund Malmo equation. PMID- 26044838 TI - CHIVA: hemodynamic concept, strategy and results. AB - The first part of this review article provides the physiologic background that sustained the CHIVA principles development. Then the venous networks anatomy and flow patterns are described with pertinent sonographic interpretations, leading to the shunt concept description and to the consequent CHIVA strategy application. An in depth explanation into the hemodynamic conservative cure approach follows, together with pertinent review of the relevant literature. PMID- 26044837 TI - Recipient obesity and outcomes after kidney transplantation: a systematic review and meta-analysis. AB - BACKGROUND: The prevalence of obesity is increasing globally and is associated with chronic kidney disease and premature mortality. However, the impact of recipient obesity on kidney transplant outcomes remains unclear. This study aimed to investigate the association between recipient obesity and mortality, death censored graft loss and delayed graft function (DGF) following kidney transplantation. METHODS: A systematic review and meta-analysis was conducted using Medline, Embase and the Cochrane Library. Observational studies or randomized controlled trials investigating the association between recipient obesity at transplantation and mortality, death-censored graft loss and DGF were included. Obesity was defined as a body mass index (BMI) of >=30 kg/m(2). Obese recipients were compared with those with a normal BMI (18.5-24.9 kg/m(2)). Pooled estimates of hazard ratios (HRs) for patient mortality or death-censored graft loss and odds ratios (ORs) for DGF were calculated. RESULTS: Seventeen studies including 138 081 patients were analysed. After adjustment, there was no significant difference in mortality risk in obese recipients [HR = 1.24, 95% confidence interval (CI) = 0.90-1.70, studies = 5, n = 83 416]. However, obesity was associated with an increased risk of death-censored graft loss (HR = 1.06, 95% CI = 1.01-1.12, studies = 5, n = 83 416) and an increased likelihood of DGF (OR = 1.68, 95% CI = 1.39-2.03, studies = 4, n = 28 847). CONCLUSIONS: Despite having a much higher likelihood of DGF, obese transplant recipients have only a slightly increased risk of graft loss and experience similar survival to recipients with normal BMI. PMID- 26044839 TI - Vascular calcification biomarkers and peripheral arterial disease. AB - BACKGROUND: The aim of this study was to evaluate the association of the calcification regulators, osteopontin (OPN) and osteoprotegerin (OPG), which are involved in vascular calcification and atherosclerosis in patients with peripheral arterial disease (PAD). METHODS: A PubMed search of the English language literature was undertaken to identify articles that examine the role of the vascular calcification markers (OPN and OPG) in patients with PAD. The search retrieved 94 articles. After excluding non-relevant articles, only 11 studies qualified for review. RESULTS: In 8 studies, OPG levels were correlated with the presence, severity, and progression of PAD, whereas in one article, OPG levels were not significantly elevated. In 2 studies, OPN levels were associated with PAD and vascular stiffness. CONCLUSIONS: The results from clinical and experimental research regarding the role of vascular calcification markers in PAD are controversial, although most of the studies suggest a positive correlation. Larger studies are needed to determine the exact pathway of vascular calcification, mediated by calcification markers, in patients with PAD. PMID- 26044840 TI - Evaluation of functionality and biological response of the multilayer flow modulator in porcine animal models. AB - BACKGROUND: This study outlines the use of non-aneurysmal porcine animal models to study device functionality and biological response of the Multilayer Flow Modulator (MFM) (Cardiatis, Isnes, Belgium), with an emphasis on preclinical device functionality and biological response characteristics in an otherwise healthy aorta. METHODS: Twelve animals were implanted with the study device in the abdominal aorta, in 6 animals for 1 month and 6 animals for 6 months. Upon completion of the study period, each animal underwent a necropsy to examine how the implanted device had affected the artery and surrounding tissue. Neointima and stenosis formation were recorded via morphometry, and endothelialization via histopathological analysis. RESULTS: The MFM devices were delivered to their respective implantation sites without difficulty. Six of the implanted stents were oversized with percentages ranging from 2.6% to 18.8%. Statistical analysis was carried out and showed no significance between the regular sized stent group and oversized stent group for neointimal area (P=0.17), neointimal thickness (P=0.17), and percentage area stenosis (P=0.65). Histopathological findings showed in most areas flattened endothelium like cells lined the luminal surface of the neointima. Scanning electron microscopy also showed the devices were well tolerated, inciting only a minimal neointimal covering and little fibrin or platelet deposition. Neointimal thickness of 239.7+/-55.6 MUm and 318.3+/-130.4 MUm, and percentage area stenosis of 9.6+/-2.6% and 12.6+/-5% were recorded at 1 and 6 months respectively. No statistical differences were found between these results. CONCLUSION: The MFM devices were delivered to their respective implantation sites without difficulty and incited little neointimal and stenosis formation in the aorta, affirming its functionality and biocompatibility. PMID- 26044841 TI - Sulodexide suppresses inflammation in patients with chronic venous insufficiency. AB - AIM: According to previously performed studies, inflammation plays a crucial role in vein wall and leg tissue injury related to chronic venous insufficiency (CVI) development. Sulodexide (SUL) is a balanced mix of glycosaminoglycans with potential anticoagulant and profibrinolytic activity, also protecting endothelial cells and suppressing inflammatory reactions in various vascular disease-related conditions. The goal of the present study was to evaluate the anti-inflammatory action of SUL in patients with CVI. METHODS: The study was performed on a group of 11 patients with chronic venous disease (stage C5 according to CEAP classification). The mean age of the patients was 58.4+/-7.7 years, and none of them were diabetic. The patients were treated for 8 weeks with orally administered SUL (2 x 500 LSU/day). Blood samples were collected at the start and at the end of the study for measurement of MMP-9, IL-6 and monocyte chemoattractant protein-1 (MCP-1). Additionally, the effect of the obtained serum samples on the function of human venous endothelial cells (HVEC) in in-vitro culture was evaluated. RESULTS: After treatment with SUL, the serum concentration of MMP-9 (ng/mL) decreased from 6.50+/-3.48 to 5.41+/-1.36, P<0.05, and the concentration of IL-6 (pg/mL) decreased from 11.5+/-3.4 to 10.1+/-2.3, P<0.005. There was also a trend of decreased serum MCP-1 (pg/mL) from 31.3+/-23.0 before treatment to 27.1+/-10.7 at the end. Intracellular generation of oxygen-derived free radicals in HVEC maintained in in-vitro culture was lower in the serum samples collected after treatment with SUL: 3.09+/-0.35 abs/MUg protein vs. 3.63+/-0.32 abs/MUg protein, at the start, P<0.05. Synthesis of IL-6 was lower in HVEC exposed in vitro to serum collected at the end of SUL treatment: 1.02+/-0.31 ng/MUg cell protein vs. 1.32+/-0.41 ng/MUg cell protein before SUL treatment. The proliferation rate of HVEC was similar in serum collected at the beginning and at the end of SUL treatment. CONCLUSION: We conclude that treatment with SUL in patients with CVI reduces intravascular inflammation and is protective for the endothelial cells and for the extracellular matrix changes related to metalloproteinase expression. PMID- 26044843 TI - XXV Nordic-Baltic Congress of Cardiology. Tallinn, Estonia, June 4-6, 2015: Abstracts. PMID- 26044842 TI - Acute limb ischemia and anticoagulation in patients with history of atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the commonest source of arterial embolization causing acute limb ischemia (ALI). The aim of this study was to assess the adherence of anticoagulation in AF patients and the treatment of underdiagnosed AF patients, presenting with ALI in our service and to evaluate the risk factors associated with morbidity and mortality. METHODS: A retrospective analysis of prospectively collected data was carried out from 115 limbs of 112 consecutive patients presenting with ALI of AF origin from 2008 until 2012 to a tertiary vascular service. RESULTS: The mean transfer time to hospital was 12+/-8.5 h. On admission, only half of the patients were aware of having AF and only 67% of those patients were receiving oral anticoagulants at the time of their admission. Nearly all patients who were on Vitamin K Antagonists (VKA) had sub-therapeutic levels preoperatively on admission (92%). The 30-day postoperative mortality and morbidity rates were 1.7% and 47% respectively. The lower limb amputation rate was 4.4% and was only associated with diabetes mellitus (DM) (P=0.009553). Reversible renal impairment was correlated with increased creatinine phosphokinase (CPK) blood levels on admission (P=0.038). CONCLUSIONS: A considerable number of patients with AF might still remain without proper anticoagulation. DM increases the risk of lower limb loss after ALI. Development of renal impairment after thromboembolectomy for ALI is more likely in the presence of elevated CPK blood levels on admission. PMID- 26044844 TI - Prevalence and correlates of tobacco use among school-going adolescents in Madagascar. AB - Approximately 90% of adults start smoking during adolescence, with limited studies conducted in low-and-middle-income countries where over 80% of global tobacco users reside. The study aims to estimate prevalence and identify predictors associated with adolescents' tobacco use in Madagascar. We utilized tobacco-related information of 1184 school-going adolescents aged 13-15 years, representing a total of 296,111 youth from the 2008 Madagascar Global Youth Tobacco Survey to determine the prevalence of tobacco use. Gender-wise multivariable logistic regression models were conducted to identify key predictors. Approximately 19% (30.7% males; 10.2% females) of adolescents currently smoke cigarettes, and 7% (8.5% males and 5.8% females) currently use non-cigarette tobacco products. Regardless of sex, peer smoking behavior was significantly associated with increased tobacco use among adolescents. In addition, exposures to tobacco industry promotions, secondhand smoke (SHS) and anti-smoking media messages were associated with tobacco use. The strong gender gap in the use of non-cigarette tobacco products, and the role of peer smoking and industry promotions in adolescent females' tobacco use should be of major advocacy and policy concern. A comprehensive tobacco control program integrating parental and peer education, creating social norms, and ban on promotions is necessary to reduce adolescents' tobacco use. PMID- 26044845 TI - Preparation of Highly Monodisperse Monopatch Particles with Orthogonal Click-Type Functionalization and Biorecognition. AB - Patchy particles are next generation colloidal building blocks for self-assembly and find further use as (bio) sensors. Progress in this direction crucially depends on developing straightforward preparation pathways able to provide patchy particles with highest uniformity and integrating precise, orthogonal, and spatially localized functionalizations to mediate interaction patterns. This continues to be one of the great challenges in colloid science. Herein, a method is shown utilizing functionalized random and block copolymers as microcontact printing inks to prepare patchy particles with outstanding control over patch size and quality. The polymeric nature and tight covalent attachment of the ink prevents flow of the ink over the particle during printing. This minimizes patch broadening and yields very small and extremely uniform patches, which is especially challenging for particle sizes below 10 MUm. Click-type (amine/active ester, alkyne/azide, biotin/avidin) reactions can be performed selectively on the patch or on the particle body, rendering the particles interesting for application in imaging, biomolecular detection, and as advanced precision colloid based building blocks. PMID- 26044846 TI - Impact of cysteine variants on the structure, activity, and stability of recombinant human alpha-galactosidase A. AB - Recombinant human alpha-galactosidase A (rhalphaGal) is a homodimeric glycoprotein deficient in Fabry disease, a lysosomal storage disorder. In this study, each cysteine residue in rhalphaGal was replaced with serine to understand the role each cysteine plays in the enzyme structure, function, and stability. Conditioned media from transfected HEK293 cells were assayed for rhalphaGal expression and enzymatic activity. Activity was only detected in the wild type control and in mutants substituting the free cysteine residues (C90S, C174S, and the C90S/C174S). Cysteine-to-serine substitutions at the other sites lead to the loss of expression and/or activity, consistent with their involvement in the disulfide bonds found in the crystal structure. Purification and further characterization confirmed that the C90S, C174S, and the C90S/C174S mutants are enzymatically active, structurally intact and thermodynamically stable as measured by circular dichroism and thermal denaturation. The purified inactive C142S mutant appeared to have lost part of its alpha-helix secondary structure and had a lower apparent melting temperature. Saturation mutagenesis study on Cys90 and Cys174 resulted in partial loss of activity for Cys174 mutants but multiple mutants at Cys90 with up to 87% higher enzymatic activity (C90T) compared to wild type, suggesting that the two free cysteines play differential roles and that the activity of the enzyme can be modulated by side chain interactions of the free Cys residues. These results enhanced our understanding of rhalphaGal structure and function, particularly the critical roles that cysteines play in structure, stability, and enzymatic activity. PMID- 26044848 TI - Congenital Brain Tumor within the First 2 Months of Life. AB - Congenital brain tumors (CBTs), defined as tumors presenting within 60 days after birth, are extremely rare and account for only 0.5-1.9% of all pediatric brain tumors. Teratoma is the most common type of CBT, although there are many other poorly described forms. Prenatal diagnosis of CBT is often difficult and usually based on clinical characteristics and radiological findings with magnetic resonance imaging and ultrasonography. The prognosis of patients with CBT depends on the histopathological features of the tumor and its location. Even after several investigations have been performed, a clear direction for diagnosis and treatment of fetal intracranial tumors is still lacking. Further studies are thus needed to clarify its clinical characteristics and establish recommendations for management. PMID- 26044847 TI - Myoepithelial and luminal breast cancer cells exhibit different responses to all trans retinoic acid. AB - PURPOSE: Breast cancer is the leading cause of death among women worldwide. The exact role of luminal epithelial (LEP) and myoephitelial (MEP) cells in breast cancer development is as yet unclear, as also how retinoids may affect their behaviour. Here, we set out to evaluate whether retinoids may differentially regulate cell type-specific processes associated with breast cancer development using the bi-cellular LM38-LP murine mammary adenocarcinoma cell line as a model. MATERIALS AND METHODS: The bi-cellular LM38-LP murine mammary cell line was used as a model throughout all experiments. LEP and MEP subpopulations were separated using inmunobeads, and the expression of genes known to be involved in epithelial to mysenchymal transition (EMT) was assessed by qPCR after all-trans retinoic acid (ATRA) treatment. In vitro invasive capacities of LM38-LP cells were evaluated using 3D Matrigel cultures in conjunction with confocal microscopy. Also, in vitro proliferation, senescence and apoptosis characteristics were evaluated in the LEP and MEP subpopulations after ATRA treatment, as well as the effects of ATRA treatment on the clonogenic, adhesive and invasive capacities of these cells. Mammosphere assays were performed to detect stem cell subpopulations. Finally, the orthotopic growth and metastatic abilities of LM38 LP monolayer and mammosphere-derived cells were evaluated in vivo. RESULTS: We found that ATRA treatment modulates a set of genes related to EMT, resulting in distinct gene expression signatures for the LEP or MEP subpopulations. We found that the MEP subpopulation responds to ATRA by increasing its adhesion to extracellular matrix (ECM) components and by reducing its invasive capacity. We also found that ATRA induces apoptosis in LEP cells, whereas the MEP compartment responded with senescence. In addition, we found that ATRA treatment results in smaller and more organized LM38-LP colonies in Matrigel. Finally, we identified a third subpopulation within the LM38-LP cell line with stem/progenitor cell characteristics, exhibiting a partial resistance to ATRA. CONCLUSIONS: Our results show that the luminal epithelial (LEP) and myoephitelial (MEP) mammary LM38-P subpopulations respond differently to ATRA, i.e., the LEP subpopulation responds with increased cell cycle arrest and apoptosis and the MEP subpopulation responds with increased senescence and adhesion, thereby decreasing its invasive capacity. Finally, we identified a third subpopulation with stem/progenitor cell characteristics within the LM38-LP mammary adenocarcinoma cell line, which appears to be non-responsive to ATRA. PMID- 26044849 TI - Analysis of angiogenic markers in oral squamous cell carcinoma-gene and protein expression. AB - PURPOSE: Therapeutic strategies attacking oral squamous cell carcinoma have not essentially succeeded to improve long-term prognosis and overall survival over the last decades. Therefore, in this study, we aimed to illuminate the molecular regulation of angiogenesis in this tumour entity in order to demask novel markers of prognosis or therapeutic approach. MATERIALS AND METHODS: A panel of significant transcriptional alterations in angiogenic genes of 83 cancer samples was established by comparison to 30 samples of healthy oral mucosa with microarray technique. Immunohistochemistry (IHC) was performed to trace the signalling cascade from gene to protein level. RESULTS: A distinctive expression profile of VEGFA, EFNB2, PECAM1/CD31, ANGPT1 and ANGPT2 was revealed: VEGFA, EFNB2, and ANGPT2 were found overexpressed in 84 % to 95 % of tumour samples. In contrast, the expression of CD31 and ANGPT1 was downregulated in 80 % to 95 % of tumour samples. IHC confirmed results of the microarray analysis. Tumours with lymphatic spread showed higher gene expression rates of VEGFA, EFNB2 and ANGPT2 in moderately differentiated tumours and of VEGFA and EFNB2 in small tumours, respectively. The ANGPT1/ ANGPT2 transcription ratio was found decreased in larger tumours and especially in tumours without lymphatic spread. CONCLUSIONS: A characteristic expression profile of angiogenic markers was established. The specific overexpression of EFNB2 in small tumours with lymphatic spread and the typical decrease of the ANGPT1/ ANGPT2 ratio in larger tumours give weight to EFNB2 and angiopoietins as prognostic factors and potential therapeutic targets. PMID- 26044850 TI - A Review of Realizing the Universal Health Coverage (UHC) Goals by 2030: Part 1- Status quo, Requirements, and Challenges. AB - This paper is the first part of a review of how to realize the Universal Health Coverage (UHC) goals by 2030. The objective of this review is to investigate the role of eHealth and technology in achieving UHC, focusing on four aspects: 1) identifying the importance of UHC and highlighting how UHC is influenced by health systems and eHealth, 2) investigating the current status of UHC worldwide and indicating the current challenges facing the realization of UHC, 3) reviewing the current research activities in the UHC domain and emphasizing the role of eHealth and technology in achieving UHC, and 4) discussing the results of the review to identify the current gaps in UHC implantation and the corresponding research lines for future investigation.This part covers the first two aspects through: providing the required background on UHC, highlighting the potential benefits of eHealth utilization in UHC, addressing the current status quo of UHC implementation worldwide, and finally concluding the lessons learned in terms of the UHC challenges and requirements.This part also described the used search methodology and selection criteria to synthesize this review. It also indicates the limitations of conducting a systematic review in this early stage of deploying UHC-oriented eHealth solutions. PMID- 26044851 TI - A Review of Realizing the Universal Health Coverage (UHC) Goals by 2030: Part 2- What is the Role of eHealth and Technology? AB - This paper is the second part of a review of how to realize the Universal Health Coverage (UHC) goals by 2030. The objective of this review is to investigate the role of eHealth and technology in achieving UHC, focusing on four aspects: 1) identifying the importance of UHC and highlighting how UHC is influenced by health systems and eHealth, 2) investigating the current status of UHC worldwide and indicating the current challenges facing the realization of UHC, 3) reviewing the current research activities in the UHC domain and emphasizing the role of eHealth and technology in achieving UHC, and 4) discussing the results of the review to identify the current gaps in UHC implantation and the corresponding research lines for future investigation. This part covers the last two aspects through providing a comprehensive understanding of the role of eHealth in the current research activities in the UHC domain. Specifically, eHealth can be extensively deployed in connecting the healthcare information systems, strengthening the health systems, building the health workforce capacity, in addition to forming frameworks of integrated mHealth strategies for achieving UHC. PMID- 26044852 TI - IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-alpha expression in monocytes: Implications for chronic obstructive pulmonary disease. AB - BACKGROUND: IL-10 is well known for its ability to block the expression and production of numerous proinflammatory cytokines, in this manner preventing the development of excessive or chronic immune activation. IL-10-induced transcriptional repression of CXCL8 and TNFA genes consists of 2 distinct phases: an early phase, occurring rapidly and in a protein synthesis-independent manner, followed by a second phase that is more delayed and dependent on protein synthesis. OBJECTIVE: We sought to identify the mechanisms through which IL-10 rapidly and directly suppresses LPS-induced CXCL8 and TNF-alpha transcription, which might be defective under pathologic conditions. METHODS: The molecular events triggered by IL-10 in LPS-activated monocytes at the CXCL8 and TNFA loci were investigated by using the chromatin immunoprecipitation assay. RESULTS: Inhibition of LPS-induced CXCL8 and TNF-alpha expression by IL-10 proceeds through a common mechanism targeting LPS-induced phosphorylation of the nuclear factor kappaB p65 serine 276 residue (pS276p65). As a result, all the pS276p65 dependent events occurring at the CXCL8 and TNFA loci are consistently reduced, ultimately leading to a reduction in transcript elongation. Additionally, IL-10 selectively controls CXCL8 transcript elongation through histone deacetylase (HDAC) 2-dependent covalent chromatin modifications, disrupting the assembly of the transcriptional machinery. Remarkably, PBMCs from patients with acute-phase chronic obstructive pulmonary disease, which express negligible HDAC2 levels, are scarcely affected by IL-10 in terms of inhibition of CXCL8 expression. CONCLUSIONS: This study provides mechanistic evidence that IL-10 creates a chromatin environment that decreases the transcriptional rate of CXCL8 and TNF alpha to Toll-like receptor 4-activating signals. Data identify novel molecular targets for therapeutic strategies aimed at dampening inflammation in pathologies such as chronic obstructive pulmonary disease, in which reduced intracellular HDAC2 levels have been described. PMID- 26044853 TI - Probiotics for the prevention of allergy: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Allergic diseases are considered a health burden because of their high and constantly increasing prevalence, high direct and indirect costs, and undesirable effects on quality of life. Probiotics have been suggested as an intervention to prevent allergic diseases. OBJECTIVE: We sought to synthesize the evidence supporting use of probiotics for the prevention of allergies and inform World Allergy Organization guidelines on probiotic use. METHODS: We performed a systematic review of randomized trials assessing the effects of any probiotic administered to pregnant women, breast-feeding mothers, and/or infants. RESULTS: Of 2403 articles published until December 2014 identified in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, 29 studies fulfilled a priori specified inclusion criteria for the analyses. Probiotics reduced the risk of eczema when used by women during the last trimester of pregnancy (relative risk [RR], 0.71; 95% CI, 0.60-0.84), when used by breast-feeding mothers (RR, 0.57; 95% CI, 0.47-0.69), or when given to infants (RR, 0.80; 95% CI, 0.68-0.94). Evidence did not support an effect on other allergies, nutrition status, or incidence of adverse effects. The certainty in the evidence according to the Grading of Recommendation Assessment Development and Evaluation approach is low or very low because of the risk of bias, inconsistency and imprecision of results, and indirectness of available research. CONCLUSION: Probiotics used by pregnant women or breast-feeding mothers and/or given to infants reduced the risk of eczema in infants; however, the certainty in the evidence is low. No effect was observed for the prevention of other allergic conditions. PMID- 26044854 TI - Exacerbation of atopic dermatitis on grass pollen exposure in an environmental challenge chamber. AB - BACKGROUND: It has frequently been speculated that pruritus and skin lesions develop after topical exposure to aeroallergens in sensitized patients with atopic dermatitis (AD). OBJECTIVE: We sought to study cutaneous reactions to grass pollen in adult patients with AD with accompanying clear IgE sensitization to grass allergen in an environmental challenge chamber using a monocenter, double-blind, placebo-controlled study design. METHODS: Subjects were challenged on 2 consecutive days with either 4000 pollen grains/m(3) of Dactylis glomerata pollen or clean air. The severity of AD was assessed at each study visit up to 5 days after challenge by (objective) scoring of AD (SCORAD). Additionally, air exposed and non-air-exposed skin areas were each scored using local SCORAD scoring and investigator global assessments. Levels of a series of serum cytokines and chemokines were determined by using a Luminex-based immunoassay. The primary end point of the study was the change in objective SCORAD scores between prechallenge and postchallenge values. RESULTS: Exposure to grass pollen induced a significant worsening of AD. A pronounced eczema flare-up of air exposed rather than covered skin areas occurred. In grass pollen-exposed subjects a significantly higher increase in CCL17, CCL22, and IL-4 serum levels was observed. CONCLUSIONS: This study demonstrates that controlled exposure to airborne allergens of patients with a so-called extrinsic IgE-mediated form of AD induced a worsening of cutaneous symptoms. PMID- 26044857 TI - Erratum. PMID- 26044855 TI - Safety, clinical, and immunologic efficacy of a Chinese herbal medicine (Food Allergy Herbal Formula-2) for food allergy. AB - BACKGROUND: Food Allergy Herbal Formula-2 (FAHF-2) is a 9-herb formula based on traditional Chinese medicine that blocks peanut-induced anaphylaxis in a murine model. In phase I studies FAHF-2 was found to be safe and well tolerated. OBJECTIVE: We sought to evaluate the safety and effectiveness of FAHF-2 as a treatment for food allergy. METHODS: In this double-blind, randomized, placebo controlled study 68 subjects aged 12 to 45 years with allergies to peanut, tree nut, sesame, fish, and/or shellfish, which were confirmed by baseline double blind, placebo-controlled oral food challenges (DBPCFCs), received FAHF-2 (n = 46) or placebo (n = 22). After 6 months of therapy, subjects underwent DBPCFCs. For those who demonstrated increases in the eliciting dose, a repeat DBPCFC was performed 3 months after stopping therapy. RESULTS: Treatment was well tolerated, with no serious adverse events. By using intent-to-treat analysis, the placebo group had a higher eliciting dose and cumulative dose (P = .05) at the end-of treatment DBPCFC. There was no difference in the requirement for epinephrine to treat reactions (P = .55). There were no significant differences in allergen specific IgE and IgG4 levels, cytokine production by PBMCs, or basophil activation between the active and placebo groups. In vitro immunologic studies performed on subjects' baseline PBMCs incubated with FAHF-2 and food allergen produced significantly less IL-5, greater IL-10 levels, and increased numbers of regulatory T cells than untreated cells. Notably, 44% of subjects had poor drug adherence for at least one third of the study period. CONCLUSION: FAHF-2 is a safe herbal medication for subjects with food allergy and shows favorable in vitro immunomodulatory effects; however, efficacy for improving tolerance to food allergens is not demonstrated at the dose and duration used. PMID- 26044856 TI - Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. AB - BACKGROUND: The management of children with pediatric mastocytosis poses a challenge. This is because there is limited information as to the application of clinical and laboratory findings and bone marrow histopathology as they relate to medical intervention and communication. OBJECTIVE: We sought to examine clinical aspects of pediatric mastocytosis in relationship to serum tryptase levels and bone marrow pathology to provide practical guidance for management. METHODS: Between 1986 and 2012, 105 children were evaluated at the National Institutes of Health. Organomegaly was confirmed by means of ultrasound. Baseline tryptase levels and at least 1 subsequent tryptase measurement was available in 84 and 37 of these children, respectively. Fifty-three children underwent a bone marrow examination. These data were used to examine relationships between clinical findings, tryptase levels, and marrow histopathology. RESULTS: In patients with high tryptase levels and severe mediator symptoms, all with organomegaly had systemic disease, and none without organomegaly had systemic disease. Serum tryptase levels differed significantly between patients with urticaria pigmentosa and those with diffuse cutaneous (P < .0001) and systemic mastocytosis (P < .0001) and in all 3 categories versus control subjects (P < .0001). Tryptase levels and symptoms decreased over time in most patients, and tryptase levels correlated with bone marrow mast cell burden in patients with systemic mastocytosis (P < .0001). There was a significant relationship between clinical resolution and the percentage decrease in tryptase levels (P = .0014). CONCLUSIONS: The majority of children experienced major or complete disease resolution (57%), whereas the remainder exhibited partial improvement. Organomegaly was a strong indicator of systemic disease. Serum tryptase levels furthered classification and reflected clinicopathologic findings, while sequential tryptase measurements were useful in supplementing clinical judgment as to disease course. PMID- 26044858 TI - Data integration: Combined imaging and electrophysiology data in the cloud. AB - There has been an increasing effort to correlate electrophysiology data with imaging in patients with refractory epilepsy over recent years. IEEG.org provides a free-access, rapidly growing archive of imaging data combined with electrophysiology data and patient metadata. It currently contains over 1200 human and animal datasets, with multiple data modalities associated with each dataset (neuroimaging, EEG, EKG, de-identified clinical and experimental data, etc.). The platform is developed around the concept that scientific data sharing requires a flexible platform that allows sharing of data from multiple file formats. IEEG.org provides high- and low-level access to the data in addition to providing an environment in which domain experts can find, visualize, and analyze data in an intuitive manner. Here, we present a summary of the current infrastructure of the platform, available datasets and goals for the near future. PMID- 26044859 TI - Gesture and word analysis: the same or different processes? AB - The present study aimed at determining whether elaboration of communicative signals (symbolic gestures and words) is always accompanied by integration with each other and, if present, this integration can be considered in support of the existence of a same control mechanism. Experiment 1 aimed at determining whether and how gesture is integrated with word. Participants were administered with a semantic priming paradigm with a lexical decision task and pronounced a target word, which was preceded by a meaningful or meaningless prime gesture. When meaningful, the gesture could be either congruent or incongruent with word meaning. Duration of prime presentation (100, 250, 400 ms) randomly varied. Voice spectra, lip kinematics, and time to response were recorded and analyzed. Formant 1 of voice spectra, and mean velocity in lip kinematics increased when the prime was meaningful and congruent with the word, as compared to meaningless gesture. In other words, parameters of voice and movement were magnified by congruence, but this occurred only when prime duration was 250 ms. Time to response to meaningful gesture was shorter in the condition of congruence compared to incongruence. Experiment 2 aimed at determining whether the mechanism of integration of a prime word with a target word is similar to that of a prime gesture with a target word. Formant 1 of the target word increased when word prime was meaningful and congruent, as compared to meaningless congruent prime. Increase was, however, present for whatever prime word duration. Experiment 3 aimed at determining whether symbolic prime gesture comprehension makes use of motor simulation. Transcranial Magnetic Stimulation was delivered to left primary motor cortex 100, 250, 500 ms after prime gesture presentation. Motor Evoked Potential of First Dorsal Interosseus increased when stimulation occurred 100 ms post-stimulus. Thus, gesture was understood within 100 ms and integrated with the target word within 250 ms. Experiment 4 excluded any hand motor simulation in order to comprehend prime word. Thus, the same type of integration with a word was present for both prime gesture and word. It was probably successive to understanding of the signal, which used motor simulation for gesture and direct access to semantics for words. PMID- 26044860 TI - The NITRC image repository. AB - The Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC - www.nitrc.org) suite of services include a resources registry, image repository and a cloud computational environment to meet the needs of the neuroimaging researcher. NITRC provides image-sharing functionality through both the NITRC Resource Registry (NITRC-R), where bulk data files can be released through the file release system (FRS), and the NITRC Image Repository (NITRC-IR), a XNAT based image data management system. Currently hosting 14 projects, 6845 subjects, and 8285 MRI imaging sessions, NITRC-IR provides a large array of structural, diffusion and resting state MRI data. Designed to be flexible about management of data access policy, NITRC provides a simple, free, NIH-funded service to support resource sharing in general, and image sharing in particular. PMID- 26044861 TI - Parallelization of enumerating tree-like chemical compounds by breadth-first search order. AB - Enumeration of chemical compounds greatly assists designing and finding new drugs, and determining chemical structures from mass spectrometry. In our previous study, we developed efficient algorithms, BfsSimEnum and BfsMulEnum for enumerating tree-like chemical compounds without and with multiple bonds, respectively. For many instances, our previously proposed algorithms were able to enumerate chemical structures faster than other existing methods. PMID- 26044862 TI - Syringetin suppresses osteoclastogenesis mediated by osteoblasts in human lung adenocarcinoma. AB - Bone metastasis in lung cancer results in an unfavorable outcome for patients by not only impairing the quality of life, yet also increasing the cancer-related death rates. In the present study, we discuss a novel treatment strategy that may benefit these patients. Human CD14+ monocytes treated with macrophage-colony stimulating factor (M-CSF)/receptor activator of nuclear factor kappaB ligand (RANKL) differentiated into osteoclasts, whereas syringetin (SGN), a flavonoid derivative found in both grapes and wine, suppressed the osteoclastogenesis in vitro in a dose-dependent manner. In addition, SGN inhibited osteoclast formation induced by human lung adenocarcinoma A549 and CL1-5 cells. The associated signaling transduction pathway in osteoclastogenesis and SGN inhibition was found to be via the AKT/mammalian target of rapamycin (mTOR) signaling pathway. Blocking AKT and mTOR by respective inhibitors significantly decreased lung adenocarcinoma-mediated osteoclastogenesis. Moreover, SGN regulated the lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts by suppressing the stimulatory effect of lung adenocarcinoma on M-CSF and RANKL production in osteoblasts, and reversing the inhibitory effect of the lung adenocarcinoma on OPG production in osteoblasts. The present study has two novel findings. It is the first to illustrate lung adenocarcinoma-mediated interaction between osteoblasts and osteoclasts, leading to osteolytic bone metastasis. It also reveals that SGN, a flavonoid derivative, directly inhibits osteoclastogenesis and reverses lung adenocarcinoma-mediated osteoclastogenesis. In conclusion, the present study suggests that SGN, a natural compound, prevents and treats bone metastasis in patients with lung cancer. PMID- 26044863 TI - A Simple and Rapid Method for Expression and Purification of Functional TNF-alpha Using GST Fusion System. AB - Tumor necrosis factor alpha (TNF-alpha) is an inflammatory cytokine, involved in both physiological and pathological pathways. Although there have been various attempts to express and purify human TNF-alpha, the current work introduces a simple, rapid, and efficient method for its production without loss of biological activity. The protein was expressed based on GST-tagged fusion system in Escherichia coli under optimized condition. The expressed GST fusion protein was applied to glutathione affinity column and then, TNF-alpha was cleaved off the GST using thrombin protease. The purity of the product was more than 95% and further size exclusion chromatography slightly improved the purity. The purified human TNF-alpha was tested for its biological activity and structural analysis, using MTT assay (EC(50) of 4.1 *10E-12 M in L929 cell death assay) and circular dichroism spectropolarimetry, respectively. The results showed that the method used in this study enables successful production of highly purified and fully functional TNF-alpha. PMID- 26044864 TI - Improving of nutraceutical features of many important mediterranean vegetables by inoculation with a new commercial product. AB - Several epidemiological studies show that fruits, vegetables and cereals can play a nutraceutical role for their content of many antioxidant phytochemicals such as carotenoids, ascorbic acid and phenolics. A commercial inoculant (MICOSAT F((r))) containing arbuscular mycorrhizal fungi (AMF) could improve the nutritional value in crops. The goal of this work was to evaluate the effect of AMF on the production level of carotenoids, AsA, phenols including antocyanins and saponins, proteins, total antioxidant activity and nitrates in fruits, vegetables, legumes and durum wheat var. grecale, whose consumption is largely recommended according to Mediterranean diet. The treatment increased the antioxidant activity in strawberries (37.50%), in giant lentils (29.17%) and in durum wheat (63.63%) but decreased it in kiwi (31.81%) and in grape (19.81%). Nitrate levels decreased significantly in strawberries (39.78%) and in tomato intended for transformation (37.79%). The application of MICOSAT F((r)) enhanced the levels of several secondary metabolites. However, the amount of phytochemicals and respective by products were reduced in some cases. Environmental conditions and modality of AMF inoculation could module both primary and secondary metabolites. PMID- 26044865 TI - Mycofabrication of gold nanoparticles and evaluation of their antioxidant activities. AB - Gold nanoparticles have found prominence in pharmaceutical applications due to their unique physical properties as well as their inert nature. Mycosynthesis of noble metal nanoparticles is less stringent and eco-friendly. In this paper, we have reported the economically-viable synthesis of gold nanoparticles, mediated by five different fungal strains Aspergillus flavus NCIM650, Phoma exigua NCIM1237, Aspergillus niger NCIM 616, Aspergillus niger NCIM 1025 and Trichoderma reesei NCIM 1186. An efficient approach for fungal growth was discussed wherein the biomass was cultivated in non-limiting conditions, followed by addition of gold salt solution. Cyclic Voltammetry studies were conducted to show the varying reducing capacities of these strains. The surface plasmon peaks for gold nanoparticles produced by Aspergillus flavus NCIM650, Phoma exigua NCIM1237, Aspergillus niger NCIM 616, Aspergillus niger NCIM 1025 and Trichoderma reesei NCIM 1186 were recorded as 536nm, 543nm, 542nm, 560nm, 537nm respectively. Based on the cyclic voltammetry studies and UV-Visible spectroscopy, transmission electron microscopy (TEM) analysis was done. Among the five strains, gold nanoparticles fabricated by Aspergillus niger NCIM 616 gave quite promising results. The antioxidant activities were evaluated using DPPH quenching assay and hydrogen peroxide assay. PMID- 26044866 TI - Neuroendocrine adaptations to bariatric surgery. AB - The global epidemic of obesity and its related disease in combination with robust physiological defence of intentional weight loss generates a pressing need for effective weight loss therapies. Bariatric surgery, which works very effectively at delivering substantial sustained weight loss, has been an enigma with respect to mechanism of action. Naive concepts of restriction and malabsorption do not explain the efficacy of the most commonly used bariatric procedures. This century has seen increased interest in unravelling the mystery of the mechanisms underlying surgery associated weight loss with a focus on integrative gastrointestinal (GI) physiology, gut-brain signalling, and beyond weight loss effects on metabolism. GI interventions, some very minor, can alter GI wall stretch and pressure receptors; a range of GI hormones affecting hunger and satiety; bile acid metabolism and signalling; the characteristics of GI microbiome; portal vein nutrient sensing; and circulating concentrations of amino acids. Understanding the mechanisms involved should present targets for less invasive effective therapies. PMID- 26044867 TI - In vitro interactions between mammary fibroblasts (Hs 578Bst) and cancer epithelial cells (MCF-7) modulate aromatase, steroid sulfatase and 17beta hydroxysteroid dehydrogenases. AB - Our objectives were to investigate the interactions between mammary cancer epithelial cells (MCF-7) and stromal cells (Hs-578Bst) at the level of the expression and inhibition of steroidogenesis enzymes by using monolayer and three dimensional co-culture models. Expressions of steroidogenesis enzymes and E2/DHT conversions in co-cultured MCF-7 and Hs-578Bst cells as well as the effects of aromatase inhibitor combined to steroid sulfatase (STS) and 17beta-hydroxysteroid dehydrogenases (17betaHSDs) inhibitors were evaluated. 17beta-HSD type 7 was mostly modulated in MCF-7 cells whereas aromatase was mostly regulated in Hs578Bst cells thereby increasing E2 conversion and MCF-7 cell growth. A combination of inhibitors toward aromatase, STS and 17beta-HSD7, was found to be the most significant treatment in decreasing E2 and elevating DHT thus inhibiting MCF-7 cell proliferation and spheroid-like cancer cell aggregation in collagen gel. The interactions between those cells modulated E2 formation in paracrine/intracrine manners by synergistically regulating aromatase, 17beta-HSD7 and STS. Among tumor-associated cells, stromal fibroblasts may participate in intratumoral E2 deposition; therefore promoting breast cancer cell growth. PMID- 26044868 TI - Downregulation of microRNA-210 inhibits osteosarcoma growth in vitro and in vivo. AB - MicroRNA-210 (miR-210), the master hypoxamir, has various roles in the development of certain cancer types. It has been reported that miR-210 expression was upregulated in patients with osteosarcoma (OS). However, little is known regarding its role in the development of human OS. In the present study, to explore the feasibility of miR-210 as an effective therapeutic target, miR-210 inhibitor was transfected into the osteosarcoma cell line MG-63 cells, and cell proliferation, colony formation, cycle, apoptosis, migration and invasion were assessed. It was found that miR-210 downregulation significantly suppressed clonogenicity, migration and invasion, as well as induced cell apoptosis, increased the percentage of cells in G1 phrase and decreased the percentage of cells in S phase in vitro. In addition, the effect of miR-210 on tumor growth was evaluated in vivo. The results indicated that miR-210 downregulation significantly suppressed tumor growth in nude mouse models. In conclusion, the findings of the present study suggested that miR-210 is a potential therapeutic agent for the treatment of OS. PMID- 26044869 TI - Experience of more than 100 preimplantation genetic diagnosis cycles for monogenetic diseases using whole genome amplification and linkage analysis in a single centre. AB - OBJECTIVE: To report the outcomes of more than 100 cycles of preimplantation genetic diagnosis for monogenetic diseases. DESIGN: Case series. SETTING: Tertiary assisted reproductive centre in Hong Kong, where patients needed to pay for the cost of preimplantation genetic diagnosis on top of standard in-vitro fertilisation charges. PATIENTS: Patients undergoing preimplantation genetic diagnosis for monogenetic diseases at the Centre of Assisted Reproduction and Embryology, Queen Mary Hospital-The University of Hong Kong between 1 August 2007 and 30 April 2014 were included. INTERVENTIONS: In-vitro fertilisation, intracytoplasmic sperm injection, embryo biopsy, and preimplantation genetic diagnosis. MAIN OUTCOME MEASURES: Ongoing pregnancy rate and implantation rate. RESULTS: Overall, 124 cycles of preimplantation genetic diagnosis were initiated in 76 patients, 101 cycles proceeded to preimplantation genetic diagnosis, and 92 cycles had embryo transfer. The ongoing pregnancy rate was 28.2% per initiated cycle and 38.0% per embryo transfer, giving an implantation rate of 35.2%. There were 16 frozen-thawed embryo transfer cycles in which, following preimplantation genetic diagnosis, cryopreserved embryos were replaced resulting in an ongoing pregnancy rate of 37.5% and implantation rate of 30.0%. The cumulative ongoing pregnancy rate was 33.1%. The most frequent indication for preimplantation genetic diagnosis was thalassaemia, followed by neurodegenerative disorder and cancer predisposition. There was no misdiagnosis. CONCLUSIONS: Preimplantation genetic diagnosis is a reliable method to prevent couples conceiving fetuses severely affected by known genetic disorders, with ongoing pregnancy and implantation rates similar to those for in-vitro fertilisation for routine infertility treatment. PMID- 26044870 TI - Avoiding hypoglycaemia: a new target of care for elderly diabetic patients. AB - Optimising glycaemic control to prevent diabetes-associated complications has received much attention. The associated risk of iatrogenic hypoglycaemia, however, is inevitable and can have a significant impact on health. The prevalence of iatrogenic hypoglycaemia tends to increase with advancing age. Elderly people are intrinsically prone to hypoglycaemia. Ageing attenuates the glucose counter-regulatory and symptomatic response to hypoglycaemia, particularly in the presence of a longer duration of diabetes. Multiple co morbidities and polypharmacy correlated with advancing age also increase the hypoglycaemic risk. In addition to the acute adverse effects of hypoglycaemia, such as fall with injury, cardiovascular events and mortality, a hypoglycaemic episode can have long-term consequences. Repeated episodes may have a significant psychological impact and are also a risk factor for dementia. Because of the heterogeneous health status of the elderly, not all will benefit from optimal glycaemic control. Setting an individual glycaemic target and formulating a management plan that takes account of the patient's circumstances combined with balancing the benefit and risk of diabetes intervention to avoid hypoglycaemia is a more practical approach to the management of elderly diabetic patients. PMID- 26044872 TI - The Addition of Inhaled Budesonide to Standard Therapy Shortens the Length of Stay in Hospital for Asthmatic Preschool Children: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Asthma exacerbations lead to frequent emergency visits and hospitalizations, and are associated with high morbidity and occasionally mortality. New therapeutic strategies are needed. We sought to investigate whether the addition of high-dose inhaled budesonide to standard therapy would shorten the length of stay (LOS) in hospital of children admitted for asthma exacerbations. METHODS: The study was designed as a single-center, double-blind, placebo-controlled and parallel-group trial. Children aged 7-72 months and admitted with an asthma exacerbation clinical asthma score (CAS) of between 3 and 9 were allocated to either the budesonide (n = 50) or the placebo (n = 50) group. Hospital LOS was compared between children who received 2 mg/day of budesonide versus placebo in addition to standard management of asthma exacerbation involving oxygen inhalation and beta2-agonist, anticholinergic and oral corticosteroid therapy. All patients were assessed every 4 h. Children with a CAS <3, a peripheral oxygen saturation >95% and normal pulmonary function, and those with a symptom-free period of at least 4 h after salbutamol treatment were discharged. RESULTS: Total hospital LOS was significantly shorter in the budesonide group than in the placebo group (median: 44 vs. 80 h, respectively; p = 0.01). When compared with placebo, the number of inpatients was significantly less in the budesonide group at all the assessed end points (Kaplan-Meier; p = 0.022). Additionally, nebulized budesonide was found to reduce the overall cost of treatment. CONCLUSION: We demonstrated that, for children hospitalized for asthma exacerbations, an additional 2 mg/day of nebulized budesonide significantly reduced hospital LOS as well as the overall cost of treatment. PMID- 26044871 TI - The HAB1 PP2C is inhibited by ABA-dependent PYL10 interaction. AB - PYL10 is a monomeric abscisic acid (ABA) receptor that inhibits protein phosphatase 2C (PP2C) activity in Arabidopsis thaliana. Previous studies reported that the PP2C phosphatase inhibition by PYL10 was ABA-independent. Here, systematic PYL10 biochemical studies demonstrated that PYL10 activity was ABA dependent, and the previously reported studies was interfered by the presence of BSA in the commercial kit. To investigate dynamic mechanism of how ABA binding to PYL10 induces PP2C phosphatase inhibiting activity, solution NMR relaxation analysis of apo-PYL10 and PYL10/ABA were conducted following backbone resonance assignments. Reduced spectrum density mapping of the backbone relaxation data revealed that PYL10 was more flexible in ABA bound form than apo-PYL10, indicating an increased conformational entropy upon ligand binding. Moreover, to illustrate conformation exchanges of PYL10 upon ABA binding, NMR line shape analysis was performed with increasing concentrations of ABA, and the results indicated that PYL10 backbone conformational changes occur at different time scales. PMID- 26044873 TI - High intensity focused ultrasound ablation for submucosal fibroids: A comparison between type I and type II. AB - OBJECTIVE: The aim of this study was to compare high-intensity focused ultrasound (HIFU) treatment for type I and type II submucosal fibroids. MATERIALS AND METHODS: From October 2011 to October 2013, 55 patients with submucosal fibroids were enrolled in this study. Based on submucosal fibroid classification, 27 patients were grouped as type I submucosal fibroids, and 28 patients were classified as type II submucosal fibroids. All patients received HIFU treatment and completed 1-, 6-, and 12-month follow-ups. Adverse effects were recorded. RESULTS: There were no significant differences in the baseline characteristics between the two groups (p > 0.05). Using similar sonication power, sonication time, and acoustic energy, the non-perfused volume (NPV) ratio was 83.0 +/- 17.3% in the type I group, and 92.0 +/- 9.5% in the type II group. All the patients tolerated the procedure well, and no serious adverse events occurred. During the follow-up intervals, the treated fibroids shrank and fibroid-related symptoms were relieved. No other reinterventional procedures were performed during the follow-up period. CONCLUSION: Based on our results with a small number of subjects, HIFU is suitable for both type I and type II submucosal fibroids. It seems that type II submucosal fibroids are more sensitive to HIFU ablation. Future studies with larger sample sizes and longer follow-up times to investigate the long-term results, including long-term symptom relief, pregnancy outcomes, and the recurrence rate as well as the reintervention rate are needed. PMID- 26044874 TI - Polysaccharide peptide from Coriolus versicolor induces interleukin 6-related extension of endotoxin fever in rats. AB - PURPOSE: Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. In a previous study we showed that PSP induced a tumour necrosis factor-alpha (TNF-alpha)-dependent anapyrexia-like response in rats. Thus, PSP appears to be a factor which modifies a number of pathophysiological responses. Because of this, PSP is suggested as a potential adjuvant for cancer therapy during which cancer patients frequently contract microbial infections accompanied by fever. The aim of the present study was to investigate whether or not PSP can modulate the course of the fever in response to an antigen such as lipopolysaccharide (LPS). MATERIALS AND METHODS: Body temperature (Tb) of male Wistar rats was measured by biotelemetry. PSP was injected intraperitoneally (i.p.) at a dose of 100 mg kg(-1), 2 h before LPS administration (50 ug kg(-1), i.p.). The levels of interleukin (IL)-6 and TNF-alpha in the plasma of rats were estimated 3 h and 14 h post-injection of PSP using a standard sandwich ELISA kit. RESULTS: We report that i.p. pre-injection of PSP 2 h before LPS administration expanded the duration of endotoxin fever in rats. This phenomenon was accompanied by a significant elevation of the blood IL-6 level of rats both 3 h and 14 h post injection of PSP. Pre-treatment i.p. of the rats with anti-IL-6 antibody (30 ug/rat) prevented the PSP-induced prolongation of endotoxin fever. CONCLUSIONS: Based on these data, we conclude that PSP modifies the LPS-induced fever in IL-6 related fashion. PMID- 26044875 TI - Coronary revascularization and adverse events in joint arthroplasty. AB - BACKGROUND: There is a paucity of literature about outcome of total joint arthroplasty in patients with the history of angioplasty and/or stent or coronary artery bypass graft (CABG). The present study aimed to evaluate perioperative complications and mortality in these patients. METHODS: We used the Nationwide Inpatient Sample data from 2002-2011. Using the Ninth Revision of the International Classification of Disease, Clinical Modification codes for disorders and procedures, we identified patients with a history of coronary revascularization (angioplasty and/or stent or CABG) and compared the inhospital adverse events in these patients with patients without a history of coronary revascularization. RESULTS: Cardiac complications occurred in 1.06% patients with a history of CABG; 0.95% of patients with a coronary angioplasty and/or stent and 0.82% of the control patients. In the multivariate analysis, neither the history of CABG (P = 0.07) nor the history of angioplasty and/or stenting (P = 0.86) was associated with a higher risk of cardiac complications. However, myocardial infarction occurred in a significantly higher proportion of patients with the history of CABG (0.66%, odds ratio, 1.24, P = 0.001) and coronary angioplasty and/or stenting (0.67%, odds ratio, 1.96, P < 0.001) compared with that in the controls (0.27%). History of coronary revascularization did not increase the risk of respiratory, renal, and wound complications, surgical site infection, and mortality. CONCLUSIONS: Based on the findings of this study, it appears that there is no increased risk of inhospital mortality and complications (except for myocardial infarction) in patients with a history of coronary artery revascularization undergoing total joint arthroplasty. We also found perioperative cardiac arrhythmia, particularly atrial fibrillation, to be an independent predictor of inhospital adverse events. PMID- 26044877 TI - Gene therapy for monogenic disorders of the bone marrow. AB - Ex-vivo gene transfer of autologous haematopoietic stem cells in patients with monogenic diseases of the bone marrow has emerged as a new therapeutic approach, mainly in patients lacking a suitable donor for transplant. The encouraging results of initial clinical trials of gene therapy for primary immunodeficiencies were tempered by the occurrence of genotoxicity in a number of patients. Over the last decade, safer viral vectors have been developed to overcome the risk of insertional mutagenesis and have led to impressive clinical outcomes with considerably improved safety. We review the efforts in specific immunodeficiencies including adenosine deaminase deficiency, X-linked severe combined immunodeficiency, chronic granulomatous disease and Wiskott Aldrich syndrome. Major recent progress has also been made in haemoglobinopathies, such as beta-thalassaemia, sickle cell disease and Fanconi anaemia, and also specific lysosomal storage diseases, which, although not strictly bone marrow specific conditions, have been effectively treated by bone marrow-based treatment. The success of these recent studies and the advent of new technologies, such as gene editing, suggest that gene therapy could become a more generally applied treatment modality for a number of haematopoietic disorders. PMID- 26044876 TI - The clinical safety, biodistribution and internal radiation dosimetry of flutemetamol (18F) injection in healthy Japanese adult volunteers. AB - OBJECTIVES: The Phase I safety, biodistribution and internal radiation dosimetry study in adult healthy Japanese males of flutemetamol ((18)F) injection, an in vivo beta-amyloid imaging agent, is reported and compared with previously obtained Caucasian data. METHODS: Whole-body PET scans of 6 healthy volunteers (age 51.8-61.7 years) were acquired approximately 4 h post-injection (administered activity 102-160 MBq). Venous blood sampling determined (18)F activity concentrations in whole blood and plasma and high-performance liquid chromatography (HPLC) established the percentages of parent [(18)F]flutemetamol and its metabolites. Voided urine activity was recorded. The decay-corrected and normalised (18)F activity of 14 source organ regions as a function of time was entered into the OLINDA/EXM software to calculate the internal radiation dosimetry and effective dose of each subject following the MIRD schema. The pharmacokinetics, biodistribution and dosimetry profiles were compared to data obtained from a cohort of healthy Caucasian adult volunteers from a previous Phase I study of [(18)F]flutemetamol. RESULTS: Flutemetamol ((18)F) injection was well tolerated. The highest mean initial uptakes were measured in the liver (15.2%), lungs (10.2%) and brain (6.6%). The highest mean radiation absorbed doses were received by the gallbladder wall (366 MUGy/MBq), upper large intestine (138 MUGy/MBq) and small intestine (121 MUGy/MBq). The mean effective dose was 34.9 MUSv/MBq. HPLC analysis demonstrated that at 5-min post-injection about 75% of plasma (18)F radioactivity was in the form of parent [(18)F]flutemetamol, reducing to 8 and 2% at 25 and 90 min, respectively, giving rise to less lipophilic (18)F-labelled metabolites. Comparisons with the Caucasian cohort showed no differences that could be regarded as clinically significant. CONCLUSION: The clinical safety of [(18)F]flutemetamol demonstrated no differences of clinical significance in the pharmacokinetics, biodistribution and internal radiation dosimetry profiles between Caucasian and Japanese adults. PMID- 26044878 TI - Structural modification of resveratrol leads to increased anti-tumor activity, but causes profound changes in the mode of action. AB - (Z)-3,5,4'-Trimethoxystilbene (Z-TMS) is a resveratrol analog with increased antiproliferative activity towards a number of cancer cell lines compared to resveratrol, which has been shown to inhibit tubulin polymerization in vitro. The purpose of this study was to investigate if Z-TMS still shows potential for the prevention of metabolic diseases as known for resveratrol. Cell growth inhibition was determined with IC50 values for Z-TMS between 0.115MUM and 0.473MUM (resveratrol: 110.7MUM to 190.2MUM). Flow cytometric analysis revealed a G2/M arrest after Z-TMS treatment, whereas resveratrol caused S phase arrest. Furthermore, Z-TMS was shown to impair microtubule polymerization. Beneficial effects on lipid accumulation were observed for resveratrol, but not for Z-TMS in an in vitro steatosis model. (E)-Resveratrol was confirmed to elevate cAMP levels, and knockdown of AMPK attenuated the antiproliferative activity, while Z TMS did not show significant effects in these experiments. SIRT1 and AMPK activities were further measured indirectly via induction of the target gene small heterodimer partner (SHP). Thereby, (E)-resveratrol, but not Z-TMS, showed potent induction of SHP mRNA levels in an AMPK- and SIRT1-dependent manner, as confirmed by knockdown experiments. We provide evidence that Z-TMS does not show beneficial metabolic effects, probably due to loss of activity towards resveratrol target genes. Moreover, our data support previous findings that Z-TMS acts as an inhibitor of tubulin polymerization. These findings confirm that the methylation of resveratrol leads to profound changes in the mode of action, which should be taken into consideration when conducting lead structure optimization approaches. PMID- 26044879 TI - Clinical effectiveness of an ultra-brief intervention for common mental health syndromes in primary care: study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Although mild to moderate mental health problems are common and often debilitating, treatment options in primary care settings in New Zealand are often severely limited for patients with these conditions. Previously, we developed an ultra-brief intervention (UBI) to address mild to moderate psychological concerns, designed to be delivered by primary care clinicians. Recent feasibility testing, including an adaptation for Maori individuals (the indigenous people of New Zealand), showed that the brief intervention was feasible and acceptable to both clinicians and their patients. This protocol describes a large pragmatic randomized controlled trial of our UBI in primary care settings across the greater Wellington region, compared with practice as usual. METHODS/DESIGN: We are using a two-arm cluster randomized controlled trial, with primary care practices randomized to exclusively deliver either the UBI or practice as usual to all their recruited participants. The structured, guided self-help UBI is delivered in three brief general practitioner (GP) appointments over a five week period. Participants are invited into the study based on partner primary health organization access criteria (youth, people with low income, or people with Maori or Pacific Island heritage). Improvements in mental health from baseline to post treatment will be compared between the intervention and control groups using a mixed-models application of analysis of covariance. Data analysis will be on an intention-to-treat basis, to increase the real-world relevance of UBI and to meet the study's objective of releasing UBI to primary care clinicians nationwide. DISCUSSION: The UBI is a first-line intervention tool for GPs that models the stepped care approach advocated in New Zealand, against a background of limited access to treatments for often-overlooked patient groups. It is proposed to be accessible to clinicians and patients alike, with the potential to be relevant to primary care clinicians across New Zealand. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000041752. PMID- 26044880 TI - Quantitative neuromuscular ultrasound in intensive care unit-acquired weakness: A systematic review. AB - Intensive care unit-acquired weakness (ICU-AW) causes significant morbidity and impairment in critically ill patients. Recent advances in neuromuscular ultrasound (NMUS) allow evaluation of neuromuscular pathology early in critical illness. Here we review application of ultrasound in ICU-AW. MEDLINE-indexed articles were searched for terms relevant to ultrasound and critical illness. Two reviewers evaluated the resulting abstracts (n = 218) and completed full-text review (n = 13). Twelve studies and 1 case report were included. Ten studies evaluated muscle thickness or cross-sectional area (CSA): 8 reported a decrease, and 2 reported no change. Two studies reported preservation of muscle thickness in response to neuromuscular electrical stimulation, and 1 found no preservation. One study found decreases in gray-scale standard deviation, but no change in echogenicity. One study described increases in echogenicity and fasciculations. Ultrasound reliability in ICU-AW is not fully established. Further investigation is needed to identify ultrasound measures that reliably predict clinical, electrodiagnostic, and pathologic findings of ICU-AW. PMID- 26044881 TI - In vivo imaging study of angiogenesis in a channelized porous scaffold. AB - The main scientific issue hindering the development of tissue engineering technologies is the lack of proper vascularization. Among the various approaches developed for boosting vascularization, scaffold design has attracted increasing interest over the last few years. The aim of this article is to illustrate a scaffold design strategy for enhancing vascularization based on sacrificial microfabrication of embedded microchannels. This approach was combined with an innovative poly(ether urethane urea) (PEUtU) porous scaffold to provide an alternative graft substitute material for the treatment of tissue defects. Fluorescent and chemiluminescent imaging combined with computed tomography were used to study the behavior of the scaffold composition within living subjects by analyzing angiogenesis and inflammation processes and observing the variation in x-ray absorption, respectively. For this purpose, an IntegriSense 680 probe was used in vivo for the localization and quantification of integrin alphavbeta3, due to its critical involvement in angiogenesis, and a XenoLight RediJect Inflammation Probe for the study of the decline in inflammation progression during healing. Overall, the collected data suggest the advantages of embedding a synthetic vascular network into a PEUtU porous matrix to enhance in vivo tissue integration, maturation, and regeneration. Moreover, our imaging approach proved to be an efficient and versatile tool for scaffold in vivo testing. PMID- 26044882 TI - Morphological and molecular characterization of Nosema pernyi, a microsporidian parasite in Antheraea pernyi. AB - Nosema pernyi is a lethal pathogen that causes microsporidiosis in the Chinese oak silkworm, Antheraea pernyi. In this study, we presented its morphological and some molecular characteristics. The mature spores were measured to be 4.36 * 1.49 MUm. The spore wall consisted of an electron-dense exospore (EX) and electron lucent endospore (EN) layer. The polar filament (PF) was isofilar with 10-12 coils that were frequently arranged in a single row. Investigation results indicated that N. pernyi can infect the gut wall, silk glands, and other tissues. A full-length SMART cDNA library of N. pernyi was constructed, and then 824 expressed sequence tags (ESTs) were sequenced. Ninety unigenes, out of 197 assembled unigenes, showed significant homology to known genes of Nosema ceranae, Nosema bombycis, Encephalitozoon cuniculi, and other microsporidian species. Based on the nucleotide sequence of the alpha- and beta-tubulin genes and amino acid sequence of actin gene, phylogenetic trees analysis showed that N. pernyi was closely related to Nosema philosamiae and Nosema antheraeae. It was correctly assigned to the Nosema group. PMID- 26044883 TI - Toxocara canis mucins among other excretory-secretory antigens induce in vitro secretion of cytokines by mouse splenocytes. AB - The effect of Toxocara larval antigens on cytokine secretion by mouse splenocytes was studied in vitro. Recombinant mucins were produced in Pichia pastoris yeast, and Toxocara excretory-secretory (TES) antigens were collected from in vitro culture of L2 larvae. Tc-MUC-2, Tc-MUC-3, Tc-MUC-4, and Tc-MUC-5 were expressed as glycoproteins and were specifically recognized by Toxocara canis-infected dog serum antibodies. Mouse splenocytes stimulated with recombinant mucins produced IL-5, IL-6, and TGF-beta. Cell stimulation with whole TES products was more effective and resulted in secretion of IL-4, IL-5, IL-6, IL-10, and TGF-beta and downregulation of TNF-alpha production. IFN-gamma and IL-17 secretion was noted only after ConA treatment. Cells originating from infected animals produced significantly smaller amounts of these two cytokines compared to control cells, which suggests that Th1 and Th17 response in infected mice is strongly inhibited. However, splenocyte stimulation with both TES and ConA upregulated the production of IFN-gamma and IL-17. This shows that TES antigens have strong immunomodulatory properties and are able to induce a broad range of effects on murine immune cells. PMID- 26044884 TI - Molecular evidence of Sarcocystis species in captive snakes in Japan. AB - Sarcocystis nesbitti, using snakes as the definitive host, is a causative agent of acute human muscular sarcocystosis in Malaysia. Therefore, it is important to explore the distribution and prevalence of S. nesbitti in snakes. Nevertheless, epizootiological information of S. nesbitti in snakes remains insufficient because few surveys have assessed Sarcocystis infection in snakes in endemic countries. In Japan, snakes are popular exotic pet animals that are imported from overseas, but the degree of Sarcocystis infection in them remains unclear. The possibility exists that muscular sarcocystosis by S. nesbitti occurs in contact with captive snakes in non-endemic countries. For a total of 125 snake faecal samples from 67 snake species collected at animal hospitals, pet shops and a zoo, this study investigated the presence of Sarcocystis using polymerase chain reaction (PCR) for the 18S ribosomal RNA gene (18S rDNA). Four (3.2%) faecal samples were positive by PCR. Phylogenetic analysis of the 18S rDNA sequences obtained from four amplification products revealed one isolate from a beauty snake (Elaphe taeniura), Sarcocystis zuoi, which uses rat snakes as the definitive host. The isolate from a Macklot's python (Liasis mackloti) was closely related with unidentified Sarcocystis sp. from reticulated pythons in Malaysia. The remaining two isolates from tree boas (Corallus spp.) were closely related with Sarcocystis lacertae, Sarcocystis gallotiae and unidentified Sarcocystis sp. from smooth snakes, Tenerife lizards and European shrews, respectively. This report is the first of a study examining the distribution of Sarcocystis species in captive snakes in Japan. PMID- 26044885 TI - Vocabulary size, translation equivalents, and efficiency in word recognition in very young bilinguals. AB - The present study examined early vocabulary development in fifty-nine French monolingual and fifty French-English bilingual infants (1;4-1;6). Vocabulary comprehension was assessed using both parental report (MacArthur-Bates Communicative Development Inventory; CDI) and the Computerized Comprehension Task (CCT). When assessing receptive vocabulary development using parental report, the bilinguals knew more words in their L1 versus their L2. However, young bilinguals were as accurate in L1 as they were in L2 on the CCT, and exhibited no difference in speed of word comprehension across languages. The proportion of translation equivalents in comprehension varied widely within this sample of young bilinguals and was linked to both measures of vocabulary size but not to speed of word retrieval or exposure to L2. Interestingly, the monolinguals outperformed the bilinguals with respect to accuracy but not reaction time in their L1 and L2. These results highlight the importance of using multiple measures to assess early vocabulary development. PMID- 26044886 TI - Cervical chordoma surgically resected via three-stage procedure with intraoperative images. PMID- 26044887 TI - Authors' Reply. PMID- 26044888 TI - Community participation in the decentralised district health systems in Tanzania: why do some health committees perform better than others? AB - Over the past two decades, community participation has emerged as an important dimension within decentralised district healthcare systems. In Tanzania, initiatives to strengthen community participation have focused on the formation of the health committees. Studies have reported variations in the performance of the committees. An exploratory case study design focusing on two districts was adopted to explore the differences in practice of the health facility committees in a well-functioning district and one that is not. In both study districts, the committees were in place. The most common activities of the health committees were assisting the clinic in day-to-day running. The health committees' influence on policy, planning and budgeting was limited. Managerial and leadership practices of the district health managers, including effective supervision and personal initiatives of the top-district health officials coupled with incentives, are the major factors for the good performance of the health facility committees and the boards. Inadequate training and low public awareness affected the performance of the committees. A greater role in governance and oversight is essential for effective and meaningful health committees. To achieve impact, health committees will require adequate training on the following: roles and functions of the health facility committees and the boards; interaction between the committees and the communities and the health workers; development of health plans and budgets at the local and district level; and monitoring and tracking. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26044890 TI - Effect of combined deferasirox and 5-azacytidine treatment on human leukemia cells in vitro. PMID- 26044889 TI - Predictors of gastrointestinal bleeding among patients with atrial fibrillation after initiating dabigatran therapy. AB - STUDY OBJECTIVES: To identify demographic and clinical risk factors associated with gastrointestinal (GI) bleeding among a large cohort of patients with atrial fibrillation (AF) who initiated dabigatran therapy for stroke prevention, and to describe patterns of subsequent anticoagulant use after occurrence of the GI bleeding event. DESIGN: Retrospective cohort study. DATA SOURCES: Large, nationwide United States commercial insurance database. PATIENTS: A total of 21,033 patients with nonvalvular AF who initiated dabigatran between October 19, 2010, and December 31, 2012. MEASUREMENTS AND MAIN RESULTS: We used multivariate Cox regression analysis to estimate the effect of baseline demographic and clinical characteristics on the probability of a GI bleeding event. Patterns of anticoagulation use after GI bleeding were also examined descriptively. Of the 21,033 patients receiving dabigatran, 446 (2.1%) experienced a GI bleed during follow-up. GI bleeding rates differed across many baseline characteristics. Male sex was associated with a lower risk (adjusted hazard ratio [aHR] 0.78, 95% confidence interval [CI] 0.64-0.95) of GI bleeding. Compared with patients younger than 55 years, those aged 55-64, 65-74, and 75 years or older yielded aHRs of 1.54 (95% CI 0.89-2.68), 2.72 (95% CI 1.59-4.65), and 4.52 (95% CI 2.68 7.64), respectively. Renal impairment (aHR 1.67, 95% CI 1.24-2.25), heart failure (aHR 1.25, 95% CI 1.01-1.56), alcohol abuse (aHR 2.57, 95%CI 1.52-4.35), previous Helicobacter pylori infection (aHR 4.75, 95% CI 1.93-11.68), antiplatelet therapy (aHR 1.49, 95% CI 1.19-1.88), and digoxin use (aHR 1.49, 95% CI 1.19-1.88) were also associated with an increased GI bleeding risk. Of the 446 patients who experienced a GI bleed, 193 (43.3%) restarted an anticoagulant, with most (65.8%) filling prescriptions for dabigatran; the mean time was 50.4 days until restarting any subsequent anticoagulant. CONCLUSION: The risk of GI bleeding in patients receiving dabigatran is highly associated with increased age and cardiovascular, renal, and other comorbidities, even after adjusting for other factors. Fewer than 50% of patients restarted an anticoagulant after experiencing a GI bleed. Clinicians should continue to monitor for these risk factors or consider whether alternative therapies may be appropriate. PMID- 26044891 TI - Thrombotic thrombocytopenic purpura in a patient with lenalidomide-responsive multiple myeloma. PMID- 26044892 TI - The use of the early cannulation prosthetic graft (AcusealTM) for angioaccess for haemodialysis. AB - OBJECTIVES: Autogenous arteriovenous (AV) accesses are the preferred choice for the delivery of haemodialysis (HD). With an increase in the prevalence of end stage renal disease and in the life expectancy of these patients, the quality and availability of superficial vessels can be limited and reduced with time. The use of prosthetic AV accesses may therefore become necessary for the delivery of HD. A new early cannulation vascular prosthesis (GORE(r) ACUSEAL Vascular Graft) has been introduced, developed to hinder suture line and cannulation needle bleeding. The authors report their experience with this new conduit at a London teaching hospital. METHODS: Between May 2011 and June 2013, 52 patients underwent 55 procedures where the ACUSEAL(r) prosthetic AV access was utilized to facilitate HD. The majority of procedures involved the placement of prosthetic brachio axillary accesses or prosthetic axillo-axillary chest accesses. RESULTS: The 1 year primary and secondary patency was found to be 46% and 61%, respectively. Successful cannulation of the newly placed AV access was performed with 24 hours of surgery in 40 patients (73%). Tunnelled vascular catheters were required in only 10 (18%) patients. Six (11%) of the patients in the study suffered early complications, and 9 (16%) patients developed AV access infection. CONCLUSIONS: These results show that, while providing patency results that compare favourably to those published for other types of regular prosthetic accesses, the conduits are amenable to very early cannulation with few cannulation-related complications. This leads to a dramatic reduction in the need for temporary or tunnelled catheters. PMID- 26044893 TI - Transradial versus transfemoral approach in coronary angiography: a matched pair analysis of cath lab equipment costs. AB - INTRODUCTION: There is an ongoing struggle to understand the potential economic benefits that radial access may offer. Cost savings are thought to primarily occur after the procedure. The aim of our study was to analyze cath lab expenses resulting from transradial (TRA) and transfemoral approaches (TFA). METHODS: A total of n = 1890 matched pairs of patients were analyzed. A traditional Judkins catheter strategy was pursued for coronary angiography. Three large databases were merged to collect and compare procedural data as material, medication costs and fluoroscopy time. RESULTS: Compared to TFA diagnostic catheterization from TRA was associated with significantly lower procedural costs (?181.0 versus ?167.5; p<0.001). Extra costs in TFA were primarily produced by frequent use of vascular closure devices (VCDs) in 86% of patients. However, the potential saving amount related to VCD use was only partly realized due to the higher number of extra catheters (0.53 +/- 0.9 versus 0.23 +/- 0.6; p<0.001) and hydrophilic guidewires (0.088 +/- 0.3 versus 0.014 +/- 0.1; p<0.001) used in TRA. Weak correlations were observed between the total number of cases and fluoroscopy time (r = -0.13; p<0.001) as well as material costs (r = 0.31; p<0.001). CONCLUSIONS: Significant cost savings can be realized by TRA at the procedural level even when adhering to a conventional Judkins catheter strategy. Hydrophilic guidewires and additional catheters are the main cost drivers in TRA. In contrast to fluoroscopy time material costs steadily increase during the early stage of the TRA learning curve. PMID- 26044894 TI - Successful obturator vein vascular access for hemodialysis catheter placement in patients with end-stage renal disease. PMID- 26044895 TI - AV fistula creation in paediatric patients: outcome is independent of demographics and fistula type reducing usage of venous catheters. AB - PURPOSE: Even though early transplantation is still the first-line therapy in paediatric patients with end-stage renal disease (ESRD), up to 30% of these patients still require haemodialysis (HD). Creating an arteriovenous fistula (AVF) is quite challenging, particularly in children, leading to disproportional use of catheters. In this paper, we describe our experience in the creation of AVF with currently no in-dwelling catheters in children and adolescents on HD. METHODS: From January 2009 to December 2013, there were 34 patients rated as unfit for transplantation for at least the next 6 months or who had already been on HD through a central venous catheter (CVC). Three patients aged between 12 months and 3 years and weighing 9-12 kg were not suitable for AVF. Finally 31 patients, from 6 to 19 years of age with a mean weight of 43.3 +/- 14.5 kg (19-80 kg), were assigned to the alternative of AVF. RESULTS: During the above-mentioned time period, 31 patients were provided with 32 AVFs; 26 received a distal radiocephalic fistula, five a Gracz-type fistula and one a brachio-basilic fistula. All but two fistulae matured primarily, within an average time of 45 (range: 16-191) days until the first dialysis. The fistula's 1-year primary and primary assisted patency rates were 78% and 94%, respectively. CONCLUSIONS: The creation of a native vascular access is an effective and durable procedure in paediatric and adolescent patients. It reduces using of CVCs and is appropriate both for long-term treatment and as a bridging procedure until renal transplantation. PMID- 26044896 TI - New technology in vascular prosthesis access. PMID- 26044897 TI - Effects of prolonged ethanol lock exposure to carbothane- and silicone-based hemodialysis catheters: a 26-week study. AB - PURPOSE: Antibiotic locks in catheter-dependent chronic hemodialysis patients reduce the rate of catheter-related bloodstream infections (CRBSIs), but may be associated with the development of resistant bacteria. Ethanol-based catheter locks may provide a better alternative; however, there are limited data on the long-term integrity of dialysis catheters exposed to ethanol. METHODS: We performed in vitro testing of two types of hemodialysis catheters-silicone (SLC) and carbothane (CBT) based-with a 70% ethanol lock (EL) versus heparin lock (HL) for 26 weeks. Lock solutions were changed thrice weekly to mimic a conventional hemodialysis schedule. We tested mechanical properties of the catheters at 0, 13 and 26 weeks by examining stress/strain relationships (SS400%) and modulus of elasticity (ME). Electron microscopy was performed to examine catheter ultrastructure at 0 and 26 weeks. RESULTS: Catheter integrity for HL versus EL in SLC (SS400%: 4.5 vs. 4.5 MPa, p = NS; ME: 4.6 vs. 4.7 MPa, p = NS) or CBT-based catheters (SS400%: 7.6 vs. 8.9 MPa, p = NS; ME: 9.6 vs. 12.2 MPa, p = NS) were all similar at 13 and 26 weeks. Scanning electron microscopy revealed no structural changes in the central and luminal wall internal surfaces of EL- versus HL-treated catheters. CONCLUSIONS: There were no significant differences in catheter integrity between SLC or CBT catheters exposed to a 70% EL for 26 weeks. Given its low cost, potential to avoid antibiotic resistance and structural integrity after 6 months of high-dose ethanol, ELs should be studied prospectively against antibiotic locks to assess the efficacy and safety in hemodialysis patients. PMID- 26044898 TI - Paclitaxel drug-eluting balloons to recurrent in-stent stenoses in autogenous dialysis fistulas: a retrospective study. AB - PURPOSE: To assess the effect of the Medtronic paclitaxel drug-eluting balloon (DEB) on re-intervention to in-stent stenoses in autogenous dialysis arteriovenous fistulas (AVFs). BACKGROUND: AVF is the optimum haemodialysis access. The commonest problem is stenosis, preventing maturation, causing inadequate dialysis or precipitating occlusion. Conventional angioplasty has a high recurrence rate. Successful drug elution in the coronary circulation led us to use DEBs in recurrent AVF stenoses since 2010. METHODS: This is a retrospective study, based on prospective audit data, using DEBs on recurrent in stent stenotic lesions in the AVF circuit of our haemodialysis population. To analyse the effect of DEBs on re-intervention, we created two Kaplan-Meier curves. The first curve compares the last "disease-free-interval" pre-DEB intervention to the first "disease-free interval" post-DEB, giving us "re intervention-free percentage at 12 months" pre- and post-DEB. The second curve takes into account the multiple pre- and post-DEB interventions to the index lesion, and uses a marginal proportional hazards model to estimate the hazard ratio for "DEBpresent vs. DEBabsent". RESULTS: From 1 September 2010 to 1 December 2013, we treated 625 AVF stenoses with endovascular techniques. In 86 of these stenoses, DEBs were used. Of the 86 DEB interventions, 37 were included for this study, 49 were excluded. In the study group, there was a significant difference in "re-intervention-free percentage at 12 months" before and after DEB: 19% vs. 69%. The hazard ratio for "DEBpresent" vs. "DEBabsent" was 0.23 (95% CI 0.14 to 0.36, p<0.001). CONCLUSIONS: This retrospective study suggests that DEBs significantly reduce re-intervention on recurrent in-stent AVF stenoses. PMID- 26044899 TI - Ultrasound-guided brachiocephalic vein catheterization in infants weighing less than five kilograms. AB - PURPOSE: To describe our experience with the use of ultrasound-guided supraclavicular brachiocephalic vein approach for central vein catheterization in infants weighing less than 5 kg. METHODS: A retrospective review was performed for infants who underwent ultrasound-guided central vein catheterization from January 2012 to November 2014. Infants weighing less than 5 kg with supraclavicular brachiocephalic vein access were included in the study. Indications for central venous access, venous access side, catheter type and complications were evaluated. RESULTS: Thirty-four catheterizations in 34 infants weighing from 1.5 to 4.9 kg (median 3.48 kg) were included in the study (aged 11 days to 7 months and 10 days, weight range 1.5 to 4.9 kg). Technical success rate was 97% (33 of 34 infants). No technical or clinical major complications were observed. CONCLUSIONS: Ultrasound-guided supraclavicular brachiocephalic vein access is a favorable alternative for central venous catheterization in low weight infants with regard to high technical success rate and absence of major complications. PMID- 26044900 TI - True aneurysm in autologous hemodialysis fistulae: definitions, classification and indications for treatment. AB - INTRODUCTION: Definition, etiology, classification and indication for treatment of the arteriovenous access (AVA) aneurysm are poorly described in medical literature. The objectives of the paper are to complete this information gap according to the extensive review of the literature. METHODS: A literature search was performed of the articles published between April 1, 1967, and March 1, 2014. The databases searched included Medline and the Cochrane Database of Systematic Reviews. The eligibility criteria in this review studies the need to assess the association of aneurysms and pseudoaneurysms with autologous AVA. Aneurysms and pseudoaneurysms involving prosthetic AVA were not included in this literature review. From a total of 327 papers, 54 non-English papers, 40 case reports and 167 papers which did not meet the eligibility criteria were removed. The remaining 66 papers were reviewed. RESULTS: Based on the literature the indication for the treatment of an AVA aneurysm is its clinical presentation related to the patient's discomfort, bleeding prevention and inadequate access flow. A new classification system of AVA aneurysm, which divides it into the four types, was also suggested. CONCLUSIONS: AVA aneurysm is characterized by an enlargement of all three vessel layers with a diameter of more than 18 mm and can be presented in four types according to the presence of stenosis and/or thrombosis. The management of an AVA aneurysm depends on several factors including skin condition, clinical symptoms, ease of cannulation and access flow. The diameter of the AVA aneurysm as a solo parameter is not an indication for the treatment. PMID- 26044901 TI - Endovascular recanalization of a port catheter-associated superior vena cava syndrome. AB - PURPOSE: Superior vena cava (SVC) syndrome owing to benign etiology is rare and endovascular techniques have been advocated as the treatment of choice. We report a case of endovascular revascularization of a port catheter-associated complete occlusion of the SVC with reversed flow in the azygos vein. METHODS: In this setting using a sheath in combination with its dilatator to pass the occlusion of the SVC after neither a diagnostic catheter nor a PTA balloon would pass the lesion may be a valid option. A dual venous approach was established using the right common femoral vein and an indwelling port catheter in the right cephalic vein to dilate and stent the lesion. Finally, a port may be implanted after the revascularization had been successful. RESULTS: Passage through the port catheter associated occlusion of the SVC was only possible by use of the sheath in combination with its dilatator. A dual venous access by the femoral approach and the indwelling central catheter is helpful in treating a SVC occlusion. CONCLUSIONS: Long-term central venous catheters may cause SVC syndrome, especially with a catheter tip located too far cranially. An endovascular revascularization of a complete occlusion of the SVC represents the therapy of choice. PMID- 26044902 TI - Safety and efficacy of combined micropuncture and shallow angle femoral artery access for neurovascular angiography. AB - INTRODUCTION: The AXERA 2 low-angle vascular access device utilizes a dual arteriotomy mechanism in which the standard access tract is compressed by a vascular sheath inserted over the second, low-angle tract. It is unknown whether this device could be effectively used with 21-gauge micropuncture access, as the micropuncture introducer makes a larger arteriotomy than the 19-gauge needle provided with the AXERA 2 system. MATERIALS AND METHODS: A retrospective review was performed on 189 patients who underwent common femoral artery access for diagnostic cerebrovascular angiography using either combined micropuncture and AXERA 2 access or standard access with manual pressure hemostasis. Demographic and procedural data were reviewed along with complications related to vascular access and times to bed elevation, ambulation and discharge. RESULTS: Combined micropuncture and AXERA 2 access was performed on 110 patients and 79 patients had standard access. The AXERA device was successfully used in 91.8% of the cases. Demographic data, anticoagulant use and sheath sizes were similar between both subsets. Use of the AXERA 2 was associated with two bleeding complications (1.8%) compared with 10 (12.7%) with manual pressure hemostasis alone. Institution-specific protocol allowed shorter mean manual compression time, as well as shorter times to ambulation and discharge with the AXERA 2. CONCLUSIONS: Use of the AXERA 2 device with micropuncture access did not infer increased bleeding risk than standard arterial access in this patient series. The considerable incidence of device use failures suggests a learning curve associated with its use. PMID- 26044904 TI - Synthesis of Indolizines through Oxidative Linkage of C-C and C-N Bonds from 2 Pyridylacetates. AB - Synthesis of indolizine-1-carboxylates through the Ortoleva-King reaction of 2 pyridylacetate followed by the Aldol condensation under mild reaction conditions has been described. This protocol is compatible with a broad range of functional groups, and it has been also successfully extended to unsaturated ketones, bringing about the regioselective formation of benzoyl-substituted indolizines through Michael addition followed by C-N bond formation, which are difficult to prepare by previous methods in a single step. PMID- 26044903 TI - Pregnancy-associated cardiomyopathy in survivors of childhood cancer. AB - PURPOSE: Current information regarding pregnancy-associated cardiomyopathy among women treated for childhood cancer is insufficient to appropriately guide counseling and patient management. This study aims to characterize its prevalence within a large cohort of females exposed to cardiotoxic therapy. METHODS: This is a retrospective cohort study of female cancer survivors treated at St. Jude Children's Research Hospital between 1963 and 2006, at least 5 years from diagnosis, >=13 years old at last follow-up, and with at least one successful pregnancy. Pregnancy-associated cardiomyopathy was defined as shortening fraction <28 % or ejection fraction <50 % or treatment for cardiomyopathy during or up to 5 months after completion of pregnancy. RESULTS: Among the 847 female cancer survivors with 1554 completed pregnancies, only 3 (0.3 %) developed pregnancy associated cardiomyopathy and 40 developed non-pregnancy-associated cardiomyopathy either 5 months postpartum (n = 14) or prior to pregnancy (n = 26). Among those with cardiomyopathy prior to pregnancy (n = 26), cardiac function deteriorated during pregnancy in eight patients (three patients with normalization of cardiac function prior to pregnancy, three with persistently abnormal cardiac function, and two for whom resolution of cardiomyopathy was unknown prior to pregnancy). Patients that developed cardiomyopathy received a higher median dose of anthracyclines compared to those that did not (321 versus 164 mg/m(2); p < 0.01). CONCLUSIONS: Pregnancy-associated cardiomyopathy in childhood cancer survivors is rare. IMPLICATIONS FOR CANCER SURVIVORS: Most female childhood cancer survivors will have no cardiac complications during or after childbirth; however, those with a history of cardiotoxic therapies should be followed carefully during pregnancy, particularly those with a history of anthracycline exposures and if they had documented previous or current subclinical or symptomatic cardiomyopathy. PMID- 26044905 TI - Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure. AB - Drug exposure during critical periods of development is known to have lasting effects, increasing one's risk for developing mental health disorders. Emerging evidence has also indicated the possibility for drug exposure to even impact subsequent generations. Our previous work demonstrated that adolescent exposure to Delta(9)-tetrahydrocannabinol (THC), the main psychoactive component of marijuana (Cannabis sativa), in a Long-Evans rat model affects reward-related behavior and gene regulation in the subsequent (F1) generation unexposed to the drug. Questions, however, remained regarding potential epigenetic consequences. In the current study, using the same rat model, we employed Enhanced Reduced Representation Bisulfite Sequencing to interrogate the epigenome of the nucleus accumbens, a key brain area involved in reward processing. This analysis compared 16 animals with parental THC exposure and 16 without to characterize relevant systems-level changes in DNA methylation. We identified 1027 differentially methylated regions (DMRs) associated with parental THC exposure in F1 adults, each represented by multiple CpGs. These DMRs fell predominantly within introns, exons, and intergenic intervals, while showing a significant depletion in gene promoters. From these, we identified a network of DMR-associated genes involved in glutamatergic synaptic regulation, which also exhibited altered mRNA expression in the nucleus accumbens. These data provide novel insight into drug related cross-generational epigenetic effects, and serve as a useful resource for investigators to explore novel neurobiological systems underlying drug abuse vulnerability. PMID- 26044906 TI - The Novel MU-Opioid Receptor Antagonist GSK1521498 Decreases Both Alcohol Seeking and Drinking: Evidence from a New Preclinical Model of Alcohol Seeking. AB - Distinct environmental and conditioned stimuli influencing ethanol-associated appetitive and consummatory behaviors may jointly contribute to alcohol addiction. To develop an effective translational animal model that illuminates this interaction, daily seeking responses, maintained by alcohol-associated conditioned stimuli (CSs), need to be dissociated from alcohol drinking behavior. For this, we established a procedure whereby alcohol seeking maintained by alcohol-associated CSs is followed by a period during which rats have the opportunity to drink alcohol. This cue-controlled alcohol-seeking procedure was used to compare the effects of naltrexone and GSK1521498, a novel selective MU opioid receptor antagonist, on both voluntary alcohol-intake and alcohol-seeking behaviors. Rederived alcohol-preferring, alcohol-nonpreferring, and high-alcohol drinking replicate 1 line of rats (Indiana University) first received 18 sessions of 24 h home cage access to 10% alcohol and water under a 2-bottle choice procedure. They were trained subsequently to respond instrumentally for access to 15% alcohol under a second-order schedule of reinforcement, in which a prolonged period of alcohol-seeking behavior was maintained by contingent presentations of an alcohol-associated CS acting as a conditioned reinforcer. This seeking period was terminated by 20 min of free alcohol drinking access that achieved significant blood alcohol concentrations. The influence of pretreatment with either naltrexone (0.1-1-3 mg/kg) or GSK1521498 (0.1-1-3 mg/kg) before instrumental sessions was measured on both seeking and drinking behaviors, as well as on drinking in the 2-bottle choice procedure. Naltrexone and GSK1521498 dose-dependently reduced both cue-controlled alcohol seeking and alcohol intake in the instrumental context as well as alcohol intake in the choice procedure. However, GSK1521498 showed significantly greater effectiveness than naltrexone, supporting its potential use for promoting abstinence and preventing relapse in alcohol addiction. PMID- 26044908 TI - Treatment patterns and survival analysis in 9014 patients with malignant pleural mesothelioma from Belgium, the Netherlands and England. AB - INTRODUCTION: Pleural mesothelioma has a dismal prognosis and is refractory to local treatment. Combination chemotherapy can increase median survival by several months and was gradually introduced in the period 2003-2006. Elderly patients may be unfit for chemotherapy but little is known about age-related treatment practice. To determine treatment patterns and current survival outcome, three large population-based registries were queried in a uniform manner. METHODS: Data from the Belgian Cancer Registry, the Netherlands Cancer Registry and the UK National Lung Cancer Audit were analyzed for patients diagnosed with pleural mesothelioma since 2007. Treatment patterns and survival rates were compared between countries and age-groups. RESULTS: The study included 900, 2306 and 5808 patients from Belgium, the Netherlands and England, respectively. Fifty-nine percent of patients were 70 years or older and 84% were men. Chemotherapy use decreased with advancing age and was used more often in Belgium (60%) than in the Netherlands (41%) and England (37%). For patients aged 70-79 years, chemotherapy use was 55%, 36% and 34% in the respective countries. Median survival was 10.7 months in Belgium versus 9.2 months for the Netherlands and 9.5 months for England. Survival rates decreased with advancing age. On average, median survival was 5.6 months longer for patients treated with chemotherapy, irrespective of age. CONCLUSIONS: Combined analysis of data from three countries with high mesothelioma rates demonstrates that chemotherapy has become standard treatment for younger patients. Elderly patients currently account for more than half of all cases and less toxic treatment options will be required to improve their prospects. PMID- 26044907 TI - Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended Access Cocaine or Saline Self-Administration. AB - The ubiquitin-proteasome system (UPS) has been implicated in the retrieval induced destabilization of cocaine- and fear-related memories in Pavlovian paradigms. However, nothing is known about its role in memory retrieval after self-administration of cocaine, an operant paradigm, or how the length of withdrawal from cocaine may influence retrieval mechanisms. Here, we examined UPS activity after an extended-access cocaine self-administration regimen that leads to withdrawal-dependent incubation of cue-induced cocaine craving. Controls self administered saline. In initial experiments, memory retrieval was elicited via a cue-induced seeking/retrieval test on withdrawal day (WD) 50-60, when craving has incubated. We found that retrieval of cocaine- and saline-associated memories produced similar increases in polyubiquitinated proteins in the nucleus accumbens (NAc), compared with rats that did not undergo a seeking/retrieval test. Measures of proteasome catalytic activity confirmed similar activation of the UPS after retrieval of saline and cocaine memories. However, in a subsequent experiment in which testing was conducted on WD1, proteasome activity in the NAc was greater after retrieval of cocaine memory than saline memory. Analysis of other brain regions confirmed that effects of cocaine memory retrieval on proteasome activity, relative to saline memory retrieval, depend on withdrawal time. These results, combined with prior studies, suggest that the relationship between UPS activity and memory retrieval depends on training paradigm, brain region, and time elapsed between training and retrieval. The observation that mechanisms underlying cocaine memory retrieval change depending on the age of the memory has implications for development of memory destabilization therapies for cue-induced relapse in cocaine addicts. PMID- 26044909 TI - Engineered Phagemids for Nonlytic, Targeted Antibacterial Therapies. AB - The increasing incidence of antibiotic-resistant bacterial infections is creating a global public health threat. Because conventional antibiotic drug discovery has failed to keep pace with the rise of resistance, a growing need exists to develop novel antibacterial methodologies. Replication-competent bacteriophages have been utilized in a limited fashion to treat bacterial infections. However, this approach can result in the release of harmful endotoxins, leading to untoward side effects. Here, we engineer bacterial phagemids to express antimicrobial peptides (AMPs) and protein toxins that disrupt intracellular processes, leading to rapid, nonlytic bacterial death. We show that this approach is highly modular, enabling one to readily alter the number and type of AMPs and toxins encoded by the phagemids. Furthermore, we demonstrate the effectiveness of engineered phagemids in an in vivo murine peritonitis infection model. This work shows that targeted, engineered phagemid therapy can serve as a viable, nonantibiotic means to treat bacterial infections, while avoiding the health issues inherent to lytic and replicative bacteriophage use. PMID- 26044910 TI - Transition, It's More Than Just An Event: Supporting Young People With Type 1 Diabetes. AB - This paper discusses the importance of holistic person-centered care coordination services for young people with type 1 diabetes as they transition to adult health services. In response to the growing need for comprehensive, flexible, person centered care for young people with chronic conditions, the new service Trapeze: a supported leap into adult health was established. Based in Sydney, Australia, Trapeze is a specialist adolescent chronic care service offering comprehensive care coordination services to young people with chronic conditions aged 14-25 years. Trapeze aims to support young people with type 1 diabetes by focusing on the individual needs of the young person and developing a mutually recognized relationship based on trust and respect, in order to facilitate a process whereby a young person feels safe enough to discuss some of the challenges they face in self-management, keeping their whole of life issues central to this process. The importance of holistic person-centered work is best exemplified through the stories of the young people enrolled in Trapeze. It is hoped that through the 'eyes' of the young people and by sharing their stories the approach to self management and care coordination can be better understood. PMID- 26044911 TI - Using Visual Scene Displays as Communication Support Options for People with Chronic, Severe Aphasia: A Summary of AAC Research and Future Research Directions. AB - Research about the effectiveness of communicative supports and advances in photographic technology has prompted changes in the way speech-language pathologists design and implement interventions for people with aphasia. The purpose of this paper is to describe the use of photographic images as a basis for developing communication supports for people with chronic aphasia secondary to sudden-onset events due to cerebrovascular accidents (strokes). Topics include the evolution of AAC-based supports as they relate to people with aphasia, the development and key features of visual scene displays (VSDs), and future directions concerning the incorporation of photographs into communication supports for people with chronic and severe aphasia. PMID- 26044912 TI - Bilateral tarsal tunnel syndrome related to intense cycling activity: proposal of a multimodal diagnostic approach. PMID- 26044913 TI - Inference of brain pathway activities for Alzheimer's disease classification. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative and progressive disorder that results in brain malfunctions. Resting-state (RS) functional magnetic resonance imaging (fMRI) techniques have been successfully applied for quantifying brain activities of both Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) patients. Region-based approaches are widely utilized to classify patients from cognitively normal subjects (CN). Nevertheless, region based approaches have a few limitations, reproducibility owing to selection of disease-specific brain regions, and heterogeneity of brain activities during disease progression. For coping with these issues, network-based approaches have been suggested in the field of molecular bioinformatics. In comparison with individual gene-based approaches, they acquired more accurate results in diverse disease classification, and reproducibility was confirmed by replication studies. In our work, we applied a similar methodology integrating brain pathway information into pathway activity inference, and permitting classification of both aMCI and AD patients based on pathway activities rather than single region activities. RESULTS: After aggregating the 59 brain pathways from literature, we estimated brain pathway activities by using exhaustive search algorithms between patients and cognitively normal subjects, and identified discriminatory pathways according to disease progression. We used three different data sets and each data set consists of two different groups. Our results show that the pathway-based approach (AUC = 0.89, 0.9, 0.75) outperformed the region-based approach (AUC = 0.69, 0.8, 0.68). Also, our approach provided enhanced diagnostic power achieving higher accuracy, sensitivity, and specificity (pathway-based approach: accuracy = 83%; sensitivity = 86%; specificity = 78%, region-based approach: accuracy = 74%; sensitivity = 78%; specificity = 76%). CONCLUSIONS: We proposed a novel method inferring brain pathway activities for disease classification. Our approach shows better classification performance than region-based approach in four classification models. We expect that brain pathway-based approach would be helpful for precise classification of brain disorders, and provide new opportunities for uncovering disrupted brain pathways caused by disease. Moreover, discriminatory pathways between patients and cognitively normal subjects may facilitate the interpretation of functional alterations during disease progression. PMID- 26044914 TI - Intestinal permeability in children with recurrent respiratory and gastrointestinal symptoms. AB - AIM: Increased intestinal permeability has been reported in asthmatic subjects as well as in patients with gastrointestinal disease, thus suggesting the involvement of all the mucosal immune system. We aimed to assess intestinal permeability according to recurrent respiratory and gastrointestinal symptoms in children with asthma and children with functional gastrointestinal disorders (FGIDs). METHODS: In 108 outpatients aged 3-14 years (45 asthmatic, 63 with FGIDs), we measured the urinary lactulose/mannitol (L/M) ratio, performed allergy skin prick tests and administered questionnaires for recurrent respiratory and gastrointestinal symptoms starting from at least 2 months which persisted over the previous 4 weeks. L/M ratios were compared with previously reported normal values yielded by our chromatographic method (liquid chromatography-mass spectrometry). RESULTS: High L/M ratios (>0.030) were less frequent in asthmatic children than in children with FGIDs (9/45: 20% vs. 41/63: 65%, P < 0.001). High L/M ratios were associated with gastrointestinal symptoms in 8/9 asthmatic (P < 0.05) and 39/41 subjects with FGIDs (P < 0.005). L/M ratios were not associated with respiratory symptoms or atopy. In a regression model, a high L/M was predicted by low height, absence of asthma and presence of gastrointestinal symptoms (r = 0.72, P < 0.001). CONCLUSIONS: Increased intestinal permeability is associated with recurrent gastrointestinal symptoms rather than with recurrent respiratory symptoms in both asthmatic children and those with FGIDs. Our findings do not support the hypothesis of mucosal intestinal damage following an inflammatory stimulus in the respiratory mucosa. PMID- 26044915 TI - Enhancement of carbon dioxide reduction and methane production by an obligate anaerobe and gas dissolution device. AB - The use of gas dissolution devices to improve the efficiency of H2 dissolution has enhanced CO2 reduction and CH4 production. In addition, the nutrients that initially existed in anaerobic sludge were exhausted over time, and the activities of anaerobic microorganisms declined. When nutrients were artificially injected, CO2 reduction and CH4 production rates climbed. Thus, assuming that the activity of the obligatory anaerobic microorganisms is maintained, a gas dissolution device will further enhance the efficiency of CO2 reduction and CH4 production. PMID- 26044916 TI - Energy transfer between Ce3+ -> Gd3+ or Tb3+ in KNaSO4 microphosphor. AB - KNaSO4 microphosphor doped with Ce,Gd and Ce,Tb and prepared by a wet chemical method was studied using X-ray diffraction (XRD), scanning electron microscopy (SEM) and photoluminescence (PL) characterization. KNaSO4 has a 5-um particle size detected by SEM. KNaSO4:Ce(3+),Tb(3+) showed blue and green emission (at 494 nm, 557 nm, 590 nm) of Tb(3+) due to (5)D(4) -> (7)F(J) (J = 4, 5, 6) transitions. KNaSO4:Ce(3+),Gd(3+) showed luminescence in the ultraviolet (UV) light region at 314 nm for an excitation at 271 nm wavelength. It was observed that efficient energy transfer took place from Ce(3+) -> Gd(3+) and Ce(3+) -> Tb(3+) sublattices indicating that Ce(3+) could effectively sensitize Gd(3+) or Tb(3+) (green emission). Ce(3+) emission weakened and Gd(3+) or Tb(3+) enhanced the emission significantly in KNaSO4. This paper discusses the development and understanding of photoluminescence and the effect of Tb(3+) and Gd(3+) on KNaSO4:Ce(3+). PMID- 26044917 TI - A Fond Farewell. PMID- 26044918 TI - Integrative Medicine Patients Have High Stress, Pain, and Psychological Symptoms. AB - CONTEXT: Integrative medicine (IM) is a rapidly growing field whose providers report clinical success in treating significant stress, chronic pain, and depressive and anxiety symptoms. While IM therapies have demonstrated efficacy for numerous medical conditions, IM for psychological symptoms has been slower to gain recognition in the medical community. OBJECTIVE AND DESIGN: This large, cross-sectional study is the first of its kind to document the psychosocial profiles of 4182 patients at 9 IM clinics that form the BraveNet Practice-Based Research Network (PBRN). RESULTS: IM patients reported higher levels of perceived stress, pain, and depressive symptoms, and lower levels of quality of life compared with national norms. Per provider reports, 60% of patients had at least one of the following: stress (9.3%), fatigue (10.2%), anxiety (7.7%), depression (7.2%), and/or sleep disorders (4.8%). Pain, having both physiological and psychological components, was also included and is the most common condition treated at IM clinics. Those with high stress, psychological conditions, and pain were most frequently treated with acupuncture, IM physician consultation, exercise, chiropractic services, diet/nutrition counseling, and massage. CONCLUSION: With baseline information on clinical presentation and service utilization, future PBRN studies can examine promising interventions delivered at the clinic to treat stress and psychological conditions. PMID- 26044919 TI - Decreased 6-Sulfatoxymelatonin Excretion in Male GH-Deficient Children and Adolescents. AB - AIM: To evaluate melatonin secretion in a group of untreated and treated male growth hormone (GH)-deficient children and adolescents. METHODS: We studied 44 male subjects: 8 untreated GH-deficient patients (GHDnt), 16 treated GH-deficient patients (GHDt) and 20 healthy children and adolescents as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24-hour samples), nocturnal (18.00-8.00 h) and diurnal samples (8.00-18.00 h). Levels of 6-SM were expressed as micrograms excreted per time interval and x0394; values (difference between nighttime and daytime values). RESULTS: Significant differences were observed among the 3 groups of pediatric subjects studied for total 6-SM (p < 0.0001), nocturnal 6-SM (p < 0.0001) and x0394; values (p < 0.0001). Subsequent analysis showed significantly higher levels for total 6-SM, nocturnal 6-SM and nighttime-daytime x0394; in the CG versus the GHDnt (p < 0.01) and in the CG versus the GHDt group (p < 0.01). No significant correlations were found between 6-SM excretion and insulin-like growth factor-1 values in the children and adolescents studied. CONCLUSIONS: GH-deficient patients showed lower levels of 6 SM. Our findings provide a different insight to a further understanding of some chronobiological disorders involved in GH deficiency in children. PMID- 26044920 TI - The effect of trauma and patient related factors on radial head fractures and associated injuries in 440 patients. AB - BACKGROUND: Radial head fractures are commonly interpreted as isolated injuries, and it is assumed that the energy transferred during trauma has its influence on the risk on associated ipsilateral upper limb injuries. However, relationships between Mason classification, mechanism of injury, and associated injuries have been reported only once before in a relatively small population. The purpose of this study was to define whether trauma mechanism and patient related factors are of influence on the type of radial head fracture and associated injuries to the ipsilateral upper limb in 440 patients. METHODS: The radiographs and medical records of 440 patients that presented with a fracture of the radial head were retrospectively analyzed. The medical records of all patients were searched for (1) the trauma mechanism and (2) associated injuries of the ipsilateral upper limb. The mechanism of injury was classified as being low-energy trauma (LET) or high-energy trauma (HET). RESULTS: Associated injuries to the ipsilateral upper limb were present in 46 patients (11%). The mean age of patients with associated injuries (52 years) was significantly higher compared to patients without associated injuries (47 years) (P = 0.038), and female patients with a radial head fracture were older than males. Injury patterns were classified as LET in 266 patients (60%) and as HET in 174 patients. HETs were significantly more common in young men. Associated injuries were not significantly different distributed between HET versus LET (P = 0.82). CONCLUSIONS: Injuries concomitant to radial head fractures were present in 11% of patients and the risk for these associated injuries increases with age. Trauma mechanism did not have a significant influence on the risk of associated injuries. Complex elbow trauma in patients with a radial head fracture seems therefore to be suspected based on patient characteristics, rather than mechanism of injury. PMID- 26044921 TI - The frequency of occurrence of certain corneal conditions by age and sex in Iranian adults. AB - PURPOSE: To determine the prevalence of posterior embryotoxon, corneal opacity, pigment on endothelium, corneal dystrophy, and corneal vascularization in a middle-aged Iranian population, and their association with age and sex. METHODS: In a cross-sectional study with multistage cluster sampling, subjects were chosen from 40 to 64-year-old residents of Shahroud in northern Iran. Participants had ophthalmic examinations before and after pupil dilation. Corneal abnormalities were diagnosed by an ophthalmologist using a slit lamp. RESULTS: Of the 6311 invitees, 5190 people (82.2%) participated; 58.6% (n=3040) were female. The prevalence of posterior embryotoxon, corneal opacity, and pigment on endothelium were 14.7% (95% CI: 13.4-16.0), 4.1% (95% CI: 3.4-4.7) and 1.2% (95% CI: 0.9 1.5), respectively, and corneal dystrophy and corneal vascularization were seen in 0.3% (95% CI: 0.2-0.5) and 3.7% (95% CI: 3.0-4.3), respectively. Unlike posterior embryotoxon, the prevalence of all studied abnormalities increased with age after adjusting for sex. The prevalence of posterior embryotoxon (p=0.023) and corneal dystrophy (p=0.038) was significantly higher in women, and the prevalence of corneal opacity (p<0.001) was significantly higher in men. After adjusting for age, sex, and cataract, cases with corneal opacity and corneal vascularization demonstrated significantly worse uncorrected and corrected visual acuity (p<0.001). CONCLUSION: This report is the first to explore the prevalence of a variety of corneal conditions in a Middle-Eastern population. The findings indicate that one out of five people may have some sort of corneal conditions, and some can impact corrected visual acuity. PMID- 26044922 TI - Concept for analyzing biomechanical parameters in clinical studies. PMID- 26044923 TI - A New Three-Dimensional Template for the Fabrication and Localization of an Autogenous Cartilage Framework during Microtia Reconstruction. AB - AIMS: To assist with the accurate fabrication and localization of a costal cartilage framework for auricular reconstruction, three-dimensional (3D) digital and solid templates including the auricle and guide plate were made for microtia patients. METHODS: The computed tomography data of 60 patients with microtia were included. The 3D digital template of the auricle and guide plate on the healthy side was shaped using MIMICS software with graphic image processing and 3D reconstruction technology. The 3D digital template on the affected side was produced by mirror technique and made into a solid template for clinical application. RESULTS: All 60 patients had a good result of the location and the appearance of the constructed auricle. The time of operation was decreased by an average of half an hour. An individualized 3D solid model of the reconstructed auricular template on the affected side was successfully produced and used in auricular reconstruction. CONCLUSIONS: The new 3D template of the auricle and guide plate may be a major contribution to the engraving, assembling and localization of the microtia auricle in auricular reconstruction. PMID- 26044924 TI - Cancer surveillance using registry data: Results and recommendations for the Lithuanian national prostate cancer early detection programme. AB - INTRODUCTION: We describe long term trends in prostate cancer epidemiology in Lithuania, where a national prostate specific antigen (PSA) test based early detection programme has been running since 2006. METHODS: We used population based cancer registry data, supplemented by information on PSA testing, life expectancy and mortality from Lithuania to examine age-specific prostate cancer incidence, mortality and survival trends among men aged 40+ between 1978 and 2009, as well as life expectancy of screening-eligible men, and the proportion of men with a first PSA test per year since the programme started. RESULTS: The number of prostate cancer patients rose from 2.237 in 1990-1994 to 15.294 in 2005 2009. By 2010, around 70% of the eligible population was tested, on average around two times. The early detection programme brought about the highest prostate cancer incidence peaks ever seen in a country to date. Recent incidence and survival rises in the age groups 75-84 suggest PSA testing in the elderly non eligible population. Life expectancy of men aged 70-74 indicates that less than 30% of patients will live for 15 years and may have a chance to benefit from early detection. CONCLUSIONS: Early detection among men aged 70-74, and particularly among the elderly (75+) may have to be reconsidered. Life expectancy assessment before testing, avoiding a second test among men with low PSA values and increasing the threshold for further evaluation and the screening interval may help reducing harm. Publishing information on treatment modalities, side effects and patient reported quality of life is recommended. PMID- 26044925 TI - Chemoradiotherapy regimens for locoregionally advanced nasopharyngeal carcinoma: A Bayesian network meta-analysis. AB - BACKGROUND: Concurrent chemoradiotherapy followed by adjuvant chemotherapy (CRT A) is often the regimen of choice in locoregionally advanced nasopharyngeal carcinoma (NPC). Many alternative regimens have been reported in the literature, however, it is unknown how effective these regimens are compared to each other due to the lack of direct comparisons. Our objective was to perform a network meta-analysis (NMA) to determine the relative survival benefits of these treatments for locoregionally advanced NPC. METHODS: We performed a systematic review following the Cochrane methodology, using MEDLINE, EMBASE and CENTRAL to identify all randomised controlled trials (RCTs) that compared different chemoradiotherapy regimens for locoregionally advanced NPC. Overall survival (OS) was the primary outcome of interest, and hazard ratios (HRs) were extracted using the Parmar method. Bayesian NMAs with random effects were conducted using WinBUGS. RESULTS: Twenty-five RCTs (5576 patients) were included in this review. All together, these trials compared seven different regimens: radiotherapy (RT), concurrent chemoradiotherapy (CRT), neoadjuvant followed by CRT (N-CRT), CRT-A, RT-A, N-RT and N-RT-A. All regimens that contained CRT performed significantly better than RT. CRT-A did not improve survival compared to CRT alone (0.98; 95% credible regions: 0.71-1.34). For N-CRT versus CRT, the HR was 1.03 (0.69-1.47). When CRT-A was compared against N-CRT, the resulting HR was 0.96 (0.64-1.48). CONCLUSIONS: Adjuvant chemotherapy does not appear to improve survival following CRT. The efficacies of CRT, CRT-A and N-CRT all appeared to be similar. Further studies are warranted to determine the value of additional chemotherapy phases in specific patient subgroups. PMID- 26044926 TI - Assessment of maternal Doppler parameters of ophthalmic artery in fetuses with growth restriction in the third trimester of pregnancy: A case-control study. AB - AIM: The aim of this study was to assess the Doppler parameters of the ophthalmic artery of pregnant women carrying fetuses with growth restriction (FGR) compared with normal fetuses. MATERIAL AND METHODS: A prospective cross-sectional study was conducted with 120 pregnant women (60 FGR and 60 normal fetuses) between 32 and 40 weeks of gestation. FGR diagnosis was based on an estimated fetal weight below the 10th percentile of the Hadlock curve. Ophthalmic artery Doppler images were obtained with a linear transducer, with color Doppler examination of the region medial to the optic nerve. The following indices were obtained: pulsatility index, resistance index, peak systolic velocity, second peak velocity (P2), end diastolic velocity, and P2 / peak systolic velocity ratio. The Mann Whitney U-test and Student's t-test were used to compare the groups with regard to quantitative variables, and the chi(2) -test was used for categorical variables. RESULTS: Pulsatility index and resistance index were significantly lower in pregnant women with FGR than in those with normal fetuses, with P < 0.001 in both indices. P2 and end diastolic velocity were significantly higher in pregnant women with FGR than in those with normal fetuses (P = 0.002 and P = 0.004, respectively). The P2 / peak systolic velocity ratio was significantly higher in the FGR group than in the control group (P < 0.001). In FGR subgroups, with (17 fetuses) and without (43 fetuses) uterine artery Doppler abnormalities, no significant changes were observed between the groups. CONCLUSION: In the third trimester of pregnancy, we observed significant differences in the ophthalmic artery Doppler parameters of pregnant women with FGR compared with those with normal fetuses. PMID- 26044927 TI - Impact of Predator Cues on Responses to Silver Nanoparticles in Daphnia carinata. AB - The past decades have witnessed a boom in nanotechnology that has led to increasing production and application of silver nanoparticles (AgNPs) in the textile industry due to their antimicrobial properties. Increase in the manufacture and use of NPs inevitably has resulted in their increased release into aquatic environments resulting in the exposure of organisms living in these environments. Recently, the risk of exposure to NPs and the potential interaction with biological systems has received increasing attention. The present study investigated the potential effects of predator cues on the toxicity of environmentally relevant concentrations of AgNPs in Daphnia carinata at organismal and biochemical levels. The results of this study show that exposure to environmentally relevant concentrations of AgNPs can result in adverse effects on daphnids with 24- and 48-h LC50 values of 3.56 and 1.75 MUg/L, respectively. Furthermore, significant inhibition of reproduction was observed at concentrations as low as 0.5 MUg/L. Exposure to predator cues alone resulted in an increase in reproduction and inhibition of superoxide dismutase activity in daphnids. However, coexposure to predator cues interacted in an antagonistic manner with AgNPs with a 24-h LC50 value of 10.81 MUg/L compared with 3.56 MUg/L for AgNPs alone. In summary, AgNPs could pose risks to aquatic invertebrates at environmentally relevant concentrations. Interestingly, the presence of other factors, such as predator cues, moderated the effects of exposure to AgNPs. Therefore, there is a need to further investigate the potential interactions between NPs and biological factors that can modulate toxicity of NPs for application to the risk assessment of aquatic invertebrates. PMID- 26044928 TI - Differentiating the Spatiotemporal Distribution of Natural and Anthropogenic Processes on River Water-Quality Variation Using a Self-Organizing Map With Factor Analysis. AB - To elucidate the historical improvement and advanced measure of river water quality in the Taipei metropolitan area, this study applied the self-organizing map (SOM) technique with factor analysis (FA) to differentiate the spatiotemporal distribution of natural and anthropogenic processes on river water-quality variation spanning two decades. The SOM clustered river water quality into five groups: very low pollution, low pollution, moderate pollution, high pollution, and very high pollution. FA was then used to extract four latent factors that dominated water quality from 1991 to 2011 including three anthropogenic process factors (organic, industrial, and copper pollution) and one natural process factor [suspended solids (SS) pollution]. The SOM revealed that the water quality improved substantially over time. However, the downstream river water quality was still classified as high pollution because of an increase in anthropogenic activity. FA showed the spatiotemporal pattern of each factor score decreasing over time, but the organic pollution factor downstream of the Tamsui River, as well as the SS factor scores in the upstream major tributary (the Dahan Stream), remained within the high pollution level. Therefore, we suggest that public sewage-treatment plants should be upgraded from their current secondary biological processing to advanced treatment processing. The conservation of water and soil must also be reinforced to decrease the SS loading of the Dahan Stream from natural erosion processes in the future. PMID- 26044929 TI - Distribution, Sources, and Potential Ecotoxicological Risk of Polycyclic Aromatic Hydrocarbons in Surface Sediments from Bahia Blanca Estuary, Argentina. AB - Thirty-four surface sediment samples were collected from Bahia Blanca Estuary, Argentina, to evaluate polycyclic aromatic hydrocarbon (PAH) contamination and ecotoxicity risk by applying sediment-quality guidelines (SQGs) and toxic equivalent factors (TEQ). Total concentrations of 17 parent PAHs, including the 16 United States Environmental Protection Agency priority PAHs, were measured using gas chromatography-mass spectrometry, and their levels ranged from 19.7 to 30,054.5 ng/g dry weight. The greatest values were found near the urban/industrial core and decreasing as the distance from that site increased. Molecular ratios determined mixed sources of PAHs with a slight imposition of pyrolitic over the petrogenic inputs. The ecotoxicological evaluation, based on the SQG model, showed that some of the individual PAHs were in excess of the effects range low (ERL) and the effects range median's threshold; then, predicted occasional (ERL) and frequent adverse effects over the surrounding biota at the area of study were determined. Total PAH levels were expressed as benzo-a-pyrene TEQ and compared with literature data. PMID- 26044930 TI - Molecular cloning of class III chitinase gene from Avicennia marina and its expression analysis in response to cadmium and lead stress. AB - Mangrove species have high tolerance to heavy metal pollution. Chitinases have been widely reported as defense proteins in response to heavy metal stress in terrestrial plants. In this study, a full-length cDNA sequence encoding an acidic and basic class III chitinase (AmCHI III) was cloned by using RT-PCR and RACE methods in Avicennia marina. AmCHI III mRNA expression in leaf of A. marina were investigated under Cd, Pb stresses on using real-time quantitative PCR. The deduced AmCHI III protein consists of 302 amino acids, including a signal putative peptide region, and a catalytic domain. Homology modeling of the catalytic domain revealed a typical molecular structure of class III plant chitinases. Results further demonstrated that the regulation of AmCHI III mRNA expression in leaves was strongly dependent on Cd, Pb stresses. AmCHI III mRNA expressions were significantly increased in response to Cd, Pb, and peaked at 7 days Cd-exposure, 7 days Pb-exposure, respectively. AmCHI III mRNA expression exhibited more sensitive to Pb stress than Cd stress. This work was the first time cloing chitinase from A. marina, and it brought evidence on chitinase gene involving in heavy metals (Cd(2+) and Pb(2+)) resistance or detoxification in plants. Further studies including the promoter and upstream regulation, gene over expression and the response of mangrove chitinases to other stresses will shed more light on the role of chitinase in mangrove plants. PMID- 26044931 TI - Cloning of the Aegiceras corniculatum class I chitinase gene (AcCHI I) and the response of AcCHI I mRNA expression to cadmium stress. AB - Chitinases in terrestrial plants have been reported these are involved in heavy metal tolerance/detoxification. This is the first attempt to reveal chitinase gene (AcCHI I) and its function on metal detoxification in mangroves Aegiceras corniculatum. RT-PCR and RACE techniques were used to clone AcCHI I, while real time quantitative PCR was employed to assess AcCHI I mRNA expressions in response to Cadmium (Cd). The deduced AcCHI I protein consists of 316 amino acids, including a signal peptide region, a chitin-binding domain (CBD) and a catalytic domain. Protein homology modeling was performed to identify potential features in AcCHI I. The CBD structure of AcCHI I might be critical for metal tolerance/homeostasis of the plant. Clear tissue-specific differences in AcCHI I expression were detected, with higher transcript levels detected in leaves. Results demonstrated that a short duration of Cd exposure (e.g., 3 days) promoted AcCHI I expression in roots. Upregulated expression was also detected in leaves under 10 mg/kg Cd concentration stress. The present study demonstrates that AcCHI I may play an important role in Cd tolerance/homeostasis in the plant. Further studies of the AcCHI I protein, gene overexpression, the promoter and upstream regulation will be necessary for clarifying the functions of AcCHI I. PMID- 26044932 TI - Mercury and cortisol in Western Hudson Bay polar bear hair. AB - Non-invasive methods of assessing animal health and life history are becoming increasingly popular in wildlife research; hair samples from polar bears (Ursus maritimus), are being used to study an ever broader range of anthropogenic and endocrine compounds. A number of contaminants are known to disrupt endocrine function in polar bears. However, the relationship between mercury and cortisol remains unknown, although mercury is an endocrine disruptor in other species. Here, we examine the relationship between concentrations of cortisol and total mercury (THg) analyzed in guard hair from 378 polar bears (184 females, 194 males) sampled in Western Hudson Bay, 2004-2012. The difference in mean cortisol concentration between female (0.8 +/- 0.6 pg/mg) and male (0.7 +/- 0.5 pg/mg) polar bears bordered on significance (p = 0.054). However, mean mercury concentration was significantly greater (p = 0.009) in females (4.7 +/- 1.4 MUg/g) than males (4.3 +/- 1.2 MUg/g). Hair cortisol in males was significantly influenced by mercury, age, and fatness, as well as interactions between mercury and year, mercury and fatness, and year and fatness (all: p < 0.03) (multiple regression analysis, whole model: r(2) = 0.14, F(7,185) = 4.43, p = 0.0001). Fatness was the only significant variable in the multiple regression analysis for females (r(2) = 0.06, F(1,182) = 13.0, p = 0.0004). In conclusion, a significant, but complex, relationship was found between mercury and cortisol concentrations in hair from male, but not female, polar bears. PMID- 26044933 TI - Plasmakinetic Vapor Enucleation of the Prostate with Button Electrode versus Plasmakinetic Resection of the Prostate for Benign Prostatic Enlargement >90 ml: Perioperative and 3-Month Follow-Up Results of a Prospective, Randomized Clinical Trial. AB - OBJECTIVE: To evaluate plasmakinetic vapor enucleation of the prostate (PVEP) with button electrode and plasmakinetic resection of the prostate (PKRP) in patients with urinary symptoms due to benign prostatic enlargement (BPE) >90 ml. METHODS: A total of 112 patients with symptomatic BPE were randomly assigned to either PKRP or PVEP prospectively from August 2012 to May 2014 in our department. Perioperative and postoperative data were investigated during a 3-month follow up. RESULTS: PVEP was significantly superior to PKRP in terms of operation time (63.9 +/- 7.7 vs. 78.1 +/- 13.6 min, p < 0.001), hemoglobin loss (1.18 +/- 0.30 vs. 1.63 +/- 0.38 g/dl, p < 0.001), serum sodium decrease (2.9 +/- 0.7 vs. 4.3 +/ 0.8 mmol/l, p < 0.001), catheterization duration (49.3 +/- 12.2 vs. 78.1 +/- 14.8 h, p < 0.001) and hospital stay (100.2 +/- 28.3 vs. 116.0 +/- 29.2 h, p = 0.004). There were no statistical differences in blood transfusion between the two groups. In addition, there were no statistical differences in maximum urinary flow rate, International Prostate Symptom Score, postvoid residual urine volume, quality-of-life score, transient incontinence, and urethral stricture at 3 months postoperatively. CONCLUSIONS: PVEP with button electrode is an equally effective technique for treatment of large BPE with PKRP, with more safety and faster recovery. It may become the superior alternative to PKRP for patients with large BPE. PMID- 26044934 TI - Preoxygenation and general anesthesia: a review. AB - Because intubation can potentially become a lengthy procedure, the risk of arterial oxygen (O2) desaturation during intubation must be considered. Preoxygenation should be routine, as oxygen reserves are not always sufficient to cover the duration of intubation. Three minutes of spontaneous breathing at FiO2=1 allows denitrogenation with FAO2 close to 95% in patients with normal lung function. Tolerable apnea time, defined as the delay until the SpO2 reaches 90%, can be extended up to almost 10 minutes after 3 minutes of classic preoxygenation. Eight deep breaths within 60 seconds allow a comparable increase in O2 reserves. For effectiveness, the equipment must be adapted and tightly fitted. Inadequate preoxygenation (FeO2 <90% after three minutes tidal volume breathing) is frequently observed. Predictive risk factors for inadequate pre oxygenation share overlap with criteria predictive of difficult mask ventilation. In cases of respiratory failure, oxygenation can be improved by positive end expiration pressure or by pressure support. In morbidly obese patients, preoxygenation is enhanced in a seated position (25 degrees ) and by use of positive pressure ventilation. O2 can also be administered during the intubation procedure; techniques include pharyngeal O2, special oxygen mask, or even pressure support ventilation for patients with spontaneous ventilation or positive pressure ventilation to the facial mask for apneic patients. Clinicians (especially anesthesiologists trained in ENT and traumatology) must be prepared to handle life-threatening emergency situations by alternate methods including trans-tracheal ventilation. The availability of equipment and training are two essential components of adequate preparation. PMID- 26044935 TI - Ethical issues associated with in-hospital emergency from the Medical Emergency Team's perspective: a national survey. AB - BACKGROUND: Medical Emergency Teams (METs) are frequently involved in ethical issues associated to in-hospital emergencies, like decisions about end-of-life care and intensive care unit (ICU) admission. MET involvement offers both advantages and disadvantages, especially when an immediate decision must be made. We performed a survey among Italian intensivists/anesthesiologists evaluating MET's perspective on the most relevant ethical aspects faced in daily practice. METHODS: A questionnaire was developed on behalf of the Italian scientific society of anesthesia and intensive care (SIAARTI) and administered to its members. Decision making criteria applied by respondents when dealing with ethical aspects, the estimated incidence of conflicts due to ethical issues and the impact on the respondents' emotional and moral distress were explored. RESULTS: The questionnaire was completed by 327 intensivists/anesthesiologists. Patient life-expectancy, wishes, and the quality of life were the factors most considered for decisions. Conflicts with ward physicians were reported by most respondents; disagreement on appropriateness of ICU admission and family unpreparedness to the imminent patient death were the most frequent reasons. Half of respondents considered that in case of conflicts the final decision should be made by the MET. Conflicts were generally recognized as causing increased and moral distress within the MET members. Few respondents reported that dedicated protocols or training were locally available. CONCLUSION: Italian intensivists/anesthesiologists reported that ethical issues associated with in hospital emergencies are occurring commonly and are having a significant negative impact on MET well-being. Conflicts with ward physicians happen frequently. They also conveyed that hospitals don't offer ethics training and have no protocols in place to address ethical issues. PMID- 26044936 TI - Repeated heart rate measurement and cardiovascular outcomes in left ventricular systolic dysfunction. AB - BACKGROUND: Elevated resting heart rate is associated with increased cardiovascular risk, particularly in patients with left ventricular systolic dysfunction. Heart rate is not monitored routinely in these patients. We hypothesized that routine monitoring of heart rate would increase its prognostic value in patients with left ventricular systolic dysfunction. METHODS: We analyzed the relationship between heart rate measurements and a range of adverse cardiovascular outcomes, including hospitalization for worsening heart failure, in the pooled placebo-treated patients from the morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) trial and Systolic Heart failure treatment with the If inhibitor ivabradine (SHIFT) Trial, using standard and time-varying covariate Cox proportional hazards models. By adjusting for other prognostic factors, models were fitted for baseline heart rate alone or for time-updated heart rate (latest heart rate) alone or corrected for baseline heart rate or for immediate previous time-updated heart rate. RESULTS: Baseline heart rate was strongly associated with all outcomes apart from hospitalization for myocardial infarction. Time-updated heart rate increased the strengths of associations for all outcomes. Adjustment for baseline heart rate or immediate previous time updated heart rate modestly reduced the prognostic importance of time-updated heart rate. For hospitalization for worsening heart failure, each 5 beats/min increase in baseline heart rate and time-updated heart rate was associated with a 15% (95% confidence interval, 12-18) and 22% (confidence interval, 19-40) increase in risk, respectively. Even after correction, the prognostic value of time-updated heart rate remained greater. CONCLUSIONS: In patients with left ventricular systolic dysfunction, time-updated heart rate is more strongly related with adverse cardiovascular outcomes than baseline heart rate. Heart rate should be measured to assess cardiovascular risk at all assessments of patients with left ventricular systolic dysfunction. PMID- 26044937 TI - Tools to Keep the Clock Ticking: Molecular Approaches to Treat Sinus Node Dysfunction. PMID- 26044941 TI - Medicaid family planning waivers in 3 States: did they reduce unwanted births? AB - Effects of Medicaid family planning waivers on unintended births and contraceptive use postpartum were examined in Illinois, New York, and Oregon using the Pregnancy Risk Assessment Monitoring System. Estimates for women who would be Medicaid eligible "if" pregnant in the waiver states and states without expansions were derived using a difference-in-differences approach. Waivers in New York and Illinois were associated with almost a 5.0 percentage point reduction in unwanted births among adults and with a 7 to 8.0 percentage point reduction, among youth less than 21 years of age. Oregon's waiver was associated with an almost 13 percentage point reduction in unintended, mostly mistimed, births. No statistically significant effects were found on contraceptive use. PMID- 26044942 TI - Extending the two faces of subjective randomness: From the gambler's and hot-hand fallacies toward a hierarchy of binary sequence perception. AB - In this study, we examined perceptions of binary sequences under uncertainty in an attempt to depict a holistic and unifying framework. The first experiment applied a projection method that motivated participants to observe binary series and provide descriptions of their possible underlying mechanisms or processes. This procedure revealed four distinct perceptual categories: two previously studied categories of chance mechanisms and human performance, associated with the gambler's and hot-hand fallacies, and two newly identified categories-periods and processes and traits and preferences. The next three experiments tested the associations between the four categories and the alternation rates of the observed sequences under three categorical decisions structures: screening, discrimination, and classification. The results reveal the relativity of binary sequence perception. They show that the categories of chance mechanisms and periods and processes reflected rather stable perception across all tested conditions, whereas the other two categories were more susceptible to the context in which they were embedded. The findings support previous research on the gambler's fallacy and show that the hot-hand fallacy is confined to comparisons of human performance and chance mechanisms. A proposed developmental hierarchy suggests that all four categories embody basic cognitive structures that assist in detecting, decoding, and interpreting both inanimate and social aspects of the environment. PMID- 26044943 TI - Deadlines in space: Selective effects of coordinate spatial processing in multitasking. AB - Many everyday activities require coordination and monitoring of multiple deadlines. One way to handle these temporal demands might be to represent future goals and deadlines as a pattern of spatial relations. We examined the hypothesis that spatial ability, in addition to executive functioning, contributes to individual differences in multitasking. In two studies, participants completed a multitasking session in which they monitored four digital clocks running at different rates. In Study 1, we found that individual differences in spatial ability and executive functions were independent predictors of multiple-task performance. In Study 2, we found that individual differences in specific spatial abilities were selectively related to multiple-task performance, as only coordinate spatial processing, but not categorical, predicted multitasking, even beyond executive functioning and numeracy. In both studies, males outperformed females in spatial ability and multitasking and in Study 2 these sex differences generalized to a simulation of everyday multitasking. Menstrual changes moderated the effects on multitasking, in that sex differences in coordinate spatial processing and multitasking were observed between males and females in the luteal phase of the menstrual cycle, but not between males and females at menses. Overall, these findings suggest that multiple-task performance reflects independent contributions of spatial ability and executive functioning. Furthermore, our results support the distinction of categorical versus coordinate spatial processing, and suggest that these two basic relational processes are selectively affected by female sex hormones and differentially effective in transforming and handling temporal patterns as spatial relations in the context of multitasking. PMID- 26044944 TI - Evaluation of clinical presentation and referral indications for ultrasound guided fine-needle aspiration biopsy of the thyroid as possible predictors of thyroid cancer. AB - BACKGROUND: Whether initial clinical presentation and thyroid ultrasonography referral indications can significantly predict malignant/suspicious for malignancy (Bethesda System for Reporting Thyroid Cytopathology [Bethesda] V/VI) thyroid ultrasound-guided fine-needle aspiration (FNA) cytology results is unknown. METHODS: Between January 2010 and May 2014, we performed 705 thyroid ultrasound-guided FNA biopsies, according to the American Thyroid Association (ATA) guidelines. Univariate analysis was used to identify significant predictors for Bethesda V/VI thyroid ultrasound-guided FNA cytology, including age, sex, imaging modality, thyroid dysfunction, neck pain, breathing difficulties, dysphagia, odynophagia, fatigue, lateral cervical mass, parotid mass, and hyperparathyroidism. RESULTS: Sixty percent of patients were referred to thyroid ultrasound-guided FNA because of thyroid incidentalomas and 40% because of palpable thyroid nodules found on physical examination. Only positron emission tomography (PET)-CT emerged as being a significant predictor for Bethesda V/VI thyroid ultrasound-guided FNA cytology (odds ratio [OR] = 5.64; 95% confidence interval [CI] = 1.16-27.33; p = .03). CONCLUSION: Patient symptomatology and initial clinical thyroid ultrasound-guided FNA referral indications cannot predict the nature of thyroid nodules. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E991-E995, 2016. PMID- 26044945 TI - Evaluation of viral load in saliva from patients with chronic hepatitis C infection. AB - Hepatitis C virus can be detected in blood and other bodily fluids, such as saliva. The aim of this study was to detect and quantify the HCV-RNA in saliva and plasma from patients with chronic hepatitis C infections, as well as check the level of viral load in sex groups (age, ethnicity and virus subtypes). Whole saliva and blood from 70 patients with chronic hepatitis C infections attended at the department of gastroenterology from University Hospital. The HCV-RNA load was performed by qRT-PCR using Sybr Green I master mix. HCV-RNA was detected in 80% (56/70) of patients in saliva and 92.85% (65/70) in plasma. The median of the viral load in the plasma was of 4.87 log10, and in saliva, it was 3.32log10, (p = 0.0005). Female patients and black patients exhibited a negative correlation between the HCV-RNA load in saliva vs. the HCV-RNA load in plasma (r = -0.3172, CI95% -0.6240 to -0.03736, p = 0.0491) and (r = -0.3141; IC95% -0.6069 to 0.05926; p = 0.0209), respectively. HCV-RNA was detected and quantified in saliva samples, and according to the quantification levels, saliva may be a possible transmission source of HCV, particularly in women and people of black ethnicity who develop chronic HCV infections. PMID- 26044946 TI - Occupational Therapy Practitioners with Occupational Musculoskeletal Injuries: Prevalence and Risk Factors. AB - PURPOSE: The purpose of this study was to examine the prevalence and risk factors of occupational musculoskeletal injuries (OMIs) among occupational therapy practitioners over a 12-month period. METHOD: A self-administered questionnaire mailed to 500 randomly selected practicing occupational therapists (OTs) and occupational therapy assistants (OTAs) living in the state of Texas. RESULTS: A response rate of 38 % was attained with 192 questionnaires returned. In a 12 months working period, 23 % of occupational therapy practitioners experienced musculoskeletal injuries. Muscle strain (52 %) was most reported injury and lower back (32 %) was most injured body part. Years of practicing experience (t = 2.83, p = 0.01), and age x(2)(2, N = 192) = 8.28, p = 0.02 were found as significant factors associated with injuries among OTAs. No factors were significantly associated with injuries among OTs. CONCLUSION: Patient handling was the primary factor associated with injuries. Also, minimal experience and older age were concluded as risk factors that might contribute to OMIs. PMID- 26044947 TI - Psychosocial Working Environment and Risk of Adverse Cardiac Events in Patients Treated for Coronary Heart Disease. AB - INTRODUCTION: During the last decades a possible association between psychosocial working environment and increased risk of coronary heart disease (CHD) has been debated and moderate evidence supports that high psychological demands, lack of social support and iso-strain (the combination of high job strain and lack of social support) is associated with primary CHD. Whether psychosocial working environment plays a role as risk factor for new cardiac events and readmissions in patients with existing cardiovascular disease is less studied. METHODS: A cohort of patients <67 years treated with percutaneous coronary intervention (PCI) was established in 2006. Three months after PCI patients answered a questionnaire about their psychosocial working environment. Patients were followed in the Danish National Patient Registry and the Danish Civil Registration System for 3+ years to identify adverse cardiac events and death. We analysed the association between psychosocial working environment and adverse cardiac events by Cox Regression. RESULTS: A number of 528 patients had returned to work 12 weeks after PCI, while 97 were still sick-listed. We identified 12 deaths and 211 other events during follow-up. We found no statistically significant associations between psychosocial working environment and risk of adverse cardiac events and readmissions or mortality. CONCLUSION: The psychosocial working environment was not associated with adverse cardiac events. PMID- 26044948 TI - Phylogeography of the arid-adapted Malagasy bullfrog, Laliostoma labrosum, influenced by past connectivity and habitat stability. AB - The rainforest biome of eastern Madagascar is renowned for its extraordinary biodiversity and restricted distribution ranges of many species, whereas the arid western region of the island is relatively species poor. We provide insight into the biogeography of western Madagascar by analyzing a multilocus phylogeographic dataset assembled for an amphibian, the widespread Malagasy bullfrog, Laliostoma labrosum. We find no cryptic species in L. labrosum (maximum 1.1% pairwise genetic distance between individuals in the 16S rRNA gene) attributable to considerable gene flow at the regional level as shown by genetic admixture in both mtDNA and three nuclear loci, especially in central Madagascar. Low breeding site fidelity, viewed as an adaptation to the unreliability of standing pools of freshwater in dry and seasonal environments, and a ubiquitous distribution within its range may underlie overall low genetic differentiation. Moreover, reductions in population size associated with periods of high aridity in western Madagascar may have purged DNA variation in this species. The mtDNA gene tree revealed seven major phylogroups within this species, five of which show mostly non-overlapping distributions. The nested positions of the northern and central mtDNA phylogroups imply a southwestern origin for all extant mtDNA lineages in L. labrosum. The current phylogeography of this species and paleo-distributions of major mtDNA lineages suggest five potential refugia in northern, western and southwestern Madagascar, likely the result of Pleistocene range fragmentation during drier and cooler climates. Lineage sorting in mtDNA and nuclear loci highlighted a main phylogeographic break between populations north and south of the Sambirano region, suggesting a role of the coastal Sambirano rainforest as a barrier to gene flow. Paleo-species distribution models and dispersal networks suggest that the persistence of some refugial populations was mainly determined by high population connectivity through space and time. PMID- 26044949 TI - Inferring drug-disease associations based on known protein complexes. AB - Inferring drug-disease associations is critical in unveiling disease mechanisms, as well as discovering novel functions of available drugs, or drug repositioning. Previous work is primarily based on drug-gene-disease relationship, which throws away many important information since genes execute their functions through interacting others. To overcome this issue, we propose a novel methodology that discover the drug-disease association based on protein complexes. Firstly, the integrated heterogeneous network consisting of drugs, protein complexes, and disease are constructed, where we assign weights to the drug-disease association by using probability. Then, from the tripartite network, we get the indirect weighted relationships between drugs and diseases. The larger the weight, the higher the reliability of the correlation. We apply our method to mental disorders and hypertension, and validate the result by using comparative toxicogenomics database. Our ranked results can be directly reinforced by existing biomedical literature, suggesting that our proposed method obtains higher specificity and sensitivity. The proposed method offers new insight into drug-disease discovery. Our method is publicly available at http://1.complexdrug.sinaapp.com/Drug_Complex_Disease/Data_Download.html. PMID- 26044950 TI - The role of targeting kinase activity by natural products in cancer chemoprevention and chemotherapy (Review). AB - The WHO clearly identifies tumors as a curable or a chronic disease. The use of natural agents in cancer prevention and therapy is currently playing an important role. Our laboratory has been investigating various natural phenolic compounds, including grifolin, neoalbaconol and epigallocatechin-3-gallate (EGCG). In the present review, we focus on the anticancer activities and the molecular mechanisms of these compounds. Grifolin, a secondary metabolite isolated from the mushroom Albatrellus confluens, has been shown to inhibit cell growth and induce cell cycle arrest in multiple cancer cell lines by targeting extracellular signal regulated kinase 1 or by upregulating death-associated protein kinase 1 (DAPK1) via p53. We also demonstrated that neoalbaconol, a novel small-molecular compound with a drimane-type sesquiterpenoid structure obtained from Albatrellus confluens, regulates cell metabolism by targeting 3-phosphoinositide-dependent protein kinase 1 (PDK1) and inhibits cancer cell growth. EGCG, a well known catechin found in tea, has gained much attention for its anticancer effects. Previously, we found that it regulates EBV lytic infection through the phosphoinositide-3 kinase/Akt (PI3K/Akt) and mitogen-activated protein kinase (MAPK) pathways in EBV-positive cancer cells. Therefore, these natural agents could be used as potential leading compounds in the prevention of tumor progression and/or EBV-related cancer. PMID- 26044951 TI - HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas. AB - Radiotherapy is an essential part of multi-modal treatment for soft tissue sarcomas. Treatment failure is commonly attributed to radioresistance, but comprehensive analyses of radiosensitivity are not available, and suitable biomarkers or candidates for targeted radiosensitization are scarce. Here, we systematically analyzed the intrinsic radioresistance of a panel of soft tissue sarcoma cell lines, and extracted scores of radioresistance by principal component analysis (PCA). To identify molecular markers of radioresistance, transcriptomic profiling of DNA damage response regulators was performed. The expression levels of HSP90 and its clients ATR, ATM, and NBS1 revealed strong, positive correlations with the PCA-derived radioresistance scores. Their functional involvement was addressed by HSP90 inhibition, which preferentially sensitized radioresistant sarcoma cells and was accompanied by delayed gamma-H2AX foci clearance and HSP90 client protein degradation. The induction of apoptosis and necrosis was not significantly enhanced, but increased levels of basal and irradiation-induced senescence upon HSP90 inhibition were detected. Finally, evaluation of our findings in the TCGA soft tissue sarcoma cohort revealed elevated expression levels of HSP90, ATR, ATM, and NBS1 in a relevant subset of cases with particularly poor prognosis, which might preferentially benefit from HSP90 inhibition in combination with radiotherapy in the future. PMID- 26044952 TI - Functional characterization of the nitrogen permease regulator-like-2 candidate tumor suppressor gene in colorectal cancer cell lines. AB - The nitrogen permease regulator-like-2 (NPRL2) gene is a candidate tumor suppressor gene, which has been identified in the 3p21.3 human chromosome region. Decreased expression levels of NPRL2 have been observed in colorectal cancer (CRC) tissues, however, the function of NPRL2 in CRC progression remains to be fully elucidated. The present study investigated the biological characteristics of the HCT116 and HT29 CRC cell lines overexpressing exogenous NPRL2. NPRL2 recombinant lentiviral vectors were also constructed and transfected in the present study. Cell growth was determined using a Cell Counting Kit-8 assay and a colony formation assay. The cell cycle and rate of apoptosis were assessed using flow cytometric analysis. Transwell assays were used to evaluate cell invasion. The protein expression of phosphorylated (p)-AKT and caspase 3, B-cell lymphoma 2 (Bcl2) and Bcl-2-associated X protein apoptosis-associated genes, were detected using western blotting. The results revealed that NPRL2 overexpression inhibited cell growth, induced cell cycle G1 phase arrest, promoted apoptosis and inhibited invasion in the two human CRC cell lines. Furthermore, the protein expression levels of p-AKT and Bcl2 were significantly reduced in the NPRL2-transfected HCT116 and HT29 cells, compared with the mock-transfected group and control group, while the protein expression of caspase-3 was increased. Therefore, NPRL2 acted as a functional tumor suppressor in the CRC cell lines. PMID- 26044954 TI - Bronchoscopy-Guided Cooled Radiofrequency Ablation as a Novel Intervention Therapy for Peripheral Lung Cancer. AB - BACKGROUND: Our previous animal and preliminary human studies indicated that bronchoscopy-guided cooled radiofrequency ablation (RFA) for the lung is a safe and feasible procedure without major complications. OBJECTIVES: The present study was performed to evaluate the safety, effectiveness and feasibility of computed tomography (CT)-guided bronchoscopy cooled RFA in patients with medically inoperable non-small-cell lung cancer (NSCLC). METHODS: Patients with pathologically diagnosed NSCLC, who had no lymph node involvement or distant metastases (T1-2aN0M0) but were not surgical candidates because of comorbidities (e.g., synchronous multiple nodules, advanced age, cardiovascular disease, poor pulmonary function, etc.) were enrolled in the present study. The diagnosis and location between the nearest bronchus and target tumor were made by CT-guided bronchoscopy before the treatment. A total of 28 bronchoscopy-guided cooled RFA procedures were performed in 20 patients. After treatment, serial CT imaging was performed as follow-up. RESULTS: Eleven lesions showed significant reductions in tumor size and 8 lesions showed stability, resulting in a local control rate of 82.6%. The median progression-free survival was 35 months (95% confidence interval: 22-45 months), and the 5-year overall survival was 61.5% (95% confidence interval: 36-87%). Three patients developed an acute ablation-related reaction (fever, chest pain) and required hospitalization but improved with conservative treatment. There were no other adverse events in the present study. CONCLUSIONS: CT-guided bronchoscopy cooled RFA is applicable for only highly selected subjects; however, our trial may be an alternative strategy, especially for disease local control in medically inoperable patients with stage I NSCLC. PMID- 26044953 TI - The pericyte as a cellular regulator of penile erection and a novel therapeutic target for erectile dysfunction. AB - Pericytes are known to play critical roles in vascular development and homeostasis. However, the distribution of cavernous pericytes and their roles in penile erection is unclear. Herein we report that the pericytes are abundantly distributed in microvessels of the subtunical area and dorsal nerve bundle of mice, followed by dorsal vein and cavernous sinusoids. We further confirmed the presence of pericytes in human corpus cavernosum tissue and successfully isolated pericytes from mouse penis. Cavernous pericyte contents from diabetic mice and tube formation of cultured pericytes in high glucose condition were greatly reduced compared with those in normal conditions. Suppression of pericyte function with anti-PDGFR-beta blocking antibody deteriorated erectile function and tube formation in vivo and in vitro diabetic condition. In contrast, enhanced pericyte function with HGF protein restored cavernous pericyte content in diabetic mice, and significantly decreased cavernous permeability in diabetic mice and in pericytes-endothelial cell co-culture system, which induced significant recovery of erectile function. Overall, these findings showed the presence and distribution of pericytes in the penis of normal or pathologic condition and documented their role in the regulation of cavernous permeability and penile erection, which ultimately explore novel therapeutics of erectile dysfunction targeting pericyte function. PMID- 26044955 TI - Dietary Elimination of Soybean Components Enhances Allergic Immune Response to Peanuts in BALB/c Mice. AB - BACKGROUND: Food allergy research is hampered by a lack of animal models that consistently mimic human food allergic responses. Laboratory mice are generally fed grain-based chow made with large amounts of soybeans rich in immunomodulatory isoflavones. We tested the role of dietary soy components in the induction of food allergic responses in the BALB/c mouse strain, which is known to be resistant to anaphylaxis when orally challenged by food allergens. METHODS: Mice were fed a soy-free diet for 2 generations. After weaning, mice were maintained on the same diet or fed a diet containing soy isoflavones, i.e. genistein and daidzein, followed by weekly oral sensitizations with crude peanut extract plus cholera toxin and finally challenged at week 7. The anaphylactic symptoms, body temperature, peanut-specific antibodies and mast cell degranulation were assessed. RESULTS: Soy-free diet mice showed significantly higher anaphylactic symptom scores and mast cell degranulation after challenge and higher peanut specific antibody levels than mice fed regular chow. Introduction of a regular soy diet or an isoflavone diet to soy-free diet mice significantly suppressed the allergic reactions compared to the soy-free diet. CONCLUSION: Rodent diet is an important variable and needs to be taken into consideration when designing experiments involving animal models. Our results indicate that elimination of soy components from the diet enhances peanut sensitization in BALB/c mice. In addition to serving as a valuable tool to mimic human food allergy, the dietary influence on the immune response could have far-reaching consequences in research involving animal models. PMID- 26044957 TI - MicroRNA-16 suppresses metastasis in an orthotopic, but not autochthonous, mouse model of soft tissue sarcoma. AB - MicroRNAs (miRNAs) can regulate tumor cell invasion and metastasis in a tumor specific manner. We recently demonstrated that global downregulation of miRNAs after deleting dicer can promote development of distant metastases in a mouse model of primary soft tissue sarcoma (STS). In this study, we identified miRNAs that are differentially downregulated in metastatic STS in both human and mouse, and investigated the role of these miRNAs in metastasis. miRNA- TaqMan PCR arrays showed a global downregulation of miRNAs in metastatic human sarcomas. Similar analysis in mouse metastatic sarcomas revealed overlap for several downregulated miRNAs including miR-16, miR-103, miR-146a, miR-223, miR-342 and miR-511. Restoration of these downregulated miRNAs in mouse primary sarcoma cell lines showed that miR-16, but not other downregulated miRNAs, was able to significantly suppress both migration and invasion in vitro, without altering cell proliferation. In addition, orthotopic transplantation of a sarcoma cell line stably expressing miR-16 into the muscle of immunocompromised mice revealed that restoration of miR-16 can significantly decrease lung metastasis in vivo. However, no change in the rate of lung metastasis was observed when miR-16 was deleted in mouse primary sarcomas at sarcoma initiation. Taken together, these results indicate that miR-16 can have metastasis-suppressing properties both in vitro and in vivo. However, the loss-of-function experiments in autochthonous tumors indicate that loss of miR-16 is not sufficient to promote metastasis in vivo. PMID- 26044956 TI - Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia. AB - Apolipoprotein C-II (APOC2) is an obligatory activator of lipoprotein lipase. Human patients with APOC2 deficiency display severe hypertriglyceridemia while consuming a normal diet, often manifesting xanthomas, lipemia retinalis and pancreatitis. Hypertriglyceridemia is also an important risk factor for development of cardiovascular disease. Animal models to study hypertriglyceridemia are limited, with no Apoc2-knockout mouse reported. To develop a genetic model of hypertriglyceridemia, we generated an apoc2 mutant zebrafish characterized by the loss of Apoc2 function. apoc2 mutants show decreased plasma lipase activity and display chylomicronemia and severe hypertriglyceridemia, which closely resemble the phenotype observed in human patients with APOC2 deficiency. The hypertriglyceridemia in apoc2 mutants is rescued by injection of plasma from wild-type zebrafish or by injection of a human APOC2 mimetic peptide. Consistent with a previous report of a transient apoc2 knockdown, apoc2 mutant larvae have a minor delay in yolk consumption and angiogenesis. Furthermore, apoc2 mutants fed a normal diet accumulate lipid and lipid-laden macrophages in the vasculature, which resemble early events in the development of human atherosclerotic lesions. In addition, apoc2 mutant embryos show ectopic overgrowth of pancreas. Taken together, our data suggest that the apoc2 mutant zebrafish is a robust and versatile animal model to study hypertriglyceridemia and the mechanisms involved in the pathogenesis of associated human diseases. PMID- 26044959 TI - Using the avian mutant talpid2 as a disease model for understanding the oral facial phenotypes of oral-facial-digital syndrome. AB - Oral-facial-digital syndrome (OFD) is a ciliopathy that is characterized by oral facial abnormalities, including cleft lip and/or palate, broad nasal root, dental anomalies, micrognathia and glossal defects. In addition, these individuals have several other characteristic abnormalities that are typical of a ciliopathy, including polysyndactyly, polycystic kidneys and hypoplasia of the cerebellum. Recently, a subset of OFD cases in humans has been linked to mutations in the centriolar protein C2 Ca(2+)-dependent domain-containing 3 (C2CD3). Our previous work identified mutations in C2CD3 as the causal genetic lesion for the avian talpid(2) mutant. Based on this common genetic etiology, we re-examined the talpid(2) mutant biochemically and phenotypically for characteristics of OFD. We found that, as in OFD-affected individuals, protein-protein interactions between C2CD3 and oral-facial-digital syndrome 1 protein (OFD1) are reduced in talpid(2) cells. Furthermore, we found that all common phenotypes were conserved between OFD-affected individuals and avian talpid(2) mutants. In light of these findings, we utilized the talpid(2) model to examine the cellular basis for the oral-facial phenotypes present in OFD. Specifically, we examined the development and differentiation of cranial neural crest cells (CNCCs) when C2CD3-dependent ciliogenesis was impaired. Our studies suggest that although disruptions of C2CD3 dependent ciliogenesis do not affect CNCC specification or proliferation, CNCC migration and differentiation are disrupted. Loss of C2CD3-dependent ciliogenesis affects the dispersion and directional persistence of migratory CNCCs. Furthermore, loss of C2CD3-dependent ciliogenesis results in dysmorphic and enlarged CNCC-derived facial cartilages. Thus, these findings suggest that aberrant CNCC migration and differentiation could contribute to the pathology of oral-facial defects in OFD. PMID- 26044958 TI - Variations in dysfunction of sister chromatid cohesion in esco2 mutant zebrafish reflect the phenotypic diversity of Roberts syndrome. AB - Mutations in ESCO2, one of two establishment of cohesion factors necessary for proper sister chromatid cohesion (SCC), cause a spectrum of developmental defects in the autosomal-recessive disorder Roberts syndrome (RBS), warranting in vivo analysis of the consequence of cohesion dysfunction. Through a genetic screen in zebrafish targeting embryonic-lethal mutants that have increased genomic instability, we have identified an esco2 mutant zebrafish. Utilizing the natural transparency of zebrafish embryos, we have developed a novel technique to observe chromosome dynamics within a single cell during mitosis in a live vertebrate embryo. Within esco2 mutant embryos, we observed premature chromatid separation, a unique chromosome scattering, prolonged mitotic delay, and genomic instability in the form of anaphase bridges and micronuclei formation. Cytogenetic studies indicated complete chromatid separation and high levels of aneuploidy within mutant embryos. Amongst aneuploid spreads, we predominantly observed decreases in chromosome number, suggesting that either cells with micronuclei or micronuclei themselves are eliminated. We also demonstrated that the genomic instability leads to p53-dependent neural tube apoptosis. Surprisingly, although many cells required Esco2 to establish cohesion, 10-20% of cells had only weakened cohesion in the absence of Esco2, suggesting that compensatory cohesion mechanisms exist in these cells that undergo a normal mitotic division. These studies provide a unique in vivo vertebrate view of the mitotic defects and consequences of cohesion establishment loss, and they provide a compensation-based model to explain the RBS phenotypes. PMID- 26044961 TI - A potential immunopathogenic role for reduced IL-35 expression in allergic asthma. AB - OBJECTIVE: Allergic asthma is a chronic airway inflammation resulting from an imbalance of T helper (Th) cell responses to allergens. Interleukin (IL)-35 has been shown to have potent immunoregulatory properties. Whether IL-35 participates in the immunopathogenesis of allergic asthma patients is still unknown. METHODS: CD4+ T cells and CD4+ CD25- T cells were obtained from peripheral blood mononuclear cells (PBMCs) using magnetic separation. The concentration of IL-35 in plasma was measured by enzyme-linked immunosorbent assay (ELISA). The mRNA expression levels of the IL-35 subunits, EBI3 and IL-12p35, were detected by quantitative real-time PCR (qPCR). The proliferative responses of CFSE-labeled CD4+ CD25- T cells in the presence or absence of rhIL-35 were evaluated by flow cytometry. Cytokine production of activated CD4+ CD25- T cells was examined by flow cytometry and ELISA. RESULTS: IL-35 protein and mRNA levels were decreased in allergic asthmatics. The frequencies of CD4+ CD25+ Foxp3+ Tregs and CD4+ IL 12p35+ T cells in allergic asthma patients were lower than in healthy controls. Moreover, the addition of rhIL-35 suppressed CFSE+ CD4+ CD25- T cell proliferation in vitro in a dose-dependent manner, and the suppression induced by rhIL-35 was associated with decreases in IL-4 but not IFN-gamma and IL-17 production of activated CD4+ CD25- T cells. The increased level of Th1/Th2 was observed in allergic asthmatics in the presence of rhIL-35. CONCLUSIONS: Our data suggest that IL-35 can effectively suppress the proliferation and IL-4 production of activated CD4+ CD25- T cells in allergic asthma, and that IL-35 may be a new immunotherapy for asthma patients. PMID- 26044960 TI - Optineurin deficiency in mice contributes to impaired cytokine secretion and neutrophil recruitment in bacteria-driven colitis. AB - Crohn's disease (CD) is associated with delayed neutrophil recruitment and bacterial clearance at sites of acute inflammation as a result of impaired secretion of proinflammatory cytokines by macrophages. To investigate the impaired cytokine secretion and confirm our previous findings, we performed transcriptomic analysis in macrophages and identified a subgroup of individuals with CD who had low expression of the autophagy receptor optineurin (OPTN). We then clarified the role of OPTN deficiency in: macrophage cytokine secretion; mouse models of bacteria-driven colitis and peritonitis; and zebrafish Salmonella infection. OPTN-deficient bone-marrow-derived macrophages (BMDMs) stimulated with heat-killed Escherichia coli secreted less proinflammatory TNFalpha and IL6 cytokines despite similar gene transcription, which normalised with lysosomal and autophagy inhibitors, suggesting that TNFalpha is mis-trafficked to lysosomes via bafilomycin-A-dependent pathways in the absence of OPTN. OPTN-deficient mice were more susceptible to Citrobacter colitis and E. coli peritonitis, and showed reduced levels of proinflammatory TNFalpha in serum, diminished neutrophil recruitment to sites of acute inflammation and greater mortality, compared with wild-type mice. Optn-knockdown zebrafish infected with Salmonella also had higher mortality. OPTN plays a role in acute inflammation and neutrophil recruitment, potentially via defective macrophage proinflammatory cytokine secretion, which suggests that diminished OPTN expression in humans might increase the risk of developing CD. PMID- 26044962 TI - Thrombectomy in patients ineligible for iv tPA (THRILL). AB - RATIONALE: A relevant proportion of patients with acute ischemic stroke are ineligible for intravenous thrombolysis with recombinant tissue plasminogen activator. Mechanical thrombectomy offers a treatment alternative for these patients; however, only few data are available on its safety and efficacy. AIMS AND/OR HYPOTHESIS: The aim of this study was to compare safety and efficacy of stent retrievers as device class with best medical care alone in acute stroke patients with large intracranial vessel occlusion in the anterior circulation who are not eligible for intravenous thrombolysis with recombinant tissue plasminogen activator up to eight-hours of symptom onset. DESIGN: 'Thrombectomy in patients ineligible for iv tPA' is a prospective, open-label, blinded end-point, binational (Germany and Austria), two-arm, randomized, controlled, post-market study. STUDY OUTCOME(S): Primary end-point is the modified Rankin Score shift analysis 90 days (+/-14) after stroke. Secondary end-points are excellent neurological outcomes (modified Rankin Score <= 1), good neurological outcomes (modified Rankin Score <= 2 or National Institutes of Health Stroke Scale improvement >= 10), difference between predicted infarct volume and actual core infarct volume (computed tomography or magnetic resonance imaging) at 30 (+/-6) h post-ictus, successful recanalization (thrombolysis in cerebral infarction score 2b or 3), functional health status 90 (+/-14) days after stroke (European Quality of Life-5 Dimensions) as well as common safety end-points (adverse event, serious adverse event, symptomatic intracranial haemorrhage at 30 (+/-6) h, death, or dependency). DISCUSSION: Whether mechanical thrombectomy in patients with acute ischemic stroke who are not eligible for intravenous thrombolysis with recombinant tissue plasminogen activator improves clinical outcomes is unclear. 'Thrombectomy in patients ineligible for iv tPA' may change clinical practice by providing evidence of an effective and safe treatment for such patients. PMID- 26044963 TI - Optimal combination treatment and vascular outcomes in recent ischemic stroke patients by premorbid risk level. AB - BACKGROUND: Optimal combination of secondary stroke prevention treatment including antihypertensives, antithrombotic agents, and lipid modifiers is associated with reduced recurrent vascular risk including stroke. It is unclear whether optimal combination treatment has a differential impact on stroke patients based on level of vascular risk. METHODS: We analyzed a clinical trial dataset comprising 3680 recent non-cardioembolic stroke patients aged >=35 years and followed for 2 years. Patients were categorized by appropriateness levels 0 to III depending on the number of the drugs prescribed divided by the number of drugs potentially indicated for each patient (0=none of the indicated medications prescribed and III=all indicated medications prescribed [optimal combination treatment]). High-risk was defined as having a history of stroke or coronary heart disease (CHD) prior to the index stroke event. Independent associations of medication appropriateness level with a major vascular event (stroke, CHD, or vascular death), ischemic stroke, and all-cause death were analyzed. RESULTS: Compared with level 0, for major vascular events, the HR of level III in the low risk group was 0.51 (95% CI: 0.20-1.28) and 0.32 (0.14-0.70) in the high-risk group; for stroke, the HR of level III in the low-risk group was 0.54 (0.16-1.77) and 0.25 (0.08-0.85) in the high-risk group; and for all-cause death, the HR of level III in the low-risk group was 0.66 (0.09-5.00) and 0.22 (0.06-0.78) in the high-risk group. CONCLUSION: Optimal combination treatment is related to a significantly lower risk of future vascular events and death among high-risk patients after a recent non-cardioembolic stroke. PMID- 26044964 TI - Perceived Stress and Atrial Fibrillation: The REasons for Geographic and Racial Differences in Stroke Study. AB - BACKGROUND: The association between perceived stress and atrial fibrillation (AF) remains unclear. PURPOSE: The aim of this study was to examine the association between perceived stress and AF. METHODS: A total of 25,530 participants (mean age 65 +/- 9.4 years; 54 % women; 41 % blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. Logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for the association between the short version of the Cohen Perceived Stress Scale and AF. RESULTS: In a multivariable analysis adjusted for demographics, cardiovascular risk factors, and potential confounders, the prevalence of AF was found to increase with higher levels of stress (none: OR = 1.0, referent; low stress: OR = 1.12, 95 % CI = 0.98, 1.27; moderate stress OR = 1.27, 95 % CI = 1.11, 1.47; high stress: OR = 1.60, 95 % CI = 1.39, 1.84). CONCLUSION: Increasing levels of perceived stress are associated with prevalent AF in REGARDS. PMID- 26044965 TI - Omega 3 polyunsaturated fatty acids enhance the protective effect of levetiracetam against seizures, cognitive impairment and hippocampal oxidative DNA damage in young kindled rats. AB - Levetiracetam (LEV) is a unique, effective, relatively safe antiepileptic drug that preferentially interacts with synaptic vesicle protein 2A (SV2A). This study aimed to explore the effect of combined treatment of LEV with omega 3 (OM3) on cognitive impairment and hippocampal oxidative stress and DNA damage induced by seizures in the PTZ-kindled young rat model. Cognitive functions, biomarkers of oxidative stress, and DNA damage were assessed in PTZ-kindled young rats pretreated with single and combined treatment of LEV (30mg/kg, i.p.) and OM3 (200mg/kg, p.o.). Pretreatment with LEV and OM3 at the tested doses significantly attenuated PTZ-induced seizures and decreased cognitive impairment in both passive avoidance and elevated plus maze tests in the PTZ-kindled rats. Moreover, the increase in hippocampal glutamate, malondialdehyde and 8-hydroxy-2 deoxyguanosine (8-OHdG) levels, as well as the decrease in reduced glutathione (GSH) levels and GSH-peroxidase and superoxide dismutase activities induced by PTZ kindling, significantly decreased. These effects were higher with combined treatment of LEV with OM3 and significantly more than the observed effects of single LEV or OM3. In conclusion, the combined treatment of LEV with OM3 is more effective in seizure control and alleviating the cognitive impairment induced by PTZ kindling in the young rat model, the effects that result from the decrease in hippocampal oxidative stress and DNA damage which can be attributed to the antioxidant properties of both LEV and OM3. These results may be promising for the use of LEV and OM3 combination in the treatment of epileptic children. PMID- 26044966 TI - Male rats with same sex preference show high experimental anxiety and lack of anxiogenic-like effect of fluoxetine in the plus maze test. AB - Homosexual men show a 2-4 higher risk to suffer anxiety in comparison with heterosexuals. It is unknown if biological factors collaborate to increase such incidence. Fluoxetine produces differential brain activation in homosexuals as compared with heterosexuals, suggesting that it may produce a divergent behavioral effect dependant on sex-preference. The first aim was to evaluate experimental anxiety in male rats that show same-sex preference in the elevated plus maze (EPM). The second goal explored the putative differential effect of fluoxetine (10mg/kg) in male rats with female and same-sex preference in the EPM. To induce same-sex preference males were prenatally treated with letrozole (0.56MUg/kg, 10-20 gestation days), while controls were males prenatally treated with letrozole that retain female-preference or which mothers received oil. In both groups we found animals with male preference, but the proportion was higher in males that prenatally received letrozole (10 vs. 27%). Males with same-sex preference spent less time and showed lower number of entries to the open arms of the EPM than males that prefer females, regardless of the prenatal treatment. In males with female preference, fluoxetine reduced the time spent and number of entries to the open arms that was absent in males with same-sex preference. These data suggest that biological factors contribute to the high levels of anxiety in subjects with same-sex preference and that fluoxetine in men may produce a divergent action depending on sexual orientation. PMID- 26044968 TI - Antidepressant/anxiolytic potential and adverse effect liabilities of melanin concentrating hormone receptor 1 antagonists in animal models. AB - Melanin-concentrating hormone receptor 1 (MCH1 receptor) is known to be involved in the control of mood and stress, in addition to the regulation of feeding. Here, we report further evidence that the blockade of the MCH1 receptor exhibits antidepressant and anxiolytic-like effects in a variety of animal models using TASP0382650 and TASP0489838, newly synthesized MCH1 receptor antagonists, with different scaffolds. Both TASP0382650 and TASP0489838 exhibited high affinities for human MCH1 receptor with IC50 values of 7.13 and 3.80nM, respectively. Both compounds showed potent antagonist activities at the MCH1 receptor, as assessed using MCH-increased [(35)S]GTPgammaS binding to human MCH1 receptor and an MCH induced [Ca(2+)]i assay in rat MCH1 receptor expressing cells. In contrast, neither TASP0382650 nor TASP0489838 showed an affinity for the MCH2 receptor, another MCH receptor subtype. The oral administration of TASP0382650 or TASP0489838 significantly reduced the immobility time during the forced swimming test in rats, and reduced hyperemotionality induced by an olfactory bulbectomy, both of which are indicative of an antidepressant-like potential. In the olfactory bulbectomy model, the antidepressant effect of TASP0382650 appeared following a single administration, suggesting a faster onset of action, compared with current medications. Moreover, both TASP0382650 and TASP0489838 exhibited anxiolytic effects in several animal models of anxiety. In contrast, both TASP0382650 and TASP0489838 did not affect spontaneous locomotor activity, motor function, spatial memory during the Morris water maze task, or the convulsion threshold to pentylenetetrazole. These findings provide additional evidence that the blockade of the MCH1 receptor exhibits antidepressant- and anxiolytic activities with no adverse effects in experimental animal models. PMID- 26044967 TI - Effects of chronic inhibition of GABA synthesis on attention and impulse control. AB - BACKGROUND: Cortical GABA regulates a number of cognitive functions including attention and working memory and is dysregulated in a number of psychiatric conditions. In schizophrenia for example, changes in GABA neurons [reduced expression of glutamic acid decarboxylase (GAD), parvalbumin (PV) and the GABA reuptake transporter (GAT1)] suggest reduced cortical GABA synthesis and release; these changes are hypothesized to cause the cognitive deficits observed in this disorder. The goals of this experiment were to determine whether chronically reducing GAD function within the rat PFC causes attention deficits and alterations in PV and GAT1 expression. METHODS: Male Sprague Dawley rats were trained on the 5-choice serial reaction time task (5CSRTT, a task of attention) until they reached criterion performance and then were implanted with a bilateral cannula aimed at the medial PFC. Cannulae were connected to osmotic minipumps that infused the GAD inhibitor l-allylglycine (LAG, 3.2MUg/0.5MUl/h) for 13days. Following a 5-day recovery from surgery rats were tested on the standard 5CSRTT for 5 consecutive days and then tested on two modifications of the 5CSRTT. Finally, locomotor activity was assessed and the rats sacrificed. Brains were rapidly extracted and flash frozen and analyzed for the expression of GAD67, PV, GAT1 and the obligatory NMDA receptor subunit NR1. RESULTS: Chronic LAG infusions transiently impaired attention, persistently impaired impulse control and increased locomotor activity. Behavioral changes were associated with an upregulation of GAD67, but no change in PV, GAT1 or NR1 expression. SUMMARY: Chronic inhibition of GABA synthesis within the medial PFC, increased impulsive behavior and locomotion, but did not impair attention; results consistent with previous research following acute inhibition of GABA synthesis. Moreover, our data do not support the hypothesis that decreasing GABA synthesis and release is sufficient to cause changes in other GABA-related proteins. PMID- 26044969 TI - Survival of childhood acute lymphoid leukaemia in Yorkshire by clinical trial era, 1990-2011. AB - Gender-specific differences in survival by clinical trial era in Yorkshire were assessed for children with acute lymphoid leukaemia (ALL) enrolled onto UKALLXI, ALL97/99 or UKALL2003 (n = 630; 1990-2011). For males, there was a non significant improvement in survival for ALL97/99 [hazard ratio (HR) = 0.77; 95% confidence interval (CI) 0.43-1.42) and a significant improvement for UKALL2003 (HR = 0.50; 95%CI 0.25-0.99) compared to UKALLXI. For females, survival was significantly improved for ALL97/99 (HR = 0.33; 95%CI 0.14-0.78), and non significantly improved for UKALL2003 (HR = 0.51; 95%CI 0.25-1.08) compared to UKALLXI. Modest overall survival improvements masked clinically important gender specific changes over time by trial era, requiring confirmation in larger population-based studies. PMID- 26044970 TI - Proximal conduction block in the pharyngeal-cervical-brachial variant of Guillain Barre syndrome. AB - INTRODUCTION: Conduction block (CB) has been included in the Rajabally criteria for axonal Guillain-Barre syndrome (GBS). Because the nerve roots may be affected early in GBS, detection of proximal CB by the triple stimulation technique (TST) can be useful. METHODS: We describe TST findings in 2 patients who presented with the pharyngeal-cervical-brachial (PCB) variant of axonal GBS. RESULTS: In the first patient, although conventional nerve conduction studies (NCS) did not fit electrodiagnostic criteria for axonal GBS, the TST detected proximal CB in the median and ulnar nerves. In the second patient, NCS fulfilled criteria for axonal GBS, and the TST detected proximal CB in the median nerve. After plasmapheresis, NCS and TST findings were normalized, suggesting reversible conduction failure rather than demyelinating CB. CONCLUSION: The TST may be useful for diagnosis of PCB when NCS remain inconclusive. The technique provides additional clues for classifying PCB into the acute nodo-paranodopathies. PMID- 26044971 TI - Hypermetabolism in the Initial Phase of Intensive Care Is Related to a Poor Outcome in Severe Sepsis Patients. AB - OBJECTIVE: To assess the incidence of hypermetabolism, defined as high resting energy expenditure, in severe sepsis ICU patients, and evaluate the suitability of excessive resting energy expenditure (REE) as a risk factor of their clinical outcome. METHODS: In a single-center, prospective, six-month observational study in China, the measured REE (MREE) was estimated daily using indirect calorimetry (IC) for the first 5 days of ICU admission. The predicted REE (PREE) was determined using the Harris-Benedict equation. ICU severity criteria (APACHE II and SOFA scores), baseline and health characteristics, and laboratory test results, were compared between the hyper-metabolic (MREE/PREE ratio >=1.3) and the normometabolic (MREE/PREE ratio <1.3) groups, and between the survivor and non-survivor groups, classified according to 28-day mortality. RESULTS: Of the 62 included ICU patients (age, 57.1 +/- 19.5 years), 34 patients (55%) were hypermetabolic. The 28-day mortality rate in the hypermetabolic and normometabolic groups was 35 and 18%, respectively (p < 0.001). The MREE/PREE ratio and C-reactive protein (CRP) plasma concentration were significantly higher in non-survivors than survivors (p = 0.017), and were significantly (p < 0.05) associated with 28-day mortality (ORMREE/PREE = 1.018, 95% CI, 1.010-2.544, p = 0.031 and ORCRP = 1.010, 95% CI, 1.005-2.173, p = 0.025, respectively). CONCLUSION: In critical sepsis patients admitted to ICU, the MREE/PREE ratio may be a valuable evaluation index of the clinical outcome. PMID- 26044972 TI - Cancer Risk Factors, Diagnosis and Sexual Identity in the Australian Longitudinal Study of Women's Health. AB - PURPOSE: We sought to examine cancer diagnosis, cancer treatment, and related risk factors among Australian, middle-aged, exclusively heterosexual women compared with sexual minority women (SMW; mainly heterosexual, bisexual, mainly lesbian, and lesbian). METHODS: Secondary data analysis of the Australian Longitudinal Study of Women's Health for women born in 1946 through 1951 (n = 10,451) included bivariate tests (i.e., contingency table analyses, independent t tests). RESULTS: SMW did not have significantly higher cancer diagnoses compared with exclusively heterosexual women, although they were more likely to report never having had a mammogram or pap smear. SMW were also significantly more likely to be high-risk drinkers (11.1% vs. 6.8%; p < .05), current smokers (15.1% vs. 8.3%; p < .001), report significantly higher rates of depression (mean +/- SD; 6.4 +/- 5.5 vs. 5.4 +/- 5.1; p < .01.), have experienced physical abuse (10.2% vs. 5.1%; p < .001), and been in a violent relationship (27.2% vs. 12.8%; p < .001). CONCLUSION: SMW had higher rates of several known cancer risk factors, ostensibly placing them at higher risk of cancer as well as chronic health conditions. Further research is needed to determine whether increased risk results in increased cancer as these women age, and to inform the development of interventions to reduce the risk of disease for SMW. PMID- 26044973 TI - 5-HT6 Receptor Antagonists: Potential Efficacy for the Treatment of Cognitive Impairment in Schizophrenia. AB - 5-hydroxytryptamine6 receptor (5-HT6R) antagonists have shown efficacy in animal models for cognitive impairment in multiple cognitive domains relevant for schizophrenia. Improvements were found with 5-HT6R antagonists in preclinical tests for episodic memory, social cognition, executive function, working memory and several other tests for both learning and memory. In contrast, there is little evidence for efficacy on attention. It will be interesting to further investigate 5-HT6R antagonists in neurodevelopmental animal models which are based on prenatal exposure to specific environmental insults, and are characterized by a high level of face, construct and predictive validity for cognitive impairments associated with schizophrenia. It is also important to do more add-on preclinical studies of 5-HT6 antagonists with antipsychotics. Possible mechanisms of action to improve cognition have been described. 5-HT6R antagonists decrease GABA release and GABAergic interneuron excitability, which subsequently disinhibits glutamate and/or acetylcholine release and results in enhancement of synaptic plasticity. Furthermore, cognition could be improved by 5 HT6R antagonists, because these compounds increase the number of NCAM PSA immunoreactive neurons in the dendate gyrus, inhibit mTOR and Fyn-tyrosine kinase and interact with DARPP-32. Interestingly, there is increasing preclinical evidence that could support additional benefits of 5-HT6R ligandson comorbid conditions in schizophrenia such as drug abuse, depression, anxiety, obesity andantipsychotic-induced EPS. Finally, we briefly give an overview of the 5-HT6R compounds that are currently in clinical development for the treatment of cognitive impairment in both schizophrenia and Alzheimer's disease. PMID- 26044976 TI - Treatment of Cognitive Impairment in Schizophrenia: Potential Value of Phosphodiesterase Inhibitors in Prefrontal Dysfunction. AB - No pharmacological treatment is available to date that shows satisfactory effects on cognitive symptoms in patients diagnosed with schizophrenia. Phosphodiesterase inhibitors (PDE-Is) improve neurotransmitter signaling by interfering in intracellular second messenger cascades. By preventing the breakdown of cAMP and/or cGMP, central neurotransmitter activity is maintained. Different PDE families exist with distinct characteristics among which substrate specificity and regional distribution. Preclinical data is promising especially with regard to inhibition of PDE2, PDE4, PDE5 and PDE10. In addition, cognitive improvement has been reported in both elderly and/or non-impaired young human subjects after PDE1 or PDE4 inhibition. Moreover, some of these studies show effects on cognitive domains relevant to schizophrenia, in particular memory. The current review incorporates an overview of the distinct molecular characteristics of the different PDE families and their relationship to the neurobiological mechanisms related to cognitive dysfunction in schizophrenia. So far, procognitive effects of only three types of PDE-Is have been assessed in patients diagnosed with schizophrenia inhibiting PDE3, PDE5 and PDE10. However, the limited data available do not allow to draw firm conclusions on the value of PDE-Is as cognitive enhancers in schizophrenia yet. The field is still in its infancy, but nevertheless different PDE-Is seem promising as candidate to optimise neural communication in the prefrontal cortex favouring cognitive functioning in patients diagnosed with schizophrenia, in particular dual inhibitors including PDE1-Is, PDE3-Is and PDE10A-Is. PMID- 26044974 TI - Targeting of alpha7 Nicotinic Acetylcholine Receptors in the Treatment of Schizophrenia and the Use of Auditory Sensory Gating as a Translational Biomarker. AB - Accumulating evidence suggests that the alpha7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a key role in inflammatory processes, thought to be involved in the pathophysiology of neuropsychiatric diseases, such as schizophrenia and Alzheimer's disease. Preclinical and clinical studies showed that the diminished suppression of P50 auditory evoked potentials in patients with schizophrenia may be associated with a decreased density of alpha7 nAChRs in the brain. This points to a role for auditory sensory gating (P50) as a translational biomarker. A number of agonists and positive allosteric modulators (PAMs) for alpha7 nAChR promoted beneficial effects in animal models with sensory gating and cognitive deficits. Additionally, several clinical studies showed that alpha7 nAChR agonists could improve suppression in auditory P50 evoked potentials, as well as cognitive deficits, and negative symptoms in patients with schizophrenia. Taken together, alpha7 nAChR presents as an extremely attractive therapeutic target for schizophrenia. In this article, the author discusses recent findings on alpha7 nAChR agonists such as DMXB-A, RG3487, TC-5619, tropisetron, EVP-6124 (encenicline), ABT-126, AQW051 and alpha7 nAChR PAMs such as JNJ-39393406, PNU- 120596 and AVL-3288 (also known as UCI-4083), and their potential as therapeutic drugs for neuropsychiatric diseases, such as schizophrenia. PMID- 26044977 TI - Neuropeptide Receptor Ligands for the Treatment of Schizophrenia: Focus on Neurotensin and Tachykinins. AB - There is a wealth of evidence that various neuropeptides and their receptor ligands modulate schizophrenia- related behaviors in preclinical animal models, suggesting that neuropeptide systems may represent potential novel therapeutic targets for the treatment of schizophrenia. In particular, neurotensin and tachykinins have been the subject of significant research efforts, generating compelling preclinical data in the schizophrenia field. However, clinical studies with notably selective tachykinin NK3 receptor antagonists in schizophrenia have been disappointing, and they were unable to confirm the promising therapeutic potential from animal studies, thereby questioning the therapeutic utility of these compounds for this condition. This article reviews preclinical and clinical findings on ligands for neurotensin and tachykinin receptors in schizophrenia, and provides possible explanations for the failure so far to develop small molecule neuropeptide ligands for the treatment of schizophrenia. PMID- 26044975 TI - Atypical antipsychotics and inverse agonism at 5-HT2 receptors. AB - It is now well accepted that receptors can regulate cellular signaling pathways in the absence of a stimulating ligand, and inverse agonists can reduce this ligand-independent or "constitutive" receptor activity. Both the serotonin 5-HT2A and 5-HT2C receptors have demonstrated constitutive receptor activity in vitro and in vivo. Each has been identified as a target for treatment of schizophrenia. Further, most, if not all, atypical antipsychotic drugs have inverse agonist properties at both 5-HT2A and 5-HT2C receptors. This paper describes our current knowledge of inverse agonism of atypical antipsychotics at 5-HT2A/2C receptor subtypes in vitro and in vivo. Exploiting inverse agonist properties of APDs may provide new avenues for drug development. PMID- 26044978 TI - When is a Proof-of-Concept (POC) not a POC? Pomaglumetad (LY2140023) as a Case Study for Antipsychotic Efficacy. AB - Pomaglumetad methionil (LY2140023) is a mGlu2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. While there was some evidence of an antipsychotic effect in these studies on an a priori specified genetically defined subpopulation based on single nucleotide polymorphisms of the 5 hydroxytryptamine2A receptor gene (HTR2A) , these effects were modest when compared to very limited effects in the overall population of schizophrenic patients responding to SOC second generation antipsychotic drugs. Post-hoc analyses also suggested antipsychotic efficacy for pomaglumetad methionil in subjects with a disease duration equal/less than 3 years or subjects previously treated with antipsychotic drugs predominantly acting at dopamine D2 receptors compared to 5-HT2A receptors. Orthogonal to these results with the mGlu2/3 receptor agonist prodrug, a 5-HT2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson's disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu2/3 receptor agonists and 5-HT2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer's disease psychosis. PMID- 26044979 TI - Do Histamine receptor 3 antagonists have a place in the therapy for schizophrenia? AB - In spite of almost 60 years of experience with the pharmacological treatment of schizophrenia, there is still a large unmet medical need for better control of especially the negative and cognitive symptoms of schizophrenia. One potential new avenue is the selective blockade of histamine H3 receptors (H3R). Based on a large basis of preclinical data, H3R antagonists or inverse agonists have been suggested to improve cognition in a variety of neurological and psychiatric indications. The aim of the present paper is to review the potential usefulness of H3R antagonists for the treatment of schizophrenia. Although, so far no H3R antagonist has been marketed and many phase II and III studies are still underway, the available data seem to indicate that H3R antagonists may not be primarily effective against the positive symptoms (i.e. the psychotic symptoms such as hallucinations and delusions) but may hold a promise as add-on therapy for selectively improving cognitive and perhaps negative symptoms. PMID- 26044980 TI - Serotonin 5-HT1A Receptors and Antipsychotics - An Update in Light of New Concepts and Drugs. AB - Schizophrenia is characterised by positive, negative, cognitive, depressive and anxiety symptoms. Over the last decades a number of novel treatment strategies with better clinical efficacy and scope, but with lower side-effect profiles have been developed. These have significantly improved the management and prognosis of the disease. Of these approaches, modulation of the serotonergic receptor system is a common, recurring, theme; particularly the use of 5-HT1A receptor agonism as part of or adjunct to existing therapies. Here we review data exploring the utility of 5-HT1A receptor agonists for extending the actions of antipsychotic agents, while limiting their side-effect profile. Notably, interest has grown concerning 5-HT1A receptor activation in schizophrenia because of the development of novel antipsychotics, such as lurasidone and cariprazine, the characterisation of 5-HT1A receptor polymorphisms in schizophrenia patients and the possible beneficial influence of 5-HT1A agonists on neurogenesis. PMID- 26044981 TI - Identification and characterization of microRNAs at different flowering developmental stages in moso bamboo (Phyllostachys edulis) by high-throughput sequencing. AB - Researching moso bamboo flowering has been difficult because of its unknown flowering interval and the rarity of florescent samples. To identify microRNAs (miRNAs) and study their expression patterns during the flower developmental process of moso bamboo, small RNAs from non-flowering leaves and four flower developmental periods were sequenced using Illumina technology. In total, 409 known miRNAs and 492 differentially expressed novel miRNAs were identified in moso bamboo. Of the known miRNAs that were differentially expressed between non flowering and flowering samples, 64 were predicted to have a total of 308 targets. Among the miRNAs, seven known and five novel miRNAs were selected, as were four of their target genes, and their expression profiles were validated using qRT-PCR. The results indicated that the miRNA expression levels were negatively correlated with those of their targets. The research comprehensively revealed that the differentially expressed miRNAs and their targets participated in diverse biological pathways and played significant regulatory roles in moso bamboo flowering. The data provide a significant resource for understanding the molecular mechanisms in moso bamboo flowering and senescence, and serve as the primary foundation for further studies on metabolic regulatory networks that involve miRNAs. PMID- 26044982 TI - Designing Assessment Programmes for the Model Curriculum for Emergency Medicine Specialists. PMID- 26044983 TI - Acute colonic pseudo-obstruction in pregnancy. AB - BACKGROUND: Acute colonic pseudo-obstruction is an uncommon but potentially morbid complication of pregnancy. The aim of the study was to review a single institution's experience with acute colonic pseudo-obstruction in post-partum patients and develop an algorithm for management based on a literature review. METHODS: This is a retrospective study where patients were identified over a 2 year period (1 December 2012 to 31 November 2014) by checking all deliveries in Christchurch Women's Hospital against diagnosis codes for bowel obstruction and ileus. Clinical records and radiology were then reviewed to identify those with acute colonic pseudo-obstruction and the management of these patients was reviewed. RESULTS: Over the study period, seven patients were identified from 10,240 deliveries. Two patients required laparotomy and the rest resolved without surgical intervention. One patient was treated with neostigmine and three with erythromycin. One patient had an unsuccessful attempt at endoscopic decompression, however, symptoms resolved without further intervention following this. A management algorithm was developed based on the literature review. CONCLUSIONS: Acute colonic pseudo-obstruction occurs in post-partum patients more frequently than suspected (one in 1500 deliveries). The management needs to be active with early correction of electrolyte abnormalities, avoidance of narcotic pain relief and early mobilization. Timely administration of neostigmine or endoscopic decompression can reduce the incidence of colonic ischaemia and perforation and the need for surgical intervention. PMID- 26044984 TI - Our Experience with a Double-Layer Surgical Technique for Preventing Fistula Development in Children and Young Adults with Hypospadias. AB - INTRODUCTION: In this study, we describe a new approach called the double-layer on and prepucial flap technique in order to prevent fistula or fissure development. MATERIAL AND METHOD: Twenty-seven patients with subcoronal hypospadias were enrolled. The prepared prepucial flap was divided into two equal parts. A double-layer flap was formed and used for reinforcing of the neourethra. Uroflowmetric analysis was used for evaluating the urethral stricture at the end of the first year. A blinded urologist and the patients' themselves evaluated the aesthetic appearance. RESULTS: The mean age was 12.17 +/- 2.79. All cases were primary. All evaluated parameters were at the end of the first year. Only three (3/27, 11.1%) of the patients had minimal external mea stricture that managed with urethral dilatation. None of them had any fistula, fissure, or dehiscence as well as infection and hematoma. The mean Qmax value was 17 ml/s and the Qave value was 9 ml/s. The mean scores with standard deviations with regard to the appearance of the patients' penis before and after operations were 3.08 +/- 0.77 and 8.25 +/- 0.73, respectively and this difference was statistically significant (p < 0.001). CONCLUSION: The double-layer dartos flap technique is a candidate to be the least risky technique to prevent complications as well as to increase the aesthetic appearance up to satisfactory levels. PMID- 26044985 TI - The negative predictive value of CT angiography in the setting of perimesencephalic subarachnoid hemorrhage. AB - BACKGROUND: Perimesencephalic subarachnoid hemorrhage (PMSAH) is only rarely associated with a ruptured cerebral aneurysm and CT angiography (CTA) has very good sensitivity and specificity for aneurysm detection. The necessity for invasive imaging with digital subtraction angiography (DSA) is therefore debatable. We chose to assess the negative predictive value (NPV) of CTA in a series of patients with PMSAH treated at our institution over a 9-year period. METHODS: We retrospectively assessed the diagnostic yield of DSA after initial negative CTA in patients with a PMSAH pattern defined as blood centered anterior to the midbrain and/or pons within the pre-pontine or interpeduncular cistern with possible quadrigeminal or ambient cistern extension; possible extension into the basal parts of the sylvian fissures but not the lateral sylvian fissures; possible extension to the cisterna magna but not centered on the cisterna magna; and possible extension into the fourth ventricle and occipital horns of the lateral ventricles. RESULTS: Using this definition of PMSAH, of 72 patients, one patient showed a potentially significant finding on DSA that was not demonstrated on initial CTA (NPV 98.61% (95% CI 92.47% to 99.77%)). However, when cisterna magna extension was excluded from the definition of PMSAH, no false negative CTAs in 56 patients were encountered (NPV 100% (95% CI 93.56% to 100.00%)). CONCLUSIONS: The NPV of normal CTA for an arterial abnormality in patients with PMSAH is high and our results therefore question the role of invasive imaging. The findings also suggest that a prospective study designed to clarify the necessity of performing DSA in this population would be feasible. PMID- 26044986 TI - National treatment practices in the management of infectious intracranial aneurysms and infective endocarditis. AB - INTRODUCTION: There is an absence of widely accepted guidelines for the management of infectious intracranial aneurysms (IIAs) owing to a dearth of high quality evidence in the literature. OBJECTIVE: To better define the incidence of IIAs, treatment practices, and patient outcomes by performing a Nationwide Inpatient Sample (NIS) database query. METHODS: We queried the NIS database from 2002 to 2011 for all patients with the primary diagnosis of infectious endocarditis (IE), subarachnoid hemorrhage (SAH), or unruptured cerebral aneurysm by ICD-9-CM codes. ICD-9 procedure codes were used to identify patients undergoing neurosurgical or cardiothoracic procedures. RESULTS: The query identified 393 patients with primary diagnosis of IE, SAH or unruptured cerebral aneurysm treated during 2002-2011. The mean age of the patients was 53.5 years; 244 (62%) were male. The majority of patients presented with SAH (361; 91.9%). Only 73 (18.6%) patients underwent neurosurgical coiling or clipping for IIA. Of patients undergoing a neurosurgical procedure, 65 had SAH (constituting only 18% of patients with SAH) and 8 had unruptured aneurysms (constituting only 25% patients with unruptured aneurysms). Cardiac procedures were performed in only 72/393 patients (18.3%) patients. Only 67 (18.6%) of the patients with SAH and 5 (15.6%) with unruptured aneurysms underwent a cardiac corrective surgical procedure. Mortality was significantly higher in those patients managed conservatively (26.7%) than in those who underwent clipping or embolization (15.1%; p<0.001). CONCLUSIONS: In this NIS database study, the majority of patients with IIAs were managed non-operatively, regardless of rupture status. Further investigation is warranted to standardize the management of these lesions. PMID- 26044988 TI - A hybrid health service accreditation program model incorporating mandated standards and continuous improvement: interview study of multiple stakeholders in Australian health care. AB - The study aim was to investigate the understandings and concerns of stakeholders regarding the evolution of health service accreditation programs in Australia. Stakeholder representatives from programs in the primary, acute and aged care sectors participated in semi-structured interviews. Across 2011-12 there were 47 group and individual interviews involving 258 participants. Interviews lasted, on average, 1 h, and were digitally recorded and transcribed. Transcriptions were analysed using textual referencing software. Four significant issues were considered to have directed the evolution of accreditation programs: altering underlying program philosophies; shifting of program content focus and details; different surveying expectations and experiences and the influence of external contextual factors upon accreditation programs. Three accreditation program models were noted by participants: regulatory compliance; continuous quality improvement and a hybrid model, incorporating elements of these two. Respondents noted the compatibility or incommensurability of the first two models. Participation in a program was reportedly experienced as ranging on a survey continuum from "malicious compliance" to "performance audits" to "quality improvement journeys". Wider contextual factors, in particular, political and community expectations, and associated media reporting, were considered significant influences on the operation and evolution of programs. A hybrid accreditation model was noted to have evolved. The hybrid model promotes minimum standards and continuous quality improvement, through examining the structure and processes of organisations and the outcomes of care. The hybrid model appears to be directing organisational and professional attention to enhance their safety cultures. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26044987 TI - [Objectives and organization for the long-term follow-up after childhood cancer]. AB - Increased survival of patients with childhood cancer has resulted in a growing population of survivors. In France approximately 50,000 alive people have been treated before 20 years old and, as survivors, are at risk for health problems due to disease or cancer therapy (surgery, chemotherapy, radiotherapy). Complications such as cardiovascular or cerebrovascular disease (after radiotherapy or chemotherapy), neurocognitive deficiency, endocrine disorders (hypopituitary axis, or thyroid dysfunction), gonadal function, and second malignancy can be life-threatening and seriously affect quality of life. Upon discharge former patients should be given 'passport', containing a summary of their medical history, treatment (surgery, chemotherapy cumulative doses, characteristics of radiotherapy and organs involved), methods used to preserve fertility, and complications during treatment. Treatments can then be linked to individualized recommendations for follow-up care. The risk of developing long term complications increases with time and can be aggravated by age-related comorbidity and environmental factors (tobacco, alcohol, obesity). Many regions and treatment centres in France have in place organised long-term follow-up procedures. PMID- 26044989 TI - Witnessing traumatic events and post-traumatic stress disorder: Insights from an animal model. AB - It is becoming increasingly recognized that post-traumatic stress disorder (PTSD) can be acquired vicariously from witnessing traumatic events. Recently, we published an animal model called the "Trauma witness model" (TWM) which mimics PTSD-like symptoms in rats from witnessing daily traumatic events (social defeat of cage mate) [14]. Our TWM does not result in any physical injury. This is a major procedural advantage over the typical intruder paradigm in which it is difficult to delineate the inflammatory response of tissue injury and the response elicited from emotional distress. Using TWM paradigm, we examined behavioral and cognitive effects in rats [14] however, the long-term persistence of PTSD-like symptoms or a time-course of these events (anxiety and depression like behaviors and cognitive deficits) and the contribution of olfactory and auditory stress vs visual reinforcement were not examined. This study demonstrates that some of the features of PTSD-like symptoms in rats are reversible after a significant time lapse of the witnessing of traumatic events. We also have established that witnessing is critical to the PTSD-like phenotype and cannot be acquired solely due to auditory or olfactory stresses. PMID- 26044990 TI - Corticotropin-releasing factor enhances inhibitory synaptic transmission to type III neurons in the bed nucleus of the stria terminalis. AB - We previously reported that corticotropin-releasing factor (CRF) increased neuronal excitability specifically in type II neurons of the dorsolateral part of the bed nucleus of the stria terminalis (dlBNST). Because the majority of type II dlBNST neurons are thought to be GABAergic interneurons, at least a portion of which are considered to regulate type III dlBNST neurons, it is possible that CRF increases inhibitory input to type III neurons through the activation of type II neurons in the dlBNST. To test this possibility, we examined the effect of CRF on type III dlBNST neurons using whole-cell voltage-clamp recordings of inhibitory postsynaptic currents (IPSCs) from rat BNST slices in the presence of kynurenic acid. Spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSCs) were recorded in the absence and presence of tetrodotoxin, respectively. Bath application of CRF significantly increased the frequency of sIPSCs, indicating that CRF enhances the inhibitory input to type III neurons. CRF application failed to increase the frequency of mIPSCs, suggesting that CRF-induced increases in sIPSCs are dependent on action potentials. Combined with our previous finding that CRF specifically depolarizes type II dlBNST neurons, these results suggest that CRF may attenuate type III neuron excitation by augmenting the inhibitory influence of type II neurons in the dlBNST. PMID- 26044991 TI - Antimicrobial Activity of Copper Alloys Against Invasive Multidrug-Resistant Nosocomial Pathogens. AB - The emergence and spread of antibiotic resistance demanded novel approaches for the prevention of nosocomial infections, and metallic copper surfaces have been suggested as an alternative for the control of multidrug-resistant (MDR) bacteria in surfaces in the hospital environment. This study aimed to evaluate the antimicrobial activity of copper material for invasive MDR nosocomial pathogens isolated over time, in comparison to stainless steel. Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) (n:4), OXA-23 and OXA-58 positive, MDR Acinetobacter baumannii (n:6) and Pseudomonas aeruginosa (n:4) were evaluated. The antimicrobial activity of coupons containing 99 % copper and a brass alloy containing 63 % copper was assessed against stainless steel. All the materials demonstrated statistically significant differences within each other for the logarithmic reduction of microorganisms. Among the three materials, the highest reduction of microorganisms was seen in 99 % copper and the least in stainless steel. The result was statistically significant especially for 0, 2, and 4 h (P = 0.05). 99 % copper showed a bactericidal effect at less than 1 h for MRSA and at 2 h for P. aeruginosa. 63 % copper showed a bactericidal effect at 24 h for P. aeruginosa strains only. Stainless steel surfaces exhibited a bacteriostatic effect after 6 h for P. aeruginosa strains only. 99 % copper reduced the number of bacteria used significantly, produced a bactericidal effect and was more effective than 63 % copper. The use of metallic copper material could aid in reducing the concentration of bacteria, especially for invasive nosocomial pathogens on hard surfaces in the hospital environment. PMID- 26044992 TI - High-Resolution Analyses of Overlap in the Microbiota Between Mothers and Their Children. AB - Understanding the transmission of the human microbiota from mother to child is of major importance. Although we are gaining knowledge using 16S rRNA gene analyses, the resolution of this gene is not sufficient to determine transmission patterns. We therefore developed an Illumina deep sequencing approach targeting the 16-23S rRNA Internal Transcribed Spacer (ITS) for high-resolution microbiota analyses. Using this approach, we analyzed the composition and potential mother to child transmission patterns of the microbiota (milk and stool) in a longitudinal cohort of 20 mother/child pairs. Our results show overlap in the infant stool microbiota with both mother's milk and stool, and that the overlap with stool increases with age. We found an Operational Taxonomic Unit resembling Streptococcus gordonii as the most widespread colonizer of both mothers and their children. In conclusion, the increased resolution of 16-23S rRNA ITS deep sequencing revealed new knowledge about potential transmission patterns of human-associated bacteria. PMID- 26044994 TI - OnabotulinumtoxinA intravesical treatment in patients affected by overactive bladder syndrome: best practice in real-life management. AB - PURPOSE: We evaluated intradetrusorial OnabotulinumtoxinA (Onabot/A) treatment protocols in patients with idiopathic overactive bladder (OAB), in order to assess the care of patients before, during and after treatment. METHODS: In 64 OAB patients injected with Onabot/A, we reviewed the length of the hospital stay, frequency of catheterization, frequency of intraoperative and postoperative complications, and patients' satisfaction to the proposed treatment protocol (as assessed by VAS). We also compared the results of the 3-day voiding diary, uroflowmetry with postvoid residual urine (PVR) and VAS to score the bother of urinary symptoms on quality of life (QoL) before and after treatment. RESULTS: Twenty-one patients were firstly treated in an 'inpatient' setting. The mean +/- SD duration of hospitalization and catheterization was 39.4 +/-12.6 and 37.8 +/- 10.6 h, respectively. The mean +/- SD VAS values of treatment satisfaction and of bother of urinary symptoms on QoL were 6.3 +/- 1.1 and 8.2 +/- 1.3, respectively. The mean +/- SD PVR value was 74.3 +/- 15.2 ml. Frequency of UTIs was 2.4 +/- 1.6. Forty-three patients were treated on an outpatient basis; the mean +/- SD duration of catheterization, the 'outpatient' stay and the mean +/- SD frequency of UTIs were lower than those of patients treated in an inpatient setting. The mean +/- SD VAS value to score QoL was high. CONCLUSIONS: Intradetrusorial Onabot/A injection is a simple and fast procedure that can be easily carried on in an outpatient setting under local anesthesia, with low rates of intraoperative and postoperative complications. PMID- 26044993 TI - Metagenomic Sequencing Unravels Gene Fragments with Phylogenetic Signatures of O2 Tolerant NiFe Membrane-Bound Hydrogenases in Lacustrine Sediment. AB - Many promising hydrogen technologies utilising hydrogenase enzymes have been slowed by the fact that most hydrogenases are extremely sensitive to O2. Within the group 1 membrane-bound NiFe hydrogenase, naturally occurring tolerant enzymes do exist, and O2 tolerance has been largely attributed to changes in iron-sulphur clusters coordinated by different numbers of cysteine residues in the enzyme's small subunit. Indeed, previous work has provided a robust phylogenetic signature of O2 tolerance [1], which when combined with new sequencing technologies makes bio prospecting in nature a far more viable endeavour. However, making sense of such a vast diversity is still challenging and could be simplified if known species with O2-tolerant enzymes were annotated with information on metabolism and natural environments. Here, we utilised a bioinformatics approach to compare O2-tolerant and sensitive membrane-bound NiFe hydrogenases from 177 bacterial species with fully sequenced genomes for differences in their taxonomy, O2 requirements, and natural environment. Following this, we interrogated a metagenome from lacustrine surface sediment for novel hydrogenases via high throughput shotgun DNA sequencing using the IlluminaTM MiSeq platform. We found 44 new NiFe group 1 membrane-bound hydrogenase sequence fragments, five of which segregated with the tolerant group on the phylogenetic tree of the enzyme's small subunit, and four with the large subunit, indicating de novo O2-tolerant protein sequences that could help engineer more efficient hydrogenases. PMID- 26044995 TI - A radiographic study of the distal femoral epiphysis. AB - PURPOSE: Previous studies have described the complex undulation pattern in the distal femoral physis. We investigated whether standard radiographs can visualize these landmarks, in order to guide hardware placement in the distal immature femur. METHODS: We studied 36 cadaveric immature femora in specimens 3 to 18 years of age. Anteroposterior (AP) and lateral radiographs were obtained with and without flexible radiodense markers placed on the major undulations and were analyzed to determine the relative height or depth of each topographical landmark. Intraclass correlation coefficients (ICCs) were calculated between measurements taken with and without markers for each undulation on each view. RESULTS: Examination of the specimens confirmed a central peak and anteromedial and posterolateral valleys as the major physeal structures. AP radiographs without markers correlated well with marked AP radiographs for all three landmarks (ICC = 0.92, 0.92, 0.91), but the lateral radiographs had lower correlations for the posterolateral valley (ICC = 0.36). The correlation between AP and lateral radiographs without markers on the posterolateral valley was also decreased compared to the other two landmarks (ICC = 0.28 versus 0.57 for the central ridge and 0.62 for the anteromedial valley). CONCLUSIONS: This is the first study to rigorously evaluate radiographic visibility of the distal femur physeal undulations. The position of the central ridge, anteromedial valley, and posterolateral valley are reliably seen on AP radiographs, while the lateral view is less consistent, especially for the posterolateral valley. We recommend that caution should be taken when placing screws near the posterolateral aspect of the epiphysis, as lateral views do not visualize those undulations well. PMID- 26044996 TI - Selective estrogen receptor modulators in T cell development and T cell dependent inflammation. AB - Lasofoxifene (las) and bazedoxifene (bza) are third generation selective estrogen receptor modulators (SERMs) with minimal estrogenic side effects, approved for treatment of postmenopausal osteoporosis. T cells are involved in the pathology of postmenopausal osteoporosis and previous studies have established an important role for 17beta-estradiol (E2) in T cell development and function. E2 causes a drastic thymic atrophy, alters the composition of thymic T cell populations, and inhibits T cell dependent inflammation. In contrast, the second generation SERM raloxifene (ral) lacks these properties. Although las and bza are drugs approved for treatment of postmenopausal bone loss, it is of importance to study their effects on other biological aspects in order to extend the potential use of these compounds. Therefore, the aim of this study was to investigate if treatment with las and bza affects T lymphopoiesis and T cell dependent inflammation. C57Bl6 mice were ovariectomized (ovx) and treated with vehicle, E2, ral, las or bza. As expected, E2 reduced both thymus weight and decreased the proportion of early T cell progenitors while increasing more mature T cell populations in the thymus. E2 also suppressed the T cell dependent delayed-type hypersensitivity (DTH) reaction to oxazolone (OXA). Ral and las, but not bza, decreased thymus weight, while none of the SERMs had any effects on T cell populations in the thymus or on inflammation in DTH. In conclusion, this study shows that treatment with las or bza does not affect T lymphopoiesis or T cell dependent inflammation. PMID- 26044997 TI - Measuring Ligand-Dependent Transport in Nanopatterned PbS Colloidal Quantum Dot Arrays Using Charge Sensing. AB - Colloidal quantum dot arrays with long organic ligands have better packing order than those with short ligands but are highly resistive, making low-bias conductance measurements impossible with conventional two-probe techniques. We use an integrated charge sensor to study transport in weakly coupled arrays in the low-bias regime, and we nanopattern the arrays to minimize packing disorder. We present the temperature and field dependence of the resistance for nanopatterned oleic-acid and n-butylamine-capped PbS arrays, measuring resistances as high as 10(18) Omega. We find that the conduction mechanism changes from nearest neighbor hopping in oleic-acid-capped PbS dots to Mott's variable range hopping in n-butylamine capped PbS dots. Our results can be understood in terms of a change in the interdot coupling strength or a change in density of trap states and highlight the importance of the capping ligand on charge transport through colloidal quantum dot arrays. PMID- 26044998 TI - The Combined Influence of Sociodemographic, Preoperative Comorbid and Intraoperative Factors on Longer Length of Stay After Elective Primary Total Knee Arthroplasty. AB - This study assessed the collective association of sociodemographic, preoperative comorbid and intraoperative factors with longer length of stay (LOS) following elective primary total knee arthroplasty. Sociodemographic characteristics examined on 2638 adult cases included age, race/ethnicity, gender and socioeconomic status (SES). Intraoperative factors included operating time and anesthesia type. The collective associations of lower SES, female gender, advanced age, non-Caucasian race/ethnicity and certain comorbidities do present a synergistically elevated risk for longer LOS. In a value-driven healthcare environment, these findings further warrant the need for policymakers and payers to consider sociodemographic status when allocating resources to hospitals serving such patients. PMID- 26044999 TI - Outcomes of Mixed Femoral Fixation Technique Using Both Cement and Ingrowth in Revision Total Hip Arthroplasty: Minimum 2-Year Follow-up. AB - The use of a modular femoral stem in revision total hip arthroplasty (THA) has been increasing recently. However, complications such as subsidence, dislocation and stem fracture are still noted, especially in hips with high grade femoral deficiency. We retrospectively studied a consecutive 41 hips (40 patients) that underwent revision THA with allograft reconstruction of the proximal femur in conjunction with hybrid fixation (proximally cemented and distally press-fit) of a modular femoral component. At a mean follow-up of 5.2 years (2 to 8 years), no hips sustained dislocation, subsidence or fracture of the stem in the follow-up period. We provided evidence that this technique may be a good alternative in the management of proximal femoral bone loss during revision THA. PMID- 26045000 TI - SFC-MS versus RPLC-MS for drug analysis in biological samples. PMID- 26045001 TI - Choosing the right bioanalytical assay platform(s) to support the PK assessment of protein biotherapeutic programs. PMID- 26045002 TI - The simultaneous detection and quantification of p-aminobenzoic acid and its phase 2 biotransformation metabolites in human urine using LC-MS/MS. AB - BACKGROUND: p-Aminobenzoic acid (PABA) can be used as a probe substance to investigate glycine conjugation, a reaction of phase 2 biotransformation. METHODOLOGY/RESULTS: An LC-MS/MS method for simultaneous quantification of PABA and its metabolites from human urine was developed and validated. The metabolites can be quantified with acceptable precision and accuracy directly from human urine samples after ingestion of 550 mg PABA. CONCLUSION: The developed LC-MS/MS assay is to our knowledge the first method available for the simultaneous quantification of PABA and its glycine conjugation metabolites in human urine and provides important quantitative data for studies of this phase 2 biotransformation pathway. PMID- 26045003 TI - The performance of five different dried blood spot cards for the analysis of six immunosuppressants. AB - BACKGROUND: The relation between hematocrit, substance concentration, extraction recovery and spot formation of tacrolimus, sirolimus, everolimus, ascomycin, temsirolimus and cyclosporin A was investigated for Whatman 31 ET CHR, Whatman FTA DMPK-C, Whatman 903, Perkin Elmer 226 and Agilent Bond Elut DMS DBS cards. RESULTS & DISCUSSION: We found that all DBS cards showed the same hematocrit and concentration-dependent recovery patterns for sirolimus, everolimus and temsirolimus. At high concentrations, the total hematocrit effects were much more pronounced than at low concentrations for tacrolimus, sirolimus, everolimus, ascomycin and temsirolimus. CONCLUSION: The tested card types showed differences in performance, especially at extreme concentrations and hematocrit values. It may be useful to investigate the performance of different types of DBS cards prior to analytical method validation. PMID- 26045004 TI - Development and validation of an enzyme-linked immunosorbent assay to measure adalimumab concentration. AB - BACKGROUND: Adalimumab is a therapeutic antibody used for treating inflammatory diseases. To understand interindividual PK variability, there is a need to develop and validate an assay to measure serum adalimumab concentrations. METHODS: An ELISA was developed on microtiter plates coated with TNF-alpha. Seven nonzero adalimumab standards ranging from 0.05 to 50 mg/l and three quality controls (0.2, 2.5 and 7 mg/l) were tested for their intra and interday precision on six occasions. RESULTS: The LOD, LLOQ and ULOQ of the assay were 0.022, 0.073 and 9 mg/l, respectively. CONCLUSION: This method is accurate, reproducible and may be useful for PK studies and for therapeutic drug monitoring of adalimumab. PMID- 26045005 TI - LC-MS/MS for the simultaneous determination of polar endogenous ADMA and CML in plasma and urine from diabetics. AB - BACKGROUND: Asymmetric dimethylarginine (ADMA) and epsilon-N-carboxymethyl-L lysine (CML) are microvascular risk factors and potential biomarkers of diabetic microvascular complication. RESULTS: Sample preparation was achieved using acetonitrile for protein precipitation step. ADMA, CML and IS CML-d2 were separated with gradient on a Welch Ultimate((r)) XB- NH2 column. The assays were validated according to current bioanalytical guidelines with respect to specificity, linearity (20-1000 ng/ml for ADMA in human plasma, 50-2000 ng/ml in urine, 10-500 ng/ml for CML in human plasma and urine), accuracy and precision, extraction recovery, matrix effect and stability. CONCLUSION: The LC-MS/MS method was successfully applied to quantification of ADMA and CML in plasma and urine samples from healthy individuals and patients with diabetic nephropathy. PMID- 26045006 TI - Maternal and neonatal hair and breast milk in the assessment of perinatal exposure to drugs of abuse. AB - Perinatal exposure to one or more drugs of abuse can affect the neonate temporarily or permanently. In addition to meconium, the evaluation of perinatal exposure to drugs of abuse has been achieved by testing biological matrices coming from the newborn (neonatal hair) and from the pregnant or nursing mother (maternal hair and breast milk). These matrices have the advantage of noninvasive collection and account for a sizable time window of active and passive exposure. Sensitive and specific analytical methods are required to determine minute amounts of drugs of abuse and metabolites in these matrices. The present manuscript reviews the newest analytical methods developed to detect drugs of abuse as well as ethanol biomarkers in maternal and neonatal hair and breast milk. PMID- 26045007 TI - Implementation of highly sophisticated flow cytometry assays in multicenter clinical studies: considerations and guidance. AB - Flow cytometry is increasingly becoming an important technology for biomarkers used in drug discovery and development. Within clinical development flow cytometry is used for the determination of PD biomarkers, disease or efficacy biomarkers or patient stratification biomarkers. Significant differences exist between flow cytometry methodology and other widely used technologies measuring soluble biomarkers including ligand binding and mass spectrometry. These differences include the very heavy reliance on aspects of sample processing techniques as well as sample stabilization to ensure viable samples. These differences also require exploration of new approaches and wider discussion regarding method validation requirements. This paper provides a review of the current challenges, solutions, regulatory environment and recommendations for the application of flow cytometry to measure biomarkers in clinical development. PMID- 26045008 TI - A randomized controlled clinical trial comparing the outcomes of circumferential subcuticular wound approximation (CSWA) with conventional wound closure after stoma reversal. AB - BACKGROUND: The creation of a stoma is commonplace in colorectal surgery. Circumferential subcuticular wound approximation (CSWA) is a method of wound closure following stoma reversal that has been reported to result in decreased wound infection rates and more desirable aesthetic outcomes. The aim of the present study was to determine the effectiveness of the CSWA method, in terms of wound infection and cosmesis by comparing the technique to the conventional method of wound closure. METHODS: All adult patients who presented for stoma reversal at the outpatient clinic of the Division of Colorectal Surgery at the Philippine General Hospital were randomized into two groups, CSWA and conventional. Patients were followed up for up to 30 days postoperatively, photographic documentation of wound appearance was obtained, and wound infections and complications were documented. Patients were asked to complete a satisfaction survey at the end of the follow-up period. RESULTS: A total of 121 patients were included in the study. One (1.6%) patient in the CSWA group developed wound infection, while six (10%) patients in the conventional group had a wound infection (p = 0.061). The CSWA group had a higher total satisfaction score than the conventional group (25 and 24, respectively, p = 0.012). CONCLUSIONS: With regard to wound infection rates, the CSWA method was better than the conventional method, although this was found to be borderline significant. With regard to patient satisfaction, the CSWA method proved to be superior to the conventional method, and this was found to be statistically significant. In addition, the technique is applicable to all forms of stoma regardless of the bowel segment involved, trephine size, and indication for diversion. PMID- 26045009 TI - Parsing clinical text: how good are the state-of-the-art parsers? AB - BACKGROUND: Parsing, which generates a syntactic structure of a sentence (a parse tree), is a critical component of natural language processing (NLP) research in any domain including medicine. Although parsers developed in the general English domain, such as the Stanford parser, have been applied to clinical text, there are no formal evaluations and comparisons of their performance in the medical domain. METHODS: In this study, we investigated the performance of three state-of the-art parsers: the Stanford parser, the Bikel parser, and the Charniak parser, using following two datasets: (1) A Treebank containing 1,100 sentences that were randomly selected from progress notes used in the 2010 i2b2 NLP challenge and manually annotated according to a Penn Treebank based guideline; and (2) the MiPACQ Treebank, which is developed based on pathology notes and clinical notes, containing 13,091 sentences. We conducted three experiments on both datasets. First, we measured the performance of the three state-of-the-art parsers on the clinical Treebanks with their default settings. Then we re-trained the parsers using the clinical Treebanks and evaluated their performance using the 10-fold cross validation method. Finally we re-trained the parsers by combining the clinical Treebanks with the Penn Treebank. RESULTS: Our results showed that the original parsers achieved lower performance in clinical text (Bracketing F measure in the range of 66.6%-70.3%) compared to general English text. After retraining on the clinical Treebank, all parsers achieved better performance, with the best performance from the Stanford parser that reached the highest Bracketing F-measure of 73.68% on progress notes and 83.72% on the MiPACQ corpus using 10-fold cross validation. When the combined clinical Treebanks and Penn Treebank was used, of the three parsers, the Charniak parser achieved the highest Bracketing F-measure of 73.53% on progress notes and the Stanford parser reached the highest F-measure of 84.15% on the MiPACQ corpus. CONCLUSIONS: Our study demonstrates that re-training using clinical Treebanks is critical for improving general English parsers' performance on clinical text, and combining clinical and open domain corpora might achieve optimal performance for parsing clinical text. PMID- 26045010 TI - Label-free proteomic analysis of PBMCs reveals gender differences in response to long-term antiretroviral therapy of HIV. AB - The association of gender with the treatment outcome during long-term antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected patients has been controversial. Here, we performed a comparative proteomic analysis of peripheral blood mononuclear cells (PBMC) by using a label-free shotgun method with nano-LC-MS/MS to investigate the gender differences in responses to long-term ART. This analysis enrolled 30 HIV-infected patients (16 males and 14 females), as well as 20 healthy adults (10 males and 10 females) as control. Quantitative real-time RT-PCR and immunoblotting were used to validate the results of proteomic approach. A total of 53 proteins showing differential expression (+/- 1.5 fold, p < 0.05) were identified in HIV-infected patients versus healthy adults. Of these proteins, 22 proteins showed identical regulation patterns in both men and women, while 31 proteins were gender-specific (21 men specific and 10 women-specific proteins). Bioinformatics analysis indicated that long-term ART causes up-regulation of apoptosis, oxidative phosphorylation and mitochondrial dysfunction while down-regulation of oxidative stress and immune system process in men compared to women. These findings point to a concept that gender has a significant influence on the outcomes of ART at protein level and women present a potential favorable immunological pattern and recovery during long-term ART. PMID- 26045011 TI - Eribulin Shows Promise in Advanced Sarcoma. PMID- 26045012 TI - Drug Improves Survival in Refractory Colorectal Cancer. PMID- 26045013 TI - Phthalimide-Conjugated Ligands Promote Selective Protein Destabilization. AB - Phthalimide conjugates induce destabilization of target proteins such as BRD4 in vitro and in vivo. PMID- 26045014 TI - Destabilization of Mutant p53 Proteins Suppresses Tumor Growth. AB - Sustained mutant p53 is required for tumor maintenance and is a therapeutic target in vivo. PMID- 26045015 TI - Selective Inhibition of BCL2 Shows Antitumor Effects in Lung Cancer. AB - The small molecule BDA-366 selectively inhibits BCL2, converting it to a cell death inducer. PMID- 26045016 TI - Localized Prostate Cancer Is Spatially and Genomically Heterogeneous. AB - Extensive intratumoral genetic heterogeneity exists among prostate tumors with similar pathology. PMID- 26045017 TI - RUNX3 Modulates Metastatic Potential in Pancreatic Ductal Adenocarcinoma. AB - RUNX3 controls the balance between proliferation and metastasis in pancreatic ductal adenocarcinoma. PMID- 26045018 TI - Sleep concerns in children and young people with cerebral palsy in their home setting. AB - AIMS: The aims were to identify in-home concerns about sleep in children and young people with cerebral palsy (CP) across age and Gross Motor Function Classification Scale (GMFCS) levels. METHODS: This was a retrospective review of clinical notes of 154 children and young people with CP, aged 1-18 years (M = 7.8; standard deviation = 5.4) who received a home-based sleep service. Reported concerns were synthesised, for analysis according to age groups (1-5, 6-13, 14 18) and GMFCS levels. RESULTS: Sixteen factors of concern were derived from the home-based assessment reports. Most children and young people had multiple factors of concern. These varied across age groups and GMFCS levels. Body position was of concern across all age groups, for over 90% at GMFCS levels IV and V, and for 10% at GMFCS level I. Settling routines were of concern for more than 90% at GMFCS levels I and II, but for less than 50% at GMFCS levels IV and V. Settling routines were of concern to over 65% of those under 6 years but less than 25% of those over 14 years. Conversely, pain and pressure care concerned less than 10% of children under 6, and more than 35% of those over 14 years. CONCLUSIONS: Concerns about sleep vary across ages and GMFCS levels of children and young people with CP. Concerns relate to impairment of body structure and function, activity, environment, and personal supports. Multi-disciplinary, home based assessment and interventions are recommended to address these concerns. PMID- 26045019 TI - The mouse gene expression database: New features and how to use them effectively. AB - The Gene Expression Database (GXD) is an extensive and freely available community resource of mouse developmental expression data. GXD curates and integrates expression data from the literature, via electronic data submissions, and by collaborations with large-scale projects. As an integral component of the Mouse Genome Informatics Resource, GXD combines expression data with genetic, functional, phenotypic, and disease-related data, and provides tools for the research community to search for and analyze expression data in this larger context. Recent enhancements include: an interactive browser to navigate the mouse developmental anatomy and find expression data for specific anatomical structures; the capability to search for expression data of genes located in specific genomic regions, supporting the identification of disease candidate genes; a summary displaying all the expression images that meet specified search criteria; interactive matrix views that provide overviews of spatio-temporal expression patterns (Tissue * Stage Matrix) and enable the comparison of expression patterns between genes (Tissue * Gene Matrix); data zoom and filter utilities to iteratively refine summary displays and data sets; and gene-based links to expression data from other model organisms, such as chicken, Xenopus, and zebrafish, fostering comparative expression analysis for species that are highly relevant for developmental research. PMID- 26045020 TI - Summary of the evidence on modifiable risk factors for cognitive decline and dementia: A population-based perspective. AB - An estimated 47 million people worldwide are living with dementia in 2015, and this number is projected to triple by 2050. In the absence of a disease-modifying treatment or cure, reducing the risk of developing dementia takes on added importance. In 2014, the World Dementia Council (WDC) requested the Alzheimer's Association evaluate and report on the state of the evidence on modifiable risk factors for cognitive decline and dementia. This report is a summary of the Association's evaluation, which was presented at the October 2014 WDC meeting. The Association believes there is sufficient evidence to support the link between several modifiable risk factors and a reduced risk for cognitive decline, and sufficient evidence to suggest that some modifiable risk factors may be associated with reduced risk of dementia. Specifically, the Association believes there is sufficiently strong evidence, from a population-based perspective, to conclude that regular physical activity and management of cardiovascular risk factors (diabetes, obesity, smoking, and hypertension) reduce the risk of cognitive decline and may reduce the risk of dementia. The Association also believes there is sufficiently strong evidence to conclude that a healthy diet and lifelong learning/cognitive training may also reduce the risk of cognitive decline. PMID- 26045021 TI - C-Peptide and 24-Hour Urinary C-Peptide as Markers to Help Classify Types of Childhood Diabetes. PMID- 26045022 TI - Integrating commercial ambulatory electronic health records with hospital systems: An evolutionary process. AB - OBJECTIVE: The increase in electronic health record implementation in all treatment venues has led to greater demands for integration within and across practice settings with different work cultures. We study the evolution of coordination processes when integrating ambulatory-specific electronic health records with hospital systems. MATERIALS AND METHODS: Longitudinal qualitative study using semi-structured interviews and archival documentation throughout a 5 year implementation and integration of obstetrical ambulatory and hospital records with a goal of achieving a perinatal continuum of care. RESULTS: As users implement and integrate electronic health records, there is an evolution in their focus from technology acceptance to structural adaptation to coordination. The users' perspective on standardization evolves from initial concern about the unintended consequences of standardization to recognition of its importance and then finally to more active acceptance. The system itself cannot drive all reengineering; the organization must impose specific work process changes and as the user's perspective evolves, more individually adapted and aligned change will occur. Computer integration alone does not result in coordination; users must value integrated information and incorporate this information within their workflows. DISCUSSION: Users initially view electronic health records as a documentation tool, but over time they come to recognize the benefits of the system for clinical information retrieval, and finally, for care coordination after the integrated information provided through electronic health records becomes more complete, accessible and adapted to meet user needs. As this occurs, coordination mechanisms move beyond pooled standardization through sequential plans coordinated by the organization to reciprocal mutual adjustments for clinical decision making by individuals. Trust in the information source, not software interoperability, is critical for information sharing. CONCLUSIONS: Organizations implementing commercial electronic health records cannot simply assume that reciprocal coordination will immediately occur. It takes time for users to adjust, and enculturate coordination goals, during which time there are adaptive structurations that require organizational response, and changes in mechanisms for achieving coordination. PMID- 26045023 TI - The Risk of Ovarian Malignancy Algorithm (ROMA) as a Predictive Marker of Peritoneal Dissemination in Epithelial Ovarian Cancer Patients. AB - BACKGROUND: This study aimed to determine the efficacy of the risk of ovarian malignancy algorithm (ROMA), calculated using the carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) levels and the menopausal status, as a predictor of peritoneal dissemination in ovarian cancer. METHODS: The CA125 and HE4 levels and the ROMA were compared between ovarian cancer patients (n = 122) with or without peritoneal dissemination. The sensitivity, specificity, positive predictive value, and negative predictive value were calculated, and the results were compared with those of computed tomography (CT). RESULTS: The CA125, HE4, and ROMA values differed significantly depending on the presence of peritoneal dissemination (p < 0.0001). The cut-off values were 181 U/ml for CA125, 161 pmol/ml for HE4, 44% for the ROMA (premenopausal), and 86% for the ROMA (postmenopausal). Among these markers, the ROMA (premenopausal) was the strongest predictor of peritoneal dissemination, with a specificity of 85.0% and a positive predictive value of 81.3%. In addition, the detection rates of small disseminations with less than 2 cm in diameter for the ROMA (93%) and HE4 (60%) were superior to that of CT (53%). CONCLUSIONS: The ROMA was a significant predictor of peritoneal dissemination and may be superior to CT for the detection of patients with small disseminations. PMID- 26045024 TI - Heterogeneous bovine acellular dermal matrix for mucosal repair in reconstructive surgery for laryngeal and hypopharyngeal carcinoma. AB - BACKGROUND: We performed this study to explore the clinical effects of a heterogeneous bovine acellular dermal matrix (ADM) used for repairing mucosal defects in reconstructive surgery following resection for laryngeal and hypopharyngeal carcinoma. PATIENTS AND METHODS: A summary analysis was carried out on the surgical data of 93 patients who underwent reconstructive surgery using a heterogeneous bovine ADM following resection of laryngeal and hypopharyngeal carcinoma. The patients underwent an electronic laryngoscope review. RESULTS: After 3-6 months, the repaired mucosa had replaced the mucosal defects in 88 patients who had undergone stage I reconstruction, recovering local function. Due to infection, 3 patients had a laryngeal fistula and 2 patients had a pharyngeal fistula; the fistula incidence rate was 5.4%. 86 patients underwent successful tracheal extubation (extubation rate, 92.5%). The duration from tracheotomy to extubation was 8-31 days; the average duration was 10.4 days. CONCLUSION: The heterogeneous bovine ADM is a new, safe, and effective material for reconstructive surgery. In patients with large mucosal defects, it avoids the trauma caused by flap repair. PMID- 26045025 TI - Late recurrent testicular seminoma: histological evidence is required. AB - INTRODUCTION: Over the past 3 decades, the appropriate management of metastatic germ cell tumours (GCT) has been defined by several phase III trials. Many follow up recommendations have been published based on expert consensus. However, common clinical scenarios can still be vexing for clinicians who are less experienced at managing patients with testicular cancer. CASE REPORT: We highlight the arduous diagnostic work-up of a suspected late relapsing metastatic GCT in a patient suffering from fatigue, weight loss and prominent retroperitoneal lymph nodes, 4 years after first-line chemotherapy for metastatic seminoma. The various explorations finally led to the diagnosis of Whipple's disease. CONCLUSION: This unusual clinical case strongly highlights the need to perform an exhaustive evaluation, with a biopsy, if a late recurrent GCT is suspected to avoid pointless and potentially harmful treatment. PMID- 26045026 TI - Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data. AB - Anaplastic lymphoma kinase(ALK) rearrangement is one of the oncogenes in non small cell lung cancer (NSCLC) identified in 2007. The PROFILE trials demonstrated that patients with ALK-rearranged NSCLC can be successfully treated with crizotinib, and that crizotinib is superior to chemotherapy in both first- and second-line settings. Furthermore, next-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to harbor excellent efficacy for NSCLC patients with ALK rearrangement. However, it is known that many cases ultimately acquire resistance to ALK inhibitors. Some potential mechanisms of resistance to ALK inhibitors are as follows: ALK dominant resistance, such as secondary mutations and copy number gain in the ALK gene; activation of the bypass tracks, including EGFR, KRAS, KIT, MET, and IGF-1R. Furthermore, treatment strategies to overcome these resistance mechanisms have been proposed, and next-generation ALK inhibitors, agents which inhibit the bypass tracks, and heat shock protein 90 inhibitors are thought to be promising. Thus, clinical and pre-clinical evidence on the resistance mechanisms to ALK inhibitors and treatment strategies to overcome the resistance have been gradually obtained. Herein, we concisely review the current clinical and pre-clinical data regarding the mechanisms of resistance to ALK inhibitors and treatments to overcome such resistance. PMID- 26045027 TI - Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. AB - Regorafenib is the first tyrosine kinase inhibitor approved for metastatic colorectal cancer. In 2 phase III trials, regorafenib significantly improved progression-free and overall survival in patients who had been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti vascular endothelial growth factor therapy, and, if (K)RAS wild type, an anti epidermal growth factor receptor therapy. Its safety profile is in line with other multikinase and/or tyrosine kinase inhibitors approved for different indications. Commonly reported adverse events specifically associated with regorafenib include hand-foot skin reaction and hypertension, whereas others such as fatigue, diarrhea, and liver dysfunction may occur during both targeted and cytotoxic treatments. These adverse events frequently occur within the first cycles of treatment, are transient, and decrease in incidence over time. Patient selection, education, and management, as well as close communication between oncologists or trained nurses and patients, are essential for prevention and mitigation of treatment toxicity as is rapid implementation of dose modifications and temporary discontinuations. Effective management of adverse events enables patients who are responding to stay on treatment for a substantial period of time and thereby receive the full benefit of regorafenib therapy. This review aims to provide guidance around prophylaxis and management of regorafenib-associated adverse events. PMID- 26045028 TI - Pyramidal lobe of the thyroid: anatomical considerations of importance in thyroid cancer surgery. AB - The pyramidal lobe is a remnant of the thyroglossal duct and is considered a normal component of the thyroid gland. The pyramidal lobe may be affected by the diseases that affect the rest of the thyroid parenchyma. A practicing endocrine surgeon should keep the anatomical variations of the pyramidal lobe in mind to achieve a completely total thyroidectomy, when indicated. This approach is especially important in thyroid cancer surgery, given the high incidence of multifocality of papillary thyroid cancer, the increased effectiveness of adjuvant radioiodine therapy following a really total thyroidectomy, and the increased sensitivity of serum thyroglobulin measurements during the follow-up of these patients. PMID- 26045029 TI - Calcium homeostasis disruption - a bridge connecting cadmium-induced apoptosis, autophagy and tumorigenesis. AB - Calcium and cadmium are divalent metals and have similar chemical properties. Both can enter cells through, albeit different, channels, or through protein dependent permeation. However, cadmium disturbs the calcium homeostasis by inhibiting calcium channels and/or related proteins. Cadmium can also alter membrane phospholipid concentrations, and so induce a calcium homeostasis disorder. The altered calcium homeostasis induced by cadmium results in cell apoptosis, autophagy or tumorigenesis. In this review, calcium homeostasis disruption is summarized as a bridge connecting cadmium-induced apoptosis, autophagy, and tumorigenesis. PMID- 26045030 TI - Successful Afatinib Therapy after Resistance to EGFR-TKI in a Patient with Advanced Adenosquamous Cell Lung Cancer. PMID- 26045031 TI - Diabetes related health knowledge, attitude and practice among diabetic patients in Nepal. AB - BACKGROUND: Globally, diabetes is the top priority chronic disease. Health literary would be cost effective for prevention and control of diabetes and its consequences. This study was conducted to determine the level of diabetes related health knowledge, attitude and practice (KAP) among diabetic patient and factors associated with KAP. METHODS: An institutional based cross-sectional study was conducted using a non-probability sampling technique to select the diabetic patients. A total of 244 diabetic patients were interviewed from July to November 2014. Data was collected by face to face interview using structured interviewer rater questionnaires. Relative risk ratio (RRR) and 95% confidence interval (CI) of associated factors were estimated by a stepwise likelihood ratio method with multinomial logistic regression. RESULTS: More than half (52.5%) of all patients were female, 18% were illiterate, and 24.6% were from rural residence. The diabetes related risk factors were common among diabetic patients; 9.8% smoker, 16% alcohol drinking, and 17.6% reported low or no physical activity. Median score for knowledge, attitude, and practice were 81, 40 and 14 respectively. Among all patients, 12.3%, 12.7% and 16% had highly satisfactory knowledge, attitude and practice respectively. Using highly insufficient knowledge as the baseline, the likelihood of having a level of highly sufficient knowledge was 17 times higher among patients who have graduated and above level of education compared to those who were illiterate. Albeit this value was comparatively lower than insufficient level of knowledge. The probability of having a sufficient level of practice among diabetic patient with a history of smoking was 0.10 times lower than in patient with no history of smoking. CONCLUSIONS: Our study reveals a variation between diabetes related health knowledge, attitude and practice in Nepal among those who are affected by diabetes. Our results show the potential diabetes health literacy needs to be improved or developed for better health promotion. PMID- 26045032 TI - Recent trends in orexin research--2010 to 2015. AB - Specific neurons in the lateral hypothalamus produce the orexin neuropeptides (orexin-A and orexin-B). The orexin-peptides are transported to areas of the brain regulating sleep-wake cycles, controlling food intake or modulating emotional states such as panic or anxiety. The orexin system, consisting of the two orexin-neuropeptides and two G-protein-coupled receptors (the orexin-1 and the orexin-2 receptor) is as well involved in reward and addictive behaviors. The review reflects on the most recent activities in the field of orexin research. PMID- 26045033 TI - Covalent modifier-type aggregation inhibitor of amyloid-beta based on a cyclo KLVFF motif. AB - Inhibition of amyloid-beta (Abeta) aggregation could be a drug development target for treating Alzheimer disease. Insufficient activity to inhibit aggregation, however, remains a key issue. Here, we report a covalent modifier-type aggregation inhibitor of Abeta, diazirine-equipped cyclo-KLVF(beta-Ph)F (2). Due to the affinity of the cyclo-KLVFF motif for Abeta, 2 selectively reacted with Abeta1-42 under UV-light irradiation to form an irreversible covalent bond. The Tyr-10 residue of Abeta1-42 was identified as the covalent modification site with 2. The extent of cross-beta-sheet structure, characteristics of amyloid aggregation, and toxicity of Abeta1-42 were strongly attenuated by this chemical modification. PMID- 26045034 TI - Pradimicin A, a D-mannose-binding antibiotic, binds pyranosides of L-fucose and L galactose in a calcium-sensitive manner. AB - Pradimicin A (PRM-A) is a unique antibiotic with a lectin-like ability to bind D mannose (D-Man) in the presence of Ca(2+) ion. Although accumulated evidences suggest that PRM-A recognizes the 2-, 3-, and 4-hydroxyl groups of D-Man, BMY 28864, an artificial PRM-A derivative, was shown not to bind L-fucose (L-Fuc) and L-galactose (lLGal), both of which share the characteristic array of the three hydroxyl groups with D-Man. To obtain a plausible explanation for this inconsistency, we performed co-precipitation experiments of PRM-A with L-Fuc, L Gal, and their methyl pyranosides (L-Fuc-OMe, L-Gal-OMe) by taking advantage of aggregate-forming propensity of the binary [PRM-A/Ca(2+)] complex. While L-Fuc and L-Gal were hardly incorporated into the aggregate, L-Fuc-OMe and L-Gal-OMe were found to exhibit significant binding to PRM-A. However, increased Ca(2+) concentration abolished this binding, raising the possibility that poor binding of L-Fuc and L-Gal to PRM-A is attributed to their chelation with Ca(2+) ion. This possibility was partly supported by (1)H NMR analysis that detected interaction of L-Fuc and L-Gal with Ca(2+) ion in aqueous solution. These results collectively indicate that PRM-A binds pyranosides of L-Fuc and L-Gal when Ca(2+) concentration is not excessive to trap these sugars by chelation but sufficient to form the [PRM-A/Ca(2+)] complex. PMID- 26045036 TI - Safety and efficacy of gadoteric acid in pediatric magnetic resonance imaging: overview of clinical trials and post-marketing studies. AB - BACKGROUND: Gadoteric acid is a paramagnetic gadolinium macrocyclic contrast agent approved for use in MRI of cerebral and spinal lesions and for body imaging. OBJECTIVE: To investigate the safety and efficacy of gadoteric acid in children by extensively reviewing clinical and post-marketing observational studies. MATERIALS AND METHODS: Data were collected from 3,810 children (ages 3 days to 17 years) investigated in seven clinical trials of central nervous system (CNS) imaging (n = 141) and six post-marketing observational studies of CNS, musculoskeletal and whole-body MR imaging (n = 3,669). Of these, 3,569 children were 2-17 years of age and 241 were younger than 2 years. Gadoteric acid was generally administered at a dose of 0.1 mmol/kg. We evaluated image quality, lesion detection and border delineation, and the safety of gadoteric acid. We also reviewed post-marketing pharmacovigilance experience. RESULTS: Consistent with findings in adults, gadoteric acid was effective in children for improving image quality compared with T1-W unenhanced sequences, providing diagnostic improvement, and often influencing the therapeutic approach, resulting in treatment modifications. In studies assessing neurological tumors, gadoteric acid improved border delineation, internal morphology and contrast enhancement compared to unenhanced MR imaging. Gadoteric acid has a well-established safety profile. Among all studies, a total of 10 children experienced 20 adverse events, 7 of which were thought to be related to gadoteric acid. No serious adverse events were reported in any study. Post-marketing pharmacovigilance experience did not find any specific safety concern. CONCLUSION: Gadoteric acid was associated with improved lesion detection and delineation and is an effective and well-tolerated contrast agent for use in children. PMID- 26045035 TI - Childhood extracranial neoplasms: the role of imaging in drug development and clinical trials. AB - Cancer is the leading cause of death in children older than 1 year of age and new drugs are necessary to improve outcomes. Imaging is crucial to the drug development process and assessment of therapeutic response. In adults, tumours are often assessed with CT using size criteria. Unfortunately, techniques established in adults are not necessarily applicable in children due to differing pathophysiology, ability to cooperate and increased susceptibility to ionising radiation. MRI, in particular quantitative MRI, has to date not been fully utilised in children with extracranial neoplasms. The specific challenges of imaging in children, the potential for functional imaging techniques to inform upon and their inclusion in clinical trials are discussed. PMID- 26045037 TI - Contamination of rice field water with sulfonylurea and phenoxy herbicides in the Muda Irrigation Scheme, Kedah, Malaysia. AB - The purpose of the present study was to investigate the potential risk of herbicide contamination (2,4-dichlorophenoxy (2,4-D), 2-methyl-4 chlorophenoxyacetic acid (MCPA), metsulfuron, bensulfuron, and pyrazosulfuron) in the rice fields of the Muda Irrigation Scheme, Kedah, Malaysia. The study included two areas with different irrigation water sources namely non-recycled (N RCL) and recycled (RCL) water. Periodic water sampling was carried out from the drainage canals during the planting period of the wet season 2006/2007 and dry season 2007. The HPLC-UV was used to detect herbicide residues in the water samples collected from the rice fields. The results showed that the concentration of sulfonylurea herbicides such as bensulfuron and metsulfuron in the rice field was 0.55 and 0.51 MUg/L, respectively. The potential risk of contamination depended on the actual dosage of each herbicide applied by farmers to their rice fields. The potential risk of water pollution by the five herbicides studied in the area with RCL water tended to be more widespread compared to the area with N RCL water due to surface water runoff with higher levels of weedicides to the surrounding areas. During the two seasons, 50-73% of the water samples collected from the area receiving RCL water contained the five herbicides studied at concentrations of more than 0.05 MUg/L, and this percentage was higher than that from the areas receiving N-RCL water (45-69%). During the wet season, the overall total mean concentration of the eight herbicides found in the samples collected from the area with RCL water (6.27 MUg/L) was significantly higher (P < 0.01) than that from the area receiving N-RCL water (2.39 MUg/L). Meanwhile, during the dry season, there was no significant difference (P > 0.05) in the herbicide concentrations between the areas receiving RCL (6.16 MUg/L) and N-RCL water (7.43 MUg/L) water. PMID- 26045038 TI - Trace element concentrations in red swamp crayfish (Procambarus clarkii) and surface sediments in Lake Preola and Gorghi Tondi natural reserve, SW Sicily. AB - Concentrations of trace elements (Cd, Pb, As, V, Cr, Ni, Cu and Zn) were determined in superficial sediments and in muscle and hepatopancreas tissues of the red swamp crayfish Procambarus clarkii from Lake Preola and Gorghi Tondi Natural Reserve (SW Sicily). In particular, hepatopancreas showed a decidedly higher content of all analysed trace elements with respect to muscles (two- to threefold higher for Cd, Cu, As, Zn and V; four- to fivefold higher for Pb and Cr and seven times higher for Ni). However, no statistically reliable differential accumulation pattern emerged with regard to length and weight for trace elements (except for Cd for which significant positive correlations with length were recorded). Trace element concentrations found in crayfish tissues were in the range considered harmful to human health (except for Cd and Cr). Moreover, the As and Pb concentrations, either in sediment or crayfish tissues, are clearly related to intense agricultural activities, with extensive use of fertilizers and pesticides, that significantly affect the levels of these toxic metals in the study area. PMID- 26045039 TI - Fabrication of novel TiO2 nanoparticles/Mn(III) salen doped carbon paste electrode: application as electrochemical sensor for the determination of hydrazine in the presence of phenol. AB - Hydrazine and phenol are two important environmental pollutants. In this work, an electrochemical sensor for the selective and sensitive detection of hydrazine in presence of phenol was developed by the bulk modification of carbon paste electrode (CPE) with TiO2 nanoparticles and Mn(III) salen. Large peak separation, good sensitivity, and stability allow this modified electrode to analyze hydrazine individually and simultaneously along with phenol. Applying square wave voltammetry (SWV), a linear dynamic range of 3 * 10(-8)-4.0 * 10(-4) M with detection limit of 10.0 nM was obtained for hydrazine. Finally, the proposed method was applied to the determination of hydrazine and phenol in some real samples. PMID- 26045040 TI - Antibiotic resistance in Escherichia coli isolates from roof-harvested rainwater tanks and urban pigeon faeces as the likely source of contamination. AB - The objective of this study was to investigate the risks associated with the use of roof-harvested rainwater (RHRW) and the implication of pigeons as the most likely source of contamination by testing for antibiotic resistance profiles of Escherichia coli. A total of 239 E. coli were isolated from thirty fresh pigeon faecal samples (130 isolates), 11 RHRW tanks from three sites in Pretoria (78) and two in Johannesburg (31). E. coli isolates were tested against a panel of 12 antibiotics which included ampicillin, amoxicillin, amikacin, cefoxitin, ceftriaxone, chloramphenicol, ciprofloxacin, cotrimoxazole, enrofloxacin, gentamicin, nalidixic acid and tetracycline. In all samples, resistance to ampicillin (22.7.9%), gentamicin (23.6%), amikacin (24%), tetracycline (17.4) and amoxicillin (16.9%) were the most frequently encountered form of resistance. However, a relatively higher proportion of isolates from pigeon faeces (67.3%) were antibiotic resistant than those from RHRW (53.3%). The highest number of phenotypes was observed for single antibiotics, and no single antibiotic resistance was observed for chloramphenicol, ceftriaxone, gentamicin, cefoxitin, cotrimoxazole, although they were detected in multiple antibiotic resistance (MAR) phenotypes. The highest multiple antibiotic resistance (MAR) phenotypes were observed for a combination of four antibiotics, on isolates from JHB (18.8%), pigeon faeces (15.2%) and Pretoria (5.1%). The most abundant resistance phenotype to four antibiotics, Ak-Gm-Cip-T was dominated by isolates from pigeon faeces (6.8%) with Pretoria and Johannesburg isolates having low proportions of 1.3 and 3.1%, respectively. Future studies should target isolates from various environmental settings in which rainwater harvesting is practiced and the characterisation of the antibiotic resistance determinant genes among the isolates. PMID- 26045041 TI - Cadmium contamination of rice from various polluted areas of China and its potential risks to human health. AB - A total of 484 rice samples were collected from five polluted areas in China to investigate the cadmium (Cd) contamination of rice and its potential health risks. The mean Cd contents of analyzed rice samples obtained from different areas ranged from 0.149 to 0.189 mg.kg(-1). Cd concentrations in more than 18% of rice samples exceeded the maximum allowable Cd concentration, and the highest level of 41.1% was observed in samples from Hezhang, Guizhou, which was characterized by serious Cd pollution. Target hazard quotient (THQ) values of 1.5 to 7.8 from rice intake indicated a significant non-carcinogenic health risk for humans, particularly for highly exposed consumers. Children are more at risk than adults, as indicated by the higher THQs. Moreover, carcinogenic risks of Cd from rice intake for average and high consumers in the selected areas were two to three and four to eight greater, respectively, than the threshold value recommended by the International Commission on Radiological Protection. PMID- 26045042 TI - Microstructural characterization and hardness properties of electric resistance welding titanium joints for dental applications. AB - The electric resistance welding procedure is used to join a titanium bar with specific implant abutments in order to produce a framework directly in the oral cavity of the patient. This investigation studied the effects of the welding process on microstructure and hardness properties of commercially pure (CP2 and CP4) Ti components. Different welding powers and cooling procedures were applied to bars and abutments, normally used to produce the framework, in order to simulate the clinical intraoral welding procedure. The analyses highlighted that the joining process did not induce appreciable changes in the geometry of the abutments. However, because of unavoidable microstructural modifications in the welded zones, the hardness decreased to values lower than those of the unwelded CP2 and CP4 Ti grades, irrespective of the welding environments and parameters. PMID- 26045043 TI - Assessment of Protein:Creatinine Ratio versus 24-Hour Urine Protein in the Diagnosis of Preeclampsia. AB - BACKGROUND/AIMS: Current evidence has tried to extrapolate the use of the protein:creatinine ratio (PCR) in a single urine sample as a rapid diagnostic tool for preeclampsia (PE). The present study addresses the effectiveness of the PCR in the differential diagnosis of the pregnancy hypertensive disorder (PHD). METHODS: This is a prospective study conducted on patients admitted during 1 year with a diagnosis of PHD. These pregnant women were assessed for the correlation between the 24-hour test and the PCR to detect significant proteinuria. A ROC curve was made to determine the PCR cutoff value that would offer the best positive predictive value (PPV) as an early predictor of global and severe PE. RESULTS: A total of 72 patients with 24-hour proteinuria and PCR were studied (49 with PE). A significant correlation between the quick and the deferred sampling was observed (r = 0.60; p < 0.001). The ROC analysis showed a PCR of 0.36 as the best cutoff value for the diagnosis of global PE (PPV 96.4%; false-positive rate 4.4%; AUC 0.8802) and a cutoff value of 4.58 (sensitivity: 100%; PPV 87.5%; false positive rate 3.5%; AUC 0.9805) as the best cutoff for the diagnosis of severe proteinuria. CONCLUSIONS: PCR proved to be an effective test for the differential diagnosis of PHS. PMID- 26045044 TI - Morphologic features of the choroidoscleral interface in a healthy population using swept-source optical coherence tomography. AB - OBJECTIVE: To analyze the morphologic features of the choroidoscleral interface in a healthy population using swept-source optical coherence tomography (SS OCT). DESIGN: Retrospective data analysis of a subgroup of eyes from a previous single center, prospective, cross-sectional, noninterventional study. METHODS: A total of 276 healthy eyes from 154 subjects were evaluated using SS OCT. Inclusion criteria were best-corrected visual acuity between 20/20 and 20/25, spherical equivalent between +/-3 diopters, and no systemic or ocular diseases. Two independent investigators analyzed the morphologic features of the choroidoscleral interface in a masked fashion, classifying the contour and shape as concave (bowl-shaped) or inflective (S-shaped contour with >=1 inflection point). RESULTS: The presence of a temporal choroidoscleral interface inflection was identified in 12.8% of the eyes. The mean choroidal thickness was 372.1 +/- 76.8 MUm and the average distance from the inflection point to the fovea was 4427.3 +/- 627.9 MUm. Nine patients showed an inflective profile in both eyes. No changes in the retinal profile were found in any of these cases. The mean age of the patients with an inflective profile was 16 +/- 19 years (range 4-82) vs 36 +/ 25 years (range 3-95) in the group with a concave contour (P = .001). The temporal choroidal thickness at 4000 and 5000 MUm from the fovea was thicker in the group with a concave contour. CONCLUSIONS: Temporal choroidoscleral interface inflection or S-shaped profile of the choroidoscleral interface with focal thinning of the choroid can be considered a normal variation without clinical significance, especially in younger populations. PMID- 26045045 TI - AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation. AB - Nuclear degradation is a key stage in keratinocyte terminal differentiation and the formation of the cornified envelope that comprises the majority of epidermal barrier function. Parakeratosis, the retention of nuclear material in the cornified layer of the epidermis, is a common histological observation in many skin diseases, notably in atopic dermatitis and psoriasis. Keratinocyte nuclear degradation is not well characterised, and it is unclear whether the retained nuclei contribute to the altered epidermal differentiation seen in eczema and psoriasis. Loss of AKT1 function strongly correlated with parakeratosis both in eczema samples and in organotypic culture models. Although levels of DNAses, including DNase1L2, were unchanged, proteomic analysis revealed an increase in Lamin A/C. AKT phosphorylates Lamin A/C, targeting it for degradation. Consistent with this, Lamin A/C degradation was inhibited and Lamin A/C was observed in the cornified layer of AKT1 knockdown organotypic cultures, surrounding retained nuclear material. Using AKT-phosphorylation-dead Lamin A constructs we show that the retention of nuclear material is sufficient to cause profound changes in epidermal terminal differentiation, specifically a reduction in Loricrin, Keratin 1, Keratin 10, and filaggrin expression. We show that preventing nuclear degradation upregulates BMP2 expression and SMAD1 signalling. Consistent with these data, we observe both parakeratosis and evidence of increased SMAD1 signalling in atopic dermatitis. We therefore present a model that, in the absence of AKT1-mediated Lamin A/C degradation, DNA degradation processes, such as those mediated by DNAse 1L2, are prevented, leading to parakeratosis and changes in epidermal differentiation. PMID- 26045046 TI - Myeloid cell leukemia-1 is an important apoptotic survival factor in triple negative breast cancer. AB - Breast cancer is the second-most frequently diagnosed malignancy in US women. The triple-negative breast cancer (TNBC) subtype, which lacks expression of the estrogen receptor, progesterone receptor and human epidermal growth factor receptor-2, afflicts 15% of patients and is refractory to current targeted therapies. Like many cancers, TNBC cells often deregulate programmed cell death by upregulating anti-apoptotic proteins of the B-cell CLL/lymphoma 2 (Bcl-2) family. One family member, myeloid cell leukemia-1 (Mcl-1), is commonly amplified in TNBC and correlates with a poor clinical prognosis. Here we show the effect of silencing Mcl-1 and Bcl-2-like protein 1 isoform 1 (Bcl-xL) expression on viability in a panel of seventeen TNBC cell lines. Cell death was observed in a subset upon Mcl-1 knockdown. In contrast, Bcl-xL knockdown only modestly reduced viability, indicating that Mcl-1 is a more important survival factor. However, dual silencing of both Mcl-1 and Bcl-xL reduced viability in most cell lines tested. These proliferation results were recapitulated by BH3 profiling experiments. Treatment with a Bcl-xL and Bcl-2 peptide had only a moderate effect on any of the TNBC cell lines, however, co-dosing an Mcl-1-selective peptide with a peptide that inhibits Bcl-xL and Bcl-2 was effective in each line tested. Similarly, the selective Bcl-xL inhibitor WEHI-539 was only weakly cytotoxic across the panel, but sensitization by Mcl-1 knockdown markedly improved its EC50. ABT-199, which selectively inhibits Bcl-2, did not synergize with Mcl-1 knockdown, indicating the relatively low importance of Bcl-2 in these lines. Mcl 1 sensitivity is not predicted by mRNA or protein levels of a single Bcl-2 family member, except for only a weak correlation for Bak and Bax protein expression. However, a more comprehensive index composed of Mcl-1, Bcl-xL, Bim, Bak and Noxa protein or mRNA expression correlates well with Mcl-1 sensitivity in TNBC and can also predict Mcl-1 dependency in non-small cell lung cancer cell lines. PMID- 26045047 TI - NIK promotes tissue destruction independently of the alternative NF-kappaB pathway through TNFR1/RIP1-induced apoptosis. AB - NF-kappaB-inducing kinase (NIK) is well-known for its role in promoting p100/NF kappaB2 processing into p52, a process defined as the alternative, or non canonical, NF-kappaB pathway. Here we reveal an unexpected new role of NIK in TNFR1-mediated RIP1-dependent apoptosis, a consequence of TNFR1 activation observed in c-IAP1/2-depleted conditions. We show that NIK stabilization, obtained by activation of the non-death TNFRs Fn14 or LTbetaR, is required for TNFalpha-mediated apoptosis. These apoptotic stimuli trigger the depletion of c IAP1/2, the phosphorylation of RIP1 and the RIP1 kinase-dependent assembly of the RIP1/FADD/caspase-8 complex. In the absence of NIK, the phosphorylation of RIP1 and the formation of RIP1/FADD/caspase-8 complex are compromised while c-IAP1/2 depletion is unaffected. In vitro kinase assays revealed that recombinant RIP1 is a bona fide substrate of NIK. In vivo, we demonstrated the requirement of NIK pro death function, but not the processing of its substrate p100 into p52, in a mouse model of TNFR1/LTbetaR-induced thymus involution. In addition, we also highlight a role for NIK in hepatocyte apoptosis in a mouse model of virus-induced TNFR1/RIP1-dependent liver damage. We conclude that NIK not only contributes to lymphoid organogenesis, inflammation and cell survival but also to TNFR1/RIP1 dependent cell death independently of the alternative NF-kappaB pathway. PMID- 26045048 TI - Protein kinase D1/2 is involved in the maturation of multivesicular bodies and secretion of exosomes in T and B lymphocytes. AB - Multivesicular bodies (MVBs) are endocytic compartments that enclose intraluminal vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, these ILV contain Fas ligand (FasL) and are secreted as 'lethal exosomes' following activation-induced fusion of the MVB with the plasma membrane. Diacylglycerol (DAG) and diacylglycerol kinase alpha (DGKalpha) regulate MVB maturation and polarized traffic, as well as subsequent secretion of pro-apoptotic exosomes, but the molecular basis underlying these phenomena remains unclear. Here we identify protein kinase D (PKD) family members as DAG effectors involved in MVB genesis and secretion. We show that the inducible secretion of exosomes is enhanced when a constitutively active PKD1 mutant is expressed in T lymphocytes, whereas exosome secretion is impaired in PKD2 deficient mouse T lymphoblasts and in PKD1/3-null B cells. Analysis of PKD2 deficient T lymphoblasts showed the presence of large, immature MVB-like vesicles and demonstrated defects in cytotoxic activity and in activation-induced cell death. Using pharmacological and genetic tools, we show that DGKalpha regulates PKD1/2 subcellular localization and activation. Our studies demonstrate that PKD1/2 is a key regulator of MVB maturation and exosome secretion, and constitutes a mediator of the DGKalpha effect on MVB secretory traffic. PMID- 26045050 TI - Expansion of the hematopoietic stem cell compartment is necessary but not sufficient for gain-of-function mutant p53 R248Q to accelerate lymphomagenesis. PMID- 26045049 TI - The BH3-only protein BIM contributes to late-stage involution in the mouse mammary gland. AB - After cessation of lactation, involution of the mouse mammary gland proceeds in two distinct phases, a reversible and an irreversible one, which leads to the death and removal of alveolar cells. Cell death is preceded by the loss of STAT5 activity, which abrogates cell differentiation and gain of STAT3 activity. Despite early observations implicating BCL2 (B cell lymphoma 2) family proteins in this process, recent evidence suggests that STAT3-controlled cathepsin activity is most critical for cell death at the early stage of involution. Somewhat surprisingly, this cell death associates with but does not depend on the activation of pro-apoptotic effector caspases. However, transgenic overexpression of BCL2, that blocks caspase activation, delays involution while conditional deletion of BclX accelerates this process, suggesting that BCL2 family proteins are needed for the effective execution of involution. Here, we report on the transcriptional induction of multiple pro-apoptotic BCL2 family proteins of the 'BH3-only' subgroup during involution and the rate-limiting role of BIM in this process. Loss of Bim delayed epithelial cell clearance during involution after forced weaning in mice, whereas the absence of related Bmf had minor and loss of Bad or Noxa no impact on this process. Consistent with a contribution of BCL2 family proteins to the second wave of cell death during involution, loss of Bim reduced the number of apoptotic cells in this irreversible phase. Notably, the expression changes observed within the BCL2 family did not depend on STAT3 signalling, in line with its initiating role early in the process, but rather appear to result from relief of repression by STAT5. Our findings support the existence of a signalling circuitry regulating the irreversible phase of involution in mice by engaging BH3-only protein-driven mitochondrial apoptosis. PMID- 26045052 TI - Electric-Pulse Current Stimulation Increases If Current in mShox2 Genetically Modified Canine Mesenchymal Stem Cells. AB - OBJECTIVE: We aimed to investigate the role of mShox2 in generating If pacemaker current in vitro by means of electric-pulse current stimulation (EPCS) of canine mesenchymal stem cells (cMSCs). METHODS: mShox2 genetically modified cMSCs were prepared with pLentis-mShox2 red fluorescent protein. After EPCS induction, we examined the kinetic characteristics of generated inward current by means of a patch clamp. We then evaluated the expression of pacemaker-related genes, such as Nkx2.5, Tbx3, HCN4, Cx43 and Cx45, by means of qRT-PCR and Western blotting. The morphological changes and the cardiomyogenic differentiation marker cTnT were investigated at the same time. RESULTS: The time- and voltage-dependent inward current recorded after mShox2 infection was confirmed to be If current. After EPCS induction, the detection rate of this If current was increased. The current amplitude and density were increased, and the channel activation curve shifted to the right. The pacemaker markers Tbx3, HCN4 and Cx45 were significantly upregulated, but the working myocardium markers Nkx2.5 and Cx43 were downregulated after mShox2 infection, and were more remarkable after EPCS induction. The cells became larger and assumed spindle and spider-like morphologies. cTnT was also detected in the experimental cells. CONCLUSIONS: Our results suggest that EPCS promotes the differentiation of mShox2 genetically modified cMSCs into pacemaker-like cells, which generates more If current. PMID- 26045051 TI - MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. AB - MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML. PMID- 26045053 TI - Pro- and Anticonvulsant Effects of the Ant Dinoponera quadriceps (Kempf) Venom in Mice. AB - Epilepsy affects at least 50 million people worldwide, and the available treatment is associated with various side effects. Approximately 20-30% of the patients develop seizures that persist despite careful monitored treatment with antiepileptic drugs. Thus, there is a clear need for the development of new antiepileptic drugs, and the venoms can be an excellent source of probes. In this context, while there are studies on venoms from snakes, scorpions, and spiders, little is known regarding venom from ants. The aim of this study was to investigate the potential pro- and anticonvulsant effects of the venom from the ant Dinoponera quadriceps (Kempf) in Swiss mice. After the injection of the crude venom (DqTx-5, 50, and 500 mg/mL) in the lateral ventricle of mice, we observed a reduction of exploration and grooming behaviors, as well as an increase in immobility duration. In addition, the crude venom induced procursive behavior and tonic-clonic seizures at the highest concentration. Conversely, the preadministration of the denatured venom (AbDq) at the concentration of 2 mg/mL protected the animals against tonic-clonic seizures (66.7%) and death (100%) induced by administration of bicuculline. Taken together, the findings demonstrate that D. quadriceps venom might be potential source of new pro- and anticonvulsants molecules. PMID- 26045054 TI - Integrated Pest Management in a Predator-Prey System with Allee Effects. AB - A commonly used biocontrol strategy to control invasive pests with Allee effects consists of the deliberate introduction of natural enemies. To enhance the effectiveness of this strategy, several tactics of control of invasive species (e.g., mass-trapping, manual removal of individuals, and pesticide spraying) are combined so as to impair pest outbreaks. This combination of strategies to control pest species dynamics are usually named integrated pest management (IPM). In this work, we devise a predator-prey dynamical model in order to assess the influence of the intensity of chemical killing on the success of an IPM. The biological and mathematical framework presented in this study can also be analyzed in the light of species conservation and food web dynamics theory. PMID- 26045055 TI - Leucophora Satellite Flies (Diptera: Anthomyiidae) as Nest Parasites of Sweat Bees (Hymenoptera: Halictidae) in the Neotropics. AB - The biology of the 10 species of Leucophora (Diptera: Anthomyiidae) recorded in the Neotropics remains unknown. The large majority of the studied species so far are kleptoparasites of bees and wasps. Here, we report the first observations of Leucophora andicola (Bigot) and Leucophora peullae (Malloch) visiting the nests of ground-nesting sweat bees Corynura (Hymenoptera: Halictidae) in Chilean Patagonia. Females of both species perch on small stones or sticks within a dense nest aggregation of the bees and then track pollen-loaded bees in flight with great precision, eventually following them into their nests. The overall behavior closely resembles that observed for many other species of the genus. Excavations of some bee nests returned only two dipteran puparia, possibly of Leucophora, suggesting a low parasitism rate. One male of L. peullae was also collected at the bee aggregation. This is the first report of host association for any Leucophora from the Neotropics and the first report of any anthomyiid fly associated with augochlorine bees. PMID- 26045056 TI - Reconstruction of femoral bone loss with a monoplane external fixator and bone transport. AB - BACKGROUND: Treatment of femoral bone loss is difficult. Ilizarov described the bone lengthening technique using a circular external fixator, but this technique is uncomfortable on the femur because of the circular fixator. We have therefore opted for use of a monoplane external fixator to treat femoral bone loss with bone lengthening. The objectives of this study were to determine whether (1) bone union can be obtained with a monoplane external fixator; (2) infections can be treated; (3) the lower limb axes and alignment can be controlled; and (4) patient satisfaction is high. HYPOTHESIS: A monoplane external fixator provides a high rate of bone union during bone transport with no risk of deformity over the long term. MATERIAL AND METHODS: Between 2007 and 2012 seven patients were treated with bone transport using a monoplane external fixator for femoral bone loss measuring a mean 8.1cm (range, 6-10cm). All were infected (osteomyelitis) or contaminated following Gustilo type IIIB fractures. The mean time from initial injury to the beginning of bone loss management was 3.9months (range, 1.5-8 months) for six of them and 108 months for one patient. RESULTS: At the mean follow-up of 4.7 years (range, 2-7 years), all of the patients showed union after a mean 11.1months (range, 8-18 months), i.e., 41.2 days/cm of transport, and all infections were resolved. Only one patient had unequal leg length measuring 2cm and another showed 3 degrees varus. Five patients were satisfied despite disappointing functional results. All could fully extend the knee but the mean flexion was 50 degrees (range, 20-90 degrees ). DISCUSSION: This series confirms that use of the monoplane external fixation with descending bone transport to treat infected femoral bone loss is efficient and provides bone union, treatment of the infection, and control of bone axes and lengths. This technique does not allow recuperation of complete knee flexion. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 26045057 TI - Surgical approaches to jugular foramen schwannomas: An anatomic study. AB - BACKGROUND: The variety of surgical approaches to jugular schwannomas makes selection of an approach difficult. The purpose of this study was to define the anatomic elements of these approaches. METHODS: Ten adult cadaveric heads were examined. RESULTS: There are lateral, posterior, and anterior routes that access various parts of the jugular foramen. Removal of the jugular process of the occipital bone provides access to the posterior aspect of the foramen, the infralabyrinthine mastoidectomy provides access to the lateral edge and dome of the jugular bulb, and the preauricular approaches provide access to the anterior margin of the bulb and foramen. Additions to these approaches may include cervical and vertebral artery exposure, facial nerve transposition, foramen magnum exposure, and external canal and condylar resection. CONCLUSION: An understanding of the anatomy of the jugular foramen is crucial in achieving total tumor removal while minimizing risk. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1041-E1053, 2016. PMID- 26045058 TI - Estimating the Recurrence Rate of Gestational Diabetes Mellitus (GDM) in Massachusetts 1998-2007: Methods and Findings. AB - OBJECTIVES: Women with gestational diabetes mellitus (GDM) may be able to reduce their risk of recurrent GDM and progression to type 2 diabetes mellitus through lifestyle change; however, there is limited population-based information on GDM recurrence rates. METHODS: We used data from a population of women delivering two sequential live singleton infants in Massachusetts (1998-2007) to estimate the prevalence of chronic diabetes mellitus (CDM) and GDM in parity one pregnancies and recurrence of GDM and progression from GDM to CDM in parity two pregnancies. We examined four diabetes classification approaches; birth certificate (BC) data alone, hospital discharge (HD) data alone, both sources hierarchically combined with a diagnosis of CDM from either source taking priority over a diagnosis of GDM, and both sources combined including only pregnancies with full agreement in diagnosis. Descriptive statistics were used to describe population characteristics, prevalence of CDM and GDM, and recurrence of diabetes in successive pregnancies. Diabetes classification agreement was assessed using the Kappa statistic. Associated maternal characteristics were examined through adjusted model-based t tests and Chi square tests. RESULTS: A total of 134,670 women with two sequential deliveries of parities one and two were identified. While there was only slight agreement on GDM classification across HD and BC records, estimates of GDM recurrence were fairly consistent; nearly half of women with GDM in their parity one pregnancy developed GDM in their subsequent pregnancy. While estimates of progression from GDM to CDM across sequential pregnancies were more variable, all approaches yielded estimates of <=5 %. The development of either GDM or CDM following a parity one pregnancy with no diagnosis of diabetes was <3 % across approaches. Women with recurrent GDM were disproportionately older and foreign born. CONCLUSION: Recurrent GDM is a serious life course public health issue; the inter-pregnancy interval provides an important window for diabetes prevention. PMID- 26045059 TI - Status of nurse staffing and nursing care delivery in Pudong, Shanghai. AB - AIM: To evaluate nurse staffing levels and nursing care delivery in adult general medical or surgical wards of hospitals in the Pudong district of Shanghai, China. BACKGROUND: Rapid economic development and improved Chinese living standards have spurred increased demands for high-quality health care. Thus, the quality of nursing services has become a focus of attention. DESIGN: A cross-sectional, descriptive design was used for the study. METHODS: We used an anonymous survey to collect data from 1614 nurses from 98 wards in seven general hospitals in Pudong, Shanghai. RESULTS: During day shifts, the nurse-to-patient ratios were >1:10. However, these ratios were much higher during evening and night shifts. The clinical frontline nursing workforce primarily consisted of nurses with junior college degrees that had limited working experience. Junior nurses with different educational backgrounds, professional levels and work experiences were assigned almost similar nursing care work as senior nurses. CONCLUSIONS: In the surveyed hospitals in the Pudong district, nurse staffing levels and skill mix may be inadequate to meet the increasing demands of patient care. The clinical nursing workforce needs to be strengthened and used effectively to enhance the quality and safety of patient care. RELEVANCE TO CLINICAL PRACTICE: We should focus on the quantity and quality of the nursing workforce, as well as nursing skill utilisation. PMID- 26045060 TI - All-trans-retinoic acid regulates aquaporin-3 expression and related cellular membrane permeability in the human amniotic environment. AB - INTRODUCTION: The aquaporins (AQP1, 3, 8, 9 and 11) are known to be expressed, and involved in the transport of water and small molecules through fetal membranes. To exert these crucial functions, these AQPs have to be finely regulated. All-trans-retinoic acid (atRA) was previously found to regulate some genes in this environment, raising the question of whether these AQPs were regulated by atRA. METHODS: Explants, and primary and established amniotic cells were cultured to determine which AQP were transcriptionally modified by atRA, using the qRT-PCR strategy. Immunohistochemistry and glycerol uptake tests were used to determine the impact of atRA on AQP protein expression and function. Specific agonists of retinoic acid receptors were used to identify the molecular mechanisms of AQP promoter activation. A classical gene AQP promoter study was also used to identify DR5 retinoic acid receptor elements (RAREs). RESULTS: Beyond these AQPs, only one specific atRA-dependent increase in AQP3 transcripts and proteins level was established in amnion (not in chorion) and in related primary and established cells. We found three DR5-RAREs essential for inducing this transcriptional AQP3 through RARalpha. This transactivation of the AQP3 coding gene was functionally related to an increase of AQP3 permeability tests by a glycerol uptake assay. DISCUSSION: Our data support an atRA regulatory model of AQP3 expression leading to an increased cellular permeability in the epithelial amniotic environment. We cast new light on AF regulation in healthy pregnancy, and advance new hypotheses for obstetrical complications linked to impairment of the retinoic signaling pathway. PMID- 26045061 TI - Peroral administration of 5-bromo-2-deoxyuridine in drinking water is not a reliable method for labeling proliferating S-phase cells in rats. AB - In rodents, peroral (p.o.) administration of 5-bromo-2'-deoxyuridine (BrdU) dissolved in drinking water is a widely used method for labeling newly formed cells over a prolonged time-period. Despite the broad applicability of this method, the pharmacokinetics of BrdU in rats or mice after p.o. administration remains unknown. Moreover, the p.o. route of administration may be limited by the relatively low amount of BrdU consumed over 24h and the characteristic drinking pattern of rats, with water intake being observed predominantly during the dark phase. Therefore, we investigated the reliability of staining proliferating S phase cells with BrdU after p.o. administration (1mg/ml) to rats using both in vitro and in vivo conditions. Flow cytometric analysis of tumor cells co cultivated with sera from experimental animals exposed to BrdU dissolved in drinking water or 25% orange juice revealed that the concentration of BrdU in the blood sera of rats throughout the day was below the detection limits of our assay. Ingested BrdU was only sufficient to label approximately 4.2+/-0.3% (water) or 4.2+/-0.3% (25% juice) of all S-phase cells. Analysis of data from in vivo conditions indicates that only 7.6+/-3.3% or 15.5+/-2.3% of all S-phase cells in the dentate gyrus of the hippocampus was labeled in animals administered drinking water containing BrdU during the light and dark phases of the day. In addition, the intensity of BrdU-positive nuclei in animals receiving p.o. administration of BrdU was significantly lower than in control animals intraperitoneally injected with BrdU. Our data indicate that the conventional approach of p.o. administration of BrdU in the drinking water to rats provides strongly inaccurate information about the number of proliferating cells in target tissues. Therefore other administration routes, such as osmotic mini pumps, should be considered for labeling of proliferating cells over a prolonged time period. PMID- 26045062 TI - The failure to detect drug-induced sensory loss in standard preclinical studies. AB - Over the years a number of drugs have been approved for human use with limited signs of toxicity noted during preclinical risk assessment study designs but then show adverse events in compliant patients taking the drugs as prescribed within the first few years on the market. Loss or impairments in sensory systems, such as hearing, vision, taste, and smell have been reported to the FDA or have been described in the literature appearing in peer-reviewed scientific journals within the first five years of widespread use. This review highlights the interactive cross-modal compensation within sensory systems that can occur that reduces the likelihood of identifying these losses in less sentient animals used in standard preclinical toxicology and safety protocols. We provide some historical and experimental evidence to substantiate these sensory effects in and highlight the critical importance of detailed training of technicians on basic ethological, species-specific behaviors of all purpose-bred laboratory animals used in these study designs. We propose that the time, effort and cost of training technicians to be better able to identify and document very subtle changes in behavior will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced sensory loss within current standard regulatory preclinical research protocols. PMID- 26045063 TI - Identification association of drug-disease by using functional gene module for breast cancer. AB - In oncology drug development, it is important to develop low risk drugs efficiently. Meanwhile, computational methods have been paid more and more attention in drug discovery. However, few studies attempt to discover the mutual gene modules shared by the drug and disease association. Here we introduce a novel method to identify repositioned drug for breast cancer by integrating the breast cancer survival data with the drug sensitivity information. Among the 140 drug candidates, we are able to filter 4 FDA approved drugs and identify 2 breast cancer drugs among 4 known breast cancer therapeutic drug in total. PMID- 26045066 TI - Effect of SCH442416 on glutamate uptake in retinal Muller cells at increased hydrostatic pressure. AB - The A2A receptor (A2AR) antagonist has been considered as an attractive option to improve the treatment of neurological disorders, and the function of A2AR antagonist may inhibit the release of glutamate and prevent neuron damage. The aim of the present study was to investigate whether SCH442416 can modulate the glutamate uptake in retinal Muller cells under increased hydrostatic pressure. The levels of glutamine synthetase (GS) and glutamate aspartate transporter (GLAST) were assessed in retinal Muller cells under 40 mmHg pressure for 24 h using reverse transcription-quantitative polymerase chain reaction and western blotting, and a glutamate uptake assay was performed using a scintillation counting method. Following treatment of the Muller cells with 100 nM SCH442416 under 40 mmHg pressure for 24 h, the mRNA and protein expression levels of GS and GLAST, and glutamate uptake activity were investigated. Under 40 mmHg pressure, the expression levels of GS and GLAST in the Muller cells, and glutamate uptake activity were significantly reduced. Treatment with SCH442416 significantly ameliorated the decreased expression levels of GS and GLAST, and improved the glutamate uptake activity in the retinal Muller cells exposed to 40 mmHg pressure, resulting in increased expression levels of GS and GLAST, and increased glutamate uptake activity in the Muller cells under pressure. These results suggested that SCH442416 may be a potential candidate as a beneficial neuroprotective agent for the treatment of glaucoma by accelerating the clearance of extracellular glutamate. PMID- 26045065 TI - miR-494 promotes cell proliferation, migration and invasion, and increased sorafenib resistance in hepatocellular carcinoma by targeting PTEN. AB - MicroRNA-494 (miR-494) acts as an oncomiR and is involved in tumor development, progression and metastasis, and confers resistance to chemotherapeutic drugs by targeting a number of molecules in several human cancers. However, the function and underlying molecular mechanism of miR-494 in hepatocellular carcinoma (HCC) has not been totally elucidated. In the present study, we determined the role played by miR-494 in HCC tissues and HCC cell lines using quantitative RT-PCR (RT qPCR). The results showed that, miR-494 was significantly upregulated in HCC tissues and HCC cell lines. Additionally, a high miR-494 expression positively correlated with tumor differentiation (P<0.01), TNM stage (P<0.01) and lymph node metastasis (P<0.01). Luciferase reporter assays confirmed that miR-494 binds to the 3'-untranslated region (3'-UTR) of the phosphatase and tensin homolog (PTEN) mRNA and represses its translation. Functional analyses indicated that the upregulation of miR-494 promoted cell viability, migration and invasion, decreased cell apoptosis and cell cycle arrest at G1 stage, and conferred sorafenib resistance to HCC cell lines. Underexpression of PTEN by siRNA significantly attenuated the inhibitory effects of anti-miR-494 on the proliferation, migration and invasion of liver cancer cells. Mechanistic investigations revealed that miR-494 suppressed the expression of PTEN but increased the expression of PI3K and p-Akt, which contribute to the promotion of proliferation, migration and invasion, and increased sorafenib resistance to HCC cell lines. These findings suggested that miR-494 is a potential candidate for HCC therapeutics. PMID- 26045067 TI - Daily and Seasonal Rhythms in Human Mucosa Phospholipid Fatty Acid Composition. AB - Fatty acids (FAs) can exert important physiological effects: for example, as precursors of eicosanoids, as signaling molecules, and, in particular, as parts of phospholipids, the major constituents of cell membranes. Animals can remodel cell membranes in terms of their FA composition in response to environmental conditions, and even endothermic mammals exhibit seasonal cycles in the FA makeup of membranes. Previous evidence pointed to the existence of both seasonal and daily cycles in phospholipid composition of human cell membranes. Therefore, we used a noninvasive method to collect human mucosa cells over 1 year in 20 healthy subjects, and we determined seasonal and daily rhythmicity of phospholipid FA content. Our results show that significant daily rhythms were detectable in 11 of 13 FAs and were largely synchronous among subjects. Also, these daily rhythms showed stable phase relationships between different FAs within subjects. In contrast, yearly rhythms in phospholipid FA content were statistically significant in only ~50% of subjects and were asynchronous between subjects. These results support the view that while human physiology is still dominated by geophysical sunrise and sunset, resulting in strong daily cycles, seasonal rhythms are less well defined, at least in Western societies. We suggest that the main physiological function underlying rhythms in cell membrane composition is the regulation of the activity of transmembrane proteins, such as ion pumps, which can be strongly affected by the fatty acyl chains of phospholipids in the surrounding membrane bilayer. Hence, among a multitude of other functions, cycles in membrane FA composition may be involved in generating the daily rhythm of metabolic rate. Rhythms in certain membrane FAs, namely polyunsaturated and monounsaturated FAs that are known to affect health, could be also involved in daily and seasonal rhythms of diseases and death. PMID- 26045068 TI - Biological safety in the medical laboratory. PMID- 26045064 TI - Association of plasma F2-isoprostanes and isofurans concentrations with erythropoiesis-stimulating agent resistance in maintenance hemodialysis patients. AB - BACKGROUND: In patients undergoing maintenance hemodialysis (HD), hyporesponsiveness to erythropoiesis stimulating agents (ESAs) is associated with adverse clinical outcomes. Systemic inflammation is highly prevalent in HD patients and is associated with ESA hyporesponsiveness. Oxidative stress is also highly prevalent in HD patients, but no previous study has determined its association with ESA response. This study assessed the association of plasma markers of oxidative stress and inflammation with ESA resistance in patients undergoing maintenance HD. METHODS: We analyzed data from 165 patients enrolled in the Provision of Antioxidant Therapy in Hemodialysis study, a randomized controlled trial evaluating antioxidant therapy in prevalent HD patients. Linear and mixed-effects regression were used to assess the association of baseline and time-averaged high sensitivity F2-isoprostanes, isofurans, C-reactive protein (hsCRP), and interleukin-6 (IL-6) with ESA resistance index (ERI), defined as the weekly weight-adjusted ESA dose divided by blood hemoglobin level. Unadjusted models as well as models adjusted for potential confounders were examined. Predicted changes in ERI per month over study follow-up among baseline biomarker quartiles were also assessed. RESULTS: Patients with time-averaged isofurans in the highest quartile had higher adjusted mean ERI compared with patients in the lowest quartile (beta = 14.9 ng/ml; 95% CI 7.70, 22.2; reference group <0.26 ng/ml). The highest quartiles of hsCRP and IL-6 were also associated with higher adjusted mean ERI (beta = 10.8 mg/l; 95% CI 3.52, 18.1 for hsCRP; beta = 10.2 pg/ml; 95% CI 2.98, 17.5 for IL-6). No significant association of F2-isoprostanes concentrations with ERI was observed. Analyses restricted to baseline exposures and ERI showed similar results. Baseline hsCRP, IL-6, and isofurans concentrations in the highest quartiles were associated with greater predicted change in ERI over study follow-up compared to the lowest quartiles (P = 0.008, P = 0.004, and P = 0.04, respectively). There was no association between baseline F2-isoprostanes quartile and change in ERI. CONCLUSIONS: In conclusion, higher concentrations of isofurans, hsCRP and IL-6, but not F2-isoprostanes, were associated with greater resistance to ESAs in prevalent HD patients. Further research is needed to test whether interventions that successfully decrease oxidative stress and inflammation in patients undergoing maintenance HD improve ESA responsiveness. PMID- 26045069 TI - Peritoneal implantation of ureter in cadaveric renal transplant. AB - We report here a case of complication of peritoneal implantation of ureter in cadaveric renal transplant. The patient presented with anuria and delayed graft function. The diagnosis was suspected upon physical examination and radiological investigation. The complication was managed with reimplantation of the ureter into the bladder and the patient recovered with good graft function. We discuss this case, review the literature on this rare complication, and share our suggestions on how it can be prevented. PMID- 26045070 TI - Three cases of atypical pneumonia caused by Chlamydophila psittaci. AB - Psittacosis is a zoonotic disease caused by Chlamydophila psittaci. The most common presentation is atypical pneumonia. Three cases of pneumonia of varying severity due to psittacosis are described. All patients had a history of avian contact. The diagnosis was confirmed by molecular detection of Chlamydophila psittaci in respiratory specimens. The cases showed good recovery with doxycycline treatment. Increased awareness of psittacosis can shorten diagnostic delay and improve patient outcomes. PMID- 26045071 TI - Technical considerations for ligation of ruptured hepatic artery aneurysm: is arterial reconstruction necessary? AB - Ruptured hepatic artery aneurysm is a rare life-threatening condition. Open surgery with ligation of the aneurysm is the treatment of choice if the patient presents with haemodynamic instability. Controversies exist on whether hepatic artery reconstruction is needed after exclusion of the aneurysm. Involvement of the gastroduodenal artery origin was proposed as an indication for reconstruction, but this might be difficult to ascertain upon laparotomy. Recent studies showed that arterial ligation distal to the gastroduodenal artery origin does not necessarily result in ischaemic liver injury, implying that reconstruction in such cases may not be required, especially in a haemodynamically unstable patient. A patient with common hepatic artery aneurysm involving the gastroduodenal artery origin presented with rupture and underwent aneurysm ligation. Adequacy of intrahepatic arterial flow was determined by intra operative Doppler ultrasonography and arterial reconstruction was not performed. The technical considerations during the operative management of ruptured hepatic artery aneurysms are discussed. PMID- 26045072 TI - Minimally invasive enteroscopically guided small bowel resection. AB - Localisation of small bowel pathology is often difficult, especially intramural small bowel lesions. Even with the use of laparoscopy, visualisation of small bowel lesion is not always possible. The most accurate method to identify such a lesion is by laparotomy with direct visualisation and palpation of the lesion. However, the recent trend in surgical development aims for minimally invasive procedures while keeping the excision of surgical pathology safe and complete, with less surgical trauma. This report illustrates a case of minimally invasive enteroscopically guided small bowel resection. PMID- 26045073 TI - Fatal bilateral lower-limb deep vein thrombosis and pulmonary embolism following single digit replantation. AB - Venous thromboembolism in hand surgery is rare. There is no report in the literature on postoperative mortality from venous thromboembolism following microsurgery in upper limbs. We report the case of a 56-year-old Chinese man who died from pulmonary embolism as a result of bilateral lower-limb deep vein thrombosis following prolonged surgery under general anaesthesia after replantation of a finger. This case raises awareness of the need for precautions against venous thromboembolism following prolonged microsurgery and identification of high-risk patients. PMID- 26045074 TI - Re: Falls prevention in the elderly. PMID- 26045075 TI - Obesity management is also part of fall prevention. PMID- 26045076 TI - Acute tumour bleeding in a patient with tuberous sclerosis and bilateral renal angiomyolipomata. PMID- 26045077 TI - Bisphosphonate-associated atypical femur fracture in a 90-year-old Caucasian woman. PMID- 26045079 TI - Exploring the Effectiveness of Mandatory Premarital Screening and Genetic Counselling Programmes for beta-Thalassaemia in the Middle East: A Scoping Review. AB - BACKGROUND: beta-Thalassaemia is a common genetic blood disorder in the Middle Eastern region. Mandatory premarital screening and genetic counselling (PMSGC) programmes are implemented in 8 Middle East countries to reduce at-risk marriages and thus disease prevalence. A scoping review was conducted to explore the effectiveness of these programmes. METHODS: The 6-stage scoping framework of Arksey and O'Malley [Int J Soc Res Methodol 2005;8:19-32] was used. Reported outcomes were analysed per country, with success defined as achieving a 65% reduction in at-risk marriages and/or thalassaemia-affected births. Emergent enablers and barriers were analysed thematically. RESULTS: Twenty-one sources were included from the 1,348 identified, discussing 7 country programmes, with 95% (20/21) published during 2003-2013. Five publications each were included for Iran and Saudi Arabia, 3 for Turkey, 2 each for Bahrain and Iraq (Kurdistan), and 1 for the United Arab Emirates, plus 2 multi-country evaluations. No programme achieved a 65% at-risk marriage cancellation rate. Though data on thalassaemia affected birth reductions were minimal, programmes in Iran, Turkey and Iraq reported at least 65% reductions. A thematic analysis found that screening timing, access to prenatal detection and abortion, socio-religious issues, awareness and counselling affected decisions. CONCLUSION: This review found that PMSGC programmes were unsuccessful in discouraging at-risk marriages but successful in reducing the prevalence of affected births in countries providing prenatal detection and therapeutic abortion. A life cycle approach to prevention, incorporation of school screening, awareness campaigns, reconsideration of therapeutic abortion, and screening and counselling of couples married prior to programme inception are likely to improve the effectiveness of such programmes in the Middle Eastern region. PMID- 26045078 TI - Role of NLRP3 Inflammasomes for Rhabdomyolysis-induced Acute Kidney Injury. AB - Rhabdomyolysis is one of the main causes of community-acquired acute kidney injury (AKI). Although inflammation is involved in the pathogenesis of rhabdomyolysis-induced AKI (RIAKI), little is known about the mechanism that triggers inflammation during RIAKI. Recent evidence has indicated that sterile inflammation triggered by tissue injury can be mediated through multiprotein complexes called the inflammasomes. Therefore, we investigated the role of NLRP3 inflammasomes in the pathogenesis of RIAKI using a glycerol-induced murine rhabdomyolysis model. Inflammasome-related molecules were upregulated in the kidney of RIAKI. Renal tubular injury and dysfunction preceded leukocyte infiltration into the kidney during the early phase of RIAKI, and they were markedly attenuated in mice deficient in NLRP3, ASC, caspase-1, and interleukin (IL)-1beta compared with those in wild-type mice. No difference in leukocyte infiltration was observed between wild-type and NLRP3-deficient mice. Furthermore, NLRP3 deficiency strikingly suppressed the expression of renal injury markers and inflammatory cytokines and apoptosis of renal tubular cells. These results demonstrated that NLRP3 inflammasomes contribute to inflammation, apoptosis, and tissue injury during the early phase of RIAKI and provide new insights into the mechanism underlying the pathogenesis of RIAKI. PMID- 26045080 TI - An Observational Study of the Diagnosis and Management of Chronic Urticaria in the UK. AB - BACKGROUND: Patients with chronic urticaria (CU) in the UK could be referred to health care professionals (HCPs) with diverse specialties using different guidelines. The aims of the present study were to determine which CU guidelines HCPs in the UK use, which tests they use for the diagnosis of CU, and how they manage CU. METHODS: In this UK-wide survey, we designed a questionnaire covering the diagnosis and management of CU based on current guidelines. The link to the questionnaire was sent to the British Society for Allergy and Clinical Immunology (BSACI), the British Association of Dermatologists (BAD), the British Society of Immunology (BSI), and the Food Allergy and Intolerance Specialist Group (FAISG) of the British Dietetic Association (BDA), who distributed the link to their members. RESULTS: The questionnaire was completed by 55 allergists/immunologists, 64 dermatologists, and 43 dietitians. More dermatologists used the BAD guidelines in comparison with allergists and immunologists (93.6 vs. 12.5%; p < 0.001). On the other hand, the BSACI guidelines (83.3 vs. 14.9%; p < 0.001) and the European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA(2)LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) guidelines (2013) (52.1 vs. 10.6%; p < 0.001) were used by more allergists and immunologists compared to dermatologists. Differences were found between allergists/immunologists and dermatologists with regard to guidelines used, investigations performed, preference of first-line antihistamine, and prescription of alternative treatment methods. CONCLUSION: In conclusion, differences in the diagnosis and management of CU between HCPs of diverse specialties were identified, which reflected differences among the guidelines used. PMID- 26045082 TI - Successful surgical treatment of descending aorta interruption in a 29-year-old woman with acute paraplegia and subarachnoid hemorrhage: a case report. AB - Interruption of the descending aorta is an extremely rare great vessel malformation. In this report, we describe a very unusual case of a 29-year-old female with a 13-year history of hypertension who was found to have an interruption of the descending aorta when she was hospitalized with a subarachnoid hemorrhage and symptoms of acute paraplegia. We successfully surgically corrected the defect using a Gore-Tex(r) graft to bypass the aortic interruption. The patient's blood pressure postoperatively returned to normal, and the patient recovered completely from her paraplegia by the time of her 5 month follow-up visit. PMID- 26045081 TI - Improved ischemic stroke outcome prediction using model estimation of outcome probability: the THRIVE-c calculation. AB - BACKGROUND AND PURPOSE: The Totaled Health Risks in Vascular Events (THRIVE) score is a previously validated ischemic stroke outcome prediction tool. Although simplified scoring systems like the THRIVE score facilitate ease-of-use, when computers or devices are available at the point of care, a more accurate and patient-specific estimation of outcome probability should be possible by computing the logistic equation with patient-specific continuous variables. METHODS: We used data from 12 207 subjects from the Virtual International Stroke Trials Archive and the Safe Implementation of Thrombolysis in Stroke - Monitoring Study to develop and validate the performance of a model-derived estimation of outcome probability, the THRIVE-c calculation. Models were built with logistic regression using the underlying predictors from the THRIVE score: age, National Institutes of Health Stroke Scale score, and the Chronic Disease Scale (presence of hypertension, diabetes mellitus, or atrial fibrillation). Receiver operator characteristics analysis was used to assess model performance and compare the THRIVE-c model to the traditional THRIVE score, using a two-tailed Chi-squared test. RESULTS: The THRIVE-c model performed similarly in the randomly chosen development cohort (n = 6194, area under the curve = 0.786, 95% confidence interval 0.774-0.798) and validation cohort (n = 6013, area under the curve = 0.784, 95% confidence interval 0.772-0.796) (P = 0.79). Similar performance was also seen in two separate external validation cohorts. The THRIVE-c model (area under the curve = 0.785, 95% confidence interval 0.777-0.793) had superior performance when compared with the traditional THRIVE score (area under the curve = 0.746, 95% confidence interval 0.737-0.755) (P < 0.001). CONCLUSION: By computing the logistic equation with patient-specific continuous variables in the THRIVE-c calculation, outcomes at the individual patient level are more accurately estimated. Given the widespread availability of computers and devices at the point of care, such calculations can be easily performed with a simple user interface. PMID- 26045083 TI - Two new phenylpropanoids and one new sesquiterpenoid from the bioactive fraction of Sambucus williamsii. AB - Two new phenylpropanoids, samwirin (1) and samwiphenol (2), and a new sesquiterpenoid, 2beta,4beta,10alpha-trihydroxy-1alphaH,5betaH-guaia-6-ene (3), together with six known compounds were isolated from the bioactive fraction of Sambucus williamsii Hance. Their structures including the absolute configurations were characterized on the basis of extensive 1D, 2D-NMR, MS, and CD spectral data. In vitro proliferation effects of all compounds on osteoblast-like UMR 106 cells were examined. Compounds 1, 4-9 significantly promoted cell proliferation. Compounds 5, 6, and 8 increased osteoblastic cell numbers separately by 24.3%, 25.2%, and 29.1% at 10(-10) M, 10(-10) M, and 10(-8) M, respectively. PMID- 26045084 TI - Imaging evaluation of patients with osteonecrosis of the femoral head. AB - Imaging modalities for the diagnosis of osteonecrosis (ON) of the femoral head have been studied extensively, but there have been few reports strictly addressing radiographic evaluation. The purpose of this report is to examine the use and role of (1) plain radiographs, (2) magnetic resonance imaging (MRI), (3) computerized tomography (CT), (4) bone scanning, and (5) positron emission topography (PET) for the diagnostic evaluation of ON. Plain radiographs are a mainstay in diagnosis but have very low sensitivity for early ON. MRI is the gold standard for diagnostic evaluation but may not identify subchondral fractures on collapse as well as CT scan or tomogram. Bone scanning should not be used for diagnosis due to its low sensitivity. PET scanning does not have a definitive role in diagnosis yet. Future research should focus on the role of new imaging technologies in evaluation. PMID- 26045085 TI - A current review of core decompression in the treatment of osteonecrosis of the femoral head. AB - The review describes the following: (1) how traditional core decompression is performed, (2) adjunctive treatments, (3) multiple percutaneous drilling technique, and (4) the overall outcomes of these procedures. Core decompression has optimal outcomes when used in the earliest, precollapse disease stages. More recent studies have reported excellent outcomes with percutaneous drilling. Furthermore, adjunct treatment methods combining core decompression with growth factors, bone morphogenic proteins, stem cells, and bone grafting have demonstrated positive results; however, larger randomized trial is needed to evaluate their overall efficacy. PMID- 26045086 TI - Outcomes of total hip arthroplasty in patients with osteonecrosis of the femoral head-a current review. AB - The purpose of this review was to analyze (1) patient-reported outcomes and implant survivorship of osteonecrosis (ON) patients following total hip arthroplasty (THA), (2) if prior hip-preserving procedures influence these outcomes, (3) if resurfacing procedures alter outcomes; and (4) how these outcomes may have been impacted by the choice of different bearing surfaces. Today, with implant innovations such as cementless constructs, ceramic bearing surfaces, and highly cross-linked polyethylene, ON patients derive great benefit and have high survivorship following THA. Most studies have shown that previous hip-preserving procedures do not have a deleterious effect on outcomes. Literature on the use of ceramic and highly cross-linked polyethylene bearing surfaces have shown that these implant designs are useful in younger and more active patients. Future research should evaluate the long-term outcomes and survivorship of these new THA constructs. PMID- 26045087 TI - Not All Deaths in CKD Are from a Broken Heart. PMID- 26045088 TI - JASN's Silver Jubilee. PMID- 26045089 TI - Cause-Specific Deaths in Non-Dialysis-Dependent CKD. AB - CKD is associated with higher risk of death, but details regarding differences in cause-specific death in CKD are unclear. We examined the leading causes of death among a non-dialysis-dependent CKD population using an electronic medical record based CKD registry in a large healthcare system and the Ohio Department of Health mortality files. We included 33,478 white and 5042 black patients with CKD who resided in Ohio between January 2005 and September 2009 and had two measurements of eGFR<60 ml/min per 1.73 m(2) obtained 90 days apart. Causes of death (before ESRD) were classified into cardiovascular, malignancy, and non-cardiovascular/non malignancy diseases and non-disease-related causes. During a median follow-up of 2.3 years, 6661 of 38,520 patients (17%) with CKD died. Cardiovascular diseases (34.7%) and malignant neoplasms (31.8%) were the leading causes of death, with malignancy-related deaths more common among those with earlier stages of kidney disease. After adjusting for covariates, each 5 ml/min per 1.73 m(2) decline in eGFR was associated with higher risk of death due to cardiovascular disease (hazard ratio [HR], 1.10; 95% confidence interval [95% CI], 1.08 to 1.12) and non cardiovascular/non-malignancy diseases (HR, 1.12; 95% CI, 1.09 to 1.14) but not to malignancy. In the adjusted models, blacks had overall-mortality hazard ratios similar to those of whites but higher hazard ratios for cardiovascular deaths. Further studies to confirm these findings and explain the mechanisms for differences are warranted. In addition to lowering cardiovascular burden in CKD, efforts to target known risk factors for cancer at the population level are needed. PMID- 26045090 TI - Ambient Melamine Exposure and Urinary Biomarkers of Early Renal Injury. AB - Information about environmental exposure to melamine and renal injury in adults is lacking. We investigated this relationship in 44 workers at two melamine tableware manufacturing factories in Taiwan (16 manufacturers, eight grinders, ten packers, and ten administrators) and 105 nonexposed workers (controls) at one shipbuilding company who were enrolled in August-December of 2012. For melamine workers, personal and area air samples were obtained at the worksite over 1 workweek (Monday-Friday). In the same week, pre- and post-shift one-spot urine samples were collected each workday and one first-spot urine sample was collected on each weekend morning and the following Monday morning. For each control, a one spot urine sample was collected on Friday morning. A blood sample was also obtained from each participant at this time. Melamine levels were measured in air, urine, and serum, and early renal injury biomarkers were measured in urine. Urinary melamine concentrations in manufacturers increased sharply between pre- and post-shift measurements on Monday, remained significantly elevated throughout the workweek, and decreased over the weekend; changes in urinary melamine concentrations were substantially lower for other melamine workers. Manufacturers were exposed to the highest concentrations of ambient melamine and had significantly higher urinary and serum melamine concentrations than did the controls (P<0.001). Urinary melamine levels were positively associated with urinary N-acetyl beta-d-glucosaminidase (NAG) levels but not microalbumin levels, and the detectable beta2-microglobulin rate increased in the manufacturers group. In conclusion, ambient melamine exposure may increase the levels of urinary biomarkers of renal tubular injury in this occupational setting. PMID- 26045091 TI - Inhibition of SET Domain-Containing Lysine Methyltransferase 7/9 Ameliorates Renal Fibrosis. AB - TGF-beta1 activity results in methylation of lysine 4 of histone H3 (H3K4) through SET domain-containing lysine methyltransferase 7/9 (SET7/9) induction, which is important for the transcriptional activation of fibrotic genes in vitro. However, in vivo studies utilizing an experimental model of renal fibrosis are required to develop therapeutic interventions that target SET7/9. In this study, we investigated the signaling pathway of TGF-beta1-induced SET7/9 expression and whether inhibition of SET7/9 suppresses renal fibrosis in unilateral ureteral obstruction (UUO) mice and kidney cell lines. Among the SET family, SET7/9 was upregulated on days 3 and 7 in UUO mice, and the upregulation was suppressed by TGF-beta1 neutralizing antibody. TGF-beta1 induced SET7/9 expression via Smad3 in normal rat kidney (NRK)-52E cells. In human kidney biopsy specimens from patients diagnosed with IgA nephropathy and membranous nephropathy, SET7/9 expression was positively correlated with the degree of interstitial fibrosis (r=0.59, P=0.001 in patients with IgA nephropathy; and r=0.58, P<0.05 in patients with membranous nephropathy). In addition, small interfering RNA-mediated knockdown of SET7/9 expression significantly attenuated renal fibrosis in UUO mice. Sinefungin, an inhibitor of SET7/9, also suppressed the expression of mesenchymal markers and extracellular matrix proteins and inhibited H3K4 mono-methylation (H3K4me1) in kidneys of UUO mice. Moreover, sinefungin had an inhibitory effect on TGF-beta1 induced alpha-smooth muscle actin expression and H3K4me1 in both NRK-52E and NRK 49F cells. In conclusion, sinefungin, a SET7/9 inhibitor, ameliorates renal fibrosis by inhibiting H3K4me1 and may be a candidate therapeutic agent. PMID- 26045092 TI - Electrospun aligned PLGA and PLGA/gelatin nanofibers embedded with silica nanoparticles for tissue engineering. AB - Aligned poly lactic-co-glycolic acid (PLGA) and PLGA/gelatin nanofibrous scaffolds embedded with mesoporous silica nanoparticles (MSNPs) were fabricated using electrospinning method. The mean diameters of nanofibers were 641+/-24 nm for the pure PLGA scaffolds vs 418+/-85 nm and 267+/-58 nm for the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds, respectively. The contact angle measurement results (102 degrees +/-6.7 for the pure PLGA scaffold vs 81 degrees +/-6.8 and 18 degrees +/-8.7 for the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds, respectively) revealed enhanced hydrophilicity of scaffolds upon incorporation of gelatin and MSNPs. Besides, embedding the scaffolds with MSNPs resulted in improved tensile mechanical properties. Cultivation of PC12 cells on the scaffolds demonstrated that introduction of MSNPs into PLGA and PLGA/gelatin matrices leads to the improved cell attachment and proliferation as well as long cellular processes. DAPI staining results indicated that cell proliferations on the PLGA/10 wt% MSNPs and the PLGA/gelatin/10 wt% MSNPs scaffolds were strikingly (nearly 2.5 and 3 folds, respectively) higher than that on the aligned pure PLGA scaffolds. These results suggest superior properties of silica nanoparticles-incorporated PLGA/gelatin eletrospun nanofibrous scaffolds for the stem cell culture and tissue engineering applications. PMID- 26045094 TI - The NHS medicines bill: running out of control? PMID- 26045093 TI - Mechanism of inhibition of mouse Slo3 (KCa 5.1) potassium channels by quinine, quinidine and barium. AB - BACKGROUND AND PURPOSE: The Slo3 (KCa 5.1) channel is a major component of mammalian KSper (sperm potassium conductance) channels and inhibition of these channels by quinine and barium alters sperm motility. The aim of this investigation was to determine the mechanism by which these drugs inhibit Slo3 channels. EXPERIMENTAL APPROACH: Mouse (m) Slo3 (KCa 5.1) channels or mutant forms were expressed in Xenopus oocytes and currents recorded with 2-electrode voltage-clamp. Gain-of-function mSlo3 mutations were used to explore the state dependence of the inhibition. The interaction between quinidine and mSlo3 channels was modelled by in silico docking. KEY RESULTS: Several drugs known to block KSper also affected mSlo3 channels with similar levels of inhibition. The inhibition induced by extracellular barium was prevented by increasing the extracellular potassium concentration. R196Q and F304Y mutations in the mSlo3 voltage sensor and pore, respectively, both increased channel activity. The F304Y mutation did not alter the effects of barium, but increased the potency of inhibition by both quinine and quinidine approximately 10-fold; this effect was not observed with the R196Q mutation. CONCLUSIONS AND IMPLICATIONS: Block of mSlo3 channels by quinine, quinidine and barium is not state-dependent. Barium inhibits mSlo3 outside the cell by interacting with the selectivity filter, whereas quinine and quinidine act from the inside, by binding in a hydrophobic pocket formed by the S6 segment of each subunit. Furthermore, we propose that the Slo3 channel activation gate lies deep within the pore between F304 in the S6 segment and the selectivity filter. PMID- 26045095 TI - Risk of Atherosclerosis in Patients with Ataxia Telangiectasia. AB - BACKGROUND AND AIMS: Evaluate the nutritional status, plasma concentration of vitamin E and markers of cardiovascular risk in ataxia telangiectasia (AT) patients. METHODS: Cross-sectional study with 13 patients with AT and 22 healthy controls, evaluating the following factors: nutritional status, food intake, lipid profile, plasma concentration of vitamin E, malondialdehyde and high sensitivity C-reactive protein, linking them with atherosclerosis risk in AT patients. RESULTS: Average age was 14.6 in the AT group, 30.8% were malnourished and 23.1% had stunting. A greater impairment of lean body mass was found in these patients. Concentrations of triglycerides (TG), total cholesterol (CT), LDL-c, non-HDL cholesterol (NHDL-c) were significantly higher in patients and HDL-c, lower. Vitamin E/total lipids and vitamin E/TG ratios were lower in the AT group, and significant inverse correlation between these ratios and NHDL-c, CT/HDL-c, and LDL-c/HDL-c, log TG/HDL-c was observed in the AT group. Alanine aminotransferase correlated directly and significantly with NHDL-c, CT/HDL-c and LDL-c/HDL-c, in patients. CONCLUSION: The alterations of lipid metabolism biomarkers suggestive of atherosclerotic risk of male AT patients coupled with lower vitamin E/total lipids ratio and low lean body mass may complicate the clinical course of the disease and emphasizes the importance of multidisciplinary care, routine monitoring of cardiovascular biomarkers and appropriate nutritional guidance. PMID- 26045096 TI - 15-year follow-up of vertical banded gastroplasty: comparison with other restrictive procedures. AB - INTRODUCTION: Vertical banded gastroplasty (VBG) has been the procedure of choice for bariatric surgeries since the 1980s. However, long-term results of VBG have been reported with different opinions, and new restrictive procedures have been innovated and showing variable results. The aim of this study is to analyze the long-term results of our VBG patients. PATIENT AND METHODS: Between June 1998 and May 2002, 652 morbidly obese patients received VBG, with the initial 40 patients having open procedures and the subsequent 612 patients using a laparoscopic approach. Operative complications, weight loss, and late complications were followed and compared with groups of laparoscopic adjustable gastric banding (LAGB) and sleeve gastrectomy (LSG). RESULTS: Mean age, preoperative weight, and body mass index (BMI) were 30.96 years, 108.83 kg, and 40.63 kg/m(2), respectively. The overall early postoperative complication rate was 3.4% (22/652). The excess weight loss percentages at 1, 2, 5, and 10 years were 61.04, 59.70, 51.11, and 42.0%, respectively. BMI at 1, 2, 5, and 10 years were 29.64, 29.71, 31.33, and 31.73 kg/m(2), respectively. This result is inferior to the 67% excess weight loss in the LSG group, but is higher than the 38% excess weight loss of the LAGB group. The revision rate is 13.19% (86/652) up to now. Revision surgery was required in 28 (14.0%) patients in the LAGB group and 8 (1.3%) in the LSG group. CONCLUSION: VBG was an operation with acceptable outcome for treating morbid obesity and metabolic disorders. It sets a standard for new restrictive procedures. PMID- 26045098 TI - Specific Needs of Patients Attending Pulmonary Rehabilitation with an Interstitial Lung Disease Associated with Rheumatological Disease. PMID- 26045097 TI - Quality of life in non-early rectal cancer treated by neoadjuvant radio chemotherapy and endoluminal loco-regional resection (ELRR) by transanal endoscopic microsurgery (TEM) versus laparoscopic total mesorectal excision. AB - BACKGROUND: In selected patients with N0 rectal cancer, endoluminal loco-regional resection (ELRR) by transanal endoscopic microsurgery (TEM) may be an alternative treatment option to laparoscopic total mesorectal excision (LTME). Aim of this study is to evaluate the short- and medium-term quality of life (QoL) from a retrospective analysis of prospectively collected data in patients with iT2-iT3 N0-N+ rectal cancer, who underwent ELRR by TEM or LTME after neoadjuvant radio chemotherapy (n-RCT). METHODS: Thirty patients with iT2-iT3 rectal cancer who underwent ELRR by TEM (n = 15) or LTME (n = 15) were enrolled in this study. The choice for one operation or the other was made on the basis of predefined criteria. QoL was evaluated by EORTC QLQ-C30 and QLQ-CR38 questionnaires at admission, after n-RCT and 1, 6, and 12 months after surgery. RESULTS: No statistically significant differences in QoL evaluation were observed between the two groups, both at admission and after n-RCT. At 1 month after surgery, significantly better results in the ELRR group were observed by QLQ-C30 in: Nausea/Vomiting (p = 0.05), Appetite Loss (p = 0.003), Constipation (p = 0.05), and by QLQ-CR38 in: Body Image (p = 0.05), Sexual Functioning (p = 0.03), Future Perspective (p = 0.05) and Weight Loss (p = 0.036). At 6 months after surgery, a statistically significant worse impact after LTME was observed by QLQ-C30 in: Global Health Status (p = 0.05), Emotional Functioning (p = 0.021), Dyspnea (p = 0.008), Insomnia (p = 0.012), Appetite Loss (p = 0.014) and by QLQ-CR38 in Body Image (p = 0.05) and Defecation Problems (p = 0.001). At 1 year, the two groups were homogenous as assessed by QLQ-C30, whereas the QLQ-CR38 still showed better results of ELRR versus LTME in Body Image (p = 0.006), Defecation Problems (p = 0.01), and Weight Loss (p = 0.005). CONCLUSIONS: Based on the present series, in selected patients, earlier restoration of patients' functions is observed after ELRR by TEM than after LTME. PMID- 26045099 TI - Red-Emissive Carbon Dots for Fluorescent, Photoacoustic, and Thermal Theranostics in Living Mice. PMID- 26045100 TI - Exome Sequencing and Epigenetic Analysis of Twins Who Are Discordant for Congenital Cataract. AB - PURPOSE: To further understand genetic factors that contribute to congenital cataracts, we sought to identify early post-twinning mutational and epigenetic events that may account for the discordant phenotypes of a twin pair. METHODS: A patient with a congenital cataract and her twin sister were assessed for genetic factors that might contribute to their discordant phenotypes by mutation screening of 11 candidate genes (CRYGC, CRYGD, CRYAA, CRYAB, CRYBA1, CRYBB1, CRYBB2, MIP, HSF4, GJA3, and GJA8), exome analysis followed by Sanger sequencing of 10 additional candidate genes (PLEKHO2, FRYL, RBP3, P2RX2, GSR, TRAM1, VEGFA, NARS2, CADPS, and TEKT4), and promoter methylation analysis of five representative genes (TRAM1, CRYAA, HSF4, VEGFA, GJA3, DCT) plus one additional candidate gene (FTL). RESULTS: Mutation screening revealed no gene mutation differences between the patient and her twin sister for the 11 candidate genes. Exome sequencing analysis revealed variations between the twins in 442 genes, 10 of which are expressed in the eye. However, these differential variants could not be confirmed by Sanger sequencing. Furthermore, epigenetic discordance was not detected in the twin pair. CONCLUSIONS: The genomic DNA mutational and epigenetic events assessed in this study could not explain the discordance in the development of phenotypic differences between the twin pair, suggesting the possible involvement of somatic mutations or environmental factors. Identification of possible causes requires further research. PMID- 26045101 TI - Feasibility of a semi-automated method for cardiac conduction velocity analysis of high-resolution activation maps. AB - Myocardial conduction velocity is important for the genesis of arrhythmias. In the normal heart, conduction is primarily dependent on fiber direction (anisotropy) and may be discontinuous at sites with tissue heterogeneities (trabeculated or fibrotic tissue). We present a semi-automated method for the accurate measurement of conduction velocity based on high-resolution activation mapping following central stimulation. The method was applied to activation maps created from myocardium from man, sheep and mouse with anisotropic and discontinuous conduction. Advantages of the presented method over existing methods are discussed. PMID- 26045102 TI - A tutorial on structural equation modeling for analysis of overlapping symptoms in co-occurring conditions using MPlus. AB - Structural equation modeling (SEM) is a very general approach to analyzing data in the presence of measurement error and complex causal relationships. In this tutorial, we describe SEM, with special attention to exploratory factor analysis, confirmatory factor analysis, and multiple indicator multiple cause modeling. The tutorial is motivated by a problem of symptom overlap routinely faced by clinicians and researchers, in which symptoms or test results are common to two or more co-occurring conditions. As a result of such overlap, diagnoses, treatment decisions, and inferences about the effectiveness of treatments for these conditions can be biased. This problem is further complicated by increasing reliance on patient-reported outcomes, which introduces systematic error based on an individual's interpretation of a test questionnaire. SEM provides flexibility in handling this type of differential item functioning and disentangling the overlap. Scales and scoring approaches can be revised to be free of this overlap, leading to better care. This tutorial uses an example of depression screening in multiple sclerosis patients in which depressive symptoms overlap with other symptoms, such as fatigue, cognitive impairment, and functional impairment. Details of how MPlus (Muthen & Muthen, Los Angeles, CA, USA) software can be used to address the symptom overlap problem, including data requirements, code and output are described in this tutorial. PMID- 26045104 TI - Antimicrobial Sulfated Glycans: Structure and Function. AB - Owing to their inherent structural features, certain sulfated glycans isolated from terrestrial or marine mammals or invertebrates, can exert therapeutic properties against infections caused by pathogenic microorganisms like bacteria, virus, fungus, and protozoan parasites. These sulfated glycans belong to a variety of classes including glycosaminoglycans (GAGs) like chondroitin sulfate, fucosylated chondroitin sulfate, dermatan sulfate, unfractionated heparin, low molecular-weight heparin, and acharan sulfate; and the less-famous algal polysaccharides known as sulfated fucans (including fucoidans), sulfated galactans (agarans and carrageenans), and sulfated heteropolysaccharides. Administration at certain concentrations of the antimicrobial sulfated glycans, especially those containing the higher amounts of the bioactive structural requirements, can lead to the interruption or disruption of the pathogen protein host GAG complex formation, leading thus to the decrease or impairment of the microbial binding onto host cells. This report aims at presenting the current background concerning the therapeutic effects of the above-mentioned sulfated glycans as new antimicrobial agents. When sufficient data are available, discussion regarding structure-activity relationship is provided. PMID- 26045103 TI - Pseudomonas aeruginosa Lon and ClpXP proteases: roles in linking carbon catabolite repression system with quorum-sensing system. AB - Quorum sensing (QS) plays critical roles in virulence gene expression and the pathogenesis of Pseudomonas aeruginosa, an important human pathogen. However, the regulatory effects, especially that occur directly upstream of the QS system, remain largely unknown. Here, we review recent advances in the understanding of the key component of carbon catabolite repression (CCR) system and protein quality control (PQC) system in regulating the QS system in P. aeruginosa. We propose that PQC proteases Lon and ClpXP may have an important role in linking CCR with QS, and thus contribute to the integration of nutritional cues into the regulatory network governing the virulence factors expression in P. aeruginosa. PMID- 26045105 TI - Quality of life and pain control following laparoscopic retroperitoneal lymph node dissection in early-stage nonseminoma. AB - AIMS AND BACKGROUND: To evaluate postoperative pain (PoP) and quality of life (QoL) in patients undergoing open (O-) or laparoscopic (L-) retroperitoneal lymph node dissection (RPLND) for clinical stage I (CS I) and normal markers CS IIA nonseminomatous germ cell tumors. METHODS: Since March 2010, a prospective nonrandomized trial evaluated dynamic and rest (R) numeric pain scale (NPS) following patient-controlled analgesia and baseline (T0), 3-month (T3), and 6 month (T6) QoL status assessed by Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire and the Italian-validated Functional Assessment of Chronic Illness Therapy (FACT-T-SG) at T6. Secondary endpoints included length of hospital stay (LHS), interval to recovery (ItR), complications, and oncologic outcomes. RESULTS: In March 2012, 69 (64 CS I) patients were enrolled. Five patients only chose O-RPLND. The PoP and complete QoL data are available in 41 and 56 patients, respectively. The R-NPS significantly improved in days 1-2 vs day 0 (p<0.0008). The FACT-G scores improved from baseline: the emotional well being scale was the most relevant at T3 (+7.0, p = 0.0001) and T6 (+6.9, p = 0.0002). The FACT-TS-G indicated high satisfaction levels. Median LHS and ItR were 3 and 15 days. Six complications required an intervention. Nodal metastases were found in 14 (20.3%) patients. Following a median follow-up of 36 months, 6 (8.9%) patients relapsed (2/12 among pN+), and 8 patients (11.9%) underwent chemotherapy. All patients maintained antegrade ejaculation and are alive and disease-free. CONCLUSIONS: Almost all patients chose L-RPLND, which is associated with a rapid improvement of postoperative pain; QoL scores improved up to 6 months. The L-RPLND may be considered as an alternative only when performed in highly experienced centers. PMID- 26045106 TI - Hope in cancer patients: the relational domain as a crucial factor. AB - AIMS AND BACKGROUND: Hope is crucial for patients with cancer. We explored the determinants of hope in patients with cancer using a questionnaire administered over the course of 1 day to an unselected sample of patients at an Italian cancer center. METHODS: A team of oncologists, statisticians, and chaplains developed a questionnaire with medical, psychological, spiritual, and religious content. A cross-sectional study was conducted on 320 patients who answered the questionnaire. RESULTS: In the group of participants, 92.8% had a religious belief. Women, patients with limited formal education, and believers were more hopeful. Patients placed trust in God, their partners and children, scientific research, and doctors. On univariate and multivariate analysis, hope was found sensitive to patients' sharing their experiences with others (including family and friends), their positive perception of the people around them, and their relationship with doctors and nurses. CONCLUSIONS: If validated in further studies, these results support the notion that a patient with cancer's sense of hope is sensitive to the quality of relationships with caregivers. This may be important to health care organization and resource allocation. PMID- 26045107 TI - Stereotactic ablative radiotherapy with CyberKnife in the treatment of locally advanced prostate cancer: preliminary results. AB - AIMS AND BACKGROUND: Recent clinical reports of stereotactic ablative radiotherapy (SABR) in the treatment of low-risk prostate cancer have been encouraging. Our study evaluates the efficacy and safety of SABR using the CyberKnife system for treating intermediate- to very-high-risk prostate cancer. METHODS AND STUDY DESIGN: Between May 2010 and June 2013, 31 patients (15 intermediate risk, 14 high risk, and 2 very high risk) without pelvic lymph node metastasis were enrolled retrospectively. The treatment consisted of 37.5 Gy in 5 fractions over 1-2 weeks using CyberKnife SABR. Twenty-five patients (81%) received androgen deprivation therapy (ADT). Biochemical failure was defined using the nadir + 2 criterion. Toxicity was assessed with the Common Terminology Criteria of Adverse Events (version 4). RESULTS: The median follow-up was 36 months (range 7-58 months). The median pretreatment prostate--pecific antigen (PSA) was 13.5 ng/mL (range 4.5-124.0 ng/mL). The median PSA decreased to 0.09 ng/mL (range <0.04-5.38 ng/mL) and 0.12 ng/mL (range <0.04-2.63 ng/mL) at 6 months and 12 months after SABR, respectively. The 3-year biochemical relapse free survival was 90.2% for all patients, 100% for the intermediate-risk patients, and 82% for the high- and very-high-risk patients (p = 0.186). No patient experienced >= grade 3 toxicity. There were 7 acute and 5 late grade 2 genitourinary toxicities and 1 acute and no late grade 2 gastrointestinal toxicity. CONCLUSIONS: Our preliminary results support that CyberKnife SABR with ADT is safe and feasible in patients with intermediate- to high-risk prostate cancer. A further large-scale clinical trial with longer follow-up is warranted. PMID- 26045108 TI - Progesterone receptor status and clinical outcome in breast cancer patients with estrogen receptor-positive locoregional recurrence. AB - AIMS AND BACKGROUND: The aim of this retrospective multicenter study was to evaluate the impact of progesterone receptor (PgR) loss on locoregional recurrence in patients with estrogen receptor (ER)-positive primary breast cancer and ER-positive locoregional recurrence. PATIENTS AND METHODS: Eight Italian oncology centers collected data from consecutive patients with ER-positive breast cancer and a subsequent ER-positive locoregional recurrence. RESULTS: Data were available for 265 patients diagnosed with breast cancer between 1990 and 2009. Median metastasis-free survival was 111 months in patients with PgR-positive primary tumors and locoregional recurrence (PgRpos), 38 months in patients with PgR-negative primary tumors and locoregional recurrence (PgRneg), and 63 months in patients with PgR-positive primary tumors and PgR-negative locoregional recurrence (PgRloss). In multivariate analysis, PgR status was independently associated with metastasis-free survival, with a hazard ratio of 2.84 (95% CI 1.34-6.00) for PgRneg compared with PgRpos, and 2.93 (95% CI: 1.51-5.70) for PgRloss compared with PgRpos. CONCLUSIONS: PgR absence was found to be a negative prognostic factor in breast cancer patients with ER-positive locoregional recurrence. Thus, PgR status could be a biological marker in ER-positive recurrent breast cancer. PMID- 26045109 TI - Neutropenia secondary to exposure to levetiracetam. AB - AIMS AND BACKGROUND: Brain metastases occur in about 30% of patients with non small-cell lung carcinoma; seizures occur in approximately 20% of them. Antiepileptic drugs are commonly given for postoperative prophylaxis after brain or metastasis tumor surgery. The incidence of seizures following supratentorial craniotomy is estimated to be 15%-20%. Postoperative seizures are more common in the first month after cranial surgery. However, the use of antiepileptic drugs postoperatively has been investigated in randomized controlled trials. In case of seizures, the recommendations are continuing antiepileptic drugs after a 1- to 4 year seizure-free interval. This decision must weigh the risk of seizure recurrence against the possible benefits of the drug. Some antiepileptic drugs have been known to cause blood dyscrasias, including neutropenia, but this is a rare occurrence. METHODS: We report a case of neutropenia related to the use of levetiracetam at first exposure. After drug administration, neutropenia was detected. Additional tests were performed. RESULTS: By exclusion, it was decided to withdraw the drug, and the patient had a reversal of neutropenia. CONCLUSIONS: Levetiracetam-induced neutropenia is infrequent but possible. It is an exclusion diagnosis. PMID- 26045110 TI - Creating beauty: the experience of a fashion collection prepared by adolescent patients at a pediatric oncology unit. AB - AIMS AND BACKGROUND: Adolescent patients with cancer need psychological support in order to face the traumatic event of cancer diagnosis and to preserve continuity with their normal lives. Creative projects or laboratories may help young patients express their thoughts and feelings. METHODS: The Youth Project developed activities dedicated to adolescents to give them a chance to vent their creative spirit and express themselves freely. In the first project, the teenagers designed their own fashion collection in all its various stages under the artistic direction of a well-known fashion designer, creating their own brand name (B.Live), and organized a fashion show. RESULTS: In all, 24 patients from 15 to 20 years old took part in the project. The fashion project proved a fundamental resource in helping the young patients involved to regain a positive self-image and the feeling that they could take action, both on themselves and in their relations with others. CONCLUSIONS: Facilitating the experience of beauty may enable hope to withstand the anguish caused by disease. This experience integrated the usual forms of psychological support to offer patients a form of expression and support during the course of their treatment. PMID- 26045111 TI - Immunological status of chronic myelogenous leukemia patients with complete cytogenetic response after treatment. AB - BACKGROUND: The aim of this study was to compare the T lymphocyte subsets of chronic myelogenous leukemia (CML) patients who had a complete cytogenetic response (CCyR) after treatment with imatinib (IM) or homoharringtonine (HHT). METHODS: T and Th lymphocyte subsets in CCyR patients treated with HHT (n = 15) or IM (n = 16) were assayed with flow cytometry. RESULTS: It was found that there were no differences in T lymphocyte subset proportions at the time of achieving CCyR0 and also no difference in the CD8+T cell proportions at the 12th month after CCyR (CCyR12), between the 2 groups. The values of CD3+T, CD4+T, CD8+T, CD4+T/CD8+T, Th1 and Th2 cells were 54.21% +/- 6.12% vs. 44.32% +/- 4.85%, 29.83% +/- 5.53% vs. 22.27% +/- 3.22%, 24.66 +/- 4.91 vs. 25.41% +/- 5.72% , 1.11 +/- 0.23 vs. 0.92 +/- 0.19, 10.23% +/- 4.24% vs. 8.34% +/- 3.45% and 11.12% +/- 3.91% vs. 13.67% +/- 4.78%, respectively in the HHT group and IM group at CCyR12, which meant that the proportions of CD3+T, CD4+T and Th1 cells and the ratio of CD4+T to CD8+T cells were higher and the CD8+T and Th2 cell proportions were lower in the HHT group than in the IM group. CONCLUSIONS: HHT has a weaker immunodepression effect on T lymphocyte subsets compared with IM. PMID- 26045112 TI - Role of HER family members in predicting prognoses in epithelial ovarian cancer: a meta-analysis. AB - AIMS AND BACKGROUND: Human epidermal receptor (HER) family receptors are commonly overexpressed in various human tumors, and their overexpression is thought to play a critical role in tumor progression. The aim of this meta-analysis was to evaluate the prognostic significance of HER family members in epithelial ovarian cancer (EOC). METHODS: Relevant studies published between January 1, 1980, and April 24, 2013, that evaluated the associations of HER family members with overall survival (OS), progression-free survival (PFS), response to platinum based chemotherapy, lymph node metastasis, or ascites in EOC were identified via searches of PubMed and EMBASE. RESULTS: We identified 37 eligible articles that met the inclusion criteria. The results of the meta-analysis revealed that significantly poorer OS of patients with EOC was predicted by high Her-2 expression levels (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.31 2.19). Furthermore, high Her-2 expression was significantly associated with poor PFS (HR 1.88, 95% CI 1.46-2.41) and an increased risk of ascites (risk ratio 1.21, 95% CI 1.02-1.42). CONCLUSIONS: High levels of expression of Her-2 are significantly related to poor survival and an increased risk of ascites in patients with EOC. Future prospective cohorts with larger samples are needed to verify the prognostic value of Her-2 expression in EOC. PMID- 26045113 TI - Bioinformatics approach reveals systematic mechanism underlying lung adenocarcinoma. AB - BACKGROUND: The purpose of this work was to explore the systematic molecular mechanism of lung adenocarcinoma and gain a deeper insight into it. METHODS: Comprehensive bioinformatics methods were applied. Initially, significant differentially expressed genes (DEGs) were analyzed from the Affymetrix microarray data (GSE27262) deposited in the Gene Expression Omnibus (GEO). Subsequently, gene ontology (GO) analysis was performed using online Database for Annotation, Visualization and Integration Discovery (DAVID) software. Finally, significant pathway crosstalk was investigated based on the information derived from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. RESULTS: According to our results, the N-terminal globular domain of the type X collagen (COL10A1) gene and transmembrane protein 100 (TMEM100) gene were identified to be the most significant DEGs in tumor tissue compared with the adjacent normal tissues. The main GO categories were biological process, cellular component and molecular function. In addition, the crosstalk was significantly different between non-small cell lung cancer pathways and inositol phosphate metabolism pathway, focal adhesion signal pathway, vascular smooth muscle contraction signal pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway and calcium signaling pathway in tumor. CONCLUSIONS: Dysfunctional genes and pathways may play key roles in the progression and development of lung adenocarcinoma. Our data provide a systematic perspective for understanding this mechanism and may be helpful in discovering an effective treatment for lung adenocarcinoma. PMID- 26045114 TI - Delayed chemotherapy-induced nausea and vomiting in autologous hematopoietic cell transplant patients: an exploratory analysis. AB - PURPOSE: Delayed chemotherapy-induced nausea and vomiting (CINV) continues to be a problem in patients undergoing a hematopoietic cell transplant (HCT) despite progress in antiemetic prophylaxis. This study investigated the clinical course of nausea and vomiting (NV) and retching over the 5 days following an autologous HCT in a transplant setting. METHODS: This longitudinal observational study was an exploratory analysis of data from a trial that assessed the efficacy of aroma in preventing NV related to dimethyl sulfoxide in 69 autologous HCT patients undergoing highly emetogenic chemotherapy (HEC; n = 56) or moderately emetogenic chemotherapy (MEC; n = 13). RESULTS: Nausea started to increase on the second day after reinfusion, with a peak between 72 and 96 hours, and decreased on the fifth day. The pattern for vomiting was similar, while retching episodes remained unchanged after the third day following transplant. Nausea and emesis were observed in 73% (n = 41) and 64% (n = 36) of HEC patients, respectively, and in 85% (n = 11) and 62% (n = 8) of MEC patients, respectively. CONCLUSIONS: Uncontrolled delayed CINV is still a challenge for autologous HCT patients. Nausea, vomiting and retching are 3 different symptoms that should be assessed and managed separately in routine clinical practice. PMID- 26045116 TI - Very late recurrence of renal cell carcinoma experiencing long-term response to sunitinib: a case report. AB - Renal cell carcinoma (RCC) is responsible for 4% of all neoplasms in adults and for 80% of all primary renal tumors. Metastatic RCC is resistant to all cytotoxic agents and generally prognosis is poor. However, the clinical behavior of RCC is unpredictable, and late recurrences of disease can occur even after several years from the initial surgical approach, so response to the currently available targeted agents is uncertain, due to the lack of reliable prognostic and predictive factors. We report the case of a patient who developed a metastatic recurrence of RCC 16 years after primary treatment, in spite of metastatic disease at diagnosis. At the time of relapse, the disease showed a surprisingly long-term response to Sunitinib, which is maintained after 74 months of treatment. This case report highlights the unpredictable behavior of RCC and underlines the presence of a subset of patients with metastatic RCC achieving long-term response to Sunitinib, despite poor clinical features. In this subset of patients, an important clinical question arises about the appropriate duration of treatment and the need to continue it indefinitely. PMID- 26045115 TI - Ethnic difference in risk of toxicity in prostate cancer patients treated with dynamic arc radiation therapy. AB - AIMS AND BACKGROUND: The objective of this study was to assess the influence of ethnicity on toxicity in patients treated with dynamic arc radiation therapy (ART) for prostate cancer (PC). METHODS: From June 2006 to May 2012, 162 cT1-T3 cN0 cM0 PC patients were treated with ART (primary diagnosis, n = 125; post prostatectomy/brachytherapy biochemical recurrence, n = 26; adjuvant post prostatectomy, n = 11) at 2 institutions. Forty-five patients were Latin Americans and 117 were Europeans. The dose prescribed to the prostate ranged between 68 Gy and 81 Gy. RESULTS: The median age was 69 years (range 43-87 years). The median follow-up was 18 months (range 2-74 months). Overall, only 3 patients died, none due to a cancer-related cause. Biochemical recurrence was seen in 7 patients. The rates of acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicities were 19.7% and 17%, respectively. Only 1 patient experienced acute grade 3 GI toxicity, whereas 11 patients (6.7%) experienced acute grade 3 GU toxicity. Multivariate analysis showed that undergoing whole pelvic lymph node irradiation was associated with a higher grade of acute GI toxicity (OR: 3.46; p = 0.003). In addition, older age was marginally associated with a higher grade of acute GI toxicity (OR: 2.10; p = 0.074). Finally, ethnicity was associated with acute GU toxicity: Europeans had lower-grade toxicity (OR: 0.27; p = 0.001). CONCLUSIONS: Our findings suggest an ethnic difference in GU toxicity for PC patients treated with ART. In addition, we found that ART is associated with a very low risk of severe toxicity and a low recurrence rate. PMID- 26045117 TI - Panitumumab after progression on cetuximab in KRAS wild-type metastatic colorectal cancer patients: a single institution experience. AB - AIMS AND BACKGROUND: Few data describe the activity of panitumumab after cetuximab-irinotecan-based regimen failure in patients with KRAS wild-type metastatic colorectal cancer (WT MCRC). METHODS: The aim of this study is to assess if panitumumab has some activity in this setting. RESULTS: We retrospectively analyzed 25 patients with KRAS WT MCRC who received panitumumab from July 2009 to January 2013 after progression on cetuximab. All patients had previously received cetuximab and irinotecan (20 patients) or oxaliplatin (5 patients). We withdrew cetuximab for intolerance in 4 patients (16%). Twenty-one patients (84%) who had previously responded to cetuximab (overall response rate [ORR] plus stable disease >=5 months) received panitumumab off-label after progression on cetuximab because they were strongly motivated to continue treatment without chemotherapy. The median number of cycles of panitumumab was 7 (range 1-54). Only 20 patients were evaluable for ORR (5 patients received 1-2 cycles and then died). We observed 1 (5%) partial response, 5 (25%) stable disease, median duration 9 months. Median progression-free survival (PFS) and overall survival (OS) were 5 (3-28) and 8 (5-41) months, respectively. All patients were evaluable for toxicity. No patients developed anemia or neutropenia. One patient (4%) developed grade 2 thrombocytopenia, 8 patients (32%) grade 2-3 dry skin or rash, and 2 patients (8%) grade 2 nausea-vomiting (Common Terminology Criteria for Adverse Events version 4.03). CONCLUSIONS: Our data, with all the limits of a retrospective analysis, show longer PFS and OS as compared to other series in the same setting, demonstrating that panitumumab has treatment effectiveness in patients with KRAS WT MCRC who progressed on prior cetuximab. Further confirmatory prospective studies with a larger series of patients are necessary. PMID- 26045118 TI - Doppler ultrasound measurement of resistance index in the diagnosis of prostate cancer. AB - Prostate cancer (PCa) remains the second leading cause of cancer diagnosis worldwide. Early diagnosis and treatment of PCa is critical since the long-term prognosis is excellent in patients with tumors confined to the prostate gland. The current meta-analysis investigates the diagnostic value of resistive index (RI) measurement using color Doppler ultrasound in patients with PCa. Electronic literature databases were exhaustively searched for relevant studies published prior to May 31, 2014. Nine studies met our predetermined inclusion criteria for the present meta-analysis. The methodologic quality of the selected studies was independently assessed by 2 reviewers based on Quality Assessment of Diagnostic Accuracy Studies tool. Our meta-analysis results showed that RI values were significantly higher in malignant prostate tissues compared to normal prostate tissues (standardized mean difference [SMD] 0.42, 95% confidence interval [CI] 0.12~0.73, p = 0.007) and benign prostate tissues (SMD 0.41, 95% CI 0.26~0.56, p<0.001). Subgroup analysis based on the diagnostic instruments used revealed that RI values were accurate in diagnosis of PCa when compared between malignant tissue vs normal tissue and malignant tissue vs benign tissue (all p<0.05). Taken together, our findings support the potential clinical applications of RI values in diagnosis of PCa. PMID- 26045119 TI - Long-term survival in metastasized leiomyosarcoma: a case report and review of the literature. AB - BACKGROUND: Leiomyosarcoma of the mesosigma is a very rare entity, with low 5 year survival rates. Treatment consists of resection of the primary tumor and, if applicable, of synchronous or metachronous metastases. Local treatment options for metastatic disease should be exploited as long as possible, as response to chemotherapy is reportedly disappointing. Stereotactic radiotherapy is a fairly new locally effective treatment option which has been well established in stereotactic radiotherapy of lung tumors. Whether repeated stereotactic radiotherapy sessions for treatment of lung metastases can be safely and successfully performed over a long time period is not yet well documented. CASE REPORT: We present the case of a 71-year-old female patient who had a primary diagnosis of lung metastases 12 years ago. Atypical resections of 4 lung metastases were performed in 2001 and 2002. Between 2004 and 2011, 7 sessions of stereotactic body irradiation of lung metastases were performed. All stereotactic treatment were tolerated well (no radiation pneumonitis, FEV1 was 1.3 L [67.8%] in 2004 and 0.99 L [56.3%] in 2011). CONCLUSIONS: The present case could demonstrate that a repetitive treatment of lung metastases with multiple stereotactic radiotherapy sessions can lead to long-term survival with a good quality of life. PMID- 26045120 TI - Adjuvant chemoradiation in gastric cancer: long-term outcomes and prognostic factors from a single institution. AB - BACKGROUND: Adjuvant chemoradiotherapy (CRT) improves relapse-free (RFS) and overall survival (OS) in patients with resected gastric cancer. However, difficulties in standardizing an optimal surgical approach and a perceived higher toxicity compared with the perioperative approach have limited its widespread application in Europe. The aim of our study was to assess toxicity and long-term outcomes of adjuvant CRT at our institution. METHODS: A retrospective review (September 2001-January 2012) was completed of patients with resected gastric cancer who received adjuvant CRT (Macdonald regimen). Adverse events and completion rates, RFS and OS were estimated. Univariate and multivariate analyses of prognostic factors for OS were performed. RESULTS: Eighty-seven patients were included. Most had diffuse (52%) and locally advanced tumors (stage III-IV; 66.7%). D2 lymphadenectomy was performed in 80.5%. The most frequent grade 3-4 toxicities were gastrointestinal (28%) and stomatitis (20%), with 78.2% completing treatment. With a median follow-up of 115 months, 58.5% had relapsed, most of them distantly. Median RFS and OS were 9 and 24 months, respectively. Univariate analysis showed that performance status, stage and lymph node burden were significant factors for OS. In the multivariate study, only stage and lymph node burden remained as independent OS predictors. CONCLUSIONS: Our implementation of the Macdonald regimen achieved worse outcomes than those reported in the INT-0116 trial. The rate of distant relapse remains unacceptably high. Higher rate of positive lymph nodes and of diffuse tumors could explain some differences. The use of perioperative chemotherapy, especially in patients with a poorer prognosis, might improve these results. PMID- 26045121 TI - Co-occurring adverse events enable early prediction of progression-free survival in metastatic renal cell carcinoma patients treated with sunitinib: a hypothesis generating study. AB - AIMS AND BACKGROUND: Clinical practice shows significant differences in treatment outcomes and toxicity of sunitinib across patients. This retrospective study assessed early predictive markers for progression-free survival (PFS) in patients with metastatic clear cell renal cell carcinoma (RCC) treated with sunitinib in the first-line setting. METHODS: We evaluated 28 patients with stage IV clear cell RCC (with good or intermediate MSKCC risk prognosis) treated at the Department of Oncology, University Hospital, Cracow between 2008 and 2013. Data included demographic profiles, adverse events during first cycle of therapy, treatment delays, and treatment outcomes. Sunitinib was administered on a standard schedule (50 mg/day, 4 weeks on, 2 weeks off). PFS values were estimated with the Kaplan-Meier method and compared using the log-rank test; we identified independent PFS predictors using multiple Cox regression models. RESULTS: PFS was significantly longer in patients who experienced at least 1 adverse event after the first cycle of sunitinib (median 17.6 months vs. 5.6; p = 0.006). Hypertension and hand-foot syndrome were significantly correlated with longer PFS (29.3 vs. 6.0 months; p = 0.002, and not reached vs. 9.8 months; p = 0.002, respectively). We observed a similar (though not significant) tendency for neutropenia (17.5 vs. 8.4 months; p = 0.055). In multiple Cox regression, hypertension was the only individual independent predictor of PFS, but the co occurrence of any 2 or 3 sunitinib-induced adverse events also predicted longer survival. CONCLUSIONS: Although small, our study suggests that hypertension and hand-foot syndrome predict longer PFS in patients with clear cell RCC treated with sunitinib. The co-occurrence of 2 or more side effects seems also a significant predictor of longer survival. Larger studies are warranted to confirm the correlation between co-occurring side effects and PFS. PMID- 26045122 TI - That tumor you're going to get tomorrow ... maybe: making an informed decision. AB - With the recent progress in predictive medicine several problems have emerged regarding the ethical aspects of genetic testing. The role of the doctor in communicating the consequences of such testing to the patient has become more important than ever in allowing the potential patient to make an informed decision. PMID- 26045123 TI - Interleukin-6 as a prognostic marker for breast cancer: a meta-analysis. AB - AIMS AND BACKGROUND: Interleukin-6 (IL-6) has been shown to promote tumor survival, metastasis, and angiogenesis, in addition to possessing antitumor activities. In light of the conflicting data, we sought to determine whether IL-6 could be used as a prognostic factor for patients with breast cancer. METHODS: Eligible studies describing the use of IL-6 as a prognostic factor for breast cancer were identified. Data describing overall survival (OS), disease-free survival (DFS), and clinicopathologic features were collected and analyzed. RESULTS: Thirteen articles containing 3,224 breast cancer patients were identified. The results showed that IL-6 expression was not associated with lymph node metastasis, tumor size, or histologic grade. Moreover, there was no correlation between IL-6 expression and DFS. However, the combined hazard ratio (95% confidence interval) for OS was 2.15 (1.46, 3.17). Sensitivity analysis further demonstrated that, for OS, the results of this meta-analysis were stable. A subgroup analysis showed that the source used to detect IL-6 levels may have altered the pooled results for OS. CONCLUSIONS: Taken together, these results indicate that IL-6 expression is associated with poor prognosis for breast cancer and the prognostic role is affected by the source used to detect IL-6 levels. PMID- 26045124 TI - Bladder and gastric metastases from lung adenocarcinoma harboring codon 13 KRAS mutation: a case report with unusual clinical outcome. AB - AIMS AND BACKGROUND: Gastric and bladder metastases are rare in non-small-cell lung cancer (NSCLC) and the differential diagnosis with primary tumors requires an in-depth examination. KRAS gene mutations are the main oncogenic driver of lung adenocarcinoma in Caucasian patients, occurring in 25%-30% of cases, but their prognostic and predictive role is complex and not fully clarified. KRAS mutations in lung adenocarcinoma are considered negatively predictive for epidermal growth factor receptor tyrosine kinase inhibitors therapy as well as for adjuvant chemotherapy. In this report, the authors describe a case of lung adenocarcinoma harboring a codon 13 KRAS mutation detected in all the biopsies performed in unusual metastatic sites during an atypical disease course. CONCLUSIONS: Recently, a different prognostic significance of various KRAS mutations in lung adenocarcinoma has been suggested. Further studies on rare biomolecular alterations to identify subgroups of patients with different prognostic/predictive characteristics are needed. PMID- 26045125 TI - B7-H1/PD-1 blockade therapy in urological malignancies: current status and future prospects. AB - The stimulatory and inhibitory coreceptors expressed by T lymphocytes are known to play critical roles in regulating cancer immunity. An array of inhibitory coreceptors involved in the inhibition of T-cell functions and the blockade of immune activation have been discovered in recent years, the most important of which are cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmmed death-1 (PD-1), and B7 homolog 1 (B7-H1). Immunotherapies targeting T-cell coinhibitory molecules have proved to be effective in cancer treatment. Several kinds of monoclonal antibodies have been tested in preclinical studies, with better outcomes than conventional therapies in many malignancies. Common urological malignancies including renal cell carcinoma, bladder cancer and prostate cancer are supposed to be immunogenic cancer types and not so sensitive to conventional therapies as other malignancies. This review will focus on B7-H1/PD-1 blockade therapy in urological malignancies, summarizing the results of clinical trials as well as the challenges and prospects of this emerging immunotherapy. PMID- 26045126 TI - Invasion and anti-invasion research of glioma cells in an improved model of organotypic brain slice culture. AB - AIMS AND BACKGROUND: Although glioblastomas infiltrate diffusely into adjacent brain, it is difficult to unequivocally identify the solitary invading glioma cell. It is necessary to develop coculture models to study the motility of glioma cells, and to monitor the cellular morphology, movement direction, migration area and invasion rate. METHODS: Cerebral slices were cultured on Millicell-CM membrane inserts in a petri dish. The neuronal viability and organizational structure of the brain sections were well maintained by experimental verification. C6 cell clones with persistent enhanced green fluorescent protein (EGFP) expression were established. EGFP-expressing glioma cells were cultured to form aggregates, which were implanted on the brain slices. The invasion area and migration rates of C6 cells on brain slices were measured. We evaluated the invasion area and depth after C6 cells were treated with the Rac1 inhibitor NSC23766. RESULTS: We successfully established the glioma cell-brain slice coculture model. In coculture, the average migration rate of C6 glioma cells within brain slices reached 11.36-15.27 MUm/hour. The polarity of C6 glioma cells was parallel to the white matter tracts after 7 days. The invasive ability of C6 cells (depth: 105.3 +/- 10.3 MUm) treated with NSC23766 was weakened compared with the control group (depth: 198 +/- 9.2 MUm) within the white matter of brain slices (t = 16.26, p<0.05). CONCLUSIONS: We developed the model to analyze the invasion features of glioma cells. The significant suppression of glioma cell invasion by NSC23766 in brain slices indicates that anti-Rac1 treatment may represent an important future therapeutic strategy for glioblastoma. PMID- 26045127 TI - Isolated cardiac metastasis from squamous cell esophageal cancer. AB - Although heart metastases are uncommon and generally a sign of disseminated disease, they are up to 40 times more frequent than primary cancers of the heart, and typically arise from melanoma or primary mediastinal cancer, but also from lymphoma, breast cancer, esophageal cancer, and leukemia. They are usually asymptomatic and found only at autopsy. Symptomatic patients generally die within a few weeks of diagnosis and usual treatments are chemotherapy, radiotherapy, or both. Surgical resection is recommended only for a single lesion, which is rare. We describe a 49-year-old man treated for squamous cell cancer of the esophagus in whom a single asymptomatic left heart metastasis was discovered incidentally during follow-up. The lesion was debulked surgically and multimodal treatment followed. The patient survived 1 year after diagnosis with good performance status during which time no other lesion was discovered. Cardiac metastasis is challenging and necessitates skilled multidisciplinary management to maximize the clinical outcome. PMID- 26045128 TI - Cancer mortality trend analysis in Italy, 1980-2010, and predictions for 2015. AB - AIMS: To update cancer mortality statistics in Italy, analyzing 1980-2010 trends, and to predict 2015 mortality rates. METHODS: World Health Organization cancer mortality and census data were extracted to calculate death rates for 30 cancer sites from 1980 to 2010. Trends were analyzed with joinpoint regression and predicted 2015 deaths rates were computed. RESULTS: In 2010 in Italy, there were 175,046 cancer deaths (98,847 men and 76,199 women), with total mortality rates, respectively, of 138.22 and 82.6/100,000. The leading cause of cancer death in men was lung cancer (25,457 deaths, 36.2/100,000), whereas in women it was breast cancer (12,115 deaths, 15.38/100,000). Total cancer mortality in men has been decreasing since the late 1980s, with an estimated annual percentage change (EAPC) of -1.8 in 1994-2010. In women, total cancer mortality rates decreased throughout the study period, with an EAPC of -1.1 in 1992-2010. Trends in mortality were decreasing for most cancers in both sexes. Only pancreatic and lung cancer trends in women were unfavorable. Total numbers of predicted cancer deaths in Italy for 2015 increased to 102,647 men and 82,047 women; however, the predicted rates decreased in men (129.1/100,000), while remaining stable in women (82.6/100,000). CONCLUSIONS: Mortality rates for the most common cancers in Italy showed favorable trends that are likely to continue in the near future, with the exception of lung cancer mortality in women. Maintaining these trends requires continuous and improved control of tobacco, alcohol, and nutrition/overweight. Further improvements in diagnosis and treatment may also have a significant impact on cancer mortality. PMID- 26045129 TI - Adnectin-targeted inhibitors: rationale and results. AB - Adnectins are a family of binding proteins derived from the 10th type III domain of human fibronectin (10Fn3), which is part of the immunoglobulin superfamily and normally binds integrin. The 10Fn3 has the potential for broad therapeutic applications given its structural stability, ability to be manipulated, and its abundance in the human body. The most commonly studied adnectin is CT-322, which is an inhibitor of vascular endothelial growth factor receptor-2. A bispecific adnectin, El-Tandem, has also been developed and binds to epidermal growth factor receptor and insulin-like growth factor-1 receptor simultaneously. Pre-clinical studies have shown promising results in relation to reducing tumor growth, decreasing microvessel density, and promoting normalization of tumor architecture. The phase I trial with CT-322 demonstrates relatively low toxicities. However, the phase II study done with CT-322 in recurrent glioblastoma does not reveal as promising results. PMID- 26045131 TI - When is it safe to omit surgery in primary peritoneal cancer with small volume disease? AB - Primary peritoneal cancer (PPC) is considered a very rare condition, with mesotheliomas deemed the only true PPC when considering the cellular content and embryological derivation of the peritoneum. However, in women, PPC are seen in much greater abundance than that in men and the type of cancer detected is often that of a serous epithelial carcinoma, histologically similar to serous ovarian carcinomas. The management is also similar, i.e. surgery and platin-based chemotherapy. The definition clinically of PPC is that of widespread carcinomatosis with normal-sized ovaries. The carcinomatosis is often extensive, and the only bulk disease may be within the omentum and achieving complete clearance of all disease at primary surgery unlikely. Thus, the concept of using chemotherapy as the main strategy is a reasonable approach and may well be the best single therapeutic option in some patients. This paper reviews the data on PPC and how this approach could be assessed. PMID- 26045130 TI - Novel agents in mantle cell lymphoma. AB - Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma, comprising approximately 6-8% of all non-Hodgkin lymphomas. MCL is biologically and clinically heterogeneous, and there is no standard treatment for MCL. Although untreated MCL often responds well to frontline combination chemotherapy, relapsed, refractory MCL can be challenging to treat and traditional cytotoxic chemotherapy is typically not highly effective. In recent years, increased insight into the molecular and genomic diversity of MCL and the pathogenesis of the disease has given rise to the development of many new biologically targeted therapies. Ibrutinib was recently FDA approved for relapsed, refractory MCL and will likely have a significant impact on treatment paradigms for MCL. In addition to ibrutinib, there are many classes of novel agents that are currently in development. This review focuses on recent developments in the management of relapsed, refractory MCL, describing the growing armamentarium of novel agents available to combat this disease. PMID- 26045132 TI - Prevention of nosocomial transmission of influenza A (H7N9) in Hong Kong. PMID- 26045133 TI - Spin kills science. PMID- 26045135 TI - Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. AB - BACKGROUND: Idiosyncratic drug-induced liver injury (iDILI) is a frequent cause of acute liver injury and a serious problem in late stage drug-development. Its diagnosis is one of the most challenging in hepatology, since it is done by exclusion and relies on expert opinion. Until now no reliable in vitro test exists to support the diagnosis of iDILI. In some instances it is impossible to determine the causative drug in polymedicated patients. AIM: To investigate if monocyte-derived hepatocyte-like (MH) cells might be a tool supporting clinical judgment for iDILI diagnosis and causality assessment. METHODS: This prospective study included 54 patients with acute liver injury and intake of at least one drug. Thirty-one patients were diagnosed with iDILI based on causality likelihood. MH cells were generated from every patient and in vitro toxicity of the respective drugs was assessed by lactate-dehydrogenase release. The results from MH cells and RUCAM, the most widely used scoring system as methods to support clinical judgement were compared. RESULTS: MH cells showed enhanced toxicity in 29 of the 31 patients with iDILI, similar to RUCAM score. MH cells exhibited negative results in the 23 non-DILI cases, whereas RUCAM indicated possible iDILI in six cases. Analysis of the comedications also showed superior specificity of MH cells. No MH cell toxicity of the drugs showing toxicity in patients with iDILI was observed in MH cells of healthy donors. CONCLUSIONS: In this pilot study in vitro testing using MH cells derived from patients with acute liver injury was able to identify patients with iDILI with an excellent sensitivity and a higher specificity than RUCAM, the most widely used current causality assessment score. Therefore, MH cells could be useful to identify the causative drugs even in polymedicated patients by adding objective data to causality assessment. TRIAL REGISTRATION NUMBER: NCT02353455. PMID- 26045136 TI - A new instrumental platform for Trans-Anal Submucosal Endoscopic Resection (TASER). PMID- 26045134 TI - Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn's disease. AB - BACKGROUND: Crohn's disease (CD)-associated dysbiosis is characterised by a loss of Faecalibacterium prausnitzii, whose culture supernatant exerts an anti inflammatory effect both in vitro and in vivo. However, the chemical nature of the anti-inflammatory compounds has not yet been determined. METHODS: Peptidomic analysis using mass spectrometry was applied to F. prausnitzii supernatant. Anti inflammatory effects of identified peptides were tested in vitro directly on intestinal epithelial cell lines and on cell lines transfected with a plasmid construction coding for the candidate protein encompassing these peptides. In vivo, the cDNA of the candidate protein was delivered to the gut by recombinant lactic acid bacteria to prevent dinitrobenzene sulfonic acid (DNBS)-colitis in mice. RESULTS: The seven peptides, identified in the F. prausnitzii culture supernatants, derived from a single microbial anti-inflammatory molecule (MAM), a protein of 15 kDa, and comprising 53% of non-polar residues. This last feature prevented the direct characterisation of the putative anti-inflammatory activity of MAM-derived peptides. Transfection of MAM cDNA in epithelial cells led to a significant decrease in the activation of the nuclear factor (NF)-kappaB pathway with a dose-dependent effect. Finally, the use of a food-grade bacterium, Lactococcus lactis, delivering a plasmid encoding MAM was able to alleviate DNBS induced colitis in mice. CONCLUSIONS: A 15 kDa protein with anti-inflammatory properties is produced by F. prausnitzii, a commensal bacterium involved in CD pathogenesis. This protein is able to inhibit the NF-kappaB pathway in intestinal epithelial cells and to prevent colitis in an animal model. PMID- 26045137 TI - A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. AB - OBJECTIVE: We used an informatics approach to identify and validate genes whose expression is unique to hepatic stellate cells and assessed the prognostic capability of their expression in cirrhosis. DESIGN: We defined a hepatic stellate cell gene signature by comparing stellate, immune and hepatic transcriptome profiles. We then created a prognostic index using a combination of hepatic stellate cell signature expression and clinical variables. This signature was derived in a retrospective-prospective cohort of hepatitis C-related early stage cirrhosis (prognostic index derivation set) and validated in an independent retrospective cohort of patients with postresection hepatocellular carcinoma (HCC). We then examined the association between hepatic stellate cell signature expression and decompensation, HCC development, progression of Child-Pugh class and survival. RESULTS: The 122-gene hepatic stellate cell signature consists of genes encoding extracellular matrix proteins and developmental factors and correlates with the extent of fibrosis in human, mouse and rat datasets. Importantly, association of clinical prognostic variables with overall survival was improved by adding the signature; we used these results to define a prognostic index in the derivation set. In the validation set, the same prognostic index was associated with overall survival. The prognostic index was associated with decompensation, HCC and progression of Child-Pugh class in the derivation set, and HCC recurrence in the validation set. CONCLUSIONS: This work highlights the unique transcriptional niche of stellate cells, and identifies potential stellate cell targets for tracking, targeting and isolation. Hepatic stellate cell signature expression may identify patients with HCV cirrhosis or postresection HCC with poor prognosis. PMID- 26045139 TI - Serum viral duplex-linear DNA proportion increases with the progression of liver disease in patients infected with HBV. AB - OBJECTIVE: HBV has two forms of genomic DNA, relaxed-circular DNA (rcDNA) and duplex-linear DNA (dlDNA). Compared to rcDNA, dlDNA has been demonstrated to integrate more frequently into host cellular chromosomes, which may have oncogenic consequences. However, the dlDNA proportion relative to total HBV DNA and its clinical significance in patients remain to be investigated. DESIGN: Based on the structural difference between rcDNA and dlDNA, we developed a peptide nucleic acid (PNA)-mediated quantitative real-time PCR (qPCR) clamping assay to measure the proportions of dlDNA in total HBV DNA in sera obtained from patients with chronic hepatitis B (CHB), liver cirrhosis (LC) or LC-developed hepatocellular carcinoma (HCC). The factors that influence the proportion of dlDNA were also investigated. RESULTS: The average dlDNA proportion was approximately 7% in the sera of chronic HBV-infected patients and was elevated in CHB patients with abnormal levels of alanine aminotransferase. The sera dlDNA proportions increased to approximately 14% and 20% in the patients with LC and HCC, respectively. Interferon-alpha treatment slightly increased the dlDNA proportion in the responders; and nucleotide analogue therapy spuriously elevated the proportion. Moreover, treatment of human hepatoma cells supporting HBV replication with inflammatory cytokines significantly altered the dlDNA proportion in vitro. CONCLUSIONS: Using a novel PNA-mediated qPCR clamping assay, we first showed that serum dlDNA proportions progressively increased during the development of HBV-related liver diseases. The dlDNA proportion can be regulated by inflammatory cytokines, suggesting an association among inflammation, increased production of HBV dlDNA and development of HCC. PMID- 26045138 TI - Antibiotics promote inflammation through the translocation of native commensal colonic bacteria. AB - OBJECTIVE: Antibiotic use is associated with an increased risk of developing multiple inflammatory disorders, which in turn are linked to alterations in the intestinal microbiota. How these alterations in the intestinal microbiota translate into an increased risk for inflammatory responses is largely unknown. Here we investigated whether and how antibiotics promote inflammation via the translocation of live native gut commensal bacteria. DESIGN: Oral antibiotics were given to wildtype and induced mutant mouse strains, and the effects on bacterial translocation, inflammatory responses and the susceptibility to colitis were evaluated. The sources of the bacteria and the pathways required for bacterial translocation were evaluated using induced mutant mouse strains, 16s rRNA sequencing to characterise the microbial communities, and in vivo and ex vivo imaging techniques. RESULTS: Oral antibiotics induced the translocation of live native commensal bacteria across the colonic epithelium, promoting inflammatory responses, and predisposing to increased disease in response to coincident injury. Bacterial translocation resulted from decreased microbial signals delivered to colonic goblet cells (GCs), was associated with the formation of colonic GC-associated antigen passages, was abolished when GCs were depleted and required CX3CR1(+) dendritic cells. Bacterial translocation occurred following a single dose of most antibiotics tested, and the predisposition for increased inflammation was only associated with antibiotics inducing bacterial translocation. CONCLUSIONS: These findings reveal an unexpected outcome of antibiotic therapy and suggest that bacterial translocation as a result of alterations in the intestinal microflora may provide a link between increasing antibiotic use and the increased incidence of inflammatory disorders. PMID- 26045141 TI - Visualization of declamping procedure during carotid endarterectomy by ICG videoangiography. AB - BACKGROUND: ICG videoangiography (ICG-VAG) is widely used in neurovascular surgery. In carotid artery disease, it has been used to assess the extent of the plaque and to confirm the removal of the plaque and patency of the artery. We introduce a novel usage of the ICG-VAG to confirm the patency of the external carotid artery (ECA) and superior thyroid artery (STA), which should work as a drainage system of possible debris in the lumen. METHOD: Consecutive 27 patients with severe internal carotid artery stenosis were employed. Carotid endarterectomy (CEA) was done in the usual fashion. After suturing the arteriotomy, ICG was injected intravenously before reperfusion. Before declamping procedure, ICG-VAG mode was started. As the declamping procedure went on, the assistant judged whether the STA and the ECA were patent by watching the ICG flow on the monitor. After confirming the patency of the ECA-CCA system, the ICA was reperfused. RESULT: The back flow from the STA was not confirmed in two cases. The back flow from the ECA was confirmed in all 27 cases. In four cases, the ICG VAG showed air bubbles in the lumen; these bubbles were washed away to the ECA or STA. CONCLUSION: Using ICG-VAG during the reperfusion procedure of CEA, the patency of the ECA and the STA can be confirmed. It may contribute to reduce embolic complication during reperfusion procedure. PMID- 26045142 TI - A constitutive model for developing blood clots with various compositions and their nonlinear viscoelastic behavior. AB - The mechanical properties determine to a large extent the functioning of a blood clot. These properties depend on the composition of the clot and have been related to many diseases. However, the various involved components and their complex interactions make it difficult at this stage to fully understand and predict properties as a function of the components. Therefore, in this study, a constitutive model is developed that describes the viscoelastic behavior of blood clots with various compositions. Hereto, clots are formed from whole blood, platelet-rich plasma and platelet-poor plasma to study the influence of red blood cells, platelets and fibrin, respectively. Rheological experiments are performed to probe the mechanical behavior of the clots during their formation. The nonlinear viscoelastic behavior of the mature clots is characterized using a large amplitude oscillatory shear deformation. The model is based on a generalized Maxwell model that accurately describes the results for the different rheological experiments by making the moduli and viscosities a function of time and the past and current deformation. Using the same model with different parameter values enables a description of clots with different compositions. A sensitivity analysis is applied to study the influence of parameter variations on the model output. The relative simplicity and flexibility make the model suitable for numerical simulations of blood clots and other materials showing similar behavior. PMID- 26045140 TI - Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas). AB - OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1 20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477. PMID- 26045143 TI - Context-based resolution of semantic conflicts in biological pathways. AB - BACKGROUND: Interactions between biological entities such as genes, proteins and metabolites, so called pathways, are key features to understand molecular mechanisms of life. As pathway information is being accumulated rapidly through various knowledge resources, there are growing interests in maintaining the integrity of the heterogeneous databases. METHODS: Here, we defined conflict as a status where two contradictory pieces of evidence (i.e. 'A increases B' and 'A decreases B') coexist in a same pathway. This conflict damages unity so that inference of simulation on the integrated pathway network might be unreliable. We defined rule and rule group. A rule consists of interaction of two entities, meta relation (increase or decrease), and contexts terms about tissue specificity or environmental conditions. The rules, which have the same interaction, are grouped into a rule group. If the rules don't have a unanimous meta-relation, the rule group and the rules are judged as being conflicting. RESULTS: This analysis revealed that almost 20% of known interactions suffer from conflicting information and conflicting information occurred much more frequently in the literature than the public database. CONCLUSIONS: By identifying and resolving the conflicts, we expect that pathway databases can be cleaned and used for better secondary analyses such as gene/protein annotation, network dynamics and qualitative/quantitative simulation. PMID- 26045144 TI - In Reply. PMID- 26045145 TI - Introduction: Facing the Challenges of Peripheral Nerve Surgery in the 21st Century. PMID- 26045146 TI - Hand infection patients presenting to an orthopaedic unit: An audit of incidence and demographics at a rural hospital. AB - OBJECTIVE: Hand infections are a common presentation to health services in the Northern Territory; however, little is known about these patients. This study aims to identify incidence, treatment and co-morbidities of hand infection patients and to pinpoint factors associated with poor outcome. DESIGN: A retrospective study of all patients presenting to Alice Springs Hospital with a hand infection during 2012. SETTING: Orthopaedic Unit at Alice Springs Hospital. PARTICIPANTS: All patients admitted with a hand infection were included. MAIN OUTCOME MEASURES: Admission duration, duration waited before first presentation, re-admission rate, duration of re-admission and rate of methicillin-resistant Staphylococcus aureus. RESULTS: One hundred fourteen cases of hand infections were admitted to Alice Springs Hospital during 2012, of which 87 (76%) were in Indigenous patients. Indigenous patients (P = 0.001) and older patients (P = 0.038) had significantly longer admissions. Indigenous patients were 9.52 times (P = 0.038) more likely to be re-admitted than non-Indigenous patients. The rate of methicillin-resistant Staphylococcus aureus was 24.6%, and this was associated with smoking (P = 0.049) and substance abuse (P = 0.036). Formal follow-up was not related to indirect measures of hand infection severity, such as admission duration or re-admissions. CONCLUSION: Hand infections are a common presentation to Alice Springs Hospital. Indigenous people are admitted 2.38 times longer after adjusting for age and alcohol abuse. They have a more than ninefold chance of being re-admitted to hospital than non-Indigenous people following a hand infection. PMID- 26045147 TI - Drug-polymer interactions at water-crystal interfaces and implications for crystallization inhibition: molecular dynamics simulations of amphiphilic block copolymer interactions with tolazamide crystals. AB - A diblock copolymer, poly(ethylene glycol)-block-poly(lactic acid) (PEG-b-PLA), modulates the crystal growth of tolazamide (TLZ), resulting in a crystal morphology change from needles to plates in aqueous media. To understand this crystal surface drug-polymer interaction, we conducted molecular dynamics simulations on crystal surfaces of TLZ in water containing PEG-b-PLA. A 130-ns simulation of the polymer in a large water box was run before initiating 50 ns simulations with each of the crystal surfaces. The simulations demonstrated differentiated drug-polymer interactions that are consistent with experimental studies. Interaction of PEG-b-PLA with the (001) face occurred more rapidly (<=10 ns) and strongly (total interaction energy of -121.1 kJ/mol/monomer) than that with the (010) face (~35 ns, -85.4 kJ/mol/monomer). There was little interaction with the (100) face. Hydrophobic and van der Waals (VDW) interactions were the dominant forces, accounting for more than 90% of total interaction energies. It suggests that polymers capable of forming strong hydrophobic and VDW interactions might be more effective in inhibiting crystallization of poorly water-soluble and hydrophobic drugs in aqueous media (such as gastrointestinal fluid) than those with hydrogen-bonding capacities. Such in-depth analysis and understanding facilitate the rational selection of polymers in designing supersaturation-based enabling formulations. PMID- 26045148 TI - Radial glial cell-specific ablation in the adult Zebrafish brain. AB - The zebrafish brain can continue to produce new neurons in widespread neurogenic brain regions throughout life. In contrast, neurogenesis in the adult mammalian brain is restricted to the subventricular zone (SVZ) and dentate gyrus (DG). In neurogenic regions in the adult brain, radial glial cells (RGCs) are considered to function as neural stem cells (NSCs). We generated a Tg(gfap:Gal4FF) transgenic zebrafish line, which enabled us to express specific genes in RGCs. To study the function of RGCs in neurogenesis in the adult zebrafish brain, we also generated a Tg(gfap: Gal4FF; UAS:nfsB-mcherry) transgenic zebrafish line, which allowed us to induce cell death exclusively within RGCs upon addition of metronidazole (Mtz) to the media. RGCs expressing nitroreductase were specifically ablated by the Mtz treatment, decreasing the number of proliferative RGCs. Using the Tg(gfap:Gal4FF; UAS:nfsB-mcherry) transgenic zebrafish line, we found that RGCs were specifically ablated in the adult zebrafish telencephalon. The Tg(gfap:Gal4FF) line could be useful to study the function of RGCs. PMID- 26045149 TI - Making females male with Dmrt1. PMID- 26045150 TI - Benefits of menopause: good fishing. PMID- 26045151 TI - Polarity and the placenta. PMID- 26045152 TI - Pops gets the polycomb. PMID- 26045153 TI - PTFE effect on the electrocatalysis of the oxygen reduction reaction in membraneless microbial fuel cells. AB - Influence of PTFE in the external Gas Diffusion Layer (GDL) of open-air cathodes applied to membraneless microbial fuel cells (MFCs) is investigated in this work. Electrochemical measurements on cathodes with different PTFE contents (200%, 100%, 80% and 60%) were carried out to characterize cathodic oxygen reduction reaction, to study the reaction kinetics. It is demonstrated that ORR is not under diffusion-limiting conditions in the tested systems. Based on cyclic voltammetry, an increase of the cathodic electrochemical active area took place with the decrease of PTFE content. This was not directly related to MFC productivity, but to the cathode wettability and the biocathode development. Low electrodic interface resistances (from 1 to 1.5 Omega at the start, to near 0.1 Omega at day 61) indicated a negligible ohmic drop. A decrease of the Tafel slopes from 120 to 80 mV during productive periods of MFCs followed the biological activity in the whole MFC system. A high PTFE content in the cathode showed a detrimental effect on the MFC productivity, acting as an inhibitor of ORR electrocatalysis in the triple contact zone. PMID- 26045154 TI - Long-Term Effects of School-Based Oral Health Program on Oral Health Knowledge and Practices and Oral Health-Related Quality of Life. AB - OBJECTIVE: To evaluate the effects of exposure to the School Oral Health Program (SOHP) during primary school years on the current oral health (OH) knowledge and practices and OH-related quality of life (OHRQoL) of Kuwait University students. SUBJECTS AND METHODS: 300 university students, aged 17.6-24.3 years, completed a validated questionnaire that consisted of 5 sections about demographics, health self-evaluation, OH knowledge and practices and OHRQoL. Of these students, 260 were female, 40 male, 262 single and 38 married. 189 participants had attended the SOHP, while 111 had not. Frequencies and means were used for data description. The Student t test was used to compare the means, while chi(2) analysis was used for the associations between SOHP and non-SOHP attendance. The odds ratios (ORs) were calculated for significant factors. RESULTS: The SOHP attendees were twice as aware of the relationship between gum problems and heart diseases than the non-SOHP (OR = 2, 95% CI = 1.15-3.48, p = 0.013). The daily activities of the non-SOHP attendees were twice as likely to be affected by dental health issues compared to those of the SOHP attendees (OR = 2.28, 95% CI = 1.41-3.68, p < 0.001). In addition, the SOHP attendees were 3 times as likely to describe their OH status as good/very good/excellent than the non-SOHP attendees (OR = 2.85, 95% CI = 1.31-6.18, p = 0.008). CONCLUSIONS: The SOHP attendees had a better OHRQoL and overall self-satisfaction with their OH than the non-SOHP attendees with insignificant differences between the 2 groups in OH knowledge and practices. PMID- 26045155 TI - Characteristic miR-24 Expression in Gastric Cancers among Atomic Bomb Survivors. AB - OBJECTIVE: To elucidate the mechanism of radiation-induced cancers, we analyzed the expression profiles of microRNAs extracted from formalin-fixed paraffin embedded (FFPE) gastric cancer (GC) tissue samples from atomic bomb survivors. METHODS: The expression levels of miR-21, miR-24, miR-34a, miR-106a, miR-143, and miR-145 were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The expression of microRNAs was measured by qRT-PCR in a Hiroshima University Hospital cohort comprising 32 patients in the high-dose exposed group and 18 patients in the low-dose-exposed group who developed GC after the bombing. The GC cases showing high expression of miR-24, miR-143, and miR-145 were more frequently found in the high-dose-exposed group than in the low dose-exposed group. We next performed qRT-PCR of miR-24, miR-143, and miR-145 in a cohort from the Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital comprising 122 patients in the high-dose-exposed group and 48 patients in the low dose-exposed group who developed GC after the bombing. High expressions of miR-24 and miR-143 were more frequently found in the high-dose-exposed group than in the low-dose-exposed group. Multivariate analysis demonstrated that only high expression of miR-24 was an independent predictor for the exposure status. CONCLUSION: These results suggest that the measurement of miR-24 expression from FFPE samples is useful to identify radiation-associated GC. PMID- 26045156 TI - 209th ENMC International Workshop: Outcome Measures and Clinical Trial Readiness in Spinal Muscular Atrophy 7-9 November 2014, Heemskerk, The Netherlands. PMID- 26045157 TI - Pyrosequencing-Based Assessment of the Microbial Community Structure of Pastoruri Glacier Area (Huascaran National Park, Peru), a Natural Extreme Acidic Environment. AB - The exposure of fresh sulfide-rich lithologies by the retracement of the Nevado Pastoruri glacier (Central Andes, Peru) is increasing the presence of heavy metals in the water as well as decreasing the pH, producing an acid rock drainage (ARD) process in the area. We describe the microbial communities of an extreme ARD site in Huascaran National Park as well as their correlation with the water physicochemistry. Microbial biodiversity was analyzed by FLX 454 sequencing of the 16S rRNA gene. The suggested geomicrobiological model of the area distinguishes three different zones. The proglacial zone is located in the upper part of the valley, where the ARD process is not evident yet. Most of the OTUs detected in this area were related to sequences associated with cold environments (i.e., psychrotolerant species of Cyanobacteria or Bacteroidetes). After the proglacial area, an ARD-influenced zone appeared, characterized by the presence of phylotypes related to acidophiles (Acidiphilium) as well as other species related to acidic and cold environments (i.e., acidophilic species of Chloroflexi, Clostridium and Verrumicrobia). Sulfur- and iron-oxidizing acidophilic bacteria (Acidithiobacillus) were also identified. The post-ARD area was characterized by the presence of OTUs related to microorganisms detected in soils, permafrost, high mountain environments, and deglaciation areas (Sphingomonadales, Caulobacter or Comamonadaceae). PMID- 26045158 TI - Effect of the Organic Loading Rate Increase and the Presence of Zeolite on Microbial Community Composition and Process Stability During Anaerobic Digestion of Chicken Wastes. AB - This study investigates the effect of the organic loading rate (OLR) increase from 1.0 to 3.5 g VS L(-1) day(-1) at constant hydraulic retention time (HRT) of 35 days on anaerobic reactors' performance and microbial diversity during mesophilic anaerobic digestion of ammonium-rich chicken wastes in the absence/presence of zeolite. The effects of anaerobic process parameters on microbial community structure and dynamics were evaluated using a 16S ribosomal RNA gene-based pyrosequencing approach. Maximum 12 % of the total ammonia nitrogen (TAN) was efficiently removed by zeolite in the fixed zeolite reactor (day 87). In addition, volatile fatty acids (VFA) in the fixed zeolite reactor accumulated in lower concentrations at high OLR of 3.2-3.5 g VS L(-1) day(-1). Microbial communities in the fixed zeolite reactor and reactor without zeolite were dominated by various members of Bacteroidales and Methanobacterium sp. at moderate TAN and VFA levels. The increase of the OLR accompanied by TAN and VFA accumulation and increase in pH led to the predominance of representatives of the family Erysipelotrichaceae and genera Clostridium and Methanosarcina. Methanosarcina sp. reached relative abundances of 94 and 57 % in the fixed zeolite reactor and reactor without zeolite at the end of the experimental period, respectively. In addition, the diminution of Synergistaceae and Crenarchaeota and increase in the abundance of Acholeplasmataceae in parallel with the increase of TAN, VFA, and pH values were observed. PMID- 26045159 TI - A key gene of the small RNA pathway in the flounder, Paralichthys olivaceus: identification and functional characterization of dicer. AB - Dicer is critical for producing mature microRNAs (miRNAs) from precursor molecules and small interfering RNAs and plays an important role in controlling development and metabolism. In the present study, we cloned the flounder dicer gene, which is 6585 nucleotides (nt), including a 5'-untranslated region (UTR) of 231 nt, a 3'-UTR of 663 nt and an open reading frame of 5691 nt encoding a polypeptide of 1897 amino acids, and analyzed the conservation and expression pattern of dicer. The tissue distribution analysis indicated that dicer is abundantly expressed in the brain, heart, liver, spleen, stomach, kidney, gill, muscle, intestine and gonad of adult fish. Temporal expression analysis indicated that dicer mRNA is highly expressed during the embryonic and early larval stages, and exhibits low expression during the metamorphic stages. Treatment with thyroid hormone (TH) or thiourea indirectly or directly up-regulated dicer mRNA levels at 17 and 23 dph, whereas treatment with TH down-regulated dicer mRNA levels at 36 dph. The dicer-specific siRNA significantly down-regulated dicer mRNA and pol-let 7d levels, while pol-let-7d precursor levels were not differentially changed compared with the control (NC). These results demonstrated that dicer plays a key role in development and metabolism through the production of mature miRNAs, providing basic information for further studies concerning the role of dicer in Paralichthys olivaceus development. PMID- 26045160 TI - Quantitation of retinaldehyde in small biological samples using ultrahigh performance liquid chromatography tandem mass spectrometry. AB - We report an ultrahigh-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method to quantify all-trans-retinal in biological samples of limited size (15-35mg), which is especially advantageous for use with adipose. To facilitate recovery, retinal and the internal standard 3,4-didehydroretinal were derivatized in situ into their O-ethyloximes. UHPLC resolution combined with high sensitivity and specificity of MS/MS allowed quantification of retinal-O ethyloximes with a 5-fmol lower limit of detection and a linear range from 5fmol to 1pmol. This assay revealed that extraocular concentrations of retinal range from approximately 2 to 40pmol/g in multiple tissues-the same range as all-trans retinoic acid. All-trans-retinoic acid has high affinity (kd?0.4nM) for its nuclear receptors (RARalpha, -beta, and -gamma), whereas retinal has low (if any) affinity for these receptors, making it unlikely that these retinal concentrations would activate RAR. We also show that the copious amount of vitamin A used in chow diets increases retinal in adipose depots 2- to 5-fold relative to levels in adipose of mice fed a vitamin A-sufficient diet, as recommended for laboratory rodents. This assay also is proficient for quantifying conversion of retinol into retinal in vitro and, therefore, provides an efficient method to study metabolism of retinol in vivo and in vitro. PMID- 26045161 TI - Assessment of Apoptotic Activity Dysregulation and Oxidative Stress in the Development of Epithelial Ovarian Cancer: A Case-Controlled Descriptive Analysis. AB - AIM: In the present study, we aimed to assess whether oxidative stress and apoptotic activity play a role in the development of epithelial ovarian cancer (EOC). METHODS: The study group included patients with EOC (n = 26) and benign ovarian tumour (BOT) (n = 25), while 30 healthy women were employed as a control group. Venous blood samples were drawn to evaluate oxidative stress parameters and serum M30/M65 antigen levels before surgery. In addition, blood samples were taken for the second time on postoperative day 8 to analyse whether the postoperative tumour load was decreased. RESULTS: When the groups were assessed regarding oxidative stress, the highest values were detected in patients with EOC. Serum M30/M65 levels were found to be higher in patients with EOC when compared to the other groups (p < 0.001). A significant decrease was determined in the M30/M65 levels of serum samples taken on postoperative day 8 from the patients in the EOC and BOT groups (p < 0.001). CONCLUSION: Our results suggest that dysregulation of apoptotic activity could be effective in the development of ovarian tumoural tissue, whereas oxidative stress could be effective in malignant transformation. PMID- 26045162 TI - High mobility group protein-mediated transcription requires DNA damage marker gamma-H2AX. AB - The eukaryotic genome is organized into chromatins, the physiological template for DNA-dependent processes including replication, recombination, repair, and transcription. Chromatin-mediated transcription regulation involves DNA methylation, chromatin remodeling, and histone modifications. However, chromatin also contains non-histone chromatin-associated proteins, of which the high mobility group (HMG) proteins are the most abundant. Although it is known that HMG proteins induce structural changes of chromatin, the processes underlying transcription regulation by HMG proteins are poorly understood. Here we decipher the molecular mechanism of transcription regulation mediated by the HMG AT-hook 2 protein (HMGA2). We combined proteomic, ChIP-seq, and transcriptome data to show that HMGA2-induced transcription requires phosphorylation of the histone variant H2AX at S139 (H2AXS139ph; gamma-H2AX) mediated by the protein kinase ataxia telangiectasia mutated (ATM). Furthermore, we demonstrate the biological relevance of this mechanism within the context of TGFbeta1 signaling. The interplay between HMGA2, ATM, and H2AX is a novel mechanism of transcription initiation. Our results link H2AXS139ph to transcription, assigning a new function for this DNA damage marker. Controlled chromatin opening during transcription may involve intermediates with DNA breaks that may require mechanisms that ensure the integrity of the genome. PMID- 26045164 TI - Functional annotation of cis-regulatory elements in human cells by dCas9/sgRNA. PMID- 26045163 TI - Metabolic reprogramming in macrophages and dendritic cells in innate immunity. AB - Activation of macrophages and dendritic cells (DCs) by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS), similar to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) plays an important role under conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid (TCA) cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-1alpha and promotes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity. PMID- 26045166 TI - KIAA1324 Suppresses Gastric Cancer Progression by Inhibiting the Oncoprotein GRP78. AB - Recent advances in genome and transcriptome analysis have contributed to the identification of many potential cancer-related genes. Furthermore, biological and clinical investigations of the candidate genes provide us with a better understanding of carcinogenesis and development of cancer treatment. Here, we report a novel role of KIAA1324 as a tumor suppressor in gastric cancer. We observed that KIAA1324 was downregulated in most gastric cancers from transcriptome sequencing data and found that histone deacetylase was involved in the suppression of KIAA1324. Low KIAA1324 levels were associated with poor prognosis in gastric cancer patients. In the xenograft model, KIAA1324 significantly reduced tumor formation of gastric cancer cells and decreased development of preformed tumors. KIAA1324 also suppressed proliferation, invasion, and drug resistance and induced apoptosis in gastric cancer cells. Through protein interaction analysis, we identified GRP78 (glucose-regulated protein 78 kDa) as a KIAA1324-binding partner. KIAA1324 blocked oncogenic activities of GRP78 by inhibiting GRP78-caspase-7 interaction and suppressing GRP78-mediated AKT activation, thereby inducing apoptosis. In conclusion, our study reveals a tumor suppressive role of KIAA1324 via inhibition of GRP78 oncoprotein activities and provides new insight into the diagnosis and treatment of gastric cancer. PMID- 26045165 TI - Angiomotin binding-induced activation of Merlin/NF2 in the Hippo pathway. AB - The tumor suppressor Merlin/NF2 functions upstream of the core Hippo pathway kinases Lats1/2 and Mst1/2, as well as the nuclear E3 ubiquitin ligase CRL4(DCAF1). Numerous mutations of Merlin have been identified in Neurofibromatosis type 2 and other cancer patients. Despite more than two decades of research, the upstream regulator of Merlin in the Hippo pathway remains unknown. Here we show by high-resolution crystal structures that the Lats1/2 binding site on the Merlin FERM domain is physically blocked by Merlin's auto inhibitory tail. Angiomotin binding releases the auto-inhibition and promotes Merlin's binding to Lats1/2. Phosphorylation of Ser518 outside the Merlin's auto inhibitory tail does not obviously alter Merlin's conformation, but instead prevents angiomotin from binding and thus inhibits Hippo pathway kinase activation. Cancer-causing mutations clustered in the angiomotin-binding domain impair angiomotin-mediated Merlin activation. Our findings reveal that angiomotin and Merlin respectively interface cortical actin filaments and core kinases in Hippo signaling, and allow construction of a complete Hippo signaling pathway. PMID- 26045168 TI - Impact of feeding tube choice on severe late dysphagia after definitive chemoradiotherapy for human papillomavirus-negative head and neck cancer. AB - BACKGROUND: Severe late dysphagia is common after chemoradiotherapy for cancers of the larynx and oropharynx. Options for reduction of severe late dysphagia are limited for human papillomavirus (HPV)-negative patients. In this study, the role of feeding tube choice in severe late dysphagia is investigated. METHODS: Patients disease-free after chemoradiotherapy for HPV-negative cancers of the laryngopharynx who received a feeding tube on-treatment were identified. The incidence of severe late dysphagia after reactive nasogastric (R-NG), proactive or reactive percutaneous gastrostomy (P-PEG or R-PEG) was assessed using log-rank and Cox analyses. RESULTS: Seventy-eight patients received a feeding tube on treatment and remained disease-free. Median follow-up was 64 months. The 5-year incidence of severe late dysphagia was 30.8% in the R-NG cohort (n = 36), 56.4% in the R-PEG (n = 17; p = .193), and 60.9% in the P-PEG (n = 25; p = .016) cohorts. On multivariate analysis, percutaneous gastrostomy (PEG) feeding was independently associated with an increased rate of severe late dysphagia. CONCLUSION: R-NG use during chemoradiotherapy is associated with less severe late dysphagia and is preferred over PEG. (c) 2015 Wiley Periodicals, Inc. Head Neck 38: E1054-E1060, 2016. PMID- 26045167 TI - IDH1 Mutation Induces Reprogramming of Pyruvate Metabolism. AB - Mutant isocitrate dehydrogenase 1 (IDH1) catalyzes the production of 2 hydroxyglutarate but also elicits additional metabolic changes. Levels of both glutamate and pyruvate dehydrogenase (PDH) activity have been shown to be affected in U87 glioblastoma cells or normal human astrocyte (NHA) cells expressing mutant IDH1, as compared with cells expressing wild-type IDH1. In this study, we show how these phenomena are linked through the effects of IDH1 mutation, which also reprograms pyruvate metabolism. Reduced PDH activity in U87 glioblastoma and NHA IDH1 mutant cells was associated with relative increases in PDH inhibitory phosphorylation, expression of pyruvate dehydrogenase kinase-3, and levels of hypoxia inducible factor-1alpha. PDH activity was monitored in these cells by hyperpolarized (13)C-magnetic resonance spectroscopy ((13)C-MRS), which revealed a reduction in metabolism of hyperpolarized 2-(13)C-pyruvate to 5 (13)C-glutamate, relative to cells expressing wild-type IDH1. (13)C-MRS also revealed a reduction in glucose flux to glutamate in IDH1 mutant cells. Notably, pharmacological activation of PDH by cell exposure to dichloroacetate (DCA) increased production of hyperpolarized 5-(13)C-glutamate in IDH1 mutant cells. Furthermore, DCA treatment also abrogated the clonogenic advantage conferred by IDH1 mutation. Using patient-derived mutant IDH1 neurosphere models, we showed that PDH activity was essential for cell proliferation. Taken together, our results established that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism, which is essential for cell proliferation and clonogenicity, with immediate therapeutic implications. PMID- 26045169 TI - New localities of Dermacentor reticulatus ticks in the Baltic countries. AB - According to previous observations in three Baltic States, Dermacentor reticulatus was found only in Lithuania where it occurred mainly in the central and western parts of the country. During the past decade, evidence about a changing distribution of D. reticulatus in the Baltic countries was provided by the occurrence of canine babesiosis in the new locations in Lithuania and Latvia. In the present study the current distribution of D. reticulatus in Lithuania and Latvia was investigated. Ticks were collected in different habitats in 2013-2014. A total of 3693 questing ticks belonging to D. reticulatus (n = 2789), Ixodes ricinus (n = 896) and I. persulcatus (n=8) were collected in Lithuania and Latvia. Questing D. reticulatus ticks were found in 73.4% (58/79) and in 44.4% (12/28) of the sampling localities in Lithuania and Latvia, respectively. Relative abundances of the ticks in different habitats were compared. All sites with high abundance of D. reticulatus ticks were localized in open areas close to a water basin and mixed forest. The present study demonstrates that during the past two decades D. reticulatus has expanded its range in the Baltic countries. D. reticulatus has been detected in 38 new localities in which this species had not been previously reported. The northern border of D. reticulatus in central Europe moved further to the north. New localities (n = 12) with D. reticulatus occurrence have been found in southern Latvia. PMID- 26045170 TI - Caffeine ingestion enhances perceptual responses during intermittent exercise in female team-game players. AB - We examined the influence of caffeine supplementation on cognitive performance and perceptual responses in female team-game players taking low-dose monophasic oral contraceptives of the same hormonal composition. Ten females (24 +/- 4 years; 59.7 +/- 3.5 kg body mass; 2-6 training sessions per week) took part in a randomised, double-blind, placebo-controlled crossover-design trial. A 90-min intermittent treadmill-running protocol was completed 60 min following ingestion of a capsule containing either 6 mg * kg(-1) anhydrous caffeine or artificial sweetener (placebo). Perceptual responses (ratings of perceived exertion (RPE), feeling scale (FS), felt arousal scale (FAS)), mood (profile of mood states (POMS)) and cognitive performance (Stroop test, choice reaction time (CRT)) were completed before, during and after the exercise protocol, as well as after ~12 h post exercise. Caffeine ingestion significantly enhanced the ratings of pleasure (P = 0.008) and arousal (P = 0.002) during the exercise protocol, as well as increased vigour (POMS; P = 0.007), while there was a tendency for reduced fatigue (POMS; P = 0.068). Caffeine ingestion showed a tendency to decrease RPE (P = 0.068) and improve reaction times in the Stroop (P = 0.072) and CRT (P = 0.087) tests. Caffeine supplementation showed a positive effect on perceptual parameters by increasing vigour and a tendency to decrease fatigue during intermittent running activity in female games players taking low-dose monophasic oral contraceptive steroids (OCS). PMID- 26045171 TI - Functional variant in methionine synthase reductase intron-1 is associated with pleiotropic congenital malformations. AB - Congenital malformations, such as neural tube defects (NTDs) and congenital heart disease (CHD), cause significant fetal mortality and childhood morbidity. NTDs are a common congenital anomaly, and are typically induced by higher maternal homocysteine (Hcy) levels and abnormal folate metabolism. The gene encoding methionine synthase reductase (MTRR) is essential for adequate remethylation of Hcy. Previous studies have focused on the coding region of genes involved in one carbon metabolism, but recent research demonstrates that an allelic change in a non-coding region of MTRR (rs326119) increases the risk of CHD. We hypothesized that this variant might contribute to the etiology of NTDs as well, based on a common role during early embryogenesis. In the present study, 244 neural tube defect cases and 407 controls from northern China were analyzed to determine any association (by chi (2) test) between rs326119 and disease phenotypes. Significant increased risk of anencephaly was seen in MTRR variant rs326119 heterozygote (het) and homozygote (hom) individuals [odds ratios (OR)het = 1.81; ORhom = 2.05)]. Furthermore, this variant was also a risk factor for congenital malformations of the adrenal gland (OR = 1.85), likely due to multiple systemic malformations in the NTDs case population. Our present data indicate that the rs326119 non-coding variant of MTRR has a pleiotropic effect on the development of multiple tissues, especially during early stages in utero. This suggests the allelic state of MTRR is a significant clinical factor affecting Hcy levels and optimal folic supplementation. PMID- 26045172 TI - ATF6 pathway of unfolded protein response mediates advanced oxidation protein product-induced hypertrophy and epithelial-to-mesenchymal transition in HK-2 cells. AB - Advanced oxidation protein products (AOPPs) accelerate the progression of chronic kidney disease. We previously demonstrated that AOPPs induce hypertrophy and epithelial-to-mesenchymal transition (EMT) in human proximal tubular cells (HK-2 cells) through induction of endoplasmic reticulum (ER) stress. However, which pathway of unfolded protein response (UPR) induced by ER stress plays crucial roles in this process remains unclear. In this study, we investigated the roles of the protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways of UPR in this process in HK-2 cells. AOPP treatment induced the overexpression of cleaved ATF6 and spliced form of X-box binding protein-1, and induced the phosphorylation of PERK, eukaryotic translation initiation factor 2alpha and IRE1. Furthermore, silencing of ATF6 increased E-cadherin and zonula occludens-1 expression, lowered the expression of vimentin, and downregulated total protein content, whereas knockdown of PERK or IRE1 resulted in no difference compared with the scramble siRNA-transfected cells. AOPP-induced phosphorylation of Src, which was reproduced by thapsigargin, an inducer of ER stress, was partly reversed by salubrinal, an inhibitor of ER stress. Furthermore, the Src inhibitor saracatinib effectively blocked AOPP-induced phosphorylation of Src, activation of ER stress, hypertrophy, and EMT in HK-2 cells. Collectively, our results indicate that AOPPs induce the PERK, ATF6, and IRE1 pathways of UPR, and the ATF6 pathway rather than the other two pathways mediates AOPP-induced HK-2-cell hypertrophy and EMT. We also suggest that the ER stress involved in this process is likely mediated by the activation of Src kinase. PMID- 26045173 TI - Expressions of Sox9, Sox5, and Sox13 transcription factors in mice testis during postnatal development. AB - SRY-related box (Sox) transcription factors are conserved among vertebrate species. These proteins regulate multiple processes including sex determination and testis differentiation of the male embryo. Although members of the Sox family have been identified in pre- and postnatal Sertoli cells, they have never been characterized in adult Leydig cells. The objectives of this research were to identify expressions of Sox9, Sox5, and Sox13 in mice Leydig cell cultures and to establish their expression profiles in postnatal mice testes at different developmental stages. Methods used include Western blots and qPCR of stimulated MA-10 cell cultures and whole mice testes. Sox9, Sox5, and Sox13 proteins were detected in MA-10 cells as well as whole mouse testis. Although Sox9, Sox5, and Sox13 mRNA levels from whole mice testes tended to increase according to postnatal development, these results were not significant. Sox members were also detected in whole mice testis by Western Blot. However, Sox9, Sox5, and Sox13 protein expressions remained relatively constant during postnatal development from postnatal (P) day 60 to P365. Being newly characterized in the mouse testis, Sox13 was mainly localized by immunofluorescence within the nuclei of cells from seminiferous tubules, possibly spermatocytes and Sertoli cells. In addition, Sox9, Sox5, and Sox13 proteins were characterized in the nuclei of MA-10 Leydig cell cultures. Their expressions and transcriptional activities remained unaffected by activators of the cAMP/PKA pathway. Thus, Sox9, Sox5, and Sox13 transcription factors are expressed in postnatal testis and may regulate multiple functions such as steroidogenesis and spermatogenesis. PMID- 26045174 TI - Estrogen deprivation does not affect vascular heat shock response in female rats: a comparison with oxidative stress markers. AB - Hot flashes, which involve a tiny rise in core temperature, are the most common complaint of peri- and post-menopausal women, being tightly related to decrease in estrogen levels. On the other hand, estradiol (E2) induces the expression of HSP72, a member of the 70 kDa family of heat shock proteins (HSP70), which are cytoprotective, cardioprotective, and heat inducible. Since HSP70 expression is compromised in age-related inflammatory diseases, we argued whether the capacity of triggering a robust heat shock (HS) response would be still present after E2 withdrawal. Hence, we studied the effects of HS treatment (hot tub) in female Wistar rats subjected to bilateral ovariectomy (OVX) after a 7-day washout period. Twelve h after HS, the animals were killed and aortic arches were surgically excised for molecular analyses. The results were compared with oxidative stress markers in the plasma (superoxide dismutase, catalase, and lipoperoxidation) because HSP70 expression is also sensitive to redox regulation. Extracellular (plasma) to intracellular HSP70 ratio, an index of systemic inflammatory status, was also investigated. The results showed that HS response was preserved in OVX animals, as inferred from HSP70 expression (up to 40% rise, p < 0.01) in the aortas, which was accompanied by no further alterations in oxidative stress, hematological parameters, and glycemic control either. This suggests that the lack of estrogen per se could not be solely ascribed as the unique source of low HSP70 expression as observed in long-term post-menopausal individuals. As a consequence, periodic evaluation of HSP70 status (iHSP70 vs. eHSP70) may be of clinical relevance because decreased HS response capacity is at the center of the onset of menopause-related dysfunctions. PMID- 26045175 TI - Regulation of GAP43/calmodulin complex formation via calcineurin-dependent mechanism in differentiated PC12 cells with altered PMCA isoforms composition. AB - Several lines of evidence suggest the contribution of age-related decline in plasma membrane calcium pump (PMCA) to the onset of neurodegenerative diseases. From four PMCA isoforms, PMCA2, and PMCA3 respond to a rapid removal of Ca(2+) and are expressed predominantly in excitable cells. We have previously shown that suppression of neuron-specific PMCAs in differentiated PC12 cells accelerated cell differentiation, but increased apoptosis in PMCA2-deficient line. We also demonstrated that altered expression of voltage-dependent calcium channels correlated with their higher contribution to Ca(2+) influx, which varied between PMCA-reduced lines. Here, we propose a mechanism unique for differentiated PC12 cells by which PMCA2 and PMCA3 regulate pGAP43/GAP43 ratio and the interaction between GAP43 and calmodulin (CaM). Although down-regulation of PMCA2 or PMCA3 altered the content of GAP43/pGAP43, of paramount importance for the regulatory mechanism is a disruption of isoform-specific inhibitory PMCA/calcineurin interaction. In result, higher endogenous calcineurin (CaN) activity leads to hypophosphorylation of GAP43 in PMCA2- or PMCA3-deficient lines and intensification of GAP43/CaM complex formation, thus potentially limiting the availability of free CaM. In overall, our results indicate that both "fast" PMCA isoforms could actively regulate the local CaN function and CaN-downstream processes. In connection with our previous observations, we also suggest a negative feedback of cooperative action of CaM, GAP43, and CaN on P/Q and L-type channels activity. PMCAs- and CaN-dependent mechanism presented here, may signify a protective action against calcium overload in neuronal cells during aging, as well a potential way for decreasing neuronal cells vulnerability to neurodegenerative insults. PMID- 26045176 TI - Distinctive pro-inflammatory gene signatures induced in articular chondrocytes by oncostatin M and IL-6 are regulated by Suppressor of Cytokine Signaling-3. AB - OBJECTIVE: To describe gene expression in murine chondrocytes stimulated with IL 6 family cytokines and the impact of deleting Suppressor of Cytokine Signaling-3 (SOCS-3) in this cell type. METHOD: Primary chondrocytes were isolated from wild type and SOCS-3-deficient (Socs3(Delta/Deltacol2)) mice and stimulated with oncostatin M (OSM), IL-6 plus the soluble IL-6 receptor (IL-6/sIL-6R), IL-11 or leukemia inhibitory factor (LIF) for 4 h. Total RNA was extracted and gene expression was evaluated by microarray analysis. Validation of the microarray results was performed using Taqman probes on RNA derived from chondrocytes stimulated for 1, 2, 4 or 8 h. Gene ontology was characterized using DAVID (database for annotation, visualization and integrated discovery). RESULTS: Multiple genes, including Bcl3, Junb, Tgm1, Angptl4 and Lrg1, were upregulated in chondrocytes stimulated with each gp130 cytokine. The gene transcription profile in response to OSM stimulation was pro-inflammatory and was highly correlated to IL-6/sIL-6R, rather than IL-11 or LIF. In the absence of SOCS-3, OSM and IL-6/sIL 6R stimulation induced an interferon (IFN)-like gene signature, including expression of IL-31ra and S100a9. CONCLUSION: While each gp130 cytokine induced a transcriptional response in chondrocytes, OSM- and IL-6/sIL-6R were the most potent members of this cytokine family. SOCS-3 plays an important regulatory role in this cell type, as it does in hematopoietic cells. Our results provide new insights into a hierarchy of gp130-induced transcriptional responses in chondrocytes that is normally restrained by SOCS-3 and suggest therapeutic inhibition of OSM may have benefit over and above antagonism of IL-6 during inflammatory arthritis. PMID- 26045177 TI - Potential for improved survival with intensification of daunorubicin based induction chemotherapy in acute myeloid leukemia patients who do not receive transplant: A multicenter retrospective study. AB - INTRODUCTION: During induction daunorubicin intensification from 45 mg/m(2)/day to 90 mg/m(2)/day has shown improved response and survival rates in AML patients. We retrospectively reviewed outcomes of daunorubicin 60 mg/m(2)/day (DNR60) versus daunorubicin 90 mg/m(2)/day (DNR90) in adult AML patients. MATERIAL AND METHODS: Newly diagnosed AML patients >=18 years who received 7+3 with or without etoposide as frontline therapy from 1/1/2006 to 5/1/2013 were identified. Chi square and Wilcoxon rank sum tests were used to compare characteristics. Kaplan Meier curves were estimated for overall survival (OS). Univariate and multivariate Cox proportional hazard regression models were developed to determine independent predictors for survival. RESULTS: A total of 128 patients were included (DNR90=48 patients, DNR60=80 patients). The estimated 3-year OS rate in the DNR90 group was 56% (95% CI 38-70%), while in the DNR60 group was 34% (95% CI 23-44%). Multivariate analysis (MVA) in non-allotransplanted patients showed that unfavorable cytogenetics and worse performance status were associated with decreased OS while DNR intensification, etoposide use and site were associated with improved OS. In MVA of allotransplanted patients re-induction based on day-14 marrow was associated with worse OS. CONCLUSIONS: Based on our retrospective study, initial DNR based induction chemotherapy intensification improved OS in non-allotransplanted patients. Prospective studies are needed to confirm this preliminary finding. PMID- 26045178 TI - Interpretation of personal genome sequencing data in terms of disease ranks based on mutual information. AB - BACKGROUND: The rapid advances in genome sequencing technologies have resulted in an unprecedented number of genome variations being discovered in humans. However, there has been very limited coverage of interpretation of the personal genome sequencing data in terms of diseases. METHODS: In this paper we present the first computational analysis scheme for interpreting personal genome data by simultaneously considering the functional impact of damaging variants and curated disease-gene association data. This method is based on mutual information as a measure of the relative closeness between the personal genome and diseases. We hypothesize that a higher mutual information score implies that the personal genome is more susceptible to a particular disease than other diseases. RESULTS: The method was applied to the sequencing data of 50 acute myeloid leukemia (AML) patients in The Cancer Genome Atlas. The utility of associations between a disease and the personal genome was explored using data of healthy (control) people obtained from the 1000 Genomes Project. The ranks of the disease terms in the AML patient group were compared with those in the healthy control group using "Leukemia, Myeloid, Acute" (C04.557.337.539.550) as the corresponding MeSH disease term. CONCLUSIONS: Overall, the area under the receiver operating characteristics curve was significantly larger for the AML patient data than for the healthy controls. This methodology could contribute to consequential discoveries and explanations for mining personal genome sequencing data in terms of diseases, and have versatility with respect to genomic-based knowledge such as drug-gene and environmental-factor-gene interactions. PMID- 26045179 TI - Functional characterization of the PCLO p.Ser4814Ala variant associated with major depressive disorder reveals cellular but not behavioral differences. AB - Genome-wide association studies have suggested a role for a genetic variation in the presynaptic gene PCLO in major depressive disorder (MDD). As with many complex traits, the PCLO variant has a small contribution to the overall heritability and the association does not always replicate. One variant (rs2522833, p.Ser4814Ala) is of particular interest given that it is a common, nonsynonymous exon variant near a calcium-sensing part of PCLO. It has been suggested that the molecular effects of such variations penetrate to a variable extent in the population due to phenotypic and genotypic heterogeneity at the population level. More robust effects may be exposed by studying such variations in isolation, in a more homogeneous context. We tested this idea by modeling PCLO variation in a mouse knock-in model expressing the Pclo(SA)(/)(SA) variant. In the highly homogeneous background of inbred mice, two functional effects of the SA-variation were observed at the cellular level: increased synaptic Piccolo levels, and 30% increased excitatory synaptic transmission in cultured neurons. Other aspects of Piccolo function were unaltered: calcium-dependent phospholipid binding, synapse formation in vitro, and synaptic accumulation of synaptic vesicles. Moreover, anxiety, cognition and depressive-like behavior were normal in Pclo(SA)(/)(SA) mice. We conclude that the PCLO p.Ser4814Ala missense variant produces mild cellular phenotypes, which do not translate into behavioral phenotypes. We propose a model explaining how (subtle) cellular phenotypes do not penetrate to the mouse behavioral level but, due to genetic and phenotypic heterogeneity and non-linearity, can produce association signals in human population studies. PMID- 26045181 TI - Effects of Slit3 silencing on the invasive ability of lung carcinoma A549 cells. AB - Slit proteins function as chemorepellents in axon guidance and neuronal migration by binding to cognate Robo receptors. The Slit/Robo signaling pathway is also involved in the regulation of tumor cell metastasis. However, whether the Slit/Robo signaling pathway exerts prometastatic or antimetastasis functions remains controversial. To date, most of the research on Slit/Robo has focused on Slit2, and the effects of Slit3 on metastasis remain largely unknown. Based on the Oncomine database, overall expression of Slit3 is low in tumor tissues compared to its level in normal tissues. The underlying mechanism for slit3 silencing in tumor tissues is likely related to hypermethylation of the slit3 promoter. However, lung carcinomas appear to be an exception. Several studies have reported that the frequency of Slit3 methylation in lung cancers is far lower than the frequency of Slit2. In the present study, high Slit3 expression at the mRNA level, yet not at the protein level, was detected in lung adenocarcinoma A549 cells. The function of Slit3 in tumor migration and invasion was examined by silencing of Slit3 expression in A549 cells. Silencing of Slit3 promoted proliferation, migration and invasion of A549 cells and induced epithelial mesenchymal transition by downregulation of E-cadherin and upregulation of vimentin. The inhibitory effects of Slit3 on tumor migration and invasion are likely related to matrix metalloproteinases (MMPs). Silencing of Slit3 in the A549 cells enhanced MMP2 and MMP9 expression. These results indicate that Slit3 is a potential tumor suppressor in lung adenocarcinoma. PMID- 26045180 TI - Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: positive clue toward SAD. AB - Among vertebrates hippocampus forms the major component of the brain in consolidating information from short-term memory to long-term memory. Aging is considered as the major risk factor for memory impairment in sporadic Alzheimer's disease (SAD) like pathology. Present study thus aims at investigating whether age-specific degeneration of neuronal-circuits in hippocampal formation (neural layout of Subiculum-hippocampus proper-dentate gyrus (DG)-entorhinal cortex (EC)) results in cognitive impairment. Furthermore, the neuroprotective effect of Resveratrol (RSV) was attempted to study in the formation of hippocampal neuronal circuits. Radial-Arm-Maze was conducted to evaluate hippocampal-dependent spatial and learning memory in control and experimental rats. Nissl staining of frontal cortex (FC), subiculum, hippocampal-proper (CA1->CA2->CA3->CA4), DG, amygdala, cerebellum, thalamus, hypothalamus, layers of temporal and parietal lobe of the neocortex were examined for pathological changes in young and aged wistar rats, with and without RSV. Hippocampal trisynaptic circuit (EC layerII->DG->CA3->CA1) forming new memory and monosynaptic circuit (EC->CA1) that strengthen old memories were found disturbed in aged rats. Loss of Granular neuron observed in DG and polymorphic cells of CA4 can lead to decreased mossy fibers disturbing neural-transmission (CA4->CA3) in perforant pathway. Further, intensity of nissl granules (stratum lacunosum moleculare (SLM)-SR-SO) of CA3 pyramidal neurons was decreased, disturbing the communication in schaffer collaterals (CA3-CA1) during aging. We also noticed disarranged neuronal cell layer in Subiculum (presubiculum (PrS)-parasubiculum (PaS)), interfering output from hippocampus to prefrontal cortex (PFC), EC, hypothalamus, and amygdala that may result in interruption of thought processes. We conclude from our observations that poor memory performance of aged rats as evidenced through radial arm maze (RAM) analysis was due to the defect in neuronal-circuits of hippocampus (DG-CA4-CA1-Sub) that were significantly damaged leading to memory impairment. Interestingly, RSV was observed to culminate pathological events in the hippocampal neuronal circuit during aging, proving them as potent therapeutic drug against age-associated neurodegeneration and memory loss. PMID- 26045182 TI - Protective effects of allicin against ischemic stroke in a rat model of middle cerebral artery occlusion. AB - Allicin, a molecule predominantly responsible for the pungent odor and the antibiotic function of garlic, exhibits various pharmacological activities and has been suggested to be beneficial in the treatment of various disorders. The present study aimed to elucidate the effect of allicin in cerebral ischemia/reperfusion (I/R) injury in rats. Rats were subjected to 1.5 h of transient middle cerebral artery occlusion (MCAO), followed by 24 h of reperfusion. Rats were randomly assigned to the sham surgery group, the MCAO group and the MCAO + allicin group. Neurological score, cerebral infarct size, brain water content, neuronal apoptosis, serum tumor necrosis factor (TNF)-alpha and myeloperoxidase (MPO) activity were measured. The results suggested that allicin reduced cerebral infarction area, brain water content, neuronal apoptosis, TNF-alpha levels and MPO activity in the serum. The results of the present study indicated that allicin protects the brain from cerebral I/R injury, which may be ascribed to its anti-apoptotic and anti-inflammatory effects. PMID- 26045183 TI - Hong Kong domestic health spending: financial years 1989/90 to 2011/12. AB - This report presents the latest estimates of Hong Kong domestic health spending for financial years 1989/90 to 2011/12, cross-stratified and categorized by financing source, provider, and function. Total expenditure on health (TEH) was HK$101 985 million in financial year 2011/12, which represents an increase of HK$8580 million or 9.2% over the preceding year. TEH grew faster relative to gross domestic product (GDP) leading to a rise in TEH as a percentage of GDP from 5.1% in 2010/11 to 5.2% in 2011/12. During the period 1989/90 to 2011/12, total health spending per capita (at constant 2012 prices) grew at an average annual rate of 4.8%, which was faster than the average annual growth rate of per capita GDP by 1.8 percentage points. In 2011/12, public and private expenditure on health increased by 8.3% and 10.0% when compared with 2010/11, reaching HK$49,262 million and HK$52,723 million respectively. Consequently, public share of total health expenditure dropped slightly from 48.7% to 48.3% over the year. Of private spending, the most important source of health financing was out-of-pocket payments by households (34.9% of TEH), followed by employer-provided group medical benefits (7.5%) and private insurance (7.4%). It is worth noting that private insurance will likely take over employers as the second largest private payer if the insurance market continues to expand at the current rate. Of the HK$101,985 million total health expenditure in 2011/12, current expenditure comprised HK$96,572 million (94.7%), whereas HK$5413 million (5.3%) was for capital expenses (ie investment in medical facilities). Analysed by health care function, services of curative care accounted for the largest share of total health spending (65.2%), which was made up of ambulatory services (33.6%), in patient curative care (26.9%), day patient hospital services (4.1%), and home care (0.5%). Notwithstanding its small share, the total spending for day patient hospital services shows an increasing trend over the period 1989/90 to 2011/12, likely as a result of policy directives to shift the emphasis from in-patient to day patient care. Hospitals accounted for an increasing share of total spending, from 28.2% in 1989/90 to 46.8% in 2002/03 and then dropped slightly to 42% to 44% during the period 2005/06 to 2011/12, which was primarily driven by reduced expenditure of Hospital Authority. As a result of the epidemics which are of public health importance (eg avian flu, SARS, swine flu) and the expansion of private health insurance market in the last two decades, spending on provision and administration of public health programmes, and general health administration and insurance accounted for increasing, though less significant, shares of total health spending over the period. Without taking into account capital expenses (ie investment in medical facilities), public current expenditure on health amounted to HK$45,321 million (46.9% of total current expenditure) in 2011/12 with the remaining HK$51,251 million made up of private sources of funds. Public current expenditure was mostly incurred at hospitals (74.1%), whereas private current expenditure was mostly incurred at providers of ambulatory health care (51.2%). Although both public and private spending were mostly expended on personal health care services and goods (91.1% of total current spending), the distributional patterns among functional categories differed. Public expenditure was targeted at in-patient care (47.3%) and substantially less on out-patient care (27.4%). In comparison, private spending was mostly concentrated on out-patient care (42.7%), whereas in-patient care (24.7%) and medical goods outside the patient care setting (19.9%) comprised the majority of the remaining share. Compared to the Organisation for Economic Co-operation and Development countries, Hong Kong has devoted a relatively low percentage of GDP to health care in the last decade. As a share of total spending, public funding (either general government revenue or social security funds) was also lower than those in most economies with comparable economic development and public revenue collection base. Nonetheless, Hong Kong health care system achieved service quality and health outcome that fared well by global standards, indicating cost efficiency and effectiveness. PMID- 26045185 TI - Ventriculoperitoneal Shunt Tip as a Rare Cause for Recurrent Pain Episodes in a Child: Think Irritable Peritoneum. AB - Ventriculoperitoneal (VP) shunting is an established treatment to regulate the drainage of cerebrospinal fluid (CSF) in posthaemorrhagic hydrocephalus. Several complications (e.g. blockage of CSF shunting, overdrainage, but also catheter related perforation of abdominal organs, etc.) may occur and may lead to painful episodes, mostly headache, in these children. Here, we report on a 7-year-old child with recurrent painful episodes after revision of a VP shunt that subsided only after repositioning of the abdominal tip of the VP shunt. Visceral irritation by a malpositioned VP shunt should be considered as a cause for recurrent pain in non-verbal children without other relevant clinical findings. PMID- 26045184 TI - Pharmacological Chaperones and Coenzyme Q10 Treatment Improves Mutant beta Glucocerebrosidase Activity and Mitochondrial Function in Neuronopathic Forms of Gaucher Disease. AB - Gaucher disease (GD) is caused by mutations in the GBA1 gene, which encodes lysosomal beta-glucocerebrosidase. Homozygosity for the L444P mutation in GBA1 is associated with high risk of neurological manifestations which are not improved by enzyme replacement therapy. Alternatively, pharmacological chaperones (PCs) capable of restoring the correct folding and trafficking of the mutant enzyme represent promising alternative therapies.Here, we report on how the L444P mutation affects mitochondrial function in primary fibroblast derived from GD patients. Mitochondrial dysfunction was associated with reduced mitochondrial membrane potential, increased reactive oxygen species (ROS), mitophagy activation and impaired autophagic flux.Both abnormalities, mitochondrial dysfunction and deficient beta-glucocerebrosidase activity, were partially restored by supplementation with coenzyme Q10 (CoQ) or a L-idonojirimycin derivative, N-[N' (4-adamantan-1-ylcarboxamidobutyl)thiocarbamoyl]-1,6-anhydro-L-idonojirimycin (NAdBT-AIJ), and more markedly by the combination of both treatments. These data suggest that targeting both mitochondria function by CoQ and protein misfolding by PCs can be promising therapies in neurological forms of GD. PMID- 26045186 TI - Using antidepressants and the risk of stroke recurrence: report from a national representative cohort study. AB - BACKGROUND: Evidence about the association between antidepressants and the risk of stroke recurrence was scanty. This study evaluated the risk of stroke recurrence according to using antidepressants in patients with stroke from a national representative cohort. METHODS: This cohort study followed 16770 patients aged > =20 years who had an incident stroke from 2000 to 2009 from the National Health Insurance Research Database in Taiwan. Records of each antidepressant prescription were obtained during follow-up. The types of antidepressants were categorized by Anatomical Therapeutic Chemical classification system: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and other antidepressants. The main outcome was a recurrent stroke during the follow-up period. The time-dependent Cox proportional hazards model was used in the analyses. RESULTS: During 63715 person-years of follow-up, we documented 3769 events for stroke recurrence. Antidepressants use was associated with an increased risk of stroke recurrence (adjusted hazard ratio [HR], 1.42; 95 % confidence interval [C.I.], 1.24-1.62), especially for ischemic stroke (HR, 1.48; 95 % C.I., 1.28-1.70), but not for hemorrhagic stroke (HR, 1.22; 95 % C.I., 0.86 1.73). The increased risk of stoke recurrence was found for TCAs use only (HR, 1.41; 95 % C.I., 1.14-1.74), SSRIs use only (HR, 1.31; 95 % C.I.,1.00-1.73),use of other types of antidepressants only(HR, 1.46; 95 % C.I.,1.15-1.84), or use of multiple types of antidepressants (HR, 1.84; 95 % C.I.,1.04-3.25). CONCLUSIONS: We demonstrated that use of antidepressants was associated with an increased risk of stroke recurrence, especially in ischemic stroke among Taiwanese. Further studies are warranted to confirm the possible underlying mechanisms of these findings. PMID- 26045187 TI - Inhibition of Glutathione S-Transferase by Ethacrynic Acid Augments Ischemia Reperfusion Damage and Apoptosis and Attenuates the Positive Effect of Ischemic Postconditioning in a Bilateral Acute Hindlimb Ischemia Rat Model. AB - AIMS: We studied the effects of the inhibition of the endogene antioxidant glutathione-S-transferase (GST) by ethacrynic acid (EA) on ischemia-reperfusion (IR) injury and postconditioning (PC) in the lower extremities. We aimed to examine the oxidative stress parameters (OSP), inflammatory response and activation of proapoptotic signaling proteins (PSP) after revascularization surgery. METHODS: Sixty Wistar rats were divided into 6 groups: control, IR, PC, EA-control, IR and administration of EA (IR/EA) and PC and administration of EA (PC/EA). The IR, PC, IR/EA and PC/EA groups underwent 60 min of infrarenal aortic cross-clamping. After that, PC was performed in the PC and PC/EA groups. In 3 of the groups, the animals were treated with EA (EA-control, IR/EA and PC/EA groups) as well. The ischemia was followed by 120 min of reperfusion. Blood samples and biopsy specimens were collected from the quadriceps muscle. Plasma malondialdehyde, reduced glutathione, thiol/sulfhydryl group levels, TNF-alpha and IL-6 concentrations and superoxide-dismutase enzyme activity were measured. RESULTS: The levels of the OSP and the inflammatory proteins were higher in the EA-administered groups. The ratio of phosphorylated PSP was higher in the EA administered groups and the protective effect of PC did not develop. CONCLUSIONS: Inhibition of GST by EA augmented the IR damage. GST inhibition was associated with a different activation of the mitogen-activated protein kinases and the PSP, regulating these pathways in the process of apoptosis and PC. PMID- 26045188 TI - Sparing of the hippocampus indicates better collateral blood flow in acute posterior cerebral artery occlusion. AB - BACKGROUND: In acute posterior cerebral artery, occlusion involvement of the hippocampus is a common finding. Nevertheless, until today, infarction and ischemic lesion evolution in the hippocampus has not been studied systematically. AIM: Evaluation of hippocampal infarction patterns in posterior cerebral artery occlusion in the very early phase (<=six-hours) and ischemic lesion evolution on follow-up magnetic resonance imaging in relation to collateral blood flow assessed by a magnetic resonance imaging-based approach was conducted. METHODS: In 28 patients [mean age 69.4 +/- 13.8 years, 19 (67.9%) males, 10 (32.1%) females] with proximal posterior cerebral artery occlusion, magnetic resonance imaging findings were analyzed, with emphasis on hippocampal infarction patterns on diffusion-weighted images and collateralization on dynamic 4D angiograms derived from perfusion-weighted raw images. RESULTS: On initial diffusion weighted images, we identified all known hippocampal infarction patterns: type 1 (complete) in 6/18 (33.3%) patients, type 2 (lateral) in 10/18 (55.6%) patients, and type 3 (dorsal) and type 4 (circumscribed) in 1/18 (5.6%) patient respectively. On dynamic 4D angiograms, the grade of collateralization was classified as 1 in 9 (32.1%), 2 in 1 (3.6%), 3 in 10 (35.7%), and 4 in 8 (28.6%) patients. On follow-up diffusion-weighted images, we found new ischemic lesions in three and infarction growth in the hippocampus in five patients. Patients with better collateralization (grades 3 and 4) less often had hippocampal infarctions on initial (P = 0.003)/follow-up diffusion-weighted images (P = 0.046) as well as type 1 on initial (P = 0.007)/follow-up diffusion-weighted images (P = 0.005). CONCLUSIONS: Involvement of the hippocampus in proximal posterior cerebral artery occlusion is frequently but not obligatorily observed and highly dependent on the extent of collateralization. The same holds true for hippocampal infarction patterns. PMID- 26045189 TI - How and why medically-trained managers undertake postgraduate management training - a qualitative study from Victoria, Australia. AB - PURPOSE: The purpose of this paper is to address the research question using qualitative research methods: how and why medically trained managers choose to undertake postgraduate management training? DESIGN/METHODOLOGY/APPROACH: This research used two qualitative methods to gather data. Both methods used purposeful sampling to select interviewees with appropriate management expertise, qualifications and experience. The first stage utilised convergent interviews and was exploratory. The five interviewees were managers and academics. The second stage used case research methodology and was confirmatory. The fifteen interviewees were medically qualified chief executives and chief medical officers. In total, 20 in-depth interviews were carried. Rigorous content analysis of data collected showed emergent themes. FINDINGS: The first theme that emerged was that doctors move into management positions without first undertaking training. The second theme was that doctors undertake such training in the form of a masters-level degree and/or a specialist fellowship. The third theme was that effective postgraduate management training for doctors requires a combination of theory and practice. The fourth theme was that clinical experience alone does not lead to required management competencies. The fifth theme was that doctors choose to undertake training to gain credibility. RESEARCH LIMITATIONS/IMPLICATIONS: This research was exploratory and descriptive in nature and limited to analytical rather than statistical generalisation. ORIGINALITY/VALUE: This research has provided insights into the importance of understanding how and why doctors undertake postgraduate management training, and may assist policy makers and training providers in the development of such training for doctors. PMID- 26045190 TI - Supporting and activating clinical governance development in Ireland: sharing our learning. AB - PURPOSE: The purpose of this paper is to present a description of the Irish national clinical governance development initiative and an evaluation of the initiative with the purpose of sharing the learning and proposing actions to activate structures and processes for quality and safety. The Quality and Patient Safety Division of the Health Service Executive established the initiative to counterbalance a possible focus on finances during the economic crisis in Ireland and bring attention to the quality of clinical care. DESIGN/METHODOLOGY/APPROACH: A clinical governance framework for quality in healthcare in Ireland was developed to clearly articulate the fundamentals of clinical governance. The project plan involved three overlapping phases. The first was designing resources for practice; the second testing the implementation of the national resources in practice; and the third phase focused on gathering feedback and learning. FINDINGS: Staff responded positively to the clinical governance framework. At a time when there are a lot of demands (measurement and scrutiny) the health services leads and responds well to focused support as they improve the quality and safety of services. Promoting the use of the term "governance for quality and safety" assisted in gaining an understanding of the more traditional term "clinical governance". The experience and outcome of the initiative informed the identification of 12 key learning points and a series of recommendations RESEARCH LIMITATIONS/IMPLICATIONS: The initial evaluation was conducted at 24 months so at this stage it is not possible to assess the broader impact of the clinical governance framework beyond the action project hospitals. PRACTICAL IMPLICATIONS: The single most important obligation for any health system is patient safety and improving the quality of care. The easily accessible, practical resources assisted project teams to lead changes in structures and processes within their services. This paper describes the fundamentals of the clinical governance framework which might serve as a guide for more integrative research endeavours on governance for quality and safety. ORIGINALITY/VALUE: Experience was gained in both the development of national guidance and their practical use in targeted action projects activating structures and processes that are a prerequisite to delivering safe quality services. PMID- 26045191 TI - Using clinical governance levers to support change in a cancer care reform. AB - PURPOSE: Introducing change is a difficult issue facing all health care systems. The use of various clinical governance levers can facilitate change in health care systems. The purpose of this paper is to define clinical governance levers, and to illustrate their use in a large-scale transformation. DESIGN/METHODOLOGY/APPROACH: The empirical analysis deals with the in-depth study of a specific case, which is the organizational model for Ontario's cancer sector. The authors used a qualitative research strategy and drew the data from three sources: semi-structured interviews, analysis of documents, and non participative observations. FINDINGS: From the results, the authors identified three phases and several steps in the reform of cancer services in this province. The authors conclude that a combination of clinical governance levers was used to transform the system. These levers operated at different levels of the system to meet the targeted objectives. PRACTICAL IMPLICATIONS: To exercise clinical governance, managers need to acquire new competencies. Mobilizing clinical governance levers requires in-depth understanding of the role and scope of clinical governance levers. ORIGINALITY/VALUE: This study provides a better understanding of clinical governance levers. Clinical governance levers are used to implement an organizational environment that is conducive to developing clinical practice, as well as to act directly on practices to improve quality of care. PMID- 26045192 TI - Women chairs in academic medicine: engendering strategic intuition. AB - PURPOSE: Because stereotypically masculine behaviors are required for effective leadership, examining female chairs' leadership in academic medicine can provide insight into the complex ways in which gender impacts on their leadership practices. The paper aims to discuss this issue. DESIGN/METHODOLOGY/APPROACH: The author interviewed three female clinical chairs and compared the findings to interviews with 28 of their faculty. Grounded theory analysis of the subsequent text gathered comprehensive, systematic, and in-depth information about this case of interest at a US top-tier academic medical center. FINDINGS: Four of five themes from the faculty were consistent with the chair's narrative with modifications: Prior Environment (Motivated by Excellence), Tough, Direct, Transparent (Developing Trust), Communal Actions (Creating Diversity of Opinion), and Building Power through Consensus (an "Artful Exercise") with an additional theme, the Significance (and Insignificance) of a Female Chair. While faculty members were acutely aware of the chair's gender, the chairs paradoxically vacillated between gender being a "non-issue" and noting that male chairs "don't do laundry." All three female chairs in this study independently and explicitly stated that gender was not a barrier, yet intuitively used successful strategies derived from the research literature. ORIGINALITY/VALUE: This study suggests that while their gender was highlighted by faculty, these women dismissed gender as a "non-issue." The duality of gender for these three female leaders was both minimized and subtly affirmed. PMID- 26045193 TI - Fiery Spirits in the context of institutional entrepreneurship in Swedish healthcare. AB - PURPOSE: Clinical governance and leadership concepts can lead to more or less successful implementations of new clinical practice. The purpose of this paper is to examine how Fiery Spirits, as institutional entrepreneurs can, working in a team, implement sustained change in hospital clinical practice. DESIGN/METHODOLOGY/APPROACH: This paper describes two case studies, conducted at two Swedish hospitals over a period of two years, in which changes in clinical practice were implemented. In both cases, key-actors, termed Fiery Spirits, played critical roles in these changes. The authors use a qualitative approach and take an intra-organizational perspective with semi-structured in-depth interviews and document analysis. FINDINGS: The new clinical practices were successfully implemented with a considerable influence of the Fiery Spirits who played a pivotal role in the change efforts. The Fiery Spirits persuasively, based on their structural and normative legitimacy and the adoption of learning processes, advocated, and supported change. PRACTICAL IMPLICATIONS: Fiery Spirits, given flexibility and opportunity, can be powerful forces for change outside the trajectory of management-inspired and management-directed change. Team members, when inspired and encouraged by Fiery Spirits, are less resistant to change and more willing to test new clinical practices. ORIGINALITY/VALUE: The paper complements literature on how the Fiery Spirit concept aligns with concepts of clinical governance and leadership and how change can be achieved. Additionally, the findings show the effects of legitimacy and learning processes on change in clinical practice. PMID- 26045194 TI - Swedish politicians' view of obstacles when dealing with priority settings in health care. AB - PURPOSE: The purpose of this paper is to identify and describe main obstacles for politicians when dealing with healthcare priority setting. DESIGN/METHODOLOGY/APPROACH: The study had an exploratory descriptive design based on interviews with 18 politicians from two different county councils in Sweden. The interviews were analyzed using inductive qualitative content analysis. FINDINGS: The politicians highlighted the importance of, and difficulties in, communicate political missions; the politicians in this study saw the media as not always being fair watchdogs, implying that possibly important but unpopular prioritizing decisions were not made because of the risks of being badly reported and therefore not re-elected. Breaking up established structures in care practice is difficult and change takes time, partly because of existing higher level financing and rules and the system's traditional separation of facilities and services. Although the politicians highlighted their limited power to influence and control resource allocation they could give small and "lower profile", low-prioritized disciplines control of their own budgets and base payments on the results the disciplines accomplished. ORIGINALITY/VALUE: This study highlights the difficulties that politicians experience, for example, having to take unpleasant decisions and thereby run the risk of being scrutinized by media, which in turn could influence how effectively tax money is being used. PMID- 26045195 TI - EM-E-11-4 increases paclitaxel uptake by inhibiting P-glycoprotein-mediated transport in Caco-2 cells. AB - P-glycoprotein (P-gp) overexpression is the main mechanism involved in chemotherapy drug resistance such as paclitaxel resistance and therapy failure. The most widely studied P-gp inhibitors still have limited ability to reverse resistance in the clinic. In this study, EM-E-11-4, a lathyrane-type diterpenoid isolated from Euphorbia micractina, was found to significantly increase paclitaxel uptake in Caco-2 cells, which functionally overexpressed P-gp. In vitro transport experiments, carried out in the Caco-2 monolayer model, indicated that EM-E-11-4 significantly reduced the efflux ratio of paclitaxel transport by inhibiting P-gp function without affecting P-gp expression. We also found that EM E-11-4 enhanced the intracellular accumulation of paclitaxel in a dose-dependent manner by LC-MS/MS and EM-E-11-4 showed low cytotoxicity. Hence, EM-E-11-4 is an effective potential agent to reverse P-gp-mediated paclitaxel resistance by inhibiting P-gp transport function and increasing the intracellular concentration of paclitaxel. PMID- 26045196 TI - Identification of Small-Molecule Inhibitors of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. AB - Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels function in the brain to limit neuronal excitability. Limiting the activity of these channels has been proposed as a therapy for major depressive disorder, but the critical role of HCN channels in cardiac pacemaking has limited efforts to develop therapies directed at the channel. Previous studies indicated that the function of HCN is tightly regulated by its auxiliary subunit, tetratricopeptide repeat containing Rab8b interacting protein (TRIP8b), which is not expressed in the heart. To target the function of the HCN channel in the brain without affecting the channel's function in the heart, we propose disrupting the interaction between HCN and TRIP8b. We developed a high-throughput fluorescence polarization (FP) assay to identify small molecules capable of disrupting this interaction. We used this FP assay to screen a 20,000-compound library and identified a number of active compounds. The active compounds were validated using an orthogonal AlphaScreen assay to identify one compound (0.005%) as the first confirmed hit for inhibiting the HCN-TRIP8b interaction. Identifying small molecules capable of disrupting the interaction between HCN and TRIP8b should enable the development of new research tools and small-molecule therapies that could benefit patients with depression. PMID- 26045197 TI - Submarine and deep-sea mine tailing placements: A review of current practices, environmental issues, natural analogs and knowledge gaps in Norway and internationally. AB - The mining sector is growing in parallel with societal demands for minerals. One of the most important environmental issues and economic burdens of industrial mining on land is the safe storage of the vast amounts of waste produced. Traditionally, tailings have been stored in land dams, but the lack of land availability, potential risk of dam failure and topography in coastal areas in certain countries results in increasing disposal of tailings into marine systems. This review describes the different submarine tailing disposal methods used in the world in general and in Norway in particular, their impact on the environment (e.g. hyper-sedimentation, toxicity, processes related to changes in grain shape and size, turbidity), current legislation and need for future research. Understanding these impacts on the habitat and biota is essential to assess potential ecosystem changes and to develop best available techniques and robust management plans. PMID- 26045198 TI - Plastic and metal ingestion in three species of coastal waterfowl wintering in Atlantic Canada. AB - Relatively little attention has been paid to the occurrence of anthropogenic debris found in coastal species, especially waterfowl. We examined the incidence of ingested plastic and metal in three waterfowl species wintering in Atlantic Canada: American black ducks (Anas rubripes) and mallards (A. platyrhynchos), two species that use marine and freshwater coastal habitats for foraging in the winter, and common eider (Somateria mollissima), a coastal marine species that feeds on intertidal and subtidal benthic organisms. Plastic was found in the stomachs of 46.1% (6/13) of mallards and 6.9% (6/87) of black ducks, the first report of ingested anthropogenic debris in these species, while 2.1% (1/48) of eider stomachs contained plastic. Metal was found in the stomachs of 30.8% (4/13) of mallards, 2.3% (2/87) of black ducks, and in 2.1% (1/48) of eiders. Our results indicate that species using coastal marine and freshwater environments are exposed to and ingest anthropogenic debris. PMID- 26045199 TI - Assessment of therapeutic efficacy and safety of artemether-lumefantrine (Coartem(r)) in the treatment of uncomplicated Plasmodium falciparum malaria patients in Bahir Dar district, Northwest Ethiopia: an observational cohort study. AB - BACKGROUND: Malaria is a complex disease, which varies in its epidemiology and clinical manifestation. Although artemether-lumefantrine has been used as first line drug for uncomplicated Plasmodium falciparum malaria in Bahir Dar district since 2004, its efficacy has not yet been assessed. The main objective of this study was to quantify the proportion of patients with uncomplicated falciparum malaria who were prescribed artemether-lumefantrine and who failed treatment after a 28-day follow-up. METHODS: The research team attempted to conduct an observational cohort study on the assessment of therapeutic efficacy and safety of artemether-lumefantrine in falciparum malaria patients aged over five years in Bahir Dar district from March to July 2012. RESULTS: Among 130 participants in the study, 60% were males with 1:5 male to female ratio. The mean of asexual parasitaemia load was 8675 parasites/MUL and 96.1% participants were free from parasitaemia at day 3. At the end of the study, 98.5% of participants showed adequate clinical and parasitological response of the drug. In the study, only 1.5% of participants were shown late parasitological failure between seventh and 14th day follow-up and 1.3% of participants were free from anaemia at the end of follow-up. CONCLUSION: According to the research findings, artemether lumefantrine fulfilled the inclusion criteria of WHO as first-line drug and continues to be the drug of choice for the treatment of uncomplicated falciparum malaria. Outputs from this study should be supported through advanced molecular techniques and blood concentration and pharmaco-vigilance of the drug. PMID- 26045200 TI - Inhibitory effects of EGb761 on the expression of matrix metalloproteinases (MMPs) and cartilage matrix destruction. AB - Cytokines such as tumor necrosis factor alpha (TNF-alpha)-induced expression of matrix metalloproteinase (MMP) play a pivotal role in the destruction of articular cartilage in patients who are suffering from osteoarthritis (OA). Collagen type II, the basis for articular cartilage, can be degraded by MMP-1, MMP-3, and 13. EGb761, the standardized extract of Ginkgo biloba produced by Dr. Willar Schwabe Pharmaceuticals, has shown its anti-inflammatory capacity. This study aimed to determine a mechanism whereby EGb761 may inhibit cartilage degradation. Our results indicated that pretreatment with EGb761 abolishes MMP-1, MMP-3, and MMP-13 gene expression and protein expression induced by TNF-alpha in human chondrocyte monolayer. In addition, the reduction of the tissue inhibitor of metalloproteinase-1(TIMP-1) and metalloproteinase-2 gene expression induced by TNF-alpha was rescued by pretreatment with EGb761. Importantly, TNF-alpha-induced degradation of collagen type II was ameliorated by EGb761 in a dose-dependent manner. Mechanistically, our results indicated that EGb761 treatment attenuated TNF-alpha-induced NF-kappaB activation. These actions of EGb761 suggest a mechanism by which EGb761 may act to prevent cartilage breakdown in arthritis. PMID- 26045201 TI - A pharmacological investigation of Hippophae salicifolia (HS) and Hippophae rhamnoides turkestanica (HRT) against multiple stress (C-H-R): an experimental study using rat model. AB - Hippophae salicifolia (HS) and Hippophae rhamnoides turkestanica (HRT) are abundantly found species of Hippophae in Himalayan region of India. As these plants thrive under extreme climatic conditions, it is suspected that these plants must have a unique adaptogenic property against high-altitude stress. To keeping these views in our mind, the present study was planned to evaluate the mechanism of action of aqueous extract of HS and aqueous extract of HRT against multiple stress [cold-hypoxia-restraint (C-H-R)] for their adaptogenic activity. The present study reported the adaptogenic activity of HS in facilitating tolerance to multiple stress, CHR in rats. Pre-treatment with aqueous extract of HS significantly attenuated reactive oxygen species (ROS) production, protein oxidation, and lipid peroxidation and also showed role in maintaining antioxidant status as similar to control rats. Since protein oxidation was decreased by pre treatment of HS, protein homeostasis was also sustained by regulation of heat shock proteins (HSP70 and HSP60). Interestingly, heme oxygenase-1 (HO-1), Vascular Endothelial Growth Factor (VEGF), and nitric oxide (NO) level was also increased in HS pre-treated rats depicted its adaptogenic activity against multiple stress, CHR. Conclusively, aqueous extract of HS could use an adaptogen for high altitude-associated multiple stress (CHR). PMID- 26045202 TI - The P5 disulfide switch: taming the aging unfolded protein response. AB - Aging cells are characterized by a loss of proteostasis and a decreased ability to survive under environmental stress. Regulation of the UPR in aging cells has been under much scrutiny, and studies have shown that the UPR in these cells differs considerably from younger cells with regard to the induction of apoptosis and chaperone activity. The role of IRE-1 and PERK in UPR-associated apoptosis makes the regulation of these signaling cascades an important target of study. The seemingly contradictory findings regarding the role of P5 in activating and deactivating these responses warrant further investigation and may hold the key to unlocking the role of this protein in various pathological conditions. Another important target for study with regard to P5 is the effects of the localization of this protein in the mitochondria and the consequences, if any, of these effects on the activation of the UPR. PMID- 26045203 TI - The role of small heat shock proteins in parasites. AB - The natural life cycle of many protozoan and helminth parasites involves exposure to several hostile environmental conditions. Under these circumstances, the parasites arouse a cellular stress response that involves the expression of heat shock proteins (HSPs). Small HSPs (sHSPs) constitute one of the main families of HSPs. The sHSPs are very divergent at the sequence level, but their secondary and tertiary structures are conserved and some of its members are related to alpha crystallin from vertebrates. They are involved in a variety of cellular processes. As other HSPs, the sHSPs act as molecular chaperones; however, they have shown other activities apparently not related to chaperone action. In this review, the diverse activities of sHSPs in the major genera of protozoan and helminth parasites are described. These include stress response, development, and immune response, among others. In addition, an analysis comparing the sequences of sHSPs from some parasites using a distance analysis is presented. Because many parasites face hostile conditions through its life cycles the study of HSPs, including sHSPs, is fundamental. PMID- 26045204 TI - Internalization of GluA2 and the underlying mechanisms of cognitive decline in aged rats following surgery and prolonged exposure to sevoflurane. AB - BACKGROUND: We revealed that a high concentration of sevoflurane exacerbated cognitive impairment in aged rats, and the inhibition of GluA2 subunit internalization facilitated neuroprotection after a cerebral ischemic injury. However, the trafficking of GluA2 in POCD and its underlying mechanism are not clear. We thus detected the effects of sevoflurane for different inhalation durations on postoperative cognitive function and investigated the role of GluA2 subunit trafficking in this process. METHODS: A rat model of orthopedic surgery was performed with different durations of 1.5 MAC sevoflurane inhalation. Cognitive function was evaluated by manipulating the Y maze and fear conditioning tests for 7 days after experiments. Western blot, ELISA and coimmunoprecipitation were applied to analyze GluA2 internalization, PI3K expression and its activity, as well as alterations to the MEF2-Arc pathway in the hippocampus. Neuron apoptosis and the spine morphology in the hippocampus were also observed. RESULTS: We found that neuron apoptosis and GluA2 internalization increased following surgery and 1.5 MAC sevoflurane inhalation for 2h, possibly due to the decrease of the PI3K-GluA2 complex and PI3K activity in the hippocampus after prolonged 1.5 MAC sevoflurane inhalation. We also observed that the MEF2-Arc pathway contributed to long-term cognitive function, which also impaired the spinal morphology after 1.5 MAC sevoflurane inhalation for 2h. CONCLUSION: The above results suggest that 1.5 MAC sevoflurane inhalation for 2h potentiated surgery-impaired cognitive function and that the inhibition of PI3K-AMPAR GluA2 as well as activation of the MEF2-Arc signal pathway contributes to different stages of POCD. PMID- 26045205 TI - PPARgamma-PI3K/AKT-NO signal pathway is involved in cardiomyocyte hypertrophy induced by high glucose and insulin. AB - OBJECTIVE: To investigate the role of the PPARgamma-PI3K/AKT-NO signaling pathway in cardiac hypertrophy induced by high glucose and insulin. METHODS: Cardiomyocyte hypertrophy induced by high glucose (25.5 mmol/L) and insulin (0.1 MUmol/L) (HGI) was characterized in rat primary cardiomyocytes by measuring the cell surface area, protein content, and atrial natriuretic factor mRNA expression level. Protein and mRNA expressions were measured by Western blotting and real time RT-PCR, respectively. A spectrophotometric assay was used to measure the enzymatic concentration of endothelial NO synthase (eNOS), and the Griess assay measured the NO concentration. RESULTS: HGI induced significant cardiomyocyte hypertrophy and decreased the expression of PPARgamma, AKT and eNOS at the mRNA and protein levels, which occurred in parallel with declining eNOS activity and NO concentration (P<0.05). The effects of HGI were inhibited by rosiglitazone (0.1 MUmol/L), a selective PPARgamma agonist (P<0.05). However, GW9662, a selective PPARgamma antagonist, abolished the effects of rosiglitazone (P<0.05). LY294002, a PI3K/AKT inhibitor, and N(G)-nitro-L-arginine-methyl ester, an NOS inhibitor, partially blocked the effects of rosiglitazone (P<0.05). CONCLUSION: These results suggest that the PPARgamma-PI3K/AKT-NO signal transduction pathway might be involved in HGI-induced cardiomyocyte hypertrophy. PMID- 26045206 TI - A Systematic Review of the Efficacy of Bioactive Compounds in Cardiovascular Disease: Carbohydrates, Active Lipids and Nitrogen Compounds. AB - BACKGROUND/AIMS: The prevalence of cardiovascular diseases (CVD) is rising and it is the prime cause of death in all developed countries. Bioactive compounds (BACs) can play a role in CVD prevention and treatment. To examine the scientific evidence supporting BACs groups' efficacy in CVD prevention and treatment, we conducted a systematized review. METHODS: All available information on Medline, LILACS and EMBASE; all randomized controlled trials (RCTs) with prospective, parallel or crossover designs in humans in which the BACs effect was compared with that of placebo/control. Vascular homeostasis, blood pressure, endothelial function, oxidative stress and inflammatory biomarkers were considered primary outcomes. RESULTS: We selected 26 articles, verifying their quality based on the Scottish Intercollegiate Guidelines Network, establishing diverse quality levels of scientific evidence according to the design and bias risk of a study. Grades of recommendation were included, depending on the evidence strength of antecedents. CONCLUSIONS: Evidence shows that certain BACs' derivative from active lipids and nitrogen compounds, mainly from horse chestnut seed extract, sterol plants, allium derivatives, and certain doses of beta-glucans, can be helpful in decreasing the prevalence of CVD risk factors. However, further rigorous evidence is necessary to support and prove BACs' effect on CVD prevention and treatment. PMID- 26045207 TI - Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy. AB - POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21-22 in one case and of exons 26-27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified. PMID- 26045208 TI - Reduced taste function and taste papillae density in children with chronic kidney disease. AB - BACKGROUND: Taste loss may contribute to the loss of appetite in children with chronic kidney disease (CKD) and other serious medical conditions that result in malnutrition. Traditional methods for measurement of taste loss commonly use aqueous tastant solutions that can induce nausea, vomiting, or even pain in the mouth. An alternative is to measure fungiform papillae density on the anterior tongue since this correlates with taste sensitivity. Here we aimed to develop a non-invasive method for assessing papillae density on the anterior tongue and to use the method to determine if CKD patients [estimated glomerular filtrate (eGFR < 60 ml/min/1.73 m(2))] have a lower density than clinical controls (CC)(eGFR > 89 ml/min/1.73 m(2)). METHODS: Thirty-five healthy adults participated in the development of a method, which was assessed by 24 children, 12 of whom were CKD patients and 12 were clinical controls. RESULTS: Similar papillae densities were found using invasive and non-invasive methods (F(1,34) = 0.647, p = 0.427). The CKD group had a significantly lower papillae density (X(2) = 7.17, p = 0.007) and poorer taste sensitivity than the CC group (p = 0.0272), and the density correlated significantly with eGFR (r = 0.56, p < 0.01). CONCLUSIONS: Loss of taste in children with CKD is due to the reduced number of papillae and their taste-sensing receptor cells. PMID- 26045209 TI - Klebsiella pneumoniae survives within macrophages by avoiding delivery to lysosomes. AB - Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Evidence indicates that Klebsiella might be able to persist intracellularly within a vacuolar compartment. This study was designed to investigate the interaction between Klebsiella and macrophages. Engulfment of K. pneumoniae was dependent on host cytoskeleton, cell plasma membrane lipid rafts and the activation of phosphoinositide 3-kinase (PI3K). Microscopy studies revealed that K. pneumoniae resides within a vacuolar compartment, the Klebsiella containing vacuole (KCV), which traffics within vacuoles associated with the endocytic pathway. In contrast to UV-killed bacteria, the majority of live bacteria did not co-localize with markers of the lysosomal compartment. Our data suggest that K. pneumoniae triggers a programmed cell death in macrophages displaying features of apoptosis. Our efforts to identify the mechanism(s) whereby K. pneumoniae prevents the fusion of the lysosomes to the KCV uncovered the central role of the PI3K-Akt-Rab14 axis to control the phagosome maturation. Our data revealed that the capsule is dispensable for Klebsiella intracellular survival if bacteria were not opsonized. Furthermore, the environment found by Klebsiella within the KCV triggered the down-regulation of the expression of cps. Altogether, this study proves evidence that K. pneumoniae survives killing by macrophages by manipulating phagosome maturation that may contribute to Klebsiella pathogenesis. PMID- 26045210 TI - Impact of Obesity on Perioperative Outcomes of Retroperitoneal Laparoscopic Adrenalectomy. AB - INTRODUCTION: Obesity is usually considered a risk factor for postoperative complications; however, previous studies conclude contradictory results in retroperitoneal laparoscopic adrenalectomy (LA). We aim to evaluate the impact of obesity on the perioperative outcomes of LA. METHODS: A retrospective cohort study from a single center including 353 patients from 2011 to 2013 was conducted. Perioperative outcomes of patients from different groups were compared according to their body mass index (BMI). RESULTS: All the patients were divided into 3 groups: normal (n = 149), overweight (n = 141) and obese (n = 63). Operative time (OT) for patients belonging to the obese group was significantly longer than that in the normal and overweight group, and the results of estimated blood loss, postoperative length of stay in hospital and postoperative complications were all similar. In the multivariate logistic regression analysis, OT was an independent risk factor for postoperative complications (odds ratio 1.020; 95% confidence interval 1.001-1.039; p = 0.037), while other factors including BMI had negligible effect. CONCLUSIONS: Retroperitoneal LA offers similar perioperative outcomes for patients with different obesity statuses, which could be safe and feasible for obese patients. PMID- 26045211 TI - Toward 3D Printing of Pure Metals by Laser-Induced Forward Transfer. AB - 3D printing of common metals is highly challenging because metals are generally solid at room conditions. Copper and gold pillars are manufactured with a resolution below 5 MUm and a height up to 2 mm, using laser-induced forward transfer to create and eject liquid metal droplets. The solidified drop's shape is crucial for 3D printing and is discussed as a function of the laser energy. PMID- 26045212 TI - Distress of Routine Activities and Perceived Safety Associated with Post Traumatic Stress, Depression, and Alcohol Use: 2002 Washington, DC, Sniper Attacks. AB - OBJECTIVE: For over 3 weeks in October 2002, a series of sniper attacks in the Washington, DC, area left 10 people dead and 3 wounded. This study examined the relationship of distress associated with routine activities and perceived safety to psychological and behavioral responses. METHODS: Participants were 1238 residents of the Washington, DC, metropolitan area (aged 18 to 90 years, mean=41.7 years) who completed an Internet survey including the Impact of Event Scale-Revised, Patient Health Questionnaire-9, and items pertaining to distress related to routine activities, perceived safety, and alcohol use. Data were collected at one time point approximately 3 weeks after the first sniper shooting and before apprehension of the suspects. Relationships of distress and perceived safety to post-traumatic stress, depressive symptoms, and increased alcohol use were examined by using linear and logistic regression analyses. RESULTS: Approximately 8% of the participants met the symptom criteria for probable post traumatic stress disorder, 22% reported mild to severe depression, and 4% reported increased alcohol use during the attacks. Distress related to routine activities and perceived safety were associated with increased post-traumatic stress and depressive symptoms and alcohol use. CONCLUSION: Distress and perceived safety are associated with specific routine activities and both contribute to psychological and behavioral responses during a terrorist attack. These findings have implications for targeted information dissemination and risk communication by community leaders. PMID- 26045213 TI - Using EEG and stimulus context to probe the modelling of auditory-visual speech. AB - We investigated whether internal models of the relationship between lip movements and corresponding speech sounds [Auditory-Visual (AV) speech] could be updated via experience. AV associations were indexed by early and late event related potentials (ERPs) and by oscillatory power and phase locking. Different AV experience was produced via a context manipulation. Participants were presented with valid (the conventional pairing) and invalid AV speech items in either a 'reliable' context (80% AVvalid items) or an 'unreliable' context (80% AVinvalid items). The results showed that for the reliable context, there was N1 facilitation for AV compared to auditory only speech. This N1 facilitation was not affected by AV validity. Later ERPs showed a difference in amplitude between valid and invalid AV speech and there was significant enhancement of power for valid versus invalid AV speech. These response patterns did not change over the context manipulation, suggesting that the internal models of AV speech were not updated by experience. The results also showed that the facilitation of N1 responses did not vary as a function of the salience of visual speech (as previously reported); in post-hoc analyses, it appeared instead that N1 facilitation varied according to the relative time of the acoustic onset, suggesting for AV events N1 may be more sensitive to the relationship of AV timing than form. PMID- 26045214 TI - Individual privacy versus public good: protecting confidentiality in health research. AB - Health and medical data are increasingly being generated, collected, and stored in electronic form in healthcare facilities and administrative agencies. Such data hold a wealth of information vital to effective health policy development and evaluation, as well as to enhanced clinical care through evidence-based practice and safety and quality monitoring. These initiatives are aimed at improving individuals' health and well-being. Nevertheless, analyses of health data archives must be conducted in such a way that individuals' privacy is not compromised. One important aspect of protecting individuals' privacy is protecting the confidentiality of their data. It is the purpose of this paper to provide a review of a number of approaches to reducing disclosure risk when making data available for research, and to present a taxonomy for such approaches. Some of these methods are widely used, whereas others are still in development. It is important to have a range of methods available because there is also a range of data-use scenarios, and it is important to be able to choose between methods suited to differing scenarios. In practice, it is necessary to find a balance between allowing the use of health and medical data for research and protecting confidentiality. This balance is often presented as a trade-off between disclosure risk and data utility, because methods that reduce disclosure risk, in general, also reduce data utility. PMID- 26045215 TI - British nurses' attitudes to electroconvulsive therapy, 1945-2000. AB - AIM: The aim of the study was to collect and analyse historical material on nurses' attitudes to electroconvulsive therapy in Britain between 1945-2000. BACKGROUND: Electroconvulsive therapy became widely used in Britain from the late 1940s onwards and remains in current use, but became one of the main targets of the 'antipsychiatry' movement of the 1960s and 1970s. DESIGN: A cultural history design was used to recreate the perspectives of mental health nurses in the period under review. METHOD: A range of primary sources including journal articles, textbooks and oral history sources were combined to create a coherent historical account. FINDINGS: The controversy surrounding electroconvulsive therapy created a deep-seated ambivalence towards it among mental health nurses. While a sizeable minority were critical of its use and may have taken steps to avoid involvement with it, most acquiesced in providing the treatment. Recorded incidents of outright refusal to participate are few. CONCLUSION: Mental health nurses' views on electroconvulsive therapy are reflective of the profession's growing knowledge of the use of evidence in debating whether particular therapies should be used. PMID- 26045216 TI - Parents are psychologically affected by their experiences when their child is in hospital because of uncertainty about prognosis and anxiety at the time of admission. PMID- 26045218 TI - How many patients with post-chikungunya chronic inflammatory rheumatism can we expect in the new endemic areas of Latin America? AB - Post-chikungunya chronic inflammatory rheumatism (pCHIK-CIR) is one of the consequences that are impacting new endemic countries, such as those in the Americas. The relative frequency of pCHIK-CIR is highly variable, ranging from 14.4 % to 87.2 % (including variable number of patients and follow-up times). Based on those non-weighted values, it is difficult to estimate which would be the expected number of patients with CHIK who will develop CIR. For these reasons, we modeled weighted estimations based on pooled data extracted from those eight representative studies in order to provide cumulative proportion of pCHIK-CIR over time and median time of it, but also estimations of the number of patients with CHIK reported in Latin American countries (within a 95 % CI). This model estimated a prevalence of 47.57 % for pCHIK-CIR (95 % CI 45.08-50.13), with a median time to 50 % of pCHIK-CIR in 20.12 months. Given the reported number of patients with acute CHIK during 2014 in the Americas, our estimates suggest that from those patients, 385,835-429,058 patients will develop pCHIK-CIR. Despite the limitations of these estimates, the provided figures of pCHIK-CIR presented here are preliminary approximations of what the future burden of related rheumatic disease in the region as a consequence of CHIK infection for 2015-2016 could be, given the timeframe of median time of occurrence. PMID- 26045217 TI - Beta-adducin and sodium-calcium exchanger 1 gene variants are associated with systemic lupus erythematosus and lupus nephritis. AB - Genetic research in systemic lupus erythematosus (SLE) is rapidly developing, and numerous sets of genes are being associated with specific clinical subphenotypes in the setting of SLE. On the other hand, basic science studies are revealing strong connections between salt-water balance and inflammation. The aim of this study was to evaluate whether variants of genes known to influence the individual susceptibility to hypertension also influence the renal function in a cohort of SLE patients with and without lupus nephritis (LN). This study is a case-control study with candidate gene approach. A total of 111 patients with SLE (50 with SLE without nephritis, 55 with LN and 6 with simple urinary sediment abnormalities) and 62 healthy controls (HC) were genotyped for NCX1 rs11893826 (NCX1a) and rs434082 (NCX1b) and ADD2 rs4984 SNPs. Patients with ADD2 CT genotype were protected from LN and skin involvement; ADD2 CC | NCX1a AA/AG genotypes were associated with the presence of anti-cardiolipin antibodies; NCX1a AA genotype was slightly more frequent in lupus patients than in HC and associated with relapse risk and higher creatinine in patients with LN. NCX1b GG patients with LN had increased chances to reach complete remission. NCX1b GG | NCX1a GG genotype is associated with joint involvement. ADD2 and NCX1 variants influence the risk and the clinical features of SLE and LN, highlighting their potential role in regulating systemic inflammation and/or the local response to immune-mediated injury. PMID- 26045219 TI - Rapidly destructive arthrosis of the hip joint in a young adult with systemic lupus erythematosus. AB - A 37-year-old female had been treated with corticosteroids for systemic lupus erythematosus clinically diagnosed at age 10. She suddenly had right hip pain without any antecedent trauma. Four months after the onset of pain, she visited her primary care physician. On magnetic resonance imaging, joint space narrowing at the weight-bearing area was already seen with bone marrow edematous lesions in both the femoral head and acetabulum. She was treated non-operatively; however, her pain continued to worsen in severity. Thirteen months after the onset of pain, she was referred to our hospital. A plain radiograph showed subluxation of the collapsed femoral head accompanied by destruction of the acetabular rim. Because of her severe intractable pain, she underwent total hip arthroplasty 1 month after her first visit. Histological examination of the resected femoral head revealed pseudogranulomatous lesions along with prominent callus formation, suggesting rapid destruction of the femoral head. PMID- 26045220 TI - Effect of 830-nm laser phototherapy on olfactory neuronal ensheathing cells grown in vitro on novel bioscaffolds. AB - BACKGROUND: The purpose of this study was to analyze olfactory ensheathing cell (OEC) proliferation and growth on Biosilicate and collagen bioscaffolds, and to determine whether the application of laser phototherapy would result in increased OEC proliferation on the scaffolds. The use of bioscaffolds is considered a promising strategy in a number of clinical applications where tissue healing is suboptimal. As in vitro OEC growth is a slow process, laser phototherapy could be useful to stimulate proliferation on bioscaffolds. METHODS: OEC cells were seeded on the Biosilicate and collagen scaffolds. Seeded scaffolds were irradiated with a single exposure of 830-nm laser. Nonirradiated seeded scaffolds acted as negative controls. Cell proliferation was assessed 7 days after irradiation. RESULTS: OECs were successfully grown on discs composed of a glass-ceramic and collagen composite. Laser irradiation produced a 32.7% decrease and a 13.2% increase in OEC proliferation on glass-ceramic discs and on collagen scaffolds, respectively, compared with controls. Laser phototherapy resulted in a reduction in cell growth on the Biosilicate scaffolds and an increase in cell proliferation on collagen scaffolds. CONCLUSIONS: These results were probably due to the nature of the materials. Future research combining laser phototherapy and glass-ceramic scaffolds should take into account possible interactions of the laser with matrix compounds. PMID- 26045221 TI - Sealing capability of implant-abutment junction under cyclic loading: a toluidine blue in vitro study. AB - PURPOSE: The aim of the present in vitro study was to evaluate the leakage observed in external hexagon (EH) and cone Morse (CM) tapered implant-abutment connections, using toluidine blue. METHODS: A total of 60 implants, 30 with a screw-retained EH abutment and 30 with a CM taper internal connection, were used. Toluidine blue was placed into the deepest portion of the internal compartment of the 2 different implant systems, and cyclic loading was applied for each group as follows: 10 samples underwent 1 * 10(6) loading cycles, 10 samples underwent 3 * 10(6) cyclic loading and the least 10 samples underwent 6 * 10(6) cyclic loading. RESULTS: No significant differences between the EH and CM groups were detected when the lowest loading cycles were applied (p = 0.2624), while differences were found when the samples were loaded with 3 x 10(6) and 6 x 10(6) cycles (p = 0.00124), with significantly lower toluidine leakage in CM group. CONCLUSIONS: In conclusion, the results of the present in vitro study demonstrated that flow of the toluidine blue to the external portion of the implant-abutment assembly occurred in both types of implant-abutment connections, with very different percentages. Indeed, the CM taper internal connection seems to be more resistant to the leakage of dyes when compared with EH connections. PMID- 26045222 TI - Effect of 1-piece post and core fabrication techniques on fracture strength. AB - PURPOSE: The purpose of this in vitro study was to evaluate and compare the fracture strengths of post and core systems produced with different fabrication techniques and materials. METHODS: Forty extracted human single-root premolars were used in this study. After root canal treatment, the teeth were randomly divided into 4 groups of 10 each as follows: group C: metallic 1-piece posts and cores fabricated by casting, and serving as the control; group CM: metallic posts and cores fabricated with the copy milled technique; group LS: 1-piece posts and cores fabricated with the laser sintering technique; and group ZR: 1-piece zirconia posts and cores fabricated with computer-aided design and computer-aided manufacturing (CAD-CAM). The posts and cores were cemented to the teeth with adhesive resin cement; then, the specimens were mounted to acrylic resin blocks, attached to an Instron Universal Testing Machine, and loaded with a crosshead speed of 1 mm/min, until fracture. Data were statistically analyzed using 1-way analysis of variance (ANOVA), followed by the post hoc Tukey test (alpha = 0.05). RESULTS: The highest fracture results were found in group ZR (315.4 +/- 53.4 N), which showed significant differences from all other groups (p<0.05). The lowest test values were found in group C (230.2 +/- 29.8 N). Group LS (250.9 +/- 29.0 N), group CM (253.0 +/- 22.4 N) and group C did not show any significant differences (p>0.05). CONCLUSIONS: Custom-made zirconia 1-piece posts and cores, fabricated using the CAD-CAM procedure, can be an alternative treatment method when compared with other techniques. PMID- 26045223 TI - Thermal and photo stability of glutathione-capped cadmium telluride quantum dots. AB - BACKGROUND: Nanoparticles (NPs) are increasingly being used in a number of applications that include biomedicine, biological labeling and cancer marker targeting, and their successful storage is important to preserve their viability. A systematic investigation of the thermal and photo stability of chemically stabilized cadmium telluride (CdTe) quantum dots (QDs) under various storage conditions either in solution or as dried nanoparticles has not been published. Here we report experiments involving chemically synthesized glutathione-capped CdTe QDs whose photoluminescence spectra were examined initially and then periodically during storage times up to 76 days. METHODS: Samples of dried QDs or QDs in solution (water or buffered) were examined under different light conditions including complete darkness, constant 12,000 lux incident light, and under diurnal sunlight; at temperatures ranging from -80 degrees C to room temperature. RESULTS: Though QDs stored in solution in the dark at -80 degrees C lost only 50% of peak fluorescence (FL510) within 2 weeks, solution-stored QDs exposed to sunlight at room temperature showed FL510 drops of 85% in the first 24 hours. In contrast, QDs precipitated from aqueous solution, dried and stored in time course experiments in the presence of atmospheric oxygen--when resuspended in water--lost an average of only 12% FL510 over 76 days under all conditions tested, even in direct sunlight. CONCLUSIONS: Glutathione-capped CdTe particles can be stored as dried nanoparticles for extended periods of time, enhancing their viability in biomedicine, biological labeling and cancer marker targeting. PMID- 26045224 TI - Solubility and pH of direct pulp capping materials: a comparative study. AB - BACKGROUND: The objective of the present study was to compare solubility and pH of 6 direct pulp capping materials. METHODS: Specimens of each material - i.e., Dycal, Calcicur, Calcimol LC, TheraCal LC, MTA Angelus and ProRoot MTA - were prepared and immersed in water. Solubility was determined after 24 hours and 2 months and analyzed statistically using a 1-way ANOVA and post hoc Tukey test. pH values were measured 3 and 24 hours after manipulation. RESULTS: All direct pulp capping materials showed low solubility; the pH of tested materials ranged from 10 to 12 and showed a nonsignificant increase/reduction after 24 hours. CONCLUSIONS: Within the limitations of this in vitro study, the direct pulp capping materials studied showed different solubility even if no changes were recorded over time. All of the materials showed a very alkaline pH. PMID- 26045225 TI - Human plasma protein adsorption onto alumina nanoparticles relevant to orthopedic wear. AB - PURPOSE: Wear of ceramic orthopedic devices generates nanoparticles in vivo that may present a different biological character from the monolithic ceramic from which they are formed. The current work investigated protein adsorption from human plasma on alumina nanoparticles and monolithic samples representative of both wear particles and the ceramic components as implanted. MATERIALS AND METHODS: A physicochemical characterization of the particles and their dispersion state was carried out, and the protein adsorption profiles were analyzed using 1D SDS-PAGE and mass spectrometry. RESULTS: Significant differences in protein binding profiles were identified where the nanoparticles selectively bound known transporter proteins rather than the more highly abundant serum proteins that were observed on the monoliths. CONCLUSIONS: Proteins associated with opsonization of particles were seen to be present in the protein corona of the nanoparticles, which raises questions regarding the role of wear particles in periprosthetic tissue inflammation and aseptic loosening. PMID- 26045226 TI - Extent of lymphadenectomy to associate with pancreaticoduodenectomy in patients with pancreatic head cancer for better tumor staging. AB - OBJECTIVES: To define the extent of lymphadenectomy to associate with surgery for pancreatic head cancer. BACKGROUND: Pancreaticoduodenectomy with extended lymphadenectomy fails to prolong patient survival. METHODS: Prospective randomized and nonrandomized controlled trials (RCTs and NRCTs), meta-analyses, retrospective reviews, consensus conferences and pre- and intraoperative diagnoses of lymph node (LN) metastases were retrieved. Standard and extended lymphadenectomies were reviewed, including their effects on postoperative complications, mortality rate and long-term survival. The minimum total number of LN examined (TNLE) for adequate tumor staging, and the incidence of metastasis to each LN station were also considered. A pros and cons analysis was performed on the removal of each LN station. RESULTS: Eleven retrospective studies (2514 patients), five prospective NRCTs (545 patients), and five prospective RCTs (586 patients) described different lymphadenectomies, which obtained similar long-term results. Five meta-analyses showed they did not influence long-term survival. However, N status is an important component of tumor staging. The recommended minimum TNLE is 15. The percent incidence of metastasis to each LN station was calculated considering at least 385 and up to 3725 patients. Preoperative imaging and intraoperative exploration frequently fail to identify metastatic nodes. A pros and cons analysis suggests that lymph node status is better established removing the following LN stations: 6, 8a-p, 12a-b-c, 13a-b, 14a-b-c-d, 16b1, 17a b. Metastasis to 16b1 LNs significantly worsens prognosis. Their removal and frozen section examination, before proceeding with resection, may contraindicate resection. CONCLUSION: A standard lymphadenectomy demands an adequate TNLE and removal of the LN stations metastasizing more frequently, without increasing the surgical risk. PMID- 26045227 TI - Action and resistance of monoclonal CD20 antibodies therapy in B-cell Non-Hodgkin Lymphomas. AB - Anti-CD20 monoclonal antibodies (mAbs) have improved patient's survival with Non Hodgkin Lymphoma, when combined with chemotherapy. Several mechanisms of action have been reported, including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and induction of apoptosis. Despite the large amount of studies and published data, the role each mechanism played in vivo is not fully understood. Furthermore, the reason why a significant percentage of patients are refractory or resistant remains unknown. Several activated intracellular signaling pathways have been implicated in the mechanisms of resistance of rituximab. In the present manuscript, we review those mechanisms and new anti-CD20 mAbs, as well as the efforts being accomplished to overcome it, focusing on new drugs targeting pathways implicated in resistance to rituximab. PMID- 26045229 TI - PAF-derived nitrogen-doped 3D Carbon Materials for Efficient Energy Conversion and Storage. AB - Owing to the shortage of the traditional fossil fuels caused by fast consumption, it is an urgent task to develop the renewable and clean energy sources. Thus, advanced technologies for both energy conversion (e.g., solar cells and fuel cells) and storage (e.g., supercapacitors and batteries) are being studied extensively. In this work, we use porous aromatic framework (PAF) as precursor to produce nitrogen-doped 3D carbon materials, i.e., N-PAF-Carbon, by exposing NH3 media. The "graphitic" and "pyridinic" N species, large surface area, and similar pore size as electrolyte ions endow the nitrogen-doped PAF-Carbon with outstanding electronic performance. Our results suggest the N-doping enhance not only the ORR electronic catalysis but also the supercapacitive performance. Actually, the N-PAF-Carbon obtains ~70 mV half-wave potential enhancement and 80% increase as to the limiting current after N doping. Moreover, the N-PAF-Carbon displays free from the CO and methanol crossover effect and better long-term durability compared with the commercial Pt/C benchmark. Moreover, N-PAF-Carbon also possesses large capacitance (385 F g(-1)) and excellent performance stability without any loss in capacitance after 9000 charge-discharge cycles. These results clearly suggest that PAF-derived N-doped carbon material is promising metal-free ORR catalyst for fuel cells and capacitor electrode materials. PMID- 26045228 TI - Dietary Approaches for Bone Health: Lessons from the Framingham Osteoporosis Study. AB - Osteoporosis is characterized by systemic impairment of bone mass, strength, and microarchitecture, resulting in increased risk for fragility fracture, disability, loss of independence, and even death. Adequate nutrition is important in achieving and maintaining optimal bone mass, as well as preventing this debilitating disease. It is widely accepted that adequate calcium and vitamin D intake are necessary for good bone health; however, nutritional benefits to bone go beyond these two nutrients. This review article will provide updated information on all nutrients and foods now understood to alter bone health. Specifically, this paper will focus on related research from the Framingham Osteoporosis Study, an ancillary study of the Framingham Heart Study, with data on more than 5000 adult men and women. PMID- 26045230 TI - Comparison of TGF-beta, PDGF, and CTGF in hepatic fibrosis models using DMN, CCl4, and TAA. AB - Three chemotoxins including dimethylnitrosamine (DMN), carbon tetrachloride (CCl4), and thioacetamide (TAA) are commonly used in hepatofibrotic models. We aimed to draw characteristics of histopathology and pro-fibrogenic cytokines including TGF-beta, PDGF and CTGF among three models. Rats were divided into six groups and intra-peritoneally injected with DMN (10 mg/kg, for three weeks, three consecutive days weekly), CCl4 (1.6 g/kg, for 10 weeks, twice weekly), TAA (200 mg/kg, for 12 weeks, twice weekly) or their corresponded treatment for each control group. The liver weights were decreased in DMN model, but not other models. Ascites were occurred as 3-, 2-, and 7-rats in DMN, CCl4, and TAA model, respectively. The lipid peroxidation was highest in CCl4 model, serum levels of liver enzymes were increased as similar severity. The hepatofibrotic alterations were remarkable in DMN and TAA model, but not CCl4 as evidenced by the Masson trichrome staining and hydroxyproline. The immunohistochemistry for alpha-SAM showed that the DMN model was most severely enhanced than other models. On the other hand, hepatic tissue levels of pro-fibrogenic cytokines including TGF-beta, PDGF, and CTGF were generally increased in three models, but totally different among models or measurement resources. Especially, serum levels of three cytokines were remarkably increased by CCl4 injection and CTGF levels in both hepatic tissue and serum were highest in CCl4 group. Our results firstly demonstrated comparative study for features of morphological finding and pro fibrogenic cytokines in serum and hepatic protein levels among three models. Above results would be a helpful reference for hepatofibrotic studies. PMID- 26045231 TI - Predicting invasions of Wedelia trilobata (L.) Hitchc. with Maxent and GARP models. AB - Wedelia trilobata (L.) Hitchc., an ornamental groundcover plant introduced to areas around the world from Central America, has become invasive in many regions. To increase understanding of its geographic distribution and potential extent of spread, two presence-only niche-based modeling approaches (Maxent and GARP) were employed to create models based on occurrence records from its: (1) native range only and (2) full range (native and invasive). Models were then projected globally to identify areas vulnerable to W. trilobata invasion. W. trilobata prefers hot and humid environments and can occur in areas with different environmental conditions than experienced in its native range. Based on native and full occurrence points, GARP and Maxent models produced consistent distributional maps of W. trilobata, although Maxent model results were more conservative. When used to estimate the global invasive distribution of the species, both modeling approaches projected the species to occur in Africa. The GARP full model succeeded in predicting the known occurrences in Australia, while the other models failed to identify favorable habitats in this region. Given the rapid spread of W. trilobata and the serious risk of this species poses to local ecosystems, practical strategies to prevent the establishment and expansion of this species should be sought. PMID- 26045232 TI - Entity linking for biomedical literature. AB - BACKGROUND: The Entity Linking (EL) task links entity mentions from an unstructured document to entities in a knowledge base. Although this problem is well-studied in news and social media, this problem has not received much attention in the life science domain. One outcome of tackling the EL problem in the life sciences domain is to enable scientists to build computational models of biological processes with more efficiency. However, simply applying a news trained entity linker produces inadequate results. METHODS: Since existing supervised approaches require a large amount of manually-labeled training data, which is currently unavailable for the life science domain, we propose a novel unsupervised collective inference approach to link entities from unstructured full texts of biomedical literature to 300 ontologies. The approach leverages the rich semantic information and structures in ontologies for similarity computation and entity ranking. RESULTS: Without using any manual annotation, our approach significantly outperforms state-of-the-art supervised EL method (9% absolute gain in linking accuracy). Furthermore, the state-of-the-art supervised EL method requires 15,000 manually annotated entity mentions for training. These promising results establish a benchmark for the EL task in the life science domain. We also provide in depth analysis and discussion on both challenges and opportunities on automatic knowledge enrichment for scientific literature. CONCLUSIONS: In this paper, we propose a novel unsupervised collective inference approach to address the EL problem in a new domain. We show that our unsupervised approach is able to outperform a current state-of-the-art supervised approach that has been trained with a large amount of manually labeled data. Life science presents an underrepresented domain for applying EL techniques. By providing a small benchmark data set and identifying opportunities, we hope to stimulate discussions across natural language processing and bioinformatics and motivate others to develop techniques for this largely untapped domain. PMID- 26045233 TI - Autologous Serum Tears for Treatment of Photoallodynia in Patients with Corneal Neuropathy: Efficacy and Evaluation with In Vivo Confocal Microscopy. AB - OBJECTIVE: Patients suffering from corneal neuropathy may present with photoallodynia; i.e., increased light sensitivity, frequently with a normal slit lamp examination. This study aimed to evaluate the efficacy of autologous serum tears (AST) for treatment of severe photoallodynia in corneal neuropathy and to correlate clinical findings with corneal subbasal nerve alterations by in vivo confocal microscopy (IVCM). METHODS: Retrospective case control study with 16 patients with neuropathy-induced severe photoallodynia compared to 16 normal controls. Symptom severity, clinical examination and bilateral corneal IVCM scans were recorded. RESULTS: All patients suffered from extreme photoallodynia (8.8+/ 1.1) with no concurrent ocular surface disease. Subbasal nerves were significantly decreased at baseline in patients compared to controls; total nerve length (9208+/-1264 vs 24714+/-1056 MUm/mm(2); P<.0001) and total nerve number (9.6+/-1.4 vs 28.6+/-2.0; P<.0001), respectively. Morphologically, significantly increased reflectivity (2.9+/-0.2 vs 1.8+/-0.1; P<.0001), beading (in 93.7%), and neuromas (in 62.5%) were seen. AST (3.6+/-2.1 months) resulted in significantly decreased symptom severity (1.6+/-1.7; P=.02). IVCM demonstrated significantly improved nerve parameters (P<.005), total nerve length (15451+/-1595 MUm/mm(2)), number (13.9+/-2.1), and reflectivity (1.9+/-0.1). Beading and neuromas were seen in only 56.2% and 7.6% of patients. CONCLUSION: Patients with corneal neuropathy induced photoallodynia show profound alterations in corneal nerves. AST restores nerve topography through nerve regeneration, and this correlated with improvement in patient-reported photoallodynia. The data support the notion that corneal nerve damage results in alterations in afferent trigeminal pathways to produce photoallodynia. PMID- 26045234 TI - Novel Therapy to Treat Corneal Epithelial Defects: A Hypothesis with Growth Hormone. AB - Impaired corneal wound healing that occurs with ocular surface disease, trauma, systemic disease, or surgical intervention can lead to persistent corneal epithelial defects (PCED), which result in corneal scarring, ulceration, opacification, corneal neovascularization, and, ultimately, visual compromise and vision loss. The current standard of care can include lubricants, ointments, bandage lenses, amniotic membranes, autologous serum eye drops, and corneal transplants. Various inherent problems exist with application and administration of these treatments, which often may not result in a completely healed surface. A topically applicable compound capable of promoting corneal epithelial cell proliferation and/or migration would be ideal to accelerate healing. We hypothesize that human growth hormone (HGH) is such a compound. In a recent study, HGH was shown to activate signal transducer and activators of transcription-5 (STAT5) signaling and promote corneal wound healing by enhancing corneal epithelial migration in a co-culture system of corneal epithelial cells and fibroblasts. These effects require an intact communication between corneal epithelia and fibroblasts. Further, HGH promotes corneal wound healing in a rabbit debridement model, thus demonstrating the effectiveness of HGH in vivo as well. In conclusion, HGH may represent an exciting and effective topical therapeutic to promote corneal wound healing. PMID- 26045236 TI - Controversies Regarding the Role of Polar Lipids in Human and Animal Tear Film Lipid Layer. PMID- 26045235 TI - High-Resolution Optical Coherence Tomography as an Adjunctive Tool in the Diagnosis of Corneal and Conjunctival Pathology. AB - PURPOSE: To evaluate the use of a commercially available, high-resolution, spectral-domain optical coherence tomography (HR-OCT) device in the diagnosis of corneal and conjunctival pathologies, with a focus on malignant lesions. METHODS: Eighty-two eyes of 71 patients were enrolled in this prospective case series, including 10 normal eyes, 21 with ocular surface squamous neoplasia (OSSN), 24 with a pterygium or pingueculum, 3 with lymphoma, 18 with pigmented conjunctival lesions (nevus, flat melanosis, or melanoma), and 6 with Salzmann nodular degeneration. Subjects were imaged using photography and HR-OCT (RTVue, Optovue, Fremont, CA). When clinically indicated, surgery was performed and histopathologic specimens were correlated with OCT images. RESULTS: HR-OCT was useful in differentiating among various lesions based on optical signs. Specifically, in OSSN, HR-OCT findings included epithelial thickening and hyper reflectivity, whereas pterygia and pinguecula showed a subepithelial mass under thinner epithelium. In lymphoma, a hypo-reflective, homogenous subepithelial mass was observed. Differentiating between pigmented lesions with HR-OCT was more difficult, but certain characteristics could be identified. Eyes with nevi and melanoma both displayed intensely hyper-reflective basal epithelial layers and discrete subepithelial lesions, but could be differentiated by the presence of cysts in nevi and intense shadowing of sublesional tissue in most melanomas. CONCLUSION: We found that a commercially available HR-OCT was a useful noninvasive adjunctive tool in the diagnosis of ocular surface lesions. PMID- 26045237 TI - Spontaneous Blinking from a Tribological Viewpoint. AB - The mechanical forces between the lid wiper and the ocular surface, and between a contact lens and the lid wiper, are reported to be related to dry eye symptoms. Furthermore, the mechanical forces between these sliding partners are assumed to be related to the ocular signs of lid-wiper epitheliopathy (LWE) and lid-parallel conjunctival folds (LIPCOF). Recent literature provides some evidence that a contact lens with a low coefficient of friction (CoF) improves wearing comfort by reducing the mechanical forces between the contact lens surface and the lid wiper. This review discusses the mechanical forces during spontaneous blinks from a tribological perspective, at both low and high sliding velocities, in a healthy subject. It concludes that the coefficient of friction of the ocular surfaces appears to be strongly comparable to that of hydrophilic polymer brushes at low sliding velocity, and that, with increased sliding velocity, there is no wear at the sliding partners' surfaces thanks to the presence of a fluid film between the two sliding partners. In contrast, in the case of dry eye, the failure to maintain a full fluid film lubrication regime at high blinking speeds may lead to increased shear rates, resulting in deformation and wear of the sliding pairs. These shear rates are most likely related to tear film viscosity. PMID- 26045238 TI - Investing in New Therapies for Ocular Surface Disease. PMID- 26045239 TI - Efficacy and Safety of Topical 0.05% Cyclosporine Eye Drops in the Treatment of Dry Eye Syndrome: A Systematic Review and Meta-analysis. AB - A systematic review was performed to evaluate the safety and efficacy of topical 0.05% cyclosporine in treating patients with dry eye syndrome (DES). Twelve qualified randomized-controlled trials incorporating 1367 patients were analyzed. In comparison to controls, patients who were on topical 0.05% cyclosporine eye drops had lower Ocular Surface Disease Index scores (mean difference [MD]=4.10, 95% CI: 0.25-7.96, P=.04), longer tear film breakup time (MD=2.30 seconds, 95% CI: 0.75-3.86, P=.004), improved Schirmer I scores (MD=2.77 mm/5min, 95% CI: 1.63 3.91, P=.00001), reduced corneal fluorescein staining (standardized mean difference [SMD]=0.61, 95% CI: 0.07-1.15, P=.03), and higher goblet cell densities (SMD=1.68, 95% CI: 0.54-2.81, P=.004). However, there were more adverse effects in the cyclosporine patient group (odds ratio=1.64, 95% CI: 1.17-2.30, P=.004). Topical 0.05% cyclosporine eye drops twice daily significantly improved both the objective and subjective outcomes in DES patients. The study limitations in the clinical, methodological and statistical heterogeneities are discussed. PMID- 26045242 TI - Errata: "Atmospheric pressure nonthermal plasmas for bacterial biofilm prevention and eradication" [Biointerphases 10, 029404 (2015)]. PMID- 26045241 TI - Impact of multiple transarterial chemoembolization treatments on hepatocellular carcinoma for patients awaiting liver transplantation. PMID- 26045240 TI - Design of Block Copolymer Costabilized Nonionic Microemulsions and Their In Vitro and In Vivo Assessment as Carriers for Sustained Regional Delivery of Ibuprofen via Topical Administration. AB - Nonionic surfactants (caprylocaproyl macrogol-8 glycerides, octoxynol-12, polysorbate-20, and polyethylene glycol-40 hydrogenated castor oil) (47.03%, w/w), costabilizer (poloxamer 407) (12%-20%, w/w), oil (isopropyl myristate) (5.22%, w/w), water (q.s. ad 100%, w/w), and ibuprofen (5%, w/w) were used to develop oil-in-water microemulsions with Newtonian flow behavior, low viscosity (from 368 +/- 38 to 916 +/- 46 mPa s), and average droplet size from 14.79 +/- 0.31 to 16.54 +/- 0.75 nm. Ibuprofen in vitro release from the microemulsions was in accordance with zero-order kinetics (R0(2) > 0.99) for at least 12 h. The maximum drug release rate (3.55%h(-1) ) was from the microemulsion M3 comprising 16%, w/w of poloxamer 407. The release rate of ibuprofen from the reference hydrogel followed Higuchi kinetics (RH(2) > 0.99), and drug amount released after the 6th hour was negligible. In a rat model of inflammation, the microemulsion M3 was significantly more efficacious than the reference hydrogel in exerting antihyperalgesic effects in prophylactic topical treatment, whereas they were comparable in therapeutic treatment as well as in producing antiedematous effect in both protocols. No obvious skin irritation was observed in in vivo studies. The developed nonionic surfactants-based microemulsions containing the optimal concentration of poloxamer 407 could be promising carriers for sustained regional delivery of ibuprofen via topical administration. PMID- 26045243 TI - Successful Rituximab Therapy in Steroid-Resistant, Cryptogenic Organizing Pneumonia: A Case Series. AB - Cryptogenic organizing pneumonia (COP) is an interstitial lung disease that is usually responsive to corticosteroid treatment. The treatment of COP has not been studied in randomized controlled trials; thus, treatment decisions are based on practice guidelines. We herein present, for the first time, 4 cases of patients with biopsy-proven COP who did not respond to corticosteroids but benefited from rituximab therapy. This report consists of a retrospective case series of patients who experienced steroid-resistant, biopsy-proven COP. Patients included in this case series suffered from acute or chronic COP and did not respond to corticosteroid treatment for a few weeks to months but later responded to rituximab. In a series of 4 patients, 1 patient had a complete radiological and clinical response after rituximab therapy, and the steroids could be gradually tapered. Three patients had a chronic course but had been able to lower steroid dosage or even discontinue the drug after being treated with rituximab. Since 40% of the patients with COP do not respond to or stay dependent on steroids, we think that even the ability to lower the steroid dosage by using rituximab as a steroid-sparing agent with a good safety profile is worth the effort. However, further studies are warranted. PMID- 26045244 TI - Determinant-based classification and revision of the Atlanta classification, which one should we choose to categorize acute pancreatitis? AB - BACKGROUND: Two new systems of acute pancreatitis (AP) severity classification, namely, the determinant-based classification (DBC) and the revision of the Atlanta classification (RAC), were recently published. Information is lacking on the differences between the two systems. METHODS: We analyzed data from adult patients with AP (973 episodes), admitted to West China Hospital from July 2012 through March 2013. We validated and compared the DBC and RAC systems by investigating the discordances between the RAC and DBC. RESULTS: Using the RAC system, 66%, 27%, and 7% of the patients were categorized as mild, moderately severe, and severe, respectively. Using the DBC system, 83%, 7%, 7%, and 2% patients were determined to have mild, moderate, severe, and critical AP, respectively. The mortality and ICU admission rates were similar between the subgroups of the severe category under the RAC system. The severe and critical categories had similar mortality rates [35% (7/20) vs. 29% (20/70), P = 0.59] based on DBC. A subgroup of severe category of DBC (IPN and no persistent OF) had significantly lower mortality rate than the other two subgroups of severe category of DBC (SPN and persistent OF; persistent OF and no PN) [0% (0/18) vs. 29% (10/34) vs. 56% (10/18), P < 0.05]. CONCLUSION: Some subgroups of severe categories under the DBC system did not accurately reflected clinical outcomes. RAC seemed to be a better choice to guide the selection of patient populations for clinical research and provide a more accurate description of AP classification in the clinical setting than DBC. PMID- 26045245 TI - Synergistic Interaction of Retigabine with Levetiracetam in the Mouse Maximal Electroshock-Induced Seizure Model: A Type II Isobolographic Analysis. AB - BACKGROUND/AIMS: To assess interactions between retigabine and levetiracetam in suppressing maximal electroshock-induced tonic seizures in Albino Swiss mice, type II isobolographic analysis was used. Total brain antiepileptic drug concentrations were measured with high pressure liquid chromatography. RESULTS: The combinations of retigabine with levetiracetam at the fixed-ratios of 1:5 and 1:10 were supra-additive (synergistic; p < 0.05) in terms of seizure suppression, while the combinations at the fixed-ratios of 1:1 and 1:2 were additive. No pharmacokinetic changes in total brain concentrations of levetiracetam and retigabine were documented, indicating the pharmacodynamic nature of interaction between these antiepileptic drugs in the mouse maximal electroshock-induced tonic seizure model. CONCLUSION: The combination of retigabine with levetiracetam at the fixed-ratios of 1:5 and 1:10 appears to be particularly beneficial combination exerting supra-additive interaction in suppressing maximal electroshock-induced tonic seizures. PMID- 26045246 TI - GLYCO 23 XXIII International Symposium on Glycoconjugates. PMID- 26045247 TI - Receptor-based virtual screening protocol for drug discovery. AB - Computational aided drug design (CADD) is presently a key component in the process of drug discovery and development as it offers great promise to drastically reduce cost and time requirements. In the pharmaceutical arena, virtual screening is normally regarded as the top CADD tool to screen large libraries of chemical structures and reduce them to a key set of likely drug candidates regarding a specific protein target. This chapter provides a comprehensive overview of the receptor-based virtual screening process and of its importance in the present drug discovery and development paradigm. Following a focused contextualization on the subject, the main stages of a virtual screening campaign, including its strengths and limitations, are the subject of particular attention in this review. In all of these stages special consideration will be given to practical issues that are normally the Achilles heel of the virtual screening process. PMID- 26045248 TI - Dynamic fluid flow induced mechanobiological modulation of in situ osteocyte calcium oscillations. AB - Distribution of intramedullary pressure (ImP) induced bone fluid flow has been suggested to influence the magnitude of mechanotransductory signals within bone. As osteocytes have been suggested as major mechanosensors in bone network, it is still unclear how osteocytes embedded within a mineralized bone matrix respond to the external mechanical stimuli derived from direct coupling of dynamic fluid flow stimulation (DFFS). While in vitro osteocytes show unique Ca(2+) oscillations to fluid shear, the objective of this study was to use a confocal imaging technique to visualize and quantify Ca(2+) responses in osteocytes in situ under DFFS into the marrow cavity of an intact ex vivo mouse femur. This study provided significant technical development for evaluating mechanotransduction mechanism in bone cell response by separation of mechanical strain and fluid flow factors using ImP stimulation, giving the ability for true real-time imaging and monitoring of bone cell activities during the stimulation. Loading frequency dependent Ca(2+) oscillations in osteocytes indicated the optimized loading at 10Hz, where such induced response was significantly diminished via blockage of the Wnt/beta-catenin signaling pathway. The results provided a pilot finding of the potential crosstalk or interaction between Wnt/beta-catenin signaling and Ca(2+) influx signaling of in situ osteocytes in response to mechanical signals. Findings from the present study make a valuable tool to investigate how in situ osteocytes respond and transduce mechanical signals, e.g. DFFS, as a central mechanosensor. PMID- 26045249 TI - How Smart are Smartphone Apps for Smoking Cessation? A Content Analysis. AB - INTRODUCTION: Smartphone technology is ideally suited to provide tailored smoking cessation support, yet it is unclear to what extent currently existing smartphone "apps" use tailoring, and if tailoring is related to app popularity and user rated quality. METHODS: We conducted a content analysis of Android smoking cessation apps (n = 225), downloaded between October 1, 2013 to May 31, 2014. We recorded app popularity (>10,000 downloads) and user-rated quality (number of stars) from Google Play, and coded the existence of tailoring features in the apps within the context of using the 5As ("ask," "advise," "assess," "assist," and "arrange follow-up"), as recommended by national clinical practice guidelines. RESULTS: Apps largely provided simplistic tools (eg, calculators, trackers), and used tailoring sparingly: on average, apps addressed 2.1 +/- 0.9 of the 5As and used tailoring for 0.7 +/- 0.9 of the 5As. Tailoring was positively related to app popularity and user-rated quality: apps that used two way interactions (odds ratio [OR] = 5.56 [2.45-12.62]), proactive alerts (OR = 3.80 [1.54-9.38]), responsiveness to quit status (OR = 5.28 [2.18-12.79]), addressed more of the 5As (OR = 1.53 [1.10-2.14]), used tailoring for more As (OR = 1.67 [1.21-2.30]), and/or used more ways of tailoring 5As content (OR = 1.35 [1.13-1.62]) were more likely to be frequently downloaded. Higher star ratings were associated with a higher number of 5As addressed (b = 0.16 [0.03-0.30]), a higher number of 5As with any level of tailoring (b = 0.14 [0.01-0.27]), and a higher number of ways of tailoring 5As content (b = 0.08 [0.002-0.15]). CONCLUSIONS: Publically available smartphone smoking cessation apps are not particularly "smart": they commonly fall short of providing tailored feedback, despite users' preference for these features. PMID- 26045250 TI - Complementing the Standard Multicomponent Treatment for Smokers With Denicotinized Cigarettes: A Randomized Trial. AB - INTRODUCTION: Standard treatments (STs) for smoking cessation typically combine pharmacotherapy and behavioral support but do not address the sensory and behavioral aspects of smoking which may play a role in maintaining smoking behavior. Replacing such sensations temporarily after cessation may enhance treatment efficacy. We hypothesized that denicotinized cigarettes (DNCs), which have a very low nicotine content but provide these sensory and behavioral stimuli, could help alleviate urges to smoke and tobacco withdrawal symptoms and in turn enhance the efficacy of ST. METHODS: Two hundred smokers seeking treatment received nine weekly behavioral support sessions and pharmacotherapy (100 used varenicline, 100 used nicotine replacement therapy). They were randomized on the target quit day to receive 280 DNCs (used ad libitum over 2 weeks in addition to ST) or ST alone. RESULTS: Urge-to-smoke frequency (2.61 vs. 2.96, P = .03) but not strength (2.85 vs. 3.10, P = .20) in the first week of abstinence was significantly lower in DNC users versus ST alone. There were no differences in composite withdrawal scores between groups. Abstinence was significantly higher among DNC users versus ST alone at 1 (OR = 2.07; 95% CI: 1.63% to 3.70%) and 4 weeks (OR = 1.83; 95% CI: 1.05% to 3.21%), but not at 12 weeks (OR = 1.42; 95% CI: 0.79% to 2.55%). DNC use was a significant predictor of abstinence at 1 and 4 weeks (OR = 2.63; 95% CI: 1.40% to 4.93% and OR = 2.38; 95% CI: 1.26% to 4.46%), but not at 12 weeks. CONCLUSIONS: Adding DNCs to ST has the potential to assist smokers early in their quit attempt, but research is needed to determine how best to utilize DNCs in treatment. PMID- 26045251 TI - Determination of Nicotine Content and Delivery in Disposable Electronic Cigarettes Available in the United States by Gas Chromatography-Mass Spectrometry. AB - INTRODUCTION: Electronic cigarettes (E-Cigs) are popular alternatives to conventional tobacco cigarettes. Disposable E-Cigs are single-use devices that emit aerosols from a nicotine-containing solution (e-liquid) by activating a heating coil during puffing. However, due to lack of regulations and standards, it is unclear how product claims are aligning with actual content and performance. Some analytical methods for characterizing E-Cigs are still in an exploratory phase. METHODS: Five products of disposable E-Cigs (purchased March April, 2014 from a local smoke shop and an on-line US distributor) were studied for nicotine content, number of puffs obtained before depletion, portion of nicotine delivered via aerosolization, and e-liquid pH. Protocols were developed to consistently extract e-liquid from puffed and unpuffed E-Cigs. An in-house mechanical puffing machine was used to consistently puff E-Cig aerosols onto filter pads. A gas chromatography-mass spectrometry method was developed that produced sensitive and repeatable nicotine determinations. RESULTS: Under our experimental parameters, results showed a disparity between nicotine content and number of puffs achieved relative to what was claimed on product packaging. The portion of nicotine delivered to filter pads was often less than half that which was available, indicating much of the nicotine may be left in the E-Cig upon depletion. CONCLUSIONS: Analyses of unpuffed E-Cigs by gas chromatography-mass spectrometry indicate the nicotine content of these products can be considerably different from manufacture's labeling. Furthermore, a large portion of the nicotine in E-Cigs may not be transferred to the user, and that which is transferred, may often be in the less bioavailable form. PMID- 26045252 TI - Effect of a Digital Social Media Campaign on Young Adult Smoking Cessation. AB - INTRODUCTION: Social media (SM) may extend the reach and impact for smoking cessation among young adult smokers. To-date, little research targeting young adults has been done on the use of SM to promote quitting smoking. We assessed the effect of an innovative multicomponent web-based and SM approach known as Break-it-Off (BIO) on young adult smoking cessation. METHODS: The study employed a quasi-experimental design with baseline and 3-month follow-up data from 19 to 29-year old smokers exposed to BIO (n = 102 at follow-up) and a comparison group of Smokers' Helpline (SHL) users (n = 136 at follow-up). Logistic regression analysis assessed differences between groups on self-reported 7-day and 30-day point prevalence cessation rates, adjusting for ethnicity, education level, and cigarette use (daily or occasional) at baseline. RESULTS: The campaign reached 37 325 unique visitors with a total of 44 172 visits. BIO users had significantly higher 7-day and 30-day quit rates compared with users of SHL. At 3-month follow up, BIO participants (32.4%) were more likely than SHL participants (14%) to have quit smoking for 30 days (odds ratio = 2.95, 95% CI = 1.56 to 5.57, P < .001) and BIO participants (91%) were more likely than SHL participants (79%) to have made a quit attempt (odds ratio = 2.69, 95% CI = 1.03 to 6.99, P = .04). CONCLUSION: The reach of the campaign and findings on quitting success indicate that a digital/SM platform can complement the traditional SHL cessation service for young adult smokers seeking help to quit. PMID- 26045253 TI - Three Decades of High-Dose Nicotine Gum Dependence Treated With Nicotine Patches. AB - INTRODUCTION: Some long-term nicotine gum users are addicted to nicotine and may need assistance to stop. There is no published evidence on the use of nicotine patches for this purpose. CASE DESCRIPTION: A 45-year old man presented with a 30 year history of high-dose nicotine gum use (up to 200mg nicotine per day). He was highly nicotine dependent and had failed repeatedly to stop using nicotine gum use in the past. Within a week of commencing nicotine patches he was able to cease nicotine gum with minimal discomfort and has remained nicotine-free for 6 months, with abstinence confirmed biochemically. His severe sweating disorder rapidly resolved with cessation of the gum. CONCLUSION: Nicotine patches may be an effective treatment for long-term nicotine gum addiction. PMID- 26045254 TI - CTCF as a multifunctional protein in genome regulation and gene expression. AB - CCCTC-binding factor (CTCF) is a highly conserved zinc finger protein and is best known as a transcription factor. It can function as a transcriptional activator, a repressor or an insulator protein, blocking the communication between enhancers and promoters. CTCF can also recruit other transcription factors while bound to chromatin domain boundaries. The three-dimensional organization of the eukaryotic genome dictates its function, and CTCF serves as one of the core architectural proteins that help establish this organization. The mapping of CTCF-binding sites in diverse species has revealed that the genome is covered with CTCF-binding sites. Here we briefly describe the diverse roles of CTCF that contribute to genome organization and gene expression. PMID- 26045255 TI - Effects of sevoflurane on tight junction protein expression and PKC-alpha translocation after pulmonary ischemia-reperfusion injury. AB - Pulmonary dysfunction caused by ischemia-reperfusion injury is the leading cause of mortality in lung transplantation. We aimed to investigate the effects of sevoflurane pretreatment on lung permeability, tight junction protein occludin and zona occludens 1 (ZO-1) expression, and translocation of protein kinase C (PKC)-alpha after ischemia-reperfusion. A lung ischemia-reperfusion injury model was established in 96 male Wistar rats following the modified Eppinger method. The rats were divided into four groups with 24 rats in each group: a control (group C), an ischemia-reperfusion group (IR group), a sevoflurane control group (sev-C group), and a sevoflurane ischemia-reperfusion group (sev-IR group). There were three time points in each group: ischemic occlusion for 45 min, reperfusion for 60 min and reperfusion for 120 min; and there were six rats per time point. For the 120-min reperfusion group, six extra rats underwent bronchoalveolar lavage. Mean arterial pressure (MAP) and pulse oxygen saturation (SpO2) were recorded at each time point. The wet/dry weight ratio and lung permeability index (LPI) were measured. Quantitative RT-PCR and Western blot were used to measure pulmonary occludin and ZO-1, and Western blot was used to measure cytosolic and membranous PKC-alpha in the lung. Lung permeability was significantly increased after ischemia-reperfusion. Sevoflurane pretreatment promoted pulmonary expression of occludin and ZO-1 after reperfusion and inhibited the translocation of PKC-alpha. In conclusion, sevoflurane pretreatment alleviated lung permeability by upregulating occludin and ZO-1 after ischemia-reperfusion. Sevoflurane pretreatment inhibited the translocation and activation of PKC-alpha, which also contributed to the lung-protective effect of sevoflurane. PMID- 26045256 TI - Stem Cells in Wound Healing: The Future of Regenerative Medicine? A Mini-Review. AB - The increased risk of disease and decreased capacity to respond to tissue insult in the setting of aging results from complex changes in homeostatic mechanisms, including the regulation of oxidative stress and cellular heterogeneity. In aged skin, the healing capacity is markedly diminished resulting in a high risk for chronic wounds. Stem cell-based therapies have the potential to enhance cutaneous regeneration, largely through trophic and paracrine activity. Candidate cell populations for therapeutic application include adult mesenchymal stem cells, embryonic stem cells and induced pluripotent stem cells. Autologous cell-based approaches are ideal to minimize immune rejection but may be limited by the declining cellular function associated with aging. One strategy to overcome age related impairments in various stem cell populations is to identify and enrich with functionally superior stem cell subsets via single cell transcriptomics. Another approach is to optimize cell delivery to the harsh environment of aged wounds via scaffold-based cell applications to enhance engraftment and paracrine activity of therapeutic stem cells. In this review, we shed light on challenges and recent advances surrounding stem cell therapies for wound healing and discuss limitations for their clinical adoption. PMID- 26045257 TI - Breaking bad: R-loops and genome integrity. AB - R-loops, nucleic acid structures consisting of an RNA-DNA hybrid and displaced single-stranded (ss) DNA, are ubiquitous in organisms from bacteria to mammals. First described in bacteria where they initiate DNA replication, it now appears that R-loops regulate diverse cellular processes such as gene expression, immunoglobulin (Ig) class switching, and DNA repair. Changes in R-loop regulation induce DNA damage and genome instability, and recently it was shown that R-loops are associated with neurodegenerative disorders. We discuss recent developments in the field; in particular, the regulation and effects of R-loops in cells, their effect on genomic and epigenomic stability, and their potential contribution to the origin of diseases including cancer and neurodegenerative disorders. PMID- 26045260 TI - Bile Acids as Signal Integrators and Metabolic Modulators. Preface. PMID- 26045259 TI - Stem cell mechanobiology: diverse lessons from bone marrow. AB - A stem cell niche is defined by various chemical and physical features that influence whether a stem cell remains quiescent, divides, or differentiates. We review mechanical determinants that affect cell fate through actomyosin forces, nucleoskeleton remodeling, and mechanosensitive translocation of transcription factors. Current methods for physical characterization of tissue microenvironments are summarized together with efforts to recapitulate niche mechanics in culture. We focus on mesenchymal stem cells, particularly in osteogenesis and adipogenesis, and on blood stem cells - both of which reside in mechanically diverse marrow microenvironments. Given the explosion of efforts with pluripotent stem cells, the evident mechanosensitivity of clinically relevant, multipotent marrow cells underscores an increasing need to examine and understand in vivo and in vitro physical properties on length scales that cells sense. PMID- 26045261 TI - Progesterone metabolites as farnesoid X receptor inhibitors. AB - Sulfated progesterone metabolites rise 100-fold in the third trimester of human pregnancy and have been shown to be elevated further in the gestational disorder intrahepatic cholestasis of pregnancy (ICP). Typical concentrations of progesterone sulfates range from 1 to 10 umol/L in an uncomplicated pregnancy and rise to approximately 40 umol/L in ICP. At this level they can influence bile acid and lipid metabolism. Studies using human and rodent specimens have shown that sulfated metabolites of progesterone competitively inhibit bile acid homeostasis pathways by functioning as partial agonists of farnesoid X receptor (FXR). This explains the loss of induction of FXR target genes in ICP, and may explain susceptibility to hypercholanaemia and dyslipidaemia in the second half of human pregnancy. Furthermore, progesterone sulfates are competitive inhibitors of biliary influx (NTCP) and efflux (BSEP) transport proteins, actions likely to further exacerbate hypercholanaemia and cholestasis. PMID- 26045262 TI - Diet1 is a regulator of fibroblast growth factor 15/19-dependent bile acid synthesis. AB - BACKGROUND: A fascinating aspect of bile acid homeostasis is the coordination between bile acid uptake in intestine and hepatic bile acid synthesis. In response to bile acid uptake in enterocytes, farnesoid X receptor is activated and induces transcription of fibroblast growth factor (FGF)15 in mice, or FGF19 in humans. FGF15/19 is secreted into the enterohepatic circulation, and through activation of hepatic receptors, leads to repression of Cyp7a1, a rate-limiting enzyme for bile acid synthesis. Using a genetic approach, we identified a novel protein, Diet1, as a control point for FGF15/19 production. KEY MESSAGES: Mice with a Diet1-null mutation have reduced FGF15 secretion, causing impaired feedback repression of hepatic bile acid synthesis, and increased fecal bile acid excretion. As a result, Diet1-deficient mice constitutively convert cholesterol to bile acids and are resistant to diet-induced hypercholesterolemia and atherosclerosis. Diet1 affects FGF15/19 production at the posttranscriptional level, and the proteins appear to have overlapping subcellular localization in enterocytes. Diet1 appears to be a control point for the production of FGF15/19 in enterocytes, and thus a regulator of bile acid and lipid homeostasis. Studies to evaluate the role of common and rare DIET1 genetic variants in human health and disease are warranted. CONCLUSIONS: Further elucidation of the Diet1-FGF15/19 interaction will provide new insights into the intricate regulatory mechanisms underlying bile acid metabolism. PMID- 26045258 TI - YAP and TAZ: a nexus for Hippo signaling and beyond. AB - The Hippo pathway is a potent regulator of cellular proliferation, differentiation, and tissue homeostasis. Here we review the regulatory mechanisms of the Hippo pathway and discuss the function of Yes-associated protein (YAP)/transcriptional coactivator with a PDZ-binding domain (TAZ), the prime mediators of the Hippo pathway, in stem cell biology and tissue regeneration. We highlight their activities in both the nucleus and the cytoplasm and discuss their role as a signaling nexus and integrator of several other prominent signaling pathways such as the Wnt, G protein-coupled receptor (GPCR), epidermal growth factor (EGF), bone morphogenetic protein (BMP)/transforming growth factor beta (TGFbeta), and Notch pathways. PMID- 26045263 TI - ATP8B1 and ATP11C: Two Lipid Flippases Important for Hepatocyte Function. AB - P4 ATPases are lipid flippases and transport phospholipids from the exoplasmic to the cytosolic leaflet of biological membranes. Lipid flipping is important for the biogenesis of transport vesicles. Recently it was shown that loss of the P4 ATPases ATP8B1 and ATP11C are associated with severe Cholestatic liver disease. Mutation of ATP8B1 cause progressive familial Intrahepatic Cholestasis type 1 (PFIC1)and benign recurrent intrahepatic cholestasis type 1 (BRIC 1). From our observations we hypothesized that ATP8B1 deficiency causes a phospholipids randomization at the canalicular membrane, which results in extraction of cholesterol due to increase sensitivity of the canalicular membrane. Deficiency of ATP11C causes conjugated hyperbilirubinemia. In our preliminary result we observed accumulation of unconjugated bile salts in Atp11c deficient mice probably because of regulation in the expression or function of OATP1B2. Similar to ATP8B1, ATP11C have regulation on membrane transporters. PMID- 26045264 TI - The Bile Acid Receptor TGR5 and Liver Regeneration. AB - BACKGROUND: Most of the literature on the bile acid (BA) membrane receptor TGR5 is dedicated to its potential role in the metabolic syndrome, through its regulatory impact on energy expenditure, insulin and GLP-1 secretion, and inflammatory processes. While the receptor was cloned in 2002, very little data are available on TGR5 functions in the normal and diseased liver. However, TGR5 is highly expressed in Kupffer cells and liver endothelial cells, and is particularly enriched in the biliary tract [cholangiocytes and gallbladder (GB) smooth muscle cells]. We recently demonstrated that TGR5 has a crucial protective impact on the liver in case of BA overload, including after partial hepatectomy. KEY MESSAGES: TGR5-KO mice after PH exhibited periportal bile infarcts, excessive hepatic inflammation and defective adaptation of biliary composition (bicarbonate and chloride). Most importantly, TGR5-KO mice had a more hydrophobic BA pool, with more secondary BA than WT animals, suggesting that TGR5-KO bile may be harmful for the liver, mainly in situations of BA overload. As GB is both the tissue displaying the highest level of TGR5 expression and a crucial physiological site for the regulation of BA pool hydrophobicity by reducing secondary BA, we investigated whether TGR5 may control BA pool composition through an impact on GB. Preliminary data suggest that in the absence of TGR5, reduced GB filling dampens the cholecystohepatic shunt, resulting in more secondary BA, more hydrophobic BA pool and extensive liver injury in case of BA overload. CONCLUSIONS: In the setting of BA overload, TGR5 is protective of the liver through the regulation of not only secretory and inflammatory processes, but also through the control of BA pool composition, at least in part by targeting the GB. Thereby, TGR5 appears to be crucial for protecting the regenerating liver from BA overload. PMID- 26045266 TI - Bile acids and stellate cells. AB - Hepatic stellate cells are mainly known for their contribution to fibrogenesis in chronic liver diseases, but their identity and function in normal liver remain unclear. They were recently identified as liver-resident mesenchymal stem cells (MSCs), which can differentiate not only into adipocytes and osteocytes, but also into liver epithelial cells such as hepatocytes and bile duct cells as investigated in vitro and in vivo. During hepatic differentiation, stellate cells and other MSCs transiently develop into liver progenitor cells with epithelial characteristics before hepatocytes are established. Transplanted stellate cells from the liver and pancreas are able to contribute to liver regeneration in stem cell-based liver injury models and can also home into the bone marrow, which is in line with their classification as MSCs. There is experimental evidence that bile acids support liver regeneration and are able to activate signaling pathways in hepatic stellate cells. For this reason, it is important to analyze the influence of bile acids on developmental fate decisions of hepatic stellate cells and other MSC populations. PMID- 26045265 TI - Bile Acids as Hormones: The FXR-FGF15/19 Pathway. AB - While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis. FGF15/19 also stimulates gallbladder filling. Thus, the bile acid-FXR-FGF15/19 signaling pathway regulates diverse aspects of the postprandial enterohepatic response. Pharmacologically, this endocrine pathway provides exciting new opportunities for treating metabolic disease and bile acid-related disorders such as primary biliary cirrhosis and bile acid diarrhea. Both FXR agonists and FGF19 analogs are currently in clinical trials. PMID- 26045268 TI - Relationship between Obesity, Gut Microbiome and Hepatocellular Carcinoma Development. AB - During the past several decades, the percentage of excess bodyweight and obese adults and children has increased dramatically, and is becoming one of the most serious public health problems worldwide. Extensive epidemiological studies have revealed that there is a strong link between obesity and some common cancers. However, the exact molecular mechanisms linking obesity and cancer are not fully understood yet. Recently, we have reported that dietary or genetic obesity provokes alterations of gut microbiota profile, thereby increasing the levels of deoxycholic acid (DCA), a secondary bile acid produced solely by the 7alpha dehydroxylation of primary bile acids carried out by gut bacteria. The enterohepatic circulation of DCA provokes DNA damage and consequent cellular senescence in hepatic stellate cells (HSCs) which, in turn, secrete various inflammatory and tumor-promoting factors in the liver, thus facilitating hepatocellular carcinoma (HCC) development in mice. Interestingly, signs of senescence-associated secretory phenotypes were also observed in the HSCs in the area of HCC arising in patients with nonalcoholic steatohepatitis, implying that a similar pathway is likely to contribute to at least certain aspects of obesity associated HCC development in humans as well. In this review, I will provide an overview of our recent work and discuss the next steps, focusing on the potential clinical implications of our findings. PMID- 26045267 TI - Gut microbiota, cirrhosis, and alcohol regulate bile acid metabolism in the gut. AB - The understanding of the complex role of the bile acid-gut microbiome axis in health and disease processes is evolving rapidly. Our focus revolves around the interaction of the gut microbiota with liver diseases, especially cirrhosis. The bile acid pool size has recently been shown to be a function of microbial metabolism of bile acid, and regulation of the microbiota by bile acids is important in the development and progression of several liver diseases. Humans produce a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in the intestine and liver. Microbes use bile acids, and via FXR signaling this results in a smaller, unconjugated hydrophobic bile acid pool. This equilibrium is critical to maintain health. The challenge is to examine the manifold functions of gut bile acids as modulators of antibiotic, probiotic, and disease progression in cirrhosis, metabolic syndrome, and alcohol use. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. With advancing liver disease and cirrhosis, there is dysbiosis in the fecal, ileal, and colonic mucosa, in addition to a decrease in bile acid concentration in the intestine due to the liver problems. This results in a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa, and increasing production of deoxycholic acid. Alcohol intake speeds up these processes in the subjects with and without cirrhosis without significant FXR feedback. Taken together, these pathways can impact intestinal and systemic inflammation while worsening dysbiosis. The interaction between bile acids, alcohol, cirrhosis, and dysbiosis is an important relationship that influences intestinal and systemic inflammation, which in turn determines progression of the overall disease process. These interactions and the impact of commonly used therapies for liver disease can provide insight into the pathogenesis of inflammation in humans. PMID- 26045269 TI - Interactions between Diet, Bile Acid Metabolism, Gut Microbiota, and Inflammatory Bowel Diseases. AB - The composite human gut microbiomes of Western populations have changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Diets high in saturated fats and refined sugars and low in fiber are leading candidates for these events and for triggering the increased prevalence of immune-mediated diseases like inflammatory bowel disease (IBD). Our studies have shown that consumption of a 'Western' diet high in saturated (milk derived) fat (MF) or n-6 polyunsaturated (safflower oil) fat have similar effects on the structure of the colonic microbiome of wild-type and IL- 10(-/-) mice, characterized by increased Bacteroidetes and decreased Firmicutes. However, the MF diet uniquely promotes the expansion of an immunogenic sulfite-reducing pathobiont, Bilophila wadsworthia, a member of the Deltaproteobacteria and minor component of the gut microbiome. This bacterial bloom results from a MF diet induced shift in hepatic conjugation of bile acids, from glycocholic to taurocholic (TC) acid, which is important for solubilizing the more hydrophobic MF diet. However, it is also responsible for delivery of taurine-derived sulfur to the distal bowel, promoting the assemblage of bile-tolerant microbes such as B. wadsworthia. The bloom of this species promotes a Th1-mediated immune response and the development of colitis in IL-10(-/-) mice. A similar bloom of B. wadsworthia is seen when IL-10(-/-) mice are fed a low-fat diet supplemented with TC. B. wadsworthia colonization of monoassociated germ-free IL-10(-/-) mice was dependent on the host consuming either a high-saturated MF diet or the gavage with TC. Together, these data provide a plausible explanation for the link between diseases such as IBD and dietary-mediated selection of gut microbial pathobionts in genetically susceptible hosts. With this knowledge, it may be possible to mitigate the bloom of these types of pathobionts by modifying the conjugation states of bile acids. PMID- 26045270 TI - Nuclear receptors in acute and chronic cholestasis. AB - BACKGROUND: Nuclear receptors (NRs) form a family of 48 members. NRs control hepatic processes such as bile acid homeostasis, lipid metabolism and mechanisms involved in fibrosis and inflammation. Due to their central role in the regulation of hepatoprotective mechanisms, NRs are promising therapeutic targets in cholestatic disorders. KEY MESSAGES: NRs can be classified into five different physiological clusters. NRs from the 'bile acids and xenobiotic metabolism' and from the 'lipid metabolism and energy homeostasis' clusters are strongly expressed in the liver. Furthermore, NRs from these clusters, such as farnesoid X receptor alpha (FXRalpha), pregnane X receptor (PXR) and peroxisome proliferator activated receptors (PPARs), have been associated with the pathogenesis and the progression of cholestasis. The latter observation is also true for vitamin D receptor (VDR), which is barely detectable in the whole liver, but has been linked to cholestatic diseases. Involvement of VDR in cholestasis is ascribed to a strong expression in nonparenchymal liver cells, such as biliary epithelial cells, Kupffer cells and hepatic stellate cells. Likewise, NRs from other physiological clusters with low hepatic expression, such as estrogen receptor alpha (ERalpha) or reverse-Erb alpha/beta (REV-ERB alpha/beta), may also control pathophysiological processes in cholestasis. CONCLUSIONS: In this review, we will describe the impact of individual NRs on cholestasis. We will then discuss the potential role of these transcription factors as therapeutic targets. PMID- 26045271 TI - Bile acid-induced cholemic nephropathy. AB - Kidney injury in deeply jaundiced patients became known as cholemic nephropathy. This umbrella term covers impaired renal function in cholestatic patients with characteristic histomorphological changes including intratubular cast formation and tubular epithelial cell injury. Cholemic nephropathy represents a widely underestimated but important cause of kidney dysfunction in patients with cholestasis and advanced liver disease. However, the nomenclature is inconsistent since there are numerous synonyms used; the underlying mechanisms of cholemic nephropathy are not entirely clear, and widely accepted diagnostic criteria are still missing. Consequently, the current article aims to summarize the present knowledge on the clinical and morphological characteristics, available preclinical models, derived potential pathomechanisms, and future diagnostic and therapeutic strategies in cholemic nephropathy. Furthermore, we provide a potential research agenda for this evolving field. PMID- 26045272 TI - Stimulation of apical sodium-dependent bile acid transporter expands the bile acid pool and generates bile acids with positive feedback properties. AB - BACKGROUND: Bile acid synthesis has been considered a prototype for how a physiological process is controlled by end product feedback inhibition. By this feedback inhibition, bile acid concentrations are kept within safe ranges. However, careful examination of published rodent data strongly suggests that bile acid synthesis is also under potent positive feedback control by hydrophilic bile acids. KEY MESSAGES: Current concepts on the regulation of bile acid synthesis are derived from mouse models. Recent data have shown that mice have farnesoid X receptor (FXR) antagonistic bile acids capable of quenching responses elicited by FXR agonistic bile acids. This is important to recognize to understand the regulation of bile acid synthesis in the mouse, and in particular to clarify if mouse model findings are valid also in the human situation. CONCLUSIONS: In addition to classic end product feedback inhibition, regulation of bile acid synthesis in the mouse largely appears also to be driven by changes in hepatic levels of murine bile acids such as alpha- and beta-muricholic acids. This has not been previously recognized. Stimulated bile acid synthesis or induction of the apical sodium-dependent bile acid transporter in the intestine, increase the availability of chenodeoxycholic acid in the liver, thereby promoting hepatic conversion of this bile acid into muricholic acids. Recognition of these mechanisms is essential for understanding the regulation of bile acid synthesis in the mouse, and for our awareness of important species differences in the regulation of bile acid synthesis in mice and humans. PMID- 26045274 TI - Sodium taurocholate cotransporting polypeptide acts as a receptor for hepatitis B and D virus. AB - Infection of hepatitis B virus (HBV) remains a major public health problem worldwide. Understanding the viral infection and developing antivirals against HBV have been hampered by the lack of convenient culture systems and animal models for the infection. Sodium taurocholate cotransporting polypeptide (NTCP), a key bile acid transporter expressed in liver, was recently identified as a critical receptor for viral entry of HBV and its satellite virus hepatitis D virus (HDV). This finding enabled a reliable cell culture system for the viruses. Detailed studies have shown that NTCP is the major determinant for the species specificity of HBV and HDV at entry level. NTCP is responsible for most sodium dependent bile salt uptake in liver. The molecular determinant critical for HBV/HDV infection overlaps with that for bile acids transporting on NTCP. We evaluated bile acids as potential antivirals for HBV and HDV infection, and developed bile acid derivatives that effectively block taurocholate transporting as well as viral infections. The discovery that NTCP acts as a receptor for HBV has opens a new door for future studies towards the ultimate goal of curative treatment of HBV infection. PMID- 26045275 TI - The Cholangiocyte Glycocalyx Stabilizes the 'Biliary HCO3 Umbrella': An Integrated Line of Defense against Toxic Bile Acids. AB - BACKGROUND: Destruction of cholangiocytes is the hallmark of chronic cholangiopathies such as primary biliary cirrhosis. Under physiologic conditions, cholangiocytes display a striking resistance to the high, millimolar concentrations of toxic bile salts present in bile. We recently showed that a 'biliary HCO3(-) umbrella', i.e. apical cholangiocellular HCO3(-) secretion, prevents cholangiotoxicity of bile acids, and speculated on a role for extracellular membrane-bound glycans in the stabilization of this protective layer. This paper summarizes published and thus far unpublished evidence supporting the role of the glycocalyx in stabilizing the 'biliary HCO3(-) umbrella' and thus preventing cholangiotoxicity of bile acids. KEY MESSAGES: The apical glycocalyx of a human cholangiocyte cell line and mouse liver sections were visualized by electron microscopy. FACS analysis was used to characterize the surface glycan profile of cultured human cholangiocytes. Using enzymatic digestion with neuraminidase the cholangiocyte glycocalyx was desialylated to test its protective function. Using lectin assays, we demonstrated that the main N-glycans in human and mouse cholangiocytes were sialylated biantennary structures, accompanied by high expression of the H-antigen (alpha1-2 fucose). Apical neuraminidase treatment induced desialylation without affecting cell viability, but lowered cholangiocellular resistance to bile acid-induced toxicity: both glycochenodeoxycholate and chenodeoxycholate (pKa >=4), but not taurochenodeoxycholate (pKa <2), displayed cholangiotoxic effects after desialylation. A 24-hour reconstitution period allowed cholangiocytes to recover to a pretreatment bile salt susceptibility pattern. CONCLUSION: Experimental evidence indicates that an apical cholangiocyte glycocalyx with glycosylated mucins and other glycan-bearing membrane glycoproteins stabilizes the 'biliary HCO3(-) umbrella', thus aiding in the protection of human cholangiocytes against bile acid toxicity. PMID- 26045273 TI - Impact of Inhibiting Ileal Apical versus Basolateral Bile Acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice. AB - BACKGROUND: Bile acid sequestrants have been used for many years to treat hypercholesterolemia by increasing hepatic conversion of cholesterol to bile acids, thereby inducing hepatic LDL receptor expression and clearance of apoB containing particles. In order to further understand the underlying molecular mechanisms linking gut-liver signaling and cholesterol homeostasis, mouse models defective in ileal apical membrane bile acid transport (Asbt-null) and ileal basolateral membrane bile acid transport (Ostalpha-null) were studied under basal and hypercholesterolemic conditions. KEY MESSAGES: Hepatic conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism and a major mechanism for cholesterol elimination. Blocking ileal apical membrane bile acid transport (Asbt-null mice) increases fecal bile acid excretion, hepatic Cyp7a1 expression, and the relative proportion of taurocholate in the bile acid pool, but decreases ileal FGF15 expression, bile acid pool size, and hepatic cholesterol content. In contrast, blocking ileal basolateral membrane bile acid transport (Ostalpha-null mice) increases ileal FGF15 expression, reduces hepatic Cyp7a1 expression, and increases the proportion of tauro-beta-muricholic acid in the bile acid pool. In the hypercholesterolemic apoE-null background, plasma cholesterol levels and measurements of atherosclerosis were reduced in Asbt/apoE null mice, but not in Ostalpha/apoE-null mice. CONCLUSIONS: Blocking the intestinal absorption of bile acids at the apical versus basolateral membrane differentially affects bile acid and cholesterol metabolism, including the development of hypercholesterolemia-associated atherosclerosis. The molecular mechanism likely involves an altered regulation of ileal FGF15 expression. PMID- 26045276 TI - Genetic contributors and modifiers of biliary atresia. AB - To date, the etiology and pathogenic underpinning of the progression of the most prevalent serious neonatal liver disease, biliary atresia, remains elusive. This disease presents as an aggressive form of neonatal cholestasis characterized by the destruction and obliteration of the extrahepatic bile ducts within the first few weeks of life and a rapid progression of biliary fibrosis, likely due to unremitting cholestasis and retention of biliary constituents including bile acids. In ~5% of patients, biliary atresia is associated with laterality features, suggesting a genetic underpinning to a disease that begins soon after birth. However, biliary atresia does not occur within families and twins are discordant, indicating an absence of strict mendelian inheritance. Despite this, genes related to bile duct dysmorphogenesis/ciliopathies overlapping with features of biliary atresia in both humans and nonhuman model systems have been proposed. Taken together, strict genetic etiologies leading to a common pathway of a neonatal cholangiopathy resulting in biliary atresia remain elusive. Contributions from fibrogenesis- and inflammation-based studies suggest that early engagement of these pathways contributes to disease progression, but a recent double-blind study did not suggest any benefit from early use of corticosteroids. However, there are genetic contributions to the adaptation and response to cholangiopathies and cholestasis that may be present in certain populations that likely impact upon the response to hepatoportoenterostomy and subsequent biliary tract function. Studies utilizing next generation sequencing technologies (e.g., exome analysis) are ongoing in several laboratories around the world; they are expected to provide insights into genetic contributions to biliary atresia outcomes. Altogether, combinations of exome sequencing and large population studies are expected to reveal causative and modifying genes relevant to patients with biliary atresia as a means to provide therapeutic targets and potential opportunities for genetic screening. PMID- 26045277 TI - Nuclear receptor variants in liver disease. AB - This snapshot reviews the current state of knowledge on genetic variants of nuclear receptors (NRs) involved in regulating various aspects of liver metabolism. Interindividual differences in responses to diet and other 'in-' and environmental stressors can be caused by variants in components of the NR regulatory gene network. We recapitulate recent evidence for the application of NRs in genetic diagnosis of monogenic liver disease. Genetic analysis of multifactorial liver diseases, such as nonalcoholic fatty liver disease and diabetes mellitus, pinpoints key players in disease predisposition and progression. In particular, NR1H4 variants have been associated with intrahepatic cholestasis of pregnancy and gallstone disease. Other examples include studies of NR1I2 and NR1I3 polymorphisms in patients with drug-induced liver injury and NR5A2 variation in cholangiocarcinoma. Associations of NR gene variants have been identified in patients with dyslipidemia and other metabolic syndrome-associated traits by genome-wide studies. Evidence from these analyses confirms a role for NR variation in common diseases, linking regulatory networks to complex and variable phenotypes. These new insights into the impact of NR variants offer perspectives for their future use in diagnosis and treatment of common diseases. PMID- 26045278 TI - TGR5 in the Cholangiociliopathies. AB - A plasma membrane-bound G protein-coupled receptor, TGR5, that transmits bile acid signaling into a cellular response primarily via the cAMP pathway is expressed in human and rodent cholangiocytes and is localized to multiple, diverse subcellular compartments, including primary cilia. Ciliary-associated TGR5 plays an important role in cholangiocyte physiology and may contribute to a group of liver diseases referred to as the 'cholangiociliopathies', which include polycystic liver disease (PLD) and, possibly, cholangiocarcinoma and primary sclerosing cholangitis. Based on our observations that (1) ciliated and nonciliated cholangiocytes respond to TGR5 activation differently (i.e. the level of cAMP increases in nonciliated cholangiocytes but decreases in ciliated cells) and (2) hepatic cysts are derived from cholangiocytes that are characterized by both malformed cilia and increased cAMP levels, we hypothesized that TGR5 mediated cAMP signaling in cystic cholangiocytes contributes to hepatic cystogenesis. Indeed, our studies show that TGR5 is overexpressed and mislocalized in cystic cholangiocytes, and when activated by ligands, results in increased intracellular cAMP levels, cholangiocyte hyperproliferation and cyst growth. Our studies also show that genetic elimination of TGR5 in an animal model of PLD inhibits hepatic cystogenesis. Collectively, these data suggest the involvement of TGR5 in PLD and that TGR5 targeting in cystic cholangiocytes may have therapeutic potential. PMID- 26045279 TI - Use of farnesoid X receptor agonists to treat nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease is a common cause of liver related morbidity and mortality. It is closely linked to underlying insulin resistance. It has recently been shown that bile acids modulate insulin signaling and can improve insulin resistance in cell based and animal studies. These effects are mediated in part by activation of farnesoid x receptors by bile acids. In human studies, FXR agonists improve insulin resistance and have recently been shown to improve NAFLD. The basis for the use of FXR agonists for the treatment of NAFLD and early human experience with such agents is reviewed in this paper. PMID- 26045280 TI - Potential of nor-Ursodeoxycholic Acid in Cholestatic and Metabolic Disorders. AB - 24-nor-ursodeoxycholic acid (norUDCA) is a side-chain shortened derivate of ursodeoxycholic acid (UDCA). Since norUDCA is only ineffectively conjugated with glycine or taurine, it has specific physicochemical and therapeutic properties distinct from UDCA. Nonamidated norUDCA undergoes cholehepatic shunting enabling 'ductular targeting' and inducing a bicarbonate-rich hypercholeresis, with cholangioprotective effects. At the same time it has direct anti-inflammatory, antilipotoxic, anti fibrotic, and antiproliferative properties targeting various liver cell populations. norUDCA appears to be one of the most promising novel treatment approaches targeting the liver and the bile duct system at multifactorial and multicellular levels. This review article is a summary of a lecture given at the XXIII International Bile Acid Meeting (Falk Symposium 194) on 'Bile Acids as Signal Integrators and Metabolic Modulators' held in Freiburg, October 8-9, 2014, and summarizes the recent progress with norUDCA as a novel therapeutic approach in cholestatic and metabolic (liver) disorders. PMID- 26045281 TI - Bile Acid Signaling: Mechanism for Bariatric Surgery, Cure for NASH? AB - Bariatric surgery is the most effective and durable treatment option for obesity today. More importantly, beyond weight loss, bariatric procedures have many advantageous metabolic effects including reversal of obesity-related liver disease--nonalcoholic steatohepatitis (NASH). NASH is an important comorbidity of obesity given that it is a precursor to the development of liver cirrhosis that may necessitate liver transplantation in the long run. Simultaneously, we and others have observed increased serum bile acids in humans and animals that undergo bariatric surgery. Specifically, our preclinical studies have included experimental procedures such as 'ileal transposition' or bile diversion and established procedures such as Roux-en-Y gastric bypass and the adjustable gastric band. Importantly, these effects are not simply the result of weight loss since our data show that the resolution of NASH and increase in serum bile acids are not seen in rodents that lose an equivalent amount of weight via food restriction. In particular, we have studied the role of altered bile acid signaling, in the potent impact of a bariatric procedure termed 'vertical sleeve gastrectomy' (VSG). In this review we focus on the mechanisms of NASH resolution and weight loss after VSG surgery. We highlight the fact that bariatric surgeries can be used as 'laboratories' to dissect the mechanisms by which these procedures work to improve obesity and fatty liver disease. We describe key bile acid signaling elements that may provide potential therapeutic targets for 'bariatric mimetic technologies' that could produce benefits similar to bariatric surgery- but without the surgery! PMID- 26045284 TI - Association rule mining in the US Vaccine Adverse Event Reporting System (VAERS). AB - PURPOSE: Spontaneous adverse event reporting systems are critical tools for monitoring the safety of licensed medical products. Commonly used signal detection algorithms identify disproportionate product-adverse event pairs and may not be sensitive to more complex potential signals. We sought to develop a computationally tractable multivariate data-mining approach to identify product multiple adverse event associations. METHODS: We describe an application of stepwise association rule mining (Step-ARM) to detect potential vaccine-symptom group associations in the US Vaccine Adverse Event Reporting System. Step-ARM identifies strong associations between one vaccine and one or more adverse events. To reduce the number of redundant association rules found by Step-ARM, we also propose a clustering method for the post-processing of association rules. RESULTS: In sample applications to a trivalent intradermal inactivated influenza virus vaccine and to measles, mumps, rubella, and varicella (MMRV) vaccine and in simulation studies, we find that Step-ARM can detect a variety of medically coherent potential vaccine-symptom group signals efficiently. In the MMRV example, Step-ARM appears to outperform univariate methods in detecting a known safety signal. CONCLUSIONS: Our approach is sensitive to potentially complex signals, which may be particularly important when monitoring novel medical countermeasure products such as pandemic influenza vaccines. The post-processing clustering algorithm improves the applicability of the approach as a screening method to identify patterns that may merit further investigation. PMID- 26045285 TI - Successful Treatment of Refractory Majocchi's Granuloma with Voriconazole and Review of Published Literature. AB - Majocchi's granuloma (MG) is a rare deep skin dermatophyte infection that can occur either in immunocompetent or in immunocompromised individuals. Oral itraconazole or terbinafine is considered to be the first choice of treatment. We report an immunocompetent man with deep nodular form of MG, the form which is generally found in immunosuppressed individuals. Previous treatment with either oral itraconazole or terbinafine yielded no apparent improvement. After a series of examination, the man was diagnosed as having Trichophyton rubrum-induced MG mixed with bacterial infection as evidenced by growth of Klebsiella pneumoniae in tissue bacterial culture. The patient was treated with a combination of cefoselis and levofloxacin for bacterial clearance followed by voriconazole treatment. After approximately 4 months of voriconazole treatment, the lesions completely resolved. Alternative medicine (voriconazole) can be considered in case of refractory infections during MG treatment. PMID- 26045286 TI - Acute Invasive Pulmonary Aspergillosis Complicating Allergic Bronchopulmonary Aspergillosis: Case Report and Systematic Review. AB - Aspergillus fumigatus can cause a variety of pulmonary syndromes including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis and invasive pulmonary aspergillosis (IPA). Occurrence of IPA and ABPA in the same patient is rare as the risk factors for ABPA and IPA are different. We describe a 45-year-old male with ABPA treated with oral methylprednisolone and itraconazole, who developed acute respiratory failure secondary to IPA, a month later. The patient subsequently improved after systemic antifungal therapy. Presumably, itraconazole by inhibiting CYP3A4 enzyme caused an increase in plasma methylprednisolone levels. This probably led to a profound immunosuppressed state, which predisposed to the development of IPA. We performed a systematic review and identified nine cases of IPA following ABPA. The disease course is fulminant, and only three of the nine patients survived. Physicians treating ABPA patients should be aware of this potentially fatal overlap. Clinical suspicion and early diagnosis are crucial to improve the patient outcomes. PMID- 26045287 TI - [Earlobe crease and cholesterol emboli]. PMID- 26045288 TI - Violence perpetrated by women who use methamphetamine. AB - Methamphetamine (meth) is widely recognized as being associated with violence and aggression. This association is found among women and men, with rates of meth related violence among women possibly being equal to or even exceeding rates among men. This study examined female-perpetrated violence from the phenomenological point of view of 30 women (aged 18-45 years; mean age of 28.5 years) in residential treatment for meth dependence. Of the 30 participants, 80% (n = 24) reported experiencing violence in their lifetimes: 67% (n = 20) had violence perpetrated against them, and 57% (n = 17) had perpetrated violence. Most participants described perpetrating violence when they were 'coming down' off of meth (i.e. withdrawing). Five women (29%) attributed their violent behaviors to meth and said they would not have been violent had they not been using meth. In contrast, 10 women (59%) described pre-existing 'anger issues' that were 'enhanced' by meth. This article describes the timing of meth-related violence, bi-directional violence, men's responses to female-perpetrated violence, aggression in the context of sexual activities, and violence perpetrated against non-partners. A biopsychosocial theoretical framework is useful to interpret the complex explanations that women provide for their perpetration of violence under the influence of chronic meth use. PMID- 26045289 TI - Cardiac contractility in Antarctic teleost is modulated by nitrite through xanthine oxidase and cytochrome p-450 nitrite reductase. AB - In mammalian and non-mammalian vertebrates, nitrite anion, the largest pool of intravascular and tissue nitric oxide storage, represents a key player of many biological processes, including cardiac modulation. As shown by our studies on Antarctic teleosts, nitrite-dependent cardiac regulation is of great relevance also in cold-blooded vertebrates. This study analysed the influence elicited by nitrite on the performance of the perfused beating heart of two Antarctic stenotherm teleosts, the haemoglobinless Chionodraco hamatus (icefish) and the red-blooded Trematomus bernacchii. Since haemoglobin is crucial in nitric oxide homeostasis, the icefish, a naturally occurring genetic knockout for this protein, provides exclusive opportunities to investigate nitric oxide/nitrite signaling. In vivo, nitrite conversion to nitric oxide requires the nitrite reductase activity of xanthine oxidase and cytochrome P-450, thus the involvement of these enzymes was also evaluated. We showed that, in C. hamatus and T. bernacchii, nitrite influenced cardiac performance by inducing a concentration dependent positive inotropic effect which was unaffected by nitric oxide scavenging by PTIO in C. hamatus, while it was abolished in T. bernacchii. Specific inhibition of xanthine oxidase and cytochrome P-450 revealed, in the two teleosts, that the nitrite-dependent inotropism required the nitrite reductase activity of both enzymes. We also found that xanthine oxidase is more expressed in C. hamatus than in T. bernacchii, while the opposite was observed concerning cytochrome P-450. Results suggested that in the heart of C. hamatus and T. bernacchii, nitrite is an integral physiological source of nitric oxide with important signaling properties, which require the nitrite reductase activity of xanthine oxidase and cytochrome P-450. PMID- 26045290 TI - Long-Term Treatment of Restless Legs Syndrome (RLS): An Approach to Management of Worsening Symptoms, Loss of Efficacy, and Augmentation. AB - Restless legs syndrome (RLS) is a common, frequently chronic, sensorimotor neurological disorder characterized by nocturnal leg dysesthesias and an irresistible urge to move the legs, usually resulting in sleep disturbance. Dopaminergic agonists, alpha-2-delta calcium-channel ligands, and opioids have all demonstrated efficacy to relieve symptoms of RLS and improve sleep. However, long-term treatment with dopamine agonists (the most commonly prescribed agents) is often characterized by worsening symptoms and loss of efficacy. A more worrisome complication of dopaminergic agents is augmentation, an iatrogenic worsening of RLS symptoms that can produce progressively more severe symptoms resulting in around-the-clock restlessness and near sleeplessness. Recent research has yielded consensus regarding a precise definition of augmentation and has contributed to improved knowledge regarding strategies for preventing this complication. When RLS symptoms worsen during the course of treatment, the clinician must consider the myriad of environmental, medical, pharmacologic, and psychiatric factors that can exacerbate RLS. In the absence of fully developed, evidence-based guidelines there remains uncertainty regarding the optimal management strategy if augmentation develops. However, we discuss several key principles based on the available published data and the authors' clinical experience. We also explore the recent increasing interest in alternative initial treatment strategies that avoid dopamine agonists and their associated complications altogether. PMID- 26045291 TI - Angioimmunoblastic T-cell lymphoma is the most common T-cell lymphoma in two distinct French information data sets. PMID- 26045292 TI - Adverse prognostic effect of homozygous TET2 mutation on the relapse risk of acute myeloid leukemia in patients of normal karyotype. PMID- 26045294 TI - BCR-ABL1-like cases in pediatric acute lymphoblastic leukemia: a comparison between DCOG/Erasmus MC and COG/St. Jude signatures. PMID- 26045293 TI - Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy. AB - High expression of the chemokine receptor 4, CXCR4, associated with a negative prognosis in acute myeloid leukemia, is related to hypoxia. Because CXCR4 expression is under the post-transcriptional control of microRNA-146a in normal and leukemic monocytic cells, we first investigated the impact of hypoxia on microRNA-146a and CXCR4 expression during monocytopoiesis and in acute monocytic leukemia. We then analyzed the effects of hypoxia on drug sensitivity of CXCR4 expressing leukemic cells. We found that microRNA-146a is a target of hypoxia inducible factor-1alpha or -2alpha in relation to the stage of monocytopoiesis and the level of hypoxia, and demonstrated the regulation of the microRNA 146a/CXCR4 pathway by hypoxia in monocytes derived from CD34(+) cells. Thus, in myeloid leukemic cell lines, hypoxia-mediated control of the microRNA-146a/CXCR4 pathway depends only on the capacity of hypoxia-inducible factor-1alpha to up regulate microRNA-146a, which in turn decreases CXCR4 expression. However, at variance with normal monocytic cells and leukemic cell lines, in acute monocytic leukemia overexpressing CXCR4, hypoxia up-modulates microRNA-146a but fails to down-modulate CXCR4 expression. We then investigated the effect of hypoxia on the response of leukemic cells to chemotherapy alone or in combination with stromal derived factor-1alpha. We found that hypoxia increases stromal-derived factor 1alpha-induced survival of leukemic cells by decreasing their sensitivity to anti leukemic drugs. Altogether, our results demonstrate that hypoxia-mediated regulation of microRNA-146a, which controls CXCR4 expression in monocytic cells, is lost in acute monocytic leukemia, thus contributing to maintaining CXCR4 overexpression and protecting the cells from anti-leukemic drugs in the hypoxic bone marrow microenvironment. PMID- 26045296 TI - Late Effects of Treatment of Pediatric Central Nervous System Tumors. AB - Central nervous system tumors represent the most common solid malignancy in childhood. Improvement in treatment approaches have led to a significant increase in survival rates, with over 70% of children now surviving beyond 5 years. As more and more children with CNS tumors have longer survival times, it is important to be aware of the long-term morbidities caused not only by the tumor itself but also by tumor treatment. The most common side effects including poor neurocognition, endocrine dysfunction, neurological and vascular late effects, as well as secondary malignancies, are discussed within this article. PMID- 26045295 TI - P-selectin is a host receptor for Plasmodium MSP7 ligands. AB - BACKGROUND: Plasmodium parasites typically elicit a non-sterile but protective immune response in human host populations, suggesting that the parasites actively modulate normal immunological mechanisms. P-selectin is a cell surface receptor expressed in mammals, that is a known component of the inflammatory response against pathogens and has been previously identified as a host factor that influences malaria-associated pathology both in human patients and rodent infection models. METHODS: To better understand the molecular mechanisms underlying the involvement of P-selectin in the pathogenesis of malaria, a systematic extracellular protein interaction screen was used to identify Plasmodium falciparum merozoite surface protein 7 (MSP7) as a binding partner of human P-selectin. This interaction, and those occurring between P-selectin and Plasmodium MSP7 homologues, was characterized biochemically. RESULTS: Plasmodium falciparum MSP7 and P-selectin were shown to bind each other directly via the N terminus of PfMSP7 and the P-selectin C-type lectin and EGF-like domains. Orthologous proteins in the murine parasite Plasmodium berghei (PbMSRP1 and PbMSRP2) and mouse P-selectin also interacted. Finally, P-selectin, when complexed with MSP7, could no longer bind to its endogenous carbohydrate ligand, Sialyl-Lewis(X). CONCLUSIONS: Novel interactions were identified between Plasmodium MSP7 protein family members and host P-selectin receptors. Since PfMSP7 could prevent interactions between P-selectin and its leukocyte ligands, these results provide a possible mechanism for the known immunomodulatory effects of both MSP7 and P-selectin in malaria infection models. PMID- 26045297 TI - Adult Quality of Life and Psychosocial Outcomes of Childhood Onset Hypopituitarism. AB - BACKGROUD/AIMS: Poor quality of life (QoL) has been reported in adults with growth hormone deficiency. Few studies have examined QoL in adults with childhood onset multiple pituitary hormone deficiencies (COMPHD). We evaluated QoL in adults with COMPHD. METHODS: COMPHD participants aged >=18 years were identified from hospital medical records and the clinics of one author (M.Z.). Age- and sex matched controls were recruited for every participant. The World Health Organization QoL Questionnaire, the Kessler Psychological Distress Scale, the Female Sexual Function Index (FSFI) and the Male Sexual Quotient (MSQ) were used to measure QoL, psychological distress and psychosexual function. RESULTS: Ninety two (68.1%) patients (males 55%; mean age 29.7 years, range 18-61) participated. COMPHD was caused by a brain tumour in 63 (68.5%), congenital hypopituitarism in 19 (20.1%), other cancers in 7 (7.6%) and trauma in 3 (3.3%) patients. COMPHD participants were shorter and more overweight, reported more childhood behavioural problems and had less education, more unemployment, lower marital rates and incomes and fewer children compared to healthy controls (p < 0.05 for each). Although they scored lower in all QoL domains (p <= 0.001) and psychosexual function (FSFI and MSQ, p < 0.001), there was no difference in reported psychological distress (p = 0.119). QoL was influenced by background diagnosis and treatment in a subgroup analysis. CONCLUSION: Adults with COMPHD have a significantly lower QoL compared to physically healthy peers. Difficulties in psychosocial and psychosexual function in these patients need to be addressed. PMID- 26045298 TI - Effect of whole-body vibration training on body composition, exercise performance and biochemical responses in middle-aged mice. AB - AIMS: Whole-body vibration (WBV) is a well-known light-resistance exercise by automatic adaptations to rapid and repeated oscillations from a vibrating platform, which is also a simple and convenient exercise for older adults. However, the potential benefits of WBV on aging-associated changes in body composition, exercise performance, and fatigue are currently unclear. The objective of the study is to investigate the beneficial effects of WBV training on body composition, exercise performance, and physical fatigue-related and biochemical responses in middle-aged mice. METHODS: In total, 24 male C57BL/6 mice aged 15 months old were randomly divided into 3 groups (n=8 per group): sedentary control (SC), relatively low-frequency WBV (5.6 Hz, 2 mm, 0.13 g) (LV), and relatively high-frequency WBV (13 Hz, 2 mm, 0.68 g) (HV). Mice in the LV and HV groups were placed inside a vibration platform and vibrated at different frequencies and fixed amplitude (2 mm) for 15 min, 5 days/week for 4 weeks. Exercise performance, core temperature and anti-fatigue function were evaluated by forelimb grip strength and levels of serum lactate, ammonia, glucose, and creatine kinase (CK) after a 15-min swimming exercise, as were changes in body composition and biochemical variables at the end of the experiment. RESULTS: Relative muscle and brown adipose tissue weight (%) was significantly higher for the HV than SC mice, but relative liver weight (%) was lower. On trend analysis, WBV increased grip strength, aerobic endurance and core temperature in mice. As well, serum lactate, ammonia and CK levels were dose-dependently decreased with vibration frequency after the swimming test. Fasting serum levels of albumin and total protein were increased and serum levels of alkaline phosphatase and creatinine decreased dose-dependently with vibration frequency. Moreover, WBV training improved the age-related abnormal morphology of skeletal muscle, liver and kidney tissues. Therefore, it could improve exercise performance and ameliorate fatigue and prevent senescence-associated biochemical and pathological alterations in middle-aged mice. CONCLUSIONS: WBV training may be an effective intervention for health promotion in the aging population. The detailed molecular mechanism of how WBV training regulates anti-aging activity warrants further functional studies. PMID- 26045300 TI - Protective effects of ginsenoside Rg1 on aging Sca-1+ hematopoietic cells. AB - In adults, bone hematopoietic cells are responsible for the lifelong production of all blood cells. It is affected in aging, with progressive loss of physiological integrity leading to impaired function by cellular intrinsic and extrinsic factors. However, intervention measures, which directly inhibit the aging of hematopoietic cells, remain to be investigated. In the present study, 10 umol/l ginsenoside Rg1 (Rg1) markedly alleviated the aging phenotypes of Sca-1+ hematopoietic cells following in vitro exposure. In addition, the protective effects of ginsenoside Rg1 on the aging of Sca-1+ hematopoietic cells was confirmed using a serial transplantation assay in C57BL/6 mice. The mechanistic investigations revealed that Rg1-mediated Sca-1+ hematopoietic cell aging alleviation was linked to a series of characteristic events, including telomere end attrition compensation, telomerase activity reconstitution and the activation of genes involved in p16-Rb signaling pathways. Based on the above results, it was concluded that ginsenoside Rg1 is a potent agent, which acts on hematopoietic cells to protect them from aging, which has implications for therapeutic approaches in hemopoietic diseases. PMID- 26045299 TI - Comparing the Developmental Genetics of Cognition and Personality over the Life Span. AB - Empirical studies of cognitive ability and personality have tended to operate in isolation of one another. We suggest that returning to a unified approach to considering the development of individual differences in both cognition and personality can enrich our understanding of human development. We draw on previous meta-analyses of longitudinal, behavior genetic studies of cognition and personality across the life span, focusing particular attention on age trends in heritability and differential stability. Both cognition and personality are moderately heritable and exhibit large increases in stability with age; however, marked differences are evident. First, the heritability of cognition increases substantially with child age, while the heritability of personality decreases modestly with age. Second, increasing stability of cognition with age is overwhelmingly mediated by genetic factors, whereas increasing stability of personality with age is entirely mediated by environmental factors. Third, the maturational time-course of stability differs: Stability of cognition nears its asymptote by the end of the first decade of life, whereas stability of personality takes three decades to near its asymptote. We discuss how proximal gene-environment dynamics, developmental processes, broad social contexts, and evolutionary pressures may intersect to give rise to these divergent patterns. PMID- 26045301 TI - The association between lesion location and functional outcome after ischemic stroke. AB - BACKGROUND: Infarct location has a critical effect on patient outcome after ischemic stroke, but the study of its role independent of overall lesion volume is challenging. We performed a retrospective, hypothesis-generating study of the effect of infarct location on three-month functional outcome in a pooled analysis of the EPITHET and DEFUSE studies. METHODS: Posttreatment MRI diffusion lesions were manually segmented and transformed into standard-space. A novel composite brain atlas derived from three standard brain atlases and encompassing 132 cortical and sub-cortical structures was used to segment the transformed lesion into different brain regions, and calculate the percentage of each region infarcted. Classification and Regression Tree (CART) analysis was performed to determine the important regions in each hemisphere associated with nonfavorable outcome at day 90 (modified Rankin score [mRS] > 1). RESULTS: Overall, 152 patients (82 left hemisphere) were included. Median diffusion lesion volume was 37.0 ml, and median baseline National Institutes of Health Stroke Score was 13. In the left hemisphere, the strongest determinants of nonfavorable outcome were infarction of the uncinate fasciculus, followed by precuneus, angular gyrus and total diffusion lesion volume. In the right hemisphere, the strongest determinants of nonfavorable outcome were infarction of the parietal lobe followed by the putamen. CONCLUSIONS: Assessment of infarct location using CART demonstrates regional characteristics associated with poor outcome. Prognostically important locations include limbic, default-mode and language areas in the left hemisphere, and visuospatial and motor regions in the right hemisphere. PMID- 26045302 TI - AS1411-conjugated gold nanospheres and their potential for breast cancer therapy. AB - AS1411 is a quadruplex-forming DNA oligonucleotide that functions as an aptamer to target nucleolin, a protein present on the surface of cancer cells. Clinical trials of AS1411 have indicated it is well tolerated with evidence of therapeutic activity, but improved pharmacology and potency may be required for optimal efficacy. In this report, we describe how conjugating AS1411 to 5 nm gold nanospheres influences its activities in vitro and in vivo. We find that the AS1411-linked gold nanospheres (AS1411-GNS) are stable in aqueous and serum containing solutions. Compared to unconjugated AS1411 or GNS linked to control oligonucleotides, AS1411-GNS have superior cellular uptake and markedly increased antiproliferative/cytotoxic effects. Similar to AS1411, AS1411-GNS show selectivity for cancer cells compared to non-malignant cells. In a mouse model of breast cancer, systemic administration of AS1411-GNS could completely inhibit tumor growth with no signs of toxicity. These results suggest AS1411-GNS are promising candidates for clinical translation. PMID- 26045303 TI - Development of APE1 enzymatic DNA repair assays: low APE1 activity is associated with increase lung cancer risk. AB - The key role of DNA repair in removing DNA damage and minimizing mutations makes it an attractive target for cancer risk assessment and prevention. Here we describe the development of a robust assay for apurinic/apyrimidinic (AP) endonuclease 1 (APE1; APEX1), an essential enzyme involved in the repair of oxidative DNA damage. APE1 DNA repair enzymatic activity was measured in peripheral blood mononuclear cell protein extracts using a radioactivity-based assay, and its association with lung cancer was determined using conditional logistic regression with specimens from a population-based case-control study with 96 lung cancer cases and 96 matched control subjects. The mean APE1 enzyme activity in case patients was 691 [95% confidence interval (CI) = 655-727] units/ng protein, significantly lower than in control subjects (mean = 793, 95% CI = 751-834 units/ng protein, P = 0.0006). The adjusted odds ratio for lung cancer associated with 1 SD (211 units) decrease in APE1 activity was 2.0 (95% CI = 1.3-3.1; P = 0.002). Comparison of radioactivity- and fluorescence-based assays showed that the two are equivalent, indicating no interference by the fluorescent tag. The APE1Asp148Glu SNP was associated neither with APE1 enzyme activity nor with lung cancer risk. Taken together, our results indicate that low APE1 activity is associated with lung cancer risk, consistent with the hypothesis that 'bad DNA repair', rather than 'bad luck', is involved in cancer etiology. Such assays may be useful, along with additional DNA repair biomarkers, for risk assessment of lung cancer and perhaps other cancers, and for selecting individuals to undergo early detection techniques such as low-dose CT. PMID- 26045304 TI - Analysis of the genetic architecture of susceptibility to cervical cancer indicates that common SNPs explain a large proportion of the heritability. AB - The genetic architecture of susceptibility to cervical cancer is not well understood. By using a genome-wide association study (GWAS) of 1034 cervical cancer patients and 3948 controls with 632668 single-nucleotide polymorphisms (SNPs), we estimated that 24.0% [standard error (SE) = 5.9%, P = 3.19*10(-6)] of variation in liability to cervical cancer is captured by autosomal SNPs, a bit lower than the heritability estimated from family study (27.0%), suggesting that a substantial proportion of the heritability is tagged by common SNPs. The remaining missing heritability most probably reflects incomplete linkage disequilibrium between causal variants and the genotyped SNPs. The variance explained by each chromosome is not related to its length (R (2) = 0.020, P = 0.516). Published genome-wide significant variants only explain 2.1% (SE = 1.5%, P = 0) of phenotypic variance, which reveals that most of the heritability has not been detected, presumably due to small individual effects. Another 2.1% (SE = 1.1%, P = 0.013) of variation is attributable to biological pathways associated with risk of cervical cancer, supporting that pathway analysis can identify part of the hidden heritability. Except for human leukocyte antigen genes and MHC class I polypeptide-related sequence A (MICA), none of the 82 candidate genes/regions reported in other association studies contributes to the heritability of cervical cancer in our dataset. This study shows that risk of cervical cancer is influenced by many common germline genetic variants of small effects. The findings are important for further study design to identify the hiding heritability that has not yet been revealed. More susceptibility loci are yet to be found in GWASs with higher power. PMID- 26045306 TI - The Combination of Vascular Endothelial Growth Factor and Stromal Cell-Derived Factor Induces Superior Angiogenic Sprouting by Outgrowth Endothelial Cells. AB - Endothelial progenitor cells are being broadly explored for the treatment of ischemic cardiovascular diseases, but their response to molecules commonly used to promote the growth of new blood vessels has not been fully characterized. In this study, angiogenic sprout formation in a 3-dimensional, in vitro model by one type of endothelial progenitor, outgrowth endothelial cells (OECs), was characterized in response to exposure to stromal cell-derived factor (SDF) and vascular endothelial growth factor (VEGF) and then compared to mature endothelial cells. Exposure to SDF alone did not increase angiogenic sprouting in comparison to control media, while a combination of VEGF and SDF demonstrated greater potency than VEGF alone for all cell types. Together, VEGF and SDF reduced the sprout initiation time and maintained sprouting levels over time. In direct competition with mature endothelial cells, OECs preferentially localized to the tip cell position, suggesting an enhanced sprouting potential. Overall, these results reveal the impact of the combination of VEGF and SDF on endothelial cell sprouting, and support the enhanced potential of OECs, as opposed to mature endothelial cells, for treating ischemic diseases. PMID- 26045305 TI - Early performance of a miniaturized leadless cardiac pacemaker: the Micra Transcatheter Pacing Study. AB - AIMS: Permanent cardiac pacing is the only effective treatment for symptomatic bradycardia, but complications associated with conventional transvenous pacing systems are commonly related to the pacing lead and pocket. We describe the early performance of a novel self-contained miniaturized pacemaker. METHODS AND RESULTS: Patients having Class I or II indication for VVI pacing underwent implantation of a Micra transcatheter pacing system, from the femoral vein and fixated in the right ventricle using four protractible nitinol tines. Prespecified objectives were >85% freedom from unanticipated serious adverse device events (safety) and <2 V 3-month mean pacing capture threshold at 0.24 ms pulse width (efficacy). Patients were implanted (n = 140) from 23 centres in 11 countries (61% male, age 77.0 +/- 10.2 years) for atrioventricular block (66%) or sinus node dysfunction (29%) indications. During mean follow-up of 1.9 +/- 1.8 months, the safety endpoint was met with no unanticipated serious adverse device events. Thirty adverse events related to the system or procedure occurred, mostly due to transient dysrhythmias or femoral access complications. One pericardial effusion without tamponade occurred after 18 device deployments. In 60 patients followed to 3 months, mean pacing threshold was 0.51 +/- 0.22 V, and no threshold was >=2 V, meeting the efficacy endpoint (P < 0.001). Average R-wave was 16.1 +/- 5.2 mV and impedance was 650.7 +/- 130 ohms. CONCLUSION: Early assessment shows the transcatheter pacemaker can safely and effectively be applied. Long-term safety and benefit of the pacemaker will further be evaluated in the trial. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID NCT02004873. PMID- 26045308 TI - Preclinical Kinetic Analysis of the Caspase-3/7 PET Tracer 18F-C-SNAT: Quantifying the Changes in Blood Flow and Tumor Retention After Chemotherapy. AB - Early detection of tumor response to therapy is crucial to the timely identification of the most efficacious treatments. We recently developed a novel apoptosis imaging tracer, (18)F-C-SNAT (C-SNAT is caspase-sensitive nanoaggregation tracer), that undergoes an intramolecular cyclization reaction after cleavage by caspase-3/7, a biomarker of apoptosis. This caspase-3/7 dependent reaction leads to an enhanced accumulation and retention of (18)F activity in apoptotic tumors. This study aimed to fully examine in vivo pharmacokinetics of the tracer through PET imaging and kinetic modeling in a preclinical mouse model of tumor response to systemic anticancer chemotherapy. METHODS: Tumor-bearing nude mice were treated 3 times with intravenous injections of doxorubicin before undergoing a 120-min dynamic (18)F-C-SNAT PET/CT scan. Time activity curves were extracted from the tumor and selected organs. A 2-tissue compartment model was fitted to the time-activity curves from tumor and muscle, using the left ventricle of the heart as input function, and the pharmacokinetic rate constants were calculated. RESULTS: Both tumor uptake (percentage injected dose per gram) and the tumor-to-muscle activity ratio were significantly higher in the treated mice than untreated mice. Pharmacokinetic rate constants calculated by the 2-tissue-compartment model showed a significant increase in delivery and accumulation of the tracer after the systemic chemotherapeutic treatment. Delivery of (18)F-C-SNAT to the tumor tissue, quantified as K1, increased from 0.31 g?(mL?min)(-1) in untreated mice to 1.03 g?(mL?min)(-1) in treated mice, a measurement closely related to changes in blood flow. Accumulation of (18)F-C-SNAT, quantified as k3, increased from 0.03 to 0.12 min( 1), proving a higher retention of (18)F-C-SNAT in treated tumors independent from changes in blood flow. An increase in delivery was also found in the muscular tissue of treated mice without increasing accumulation. CONCLUSION: (18)F-C-SNAT has significantly increased tumor uptake and significantly increased tumor-to muscle ratio in a preclinical mouse model of tumor therapy. Furthermore, our kinetic modeling of (18)F-C-SNAT shows that chemotherapeutic treatment increased accumulation (k3) in the treated tumors, independent of increased delivery (K1). PMID- 26045310 TI - Breast Cancer Staging: To Which Women Should 18F-FDG PET/CT Be Offered? PMID- 26045309 TI - Relative 11C-PiB Delivery as a Proxy of Relative CBF: Quantitative Evaluation Using Single-Session 15O-Water and 11C-PiB PET. AB - The primary goal of this study was to assess the suitability of (11)C-Pittsburgh compound B ((11)C-PiB) blood-brain barrier delivery (K1) and relative delivery (R1) parameters as surrogate indices of cerebral blood flow (CBF), with a secondary goal of directly examining the extent to which simplified uptake measures of (11)C-PiB retention (amyloid-beta load) may be influenced by CBF, in a cohort of controls and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD). METHODS: Nineteen participants (6 controls, 5 AD, 8 MCI) underwent MR imaging, (15)O-water PET, and (11)C-PiB PET in a single session. Fourteen regions of interest (including cerebellar reference region) were defined on MR imaging and applied to dynamic coregistered PET to generate time-activity curves. Multiple analysis approaches provided regional (15)O-water and (11)C-PiB measures of delivery and (11)C-PiB retention that included compartmental modeling distribution volume ratio (DVR), arterial- and reference-based Logan DVR, simplified reference tissue modeling 2 (SRTM2) DVR, and standardized uptake value ratios. Spearman correlation was performed among delivery measures (i.e., (15)O water K1 and (11)C-PiB K1, relative K1 normalized to cerebellum [Rel-K1-Water and Rel-K1-PiB], and (11)C-PiB SRTM2-R1) and between delivery measures and (11)C-PiB retention, using the Bonferroni method for multiple-comparison correction. RESULTS: Primary analysis showed positive correlations (rho ~0.2-0.5) between (15)O-water K1 and (11)C-PiB K1 that did not survive Bonferroni adjustment. Significant positive correlations were found between Rel-K1-Water and Rel-K1-PiB and between Rel-K1-Water and (11)C-PiB SRTM2-R1 (rho ~0.5-0.8, P < 0.0036) across primary cortical regions. Secondary analysis showed few significant correlations between (11)C-PiB retention and relative (11)C-PiB delivery measures (but not (15)O-water delivery measures) in primary cortical areas that arose only after accounting for cerebrospinal fluid dilution. CONCLUSION: (11)C-PiB SRTM2-R1 is highly correlated with regional relative CBF, as measured by (15)O-water K1 normalized to cerebellum, and cross-sectional (11)C-PiB retention did not strongly depend on CBF across primary cortical regions. These results provide further support for potential dual-imaging assessments of regional brain status (i.e., amyloid-beta load and relative CBF) through dynamic (11)C-PiB imaging. PMID- 26045311 TI - Metabolic Tumor Volume on 18F-FDG PET/CT Improves Preoperative Identification of High-Risk Endometrial Carcinoma Patients. AB - Our objective was to prospectively explore the diagnostic value of (18)F-FDG PET/CT for preoperative staging in endometrial carcinomas and to investigate whether (18)F-FDG PET-specific quantitative tumor parameters reflect clinical and histologic characteristics. METHODS: Preoperative (18)F-FDG PET/CT was prospectively performed on 129 consecutive endometrial carcinoma patients. Two physicians who did not know the clinical findings or staging results independently reviewed the images, assessing primary tumor, cervical stroma involvement and metastatic spread, and determining maximum and mean standardized uptake value (SUVmax and SUVmean, respectively) for tumor, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). All parameters were analyzed in relation to histomorphologic and clinical tumor characteristics. Receiver operating-characteristic curves for identification of deep myometrial invasion and lymph node metastases were generated, and MTV cutoffs for predicting deep myometrial invasion and lymph node metastases were calculated. RESULTS: The sensitivity, specificity, and accuracy of (18)F-FDG PET/CT for the detection of lymph node metastases were 77%-85%, 91%-96%, and 89%-93%, respectively. SUVmax, SUVmean, MTV, and TLG were significantly related to deep myometrial invasion, presence of lymph node metastases, and high histologic grade (P < 0.015 for all) and independently predicted deep myometrial invasion (P < 0.015) and lymph node metastases (P < 0.025) after adjustment for preoperative histologic risk (based on subtype and grade) in endometrial biopsies. Optimal cutoffs for MTV in predicting deep myometrial invasion (20 mL) and the presence of lymph node metastases (30 mL) yielded odds ratios of 7.8 (P < 0.001) and 16.5 (P = 0.001), respectively. CONCLUSION: (18)F-FDG PET/CT represents a clinically valuable tool for preoperatively evaluating the presence of lymph node metastases in endometrial carcinoma patients. Applying MTV cutoffs for the prediction of deep myometrial invasion and lymph node metastases may increase diagnostic accuracy and aid preoperative identification of high-risk patients, enabling restriction of lymphadenectomy for patients with a low risk of aggressive disease. PMID- 26045312 TI - Significant Therapeutic Efficacy with Combined Radioimmunotherapy and Cetuximab in Preclinical Models of Colorectal Cancer. AB - Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced disease offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. We evaluated the preclinical efficacy of combination radioimmunotherapy, using a humanized (131)I-labeled anti-carcinoembryonic antigen antibody ((131)I-huA5B7), with cetuximab in colorectal cancer (CRC). METHODS: Three human CRC cell lines--SW1222, LoVo, and LS174T--were used to generate subcutaneous xenografts, and stably luciferase-transfected SW1222 cells were used to establish a model of hepatic metastases in immunocompromised mice. Imaging and biodistribution studies were conducted to confirm the selective tumor localization of (131)I-huA5B7. Efficacy was evaluated on the basis of tumor growth delay and survival, along with markers of DNA damage response, cell cycle, proliferation, and apoptosis. RESULTS: Selective tumor targeting was achieved with (131)I-huA5B7 alone or in combination with cetuximab without observable toxicity. Compared with monotherapy, combining cetuximab with radioimmunotherapy significantly and synergistically reduced tumor growth and prolonged survival of mice in 2 of the subcutaneous and in the metastatic tumor model. Evidence of DNA damage, G2/M arrest, significantly decreased proliferation, and increased apoptosis were observed with radioimmunotherapy and the combination therapy. However, a significant decrease in DNA-protein kinase expression with the combination regimen suggests that the addition of cetuximab suppressed DNA repair. CONCLUSION: Our results demonstrate enhanced therapeutic efficacy with the combination of cetuximab and radioimmunotherapy in CRC, which could potentially translate into successful clinical outcomes. This strategy could improve the treatment of residual disease postoperatively and ultimately prevent or delay recurrence. Furthermore, other carcinoembryonic antigen-expressing malignancies could also benefit from this approach. PMID- 26045313 TI - Metabolic Activity of Red Nucleus and Its Correlation with Cerebral Cortex and Cerebellum: A Study Using a High-Resolution Semiconductor PET System. AB - The red nucleus (RN) is a pair of small gray matter structures located in the midbrain and involved in muscle movement and cognitive functions. This retrospective study aimed to investigate the metabolism of human RN and its correlation to other brain regions. METHODS: We developed a high-resolution semiconductor PET system to image small brain structures. Twenty patients without neurologic disorders underwent whole-brain scanning after injection of 400 MBq of (18)F-FDG. The individual brain (18)F-FDG PET images were spatially normalized to generate a surface projection map using a 3-dimensional stereotactic surface projection technique. The correlation between the RN and each voxel on the cerebral and cerebellar cortices was estimated with Pearson product-moment correlation analysis. RESULTS: Both right and left RNs were visualized with higher uptake than that in the background midbrain. The maximum standardized uptake values of RN were 7.64 +/- 1.92; these were higher than the values for the dentate nucleus but lower than those for the caudate nucleus, putamen, and thalamus. The voxel-by-voxel analysis demonstrated that the right RN was correlated more with ipsilateral association cortices than contralateral cortices, whereas the left RN was equally correlated with ipsilateral and contralateral cortices. The left RN showed a stronger correlation with the motor cortices and cerebellum than the right RN did. CONCLUSION: Although nonspecific background activity around RNs might have influenced the correlation patterns, these metabolic relationships suggested that RN cooperates with association cortices and limbic areas to conduct higher brain functions. PMID- 26045314 TI - Accuracy of 18F-FDG PET/CT, Multidetector CT, and MR Imaging in the Diagnosis of Pancreatic Cysts: A Prospective Single-Center Study. AB - Accurate diagnosis of the nature of pancreatic cysts is challenging but more important than ever, in part because of the increasing number of incidental cystic findings in the pancreas. Preliminary data suggest that (18)F-FDG PET/CT may have a significant influence on clinical decision making, although its role is still evolving. Our aim was to prospectively compare the accuracy of combined (18)F-FDG PET and contrast-enhanced CT ((18)F-FDG PET/CT), multidetector CT (MDCT), and MR imaging in differentiating malignant from benign pancreatic cysts. METHODS: Thirty-one consecutive patients with pancreatic cysts were enrolled in the study. They underwent a protocol including (18)F-FDG PET/CT, MDCT, and MR imaging combined with MR cholangiopancreatography, all of which were evaluated in a masked manner. The findings were confirmed macroscopically at surgery or histopathologic analysis (n = 22) or at follow-up (n = 9). RESULTS: Of the 31 patients, 6 had malignant and 25 had benign lesions. The diagnostic accuracy was 94% for (18)F-FDG PET/CT, compared with 77% and 87% for MDCT (P < 0.05) and MR imaging, respectively. (18)F-FDG PET/CT had a negative predictive value of 100% and a positive predictive value of 75% for pancreatic cysts. The maximum standardized uptake value was significantly higher in malignant (7.4 +/- 2.6) than in benign lesions (2.4 +/- 0.8) (P < 0.05). When the maximum standardized uptake value was set at 3.6, the sensitivity and specificity were 100% and 88%, respectively. Furthermore, when compared with MDCT and MR imaging, respectively, (18)F-FDG PET/CT altered the clinical management of 5 and 3 patients, respectively. CONCLUSION: (18)F-FDG PET/CT is an accurate imaging modality for differentiating between benign and malignant pancreatic cysts. We recommend the use of (18)F-FDG PET/CT in the evaluation of diagnostically challenging pancreatic cysts. PMID- 26045316 TI - Human microsomal cyttrochrome P450-mediated reduction of oxysophocarpine, an active and highly toxic constituent derived from Sophora flavescens species, and its intestinal absorption and metabolism in rat. AB - Oxysophocarpine (OSC), an active and toxic quinolizidine alkaloid, is highly valued in Sophora flavescens Ait. and Subprostrate sophora Root. OSC is used to treat inflammation and hepatitis for thousands of years in China. This study aims to investigate the CYP450-mediated reduction responsible for metabolizing OSC and to evaluate the absorption and metabolism of OSC in rat in situ. Four metabolites were identified, with sophocarpine (SC) as the major metabolite. SC formation was rapid in human and rat liver microsomes (HLMs and RLMs, respectively). The reduction rates in the liver are two fold higher than in the intestine, both in humans and rats. In HLMs, inhibitors of CYP2C9, 3A4/5, 2D6, and 2B6 had strong inhibitory effects on SC formation. Meanwhile, inhibitors of CYP3A and CYP2D6 had significant inhibition on SC formation in RLMs. Human recombinant CYP3A4/5, 2B6, 2D6, and 2C9 contributed significantly to SC production. The permeability in rat intestine and the excretion rates of metabolites were highest in the duodenum (p<0.05), and the absorbed amount of OSC in duodenum and jejunum was concentration-dependent. The metabolism could be significantly decreased by CYP3A inhibitor ketoconazole. In conclusion, the liver was the main organ responsible for OSC metabolism. First-pass metabolism via CYP3A4/5, 2B6, 2D6, and 2C9 may be the main reason for the poor OSC bioavailability. PMID- 26045315 TI - Malignant mesothelioma due to non-occupational asbestos exposure from the Italian national surveillance system (ReNaM): epidemiology and public health issues. AB - INTRODUCTION: Italy produced and imported a large amount of raw asbestos, up to the ban in 1992, with a peak in the period between 1976 and 1980 at about 160,000 tons/year. The National Register of Mesotheliomas (ReNaM, "Registro Nazionale dei Mesoteliomi" in Italian), a surveillance system of mesothelioma incidence, has been active since 2002, operating through a regional structure. METHODS: The Operating Regional Center (COR) actively researches cases and defines asbestos exposure on the basis of national guidelines. Diagnostic, demographic and exposure characteristics of non-occupationally exposed cases are analysed and described with respect to occupationally exposed cases. RESULTS: Standardised incidence rates for pleural mesothelioma in 2008 were 3.84 (per 100,000) for men and 1.45 for women, respectively. Among the 15,845 mesothelioma cases registered between 1993 and 2008, exposure to asbestos fibres was investigated for 12,065 individuals (76.1%), identifying 530 (4.4%) with familial exposure (they lived with an occupationally exposed cohabitant), 514 (4.3%) with environmental exposure to asbestos (they lived near sources of asbestos pollution and were never occupationally exposed) and 188 (1.6%) exposed through hobby-related or other leisure activities. Clusters of cases due to environmental exposure are mainly related to the presence of asbestos-cement industry plants (Casale Monferrato, Broni, Bari), to shipbuilding and repair activities (Monfalcone, Trieste, La Spezia, Genova) and soil contamination (Biancavilla in Sicily). CONCLUSIONS: Asbestos pollution outside the workplace contributes significantly to the burden of asbestos-related diseases, suggesting the need to prevent exposures and to discuss how to deal with compensation rights for malignant mesothelioma cases induced by non-occupational exposure to asbestos. PMID- 26045317 TI - Step-Index Optical Fiber Made of Biocompatible Hydrogels. AB - A biocompatible step-index optical fiber made of poly(ethylene glycol) and alginate hydrogels is demonstrated. The fabricated fiber exhibits excellent light guiding efficiency in biological tissues. Moreover, the core of hydrogel fibers can be easily doped with functional molecules and nanoparticles for localized light emission, sensing, and therapy. PMID- 26045318 TI - Phage display-based on-slide selection of tumor-specific antibodies on formalin fixed paraffin-embedded human tissue biopsies. AB - Phage display is an effective method for the generation of target-specific human antibodies. Standard phage display panning use purified proteins, antigen transfected cells or tumor cell lines as target structure to generate specific antibodies. However, recombinant proteins can be difficult to express and purify in their native conformation and suitable cell lines are not always available. Additionally the antigen expression profile may change during cultivation and thus differ from the malignant cells in patient. Here we describe a method for the selection of specific antibodies from phage display libraries by panning against formalin-fixed paraffin-embedded (FFPE) tissue biopsies immobilized on glass slides, using small cell lung cancer (SCLC) as a case study. The human Tomlinson single-chain variable fragment (scFv) phage libraries I and J were panned against SCLC FFPE tissue slides for positive selection and healthy lung tissue for subtraction. The specificity of the selected scFv antibodies was confirmed in vitro by ELISA on immobilized SCLC cell membranes, by flow cytometry using the SCLC cell lines NCI-H69, NCI-H82 and DMS 273, and ex vivo against tissue microarrays containing 35 different SCLC samples and 20 types of normal organs. We monitored the internalization of three selected scFv antibodies and fused them with Pseudomonas exotoxin A (ETA') to produce immunotoxins whose cytotoxicity was confirmed by cell viability and apoptosis assays on different SCLC cell lines, achieving IC50 values of up to 23nM. The selection of SCLC specific scFv antibodies by panning against FFPE tissue slides circumvents the challenges of using purified antigens or cell lines for antibody selection. PMID- 26045319 TI - Lack of association between the Duffy antigen receptor for chemokines (DARC) expression and clinical outcome of children with sickle cell anemia. PMID- 26045320 TI - Coenzyme Q10 suppresses Th17 cells and osteoclast differentiation and ameliorates experimental autoimmune arthritis mice. AB - Coenzyme Q10 (CoQ10) is a lipid-soluble antioxidant synthesized in human body. This enzyme promotes immune system function and can be used as a dietary supplement. Rheumatoid arthritis (RA) is an autoimmune disease leading to chronic joint inflammation. RA results in severe destruction of cartilage and disability. This study aimed to investigate the effect of CoQ10 on inflammation and Th17 cell proliferation on an experimental rheumatoid arthritis (RA) mice model. CoQ10 or cotton seed oil as control was orally administrated once a day for seven weeks to mice with zymosan-induced arthritis (ZIA). Histological analysis of the joints was conducted using immunohistochemistry. Germinal center (GC) B cells, Th17 cells and Treg cells of the spleen tissue were examined by confocal microscopy staining. mRNA expression was measured by real-time PCR and protein levels were estimated by enzyme-linked immunosorbent assay (ELISA). Flow cytometric analysis (FACS) was used to evaluate Th17 cells and Treg cells. CoQ10 mitigated the severity of ZIA and decreased serum immunoglobulin concentrations. CoQ10 also reduced RANKL-induced osteoclastogenesis, inflammatory mediators and oxidant factors. Th17/Treg axis was reciprocally controlled by CoQ10 treatment. Moreover, CoQ10 treatment on normal mouse and human cells cultured in Th17 conditions decreased the number of Th17 cells and enhanced the number of Treg cells. CoQ10 alleviates arthritis in mice with ZIA declining inflammation, Th17 cells and osteoclast differentiation. These findings suggest that CoQ10 can be a potential therapeutic substance for RA. PMID- 26045321 TI - MicroRNA-138 regulates the balance of Th1/Th2 via targeting RUNX3 in psoriasis. AB - Psoriasis is a common chronic inflammatory and T cell-meditated autoimmune skin disease. A recent study found that Runt-related transcription factor 3 (RUNX3) is a susceptibility gene for psoriasis; however, its biological role in the disease has not been studied. RUNX3 was predicted to be the target gene of microRNA-138 (miR-138). The current research was designed to delineate the mechanism of miR 138 in regulating psoriasis via targeting RUNX3. In this study, we found that the expression of RUNX3 is increased significantly while the expression of miR-138 decreased significantly in CD4(+) T cells from psoriasis patients. Moreover, the luciferase report confirmed the targeting reaction between miR-138 and RUNX3. After transfection with the miR-138 inhibitor into CD4(+) T cells from healthy controls, we found that the inhibition of miR-138 increases RUNX3 expression and increased the ratio of Th1/Th2. Furthermore, the miR-138 mimic was transfected into CD4(+) T cells from psoriasis patients. The results showed that the overexpression of miR-138 inhibits RUNX3 expression and decreased the ratio of Th1/Th2 in CD4(+) T cells. Taken together, our study suggests that increased miR 138 regulates the balance of Th1/Th2 through inhibiting RUNX3 expression in psoriasis, providing a potential therapeutic target for psoriasis. PMID- 26045322 TI - Health economics and nutrition: over- and undernutrition. PMID- 26045323 TI - The global burden of obesity and the challenges of prevention. AB - The prevalence of obesity is increasing at an alarming rate in many parts of the world. About 2 billion people are overweight and one third of them obese. The plight of the most affected populations, like those in high-income countries in North America, Australasia and Europe, has been well publicized. However, the more recent increases in population obesity in low- and middle-income countries that are now increasingly being observed have been less recognized. Based on the existing prevalence and trend data and the epidemiological evidence linking obesity with a range of physical and psychosocial health conditions, it is reasonable to describe obesity as a public health crisis that severely impairs the health and quality of life of people and adds considerably to national health care budgets. Intersectoral action to manage and prevent obesity is urgently required to reverse current trends. PMID- 26045324 TI - Gestational diabetes mellitus and macrosomia: a literature review. AB - BACKGROUND: Fetal macrosomia, defined as a birth weight >= 4,000 g, may affect 12% of newborns of normal women and 15-45% of newborns of women with gestational diabetes mellitus (GDM). The increased risk of macrosomia in GDM is mainly due to the increased insulin resistance of the mother. In GDM, a higher amount of blood glucose passes through the placenta into the fetal circulation. As a result, extra glucose in the fetus is stored as body fat causing macrosomia, which is also called 'large for gestational age'. This paper reviews studies that explored the impact of GDM and fetal macrosomia as well as macrosomia-related complications on birth outcomes and offers an evaluation of maternal and fetal health. SUMMARY: Fetal macrosomia is a common adverse infant outcome of GDM if unrecognized and untreated in time. For the infant, macrosomia increases the risk of shoulder dystocia, clavicle fractures and brachial plexus injury and increases the rate of admissions to the neonatal intensive care unit. For the mother, the risks associated with macrosomia are cesarean delivery, postpartum hemorrhage and vaginal lacerations. Infants of women with GDM are at an increased risk of becoming overweight or obese at a young age (during adolescence) and are more likely to develop type II diabetes later in life. Besides, the findings of several studies that epigenetic alterations of different genes of the fetus of a GDM mother in utero could result in the transgenerational transmission of GDM and type II diabetes are of concern. PMID- 26045325 TI - The epidemiology of global micronutrient deficiencies. AB - Micronutrients are essential to sustain life and for optimal physiological function. Widespread global micronutrient deficiencies (MNDs) exist, with pregnant women and their children under 5 years at the highest risk. Iron, iodine, folate, vitamin A, and zinc deficiencies are the most widespread MNDs, and all these MNDs are common contributors to poor growth, intellectual impairments, perinatal complications, and increased risk of morbidity and mortality. Iron deficiency is the most common MND worldwide and leads to microcytic anemia, decreased capacity for work, as well as impaired immune and endocrine function. Iodine deficiency disorder is also widespread and results in goiter, mental retardation, or reduced cognitive function. Adequate zinc is necessary for optimal immune function, and deficiency is associated with an increased incidence of diarrhea and acute respiratory infections, major causes of death in those <5 years of age. Folic acid taken in early pregnancy can prevent neural tube defects. Folate is essential for DNA synthesis and repair, and deficiency results in macrocytic anemia. Vitamin A deficiency is the leading cause of blindness worldwide and also impairs immune function and cell differentiation. Single MNDs rarely occur alone; often, multiple MNDs coexist. The long-term consequences of MNDs are not only seen at the individual level but also have deleterious impacts on the economic development and human capital at the country level. Perhaps of greatest concern is the cycle of MNDs that persists over generations and the intergenerational consequences of MNDs that we are only beginning to understand. Prevention of MNDs is critical and traditionally has been accomplished through supplementation, fortification, and food-based approaches including diversification. It is widely accepted that intervention in the first 1,000 days is critical to break the cycle of malnutrition; however, a coordinated, sustainable commitment to scaling up nutrition at the global level is still needed. Understanding the epidemiology of MNDs is critical to understand what intervention strategies will work best under different conditions. PMID- 26045326 TI - Food fortification for addressing iron deficiency in Filipino children: benefits and cost-effectiveness. AB - Iron deficiency is one of the most widespread nutritional disorders in both developing and industrialized countries, making it a global public health concern. Anemia, mainly due to iron deficiency, affects one third of the world's population and is concentrated in women and children below 5 years of age. Iron deficiency anemia has a profound impact on human health and productivity, and the effects of iron deficiency are especially pronounced in the first 1,000 days of life. This critical window of time sets the stage for an individual's future physiological and cognitive health, underscoring the importance of addressing iron deficiency in infants and young children. This review focuses on the use of fortified foods as a cost-effective tool for addressing iron deficiency in infants and young children in the Philippines. PMID- 26045327 TI - Erratum to: Identification of the epitopes of monoclonal antibodies against P74 of Helicoverpa armigera nucleopolyhedrovirus. PMID- 26045328 TI - A retrospective audit of antibiotic prescriptions in primary health-care facilities in Eastern Region, Ghana. AB - Resistance to antibiotics is increasing globally and is a threat to public health. Research has demonstrated a correlation between antibiotic use and resistance development. Developing countries are the most affected by resistance because of high infectious disease burden, limited access to quality assured antibiotics and more optimal drugs and poor antibiotic use practices. The appropriate use of antibiotics to slow the pace of resistance development is crucial. The study retrospectively assessed antibiotic prescription practices in four public and private primary health-care facilities in Eastern Region, Ghana using the WHO/International Network for the Rational Use of Drugs rational drug use indicators. Using a systematic sampling procedure, 400 prescriptions were selected per facility for the period April 2010 to March 2011. Rational drug use indicators were assessed in the descriptive analysis and logistic regression was used to explore for predictors of antibiotic prescription. Average number of medicines prescribed per encounter was 4.01, and 59.9% of prescriptions had antibiotics whilst 24.2% had injections. In total, 79.2% and 88.1% of prescribed medicines were generics and from the national essential medicine list, respectively. In the multivariate analysis, health facility type (odds ratio [OR] = 2.05; 95% confidence interval [CI]: 1.42, 2.95), patient age (OR = 0.97; 95% CI: 0.97, 0.98), number of medicines on a prescription (OR = 1.85; 95% CI: 1.63, 2.10) and 'no malaria drug' on prescription (OR = 5.05; 95% CI: 2.08, 12.25) were associated with an antibiotic prescription. A diagnosis of upper respiratory tract infection was positively associated with antibiotic use. The level of antibiotic use varied depending on the health facility type and was generally high compared with the national average estimated in 2008. Interventions that reduce diagnostic uncertainty in illness management should be considered. The National Health Insurance Scheme, as the main purchaser of health services in Ghana, offers an opportunity that should be exploited to introduce policies in support of rational drug use. PMID- 26045329 TI - Necrosis-induced TLR3 Activation Promotes TLR2 Expression in Gingival Cells. AB - Damage-associated molecular patterns (DAMPs), endogenous molecules released from injured or dying cells, evoke sterile inflammation that is not induced by microbial pathogens. Periodontal diseases are infectious diseases caused by oral microorganisms; however, in some circumstances, DAMPs might initiate inflammatory responses before host cells recognize pathogen-associated molecular patterns. Here, we showed that the necrotic cell supernatant (NCS) functioned as an endogenous danger signal when released from necrotic epithelial cells exposed to repeat freeze thawing. The NCS contained RNA and stimulated the production of inflammatory cytokines interleukin 6 (IL-6) and IL-8 from gingival epithelial cells and gingival fibroblasts. Targeted knockdown of Toll-like receptor 3 (TLR3) in these cells significantly suppressed the ability of the NCS to induce IL-6 and IL-8 production. Epithelial cells and fibroblasts recognized the NCS from heterologous cells. Interestingly, the activation of TLR3, rather than other TLRs, induced TLR2 mRNA expression and proteins in gingival epithelial cells, and pretreatment with the NCS or polyinosinic:polycytidylic acid (Poly(I:C)), a strong TLR3 activator, enhanced inflammatory cytokine production induced by subsequent stimulation with Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide, a TLR2 agonist. Moreover, the NCS reduced the expression of epithelial tight junction molecules zona occludens 1 and occludin and increased the permeability of epithelial tight junctions. These findings suggest that endogenous danger signal molecules such as self-RNA released from necrotic cells are recognized by TLR3 and that a subsequent increase of TLR2 expression in periodontal compartments such as gingival epithelial cells and gingival fibroblasts may enhance the inflammatory response to periodontopathic microbes recognized by TLR2 such as P. gingivalis, which also disrupts epithelial barrier functions. Thus, DAMPs may be involved in the development and prolongation of periodontal disease. PMID- 26045330 TI - Modeling seasonal migration of fall armyworm moths. AB - Fall armyworm, Spodoptera frugiperda (J.E. Smith), is a highly mobile insect pest of a wide range of host crops. However, this pest of tropical origin cannot survive extended periods of freezing temperature but must migrate northward each spring if it is to re-infest cropping areas in temperate regions. The northward limit of the winter-breeding region for North America extends to southern regions of Texas and Florida, but infestations are regularly reported as far north as Quebec and Ontario provinces in Canada by the end of summer. Recent genetic analyses have characterized migratory pathways from these winter-breeding regions, but knowledge is lacking on the atmosphere's role in influencing the timing, distance, and direction of migratory flights. The Hybrid Single-Particle Lagrangian Integrated Trajectory (HYSPLIT) model was used to simulate migratory flight of fall armyworm moths from distinct winter-breeding source areas. Model simulations identified regions of dominant immigration from the Florida and Texas source areas and overlapping immigrant populations in the Alabama-Georgia and Pennsylvania-Mid-Atlantic regions. This simulated migratory pattern corroborates a previous migratory map based on the distribution of fall armyworm haplotype profiles. We found a significant regression between the simulated first week of moth immigration and first week of moth capture (for locations which captured >= 10 moths), which on average indicated that the model simulated first immigration 2 weeks before first captures in pheromone traps. The results contribute to knowledge of fall armyworm population ecology on a continental scale and will aid in the prediction and interpretation of inter-annual variability of insect migration patterns including those in response to climatic change and adoption rates of transgenic cultivars. PMID- 26045332 TI - Simultaneous utilization of glucose and xylose via novel mechanisms in engineered Escherichia coli. AB - After glucose, xylose is the most abundant sugar in lignocellulosic carbon sources. However, wild-type Escherichia coli is unable to simultaneously utilize both sugars due to carbon catabolite repression (CCR). In this paper, we describe GX50, an engineered strain capable of utilizing glucose and xylose simultaneously. This strain was obtained by evolving a mutant from which araC has been deleted, and in which genes required for pentose metabolism are constitutively expressed. The strain acquired four additional mutations during adaptive evolution, including intergenic mutations in the 5'-flanking region of xylA and pyrE, and missense mutations in araE (S91I) and ybjG (D99G). In contrast to wild type E. coli, GX50 rapidly converts xylose to xylitol even if glucose is available. Notably, the strain grows well when cultured on glucose, unlike some well-known CCR-insensitive mutants defective in the glucose phosphotransferase system. Our work will advance efforts to design a metabolically efficient platform strain for potential use in producing chemicals from lignocellulose. PMID- 26045331 TI - The association between diurnal temperature range and childhood bacillary dysentery. AB - Previous studies have found that mean, maximum, and minimum temperatures were associated with bacillary dysentery (BD). However, little is known about whether the within-day variation of temperature has any impact on bacillary dysentery. The current study aimed to identify the relationship between diurnal temperature range (DTR) and BD in Hefei, China. Daily data on BD counts among children aged 0 14 years from 1 January 2006 to 31 December 2012 were retrieved from Hefei Center for Disease Control and Prevention. Daily data on ambient temperature and relative humidity covering the same period were collected from the Hefei Bureau of Meteorology. A Poisson generalized linear regression model combined with a distributed lag non-linear model (DLNM) was used in the analysis after controlling the effects of season, long-term trends, mean temperature, and relative humidity. The results showed that there existed a statistically significant relationship between DTR and childhood BD. The DTR effect on childhood bacillary dysentery increased when DTR was over 8 degrees C. And it was greatest at 1-day lag, with an 8% (95% CI = 2.9-13.4%) increase of BD cases per 5 degrees C increment of DTR. Male children and children aged 0-5 years appeared to be more vulnerable to the DTR effect. The data indicate that large DTR may increase the incidence of childhood BD. Caregivers and health practitioners should be made aware of the potential threat posed by large DTR. Therefore, DTR should be taken into consideration when making targeted health policies and programs to protect children from being harmed by climate impacts. PMID- 26045333 TI - Carotenoids are essential for the assembly of cyanobacterial photosynthetic complexes. AB - In photosynthetic organisms, carotenoids (carotenes and xanthophylls) are important for light harvesting, photoprotection and structural stability of a variety of pigment-protein complexes. Here, we investigated the consequences of altered carotenoid composition for the functional organization of photosynthetic complexes in wild-type and various mutant strains of the cyanobacterium Synechocystis sp. PCC 6803. Although it is generally accepted that xanthophylls do not play a role in cyanobacterial photosynthesis in low-light conditions, we have found that the absence of xanthophylls leads to reduced oligomerization of photosystems I and II. This is remarkable because these complexes do not bind xanthophylls. Oligomerization is even more disturbed in crtH mutant cells, which show limited carotenoid synthesis; in these cells also the phycobilisomes are distorted despite the fact that these extramembranous light-harvesting complexes do not contain carotenoids. The number of phycocyanin rods connected to the phycobilisome core is strongly reduced leading to high amounts of unattached phycocyanin units. In the absence of carotenoids the overall organization of the thylakoid membranes is disturbed: Photosystem II is not formed, photosystem I hardly oligomerizes and the assembly of phycobilisomes remains incomplete. These data underline the importance of carotenoids in the structural and functional organization of the cyanobacterial photosynthetic machinery. PMID- 26045334 TI - [Practical judgment and burn-out syndrome among physicians]. AB - The growing incidence of burn-out syndrome among physicians has become a major concern for public policy. The root causes are not fully understood. We make the assumption that the most powerful cause of their suffering at work is the challenging of physician's practical judgment. Practical judgment is the faculty, which connects knowledge and reason, science and experience, general and individual issues. It lies at the core of medical action and its exercise is closely associated with a pleasure at work. The evolution of medicine, particularly the proliferation of procedures, has a harmful influence on its training and its exercise. PMID- 26045335 TI - [Drug-induced pancreatitis. A review of French spontaneous reports]. AB - PURPOSE: Identify the main pharmacological classes inducing pancreatitis using spontaneous reports recorded in the French pharmacovigilance database (FPVD). METHODS: Cases of pancreatitis recorded in FPVD between January 1st 1985 and December 31st 2013 were selected using the 2001 consensus conference criteria of the French High Health Authority. RESULTS: During this period, 2975 observations were selected with 1151 fulfilling criteria of drug-induced pancreatitis (i.e. 0.22% of total notifications in the FPVD). According to ATC classification, the pharmacological classes most frequently found were antiretroviral, analgesic, lipid-lowering, immunosuppressive and insulin secreting drugs. For some drugs (metformin, omeprazole, etc.) pancreatitis was "unlabelled" in the summary of product characteristics. CONCLUSION: This review allows to identify the main drug classes currently involved in spontaneous reporting of pancreatitis in France. PMID- 26045336 TI - [Rituximab in inflammatory myopathies: "A neolithic revolution"]. PMID- 26045337 TI - [Patients' intervention in a therapeutic education program dedicated to systemic lupus: definitions, setting and benefits]. AB - PURPOSE: Though recommended, participation of patients with specific expertise in therapeutic education programs (TEP) is rare. This work reports the experience of a national reference centre for rare systemic diseases. PATIENTS AND METHODS: Involvement of "expert patients" (EP) has been planned from the development of a TEP dedicated to systemic lupus: patients' roles and required expertise have been defined and linked to the pedagogical tools. Such patients have been recruited during individual interviews and called to participate to specific pedagogical training. EP intervention have been evaluated by questionnaire to EP and health care providers. RESULTS: Three EP's functions have been identified: sharing experiences, giving "tips and tricks" and promoting dialogue. EP's interventions has been organised into a hierarchy (from sharing to co-animation). Among 298 patients enrolled in the TEP, 25 (8.4%) have been identified as possible EP. Eight of them (32%) benefited from a specific training of 12 hours. Among these patients, two (25%) regularly participate to the education sessions. For EP as well as for health care providers, EP's intervention seems beneficial (visual scale scores of 7.5 and 9.5, respectively). CONCLUSIONS: Though difficult to organise, EP's intervention in TEP dedicated to rare systemic diseases seems useful and would earn to be increase. PMID- 26045338 TI - High-efficient thermoelectric materials: The case of orthorhombic IV-VI compounds. AB - Improving the thermoelectric efficiency is one of the greatest challenges in materials science. The recent discovery of excellent thermoelectric performance in simple orthorhombic SnSe crystal offers new promise in this prospect [Zhao et al. Nature 508, 373 (2014)]. By calculating the thermoelectric properties of orthorhombic IV-VI compounds GeS,GeSe,SnS, and SnSe based on the first-principles combined with the Boltzmann transport theory, we show that the Seebeck coefficient, electrical conductivity, and thermal conductivity of orthorhombic SnSe are in agreement with the recent experiment. Importantly, GeS, GeSe, and SnS exhibit comparative thermoelectric performance compared to SnSe. Especially, the Seebeck coefficients of GeS, GeSe, and SnS are even larger than that of SnSe under the studied carrier concentration and temperature region. We also use the Cahill's model to estimate the lattice thermal conductivities at the room temperature. The large Seebeck coefficients, high power factors, and low thermal conductivities make these four orthorhombic IV-VI compounds promising candidates for high-efficient thermoelectric materials. PMID- 26045339 TI - PTEN loss is a context-dependent outcome determinant in obese and non-obese endometrioid endometrial cancer patients. AB - Endometrial cancer incidence is increasing, due in part to a strong association with obesity. Mutations in the phosphatidylinositol 3-kinase (PI3K) pathway, the central relay pathway of insulin signals, occur in the majority of endometrioid adenocarcinomas, the most common form of endometrial cancer. We sought to determine the impact of PI3K pathway alterations on progression free survival in a cohort of endometrioid endometrial cancers. Prognostic utility of PIK3CA, PIK3R1, and PTEN mutations, as well as PTEN protein loss by immunohistochemistry, was explored in the context of patient body mass index. Reverse-phase protein arrays were utilized to assess protein expression based on PTEN status. Among 187 endometrioid endometrial cancers, there were no statistically significant associations between PFS and PIK3CA, PIK3R1, PTEN mutation or loss. When stratified by body mass index, PTEN loss was associated with improved progression free survival (P < 0.006) in obese (body mass index >= 30) patients. PTEN loss resulted in distinct protein changes: Canonical PI3K pathway activation was observed only in the non-obese population while decreased expression of beta CATENIN and phosphorylated FOXO3A was observed in obese patients. These data suggest the impact of PTEN loss on tumor biology and clinical outcomes must be interpreted in the context of body mass index, and provide a potential explanation for discrepant reports on the effect of PTEN status and obesity on prognosis in endometrial cancer. This reveals a clinically important interaction between metabolic state and tumor genetics that may unveil the biologic underpinning of obesity-related cancers and impact ongoing clinical trials with PI3K pathway inhibitors. PMID- 26045341 TI - Anti-EGFR monoclonal antibodies in lung cancer treatment. PMID- 26045343 TI - Good gibbons and evil macaques: a historical review on cognitive features of non human primates in Chinese traditional culture. AB - For several thousand years the ancient Chinese have accumulated rich knowledge, in the form of written literature and folklore, on the non-human primates widely distributed in China. I have used critical text analysis and discourse analysis to clarify when and how ancient Chinese distinguished gibbons from macaques. I divided the progress into four main stages, the Pre-Shang to Shang dynasty (before 1046 BC), the Zhou to Han dynasty (1046 BC-220 AD), the six dynasties to Song dynasty (220-1279 AD), and the Yuan to Qing dynasties (1279-1840 AD). I found that China's traditional cognition of gibbons and macaques emphasized the appearance of animals, organoleptic performance, or even whether or not their behavior was "moral". They described them as human-like animals by ethical standards but ignored the species itself. This kind of cognitive style actually embodies the "pursuit of goodness", which is the feature of Chinese traditional culture. This study presents some original views on Chinese traditional knowledge of non-human primates. PMID- 26045342 TI - Anti-hyperalgesic and Anti-inflammatory Activity of Alternanthera Maritima Extract and 2"-O-alpha-L-rhamnopyranosylvitexin in Mice. AB - Alternanthera maritima are used in Brazilian popular medicine for the treatment of inflammatory and infectious diseases. Species of Alternanthera have demonstrated biological activities in previous scientific studies. The aim of this study was to determine whether the ethanol extract of the aerial parts of A. maritima (EEAM) and the isolated compound 2"-O-alpha-L-rhamnopyranosyl-vitexin inhibit mechanical hyperalgesia and parameters of inflammation in mice. The oral administration of EEAM significantly inhibited carrageenan (Cg)-induced paw edema and reduced leukocyte migration into the pleural cavity. 2"-O-alpha-L rhamnopyranosylvitexin significantly inhibited paw edema and reduced both leukocyte migration and the leakage of protein into the pleural cavity. Both EEAM and 2"-O-alpha-L-rhamnopyranosylvitexin significantly prevented the Cg-induced hyperalgesia. Local administration of 2"-O-alpha-L-rhamnopyranosylvitexin significantly prevented the Cg- and tumor necrosis factor (TNF)-induced hyperalgesia. In conclusion, this study demonstrated that EEAM is an anti inflammatory and anti-hyperalgesic agent, and the results suggested that 2"-O alpha-L-rhamnopyranosylvitexin is responsible for the effects of EEAM and the mechanism involves the TNF pathway. PMID- 26045344 TI - The prevalence of tenosynovitis of the interosseous tendons of the hand in patients with rheumatoid arthritis. AB - AIM: The aim of this study was to establish the prevalence of tenosynovitis affecting the interosseous tendons of the hand in a rheumatoid arthritis (RA) population and to assess for association with metacarpophalangeal (MCP) joint synovitis, flexor tendon tenosynovitis or ulnar drift. METHODS: Forty-four patients with RA underwent hand MRI along with 20 normal controls. Coronal 3D T1 VIBE sequences pre- and post-contrast were performed and reconstructed. The presence of interosseous tendon tenosynovitis was recorded alongside MCP joint synovitis, flexor tendon tenosynovitis and ulnar drift. RESULTS: Twenty-one (47.7%) patients with RA showed interosseous tendon tenosynovitis. Fifty-two (14.8%) interosseous tendons showed tenosynovitis amongst the RA patients. Interosseous tendon tenosynovitis was more commonly seen in association with adjacent MCP joint synovitis (p < 0.001), but nine MCP joints (5.1%) showed adjacent interosseous tenosynovitis in the absence of joint synovitis. Interosseous tendon tenosynovitis was more frequently seen in fingers which also showed flexor tendon tenosynovitis (p < 0.001) and in patients with ulnar drift of the fingers (p = 0.01). CONCLUSION: Tenosynovitis of the hand interosseous tendons was found in 47.7% of patients with RA. In the majority of cases this was adjacent to MCP joint synovitis; however, interosseous tendon tenosynovitis was also seen in isolation. KEY POINTS: * Tenosynovitis of the interosseous tendons of the hand occurs in rheumatoid arthritis. * Interosseous tendon tenosynovitis has a prevalence of 47.7% in patients with RA. * Interosseous tendon tenosynovitis is related to MCP joint synovitis in the adjacent joints. PMID- 26045340 TI - Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): an open-label, randomised, controlled phase 3 trial. AB - BACKGROUND: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. METHODS: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m(2) administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash- a class effect of EGFR antibodies--that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. FINDINGS: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11.5 months [95% CI 10.4-12.6]) vs 9.9 months [8.9-11.1]; stratified hazard ratio 0.84 [95% CI 0.74-0.96; p=0.01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [<1%]). Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12%) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11%) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3%) and ten (2%) patients, respectively. Overall, we found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations. INTERPRETATION: Our findings show that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improves overall survival in patients with advanced squamous non small-cell lung cancer and represents a new first-line treatment option for this disease. FUNDING: Eli Lilly and Company. PMID- 26045345 TI - Comparison of cone-beam CT-guided and CT fluoroscopy-guided transthoracic needle biopsy of lung nodules. AB - PURPOSE: To compare the diagnostic performance of cone-beam CT (CBCT)-guided and CT fluoroscopy (fluoro-CT)-guided technique for transthoracic needle biopsy (TNB) of lung nodules. METHODS: The hospital records of 319 consecutive patients undergoing 324 TNBs of lung nodules in a single radiology unit in 2009-2013 were retrospectively evaluated. The newly introduced CBCT technology was used to biopsy 123 nodules; 201 nodules were biopsied by conventional fluoro-CT-guided technique. We assessed the performance of the two biopsy systems for diagnosis of malignancy and the radiation exposure. RESULTS: Nodules biopsied by CBCT-guided and by fluoro-CT-guided technique had similar characteristics: size, 20 +/- 6.5 mm (mean +/- standard deviation) vs. 20 +/- 6.8 mm (p = 0.845); depth from pleura, 15 +/- 15 mm vs. 15 +/- 16 mm (p = 0.595); malignant, 60% vs. 66% (p = 0.378). After a learning period, the newly introduced CBCT-guided biopsy system and the conventional fluoro-CT-guided system showed similar sensitivity (95% and 92%), specificity (100% and 100%), accuracy for diagnosis of malignancy (96% and 94%), and delivered non-significantly different median effective doses [11.1 mSv (95 % CI 8.9-16.0) vs. 14.5 mSv (95% CI 9.5-18.1); p = 0.330]. CONCLUSION: The CBCT-guided and fluoro-CT-guided systems for lung nodule biopsy are similar in terms of diagnostic performance and effective dose, and may be alternatively used to optimize the available technological resources. KEY POINTS: * CBCT-guided and fluoro-CT-guided lung nodule biopsy provided high and similar diagnostic accuracy. * Effective dose from CBCT-guided and fluoro-CT-guided lung nodule biopsy was similar. * To optimize resources, CBCT-guided lung nodule biopsy may be an alternative to fluoro-CT-guided. PMID- 26045346 TI - Neural substrates of cognitive flexibility in cocaine and gambling addictions. AB - BACKGROUND: Individuals with cocaine and gambling addictions exhibit cognitive flexibility deficits that may underlie persistence of harmful behaviours. AIMS: We investigated the neural substrates of cognitive inflexibility in cocaine users v. pathological gamblers, aiming to disambiguate common mechanisms v. cocaine effects. METHOD: Eighteen cocaine users, 18 pathological gamblers and 18 controls performed a probabilistic reversal learning task during functional magnetic resonance imaging, and were genotyped for the DRD2/ANKK Taq1A polymorphism. RESULTS: Cocaine users and pathological gamblers exhibited reduced ventrolateral prefrontal cortex (PFC) signal during reversal shifting. Cocaine users further showed increased dorsomedial PFC (dmPFC) activation relative to pathological gamblers during perseveration, and decreased dorsolateral PFC activation relative to pathological gamblers and controls during shifting. Preliminary genetic findings indicated that cocaine users carrying the DRD2/ANKK Taq1A1+ genotype may derive unique stimulatory effects on shifting-related ventrolateral PFC signal. CONCLUSIONS: Reduced ventrolateral PFC activation during shifting may constitute a common neural marker across gambling and cocaine addictions. Additional cocaine related effects relate to a wider pattern of task-related dysregulation, reflected in signal abnormalities in dorsolateral and dmPFC. PMID- 26045347 TI - An evidence-based algorithm for the utility of FDG-PET for diagnosing Alzheimer's disease according to presence of medial temporal lobe atrophy. AB - BACKGROUND: Imaging biomarkers for Alzheimer's disease include medial temporal lobe atrophy (MTLA) depicted on computed tomography (CT) or magnetic resonance imaging (MRI) and patterns of reduced metabolism on fluorodeoxyglucose positron emission tomography (FDG-PET). AIMS: To investigate whether MTLA on head CT predicts the diagnostic usefulness of an additional FDG-PET scan. METHOD: Participants had a clinical diagnosis of Alzheimer's disease (n = 37) or dementia with Lewy bodies (DLB; n = 30) or were similarly aged controls (n = 30). We visually rated MTLA on coronally reconstructed CT scans and, separately and blind to CT ratings, abnormal appearances on FDG-PET scans. RESULTS: Using a pre defined cut-off of MTLA ?5 on the Scheltens (0-8) scale, 0/30 controls, 6/30 DLB and 23/30 Alzheimer's disease had marked MTLA. FDG-PET performed well for diagnosing Alzheimer's disease v DLB in the low-MTLA group (sensitivity/specificity of 71%/79%), but in the high-MTLA group diagnostic performance of FDG-PET was not better than chance. CONCLUSIONS: In the presence of a high degree of MTLA, the most likely diagnosis is Alzheimer's disease, and an FDG-PET scan will probably not provide significant diagnostic information. However, in cases without MTLA, if the diagnosis is unclear, an FDG-PET scan may provide additional clinically useful diagnostic information. PMID- 26045348 TI - Duration of untreated psychosis and need for admission in patients who engage with mental health services in the prodromal phase. AB - BACKGROUND: It is unknown whether prodromal services improve outcomes in those who go on to develop psychosis, and whether these patients are demographically different from the overall first-episode population. AIMS: To compare sociodemographic features, duration of untreated psychosis, hospital admission and frequency of compulsory treatment in the first year after the onset of psychosis in patients who present to prodromal services with patients who did not present to services until the first episode of psychosis. METHOD: We compared two groups of patients with first-episode psychosis: one who made transition after presenting in the prodromal phase and the other who had presented with a first episode. RESULTS: The patients who had presented before the first episode were more likely to be employed and less likely to belong to an ethnic minority group. They had a shorter duration of untreated psychosis, and were less likely to have been admitted to hospital and to have required compulsory treatment. CONCLUSIONS: Patients who develop psychosis after being engaged in the prodromal phase have a better short-term clinical outcome than patients who do not present until the first episode. Patients who present during first episodes may be more likely to have sociodemographic features associated with relatively poor outcomes. PMID- 26045349 TI - Recent intimate partner violence among people with chronic mental illness: findings from a national cross-sectional survey. AB - BACKGROUND: People with mental illness are at increased risk of intimate partner violence (IPV) victimisation, but little is known about their risk for different forms of IPV, related health impact and help-seeking. AIMS: To estimate the odds for past-year IPV, related impact and disclosure among people with and without pre-existing chronic mental illness (CMI). METHOD: We analysed data from 23 222 adult participants in the 2010/2011 British Crime Survey using multivariate logistic regression. RESULTS: Past-year IPV was reported by 21% and 10% of women and men with CMI, respectively. The adjusted relative odds for emotional, physical and sexual IPV among women with versus without CMI were 2.8 (CI = 1.9 4.0), 2.6 (CI = 1.6-4.3) and 5.4 (CI = 2.4-11.9), respectively. People with CMI were more likely to attempt suicide as result of IPV (aOR = 5.4, CI = 2.3-12.9), less likely to seek help from informal networks (aOR = 0.5, CI = 0.3-0.8) and more likely to seek help exclusively from health professionals (aOR = 6.9, CI = 2.6-18.3). CONCLUSIONS: People with CMI are not only at increased risk of all forms of IPV, but they are more likely to suffer subsequent ill health and to disclose exclusively to health professionals. Therefore, health professionals play a key role in addressing IPV in this population. PMID- 26045350 TI - Risk and protective factors for suicidal ideation and behaviour in Rwandan children. AB - BACKGROUND: Suicide is a leading cause of death for young people. Children living in sub-Saharan Africa, where HIV rates are disproportionately high, may be at increased risk. AIMS: To identify predictors, including HIV status, of suicidal ideation and behaviour in Rwandan children aged 10-17. METHOD: Matched case control study of 683 HIV-positive, HIV-affected (seronegative children with an HIV-positive caregiver), and unaffected children and their caregivers. RESULTS: Over 20% of HIV-positive and affected children engaged in suicidal behaviour in the previous 6 months, compared with 13% of unaffected children. Children were at increased risk if they met criteria for depression, were at high-risk for conduct disorder, reported poor parenting or had caregivers with mental health problems. CONCLUSIONS: Policies and programmes that address mental health concerns and support positive parenting may prevent suicidal ideation and behaviour in children at increased risk related to HIV. PMID- 26045351 TI - Neuroimaging distinction between neurological and psychiatric disorders. AB - BACKGROUND: It is unclear to what extent the traditional distinction between neurological and psychiatric disorders reflects biological differences. AIMS: To examine neuroimaging evidence for the distinction between neurological and psychiatric disorders. METHOD: We performed an activation likelihood estimation meta-analysis on voxel-based morphometry studies reporting decreased grey matter in 14 neurological and 10 psychiatric disorders, and compared the regional and network-level alterations for these two classes of disease. In addition, we estimated neuroanatomical heterogeneity within and between the two classes. RESULTS: Basal ganglia, insula, sensorimotor and temporal cortex showed greater impairment in neurological disorders; whereas cingulate, medial frontal, superior frontal and occipital cortex showed greater impairment in psychiatric disorders. The two classes of disorders affected distinct functional networks. Similarity within classes was higher than between classes; furthermore, similarity within class was higher for neurological than psychiatric disorders. CONCLUSIONS: From a neuroimaging perspective, neurological and psychiatric disorders represent two distinct classes of disorders. PMID- 26045352 TI - Maternal depression during pregnancy and offspring depression in adulthood: role of child maltreatment. AB - BACKGROUND: Studies have shown that maternal depression during pregnancy predicts offspring depression in adolescence. Child maltreatment is also a risk factor for depression. AIMS: To investigate (a) whether there is an association between offspring exposure to maternal depression in pregnancy and depression in early adulthood, and (b) whether offspring child maltreatment mediates this association. METHOD: Prospectively collected data on maternal clinical depression in pregnancy, offspring child maltreatment and offspring adulthood (18-25 years) DSM-IV depression were analysed in 103 mother-offspring dyads of the South London Child Development Study. RESULTS: Adult offspring exposed to maternal depression in pregnancy were 3.4 times more likely to have a DSM-IV depressive disorder, and 2.4 times more likely to have experienced child maltreatment, compared with non exposed offspring. Path analysis revealed that offspring experience of child maltreatment mediated the association between exposure to maternal depression in pregnancy and depression in adulthood. CONCLUSIONS: Maternal depression in pregnancy is a key vulnerability factor for offspring depression in early adulthood. PMID- 26045353 TI - Shell Cross-Linked Polymeric Micelles as Camptothecin Nanocarriers for Anti-HCV Therapy. AB - A suitable carrier for camptothecin to act as therapy against the hepatitis C virus is presented. The carrier relies on an amphiphilic hybrid dendritic-linear dendritic block copolymer, derived from pluronic F127 and bis-MPA dendrons, that forms micelles in aqueous solution. The dendrons admit the incorporation of multiple photoreactive groups that allow the clean and effective preparation of covalently cross-linked polymeric micelles (CLPM), susceptible of loading hydrophilic and lipophilic molecules. Cell-uptake experiments using a newly designed fluorophore, derived from rhodamine B, demonstrate that the carrier favors the accumulation of its cargo within the cell. Furthermore, loaded with camptothecin, it is efficient in fighting against the hepatitis C virus while shows lower cytotoxicity than the free drug. PMID- 26045354 TI - The generation gap: Proteome changes and strain variation during encystation in Giardia duodenalis. AB - The prevalence of Giardia duodenalis in humans is partly owed to its direct and simple life cycle, as well as the formation of the environmentally resistant and infective cysts. Proteomic and transcriptomic studies have previously analysed the encystation process using the well-characterised laboratory genomic strain, WB C6. This study presents the first quantitative study of encystation using pathogenically relevant and alternative assemblage A strains: the human-derived BRIS/82/HEPU/106 (H-106)and avian-derived BRIS/95/HEPU/2041 (B-2041). We utilised tandem MS/MS with a label-free quantitative approach to compare cysts and trophozoite life stages for strain variation, as well as confirm universal encystation markers of assemblage A. A total of 1061 non-redundant proteins were identified from both strains, including trophozoite- and cyst-specific proteomes and life-stage differentially expressed proteins. Additionally, 24 proteins previously classified in the literature as encystation-specific were confirmed as strain-independent markers of encystation. Functional cluster analysis of differentially expressed proteins saw significant overlap between strains, including protein trafficking and localisation in cysts, NEK kinase function, and carbohydrate metabolism in trophozoites. Two significant points of strain specific adaptations in cysts were also identified. B-2041 possessed major up regulation of the ankyrin repeat protein 21.1 family compared to H-106. Furthermore, cysts of B-2041 retained near-complete VSP variant diversity between cysts and trophozoites, while H-106 lost 45% of its VSP variant diversity between life cycle stages, a constriction previously observed in studies of WB C6. This is the first report of strain variation in the cyst stage in G. duodenalis, and highlights cyst variation and its impacts on reinfection and life cycle success. PMID- 26045355 TI - Thrombolytic protocol minimizes ischemic-type biliary complications in liver transplantation from donation after circulatory death donors. PMID- 26045356 TI - Risk factors for epistaxis in jump racing in Great Britain (2001-2009). AB - The aim of this study was to evaluate risk factors associated with developing epistaxis in jump racing in Great Britain (GB). A retrospective analysis of records from horses running in all hurdle and steeplechase races in GB between 2001 and 2009 identified diagnoses of epistaxis whilst still at the racecourse. Data were used from 603 starts resulting in epistaxis (event) and 169,065 starts resulting in no epistaxis (non-event) in hurdle racing, and from 550 event starts and 102,344 non-event starts in steeplechase racing. Two multivariable logistic regression models to evaluate risk factors associated with epistaxis were produced. The potential effect of clustering of data (within horse, horse dam, horse sire, trainer, jockey, course, race and race meet) on the associations between risk factors and epistaxis was examined using mixed-effects models. Multiple factors associated with increased risk of epistaxis were identified. Those identified in both types of jump racing included running on firmer ground; horses with >75% of career starts in flat racing and a previous episode of epistaxis recorded during racing. Risk factors identified only in hurdle racing included racing in the spring and increased age at first race; and those identified only in steeplechase racing included running in a claiming race and more starts in the previous 3-6 months. The risk factors identified provide important information about the risk of developing epistaxis. Multiple avenues for further investigation are highlighted, including unmeasured variables at the level of the racecourse. The results of this study can be used to guide the development of interventions to minimise the risk of epistaxis in jump racing. PMID- 26045357 TI - Circumferential hoof clamp method of lameness induction in the horse. AB - A circumferential hoof clamp method to induce controlled and reversible lameness in the forelimbs of eight horses was assessed. Peak vertical forces and vertical impulses were recorded using a force plate to verify induced lameness. Video recordings were used by blinded observers to determine subjective lameness using a 0-5 scale and any residual lameness following clamp loosening. Tightening of clamps resulted in consistent, visible lameness in the selected limbs in all horses. Lameness was confirmed by significant decreases from baseline in the peak vertical force (P <0.01). Lameness was also confirmed subjectively by elevated median scores (0 at baseline and 2 during lameness). Lameness was not immediately reversible after clamp loosening (median score 1.5), but horses were not obviously lame after clamp removal and were no different from initial baseline (median score 0.5) approximately 3 days later. PMID- 26045358 TI - Yoga for secondary prevention of coronary heart disease. AB - BACKGROUND: Coronary heart disease (CHD) is the major cause of early morbidity and mortality in most developed countries. Secondary prevention aims to prevent repeat cardiac events and death in people with established CHD. Lifestyle modifications play an important role in secondary prevention. Yoga has been regarded as a type of physical activity as well as a stress management strategy. Growing evidence suggests the beneficial effects of yoga on various ailments. OBJECTIVES: To determine the effectiveness of yoga for the secondary prevention of mortality and morbidity in, and on the health-related quality of life of, individuals with CHD. SEARCH METHODS: This is an update of a review previously published in 2012. For this updated review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1 of 12, 2014), MEDLINE (1948 to February week 1 2014), EMBASE (1980 to 2014 week 6), Web of Science (Thomson Reuters, 1970 to 12 February 2014), China Journal Net (1994 to May 2014), WanFang Data (1990 to May 2014), and Index to Chinese Periodicals of Hong Kong (HKInChiP) (from 1980). Ongoing studies were identified in the metaRegister of Controlled Trials (May 2014) and the World Health Organization International Clinical Trials Registry Platform (May 2014). We applied no language restrictions. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) investigating the influence of yoga practice on CHD outcomes in men and women (aged 18 years and over) with a diagnosis of acute or chronic CHD. Studies were eligible for inclusion if they had a follow-up duration of six months or more. We considered studies that compared one group practicing a type of yoga with a control group receiving either no intervention or interventions other than yoga. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies according to prespecified inclusion criteria. We resolved disagreements either by consensus or by discussion with a third author. MAIN RESULTS: We found no eligible RCTs that met the inclusion criteria of the review and thus we were unable to perform a meta-analysis. AUTHORS' CONCLUSIONS: The effectiveness of yoga for secondary prevention in CHD remains uncertain. Large RCTs of high quality are needed. PMID- 26045359 TI - Patient-Reported Symptoms Over 48 Weeks in a Randomized, Open-Label, Phase IIIb Non-Inferiority Trial of Adults with HIV Switching to Co-Formulated Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF versus Continuation of Non-Nucleoside Reverse Transcriptase Inhibitor with Emtricitabine and Tenofovir DF. AB - BACKGROUND: Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF; Stribild((r))) is a guideline-recommended regimen for HIV treatment-naive patients and a switch option for virologically suppressed patients. OBJECTIVE: The purpose of this analysis was to understand how HIV patients' symptoms change after switching to Stribild((r)) versus continuing a regimen consisting of a non-nucleoside reverse transcriptase inhibitor (NNRTI) with emtricitabine and tenofovir disoproxil fumarate. METHODS: A secondary analysis was conducted of the STRATEGY-NNRTI study (GS-US-236-0121), a randomized, open-label, phase IIIb trial of HIV-infected adults who were taking an NNRTI plus FTC/TDF and were randomly assigned (2:1) either to Stribild((r)) ('switch') or to continue on their existing regimen ('no-switch'). Logistic regressions and longitudinal modeling were conducted to evaluate the relationship of treatment with bothersome symptoms. These models adjusted for age, sex, race, number of bothersome symptoms at baseline, Veterans Aging Cohort Study Risk (VACS) Index score, years since HIV diagnosis, and first antiretroviral therapy use, NNRTI type, serious mental illness, and baseline depression and health related quality of life (HRQL) scores. RESULTS: At baseline, the prevalence of nightmares, vivid dreams, weird/intense dreams, muscle aches/joint pain, and fevers/chills/sweats was greater in the switch group. The prevalence of nightmare, vivid dreams, weird/intense dreams, dizzy/lightheadedness, fatigue/loss of energy, and pain/numbness/tingling in hands/feet deceased in the switch group at week 4, and these benefits were maintained over time. Nervous/anxious, drowsiness, trouble remembering, off balance, and body changes decreased in the switch group at week 4 but were not maintained over time. Difficulty sleeping, diarrhea/loose bowels, and bloating did not differ in prevalence at week 4 or 48, but longitudinal models suggested differences between groups over time. HRQL did not differ between groups and was unchanged over time. CONCLUSIONS: In this study sample, a switch to co-formulated EVG/COBI/FTC/TDF was associated with significant persistent improvements in six patient-reported HIV symptoms. PMID- 26045360 TI - Metronomic chemotherapy with daily low-dose temozolomide and celecoxib in elderly patients with newly diagnosed glioblastoma multiforme: a retrospective analysis. AB - Chemotherapy is often omitted in elderly patients with glioblastoma multiforme due to a fear of side effects. We applied metronomic chemotherapy with low-dose temozolomide and celecoxib (LD-TEM/CEL) during and after external beam radiotherapy (EBRT) and here report on how this regimen compares to standard temozolomide radiochemotherapy (SD-TEM) in elderly patients. We retrospectively analyzed records of 146 patients aged 65 years and older that underwent EBRT. Factors of interest were age, performance status, comorbidities, MGMT status, therapy (resection/biopsy, radiotherapy/dose, chemotherapy/regimen/dose), progression-free (PFS) and overall survival (OS) status. Irrespective of the regimen, addition of chemotherapy more than doubled median survival rates (EBRT only: 4.2 months; EBRT + LD-TEM/CEL: 8.5 months; EBRT + SD-TEM: 10.8 months; p <= 0.008). Although patients receiving metronomic LD-TEM/CEL were significantly older (62 % were >=75 years vs. 22 %; p < 0.001), had significantly lower performance scores (50 % had a KPS <70 vs. 28 %; p = 0.049) and were significantly more comorbid (73 % had >=4 comorbidities vs. 37 %; p = 0.002) than patients of the SD-TEM group, there were no significant differences in PFS and OS. Independent of other factors, omission of chemotherapy significantly impairs progression-free and overall survival. With all the limitations of a retrospective analysis, our data suggest that metronomic chemotherapy with LD TEM/CEL may be equieffective and eventually better tolerated than SD-TEM. It may be offered to elderly patients that are not eligible for standard chemotherapy. PMID- 26045362 TI - Statistical Challenges in Risk Prediction. PMID- 26045361 TI - Glioblastoma antigen discovery--foundations for immunotherapy. AB - Prognosis for patients with glioblastoma (GBM), the most common high-grade primary central nervous system (CNS) tumor, remains discouraging despite multiple discoveries and clinical advances. Immunotherapy has emerged as a promising approach to GBM therapy as the idea the human CNS is immunoprivileged is being challenged. Early clinical studies of vaccine-based approaches have been encouraging, but further investigation is required before these therapies become clinically meaningful. A key challenge in immunotherapy involves identification of target antigens that are specific and sensitive for GBM. Here we discuss tumor associated antigens that have been targeted for GBM therapy, strategies for discovery of novel antigens, and the theory of epitope spreading as it applies to GBM immunotherapy. PMID- 26045363 TI - Anatomic Predictive Factors of Acute Corneal Hydrops in Keratoconus: An Optical Coherence Tomography Study. AB - PURPOSE: To define the optical coherence tomography (OCT) corneal changes predisposing to acute corneal hydrops among patients with advanced keratoconus. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 191 advanced keratoconic eyes from 191 patients with advanced keratoconus cases were studied. METHODS: Data collected from patients with advanced keratoconus cases were studied during a minimum period of 24 months of follow-up. High-resolution Fourier-domain corneal OCT (5 MUm of axial resolution) and corneal topography were performed every 4 months during the follow-up. Several anatomic features at the keratoconus cone were analyzed with OCT, including epithelial and stromal thicknesses, the aspect of Bowman's layer, the presence of Vogt's striae, and stromal opacities. A comparative analysis between anatomic corneal features in eyes that developed corneal hydrops and those that did not develop this complication during the follow-up was performed. MAIN OUTCOME MEASURES: Evaluation of anatomic corneal changes at risk of developing a corneal hydrops on the basis of OCT findings. RESULTS: Eleven cases of corneal hydrops (5.8%) occurred in our series during a mean follow-up of 30 months (24-36 months). All of these patients were male and younger (23.7+/-5.9 years) than patients with no acute keratoconus (32.7+/-11.3 years). Increased epithelial thickening with stromal thinning at the conus and the presence of anterior hyperreflectives at the Bowman's layer level were significantly associated with corneal hydrops, whereas the presence of corneal scarring was a preventive factor. At the healing stage, a pan-stromal scar occurs, with a significant stromal thickening and cornea flattening. CONCLUSIONS: Increased epithelial thickening, stromal thinning at the keratoconus cone, anterior hyperreflectives at the Bowman's layer level, and the absence of stromal scarring are associated with a high risk of developing corneal hydrops. These aspects should be taken into account by the clinician in the evaluation of keratoconus eyes and in the planning of corneal keratoplasty. PMID- 26045365 TI - Use of a Physiologically Based Pharmacokinetic Model for Quantitative Prediction of Drug-Drug Interactions via CYP3A4 and Estimation of the Intestinal Availability of CYP3A4 Substrates. AB - The purpose of this study was to predict the drug-drug interactions (DDIs) via CYP3A4 by estimating the extent of hepatic CYP3A4 inhibition based on a physiologically based pharmacokinetic (PBPK) model of both substrate and inhibitor and the increase in the intestinal availability (Fg ) due to the enzyme inhibition. For the DDIs resulting from reversible inhibition of CYP3A4, the prediction using in vivo Ki values estimated from other clinical DDI studies and predicted in vivo Ki values calculated using the correlation between the log P and the in vivo Ki /in vitro Ki ratio was more accurate than that using in vitro Ki values. Incorporating inhibition of both intestinal and hepatic metabolism resulted in better prediction than that obtained considering inhibition in the liver alone, and all the DDIs (AUC increase by the inhibitor) were predicted within 2-fold accuracy when in vivo Ki values were used. In addition, Fg values were successfully back-calculated from the clinical DDI data based on the present model. In conclusion, the present PBPK model incorporating the in vivo Ki values was found to be useful for quantitative prediction of clinical DDIs and for estimation of the Fg values for CYP3A4 substrates for which intravenous data were not available. PMID- 26045364 TI - Characteristics of Endophthalmitis after Cataract Surgery in the United States Medicare Population. AB - PURPOSE: Endophthalmitis is a rare but sight-threatening infection after cataract surgery. Roughly one third of eyes remain blind after treatment. We report United States population-based data on microbiological investigations and treatment patterns plus risk factors for poor outcomes. DESIGN: Retrospective cohort study. PARTICIPANTS: Medicare beneficiaries from 5 states in whom endophthalmitis developed within 6 weeks after cataract surgery in 2003 and 2004. METHODS: We identified endophthalmitis cases occurring after cataract surgery using Medicare billing claims. We contacted treating physicians and requested they complete a questionnaire on clinical and microbiological data and submit relevant medical records. Two independent observers reviewed materials to confirm that cases met a standardized definition. MAIN OUTCOME MEASURES: Positive culture results, vitrectomy status, microbiology spectrum, and final visual acuity. RESULTS: In total, 615 cases met our case definition. Initial visual acuity was counting fingers or worse for 72%. Among 502 cases with known culture results, 291 (58%) had culture positive results. Twelve percent had positive results for streptococci. More than 99% of cases were treated with intravitreal vancomycin. Vitrectomy was performed in 279 cases (45%), including 201 cases with initial acuity better than light perception. Rates of vitrectomy varied across states, with California having the highest rate and Michigan having the lowest (56% and 19% of cases, respectively). Overall, 43% of individuals achieved visual acuity of 20/40 or better. Poor initial acuity (adjusted odds ratio [OR], 1.08; 95% confidence interval [CI], 1.04-1.12 per 0.10 logarithm of the minimum angle of resolution units), older age at diagnosis (OR, 1.22; 95% CI, 1.03-1.45 per 5-year increase), and more virulent organisms were important predictors of poor final visual acuity. Cases with streptococci infection were 10 times more likely to have poor final acuity than coagulase-negative staphylococci cases (adjusted OR, 11.28; 95% CI, 3.63-35.03). Vitrectomy was not predictive of final visual acuity (adjusted OR, 1.26; 95% CI, 0.78-2.04). CONCLUSIONS: Population-based data on the microbiology of acute postoperative endophthalmitis in the United States after cataract surgery are consistent with prior reports. Vitrectomy usage is higher than that recommended from the Endophthalmitis Vitrectomy Study, with no evidence of increased benefit. PMID- 26045366 TI - The role of Duffy antigen receptor for chemokines in keloids. AB - This study aims to determine the relationship between Duffy antigen receptor for chemokines (DARC) and keloid pathogenesis. DARC expression was determined by immunohistochemistry, real-time PCR, and Western blot analysis. Cell proliferation was assessed by CCK-8 assay. Cell migration and invasion abilities were measured by the shift assay. Levels of CC chemokine ligand 2 (CCL2), CXC chemokine ligand 8 (CXCL8), and matrix metalloproteinase 2 (MMP2) were detected by real-time PCR and ELISA. Our results showed that DARC levels were elevated in human keloid fibroblasts. After knocking down DARC, cell proliferation was not altered, whereas the migration and invasion abilities of keloid fibroblasts were significantly elevated. Additionally, the mRNA expression levels of CCL2, CXCL8, and MMP2 were not influenced by DARC knockdown. However, the secretion of CCL2, but not CXCL8 or MMP2, was significantly increased after DARC knockdown. Our results suggest that DARC might inhibit the secretion of CCL2. Moreover, DARC knockdown increases the migration and invasion abilities of keloid fibroblasts. PMID- 26045367 TI - Reveal genes functionally associated with ACADS by a network study. AB - Establishing a systematic network is aimed at finding essential human gene gene/gene-disease pathway by means of network inter-connecting patterns and functional annotation analysis. In the present study, we have analyzed functional gene interactions of short-chain acyl-coenzyme A dehydrogenase gene (ACADS). ACADS plays a vital role in free fatty acid beta-oxidation and regulates energy homeostasis. Modules of highly inter-connected genes in disease-specific ACADS network are derived by integrating gene function and protein interaction data. Among the 8 genes in ACADS web retrieved from both STRING and GeneMANIA, ACADS is effectively conjoined with 4 genes including HAHDA, HADHB, ECHS1 and ACAT1. The functional analysis is done via ontological briefing and candidate disease identification. We observed that the highly efficient-interlinked genes connected with ACADS are HAHDA, HADHB, ECHS1 and ACAT1. Interestingly, the ontological aspect of genes in the ACADS network reveals that ACADS, HAHDA and HADHB play equally vital roles in fatty acid metabolism. The gene ACAT1 together with ACADS indulges in ketone metabolism. Our computational gene web analysis also predicts potential candidate disease recognition, thus indicating the involvement of ACADS, HAHDA, HADHB, ECHS1 and ACAT1 not only with lipid metabolism but also with infant death syndrome, skeletal myopathy, acute hepatic encephalopathy, Reye-like syndrome, episodic ketosis, and metabolic acidosis. The current study presents a comprehensible layout of ACADS network, its functional strategies and candidate disease approach associated with ACADS network. PMID- 26045368 TI - Engineering mammalian cell factories with SINEUP noncoding RNAs to improve translation of secreted proteins. AB - Whenever the function of a recombinant protein depends on post-translational processing, mammalian cells become an indispensable tool for their production. This is particularly true for biologics and therapeutic monoclonal antibodies (MAbs). Despite some drawbacks, Chinese Hamster Ovary (CHO) cells are the workhorse for MAbs production in academia and industry. Several methodologies have been adopted to improve expression and stability, including methods based on selective pressure or cell engineering. We have previously identified SINEUPs as a new functional class of natural and synthetic long non-coding RNAs that through the activity of an inverted SINEB2 element are able to promote translation of partially overlapping sense coding mRNAs. Here we show that by taking advantage of their modular structure, synthetic SINEUPs can be designed to increase production of secreted proteins. Furthermore, by experimentally validating antisense to elastin (AS-eln) RNA as a natural SINEUP, we show that SINEUP mediated control may target extracellular proteins. These results lead us to propose synthetic SINEUPs as new versatile tools to optimize production of secreted proteins in manufacturing pipelines and natural SINEUPs as new regulatory RNAs in the secretory pathways. PMID- 26045369 TI - Stroke, mTBI, infection, antibiotics and beta blockade: Connecting the dots. AB - Several themes supported by a robust literature are addressed in this clinical translational review and research paper: (1) the inadequate standard of care for minimal traumatic brain injury (mTBI)/concussion when compared to stroke because diagnosis and care for mTBI/concussion are based primarily on a symptom only framework; (2) the treatment of stroke (brain injury) infection with select antibiotics; (3) the use of beta blockade in stroke (brain injury). The various etiologies of brain injury appear to coalesce to common endpoints: potential neuronal demise, cognitive and functional losses, immune suppression and infection. The use of principles patterned after 'Koch's Postulates' (show/prove the presence of infection/illness/disease, treat until resolved, and prove objectively that the disease/illness is gone/healed/cured) appears to be marginalized in establishing a diagnosis and recovery from mTBI/TBI. The pathways of immune system interactions in stroke (brain injury) and infection are briefly discussed. The suggestion of combined specific antibiotic and beta blockade for ischemic stroke (brain injury) and mTBI is advanced for treatment and expeditious further study. Stroke is considered a brain injury in this paper. Stroke is also considered and recommended as a study model for mTBI therapy because of their common end points from brain damage. It is suggested that potential transfer or translation of therapy for stroke may be useful in mTBI. PMID- 26045371 TI - In vivo evaluation & safety profile evaluation of Arctostaphylos uva-ursi (L.) Spreng. extract in rabbits. AB - The aim of our research work was to investigate the effects of low dose of Arctostaphylos uva-ursi (L.) Spreng. on rabbits. Crude extract was administered for 90 days in rabbits and hematology, biochemistry parameters and histopathology changes were analyzed. In result of it gender-based variations were observed in hematological, kidney function, liver function, cardiac enzymes and lipid profile. Urine analysis revealed same results as that of standard and control drug. No significant pathology was observed in heart, stomach, liver and kidney tissues of rabbits, treated with A.uva-ursi in a dose of 25 mg/kg/day. Our results justify the use of A. uva-ursi in medicine for treatment of variable pathologies. PMID- 26045372 TI - Effect of risk factors like age, gender, hypertension, diabetes, smoking, dyslipidemia on coronary artery disease in Karachiites with angiographical data of local population: Number, site, severity of coronary lesion. AB - The aim of this study was to determine the effect of major risk factors like age, gender, hypertension, diabetes, smoking, dyslipidemia on coronary artery disease in Karachiites and highlighted the angiographic data of local population like number of vessels involvement, site and severity of coronary lesions. This was a cross sectional analytical prospective study which was carried out at Abbasi Shaheed Hospital Karachi from August 2004 - July 2014. We includedfive hundred (500) consecutive patients (188 female & 312 male) between 26-80 years old, who came for coronary angiography with suspecting ischemic heart disease clinically or otherwise proven by relevant tests like ETT, ECHO, and Thallium stress test. Post PCI and CABG patients were excluded from study. During this study variables like age, gender, hypertension, diabetes, smoking and dyslipidemia were taken into account in relation to coronary artery disease in Karachiites. In addition we also assorted some important findings of coronary angiography like: number of vessels involved, site and severity lesions in our population and compared them with existing literature. Our study revealed that in our local population not only old age and male gender are potential threat for an early coronary artery disease but other variables like hypertension, diabetes, smoking, and dyslipidemia are also playing important role in coronary artery disease. It is also concluded that our population is more prone to multiple vessels involvement with almost involvement of LAD in majority of population. PMID- 26045370 TI - Methodological considerations in assessing the effectiveness of antidepressant medication continuation during pregnancy using administrative data. AB - PURPOSE: The decision whether to continue antidepressant use for depression during pregnancy requires weighing maternal and child risks and benefits. Little is known about the effectiveness of antidepressant therapy during pregnancy. The goal of this study is to evaluate whether standard administrative claims data can be used to evaluate the effectiveness of antidepressants. METHODS: Using prescription and healthcare visit Medicaid claims (2000-2007), we identified 28 493 women with a depression diagnosis and antidepressant fill in the 90 days before their last menstrual period. Antidepressant continuation was defined based on prescription fills during the first trimester. Depression hospitalizations and deliberate self-harm served as measures of the effectiveness of treatment continuation during pregnancy. Propensity score and instrumental variable analyses were used to attempt to account for confounding. RESULTS: Relative to women who discontinued antidepressant therapy, women who continued were more likely to have a depression inpatient stay (odds ratio [OR] = 2.2, 95% confidence interval [95%CI]: 2.0-2.4) and deliberate self-harm code (OR = 1.4, 95%CI: 0.7 2.7). Accounting for measured covariates in the propensity score analysis, including age, race, comorbidities, comedications, features of the depression diagnosis, and antidepressant class, led to slightly attenuated estimates (OR = 2.0, 95%CI: 1.8-2.2; OR = 1.1, 95%CI: 0.5-2.4). Similar associations were estimated in subgroups with different levels of baseline depression severity. Proposed preference-time, calendar-time-based, and geography-based instruments were unlikely to meet the required conditions for a valid analysis. CONCLUSIONS: Our findings suggest that either antidepressant medications do not reduce the risk of depression relapse in pregnant women, or that administrative data alone could not be used to validly estimate the effectiveness of psychotropic medications during pregnancy. PMID- 26045373 TI - Toxicity studies on herbal formulation used in diabetes mellitus. AB - In current study herbal formulation was prepared for Diabetes mellitus (type 2). It consists of the extracts of Salacia reticulate, Cinnamomum zeylanicum,Lagerstroemia speciosa, Camellia sinensis and Gymnema sylvester. Toxicitystudies were carried out on heart, liver, kidney and blood of both male and female rabbits. Drug was administered in a dose of 15mg/kg body weight daily for 90 days. On 91th day, blood was drawn from animals and investigated for changes in biochemical and hematological levels. After that animals were sacrificed and their organs (liver, heart and kidney) were analyzed for histo pathological changes. In biochemical tests for lipid profile, significant decreased (male-70.64 +/- 0.321; female-69.80 +/- 0.365) in triglycerides level were observed, no significant change was recorded in Cholesterol HDL ratio, LDL, VLDL level. A significant increase (male-16.00 +/- 1.418; female-10.00 +/- 0.709) was observed in HDL level. In liver function test significant decrease was observed in Gamma GT (male-10.08 +/- 0.862; female-7.00 +/- 0.709). Alkaline phosphatase (male-79 +/- 0.838; female-51.1 +/- 1.810), SGPT (male-54 +/- 0.709; female-43.04 +/- 2.060), direct bilirubin (male-0.024 +/- 0.005; female-0.014 +/- 0.002) and total bilirubin (male-0.109 +/- 0.003; 0.106 +/- 0.049) were observed. Non-significant changes were observed in serum total protein, globulins, albumin and A/G ratio. No significant changes were noticed in urea level and serum electrolytes. In cardiac enzymes significant decrease was observed in LDH (male 443 +/- 5.61; female-360 +/- 1.848) and SGOT (male-27 +/- 0.709; female-28 +/- 1.418) level and highly significant rise in CPK (male- 3128 +/- 8.478; female 1598 +/- 7.483) and CK-MB (male-446 +/- 2.308; female-438 +/- 2.819). In hematological profile, significant decrease was observed in Hb (male-12.3 +/- 0.392; female-12.4 +/- 0.1), RBC count (male-6.60 +/- 0.167; female-5.74 +/- 0.25) and Hematocrit (HCT/PCV) % in both male and female rabbits (male-45.70 +/- 0.255; female-43.50 +/- 0.448) and significant (p<0.5) increased in WBC count (male-8.40 +/- 0.401; female-9.10 +/- 0.054). Significant (p<0.5) decrease in blood glucose level and HbA1c (male-3.36 +/- 0.113; female-3.16 +/- 0.076) was observed. In histopathological studies mild edema was observed in heart and there was no change in histo-architecture of liver and kidneys. It is concluded that formulation does not showed any chronic toxicity in adult dose. PMID- 26045374 TI - Antidiarrhoeal, Anti-inflammatory and analgesic activities of Symplocos racemesa roxb. Bark. AB - The antidiarrheal activity of the drug Symplocos racemosa was performed in-vivo on isolated rabbit intestine. The effects of crude extract and fractions were observed at different doses. The overall response of the crude extract on isolated tissue of rabbit intestine was decreased in the tone of smooth muscle. Further studies were carried out on different fractions (ethylacetate, chloroform, n-butanol and aqueous) of crude extract of S. racemosa. The standard drugs were also used for further screening of the fractions of S. racemosa. Hot plate, writhing test, formalin test and carrageenan-induced paw edema in mice and rats were performed for determination of analgesic and anti-inflammatory activities respectively on S. racemosa bark extract. The results exhibited significant anti-inflammatory and analgesic effect at 300 and 500mg/kg doses. PMID- 26045375 TI - Evaluation of phytoconstituents of three plants Acorus calamus linn. Artemisia absinthium Linn and Bergenia himalaica boriss by FTIR spectroscopic analysis. AB - Qualitative and quantitative analysis of plant extracts can be achieved by using different spectroscopic techniques. In current research work we deal with the nature of the absorption and spectra of extract of Acorus calamus, Artemisia absinthium and Bergenia himalaica using FTIR spectroscopic technique. The present study was focused on standardization of crude extracts by utilization of infrared light. The spectra of crude extracts (A. calamus, A. absinthium and B. himalaica) displayed very clear diagnostic peaks of functional groups i.e. O-H alcoholic/acid, C-H alkyl & aromatic ring, carbonyl, and C-O-C groups. The spectra of all the three plants did not show any peak at 2220-2260 cm(-1), which is indicative of the absence of nitrogen containing groups. These results exhibited that these plants does not contain any toxic substances. PMID- 26045376 TI - Prevalence of vitamin D deficiency and insufficiency among adult asthmatic patients in Karachi. AB - Vitamin D deficiency has assumed pandemic proportions all over the world. It has been documented as a frequent problem in studies of young adults, elderly person and children in other countries, but there is no reliable data on vitamin D status of adult asthmatic patients in Pakistan. To determine the prevalence of vitamin D deficiency and insufficiency in adult asthmatic patients with moderate to severe asthma using a cross-sectional study design in Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre, Karachi.311 adult asthmatic patients with moderate to severe asthma were recruited from JPMC, tertiary care hospital in Karachi. Questionnaires were administered together demographics, height, weight, nutritional and physical activity assessment. Blood samples for vitamin D measurement were also taken. Results show high prevalence of vitamin D deficiency and insufficiency (88.10%) in adult patients with moderate to severe persistent asthma. Vitamin D deficiency and insufficiency was more frequently observed in female than in male patients.67.66% of the female patients had serum vitamin D level less than 20 ng/ml as compare to 56.1% of the male patients (p=0.01). PMID- 26045377 TI - Antibacterial, Antifungal and antioxidant activities of some medicinal plants. AB - The purpose of this study was to evaluate the antibacterial, antifungal and antioxidant activities of medicinal plants. The antibacterial activity of methanolic extracts of three medicinal plants (Swertia chirata, Terminalia bellerica and Zanthoxylum armatum) were tested against Gentamicin (standard drug) on eleven gram positive and seventeen gram negative bacteria by agar well method. It was revealed that seven-gram negative and six gram positive bacterial species were inhibited by these plant extracts. Minimum inhibitory concentrations (MIC) of the extracts were determined by broth micro-dilution method. The significant MIC value of Swertia chirata was 20mg/ml against Serratia marcesens, Zanthoxylum armatum was 10 mg/ml against Aeromonas hydrophila and Terminali bellerica was 20mg/ml against Acinetobacter baumanii as well as Serratia marcesens. Antifungal screening was done for methanolic extracts of these plants by agar well method with the 6 saprophytic, 5 dermatophytic and 6 yeasts. In this case Griseofulvin was used as a standard. All saprophytes and dermatophytes were showed resistance by these plants extracts except Microsporum canis, which was inhibited by Z. armatum and S. chirata extracts. The significant MIC value of Zanthoxylum armatum was 10mg/ml against Microsporum canis and Swertia chirata was 10mg/ml against Candida tropicalis. The anti-oxidant study was performed by DPPH free radical scavenging assay using ascorbic acid as a reference standard. Significant antioxidant activities were observed by Swertia chirata and Zanthoxylum armatum at concentration 200MUg/ml was 70% DPPH scavenging activity (EC50=937.5MUg/ml) while Terminalia bellerica showed 55.6% DPPH scavenging activity (EC50=100MUg/ml). This study has shown that these plants could provide potent antibacterial compounds and may possible preventive agents in ROS related ailments. PMID- 26045378 TI - The relationship between sleep and cognitive functioning in adult people. AB - The purpose of the current study is to find out if subjective sleep complaints will have less cognitive functioning in older people (50 years and above). Sleep was assessed with the subscale Sleep Problems of the Symptoms Checklist-90 (Arrendell & Ettema 1986). Cognitive performance was measured with the Mini Mental Status Examination (Folstein, et al 1975) which is used as a dependent variable. Subjective complaints would be negatively associated with cognitive performance, since in elder people biological sleep is likely to be related with cognitive changes. A group of 12 people were given the task of collecting data through purposeful sampling techniques. Sample size of 120 participants was assessed. Each member of the group collected data from 10 subjects. Pearson Correlation Moment was applied for data analysis. In older persons the coefficient of falling asleep difficulty was -0.05 (p=0.33) and for waking up too early the coefficient was -0.13 (p=0.012) while for restless sleep coefficient was calculated as -0.09 (p=0.094). The assumption was verified that sleep problems negatively associated with cognitive functioning. PMID- 26045379 TI - Effect of exercise training program in post-CRET post-CABG patients with normal and subnormal ejection fraction (EF > 50% or < 50%) after coronary artery bypass grafting surgery. AB - The aim of the present study is to compare the effect of exercise training program in post-Cardiac Rehabilitation Exercise Training (CRET), post-CABG patients with normal & subnormal ejection fraction (EF >50% or <50%) who have undergoing coronary artery bypass grafting (CABG) surgery. The study was conducted on 100 cardiac patients of both sexes (age: 57-65 years) who after CABG surgery, were referred to the department of Physiotherapy and Rehabilitation between 2008 and 2010 at Liaquat National Hospital & Medical College, Karachi. The patients undertook exercise training program (using treadmill, Recumbent Bike), keeping in view the Borg's scale of perceived exertion, for 6 weeks. Heart Rate (HR) and Blood Pressure (BP) were measured & compared in post CABG Patients with EF (>50% or <50%) at the start and end of the exercise training program. Statistical formulae were applied to analyze the improvement in cardiac functional indicators. Exercise significantly restores the values of HR and BP (systolic) in post CABGT Patients with EF (>50% or <50%) from the baseline to the last session of the training program. There appeared significant improvement in cardiac function four to six weeks of treadmill exercise training program. After CABG all patients showed similar improvement in cardiac function with exercise training program. The exercise training program is beneficial for improving exercise capacity linked with recovery cardiac function in Pakistani CABG patients. PMID- 26045380 TI - Retrieval of gallbladder through epigastric port as compared to umbilical port after laparoscopic cholecystectomy. AB - This comparative prospective study was conducted at the Ghulam Muhammad Mahar Medical College Hospital and Red Crescent General Hospital, Sukkur, Pakistan, for a period of two years from July 2012 to June 2014. The study included 1800 patients who underwent laparoscopic cholecystectomy for symptomatic cholethiasis. These patients were divided in to two groups. Group I included 900 patients, who underwent conventional laparoscopic cholecystectomy with the four port technique. In these patients, the gall-bladder was retrieved through umbilical port by a sterile surgical hand glove (size 6 1/2 or 7 inches) endobag. The fascial defect of 10 mm umbilical port was closed by vicryl "0" with J-shaped needle, while three 5 mm ports closed by applying steri strips. Group-II also included 900 patients. In these patients laparoscopic cholecystectomy was done by using three ports, 10 mm epigastric working port, 5 mm umbilical port for 5 mm telescope and lateral 5 mm port for assistant. The gall-bladder was retrieved through epigastric port without endobag. The results of both these techniques were collected and analyzed on SPSS version 14. The mean age of patients was 45 years. The male to female ratio was 1:3. In group-I, after laparoscopic cholecystectomy, gall-bladder was retrieved safely through 10 mm umbilical port in surgical glove endobag. In acutely inflamed cases, the gall-bladder was opened at the umbilical port site inside the endobag and decompressed before retrieval. In this group, wound infection of umbilical port occurred in 5.11% patients, port-site hernia in 3.66%, port-site bleeding in 1.33% while difficulty in retrieval of gall-bladder in acutely inflamed cases in 1.88% patients. In group-II, wound infection in epigastric port was found in 1.55% patients, port-site hernia in 0.11%, port-site bleeding in 4%, difficulty in retrieval of gall-bladder in 5.33% while leakage /perforation of gall-bladder in 4.11% patients. The serious complications like wound infection and port-site hernia are more frequently found in group-I patients as compared to group-II. PMID- 26045381 TI - Pitavastatin is a potent anti-inflammatory agent in the rat paw model of acute inflammation. AB - Statins are used extensively as anti-hyperlipidemic agents. In addition to curtailing cholesterol synthesis they have been found to have multiple actions unrelated to cholesterol lowering "the pleiotropic effects," which includes inhibition of inflammation. We aimed at investigating the effect of pitavastatin a 3rd generation statin, in suppressing acute inflammation in rat paw edema model. Male Sprague-Dawley rats were randomly assigned to one of five groups (n=8): Control, indomethacin and pitavastatin (0.2mg/kg, 0.4mg/kg, 0.8mg/kg) treated. 1hour following treatment, inflammation was induced by sub-planter injection of egg albumin into the hind paw. Anti-inflammatory effect was evaluated by measurement of edema formation every half hour for three hours, assessment of polymorphonuclear leukocyte (PMNL) infiltration and measurement of tissue damage in skin biopsies. Ascending doses of pitavastatin were found to attenuate these parameters. The lowest dose of pitavastatin (0.2mg/kg) was found to significantly reduce edema volume, PMNL infiltration and tissue damage. The efficacy of the smallest dose was found comparable to indomethacin. PMID- 26045382 TI - Anti-nociceptive activity of seed extract of Vernonia anthelmintica willd. AB - Vernonia anthelmintica is commonly known as kali ziri. Its seeds are used for several therapeutical purposes. Its seeds contain many constituents of medicinal importance as vernodlin, vernodalol, and vernolic acid. It is commonly used psoriasis and leucoderma or white leprosy. It is potent wormicidal agent. The present study was conducted on seed's extract of V. anthelmintica to determine its analgesic potency. The activity was conducted on mice by using acetic acid induced writhes,hot plate method and by tail flick method using water bath. The results of the writhing test were highly significant and comparable with Aspirin, which produced 26 and 20 writhes. The percentage of inhibition of writhes with the two doses of crude extract was 65.45% and 64.28% at 300mg/kg, while 83.63% and 71.42% at 500mg/kg, where as with Aspirin it was 52.72% and 28.57% in first and second phase respectively. Hot plate and tail flick method also indicated that vernonia has potent analgesic activity. The drug can be utilized as anti nociceptive agent. PMID- 26045383 TI - Analgesic, Anti-inflammatory and neuropharmacological effects of Atropa belladonna. AB - The present study was carried out to investigate, in vivo, analgesic, anti inflammatory and neuro-pharmacological activities of the methanolic extract of Atropa belladonna. The analgesic activity was measured by acetic acid induced writhing inhibition test. The neuro-pharmacological activities were evaluated by open field, rearing test, cage cross, swim test, head dip and traction tests. The anti-inflammatory activity was assessed by formalin induce inflammation on hind paw. The extract showed highly significant (p<0.001) analgesic activity with % inhibitions of writhing response at doses 100 and 300mg/kg body weight were 28.5% and 57.1%, respectively. The extract at both doses showed significant (p<0.05) sedative effect in-cage cross test and highly significance value (p<0.001) in high dose. In-open field test, the extract showed significant (P<0.05) anxiolytic activity at higher dose whereas in rearing test activity shows significant p value at both doses. The extract also showed significant value for anti inflammatory activity. The findings of the study clearly indicated the presence of significant analgesic, neuro-pharmacological and anti-inflammatory properties of the plant, which demands further investigation including, compounds isolation. PMID- 26045384 TI - Hepatoprotective and toxicological studies of Salvia bucharica methanolic extract in rabbits. AB - Most of the species of genus Salvia are famous for having medicinal properties due to their chemical constituents. Salvia bucharica (Lamiacea) is found in Balochistan near Quetta in Hannaurak and Kalat. It is used in traditional system of medicine and claims to cure liver ailments. In current study crude methanolic extract (CME) of Salvia bucharica was obtained from the leaves and tested for hepatoprotective activity and possible toxicity in rabbits. Liver toxicity was induced in rabbits by administration of carbon tetra chloride (CCl4) and evaluated by biochemical tests and histopathology of tissues. In this study rabbits were divided in to 3 groups (5 rabbit in each group). Rabbits of group I (control) were administered only vehicle (0.9% sodium chloride) orally. Rabbits of group II were given CCl4 and group III were treated with CCl4 and S. bucharica CME orally. For hepatoprotective effect serum enzyme level and total protein level were calculated. Histopathology of liver sections of rabbits was also carried out to observe protective effect. Biochemical, hematological and histoptahological parameters were studied on rabbits for toxicological studies. S. bucharica CME showed significant liver protection with reduction in total bilirubin, direct bilirubin, Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), gamma glutamyl transpeptidase (gamma-GT). And decrease in Albumin and globulin. In toxicological studies, biochemical and histoptahological parameters showed no significant toxicity in liver, heart and kidneys. It is concluded that S. bucharica CME showed hepatoprotective effects with nontoxic profile. PMID- 26045385 TI - Compatibility and stability of polygeline (Haemaccel) with different drug products. AB - Compatibility and stability of the polygeline-based blood plasma expander/plasma substitute Haemaccel with different drug products i.e., Profenid, Stemetil, and Lasix were examined in the context of its potential use in surgical, spinal, septic shock and in circulatory insufficiency, because treatment, safety, acceptability and efficacy of drug product may be affected by drug instability or incompatibility. Therefore, drug stability and compatibility are critical elements in accurate and appropriate delivery of drug therapy to patients. This study was initiated to specifically and critically assess the compatibility of Haemaccel with different drug products with the aim of delivering safe, suitable, acceptable and efficacious administration of two different drug products simultaneously in emergency conditions. All of these different brands of drug products were physically and chemically compatible with Haemaccel and all of the test results were almost similar before and after mixing different drugs in Haemaccel. This study revealed that Lasix, Profenid and Stemetil can be administered/co-administered with Haemaccel safely. Different drug product must be studies in detail before it's co-administration with Haemaccel. PMID- 26045386 TI - Biochemical analysis of the crude extract of Momordica charantia (L.). AB - Momordica charantia (L.) commonly referred as bitter gourd, karela and balsam pear. Its fruit is used for the treatment of diabetes and related conditions amongst the indigenous populations of Asia, South America, India and East Africa. The study was conducted to find out the biochemical aspects of crude extract of whole fruit of M. charantia including seeds which includes blood test (Hemoglobin, RBC, Total leukocyte count, platelets count, HbA1C (Glycocylated heamoglobin Type A1C)), Lipid profile test and electrolyte balance. Hemoglobin (7.1+/-0.14), platelets count (827 *109+/-1.95), Cholesterol level (111+/-2), HDL (high density lipoproteins) (20+/-1.22) at 10mg shows marked increase in values as compared to control. While 25 mg dose shows insignificant result. Electrolyte balance are found significant at 10mg and 25mg except bicarbonates (Na(+!)=143+/ 1.87, K-=3.45+/-0.35, Cl(-) =108+/-1.48). Another important property of M. charantia is the elevation of platelet counts, heamoglobin and specifically high density lipoproteins (HDL). It also controls cholesterol, triglycerides, HDL, LDL and VLDL at low dosage (10mg). Further studies can be conducted to find out which phytochemical components acts on specific biochemical activity. PMID- 26045387 TI - Assessment of anti-inflammatory, anti-ulcer and neuro-pharmacological activities of Cyperus rotundus Linn. AB - This article reports the assessment of anti-inflammatory, antiulcer and neuropharmacological activities of crude extract of Cyperus rotundus. The plant exhibited significant property to act as an anti inflammatory agent. In experimental design, inflammation was produced by carrageenan in rats and compare with saline treated and Aspirin treated group. Simultaneously the drug was also observed for its antiulcer response and found effective enough (these two activities were observed at the dosage of 300mg/kg and 500mg/kg). The anti ulcer activity was observed 41.2% as a dosage of 500mg/kg. Neuropharmacological activities (open field, head dip, rearing traction and forced swimming test) were also observed at 300 and 500mg/kg of C. rotundus extract. The crude extract showed mild decreased in all test and exhibited slight muscle relaxant effect. Powder drug studies and FTIR analysis were performed for the authentication of C. rotundus. PMID- 26045388 TI - Histopathologic changes in liver and kidney of male sprague dawley rats treated with extract of Cardiospermum halicacabum L. AB - In traditional medicine Cardiospermum halicacabum L. (Sapindeaceae) is used against various ailments such as rheumatism, nervous diseases, stiffness of the limbs and snakebite. Leaves are crushed and made into a tea, which aids itchy skin. Salted leaves are used as a poultice on swellings. Young leaves can be cooked and used as vegetables. The leaf juice has been used as a treatment for earache as well. In this study we evaluate acute toxicity (10, 50, 100 and 500 mg/kg) and pathologic changes in esophagus, stomach, liver and kidney tissues with a magnifying glass and microscope in a row to mark changes to both morphological and histological in comparison to control with the treatment of ethyl acetate extract (dose of 40mg/kg) in male Sprague Dawley rats. The rats were divided into 4 groups consisting of 3 rats per group for acute toxicity and histopathological change. In conclusion, no lethality was observed in acute toxicity study for 7 days. The treatment of ethyl acetate extracts at 40 mg/kg did not show lethal toxicological changes as observed by histopathological examination in the kidney and liver tissues. PMID- 26045389 TI - Fabrication of Chemical Graphene Nanoribbons via Edge-Selective Covalent Modification. AB - Chemical graphene nanoribbons (CGNRs), a new type of quantum-confinement graphene nanostructure with tunable electrical conduction channels and bandgaps, are fabricated by chemically narrowing the conduction channels of the graphene based on an edge-selective covalent reaction. Such CGNRs behave as semiconductors with tunable on/off ratios ranging from a few hundreds to ~10(4) . PMID- 26045390 TI - Virtual-system-coupled adaptive umbrella sampling to compute free-energy landscape for flexible molecular docking. AB - A novel enhanced conformational sampling method, virtual-system-coupled adaptive umbrella sampling (V-AUS), was proposed to compute 300-K free-energy landscape for flexible molecular docking, where a virtual degrees of freedom was introduced to control the sampling. This degree of freedom interacts with the biomolecular system. V-AUS was applied to complex formation of two disordered amyloid-beta (Abeta30-35 ) peptides in a periodic box filled by an explicit solvent. An interpeptide distance was defined as the reaction coordinate, along which sampling was enhanced. A uniform conformational distribution was obtained covering a wide interpeptide distance ranging from the bound to unbound states. The 300-K free-energy landscape was characterized by thermodynamically stable basins of antiparallel and parallel beta-sheet complexes and some other complex forms. Helices were frequently observed, when the two peptides contacted loosely or fluctuated freely without interpeptide contacts. We observed that V-AUS converged to uniform distribution more effectively than conventional AUS sampling did. PMID- 26045391 TI - Identification of differentially expressed signatures of long non-coding RNAs associated with different metastatic potentials in gastric cancer. AB - BACKGROUND: Gastric cancer (GC) is known for its lymph node metastasis and outstanding morbidity and mortality. Thus, improvement in the current knowledge regarding the molecular mechanism of GC is urgently needed to discover novel biomarkers involved in its progression and prognosis. Several long, non-coding RNAs (lncRNAs) play important roles in gastric tumorigenesis and metastasis. However, the signature of lncRNA-associated metastasis in GC is not fully clarified. METHODS: We determined the lncRNA and mRNA expression profiles correlating to GC with or without lymph node-metastasis based on microarray analysis. Twelve differentially expressed lncRNAs and six differentially expressed mRNAs were validated by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. RESULTS: The relationships between the aberrantly expressed lncRNAs XLOC_010235 or RP11-789C1.1 and lymph node metastasis, pathologic metastasis status, distal metastasis and TNM (tumour, node, and metastasis) stage were found to be significantly different. Via survival analysis, patients who had high-expressed XLOC_010235 or low-expressed RP11-789C1.1 showed significantly worse survival than patients with inverse expressed XLOC_010235 or RP11-789C1.1. CONCLUSION: In summary, this current study highlights some evidence regarding the potential role of lncRNAs in GC and posits that specific lncRNAs can be identified as novel, poor prognostic biomarkers in GC. PMID- 26045392 TI - Preoperative Prognostic Nutritional Index is a Significant Predictor of Survival in Renal Cell Carcinoma Patients Undergoing Nephrectomy. AB - BACKGROUND: Preoperative assessment of patients' immunologic and nutritional conditions is required to predict the outcome of patients with malignant tumors. The aim of the current study was to clarify the significance of the prognostic nutritional index (PNI), which simply accounts for immunological and nutritional conditions, in patients with renal cell carcinoma (RCC). METHODS: We included 1437 patients who underwent nephrectomy for RCC between 1994 and 2008. PNI was calculated using the following formula: 10 * serum albumin concentration (g/dL) + 0.005 * lymphocyte counts (number/mm(2)) in peripheral blood. We examined the correlation of the preoperative PNI value with clinicopathological features. A Cox regression model and the Harrell concordance index with variables only or combined PNI data were used to evaluate the prognostic significance in the T1 4NallMall and T1-4N0M0 groups. RESULTS: The mean preoperative PNI value was 52.7 +/- 6.3 (range 27.7-85.3). The mean PNI values were significantly lower in patients with more advanced tumor T stage, regional lymph node metastasis, distant metastases, higher Fuhrman grade, and sarcomatoid differentiation than in patients without such factors (p < 0.001). Patients with low PNI (<51) had poor survival rates compared to those with high PNI in univariate analysis (>51, p < 0.001). Multivariate analysis showed that low PNI was significantly associated with cancer-specific survival (p = 0.026 and p = 0.009) and overall survival (p = 0.013 and p = 0.011) in the T1-4NallMall and T1-4N0M0 groups, respectively, after correcting for other clinicopathological factors. CONCLUSIONS: PNI is an independent prognostic factor for predicting survival after nephrectomy in patients with RCC. PMID- 26045393 TI - Time trends in the incidence and treatment of extra-abdominal and abdominal aggressive fibromatosis: a population-based study. AB - BACKGROUND: Aggressive fibromatosis (AF) is a locally infiltrating soft-tissue tumor. In a population-based study in the Netherlands, we evaluated time trends for the incidence and treatment of AF. METHODS: In PALGA: Dutch Pathology Registry, all patients diagnosed between 1993 and 2013 as having extra-abdominal or abdominal wall aggressive fibromatosis were identified and available pathology data of the patients were evaluated. Epidemiological and treatment-related factors were analyzed with chi (2)and regression analysis. RESULTS: During the study period, 1134 patients were identified. The incidence increased from 2.10 to 5.36 per million people per year. Median age at the time of diagnosis increased annually by B 0.285 (P = 0.001). Female gender prevailed and increased over time [annual odds ratio (OR) 1.022; P = 0.058]. All anatomic localizations, but in particular truncal tumors, became more frequent. During the study period diagnostic histological biopsies were performed more often (annual OR 1.096; P < 0.001). The proportion of patients who underwent surgical treatment decreased (annual OR 0.928; P < 0.001). When resection was preceded by biopsy, 49.8 % of the patients had R0-resection versus 30.7 % in patients without biopsy (P < 0.001). CONCLUSIONS: In this population-based study, an increasing incidence of extra-abdominal and abdominal-wall aggressive fibromatosis was observed. The workup of patients improved and a trend towards a nonsurgical treatment policy was observed. PMID- 26045394 TI - Attitudes of Agricultural Experts Toward Genetically Modified Crops: A Case Study in Southwest Iran. AB - The production of genetically modified (GM) crops is growing around the world, and with it possible opportunities to combat food insecurity and hunger, as well as solutions to current problems facing conventional agriculture. In this regard the use of GMOs in food and agricultural applications has increased greatly over the past decade. However, the development of GM crops has been a matter of considerable interest and worldwide public controversy. This, in addition to skepticism, has stifled the use of this practice on a large scale in many areas, including Iran. It stands to reason that a greater understanding of this practice could be formed after a review of the existing expert opinions surrounding GM crops. Therefore, the purpose of this study was to analyze the predictors that influence agricultural experts' attitudes toward the development of and policies related to GM crops. Using a descriptive correlational research method, questionnaire data was collected from 65 experts from the Agricultural Organization in the Gotvand district in Southwest Iran. Results indicated that agricultural experts were aware of the environmental benefits and possible risks associated with GM crops. The majority of participants agreed that GM crops could improve food security and accelerate rural development, and were proponents of labeling practices for GM crops. Finally, there was a positive correlation between the perception of benefits and attitudes towards GM crops. PMID- 26045395 TI - A review of the risk factors for lower extremity overuse injuries in young elite female ballet dancers. AB - The objective of this study was to review the evidence for selected risk factors of lower extremity overuse injuries in young elite female ballet dancers. An electronic search of key databases from 1969 to July 2013 was conducted using the keywords dancers, ballet dancers, athletes, adolescent, adolescence, young, injury, injuries, risk, overuse, lower limb, lower extremity, lower extremities, growth, maturation, menarche, alignment, and biomechanics. Thirteen published studies were retained for review. Results indicated that there is a high incidence of lower extremity overuse injuries in the target population. Primary risk factors identified included maturation, growth, and poor lower extremity alignment. Strong evidence from well-designed studies indicates that young elite female ballet dancers suffer from delayed onset of growth, maturation, menarche, and menstrual irregularities. However, there is little evidence that this deficit increases the risk of overuse injury, with the exception of stress fractures. Similarly, there is minimal evidence linking poor lower extremity alignment to increased risk of overuse injury. It is concluded that further prospective, longitudinal studies are required to clarify the relationship between growth, maturation, menarche, and lower extremity alignment, and the risk of lower extremity overuse injury in young elite female ballet dancers. PMID- 26045396 TI - Assessment of Compensated Turnout Characteristics and their Relationship to Injuries in University Level Modern Dancers. AB - Dancers may compensate alignment at the spine, hip, knees, ankles, and feet to achieve a greater turnout than is available at the hip alone. Such compensations are believed to lead to many of the musculoskeletal injuries experienced by dancers, especially overuse injuries. The aim of this study was to explore the relationship between compensated turnout and injury of the lower extremities and low back. Twenty-two university level modern dancers age 19 to 23 participated. Measurements were taken of active hip external rotation (AHER) prone and functional turnout (FTO) in first position. The difference between FTO and AHER was designated as compensated turnout (CTO). A questionnaire was conducted to gather information about dancers' injuries within the past 2 years. A total of 17 participants (77%) reported experiencing at least one injury in the 24 month period. All dancers compensated turnout. Results revealed a large variability in CTO among participants, ranging from 3 degrees to 72 degrees . Statistical analysis showed a significant relationship (r = 0.45, N = 22, p = 0.04) between CTO and the number of injuries experienced, especially as related to low back pain (r = 0.50, N = 22, p = 0.02). Students with no injury had a CTO mean of 26 degrees , while those with two or more injuries had a CTO mean of 43 degrees . Results contribute to previous studies that have examined the effects of CTO in ballet dancers and further indicate that compensatory patterns of turnout may increase the risk of experiencing more than one injury in university level modern dancers. PMID- 26045397 TI - Motor imagery modality in expert dancers: an investigation of hip and pelvis kinematics in demi-plie and saute. AB - Elite dancers often engage in mental practice during training, but little is known about the effects of discrete, repetitive motor imagery on dance movement performance. This study compared the effects of two motor imagery modalities, third-person visual imagery and kinesthetic imagery, on hip and pelvis kinematics during two technical dance movements, plie and saute. Twenty-four female dancers (mean age: 26.04; mean years of training: 19.63) were randomly assigned to a type of imagery practice: visual imagery (VI), kinesthetic imagery (KI), or a mental arithmetic task control condition (MAT). No statistically significant effects of imagery group or task type were found for external hip rotation, sagittal pelvic excursion, or a ratio relating hip to pelvic movement, suggesting that imagery practice did not affect either temporal or kinematic characteristics of the plie or saute. PMID- 26045398 TI - Kinematic evaluation of the classical ballet step "plie". AB - Lack of alignment between the lowerlimb structures, such as the hips, knees, and longitudinal arches of the feet, has been described as an important predisposing factor in musculoskeletal injury among classical ballet dancers. However, no studies were found that analyzed basic ballet movements with quantification of objective criteria of the movements. The purposes of this study were: 1. to establish a methodology to quantify, using kinematic evaluation, the technical criteria that guide the correct execution of all phases of the plie (simultaneous flexion of the hips, knees, and ankle joints); and 2. to explore whether experienced ballet dancers respect those criteria when performing the plie. The technical criteria considered were the following: 1. midfoot stability; 2. pelvic positioning in a neutral alignment; 3. pelvic stability, represented by pelvic angle variation; and 4. vertical alignment of the knee joint with the second toe of the ipsilateral foot. Twenty dancers from Porto Alegre, Brazil, with 18 years of uninterrupted ballet training, were filmed while performing plie using four synchronized cameras. The descriptive statistical analysis involved calculating the median, minimum, and maximum of each of the technical criteria. Results showed that for criterion 1, the 20 dancers showed great stabilization of the midfoot; for criteria 2 and 3, 18 dancers displayed pelvic instability tending toward retroversion throughout execution of the plie; and for criterion 4, 13 dancers presented with medial misalignment of the knees at all phases of the plie. Using these criteria, it was possible to characterize the plie from a kinematic point of view. PMID- 26045399 TI - Superficial peroneal nerve paresis in a dancer caused by a midfoot ganglion: case report. AB - Ganglion cysts are common benign masses, usually occurring in the hands and feet. This report describes the case of a young female Irish dancer who presented with paresthesia of her foot due to a ganglion in near proximity to the superficial peroneal nerve. Midfoot ganglia in young girls engaged in Irish dance can limit their ability to participate. This pathology requires further epidemiological studies to investigate its prevalence. In the event of failed conservative management, surgical intervention to excise the cyst and decompress the nerve is an effective treatment to facilitate return to dancing. PMID- 26045400 TI - Stress fracture of the second metatarsal and sprain of lisfranc joint in a pre professional ballet dancer. AB - We present the case of a 14-year-old pre-professional ballerina that demonstrates common features of two conditions affecting the midfoot that are often missed or subject to delay in diagnosis in such young athletes: 1. stress fractures at the base of the second metatarsal, and 2. sprain of the Lisfranc joint complex. While these represent potentially career-altering injuries in the professional dancer, this case demonstrates that a high index of clinical suspicion, careful physical exam, appropriate radiographic assessment, and prompt treatment are essential to achieving the best possible outcome. PMID- 26045401 TI - Deep-subwavelength imaging of both electric and magnetic localized optical fields by plasmonic campanile nanoantenna. AB - Tailoring the electromagnetic field at the nanoscale has led to artificial materials exhibiting fascinating optical properties unavailable in naturally occurring substances. Besides having fundamental implications for classical and quantum optics, nanoscale metamaterials provide a platform for developing disruptive novel technologies, in which a combination of both the electric and magnetic radiation field components at optical frequencies is relevant to engineer the light-matter interaction. Thus, an experimental investigation of the spatial distribution of the photonic states at the nanoscale for both field components is of crucial importance. Here we experimentally demonstrate a concomitant deep-subwavelength near-field imaging of the electric and magnetic intensities of the optical modes localized in a photonic crystal nanocavity. We take advantage of the "campanile tip", a plasmonic near-field probe that efficiently combines broadband field enhancement with strong far-field to near field coupling. By exploiting the electric and magnetic polarizability components of the campanile tip along with the perturbation imaging method, we are able to map in a single measurement both the electric and magnetic localized near-field distributions. PMID- 26045402 TI - The impact of days off between cases on perioperative outcomes for robotic assisted laparoscopic prostatectomy. AB - PURPOSE: To examine the effect of days off between cases on perioperative outcomes for robotic-assisted laparoscopic prostatectomy (RALP). METHODS: We analyzed a single-surgeon series of 2036 RALP cases between 2003 and 2014. Days between cases (DBC) was calculated as the number of days elapsed since the surgeon's previous RALP with the second start cases assigned 0 DBC. Surgeon experience was assessed by dividing sequential case experience into cases 0-99, cases 100-249, cases 250-999, and cases 1000+ based on previously reported learning curve data for RALP. Outcomes included estimated blood loss (EBL), operative time (OT), and positive surgical margins (PSMs). Multiple linear regression was used to assess the impact of the DBC and surgeon experience on EBL, OT, and PSM, while controlling for patient characteristics, surgical technique, and pathologic variables. RESULTS: Overall median DBC was 1 day (0-3) and declined with increasing surgeon case experience. Multiple linear regression demonstrated that each additional DBC was independently associated with increased EBL [beta = 3.7, 95% CI (1.3-6.2), p < 0.01] and OT [beta = 2.3 (1.4-3.2), p < 0.01], but was not associated with rate of PSM [beta = 0.004 (-0.003-0.010), p = 0.2]. Increased experience was also associated with reductions in EBL and OT (p < 0.01). Surgeon experience of 1000+ cases was associated with a 10% reduction in PSM rate (p = 0.03) compared to cases 0-99. CONCLUSIONS: In a large single surgeon RALP series, DBC was associated with increased blood loss and operative time, but not associated with positive surgical margins, when controlling for surgeon experience. PMID- 26045403 TI - Development of a radical foster care intervention in Glasgow, Scotland. AB - Services for maltreated children are inadequate and lack infant mental health input in many parts of the world. A recent audit of Glasgow services revealed that children frequently 'revolve' between maltreating birth parents and various temporary foster placements for many years. Addressing infant mental health in this population will require radical change to current services. The New Orleans programme developed by the Tulane Infant Team in Louisiana is one such radical programme. Prior to the design of a randomized controlled trial (RCT) to test this programme in Glasgow, it was essential that policy-makers had some insight into the local model of service delivery and how a New Orleans model could impact. This article explores the structure and costs of the current Glasgow system and the potential costs and consequence impact of implementing a New Orleans model in Glasgow, using data obtained from the research literature, Glasgow City Council audit data and expert's opinion. A New Orleans-Glasgow model would likely shift resources from social services on to the NHS. The resource intensive nature of this model could increase the cost of an episode in care from L66 300 in the current system to L86 070; however, the probability of repeated episodes in care is likely to fall substantially, making the cost per child fall from L95 500 in the current system to L88 600. This study informed the design of a phase II explorative RCT, identified appropriate outcomes for measurement and areas of uncertainty for further research. PMID- 26045404 TI - Sodium-Doped Mesoporous Ni2P2O7 Hexagonal Tablets for High-Performance Flexible All-Solid-State Hybrid Supercapacitors. AB - A simple hydrothermal method has been developed to prepare hexagonal tablet precursors, which are then transformed into porous sodium-doped Ni2P2O7 hexagonal tablets by a simple calcination method. The obtained samples were evaluated as electrode materials for supercapacitors. Electrochemical measurements show that the electrode based on the porous sodium-doped Ni2P2O7 hexagonal tablets exhibits a specific capacitance of 557.7 F g(-1) at a current density of 1.2 A g(-1) . Furthermore, the porous sodium-doped Ni2P2O7 hexagonal tablets were successfully used to construct flexible solid-state hybrid supercapacitors. The device is highly flexible and achieves a maximum energy density of 23.4 Wh kg(-1) and a good cycling stability after 5000 cycles, which confirms that the porous sodium doped Ni2P2 O7 hexagonal tablets are promising active materials for flexible supercapacitors. PMID- 26045405 TI - Pure laparoscopic management of early biliary leakage after liver transplantation: Abdominal lavage and T-Tube placement. PMID- 26045406 TI - Computed tomography versus magnetic resonance imaging versus bone scintigraphy for clinically suspected scaphoid fractures in patients with negative plain radiographs. AB - BACKGROUND: In clinically suspected scaphoid fractures, early diagnosis reduces the risk of non-union and minimises loss in productivity resulting from unnecessary cast immobilisation. Since initial radiographs do not exclude the possibility of a fracture, additional imaging is needed. Computed tomography (CT), magnetic resonance imaging (MRI) and bone scintigraphy (BS) are widely used to establish a definitive diagnosis, but there is uncertainty about the most appropriate method. OBJECTIVES: The primary aim of this study is to identify the most suitable diagnostic imaging strategy for identifying clinically suspected fractures of the scaphoid bone in patients with normal radiographs. Therefore we looked at the diagnostic performance characteristics of the most used imaging modalities for this purpose: computed tomography, magnetic resonance imaging and bone scintigraphy. SEARCH METHODS: In July 2012, we searched the Cochrane Register of Diagnostic Test Accuracy Studies, MEDLINE, EMBASE, the Database of Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials, the NHS Economic Evaluation Database. In September 2012, we searched MEDION, ARIF, Current Controlled Trials, the World Health Organization (WHO) International Clinical Trials Registry Platform, conference proceedings and reference lists of all articles. SELECTION CRITERIA: We included all prospective or retrospective studies involving a consecutive series of patients of all ages that evaluated the accuracy of BS, CT or MRI, or any combination of these, for diagnosing suspected scaphoid fractures. We considered the use of one or two index tests or six-week follow-up radiographs as adequate reference standards. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts and assessed full-text reports of potentially eligible studies. The same authors extracted data from full-text reports and assessed methodological quality using the QUADAS checklist. For each index test, estimates of sensitivity and specificity from each study were plotted in ROC space; and forest plots were constructed for visual examination of variation in test accuracy. We performed meta-analyses using the HSROC model to produce summary estimates of sensitivity and specificity. MAIN RESULTS: We included 11 studies that looked at diagnostic accuracy of one or two index tests: four studies (277 suspected fractures) looked at CT, five studies (221 suspected fractures) looked at MRI and six studies (543 suspected fractures) looked at BS. Four of the studies made direct comparisons: two studies compared CT and MRI, one study compared CT and BS, and one study compared MRI and BS. Overall, the studies were of moderate to good quality, but relevant clinical information during evaluation of CT, MRI or BS was mostly unclear or unavailable.As few studies made direct comparisons between tests with the same participants, our results are based on data from indirect comparisons, which means that these results are more susceptible to bias due to confounding. Nonetheless, the direct comparisons showed similar patterns of differences in sensitivity and specificity as for the pooled indirect comparisons.Summary sensitivity and specificity of CT were 0.72 (95% confidence interval (CI) 0.36 to 0.92) and 0.99 (95% CI 0.71 to 1.00); for MRI, these were 0.88 (95% CI 0.64 to 0.97) and 1.00 (95% CI 0.38 to 1.00); for BS, these were 0.99 (95% CI 0.69 to 1.00) and 0.86 (95% CI 0.73 to 0.94). Indirect comparisons suggest that diagnostic accuracy of BS was significantly higher than CT and MRI; and CT and MRI have comparable diagnostic accuracy. The low prevalence of a true fracture among suspected fractures (median = 20%) means the lower specificity for BS is problematic. For example, in a cohort of 1000 patients, 112 will be over-treated when BS is used for diagnosis. If CT is used, only 8 will receive unnecessary treatment. In terms of missed fractures, BS will miss 2 fractures and CT will miss 56 fractures. AUTHORS' CONCLUSIONS: Although quality of the included studies is moderate to good, findings are based on only 11 studies and the confidence intervals for the summary estimates are wide for all three tests. Well-designed direct comparison studies including CT, MRI and BS could give valuable additional information.Bone scintigraphy is statistically the best diagnostic modality to establish a definitive diagnosis in clinically suspected fractures when radiographs appear normal. However, physicians must keep in mind that BS is more invasive than the other modalities, with safety issues due to level of radiation exposure, as well as diagnostic delay of at least 72 hours. The number of overtreated patients is substantially lower with CT and MRI.Prior to performing comparative studies, there is a need to raise the initially detected prevalence of true fractures in order to reduce the effect of the relatively low specificity in daily practice. This can be achieved by improving clinical evaluation and initial radiographical assessment. PMID- 26045409 TI - Climate science. Lost and found: Earth's missing heat. PMID- 26045407 TI - Protecting isolated tribes. PMID- 26045410 TI - Science policy. Russian foundation tarred with 'foreign' label. PMID- 26045411 TI - Genetics. Did good genes help people outlast brutal Leningrad siege? PMID- 26045412 TI - Astronomy. Hawaii's governor proposes telescope swap. PMID- 26045413 TI - Geophysics. Polar scientists to peer beneath largest ice shelf. PMID- 26045414 TI - Making contact. PMID- 26045415 TI - The poisoned necklace. PMID- 26045416 TI - Mercy on these people, and give us a road. PMID- 26045417 TI - In peril. PMID- 26045418 TI - How to court an isolated tribe. PMID- 26045419 TI - Oceans. Invisible barriers to dispersal. PMID- 26045420 TI - Friction. Slippery when dry. PMID- 26045421 TI - Physics. Controlling friction atom by atom. PMID- 26045422 TI - Cell biology. Centrioles, in absentia. PMID- 26045423 TI - Medicine. Progeria accelerates adult stem cell aging. PMID- 26045424 TI - Epigenetics. Exceptional epigenetics in the brain. PMID- 26045425 TI - Atmosphere. Challenges of a lowered U.S. ozone standard. PMID- 26045426 TI - Editor's note. PMID- 26045427 TI - Antibiotics crisis in China. PMID- 26045428 TI - Human evolution. Comment on "Human-like hand use in Australopithecus africanus". AB - Skinner and colleagues (Research Article, 23 January 2015, p. 395), based on metacarpal trabecular bone structure, argue that Australopithecus africanus employed human-like dexterity for stone tool making and use 3 million years ago. However, their evolutionary and biological assumptions are misinformed, failing to refute the previously existing hypothesis that human-like manipulation preceded systematized stone tool manufacture, as indicated by the fossil record. PMID- 26045429 TI - Human evolution. Response to Comment on "Human-like hand use in Australopithecus africanus". AB - Almecija and colleagues claim that we apply a simplified understanding of bone functional adaptation and that our results of human-like hand use in Australopithecus africanus are not novel. We argue that our results speak to actual behavior, rather than potential behaviors, and our functional interpretation is well supported by our methodological approach, comparative sample, and previous experimental data. PMID- 26045431 TI - Multiferroics. Magnetoelectric domain control in multiferroic TbMnO3. AB - The manipulation of domains by external fields in ferroic materials is of major interest for applications. In multiferroics with strongly coupled magnetic and electric order, however, the magnetoelectric coupling on the level of the domains is largely unexplored. We investigated the field-induced domain dynamics of TbMnO3 in the multiferroic ground state and across a first-order spin-flop transition. In spite of the discontinuous nature of this transition, the reorientation of the order parameters is deterministic and preserves the multiferroic domain pattern. Landau-Lifshitz-Gilbert simulations reveal that this behavior is intrinsic. Such magnetoelectric correlations in spin-driven ferroelectrics may lead to domain wall-based nanoelectronics devices. PMID- 26045430 TI - Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins. AB - The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification. PMID- 26045432 TI - Friction. Tuning friction atom-by-atom in an ion-crystal simulator. AB - Friction between ordered, atomically smooth surfaces at the nanoscale (nanofriction) is often governed by stick-slip processes. To test long-standing atomistic models of such processes, we implemented a synthetic nanofriction interface between a laser-cooled Coulomb crystal of individually addressable ions as the moving object and a periodic light-field potential as the substrate. We show that stick-slip friction can be tuned from maximal to nearly frictionless via arrangement of the ions relative to the substrate. By varying the ion number, we also show that this strong dependence of friction on the structural mismatch, as predicted by many-particle models, already emerges at the level of two or three atoms. This model system enables a microscopic and systematic investigation of friction, potentially even into the quantum many-body regime. PMID- 26045433 TI - Organic thin films. Rational synthesis of organic thin films with exceptional long-range structural integrity. AB - Highly oriented, domain-boundary-free organic thin films could find use in various high-performance organic materials and devices. However, even with state of-the-art supramolecular chemistry, it is difficult to construct organic thin films with structural integrity in a size regime beyond the micrometer length scale. We show that a space-filling design, relying on the two-dimensional (2D) nested hexagonal packing of a particular type of triptycene, enables the formation of large-area molecular films with long-range 2D structural integrity up to the centimeter length scale by vacuum evaporation, spin-coating, and cooling from the isotropic liquid of the triptycene. X-ray diffraction analysis and microscopic observations reveal that triptycene molecules form a completely oriented 2D (hexagonal triptycene array) + 1D (layer stacking) structure, which is key for the long-range propagation of structural order. PMID- 26045434 TI - Nitrogen cycling. Rapid nitrous oxide cycling in the suboxic ocean. AB - Nitrous oxide (N2O) is a powerful greenhouse gas and a major cause of stratospheric ozone depletion, yet its sources and sinks remain poorly quantified in the oceans. We used isotope tracers to directly measure N2O reduction rates in the eastern tropical North Pacific. Because of incomplete denitrification, N2O cycling rates are an order of magnitude higher than predicted by current models in suboxic regions, and the spatial distribution suggests strong dependence on both organic carbon and dissolved oxygen concentrations. Furthermore, N2O turnover is 20 times higher than the net atmospheric efflux. The rapid rate of this cycling coupled to an expected expansion of suboxic ocean waters implies future increases in N2O emissions. PMID- 26045435 TI - Ecophysiology. Climate change tightens a metabolic constraint on marine habitats. AB - Warming of the oceans and consequent loss of dissolved oxygen (O2) will alter marine ecosystems, but a mechanistic framework to predict the impact of multiple stressors on viable habitat is lacking. Here, we integrate physiological, climatic, and biogeographic data to calibrate and then map a key metabolic index the ratio of O2 supply to resting metabolic O2 demand-across geographic ranges of several marine ectotherms. These species differ in thermal and hypoxic tolerances, but their contemporary distributions are all bounded at the equatorward edge by a minimum metabolic index of ~2 to 5, indicative of a critical energetic requirement for organismal activity. The combined effects of warming and O2 loss this century are projected to reduce the upper ocean's metabolic index by ~20% globally and by ~50% in northern high-latitude regions, forcing poleward and vertical contraction of metabolically viable habitats and species ranges. PMID- 26045436 TI - Coral reefs. Limited scope for latitudinal extension of reef corals. AB - An analysis of present-day global depth distributions of reef-building corals and underlying environmental drivers contradicts a commonly held belief that ocean warming will promote tropical coral expansion into temperate latitudes. Using a global data set of a major group of reef corals, we found that corals were confined to shallower depths at higher latitudes (up to 0.6 meters of predicted shallowing per additional degree of latitude). Latitudinal attenuation of the most important driver of this phenomenon-the dose of photosynthetically available radiation over winter-would severely constrain latitudinal coral range extension in response to ocean warming. Latitudinal gradients in species richness for the group also suggest that higher winter irradiance at depth in low latitudes allowed a deep-water fauna that was not viable at higher latitudes. PMID- 26045437 TI - Human oocytes. Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes. AB - Aneuploidy in human eggs is the leading cause of pregnancy loss and several genetic disorders such as Down syndrome. Most aneuploidy results from chromosome segregation errors during the meiotic divisions of an oocyte, the egg's progenitor cell. The basis for particularly error-prone chromosome segregation in human oocytes is not known. We analyzed meiosis in more than 100 live human oocytes and identified an error-prone chromosome-mediated spindle assembly mechanism as a major contributor to chromosome segregation defects. Human oocytes assembled a meiotic spindle independently of either centrosomes or other microtubule organizing centers. Instead, spindle assembly was mediated by chromosomes and the small guanosine triphosphatase Ran in a process requiring ~16 hours. This unusually long spindle assembly period was marked by intrinsic spindle instability and abnormal kinetochore-microtubule attachments, which favor chromosome segregation errors and provide a possible explanation for high rates of aneuploidy in human eggs. PMID- 26045438 TI - From physics to revolution and back. PMID- 26045439 TI - Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. AB - The human virome plays important roles in health and immunity. However, current methods for detecting viral infections and antiviral responses have limited throughput and coverage. Here, we present VirScan, a high-throughput method to comprehensively analyze antiviral antibodies using immunoprecipitation and massively parallel DNA sequencing of a bacteriophage library displaying proteome wide peptides from all human viruses. We assayed over 10(8) antibody-peptide interactions in 569 humans across four continents, nearly doubling the number of previously established viral epitopes. We detected antibodies to an average of 10 viral species per person and 84 species in at least two individuals. Although rates of specific virus exposure were heterogeneous across populations, antibody responses targeted strongly conserved "public epitopes" for each virus, suggesting that they may elicit highly similar antibodies. VirScan is a powerful approach for studying interactions between the virome and the immune system. PMID- 26045440 TI - Mitochondrial Sirt3 Expression is Decreased in APP/PS1 Double Transgenic Mouse Model of Alzheimer's Disease. AB - Emerging data suggests that mitochondrial dysfunction is prominently involved in Alzheimer disease (AD) progression. Sirtuin-3 (Sirt3) is a member of the sirtuin family of nicotinamide adenine dinucleotide dependent deacetylases that regulates a variety of mitochondrial functions and suppresses mitochondria-related physiology. Here, we determined sirt3 expression in a mouse model of AD. Spatial learning and memory were tested by Morris water maze in APP/PS1 double transgenic mice. The expression of sirt3 was assayed by real-time quantitative PCR and western blotting. Age-and gender-matched wild-type (WT) littermates were used as controls. Cortical sirt3 localization was assessed using immunohistochemistry. The expression of sirt3 mRNA was significantly lower in the cortex of APP/PS1 double transgenic mice than in WT littermates (0.83 +/- 0.24 vs. 1.10 +/- 0.21, P < 0.05). A comparable reduction was found in sirt3 protein levels using western blotting. The ratio of mean optical density (MOD) of total sirt3/beta-actin in the cortex was 0.77 +/- 0.11 in APP/PS1 double transgenic mice and 1.34 +/- 0.17 in the WT littermates (P < 0.01). Immunohistochemistry showed the same change as western blotting. The ratio of MOD of integral optical density/total area in APP/PS1 and WT littermates was 0.58 +/- 0.02 and 0.71 +/- 0.05 (P < 0.01). These data show that sirt3 was depleted in APP/PS1 double transgenic mice. The results suggest that mitochondrial sirt3 might participate in the development of AD via mitochondrial dysfunction. PMID- 26045441 TI - In-Line Monitoring of a Pharmaceutical Pan Coating Process by Optical Coherence Tomography. AB - This work demonstrates a new in-line measurement technique for monitoring the coating growth of randomly moving tablets in a pan coating process. In-line quality control is performed by an optical coherence tomography (OCT) sensor allowing nondestructive and contact-free acquisition of cross-section images of film coatings in real time. The coating thickness can be determined directly from these OCT images and no chemometric calibration models are required for quantification. Coating thickness measurements are extracted from the images by a fully automated algorithm. Results of the in-line measurements are validated using off-line OCT images, thickness calculations from tablet dimension measurements, and weight gain measurements. Validation measurements are performed on sample tablets periodically removed from the process during production. Reproducibility of the results is demonstrated by three batches produced under the same process conditions. OCT enables a multiple direct measurement of the coating thickness on individual tablets rather than providing the average coating thickness of a large number of tablets. This gives substantially more information about the coating quality, that is, intra- and intertablet coating variability, than standard quality control methods. PMID- 26045442 TI - The view from the Ebola Treatment Centre, Makeni, central Sierra Leone. PMID- 26045443 TI - End-tidal CO2 detection during cadaveric ventilation. AB - 'Life like' end-tidal CO2 production has been reported in frozen cadaver during intubation training. We report the same phenomenon in a non-frozen cadaveric model used to undertake CT postmortem, with the additional findings of an increase in CO2 with chest compressions and an increase in CO2 after a pause in ventilation. PMID- 26045444 TI - Utility analysis of management strategies for suspected subarachnoid haemorrhage in patients with thunderclap headache with negative CT result. AB - PURPOSE: To determine the most effective follow-up strategy for evaluation of patients with thunderclap headache and negative initial non-contrast CT for acute subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Institutional review was performed to assess the frequency of CT angiography (CTA) in screening patients with negative non-contrast CT. A comparative effectiveness analysis based on decision tree modelling was subsequently performed to assess three different strategies--no follow-up, lumbar puncture (LP) and CTA. The clinical probabilities and utilities from literature were used to design the decision tree. Base-case scenario utility calculations, sensitivity analyses and probabilistic Monte Carlo simulation were performed. RESULTS: Institutional review of recent data in the last two years demonstrates frequent use of CTA in patients with thunderclap headache with limited utility. The decision tree analysis shows CT with LP follow-up to be the most effective strategy with the highest expected utility of 0.79926 quality-adjusted life-year (QALY) compared with 0.79875 QALY for no follow-up and 0.79869 QALY for CTA follow-up. Monte Carlo simulation showed LP was the best strategy in 86.4% of all iterations. Sensitivity analyses demonstrate that CT without follow-up is the best strategy only when the sensitivity of CT is very high (99.6%) or the pre-test probability of SAH in a patients with thunderclap headache with negative initial CT is low (1.6%). CONCLUSIONS: CT with no follow-up was shown to be the best strategy when the pre-test probability of SAH is low (<1.6%) or the sensitivity of initial non contrast CT for blood is high (>99.6%). Otherwise, LP should be the preferred strategy for follow-up. PMID- 26045445 TI - A family of ROP proteins that suppresses actin dynamics, and is essential for polarized growth and cell adhesion. AB - In plants, the ROP family of small GTPases has been implicated in the polarized growth of tip-growing cells, such as root hairs and pollen tubes; however, most of the data derive from overexpressing ROP genes or constitutively active and dominant-negative isoforms, whereas confirmation by using loss-of-function studies has generally been lacking. Here, in the model moss Physcomitrella patens, we study ROP signaling during tip growth by using a loss-of-function approach based on RNA interference (RNAi) to silence the entire moss ROP family. We find that plants with reduced expression of ROP genes, in addition to failing to initiate tip growth, have perturbed cell wall staining, reduced cell adhesion and have increased actin-filament dynamics. Although plants subjected to RNAi against the ROP family also have reduced microtubule dynamics, this reduction is not specific to loss of ROP genes, as it occurs when actin function is compromised chemically or genetically. Our data suggest that ROP proteins polarize the actin cytoskeleton by suppressing actin-filament dynamics, leading to an increase in actin filaments at the site of polarized secretion. PMID- 26045446 TI - Sphingolipids regulate telomere clustering by affecting the transcription of genes involved in telomere homeostasis. AB - In eukaryotic organisms, including mammals, nematodes and yeasts, the ends of chromosomes, telomeres are clustered at the nuclear periphery. Telomere clustering is assumed to be functionally important because proper organization of chromosomes is necessary for proper genome function and stability. However, the mechanisms and physiological roles of telomere clustering remain poorly understood. In this study, we demonstrate a role for sphingolipids in telomere clustering in the budding yeast Saccharomyces cerevisiae. Because abnormal sphingolipid metabolism causes downregulation of expression levels of genes involved in telomere organization, sphingolipids appear to control telomere clustering at the transcriptional level. In addition, the data presented here provide evidence that telomere clustering is required to protect chromosome ends from DNA-damage checkpoint signaling. As sphingolipids are found in all eukaryotes, we speculate that sphingolipid-based regulation of telomere clustering and the protective role of telomere clusters in maintaining genome stability might be conserved in eukaryotes. PMID- 26045447 TI - Association of intracellular and synaptic organization in cochlear inner hair cells revealed by 3D electron microscopy. AB - The ways in which cell architecture is modelled to meet cell function is a poorly understood facet of cell biology. To address this question, we have studied the cytoarchitecture of a cell with highly specialised organisation, the cochlear inner hair cell (IHC), using multiple hierarchies of three-dimensional (3D) electron microscopy analyses. We show that synaptic terminal distribution on the IHC surface correlates with cell shape, and the distribution of a highly organised network of membranes and mitochondria encompassing the infranuclear region of the cell. This network is juxtaposed to a population of small vesicles, which represents a potential new source of neurotransmitter vesicles for replenishment of the synapses. Structural linkages between organelles that underlie this organisation were identified by high-resolution imaging. Taken together, these results describe a cell-encompassing network of membranes and mitochondria present in IHCs that support efficient coding and transmission of auditory signals. Such techniques also have the potential for clarifying functionally specialised cytoarchitecture of other cell types. PMID- 26045449 TI - Comparison of Methods for Determining ABO Blood Type in Cynomolgus Macaques (Macaca fascicularis). AB - Thorough examination of ABO blood type in cynomolgus monkeys is an essential experimental step to prevent humoral rejection during transplantation research. In the present study, we evaluated current methods of ABO blood-antigen typing in cynomolgus monkeys by comparing the outcomes obtained by reverse hemagglutination, single-nucleotide polymorphism (SNP) analysis, and buccal mucosal immunohistochemistry. Among 21 animals, 5 were type A regardless of the method. However, of 8 serologically type B animals, 3 had a heterozygous type AB SNP profile, among which 2 failed to express A antigen, as shown by immunohistochemical analysis. Among 8 serologically type AB animals, 2 appeared to be type A by SNP analysis and immunohistochemistry. None of the methods identified any type O subjects. We conclude that the expression of ABO blood group antigens is regulated by an incompletely understood process and that using both SNP and immunohistochemistry might minimize the risk of incorrect results obtained from the conventional hemagglutination assay. PMID- 26045450 TI - Lack of negative effects on Syrian hamsters and Mongolian gerbils housed in the same secondary enclosure. AB - In cases where different species might be housed in the same room or secondary enclosure, the Guide for the Care and Use of Laboratory Animals recommends that the animals should be behaviorally compatible and have the same health status. Syrian hamsters and Mongolian gerbils, both desert-dwelling rodents, appear to be reasonable candidates for such a combination. This study was undertaken to evaluate whether housing hamsters and gerbils in the same secondary enclosure is an acceptable practice. Weanling and breeding-age hamsters and gerbils were housed in open-topped cages in an isolator for 5 mo; the isolator also contained with nude and haired mice, which acted as sentinels. Cages housing hamsters and gerbils were rotated between species, and dirty bedding was exchanged between species in an effort to transmit microorganisms. In addition, sentinel mice housed in the isolator were supplied with dirty bedding from both hamsters and gerbils. Neither species showed clinical signs of illness, the health status of neither the hamsters nor the gerbils changed significantly, and the sentinel mice acquired only 2 infectious organisms, a Helicobacter species and Staphylococcus aureus. Both hamsters and gerbils bred successfully when housed together in the same isolator, and no infanticide or mortality was seen. Breeding performance did not differ between isolator breeding and barrier breeding. This study supports the housing of hamsters and gerbils in the same secondary enclosure. PMID- 26045451 TI - Effects of Changing to Individually Ventilated Caging on Guinea Pigs (Cavia porcellus). AB - The goal of this study was to evaluate the effect of changing to IVC housing on guinea pigs by recording several physiologic parameters in guinea pigs housed sequentially in open-top cages (OTC) and IVC. To register heart rate and locomotor activity, 10 male Dunkin-Hartley guinea pigs implanted with telemetric transmitters were moved from OTC to new, freshly prepared OTC or IVC and subsequently monitored by telemetry during the 4 d after the first cage change. Body weight and food consumption were measured twice during the study. Comparison of data from OTC- and IVC-housed guinea pigs showed no relevant differences in heart rate (mean +/- 1 SD; 213 +/- 10 bpm and 207 +/- 9 bpm, respectively) at any time point. In contrast, locomotor activity varied: whereas activity during the first 4 h after the change of cage type was greater in IVC-housed animals, that during the following 24 h was greater in OTC but was similar between groups thereafter. Animals housed in OTC consumed more food than did those in IVC and, under both conditions, consumption was statistically related to body weight changes. Together, these results show that a change to IVC housing induced only transient increases in locomotor activity in guinea pigs without a marked increase in heart rate but with a decrease in food consumption. Because decreased food consumption was the only stress-associated sign during the 4-d observation, longer studies are needed to ascertain the importance of this finding. PMID- 26045452 TI - Advantages and Risks of Husbandry and Housing Changes to Improve Animal Wellbeing in a Breeding Colony of Common Marmosets (Callithrix jacchus). AB - Between 1975 and 2014, housing conditions for laboratory-housed marmosets changed dramatically after the introduction of new guidelines designed to improve their care and wellbeing. According to these guidelines, our facility provided marmosets with outside enclosures, switched to deep litter as bedding material, and discontinued the use of disinfectant agents in animal enclosures. However, both deep litter and access to outside enclosures hypothetically increase the risk of potential exposure to pathogenic microorganisms. We evaluated whether these housing and husbandry modifications constituted an increased veterinary risk for laboratory-housed common marmosets (Callithrix jacchus). After the animals had been exposed to these new housing conditions for 2.5 y, we examined their intestinal bacterial flora and feces, the deep litter, and insects present in the housing. In addition, we assessed the marmosets' general health and the effect of outdoor housing on, for example, vitamin D levels. Although numerous bacterial strains--from nonpathogenic to potentially pathogenic--were cultured, we noted no increase in illness, mortality, or breeding problems related to this environmental microflora. Housing laboratory marmosets in large enriched cages, with both indoor and outdoor enclosures, providing them with deep litter, and eliminating the use of disinfectants present an increased veterinary risk. However, after evaluating all of the collected data, we estimate that the veterinary risk of the new housing conditions is minimal to none in terms of clinical disease, disease outbreaks, abnormal behavior, and negative effects on reproduction. PMID- 26045453 TI - The Behavioral Effects of Single Housing and Environmental Enrichment on Adult Zebrafish (Danio rerio). AB - Environmental enrichment provides laboratory-housed species the opportunity to express natural behavior and exert control over their home environment, thereby minimizing stress. We sought to determine whether providing an artificial plant in the holding tank as enrichment influenced anxiety-like behaviors and place preference choice in adult zebrafish. Fish were housed singly or in social groups of 5 for 3 wk in 1 of 4 experimental housing environments: single-housed enriched (n = 30), single-housed barren (n = 30), group-housed enriched (n = 30), and group-housed barren (n = 30). On week 4, individual fish were selected randomly from each of the experimental housing environments and tested by using novel tank, light-dark, and place-preference tests. Housing fish singly in a barren environment increased anxiety-like behaviors in the novel-tank and light-dark behavioral tests. Single-housed zebrafish in barren tanks as well as zebrafish group-housed with conspecifics, both with and without plant enrichment, spent more time associating with conspecifics than with the artificial plant enrichment device during the place-preference test. Single-housed fish maintained in enriched tanks displayed no preference between a compartment with conspecifics or an artificial plant. Our results suggest the addition of an artificial plant as enrichment may benefit single-housed zebrafish when social housing is not possible. PMID- 26045454 TI - Comparison of a ferret model with an inanimate simulator for training novices in techniques for intubating neonates. AB - Simulators for neonatal intubation training have improved, prompting us to compare a state-of-the-art simulator with live ferrets for training novice family medicine residents in this crucial skill. After a scripted didactic presentation, we used a crossover study design and randomly assigned residents to receive simulator or live ferret training, after which they repeated the procedure by using the opposite method. Participants were asked to report their level of confidence and competence before and after each training session and the usefulness of each training method. In addition, residents were videotaped performing the procedure and evaluated by using a modified global rating scale. The 2 methods did not differ in regard to self-reported confidence, competence, or usefulness of each training procedure. A majority of participants indicated that they preferred using the ferrets over the simulator, with realism cited most frequently as the reason for their choice. Videotape scores for time and motion and flow of the procedure were higher when the simulator was used, but higher for instrument handling when ferrets were intubated. Overall scores were higher for videotaped evaluations with the simulator compared with the ferrets. According to these findings, the simulator appears to provide adequate instruction for the initial training of novice learners in neonatal intubation techniques. PMID- 26045456 TI - Effects of Dexmedetomidine and Ketamine-Dexmedetomidine with and without Buprenorphine on Corticoadrenal Function in Rabbits. AB - Anesthetics may influence adrenal function and consequently alter serum glucocorticoid concentrations, leading to erroneous interpretations of results from anesthetized rabbits. However, decreases in glucocorticoid concentrations may be advantageous in protocols designed to minimize the stress response to surgery. This study characterized the variations in adrenocortical function based on changes in corticosterone and cortisol levels after various doses and combinations of dexmedetomidine, ketamine, and buprenorphine. Each rabbit received all treatments with a minimal interexperiment interval of 10 d. Rabbits were allocated to 7 groups (n = 10 per group) and received either 1 mL saline solution; dexmedetomidine at 0.05, 0.15, or 0.25 mg/kg; ketamine (35 mg/kg) and dexmedetomidine (0.25 mg/kg) without or with buprenorphine (0.03 mg/kg); or ketamine (35 mg/kg) and buprenorphine (0.03 mg/kg). Blood was sampled before drug administration and at 10, 30, 60, and 120 min and 24 h afterward. Serum glucocorticoid levels fell in all treatment groups except the one receiving ketamine-dexmedetomidine; in that group, serum glucocorticoids increased. Rabbits that received ketamine-dexmedetomidine-buprenorphine had the lowest serum glucocorticoid levels overall. In conclusion, dexmedetomidine reduces glucocorticoid secretion in rabbits but, when combined with ketamine, increases corticosterone and cortisol levels as well as heart and respiratory rates. The addition of buprenorphine to the ketamine-dexmedetomidine mixture reduces serum glucocorticoid levels. The influence of anesthetic drugs should be considered when designing a protocol to minimize the glucocorticoid response to surgery or when measuring glucocorticoid levels in rabbits. PMID- 26045455 TI - Adverse effects of vapocoolant and topical anesthesia for tail biopsy of preweanling mice. AB - Tail biopsy of laboratory mice for genotyping purposes has been studied extensively to develop refinements for this common procedure. Our prior work assessed tail vertebral development in different mouse strains (age, 3 to 42 d) and analyzed behavior and activity in mice (age, 21 to 45 d) biopsied under isoflurane anesthesia. To assess the effects of biopsy on preweanling mice, we here evaluated BALB/cAnNCrl mice (n = 80; age, 18 to 21 d) that received topical vapocoolant (ethyl chloride), topical anesthetic (Cetacaine), or isoflurane anesthesia before undergoing a 5-mm or sham biopsy. Control mice did not receive any anesthetic intervention. Regardless of the anesthetic used, acute observation scores indicative of distress were increased at 10 min after biopsy, and locomotor activity was decreased, in biopsied compared with control mice. Acute observation scores at 10 min after biopsy were higher in mice that received ethyl chloride compared with isoflurane or no anesthesia. Microscopic analysis revealed that inflammatory changes in the distal tail remained elevated until 7 d after biopsy and were higher in tails exposed to ethyl chloride. Our findings indicate that vapocoolant, topical anesthesia, and inhaled isoflurane do not enhance the wellbeing of preweanling mice undergoing tail biopsy. Due to the lack of appreciable benefits and the presence of notable adverse effects, using vapocoolants or Cetacaine for this tail biopsy procedure in laboratory mice is unadvisable and we encourage the removal of these agents from institutional tail biopsy guidelines. PMID- 26045457 TI - Observational Evaluations of Mice during Cerebral Microdialysis for Pediatric Brain Tumor Research. AB - In vivo animal experiments are critical in the process of finding and developing new treatments for children with CNS tumors. Cerebral microdialysis, which enables researchers to measure drug concentrations in the brain or tumor tissue of unanesthetized mice, is a highly specialized procedure that provides valuable information that cannot be gained by using an in vitro system. When designing any in vivo animal study, 3 Rs principles (replacement, reduction, and refinement) must be considered to ensure that the highest standards of care are followed. As part of the refinement process, the objectives of this study were to collect behavioral monitoring data from mice undergoing cerebral microdialysis, to identify any behaviors predictive of significant pain or distress that could affect the animal's welfare, and to use these data to refine the existing monitoring checklist and schedule for its use by others performing this procedure. We developed a monitoring checklist for assessing wellbeing and distress of mice during cerebral microdialysis experiments. Comparison of 79 mice that underwent cerebral microdialysis experiments with a control group of 20 mice revealed that cerebral microdialysis and tethering of mice are well tolerated for as long as 24 h with only minor evidence of stress. PMID- 26045458 TI - Performance analysis of exam gloves used for aseptic rodent surgery. AB - Aseptic technique includes the use of sterile surgical gloves for survival surgeries in rodents to minimize the incidence of infections. Exam gloves are much less expensive than are surgical gloves and may represent a cost-effective, readily available option for use in rodent surgery. This study examined the effectiveness of surface disinfection of exam gloves with 70% isopropyl alcohol or a solution of hydrogen peroxide and peracetic acid (HP-PA) in reducing bacterial contamination. Performance levels for asepsis were met when gloves were negative for bacterial contamination after surface disinfection and sham 'exertion' activity. According to these criteria, 94% of HP-PA-disinfected gloves passed, compared with 47% of alcohol-disinfected gloves. In addition, the effect of autoclaving on the integrity of exam gloves was examined, given that autoclaving is another readily available option for aseptic preparation. Performance criteria for glove integrity after autoclaving consisted of: the ability to don the gloves followed by successful simulation of wound closure and completion of stretch tests without tearing or observable defects. Using this criteria, 98% of autoclaved nitrile exam gloves and 76% of autoclaved latex exam gloves met performance expectations compared with the performance of standard surgical gloves (88% nitrile, 100% latex). The results of this study support the use of HP-PA-disinfected latex and nitrile exam gloves or autoclaved nitrile exam gloves as viable cost-effective alternatives to sterile surgical gloves for rodent surgeries. PMID- 26045459 TI - Type, duration, and incidence of pathologic findings after retroorbital bleeding of mice by experienced and novice personnel. AB - Retroorbital blood collection is a common technique in laboratory rodents due to the ease with which it can be performed and the sample volumes obtained for subsequent blood analyses. However, its use has been discouraged recently due to aesthetic discomfort and anecdotal reports of potential for ocular injury during blood collection. We hypothesized that a single standardized session of in-person training would be sufficient to learn the appropriate technique and minimize the likelihood for adverse outcomes. Experienced instructors (n = 2) conducted hands on training classes to teach novice personnel (n = 40) to perform this procedure. Blood was collected from anesthetized mice (n = 40) via a capillary tube first placed at the medial canthus of the right eye and then advanced into the retroorbital space; the left retroorbital spaces served as unmanipulated controls. For comparison, the experienced instructors similarly collected blood from 40 additional mice. The tube could be inserted only once in each mouse, with the goal of obtaining 50 to 100 MUL blood. Overall, 79 of 80 mice (98.8%) showed normal body condition, posture, and behavior throughout the 14-d study. Thus, any clinical observation scores pertained specifically to ocular lesions, which occurred at least once after sampling in 43 (53.8%) of the mice. Clinical and histopathologic scores of mice after bleeding did not differ between experienced and novice personnel. We conclude that a coordinated hands-on training program can provide consistent and sufficient instruction for research personnel to conduct retroorbital blood collection with competence in anesthetized laboratory mice. PMID- 26045460 TI - Enucleation for treating rodent ocular disease. AB - Our standard of care for rodent corneal lesions previously included treatment of the primary lesion, application of topical NSAIDs, and systemic NSAIDs in severe cases. When intensive medical management was unsuccessful, animals were euthanized, leading to premature loss of valuable genetically modified animals and those on long-term studies. We investigated enucleation surgery as a treatment for 15 cases of rodent corneal disease that did not respond to medical management. Enucleation was performed under isoflurane anesthesia and involved removal of the globe, extensive hemostasis, and packing the orbital space with absorbable gelatin sponge. The lid margins were closed by tarsorrhaphy and tissue glue. Analgesia was provided by using buprenorphine preoperatively and carprofen chew tabs postoperatively. To date, we have a 100% success rate with this procedure (n = 20; 15 clinically affected rodents [2 rats, 13 mice], 5 healthy controls), which included a 60-d follow-up period. The single complication involved dehiscence of the tarsorrhaphy site and was repaired by trimming the lid margins to provide fresh tissue for closure. Histologic examination at both 1 and 3 mo after surgery revealed no evidence of infection of the enucleation site. Enucleation in rodents is a straightforward procedure that represents a refinement to our current standard of care for rodents, does not cause significant inflammation of remaining periocular structures, and has reduced the number of animals euthanized prior to study endpoint because of severe ocular lesions. PMID- 26045461 TI - Foot Embolization During Limb Salvage Procedures in Critical Limb Ischemia Patients Successfully Managed With Mechanical Thromboaspiration: A Technical Note. AB - PURPOSE: To illustrate the use of a mechanical thromboaspiration device originally designed for clot retrieval in acute stroke in the treatment of acute distal embolism occurring during percutaneous revascularization of the femoropopliteal and below-the-knee arterial segments. TECHNIQUE: The Penumbra system was adapted for aspiration of thrombus in the distal foot arteries as a standalone device. The 2 over-the-wire, tapered lumen catheters have long working lengths (139 cm for the 4MAX to 153 cm for the 3MAX) that allow advancement below the ankle even with a retrograde contralateral approach. Once the occluded arterial segment is reached, the catheters are connected to the dedicated pump for continuous vacuum aspiration. The use of the device is illustrated in 3 diabetic patients (1 woman and 2 men; ages 88, 70, and 73 years, respectively) undergoing limb salvage procedures who experienced distal embolization that would have seriously jeopardized the foot circulation. The lumens of the occluded arteries were restored without complication. CONCLUSION: While further evaluation in a larger cohort of patients is needed, this initial experience using the Penumbra system in the peripheral vasculature suggests that this is a rapid, effective approach to address intraprocedural foot embolization and avoid possible grave clinical sequelae. PMID- 26045462 TI - Impact of Renal Artery Angulation on Procedure Efficiency During Fenestrated and Snorkel/Chimney Endovascular Aneurysm Repair. AB - PURPOSE: To determine the impact of renal artery angulation on time to successful renal artery cannulation and procedure efficiency during fenestrated and snorkel/chimney endovascular aneurysm repair (EVAR). METHODS: The imaging and procedure logs of 77 patients (mean age 74.2 years; 63 men) who underwent complex EVAR (24 fenestrated, 53 snorkel/chimney) from 2009 to 2013 were reviewed. Renal artery angulation was measured on preoperative computed tomographic angiography scans. Time to renal artery cannulation was retrieved from the EVAR procedure logs and compared to preoperative renal artery angulation and other metrics of procedure efficiency (eg, procedure time, fluoroscopy time, blood loss, etc). In all, 111 renal arteries were available for renal artery angulation measurement (39 fenestrated, 72 snorkel/chimney); 22 renal cannulations were inappropriate for the comparative analyses due to concomitant visceral artery stenting (n=15), combined procedures (n=6), or unsuccessful cannulation (n=1). RESULTS: For patients undergoing fenestrated EVAR, mean renal artery angulation was -28 degrees +/-21 degrees (range +37 degrees to -60 degrees ), not significantly different (p=0.66) from patients receiving snorkel/chimney grafts (mean -30 degrees +/-19 degrees , range +22 degrees to -65 degrees ). Comparative analysis using median renal artery angulation (-30 degrees for both groups) demonstrated that renal artery cannulation during fenestrated EVAR was performed significantly faster in arteries with less downward (>= -30 degrees ) angulation (16.0 vs 32.8 minutes, p=0.04), whereas cannulation in snorkel/chimneys was faster in arteries with greater downward (< -30 degrees ) angulation (10.9 vs 17.3 minutes, p=0.05). Fenestrated EVAR cases involving less downward (>= -30 degrees ) renal artery angulation were also associated with shorter overall procedure time (187.7 vs 246.2 minutes, p=0.01) and decreased fluoroscopy time (70.3 vs 98.2 minutes, p=0.04). Immediate renal function decline, procedural complications, and postoperative issues were not associated with renal artery angulation. CONCLUSION: Procedural efficiency may be optimized by considering renal artery angulation as one of several objective variables used in the selection of an appropriate endovascular strategy. The fenestrated approach is more efficient with less downward angulation to the renal arteries, while the snorkel/chimney strategy is facilitated by more downward renal artery angulation. PMID- 26045463 TI - A Novel Bubble-Mixture Method to Improve Dynamic Images in Carbon Dioxide Angiography. AB - PURPOSE: To present a novel method of preparing carbon dioxide (CO2) for contrast enhancement. TECHNIQUE: CO2 angiography can often produce poor image enhancement, especially in dependent vessels due to buoyancy of the gas. A new technique for premixing the CO2 gas with the patient's blood and dispersing it into the bubble mixture before injection was developed. Comparative dynamic images showed bubble mixed CO2 angiography had less fragmentation, more even distribution, and more sustainability than the same volume of pure CO2. CONCLUSION: The alteration of CO2 gas toward a semiliquid form demonstrates an easy and reproducible concept to improve the dynamic image quality of traditional CO2 angiography. PMID- 26045465 TI - A mathematical model relating cortical oxygenated and deoxygenated hemoglobin flows and volumes to neural activity. AB - OBJECTIVE: To describe a toolkit of components for mathematical models of the relationship between cortical neural activity and space-resolved and time resolved flows and volumes of oxygenated and deoxygenated hemoglobin motivated by optical intrinsic signal imaging (OISI). APPROACH: Both blood flow and blood volume and both oxygenated and deoxygenated hemoglobin and their interconversion are accounted for. Flow and volume are described by including analogies to both resistive and capacitive electrical circuit elements. Oxygenated and deoxygenated hemoglobin and their interconversion are described by generalization of Kirchhoff's laws based on well-mixed compartments. MAIN RESULTS: Mathematical models built from this toolkit are able to reproduce experimental single-stimulus OISI results that are described in papers from other research groups and are able to describe the response to multiple-stimuli experiments as a sublinear superposition of responses to the individual stimuli. SIGNIFICANCE: The same assembly of tools from the toolkit but with different parameter values is able to describe effects that are considered distinctive, such as the presence or absence of an initial decrease in oxygenated hemoglobin concentration, indicating that the differences might be due to unique parameter values in a subject rather than different fundamental mechanisms. PMID- 26045464 TI - Cross-Species Network Analysis Uncovers Conserved Nitrogen-Regulated Network Modules in Rice. AB - In this study, we used a cross-species network approach to uncover nitrogen (N) regulated network modules conserved across a model and a crop species. By translating gene network knowledge from the data-rich model Arabidopsis (Arabidopsis thaliana) to a crop, rice (Oryza sativa), we identified evolutionarily conserved N-regulatory modules as targets for translational studies to improve N use efficiency in transgenic plants. To uncover such conserved N-regulatory network modules, we first generated an N-regulatory network based solely on rice transcriptome and gene interaction data. Next, we enhanced the network knowledge in the rice N-regulatory network using transcriptome and gene interaction data from Arabidopsis and new data from Arabidopsis and rice plants exposed to the same N treatment conditions. This cross-species network analysis uncovered a set of N-regulated transcription factors (TFs) predicted to target the same genes and network modules in both species. Supernode analysis of the TFs and their targets in these conserved network modules uncovered genes directly related to N use (e.g. N assimilation) and to other shared biological processes indirectly related to N. This cross species network approach was validated with members of two TF families in the supernode network, BASIC-LEUCINE ZIPPER TRANSCRIPTION FACTOR1-TGA and HYPERSENSITIVITY TO LOW PI-ELICITED PRIMARY ROOT SHORTENING1 (HRS1)/HRS1 Homolog family, which have recently been experimentally validated to mediate the N response in Arabidopsis. PMID- 26045466 TI - Male meiotic cytokinesis requires ceramide synthase 3-dependent sphingolipids with unique membrane anchors. AB - Somatic cell cytokinesis was shown to involve the insertion of sphingolipids (SLs) to midbodies prior to abscission. Spermatogenic midbodies transform into stable intercellular bridges (ICBs) connecting clonal daughter cells in a syncytium. This process requires specialized SL structures. (1) Using high resolution-mass spectrometric imaging, we show in situ a biphasic pattern of SL synthesis with testis-specific anchors. This pattern correlates with and depends on ceramide synthase 3 (CerS3) localization in both, pachytene spermatocytes until completion of meiosis and elongating spermatids. (2) Blocking the pathways to germ cell-specific ceramides (CerS3-KO) and further to glycosphingolipids (glucosylceramide synthase-KO) in mice highlights the need for special SLs for spermatid ICB stability. In contrast to somatic mitosis these SLs require ultra long polyunsaturated anchors with unique physico-chemical properties, which can only be provided by CerS3. Loss of these anchors causes enhanced apoptosis during meiosis, formation of multinuclear giant cells and spermatogenic arrest. Hence, testis-specific SLs, which we also link to CerS3 in human testis, are quintessential for male fertility. PMID- 26045468 TI - Silicene: a review of recent experimental and theoretical investigations. AB - Silicene is the silicon counterpart of graphene, i.e. it consists in a single layer of Si atoms with a hexagonal arrangement. We present a review of recent theoretical and experimental works on this novel two dimensional material. We discuss first the structural, electronic and vibrational properties of free standing silicene, as predicted from first-principles calculations. We next review theoretical studies on the interaction of silicene with different substrates. The growth and experimental characterization of silicene on Ag(1 1 1) is next discussed, providing insights into the different phases or atomic arrangements of silicene observed on this metallic surface, as well as on its electronic structure. Recent experimental findings about the likely formation of hexagonal Si nanosheets on MoS2 are also highlighted. PMID- 26045467 TI - Factors associated with uptake of services to prevent mother-to-child transmission of HIV in a community cohort in rural Tanzania. AB - OBJECTIVES: This study aimed to identify factors associated with access to HIV care and antiretroviral (ARV) drugs for prevention of mother-to-child transmission (PMTCT) of HIV among HIV-positive pregnant women in a community cohort in rural Tanzania (Kisesa). METHODS: Kisesa-resident women who tested HIV positive during HIV serosurveillance and were pregnant (while HIV-positive) between 2005 and 2012 were eligible. Community cohort records were linked to PMTCT and HIV clinic data from four facilities (PMTCT programme implemented in 2009; referrals to city-based hospitals since 2005) to ascertain service use. Factors associated with access to HIV care and ARVs during pregnancy were analysed using logistic regression. RESULTS: Overall, 24% of women accessed HIV care and 12% accessed ARVs during pregnancy (n=756 pregnancies to 420 women); these proportions increased over time. In multivariate analyses for 2005-2012, being married, prior voluntary counselling and testing, increasing age, increasing year of pregnancy and increasing duration of infection were independently associated with access to care and ARVs. Residence in roadside areas was an independent predictor of access to care but not ARVs. There was no evidence of an interaction with time period. CONCLUSIONS: Access to PMTCT services was low in this rural setting but improved markedly over time. There were fairly few sociodemographic differentials although support for young women and those without partners may be needed. Further decentralisation of HIV services to more remote areas, promotion of voluntary counselling and testing and implementation of Option B+ are likely to improve uptake and may bring women into care and treatment sooner after infection. PMID- 26045469 TI - Interplay between intrinsic point defects and low-angle grain boundary in bcc tungsten: effects of local stress field. AB - We have used molecular statics in conjunction with an embedded atom method to explore the interplay between native point defects (vacancies and self interstitials (SIAs)) and a low-angle grain boundary (GB) in bcc tungsten. The low-angle GB has biased absorption of SIAs over vacancies. We emphasize the significance of phenomena such as vacancy delocalization and SIA instant absorption around the GB dislocation cores in stabilizing the defect structures. Interstitial loading into the GB can dramatically enhance the interaction strength between the point defects and the GB due to SIA clustering (SIA cloud formation) or SIA vacancy recombination. We propose that the 'maximum atom displacement' can complement the 'vacancy formation energy' in evaluating unstable vacancy sites. Calculations of point defect migration barriers in the vicinity of GB dislocation cores show that vacancies and SIAs preferentially migrate along the pathways in the planes immediately above and below the core, respectively. PMID- 26045470 TI - 15 YEARS OF PARAGANGLIOMA: Imaging and imaging-based treatment of pheochromocytoma and paraganglioma. AB - Although anatomic imaging to assess the precise localization of pheochromocytomas/paragangliomas (PHEOs/PGLs) is unavoidable before any surgical intervention on these tumors, functional imaging is becoming an inseparable portion of the imaging algorithm for these tumors. This review article presents applications of the most up-to-date functional imaging modalities and image-based treatment to PHEOs/PGLs patients. Functional imaging techniques provide whole body localization (number of tumors present along with metastatic deposits) together with genetic-specific imaging approaches to PHEOs/PGLs, thus enabling highly specific and sensitive PHEO/PGL detection and delineation that now greatly impact the management of patients. Radionuclide imaging techniques also play a crucial role in the prediction of possible radioactive treatment options for PHEO/PGL. In contrast to previous imaging algorithms used for either assessement of these patients or their follow-up, endocrinologists, surgeons, oncologists, pediatricians, and other specialists require functional imaging before any therapeutic plan is outlined to the patient, and follow-up, especially in patients with metastatic disease, is based on the periodic use of functional imaging, often reducing or substituting for anatomical imaging. In similar specific indications, this will be further powered by using PET/MR in the assessment of these tumors. In the near future, it is expected that PHEO/PGL patients will benefit even more from an assessement of the functional characteristics of these tumors and new imaging-based treatment options. Finally, due to the use of new targeting moieties, gene-targeted radiotherapeutics and nanobodies-based theranostic approaches are expected to become a reality in the near future. PMID- 26045471 TI - Glutamine promotes ovarian cancer cell proliferation through the mTOR/S6 pathway. AB - Glutamine is one of the main nutrients used by tumor cells for biosynthesis. Therefore, targeted inhibition of glutamine metabolism may have anti-tumorigenic implications. In the present study, we aimed to evaluate the effects of glutamine on ovarian cancer cell growth. Three ovarian cancer cell lines, HEY, SKOV3, and IGROV-1, were assayed for glutamine dependence by analyzing cytotoxicity, cell cycle progression, apoptosis, cell stress, and glucose/glutamine metabolism. Our results revealed that administration of glutamine increased cell proliferation in all three ovarian cancer cell lines in a dose dependent manner. Depletion of glutamine induced reactive oxygen species and expression of endoplasmic reticulum stress proteins. In addition, glutamine increased the activity of glutaminase (GLS) and glutamate dehydrogenase (GDH) by modulating the mTOR/S6 and MAPK pathways. Inhibition of mTOR activity by rapamycin or blocking S6 expression by siRNA inhibited GDH and GLS activity, leading to a decrease in glutamine-induced cell proliferation. These studies suggest that targeting glutamine metabolism may be a promising therapeutic strategy in the treatment of ovarian cancer. PMID- 26045472 TI - Attitudes towards HIV testing via home-sampling kits ordered online (RUClear pilots 2011-12). AB - BACKGROUND: The burden of disease relating to undiagnosed HIV infection is significant in the UK. BHIVA (British HIV Association) recommends population screening in high prevalence areas, expanding outside traditional antenatal/GUM settings. METHODS: RUClear 2011-12 piloted expanding HIV testing outside traditional settings using home-sampling kits (dry-blood-spot testing) ordered online. Greater Manchester residents (>=age 16) could request testing via an established, online chlamydia testing service (www.ruclear.co.uk). Participant attitudes towards this new service were assessed. Qualitative methods (thematic analysis) were used to analyse free-text data submitted by participants via hard copy questionnaires issued in all testing kits. RESULTS: 79.9% (2447/3062) participants completed questionnaires, of which 30.9% (756/2447) provided free text data. Participants overwhelmingly supported the service, valuing particularly accessibility and convenience, allowing individuals to order tests any time of day and self-sample comfortably at home; avoiding the invasive nature of venipuncture and avoiding the need for face-to-face interaction with health services. The pilot was also clinically and cost-effective. CONCLUSION: Testing via home-sampling kits ordered online (dry-blood-spot testing) was felt to be an acceptable and convenient method for accessing a HIV test. Many individuals undertook HIV testing where they would otherwise not have been tested at all. Expansion of similar services may increase the uptake of HIV testing. PMID- 26045473 TI - Public health education in UK medical schools-towards consensus. PMID- 26045474 TI - Cannabis, Cigarettes, and Their Co-Occurring Use: Disentangling Differences in Gray Matter Volume. AB - BACKGROUND: Structural magnetic resonance imaging techniques are powerful tools for examining the effects of drug use on the brain. The nicotine and cannabis literature has demonstrated differences between nicotine cigarette smokers and cannabis users compared to controls in brain structure; however, less is known about the effects of co-occurring cannabis and tobacco use. METHODS: We used voxel-based morphometry to examine gray matter volume differences between four groups: (1) cannabis-dependent individuals who do not smoke tobacco (Cs); (2) cannabis-dependent individuals who smoke tobacco (CTs); (3) cannabis-naive, nicotine-dependent individuals who smoke tobacco (Ts); and (4) healthy controls (HCs). We also explored associations between gray matter volume and measures of cannabis and tobacco use. RESULTS: A significant group effect was observed in the left putamen, thalamus, right precentral gyrus, and left cerebellum. Compared to HCs, the Cs, CTs, and Ts exhibited larger gray matter volumes in the left putamen. Cs also had larger gray matter volume than HCs in the right precentral gyrus. Cs and CTs exhibited smaller gray matter volume than HCs in the thalamus, and CTs and Ts had smaller left cerebellar gray matter volume than HCs. CONCLUSIONS: This study extends previous research that independently examined the effects of cannabis or tobacco use on brain structure by including an examination of co-occurring cannabis and tobacco use, and provides evidence that cannabis and tobacco exposure are associated with alterations in brain regions associated with addiction. PMID- 26045477 TI - Light emission from Ag(111) driven by inelastic tunneling in the field emission regime. AB - We study the light emission from a Ag(111) surface when the bias voltage on a scanning tunneling microscope (STM) junction is ramped into the field emission regime. Above the vacuum level, scanning tunneling spectroscopy (STS) shows a series of well defined resonances associated with the image states of the surface, which are Stark shifted due to the electric field provided by the STM tip. We present photon-energy resolved measurements that unambiguously show that the mechanism for light emission is the radiative decay of surface localized plasmons excited by the electrons that tunnel inelastically into the Stark shifted image states. Our work illustrates the effect of the tip radius both in the STS spectrum and the light emission maps by repeating the experiment with different tips. PMID- 26045476 TI - Combination therapy with remote ischaemic conditioning and insulin or exenatide enhances infarct size limitation in pigs. AB - AIMS: Remote ischaemic conditioning (RIC) has been shown to reduce myocardial infarct size in patients. Our objective was to investigate whether the combination of RIC with either exenatide or glucose-insulin-potassium (GIK) is more effective than RIC alone. METHODS AND RESULTS: Pigs were submitted to 40 min of coronary occlusion followed by reperfusion, and received (i) no treatment, (ii) one of the following treatments: RIC (5 min ischemia/5 min reperfusion * 4), GIK, or exenatide (at doses reducing infarct size in clinical trials), or (iii) a combination of two of these treatments (RIC + GIK or RIC + exenatide). After 5 min of reperfusion (n = 4/group), prominent phosphorylation of Akt and endothelial nitric oxide synthase (eNOS) was observed, both in control and reperfused myocardium, in animals receiving GIK, and mitochondria from these hearts showed reduced ADP-stimulated respiration. (1)H NMR-based metabonomics disclosed a shift towards increased glycolysis in GIK and exenatide groups. In contrast, oxidative stress (myocardial nitrotyrosine levels) and eNOS uncoupling were significantly reduced only by RIC. In additional experiments (n = 7 10/group), ANOVA demonstrated a significant effect of the number of treatments after 2 h of reperfusion on infarct size (triphenyltetrazolium, % of the area at risk; 59.21 +/- 3.34, 36.64 +/- 3.03, and 21.04 +/- 2.38% for none, one, and two treatments, respectively), and significant differences between one and two treatments (P = 0.004) but not among individual treatments or between RIC + GIK and RIC + exenatide. CONCLUSIONS: GIK and exenatide activate cardioprotective pathways different from those of RIC, and have additive effects with RIC on infarct size reduction in pigs. PMID- 26045475 TI - Cardiac myosin light chain phosphorylation and inotropic effects of a biased ligand, TRV120023, in a dilated cardiomyopathy model. AB - AIMS: Therapeutic approaches to treat familial dilated cardiomyopathy (DCM), which is characterized by depressed sarcomeric tension and susceptibility to Ca(2+)-related arrhythmias, have been generally unsuccessful. Our objective in the present work was to determine the effect of the angiotensin II type 1 receptor (AT1R) biased ligand, TRV120023, on contractility of hearts of a transgenic mouse model of familial DCM with mutation in tropomyosin at position 54 (TG-E54K). Our rationale is based on previous studies, which have supported the hypothesis that biased G-protein-coupled receptor ligands, signalling via beta-arrestin, increase cardiac contractility with no effect on Ca(2+) transients. Our previous work demonstrated that the biased ligand TRV120023 is able to block angiotensin-induced hypertrophy, while promoting an increase in sarcomere Ca(2+) response. METHODS AND RESULTS: We tested the hypothesis that the depression in cardiac function associated with DCM can be offset by infusion of the AT1R biased ligand, TRV120023. We intravenously infused saline, TRV120023, or the unbiased ligand, losartan, for 15 min in TG-E54K and non-transgenic mice to obtain left ventricular pressure-volume relations. Hearts were analysed for sarcomeric protein phosphorylation. Results showed that the AT1R biased ligand increases cardiac performance in TG-E54K mice in association with increased myosin light chain-2 phosphorylation. CONCLUSION: Treatment of mice with an AT1R biased ligand, acting via beta-arrestin signalling, is able to induce an increase in cardiac contractility associated with an increase in ventricular myosin light chain-2 phosphorylation. AT1R biased ligands may prove to be a novel inotropic approach in familial DCM. PMID- 26045478 TI - Topological phase transitions of (BixSb1-x)2Se3 alloys by density functional theory. AB - We have performed an ab initio total energy investigation of the topological phase transition, and the electronic properties of topologically protected surface states of (BixSb1-x)2Se3 alloys. In order to provide an accurate alloy concentration for the phase transition, we have considered the special quasirandom structures to describe the alloy system. The trivial -> topological transition concentration was obtained by (i) the calculation of the band gap closing as a function of Bi concentration (x), and (ii) the calculation of the Z2 topological invariant number. We show that there is a topological phase transition, for x around 0.4, verified for both procedures (i) and (ii). We also show that in the concentration range 0.4 < x < 0.7, the alloy does not present any other band at the Fermi level besides the Dirac cone, where the Dirac point is far from the bulk states. This indicates that a possible suppression of the scattering process due to bulk states will occur. PMID- 26045479 TI - A pilot study exploring the effects of musical genres on the depth of general anaesthesia assessed by haemodynamic responses. AB - OBJECTIVES: This pilot study aimed to investigate whether and how music and musical genres may influence the depth of anaesthesia, as measured using changes in arterial blood pressure (ABP), including systolic blood pressure (SBP), and heart rate (HR) across three different surgical time points. METHODS: This work focused on a sample of 12 female cats (Felis catus) that were subjected to an elective ovariohysterectomy (OVH), and three different surgical time points were considered (T1, coeliotomy; T2, ligature placement and transection of the ovarian pedicle; and T3, ligature placement and transection of the uterine body). All of the cats were subjected to stimulation with 2 min segments of three music tracks from different genres (pop [PM], classical [CM] and heavy metal [HM]). At the same time, ABP and HR measurements were obtained using a multi-parametric monitor. For statistical analysis, P values <0.05 were considered significant. RESULTS: For all cats, music exposure induced statistically significant changes in the parameters under study; the same finding was observed for the genre of music. The majority of cats experienced the same variation pattern, with lower values when exposed to CM, intermediate values when exposed to PM and higher values when exposed to HM. CONCLUSIONS AND RELEVANCE: Our results indicate that the development of sensory processing of acoustic stimuli is maintained by cats under general anaesthesia and reveal the influence of music on the autonomous nervous system, as measured using HR and SBP. PMID- 26045480 TI - Computed tomographic findings in cats with mycobacterial infection. AB - OBJECTIVES: The objective of this study was to describe the CT imaging findings associated with confirmed mycobacterial infection in cats. METHODS: CT images from 20 cats with confirmed mycobacterial disease were retrospectively reviewed. Five cats underwent conscious full-body CT in a VetMouseTrap device. All other cats had thoracic CT performed under general anaesthesia, with the addition of CT investigation of the head/neck, abdomen and limbs in some cases. RESULTS: Mycobacterial infection was seen most frequently in adult (mean age 7.4 years; range 0.6-14 years) neutered male cats (11/20). The most common infections were Mycobacterium microti (6/20) and Mycobacterium bovis (6/20). CT abnormalities were most commonly seen in the thorax, consisting of bronchial (9/20), alveolar (8/20), ground glass (6/20) or structured interstitial (15/20) lung patterns, which were often mixed. Tracheobronchial, sternal and cranial mediastinal lymphadenomegaly were common (16/20). Other abnormalities included abdominal (8/13) or peripheral (10/18) lymphadenomegaly, hepatosplenomegaly (7/13), mixed osteolytic/osteoproliferative skeletal lesions (7/20) and cutaneous or subcutaneous soft tissue masses/nodules (4/20). CONCLUSIONS AND RELEVANCE: CT of feline mycobacteriosis shows a wide range of abnormalities, often involving multiple organ systems and mimicking many other feline diseases. Mycobacteriosis should be considered in the differential diagnosis of thoracic, abdominal and skeletal disorders in cats. PMID- 26045481 TI - Rebound hyperglycaemia in diabetic cats. AB - OBJECTIVES: Rebound hyperglycaemia (also termed Somogyi effect) is defined as hyperglycaemia caused by the release of counter-regulatory hormones in response to insulin-induced hypoglycaemia, and is widely believed to be common in diabetic cats. However, studies in human diabetic patients over the past quarter century have rejected the common occurrence of this phenomenon. Therefore, we evaluated the occurrence and prevalence of rebound hyperglycaemia in diabetic cats. METHODS: In a retrospective study, 10,767 blood glucose curves of 55 cats treated with glargine using an intensive blood glucose regulation protocol with a median of five blood glucose measurements per day were evaluated for evidence of rebound hyperglycaemic events, defined in two different ways (with and without an insulin resistance component). RESULTS: While biochemical hypoglycaemia occurred frequently, blood glucose curves consistent with rebound hyperglycaemia with insulin resistance was confined to four single events in four different cats. In 14/55 cats (25%), a median of 1.5% (range 0.32-7.7%) of blood glucose curves were consistent with rebound hyperglycaemia without an insulin resistance component; this represented 0.42% of blood glucose curves in both affected and unaffected cats. CONCLUSIONS AND RELEVANCE: We conclude that despite the frequent occurrence of biochemical hypoglycaemia, rebound hyperglycaemia is rare in cats treated with glargine on a protocol aimed at tight glycaemic control. For glargine-treated cats, insulin dose should not be reduced when there is hyperglycaemia in the absence of biochemical or clinical evidence of hypoglycaemia. PMID- 26045482 TI - New cooperative medical financing policy and hospitalization in rural China: multi-stage cross-sectional surveys. AB - BACKGROUND: In 2003 China began to implement the New-type rural Cooperative Medical System (NCMS). This provided enhanced funding for hospital-based medical services among farmers. We examined self-reported utilization data for evidence of changes following the new policy. METHODS: We conducted a multistage stratified random cluster sampling method for Jiangxi Province, China. Data were collected via five surveys in 2003-4, 2006, 2008, 2010, and 2012. The study compared the rates of hospitalization, early discharge, and hospital avoidance as descriptive indices after weighting the data. Weighted multiple logistic regression analysis was used. Multi-stage cross-sectional analysis was used to explore the reasons for early discharge and for avoiding the hospital during illness. RESULTS: We found that the rates of hospitalization, early discharge and hospital avoidance showed upward, downward and downward changes respectively. The logistic regression analysis showed that, controlling for other factors, the financing level significantly affected the changes of the three indexes (p<0.05). The proportion of finance-related early discharge and hospital avoidance dropped significantly (p<0.05). CONCLUSIONS: NCMS improved the utilization of in-hospital services step by step as time went on, and greatly alleviated cost-related barriers to accessing health services. Even so, because costs continue to restrict access to services we should continue the NCMS policy and improve its guarantee levels. PMID- 26045483 TI - Conduction electron spin resonance in the alpha-Yb1-xFexAlB4 (0 ? x ? 0.50) and alpha-LuAlB4 compounds. AB - beta-YbAlB4 has become one of the most studied heavy fermion systems since its discovery due to its remarkable physical properties. This system is the first reported Yb-based heavy-fermion superconductor (HFS) for which the low-T superconducting state emerges from a non-fermi-liquid (NFL) normal state associated with quantum criticality Nakatsuji et al 2008 Nature 4 603. Additionally, it presents a striking and unprecedented electron spin resonance (ESR) signal which behaves as a conduction electron spin resonance (CESR) at high temperatures and acquires features of the Yb(3+) local moment ESR at low temperatures. The latter, also named Kondo quasiparticles spin resonance (KQSR), has been defined as a 4f-ce strongly coupled ESR mode that behaves as a local probe of the Kondo quasiparticles in a quantum critical regime, Holanda et al 2011 Phys. Rev. Lett. 107 026402. Interestingly, beta-YbAlB4 possesses a previously known structural variant, namely the alpha-YbAlB4, phase which is a paramagnetic Fermi liquid (FL) at low temperatures Macaluso et al 2007 Chem. Mater. 19 1918. However, it has been recently suggested that the alpha-YbAlB4 phase may be tuned to NFL behavior and/or magnetic ordering as the compound is doped with Fe. Here we report ESR studies on the alpha-Yb1-xFexAlB4 (0 ? x ? 0.50) series as well as on the reference compound alpha-LuAlB4. For all measured samples, the observed ESR signal behaves as a CESR in the entire temperature range (10 K ? T ? 300 K) in clear contrast with what has been observed for beta YbAlB4. This striking result indicates that the proximity to a quantum critical point is crucial to the occurrence of a KQSR signal. PMID- 26045484 TI - Exercise ASKARI SERPENT: enabling clinical data collection during exercises and operations to support future contingency planning and assurance of category-based reporting systems. AB - INTRODUCTION: Exercise ASKARI SERPENT (Ex AS) is a British Army exercise that provides primary healthcare (PHC) to Kenyan civilians in support of local health authorities. It is conducted in partnership with the Kenya Defence Force Medical Services (KDFMS). Accurate epidemiological data is critical in planning the exercise and for any future short-notice contingency operations in similar environments. This paper reports epidemiological data for Ex AS using a novel data collection system. METHODS: PHC on Ex AS was delivered by trained and validated combat medical technicians (CMTs) using a set of Read-coded protocols. The CMTs were also directly supported and supervised by medical officers and nurses. RESULTS: A total of 3093 consultations were conducted over a 16-day period. Of these, 2707 (87.5%) consultations fell within the remit of the CMT protocols, with only 386 consultations (12.5%) being conducted exclusively by the medical officers or nurses. DISCUSSION: A Read-coded matrix built on CMT protocols is a simple and useful tool, particularly in civilian populations, for collecting morbidity data with the vast majority of conditions accounted for in the protocols. It is anticipated that such a system can better inform training, manning, medical material and pharmaceutical procurement than current category based morbidity surveillance systems such as EPINATO (NATO epidemiological data). There is clear advantage to directly linking data capture to treatment algorithms. Accuracy, both in terms of numbers and condition, is likely improved. Data is also captured contemporaneously rather than after indeterminate time. Read coding has the added benefit of being an established electronic standard. In addition, the system would support traditional reporting methods such as EPINATO by providing increased assurance. PMID- 26045485 TI - Upper extremity deep vein thrombosis in a military patient. AB - We describe the case of a 23-year-old serviceman on overseas deployment who presented with a painful, swollen arm. Investigations showed an upper extremity deep vein thrombosis (UEDVT) of the right arm with an associated asymptomatic pulmonary embolism, which was treated with warfarin anticoagulation. Further investigation identified positional obstruction at the thoracic outlet, and the patient was diagnosed with Paget-Schroetter syndrome. He underwent elective resection of the first rib, and has now returned to normal duties. After review of the literature on UEDVT, it is suggested that in this military patient, the occurrence of an anatomical variant put him at risk of upper limb venous thrombosis, which was probably potentiated by the occupational factor of carrying a rifle. The external compression of the subclavian vein from the rifle butt and hypertrophied muscles, in addition to the anatomical variation, caused repetitive microtrauma of the vessel intima, which precipitated venous thrombosis. PMID- 26045488 TI - Double-orifice mitral valve treated by percutaneous balloon valvuloplasty. AB - Double-orifice mitral valve is an rare anomaly characterized by a mitral valve with a single fibrous annulus and 2 orifices that open into the left ventricle. It is often associated with other congenital anomalies, most commonly atrioventricular canal defects, and rarely associated with a stenotic or regurgitant mitral valve. A patient who was diagnosed with congenital double orifice mitral valve with severe mitral stenosis was treated successfully by percutaneous balloon mitral valvotomy rather than the conventional open surgical approach, demonstrating the utility of percutaneous correction of this anomaly. PMID- 26045489 TI - Ruptured intracardiac hydatid cyst presenting as acute coronary syndrome. AB - Hydatid disease is a parasitic infection caused by the larvae of Echinococcus granulosus, which is still endemic in many developing countries. Cardiac involvement is rare but potentially very serious on account of various clinical presentations and nonspecific symptoms that occasionally mimic acute coronary syndrome. We describe a case of ruptured left ventricular hydatid cyst presenting as acute inferolateral myocardial infarction with electrocardiographic changes. Because coronary angiography revealed normal coronary arteries, the final diagnosis was made on the basis of echocardiography and magnetic resonance imaging. On-pump surgical resection followed by albendazole therapy yielded an excellent outcome. PMID- 26045490 TI - Cardiac herniation after left intrapericardial pneumonectomy. AB - Postoperative cardiac herniation is a rare fatal complication that requires urgent surgical reduction and closure of the pericardial defect. Cardiac herniation occurred 8 h after a left intrapericardial pneumonectomy. Although the patient was completely asymptomatic, acute hemodynamic failure with electrocardiographic changes occurred. Chest radiographs were not helpful in showing cardiac herniation. The patient was immediately brought back to the operating room. Cardiac herniation was found to be caused by a pericardial defect, and the heart was strangulated at the atrioventricular groove level. The heart was repositioned, but hemodynamic instability inherent to ischemic strangulation lesions persisted despite extracorporeal membrane oxygenation. PMID- 26045491 TI - Large tracheobronchial fistula due to esophageal stent migration: Let it be! AB - We report tracheal-bronchial migration of a covered esophageal self-expanding metal stent used to relieve dysphagia in a patient with advanced esophageal cancer. The stent eroded the trachea and completely occluded the main left bronchus. Surgery was contraindicated due to her poor clinical condition, and insertion of another stent in the trachea, esophagus, or both was contraindicated due to extension of the fistula. Esophageal exclusion with a combination of cervical esophagostomy and an enteral feeding tube was the only feasible treatment to minimize spoilage by aspirated saliva and provide enteral nutrition. PMID- 26045492 TI - Chronic restraint-induced stress has little modifying effect on radiation hematopoietic toxicity in mice. AB - Both radiation and stresses cause detrimental effects on humans. Besides possible health effects resulting directly from radiation exposure, the nuclear plant accident is a cause of social psychological stresses. A recent study showed that chronic restraint-induced stresses (CRIS) attenuated Trp53 functions and increased carcinogenesis susceptibility of Trp53-heterozygous mice to total-body X-irradiation (TBXI), having a big impact on the academic world and a sensational effect on the public, especially the residents living in radioactively contaminated areas. It is important to investigate the possible modification effects from CRIS on radiation-induced health consequences in Trp53 wild-type (Trp53wt) animals. Prior to a carcinogenesis study, effects of TBXI on the hematopoietic system under CRIS were investigated in terms of hematological abnormality in the peripheral blood and residual damage in the bone marrow erythrocytes using a mouse restraint model. Five-week-old male Trp53wt C57BL/6J mice were restrained 6 h per day for 28 consecutive days, and TBXI (4 Gy) was given on the 8th day. Results showed that CRIS alone induced a marked decrease in the red blood cell (RBC) and the white blood cell (WBC) count, while TBXI caused significantly lower counts of RBCs, WBCs and blood platelets, and a lower concentration of hemoglobin regardless of CRIS. CRIS alone did not show any significant effect on erythrocyte proliferation and on induction of micronucleated erythrocytes, whereas TBXI markedly inhibited erythrocyte proliferation and induced a significant increase in the incidences of micronucleated erythrocytes, regardless of CRIS. These findings suggest that CRIS does not have a significant impact on radiation-induced detrimental effects on the hematopoietic system in Trp53wt mice. PMID- 26045493 TI - Reply to Turin et al.: Vibrational theory of olfaction is implausible. PMID- 26045494 TI - Plausibility of the vibrational theory of olfaction. PMID- 26045495 TI - Antimicrobial use in aquaculture: Some complementing facts. PMID- 26045496 TI - Two-level inhibition of galK expression by Spot 42: Degradation of mRNA mK2 and enhanced transcription termination before the galK gene. AB - The Escherichia coli gal operon has the structure Pgal-galE-galT-galK-galM. During early log growth, a gradient in gene expression, named type 2 polarity, is established, as follows: galE > galT > galK > galM. However, during late-log growth, type 1 polarity is established in which galK is greater than galT, as follows: galE > galK > galT > galM. We found that type 2 polarity occurs as a result of the down-regulation of galK, which is caused by two different molecular mechanisms: Spot 42-mediated degradation of the galK-specific mRNA, mK2, and Spot 42-mediated Rho-dependent transcription termination at the end of galT. Because the concentration of Spot 42 drops during the transition period of the polarity type switch, these results demonstrate that type 1 polarity is the result of alleviation of Spot 42-mediated galK down-regulation. Because the Spot 42-binding site overlaps with a putative Rho-binding site, a molecular mechanism is proposed to explain how Spot 42, possibly with Hfq, enhances Rho-mediated transcription termination at the end of galT. PMID- 26045498 TI - Correction for Chow et al., CDK5 activator protein p25 preferentially binds and activates GSK3beta. PMID- 26045497 TI - Ionic imbalance, in addition to molecular crowding, abates cytoskeletal dynamics and vesicle motility during hypertonic stress. AB - Cell volume homeostasis is vital for the maintenance of optimal protein density and cellular function. Numerous mammalian cell types are routinely exposed to acute hypertonic challenge and shrink. Molecular crowding modifies biochemical reaction rates and decreases macromolecule diffusion. Cell volume is restored rapidly by ion influx but at the expense of elevated intracellular sodium and chloride levels that persist long after challenge. Although recent studies have highlighted the role of molecular crowding on the effects of hypertonicity, the effects of ionic imbalance on cellular trafficking dynamics in living cells are largely unexplored. By tracking distinct fluorescently labeled endosome/vesicle populations by live-cell imaging, we show that vesicle motility is reduced dramatically in a variety of cell types at the onset of hypertonic challenge. Live-cell imaging of actin and tubulin revealed similar arrested microfilament motility upon challenge. Vesicle motility recovered long after cell volume, a process that required functional regulatory volume increase and was accelerated by a return of extracellular osmolality to isosmotic levels. This delay suggests that, although volume-induced molecular crowding contributes to trafficking defects, it alone cannot explain the observed effects. Using fluorescent indicators and FRET-based probes, we found that intracellular ATP abundance and mitochondrial potential were reduced by hypertonicity and recovered after longer periods of time. Similar to the effects of osmotic challenge, isovolumetric elevation of intracellular chloride concentration by ionophores transiently decreased ATP production by mitochondria and abated microfilament and vesicle motility. These data illustrate how perturbed ionic balance, in addition to molecular crowding, affects membrane trafficking. PMID- 26045499 TI - A Thematic Analysis of the Motivation Behind Sexual Homicide From the Perspective of the Killer. AB - Using thematic analysis, this study explores the motivation to commit sexual homicide from the perspective of the perpetrator. In the process, it revisits motivational models and offender typologies that have been put forward to explain such offenses. From the homicide narratives of eight sexual homicide offenders detained in a high security hospital in the United Kingdom, four themes were found which appeared significant in terms of understanding the offenses committed. These themes were labeled as follows: (a) avenging sexual abuse, (b) events leading to a catathymic reaction, (c) homicidal impulse, and (d) emotional loneliness. Although these findings are not inconsistent with previous research, we argue that the current literature fails to capture the complexity associated with these offenses. We also argue that the context or situation in which sexual homicide occurs is a crucial feature of the offense, and one which has not been adequately taken into account by motivational models. PMID- 26045500 TI - Up for Grabs? Sexual Objectification as a Mediator Between Women's Alcohol Use and Sexual Victimization. AB - Sexual objectification, the tendency to reduce women to their bodies, body parts, or sexual functions for use by others, has been theorized to set the stage for more severe acts of violence but has been largely absent from the existing sexual victimization literature. The purpose of this study was to explore the role of sexual objectification in mediating the well-established link between women's alcohol use and sexual victimization. A large sample of undergraduate women ( N = 673) reported their alcohol use (frequency and quantity), experiences of sexual objectification (body evaluation and unwanted explicit sexual advances), and sexual victimization. Results indicated positive bivariate correlations among all study variables. Path analyses showed that mild forms of sexual objectification (body evaluation) mediated the link between the frequency of alcohol use and more extreme forms of sexual objectification (unwanted advances). Furthermore, the combined effect of sexual objectification (body evaluation and unwanted advances) mediated the link between alcohol use (frequency and quantity) and sexual victimization. The current findings are among the first to evaluate sexual objectification as a mechanism in the link between alcohol use and sexual victimization. Results suggest that efforts to prevent alcohol-related sexual violence may benefit from addressing sexual objectification. PMID- 26045501 TI - More Than a Magazine: Exploring the Links Between Lads' Mags, Rape Myth Acceptance, and Rape Proclivity. AB - Exposure to some magazines aimed at young male readers- lads' mags-has recently been associated with behaviors and attitudes that are derogatory toward women, including sexual violence. In the present study, a group of Spanish adult men was exposed to the covers of a lads' mag while a second group was exposed to the covers of a neutral magazine. Results showed that, compared with participants in the second group, participants who were exposed to covers of lads' mags who also showed high rape myth acceptance and legitimized the consumption of such magazines reported higher rape proclivity in a hypothetical situation. These findings suggest the need to further explore the possible detrimental effects of some sexualized media that are widely accepted in many Western countries. PMID- 26045502 TI - A potential pitfall of the modified 12 lead electrocardiogram (Mason-Likar modification) in catheter ablation of idiopathic ventricular arrhythmias originating from the outflow tract. AB - AIMS: The Mason-Likar modified electrocardiogram (ML-ECG) can be interchanged with standard 12 lead ECG electrode positions (standard ECG) without affecting the diagnostic interpretation during sinus rhythm, but the morphological differences during ventricular arrhythmias have not been sufficiently evaluated. This study aimed to elucidate the morphological changes in the ML-ECG precordial leads. METHODS AND RESULTS: In 53 consecutive patients with premature ventricular contractions predicted to originate from the outflow tract (OT-PVCs), the arrhythmias were analysed by those two ECG methods. The OT-PVC origin sites, which were predicted by currently published criteria with the respective ECG methods prior to catheter ablation, were compared with the successful ablation sites. Compared with the standard-ECG, S-waves in the ML-ECG became shallower in leads V1-4 (P < 0.05 in lead V1; P < 0.001 in leads V2-4), and pseudo-R-waves in lead V1 appeared in seven patients. The precordial leads transition zone shifted counter-clockwise in 18 patients in the ML-ECG. In leads I and aVL, the negative deflection amplitudes of the ML-ECG were greater than those of the standard ECG (P < 0.001), and polarity reversals in lead I appeared in 18 patients. The R-wave amplitudes in all ML-ECG inferior leads were greater than those in the standard ECG leads (all for P < 0.001). Those changes had an effect on the diagnostic indexes for the localization, and the specificity of the criteria for the ML-ECG was poorer than that for the standard-ECG. CONCLUSION: Great differences were found between those two ECG methods. Predicting OT-PVC origins by diagnostic criteria with the ML-ECG might result in a misdiagnosis and inefficient ablation. PMID- 26045503 TI - Recent scientific documents from the European Heart Rhythm Association (EHRA). PMID- 26045504 TI - Adherence to treatment with non-vitamin K antagonist anticoagulants: once- vs. twice-daily regimens. PMID- 26045505 TI - Medication adherence and non-vitamin K antagonist oral anticoagulants: what do we really know? PMID- 26045506 TI - Non-vitamin K antagonist oral anticoagulants (NOAC): considerations on once- vs. twice-daily regimens and their potential impact on medication adherence. PMID- 26045507 TI - Season and preterm birth in Norway: A cautionary tale. AB - BACKGROUND: Preterm birth is a common, costly and dangerous pregnancy complication. Seasonality of risk would suggest modifiable causes. METHODS: We examine seasonal effects on preterm birth, using data from the Medical Birth Registry of Norway (2,321,652 births), and show that results based on births are misleading and a fetuses-at-risk approach is essential. In our harmonic regression Cox proportional hazards model we consider fetal risk of birth between 22 and 37 completed weeks of gestation. We examine effects of both day of year of conception (for early effects) and day of ongoing gestation (for seasonal effects on labour onset) as modifiers of gestational-age-based risk. RESULTS: Naive analysis of preterm rates across days of birth shows compelling evidence for seasonality (P < 10(-152)). However, the reconstructed numbers of conceptions also vary with season (P < 10(-307)), confounding results by inducing seasonal variation in the age distribution of the fetal population at risk. When we instead properly treat fetuses as the individuals at risk, restrict analysis to pregnancies with relatively accurate ultrasound-based assessment of gestational age (available since 1998) and adjust for socio-demographic factors and maternal smoking, we find modest effects of both time of year of conception and time of year at risk, with peaks for early preterm near early January and early July. CONCLUSIONS: Analyses of seasonal effects on preterm birth are demonstrably vulnerable to confounding by seasonality of conception, measurement error in conception dating, and socio-demographic factors. The seasonal variation based on fetuses reveals two peaks for early preterm, coinciding with New Year's Day and the early July beginning of Norway's summer break, and may simply reflect a holiday-related pattern of unintended conception. PMID- 26045509 TI - Cohort Profile: The Inflammatory Bowel Disease South Limburg Cohort (IBDSL). PMID- 26045508 TI - Maternal body mass index during early pregnancy, gestational weight gain, and risk of autism spectrum disorders: Results from a Swedish total population and discordant sibling study. AB - BACKGROUND: Prenatal environmental factors such as maternal adiposity may influence the risk of offspring autism spectrum disorders (ASD), though current evidence is inconsistent. The objective of this study was to assess the relationship of parental BMI and gestational weight gain (GWG) with risk of offspring ASD in a population-based cohort study using family-based study designs. METHODS: The cohort was based in Stockholm County, Sweden, including 333,057 individuals born 1984-2007, of whom 6420 were diagnosed with an ASD. We evaluated maternal body mass index (BMI) at first antenatal visit, GWG and paternal BMI at the time of conscription into the Swedish military as exposures using general estimating equation (GEE) models with logit link. RESULTS: At the population level, maternal overweight/obesity was associated with increased risk of offspring ASD [odds ratio (OR)25 <= BMI < 30 1.31, 95% confidence interval = 1.21-1.41; ORBMI >= 30 1.94, 1.72-2.17], as was paternal underweight (ORBMI < 18.5, 1.19, 1.06-1.33) and obesity (ORBMI >= 30 1.47, 1.12-1.92) in mutually adjusted models. However, in matched sibling analyses, the relationship between elevated maternal BMI and ASD risk was not apparent. GWG had a U-shaped association with offspring ASD at the population level (ORinsufficient 1.22, 1.07 1.40; ORexcessive 1.23, 1.08-1.40). Matched sibling analyses were suggestive of elevated risk with excessive GWG (ORinsufficient 1.12, 0.68-1.84; ORexcessive 1.48, 0.93-2.38). CONCLUSIONS: Whereas population-level results suggested that maternal BMI was associated with ASD, sibling analyses and paternal BMI analyses indicate that maternal BMI may also be a proxy marker for other familial risk factors. Evidence is stronger for a direct link between GWG and ASD risk. PMID- 26045510 TI - Do questions help? The impact of audience response systems on medical student learning: a randomised controlled trial. AB - BACKGROUND: Audience response systems (ARSs) are electronic devices that allow educators to pose questions during lectures and receive immediate feedback on student knowledge. The current literature on the effectiveness of ARSs is contradictory, and their impact on student learning remains unclear. OBJECTIVES: This randomised controlled trial was designed to isolate the impact of ARSs on student learning and students' perception of ARSs during a lecture. METHODS: First-year medical student volunteers at Johns Hopkins were randomly assigned to either (i) watch a recorded lecture on an unfamiliar topic in which three ARS questions were embedded or (ii) watch the same lecture without the ARS questions. Immediately after the lecture on 5 June 2012, and again 2 weeks later, both groups were asked to complete a questionnaire to assess their knowledge of the lecture content and satisfaction with the learning experience. RESULTS: 92 students participated. The mean (95% CI) initial knowledge assessment score was 7.63 (7.17 to 8.09) for the ARS group (N=45) and 6.39 (5.81 to 6.97) for the control group (N=47), p=0.001. Similarly, the second knowledge assessment mean score was 6.95 (6.38 to 7.52) for the ARS group and 5.88 (5.29 to 6.47) for the control group, p=0.001. The ARS group also reported higher levels of engagement and enjoyment. CONCLUSIONS: Embedding three ARS questions within a 30 min lecture increased students' knowledge immediately after the lecture and 2 weeks later. We hypothesise that this increase was due to forced information retrieval by students during the learning process, a form of the testing effect. PMID- 26045511 TI - Combined administration of buprenorphine and naltrexone produces antidepressant like effects in mice. AB - Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focused on the development of kappa opioid receptor (kappa-receptor) antagonists. Buprenorphine acts as a partial u-opioid receptor agonist and a kappa-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of u-opioid receptors will be reduced and the kappa-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) functions as a short-acting kappa-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm, and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1 mg/kg) with naltrexone (1 mg/kg) in CD-1 mice produced an antidepressant-like response in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression. PMID- 26045513 TI - Chronic kidney disease and worsening renal function in acute heart failure: different phenotypes with similar prognostic impact? AB - Nearly a third of patients with acute heart failure experience concomitant renal dysfunction. This condition is often associated with increased costs of care, length of hospitalisation and high mortality. Although the clinical impact of chronic kidney disease (CKD) has been well established, the exact clinical significance of worsening renal function (WRF) during the acute and post hospitalisation phases is not completely understood. Therefore, it is still unclear which of the common laboratory markers are able to identify WRF at an early stage. Recent studies comparing CKD with WRF showed contradictory results; this could depend on a different WRF definition, clinical characteristics, haemodynamic disorders and the presence of prior renal dysfunction in the population enrolled. The current definition of acute cardiorenal syndrome focuses on both the heart and kidney but it lacks precise laboratory marker cut-offs and a specific diagnostic approach. WRF and CKD could represent different pathophysiological mechanisms in the setting of acute heart failure; the traditional view includes reduced cardiac output with systemic and renal vasoconstriction. Nevertheless, it has become a mixed model that encompasses both forward and backward haemodynamic dysfunction. Increased central venous pressure, renal congestion with tubular obliteration, tubulo-glomerular feedback and increased abdominal pressure are all potential additional contributors. The impact of WRF on patients who experience preserved renal function and individuals affected with CKD is currently unknown. Therefore it is extremely important to understand the origins, the clinical significance and the prognostic impact of WRF on CKD. PMID- 26045512 TI - Secondary forms of Takotsubo cardiomyopathy: A whole different prognosis. AB - BACKGROUND: Takotsubo syndrome (TKS) usually mimics an acute coronary syndrome. However, several clinical forms have been reported. Our aim was to assess if different stressful triggers had prognostic influence on TKS, and to establish a working classification. METHODS: We performed an analysis including patients with TKS between 2003-2013 from our prospective local database and the RETAKO National Registry, fulfilling Mayo criteria. Patients were divided in two groups regarding their potential triggers: (a) none/psychic stress as 'primary forms' and (b) physical factors (asthma, surgery, trauma, etc.) as 'secondary forms'. RESULTS: Finally, 328 patients were included, 90.2% women, with a mean age of 69.7 years. Patients were divided into primary TKS (n=265) and 63 secondary TKS groups. Age, gender, previous functional class and cardiovascular risk profile displayed no differences between groups before admission. However, primary-TKS patients suffered a main complaint of chest pain (89.4% vs 50.7%, p<0.0001) with frequent vegetative symptoms. Regarding treatment before admission, there were no differences either. During admission, differences were related to more intensive antithrombotic and anxiolytic drug use in the primary TKS group. Inotropic and mechanical ventilation use was higher in the secondary cohort. After discharge, a more frequent prescription of beta-blockers and statins in primary-TKS patients was seen. Secondary forms displayed more in-hospital stay and evolutive complications: death (hazard ratio (HR): 3.41; 95% confidence interval (CI): 1.14 10.16, p=0.02), combined event variable (MACE) (HR: 1.61; 95% CI: 1.01-2.6, p=0.04) and recurrences (HR: 1.85; 95% CI: 1.06-3.22, p=0.02). CONCLUSION: Secondary TKS could present or mark worse short and long-term prognoses in terms of mortality, recurrences and readmissions. We propose a simple working nomenclature for TKS. PMID- 26045514 TI - Capturing diagnosis-timing in ICD-coded hospital data: recommendations from the WHO ICD-11 topic advisory group on quality and safety. AB - PURPOSE: To develop a consensus opinion regarding capturing diagnosis-timing in coded hospital data. METHODS: As part of the World Health Organization International Classification of Diseases-11th Revision initiative, the Quality and Safety Topic Advisory Group is charged with enhancing the capture of quality and patient safety information in morbidity data sets. One such feature is a diagnosis-timing flag. The Group has undertaken a narrative literature review, scanned national experiences focusing on countries currently using timing flags, and held a series of meetings to derive formal recommendations regarding diagnosis-timing reporting. RESULTS: The completeness of diagnosis-timing reporting continues to improve with experience and use; studies indicate that it enhances risk-adjustment and may have a substantial impact on hospital performance estimates, especially for conditions/procedures that involve acutely ill patients. However, studies suggest that its reliability varies, is better for surgical than medical patients (kappa in hip fracture patients of 0.7-1.0 versus kappa in pneumonia of 0.2-0.6) and is dependent on coder training and setting. It may allow simpler and more precise specification of quality indicators. CONCLUSIONS: As the evidence indicates that a diagnosis-timing flag improves the ability of routinely collected, coded hospital data to support outcomes research and the development of quality and safety indicators, the Group recommends that a classification of 'arising after admission' (yes/no), with permitted designations of 'unknown or clinically undetermined', will facilitate coding while providing flexibility when there is uncertainty. Clear coding standards and guidelines with ongoing coder education will be necessary to ensure reliability of the diagnosis timing flag. PMID- 26045516 TI - Transient osteoporosis of the hip in a non-pregnant woman. AB - Transient osteoporosis of the hip is a rare, self-limiting condition, occurring most commonly in middle-aged men, but also sometimes in women, usually in late pregnancy. It is characterised by gradual onset of hip pain aggravated by weight bearing without any associated history of trauma and systemic illness. It is usually of unknown aetiology, but pregnancy is a recognised risk factor for women. Other conditions that can mimic transient osteoporosis of the hip on MRI are osteonecrosis, osteomyelitis and neoplasms. We present a case of a 38-year old non-pregnant woman with transient osteoporosis of the hip, managed conservatively, leading to a full recovery. Treatment is conservative, including protected weight bearing, physical therapy and non-steroidal analgesics. The patient was completely painless and symptom free at 2-year follow-up. PMID- 26045515 TI - Arterial Stiffness as a Biomarker of Radiation-Induced Carotid Atherosclerosis. AB - Arterial stiffness is thought to be a precursor to atherosclerosis. Conventional arterial stiffness parameters as potential biomarkers of radiation-induced damage were investigated. Patients with head and neck cancer treated with radiotherapy >=2 years previously to one side of the neck were included. The unirradiated side was the internal control. Beta stiffness index (B) and elastic modulus (Ep) were used to assess arterial stiffness and were measured in proximal, mid, and distal common carotid artery (CCA) and compared with the corresponding unirradiated segments. Fifty patients (68% male; median age 58 years; interquartile range 50 62) were included. Mean +/- standard deviation maximum doses to irradiated and unirradiated arteries were 53 +/- 13 and 1.9 +/- 3.7 Gy, respectively. Differences in B were not significant. Significant differences in Ep were demonstrated-proximal CCA: 1301 +/- 1223 versus 801 +/- 492 (P < .0001), mid CCA: 1064 +/- 818 versus 935.5 +/- 793 (P < .0001), and distal CCA: 1267 +/- 1084 versus 775.3 +/- 551.9 (P < .0001). Surgery had no impact on arterial stiffness. Arterial stiffness is increased in irradiated arteries, in keeping with radiation induced damage. Prospective data may show an association between arterial stiffness and atherosclerosis in this setting. PMID- 26045517 TI - Thoracic outlet syndrome secondary to a mid-clavicle malunion. AB - A 22-year-old man presented with a painful 'clunking' sensation in the right mid clavicle, and pain and dysaesthesia along the medial aspect of his right arm and hand. Three months earlier, he had been involved in a vehicle accident and sustained a right clavicle fracture. He had a large step off of the right clavicle with a medialisation of the right shoulder. At 90 degrees abduction in external rotation of both shoulders he developed pain, paraesthesia and disappearance of the right radial artery pulsation. CT of the right shoulder in the neutral position demonstrated the clavicle-to-first rib distance of 5.5 mm, MRI showed the clavicular bone callus had a mass effect with effacement of anterior fat adjacent to the brachial plexus cords. He was diagnosed with thoracic outlet syndrome and underwent a corrective right clavicle osteotomy with the use of an AcuMed superior clavicle plate. PMID- 26045518 TI - Unusual association of keratoconus with situs inversus and micronystagmus. AB - Keratoconus is a bilateral non-inflammatory ectasia of the cornea and the presentation is usually as an isolated condition. A few ocular and a number of systemic associations have been described. Situs inversus of retinal vessels is a rare developmental anomaly due to anomalous insertion of optic stalk into the optic vesicle. In this case report, we describe an unusual association of keratoconus with situs inversus and micronystagmus in a young man. An additional feature, a blue dot cataract, was also present. To the best of our knowledge, such a conglomeration of multiple ocular features has not been described previously. PMID- 26045519 TI - Ameloblastic fibro-odontoma. AB - Ameloblastic fibro-odontoma is a slow growing, benign, expansile epithelial odontogenic tumour with odontogenic mesenchyme, accounting for 0.3-1.7% of jaw tumours, signifying its rarity. The WHO defines it as "a neoplasm composed of proliferating odontogenic epithelium in a cellular ectomesenchymal tissue with varying degrees of inductive changes and dental hard tissue formation". We report a case of an 11-year-old girl who presented to the Department of Maxillo-Facial Medicine and Radiology for the evaluation of a swelling in the left posterior mandible. Her clinical chart and investigations unveiled it as ameloblastic fibro odontoma. After a promising presurgical evaluation, the lesion was enucleated using an intraoral approach followed by osteoplasty. Osteogenesis was attained despite of any definitive techniques to promote bone regeneration. Immediate postoperative inter-maxillary fixation was performed to prevent pathological fractures for a period of 3 weeks. In an 8-month follow-up, no untoward complications were noticed. PMID- 26045521 TI - Presumed latent ocular tuberculosis diagnosed with the positive quantiFERON-TB Gold In-Tube Test in a HLA-A29-positive patient. AB - A 59-year-old Hispanic woman presented with a 3-year history of floaters associated with bilateral reduced visual acuity. Her best-corrected visual acuity (BCVA) was 20/40. Both anterior segments were without inflammation, but fundoscopy showed mild vitreous inflammation and multiple inflammatory choroidal lesions. Tests for inflammatory and infectious diseases were negative except for human leucocyte antigen A29. The patient was diagnosed with birdshot choroidoretinopathy, and treatment was initiated with cyclosporine A 2.5 mg/kg/day. One year after treatment, the patient reported systemic symptoms with no improvement in visual acuity. Fundus findings remained with vitreal inflammation. QuantiFERON-TB Gold In-Tube Test was positive, and a diagnosis of presumed latent ocular tuberculosis (TB) was made. We initiated anti-TB treatment for 9 months. At 6 months of anti-TB therapy, there was no active inflammation. The patient was followed for 2 years with no medications and no active inflammation. Her final BCVA was 20/25. PMID- 26045520 TI - Lupus or syphilis? That is the question! AB - A 47-year-old man presented with fever, a maculopapular rash of the palms and soles, muscular weakness, weight loss, faecal incontinence, urinary retention and mental confusion with 1 month of evolution. Neurological examination revealed paraparesis and tactile hypoesthesia with distal predominance, and no sensory level. Laboratory investigations revealed a venereal disease research laboratory (VDRL) titre of 1/4 and Treponema pallidum haemagluttin antigen (TPHA) of 1/640, positive anti-nuclear antibodies of 1/640 and nephrotic proteinuria (3.6 g/24 h). Lumbar puncture excluded neurosyphilis, due to the absence of TPHA and VDRL. The diagnosis of systemic lupus erythematosus (SLE) was established and even though transverse myelitis as a rare presentation of SLE has a poor outcome, the patient improved with cyclophosphamide, high-dose corticosteroids and hydroxychloroquine. A diagnosis of secondary syphilis was also established and the patient was treated with intramuscular benzathine penicillin G. PMID- 26045522 TI - Peripheral ameloblastoma of gingiva with cytokeratin 19 analysis. AB - A 42-year-old woman presented with a gingival mass in the lingual vestibule of the mandibular incisor premolar region. On intraoral examination, the swelling was non-tender and firm. Surgical excision was carried out and subsequent histopathological examination revealed areas resembling ameloblastoma-like and basaloid areas with atypical features suggestive of basal cell carcinoma. Immunohistochemical analysis was carried out to ascertain the origin of the lesion. PMID- 26045523 TI - Macrofocal multiple myeloma with frontal plasmacytoma. PMID- 26045524 TI - The impacts of job loss and job recovery on self-rated health: testing the mediating role of financial strain and income. AB - BACKGROUND: Is regaining a job sufficient to reverse the harmful impacts on health of job loss during the Great Recession? We tested whether unemployed persons who found work within 1 year of job loss experienced a full recovery of their health. Additionally, we tested the mediating role of financial strain and household income. METHODS: Linear regression models were used to assess the effects of job loss and recovery on self-rated health using the longitudinal EU SILC, covering individuals from 27 European countries. We constructed a baseline of employed persons (n = 70 611) in year 2007. We evaluated income and financial strain as potential mediating factors. RESULTS: Job loss was associated with worse self-rated health in both men (beta = 0.12, 95%CI: 0.09-0.15) and women (beta = 0.13, 95%CI: 0.10-0.16). Financial strain explains about one-third of the association between job loss and health, but income did not mediate this relation. Women who regained employment within 1 year after job loss were found to be similarly healthy to those who did not lose jobs. In contrast, men whose employment recovered had an enduring health disadvantage compared with those who had not lost jobs (beta = 0.11, 95%CI: 0.05-0.16). Unemployment cash benefits mitigated financial strain but were too low to substantially reduce perceived financial strain among men. CONCLUSIONS: Men and women's health appears to suffer equally from job loss but differs in recovery. For men, employment recovery was insufficient to alleviate financial strain and associated health consequences, whereas in women regaining employment leads to health recovery. PMID- 26045525 TI - Growing inequalities in child injury deaths in Europe. AB - In this short report, we describe and compare mortality data for injuries in children aged <15 years in the WHO European region as estimated by the WHO Global Health Estimates for 2000 and 2011. Child injury deaths have decreased overall. Mortality rate ratios between low- and middle-income countries (LMIC) and high income countries in the region show an increase in relative inequalities for childhood deaths from unintentional injuries and a narrowing from intentional injury. This growing inequality in unintentional injury is a public health concern and calls for renewed efforts to reduce childhood injuries in LMIC the region. PMID- 26045526 TI - Children's snack consumption: role of parents, peers and child snack-purchasing behaviour. Results from the INPACT study. AB - BACKGROUND: Parents and peers are both likely to influence children's dietary behaviour. However, their actual influence may depend on the age and life stage of the individual child. Therefore, this study examined the influence of parents (home snack availability and consumption rules) and peers on 11-year-old children's snack consumption, and whether these associations were mediated by children's snack-purchasing behaviour. It was hypothesized that children are more likely to buy unhealthy snacks if these are not always available at home, if restrictive rules apply to their consumption and if a child is sensitive to peer influence. It was also assumed that children who buy snacks out of their pocket money would consume more snacks. METHODS: Data were taken from 1203 parent-child dyads who completed a questionnaire in the INPACT study (IVO Physical Activity Child cohorT). Multivariable regression models were used to (i) analyze associations between children's consumption and parents' and peers' influence and (ii) determine whether these associations were mediated by children's snack purchasing behaviour. RESULTS: Of the parental factors, home availability of snacks was associated with higher snack consumption (B = 1.03, P < 0.05). Parental factors and children's snack-purchasing behaviour were not associated. Children who were sensitive to peer influence consumed more snacks (B = 3c07, P < 0.01) and bought more snacks out of their pocket money (odds ratio 3.27, P < 0.0.01). Children's snack-purchasing behaviour explained part (8.6%) of the association between peer influence and children's snack consumption. CONCLUSION: As these findings indicate that both parents and peers influence children's snack consumption, health promotion may benefit from targeting the broader social environment. PMID- 26045527 TI - The DSM-5 and the diagnosis of substance use disorders: Reflection about validity of the new criteria and possible 'missing pieces' in the puzzle. PMID- 26045528 TI - Identification of novel mutations associated with clofazimine resistance in Mycobacterium tuberculosis. AB - OBJECTIVES: Although clofazimine has been traditionally used to treat leprosy, there is recent interest in using clofazimine for the treatment of MDR-TB and drug-susceptible TB. However, the mechanisms of resistance to clofazimine are poorly understood. Here, we investigated the molecular basis of clofazimine resistance using resistant mutants isolated in vitro. METHODS: We isolated 96 mutants of Mycobacterium tuberculosis resistant to clofazimine and performed WGS and Sanger sequencing to identify possible mutations associated with clofazimine resistance. RESULTS: We found that 97% (93/96) of clofazimine-resistant mutants had a mutation in rv0678 encoding a transcription repressor for efflux pump MmpL5. Two mutational hot spots at nucleotide positions 193 and 466 in rv0678 accounted for 43.8% (42/96) and 11.5% (11/96) of the mutations, respectively. The previously reported A202G mutation (S68G) in rv0678 occurred less frequently, in 5 of 96 mutants. The remaining 34 mutations were scattered along the entire rv0678 gene. We discovered two new genes (rv1979c and rv2535c) associated with clofazimine resistance in mutants without rv0678 mutations. CONCLUSIONS: Mutations in rv0678 are a major mechanism of clofazimine resistance. Our findings provide useful information for the design of new molecular tests for rapid detection of clofazimine resistance. Further studies are needed to address the role of rv1979c and rv2535c in clofazimine resistance and mechanisms of action. PMID- 26045529 TI - Molecular characterization of MRSA isolates bracketing the current EUCAST ceftaroline-susceptible breakpoint for Staphylococcus aureus: the role of PBP2a in the activity of ceftaroline. AB - OBJECTIVES: The objectives of this study were to characterize contemporary MRSA isolates and understand the prevalence and impact of sequence variability in PBP2a on ceftaroline susceptibility. METHODS: A total of 184 MRSA isolates collected from 28 countries were collected and characterized. RESULTS: WT PBP2a proteins were found in MRSA distributed evenly over the ceftaroline MIC range of 0.5-2 mg/L (n=56). PBP2a variations found in 124 isolates fell into two categories: (i) 12 isolates contained a substitution in the transpeptidase pocket located in the penicillin-binding domain and exhibited significantly decreased ceftaroline susceptibility (typically 8 mg/L); and (ii) isolates with substitutions in the non-penicillin-binding domain (nPBD) in a region proposed to be functionally important for cell wall biogenesis. The majority (71%) of isolates containing only nPBD variations were inhibited by 2 mg/L ceftaroline, 23% by <=1 mg/L and 6% by 4 mg/L. These data suggest that the WT MRSA distribution extends beyond the current EUCAST and CLSI susceptible breakpoints and includes isolates inhibited by 2 mg/L ceftaroline. SCCmec type IV was the predominant type in the ceftaroline-susceptible population (68%), whereas it only represented 6% of the non-susceptible population. The variations of MLST lineages were fewer among the non-susceptible group. CONCLUSIONS: This study suggests that MRSA populations with a WT PBP2a and those with nPBD variations overlap significantly and that PBP2a sequence-independent factors contribute to ceftaroline susceptibility. Whereas characterization of isolates with a ceftaroline MIC of 2 mg/L enriched for isolates with nPBD variations, it was not a discrete population. In contrast, the rare isolates containing a substitution in the transpeptidase-binding pocket were readily differentiated. PMID- 26045530 TI - Corrigendum: on the precipice of a "majority-minority" america: perceived status threat from the racial demographic shift affects white Americans' political ideology. AB - Craig, M. A., & Richeson, J. A. (2014). On the precipice of a "majority-minority" America: Perceived status threat from the racial demographic shift affects White Americans' political ideology. Psychological Science, 25, 1189-1197. (Original DOI: 10.1177/0956797614527113). PMID- 26045532 TI - Evaluating the Hemodynamic Basis of Age-Related Central Blood Pressure Change Using Aortic Flow Triangulation. AB - BACKGROUND: Pulsatile blood pressure rises with age, especially in the aorta. The comparative role of forward and reflected pressure waves (FW and RW, respectively), determined by aortic flow triangulation has not previously been explored in a large clinical cohort. This study aimed to identify the role of FW and RW in the rise in aortic pulse pressure with age. METHODS: For 879 outpatients, aortic pressure waveforms were generated using a validated generalized transfer function applied to radial pressure waves recorded using applanation tonometry. FW and RW were subsequently determined using aortic flow triangulation. Contributions of FW and RW to rise in aortic pulse pressure with age were determined using multivariate linear regression and product of coefficient mediation analysis, with adjustment for height, weight, heart rate, and mean arterial pressure. Comparisons were made by gender and before and after age 60. RESULTS: In subjects aged 60 and below, RW was an important contributor to pulsatile pressure elevation with age, but FW was non-contributory in either gender after multivariate correction. In subjects aged above 60, both FW and RW were significant and equal contributors in both genders. CONCLUSIONS: In a clinical setting, both FW and RW are important to pulsatile aortic blood pressure across the lifespan, but RW appears to have a more pronounced effect across all ages, whereas FW has less effect in younger persons. PMID- 26045531 TI - Correlates of Segmental Pulse Wave Velocity in Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Carotid-femoral PWV (cfPWV) is a well-established measure of central arterial stiffness, while brachial-ankle PWV (baPWV) is being used more frequently in East Asian countries. Few studies have simultaneously characterized the distributions and correlates of segment-specific PWV measures and their associations with cardiovascular risk factors. METHODS: We evaluated segment specific PWV (cfPWV, baPWV, and femoral-ankle (faPWV)) in 4,974 older-aged African American and Caucasian adults in the community-based Atherosclerosis Risk in Communities (ARIC) Study using a standardized protocol and the OMRON VP-1000 Plus system. We examined the distribution and multivariable-adjusted correlates of PWV measures by race and sex. RESULTS: Mean age ranged from 74 +/- 5 to 76 +/- 5 years across race-sex groups. In all race-sex groups, cfPWV correlated with baPWV but not with faPWV, and cfPWV and baPWV were higher with age, whereas faPWV was not. Heart rate and systolic blood pressure (SBP) were positively associated and weight was negatively associated with all PWV measures; however, the associations with age, glycated hemoglobin, triglycerides, and high-density lipoprotein (HDL) cholesterol varied by segment and race-sex group. CONCLUSIONS: Our findings indicate that cfPWV and faPWV reflect distinct aspects of segment specific vascular stiffness and their associated profile of cardiovascular risk factors. Even among older adults, age is associated with higher cfPWV and baPWV, but not with faPWV. Understanding factors that ostensibly play a role in increasing arterial stiffness in different arterial territories can inform opportunities for cardiovascular disease (CVD) prevention and risk management. PMID- 26045534 TI - Response to "Right Analysis-Wrong Conclusion: Obese Youth With Higher BP Are at Risk for Target Organ Damage". PMID- 26045533 TI - Clock Genes Explain a Large Proportion of Phenotypic Variance in Systolic Blood Pressure and This Control Is Not Modified by Environmental Temperature. AB - BACKGROUND: Diurnal variation in blood pressure (BP) is regulated, in part, by an endogenous circadian clock; however, few human studies have identified associations between clock genes and BP. Accounting for environmental temperature may be necessary to correct for seasonal bias. METHODS: We examined whether environmental temperature on the day of participants' assessment was associated with BP, using adjusted linear regression models in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) (n = 819) and the Boston Puerto Rican Health Study (BPRHS) (n = 1,248) cohorts. We estimated phenotypic variance in BP by 18 clock genes and examined individual single-nucleotide polymorphism (SNP) associations with BP using an additive genetic model, with further consideration of environmental temperature. RESULTS: In GOLDN, each additional 1 degrees C increase in environmental temperature was associated with 0.18 mm Hg lower systolic BP [SBP; beta +/- SE = -0.18 +/- 0.05 mm Hg; P = 0.0001] and 0.10mm Hg lower diastolic BP [DBP; -0.10 +/- 0.03 mm Hg; P = 0.001]. Similar results were seen in the BPRHS for SBP only. Clock genes explained a statistically significant proportion of the variance in SBP [V G/V P +/- SE = 0.071 +/- 0.03; P = 0.001] in GOLDN, but not in the BPRHS, and we did not observe associations between individual SNPs and BP. Environmental temperature did not influence the identified genetic associations. CONCLUSIONS: We identified clock genes that explained a statistically significant proportion of the phenotypic variance in SBP, supporting the importance of the circadian pathway underlying cardiac physiology. Although temperature was associated with BP, it did not affect results with genetic markers in either study. Therefore, it does not appear that temperature measures are necessary for interpreting associations between clock genes and BP. CLINICAL TRIAL REGISTRATION: Trials related to this study were registered at clinicaltrials.gov as NCT00083369 (Genetic and Environmental Determinants of Triglycerides) and NCT01231958 (Boston Puerto Rican Health Study). PMID- 26045535 TI - Cytosolic Phospholipase A2alpha Is Essential for Renal Dysfunction and End-Organ Damage Associated With Angiotensin II-Induced Hypertension. AB - BACKGROUND: The kidney plays an important role in regulating blood pressure (BP). cPLA2alpha in the kidney is activated by various agents including angiotensin II (Ang II) and selectively releases arachidonic acid (AA) from tissue lipids, generating pro- and antihypertensive eicosanoids. Since activation of cPLA2alpha is the rate-limiting step in AA release, this study was conducted to determine its contribution to renal dysfunction and end-organ damage associated with Ang II induced hypertension. METHODS: cPLA2alpha(+/+) and cPLA2alpha(-/-) mice were infused with Ang II (700 ng/ kg/min) or its vehicle for 13 days. Mice were placed in metabolic cages to monitor their food and water intake, and urine was collected and its volume was measured. Doppler imaging was performed to assess renal hemodynamics. On the 13th day of Ang II infusion, mice were sacrificed and their tissues and blood collected for further analysis. RESULTS: Ang II increased renal vascular resistance, water intake, and urine output and Na(+) excretion, decreased urine osmolality, and produced proteinuria in cPLA2alpha(+/+) mice. Ang II also caused accumulation of F4/80(+) macrophages and CD3(+) T cells and renal fibrosis, and increased oxidative stress in the kidneys of cPLA2alpha(+/+) mice. All these effects of Ang II were minimized in cPLA2alpha(-/-) mice. CONCLUSION: cPLA2alpha contributes to renal dysfunction, inflammation, and end-organ damage, most likely via the action of pro-hypertensive eicosanoids and increased oxidative stress associated with Ang II-induced hypertension. Thus, cPLA2alpha could serve as a potential therapeutic target for treating renal dysfunction and end-organ damage in hypertension. PMID- 26045536 TI - Xenorhabdus bovienii Strain Diversity Impacts Coevolution and Symbiotic Maintenance with Steinernema spp. Nematode Hosts. AB - Microbial symbionts provide benefits that contribute to the ecology and fitness of host plants and animals. Therefore, the evolutionary success of plants and animals fundamentally depends on long-term maintenance of beneficial associations. Most work investigating coevolution and symbiotic maintenance has focused on species-level associations, and studies are lacking that assess the impact of bacterial strain diversity on symbiotic associations within a coevolutionary framework. Here, we demonstrate that fitness in mutualism varies depending on bacterial strain identity, and this is consistent with variation shaping phylogenetic patterns and maintenance through fitness benefits. Through genome sequencing of nine bacterial symbiont strains and cophylogenetic analysis, we demonstrate diversity among Xenorhabdus bovienii bacteria. Further, we identified cocladogenesis between Steinernema feltiae nematode hosts and their corresponding X. bovienii symbiont strains, indicating potential specificity within the association. To test the specificity, we performed laboratory crosses of nematode hosts with native and nonnative symbiont strains, which revealed that combinations with the native bacterial symbiont and closely related strains performed significantly better than those with more divergent symbionts. Through genomic analyses we also defined potential factors contributing to specificity between nematode hosts and bacterial symbionts. These results suggest that strain level diversity (e.g., subspecies-level differences) in microbial symbionts can drive variation in the success of host-microbe associations, and this suggests that these differences in symbiotic success could contribute to maintenance of the symbiosis over an evolutionary time scale. IMPORTANCE: Beneficial symbioses between microbes and plant or animal hosts are ubiquitous, and in these associations, microbial symbionts provide key benefits to their hosts. As such, host success is fundamentally dependent on long-term maintenance of beneficial associations. Prolonged association between partners in evolutionary time is expected to result in interactions in which only specific partners can fully support symbiosis. The contribution of bacterial strain diversity on specificity and coevolution in a beneficial symbiosis remains unclear. In this study, we demonstrate that strain-level differences in fitness benefits occur in beneficial host-microbe interactions, and this variation likely shapes phylogenetic patterns and symbiotic maintenance. This highlights that symbiont contributions to host biology can vary significantly based on very-fine-scale differences among members of a microbial species. Further, this work emphasizes the need for greater phylogenetic resolution when considering the causes and consequences of host microbe interactions. PMID- 26045537 TI - Bovine Staphylococcus aureus Secretes the Leukocidin LukMF' To Kill Migrating Neutrophils through CCR1. AB - Although Staphylococcus aureus is best known for infecting humans, bovine specific strains are a major cause of mastitis in dairy cattle. The bicomponent leukocidin LukMF', exclusively harbored by S. aureus of ruminant origin, is a virulence factor associated with bovine infections. In this study, the molecular basis of the host specificity of LukMF' is elucidated by identification of chemokine receptor CCR1 as its target. Bovine neutrophils, the major effector cells in the defense against staphylococci, express significant cell surface levels of CCR1, whereas human neutrophils do not. This causes the particular susceptibility of bovine neutrophils to pore formation induced by LukMF'. Bovine S. aureus strains produce high levels of LukMF' in vitro. In culture supernatant of the mastitis field isolate S1444, LukMF' was the most important cytotoxic agent for bovine neutrophils. In a fibrin gel matrix, the effects of the in situ secreted toxins on neutrophils migrating toward S. aureus were visualized. Under these physiological ex vivo conditions, bovine S. aureus S1444 efficiently killed approaching neutrophils at a distance through secretion of LukMF'. Altogether, our findings illustrate the coevolution of pathogen and host, provide new targets for therapeutic and vaccine approaches to treat staphylococcal diseases in the cow, and emphasize the importance of staphylococcal toxins in general. IMPORTANCE: This study explains the mechanism of action of LukMF', a bicomponent toxin found in bovine lineages of S. aureus that is associated with mastitis in cattle. At a molecular level, we describe how LukMF' can specifically kill bovine neutrophils. Here, we demonstrate the contribution of toxins in the determination of host specificity and contribute to the understanding of mechanisms of coevolution of pathogen and host. Our study provides new targets that can be used in therapeutic and vaccine approaches to treat staphylococcal diseases in the cow. We also demonstrate the importance of toxins in specific elimination of immune cells, which has broader implications, especially in human infections. PMID- 26045538 TI - Erratum for "New Insights into Dissemination and Variation of the Health Care Associated Pathogen Acinetobacter baumannii from Genomic Analysis". PMID- 26045539 TI - Development of a Model System for Tick-Borne Flavivirus Persistence in HEK 293T Cells. AB - We devised a model system to study persistent infection by the tick-borne flavivirus Langat virus (LGTV) in 293T cells. Infection with a molecularly cloned LGTV strain produced an acute lytic crisis that left few surviving cells. The culture was repopulated by cells that were ~90% positive for LGTV E protein, thus initiating a persistent infection that was maintained for at least 35 weeks without additional lytic crises. Staining of cells for viral proteins and ultrastructural analysis revealed only minor differences from the acute phase of infection. Infectious LGTV decreased markedly over the study period, but the number of viral genomes remained relatively constant, suggesting the development of defective interfering particles (DIPs). Viral genome changes were investigated by RNA deep sequencing. At the initiation of persistent infection, levels of DIPs were below the limit of detection at a coverage depth of 11,288-fold, implying that DIPs are not required for initiation of persistence. However, after 15 passages, DIPs constituted approximately 34% of the total LGTV population (coverage of 1,293-fold). Furthermore, at this point, one specific DIP population predominated in which nucleotides 1058 to 2881 had been deleted. This defective genome specified an intact polyprotein that coded for a truncated fusion protein containing 28 N-terminal residues of E and 134 C-terminal residues of NS1. Such a fusion protein has not previously been described, and a possible function in persistent infection is uncertain. DIPs are not required for the initiation of persistent LGTV infection but may play a role in the maintenance of viral persistence. IMPORTANCE: Tick-borne flaviviruses are significant infectious agents that cause serious disease and death in humans worldwide. Infections are characterized by severe neurological symptoms, such as meningitis and encephalitis. A high percentage of people who get infected and recuperate from the acute phase of infection continue to suffer from chronic debilitating neurological sequelae, most likely as a result of nervous tissue damage, viral persistence, or both. However, little is known about mechanisms of viral persistence. Therefore, we undertook studies to investigate the persistence of Langat virus, a member of the tick-borne flavivirus group, in a mammalian cell line. Using next-generation sequencing, we determined that defective viral genomes do not play a role in the initiation of persistence, but their occurrence seems to be nonstochastic and could play a role in the maintenance of viral persistence via the expression of a novel envelope-NS1 fusion protein. PMID- 26045540 TI - Kaposi Sarcoma Herpesvirus Induces HO-1 during De Novo Infection of Endothelial Cells via Viral miRNA-Dependent and -Independent Mechanisms. AB - Kaposi sarcoma (KS) herpesvirus (KSHV) infection of endothelial cells (EC) is associated with strong induction of heme oxygenase-1 (HO-1), a stress-inducible host gene that encodes the rate-limiting enzyme responsible for heme catabolism. KS is an angioproliferative tumor characterized by the proliferation of KSHV infected spindle cells, and HO-1 is highly expressed in such cells. HO-1 converts the pro-oxidant, proinflammatory heme molecule into metabolites with antioxidant, anti-inflammatory, and proliferative activities. Previously published work has shown that KSHV-infected EC in vitro proliferate in response to free heme in a HO 1-dependent manner, thus implicating virus-enhanced HO-1 activity in KS tumorigenesis. The present study investigated the molecular mechanisms underlying KSHV induction of HO-1 in lymphatic EC (LEC), which are the likely spindle cell precursors. In a time course analysis of KSHV-infected cells, HO-1 expression displays biphasic kinetics characterized by an early transient induction that is followed by a more sustained upregulation coincident with the establishment of viral latency. A viral microRNA miR-K12-11 deletion mutant of KSHV was found to be defective for induction of HO-1 during latency. A potential mechanism for this phenotype was provided by BACH1, a cellular HO-1 transcriptional repressor targeted by miR-K12-11. In fact, in KSHV-infected LEC, the BACH1 message level is reduced, BACH1 subcellular localization is altered, and miR-K12-11 mediates the inverse regulation of HO-1 and BACH1 during viral latency. Interestingly, the data indicate that neither miR-K12-11 nor de novo KSHV gene expression is required for the burst of HO-1 expression observed at early times postinfection, which suggests that additional virion components promote this phenotype. IMPORTANCE: While the mechanisms underlying KSHV induction of HO-1 remain unknown, the cellular mechanisms that regulate HO-1 expression have been extensively investigated in the context of basal and pathophysiological states. The detoxifying action of HO-1 is critical for the protection of cells exposed to high heme levels. KS spindle cells are erythrophagocytic and contain erythrocyte ghosts. Erythrocyte degeneration leads to the localized release of heme, creating oxidative stress that may be further exacerbated by environmental or other cofactors. Our previous work showed that KSHV-infected cells proliferate in response to heme and that this occurs in a HO-1-dependent manner. We therefore hypothesize that KSHV induction of HO-1 contributes to KS tumor development via heme metabolism and propose that HO-1 be evaluated as a therapeutic target for KS. Our present work, which aimed to understand the mechanisms whereby KSHV induces HO-1, will be important for the design and implementation of such a strategy. PMID- 26045542 TI - The effect of diagnostic labels on the affective responses of college students towards peers with 'Asperger's Syndrome' and 'Autism Spectrum Disorder'. AB - Given the removal of Asperger's Syndrome label in Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition, the impact of clinical labels upon the affective responses of college students was explored. A total of 120 college students read two vignettes depicting social interactions typical of a person with autism spectrum disorder. In one vignette, they were informed that the character was a typical college student and in the other, the character had a clinical disorder (either autism spectrum disorder, Asperger's Syndrome or Schizophrenia). Participants' affective responses were measured on the Positive and Negative Affect Scale. No significant differences in positive and negative affective responses were found between the clinical labels. However, affective responses were significantly more positive and less negative towards behaviours associated with clinical groups compared to the typical college student. The implications for students disclosing their diagnosis at university are discussed. PMID- 26045541 TI - Burkholderia cenocepacia Lipopolysaccharide Modification and Flagellin Glycosylation Affect Virulence but Not Innate Immune Recognition in Plants. AB - Burkholderia cenocepacia causes opportunistic infections in plants, insects, animals, and humans, suggesting that "virulence" depends on the host and its innate susceptibility to infection. We hypothesized that modifications in key bacterial molecules recognized by the innate immune system modulate host responses to B. cenocepacia. Indeed, modification of lipopolysaccharide (LPS) with 4-amino-4-deoxy-L-arabinose and flagellin glycosylation attenuates B. cenocepacia infection in Arabidopsis thaliana and Galleria mellonella insect larvae. However, B. cenocepacia LPS and flagellin triggered rapid bursts of nitric oxide and reactive oxygen species in A. thaliana leading to activation of the PR-1 defense gene. These responses were drastically reduced in plants with fls2 (flagellin FLS2 host receptor kinase), Atnoa1 (nitric oxide-associated protein 1), and dnd1-1 (reduced production of nitric oxide) null mutations. Together, our results indicate that LPS modification and flagellin glycosylation do not affect recognition by plant receptors but are required for bacteria to establish overt infection. IMPORTANCE: Virulence and pathogenicity are properties ascribed to microbes, which actually require careful consideration of the host. Using the term "pathogen" to define a microbe without considering its host has recently been debated, since the microbe's capacity to establish a niche in a given host is a critical feature associated with infection. Opportunistic bacteria are a perfect example of microbes whose ability to cause disease is intimately related to the host's ability to recognize and respond to the infection. Here, we use the opportunistic bacterium Burkholderia cenocepacia and the host plant Arabidopsis thaliana to investigate the role of bacterial surface molecules, namely, lipopolysaccharide and flagellin, in contributing to infection and also in eliciting a host response. We reveal that both molecules can be modified by glycosylation, and although the modifications are critical for the bacteria to establish an infection, they do not impact the host's ability to recognize the pathogen. PMID- 26045543 TI - Group social skills interventions for adults with high-functioning autism spectrum disorders: A systematic review. AB - Autism spectrum disorders are characterised by impairments in communication and social interaction. Social skills interventions have been found to ameliorate socio-communication deficits in children and adolescents with autism spectrum disorders. Little is known about the effectiveness of social skills interventions for adults with high-functioning autism spectrum disorders (hf-ASD) - a clinical population who can present with more subtle core deficits, but comparable levels of impairment and secondary difficulties. A systematic review was undertaken to investigate the effectiveness of social skills interventions for adults with high functioning autism spectrum disorders. Five studies met the pre-specified review inclusion criteria: two quasi-experimental comparative trials and three single arm interventions. There was a degree of variation in the structure, duration and content of the social skills interventions delivered, as well as several methodological limitations associated with included studies. Nevertheless, narrative analysis tentatively indicates that group social skills interventions may be effective for enhancing social knowledge and understanding, improving social functioning, reducing loneliness and potentially alleviating co-morbid psychiatric symptoms. PMID- 26045544 TI - Validity of a clinical model to predict influenza in patients presenting with symptoms of lower respiratory tract infection in primary care. AB - BACKGROUND: Valid clinical predictors of influenza in patients presenting with lower respiratory tract infection (LRTI) symptoms would provide adequate patient information and reassurance. AIM: Assessing the validity of an existing diagnostic model (Flu Score) to detect influenza in LRTI patients. DESIGN AND SETTING: A European diagnostic study recruited 1801 adult primary care patients with LRTI-like symptoms existing <=7 days between October and April 2007-2010. METHOD: History and physical examination findings were recorded and nasopharyngeal swabs taken. Polymerase chain reaction (PCR) for influenza A/B was performed as reference test. Diagnostic accuracy of the Flu Score (1* onset <48 hours + 2* myalgia + 1* chills or sweats + 2* fever and cough) was expressed as area under the curve (AUC), calibration slopes and likelihood ratios (LRs). RESULTS: A total of 273 patients (15%) had influenza on PCR. The AUC of the Flu Score during winter months was 0.66 [95% CI (95% confidence internal) 0.63-0.70]. During peak influenza season, both influenza prevalence (24%) and AUC were higher [0.71 (95% CI 0.66-0.76], but calibration remained poor. The Flu Score assigned 64% of the patients as 'low-risk' (10% had influenza, LR - 0.6). About 12% were classified as 'high risk' of whom 32% had influenza (LR + 2.7). During peak influenza season, 60% and 14% of patients were classified as low and high risk, respectively, with influenza prevalences being 14% (LR - 0.5) and 50% (LR + 3.2). CONCLUSION: The Flu-Score attributes a small subgroup of patients with a high influenza risk (prevalence 32%). However, clinical usefulness is limited because this group is small and the association between predicted and observed risks is poor. Considerable diagnostic imprecision remains when it comes to differentiating those with influenza on clinical grounds from the many other causes of LRTI in primary care. New point of care tests are required that accurately, rapidly and cost effectively detect influenza in patients with respiratory tract symptoms in primary care. PMID- 26045545 TI - Synergistic effect of pain and deficits in ADL towards general practitioner visits. AB - BACKGROUND: Pain and activities of daily living (ADLs) deficits are common problems among elderly people who visit general practitioners (GPs). OBJECTIVE: To examine whether the probability of visiting a GP is related to deficits in ADLs and pain, and whether these factors act synergistically towards GP visits. METHODS: A total of 3097 subjects aged >=65 years from the Austrian Health Interview Survey formed the cohort. Visiting the GP in the last 4 weeks, chronic pain (CP; pain for at least 3 months) and deficits in ADLs across 11 dimensions were reported. Binary logistic regression models were applied and were stepwise controlled for possible confounders. Based on odds ratios (OR), the synergy index (SI), population attributable fraction (PAF) and relative excess risk due to interaction (RERI) were calculated. RESULTS: Overall, 61.0% visited their GP; 51.2% were affected by ADL deficits and 42.2% by CP. In subjects with ADL deficits, the OR for GP consultation was 1.32 (95% confidence interval [CI] 1.11 1.56) and in subjects with CP, 1.93 (95% CI 1.63-2.27) in the fully adjusted model. The OR for those affected by both was 2.56 (95% CI 2.08-3.15); SI was 1.82 (95% CI 1.04-3.18), PAF was 0.27 (95% CI 0.08-0.47) and RERI was 0.70 (95% CI 0.13-1.27). CONCLUSION: There is a strong synergistic effect of CP and deficits in ADL in patients >=65 years on visiting the GP. Prevention, screening, treatment and rehabilitation in this population should focus on both CP and ADL deficits. PMID- 26045546 TI - d-Dimer as a Screening Marker for Venous Thromboembolism After Surgery Among Patients Younger Than 50 With Lower Limb Fractures. AB - OBJECTIVE: For the present study, the authors hypothesized that the d-dimer levels would be systematically raised in a postoperative population of patients younger than 50 with lower limb fractures and to define a feasible cutoff value for identification of venous thromboembolism (VTE). METHODS: Doppler ultrasonography of lower limbs was performed pre- and postoperatively to evaluate for deep vein thrombosis in 150 patients who underwent open reduction and internal fixation (ORIF). Plasma d-dimer levels were assessed 2 days before surgery and on the 3rd, 7th, and 10th days after surgery. Statistical analysis was carried out to define a feasible threshold for the d-dimer levels. RESULTS: Plasma d-dimer levels were found to be systematically raised postoperatively, and they differed between patients with and without VTE significantly. On the third day after surgery, d-dimer levels of more than 3 mg/L indicated VTE with a sensitivity of 88.37% and a specificity of 96.96%, allowing for the definition of a feasible cutoff value. Duration of surgery, duration of tourniquet, ventilation time, and time of postoperative immobility of lower limbs were identified as highly significant risk factors for the development of VTE. CONCLUSION: Using a threshold of 3 mg/L, the d-dimer levels will screen out VTE with a high degree of sensitivity and specificity in younger patients who have undergone ORIF for lower limb fractures. PMID- 26045547 TI - Disruption of the NF-kappaB/NLRP3 connection by melatonin requires retinoid related orphan receptor-alpha and blocks the septic response in mice. AB - We determined the NF-kappaB- and NOD-like receptor (NLR)P3-dependent molecular mechanisms involved in sepsis and evaluated the role of retinoid-related orphan receptor (ROR)-alpha in melatonin's anti-inflammatory actions. Western blot, RT PCR, ELISA, and spectrophotometric analysis revealed that NF-kappaB and NLRP3 closely interact, leading to proinflammatory and pro-oxidant status in heart tissue of septic C57BL/6J mice. Moreover, mitochondrial oxygen consumption was reduced by 80% in septic mice. In vivo and in vitro analysis showed that melatonin administration blunts NF-kappaB transcriptional activity through a sirtuin1-dependent NF-kappaB deacetylation in septic mice. Melatonin also decreased NF-kappaB-dependent proinflammatory response and restored redox balance and mitochondrial homeostasis, thus inhibiting the NLRP3 inflammasome. In an important finding, the inhibition of NF-kappaB by melatonin, but not that of NLRP3, was blunted in RORalpha (sg/sg) mice, indicating that functional RORalpha transcription factor is necessary for the initiation of the innate immune response against inflammation. Our results are evidence of the NF-kappaB/NLRP3 connection during sepsis and identify NLRP3 as a novel molecular target for melatonin. The multiple molecular targets of melatonin in this study explain its potent anti-inflammatory efficacy against systemic innate immune activation and herald a promising therapeutic application for melatonin in the treatment of sepsis. PMID- 26045548 TI - Ulipristal Acetate Antagonizes the Inhibitory Effect of Progesterone on Ciliary Beat Frequency and Upregulates Steroid Receptor Expression Levels in Human Fallopian Tubes. AB - Ulipristal acetate (UPA) is a new selective progesterone receptor (PR) modulator used for emergency contraception. However, our understanding of its mechanisms of action on oviductal cilia is limited. The present study focused on the in vitro effects of UPA (0.1, 1, and 10 MUmol/L) on the cilia and steroid receptors of human fallopian tubes. The ciliary beat frequency (CBF), the ultrastructure of cilia, and the levels of steroid receptors were measured. The effects of UPA on the progesterone-induced CBF reduction were also studied. Our results show that UPA dose dependently antagonizes the progesterone-induced CBF decrease, but it does not affect the CBF or the ultrastructure of the cilia. The UPA also upregulates the expression levels of the estrogen receptor alpha and the PR in the fallopian tubes. The results enable us to better understand the mechanisms by which UPA works as an emergency contraceptive and provides a scientific basis for its clinical application. PMID- 26045550 TI - Expression of DROSHA in the Uterus of Mice in Early Pregnancy and Its Potential Significance During Embryo Implantation. AB - Previous studies have shown that microRNAs are involved in the process of implantation. They play an important role in cell growth and proliferation. DROSHA is the microRNA-processing enzyme and is required for the maturation of microRNAs. However, its expression and function during early pregnancy in mice still remain unclear. In the present study, we analyzed the expression pattern of DROSHA in the mouse uterus during early pregnancy, pseudopregnancy, artificially induced decidualization, and in the ovariectomized mouse uterus using real-time quantitative polymerase chain reaction, Western blotting analyses, and immunohistochemistry. We found that DROSHA was spatiotemporally expressed in decidualizing stromal cells during early pregnancy and in pseudopregnant mice in which decidualization was artificially induced. In the ovariectomized mouse uterus, the expression of DROSHA was upregulated after progesterone treatment. In a stromal cell culture model, the expression of DROSHA gradually increased with the progression of stromal decidualization. Taken together, our findings suggest that DROSHA is involved in stromal decidualization and may play an important role in embryo implantation in mice. PMID- 26045549 TI - Delayed Start Versus Conventional GnRH Antagonist Protocol in Poor Responders Pretreated With Estradiol in Luteal Phase: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the new delayed start protocol against the conventional gonadotropin (Gn)-releasing hormone antagonist protocol in poor responders (PORs). STUDY DESIGN: A total of 160 women with poor response to previous in vitro fertilization (IVF) cycle were randomized either to start Gn then Cetrotide 0.25 subcutaneously (sc) added when leading follicle (DF) reach >12 mm or Cetrotide 0.25 mg sc started first from day 2 to day 8 then Gn therapy was added and Cetrotide restarted when DF reach >12 mm. RESULTS: There was a statistically significant difference between conventional and delayed start protocols regarding the needed dose of Gn for stimulation (4368 +/- 643 and 3798 +/- 515), level of estradiol (E2; 778 +/- 371 and 1076 +/- 453), and endometrial thickness at human chorionic gonadotropin triggering (8.6 +/- 1.8 and 9.8 +/- 1.9), the number of DF (3.4 +/- 1.5 and 4.9 +/- 2.1), the number of retrieved follicles (2.4 +/- 2.1 and 4.3 +/- 2.5), and successful embryo transfer (13 vs 16), respectively (P < .05). There was a highly statistically significant difference between the 2 study groups regarding the number of oocytes fertilized (1.2 +/- 2.0 vs 3.3 +/- 1.4), metaphase II oocytes (0.9 +/- 1.0 vs 2.7 + 1.6), and grade I embryos (0.7 +/- 0.9 vs 2.1 + 1.1; P < .001). The chemical pregnancy, clinical pregnancy, and abortion rate showed a statistically significant difference between the 2 study groups (P value .003 and .006, respectively). CONCLUSION: Delayed start protocol significantly improved clinical pregnancy rate and IVF cycle parameters in PORs. PMID- 26045551 TI - Differential expression profile of membrane proteins in L-02 cells exposed to trichloroethylene. AB - Trichloroethylene (TCE), a halogenated organic solvent widely used in industries, is known to cause severe hepatotoxicity. However, the mechanisms underlying TCE hepatotoxicity are still not well understood. It is predicted that membrane proteins are responsible for key biological functions, and recent studies have revealed that TCE exposure can induce abnormal levels of membrane proteins in body fluids and cultured cells. The aim of this study is to investigate the TCE induced alterations of membrane proteins profiles in human hepatic L-02 liver cells. A comparative membrane proteomics analysis was performed in combination with two-dimensional fluorescence difference gel electrophoresis and matrix assisted laser desorption/ionization time-of-flight tandem mass spectrometry. A total of 15 proteins were identified as differentially expressed (4 upregulated and 11 downregulated) between TCE-treated cells and normal controls. Among this, 14 of them are suggested as membrane-associated proteins by their transmembrane domain and/or subcellular location. Furthermore, the differential expression of beta subunit of adenosine triphosphate synthase (ATP5B) and prolyl 4-hydroxylase, beta polypeptide (P4HB) were verified by Western blot analysis in TCE-treated L 02 cells. Our work not only reveals the association between TCE exposure and altered expression of membrane proteins but also provides a novel strategy to discover membrane biomarkers and elucidate the potential mechanisms involving with membrane proteins response to chemical-induced toxic effect. PMID- 26045552 TI - Myrtus communis L. Freeze-Dried Aqueous Extract Versus Omeprazol in Gastrointestinal Reflux Disease: A Double-Blind Randomized Controlled Clinical Trial. AB - The current work assessed a pharmaceutical dosage form of Myrtus communis L. (myrtle) in reflux disease compared with omeprazol via a 6-week double-blind randomized controlled clinical trial. Forty-five participants were assigned randomly to 3 groups as A (myrtle berries freeze-dried aqueous extract, 1000 mg/d), B (omeprazol capsules, 20 mg/d), and C (A and B). The assessment at the beginning and the end of the study was done by using a standardized questionnaire of frequency scale for the symptoms of gastroesophageal reflux disease (FSSG). In all groups, both reflux and dyspeptic scores significantly decreased in comparison with the respective baselines. Concerning each group, significant changes were found in FSSG, dysmotility-like symptoms and acid reflux related scores. No significant differences were observed between all groups in final FSSG total scores (FSSG2). Further studies with more precise design and larger sample size may lead to a better outcome to suggest the preparation as an alternative intervention. PMID- 26045553 TI - Effects of Malva sylvestris and Its Isolated Polysaccharide on Experimental Ulcerative Colitis in Rats. AB - Malva sylvestris is an edible plant that is consumed as a herbal supplement for its antiulcer and colon cleansing properties in traditional Persian medicine. This study was designed to evaluate its effects on ulcerative colitis, which is a chronic gastrointestinal inflammation. Colitis was induced by rectal instillation of acetic acid solution. Rats in different groups received aqueous, n-hexane, or ethanolic fractions of the plant before induction of colitis. Isolated polysaccharide of plant was also tested in 2 groups before and after induction of colitis. Macroscopic and microscopic evaluation of colitis showed that the aqueous fraction was very effective in preventing the inflammation and efficacy was lower for ethanolic and n-hexane fractions. Polysaccharide was effective in reducing signs of inflammation, especially as pretreatment. These beneficial effects provide evidences that this plant can be suggested for patients with this disease to improve their health condition or to reduce adverse effects of their medication. PMID- 26045554 TI - Two N-glycosylation Sites in the GluN1 Subunit Are Essential for Releasing N methyl-d-aspartate (NMDA) Receptors from the Endoplasmic Reticulum. AB - NMDA receptors (NMDARs) comprise a subclass of neurotransmitter receptors whose surface expression is regulated at multiple levels, including processing in the endoplasmic reticulum (ER), intracellular trafficking via the Golgi apparatus, internalization, recycling, and degradation. With respect to early processing, NMDARs are regulated by the availability of GluN subunits within the ER, the presence of ER retention and export signals, and posttranslational modifications, including phosphorylation and palmitoylation. However, the role of N glycosylation, one of the most common posttranslational modifications, in regulating NMDAR processing has not been studied in detail. Using biochemistry, confocal and electron microscopy, and electrophysiology in conjunction with a lentivirus-based molecular replacement strategy, we found that NMDARs are released from the ER only when two asparagine residues in the GluN1 subunit (Asn 203 and Asn-368) are N-glycosylated. Although the GluN2A and GluN2B subunits are also N-glycosylated, their N-glycosylation sites do not appear to be essential for surface delivery of NMDARs. Furthermore, we found that removing N-glycans from native NMDARs altered the receptor affinity for glutamate. Our results suggest a novel mechanism by which neurons ensure that postsynaptic membranes contain sufficient numbers of functional NMDARs. PMID- 26045555 TI - Crystal Structure of the Vaccinia Virus Uracil-DNA Glycosylase in Complex with DNA. AB - Vaccinia virus polymerase holoenzyme is composed of the DNA polymerase catalytic subunit E9 associated with its heterodimeric co-factor A20.D4 required for processive genome synthesis. Although A20 has no known enzymatic activity, D4 is an active uracil-DNA glycosylase (UNG). The presence of a repair enzyme as a component of the viral replication machinery suggests that, for poxviruses, DNA synthesis and base excision repair is coupled. We present the 2.7 A crystal structure of the complex formed by D4 and the first 50 amino acids of A20 (D4.A201-50) bound to a 10-mer DNA duplex containing an abasic site resulting from the cleavage of a uracil base. Comparison of the viral complex with its human counterpart revealed major divergences in the contacts between protein and DNA and in the enzyme orientation on the DNA. However, the conformation of the dsDNA within both structures is very similar, suggesting a dominant role of the DNA conformation for UNG function. In contrast to human UNG, D4 appears rigid, and we do not observe a conformational change upon DNA binding. We also studied the interaction of D4.A201-50 with different DNA oligomers by surface plasmon resonance. D4 binds weakly to nonspecific DNA and to uracil-containing substrates but binds abasic sites with a Kd of <1.4 MUm. This second DNA complex structure of a family I UNG gives new insight into the role of D4 as a co-factor of vaccinia virus DNA polymerase and allows a better understanding of the structural determinants required for UNG action. PMID- 26045556 TI - Structural Basis of Clade-specific Engagement of SAMHD1 (Sterile alpha Motif and Histidine/Aspartate-containing Protein 1) Restriction Factors by Lentiviral Viral Protein X (Vpx) Virulence Factors. AB - Sterile alpha motif (SAM) and histidine/aspartate (HD)-containing protein 1 (SAMHD1) restricts human/simian immunodeficiency virus infection in certain cell types and is counteracted by the virulence factor Vpx. Current evidence indicates that Vpx recruits SAMHD1 to the Cullin4-Ring Finger E3 ubiquitin ligase (CRL4) by facilitating an interaction between SAMHD1 and the substrate receptor DDB1- and Cullin4-associated factor 1 (DCAF1), thereby targeting SAMHD1 for proteasome dependent down-regulation. Host-pathogen co-evolution and positive selection at the interfaces of host-pathogen complexes are associated with sequence divergence and varying functional consequences. Two alternative interaction interfaces are used by SAMHD1 and Vpx: the SAMHD1 N-terminal tail and the adjacent SAM domain or the C-terminal tail proceeding the HD domain are targeted by different Vpx variants in a unique fashion. In contrast, the C-terminal WD40 domain of DCAF1 interfaces similarly with the two above complexes. Comprehensive biochemical and structural biology approaches permitted us to delineate details of clade-specific recognition of SAMHD1 by lentiviral Vpx proteins. We show that not only the SAM domain but also the N-terminal tail engages in the DCAF1-Vpx interaction. Furthermore, we show that changing the single Ser-52 in human SAMHD1 to Phe, the residue found in SAMHD1 of Red-capped monkey and Mandrill, allows it to be recognized by Vpx proteins of simian viruses infecting those primate species, which normally does not target wild type human SAMHD1 for degradation. PMID- 26045557 TI - Engineering a Nickase on the Homing Endonuclease I-DmoI Scaffold. AB - Homing endonucleases are useful tools for genome modification because of their capability to recognize and cleave specifically large DNA targets. These endonucleases generate a DNA double strand break that can be repaired by the DNA damage response machinery. The break can be repaired by homologous recombination, an error-free mechanism, or by non-homologous end joining, a process susceptible to introducing errors in the repaired sequence. The type of DNA cleavage might alter the balance between these two alternatives. The use of "nickases" producing a specific single strand break instead of a double strand break could be an approach to reduce the toxicity associated with non-homologous end joining by promoting the use of homologous recombination to repair the cleavage of a single DNA break. Taking advantage of the sequential DNA cleavage mechanism of I-DmoI LAGLIDADG homing endonuclease, we have developed a new variant that is able to cut preferentially the coding DNA strand, generating a nicked DNA target. Our structural and biochemical analysis shows that by decoupling the action of the catalytic residues acting on each strand we can inhibit one of them while keeping the other functional. PMID- 26045558 TI - Transcription Factor PAX6 (Paired Box 6) Controls Limbal Stem Cell Lineage in Development and Disease. AB - PAX6 is a master regulatory gene involved in neuronal cell fate specification. It also plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development. Defects in Pax6 cause aniridia and LSC deficiency in humans and the Sey (Small eye) phenotype in mice (Masse, K., Bhamra, S., Eason, R., Dale, N., and Jones, E. A. (2007) Nature 449, 1058-1062). However, how PAX6 specifies LSC and corneal fates during eye development is not well understood. Here, we show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development. In contrast, p63 expression commences after that of PAX6 in ocular adnexal and skin tissue progenitors and later in LSCs. Using an in vitro feeder-free culture system, we show that PAX6 knockdown in LSCs led to up-regulation of skin epidermis-specific keratins concomitant with differentiation to a skin fate. Using gene expression analysis, we identified the involvement of Notch, Wnt, and TGF-beta signaling pathways in LSC fate determination. Thus, loss of PAX6 converts LSCs to epidermal stem cells, as demonstrated by a switch in the keratin gene expression profile and by the appearance of congenital dermoid tissue. PMID- 26045560 TI - Writing is an essential communication skill: let's start teaching it. PMID- 26045559 TI - An RNA-binding Protein, Lin28, Recognizes and Remodels G-quartets in the MicroRNAs (miRNAs) and mRNAs It Regulates. AB - Lin28 is an evolutionarily conserved RNA-binding protein that inhibits processing of pre-let-7 microRNAs (miRNAs) and regulates translation of mRNAs that control developmental timing, pluripotency, metabolism, and tumorigenesis. The RNA features that mediate Lin28 binding to the terminal loops of let-7 pre-miRNAs and to Lin28-responsive elements (LREs) in mRNAs are not well defined. Here we show that Lin28 target datasets are enriched for RNA sequences predicted to contain stable planar structures of 4 guanines known as G-quartets (G4s). The imino NMR spectra of pre-let-7 loops and LREs contain resonances characteristic of G4 hydrogen bonds. These sequences bind to a G4-binding fluorescent dye, N-methyl mesoporphyrin IX (NMM). Mutations and truncations in the RNA sequence that prevent G4 formation also prevent Lin28 binding. The addition of Lin28 to a pre let-7 loop or an LRE reduces G4 resonance intensity and NMM binding, suggesting that Lin28 may function to remodel G4s. Further, we show that NMM inhibits Lin28 binding. Incubation of a human embryonal carcinoma cell line with NMM reduces its stem cell traits. In particular it increases mature let-7 levels, decreases OCT4, HMGA1, CCNB1, CDK4, and Lin28A protein, decreases sphere formation, and inhibits colony formation. Our results suggest a previously unknown structural feature of Lin28 targets and a new strategy for manipulating Lin28 function. PMID- 26045561 TI - Clinicopathological correlates of adrenal Cushing's syndrome. AB - Endogenous Cushing's syndrome is a rare endocrine disorder that incurs significant cardiovascular morbidity and mortality, due to glucocorticoid excess. It comprises adrenal (20%) and non-adrenal (80%) aetiologies. While the majority of cases are attributed to pituitary or ectopic corticotropin (ACTH) overproduction, primary cortisol-producing adrenal cortical lesions are increasingly recognised in the pathophysiology of Cushing's syndrome. Our understanding of this disease has progressed substantially over the past decade. Recently, important mechanisms underlying the pathogenesis of adrenal hypercortisolism have been elucidated with the discovery of mutations in cyclic AMP signalling (PRKACA, PRKAR1A, GNAS, PDE11A, PDE8B), armadillo repeat containing 5 gene (ARMC5) a putative tumour suppressor gene, aberrant G-protein coupled receptors, and intra-adrenal secretion of ACTH. Accurate subtyping of Cushing's syndrome is crucial for treatment decision-making and requires a complete integration of clinical, biochemical, imaging and pathology findings. Pathological correlates in the adrenal glands include hyperplasia, adenoma and carcinoma. While the most common presentation is diffuse adrenocortical hyperplasia secondary to excess ACTH production, this entity is usually treated with pituitary or ectopic tumour resection. Therefore, when confronted with adrenalectomy specimens in the setting of Cushing's syndrome, surgical pathologists are most commonly exposed to adrenocortical adenomas, carcinomas and primary macronodular or micronodular hyperplasia. This review provides an update on the rapidly evolving knowledge of adrenal Cushing's syndrome and discusses the clinicopathological correlations of this important disease. PMID- 26045563 TI - What's the point of reflective writing? PMID- 26045562 TI - How to study improvement interventions: a brief overview of possible study types. AB - Improvement (defined broadly as purposive efforts to secure positive change) has become an increasingly important activity and field of inquiry within healthcare. This article offers an overview of possible methods for the study of improvement interventions. The choice of available designs is wide, but debates continue about how far improvement efforts can be simultaneously practical (aimed at producing change) and scientific (aimed at producing new knowledge), and whether the distinction between the practical and the scientific is a real and useful one. Quality improvement projects tend to be applied and, in some senses, self evaluating. They are not necessarily directed at generating new knowledge, but reports of such projects if well conducted and cautious in their inferences may be of considerable value. They can be distinguished heuristically from research studies, which are motivated by and set out explicitly to test a hypothesis, or otherwise generate new knowledge, and from formal evaluations of improvement projects. We discuss variants of trial designs, quasi-experimental designs, systematic reviews, programme evaluations, process evaluations, qualitative studies, and economic evaluations. We note that designs that are better suited to the evaluation of clearly defined and static interventions may be adopted without giving sufficient attention to the challenges associated with the dynamic nature of improvement interventions and their interactions with contextual factors. Reconciling pragmatism and research rigour is highly desirable in the study of improvement. Trade-offs need to be made wisely, taking into account the objectives involved and inferences to be made. PMID- 26045565 TI - Selective Neural Synchrony Suppression as a Forward Gatekeeper to Piecemeal Conscious Perception. AB - The emergence of conscious visual perception is assumed to ignite late (~250 ms) gamma-band oscillations shortly after an initial (~100 ms) forward sweep of neural sensory (nonconscious) information. However, this neural evidence is not utterly congruent with rich behavioral data which rather point to piecemeal (i.e., graded) perceptual processing. To address the unexplored neural mechanisms of piecemeal ignition of conscious perception, hierarchical script sensitivity of the putative visual word form area (VWFA) was exploited to signal null (i.e., sensory), partial (i.e., letter-level), and full (i.e., word-level) conscious perception. Two magnetoencephalography experiments were conducted in which healthy human participants viewed masked words (Experiment I: active task, Dutch words; Experiment II: passive task, Hebrew words) while high-frequency (broadband gamma) brain activity was measured. Findings revealed that piecemeal conscious perception did not ignite a linear piecemeal increase in oscillations. Instead, whereas late (~250 ms) gamma-band oscillations signaled full conscious perception (i.e., word-level), partial conscious perception (i.e., letter-level) was signaled via the inhibition of the early (~100 ms) forward sweep. This inhibition regulates the downstream broadcast to filter out irrelevant (i.e., masks) information. The findings thus highlight a local (VWFA) gatekeeping mechanism for conscious perception, operating by filtering out and in selective percepts. PMID- 26045566 TI - Probing the Cognitive Mechanism of Mental Representational Change During Chunk Decomposition: A Parametric fMRI Study. AB - Chunk decomposition plays an important role in cognitive flexibility in particular with regards to representational change, which is critical for insight problem solving and creative thinking. In this study, we investigated the cognitive mechanism of decomposing Chinese character chunks through a parametric fMRI design. Our results from this parametric manipulation revealed widely distributed activations in frontal, parietal, and occipital cortex and negative activations in parietal and visual areas in response to chunk tightness during decomposition. To mentally manipulate the element of a given old chunk, superior parietal lobe appears to support element restructuring in a goal-directed way, whereas the negatively activated inferior parietal lobe may support preventing irrelevant objects from being attended. Moreover, determining alternative ways of restructuring requires a constellation of frontal areas in the cognitive control network, such as the right lateral prefrontal cortex in inhibiting the predominant chunk representations, the presupplementary motor area in initiating a transition of mental task set, and the inferior frontal junction in establishing task sets. In conclusion, this suggests that chunk decomposition reflects mental transformation of problem representation from an inappropriate state to a new one alongside with an evaluation of novel and insightful solutions by the caudate in the dorsal striatum. PMID- 26045564 TI - Ketamine Alters Outcome-Related Local Field Potentials in Monkey Prefrontal Cortex. AB - A subanesthetic dose of the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine is known to induce a schizophrenia-like phenotype in humans and nonhuman primates alike. The transient behavioral changes mimic the positive, negative, and cognitive symptoms of the disease but the neural mechanisms behind these changes are poorly understood. A growing body of evidence indicates that the cognitive control processes associated with prefrontal cortex (PFC) regions relies on groups of neurons synchronizing at narrow-band frequencies measurable in the local field potential (LFP). Here, we recorded LFPs from the caudo-lateral PFC of 2 macaque monkeys performing an antisaccade task, which requires the suppression of an automatic saccade toward a stimulus and the initiation of a goal-directed saccade in the opposite direction. Preketamine injection activity showed significant differences in a narrow 20-30 Hz beta frequency band between correct and error trials in the postsaccade response epoch. Ketamine significantly impaired the animals' performance and was associated with a loss of the differences in outcome-specific beta-band power. Instead, we observed a large increase in high-gamma-band activity. Our results suggest that the PFC employs beta-band synchronization to prepare for top-down cognitive control of saccades and the monitoring of task outcome. PMID- 26045567 TI - Are Developmental Trajectories of Cortical Folding Comparable Between Cross sectional Datasets of Fetuses and Preterm Newborns? AB - Magnetic resonance imaging has proved to be suitable and efficient for in vivo investigation of the early process of brain gyrification in fetuses and preterm newborns but the question remains as to whether cortical-related measurements derived from both cases are comparable or not. Indeed, the developmental folding trajectories drawn up from both populations have not been compared so far, neither from cross-sectional nor from longitudinal datasets. The present study aimed to compare features of cortical folding between healthy fetuses and early imaged preterm newborns on a cross-sectional basis, over a developmental period critical for the folding process (21-36 weeks of gestational age [GA]). A particular attention was carried out to reduce the methodological biases between the 2 populations. To provide an accurate group comparison, several global parameters characterizing the cortical morphometry were derived. In both groups, those metrics provided good proxies for the dramatic brain growth and cortical folding over this developmental period. Except for the cortical volume and the rate of sulci appearance, they depicted different trajectories in both groups suggesting that the transition from into ex utero has a visible impact on cortical morphology that is at least dependent on the GA at birth in preterm newborns. PMID- 26045568 TI - Selective Thalamic Innervation of Rat Frontal Cortical Neurons. AB - Most glutamatergic inputs in the neocortex originate from the thalamus or neocortical pyramidal cells. To test whether thalamocortical afferents selectively innervate specific cortical cell subtypes and surface domains, we investigated the distribution patterns of thalamocortical and corticocortical excitatory synaptic inputs in identified postsynaptic cortical cell subtypes using intracellular and immunohistochemical staining combined with confocal laser scanning and electron microscopic observations in 2 thalamorecipient sublayers, lower layer 2/3 (L2/3b) and lower layer 5 (L5b) of rat frontal cortex. The dendrites of GABAergic parvalbumin (PV) cells preferentially received corticocortical inputs in both sublayers. The somata of L2/3b PV cells received thalamic inputs in similar proportions to the basal dendritic spines of L2/3b pyramidal cells, whereas L5b PV somata were mostly innervated by cortical inputs. The basal dendrites of L2/3b pyramidal and L5b corticopontine pyramidal cells received cortical and thalamic glutamatergic inputs in proportion to their local abundance, whereas crossed-corticostriatal pyramidal cells in L5b exhibited a preference for thalamic inputs, particularly in their distal dendrites. Our data demonstrate an exquisite selectivity among thalamocortical afferents in which synaptic connectivity is dependent on the postsynaptic neuron subtype, cortical sublayer, and cell surface domain. PMID- 26045569 TI - CREB1 Genotype Modulates Adaptive Reward-Based Decisions in Humans. AB - Cyclic AMP response element-binding protein (CREB) contributes to adaptation of mesocorticolimbic networks by modulating activity-regulated transcription and plasticity in neurons. Activity or expression changes of CREB in the nucleus accumbens (NAc) and orbital frontal cortex (OFC) interact with behavioral changes during reward-motivated learning. However, these findings from animal models have not been evaluated in humans. We tested whether CREB1 genotypes affect reward motivated decisions and related brain activation, using BOLD fMRI in 224 young and healthy participants. More specifically, participants needed to adapt their decision to either pursue or resist immediate rewards to optimize the reward outcome. We found significant CREB1 genotype effects on choices to pursue increases of the reward outcome and on BOLD signal in the NAc, OFC, insula cortex, cingulate gyrus, hippocampus, amygdala, and precuneus during these decisions in comparison with those decisions avoiding total reward loss. Our results suggest that CREB1 genotype effects in these regions could contribute to individual differences in reward- and associative memory-based decision-making. PMID- 26045570 TI - Differential Recruitment of Dentate Gyrus Interneuron Types by Commissural Versus Perforant Pathways. AB - Gamma-aminobutyric acidergic (GABAergic) interneurons (INs) in the dentate gyrus (DG) provide inhibitory control to granule cell (GC) activity and thus gate incoming signals to the hippocampus. However, how various IN subtypes inhibit GCs in response to different excitatory input pathways remains mostly unknown. By using electrophysiology and optogenetics, we investigated neurotransmission of the hilar commissural pathway (COM) and the medial perforant path (MPP) to the DG in acutely prepared mouse slices. We found that the short-term dynamics of excitatory COM-GC and MPP-GC synapses was similar, but that the dynamics of COM- and MPP-mediated inhibition measured in GCs was remarkably different, during theta-frequency stimulation. This resulted in the increased inhibition-excitation (I/E) ratios in single GCs for COM stimulation, but decreased I/E ratios for MPP stimulation. Further analysis of pathway-specific responses in identified INs revealed that basket cell-like INs, total molecular layer- and molecular layer like cells, received greater excitation and were more reliably recruited by the COM than by the MPP inputs. In contrast, hilar perforant path-associated and hilar commissural-associational pathway-related-like cells were minimally activated by both inputs. These results demonstrate that distinct IN subtypes are preferentially recruited by different inputs to the DG, and reveal their relative contributions in COM-mediated feedforward inhibition. PMID- 26045571 TI - Cannabis use and violence in three remote Aboriginal Australian communities: Analysis of clinic presentations. AB - Anecdotal reports have linked cannabis use to violence in some remote Australian Aboriginal communities. We examine the relationship between cannabis use and presentations to local clinics for violence-related trauma at a population level. As part of a larger study, estimates of cannabis and alcohol use status were obtained for 264 randomly selected individuals aged 14-42. These estimates were collected from Aboriginal health workers and respected community informants using a previously validated approach. Clinic records for the sample were audited for physical trauma presentations between January 2004 and June 2006. One in 3 individuals (n = 88/264) presented to the clinic with physical trauma. Of these, the majority (65.9%, n = 58/88) had at least one presentation that was violence related. Nearly 2 in every 3 of the total presentations for trauma following violence (n = 40/63) involved the use of a weapon. Hunting tools were most often used, followed by wooden or rock implements. Individuals who reported any current cannabis use were nearly 4 times more likely than nonusers to present at least once for violent trauma after adjusting for current alcohol use, age, and sex (OR = 3.8, 95% CI [1.5, 9.8]). Aboriginal individuals in these remote communities experience high rates of physical trauma and violence, often involving weapons. A comprehensive study is needed to explore the association between cannabis and violence. At the same time, an investment in local programmes is needed to address cannabis use and underlying risk factors for substance use and for violence. PMID- 26045572 TI - Sleep and Quality of Life in People With COPD: A Descriptive-Correlational Study. AB - Sleep disorders are very common in patients with chronic obstructive pulmonary disease (COPD). However, it is not clear how sleep disorders and quality of life (QoL) affect each other in the different stages of disease progression. This descriptive-correlational study investigated the relationship between QoL, quality of sleep, and degree of disease progression in 102 outpatients with COPD. The results showed that the QoL in patients with COPD is compromised and worsens with disease progression, and the quality of sleep is significantly associated with QoL and worsened as the disease progressed. The early identification of a risk of alteration of the quality of sleep, especially in nursing care, could facilitate a preventive approach for COPD patients that could positively affect their QoL. PMID- 26045573 TI - Characterization of Craniocervical Artery Dissection by Simultaneous MR Noncontrast Angiography and Intraplaque Hemorrhage Imaging at 3T. AB - BACKGROUND AND PURPOSE: Craniocervical artery dissection is the most common cause of ischemic stroke identified in young adults. For the diagnosis of craniocervical artery dissection, multisequence MR imaging is recommended but is time-consuming. Recently, investigators proposed a simultaneous noncontrast angiography and intraplaque hemorrhage imaging technique allowing simultaneous noncontrast MRA and vessel wall imaging in a single scan. This study sought to investigate the feasibility of 3D simultaneous noncontrast angiography and intraplaque hemorrhage MR imaging in the characterization of craniocervical artery dissection. MATERIALS AND METHODS: Twenty-four symptomatic patients (mean age, 45.0 +/- 16.1 years; 21 men) with suspected craniocervical artery dissection were recruited. The 3D simultaneous noncontrast angiography and intraplaque hemorrhage 3D TOF MRA and black-blood imaging sequences were performed on a 3T MR imaging scanner. The agreement between simultaneous noncontrast angiography and intraplaque hemorrhage imaging and multisequence MR imaging in evaluating arterial dissection was determined. RESULTS: Dissection was found to involve 1 artery in 22 patients and 2 arteries in 2 patients. The intramural hematoma and luminal occlusion were detected in 19 (79.2%) and 11 (45.8%) patients, respectively. In measuring stenosis, the Cohen kappa value between 3D TOF MRA and simultaneous noncontrast angiography and intraplaque hemorrhage imaging was 0.82 (P < .001). All intramural hematomas on multisequence imaging were successfully identified by simultaneous noncontrast angiography and intraplaque hemorrhage imaging. CONCLUSIONS: 3D simultaneous noncontrast angiography and intraplaque hemorrhage imaging showed excellent agreement with multisequence MR imaging in evaluating luminal stenosis and intramural hematoma in patients with craniocervical artery dissection. The simultaneous noncontrast angiography and intraplaque hemorrhage imaging saved nearly 50% of scanning time compared with multisequence MR imaging. Our findings suggest that 3D simultaneous noncontrast angiography and intraplaque hemorrhage imaging might be an alternative, time efficient diagnostic tool for craniocervical artery dissection. PMID- 26045574 TI - Endovascular Recanalization in Acute Ischemic Stroke Using the Solitaire FR Revascularization Device with Adjunctive C-Arm CT Imaging. AB - In this clinical report, we examined a single-center experience by using the Solitaire FR Revascularization Device in the treatment of acute ischemic stroke in which there was poor initial visualization of the occluded arterial branches by using biplanar cerebral angiography. In all cases, adjunctive C-arm CT was used during the deployment of the thrombectomy device to gain additional information regarding device placement and expansion. Outcome measures included the extent of reperfusion, posttreatment changes in NIHSS scores, posttreatment TICI scores, cerebral hemorrhage, and survival. Clot removal with successful arterial recanalization was achieved in 15/18 cases (83.3%) with TICI scores of 2b/3 in all patients who had initial recanalization. The NIHSS score improved, on average, from 19 pretreatment to 11 posttreatment, and 72% of patients survived. In cases of acute stroke in which there is little information available regarding the positioning and deployment of a retrievable stent during mechanical thrombectomy, the use of C-arm CT may provide more information about device placement across an area of thrombus. PMID- 26045575 TI - Memory Part 3: The Role of the Fornix and Clinical Cases. PMID- 26045576 TI - CTP in Transient Global Amnesia: A Single-Center Experience of 30 Patients. AB - BACKGROUND AND PURPOSE: Medial temporal lobe abnormalities on DWI and functional imaging are occasionally observed in patients with transient global amnesia. We used CTP to study these patients during or briefly after resolution of their amnesic syndrome. MATERIALS AND METHODS: From 2002 onward, patients satisfying clinical criteria for transient global amnesia who underwent CTP were included. Patients with additional clinical features suggesting transient ischemic attack or stroke and those with an ischemic lesion on subsequent DWI were excluded. If deemed necessary by the clinician, DWI was performed within 10 days. RESULTS: Thirty patients with transient global amnesia underwent CTP at a median latency of 5.9 hours (interquartile range, 4.3-9.7 hours) after symptom onset. All findings, except for those in 1 patient, were normal, including those in the 14 patients with well-imaged hippocampi. In the patient with abnormal findings, CTP and PWI showed hypoperfusion in both lentiform nuclei extending into the insulae, with normalization on the repeat CTP 6 days later. In 10 patients, DWI was performed at a median latency of 2 days (interquartile range, 0-9 days). Of these, 2 showed punctate hippocampal lesions, often seen in transient global amnesia. In 2 patients excluded because of mildly atypical transient global amnesia and ischemic lesions on subsequent DWI, acute CTP findings were also normal. CONCLUSIONS: Patients with transient global amnesia had normal CTP findings in the acute phase with the exception of 1 patient with transient hypoperfusion in both basal ganglia. If imaging is performed for typical and atypical transient global amnesia, DWI should be the preferred method. PMID- 26045577 TI - Hot Topics in Research: Preventive Neuroradiology in Brain Aging and Cognitive Decline. AB - Preventive neuroradiology is a new concept supported by growing literature. The main rationale of preventive neuroradiology is the application of multimodal brain imaging toward early and subclinical detection of brain disease and subsequent preventive actions through identification of modifiable risk factors. An insightful example of this is in the area of age-related cognitive decline, mild cognitive impairment, and dementia with potentially modifiable risk factors such as obesity, diet, sleep, hypertension, diabetes, depression, supplementation, smoking, and physical activity. In studying this link between lifestyle and cognitive decline, brain imaging markers may be instrumental as quantitative measures or even indicators of early disease. The purpose of this article is to provide an overview of the major studies reflecting how lifestyle factors affect the brain and cognition aging. In this hot topics review, we will specifically focus on obesity and physical activity. PMID- 26045578 TI - Assessment of MRI-Based Automated Fetal Cerebral Cortical Folding Measures in Prediction of Gestational Age in the Third Trimester. AB - BACKGROUND AND PURPOSE: Traditional methods of dating a pregnancy based on history or sonographic assessment have a large variation in the third trimester. We aimed to assess the ability of various quantitative measures of brain cortical folding on MR imaging in determining fetal gestational age in the third trimester. MATERIALS AND METHODS: We evaluated 8 different quantitative cortical folding measures to predict gestational age in 33 healthy fetuses by using T2 weighted fetal MR imaging. We compared the accuracy of the prediction of gestational age by these cortical folding measures with the accuracy of prediction by brain volume measurement and by a previously reported semiquantitative visual scale of brain maturity. Regression models were constructed, and measurement biases and variances were determined via a cross validation procedure. RESULTS: The cortical folding measures are accurate in the estimation and prediction of gestational age (mean of the absolute error, 0.43 +/ 0.45 weeks) and perform better than (P = .024) brain volume (mean of the absolute error, 0.72 +/- 0.61 weeks) or sonography measures (SDs approximately 1.5 weeks, as reported in literature). Prediction accuracy is comparable with that of the semiquantitative visual assessment score (mean, 0.57 +/- 0.41 weeks). CONCLUSIONS: Quantitative cortical folding measures such as global average curvedness can be an accurate and reliable estimator of gestational age and brain maturity for healthy fetuses in the third trimester and have the potential to be an indicator of brain-growth delays for at-risk fetuses and preterm neonates. PMID- 26045579 TI - MR Elastography Can Be Used to Measure Brain Stiffness Changes as a Result of Altered Cranial Venous Drainage During Jugular Compression. AB - BACKGROUND AND PURPOSE: Compressing the internal jugular veins can reverse ventriculomegaly in the syndrome of inappropriately low pressure acute hydrocephalus, and it has been suggested that this works by "stiffening" the brain tissue. Jugular compression may also alter blood and CSF flow in other conditions. We aimed to understand the effect of jugular compression on brain tissue stiffness and CSF flow. MATERIALS AND METHODS: The head and neck of 9 healthy volunteers were studied with and without jugular compression. Brain stiffness (shear modulus) was measured by using MR elastography. Phase-contrast MR imaging was used to measure CSF flow in the cerebral aqueduct and blood flow in the neck. RESULTS: The shear moduli of the brain tissue increased with the percentage of blood draining through the internal jugular veins during venous compression. Peak velocity of caudally directed CSF in the aqueduct increased significantly with jugular compression (P < .001). The mean jugular venous flow rate, amplitude, and vessel area were significantly reduced with jugular compression, while cranial arterial flow parameters were unaffected. CONCLUSIONS: Jugular compression influences cerebral CSF hydrodynamics in healthy subjects and can increase brain tissue stiffness, but the magnitude of the stiffening depends on the percentage of cranial blood draining through the internal jugular veins during compression-that is, subjects who maintain venous drainage through the internal jugular veins during jugular compression have stiffer brains than those who divert venous blood through alternative pathways. These methods may be useful for studying this phenomenon in patients with the syndrome of inappropriately low pressure acute hydrocephalus and other conditions. PMID- 26045580 TI - The Impact of Inmate and Prison Characteristics on Prisoner Victimization. AB - A considerable amount of research has been directed at understanding the sources of inmate misconduct (offending within prison), whereas few studies have focused on identifying the causes and correlates of prisoner victimization. The sources of inmate victimization should be distinguished from those of offending, however, because the policy implications of each focus differ to some extent. In order to determine the predictors of inmate victimization and stimulate further research on the topic, we systematically reviewed studies of the causes/correlates of prisoner victimization published between 1980 and 2014. Our findings revealed that predictor variables reflecting inmates' background characteristics (e.g., history of victimization), their institutional routines and experiences (e.g., history of misconduct), and prison characteristics (e.g., population size) all influence victimization. PMID- 26045581 TI - Diagnosing dopamine-responsive dystonias. AB - The clinical spectrum of dopamine-responsive dystonias (DRDs) has expanded over the last decade to comprise several distinct disorders. At the milder end of the clinical spectrum is the autosomal-dominant guanosine triphosphate cyclohydrolase deficiency syndrome (GTPCH-DRD), and at the more severe end is the much less common autosomal recessive tyrosine hydroxylase deficiency syndrome (TH-DRD), with intermediate forms in between. Understanding the pathophysiology of DRDs can help in their optimal diagnosis and management. These are conditions with the potential to be either underdiagnosed when not considered or overdiagnosed if there is an equivocal L-dopa (levo-3,4-dihydroxyphenylalanine) response. In this article, we discuss the clinical phenotypes of these disorders, and we outline how investigations can help in confirming the diagnosis. PMID- 26045582 TI - Retraction. PMID- 26045583 TI - Determination of mannitol sorbitol and myo-inositol in olive tree roots and rhizospheric soil by gas chromatography and effect of severe drought conditions on their profiles. AB - This study reports a method for the analysis of mannitol, sorbitol and myo inositol in olive tree roots and rhizospheric soil with gas chromatography. The analytical method consists of extraction with a mixture of dichloromethane:methanol (2:1, v/v) for soil samples and a mixture of ethanol:water (80:20) for root samples, silylation using pyridine, hexamethyldisilazane (HMDS) and trimethylchlorosilane (TMCS). The recovery of mannitol sorbitol and myo-inositol (for extraction and analysis in dichloromethane:methanol and ethanol:water) was acceptable and ranged from 100.3 to 114.7%. The time of analysis was <24 min. Among identified polyols extracted from rhizosphere and roots of olive plants, mannitol was the major compound. A marked increase in mannitol content occurred in rhizosphere and roots of water stressed plants, suggesting a much broader role of mannitol in stress response based on its ability to act as a compatible solute. PMID- 26045584 TI - Modeling of dispersive liquid-liquid microextraction for determination of essential oil from Borago officinalis L. by using combination of artificial neural network and genetic algorithm method. AB - Dispersive liquid-liquid microextraction (DLLME) coupled with gas chromatography was applied for the extraction and determination of essential oil constituents of the Borago officinalis L. In this study, an experimental data-based artificial neural network (ANN) model was constructed to describe the performance of DLLME method for various operating conditions. The volume of extraction and dispersive solvents, extraction time and salt effect were the input variables of this process, whereas the extraction efficiency was the output. The ANN method was found to be capable of modeling this procedure accurately. The overall agreement between the experimental data and ANN predictions was satisfactory showing a determination coefficient of 0.982. The optimum operating condition was then determined by the genetic algorithm method. The optimal conditions were 248 uL volume of extraction solvent, 260 uL volume of dispersive solvent, 2.5 min extraction time and 0.16 mol L(-1) of salt. The limit of detection and linear dynamic range were 0.15-24.0 and 1.2-1,800 ng mL(-1), respectively. The main components of the essential oil were delta-cadinene (31.02%), carvacrol (24.91%), alpha-pinene (20.89%) and alpha-cadinol (16.47%). PMID- 26045585 TI - Validation of RP-HPLC Method for Simultaneous Quantification of Bicalutamide and Hesperetin in Polycaprolactone-Bicalutamide-Hesperetin-Chitosan Nanoparticles. AB - Bicalutamide is a non-steroidal anti-androgen drug used for the treatment of androgen-dependent prostate cancer. Hesperetin is a natural bioflavonoid that can be used in combination with bicalutamide to improve efficacy and decrease tolerance. The aim of the present work was to develop and validate a simple, sensitive, rapid reverse phase-high performance liquid chromatographic method for simultaneous estimation of bicalutamide and hesperetin. The validation parameters such as specificity, linearity, precision and accuracy, limit of detection (LOD) and limit of quantification (LOQ) were determined according to International Conference on Harmonization ICH Q2 (R1) guidelines. Chromatographic separation was achieved on Lichrocart((r)) CN column (250 * 4 mm, 5 um, MERCK) with isocratic elution. The retention times and detection wavelength, for hesperetin and bicalutamide were 4.28 min, 288 nm and 5.90 min, 270 nm respectively. The intra-day and inter-day assay precision and accuracy were found to be <2% over linearity of 50-2000 ng/mL with R(2) 0.999. LOD and LOQ, of bicalutamide and hesperetin was 14.70, 44.57 ng/mL and 16.11, 48.84 ng/mL, respectively. The method was successfully applied for encapsulation efficiency and drug release studies from bicalutamide and hesperetin loaded nanoparticles. PMID- 26045586 TI - Why So Blue? PMID- 26045587 TI - Could Poor Parental Recall of HPV Vaccination Contribute to Low Vaccination Rates? AB - INTRODUCTION: Rates of initiation and completion of the human papillomavirus (HPV) vaccine series remain below national goals. Because parents are responsible for ensuring vaccination of their children, we examined the accuracy of parental recall of the number of shots their daughters received. METHODS: Parents/guardians of girls aged 11 to 17 years were asked to recall the number of HPV doses received by their daughters. Dose number was confirmed using provider verified medical records. Logistic regression assessed variables associated with correct recall. RESULTS: A total of 79 (63%) parents/guardians correctly identified the number of shots their daughters received. Ninety-one (73%) were aware of whether their daughter started the series at all. The only factor significantly associated with accurate recall in logistic regression models was female gender of parent/guardian. CONCLUSION: Nearly 40% of parents/guardians inaccurately recalled the number of HPV shots their children received, which may contribute to low rates of vaccine initiation and completion. PMID- 26045588 TI - Association Between Atypical/Incomplete Kawasaki Disease and Sensorineural Hearing Loss: A Case Report. PMID- 26045589 TI - Between practice, policy and politics: Music therapy and the Dementia Strategy, 2009. AB - Does current music therapy practice address the goals encapsulated in the UK Department of Health document, Living well with dementia: a national dementia strategy (the Dementia Strategy) published in 2009? A survey elicited the views of clients, family members, music therapists, care home staff and care home managers, about this question by focusing on the relationship between music therapy and the 17 objectives outlined in the Dementia Strategy. The results showed that the objectives that are related to direct activity of the music therapists (such as care and understanding of the condition) were seen as most fulfilled by music therapy, while those regarding practicalities (such as living within the community) were seen as least fulfilled. Although the responses from the four groups of participants were similar, differences for some questions suggest that people's direct experience of music therapy influences their views. This study suggests that many aspects of the Dementia Strategy are already seen as being achieved. The findings suggest that developments of both music therapy practices and government strategies on dementia care may benefit from being mutually informed. PMID- 26045590 TI - The dark side of T memory stem cells. AB - In this issue of Blood, Nagai et al provide evidence that adult T-cell leukemia is hierarchically organized and sustained by a small population of transformed T memory stem cells. PMID- 26045591 TI - Gene therapy outpaces haplo for SCID-X1. AB - In this issue of Blood, Touzot et al report that autologous gene therapy/hematopoietic stem cell transplantation (HSCT) for infants with X-linked severe combined immune deficiency (SCID-X1) lacking a matched sibling donor may have better outcomes than haploidentical (haplo) HSCT. Because gene therapy represents an autologous transplant, it obviates immune suppression before and after transplant, eliminates risks of graft versus host disease (GVHD), and, as the authors report, led to faster immunological reconstitution after transplant than did haplo transplant. PMID- 26045592 TI - DUB-ling down on B-cell malignancies. AB - In this issue of Blood, Peterson et al demonstrate that inhibition of both Usp9x and Usp24 results in efficient degradation of Mcl-1, induction of apoptosis, and inhibition of tumor growth in B-cell malignancies. PMID- 26045593 TI - A paradigm shift in platelet transfusion therapy. AB - In this issue of Blood, Wang et al report that ex vivo-derived human megakaryocytes infused into mice are trapped in the pulmonary vasculature and release functional platelets into the circulation. Because of the difficulty in scalable generation of ex vivo-derived functional platelets, this strategy may be a substitute for platelet transfusion therapy. PMID- 26045594 TI - Atypical HUS may become a diagnosis of inclusion. AB - In this issue of Blood, Gavriilaki and colleagues describe an assay that could convert atypical hemolytic uremic syndrome (aHUS) from a diagnosis of exclusion into a direct pathophysiologic diagnosis. PMID- 26045595 TI - Survival in patients with familial and sporadic myeloproliferative neoplasms. PMID- 26045596 TI - How does dapsone work in immune thrombocytopenia? Implications for dosing. PMID- 26045597 TI - Phase 1/2 trial of vorinostat in patients with sickle cell disease who have not benefitted from hydroxyurea. PMID- 26045598 TI - Serum hepcidin levels predict response to intravenous iron and darbepoetin in chemotherapy-associated anemia. PMID- 26045599 TI - Developing Cellular Therapies for Stroke. PMID- 26045600 TI - Imaging in StrokeNet: Realizing the Potential of Big Data. PMID- 26045601 TI - Synergistic Effects of Transplanted Endothelial Progenitor Cells and RWJ 67657 in Diabetic Ischemic Stroke Models. AB - BACKGROUND AND PURPOSE: An immature vascular phenotype in diabetes mellitus may cause more severe vascular damage and poorer functional outcomes after stroke, and it would be feasible to repair damaged functional vessels using endothelial progenitor cell (EPC) transplantation. However, high glucose induces p38 mitogen activated protein kinase activation, which can accelerate the senescence and apoptosis of EPCs. The aim of this study was to investigate the combined effects of EPC transplantation and p38 mitogen-activated protein kinase inhibitor administration on diabetic stroke outcomes. METHODS: Bone marrow-derived EPCs were injected intra-arterially into db/db mice after ischemic stroke induction. RWJ 67657 (RWJ), a p38 mitogen-activated protein kinase inhibitor, was administered orally for 7 consecutive days, with the first dose given 30 minutes before stroke induction. Functional outcome was determined at days 0, 1, 7, 14, and 21. Angiogenesis, neurogenesis, infarct volume, and Western blotting assays were performed on day 7, and white matter remodeling was determined on day 14. RESULTS: Neither EPC transplantation nor RWJ administration alone significantly improved diabetic stroke outcome although RWJ displayed a potent anti inflammatory effect. By both improving the functioning of EPCs and reducing inflammation, EPC transplantation plus RWJ administration in vivo synergistically promoted angiogenesis and neurogenesis after diabetic stroke. In addition, the white matter remodeling, behavioral scores, and expressions of vascular endothelial growth factor and brain-derived neurotrophic factor were significantly increased in diabetic mice treated with both EPCs and RWJ. CONCLUSIONS: The combination of EPC transplantation and RWJ administration accelerated recovery from diabetic stroke, which might have been caused by increased levels of proangiogenic and neurotrophic factors. PMID- 26045602 TI - Long-Term Excess Mortality After Aneurysmal Subarachnoid Hemorrhage: Patients With Multiple Aneurysms at Risk. AB - BACKGROUND AND PURPOSE: There is high case-fatality rate and loss of productive life-years related to aneurysmal subarachnoid hemorrhage (aSAH) but data on long term survival of patients with aSAH are scarce. We aim to evaluate long-term excess mortality and related risk factors after an aSAH event. METHODS: Survivors (n=3078) of aSAH who had survived for >=1 year were reviewed for this retrospective follow-up study, which was conducted in the Department of Neurosurgery in Helsinki between 1980 and 2007. Follow-up started 1 year after the aSAH and continued until death or the end of 2012 (48 918 patient-years). Mortality and relative survival ratios were derived using a matched general population. RESULTS: Survivors of aSAH after 20 years showed 17% excess mortality compared with the general population. Even young patients and patients with good recovery showed excess mortality. The highest excess mortality was among patients with multiple aneurysms, old age, poor preoperative clinical condition, conservative aneurysm treatment, and unfavorable clinical outcome at 1 year. CONCLUSIONS: Even after initially favorable recovery from an aSAH, survivors experience excess mortality in the long run in comparison to a matched general population. Cardiovascular disease at younger age and cerebrovascular events were overrepresented as causes of death, which indicates the importance of treatment of vascular risk factors. Young patients and patients with multiple aneurysms who are recovering from an aSAH should be followed-up and treated most actively. PMID- 26045603 TI - Assessing the Reliability and Validity of a Physical Therapy Functional Measurement Tool--the Modified Iowa Level of Assistance Scale--in Acute Hospital Inpatients. AB - BACKGROUND: Functional outcome measurement tools exist for individual diagnoses (eg, stroke), but no prospectively validated mobility measure is available for physical therapists' use across the breadth of acute hospital inpatients. The modified Iowa Level of Assistance Scale (mILOA), a scale measuring assistance required to achieve functional tasks, has demonstrated functional change in inpatients with orthopedic conditions and trauma, although its psychometric properties are unknown. OBJECTIVE: The aim of this study was to assess interrater reliability, known-groups validity, and responsiveness of the mILOA in acute hospital inpatients. DESIGN: This was a cohort, measurement-focused study. METHODS: Patients at a large teaching hospital in Melbourne, Australia, were recruited. One hundred fifty-two inpatients who were functionally stable across 5 clinical groups had an mILOA score calculated during 2 independent physical therapy sessions to assess interrater reliability. Known-groups validity ("ready for discharge"/"not ready for discharge") and responsiveness also were assessed. RESULTS: The mean age of participants in the reliability phase of the study was 62.5 years (SD=17.7). The interrater reliability was excellent (intraclass correlation coefficient [2,1]=.975; 95% confidence interval=.965, .982), with a mean difference between scores of -.270 and limits of agreement of +/-5.64. The mILOA score displayed a mean difference between 2 known groups of 15.3 points. Responsiveness was demonstrated with a minimal detectable change of 5.8 points. LIMITATIONS: Participants were included in the study if able to give consent for themselves, thereby limiting generalizability. Construct validity was not assessed due to the lack of a gold standard. CONCLUSIONS: The mILOA has excellent interrater reliability and good known-groups validity and responsiveness to functional change across acute hospital inpatients with a variety of diagnoses. It may provide opportunities for physical therapists to collect a functional outcome measure to demonstrate the effectiveness of inpatient therapy and allow for benchmarking across institutions. PMID- 26045604 TI - Physical Therapist Practice in the Intensive Care Unit: Results of a National Survey. AB - BACKGROUND: Early rehabilitation improves outcomes, and increased use of physical therapist services in the intensive care unit (ICU) has been recommended. Little is known about the implementation of early rehabilitation programs or physical therapists' preparation and perceptions of care in the United States. OBJECTIVE: A national survey was conducted to determine the current status of physical therapist practice in the ICU. DESIGN: This study used a cross-sectional, observational design. METHODS: Self-report surveys were mailed to members of the Acute Care Section of the American Physical Therapy Association. Questions addressed staffing, training, barriers, and protocols, and case scenarios were used to determine perceptions about providing rehabilitation. RESULTS: The response rate was 29% (667/2,320). Staffing, defined as the number of physical therapists per 100 ICU beds, was highest in community hospitals (academic: median=5.4 [range=3.6-9.2]; community: median=6.7 [range=4.4-10.0]) and in the western United States (median=7.5 [range=4.2-12.9]). Twelve percent of physical therapists reported no training. Barriers to providing ICU rehabilitation included insufficient staffing and training, departmental prioritization policies, and inadequate consultation criteria. Responses to case scenarios demonstrated differences in the likelihood of consultation and physical therapists' prescribed frequency and intensity of care based on medical interventions rather than characteristics of patients. Physical therapists in academic hospitals were more likely to be involved in the care of patients in each scenario and were more likely to perform higher-intensity mobilization. LIMITATIONS: Members of the Acute Care Section of the American Physical Therapy Association may not represent most practicing physical therapists, and the 29% return rate may have contributed to response bias. CONCLUSIONS: Although staffing was higher in community hospitals, therapists in academic and community hospitals cited insufficient staffing as the most common barrier to providing rehabilitation in the ICU. Implementing strategies to overcome barriers identified in this study may improve the delivery of ICU rehabilitation services. PMID- 26045605 TI - Activities of Daily Living in Children With Developmental Coordination Disorder: Performance, Learning, and Participation. AB - BACKGROUND: Children with developmental coordination disorder (DCD) face evident motor difficulties in daily functioning. Little is known, however, about their difficulties in specific activities of daily living (ADL). OBJECTIVE: The purposes of this study were: (1) to investigate differences between children with DCD and their peers with typical development for ADL performance, learning, and participation, and (2) to explore the predictive values of these aspects. DESIGN: This was a cross-sectional study. METHODS: In both a clinical sample of children diagnosed with DCD (n=25 [21 male, 4 female], age range=5-8 years) and a group of peers with typical development (25 matched controls), the children's parents completed the DCDDaily-Q. Differences in scores between the groups were investigated using t tests for performance and participation and Pearson chi square analysis for learning. Multiple regression analyses were performed to explore the predictive values of performance, learning, and participation. RESULTS: Compared with their peers, children with DCD showed poor performance of ADL and less frequent participation in some ADL. Children with DCD demonstrated heterogeneous patterns of performance (poor in 10%-80% of the items) and learning (delayed in 0%-100% of the items). In the DCD group, delays in learning of ADL were a predictor for poor performance of ADL, and poor performance of ADL was a predictor for less frequent participation in ADL compared with the control group. LIMITATIONS: A limited number of children with DCD were addressed in this study. CONCLUSIONS: This study highlights the impact of DCD on children's daily lives and the need for tailored intervention. PMID- 26045606 TI - Diagnostic Value of Clinical Cervical Spine Tests in Patients With Cervicogenic Somatic Tinnitus. AB - BACKGROUND: Tinnitus can be related to many different etiologies, such as hearing loss or a noise trauma, but it also can be related to the somatosensory system of the cervical spine. The diagnosis of cervicogenic somatic tinnitus (CST) is made when the predominant feature is the temporal coincidence of appearance or increase of both neck pain and tinnitus. OBJECTIVE: The aim of this study was to assess the diagnostic value of clinical cervical spine tests in people with CST. DESIGN: A cross-sectional study was conducted. SETTING: The study was conducted at a tertiary referral center. PATIENTS: Consecutive adult patients with chronic subjective nonpulsatile tinnitus were included. Exclusion criteria were vertigo, Meniere disease, middle ear pathology, intracranial pathology, cervical spine surgery, whiplash trauma, and temporomandibular dysfunction. MEASUREMENTS: A full ear, nose, and throat examination was conducted to classify patients into CST and non-CST groups. The physical therapist examination included completion of the Neck Bournemouth Questionnaire (NBQ) and the following clinical cervical spine tests: manual rotation test, adapted Spurling test (AST), trigger point tests, and tests for strength and endurance of the deep neck flexors. RESULTS: Eighty seven patients with tinnitus were included, of whom 37 (43%) were diagnosed with CST. The diagnosis of CST becomes less likely with NBQ scores of <14 points (sensitivity of 80%, likelihood ratio [LR] of 0.3, and posttest probability of 19%). Absence of trigger points corresponded to an LR of 0.3, a sensitivity of 82%, and a posttest probability of 22%. A positive manual rotation test and AST indicate a higher probability of CST (LR of 5, specificity of 90%, and posttest probability of 78%). LIMITATIONS: A limited number of clinical cervical spine tests were used in this study. Although tests with good validity and reliability were included, additional tests could provide more information on cervical spine dysfunction in patients with CST. CONCLUSIONS: Clinical cervical spine tests can support the diagnostic process for CST. An NBQ score of <14 points and the absence of trigger points can help to exclude CST. In contrast, a positive manual rotation test and AST can help to include CST. In future studies, these tests should be included in a multidisciplinary assessment of patients with suspected CST. PMID- 26045607 TI - Characterization of mice harboring a variant of EPCR with impaired ability to bind protein C: novel role of EPCR in hematopoiesis. AB - The interaction of protein C (PC) with the endothelial PC receptor (EPCR) enhances activated PC (APC) generation. The physiological importance of EPCR has been demonstrated in EPCR knockout mice which show early embryonic lethality due to placental thrombosis. In order to study the role of EPCR independent of PC interaction, we generated an EPCR point mutation knock-in mouse (EPCR(R84A/R84A)) which lacks the ability to bind PC/APC. EPCR(R84A/R84A) mice are viable and reproduce normally. In response to thrombotic challenge with factor Xa/phospholipids, EPCR(R84A/R84A) mice generate more thrombin, less APC, and show increased fibrin deposition in lungs and heart compared with wild-type (WT) mice. EPCR(R84A/R84A) mice challenged with lipopolysaccharide generate less APC, more interleukin-6, and show increased neutrophil infiltration in the lungs compared with WT controls. Interestingly, EPCR(R84A/R84A) mice develop splenomegaly as a result of bone marrow (BM) failure. BM transplant experiments suggest a role for EPCR on hematopoietic stem cells and BM stromal cells in modulating hematopoiesis. Taken together, our studies suggest that impaired EPCR/PC-binding interactions not only result in procoagulant and proinflammatory effects, but also impact hematopoiesis. PMID- 26045608 TI - Cartilage oligomeric matrix protein is a natural inhibitor of thrombin. AB - Thrombin is an effector enzyme for hemostasis and thrombosis; however, endogenous regulators of thrombin remain elusive. Cartilage oligomeric matrix protein (COMP), a matricellular protein also known as thrombospondin-5, is essential for maintaining vascular homeostasis. Here, we asked whether COMP is involved in the process of blood coagulation. COMP deficiency shortened tail-bleeding and clotting time and accelerated ferric-chloride-induced thrombosis in mice. The absence of COMP had no effect on platelet count. In contrast, COMP specifically inhibited thrombin-induced platelet aggregation, activation, and retraction and the thrombin-mediated cleavage of fibrinogen. Furthermore, surface plasmon resonance analysis revealed direct thrombin-COMP binding (KD = 1.38 +/- 0.24 MUM). In particular, blockage of thrombin exosites with compounds specific for exosite I (hirudin and HD1 aptamer) or exosite II (heparin and HD22 aptamer) impaired the COMP-thrombin interaction, indicating a 2-site binding mechanism. Additionally, epidermal growth factor-like repeats (amino acids 84-261) were identified as a COMP binding site for thrombin. Moreover, COMP was expressed in and secreted by platelets. Using bone marrow transplantation and platelet transfusion to create chimeric mice, platelet-derived but not vessel-wall-derived COMP was demonstrated to inhibit coagulation. Taken together, COMP is an endogenous thrombin inhibitor and negative regulator of hemostasis and thrombosis. PMID- 26045610 TI - Circular and longitudinal muscles shortening indicates sliding patterns during peristalsis and transient lower esophageal sphincter relaxation. AB - Esophageal axial shortening is caused by longitudinal muscle (LM) contraction, but circular muscle (CM) may also contribute to axial shortening because of its spiral morphology. The goal of our study was to show patterns of contraction of CM and LM layers during peristalsis and transient lower esophageal sphincter (LES) relaxation (TLESR). In rats, esophageal and LES morphology was assessed by histology and immunohistochemistry, and function with the use of piezo-electric crystals and manometry. Electrical stimulation of the vagus nerve was used to induce esophageal contractions. In 18 healthy subjects, manometry and high frequency intraluminal ultrasound imaging during swallow-induced esophageal contractions and TLESR were evaluated. CM and LM thicknesses were measured (40 swallows and 30 TLESRs) as markers of axial shortening, before and at peak contraction, as well as during TLESRs. Animal studies revealed muscular connections between the LM and CM layers of the LES but not in the esophagus. During vagal stimulated esophageal contraction there was relative movement between the LM and CM. Human studies show that LM-to-CM (LM/CM) thickness ratio at baseline was 1. At the peak of swallow-induced contraction LM/CM ratio decreased significantly (<1), whereas the reverse was the case during TLESR (>2). The pattern of contraction of CM and LM suggests sliding of the two muscles. Furthermore, the sliding patterns are in the opposite direction during peristalsis and TLESR. PMID- 26045609 TI - Inhibition of Mcl-1 with the pan-Bcl-2 family inhibitor (-)BI97D6 overcomes ABT 737 resistance in acute myeloid leukemia. AB - Overexpression of antiapoptotic Bcl-2 proteins such as Bcl-2, Bcl-xL, and Mcl-1 is widely associated with tumor initiation, progression, and chemoresistance. Furthermore, it has been demonstrated that Mcl-1 upregulation renders several types of cancers resistant to the Bcl-2/Bcl-xL inhibitors ABT-737 and ABT-263. The emerging importance of Mcl-1 in pathogenesis and drug resistance makes it a high-priority therapeutic target. In this study, we showed that inhibition of Mcl 1 with a novel pan-Bcl-2 inhibitor (-)BI97D6 potently induced apoptosis in acute myeloid leukemia (AML) cells. (-)BI97D6 induced hallmarks of mitochondrial apoptosis, disrupted Mcl-1/Bim and Bcl-2/Bax interactions, and stimulated cell death via the Bak/Bax-dependent mitochondrial apoptosis pathway, suggesting on target mechanisms. As a single agent, this pan-Bcl-2 inhibitor effectively overcame AML cell apoptosis resistance mediated by Mcl-1 or by interactions with bone marrow mesenchymal stromal cells. (-)BI97D6 was also potent in killing refractory primary AML cells. Importantly, (-)BI97D6 killed AML leukemia stem/progenitor cells while largely sparing normal hematopoietic stem/progenitor cells. These findings demonstrate that pan-Bcl-2 inhibition by an Mcl-1-targeting inhibitor not only overcomes intrinsic drug resistance ensuing from functional redundancy of Bcl-2 proteins, but also abrogates extrinsic resistance caused by the protective tumor microenvironment. PMID- 26045611 TI - Differential expression of proteins involved in energy production along the crypt villus axis in early-weaning pig small intestine. AB - Weaning of piglets reflects intestinal dysfunction and atrophy and affected the physiological state of enterocytes. However, few studies have defined physiological state of enterocytes along the crypt-villus axis in early-weaning piglets. A total of 16 piglets from 8 litters were used in the experiment. One group of piglets was nursed by sows until age 21 days, and another group was weaned at age 14 days and then fed creep feed instead of breast milk for 7 days. Piglets were killed at 21 days, and the jejunum segments were dissected. After sequential isolation of jejunum epithelial cells along the crypt-villus axis, their proteins were analyzed through the isobaric tags for relative and absolute quantification, and proteins involved in the mammalian target of rapamycin signaling pathway and proliferating cell nuclear antigen abundances in jejunal epithelial cells of weaning or suckling group were determined by Western blotting. The differential proteins in three cell fractions were identified and analyzed. The results showed that proteins involved in the tricarboxylic acid cycle, beta-oxidation, and the glycolysis pathway were significantly downregulated in the upper and middle villus of the early-weaned group. However, proteins involved in glycolysis were significantly upregulated in crypt cells. In addition, Western blot analysis showed that the expression of mammalian target of rapamycin pathway-related proteins was decreased (P < 0.05) in the early-weaned group. The present results showed that early-weaning differentially affect the expression of proteins involved in energy production of enterocytes along the jejunal crypt-villus axis. PMID- 26045612 TI - Neuroenteric axis modulates the balance of regulatory T cells and T-helper 17 cells in the mesenteric lymph node following trauma/hemorrhagic shock. AB - CD103(+) dendritic cells (DCs) continuously migrate from the intestine to the mesenteric lymph nodes (MLNs) and maintain tolerance by driving the development of regulatory T cells (Treg) in the gut. The relative expression of Treg and T helper 17 (Th17) cells determines the balance between tolerance and immunity in the gut. We hypothesized that trauma/hemorrhagic shock (T/HS) would decrease the CD103(+) DC population in the mesenteric lymph and alter the Treg-to-Th17 ratio in the MLN. We further hypothesized that vagus nerve stimulation (VNS) would promote tolerance to inflammation by increasing the Treg-to-Th17 ratio in the MLN after injury. Male rats were assigned to sham shock (SS), trauma/sham shock (T/SS), or T/HS. T/HS was induced by laparotomy and 60 min of HS (blood pressure 35 mmHg) followed by fluid resuscitation. A separate cohort of animals underwent cervical VNS after the HS phase. MLN samples were collected 24 h after resuscitation. The CD103(+) DC population and Treg-to-Th17 cell ratio in the MLN were decreased after T/HS compared with SS and T/SS, suggesting a shift to an inflammatory response. VNS prevented the T/HS-induced decrease in the CD103(+) DC population and increased the Treg-to-Th17 ratio compared with T/HS alone. VNS alters the gut inflammatory response to injury by modulating the Treg-Th17 cell balance in the MLN. VNS promotes tolerance to inflammation in the gut, further supporting its ability to modulate the inflammatory set point and alter the response to injury. PMID- 26045613 TI - Helicobacter pylori virulence factors affecting gastric proton pump expression and acid secretion. AB - Acute Helicobacter pylori infection of gastric epithelial cells and human gastric biopsies represses H,K-ATPase alpha subunit (HKalpha) gene expression and inhibits acid secretion, causing transient hypochlorhydria and supporting gastric H. pylori colonization. Infection by H. pylori strains deficient in the cag pathogenicity island (cag PAI) genes cagL, cagE, or cagM, which do not transfer CagA into host cells or induce interleukin-8 secretion, does not inhibit HKalpha expression, nor does a cagA-deficient strain that induces IL-8. To test the hypothesis that virulence factors other than those mediating CagA translocation or IL-8 induction participate in HKalpha repression by activating NF-kappaB, AGS cells transfected with HKalpha promoter-Luc reporter constructs containing an intact or mutated NF-kappaB binding site were infected with wild-type H. pylori strain 7.13, isogenic mutants lacking cag PAI genes responsible for CagA translocation and/or IL-8 induction (cagA, cagzeta, cagepsilon, cagZ, and cagbeta), or deficient in genes encoding two peptidoglycan hydrolases (slt and caggamma). H. pylori-induced AGS cell HKalpha promoter activities, translocated CagA, and IL-8 secretion were measured by luminometry, immunoblotting, and ELISA, respectively. Human gastric biopsy acid secretion was measured by microphysiometry. Taken together, the data showed that HKalpha repression is independent of IL-8 expression, and that CagA translocation together with H. pylori transglycosylases encoded by slt and caggamma participate in NF-kappaB dependent HKalpha repression and acid inhibition. The findings are significant because H. pylori factors other than CagA and IL-8 secretion are now implicated in transient hypochlorhydria which facilitates gastric colonization and potential triggering of epithelial progression to neoplasia. PMID- 26045615 TI - A gamma variate model that includes stretched exponential is a better fit for gastric emptying data from mice. AB - Noninvasive breath tests for gastric emptying are important techniques for understanding the changes in gastric motility that occur in disease or in response to drugs. Mice are often used as an animal model; however, the gamma variate model currently used for data analysis does not always fit the data appropriately. The aim of this study was to determine appropriate mathematical models to better fit mouse gastric emptying data including when two peaks are present in the gastric emptying curve. We fitted 175 gastric emptying data sets with two standard models (gamma variate and power exponential), with a gamma variate model that includes stretched exponential and with a proposed two component model. The appropriateness of the fit was assessed by the Akaike Information Criterion. We found that extension of the gamma variate model to include a stretched exponential improves the fit, which allows for a better estimation of T1/2 and Tlag. When two distinct peaks in gastric emptying are present, a two-component model is required for the most appropriate fit. We conclude that use of a stretched exponential gamma variate model and when appropriate a two-component model will result in a better estimate of physiologically relevant parameters when analyzing mouse gastric emptying data. PMID- 26045614 TI - Transforming growth factor-beta2 is sequestered in preterm human milk by chondroitin sulfate proteoglycans. AB - Human milk contains biologically important amounts of transforming growth factor beta2 isoform (TGF-beta2), which is presumed to protect against inflammatory gut mucosal injury in the neonate. In preclinical models, enterally administered TGF beta2 can protect against experimental necrotizing enterocolitis, an inflammatory bowel necrosis of premature infants. In this study, we investigated whether TGF beta bioactivity in human preterm milk could be enhanced for therapeutic purposes by adding recombinant TGF-beta2 (rTGF-beta2) to milk prior to feeding. Milk-borne TGF-beta bioactivity was measured by established luciferase reporter assays. Molecular interactions of TGF-beta2 were investigated by nondenaturing gel electrophoresis and immunoblots, computational molecular modeling, and affinity capillary electrophoresis. Addition of rTGF-beta2 (20-40 nM) to human preterm milk samples failed to increase TGF-beta bioactivity in milk. Milk-borne TGF beta2 was bound to chondroitin sulfate (CS) containing proteoglycan(s) such as biglycan, which are expressed in high concentrations in milk. Chondroitinase treatment of milk increased the bioactivity of both endogenous and rTGF-beta2, and consequently, enhanced the ability of preterm milk to suppress LPS-induced NF kappaB activation in macrophages. These findings provide a mechanism for the normally low bioavailability of milk-borne TGF-beta2 and identify chondroitinase digestion of milk as a potential therapeutic strategy to enhance the anti inflammatory effects of preterm milk. PMID- 26045616 TI - Metformin prevents ischemia reperfusion-induced oxidative stress in the fatty liver by attenuation of reactive oxygen species formation. AB - Nonalcoholic fatty liver disease is associated with chronic oxidative stress. In our study, we explored the antioxidant effect of antidiabetic metformin on chronic [high-fat diet (HFD)-induced] and acute oxidative stress induced by short term warm partial ischemia-reperfusion (I/R) or on a combination of both in the liver. Wistar rats were fed a standard diet (SD) or HFD for 10 wk, half of them being administered metformin (150 mg.kg body wt(-1).day(-1)). Metformin treatment prevented acute stress-induced necroinflammatory reaction, reduced alanine aminotransferase and aspartate aminotransferase serum activity, and diminished lipoperoxidation. The effect was more pronounced in the HFD than in the SD group. The metformin-treated groups exhibited less severe mitochondrial damage (markers: cytochrome c release, citrate synthase activity, mtDNA copy number, mitochondrial respiration) and apoptosis (caspase 9 and caspase 3 activation). Metformin treated HFD-fed rats subjected to I/R exhibited increased antioxidant enzyme activity as well as attenuated mitochondrial respiratory capacity and ATP resynthesis. The exposure to I/R significantly increased NADH- and succinate related reactive oxygen species (ROS) mitochondrial production in vitro. The effect of I/R was significantly alleviated by previous metformin treatment. Metformin downregulated the I/R-induced expression of proinflammatory (TNF-alpha, TLR4, IL-1beta, Ccr2) and infiltrating monocyte (Ly6c) and macrophage (CD11b) markers. Our data indicate that metformin reduces mitochondrial performance but concomitantly protects the liver from I/R-induced injury. We propose that the beneficial effect of metformin action is based on a combination of three contributory mechanisms: increased antioxidant enzyme activity, lower mitochondrial ROS production, and reduction of postischemic inflammation. PMID- 26045619 TI - Self rated "health score" can predict risk of death in next five years, researchers say. PMID- 26045617 TI - Selenium and inflammatory bowel disease. AB - Dietary intake of the micronutrient selenium is essential for normal immune functions. Selenium is cotranslationally incorporated as the 21st amino acid, selenocysteine, into selenoproteins that function to modulate pathways involved in inflammation. Epidemiological studies have suggested an inverse association between selenium levels and inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis that can potentially progress to colon cancer. However, the underlying mechanisms are not well understood. Here we summarize the current literature on the pathophysiology of IBD, which is multifactorial in origin with unknown etiology. We have focused on a few selenoproteins that mediate gastrointestinal inflammation and activate the host immune response, wherein macrophages play a pivotal role. Changes in cellular oxidative state coupled with altered expression of selenoproteins in macrophages drive the switch from a proinflammatory phenotype to an anti-inflammatory phenotype to efficiently resolve inflammation in the gut and restore epithelial barrier integrity. Such a phenotypic plasticity is accompanied by changes in cytokines, chemokines, and bioactive metabolites, including eicosanoids that not only mitigate inflammation but also partake in restoring gut homeostasis through diverse pathways involving differential regulation of transcription factors such as nuclear factor-kappaB and peroxisome proliferator-activated receptor-gamma. The role of the intestinal microbiome in modulating inflammation and aiding in selenium-dependent resolution of gut injury is highlighted to provide novel insights into the beneficial effects of selenium in IBD. PMID- 26045618 TI - Mitochondrial STAT3 contributes to transformation of Barrett's epithelial cells that express oncogenic Ras in a p53-independent fashion. AB - Metaplastic epithelial cells of Barrett's esophagus transformed by the combination of p53-knockdown and oncogenic Ras expression are known to activate signal transducer and activator of transcription 3 (STAT3). When phosphorylated at tyrosine 705 (Tyr705), STAT3 functions as a nuclear transcription factor that can contribute to oncogenesis. STAT3 phosphorylated at serine 727 (Ser727) localizes in mitochondria, but little is known about mitochondrial STAT3's contribution to carcinogenesis in Barrett's esophagus, which is the focus of this study. We introduced a constitutively active variant of human STAT3 (STAT3CA) into the following: 1) non-neoplastic Barrett's (BAR-T) cells; 2) BAR-T cells with p53 knockdown; and 3) BAR-T cells that express oncogenic H-Ras(G12V). STAT3CA transformed only the H-Ras(G12V)-expressing BAR-T cells (evidenced by loss of contact inhibition, formation of colonies in soft agar, and generation of tumors in immunodeficient mice), and did so in a p53-independent fashion. The transformed cells had elevated levels of both mitochondrial (Ser727) and nuclear (Tyr705) phospho-STAT3. Introduction of a STAT3CA construct with a mutated tyrosine phosphorylation site into H-Ras(G12V)-expressing Barrett's cells resulted in high levels of mitochondrial phospho-STAT3 (Ser727) with little or no nuclear phospho-STAT3 (Tyr705), and the cells still formed tumors in immunodeficient mice. Thus tyrosine phosphorylation of STAT3 is not required for tumor formation in Ras-expressing Barrett's cells. We conclude that mitochondrial STAT3 (Ser727) can contribute to oncogenesis in Barrett's cells that express oncogenic Ras. These findings suggest that agents targeting STAT3 might be useful for chemoprevention in patients with Barrett's esophagus. PMID- 26045621 TI - Benefits of mammography in women aged 50-69 outweigh risks, says expert panel. PMID- 26045620 TI - Noninjured Knees of Patients With Noncontact ACL Injuries Display Higher Average Anterior and Internal Rotational Knee Laxity Compared With Healthy Knees of a Noninjured Population. AB - BACKGROUND: Excessive physiological anterior and rotational knee laxity is thought to be a risk factor for noncontact anterior cruciate ligament (ACL) injuries and inferior reconstruction outcomes, but no thresholds have been established to identify patients with increased laxity. PURPOSE: (1) To determine if the healthy contralateral knees of ACL-injured patients have greater anterior and rotational knee laxity, leading to different laxity profiles (combination of laxities), compared with healthy control knees and (2) to set a threshold to help discriminate anterior and rotational knee laxity between these groups. STUDY DESIGN: Case-sectional study; Level of evidence, 3. METHODS: A total of 171 healthy contralateral knees of noncontact ACL-injured patients (ACL-H group) and 104 healthy knees of control participants (CTL group) were tested for anterior and rotational laxity. Laxity scores (measurements corrected for sex and body mass) were used to classify knees as hypolax (score <-1), normolax (between -1 and 1), or hyperlax (>1). Proportions of patients in each group were compared using chi(2) tests. Receiver operating characteristic curves were computed to discriminate laxity between the groups. Odds ratios were calculated to determine the probability of being in the ACL-H group. RESULTS: The ACL-H group displayed greater laxity scores for anterior displacement and internal rotation in their uninjured knee compared with the CTL group (P < .05). Laxity profiles were different between the groups for the following associations: normolax in anterior displacement/hypolax in internal rotation (6% [ACL-H] vs 15% [CTL]; P = .02) and hyperlax in anterior displacement/normolax in internal rotation (27% [ACL-H] vs 10% [CTL]; P < .01). The laxity score thresholds were 0.75 for anterior laxity and -0.55 for internal rotation. With both scores above these thresholds, a patient was 3.18-fold more likely to be in the ACL-H group (95% CI, 1.74-5.83). CONCLUSION: The healthy contralateral knees of patients with noncontact ACL injuries display different laxity values both for internal rotation and anterior displacement compared with healthy control knees. The identification of knee laxity profiles may be of relevance for primary and secondary prevention programs of noncontact ACL injuries. PMID- 26045622 TI - US melanoma prevalence has doubled over past 30 years. PMID- 26045623 TI - Canadian tobacco firms are ordered to pay L8bn for damage from smoking. PMID- 26045624 TI - NHS in Scotland needs urgent change for it to survive, say colleges. PMID- 26045625 TI - More could be done to protect people from heatwave in India, say campaigners. PMID- 26045626 TI - Electrical pulse fabrication of graphene nanopores in electrolyte solution. AB - Nanopores in graphene membranes can potentially offer unprecedented spatial resolution for single molecule sensing, but their fabrication has thus far been difficult, poorly scalable, and prone to contamination. We demonstrate an in-situ fabrication method that nucleates and controllably enlarges nanopores in electrolyte solution by applying ultra-short, high-voltage pulses across the graphene membrane. This method can be used to rapidly produce graphene nanopores with subnanometer size accuracy in an apparatus free of nanoscale beams or tips. PMID- 26045627 TI - Nonlinear photoacoustic spectroscopy of hemoglobin. AB - As light intensity increases in photoacoustic imaging, the saturation of optical absorption and the temperature dependence of the thermal expansion coefficient result in a measurable nonlinear dependence of the photoacoustic (PA) signal on the excitation pulse fluence. Here, under controlled conditions, we investigate the intensity-dependent photoacoustic signals from oxygenated and deoxygenated hemoglobin at varied optical wavelengths and molecular concentrations. The wavelength and concentration dependencies of the nonlinear PA spectrum are found to be significantly greater in oxygenated hemoglobin than in deoxygenated hemoglobin. These effects are further influenced by the hemoglobin concentration. These nonlinear phenomena provide insights into applications of photoacoustics, such as measurements of average inter-molecular distances on a nm scale or with a tuned selection of wavelengths, a more accurate quantitative PA tomography. PMID- 26045628 TI - [Fe-Fe]-hydrogenase Reactivated by Residue Mutations as Bridging Carbonyl Rearranges: A QM/MM Study. AB - In the current work, we found aqueous enzyme phase reaction pathways for the reactivation of the exogenously inhibited [Fe-Fe]-hydrogenases by O2, or OH-, which metabolizes to H2O1,2. We used the hybrid quantum mechanics/molecular mechanics (QM/MM) method to study the reactivation pathways of the exogenously inhibited enzyme matrix. The ONIOM calculations performed on the enzyme agree with experimental results3, i.e., wild-type [Fe-Fe]-hydrogenase H-cluster is inhibited by oxygen metabolites. An enzyme spherical region with a radius of 8 A (from the distal iron, Fed) has been screened for residues that prevent H2O from leaving the catalytic site and reactivate the [Fe-Fe]-hydrogenase H-cluster. In the screening process, polar residues were removed, one at a time, and frequency calculations provided the change in the Gibbs' energy for the dissociation of water (due to their deletion). When residue deletion resulted in significant Gibbs' energy decrease, further residue substitutions have been carried out. Following each substitution, geometry optimization and frequency calculations have been performed to assess the change in the Gibbs' energy for the elimination H2O. Favorable thermodynamic results have been obtained for both single residue removal (DeltaGDeltaGlu374 = -1.6 kcal/mol), single substitution (DeltaGGlu374His = -3.1 kcal/mol), and combined residue substitutions (DeltaGArg111Glu;Thr145Val;Glu374His;Tyr375Phe = -7.5 kcal/mol). Because the wild type enzyme has only an endergonic step to overcome, i.e., for H2O removal, by eliminating several residues, one at a time, the endergonic step was made to proceed spontaneously. Thus, the most promising residue deletions which enhance H2O elimination are DeltaArg111, DeltaThr145, DeltaSer177, DeltaGlu240, DeltaGlu374, and DeltaTyr375. The thermodynamics and electronic structure analyses show that the bridging carbonyl (COb) of the H-cluster plays a concomitant role in the enzyme inhibition/reactivation. In gas phase, COb shifts towards Fed to compensate for the electron density donated to oxygen upon the elimination of H2O. However, this is not possible in the wild-type enzyme because the protein matrix hinders the displacement of COb towards Fed, which leads to enzyme inhibition. However, enzyme reactivation can be achieved by means of appropriate amino acid substitutions. PMID- 26045629 TI - The Effect of Providing Peer Information on Retirement Savings Decisions. AB - Using a field experiment in a 401(k) plan, we measure the effect of disseminating information about peer behavior on savings. Low-saving employees received simplified plan enrollment or contribution increase forms. A randomized subset of forms stated the fraction of age-matched coworkers participating in the plan or age-matched participants contributing at least 6% of pay to the plan. We document an oppositional reaction: the presence of peer information decreased the savings of nonparticipants who were ineligible for 401(k) automatic enrollment, and higher observed peer savings rates also decreased savings. Discouragement from upward social comparisons seems to drive this reaction. PMID- 26045630 TI - Aligning Task Control with Desire for Control: Implications for Performance. AB - The current study examined whether matches between task control and participants' desire for control over their environment lead to better task performance than mismatches. Work control and desire for control were manipulated, and participants engaged in timed tasks. As predicted, performance was higher in cases of match, even when task control and desire for control were low. Task control and desire for control may predict work performance in combination, highlighting the importance of Person-Environment Fit theory for both selection and work design. By manipulating desire for control, our research also explores the potentially state-dependent quality of this individual difference variable. PMID- 26045631 TI - Dual-Energy Imaging of Bone Marrow Edema on a Dedicated Multi-Source Cone-Beam CT System for the Extremities. AB - PURPOSE: Arthritis and bone trauma are often accompanied by bone marrow edema (BME). BME is challenging to detect in CT due to the overlaying trabecular structure but can be visualized using dual-energy (DE) techniques to discriminate water and fat. We investigate the feasibility of DE imaging of BME on a dedicated flat-panel detector (FPD) extremities cone-beam CT (CBCT) with a unique x-ray tube with three longitudinally mounted sources. METHODS: Simulations involved a digital BME knee phantom imaged with a 60 kVp low-energy beam (LE) and 105 kVp high-energy beam (HE) (+0.25 mm Ag filter). Experiments were also performed on a test-bench with a Varian 4030CB FPD using the same beam energies as the simulation study. A three-source configuration was implemented with x-ray sources distributed along the longitudinal axis and DE CBCT acquisition in which the superior and inferior sources operate at HE (and collect half of the projection angles each) and the central source operates at LE. Three-source DE CBCT was compared to a double-scan, single-source orbit. Experiments were performed with a wrist phantom containing a 50 mg/ml densitometry insert submerged in alcohol (simulating fat) with drilled trabeculae down to ~1 mm to emulate the trabecular matrix. Reconstruction-based three-material decomposition of fat, soft tissue, and bone was performed. RESULTS: For a low-dose scan (36 mAs in the HE and LE data), DE CBCT achieved combined accuracy of ~0.80 for a pattern of BME spherical lesions ranging 2.5 - 10 mm diameter in the knee phantom. The accuracy increased to ~0.90 for a 360 mAs scan. Excellent DE discrimination of the base materials was achieved in the experiments. Approximately 80% of the alcohol (fat) voxels in the trabecular phantom was properly identified both for single and 3-source acquisitions, indicating the ability to detect edemous tissue (water-equivalent plastic in the body of the densitometry insert) from the fat inside the trabecular matrix (emulating normal trabecular bone with significant fraction of yellow marrow). CONCLUSION: Detection of BME and quantification of water and fat content were achieved in extremities DE CBCT with a longitudinal configuration of sources providing DE imaging in a single gantry rotation. The findings support the development of DE imaging capability for CBCT of the extremities in areas conventionally in the domain of MRI. PMID- 26045632 TI - Stochastic dynamic models and Chebyshev splines. AB - In this article, we establish a connection between a stochastic dynamic model (SDM) driven by a linear stochastic differential equation (SDE) and a Chebyshev spline, which enables researchers to borrow strength across fields both theoretically and numerically. We construct a differential operator for the penalty function and develop a reproducing kernel Hilbert space (RKHS) induced by the SDM and the Chebyshev spline. The general form of the linear SDE allows us to extend the well-known connection between an integrated Brownian motion and a polynomial spline to a connection between more complex diffusion processes and Chebyshev splines. One interesting special case is connection between an integrated Ornstein-Uhlenbeck process and an exponential spline. We use two real data sets to illustrate the integrated Ornstein-Uhlenbeck process model and exponential spline model and show their estimates are almost identical. PMID- 26045633 TI - Microscale synthesis and kinetic isotope effect analysis of (4R)-[Ad-14C, 4-2H] NADPH and (4R)-[Ad-3H,4-2H] NADPH. AB - We present a one-pot chemo-enzymatic microscale synthesis of NADPH with two different patterns of isotopic labels: (4R)-[Ad-14C,4-2H] NADPH and (4R)-[Ad-3H,4 2H] NADPH. These co-factors are required by an enormous range of enzymes, and isotopically labeled nicotinamides are consequently of significant interest to researchers. In the current procedure, [Ad-14C] NAD+ and [Ad-3H] NAD+ were phosphorylated by NAD+ kinase to produce [Ad-14C] NADP+ and [Ad-3H] NADP+, respectively. Thermoanaerobium brockii alcohol dehydrogenase was then used to stereospecifically transfer deuterium from C2 of isopropanol to the re face of C4 of NADP+. After purification by HPLC, NMR analysis indicated the deuterium content at the 4R position is more than 99.7 %. The labeled cofactors were then used to successfully and sensitively measure kinetic isotope effects for R67 dihydrofolate reductase, providing strong evidence for the utility of this synthetic methodology. PMID- 26045634 TI - Dementia at the Opera: The Lion's Face. PMID- 26045635 TI - Near-bottom circulation and dispersion of sediment containing Alexandrium fundyense cysts in the Gulf of Maine during 2010-2011. AB - The life cycle of Alexandrium fundyense in the Gulf of Maine includes a dormant cyst stage that spends the winter predominantly in the bottom sediment. Wave current bottom stress caused by storms and tides induces resuspension of cyst containing sediment during winter and spring. Resuspended sediment could be transported by water flow to different locations in the Gulf and the redistribution of sediment containing A. fundyense cysts could alter the spatial and temporal manifestation of its spring bloom. The present study evaluates model near-bottom flow during storms, when sediment resuspension and redistribution are most likely to occur, between October and May when A. fundyense cells are predominantly in cyst form. Simulated water column sediment (mud) concentrations from representative locations of the Gulf are used to initialize particle tracking simulations for the period October 2010-May 2011. Particles are tracked in full three-dimensional model solutions including a sinking velocity characteristic of cyst and aggregated mud settling (0.1 mm s-1). Although most of the material was redeposited near the source areas, small percentages of total resuspended sediment from some locations in the western (~4%) and eastern (2%) Maine shelf and the Bay of Fundy (1%) traveled distances longer than 100 km before resettling. The redistribution changed seasonally and was sensitive to the prescribed sinking rate. Estimates of the amount of cysts redistributed with the sediment are small compared to the inventory of cysts in the upper few centimeters of sediment. PMID- 26045636 TI - Seasonal and Interannual Variability in Gulf of Maine Hydrodynamics: 2002-2011. AB - In situ observations including long-term moored meteorological and oceanographic measurements and multi-year gulf-wide ship survey data are used to quantify interannual variability of surface wind, river runoff, and hydrographic conditions in the Gulf of Maine during summers 2002-2011. The cumulative upwelling index shows that upwelling (downwelling)-favorable wind conditions were most persistent in 2010 (2005) over the 10-year study period. River discharge was highest in 2005; peak runoff occurred in early April in 2010 as opposed to late April to middle May in other years. Moored time series show that coastal water temperature was 0.5-2 degrees C warmer than average in summer 2010, and about 2 degrees C colder than average in 2004. Coastal salinity in April 2010 was the lowest in the 10-year study period. Both moored Acoustic Doppler Current Profiler (ADCP) current measurements and dynamic height/geostrophic velocity calculations based on gulf-wide ship survey data show May-June 2010 had one of the weakest alongshore transports in the western Gulf of Maine during the 10-year study period, likely associated with intrusions of warm slope water and fresher-than usual Scotian Shelf water. Comparisons of coastal currents to the Paralytic Shellfish Poisoning (PSP) closure maps resulting from A. fundyense blooms suggest a linkage between alongshore transport and the downstream extent of toxicity. PMID- 26045637 TI - Ethnographic Evidence of an Emerging Transnational Arts Practice?: Perspectives on U.K. and Mexican Participatory Artists' Processes for Catalysing Change, and Facilitating Health and Flourishing. AB - This article reports new ethnographic research exploring community-based, participatory arts practice in Northern England and Mexico City. Noting the value of an ethnographic approach, the study investigated whether commonalities discovered in practitioners' approaches are significant enough to constitute a generalisable participatory arts methodology, transcending significant contextual differences, and recognisable across national boundaries. Shared characteristics emerged in practitioners' modes of engagement with groups, and strategies for catalysing change; clear convergences from which a core methodology in community based participatory arts for change is distilled. It suggests the opening of liminal spaces in which participants can reflect, rehearsing fresh ways of engaging in transformative dialogues in relation to the world in which they live. This article presents the study findings as a grounded characterisation of 'participatory arts practice': a complex but potentially powerful mechanism, in use within numerous community health projects, and evident in diverse settings, despite little or no exchange of ideas between practitioners. PMID- 26045638 TI - Take-home naloxone to prevent fatalities from opiate-overdose: Protocol for Scotland's public health policy evaluation, and a new measure to assess impact. AB - Aims: Scotland was the first country to adopt take-home naloxone (THN) as a funded public health policy. We summarise the background and rigorous set-up for before/after monitoring to assess the impact on high-risk opiate-fatalities. Methods: Evidence-synthesis of prospectively monitored small-scale THN schemes led to a performance indicator for distribution of THN-kits relative to opiate related deaths. Next, we explain the primary outcome and statistical power for Scotland's before/after monitoring. Results: Fatality-rate at opiate overdoses witnessed by THN-trainees was 6% (9/153, 95% CI: 2-11%). National THN-schemes should aim to issue 20 times as many THN-kits as there are opiate-related deaths per annum; and at least nine times as many. Primary outcome for evaluating Scotland's THN policy is reduction in the percentage of all opiate-related deaths with prison-release as a 4-week antecedent. Scotland's baseline period is 2006 10, giving a denominator of 1970 opiate-related deaths. A priori plausible effectiveness was 20-30% reduction, relative to baseline, in the proportion of opiate-related deaths that had prison-release as a 4-week antecedent. A secondary outcome was also defined. Conclusion: If Scotland's THN evaluation shifts the policy ground seismically, our new performance measure may prove useful on how many THN-kits nations should provide annually. PMID- 26045640 TI - Understanding English alcohol policy as a neoliberal condemnation of the carnivalesque. AB - Much academic work has argued that alcohol policy in England over the past 25 years can be characterised as neoliberal, particularly in regard to the night time economy and attempts to address "binge" drinking. Understanding neoliberalism as a particular "mentality of government" that circumscribes the range of policy options considered appropriate and practical for a government to take, this article notes how the particular application of policy can vary by local context. This article argues that the approach of successive governments in relation to alcohol should be seen as based on a fear and condemnation of the carnivalesque, understood as a time when everyday norms and conventions are set aside, and the world is - for a limited period only - turned inside out. This analysis is contrasted with previous interpretations that have characterised government as condemning intoxication and particular forms of pleasure taken in drinking. Although these concepts are useful in such analysis, this article suggests that government concerns are broader and relate to wider cultures surrounding drunkenness. Moreover, there is an ambivalence to policy in relation to alcohol that is better conveyed by the concept of the carnivalesque than imagining simply a condemnation of pleasure or intoxication. PMID- 26045639 TI - How did policy actors use mass media to influence the Scottish alcohol minimum unit pricing debate? Comparative analysis of newspapers, evidence submissions and interviews. AB - Aims: To explore how policy actors attempted to deliberately frame public debate around alcohol minimum unit pricing (MUP) in the UK by comparing and contrasting their constructions of the policy in public (newspapers), semi-public (evidence submissions) and private (interviews). Methods: Content analysis was conducted on articles published in ten national newspapers between 1 January 2005 and 30 June 2012. Newsprint data were contrasted with alcohol policy documents, evidence submissions to the Scottish Parliament's Health and Sport Committee and 36 confidential interviews with policy stakeholders (academics, advocates, industry representatives, politicians and civil servants). Findings: A range of policy actors exerted influence both directly (through Parliamentary institutions and political representatives) and indirectly through the mass media. Policy actors were acutely aware of mass media's importance in shaping public opinion and used it tactically to influence policy. They often framed messages in subtly different ways, depending on target audiences. In general, newspapers presented the policy debate in a "balanced" way, but this arguably over-represented hostile perspective and suggested greater disagreement around the evidence base than is the case. Conclusions: The roles of policy actors vary between public and policy spheres, and how messages are communicated in policy debates depends on perceived strategic advantage. PMID- 26045642 TI - The FDA may change pharmacists' access to prescribing information: a website would replace paper package inserts. AB - Pharmacist access to prescribing information may change. PMID- 26045641 TI - Mismatched prescribing and pharmacy templates for parenteral nutrition lead to data-entry errors. AB - Mismatched prescribing and pharmacy templates for parenteral nutrition can cause errors. PMID- 26045644 TI - Pharmaceutical approval update. AB - Ivabradine (Corlanor) for heart failure, anthrax immune globulin intravenous (human) (Anthrasil) for inhalational anthrax, and glatiramer acetate (Glatopa) for relapsing forms of multiple sclerosis. PMID- 26045645 TI - Empagliflozin (Jardiance): A Novel SGLT2 Inhibitor for the Treatment of Type-2 Diabetes. AB - Empagliflozin (Jardiance): a novel SGLT2 inhibitor for the treatment of type-2 diabetes. PMID- 26045646 TI - Pharmacists Step Up Efforts to Combat Opioid Abuse: The CDC and Congress Are Trying to Pitch In. AB - State and national professional and regulatory bodies are focusing on opioid drug abuse by upgrading requirements for health care practitioners to ensure that all controlled substances are prescribed and dispensed for legitimate medical purposes. PMID- 26045649 TI - American academy of dermatology. AB - Notable sessions at the American Academy of Dermatology meeting focused on pediatric eczema, infantile hemangiomas, and vaccines. The 2015 Aging in America Conference featured discussions on managing medication use in elderly patients. PMID- 26045648 TI - Pharmacological therapies for autism spectrum disorder: a review. AB - Medications are often added to behavioral therapy to help patients with autism spectrum disorder function successfully. This review discusses approved and off label pharmacotherapeutic options for the various symptoms of the disorder. PMID- 26045647 TI - Pharmacological treatment of diabetic peripheral neuropathy. AB - Pain modulation is a key treatment goal for diabetic peripheral neuropathy patients. Guidelines have recommended antidepressant, anticonvulsant, analgesic, and topical medications-both approved and off-label-to reduce pain in this population. PMID- 26045650 TI - Dyslipidemia: blockbuster therapies are on the horizon. AB - Potential blockbuster therapies, such as proprotein convertase subtilisin/kexin type 9 inhibitors, are expected to revolutionize dyslipidemia treatment and raise global sales. PMID- 26045651 TI - Predictors of Therapist Adherence and Emotional Bond in Multisystemic Therapy: Testing Ethnicity as a Moderator. AB - This study examined the interaction between problem severity and race?ethnicity as a predictor of therapist adherence and family-therapist emotional bond. Data for this study came from a longitudinal evaluation of Multisystemic Therapy (MST) provided by licensed MST provider organizations in community settings. Outcome variables included mid-treatment levels of caregiver report of therapist adherence, changes in caregiver report of therapist adherence over the course of treatment, and overall levels of caregiver-therapist and youth-therapist emotional bond. Hypothesized predictors included race?ethnicity and levels of poly-substance use, externalizing behavior, and youth self-report of delinquency early in treatment as well as pre-treatment number of arrests. Participants were 185 adolescents (M age = 15.35, SD = 1.29) and their caregivers. Of the participating youth, 48 % self-identified as Caucasian, 20 % as African-American, 28 % as Hispanic?Latino, and 4 % as "other." Two-level Hierarchical Linear Modeling analyses revealed that for Caucasian youth, lower rates of self-reported delinquency were associated with greater increases in caregiver report of therapist adherence over the course of MST. For His-panic?Latino caregivers, higher externalizing behavior and poly-substance use were associated with reports of lower therapist adherence at mid-treatment and poorer overall levels of emotional bonding with therapists. In contrast, for African-American participants, higher levels of youth externalizing behavior and poly-substance use were associated with higher overall levels of caregiver and youth report of emotional bonding with therapists, respectively. Results provide evidence that race?ethnicity interacts with problem severity in predicting therapist adherence and family-therapist emotional bond within real-world practice settings and suggest possible therapeutic process differences across race. PMID- 26045652 TI - The Effect of Product Safety Courses on the Adoption and Outcomes of LESS Surgery. AB - BACKGROUND AND OBJECTIVES: As technology in surgery evolves, the medical instrument industry is inevitability involved in promoting the use and appropriate (ie, effective and safe) application of its products. This study was undertaken to evaluate industry-supported product safety courses in laparoendoscopic single-site (LESS) surgery, by using the metrics of surgeons' adoption of the technique, safety of the procedure, and surgeons' perception of the surgery. METHODS: LESS surgery courses that involved didactic lectures, operative videos, operation observation, collaborative learning, and simulation, were attended by 226 surgeons. With Florida Hospital Tampa Institutional Review Board approval, the surgeons were queried before and immediately after the course, to assess their attitudes toward LESS surgery. Then, well after the course, the surgeons were contacted, repeatedly if necessary, to complete questionnaires. RESULTS: Before the course, 82% of the surgeons undertook more than 10 laparoscopic operations per month. Immediately after the course, 86% were confident that they were prepared to perform LESS surgery. Months after the course, 77% of the respondents had adopted LESS surgery, primarily cholecystectomy; 59% had added 1 or more trocars in 0-20% of their procedures; and 73% held the opinion that operating room observation was the most helpful learning experience. Complications with LESS surgery were noted 12% of the time. Advantages of the technique were better cosmesis (58%) and patient satisfaction (38%). Disadvantages included risk of complications (37%) and higher technical demand (25%). Seventy-eight percent viewed LESS surgery as an advancement in surgical technique. CONCLUSION: In multifaceted product safety courses, operating room observation is thought to provide the most helpful instruction for those wanting to undertake LESS surgery. The procedure has been safely adopted by surgeons who frequently perform laparoscopies. The tradeoff is in performing a more difficult technique to obtain better cosmesis for the patient. We must continue to conduct critical evaluations of product safety courses for the introduction of new technology in surgery. PMID- 26045653 TI - Construct validation: simulation of thoracoscopic intrathoracic anastomosis. AB - BACKGROUND AND OBJECTIVES: We sought to develop a simulation model that accurately replicates the challenges of the thoracoscopic intrathoracic anastomosis. This model is intended to serve as a teaching tool during the introduction to, and development of, the skills required to perform a thoracoscopic intrathoracic anastomosis during an Ivor Lewis minimally invasive esophagectomy. METHODS: The simulation model uses porcine tissue placed within an artificial hemithorax and covered with a synthetic skin. The model is draped to simulate a realistic operative setting, and ports are placed in standard surgical fashion. Dissection of the esophagus from the mediastinum is then performed, followed by the creation of an esophagogastric anastomosis. The effectiveness of the training model was evaluated using volunteer general and thoracic surgery residents at varying stages of surgical training. The quality of the anastomoses created were evaluated using both objective and subjective criteria, and successful anastomoses were tested for leaks using hydrostatic pressure. RESULTS: Objective evaluation showed that successful completion of the anastomosis task increased with the number of attempts, with 100% of participants successfully completing an anastomosis by the final attempt. The time to completion of a successful anastomosis also improved across successive attempts. Moreover, objective measures also showed improvement over time based on the graded quality of the completed anastomosis. CONCLUSION: As surgical techniques continue to evolve, so must the means by which they are taught. This simulation model shows effectiveness in the training of general and thoracic surgery residents performing thoracoscopic intrathoracic anastomosis during the Ivor Lewis minimally invasive esophagectomy. PMID- 26045654 TI - From "directed differentiation" to "neuronal induction": modeling neuropsychiatric disease. AB - Aberrant behavior and function of neurons are believed to be the primary causes of most neurological diseases and psychiatric disorders. Human postmortem samples have limited availability and, while they provide clues to the state of the brain after a prolonged illness, they offer limited insight into the factors contributing to disease onset. Conversely, animal models cannot recapitulate the polygenic origins of neuropsychiatric disease. Novel methods, such as somatic cell reprogramming, deliver nearly limitless numbers of pathogenic human neurons for the study of the mechanism of neuropsychiatric disease initiation and progression. First, this article reviews the advent of human induced pluripotent stem cell (hiPSC) technology and introduces two major methods, "directed differentiation" and "neuronal induction," by which it is now possible to generate neurons for modeling neuropsychiatric disease. Second, it discusses the recent applications, and the limitations, of these technologies to in vitro studies of psychiatric disorders. PMID- 26045655 TI - Management of exfoliative glaucoma: challenges and solutions. AB - Exfoliative glaucoma is the most common type of secondary open-angle glaucoma worldwide. It is characterized by high intraocular pressure (IOP) and worse 24 hour IOP characteristics. In order to minimize progression, treatment of exfoliative glaucoma has to provide a low long-term mean IOP and good 24-hour IOP control. To achieve these goals, fixed-dose combination eye drops, argon and selective laser trabeculoplasty, and various forms of surgery (trabeculectomy, deep sclerectomy, viscocanalostomy, ab interno trabeculotomy, trabecular aspiration, and cataract surgery) all need to be considered during the long-term management of the disease. Since exfoliative glaucoma is a disease of the elderly, and is frequently associated with systemic vascular disease, interdisciplinary consultations are of great clinical importance. These management aspects and the current medical, laser, and surgical results are covered in this review, with a special focus on the needs of the general ophthalmologist. PMID- 26045656 TI - Cataract surgery and methods of wound closure: a review. AB - Clear corneal incisions are routinely used in cataract surgery, but watertight wound closure may not always be achieved, which can increase the risk for anterior chamber fluid egress or ocular surface fluid ingress. A new US Food and Drug Administration-approved ocular sealant appears to have good efficacy in sealing clear corneal incisions; its use may be indicated when wound integrity is in question. PMID- 26045657 TI - Diabetic glomerulosclerosis can be the pathogenesis of refractory diabetic macular edema. AB - BACKGROUND: Kidney failure provoked by glomerulosclerosis leads to fluid filtration deficits and other disorders of kidney function. Refractory diabetic macular edema (DME) can be another warning sign of glomerulosclerosis in diabetic patients. CASE: A 40-year-old Saudi male presented with macular edema that was refractory to all possible medical and surgical ophthalmic interventions in both eyes. The macular edema significantly improved once the patient began systemic treatment for newly diagnosed diabetic glomerulosclerosis. This case report is presented with optical coherence tomography (OCT) documentation of before and after each medical and surgical intervention. OBSERVATIONS: Considerable improvement occurred after treatment with a systemic angiotensin-converting enzyme inhibitor and diuretic treatment due to newly diagnosed diabetic glomerulosclerosis. CONCLUSION: Refractory DME can be secondary to diabetic glomerulosclerosis. This case indicates the possibility that systemic intervention may be warranted in cases of refractory DME, and the importance of collaboration between ophthalmologists, endocrinologists, and internists in these cases. PMID- 26045658 TI - Optical coherence tomography to evaluate the interaction of different edge designs of four different silicone hydrogel lenses with the ocular surface. AB - PURPOSE: To evaluate the lens edge interaction with the ocular surface with different edge designs using optical coherence tomography and to examine the effect of lens power on the lens edge interactions. METHODS: Four types of silicone hydrogel lenses with different edge designs (round-, semi-round-, chisel , and knife-edged) at six different powers (+5.0, +3.0, +1.0, -1.0, -3.0, and 5.0 diopters) were fitted to both eyes of 20 healthy volunteers. Optical coherence tomography images were taken at the corneal center and at the limbus within 15-30 minutes after insertion. The images were evaluated with respect to two parameters: conjunctival indentation exerted by the lens edge; and the tear film gaps between the posterior surface of the lens and the ocular surface. The amount of conjunctival indentation was measured with the distortion angle of the conjunctiva at the lens edge. RESULTS: The degree of conjunctival indentation was highest with the chisel-edged design followed by the semi-round design (P<0.0001). Knife- and round-edged lenses exerted similar levels of conjunctival indentation that was significantly lower compared to chisel-edged lens (P<0.001). For each one of the tested lens edge designs, no significant difference was observed in the conjunctival indentation with respect to lens power. The chisel edged lens produced the highest amount of conjunctival indentation for each one of the six lens powers (P<0.0001). Post-lens tear film gaps at the limbus were observed at most in the round-edge design (P=0.001). CONCLUSION: The fitting properties of contact lenses may be influenced by their edge design but not by their lens power. PMID- 26045660 TI - Soluplus(r)/TPGS-based solid dispersions prepared by hot-melt extrusion equipped with twin-screw systems for enhancing oral bioavailability of valsartan. AB - BACKGROUND: Soluplus((r)) (SP) and D-alpha-tocopherol polyethylene glycol 1000 succinate (TPGS)-based solid dispersion (SD) formulations were developed by hot melt extrusion (HME) to improve oral bioavailability of valsartan (VST). METHODS: HME process with twin-screw configuration for generating a high shear stress was used to prepare VST SD formulations. The thermodynamic state of the drug and its dispersion in the polymers were evaluated by solid-state studies, including Fourier-transform infrared, X-ray diffraction, and differential scanning calorimetry. Drug release from the SD formulations was assessed at pH values of 1.2, 4.0, and 6.8. Pharmacokinetic study was performed in rats to estimate the oral absorption of VST. RESULTS: HME with a high shear rate produced by the twin screw system was successfully applied to prepare VST-loaded SD formulations. Drug amorphization and its molecular dispersion in the polymer matrix were verified by several solid-state studies. Drug release from SD formulations was improved, compared to the pure drug, particularly at pH 6.8. Oral absorption of drug in rats was also enhanced in SP and TPGS-based SD groups compared to that in the pure drug group. CONCLUSION: SP and TPGS-based SDs, prepared by the HME process, could be used to improve aqueous solubility, dissolution, and oral absorption of poorly water-soluble drugs. PMID- 26045659 TI - Synthesis and characterization of tumor-targeted copolymer nanocarrier modified by transferrin. AB - To increase the encapsulation of hydrophilic antitumor agent daunorubicin (DNR) and multidrug resistance reversal agent tetrandrine (Tet) in the drug delivery system of nano-particles (NPs), a functional copolymer NP composed of poly(lactic co-glycolic acid) (PLGA), poly-L-lysine (PLL), and polyethylene glycol (PEG) was synthesized and then loaded with DNR and Tet simultaneously to construct DNR/Tet PLGA-PLL-PEG-NPs using a modified double-emulsion solvent evaporation/diffusion method. And to increase the targeted antitumor effect, DNR/Tet-PLGA-PLL-PEG-NPs were further modified with transferrin (Tf) due to its specific binding to Tf receptors (TfR), which is highly expressed on the surface of tumor cells. In this study, the influence of the diversity of formulation parameters was investigated systematically, such as drug loading, mean particle size, molecular weight, the concentration of PLGA-PLL-PEG-Tf, volume ratio of acetone to dichloromethane, the concentration of polyvinyl alcohol (PVA) in the external aqueous phase, the volume ratio of the internal aqueous phase to the external aqueous phase, and the type of surfactants in the internal aqueous phase. Meanwhile, its possible effect on cell viability was evaluated. Our results showed that the regular spherical DNR/Tet-PLGA-PLL-PEG-Tf-NPs with a smooth surface, a relatively low polydispersity index, and a diameter of 213.0+/-12.0 nm could be produced. The encapsulation efficiency was 70.23%+/-1.91% for DNR and 86.5%+/-0.70% for Tet, the moderate drug loading was 3.63%+/-0.15% for DNR and 4.27%+/-0.13% for Tet. Notably, the accumulated release of DNR and Tet could be sustained over 1 week, and the Tf content was 2.18%+/-0.04%. In cell viability tests, DNR/Tet-PLGA-PLL PEG-Tf-NPs could inhibit the proliferation of K562/ADR cells in a dose-dependent manner, and the half maximal inhibitory concentration value (total drug) of DNR/Tet-PLGA-PLL-PEG-Tf-NPs was lower than that of DNR, a mixture of DNR and Tet, and DNR/Tet-PLGA-PLL-PEG-NPs. These results clearly indicate that the PLGA-PLL PEG formulation is a potential drug delivery system for hydrophilic and hydrophobic drugs, and that Tf modification may increase its targeting properties. PMID- 26045662 TI - Contraceptive prevalence and preference in a cohort of south-east Nigerian women. AB - BACKGROUND: Rates of fertility, population growth, and maternal deaths in Nigeria are among the highest in the world, with an estimated 4% of all births being unwanted and 7% mistimed. These are caused mainly by nonuse, inappropriate choice, and difficulty in accessing contraceptive commodities. The purpose of this study was to determine the prevalence and factors influencing the choice and sources of contraceptive options among market women in Ebonyi State, Nigeria. METHODS: This was a questionnaire-based, cross-sectional, descriptive study involving 330 market women of reproductive age in Abakaliki, Ebonyi State, Nigeria. A survey was carried out to identify their knowledge, use, and sources of contraception and the factors that influence their contraceptive practices. RESULTS: Knowledge of contraception was high (275 [83.3%]), and 229 (69.4%) of the study population approved of contraceptive use. However, only 93 (28.3%) of the respondents were currently using any form of contraception. Fifty-four women (16.3%) were using modern methods. The commonly used forms of modern contraception were the barrier method (male condoms, 27 [8.2%]), the oral contraceptive pill (10 [3.0%]), injectables (8 [2.5%]), and the intrauterine contraceptive device (7 [2.0%]). The most common source of contraceptive products was patent medicine dealers (58 [51%]). The main barriers to use of contraception were desire for more children (86 [26.1%]), religious prohibition (62 [18.8%]), spousal disapproval (32 [9.7%]), and the perceived side effects of modern contraceptives (25 [7.6%]). There was a significant association for approval of contraception when the model was adjusted for religion (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.18-0.84; P=0.02); educational status (OR 2.84, 95% CI 0.96-8.40; P=0.04); parity (OR 1.78, 95% CI 1.09-2.85; P=0.03); and social class (OR 2.54, 95% CI 1.26-5.11; P=0.01). CONCLUSION: There is good knowledge about contraception among Nigerian women, but use of these products is low. The main barriers to use of contraception are the desire for more children, religious prohibition, and spousal disapproval. PMID- 26045661 TI - Combination therapy of fenofibrate and ursodeoxycholic acid in patients with primary biliary cirrhosis who respond incompletely to UDCA monotherapy: a meta analysis. AB - BACKGROUND: Although the effectiveness of treatment with ursodeoxycholic acid (UDCA) and fenofibrate for primary biliary cirrhosis (PBC) has been suggested by small trials, a systematic review to summarize the evidence has not yet been carried out. METHODS: A meta-analysis of all long-term randomized controlled trials comparing the combination of UDCA and fenofibrate with UDCA monotherapy was performed via electronic searches. RESULTS: Six trials, which included 84 patients, were assessed. Combination therapy with UDCA and fenofibrate was more effective than UDCA monotherapy in improving alkaline phosphatase (mean difference [MD]: -90.44 IU/L; 95% confidence interval [CI]: -119.95 to -60.92; P<0.00001), gamma-glutamyl transferase (MD: -61.58 IU/L; 95% CI: -122.80 to 0.35; P=0.05), immunoglobulin M (MD: -38.45 mg/dL; 95% CI: -64.38 to -12.51; P=0.004), and triglycerides (MD: -0.41 mg/dL; 95% CI: -0.82 to -0.01; P=0.05). However, their effects on pruritus (odds ratio [OR]: 0.39; 95% CI: 0.09-1.78; P=0.23), total bilirubin (MD: -0.05 mg/dL; 95% CI: -0.21 to 0.12; P=0.58), and alanine aminotransferase (MD: -3.31 IU/L; 95% CI: -14.60 to 7.97; P=0.56) did not differ significantly. This meta-analysis revealed no significant differences in the incidence of adverse events (OR: 0.21; 95% CI: 0.03-1.25; P=0.09) between patients treated with combination therapy and those treated with monotherapy. CONCLUSION: In this meta-analysis, combination therapy with UDCA and fenofibrate was more effective in reducing alkaline phosphatase than UDCA monotherapy, but it did not improve clinical symptoms. There did not appear to be an increase in adverse events with combination therapy. PMID- 26045663 TI - Upconversion nanoparticle-mediated photodynamic therapy induces THP-1 macrophage apoptosis via ROS bursts and activation of the mitochondrial caspase pathway. AB - Atherosclerosis (AS) is the most vital cardiovascular disease, which poses a great threat to human health. Macrophages play an important role in the progression of AS. Photodynamic therapy (PDT) has emerged as a useful therapeutic modality not only in the treatment of cancer but also in the treatment of AS. The purpose of this study was to determine the molecular mechanisms underlying the activity of PDT, using mesoporous-silica-coated upconversion fluorescent nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) in the induction of apoptosis in THP-1 macrophages. Here, we investigated the ability of UCNPs-Ce6-mediated PDT to induce THP-1 macrophage apoptosis by facilitating the induction of reactive oxygen species (ROS) and regulation of mitochondrial permeability transition pore (MPTP) to depolarize mitochondrial membrane potential (MMP). Both Bax translocation and the release of cytochrome C were examined using immunofluorescence and Western blotting. Our results indicated that the levels of ROS were significantly increased in the PDT group, resulting in both MPTP opening and MMP depolarization, which led to apoptosis. In addition, immunofluorescence and Western blotting revealed that PDT induced both Bax translocation and the release of cytochrome C, as well as upregulation of cleaved caspase-9, cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. Therefore, we demonstrated that UCNPs-Ce6-mediated PDT induces apoptosis in THP-1 macrophages via ROS bursts. The proapoptotic factor Bax subsequently translocates from the cytosol to the mitochondria, resulting in the MPTP opening and cytochrome C release. This study demonstrated the great potential of UCNPs-Ce6-mediated PDT in the treatment of AS. PMID- 26045664 TI - Delivery of baicalein and paclitaxel using self-assembled nanoparticles: synergistic antitumor effect in vitro and in vivo. AB - PURPOSE: Combination anticancer therapy is promising to generate synergistic anticancer effects to maximize the treatment effect and overcome multidrug resistance. The aim of the study reported here was to develop multifunctional, dual-ligand, modified, self-assembled nanoparticles (NPs) for the combination delivery of baicalein (BCL) and paclitaxel (PTX) prodrugs. METHODS: Prodrug of PTX and prodrug of BCL, containing dual-targeted ligands of folate (FA) and hyaluronic acid (HA), were synthesized. Multifunctional self-assembled NPs for combination delivery of PTX prodrug and BCL prodrug (PTX-BCL) were prepared and the synergistic antitumor effect was evaluated in vitro and in vivo. The in vitro transfection efficiency of the novel modified vectors was evaluated in human lung cancer A549 cells and drug-resistant lung cancer A549/PTX cells. The in vivo antitumor efficiency and systemic toxicity of different formulations were further investigated in mice bearing A549/PTX drug-resistant human lung cancer xenografts. RESULTS: The size of the PTX-BCL NPs was approximately 90 nm, with a positive zeta potential of +3.3. The PTX-BCL NPs displayed remarkably better antitumor activity over a wide range of drug concentrations, and showed an obvious synergism effect with CI50 values of 0.707 and 0.513, indicating that double-ligand modification and the co-delivery of PTX and BCL prodrugs with self assembled NPs had remarkable superiority over other formulations. CONCLUSION: The prepared PTX-BCL NP drug-delivery system was proven efficient by its targeting of drug-resistant human lung cancer cells and delivering of BCL and PTX prodrugs. Enhanced synergistic anticancer effects were achieved by PTX-BCL NPs, and multidrug resistance of PTX was overcome by this promising targeted nanomedicine. PMID- 26045665 TI - Nanoalumina induces apoptosis by impairing antioxidant enzyme systems in human hepatocarcinoma cells. AB - Alumina nanoparticles (Al2O3NPs) are gradually used in various areas, including nanomedicine, biosensors, and electronics. The current study aimed to explore the DNA damage and cytotoxicity due to Al2O3NPs on human hepatocarcinoma cells (HepG2). The MTT and neutral red uptake assays showed that Al2O3NPs induce significant cell death in a dose- and time-dependent manner. However, Al2O3NPs induced significant intracellular reactive oxygen species production and elevated lipid peroxidation and superoxide dismutase levels in the HepG2 cells. Al2O3NPs also induced significant decrease in reduced glutathione levels and increase caspase-3 activity in HepG2 cells. DNA fragmentation analysis using the alkaline single-cell gel electrophoresis showed that Al2O3NPs cause genotoxicity in dose- and time-dependent manner. However, they induce reactive oxygen species production and oxidative stress, leading to oxidative DNA damage, a probable mechanism of genotoxicity. This study warrants more careful assessment of Al2O3NPs before their industrial application. PMID- 26045666 TI - Transtracheal single-point stent fixation in posttracheotomy tracheomalacia under cone-beam computer tomography guidance by transmural suturing with the Berci needle - a perspective on a new tool to avoid stent migration of Dumon stents. AB - Tracheomalacia or tracheobronchomalacia (TM or TBM) is a common problem especially for elderly patients often unfit for surgical techniques. Several surgical or minimally invasive techniques have already been described. Stenting is one option but in general long-time stenting is accompanied by a high complication rate. Stent removal is more difficult in case of self-expandable nitinol stents or metallic stents in general in comparison to silicone stents. The main disadvantage of silicone stents in comparison to uncovered metallic stents is migration and plugging. We compared the operation time and in particular the duration of a sufficient Dumon stent fixation with different techniques in a patient with severe posttracheotomy TM and strongly reduced mobility of the vocal cords due to Parkinson's disease. The combined approach with simultaneous Dumon stenting and endoluminal transtracheal externalized suture under cone-beam computer tomography guidance with the Berci needle was by far the fastest approach compared to a (not performed) surgical intervention, or even purely endoluminal suturing through the rigid bronchoscope. The duration of the endoluminal transtracheal externalized suture was between 5 minutes and 9 minutes with the Berci needle; the pure endoluminal approach needed 51 minutes. The alternative of tracheobronchoplasty was refused by the patient. In general, 180 minutes for this surgical approach is calculated. The costs of the different approaches are supposed to vary widely due to the fact that in Germany 1 minute in an operation room costs on average approximately 50-60? inclusive of taxes. In our own hospital (tertiary level), it is nearly 30? per minute in an operation room for a surgical approach. Calculating an additional 15 minutes for patient preparation and transfer to wake-up room, therefore a total duration inside the investigation room of 30 minutes, the cost per flexible bronchoscopy is per minute on average less than 6?. Although the Dumon stenting requires a set-up with more expensive anesthesiology accompaniment, which takes longer than a flexible investigation estimated at 1 hour in an operation room, still without calculation of the costs of the materials and specialized staff that the surgical approach would consume at least 3,000? more than a minimally invasive approach performed with the Berci needle. This difference is due to the longer time of the surgical intervention which is calculated at approximately 180 minutes in comparison to the achieved non-surgical approach of 60 minutes in the operation suite. PMID- 26045667 TI - New developments in the management of severe skin and deep skin structure infections - focus on tedizolid. AB - Tedizolid, a novel oxazolidinone, is approved for treatment of acute bacterial skin and skin structure infections (ABSSSIs). Tedizolid offers several potential advantages over current ABSSSI treatment options. First, tedizolid has a prolonged half-life, which allows for once-daily dosing. Second, tedizolid has broad spectrum activity against Gram-positive organisms including methicillin resistant Staphylococcus aureus, coagulase-negative staphylococci, and enterococci. Third, tedizolid, available in both intravenous and oral formulations, has high oral bioavailability, allowing for easy oral step-down therapy. Fourth, in patients who have been prescribed selective serotonin reuptake inhibitors or monoamine oxidase inhibitors, tedizolid may have fewer drug interactions than linezolid. Finally, tedizolid may have fewer or comparatively delayed onset side effects than linezolid, including thrombocytopenia and nausea. This review covers the microbiology, pharmacology, mode of action, and pharmacokinetics of tedizolid as well as patient-focused perspectives such as quality of life, patient satisfaction/acceptability, adherence, and uptake and provides expert opinion on the current use of tedizolid for ABSSSIs and potential future therapeutic applications. PMID- 26045668 TI - The incidence and risk factors of peripherally inserted central catheter-related infection among cancer patients. AB - BACKGROUND: As the use of peripherally inserted central catheters (PICCs) increased in chemotherapy, the identification of complications and risk factors became essential to prevent patient harm. But little is known about PICC-related infection and risk factors among patients with cancer. Our study was to identify the prevalence, patterns, and risk factors of catheter-related infections associated with PICCs. METHODS: A 3-year prospective cohort study was conducted in a university-affiliated hospital. All patients with cancer who met inclusion criteria were enrolled. The patients were followed up until catheter removal. Tip cultures were routinely performed at the time of catheter removal. The general information was recorded at the time of PICC insertion, weekly care, and removal. Univariable and multivariable logistic regression analyses were applied for identification of risk factors. RESULTS: In total, 912 cancer patients with 912 PICCs of 96,307 catheter days were enrolled. Ninety-four developed PICC-related infection; 46 were exit-site infection, 43 were catheter bacterial colonization, and five were PICC-related bloodstream infection. The median time from catheter insertion to infection was 98.26 days. Multivariate analysis showed StatLock fixing (odds ratio [OR] =0.555, 95% confidence interval [CI]: 0.326-0.945) and tip position located in the lower one-third of the superior vena cava (OR =0.340, 95% CI: 0.202-0.571) were associated with lower PICC infection rate. Catheter care delay (OR =2.612, 95% CI: 1.373-4.969) and indwelling mostly in summer (OR =4.784, 95% CI: 2.681-8.538) were associated with higher infection incidence. CONCLUSION: StatLock fixing and tip position located in the lower one-third of the superior vena cava were protective factors against PICC-related infection, while catheter care delay and indwelling mostly in summer were risk factors. Policy and measures targeting these factors may be necessary to reduce the risk of infection. PMID- 26045669 TI - Tracking the 2015 Gastrointestinal Cancers Symposium: bridging cancer biology to clinical gastrointestinal oncology. AB - The 2015 Gastrointestinal Cancers Symposium (San Francisco, CA, USA; January 15 17) is the world-class conference co-sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, the American Gastroenterological Association Institute, and the Society of Surgical Oncology, in which the most innovative research results in digestive tract oncology are presented and discussed. In its twelfth edition, the meeting has provided new insights focusing on the underpinning biology and clinical management of gastrointestinal malignancies. More than 3,400 health care professionals gathered from all over the world to share their experiences on how to bridge the recent novelties in cancer biology with everyday medical practice. In this article, the authors report on the most significant advances, didactically moving on three different anatomic tracks: gastroesophageal malignancies, pancreatic and biliary cancers, and colorectal adenocarcinomas. PMID- 26045670 TI - The prognostic significance of fibroblast growth factor receptor 4 in non-small cell lung cancer. AB - BACKGROUND: Fibroblast growth factor receptor 4 (FGFR4) has been proved to be correlated with progression and prognosis in many cancers. However, the significance of FGFR4 in non-small-cell lung cancer (NSCLC) is still not well elucidated. METHODS: In our experiment, we detected FGFR4 expression in 237 samples of NSCLC with immunohistochemistry, and further analyzed the correlation between FGFR4 and clinicopathologic features of NSCLC with chi-square test. Moreover, we evaluated the prognostic value of FGFR4 by Kaplan-Meier survival curve and Cox regression model. By regulating the expression of FGFR4 by overexpression or knockdown, we assessed the role of FGFR4 on NSCLC cell proliferation. RESULTS: FGFR4 expression was high in NSCLC (46.8%, 111/237). FGFR4 expression was significantly associated with tumor diameter (P=0.039). With univariate (P=0.009) and multivariate (P=0.002) analysis, FGFR4 was identified as an independent prognostic factor in NSCLC (P=0.009). Moreover, FGFR4 can promote the proliferation of NSCLC cell lines. CONCLUSION: FGFR4 is an independent prognostic biomarker in NSCLC. FGFR4 can accelerate the proliferation of NSCLC cell lines, indicating FGFR4 could be a potential drug target of NSCLC. PMID- 26045671 TI - Association of the CYP24A1-rs2296241 polymorphism of the vitamin D catabolism enzyme with hormone-related cancer risk: a meta-analysis. AB - BACKGROUND: The evidence for vitamin D reducing cancer risk is inconsistent, and it is not clear whether this reduction is related to variation in cytochrome P450 (CYP)24A1, the only enzyme known to degrade active vitamin D. We focused on evaluating the association of CYP24A1-rs2296241 polymorphism with hormone-related cancer risk by conducting a meta-analysis. METHODS: A systematic literature search was conducted in April 2014 (updated in December 2014) to identify eligible studies. A random-effects model was used to pool the odds ratio (OR). RESULTS: Eleven studies including 5,145 cases and 5,136 controls were considered for the allelic model, and eight studies of 3,959 cases and 3,560 controls were utilized for the additive, recessive, and dominant models. There was no significant association between CYP24A1-rs2296241 and hormone-related cancer risk in any of the models, yet substantial heterogeneity was observed. Subgroup analyses indicated that CYP24A1-rs2296241 variation reduced the prostate cancer risk in the additive (OR 0.91, 95% confidence interval 0.85-0.97) and recessive (OR 0.80, 95% confidence interval 0.67-0.95) models, with no evidence of heterogeneity. CONCLUSION: This meta-analysis indicated that CYP24A1-rs2296241 polymorphism reduced the androgen-related prostate cancer risk in additive and recessive models. More genetic loci are needed to confirm the effect of CYP24A1 variation on the risk of prostate cancer. PMID- 26045672 TI - HGF and NRG1 protein expression are not poor prognostic markers in surgically resected lung adenocarcinoma. AB - PURPOSE: Although over-expression of hepatocyte growth factor (HGF) and neuregulin-1 (NRG1) are important mechanisms involved in acquired drug-resistance in many cancers, few reports have evaluated their clinicopathologic features and prognostic significance. The aim of our study was to investigate protein expressions of HGF and NRG1 in lung adenocarcinomas and their association with clinicopathologic parameters, oncogenic mutations, and the prognosis. METHODS: HGF and NRG1 protein tumor/stroma expressions were evaluated by immunohistochemistry (IHC) in 115 surgically resected lung adenocarcinomas and were correlated with clinicopathologic and molecular variables including tumor size, tumor node metastasis stage, differentiation, oncogenic mutations (EGFR, KRAS, HER2, BRAF) and ALK fusions, relapse-free survival, and overall survival. RESULTS: Positive IHC HGF tumor and stroma staining were found in 49 (42.61%) and 12 (10.43%) cases, respectively, while positive IHC NRG1 tumor and stroma staining were found in 56 (48.70%) and eleven (9.57%) cases, respectively. Dual positive IHC HGF and NRG1 tumor staining was 12.17%. EML4-ALK fusion more significantly existed in HGF-tumor positive samples (P=0.03), positive NRG1 protein stroma expression was significantly associated with male sex (P=0.04), while HGF and NRG1 dual tumor-positive mainly existed in the tumor size >3 cm group (P=0.0231). No significant clinically prognostic difference was found between patients with HGF/NRG1-positive expression and those with HGF/NRG1 negative expression. CONCLUSION: This study represents the first comprehensive analysis of HGF and NRG1 tumor and stroma expressions in patients with surgically resected lung adenocarcinomas. Our molecular data, in conjunction with clinical and pathological features, as well as their effects on survival indicated to us that patients with HGF- and NRG1-negative expression tended to have better survival, but these results probably did not warrant these markers to be indicators of poor prognosis. PMID- 26045673 TI - The impact of parental history on children's risk of asthma: a study based on the National Health and Nutrition Examination Survey-III. AB - PURPOSE: This study aimed to examine the separate effects of maternal and paternal history on the onset of asthma in children and evaluate the relationship between age of asthma onset in parents and risk of asthma in their children. METHODS: We used data from the third National Health and Nutrition Examination Survey. We developed new continuous standardized scores for survey data to quantify parental history that incorporated both the occurrence of asthma and the age at onset, and associated these scores with asthma risk in the children. The association analysis was adjusted for sex and obesity status. RESULTS: Children with maternal history have elevated asthma risk (hazard ratio of 3.71, 95% CI: 1.19-11.60) than those without, and those whose mothers had earlier age of onset have increased risk of asthma compared to those whose mothers had later age of onset. On the contrary, paternal history had a relatively smaller effect that may be only detectable in larger samples (hazard ratio of 2.17, 95% CI: 0.69-6.79). CONCLUSION: Maternal asthma history was strongly associated with the onset of asthma in the second generation, and children whose mother had an earlier age of onset had an increased risk of 3.71. For an approximately 10-year decrease in mother's age at onset of asthma, the risk of asthma for the offspring increased by 1.37-fold. Using our new risk scores led to smaller standard errors and thus more precise estimates than using a binary indicator. PMID- 26045675 TI - Erratum: A review of opioid prescription in a teaching hospital in Colombia [Corrigendum]. PMID- 26045674 TI - Modeling the budget impact of long-acting injectable paliperidone palmitate in the treatment of schizophrenia in Japan. AB - BACKGROUND: The cost of schizophrenia in Japan is high and new long-acting injectable (LAI) antipsychotics might be able to reduce costs by causing a reduction of hospital stays. We aim to estimate budget effects of the introduction of a new 1-month LAI, paliperidone palmitate, in Japan. METHODS: A budget impact analysis was conducted from a payer perspective. The model took direct costs of illness into account (ie, costs for inpatient and outpatient services, as well as drug costs). The robustness of the model was checked using a sensitivity analysis. RESULTS: According to our calculations, direct total costs of schizophrenia reach 710,500 million yen a year (US$6 billion). These costs decrease to 691,000 million yen (US$5.9 billion) 3 years after the introduction of paliperidone palmitate. CONCLUSION: From a payer point of view, the introduction of a new treatment for schizophrenia in Japan helps to save resources and is not associated with a higher financial burden. PMID- 26045676 TI - Is chronic post-herniorrhaphy pain always chronic? A literature review. AB - INTRODUCTION: Chronic post-surgery pain (CPSP) has gained increased recognition as a major factor influencing health-related quality-of-life following most surgical procedures, in particular following surgery for benign conditions. The natural course of CPSP, however, is not well-known. METHODS: A literature review was undertaken, searching for studies with repeated estimates of post herniorrhaphy pain. The hypothetical halvation time was calculated from the repeat estimates. RESULTS: Eight studies fulfilling the criteria were identified. With one exception, the extrapolated halvation times ranged from 1.3 to 9.2 years. DISCUSSION: Even if CPSP is generally very treatment-resistant, in many cases it eventually dissipates with time. Further studies are required to evaluate the prevalence of pain beyond the first decade. PMID- 26045677 TI - Two-year follow-up of low-level laser therapy for elderly with painful adhesive capsulitis of the shoulder. AB - INTRODUCTION: This paper reports on the medium-term mean 2-year prospective follow-up of a patient cohort of 35 unselected elderly patients with mean age of 65 years who visited our tertiary referral pain center for painful adhesive capsulitis of the shoulder managed with low-level laser therapy (LLLT). MATERIALS AND METHODS: All patients in this prospective cohort study had documentation of the diagnosis by contrast-enhanced magnetic resonance imaging before study entry and all had failed to respond to a combination of conventional physical therapy and nonsteroidal anti-inflammatory medications for not fewer than 4 weeks. LLLT, at a wavelength of 810 nm emitted from a GaAIAs semiconductor laser device with 5.4 J per point and a power density of 20 mW/cm(2), was employed to irradiate six predetermined anatomic points and two acupuncture points. The treatment regimen consisted of three sessions of treatment per week for 8 consecutive weeks. Each treatment session lasted 180 seconds. Serial clinical assessment was undertaken using the Constant-Murley shoulder score. RESULTS: A total of 50 painful shoulder joints were treated, as a number of elderly presented with bilateral symptoms. All but four painful shoulders showed significant improvement in Constant-Murley shoulder score at the end of 8-weeks' LLLT treatment and, surprisingly, the improvement was found maintained at follow-up assessments at 1 year and 2 years. CONCLUSION: We conclude that LLLT is a viable option in the conservative treatment of shoulder pain arising from adhesive capsulitis of the shoulder in the elderly, with a positive clinical result of more than 90% and with clinical efficacy both in the short-term and the medium-term. PMID- 26045678 TI - Unusual mechanism of myocardial infarction in prosthetic valve endocarditis. AB - A 46-year-old man with bicuspid aortic valve and severe calcific aortic stenosis was submitted to aortic valve replacement with a stented bioprosthesis. He developed Staphylococcus epidermidis prosthetic valve endocarditis a month later, presenting in the emergency room with acute myocardial infarction. The mechanism of myocardial ischemia was a large aortic root abscess causing left main extrinsic compression. He was urgently taken to the operating room, and an aortic root replacement with cryopreserved homograft was performed, associated with autologous pericardium patch closure of aortic to right atrium fistula and coronary artery bypass grafting of the left anterior descending. After a difficult postoperative period with multiple problems, he was eventually discharged home. At 36-month follow-up, he is asymptomatic with no recurrent infection, and the left main coronary artery is widely patent on control chest computed tomography. PMID- 26045679 TI - Overuse injuries in youth basketball and floorball. AB - BACKGROUND: The popularity of team sports is growing among young people. High training volume and intensity may predispose young athletes to overuse injuries. Research to date has tended to focus on acute injuries rather than overuse injuries. The purpose of this study was to examine the occurrence, nature, and severity of overuse injuries in youth basketball and floorball, with the hypothesis that overuse injuries are frequent in youth team sports. METHODS: The study comprised a total of 401 Finnish team sports athletes (207 basketball and 194 floorball players). The data were collected using a detailed questionnaire. The participants (mean age 15.8+/-1.9 years) responded to the questionnaire covering information on overuse injuries during the previous 12 months. RESULTS: A total of 190 overuse injuries was reported (97 in basketball and 93 in floorball). In both sports, most of the injuries involved the lower extremities (66% and 55% of all injuries in basketball and floorball, respectively). In basketball, the most commonly injured site was the knee (44 cases, 45%). In floorball, the most commonly injured sites were the lower back/pelvis (36 cases, 39%) and knee (32 cases, 34%). Overuse injuries caused an average time loss from full participation of 26+/-50 (median 7) days in basketball and 16+/-37 (median 5) days in floorball. CONCLUSION: Overuse injuries are a common problem in youth team sports, and often cause long-term absence from full participation. The findings suggest that injury reduction and training load monitoring strategies are needed in the field. More research using explicit prospective data collection is needed to better understand the problem. PMID- 26045680 TI - Unmet needs of patients with narcolepsy: perspectives on emerging treatment options. AB - The treatment options currently available for narcolepsy are often unsatisfactory due to suboptimal efficacy, troublesome side effects, development of drug tolerance, and inconvenience. Our understanding of the neurobiology of narcolepsy has greatly improved over the last decade. This knowledge has not yet translated into additional therapeutic options for patients, but progress is being made. Some compounds, such as histaminergic H3 receptor antagonists, may prove useful in symptom control of narcolepsy. The prospect of finding a cure still seems distant, but hypocretin replacement therapy offers some promise. In this narrative review, we describe these developments and others which may yield more effective narcolepsy treatments in the future. PMID- 26045681 TI - Review of cases of patient risk associated with ginseng abuse and misuse. AB - Ginseng has long been used as a functional food or therapeutic supplement and it is empirically known to be safe and nontoxic. During recent decades, a number of in vitro and in vivo experiments, as well as human studies have been conducted to prove the safety of various types of ginseng samples and their components. Clinical trials, case reports, and in vitro and in vivo research articles addressing the safety, toxicity, and other adverse events of ginseng application were selected and reviewed. Patient risks associated with ginseng abuse and misuse such as affective disorder, allergy, cardiovascular and renal toxicity, genital organ bleeding, gynecomastia, hepatotoxicity, hypertension, reproductive toxicity, and anticoagulant-ginseng interaction were reviewed and summarized. There are some cases of patient risk associated with ginseng abuse and misuse depending on patients' conditions although further investigation in more cases is required to clarify these issues. PMID- 26045682 TI - Characteristics of Korean ginseng varieties of Gumpoong, Sunun, Sunpoong, Sunone, Cheongsun, and Sunhyang. AB - BACKGROUND: Ginseng (Panax ginseng Meyer) is an important medicinal herbs in Asia. However, ginseng varieties are less developed. METHOD: To developed ginseng varieties, a pure line selection method was applied in this study. RESULTS: Gumpoong was testing of 4-yr-old specimens in 2002, the proportions of the below ground roots that were rusty colored for Gumpoong was 1.29 in Daejeon and 1.45 in Eumseong, whereas the proportions for its yellow berry variant were 2.60 and 2.45 in the two regions, respectively. Thus the Gumpoong was resistant to root rust. Sunpoong has a high yielding property. Its average root weight is 70.6 g for 6-yr old roots. Its yield is 2.9 kg/1.62m(2) and the rate of heaven- and earth-grade product is 20.9%, which is very high compared to 9.4% for Yunpoong. Sunone is resistance to root rot and the survival rate of 4-yr-old roots was 44.4% in 1997, whereas that of the violet-stem variant landrace was 21.7%. Sunhyang has content of arginyl-fructosyl-glucose (AFG), which produces the unique scent of red ginseng, is 95.1 MUmol/g and greater than the 30.8 MUmol/g of Chunpoong in 6-yr old plants. Sunun and Cheongsun are being nurtured to protect genetic resources. CONCLUSION: Developed ginsneg varieties will be used as the basis for the protection of genetic resources and breeding. PMID- 26045683 TI - Korean Red Ginseng attenuates ethanol-induced steatosis and oxidative stress via AMPK/Sirt1 activation. AB - BACKGROUND: Alcoholic steatosis is the earliest and most common liver disease, and may precede the onset of more severe forms of liver injury. METHODS: The effect of Korean Red Ginseng extract (RGE) was tested in two murine models of ethanol (EtOH)-feeding and EtOH-treated hepatocytes. RESULTS: Blood biochemistry analysis demonstrated that RGE treatment improved liver function. Histopathology and measurement of hepatic triglyceride content verified the ability of RGE to inhibit fat accumulation. Consistent with this, RGE administration downregulated hepatic lipogenic gene induction and restored hepatic lipolytic gene repression by EtOH. The role of oxidative stress in the pathogenesis of alcoholic liver diseases is well established. Treatment with RGE attenuated EtOH-induced cytochrome P450 2E1, 4-hydroxynonenal, and nitrotyrosine levels. Alcohol consumption also decreased phosphorylation of adenosine monophosphate-activated protein kinase, which was restored by RGE. Moreover, RGE markedly inhibited fat accumulation in EtOH-treated hepatocytes, which correlated with a decrease in sterol regulatory element-binding protein-1 and a commensurate increase in sirtuin 1 and peroxisome proliferator-activated receptor-alpha expression. Interestingly, the ginsenosides Rb2 and Rd, but not Rb1, significantly inhibited fat accumulation in hepatocytes. CONCLUSION: These results demonstrate that RGE and its ginsenoside components inhibit alcoholic steatosis and liver injury by adenosine monophosphate-activated protein kinase/sirtuin 1 activation both in vivo and in vitro, suggesting that RGE may have a potential to treat alcoholic liver disease. PMID- 26045685 TI - Anti-breast cancer activity of Fine Black ginseng (Panax ginseng Meyer) and ginsenoside Rg5. AB - BACKGROUND: Black ginseng (Ginseng Radix nigra, BG) refers to the ginseng steamed for nine times and fine roots (hairy roots) of that is called fine black ginseng (FBG). It is known that the content of saponin of FBG is higher than that of BG. Therefore, in this study, we examined antitumor effects against MCF-7 breast cancer cells to target the FBG extract and its main component, ginsenoside Rg5 (Rg5). METHODS: Action mechanism was determined by MTT assay, cell cycle assay and western blot analysis. RESULTS: The results from MTT assay showed that MCF-7 cell proliferation was inhibited by Rg5 treatment for 24, 48 and 72 h in a dose dependent manner. Rg5 at different concentrations (0, 25, 50 and 100 MUM), induced cell cycle arrest in G0/G1 phase through regulation of cell cycle-related proteins in MCF-7 cells. As shown in the results from western blot analysis, Rg5 increased expression of p53, p21(WAF1/CIP1) and p15(INK4B) and decreased expression of Cyclin D1, Cyclin E2 and CDK4. Expression of apoptosis-related proteins including Bax, PARP and Cytochrome c was also regulated by Rg5. These results indicate that Rg5 stimulated cell apoptosis and cell cycle arrest at G0/G1 phase via regulation of cell cycle-associated proteins in MCF-7 cells. CONCLUSION: Rg5 promotes breast cancer cell apoptosis in a multi-path manner with higher potency compared to 20(S)-ginsenoside Rg3 (Rg3) in MCF-7 (HER2-/ER+) and MDA-MB-453 (HER2+/ER-) human breast cancer cell lines, and this suggests that Rg5 might be an effective natural new material in improving breast cancer. PMID- 26045684 TI - Ginseng improves cognitive deficit via the RAGE/NF-kappaB pathway in advanced glycation end product-induced rats. AB - BACKGROUND: Ginseng, the root of Panax ginseng (PG), is used widely as a herbal medicine to prevent and treat various diseases. Panax ginseng has pharmacological effects on neurodegenerative diseases such as Alzheimer's disease (AD). The present study evaluated the neuroprotective effects of PG and its possible neuroprotective mechanisms in advanced glycation end product (AGE)-induced AD in a rat model. METHODS: Advanced glycation end products were injected bilaterally into the CA3 region of the rats' brains. The Morris water maze test and step-down type passive avoidance test were performed to evaluate their memory and cognitive abilities. The oxidation indexes in the hippocampus were detected. Immunohistochemistry was conducted to visualize the receptors for advanced glycation end products (RAGEs) and nuclear factor-kappa-light-chain-enhancer of activated B cell (NF-kappaB). RESULTS: Behavioral results showed that PG (1 g/kg, 0.5 g/kg, and 0.25 g/kg) significantly shortened the escape latency, remarkably increased the number of crossing times, significantly decreased the number of errors, and prolonged the latency in rats with AGE-induced AD. Panax ginseng also significantly reduced the malondialdehyde level, increased the glutathione content, and increased superoxide dismutase activity in the hippocampus. Panax ginseng significantly decreased the expression of RAGE and NF-kappaB. The blockade of anti-RAGE antibody could significantly reduce AGE-induced impairments and regulate these expressions. CONCLUSION: Our results demonstrated that PG significantly inhibits AGE-induced memory impairment and attenuates Alzheimer like pathophysiological changes. These neuroprotective effects of PG may be associated with the RAGE/NF-kappaB pathway. Our results provided the experimental basis for applying PG in preventing and treating AD. PMID- 26045686 TI - Micromorphology and development of the epicuticular structure on the epidermal cell of ginseng leaves. AB - BACKGROUND: A leaf cuticle has different structures and functions as a barrier to water loss and as protection from various environmental stressors. METHODS: Leaves of Panax ginseng were examined by scanning electron microscopy and transmission electron microscopy to investigate the characteristics and development of the epicuticular structure. RESULTS: Along the epidermal wall surface, the uniformly protuberant fine structure was on the adaxial surface of the cuticle. This epicuticular structure was highly wrinkled and radially extended to the marginal region of epidermal cells. The cuticle at the protuberant positions maintained the same thickness. The density of the wall matrix under the structures was also similar to that of the other wall region. By contrast, none of this structure was distributed on the abaxial surface, except in the region of the stoma. During the early developmental phase of the epicuticular structure, small vesicles appeared on wall-cuticle interface in the peripheral wall of epidermal cells. Some electron-opaque vesicles adjacent to the cuticle were fused and formed the cuticle layer, whereas electron-translucent vesicles contacted each other and progressively increased in size within the epidermal wall. CONCLUSION: The outwardly projected cuticle and epidermal cell wall (i.e., an epicuticular wrinkle) acts as a major barrier to block out sunlight in ginseng leaves. The small vesicles in the peripheral region of epidermal cells may suppress the cuticle and parts of epidermal wall, push it upward, and consequently contribute to the formation of the epicuticular structure. PMID- 26045687 TI - Structural investigation of ginsenoside Rf with PPARgamma major transcriptional factor of adipogenesis and its impact on adipocyte. AB - BACKGROUND: Adipocytes, which are the main cellular component of adipose tissue, are the building blocks of obesity. The nuclear hormone receptor PPARgamma is a major regulator of adipocyte differentiation and development. Obesity, which is one of the most dangerous yet silent diseases of all time, is fast becoming a critical area of research focus. METHODS: In this study, we initially aimed to investigate whether the ginsenoside Rf, a compound that is only present in Panax ginseng Meyer, interacts with PPARgamma by molecular docking simulations. After we performed the docking simulation the result has been analyzed with several different software programs, including Discovery Studio, Pymol, Chimera, Ligplus, and Pose View. All of the programs identified the same mechanism of interaction between PPARgamma and Rf, at the same active site. To determine the drug-like and biological activities of Rf, we calculate its absorption, distribution, metabolism, excretion, and toxic (ADMET) and prediction of activity spectra for substances (PASS) properties. Considering the results obtained from the computational investigations, the focus was on the in vitro experiments. RESULTS: Because the docking simulations predicted the formation of structural bonds between Rf and PPARgamma, we also investigated whether any evidence for these bonds could be observed at the cellular level. These experiments revealed that Rf treatment of 3T3-L1 adipocytes downregulated the expression levels of PPARgamma and perilipin, and also decreased the amount of lipid accumulated at different doses. CONCLUSION: The ginsenoside Rf appears to be promising compound that could prove useful in antiobesity treatments. PMID- 26045688 TI - Korean Red Ginseng protects dopaminergic neurons by suppressing the cleavage of p35 to p25 in a Parkinson's disease mouse model. AB - BACKGROUND: Ginseng is known to have antiapoptotic, anti-inflammatory, and antioxidant effects. The present study investigated a possible role of Korean Red Ginseng (KRG) in suppressing dopaminergic neuronal cell death and the cleavage of p35 to p25 in the substantia nigra (SN) and striatum (ST) using a 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease mouse model. METHODS: Ten-week-old male C57BL/6 mice were injected intraperitoneally with 30 mg/kg of MPTP at 24-h intervals for 5 d, and then administered KRG (1 mg/kg, 10 mg/kg, or 100 mg/kg) once a day for 12 consecutive days from the first injection. Pole tests were performed to assess the motor function of the mice, dopaminergic neuronal survival in the SN and ST was evaluated using tyrosine hydroxylase immunohistochemistry, and the expressions of cyclin-dependent kinase 5 (Cdk5), p35, and p25 in the SN and ST were measured using Western blotting. RESULTS: MPTP administration caused behavioral impairment, dopaminergic neuronal death, increased Cdk5 and p25 expression, and decreased p35 expression in the nigrostriatal system of mice, whereas KRG dose-dependently alleviated these MPTP induced changes. CONCLUSION: These results indicate that KRG can inhibit MPTP induced dopaminergic neuronal death and suppress the cleavage of p35 to p25 in the SN and the ST, suggesting a possible role for KRG in the treatment of Parkinson's disease. PMID- 26045689 TI - Anti-inflammatory activity of AP-SF, a ginsenoside-enriched fraction, from Korean ginseng. AB - BACKGROUND: Korean ginseng is an ethnopharmacologically valuable herbal plant with various biological properties including anticancer, antiatherosclerosis, antidiabetic, and anti-inflammatory activities. Since there is currently no drug or therapeutic remedy derived from Korean ginseng, we developed a ginsenoside enriched fraction (AP-SF) for prevention of various inflammatory symptoms. METHODS: The anti-inflammatory efficacy of AP-SF was tested under in vitro inflammatory conditions including nitric oxide (NO) production and inflammatory gene expression. The molecular events of inflammatory responses were explored by immunoblot analysis. RESULTS: AP-SF led to a significant suppression of NO production compared with a conventional Korean ginseng saponin fraction, induced by both lipopolysaccharide and zymosan A. Interestingly, AP-SF strongly downregulated the mRNA levels of genes for inducible NO synthase, tumor necrosis factor-alpha, and cyclooxygenase) without affecting cell viability. In agreement with these observations, AP-SF blocked the nuclear translocation of c-Jun at 2 h and also reduced phosphorylation of p38, c-Jun N-terminal kinase, and TAK-1, all of which are important for c-Jun translocation. CONCLUSION: Our results suggest that AP-SF inhibits activation of c-Jun-dependent inflammatory events. Thus, AP SF may be useful as a novel anti-inflammatory remedy. PMID- 26045690 TI - Glycosyl glycerides from hydroponic Panax ginseng inhibited NO production in lipopolysaccharide-stimulated RAW264.7 cells. AB - BACKGROUND: Although the aerial parts of hydroponic Panax ginseng are reported to contain higher contents of total ginsenosides than those of roots, the isolation and identification of active metabolites from the aerial parts of hydroponic P. ginseng have not been carried out so far. METHODS: The aerial parts of hydroponic P. ginseng were applied on repeated silica gel and octadecylsilane columns to yield four glycosyl glycerides (Compounds 1-4), which were identified based on nuclear magnetic resonance, infrared, fast atom bombardment mass spectrometry, and gas chromatography/mass spectrometry data. Compounds 1-4 were evaluated for inhibition activity on NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. RESULTS AND CONCLUSION: The glycosyl glycerides were identified to be (2S)-1-O-7(Z),10(Z),13(Z)-hexadecatrienoyl-3-O-beta-d-galactopyranosyl-sn glycerol (1), (2S)-1-O-linolenoyl-3-O-beta-d-galactopyranosyl-sn-glycerol (2), (2S)-1-O-linolenoyl-2-O-linolenoyl-3-O-beta-d-galactopyranosyl-sn-glycerol (3), and 2(S)-1-O-linoleoyl-2-O-linoleoyl-3-O-beta-d-galactopyranosyl-sn-glycerol (4). Compounds 1 and 2 showed moderate inhibition activity on NO production in LPS stimulated RAW264.7 cells [half maximal inhibitory concentration (IC50): 63.8 +/- 6.4MUM and 59.4 +/- 6.8MUM, respectively] without cytotoxicity at concentrations < 100MUM, whereas Compounds 3 and 4 showed good inhibition effect (IC50: 7.7 +/- 0.6MUM and 8.0 +/- 0.9MUM, respectively) without cytotoxicity at concentrations < 20MUM. All isolated compounds showed reduced messenger RNA (mRNA) expression of interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha in LPS induced macrophage cells with strong inhibition of mRNA activity observed for Compounds 3 and 4. PMID- 26045691 TI - Inhibition of L-type Ca(2+) current by ginsenoside Rd in rat ventricular myocytes. AB - BACKGROUND: Ginsenoside Rd (GSRd), one of the most abundant ingredients of Panax ginseng, protects the heart via multiple mechanisms including the inhibition of Ca(2+) influx. We intended to explore the effects of GSRd on L-type Ca(2+) current (I Ca,L) and define the mechanism of the suppression of I Ca,L by GSRd. METHODS: Perforated-patch recording and whole-cell voltage clamp techniques were applied in isolated rat ventricular myocytes. RESULTS: (1) GSRd reduced I Ca,L peak amplitude in a concentration-dependent manner [half-maximal inhibitory concentration (IC50) = 32.4 +/- 7.1 MUmol/L] and up-shifted the current-voltage (I-V) curve. (2) GSRd (30 MUmol/L) significantly changed the steady-state activation curve of I Ca,L (V 0.5: -19.12 +/- 0.68 vs. -16.26 +/- 0.38 mV; n = 5, p < 0.05) and slowed down the recovery of I Ca,L from inactivation [the time content (zeta) from 91 ms to 136 ms, n = 5, p < 0.01]. (3) A more significant inhibitive effect of GSRd (100 MUmol/L) was identified in perforated-patch recording when compared with whole-cell recording [65.7 +/- 3.2% (n = 10) vs. 31.4 +/- 5.2% (n = 5), p < 0.01]. (4) Pertussis toxin (G i protein inhibitor) completely abolished the I Ca,L inhibition induced by GSRd. There was a significant difference in inhibition potency between the two cyclic adenosine monophosphate elevating agents (isoprenaline and forskolin) prestimulation [55 +/ 7.8% (n = 5) vs. 17.2 +/- 3.5% (n = 5), p < 0.01]. (5) 1H-[1,2,4]Oxadiazolo[4,3 a]-quinoxalin-1-one (a guanylate cyclase inhibitor) and N-acetyl-l-cysteine (a nitric oxide scavenger) partly recovered the I Ca,L inhibition induced by GSRd. (6) Phorbol-12-myristate-13-acetate (a protein kinase C activator) and GF109203X (a protein kinase C inhibitor) did not contribute to the inhibition of GSRd. CONCLUSION: These findings suggest that GSRd could inhibit I Ca,L through pertussis toxin-sensitive G protein (Gi) and a nitric oxide-cyclic guanosine monophosphate-dependent mechanism. PMID- 26045692 TI - Quality and antioxidant activity of ginseng seed processed by fermentation strains. AB - BACKGROUND: Fermentation technology is widely used to alter the effective components of ginseng. This study was carried out to analyze the characteristics and antioxidant activity of ginseng seeds fermented by Bacillus, Lactobacillus, and Pediococcus strains. METHODS: For ginseng seed fermentation, 1% of each strain was inoculated on sterilized ginseng seeds and then incubated at 30 degrees C for 24 h in an incubator. RESULTS: The total sugar content, acidic polysaccharides, and phenolic compounds, including p-coumaric acid, were higher in extracts of fermented ginseng seeds compared to a nonfermented control, and highest in extracts fermented with B. subtilis KFRI 1127. Fermentation led to higher antioxidant activity. The 2,2'-azine-bis-(3-ethylbenzothiazoline-6 sulfonic acid (ABTS) radical scavenging activity was higher in ginseng seeds fermented by Bacillus subtilis than by Lactobacillus and Pediococcus, but Superoxide dismutase (SOD) enzyme activity was higher in ginseng seeds fermented by Lactobacillus and Pediococcus. CONCLUSION: Antioxidant activities measured by ABTS and SOD were higher in fermented ginseng seeds compared to nonfermented ginseng seeds. These results may contribute to improving the antioxidant activity and quality of ginseng subjected to fermentation treatments. PMID- 26045693 TI - A prebiotic fiber increases the formation and subsequent absorption of compound K following oral administration of ginseng in rats. AB - BACKGROUND: Gut microflora play a crucial role in the biotransformation of ginsenosides to compound K (CK), which may affect the pharmacological effects of ginseng. Prebiotics, such as NUTRIOSE, could enhance the formation and consequent absorption of CK through the modulation of gut microbial metabolic activities. In this study, the effect of a prebiotic fiber (NUTRIOSE) on the pharmacokinetics of ginsenoside CK, a bioactive metabolite of ginsenosides, and its mechanism of action were investigated. METHODS: Male Sprague-Dawley rats were given control or NUTRIOSE-containing diets (control diet + NUTRIOSE) for 2 wk, and ginseng extract or vehicle was then orally administered. Blood samples were collected to investigate the pharmacokinetics of CK using liquid chromatography-tandem mass spectrometry. Fecal activities that metabolize ginsenoside Rb1 to CK were assayed with fecal specimens or bacteria cultures. RESULTS: When ginseng extract was orally administered to rats fed with 2.5%, 5%, or 10% NUTRIOSE containing diets, the maximum plasma concentration (C max) and area under the plasma concentration time curve values of CK significantly increased in a NUTRIOSE content-dependent manner. NUTRIOSE intake increased glycosidase activity and CK formation in rat intestinal contents. The CK-forming activities of intestinal microbiota cultured in vitro were significantly induced by NUTRIOSE. CONCLUSION: These results show that prebiotic diets, such as NUTRIOSE, may promote the metabolic conversion of ginsenosides to CK and the subsequent absorption of CK in the gastrointestinal tract and may potentiate the pharmacological effects of ginseng. PMID- 26045694 TI - Lewis' law revisited: the role of anisotropy in size-topology correlations. AB - Since F T Lewis' pioneering work in the 1920s, a linear correlation between the average in-plane area of domains in a two-dimensional (2D) cellular structure and the number of neighbors of the domains has been empirically proposed, with many supporting and dissenting findings in the ensuing decades. Revisiting Lewis' original experiment, we take a larger set of more detailed data on the cells in the epidermal layer of Cucumis, and analyze the data in the light of recent results on size-topology correlations. We find that the correlation between the number-of-neighbor distribution (topology) and the area distribution is altered over that of many other 2D cellular systems (such as foams or disc packings), and that the systematic deviation can be explained by the anisotropic shape of the Cucumis cells. We develop a novel theory of size-topology correlation taking into account the characteristic aspect ratio of the cells within the framework of a granocentric model, and show that both Lewis' and our experimental data is consistent with the theory. In contrast to the granocentric model for isotropic domains, the new theory results in an approximately linear correlation consistent with Lewis' law. These statistical effects can be understood from the increased number of configurations available to a plane-filling domain system with non isotropic elements, for the first time providing a firm explanation of why Lewis' law is valid in some systems and fails in others. PMID- 26045695 TI - The significance of information after discharge for colorectal cancer surgery-a qualitative study. AB - BACKGROUND: The aim was to explore patients' experiences of information and their information needs after discharge for colorectal cancer surgery. METHODS: Thirty one interviews were performed with sixteen patients during the first seven weeks at home after discharge. Patients were included from three hospitals in the south of Sweden, two of which used an enhanced recovery programme. RESULTS: Trying to regain control in life by using information was the overall theme emerging from the interviews. Patients experienced the bodily changes after surgery and the emotional impact of the cancer disease, and these combined experiences seriou/sly affected their ability to manage their daily lives. They both needed, and were in search of, information to increase participation in their own cancer trajectory and to facilitate the regaining of some measure of control in their lives. Waiting for different kinds of information increased the anguish and fear in the face of an unknown future. CONCLUSIONS: This study showed that receiving information was vital when patients tried to regain control in life after colorectal cancer surgery. The information was necessary in order to facilitate and manage the transition from hospital to home, and the need varied between different transitions. Patients needed more information to manage the daily life at home, but also to understand what the cancer disease really meant to them. This suggests a need for patients to participate more actively in the information and the discharge planning. PMID- 26045696 TI - Analysis of the accuracy of the Wells scale in assessing the probability of lower limb deep vein thrombosis in primary care patients practice. AB - BACKGROUND: The clinical picture of deep vein thrombosis (DVT) is nonspecific. Therefore assessment of the probability of occurrence of DVT plays a very important part in making a correct diagnosis of DVT. The aim of our prospective study was to assess the accuracy of the Wells scale in primary care setting in diagnostic procedure of suspected deep vein thrombosis. METHODS: In the period of 20 - months (from 2007 to 2009) a group of residents from one of the urban districts of Warsaw, who reported to family doctors (22 primary care physicians were involved in the study) with symptoms of DVT were assessed on the probability of occurrence of deep vein thrombosis using the Wells scale. Family doctors were aware of symptoms of DVT and inclusion patients to this study was based on clinical suspicion of DVT. Patients were divided into three groups, reflecting probability of DVT of the lower limbs. To confirm DVT a compression ultrasound (CUS) test was established. We analyzed the relationship between a qualitative variable and a variable defined on an original scale (incidence of DVT versus Wells scale count) using the Mann-Whitney test. Chi-square test compared rates of DVT events in all clinical probability groups. Patient were follow up during 3 months in primary care setting. RESULTS: In the period of 20 months (from 2007 to 2009) a total number of 1048 patients (male: 250 , female: 798 mean age: 61.4) with symptoms suggestive of DVT of the lower extremities entered the study. Among the 100 patients classified in the group with a high probability of DVT of the lower extremities, 40 (40%) patients (proximal DVT - 13; distal DVT - 27) were diagnosed with it (95% CI [30.94% -49.80%]). In the group with a moderate probability consisting of 302 patients, DVT of the lower extremities was diagnosed in 19 (6.29%) patients (95% CI [4.06% -9.62%]), (proximal DVT - 1; distal DVT - 18). Of the 646 patients with a low probability of DVT of the lower extremities distal DVT was diagnosed in 1 (0.15%) patient (95% CI [0.03% 0.87%]). CONCLUSION: The Wells scale used in primary care setting demonstrated a high degree of accuracy. PMID- 26045697 TI - Should additional domains be added to the EQ-5D health-related quality of life instrument for community-based studies? An analytical descriptive study. AB - BACKGROUND: There is increasing interest in monitoring the health-related quality of life (HRQoL) of populations as opposed to clinical populations. The EQ-5D identifies five domains as being most able to capture the HRQoL construct. The question arises as to whether these domains are adequate within a community-based population or whether additional domains would add to the explanatory power of the instrument. METHODS: As part of a community-based survey, the responses of 310 informants who reported at least one problem in one domain filled in the EQ 5D three-level version and the WHOQOL-BREF (World Health Organization Quality of Life Scale - Abbreviated version). Using the EQ-5D visual analogue scale (VAS) of rating of health as a dependent variable, the five EQ-5D and four selected WHOQOL BREF items were entered as dummy variables in multiple regression analysis. RESULTS: The additional domains increased the explanatory power of the model from 52 % (EQ-5D only) to 57 % (all domains). The coefficients of Self-Care and Usual Activities were not significant in any model. The most parsimonious model included the EQ-5D domains of Mobility, Pain/Discomfort, Anxiety/Depression, Concentration, and Sleep (adjusted r(2) = .57). CONCLUSIONS: The EQ-5D-3L performed well, but the addition of domains such as Concentration and Sleep increased the explanatory power. The user needs to weigh the advantage of using the EQ-5D, which allows for the calculation of a single summary index, against the use of a set of domains that are likely to be more responsive to differences in HRQoL within community living respondents. The poor predictive power of the Self-Care and Usual Activities domains within this context needs to be further examined. PMID- 26045698 TI - Religious Media Use Among African Americans, Black Caribbeans, and Non-Hispanic Whites: Findings from the National Survey of American Life. AB - The purpose of this study was to examine the correlates of watching religious television programs and listening to religious radio programs. Data are taken from the National Survey of American Life, a nationally representative study of African Americans, Black Caribbeans, and non-Hispanic Whites. Several significant findings were noted. Both African Americans and Black Caribbeans watched religious television programs and listened to religious radio programs significantly more frequently than non-Hispanic whites. These differences in electronic religious media consumption were particularly large, especially listening to religious radio programming. Among African Americans and Black Caribbeans, several significant demographic differences in frequency of consuming religious programming (e.g., age, gender, region, marital status, immigration status) emerged. Lastly, our analysis found that consuming electronic religious programming did not substitute for attending church service but, instead, complemented weekly service attendance. PMID- 26045700 TI - Duct-to-Duct Biliary Anastomosis Yields Similar Outcomes to Roux-en-Y Hepaticojejunostomy in Liver Transplantation for Primary Sclerosing Cholangitis. AB - BACKGROUND: While Roux-en-Y hepaticojejunostomy (RYH) is the common anastomotic technique for liver transplantation (LT) in patients with primary sclerosing cholangitis (PSC), duct-to-duct (DD) reconstruction may be used if the recipient common bile duct is normal. There are conflicting observational data on the rate of success of DD reconstruction versus RYH, in PSC. OBJECTIVES: The aim of this study was to assess the safety and efficacy of DD anastomosis, compared to RYH reconstruction, among adults transplanted for PSC. PATIENTS AND METHODS: All adult patients, who underwent primary LT for PSC between 1990 and 2012, were evaluated, according to type of biliary reconstruction. Recipient and graft survival, postoperative medical and surgical complications, and postoperative resource utilization rates were compared between the two groups. RESULTS: Totally, 73 patients fulfilled the inclusion criteria. Of them, 58 had RYH and 15 had DD reconstruction. A total of 53 subjects (73%) were male, with the mean age +/- standard deviation at LT of 43.3 +/- 14.4 years. Rates of recipient mortality, graft failure, biliary complications, acute cellular rejection, and reoperation were similar in both groups. Postoperative cholangiography was used more frequently in patients with DD reconstruction (33.3% vs. 8.6%, P = 0.026). CONCLUSIONS: In selected recipients with PSC, DD reconstruction is a safe and efficacious technique, with long-term clinical outcomes comparable to RYH. PMID- 26045699 TI - Optimism and Planning for Future Care Needs among Older Adults. AB - Aging is associated with an increase in need for assistance. Preparation for future care (PFC) is related to improved coping ability as well as better mental and physical health outcomes among older adults. We examined the association of optimism with components of PFC among older adults. We also explored race differences in the relationship between optimism and PFC. In Study 1, multiple regression showed that optimism was positively related to concrete planning. In Study 2, optimism was related to gathering information. An exploratory analysis combining the samples yielded a race interaction: For Whites higher optimism, but for Blacks lower optimism was associated with more planning. High optimism may be a barrier to future planning in certain social and cultural contexts. PMID- 26045701 TI - Prevalence of National Responsiveness to HBV Vaccine After 22 Years of Iranian Expanded Program on Immunization (EPI): A Systematic Review and Meta-Analysis Study. AB - CONTEXT: Hepatitis B Virus expanded program on immunization (EPI) started on 1993 in Iran. Most surveys have assessed the level of response to vaccine by measuring the titers of anti-HBs. This meta- analysis aimed to summarize the Iranian published data on the rate of vaccine-responders versus non-responders. Moreover, the impact of variables such as age, gender, type of vaccine, etc. on the levels of responsiveness was evaluated. EVIDENCE ACQUISITION: All published papers on this topic in Iranian and international journals with affiliation of "Iran" were reviewed using standard keywords up to 2014. We included our study to healthy participants with no previous HBV infection and who had already received a complete course of HB vaccine. The estimated prevalence and 95% confidence intervals in 28 eligible articles for HBV vaccine responders (anti-HBs > 10 IU/mL) and non-responders (10 <) were analyzed by random effect method due to between-study heterogeneity. RESULTS: The age of subjects was between 6 months and 15 years old. Overall, 5991 (51.5%) were male and 4571 (48.5%) females. Overall, 80% were responders to vaccine versus 20% nonresponders. With increase in age, the number of responders to vaccine decreased significantly (P = 0.001). There was no strong difference between responders versus nonresponders to vaccine for gender, types of vaccine, ethnicity and living area. CONCLUSIONS: The results arose from this meta-analysis highlighted the safety of vaccine and its effectiveness in stimulating immune response of vaccines, despite being different in generation, manufacturers and types. Moreover, there was no substantial difference between Iranian and other international investigations in the rate of nonresponsiveness to HBV vaccine. PMID- 26045703 TI - Knowledge, attitude, and behavior of hepatitis B virus infection among chinese dental interns. AB - BACKGROUND: Blood is frequently involved in dental treatment procedures, which increases the exposure of dentists to a variety of blood-borne pathogens and microorganisms such as Hepatitis B Virus. OBJECTIVES: The current study aimed to assess Chinese dental and medical interns' knowledge, attitude and behavior (KAB) towards Hepatitis B Virus (HBV) infection and to evaluate which exact KAB phase respondents were involved in. PATIENTS AND METHODS: A self-administered questionnaire survey was conducted on 313 fifth to eighth year students. Descriptive statistics and bivariate analyses were used to identify correlations between KAB and the results obtained from different grades. RESULTS: Despite the fact that Chinese dental interns had good general knowledge level, they lacked the experience with active and artificial immunities against HBV. Graduates forgot basic knowledge and applied the methods without understanding the terms. Compared with the medical interns, dental interns were less willing to treat patients with HBV infection. All three required vaccination doses were received by a significant number of dental interns. However the frequency of antibody titer status check and the use of eye wear or face mask were not satisfying. CONCLUSIONS: It is therefore recommended that Chinese dental interns continue improving knowledge level, assume more positive attitude by accumulating clinical experience, and pay more attention to the overlooked procedures. The results of the current study can help the Chinese dental interns on theoretical studies and clinical practices regarding HBV. PMID- 26045702 TI - Distribution and epidemiologic trends of HBV genotypes and subtypes in 14 countries neighboring china. AB - BACKGROUND: The number of cases of HBV infection reported by the WHO for each district and country is positively correlated with the number of HBV sequences in the database isolated from the corresponding district and country. OBJECTIVES: This study determined distribution characteristics of HBV genotypes and subtypes in 14 countries neighboring China. The progress made in genomic research involving HBV was also reviewed. MATERIALS AND METHODS: Nine hundred fifty-one complete genome sequences of HBV from 14 countries neighboring China were selected from NCBI. The sequence-related information was analyzed and recorded. One hundred seventy-two sequences of HBV genotype B were screened for alignment using DNA star and MEGA 5.1. RESULTS: Dominant HBV genotypes in the countries neighboring China were genotypes B, C and D and dominant subtypes were adw2 and adrq+. The association between genotype and serotype of HBV in these countries was shown to differ from previous research results. As shown by sequence alignment, the sequence divergence between five subgenotypes (B3, B5, B7, B8 and B9) was below 4%. The B subgenotypes shared six common specific amino acid sites in the S region. CONCLUSIONS: The B3, B5, B7, B8 and B9 subgenotypes can be clustered into quasi-sub-genotype B3 and the open reading frame of HBV has a start codon preference; however, whether a mutation in the start codon in the pre S2 region has an impact on survival and replication of HBV remains to be determined. PMID- 26045704 TI - Clinical values of elevated serum cytokeratin-18 levels in hepatitis: a meta analysis. AB - BACKGROUND: As an important intermediate filament protein within liver cells, cytokeratin-18 (CK-18) has been confirmed as a potential indicator in various hepatitis progressions. OBJECTIVES: We sought to clarify the connection between serum CK-18 levels and hepatitis pathogenesis in the present meta-analysis. MATERIALS AND METHODS: With the application of various computerized databases, including PubMed, Embase, Cochrane Library, Google Scholar, Web of Science, China BioMedicine (CBM), China National Knowledge Infrastructure (CNKI), published papers that assessed the relationship between serum CK-18 levels and hepatitis were obtained. The main key words used are "Hepatitis", "hepatitides", "Cytokeratin-18", "Keratin-18" and "CK-18". Statistical analysis was conducted using the STATA software (version 12.0). RESULTS: Eight case-control studies published between 2010 and 2014 were confirmed eligible, according to our selection criteria. The results of the meta-analysis showed that serum levels of CK-18 in hepatitis patients were higher compared to healthy controls (standardized mean difference (SMD) = 3.71, 95%CI: 2.27-5.14, P < 0.001). Subgroup analysis by ethnicity and disease implicated that high serum CK-18 levels might be a risk factor for non-alcoholic steatohepatitis (NASH), chronic hepatitis C (CHC), and chronic hepatitis B (CHB) (all P < 0.05) among Asians (SMD = 2.89, 95%CI: 2.35-3.43, P < 0.001), Africans (SMD = 0.69, 95%CI: 0.12-1.26, P = 0.017), and Caucasians (SMD = 4.86, 95%CI: 1.82-7.89, P = 0.002). CONCLUSIONS: Serum CK-18 levels in hepatitis patients were higher, compared with healthy controls. Our results revealed the clinical values of CK-18, in combination with other apoptosis markers, in identifying the development of hepatitis. PMID- 26045705 TI - Efficacy of tenofovir disoproxil fumarate therapy in nucleoside-analogue naive Iranian patients treated for chronic hepatitis B. AB - BACKGROUND: Tenofovir disoproxil fumarate (TDF) is a new effective treatment option for patients with chronic hepatitis B (CHB). OBJECTIVES: To evaluate TDF efficacy in nucleos(t)ide analogues (NAs)-naive Iranian patients with CHB. PATIENTS AND METHODS: The NA-naive patients received TDF for at least six months. The primary endpoint was the proportion of patients achieving a complete virological response (CVR) during the treatment. Multivariate Cox regression analysis determined predictive factors independently associated with the time to CVR. The secondary endpoints were biochemical and serological responses, frequency of virological breakthrough, genotypic resistance development, safety and tolerability. RESULTS: In all, 93 patients (64.5% hepatitis B e antigen [HBeAg]-negative) were eligible. Of these, 70 patients completed 24 months of treatment. The cumulative CVR rates in HBeAg-negative and HBeAg-positive patients were 87% versus 53% at 24 months, respectively. The multivariate Cox regression model showed only HBeAg positivity at baseline and a high baseline HBV DNA level were independent factors predicting a CVR. No patient achieved hepatitis B surface antigen (HBsAg) and HBeAg loss or seroconversion and no virologic breakthrough occurred. A new amino acid substitution (rtD263E) was observed to develop in 60% of patients with viremia. CONCLUSIONS: The cumulative CVR rates showed that patients with HBeAg-negative have better virologic respond than those with HBeAg-positive during the same period. The rtD263E mutation might be associated with partial resistance to TDF. PMID- 26045706 TI - Seroprevalence of hepatitis e among hemodialysis patients: a report from hamadan, iran. AB - BACKGROUND: Previous studies have documented a high prevalence of hepatitis E among patients undergoing maintenance hemodialysis. Available studies reporting on the seroprevalence of hepatitis E in hemodialysis patients in Iran, an endemic region for the disease, are sparse. OBJECTIVES: The present study aimed to determine the prevalence rate of anti-hepatitis E antibody in hemodialysis patients in Hamadan, Iran. PATIENTS AND METHODS: In this cross-sectional study, all 153 consecutive patients undergoing hemodialysis in two centers were enrolled. Patients' demographic and clinical data were collected, using a standard questionnaire and from medical records. Serum immunoglobulin G concentrations against hepatitis E were determined using the enzyme linked immunosorbent assay method. RESULTS: Thirty patients (19.2%), were seropositive. Seropositive patients were not significantly different from seronegative patients, with regard to age, sex, level of education, access to filtered water, and duration and frequency of hemodialysis. The proportions of patients with hepatitis B, C, and HIV infection were comparable between the two groups. CONCLUSIONS: One in five patients undergoing maintenance dialysis in Hamadan is seropositive for hepatitis E immunoglobulin G antibody. Future studies are needed to investigate the factors contributing to the observed high prevalence rate and the possibility of parenteral transmission of hepatitis E. PMID- 26045707 TI - A comprehensive long-term prognosis of chronic hepatitis C patients with antiviral therapy: a meta-analysis of studies from 2008 to 2014. AB - CONTEXT: Attaining a sustained virological response with antiviral therapy is a sign of clinical cure for chronic hepatitis C patients. The aim of this meta analysis was to evaluate the long-term efficiency and outcome of antiviral therapy in patients with hepatitis C who attained a sustained virological response. EVIDENCE ACQUISITION: A literature search was performed on published articles between January 2008 and February 2014. Patients with Hepatitis C who received interferon with or without ribavirin therapy were enrolled. Relative risks were estimated using either fixed or random effect models. RESULTS: Patients who attained sustained virological response had a less risk (85%) for all-cause mortality and about 63% reduced risk of hepatocellular carcinoma incidence than those who did not achieve sustained virological response. Based on deeply analysis, the stage of liver fibrosis was a risk factor at baseline for the incidence of hepatocellular carcinoma. CONCLUSIONS: Sustained virological response can reduce all-cause mortality and the incidence of hepatocellular carcinoma of patients with hepatitis C. Advanced liver fibrosis is still a risk factor for the incidence of hepatocellular carcinoma, in spite of hepatitis C patients attained a sustained virological response. PMID- 26045708 TI - Molecular mechanisms for alcoholic hepatitis based on analysis of gene expression profile. AB - BACKGROUND: Alcoholic hepatitis (AH) is an acute manifestation of alcoholic liver disease with high mortality rates. OBJECTIVES: Our aim was to study the molecular mechanisms of AH. MATERIALS AND METHODS: The differentially expressed genes (DEGs) in liver between AH and control cases were identified by analyzing the GSE28619 microarray data using t-test. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) enrichment analyses were performed using DAVID online tool. The protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes (STRING) and the subnetwork was identified by BioNet. Both PPI network and subnetwork were visualized using the Cytoscape software. RESULTS: Total 908 DEGs (551 up- and 357 down-regulated DEGs) were obtained. The up-regulated DEGs were significantly enriched in 15 pathways and 112 GO biological processes. The down-regulated DEGs were significantly enriched in 22 pathways and 84 GO biological processes. The PPI network with 608 nodes and 2878 interactions was constructed and the subnetwork with 53 nodes and 131 interactions was also identified. The hub DEGs (TSPO, PPIB, NME1 and NME2) were extracted in this subnetwork. CONCLUSIONS: TSPO might contribute to the liver damage and AH progression induced by mitochondrial dysfunction through oxidative stress of liver. TSPO interacted with PPIB might play important roles in liver damage in AH. The interaction between NME1 and NME2 might contribute to the transformation from AH to hepatocellular carcinoma. PMID- 26045709 TI - Saturated Fatty Acid inhibits viral replication in chronic hepatitis B virus infection with nonalcoholic Fatty liver disease by toll-like receptor 4-mediated innate immune response. AB - BACKGROUND: Chronic Hepatitis B (CHB) infection is common in patients with Non Alcoholic Fatty Liver Disease (NAFLD). The replication level of Hepatitis B Virus (HBV) was inversely correlated with hepatic steatosis. Toll-Like Receptor (TLR) 4 mediated innate immunity plays a pivotal role in the occurrence of NAFLD and controls HBV replication. OBJECTIVES: This study aimed to investigate whether the TLR4-mediated innate immunity stimulates the pathogenesis of CHB in patients with NAFLD and to determine whether TLR4 plays a role in inhibiting HBV replication. MATERIALS AND METHODS: The HBV transgenic mice were randomized into the HBV and HBV/NAFLD groups. HepG2.2.15 cells were treated with different concentrations (0 200 MUM) of Stearic Acid (SA) to induce steatosis. The total RNA of the liver tissue was extracted for Real-Time Polymerase Chain Reaction (RT-PCR) detection, and immunohistochemistry or western blot was conducted for further validation. The Enzyme-Linked Immunosorbent Assay (ELISA) analysis was applied to evaluate the production of Interleukin 6 (IL-6), Tumor necrosis factor alpha (TNF-alpha) and Interferon beta (IFN-beta). Moreover, viral dynamics were analyzed using HBV DNA and HBV-related antigens (HBsAg and HBeAg). RESULTS: Non-alcoholic fatty liver disease was induced in HBV-transgenic mice fed with High Fat Diet (HFD) for 8 - 24 weeks. Oil red-O staining positive droplets and the content of Triglyceride (TG) were increased in HepG2.2.15 cells treated with SA. TLR4, Myeloid differentiation factor 88 (MyD88), IL-6 and TNF-alpha expression levels were significantly higher in the HBV/NAFLD group and the steatotic HepG2.2.15 cells than those in their respective controls. Compared to the HBV group, significant reductions in serum levels of HBsAg, HBeAg, and HBV DNA titers occurred in the HBV/NAFLD group at 24 weeks, but the IFN-beta level was remarkably increased. Similar data were also obtained from the steatoric HepG2.2.15 cells. CONCLUSIONS: Saturated Fatty Acids (SFAs) served as a potential ligand for TLR4 and activated TLR4 signaling pathway, which might be involved in the pathogenesis. Thus, SFAs can accelerate the mechanism of inhibiting HBV replication in CHB with NAFLD. PMID- 26045710 TI - LRRFIP1 Inhibits Hepatitis C Virus Replication by Inducing Type I Interferon in Hepatocytes. AB - BACKGROUND: Hepatitis C virus infection is one of the leading causes of end stage liver diseases. The innate immune response slows down viral replication by activating cytokines such as type I interferon (IFN-alpha/beta), which trigger the synthesis of antiviral proteins and modulate the adaptive immune system. Recently, leucine-rich repeat (in Flightless I) interacting protein-1 (LRRFIP1) was reported contributing to the production of interferon-beta in macrophages. OBJECTIVES: The aim of this study was to assess the role of LRRFIP1 in induction of IFN-beta and inhibition of HCV infection in hepatocytes. MATERIALS AND METHODS: Induction of IFN-beta by LRRFIP1 in Huh7 and Huh7.5.1 was determined by real-time PCR and western blotting in vitro. Inhibition of HCV replication by LRRFIP1 overexpression in hepatocytes was assessed. RESULTS: LRRFIP1 increased the expression of IFN-beta in hepatocytes with or without HCV infection. Induction of IFN-beta by LRRFIP1 was enhanced with the presence of hepatitis C virus. Overexpression of LRRFIP1 in hepatocytes inhibited HCV replication. However, HCV infection did not regulate intracellular expression of LRRFIP1. CONCLUSIONS: LRRFIP1 and its mediated production of type I interferon play a role in controlling HCV infection. The findings of this study provide new target for HCV treatment and contribute to development of anti-HCV drugs. PMID- 26045711 TI - Are platelets count useful for detecting the grade of steatosis? PMID- 26045712 TI - Overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient. AB - A 21 year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay(r)) and tenofovir disaproxil fumarate/emtricitabine (Truvada(r)) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6 hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5 days after the day of intoxication, serum creatinine levels increased to high normal values (1.2 mg/dl). However, levels never exceeded the upper threshold. 8 and 12 weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments. PMID- 26045713 TI - Chlorogenic acid/chromium supplement rescues diet-induced insulin resistance and obesity in mice. AB - Abdominal obesity is a major risk factor for insulin resistance, type 2 diabetes and cardiovascular diseases. Dietary fat induces insulin resistance in humans and rodents. The current study investigates whether a Chlorogenic acid/Chromium III supplement rescues obesity and insulin resistance caused by high-fat feeding of male C57BL/6 J mice for 7 weeks. Administering an oral daily dose of this supplement in the last 3 weeks of feeding reversed diet-induced body weight gain and insulin resistance, assessed by hyperglycemia, glucose intolerance and insulin intolerance. Indirect calorimetry analysis revealed that this effect is mediated at least partly, by increasing energy expenditure and spontaneous locomoter activity. These findings underscore the important role that chlorogenic acid and chromium play in maintaining glucose metabolism and insulin response in mice fed a high-fat diet. PMID- 26045714 TI - Taking Stock of Unrealistic Optimism. AB - Researchers have used terms such as unrealistic optimism and optimistic bias to refer to concepts that are similar but not synonymous. Drawing from three decades of research, we critically discuss how researchers define unrealistic optimism and we identify four types that reflect different measurement approaches: unrealistic absolute optimism at the individual and group level and unrealistic comparative optimism at the individual and group level. In addition, we discuss methodological criticisms leveled against research on unrealistic optimism and note that the criticisms are primarily relevant to only one type-the group form of unrealistic comparative optimism. We further clarify how the criticisms are not nearly as problematic even for unrealistic comparative optimism as they might seem. Finally, we note boundary conditions on the different types of unrealistic optimism and reflect on five broad questions that deserve further attention. PMID- 26045715 TI - Unemployment and prostate cancer mortality in the OECD, 1990-2009. AB - The global economic downturn has been associated with increased unemployment in many countries. Insights into the impact of unemployment on specific health conditions remain limited. We determined the association between unemployment and prostate cancer mortality in members of the Organisation for Economic Co operation and Development (OECD). We used multivariate regression analysis to assess the association between changes in unemployment and prostate cancer mortality in OECD member states between 1990 and 2009. Country-specific differences in healthcare infrastructure, population structure, and population size were controlled for and lag analyses conducted. Several robustness checks were also performed. Time trend analyses were used to predict the number of excess deaths from prostate cancer following the 2008 global recession. Between 1990 and 2009, a 1% rise in unemployment was associated with an increase in prostate cancer mortality. Lag analysis showed a continued increase in mortality years after unemployment rises. The association between unemployment and prostate cancer mortality remained significant in robustness checks with 46 controls. Eight of the 21 OECD countries for which a time trend analysis was conducted, exhibited an estimated excess of prostate cancer deaths in at least one of 2008, 2009, or 2010, based on 2000-2007 trends. Rises in unemployment are associated with significant increases in prostate cancer mortality. Initiatives that bolster employment may help to minimise prostate cancer mortality during times of economic hardship. PMID- 26045716 TI - Genetic susceptibility in childhood acute leukaemias: a systematic review. AB - Acute leukaemias (AL) correspond to 25-35% of all cancer cases in children. The aetiology is still sheltered, although several factors are implicated in causality of AL subtypes. Childhood acute leukaemias are associated with genetic syndromes (5%) and ionising radiation as risk factors. Somatic genomic alterations occur during fetal life and are initiating events to childhood leukaemia. Genetic susceptibility has been explored as a risk factor, since environmental exposure of the child to xenobiotics, direct or indirectly, can contribute to the accumulation of somatic mutations. Hence, a systematic review was conducted in order to understand the association between gene polymorphisms and childhood leukaemia risk. The search was performed in the electronic databases PubMed, Lilacs, and Scielo, selecting articles published between 1995 and 2013. This review included 90 case-control publications, which were classified into four groups: xenobiotic system (n = 50), DNA repair (n = 16), regulatory genes (n = 15), and genome wide association studies (GWAS) (n = 9). We observed that the most frequently investigated genes were: NQO1, GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, CYP2D6, CYP2E1, MDR1 (ABCB1), XRCC1, ARID5B, and IKZF1. The collected evidence suggests that genetic polymorphisms in CYP2E1, GSTM1, NQO1, NAT2, MDR1, and XRCC1 are capable of modulating leukaemia risk, mainly when associated with environmental exposures, such as domestic pesticides and insecticides, smoking, trihalomethanes, alcohol consumption, and x-rays. More recently, genome wide association studies identified significant associations between genetic polymorphisms in ARID5B e IKZF1 and acute lymphoblastic leukaemia, but only a few studies have replicated these results until now. In conclusion, genetic susceptibility contributes to the risk of childhood leukaemia through the effects of gene-gene and gene-environment interactions. PMID- 26045717 TI - Current issues in patient safety in surgery: a review. AB - Current surgical safety guidelines and checklists are generic and are not specifically tailored to address patient issues and risk factors in surgical subspecialties. Patient safety in surgical subspecialties should be templated on general patient safety guidelines from other areas of medicine and mental health but include and develop specific processes dedicated for the care of the surgical patients. Safety redundant systems must be in place to decrease errors in surgery. Therefore, different surgical subspecialties should develop a specific curriculum in patient safety addressing training in academic centers and application of these guidelines in all practices. Clearly, redundant safety systems must be in place to decrease errors in surgery, in analogy to safety measures in other high-risk industries. Specific surgical subspecialties are encouraged to develop a specific patient safety curriculum that address training in academic centers and applicability to daily practice, with the goal of keeping our surgical patients safe in all disciplines. The present review article is designed to outline patient safety practices that should be adapted and followed to fit particular specialties. PMID- 26045719 TI - Repbase Update, a database of repetitive elements in eukaryotic genomes. AB - Repbase Update (RU) is a database of representative repeat sequences in eukaryotic genomes. Since its first development as a database of human repetitive sequences in 1992, RU has been serving as a well-curated reference database fundamental for almost all eukaryotic genome sequence analyses. Here, we introduce recent updates of RU, focusing on technical issues concerning the submission and updating of Repbase entries and will give short examples of using RU data. RU sincerely invites a broader submission of repeat sequences from the research community. PMID- 26045720 TI - Diabetic foot complications in a secondary foot hospital: A clinical audit. AB - BACKGROUND: Previous studies conducted in Australian hospital settings suggest high variability in assessments, investigations, and management of diabetic foot infections and poor adherence to widely accessible evidence-based protocols and guidelines. Diabetic foot complications require a multidisciplinary approach and often involve both medical and surgical teams during inpatient care. AIMS: The aim of this clinical audit was to better understand the scope of diabetes-related foot complications, evaluate whether current assessment and management strategies are in line with best practice guidelines, and to formulate future models of care. METHODS: A retrospective review of patients was carried out between 12 July 2012 and 11 July 2013. Recorded assessments of inpatient care, including risk factors, surgery, length of stay, interdepartmental referrals, and antibiotic administration were reviewed. RESULTS: There were 24 admissions in 12 months (total patients n=19). Fifty-eight per cent of patients were admitted to the medical ward. More than one-quarter had evidence of osteomyelitis. While one patient required intensive care unit (ICU) management, there was no inpatient mortality. Two patients experienced significant delay to undergo initial surgical intervention presumably because of failed medical treatment. Clinical data was recorded poorly, especially regarding neuropathy, HbA1c, and clinical examination findings. Twelve per cent of patients did not undergo any follow-up. The average length of stay was 12 days. One-half of the cohort was not evaluated by the endocrinology department. CONCLUSION: This audit highlights the need for improved care for patients with diabetic foot complications and better coordination among the multidisciplinary teams involved. PMID- 26045718 TI - Connectivity and circuitry in a dish versus in a brain. AB - In order to understand and find therapeutic strategies for neurological disorders, disease models that recapitulate the connectivity and circuitry of patients' brain are needed. Owing to many limitations of animal disease models, in vitro neuronal models using patient-derived stem cells are currently being developed. However, prior to employing neurons as a model in a dish, they need to be evaluated for their electrophysiological properties, including both passive and active membrane properties, dynamics of neurotransmitter release, and capacity to undergo synaptic plasticity. In this review, we survey recent attempts to study these issues in human induced pluripotent stem cell-derived neurons. Although progress has been made, there are still many hurdles to overcome before human induced pluripotent stem cell-derived neurons can fully recapitulate all of the above physiological properties of adult mature neurons. Moreover, proper integration of neurons into pre-existing circuitry still needs to be achieved. Nevertheless, in vitro neuronal stem cell-derived models hold great promise for clinical application in neurological diseases in the future. PMID- 26045721 TI - Muscular strength, aerobic capacity, and adipocytokines in obese youth after resistance training: A pilot study. AB - BACKGROUND: Exercise has shown positive training effects on obesity-related inflammation, however, resistance training has shown mixed results concerning adipocytokine levels. AIMS: The purpose of this pilot study was to explore the effects of resistance training on blood adipocytokine concentrations in obese youth, with specific examination of the relationship between these biomarkers and improved fitness (i.e., aerobic capacity, muscular strength). METHODS: Fourteen obese adolescents (16.1 +/-1.6 y; BMI: 32.3 +/-3.9 kg/m(2)) participated in a 16 week resistance training intervention. Body composition, fasting blood concentrations of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), adiponectin, and leptin were measured pre- and post-training. Aerobic capacity was assessed via a maximal discontinuous exercise test. The rate of gain in muscular strength was calculated as the slope of progression in 1-repetition maximum throughout the intervention. RESULTS: Resistance training increased lean mass (total, trunk) and decreased per cent body fat (total, trunk). The training also caused moderate clear decreases in IL-6 and TNF-alpha concentrations. A small increase in adiponectin was also observed before and after intervention. When the group was stratified by changes in aerobic capacity, there were substantially larger decreases in leptin levels for those with improved capacity. Correlation analyses also revealed a negative relationship between log transformed leptin and aerobic capacity at rest. Improvement in quadriceps strength was positively correlated with IL-6 and TNF-alpha, while improvement in shoulder adductor strength was positively correlated with IL-6 only. CONCLUSION: Resistance training improved adipocytokine markers, which were partially associated with improved physical fitness. Specifically, the relationship between strength improvements and IL-6 and TNF-alpha suggests an exercise-induced signalling pathway that results in overall adaptive decreases in systemic inflammation in obese youth. PMID- 26045722 TI - More than just teaching procedural skills: How RN clinical tutors perceive they contribute to medical students' professional identity development. AB - BACKGROUND: On their journey to "becoming" doctors, medical students encounter a range of health professionals who contribute to their socialisation into clinical practice. Amongst these individuals are registered nurses (RNs) in clinical practice who are often employed by medical schools as clinical tutors. These RNs will encounter medical students on campus and later in the clinical setting. AIMS: This qualitative study explored RNs' perceptions of their contribution to medical students' developing professional identities in order to provide a greater understanding of this process and ultimately inform future curriculum. METHODS: This qualitative study took place in 2012 at one Australian medical school as part of a broader study exploring medical students' professional identity development from the perspectives of their teachers and trainers. Eight of the nine RNs involved in teaching procedural skills were interviewed. Recorded interviews were transcribed verbatim. Data were analysed inductively by the research team. RESULTS: Two major themes emerged: RNs as change agents and RNs as facilitators of medical students' transition to the clinical environment. RNs as change agents related to their role modelling good practice, being patient centred, and by emphasising factors contributing to good teamwork such as recognising and respecting individual professional roles. They facilitated students' transition to the clinical environment often through personal narratives, by offering advice on how to behave and work with members of the healthcare team, and by being a point of contact in the hospital. CONCLUSION: Based on their descriptions of how they role modelled good practice and how they facilitated students' transition to clinical practice, we believe that RN clinical tutors do have the experience and expertise in clinical practice and a professional approach to patients to contribute to medical students' developing professional identities as future doctors. PMID- 26045723 TI - Pharmacoeconomic evaluation of hospitalised pre-dialysis and dialysis patients: A comparative study. AB - BACKGROUND: The progression of chronic kidney disease (CKD) can be attributed to various factors, including lack of medical services, delayed referral, lack of awareness about the disease, drugs, and financial support. AIMS: To compare the pharmacoeconomic-related direct medical and non-medical costs among hospitalised pre-dialysis and dialysis patients. METHODS: A prospective observational study was conducted on the inpatients admitted to the Department of Nephrology. Patients undergoing maintenance dialysis or initiated on renal replacement therapy were included in the dialysis patients group and other CKD patients in the pre-dialysis group. The data pertaining to the pharmacoeconomic-related direct medical and non-medical costs were collected from the patient records, medical bills, and other relevant sources. RESULTS: Out of 100 patients, 43 were in the pre-dialysis group and 57 were in the dialysis group. The median direct medical costs (INR 4,731.62, USD $76.47) for dialysis group patients were significantly higher than for the pre-dialysis group (INR 1,820.95, USD $29.43). The median direct non-medical costs (INR 550, USD $8.88) for pre-dialysis group patients were not significantly higher than for the dialysis group (INR 480, USD $7.75). CONCLUSION: There was a significant difference in the median direct total costs between pre-dialysis and dialysis patients. The number of medications per prescription and length of hospital stay are the factors that influence the median direct total costs. PMID- 26045724 TI - Still leaving stains on teeth-the legacy of minocycline? AB - Minocycline is widely used as a first-line agent for papulopustular acne, and has previously been reported as causing stains on teeth that are still forming. This article reports a case of staining to only the crowns of unerupted third molars in a girl prescribed minocycline at age 16 for papulopustular acne. We review the literature in the area of minocycline teeth staining, consider the role of minocycline as a first-line agent for papulopustular acne, and outline strategies on the prevention of minocycline teeth staining. The case highlights current deficiencies in the disclosure information for minocycline, and provides information that is relevant to practitioners who may prescribe this drug. PMID- 26045725 TI - Celebrating successes in oral health and looking to an innovative future. PMID- 26045726 TI - Quantitative Assessment Of Bone And Joint Health On A Dedicated Extremities Cone Beam CT System. PMID- 26045727 TI - Impact of microfluidic processing on bacterial ribonucleic acid expression. AB - Bacterial transcriptomics is widely used to investigate gene regulation, bacterial susceptibility to antibiotics, host-pathogen interactions, and pathogenesis. Transcriptomics is crucially dependent on suitable methods to isolate and detect bacterial RNA. Microfluidics offer ways of creating integrated point-of-care systems, analysing a sample from preparation, and RNA isolation to detection. A critical requirement for on-chip diagnostics to deliver on their promise is that mRNA expression is not altered via microfluidic sample processing. This article investigates the impact of the use of microfluidics upon RNA expression of bacteria isolated from blood, a key step towards proving the suitability of such systems for further development. PMID- 26045728 TI - The microfluidics of the eccrine sweat gland, including biomarker partitioning, transport, and biosensing implications. AB - Non-invasive and accurate access of biomarkers remains a holy grail of the biomedical community. Human eccrine sweat is a surprisingly biomarker-rich fluid which is gaining increasing attention. This is especially true in applications of continuous bio-monitoring where other biofluids prove more challenging, if not impossible. However, much confusion on the topic exists as the microfluidics of the eccrine sweat gland has never been comprehensively presented and models of biomarker partitioning into sweat are either underdeveloped and/or highly scattered across literature. Reported here are microfluidic models for eccrine sweat generation and flow which are coupled with review of blood-to-sweat biomarker partition pathways, therefore providing insights such as how biomarker concentration changes with sweat flow rate. Additionally, it is shown that both flow rate and biomarker diffusion determine the effective sampling rate of biomarkers at the skin surface (chronological resolution). The discussion covers a broad class of biomarkers including ions (Na(+), Cl(-), K(+), NH4 (+)), small molecules (ethanol, cortisol, urea, and lactate), and even peptides or small proteins (neuropeptides and cytokines). The models are not meant to be exhaustive for all biomarkers, yet collectively serve as a foundational guide for further development of sweat-based diagnostics and for those beginning exploration of new biomarker opportunities in sweat. PMID- 26045729 TI - The dynamics and stability of lubricating oil films during droplet transport by electrowetting in microfluidic devices. AB - The operation of digital microfluidic devices with water droplets manipulated by electrowetting is critically dependent on the static and dynamic stability and lubrication properties of the oil films that separate the droplets from the solid surfaces. The factors determining the stability of the films and preventing surface fouling in such systems are not yet thoroughly understood and were experimentally investigated in this study. The experiments were performed using a standard digital microfluidic cartridge in which water droplets enclosed in a thin, oil-filled gap were transported over an array of electrodes. Stable, continuous oil films separated the droplets from the surfaces when the droplets were stationary. During droplet transport, capillary waves formed in the films on the electrode surfaces as the oil menisci receded. The waves evolved into dome shaped oil lenses. Droplet deformation and oil displacement caused the films at the surface opposite the electrode array to transform into dimples of oil trapped over the centers of the droplets. Lower actuation voltages were associated with slower film thinning and formation of fewer, but larger, oil lenses. Lower ac frequencies induced oscillations in the droplets that caused the films to rupture. Films were also destabilized by addition of surfactants to the oil or droplet phases. Such a comprehensive understanding of the oil film behavior will enable more robust electrowetting-actuated lab-on-a-chip devices through prevention of loss of species from droplets and contamination of surfaces at points where films may break. PMID- 26045730 TI - Microscale flow propulsion through bioinspired and magnetically actuated artificial cilia. AB - Recent advances in microscale flow propulsion through bioinspired artificial cilia provide a promising alternative for lab-on-a-chip applications. However, the ability of actuating artificial cilia to achieve a time-dependent local flow control with high accuracy together with the elegance of full integration into the biocompatible microfluidic platforms remains remote. Driven by this motive, the current work has constructed a series of artificial cilia inside a microchannel to facilitate the time-dependent flow propulsion through artificial cilia actuation with high-speed (>40 Hz) circular beating behavior. The generated flow was quantified using micro-particle image velocimetry and particle tracking with instantaneous net flow velocity of up to 10(1 ) MUm/s. Induced flow patterns caused by the tilted conical motion of artificial cilia constitutes efficient fluid propulsion at microscale. This flow phenomenon was further measured and illustrated by examining the induced flow behavior across the depth of the microchannel to provide a global view of the underlying flow propulsion mechanism. The presented analytic paradigms and substantial flow evidence present novel insights into the area of flow manipulation at microscale. PMID- 26045731 TI - Robust fluidic connections to freestanding microfluidic hydrogels. AB - Biomimetic scaffolds approaching physiological scale, whose size and large cellular load far exceed the limits of diffusion, require incorporation of a fluidic means to achieve adequate nutrient/metabolite exchange. This need has driven the extension of microfluidic technologies into the area of biomaterials. While construction of perfusable scaffolds is essentially a problem of microfluidic device fabrication, functional implementation of free-standing, thick-tissue constructs depends upon successful integration of external pumping mechanisms through optimized connective assemblies. However, a critical analysis to identify optimal materials/assembly components for hydrogel substrates has received little focus to date. This investigation addresses this issue directly by evaluating the efficacy of a range of adhesive and mechanical fluidic connection methods to gelatin hydrogel constructs based upon both mechanical property analysis and cell compatibility. Results identify a novel bioadhesive, comprised of two enzymatically modified gelatin compounds, for connecting tubing to hydrogel constructs that is both structurally robust and non-cytotoxic. Furthermore, outcomes from this study provide clear evidence that fluidic interconnect success varies with substrate composition (specifically hydrogel versus polydimethylsiloxane), highlighting not only the importance of selecting the appropriately tailored components for fluidic hydrogel systems but also that of encouraging ongoing, targeted exploration of this issue. The optimization of such interconnect systems will ultimately promote exciting scientific and therapeutic developments provided by microfluidic, cell-laden scaffolds. PMID- 26045732 TI - Helium Droplets Doped with Sulfur and C60. AB - Clusters of sulfur are grown by passing superfluid helium nanodroplets through a pickup cell filled with sulfur vapor. In some experiments the droplets are codoped with C60. The doped droplets are collided with energetic electrons and the abundance distributions of positively and negatively charged cluster ions are recorded. We report, specifically, distributions of S m+, S m-, and C60S m- containing up to 41 sulfur atoms. We also observe complexes of sulfur cluster anions with helium; distributions are presented for He n S m- with n <= 31 and m <= 3. The similarity between anionic and cationic C60S m+/- spectra is in striking contrast to the large differences between spectra of S m+ and S m-. PMID- 26045733 TI - Water-Gas Shift and Methane Reactivity on Reducible Perovskite-Type Oxides. AB - Comparative (electro)catalytic, structural, and spectroscopic studies in hydrogen electro-oxidation, the (inverse) water-gas shift reaction, and methane conversion on two representative mixed ionic-electronic conducting perovskite-type materials La0.6Sr0.4FeO3-delta (LSF) and SrTi0.7Fe0.3O3-delta (STF) were performed with the aim of eventually correlating (electro)catalytic activity and associated structural changes and to highlight intrinsic reactivity characteristics as a function of the reduction state. Starting from a strongly prereduced (vacancy rich) initial state, only (inverse) water-gas shift activity has been observed on both materials beyond ca. 450 degrees C but no catalytic methane reforming or methane decomposition reactivity up to 600 degrees C. In contrast, when starting from the fully oxidized state, total methane oxidation to CO2 was observed on both materials. The catalytic performance of both perovskite-type oxides is thus strongly dependent on the degree/depth of reduction, on the associated reactivity of the remaining lattice oxygen, and on the reduction-induced oxygen vacancies. The latter are clearly more reactive toward water on LSF, and this higher reactivity is linked to the superior electrocatalytic performance of LSF in hydrogen oxidation. Combined electron microscopy, X-ray diffraction, and Raman measurements in turn also revealed altered surface and bulk structures and reactivities. PMID- 26045734 TI - Molecular pathology and potential therapeutic targets in esophageal basaloid squamous cell carcinoma. AB - Basaloid squamous cell carcinoma (BSCC) is a rare and poorly differentiated variant of typical squamous cell carcinoma. Emerging studies show that genetic alterations are more frequent in BSCC than in conventional SCC, and some of which led to the identification of potential therapeutic targets in esophageal BSCC. Approximately half of the esophageal BSCC cases harbor either an EGFR mutation or amplification, and these occur in a mutually exclusive fashion. Therefore, the application of tyrosine kinase inhibitors may be beneficial to esophageal BSCC patients. This tumor is partly characterized by the activation of the Wnt and Hedgehog (HH) signaling pathways. Wnt signaling is activated by SFRP2 promoter hypermethylation and HH signaling is activated by the frequent mutations in PTCH1. Increasing evidence shows that the Wnt signaling pathway is involved in cross-talk with other developmental pathways, including the HH pathway. Therefore, pharmaceutical therapy targeting both the HH and Wnt pathways would be quite effective in patients with esophageal BSCC with highly malignant potential. In this review, we discuss the pathology, prognostic factors, genetic alterations and potential therapeutic targets in BSCC of esophagus. PMID- 26045735 TI - Silent information regulator 1 (SIRT1) promotes the migration and proliferation of endothelial progenitor cells through the PI3K/Akt/eNOS signaling pathway. AB - Silent information regulator 1 (SIRT1) mediates many effects of caloric restriction (CR) on an organism's lifespan and metabolic pathways. Recent reports have also emphasized its role in vascular function. The present study was designed to investigate the effects of SIRT1 on the properties of mouse spleen derived endothelial progenitor cells (EPCs). SIRT1 in EPCs was significantly increased by serum and by vascular endothelial growth factor (VEGF). Moreover, an adenovirus (Ad) vector expressing SIRT1 (Ad-SIRT1)-mediated overexpression of SIRT1 directly enhanced migration and proliferation of EPCs, whereas silencing of endogenous SIRT1 in EPCs inhibited cell functions. In addition, LY294002 (a PI3K inhibitor), sc-221226 (an Akt inhibitor), and L-NAME (an NOS inhibitor) abolished Ad-SIRT1-induced migration and proliferation of EPCs, and prevented nitric oxide (NO) production. Phosphorylation of Akt, PI3K, and endothelial nitricoxide synthase (eNOS) were up-regulated by Ad-SIRT1, which was attenuated by LY294002, sc-221226, and L-NAME. Together, the results suggested that through the PI3K/Akt/eNOS signaling pathway, SIRT1 plays an important role in the biological properties of EPCs. PMID- 26045736 TI - Relationship of advanced glycation end products and their receptor to pelvic organ prolapse. AB - OBJECTIVE: The aims of this study are to detect levels of AGEs and RAGE and SNPs for RAGE in vaginal tissues of women with POP and rats in a repair location, and to explore the relationship between AGEs-RAGE pathway and POP. METHODS: This study involved human vaginal tissues in fornix from 44 women with POP and 46 women without POP who were assigned to pelvic floor reconstruction or LAVH. The proteins of AGEs, collagen I, and RAGE were detected by immunohistochemistry and Western blot with appropriate primary antibodies. The entire RAGE gene of 24 women with POP and 25 controls were sequenced, and SNPs within were detected. Then, sixty 8-week-old female Sprague-Dawley rats subjected to abdominal defect were divided into three surgical pelvic floor reconstruction repair groups (n=20/group): A, repair with non-absorable prolene mesh; B, repair with absorbable SIS mesh; and C, a no repair control group. 3, 9, 15, and 21 months after operation, rats were sacrificed and the expression of AGEs, RAGE and collagen I in the tissues of repair location were detected in the various experimental groups. Statistical analysis included comparison of means (Student's t-test) and proportions (Chi-square test or Fisher test). RESULTS: By both immunohistochemistry and Western blot, patients with POP showed higher protein expression of AGEs of POP than controls (P<0.05). In contrast, the expression of collagen I was lower in POP patients than in the control group (P<0.05). No differences in the expression of RAGE between the POP patients and controls were observed (P>0.05). In POP patients, the expression of collagen I decreased particularly in patients>=60 years old (P<0.05), but there were no different in the expression of AGEs and RAGE dependent on age (P>0.05). RAGE gene sequence variance analysis identified 18 variable loci, but only two of these were potential SNPs: rs184003 (1806), rs55640627 (2346) (P<0.05). Both rs184003 and rs55640627 are both intronic variants, indicating that they may not influence the structure of RAGE. In rat surgical repair model, group B showed a greater extent of abdominal prolapse than groups A and C (P<0.05). Consistent with this, the expression of AGEs in group B was higher than groups A and C (P<0.05), and collagen I in group B was lower than the two others, further supporting our notion that AGEs are inversely related to type I collagen content. CONCLUSIONS: In summary, this study demonstrates that AGEs and RAGE might play important roles in the physiopathology of POP. Further studies are required to explore mechanisms of how AGEs-RAGE pathway may contribute to tissue degeneration and fragility in POP. PMID- 26045737 TI - shRNA-mediated silencing of sorcin increases drug chemosensitivity in myeloma KM3/DDP and U266/ADM cell lines. AB - Sorcin is a penta-EF hand calcium binding protein, which is involved in the resistance to chemotherapeutics in cancer cells, and is overexpressed in various cancer cells. However, tumor relapse combined with the development of drug resistance remains a significant problem. Here, we demonstrated that silencing of Sorcin in chemotherapy resistance myeloma U266/ADM and KM3/DDP cell lines resulted in reduced cell proliferation, cell cycle arrest and cell apoptosis. Sorcin siRNA successfully silenced Sorcin mRNA and protein expression. Silencing of Sorcin also significantly reduced the mRNA and protein expression levels of MDR1, MRP1, GST-pi, Survinvin, Livin, Bcl-2, Cyclin-D1, phospho-Src, C-myc, p21, NF-kappaB and phospho-AKT, while p53 expression and caspase-3 and caspase-8 activity significantly increased when compared with control group. Silencing of Sorcin significantly increased the sensitivity of KM3/DDP cells to cisplatin and the sensitivity of U266/ADM to adriamycin, compared to cells untransfected and transfected with negative control shRNA. In addition, intracellular accumulation of Rhodamine 123 significantly increased in KM3/DDP and U266/ADM cells. In summary, our studies indicate that drug resistance can be effectively reversed in cisplatin-resistance and adriamycin-resistant myeloma cells through delivery of siRNAs targeting Sorcin. Assessment of potential as a target for human myeloma treatment is clearly warranted. PMID- 26045738 TI - Protective effects of isorhamnetin on apoptosis and inflammation in TNF-alpha induced HUVECs injury. AB - Little is known about the role of isorhamnetin on endothelial cell apoptosis and inflammation when insulted by TNF-alpha injury. In our study, HUVECs were treated with TNF-alpha for 6 hours. HUVECs apoptosis were detected using flow cytometry. The expressions of ICAM-1, VCAM-1, E-selectin, NF-kappaB, AP-1 and eNOS were determined with western blotting or flow cytometry. The results showed TNF-alpha increased of apoptosis and the expression of ICAM-1, VCAM-1 and E-selectin in HUVECs, accompanied by significant augmentation of NF-kappaB and AP-1 expression. Pretreatment with isorhamnetin significantly reduced apoptosis in TNF-alpha treated HUVECs. Moreover, isorhamnetin significantly attenuated TNF-alpha-induced upregulation of ICAM-1, VCAM-1, AP-1, E-selectin and NF-kappaB expression. Meanwhile, isorhamnetin also increased the expression of eNOS. So, isorhamnetin could suppress TNF-alpha-induced apoptosis and inflammation by blocking NF-kappaB and AP-1 signaling in HUVECs, which might be one of the underlying mechanisms for treatment of coronary heart disease. PMID- 26045739 TI - Reduced beta 2 glycoprotein I improves diabetic nephropathy via inhibiting TGF beta1-p38 MAPK pathway. AB - PURPOSE: Beta 2 glycoprotein I (beta2GPI) has been shown the positive effect on diabetic atherosclerosis and retinal neovascularization. beta2GPI can be reduced by thioredoxin-1, resulting in the reduced state of beta2GPI. The possible protective effects of beta2GPI and reduced beta2GPI on diabetic nephropathy (DN) are not fully elucidated. The purpose of this study was to test a hypothesis that beta2GPI and reduced beta2GPI would improve DN in streptozotocin (STZ) induced diabetic mice and high-glucose (HG) exposed rat mesangial cell (RMC). METHODS: The STZ-induced Balb/c mice and HG exposed RMCs were administrated with beta2-GPI and reduced beta2-GPI at different time and concentrations gradient respectively. The changes of glomerular structure and expression of collagen IV, TGF-beta1, p38 MAPK and phospho-p38 MAPK in renal cortical and mesangial cells were observed by immunohistochemical techniques, quantitative real-time PCR and western blot with or without the treatment of beta2-GPI and reduced beta2-GPI. RESULTS: beta2GPI and reduced beta2GPI improved early clinical and pathological changes of DN in STZ-diabetic mice. Treatment with beta2GPI and reduced beta2GPI in the STZ diabetic mice and HG exposed RMCs resulted in decrease expression levels of TGF beta1 and collagen IV, with concomitant decrease in phospho-p38 MAPK expression. CONCLUSIONS: beta2GPI and reduced beta2GPI improved renal structural damage and kidney function. The renoprotective and antifibrosis effects of beta2GPI and reduced beta2GPI on DN were closely associated with suppressing the activation of the TGF-beta1-p38 MAPK pathway. PMID- 26045740 TI - Clinico-pathological association of Henoch-Schoenlein purpura nephritis and IgA nephropathy in children. AB - OBJECTIVE: Henoch-Schonlein purpura nephritis (HSPN) and IgA nephropathy (IgAN) are similar syndromes. We aimed to determine whether the crescent formation/immunocomplex in glomeruli is associated with the differences of the biochemical indexes between HSPN and IgAN. METHODS: We investigated the medical records of 137 HSPN cases and 41 IgAN cases from January 2009 to April 2014 in Nanjing Children's Hospital of Nanjing Medical University. The clinical and pathological data were analyzed and compared between HSPN and IgAN. RESULTS: HSPN patients had markedly higher levels of blood white blood cell (WBC), hemoglobulin (Hb) and platelet (PLT), lower levels of hematuria, blood nitrogen (BUN) and C4 compared with IgAN cases. Crescents formation and C3 deposition in the kidney did not affect these differences. Significantly lower levels of hematuria, blood IgG, IgM and C4 in HSPN compared with IgAN cases were observed among patients with IgG deposition. Markedly higher levels of WBC and Hb, lower levels of hematuria, creatinine (Cr), C4 in HSPN compared with IgAN cases were observed among patients with IgM deposition. No marked differences of the biochemical indexes were noted between HSPN and IgAN cases among patients with C1q deposition. Markedly higher levels of WBC and Hb, lower level of blood C4 in HSPN compared with IgAN cases were observed among patients with fibrogen deposition. CONCLUSIONS: The different levels of biochemical indexes at presentation between HSPN and IgAN may be associated with the deposition of IgG, IgM, C1q and fibrogen in the kidney. PMID- 26045741 TI - Pulsed magnetic field promotes proliferation and neurotrophic genes expression in Schwann cells in vitro. AB - As one of the most classic supportive cells, Schwann cells (SCs) have been considered as potential candidates for nerve regeneration. However, SCs cultured in vitro are found with attenuated biological activities, which limits their application. Pulsed magnetic field (PMF) has been demonstrated to be safe and efficient to regulate several cells activities. However, it is still unclear the effect of PMF on proliferation and expression of neurotrophic factors in SCs. Therefore, the present study was designed to examine such possible effects. The tolerance of SCs to PMF was examined by flow cytometry and scanning electron microscopy (SEM). The proliferation of cells was detected by an EdU labeling assay and a Prestoblue assay. The expression and secretion of neurotrophic factors in SCs was assayed by RT-PCR and ELISA. We found that 2.0 mT was the optimal intensity that caused relatively little apoptosis with profound proliferation in SCs. The gene expression and protein level of brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF) were up-regulated following PMF stimulation, additionally, the gene expression and protein level of neurotrophin 3 (NT-3) was not enhanced by PMF. Our results suggested that PMF could improve SC proliferation and biological function, which might shed a light on the potential utilization of PMF in nerve regeneration via SC activation. PMID- 26045742 TI - Neuroprotective effect of fasudil on inflammation through PI3K/Akt and Wnt/beta catenin dependent pathways in a mice model of Parkinson's disease. AB - OBJECTIVE: Fasudil, a Rho kinase inhibitor, has neuroprotection in the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP)-based Parkinson's disease (PD). This study aims to investigate the mechanism underlying the neuroprotection of fasudil in the PD mice model. METHODS: Female MPTP-intoxication C57BL/6 mice were treated with normal saline or fasudil on day 15 after first administration of MPTP. Pole test was used for the behavioral analysis of mice. Expression of interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF-alpha) in brain tissue were detected by ELISA. Expression of tyrosine hydroxylase (TH), p-MYPT1, p-nuclear transcription factor NF-kappaB, toll-like receptor 2 (TLR2), arginase1, inducible nitric oxide synthase (iNOS), bromodeoxyuridine (BrdU), glial cell line-derived neurotrophic factor (GDNF), p-GSK-3b, p110-PI3K, p-Akt, WNT1, Fzd1 and beta catenin were determined by western blot and immunofluorescence analysis. RESULTS: Fasudil enhanced the number of TH neurons which was decreased by MPTP treatment. Behavioral test showed that the motor performance of mice was improved after fasudil treatment. The expression of IL-1beta, TNF-alpha, TLR2 and p-NF-kappaB and iNOS were lower after fasudil treatment (P<0.05) while the expression of arginase1 was increased (P<0.05). Further, we could observe the increase of GDNF expression in the microglial cells. The expression of p110-PI3K, p-Akt, WNT1, Fzd1 and beta-catenin were increased after fasudil administration (P<0.05) in MPTP-based mice model. CONCLUSIONS: Maybe fasudil protect dopamine neurons from loss in the MPTP mice model of PD through inflammatory inhibition via activation of PI3K/p-Akt and WNT1/Fzd1/beta-catenin cell signaling pathways. PMID- 26045743 TI - Sclareol exerts anti-osteoarthritic activities in interleukin-1beta-induced rabbit chondrocytes and a rabbit osteoarthritis model. AB - Sclareol is a natural product initially isolated form Salvia sclarea which possesses immune-regulation and anti-inflammatory activities. However, the anti osteoarthritic properties of sclareol have not been investigated. The present study is aimed at evaluating the potential effects of sclareol in interleukin 1beta (IL-1beta)-induced rabbit chondrocytes as well as an experimental rabbit knee osteoarthritis model induced by anterior cruciate ligament transection (ACLT). Cultured rabbit chondrocytes were pretreated with 1, 5 and 10 MUg/mL sclareol for 1 h and followed by stimulation of IL-1beta (10 ng/mL) for 24 h. Gene expression of matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13, tissue inhibitors of metalloproteinase-1 (TIMP-1), inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 was determined by quantitative real-time polymerase chain reaction (qRT-PCR). MMP-3, TIMP-1, iNOS and COX-2 proteins were measured by Western blotting. Enzyme-linked immunosorbent assay (ELISA) was applied for nitric oxide (NO) and prostaglandin E2 (PGE2) assessment. For the in vivo study, rabbits received six weekly 0.3 mL sclareol (10 MUg/mL) intra articular injections in the knees four weeks after ACLT surgery. Cartilage was harvested for measurement of MMP-1, MMP-3, MMP-13, TIMP-1, iNOS and COX-2 by qRT PCR, while femoral condyles were used for histological evaluation. The in vitro results we obtained showed that sclareol inhibited the MMPs, iNOS and COX-2 expression on mRNA and protein levels, while increased the TIMP-1 expression. And over-production of NO and PGE2 was also suppressed. For the in vivo study, both qRT-PCR results and histological evaluation confirmed that sclareol ameliorated cartilage degradation. Hence, we speculated that sclareol may be an ideal approach for treating osteoarthritis. PMID- 26045744 TI - Effect of pollen typhae on inhibiting autophagy in spinal cord injury of rats and its mechanisms. AB - PURPOSE: To investigate the effects and mechanism of pollen typhae on spinal cord injury (SCI) in rats. METHODS: The SCI model was built and animals were randomly divided into three groups according to different concentrations of pollen typhae. Protein, mRNA, and fluorescence expression levels of light-chain-3 (LC-3) and Beclin-1 were determined by western blotting (WB), real-time PCR and immunofluorescence, along as Akt and mammalian target of rapamycin (mROT) by WB. The demyelination area and integrated optical density (IOD) were analyzed by luxol fast blue (LFB) and Nissl staining, respectively; Behavioral assessments were assessed by Basso Beattie Bresnahan (BBB) scale. RESULTS: Protein, mRNA, and fluorescence expression levels of LC-3 and Beclin-1 were significantly increased after SCI, while were obviously decreased by administration of pollen typhae, along with protein level of Akt and mROT. The demyelination area was significantly reduced, while IOD and BBB were significantly increased compared with the model group. CONCLUSION: Autophagic activity increased in damaged neural tissue after SCI, and pollen typhae have certain therapeutic effect on SCI, the higher concentration of pollen typhae, the more effective. Besides, pollen typhae also provided neuroprotective effect and improved locomotor function. The effects may be produced by blockade of Akt/mTOR pathway. PMID- 26045745 TI - Down-regulation of GPX3 is associated with favorable/intermediate karyotypes in de novo acute myeloid leukemia. AB - Decreased glutathione peroxidase 3 (GPX3) expression has been identified in numerous solid tumors. However, GPX3 expression pattern in acute myeloid leukemia (AML) remains poorly known. Our study was intended to explore GPX3 expression status and further analyze the clinical relevance of GPX3 expression in AML. GPX3 mRNA level was detected by real-time quantitative PCR in 122 de novo AML patients and 44 normal controls. GPX3 transcript level was significantly decreased compared with normal controls (P<0.001). The patients with low GPX3 expression had significantly higher hemoglobin and platelets than those with high GPX3 expression (P=0.049 and 0.020). The frequency of low GPX3 expression in favorable karyotype (66%, 23/35) and intermediate karyotype (65%, 45/69) was higher than in poor karyotype (29%, 4/14) (P=0.017). No significant differences were observed in both complete remission and overall survival between the GPX3 low-expressed and high-expressed patients (P>0.05). Reduced GPX3 expression is associated with favorable/intermediate karyotypes but not with survival in de novo AML patients. PMID- 26045747 TI - Inhibition of gamma-secretase by retinoic acid chalcone (RAC) induces G2/M arrest and triggers apoptosis in renal cell carcinoma. AB - The present study was devised to investigate the effect of RAC on inhibition of cell proliferation and apoptosis of renal carcinoma cells. MTT assay and flow cytometry analysis were used to determine cell proliferation and apoptosis along with cell cycle examination. Western blot analysis and immunohistochemistry were used for the detection of expression levels of Notch1 and Jagged1 in renal cell carcinoma (RCC) and normal kidney tissues. The results revealed a significant inhibition of cell proliferation, G2/M phase cell cycle arrest and cell apoptosis at 30 MUM concentration of RAC after 72 h. In ACHN and 769-P cells, the population in G2/M phase was increased to 45.27, and 54.23% respectively on treatment with 30 MUM RAC for 72 h. In 769-P and ACHN renal carcinoma cells treatment with 30 MUM RAC caused 69.71 and 59.27% of the cells to undergo apoptosis compared to 5.23 and 4.93% respectively in control cells. The positive staining rates of Notch1 and Jagged1 in renal carcinoma tissues were 95.3 and 93.0% compared to normal kidney tissues 36.4 and 42.4% respectively. Treatment of renal carcinoma tissues caused a significant decrease in staining rates of Notch1 and Jagged1 after 96 h. Thus RAC can be a potent agent in the treatment of renal cell carcinoma. PMID- 26045746 TI - Associations of deregulation of mir-365 and its target mRNA TTF-1 and survival in patients with NSCLC. AB - microRNA (mir)-365 exerts tumor suppressor function by targeting thyroid transcription factor-1 (TTF-1) in lung cancer cells. The purpose of the present study was to assess mir-365 and its target mRNA TTF-1 in lung cancer and their correlations with patients' survival. Quantitative real-time PCR was used to examine the expression levels of mir-365 and TTF-1 in tumor tissue and its adjacent noncancerous tissue of 126 patients with non-small cell lung cancer (NSCLC). Our results showed that mir-365 was significantly decreased in tumor tissue than that in normal tissue (P=0.006), however, TTF-1 was significantly increased in tumor tissue than in normal tissue (P<0.001). Besides, significant correlations between decreased mir-365 and advanced tumor-node-metastasis (TNM) stage (P=0.001) and regional lymph node involvement (P=0.037) was observed. The similar result was also found between increased TTF-1 and TNM stage (P=0.003). Furthermore, mir-365 downregulation or TTF-1 upregulation were associated with poor outcome of patients than mir-365 upregulation or TTF-1 downregulation (for mir-365: P<0.001; for TTF-1: P=0.002). Of note, combination of decreased mir-365 and increased TTF-1 had worst overall survival (P<0.001). In conclusion, aberrant expression of mir-365/TTF-1 may be involved in the tumor development in patients with NSCLC. Moreover, mir-365 and TTF-1 could jointly predict the prognosis of patients and their combination may serve as a biomarker to predict risk of poor survival in NSCLC patients. Mir-365/TTF-1 might serve as a potential therapeutic target for clinical treatment of NSCLC. PMID- 26045748 TI - CD-163 correlated with symptoms (pain or discomfort) of prostatic inflammation. AB - The purpose of this study is to identify significant immune-system related for symptom of patients with prostatic inflammation in order to investigate the etiology of prostatic inflammation which may relate to potentially chronic prostatitis (CP). We investigated the expression of immune system-related biomarkers such as Interleukin (IL) -6 (humoral immunity), CD-3 (T-lymphocyte), and CD-163 (macrophage) in prostate biopsy (PBx) specimens from patients with prostatic inflammation (without cancer) which had been neither clinically diagnosed benign prostatic hyperplasia nor chronic prostatitis. We examined the correlation between these markers' expressions and the symptom scores using the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score (IPSS)/quality of life (QOL) which are the index for lower urinary tract symptoms (LUTS). Our results showed CD-163 (macrophage) reflected pain or discomfort on NIH-CPSI scores (P=0.0389 and r=0.3307) in the patients with prostatic inflammation; however, the control patients had no significant correlation between symptom scores and those immune related markers' expression. These results suggest that pain or discomfort related to macrophages in the relationship between immune-system and the symptom of prostatic inflammation. In conclusion, CD-163, related to immune-system (macrophage), correlated with symptoms (pain or discomfort) of prostatic inflammation and might represent a significant immune-system related biomarker for pain or LUTS score in potentially CP. PMID- 26045749 TI - Prognostic factors of laryngeal solitary extramedullary plasmacytoma: a case report and review of literature. AB - A paucity of data exists concerning the presentation, natural course and outcome of extramedullary plasmcytoma (EMP). It is difficult to determine the optimal treatment strategy and prognostic factors for EMP. We present an additional case of laryngeal EMP and systemic review relevant reports in the English and Chinese literature. We found, to our knowledge, 147 cases in larynx in the English language literature and Chinese-literature. The most common treatment modality was radiotherapy alone. The mean survival duration was ~184 months, and the 5- and 10- year survival rates were 76.1% and 67.4%, respectively. The univariate analysis suggested that progression to multiple myeloma and amyloid deposits may be poor prognostic factors. The multivariate analysis suggested that only progression to multiple myeloma may be a poor prognostic factor. Laryngeal EMP is uncommon. Progression to multiple myeloma may be a poor prognostic factor. PMID- 26045750 TI - Decrease in prosaposin in spermatozoon is associated with polychlorinated biphenyl exposure. AB - Polychlorinated biphenyls (PCBs) are a class of ubiquitous persistent organic pollutants and they have been associated with declining male fertility. In the present study, we aimed to determine the responsiveness of prosaposin (Psap) expression to PCB exposure. Male C57 mice were exposed to PCB mixture (Aroclor 1254) of environmental related doses by oral gavage. After exposure for 50 days, the expression of Psap was significantly decreased by PCB exposure in epididymides and epydidymal spermatozoa, but not in testis. The Psap abundance in sperm was decreased in a dose-dependent manner. Benchmark dose modeling revealed the 95% lower confidence limit on the benchmark dose (BMDL) and Benchmark Dose (BMD) for Psap reduction were 1.25 and 8.89 MUg/kg Aroclor 1254, and for sperm motility reduction were 11.85 and 61.9 MUg/kg Aroclor 1254. The depressed Psap level also showed a significant correlation (P<0.01, r=-0.531) with PCB accumulation in liver. In men with detectable PCB exposure in semen, Psap expression in sperm was significantly decreased whereas the semen parameters were unaffected. Linear regression showed that a negative association between total PCB level in seminal plasma and Psap level in ejaculated spermatozoa (P<0.05, r= 0.396). In conclusion, our data suggested that the abundance of Psap in sperm sample may be a sensitive endpoint to predict PCB exposure. PMID- 26045751 TI - Co-expression of CXCR4 and CXCR7 in human endometrial stromal cells is modulated by steroid hormones. AB - Endometrium modulated by estrogen (E) and progesterone (P) is important for implantation and pregnancy. The present study compared the expression of chemokine CXCL12 and chemokine receptor CXCR4 and CXCR7 between human cycling and early pregnant endometria by immunohistochemistry (IHC). Then the modulation of E and P on expression of CXCL12, CXCR4 and CXCR7 in human endometrial stromal cells (ESCs) was explored at both mRNA and protein level. The result of IHC showed that human ESCs of the menstrual period did not express CXCL12, CXCR4 or CXCR7 protein, however, the expression of CXCR4 and CXCR7 but not CXCL12 in ESCs increased in the proliferative and secretory phase, and the expression intensity for CXCR4 and CXCR7 in ESCs was the highest in the first trimester. Moreover, E and P were able to up-regulate the mRNA and protein expression of CXCR4 and protein expression of CXCR7 in ESCs (P<0.01). Thus, ESCs spatiotemporally co express CXCR4 and CXCR7 rather than CXCL12, and E and P are able to regulate the expression of CXCR4 and CXCR7 in ESCs, suggesting the modulation of steroid hormones on chemokine receptor expression in ESCs. PMID- 26045752 TI - MicroRNA-196a overexpression promotes cell proliferation and inhibits cell apoptosis through PTEN/Akt/FOXO1 pathway. AB - MicroRNAs (miRNAs) are endogenous, non-coding, small RNAs, which play a critical role in regulating varieties of the biological and pathologic processes. MiR-196a has been reported to take part in tumorigenic progression of osteosarcoma (OS). However, the effects of miR-196a on OS are still unclear. The objective of this study is to investigate the molecular mechanism of miR-196a in osteosarcoma cells. In the present study, the expression of miR-196a in OS cell lines was detected by real-time PCR. We found that the expression level of miR-196a was markedly up-regulated in osteosarcoma cell lines compared with normal osteoblastic cells. Then, the miR-196a mimic was transiently transfected into MG63 and U2OS cells using LipofectamineTM 2000 reagent. Subsequently, the MTT and Brdu-ELISA results showed that up-regulation of miR-196a promoted the cell viability and proliferation. Our results also showed that miR-196a mimic accelerated cell cycle progression of MG63 and U2OS cells by down regulation of p21 and p27, and upregulation of cyclin D1. In addition, overexpression of miR 196a suppressed apoptosis of MG63 and U2OS cells due to increasing BCL2L2 and MCL 1 expressions, and then inactivating caspase-3. Eventually, the effect of miR 196a mimic on the PTEN/phosphoinositide 3-kinase (PI3K)/Akt signaling pathway was explored by Western blot. From our results, transfection of miR-196a decreased the expression of PTEN and increased the phosphorylation of PI3K and Akt. Taken together, miR-196a should be an oncogene in osteosarcoma. The possible mechanism was that overexpression of miR-196a promoted proliferation of MG63 and U2OS cells by modulating the PTEN/PI3K/Akt signaling pathway. PMID- 26045753 TI - Lithium enhanced cell proliferation and differentiation of mesenchymal stem cells to neural cells in rat spinal cord. AB - Lithium has been shown to inhibit apoptosis of neural progenitor cells (NPCs) and promote differentiation of NPCs. However, there was rare data to discuss the effects of lithium on neural differentiation of mesenchymal stem cells (MSCs). Here, we investigated the potential promotion of lithium to MSC proliferation and neural differentiation in vitro and after transplanted into the ventral horn of rat spinal cord in vivo. We found that lithium possesses the ability to promote proliferation of GFP-MSCs in a dose dependent manner as verified by growth curve and bromodeoxyuridine (BrdU) incorporation assays; While in neural induction medium, lithium (0.1 mM) promotes neural differentiation of GFP-MSCs as verified by immunostaining and quantitative analysis. After transplantation of GFP-MSCs into the rat spinal cord, lithium treatment enhanced cell survival and neural differentiation after transplantation as verified by immunohistochemistry. These data suggested that lithium could be a potential drug to augment the therapeutic efficiency of MSCs transplantation therapy in central nervous system (CNS) disorders. PMID- 26045754 TI - Ginsenoside Rg1 suppressed inflammation and neuron apoptosis by activating PPARgamma/HO-1 in hippocampus in rat model of cerebral ischemia-reperfusion injury. AB - Generally accepted, inflammation and neuron apoptosis are two characterized pathological features of cerebral ischemia-reperfusion (IR) injury. Ginsenoside Rg1 was reported showing distinct neuroprotective effect in cerebral IR injury but the underlying mechanisms are still unclear. PPARgamma/Heme oxygenase-1 (HO 1) signaling was proved effective in suppressing both apoptosis and inflammation. This study was aimed to investigate whether PPARgamma/HO-1 signaling was involved in cerebral IR injury and ginsenoside Rg1's neuroprotective effect in cerebral IR injury. Cerebral IR injury was induced by middle cerebral artery occlusion in rats. The PPARgamma agonist rosiglitazone (ROZ) and the HO-1 inhibitor zinc protoporphyrin-IX (ZnPP) and ginsenoside Rg1 at various concentrations were used to treat the modeled rats. Neurological deficits, apoptosis and inflammation in hippocampus were evaluated. Furthermore, HO-1 enzymatic activity, expression levels of apoptosis-related and inflammation-related proteins, concentrations of inflammatory cytokines were also determined. The results showed that PPARgamma activation by ROZ significantly attenuated neurological deficits, apoptosis and inflammation in hippocampus in cerebral IR rats. However, the neuroprotective effect of ROZ was then impaired by HO-1 inhibitor ZnPP. This effect was evidenced by changes of expression levels of PPARgamma, bcl-2, cleaved caspase-3, cleaved caspase-9, IL-1beta, TNF-alpha, HMGB1, and RAGE in hippocampus of modeled animals. Ginsenoside Rg1 showed similar effect to ROZ in activating PPARgamma/HO 1 in protecting against apoptosis and inflammation but also impaired by ZnPP administration. In conclusion, PPARgamma/HO-1 signaling was critical in mediating apoptosis and inflammation, which was also the therapeutic target of ginsenoside Rg1 in cerebral IR injury. PMID- 26045755 TI - Clinical characteristics and peripheral T cell subsets in Parkinson's disease patients with constipation. AB - Constipation is frequently reported in Parkinson's disease (PD). We evaluated the characteristics of patients with PD and constipation and explored the role of T cell subsets in PD-associated constipation. One hundred and two patients with PD treated at the First Affiliated Hospital of Bengbu Medical College were enrolled in this study between January 2012 and October 2013. All patients completed KESS questionnaires and constipation was rated. The proportions of peripheral blood Thl7 and Treg cells were assessed by flow cytometry in 45 patients. Colonoscopies were performed in six patients. Thirty-one patients with PD reported slow-transit constipation (STC), 15 rectal evacuation disorder (RED) and 33 mixed constipation (Mixed). STC most frequently occurred before onset of PD motor symptoms, while Mixed occurred before or after motor symptoms, and RED occurred most frequently after motor symptoms. CD4+ T cell infiltration in the colonic mucosa was observed in patients with PD and constipation. The frequency of Th17 and Treg cells in patients with PD and constipation was significantly higher than in those without constipation (P<0.001). Among patients with PD and constipation, the frequency of Th17 and Treg cells in STC was the highest. However, there was no difference in the ratio of Th17/Tregs between the patients with PD with and without constipation, or patients with PD and different types of constipations (P>0.05). Constipation reported before the onset of PD motor symptoms was most often STC or Mixed, and PD constipation may be associated with immune activation in the colonic mucosa. PMID- 26045756 TI - Local renin-angiotensin system regulates hypoxia-induced vascular endothelial growth factor synthesis in mesenchymal stem cells. AB - The use of mesenchymal stem cell (MSC) transplantation for ischemic heart disease has been reported for several years. The main mechanisms responsible for the efficacy of this technique include the differentiation of MSCs into cardiomyocytes and endothelial cells, as well as paracrine effects. However, the differentiation rates of MSCs are very low, and the differentiated cells are not mature. In addition, MSCs undergo massive cell death within a few days after transplantation to the ischemic myocardium. Paracrine effects may thus play a major role in MSCs transplantation. Angiotensin II (Ang II) is known to be produced locally in the ischemic myocardium, but the effects of hypoxia on the local renin-angiotensin system (RAS) in MSCs, and the role of the RAS in hypoxia induced vascular endothelial growth factor (VEGF) secretion remain unknown. In this study, we demonstrated that hypoxia stimulated the local RAS in MSCs, while pretreatment with the Ang II type 1 (AT1) receptor antagonist losartan reduced hypoxia-induced hypoxia-inducible factor 1alpha (HIF-1alpha) and VEGF production. The ERK1/2 inhibitor U0126 and the Akt inhibitor LY294002 also inhibited hypoxia induced HIF-1alpha and VEGF production. Overall, these results indicate that the local RAS in MSCs regulates hypoxia-induced VEGF production through ERK1/2, Akt and HIF-1alpha pathways via the AT1 receptor. PMID- 26045757 TI - Astragalus polysaccharide suppresses palmitate-induced apoptosis in human cardiac myocytes: the role of Nrf1 and antioxidant response. AB - OBJECTIVE: Previous studies have shown that Astragalus polysaccharides (APS) can be used to ameliorate cardiotoxicity due to chemotherapy and improve the cardiac function. However, the mechanism by which APS mediate this effect is unclear. In the present study, the effects of APS, which suppressed ROS-mediated apoptosis through Nrf1 accumulation in human cardiac myocytes (HCMs), was investigated. METHODS: The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining. Expression of genes and proteins were analyzed by real-time PCR and western blotting respectively. Nrf1 gene was overexpressed using a lentiviral expression vector in HCMs in vitro, in order to explore the mechanism by which the Nrf1 promoted cell growth. RESULTS: CCK8 and Annexin V-PI double-labeling showed that PAL induced cell death in a concentration-dependent manner, and suppressed HCMs proliferation. The combination PAL with APS was significantly decreased the percentage of the early phase of apoptosis cells. ROS levels were increased in HCMs by exposure to PAL. APS treatment significantly inhibited generation of ROS in response to palmitate. Moreover, PAL administration significantly decreased the mRNA and proteins expression of Bcl-2 as well as increased the mRNA expression of BAX and the protein expression of caspase-3 and caspase-8 as compare to those of control group, but APS treatment could reverse PA-induced HCMs apoptosis. The levels of reactive oxygen species (ROS), which was an oxidative stress marker, was significantly increased in cardiomyocytes by exposure to PAL, but overexpressing Nrf1 could ameliorate ROS-induced cardiomyocyte toxicity and increase the expression of SOD1 and SOD2 in HCMs by overexpressing Nrf1. CONCLUSIONS: This study demonstrated that the PAL could induce HCMs apoptosis. However, APS could reverse PAL-induced cardiomyocyte toxicity, at least partially, through suppression ROS and Nrf1 accumulation in HCMs. PMID- 26045758 TI - Effect of piperlongumine on drug resistance reversal in human retinoblastoma HXO RB44/VCR and SO-Rb50/CBP cell lines. AB - Piperlongumine (PLGM) was considered as an anti-cancer agent since it was involved in suppressing of many types of cancer. To investigate the functions and mechanisms of PLGM on drug resistance reversal in human retinoblastoma cell lines, drug resistance cell lines HXO-RB44/VCR and SO-Rb50/CBP were established. We found that after treatment with PLGM, drug sensitivity and apoptosis rate of these drug resistance cancer cells were improved, cell cycle was arrested, the expressions of P-gp, MDR1, MRP1, Top-II, GST-pi, Survivin, Bcl-2, CDK1, ABCB1 and ABCG1 was decreased, while the activities of caspase-3/8 and intracellular content of Rh-123 was increased. Furthermore, the activities of PI3K/AKT and PKCzeta pathways were suppressed following PLGM treatment. Therefore, this study suggests that PLGM could reverse the drug resistance of human retinoblastoma cell lines HXO-RB44/VCR and SO-Rb50/CBP. This drug resistance reversing effect might exert via PI3K/AKT and PKCzeta pathways. PMID- 26045759 TI - Radiotherapy suppressed tumor-specific recruitment of regulator T cells via up regulating microR-545 in Lewis lung carcinoma cells. AB - OBJECTIVE: Radiotherapy is an important treatment for cancer. The main irradiated action is thought to be the irreversible damage to tumor cell DNA, but recent studies showed that high dose radiotherapy related to the tumor immune response. This study was designed to determine the relationship between Lewis lung tumor radiosensitivity and CD4+CD25+ regulatory T cells (Tregs) infiltration and elucidate the underlying mechanisms in vitro. METHODS: With tumor transplantation method to establish mice Lewis lung tumor mice model, to observe the inhibition rate of radiotherapy to tumor growth. Proliferation profiles of CD4+CD25+ Tregs and CD4+ T cells were assessed by flow cytometry. MiR-545 and CCL-22 mRNA were determined by Quantitative Real-Time PCR. CCL-22 protein was determined by western blot assay. RESULTS: Radiotherapy caused a time-dependent inhibition of tumor growth as well as a decrease in the percentage of tumor-infiltrating CD4+CD25+ Tregs of CD4+ T cells compared with no treatment group. And the miR-545 was significantly upregulated and CCL-22 was significantly down-regulated in irradiated tumor and Lewis lung cancer cells. In Lewis lung cancer cell transfection experiments, mimic or inhibitor for miR-545 negatively regulated CCL 22 expression when cells treated or treated without irradiation. Silenced miR-545 promotes CD4+CD25+ Treg proliferation. Additionally, silenced miR-545 reversed radiosensitivity of Lewis lung cancer. CONCLUSION: Radiotherapy suppressed specific recruitment of regulator CD4+CD25+ Treg cells in Lewis lung carcinoma via up-regulating microR-545. PMID- 26045760 TI - Globular adiponectin reduces vascular calcification via inhibition of ER-stress mediated smooth muscle cell apoptosis. AB - OBJECTIVE: This study aims to explore the mechanism of globular adiponectin inhibiting vascular calcification. METHODS: We established drug-induced rat vascular calcification model, globular adiponectin was given to observe the effect of globular Adiponectin on the degree of calcification. The markers of vascular calcification and apoptosis were also investigated. Meanwhile, the in vitro effect of globular Adiponectin on vascular calcification was also evaluated using primary cultured rat vascular smooth muscle cells. RESULTS: We found that globular adiponectin could inhibit drug-induced rat vascular calcification significantly in vivo. The apoptosis of vascular smooth muscle cells was also reduced. The possible mechanism could be the down-regulation of endoplasmic reticulum stress by globular adiponectin. Experiments in primary cultured vascular smooth muscle cells also confirmed that globular adiponectin could reduce cell apoptosis to suppress vascular calcification via inhibition of endoplasmic reticulum stress. CONCLUSIONS: This study confirmed that globular adiponectin could suppress vascular calcification; one of the mechanisms could be inhibition of endoplasmic reticulum stress to reduce cell apoptosis. It could provide an effective method in the therapy of vascular calcification-associated diseases. PMID- 26045761 TI - Decreased expression of microRNA-130a correlates with TNF-alpha in the development of osteoarthritis. AB - OBJECTIVE: Increased expression of tumor necrosis factor a (TNF-alpha) has emerged as an important inflammatory factor in osteoarthritis (OA) and other joint diseases. The study was performed to investigate whether the expression of TNF-alpha in human chondrocytes was regulated by miRNAs. METHODS: MiRNA-130a and TNF-alpha expression in cartilage specimens was examined in patients with knee osteoarthritis, chondrocytes and osteoarthritis rat model. Chondrocytes were transfected with siRNAs as a gene silencing methods. Expression of genes and proteins were analyzed by real-time PCR and western blotting respectively. RESULTS: Increased TNF-alpha and decreased miRNA-130a were observed in tissues from osteoarthritis patients. Moreover, we found a highly negitive correlation between miRNA-130a and TNF-alpha. Next, miRNA-130a loss-of-function increased the expression of TNF-alpha and promoted inflammation in chondrocytes. It was reasonable that miRNA-130a regulated a distinct underlying molecular and pathogenic mechanism of OA by forming a negative feedback loop with TNF-alpha. Furthermore, there were the abnormalities of bone metabolism in OA rat, which showed the miRNA-130a and TNF-alpha dysfunction that was one of important factors for the occurrence and development of OA. CONCLUSIONS: Our results indicated that miR-130a played an important role in regulating the expression of TNF-alpha in human chondrocytes and identified miR-130a as a novel therapeutic target in OA. PMID- 26045762 TI - XB130 expression in human osteosarcoma: a clinical and experimental study. AB - Identifying prognostic factors for osteosarcoma (OS) aids in the selection of patients who require more aggressive management. XB130 is a newly characterized adaptor protein that was reported to be a prognostic factor of certain tumor types. However, the association between XB130 expression and the prognosis of OS remains unknown. In the present study, we investigated the association between XB130 expression and clinicopathologic features and prognosis in patients suffering OS, and further investigated its potential role on OS cells in vitro and vivo. A retrospective immunohistochemical study of XB130 was performed on archival formalin-fixed paraffin-embedded specimens from 60 pairs of osteosarcoma and noncancerous bone tissues, and compared the expression of XB130 with clinicopathological parameters. We then investigate the effect of XB130 sliencing on invasion in vitro and lung metastasis in vivo of the human OS cell line. Immunohistochemical assays revealed that XB130 expression in OS tissues was significantly higher than that in corresponding noncancerous bone tissues (P=0.001). In addition, high XB130 expression more frequently occurred in OS tissues with advanced clinical stage (P=0.002) and positive distant metastasis (P=0.001). Moreover, OS patients with high XB130 expression had significantly shorter overall survival and disease-free survival (both P<0.001) when compared with patients with the low expression of XB130. The univariate analysis and multivariate analysis shown that high XB130 expression and distant metastasis were the independent poor prognostic factor.We showed that XB130 depletion by RNA interference inhibited invasion of XB130-rich U2OS cells in vitro and lung metastasis in vivo. This is the first study to reveal that XB130 overexpression may be related to the prediction of metastasis potency and poor prognosis for OS patients, suggesting that XB130 may serve as a prognostic marker for the optimization of clinical treatments. Furthermore, XB130 is the potential molecular target for OS therapy. PMID- 26045763 TI - NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway. AB - Neurensin-2 (NRSN2), a small neural membrane protein which localized in small vesicles in neural cells. Recent report suggested that Neurensin-2 might play a suppressive role in tumor. While the biological functions and molecular mechanisms in cancer progression remain unknown. We retrieved Oncomine Database and found that NRSN2 is commonly highly expressed in non-small cell lung cancer (NSCLC). We examined the levels of NRSN2 in 18 pairs of NSCLC and adjacent tissues and found that NRSN2 was overexpressed in malignant tissues. Both loss and gain of function experiments in NSCLC cell lines suggest that NRSN2 promotes cell growth, but no effects in cell invasion. Further investigation show that NRSN2 could affect phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling. Taken together, our findings suggest that NRSN2 promotes non-small cell lung cancer cell growth through PI3K/Akt/mTOR pathway. PMID- 26045764 TI - Cardiac hypertrophy is positively regulated by long non-coding RNA PVT1. AB - The aim of this study was to determine whether long non-coding RNA PVT1 can participate in the regulation of cardiac hypertrophy. A C57BL/6 mouse cardiac hypertrophic model was established using transverse aortic constriction (TAC). The animals subjected to sham operation were used as controls. Transcripts of PVT1 were analyzed in hearts of model and sham control groups after TAC for 4 weeks using quantitative real-time PCR (qRT-PCR). Additionally, to investigate whether PVT1 was involved in cardiac hypertrophy, 1 MUM angiotensin II (Ang II) was used to induce hypertrophy and PVT1 siRNA was performed in the cultured neonatal mouse cardiac cardiomyocytes. Cell size was measured by cell surface area and total protein content analyses in response to Ang II treatment. Moreover, some hypertrophic markers including atrial natriuretic peptide (ANP), B type natriuretic peptide (BNP), and beta-myosin heavy chain (beta-MHC) were also quantified using qRT-PCR. As a result, PVT1 was up-regulated by 2.5-fold (P<0.05) in hypertrophic hearts after TAC for 4 weeks as compared to sham group. In addition, siRNA of endogenous PVT1 in cardiomyocytes significantly reduced (P<0.05) Ang II-induced increase of cell size in terms of cell surface area (by 5.6-fold) and total protein content (by 23.0%). PVT1 siRNA also obviously attenuated Ang II-induced ANP and beta-MHC expression by 40.9% and 41.5%, respectively (P<0.05), but had no effect on BNP mRNA expression. Our results demonstrated that PVT1 was essential for the maintenance of cell size of cardiomyocytes and might play a role in the regulation of cardiac hypertrophy. PMID- 26045765 TI - Aberrant Cosmc genes result in Tn antigen expression in human colorectal carcinoma cell line HT-29. AB - The Tn antigen, which arises from mutation in the Cosmc gene is one of the most common tumor associated carbohydrate antigens. Cosmc resides in X24 encoded by a single gene and functions as a specific molecular chaperone for T-synthase. While the Tn antigen cannot be detected in normal cells, Cosmc mutations inactivate T synthase and consequently result in Tn antigen expression within certain cancers. In addition to this Cosmc mutation-induced expression, the Tn antigen is also expressed in such cell lines as Jurkat T, LSC and LS174T. Whether the Cosmc mutation is present in the colon cancer cell line HT-29 is still unclear. Here, we isolate HT-29-Tn+ cells from HT-29 cells derived from a female colon cancer patient. These HT-29-Tn+ cells show a loss of the Cosmc gene coding sequence (CDS) leading to an absence of T-synthase activity and Tn antigen expression. Additionally, almost no methylation of Cosmc CpG islands was detected in HT-29 Tn+ as well as in HT-29-Tn- and Tn- tumor cells from male patients. In contrast, the methylation frequency of CpG island of Cosmc in normal female cells was ~50%. Only one active allele of Cosmc existed in HT-29-Tn+ and HT-29-Tn- cells as based upon detection of SNP sites. These results indicate that Tn antigens expression and T-synthase inactivity in HT-29-Tn+ cells can be related to the absence of CDS in Cosmc active alleles, while an inactive allele deletion of Cosmc in HT-29 cells has no influence on Cosmc function. PMID- 26045766 TI - Immunity of fungal infections alleviated graft reject in liver transplantation compared with non-fungus recipients. AB - OBJECTIVE: To evaluate of the immune tolerance in adult LT recipients with Invasive fungal infections (IFIs). METHODS: 109 consecutive LT recipients who received LT were included. Percentage of T subsets (CD4+CD25hiCD127- T cells, CD4+CD25loCD45RA+ T cells, CD4+CD25loCD45RA- and CD4+CD45RA-CD45RO+ T cells populations), levels of cytokines (IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, IFN gamma, IL-12p70, IL-17, TNF-alpha, TNF-beta and GM-CSF) were detected by FACS and Bioplex in peripheral blood. Biopsy specimens were fixed, monoclonal antibodies against CD4, Foxp3 and IL-17 were applied to the above sections and FISH was performed. RESULTS: The risk of acute rejection was decreased in fungal infected liver transplant recipients comparing with non-fungal infected group. CD4+CD25hiCD127T cell population was increased in peripheral blood and memory CD4+CD45RA-CD45RO+ T cell population decreased. There was significant lower levels observed in naive CD4+CD25loCD45RA+ and CD4+CD25loCD45RA- T cell populations in fungal infected liver transplant. Moreover, IL-2, IL-6, IL-10 and GM-CSF were decreased. However, no significant difference with IL-4 and IL-8 in serum in two infected LT recipients. CONCLUSION: The incidence of graft rejection in liver transplantation recipients with fungal infections was lower than the non fungal group. It is important to assess the risk during pretransplant and postoperation for liver transplantation. PMID- 26045767 TI - Screening and identification of the differential proteins in kidney with complete unilateral ureteral obstruction. AB - Obstructive nephropathy is a major cause of renal failure, particularly in infants and children, and indications for therapeutic intervention remain highly controversial. There is a great need for the development of new methods to monitor patients, and the biomarker research field is a promising approach for this purpose to be used as prognostic tools for early disease detection and the choice of the optimal treatment and monitoring. Here, we presented our comparative proteomics study of rat kidney with complete unilateral ureteral obstruction (CUUO). Proteins from the groups of CUUO and corresponding sham rat kidney tissues were subjected to 2-D gel electrophoresis, and then protein identification by mass spectrometry. We identified 39 proteins with differential expression between kidney tissues from sham operated group and those with CUUO. These identified proteins were reported to be involved in cell apoptosis, energy metabolism and injuries of mitochondrion and oxidative stress, and so on. We confirmed 3 identified proteins by immunoblot analysis and immunofluorescence staining and assessed their mRNA levels in renal tissues. Our results demonstrate protein alterations that reflect the pathological situation of the obstructed kidneys, which may help understand the relationship between oxidative stress and obstructive nephropathy. PMID- 26045768 TI - CD4+CD29+T cells are blamed for the persistent inflammatory response in ulcerative colitis. AB - Ulcerative colitis (UC) is a chronic gastrointestinal disorder eliciting occurrence of colorectal cancer, the third most common human malignancy. The diagnosis of UC is based on clinical symptoms combined with typical findings on endoscopy, radiology, and ultimately pathology. We investigated the variation trend of CD4+CD29+T cells together with MPO, VCAM-1 in different periods of rat UC model and UC patients. We also evaluated the relationship between CD4+CD29+T cells and disease severity. UC model was induced by administering DNCB liquid and acetate solution. We found upregulated expression of CD4+CD29+T cells in both peripheral blood and colon from rats, and a similar trend for MPO and VCAM-1 in colon (P<0.05); the expression was especially enhanced in UC rats at two weeks after the model was established (P<0.01). Such upregulation was also indicated in active and remission UC patients as compared to the healthy and enteritis groups (P<0.05), with the highest expression level detected in the active UC patients (P<0.01). Pearson correlation analysis showed a positive correlation of CD4+CD29+T cells in rat and human peripheral blood with DAI score (rrat=0.712, rhuman=0.677, P<0.01), and MPO in colon (rrat=0.514, rhuman=0.682, P<0.05). These results suggest that CD4+CD29+T cells may act as major effector cell subsets in persistent inflammatory responses for UC and that infiltration into colon inflammation may be induced by the combination of VCAM-1 and CD29. PMID- 26045769 TI - Downregulation of NUF2 inhibits tumor growth and induces apoptosis by regulating lncRNA AF339813. AB - Recent studies have shown that NUF2 (Ndc80 kinetochore complex component) play important roles in multiple human cancers. In our previous report, NUF2 expression was stronger in tumor tissues than in normal pancreatic tissues. However, whether and how NUF2 play a role in pancreatic cancer progression remains largely unknown. The aim of our study is to investigate the expression and functional role of NUF2 in human PC. NUF2 expression was measured in 10 pairs of PC cancerous and noncancerous tissue samples by quantitative real-time PCR. The effects of NUF2 on PC cells were studied by RNA interference. Apoptosis and cell cycle were analyzed by flow cytometry. Cells viability was evaluated using MTT. CDK4/CDK6 activity was measured by Western blot assay. LncRNAs regulated by NUF2 were gained from bioinformatics analysis. The role of LncRNA AF339813, regulated by NUF2, was finally characterized in PC cells by siRNA. Our results showed that NUF2 mRNA and protein were significantly overexpressed in Human PC tissues and several PC cell lines. Through bioinformatics analysis and knockdown NUF2 in PC cells, we found LncRNA AF339813 was positively regulated by NUF2. We further demonstrated that knockdown of AF339813 by siRNA in PC cells significantly reduced cell proliferation and promoted apoptosis. Thus, we conclude that NUF2 is consistently overexpressed in human PC and NUF2 is closely linked with human PC progression through the meditator LncRNA AF339813. Our studies may contribute to understand the molecular mechanism of PC pathogenesis and clinical therapy. PMID- 26045770 TI - Hydroxycamptothecin-induced apoptotic gene expression profiling by PCR array in human Tenon's capsule fibroblasts. AB - Studies have indicated that hydroxycamptothecin (HCPT) induces apoptosis of fibroblasts. In this study, we investigated the apoptotic gene expression profiling in HCPT-treated -human Tenon's capsule fibroblasts (HTCFs) and identify the most implicated gene in apoptotic signaling of HTCFs by HCPT. Method HTCFs were incubated with HCPT at 0, 0.25 and 4 mg/L for 24, 48 and 72 h, respectively. Anti-proliferative effects were measured by MTT assay. Apoptosis was determined using the Annexin V-FITC/PI apoptosis detection kit and apoptotic cells were identified by flow cytometry. A PCR array was employed to analyze the most implicated apoptotic genes during HCPT-induced apoptosis in HTCFs. Results from our studies showed that HCPT induced apoptosis in HTCFs in a concentration-and time-dependent manner. The apoptotic HTCFs was increased by 9.38% with a multiplicity at 4 mg/L HCPT. PCR array demonstrated remarkable changes in 88 apoptotic genes, including 9 up-regulated genes and 36 down-regulated genes. HCPT treatment induced the upregulation of CHOP and downregulation of XIAP in HTCFs. To conclude, our results support HCPT induced the apoptosis of HTCFs, involving the activation of mitochondrial and endoplasmic reticulum stresses as well as the downregulation expression of XIAP. PMID- 26045771 TI - Effects of skin-derived precursors on wound healing of denervated skin in a nude mouse model. AB - Denervated skin could result in impaired healing of wounds, such as decubitus ulcers and diabetic foot ulcers. Other studies indicated that cutaneous fiber density is reduced after inner nerve transection and that neuropeptide level depletes after denervation, leading to reduced cell proliferation around the wound and thus wound healing problems. Recent studies have revealed that skin derived precursors (SKPs), which form a neural crest-related stem cell population in the dermis of skin, participate in cutaneous nerve regeneration. We hypothesized that injecting SKPs into denervated wound promotes healing. A bilateral denervation wound model was established followed by SKP transplantation. The wound healing rate was determined at 7, 14, and 21 d after injury. Cell proliferation activity during wound healing was analyzed by proliferating cell nuclear antigen immunohistochemistry (IHC). Nerve fiber density was measured by S-100 IHC. The contents of nerve growth factor, substance P, and calcitonin gene-related peptide were examined by enzyme-linked immunosorbent assay. The rate of epithelization in the SKP-treated group was faster than that in the control group. Wound cell proliferation and nerve fiber density were obviously higher in the SKP-treated group than in the control group. In addition, the content of neuropeptides was higher in the SKP-treated group than in the control group during wound healing. In conclusion, SKPs can promote denervated wound healing through cell proliferation and nerve fiber regeneration, and can facilitate the release of neuropeptides. PMID- 26045772 TI - A crosstalk triggered by hypoxia and maintained by MCP-1/miR-98/IL-6/p38 regulatory loop between human aortic smooth muscle cells and macrophages leads to aortic smooth muscle cells apoptosis via Stat1 activation. AB - Hypoxia and inflammation are central characteristics of the abdominal aortic aneurysm (AAA), but the mechanisms for their relationship and actual role remain far from full understood. Here, we showed MCP-1 (monocyte chemotactic protein-1) induced by hypoxia in primary human Aortic Smooth Muscle Cells (hASMCs) increased the chemotaxis of THP-1 macrophages and MCP-1 induced IL-6 expression in THP-1 cells via downregulating miR-98 which directly targets IL-6. In addition, IL-6 positively feedback regulated MCP-1 expression in hASMCs via p38 signal that is independent on hypoxia, and inhibition of p38 signal blocked the effect of IL-6 on MCP-1 expression regulation. Moreover, IL-6 exposure time-dependently induces phASMCs apoptosis via Stat1 activation. Collectively, our data provide compelling evidence on the association between hypoxia and inflammation triggered by hypoxia and then mediated by MCP-1/miR-98/IL-6/p38 regulatory loop, which leads to hASMCs apoptosis via Stat1 activation to contribute to AAA formation and progression. PMID- 26045773 TI - Inhalation of hydrogen gas ameliorates glyoxylate-induced calcium oxalate deposition and renal oxidative stress in mice. AB - The aim of this study is to evaluate the protective effect and underlying mechanism of hydrogen gas (H2) to glyoxylate induced renal calcium oxalate (CaOx) crystal deposition in mice. In present work, rodent renal CaOx crystal deposition model was introduced by intra-abdominal injection of glyoxylate (100 mg/kg/d) for 5 days. Two days before administration of glyoxylate, inhalation of H2 for 30 min per day was initiated and continued for 7 days. By the end of the study, the samples of 24 hours urine, serum and renal tissue were collected for biochemical and pathological assay. According to levels of urine calcium excretion, renal calcium deposition, a serum excretion of kidney injury molecule-1 (KIM-1) assay and a TUNEL assay, inhalation of H2 could successfully decrease the CaOx crystallizations and protect against renal injury. Crystal deposition in the kidneys is associated with oxidative stress, which was indicated by increased levels of renal malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) and decreased activities of superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT). These effects were reversed by a high-dose H2 pretreatment. The renal expressions of osteopontin (OPN), CD44, monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10) were markedly increased in glyoxylate-treated mice, and H2 significantly attenuated the increase of OPN, CD44 and MCP-1 but upregulated the expression of IL-10. Our findings demonstrate that inhalation of H2 reduces renal crystallization, renal oxidative injury and inflammation and it may be a candidate agent with few adverse effects for prevention of nephrolithiasis. PMID- 26045774 TI - TMED6-COG8 is a novel molecular marker of TFE3 translocation renal cell carcinoma. AB - TFE3 translocation renal cell carcinoma is a highly aggressive malignancy which often occurs primarily in children and young adults. The pathognomonic molecular lesion in this subtype is a translocation event involving the TFE3 transcription factor at chromosome Xp11.2. Hence, the pathological diagnosis of an Xp11.2 translocation RCC is based upon morphology, TFE3 immunohistochemistry, or genetic analyses. However, due to the false-positive immunoreactivity for TFE3 IHC and expensive for TFE3 break-apart FISH assay, additional molecular markers are necessary to help provide early diagnose and individualization treatment. Owing to recent advances in microarray and RNA-Seq, Pflueger et al. have discovered that TMED6-COG8 is dramatically increased in TFE3 translocation RCCs, compared with clear cell RCCs and papillary RCCs, implying that TMED6-COG8 might be a new molecular tumor marker of TFE3 translocation RCCs. To extend this observation, we firstly validated the TMED6-COG8 expression level by qRT-PCR in RCCs including Xp11.2 translocation RCCs (n=5), clear cell RCCs (n=7) and papillary RCCs (n=5). Then, we also examined the expression level of TMED6-COG8 chimera in Xp11.2 translocation alveolar soft part sarcoma. We found that TMED6-COG8 chimera expression level was higher in Xp11.2 translocation RCCs than in ASPS (P<0.05). What's more, the expression levels of TMED6-COG8 chimera in esophagus cancers (n=32), gastric cancers (n=11), colorectal cancers (n=12), hepatocellular carcinomas (n=10) and non-small-cell lung cancers (n=12) were assessed. Unexpectedly, TMED6-COG8 chimera was decreased in these five human types. Therefore, our observations from this study indicated that TMED6-COG8 chimera might act as a novel diagnostic marker in Xp11.2 translocation RCCs. PMID- 26045775 TI - Notoginsenoside R1 reduces blood pressure in spontaneously hypertensive rats through a long non-coding RNA AK094457. AB - Notoginsenoside R1 (NR1) is the main bioactive component in panaxnotoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of NR1 on antihypertension and the underlying mechanisms are still not clear. This study is aim to investigate the effect and elicit the mechanism of NR1 in antihypertension. Firstly, to assess the ability of NR1 in antihypertension, NR1 was injected in spontaneously hypertensive rats (SHR) via the vena caudalis. Then we examined the rats systolic blood pressure and inducible nitric oxide synthase (iNOS) activation in rats thoracoabdominal aortic. To further investigate the molecular mechanism of NR1 reduce blood pressure, primary SHR and WYK rat vascular endothelial cells (RVECs) were used for next study. LncRNAs related to hypertension were gained from bioinformatics analysis. The role of LncRNAs was finally characterized in RVECs by siRNA. Our results showed that NR1 significantly reduce blood pressure in SHR and induce nitric oxide (NO) generation through increasing the phosphorylation of iNOS. Through bioinformatics analysis and knockdown LncRNA AK094457 in RVECs, we also found LncRNA AK094457 promoted iNOS expression and NO concentration. Thus, we conclude that NR1 reduces the caudal blood pressure of SHR through induction of iNOS regulated by long non coding RNA AK094457. These findings may have important implications for understanding the mechanisms of NR1 regulation blood pressure. PMID- 26045776 TI - MCT1 promotes the cisplatin-resistance by antagonizing Fas in epithelial ovarian cancer. AB - This study was designed to investigate the role of MCT1 in the development of cisplatin-resistant ovarian cancer and its possible relationship with Fas. We found the expression of MCT1 was obviously increased both in cisplatin-resistant ovarian cancer tissue and A2780/CP cells compared with sensitive ovarian cancer tissue and cell lines A2780. And in A2780 cells treated with Cisplatin, the expression of MCT1 increased in a concentration-dependent manner, MCT1 knockdown attenuates cisplatin-induced cell viability. In A2780 and A2780/CP cells transfected with MCT1 siRNA, the activation of several downstream targets of Fas, including FasL and FAP-1 were largely prevented, whereas the expression of Caspase-3 was increased, accompanying with increased abundance of Fas. Coimmunoprecipitation and immunofluorescence showed that there is interaction between endogenous MCT1 with Fas in vivo and in vitro. In vivo, depletion of MCT1 by shRNA reverses cisplatin-resistance and the expression of Fas. This study showed that down regulation of MCT1 promote the sensibility to Cisplatin in ovarian cancer cell line. And this effect appeared to be mediated via antagonizing the effect of Fas. PMID- 26045777 TI - Transient downregulation of microRNA-206 protects alkali burn injury in mouse cornea by regulating connexin 43. AB - PURPOSE: Chemical burn in cornea may cause permanent visual problem or complete blindness. In the present study, we investigated the role of microRNA 206 (miR 206) in relieving chemical burn in mouse cornea. METHOD: An alkali burn model was established in C57BL/6 mice to induce chemical corneal injury. Within 72 hours, the transient inflammatory responses in alkali-treated corneas were measured by opacity and corneal neovascularization (CNV) levels, and the gene expression profile of miR-206 was measured by quantitative real-time PCR (qPCR). Inhibitory oligonucleotides of miR-206, miR-206-I, were intrastromally injected into alkali burned corneas. The possible protective effects of down-regulating miR-206 were assessed by both in vivo measurements of inflammatory responses and in vitro histochemical examinations of corneal epithelium sections. The possible binding of miR-206 on its molecular target, connexin43 (Cx43), was assessed by luciferase reporter (LR) and western blot (WB) assays. Cx43 was silenced by siRNA to examine its effect on regulating miR-206 modulation in alkali-burned cornea. RESULTS: Opacity and CNV levels, along with gene expression of miR-206, were all transiently elevated within 72 hours of alkali-burned mouse cornea. Intrastromal injection of miR-206-I into alkali-burned cornea down-regulated miR-206 and ameliorated inflammatory responses both in vivo and in vitro. LR and WB assays confirmed that Cx43 was directly targeted by miR-206 in mouse cornea. Genetic silencing of Cx43 reversed the protective effect of miR-206 down-regulation in alkali-burned cornea. CONCLUSION: miR-206, associated with Cx43, is a novel molecular modulator in alkali burn in mouse cornea. PMID- 26045778 TI - Upregulation of arginase activity contributes to intracellular ROS production induced by high glucose in H9c2 cells. AB - Arginase is upregulated in some tissues under diabetes states. Arginase can compete with nitroxide synthase (NOS) for the common substrate L-arginine and thus increases oxidative stress by NOS uncoupling. We want to analyze whether arginase is upregulated and contribute to oxidative stress in H9c2 cells during high glucose treatment. H9c2 cells were cultured in normal or high glucose DMEM. Arginase activity increased in parallel with increased cell death and oxidative stress. Arginase inhibitor N omega-hydroxy-nor-l-arginine (nor-NOHA) and NOS inhibitor N omega-nitro-l-arginine methyl ester (L-NAME) could reverse these effects. Despite of upregulated NOS activity, NO production was impaired which could be preserved by nor-NOHA, suggesting a decreased substrate availability of NOS due to increased arginase activity. L-arginine supplementation decreased superoxide production while it could not protect cells from death. Upregulated arginase activity in H9c2 treated with high glucose can cause NOS uncoupling and subsequently reactive oxygen species augmentation and cell death. These findings suggest that arginase will be a novel therapeutic target for treatment of diabetic cardiomyopathy. PMID- 26045779 TI - Involvement of Notch1/Hes signaling pathway in ankylosing spondylitis. AB - We aimed to investigate the role of Notch1/Hes signaling pathway in the pathogenesis of abnormal ossification of hip ligament in patients with ankylosing spondylitis (AS). 22 AS patients scheduled for artificial hip arthroplasty were randomly chosen as AS group. As controls, we used 4 patients diagnosed with transcervical fracture who underwent hip replacement surgery. Notch1 and Hes mRNA expressions were detected by real-time fluorescent quantitative polymerase chain reaction (RFQ-PCR). Immunohistochemistry (IHC) was used to detect Notch1 and Hes protein expression. Correlation analyses of Notch-l and Hes with AS-related clinical factors were conducted with spearman's correlation analysis and partial correlation analysis. RFQ-PCR results showed significant differences in Notch1 and Hes mRNA expressions between AS group and the control group (all P<0.05). IHC analysis further indicated positive nuclear signals of Notch1 and Hes protein, indicating functional activation of the Notch1 and Hes pathways. Semi quantitative IHC showed a higher Notch1 and Hes expression levels in AS group compared to the control group (all P<0.05). Correlation analysis suggested that Hes protein expression was positively associated with the clinical course of the disease in AS patients. In conclusion, Notch1 and Hes overexpression was clearly detected in hip joint ligaments of AS patients, Hes protein expression was associated with the clinical course of AS. Taken together, we suggest that signaling pathways mediated by Notch1-Hes may contribute to ligament ossification of hip joints in AS patients. PMID- 26045780 TI - Histone acetyltransferase inhibitor C646 reverses epithelial to mesenchymal transition of human peritoneal mesothelial cells via blocking TGF-beta1/Smad3 signaling pathway in vitro. AB - Peritoneal fibrosis resulting from long-term peritoneal dialysis is a major cause of failure of peritoneal ultrafiltration function and main reason of dropout from peritoneal dialysis. Epithelial-mesenchymal transition (EMT) of peritoneal mesochelial cells (HPMCs) is a major contributor of peritoneal fibrosis. Recently, the association between histone acetylation and kinds of fibrosis including liver, lung and kidney fibrosis is well established. Thus, in this study we tried to profile whether histone acetylation is also operates EMT process in HPMCs and what's the regulatory mechanism. We established an EMT model of HPMCs through high glucose treatment. And hyperacetylation of H3 histone was found using western blot in EMT model. After treated with C646, a histone acetyltransferase (HAT) inhibitor, high glucose-induced EMT in HPMCs was counteracted. To further understand the molecular mechanism of C646 rescues high glucose-induced EMT, CHIP-qPCRwas used to examine the modulation of histone H3 acetylation at promoters of series signaling target genes. We found that the H3 acetylation level at TGF-beta1 gene promoter was down-regulation by C646 treatment. Moreover, we also found that TGF-beta1/Smad3 signaling was blocked. Hence, our results suggest that histone H3 acetylation activated TGF-beta1/Smad3 signaling during EMT of HPMCs, and C646 can rescue the mesenchymal phenotype transition. These findings may provide a novel pathogenic mechanism and therapeutic target for peritoneal fibrosis. PMID- 26045781 TI - Resveratrol induces apoptosis of leukemia cell line K562 by modulation of sphingosine kinase-1 pathway. AB - To explore the effects of resveratrol in a human myelogenous leukemia cell line K562 and its potential molecular mechanisms. The anti-proliferation effect of resveratrol-induced apoptosis on K562 cells were detected using MTT assay. Western blotting was performed for detecting changes of SphK1 expression in total cell protein and membrane/cytosol protein in K562 cells respectively after exposure to resveratrol. A biochemical assay was used to measure the activity of SphK after treatment of resveratrol, and then S1P and ceramide levels were examined using ELISA kits. Hochest 33258 staining and flow cytometry were applied to detect the apoptosis condition of K562 cells treated with resveratrol. Resveratrol inhibited the proliferation and induced apoptosis in K562 cells in a dose and time-dependent manner. Western blotting revealed that resveratrol did not affect total SphK1 expression level in K562 cells, but significantly changed the translocation of SphK1, the membrane SphK1 was decreased while cytosol SphK1 level was elevated. The activity of SphK1 in resveratrol treated groups was decreased compared to control group with a significant decrease of S1P and increase of ceramide level. Furthermore, Hoechst 33258 staining and Annexin V FITC analysis confirmed the notable apoptotic effect of resveratrol in its anti leukemia process. Resveratrol-induced proliferation inhibition of K562 cells might be mediated through its modulation activity of SphK1 pathway by regulating S1P and ceramide levels, which then affected the proliferation and apoptosis process of leukemia cells. SphK1/S1P pathway represents a target of resveratrol in human leukemia. PMID- 26045782 TI - Altered expression of AT-rich interactive domain 1A in hepatocellular carcinoma. AB - AT-rich interactive domain 1A (ARID1A) is a subunit of the Switch/Sucrose non fermentable (SWI/SNF) chromatin remodeling complex. Recently, genome-wide whole exome sequencing revealed frequent mutations of ARID1A in hepatocellular carcinoma, but clinicopathological significance of ARID1A alteration has not been clarified yet. In this study, expression of ARID1A was investigated immunohistochemically in 290 cases of hepatocellular carcinomas. In the evaluation of tissue microarrays, cases of ARID1A alteration (63 total cases, 21.7%) consisted of 11 (3.8%) cases showing loss of expression and 52 (17.9%) with weak expression. Alteration of ARID1A was correlated with larger tumor size (P=0.034) and well or moderate differentiation of tumor histology (P=0.035). There was no significant correlation with age, sex, cirrhosis, TNM stage, tumor size, number of tumors, vascular invasion, patient survival, HBV infection, HCV infection, heavy use of alcohol, nor diabetes mellitus. EBER in situ hybridization was negative in all 11 cases with loss of ARID1A. Altered expression of ARID1A was inversely correlated with nuclear expression of p53 (P=0.018) or beta-catenin (P=0.025). There was some heterogeneity of ARID1A alteration within each case, and immunohistochemistry of the whole sections demonstrated that four of 11 cases with loss of ARID1A in TMA analysis showed localized positive area within the tumor. Alteration of ARID1A may accelerate tumor growth in a subset of hepatocellular carcinoma, and this pathway may be distinct from p53 and beta-catenin pathways. PMID- 26045784 TI - Gab2 is a novel prognostic factor for colorectal cancer patients. AB - Gab2 (Grb2-associated binder 2), a member of the DOS/Gab family of scaffolding adapters, serves as a critical signal amplifier downstream of various growth factor receptors. Recent studies have identified that Gab2 is overexpressed in several cancer types and that increased Gab2 expression promotes cell proliferation, cell transformation, and tumor progression. Here, we show for the first time that Gab2 protein is overexpressed in clinical colorectal cancer (CRC) specimens. Elevated mRNA (P=0.014) expression and protein (P=0.003) expression of Gab2 were found in most CRC tissues compared with the matched adjacent non-tumor tissues using real-time quantitative reverse transcription PCR (qRT-PCR) and western blotting, respectively. Immunohistochemical analyses showed that Gab2 protein was upregulated in CRC tissues relative to adjacent normal tissues (P<0.001), and this overexpression was significantly correlated with lymph node metastasis (P=0.007), distant metastasis (P<0.001) and TNM stage (P=0.002). According to Kaplan-Meier model, CRC patients with Gab2-positive had a significantly poorer prognosis compared to those with Gab2-negative (P=0.007). Multivariate analysis suggested that the positive expression of Gab2 protein was an independent prognostic factor for CRC patients. In conclusion, our data demonstrated that Gab2 expression may play an important role in the progression of CRC, and underscored that Gab2 has the potential value as a prognostic predictor for CRC patients. PMID- 26045783 TI - FoxM1 influences mouse hepatocellular carcinoma metastasis in vitro. AB - Lymph node metastasis is recognized as an important mode of liver cancer metastasis. Two hepatocarcinoma cell lines, Hca-F get high (75%) and Hca-P get low (25%) incidences of lymph node metastasis. Forkhead box M1 (FoxM1) is described as a major oncogenic transcription factor in tumor initiation, promotion, and progression. Ezrin is linked to aggressive tumor behavior by involving all stages of tumor metastasis. We firstly compared the expression of FoxM1 and Ezrin between two cells. Then we transiently transfected Hca-P cells with over-FoxM1 plasmid and Hca-F cells with sh-FoxM1 plasmid. We found that both FoxM1 and Ezrin expressed higher in Hca-F than Hca-P. We successfully down regulated or up-regulated FoxM1 expression in Hca-F or Hca-P cells. And we found that FoxM1 had correlation with proliferation, invasion and migration in mouse hepatocellular carcinoma cell lines. PMID- 26045785 TI - PCSK9 regulates apoptosis in human neuroglioma u251 cells via mitochondrial signaling pathways. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9), belongs to a family of proprotein convertases (PCs), encodes a neural apoptosis-regulated convertase 1. However, the precise role of PCSK9 during glioma cells apoptosis has not been reported. Therefore, we examined the effects of knockdown and overexpression of PCSK9 on apoptosis of human neuroglioma U251 cells, and investigated the underlying mechanisms of apoptosis. We found that PCSK9 regulated cells proliferation as determined by CCK-8 and Hoechst staining analysis. In addition, western blot results showed that PCSK9 siRNA promote apoptosis via activation of caspase-3 and down-regulation of the anti-apoptotic proteins, XIAP and p-Akt, while PCSK9 overexpression inhibited apoptosis. Moreover, PCSK9 siRNA improved the ratio of Bax/Bcl-2 which leads to the release of cytochrome c, while PCSK9 overexpression decreased it. Taken together, these data demonstrate that PCSK9 may regulate apoptosis through mitochondrial pathway and is expected to be a promising therapeutic strategy for the malignant glioma. PMID- 26045786 TI - An immunohistochemical analysis of stathmin 1 expression in uterine smooth muscle tumors: differential expression in leiomyosarcomas and leiomyomas. AB - The oncogenic phosphatidylinositol 3-kinase-AKT-mammlian target of rapamycin pathway (PI3K-AKT-mTOR) pathway is known to be activated in uterine smooth muscle tumors, and Stathmin 1 (STMN1) expression has been identified as a marker of PI3K AKT-mTOR pathway activation. We hypothesized that STMN1 may have some diagnostic utility and explored how well STMN1 expression correlated with histologic classifications of uterine smooth muscle tumors into benign and malignant groupings. 84 smooth muscle tumors were assessed for STMN1 expression by immunohistochemistry. These included spindle cell leiomyosarcoma (n=32), conventional spindle cell leiomyomas (n=30), atypical (symplastic) leiomyoma (n=5), cellular leiomyoma (n=7), smooth muscle tumor of uncertain malignant potential (n=4), mitotically active leiomyomas (n=2), benign metastasizing leiomyoma (n=3), and cotyledonoid dissecting leiomyoma (n=1). All spindle cell leiomyosarcomas were positive (32/32 positive; 100%) as compared with conventional leiomyomata (11/30; 37%) (P<0.0001). The average immunohistochemical score (0-12+, reflective of intensity and extent) for leiomyosarcomas was 8.7 (+/ 1.43) whereas the conventional leiomyomata average score was 1.6 (+/-1.07) (P<0.0001). This difference in scores was reflected in the patterns of expression: leiomyosarcomas were predominantly strongly and diffusely positive whereas leiomyomata were predominantly weakly, albeit diffusely positive when expression was present. The sensitivity of STMN1 expression for leiomyosarcomas was 100%. However, the specificity was found to be only 55% (CI=43-68%). The negative and positive predictive values for leiomyosarcomas were 100% and 52% respectively. The odds ratio (OR) for any STMN1 expression in predicting a spindle cell leiomyosarcoma diagnosis from this dataset was highly significant (OR=144, P=0.0006). Thirteen non-smooth muscle tumors that involved the uterus all showed at least focal STMN1 immunoreactivity. In summary, STMN1 is a highly sensitive marker for leiomyosarcoma but is suboptimally specific for diagnostic purposes. The 100% negative predictive value for leiomyosarcoma may offer some diagnostic utility in a small sample, since the absence of STMN1 immunoreactivity in a putative leiomyosarcoma is a strong argument against this diagnostic possibility. PMID- 26045787 TI - Screening of APP interaction proteins by DUALmembrane yeast two-hybrid system. AB - Alzheimer's disease (AD) is one of the most common forms of neurodegenerative disease. There is a growing interest in the amyloid precursor protein (APP) over the years due to its involvement in AD. Besides its role in pathological mechanisms of AD, APP participates in many signaling pathways as well. APP functions through protein-protein interactions, and in this report staufen 1 (STAU1) is demonstrated to have interaction with APP, using yeast two-hybrid screening and co-immunoprecipitation in mammalian system. STAU1 belongs to the double-stranded RNA binding protein family and can mediate mRNA degradation in mammalian system, implicating that APP may be involved in the regulation of mRNA as well. PMID- 26045788 TI - CSN5 silencing inhibits invasion and arrests cell cycle progression in human colorectal cancer SW480 and LS174T cells in vitro. AB - CSN5 has been implicated as a candidate oncogene in human cancers by genetic linkage with activation of the poor-prognosis, wound response gene expression signature. The present study aimed to investigate the effect of silencing CSN5 on invasion and cell cycle progression of human colorectal cancer cells, and to determine the potential molecular mechanisms that are involved. The CSN5 specific small interfering RNA (shRNA) plasmid vector was constructed and then transfected into colorectal cancer cells. The expression of CSN5 mRNA and protein was detected by quantitative polymerase chain reaction and western blot analysis, respectively. Cell adhesion and invasion were analyzed using MTS and Transwell assays, respectively, and cell cycle progression was analyzed using flow cytometry. Adhesion, invasion, and cell cycle distribution were assessed following knockdown of CSN5 by RNA interference (RNAi). Furthermore, knockdown of CSN5 significantly inhibited cell adhesion and reduced the number of invasive cells, while increasing the percentage of cells in the G0/G1 phase (P<0.05). Western blot and real-time PCR analysis were used to identify differentially expressed invasion and cell cycle associated proteins in cells with silenced CSN5. The expression levels of CSN5 in colorectal cancer cells transfected with siRNA were decreased, leading to a significant inhibition of colorectal cancer cell adhesion and invasion. Western blot analysis revealed that silencing of CSN5 may inhibit CD44, matrix metalloproteinase (MMP) 2 and MMP 9 protein expression, significantly promoted cell cycle-related genes P53 and P27 expression. In addition, CSN5 silencing may induce activation PI3K/AKT signal regulated cell invasion. Moreover, CSN5 silencing inhibited the secretion of TGF-beta, IL-1beta and IL-6 and the transcriptional activity of transcription factor NF-kappaB and Twist in human colorectal cancer cells. Taken together, down regulation of CSN5 may inhibit invasion and arrests cell cycle progression in colorectal cancer via PI3K/AKT/NF-kappaB signal pathway, which indicates that there is a potential of targeting CSN5 as a novel gene therapy approach for the treatment of colorectal cancer. PMID- 26045789 TI - Differentiation of immortalized human precartilaginous stem cells into nucleus pulposus-like cells. AB - OBJECTIVE: We aimed to explore the differentiation of immortalized human precartilaginous stem cells (IPSCs) into nucleus pulposus (NP)-like cells induced by transforming growth factor-beta1 (TGF-beta1) and examine its biological characteristics. METHODS: The IPSCs were seeded onto chitosan/glycerophosphate (C/GP) scaffolds and induced into NP-like cells by adding TGF-beta1 under hypoxic conditions. The growth and differentiation of IPSCs were observed, and the formation of glycosaminoglycans (GAG) in the extracellular matrix of differentiating cells was detected by Alcian Blue staining. The expressions of type II collagen and aggrecan genes in NP-like cells were examined by reverse transcription-polymerase chain reaction (RT-PCR). The expressions of Sox9 and beta-catenin were analyzed by Western blotting. RESULTS: The IPSCs were observed to grow well on the C/GP scaffolds. After 7 days, Alcian Blue staining demonstrated the formation of GAG. The RT-PCR results showed that expression of type II collagen and aggrecan were upregulated compared with control group (P<0.05, P<0.05). Likewise, western blotting results showed that the expression of Sox9 and beta-catenin was upregulated compared with control group (P<0.05, P<0.05). CONCLUSIONS: The findings demonstrate that IPSCs could be differentiated into NP-like cells following induction by TGF-beta1. PMID- 26045790 TI - Combination of metformin and valproic acid synergistically induces cell cycle arrest and apoptosis in clear cell renal cell carcinoma. AB - OBJECTIVE: To investigate the antitumor activity of metformin combined with valproic acid (VPA) on renal cell carcinoma (RCC) cell lines. METHODS: The effects of metformin combined with VPA on the viability of 786-O and caki-2 cell lines were evaluated by MTT assay. The inhibitory effect of combination of the two drugs was analyzed by the Chou and Talalay method. Flow cytometry was employed to analyze cell cycle and cell apoptosis. RESULTS: MTT assay showed that both metformin and VPA decreased 786-O and Caki-2 cells viability in a dose dependent and time-dependent manner. In 786-O cells, metformin combined with VPA had a synergistic inhibitory effect (CI<1) when the inhibition effect was >=0.3. In Caki-2 cells, metformin combined with VPA had a synergistic inhibitory effect (CI<1) when the inhibition effect was >=0.4. Metformin and VPA combination elicited significant apoptosis compared to drug used alone (P<0.05). Furthermore, metformin and VPA acted synergistically to arrest 786-O and Caki-2 cells in G0/G1 phase. CONCLUSION: We highlighted for the first time that metformin combined with VPA could significantly increase anti-ccRCC effect through synergetic effect; its possible mechanisms were inducing apoptosis and adjusting cell cycle. PMID- 26045791 TI - MicroRNA-570 promotes lung carcinoma proliferation through targeting tumor suppressor KLF9. AB - Increasing studies have shown that MicroRNAs (miRNAs) play critical roles in the progression of lung carcinoma. In the present study, the expression and functions of miR-570 were investigated. We found that miR-570 was significantly up regulated in lung cancer tissues, compared with adjacent non-cancerous tissues. In vitro studies further showed that miR-570 mimics could promote, while its antisense oligos inhibit cell proliferation and invasion. At the molecular level, kruppel-like factor 9 (KLF9), a tumor suppressor gene, was identified as a potential target of miR-570 in lung cancer cells. Indeed, miR-570 could negatively regulate protein levels of KLF9 through targeting its 3'-untranslated region. Taken together, our results suggest a previously unknown miR-570/KLF9 molecular network controlling lung carcinoma progression. PMID- 26045792 TI - Effect of transforming growth factor-beta1 869C/T polymorphism and radiation pneumonitis. AB - BACKGROUND: The Transforming growth factor-beta1 (TGFbeta1) 869C/T polymorphism was associated with radiation pneumonitis (RP) susceptibility. However, the results remained controversial. Thus, a meta-analysis was conducted. METHODS: Relevant studies were systematically searched by using the NCBI, Medline, Web of Science and Embase databases. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using random-effects models. RESULTS: There was a significant association between TGFbeta1 869C/T polymorphism and RP susceptibility (OR=1.77; 95% CI, 1.27-2.47; P=0.0007). CONCLUSION: This study suggested that TGFbeta1 869C/T polymorphism was a risk factor of RP. PMID- 26045793 TI - The potential value of miR-1 and miR-374b as biomarkers for colorectal cancer. AB - The mortality of colorectal cancer (CRC) is growing due to the unsatisfactory specificity and sensitivity of the existing screening methods. Previous studies have focused on the role of miRNAs as CRC biomarkers. However, few studies have examined the miRNA profiles at each stage. The objective of this study was to identify miRNAs that distinguish CRC patients from normal people to prevent the misdiagnosis of patients with certain stages of CRC. We performed miRNA profiling of 1547 human miRNAs by qRT-PCR in CRC patients with stage II and stage III disease. The statistical analyses showed that there were 96 miRNAs that were significantly dysregulated in CRC relative to normal tissues (P<0.05). There were 28 dysregulated miRNAs associated with separate or combined stages II and III disease. There were 25 downregulated miRNAs, including the following: miR-1, 145, -145*, -137, -363, -143, -4770, -490-5p, -9, -144*, -99a, -99b, -23b, -143*, -100, -768-3p, -24-1*, -125a-5p, -30e*, -574-3p, -126, let-7b, miR-1979, -374b, and -140-3p. We found an upregulation of miR-203, 182, and 96. Our results demonstrated that the expression of miR-1 and miR-374b was significantly decreased in each stage and may function as a biomarker of CRC. Furthermore, 20 miRNAs were dysregulated both in stage II disease without lymph node or distant metastasis and in stage II-III tumors but not in stage III tumors. Only miR-4794 was involved exclusively with stage II tumors, and there were 19 miRNAs that were dysregulated only in stage III disease with lymph node metastasis and in stage II III disease. There were only 6 miRNAs that were uniquely dysregulated in stage III. Our results indicate that miRNA expression may be valuable in the clinic. However, large prospective studies are required to confirm the role of miRNAs. This study provides a new model for analyzing novel CRC biomarkers by considering more clinical factors. PMID- 26045794 TI - Identification of functional tag single nucleotide polmorphisms within the entire CAT gene and their clinical relevance in patients with noise-induced hearing loss. AB - OBJECTIVES: Noise-induced hearing loss (NIHL) is an important occupational disease which results from an interaction between genetic and environmental factors. More and more evidences suggested that Catalase (CAT) gene polymorphism plays an important role in the development of NIHL. The aim of this study was to investigate the association of CAT gene polymorphisms with NIHL in a case-control study. DESIGN: A total of 719 unrelated adult Chinese Han population, including 225 healthy volunteers and 494 noise-exposed workers were recruited in this study. Six tag single-nucleotide polymorphisms (tSNPs) were genotyped using an improved multiplex ligation detection reaction technique. Subsequently, the interaction between noise exposure level and genotypes and their effect on NIHL were analyzed using logistic regression. RESULTS: Among six tSNPs, two of them (rs208679 and rs769217) were significantly associated with noise exposure level. For rs208679 recessive effect, GG genotype had a significantly increased of NIHL risk in the exposure level of <85 dB; and for rs769217 dominant effect, the combined genotypes TT/TC had a significantly increased of NIHL risk in the exposure level of 85 dB~92 dB; and the haplotype A-G-T-C-A-C had a risk effect on the NIHL in the exposure level of 85 dB~92 dB. In addition, the rs769217 polymorphism could enhance the transcription activities of the CAT gene. CONCLUSIONS: This study identified CAT is a NIHL susceptibility gene when noise exposure levels are taken into account. Rs208679 and rs769217 polymorphisms might be used as relevant risk estimates for the development of NIHL in population with different noise exposure levels. PMID- 26045795 TI - miR-200a/miR-141 and miR-205 upregulation might be associated with hormone receptor status and prognosis in endometrial carcinomas. AB - The aim of this study was to compare the clinicopathological significance of miR 200a/miR-141 and miR-205 expression in endometrioid carcinomas (ECs) versus nonendometrioid carcinomas (NECs) and to assess their correlation with hormone receptor status. miR-200a/miR-141 and miR-205 expression in 154 endometrial cancers was determined by qRT-PCR. The status of estrogen and progesterone receptor (ER/PR) was assessed using immunohistochemistry. miR-200a/miR-141 and miR-205 increased significantly in ECs and in NECs. The expression level of miR 200a was significantly higher in NECs than in ECs (P=0.025). Furthermore, there was a trend that NECs with worse clinicopathological variables had a higher miR 200a expression, while an inverse trend existed in ECs. miR-205 upregulation occurred frequently in NECs without lymph node metastases (P=0.030), whereas such association was not present in ECs. Interestingly, In ECs, miR-200a/miR-141 upregulation occurred frequently in the hormone receptor positive subgroups than the negative subgroups (P<0.05). Similarly, the expression level of miR-205 was higher in the hormone receptor positive subgroups and the association between miR 205 and PR reached statistical significance (P=0.024). In contrast, in NECs, a negative correlation was found between miR-200a/miR-141 and ER or PR status. Meanwhile, in ECs, miR-200a upregulation correlated with prolonged survival in the ER positive subgroup (P=0.046), whereas an inverse trend existed in the ER negative subgroup. Our findings suggest that miR-200a/miR-141 and miR-205 increased significantly in ECs and in NECs. However, they might behave differently in ECs versus NECs. miR-200a/miR-141 and miR-205 might be associated with hormone receptor status in endometrial cancer and may possess prognostic impacts. PMID- 26045796 TI - Malignant fibrous histiocytoma of visceral organs: clinicopathologic features and diagnostic value of ezrin and HMG-CoA reductase. AB - Malignant fibrous histiocytoma (MFH) of the breast and visceral organs is extremely rare. There is an incomplete understanding of the clinical pathology of the primary MFH originating from the breast and visceral organs, especially in comparison with other soft tissue sarcomas. As a consequence we searched and analyzed the clinical and pathological records of all the nine patients with diagnosed breast and visceral MFH in our hospital. Immunohistochemical staining was performed for ezrin and HMG-CoA reductase in these MFH cases and relevant mesenchymal sarcomas. The 9 MFH cases presented with nonspecific symptoms and imaging manifestations. 6 cases were classified as storiform-pleomorphic MFH, 2 cases as inflammatory MFH, and the remaining 1 case as giant cell MFH. The results showed that ezrin expression, as well as HMG-CoA reductase expression, was significantly stronger in MFH cases than other non-MFH sarcomas. Poor prognosis seemed to be associated with younger age. Certain characteristics and clinicopathologic features can help us making the diagnosis of MFH. In conclusion, our study provided the potential value of ezrin and HMG-CoA reductase for diagnosis and differential diagnosis of MFH located in the breast and visceral organs. More accurate prognostic information of this rare disease needed to be further investigated. PMID- 26045797 TI - Biomarkers of erlotinib response in non-small cell lung cancer tumors that do not harbor the more common epidermal growth factor receptor mutations. AB - Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancers, which are the leading cause of cancer-related deaths in the world. Tyrosine kinase inhibitors such as erlotinib represent one therapeutic options presently recommended for tumors produced by activating mutations in the gene coding of epidermal growth factor receptor (EGFR). The aim of this study is the identification of possible biomarkers for tumor sensitivity to erlotinib in the absence of the main EGFR mutations. The erlotinib sensitivity of cells isolated from 41 untreated NSCLC patients was determined and compared with the presence of the more frequent EGFR mutations. Several patients had tumor cells highly sensitive to erlitinib in the absence of the EGFR mutations analyzed. The gene expression profile of 3 erlotinib-sensitive tumors was compared with that of 4 resistant tumors by DNA microarray hybridization. Sixteen genes were expressed at significantly higher levels in the resistant tumors than in the sensitive tumors. The possible correlation between erlotinib sensitivity and the expression of these genes was further analyzed using the data for the NSCLC, breast cancer and colon cancer cell lines of the NCI60 collection. The expression of these genes was correlated with the overall survival of 5 patients treated with erlotinib, according to The Cancer Genome Atlas (TCGA) database. Overlapping groups of 7, 5 and 3 genes, including UGT1A6, TRIB3, MET, MMP7, COL17A1, LCN2 and PTPRZ1, whose expression correlated with erlotinib activity was identified. In particular, low MET expression levels showed the strongest correlation. PMID- 26045798 TI - Basal cell adenoma of the parotid gland: clinical and pathological findings in 29 cases. AB - OBJECTIVE: To determine the clinical and pathological features of basal cell adenoma (BCA) of the parotid gland. METHODS: This is a retrospective study of 29 parotid BCAs in 28 patients who underwent surgery at the Department of Otolaryngology Head and Neck Surgery, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, between October 2000 and June 2013. The tumors were categorized according to their location in the parotid gland as superior superficial lobe, inferior superficial lobe and deep lobe. RESULTS: The mean age was 57.0 years (range, 32-83 years). The clinical manifestations of parotid BCAs were consistent with those of other benign parotid tumors. There were no significant differences in age, average disease duration and tumor size among the three tumor groups. There were 11 deep tumors (11/29, 37.9%), and five of them exhibited cystic degeneration (5/11, 45.5%). A total of 15 patients underwent FNAB examination, and the results were positive in seven patients (7/15, 46.7%). Mild facial nerve function impairment occurred in five patients (House-Brackmann grade II), of whom, three had recovered by the 6-month follow-up. No cases of local recurrence or malignant transformation were observed during follow-up. CONCLUSION: The clinical features of BCA are consistent with those of other benign tumors. The deep lobe of the parotid gland is more likely to develop BCAs, and thus, this diagnosis should be considered in patients with deep-lobe tumors, especially when accompanied with cystic degeneration. FNAB can increase the rate of preoperative diagnoses. PMID- 26045799 TI - Association between KIAA1199 overexpression and tumor invasion, TNM stage, and poor prognosis in colorectal cancer. AB - To investigate the expression of KIAA1199 in tumor tissue and its potential value as a prognostic indicator of survival in patients with colorectal cancer (CRC). The expression of KIAA1199 mRNA in CRC was characterized using real-time PCR and 20 pairs of fresh-frozen CRC tissues and corresponding non-cancerous tissues. KIAA1199 protein expression was confirmed using immunohistochemistry on a tissue microarray chip from 202 patients with CRC. Then, we correlated KIAA1199 protein expression to CRC conventional clinicopathological features and patient's outcome. The expression of KIAA1199 mRNA and protein were up-regulated in CRC compared to normal tissues (P=0.015 and P<0.001, individually). KIAA1199 protein expression was related to tumor invasion depth (P=0.013) and lymph node metastasis (P=0.003). Kaplan-Meier survival and Cox regression analyses revealed that high KIAA1199 expression (P<0.001) and serum carcinoembryonic antigen (CEA) level post operation (P=0.005) were independent factors predicting poor prognosis of patients with CRC. We present evidence that high expression of KIAA1199 is associated with tumor invasion depth, TNM stage, and poor prognosis in CRC. Our findings suggest KIAA1199 could be used as a prognostic factor and novel therapeutic target for CRC. PMID- 26045800 TI - ING4 enhances paclitaxel's effect on colorectal cancer growth in vitro and in vivo. AB - Inhibitor of growth 4 (ING4) is a tumor suppressor that can inhibit cell growth and induce apoptosis. ING4 expression levels show negative correlation with the clinical stage, histological grade, and lymph node metastasis of colorectal cancer. Further insights are needed to analyze the effect of adenovirus-mediated ING4 on colorectal cancer cell growth and the response to paclitaxel treatment. In this study, we found adenovirus-mediated ING4 expression reduced proliferation and enhanced apoptosis in the SW1116 cells. p-Stat3 and Ki-67 expression significantly decreased in the SW1116 cells treated with Ad-ING4, PTX, or Ad ING4+PTX compared with those treated with PBS or Ad-GFP both in vitro and in vivo (P<0.05). In animal experiments, the mice treated with Ad-ING4, PTX, or Ad ING4+PTX exhibited significantly inhibited growth of SW1116 xenografts compared with those treated with PBS or Ad-GFP (P<0.05) and the combination (Ad-ING4+PTX) treatment exhibited the highest inhibition. Our results highlight that Ad-ING4 significantly inhibits growth and induces apoptosis in SW1116 colorectal cancer cells and suppresses tumor growth in SW1116 xenografts by downregulating p-Stat3 and Ki-67 expression. A combination of Ad-ING4 and PTX exhibits the highest inhibition, indicating that ING4 enhances sensitivity to chemotherapy. PMID- 26045801 TI - Intravenously delivered neural stem cells migrate into ischemic brain, differentiate and improve functional recovery after transient ischemic stroke in adult rats. AB - Stem cell transplantation may provide an alternative therapy to promote functional recovery after various neurological disorders including cerebral infarct. Due to the minimal immunogenicity and neuronal differentiation potential of neural stem cells (NSCs), we tested whether intravenous administration of mice derived C17.2 NSCs could improve neurological function deficit and cerebral infarction volume after ischemic stroke in rats. Additionally, we evaluated the survival, migration, proliferation, and differentiation capacity of transplanted NSCs in the rat brain. Intravenous infusion of NSCs after middle cerebral artery occlusion (MCAO) showed better performance in neurobiological severity scores after MCAO compared to control. However, the volume of cerebral infarction was not different at 7 days after MCAO compared with control. Transplanted NSCs were detected in the ischemic region but not in the contralateral hemisphere. NSCs differentiated into neurons or astrocytes after MCAO. These data suggest that intravenously transplanted NSCs can migrate, proliferate, and differentiate into neurons and astrocytes in the rat brain with focal ischemia and improve functional recovery. PMID- 26045802 TI - Expression of ETV6/TEL is associated with prognosis in non-small cell lung cancer. AB - The ETV6/TEL gene is a member of the ETS family of transcription factors that has been mainly studied in hematological diseases. This study provides the first investigation of ETV6 expression in non-small cell lung cancer (NSCLC). In this study, ETV6 expression was immunohistochemically studied in 170 consecutive patients with NSCLC. The association between ETV6 expression and clinicopathological parameters was evaluated. Kaplan-Meier survival analysis and Cox proportional hazards models were used to estimate the effect of ETV6 expression on survival. ETV6 expression was observed in 135 of the 170 (79.4%) patients. ETV6 expression was positive for nuclear staining. From the clinicopathological standpoint, the expression of ETV6 was significantly correlated with age (P=0.014). The overall survival was significantly enhanced in the group with a low expression of ETV6 compared with the group with a high expression of ETV6 (five-year survival rates, 56.53% versus 29.88%; P=0.002), and the same finding was obtained for disease-free survival (five-year survival rates, 52.24% versus 30.47%; P=0.001). Multivariable analysis confirmed that ETV6 expression increased the hazard of death after adjusting for other clinicopathological factors (hazard ratio, 2.002; 95% confidence interval, 1.303 3.074; P=0.002). Our study demonstrated that ETV6 was markedly involved in the development of NSCLC and could serve as a potential prognostic marker for this deadly disease. PMID- 26045803 TI - Bone morphogenetic protein is required for fibroblast growth factor 2-dependent later-stage osteoblastic differentiation in cranial suture cells. AB - BACKGROUND: Understanding the pathophysiological process of calvarial bones development is important for the treatments on relative diseases such as craniosynostosis. While, the role of fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) and how they interacted in osteoblast differentiation remain unclear. METHODS: we digested bone fragments around the coronal and sagittal sutures from newborn rats to harvest suture cells. Markers expression at different osteoblast differentiation stage was analyzed by increasing FGF2 concentration and BMP2 blocking in these cells. RESULTS: BMP2 expression could be stimulated by FGF2 in a dose and time dependent manner. FGF2 stimulation may decrease early marker of osteoblast differentiation (collagen type-1, COL-1) and increase the expression of continuously-expressed or late markers (alkaline phosphatase, ALP; osteocalcin, OC and bone sialoprotein, BSP) to accelerate mineralization. Inhibition of BMP2 signaling by Noggin weakens the effect of FGF2 on induction of later-stage osteoblastic differentiation of cranial suture cells. CONCLUSION: Our data suggest that BMP2 signaling is required for FGF2-dependent induction of later-stage of cranial suture cell osteoblastic differentiation. PMID- 26045804 TI - The mTOR inhibitor sirolimus suppresses renal, hepatic, and cardiac tissue cellular respiration. AB - The purpose of this in vitro study was to develop a useful biomarker (e.g., cellular respiration, or mitochondrial O2 consumption) for measuring activities of mTOR inhibitors. It measured the effects of commonly used immunosuppressants (sirolimus-rapamycin, tacrolimus, and cyclosporine) on cellular respiration in target tissues (kidney, liver, and heart) from C57BL/6 mice. The mammalian target of rapamycin (mTOR), a serine/ threonine kinase that supports nutrient-dependent cell growth and survival, is known to control energy conversion processes within the mitochondria. Consistently, inhibitors of mTOR (e.g., rapamycin, also known as sirolimus or Rapamune(r)) have been shown to impair mitochondrial function. Inhibitors of the calcium-dependent serine/threonine phosphatase calcineurin (e.g., tacrolimus and cyclosporine), on the other hand, strictly prevent lymphokine production leading to a reduced T-cell function. Sirolimus (10 MUM) inhibited renal (22%, P=0.002), hepatic (39%, P<0.001), and cardiac (42%, P=0.005) cellular respiration. Tacrolimus and cyclosporine had no or minimum effects on cellular respiration in these tissues. Thus, these results clearly demonstrate that impaired cellular respiration (bioenergetics) is a sensitive biomarker of the immunosuppressants that target mTOR. PMID- 26045805 TI - Activation of FOXO3a suggests good prognosis of patients with radically resected gastric cancer. AB - OBJECTIVE: This study sought to investigate the role of the forkhead transcription factor FOXO3a in the prognosis of stage II/III gastric cancer patients. MATERIALS AND METHODS: A single-institution cohort of 289 patients with stage II/III gastric cancer was studied. Formalin-fixed paraffin-embedded tumor and adjacent normal specimens were used for tissue microarray construction. Tissue sections were immunostained with FOXO3a. Microscopic evaluation to assess the presence and localization of FOXO3a in tumor and adjacent normal tissues was performed. Results were analyzed for association with clinicopathological characters and overall survival (OS). RESULTS: FOXO3a expression was significantly higher in tumor tissues compared with adjacent normal tissues, and nuclear FOXO3a staining was observed to be more common in tumor samples than adjacent normal tissues. Poorer prognosis was seen in patients with tumors harboring lower expression of FOXO3a and also patients with adjacent normal tissues harboring higher expression of FOXO3a. High expression of FOXO3a in tumor tissues served as a good prognostic marker with multivariate hazard ratio (HR) of 0.737 (95% CI, 0.574 to 0.947; P=0.017) for OS. CONCLUSION: The expression of FOXO3a was upregulated and activated in gastric cancer tissues, and was significantly associated with a favorable prognosis in stage II/III gastric cancer patients. PMID- 26045806 TI - Surfactant protein B gene polymorphisms is associated with risk of bronchopulmonary dysplasia in Chinese Han population. AB - OBJECTIVE: To investigate the relationship between Surfactant protein B (SP-B) gene polymorphisms and bronchopulmonary dysplasia (BPD) development in preterm infants of China Han ethnic population. METHODS: SP-B gene polymorphisms were studied in 134 neonates who were born at <32 weeks of gestation, with the diagnosis of BPD and in a control group of 168 preterm infants without BPD. Genotyping for SP-B was performed by polymerase chain reaction (PCR) and gene sequencing. RESULTS: In this study, three of the SNP genotypes, -18C/A, 1580C/T and 4564T/C were common identified in SP-B gene. The -18C/A genotype was found to be significantly associated with BPD (chi2=10.741, P<0.01), with P<0.01 for the dominant model (OR=1.712, 95% CI=1.228-2.3894) and the allelic model (OR=1.787, 95% CI=1.276-2.502). The 1580C/T genotype was found to be associated with BPD (chi2=7.014, P<0.05), with P<0.05 for the dominant model (OR=0.752, 95% CI=0.593 0.954) and P<0.01 for the allelic model (OR=0.706, 95% CI=0.548-0.909). The 4564T/C genotypes and alleles were found not to be associated with BPD (chi2=3.399 and 3.227, P>0.05). CONCLUSION: SP-B -18C/A and 1580C/T polymorphisms are associated with BPD. The 1580C/T polymorphism was protective while the -18C/A polymorphism increased the risk for BPD. SP-B 4564T/C polymorphism is not associated with BPD. PMID- 26045807 TI - P16 and Ki-67 expression improves the diagnostic accuracy of cervical lesions but not predict persistent high risk human papillomavirus infection with CIN1. AB - OBJECTIVE: To determine the association between the expression of p16 and Ki-67 and cervical lesions, and to evaluate the role of p16 and Ki-67 as prognostic markers for persistent high risk human papillomavirus (hr-HPV) infection. METHODS: Totally 1,154 cases of cervical biopsies were enrolled, 331 cases with negative for dysplasia (NEG), 462 with cervical intraepithelial neoplasia 1 (CIN1), 176 with CIN2, 163 with CIN3 and 22 with cervical squamous cell carcinoma (SCC). Furthermore, 283 women with CIN1 were recruited into 12-month follow-up, and HPV specific gene detection by polymerase chain reaction was used to detect hr-HPV of cervical secretions at 6-month-interval for 12-month follow-up period. 40 women were infected with persistent hr-HPV, 182 with transient infection and 61 unfected with hr-HPV. The expression of p16 and Ki-67 were evaluated by immunohistochemical method. The immunostaining results of p16 and Ki-67 were classified into four categories: negative, 1+, 2+ and 3+. RESULTS: There was significant increase in the expression of p16 (P<0.001) and Ki-67 (P<0.001) from NEG to SCC. The expression of Ki-67 (P<0.001) but not p16 (P=0.254) significantly increased in CIN2, CIN3. Ratio of p16 (P=0.215) and Ki-67 (P=0.495) positivity were not correlated with persistent hr-HPV infection. CONCLUSION: P16 and Ki-67 can improve the diagnostic accuracy of cervical lesions but can not predict persistent hr-HPV infection with CIN1. PMID- 26045808 TI - Expression of phosphorylated mTOR and its clinical significances in small cell lung cancer. AB - The mammalian target of rapamycin (mTOR) is a serine/threonine kinase regulating the cell cycle and protein synthesis, and is an attractive molecule for novel molecular targeting therapy in various cancers, including non-small cell lung cancer (NSCLC). In contrast with NSCLC, mTOR expression has not been fully investigated in SCLC. In this study, we evaluated the correlations between mTOR expression and clinical characteristics in SCLC. Immunohistochemical staining for phosphorylated mTOR (p-mTOR) was performed and histoscores were calculated on 115 SCLC tissue specimens. Based on the distribution of the data, a histoscore of 60 was used as a cutoff to dichotomize SCLCs into low versus high expression groups. Extended-stage SCLCs showed significantly lower p-mTOR expression than those of a limited-stage (P=0.008). Lymph node metastasis was more frequently detected in the low than high expression group (P=0.074). The high p-mTOR expression group had a weak tendency toward prolonged overall survival, but the difference was not statistically significant (P=0.170). We found that there is a significant difference in p-mTOR expression between different clinical stages in SCLC. This result indicates that p-mTOR might play a more pivotal role in the biologic behavior of early SCLCs than advanced ones and the effectiveness of mTOR inhibitors might vary according to the extent of disease. PMID- 26045809 TI - Increased expression of lncRNA HULC indicates a poor prognosis and promotes cell metastasis in osteosarcoma. AB - INTRODUCTION: Long non-coding RNAs (lncRNAs) are aberrantly expressed in many diseases including cancer. LncRNA HULC (highly up-regulated in liver cancer) has recently been revealed to be involved in hepatocellular carcinoma development and progression. However, the role and function of HULC in human osteosarcoma remains unknown. METHODS: LncRNA HULC expression in osteosarcoma tissues and cell lines was detected by quantitative real-time PCR. Then, the association of HULC level with survival of osteosarcoma patients was performed by the Kaplan-Meier and Cox proportional regression analyses. Furthermore, the effects of HULC on tumorigenicity of osteosarcoma cells were evaluated by in vitro assays. RESULTS: In the present study, we demonstrated that HULC was significantly up-regulated in osteosarcoma tissues and cell lines compared with normal controls, and over expression of HULC was correlated with clinical stage and distant metastasis. Moreover, higher HULC expression was associated with shorter overall survival of osteosarcoma patients. Furthermore, decreased expression of HULC markedly suppressed osteosarcoma cell proliferation, migration, and invasion. CONCLUSIONS: Our results indicated that HULC is a novel molecule involved in osteosarcoma progression, which may provide a new marker of poor prognosis and a potential therapeutic target for osteosarcoma intervention. PMID- 26045810 TI - Pulmonary mucoepidermoid carcinoma in Chinese population: a clinicopathological and radiological analysis. AB - BACKGROUND: Pulmonary mucoepidermoid carcinoma (PMEC) is a rare malignant neoplasm with remarkable resemblance to mucoepidermoid carcinoma of the salivary glands. It constitutes a unique set of patient population. In this study we briefly discussed the current state of knowledge of PMEC and described the clinical presentation and management of 27 PMEC cases. This study aimed to discuss the utility of surgical treatment in the patients with pulmonary mucoepidermoid carcinoma. METHODS: We retrospectively studied 27 cases with the diagnosis of PMEC, divided into low grade and high grade based on histopathological characteristics. The clinical symptoms, radiological manifestations, pathological characteristics, treatment strategy and prognosis were systemically analyzed. RESULTS: The tumor could occur in any lobe of the lungs. The treatment included surgical intervention and/or adjuvant therapies. While the sex-age distribution and initial staging was not different between low- and high- grade PMEC, the disease control rate (95%) and 5 year survival (95%) were much higher in low-grade PMEC than the high-grade cases (57.1% and 42.9%, respectively). CONCLUSION: The clinical, radiographical and pathological features of PMECs were systemically analyzed and summarized, and the utility of pathological grading system as the independent prognostic factor in addition to clinical staging was confirmed. PMID- 26045811 TI - Folate ameliorates dexamethasone-induced fetal and placental growth restriction potentially via improvement of trophoblast migration. AB - Overexposure to prenatal dexamethasone (Dex) leads to small placental and fetal size and the alteration of fetal programming. Folate plays important roles in processes associated with successful pregnancy, including angiogenesis and trophoblast invasion. Placental folate transport is altered with prenatal Dex administration. The purpose of this study was to investigate the protective role of maternal folate administration in placentas exposed to Dex. In vitro, four groups of C57BL/6J pregnant mice were utilized: 1) normal drinking water+Saline injection group (NN); 2) normal drinking water+Dex injection group (ND); 3) drinking water with folate+Saline injection group (FN); and 4) drinking water with folate+Dex injection group (FD). In vivo, four treatment groups of the human extravillous trophoblast HTR-8/SVneo cells were classified: 1) control (NN); 2) Dex treatment (ND); 3) folate treatment (FN); and 4) folate and Dex treatment (FD). The results showed the maternal folate increases the placental size, birth weight, and expression of matrix metalloproteinases 9 (MMP9) in a mice model of Dex overexposure. In human extravillous trophoblast HTR8/SVneo, folate ameliorated the Dex-induced supress of cell migration and improved the expression/activity of MMP2 and MMP9. In conclusion, folate might be a potential therapy intervention to reduce the adverse effects of prenatal Dex exposure partially via improved trophoblast migration. PMID- 26045812 TI - A new mouse model for wound healing in hemophilia A. AB - PURPOSE: To establish a new mouse model for wound healing studies on hemophilia A. METHODS: Total 54 male mice with different genotypes including wild-type nude mice, heterozygous mice (FVIII-/-/Nu) and FVIII deficient mice (FVIII-/-) were generated and verified by PCR. Mice were subjected to wound healing research by making a 5 mm-thickness wound on mice skin and applying recombinant human epidermal growth factor (EGF, 10 MUg/g) ointment, FVIII ointment (30 IU) or the ointment base to heal the wounds. Furthermore, keratinocytes were isolated from these newborn mice and subjected to migration assay by stimulation of EGF (ng/ml), insulin (10 MUM) or vehicle. RESULTS: A new hemophilic mouse model (FVIII-/-/Nu) was constructed successfully after genotyping verified by PCR. Compared to FVIII-/- mice, FVIII-/-/Nu and Nu mice showed greater degree of wound contraction and loss of the crust. Topical treatment with EGF exhibited faster wound healing than FVIII and ointment base. Insulin treatment showed more increased migration distance than treated with EGF or vehicle. FVIII-/-/Nu mice showed greater migration than FVIII-/- and Nu mice. CONCLUSIONS: A new mouse model (FVIII-/-/Nu) for wound healing in hemophilia A was constructed, and topical treatment of insulin may be a better therapy than EGF for healing wounds in hemophilia A. PMID- 26045813 TI - Correlation between biochemical indicators of blood lipid with cerebral vascular diseases. AB - OBJECTIVE: The objective of this study was to investigate correlation of the changes in serum levels of cholesterol (chol), lipoprotein (a) (Lpa) and homocysteine (HCY) with incident cerebral infarction and cerebral hemorrhage. METHODS: Data on a total of 418 patients (318 cerebral infarction events and 100 cerebral hemorrhage cases) were analyzed in this study. Serum chol and HCY levels were tested by means of GPO-PAP. Serum Lpa levels were measured using latex agglutination turbidimetry. RESULTS: Patients with cerebral infarction showed significantly higher serum Lpa levels and anomaly ratio than those with cerebral hemorrhage (P<0.05), while no significant changes were identified for chol and HCY (P>0.05). Analyses by age indicated substantially increased Lpa concentration among cerebral infarction patients>60 years of age (P<0.05). No statistical significance was observed in other analyses carried out in the study. CONCLUSION: These results demonstrate that Lpa concentration is clearly correlated with cerebral infarction incidence. Lpa may act as an independent risk factor and could be used as a biomarker for this disease. PMID- 26045814 TI - Interaction of key pathways in sorafenib-treated hepatocellular carcinoma based on a PCR-array. AB - This study aimed to identify the key pathways and to explore the mechanism of sorafenib in inhibiting hepatocellular carcinoma (HCC). The gene expression profile of GSE33621, including 6 sorafenib treated group and 6 control samples, was downloaded from the GEO (Gene Expression Omnibus) database. The differentially expressed genes (DEGs) in HCC samples were screened using the DeltaDeltaCt method with the homogenized internal GAPDH. Also, the functions and pathways of DEGs were analyzed using the DAVID. Moreover, the significant pathways of DEGs that involved in HCC were analyzed based on the Latent pathway identification analysis (LPIA). A total of 44 down-regulated DEGs were selected in HCC samples. Also, there were 84 biological pathways that these 44 DEGs involved in. Also, LPIA showed that Osteoclast differentiation and hsa04664-Fc epsilon RI signaling pathway was the most significant interaction pathways. Moreover, Apoptosis, Toll-like receptor signaling pathway, Chagas disease, and T cell receptor signaling pathway were the significant pathways that interacted with hsa04664. In addition, DEGs such as AKT1 (v-akt murine thymoma viral oncogene homolog 1), TNF (tumor necrosis factor), SYK (spleen tyrosine kinase), and PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1 (alpha)) were the common genes that involved in the significant pathways. Several pathway interaction pairs that caused by several downregulated genes such as SYK, PI3K, AKT1, and TNF, were identified play curial role in sorafenib treated HCC. Sorafenib played important inhibition roles in HCC by affecting a complicate pathway interaction network. PMID- 26045815 TI - Primary extranodal marginal zone lymphoma of the endometrium: report of four cases and review of literature. AB - Primary extranodal marginal zone lymphoma of the endometrium (PEMZL-EM) is exceedingly rare and has not been well characterized. Herein, we study the clinicopathological, cytogenetic and molecular features of four cases, the largest case series reported to date. The median age of the four patients was 59 years. Clinical presentations included abnormal vaginal bleeding (three cases) and incidental finding (one case). There were no constitutional symptoms in any of the cases. None of the patients had evidence of lymphoma in any other anatomic sites including bone marrow. Histologically, the lymphoma was characterized by a nodular proliferation of small lymphocytes admixed with occasional immunoblasts and variable number of plasma cells, which was restricted to the endometrium in most cases. Lymphoepithelial lesions were not identified in any of the cases. All cases displayed the immunophenotype of marginal zone B-cell lymphoma. Cytogenetics and FISH studies revealed absence of characteristic chromosomal translocations. Molecular analysis demonstrated immunoglobulin heavy chain gene rearrangement in all cases, two of which were found to use IgVH3-30 gene by DNA sequencing. Three of the four patients were still alive after a median follow-up of three years. PEMZL-EM predominantly affects postmenopausal women and is characterized by distinct histological patterns, lack of specific genomic alterations, and indolent clinical course. PMID- 26045816 TI - Clinicopathological significance of wnt/beta-catenin signaling pathway in esophageal squamous cell carcinoma. AB - BACKGROUND/AIM: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors. It has been reported that Wnt signaling pathway plays an important role in Esophageal Cancer progression, metastasis and invasion. However the clinicopathological significance of Wnt2, GSK3beta, and beta-catenin in ESCC has been little reported. In the present study, the aim of this study was to investigate the clinicopathologic and prognosis roles of Wnt2, GSK3beta, and beta catenin in ESCC tissue. METHODS: 265 ESCC samples were analyzed by immunohistochemistry using Wnt2, GSK3beta, and beta-catenin antibodies. Then, correlation of Wnt2, GSK3beta, and beta-catenin expression with clinicopathological features and prognosis of ESCC patients was statistically analyzed. RESULTS: Cytoplasmic Wnt2 overexpression was detected in 55.5% (147 of 265) ESCCs, which was significantly correlated with the degree of differentiation (P=0.031). Cytoplasmic GSK3beta overexpression was detected in 7.2% (19 of 265) ESCCs, and aberrant beta-catenin expression was identified in 54.3% (144 of 265) of ESCCs. The positive rate of Wnt2 significantly increased with the malignant degree of Kazak ESCC patients. The aberrant beta-catenin expression in GSK3beta negative ESCC was significantly associated with the ethnic, tumor size, tumor location, degree of differentiation, AJCC stage, lymph node status. Furthermore, the expression of beta-catenin implicated the ethnic difference (P=0.019). In Kaplan-Meier curve analysis, no significant correlation was observed between the expression of Wnt2, GSK3beta, beta-catenin and the poor prognosis of ESCCs. CONCLUSION: The aberrant beta-catenin expression could be an adverse underlying factor in carcinogenesis and progression of ESCC. There was a different statistical signification for beta-catenin in Kazakhs to compare with Hans. PMID- 26045818 TI - Expression of vascular endothelial growth factor and basic fibroblast growth factor in extramammary Paget disease. AB - Extramammary Paget's disease (EMPD) is a special type of cancers. The etiology of the disease is still unclear. We aimed to study the expression differences of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in EMPD tissues and corresponding adjacent normal tissues. The mRNA expression was detected by RT-PCR and the protein expression was explored by immunohistochemistry. Higher immunostaining signal scores of bFGF and VEGF in EMPD tissues had been found (z=-3.827, P<0.001, z=-3.729, P<0.001, respectively). In addition, the mRNA expression of bFGF and VEGF was higher in EMPD tissues, which had been validated by RT-PCR (t=5.771, P<0.001, t=3.304, P=0.004, respectively). The VEGF and bFGF might be the key signaling proteins in angiogenesis of EMPD. How to block the VEGF and bFGF in EMPD and to destroy the blood supply of the tumor cells becomes the focus of our future research. PMID- 26045817 TI - Overexpression of CD9 correlates with tumor stage and lymph node metastasis in esophageal squamous cell carcinoma. AB - OBJECTIVE: Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer deaths worldwide. CD9 has been reported to play a critical role in cell motility, growth and metastasis of multiple cancers. The present study investigated the clinicopathological features of CD9, and its biological characteristics in ESCC. METHODS: Fifteen normal esophageal tissue specimens, fifty-three ESCC adjacent tissues and one hundred and four ESCC tissues were included in this study. Using immunohistochemistry (IHC), the expression levels of CD9 were evaluated among different samples. And its clinicopathological parameters and its prognostic factors were analyzed. Western blotting was used to measure CD9 expression and colony formation was performed to determine the effect of CD9 on cell growth in ESCC TE-1 cells. RESULTS: Compared with normal esophageal tissues and tumor adjacent tissues, CD9 expression level is significantly higher in ESCC tissues. CD9 expression correlated with tumor stage (P=0.022) and lymph node metastasis (P=0.019) in ESCC patients. Furthermore, the small interfering RNA-mediated silencing of CD9 expression in TE-1 cells resulted in increased proliferation as evidenced by increased colony number and colony size. CONCLUSION: CD9 expression is upregulated in ESCC tissues and its expression is correlated with tumor stage and lymph node metastasis in ESCC patients. CD9 suppresses the proliferation of TE-1 cells. CD9 may present a potential in tumor progression in ESCC. PMID- 26045819 TI - CD4+ cells, macrophages, MHC-I and C5b-9 involve the pathogenesis of dysferlinopathy. AB - OBJECTIVE: Dysferlin is a sarcolemmal protein that plays an important role in membrane repair by regulating vesicle fusion with the sarcolemma. Mutations in the dysferlin gene (DYSF) lead to multiple clinical phenotypes, including Miyoshi myopathy (MM), limb girdle muscular dystrophy type 2B (LGMD 2B), and distal myopathy with anterior tibial onset (DMAT). Patients with dysferlinopathy also show muscle inflammation, which often leads to a misdiagnosis as inflammatory myopathy. In this study, we examined and analyzed the dyferlinopathy-associated immunological features. METHODS: Comparative immunohistochemical analysis of inflammatory cell infiltration, and muscle expression of MHC-I and C5b-9 was performed using muscle biopsy samples from 14 patients with dysferlinopathy, 7 patients with polymyositis, and 8 patients with either Duchenne muscular dystrophy or Becker muscular dystrophy (DMD/BMD). RESULTS: Immunohistochemical analysis revealed positive staining for immune response-related CD4+ cells, macrophages, MHC-I and C5b-9 in dysferlinopathy, which is in a different mode of polymyositis and DMD/BMD. CONCLUSION: These results demonstrated the involvement of immune factors in the pathogenesis of dysferlinopathy. PMID- 26045820 TI - High expression of long non-coding RNA ANRIL is associated with poor prognosis in hepatocellular carcinoma. AB - INTRODUCTION: long non-coding RNA ANRIL (lncRNA ANRIL) has been demonstrated to play a crucial role in cancer progression. However, its effects in hepatocellular carcinoma (HCC) have not been explored. The aim of this study was to investigate the clinical significance of lncRNA NRIL in human HCC. METHODS: In this study, we determined for the first time the expression of lncRNA ANRIL in human HCC by quantitative Real-time-PCR analysis. Kaplan-Meier curves and multivariate Cox proportional models were used to study the impact on clinical outcome. Small interfering RNA (siRNA) was used to silence lncRNA ANRIL and to explore the effects of reduced lncRNA ANRIL expression on cell growth and metastasis. RESULTS: lncRNA ANRIL expression in HCC tissues was significantly higher than in the adjacent non-tumor tissues (P<0.05). The expression of lncRNA ANRIL was remarkably associated with the histologic grade and TNM stage of HCC patients (P<0.05). In addition, HCC patients with higher lncRNA ANRIL expression had significantly poorer overall survival (P<0.05). Multivariate analysis suggested that high lncRNA ANRIL expression was an independent predictor of poor prognosis (P<0.05). Moreover, in vitro assays revealed that the decreased expression of lncRNA ANRIL could suppress the cell proliferation, migration and invasion HCC cells. CONCLUSIONS: Our results suggest that lncRNA ANRIL may serve as an efficient clinical biomarker and a therapeutic target for HCC patients. PMID- 26045821 TI - Two SNPs of ATP-binding cassette B1 gene on the risk and prognosis of colorectal cancer. AB - We conducted a case-control study to investigate the role of ABCB1 C3435T and G2677T/A in the susceptibility and prognosis of colorectal cancer patients. A total of 316 patients with colorectal cancer and 316 controls were collected between January 2009 and January 2011. Genotyping of ABCB1 C3435T and G2677T/A was conducted by the methods of Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Conditional logistic regression analysis showed that subjects carrying CT and CC genotypes of ABCB1 C3435T were more frequently observed in colorectal cancer patients when compared with controls, and the adjusted ORs were 1.62 (1.05-2.52) and 2.05 (1.25-3.36), respectively. By Cox regression analysis, we found that the TT genotype of ABCB1 C3435T was significantly associated with shorter PFS and OS in patients with colorectal cancer when compared with CC genotype, with adjusted HR (95% CI) of 2.57 (1.14 6.04) and 2.54 (1.05-6.61), respectively. We found that the ABCB1 C3435T polymorphism could affect the susceptibility and clinical outcome of colorectal cancer patients. PMID- 26045822 TI - Effects of dexamethasone on aquaporin-4 expression in brain tissue of rat with bacterial meningitis. AB - Aquaporin-4 (AQP4) is the most popular water channel protein expressed in brain tissue and plays a very important role in regulating the water balance in and outside of brain parenchyma. To investigate the expression of aquaporin-4 in the rat brain tissue after dexamethasone therapy of meningitis induced by Streptococcus pneumonia, total 40 of 3-week old Sprague-Dawley rats were divided into infection group (n=30) and normal control group (n=10). The meningitis groups were infected with 1*10(7) cfu/ml of Streptococcus pneumoniae and then randomized into no treatment (untreated group, n=10), treatment with ceftriaxone (CTRX group, n=10) and treatment with dexamethasone combined ceftriaxone (CTRX+DEXA group, n=10). The normal control group was established by using saline. The rats were euthanized when they reached terminal illness or five days after infection, followed by detection of AQP4 through using immunohistochemistry and Western blot methods. Data has showed that expression of AQP4 in model group remained higher than the control and treatment group (P<0.05). AQP4 expression in CTRX+DEXA group was lower than that in CTRX group (P<0.05). There was no statistical difference between CTRX+DEXA group and the control group (P>0.05). These data suggested that Dexamethasone could down-regulate the expression of AQP4 in the brain tissue of rats with meningitis and provides evidence for the mechanism of protective effect of Dexamethasone on central neurosystem. PMID- 26045823 TI - Decreased serum microRNA-206 level predicts unfavorable prognosis in patients with melanoma. AB - BACKGROUND AND PURPOSE: MicroRNA-206 (miR-206) acts as a tumor suppressor in melanoma cell lines. However, its clinical significance remains unclear. The aim of this study was to detect the serum level of miR-206 in patients with melanoma and to determine the feasibility of using it as a noninvasive prognostic biomarker. METHODS: Expression levels of miR-206 in serum samples from 60 patients with melanoma and 30 healthy controls were detected by real-time quantitative polymerase chain reaction (q-PCR). RESULTS: Expression levels of miR 206 in serum samples from patients with melanoma were significantly lower than those in healthy controls (P<0.001). In addition, low serum miR-206 level was more frequently observed in patients with two or more metastatic sites (P=0.02). Its serum level was also significantly associated with the response to treatment (P=0.01). Moreover, melanoma patients with low serum miR-206 levels had higher clinical stage than those with high serum miR-206 levels (P<0.001). Furthermore, melanoma patients with low serum miR-206 level had a dramatically shorter 5-year overall and disease-free survival than those with high serum miR-206 level (both P=0.001). Multivariate analysis also identified the serum miR-206 level as an independent marker for both 5-year overall and disease-free survivals (both P=0.01) in patients with melanoma. CONCLUSIONS: Our results offer the convincing evidence that miR-206 may be implicated in aggressive progression of melanoma. More importantly, the serum level of miR-206 may be a noninvasive prognostic biomarker for the patients with melanoma. PMID- 26045824 TI - High expression of E-cadherin in pleural effusion cells predicts better prognosis in lung adenocarcinoma patients. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) is of great importance in tumor metastasis. Our previous study demonstrates that epithelial phenotype is related to epidermal growth factor receptor (EGFR) mutation and the sensitivity of EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) patients. However, the role of EMT phenotype in malignant pleural effusions in predicting prognosis is unknown in lung adenocarcinoma patients. METHOD: Pleural effusions of lung adenocarcinoma patients were collected and made into cell block (CB). EGFR mutation was detected using amplification refractory mutation system (ARMS) PCR method and H-score system was applied to evaluate the staining intensity of EMT marker and tumor cell ratio. RESULTS: Forty-three CB samples, including 22 samples before any treatment (baseline, group 1) and 21 with disease progression (group 2) after first-line chemotherapy, were enrolled in this study. The expression of N-cadherin and vimentin were low in the CB tumor cells. There was no significant difference in the tumor cell radio and E-cadherin expression in the two groups. E-cadherin expression had no association with sex, age and smoking status and also patient response in both the two groups. However, high E-cadherin expression was related to EGFR mutation (P=0.032) and long progression-free survival (PFS) (P=0.015) in group 1 but not group 2 samples. CONCLUSION: E-cadherin expression in CB samples was associated with EGFR mutation status and patient prognosis in lung adenocarcinoma patients in first-line chemotherapy. PMID- 26045825 TI - Osteoinductive factor is a novel biomarker for the diagnosis of early diabetic nephropathy. AB - BACKGROUND: Microalbuminuria is the earliest clinical sign of diabetic nephropathy (DN). However, earlier markers as a diagnostic tool for DN was required for the invalid of microalbuminuria in some cases. Osteoinductive factor (OIF) was known to be an essential component of the normal vascular matrix. We aimed to research the relationship between DN and OIF, and discussed the availability of the serological markers for earlier stage of DN. METHOD: One hundred twenty Chinese subjects, who included patients with type 2 diabetes mellitus (T2DM), DN with microalbuminuria, and DN with macroalbuminuria, as well as healthy controls, were enrolled in this study. Serum OIF levels were examined by ELISA and other clinical biochemical parameters were tested based on standard methods. RESULTS: Our results indicated that, serum OIF levels were significantly increased in DN subjects compared with healthy and T2DM subjects (P<0.05 respectively). However, no significant changes in serum OIF levels were found between T2DM and healthy subjects. Furthermore, serum OIF had negative correlation with estimated glomerular filtration rate (eGFR) and positive correlation with blood urea nitrogen(BUN) and creatinine. ROC curve analysis showed that serum OIF level was a good sensitive and specificity marker for microalbuminuria and early renal damage with sensitivity of 86.7% and specificity of 95%, as well as for macroalbuminuria and damage progress with sensitivity of 90% and specificity of 95%. CONCLUSION: OIF may be an indicator of the earlier stage DN in subjects with T2DM. Understanding the exact mechanism of up-regulated OIF in subjects with DN requires further study. PMID- 26045826 TI - ABCA1 mRNA expression and cholesterol outflow in U937 cells. AB - OBJECTIVE: To investigate the oxidized low density lipoprotein (oxLDL) on U937 cell ATP-binding cassette transporter A1 (ABCA1) mRNA expression and cholesterol efflux situation. METHODS: Human U937 cells were incubated with gradient concentrations of oxLDL (0, 25, 50, 75, 100, 125 mg/L), and then dyed by oil red O to estimate the content of intracelluar lipid and detect the expressing quantity of ABCA1 mRNA by Real-time Fluorescence quantitative PCR simultaneously. Calculating the cholesterol efflux rates by using the scintillation counter to detect the amount of H(3)-cholesterol in each well cell culture plate and medium. RESULTS: Real-time Fluorescence quantitative PCR analysis showed that the expression levels of ABCA1 mRNA in monocytes were lower than basal line when not intervened with oxLDL, and increased drastically with oxLDL stimulation, significant difference compared with controls (P<0.01), and reached the highest level at oxLDL 50 mg/L, nevertheless, continuously increasing the concentration of oxLDL above 50 mg/L, the expression decreased. So is the outflowing rate of intracelluar lipid. Oil red O dyeing results also suggested that celluar lipid content was the highest when intervened with 125 mg/L oxLDL, and increased most obviously at 50 mg/L oxLDL. Cholesterol outflow result also demonstrated that cholesterol outflow rate related with the ABCA1 mRNA expressing quantity. CONCLUSION: With the increase of intervening concentration of oxLDL on U937cells, the exprssion of ABCAl mRNA represented that rising before 50 mg/L oxLDL, and then decreasing, reaching the top point at 50 mg/L oxLDL. So was the change in the outflowing rate of intracelluar lipid. PMID- 26045827 TI - Renal mucinous tubular and spindle cell carcinoma: report of four cases and literature review. AB - Mucinous tubular and spindle cell carcinoma of the kidney (MTSCC-K) is an unusual renal tumor. It is important to increase the recognition of the clinicopathological features of MTSCC-K and improve its clinical and differential diagnosis. This report described four cases of MTSCC-K with clinical, imaging, and pathological examination and showed that the tumor boundaries of MTSCC-K were clear, and tumor cells arranged into tubules and cord-like beams, between which was lightly stained myxoid stroma. The tumor cells were smaller and cube- or oval shaped, with single small eosinophilic nucleoli, low-grade nuclei, and little nuclear fission. The myxoid stroma was scattered around lymphocytes and plasma cells. Immunohistochemical markers including CK7, CD117, EMA (epithelial membrane antigen), vimentin, and CK8/18, showed positive expression in tumor cells, but the tumor cells were negative for CD10 and villin. The proliferation index of Ki 67 was 5-10%. Since MTSCC-K is a rare low-grade malignancy, with unique histological and immunohistochemical characteristics, it is important for clinicians and pathologists to have a defined awareness of this tumor type in order to decrease the rate of misdiagnosis. PMID- 26045828 TI - TNF-alpha-308G/A polymorphism associated with TNF-alpha protein expression in patients with diabetic nephropathy. AB - AIMS: This study was to clarify the regulated effects of TNF-alpha -308G/A polymorphism on TNF-alpha and investigate the relationship of -308G/A polymorphisms with diabetic nephropathy (DN) susceptibility. METHODS: 86 DN patients and 94 healthy individuals were enrolled in our study. Polymerase chain reaction-sequence specific primer (PCR-SSP) detection technology was used to testify single nucleotide polymorphism (SNP) of TNF-alpha gene. Enzyme-linked immunosorbent assay (ELISA) was used to measure the content of TNF-alpha protein. Odds ratio (OR) with 95% CI were used to evaluate the association of TNF-alpha 308G/A polymorphism and DN susceptibility. RESULTS: The level of TNF-alpha protein was much higher in DN patients compared to that of controls (P<0.05). For TNF-alpha -308G/A, G/A genotype could increase the risk for DN (OR=2.15, 95% CI=1.08-4.30). Moreover, a allele frequency was found higher in cases compared with controls, which suggested that A allele served as an genetic-susceptibility factor for DN (OR=1.89, 95% CI=1.10-3.26). Further analysis indicated that level of TNF-alpha for individuals with mutant genotype (GA and AA) were higher than that of individuals with wild genotype (P<0.05). However, AA genotype showed no effects on DN susceptibility (OR=2.08, 95% CI=0.56-7.33). CONCLUSION: TNF-alpha 308G/A polymorphism was associated with expression level of TNF-alpha and served as an genetic-susceptibility factor for DN. PMID- 26045829 TI - Polymorphisms in ERCC1 and XPF gene and response to chemotherapy and overall survival of non-small cell lung cancer. AB - We conducted a perspective study to assess the association between ERCC1 and XPF polymorphisms and response to chemotherapy and clinical outcome of NSCLC receiving chemotherapy. Between May 2009 and May 2011, a prospective study was conducted on 240 NSCLC cases. Genotypes of ERCC1 (rs11615, rs3212986 and rs2298881) and XPF (rs2276465 and rs6498486) were performed by Polymerase Chain Reaction Restriction Fragment Length Polymorphism (PCR-RFLP) assay. By conditional logistic regression analysis, patients carrying AA genotype of ERCC1 rs11615 showed more CR+PR to chemotherapy when compared with GG genotype, and the adjusted OR (95% CI) was 2.73 (1.21-6.18). By Cox regression analysis, AA genotype of ERCC1 rs11615 was associated with longer overall survival of NSCLC, and the adjusted HR (95% CI) was 0.38 (0.14-0.96). In conclusion, our study found that ERCC1 rs11615 polymorphism can influence the chemotherapy response and overall survival of NSCLC patients receiving cisplatin-based chemotherapy. PMID- 26045830 TI - PPARG, AGTR1, CXCL16 and LGALS2 polymorphisms are correlated with the risk for coronary heart disease. AB - PURPOSE: Our study was designed to explore the interaction between genes of PPARG, AGTR1, CXCL16 and LGALS2 and further investigate the association between genes polymorphisms and coronary heart disease (CHD). METHODS: 90 CHD patients and 80 healthy individuals were enrolled in our study. Gene chip technology was used for checking four single nucleotide polymorphisms (SNPs) (PPARG rs1152002, AGTR1 rs5186, CXCL16 rs3744700 and LGALS2 rs7291467). MDR software was used to analyze gene-gene interactions. Odds ratio (OR) with 95% confidence interval (CI) were employed to evaluate the association of genes and CHD risk. RESULTS: Genotypes and alleles distribution in case and control groups showed significant difference (P<0.05). And there exists interaction among genes. The model of PPARG*CXCL16 showed effects on the occurrence of CHD (OR=2.92, 95% CI=1.44-5.94). Meanwhile, the PPARG*AGTR1*CXCL16*LGALS2 model was associated with CHD susceptibility (OR=3.97, 95% CI=2.01-7.84). Moreover, we found that PPARG*LGALS2*CXCL16, was the best interaction model and it could significantly increase the risk for CHD (OR=3.37, 95% CI=1.71-6.63). CONCLUSION: PPARG rs1152002, AGTR1 rs5186, CXCL16 rs3744700 and LGALS2 rs7291467 polymorphisms may be closely related to the development of CHD. Moreover, there exist gene-gene interactions among these susceptibility genes. PMID- 26045831 TI - Effects of dexmedetomidine pretreatment on heme oxygenase-1 expression and oxidative stress during one-lung ventilation. AB - PURPOSE: This study aimed to explore effects of dexmedetomidine pretreatment on heme oxygenase-1 (HO-1) expression and oxidative stress during one-lung ventilation (OLV) in lung cancer patients. METHODS: Fifty patients with lung carcinoma (ASA I-II, 40-65 years old, body mass index [BMI]<30 kg/m2) undergoing pulmonary lobectomy were enrolled. They were divided randomly into two equal groups before anaesthesia induction to receive either intravenous injection of 1 MUg/kg dexmedetomidine for 20 min (Dexmedetomidine) or not (Control). RESULTS: The results showed no difference in heart rate (HR), mean arterial pressure (MAP) and bispectral index (BIS) between the two groups, as well as liquid intake and output volume (LIO), duration of OLV and time from surgery beginning to excision of pathological tissues (P>0.05). Levels of tumor necrosis factor (TNF-alpha) and malondialdehyde (MDA) in Dexmedetomidine group were lower than that of Control at OLV 60 and 90 (P<0.05). Superoxide dismutase (SOD) activity and the expression level of HO-1 were higher in Dexmedetomidine group than in Control (P<0.05). CONCLUSIONS: Dexmedetomidine pretreatment could upregulated expression of HO-1 in lung tissue and reduce oxidative stress and inflammation during OLV. Thus dexmedetomidine played a role in protecting lung injury by promoting HO-1 expression. PMID- 26045832 TI - Expression of E-cadherin and vimentin in oral squamous cell carcinoma. AB - The aim of the study is to determine the levels of E-cadherin, vimentin expression in tumor tissues from patients with oral squamous cell carcinoma (OSCC), and the relationship between the expression of E-cadherin, vimentin and epithelial-mesenchymal transition, in order to explore its values for predicting the invasion and metastasis of oral squamous cell carcinoma, short survival of patients in many types of cancer. E-cadherin and vimentin expression of 10 benign and 42 OSCC tumor tissues was examined by immunohistochemical staining. E cadherin is positively expressed in normal oral mucosa epithelium, but vimentin expression is not found in normal oral mucosa epithelia; the E-cadherin and vimentin were expressed in 26 of 42 (61.9%) and 16 of 42 (38.1%), respectively. No statistically difference was found for E-cadherin and vimentin expression in patients with different age, gender and tumor location, E-cadherin and vimentin expression was significantly associated with lymph node metastasis and tissue location (P<0.05); E-cadherin expression was also significantly associated with tumor stage (P<0.05); there are significantly difference between infiltrative margin and central area in patients with oral squamous cell carcinoma for E cadherin and vimentin positive expression (P<0.05). E-cadherin and vimentin positive expression was associated with tumor metastasis of oral squamous cell carcinoma. Our study preliminarily confirmed that EMT phenomenon is existed during the development of oral squamous cell carcinoma. Co-evaluation of E cadherin and vimentin might be a valuable tool for predicting OSCC patient outcome. PMID- 26045833 TI - Ultrasound-guided fine-needle aspiration of thyroid nodules: does the size limit its efficiency? AB - PURPOSE: The management criterion of thyroid nodules is to evaluate the risk of malignancy, based on cytological examinations. Ultrasound-guided fine-needle aspiration biopsy (US-FNAB) has a highly diagnostic value for thyroid nodules. The aim of this study was to compare the efficacy of US-FNAB for thyroid nodules with different sizes. MATERIAL AND METHODS: From August 2013 to November 2013, 344patients with thyroid nodules who had undergone US-FNAB were divided into three groups, according to the largest diameter of their nodules (group A, <=5.0 mm; group B, 5.1-10.0 mm; group C, >10.0 mm). All the nodules were subsequently verified by histology or follow-up findings. The accuracy, sensitivity, specificity, positive predictive value, negative predictive value of aspiration cytology in each group was compared. RESULTS: Among 344 thyroid nodules diagnosed by cytology, the cytology was classified as nondiagnostic or unsatisfactory for 53 (15.4%) lesions, benign for 144 (41.9%) lesions, atypia of undetermined significance or follicular lesion of undetermined significance for 20 (5.8%) lesions, follicular neoplasm or suspicious for a follicular neoplasm for 26 (7.6%) lesions, suspicious for malignancy for 36 (10.5%) lesions, malignant for 65 (18.9%) lesions. There were 243 benign and 101 malignant nodules confirmed by the pathological or follow-up ultrasound. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were confirmed to be 87.5% (14/16), 92.5% (37/40), 91% (51/56), 82.3% (14/17), and 94.8% (37/39) in group A; 92.3% (36/39), 96.9% (94/97), 95.5% (130/136), 92.3% (36/39), and 96.9% (94/97) in group B; and 91.3% (42/46), 93.4% (99/106), 92.7% (141/152) 85.7% (42/49), and 96.1% (99/103), in group C. There were no statistical differences in accuracy, sensitivity, specificity, false positive accuracy, false negative rate of fine needle aspiration of thyroid nodules with different sizes (P>0.05). CONCLUSION: US-FNAB has similar diagnostic efficacy to thyroid nodules with different sizes. PMID- 26045834 TI - Association between XRCC1 and XRCC3 gene polymorphisms and risk of thyroid cancer. AB - We conducted a case-control study to examine the role of genetic polymorphisms in XRCC1 at codons 194 (Arg>Trp), 280 (Arg>His) and 399 (Arg>Gln) and XRCC3 at codon 241 (Thr>Met) in the risk of TC. This study included 276 consecutive primary TC patients and 552 control subjects. The genotypes of XRCC1 at codons 194 (Arg>Trp), 280 (Arg>His) and 399 (Arg>Gln) and XRCC3 at codon 241 (Thr>Met) were analyzed by PCR-RFLP. TT and CT+TT genotypes of XRCC1 194 (Arg>Trp) were significantly associated with increased risk of TC, and CC and TC+CC genotypes of XRCC3 241 (Thr>Met) revealed a significant associated with the TC risk. We only found that XRCC1 194 (Arg>Trp) and XRCC3 241 (Thr>Met) polymorphisms had interaction with smoking and drinking habits. In conclusion, the current study suggests that XRCC1 194 (Arg>Trp) and XRCC3 241 (Thr>Met) polymorphisms may be associated with TC risk in a Chinese population, especially in smokers and drinkers. PMID- 26045835 TI - Association between COX-2 polymorphisms and non-small cell lung cancer susceptibility. AB - AIM: To explore the association between COX-2 polymorphisms and non-small cell lung cancer (NSCLC) susceptibility. METHODS: We collected fasting peripheral venous blood from 60 cases with NSCLC and 62 healthy controls through physical examinations, and applied PCR-RFLP to analyze COX-2 polymorphisms of two groups. RESULTS: With respect to detecting COX-2 rs689466 and rs5275 polymorphisms, the distribution frequency of mutant genotype AA of COX-2 rs689466 in case group was higher than that in control group, which possessed significant difference between two groups (P<0.05). Carriers with AA genotype were 4.05 times at risk of NSCLC than those with GG genotype (P = 0.04, OR=4.05, 95% CI=1.14-14.43). The distribution of mutant genotype CC of COX-2 rs5275 was different between two groups, and carriers with genotype CC were at 5.70 times higher risk of NSCLC than those with genotype TT. After corrected by sex, gender, smoking and drinking factors, AA genotype of COX-2 rs689466 and CC genotype of COX-2 rs5275 still contributed to increased risk of NSCLC (OR=4.22, 95% CI=1.10-16.17, OR=6.95, 95% CI=1.27-38.11). After analyzed of linkage disequilibrium (LD) and haplotypes of alleles in two SNPs, the distribution frequency of A-C haplotype in case group was higher than that in control group, with significant difference between two groups (P<0.05). After corrected by sex, gender, smoking and drinking factors, statistical difference was still found in the total distribution of A-C haplotype between two groups (P=0.03, OR=6.11, 95% CI=1.16-32.2). CONCLUSIONS: COX-2 rs689466 and rs5275 polymorphisms may be related to NSCLC susceptibility. And A-C haplotype might be a susceptibility haplotype for NSCLC. PMID- 26045836 TI - Haplotypes of RHO polymorphisms and susceptibility to age-related macular degeneration. AB - OBJECTIVE: To investigate whether haplotypes of rhodopsin (RHO) polymorphisms including rs7984, rs2855552, rs2855557 and rs2410 were associated with age related macular degeneration (AMD) risk in Chinese Han population. METHODS: Genotypes of rs7984, rs2855552, rs2855557 and rs2410 were detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 186 cases and 196 healthy controls. Then, the haplotypes were established with Haploview 4.2 software. And the effects of clinical charactersitics on the frequency of GTTG haplotype were also analyzed. Odds ratios (ORs) with 95% confidence interval (95% CI) were utilized to assess the relationship of haplotypes and genotypes of RHO polymorphisms with susceptibility to AMD. RESULTS: Genotype distribution of all polymorphisms in control group were all in agreement with Hardy-Weinberg equilibrium (HWE) (P>0.05). In the analysis, we found that mutant alleles of rs7984 and rs2855557 were both associated with increased risk of AMD. For genotype analysis, rs7984 AA and rs2855557AA, rs2410GG genotypes all could increase the risk for AMD (OR=1.905, 95% CI=1.143-3.174; OR=2.226, 95% CI=1.261-3.932; OR=2.073, 95% CI=1.105-3.888). However, rs2855552 showed no effects on the onset of AMD. Compared with GTTA, the haplotypes of GGTG, ATAA and GTTG were all related with AMD susceptibility. Further analysis suggested that age, hypertension and hyperlipidemia history play important roles in the frequency alteration of GTTG haplotype. CONCLUSION: RHO polymorphisms (rs7984, rs2855557 and rs2410) and haplotypes may confer remarkable susceptibility to AMD. Further investigation showed that gene and environmental factors may work together in the pathogenesis of AMD. PMID- 26045837 TI - Association of single nucleotide polymorphisms of DNA repair gene and susceptibility to pancreatic cancer. AB - We conducted a case-control study to assess the XRCC4 genes polymorphism and development of pancreatic cancer. A case-control study including 248 cases and 496 controls was conducted in a Chinese population. Genotypes of XRCC4 rs2075685, rs10040363, rs963248 and rs1805377 were determined using Polymerase Chain Reaction combined with a restriction fragment length polymorphism (PCR-RFLP) assay (Applied Biosystems, Foster City, CA, USA). Pancreatic cancer cases were more likely to have a history of diabetes, a higher BMI, family history of cancer and a habit of alcohol drinking when compared with control. Conditional logistic regression analysis showed that individuals carrying TT genotype of XRCC4 rs2075685 was associated with increased risk of pancreatic cancer when compared with GG genotype, and the OR (95% CI) was 1.62 (1.04-2.52). Individuals with GT+TT genotype of XRCC4 rs2075685 were significantly associated with increased risk of pancreatic cancer in those with ever tobacco smoking habit, and the OR (95% CI) was 1.77 (1.07-2.98). In conclusion, our results suggest that XRCC4 rs2075685 polymorphism plays an important role in the risk of pancreatic cancer in a Chinese population, especially in tobacco smokers. PMID- 26045838 TI - Association of complement factor H gene polymorphisms with age-related macular egeneration susceptibility. AB - OBJECTIVE: This study was aimed to confirm whether I62V and Y402H polymorphisms of complement factor H (CFH) were risk factors for age-related macular degeneration (AMD). METHOD: 109 AMD patients and 165 AMD-free controls were enrolled in the study. The I62V and Y402H polymorphisms were analyzed by polymerase chain reaction-restriction fragment length of polymorphism (PCR-RFLP). Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by the X2 test to assess the relationship of I62V and Y402H polymorphisms with AMD risk. Analysis of haplotype and stratification by age and smoking status was conducted as well. RESULTS: AA genotype and A allele of I62V polymorphism was significantly associated with increased risk for AMD (OR=3.75, 95% CI=1.70-8.30; OR=1.64, 95% CI=1.14-2.36). For Y402H polymorphism, CT genotype showed strong effects on the occurrence of AMD (OR=2.10, 95% CI=1.04-4.27). Moreover, C allele was also a risk factor for AMD (OR=1.95, 95% CI=1.02-3.72). The haplotypes analysis suggested that the risk for AT haplotype carriers was high, compared with GT haplotype (OR=3.91, 95% CI=2.58-5.94). In addition, we found that smoking status could affect the genotype distribution of Y402H polymorphism (P<0.05). CONCLUSIONS: Our results revealed that CFH polymorphisms I62V and Y402H might be associated with the susceptibility to AMD in Chinese population. PMID- 26045839 TI - Association between ERCC5 gene polymorphisms and breast cancer risk. AB - We conducted a case-control study to evaluate the association between ERCC5 polymorphism and breast cancer risk. 325 breast cancer patients and 325 controls were recruited in our study between January 2011 and March 2014. ERCC5 rs1047768, rs2094258, rs2296147, rs751402 and rs873601 polymorphisms were genotyped, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. By logistic regression analysis, we found that individuals with AA genotype of rs2094258 was associated with increased risk of breast cancer when compared with wide-type genotype, and the OR (95% CI) was 1.80 (1.12-2.92) for AA genotype. Individuals with GA+GG genotype of rs2094258 were significantly correlated with increased risk of breast cancer in tobacco smokers, and the OR (95% CI) was 7.35 (1.21-47.20). In conclusion, our study indicated that ERCC5 rs2094258 polymorphism may contribute to the risk of breast cancer. PMID- 26045840 TI - Polymorphisms in TP53 are associated with risk and survival of osteosarcoma in a Chinese population. AB - Osteosarcoma (OS) is the most frequent histological form of primary bone cancer in adolescence. TP53 is a tumor suppressor gene which is essential for regulating cell division and preventing tumor formation. The purpose of this study is to examine whether genetic mutations in the TP53 gene are associated with OS risk and survival in a Chinese population. Five polymorphisms in the TP53 gene were selected in a case-control study, including 210 OS patients and 420 cancer-free controls. We found that subjects carrying rs12951053 CC genotype and rs1042522 GG genotype were significantly associated with risk of OS [odds ratio (OR)=1.68, 95% confidence intervals (CI): 1.05-2.68; OR=1.89, 95% CI: 1.16-3.07] compared with subjects carrying the common genotypes. Results of haplotype analysis also showed that A-G-G-A-C haplotype (rs12951053, rs1042522, rs8064946, rs9895829 and rs12602273) conferred significant decreased risk of OS (OR=0.37, 95% CI: 0.19 0.72) compared with A-C-G-A-C haplotype. Besides, rs1042522 was an independent prognostic factor for OS with hazard radio (HR)=1.94 (95% CI: 1.03-3.65) in GG genotype than in CC genotype. Our data suggest that genetic mutations in the TP53 gene are associated with risk and survival of OS in Chinese population. PMID- 26045841 TI - Incidence of anticardiolipin antibodies and lupus anticoagulant factor among women experiencing unexplained recurrent abortion and intrauterine fetal death. AB - The aim of this research study was to estimate anticardiolipin (IgG & IgM) antibodies (aCL) and lupus anticoagulant (LA) factor in patients of recurrent unexplained pregnancy loss and intrauterine fetal deaths (IUFD). 82 women were selected for this study by virtue of having more than two consecutive unexplained pregnancy losses in their first trimester and were referred by the department of Obstetrics and Gynecology, King Saud Medical City Hospital, Riyadh, KSA. All patients had gone through a standardized investigation sequence. Lupus anticoagulants and Anticardiolipin antibodies (IgM and IgG) were detected in the serum by the enzyme linked immunosorbent assay method. To check the significance of aCL and LA, two-tailed t-test was done. Non parametric data was calculated either by Chi-Square test or Fischer exact test when relevant. Total 82 females grouped as 52 cases of recurrent (>=2) mainly first and second trimester miscarriage and 30 cases of recurrent (>=2) late intrauterine fetal death. Lupus anticoagulants was observed in twenty one (21) cases (25.6%) while anticardiolipin antibodies IgM and or IgG positive cases were estimated in forty four (44) cases (53.65%). The prevalence of APS in both studied group was thirty five (35) cases (42.68%). Antiphospholipid antibodies are calculated as the most important reason for recurrent abortion. The patients with unexplained recurrent pregnancy loss must be advised to go for a screening test for all this aPL antibodies. PMID- 26045842 TI - Impact of 63-bp deletion and single-base mutation in mpt64 gene on M.tb diagnosis. AB - After previous research, which selected 180 clinical isolates of the Mycobacterium tuberculosis complex (MTC) from patients in China and performed comparative sequence analysis of the mpt64 gene after amplification and found the polymorphisms of the mpt64 gene in MTC, in order to further investigate the impact of polymorphism of antigen MPT64 on the diagnostic accuracy of MPT64-based test kit, testing on 180 strains by MPT64-based immunochromatographic test (ICT) was conducted. As a result, 180 strains were detected positive except 8 isolates were negative. First, 8 strains harbored 63-bp deletion had a major impact on the biological function of mpt64 and led to the negative results; however, 4 isolates had nonsynonymous nucleotide mutation which led to rare changes in protein structure, did not led to functional change as those 4 strains detected positive by ICT; one strain with a single-base insertion, as the insertion occurred in the last amino acid codon that did not affect T-cell epitopes in MPT64, detected positive by this method. These demonstrate that different mutations in mpt64 gene had impact on diagnostic test kit inconsistently, this was different with some previous studies. And the performance of the mpt64-based diagnostic test kit was still very well with a sensitivity of 95.6% (172/180). PMID- 26045843 TI - Combined effect of tnf-alpha polymorphisms and hypoxia on steroid-induced osteonecrosis of femoral head. AB - OBJECTIVE: Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine, some studies reported that TNF-alpha gene plays important role in the pathogenesis of SONFH. And the polymorphisms of TNF-alpha were presented as risk factors for steroid-induced osteonecrosis of the femoral head (SONFH). Meanwhile, various environment factors involve in the pathogenesis of SONFH. Our study aimed to investigate the interaction effect of TNF-alpha polymorphisms and hypoxia factor on SONFH. METHODS: 120 patients with SONFH and 100 healthy people, matched with the cases on age and sex, participated in this study. DNA was extracted from all participants. According to previous studies, genotyping of TNF-alpha polymorphisms (rs1800629, rs1799964 and rs1800630) was tested with the method of PCR-RDB (Reverse Dot Blot). Environmental factors were also chose. Logistic regression analysis was used to analyze the interaction between TNF-alpha polymorphisms and environment factors on SONFH. RESULTS: The polymorphisms of rs1800629 and rs1800630 were significantly associated with SONFH (OR: 3.70, 9.93). Patients with hypoxia history were found higher (65.00%) compared with the healthy controls (43.00%). For the person with hypoxic history, GG and AG+AA genotypes of rs1800629 could increase their risk to suffer SONFH (OR: 2.12, 3.78). If the patients with the variant genotypes of rs1800630 experienced hypoxia state, then the risk for SONFH increased 2.41 folds. CONCLUSION: We concluded that the onset of SONFH was influenced by TNF-alpha and hypoxia history. There existed strong interaction between TNF-alpha and hypoxia history. PMID- 26045844 TI - Association of fibronectin Msp iv polymorphism and diabetic nephropathy susceptibility in Chinese Han population. AB - AIM: Our study was aimed to study the distributional characteristics of fibronectin (Fn) Msp iv polymorphism in Chinese Han Population and investigate its association with susceptibility and clinicopathologic features of diabetic nephropathy (DN). METHODS: Polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were applied to testify Fn Msp iv genotypes among 108 patients with DN and 86 healthy individuals. Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of Fn Msp iv polymorphism and onset risk and clinicopathologic stages of DN. RESULTS: The comparison of genotype and allele distribution in normal, micro and massive proteinuria groups showed that genotype and allele distribution in massive proteinuria group showed great differences, compared with those of control group (P=0.006, P=0.004). Further analysis on the association of Fn Msp iv polymorphism and occurrence of abnormal proteinuria suggested that DD genotype and D allele appeared to be a risk factor for abnormal proteinuria (OR=3.553, 95% CI=1.278 9.875; OR=2.442, 95% CI=1.378-4.327). Then, we analyzed the effects of Fn Msp iv polymorphism on the clinicopathologic stages of DN, the result showed that DD genotype showed great effect on the occurrence of early-onset DN (OR=7.500, 95% CI=1.691-33.272). For the DN patients with D allele, the risk for early-onset DN was increased 3.445 folds (OR=4.445, 95% CI=1.869-33.10.574). CONCLUSION: Fn Msp iv polymorphism appeared to be associated with DN susceptibility. PMID- 26045845 TI - StIL-17 gene polymorphisms in the development of pulmonary tuberculosis. AB - We conduct a case-control study to explore the possible association between IL-17 gene polymorphisms and development of TB. METHODS: The study population comprised 428 TB subjects and 428 control subjects between January 2013 and June 2014. Genotyping analyses of IL-17A rs2275913 and rs3748067 and IL-17F rs763780 and rs9382084 were analyzed using polymerase chain reaction-restriction fragment length of polymorphism (PCR-RFLP). RESULTS: The TB cases were more likely to have a habit of smoking when comparing with controls. By conditional logistic regression analysis, individuals carrying CC genotype of rs763780 were more likely to have a significantly increased risk of TB when compared with TT genotype. The OR (95% CI) for CC genotype of rs763780 was 2.98 (1.58-5.92). CONCLUSION: In conclusion, we suggest that rs763780 play a critical role in the etiology of TB. These findings could be helpful in identifying individuals at increased risk for developing TB. PMID- 26045846 TI - Effects of intra-abdominal pressure on adrenal gland function and morphology in rats. AB - Intra-abdominal hypertension and abdominal compartment syndrome (IAH/ACS) are life-threatening conditions and caused by several clinical status. Although there is insufficient data regarding its effects on adrenal glands. This study aimed to identify whether elevated intra-abdominal pressure (IAP) caused any alteration on the morphology and function of adrenal glands in a rat model. Twenty four Sprague Dawley male rats were included in the study. Animals were allocated into 4 groups. IAP was elevated to 15 mmHg for one hour and four hours in group 2 and 4. Group 1 and 3 were sham groups. Blood samples were taken for the assessment of plasma adrenaline, noradrenaline, and corticosterone levels and adrenalectomies were performed to evaluate apoptosis. Blood adrenaline, noradrenaline and corticosterone levels were significantly higher in the study groups compared with the sham groups. However, there were no significant changes in apoptotic index scores in the study groups as compared to sham groups. These results support that increased IAH leads to discharge of catecholamine and corticosterone from the adrenal glands. Failure to demonstrate similar changes in apoptotic index score may be concluded as apoptosis is not a leading pathway for impairment of adrenal glands during IAH period. PMID- 26045847 TI - Role of CD11b+Gr-1+ myeloid cells in AGEs-induced myocardial injury in a mice model of acute myocardial infarction. AB - AIMS: Polymorph neutrophils are the predominant inflammatory cells and play a crucial role on the pathogenesis of myocardial injury at the early stage of acute myocardial infarction (AMI). However, the precursors and the differentiation of neutrophils are not fully understood. Here we explored the role of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) on myocardial injury in the absence and presence of advanced glycation end-products (AGEs) in a mice model of AMI. METHODS AND RESULTS: Male C57BL/6J mice were selected. Fluorescent actived cell sortor (FACS) data demonstrated significantly increased CD11b+Gr-1+ MDSCs both in peripheral blood circulation and in the ischemic myocardium at 24 hours post AMI. Quantitative-real-time PCR results also revealed significantly upregulated CD11b and Ly6G mRNA expression in the ischemic myocardium. AGEs treatment further aggravated these changes in AMI mice but not in sham mice. Moreover, AGEs treatment also significantly increased infarction size and enhanced cardiomyocyte apoptosis. The mRNA expression of pro-inflammatory cytokine IL-6 and iNOS2 was also significantly increased in AMI + AGEs group compared to AMI group. CONCLUSION: These data suggest enhanced infiltration of MDSCs by AGEs contributes to aggravated myocardial injury in AMI mice, which might be one of the mechanisms responsible for severer myocardial injury in AMI patients complicating diabetes. PMID- 26045848 TI - Metanephric adenofibroma in a 10-year-old boy: report of a case and review of the literature. AB - We reported a case of metanephric adenofibroma in a 10-year-old boy to describe the clinical, radiologic, and pathologic features and discuss its treatment and differential diagnosis. Nephrectomy was performed for the patient; final histopathologic evaluation was that of a metanephric adenofibroma. Epithelial and stromal elements were both positive for WT-1, Vimentin, PAX2, and the epithelial tumor cells were also positive for S100, AE1/AE3, PAX8, CK8/18, EMA and a few cells were positive for CK7. Larger vessel wall components were positive for SMA, Des, caldesmon while capillary components were positive for CD10, CD31, and CD34. CA-9, alpha-inhibin and CD-56 were negative in the neoplasm. The Ki-67 labeling index was <1%. Metanephric adenofibroma is a rare benign renal tumor; the diagnosis of it relies on pathology and immunohistochemistry. As its rarity, there is no standard treatment for this disease. The majority of patients underwent nephrectomy and had good prognosis, as it is a benign neoplasm. PMID- 26045849 TI - Concomitant non-Hodgkin's lymphoma in colon and liver: report of a rare case and review of literature. AB - A 58-year-old male patient was admitted with right upper abdominal pain. Initial hematologic evaluation revealed mildly elevated serum carcinoembryonic antigen and carbohydrate antigen (CA) 19-9 tests, while an abdominal CT-scan showed a circumferential mass along the distal ascending colon and the right flexure of colon, simultaneously a liver lesion in segment 8 is considered metastases from colorectal. colonoscopic examination revealed a circumferential growth tumor in the right flexure of colon and the colonoscopy can not reach the proximal of the tumor. We performed a right hemihepatoectomy and a right hemicolectomy associated with loco-regional lymphadenectomy. Histological examination showed diffuse large B-cell lymphomas in resected right colon as well as liver tumors. The patient received six courses of chemotherapy with CHOP-based regimens. At 14-month follow up before this report, the patient is still alive and free of disease. PMID- 26045850 TI - Cystic synovial sarcoma of the pleura mimicking a cystic thymoma: a case report illustrating the role of decreased INI-1 expression in differential diagnosis. AB - Less than 40 cases of primary pleural synovial sarcoma (SS) have been reported to date. Furthermore, only three cases of cystic SS have been documented in the English literature, including cases originating from sites other than the pleura. Herein, we present an exceedingly rare case of cystic SS originating from the mediastinal side of the visceral pleura in an asymptomatic 47-year-old man, which was detected during a checkup. On contrast-enhanced computed tomography, distinguishing between cystic SS and cystic thymoma was difficult because the tumor was attached to the anterior mediastinum where the latter type of malignancy is more often detected. Histopathological examination showed tumor cells with spindled morphology showing hypercellularity and moderate nuclear atypia, with less than one mitotic figure per high-power field. As these features are associated with both monophasic fibrous SS and type A thymoma, more data was required to determine proper diagnosis, and therefore, immunohistochemistry was performed. Along with a conventional panel of markers, the SS-specific marker integrase interactor 1 (INI-1) was applied and found to be decreased; decreased expression of INI-1 is characteristic of SS. A diagnosis of SS was confirmed by detection of the SYT-SSX fusion gene via fluorescence in situ hybridization. Given the relatively common availability of INI-1 testing in departments of pathology, this protein would be helpful incorporated into the standard panel of markers for diagnosing SS. PMID- 26045851 TI - Sarcomatous transformation of EGFR and TP53 mutation-positive metastatic adenocarcinoma of the lungs, masquerading as a primary pleomorphic sarcoma of the proximal femur. AB - We investigated a case of metastatic adenocarcinoma of the lungs at the left proximal femur, masquerading as a primary pleomorphic sarcoma. A 72-year-old woman presented with pain in her left thigh in conjunction with a mass that had been gradually growing over a few months. She was being treated with gefitinib for lung adenocarcinoma positive for the epidermal growth factor receptor (EGFR) mutation L858R, and had multiple bone metastases. The lung adenocarcinoma and metastases had stabilized with the treatment. The metastatic lesions in the bone had also received radiation; however, a tumor in the proximal femur kept growing despite treatment. A biopsy specimen from the proximal femur revealed the proliferation of spindle-shaped cells without an epithelial glandular component. The patient underwent en bloc resection of the proximal femur that was replaced by prosthesis. Histologically, the resected tumor was entirely composed of pleomorphic cells and tumor giant cells exhibiting no apparent glandular structures. Tumor cells were diffusely positive for p53 and focally positive for epithelial markers and EGFR, but were negative for thyroid transcription factor 1, suggesting an initial diagnosis of primary pleomorphic sarcoma. Genetic examination revealed mutations in EGFR and p53 that were of the same type as the lung tumor, leading to the final diagnosis of the femoral mass as a sarcomatous transformation of metastatic lung adenocarcinoma. However, secondary genetic alterations that might explain the acquired resistance to gefitinib could not be found in the proximal femoral tumor. The patient remains alive and the remaining lesions are well controlled. PMID- 26045852 TI - Low-grade extraskeletal osteosarcoma of the mediastinum: report of a case and review of literature. AB - Extraskeletal osteosarcoma (ESOS) is a rare soft tissue sarcoma, typically characterized by a bone-producing neoplasm. Low-grade extraskeletal osteosarcoma (LGESOS) is an extremely rare soft tissue tumor, and patients with LGESOS tend to have a better prognosis. Here, we reported a case of LGESOS of the mediastinum with lung metastasis, and describe its clinical, pathological and radiological features, and compared them with those of the reported cases. PMID- 26045853 TI - Primary lymphoepithelioma-like hepatocellular carcinoma: report of a locally advanced case and review of literature. AB - Lymphoepithelioma-like hepatocellular carcinoma is rare, which has been recognized as a variant of hepatocellular carcinoma. Here we report a locally advanced case of lymphoepithelioma-like hepatocellular carcinoma. A 50-year-old man with chronic hepatitis B virus infection presented with a single mass in the liver and two enlarged lymph nodes in retroperitoneum suspected to be hepatocellular carcinoma with lymph node metastasis. After discussion by multidisciplinary team, the patient underwent hepatectomy of VIII segment and dissection of two enlarged lymph nodes. One month after the operation, pre chemotherapy abdominal computed tomography (CT) showed retroperitoneal enlarged lymph nodes, considered as local recurrence. Therefore, 3 cycles of oxaliplatin and tegafur gimeracil oteracil potassium capsule and 3 cycles of paclitaxel and cisplatin were offered, and post-chemotherapy abdominal CT revealed disease remained stable. The patient has been alive for 6 months since performance of surgery. Our report suggests that even locally advanced lymphoepithelioma-like hepatocellular carcinoma may have a good prognosis and operation and postoperative chemotherapy may benefit the patient. PMID- 26045854 TI - Transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma as a pivot connection between diverse morphologies of bladder carcinoma: a case report of urothelial carcinoma with villoglandular differentiation. AB - Urothelial carcinoma has numerous histological variants, and these variants may coexist in a single case. Here, we present a case of a 70-year-old man with urothelial carcinoma of the bladder with a maximal diameter of 5 mm that involved micropapillary and plasmacytoid variants, with villoglandular differentiation. The presence of these variants was confirmed by pathological examination of a transurethral resection specimen, and high-grade urothelial carcinoma was found as a minor component. Although this bladder carcinoma was classified as pT1, cystoprostatectomy, urethrectomy, and lymphadenectomy were performed due to the presence of the micropapillary and plasmacytoid variants, which are known to be aggressive. Examination of a surgically resected specimen revealed no carcinoma. A transition between urothelial carcinoma in situ and non-invasive micropapillary carcinoma was found to be a pivot point connecting the diverse morphologies of this bladder carcinoma, from which there existed two pathways. One pathway was from urothelial carcinoma in situ to the plasmacytoid variant through invasive high-grade urothelial carcinoma, and the other was from non-invasive micropapillary carcinoma to urothelial carcinoma with villoglandular differentiation or to the micropapillary variant. This is the 16th reported case of urothelial carcinoma with villoglandular differentiation in the literature. As urothelial carcinoma with villoglandular differentiation is often associated with aggressive variants, as shown in our case, it should be reported whenever encountered in routine pathological practice. PMID- 26045855 TI - BRAFV600 mutant non-small-cell lung cancer resistant to Vemurafenib. AB - Vemurafenib has shown significant activity in V600 mutant melanoma; however the role of this agent in Lung adenocarcinoma with an activating BRAF mutation is still evolving. One of our patients had a rare activating BRAF mutation detected through tumor exome sequencing, which led to a switch from her successful therapy to Vemurafenib and ultimately tumor progression. The lack of adequate response was disappointing both in terms of lost disease free survival and heavy financial burden to the patient who had to cover the charges of her unsuccessful off-label therapy. This experience, despite its highlight of treatment failure, puts into question the use of next generation sequencing and the trend for using off-label agents in pursuit of an optimal response without the support of strong clinical evidence. PMID- 26045856 TI - Spindle cell lipoma of the wrist, occurring in a distinctly rare location: a case report with review of literature. AB - Spindle cell lipoma (SCL) is a rare, benign adipocytic tumor commonly arising in the upper neck, back, and shoulder regions. To the best of our knowledge, only one case of SCL of the wrist has previously been reported. We herein report a rare case of SCL arising at the wrist. A 77-year-old man presented with a 4-year history of a mass in the right wrist. Radiography showed no significant findings, and magnetic resonance imaging demonstrated the presence of a mass on the radial dorsal side of the right wrist. Needle biopsy suggested the tumor was SCL, and total excision was performed. Macroscopically, the tumor was circumscribed by fibrous membrane with a yellowish to partly white surface. Histologically, the tumor was composed of mature adipocytes and proliferation of the less atypical spindle cells in a ropey-like collagen background. Immunohistochemically, the tumor cells showed diffuse and strong expression for CD34. The final diagnosis of SCL was made on the basis of these pathological and radiological findings. The patient was successfully treated and shows no evidence of disease at 3 months after surgery. PMID- 26045857 TI - Erythema, papules, and arthralgia associated with liver cancer: report of a rare case of multicentric reticulohistiocytosis. AB - We report a rare case of multicentric reticulohistiocytosis (MRH) associated with liver carcinoma. A 36-year-old man who had been diagnosed as having liver carcinoma for 2 years presented with a 2-month history of multiple papulonodules on the face, ears, neck, and upper chest, accompanied by progressive polyarthralgia of the hands, wrists, elbows and knee joints without fever or chills. Skin histology revealed well defined dermal infiltrate consisting of multinucleated giant cells and macrophages having abundant eosinophilic finely granular cytoplasm with ground glass appearance. Further immunohistochemical studies characterized the lesions as positive for CD68, CD45 and Vimentin. A diagnosis of MRH that was associated with liver cancer was made. Treatment with prednisolone for 2 months resulted in a significant improvement of the skin and joint symptoms, but was discontinued due to his significant enlargement and extensive metastases of the liver carcinoma. PMID- 26045858 TI - Toxoplasmosis presented as a submental mass: a common disease, uncommon presentation. AB - Submental mass secondary to toxoplasmosis is not common in clinical work. A diagnosis of toxoplasmosis is rarely considered by physicians. Here we describe a 50-year-old woman presented with a progressive, painful, submental and left neck swelling for 1 month. After having obtained an insufficient evidence from the fine-needle biopsy, the patient finally received an excisional biopsy which highly indicated the possibility of lymphadenopathy consistent with toxoplasmosis. Diagnosis of toxoplasmosis was finally established by a combination of the pathological criteria, together with the positive serological finding. According to review the clinical presentations, pathological characteristics, diagnostic standard and treatment of this disease, the article aims to remind otolaryngologists who are evaluating a neck mass should be aware of the infectious cause of lymphadenopathy and the possibility of toxoplasmosis. PMID- 26045859 TI - IgG4-related lung disease manifested as pneumonia in puerperium: a case report. AB - IgG4-related lung disease (IgG4-RLD) is recently emerging entity. Several reports concerned with the clinicopathologic feature have been described, but this disease in puerperium has not been reported previously. Here, we report a 24-year old woman diagnosed as IgG4-RLD in puerperium, who developed dry cough, low fever and exertional dyspnea following the delivery. The inflammatory markers and pulmonary lesions of the patient suggested pneumonia. However, there was no improvement after antibiotic treatment. The infiltration of IgG4-positive lymphoplasmacytes was found in lung biopsy by video-assisted thoracic surgery (VATS). And the serum IgG4 level was high. The patient was effectively treated with corticosteroids. This unique case highlights the occurrence of IgG4-RLD in puerperium and underscores it should be taken into consideration as a possible differential diagnosis when dense lymphoplasmacytic infiltration was found in pulmonary consolidation in complex puerperal respiratory cases. PMID- 26045860 TI - Fibromyxoid variant of endometrial stromal sarcoma with atypical bizarre nuclei. AB - Endometrial stromal sarcoma (ESS) is the second most common malignant uterine mesenchymal tumor. It affects women primarily in the perimenopausal age group. ESSs are morphologically heterogeneous. The distinction between uterine smooth muscle tumors such as cellular leiomyoma and myxoid leiomyosarcoma and low-grade ESS can be problematic when stromal sarcomas show prominent smooth muscle differentiation and abundant myxoid stroma, respectively. We herein present a rare case of fibromyxoid variant of ESS, which was misdiagnosed as hydropic leiomyoma on intraoperative frozen section examination. Grossly, the uterine mass consisted of intracavitary and intramural portions. The intracavitary portion with extensive hydropic degeneration mimicked a hydropic leiomyoma. In contrast, the intramural portion displayed an obvious tongue-like myometrial invasion. Histologically, the tumor consisted of both cellular (20%) and myxoid (80%) areas. In the cellular areas, oval to spindle-shaped tumor cells with bland nuclear features were found to surround concentrically a rich vascular network of arterioles, a characteristic of ESS. In addition, two relatively well circumscribed nodular lesions showing atypical bizarre nuclei were identified in the myxoid area. Immunohistochemically, the tumor cells were diffusely and strongly positive for CD10. The present case indicates a wide morphological spectrum of ESS. Fibromyxoid variant of ESS should be considered in the differential diagnosis of intracavitary and/or intramural uterine mesenchymal tumors with myxoid differentiation. It is important to avoid confusion between fibromyxoid ESS and myxoid leiomyosarcoma because of the differences in their clinical course, treatment, and prognosis. PMID- 26045862 TI - A case of a CD56-expressing ectomesenchymal chondromyxoid tumor of the tongue: potential diagnostic usefulness of commonly available CD56 over CD57. AB - Ectomesenchymal chondromyxoid tumors (ECTs) are rare. Only approximately 55 cases have been reported in the English literature. Distinguishing ECTs from soft tissue myoepithelioma (STM) is often difficult owing to morphological and immunohistochemical similarities. Here, we present a case of an ECT arising from the anterior dorsum of the tongue in a 24-year-old woman. Grossly, the tumor was soft, had a myxoid appearance, and measured 8*7*7 mm. Microscopically, it was well-demarcated, lacked a fibrous capsule, and predominantly consisted of short, spindle to ovoid cells in a myxoid background. Vimentin, glial fibrillary acidic protein (GFAP), and S-100 protein were strongly positive on immunohistochemical analysis. While CD56 was moderately immunopositive, cytokeratin (AE1/AE3) and alpha-smooth muscle actin (alphaSMA) showed focal weak positivity. Thus, the immunohistochemical findings suggested a diverse immunophenotype, indicating mesenchymal (vimentin and alphaSMA positive), neurogenic (S100, GFAP, and CD56 positive), and epithelial differentiation (cytokeratin positive). This reflected the fact that ECTs probably arise from uncommitted ectomesenchymal cells that have the potential for multilineage differentiation. The immunohistochemical staining pattern observed for ECTs slightly differs from that of STMs. Strongly positive staining for GFAP and weakly positive staining for cytokeratin are observed in ECTs, whereas the opposite is typically observed for STMs. These findings indicated that the patterns of expression on immunohistochemistry differ between ECTs and STMs, although inevitably, there was some overlap. Thus, CD56 expression in the case presented here is noteworthy, and it could potentially become an adjunct diagnostic marker for ECT instead of previously used CD57. PMID- 26045861 TI - A rare case of secretory breast carcinoma in a male adult with axillary lymph node metastasis. AB - Secretory breast carcinoma is a rare tumor originally described in children but occurring equally in adult population, especially in women. This unusual subtype has a generally favorable prognosis, although several cases have been described in adults with increased aggressiveness and a risk of metastases even death. So far, merely ten cases of secretory breast carcinoma with metastatic axillary lymph node in male were reported. Here, we describe the eleventh case, a 24-years old male who presented with a painless mass in the right breast was diagnosed to be "secretary breast carcinoma", and subsequently underwent modified radical mastectomy and adjuvant chemotherapy. PMID- 26045863 TI - Necrotizing fasciitis caused by perforated appendicitis: a case report. AB - Acute appendicitis is one of the most common causes of acute abdominal pain. Accurate diagnosis is often hindered due to various presentations that differ from the typical signs of appendicitis, especially the position of the appendix. A delay in diagnosis or treatment may result in increased risks of complications, such as perforation, which is associated with increased morbidity and mortality rates. Necrotizing fasciitis caused by perforated appendicitis is extremely rare. We herein report a case of 50-year-old man presenting with an appendiceal abscess in local hospital. After ten days of conservative treatment with intravenous antibiotics, the patient complained about pain and swelling of the right lower limb and computed tomography (CT) demonstrated a perforated appendix and gas and fluid collection extending from his retroperitoneal cavity to the subcutaneous layer of his right loin and right lower limb. He was transferred to our hospital and was diagnosed with necrotizing fasciitis caused by perforated appendicitis. Emergency surgery including surgical debridement and appendectomy was performed. However, the patient died of severe sepsis and multiple organ failure two days after the operation. This case represents an unusual complication of a common disease and we should bear in mind that retroperitoneal inflammation and/or abscesses may cause necrotizing fasciitis through lumbar triangles. PMID- 26045864 TI - Intravascular large B-cell lymphoma secondary to lymphoplasmacytic lymphoma: a case report and review of literature with clonality analysis. AB - Intravascular large B-cell lymphoma (IVLBCL) can be a fatal malignancy mainly because of difficulty in early detection. Due to the lack of specific clinical manifestations, early detection of IVLBCL remains a challenge, especially in the presence of comorbidities. Lymphoplasmacytic lymphoma (LPL) is an indolent B-cell lymphoma accompanied by monoclonal immunoglobulin M protein in most patients, and known to be associated with high risk of secondary hematological malignancies. Here, we report a patient who developed IVLBCL during treatment for LPL that presented a diagnostic challenge. Rearrangement analysis of the immunoglobulin heavy chain revealed the different clonal origins of two lymphomas, implying a predisposition of LPL to develop unrelated secondary lymphoma. Secondary lymphoma including IVLBCL during the treatment for LPL deserves consideration in order to facilitate early diagnosis and intervention. PMID- 26045865 TI - Different histopathology but the same clonality: ALK rearrangement in a patient with metastatic non-small-cell lung cancer. AB - EML4-ALK rearrangement is detected in 2% to 7% of lung adenocarcinomas, these tumors are sensitive to crizotinib. The histologic feature of ALK translocated non-small-cell lung cancer (NSCLC) has been studied, presence of signet-ring cells was a powerful histologic indicator of ALK rearrangement, and this characteristic histology was present both in primary sites and metastases. However, the case we discribed here has different histomorphology in primary sites and metastases, but has the same genotype which both present ALK rearrangement, while absent of EGFR mutation, KRAS mutation and ROS1 rearrangement. This histologic heterogeneity may be a supplement of the histologic feature of ALK rearranged tumor. Moreover, genomic analysis can help distinguish clonal tumors from independent primaries. PMID- 26045866 TI - Anal malignant proliferative trichilemmoma: report of a rare case with review of literature. AB - Trichilemmoma is a rare type of benign cutaneous neoplasm, which derives from outer sheath of hair follicle. It barely develops malignant progression and has rarely been reported in anal cancer. In this article, we report a case of a 73 year-old woman who presented to the outer-patient department with complaints of a ruptured and longstanding anal phyma. All the appearances were atypical. Blood routine examination showed that neutrophilic granulocyte percentage was elevated and suggest it was a simple inflammation response. No evidence of malignancy was detected upon the laboratory examinations. Then we performed an abscess incision drainage for the patient. A few days later, the biopsy pathological report suggested the specimen is a malignant proliferative trichilemmoma. We decided to perform a wide local excision instead of an extended radical operation in order to preserve anus. After the surgery, we chose not to give chemoradio-treatment for fear of side effects and complications. Careful follow-up indicates that peri anal malignant proliferative trichilemmoma may have a good prognosis and our treatment is a good choice for the patients with this tumor. Because of the low occurrence rate of anal cancer, especially malignant trichilemmoma, any clinical manifestation and experience are valuable. On one hand, our case may help to take the consideration of the diagnosis of malignant trichilemmoma in case of longtime suffered peri-anal mass, on the other hand it propose a different treatment method from other anal cancers for clinical doctors. PMID- 26045867 TI - A case of invasive Langerhans cell histiocytosis localizing only in the lung and diagnosed as pneumothorax in an adolescent female. AB - In infants, Langerhans cell histiocytosis (LCH) is associated with poor clinical outcomes as Langerhans cells invade and damage multiple organs, a presentation that is different from that in adults. Here, we present a case of a 15-year-old female who visited ourclinic complaining of right chest pain and dyspnea. She was diagnosed with right pneumothorax by chest X-ray. Chest computed tomography showed multiple cystic changes in the bilateral lung. Additionally, bullous lesions occupying the upper lobe and multiple white tiny nodules on the surface of the lung were observed by thoracoscopy. These nodules comprised proliferating atypical CD1a/S-100-positive cells invading the pulmonary parenchyma, leading to the diagnosis of LCH. Because of the extensive invasion into the pulmonary parenchyma, chemotherapy was administered. This case of LCH was unique in that the age of onset was atypical and the tumor cells occupied a single organ, despite their malignant behavior. PMID- 26045868 TI - Paratesticular solitary fibrous tumor: a case report and review of literature. AB - Solitary fibrous tumor (SFT) is a rare spindle cell neoplasm that usually arising from the pleura, but has been reported in diverse extrapleural sites. Urogenital localization is rare, and only several cases of paratesticular SFT have been reported. In the present report, we present the case of a 61-year-old male suffering from a paratesticular SFT. A surgical excision of the lesion was performed. The tumor was well circumscribed and consisted of a mixture of bland spindle cells and dense collagen bands. Immunohistochemical studies showed positive reactivity for CD34, CD99 and vimentin, but stained negative for CD117, S100, SMA, HMB45, Desmin and CD68. All these clinicopathologic features are suggestive of the diagnosis of paratesticular SFT. PMID- 26045869 TI - A rare stroma-rich variant of hyaline-vascular Castleman's disease associated with calcifying fibrous pseudotumor. AB - OBJECTIVES: The stroma-rich variant of hyaline-vascular type of Castleman's disease (SR-HVCD) should be differentiated from vascular or follicular dendritic reticulum cell neoplasms. In this paper, we present a rare case of HVCD. We also suspect a possible association between SR-HVCD and calcifying fibrous pseudotumor. METHODS: A 34-year-old man was found an abdominal mass by computed tomography (CT) in a general health checkup. The mass was resected from the mesenteric root. The specimens were evaluated for detailed characterizations through gross examination, microscopy and immunohistochemistry. RESULTS: The mass showed histologic patterns and immunohistochemical results of HVCD with significant angiomyoid proliferations, collagenation and focal calcification. Histologically, stromal elements of HVCD in our case were similar to those of a calcifying fibrous pseudotumour. CONCLUSIONS: A possible association was suspected between SR-HVCD and calcifying fibrous pseudotumor. To the best of our knowledge, this is the fourth report of describing an association between the two diseases in the English literature. PMID- 26045870 TI - Mantle cell lymphoma concurrent with T-large granular lymphocytic leukemia: report of a case and review of literature. AB - Mantle cell lymphoma is one of the B-cell lymphomas. The concurrent presentation of mantle cell lymphoma with large granular lymphocytic leukemia simultaneously has never been reported. In this case we present an old man with concomitant mantle cell lymphoma and large granular lymphocytic leukemia diagnosed by the morphology of the bone marrow aspiration, immunophenotyping of the peripheral blood by flow cytometry detecting the increased CD3+CD4-CD8+ cells, immunohistochemical studies of lymph node showed cyclinD1+, chromosome analysis by fluorescence in situ hybridization (FISH) showed t(11,14), positive results of IGH and TCR rearrangement studies. The patient discharged from the hospital voluntarily and lost the follow-up. A brief discussion is also presented. PMID- 26045871 TI - Nodular smooth muscle metaplasia in multiple peritoneal endometriosis. AB - We report here an unusual presentation of peritoneal endometriosis with smooth muscle metaplasia as multiple protruding masses on the lateral pelvic wall. Smooth muscle metaplasia is a common finding in rectovaginal endometriosis, whereas in peritoneal endometriosis, smooth muscle metaplasia is uncommon and its nodular presentation on the pelvic wall is even rarer. To the best of our knowledge, this is the first case of nodular smooth muscle metaplasia occurring in peritoneal endometriosis. As observed in this case, when performing laparoscopic surgery in order to excise malignant tumors of intra-abdominal or pelvic organs, it can be difficult for surgeons to distinguish the metastatic tumors from benign nodular pelvic wall lesions, including endometriosis, based on the gross findings only. Therefore, an intraoperative frozen section biopsy of the pelvic wall nodules should be performed to evaluate the peritoneal involvement by malignant tumors. Moreover, this report implies that peritoneal endometriosis, as well as rectovaginal endometriosis, can clinically present as nodular lesions if obvious smooth muscle metaplasia is present. The pathological investigation of smooth muscle cells in peritoneal lesions can contribute not only to the precise diagnosis but also to the structure and function of smooth muscle cells and related cells involved in the histogenesis of peritoneal endometriosis. PMID- 26045872 TI - Fibrous hamartoma of infancy: a clinical pathological analysis of seventeen cases. AB - To discuss the clinical and pathological features, differential diagnosis and prognosis of fibrous hamartoma of infancy (FHI), seventeen FHI specimens were analyzed with H&E staining and strepavidin peroxidase (SP) immunohistochemistry to detect distinguishing tissue markers. The long-term outcomes of select cases were also obtained. Among the 17 patients (13 males, 4 females, average age 16 months), FHI manifested as a subcutaneous painless mass, primarily on the back of the neck, the upper arms and buttocks. One recurrence was noted among six follow up cases. The tumors consisted of three main components: fibrous connective tissue; mature fat; and undifferentiated mesenchymal tissue. Immunohistochemistry revealed that fibrous connective tissue was positive for SMA and actin, mature fat tissue was positive for S-100 protein, and undifferentiated mesenchymal tissue was positive for CD34 and was partially positive for actin and SMA. The tumors were negative for desmin, NSE, bcl-2, beta-catenin and Ki-67. In brief, FHI is a benign, fibroblastic/myofibroblastic proliferative lesion. Defined histologic features of FHI as presented here would distinguish FHI from similar invasive tumors including infant fibromatosis, calcifying aponeurotic fibroma, fibrous fatty tumor and embryonal rhabdomyosarcoma. Once clearly identified, FHI is curable with complete resection. PMID- 26045873 TI - Disseminated Kaposi sarcoma in a HIV negative patient. AB - Kaposi sarcoma (KS) is a neoplasm of the endothelial cells. It often manifests with multiple vascular nodules on the skin and other organs. It is a systemic, malignant and multifactor disease and has a variable course. We describe an elderly Chinese man who had a rapidly growing maroon nodule on his right foot, both arms and cheekbones. KS in HIV-negative patients has only been reported sporadically. PMID- 26045874 TI - Sclerosing extramedullary hematopoietic tumor presenting as an inguinal mass in a patient with primary myelofibrosis: a diagnostic pitfall. AB - Sclerosing extramedullary hematopoietic tumor (SEMHT) is a rare lesion and presented as retroperitoneal or serosal-based mass. A 53-year-old man with a long history of primary myelofibrosis, presented with abdominal distension and inguinal mass. Pathologic examination of inguinal mass revealed a prominent sclerotic background with thick collagen deposits and mono, bi, or tri-lineage hematopoietic tissue containing atypical megakaryocytes and variable proportions of myeloid and erythroid series. The atypical megakaryocytes were positive for Factor VIII and CD61. SEMHT may be misdiagnosed as lymphocyte depleted Hodgkin's disease, as a mesenchymal neoplasm, or as carcinoma, because of the presence of large atypical cells and marked fibrosis when clinical information regarding PMF is unknown. Awareness of the bizarre atypical megakaryocyte morphology with immature hematopoietic cells and of clinical history is essential to prevent misdiagnosis. PMID- 26045875 TI - Comments on the article of Bu, et al entitled "P16INK4a overexpression and survival in osteosarcoma patients: a meta analysis". PMID- 26045876 TI - Down-regulated FSTL5 promotes cell proliferation and survival by affecting Wnt/beta-catenin signaling in hepatocellular carcinoma. AB - Follistatin-like 5 (FSTL5), a member of the follistatin family of genes, encodes a secretory glycoprotein. Previous study revealed that it might play a suppressive role in hepatocellular carcinoma (HCC). However, its clinical significances, biological functions and molecular mechanisms in HCC development are poorly understood. To gain insight to the functions of FSTL5 in HCC, We examined FSTL5 expression pattern in 117 HCC tissue samples. The results of immunohistochemical staining analysis showed that FSTL5 is more commonly down regulated in HCC compared to adjacent tissues and further clinicopathological analysis showed that its expression level is closely correlated with tumor size, TNM stage, local infiltration and patient prognosis. Both gain function assays and recombinant human FSTL5 protein treatment assays in vitro revealed that over expressing FSTL5 could inhibit the abilities of cancer cell proliferation and survival. Further, we found that those effects on HCC growth and survival are associated with Wnt/beta-catenin signaling. Taken together, all of our results validate that FSTL5 plays a suppressive role in HCC and suggest that down regulated FSTL5 could elevate abilities of growth and survival of HCC cells by activation of Wnt/beta-catenin signaling. PMID- 26045877 TI - Neovibsanin B increases extracellular matrix proteins in optic nerve head cells via activation of Smad signalling pathway. AB - The present study demonstrates the effect of neovibsanin B on the synthesis and deposition of ECM proteins and the signalling pathways used in optic nerve head (ONH) astrocytes and lamina cribrosa (LC) cells. For investigation of the signalling pathway used by neovibsanin B, ONH cells were treated with neovibsanin B. Western blot and immunostaining analyses were used to examine the phosphorylation of proteins involved in Smad and non-Smad signalling pathway. The results revealed that ONH cells on treatment with neovibsanin B showed enhanced synthesis of extracellular matrix (ECM) proteins. Neovibsanin B induced phosphorylation of canonical signalling proteins, Smad2/3. However phosphorylation of non-canonical signalling proteins, extracellular signal regulated kinases, p38, and c-Jun N-terminal kinases (JNK) 1/2 remained unaffected. There was also increase in co-localization of pSmad2/3 with Co-Smad4 in the nucleus of ONH astrocytes and LC cells indicating activation of the canonical Smad signalling pathway. Treatment of ONH cells with SIS3, inhibitor of Smad3 phosphorylation reversed the neovibsanin B stimulated ECM expression as well as activation of canonical pathway signalling molecules. In addition, inhibition of Smad2 or Smad3 using small interfering RNA (siRNA) also suppressed neovibsanin B stimulated ECM protein synthesis in ONH astrocytes and LC cells. Thus neovibsanin B utilizes the canonical Smad signalling pathway to stimulate ECM synthesis in human ONH cells. The neovibsanin B induced ECM synthesis and activation of the canonical Smad signalling pathway may be due to its effect on transforming growth factor-beta2 (TGF-beta2). However, further studies are under process to understand the mechanism. PMID- 26045878 TI - Relationship of different surgical margins with recurrence-free survival in patients with hepatocellular carcinoma. AB - To investigate the impact of different surgical margin and recurrence-free survival in patients with hepatocellular carcinoma (HCC). The data of 601 patients who underwent curative hepatectomy for HCC between January 1997 and December 2009 were analyzed. Milan group and exceeding Milan group were divided according to the Milan Criteria. Each of them was divided into 3 groups: group A (surgical margin<=1 mm), group B (1 mm=10 mm). The relationship between surgical margin and recurrence free survival in different groups was analyzed. In Milan group recurrence-free survival of group C was more than group B and group B more than group A (P<0.05). And in the exceeding Milan group recurrence-free surgical of group B was more than group A. There were no statistic differences within groups of B and C. Enlarging surgical margin may increase recurrence-free survival in HCC under Milan criteria.1mm in cases of exceeding Milan criteria may be regarded as the suitable surgical margin for operation of HCC. PMID- 26045879 TI - Effects of angiotensin-converting enzyme inhibition and bradykinin peptides in rats with myocardial infarction. AB - BACKGROUND AND OBJECTIVE: Angiotensin-converting enzyme (ACE) inhibitors have been reported to decrease myocardial remodeling and faciliate cardiac function improvement in the setting myocardial infarction by affecting bradykinin. The purpose of this study was to evaluate the combination effects of perindopril and bradykinin (BK) in rats with myocardial infarction. METHODS: Wistar Rats underwent to left anterior descending (LAD) coronary artery ligation were allocated into MI group (n=6); Perindopril group (n=7); Perindopril+BK group (n=7). An additional sham operation group (Sham group, n=6) were also established. After 4 weeks, the left ventricle function, myocardial tissue morphology, myocardial collagen volume faction, infracted ventricular wall thickness, myocardial infarction area and neovascular formation were evaluated. RESULTS: Combination treatment with perindopril and BK were showed significant improvement on LVEDV, LVEF and LVFS than MI group. Moreover, a significant improvement on LVEF was found in Perindopril+BK group than Perindopril group but not on LVEDV and LVFS between these two groups. Furthermore, neo-vessel density was significantly increased in Perindopril+BK group than other groups while no significant improvement on vessel density was found after the treatment of perindopril. In addition, myocardial infarction thickness improvement was found in Perindopril and group than MI group while combination treatment with perindopril and BK can significant improve the myocardial infarction thickness than perindopril only. CONCLUSIONS: Combination treatment with ACE inhibitor perindopril and BK can significantly improve the ventricle function in the rat model of myocardial infarction. Our data suggest BK can serve as adjuvant treatment in myocardial infarction treatment. PMID- 26045880 TI - Emodin plays an interventional role in epileptic rats via multidrug resistance gene 1 (MDR1). AB - OBJECTIVE: To observe the interventional effects of emodin in epileptic rats and elucidate its possible mechanism of action. METHODS: Thirty-six female Wistar rats were randomly divided into normal control group, model group (intraperitoneal injection of kainic acid) and emodin group (intraperitoneal injection of kainic acid+emodin intervention). The rat epilepsy model was confirmed by behavioral tests and electroencephalography. The protein levels of P glycoprotein and N-methyl-D-aspartate (NMDA) receptor in cerebral vascular tissue were analyzed by western blotting, and mRNA levels of multidrug resistance gene 1 (MDR1) and cyclooxygenase-2 (COX-2) were analyzed by real-time PCR. COX-2 and P glycoprotein levels in the brains were detected by immunohistochemical assay. RESULTS: The seizures were relieved in emodin group. Laser scanning confocal microscopy showed P-glycoprotein fluorescence increased significantly after seizures, indicating that epilepsy can induce overexpression of P-glycoprotein. Compared with control group, protein levels of P-glycoprotein and NMDA receptor in cerebral vascular tissue were significantly higher in model group, and mRNA levels of MDR1 and COX-2 were also significantly increased. Compared with model group, P-glycoprotein and NMDA receptor levels in cerebral vascular tissue were significantly decreased in emodin group (P<0.05), and the levels of MDR1 and COX 2 were down-regulated (P<0.05). In the rat brain, seizures could significantly increase COX-2 and P-glycoprotein levels, while emodin intervention was able to significantly reduce the levels of both. DISCUSSION: These findings suggest that epileptic seizures are tightly associated with up-regulated MDR1 gene, and emodin shows good antagonistic effects on epileptic rats, possibly through inhibition of MDR1 gene and its associated genes. PMID- 26045881 TI - [Not Available]. PMID- 26045882 TI - Abstracts of Poster Presentations: MauiDerm 2015: January 26-30, 2015 Maui, Hawaii. PMID- 26045883 TI - Introduction to next generation of endothelial progenitor cell therapy: a promise in vascular medicine. AB - The concept of Endothelial Progenitor Cells (EPCs) therapy for adult neovascularization has continuously received attention. They are believed to participate in endothelial repair and post natal angiogenesis due to their abilities in differentiating into endothelial cells and producing protective cytokines and growth factors. Abundant evidence supports the involvement of EPCs in capillary growth and in participating in the formation of collateral vessels, which lead to improved vascular perfusion and functional recovery in target tissue. Autologous EPC now is becoming a novel treatment option for therapeutic revascularization and vascular repair in ischemic diseases. However, various diseases such as diabetes, heart disease and ischemic diseases are related to EPC dysfunction and give rise to additional challenges of autologous EPC therapy. A novel strategy to enhance the number and function of EPCs is needed to be established to provide successful autologous EPCs therapy. Currently, clinical trials for the new generation of EPC therapy in treating peripheral ischemic diseases are underway. In this review we provide an overview and the limitations of current EPCs therapy with an introduction to the new strategies of next generation EPC therapy for more promising vascular and tissue regeneration therapy. PMID- 26045884 TI - Accelerated RBC senescence as a novel pathologic mechanism of blood stasis syndrome in traditional East Asian medicine. AB - Blood stasis syndrome (BSS) is an important pathologic condition in traditional East Asian medicine, characterized by multiple signs and symptoms, including sublingual varicosis, angiotelectasis, slow and choppy pulse, local fixed pain, nyctalgia, menstrual cramps, dark-purple tongue and infra-orbital darkness. However, recent studies have been restricted to the circulatory disorder and could not suggest the pathologic core to explain all of the characteristics of BSS. Here, we review the current research on the senescence of red blood cells (RBCs), focusing on the correlation between the pathologic properties of senescent RBCs and BSS-specific manifestations. The accumulation of senescent RBCs and their products induce pathological conditions that affect blood flow resistance and cause thrombosis, vasoconstriction and methemoglobinemia. These pathological alterations are identical to the characteristics of BSS, therefore supporting the hypothesis that accelerated RBC aging could be considered as a novel pathologic mechanism of BSS. PMID- 26045885 TI - Pulsed electromagnetic field improves postnatal neovascularization in response to hindlimb ischemia. AB - Pulsed electromagnetic fields (PEMF) have been shown to promote proliferation and regeneration in the damaged tissue. Here, we examined whether PEMF therapy improved postnatal neovascularization using murine model of hindlimb ischemia, and the underlying cellular/molecular mechanisms were further investigated. Hindlimb ischemia was induced by unilateral femoral artery resection using 6-8 week-old male C57BL6 mice. Then, mice were exposed to extracorporeal PEMF therapy (4 cycles, 8min/cycle, 30 +/- 3 Hz, 5 mT) every day until day 14. Our data demonstrated that PEMF therapy significantly accelerated wound healing, decreased prevalence of gangrene and increased postnatal neovascularization. Moreover, the levels of vascular endothelial growth factor (VEGF), endothelial nitric oxide synthase (eNOS) and Akt phosphorylation in ischemic muscles were markedly enhanced following PEMF therapy. In vitro, PEMF inhibited the process of hypoxia induced apoptosis and augmented tube formation, migration and proliferative capacities of human umbilical vein endothelial cells (HUVECs). Additionally, PEMF exposure increased VEGF secretion, as well as the eNOS and Akt phosphorylation, and these benefits could be blocked by either phosphoinositide 3-kinase (PI3K) or eNOS inhibitor. In conclusion, our data indicated that PEMF therapy enhanced ischemia-mediated angiogenesis, through up-regulating VEGF expression and activating the PI3K-Akt-eNOS pathway. Therefore, PEMF should be a valuable treatment for the patients with critical limb ischemia. PMID- 26045886 TI - Exendin-4 protected against critical limb ischemia in obese mice. AB - This study tested the hypothesis that exendin-4 protects against critical limb ischemia (CLI) in obese mice undergoing hypoxic stress (H). B6 mice were categorized into aged-matched control (C)-H (group 1-A), obesity (induced by high fat diet) (O)-H (group 1-B), C-H-CLI (group 2-A), O-H-CLI (group 2-B), C-H-CLI exendin-4 (group 3-A) and O-H-CLI-exendin-4 (group 3-B). Animals were sacrificed by day 14 after CLI procedure. By day 14, laser Doppler results showed that blood flow in CLI area was higher in group 3-A than group 2-A, higher in group 3-B than group 2-B, highest in groups 1-A and 1-B, higher in group 2-A than in group 2-B, and higher in group 3-A than in group 3-B (all p<0.001), but not significantly different between groups 1-A and 1-B. Furthermore, circulating numbers of endothelial progenitor cells (EPCs) (c-kit/CD31+, Sca-1/KDR+) showed an identical pattern of blood flow in CLI area among groups 2-A, 2-B, 3-A and 3-B, except that these biomarkers were lowest in groups 1-A and 1-B (all p<0.001). Protein and cellular levels of angiogenesis factors (VEGF, CXCR4, SDF-1alpha) exhibited an identical pattern of circulating EPC numbers among all groups (all p<0.001). Protein levels of apoptotic (cytosolic cytochrome-C, mitochondrial Bax, cleaved caspase 3 and PARP) and fibrotic (Samd 3, TGF-beta) biomarkers showed an opposite pattern of blood flow in CLI area among groups 2-A, 2-B, 3-A and 3-B, but were lowest in groups 1-A and 1-B (all p<0.001). This finding suggests exendin-4 protected against CLI in obese mice undergoing hypoxic stress mainly through enhancing angiogenesis and inhibiting apoptosis. PMID- 26045887 TI - The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy. AB - Tumors exploit immunoregulatory checkpoints to attenuate T cell responses as a means of circumventing immunologic rejection. By activating the inhibitory costimulatory pathway of Programmed Death 1 (PD1)/PDL1 which provides tumor cells an escape mechanism from immune surveillance, Programmed Death Ligand1 (PDL1)(+) tumors hamper activated tumor-specific T cell functions and render them functionally exhausted. To overcome the inhibitory costimulatory effects of PDL1 on the adoptively transferred T cells, we sought to convert PD1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with CD28 and 4-1BB signaling domains (PD1-CD28-4-1BB, PD1-ACR), anticipating the genetically modified effector T lymphocytes expressing PD1-ACR would exhibit enhanced functional attributes. And the results showed that PD1-ACR expressed T cells retained the ability to bind PDL1, resulting in T cell activation as evidenced by the elevated activity of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), the augmentation of cytokine secretion and the increased proliferative capacity. Moreover, when systemically administered in the mouse model of glioblastoma metastases, PD1-ACR T cells localized at the area of U87 invasive tumor, which results in suppressed tumor growth and enhanced survival of mice with established U87 glioblastoma. Together, these data demonstrated that PD1-ACR has a high potential to serve as a novel strategy to overcome PDL1 mediated immunosuppression of T cells for cancer therapy. PMID- 26045888 TI - Granulocyte/macrophage colony-stimulating factor attenuates endothelial hyperpermeability after thermal injury. AB - Microvascular hyperpermeability followed by burn injury is the main cause of shock, and cardiovascular collapse can result if the condition is treated improperly. Our previous studies demonstrated that granulocyte/macrophage colony stimulating factor (GM-CSF) clearly reduces microvascular permeability and protects microvessels against burn injury. However, the mechanism underlying the protective function of GM-CSF on burn-injured microvessels remains unknown. This study aimed to investigate the effect and mechanism of GM-CSF on endothelial cells after exposure to burn serum. We demonstrated that GM-CSF reduced post-burn endothelial "capillary leak" by inhibiting the activity of RhoA and maintaining the membrane localization of VE-cadherin. Membranous VE-cadherin enhances adherens junctions between endothelial cells and co-localizes with and activates VEGFR2, which protect cells from burn serum-induced apoptosis. Our findings suggest that the protective mechanism of GM-CSF on burn serum-injured endothelial monolayer hyperpermeability is achieved by strengthening cell adherens junctions and improving cell viability. PMID- 26045889 TI - Evaluation of miR-29c inhibits endotheliocyte migration and angiogenesis of human endothelial cells by suppressing the insulin like growth factor 1. AB - MicroRNAs, a class of 22-nucleotide non-coding RNAs, modulate gene expression by associating with the 3'-untranslated regions (3'-UTRs) of messenger RNAs (mRNAs). Although multiple miRNAs are known to be regulated during angiogenesis, their individual roles in blood vessel development are still not fully understood. Herein, we investigate the role of miR-29c in regulating cell cycle and angiogenic phenotype of endothelial cells. The results showed that IGF-1 is highly expressed and down-regulated by miR-29c in human umbilical vein endothelial cells (HUVEC). Consistent with this preliminary finding, introduction of exogenous miR-29c or miR-29c inhibitor alters cell cycle progression, proliferation and tube formation of HUVEC, respectively. Furthermore, by using luciferase reporter assay, we find that the expression of IGF-1, a suppressor transcription factor, is directly regulated by miR-29c through 3'-UTR. In addition, we show that the selective inhibition of PI3K/AKT pathway prior to miR 29c stimulation prevents the expression of angiogenesis suppressor miRNAs that are family and cluster specific. As a conclusion, we find that miR-29c plays a significant role in regulating cell cycle, proliferation and angiogenic properties of HUVECs. This function is likely mediated through IGF-1 proteins at the post-transcriptional level. As a novel molecular target, miR-29c may have a potential value in the treatment of angiogenesis-associated diseases, such as cardiovascular diseases and cancers. PMID- 26045890 TI - Normal peripheral prostate stromal cells stimulate prostate cancer development: roles of c-kit signal. AB - BACKGROUND: To investigated the peripheral stromal cell conditioned medium (CM) stimulated c-kit-JAK2-STAT1 pathway in prostate cancer. METHODS: CM harvested from normal prostate peripheral stromal cells was added to DU145 cells. DU145 cell viability and migration were measured by cell counting kit-8 reagent and Transwell analysis respectively. Colony and sphere formation efficiencies of DU145 cells co-cultured with CM from human prostate stromal cells were also measured. DU145cells were stably transfected with lentivirus-mediated shRNA for c kit silencing. RESULTS: C-kit expression in prostate cancer was found to be significantly higher than in benign prostatic hyperplasia and positively associated with Gleason scores. The growth, migration and capacity of clonogenic property of DU145 cells significantly increased upon exposure to peripheral stromal CM and then were inhibited after silencing the expression of c-kit. The levels of c-kit, pJAK2 and pSTAT1 were significantly induced by peripheral zone stromal CM compared with controls in serum free medium and the levels of pJAK2 and pSTAT1 decreased after c-kit silencing. CONCLUSIONS: C-kit hyper-expression promotes the development of prostate cancer. The peripheral stromal cell CM stimulated c-kit-JAK2-STAT1 pathway in prostate cancer cell viability, migration, and capacity of clonogenic property. This may lead to a greater understanding of the role of c-kit in prostate cancer and provide a potential therapeutic target for prostate cancer. PMID- 26045891 TI - Prokinetic effects of large-dose lubiprostone on gastrointestinal transit in dogs and its mechanisms. AB - OBJECTIVE: To systemically explore effects of large dose of lubiprostone on gastrointestinal (GI) transit and contractions and its safety in dogs. METHODS: 12 healthy dogs were studied. 6 dogs were operated to receive duodenal cannula and colon cannula and the other 6 dogs received gastric cannula. Lubiprostone was orally administrated at a dose of 24 ug or 48 ug 1 hr prior to the experiments. Gastric emptying (GE) of solids and small bowel transit were evaluated by collecting the effluents from the duodenal cannula and from the colon cannula. Gastric accommodation was measured by barostat. Gastric and intestinal contractions were by manometry. Colon transit was by X-ray pictures. RESULTS: 1) Lubiprostone 48 ug not 24 ug accelerated GE. Atropine could block the effect; 2) Average motility index (MI) of gastric antrum in lubiprostone 48 ug session was significantly higher in both fasting state (P = 0.01) and fed state (P = 0.03). Gastric accommodation was not significantly different; 3) Lubiprostone 48 ug accelerated small bowel and colon transit. Atropine could block the effect on small bowel transit; 4) Lubiprostone 48 ug increased postprandial small bowel MI (P = 0.0008) and colon MI (P = 0.002). 5) No other adverse effects except for diarrhea were observed. CONCLUSION: Acute administration of lubiprostone at a dose of 48 ug accelerates GI motility and enhances GI contractions in the postprandial state. The findings suggest that lubiprostone may have an indirect prokinetic effects on the GI tract and vagal activity may be involved. Lubiprostone may be safely used. PMID- 26045892 TI - Estrogen fails to facilitate resuscitation from ventricular fibrillation in male rats. AB - Administration of 17beta-estradiol has been shown to exert myocardial protective effects in hemorrhagic shock. We hypothesized that similar protective effects could help improve resuscitation from cardiac arrest. Three series of 18, 40, and 12 rats each, underwent ventricular fibrillation for 8 minutes followed by 8 minutes of chest compression and delivery of electrical shocks. In series-1, rats were randomized 1:1 to receive a bolus dose of 17beta-estradiol (1 mg/kg) or 0.9% NaCl before chest compression; in series-2, rats were randomized 1:1:1:1 to receive a continuous infusion of 0.9% NaCl or a 17beta-estradiol solution designed to attain a plasma level of 10(0), 10(2), or 10(4) nM during chest compression; and in series-3, rats were randomized 1:1 to receive a continuous infusion of 17beta-estradiol to attain a plasma level of 10(2) nM or 0.9% NaCl during chest compression, providing inotropic support during the post resuscitation interval using dobutamine infusion. 17beta-estradiol failed to facilitate resuscitation in each of the 3 series. In series-1 and series-2, resuscitability and short-term survival was reduced in 17beta-estradiol groups attaining statistical significance in series-2 when the three 17beta-estradiol groups were combined (p = 0.035). In series-3, all rats were resuscitated and survived for 180 minutes aided by dobutamine which partially reversed post resuscitation myocardial dysfunction but without additional benefits on myocardial function in the 17beta-estradiol group. The present study failed to support a beneficial effect of 17beta-estradiol for resuscitation from cardiac arrest and raised the possibility of detrimental cardiac effects compromising initial resuscitability and subsequent survival in a male rat model of ventricular fibrillation and closed chest resuscitation. PMID- 26045893 TI - Using semi-quantitative dynamic contrast-enhanced magnetic resonance imaging parameters to evaluate tumor hypoxia: a preclinical feasibility study in a maxillofacial VX2 rabbit model. AB - PURPOSE: To test the feasibility of semi-quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters for evaluating tumor hypoxia in a maxillofacial VX2 rabbit model. METHODS: Eight New Zealand rabbits were inoculated with VX2 cell solution to establish a maxillofacial VX2 rabbit model. DCE-MRI were carried out using a 1.5 Tesla scanner. Semi-quantitative DCE-MRI parameters, maximal enhancement ratio (MER) and slope of enhancement (SLE), were calculated and analyzed. The tumor samples from rabbits underwent hematoxylin eosin (HE), pimonidazole (PIMO) and vascular endothelial growth factor (VEGF) immunohistochemistry (IHC) staining, and the PIMO area fraction and VEGF IHC score were calculated. Spearman's rank correlation analysis was used for statistical analysis. RESULTS: The MER values of eight VX2 tumors ranged from 1.132 to 1.773 (1.406 +/- 0.258) and these values were negatively correlated with the corresponding PIMO area fraction (p = 0.0000002), but there was no significant correlation with the matched VEGF IHC score (p = 0.578). The SLE values of the eight VX2 tumors ranged from 0.0198 to 0.0532 s(-1) (0.030 +/- 0.011 s(-1)). Correlation analysis showed that there was a positive correlation between SLE and the corresponding VEGF IHC score (p = 0.0149). However, no correlation was found between SLE and the matched PIMO area fraction (p = 0.662). The VEGF positive staining distribution predominantly overlapped with the PIMO adducts area, except for the area adjacent to the tumor blood vessel. CONCLUSIONS: The semi-quantitative parameters of DCE-MRI, MER and SLE allowed for reliable measurements of the tumor hypoxia, and could be used to noninvasively evaluate hypoxia during tumor treatment. PMID- 26045894 TI - A novel injectable porous surface modified bioactive bone cement for vertebroplasty: an in vivo biomechanical and osteogenic study in a rabbit osteoporosis model. AB - PURPOSE: The aim of this study is to determine the feasibility and effectiveness of a novel injectable Porous Surface Modified Bioactive Bone Cement (PSMBBC) for vertebroplasty of aiding osteoporotic vertebrae in an osteoporosis model. METHODS: 72 osteoporosis rabbits were randomly divided into three groups: the Polymethyl Methacrylate (PMMA) group, the PSMBBC group and the control group. PMMA and PSMBBC were administrated to osteoporotic vertebrae in vertebroplasty, respectively. The animals were sacrificed at 1w, 4w, 12w after the procedure. Micro-CT analysis, biomechanical tests and histological analysis were performed at each time point. RESULTS: From 4 to 12 weeks after the implantation of bone cements, the bone volume fraction (BV/TV) of the PSMBBC group increased from 28.27 +/- 1.69% to 38.43 +/- 1.34%. However, the BV/TV of the PMMA group showed no significant difference after the implantation. At 4 weeks, direct contact between the bone and the bone cement was observed in the PSMBBC group. At 12 weeks, it was discovered that new intact bone trabecular was formed in PSMBBC group. Furthermore, the maximum compressive strength values of the PSMBBC group were significantly higher than those of the control group at each time point after implantation. CONCLUSIONS: In summary, this study was the first investigation to evaluate the potential application of PSMBBC for vertebroplasty. RESULTS demonstrated its beneficial effects on the trabecular ingrowth of new bone and bone mineral density increase. With further validation, PSMBBC can become a valuable biomaterial for aiding osteoporotic vertebrae and usable bone cement applied in vertebroplasty. PMID- 26045895 TI - In vitro comparative study of two decellularization protocols in search of an optimal myocardial scaffold for recellularization. AB - INTRODUCTION: Selection of a biomaterial-based scaffold that mimics native myocardial extracellular matrix (ECM) architecture can facilitate functional cell attachment and differentiation. Although decellularized myocardial ECM accomplishes these premises, decellularization processes may variably distort or degrade ECM structure. MATERIALS AND METHODS: Two decellularization protocols (DP) were tested on porcine heart samples (epicardium, mid myocardium and endocardium). One protocol, DP1, was detergent-based (SDS and Triton X-100), followed by DNase I treatment. The other protocol, DP2, was focused in trypsin and acid with Triton X-100 treatments. Decellularized myocardial scaffolds were reseeded by embedding them in RAD16-I peptidic hydrogel with adipose tissue derived progenitor cells (ATDPCs). RESULTS: Both protocols yielded acellular myocardial scaffolds (~82% and ~94% DNA reduction for DP1 and DP2, respectively). Ultramicroscopic assessment of scaffolds was similar for both protocols and showed filamentous ECM with preserved fiber disposition and structure. DP1 resulted in more biodegradable scaffolds (P = 0.04). Atomic force microscopy revealed no substantial ECM stiffness changes post-decellularization compared to native tissue. The Young's modulus did not differ between heart layers (P = 0.69) or decellularization protocols (P = 0.15). After one week, recellularized DP1 scaffolds contained higher cell density (236 +/- 106 and 98 +/- 56 cells/mm(2) for recellularized DP1 and DP2 scaffolds, respectively; P = 0.04). ATDPCs in both DP1 and DP2 scaffolds expressed the endothelial marker isolectin B4, but only in the DP1 scaffold ATDPCs expressed the cardiac markers GATA4, connexin43 and cardiac troponin T. CONCLUSIONS: In our hands, DP1 produced myocardial scaffolds with higher cell repopulation and promotes ATDPCs expression of endothelial and cardiomyogenic markers. PMID- 26045896 TI - Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action. AB - Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resistance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-dependent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demonstrate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5alpha dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR expression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investigated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metformin induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/PI3K/Akt/mTOR signaling network. PMID- 26045897 TI - Inhibiting the mobilization of Ly6C(high) monocytes after acute myocardial infarction enhances the efficiency of mesenchymal stromal cell transplantation and curbs myocardial remodeling. AB - BACKGROUND: Ischemia related inflammation is the most critical factor for the survival of transplanted mesenchymal stem cells (MSCs), and strategies for controlling excessive inflammation after acute myocardial infarction (AMI) are essential and necessary for cell transplantation therapy. Our present study tested the effect of decreased Ly6C(high) monocytes on mouse MSCs transplantation after AMI. METHODS: BALB/c AMI mice were treated systemically with a CCR2 antagonist (RS 504393, 2 mg/kg, subcutaneously) or normal saline (control group). Next, 10(5) EdU-labeled MSCs were administered by intramyocardial injection to the mice in each group. TUNEL kits were used to identify the apoptotic cardiomyocytes in the infarct. The slides of the infarct border zone were stained with wheat germ agglutinin to measure the vessel density, and anti-myosin heavy chain eFluor 660 was used to measure the cardiac myosin-positive area. A transwell chamber was used to examine the interactions between Ly6C(high) monocytes and MSCs. The inflammatory cytokines expressed by Ly6C(high) monocytes and the SDF-1 expressed by MSCs were detected using ELISA kits. MSC viability was further examined by MTT and mitochondrial membrane potential assays by flow cytometry using JC-1 kits. RESULTS: We first observed the increased survival of transplanted MSCs (11.2 +/- 3.4/mm(2) vs. 3.5 +/- 1.6/mm(2), p < 0.001), and the decreased apoptosis of cardiomyocytes (11.20% +/- 3.55% vs. 20.51% +/- 8.17%, p < 0.001) in the infarcts at 3 days in the CCR2 antagonist group. An increased number of capillaries and small arterioles (139.6 +/- 21.7/mm(2) vs. 95.4 +/- 17.6/mm(2), p < 0.001) and an increased cardiac myosin-positive area (17.9% +/- 6.6% vs. 11.8% +/- 3.5%, p < 0.001) were also observed in the infarct zone at 21 days post MSC infusion in the CCR2 antagonist group. In addition, a significantly increased LvEF% (50.17 +/- 10.06 vs. 45.44 +/- 9.45, p < 0.001) was detected at the same time compared to the control mice. We further demonstrated that both the mitochondrial membrane potential of the MSCs (0.45 +/- 0.11 vs. 3.4 +/- 0.3, p < 0.001) and stromal cell-derived factor-1 (SDF-1) secreted by the MSCs significantly decreased (80.77 +/- 39.02 pg/ml vs. 435.5 +/- 77.41 pg/ml, p < 0.001) when co-cultured with Ly6C(high) monocytes. This is possibly mediated by the over-expressed cytokines secreted by the Ly6C(high) monocytes compared to the Ly6C(low) monocytes, including IL-1 (139.45 +/- 30.44 vs. 80.05 +/- 19.33, p < 0.001), IL-6 (187.82 +/- 40.43 vs. 135.5 +/- 22.09, p < 0.001), TNF-alpha (121.77 +/- 31.65 vs. 75.3 +/- 22.14, p < 0.001) and IFN-gamma (142.46 +/- 27.55 vs. 88.25 +/- 19.91, p < 0.001). PMID- 26045898 TI - BOLD-MRI evaluation of subcutaneous and visceral adipose tissue oxygenation status: effect of dietary salt intake. AB - To investigate the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) in evaluating human subcutaneous and visceral adipose tissue (AT) oxygenation status, as well as their responses to dietary salt loading/depletion, we enrolled 16 healthy subjects [mean body mass index (BMI): 24.8 +/- 2.7 kg/m(2)] to conduct a dietary intervention study, beginning with a 3 day run-in period for usual diet, followed by a 7-day high-salt diet (>= 15 g NaCl/day) and a 7-day low-salt diet (<= 5 g NaCl/day). Abdominal BOLD-MRI scan was performed to evaluate oxygenation in waist subcutaneous and perirenal (visceral) AT. Two subjects with lower BMI were excluded because of the difficulty to identify subcutaneous AT. High salt diet led to a consistent increase in R2* signal (a parameter for increased hypoxia) both in subcutaneous and visceral AT (all P < 0.0001), which was completely regressed to baseline levels by low salt diet. In addition, subcutaneous AT R2* values at any time points, were all higher than that of visceral AT (all P < 0.0001). Pearson correlation analysis revealed that the visceral AT R2* levels were negatively associated obesity indicators (waist circumference, waist-to-hip ratio and BMI). On the contrary, although a trend towards negative associations between the subcutaneous AT R2* and obesity indicators was observed, none of the associations reached statistical significances. Thus, our data demonstrate the possibility of simultaneous detection of human subcutaneous and visceral AT oxygenation status using BOLD-MRI. In addition, there is a more close relationship visceral AT oxygenation status and the development of obesity. PMID- 26045899 TI - Activation of toll-like receptor 2 promotes invasion by upregulating MMPs in glioma stem cells. AB - Invasion is one of the deadly characteristics of malignant glioma with unknown underlying cellular and molecular mechanisms. In the present study, we investigated the role of toll-like receptor 2 (TLR2) in the invasiveness of malignant glioma. We enriched glioma stem cells (GSCs) from mouse GL261 cell line by means of tumor sphere formation, and found that GSCs expressed a significantly higher level of TLR2 than committed GL261 cells at the levels of mRNA and protein. Stimulation with Pam3CSK4, a ligand of TLR2, significantly increased the migration and invasion capability of GSCs. Knockdown of TLR2 attenuated the stimulating effect of Pam3CSK4 and the invasion capability of GSCs. An orthotopic allograft tumor model showed that TLR2-knockdown decreased the invasion capability of GSCs and prolonged survival span of tumor-bearing mice. The expressions of matrix metalloproteinases 2, 9 (MMP2 and MMP9) by GSCs were enhanced by treatment of Pam3CSK4 and decreased by TLR2 knockdown, implying that MMP2 and MMP9 were involved in TLR2-mediated invasion of GSCs. Our findings indicate that the activation of TLR2 up-regulates MMPs to promote invasion of GSCs, and suggest that TLR2 might be a potential therapeutic target for treatment of glioma patients. PMID- 26045900 TI - Knockdown of YEATS4 inhibits colorectal cancer cell proliferation and induces apoptosis. AB - YEATS domain containing 4 (YEATS4) is usually amplified and functions as an oncogene in human glioma. However, the biological role of YEATS4 in colorectal cancer (CRC) has not yet been discussed. In this study, we investigated the expression level of YEATS4 in 85 pairs of CRC and paracancerous tissues, and knocked down YEATS4 via a lentivirus system in RKO CRC cell line. Although YEATS4 was upregulated in CRC tissues, YEATS4 expression showed no association with any clinical features and overall survival. Inhibition of YEATS4 significantly suppressed cell proliferation and colony formation. Flow cytometry revealed that cell cycle was arrested in the G0/G1 phase and the number of apoptotic cells were significantly increased when YEATS4 expression was inhibited. In conclusion, our findings provide first evidence that YEATS4 may be an important regulator of cell proliferation and apoptosis in CRC cells. PMID- 26045901 TI - Internal relationship between symptomatic venous thromboembolism and risk factors: up-regulation of integrin beta1, beta2 and beta3 levels. AB - BACKGROUND: To compare different expression of core proteins among venous thromboembolism (VTE) and those with risk factor groups and analyze the relative risk for VTE after integrating integrin beta1, beta2 and beta3 expression. METHODS: A total of 1006 subjects were recruited and divided into VTE group, risk factor groups and control (non- risk factor) group. Flow cytometry was performed to detect the expression of integrin beta1, beta2 and beta3. The relative risk for VTE was evaluated with independent, parallel and serial methods. RESULTS: The expression of integrin beta1 increased markedly in VTE patients, and those with risk factors (acute infection, malignancy, and autoimmune diseases), respectively (P < 0.001 or 0.01). The expression of integrin beta1 in trauma/surgery group was not significantly different with control group (P > 0.05). The expression of integrin beta2 or beta3 significantly increased in VTE group, but that in risk factor groups was not significantly increased (P > 0.05). Multivariate analysis revealed the trauma/surgery groups had no significantly increased risk for VTE. CONCLUSIONS: VTE group patients have significantly increased expression of integrin beta1, beta2 and beta3, and risk factor groups (acute infection, malignancy and autoimmune disease) have significantly increased expression of integrin beta1. The significant increase in integrin beta2, beta3 expression is a marker differentiating of VTE group patients with other risk factor groups. Trauma/surgery group has no increased expression of integrin beta1, beta2 and beta3 as other risk factors. Thus, that trauma/surgery may be not the "true" risk factor for VTE. PMID- 26045902 TI - BCR-ABL1 and CD66c exhibit high concordance in minimal residual disease detection of adult B-acute lymphoblastic leukemia. AB - OBJECTIVE: To investigate the relationship between surface expression of CD66c and the breakpoint cluster region-Abelson (BCR-ABL1) fusion gene in B-acute lymphoblastic leukemia (B-ALL) at primary diagnosis, and their concordance during minimal residual disease (MRD) monitoring. METHODS: Bone marrow biopsies were collected from newly diagnosed B-ALL patients (n = 43) between September 2011 and September 2014. Karyotyping was used to detect Philadelphia chromosome (Ph), and fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR) were used to detect BCR-ABL1 fusion gene. Immunophenotyping was performed by flow cytometry for leukemia. Patients with both CD66c expression and BCR-ABL1 were further assessed for MRD during treatment. RESULTS: Overall, 26/43 (60.5%) B-ALL patients were positive for BCR ABL1 fusion gene expression, and all Ph positive cases (17/43; 39.5%) expressed BCR-ABL1 and CD66c. CD66c was expressed at significantly higher levels in BCR ABL1 positive than negative patients (24/26, 92.3% vs. 11/17, 64.7%; P = 0.042), and furthermore, in all Ph positive cases (17/17, 100% vs. 18/26, 69.2%; P = 0.014). When BCR-ABL1 was set as the gold standard for the presence or absence of MRD after treatment, both CD66c alone and the MRD panel including CD66c demonstrated high diagnostic performance for the detection of MRD, with values of area under the receptor operation curve (ROC) of 0.881 vs. 0.891 respectively. CONCLUSIONS: The stable expression pattern of CD66c has noteworthy clinical value in B-ALL not only in the recognition of abnormal leukemia cells at primary diagnosis but also in monitoring of MRD during the treatment, especially in patients without definitely cytogenetic or molecular abnormal, and thus, warrants further investigation as a routine clinical marker for MRD detection by flow cytometry. PMID- 26045903 TI - Prognostic value and in vitro biological relevance of Neuropilin 1 and Neuropilin 2 in osteosarcoma. AB - Neoadjuvant chemotherapy in osteosarcoma increased the long-term survival of patients with localized disease considerably but metastasizing osteosarcoma remained largely treatment resistant. Neuropilins, transmembrane glycoproteins, are important receptors for VEGF dependent hyper-vascularization in tumor angiogenesis and their aberrant expression promotes tumorigenesis and metastasis in many solid tumors. Our analysis of Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2) immunostaining in a tissue microarray of 66 osteosarcoma patients identified NRP2 as an indicator of poor overall, metastasis-free and progression free survival while NRP1 had no predictive value. Patients with tumors that expressed NRP2 in the absence of NRP1 had a significantly worse prognosis than NRP1(-)/NRP2(-), NRP1(+) or NRP1(+)/NRP2(+) tumors. Moreover, patients with overt metastases and with NRP2-positive primary tumors had a significantly shorter survival rate than patients with metastases but NRP2-negative tumors. Furthermore, the expression of both NRP1 and NRP2 in osteosarcoma cell lines correlated to a variable degree with the metastatic potential of the respective cell line. To address the functional relevance of Neuropilins for VEGF signaling we used shRNA mediated down-regulation and blocking antibodies of NRP1 and NRP2 in the metastatic 143B and HuO9-M132 cell lines. In 143B cells, VEGFA signaling monitored by AKT phosphorylation was more inhibited by blocking of NRP1, whereas in HuO9-M132 cells NRP2 blocking was more effective indicating that NRP1 and NRP2 can substitute each other in the functional interaction with VEGFR1. Altogether, these data point to NRP2 as a powerful prognostic marker in osteosarcoma and together with NRP1 as a novel target for tumor-suppressive therapy. PMID- 26045905 TI - Determinants of conductive hearing loss in tympanic membrane perforation. AB - OBJECTIVES: Tympanic membrane perforations are common, but there have been few studies of the factors determining the extent of the resulting conductive hearing loss. The aims of this study were to determine whether the size of tympanic membrane perforation, pneumatization of middle ear & mastoid cavity, and location of perforation were correlated with air-bone gap (ABG) of patients. METHODS: Forty-two patients who underwent tympanoplasty type I or myringoplasty were included and preoperative audiometry were analyzed. Digital image processing was applied in computed tomography for the estimation of middle ear & mastoid pneumatization volume and tympanic membrane photograph for the evaluation of perforation size and location. RESULTS: Preoperative mean ABG increased with perforation size (P=0.018), and correlated inversely with the middle ear & mastoid volume (P=0.005). However, perforations in anterior versus posterior locations showed no significant differences in mean ABG (P=0.924). CONCLUSION: The degree of conductive hearing loss resulting from a tympanic membrane perforation would be expected with the size of perforation and pneumatization of middle ear and mastoid. PMID- 26045904 TI - Neural-induced human mesenchymal stem cells promote cochlear cell regeneration in deaf Guinea pigs. AB - OBJECTIVES: In mammals, cochlear hair cell loss is irreversible and may result in a permanent sensorineural hearing loss. Secondary to this hair cell loss, a progressive loss of spiral ganglion neurons (SGNs) is presented. In this study, we have investigated the effects of neural-induced human mesenchymal stem cells (NI-hMSCs) from human bone marrow on sensory neuronal regeneration from neomycin treated deafened guinea pig cochleae. METHODS: HMSCs were isolated from the bone marrow which was obtained from the mastoid process during mastoidectomy for ear surgery. Following neural induction with basic fibroblast growth factor and forskolin, we studied the several neural marker and performed electrophysiological analysis. NI-hMSCs were transplanted into the neomycin treated deafened guinea pig cochlea. Engraftment of NI-hMSCs was evaluated immunohistologically at 8 weeks after transplantation. RESULTS: Following neural differentiation, hMSCs expressed high levels of neural markers, ionic channel markers, which are important in neural function, and tetrodotoxin-sensitive voltage-dependent sodium currents. After transplantation into the scala tympani of damaged cochlea, NI-hMSCs-injected animals exhibited a significant increase in the number of SGNs compared to Hanks balanced salt solution-injected animals. Transplanted NI-hMSCs were found within the perilymphatic space, the organ of Corti, along the cochlear nerve fibers, and in the spiral ganglion. Furthermore, the grafted NI-hMSCs migrated into the spiral ganglion where they expressed the neuron-specific marker, NeuN. CONCLUSION: The results show the potential of NI hMSCs to give rise to replace the lost cochlear cells in hearing loss mammals. PMID- 26045906 TI - The evaluation of oxidative stress in the serum and tissue specimens of patients with chronic otitis media. AB - OBJECTIVES: To underline the effect of oxidative stress in chronic otitis media with and without cholesteatoma and to compare the oxidative stress values in the serum and tissue specimens in these two forms. METHODS: The study included a total of 75 individuals, 35 cases with chronic otitis media (COM; 16 females and 19 males) and a healthy control group of 40 cases (20 females and 20 males). The COM patient group was comprised of 18 patients with cholesteatoma and 17 patients without cholesteatoma. All patients underwent mastoidectomy. Serum specimens were taken prior to surgery and diseased tissue specimens from the ear were obtained during surgery from all patients. Only serum specimens were taken from the healthy control cases. The malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GHPx) were measured in the serum and tissue samples of the patient group and in the serum specimens of the control group. RESULTS: The age ranged from 14 to 48 years in the patient group (mean age, 20.4+/-12.2 years) and from 19 to 40 years in the control group (mean age, 26.4+/-4.64 years). When the serum values of all COM patients were compared with those of the control group, in the patient group MDA, which reflects lipid peroxidation, was found to be significantly higher (P<0.01) whereas the antioxidant enzymes SOD, CAT, and GHPx were found to be significantly lower (P<0.01). When the serum and tissue MDA, SOD, CAT, and GHPx values in patients with and without cholesteatoma were compared, no significant difference was found these parameters (P>0.01). CONCLUSION: Although oxidative stress plays a role in the pathogenesis of COM with or without cholesteatoma, it may not reflect the severity of the disease. In patients with COM, the evaluation of only serum oxidative stress values without tissue evaluation may be sufficient for assessing oxidative stress. PMID- 26045907 TI - Effects of the simultaneous application of nonlinear frequency compression and dichotic hearing on the speech recognition of severely hearing-impaired subjects: simulation test. AB - OBJECTIVES: The clinical effects of the simultaneous application of nonlinear frequency compression and dichotic hearing on people with hearing impairments have not been evaluated previously. In this study, the clinical effects of the simultaneous application of these two techniques on the recognition of consonant vowel-consonant (CVC) words with fricatives were evaluated using normal-hearing subjects and a hearing loss simulator operated in the severe hearing loss setting. METHODS: A total of 21 normal-hearing volunteers whose native language was English were recruited for this study, and two different hearing loss simulators, which were configured for severe hearing loss in the high-frequency range, were utilized. The subjects heard 82 English CVC words, and the word recognition score and response time were measured. RESULTS: The experimental results demonstrated that the simultaneous application of these two techniques showed almost even performance compared to the sole application of nonlinear frequency compression in a severe hearing loss setting. CONCLUSION: Though it is generally accepted that dichotic hearing can decrease the spectral masking thresholds of an hearing-impaired person, simultaneous application of the nonlinear frequency compression and dichotic hearing techniques did not significantly improve the recognition of words with fricatives compared to the sole application of nonlinear frequency compression in a severe hearing loss setting. PMID- 26045908 TI - Degree of sigmoid sinus compression and the symptom relief using magnetic resonance angiography in venous pulsating tinnitus. AB - OBJECTIVES: To show that mechanical compression of sigmoid sinus is effective for treatment of pulsatile tinnitus caused by sigmoid sinus enlargement, and to evaluate the relationship between the compression degree of sigmoid sinus and the tinnitus symptom relief using magnetic resonance angiography. METHODS: Medical records of twenty-four patients who were diagnosed with venous tinnitus caused by sigmoid sinus enlargement and underwent mechanical compression of sigmoid sinus were reviewed between April 2009 and May 2013. All these patients received computed tomography and magnetic resonance venography study before undergoing surgery and were followed for at least 4 months. RESULTS: Twenty-three patients felt relief from tinnitus three months after the surgery, and the cross-sectional area of the sigmoid sinus on the tinnitus side was compressed approximately by half (46%-69%) after the surgery. There were 4 patients whose tinnitus suddenly disappeared while lying on the operating table before operation, which may be a result of the patient's emotional tension or postural changes from standing. One of the four patients felt no relief from tinnitus after the surgery, with the cross-sectional area of the sigmoid sinus only compressed by 30%. And two patients of them had a recurrence of tinnitus about 6 months after the surgery. Seven patients had sigmoid sinus diverticula, and tinnitus would not disappear merely by eliminating the diverticulum until by compressing the sigmoid sinus to certain degree. There were 3 minor complications, including aural fullness, head fullness and hyperacusis. The preoperative low frequency conductive and sensorineural hearing loss of 7 subjects subsided. CONCLUSION: Mechanical compression of sigmoid sinus is an effective treatment for pulsatile tinnitus caused by sigmoid sinus enlargement, even if it might be accompanied by sigmoid sinus diverticulum. A compression degree of sigmoid sinus about 54% is adequate for the relief of tinnitus symptom. Cases in which patients' tinnitus suddenly disappeared before the surgery might be excluded to improve the efficacy of surgery. PMID- 26045909 TI - Clinical outcomes of silk patch in acute tympanic membrane perforation. AB - OBJECTIVES: The silk patch is a thin transparent patch that is produced from silk fibroin. In this study, we investigated the treatment effects of the silk patch in patients with traumatic tympanic membrane perforation (TTMP). METHODS: The closure rate, otorrhea rate, and closure time in all patients and the closure time in successful patients were compared between the paper patch and silk patch groups. RESULTS: Demographic data (gender, site, age, traumatic duration, preoperative air-bone gap, and perforation size and location) were not significantly different between the two groups. The closure rate and otorrhea rate were not significantly different between the two groups. However, the closure time was different between the two groups (closure time of all patients, P=0.031; closure time of successful patients, P=0.037). CONCLUSION: The silk patch which has transparent, elastic, adhesive, and hyper-keratinizing properties results in a more efficient closure time than the paper patch in the treatment of TTMP patients. We therefore believe that the silk patch should be recommended for the treatment of acute tympanic membrane perforation. PMID- 26045910 TI - Increase in the Level of Proinflammatory Cytokine HMGB1 in Nasal Fluids of Patients With Rhinitis and its Sequestration by Glycyrrhizin Induces Eosinophil Cell Death. AB - OBJECTIVES: The nuclear protein high mobility group protein box 1 (HMGB1) is a proinflammatory mediator that belongs to the alarmin family of proinflammatory mediators, and it has recently emerged as a key player in different acute and chronic immune disorders. Several lines of evidence demonstrate that HMGB1 is actively released extracellularly from immune cells or passively released from necrotic cells. Because of the ability of HMGB1 to sustain chronic inflammation, we investigated whether the protein is present in nasal fluids of patients with different forms of rhinitis. METHODS: HMGB1 levels were evaluated in nasal fluids of healthy subjects or rhinitis patients who were treated or not treated with different treatments. RESULTS: We report that the level of HMGB1 was significantly increased in nasal fluids of patients with allergic rhinitis, patients with NARES (nonallergic rhinitis with eosinophiliac syndrome), as well as patients with polyps. We also found that a formulation containing the HMGB1 binding compound glycyrrhizin (GLT) reduced the HMGB1 content in nasal fluids of rhinitis patients to an extent similar to that with nasal budesonide treatment. We also found that among the cultured human leukocyte populations, eosinophils released higher amounts of HMGB1. Based on the ability of HMGB1 to sustain eosinophil survival and the ability of GLT to inactivate HMGB1, we report that GLT selectively killed cultured eosinophils and had no effect on neutrophils, macrophages, and lymphocytes. CONCLUSION: Collectively, these data underscore the role of HMGB1 in rhinitis pathogenesis and the therapeutic potential of GLT formulations in treatment of chronic inflammatory disorders of the nasal mucosa. PMID- 26045911 TI - A Comparison of Cefditoren Pivoxil 8-12 mg/kg/day and Cefditoren Pivoxil 16-20 mg/kg/day in Treatment of Children With Acute Presumed Bacterial Rhinosinusitis: A Prospective, Randomized, Investigator-Blinded, Parallel-Group Study. AB - OBJECTIVES: Cefditoren pivoxil (CDT) has been used in the treatment of rhinosinusitis. However, little is known about the efficacy of this drug at low and high doses. This study was to compare the efficacy and safety of low dose (8 12 mg/kg/day) and high dose (16-20 mg/kg/day) CDT in the treatment of children with uncomplicated acute rhinosinusitis (ARS). METHODS: This investigation was a randomized, investigator-blinded, and parallel study, conducted in patients (aged 1-15 years) with a clinical diagnosis of uncomplicated ARS. Two groups of patients randomly received low dose or high dose CDT for 14 days. Patients' symptoms were assessed quantitatively using a quantitative symptom score (the S5 score). The changes in sinus symptoms and adverse events were provided by patients and their parents/caregivers. The response rate and adverse effects were evaluated at days 7 and 14. The relapse rate was recorded at days 21 and 28. The recurrences of sinus symptoms at day 60 were also assessed. RESULTS: One hundred forty patients were recruited and randomized; 72 received low dose CDT (group I) and 68 received high dose CDT (group II). There were no significant differences in demographic data including sex, age, presenting symptoms, medical history, and X-ray findings between two groups. The responses rate at day 14 in groups I and II were 95.5% and 95.4%, respectively (P>0.99). There were no significant differences between groups in relapse rate at day 28 and no recurrence at day 60 in either group. The most common treatment-related adverse events were diarrhea (4.2% in group I vs. 2.9% in group II) and vomiting (2.8% in group I vs. 10.3% in group II). There was no statistically significant difference in adverse events between groups. CONCLUSION: Both low and high doses regimens of CDT appeared a similar clinical outcome for treatment in uncomplicated ARS in pediatric patients. PMID- 26045912 TI - A Prospective Study of the Surgical Outcome of Simple Uvulopalatopharyngoplasty (UPPP), UPPP Combined With Genioglossus Advancement or Tongue Base Advancement for Obstructive Sleep Apnea Hypopnea Syndrome Patients With Multilevel Obstruction. AB - OBJECTIVES: To investigate the surgical outcomes of different uvulopalatopharyngoplasty (UPPP). METHODS: All subjects underwent overnight polysomnography and were evaluated using the Epworth sleepiness scale (ESS), the Quebec sleep questionnaire and the snoring scale at the baseline and 3 and 12 months following operation. The primary endpoint was the overall effective rate representing the sum of the surgical success rate and effective rate. RESULTS: The overall effective rate at 12 months post surgery was 55.6% for simple UPPP, 95.8% for UPPP+GA, and 92.3% for UPPP+TBA. The surgical success rate at 3 and 12 months postoperation for UPPP+GA or UPPP+TBA was significantly higher than simple UPPP (P<0.05). Marked improvement was observed in all patients in the snoring scale score and the ESS score 3 and 12 months following surgery compared to the baseline (P<0.05 in all). CONCLUSION: UPPP, UPPP+GA, and UPPP+TBA are all effective in improving the surgical outcome of obstructive sleep apnea hypopnea syndrome (OSAHS) patients with multilevel obstruction. UPPP+TBA appears to be the most effective in treating OSAHS patients. PMID- 26045913 TI - Prognostic value of volume-based positron emission tomography/computed tomography in patients with nasopharyngeal carcinoma treated with concurrent chemoradiotherapy. AB - OBJECTIVES: The aim of this study was to evaluate the prognostic value of volume based metabolic parameters measured by (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) in patients with nasopharyngeal carcinoma (NPC). METHODS: Forty-four NPC patients who underwent (18)F-FDG PET/CT for initial staging work-up before concurrent chemoradiotherapy (CCRT) were retrospectively evaluated. Maximum standardized uptake value (SUV), mean SUV, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumors were measured. The prognostic significance and predictive performance of these parameters were assessed by Cox proportional hazards regression analysis and time dependent receiver operating characteristics (ROC) curve analysis. RESULTS: Multivariate analysis showed that American Joint Committee on Cancer stage 7th edition (hazard ratio [HR], 1.525; 95% confidence interval [CI], 1.062 to 2.188; P=0.022), and TLG (HR, 7.799; 95% CI, 2.622 to 23.198; P<=0.001) were independent predictive factors associated with decreased disease-free survival (DFS). Time dependent ROC curve analysis indicated that TLG was a better predictor of DFS than MTV (P=0.008). CONCLUSION: The TLG of the primary tumor was a significant independent metabolic prognostic factor of DFS in patients with NPC treated with CCRT. PMID- 26045914 TI - Nationwide multicenter survey for current status of endoscopic thyroidectomy in Korea. AB - OBJECTIVES: We evaluated the current status of endoscopic thyroidectomy procedures in Korea in terms of indications, contraindications, advantages, disadvantages, complications, and limitations of each approach. METHODS: An email survey, consisting of 15 questions, was sent to 29 experienced endoscopic thyroidectomy surgeons. RESULTS: The most commonly used approach was the gasless transaxillary approach (66.7%), followed by the bilateral axillo-breast approach with gas insufflation (23.8%). The most common indication was less than 1 cm, single papillary thyroid cancer. The role of endoscopic thyroidectomy is not still established; some consider it a novel procedure (34.8%), others a transition to robotic thyroidectomy (34.8%). CONCLUSION: Our results shed light on the general consensus of opinions about endoscopic thyroidectomy, such as the advantages, disadvantages, complications, limitations, and even its future role. PMID- 26045915 TI - The effect of total thyroidectomy on the speech production. AB - OBJECTIVES: Voice and speech alternations that can occur after total thyroidectomy are usually due to recurrent or superior laryngeal nerve injury. These alterations may also be associated with other extralaryngeal factors, such as neck muscle dysfunction and scar contracture of the neck. We performed a prospective acoustic analysis on speech changes after surgery, in the absence of laryngeal nerve injury. METHODS: Patients aged 19 to 58 years undergoing total thyroidectomy, in the absence of laryngeal/pulmonary disease, previous neck surgery, or other malignant diseases, were recruited prospectively. For the running speech analysis, the speaking fundamental frequencies (SFo), range of SFo and speaking intensity were evaluated before surgery, 7 days, and 1 and 3 months after surgery. For consonant analysis, the acoustic distinctions of stop consonant, the voice onset time (VOT), vowel duration and closure duration were evaluated at the same periods. RESULTS: SFo and range of SFo were specifically diminished after surgery, while speaking intensities were not changed significantly after surgery. The thyroidectomized speakers displayed systematically varied VOT for the consonant production, which was phonetically representative. However, VOT after surgery could be longer in the strong aspirated and glottalized stops, but not in the lax stop than before surgery. The vowel and closure durations were not affected before and after surgery. CONCLUSION: Patients with thyroidectomy have some difficulty of pitch control and consonant articulation during speaking. VOT is also one of the meaningful acoustic parameters and provide a reference for comparing acoustic measures before and after thyroidectomy. PMID- 26045916 TI - Changes in the flow-volume curve according to the degree of stenosis in patients with unilateral main bronchial stenosis. AB - OBJECTIVES: The shape of the flow-volume (F-V) curve is known to change to showing a prominent plateau as stenosis progresses in patients with tracheal stenosis. However, no study has evaluated changes in the F-V curve according to the degree of bronchial stenosis in patients with unilateral main bronchial stenosis. METHODS: We performed an analysis of F-V curves in 29 patients with unilateral bronchial stenosis with the aid of a graphic digitizer between January 2005 and December 2011. RESULTS: The primary diseases causing unilateral main bronchial stenosis were endobronchial tuberculosis (86%), followed by benign bronchial tumor (10%), and carcinoid (3%). All unilateral main bronchial stenoses were classified into one of five grades (I, <=25%; II, 26%-50%; III, 51%-75%; IV, 76%-90%; V, >90% to near-complete obstruction without ipsilateral lung collapse). A monophasic F-V curve was observed in patients with grade I stenosis and biphasic curves were observed for grade II-IV stenosis. Both monophasic (81%) and biphasic shapes (18%) were observed in grade V stenosis. After standardization of the biphasic shape of the F-V curve, the breakpoints of the biphasic curve moved in the direction of high volume (x-axis) and low flow (y-axis) according to the progression of stenosis. CONCLUSION: In unilateral bronchial stenosis, a biphasic F-V curve appeared when bronchial stenosis was >25% and disappeared when obstruction was near complete. In addition, the breakpoint moved in the direction of high volume and low flow with the progression of stenosis. PMID- 26045917 TI - Results of free flap reconstruction after ablative surgery in the head and neck. AB - OBJECTIVES: Due to the complex anatomy and function of the head and neck region, the reconstruction of ablative defects in this area is challenging. In addition, an increasing interest in improving the quality of life of patients and achieving good functional results has highlighted the importance of free flaps. The aim of this study was to summarize the results of free flap reconstruction and salvage of free flaps in a single institute, and to analyze differences in the results by the flap donor site, recipient site, and learning curve. METHODS: The medical records of patients who underwent free flap reconstruction from 2004-2012 were reviewed retrospectively. One hundred and fifty free flaps were used in 134 patients, who had an average age of 57.7 years. The types of flaps applied, primary defect sites, success rates, results of salvage operations for compromised flap, and the learning curve were analyzed. RESULTS: The anterolateral thigh flap was preferred for the reconstruction of head and neck defects. The overall success rate was 90.7%, with 14 cases of failure. A total of 19 salvage operations (12.7%) for compromised flap were performed, and 12 flaps (63.2%) were salvaged successfully. Dependency on the facial vessels as recipient vessels was statistically different when oral and oropharyngeal defects were compared to hypopharyngeal and laryngeal defects. The learning curve for microvascular surgery showed decrease in the failure rate after 50 cases. CONCLUSION: The free flap technique is safe but involves a significant learning period and requires careful postoperative monitoring of the patient. Early intervention is important for the salvage of free flaps and for lowering the failure rate. PMID- 26045918 TI - Multifocality and bilaterality of papillary thyroid microcarcinoma. AB - OBJECTIVES: Papillary thyroid carcinomas frequently occur as two or more separate foci within the thyroid gland (18%-87%). However, those multifocal tumors are easy to be undetected by preoperative radiologic evaluations, which lead to remnant disease after initial surgery. We aimed to study the incidence of multifocal papillary thyroid microcarcinomas (PTMCs), diagnostic accuracy of preoperative radiologic evaluation, predictive factors, and the chance of bilateral tumors. METHODS: Two hundred and seventy-seven patients with PTMC were included in this study. All patients underwent total thyroidectomy as an initial treatment. Medical records, pathologic reports, and radiological reports were reviewed for analysis. RESULTS: Multifocal PTMCs were detected in 100 of 277 patients (36.1%). The mean number of tumors in each patient was 1.6+/-1.1, ranging from 1 to 10. The additional tumor foci were significantly smaller (0.32+/-0.18 cm) than the primary tumors (0.63+/-0.22 cm) (P<0.001). There was no significant relationship between primary tumor size and the presence of contralateral tumors. With more tumors detected in one lobe, there was greater chance of contralateral tumors; 18.8% with single tumor focus, 30.2% with 2 tumor foci, and 46.2% with 3 or more tumor foci in one lobe. Sensitivity of preoperative sonography was 42.7% for multifocal tumors and 49.0% for bilateral tumors. With multivariate analysis, nodular hyperplasia was the only significant factor for multifocal tumors. CONCLUSION: In cases of PTMCs, the incidence of multifocal tumors is high. However, additional tumor foci are too small to be diagnosed preoperatively, especially under the recent guidelines on radiologic screening tests for papillary thyroid carcinoma. Multifocal PTMCs have high risk of bilateral tumors, necessitating more extensive surgery or more thorough follow up. PMID- 26045919 TI - Tinnitus severity and the sound therapy outcome. PMID- 26045920 TI - In Reply: Broad Band Noise May be Preferable, Even After Controlling the Pretreatment Severity of Tinnitus Induced Distress. PMID- 26045921 TI - Volatile anesthetics and ischemia-reperfusion injury. PMID- 26045923 TI - Standard deviation and standard error of the mean. AB - In most clinical and experimental studies, the standard deviation (SD) and the estimated standard error of the mean (SEM) are used to present the characteristics of sample data and to explain statistical analysis results. However, some authors occasionally muddle the distinctive usage between the SD and SEM in medical literature. Because the process of calculating the SD and SEM includes different statistical inferences, each of them has its own meaning. SD is the dispersion of data in a normal distribution. In other words, SD indicates how accurately the mean represents sample data. However the meaning of SEM includes statistical inference based on the sampling distribution. SEM is the SD of the theoretical distribution of the sample means (the sampling distribution). While either SD or SEM can be applied to describe data and statistical results, one should be aware of reasonable methods with which to use SD and SEM. We aim to elucidate the distinctions between SD and SEM and to provide proper usage guidelines for both, which summarize data and describe statistical results. PMID- 26045922 TI - Airway management of patients with traumatic brain injury/C-spine injury. AB - Traumatic brain injury (TBI) is usually combined with cervical spine (C-spine) injury. The possibility of C-spine injury is always considered when performing endotracheal intubation in these patients. Rapid sequence intubation is recommended with adequate sedative or analgesics and a muscle relaxant to prevent an increase in intracranial pressure during intubation in TBI patients. Normocapnia and mild hyperoxemia should be maintained to prevent secondary brain injury. The manual-in-line-stabilization (MILS) technique effectively lessens C spine movement during intubation. However, the MILS technique can reduce mouth opening and lead to a poor laryngoscopic view. The newly introduced video laryngoscope can manage these problems. The AirWay Scope(r) (AWS) and AirTraq laryngoscope decreased the extension movement of C-spines at the occiput-C1 and C2-C4 levels, improving intubation conditions and shortening the time to complete tracheal intubation compared with a direct laryngoscope. The Glidescope(r) also decreased cervical movement in the C2-C5 levels during intubation and improved vocal cord visualization, but a longer duration was required to complete intubation compared with other devices. A lightwand also reduced cervical motion across all segments. A fiberoptic bronchoscope-guided nasal intubation is the best method to reduce cervical movement, but a skilled operator is required. In conclusion, a video laryngoscope assists airway management in TBI patients with C spine injury. PMID- 26045924 TI - The effects of deep and light propofol anesthesia on stress response in patients undergoing open lung surgery: a randomized controlled trial. AB - BACKGROUND: This prospective, randomized controlled study was undertaken to compare stress hormone response to open thoracotomy for lung resection at different anesthetic depths, as determined by bispectral index (BIS) monitoring, in patients under propofol-remifentanil anesthesia. METHODS: Forty-eight adult patients scheduled for lung resection surgery using one-lung ventilation were randomly assigned to either a deep anesthesia group (BIS score of 40 +/- 5, n = 24) or a light anesthesia group (BIS score of 60 +/- 5, n = 24) by adjusting propofol infusion rates. Blood norepinephrine, epinephrine, adrenocorticotropic hormone, and cortisol levels were measured before the induction of anesthesia, at the end of surgery, and at 2 hours postoperatively. Blood glucose, hemodynamic, and oxygenation-ventilation variables, and postoperative outcomes were also measured. RESULTS: Norepinephrine and epinephrine levels remained unchanged over time in the deep group, but norepinephrine levels significantly increased in the light group at 2 h after surgery than at baseline (P = 0.007 and 0.004, respectively). Temporal changes in norepinephrine, but not in epinephrine, were significantly different between the two groups (P = 0.036). Plasma glucose levels in the light group increased with time and were significantly higher than in the deep group at the end of surgery (P = 0.002). CONCLUSIONS: A deep level of anesthesia achieved using high propofol infusion rates during lung surgery provided lower perioperative norepinephrine and glucose responses than light level of anesthesia during the early postoperative period but failed to affect immediate postoperative outcomes. PMID- 26045925 TI - Vasopressin ameliorates hypotension induced by beach chair positioning in a dose dependent manner in patients undergoing arthroscopic shoulder surgery under general anesthesia. AB - BACKGROUND: The beach chair position (BCP) is associated with hypotension that may lead to cerebral ischemia. Arginine vasopressin (AVP), a potent vasoconstrictor, has been shown to prevent hypotension in BCP. It also improves cerebral oxygenation in different animal models. The present study examined the effect of escalating doses of AVP on systemic hemodynamics and cerebral oxygenation during surgery in BCP under general anesthesia. METHODS: Sixty patients undergoing arthroscopic shoulder surgery in BCP under general anesthesia were randomly allocated to receive either saline (control, n = 15) or three different doses of AVP (0.025, 0.05, or 0.075 U/kg; n = 15 each) 2 minutes before BCP. Mean arterial pressure (MAP), heart rate (HR), regional cerebral oxygen saturation (SctO2), and jugular venous oxygen saturation (SjvO2) were measured after induction of anesthesia and before (presitting in supine position) and after BCP. RESULTS: AVP per se given before BCP increased MAP, and decreased SjvO2, SctO2, and HR in all patients (P < 0.05 for all). BCP decreased MAP, the magnitude of which and hence the incidence of hypotension was decreased by AVP in a dose-dependent manner. While in BCP, every dose of AVP reduced the HR and SctO2. Accordingly, it increased the incidence of cerebral desaturation (> 20% SctO2 decrease from the baseline value) with no differences in SjvO2 and the incidence of SjvO2 < 50% or SjvO2 < 40% among the groups. CONCLUSIONS: AVP ameliorates hypotension associated with BCP in a dose-dependent manner in patients undergoing shoulder surgery under general anesthesia. However, AVP may have negative effects on SctO2 before and after BCP and on SjvO2 before BCP. PMID- 26045926 TI - Predictive value of rotational thromboelastometry during cardiopulmonary bypass for thrombocytopenia and hypofibrinogenemia after weaning of cardiopulmonary bypass. AB - BACKGROUND: The early detection of coagulopathy helps guide decisions regarding optimal transfusion management during cardiac surgery. This study aimed to determine whether rotational thromboelastometry (ROTEM) analysis during cardiopulmonary bypass (CPB) could predict thrombocytopenia and hypofibrinogenemia after CPB. METHODS: We analyzed 138 cardiac surgical patients for whom ROTEM tests and conventional laboratory tests were performed simultaneously both during and after CPB. An extrinsically activated ROTEM test (EXTEM), a fibrin-specific ROTEM test (FIBTEM) and PLTEM calculated by subtracting FIBTEM from EXTEM were evaluated. Correlations between clot amplitude at 10 min (A10), maximal clot firmness, platelet count, and fibrinogen concentrations at each time point were calculated. A receiver operating characteristic analysis with area under the curve (AUC) was used to assess the thresholds of EXTEM, PLTEM and FIBTEM parameters during CPB and for predicting thrombocytopenia and hypofibrinogenemia after weaning of CPB. RESULTS: The A10 on EXTEM, PLTEM, and FIBTEM during CPB showed a good correlation with platelet counts (r = 0.622 on EXTEM and r = 0.637 on PLTEM; P < 0.0001 for each value) and fibrinogen levels (r = 0.780; P < 0.0001) after CPB. A10 on a FIBTEM threshold of 8 mm during the CPB predicted a fibrinogen concentration < 150 mg/dl (AUC = 0.853) after CPB. Additionally, the threshold level of A10 on EXTEM during CPB for predicting platelet counts < 100,000 /ul after CPB was 42 mm (AUC = 0.768). CONCLUSIONS: EXTEM, PLTEM, and FIBTEM parameters during CPB may be useful for predicting thrombocytopenia and hypofibrinogenemia after weaning of CPB. PMID- 26045927 TI - The degree of labor pain at the time of epidural analgesia in nulliparous women influences the obstetric outcome. AB - BACKGROUND: The increased pain at the latent phase can be associated with dysfunctional labor as well as increases in cesarean delivery frequency. We aimed to research the effect of the degree of pain at the time of epidural analgesia on the entire labor process including the mode of delivery. METHODS: We performed epidural analgesia to 102 nulliparous women on patients' request. We divided the group into three based on NRS (numeric rating scale) at the moment of epidural analgesia; mild pain, NRS 1-4; moderate pain, NRS 5-7; severe pain, NRS 8-10. The primary outcome was the mode of delivery (normal labor or cesarean delivery). RESULTS: There were significant differences in the mode of delivery among groups. Patients with severe labor pain had a significantly higher cesarean delivery compared to patients with moderate labor pain (P = 0.006). The duration of the first and second stage of labor, fetal heart rate, use of oxytocin and premature rupture of membranes had no differences in the three groups. CONCLUSIONS: Our research showed that the degree of pain at the time of epidural analgesia request might influence the rate of cesarean delivery. Further research would be necessary for clarifying the mechanism that the augmentation of pain affects the mode of delivery. PMID- 26045928 TI - Comparison of dexmedetomidine and dexamethasone for prevention of postoperative nausea and vomiting after laparoscopic cholecystectomy. AB - BACKGROUND: Postoperative nausea and vomiting (PONV) are common following laparoscopic cholecystectomy (LC). Dexamethasone has been reported to reduce PONV. However, there is insufficient evidence regarding the effect of dexmedetomidine in decreasing PONV. This study was designed to compare the effects of a single dose of dexmedetomidine to dexamethasone for reducing PONV after LC. METHODS: Eighty-six adult patients scheduled for LC were randomized to receive either single dose 1 ug/kg of dexmedetomidine (Dexmed group, N = 43) or 8 mg dexamethasone (Dexa group, N = 43) before skin incision. During the first 24 h postoperatively, the incidence and severity of PONV were assessed. Pain and sedation scores were assessed on arrival in the recovery room and early postoperatively. Analgesic and antiemetic consumption during the 24 h after surgery were calculated. Intra-operative and postoperative hemodynamics were recorded. RESULTS: Twenty-one percent of the patients in the Dexmed group developed PONV compared to 28% in the Dexa group (P = 0.6). Severity of PONV was similar between the two groups (P = 0.07). Early postoperatively, pain severity was significantly lower in the Dexmed group, but sedation scores were significantly higher. The first analgesic request was significantly delayed in the Dexmed group (P = 0.02). The total amounts of intraoperative fentanyl and postoperative tramadol administered were significantly lower in the Dexmed group. No difference in ondansetron was noted between the two groups. Mean arterial pressure and heart rate were significantly lower in the Dexmed group after administration of dexmedetomidine. No major side effects were reported. CONCLUSIONS: Dexmedetomidine reduces the incidence and severity of PONV, similar to dexamethasone. It is superior to dexamethasone in reducing postoperative pain and total analgesic consumption during the first 24 h after LC. PMID- 26045929 TI - A comparison of oxycodone and fentanyl in intravenous patient-controlled analgesia after laparoscopic hysterectomy. AB - BACKGROUND: We planned to compare the effect of intravenous oxycodone and fentanyl on post-operative pain after laparoscopic hysterectomy. METHODS: We examined 60 patients were randomized to postoperative pain treatment with either oxycodone (n = 30, Group O) or fentanyl (n = 30, Group F). The patients received 10 mg oxycodone/100 ug fentanyl with ketorolac 30 mg before the end of anesthesia and then continued with patient-controlled analgesia for 48 h postoperatively. RESULTS: The accumulated oxycodone consumption was less than fentanyl during 8, 24 and 48 h postoperatively. Numeric rating score of Group O showed significantly lower than that of Group F during 30 min, 2, 4, 8 and 24 h postoperatively. The incidences of adverse reactions were similar in the two groups, though the incidence of nausea was higher in the Group O during the 24 and 48 h postoperative period. CONCLUSIONS: Oxycodone IV-PCA was more advantageous than fentanyl IV-PCA for laparoscopic hysterectomy in view of accumulated oxycodone consumption, pain control and cost beneficial effect. However, patient satisfaction was not good in the group O compared to group F. PMID- 26045930 TI - The effect of combination treatment using palonosetron and dexamethasone for the prevention of postoperative nausea and vomiting versus dexamethasone alone in women receiving intravenous patient-controlled analgesia. AB - BACKGROUND: The purpose of this study was to evaluate the effect of palonosetron combined with dexamethasone for the prevention of PONV compared to dexamethasone alone in women who received intravenous patient-controlled analgesia (IV-PCA) using fentanyl. METHODS: In this randomized, double-blinded, placebo-controlled study, 204 healthy female patients who were scheduled to undergo elective surgery under general anesthesia followed by IV-PCA for postoperative pain control were enrolled. Patients were divided into two groups: the PD group (palonosetron 0.075 mg and dexamethasone 5 mg IV; n = 102) and the D group (dexamethasone 5 mg IV; n = 102). The treatments were given after the induction of anesthesia. The incidence of nausea, vomiting, severity of nausea, and the use of rescue anti emetics during the first 48 hours after surgery were evaluated. RESULTS: The incidence of PONV was significantly lower in the PD group compared with the D group during the 0-24 hours (43 vs. 59%) and 0-48 hours after surgery (45 vs. 63%) (P < 0.05). The severity of nausea during the 6-24 hours after surgery was significantly less in the PD group compared with the D group (P < 0.05). The incidence of rescue antiemetic used was significantly lower in the PD group than in the D group during the 0-6 hours after surgery (13.1 vs. 24.5%) (P < 0.05). CONCLUSIONS: Palonosetron combined with dexamethasone was more effective in preventing PONV compared to dexamethasone alone in women receiving IV-PCA using fentanyl. PMID- 26045931 TI - Adsorption of desflurane by the silica gel filters in breathing circuits: an in vitro study. AB - BACKGROUND: During general anesthesia, a heated breathing circuit (HBC) is used to replace the heat and moisture exchange function of the upper airway. One HBC uses an air dryer filter that employs silica gel (SG) as a desiccant. SG is capable of adsorbing many organic compounds. Therefore, we undertook an in vitro study of the adsorption of desflurane by SG filters. METHODS: An HBC was connected to an anesthesia machine, and a test lung was connected to the circuit. The test lung was mechanically ventilated with 2 or 4 L/min of fresh gas flow, with and without the air dryer filter. Desflurane was administered at a 6 vol% on the vaporizer dial setting. The experiment was repeated 15 times in each group. The end-tidal concentrations were measured during the experiments. The air dryer filter weights were measured before and after the experiments, and the times required to achieve the specific end-tidal desflurane concentrations were determined. RESULTS: Significant differences in the end-tidal concentrations of desflurane were observed between the control and filter groups (P < 0.001). The filter weights increased significantly after the experiments (P < 0.001). The times required to achieve the same end-tidal desflurane concentrations were different with the application of the air dryer filter (P < 0.001). CONCLUSIONS: The adsorption of desflurane with the use of an air dryer filter was verified in this in vitro study. Careful attention is needed when using air dryer gel filters during general anesthesia. PMID- 26045932 TI - Effect of isoflurane post-treatment on tPA-exaggerated brain injury in a rat ischemic stroke model. AB - BACKGROUND: Intravenous tissue-type plasminogen activator (tPA) is recognized as the standard treatment for ischemic stroke. However, its narrow therapeutic window and association with an increased risk of intracranial hemorrhage have required caution when used. In this context, several approaches are required to deal with the shortcomings of such a double-edged drug. Anesthetics are known to protect against ischemic reperfusion injury, and their protective role in ischemic post-conditioning is crucial for reducing ischemia-related injury. The aim of this study was to assess the effect of isoflurane post-treatment on intracranial hemorrhage and cerebral infarction after tPA treatment for transient cerebral ischemia. METHODS: Cerebral ischemia was modeled in male Sprague-Dawley rats (n = 32) by occluding the right middle cerebral artery for 1 h, followed by intravenous tPA administration. Rats were randomly divided into control and isoflurane post-treatment group, and isoflurane post-treatment group was post treated by administering 1.5% isoflurane for 1 h from the start of reperfusion. Twenty-four h after reperfusion, neurobehavioral changes were assessed. The extent of cerebral infarction and intracranial hemorrhage were also assessed by quantification of infarction volume and cerebral hemoglobin concentration from brain tissue, respectively. RESULTS: Neurobehavioral testing showed better functional outcomes in the isoflurane post-treatment group than the control group. The extent of cerebral infarction and intracranial hemorrhage were both reduced in isoflurane post-treatment group compared to control group. CONCLUSIONS: Isoflurane post-treatment may mitigate infarction volume and intracranial hemorrhage in tPA-exaggerated brain injury. Our findings provide an encouraging novel approach for enhancing clinical outcomes in tPA-exaggerated brain injury. PMID- 26045933 TI - Transection of a Coopdech bronchial blocker tip during bronchial resection for right upper lobectomy: a case report. AB - A bronchial blocker (BB) is preferred for lung separation in patients with difficult airways. However, BBs, unlike double-lumen tubes, must be placed in the bronchus of the lung being operated on, hence can be damaged by surgical manipulation. Intubation was unexpectedly difficult in this male patient, so a Coopdech BB was placed in the right mainstem bronchus through a single-lumen tracheoscopic ventilation tube for a thoracoscopic right upper lobectomy. During the bronchial resection, however, the distal tip of the BB was transected and pinched in the staple line, so the staple line was partially opened, and the BB was withdrawn into the trachea. The opened bronchial stump was sutured manually under apnea without conversion to an open thoracotomy, and there was no significant air leakage through the suture line. This case underlines the importance of frequently evaluating the position of a BB during lung surgery. PMID- 26045934 TI - Transesophageal imaging of a left main coronary artery ostium occlusion in infective endocarditis: a case report. AB - A 43-year-old woman was admitted due to fever, chills, and headache for several days and was diagnosed as infective endocarditis. Intraoperative transesophageal echocardiography (TEE) examination confirmed severe aortic stenosis and showed relatively fresh 1.5 cm vegetation on the left coronary cusp of the aortic valve (AV) with frequent diastolic prolapse into the aortic root. This mobile vegetation partially occluded left coronary ostium, but it did not cause cardiac failure. TEE showed the vegetation to be in good position across the AV. The AV replacement with removal of vegetation and mitral valvuloplasty were performed. The patient was weaned from cardiopulmonary bypass without any hemodynamic instability or changes in ST segment on electrocardiography. She was discharged on the 28th postoperative day without any complication. PMID- 26045935 TI - Anesthetic management for separation of thoracopagus twins with complex congenital heart disease: a case report. AB - Although thoracopagus twins joined at the upper chest are the most common type of conjoined twins, the separation surgery in these cases has a higher mortality rate. Here, we describe an anesthetic management approach for the separation of thoracopagus conjoined twins sharing parts of a congenitally defective heart and liver. We emphasize the importance of vigilant intraoperative hemodynamic monitoring for early detection of unexpected events. Specifically, real-time continuous monitoring of cerebral oximetry using near-infrared spectroscopy allowed us to promptly detect cardiac arrest and hemodynamic deterioration. PMID- 26045936 TI - Acute unilateral anesthesia mumps after hysteroscopic surgery under general anesthesia: a case report. AB - Acute unilateral parotid gland swelling after general anesthesia, anesthesia mumps is rare and when occurred, it is associated with the patient's position and with long-lasting surgery. The exact mechanism or etiology has not been fully established but stasis of gland secretion, blockage of Stensen's duct by direct compression, or retrograde flow of air by increased the oral cavity pressure are suspicious reasons. We experienced a case of soft tissue swelling in the left preauricular and submandibular regions in a 40-year-old female patient after short-lasting, hysteroscopic myomectomy performed in the lithotomy position with no suspicious predisposing factor. It is required to pay attention on the fact that even with the usual face mask ventilation can lead to the development of anesthesia mumps. PMID- 26045937 TI - General anesthesia in a patient with multicentric Castleman's disease: a case report. AB - Castleman's disease (CD) is a rare lymphoproliferative disorder of undetermined etiology. Unicentric Castleman's disease is confined to a single lymph node; it is usually asymptomatic though sometimes has local manifestations related to mass effects. In contrast, multicentric Castleman's disease (MCD) typically presents with lymphoid hyperplasia at multiple sites; it is associated with systemic symptoms and abnormal laboratory findings, with a less favorable prognosis. In case of anesthesia in CD, an exhaustive preanesthetic evaluation is essential to identify associated clinical manifestations which may influence the management of the anesthesia. Perioperative careful monitoring and proper anesthetic management are both important. We report a case of general anesthesia with anesthetic management in a patient with MCD that has not been documented in the literature. PMID- 26045938 TI - Liver transplantation in a child with osteogenesis imperfecta. PMID- 26045939 TI - Corrigendum: The time-course and RNA interference of TNF-alpha, IL-6, and IL 1beta expression on neuropathic pain induced by L5 spinal nerve transection in rats (Korean J Anesthesiol 2015 April 68(2): 159-169). AB - [This corrects the article on p. 159 in vol. 68, PMID: 25844135.]. PMID- 26045940 TI - Corrigendum: Expression of the spinal 5-HT7 receptor and p-ERK pathway in the carrageenan inflammatory pain of rats (Korean J Anesthesiol 2015 April 68(2): 170 174). AB - [This corrects the article on p. 170 in vol. 68, PMID: 25844136.]. PMID- 26045941 TI - Phenotypic and functional analysis of SHANK3 stop mutations identified in individuals with ASD and/or ID. AB - BACKGROUND: SHANK proteins are crucial for the formation and plasticity of excitatory synapses. Although mutations in all three SHANK genes are associated with autism spectrum disorder (ASD), SHANK3 appears to be the major ASD gene with a prevalence of approximately 0.5% for SHANK3 mutations in ASD, with higher rates in individuals with ASD and intellectual disability (ID). Interestingly, the most relevant mutations are typically de novo and often are frameshift or nonsense mutations resulting in a premature stop and a truncation of SHANK3 protein. METHODS: We analyzed three different SHANK3 stop mutations that we identified in individuals with ASD and/or ID, one novel (c.5008A > T) and two that we recently described (c.1527G > A, c.2497delG). The mutations were inserted into the human SHANK3a sequence and analyzed for effects on subcellular localization and neuronal morphology when overexpressed in rat primary hippocampal neurons. RESULTS: Clinically, all three individuals harboring these mutations had global developmental delays and ID. In our in vitro assay, c.1527G > A and c.2497delG both result in proteins that lack most of the SHANK3a C-terminus and accumulate in the nucleus of transfected cells. Cells expressing these mutants exhibit converging morphological phenotypes including reduced complexity of the dendritic tree, less spines, and less excitatory, but not inhibitory synapses. In contrast, the truncated protein based on c.5008A > T, which lacks only a short part of the sterile alpha motif (SAM) domain in the very SHANK3a C-terminus, does not accumulate in the nucleus and has minor effects on neuronal morphology. CONCLUSIONS: In spite of the prevalence of SHANK3 disruptions in ASD and ID, only a few human mutations have been functionally characterized; here we characterize three additional mutations. Considering the transcriptional and functional complexity of SHANK3 in healthy neurons, we propose that any heterozygous stop mutation in SHANK3 will lead to a dysequilibrium of SHANK3 isoform expression and alterations in the stoichiometry of SHANK3 protein complexes, resulting in a distinct perturbation of neuronal morphology. This could explain why the clinical phenotype in all three individuals included in this study remains quite severe - regardless of whether there are disruptions in one or more SHANK3 interaction domains. PMID- 26045942 TI - Regional brain volume differences between males with and without autism spectrum disorder are highly age-dependent. AB - BACKGROUND: Neuroanatomical differences between individuals with and without autism spectrum disorder (ASD) were inconsistent in the literature. Such heterogeneity may substantially originate from age-differential effects. METHODS: Voxel-based morphometry was applied in 86 males with ASD and 90 typically developing control (TDC) males (aged 7 to 29 years). Three steps of statistical modeling (model 1, multiple regression with age as a covariate; model 2, multiple regression further considering diagnosis-by-age interaction; model 3, age stratified analyses) were performed to dissect the moderating effects of age on diagnostic group differences in neuroanatomy. RESULTS: Across ages, males with and without ASD did not differ significantly in total gray matter (GM) or white matter (WM) volumes. For both groups, total GM volumes decreased and WM volumes increased with age. For regional volume, comparing with the model only held the age constant (model 1), the main effect of group altered when diagnosis-by-age interaction effects were considered (model 2). Here, participants with ASD had significantly greater relative regional GM volumes than TDC in the right inferior orbitofrontal cortex and bilateral thalamus; for WM, participants with ASD were larger than TDC in the bilateral splenium of corpus callosum and right anterior corona radiata. Importantly, significant diagnosis-by-age interactions were identified at the bilateral anterior prefrontal cortex, bilateral cuneus, bilateral caudate, and the left cerebellum Crus I for GM and left forceps minor for WM. Finally, age-stratified analyses (model 3) showed distinct patterns in GM and WM volumetric alterations in ASD among subsamples of children, adolescents, and adults. CONCLUSIONS: Our findings suggest that the heterogeneous reports on the atypical neuroanatomy of ASD may substantially originate from age variation in the study samples. Age variation and its methodological and biological implications have to be carefully delineated in future studies of the neurobiology of ASD. PMID- 26045943 TI - Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study. AB - BACKGROUND: The increased male prevalence of autism spectrum disorder (ASD) may be mirrored by the early emergence of sex differences in ASD symptoms and cognitive functioning. The female protective effect hypothesis posits that ASD recurrence and symptoms will be higher among relatives of female probands. This study examined sex differences and sex of proband differences in ASD outcome and in the development of ASD symptoms and cognitive functioning among the high-risk younger siblings of ASD probands and low-risk children. METHODS: Prior to 18 months of age, 1824 infants (1241 high-risk siblings, 583 low-risk) from 15 sites were recruited. Hierarchical generalized linear model (HGLM) analyses of younger sibling and proband sex differences in ASD recurrence among high-risk siblings were followed by HGLM analyses of sex differences and group differences (high risk ASD, high-risk non-ASD, and low-risk) on the Mullen Scales of Early Learning (MSEL) subscales (Expressive and Receptive Language, Fine Motor, and Visual Reception) at 18, 24, and 36 months and Autism Diagnostic Observation Schedule (ADOS) domain scores (social affect (SA) and restricted and repetitive behaviors (RRB)) at 24 and 36 months. RESULTS: Of 1241 high-risk siblings, 252 had ASD outcomes. Male recurrence was 26.7 % and female recurrence 10.3 %, with a 3.18 odds ratio. The HR-ASD group had lower MSEL subscale scores and higher RRB and SA scores than the HR non-ASD group, which had lower MSEL subscale scores and higher RRB scores than the LR group. Regardless of group, males obtained lower MSEL subscale scores, and higher ADOS RRB scores, than females. There were, however, no significant interactions between sex and group on either the MSEL or ADOS. Proband sex did not affect ASD outcome, MSEL subscale, or ADOS domain scores. CONCLUSIONS: A 3.2:1 male:female odds ratio emerged among a large sample of prospectively followed high-risk siblings. Sex differences in cognitive performance and repetitive behaviors were apparent not only in high-risk children with ASD, but also in high-risk children without ASD and in low-risk children. Sex differences in young children with ASD do not appear to be ASD-specific but instead reflect typically occurring sex differences seen in children without ASD. Results did not support a female protective effect hypothesis. PMID- 26045944 TI - Recombinant disintegrin (r-Cam-dis) from Crotalus adamanteus inhibits adhesion of human pancreatic cancer cell lines to laminin-1 and vitronectin. AB - Pancreatic cancer is a malignant cancer common worldwide having poor prognosis, even when diagnosed at its early stage. Cell adhesion plays a critical role in cancer invasion and metastasis. Integrins are major mediators of cell adhesion and play an important role in invasion and metastatic growth of human pancreatic cancer cells. Snake disintegrins are the most potent ligands of several integrins and have potential therapeutic applications for cancers. We have previously cloned and expressed a new recombinant RGD-disintegrin from Crotalus adamanteus (r-Cam-dis). This recently published r-Cam-dis has an extra nine amino acids derived from the vector (SPGARGSEF) at the N-terminus end and has strong anti platelet activity. However, this r-Cam-dis contains the contamination of the cleavage of the N-terminal end of the pET-43.1a cloning vector. In this study, we have cloned r-Cam-dis in a different cloning vector (pGEX-4T-1) showing five different amino acids (GSPEF) at the N-terminal part. This new r-Cam-dis was expressed and tested for inhibition of platelet aggregation, specific binding activity with seven different integrins, and inhibition of adhesion of three different pancreatic cancer cell lines on laminin-1 and vitronectin. The r-Cam dis showed potent binding to alphavbeta3 integrin, but was moderate to weak with alphavbeta5, alphavbeta6, alpha2beta1, and alpha6beta1. Interestingly, the inhibition of r-Cam-dis on pancreatic cancer cell lines adhesion to laminin-1 was more effective than that to vitronectin. Based on our binding results to integrin receptors and previous adhesion studies using function-blocking monoclonal antibodies, it is suggested that r-Cam-dis could be inhibiting adhesion of pancreatic cancer cell lines through integrins alpha2beta1, alpha6beta1, alphavbeta5, and alphavbeta6. PMID- 26045945 TI - Inhibitory effects of Mycoepoxydiene on macrophage foam cell formation and atherosclerosis in ApoE-deficient mice. AB - BACKGROUND: Mycoepoxydiene (MED) is a polyketide that can be isolated from a marine fungus and is associated with various activities, including antitumor and anti-inflammatory functions. However, its effects on atherosclerosis remain unknown. Macrophage-derived foam cells play crucial roles in the initiation and progression of atherosclerotic plaques. In this study, we investigated the effects of MED on oxidized low-density lipoprotein (ox-LDL)-induced macrophage foam cell formation and activation, and on high fat diet (HFD)-induced atherosclerosis in ApoE-deficient (ApoE (-/-) ) mice. RESULTS: Our findings show that MED could significantly inhibit ox-LDL-induced macrophage foam cell formation and suppress the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), which is a receptor for ox-LDL. Additionally, MED could significantly inhibit the secretion of proinflammatory cytokines, such as tumor necrosis factor (TNF-alpha), interleukin (IL)-6, and IL-1beta. Mechanistically, MED inhibited NF-kappaB activation by blocking IkappaB-alpha degradation and reducing NF-kappaB DNA binding activity. Moreover, MED dramatically reduced the occurrence of HFD-induced atherosclerotic lesions in ApoE (-/-) mice. CONCLUSIONS: Our study shows that MED can inhibit macrophage foam cell formation and activation by inhibiting NF-kappaB activation, thereby protecting ApoE (-/-) mice from HFD-induced atherosclerosis. Our findings suggest that MED might be a potential lead compound for the development of antiatherosclerotic therapeutics. PMID- 26045946 TI - Invasiveness of plants is predicted by size and fecundity in the native range. AB - An important goal for invasive species research is to find key traits of species that predispose them to being invasive outside their native range. Comparative studies have revealed phenotypic and demographic traits that correlate with invasiveness among plants. However, all but a few previous studies have been performed in the invaded range, an approach which potentially conflates predictors of invasiveness with changes that happen during the invasion process itself. Here, we focus on wild plants in their native range to compare life history traits of species known to be invasive elsewhere, with their exported but noninvasive relatives. Specifically, we test four hypotheses: that invasive plant species (1) are larger; (2) are more fecund; (3) exhibit higher fecundity for a given size; and (4) attempt to make seed more frequently, than their noninvasive relatives in the native range. We control for the effects of environment and phylogeny using sympatric congeneric or confamilial pairs in the native range. We find that invasive species are larger than noninvasive relatives. Greater size yields greater fecundity, but we also find that invasives are more fecund per unit-size. SYNTHESIS: We provide the first multispecies, taxonomically controlled comparison of size, and fecundity of invasive versus noninvasive plants in their native range. We find that invasive species are bigger, and produce more seeds, even when we account for their differences in size. Our findings demonstrate that invasive plant species are likely to be invasive as a result of both greater size and constitutively higher fecundity. This suggests that size and fecundity, relative to related species, could be used to predict which plants should be quarantined. PMID- 26045947 TI - Retaining biodiversity in intensive farmland: epiphyte removal in oil palm plantations does not affect yield. AB - The expansion of agriculture into tropical forest frontiers is one of the primary drivers of the global extinction crisis, resulting in calls to intensify tropical agriculture to reduce demand for more forest land and thus spare land for nature. Intensification is likely to reduce habitat complexity, with profound consequences for biodiversity within agricultural landscapes. Understanding which features of habitat complexity are essential for maintaining biodiversity and associated ecosystem services within agricultural landscapes without compromising productivity is therefore key to limiting the environmental damage associated with producing food intensively. Here, we focus on oil palm, a rapidly expanding crop in the tropics and subject to frequent calls for increased intensification. One promoted strategy is to remove epiphytes that cover the trunks of oil palms, and we ask whether this treatment affects either biodiversity or yield. We experimentally tested this by removing epiphytes from four-hectare plots and seeing if the biodiversity and production of fruit bunches 2 months and 16 months later differed from equivalent control plots where epiphytes were left uncut. We found a species-rich and taxonomically diverse epiphyte community of 58 species from 31 families. Epiphyte removal did not affect the production of fresh fruit bunches, or the species richness and community composition of birds and ants, although the impact on other components of biodiversity remains unknown. We conclude that as they do not adversely affect palm oil production, the diverse epiphyte flora should be left uncut. Our results underscore the importance of experimentally determining the effects of habitat complexity on yield before introducing intensive methods with no discernible benefits. PMID- 26045948 TI - Landscape characteristics influencing the genetic structure of greater sage grouse within the stronghold of their range: a holistic modeling approach. AB - Given the significance of animal dispersal to population dynamics and geographic variability, understanding how dispersal is impacted by landscape patterns has major ecological and conservation importance. Speaking to the importance of dispersal, the use of linear mixed models to compare genetic differentiation with pairwise resistance derived from landscape resistance surfaces has presented new opportunities to disentangle the menagerie of factors behind effective dispersal across a given landscape. Here, we combine these approaches with novel resistance surface parameterization to determine how the distribution of high- and low quality seasonal habitat and individual landscape components shape patterns of gene flow for the greater sage-grouse (Centrocercus urophasianus) across Wyoming. We found that pairwise resistance derived from the distribution of low-quality nesting and winter, but not summer, seasonal habitat had the strongest correlation with genetic differentiation. Although the patterns were not as strong as with habitat distribution, multivariate models with sagebrush cover and landscape ruggedness or forest cover and ruggedness similarly had a much stronger fit with genetic differentiation than an undifferentiated landscape. In most cases, landscape resistance surfaces transformed with 17.33-km-diameter moving windows were preferred, suggesting small-scale differences in habitat were unimportant at this large spatial extent. Despite the emergence of these overall patterns, there were differences in the selection of top models depending on the model selection criteria, suggesting research into the most appropriate criteria for landscape genetics is required. Overall, our results highlight the importance of differences in seasonal habitat preferences to patterns of gene flow and suggest the combination of habitat suitability modeling and linear mixed models with our resistance parameterization is a powerful approach to discerning the effects of landscape on gene flow. PMID- 26045949 TI - The relationship between manuscript title structure and success: editorial decisions and citation performance for an ecological journal. AB - A poorly chosen article title may make a paper difficult to discover or discourage readership when discovered, reducing an article's impact. Yet, it is unclear how the structure of a manuscript's title influences readership and impact. We used manuscript tracking data for all manuscripts submitted to the journal Functional Ecology from 2004 to 2013 and citation data for papers published in this journal from 1987 to 2011 to examine how title features changed and whether a manuscript's title structure was predictive of success during the manuscript review process and/or impact (citation) after publication. Titles of manuscripts submitted to Functional Ecology became marginally longer (after controlling for other variables), broader in focus (less frequent inclusion of genus and species names), and included more humor and subtitles over the period of the study. Papers with subtitles were less likely to be rejected by editors both pre- and post-peer review, although both effects were small and the presence of subtitles in published papers was not predictive of citations. Papers with specific names of study organisms in their titles fared poorly during editorial (but not peer) review and, if published, were less well cited than papers whose titles did not include specific names. Papers with intermediate length titles were more successful during editorial review, although the effect was small and title word count was not predictive of citations. No features of titles were predictive of reviewer willingness to review papers or the length of time a paper was in peer review. We conclude that titles have changed in structure over time, but features of title structure have only small or no relationship with success during editorial review and post-publication impact. The title feature that was most predictive of manuscript success: papers whose titles emphasize broader conceptual or comparative issues fare better both pre- and post-publication than do papers with organism-specific titles. PMID- 26045950 TI - The evolution of pattern camouflage strategies in waterfowl and game birds. AB - Visual patterns are common in animals. A broad survey of the literature has revealed that different patterns have distinct functions. Irregular patterns (e.g., stipples) typically function in static camouflage, whereas regular patterns (e.g., stripes) have a dual function in both motion camouflage and communication. Moreover, irregular and regular patterns located on different body regions ("bimodal" patterning) can provide an effective compromise between camouflage and communication and/or enhanced concealment via both static and motion camouflage. Here, we compared the frequency of these three pattern types and traced their evolutionary history using Bayesian comparative modeling in aquatic waterfowl (Anseriformes: 118 spp.), which typically escape predators by flight, and terrestrial game birds (Galliformes: 170 spp.), which mainly use a "sit and hide" strategy to avoid predation. Given these life histories, we predicted that selection would favor regular patterning in Anseriformes and irregular or bimodal patterning in Galliformes and that pattern function complexity should increase over the course of evolution. Regular patterns were predominant in Anseriformes whereas regular and bimodal patterns were most frequent in Galliformes, suggesting that patterns with multiple functions are broadly favored by selection over patterns with a single function in static camouflage. We found that the first patterns to evolve were either regular or bimodal in Anseriformes and either irregular or regular in Galliformes. In both orders, irregular patterns could evolve into regular patterns but not the reverse. Our hypothesis of increasing complexity in pattern camouflage function was supported in Galliformes but not in Anseriformes. These results reveal a trajectory of pattern evolution linked to increasing function complexity in Galliformes although not in Anseriformes, suggesting that both ecology and function complexity can have a profound influence on pattern evolution. PMID- 26045951 TI - Spatial and temporal variation in harvest probabilities for American black duck. AB - Assessing spatial variation in waterfowl harvest probabilities from banding data is challenging because reporting and recovery probabilities have distinct spatial patterns that covary temporally with harvesting regulations, hunter effort, and reporting methods. We analyzed direct band recovery data from American black ducks banded on the Canadian breeding grounds from 1970 through 2010. Data were registered to a 1-degree grid and analyzed using hierarchical logistic regression models with spatially correlated errors to estimate the annual probabilities of band recovery and the proportion of individuals recovered in Canada. Probability of harvest was estimated from these values, in combination with independent estimates of reporting probabilities in Canada and the USA. Model covariates included estimates of hunting effort and factors for harvest regulation and band reporting methods. Both the band recovery processes and the proportion of individuals recovered in Canada had significant spatial structure. Recovery probabilities were highest in southern Ontario, along the Saint Lawrence River in Quebec, and in Nova Scotia. Black ducks breeding in Nova Scotia and southern Quebec were harvested predominantly in Canada. Recovery probabilities for juveniles were correlated with hunter effort, while the adult recoveries were weakly correlated with the implementation of stricter harvest regulations in the early 1980s. Mean harvest probability decreased in the northern portion of the survey area but remained stable or even increased in the south. Harvest probabilities for juveniles in 2010 exceeded 20% in southern Quebec and the Atlantic provinces. Our results demonstrate fine-scale variation in harvest probabilities for black duck on the Canadian breeding ground. In particular, harvest probabilities should be closely monitored along the Saint Lawrence River system and in the Atlantic provinces to avoid overexploitation. PMID- 26045952 TI - Genetic structure and historical diversification of catfish Brachyplatystoma platynemum (Siluriformes: Pimelodidae) in the Amazon basin with implications for its conservation. AB - Brachyplatystoma platynemum is a catfish species widely distributed in the Amazon basin. Despite being considered of little commercial interest, the decline in other fish populations has contributed to the increase in the catches of this species. The structure, population genetic variability, and evolutionary process that have driven the diversification of this species are presently unknown. Considering that, in order to better understand the genetic structure of this species, we analyzed individuals from seven locations of the Amazon basin using eight molecular markers: control region and cytochrome b mtDNA sequences, and a set of six nuclear microsatellite loci. The results show high levels of haplotype diversity and point to the occurrence of two structured populations (Amazon River and the Madeira River) with high values for F ST. Divergence time estimates based on mtDNA indicated that these populations diverged about 1.0 Mya (0.2-2.5 Mya 95% HPD) using cytochrome b and 1.4 Mya (0.2-2.7 Mya 95% HPD) using control region. During that time, the influence of climate changes and hydrological events such as sea level oscillations and drainage isolation as a result of geological processes in the Pleistocene may have contributed to the current structure of B. platynemum populations, as well as of differences in water chemistry in Madeira River. The strong genetic structure and the time of genetic divergence estimated for the groups may indicate the existence of strong structure populations of B. platynemum in the Amazon basin. PMID- 26045953 TI - Strategies of zooplanktivory shape the dynamics and diversity of littoral plankton communities: a mesocosm approach. AB - Planktivorous fish can exert strong top-down control on zooplankton communities. By incorporating different feeding strategies, from selective particulate feeding to cruising filter feeding, fish species target distinct prey. In this study, we investigated the effects of two species with different feeding strategies, the three-spined stickleback (Gasterosteus aculeatus (L.)) and roach (Rutilus rutilus (L.)), on a low-diversity brackish water zooplankton community using a 16-day mesocosm experiment. The experiment was conducted on a small-bodied spring zooplankton community in high-nutrient conditions, as well as a large-bodied summer community in low-nutrient conditions. Effects were highly dependent on the initial zooplankton community structure and hence seasonal variation. In a small bodied community with high predation pressure and no dispersal or migration, the selective particulate-feeding stickleback depleted the zooplankton community and decreased its diversity more radically than the cruising filter-feeding roach. Cladocerans rather than copepods were efficiently removed by predation, and their removal caused altered patterns in rotifer abundance. In a large-bodied summer community with initial high taxonomic and functional diversity, predation pressure was lower and resource availability was high for omnivorous crustaceans preying on other zooplankton. In this community, predation maintained diversity, regardless of predator species. During both experimental periods, predation influenced the competitive relationship between the dominant calanoid copepods, and altered species composition and size structure of the zooplankton community. Changes also occurred to an extent at the level of nontarget prey, such as microzooplankton and rotifers, emphasizing the importance of subtle predation effects. We discuss our results in the context of the adaptive foraging mechanism and relate them to the natural littoral community. PMID- 26045954 TI - Modeling ecological traps for the control of feral pigs. AB - Ecological traps are habitat sinks that are preferred by dispersing animals but have higher mortality or reduced fecundity compared to source habitats. Theory suggests that if mortality rates are sufficiently high, then ecological traps can result in extinction. An ecological trap may be created when pest animals are controlled in one area, but not in another area of equal habitat quality, and when there is density-dependent immigration from the high-density uncontrolled area to the low-density controlled area. We used a logistic population model to explore how varying the proportion of habitat controlled, control mortality rate, and strength of density-dependent immigration for feral pigs could affect the long-term population abundance and time to extinction. Increasing control mortality, the proportion of habitat controlled and the strength of density dependent immigration decreased abundance both within and outside the area controlled. At higher levels of these parameters, extinction was achieved for feral pigs. We extended the analysis with a more complex stochastic, interactive model of feral pig dynamics in the Australian rangelands to examine how the same variables as the logistic model affected long-term abundance in the controlled and uncontrolled area and time to extinction. Compared to the logistic model of feral pig dynamics, the stochastic interactive model predicted lower abundances and extinction at lower control mortalities and proportions of habitat controlled. To improve the realism of the stochastic interactive model, we substituted fixed mortality rates with a density-dependent control mortality function, empirically derived from helicopter shooting exercises in Australia. Compared to the stochastic interactive model with fixed mortality rates, the model with the density-dependent control mortality function did not predict as substantial decline in abundance in controlled or uncontrolled areas or extinction for any combination of variables. These models demonstrate that pest eradication is theoretically possible without the pest being controlled throughout its range because of density-dependent immigration into the area controlled. The stronger the density-dependent immigration, the better the overall control in controlled and uncontrolled habitat combined. However, the stronger the density-dependent immigration, the poorer the control in the area controlled. For feral pigs, incorporating environmental stochasticity improves the prospects for eradication, but adding a realistic density-dependent control function eliminates these prospects. PMID- 26045955 TI - Diet quality influences isotopic discrimination among amino acids in an aquatic vertebrate. AB - Stable nitrogen isotopic composition of amino acids (delta (15)NAA) has recently been employed as a powerful tool in ecological food web studies, particularly for estimating the trophic position (TP) of animal species in food webs. However, the validity of these estimates depends on the consistency of the trophic discrimination factor (TDF; - Deltadelta (15)NAA at each shift of trophic level) among a suite of amino acids within the tissues of consumer species. In this study, we determined the TDF values of amino acids in tadpoles (the Japanese toad, Bufo japonicus) reared exclusively on one of three diets that differed in nutritional quality. The diets were commercial fish-food pellets (plant and animal biomass), bloodworms (animal biomass), and boiled white rice (plant carbohydrate), representing a balanced, protein-rich, and protein-poor diet, respectively. The TDF values of two "source amino acids" (Src-AAs), methionine and phenylalanine, were close to zero (0.3-0.50/00) among the three diets, typifying the values reported in the literature (~0.50/00 and ~0.40/00, respectively). However, TDF values of "trophic amino acids" (Tr-AAs) including alanine, valine, leucine, isoleucine, and glutamic acid varied by diet: for example, the glutamic acid TDF was similar to the standard value (~8.00/00) when tadpoles were fed either the commercial pellets (8.00/00) or bloodworms (7.90/00), but when they were fed boiled rice, the TDF was significantly reduced (0.60/00). These results suggest that a profound lack of dietary protein may alter the TDF values of glutamic acid (and other Tr-AAs and glycine) within consumer species, but not the two Src-AAs (i.e., methionine and phenylalanine). Knowledge of how a nutritionally poor diet can influence the TDF of Tr- and Src AAs will allow amino acid isotopic analyses to better estimate TP among free roaming animals. PMID- 26045956 TI - Alternative reproductive tactics in snail shell-brooding cichlids diverge in energy reserve allocation. AB - Life history theory predicts that the amount of resources allocated to reproduction should maximize an individual's lifetime reproductive success. So far, resource allocation in reproduction has been studied mainly in females. Intraspecific variation of endogenous energy storage and utilization patterns of males has received little attention, although these patterns may vary greatly between individuals pursuing alternative reproductive tactics (ARTs). ARTs are characterized by systematic variation of behavioral, physiological, and often morphological traits among same-sex conspecifics. Some individuals may rely on previously accumulated reserves, because of limited foraging opportunities during reproduction. Others may be able to continue foraging during reproduction, thus relying on reserves to a lesser extent. We therefore predicted that, if male tactics involve such divergent limitations and trade-offs within a species, ARTs should correspondingly differ in energy reserve allocation and utilization. To test this prediction, we studied short-term and long-term reserve storage patterns of males in the shell-brooding cichlid Lamprologus callipterus. In this species, bourgeois males investing in territory defense, courtship, and guarding of broods coexist with two distinct parasitic male tactics: (1) opportunistic sneaker males attempting to fertilize eggs by releasing sperm into the shell opening when a female is spawning; and (2) specialized dwarf males attempting to enter the shell past the spawning female to fertilize eggs from inside the shell. Sneaker males differed from other male types by showing the highest amount of accumulated short-term and long-term fat stores, apparently anticipating their upcoming adoption of the nest male status. In contrast, nest males depleted previously accumulated energy reserves with increasing nest holding period, as they invest heavily into costly reproductive behaviors while not taking up any food. This conforms to a capital breeder strategy. Dwarf males did not accumulate long-term fat stores at all, which they can afford due to their small behavioral effort during reproduction and their continued feeding activity, conforming to an income breeder strategy. Our data confirm that the resource storage patterns of males pursuing ARTs can diverge substantially, which adds to our understanding of the coexistence and maintenance of alternative reproductive patterns within species. PMID- 26045957 TI - Behavioral responses of Atlantic cod to sea temperature changes. AB - Understanding responses of marine species to temperature variability is essential to predict impacts of future climate change in the oceans. Most ectotherms are expected to adjust their behavior to avoid extreme temperatures and minimize acute changes in body temperature. However, measuring such behavioral plasticity in the wild is challenging. Combining 4 years of telemetry-derived behavioral data on juvenile and adult (30-80 cm) Atlantic cod (Gadus morhua), and in situ ocean temperature measurements, we found a significant effect of sea temperature on cod depth use and activity level in coastal Skagerrak. During summer, cod were found in deeper waters when sea surface temperature increased. Further, this effect of temperature was stronger on larger cod. Diel vertical migration, which consists in a nighttime rise to shallow feeding habitats, was stronger among smaller cod. As surface temperature increased beyond ~15 degrees C, their vertical migration was limited to deeper waters. In addition to larger diel vertical migrations, smaller cod were more active and travelled larger distances compared to larger specimens. Cold temperatures during winter tended, however, to reduce the magnitude of diel vertical migrations, as well as the activity level and distance moved by those smaller individuals. Our findings suggest that future and ongoing rises in sea surface temperature may increasingly deprive cod in this region from shallow feeding areas during summer, which may be detrimental for local populations of the species. PMID- 26045958 TI - Mother-offspring distances reflect sex differences in fine-scale genetic structure of eastern grey kangaroos. AB - Natal dispersal affects life history and population biology and causes gene flow. In mammals, dispersal is usually male-biased so that females tend to be philopatric and surrounded by matrilineal kin, which may lead to preferential associations among female kin. Here we combine genetic analyses and behavioral observations to investigate spatial genetic structure and sex-biased dispersal patterns in a high-density population of mammals showing fission-fusion group dynamics. We studied eastern grey kangaroos (Macropus giganteus) over 2 years at Wilsons Promontory National Park, Australia, and found weak fine-scale genetic structure among adult females in both years but no structure among adult males. Immature male kangaroos moved away from their mothers at 18-25 months of age, while immature females remained near their mothers until older. A higher proportion of male (34%) than female (6%) subadults and young adults were observed to disperse, although median distances of detected dispersals were similar for both sexes. Adult females had overlapping ranges that were far wider than the maximum extent of spatial genetic structure found. Female kangaroos, although weakly philopatric, mostly encounter nonrelatives in fission-fusion groups at high density, and therefore kinship is unlikely to strongly affect sociality. PMID- 26045959 TI - Testing Taxon Tenacity of Tortoises: evidence for a geographical selection gradient at a secondary contact zone. AB - We examined a secondary contact zone between two species of desert tortoise, Gopherus agassizii and G. morafkai. The taxa were isolated from a common ancestor during the formation of the Colorado River (4-8 mya) and are a classic example of allopatric speciation. However, an anomalous population of G. agassizii comes into secondary contact with G. morafkai east of the Colorado River in the Black Mountains of Arizona and provides an opportunity to examine reinforcement of species' boundaries under natural conditions. We sampled 234 tortoises representing G. agassizii in California (n - 103), G. morafkai in Arizona (n - 78), and 53 individuals of undetermined assignment in the contact zone including and surrounding the Black Mountains. We genotyped individuals for 25 STR loci and determined maternal lineage using mtDNA sequence data. We performed multilocus genetic clustering analyses and used multiple statistical methods to detect levels of hybridization. We tested hypotheses about habitat use between G. agassizii and G. morafkai in the region where they co-occur using habitat suitability models. Gopherus agassizii and G. morafkai maintain independent taxonomic identities likely due to ecological niche partitioning, and the maintenance of the hybrid zone is best described by a geographical selection gradient model. PMID- 26045960 TI - Analyzing large-scale conservation interventions with Bayesian hierarchical models: a case study of supplementing threatened Pacific salmon. AB - Myriad human activities increasingly threaten the existence of many species. A variety of conservation interventions such as habitat restoration, protected areas, and captive breeding have been used to prevent extinctions. Evaluating the effectiveness of these interventions requires appropriate statistical methods, given the quantity and quality of available data. Historically, analysis of variance has been used with some form of predetermined before-after control impact design to estimate the effects of large-scale experiments or conservation interventions. However, ad hoc retrospective study designs or the presence of random effects at multiple scales may preclude the use of these tools. We evaluated the effects of a large-scale supplementation program on the density of adult Chinook salmon Oncorhynchus tshawytscha from the Snake River basin in the northwestern United States currently listed under the U.S. Endangered Species Act. We analyzed 43 years of data from 22 populations, accounting for random effects across time and space using a form of Bayesian hierarchical time-series model common in analyses of financial markets. We found that varying degrees of supplementation over a period of 25 years increased the density of natural-origin adults, on average, by 0-8% relative to nonsupplementation years. Thirty-nine of the 43 year effects were at least two times larger in magnitude than the mean supplementation effect, suggesting common environmental variables play a more important role in driving interannual variability in adult density. Additional residual variation in density varied considerably across the region, but there was no systematic difference between supplemented and reference populations. Our results demonstrate the power of hierarchical Bayesian models to detect the diffuse effects of management interventions and to quantitatively describe the variability of intervention success. Nevertheless, our study could not address whether ecological factors (e.g., competition) were more important than genetic considerations (e.g., inbreeding depression) in determining the response to supplementation. PMID- 26045962 TI - A quantitative assessment of the Hadoop framework for analyzing massively parallel DNA sequencing data. AB - BACKGROUND: New high-throughput technologies, such as massively parallel sequencing, have transformed the life sciences into a data-intensive field. The most common e-infrastructure for analyzing this data consists of batch systems that are based on high-performance computing resources; however, the bioinformatics software that is built on this platform does not scale well in the general case. Recently, the Hadoop platform has emerged as an interesting option to address the challenges of increasingly large datasets with distributed storage, distributed processing, built-in data locality, fault tolerance, and an appealing programming methodology. RESULTS: In this work we introduce metrics and report on a quantitative comparison between Hadoop and a single node of conventional high-performance computing resources for the tasks of short read mapping and variant calling. We calculate efficiency as a function of data size and observe that the Hadoop platform is more efficient for biologically relevant data sizes in terms of computing hours for both split and un-split data files. We also quantify the advantages of the data locality provided by Hadoop for NGS problems, and show that a classical architecture with network-attached storage will not scale when computing resources increase in numbers. Measurements were performed using ten datasets of different sizes, up to 100 gigabases, using the pipeline implemented in Crossbow. To make a fair comparison, we implemented an improved preprocessor for Hadoop with better performance for splittable data files. For improved usability, we implemented a graphical user interface for Crossbow in a private cloud environment using the CloudGene platform. All of the code and data in this study are freely available as open source in public repositories. CONCLUSIONS: From our experiments we can conclude that the improved Hadoop pipeline scales better than the same pipeline on high-performance computing resources, we also conclude that Hadoop is an economically viable option for the common data sizes that are currently used in massively parallel sequencing. Given that datasets are expected to increase over time, Hadoop is a framework that we envision will have an increasingly important role in future biological data analysis. PMID- 26045963 TI - Effect of difference doses of Newcastle disease vaccine immunization on growth performance, plasma variables and immune response of broilers. AB - BACKGROUND: As a member of the Paramyxoviridae group, Newcastle disease virus (NDV) is the key causative agent of Newcastle disease (ND) that attacks chickens, turkeys and other avian birds. Surviving birds showed lower feed utilization, growth performance or egg production, which results in severe economic losses. The purpose of this study was to determine the effect of different doses of NDV immunization on growth performance, plasma variables and immune response of broiler chickens. METHODS: A total of 480 one-day-old Arbor Acres broilers were randomly administrated with 0, 4, 6 or 8 doses of NDV at 12 d and 28 d, respectively. Each group consisted of ten replicates with 12 birds each. Growth performance and organ weight were recorded. Plasma concentration of glucose, total protein, cholesterol, triglycerides and nonesterified fatty acid was determined using commercial kits. The concentration of plasma corticosterone and insulin was measured using commercially available radio immune assay kits. Serum antibody titer and peripheral blood lymphocyte proliferation were also recorded. RESULTS: The results showed that NDV decreased body weight gain (BWG), and increased Feed:Gain ratio at 1-21 d at all doses (P < 0.05). Plasma insulin concentration was lower in all immunization groups after the first immunization at 12 d (P < 0.01). The rest of the plasma indexes were not affected by NDV immunization, including glucose, total protein, cholesterol, triglycerides, nonesterified fatty acid, heterophil/lymphocyte ratio, as well as the proliferation of peripheral blood lymphocyte (P > 0.05). Compared with the control group, NDV treatment elevated NDV antibody titer at 10 d after the first inoculation (P < 0.05), and at d 5, 9 and 13 after the second inoculation (P < 0.05). Repeated NDV inoculation had no deleterious impacts on body composition at 42 d, and nutrient accretion rates at 8-42 d (P > 0.05). CONCLUSIONS: In conclusion, NDV challenge decreased BWG and feed efficiency in earlier stage of growth. However, NDV treatment at 6 doses down-regulated the Feed:Gain ratio by 6.36 % throughout the whole growing period. These data suggest that appropriate lower doses of NDV inoculation increase feed efficiency of broiler chickens. PMID- 26045964 TI - High-intensity focused ultrasound ablation enhancement in vivo via phase-shift nanodroplets compared to microbubbles. AB - BACKGROUND: During high-intensity focused ultrasound (HIFU) surgical procedures, there is a need to rapidly ablate pathological tissue while minimizing damage to healthy tissue. Current techniques are limited by relatively long procedure times and risks of off-target heating of healthy tissue. One possible solution is the use of microbubbles, which can improve the efficiency of thermal energy delivery during HIFU procedures. However, microbubbles also suffer from limitations such as low spatial selectivity and short circulation time in vivo. In this study, the use of a dual-perfluorocarbon nanodroplet that can enhance thermal ablation, yet retains high spatial selectivity and circulation half-life, was evaluated in vivo and compared to traditional microbubble agents during HIFU ablations of rat liver. METHODS: High-intensity focused ultrasound (1.1 MHz, 4.1 MPa, 15-s continuous wave) was applied to rat liver in vivo, and heating was monitored during sonication by magnetic resonance thermometry. Thermometry data were analyzed to quantify temperature rise and ablated area, both at the target and prefocally, for HIFU applied 5, 15, or 95 min after intravenous injection of either nanodroplet or microbubble agents. Sham control experiments (no injected agents) were also performed. RESULTS: At all three time points, nanodroplets significantly enhanced thermal delivery to the target, achieving temperatures 130 % higher and ablated areas 30 times larger than no-agent control sonications. Nanodroplets did not significantly enhance off-target surface heating. Microbubbles also resulted in significantly greater thermal delivery, but heating was concentrated at the proximal surface of the animal, causing skin burns. Furthermore, microbubbles resulted in lower thermal delivery to the desired target than even the control case, with the notable exception of the 95-min time point. CONCLUSIONS: Results indicate that the nanodroplet formulation studied here can substantially increase thermal delivery at the acoustic focus while avoiding prefocal heating. In contrast, microbubbles resulted in greater prefocal heating and less heating at the target. Furthermore, nanodroplets are sufficiently stable to enhance HIFU ablation in vivo for at least 1.5 h after injection. The use of a dual-perfluorocarbon nanodroplet formulation as described herein could substantially reduce HIFU procedure times without increasing the risk of skin burns. PMID- 26045966 TI - Prevalence and correlates of anemia among HIV infected patients on highly active anti-retroviral therapy at Zewditu Memorial Hospital, Ethiopia. AB - BACKGROUND: Ethiopia is one of the most seriously HIV affected countries in Sub Saharan Africa. Anemia is a known predictor of disease progression and death among HIV infected patients. In this study, we investigated the magnitude and correlates of anemia among HIV infected patients receiving HAART at a referral hospital in Ethiopia. METHODS: A retrospective cohort study was conducted from November 2011 to February 2012 in Zewditu Memorial Hospital, Addis Ababa, Ethiopia. Records of 1061 patients on HAART were selected using simple random sampling technique. Socio-demographic and clinical characteristics of the study patients were collected using standardized data extraction instrument. Data were analyzed using STATA version 11.0. Odds ratios with 95% confidence intervals were used to quantify the strength of association between anemia and its potential predictors. RESULTS: The prevalence of anemia at baseline was 42.9%. However, the prevalence significantly decreased to 20.9% at 6 months (p < 0.001) and to 14.3% at 12 months (p = 0.001) after HAART initiation. At baseline, male sex (AOR = 1.55; 95% CI: 1.18-2.03), clinical stage III/IV (AOR = 2.03; 95% CI: 1.45-2.83) and TB co-infection (AOR = 1.52; 95% CI: 1.08-2.13) were independently associated with the odds of being anemic. After 6 months of HAART, male sex (AOR = 1.59; 95% CI: 1.13-2.23), baseline anemia (AOR = 2.38; 95% CI: 1.71-3.33) and TDF-based HAART (AOR = 2.87; 95% CI: 1.80-4.60) were independently associated with the odds of being anemic. Besides, anemia was independently associated with older age at 6 months. After 12 months of HAART, baseline anemia (AOR = 2.01; 95% CI: 1.36 2.97), age group 25-34 years (AOR = 5.92; 95% CI: 1.39-25.15), age group 45-54 years (AOR = 4.78; 95% CI: 1.07-21.36), CD4 count below 200 cells/mm(3) (AOR = 2.15; 95% CI: 1.21-3.82) and 200-350 cells/mm(3) (AOR = 1.91; 95% CI: 1.13-3.25) were independently associated with the odds of being anemic. CONCLUSIONS: Although a remarkable reduction in the prevalence of anemia was observed following initiation of HAART, a significant proportion of HIV patients remained anemic after 12 months of HAART suggesting the need for routine screening and proper treatment of anemia to mitigate its adverse effects. PMID- 26045965 TI - Mechanical ventilation of acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) has been intensively and continuously studied in various settings, but its mortality is still as high as 30-40 %. For the last 20 years, lung protective strategy has become a standard care for ARDS, but we still do not know the best way to ventilate patients with ARDS. Tidal volume itself does not seem to have an important role to develop ventilator induced lung injury (VILI), but the driving pressure, which is inspiratory plateau pressure-PEEP, is the most important to predict and affect the outcome of ARDS, though there is no safe limit for the driving pressure. There is so much controversy regarding what the best PEEP is, whether collapsed lung should be recruited, and what parameters should be measured and evaluated to improve the outcome of ARDS. Since the mechanical ventilation for patients with respiratory failure, including ARDS, is a standard care, we need more dynamic and regional information of ventilation and pulmonary circulation in the injured lungs to evaluate the efficacy of new type of treatment strategy. In addition to the CT scanning of the lung as the gold standard of evaluation, the electrical impedance tomography (EIT) of the lung has been clinically available to provide such information non-invasively and at the bedside. Various parameters have been tested to evaluate the homogeneity of regional ventilation, and EIT could provide us with the information of ventilator settings to minimize VILI. PMID- 26045967 TI - Heavy metals determination in honey samples using inductively coupled plasma optical emission spectrometry. AB - BACKGROUND: Honey contains a complex mixture of carbohydrates and other minor substances. Elements are minor constituents of honey that may threaten the human health in excess concentrations. So, determining the metals in honey helps its quality control as a food product. The aim of this study was to determine the concentrations of some metals in Iranian honey. METHODS: This study was performed in four regions of Ardabil, a province of Iran. Honey samples (n = 25) were digested in microwave oven by nitric acid and hydrogen peroxide, then analyzed using inductively coupled plasma- optic emission spectrophotometry (ICP-OES). RESULTS: No significant differences were observed in cadmium, zinc, nickel, and chromium levels between regions (P > 0.05). Zinc was the most abundant metal in honey samples (1481.64 MUg/kg). Some metals had higher concentrations in the East region because of existence more industries there. The highest mean of lead level was 935.48 MUg/kg in the East and the lowest was 205.4 MUg/kg in the South region. The concentrations of metals were compared with recommended limits for foods. Some of them were higher than standard levels (lead) and some were lower than those (cadmium). CONCLUSIONS: Metals are released into the environment through their use in industrial processes and enter the food chain from uptake by plants from contaminated soil or water. Metals concentration in various places depends on many variables, leading to their different concentrations in honey. Some control measures like the quality control of food products, monitoring the soil in agricultural regions and limiting the use of fertilizers are recommended. PMID- 26045968 TI - Impact of noise on hearing in the military. AB - Hearing plays a vital role in the performance of a soldier and is important for speech processing. Noise-induced hearing loss is a significant impairment in the military and can affect combat performance. Military personnel are constantly exposed to high levels of noise and it is not surprising that noise induced hearing loss and tinnitus remain the second most prevalent service-connected disabilities. Much of the noise experienced by military personnel exceeds that of maximum protection achievable with double hearing protection. Unfortunately, unlike civilian personnel, military personnel have little option but to remain in noisy environments in order to complete specific tasks and missions. Use of hearing protection devices and follow-up audiological tests have become the mainstay of prevention of noise-induced hearing loss. This review focuses on sources of noise within the military, pathophysiology and management of patients with noise induced hearing loss. PMID- 26045970 TI - Mass poisoning after consumption of a hawksbill turtle, Federated States of Micronesia, 2010. AB - BACKGROUND: Marine turtles of all species are capable of being toxic. On 17 October 2010, health authorities in the Federated States of Micronesia were notified of the sudden death of three children and the sickening of approximately 20 other people on Murilo Atoll in Chuuk State. The illnesses were suspected to be the result of mass consumption of a hawksbill turtle (Eretmochelys imbricata). An investigation team was assembled to confirm the cause of the outbreak, describe the epidemiology of cases and provide recommendations for control. METHODS: We conducted chart reviews, interviewed key informants, collected samples for laboratory analysis, performed environmental investigations and conducted a cohort study. RESULTS: Four children and two adults died in the outbreak and 95 others were sickened; 84% of those who ate the turtle became ill (n = 101). The relative risk for developing illness after consuming the turtle was 11.1 (95% confidence inteval: 4.8-25.9); there was a dose-dependent relationship between amount of turtle meat consumed and risk of illness. Environmental and epidemiological investigations revealed no alternative explanation for the mass illness. Laboratory testing failed to identify a causative agent. CONCLUSION: We concluded that turtle poisoning (also called chelonitoxism) was the cause of the outbreak on Murilo. The range of illness described in this investigation is consistent with previously reported cases of chelonitoxism. This devastating incident highlights the dangers, particularly to children, of consuming turtle meat. Future incidents are certain to occur unless action is taken to alter turtle-eating behaviour in coastal communities throughout the world. PMID- 26045971 TI - Associations between birth and one year anthropometric measurements and IGF2 and IGF2R genetic variants in African American and Caucasian American infants. AB - Insulin-like growth factor 2 receptor (IGF2R) and insulin-like growth factor 2 (IGF2) genetic variants have been inconsistently associated with low birth weight and birth length in Caucasian and Asian infants, however few studies have included African Americans (AA). Generalized linear models and logistic regression models were used to examine associations between IGF2R single nucleotide polymorphisms (SNP) rs629849 and rs8191754, and IGF2 SNP rs680 and infant anthropometric measurements, in a racially diverse birth cohort in Durham County, North Carolina. Caucasian American (CA) carriers of the IGF2R SNP rs629849 were heavier (P = 0.02) and longer (P = 0.003) at birth, however body size at age 1 yr was similar to that of AA. Birth length significantly differed between carriers and non-carriers of the IGF2 rs680 variant in both AA (P = 0.04) and CA infants (P = 0.03). Both AA and CA carriers were 1 cm shorter at birth compared to non-carriers. We found no evidence for an association between rs8191754 and infant anthropometric measurements. Associations between SNPs andone year weight gain were only observed for rs680; CA infant carriers of rs680 variants weighed less than non-carriers at year one (P = 0.03); however, no associations were found in AA infants at year one. Larger studies using ancestral markers are required to disentangle these associations. PMID- 26045969 TI - Programmed cell death and its role in inflammation. AB - Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases. PMID- 26045973 TI - Identification of a Peptide from In vivo Bacteriophage Display with Homology to EGFL6: A Candidate Tumor Vasculature Ligand in Breast Cancer. AB - BACKGROUND: A crucial step in tumorigenesis is the recruitment of novel vasculature to the site of neoplasia. Currently, a number of high throughput techniques are employed to identify genes, mRNA and proteins that are aberrantly expressed in tumor vasculature. One drawback of such techniques is the lack of functional in vivo data that they provide. Bacteriophage (phage) display has been demonstrated in vivo to select peptides that home to tumors and tumor vasculature. The peptides can be compared to sequences of putative cancer-related proteins, in order to identify novel proteins essential for tumorigenesis. OBJECTIVES: It was hypothesized that an in vivo selection for phage which targeted human breast cancer xenografts could identify peptides with homology to cancer-related proteins for in vivo imaging of breast cancer. METHODS: Following four rounds of in vivo selection in human MDA-MB-435 breast cancer xenografted mice, peptide 3-G03 was discovered with significant homology to a putative secreted protein termed EGFL6. Egfl6 mRNA is upregulated in several transcriptomic analyses of human cancer biopsies, and the protein may play a role in tumor vascularization. RESULTS: Egfl6 mRNA expression was demonstrated in MDA MB-435 cells and EGFL6 protein was secreted from these cells. Based on homology of 3-G03 to EGFL6, an EGFL6 peptide was synthesized and shown to target MDA-MB 435 cells. EGFL6 peptide was radiolabeled with 111In and analyzed for biodistribution and tumor imaging capabilities. Single photon emission computed tomography imaging revealed uptake of the peptide in a manner consistent with other tumor vasculature targeting agents. PMID- 26045972 TI - Interleukin-34 induces monocytic-like differentiation in leukemia cell lines. AB - Interleukin-34 (IL-34) is a cytokine consisting of a 39kD homodimer, shown to be a ligand for both the Macrophage Colony Stimulating Factor (M-CSF/CSF-1) receptor and the Receptor-like protein tyrosine phosphatase-zeta (RPTP-e). IL-34 has been shown to promote monocyte viability and proliferation as well as the differentiation of bone marrow cells into macrophage progenitors. Published work on IL-34 involves its effects on normal hematopoietic and osteoclast progenitors. However, it is not known whether IL-34 has biologic effects in cancer, including leukemia. Here we report that the biological effects of IL-34 include induction of differential expression of Interleukins-1alpha and -1beta as well as induction of differentiation of U937, HL-60 and THP-1 leukemia cell lines demonstrating monocyte-like characteristics. The ability of IL-34 to induce monocytic-like differentiation is supported by strong morphological and functional evidence. Cell surface markers of myeloid lineage, CD64 and CD86, remain constant while the levels of CD11b and CD71 decline with IL-34 treatment. IL-34 also induced increases in CD14 and CD68 expression, further supporting maturation toward monocytic character. IL-34-induced differentiated U937 and THP-1 cell lines exhibited biological functions such as endocytosis and respiratory burst activities. Collectively, we conclude that while IL-34 does not induce cell growth or proliferation, it is able to induce differentiation of leukemia cell lines from monoblastic precursor cells towards monocyte- and macrophage-like cells, mediated through the JAK/STAT and PI3K/Akt pathways. To our knowledge, this is the first report that IL-34 induces differentiation in human leukemic cells, let alone any cancer model. PMID- 26045974 TI - Tubal origin of ovarian endometriosis and clear cell and endometrioid carcinoma. AB - Current research has strongly proposed that contrary to prior beliefs, many ovarian epithelial cancers (OECs) do not, as their name suggests, originate in the ovaries. Recent findings regarding both high-grade and low-grade serous carcinomas has implicated the fallopian tube as a cell source for these OECs, but until now, there has been little insight into the cellular source for clear cell and endometrioid carcinomas. In this commentary review article, we aimed to discuss the new findings that support the possible contribution from the fallopian tube in clear cell and endometrioid carcinomas. Specifically, we have provided results that showcased ovarian surface epithelia (OSE) and ovarian epithelial inclusions (OEIs) as having mesothelial and tubal origins and have strongly recognized the secondary mullerian system and the ability for tubal epithelia to implant upon the ovarian surface as contributing to fallopian tube derived OEIs (F-OEIs). We have provided initial indications of these F-OEIs and their relationship to endometriosis and then clear cell and endometrioid carcinomas and subsequently offer our new proposal of a probable tubal origin. This new proposal is a paradigm that drastically changes the understanding behind the origin of these OECs and has significant clinical implications in the near future. PMID- 26045975 TI - Chemotherapy targeting cancer stem cells. AB - Conventional chemotherapy is the main treatment for cancer and benefits patients in the form of decreased relapse and metastasis and longer overall survival. However, as the target therapy drugs and delivery systems are not wholly precise, it also results in quite a few side effects, and is less efficient in many cancers due to the spared cancer stem cells, which are considered the reason for chemotherapy resistance, relapse, and metastasis. Conventional chemotherapy limitations and the cancer stem cell hypothesis inspired our search for a novel chemotherapy targeting cancer stem cells. In this review, we summarize cancer stem cell enrichment methods, the search for new efficient drugs, and the delivery of drugs targeting cancer stem cells. We also discuss cancer stem cell hierarchy complexity and the corresponding combination therapy for both cancer stem and non-stem cells. Learning from cancer stem cells may reveal novel strategies for chemotherapy in the future. PMID- 26045976 TI - Pancreatic cancer stem cells. AB - Studies are emerging in support of the cancer stem cells (CSCs) theory which considers that a tiny subset of cancer cells is exclusively responsible for the initiation and malignant behavior of a cancer. This cell population, also termed CSCs, possesses the capacity both to self-renew, producing progeny that have the identical tumorigenic potential, and to differentiate into the bulk of cancer cells, helping serve the formation of the tumor entities, which, altogether, build the hierarchically organized structure of a cancer. In this review, we try to articulate the complicated signaling pathways regulating the retention of the characteristics of pancreatic CSCs, and in the wake of which, we seek to offer insights into the CSCs-relevant targeted therapeutics which are, in the meantime, confronted with bigger challenges than ever. PMID- 26045977 TI - Long non-coding RNAs in gastric cancer: versatile mechanisms and potential for clinical translation. AB - Gastric cancer (GC) remains a serious threat to many people, representing the second leading cause of cancer-related death worldwide. The lack of early diagnostic biomarkers, effective prognostic indicators and therapeutic targets all account for the poor prognosis of GC. Therefore, the identification of novel molecular biomarkers for early diagnosis, therapeutic response, and prognosis are urgently needed. High-throughput sequencing has identified a large number of transcribed long non-coding RNAs (lncRNAs) throughout the human genome. Accumulating evidence demonstrates that these lncRNAs play multiple roles in regulating gene expression at the transcriptional, post-transcriptional, and epigenetic levels. Aberrant expression of lncRNAs occurs in various pathological processes, including GC. Many dysregulated lncRNAs in GC have been significantly associated with a larger tumor size, higher degree of tumor invasion, lymph node and distant metastasis, and poorer survival outcome. In this review, we will provide an overview of the pathogenesis of GC, the characteristics and regulatory functions of lncRNAs, and the versatile mechanisms of lncRNAs in GC development, as well as evaluate the translational potential of lncRNAs as novel diagnostic and prognostic biomarkers and therapeutic targets in GC. PMID- 26045978 TI - Homeostasis of redox status derived from glucose metabolic pathway could be the key to understanding the Warburg effect. AB - Glucose metabolism in mitochondria through oxidative phosphorylation (OXPHOS) for generation of adenosine triphosphate (ATP) is vital for cell function. However, reactive oxygen species (ROS), a by-product from OXPHOS, is a major source of endogenously produced toxic stressors on the genome. In fact, ATP could be efficiently produced in a high throughput manner without ROS generation in cytosol through glycolysis, which could be a unique and critical metabolic pathway to prevent spontaneous mutation during DNA replication. Therefore glycolysis is dominant in robust proliferating cells. Indeed, aerobic glycolysis, or the Warburg effect, in normal proliferating cells is an example of homeostasis of redox status by transiently shifting metabolic flux from OXPHOS to glycolysis to avoid ROS generation during DNA synthesis and protect genome integrity. The process of maintaining redox homeostasis is driven by genome wide transcriptional clustering with mitochondrial retrograde signaling and coupled with the glucose metabolic pathway and cell division cycle. On the contrary, the Warburg effect in cancer cells is the results of the alteration of redox status from a reprogramed glucose metabolic pathway caused by the dysfunctional OXPHOS. Mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) disrupt mitochondrial structural integrity, leading to reduced OXPHOS capacity, sustained glycolysis and excessive ROS leak, all of which are responsible for tumor initiation, progression and metastasis. A "plumbing model" is used to illustrate how redox status could be regulated through glucose metabolic pathway and provide a new insight into the understanding of the Warburg effect in both normal and cancer cells. PMID- 26045979 TI - TGF-beta signaling and its targeting for glioma treatment. AB - Transforming growth factor-beta (TGF-beta) is a pleiotropic cytokine, secreted by a variety of cells including immune cells, tumor cells, and stromal cells. TGF beta signaling is dysregulated in cancer patients, and this aberrant signaling at least in part contributes to initiation and progression of many cancers including glioma. The dysregulated signaling components provide molecular targets for the treatment of glioma. In this article, we review TGF-beta signaling and its targeting in glioma. PMID- 26045980 TI - Epigenetic modulation of insulin-like growth factor-II overexpression by hepatitis B virus X protein in hepatocellular carcinoma. AB - Hepatitis B virus X protein (HBx) is involved in the pathogenesis of hepatocellular carcinoma (HCC). Overexpression of the transcripts from the P3 and P4 promoters of the insulin-like growth factor-II (IGF-II) gene is observed in HCC. The present study investigated the involvement of HBx in IGF-II overexpression and its epigenetic regulation. Firstly, the effects of HBx on P3 and P4 mRNA expression, the methylation status of the P3 and P4 promoters, and MBD2 expression were analyzed in human HCC cells and HCC samples. Next, interaction between HBx and MBD2 or CBP/p300 was assessed by co immunoprecipitation, and HBx-mediated binding of MBD2 and CBP/p300 to the P3 and P4 promoters and the acetylation of the corresponding histones H3 and H4 were evaluated by quantitative chromatin immunoprecipitation. Finally, using siRNA knockdown, we investigated the roles of MBD2 and CBP/p300 in IGF-II overexpression and its epigenetic regulation. Our results showed that HBx promotes IGF-II expression via inducing the hypomethylation of the P3 and P4 promoters, and that HBx increases MBD2 expression, directly interacts with MBD2 and CBP/p300, and elevates their recruitment to the hypomethylated P3 and P4 promoters with increased acetylation levels of the corresponding histones H3 and H4. Further results showed that endogenous MBD2 and CBP/p300 are necessary for HBx-induced IGF-II overexpression and that CBP/p300 presence and CBP/p300 mediated acetylation of histones H3 and H4 are partially required for MBD2 binding and its demethylase activity. These data suggest that HBx induces MBD2 HBx-CBP/p300 complex formation via interaction with MBD2 and CBP/p300, which contributes to the hypomethylation and transcriptional activation of the IGF-II P3 and P4 promoters and that CBP/p300-mediated acetylation of histones H3 and H4 may be a rate-limiting step for the hypomethylation and activation of these two promoters. This study provides an alternative mechanism for understanding the pathogenesis of HBx-mediated HCC. PMID- 26045981 TI - Status of epigenetic chromatin modification enzymes and esophageal squamous cell carcinoma risk in northeast Indian population. AB - Esophageal cancer incidence is reported in high frequency in northeast India. The etiology is different from other population at India due to wide variations in dietary habits or nutritional factors, tobacco/betel quid chewing and alcohol habits. Since DNA methylation, histone modification and miRNA-mediated epigenetic processes alter the gene expression, the involvement of these processes might be useful to find out epigenetic markers of esophageal cancer risk in northeast Indian population. The present investigation was aimed to carryout differential expression profiling of chromatin modification enzymes in tumor and normal tissue collected from esophageal squamous cell carcinoma (ESCC) patients. Differential mRNA expression profiling and their validation was done by quantitative real time PCR and tissue microarray respectively. Univariate and multiple logistic regression analysis were used to analyze the epidemiological data. mRNA expression data was analyzed by Student t-test. Fisher exact test was used for tissue microarray data analysis. Higher expression of enzymes regulating methylation (DOT1L and PRMT1) and acetylation (KAT7, KAT8, KAT2A and KAT6A) of histone was found associated with ESCC risk. Tissue microarray done in independent cohort of 75 patients revealed higher nuclear protein expression of KAT8 and PRMT1 in tumor similar to mRNA expression. Expression status of PRMT1 and KAT8 was found declined as we move from low grade to high grade tumor. Betel nut chewing, alcohol drinking and dried fish intake were significantly associated with increased risk of esophageal cancer among the study subject. Study suggests the association of PRMT1 and KAT8 with esophageal cancer risk and its involvement in the transition process of low to high grade tumor formation. The study exposes the differential status of chromatin modification enzymes between tumor and normal tissue and points out that relaxed state of chromatin facilitates more transcriptionally active genome in esophageal carcinogenesis. PMID- 26045982 TI - Effect of HM910, a novel camptothecin derivative, on the inhibition of multiple myeloma cell growth in vitro and in vivo. AB - Despite a variety of novel therapeutic agents, such as bortezomib, thalidomide and topotecan, multiple myeloma (MM) remains an incurable disease, thus the development of new chemotherapeutical agents is of high priority. We found HM910, a novel camptothecin (CPT) derivative, exhibited potent inhibition of MM cell growth in vitro and in xenografts of nude mice. Mechanistically, HM910 reduced the mitochondrial transmembrane potential (DeltaPsim) via an increase in reactive oxygen species (ROS), which eventually resulting in the release of cytochrome c and the activation of mitochondrial-dependent apoptotic pathway. On the other hand, HM910 significantly triggered cell cycle arrest in G1 phase via downregulating the expressions of cyclin dependent kinase (CDK) 4 and 6, resulting in down-regulation of cyclin D1. Therefore, HM910 maybe a promising candidate for treating MM patients and is currently in phase I clinical trial in China. PMID- 26045983 TI - Increased sensitivity of HPV-positive head and neck cancer cell lines to x irradiation +/- Cisplatin due to decreased expression of E6 and E7 oncoproteins and enhanced apoptosis. AB - Squamous cell carcinoma of the head and neck region (HNSCC), which is related to an infection with human papilloma virus (HPV), responds better to simultaneous radio-chemotherapy with Cisplatin based regimens than HPV-negative tumors. The underlying molecular mechanisms for this clinical observation are not fully understood. Therefore, the response of four HPV-positive (HPV+) (UM-SCC-47, UM SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (HPV-) (UD-SCC-1, UM-SCC 6, UM-SCC-11b, UT-SCC-33) HNSCC cell lines to x-irradiation +/- Cisplatin incubation in terms of clonogenic survival, cell cycle progression, protein expression (cyclin A2, cyclin E2, E6, E7, p53) and induction of apoptosis, was investigated. HPV+ cells were more radio- and chemosensitive and were more effectively sensitized to x-irradiation by simultaneous Cisplatin incubation than HPV- cell lines. HPV+ cell lines revealed an increased and prolonged G2/M arrest after irradiation, whereas Cisplatin induced a blockage of cells in S phase. In comparison to irradiation only, addition of Cisplatin significantly enhanced apoptosis especially in HPV+ cell lines. While irradiation alone increased the amount of HPV E6 and E7 proteins, both were down-regulated by Cisplatin incubation either alone or in combination with x-rays, which however did not increase the expression of endogenous p53. Our results demonstrate that cell cycle deregulation together with downregulation of HPV E6 and E7 proteins facilitating apoptosis after Cisplatin incubation promote the enhanced sensitivity of HPV+ HNSCC cells to simultaneous radio-chemotherapy. Combined effects of irradiation and Cisplatin appear to be relevant in mediating the enhanced therapeutic response of HPV-related HNSCC and are indicative of the benefit of combined modality approaches in future treatment optimization strategies. PMID- 26045984 TI - Wnt2 promotes non-small cell lung cancer progression by activating WNT/beta catenin pathway. AB - BACKGROUND: Wnt2 is overexpressed and able to promote tumorigenesis in many types of cancer. However, its expression and role in lung cancer has not been well clarified yet. In this study, we aims to investigate the expression pattern, clinical significance and the underlying molecular mechanism of Wnt2 in non-small lung cancer (NSCLC). METHODS: Immunohistochemical staining and ELISA assays were applied to detect Wnt2 level in tumor tissue and serum. EDU incorporation assays and colony formation assays were used to evaluate the growth-promoting effect of Wnt2 in vitro. Then we performed western blot and immunofluorescence assays to detect the activation of WNT signaling pathway. Finally mice engrafted with NSCLC tumor cells were used to assess the role of Wnt2 in vivo. RESULTS: Immunohistochemical staining consisting of 264 NSCLC tumor tissues showed that a high level of Wnt2 was associated with a poor overall survival (OS) and relapse free survival (RFS) of NSCLC patients (P = 0.002 and 0.0005, respectively). Multivariate analysis presented that Wnt2 level in tumor tissue was an independent prognostic factor (P = 0.049 for OS and P = 0.002 for RFS, respectively). Furthermore, ELISA assays for 181 individuals (116 NSCLC and 65 controls) revealed that serum Wnt2 levels in adenocarcinoma was significantly higher than that in healthy volunteers (P < 0.0001). In vitro H460 cell line stably overexpressing Wnt2 showed enhanced growth activity than the control cells whereas knockdown of Wnt2 by siRNA in H1299 cells resulted in decreased growth activity. Additionally, Wnt2 level in tumor tissues was significantly associated with Ki-67 level (rs: 0.316; P < 0.0001). Immunofluorescence and Western blot assays detected the translocation of beta-catenin from cytoplasm into nucleus, which indicated that Wnt2 probably promotes proliferation by activating WNT/beta catenin pathway. In vivo H460 cells expressing exogenous Wnt2 showed increased growth-promoting effect in Balb/c nude mice than control cells. CONCLUSIONS: The present study for the first time suggested that Wnt2 was both a prognostic and a diagnostic biomarker for NSCLC. Tumor-derived Wnt2 can promote growth activity of NSCLC cells through activating WNT/beta-catenin signaling pathway. PMID- 26045985 TI - Hispidulin prevents hypoxia-induced epithelial-mesenchymal transition in human colon carcinoma cells. AB - Epithelial-mesenchymal transition (EMT) is considered as the most important mechanism that underlies the initiation of cancer metastasis. Here we report that the naturally existing flavonoid, hispidulin is capable of preventing human colorectal cancer cells from hypoxia-induced EMT. The treatment of the cells with hispidulin reversed the EMT-related phenotype that has the morphological changes, down-regulation of E-cadherin, and hypoxia-induced cell migration and invasion. The effect was mediated at least in part by inhibiting the mRNA and protein expressions of HIF-1alpha via modulation of PTEN/PI3K/Akt pathway. In addition, we found that hispidulin-mediated prevention of the E-cadherin down-regulation and cell motility involved blockade of the hypoxia-induced up-regulation of Snail, Slug and Twist. Hispidulin was also effective in increasing expression of E-cadherin mRNA in HT29 colorectal cancer xenografts implanted in the nude mice. In summary, this study showed that hispidulin can prevent EMT induced by hypoxia, the environment that commonly exists in the center of a solid tumor. Given the low toxicity of hispidulin to the healthy tissues, our study suggests that hispidulin can serve as a safe therapeutic agent for suppressing cancer metastasis. PMID- 26045986 TI - MicroRNA-330-3p functions as an oncogene in human esophageal cancer by targeting programmed cell death 4. AB - MicroRNAs comprise a family of small non-coding RNA molecules that have emerged as key post-transcriptional regulators of gene expression. Aberrant miRNA expression has been linked to various human tumors. This study was aimed to identify novel miRNAs involved in the carcinogenesis of esophageal squamous cell carcinoma (ESCC) and their potential functions. We performed miRNA microarray and found that miR-330-3p was highly expressed in ESCC tumor tissues. qRT-PCR further confirmed the result in other 35 pairs of ESCC tumor tissues and ESCC cell lines. Ectopic expression of miR-330-3p significantly promoted ESCC cell proliferation, survival, migration, invasion in vitro and stimulated tumor formation in nude mice. Knockdown of miR-330-3p leaded to the opposite effects. The luciferase assay confirmed that miR-330-3p directly interacted with the PDCD4 mRNA 3' un translated region (UTR). Moreover, expression of PDCD4 was inversely associated with miR-330-3p in ESCC tissues. Silencing of PDCD4 significantly promoted cell growth, cell migration, invasion and inhibited cisplatin-induced apoptosis in ESCC cells. This study suggested that miR-330-3p might play an oncogenic role in the development of ESCC partially via suppression of PDCD4 expression. PMID- 26045987 TI - c-Myc plays a key role in TADs-induced apoptosis and cell cycle arrest in human hepatocellular carcinoma cells. AB - Cancer cell growth is complicated progression which is regulated and controlled by multiple factors including cell cycle, migration and apoptosis. In present study, we report that TADs, a novel derivative of taspine, has an essential role in resisting hepatocellular carcinoma growth (including arrest cell cycle) and migration, and inducing cell apoptosis. Our findings demonstrated that the TADs showed good inhibition on the hepatoma cell growth and migration, and good action on apoptosis induction. Using genome-wide microarray analysis, we found the down regulated growth and apoptosis factors, and selected down-regulated genes were confirmed by Western blot. Knockdown of a checkpoint c-Myc by siRNA significantly attenuated tumor inhibition and apoptosis effects of TADs. Moreover, our results indicated TADs could simultaneously increase cyclin D1 protein levels and decrease amount of cyclin E, cyclin B1 and cdc2 of the cycle proteins, and also TADs reduced Bcl-2 expression, and upregulated Bad, Bak and Bax activities. In conclusion, these results illustrated that TADs is a key factor in growth and apoptosis signaling inhibitor, has potential in cancer therapy. PMID- 26045988 TI - Musashi-2 promotes hepatitis Bvirus related hepatocellular carcinoma progression via the Wnt/beta-catenin pathway. AB - Our recent study observed that the expression of Musashi-2 (MSI2), a member of the Musashi family, was up-regulated in hepatitis B virus (HBV) related hepatocellular carcinoma parenchymal cells. Using quantitative PCR, tissue microarray (TMA) and immunohistochemical staining, we evaluated MSI2 mRNA and protein levels in tumor tissues from patients with different stages of hepatocellular carcinoma with paired adjacent noncancerous sample sets. The following techniques were used to further investigate MSI2 function and its potential molecular mechanism: RNAi, wound healing assay, Transwell assay, quantitative PCR and western blot analysis. Immunohistochemical detection of MSI2 on a TMA containing 106 paired specimens showed that increased cytoplasmic and nuclear MSI2 staining was significantly associated with tumor size, tumor differentiation, recurrence, TNM stage, vessel invasion and Ki-67 proliferative index. Patients with MSI2-positive tumors had a significantly higher disease recurrence rate and poorer survival than patients with MSI2-negative tumors after radical surgery. Based on univariate analysis, MSI2 expression showed an unfavorable influence on both disease-free survival and overall survival. Multivariate analysis revealed that higher MSI2 expression, together with tumor size, tumor differentiation, tumor thrombus, and Ki-67 expression were independent predictors of overall survival. With MSI2 knockdown, hepatoma cell migration and invasion were inhibited and the expression of beta-catenin, T cell factor (TCF) and lymphoid enhancer factor (LEF) were dysregulated. Thus, we propose that MSI2 may predict unfavorable outcomes in hepatitis B virus related hepatocellular carcinoma and promote cancer progression via the Wnt/beta-catenin signaling pathway. PMID- 26045989 TI - Upregulated beta1-6 branch N-glycan marks early gliomagenesis but exhibited biphasic expression in the progression of astrocytic glioma. AB - Glioma is the world's commonest primary brain malignancy with much of its biology relating to translational and post-translational events still unknown. In this study, we investigated the clinicopathological significance of N-linked beta1-6 GlcNAc branches and GnT-V enzyme in the development and progression of astrocytic glioma. Expression of GnT-V and its GlcNAc-beta1-6 oligosaccharides by-product together with Con-A binding sugars were assessed immunohistochemically on tissue microarrays of 16 normal brain and 159 tissue samples of astrocytomas of variable grades and histology. Although tissues of both grade I astrocytomas and normal brain showed considerably higher GnT-V expression, GlcNAc-beta1-6 expression was significantly high only in tissues of grade I astrocytomas (p < 0.001), which is attributable to elevated levels of the precursor Con-A binding sugar moieties (p < 0.001). The activity of GnT-V enzyme was found to be dependent on the degree of glioma pathogenesis, as the GlcNAc-beta1-6 branched expression diminished with every progressive grade of glioma, reaching minimum in glioblastoma (p < 0.001). Having biphasic activity in gliomagenesis, the role of GnT-V in glioma was deciphered by generating different ectopic GnT-V expressions in U-87 cells, which showed the highest GnT-V expression among selected glioma cell lines. Transient GnT-V rescue was achieved in knockdown clones by transfection with GnT-V expression vector. Suppression of GnT-V in U-87 cells slowed cell proliferation with G0/G1 cell cycle phase arrest. Reduced tumorigenicity, invasiveness and cell ECM interactions were also associated with suppressed in vitro GnT-V activity suggesting GnT-V may act as an oncoprotein. We report for the first time that GnT V products are involved in early gliomagenesis but their reduced expression, correlating with low Con-A binding sugars level found in high tumor grades predicts the loss of total N-glycosylation in glioma development and may be of potential diagnostic and/or prognostic value in astrocytoma. PMID- 26045990 TI - Correlated expression levels of endothelin receptor B and Plexin C1 in melanoma. AB - Discussion concerning the effect of endothelin receptor B (Ednrb) on melanoma continues because Ednrb has been reported to have both tumor promoting and suppressive effects for melanoma. In order to examine Ednrb-related signaling in melanomagenesis, DNA microarray analysis for a melanoma from a RFP/RET-transgenic mouse (RET-mouse) and a melanoma from an Ednrb-heterozygously deleted RET-mouse [Ednrb(+/-);RET-mouse], in both of which melanoma spontaneously develops, was performed in this study. We found that the expression level of Plexin C1 (PlxnC1), a suppressor for melanoma, in a melanoma from an Ednrb(+/-);RET-mouse was drastically decreased compared to that in a melanoma from a RET-mouse. Therefore, we further examined the correlation between Ednrb and PlxnC1 expression levels in melanomas. PlxnC1 transcript expression levels in melanomas from Ednrb(+/-);RET-mice were lower than those in melanomas from RET-mice. A strong correlation between Ednrb and PlxnC1 transcript expression levels (R = 0.78, p < 0.01) was also found in melanomas from both RET-mice and Ednrb(+/-);RET mice. Correspondingly, there was a significant correlation between transcript (R = 0.80; p < 0.01) and protein (R = 0.60; p < 0.01) expression levels of EDNRB and PLXNC1 in human primary melanomas. Together with our results showing that the expression level of PLXNC1 transcript was reduced in EDNRB-depleted human melanoma cells, our results showing positively correlated expression levels of Ednrb/EDNRB and PlxnC1/PLXNC1 in melanoma suggest that PlxnC1/PLXNC1 is involved in the Ednrb/EDNRB-mediated suppressive effect on melanoma. PMID- 26045991 TI - LEF1 targeting EMT in prostate cancer invasion is mediated by miR-181a. AB - Lymphoid enhancer-binding factor-1 (LEF1) is a key transcription factor mediating Wnt signaling pathway. Our previous studies indicate that LEF1 is highly expressed in androgen-independent prostate cancer (PCa) and enhances invasion ability in androgen-independent PCa cells. However, the molecular mechanism of LEF1 effect on invasion remains largely unknown. Using microRNA profiling analysis comparing androgen-independent LNCaP-AI PCa cells with high levels of endogenous LEF1 to LNCaP-AI cells with LEF1 knockdown by LEF1shRNA, we found miR 181a to be increased 12.3-fold in LNCaP-AI cells. We confirmed a positive correlation between LEF1 and miR-181a expression across multiple PCa cell lines. Additionally, we showed that in PCa cells, overexpression of LEF1 increased miR 181a expression and subsequently induced EMT associated migration and invasion, whereas LEF1 knockdown decreased miR-181a expression and subsequently resulted in inhibition of EMT, migration and invasion. Mechanistically, we demonstrated by chromatin immunoprecipitation assays that LEF1 could enhance miR-181a expression via its binding to the promoter regions of hsa-miR-181a. Overall, this study identified a novel LEF1-miR-181a-EMT axis in regulation of PCa migration and invasion. PMID- 26045992 TI - Inhibition of Aurora A promotes chemosensitivity via inducing cell cycle arrest and apoptosis in cervical cancer cells. AB - Aurora kinase A (AurA) regulates genomic instability and tumorigenesis in multiple cancer types. Although some studies have reported that Aur A may predict cervical cancer outcomes, its precise function and molecular mechanism in cervical cancer pathogenesis remain unclear. In this study, by overexpression or silencing of Aur A in cervical cancer cell lines, we found that overexpression of Aur A promoted cell proliferation through G1/S cell cycle transition and anti apoptosis, xenograft tumor growth and chemoresistance to Taxol. We further found that inhibition of Aur A with its specific inhibitor VX-680 enhanced the antitumor effect of Taxol via inducing apoptosis. Moreover, the clinical analysis from tissue samples demonstrated that Aur A was overexpressed, and the expression of Aur A and pERK1/2 was negatively correlated in cervical cancer tissues. The above results may provide some potential insights in treatment of cervical cancer in clinic. PMID- 26045993 TI - Fibroblast ERalpha promotes bladder cancer invasion via increasing the CCL1 and IL-6 signals in the tumor microenvironment. AB - Epidemiological studies indicate that women have a higher chance of developing muscle invasive bladder cancer (BCa) than men, suggesting that estrogen and estrogen receptors (ERs) may play critical roles in BCa progression. However, the ERs roles in the bladder tumor microenvironment and impacts on BCa progression remain largely unclear. Using IHC staining in human BCa samples, we found that higher ERalpha expression in the stromal compartment of BCa may be correlated with unfavorable clinical outcomes. Results from cell line studies revealed that co-culturing with fibroblasts could promote BCa T24, UMUC3 and 5637 cells invasion. Importantly, addition of ERalpha in fibroblasts further enhanced the BCa cell invasion and knock-down of ERalpha in fibroblasts could then partially reduce the fibroblasts-enhanced BCa invasion. Mechanism dissection suggested that ERalpha could function through modulating the CCL cytokines expression in fibroblasts to increase the BCa IL-6 expression. An interruption approach using IL-6 neutralizing antibody then reversed the fibroblast ERalpha-enhanced BCa cell invasion. Together, these data suggest that the higher expression of ERalpha in fibroblasts may be the result of modulating the CCL1 expression in fibroblasts and/or IL-6 production in BCa cells to enhance BCa cells invasion. Targeting these individual molecules in this newly identified ERalpha-stimulated CCL1 and IL-6 signal pathways may become an alternative therapy to better suppress the BCa cell invasion. PMID- 26045994 TI - miR-222/VGLL4/YAP-TEAD1 regulatory loop promotes proliferation and invasion of gastric cancer cells. AB - Gastric cancer (GC) is one of the most common malignant tumors and recent data demonstrates the tumor suppressor role of VGLL4 in GC, but the mechanisms for VGLL4 downregulation in GC remain to be elucidated. Here, we confirmed the suppressor role of VGLL4 on proliferation and invasion in GC cells with over activated YAP-TEAD signal, and indicated the reverse correlation between expression patters of VGLL4 and miR-222. Bioinformatics analysis combined with experimental confirmation revealed VGLL4 is a direct target of miR-222 in GC cells. Functionally, miR-222 inhibitor significantly inhibited GC cells proliferation and invasion and VGLL4 knockdown abolished the effects of miR-222 inhibitor. Moreover, TEAD1 knockdown resulted in decrease of miR-222 expression and increase of VGLL4 expression, and also resulted in reduction of luciferase activity driven by miR-222 promoter in GC cells, suggesting over-activated TEAD1 positively feedback transcriptionally regulates miR-222 expression via physically binding to the miR-222 promoter indicated by ChIP assay. Collectively, our findings implied the important role of miR-222/VGLL4/YAP-TEAD1 regulatory loop maintaining over-activated YAP-TEAD1 signal in GC cells, and enriched the rationale of VGLL4 in GC based on which a promising therapeutic strategy will be developed. PMID- 26045995 TI - Interleukin-17-induced EMT promotes lung cancer cell migration and invasion via NF-kappaB/ZEB1 signal pathway. AB - Inflammatory cytokine interleukin-17 (IL-17) has been associated with the risk of progressive cancers including lung cancer. However, it remains unclear how IL-17 may contribute to the invasion and development of these inflammation-associated malignancies. Here we aimed to investigate the role of IL-17 in lung cancer cell development. Epithelial-mesenchymal transition (EMT) has been recently proposed as a developmental process which plays an important role in cancer progression and metastases. Here we show that IL-17 might promote EMT in lung cancer cells by inducing the transcriptional repressor ZEB1. Exposure to IL-17 upregulated the signature EMT phenotypic markers vimentin and E-cadherin in lung cancer cells, and compared with controls, increased cell migration was observed in IL-17 treated lung cancer cells. ZEB1 mRNA and protein expression was induced by IL-17, and IL-17 stimulated nuclear localization of phosphorylated ZEB1. Conversely, suppressing ZEB1 expression by ZEB1 siRNA abrogated IL-17-stimulated vimentin expression and cell migration. Moreover, the phosphorylation of IkappaBalpha was required for IL-17-induced expression of ZEB1, suggesting the involvement of canonical NF-kappaB signaling. To check this hypothesis, we used IKK inhibitor BAY 11-7028 to block NF-kappaB activity. We found that BAY 11-7028 abrogated IL 17-induced ZEB1 expression, cell migration, and EMT, thus confirming that NF kappaB is required for IL-17 to induce these aggressive phenotypes in lung cancer cells. Taken together, our data support the idea that IL-17-induced EMT promotes lung cancer cell migration and invasion via NF-kappaB-mediated upregulation of ZEB1. This study reveals a new signaling axis through which the tumor microenvironment causes ZEB1 expression to promote cancer metastasis. We suggest that targeting IL-17-induced ZEB1 expression may offer an effective therapeutic strategy for lung cancer treatment. PMID- 26045996 TI - MiRNA-1469 promotes lung cancer cells apoptosis through targeting STAT5a. AB - MicroRNAs play key roles in cell growth, differentiation, and apoptosis. In this study, we described the regulation and function of miR-1469 in apoptosis of lung cancer cells (A549 and NCI-H1650). Expression analysis verified that miR-1469 expression significantly increased in apoptotic cells. Overexpression of miR-1469 in lung cancer cells increased cell apoptosis induced by etoposide. Additionally, we identified that Stat5a is a downstream target of miR-1469, which can bind directly to the 3'-untranslated region of the Stat5a, subsequently reducing both the mRNA and protein levels of Stat5a. Finally, co-expression of miR-1469 and Stat5a in A549 and NCI-H1650 cells partially abrogated the effect of miR-1469 on cell apoptosis. Our results show that miR-1469 functions as an apoptosis enhancer to regulate lung cancer apoptosis through targeting Stat5a and may become a critical therapeutic target in lung cancer. PMID- 26045997 TI - Elevated expression of HABP1 is correlated with metastasis and poor survival in breast cancer patients. AB - Hyaluronan-binding protein 1 (HABP1) is a protein with high affinity for HA, and has been reported to be upregulated in cancer cells. In this study, we show that silencing HABP1 inhibits proliferation, and suppresses the migration and invasion ability of breast cancer cell lines. In addition, silencing HABP1 remarkably slows down tumor growth in mice. We examined the correlation between HABP1 expression and clinicopathological parameters using immunohistochemistry in patients with breast cancer. The results indicate that HABP1 is overexpressed in cancer tissue, and its high levels are related to lymph node metastasis (P = 0.032) and tumor stage (P = 0.041). Moreover, high HABP1 expression is correlated with poor overall survival in breast cancer patients (P = 0.018), and is a signifi cant independent prognostic indicator. Our fi ndings suggest that HABP1 regulates proliferation and migration of breast cancer cells. HABP1 may be a useful independent predictor of outcomes in patients with breast cancer. PMID- 26045998 TI - Nicotinamide adenine dinucleotide (NAD) may affect DNA methyltransferase 1 through regulation of BRCA1 in ovarian cancer. AB - Nicotinamide adenine dinucleotide (NAD) is a crucial molecule of energy production and signal transduction processes that have been linked to ovarian cancer development. Notably, emerging evidence has led to considerable interest in the role of DNA methyltransferase 1 (DNMT1) in the initiation and progression of ovarian cancer. However, dynamic crosstalk between NAD and DNMT1 is poorly understood. Here, we show that DNMT1 levels are upregulated, along with increased NAD levels in non-BRCA1-mutated ovarian cancer cells. In contrast, DNMT1 levels are not affected by increasing NAD levels in BRCA1-mutated ovarian cancer cells. Mechanistically, BRCA1 inactivity-mediated loss of H3K9ac enrichment around the core promoter inhibits DNMT1 transcription. Consistent with this, BRCA1 levels correlate with DNMT1 levels (R = 0.534, R < 0.001) in human ovarian cancer specimens. Therefore, these results highlight a novel regulatory effect of NAD on DNMT1, and further correlate the physiological properties of NAD metabolism with DNMT1-mediated biological processes. All of this may improve our understanding of the basic molecular mechanism underlying NAD- and DNMT1-related ovarian cancer progression. PMID- 26045999 TI - High copy number of mitochondrial DNA (mtDNA) predicts good prognosis in glioma patients. AB - Alterations in mitochondrial DNA (mtDNA) copy number have been widely identified in many types of human cancers and are considered a common cancer hallmark. However, the prognostic value of altered mtDNA content in gliomas remains largely unknown. The aim of this study was to investigate mtDNA copy number in a cohort of gliomas (n = 124) and non-neoplastic brain tissues (control subjects; n = 27) and to explore the association between variable mtDNA content and clinical outcomes in glioma patients. Using real-time quantitative PCR assay, we demonstrated that glioma patients had an increased mtDNA content as compared with control subjects. In addition, our data showed that increased mtDNA copy number was significantly negatively associated with tumor grade, recurrence and cancer related death, whereas there was a significantly positively relationship between increased mtDNA content and seizures. More importantly, increased mtDNA content were closely relevant to longer survival in glioma patients. Taken together, our data provide the strong evidences that high copy number of mtDNA may be a useful good prognostic factor in glioma patients. PMID- 26046000 TI - Increased expression of iASPP correlates with poor prognosis in FIGO IA2-IIA cervical adenocarcinoma following a curative resection. AB - BACKGROUND: The function of iASPP (inhibitory member of the ASPP family) in cervical adenocarcinoma remains unknown. The aim of this study was to explore the expression and clinical relevance of iASPP in early stage cervical adenocarcinoma. Methods The clinical data of 75 patients with FIGO stage IA2-IIA cervical adenocarcinoma who were treated with radical hysterectomy from January 2004 to March 2008 was collected. The mRNA and protein expression levels of iASPP from the paired tumor specimens and adjacent normal cervical tissues were determined by real-time qRT-PCR and Western blot, and its relationship with clinicopathologic factors and prognosis of cervical cancer patients was retrospectively analyzed. RESULTS: The mRNA and protein expression levels of iASPP were significantly elevated in cervical cancer tissues. The increased iASPP expression was correlated strongly with higher FIGO staging (p = 0.034), worse differentiation (p = 0.046), less pelvic lymph node metastasis (p = 0.014), and poor overall and disease-free survival of patients with cervical cancer (both P > 0.05). Multivariate Cox analysis indicated that high iASPP expression was an independent prognostic factor (P > 0.05). CONCLUSIONS: This study demonstrates that iASPP is highly elevated in cervical adenocarcinoma, and that overexpression is an independent poor prognostic indicator for early stage cervical cancer patients, suggesting that iASPP might serve as a novel potential prognostic marker and therapeutic target for cervical adenocarcinoma. PMID- 26046001 TI - Prognostic value of Ki-67 expression in conversion therapy for colorectal liver limited metastases. AB - INTRODUCTION: The objective of this study was to examine the prognostic value of Ki-67 expression in conversion therapy for colorectal liver-confined metastases. METHODS: We enrolled a total of 96 patients including 54 patients who received oxaliplatin- or irinotecan-based chemotherapy and curative hepatectomy for initially unresectable metastases (conversion group) and 42 patients with initially resectable liver metastases (straight hepatectomy group). Ki-67 expression was examined in 96 resected specimens but excluded the 2 specimens that revealed no residual cancer cells in conversion group. RESULTS: Conversion therapy leads to greater survival that is equivalent to that straight hepatectomy group. In conversion group, high Ki-67 expression (> 30%) levels were detectable in 33 patients (64%) after chemotherapy prior to conversion therapy. High Ki-67 expression was significantly associated with shorter disease-free survival and worse overall survival (P < 0.01 in both), and was an independent worse prognostic factor of disease-free survival and overall survival (hazard ratio [HR] and P-values were 5.608, 0.001 and 5.366, 0.04, respectively) in patients with conversion therapy. Interestingly, even in the patients with RECIST PR (n = 32), high Ki-67 expression was significantly shorter disease-free survival compared to low Ki-67 expression (P < 0.001). In contrast to conversion group, there was no significant difference in disease free survival and overall survival between low (n = 14, 33%) and high (n = 28, 67%) Ki-67 expressions in patients with straight hepatectomy (P = 0.14 and 0.74, respectively). CONCLUSIONS: Residual Ki-67 expression is a useful biomarker for worse prognostic outcomes after conversion therapy. High Ki-67 expression may be a biomarker of micrometastases containing aggressive cancer cells. PMID- 26046002 TI - Association between WT1 polymorphisms and susceptibility to breast cancer: results from a case-control study in a southwestern Chinese population. AB - Wilms' tumor gene 1 (WT1) single nucleotide polymorphism (SNP), rs16754, has been considered as an independent prognostic factor in patients with acute myeloid leukemia and renal cell carcinoma. However, its biological role in breast cancer has not been reported. To test whether WT1 SNPs can be used as a molecular marker in order to improve the risk stratification of breast cancer, we performed a case control study including 709 female sporadic breast cancer patients and 749 female healthy control subjects in the Southeast China. Five WT1 SNPs (rs16754, rs3930513, rs5030141, rs5030317, rs5030320) were selected and determined by polymerase chain reaction-ligase detection reaction to assess their associations with breast cancer risk. Results showed the distributions of the alleles of these WT1 SNPs were consistent with data from Chinese population as suggested by the International HapMap Project. Individuals with the minor alleles of rs16754, rs5030317 and rs5030320 showed a significant decrease of breast cancer risk in codominant model (OR = 0.6370, 95% CI: 0.4260-0.9520 for rs16754; OR = 0.5940, 95% CI: 0.3890-0.9070 for rs5030317; OR = 0.5870, 95% CI: 0.3850-0.8960 for 5030320, respectively) and recessive model. Stratified analyses showed the protective effects were more evident in the subjects with age <= 50 years or in pre-menopausal status. To explore the potential mechanism, we conducted bioinformatics genotype-phenotype correlation analysis, and found that the mRNA expression level for homozygous rare allele of WT1 gene was lower than that in wild-type and heterozygous group (P = 0.0021) in Chinese population. In summary, our findings indicated that minor alleles of rs16754, rs5030317 and rs5030320 are associated with reduced risk of breast cancer, suggesting that WT1 SNPs may be a potential biomarker of individualized prediction of susceptibility to breast cancer. However, large prospective and molecular epidemiology studies are needed to verify this correlation and clarify its underlying mechanisms. PMID- 26046003 TI - Contribution of microRNAs in understanding the pancreatic tumor microenvironment involving cancer associated stellate and fibroblast cells. AB - Understanding of molecular events associated with tumor microenvironment in pancreatic cancer (PC) is an active area of research especially because of the rich desmoplasia seen in human PC. Desmoplasia is contributed by several cell types including cancer-associated fibroblast (CAF) and stellate cells (PSCs), which are believed to play critical roles in conferring aggressiveness to PC. The aberrant expression of microRNAs (miRNAs) in PSCs and CAF cells appears to play a pivotal role in the development and progression of PC. In this study, expression analysis of miR-21/miR-221 in conditioned media derived from PSCs/CAF cells, and from PSCs/CAF cells showed up-regulation of both miRNAs compared to MIAPaCa-2 PC cells. In addition, miR-21 expression in stellate cells derived from normal pancreas was substantially lower when compared to PSCs or CAF cells. COLO-357 PC cells cultured in the presence of conditioned media derived from PSC/CAF cells led to a significant increase in clonogenicity and pancreatosphere formation. Furthermore, inhibition of miR-21 with antisense oligonucleotide (ASO) transfection resulted in decreased migration/invasive capacity of PSCs. Similarly, the effect of ASO-miR-221 transfection in CAF cells reduced the expression of NF-kappaB and K-Ras (target of miR-221) along with inhibition of migration/invasion. Moreover, miRNA expression profiling of PSCs, MIAPaCa-2, and COLO-357 cells, and further validation by real-time PCR, showed several differentially expressed miRNAs, among which four was significantly up-regulated. Collectively, these results suggest a crosstalk between PSCs/CAF cells and PC cells, resulting in the up-regulation of miR-21/miR-221 expression which in part may confer aggressiveness to PC. We conclude that targeting these miRNAs could be useful for developing precision medicine for the prevention of tumor progression and/or for the treatment of PC. PMID- 26046004 TI - Nonantibestrophin Anti-RPE Antibodies in Paraneoplastic Exudative Polymorphous Vitelliform Maculopathy. AB - PURPOSE: A previous report demonstrated antibodies to bestrophin in paraneoplastic exudative polymorphous vitelliform maculopathy (PEPVM). Other cases demonstrated antibodies to different proteins in the retinal pigment epithelium (RPE). In this report, serum was analyzed to determine whether a patient with PEPVM and a reduced Arden ratio had developed autoantibodies to human Bestrophin-1 (Best1). METHODS: Human embryonic kidney 293 cells (HEK293) were transfected with Best1 and stained with an antibody specific to Best1 (E6 6), or patient serum. Staining patterns were compared with those of untransfected cells stained with E6-6, patient serum, control serum, or secondary antibody alone. Western blots were performed using lysed RPE and stained with E6-6, patient serum, control serum, or secondary antibody alone. RESULTS: Immunofluorescence staining of HEK-293 cells or HEK-293 cells expressing Best1 did not differ between patient and control sera or show a staining pattern consistent with recognition of Best1. Immunoblotting of human RPE lysate with patient serum did not identify Best1 (68 kDa) but did recognize a band at approximately 48 kDa that was absent in blots using control serum. CONCLUSIONS: To our knowledge, this is the first report of PEPVM with an autoantibody to an approximately 48-kDa RPE protein, but previous reports have demonstrated autoantibodies to other RPE proteins, suggesting that autoantibody formation is an important component of PEPVM. TRANSLATIONAL RELEVANCE: This research emphasizes the role that autoantibodies play in PEPVM. The fact that different autoantibodies appear to cause similar patterns demonstrates the heterogeneity of causes of vitelliform lesions. PMID- 26046005 TI - Enhancement of Corneal Visibility in Optical Coherence Tomography Images Using Corneal Adaptive Compensation. AB - PURPOSE: To improve the contrast of optical coherence tomography (OCT) images of the cornea (post processing). METHODS: We have recently developed standard compensation (SC) algorithms to remove light attenuation artifacts. A more recent approach, namely adaptive compensation (AC), further limited noise overamplification within deep tissue regions. AC was shown to work efficiently when all A-scan signals were fully attenuated at high depth. But in many imaging applications (e.g., OCT imaging of the cornea), such an assumption is not satisfied, which can result in strong noise overamplification. A corneal adaptive compensation (CAC) algorithm was therefore developed to overcome such limitation. CAC benefited from local A-scan processing (rather than global as in AC) and its performance was compared with that of SC and AC using Fourier-domain OCT images of four human corneas. RESULTS: CAC provided considerably superior image contrast improvement than SC or AC did, with excellent visibility of the corneal stroma, low noise overamplification, homogeneous signal amplification, and high contrast. Specifically, CAC provided mean interlayer contrasts (a measure of high stromal visibility and low noise) greater than 0.97, while SC and AC provided lower values ranging from 0.38 to 1.00. CONCLUSION: CAC provided considerable improvement compared with SC and AC by eliminating noise overamplification, while maintaining all benefits of compensation, thus making the corneal endothelium and corneal thickness easily identifiable. TRANSLATIONAL RELEVANCE: CAC may find wide applicability in clinical practice and could contribute to improved morphometric and biomechanical understanding of the cornea. PMID- 26046006 TI - Effect of Two Novel Sustained-Release Drug Delivery Systems on Bleb Fibrosis: An In Vivo Glaucoma Drainage Device Study in a Rabbit Model. AB - PURPOSE: To evaluate two drug delivery systems, a nonbiodegradable poly(2 hydroxyethyl methacrylate) (P[HEMA]) system with mitomycin C (MMC) and a biodegradable poly(lactic-co-glycolic acid) (PLGA) system with 5-fluorouracil (5 FU) with and without MMC for their ability to reduce fibrosis when attached to an Ahmed glaucoma valve (AGV) and implanted in a rabbit model. METHODS: New Zealand albino rabbits (48) were divided into six equal groups, and AGVs, modified as described below, were implanted in the right eye of each rabbit. The groups included (1) PLGA alone; (2) P(HEMA) plus MMC (6.5 MUg); (3) PLGA plus 5-FU (0.45 mg); (4) PLGA plus 5-FU (1.35 mg); (5) PLGA plus 5-FU and MMC (0.45 mg and 0.65 MUg, respectively); (6) PLGA plus 5-FU and MMC (1.35 mg and 0.65 MUg, respectively). The rabbits were followed for 3 months prior to euthanasia. RESULTS: The bleb wall thickness was significantly less in groups 2, 5, and 6 compared to the rest. At 3 months, the PLGA polymer had completely disappeared, while the P(HEMA) polymer remained intact. There were no statistical differences in the degree of clinically graded conjunctival injection, histologic inflammation, or histologic fibrosis among the six groups. CONCLUSIONS: We successfully created a sustained-release drug delivery system that decreased the postoperative fibrosis using both a nonbiodegradable P(HEMA) polymer and a biodegradable (PLGA) polymer. Both systems appear to work equally well with no side effects. TRANSLATIONAL RELEVANCE: These results are supportive of the antifibrotic effect of the slow-release drug delivery system following glaucoma drainage device implantation, thus paving the way for human pilot studies. PMID- 26046007 TI - Relationship Between Motor Vehicle Collisions and Results of Perimetry, Useful Field of View, and Driving Simulation in Drivers With Glaucoma. AB - PURPOSE: To examine the relationship between Motor Vehicle Collisions (MVCs) in drivers with glaucoma and standard automated perimetry (SAP), Useful Field of View (UFOV), and driving simulator assessment of divided attention. METHODS: A cross-sectional study of 153 drivers from the Diagnostic Innovations in Glaucoma Study. All subjects had SAP and divided attention was assessed using UFOV and driving simulation using low-, medium-, and high-contrast peripheral stimuli presented during curve negotiation and car following tasks. Self-reported history of MVCs and average mileage driven were recorded. RESULTS: Eighteen of 153 subjects (11.8%) reported a MVC. There was no difference in visual acuity but the MVC group was older, drove fewer miles, and had worse binocular SAP sensitivity, contrast sensitivity, and ability to divide attention (UFOV and driving simulation). Low contrast driving simulator tasks were the best discriminators of MVC (AUC 0.80 for curve negotiation versus 0.69 for binocular SAP and 0.59 for UFOV). Adjusting for confounding factors, longer reaction times to driving simulator divided attention tasks provided additional value compared with SAP and UFOV, with a 1 standard deviation (SD) increase in reaction time (approximately 0.75 s) associated with almost two-fold increased odds of MVC. CONCLUSIONS: Reaction times to low contrast divided attention tasks during driving simulation were significantly associated with history of MVC, performing better than conventional perimetric tests and UFOV. TRANSLATIONAL RELEVANCE: The association between conventional tests of visual function and MVCs in drivers with glaucoma is weak, however, tests of divided attention, particularly using driving simulation, may improve risk assessment. PMID- 26046008 TI - Speech function of the oropharyngeal isthmus: A modeling study. AB - A finite element method (FEM) based numerical model of upper airway structures (jaw, tongue, maxilla, soft palate) was implemented to observe interactions between the soft palate and tongue, and in particular to distinguish the contributions of individual muscles in producing speech-relevant constrictions of the oropharyngeal isthmus (OPI), or "uvular" region of the oral tract. Simulations revealed a sphincter-like general operation for the OPI, particularly with regard to the function of the palatoglossus muscle. Further, as has been observed with the lips, the OPI can be controlled by multiple distinct muscular mechanisms, each reliably producing a different sized opening and robust to activation noise, suggestive of a modular view of speech motor control. As off midline structures of the OPI are difficult to observe during speech production, biomechanical simulation offers a promising approach to studying these structures. PMID- 26046009 TI - Semiparametric Estimation of the Impacts of Longitudinal Interventions on Adolescent Obesity using Targeted Maximum-Likelihood: Accessible Estimation with the ltmle Package. AB - While child and adolescent obesity is a serious public health concern, few studies have utilized parameters based on the causal inference literature to examine the potential impacts of early intervention. The purpose of this analysis was to estimate the causal effects of early interventions to improve physical activity and diet during adolescence on body mass index (BMI), a measure of adiposity, using improved techniques. The most widespread statistical method in studies of child and adolescent obesity is multi-variable regression, with the parameter of interest being the coefficient on the variable of interest. This approach does not appropriately adjust for time-dependent confounding, and the modeling assumptions may not always be met. An alternative parameter to estimate is one motivated by the causal inference literature, which can be interpreted as the mean change in the outcome under interventions to set the exposure of interest. The underlying data-generating distribution, upon which the estimator is based, can be estimated via a parametric or semi-parametric approach. Using data from the National Heart, Lung, and Blood Institute Growth and Health Study, a 10-year prospective cohort study of adolescent girls, we estimated the longitudinal impact of physical activity and diet interventions on 10-year BMI z scores via a parameter motivated by the causal inference literature, using both parametric and semi-parametric estimation approaches. The parameters of interest were estimated with a recently released R package, ltmle, for estimating means based upon general longitudinal treatment regimes. We found that early, sustained intervention on total calories had a greater impact than a physical activity intervention or non-sustained interventions. Multivariable linear regression yielded inflated effect estimates compared to estimates based on targeted maximum likelihood estimation and data-adaptive super learning. Our analysis demonstrates that sophisticated, optimal semiparametric estimation of longitudinal treatment specific means via ltmle provides an incredibly powerful, yet easy-to-use tool, removing impediments for putting theory into practice. PMID- 26046010 TI - Neuromythology of Manganism. AB - Manganese is an essential trace element with neurotoxicant properties at high levels that were first described in the mid-nineteenth century. The largest sources of occupational and environmental exposures are mining, fossil fuel combustion, and iron and steel industries. Manganese neurotoxicity has been described in many workers with high levels of occupational manganese exposure and can cause a distinct neurologic phenotype known as manganism. Recently, our understanding of the clinical syndrome and pathophysiology of manganese toxicity has shifted. Modern day manganese exposures, which are an order of magnitude lower than previously described in cases of manganism, result in different clinical, imaging, and pathologic phenotypes. Here we will review three neurologic "myths" of manganism in the twenty-first century and will provide evidence that Mn is associated with a clinical syndrome of parkinsonism that resembles Parkinson disease, dopaminergic dysfunction on molecular imaging, and an inflammatory neuropathology in the striatum. PMID- 26046011 TI - Performance assessment of a NaI(Tl) gamma counter for PET applications with methods for improved quantitative accuracy and greater standardization. AB - BACKGROUND: Although NaI(Tl) gamma counters play an important role in many quantitative positron emission tomography (PET) protocols, their calibration for positron-emitting samples has not been standardized across imaging sites. In this study, we characterized the operational range of a gamma counter specifically for positron-emitting radionuclides, and we assessed the role of traceable (68)Ge/(68)Ga sources for standardizing system calibration. METHODS: A NaI(Tl) gamma counter was characterized with respect to count rate performance, adequacy of detector shielding, system stability, and sample volume effects using positron emitting radionuclides (409- to 613-keV energy window). System efficiency was measured using (18)F and compared with corresponding data obtained using a long lived (68)Ge/(68)Ga source that was implicitly traceable to a national standard. RESULTS: One percent count loss was measured at 450 * 10(3) counts per minute. Penetration of the detector shielding by 511-keV photons gave rise to a negligible background count rate. System stability tests showed a coefficient of variation of 0.13% over 100 days. For a sample volume of 4 mL, the efficiencies relative to those at 0.1 mL were 0.96, 0.94, 0.91, 0.78, and 0.72 for (11)C, (18)F, (125)I, (99m)Tc, and (51)Cr, respectively. The efficiency of a traceable (68)Ge/(68)Ga source was 30.1% +/- 0.07% and was found to be in close agreement with the efficiency for (18)F after consideration of the different positron fractions. CONCLUSIONS: Long-lived (68)Ge/(68)Ga reference sources, implicitly traceable to a national metrology institute, can aid standardization of gamma counter calibration for (18)F. A characteristic feature of positron emitters meant that accurate calibration could be maintained over a wide range of sample volumes by using a narrow energy window centered on the 511-keV peak. PMID- 26046013 TI - Associations between Poor Sleep Quality and Stages of Change of Multiple Health Behaviors among Participants of Employee Wellness Program. AB - OBJECTIVE: Using the Transtheoretical Model of behavioral change, this study evaluates the relationship between sleep quality and the motivation and maintenance processes of healthy behavior change. METHODS: The current study is an analysis of data collected in 2008 from an online health risk assessment (HRA) survey completed by participants of the Kansas State employee wellness program (N=13,322). Using multinomial logistic regression, associations between self reported sleep quality and stages of change (i.e. precontemplation, contemplation, preparation, action, maintenance) in five health behaviors (stress management, weight management, physical activities, alcohol use, and smoking) were analyzed. RESULTS: Adjusted for covariates, poor sleep quality was associated with an increased likelihood of contemplation, preparation, and in some cases action stage when engaging in the health behavior change process, but generally a lower likelihood of maintenance of the healthy behavior. CONCLUSIONS: The present study demonstrated that poor sleep quality was associated with an elevated likelihood of contemplating or initiating behavior change, but a decreased likelihood of maintaining healthy behavior change. It is important to include sleep improvement as one of the lifestyle management interventions offered in EWP to comprehensively reduce health risks and promote the health of a large employee population. PMID- 26046012 TI - Sleep in Autism Spectrum Disorders. AB - Autism spectrum disorders (ASD) are common neurodevelopmental conditions, affecting 1 in 68 children. Sleep disturbance, particularly insomnia, is very common in children diagnosed with ASD, with evidence supporting overlapping neurobiological and genetic underpinnings. Disturbed sleep exacerbates core and related ASD symptoms and has a substantial negative impact on the entire family. Treatment of sleep disturbance holds promise for ameliorating many of the challenging behavioral symptoms that children with ASD and their families face. Behavioral and pharmacological studies indicate promising approaches to treating sleep disturbances in this population. Awareness of treatment options is particularly important as parents and clinicians may believe that sleep disturbance is part of autism and refractory to therapy. In addition, autism symptoms refractory to treatment with conventional psychiatric medications may improve when sleep is addressed. Additional evidence-based studies are needed, including those that address the underlying biology of this condition. PMID- 26046014 TI - Testing Interventions to Motivate and Educate (TIME): A multi-level intervention to improve colorectal cancer screening. AB - OBJECTIVE: To test the effectiveness of a colorectal cancer (CRC) screening intervention directed at three levels (clinic, provider, patient) in a primary care setting. METHOD: We conducted a group randomized trial (Clinical Trials registration no. NCT01568151) among 10 primary care clinics in Columbus, Ohio that were randomized to a study condition (intervention or usual care). We determined the effect of a multi-level, stepped behavioral intervention on receipt of a CRC screening test among average-risk patients from these clinics over the study period. RESULTS: Patients (n=527) who were outside of CRC screening recommendations were recruited. Overall, 35.4% of participants in the intervention clinics had received CRC screening by the end of the study compared to 35.1% of participants who were in the usual care clinics. Time to CRC screening was also similar across arms (HR=0.97, 95% CI=0.65-1.45). CONCLUSION: The multi-level intervention was not effective in increasing CRC screening among participants who needed a test, perhaps due to low participation of patients in the stepped intervention. Future studies utilizing evidence-based strategies to encourage CRC screening are needed. PMID- 26046015 TI - Physical Activity and White Matter Hyperintensities: A Systematic Review of Quantitative Studies. AB - OBJECTIVE: White matter hyperintensities (WMH) are markers of brain white matter injury seen on magnetic resonance imaging. WMH increase with age and are associated with neuropsychiatric disorders. WMH progression can be slowed by controlling vascular risk factors in individuals with advanced disease. Since physical activity can decrease vascular risk factors, physical activity may slow the progression of WMH in individuals without advanced disease, thereby preventing neuropsychiatric disorders. The purpose of this systematic review was to examine the association between physical activity and WMH in individuals without advanced disease. METHODS: Articles published in English through March 18, 2014 were searched using PubMed, Web of Science, Cochrane Library and EBSCOhost. RESULTS: Six studies found that more physical activity was associated with less WMH, while 6 found no association. Physical activity is associated with less WMH in individuals without advanced disease when studies are longitudinal or take into consideration physical activity across the lifespan, have a younger sample of older adults, measure different types of physical activity beyond leisure or objectively measure fitness via V02max, measure WMH manually or semi automatically, and control for risk factors associated with WMH. CONCLUSION: More physical activity was associated with less white matter hyperintensities in individuals without advanced disease. PMID- 26046016 TI - Clindamycin Resistance among Staphylococcus Aureus Isolated at Mbarara Regional Referral Hospital, in South Western Uganda. AB - AIMS: The study was conducted to determine the prevalence of Clindamycin (CL) resistance and antimicrobial susceptibility among clinical isolates of Staphylococcus aureus (S. aureus) from Mbarara Regional Referral Hospital (MRRH) in Southwestern Uganda. STUDY DESIGN: Laboratory based cross sectional study. PLACE AND DURATION OF THE STUDY: The study was conducted at the Microbiology department of Mbarara Regional referral hospital between November 2012 and December 2013. METHODOLOGY: In our study, we recruited 300 S. aureus isolates that were stored in the laboratory and were obtained from different clinical samples. The isolates were tested for antimicrobial susceptibility by phenotypic methods and for the genotypic expression of Macrolide Lincosamide StreptograminB (MLSB) resistance genes (ermA, ermB, ermC, and msrA). The D-test was also performed. RESULTS: Phenotypically, a total of 109 (36%) S. aureus isolates were resistant to CL, of which 9 (3%) were constitutively resistant while 100 (33.3%) were inducibly resistant. Genotypicaly, 134/300 (44.7%) isolates possessed at least one of the MLSB resistance genes. 23/300 (7.7%) tested positive for ermB, 98/300 (32.7%) tested positive for the ermC and 43/300 (14.3%) tested positive for the msrA genes with none possessing the ermA gene. Isolates were highly resistant to Sulfamethoxazole/trimethoprim, Erythromycin and Oxacillin with moderate resistance to Vancomycin and Imipenem and least resistance to Linezolid. CONCLUSION: S. aureus resistance to CL was high in this set up. There was also high resistance to Sulfamethoxazole/trimethoprim, Erythromycin and Oxacillin but low resistance to Linezolid. PMID- 26046017 TI - Free radicals and antioxidant status in chronic osteomyelitis patients: a case control study. AB - INTRODUCTION: Osteomyelitis (OM) is a local or generalized infection of the bone and bone marrow which may be multifactorial in its causation. Chronic infection is characterised by sequestrum and involucrum formation. AIM: The present study has been carried out for assessing the oxidative stress in chronic OM by measurement of serum oxidants {such as malondialdehyde (MDA), protein carbonyl (PC), nitrite} and the serum antioxidants {such as ascorbic acid, superoxide dismutase (SOD), ceruloplasmin (Cp), blood glutathione} by spectrophotometric method. MATERIALS AND METHODS: This was a case control study. About 5 ml of venous blood was collected for the estimation of biochemical parameters. This study comprised of 50 OM patients diagnosed at SSLH Hospital, Varanasi and 50 healthy ages (15-35 y) and sex matched individuals. RESULTS: Significantly increased (p<0.0001) levels of serum oxidants and significantly decreased (p<0.0001) levels of all serum antioxidants except ceruloplasmin indicated significantly increased (p<0.0001) levels in response to infections in chronic OM patients as compared to the healthy controls. CONCLUSION: These results suggest that there occurs an imbalance between oxidants and antioxidants, especially an increase in oxidative stress, as measured by the levels of the parameters: serum MDA, serum protein carbonyl and serum nitrite. PMID- 26046018 TI - Phenotypic and Molecular Characterization of Plasmid Mediated AmpC among Clinical Isolates of Klebsiella pneumoniae Isolated from Different Hospitals in Tehran. AB - INTRODUCTION: Klebsiella pneumoniae is one of the main opportunistic pathogens which can cause different types of infections. Production of beta-lactamases like AmpC and ESBL mostly lead to beta-lactam resistance in these Gram-Negative bacteria. The aim of this study was the detection of AmpC-producing K. pneumoniae in clinical isolates. MATERIALS AND METHODS: Three hundred and three isolates of K. pneumoniae were identified. Double disc method including cefoxitin with cefepime and using boronic acid with cloxacillin were performed as two phenotypic methods for detection of AmpC. Amplification of AmpC gene was performed by PCR. RESULTS: Eight and three isolates showed positive results in double disc method and by using boronic acid with cloxacillin, respectively. Five isolates had specific band for AmpC gene after electrophoresis. CONCLUSION: Our results were indicated the low prevalence of AmpC-producer-K. pnemoniae in Iran. On the other hand these two tested phenotypic methods showed low sensitivity for detection of AmpC. PMID- 26046019 TI - Treatment paradox in musculo-skeletal tuberculosis in an immunocompetent adult male; a case report from a tertiary care hospital. AB - Paradoxical reactions like immune reconstitution inflammatory syndrome (IRIS) as seen with patients on retroviral treatment in HIV infection, have also been identified in HIV sero-negative patients with extra pulmonary tuberculosis especially lymph-node tuberculosis. Musculo-skeletal tuberculosis presenting as a cold abscess of the anterior chest wall is a rare entity which poses diagnostic and therapeutic challenge. A 35-year-old immunocompetent male came with complains of painless lump on right side of his chest over 9th and 10th intercostal space which gradually increased and extended upto 11th rib area. Clinically, diagnosis of cold abscess was made and anti-tubercular therapy (ATT) was started. Despite of being on ATT for 3 weeks, patient developed pain and signs of inflammation. Fluid was aspirated and sent for biochemical and microbiological investigations. The aspirated fluid was positive for acid fast bacilli by ZN stain and grew Mycobacterium tuberculosis in culture, sensitive to first line ATT. Pyogenic and fungal culture was negative. This case presented as an anterior chest wall cold abscess which deteriorated on initiation of first line ATT, thus creating a suspicion of resistance to ATT which was cleared on ATT susceptibility testing. Hence, this case underlines the possibility of treatment paradoxes seen in immunocompetent musculo-skeletal tuberculosis. PMID- 26046020 TI - Effect of silymarin in the prevention of Cisplatin nephrotoxicity, a clinical trial study. AB - BACKGROUND: Reno-protective effect of Silymarin was studied in some studies mainly on rats. In some of these studies, Silymarin was shown to have positive effects on preventing or decreasing severity of Cisplatin nephrotoxicity. OBJECTIVE: The aim of this study was to evaluate the protective effect of Silymarin on Cisplatin nephrotoxicity in adult patients with malignancy. MATERIALS AND METHODS: In this clinical trial study, 60 patients with malignancy, candidate of Cisplatin treatment were randomly enrolled in two equal groups. In patients of case group, Silymarin tablet 140 mg/bid was administrated seven days before Cisplatin administration together with Cisplatin, and in control group, Cisplatin was prescribed. Blood Urea Nitrogen (BUN) and serum Creatinine (Cr) were checked at the same day and 3 and 7 days after administration of Cisplatin. RESULTS: Mean age of the patients in case and control groups were 51.1+/-14.3 y and 51.1+/-13.7 y respectively (p=0.99). There was no significant difference based on BUN and serum Cr in the beginning of study and three days after administration of Cisplatin in two groups of patients; however, after two weeks, BUN and serum Cr were significantly lower in the case group compared to the control group. Also, in the case group, BUN and serum Cr decreased and in the control group, they increased after two weeks after Cisplatin administration. CONCLUSION: This study showed that Silymarin can decrease Cisplatin nephrotoxicity, so because of safety profile and minor adverse effect of Silymarin, we can use it as prophylaxis against Cisplatin nephrotoxicity in various Cisplatin-contained chemotherapy regimens. PMID- 26046021 TI - POSSUM: A Scoring System for Perforative Peritonitis. AB - BACKGROUND AND OBJECTIVES: Perforative peritonitis carries considerable morbidity and mortality with the postoperative period unpredictable most of the times. It therefore becomes necessary for a scoring system that predicts the post-operative outcome. POSSUM (Physiological and Operative Severity Score for the enumeration of Mortality and Morbidity) helps in predicting the post-operative morbidity and mortality in these patients. POSSUM scores are based on 12 physiological factors and 6 operative factors. In our study, we included two more factors, which are specifically important in perforative peritonitis; they are, perforation to operation time and the presence of co-morbidity. The presence of these factors significantly affects the post-operative status. Through this prospective study, we can predict which patients are at a higher risk of death or complication and give appropriate management as necessary. MATERIALS AND METHODS: Our sample size was 50 patients with perforative peritonitis. The study was conducted in single unit from September 2013 to August 2014. Data was collected based on POSSUM scoring system. Outcome of the patients was recorded as death / alive; complicated / uncomplicated and statistical analysis was done by comparing the expected and observed outcomes. RESULTS: By applying linear analysis, an observed to expected ratio of 1.005 was obtained for mortality and 1.001 for morbidity. There was no statistically significant difference between the observed and expected mortality rates (chi(2) = 3.54, p = 0.316) and morbidity rates (chi(2) = 2.40, p = 0.792). It was found to be comparable with other studies. The factors independently studied; perforation to operation time and presence of co-morbidity were statistically significant with respect to outcome (p<0.05). CONCLUSION: Although a small sample size is the limitation of this study, POSSUM scoring system is a good indicator of postoperative outcome in patients with perforative peritonitis and was applicable in our setup. It is useful in identifying high risk patients and give preferential care to them for better outcome. Inclusion of factors like perforation to operation time and co-morbid status can improve the scoring system and better care can be provided. PMID- 26046023 TI - What should constitute the clinical component in fellowship examinations in surgery. AB - The consensus of opinion is that in all medical examinations, a failure in the clinical aspect of the examination automatically means a failure in the whole examination regardless of what the total score may be. But opinion differs as to what constitutes the "clinical aspect" of the examination. Some think it should be the average score of only long case and short cases. Others think it should be the total score of long case, short cases and viva voce. Yet others think when the orals are of two parts it should be the average score of long case, short cases and a part of the orals. We therefore used the result of 197 surgical residents that sat for the part 1 fellowship examination of the West African College of Surgeons in April 2012 for this study. We collated the scores of various categories of clinical aspect of the examination to see whether there is any difference in the pass rate of the group. PMID- 26046022 TI - Prevalence of abnormal bone mineral density in hiv-positive patients in ibadan, Nigeria. AB - BACKGROUND: There have been reports of high rate of abnormal bone mineral densities (BMD) among people living with HIV. Following the introduction of combination antiretroviral therapy (CART) into Nigeria, the country is now home to increasing population of HIV positive patients. There is paucity of data about osteoporosis/osteopaenia and bone mineral density in this population. AIM AND OBJECTIVES: The aim of the study was to determine the prevalence and determinants of osteopaenia/osteoporosis in a cohort of HIV-positive patients in Nigeria. PATIENTS AND METHODS: The BMD of a group of patients attending the outpatient clinic of the University of Ibadan, Nigeria was assessed using a DXA machine. The relationship of bone mineral density to body weight, CART status, protease inhibitor use, and gender was investigated. Their CD4 counts and viral load were also estimated. RESULTS: A total of 1005 patients participated with a mean age of 41.3 +/- 10 years. There were 724 females (72.0%) and 29.7% were single. The median length of diagnosis was 2 years (Range 1-18 years). The Median CD4 count was 371cells/ml and Median viral load was 200 copies/ml. Of this sample, 785 (78.1%) were on CART with 99 (12.6%) on protease inhibitor. The mean body mass index (BMI) was 23.7+/-4.7 with 9.2% underweight and 10% obese. The prevalence of osteopaenia and osteoporosis were 46.6% and 31.9% respectively, while 19.6% had normal bone mineral density (BMD). Osteoporosis was significantly higher in those aged above 40 years (p= 0.00001), the females (p= 0.022), the single (p=0.028) and the underweight (p=0.0001). There was no significant difference in BMD of those with or without protease inhibitor containing medications as well as treatment naive patients. CONCLUSION: A high prevalence of abnormal bone mineral density was found in HIV positive patients in Nigeria. Patient age above 40 years and a body mass index class of underweight were significant associated factors. Routine bone mineral density assessment is recommended as an adjunct in the evaluation of HIV positive patients in Nigeria. PMID- 26046024 TI - Knowledge and attitude of some nigerian school teachers on the emergency management of avulsed permanent incisor. AB - BACKGROUND: Tooth avulsion has been known to be the most severe of all dental injuries. The immediate action taken at the accident site will determine the prognosis of the tooth. Replantation of an avulsed tooth is the treatment of choice. AIM & OBJECTIVES: To assess the knowledge and attitude of primary and secondary (Basic educational) school teachers on the emergency management of avulsed permanent incisors. SETTING: Twenty public and private basic educational schools were randomly selected from Lagos State. SUBJECTS & METHODS: Descriptive cross-sectional study. A 23 item self administered questionnaire was distributed to teachers to determine their knowledge and attitude on the emergency management of avulsed permanent incisors. Data was analysed using SPSS (Statistical Package for Social Sciences), Version 21.0. The responses obtained were tabulated and expressed as frequency distributions and then computed in percentages. Chi-square was used to test the association between knowledge of the schools teachers regarding the emergency management of avulsed permanent incisors and their socio demographic variables. Multivariate analysis was used to adjust for confounding variables. The level of significance was set at P <=0.05. RESULTS: A total of 320 teachers answered the questionnaires. Most of the teachers were female (63.1%). Only (30.9%) had received first aid training which included emergency management of dental trauma. Forty- two percent (134) didn't know that an avulsed permanent tooth could be replanted. Twenty teachers (44.4%) would clean an avulsed tooth with toothbrush and toothpaste. A greater proportion of the respondents 130 (40.6%) would transport an avulsed tooth using a clean white handkerchief. The overall knowledge of the school teachers was poor (84%).There was a statistically significant association between the knowledge of the school teachers and the inclusion of emergency management of dental trauma in the first aid training of the teachers P=0.05. Predictors of teachers' level of knowledge of emergency management of avulsed teeth were receipt of advise on management of traumatic dental injuries (OR= 2.5, CI=1.19-4.28) and type of school (OR=0.93, CI=0.206 0.750). CONCLUSION: The school teachers had insufficient knowledge about the emergency management of avulsed permanent teeth. School oral health campaigns with regards to emergency management of avulsed teeth will help improve teachers' knowledge and modify their behaviour. PMID- 26046025 TI - The effectiveness of oral health education conducted at a rural community market setting. AB - BACKGROUND: The workplace is one of the avenues for educating the public about their oral health in developing countries; particularly in rural communities where the workplace plays a major role in communal living. It is therefore necessary to find out if the market is appropriate for achieving the set aim of improving oral health awareness among the populace in rural communities. AIM AND OBJECTIVES: The aim of this study was to determine the effectiveness of oral health education conducted in a market in a rural community by comparing the oral health practices of market women involved in the oral health education programme to those not involved in the programme. DESIGN: A prospective study. SETTING: A rural community in South-western Nigeria. MATERIALS AND METHODS: A prospective interventional study was conducted among market women in Igboora, a rural community in South-western Nigeria. The intervention was oral health education differentiating between the intervention group and the control group. Structured interviewer administered questionnaires were used to obtain information from the participants on their oral hygiene measures, fluoride use, dental attendance and the demographics of the participants. Data collected was analyzed using SPSS and p-value set at <0.05. RESULTS: Two hundred market women participated in the study with a mean age of 45.2 +/- 17 years. The interventional group was made up of 106 market women while the control group was made up of 94 market women. There were no significant differences in the sociodemographic characteristics of women in both the intervention and control groups. Women in the intervention group engaged in more frequent cleaning of their teeth and tongue than those in the control group (p < 0.001). Market women who had participated in the oral health education subsequently visited the dentist more often than those in the control group (p = 0.010). CONCLUSION: The study showed that oral health education conducted at a market was effective in improving some oral health practices of participants. It is recommended that oral health practices be extended to major markets in our communities. PMID- 26046026 TI - Trend of posterior teeth restoration at ibadan, Nigeria. AB - BACKGROUND: A Dental amalgam is the most used restorative material in the posterior region of the mouth and has proven to be remarkably durable; however there has been a global change in recent years to restore posterior teeth with composite resin. AIM & OBJECTIVES: To ascertain the trend of posterior teeth cavity restorations at the University College Hospital (UCH) Ibadan, Nigeria. METHODOLOGY: A-5year retrospective analysis of all the restored posterior cavities at the Dental Conservation Clinic, University College Hospital, Ibadan, Nigeria. Class of cavities, the teeth affected, and the type of restoration made, the outcome and the demographics of the patients were part recorded. The data were analyzed using SPSS Version 20, for frequencies, and means were used for continuous variables while chi square was used to compare the categorical variables (P <=0.05). RESULTS: A total of 845 teeth were restored during the study period in 368(43.6 %) males and 477(56.4 %) females with mean age of 40.4 +/-15.92 years and male to female ratio of 1:1.3. While the first and second molars were the most (62.6%) restored teeth, Class I cavity was the most restored (42.4%) cavity and the majority (80.4%) of the restorations was done with composite. There was a statistical significant reduction in use of amalgam in restoring posterior teeth over the 5 year period. (p=0.000). CONCLUSION: The use of amalgam as choice material for restoration of posterior teeth is gradually being replaced by composite in our environment which emphasizes the need to ensure the quality and durability of the composites used. PMID- 26046027 TI - Radiological features of juvenile nasopharyngeal angiofibroma. AB - Juvenile nasopharyngeal angiofibroma is a rare nasopharyngeal tumour that presents with recurrent epistaxis. A case report and the role of radiologic imaging modalities in diagnosing this entity is presented. PMID- 26046028 TI - Necrotic melanocytoma associated with polycystic liver disease and cutaneous neurofribomata. AB - Melanocytoma, a specific variant of melanocytic naevus may occur anywhere along the uveal tract but most commonly it is on the optic disk and adjacent choroid. We report a case of necrotic melanocytoma with associated polycystic liver disease and peripheral neurofibromatosis in a 70-year old man who was referred to the eye unit of the Korle bu Teaching hospital, Accra, Ghana with a CT scan suggestive of choroidal melanoma. Histopathological features of the enucleated eye revealed necrotic melanocytoma. He also had other systemic conditions. The case is presented and the literature reviewed. PMID- 26046029 TI - Urological complications from obstetrics & gynaecological procedures in ilorin, Nigeria - case series. AB - BACKGROUND: Despite the advances and improvement in science and surgical skills, post-surgical operation complications are oftentimes inevitable, although they could be minimized. Generally, complications occur because of several reasons including patient factors, the disease condition, management option, skills and expertise of the managing team as well as technical factors. Analysis of postoperative complications will help to understand their pathogeneses and identify ways of preventing such complications in the future. AIM & OBJECTIVES: To retrospectively analyse the urological complications arising from obstetrics and gynaecological procedures at the University of Ilorin Teaching Hospital, Ilorin, Nigeria. METHODOLOGY: Retrospective analysis of available records of patients with urological complications following either obstetrics or gynaecological procedures between the year 2010 - 2012 managed by the urology unit of the University of Ilorin Teaching Hospital, Ilorin, Nigeria. The patients were identified from the unit and theatre records. From the patients' clinical records, the data retrieved included the biodata, presentation, details of the gynaecological operations (calibre of surgeons, notable events at operations) and the complications that were recorded. The urological interventions and outcomes were also recorded. RESULTS: There were 11 patients with urological complications during the three year period. Their ages ranged from 28 and 65years (mean 43.8 +/ 0.05 years), about 60% had hysterectomy for uterine fibroids. Various complications such as urinary fistulae (45.5%), ureteric obstructions (36.5%), retained surgical foreign bodies (9%) and ureteric transection (9%) were recorded. Corrective urological interventions were successful in majority (72.7 %) of them. CONCLUSION: Urological complications associated with gynaecological and obstetrics procedures are sometimes inevitable but their occurrence could be reduced when standard practices are observed. PMID- 26046030 TI - Urological complications of abdominal surgery. PMID- 26046031 TI - New antiresorptive therapies for postmenopausal osteoporosis. AB - Osteoporosis is a systemic skeletal disease whose risk increases with age and it is common among postmenopausal women. Currently, almost all pharmacological agents for osteoporosis target the bone resorption component of bone remodeling activity. Current antiresorptive agents are effective, but the effectiveness of some agents is limited by real or perceived intolerance, longterm adverse events (AEs), coexisting comorbidities, and inadequate long-term adherence. New antiresorptive therapies that may expand options for the prevention and treatment of osteoporosis include denosumab, combination of conjugated estrogen/bazedoxifene and cathepsin K inhibitors. However, the long-term efficacy and AEs of these antiresorptive therapies need to be confirmed in studies with a longer follow-up period. PMID- 26046032 TI - A flood of health functional foods: what is to be recommended? AB - Health functional food is referred to a food prepared or processed from specific components or ingredients for functionality beneficial to the body through extraction, concentration, purification, blending and other methods. The demand for health functional foods is steadily increasing, and red ginseng is the most demanded food among women in the 50s, followed by multivitamin, omega-3, glucosamine and aloe. To date, there is insufficient evidence on the effect of red ginseng on exercise capacity, somatic symptom and cognitive performance in healthy individuals. Moreover, evidence is insufficient that a nutritional dose of vitamin or mineral reduces the incidence of cardiovascular disease and cancer, or mortality rate. A steady intake of oily fish is recommended to prevent the incidence of cardiovascular disease for postmenopausal women. Consumption of omega-3 fatty acids is expected to prevent cardiovascular disease in postmenopausal women with almost no intake of oily fish and those not taking statins. It still remains controversial whether glucosamine is effective in the treatment of osteoarthritis. Hence, physicians should fully inform patients with all controversial information about the effectiveness of glucosamine when prescribing glucosamine for patients with osteoarthritis. PMID- 26046033 TI - Prevention of cognitive impairment in the midlife women. AB - Forgetfulness is common symptom with age. Especially for midlife women, hormonal cessation by menopausal change is one of the causes in cognitive disorders. And neuropathological changes in brain can lead to mild cognitive impairment (MCI) and eventually dementia. Prevention of MCI is important for decreasing progression to dementia. This article presents therapeutic approaches based on pathophysiologic changes in brain for preventing cognitive decline. PMID- 26046034 TI - Neutral sphingomyelinase and breast cancer research. AB - Our understanding of the functions of neutral sphingomyelinase (N-SMase) signaling has advanced over the past decade. In this review, we focus on the roles and regulation of N-SMase 1, N-SMase 2, N-SMase 3, an enzyme that generates the bioactive lipid ceramide through the hydrolysis of the membrane lipid sphingomyelin. A large body of work has now implicated N-SMase 2 in a diverse set of cellular functions, physiological processes, and disease pathologies. We focus on different aspects of this enzyme's regulation from transcriptional, post translational, and biochemical. Furthermore, we expected N-SMase involvement in cellular processes including inflammatory signaling, cell growth, apoptosis, and tumor necrosis factor which in turn play important roles in pathologies such as cancer metastasis, variable disease, and other organ system disorders. Lastly, we examine avenues where targeted N-SMase inhibition may be clinically beneficial in disease scenarios. PMID- 26046035 TI - Is complementary and alternative therapy effective for women in the climacteric period? AB - Vasomotor symptoms start about 2 years prior to menopause in women who are approaching menopause, and early menopause symptoms appear including emotional disturbance and anxiety, followed by physical changes such as vaginal dryness, urinary incontinence and skin wrinkles. As time progresses, osteoporosis, cardiovascular diseases, and dementia occur consecutively. Hormone therapy is primarily considered for the relief of menopause symptoms in postmenopausal women. However, as hormone replacement has emerged as a therapy that increases the potential risk of thrombosis, cerebral infarction and breast cancer, complementary and alternative medicine has drawn much attention. This study aimed to examine the types and effects of evidence-based complementary and alternative therapies that are currently used. PMID- 26046036 TI - Evaluation of bone density measurement in type 2 diabetic postmenopausal women with hypertension and hyperlipidemia. AB - OBJECTIVES: The aim of the study was to compare bone mineral density (BMD) in healthy postmenopausal women to BMD in type 2 diabetic hypertensive postmenopausal women with hyperlipidemia. METHODS: Fifty type 2 diabetic and hypertensive postmenopausal women with hyperlipidemia and 51 age and body mass index (BMI) matched healthy postmenopausal women were included. Lumbar spine and femoral neck BMD were noted in both groups. BMD was measured using dual energy X ray absorptiometry (DXA). Serum alkaline phosphatase (ALP), calcium and phosphorous were also measured. Pearson correlation coefficients were used to establish the relationship between various clinical characteristics. RESULTS: There were no significant differences between two groups in respect to lumbar and vertebral BMD values, age, BMI, gravidity, parity. Serum cholesterol and fasting glucose levels were significantly different between each groups (P = 0.0001, P = 0.002). CONCLUSION: We found that, accompanying chronic diseases such as diabetes, hypertension and hyperlipidemia don't affect the BMD measurements at postmenopausal period. So these postmenopausal women don't have excess risk regarding osteoporosis. PMID- 26046037 TI - A pilot study of the impacts of menopause on the anogenital distance. AB - OBJECTIVES: It has been known that there is a difference in anogenital distance (AGD) in the animals and newborn depending on the exposure of androgenic hormones. The anatomical changes occur in the female genitalia in women after menopause. This was pilot study to find out whether the menopause affects AGD. METHODS: We evaluated a total of 50 women targeted for premenopausal and postmenopausal group in each 25 people. AGD was defined as a length between the posterior commissure of labia and anal center. AGD was measured in lithotomy position using sterile paper ruler. In order to control bias of the height and weight, which could influence the AGD, anogenital index (AGI) is defined as the weight divided by the AGD value. We used a Mann-Whitney U test to analyze the relationship between AGD and menopause for statistical analysis. RESULTS: AGD was significantly longer in premenopausal women compared to postmenopausal women (34.8 +/- 6.4 vs. 30.3 +/- 6.6, P = 0.019). AGI was significantly higher in premenopausal women than postmenopausal women (1.7 +/- 0.4 vs. 1.3 +/- 0.3, P <= 0.000). CONCLUSION: The changes of AGD and AGI in postmenopausal women demonstrated to have potential to be used as on scale predicting the physical changes that may occur after menopause. This study could be used as the cornerstone of a large-scale studies in the future. PMID- 26046038 TI - Comparison of Surgical Outcomes according to Suturing Methods in Single Port Access Laparoscopic Myomectomy. AB - OBJECTIVES: This study was performed to consider the clinical experience of surgical outcome of single port access (SPA) laparoscopic myomectomy according to suturing methods. METHODS: The authors operated with 2 suturing method in SPA laparoscopic myomectomy for 246 patients and compared the surgical outcomes. RESULTS: The some significant difference of surgical outcome according to two suturing methods was demonstrated. Operating time was 100.50 minutes (+/- 42.09 minutes) in interrupted suture method group than 121.04 minutes (+/- 61.56 minutes) in continuous interlocking suture method group (P = 0.021). Estimated blood loss was less 222.59 mL (+/- 144.94 mL) in interrupted suture group than 340.11 mL (+/- 380.62 mL) in continuous interlocking suture method group (P = 0.042). CONCLUSION: This experience suggests that interrupted suture method was effective for operating time and estimated blood loss than continuous interlocking method in SPA laparoscopic myomectomy. PMID- 26046039 TI - Postmenopausal Meigs' Syndrome in Elevated CA-125: A Case Report. AB - Meigs' syndrome is a benign ovarian tumor associated with ascites and pleural effusion. Elevated cancer antigen 125 (CA-125) in Meigs' syndrome is an unusual clinical condition reported in few cases. We report here on a 61-year-old woman who presented with dyspnea; in imaging assessment, a heterogeneous pelvic mass measuring 12 * 11 cm with ascitic fluid was reported. Pleural effusion was detected on Chest X-ray. Aspiration of pleural fluid showed no evidence of malignancy. CA-125 level was 347 IU/mL. The patient underwent laparotomy during which a mass measuring 12 * 11 cm was detected in her left adnexa. Histology showed ovarian thecoma. The mass was resected, and, after that, the symptoms disappeared and CA-125 level reached 19 IU/mL. The patient had experienced no problem after 12 months of follow up. Although postmenopausal women with ovarian tumor, ascites, pleural effusion, and elevation of CA-125 levels probably have malignant ovarian tumors, Meigs' syndrome must be considered in the differential diagnosis. PMID- 26046040 TI - Non-intubated thoracic surgery: nostalgic or reasonable? PMID- 26046041 TI - Awake video-assisted thoracic surgery in acute infectious pulmonary destruction. AB - BACKGROUND: Many of thoracic minimally invasive interventions have been proven to be possible without general anesthesia. This article presents results of video assisted thoracic surgery (VATS) application under local anesthesia in patients with lung abscesses and discusses its indications in detail. METHODS: The study involved prospective analysis of treatment outcomes for all acute infectious pulmonary destruction (AIPD) patients undergoing VATS under local anesthesia and sedation since January 1, 2010, till December 31, 2013. Patients with pulmonary destruction cavity at periphery of large size (>5 cm) underwent non-intubated video abscessoscopy (NIVAS). Patients with pyopneumothorax (lung abscess penetration into pleural cavity) underwent non-intubated video thoracoscopy (NIVTS). Indications for NIVAS and NIVTS were as follows: cavity debridement and washing, necrotic sequestra removal, adhesion split, biopsy. All interventions were done under local anesthesia and sedation without trachea intubation and epidural anesthesia. RESULTS: Sixty-five enrolled patients had 42 NIVAS and 32 NIVTS interventions, nine patients underwent two surgeries. None of the patients required trachea intubation or epidural anesthesia. In none of our cases with conversion to thoracotomy was required. Post-surgical complications developed after 11 interventions (13%): subcutaneous emphysema (five cases), chest wall phlegmon (three cases), pulmonary bleeding (two cases), and pneumothorax (one case). One patient died due to the main disease progression. In 50 patients NIVAS and NIVTS were done within 5 to 8 days after abscess/pleural cavity draining, while in other 15 patients-immediately prior to draining; both pulmonary bleeding episodes and all cases of chest wall phlegmon took place in the latter group. CONCLUSIONS: NIVAS and NIVTS under local anesthesia and sedation are well tolerated by patients, safe and should be used more often in AIPD cases. Timing of NIVAS and NIVTS procedures was found to be of paramount importance for ensuring complete therapeutic effectiveness. PMID- 26046042 TI - Non-intubated video-assisted thoracic surgery in patients aged 80 years and older. AB - BACKGROUND: Video-assisted thoracic surgery (VATS) is routinely performed with general anesthesia and double-lumen endotracheal intubation, but this technique may stress an elderly patient's functional reserve. We chose to study the safety and efficacy of non-intubated VATS, utilizing local anesthesia, sedation, and spontaneous ventilation in the elderly. METHODS: The medical records of all patients aged 80 years and older who underwent VATS under local anesthesia and sedation during the time period 6/1/2002 to 6/1/2010 at Geisinger Health System (Pennsylvania, USA) and 10/1/2011 to 12/31/2014 at Sinai Hospital (Maryland, USA) were retrospectively reviewed. Unsuccessful attempts at this technique were eligible for inclusion but there were none. No patient was excluded based on comorbidity. RESULTS: A total of 96 patients ranging in age from 80 to 104 years underwent 102 non-intubated VATS procedures: pleural biopsy/effusion drainage with or without talc 73, drainage of empyema 17, evacuate hemothorax 4, pericardial window 3, lung biopsy 2, treat chylothorax 2, treat pneumothorax 1. No patient required intubation or conversion to thoracotomy. No patient required a subsequent procedure or biopsy. Complications occurred in three patients (3.1% morbidity): cerebrovascular accident, pulmonary embolism, prolonged air leak. One 94-year-old patient died from overanticoagulation and two 84-year-old patients died of their advanced lung cancers (3.1% morbidity). CONCLUSIONS: Non-intubated VATS utilizing local anesthesia and sedation in the elderly is well tolerated and safe for a number of indications. PMID- 26046043 TI - Non-intubated video-assisted thoracoscopic surgery anatomical resections: a new perspective for treatment of lung cancer. AB - The lung isolation under general anaesthesia with double lumen tubes has become an indispensable part of video-assisted thoracoscopic surgery (VATS) for lung cancer. However, with an attempt to avoid the residual effects of muscle relaxants and the systemic complications due to tracheal intubation, anesthesia without tracheal intubation has also been applied in VATS surgeries for lung cancer. Currently, non-intubated anesthesia under spontaneous breathing has been widely applied in VATS, contributing to more stable anesthesia and lower rate of switching to intubated anesthesia. It can be applied in most VATS procedures including anatomical pulmonary lobectomy, anatomical segmentectomy, and radical resection for lung cancer. In the selected lung cancer patients, non-intubated anesthesia under spontaneous breathing makes the VATS procedures safer and more feasible. With an equal chance for surgery as the intubated anesthesia, this technique lowers the incidences of peri-operative complications and speeds up post-operative recovery. As a novel surgical option, the anatomic VATS under non intubated anesthesia under spontaneous breathing have shown to be promising. Nevertheless, the long-term outcomes require further evaluation in more multi center prospective clinical trials with larger sample sizes. PMID- 26046044 TI - Non-intubated video-assisted thoracic surgery as the modality of choice for treatment of recurrent pleural effusions. AB - This review will establish that the best mode of treatment for recurrent pleural effusions is non-intubated video-assisted thoracic surgery (VATS) with chemical talc pleurodesis. The nature of recurrent pleural effusions mandates that any definitive and effective treatment of this condition should ideally provide direct visualization of the effusion, complete initial drainage, a low risk outpatient procedure, a high patient satisfaction rate, a high rate of pleurodesis and a high diagnostic yield for tissue diagnosis. There are various methods available for treatment of this condition including thoracostomy tube placement with bedside chemical pleurodesis, thoracentesis, placement of an indwelling pleural catheter, pleurectomy and VATS drainage with talc pleurodesis. Of these treatment options VATS drainage with the use of local anesthetic and intravenous sedation is the method that offers most of the desired outcomes, thus making it the best treatment modality. PMID- 26046045 TI - Non-intubated video-assisted thoracic surgery management of secondary spontaneous pneumothorax. AB - Secondary spontaneous pneumothorax (SSP) is serious entity, usually due to underlying disease, mainly chronic obstructive pulmonary disease (COPD). Its morbidity and mortality is high due to the pulmonary compromised status of these patients, and the recurrence rate is almost 50%, increasing mortality with each episode. For persistent or recurrent SSP, surgery under general anesthesia (GA) and mechanical ventilation (MV) with lung isolation is the gold standard, but ventilator-induced damages and dependency, and postoperative pulmonary complications are frequent. In the last two decades, several groups have reported successful results with non-intubated video-assisted thoracic surgery (NI-VATS) with thoracic epidural anesthesia (TEA) and/or local anesthesia under spontaneous breathing. Main benefits reported are operative time, operation room time and hospital stay reduction, and postoperative respiratory complications decrease when comparing to GA, thus encouraging for further research in these moderate to high risk patients many times rejected for the standard regimen. There are also reports of special situations with satisfactory results, as in contralateral pneumonectomy and lung transplantation. The aim of this review is to collect, analyze and discuss all the available evidence, and seek for future lines of investigation. PMID- 26046046 TI - Nonintubated video-assisted thoracoscopic surgery for management of indeterminate pulmonary nodules. AB - Indeterminate pulmonary nodules are common findings in clinical practice, especially after widespread use of high-resolution computed tomographic scans for cancer screening. To determine whether the nodule is malignant or not, surgery is usually required for either diagnostic or therapeutic purposes in the early stages. Current development in minimally invasive surgery and anesthesia using video-assisted thoracoscopic surgery without tracheal intubation (nonintubated VATS) are feasible and safe for resection of peripheral lung nodules, including nonintubated needlescopic or uniportal approaches. In addition, nonintubated VATS may offer high-risk patients for intubated general anesthesia opportunities to receive surgery. Therefore, nonintubated VATS can provide an attractive alternative for early diagnosis and treatment of indeterminate lung nodules. PMID- 26046047 TI - Surgical pneumothorax under spontaneous ventilation-effect on oxygenation and ventilation. AB - Surgical pneumothorax allows obtaining comfortable surgical space for minimally invasive thoracic surgery, under spontaneous ventilation and thoracic epidural anesthesia, without need to provide general anesthesia and neuromuscular blockade. One lung ventilation (OLV) by iatrogenic lung collapse, associated with spontaneous breathing and lateral position required for the surgery, involves pathophysiological consequences for the patient, giving rise to hypoxia, hypercapnia, and hypoxic pulmonary vasoconstriction (HPV). Knowledge of these changes is critical to safely conduct this type of surgery. Surgical pneumothorax can be now considered a safe technique that allows the realization of minimally invasive thoracic surgery in awake patients with spontaneous breathing, avoiding the risks of general anesthesia and ensuring a more physiological surgical course. PMID- 26046048 TI - Effects on respiration of nonintubated anesthesia in thoracoscopic surgery under spontaneous ventilation. AB - Thoracoscopic surgery without tracheal intubation [nonintubated video-assisted thoracoscopic surgery (VATS)] is an emerging treatment modality for a wide variety of thoracic procedures. By surgically induced open pneumothorax, the operated lung collapse progressively while the dependent lung is responsible for sufficiency of respiratory function, including oxygenation and ventilation. Encouraging results showed that ventilatory changes and oxygenation could be adequately maintained in major lung resection surgery and in patients with impaired respiratory function. In spite of a relative hypoventilation, mild hypercapnia is inevitable but clinically well tolerated. An understanding the respiratory physiology during surgical pneumothorax, either in awake or sedative status, and an established protocol for conversion into tracheal intubation are essential for patient safety during nonintubated VATS. PMID- 26046049 TI - The complex care of severe emphysema: role of awake lung volume reduction surgery. AB - The resectional lung volume reduction surgery (LVRS) procedure entailing nonanatomic resection of destroyed lung regions through general anesthesia with single-lung ventilation has shown to offer significant and long-lasting improvements in respiratory function, exercise capacity, quality of life and survival, particularly in patients with upper-lobe predominant emphysema and low exercise capacity. However mortality and morbidity rates as high as 5% and 59%, respectively, have led to a progressive underuse and have stimulated investigation towards less invasive surgical and bronchoscopic nonresectional methods that could assure equivalent clinical results with less morbidity. We have developed an original nonresectional LVRS method, which entails plication of the most severely emphysematous target areas performed in awake patients through thoracic epidural anesthesia (TEA). Clinical results of this ultra-minimally invasive procedure have been highly encouraging and in a uni-center randomized study, intermediate-term outcomes paralleled those of resectional LVRS with shorter hospital stay and fewer side-effects. In this review article we analyze indications, technical details and results of awake LVRS taking into consideration the available data from the literature. PMID- 26046050 TI - Non-intubated anesthesia in thoracic surgery-technical issues. AB - Performing awake thoracic surgery (ATS) is technically more challenging than thoracic surgery under general anesthesia (GA), but it can result in a greater benefit for the patient. Local wound infiltration and lidocaine administration in the pleural space can be considered for ATS. More invasive techniques are local wound infiltration with wound catheter insertion, thoracic wall blocks, selective intercostal nerve blockade, thoracic paravertebral blockade and thoracic epidural analgesia, offering the advantage of a catheter placement which can also be continued for postoperative analgesia. PMID- 26046051 TI - Nonintubated anesthesia in thoracic surgery: general issues. AB - Anesthetic management for awake thoracic surgery (ATS) is more difficult than under general anesthesia (GA), being technically extremely challenging for the anesthesiologist. Therefore, thorough preparation and vigilance are paramount for successful patient management. In this review, important considerations of nonintubated anesthesia for thoracic surgery are discussed in view of careful patient selection, anesthetic preparation, potential perioperative difficulties and the management of its complications. PMID- 26046052 TI - Intraoperative crisis resource management during a non-intubated video-assisted thoracoscopic surgery. AB - The management of surgical and medical intraoperative emergencies are included in the group of high acuity (high potential severity of an event and the patient impact) and low opportunity (the frequency in which the team is required to manage the event). This combination places the patient into a situation where medical errors could happen more frequently. Although medical error are ubiquitous and inevitable we should try to establish the necessary knowledge, skills and attitudes needed for effective team performance and to guide the development of a critical event. This strategy would probably reduce the incidence of error and improve decision-making. The way to apply it comes from the application of the management of critical events in the airline industry. Its use in a surgical environment is through the crisis resource management (CRM) principles. The CRM tries to develop all the non-technical skills necessary in a critical situation, but not only that, also includes all the tools needed to prevent them. The purpose of this special issue is to appraise and summarize the design, implementation, and efficacy of simulation-based CRM training programs for a specific surgery such as the non-intubated video-assisted thoracoscopic surgery. PMID- 26046053 TI - Urgent awake thoracoscopic treatment of retained haemothorax associated with respiratory failure. AB - A number of video-assisted thoracoscopic surgery (VATS) procedures are being increasingly performed by awake anesthesia in an attempt of minimizing the surgical- and anesthesia-related traumas. However, so far the usefulness of awake VATS for urgent management of retained haemothorax has been scarcely investigated. Herein we present two patients with retained haemothorax following previous thoracentesis and blunt chest trauma, respectively, who developed acute respiratory failure and underwent successful urgent awake VATS management under local anesthesia through a single trocar access. PMID- 26046054 TI - Mechanisms of Gaucher disease pathogenesis. PMID- 26046055 TI - How long should dual antiplatelet therapy be continued following implantation of drug eluting stents? PMID- 26046056 TI - Safe anticoagulation when heart and lungs are "on vacation". AB - Circulation and oxygenation of blood outside the body is commonly required during complex surgical interventions involving coronary pulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO). Both CPB and ECMO are life-supporting procedures utilizing a heart-lung machine, which subjects the blood to unphysiological conditions, potentially promoting undesirable blood coagulation. Traditionally, thrombotic complications from CPB and ECMO are resolved by heparin, an inexpensive broad spectrum anticoagulant that prevents blood clotting, but often results in bleeding. Despite hemostatic support therapy and constant monitoring, the lives of patients undergoing CPB and ECMO are often threatened by uncontrolled bleeding. There is an urgent need for novel strategies which provide safe anti-coagulation alternatives during CPB and ECMO procedures. Several non-traditional approaches, including nitric oxide donors as well as various protease and contact activation inhibitors, have been investigated and shown some success. More recently, Larsson et al. isolated a recombinant fully human (3F7) antibody inhibiting Factor XIIa. The antibody was shown to be both an efficacious and safe alternative to heparin. Below we will examine this study in more detail and offer considerations for translation of this novel concept to the clinic. PMID- 26046057 TI - Application of 3D printing in orthopedics: status quo and opportunities in China. PMID- 26046058 TI - Healing the scars of life-targeting redox imbalance in fibrotic disorders of the elderly. PMID- 26046059 TI - The prognostic value of HPV in head and neck cancer patients undergoing postoperative chemoradiotherapy. PMID- 26046060 TI - A pioneering countermeasure against measles virus. PMID- 26046061 TI - The role of the Th1 chemokine CXCL10 in vitiligo. PMID- 26046062 TI - Human somatic stem cell-based therapy for cartilage regeneration. PMID- 26046063 TI - Topical intra-articular and intravenous tranexamic acid to reduce blood loss in total knee arthroplasty. PMID- 26046064 TI - Current progress in genetic research of adolescent idiopathic scoliosis. AB - Previous genetic linkage analysis and candidate gene association analysis have unveiled dozens of variants associated with the development of adolescent idiopathic scoliosis (AIS), which however can seldom be replicated in different ethnics. Recently, two genome-wide association studies of AIS performed in Japan revealed that ladybird homeobox 1 (LBX1) gene and G protein-coupled receptor 126 (GPR126) gene could play a role in the etiopathogenesis of the disease. Since the association between these two genes and AIS were successfully validated in the Caucasian and the Chinese population, LBX1 gene and GPR126 gene were the most reliable genetic variants underling the development of AIS. PMID- 26046065 TI - Editorial on the original article entitled "3D printing of composite calcium phosphate and collagen scaffolds for bone regeneration" published in the Biomaterials on February 14, 2014. AB - The paper entitled "3D printing of composite calcium phosphate and collagen scaffolds for bone regeneration" published in the Biomaterials recently illuminated the way to make particular scaffolds with calcium phosphate (CaP) powder, phosphoric acid, type I collagen and Tween 80 in low temperature. After the optimal concentration of each component was determined, the scaffolds were evaluated in a critically sized murine femoral defect model and exhibited good material properties. We made some related introduction of materials applied in 3D printing for bone tissue engineering based on this article to demonstrate the current progress in this field of study. PMID- 26046066 TI - Inhibition of factor XIIa, a new approach in management of thrombosis. PMID- 26046067 TI - Clostridium to treat cancer: dream or reality? AB - In their paper "Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses", Roberts et al. describe the induction of antitumor responses following local spore administration of an attenuated C. novyi strain (C. novyi-NT). Stereotactic intratumoral spore injection led to significant survival advantages in a murine orthotopic brain model and local bacterial treatment produced robust responses in a set of spontaneous canine soft tissue carcinomas. Their preclinical findings in both models, provided the basis for a phase 1 investigational clinical study in patients with solid tumors that were either refractory to standard treatment or without an available standard treatment available (NCT01924689). The results of the first patient enrolled in this trial, a 53-year-old female with a retroperitoneal leiomyosarcoma, are described. Next to the non-armed C. novyi-NT described in this paper, very potent genetically modified Clostridium expressing anti-cancer therapeutic genes are also being developed. Are treatments with these non-pathogenic clostridia a viable alternative cancer treatment? PMID- 26046068 TI - gammadelta T cells and immunity to human malaria in endemic regions. PMID- 26046069 TI - Reactive aldehydes: a new player in inflammatory pain. PMID- 26046070 TI - The holy grail of cystic fibrosis research: pharmacological repair of the F508del CFTR mutation. PMID- 26046071 TI - The arthroscopic Latarjet procedure: effective and safe. PMID- 26046072 TI - SNPping away at the genetic basis of adolescent idiopathic scoliosis. AB - Adolescent idiopathic scoliosis (AIS) is a genetically complex disorder of spine development, defined by a lateral curvature of the spine of 10o or greater which affects children during their pubertal growth spurt. Prior linkage and candidate gene approaches to elucidating the genetic basis of AIS have been of limited use for identification of candidate genes for this condition. Genome wide association studies (GWAS) have recently identified single nucleotide polymorphisms (SNPs) in LBX1 and G protein-coupled receptor 126 (GPR126) that contribute to AIS occurrence. These discoveries support prior etiologic hypotheses regarding altered somatosensory function and skeletal growth in AIS. However, these loci account for a small percentage of the phenotypic variance associated with AIS, indicating the vast majority of the genetic causes of AIS remain to be delineated. A major translational application regarding understanding the genetic contributions to AIS relates to bracing efficacy. PMID- 26046073 TI - Editorial on the original article entitled "Genetic validation of a therapeutic target in a mouse model of ALS" published in the Science Translational Medicine on August 6, 2014. AB - Amyotrophic lateral sclerosis (ALS) still remains a deadly neurodegenerative disease, mainly characterized by the combined degeneration of both upper and lower motor neurons (MNs). The pathology perspective is changed after 2006 due to the demonstration of common inclusions in ALS and Frontotemporal Dementia (non tauFTD). Genetics largely contributed to further define the common mechanisms of both diseases but the large numbers of sporadic cases still remain unsolved. Transgenic mice models demonstrated the non-cell autonomous nature of ALS, being surrounding cells as astrocytes, microglial cells, and olygodendrocytes crucial in determining MN degeneration. More recently, the use of embryonic stem cells (ESCs) and/or IPSCs contributed to provide in vitro models for the ALS pathology and biological assay of clinical relevance. The combined use of ESC and SOD1 transgenic model of ALS has been pioneering used. The prostanoid receptor DP1 has been elegantly demonstrated to mediate the glial toxicity to stem-cell derived MNs in vitro. This evidence has been translated in vivo: the genetic ablation of DP1 in the SOD1G93A mice extended life span, decreasing microglial activation and MN loss. This paper is quite compelling, at the cutting edge of the stem cell transgenic translation, demonstrating that discoveries derived from stem cells can be corroborated in vivo and possibly translated to humans. PMID- 26046074 TI - Gene therapy for GM1 gangliosidosis: challenges of translational medicine. PMID- 26046075 TI - Communication in locked-in state after brainstem stroke: a brain-computer interface approach. PMID- 26046076 TI - Blocking the 'MIDAS' touch of Enterococcus faecalis. PMID- 26046077 TI - When the capsule matters. PMID- 26046078 TI - Reducing affinity of alphavbeta8 interactions with latent TGFbeta: dialling down fibrosis. PMID- 26046079 TI - Apyrase as a novel therapeutic inhibitor of heterotopic ossification. PMID- 26046080 TI - The Mkx homeoprotein promotes tenogenesis in stem cells and improves tendon repair. PMID- 26046081 TI - Dysfunctional gammadelta T cells: a contributing factor for clinical tolerance to malaria? PMID- 26046082 TI - Genetics of adolescent idiopathic scoliosis in the post-genome-wide association study era. PMID- 26046083 TI - Towards a genotype-based approach for a patient-centered pharmacologic therapy of type 2 diabetes. AB - The recent data reported by Tang and colleagues in Science Translational Medicine suggest that alpha-2 adrenoceptors (alpha2AAR) genetic heterogeneity may explain diverging results regarding the effects of alpha2AAR antagonists on insulin secretion and glucose control in patients with type 2 diabetes. They first confirmed that the risk variant for rs553668 (the A allele for a single nucleotide polymorphism in ADRA2A) is likely to cause defective insulin secretion in human pancreatic islets. Second they showed that blocking alpha2AAR with yohimbine dose-dependently improves the reduced insulin secretion during an oral glucose tolerance test in patients with the risk variant. The successful translation of genomic information into clinical intervention in patients with type 2 diabetes provides proof of concept for the feasibility of individualized treatment based on genotype. PMID- 26046084 TI - Host directed therapies (HDTs) and immune response signatures: insights into a role for interleukin-32. PMID- 26046085 TI - Hospital readmission rates following primary total hip arthroplasty: present and future in sight. PMID- 26046086 TI - Efficacy of combined use of intraarticular and intravenous tranexamic acid in total knee arthroplasty. PMID- 26046087 TI - Broad spectrum antiviral T cells for viral complications after hematopoietic stem cell transplantation. AB - Major complications of hematopoietic stem cell transplantation (HSCT) or solid organ transplantation (SOT), such as graft rejection and graft-versus-host disease (GvHD), are countered by suppressing the host immune system via chemotherapy and radiation, immunosuppressive drugs, or conditioning regimens such as in vivo or in vitro T-cell depletion. While immunocompromised, the patient is rendered susceptible to a number of viral infections and reactivations mainly caused by endogenous herpes viruses like cytomegalovirus (CMV) and Epstein Barr virus (EBV) and by lytic agents such as adenovirus (ADV). In the paper entitled "Activity of broad-spectrum T cells as treatment for ADV, EBV, CMV, BKV, and HHV6 Infections after HSCT" published recently in Science Translational Medicine, Anastasia Papadopoulou and colleagues reported a suitable technology for rapid generation of antiviral T cells with a broad specificity in a single culture for clinical application. In a small clinical trial with 11 patients they demonstrated safety and efficacy of adoptive multivirus-specific T-cell transfer. PMID- 26046088 TI - Tranexamic acid for the reduction of blood loss in total knee arthroplasty. AB - The Journal of Arthroplasty recently published a paper entitled "The Efficacy of Combined Use of Intraarticular and Intravenous Tranexamic Acid on Reducing Blood Loss and Transfusion Rate in Total Knee Arthroplasty". Tranexamic acid (TXA) is an antifibrinolytic drug whose administration during the perioperative period either by intravenous route or topically applied to the surgical field has been shown to reliably reduce blood loss and need for transfusion in patients undergoing total knee arthroplasty (TKA). Although randomized trials and meta analyses did not show an increase in thromboembolic events, concerns remain about its repeated systemic application. The authors of the study introduced a novel regimen of TXA administration combining a preoperative intravenous bolus followed by local infiltration at the end of surgery with the idea of maximizing drug concentration at the surgical site while minimizing systemic antifibrinolytic effects. The combined dosage regimen appears to be more effective than single dose local application in reducing blood loss and transfusion rate without any complications noted. PMID- 26046089 TI - Lung cancer screening with low dose computed tomography (LDCT): looking back and moving forward. PMID- 26046090 TI - Lateral retinacular release and reconstruction. PMID- 26046091 TI - Tricks to translating TB transcriptomics. AB - Transcriptomics and other high-throughput methods are increasingly applied to questions relating to tuberculosis (TB) pathogenesis. Whole blood transcriptomics has repeatedly been applied to define correlates of TB risk and has produced new insight into the late stage of disease pathogenesis. In a novel approach, authors of a recently published study in Science Translational Medicine applied complex data analysis of existing TB transcriptomic datasets, and in vitro models, in an attempt to identify correlates of protection in TB, which are crucially required for the development of novel TB diagnostics and therapeutics to halt this global epidemic. Utilizing latent TB infection (LTBI) as a surrogate of protection, they identified IL-32 as a mediator of interferon gamma (IFNgamma)-vitamin D dependent antimicrobial immunity and a marker of LTBI. Here, we provide a review of all TB whole-blood transcriptomic studies to date in the context of identifying correlates of protection, discuss potential pitfalls of combining complex analyses originating from such studies, the importance of detailed metadata to interpret differential patient classification algorithms, the effect of differing circulating cell populations between patient groups on the interpretation of resulting biomarkers and we decipher weighted gene co-expression network analysis (WGCNA), a recently developed systems biology tool which holds promise of identifying novel pathway interactions in disease pathogenesis. In conclusion, we propose the development of an integrated OMICS platform and open access to detailed metadata, in order for the TB research community to leverage the vast array of OMICS data being generated with the aim of unraveling the holy grail of TB research: correlates of protection. PMID- 26046092 TI - Brain injury requires lung protection. AB - The paper entitled "The high-mobility group protein B1-Receptor for advanced glycation endproducts (HMGB1-RAGE) axis mediates traumatic brain injury (TBI) induced pulmonary dysfunction in lung transplantation" published recently in Science Translational Medicine links lung failure after transplantation with alterations in the axis HMGB1-RAGE after TBI, opening a new field for exploring indicators for the early detection of patients at risk of developing acute lung injury (ALI). The lung is one of the organs most vulnerable to the inflammatory cascade triggered by TBI. HMGB1 is an alarm in that can be released from activated immune cells in response to tissue injury. Increased systemic HMGB1 concentration correlates with poor lung function before and after lung transplant, confirming its role in acute ALI after TBI. HMGB1 exerts its influence by interacting with several receptors, including the RAGE receptor. RAGE also plays an important role in the onset of innate immune inflammatory responses, and systemic levels of RAGE are strongly associated with ALI and clinical outcomes in ventilator-induced lung injury. RAGE ligation to HMGB1 triggers the amplification of the inflammatory cascade involving nuclear factor kappaB (NF-kappaB) activation. Identifying early biomarkers that mediate pulmonary dysfunction will improve outcomes not only in lung transplantation, but also in other scenarios. These novel findings show that upregulation of the HMGB1 RAGE axis plays an important role in brain-lung crosstalk. PMID- 26046093 TI - Editorial on "Broadly neutralizing antibodies abrogate established hepatitis C virus infection" published in Science Translational Medicine on 17th September 2014. AB - Hepatitis C virus (HCV) is a blood borne pathogen that causes chronic liver disease and afflicts 170 million people world-wide. While direct acting antivirals now provide a highly effective means to cure those infected with HCV, there is no vaccine to prevent infection. Published in Science Translational Medicine, de Jong et al. [2014] show that highly potent neutralizing antibodies (NAbs) directed to one of the surface glycoproteins of HCV, E2, can not only prevent infection but can also eliminate established infection in experimental animal models of HCV. They provide compelling evidence that for HCV to maintain a chronic infection, it must infect new hepatocytes; infection cannot be sustained in reservoirs of infected cells alone and that E2-specific NAbs are sufficient to cure an infection. In addition, the manuscript further supports the importance of NAbs in preventing, controlling and possibly curing HCV. Thus NAbs are not only essential to the development of prophylactic vaccines but may yet have a role in therapeutic approaches to HCV treatment. PMID- 26046094 TI - A variant of FGF19 for treatment of disorders of cholestasis and bile acid metabolism. PMID- 26046095 TI - Generation of new cardiomyocytes after injury: de novo formation from resident progenitors vs. replication of pre-existing cardiomyocytes. PMID- 26046096 TI - Long term outcomes of Charnley THA in patients under the age of 50: an editorial comment on recently published article by Warth et al. PMID- 26046097 TI - ArfGAPs: key regulators for receptor sorting. AB - Mammalian cells have many membranous organelles that require proper composition of proteins and lipids. Cargo sorting is a process required for transporting specific proteins and lipids to appropriate organelles, and if this process is disrupted, organelle function as well as cell function is disrupted. ArfGAP family proteins have been found to be critical for receptor sorting. In this review, we summarize our recent knowledge about the mechanism of cargo sorting that require function of ArfGAPs in promoting the formation of transport vesicles, and discuss the involvement of specific ArfGAPs for the sorting of a variety of receptors, such as MPR, EGFR, TfR, Glut4, TRAIL-R1/DR4, M5-muscarinic receptor, c-KIT, rhodopsin and beta1-integrin. Given the importance of many of these receptors to human disease, the studies of ArfGAPs may provide novel therapeutic strategies in addition to providing mechanistic insight of receptor sorting. PMID- 26046098 TI - Chronic High Fat Diet Consumption Impairs Metabolic Health of Male Mice. AB - We show that chronic high fat diet (HFD) feeding affects the hypothalamus of male but not female mice. In our study we demonstrate that palmitic acid and sphingolipids accumulate in the central nervous system of HFD-fed males. Additionally, we show that HFD-feeding reduces proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) thus reducing estrogen receptor alpha (ERalpha) and driving hypothalamic inflammation in male but not female mice. Hypothalamic inflammation correlates with markers of metabolic dysregulation as indicated by dysregulation in glucose intolerance and myocardial function. Lastly, we demonstrate that there are blockages in mitophagy and lipophagy in hypothalamic tissues in males. Our data suggest there is a sexually dimorphic response to chronic HDF exposure, females; despite gaining the same amount of body weight following HFD-feeding, appear to be protected from the adverse metabolic effects of the HFD. PMID- 26046099 TI - Diagnostic challenges of low-grade central osteosarcoma of jaw: a literature review. AB - Low Grade Central Osteosarcoma (LGCO) is a rare subtype of osteosarcoma that is less aggressive than conventional osteosarcoma. The importance of LGCO lies in the fact that regarding microscopic and radiographic features, it occasionally simulates some benign jaw lesions and would consequently be misdiagnosed in many patients. The present study was conducted to collect the information and descriptive analyses related to ten cases reported between 1987 and 2010, including a sample reported by the authors emphasizing on diagnostic errors and the prevailing misdiagnosis. The aforementioned reports were gathered in full texts through Google and PubMed search engines. CONCLUSION: The results of this study showed that the pathologists should exactly evaluate the clinical, radiographic, and histopathologic features in order to observe the evidence of invasion. PMID- 26046100 TI - The Effect of Epigallocatechin Gallate on the Dentin Bond Durability of Two Self etch Adhesives. AB - STATEMENT OF THE PROBLEM: Self-etch adhesives can activate matrix metalloproteinase (MMP) which hydrolyzes organic matrix of demineralized dentin. Epigallocatechin gallate (EGCG), especially found in green tea, could inhibit the activation of MMP. PURPOSE: The aim of this study was to evaluate the effect of adding Epigallocatechin gallate (EGCG) into two types of adhesives on dentin bond strength. MATERIALS AND METHOD: In this experimental study, 64 extracted third molars were randomly divided into 16 groups. Clearfil SE Bond and Filtek Silorane System with 0 uM, 25uM, 50uM, and 100uM concentration of 95% EGCG were used for bonding. Following the bonding and fabrication of beams (1+/-0.1 mm(2)) and storage in distilled water, the specimens were subjected to thermal cycles. Microtensile bond strengths of 8 groups were examined after 24 hours and others were tested after 6 months. The fracture modes of specimens were evaluated by stereomicroscope and SEM. Data were analyzed by three-way ANOVA and t-test (alpha = 0.05). RESULTS: The results of the three- way ANOVA test showed that types of bonding, storage time and interactive effect of EGCG concentration and bonding influenced the bond strength of specimens significantly (p<0.05). The results of the t-test indicated that storage time only had significant effect on bond strength of Clearfil SE Bond with no EGCG (p= 0.017). The most common failure modes in Filtek Silorane System groups and Clearfil SE Bond groups were adhesive and mixed/cohesive, respectively. The results of SEM at different magnifications showed that most fractures have occurred in the hybrid layer. CONCLUSION: Although adding 100 uM volume of EGCG to Clearfil SE Bond can preserve the dentin bond, incorporation of EGCG in the silorane system, especially in high concentrations, decreases the bond strength after 6 months. PMID- 26046101 TI - Frequency of tonsilloliths in panoramic views of a selected population in southern iran. AB - STATEMENT OF THE PROBLEM: Tonsilloliths are relatively common clusters of dystrophic calcified material that form in the tonsillar crypts, mostly the palatine tonsils. Although they may be asymptomatic, some cause halitosis, cough, dysphagia, and foreign body sensation, as well as otalgia. Since tonsilloliths can be detected on panoramic views as radiopaque lesions, and misdiagnosis may lead to wasting time and cost, dentist should be familiar with radiographic characteristics of this type of calcification. PURPOSE: This study was conducted to determine the prevalence and the pattern of distribution of tonsilloliths on panoramic radiographs. MATERIALS AND METHOD: This cross-sectional study was based on 2000 panoramic radiographs from 1030 female and 970 male aged 6-75 years old evaluated for the presence and pattern of tonsillolithiasis, between 2011 and 2013 in Shiraz, Iran. Chi-square test and odds ratio were used to evaluate the relationship between tonsillolithiasis and gender. p< 0.05 was considered as statistically significant. RESULTS: Out of the 2000 individuals, 101 cases (5.05%) had tonsilloliths on panoramic radiographs out of which 61 were male (60.4%) and 40 were female (39.6%), with age range of 18 to 65. Forty patients (39.6%) had both left and right sides involved, 25 of tonsilloliths (24.75%) were located on the right and 36 on the left side (35.65%). Men were more likely to develop tonsilloliths (p= 0.014). CONCLUSION: Tonsilloliths are not very common finding and can be detected on nearly 5.05% of panoramic radiographs. Most of the cases are unilateral with a diameter less than 2mm. PMID- 26046102 TI - The Effect of Iranian Customary Used Probiotic Yogurt on the Children's Salivary Cariogenic Microflora. AB - STATEMENT OF THE PROBLEM: Dental caries is the most common disease of childhood. Using probiotics has recently been introduced to reduce the incidence of dental caries.It consists of live microbial food supplements that beneficially affect the host, and hence are considered an alternative way to eradicate the infections. PURPOSE: The aim of this study is to evaluate the effect of consumption of probiotic yogurt on the children's salivary cariogenic microflora. MATERIALS AND METHOD: A double-blind randomized study was performed recruiting 2 parallel groups; 24 healthy children in the case and 25 children in the control group. All healthy children were followed- up over 4 periods. Periods 1 and 3 were wash-out periods with duration of 1 and 2 weeks, respectively. During periods 2 and 4 (2weeks duration each), the case group consumed 200g yogurt containing Bifidobacterium lactis (1*10(6) per gram) once daily and the control group consumed normal yogurt. Salivary Streptococci mutans and Lactobacilli were enumerated before and after the yogurt consumption periods. Pre- and post treatment values within and between regimens were compared using the t-test and paired samples. RESULTS: There was a reduction in Streptococcus mutans and Lactobacillus counts in the control group, but for Streptococcus mutans, the count reduction between phases 1 and 4 was statistically significant (p= 0.009). In the case group, neither the Streptococcus mutans count nor the Lactobacilli count was significantly reduced. CONCLUSION: Based on the findings of this study, short-term daily consumption of probiotic yogurt containing Bifidobacterium lactis could not reduce the levels of salivary Streptococcus mutans and Lactobacilli in 6 to 12 year-old children, while normal yogurt could reduce the Streptococcus mutans counts significantly. PMID- 26046103 TI - Evaluation of Minichromosome Maintenance-3 (MCM3) in Oral Squamous Cell Carcinoma. AB - STATEMENT OF THE PROBLEM: The expression of minichromosome maintenance-3 (MCM3) proteins and their diagnostic value in oral mucosal dysplasia and squamous cell carcinoma (SCC) is not well known. PURPOSE: This study was conducted to evaluate the usefulness of minichromosome maintenance 3 (MCM3) as a biomarker for diagnosis of oral premalignant lesions and SCC. MATERIALS AND METHOD: In this study, 31 oral SCC, 20 dysplastic epithelium and 20 controls were selected and immunohistochemical staining was done for MCM3. ANOVA, Tukey HSD, Mann-Whitney and Kruskal-Wallis tests were used to compare the groups and the correlation between different grades. RESULTS: There was increasing trend of MCM3 from control to dysplastic epithelium and from dysplastic epithelium to SCC both in suprabasal layers and in total epithelial layers. MCM3 expression was elevated with increasing the grade of dysplasia, but there was no statistically significant difference (p= 0.93). The expression was also increased in high grades of SCC compared to lower grades. CONCLUSION: MCM3 can be used as a useful biomarker in the diagnosis of premalignant lesions and oral SCC. PMID- 26046104 TI - Relationship of elongated styloid process in digital panoramic radiography with carotid intima thickness and carotid atheroma in Doppler ultrasonography in osteoporotic females. AB - STATEMENT OF THE PROBLEM: Cardiovascular disease and osteoporosis are major health dilemmas. Osteoporotic patients frequently display vascular calcification that consequently increases the cardiovascular morbidity and mortality. PURPOSE: This study aimed to investigate the relation of osteoporosis, vascular calcification (atheroma, intima-media thickness (IMT)) and elongated styloid process (ESP) in a sample of osteoporotic and normal female individuals. MATERIALS AND METHOD: This study recruited 78 women who were assessed for bone mass density (BMD). Sample included individuals with normal BMD (n=13, 17 %), osteopenia (n=36, 46 %), and osteoporosis (n=29, 37%). The presence of atheroma and IMT was examined using color Doppler ultrasonography (CD-US). In addition, digital panoramic radiographs (PRs) were obtained to assess ESP. RESULTS: In this study, 55 subjects (70%) with low BMD exhibited at least one side ESP. Femoral BMD decreased significantly in subjects with ESP (p= 0.03). Bilateral ESP was correlated with the presence of atheroma (p= 0.029). The CIMT was greater in patients with ESP, although the relation was not significant. CONCLUSION: The obtained data suggest referring the aged individuals with ESP for BMD assessment and individuals with low bone mass and ESP for more cardiovascular risk assessment. PMID- 26046105 TI - Microleakage of Class V Methacrylate and Silorane-based Composites and Nano ionomer Restorations in Fluorosed Teeth. AB - STATEMENT OF THE PROBLEM: Enamel and dentin marginal sealing ability of the new adhesive materials could play an important role in successful restoration on fluorosed teeth. PURPOSE: The aim of this in vitro study was to evaluate the marginal microleakage of low-shrinkage silorane-based composite, nano-ionomer, and methacrylate-based composite through self-etching approach or with enamel acid etching. MATERIALS AND METHOD: Seventy-two extracted human molars with moderate fluorosed (according to Thylstrup and Fejerskov index, TFI= 4-6) were randomly divided into six groups (n=12). Class V cavities were prepared on the buccal surface at the cementoenamel junction and restored with Clearfil SE Bond/Clearfil AP-X (methacrylate composite), Silorane Adhesive System/Filtek P90 , and nano primer/nano-ionomer according to the manufacturer's instructions (self etching approach) or with additional selective enamel acid etching before primer application for each adhesive. After water storage and thermocycling, microleakages of the samples were assessed using dye-penetration technique at the enamel and dentin margins. Data were analyzed using non-parametric tests (alpha = 0.05). RESULTS: There was a significant difference among the six groups at the enamel margin (p= 0.001), but not at the dentin margin (p= 0.7). For all the three adhesive materials, additional enamel etching resulted in significantly reduced microleakage at the enamel margin (p< 0.05). CONCLUSION: Methacrylate- and silorane-based composites and nano-ionomer revealed a similar and good performance in terms of dentin marginal sealing, but not at the enamel margin. The additional selective enamel etching might improve enamel sealing for the three materials. PMID- 26046106 TI - Comparison of commercially available arch wires with normal dental arch in a group of Iranian population. AB - STATEMENT OF THE PROBLEM: The stability of orthodontic treatment depends on preserving the patient's pretreatment arch form and arch size during and after treatment. PURPOSE: This investigation was aimed to study the size and shape of Iranian mandibular dental arch and evaluate the correlation of their average dental arch with commercially available preformed rectangular nickel-titanium arch wires. MATERIALS AND METHOD: In this study, 148 subjects were selected among students of Shiraz University of Medical Sciences. The inclusion criteria were having Angle class I in molar and canine relationships, and normal growth pattern. Intercanine and intermolar widths were measured after scanning their mandibular dental casts. Three main arch form templates; square, ovoid and tapered (Orthoform (TM); 3M, Unitek, CA, USA) and 12 commercially available preformed mandibular nickel-titanium arch wires were scanned. Intercanine and intermolar widths of arch wires were compared with dental arch widths of the study samples. Arch width, arch form and the most appropriate arch wire were determined for each cast. Student's t-test was used to compare arch widths and arch depths of male and female subjects. Coefficient of variance was used to determine the variability of indices in the study samples. RESULTS: Most preformed arch wires were wider than the average width of the normal Iranian dental arch. The most frequent arch form in Iranian population was tapered. Inter molar width was the only statistically significant variable between males and females. CONCLUSION: Variation in available preformed arch wires does not entirely cover the range of diversity of the normal dental arch of our population. Narrow arch wires with a tapered shape are better consistent with the Iranian lower arch. PMID- 26046107 TI - The effect of porcelain firing and type of finish line on the marginal fit of zirconia copings. AB - STATEMENT OF THE PROBLEM: Although all-ceramic restorations are broadly used, there is a lack of information concerning how their fit is affected by fabrication procedure and marginal configuration. PURPOSE: The purpose of this study was to evaluate the marginal fit of zirconia CAD/CAM ceramic crowns before and after porcelain firing. The influence of finish line configuration on the marginal fit was also evaluated. MATERIALS AND METHOD: Twenty standardized zirconia CAD/CAM copings were fabricated for chamfer and shoulder finish line designs (n=10). The marginal fit of specimens was measured on 18 points, marked on the master metal die by using a digital microscope. After the crowns were finalized by porcelain veneering, the measurements of marginal fit were performed again. The means and standard deviations were calculated and data were analyzed using student's t-test and paired t-test (alpha=0.05). RESULTS: There were significant differences between marginal fit of chamfer and shoulder finish line groups before and after porcelain firing (p= 0.014 and p= 0.000, respectively). The marginal gap of copings with shoulder finish line was significantly smaller than those with chamfer configuration (p= 0.000), but there were no significant differences between the two marginal designs, after porcelain firing (p= 0.341). CONCLUSION: Porcelain veneering was found to have a statistically significant influence on the marginal fit of zirconia CAD/CAM crowns. Both margin configurations showed marginal gaps that were within a reported clinically acceptable range of marginal discrepancy. PMID- 26046108 TI - Evaluation of Retention of two Different Cast Post-Core Systems and Fracture Resistance of the Restored Teeth. AB - STATEMENT OF THE PROBLEM: The survival of pulpless teeth restored with different post and core systems is still a controversial issue. PURPOSE: This study compared the retention of two different post and core systems and also the fracture resistance of teeth restored with these systems. MATERIAL AND METHOD: Eighty endodontically treated maxillary central incisors were sectioned perpendicular to the long axis at a point 2mm incisal to the cemento-enamel junction (CEJ) and then the root canals were obturated. The restored teeth were randomly divided into two equal groups of 40. One group was restored with Nickel Chromium (Ni-Cr) post and core system and the other group with Non-Precious Gold alloy (NPG) system. For evaluation of fracture resistance of the restored teeth, the specimens (n=20 per each group) were mounted in acrylic resin blocks and a layer of polyvinyl siloxane was applied to cover the roots. Loads were applied at an angle of 45 degrees to the long axis of the teeth and measured with a universal testing machine. The axial retention values of the studied groups (no=20) were measured on an Instron testing machine at a crosshead speed of 0.5 mm/min. Statistical analyses were performed using SPSS version 19.00 and student's t-test (alpha=0.05). RESULTS: Although retention failure load for Ni-Cr system was lower than NPG system, there was no significant difference between the two systems (p= 0.7). However, fracture resistance of the teeth restored with Ni Cr post and core system was significantly higher than NPG group (p= 0.000). CONCLUSION: There was no significant difference between the retention of the studied post and core systems. Although significantly higher fracture thresholds were recorded for Ni-Cr post and core group, the failure loads of both systems may rarely occur clinically. PMID- 26046109 TI - The Effect of two Shading Techniques on Value of Zirconia-Based Crowns. AB - STATEMENT OF THE PROBLEM: By introducing the coloring liquids, it is claimed that it is possible to make the color of frameworks fabricated from zirconium oxide extremely close to the natural tooth color. PURPOSE: The purpose of this research was to evaluate the effect of two staining techniques on value changing in zirconia crowns. MATERIALS AND METHOD: Three groups A, B, and C, each containing ten zirconia crowns, were used. The zirconium cores samples were fabricated by a CAD/CAM device. Group A was left uncolored, Groups B was submerged for two minutes in A2 coloring liquid and Group C was stained with brush. Then all cores were sintered and the porcelain was applied by using the layering technique. Ultimately, the crowns color was determined using a spectrophotometer. Their color changing (?E) and value changing (?L) in relation to A2 color were also assessed. The data were analyzed with one-sample t-test, post-hoc Tukey, and one way ANOVA tests with significant level set at 0.05. RESULTS: The mean value in all groups was higher than the value obtained from A2 color samples (p= 0.001). The highest mean value was 78.31+/-1.22 belonging to group C (staining with brush) and the lowest mean value was 76.99+/-0.65 belonging to group B (submerging). The results of post-hoc Tukey regarding both ?E and ?L variables showed a significant difference between groups A (uncolored) and C (staining with brush) with P?E=0.006 and P?L=0.039, respectively. A significant difference between group B (submerging technique) and C (staining with brush) were shown when these two variables were compared (P?E=0.001, P?L=0.015). CONCLUSION: Due to the higher value increase in surface staining (brush), it is recommended to use the submerging technique for staining zirconia cores. PMID- 26046110 TI - Actinomyces colonization in keratocystic odontogenic tumor: a case report. AB - Actinomycosis is an anaerobic infection that involves the craniofacial region and its colonization has rarely been reported in the developmental odontogenic cysts. In the present report, a case of odontogenic keratocyst (which is now called keratocystic odontogenic tumor) with the colonization of actinomyces is introduced and its significance is discussed. PMID- 26046111 TI - Editorial: Conceptions, conspiracies, and knowledge: our role in bridging the gap. PMID- 26046112 TI - Halitosis: measurement in daily practice. AB - Bad breath is a widespread but still largely taboo problem. The dentist is often the first point of contact for affected patients. Initially, the diagnosis and quantification of halitosis provides objective evidence and helps to find the underlying causes, but it is equally important for monitoring the treatment progress. Most often, halitosis is caused intraorally, thus the dentist will also be responsible for initiating an appropriate treatment. Apart from the simple organoleptic examination without the need for additional instruments, several devices for the measurement of halitosis are available which provide a differentiated analysis of the exhaled air by determining and quantifying the detected volatile sulfur compounds. PMID- 26046113 TI - Experiences of lesbian and gay occupational therapists in the healthcare system. AB - Narrative data from open-ended questions from a descriptive cross-sectional survey surrounding the experience of 24 lesbian and gay occupational therapists in their work and patient roles are discussed. An iterative and inductive analysis of therapists' responses resulted in identification of three emergent themes: deciding when to come out, the culture of the setting impacts if and to whom I come out, and shades of discrimination affect the work and patient role. Findings are discussed in relation to the implications for occupational therapists and other allied healthcare providers as a way to inform professionals and educators of the lived experience of lesbian and gay therapists, the impact of embracing diversity through one's attitude, knowledge and skill through education, and advocacy at the professional and pre-service levels. PMID- 26046114 TI - Assessment and evaluation in interprofessional education: exploring the field. AB - BACKGROUND: The practice of interprofessional education (IPE) is expanding rapidly in the United States and globally. The publication of competencies from the Interprofessional Education Collaborative (IPEC) was a significant step forward to recognize the importance of health professions collaboration and to guide institutions for educational program development. However, there remains substantial difficulty in implementation, as well as considerable variability in assessment of learners' interprofessional collaborative knowledge and skills and evaluation of IPE programs. METHODS: We conducted a multi-methods project which included 20 key informant interviews, a literature review, and a meeting of an expert panel. Our goals were 1) explore the current field of IPE, 2) identify and disseminate best practices to institutions wishing to implement/augment IPE assessment and evaluation processes, 3) uncover gaps in current IPE assessment and evaluation practices, and 4) recommend next steps for the field. RESULTS: A small and growing literature indicates evidence of the effectiveness of IPE. A diverse collection of methods and tools are used to assess and evaluate IPE learners and programs; these are often used without an explicit program evaluation framework. CONCLUSIONS: For the field to advance and to align with the demands of changing clinical care systems, robust assessment and evaluation methods, standardized use of common tools, and longitudinal assessment from diverse data streams are needed for IPE. PMID- 26046116 TI - The SEARCH Project: Acquainting Students in the Health Professions with Interprofessional Care. AB - The SEARCH NH project (Student Experiences and Rotations in Community Health in New Hampshire) was a 3-year collaboration of the New Hampshire Area Health Education Center, four educational institutions, and four community health centers. The purpose was to introduce students in the health professions to interprofessional care in underserved areas. It was funded by the National Health Services Corps. The background of the project, its development, and findings are described. Seventy-four students from undergraduate and graduate nursing programs, a physician assistant program, and a medical school participated. Prior to a focused immersion experience in a community health center, they were exposed didactically to concepts of interprofessional care. Findings from the collaborative project are reported using a clinical microsystems framework to analyze student reflections on their experiences and resultant learning. In quotes offered as exemplars, students report increased appreciation of the clinical microsystem's 5 Ps: purpose, professionals, patients, patterns, and processes in interprofessional work. PMID- 26046115 TI - Investigating and predicting early lumbar spine surgery outcomes. AB - OBJECTIVE: To examine short-term changes in patients' clinical status following lumbar spine surgery (LSS) and to explore presurgical variables that predict surgical outcomes. METHODS: Prospective cohort study. A total of 46 patients underwent LSS. Patients completed the following questionnaires 1 week before LSS and 2 weeks after discharge from the hospital: back and leg visual pain analogue scale, Ronald Morris questionnaire (RMQ), Modified Somatic Perception questionnaire (MSPQ), SF-36, Fear-Avoidance Beliefs Questionnaire, Beck's Depression Inventory, EuroQol questionnaire, and patient-perception of improvement. Regression models were constructed to examine predictors of pain, function, quality of life, and patient-perception of improvement at 2 weeks postsurgery. RESULTS: Patients demonstrated significant improvement in back and leg pain and function. MSPQ and symptom duration were significant predictors of back pain, while type of diagnosis and use of opioids were significant predictors of leg pain. Preoperative MSPQ and RMQ were significant predictors of postoperative RMQ. MSPQ, gender, and back pain were significant predictors of quality of life. Back pain, leg pain, depression, smoking, and worker's compensation were significantly associated with patient-perception of improvement. CONCLUSIONS: This preliminary study could be viewed as a directory to identify potential risk factors for unfavorable outcomes at early stages following LSS. PMID- 26046117 TI - An observational study exploring academic mentorship in physical therapy. AB - BACKGROUND: Health professions faculty members often come to the academy without formal training as a professor. A challenge that exists for many new professors is the expectation that they will effectively balance their tripartite roles, which include ensuring teaching excellence, research rigor, and service to the university community. Mentoring has been suggested to be a way that new faculty can be supported as they seek to meet these expectations. Currently, there is limited information on faculty mentoring for physical therapy (PT) faculty. OBJECTIVE: The purpose of this study was to discover if and to what extent mentoring is occurring in entry-level PT education for new full-time PT faculty. DESIGN: Exploratory, cross-sectional survey research design. METHODS: Using the Health Sciences Faculty Mentoring Survey, the authors gathered descriptive data regarding faculty mentoring across entry-level PT education. RESULTS: Of the 66 respondents in this study, only 15 faculty members (22.7%) reported having a faculty mentor, with only 10 of these receiving mentorship from within their own PT department. While the sample size was small, the data provide specific information on current mentorship practices in the PT academic community. CONCLUSION: The findings indicate that the presence of academic mentorship in PT is limited. In light of this finding, the authors sought to provide insight on PT faculty perceptions regarding mentorship in the academy and discuss possible frameworks that can be used to develop and support the tripartite roles of novice faculty as they transition into the academy. PMID- 26046118 TI - Dietetic student preparedness and performance on clinical placements: perspectives of clinical educators. AB - Clinical educators (CEs) play a key role in student learning, yet their insights of student preparedness and performance during initial clinical placements are often under-recognised. AIM: To explore the experience of hospital-based CEs on the preparedness and performance of student dietitians on clinical placements to inform curriculum planning. METHODS: Eight semi-structured focus groups consisted of dietetic CEs (n=20) involved in the training of third-year students commencing their first clinical placement. Focus groups were conducted up to 2 months' post placement completion and thematically analysed grounded in phenomenology. RESULTS: Six themes emerged: 1) role of professional skills, 2) clinical skills and knowledge, 3) anxiety and confidence, 4) unique needs of culturally and linguistically diverse (CALD) students, 5) impact of student training on CEs, and 6) variation in expectations of student preparedness. CONCLUSIONS: CEs valued professional skills of students and they reported students exhibited a range of developed traits. Anxiety and knowledge gaps hindered placement progress, and CALD students were reported to provide particular challenges. Expectations of CEs, the university, and students are not always congruent, and there were similar variations between CEs themselves. The findings have been used to address these challenges and improve collaboration between university and clinical placements. PMID- 26046119 TI - The integrated model for interprofessional education: a design for preparing health professions' students to work in interprofessional teams. AB - An important element in the process of helping students learn to work interprofessionally is figuring out how to design high-impact learning experiences that engage students in meaningful learning that is collaborative and experiential and can transform students understanding of their own and others' roles in the health care process. In this article, a model for interprofessional education, the Integrated Model for Interprofessional Education (IMIPE), is shared for introducing students in the health professions to the roles and responsibilities of some of the other healthcare professionals with whom they will work in practice. The IMIPE is a process model developed by an interprofessional faculty team used as the focal point of a pilot educational event for students from nursing, occupational therapy, physician assistant studies, and social work. The IMIPE is a derived model that combines concepts of holism, participation, and practical education, grounded in the adult educational philosophy of progressivism. Progressive adult education is focused on practical knowledge and problem-solving skills. The model uses collaborative, experiential, and transformative learning approaches to foster outcomes of communication, critical reflection, teamwork, ethics, and recognition of patient-client needs. These outcomes represent those identified by the World Health Organization and the Interprofessional Education Collaborative Expert Panel. PMID- 26046120 TI - The Minority Are the Majority: Today's Smoker. AB - The smoking rate in America has decreased substantially over the past 50 years; however, this decrease is disproportionately accounted for by the high quit rates and lower initiation rates of middle class smokers with no medical or psychiatric comorbidities. The majority of modern smokers' cessations efforts are complicated by one or more forms of "disadvantage, " such as social, economic, legal, or psychiatric problems. The next step in reducing the national smoking prevalence is to reduce the prevalence in the most neglected portions of the population. In this paper, the characteristics of modern smokers are discussed in light of the 2014 Surgeon General's Report and the Affordable Care Act. Implications for current treatment and future research are suggested in an effort to take advantage of the progress that has been made and the new opportunities provided by healthcare reform. PMID- 26046121 TI - An innovative dietetic student placement model in rural new South wales, australia. AB - Over the past 10 years, the University of Newcastle Department of Rural Health, based in Tamworth, New South Wales, has supported increased opportunities for short- and long-term rural dietetic placements through an ongoing collaboration between Hunter New England Local Health District dietitians and University of Newcastle academic staff, using an innovative student placement model. A recent strategy has been the implementation of year-long student attachments to a rural area in an attempt to improve long-term recruitment and retention of staff to rural and remote areas. This paper describes the dietetic student placement model and outcomes to date. There has been an increase in the number and diversity of student placements in Tamworth, from 2 student placements in 2002 to 33 in 2013 and a maximum increase of 317 student weeks. Students have rated the short- and long-term options highly. Intention to work rurally after graduation was reported at 49% for the 2011/2012 cohort of students. Seventy-three percent of all year long students have obtained work in a rural setting after graduation. An increased exposure to a rural location has the potential to increase the recruitment of staff in rural areas. PMID- 26046122 TI - Advocacy Priorities and Strategies for ASAHP: A Survey of the ASAHP Membership. AB - The Association of Schools of Allied Health Professions (ASAHP) recently established a strategic goal to increase advocacy efforts. The purpose of this study was to identify advocacy priorities and preferred advocacy strategies among the ASAHP membership. A brief Advocacy Priorities and Strategies Survey was sent to 234 ASAHP members included in the ASAHP email list using an online survey software. Forty-eight members (20%) completed the survey. Data were analyzed using the online survey software and response frequency counts. ASAHP members identified the following federal advocacy priorities: 1) support for students entering allied health professions, 2) support for faculty seeking higher degrees to enhance quality of education in allied health programs, 3) support for higher education institutions to increase capacity of professional programs to address projected allied health workforce needs identified by the Bureau of Labor Statistics, and 4) support for research funding from federal agencies for allied health. The need for education regarding allied health professions to enhance advocacy efforts was also reported. Preferred advocacy strategies included scheduling ASAHP conferences in Washington, DC, to facilitate trips to Capitol Hill and visiting legislators in home states. Members also indicated a need to participate in advocacy training to enhance their advocacy skills. PMID- 26046123 TI - How should we prepare rehabilitation sciences students to work with low English proficient Spanish-speaking patients? AB - Misinterpretations or lack of compliance with national standards established to guide health professionals working with low-English-proficient (LEP) patients continue to negatively impact patient care. Most of the literature on training health professionals to work with interpreters focuses on physicians. We reviewed this current literature and propose an interprofessional educational module to extend the interpreter training to other health professions. Our module trains rehabilitation science students from different health disciplines (physical therapy, occupational therapy, and speech-language pathology) using strategies from the literature. The educational module is tailored to student's bilingual proficiency, suggests relevant outcomes measures, and highlights unanswered questions and areas for future research. PMID- 26046124 TI - Development and evaluation of a regional, large-scale interprofessional collaborative care summit. AB - The Northeastern/Central Pennsylvania Interprofessional Education Coalition (NECPA IPEC) is a coalition of faculty from multiple smaller academic institutions with a mission to promote interprofessional education. An interprofessional learning program was organized, which involved 676 learners from 10 different institutions representing 16 unique professions, and took place at seven different institutions simultaneously. The program was a 3-hour long summit which focused on the management of a patient with ischemic stroke. A questionnaire consisting of the Interprofessional Education Perception Scale (IEPS) questionnaire (pre-post summit), Likert-type questions, and open comment questions explored the learners' perceptions of the session and their attitudes toward interprofessional learning. Responses were analyzed using descriptive statistics and statistical tests for difference and qualitative thematic coding. The attitude of learners toward interprofessional education (as measured by the IEPS) was quite high even prior to the summit, so there were no significant changes after the summit. However, a high percentage of learners and facilitators agreed that the summit met its objective and was effective. In addition, the thematic analysis of the open-ended questions confirmed that students learned from the experience with a sense of the core competencies of interprofessional education and practice. A collaborative approach to delivering interprofessional learning is time and work intensive but beneficial to learners. PMID- 26046125 TI - The anti-obesity effects of a tuna peptide on 3T3-L1 adipocytes are mediated by the inhibition of the expression of lipogenic and adipogenic genes and by the activation of the Wnt/beta-catenin signaling pathway. AB - The differentiation of 3T3-L1 cells into adipocytes involves the activation of an organized system of obesity-related genes, of which those encoding CCAAT/enhancer binding proteins (C/EBPs) and the Wnt-10b protein may play integral roles. In a previous study of ours, we found that a specific peptide found in tuna (sequence D-I-V-D-K-I-E-I; termed TP-D) inhibited 3T3-L1 cell differentiation. In the present study, we observed that the expression of expression of C/EBPs and Wnt 10b was associated with obesity. The initial step of 3T3-L1 cell differentiation involved the upregulation of C/EBP-alpha expression, which in turn activated various subfactors. An upstream effector of glycogen synthase kinase-3beta (GSK 3beta) inhibited Wnt-10b expression in 3T3-L1 adipocytes. In a previous study of ours, we sequenced the tuna peptide via sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and quadrupole time-of-flight mass spectrometry (Q-TOF MS/MS) and confirmed the anti-obesity effects thereof in 3T3-L1 adipocytes. In the present study, we demonstrate that TP-D inhibits C/EBP and promotes Wnt-10b mRNA expression, thus activating the Wnt pathway. The inhibition of lipid accumulation was measured using a glucose and triglyceride (TG) assay. Our results confirmed that TP-D altered the expression levels of C/EBP-related genes in a dose-dependent manner and activated the Wnt signaling pathway. In addition, we confirmed that total adiponectin and high-molecular weight (HMW) adiponectin levels were reduced by treatment with TP-D. These data indicate that TP-D inhibits adipocyte differentiation through the inhibition of C/EBP genes and the subsequent activation of the Wnt/beta-catenin signaling pathway. PMID- 26046126 TI - IQGAP1 modulates the proliferation and invasion of thyroid cancer cells in response to estrogen. AB - Thyroid cancer is an endocrine malignancy with a high incidence rate, which is affected by female hormones, particularly estrogens, in its growth and progression. IQ-domain GTPase-activating protein 1 (IQGAP1) is overexpressed in a range of types of cancer and is reported to interact with estrogen receptor alpha (ERalpha) in breast cancer cells. However, the association between IQGAP1 and ERalpha in thyroid cancer cells remains to be elucidated. In this study, the role of IQGAP1 in thyroid cancer cells was examined. The expression of IQGAP1 (190 kDa) was analyzed using western blot analysis, which indicated that IQGAP1 was overexpressed in thyroid cancer tissues and FTC133 cells. However, IQGAP1 knockdown in the FTC133 cells led to a significant downregulation in ERalpha transcriptional activity, cell proliferation, cell adhesion and cell invasion under 17beta-estradiol (E2) conditions. Furthermore, ERalpha knockdown inhibited the enhanced protein expression levels of phosphorylated ERK1/2 and cyclin D1, which were induced by the overexpression of IQGAP1. Co-immunoprecipitation was also performed in thyroid cancer cells and the results suggested that IQGAP1 directly interacted with ERalpha in the FTC133 cells and the co-transfected COS-7 cells. Taken together, these findings revealed that IQGAP1 may directly interact with ERalpha and serve as a signal integrator, mediating ERalpha transcriptional activity, cell proliferation and cell invasion during the progression of thyroid cancer. PMID- 26046128 TI - DUOX2 promotes the elimination of the Klebsiella pneumoniae strain K5 from T24 cells through the reactive oxygen species pathway. AB - Dual oxidase 2 (DUOX2) plays a major role in host defense in intestinal and airway epithelial cells through the reactive oxygen species (ROS) pathway. Klebsiella pneumoniae is a uropathogen that causes urinary tract infections. It is not known whether DUOX2 plays a role in host defense in bladder cancer epithelial cells. It is also not known whether Klebsiella pneumoniae invades T24 human bladder carcinoma cells and whether DUOX2 plays a role in eliminating the Klebsiella pneumoniae strain K5 through the ROS pathway in T24 cells. Thus, in the present study, we aimed to investigate the infectious capability of the Klebsiella pneumoniae K5 strain and the immunity-promoting capability of DUOX2 in T24 cells. We quantified the number of viable intracellular bacteria using the plate count method. DUOX2 expression was evaluated by western blot analysis and reverse transcription-quantitative PCR (RT-qPCR) following treatment with or without multiple cytokines, phorbol 12-myristate 13-acetate (PMA), muramyl dipeptide (MDP), N-acetylmuramyl-D-alanyl-D-isoglutamine (MDP-DD), H2O2 inhibitor, catalase (CAT), the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) oxidase inhibitor, diphenyleneiodonium (DPI), or siRNA targeting DUOX2 (siDUOX2). The levels of ROS in the T24 cells infected with the K5 strain were examined following treatment with DPI, CAT or siDUOX2. Our results revealed that DUOX2 expression increased and the number of viable intracellular bacteria decreased in the T24 cells following infection with the K4 bacteria. Treatment with the cytokines and MDP and PMA also induced DUOX2 expression and decreased the number of viable intracellular bacteria. The levels of ROS also increased following treatment with the cytokines and MDP and PMA. However, when the cells were treated with the inhibitors (DPI or CAT), these effects were all reversed. Our data demonstrated that DUOX2 played an important role in innate immunity against bacterial cytoinvasion through the ROS pathway in T24 cells. Our findings also provide insight into the protection of uroepithelial cells from Klebsiella pneumoniae K5 bacterial cytoinvasion, and thus lay the foundation for the development of novel therapies for urinary tract infections. PMID- 26046127 TI - Urine and serum metabolomic profiling reveals that bile acids and carnitine may be potential biomarkers of primary biliary cirrhosis. AB - In order to provide non-invasive, reliable and sensitive laboratory parameters for the diagnosis of primary biliary cirrhosis (PBC), metabolic technology of ultraperformance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS) was used to compare small molecule metabolites in blood and urine from patients with PBC and healthy controls. We then screened for bio-markers in the blood and urine of the patients with PBC. Data were processed by Bruker ProfileAnalysis metabonomic software and imported to SIMCA-P software, which utilized principal component analysis (PCA) to create models of patients with PBC and healthy controls. In total, 18 urinary markers were found and the levels of 11 of these urinary markers were elevated in the patients with PBC, whereas the levels of the remaining 7 markers were lower in the PBC group compared to the control group. We also identified 20 blood-based biomarkers in the patients with PBC and the levels of 9 of these markers were higher in the PBC group, whereas the levels of the remaining 11 markers were lower in the patients with PBC compared to the controls. Among these biomarkers, the levels of bile acids increased with the progression of PBC, while the levels of carnitines, such as propionyl carnitine and butyryl carnitine, decreased with the progression of PBC. In conclusion, the findings of the present study suggest that the circulating levels of bile acids and carnitine are differentially altered in patients with PBC. PMID- 26046129 TI - Preparation of human tau exon-2- and -10-specific monoclonal antibodies for the recognition of brain tau proteins in various mammals. AB - The aggregations of tau protein in brain tissue have been described in a large number of neurodegenerative diseases; however, due to the lack of tau isoform- or exon-specific antibodies, the exact situations under which various brain tau isoforms can be found and their exact contributions during disease progression remain unknown. Therefore, in this study, we prepared tau exon-specific monoclonal antibodies (mAbs) that recognize different mammalian tau isoforms. Briefly, 3 Balb/c mice were separately immunized (3 mice per antigen) with the recombinant GST-fusion proteins, GST-tE2 and GST-tE10. Two hybridoma cell lines, 4A8 and 3E12, secreting antibodies against human tau exon-2 and -10 were established using the hybridoma technique. The sensitivity and specificity of the prepared mAbs were evaluated using indirect ELISA and western blot analysis. The ability of the prepared mAbs, 4A8 and 3E12, to recognize endogenous tau protein in the brain tissues of various mammals was estimated by immunoprecipitation. Based on the results of various verification methods, we found that the prepared mAbs, 4A8 and 3E12, not only specifically reacted with the individual recombinant GST tau exon fusion proteins, but also correctly recognized the recombinant human tau isoforms containing respective exon sequences, as shown by western blot analysis. Furthermore, western blot analysis and immunoprecipitation assays verified that the mAbs, 4A8 and 3E12, recognized endogenous tau proteins in human brain tissue, as well as tau proteins in a series of mammalian tissues, including goat, bovine, rabbit, hamster and mouse. Thus, in the present study, using the hybridoma technique, we successfully prepared the mAbs, 4A8 against tau exon-2 and 3E12 against tau exon-10, which provide useful tools for determining potential alternations of tau isoforms in neurodegenerative diseases. PMID- 26046130 TI - Association between histone deacetylases and the loss of cochlear hair cells: Role of the former in noise-induced hearing loss. AB - Noise-induced hearing loss (NIHL) is one of the most frequent disabilities in industrialized countries. It has been demonstrated that hair cell loss in the auditory end organ may account for the majority of ear pathological conditions. Previous studies have indicated that histone deacetylases (HDACs) play an important role in neurodegenerative diseases, including hearing impairment, in older persons. Thus, we hypothesized that the inhibition of HDACs would prevent hair cell loss and, consequently, NIHL. In the present study, a CBA/J mouse model of NIHL was established. Following an injection with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), the expression levels of HDAC1, HDAC4 and acetyl-histone H3 (Lys9) (H3-AcK9) were measured. The number of hair cells was quantified and their morphology was observed. The results revealed that 1 h following exposure to 110 dB SPL broadband noise, there was a significant increase in HDAC1 and HDAC4 expression, and a marked decrease in the H3-AcK9 protein levels, as shown by western blot analysis. Pre-treatment with SAHA significantly inhibited these effects. Two weeks following exposure to noise, the mice exhibited significant hearing impairment and an obvious loss in the number of outer hair cells. An abnormal cell morphology with cilia damage was also observed. Pre-treatment with SAHA markedly attenuated these noise-induced effects. Taken together, the findings of our study suggest that HDAC expression is associated with outer hair cell function and plays a significant role in NIHL. Our data indicate that SAHA may be a potential therapeutic agent for the prevention of NIHL. PMID- 26046131 TI - Integrative genomic analyses of the RNA-binding protein, RNPC1, and its potential role in cancer prediction. AB - The RNA binding motif protein 38 (RBM38, also known as RNPC1) plays a pivotal role in regulating a wide range of biological processes, from cell proliferation and cell cycle arrest to cell myogenic differentiation. It was originally recognized as an oncogene, and was frequently found to be amplified in prostate, ovarian and colorectal cancer, chronic lymphocytic leukemia, colon carcinoma, esophageal cancer, dog lymphomas and breast cancer. In the present study, the complete RNPC1 gene was identified in a number of vertebrate genomes, suggesting that RNPC1 exists in all types of vertebrates, including fish, amphibians, birds and mammals. In the different genomes, the gene had a similar 4 exon/3 intron organization, and all the genetic loci were syntenically conserved. The phylogenetic tree demonstrated that the RNPC1 gene from the mammalian, bird, reptile and teleost lineage formed a species-specific cluster. A total of 34 functionally relevant single nucleotide polymorphisms (SNPs), including 14 SNPs causing missense mutations, 8 exonic splicing enhancer SNPs and 12 SNPs causing nonsense mutations, were identified in the human RNPC1 gene. RNPC1 was found to be expressed in bladder, blood, brain, breast, colorectal, eye, head and neck, lung, ovarian, skin and soft tissue cancer. In 14 of the 94 tests, an association between RNPC1 gene expression and cancer prognosis was observed. We found that the association between the expression of RNPC1 and prognosis varied in different types of cancer, and even in the same type of cancer from the different databases used. This suggests that the function of RNPC1 in these tumors may be multidimensional. The sex determining region Y (SRY)-box 5 (Sox5), runt-related transcription factor 3 (RUNX3), CCAAT displacement protein 1 (CUTL1), v-rel avian reticuloendotheliosis viral oncogene homolog (Rel)A, peroxisome proliferator activated receptor gamma isoform 2 (PPARgamma2) and activating transcription factor 6 (ATF6) regulatory transcription factor binding sites were identified in the upstream (promoter) region of the RNPC1 gene, and may thus be involved in the effects of RNPC1 in tumors. PMID- 26046132 TI - Target-specific cytotoxic effects on HER2-expressing cells by the tripartite fusion toxin ZHER2:2891-ABD-PE38X8, including a targeting affibody molecule and a half-life extension domain. AB - Development of cancer treatment regimens including immunotoxins is partly hampered by their immunogenicity. Recently, deimmunized versions of toxins have been described, potentially being better suited for translation to the clinic. In this study, a recombinant tripartite fusion toxin consisting of a deimmunized version of exotoxin A from Pseudomonas aeruginosa (PE38) genetically fused to an affibody molecule specifically interacting with the human epidermal growth factor receptor 2 (HER2), and also an albumin binding domain (ABD) for half-life extension, has been produced and characterized in terms of functionality of the three moieties. Biosensor based assays showed that the fusion toxin was able to interact with human and mouse serum albumin, but not with bovine serum albumin and that it interacted with HER2 (KD=5 nM). Interestingly, a complex of the fusion toxin and human serum albumin also interacted with HER2 but with a somewhat weaker affinity (KD=12 nM). The IC50-values of the fusion toxin ranged from 6 to 300 pM on SKOV-3, SKBR-3 and A549 cells and was lower for cells with higher surface densities of HER2. The fusion toxin was found specific for HER2 as shown by blocking available HER2 receptors with free affibody molecule before subjecting the cells to the toxin. Analysis of contact time showed that 10 min was sufficient to kill 50% of the cells. In conclusion, all three regions of the fusion toxin were found to be functional. PMID- 26046134 TI - Research continuity: Be prepared. PMID- 26046133 TI - Vitamin K2 and cotylenin A synergistically induce monocytic differentiation and growth arrest along with the suppression of c-MYC expression and induction of cyclin G2 expression in human leukemia HL-60 cells. AB - Although all-trans retinoic acid (ATRA) is a standard and effective drug used for differentiation therapy in acute promyelocytic leukemia, ATRA-resistant leukemia cells ultimately emerge during this treatment. Therefore, the development of new drugs or effective combination therapy is urgently needed. We demonstrate that the combined treatment of vitamin K2 and cotylenin A synergistically induced monocytic differentiation in HL-60 cells. This combined treatment also synergistically induced NBT-reducing activity and non-specific esterase-positive cells as well as morphological changes to monocyte/macrophage-like cells. Vitamin K2 and cotylenin A cooperatively inhibited the proliferation of HL-60 cells in short-term and long-term cultures. This treatment also induced growth arrest at the G1 phase. Although 5 ug/ml cotylenin A or 5 uM vitamin K2 alone reduced c-MYC gene expression in HL-60 cells to approximately 45% or 80% that of control cells, respectively, the combined treatment almost completely suppressed c-MYC gene expression. We also demonstrated that the combined treatment of vitamin K2 and cotylenin A synergistically induced the expression of cyclin G2, which had a positive effect on the promotion and maintenance of cell cycle arrest. These results suggest that the combination of vitamin K2 and cotylenin A has therapeutic value in the treatment of acute myeloid leukemia. PMID- 26046135 TI - Outcomes of pregnancy after bariatric surgery. PMID- 26046136 TI - Vitamin D therapy in inflammatory bowel diseases: who, in what form, and how much? AB - BACKGROUND: The north-south geographical gradient of inflammatory bowel disease (IBD) prevalence, its epidemiology, the genetic association of vitamin D receptor polymorphisms, and results in animal models suggest that vitamin D plays an important role in the pathogenesis of IBD. AIMS: The purpose of this review was to critically appraise the effectiveness and safety of vitamin D therapy in patients with IBD. METHODS: MEDLINE, Scopus and Google Scholar were searched from inception to May 20, 2014 using the terms 'Crohn's disease', 'ulcerative colitis' and 'vitamin D'. Results: Vitamin D deficiency is common in patients with IBD. Limited clinical data suggest an association between low vitamin D concentration and increased disease activity in both ulcerative colitis (UC) and Crohn's disease (CD). To date, only two small open label trials and one randomized controlled trial have shown a positive effect of vitamin D supplementation on disease activity in patients with CD; no effect has been shown for UC. An optimal vitamin D supplementation protocol for patients with IBD remains undetermined, but targeting serum 25-hydroxy vitamin D [25(OH)D] levels between 30 and 50 ng/mL appears safe and may have benefits for IBD disease activity. Depending on baseline vitamin D serum concentration, ileal involvement in CD, body mass index, and perhaps smoking status, daily vitamin D doses between 1800-10,000 international units/day are probably necessary. CONCLUSION: Increasing preclinical and clinical evidence suggests a role for vitamin D deficiency in the development and severity of IBD. The possible therapeutic role of vitamin D in patients with IBD merits continued investigation. PMID- 26046139 TI - Clinical pathologic conference case 1: three week history of painless swelling of the right mandible. PMID- 26046137 TI - The nuclear pore complex--structure and function at a glance. AB - Nuclear pore complexes (NPCs) are indispensable for cell function and are at the center of several human diseases. NPCs provide access to the nucleus and regulate the transport of proteins and RNA across the nuclear envelope. They are aqueous channels generated from a complex network of evolutionarily conserved proteins known as nucleporins. In this Cell Science at a Glance article and the accompanying poster, we discuss how transport between the nucleoplasm and the cytoplasm is regulated, what we currently know about the structure of individual nucleoporins and the assembled NPC, and how the cell regulates assembly and disassembly of such a massive structure. Our aim is to provide a general overview on what we currently know about the nuclear pore and point out directions of research this area is heading to. PMID- 26046140 TI - Clinical pathologic conference case 2: gingival ulcer in a 34-year-old man. PMID- 26046141 TI - Clinical pathologic conference case 3: a thick, granular white gingival plaque in an adult male. PMID- 26046138 TI - Connections matter--how viruses use cell-cell adhesion components. AB - The epithelium is a highly organized type of animal tissue. Except for blood and lymph vessels, epithelial cells cover the body, line its cavities in single or stratified layers and support exchange between compartments. In addition, epithelia offer to the body a barrier to pathogen invasion. To transit through or to replicate in epithelia, viruses have to face several obstacles, starting from cilia and glycocalyx where they can be neutralized by secreted immunoglobulins. Tight junctions and adherens junctions also prevent viruses to cross the epithelial barrier. However, viruses have developed multiple strategies to blaze their path through the epithelium by utilizing components of cell-cell adhesion structures as receptors. In this Commentary, we discuss how viruses take advantage of the apical junction complex to spread. Whereas some viruses quickly disrupt epithelium integrity, others carefully preserve it and use cell adhesion proteins and their cytoskeletal connections to rapidly spread laterally. This is exemplified by the hidden transmission of enveloped viruses that use nectins as receptors. Finally, several viruses that replicate preferentially in cancer cells are currently used as experimental cancer therapeutics. Remarkably, these viruses use cell adhesion molecules as receptors, probably because--to reach tumors and metastases--ncolytic viruses must efficiently traverse or break epithelia. PMID- 26046142 TI - Clinical pathologic conference case 4: just an extravasation mucocele? PMID- 26046143 TI - Dendrobium micropropagation: a review. AB - Dendrobium is one of the largest and most important (ornamentally and medicinally) orchid genera. Tissue culture is now an established method for the effective propagation of members of this genus. This review provides a detailed overview of the Dendrobium micropropagation literature. Through a chronological analysis, aspects such as explant, basal medium, plant growth regulators, culture conditions and final organogenic outcome are chronicled in detail. This review will allow Dendrobium specialists to use the information that has been documented to establish, more efficiently, protocols for their own germplasm and to improve in vitro culture conditions based on the optimized parameters detailed in this review. Not only will this expand the use for mass propagation, but will also allow for the conservation of important germplasm. Information on the in vitro responses of Dendrobium for developing efficient protocols for breeding techniques based on tissue culture, such as polyploidization, somatic hybridization, isolation of mutants and somaclonal variants and for synthetic seed and bioreactor technology, or for genetic transformation, is discussed in this review. This is the first such review on this genus and represents half a decade of literature dedicated to Dendrobium micropropagation. PMID- 26046144 TI - Cost-effectiveness of screening for HLA-A*31:01 prior to initiation of carbamazepine in epilepsy. AB - OBJECTIVE: Carbamazepine causes severe cutaneous adverse drug reactions that may be predicted by the presence of the HLA-A*31:01 allele in northern European populations. There is uncertainty as to whether routine testing of patients with epilepsy is cost-effective. We conducted an economic evaluation of HLA-A*31:01 testing from the perspective of the National Health Service (NHS) in the United Kingdom. METHODS: A short-term, decision analytic model was developed to estimate the outcomes and costs associated with a policy of routine testing (with lamotrigine prescribed for patients who test positive) versus the current standard of care, which is carbamazepine prescribed without testing. A Markov model was used to estimate total costs and quality-adjusted life-years (QALYs) over a lifetime to account for differences in drug effectiveness and the long term consequences of adverse drug reactions. RESULTS: Testing reduced the expected rate of cutaneous adverse drug reactions from 780 to 700 per 10,000 patients. The incremental cost-effectiveness ratio for pharmacogenetic testing versus standard care was L12,808 per QALY gained. The probability of testing being cost-effective at a threshold of L20,000 per QALY was 0.80, but the results were sensitive to estimated remission rates for alternative antiepileptic drugs (AEDs). SIGNIFICANCE: Routine testing for HLA-A*31:01 in order to reduce the incidence of cutaneous adverse drug reactions in patients being prescribed carbamazepine for epilepsy is likely to represent a cost-effective use of health care resources. PMID- 26046145 TI - Reflections: neurology and the humanities. Better you than me. PMID- 26046147 TI - The humanistic side of medical education. PMID- 26046146 TI - Editorialist response. PMID- 26046148 TI - Injury severity in relation to seatbelt use. PMID- 26046149 TI - Driving innovation, leadership and change at Groote Schuur Hospital, Cape Town, South Africa. PMID- 26046150 TI - Mental health under-budgeting undermining SA's economy. PMID- 26046151 TI - Turning 'fate' into destiny by seizing a second chance at life. PMID- 26046152 TI - Basson unrepentant as drawn-out sentencing argument begins. PMID- 26046153 TI - SA's ailing public health sector 'responding to treatment'? PMID- 26046154 TI - Litigation benefits state-delivered medicine--but for how long? PMID- 26046155 TI - Listerial brainstem encephalitis--treatable, but easily missed. AB - Listerial brainstem encephalitis (LBE) is an uncommon form of listerial central nervous system infection that progresses rapidly and is invariably fatal unless detected and treated early. We report on six adult patients with LBE, of whom five were managed or co-managed by our unit during the period January - June 2012. All presented with a short prodromal illness followed by a combination of brainstem signs, including multiple cranial nerve palsies with emphasis on the lower cranial nerves, ataxia, motor and sensory long-tract signs, a depressed level of consciousness and apnoea. In two cases the diagnosis was delayed with adverse outcomes. LBE may be difficult to diagnose: clinicians may not be aware of this condition, the brainstem location may not be recognised readily, general markers of inflammation such as the erythrocyte sedimentation rate, C-reactive protein level or white cell count may be normal, and the cerebrospinal fluid is typically normal or there are only mild and nonspecific findings. Serological tests are unreliable, and diagnosis is achieved through blood cultures, magnetic resonance imaging and clinical recognition. PMID- 26046156 TI - The research component of specialist registration--a question of alligators and swamps? A personal view. AB - The recent implementation of the research requirement for specialist registration presents difficulties with regard to the provision of research supervision, particularly in those medical schools that previously followed the path of qualification via the Colleges of Medicine of South Africa examinations. The differences between the requirements for research supervision as stated in the Health Professions Council of South Africa memorandum and those of the Committee for Higher Education are causing disparities between medical schools similar to those that led to the memorandum in the first place. While the research component of specialist training can only improve the quality of both patient care and academic endeavour, it requires an enormous investment of time on the part of both the specialist trainees and their supervisors. In order to deal with this, specific issues outlined in the article need to be addressed. PMID- 26046157 TI - No evidence for clinical utility in investigating the connexin genes GJB2, GJB6 and GJA1 in non-syndromic hearing loss in black Africans. AB - BACKGROUND: Deafness is the most common sensory disability in the world. Globally, mutations in GJB2 (connexin 26) have been shown to play a major role in non-syndromic deafness. Two other connexin genes, GJB6 (connexin 30) and GJA1 (connexin 43), have been implicated in hearing loss, but these genes have seldom been investigated in black Africans. We aimed to validate the utility of testing for GJB2, GJB6 and GJA1 in an African context. METHODS: Two hundred and five patients with non-syndromic deafness from Cameroon and South Africa had the full coding regions of GJB2 sequenced. Subsequently, a carefully selected subset of 100 patients was further sequenced for GJB6 and GJA1 using Sanger cycle sequencing. In addition, the large-scale GJB6-D3S1830 deletion was investigated. RESULTS: No pathogenic mutations that could explain the hearing loss were detected in GJB2, GJB6 or GJA1, and the GJB6-D3S1830 deletion was not detected. There were no statistically significant differences in genomic variations in these genes between patients and controls. A comprehensive literature review supported these findings. CONCLUSION: Mutations in GJB2, GJB6 and GJA1 are not a major cause of non-syndromic deafness in black Africans and should not be investigated routinely in clinical practice. PMID- 26046158 TI - Medical certification of death in South Africa--moving forward. AB - Despite improvements to the Death Notification Form (DNF) used in South Africa (SA), the quality of cause-of-death information remains suboptimal. To address these inadequacies, the government ran a train-the-trainer programme on completion of the DNF, targeting doctors in public sector hospitals. Training materials were developed and workshops were held in all provinces. This article reflects on the lessons learnt from the training and highlights issues that need to be addressed to improve medical certification and cause-of-death data in SA. The DNF should be completed truthfully and accurately, and confidentiality of the information on the form should be maintained. The underlying cause of death should be entered on the lowest completed line in the cause-of-death section, and if appropriate, HIV should be entered here. Exclusion clauses for HIV in life insurance policies with Association of Savings and Investments South Africa companies were scrapped in 2005. Interactive workshops provide a good learning environment, but are logistically challenging. More use should be made of online training resources, particularly with continuing professional development accreditation and helpline support. In addition, training in the completion of the DNF should become part of the curriculum in all medical schools, and part of the orientation of interns and community service doctors in all facilities. PMID- 26046159 TI - Turning up the volume on hearing loss in South Africa. PMID- 26046160 TI - Cervical cancer prevention in South Africa: HPV vaccination and screening both essential to achieve and maintain a reduction in incidence. PMID- 26046161 TI - Hearing loss in the developing world: evaluating the iPhone mobile device as a screening tool. AB - BACKGROUND: Developing countries have the world's highest prevalence of hearing loss, and hearing screening programmes are scarce. Mobile devices such as smartphones have potential for audiometric testing. OBJECTIVES: To evaluate the uHear app using an Apple iPhone as a possible hearing screening tool in the developing world, and to determine accuracy of certain hearing thresholds that could prove useful in early detection of hearing loss for high-risk populations in resource-poor communities. METHODS: This was a quasi-experimental study design. Participants recruited from the Otolaryngology Clinic, Groote Schuur Hospital, Cape Town, South Africa, completed a uHear test in three settings- waiting room (WR), quiet roon (QR) and soundproof room (SR). Thresholds were compared with formal audiograms. RESULTS: Twenty-five patients were tested (50 ears). The uHear test detected moderate or worse hearing loss (pure-tone average (PTA) > 40 dB accurately with a sensitivity of 100% in all three environments. Specificity was 88% (SR), 73% (QR) and 68% (WR). Its was highly accurate in detecting high-frequency hearing loss (2 000, 4 000, 6 000 Hz) in the QR and SR with 'good' and 'very good' kappa values, showing statistical significance (p < 0.05). It was moderately accurate in low-frequency hearing loss (250, 500, 1 000 Hz) in the SR, and poor in the QR and WR. CONCLUSION: Using the iPhone, uHear is a feasible screening test to rule out significant hearing loss (PTA > 40 dB). It is highly sensitive for detecting threshold changes at high frequencies, making it reasonably well suited to detect presbycusis and ototoxic hearing loss from HIV, tuberculosis therapy and chemotherapy. Portability and ease of use make it appropriate to use in developing world communities that lack screening programmes. PMID- 26046162 TI - The vaccine and cervical cancer screen (VACCS) project: acceptance of human papillomavirus vaccination in a school-based programme in two provinces of South Africa. AB - BACKGROUND: The incidence of cervical cancer in South Africa (SA) remains high, and the current screening programme has had limited success. New approaches to prevention and screening tactics are needed. OBJECTIVES: To investigate acceptance of school-based human papillomavirus (HPV) vaccination, as well as the information provided, methods of obtaining consent and assent, and completion rates achieved. METHODS: Information on cervical cancer and HPV vaccination was provided to 19 primary schools in Western Cape and Gauteng provinces participating in the study. Girls with parental consent and child assent were vaccinated during school hours at their schools. RESULTS: A total of 3 465 girls were invited to receive HPV vaccine, of whom 2 046 provided written parental consent as well as child assent. At least one dose of vaccine was delivered to 2 030 girls (99.2% of the consented cohort), while a total of 1 782 girls received all three doses. Sufficient vaccination was achieved in 91.6% of the vaccinated cohort. Of all invited girls, 56.9% in Gauteng and 50.7% in the Western Cape were sufficiently vaccinated. CONCLUSION: This implementation project demonstrated that HPV vaccination is practical and safe in SA schools. Political and community acceptance was good, and positive attitudes towards vaccination were encountered. During the study, which mimicked a governmental vaccine roll-out programme, high completion rates were achieved in spite of several challenges encountered. PMID- 26046163 TI - Severe blunt thoracic trauma: differences between adults and children in a level I trauma centre. AB - BACKGROUND: Trauma is a leading cause of death in the developing world. Blunt thoracic trauma represents a major burden of disease in both adults and children. Few studies have investigated the differences between these two patient groups. OBJECTIVE: To compare mechanism of injury, presentation, management and outcome in children and adults with blunt thoracic trauma. METHODS: Patients were identified from the database of the trauma intensive care unit at Inkosi Albert Luthuli Central Hospital, Durban, South Africa. Demographics and relevant data were extracted from a pre-existing database. RESULTS: Of 415 patients admitted to the unit, 331 (79.7%) were adults and 84 (20.2%) children aged < 18 years. The median injury severity score (ISS) was similar for both age groups (32 v. 34; p = 0.812). Adults had a higher lactate level at presentation (3.94 v. 2.60 mmol/L; p = 0.001). Of the children, 96.4% were injured in motor vehicle collisions, 75.0% as pedestrians. Compared with adults, children had significantly fewer rib fractures (20.2% v. 42.0%; p < 0.001), flail chests (2.4% v. 26.3%; p<0.001) and.blunt cardiac injuries (BCIs) (9.5% v. 23.6%; p = 0.004), but sustained more lung contusions (79.8% v. 65.6%; p = 0.013). Mortality in children was significantly lower than in adults (16.7% v. 27.8%; p = 0.037). CONCLUSION: Thoracic injuries in children are the result of pedestrian collisions more often than in adults. They suffer fewer rib fractures and BCIs, but more lung contusions. Despite similar ISSs, children have significantly lower mortality than adults. More effort needs to be concentrated on child safety and preventing pedestrian injury. PMID- 26046165 TI - Hear that alarm ringing? PMID- 26046164 TI - South African food allergy consensus document 2014. AB - The prevalence of food allergy is increasing worldwide and is an important cause of anaphylaxis. There are no local South African food allergy guidelines. This document was devised by the Allergy Society of South Africa (ALLSA), the South African Gastroenterology Society (SAGES) and the Association for Dietetics in South Africa (ADSA). Subjects may have reactions to more than one food, and different types and severity of reactions to different foods may coexist in one individual. A detailed history directed at identifying the type and severity of possible reactions is essential for every food allergen under consideration. Skin prick tests and specific immunoglobulin E (IgE) (ImmunoCAP) tests prove IgE sensitisation rather than clinical reactivity. The magnitude of sensitisation combined with the history may be sufficient to ascribe causality, but where this is not possible an incremental oral food challenge may be required to assess tolerance or clinical allergy. For milder non-IgE-mediated conditions a diagnostic elimination diet may be followed with food re-introduction at home to assess causality. The primary therapy for food allergy is strict avoidance of the offending food/s, taking into account nutritional status and provision of alternative sources of nutrients. Acute management of severe reactions requires prompt intramuscular administration of adrenaline 0.01 mg/kg and basic resuscitation. Adjunctive therapy includes antihistamines, bronchodilators and corticosteroids. Subjects with food allergy require risk assessment and those at increased risk for future severe reactions require the implementation of risk reduction strategies, including education of the patient, families and all caregivers (including teachers), the provision of a written emergency action plan, a MedicAlert necklace or bracelet and injectable adrenaline (preferably via auto-injector) where necessary. PMID- 26046166 TI - Designed to help, can cause harm. PMID- 26046167 TI - Feeling put upon by RACs? There is a reason. PMID- 26046168 TI - Near misses, harm from devices regular occurrence, say nurses. PMID- 26046169 TI - Beware the weekend. PMID- 26046170 TI - Getting ready for baby. PMID- 26046171 TI - Consensus on allergen specific immunotherapy. PMID- 26046172 TI - The larvae of Drusus franzressli Malicky 1974 and Drusus spelaeus (Ulmer 1920) (Trichoptera: Limnephilidae: Drusinae) with notes on ecology and zoogeography. AB - Water quality monitoring is greatly dependent on identification tools for aquatic and semi-aquatic insects. Species-level identification improves resolution and precision of water quality assessment and requires comprehensive keys. With the aim of increasing the suitability of Drusinae for such applications, this paper gives a description of the hitherto unknown larvae of Drusus franzressli Malicky 1974 and Drusus spelaeus (Ulmer 1920). Information on the morphology of the larvae is given and the most important diagnostic features are illustrated. In the context of already available keys, the larvae of D. franzressli and D. spelaeus key together with Metanoea flavipennis (Pictet 1834), M. rhaetica Schmid 1956, D. improvisus McLachlan 1884, D. nigrescens Meyer-Dur 1875 and Ecclisopteryx malickyi Moretti 1991. These species are easily separated by differences in larval morphology (dorsal outline and sculpturing of pronotum, presence/absence of lateral gills at 2nd and 3rd abdominal segments, start of lateral fringe) and their distribution ranges. Drusus franzressli is endemic to the Hellenic western Balkans whereas D. spelaeus is endemic to the western Alps (Grenoble area). In addition, ecological characteristics are briefly discussed. PMID- 26046173 TI - New taxa and notes of some described species of scaly crickets (Orthoptera: Mogoplistidae: Mogoplistinae) from Singapore. AB - Two new species of Mogoplistinae from Singapore are described: Micrornebius kopisua sp. n. and Ornebius insculpta sp. n. The first record and description of males of Ornebius albipalpus Ingrisch, 2006 and females of Ornebius tampines Tan & Robillard, 2012 are given. The occurrence of Ornebius rufonigrus Ingrisch, 1987 in Singapore is confirmed while confirming the identity of another Ornebius species from Singapore with Ornebius cf. pullus Ingrisch, 2006 requires further investigation. A key to the species of Mogoplistinae from Singapore is provided. PMID- 26046174 TI - Hydraena lotti sp. nov., a new member of the "Haenydra" lineage from the Peloponnese (Greece), with additional records of Hydraena species in the region (Coleoptera, Hydraenidae). AB - Hydraena lotti sp. nov. (Coleoptera, Hydraenidae) is described from the southern Peloponnese, Greece; the 92nd known member of the "Haenydra" lineage. The new species belongs to the H. emarginata complex, being closest morphologically to Hydraena pelops Jach, 1995, from the south and east of the Taygetos range, H. pangaei Jach, 1992, endemic to Mount Pangaeon in northeastern Greece, and H. samnitica Fiori, 1904, from central Italy. Characters on which the species can be distinguished are discussed; male genitalia and female elytral apices being particularly diagnostic. The ecology of H. lotti is described in the context of other members of the genus in the region. To date, the new species has only been found in small headwater streams at altitudes above 1,000 m in the northwest of the Taygetos range, where it can, however, be locally frequent. The opportunity is taken to provide an updated checklist of Peloponnese "Haenydra", together with new distributional records of selected Hydraena species, including H. arachthi Ferro & Jach, 2000, which is reported from the peninsula for the first time. PMID- 26046175 TI - A new species of Balera Young and redescription of Habralebra gillettei Young (Hemiptera, Cicadellidae, Typhlocybinae) from Vicosa, Minas Gerais State, Brazil. AB - Balera fiuzai sp. nov. is described based on male specimens obtained from light trap collections at Mata do Paraiso, Municipality of Vicosa, Minas Gerais State, Brazil. An identification key to the species of Balera is given. Additionally, Habralebra gillettei Young is redescribed from the same locality. These specimens of H. gillettei differ somewhat from previously described specimens, but are considered intra-specific variations. Both genera, Balera Young and Habralebra Young, are recorded from Minas Gerais State for the first time. PMID- 26046176 TI - Redescription of Tyrus Aube and T. sinensis Raffray (Coleoptera: Staphylinidae: Pselaphinae), and two new species from Sichuan, Southwest China. AB - The genus Tyrus Aube is redescribed with major diagnostic features illustrated. The first male specimen of T. sinensis Raffray (Type locality: Yunnan, China) is reported from Xizang, China, and two new species, Tyrus sichuanicus Yin & Nomura, sp. n. and Tyrus yajiangensis Yin & Li, sp. n., are described from Sichuan, China. All treated species are (re-)described, illustrated and distinguished. PMID- 26046177 TI - Review of Chinese species of genus Scaphomonus Viraktamath, 2009 (Hemiptera: Cicadellidae: Deltocephalinae), with description of a new species. AB - The Chinese leafhopper species of the genus Scaphomonus Viraktamath are reviewed, and one new species Scaphomonus furcatus sp. nov. is described and illustrated. A key is given to distinguish Chinese species of the genus. The type specimens of the new species are deposited in the Institute of Entomology, Guizhou University, Guiyang, China (GUGC). PMID- 26046178 TI - A new species of Pachytrechodes Jeannel, 1960 (Coleoptera: Carabidae: Trechinae) from Tanzania, with a key to species. AB - Pachytrechodes brevis Belousov & Nyundo, new species, is described from the Udzungwa Mountains, Tanzania. This species is the first member of the genus found outside of the Uluguru Mountains. A key to the four currently known species of Pachytrechodes is included, based on Ueno's (1987) key. The distribution of all species is mapped. PMID- 26046179 TI - Two new species of the Empis subgenus Lissempis (Diptera: Empididae) from the Caucasus. AB - Two new species of the genus Empis subgenus Lissempis Bezzi, 1909 are described from the Caucasus: Empis (Lissempis) azishtauensis sp. nov. (Russia: Adygea, Krasnodar Territory) and E. (L.) krasnodarensis sp. nov. (Russia: Krasnodar Territory). An updated key to European species of the subgenus is given. PMID- 26046180 TI - The discovery of genus Fredegunda Fitton, Shaw & Gauld in China, with description of a new species (Hymenoptera, Ichneumonidae, Pimplinae). AB - The genus Fredegunda Fitton, Shaw & Gauld (Ichneumonidae, Pimplinae) is newly reported both from China and the Oriental region. A new species, Fredegunda sinica sp. nov. from Fujian, China is described and illustrated. A key to the known species of Fredegunda is provided. PMID- 26046181 TI - The discovery of the genus Guaygata Marsh (Hymenoptera, Braconidae, Doryctinae) from China, with description of a new species. AB - The genus Guaygata Marsh, 1993 is recorded from China for the first time. Two species, i.e. G. mariae (Belokobylskij, 1993) and G. fujianensis sp. nov., are recognized. The new species is fully described and illustrated. A key to Asian species of Guaygata is provided. PMID- 26046182 TI - Two new species of Empoascanara Distant (Hemiptera: Cicadellidae: Typhlocybinae) from Yunnan Province, China. AB - Two new species, Empoascanara conchata, E. longiaedeaga spp. nov. from Yunnan are described and illustrated, and a key to the species recorded from China is provided. PMID- 26046183 TI - Significant range extensions for two caddid harvestmen in eastern North America, Caddo pepperella and Acropsopilio boopis (Opiliones: Eupnoi: Caddidae). PMID- 26046184 TI - A new species of Leotichius Distant (Hemiptera: Heteroptera: Leptopodidae) from Cambodia. AB - One new species, Leotichius schuhi Jung sp. nov., that shared habitat with the larvae of xeric adapted ant-lions (Neuroptera), is described from northern Cambodia. Diagnosis, description and biological notes of the new species are presented. PMID- 26046185 TI - New species of hippolytid shrimps (Crustacea: Decapoda: Caridea: Hippolytidae) from a southwest Indian Ocean seamount. AB - Two specimens representing two hippolytid genera were sampled recently from the Coral Seamount, southwest Indian Ocean, at 732 m water depth. Lebbeus ketophilos sp. nov. and Eualus oreios sp. nov. are described and illustrated and their morphologies are compared with those of previously described species. The new species are closest in morphology to L. indicus Holthuis, 1947 and E. kinzeri Tiefenbacher, 1990 respectively. They are distinguished clearly from these and other species by a suite of morphological features. This record enhances our present knowledge of seamount biodiversity and species richness of decapod crustaceans in the Indian Ocean. PMID- 26046186 TI - Phytocoetes sinensis n. sp. and Telmatactis clavata (Stimpson, 1855), two poorly known species of Metridioidea (Cnidaria: Anthozoa: Actiniaria) from Chinese waters. AB - Two acontiate sea anemones, Phytocoetes sinensis n. sp. within the family Halcampactinidae and Telmatactis clavata (Stimpson, 1855) within the family Andvakiidae, are described from the coastal region of Chinese waters. Phytocoetes sinensis is an elongated sea anemone discovered from the intertidal mudflat in the East China Sea. The new species is very similar to its only congener P. gangeticus, but differs distinctly by the larger body size (length usually 61-130 mm vs. no more than 30 mm) and a higher number of mesenteries (48 pairs vs. 12 or probably 24 pairs) and tentacles (usually 72-118 vs. 50-65). This is the first record of Halcampactinidae in China. Telmatactis clavata has been reported only from the warm waters of Japan. We redescribed the species in more details based on specimens collected from the South China Sea. So far the species is known only from warm waters in the western Pacific. PMID- 26046187 TI - The morphology and SSU rRNA gene sequence analysis of a poorly-known brackish water ciliate, Pinacocoleps tesselatus (Kahl, 1930) (Ciliophora, Colepidae) from Hangzhou Bay, China. AB - The morphology and infraciliature of a poorly-known colepid ciliate, Pinacocoleps tesselatus (Kahl, 1930) Foissner et al., 2008, collected from brackish-water biotope (salinity 12 per thousand) in Hangzhou Bay, China, were investigated using live observations and silver impregnations. This species is characterized by its length of 60-85 MUm in vivo, ovular shape, two anterior and three posterior spines, 21-25 longitudinal and 11 transverse ciliary rows on average, a macro and micro nucleus, and one terminal contractile vacuole. The key to all known seven Pinacocoleps species is updated. Additionally, we characterized the taxon P. tesselatus via small subunit rRNA gene data. Our phylogenetic analyses performed using both maximum-likelihood and Bayesian methods indicate that P. tesselatus falls into the core assemblage of the family Colepidae. PMID- 26046188 TI - Three new species of the genus Suctobelbella (Acari: Oribatida: Suctobelbidae) from Sanjiang Plain, Northeast China. AB - Three new species of the genus Suctobelbella from Sanjiang Plain in Northeast China are described: S. triangulata sp. nov., S. obtusa sp. nov., S. sanjiangensis sp. nov., and a key to all known species of China is provided. PMID- 26046189 TI - New species of the neotropical spider genus Celaetycheus Simon, 1897 (Araneae: Ctenidae). AB - Nine species of the Neotropical spider genus Celaetycheus Simon, 1897 are newly described. All the species are endemic to the State of Bahia, northeast of Brazil: Celaetycheus abara sp. nov., C. aberen sp. nov., C. acaraje sp. nov., C. beiju sp. nov., C. bobo sp. nov., C. caruru sp. nov., C. moqueca sp. nov., C. mungunza sp. nov. and C. vatapa sp. nov. A new generic diagnosis, species diagnoses and distributional maps are provided. PMID- 26046190 TI - A new species of cat snake (Reptilia: Serpentes: Colubridae: Boiga) from dry forests of eastern Peninsular India. AB - A new species of cat snake, related to Boiga beddomei (Wall, 1909), is described from the dry forests of eastern Peninsular India. It occupies a large geographic range from Berhampore (type locality), near the River Mahanadi in the northeast to Kaigal near the southern Eastern Ghats in the southwest. The new species is diagnosed by having the following combination of characters: 19 dorsal scale rows at midbody, a high number of ventral scales for the genus Boiga (248-259), a yellowish-green dorsal colouration with numerous faint black bands, an uniform, unpatterned yellow-coloured venter and a relatively short tail (0.180-0.200 of the total length). PMID- 26046191 TI - Eviota nigramembrana, a new dwarfgoby from the Western Pacific (Teleostei: Gobiidae). AB - Eviota nigramembrana is described from the Ryukyu Islands, Japan and also recorded from the Philippine Islands. It belongs to the cephalic sensory-pore system pattern group I (complete), has a dorsal/anal fin-ray formula of 8/8, 5th pelvic-fin ray absent, some lower pectoral-fin rays branched, five dark internal bands between anal-fin origin and caudal fin, no distinct marking on pectoral-fin base, dark internal rectangular mark above midline of ural centrum, a light spinous dorsal fin, and black pigment on the opercular membrane. PMID- 26046192 TI - The leucosiid crabs described by Thomas Bell in 1855: original description and dates of publication (Crustacea: Decapoda: Brachyura). AB - Thomas Bell proposed 37 species- and 5 genus-group names for the Leucosiidae in four publications that appeared in 1855. The version appearing in the Proceedings of the Linnean Society of London is the earliest of these publications and the first available description of these taxa. PMID- 26046193 TI - A new species of Agrilozodes Thery, 1927, new record for A. pygmaeus (Kerremans, 1897) and a key for the genus (Coleoptera, Buprestidae). AB - Agrilozodes bellamyi sp. nov. from the Caatinga Biome (type locality: Juazeirinho, Paraiba, Brazil) is described and illustrated. It differs from the other five known species mainly by the moderate longitudinal elevation between the eyes, posterolateral angles of pronotum acute and oblique, mesoepisternum excavated, elytral color pattern and elevation of interestriae 2 and 4. The distribution of A. pygmaeus is extended to Rio de Janeiro, Brazil. Photographs of six species as well as a key to the six species of the genus are provided. PMID- 26046194 TI - Rediscovery of Sinopla humeralis Signoret, 1864 (Hemiptera: Heteroptera: Acanthosomatidae). AB - Sinopla humeralis Signoret, 1864 is revalidated and removed from the synonymy of Sniploa obsoletus Signoret, 1864. The first formal records from it original description and first data about its biology are provided. The type species of the genus Sinopla is discussed and the concept of the genus is expanded. The association of Sinopla humeralis with the southern beech Nothofagus Blume and it distribution from Maule Region to Magallanes Region in Chile, are inncluded. PMID- 26046195 TI - Two new species of Papeocoris (Hemiptera: Heteroptera: Coreidae: Coreinae: Nematopodini) from Peru. AB - Two new species of Papeocoris are described from Peru, P. nitens sp. nov. and P. vittatus sp. nov. A key to species is provided together with dorsal view photographs. PMID- 26046196 TI - A taxonomic revision of the genus Platycranus Fieber, 1870 (Hemiptera: Heteroptera: Miridae: Orthotylinae). AB - The Mediterranean orthotyline genus Platycranus is revised. Updated diagnoses and descriptions, data on distribution and hosts are provided for the genus and included species, and a key is presented to facilitate identification of species. Pictures of the dorsal habitus, scanning electron micrographs, and figures of genital structures are given. The following new synonymies are established: P. putoni Reuter, 1879 = P. eckerleini Wagner, 1962 = P. jordanicus Linnavuori, 1984; P. metriorrhynchus Reuter 1883 = P. longicornis Wagner, 1955 = P. rumelicus Simov, 2006; P. remanei Wagner, 1955 = P. minutus Wagner, 1955 = P. orientalis Linnavuori, 1965 = P. jurineae Putshkov, 1985 = P. boreae Gogala, 2002. P. erberi Fieber, 1870 is for the first time reported from Syria, and P. remanei is reported as new to Portugal. PMID- 26046197 TI - Adoribatella, Ferolocella, Joelia and Ophidiotrichus (Acari, Oribatida, Oribatellidae) of North America. AB - In North America, species diversity in the oribatid family Oribatellidae is primarily in the genus Oribatella Banks, but the genera Adoribatella Woolley, Ferolocella Grabowski, Joelia Oudemans and Ophidiotrichus Grandjean are also represented. I provide detailed diagnoses for these genera and the previously described species, Adoribatella punctata Woolley, known from Colorado and Oregon, USA, and Alberta, Canada, Ferolocella tessalata Berlese known from Missouri, Virginia, West Virginia, Georgia, Wisconsin, Ohio, Alabama, Arkansas and Texas, USA, and Ophidiotrichus exastus Woolley, known from North Carolina, Alabama, Missouri, Tennessee and Georgia, USA. I describe Joelia appalachia sp. nov., based on adult specimens, from West Virginia. A key is given to distinguish adults of these genera from those of Oribatella. Character states shared by adults of Oribatellidae are discussed, the synonymy of Gendzella Kuliev with Ferolocella is rejected, and arguments are presented for movement of Adoribatella from Oribatellidae to the Ceratozetoidea. PMID- 26046198 TI - A revision of the Lutrochidae (Coleoptera) of Venezuela, with description of six new species. AB - The species of Lutrochidae occurring in Venezuela are revised. The only previously recorded species, Lutrochus acuminatus Grouvelle, is redescribed and a lectotype is designated. Lutrochus vestitus Sharp, is recorded from Venezuela and French Guiana for the first time. Six new species Lutrochus gustafsoni n. sp., L. cauraensis n. sp., L. maldonadoi n. sp., L. meridaensis n. sp., L. minutus n. sp., and L. violaceus n. sp. are described. Notes on habitat and habits for most species are provided, as well as a key to the eight species of Lutrochidae occurring in Venezuela. The family is reported from hygropetric habitats for the first time. PMID- 26046199 TI - Two new species of Squalius, S. adanaensis and S. seyhanensis (Teleostei: Cyprinidae), from the Seyhan River in Turkey. AB - Two new species of Squalius are described from the Seyhan River drainage in Turkey: S. adanaensis from the lower part of the drainage and S. seyhanensis from the upper part. Squalius adanaensis is distinguished from the other species of the genus in Anatolia, among other characters, by having the flank scales with a dark spot on each scale pocket but covered by the posterior margin of the previous scale, and very few melanophores along the posterior margin; 38-42 + 1-2 lateral line scales; and a maximum known size of 157 mm SL. Squalius seyhanensis is distinguished from other species of the genus in Anatolia, among other characters, by having the flank scales with a dark spot on each scale pocket, exposed, and densely-set melanophores along the posterior margin, forming a conspicuous reticulate pattern; 42-44 + 1-2 lateral line scales; and a maximum know size of 240 mm SL. PMID- 26046200 TI - The genera Nothacrobeles Allen & Noffsinger, 1971 and Zeldia Thorne, 1937 (Nematoda: Rhabditida: Cephalobidae) from southern Iran, with description of N. abolafiai sp. n. AB - A new species of the genus Nothacrobeles Allen & Noffsinger, 1971 is described from a natural area in Kerman Province, Iran. Nothacrobeles abolafiai sp. n. is characterized by its body length (518-655 MUm in females), "single" cuticle, lateral field with three incisures, labial probolae 8.5-9.4 MUm long, bifurcated and without tines, bearing a minor curvature at the tip, pharyngeal corpus 3.3 4.1 times isthmus length, R(ex) = 25-32, spermatheca 22-30 MUm long or 0.8-1.2 times the corresponding body diameter, postuterine sac 15-18 MUm long or 0.5-0.7 times the corresponding body diameter, female tail conical with rounded terminus (31-43 MUm, c = 11.9-18.1, c' = 1.7-2.4), and phasmid at 38-43% of tail length. In addition, two species of the genus Zeldia Thorne, 1937: Z. punctata (Thorne, 1925) Thorne, 1937 and Z. spannata Waceke, Bumbarger, Mundo-Ocampo, Subbotin & Baldwin, 2005, were recovered. The latter is recorded for the first time from Iran. Description, measurements, illustrations and LM pictures are provided for these three species. Furthermore, comparative morphometrics for the species of Nothacrobeles are given. Molecular analysis based on 28S rDNA (D2-D3 expansion) places this new species of Nothacrobeles in a different clade to other Nothacrobeles species. The results suggest that the genus Nothacrobeles may be a paraphyletic taxon. PMID- 26046201 TI - Larvae of Australian Buprestidae (Coleoptera). Part 4. Genus Julodimorpha. AB - The mature larva of the Australian buprestid genus Julodimorpha Gemminger and Harold, 1869 (J. saundersii Thomson, 1878) is fully described, illustrated and compared with the larvae of Julodinae, Polycestinae, Chrysochroinae, and Buprestinae. In situ observations confirm the soil inhabiting life-strategy of Julodimorpha larva. The comparative morphological study of the Julodimorpha larva proves its buprestine-chrysochroine affinities, while the superficial similarity of Julodimorpha and Julodinae adults, with their identical life-strategies, due to convergence. PMID- 26046202 TI - A new fossil jewel beetle (Coleoptera: Buprestidae) from the early Cretaceous of Inner Mongolia, China. AB - A new fossil buprestid, Trapezitergum grande Yu, Slipinski et Shih, gen. et sp. nov., from the Early Cretaceous Yixian Formation of Liutiaogou Village, Tianyi County, Inner Mongolia, China, is described and placed in the subfamily Buprestinae. PMID- 26046203 TI - The genus Leucophenga (Diptera, Drosophilidae), Part I: The abbreviata species group from the Oriental region with morphological and molecular evidence. AB - A new species group, the abbreviata group is established within the genus Leucophenga based on one known and three new species, all of which are endemic to the Oriental region: L. abbreviata (de Meijere, 1911), L. brevivena sp. nov., L. sujuanae sp. nov. and L. zhenfangae sp. nov. A key to four species of the abbreviata group and the DNA barcoding are provided. Twenty-three mtDNA COI sequences belonging to the above species are analyzed; the molecular data are used as interactive evidence to evaluate the species boundaries defined by the morphological data. PMID- 26046204 TI - Description of a new species of Anthaxia Eschscholtz, 1829 from Jordan, with notes on the Anthaxia winkleri species-group (Coleoptera, Buprestidae). AB - A new species of Anthaxia Eschscholtz, 1829 endemic to Jordan, Anthaxia (Haplanthaxia) nabataea sp. nov., is described and illustrated. The new taxon is compared to its most similar species, and data about its distribution, bionomy and taxonomic position are given, together with some notes on the Anthaxia (Haplanthaxia) winkleri species-group. PMID- 26046205 TI - Description of the mature larva of Ampulicomorpha schajovskoyi De Santis & Vidal Sarmiento (Hymenoptera: Embolemidae). AB - The mature larva of Ampulicomorpha schajovskoyi De Santis & Vidal Sarmiento, 1977, is described and figured for the first time. Larval characters of Dryinidae and Embolemidae are discussed in regard to possible synapomorphies of each family and of both families together (Dryinidae + Embolemidae) as monophyletic groups. Some larval characters are compared with the corresponding conditions in other Chrysidoidea families. PMID- 26046206 TI - The description of Alloxysta chinensis, a new Charipinae species from China (Hymenoptera, Figitidae). AB - A new figitid species, Alloxysta chinensis Fulop & Miko sp nova, based on females, is described from China and South Korea. The functional morphology and the phylogenetic implication of some anatomical structures frequently used in Charipinae and the validity of the genus Carvercharips is discussed. This manuscript is the first of its kind linking descriptive terminology to Hymenoptera Anatomy Ontology classes, which provides persistent links to definitions for terms used within this manuscript. PMID- 26046207 TI - Nannoperca pygmaea, a new species of pygmy perch (Teleostei: Percichthyidae) from Western Australia. AB - A new species of pygmy perch (Percichthyidae) from south-western Australia is described on the basis of 15 specimens collected from the Hay River system. Nannoperca pygmaea sp. nov. differs from the sympatric congener N. vittata (Castelnau) by the absence of dark pigment on the ventral surface anterior to the anus, the possession of thin latero-ventral stripes, generally fewer dorsal rays and fewer anal rays, hind margin of scales on caudal peduncle without distinct pigment, and a more pronounced spot (ocellus) that is surrounded by a halo at the termination of the caudal peduncle. The new species is distinguished from congeners Nannoperca australis Gunther, N. oxleyana Whitley and N. variegata Kuiter and Allen in possessing an exposed and serrated preorbital bone and jaws that may just reach to below the anterior margin of the eye, versus a smooth and hidden preorbital and the jaws reaching to at least below the pupil; and from the remaining congener, N. obscura (Klunzinger) in possessing a distinct haloed ocellus at base of caudal fin versus an indistinct barring, as well as a dark spot behind operculum, and the lack of dusky scale margins. It differs from the other sympatric pygmy perch found in the region, N. balstoni Regan, by the presence of an exposed rear edge of the preorbital (vs. hidden under skin), fewer transverse scale rows (13 vs. 15-16), small mouth (rarely reaching eye vs. reaching well beyond eye), ctenoid (vs. cycloid) body scales, generally fewer pectoral rays and smaller maximum size. Allozyme analyses unequivocally demonstrate that sympatric populations of N. pygmaea sp. nov. and N. vittata belong in different genetic lineages, display no genetic intermediates, and are diagnosable by fixed allozyme differences at 15 different loci. Due to its extremely restricted range, where it is known from only 0.06 km2, N. pygmaea sp. nov. requires urgent legislative protection. PMID- 26046208 TI - Re-examination of the eastern Pacific and Atlantic material of Alpheus malleator Dana, 1852, with the description of Alpheus wonkimi sp. nov. (Crustacea, Decapoda, Alpheidae). AB - The bumpy-clawed snapping shrimp, Alpheus malleator Dana, 1852 (Alpheidae), is revised based on the recently collected and older museum material from the eastern Pacific (Panama, Ecuador), Caribbean (Panama, Puerto Rico, Trinidad & Tobago), Brazil (Sao Paulo), and West Africa (Cape Verde, Senegal, Guinea, Equatorial Guinea, Congo). The eastern Pacific material is assigned to A. wonkimi sp. nov., based on one morphological difference in the colour and thickness of the uropodal spiniform seta, as well as previously published molecular data. The Caribbean, Brazilian and West African material is considered to represent a single, widespread, morphologically variable, amphi-Atlantic taxon, A. malleator. Alpheus pugilator A. Milne-Edwards, 1878 is retained as ajunior synonym of A. malleator, whereas A. tuberculosus Osorio, 1892, A. malleator var. edentatus Zimmer, 1913 and A. belli Coutiere, 1898, the latter two based on juvenile specimens, are tentatively placed in the synonymy of A. malleator. Illustrations, including colour photographs, are provided for A. wonkimi sp. nov. and A. malleator and their morphological variability is discussed and illustrated. PMID- 26046209 TI - New Zealand species of the genus Tripyla Bastian, 1865 (Nematoda: Triplonchida: Tripylidae). II: Two new, a known species and key to species. AB - This paper describes three species of the genus Tripyla from New Zealand and provides a key to species based on the morphology of females. Tripyla daviesae sp. nov. is characterized by its short body length (L = 1143-1363 MUm), relatively anterior vulva (V = 50-51%), and the length of the gubernaculum (13-17 MUm). Tripyla tirau sp. nov. is characterized by its relatively posterior vulva (V = 55.5-59.5%), relatively short body length (930-1214 MUm) and relatively short tail (c = 7.9-9.8). Tripyla affinis de Man, 1880 was recorded from New Zealand but without a detailed description which is provided here. In addition, the phylogenetic relationships among the species were analyzed using data from the near full length small subunit (SSU) of the ribosomal rRNA genes, and confirmed that T daviesae sp. nov. and T tirau sp. nov. are distinct from all other species for which sequences are available. PMID- 26046210 TI - Descriptions of two new Brazilian Subrasaca species and redescriptions of S. flavolineata (Signoret, 1855) and S. curvovittata (Stal, 1862) comb. nov. (Hemiptera: Cicadellidae: Cicadellini). AB - The species of Subrasaca Young, 1977 with longitudinal dark brown to black stripes on the forewings are reviewed. Two new taxa are described and illustrated: S. constricta sp. nov. (from the State of Bahia, NE. Brazil, new record for the genus) and S. bimaculata sp. nov. (from the states of Minas Gerais and Sao Paulo, SE. Brazil and the State of Parana, S. Brazil). Two other species from SE. Brazil are treated: S. flavolineata (Signoret, 1855) is redescribed and Tettigonia curvovittata Stal, 1862, previously considered a junior synonym of S. flavolineata, is recognized as a valid Subrasaca species (new combination) and also redescribed. In addition to the external morphology, color pattern, and male genitalia, this paper includes the first detailed description and illustrations of the female genitalia of a Subrasaca species. PMID- 26046211 TI - Three new species of Gnaptorina Reitter (Coleoptera, Tenebrionidae: Blaptini) from Tibet, China. AB - Three new species of Gnaptorina Reitter, 1887, G (Hesperoptorina) medvedevi, sp. nov., G (H.) dongdashanensis, sp nov. and G (H.) cuonaensis, sp. nov. are described from Tibet, China. A key to the known species of the subgenus Hesperoptorina is given. PMID- 26046212 TI - The larvae of the Aegean endemic caddisflies Hydropsyche debirasi Malicky 1974 and Hydropsyche kleobis Malicky 2001 (Trichoptera: Hydropsychidae) with notes on their ecology and zoogeography. AB - The larvae of Hydropsyche debirasi Malicky 1974 and Hydropsyche kleobis Malicky 2001, endemics of the Aegean Islands, Greece, are described for the first time. The diagnostic features of the species are described and illustrated and some information regarding their ecology and zoogeography are included. PMID- 26046213 TI - Neotypification of Larus cachinnans Pallas, 1811 (Aves: Laridae). PMID- 26046214 TI - Synonyms for some species of Mexican anoles (Squamata: Dactyloidae). AB - We studied type material and freshly collected topotypical specimens to assess the taxonomic status of five names associated with species of Mexican Anolis. We find A. schmidti to be a junior synonym of A. nebulosus, A. breedlovei to be a junior synonym of A. cuprinus, A. polyrhachis to be a junior synonym of A. rubiginosus, A. simmonsi to be a junior synonym of A. nebuloides, and A. adleri to be a junior synonym of A. liogaster. PMID- 26046215 TI - Description of a second specimen of Leptotyphlops parkeri (Squamata: Leptotyphlopidae), with comments on its generic placement. PMID- 26046216 TI - Correcting the nomenclature of two Helix dejecta: Helicopsis arenosa (Krynicki, 1836) (Gastropoda: Hygromiidae) from Eastern Europe and Streptartemon dejectus (Moricand, 1836) (Gastropoda: Streptaxidae) from Brazil. PMID- 26046217 TI - Catalogue of Opiliones (Arachnida) types deposited in the Arachnida and Myriapoda collection of the Instituto Butantan, Sao Paulo, Brazil. AB - A catalogue of the Opiliones types of the "Instituto Butantan", Sao Paulo, Brazil is given, surveying the collection after severe fire damaged in 2010. Of a total of 91 species with type material listed for the collection, 69 could be located, and 22 are considered lost. The species are arranged according to their families and genera. The collection of Salvador de Toledo Piza Jr., housed at the Museu de Zoologia "Luiz de Queiroz", was donated to the Instituto Butantan in 2009. These types received a new accession number and are listed under this new affiliation for the first time. PMID- 26046218 TI - New species of mouse spiders (Araneae: Mygalomorphae: Actinopodidae: Missulena) from the Pilbara region, Western Australia. AB - Two new species of Mouse Spiders, genus Missulena, from the Pilbara region in Western Australia are described based on morphological features of males. Missulena faulderi sp. nov. and Missulena langlandsi sp. nov. are currently known from a small area in the southern Pilbara only. Mitochondrial cytochrome c oxidase subunit I (COI) sequence divergence failed in clearly delimiting species in Missulena, but provided a useful, independent line of evidence for taxonomic work in addition to morphology. PMID- 26046219 TI - Taxonomic review of the Sebastes pachycephalus complex (Scorpaeniformes: Scorpaenidae). AB - A taxonomic review of the Sebastes pachycephalus complex established the existence of two valid species, S. pachycephalus and S. nudus. Similarities between them include: cranium armed dorsally with robust preocular, supraocular, postocular, and parietal spines; interorbital space concave; lower jaw lacking scales, shorter than upper jaw; thickened rays in ventral half of pectoral fin; dorsal fin usually with 13 spines and 12 soft-rays; pored lateral line scales 27 35 (usually 29-33). However, S. pachycephalus is distinguishable from the latter in having minute scales below the entire dorsal-fin spine base (vs. lacking minute scales below first to fifth or variously to the posteriormost spine in the latter), dark spots scattered on the dorsal, anal and caudal fins (vs. no distinct dark spots), and lacking distinct colored markings on the dorsum (vs. yellow or reddish-brown markings present). Although both species occur off the southern Korean Peninsula and in the Bohai and Yellow Seas, in Japanese waters, the former is distributed from northern Honshu Is. southward to southern Kyushu Is., whereas the latter extends from southern Hokkaido southward along the Pacific coast of Japan to Kanagawa, and along the Sea of Japan coast to northern Kyushu Is., including the Seto Inland Sea. Sebastes nigricaus, S. nigricans, and S. latus are confirmed as junior synonyms of S. pachycephalus, and S. chalcogrammus as junior synonym of S. nudus, based on the examination of type specimens. PMID- 26046220 TI - Species of the family Nemouridae (Plecoptera) from Taihang Mountains of northern China, with description of Nemoura taihangshana sp. n. AB - A distinctive new species of the genus Nemoura is described from the Taihang Mountains of northern China, N. taihangshana. The new species is compared with similar species. Amphinemura sinensis (Wu, 1926) is redescribed and the first record of N. geei Wu, 1929 from Henan Province is also given. PMID- 26046221 TI - Larval morphology of dart-poison frogs (Anura: Dendrobatoidea: Aromobatidae and Dendrobatidae). AB - Tadpoles in the superfamily Dendrobatoidea (families Aromobatidae and Dendrobatidae), housed in zoological collections or illustrated in publications, were studied. For the most part, tadpoles of species within the family Aromobatidae, the subfamilies Colostethinae and Hyloxalinae (of the family Dendrobatidae), and those of the genus Phyllobates, Dendrobatinae (Dendrobatidae) have slender anterior jaw sheaths with a medial notch and slender lateral processes, triangular fleshy projections on the inner margin of the nostrils and digestive tube with constant diameter and color and its axis sinistrally directed, concealing the liver and other organs. These morphologies are different from the ones observed in tadpoles of species included in the Dendrobatinae (minus Phyllobates). Exceptions to these morphological arrangements are noted, being the digestive system arrangement and the nostril ornamentation more plastic than the shape of the upperjaw sheath. Tadpoles of all species of the Dendrobatoidea have similar disposition of digestive organs in early stages, but differentiate in late stages of development. Classifying the upper jaw sheath into the two recognized states is possible from very early stages of development, but gut disposition and nostril ornamentation cannot be determined until late in development, making classification and taxonomic assignment of tadpoles based on these morphological features challenging. PMID- 26046222 TI - A new species of the genus Mantisgebia Sakai, 2006 (Crustacea, Decapoda, Gebiidea, Upogebiidae) from the South China Sea. AB - A new species of the genus Mantisgebia Sakai, 2006, M. multispinosa sp. nov., collected from the South China Sea, is described and illustrated. It is readily distinguished from the other three species of the genus by the numerous spines on the cervical groove, hepatic region, and lower margins of the antennular and antennal peduncles. PMID- 26046223 TI - A new species of Brasilycus (Coleoptera: Lycidae) from Peru. AB - Brasilycus peruanus sp. nov. is proposed as new to science. Photographs of the habitus, antenna, pronotum, and aedeagus of the single specimen are presented. This new species represents the first record of the genus Brasilycus from Peru and is the fourth species in the genus recorded from South America. PMID- 26046224 TI - Race, self-selection, and the job search process. AB - While existing research has documented persistent barriers facing African American job seekers, far less research has questioned how job seekers respond to this reality. Do minorities self-select into particular segments of the labor market to avoid discrimination? Such questions have remained unanswered due to the lack of data available on the positions to which job seekers apply. Drawing on two original data sets with application-specific information, we find little evidence that blacks target or avoid particular job types. Rather, blacks cast a wider net in their search than similarly situated whites, including a greater range of occupational categories and characteristics in their pool of job applications. Additionally, we show that perceptions of discrimination are associated with increased search breadth, suggesting that broad search among African-Americans represents an adaptation to labor market discrimination. Together these findings provide novel evidence on the role of race and self selection in the job search process. PMID- 26046225 TI - Emergent ghettos: black neighborhoods in New York and Chicago, 1880-1940. AB - This article studies in detail the settlement patterns of blacks in the urban North from before the Great Migration and through 1940, focusing on the cases of New York and Chicago. It relies on new and rarely used data sources, including census geocoded microdata from the 1880 census (allowing segregation patterns and processes to be studied at any geographic scale) and census data for 1900-1940 aggregated to enumeration districts. It is shown that blacks were unusually highly isolated in 1880 given their small share of the total population and that segregation reached high levels in both cities earlier than previously reported. Regarding sources of racial separation, neither higher class standing nor northern birth had much effect on whether blacks lived within or outside black neighborhoods in 1880 or 1940, and it is concluded that the processes that created large black ghettos were already in place several decades before 1940. PMID- 26046226 TI - Where do inmmigrants fare worse? Modeling workplace wage gap variation with longitudinal employer-employee data. AB - The authors propose a strategy for observing and explaining workplace variance in categorically linked inequalities. Using Swedish economy-wide linked employer employee panel data, the authors examine variation in workplace wage inequalities between native Swedes and non-Western immigrants. Consistent with relational inequality theory, the authors' findings are that immigrant-native wage gaps vary dramatically across workplaces, even net of strong human capital controls. The authors also find that, net of observed and fixed-effect controls for individual traits, workplace immigrant-native wage gaps decline with increased workplace immigrant employment and managerial representation and increase when job segregation rises. These results are stronger in high-inequality workplaces and for white-collar employees: contexts in which one expects status-based claims on organizational resources, the central causal mechanism identified by relational inequality theory, to be stronger. The authors conclude that workplace variation in the non-Western immigrant-native wage gaps is contingent on organizational variationin the relative power of groups and the institutional context in which that power is exercised. PMID- 26046227 TI - Game changer: the topology of creativity. AB - This article examines the sociological factors that explain why some creative teams are able to produce game changers--cultural products that stand out as distinctive while also being critically recognized as outstanding. The authors build on work pointing to structural folding--the network property of a cohesive group whose membership overlaps with that of another cohesive group. They hypothesize that the effects of structural folding on game changing success are especially strong when overlapping groups are cognitively distant. Measuring social distance separately from cognitive distance and distinctiveness independently from critical acclaim, the authors test their hypothesis about structural folding and cognitive diversity by analyzing team reassembly for 12,422 video games and the career histories of 139,727 video game developers. When combined with cognitive distance, structural folding channels and mobilizes a productive tension of rules, roles, and codes that promotes successful innovation. In addition to serving as pipes and prisms, network ties are also the source of tools and tensions. PMID- 26046229 TI - Acoustic radiation force impulse (ARFI) elastography of kidneys in healthy adult cats: preliminary results. AB - OBJECTIVES: To describe acoustic radiation impulse force elastography in evaluation of kidneys of adult cats. MATERIALS AND METHODS: Ten healthy adult short-haired cats were included. Echogenicity and texture, cortico-medullary relationship, size and edges of kidney were assessed by B-mode and by qualitative elastography to detect the presence of deformities and shear velocities of different portions (cranial, middle and caudal of cortex and medulla). RESULTS: Findings of ultrasonography were normal in all cats. Qualitative elastography demonstrated that the renal cortex was not deformable and had homogeneous dark gray areas; the renal pelvis had lower stiffness (white); and the medulla showed a mosaic pattern. The results of shear wave velocity were different in cranial, middle and caudal regions of cortex and medulla: 2.46 +/-0.45, 2.46 +/-0.48 and 2.37 +/-0.42 (P=0.795) in cortex and 1.61 +/-0.69, 1.75 +/-0.66 and 2.00 +/-0.55 m/s (P=0.156) in medulla, respectively. CLINICAL SIGNIFICANCE: Quantitative and qualitative acoustic radiation impulse force elastography of the kidney in adult cats was easily performed and this study provides base line data to allow the use of acoustic radiation impulse force in diseased animals. PMID- 26046228 TI - Family structure instability, genetic sensitivity, and child well-being. AB - The association between family structure instability and children's life chances is well documented, with children reared in stable, two-parent families experiencing more favorable outcomes than children in other family arrangements. This study examines father household entrances and exits, distinguishing between the entrance of a biological father and a social father and testing for interactions between family structure instability and children's age, gender, and genetic characteristics. Using data from the Fragile Families and Child Wellbeing Study and focusing on changes in family structure by age (years 0-9), the authors show that father exits are associated with increases in children's antisocial behavior, a strong predictor of health and well-being in adulthood. The pattern for father entrances is more complicated, with entrances for the biological father being associated with lower antisocial behavior among boys and social father entrances being associated with higher antisocial behavior. Child's age does not moderate the association; however, genetic information in the models sharpens the findings substantially. PMID- 26046234 TI - Erratum. PMID- 26046235 TI - K5Mo4O14F: A Novel Fluorinated Polyoxomolybdate and Its Structural Stability. AB - We successfully synthesized a novel fluorinated polyoxomolybdate, K5Mo4O14F, in which the unusual polyanion [Mo4O14F](5-) consists of face-sharing [Mo2O8F] bioctahedra linked with [MoO4] tetrahedra. This unique structural feature provides the very rare case that simultaneously violates Pauling's electrostatic valence (II) and atomic coordination (IV) rules, as well as the stable tendency governed by the polyhedral sharing (III) rule. The structural stability of K5Mo4O14F was confirmed from thermal experiments over a wide temperature range and further elucidated by first-principles calculations. PMID- 26046236 TI - Changes in HbA1c, insulin dose and incidence of hypoglycemia in patients with type 1 diabetes after switching to insulin degludec in an outpatient setting: an observational study. AB - OBJECTIVE: Insulin degludec, a basal insulin with an ultra-long duration of action, became available in Sweden from July 2013. The diabetes team at Danderyd Hospital decided to perform a clinical follow-up of patients with type 1 diabetes switching to insulin degludec to evaluate its clinical performance, using a simple form and available measures, thereby indirectly assessing cost effectiveness. RESEARCH DESIGN AND METHODS: This was a prospective, open-label, single-arm, observational, clinical follow-up from August 2013 to February 2015 of consecutive patients who switched to insulin degludec according to predefined indications (i.e., currently administering basal insulin twice daily, unacceptable HbA1c, repeated hypoglycemic events and/or unstable glucose, difficulty with fixed-time administration) in conjunction with professional judgment and patient wishes. Information about HbA1c, insulin dose and frequency of hypoglycemia (self-reported by patient recall) was collected at baseline and repeated after 4-6 months. RESULTS: In February 2015, data were available on 357 patients. Median time to follow-up was 20 weeks. Mean (SD) HbA1c decreased from 68.9 (15.7) to 65.8 (14.3) mmol/mol, p < 0.0001, and this improvement was achieved despite less insulin. Median reduction of the total insulin dose (basal + prandial) was 12% (interquartile range [IQR] -20% to -3%). The mean (SD) number of self-reported hypoglycemic events in the previous 4 weeks decreased from 8.2 (8.9) to 6.4 (7.6) events, p < 0.0001, and nocturnal hypoglycemic events were reduced from 1.6 (2.9) to 0.7 (2.0) events, p < 0.0001. CONCLUSION: Due to improvement in glycemic control, reduction of hypoglycemic events and reduction of insulin dose, we concluded that insulin degludec was clinically useful and economically justifiable for our patients with type 1 diabetes. Not every patient may benefit to the same degree after switching to insulin degludec. Controlled studies are needed to confirm these benefits in a larger sample of real-world patients. PMID- 26046237 TI - The symphony of autophagy and calcium signaling. AB - Posttranslational regulation of macroautophagy (hereafter autophagy), including phosphorylating and dephosphorylating components of the autophagy-related (Atg) core machinery and the corresponding upstream transcriptional factors, is important for the precise modulation of autophagy levels. Several kinases that are involved in phosphorylating autophagy-related proteins have been identified in both yeast and mammalian cells. However, there has been much less research published with regard to the identification of the complementary phosphatases that function in autophagy. A recent study identified PPP3/calcineurin, a calcium dependent phosphatase, as a regulator of autophagy, and demonstrated that one of the key targets of PPP3/calcineurin is TFEB, a master transcriptional factor that controls autophagy and lysosomal function in mammalian cells. PMID- 26046238 TI - Tightly Bound Trions in Transition Metal Dichalcogenide Heterostructures. AB - We report the observation of trions at room temperature in a van der Waals heterostructure composed of MoSe2 and WS2 monolayers. These trions are formed by excitons excited in the WS2 layer and electrons transferred from the MoSe2 layer. Recombination of trions results in a peak in the photoluminescence spectra, which is absent in monolayer WS2 that is not in contact with MoSe2. The trion origin of this peak is further confirmed by the linear dependence of the peak position on excitation intensity. We deduced a zero-density trion binding energy of 62 meV. The trion formation facilitates electrical control of exciton transport in transition metal dichalcogenide heterostructures, which can be utilized in various optoelectronic applications. PMID- 26046239 TI - On the Gut Microbiome-Brain Axis and Altruism. PMID- 26046240 TI - Potential Etiologic Factors of Microbiome Disruption in Autism. AB - PURPOSE: The primary purpose of this article was to consider the candidate disruptors of the development of a healthy microbiome in patients with autism. The reported abnormalities in the microbiome of individuals with autism are discussed. METHODS: This selected review used data from published articles related to the assessment of microbiota in autism. Evidence-based support of factors known to affect the intestinal microbiome in individuals with autism are presented. Proposed interventions are evaluated and discussed. FINDINGS: Studies that have investigated the intestinal microbiome in patients with autism have reported significant differences versus unaffected controls. Increased clostridial species in autism have been reported in several studies. These differences may have resulted from a number of environmental factors. Microbiome alterations that might contribute to the development of autism include altered immune function and bacterial metabolites. IMPLICATIONS: Efforts to modify microbial imbalances through a variety of interventions are addressed. Focusing on mechanisms that drive imbalances in the microbiome may affect the development of disease. Altered intestinal health may contribute to the development of autistic behaviors or autism itself. Interventions aimed at improving intestinal health may favorably affect the microbiome and autism. PMID- 26046242 TI - Lack of Vitamin D Receptor Causes Dysbiosis and Changes the Functions of the Murine Intestinal Microbiome. AB - PURPOSE: The microbiome modulates numerous aspects of human physiology and is a crucial factor in the development of various human diseases. Vitamin D deficiency and downregulation of the vitamin D receptor (VDR) are also associated with the pathogenesis of diseases such as inflammatory bowel disease, cancers, obesity, diabetes, and asthma. VDR is a nuclear receptor that regulates the expression of antimicrobial peptides and autophagy regulator ATG16L1. Vitamin D may promote a balanced intestinal microbiome and improve glucose homeostasis in diabetes. However, how VDR regulates microbiome is not well known. In the current study, we hypothesize that VDR status regulates the composition and functions of the intestinal bacterial community. METHODS: Fecal and cecal stool samples were harvested from Vdr knockout (Vdr(-/-)) and wild-type mice for bacterial DNA and then sequenced with 454 pyrosequencing. The sequences were denoised and clustered into operational taxonomic units, then queried against the National Center for Biotechnology Information database. Metagenomics were analyzed, and the abundances of genes involved in metabolic pathways were compared by reference to the Kyoto Encyclopedia of Genes and Genomes and Clusters of Orthologous Groups databases. FINDINGS: In the Vdr(-/-) mice, Lactobacillus was depleted in the fecal stool, whereas Clostridium and Bacteroides were enriched. Bacterial taxa along the Sphingobacteria-to-Sphingobacteriaceae lineage were enriched, but no genera reached statistical significance. In the cecal stool, Alistipes and Odoribacter were depleted, and Eggerthella was enriched. Notably, all of the taxa upstream of Eggerthella remained unchanged. A comparison of Vdr(-/-) and wild type samples revealed 40 (26 enriched, 14 depleted) and 72 (41 enriched, 31 depleted) functional modules that were significantly altered in the cecal and fecal microbiomes, respectively (both, P < 0.05), due to the loss of Vdr. In addition to phylogenetic differences in gut microbiome with different intestinal origins, we identify several important pathways, such as nucleotide-binding oligomerization domain-like receptor, affected by Vdr status, including amino acid, carbohydrate, and fatty acid synthesis and metabolism, detoxification, infections, signal transduction, and cancer and other diseases. IMPLICATIONS: Our study fills knowledge gaps by having investigated the microbial profile affected by VDR. Insights from our findings can be exploited to develop novel strategies to treat or prevent various diseases by restoring VDR function and healthy microbe-host interactions. PMID- 26046243 TI - Perioperative Skin Preparation and Draping in Modern Total Joint Arthroplasty: Current Evidence. AB - BACKGROUND: Besides the vast success and reliability of lower extremity joint replacement, deep and periprosthetic infection remains a serious complication of such operations. Many publications addressing periprosthetic infection have remarked about this "devastating" complication, with a risk around 1% after total hip arthroplasty and between 1% and 2% after total knee arthroplasty. The purpose of this study is to assess current trends in prevention of contamination with improved up-to-date pre-operative skin preparation methods and intra-operative draping. METHODS: A literature review was conducted in MEDLINE, Web of Science, and the Cochrane database, looking for high-quality papers summarizing the most widely held and up-to-date concepts of perioperative measures for reducing infection, focusing on the best available evidence concerning skin preparation for joint arthroplasty (THR and THR) and surgical draping. RESULTS: Current evidence suggests the use of alcohol solutions for pre-operative painting with emphasis on the use of chlorhexidine gluconate solutions beginning the night before surgery. Hair removal should be performed in the operating room with electric clippers, not razor blades. In order to enhance drape adhesion to the skin, the use of iodophor-in-alcohol solutions is recommended over the traditional scrub-and-paint technique. Disposable non-woven drapes are superior to reusable woven cotton/linen drapes in resisting bacterial penetration. Finally, the use of adherent plastic adhesive incision drapes for the prophylaxis of post-operative surgical site infections is considered not necessary in orthopedic surgery. CONCLUSIONS: The importance of skin preparation and adequate and reliable draping cannot be overemphasized for infection prevention, especially in clean operations such as THR and TKR. Thorough and strict protocols are mandatory for every department, as well as education curricula for operating room personnel. Further randomized studies are mandatory to specify the effect of the above measures, their pitfalls, and their improvement, along with further crucial details such as cost-benefit analysis of different pre-operative preparations in preventing infections. PMID- 26046241 TI - Gut-Microbiota-Brain Axis and Its Effect on Neuropsychiatric Disorders With Suspected Immune Dysregulation. AB - PURPOSE: Gut microbiota regulate intestinal function and health. However, mounting evidence indicates that they can also influence the immune and nervous systems and vice versa. This article reviews the bidirectional relationship between the gut microbiota and the brain, termed the microbiota-gut-brain (MGB) axis, and discusses how it contributes to the pathogenesis of certain disorders that may involve brain inflammation. METHODS: Articles were identified with a search of Medline (starting in 1980) by using the key words anxiety, attention deficit hypersensitivity disorder (ADHD), autism, cytokines, depression, gut, hypothalamic-pituitary-adrenal (HPA) axis, inflammation, immune system, microbiota, nervous system, neurologic, neurotransmitters, neuroimmune conditions, psychiatric, and stress. FINDINGS: Various afferent or efferent pathways are involved in the MGB axis. Antibiotics, environmental and infectious agents, intestinal neurotransmitters/neuromodulators, sensory vagal fibers, cytokines, and essential metabolites all convey information to the central nervous system about the intestinal state. Conversely, the hypothalamic-pituitary adrenal axis, the central nervous system regulatory areas of satiety, and neuropeptides released from sensory nerve fibers affect the gut microbiota composition directly or through nutrient availability. Such interactions seem to influence the pathogenesis of a number of disorders in which inflammation is implicated, such as mood disorder, autism-spectrum disorders, attention-deficit hypersensitivity disorder, multiple sclerosis, and obesity. IMPLICATIONS: Recognition of the relationship between the MGB axis and the neuroimmune systems provides a novel approach for better understanding and management of these disorders. Appropriate preventive measures early in life or corrective measures such as use of psychobiotics, fecal microbiota transplantation, and flavonoids are discussed. PMID- 26046244 TI - Odontogenic Maxillofacial Infections: A Ten-Year Retrospective Analysis. AB - BACKGROUND: To analyze treatment modalities and results in patients with severe odontogenic maxillofacial infections during a 10-y period. METHODS: Medical records of 1,077 patients hospitalized because of severe odontogenic maxillofacial infections during 2003-2012 were reviewed. The sample consisted of the records that matched inclusion criteria. For each patient the following data were collected: Age, gender, presence of systemic diseases, length of hospital stay, causal tooth, location of inflammation, treatment, results of bacteriologic sampling, and anti-bacterial susceptibility. RESULTS: Male to female ratio was 1.4:1. Two or more anatomic spaces were involved in 42.9% of cases, 37.3% of which involved the floor of the mouth. Penicillin in combination with gentamicin or metronidazole was prescribed in 69% of cases. Sixty-two different micro organism species were identified with predominance of Streptococcus haemolyticus (42.9%). The microbial analysis showed the highest susceptibility of predominant micro-organisms to penicillin was 76.9% and the highest resistance was to metronidazole (27.9%). CONCLUSIONS: The frequency of odontogenic maxillofacial infection remained almost unchanged during a 10-y period. Single-space infections were more common (57.1%) than infections involving two or more spaces. Susceptibility to penicillin remains relatively high; therefore, penicillin can remain part of the armamentarium for treatment of odontogenic maxillofacial infections. PMID- 26046245 TI - Cryptic Bacteria of Lower Limb Deep Tissues as a Possible Cause of Inflammatory and Necrotic Changes in Ischemia, Venous Stasis and Varices, and Lymphedema. AB - BACKGROUND: Infections and inflammation of the lower limb skin, soft tissues, and vessels are more common than in other body regions. The aim was to determine whether cryptic bacteria dwelling in deep tissues are the cause. METHODS: We performed bacteriologic studies of specimens harvested from arteries of amputated ischemic legs, leg varices, and tissue fluid/lymph and lymphatics in lymphedema. RESULTS: Calf arteries contained isolates in 61% and femoral arteries in 36%, whereas normal cadaveric organ donors' arteries in 11%. Bacterial deoxyribonucleic acid (DNA) was detected in 70%. The majority of isolates belonged to the coagulase-negative staphylococci and Staphylococcus aureus; however, highly pathogenic bacteria were also detected. All were sensitive to all antibiotics except penicillin. Saphenous vein varices contained bacterial cells in 40% and controls 4%; bacterial DNA was found in 69%. The majority of bacteria were S. epidermidis and S. aureus susceptible to all antibiotics except penicillin, Lymph and epifascial lymphatics limb contained bacteria in 60% and 33% samples, respectively and controls in 7%. Most were S. epidermidis susceptible to all antibiotics except penicillin. CONCLUSION: Cryptic bacteria are present in lower limb tissues and may play a pathologic role in surgical site infections. Proper antibacterial prophylaxis should be considered when planning surgical interventions. PMID- 26046246 TI - Deep Infections after Endoprosthetic Replacement Operations in Orthopedic Oncology Patients. AB - BACKGROUND: Numerous studies have described various complications after endoprosthetic reconstructive operations. However, there are limited reports that focus specifically on deep infections (e.g., deep incisional surgical site infections), which remain one of the most dreaded complications of these operations, with rates ranging from 10% to 17%. Thus, this study was undertaken to determine the deep infection rates and to analyze possible risk factors, clinico-pathologic characteristics, and treatment modalities of endoprosthetic infections. METHODS: We reviewed retrospectively the records of 105 consecutive patients who underwent endoprosthesis replacements from January 2007 to September 2011, with a minimal follow-up period of 32 mo. Comparison was made between patients with and without endoprosthetic infections. RESULTS: Thirteen of the 150 patients (12.38%) who underwent endoprosthetic operations developed deep infections. Ninety-seven (92.4%) patients presented with a primary bone/soft tissue tumor, 5 (4.8%) with bone metastasis, and 3 (2.9%) with non-tumor conditions. Distal femoral was the most common implant location (42%). The majority of the infections (6/13) occurred within 3 mo post-operation. An elevated C-reactive protein concentration or erythrocyte sedimentation rate were present consistently in all patients at time of diagnosis, whereas clinical presentations and leukocytosis were inconsistent in determining infection. Staphylococcus aureus and coagulase-negative staphylococci (CoNS) were the most common organisms isolated, with high numbers demonstrating methicillin resistance. Overall, multi-drug resistance was noted in 52.6% of the isolated strains. Four risk factors were associated independently with deep infection by multivariable analysis (p<0.05) and these were proximal tibia endoprosthesis, pelvic endoprosthesis, pre-operative duration of hospitalization of more than 48 h, and additional surgical procedures performed after the initial endoprosthetic insertion. Overall, infection was eradicated successfully in 53.8% (7/13) of the patients. Two-stage revision successfully treated the infection in 80% (4/5) of the patients, whereas surgical debridement without a change of implant was successful in only 42.8% (3/7) of patients. Amputation was performed in three patients. CONCLUSIONS: Patients undergoing endoprosthetic replacement for various orthopedic oncologic conditions have high infection rates. The present study allows early identification of such patients in view of the high morbidity associated with this condition. This report also highlights the high rate of multi-drug-resistant infections, especially methicillin-resistant strains of S. aureus and CoNS encountered, which complicates further the management of these patients. PMID- 26046247 TI - Role of Pre-Operative Blood Transfusion and Subcutaneous Fat Thickness as Risk Factors for Surgical Site Infection after Posterior Thoracic Spine Stabilization. AB - BACKGROUND: Surgical site infections (SSIs) increase morbidity and mortality rates and generate additional cost for the healthcare system. Pre-operative blood transfusion and the subcutaneous fat thickness (SFT) have been described as risk factors for SSI in other surgical areas. The purpose of this study was to assess the impact of pre-operative blood transfusion and the SFT on the occurrence of SSI in posterior thoracic spine surgery. METHODS: In total, 244 patients (median age 55 y; 97 female) who underwent posterior thoracic spine fusions from 2008 to 2012 were reviewed retrospectively. Patient-specific characteristics, pre operative hemoglobin concentration/hematocrit values, the amount of blood transfused, and the occurrence of a post-operative SSI were documented. The SFT was measured on pre-operative computed tomography scans. RESULTS: Surgical site infection was observed in 26 patients (11%). The SFT was 13 mm in patients without SSI and 14 mm in those with infection (p=0.195). The odds ratio for patients with pre-operative blood transfusion to present with SSI was 3.1 (confidence interval [CI] 1.4-7.2) and 2.7 (CI 1.1-6.4) when adjusted for age. There was no difference between the groups with regard to pre-operative hemoglobin concentration (p=0.519) or hematocrit (p=0.908). The SFT did not differ in the two groups. CONCLUSIONS: Allogeneic red blood cell transfusion within 48 h prior to surgery was an independent risk factor for SSI after posterior fusion for the fixation of thoracic spine instabilities. Pre-operative blood transfusion tripled the risk, whereas SFT had no influence on the occurrence of SSI. PMID- 26046248 TI - Nosocomial Infections and Microbiologic Spectrum after Major Elective Surgery of the Pancreas, Liver, Stomach, and Esophagus. AB - BACKGROUND: The majority of infections treated by surgeons are nosocomial infections (NI). The frequency of these infections in relation to the organ operated on as well as the organisms involved are not well defined. Detailed knowledge of these issues is essential for optimal care of surgical patients. This study aimed to determine infection rates and the responsible pathogens after major elective surgery of the pancreas, liver, stomach, and esophagus. METHODS: Between January 1, 2005 and August 31, 2007, the records of all patients of the Department of General, Abdominal and Vascular Surgery, University Hospital Magdeburg (Germany) with elective resection of the pancreas, liver, stomach, and esophagus were evaluated retrospectively. Study parameters were: Patient number, age, gender, body mass index (BMI), American Society of Anesthesiologists (ASA) classification, indication for resection, operation duration, length of stay (LOS) in the intensive care unit (ICU) and in hospital, mortality, organ-related rate and kind of NI, and microbiologic spectrum. Nosocomial infections were defined as: Surgical site infection (U.S. Centers for Disease Control and Prevention [CDC] 1 or 2) and intra-abdominal infection (CDC 3), urinary tract infection, clinical sepsis, blood stream and catheter-related infection, respiratory tract infection, and pneumonia. RESULTS: A total of 358 patients were included: 150 (42%) with pancreas resection, 91 (25%) with liver resection, 105 (29%) with gastric resection, and 12 (3%) with esophagus resection. Median LOS in the ICU for all groups was 48.8 h (interquartile range [IQR] 24.9-91.8 h), median LOS in hospital was 16 d (IQR 13-23 d), and in-hospital mortality was 4.5%. Patients with NI had significantly greater in-hospital death and prolonged stay in hospital and ICU (p<0.001). In 120 (33.5%) patients, one or more NI occurred (range, 83% in esophagus patients to 21% in liver patients). Intra-abdominal (16.5%) and surgical site infections (12.3%) were most frequent; 80.8% of the NI were culture-positive. The most frequent clinically relevant isolates were Escherichia coli (12.4%), coagulase-negative staphylococci (CoNS) (12.2%), and Enterococcus faecium (9.7%). The highest resistance rates were found for Staphylococcus aureus (methicillin-resistant S. aureus [MRSA] 29.4%) and Pseudomonas aeruginosa (23.5%). CONCLUSIONS: For patients undergoing elective surgery of the pancreas, liver, stomach, and esophagus, considerable differences in demographic factors, frequency, and kind of NI exist. The consequences of NI force surgeons to analyze pre-operative risk factors carefully, assess indications for operation thoroughly, and optimize all controllable parameters. PMID- 26046249 TI - Biomarkers (Procalcitonin, C Reactive Protein, and Lactate) as Predictors of Mortality in Surgical Patients with Complicated Intra-Abdominal Infection. AB - BACKGROUND: An accurate and readily available biomarker for identifying patients with complicated intra-abdominal infection needing special attention in critical care units because of their greater risk of dying would be of value for intensivists. METHODS: A multi-center, observational, retrospective study explored blood lactate, C-reactive protein (CRP), and procalcitonin (PCT) concentrations, and also Sequential Organ Failure Assessment (SOFA) and Simplified Acute Physiology Score (SAPS II) as mortality predictors in all adult patients with complicated intra-abdominal infection (cIAI) admitted to Surgical Critical Care Units (SCCUs) for >=48 h in four Spanish hospitals (June 2012-June 2013). Logistic regression models (step-wise procedure) were constructed using as dependent variables "intra-SCCU mortality" or "overall mortality," and variables showing differences (p<=0.1) in bivariate analyses as independent variables. RESULTS: One hundred twenty-one cases were included. Mortality intra-SCCU (R(2)=0.189, p=0.001) was associated with SAPS II (categorized as high if >=47) (OR=9.55; 95% CI, 1.09-83.85; p=0.042) and 24 h-lactate (>=5.87 categorized as high) (OR=6.90; 95% CI, 1.28-37.08). Overall mortality (R(2)=0.275, p=0.001) was associated with peak PCT (>=100 categorized as high) (OR=11.28; 95% CI, 1.80 70.20), peak lactate (>=1.8 categorized as high) (OR=8.86; 95% CI, 1.51-52.10) and SOFA at admission (>=7 categorized as high) (OR=8.14; 95% CI, 1.69-39.20), but was predicted better (R(2)=0.275, p=0.001) by a single dummy variable (high peak PCT-high peak lactate concentrations) (OR=99.11; 95% CI, 5.21-1885.97; p=0.002). CONCLUSIONS: In the present study, SAPS II and 24 h-lactate concentrations predicted intra-SCCU mortality whereas overall mortality was predicted better by concurrent high PCT and lactate peak concentrations than by clinical scores or by each biomarker separately. PMID- 26046250 TI - Efficacy of (99m)Tc-Labeled Ceftizoxime in the Diagnosis of Subclinical Infections Associated with Titanium Implants in Rats. AB - BACKGROUND: Metal implants are used frequently in orthopedic procedures and the occurrence of subclinical low-virulence infection is difficult to diagnose. The objective of this study was to examine the hypothesis that peri-prosthetic subclinical infections may be diagnosed effectively in a murine model system using scintigraphic imaging with (99m)Tc-labeled ceftizoxime. METHODS: A sample population of 3-mo old Wistar rats (mean weight 327 g) was divided randomly into a control group (n=6), which received sterile implants, and an experimental group (n=6), which received implants contaminated with Staphylococcus aureus strain ATCC6538-P. Animals were anesthetized and femoral titanium implants were fixed beneath muscle tissue in left hind limbs. Three weeks after surgery, animals were injected with (99m)Tc-ceftizoxime solution (62.9 MBq) and scintigraphic images were obtained at 3.5 and 6.5 h after tracer injection. RESULTS: According to the scintigraphic images, the radiopharmaceutical showed affinity for the operated thigh areas of experimental animals but not for those of the control group. There was no difference between the control and experimental groups regarding the amount of radioactivity in the regions of interest measured at 3.5 h after injection of radiolabeled antibiotic, but the between-group difference determined at 6.5 h after treatment was statistically significant (p=0.026). Moreover, the level of radioactivity recorded in resected thigh tissues derived from experimental animals was greater than that of the control group (p=0.035). CONCLUSION: (99m)Tc-ceftizoxime scintigraphy can localize preferentially periprosthetic-infected areas adjacent to metal implants in a murine model. Furthermore, the radiolabeled antibiotic appears to be capable of detecting alterations in the micro-environment close to the implant and of reaching the bacteria attached to the implant surface. PMID- 26046253 TI - Temporal relationships between adipocytokines and diabetes risk in Hispanic adolescents with obesity. AB - OBJECTIVE: Circulating cytokines are frequently cited as contributors to insulin resistance in children with obesity. This study examined whether circulating adipocytokines, independent of adiposity, predicted pubertal changes in insulin sensitivity (SI), insulin secretion (AIR), and beta-cell function in high-risk adolescents. METHODS: 158 Hispanic adolescents with overweight or obesity were followed for a median of 4 years. Adipocytokines were measured using Luminex technology. SI, AIR, and the disposition index were derived from an intravenous glucose tolerance test and minimal modeling. Total fat mass was measured by DXA and visceral adipose tissue (VAT) by MRI. RESULTS: Surprisingly, mean IL-8, IL 1beta, IL-6, and TNF-alpha decreased between 5% and 6.5% per year from baseline (P < 0.001). Despite the general temporal trends, gaining 1-SD of VAT was associated with a 2% and 5% increase in MCP-1 and IL-8 (P < 0.05). In addition, a 1-SD higher MCP-1 or IL-6 concentration at baseline was associated with a 16% and 21% greater decline in SI during puberty vs. prepuberty (P < 0.05). CONCLUSIONS: Several adipocytokines decreased during adolescence and were weakly associated with VAT and lower SI during puberty. Circulating adipocytokines have relatively limited associations with pubertal changes in diabetes risk; however, the consistent findings with MCP-1 warrant further investigation. PMID- 26046254 TI - From diamonds to black stone; myth to reality: Acute kidney injury with paraphenylene diamine poisoning. AB - AIM: We report here, a case series of patients with acute kidney injury (AKI) after ingestion of paraphenylene diamine (PPD) a derivative of analine. It is used as a colouring agent to dye hair, fur and plastic and in photographic films. METHODS: Subjects for the study reported here comprised a cohort of 100 patients coming to this institution with AKI following PPD poisoning. AKI was defined according to RIFLE criteria and PPD poisoning on the basis of history and presenting features. All patients had normal sized kidneys on ultrasonography and no previous co- morbidity. RESULTS: One hundred patients with AKI after PPD exposure were brought to this institute between May 2010 and February 2015. Among these, 56 were females, with mean age of 23.11 +/- 7.94 years. Cause of AKI was toxic rhabdomyolysis as indicated by marked rise in muscle enzymes with mean lactate dehydrogenase and creatinine phosphokinase levels of 6665.22 +/- 6272.04 and 194 486.66 +/- 301 905.80, respectively. Hepatotoxicity with raised aspartate aminotransferase and alanine aminotransferase was a main feature of the studied population. Renal replacement was required in 97% of patients. Complete renal recovery was observed in 77 patients, while 16 died during the acute phase of illness. Respiratory failure and recurrent hyperkalaemia were the main causes of mortality. CONCLUSION: Easy availability and low cost of PPD has lead to a remarkable increase in the use of this substance, especially for suicidal purposes. Awareness of its effects among health professionals, as well as at a societal and government level, is needed at this time. PMID- 26046255 TI - Symbiosis with an endobacterium increases the fitness of a mycorrhizal fungus, raising its bioenergetic potential. AB - Arbuscular mycorrhizal fungi (AMF) occur in the rhizosphere and in plant tissues as obligate symbionts, having key roles in plant evolution and nutrition. AMF possess endobacteria, and genome sequencing of the endobacterium Candidatus Glomeribacter gigasporarum revealed a reduced genome and a dependence on the fungal host. To understand the effect of bacteria on fungal fitness, we used next generation sequencing to analyse the transcriptional profile of Gigaspora margarita in the presence and in the absence of its endobacterium. Genomic data on AMF are limited; therefore, we first generated a gene catalogue for G. margarita. Transcriptome analysis revealed that the endobacterium has a stronger effect on the pre-symbiotic phase of the fungus. Coupling transcriptomics with cell biology and physiological approaches, we demonstrate that the bacterium increases the fungal sporulation success, raises the fungal bioenergetic capacity, increasing ATP production, and eliciting mechanisms to detoxify reactive oxygen species. By using TAT peptide to translocate the bioluminescent calcium reporter aequorin, we demonstrated that the line with endobacteria had a lower basal intracellular calcium concentration than the cured line. Lastly, the bacteria seem to enhance the fungal responsiveness to strigolactones, the plant molecules that AMF perceive as branching factors. Although the endobacterium exacts a nutritional cost on the AMF, endobacterial symbiosis improves the fungal ecological fitness by priming mitochondrial metabolic pathways and giving the AMF more tools to face environmental stresses. Thus, we hypothesise that, as described for the human microbiota, endobacteria may increase AMF innate immunity. PMID- 26046256 TI - Directed assembly of a bacterial quorum. AB - Many reports have elucidated the mechanisms and consequences of bacterial quorum sensing (QS), a molecular communication system by which bacterial cells enumerate their cell density and organize collective behavior. In few cases, however, the numbers of bacteria exhibiting this collective behavior have been reported, either as a number concentration or a fraction of the whole. Not all cells in the population, for example, take on the collective phenotype. Thus, the specific attribution of the postulated benefit can remain obscure. This is partly due to our inability to independently assemble a defined quorum, for natural and most artificial systems the quorum itself is a consequence of the biological context (niche and signaling mechanisms). Here, we describe the intentional assembly of quantized quorums. These are made possible by independently engineering the autoinducer signal transduction cascade of Escherichia coli (E. coli) and the sensitivity of detector cells so that upon encountering a particular autoinducer level, a discretized sub-population of cells emerges with the desired phenotype. In our case, the emergent cells all express an equivalent amount of marker protein, DsRed, as an indicator of a specific QS-mediated activity. The process is robust, as detector cells are engineered to target both large and small quorums. The process takes about 6 h, irrespective of quorum level. We demonstrate sensitive detection of autoinducer-2 (AI-2) as an application stemming from quantized quorums. We then demonstrate sub-population partitioning in that AI-2-secreting cells can 'call' groups neighboring cells that 'travel' and establish a QS-mediated phenotype upon reaching the new locale. PMID- 26046257 TI - Metagenomic resolution of microbial functions in deep-sea hydrothermal plumes across the Eastern Lau Spreading Center. AB - Microbial processes within deep-sea hydrothermal plumes affect ocean biogeochemistry on global scales. In rising hydrothermal plumes, a combination of microbial metabolism and particle formation processes initiate the transformation of reduced chemicals like hydrogen sulfide, hydrogen, methane, iron, manganese and ammonia that are abundant in hydrothermal vent fluids. Despite the biogeochemical importance of this rising portion of plumes, it is understudied in comparison to neutrally buoyant plumes. Here we use metagenomics and bioenergetic modeling to describe the abundance and genetic potential of microorganisms in relation to available electron donors in five different hydrothermal plumes and three associated background deep-sea waters from the Eastern Lau Spreading Center located in the Western Pacific Ocean. Three hundred and thirty one distinct genomic 'bins' were identified, comprising an estimated 951 genomes of archaea, bacteria, eukarya and viruses. A significant proportion of these genomes is from novel microorganisms and thus reveals insights into the energy metabolism of heretofore unknown microbial groups. Community-wide analyses of genes encoding enzymes that oxidize inorganic energy sources showed that sulfur oxidation was the most abundant and diverse chemolithotrophic microbial metabolism in the community. Genes for sulfur oxidation were commonly present in genomic bins that also contained genes for oxidation of hydrogen and methane, suggesting metabolic versatility in these microbial groups. The relative diversity and abundance of genes encoding hydrogen oxidation was moderate, whereas that of genes for methane and ammonia oxidation was low in comparison to sulfur oxidation. Bioenergetic thermodynamic modeling supports the metagenomic analyses, showing that oxidation of elemental sulfur with oxygen is the most dominant catabolic reaction in the hydrothermal plumes. We conclude that the energy metabolism of microbial communities inhabiting rising hydrothermal plumes is dictated by the underlying plume chemistry, with a dominant role for sulfur-based chemolithoautotrophy. PMID- 26046258 TI - Microbial response to simulated global change is phylogenetically conserved and linked with functional potential. AB - The high diversity of microbial communities hampers predictions about their responses to global change. Here we investigate the potential for using a phylogenetic, trait-based framework to capture the response of bacteria and fungi to global change manipulations. Replicated grassland plots were subjected to 3+ years of drought and nitrogen fertilization. The responses of leaf litter bacteria and fungi to these simulated changes were significantly phylogenetically conserved. Proportional changes in abundance were highly correlated among related organisms, such that relatives with approximately 5% ribosomal DNA genetic distance showed similar responses to the treatments. A microbe's change in relative abundance was significantly correlated between the treatments, suggesting a compromise between numerical abundance in undisturbed environments and resistance to change in general, independent of disturbance type. Lineages in which at least 90% of the microbes shared the same response were circumscribed at a modest phylogenetic depth (tauD 0.014-0.021), but significantly larger than randomized simulations predict. In several clades, phylogenetic depth of trait consensus was higher. Fungal response to drought was more conserved than was response to nitrogen fertilization, whereas bacteria responded equally to both treatments. Finally, we show that a bacterium's response to the manipulations is correlated with its potential functional traits (measured here as the number of glycoside hydrolase genes encoding the capacity to degrade different types of carbohydrates). Together, these results suggest that a phylogenetic, trait-based framework may be useful for predicting shifts in microbial composition and functioning in the face of global change. PMID- 26046259 TI - Calcium and P-glycoprotein independent synergism between schweinfurthins and verapamil. AB - Schweinfurthins are intriguing natural products with anti-cancer activities and as yet incompletely understood mechanisms of action. We investigated whether inhibitors of P-glycoprotein (Pgp), in a manner analogous to other natural products, might enhance schweinfurthins' growth inhibitory actions by increasing intracellular schweinfurthin levels. Both the schweinfurthin-sensitive glioblastoma multiforme cell line SF-295 and relatively insensitive lung carcinoma cell line A549 were treated with 2 schweinfurthin analogs: 3 deoxyschweinfurthin B-p-nitro bis-stilbene (3dSB-PNBS) and 5' methylschweinfurthin G (methyl-G). There was a synergistic enhancement of growth inhibition with the combination of the Pgp inhibitor verapamil and both analogs in SF-295 cells. Methyl-G, verapamil, and the combination did not result in alterations to intracellular calcium concentration. Verapamil increased the intracellular concentration of 3dSB-PNBS in both SF-295 and A549 cells in a Pgp independent manner. Methyl-G, verapamil, and the combination do not result in increased ER stress. Methyl-G increased the intracellular concentration of a known Pgp substrate, Rhodamine 123 in SF-295 cells. Reduction of cellular cholesterol leads to the accumulation of Pgp substrates, as Pgp requires cholesterol for proper function. Since 3dSB enhances lovastatin-induced upregulation of the cholesterol efflux pump ABCA1, it is intriguing that co treatment with cholesterol rescued the methyl-G-induced increase in Rhodamine 123 intracellular concentration. These studies support the hypothesis that verapamil potentiates the schweinfurthin growth inhibitory effect by increasing its intracellular concentration. PMID- 26046260 TI - In vitro biocompatibility of Ti-Mg alloys fabricated by direct current magnetron sputtering. AB - Ti-xMg (x=17, 33, and 55 mass%) alloy films, which cannot be prepared by conventional melting processes owing to the absence of a solid-solution phase in the phase diagram, were prepared by direct current magnetron sputtering in order to investigate their biocompatibility. Ti and Mg films were also prepared by the same process for comparison. The crystal structures were examined by X-ray diffraction (XRD) analysis and the surfaces were analyzed by X-ray photoelectron spectroscopy. The Ti, Ti-xMg alloy, and Mg films were immersed in a 0.9% NaCl solution at 310 K for 7d to evaluate the dissolution amounts of Ti and Mg. In addition, to evaluate the formation ability of calcium phosphate in vitro, the Ti, Ti-xMg alloy, and Mg films were immersed in Hanks' solution at 310 K for 30 d. Ti and Mg form solid-solution alloys because the peaks attributed to pure Ti and Mg do not appear in the XRD patterns of any of the Ti-xMg alloy films. The surfaces of the Ti-17 Mg alloy and Ti-33 Mg alloy films contain Ti oxides and MgO, whereas MgO is the main component of the surface oxide of the Ti-55 Mg alloy and Mg films. The dissolution amounts of Ti from all films are below or near the detection limit of inductively coupled plasma-optical emission spectroscopy. On the other hand, the Ti-17 Mg alloy, Ti-33 Mg alloy, Ti-55 Mg alloy, and Mg films exhibit Mg dissolution amounts of approximately 2.5, 1.4, 21, and 41 MUg/cm(2), respectively. The diffraction peaks attributed to calcium phosphate are present in the XRD patterns of the Ti-33 Mg alloy, Ti-55 Mg alloy, and Mg films after the immersion in Hanks' solution. Spherical calcium phosphate particles precipitate on the surface of the Ti-33 Mg film. However, many cracks are observed in the Ti 55 Mg film, and delamination of the film occurs after the immersion in Hanks' solution. The Mg film is dissolved in Hanks' solution and calcium phosphate particles precipitate on the glass substrate. Consequently, it is revealed that the Ti-33 Mg alloy film evaluated in this study is suitable for biomedical applications. PMID- 26046261 TI - Antibacterial and hemolysis activity of polypyrrole nanotubes decorated with silver nanoparticles by an in-situ reduction process. AB - Polypyrrole nanotube-silver nanoparticle nanocomposites (PPy-NTs:Ag-NPs) have been synthesized by in-situ reduction of silver nitrate (AgNO3) to suppress the agglomeration of Ag-NPs. The morphology and chemical structure of the nanocomposites have been studied by HRTEM, SEM, XRD, FTIR and UV-vis spectroscopy. The average diameter of the polypyrrole nanotubes (PPy-NTs) is measured to be 130.59+/-5.5 nm with their length in the micrometer range, while the silver nanoparticles (Ag-NPs) exhibit spherical shape with an average diameter of 23.12+/-3.23 nm. In-vitro blood compatibility of the nanocomposites has been carried out via hemolysis assay. Antimicrobial activity of the nanocomposites has been investigated with Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) bacteria. The results depict that the hemolysis and antimicrobial activities of the nanocomposites increase with increasing Ag-NP concentration that can be controlled by the AgNO3 precursor concentration in the in-situ process. PMID- 26046262 TI - Cross-linked chitosan improves the mechanical properties of calcium phosphate chitosan cement. AB - Calcium phosphate (CaP) cements are highly applicable and valuable materials for filling bone defects by minimally invasive procedures. The chitosan (CS) biopolymer is also considered as one of the promising biomaterial candidates in bone tissue engineering. In the present study, some key features of CaP-CS were significantly improved by developing a novel CaP-CS composite. For this purpose, CS was the first cross-linked with tripolyphosphate (TPP) and then mixed with CaP matrix. A group of CaP-CS samples without cross-linking was also prepared. Samples were fabricated and tested based on the known standards. Additionally, the effect of different powder (P) to liquid (L) ratios was also investigated. Both cross-linked and uncross-linked CaP-CS samples showed excellent washout resistance. The most significant effects were observed on Young's modulus and compressive strength in wet condition as well as surface hardness. In dry conditions, the Young's modulus of cross-linked samples was slightly improved. Based on the presented results, cross-linking does not have a significant effect on porosity. As expected, by increasing the P/L ratio of a sample, ductility and injectability were decreased. However, in the most cases, mechanical properties were enhanced. The results have shown that cross-linking can improve the mechanical properties of CaP-CS and hence it can be used for bone tissue engineering applications. PMID- 26046263 TI - Preparation and characterization of nano-sized hydroxyapatite/alginate/chitosan composite scaffolds for bone tissue engineering. AB - The aim of this study was to develop chitosan composite scaffolds with high strength and controlled pore structures by homogenously dispersed nano-sized hydroxyapatite (nano-HAp) powders. In the fabrication of composite scaffolds, nano-HAp powders distributed in an alginate (AG) solution with a pH higher than 10 were mixed with a chitosan (CS) solution and then freeze dried. While the HAp content increased up to 70 wt.%, the compressive strength and the elastic modulus of the composite scaffolds significantly increased from 0.27 MPa and 4.42 MPa to 0.68 MPa and 13.35 MPa, respectively. Higher content of the HAp also helped develop more differentiation and mineralization of the MC3T3-E1 cells on the composite scaffolds. The uniform pore structure and the excellent mechanical properties of the HAp/CS composite scaffolds likely resulted from the use of the AG solution at pH 10 as a dispersant for the nano-HAp powders. PMID- 26046264 TI - Development and performance optimization of knitted antibacterial materials using polyester-silver nanocomposite fibres. AB - The development and performance optimization of knitted antibacterial materials made from polyester-silver nanocomposite fibres have been attempted in this research. Inherently antibacterial polyester-silver nanocomposite fibres were blended with normal polyester fibres in different weight proportions to prepare yarns. Three parameters, namely blend percentage (wt.%) of nanocomposite fibres, yarn count and knitting machine gauge were varied for producing a large number of knitted samples. The knitted materials were tested for antibacterial activity against Gram-positive bacteria Staphylococcus aureus. Statistical analysis revealed that all the three parameters were significant and the blend percentage of nanocomposite fibre was the most dominant factor influencing the antibacterial activity of knitted materials. The antibacterial activity of the developed materials was found to be extremely durable as there was only about 1% loss even after 25 washes. Linear programming approach was used to optimize the parameters, namely antibacterial activity, air permeability and areal density of knitted materials considering cost minimization as the objective. The properties of validation samples were found to be very close to the targeted values. PMID- 26046265 TI - Functional Surface of the golden mussel's foot: morphology, structures and the role of cilia on underwater adhesion. AB - In this study we characterized the surface morphology and ultrastructure of the foot of the golden mussel, Limnoperna fortunei (Dunker, 1857), relating its characteristics to the attaching mechanisms of this mollusk. The observation of the foot of this bivalve reveals the presence of micro-scaled cilia with a unique shape, which has a narrowing at its end. This characteristic was associated to the capacity for underwater adhesion to substrates through the employment of van der Waals forces, resembling the adhesion phenomenon of the gecko foot. The temporary attachment during locomotion by means of the foot to substrates was observed to be strong even on smooth surfaces, like glass, or hydrophobic waxy surfaces. Comparing TEM and light microscopy results it was possible to associate the mucous secretions and secreting cells found along the tissues to the production of the byssus inside the groove on the ventral portion of the foot. Not only our experiments, but also the state of the art allowed us to discard the involvement of secretions produced in the foot of the mussel to the temporary adhesion. Through SEM images it was possible to build a virtual three-dimensional model where total foot surface was measured for the estimated calculation of van der Waals forces. Also, some theoretical analysis and considerations have been made concerning the characteristics of the functional surface of L. fortunei foot. PMID- 26046266 TI - Spectrofluorometric and thermal gravimetric study on binding interaction of thiabendazole with hemoglobin on epoxy-functionalized magnetic nanoparticles. AB - The interaction of thiabendazole (Tbz) with hemoglobin (Hb) on epoxy functionalized iron oxide nanoparticles was presented in this study. The binding capacity of Tbz was determined by measuring at an excitation wavelength of 299 nm using fluorescence spectroscopy. The thermodynamic parameters of the Hb-Tbz interaction were calculated from Stern-Volmer and van't Hoff equations. The values of enthalpy change, ?H, and entropy change, ?S, were found to be 0.20 kJ mol(-1) and 0.70 J mol(-1) K(-1), respectively, which indicates that the hydrophilic interaction plays a main role in the binding process. The interaction ability was confirmed by Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM). Also, the thermal behavior of the Hb-Tbz interaction on functionalized iron oxide nanoparticles was studied by using the thermogravimetric analysis (TGA) technique in the temperature range of 25-950 degrees C, and then the kinetic parameters for the thermal decomposition were determined using the Horowitz-Metzger method. PMID- 26046267 TI - The effect of coating type on mechanical properties and controlled drug release of PCL/zein coated 45S5 bioactive glass scaffolds for bone tissue engineering. PMID- 26046268 TI - Translationally controlled tumor protein supplemented chitosan modified glass ionomer cement promotes osteoblast proliferation and function. AB - The objective of this study was to evaluate the effect of translationally controlled tumor protein (TCTP) supplemented in a novel glass ionomer cement (BIO GIC) on normal human osteoblasts (NHost cells). BIO-GIC was a glass ionomer cement (GIC) modified by adding chitosan and albumin to promote the release of TCTP. NHost cells were seeded on specimens of GIC, GIC+TCTP, BIO-GIC and BIO GIC+TCTP. Cell proliferation was determined by BrdU assay. It was found that BIO GIC+TCTP had significantly higher proliferation of cells than other specimens. Bone morphogenetic protein-2 (BMP-2) and osteopontin (OPN) gene expressions assessed by quantitative real time PCR and alkaline phosphatase (ALP) activity were used to determine cell differentiation. Bone cell function was investigated by calcium deposition using alizarin assay. Both BMP-2 and OPN gene expressions of cells cultured on specimens with added TCTP increased gradually up-regulation after day 1 and reached the highest on day 3 then down-regulation on day 7. The ALP activity of cells cultured on BIO-GIC+TCTP for 7 days and calcium content after 14 days were significantly higher than other groups. BIO-GIC+TCTP can promote osteoblast cells proliferation, differentiation and function. PMID- 26046269 TI - Effects of temperature change and beverage on mechanical and tribological properties of dental restorative composites. AB - The aim of this study was to investigate the effects of temperature change and immersion in two common beverages on the mechanical and tribological properties for three different types of dental restorative materials. Thermocycling procedure was performed for simulating temperature changes in oral conditions. Black tea and soft drink were considered for beverages. Universal composite, universal nanohybrid composite and universal nanofilled composite, were used as dental materials. The nanoindentation and nanoscratch experiments were utilized to determine the elastic modulus, hardness, plasticity index and wear resistance of the test specimens. The results showed that thermocycling and immersion in each beverage had different effects on the tested dental materials. The mechanical and tribological properties of nanohybrid composite and nanocomposite were less sensitive to temperature change and to immersion in beverages in comparison with those of the conventional dental composite. PMID- 26046270 TI - Osteogenic differentiation of human mesenchymal stem cells in freeze-gelled chitosan/nano beta-tricalcium phosphate porous scaffolds crosslinked with genipin. AB - The objective of this work was to investigate material properties and osteogenic differentiation of human mesenchymal stem cells (hMSCs) in genipin (GN) crosslinked chitosan/nano beta-tricalcium phosphate (CS/nano beta-TCP) scaffolds, and compare the results with tripolyphosphate (TPP) crosslinked scaffolds. Porous crosslinked CS/nano beta-TCP scaffolds were produced by freeze-gelation using GN (CBG scaffold) and TPP (CBT scaffold) as crosslinkers. The prepared CBT and CBG scaffolds were characterized with respect to porosity, pore size, water content, wettability, compressive strength, mass loss, and osteogenic differentiation of hMSCs. All scaffolds displayed interconnected honeycomb-like microstructures. There was a significant difference between the average pore size, porosity, contact angle, and percent swelling of CBT and CBG scaffolds. The average pore size of CBG scaffolds was higher than CBT, the porosity of CBG was lower than CBT, the water contact angle of CBG was higher than CBT, and the percent swelling of CBG was lower than CBT. At a given crosslinker concentration, there was not a significant difference in compressive modulus and mass loss of CBG and CBT scaffolds. Metabolic activity of hMSCs seeded in CBG scaffolds was slightly higher than CBT. Furthermore, CBG scaffolds displayed slightly higher extent of mineralization after 21 days of incubation in osteogenic medium compared to CBT. PMID- 26046271 TI - Peptide aptamers: Novel coatings for orthopaedic implants. AB - Current processes for coating titanium implants with ceramics involve very high energy techniques with associated high cost and disadvantages such as heterogeneity of the coatings, phase transformations and inability to coat complex structures. In order to address the above problems, we propose a biomimetic hydroxyapatite coating process with the use of peptides that can bind both on titanium surfaces and hydroxyapatite. The peptides enabled homogeneous coating of a titanium surface with hydroxyapatite. The hydroxyapatite-peptide sandwich coating showed no adverse effects on cell number or collagen deposition. This makes the sandwich coated titanium a good candidate for titanium implants used in orthopaedics and dentistry. PMID- 26046272 TI - Revival of pure titanium for dynamically loaded porous implants using additive manufacturing. AB - Additive manufacturing techniques are getting more and more established as reliable methods for producing porous metal implants thanks to the almost full geometrical and mechanical control of the designed porous biomaterial. Today, Ti6Al4V ELI is still the most widely used material for porous implants, and none or little interest goes to pure titanium for use in orthopedic or load-bearing implants. Given the special mechanical behavior of cellular structures and the material properties inherent to the additive manufacturing of metals, the aim of this study is to investigate the properties of selective laser melted pure unalloyed titanium porous structures. Therefore, the static and dynamic compressive properties of pure titanium structures are determined and compared to previously reported results for identical structures made from Ti6Al4V ELI and tantalum. The results show that porous Ti6Al4V ELI still remains the strongest material for statically loaded applications, whereas pure titanium has a mechanical behavior similar to tantalum and is the material of choice for cyclically loaded porous implants. These findings are considered to be important for future implant developments since it announces a potential revival of the use of pure titanium for additively manufactured porous implants. PMID- 26046273 TI - Small diameter electrospun silk fibroin vascular grafts: Mechanical properties, in vitro biodegradability, and in vivo biocompatibility. AB - To overcome the drawbacks of autologous grafts currently used in clinical practice, vascular tissue engineering represents an alternative approach for the replacement of small diameter blood vessels. In the present work, the production and characterization of small diameter tubular matrices (inner diameter (ID)=4.5 and 1.5 mm), obtained by electrospinning (ES) of Bombyx mori silk fibroin (SF), have been considered. ES-SF tubular scaffolds with ID=1.5 mm are original, and can be used as vascular grafts in pediatrics or in hand microsurgery. Axial and circumferential tensile tests on ES-SF tubes showed appropriate properties for the specific application. The burst pressure and the compliance of ES-SF tubes were estimated using the Laplace's law. Specifically, the estimated burst pressure was higher than the physiological pressures and the estimated compliance was similar or higher than that of native rat aorta and Goretex(r) prosthesis. Enzymatic in vitro degradation tests demonstrated a decrease of order and crystallinity of the SF outer surface as a consequence of the enzyme activity. The in vitro cytocompatibility of the ES-SF tubes was confirmed by the adhesion and growth of primary porcine smooth muscle cells. The in vivo subcutaneous implant into the rat dorsal tissue indicated that ES-SF matrices caused a mild host reaction. Thus, the results of this investigation, in which comprehensive morphological and mechanical aspects, in vitro degradation and in vitro and in vivo biocompatibility were considered, indicate the potential suitability of these ES-SF tubular matrices as scaffolds for the regeneration of small diameter blood vessels. PMID- 26046274 TI - Biocompatible surgical meshes based on decellularized human amniotic membrane. AB - Meshes play important roles to repair human tissue defect. In this work, human amniotic membrane (HAM) was decellularized and explored the efficacy as an implantable biological mesh. Surfactant, hypertonic saline, lipase and DNAase were used individually or collectively to remove all cell components and remain the extracellular matrix. Results of H&E and DAPI staining demonstrated that the method of surfactant and lipase combining with DNAase is the most effective treatment for HAM decellularization. Primary smooth muscle cells were seeded to evaluate the decellularized HAM's (dHAM) in vitro cytocompatibility. The in vivo test was performed via implantation at rabbits' uterus with clinic polypropylene mesh (PP) as the control. The results indicated that dHAM possessed good biocompatibility and will be a potential candidate for biological mesh. PMID- 26046275 TI - Fabrication and characterization of a biodegradable Mg-2Zn-0.5Ca/1beta-TCP composite. AB - A biodegradable magnesium matrix and beta-tricalcium phosphate (beta-TCP) particles reinforced composite Mg-2Zn-0.5Ca/1beta-TCP (wt.%) was fabricated for biomedical applications by the novel route of combined high shear solidification (HSS) and equal channel angular extrusion (ECAE). The as-cast composite obtained by HSS showed a fine and equiaxed grain structure with globally uniformly distributed beta-TCP particles in aggregates of 2-25 MUm in size. The ECAE processing at 300 degrees C resulted in further microstructural refinement and the improvement of beta-TCP particle distribution. During ECAE, the beta-TCP aggregates were broken into smaller ones or individual particles, forming a dispersion in the matrix. Such fabricated composite exhibited enhanced hardness and in vitro corrosion resistance. The enhanced hardness was attributed to both the addition of beta-TCP particles and grain refinement while the development of a Ca-P rich surface layer from beta-TCP during corrosion was responsible for the improvement in corrosion resistance. The composite was characterized in terms of microstructural evolution during fabrication, mechanical properties and electrochemical performance during polarization and immersion tests in a simulated body fluid. Discussions are made on the benefits of both HSS and ECAE and the mechanisms responsible for the enhanced corrosion resistance. PMID- 26046276 TI - Histochemical examination of adipose derived stem cells combined with beta-TCP for bone defects restoration under systemic administration of 1alpha,25(OH)2D3. AB - The purpose of this study was to evaluate the effects of osteogenic differentiated adipose-derived stem cell (ADSC) loaded beta-tricalcium phosphate (beta-TCP) in the restoration of bone defects under intraperitoneal administration of 1alpha,25-dihydroxyvitamin D3(1alpha,25(OH)2D3). ADSCs were isolated from the fat tissue of 8 week old Wister rats and co-cultured with beta TCP for 21 days under osteogenic induction. Then the ADSC-beta-TCP complexes were implanted into bone defects in the femora of rats. 1alpha,25(OH)2D3 (VD) or normal saline (NS) was administrated intraperitoneally every other day after the surgery. Femora were harvested at day 7, day 14 and day 28 post-surgery. There were 4 groups for all specimens: beta-TCP-NS group; beta-TCP-ADSC-NS group; beta TCP-VD group and beta-TCP-ADSC-VD group. Alkaline phosphatase (ALP) was up regulated obviously in ADSC groups compared with non-ADSC groups at day 7, day 14 and day 28, although high expression of runt-related transcription factor 2 (RUNX2) was only seen at day 7. Furthermore, the number of TRAP-positive osteoclasts and the expression of cathepsin K (CK) were significantly decreased in VD groups compared with non-VD groups at day 7 and day 14. As a most significant finding, the beta-TCP-ADSC-VD group showed the highest BV/TV ratio compared with the other three groups at day 28. Taken together, ADSC-loaded beta TCP under the administration of 1alpha,25(OH)2D3 made a promising therapy for bone defects restoration. PMID- 26046277 TI - Gold nanorod delivery of LSD1 siRNA induces human mesenchymal stem cell differentiation. AB - Over the past decade, theranostic nanoparticles with microsize and multifunctional ability have emerged as a new platform in biomedical field, such as cancer therapy, optical imaging and gene therapy. Gene therapy has been recently shown as a promising tool for tissue engineering as safe and effective nanotechnology-based delivery methods are developed. Controlling adhesion and differentiation of stem cells is critical for tissue regeneration. In this study, we have developed poly-sodium 4-styrenesulfonate (PSS) and poly-allylamine hydrochloride (PAH) coated AuNR-based nanocarriers, which are capable of delivering small interfering RNA (siRNA) against LSD1 to induce the differentiation of human mesenchymal stem cells. To further study the mechanism, we tested the stemness and differentiation genes and found that they have been changed with LSD1 down-regulation. In addition, with the hepatocyte growth factor (HGF), LSD1 siRNA delivery by AuNRs could promote the differentiation of the human mesenchymal stem cells (human MSCs) into a hepatocyte lineage in vitro. Our results suggest for the first time use of AuNRs as nanocarriers of delivery LSD1 siRNA to induce the differentiation of human MSCs into a hepatocyte lineage, and envision the potential application of nanotechnology in tissue remodeling (such as liver and bone) in vivo, eventually translating to clinical applications. PMID- 26046278 TI - In situ synthesis carbonated hydroxyapatite layers on enamel slices with acidic amino acids by a novel two-step method. AB - In situ fabrication of carbonated hydroxyapatite (CHA) remineralization layer on an enamel slice was completed in a novel, biomimetic two-step method. First, a CaCO3 layer was synthesized on the surface of demineralized enamel using an acidic amino acid (aspartic acid or glutamate acid) as a soft template. Second, at the same concentration of the acidic amino acid, rod-like carbonated hydroxyapatite was produced with the CaCO3 layer as a sacrificial template and a reactant. The morphology, crystallinity and other physicochemical properties of the crystals were characterized using field emission scanning electron microscopy (FESEM), Fourier transform infrared spectrometry (FTIR), X-ray diffraction (XRD) and energy-dispersive X-ray analysis (EDAX), respectively. Acidic amino acid could promote the uniform deposition of hydroxyapatite with rod-like crystals via absorption of phosphate and carbonate ions from the reaction solution. Moreover, compared with hydroxyapatite crystals coated on the enamel when synthesized by a one-step method, the CaCO3 coating that was synthesized in the first step acted as an active bridge layer and sacrificial template. It played a vital role in orienting the artificial coating layer through the template effect. The results show that the rod-like carbonated hydroxyapatite crystals grow into bundles, which are similar in size and appearance to prisms in human enamel, when using the two-step method with either aspartic acid or acidic glutamate (20.00 mmol/L). PMID- 26046279 TI - Tailoring the properties and functions of phosphate/silk/Ag/chitosan scaffolds. AB - Two novel silk composites of phosphatic phases with nanosilver/chitosan having enhanced biocompatibility were achieved. Hydroxyapatite and octa calcium phosphates were synthesized in situ within silk fibroin/chitosan/nanosilver composites recently studied. Thermo-gravimetric analysis (TGA) and Differential Scanning Calorimetry (DSC) verified their thermal behavior. The structural aspects were characterized applying X-ray diffraction analysis (XRD), transmission electron microscopy (TEM) and field emission scanning electron microscope (FESEM) with EDAX. Additionally X-ray Photoelectron Spectroscopy (XPS) and Fourier Transform Infrared spectroscopy (FTIR) were applied. Mercury porosimeter was used to verify the pore size distribution. The in vitro degradation was followed in D-MEM for 48 h in a cumulative manner for five successive periods. Biochemical analyses of Ca, P and total protein using relevant chemical kits and atomic absorption for silver were performed. ANOVA statistics was carried out. Phosphatic crystalline phases along with the presence of silk, chitosan and nano-silver were developed. The diameters of hydroxyapatite and octa calcium phosphate particles were ~8-17 nm and 15-22 nm respectively. Comparatively higher degradation of Octa composite possessing higher porosity proved in turn more osteoinduction with in situ apatitic development. PMID- 26046280 TI - Design of modified xanthan mini-matrices for monitoring oral discharge of highly soluble Soluplus(r)-glibenclamide dispersion. AB - In this work, Soluplus((r)) was used as a hydrophilic carrier for the preparation of solid dispersion (SD) of a model BCS class II drug, glibenclamide by applying hot melting process and microwave irradiation in combination. Increasing the concentration of carrier relative to drug significantly increased the drug solubility, which corresponded to a maximum 75 fold increase at a drug:carrier ratio of 1:7. Scanning electron microscopy, differential scanning calorimetry, and x-ray diffraction analyses confirmed complete amorphization of the drug in SD. In animal study, about two fold reductions in hyperglycemic level were achieved by SD compared to pure drug. SD-loaded O-carboxymethyl xanthan mini matrices controlled the release of drug into gastro-luminal fluid over longer duration. The drug release corroborated with pH-dependent swelling behavior of the matrices and approximated anomalous diffusion mechanism. This study proved the potential of Soluplus((r))-based dispersion in improving the clinical performance of the drug, especially when embedded in modified xanthan mini matrices. PMID- 26046281 TI - Two approaches to the model drug immobilization into conjugated polymer matrix. AB - The purpose of this study is to develop biocompatible and conducting coating being carrier of biologically active compounds with the potential use in neuroprosthetics. Conducting polypyrrole matrix has been used to immobilize and release model drugs, quercetin and ciprofloxacin. Two routes of immobilization are described: drugs have been incorporated in the polymer matrix in the course of the electropolymerization process or after polymerization, in the course of polymer oxidation. Using UV/Vis spectroscopic detection we demonstrate that both immobilization approaches display different drug-loading efficiencies. In the case of ciprofloxacin, drug incorporation following synthesis is a more efficient immobilization approach (final drug concentration: 43.3 (+/-9.5) MUM/cm(2)), while for quercetin the highest loading is accomplished by drug incorporation during synthesis (final drug concentration: 29.1 (+/-5.9) MUM/cm(2)). The process of drug incorporation results in the variation of surface morphology with respect to the method of immobilization as well as the choice of drug. The results prove that electrochemical methods are efficient procedures for making multifunctional polymer matrices which might be perspective bioactive coatings for implantable neuroprosthetic devices. PMID- 26046282 TI - Hydrophilic polyurethane matrix promotes chondrogenesis of mesenchymal stem cells. AB - Segmental polyurethanes exhibit biphasic morphology and can control cell fate by providing distinct matrix guided signals to increase the chondrogenic potential of mesenchymal stem cells (MSCs). Polyethylene glycol (PEG) based hydrophilic polyurethanes can deliver differential signals to MSCs through their matrix phases where hard segments are cell-interactive domains and PEG based soft segments are minimally interactive with cells. These coordinated communications can modulate cell-matrix interactions to control cell shape and size for chondrogenesis. Biphasic character and hydrophilicity of polyurethanes with gel like architecture provide a synthetic matrix conducive for chondrogenesis of MSCs, as evidenced by deposition of cartilage-associated extracellular matrix. Compared to monophasic hydrogels, presence of cell interactive domains in hydrophilic polyurethanes gels can balance cell-cell and cell-matrix interactions. These results demonstrate the correlation between lineage commitment and the changes in cell shape, cell-matrix interaction, and cell-cell adhesion during chondrogenic differentiation which is regulated by polyurethane phase morphology, and thus, represent hydrophilic polyurethanes as promising synthetic matrices for cartilage regeneration. PMID- 26046284 TI - Experimentally-based multiscale model of the elastic moduli of bovine trabecular bone and its constituents. AB - The elastic moduli of trabecular bone were modeled using an analytical multiscale approach. Trabecular bone was represented as a porous nanocomposite material with a hierarchical structure spanning from the collagen-mineral level to the trabecular architecture level. In parallel, compression testing was done on bovine femoral trabecular bone samples in two anatomical directions, parallel to the femoral neck axis and perpendicular to it, and the measured elastic moduli were compared with the corresponding theoretical results. To gain insights on the interaction of collagen and minerals at the nanoscale, bone samples were deproteinized or demineralized. After such processing, the treated samples remained as self-standing structures and were tested in compression. Micro computed tomography was used to characterize the hierarchical structure of these three bone types and to quantify the amount of bone porosity. The obtained experimental data served as inputs to the multiscale model and guided us to represent bone as an interpenetrating composite material. Good agreement was found between the theory and experiments for the elastic moduli of the untreated, deproteinized, and demineralized trabecular bone. PMID- 26046283 TI - Micro-arc oxidation as a tool to develop multifunctional calcium-rich surfaces for dental implant applications. AB - Titanium (Ti) is commonly used in dental implant applications. Surface modification strategies are being followed in last years in order to build Ti oxide-based surfaces that can fulfill, simultaneously, the following requirements: induced cell attachment and adhesion, while providing a superior corrosion and tribocorrosion performance. In this work micro-arc oxidation (MAO) was used as a tool for the growth of a nanostructured bioactive titanium oxide layer aimed to enhance cell attachment and adhesion for dental implant applications. Characterization of the surfaces was performed, in terms of morphology, topography, chemical composition and crystalline structure. Primary human osteoblast adhesion on the developed surfaces was investigated in detail by electronic and atomic force microscopy as well as immunocytochemistry. Also an investigation on the early cytokine production was performed. Results show that a relatively thick hybrid and graded oxide layer was produced on the Ti surface, being constituted by a mixture of anatase, rutile and amorphous phases where calcium (Ca) and phosphorous (P) were incorporated. An outermost nanometric-thick amorphous oxide layer rich in Ca was present in the film. This amorphous layer, rich in Ca, improved fibroblast viability and metabolic activity as well as osteoblast adhesion. High-resolution techniques allowed to understand that osteoblasts adhered less in the crystalline-rich regions while they preferentially adhere and spread over in the Ca-rich amorphous oxide layer. Also, these surfaces induce higher amounts of IFN-gamma cytokine secretion, which is known to regulate inflammatory responses, bone microarchitecture as well as cytoskeleton reorganization and cellular spreading. These surfaces are promising in the context of dental implants, since they might lead to faster osseointegration. PMID- 26046285 TI - Potential transducers based man-tailored biomimetic sensors for selective recognition of dextromethorphan as an antitussive drug. AB - A biomimetic potentiometric sensor for specific recognition of dextromethorphan (DXM), a drug classified according to the Drug Enforcement Administration (DEA) as a "drug of concern", is designed and characterized. A molecularly imprinted polymer (MIP), with special molecular recognition properties of DXM, was prepared by thermal polymerization in which DXM acted as template molecule, methacrylic acid (MAA) and acrylonitrile (AN) acted as functional monomers in the presence of ethylene glycol dimethacrylate (EGDMA) as crosslinker. The sensors showed a high selectivity and a sensitive response to the template in aqueous system. Electrochemical evaluation of these sensors revealed near-Nernstian response with slopes of 49.6+/-0.5 and 53.4+/-0.5 mV decade(-1) with a detection limit of 1.9*10(-6), and 1.0*10(-6) mol L(-1) DXM with MIP/MAA and MIP/AN membrane based sensors, respectively. Significantly improved accuracy, precision, response time, stability, selectivity and sensitivity were offered by these simple and cost effective potentiometric sensors compared with other standard techniques. The method has the requisite accuracy, sensitivity and precision to assay DXM in pharmaceutical products. PMID- 26046286 TI - Vascularisation in regenerative therapeutics and surgery. AB - Vascularisation is often deemed the holy grail of tissue engineering because it is one of the key preconditions that determine the in vivo viability of tissue constructs. Given that a well-developed vascular network allows greater complexity in tissue design and helps regulate tissue metabolism, it appears that the overall outcome of engineered tissue implants depends on the success of microvessel formation, maturation and patterning. Current approaches to vascularising tissue include both in vivo and ex vivo techniques, where blood vessel formation is either spontaneous or guided by physical or biochemical factors. The success of these strategies can then be monitored and evaluated for clinical benefit through numerous standard and novel strategies. Despite the impressive progress in the field of tissue engineering in recent times, there are still numerous technical, immunological, surgical and ethical challenges to overcome. Future prospects in this field are likely to depend on the adoption of a wide-ranging approach incorporating a combination of salient themes such as genetic manipulation, modular assembly and bioreactor coupling. Where applicable, the potential contributions of nanobiotechnology to tissue vascularisation will be discussed as appropriate. PMID- 26046287 TI - Insulin particles as building blocks for controlled insulin release multilayer nano-films. AB - Insulin nanoparticles (NPs) were prepared by pH-shift precipitation and a newly developed disassembly method at room temperature. Then, an electrostatic interaction-based, layer-by-layer (LbL) multilayer film incorporating insulin NPs was fabricated with poly(acrylic acid) (PAA) and poly(allylamine hydrochloride) (PAH), which is described herein as Si/(PAH/PAA)5(PAH/PAA-insulin NPs)n. The positively charged insulin NPs were introduced into the LbL film in the form of biocompatible PAA-insulin NP aggregates at a pH of 4.5 and were released in phosphate-buffered saline (pH7.4), triggered by changes in the charges of the insulin molecules. In addition, the insulin-incorporated multilayer was swollen because of the different ionic environment, leading also to insulin release. Eighty percent of the insulin was released from the LBL film in the first stage of 3h, and sustained release could be maintained in the second stage for up to 7 days in vitro, which is very critical for specific diabetic patients. These striking findings could offer novel directions to researchers in establishing insulin delivery systems for diabetic therapy and fabricating other protein nanoparticles applied to various biomedical platforms. PMID- 26046288 TI - Microstructure, corrosion behavior and cytotoxicity of biodegradable Mg-Sn implant alloys prepared by sub-rapid solidification. AB - In this study, biodegradable Mg-Sn alloys were fabricated by sub-rapid solidification, and their microstructure, corrosion behavior and cytotoxicity were investigated by using optical microscopy, scanning electron microscopy equipped with an energy dispersive X-ray spectroscopy, X-ray diffraction, immersion test, potentiodynamic polarization test and cytotoxicity test. The results showed that the microstructure of Mg-1Sn alloy was almost equiaxed grain, while the Mg-Sn alloys with higher Sn content (Sn>=3 wt.%) displayed alpha-Mg dendrites, and the secondary dendrite arm spacing of the primary alpha-Mg decreased significantly with increasing Sn content. The Mg-Sn alloys consisted of primary alpha-Mg matrix, Sn-rich segregation and Mg2Sn phase, and the amount of Mg2Sn phases increased with increasing Sn content. Potentiodynamic polarization and immersion tests revealed that the corrosion rates of Mg-Sn alloys increased with increasing Sn content. Cytotoxicity test showed that Mg-1Sn and Mg-3Sn alloys were harmless to MG63 cells. These results of the present study indicated that Mg-1Sn and Mg-3Sn alloys were promising to be used as biodegradable implants. PMID- 26046289 TI - Electrospun nanofibers of polyCD/PMAA polymers and their potential application as drug delivery system. AB - Herein, we used an electrospinning process to develop highly efficacious and hydrophobic coaxial nanofibers based on poly-cyclodextrin (polyCD) associated with poly(methacrylic acid) (PMAA) that combines polymeric and supramolecular features for modulating the release of the hydrophilic drug, propranolol hydrochloride (PROP). For this purpose, polyCD was synthesized and characterized, and its biocompatibility was assessed using fibroblast cytotoxicity tests. Moreover, the interactions between the guest PROP molecule and both polyCD and betaCD were found to be spontaneous. Subsequently, PROP was encapsulated in uniaxial and coaxial polyCD/PMAA nanofibers. A lower PROP burst effect (reduction of approximately 50%) and higher modulation were observed from the coaxial than from the uniaxial fibers. Thus, the coaxial nanofibers could potentially be a useful strategy for developing a controlled release system for hydrophilic molecules. PMID- 26046290 TI - The novel HLA-B*44 allele, HLA-B*44:220, identified by Single Molecule Real-Time DNA sequencing in a British Caucasoid male. AB - The genomic sequence of the novel HLA-B*44:220 allele identified in a British Caucasoid male. PMID- 26046291 TI - Offspring size in a resident species affects community assembly. AB - Offspring size is a trait of fundamental importance that affects the ecology and evolution of a range of organisms. Despite the pervasive impact of offspring size for those offspring, the influence of offspring size on other species in the broader community remains unexplored. Such community-wide effects of offspring size are likely, but they have not been anticipated by theory or explored empirically. For a marine invertebrate community, we manipulated the size and density of offspring of a resident species (Watersipora subtorquata) in the field and examined subsequent community assembly around that resident species. Communities that assembled around larger offspring were denser and less diverse than communities that assembled around smaller offspring. Differences in niche usage by colonies from smaller and larger offspring may be driving these community-level effects. Our results suggest that offspring size is an important but unexplored source of ecological variation and that life-history theory must accommodate the effects of offspring size on community assembly. Life-history theory often assumes that environmental variation drives intraspecific variation in offspring size, and our results show that the converse can also occur. PMID- 26046292 TI - Administering different levels of parenteral phosphate and amino acids did not influence growth in extremely preterm infants. AB - AIM: When a new high amino acid parenteral nutrition (PN) solution was introduced to our hospital, a design error led to decreased phosphate levels. This prompted us to examine the effect of three different PN solutions on plasma phosphate, plasma calcium and weight increases on extremely preterm infants. METHOD: This was a retrospective study of 186 infants with a gestational age of <28 weeks during their first month of life. They were divided into three groups based on the PN they received during hospitalisation. Group one received high levels of phosphate and low levels of amino acids. Group two received low levels of phosphate and high levels of amino acids. Group three received high levels of both phosphate and amino acids. RESULTS: The lowest plasma phosphate values varied significantly between groups one (1.80 +/- 0.46 mmol/L), two (1.05 +/- 0.48 mmol/L) and three (1.40 +/- 0.37 mmol/L) (p < 0.001), but no significant difference in weight increase was seen (p = 0.497). CONCLUSION: The phosphate content of the PN influenced plasma phosphate and plasma calcium levels, but increasing the levels of both phosphate and amino acids did not improve weight gain during the first month of life. PMID- 26046293 TI - FunPat: function-based pattern analysis on RNA-seq time series data. AB - BACKGROUND: Dynamic expression data, nowadays obtained using high-throughput RNA sequencing, are essential to monitor transient gene expression changes and to study the dynamics of their transcriptional activity in the cell or response to stimuli. Several methods for data selection, clustering and functional analysis are available; however, these steps are usually performed independently, without exploiting and integrating the information derived from each step of the analysis. METHODS: Here we present FunPat, an R package for time series RNA sequencing data that integrates gene selection, clustering and functional annotation into a single framework. FunPat exploits functional annotations by performing for each functional term, e.g. a Gene Ontology term, an integrated selection-clustering analysis to select differentially expressed genes that share, besides annotation, a common dynamic expression profile. RESULTS: FunPat performance was assessed on both simulated and real data. With respect to a stand alone selection step, the integration of the clustering step is able to improve the recall without altering the false discovery rate. FunPat also shows high precision and recall in detecting the correct temporal expression patterns; in particular, the recall is significantly higher than hierarchical, k-means and a model-based clustering approach specifically designed for RNA sequencing data. Moreover, when biological replicates are missing, FunPat is able to provide reproducible lists of significant genes. The application to real time series expression data shows the ability of FunPat to select differentially expressed genes with high reproducibility, indirectly confirming high precision and recall in gene selection. Moreover, the expression patterns obtained as output allow an easy interpretation of the results. CONCLUSIONS: A novel analysis pipeline was developed to search the main temporal patterns in classes of genes similarly annotated, improving the sensitivity of gene selection by integrating the statistical evidence of differential expression with the information on temporal profiles and the functional annotations. Significant genes are associated to both the most informative functional terms, avoiding redundancy of information, and the most representative temporal patterns, thus improving the readability of the results. FunPat package is provided in R/Bioconductor at link: http://sysbiobig.dei.unipd.it/?q=node/79. PMID- 26046294 TI - Quantum Oscillations in a Two-Dimensional Electron Gas at the Rocksalt/Zincblende Interface of PbTe/CdTe (111) Heterostructures. AB - Quantum oscillations are observed in the 2DEG system at the interface of novel heterostructures, PbTe/CdTe (111), with nearly identical lattice parameters (a(PbTe) = 0.6462 nm, a(CdTe) = 0.648 nm) but very different lattice structures (PbTe: rock salt, CdTe: zinc blende). The 2DEG formation mechanism, a mismatch in the bonding configurations of the valence electrons at the interface, is uniquely different from the other known 2DEG systems. The aberration-corrected scanning transmission electron microscope (AC-STEM) characterization indicates an abrupt interface without cation interdiffusion due to a large miscibility gap between the two constituent materials. Electronic transport measurements under magnetic field up to 60 T, with the observation of Landau level filling factor nu = 1, unambiguously reveal a pi Berry phase, suggesting the Dirac Fermion nature of the 2DEG at the heterostructure interface, and the PbTe/CdTe heterostructure being a new candidate for 2D topological crystalline insulators. PMID- 26046295 TI - De novo Assembly and Characterization of the Testis Transcriptome and Development of EST-SSR Markers in the Cockroach Periplaneta americana. AB - The cockroach Periplaneta americana is a notorious pest and threat to health worldwide, with a high reproductive ability. However, a limited amount of data is available on the developmental stage-specific transcriptomes of P. americana. To identify genes involved in developmental processes and to develop additional SSR markers in P. americana, we carried out de novo assembly of the P. americana transcriptome using Illumina sequencing. After removing low-quality sequences, we obtained 64,954,709 contigs, which were further assembled into 125,390 unigenes with an average length of 711 bp. Based on similarity searches against known proteins, we identified 48,300 unigenes based on a cut-off E-value of 10(-5). The assembled sequences were annotated according to gene descriptions, gene ontology and clusters of orthologous groups. A total of 14,195 potential SSRs were identified, and 41 of 63 randomly chosen primer pairs successfully amplified the predicted SSR markers, seven of which were polymorphic in size in P. americana. Furthermore, the Spag6 gene was confirmed to be testes specific, and the fru and RPSA genes were related to the development of the testis. This is the special report of a P. americana transcriptome obtained using Illumina sequencing technology, and a large number of molecular markers were developed. PMID- 26046296 TI - Nanostructure-Preserved Hematite Thin Film for Efficient Solar Water Splitting. AB - High-temperature annealing above 700 degrees C improves the activity of photoelectrochemical water oxidation by hematite photoanodes by increasing its crystallinity. Yet, it brings severe agglomeration of nanostructured hematite thin films and deteriorates electrical conductivity of the transparent conducting oxide (TCO) substrate. We report here that the nanostructure of the hematite and the conductivity of TCO could be preserved, while the high crystallinity is attained, by hybrid microwave annealing (HMA) utilizing a graphite susceptor for efficient microwave absorption. Thus, the hematite thin-film photoanodes treated by HMA record 2 times higher water oxidation photocurrents compared to a conventional thermal-annealed photoanode. The enhanced performance can be attributed to the synergistic effect of a smaller feature size of nanostructure preserved hematite and a good electrical conductivity of TCO. The method could be generally applied to the fabrication of efficient photoelectrodes with small feature sizes and high crystallinity, which have been mutually conflicting requirements with conventional thermal annealing processes. PMID- 26046297 TI - Acoustic duetting in Drosophila virilis relies on the integration of auditory and tactile signals. AB - Many animal species, including insects, are capable of acoustic duetting, a complex social behavior in which males and females tightly control the rate and timing of their courtship song syllables relative to each other. The mechanisms underlying duetting remain largely unknown across model systems. Most studies of duetting focus exclusively on acoustic interactions, but the use of multisensory cues should aid in coordinating behavior between individuals. To test this hypothesis, we develop Drosophila virilis as a new model for studies of duetting. By combining sensory manipulations, quantitative behavioral assays, and statistical modeling, we show that virilis females combine precisely timed auditory and tactile cues to drive song production and duetting. Tactile cues delivered to the abdomen and genitalia play the larger role in females, as even headless females continue to coordinate song production with courting males. These data, therefore, reveal a novel, non-acoustic, mechanism for acoustic duetting. Finally, our results indicate that female-duetting circuits are not sexually differentiated, as males can also produce 'female-like' duets in a context-dependent manner. PMID- 26046298 TI - An alternative to force. AB - Researchers have discovered a synthetic small molecule that activates a mechanosensitive ion channel involved in a blood disorder. PMID- 26046299 TI - Place memory and dementia: Findings from participatory film-making in long-term social care. AB - A participatory film-making study carried out in long-term social care with 10 people with Alzheimer-type dementia found that places the participants had known early in life were spontaneously foregrounded. Participants' memories of such places were well-preserved, particularly when photo-elicitation techniques, using visual images as prompts, were employed. Consistent with previous work on the 'reminiscence bump' in dementia, the foregrounded memories belonged in all cases to the period of life between approximately 5 and 30 years. Frequently the remembered places were connected with major life events which continued to have a strong emotional component. The continuing significance of place in the context of long-term dementia care is considered from a psychogeographical perspective. PMID- 26046300 TI - Chronic Cocaine Use Causes Changes in the Striatal Proteome Depending on the Endogenous Expression of Pleiotrophin. AB - The neurotrophic factor pleiotrophin (PTN) is upregulated in different brain areas after the administration of different drugs of abuse, including psychostimulants. PTN has been shown to prevent cocaine-induced cytotoxicity in NG108-15 and PC12 cells. We previously demonstrated that specific phosphoproteins related to neurodegeneration processes are differentially regulated in the mouse striatum by a single cocaine (15 mg/kg) administration depending on the endogenous expression of PTN. Since neurodegenerative processes are usually observed in patients exposed to toxicants for longer duration, we have now performed a striatal proteomic study using samples enriched in phosphorylated proteins from PTN knockout (PTN-/-) mice, from mice with transgenic PTN overexpression (PTN-Tg) in the brain, and from wild type (WT) mice after a chronic treatment with cocaine (15 mg/kg/day for 7 days). We have successfully identified 23 proteins significantly affected by chronic cocaine exposure, genotype, or both. Most of these proteins, including peroxiredoxin-6 (PRDX6), triosephosphate isomerase (TPI1), ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1), and annexins A5 (ANXA5) and A7 (ANXA7), may be of significant importance because they were previously identified in proteomic studies in animals treated with psychostimulants and/or because they are related to neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease. The data support a protective role of PTN against chronic cocaine-induced neural alterations. PMID- 26046301 TI - Rice potassium transporter OsHAK1 is essential for maintaining potassium-mediated growth and functions in salt tolerance over low and high potassium concentration ranges. AB - Potassium (K) absorption and translocation in plants rely upon multiple K transporters for adapting varied K supply and saline conditions. Here, we report the expression patterns and physiological roles of OsHAK1, a member belonging to the KT/KUP/HAK gene family in rice (Oryza sativa L.). The expression of OsHAK1 is up-regulated by K deficiency or salt stress in various tissues, particularly in the root and shoot apical meristem, the epidermises and steles of root, and vascular bundles of shoot. Both oshak1 knockout mutants in comparison to their respective Dongjin or Manan wild types showed a dramatic reduction in K concentration and stunted root and shoot growth. Knockout of OsHAK1 reduced the K absorption rate of unit root surface area by ~50-55 and ~30%, and total K uptake by ~80 and ~65% at 0.05-0.1 and 1 mm K supply level, respectively. The root net high-affinity K uptake of oshak1 mutants was sensitive to salt stress but not to ammonium supply. Overexpression of OsHAK1 in rice increased K uptake and K/Na ratio. The positive relationship between K concentration and shoot biomass in the mutants suggests that OsHAK1 plays an essential role in K-mediated rice growth and salt tolerance over low and high K concentration ranges. PMID- 26046302 TI - Polo-like kinase 1 inhibition sensitizes neuroblastoma cells for vinca alkaloid induced apoptosis. AB - High polo-like kinase 1 (PLK1) expression has been linked to poor outcome in neuroblastoma (NB), indicating that it represents a relevant therapeutic target in this malignancy. Here, we identify a synergistic induction of apoptosis by the PLK1 inhibitor BI 2536 and vinca alkaloids in NB cells. Synergistic drug interaction of BI 2536 together with vincristine (VCR), vinblastine (VBL) or vinorelbine (VNR) is confirmed by calculation of combination index (CI). Also, BI 2536 and VCR act in concert to reduce long-term clonogenic survival. Importantly, BI 2536 significantly enhances the antitumor activity of VCR in an in vivo model of NB. Mechanistically, BI 2536/VCR co-treatment triggers prolonged mitotic arrest, which is necessary for BI 2536/VCR-mediated apoptosis, since pharmacological inhibition of mitotic arrest by the CDK1 inhibitor RO-3306 significantly reduces cell death. Prolonged mitotic arrest leads to phosphorylation-mediated inactivation of BCL-2 and BCL-XL as well as downregulation of MCL-1, since inhibition of mitotic arrest by RO-3306 also prevents phosphorylation of BCL-2 and BCL-XL and MCL-1 downregulation. This inactivation of antiapoptotic BCL-2 proteins promotes activation of BAX and BAK, cleavage of caspase-9 and -3 and caspase-dependent apoptosis. Engagement of the mitochondrial pathway of apoptosis is critically required for BI 2536/VCR-induced apoptosis, since ectopic expression of a non-degradable MCL-1 phospho-mutant, BCL 2 overexpression or BAK knockdown significantly reduce BI 2536/VCR-mediated apoptosis. Thus, PLK1 inhibitors may open new perspectives for chemosensitization of NB. PMID- 26046303 TI - Rapamycin inhibits Erk1/2-mediated neuronal apoptosis caused by cadmium. AB - Cadmium (Cd), an environmental contaminant, causes neurodegenerative disorders. Recently we have shown that rapamycin prevents Cd-induced neuronal cell death by inhibiting mTOR signaling pathway. Here we found that rapamycin exerted its prevention against Cd-induced neuronal cell death also partially via blocking Erk1/2 pathway. Inhibiting Erk1/2 with PD98059 or silencing Erk1/2 potentiated rapamycin's inhibition of Cd-induced phosphorylation of Erk1/2 and apoptosis in neuronal cells. Both PP2A and PTEN/Akt were involved in the regulation of Erk1/2 activation and cell death triggered by Cd. Inhibition of PP2A with okadaic acid or ectopic expression of dominant negative PP2A attenuated rapamycin's inhibition of Cd-induced phospho-Erk1/2 and apoptosis, whereas over-expression of wild-type PP2A enhanced rapamycin's effects; Over-expression of wild-type PTEN or dominant negative Akt, or inhibition of Akt with Akt inhibitor X strengthened rapamycin's inhibition of Cd-induced phospho-Erk1/2 and cell death. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T) blocked rapamycin's inhibitory effects on Cd-induced inhibition of PP2A, down-regulation of PTEN, and activation of Akt, leading to Erk1/2 activation and cell death, whereas silencing mTOR mimicked rapamycin's effects. The results uncover that rapamycin inhibits Cd activation of Erk1/2-mediated neuronal apoptosis through intervening mTOR PP2A/PTEN signaling network. PMID- 26046305 TI - Does the Relative Strength of Grouping Principles Modulate the Interactions between them? AB - This study examines the influence of the relative strength of grouping principles on interactions between the intrinsic principle of proximity and the extrinsic principle of common region in the process of perceptual organization. Cooperation and competition between intrinsic and extrinsic principles were examined by presenting the principle either alone or conjoined with another principle. The relative grouping strength of the principles operating alone was varied in two different groups of participants so that it was similar for one group and very different for the other group. Results showed that, when principles acting alone had different strengths, the grouping effect of the strongest principle was similar to that of the cooperation condition, and the effect of the weakest principle was similar to that of competing conjoined principles. In contrast, when the strength of principles acting alone was similar, the effect of conjoined cooperating principles was greater than that of either principle acting alone. Moreover, the effect of conjoined competing principles was smaller than that of either principle operating alone. Results show that cooperation and competition between intrinsic and extrinsic principles are modulated by the relative grouping strength of principles acting alone. Furthermore, performance in these conditions could be predicted on the basis of performance in single-principle conditions. PMID- 26046304 TI - Targeted DNA and RNA sequencing of fine-needle biopsy FFPE specimens in patients with unresectable hepatocellular carcinoma treated with sorafenib. AB - The multi-kinase inhibitor sorafenib is now used as standard therapy for advanced hepatocellular carcinoma (HCC). Predictive biomarkers of response to sorafenib are thus necessary. The purpose of this study was to assess the feasibility of using targeted DNA and RNA sequencing to elucidate candidate biomarkers of sorafenib response using fine-needle biopsy, formalin-fixed paraffin-embedded (FFPE) specimens in patients with HCC. Targeted DNA and RNA deep sequencing were feasible for the evaluation of fine-needle biopsy FFPE specimens obtained from 46 patients with HCC treated with sorafenib. Frequent mutations of suppressor genes, such as CTNNB1 (34.8%) and TP53 (26.1%), were detected in the HCC tumors. After excluding these suppressor genes, the average numbers of detected oncogene mutations differed significantly between the non-PD and PD groups (P = 0.0446). This result suggests that the oncogene mutational burden in the tumor might be associated with the clinical response to sorafenib. We have identified candidate gene expression (TGFa, PECAM1, and NRG1) in tumor for the prediction of sorafenib response and PFS by RNA sequencing. Our findings provide new insights into biomarkers for sorafenib therapy and allow us to discuss future therapeutic strategies. PMID- 26046306 TI - Discrepancies in recommended criteria for grading of carotid stenosis with ultrasound. AB - The accuracy of duplex ultrasound for grading of internal carotid artery stenosis has been widely tested and shown to be high. However, different methods for measurement of the degree of carotid stenosis with the golden standard conventional angiography have been used in the different studies. This, together with other factors, has led to some confusion regarding the relation between the ultrasonographically measured flow velocity and the angiographically measured degree of stenosis. The ultrasound criteria that are used in Sweden (and in Germany) differ in an important way from the criteria recommended in North America and the United Kingdom for the same degree of angiographic stenoses. Possible reasons for the discrepancies are discussed in this article. The authors recommend absolute agreement locally whether ECST or NASCET criteria shall be used in the communication between radiologists, clinical physiologists, vascular surgeons, neurologists and other physicians involved in patient management decisions. Angle-dependent ultrasound criteria should be used and flow velocity measurements with ultrasound should be combined with assessment of plaque burden on 2D picture. PMID- 26046308 TI - Breastfeeding and the Risk of Ovarian Cancer: A Meta-Analysis. PMID- 26046307 TI - Itch and brain. AB - Itch is an unpleasant somatic sensation that evokes the urge to scratch. Chronic itch is a severe problem that diminishes quality of life. There are many patients suffering from chronic itch across the world. The brain is the final terminal to receive itch-related signals from the body and plays an important role in perceiving the itch sensation. Thus, to understand the cerebral mechanism of itch perception and how this mechanism differs between healthy subjects and chronic itch patients is important for advancing our understanding on the pathophysiology of chronic itch. Itch is suppressed by scratching or applying painful stimuli. The pleasurable sensation evoked by scratching an itch increases the urge to scratch. Viewing others in itch or imagining the itch sensation may evoke real itch sensations and the scratching response. To understand the mechanisms responsible for these phenomena may provide useful information for the development of treatment of itch and advance our understanding of the cerebral mechanism of itch and scratch. Several functional brain imaging studies have addressed these issues and reported interesting findings. In this review article, the authors discussed the findings of previous studies and how they have advanced our understanding of the central mechanisms of itch, scratch and chronic itch. PMID- 26046309 TI - Assessment of environmental data quality and its effect on modelling error of full-scale plants with a closed-loop mass balancing. AB - Environmental plants are notorious for poor data quality and sensor reliability due to the hostile environment in which the measurement equipment has to function, where the measurements and flow rate equipment in plants must be mutually consistent. The aim of this study is to detect any error in the measured data in an environmental plant and reconcile the data with some gross errors by using a closed data reconciliation of mass balance and the Lagrange multiplier method. A data reconciliation method based on closed-loop mass balance is suggested in order to reduce or remove error within data and obtain reliable process data. The proposed method is applied to a full-scale plant to detect the gross error in measured data, investigate the effects of erroneous data on modelling errors and compare the modelling performances of the faulty data and reconciled data. The results show that the proposed method can efficiently detect any gross error in data, estimate the error-free data by a reconciliation method and enhance the modelling accuracy by using reconciled data. This study provides a simple way to incorporate prior knowledge of plant modelling of a closed-loop mass balancing to identify any gross error and reconcile the faulty measurements. PMID- 26046310 TI - Infectious Bursal Disease Virus non-structural protein VP5 is not a transmembrane protein. AB - Infectious Bursal Disease Virus (IBDV) causes a highly relevant poultry disease that affects young chickens causing, among other effects, immunosuppression. IBDV is a bi-segmented double stranded RNA virus. The smaller ORF of larger RNA segment encodes VP5, a 17-kDa non-structural protein. Although it is an important protein for viral replication cycle, the definition of its specific role and subcellular localization remains unclear. In the present work we demonstrate, using imaging techniques, that VP5 is not a type II transmembrane protein but an intracellular membrane-associated protein. This finding might provide evidences of VP5 interaction with cellular proteins and its functions. PMID- 26046311 TI - QSAR Modeling Using Large-Scale Databases: Case Study for HIV-1 Reverse Transcriptase Inhibitors. AB - Large-scale databases are important sources of training sets for various QSAR modeling approaches. Generally, these databases contain information extracted from different sources. This variety of sources can produce inconsistency in the data, defined as sometimes widely diverging activity results for the same compound against the same target. Because such inconsistency can reduce the accuracy of predictive models built from these data, we are addressing the question of how best to use data from publicly and commercially accessible databases to create accurate and predictive QSAR models. We investigate the suitability of commercially and publicly available databases to QSAR modeling of antiviral activity (HIV-1 reverse transcriptase (RT) inhibition). We present several methods for the creation of modeling (i.e., training and test) sets from two, either commercially or freely available, databases: Thomson Reuters Integrity and ChEMBL. We found that the typical predictivities of QSAR models obtained using these different modeling set compilation methods differ significantly from each other. The best results were obtained using training sets compiled for compounds tested using only one method and material (i.e., a specific type of biological assay). Compound sets aggregated by target only typically yielded poorly predictive models. We discuss the possibility of "mix and-matching" assay data across aggregating databases such as ChEMBL and Integrity and their current severe limitations for this purpose. One of them is the general lack of complete and semantic/computer-parsable descriptions of assay methodology carried by these databases that would allow one to determine mix-and matchability of result sets at the assay level. PMID- 26046312 TI - Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors. AB - A novel series of 4-alkynyl-quinoline derivatives were designed, synthesized and biologically evaluated for their PI3Kalpha inhibitory activities and anti proliferative effects against two cancer cell lines PC-3 and HCT-116. Most of them showed potent PI3Kalpha inhibitory activities with IC50 values at low nanomolar level and good to excellent anti-proliferative effects against both cell lines. Among them, compound 15d, the most potent one, was selected for further biological evaluation. As a result, 15d displayed strong inhibitory activity against other class I PI3K isoforms (PI3Kbeta, PI3Kgamma and PI3Kdelta) and mTOR with an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that the phosphorylation of Akt, another downstream effector of PI3K, can be remarkably suppressed by 15d at cellular level. All these experimental results suggested that 15d is a potent PI3K/mTOR dual inhibitor and could serve as a promising lead compound for the development of anticancer agents. PMID- 26046313 TI - Design, synthesis and biological evaluation of novel 5-oxo-2-thioxoimidazolidine derivatives as potent androgen receptor antagonists. AB - A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2 (trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency. PMID- 26046314 TI - Diosgenin-based thio(seleno)ureas and triazolyl glycoconjugates as hybrid drugs. Antioxidant and antiproliferative profile. AB - The stereoselective preparation of diosgenin-derived thio(seleno)ureas and glycomimetics bearing a 1,2,3-triazolyl tether on C-3 has been accomplished. The key steps in the synthetic pathway are the incorporation of an amino moiety and its further transformation into thio- and selenoureas, and also a click chemistry reaction involving a propargyl residue and an azido moiety to afford carbohydrate derived 1,2,3-triazoles; subsequent BF3-promoted acetolysis of the spiranic moiety afforded the corresponding 22-oxocholestanic structure. The N-phenyl selenourea, an hitherto unknown steroidal derivative, turned out to be a potent ROS scavenger, in particular against free radicals (EC50 = 29.47 +/- 2.33 MUM, DPPH method), and as a glutathione peroxidase mimic in the elimination of H2O2 (t1/2 = 4.8 min, 1% molar ratio). 22-Oxocholestane structures bearing a C-3 azido, propargyl, thioureido, and particularly selenoureido moiety behaved as strong antiproliferative agents against HeLa cells (IC50 1.87-11.80 MUM). N phenyl selenourea also exhibited IC50 values lower than 6.50 MUM for MDA-MB-231, MCF-7 and HepG2 cancer cells; apoptosis was found to be involved in its mode of action. Such compound was also capable of efficiently eliminating ROS endogenously produced by HeLa cells. Antiproliferative properties of thioxo and selenoxo derivatives were stronger than diosgenin. PMID- 26046315 TI - Genetic variants in 3'-UTRs of methylenetetrahydrofolate reductase (MTHFR) predict colorectal cancer susceptibility in Koreans. AB - Polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) play important roles in tumor development, progression, and metastasis. Moreover, recent studies have reported that a number of 3'-UTR polymorphisms potentially bind to specific microRNAs in a variety of cancers. The aim of this study was to investigate the association of four MTHFR polymorphisms, 2572C>A [rs4846049], 4869C>G [rs1537514], 5488C>T [rs3737967], and 6685T>C [rs4846048] with colorectal cancer (CRC) in Koreans. A total of 850 participants (450 CRC patients and 400 controls) were enrolled in the study. The genotyping of MTHFR 3'-UTR polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis or TaqMan allelic discrimination assay. We found that MTHFR 2572C>A, 4869C>G, and 5488C>T genotypes were substantially associated with CRC susceptibility. Of the potentially susceptible polymorphisms, MTHFR 2572C>A was associated with increased homocysteine and decreased folate levels in the plasma based on MTHFR 677CC. Our study provides the evidences for 3'-UTR variants in MTHFR gene as potential biomarkers for use in CRC prevention. PMID- 26046316 TI - Metallic nanocrystallites-incorporated ordered mesoporous carbon as labels for a sensitive simultaneous multianalyte electrochemical immunoassay. AB - This work reports on a facile, novel multianalyte electrochemical immunoassay for simultaneous detection of a-fetoprotein (AFP) and human epidermal growth factor receptor type-2 (HER-2) using metal-containing nanomaterials confined in the ordered mesoporous carbon matrix (OMC-M) as labels. Well-dispersed uniform metallic nanocrystallites incorporated OMC materials were fabricated through a simple, economical, and green preparative strategy toward phenolic resol as a carbon source and metal nitrate as metal sources. The large amount of metallic nanocrystallites loading on the OMC nanomaterials, greatly amplified the detection signals, and the good biocompatibility of carbon nanotubes-chitosan retained excellent stability for the sandwich-type immunoassay. Under optimal experimental conditions, the proposed immunoassay exhibited high sensitivity and selectivity for the detection of analytes, providing a better linear response range from 0.001 to 150 ng/mL for AFP and for HER-2, with a lower limit of detectionof 0.6p g/mL and 0.35 pg/mL (S/N=3), respectively. The immunosensor exhibited convenience, low cost, rapidity, good specificity, acceptable stability and reproducibility. Moreover, satisfactory results were obtained for the determination of AFP and HER-2 in real human serum samples, indicating that the developed immunoassay has the potential to find application in clinical detection of AFP and HER-2 and other tumor markers as an alternative approach. PMID- 26046317 TI - Noninvasive imaging of sialyltransferase activity in living cells by chemoselective recognition. AB - To elucidate the biological and pathological functions of sialyltransferases (STs), intracellular ST activity evaluation is necessary. Focusing on the lack of noninvasive methods for obtaining the dynamic activity information, this work designs a sensing platform for in situ FRET imaging of intracellular ST activity and tracing of sialylation process. The system uses tetramethylrhodamine isothiocyanate labeled asialofetuin (TRITC-AF) as a ST substrate and fluorescein isothiocyanate labeled 3-aminophenylboronic acid (FITC-APBA) as the chemoselective recognition probe of sialylation product, both of which are encapsulated in a liposome vesicle for cellular delivery. The recognition of FITC APBA to sialylated TRITC-AF leads to the FRET signal that is analyzed by FRET efficiency images. This strategy has been used to evaluate the correlation of ST activity with malignancy and cell surface sialylation, and the sialylation inhibition activity of inhibitors. This work provides a powerful noninvasive tool for glycan biosynthesis mechanism research, cancer diagnostics and drug development. PMID- 26046318 TI - Fabrication of solid-state nanopores and its perspectives. AB - Nanofluidics is becoming an extensively developing technique in the field of bioanalytical chemistry. Nanoscale hole embed in an insulating membrane is employed in a vast variety of sensing platforms and applications. Although, biological nanopores have several attractive characteristics, in this paper, we focused on the solid-state nanopores due to their advantages as high stability, possibility of diameter control, and ease of surface functionalizing. A detection method, based on the translocation of analyzed molecules through nanochannels under applied voltage bias and resistive pulse sensing, is well established. Nevertheless, it seems that the new detection methods like measuring of transverse electron tunneling using nanogap electrodes or optical detection can offer significant additional advantages. The aim of this review is not to cite all related articles, but highlight the steps, which in our opinion, meant important progresses in solid-state nanopore analysis. PMID- 26046319 TI - Synthesis of a Novel Cysteine-Incorporated Anthraquinone Derivative and Its Structural Properties. AB - A novel cysteine-incorporated anthraquinone derivative was synthesized, and its molecular structure was determined by X-ray crystal analysis. Each mercapto group was located separately and did not form a disulfide bond, and hydrogen bondings and pi-pi interaction were observed from the packing structure. PMID- 26046320 TI - Developments in Synthetic Application of Selenium(IV) Oxide and Organoselenium Compounds as Oxygen Donors and Oxygen-Transfer Agents. AB - A variety of selenium compounds were proven to be useful reagents and catalysts for organic synthesis over the past several decades. The most interesting aspect, which emerged in recent years, concerns application of hydroperoxide/selenium(IV) oxide and hydroperoxide/organoselenium catalyst systems, as "green reagents" for the oxidation of different organic functional groups. The topic of oxidations catalyzed by organoselenium derivatives has rapidly expanded in the last fifteen years This paper is devoted to the synthetic applications of the oxidation reactions mediated by selenium compounds such as selenium(IV) oxide, areneseleninic acids, their anhydrides, selenides, diselenides, benzisoselenazol 3(2H)-ones and other less often used other organoselenium compounds. All these compounds have been successfully applied for various oxidations useful in practical organic syntheses such as epoxidation, 1,2-dihydroxylation, and alpha oxyfunctionalization of alkenes, as well as for ring contraction of cycloalkanones, conversion of halomethyl, hydroxymethyl or active methylene groups into formyl groups, oxidation of carbonyl compounds into carboxylic acids and/or lactones, sulfides into sulfoxides, and secondary amines into nitrones and regeneration of parent carbonyl compounds from their azomethine derivatives. Other reactions such as dehydrogenation and aromatization, active carbon-carbon bond cleavage, oxidative amidation, bromolactonization and oxidation of bromide for subsequent reactions with alkenes are also successfully mediated by selenium (IV) oxide or organoselenium compounds. The oxidation mechanisms of ionic or free radical character depending on the substrate and oxidant are discussed. Coverage of the literature up to early 2015 is provided. Links have been made to reviews that summarize earlier literature and to the methods of preparation of organoselenium reagents and catalysts. PMID- 26046321 TI - Effect of Methoxy Substituents on the Activation Barriers of the Glutathione Peroxidase-Like Mechanism of an Aromatic Cyclic Seleninate. AB - Density functional theory (DFT) models including explicit water molecules have been used to model the redox scavenging mechanism of aromatic cyclic seleninates. Experimental studies have shown that methoxy substitutions affect the rate of scavenging of reactive oxygen species differently depending upon the position. Activities are enhanced in the para position, unaffected in the meta, and decreased in the ortho. DFT calculations show that the activation barrier for the oxidation of the selenenyl sulfide, a proposed key intermediate, is higher for the ortho methoxy derivative than for other positions, consistent with the low experimental conversion rate. PMID- 26046322 TI - Synthesis of Phospholipid-Protein Conjugates as New Antigens for Autoimmune Antibodies. AB - Copper(I)-catalyzed azide-alkyne cycloaddition, or CuAAC click chemistry, is an efficient method for bioconjugation aiming at chemical and biological applications. Herein, we demonstrate how the CuAAC method can provide novel phospholipid-protein conjugates with a high potential for the diagnostics and therapy of autoimmune conditions. In doing this, we, for the first time, covalently bind via 1,2,3-triazole linker biologically complementary molecules, namely phosphoethanol amine with human beta2-glycoprotein I and prothrombin. The resulting phospholipid-protein conjugates show high binding affinity and specificity for the autoimmune antibodies against autoimmune complexes. Thus, the development of this work might become a milestone in further diagnostics and therapy of autoimmune diseases that involve the production of autoantibodies against the aforementioned phospholipids and proteins, such as antiphospholipid syndrome and systemic lupus erythematosus. PMID- 26046323 TI - Sevoflurane-Sulfobutylether-beta-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies. AB - The objective of the present investigation was to study the ability of sulfobutylether-beta-cyclodextrin (SBEbetaCD) to form an inclusion complex with sevoflurane (SEV), a volatile anesthetic with poor water solubility. The inclusion complex was prepared, characterized and its cellular toxicity and blood brain barrier (BBB) permeation potential of the formulated SEV have also been examined for the purpose of controlled drug delivery. The SEV-SBEbetaCD complex was nontoxic to the primary brain microvascular endothelial (pEND) cells at a clinically relevant concentration of sevoflurane. The inclusion complex exhibited significantly higher BBB permeation profiles as compared with the reference substance (propranolol) concerning calculated apparent permeability values (Papp). In addition, SEV binding affinity to SBEbetaCD was confirmed by a minimal Gibbs free energy of binding (DeltaGbind) value of -1.727 +/- 0.042 kcal.mol-1 and an average binding constant (Kb) of 53.66 +/- 9.24 mM indicating rapid drug liberation from the cyclodextrin amphiphilic cavity. PMID- 26046324 TI - gamma-Tocotrienol and 6-Gingerol in Combination Synergistically Induce Cytotoxicity and Apoptosis in HT-29 and SW837 Human Colorectal Cancer Cells. AB - Numerous bioactive compounds have cytotoxic properties towards cancer cells. However, most studies have used single compounds when bioactives may target different pathways and exert greater cytotoxic effects when used in combination. Therefore, the objective of this study was to determine the anti-proliferative effect of gamma-tocotrienol (gamma-T3) and 6-gingerol (6G) in combination by evaluating apoptosis and active caspase-3 in HT-29 and SW837 colorectal cancer cells. MTS assays were performed to determine the anti-proliferative and cytotoxicity effect of gamma-T3 (0-150 ug/mL) and 6G (0-300 ug/mL) on the cells. The half maximal inhibitory concentration (IC50) value of 6G+ gamma-T3 for HT-29 was 105 + 67 ug/mL and for SW837 it was 70 + 20 ug/mL. Apoptosis, active caspase 3 and annexin V FITC assays were performed after 24 h of treatment using flow cytometry. These bioactives in combination showed synergistic effect on HT-29 (CI: 0.89 +/- 0.02,) and SW837 (CI: 0.79 +/- 0.10) apoptosis was increased by 21.2% in HT-29 and 55.4% in SW837 (p < 0.05) after 24 h treatment, while normal hepatic WRL-68 cells were unaffected. Increased apoptosis by the combined treatments was also observed morphologically, with effects like cell shrinkage and pyknosis. In conclusion, although further studies need to be done, gamma-T3 and 6G when used in combination act synergistically increasing cytotoxicity and apoptosis in cancer cells. PMID- 26046325 TI - An Effective Quality Control of Pharmacologically Active Volatiles of Houttuynia cordata Thunb by Fast Gas Chromatography-Surface Acoustic Wave Sensor. AB - Fast gas chromatography-surface acoustic wave sensor (GC/SAW) has been applied for the detection of the pharmacological volatiles emanated from Houttuynia cordata Thunb which is from South Korea. H. cordata Thunb with unpleasant and fishy odors shows a variety of pharmacological activities such as anti-microbial, anti-inflammatory, anti-cancer, and insect repellent. The aim of this study is to show a novel quality control by GC/SAW methodology for the discrimination of the three different parts of the plant such as leaves, aerial stems, and underground stems for H. cordata Thunb. Sixteen compounds were identified. beta-Myrcene, cis ocimene and decanal are the dominant volatiles for leaves (71.0%) and aerial stems (50.1%). While, monoterpenes (74.6%) are the dominant volatiles for underground stems. 2-Undecanone (1.3%) and lauraldehyde (3.5%) were found to be the characteristic components for leaves. Each part of the plant has its own characteristic fragrance pattern owing to its individual chemical compositions. Moreover, its individual characteristic fragrance patterns are conducive to discrimination of the three different parts of the plant. Consequently, fast GC/SAW can be a useful analytical method for quality control of the different parts of the plant with pharmacological volatiles as it provides second unit analysis, a simple and fragrant pattern recognition. PMID- 26046328 TI - Erratum. PMID- 26046327 TI - Myostatin Gene Polymorphism in an Elderly Sarcopenic Turkish Population. AB - INTRODUCTION: One of the genetic contributors to sarcopenia predisposition is Myostatin (MSTN), which in humans encodes myostatin, a 376 amino acid growth factor protein that negatively regulates muscle growth. The aim of this study was to investigate MSTN polymorphisms in an elderly sarcopenic population in Turkey and determine how they relate to sarcopenia. MATERIALS AND METHODS: The study included nursing home residents who were aged >=65 years. Sarcopenia screening was performed using "The European Working Group on Sarcopenia in Older People" guidelines. Blood sample was taken from each participant and DNA was obtained from the peripheral blood. MSTN polymorphisms were genotyped by polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: A total of 152 elderly patients were included in the study. The rate of sarcopenia was determined to be 41.4%. The DNA nucleotide sequence of all three MSTN exons was determined for each study participant. Among the 152 patients, only 6 (3.9%) showed an MSTN K153R heterozygous mutation. Among these, three participants were sarcopenic and three were nonsarcopenic. No statistically significant difference in the polymorphism frequency between the sarcopenic and control groups was observed (p=0.664). CONCLUSIONS: MSTN genotyping revealed that only 3.9% (6/152) of participants had the MSTN K153R heterozygous mutation. Despite the detection of this mutation in the study group, no relationship was found between this mutation and sarcopenia. PMID- 26046326 TI - Neonatal regulatory T cells have reduced capacity to suppress dendritic cell function. AB - Regulatory T cells (Treg cells) limit contact between dendritic cells (DCs) and conventional T cells (Tcons), decreasing the formation of aggregates as well as down-modulating the expression of co-stimulatory molecules by DCs, thus decreasing DC immunogenicity and abrogating T-cell activation. Despite the importance of this Treg-cell function, the capacity of Treg cells from term and preterm neonates to suppress DCs, and the suppressive mechanisms they use, are still undefined. We found that, relative to adult Treg cells, activated Treg cells from human neonates expressed lower FOXP3 and CTLA-4, but contained higher levels of cAMP. We developed an in vitro model in which Treg function was measured at a physiological ratio of 1 Treg for 10 Tcon and 1 monocyte-derived DC, as Treg target. Term and preterm Treg cells failed to suppress the formation of DC-Tcon aggregates, in contrast to naive and memory Treg cells from adults. However, neonatal Treg cells diminished DC and Tcon activation as well as actin polymerization at the immunological synapses. In addition, CTLA-4 and cAMP were the main suppressive molecules used by neonatal Treg. Altogether, both preterm and term neonatal Treg cells appear less functional than adult Treg cells, and this defect is consistent with the general impairment of CD4 cell function in newborns. PMID- 26046329 TI - Hypertension-Management of Hypertensive Disorders of Pregnancy According to International Guidelines: A Panel Discussion (Case 5: Postpartum Eclampsia). PMID- 26046330 TI - The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice. AB - Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2(-/-) mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down regulation of Egr1-p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes. PMID- 26046331 TI - DNA double-strand breaks alter the spatial arrangement of homologous loci in plant cells. AB - Chromatin dynamics and arrangement are involved in many biological processes in nuclei of eukaryotes including plants. Plants have to respond rapidly to various environmental stimuli to achieve growth and development because they cannot move. It is assumed that the alteration of chromatin dynamics and arrangement support the response to these stimuli; however, there is little information in plants. In this study, we investigated the chromatin dynamics and arrangement with DNA damage in Arabidopsis thaliana by live-cell imaging with the lacO/LacI-EGFP system and simulation analysis. It was revealed that homologous loci kept a constant distance in nuclei of A. thaliana roots in general growth. We also found that DNA double-strand breaks (DSBs) induce the approach of the homologous loci with gamma-irradiation. Furthermore, AtRAD54, which performs an important role in the homologous recombination repair pathway, was involved in the pairing of homologous loci with gamma-irradiation. These results suggest that homologous loci approach each other to repair DSBs, and AtRAD54 mediates these phenomena. PMID- 26046332 TI - Signal honesty and predation risk among a closely related group of aposematic species. AB - Many animals have bright colours to warn predators that they have defences and are not worth attacking. However, it remains unclear whether the strength of warning colours reliably indicate levels of defence. Few studies have unambiguously established if warning signals are honest, and have rarely considered predator vision or conspicuousness against the background. Importantly, little data exists either on how differences in signal strength translate into survival advantages. Ladybirds exhibit impressive variation in coloration both among and within species. Here we demonstrate that different levels of toxicity exist among and within ladybird species, and that signal contrast against the background is a good predictor of toxicity, showing that the colours are honest signals. Furthermore, field experiments with ladybird models created with regards to predator vision show that models with lower conspicuousness were attacked more frequently. This provides one of the most comprehensive studies on signal honesty in warning coloration to date. PMID- 26046333 TI - Microbial physiology and soil CO2 efflux after 9 years of soil warming in a temperate forest - no indications for thermal adaptations. AB - Thermal adaptations of soil microorganisms could mitigate or facilitate global warming effects on soil organic matter (SOM) decomposition and soil CO2 efflux. We incubated soil from warmed and control subplots of a forest soil warming experiment to assess whether 9 years of soil warming affected the rates and the temperature sensitivity of the soil CO2 efflux, extracellular enzyme activities, microbial efficiency, and gross N mineralization. Mineral soil (0-10 cm depth) was incubated at temperatures ranging from 3 to 23 degrees C. No adaptations to long-term warming were observed regarding the heterotrophic soil CO2 efflux (R10 warmed: 2.31 +/- 0.15 MUmol m(-2) s(-1) , control: 2.34 +/- 0.29 MUmol m(-2) s( 1) ; Q10 warmed: 2.45 +/- 0.06, control: 2.45 +/- 0.04). Potential enzyme activities increased with incubation temperature, but the temperature sensitivity of the enzymes did not differ between the warmed and the control soils. The ratio of C : N acquiring enzyme activities was significantly higher in the warmed soil. Microbial biomass-specific respiration rates increased with incubation temperature, but the rates and the temperature sensitivity (Q10 warmed: 2.54 +/- 0.23, control 2.75 +/- 0.17) did not differ between warmed and control soils. Microbial substrate use efficiency (SUE) declined with increasing incubation temperature in both, warmed and control, soils. SUE and its temperature sensitivity (Q10 warmed: 0.84 +/- 0.03, control: 0.88 +/- 0.01) did not differ between warmed and control soils either. Gross N mineralization was invariant to incubation temperature and was not affected by long-term soil warming. Our results indicate that thermal adaptations of the microbial decomposer community are unlikely to occur in C-rich calcareous temperate forest soils. PMID- 26046334 TI - Herbicide toxicity on river biofilms assessed by pulse amplitude modulated (PAM) fluorometry. AB - The use of Rapid light curves (RLCs) as a toxicity endpoint for river biofilms was examined in this study and compared to "classical fluorescence parameters" i.e. minimal fluorescence (F0), optimal and effective quantum yields of photosystem II (Fv/Fm and FPSII). Measurements were performed after exposure to five concentrations of diuron (from 0.3 to 33.4MUgL(-1)), its main degradation product (DCPMU) (from 1.0 to 1014MUgL(-1)) and norflurazon (from 0.6 to 585MUgL( 1)) with the lowest exposure concentrations corresponding to levels regularly encountered in chronically contaminated sites. Biofilm responses were evaluated after 1, 5, 7 and 14 days of exposure to the different toxicants. Overall, the responses of both "classical fluorescence parameters" and RLC endpoints were highly time dependent and related to the mode of action of the different compounds. Interestingly, parameters calculated from RLCs (alpha, ETRmax and Ik) were useful early markers of pesticide exposure since they revealed significant effects of all the tested toxicants from the first day of exposure. In comparison, classical fluorescence endpoints (F0 and Fv/Fm) measured at day 1 were only affected in the DCPMU treatment. Our results demonstrated the interest of RLCs as early markers of toxicant exposure particularly when working with toxicants with less specific mode of action than PSII inhibitors. PMID- 26046335 TI - Inverse colloidal crystal membranes for hydrophobic interaction membrane chromatography. AB - Hydrophobic interaction membrane chromatography has gained interest due to its excellent performance in the purification of humanized monoclonal antibodies. The membrane material used in hydrophobic interaction membrane chromatography has typically been commercially available polyvinylidene fluoride. In this contribution, newly developed inverse colloidal crystal membranes that have uniform pores, high porosity and, therefore, high surface area for protein binding are used as hydrophobic interaction membrane chromatography membranes for humanized monoclonal antibody immunoglobulin G purification. The capacity of the inverse colloidal crystal membranes developed here is up to ten times greater than commercially available polyvinylidene fluoride membranes with a similar pore size. This work highlights the importance of developing uniform pore size high porosity membranes in order to maximize the capacity of hydrophobic interaction membrane chromatography. PMID- 26046336 TI - Psychosis Prevention: A Modified Clinical High Risk Perspective From the Recognition and Prevention (RAP) Program. AB - OBJECTIVE: Early intervention and prevention of psychosis remain a major challenge. Prediction would be greatly advanced with improved ability to identify individuals at true risk, which, at present, is moderate at best. The authors tested a modified strategy to improve prediction by selecting a more homogeneous high-risk sample (attenuated positive symptom criteria only, age range of mid teens to early 20s) than is currently standard, combined with a systematic selection of neurodevelopmental deficits. METHOD: A sample of 101 treatment seeking adolescents (mean age, 15.9 years) at clinical high risk for psychosis were followed clinically for up to 5 years (mean follow-up time, 3.0 years, SD=1.6). Adolescents were included only if they exhibited one or more attenuated positive symptoms at moderate to severe, but not psychotic, severity levels. Cox regression was used to derive a risk index. RESULTS: The overall conversion rate to psychosis was 28.3%. The final predictor model, with a positive predictive validity of 81.8%, consisted of four variables: disorganized communication, suspiciousness, verbal memory deficits, and decline in social functioning during follow-up. Significant effects also suggest narrowing the risk age range to 15-22 years. CONCLUSIONS: Clinical high risk criteria that emphasize disorganized communication and suspiciousness while also including compromised verbal memory and declining social functioning have the potential to improve predictive accuracy compared with attenuated positive symptoms used alone. On the resulting risk index (a weighted combination of the predictors), low scores were interpreted as signifying minimal risk, with little treatment necessary, high scores as suggesting aggressive intervention, and intermediate scores, although less informative, as supporting psychosocial treatment. PMID- 26046337 TI - Pediatric-Onset and Adult-Onset Separation Anxiety Disorder Across Countries in the World Mental Health Survey. AB - OBJECTIVE: The age-at-onset criterion for separation anxiety disorder was removed in DSM-5, making it timely to examine the epidemiology of separation anxiety disorder as a disorder with onsets spanning the life course, using cross-country data. METHOD: The sample included 38,993 adults in 18 countries in the World Health Organization (WHO) World Mental Health Surveys. The WHO Composite International Diagnostic Interview was used to assess a range of DSM-IV disorders that included an expanded definition of separation anxiety disorder allowing onsets in adulthood. Analyses focused on prevalence, age at onset, comorbidity, predictors of onset and persistence, and separation anxiety-related role impairment. RESULTS: Lifetime separation anxiety disorder prevalence averaged 4.8% across countries (interquartile range [25th-75th percentiles]=1.4%-6.4%), with 43.1% of lifetime onsets occurring after age 18. Significant time-lagged associations were found between earlier separation anxiety disorder and subsequent onset of internalizing and externalizing DSM-IV disorders and conversely between these disorders and subsequent onset of separation anxiety disorder. Other consistently significant predictors of lifetime separation anxiety disorder included female gender, retrospectively reported childhood adversities, and lifetime traumatic events. These predictors were largely comparable for separation anxiety disorder onsets in childhood, adolescence, and adulthood and across country income groups. Twelve-month separation anxiety disorder prevalence was considerably lower than lifetime prevalence (1.0% of the total sample; interquartile range=0.2%-1.2%). Severe separation anxiety-related 12-month role impairment was significantly more common in the presence (42.4%) than absence (18.3%) of 12-month comorbidity. CONCLUSIONS: Separation anxiety disorder is a common and highly comorbid disorder that can have onset across the lifespan. Childhood adversity and lifetime trauma are important antecedents, and adverse effects on role function make it a significant target for treatment. PMID- 26046338 TI - Early Improvement As a Predictor of Later Response to Antipsychotics in Schizophrenia: A Diagnostic Test Review. AB - OBJECTIVE: How long clinicians should wait before considering an antipsychotic ineffective and changing treatment in schizophrenia is an unresolved clinical question. Guidelines differ substantially in this regard. The authors conducted a diagnostic test meta-analysis using mostly individual patient data to assess whether lack of improvement at week 2 predicts later nonresponse. METHOD: The search included EMBASE, MEDLINE, BIOSIS, PsycINFO, Cochrane Library, CINAHL, and reference lists of relevant articles, supplemented by requests to authors of all relevant studies. The main outcome was prediction of nonresponse, defined as <50% reduction in total score on either the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) (corresponding to at least much improved) from baseline to endpoint (4-12 weeks), by <20% PANSS or BPRS improvement (corresponding to less than minimally improved) at week 2. Secondary outcomes were absent cross-sectional symptomatic remission and <20% PANSS or BPRS reduction at endpoint. Potential moderator variables were examined by meta regression. RESULTS: In 34 studies (N=9,460) a <20% PANSS or BPRS reduction at week 2 predicted nonresponse at endpoint with a specificity of 86% and a positive predictive value (PPV) of 90%. Using data for observed cases (specificity=86%, PPV=85%) or lack of remission (specificity=77%, PPV=88%) yielded similar results. Conversely, using the definition of <20% reduction at endpoint yielded worse results (specificity=70%, PPV=55%). The test specificity was significantly moderated by a trial duration of <6 weeks, higher baseline illness severity, and shorter illness duration. CONCLUSIONS: Patients not even minimally improved by week 2 of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change. PMID- 26046340 TI - "I hope I Get Movie-Star Teeth" - Doing the Exceptional Normal in Orthodontic Practice for Young People. AB - Orthodontics offer young people the chance to improve their bite and adjust their appearances. The most common reasons for orthodontic treatment concern general dentists', parents' or children's dissatisfaction with the esthetics of the bite. My aim is to analyze how esthetic norms are 'done' during three activities preceding possible treatment with fixed appliances. The evaluation indexes signal definitiveness and are the essential grounds for decision-making. In parallel, practitioners and patients refer to self-perceived satisfaction with appearances. Visualizations of divergences and the improved future bite become part of an interactive process that upholds what I conceptualize as 'the exceptional normal.' Insights into this process contribute to a better understanding of how medical practices intended to measure and safeguard children's and young people's health at the same time mobilize patients to look and feel better. The article is based on an ethnographic study at two orthodontic clinics. This article is protected by copyright. All rights reserved. PMID- 26046339 TI - Smoking and schizophrenia in population cohorts of Swedish women and men: a prospective co-relative control study. AB - OBJECTIVE: The purpose of this study was to clarify the causes of the smoking schizophrenia association. METHOD: Using Cox proportional hazard and co-relative control models, the authors predicted future risk for a diagnosis of schizophrenia or nonaffective psychosis from the smoking status of 1,413,849 women and 233,879 men from, respectively, the Swedish birth and conscript registries. RESULTS: Smoking was assessed in women at a mean age of 27 and in men at a mean age of 18. The mean age at end of follow-up was 46 for women and 26 for men. Hazard ratios for first-onset schizophrenia were elevated both for light smoking (2.21 [95% CI=1.90-2.56] for women and 2.15 [95% CI=1.25-3.44] for men) and heavy smoking (3.45 [95% CI=2.95-4.03] for women and 3.80 [95% CI=1.19-6.60] for men). These associations did not decline when schizophrenia onsets 3-5 years after smoking assessment were censored. When age, socioeconomic status, and drug abuse were controlled for, hazard ratios declined only modestly in both samples. Women who smoked into late pregnancy had a much higher risk for schizophrenia than those who quit early. Hazard ratios predicting nonaffective psychosis in the general population, in cousins, in half siblings, and in full siblings discordant for heavy smoking were, respectively, 2.67, 2.71, 2.54, and 2.18. A model utilizing all relative pairs predicted a hazard ratio of 1.69 (95% CI=1.17-2.44) for nonaffective psychosis in the heavy-smoking member of discordant monozygotic twin pairs. CONCLUSIONS: Smoking prospectively predicts risk for schizophrenia. This association does not arise from smoking onset during a schizophrenic prodrome and demonstrates a clear dose-response relationship. While little of this association is explained by epidemiological confounders, a portion arises from common familial/genetic risk factors. However, in full siblings and especially monozygotic twins discordant for smoking, risk for nonaffective psychosis is appreciably higher in the smoking member. These results can help in evaluating the plausibility of various etiological hypotheses for the smoking schizophrenia association. PMID- 26046344 TI - N-Terminal Pro-Brain Natriuretic Peptide Is Associated with a Future Diagnosis of Cancer in Patients with Coronary Artery Disease. AB - OBJECTIVE: Several papers have reported elevated plasma levels of natriuretic peptides in patients with a previous diagnosis of cancer. We have explored whether N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels predict a future diagnosis of cancer in patients with coronary artery disease (CAD). METHODS: We studied 699 patients with CAD free of cancer. At baseline, NT proBNP, galectin-3, monocyte chemoattractant protein-1, soluble tumor necrosis factor-like weak inducer of apoptosis, high-sensitivity C-reactive protein, and high-sensitivity cardiac troponin I plasma levels were assessed. The primary outcome was new cancer diagnosis. The secondary outcome was cancer diagnosis, heart failure requiring hospitalization, or death. RESULTS: After 2.15+/-0.98 years of follow-up, 24 patients developed cancer. They were older (68.5 [61.5, 75.8] vs 60.0 [52.0, 72.0] years; p=0.011), had higher NT-proBNP (302.0 [134.8, 919.8] vs 165.5 [87.4, 407.5] pg/ml; p=0.040) and high-sensitivity C-reactive protein (3.27 [1.33, 5.94] vs 1.92 [0.83, 4.00] mg/L; p=0.030), and lower triglyceride (92.5 [70.5, 132.8] vs 112.0 [82.0, 157.0] mg/dl; p=0.044) plasma levels than those without cancer. NT-proBNP (Hazard Ratio [HR]=1.030; 95% Confidence Interval [CI]=1.008-1.053; p=0.007) and triglyceride levels (HR=0.987; 95%CI=0.975-0.998; p=0.024) were independent predictors of a new cancer diagnosis (multivariate Cox regression analysis). When patients in whom the suspicion of cancer appeared in the first one-hundred days after blood extraction were excluded, NT-proBNP was the only predictor of cancer (HR=1.061; 95%CI=1.034 1.088; p<0.001). NT-proBNP was an independent predictor of cancer, heart failure, or death (HR=1.038; 95%CI=1.023-1.052; p<0.001) along with age, and use of insulin and acenocumarol. CONCLUSIONS: NT-proBNP is an independent predictor of malignancies in patients with CAD. New studies in large populations are needed to confirm these findings. PMID- 26046345 TI - Antimicrobial Activity of Novel Synthetic Peptides Derived from Indolicidin and Ranalexin against Streptococcus pneumoniae. AB - Antimicrobial peptides (AMPs) represent promising alternatives to conventional antibiotics in order to defeat multidrug-resistant bacteria such as Streptococcus pneumoniae. In this study, thirteen antimicrobial peptides were designed based on two natural peptides indolicidin and ranalexin. Our results revealed that four hybrid peptides RN7-IN10, RN7-IN9, RN7-IN8, and RN7-IN6 possess potent antibacterial activity against 30 pneumococcal clinical isolates (MIC 7.81 15.62ug/ml). These four hybrid peptides also showed broad spectrum antibacterial activity (7.81ug/ml) against S. aureus, methicillin resistant S. aureus (MRSA), and E. coli. Furthermore, the time killing assay results showed that the hybrid peptides were able to eliminate S. pneumoniae within less than one hour which is faster than the standard drugs erythromycin and ceftriaxone. The cytotoxic effects of peptides were tested against human erythrocytes, WRL-68 normal liver cell line, and NL-20 normal lung cell line. The results revealed that none of the thirteen peptides have cytotoxic or hemolytic effects at their MIC values. The in silico molecular docking study was carried out to investigate the binding properties of peptides with three pneumococcal virulent targets by Autodock Vina. RN7IN6 showed a strong affinity to target proteins; autolysin, pneumolysin, and pneumococcal surface protein A (PspA) based on rigid docking studies. Our results suggest that the hybrid peptides could be suitable candidates for antibacterial drug development. PMID- 26046346 TI - Tight Chk1 Levels Control Replication Cluster Activation in Xenopus. AB - DNA replication in higher eukaryotes initiates at thousands of origins according to a spatio-temporal program. The ATR/Chk1 dependent replication checkpoint inhibits the activation of later firing origins. In the Xenopus in vitro system initiations are not sequence dependent and 2-5 origins are grouped in clusters that fire at different times despite a very short S phase. We have shown that the temporal program is stochastic at the level of single origins and replication clusters. It is unclear how the replication checkpoint inhibits late origins but permits origin activation in early clusters. Here, we analyze the role of Chk1 in the replication program in sperm nuclei replicating in Xenopus egg extracts by a combination of experimental and modelling approaches. After Chk1 inhibition or immunodepletion, we observed an increase of the replication extent and fork density in the presence or absence of external stress. However, overexpression of Chk1 in the absence of external replication stress inhibited DNA replication by decreasing fork densities due to lower Cdk2 kinase activity. Thus, Chk1 levels need to be tightly controlled in order to properly regulate the replication program even during normal S phase. DNA combing experiments showed that Chk1 inhibits origins outside, but not inside, already active clusters. Numerical simulations of initiation frequencies in the absence and presence of Chk1 activity are consistent with a global inhibition of origins by Chk1 at the level of clusters but need to be combined with a local repression of Chk1 action close to activated origins to fit our data. PMID- 26046347 TI - Inhibition of NOS-NO System Prevents Autoimmune Orchitis Development in Rats: Relevance of NO Released by Testicular Macrophages in Germ Cell Apoptosis and Testosterone Secretion. AB - BACKGROUND: Although the testis is considered an immunoprivileged organ it can orchestrate immune responses against pathological insults such as infection and trauma. Experimental autoimmune orchitis (EAO) is a model of chronic inflammation whose main histopathological features it shares with human orchitis. In EAO an increased number of macrophages infiltrate the interstitium concomitantly with progressive germ cell degeneration and impaired steroidogenesis. Up-regulation of nitric oxide (NO)-NO synthase (NOS) system occurs, macrophages being the main producers of NO. OBJECTIVE: The aim of our study was to evaluate the role of NO NOS system in orchitis development and determine the involvement of NO released by testicular macrophages on germ cell apoptosis and testosterone secretion. METHOD AND RESULTS: EAO was induced in rats by immunization with testicular homogenate and adjuvants (E group) and a group of untreated normal rats (N) was also studied. Blockage of NOS by i.p. injection of E rats with a competitive inhibitor of NOS, L-NAME (8mg/kg), significantly reduced the incidence and severity of orchitis and lowered testicular nitrite content. L-NAME reduced germ cell apoptosis and restored intratesticular testosterone levels, without variations in serum LH. Co-culture of N testicular fragments with testicular macrophages obtained from EAO rats significantly increased germ cell apoptosis and testosterone secretion, whereas addition of L-NAME lowered both effects and reduced nitrite content. Incubation of testicular fragments from N rats with a NO donor DETA-NOnoate (DETA-NO) induced germ cell apoptosis through external and internal apoptotic pathways, an effect prevented by N-acetyl-L-cysteine (NAC). DETA-NO inhibited testosterone released from Leydig cells, whereas NAC (from 2.5 to 15 mM) did not prevent this effect. CONCLUSIONS: We demonstrated that NO-NOS system is involved in the impairment of testicular function in orchitis. NO secreted mainly by testicular macrophages could promote oxidative stress inducing ST damage and interfering in Leydig cell function. PMID- 26046348 TI - Male Sex Is Independently Associated with Faster Disability Accumulation in Relapse-Onset MS but Not in Primary Progressive MS. AB - BACKGROUND: Multiple Sclerosis is more common in women than men and females have more relapses than men. In a large international cohort we have evaluated the effect of gender on disability accumulation and disease progression to determine if male MS patients have a worse clinical outcome than females. METHODS: Using the MSBase Registry, data from 15,826 MS patients from 25 countries was analysed. Changes in the severity of MS (EDSS) were compared between sexes using a repeated measures analysis in generalised linear mixed models. Kaplan-Meier analysis was used to test for sex difference in the time to reach EDSS milestones 3 and 6 and the secondary progressive MS. RESULTS: In relapse onset MS patients (n = 14,453), males progressed significantly faster in their EDSS than females (0.133 vs 0.112 per year, P<0.001,). Females had a reduced risk of secondary progressive MS (HR (95% CI) = 0.77 (0.67 to 0.90) P = 0.001). In primary progressive MS (n = 1,373), there was a significant increase in EDSS over time in males and females (P<0.001) but there was no significant sex effect on the annualized rate of EDSS change. CONCLUSION: Among registrants of MSBase, male relapse-onset patients accumulate disability faster than female patients. In contrast, the rate of disability accumulation between male and female patients with primary progressive MS is similar. PMID- 26046349 TI - Obesity and Cardio-Metabolic Risk Factors in an Urban and Rural Population in the Ashanti Region-Ghana: A Comparative Cross-Sectional Study. AB - There is a surge in chronic diseases in the developing world, driven by a high prevalence of cardio-metabolic risk factors. This study described differences in prevalence of obesity and cardio-metabolic risk factors between urban and rural settlements in the Ashanti Region of Ghana. This comparative cross-sectional study included 672 participants (median age 50 years), of which 312 were from Kumasi (urban) and 360 from Jachie-Pramso (rural). Demographic, anthropometric and other cardio-metabolic risk factors were gathered and venous blood samples were drawn for biochemical assays. Results suggested significant differences in diastolic blood pressure (80.0 mmHg vs 79.5 mmHg; p = 0.0078), and fasting blood sugar (5.0 mmo/l vs 4.5 mmol/l; p < 0.0001) between the two groups. Further differences in anthropometric measures suggested greater adiposity amongst participants in the urban area. Participants in the urban area were more likely than rural participants, to have high total cholesterol and LDL-c (p < 0.0001 respectively). Risk factors including BMI >= 25 (p < 0.0001), BMI >= 30 (p < 0.0001), high waist circumference (p < 0.0001), high waist-to-height ratio (p < 0.0001) and alcohol consumption (p = 0.0186) were more prevalent amongst participants in the urban area. Markers of adiposity were higher amongst females than males in both areas (p < 0.05). In the urban area, hypertension, diabetes and lifestyle risk factors were more prevalent amongst males than females. Differences in risk factors by urban/rural residence remained significant after adjusting for gender and age. Obesity and cardio-metabolic risk factors are more prevalent amongst urban settlers, highlighting an urgent need to avert the rise of diet and lifestyle-related chronic diseases. PMID- 26046350 TI - Identification of Novel Small Molecule Inhibitors of Oncogenic RET Kinase. AB - Oncogenic mutation of the RET receptor tyrosine kinase is observed in several human malignancies. Here, we describe three novel type II RET tyrosine kinase inhibitors (TKI), ALW-II-41-27, XMD15-44 and HG-6-63-01, that inhibit the cellular activity of oncogenic RET mutants at two digit nanomolar concentration. These three compounds shared a 3-trifluoromethyl-4-methylpiperazinephenyl pharmacophore that stabilizes the 'DFG-out' inactive conformation of RET activation loop. They blocked RET-mediated signaling and proliferation with an IC50 in the nM range in fibroblasts transformed by the RET/C634R and RET/M918T oncogenes. They also inhibited autophosphorylation of several additional oncogenic RET-derived point mutants and chimeric oncogenes. At a concentration of 10 nM, ALW-II-41-27, XMD15-44 and HG-6-63-01 inhibited RET kinase and signaling in human thyroid cancer cell lines carrying oncogenic RET alleles; they also inhibited proliferation of cancer, but not non-tumoral Nthy-ori-3-1, thyroid cells, with an IC50 in the nM range. The three compounds were capable of inhibiting the 'gatekeeper' V804M mutant which confers substantial resistance to established RET inhibitors. In conclusion, we have identified a type II TKI scaffold, shared by ALW-II-41-27, XMD15-44 and HG-6-63-01, that may be used as novel lead for the development of novel agents for the treatment of cancers harboring oncogenic activation of RET. PMID- 26046351 TI - Genetic Evidence of Hybridization between the Endangered Native Species Iguana delicatissima and the Invasive Iguana iguana (Reptilia, Iguanidae) in the Lesser Antilles: Management Implications. AB - The worldwide increase of hybridization in different groups is thought to have become more important with the loss of isolating barriers and the introduction of invasive species. This phenomenon could result in the extinction of endemic species. This study aims at investigating the hybridization dynamics between the endemic and threatened Lesser Antillean iguana (Iguana delicatissima) and the invasive common green iguana (Iguana iguana) in the Lesser Antilles, as well as assessing the impact of interspecific hybridization on the decline of I. delicatissima. 59 I. delicatissima (5 localities), 47 I. iguana (12 localities) and 27 hybrids (5 localities), who were all identified based on morphological characters, have been genotyped at 15 microsatellites markers. We also sequenced hybrids using ND4 mitochondrial loci to further investigate mitochondrial introgression. The genetic clustering of species and hybrid genetic assignment were performed using a comparative approach, through the implementation of a Discriminant Analysis of Principal Component (DAPC) based on statistics, as well as genetic clustering approaches based on the genetic models of several populations (Structure, NewHybrids and HIest), in order to get full characterization of hybridization patterns and introgression dynamics across the islands. The iguanas identified as hybrids in the wild, thanks to morphological analysis, were all genetically F1, F2, or backcrosses. A high proportion of individuals were also the result of a longer-term admixture. The absence of reproductive barriers between species leads to hybridization when species are in contact. Yet morphological and behavioral differences between species could explain why males I. iguana may dominate I. delicatissima, thus resulting in short-term species displacement and extinction by hybridization and recurrent introgression from I. iguana toward I. delicatissima. As a consequence, I. delicatissima gets eliminated through introgression, as observed in recent population history over several islands. These results have profound implications for species management of the endangered I. delicatissima and practical conservation recommendations are being discussed in the light of these findings. PMID- 26046352 TI - Personality, Attentional Biases towards Emotional Faces and Symptoms of Mental Disorders in an Adolescent Sample. AB - OBJECTIVE: To investigate the role of personality factors and attentional biases towards emotional faces, in establishing concurrent and prospective risk for mental disorder diagnosis in adolescence. METHOD: Data were obtained as part of the IMAGEN study, conducted across 8 European sites, with a community sample of 2257 adolescents. At 14 years, participants completed an emotional variant of the dot-probe task, as well two personality measures, namely the Substance Use Risk Profile Scale and the revised NEO Personality Inventory. At 14 and 16 years, participants and their parents were interviewed to determine symptoms of mental disorders. RESULTS: Personality traits were general and specific risk indicators for mental disorders at 14 years. Increased specificity was obtained when investigating the likelihood of mental disorders over a 2-year period, with the Substance Use Risk Profile Scale showing incremental validity over the NEO Personality Inventory. Attentional biases to emotional faces did not characterise or predict mental disorders examined in the current sample. DISCUSSION: Personality traits can indicate concurrent and prospective risk for mental disorders in a community youth sample, and identify at-risk youth beyond the impact of baseline symptoms. This study does not support the hypothesis that attentional biases mediate the relationship between personality and psychopathology in a community sample. Task and sample characteristics that contribute to differing results among studies are discussed. PMID- 26046353 TI - A Meta-Analysis of Concurrent Chemoradiotherapy for Advanced Esophageal Cancer. AB - BACKGROUND: Concurrent chemoradiotherapy is a standard treatment for local advanced esophageal cancer, but the outcomes are controversial. Our goals were to compare the therapeutic effects of concurrent chemoradiotherapy and radiotherapy alone in local advanced esophageal cancer using meta-analysis. METHODS: MEDLINE, EMBASE and the Cochrane library were searched for studies comparing chemoradiotherapy with radiotherapy alone for advanced esophageal cancer. Only randomized controlled trials were included, and extracted data were analyzed with Review Manager Version 5.2. The pooled relative risks (RR) and their 95% confidence intervals (CI) were calculated for statistical analysis. RESULTS: Nine studies were included. Of 1,135 cases, 612 received concurrent chemoradiotherapy and 523 were treated with radiotherapy alone. The overall response rate (complete remission and partial remission) was 93.4% for concurrent chemoradiotherapy and 83.7% for radiotherapy alone (P = 0.05). The RR values of 1-year, 3-year, and 5 year survival rates were 1.14 (95% CI: 1.04 - 1.24, P = 0.006), 1.66 (95% CI: 1.34 - 2.06, P < 0.001), and 2.43 (95% CI: 1.63 - 3.63, P < 0.001), respectively. The RR value of the merged occurrence rate of acute toxic effects was 2.34 (95% CI: 1.90 - 2.90, P <0.001). There was no difference in the incidence of late toxic effects, which had an RR value of 1.21 (95% CI: 0.96 - 1.54, P = 0.11). The RR level of persistence and recurrence was 0.71 (95% CI: 0.62 - 0.81, P <0.001), and for the distant metastasis rate, the RR value was 0.79 (95% CI: 0.61 - 1.02, P = 0.07). CONCLUSIONS: Concurrent chemoradiotherapy significantly improved overall survival rate, reduced the risk of persistence and recurrence, but had little effect on the primary tumor response, and increased the occurrence of acute toxic effects. PMID- 26046354 TI - Non-Anticoagulant Fractions of Enoxaparin Suppress Inflammatory Cytokine Release from Peripheral Blood Mononuclear Cells of Allergic Asthmatic Individuals. AB - BACKGROUND: Enoxaparin, a low-molecular-weight heparin, is known to possess anti inflammatory properties. However, its clinical exploitation as an anti inflammatory agent is hampered by its anticoagulant effect and the associated risk of bleeding. OBJECTIVE: The aim of the current study was to examine the ability of non-anticoagulant fractions of enoxaparin to inhibit the release of key inflammatory cytokines in primed peripheral blood mononuclear cells derived from allergic mild asthmatics. METHODS: Peripheral blood mononuclear cells from allergic asthmatics were activated with phytohaemag glutinin (PHA), concanavalin A (ConA) or phorbol 12-myristate 13-acetate (PMA) in the presence or absence of enoxaparin fractions before cytokine levels were quantified using specific cytokine bead arrays. Together with nuclear magnetic resonance analysis,time dependent and target-specific effects of enoxaparin fractions were used to elucidate structural determinants for their anti-inflammatory effect and gain mechanistic insights into their anti-inflammatory activity. RESULTS: Two non anticoagulant fractions of enoxaparin were identified that significantly inhibited T-cell activation. A disaccharide fraction of enoxaparin inhibited the release of IL-4, IL-5, IL-13 and TNF-alpha by more than 57% while a tetrasaccharide fraction was found to inhibit the release of tested cytokines by more than 68%. Our data suggest that the observed response is likely to be due to an interaction of 6-O-sulfated tetrasaccharide with cellular receptor(s). CONCLUSION AND CLINICAL RELEVANCE: The two identified anti-inflammatory fractions lacked anticoagulant activity and are therefore not associated with risk of bleeding. The findings highlight the potential therapeutic use of enoxaparin derived fractions, in particular tetrasaccharide, in patients with chronic inflammatory disorders. PMID- 26046355 TI - Release of Phosphorylated HSP27 (HSPB1) from Platelets Is Accompanied with the Acceleration of Aggregation in Diabetic Patients. AB - We investigated the relationship between HSP27 phosphorylation and collagen stimulated activation of platelets in patients with diabetes mellitus (DM). Platelet-rich plasma was prepared from blood of type 2 DM patients. The platelet aggregation was analyzed in size of aggregates by an aggregometer using a laser scattering method. The protein phosphorylation was analyzed by Western blotting. Phosphorylated-HSP27 and PDGF-AB released from platelets were measured by ELISA. The phosphorylated-HSP27 levels at Ser-78 and Ser-82 induced by collagen were directly proportional to the platelet aggregation. Total HSP27 levels in platelets were decreased concomitantly with the phosphorylation. The released HSP27 levels were significantly correlated with the phosphorylated levels of HSP27 in the platelets stimulated by 0.3 MUg/ml collagen. The low dose collagen stimulated release of HSP27 was detected but relatively small in healthy donors. The released levels of PDGF-AB were in parallel with the levels of released HSP27. Area under the curve (AUC) of small aggregation (9-25 MUm) induced by 0.3 MUg/ml collagen was inversely proportional to the levels of released HSP27. AUC of large aggregation (50-70 MUm) was directly proportional to the levels of released HSP27. Exogenous recombinant phosphorylated- HSP27 hardly affected the aggregation or the released levels of PDGF-AB induced by collagen. These results strongly suggest that HSP27 is released from human platelets accompanied with its phosphorylation induced by collagen, which is correlated with the acceleration of platelet aggregation in type 2 DM patients. PMID- 26046357 TI - Correction: Dynamic Impedance Model of the Skin-Electrode Interface for Transcutaneous Electrical Stimulation. PMID- 26046356 TI - Vitamin D Binding Protein Isoforms and Apolipoprotein E in Cerebrospinal Fluid as Prognostic Biomarkers of Multiple Sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a multifactorial autoimmune disease of the central nervous system with a heterogeneous and unpredictable course. To date there are no prognostic biomarkers even if they would be extremely useful for early patient intervention with personalized therapies. In this context, the analysis of inter-individual differences in cerebrospinal fluid (CSF) proteome may lead to the discovery of biological markers that are able to distinguish the various clinical forms at diagnosis. METHODS: To this aim, a two dimensional electrophoresis (2-DE) study was carried out on individual CSF samples from 24 untreated women who underwent lumbar puncture (LP) for suspected MS. The patients were clinically monitored for 5 years and then classified according to the degree of disease aggressiveness and the disease-modifying therapies prescribed during follow up. RESULTS: The hierarchical cluster analysis of 2-DE dataset revealed three protein spots which were identified by means of mass spectrometry as Apolipoprotein E (ApoE) and two isoforms of vitamin D binding protein (DBP). These three protein spots enabled us to subdivide the patients into subgroups correlated with clinical classification (MS aggressive forms identification: 80%). In particular, we observed an opposite trend of values for the two protein spots corresponding to different DBP isoforms suggesting a role of a post translational modification rather than the total protein content in patient categorization. CONCLUSIONS: These findings proved to be very interesting and innovative and may be developed as new candidate prognostic biomarkers of MS aggressiveness, if confirmed. PMID- 26046358 TI - MicroRNA Stability in Postmortem FFPE Tissues: Quantitative Analysis Using Autoptic Samples from Acute Myocardial Infarction Patients. AB - MicroRNAs (miRNAs) are very short (18-24 nucleotides) nucleic acids that are expressed in a number of biological tissues and have been shown to be more resistant to extreme temperatures and pH compared to longer RNA molecules, like mRNAs. As miRNAs contribute to diverse biological process and respond to various kinds of cellular stress, their utility as diagnostic biomarkers and/or therapeutic targets has recently been explored. Here, we have evaluated the usefulness of miRNA quantification during postmortem examination of cardiac tissue from acute myocardial infarction (AMI) patients. Cardiac tissue was collected within one week of the patient's death and either frozen (19 samples) or fixed in formalin for up to three years (36 samples). RNA integrity was evaluated with an electropherogram, and it appears that longer RNAs are fragmented after death in the long-term fixed samples. Quantitative PCR was also performed for seven miRNAs and three other small RNAs in order to determine the appropriate controls for our postmortem analysis. Our data indicate that miR-191 and miR-26b are more suitable than the other types of small RNA molecules as they are stably detected after death and long-term fixation. Further, we also applied our quantitation method, using these endogenous controls, to evaluate the expression of three previously identified miRNA biomarkers, miR-1, miR-208b, and miR-499a, in formalin-fixed tissues from AMI patients. Although miR-1 and miR 208b decreased (1.4-fold) and increased (1.2-fold), respectively, in the AMI samples compared to the controls, the significance of these changes was limited by our sample size. In contrast, the relative level of miR-499a was significantly decreased in the AMI samples (2.1-fold). This study highlights the stability of miRNAs after death and long-term fixation, validating their use as reliable biomarkers for AMI during postmortem examination. PMID- 26046359 TI - Exposure to an Indoor Cooking Fire and Risk of Trachoma in Children of Kongwa, Tanzania. AB - BACKGROUND: Elimination of blinding trachoma by 2020 can only be achieved if affected areas have effective control programs in place before the target date. Identifying risk factors for active disease that are amenable to intervention is important to successfully design such programs. Previous studies have linked sleeping by a cooking fire to trachoma in children, but not fully explored the mechanism and risks. We propose to determine the risk for active trachoma in children with exposure to cooking fires by severity of trachoma, adjusting for other known risk factors. METHODS: Complete census of 52 communities in Kongwa, Tanzania, was conducted to collect basic household characteristics and demographic information on each family member. Information on exposure to indoor cooking fires while the mother was cooking and while sleeping for each child was collected. 6656 randomly selected children ages 1-9 yrs were invited to a survey where both eyelids were graded for follicular (TF) and intense trachoma (TI) using the WHO simplified grading scheme. Ocular swab were taken to assess the presence of Chlamydia trachomatis. FINDINGS: 5240 (79%) of the invited children participated in the study. Overall prevalence for trachoma was 6.1%. Odds for trachoma and increased severity were higher in children sleeping without ventilation and a cooking fire in their room (TF OR = 1.81, 1.00-3.27 and TI OR 4.06, 1.96-8.42). Children with TF or TI who were exposed were more likely to have infection than children with TF or TI who were not exposed. There was no increased risk with exposure to a cooking fire while the mother was cooking. CONCLUSIONS: In addition to known risk factors for trachoma, sleeping by an indoor cooking fire in a room without ventilation was associated with active trachoma and appears to substantially increase the risk of intense inflammation. PMID- 26046360 TI - Detection of Phosphatidylcholine-Coated Gold Nanoparticles in Orthotopic Pancreatic Adenocarcinoma using Hyperspectral Imaging. AB - Nanoparticle uptake and distribution to solid tumors are limited by reticuloendothelial system systemic filtering and transport limitations induced by irregular intra-tumoral vascularization. Although vascular enhanced permeability and retention can aid targeting, high interstitial fluid pressure and dense extracellular matrix may hinder local penetration. Extravascular diffusivity depends upon nanoparticle size, surface modifications, and tissue vascularization. Gold nanoparticles functionalized with biologically-compatible layers may achieve improved uptake and distribution while enabling cytotoxicity through synergistic combination of chemotherapy and thermal ablation. Evaluation of nanoparticle uptake in vivo remains difficult, as detection methods are limited. We employ hyperspectral imaging of histology sections to analyze uptake and distribution of phosphatidylcholine-coated citrate gold nanoparticles (CGN) and silica-gold nanoshells (SGN) after tail-vein injection in mice bearing orthotopic pancreatic adenocarcinoma. For CGN, the liver and tumor showed 26.5 +/ 8.2 and 23.3 +/- 4.1 particles/100 MUm2 within 10 MUm from the nearest source and few nanoparticles beyond 50 MUm, respectively. The spleen had 35.5 +/- 9.3 particles/100 MUm2 within 10 MUm with penetration also limited to 50 MUm. For SGN, the liver showed 31.1 +/- 4.1 particles/100 MUm2 within 10 MUm of the nearest source with penetration hindered beyond 30 MUm. The spleen and tumor showed uptake of 22.1 +/- 6.2 and 15.8 +/- 6.1 particles/100 MUm2 within 10 MUm, respectively, with penetration similarly hindered. CGH average concentration (nanoparticles/MUm2) was 1.09 +/- 0.14 in the liver, 0.74 +/- 0.12 in the spleen, and 0.43 +/- 0.07 in the tumor. SGN average concentration (nanoparticles/MUm2) was 0.43 +/- 0.07 in the liver, 0.30 +/- 0.06 in the spleen, and 0.20 +/- 0.04 in the tumor. Hyperspectral imaging of histology sections enables analysis of phosphatidylcholine-coated gold-based nanoparticles in pancreatic tumors with the goal to improve nanotherapeutic efficacy. PMID- 26046361 TI - Prognostic Value of Beta-Tubulin-3 and c-Myc in Muscle Invasive Urothelial Carcinoma of the Bladder. AB - BACKGROUND: To date, putative prognostic biomarkers have shown limited utility from the clinical perspective for bladder urothelial carcinoma. Herein, the expression of beta-tubulin-3 and c-Myc was evaluated to determine their prognostic potential. METHODS: In formalin fixed-paraffin embedded blocks, immunohistochemical expression of c-Myc and beta-tubulin-3 was evaluated. H score ranging from 0 to 300 was obtained by multiplying the percentage of positive cells by intensity (0-3); c-Myc and beta-tubulin-3 expression was defined: 0: negative, 1: weakly positive, 2: strongly positive. RESULTS: beta-tubulin-3 and c Myc immunoexpression was available for 46 cases. At the univariate analysis, node involvement, beta-tubulin-3 and c-Myc overexpression discriminate shorter DFS (HR 2.19, p = 0.043; HR 3.10, p = 0.24 and HR 3.05, p = 0.011, respectively); 2-yrs DFS log-rank analysis according to low versus high level of immunoexpression were statistically significant; beta-tubulin-3, 53% low vs 12.7% high (p = value 0.02) and c-Myc 28 low vs 8 high (p-value 0.007). Patients displaying negative beta tubulin-3/c-Myc had statistically significant better 2-yrs DFS than those with mixed expression or double positivity (54.5% versus 18.7% versus 0%, log-rank p = 0.006). CONCLUSIONS: c-Myc and beta-tubulin-3 show improvement for prognostic risk stratification in patients with muscle invasive bladder urothelial carcinoma. These molecular pathways may also be candidate to improve predictiveness to targeted therapies. PMID- 26046363 TI - Implementing Gerontological Nursing Evidence-Based Practice Guidelines in a BSN Curriculum. PMID- 26046362 TI - Micro-RNAs Let7e and 126 in Plasma as Markers of Metabolic Dysfunction in 10 to 12 Years Old Children. AB - BACKGROUND: Growing evidence shows that metabolic syndrome (MetS) is already starting in childhood however there is no consensus regarding how to diagnose this condition in pediatric population. Studies in adults show that altered levels of specific micro-RNAs are related with components of the MetS. OBJECTIVE: We determined the plasma levels of four MetS-associated micro-RNAs (miR-126, miR 132, mir-145 and Let-7e) in 10 to 12 years old children with or without MetS traits. DESIGN: Pediatric subjects were selected from a cohort of 3325 school-age children, and clustered by the absence (control, n = 30), or the presence of 1 (n = 50), 2 (n = 41) or 3 (n = 35) MetS traits according to Cook's criteria. Micro RNAs were isolated from plasma, and levels of miR-126, miR-132, miR-145 and Let 7e were determined by Taqman qPCR. RESULTS: Regression analysis of the different MetS traits regarding the different miRNAs analyzed showed that Let-7e presented a negative association with HDL-C levels, but a positive correlation with the number of MetS traits. Levels of miR-126 presented a positive correlation with waist circumference, waist to hip ratio, BMI, and plasma triglycerides and VLDL C. Levels of miR-132 showed a positive correlation with waist to hip ratio. Plasma levels of Let-7e were increased (~3.4 fold) in subjects with 3 MetS traits, and showed significant AUC (0.681; 95%CI = [0.58, 0.78]; p < 0.001) in the ROC analysis which were improved when miR-126 was included in the analysis (AUC 0.729; p < 0.001). In silico analysis of the interaction of proteins derived from mRNAs targeted by Let7 and miR-126 showed an important effect of both Let-7e and miR-126 regulating the insulin signaling pathway. CONCLUSIONS: These results suggest that changes in the plasma levels of Let-7e and miR-126 could represent early markers of metabolic dysfunction in children with MetS traits. PMID- 26046364 TI - Comparing Person-Centered Communication Education in Long-Term Care Using Onsite and Online Formats. AB - Educating nursing home (NH) staff to provide person-centered care is complicated by scheduling, costs, and other feasibility issues. The current study compared outcomes for an in-service program focused on person-centered communication provided in onsite and online formats. The Changing Talk program was provided onsite in seven NHs (n = 327 staff). The online program included eight NHs (n = 211 staff). Analysis of variance revealed an interaction between format type and pre-/post-test scores with improved recognition of person-centered communication in the onsite group only. Group program evaluations based on the modified Diffusion of Innovation in Long-Term Care Battery indicated no significant differences between training formats. Staff perception of the program was similar. Although statistically significant gains were noted in posttest scores indicating awareness of person-centered communication for the onsite group, gains were of limited clinical significance. Feasibility and effectiveness are important considerations for in-service education supporting NH culture change. PMID- 26046365 TI - If They Were Real: Lessons Learned from Literary Characters With Dementia. AB - Dementia and its side effects often leave individuals unable to tell their stories or experiences. Consequently, nurses must rely strictly on clinical observations as a basis for understanding dementia--an understanding that is necessary to provide the best possible care. Relying on clinical observations leads to challenges in fully understanding the experience of living with dementia. Fictional literature gives authors license to write about individuals with dementia rather than the clinical aspects of the disease, which provides insight into the patient and family experience and illustrates their needs. The current article explores dementia through an analysis of eight literary works and insights that may help expand the quality of geriatric nursing care. PMID- 26046366 TI - Individualized iterative phenotyping for genome-wide analysis of loss-of-function mutations. AB - Next-generation sequencing provides the opportunity to practice predictive medicine based on identified variants. Putative loss-of-function (pLOF) variants are common in genomes and understanding their contribution to disease is critical for predictive medicine. To this end, we characterized the consequences of pLOF variants in an exome cohort by iterative phenotyping. Exome data were generated on 951 participants from the ClinSeq cohort and filtered for pLOF variants in genes likely to cause a phenotype in heterozygotes. 103 of 951 exomes had such a pLOF variant and 79 participants were evaluated. Of those 79, 34 had findings or family histories that could be attributed to the variant (28 variants in 18 genes), 2 had indeterminate findings (2 variants in 2 genes), and 43 had no findings or a negative family history for the trait (34 variants in 28 genes). The presence of a phenotype was correlated with two mutation attributes: prior report of pathogenicity for the variant (p = 0.0001) and prior report of other mutations in the same exon (p = 0.0001). We conclude that 1/30 unselected individuals harbor a pLOF mutation associated with a phenotype either in themselves or their family. This is more common than has been assumed and has implications for the setting of prior probabilities of affection status for predictive medicine. PMID- 26046369 TI - Erratum. Rectally administrated misoprostol as an alternative to intravenous oxytocin infusion for preventing post-partum hemorrhage after cesarean delivery. PMID- 26046367 TI - Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy. AB - Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain. PMID- 26046368 TI - Mutations in the gene encoding the E2 conjugating enzyme UBE2T cause Fanconi anemia. AB - Fanconi anemia (FA) is a rare genetic disorder characterized by genome instability, increased cancer susceptibility, progressive bone marrow failure (BMF), and various developmental abnormalities resulting from the defective FA pathway. FA is caused by mutations in genes that mediate repair processes of interstrand crosslinks and/or DNA adducts generated by endogenous aldehydes. The UBE2T E2 ubiquitin conjugating enzyme acts in FANCD2/FANCI monoubiquitination, a critical event in the pathway. Here we identified two unrelated FA-affected individuals, each harboring biallelic mutations in UBE2T. They both produced a defective UBE2T protein with the same missense alteration (p.Gln2Glu) that abolished FANCD2 monoubiquitination and interaction with FANCL. We suggest this FA complementation group be named FA-T. PMID- 26046370 TI - Canine hemifacial spasm: a misnomer? PMID- 26046371 TI - A prospective study of direct medical costs in a large cohort of consecutively enrolled patients with refractory epilepsy in Italy. AB - OBJECTIVE: To evaluate direct medical costs and their predictors in patients with refractory epilepsy enrolled into the SOPHIE study (Study of Outcomes of PHarmacoresistance In Epilepsy) in Italy. METHODS: Adults and children with refractory epilepsy were enrolled consecutively at 11 tertiary referral centers and followed for 18 months. At entry, all subjects underwent a structured interview and a medical examination, and were asked to keep records of diagnostic examinations, laboratory tests, specialist consultations, treatments, hospital admissions, and day-hospital days during follow-up. Study visits included assessments every 6 months of seizure frequency, health-related quality of life (Quality of Life in Epilepsy Inventory 31), medication-related adverse events (Adverse Event Profile) and mood state (Beck Depression Inventory-II). Cost items were priced by applying Italian tariffs. Cost estimates were adjusted to 2013 values. RESULTS: Of 1,124 enrolled individuals, 1,040 completed follow-up. Average annual cost per patient was ? 4,677. The highest cost was for antiepileptic drug (AED) treatment (50%), followed by hospital admissions (29% of overall costs). AED polytherapy, seizure frequency during follow-up, grade III pharmacoresistance, medical and psychiatric comorbidities, and occurrence of status epilepticus during follow-up were identified as significant predictors of higher costs. Age between 6 and 11 years, and genetic (idiopathic) generalized epilepsies were associated with the lowest costs. Costs showed prominent variation across centers, largely due to differences in the clinical characteristics of cohorts enrolled at each center and the prescribing of second generation AEDs. Individual outliers associated with high costs related to hospital admissions had a major influence on costs in many centers. SIGNIFICANCE: Refractory epilepsy is associated with high costs that affect individuals and society. Costs differ across centers in relation to the characteristics of patients and the extent of use of more expensive, second-generation AEDs. Epilepsy-specific costs cannot be easily differentiated from costs related to comorbidities. PMID- 26046372 TI - Measuring resting energy expenditure during extracorporeal membrane oxygenation: preliminary clinical experience with a proposed theoretical model. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is increasingly used in patients with severe respiratory failure. Indirect calorimetry (IC) is a safe and non-invasive method for measuring resting energy expenditure (REE). No data exist on the use of IC in ECMO-treated patients as oxygen uptake and carbon dioxide elimination are divided between mechanical ventilation and the artificial lung. We report our preliminary clinical experience with a theoretical model that derives REE from IC measurements obtained separately on the ventilator and on the artificial lung. METHODS: A patient undergoing veno-venous ECMO for acute respiratory failure due to bilateral pneumonia was studied. The calorimeter was first connected to the ventilator and oxygen consumption (VO2 ) and carbon dioxide transport (VCO2 ) were measured until steady state was reached. Subsequently, the IC was connected to the membrane oxygenator and similar gas analysis was performed. VO2 and VCO2 values at the native and artificial lung were summed and incorporated in the Weir equation to obtain a REEcomposite . RESULTS: At the ventilator level, VO2 and VCO2 were 29.5 ml/min and 16 ml/min. VO2 and VCO2 at the artificial lung level were 213 ml/min and 187 ml/min. Based on these values, a REEcomposite of 1703 kcal/day was obtained. The Faisy-Fagon and Harris-Benedict equations calculated a REE of 1373 and 1563 kcal/day. CONCLUSION: We present IC-acquired gas analysis in ECMO patients. We propose to insert individually obtained IC measurements at the native and the artificial lung in the Weir equation for retrieving a measured REEcomposite . PMID- 26046373 TI - Assessing sex-related chick provisioning in greater flamingo Phoenicopterus roseus parents using capture-recapture models. AB - In sexually dimorphic species, the parental effort of the smaller sex may be reduced due to competitive exclusion in the feeding areas by the larger sex or physiological constraints. However, to determine gender effects on provisioning patterns, other intrinsic and extrinsic factors affecting parental effort should be accounted for. Greater flamingos (Phoenicopterus roseus) exhibit sexual size dimorphism. In Fuente de Piedra colony, the lake dries out almost completely during the breeding season and both parents commute between breeding and foraging sites >130 km away during the chick-rearing period. Applying multistate capture recapture models to daily observations of marked parents, we determined the effects of sex, and their interactions with other intrinsic and extrinsic factors, on the probability of chick desertion and sojourn in the colony and feeding areas. Moreover, using stable isotopes in the secretions that parents produce to feed their chicks, we evaluated sex-specific use of wetlands. The probability of chick attendance (complementary to chick desertion) was >0.98. Chick desertion was independent of parental sex, but decreased with parental age. Females stayed in the feeding areas for shorter periods [mean: 7.5 (95% CI: 6.0 9.4) days] than males [9.2 (7.3-11.8) days]. Isotopic signatures of secretions did not show sex differences in delta(13)C, but males' secretions were enriched in delta(15)N, suggesting they fed on prey of higher trophic levels than females. Both parents spent approximately 1 day in the colony, but females prolonged their mean stay when the lake dried out. Females also allocated more time to foraging in the flooded areas remaining in the colony, likely because they were energetically more stressed than males. The results indicate that sex-specific provisioning behaviour in greater flamingo is related to differential effects of both intrinsic and extrinsic factors. Males seem forage less efficiently than females, whereas females' body condition seems to be lower after feeding the chick. Our methodology may be extended to species that feed on distant food sources and that do not visit their offspring daily, to elucidate patterns of chick-provisioning behaviour. PMID- 26046374 TI - The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells. AB - Glioma cells release glutamate through expression of system xc-, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARgamma) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of >= 30 MUM pioglitazone (p < 0.05). The PPARgamma antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARgamma dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at >= 30 MUM and 100 MUM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 MUM and 30 MUM (p < 0.05) respectively. The effect on viability was partially dependent on PPARgamma activation in U87MG cells but not U251MG cells, whereby PPARgamma blockade with GW9662 had a synergistic effect. We conclude that PPARgamma agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate. PMID- 26046376 TI - Enhanced Catalysis Activity in a Coordinatively Unsaturated Cobalt-MOF Generated via Single-Crystal-to-Single-Crystal Dehydration. AB - Hydrothermal reaction of Co(NO3)2 and terphenyl-3,2",5",3'-tetracarboxyate (H4tpta) generated Co3(OH)2 chains based 3D coordination framework Co3(OH)2(tpta)(H2O)4 (1) that suffered from single-crystal-to-single-crystal dehydration by heating at 160 degrees C and was transformed into dehydrated Co3(OH)2(tpta) (1a). During the dehydration course, the local coordination environment of part of the Co atoms was transformed from saturated octahedron to coordinatively unsaturated tetrahedron. Heterogenous catalytic experiments on allylic oxidation of cyclohexene show that dehydrated 1a has 6 times enhanced catalytic activity than as-synthesized 1 by using tert-butyl hydroperoxide (t BuOOH) as oxidant. The activation energy for the oxidation of cylcohexene with 1a catalyst was 67.3 kJ/mol, far below the value with 1 catalysts, which clearly suggested that coordinatively unsaturated Co(II) sites in 1a have played a significant role in decreasing the activation energy. It is interestingly found that heterogeneous catalytic oxidation of cyclohexene in 1a not only gives the higher conversion of 73.6% but also shows very high selectivity toward 2 cyclohexene-1-one (ca. 64.9%), as evidenced in high turnover numbers (ca. 161) based on the open Co(II) sites of 1a catalyst. Further experiments with a radical trap indicate a radical chain mechanism. This work demonstrates that creativity of coordinatively unsaturated metal sites in MOFs could significantly enhance heterogeneous catalytic activity and selectivity. PMID- 26046375 TI - MUC16-mediated activation of mTOR and c-Myc reprograms pancreatic cancer metabolism. AB - MUC16, a transmembrane mucin, facilitates pancreatic adenocarcinoma progression and metastasis. In the current studies, we observed that MUC16 knockdown pancreatic cancer cells exhibit reduced glucose uptake and lactate secretion along with reduced migration and invasion potential, which can be restored by supplementing the culture media with lactate, an end product of aerobic glycolysis. MUC16 knockdown leads to inhibition of mTOR activity and reduced expression of its downstream target c-MYC, a key player in cellular growth, proliferation and metabolism. Ectopic expression of c-MYC in MUC16 knockdown pancreatic cancer cells restores the altered cellular physiology. Our LC-MS/MS based metabolomics studies indicate global metabolic alterations in MUC16 knockdown pancreatic cancer cells, as compared to the controls. Specifically, glycolytic and nucleotide metabolite pools were significantly decreased. We observed similar metabolic alterations that correlated with MUC16 expression in primary tumor tissue specimens from human pancreatic adenocarcinoma cancer patients. Overall, our results demonstrate that MUC16 plays an important role in metabolic reprogramming of pancreatic cancer cells by increasing glycolysis and enhancing motility and invasiveness. PMID- 26046377 TI - Ultrasound measurements of carotid intima-media thickness by two semi-automated analysis systems. AB - Increased carotid intima-media thickness (cIMT) is associated with an increased risk of cardiac events and stroke. Several semi-automated edge-detection techniques for measuring cIMT are used for research and in clinical practice. Our aim was to compare two currently available semi-automated techniques for the measurement of cIMT. Carotid ultrasound recordings were obtained from 99 subjects (mean age 54.4 +/- 8.9 years, range 33-69) without known cardiovascular diseases using a General Electric (GE) Vivid 7 ultrasound scanner, 8-MHz transducer. The far-wall cIMT was evaluated 1-2 cm proximal to the carotid bulb. Three diastolic images (ECG R-wave) from the left and three images from the right common carotid arteries were analysed using GE and Artery Measurement System (AMS) semi automated softwares. Mean systolic and diastolic blood pressures were 120 +/- 13 and 76 +/- 8 mmHg, respectively. The cIMTmean (left + right)/2 by GE and cIMTmean (left + right)/2 AMS were highly correlated (r = 0.92, P<0.001). Higher values were measured by GE (0.72 +/- 0.12 mm) compared with AMS (0.69 +/- 0.12 mm), and this was significant (P<0.001). The coefficients of variation for the intra observer variability of cIMTmean (left + right)/2 were 1.0% (GE) and 2.2% (AMS). cIMTmean measured by GE's semi-automated edge-detection method correlated well with that measured by AMS. However, there were small but significant systematic differences between the cIMTmean values measured by the two techniques. Thus, the use of only one type of measurement program seems favourable in follow-up studies and when evaluating treatment effects. PMID- 26046378 TI - Influence of age on IgE response in peanut-allergic children and adolescents from the Mediterranean area. AB - BACKGROUND: Peanut allergens are common triggers of food allergy. Analyses of sensitization patterns, relationships with other allergens, clinical symptoms, and variation with age are needed. We studied sensitization to Ara h 2, Ara h 9, and Pru p 3 in a peanut allergic children/adolescents and the relationship with peach and pollen. METHODS: Peanut allergic patients aged between 1 and 20 years old were classified into two groups: A) allergic to peanut only and B) allergic to peach and peanut. The IgE response was measured to Ara h 2, Ara h 9, and Pru p 3. RESULTS: Of 964 subjects evaluated, 28% were allergic to peanut. From this group, 68% were also sensitized to pollen. Urticaria was the most frequent entity followed by anaphylaxis and OAS. Fifty-eight percent had Ara h 2- and/or Ara h 9 specific IgE. More than half reported symptoms with peanut alone (Group A) and 35% to peanut and peach (Group B). We observed significant differences in sex, age, onset of symptoms, and sensitization to Artemisia between groups. IgE response to Ara h 2 was more frequent in Group A, and Ara h 9 and Pru p 3 in Group B. We observed a decrease in sensitization to Ara h 2 and an increase to Ara h 9 and Pru p 3 with increasing age. CONCLUSION: Peanut allergy is frequent in subjects with allergy to plant foods, with Ara h 2 and Ara h 9 being two important allergens. In younger patients, Ara h 2 predominates over Ara h 9. The reverse was observed in older patients. PMID- 26046379 TI - The potassium transporter OsHAK21 functions in the maintenance of ion homeostasis and tolerance to salt stress in rice. AB - The intracellular potassium (K(+) ) homeostasis, which is crucial for plant survival in saline environments, is modulated by K(+) channels and transporters. Some members of the high-affinity K(+) transporter (HAK) family are believed to function in the regulation of plant salt tolerance, but the physiological mechanisms remain unclear. Here, we report a significant inducement of OsHAK21 expression by high-salinity treatment and provide genetic evidence of the involvement of OsHAK21 in rice salt tolerance. Disruption of OsHAK21 rendered plants sensitive to salt stress. Compared with the wild type, oshak21 accumulated less K(+) and considerably more Na(+) in both shoots and roots, and had a significantly lower K(+) net uptake rate but higher Na(+) uptake rate. Our analyses of subcellular localizations and expression patterns showed that OsHAK21 was localized in the plasma membrane and expressed in xylem parenchyma and individual endodermal cells (putative passage cells). Further functional characterizations of OsHAK21 in K(+) uptake-deficient yeast and Arabidopsis revealed that OsHAK21 possesses K(+) transporter activity. These results demonstrate that OsHAK21 may mediate K(+) absorption by the plasma membrane and play crucial roles in the maintenance of the Na(+) /K(+) homeostasis in rice under salt stress. PMID- 26046383 TI - Differential Expression of Cancer Stem Cell Markers ALDH1 and CD133 in Various Lung Cancer Subtypes. AB - Cancer stem cells (CSCs) are hypothesized to be the main culprit of lung cancer progression. Clinicopathological significance of stem cell markers CD133 and ALDH1 in a large group of lung cancer patients was evaluated. ALDH1 and CD133 had higher expression levels in the NSCLC compared to the SCLC. Over-expression of both ALDH1 and CD133 markers was exclusively found in SCC and ADC. Low level of ALDH1 expression was strongly correlated with poor differentiation in ADC cases. Thus, ALDH1(high)/CD133(high) phenotype can be considered as a CSC marker in some lung cancer subtypes. PMID- 26046384 TI - Aluminum Nanoarrays for Plasmon-Enhanced Light Harvesting. AB - The practical limits of coinage-metal-based plasmonic materials demand sustainable, abundant alternatives with a wide plasmonic range of the solar energy spectrum. Aluminum (Al) is an emerging alternative, but its instability in aqueous environments critically limits its applicability to various light harvesting systems. Here, we report a design strategy to achieve a robust platform for plasmon-enhanced light harvesting using Al nanostructures. The incorporation of mussel-inspired polydopamine nanolayers in the Al nanoarrays allowed for the reliable use of Al plasmonic resonances in a highly corrosive photocatalytic redox solution and provided nanoscale arrangement of organic photosensitizers on Al surfaces. The Al-photosensitizer core-shell assemblies exhibited plasmon-enhanced light absorption, which resulted in a 300% efficiency increase in photo-to-chemical conversion. Our strategy enables stable and advanced use of aluminum for plasmonic light harvesting. PMID- 26046385 TI - Inflammatory epidermolysis bullosa acquisita in a 4-year-old girl. AB - This study presents a case of linear immunoglobulin A dermatosis-like epidermolysis bullosa acquisita in a 4-year-old girl showing rapid, widespread and inflammatory skin lesions. The diagnosis was confirmed by histopathology, direct and indirect immunofluorescence, various immunoblotting analyses and enzyme-linked immunosorbent assays. Despite the severe clinical manifestations, the disease was successfully controlled by combination therapy of oral prednisolone and dapsone. PMID- 26046386 TI - Feedback regulation between autophagy and PKA. AB - Protein kinase A (PKA) controls diverse cellular processes and homeostasis in eukaryotic cells. Many processes and substrates of PKA have been described and among them are direct regulators of autophagy. The mechanisms of PKA regulation and how they relate to autophagy remain to be fully understood. We constructed a reporter of PKA activity in yeast to identify genes affecting PKA regulation. The assay systematically measures relative protein-protein interactions between the regulatory and catalytic subunits of the PKA complex in a systematic set of genetic backgrounds. The candidate PKA regulators we identified span multiple processes and molecular functions (autophagy, methionine biosynthesis, TORC signaling, protein acetylation, and DNA repair), which themselves include processes regulated by PKA. These observations suggest the presence of many feedback loops acting through this key regulator. Many of the candidate regulators include genes involved in autophagy, suggesting that not only does PKA regulate autophagy but that autophagy also sends signals back to PKA. PMID- 26046387 TI - 5'-O-Alkylpyridoxamines: Lipophilic Analogues of Pyridoxamine Are Potent Scavengers of 1,2-Dicarbonyls. AB - Pyridoxamine (PM) is a prospective drug for the treatment of diabetic complications. In order to make zwitterionic PM more lipophilic and improve its tissue distribution, PM derivatives containing medium length alkyl groups on the hydroxymethyl side chain were prepared. The synthesis of these alkylpyridoxamines (alkyl-PMs) starting from pyridoxine offers high yields and is amenable to bulk preparations. Interestingly, alkyl-PMs were found to react with methylglyoxal (MGO), a major toxic product of glucose metabolism and autoxidation, several orders of magnitude faster than PM. This suggests the formation of nonionic pyrido-1,3-oxazine as the key step in the reaction of PM with MGO. Since the primary target of MGO in proteins is the guanidine side chain of arginine, alkyl PMs were shown to be more effective than PM in reducing the modification of N alpha-benzoylarginine by MGO. Alkyl-PMs in the presence of MGO also protected the enzymatic activity of lysozyme that contains several arginine residues next to its active site. Alkyl-PMs can be expected to trap MGO and other toxic 1,2 carbonyl compounds more effectively than PM, especially in lipophilic tissue environments, thus protecting macromolecules from functional damage. This suggests potential therapeutic uses for alkyl-PMs in diabetes and other diseases characterized by the elevated levels of toxic dicarbonyl compounds. PMID- 26046388 TI - Controlled Synthesis of Nanoscopic Metal Cages. AB - Here we show an elegant and general route to the assembly of a giant {M12C24} cage from 12 palladium ions (M) and 24 heterometallic octanuclear coordination cages (C = {Cr7Ni-Py2}). The molecule is 8 nm in size, and the methods for its synthesis and characterization provide a basis for future developments at this scale. PMID- 26046389 TI - Decreased SMAD4 expression is associated with induction of epithelial-to mesenchymal transition and cetuximab resistance in head and neck squamous cell carcinoma. AB - Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and cetuximab, a monoclonal antibody targeting this receptor, is widely used to treat these patients. In the following investigation, we examined the role of SMAD4 down-regulation in mediating epithelial-to-mesenchymal transition (EMT) and cetuximab resistance in HNSCC. We determined that SMAD4 downregulation was significantly associated with increased cell motility, increased expression of vimentin, and cetuximab resistance in HNSCC cell lines. In the HNSCC genomic dataset obtained from The Cancer Genome Atlas, SMAD4 was altered in 20/279 (7%) of HNSCC via homozygous deletion, and nonsense, missense, and silent mutations. When SMAD4 expression was compared with respect to human papillomavirus (HPV) status, HPV-positive tumors had higher expression compared to HPV-negative tumors. Furthermore, higher SMAD4 expression also correlated with higher CDKN2A (p16) expression. Our data suggest that SMAD4 down-regulation plays an important role in the induction of EMT and cetuximab resistance. Patients with higher SMAD4 expression may benefit from cetuximab use in the clinic. PMID- 26046390 TI - Surface-Effect-Induced Optical Bandgap Shrinkage in GaN Nanotubes. AB - We investigate nontrivial surface effects on the optical properties of self assembled crystalline GaN nanotubes grown on Si substrates. The excitonic emission is observed to redshift by ~100 meV with respect to that of bulk GaN. We find that the conduction band edge is mainly dominated by surface atoms, and that a larger number of surface atoms for the tube is likely to increase the bandwidth, thus reducing the optical bandgap. The experimental findings can have important impacts in the understanding of the role of surfaces in nanostructured semiconductors with an enhanced surface/volume ratio. PMID- 26046391 TI - Task variation during simulated, repetitive, low-intensity work--influence on manifestation of shoulder muscle fatigue, perceived discomfort and upper-body postures. AB - Work-related musculoskeletal disorders are increasing due to industrialisation of work processes. Task variation has been suggested as potential intervention. The objectives of this study were to investigate, first, the influence of task variation on electromyographic (EMG) manifestations of shoulder muscle fatigue and discomfort; second, noticeable postural shoulder changes over time; third, if the association between task variation and EMG might be biased by postural changes. Outcome parameters were recorded using multichannel EMG, Optotrak and the Borg scale. Fourteen participants performed a one-hour repetitive Pegboard task in one continuous and two interrupted conditions with rest and a pick-and place task, respectively. Manifestations of shoulder muscle fatigue and discomfort feelings were observed throughout the conditions but these were not significantly influenced by task variation. After correction for joint angles, the relation between task variation and EMG was significantly biased but significant effects of task variation remained absent. PRACTITIONER SUMMARY: Comparing a one-hour continuous, repetitive Pegboard task with two interrupted conditions revealed no significant influences of task variation. We did observe that the relation between task variation and EMG was biased by posture and therefore advise taking account for posture when investigating manifestations of muscle fatigue in assembly tasks. PMID- 26046392 TI - Highly Crystalline Low Band Gap Polymer Based on Thieno[3,4-c]pyrrole-4,6-dione for High-Performance Polymer Solar Cells with a >400 nm Thick Active Layer. AB - Two thieno[3,4-c]pyrrole-4,6-dione (TPD)-based copolymers combined with 2,2' bithiophene (BT) or (E)-2-(2-(thiophen-2-yl)vinyl)thiophene (TV) have been designed and synthesized to investigate the effect of the introduction of a vinylene group in the polymer backbone on the optical, electrochemical, and photovoltaic properties of the polymers. Although both polymers have shown similar optical band gaps and frontier energy levels, regardless of the introduction of vinylene bridge, the introduction of a pi-extended vinylene group in the polymer backbone substantially enhances the charge transport characteristics of the resulting polymer due to its strong tendency to self assemble and thus to enhance the crystallinity. An analysis on charge recombination in the active layer of a solar cell device indicates that the outstanding charge transport (MU = 1.90 cm(2).V(-1).s(-1)) of PTVTPD with a vinylene group effectively suppresses the bimolecular recombination, leading to a high power conversion efficiency (PCE) up to 7.16%, which is 20% higher than that (5.98%) of the counterpart polymer without a vinylene group (PBTTPD). More importantly, PTVTPD-based devices do not show a large variation of photovoltaic performance with the active layer thickness; that is, the PCE remains at 6% as the active layer thickness increases up to 450 nm, demonstrating that the PTVTPD based solar cell is very compatible with industrial processing. PMID- 26046393 TI - Generating Effective Models and Parameters for RNA Genetic Circuits. AB - RNA genetic circuitry is emerging as a powerful tool to control gene expression. However, little work has been done to create a theoretical foundation for RNA circuit design. A prerequisite to this is a quantitative modeling framework that accurately describes the dynamics of RNA circuits. In this work, we develop an ordinary differential equation model of transcriptional RNA genetic circuitry, using an RNA cascade as a test case. We show that parameter sensitivity analysis can be used to design a set of four simple experiments that can be performed in parallel using rapid cell-free transcription-translation (TX-TL) reactions to determine the 13 parameters of the model. The resulting model accurately recapitulates the dynamic behavior of the cascade, and can be easily extended to predict the function of new cascade variants that utilize new elements with limited additional characterization experiments. Interestingly, we show that inconsistencies between model predictions and experiments led to the model-guided discovery of a previously unknown maturation step required for RNA regulator function. We also determine circuit parameters in two different batches of TX-TL, and show that batch-to-batch variation can be attributed to differences in parameters that are directly related to the concentrations of core gene expression machinery. We anticipate the RNA circuit models developed here will inform the creation of computer aided genetic circuit design tools that can incorporate the growing number of RNA regulators, and that the parametrization method will find use in determining functional parameters of a broad array of natural and synthetic regulatory systems. PMID- 26046398 TI - Matched Backprojection Operator for Combined Scanning Transmission Electron Microscopy Tilt- and Focal Series. AB - Combined tilt- and focal series scanning transmission electron microscopy is a recently developed method to obtain nanoscale three-dimensional (3D) information of thin specimens. In this study, we formulate the forward projection in this acquisition scheme as a linear operator and prove that it is a generalization of the Ray transform for parallel illumination. We analytically derive the corresponding backprojection operator as the adjoint of the forward projection. We further demonstrate that the matched backprojection operator drastically improves the convergence rate of iterative 3D reconstruction compared to the case where a backprojection based on heuristic weighting is used. In addition, we show that the 3D reconstruction is of better quality. PMID- 26046395 TI - Crosstalk between Zinc Status and Giardia Infection: A New Approach. AB - Zinc supplementation has been shown to reduce the incidence and prevalence of diarrhea; however, its anti-diarrheal effect remains only partially understood. There is now growing evidence that zinc can have pathogen-specific protective effects. Giardiasis is a common yet neglected cause of acute-chronic diarrheal illness worldwide which causes disturbances in zinc metabolism of infected children, representing a risk factor for zinc deficiency. How zinc metabolism is compromised by Giardia is not well understood; zinc status could be altered by intestinal malabsorption, organ redistribution or host-pathogen competition. The potential metal-binding properties of Giardia suggest unusual ways that the parasite may interact with its host. Zinc supplementation was recently found to reduce the rate of diarrhea caused by Giardia in children and to upregulate humoral immune response in Giardia-infected mice; in vitro and in vivo, zinc salts enhanced the activity of bacitracin in a zinc-dose-dependent way, and this was not due to zinc toxicity. These findings reflect biological effect of zinc that may impact significantly public health in endemic areas of infection. In this paper, we shall explore one direction of this complex interaction, discussing recent information regarding zinc status and its possible contribution to the outcome of the encounter between the host and Giardia. PMID- 26046396 TI - Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) Is a Novel Nutritional Therapeutic Target for Hyperlipidemia, Non-Alcoholic Fatty Liver Disease, and Atherosclerosis. AB - Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low density lipoprotein receptor family and has a unique structure, which facilitates its multiple functions as a co-receptor for Wnt/beta-catenin signaling and as a ligand receptor for endocytosis. The role LRP6 plays in metabolic regulation, specifically in the nutrient-sensing pathway, has recently garnered considerable interest. Patients carrying an LRP6 mutation exhibit elevated levels of LDL cholesterol, triglycerides, and fasting glucose, which cooperatively constitute the risk factors of metabolic syndrome and atherosclerosis. Since the discovery of this mutation, the general role of LRP6 in lipid homeostasis, glucose metabolism, and atherosclerosis has been thoroughly researched. These studies have demonstrated that LRP6 plays a role in LDL receptor-mediated LDL uptake. In addition, when the LRP6 mutant impaired Wnt-LRP6 signaling, hyperlipidemia, non alcoholic fatty liver disease, and atherosclerosis developed. LRP6 regulates lipid homeostasis and body fat mass via the nutrient-sensing mechanistic target of the rapamycin (mTOR) pathway. Furthermore, the mutant LRP6 triggers atherosclerosis by activating platelet-derived growth factor (PDGF)-dependent vascular smooth muscle cell differentiation. This review highlights the exceptional opportunities to study the pathophysiologic contributions of LRP6 to metabolic syndrome and cardiovascular diseases, which implicate LRP6 as a latent regulator of lipid metabolism and a novel therapeutic target for nutritional intervention. PMID- 26046399 TI - Drug delivery approaches for the treatment of glioblastoma multiforme. AB - CONTEXT: Glioblastoma multiforme (GBM) is by far the most common and aggressive form of glial tumor. It is characterized by a highly proliferative population of cells that invade surrounding tissue and that frequently recur after surgical resection and chemotherapy. Over the last decades, a number of promising novel pharmacological approaches have been investigated, but most of them have failed clinical trials due to some side-effects such as toxicity and poor drug delivery to the brain. The major obstacle in the treatment of GBM is the presence of the blood-brain barrier (BBB). Due to their relatively high molecular weight, most therapeutic drugs fail to cross the BBB from the blood circulation. OBJECTIVE: This paper sheds light on the characteristics of GBM and the challenges of current pharmacological treatments. A closer look is given to the role of nanotechnology in the field of drug delivery, and its application in the treatment of brain tumors such as GBM. METHOD: For this purpose, effort was made to select the most recent studies using predefined search criteria that included at least one of the following keywords in the PubMed and Medline databases: glioblastoma, drug delivery, blood-brain barrier, nanotechnology, and nanoparticle. CONCLUSION: Breakthrough in nanotechnology offers promising applications in cancer therapy and targeted drug delivery. However, more efforts need to be devoted to the development of novel therapeutic strategies that enable the delivery of drugs to desired areas of the brain with limited side-effects and higher therapeutic efficiency. PMID- 26046401 TI - Changes in use of cigarettes and non-cigarette alternative products among college students. AB - INTRODUCTION: The present study examined change in use of various smoked and smokeless non-cigarette alternative products in a sample of college students, stratified by current, or past 30-day, cigarette smoking status. METHODS: Participants were 698 students from seven four-year colleges in Texas. Participants completed two waves of online surveys regarding tobacco use, knowledge, and attitudes, with 14 months between each wave. RESULTS: The most prevalent products used by the entire sample at Wave 1 were cigarettes, followed by hookah, cigars/cigarillos/little cigars, and electronic cigarettes (e cigarettes). At Wave 2, prevalence of e-cigarette use surpassed use of cigars/cigarillos/little cigars. Snus and chew/snuff/dip were relatively uncommon at both waves. Examination of change in use indicated that e-cigarette use increased across time among both current cigarette smokers and non-cigarette smokers. Prevalence of current e-cigarette use doubled across the 14-month period to 25% among current smokers and tripled to 3% among non-cigarette smokers. Hookah use also increased across time, but only among non-cigarette smokers, whereas it decreased among current cigarette smokers. Use of all other non cigarette alternatives remained unchanged across time. Logistic regression analysis was used to examine the socio-demographic predictors of Wave 2 e cigarette use, the only product that increased in use among both current cigarette smokers and non-cigarette smokers. Results indicated that Wave 1 current cigarette use and Wave 1 current e-cigarette use, but not gender, age, or race/ethnicity, were significantly associated with Wave 2 e-cigarette use. CONCLUSIONS: Findings underscore the need to track changes in the use of non cigarette alternatives and call for additional research examining the factors contributing to change in use. PMID- 26046400 TI - Maternal risk taking on the balloon analogue risk task as a prospective predictor of youth alcohol use escalation. AB - The transition from late childhood through middle adolescence represents a critical developmental period during which there is a rapid increase in the initiation and escalation of alcohol use. Alcohol use is part of a constellation of risk taking behaviors that increase during this developmental transition, which can be explained by environmental and genetic factors. Social learning theory (SLT) implicates observations of parental drinking in the development of alcohol use in youth. Parental risk taking more broadly has not previously been examined as a factor predictive of alcohol use escalation in youth across adolescence. The current study examined the relative contributions of maternal risk taking on the Balloon Analogue Risk Task (BART) and maternal alcohol use in the prediction of alcohol escalation among youth over three years. Participants were a sample of 245 youth (55.0% male, 49.6% Caucasian) who participated annually between grades 8 and 10, drawn from a larger study of adolescent risk taking. Within our sample, maternal risk taking, as measured by the BART, predicted increases in alcohol use. Interestingly, maternal alcohol use and other youth factors were not predictive of escalations in youth alcohol use. Our findings suggest the importance of considering maternal riskiness more broadly, rather than solely focusing on maternal alcohol use when attempting to understand youth alcohol use across adolescence. These findings emphasize the relevance of maternal risk taking as measured by a behavioral task and suggest a general level of riskiness displayed by mothers might encourage youth to behave in a riskier manner themselves. PMID- 26046402 TI - The green eyed monster in the bottle: Relationship contingent self-esteem, romantic jealousy, and alcohol-related problems. AB - Previous research suggests that both jealousy and relationship contingent self esteem (RCSE) are related to alcohol use and alcohol-related problems. No work, however, has examined these two constructs together as they relate to motives for alcohol use and alcohol-related problems. The current study aims to build upon emerging literature examining different types of jealousy (i.e., emotional, cognitive, and behavioral), relationship quality (i.e., satisfaction, commitment, closeness), RCSE, and alcohol use. More specifically, the current study aimed to examine the associations between RCSE and drinking to cope and RCSE and alcohol related problems, in the context of the different types of jealousy. Moreover, the current study aimed to assess whether the associations between RCSE, jealousy, and drinking outcomes vary as a function of relationship quality. Two hundred and seventy seven individuals (87% female) at a large southern university participated in the study. They completed measures of RCSE, relationship satisfaction, commitment, closeness, and jealousy as well as alcohol-related outcomes. Using PROCESS, moderated mediational analyses were used to evaluate different types of jealousy as mediators of the association between RCSE and drinking to cope/alcohol-related problems. Further, we aimed to examine whether relationship quality moderated the association between RCSE and jealousy in predicting alcohol-related variables. Results indicated that cognitive jealousy mediated the association between both RCSE and drinking to cope and RCSE and alcohol-related problems. Further, relationship satisfaction, commitment, and closeness were all found to moderate the association between RSCE and cognitive jealousy such that at lower, but not higher levels of satisfaction, commitment, and closeness, cognitive jealousy mediated the association between RCSE and drinking to cope and RCSE and alcohol-related problems. PMID- 26046403 TI - Efficient multi-atlas abdominal segmentation on clinically acquired CT with SIMPLE context learning. AB - Abdominal segmentation on clinically acquired computed tomography (CT) has been a challenging problem given the inter-subject variance of human abdomens and complex 3-D relationships among organs. Multi-atlas segmentation (MAS) provides a potentially robust solution by leveraging label atlases via image registration and statistical fusion. We posit that the efficiency of atlas selection requires further exploration in the context of substantial registration errors. The selective and iterative method for performance level estimation (SIMPLE) method is a MAS technique integrating atlas selection and label fusion that has proven effective for prostate radiotherapy planning. Herein, we revisit atlas selection and fusion techniques for segmenting 12 abdominal structures using clinically acquired CT. Using a re-derived SIMPLE algorithm, we show that performance on multi-organ classification can be improved by accounting for exogenous information through Bayesian priors (so called context learning). These innovations are integrated with the joint label fusion (JLF) approach to reduce the impact of correlated errors among selected atlases for each organ, and a graph cut technique is used to regularize the combined segmentation. In a study of 100 subjects, the proposed method outperformed other comparable MAS approaches, including majority vote, SIMPLE, JLF, and the Wolz locally weighted vote technique. The proposed technique provides consistent improvement over state of-the-art approaches (median improvement of 7.0% and 16.2% in DSC over JLF and Wolz, respectively) and moves toward efficient segmentation of large-scale clinically acquired CT data for biomarker screening, surgical navigation, and data mining. PMID- 26046404 TI - Clinical Implementation of Cardiovascular Pharmacogenomics. PMID- 26046405 TI - Mandatory CPR Training in US High Schools. PMID- 26046406 TI - Having It All: Medicine and a Family. PMID- 26046407 TI - Evidence for Clinical Implementation of Pharmacogenomics in Cardiac Drugs. AB - OBJECTIVE: To comprehensively assess the pharmacogenomic evidence of routinely used drugs for clinical utility. METHODS: Between January 2, 2011, and May 31, 2013, we assessed 71 drugs by identifying all drug/genetic variant combinations with published clinical pharmacogenomic evidence. Literature supporting each drug/variant pair was assessed for study design and methods, outcomes, statistical significance, and clinical relevance. Proposed clinical summaries were formally scored using a modified AGREE (Appraisal of Guidelines for Research and Evaluation) II instrument, including recommendation for or against guideline implementation. RESULTS: Positive pharmacogenomic findings were identified for 51 of 71 cardiovascular drugs (71.8%), representing 884 unique drug/variant pairs from 597 publications. After analysis for quality and clinical relevance, 92 drug/variant pairs were proposed for translation into clinical summaries, encompassing 23 drugs (32.4% of drugs reviewed). All were recommended for clinical implementation using AGREE II, with mean +/- SD overall quality scores of 5.18+/-0.91 (of 7.0; range, 3.67-7.0). Drug guidelines had highest mean +/- SD scores in AGREE II domain 1 (Scope) (91.9+/-6.1 of 100) and moderate but still robust mean +/- SD scores in domain 3 (Rigor) (73.1+/-11.1), domain 4 (Clarity) (67.8+/-12.5), and domain 5 (Applicability) (65.8+/-10.0). Clopidogrel (CYP2C19), metoprolol (CYP2D6), simvastatin (rs4149056), dabigatran (rs2244613), hydralazine (rs1799983, rs1799998), and warfarin (CYP2C9/VKORC1) were distinguished by the highest scores. Seven of the 9 most commonly prescribed drugs warranted translation guidelines summarizing clinical pharmacogenomic information. CONCLUSION: Considerable clinically actionable pharmacogenomic information for cardiovascular drugs exists, supporting the idea that consideration of such information when prescribing is warranted. PMID- 26046408 TI - Blockers of Angiotensin Other Than Olmesartan in Patients With Villous Atrophy: A Nationwide Case-Control Study. AB - OBJECTIVE: To examine the association between the previous use of nonolmesartan angiotensin receptor blockers (ARBs) or any angiotensin-converting enzyme inhibitor (ACEI) and subsequent villous atrophy (VA) in patients with small intestinal VA as compared with general population-matched controls. PATIENTS AND METHODS: A case-control study was used to link nationwide histopathology data on 2933 individuals with VA (Marsh grade 3) to the Swedish Prescribed Drug Register to examine the association between the use of ACEIs as well as the specific use of ARBs other than olmesartan and subsequent VA. Olmesartan is not available in Sweden, so this exposure was not examined. All individuals with VA had biopsies performed between July 1, 2005, and January 29, 2008, and matched on age, sex, calendar period of birth, and county of residence to 14,571 controls from the general population. RESULTS: Use of nonolmesartan ARBs was not associated with VA (odds ratio, 0.84; 95% CI, 0.64-1.09; P=.19). Neither was VA associated with a previous medication of any ACEI (odds ratio, 1.08; 95% CI, 0.90-1.30; P=.41). Restricting the analysis to individuals with repeated prescriptions for ACEIs or ARBs revealed only marginally changed risk estimates for VA. CONCLUSION: The lack of association between the use of ACEIs and nonolmesartan ARBs and subsequent VA suggests that these medications are not a major risk factor for the development of VA in the general population. PMID- 26046409 TI - Long-Term Follow-Up of Crohn Disease Fistulas After Local Injections of Bone Marrow-Derived Mesenchymal Stem Cells. AB - OBJECTIVE: To assess the long-term outcome of patients treated with serial intrafistular injections of autologous bone marrow-derived mesenchymal stem cells (MSCs) for refractory Crohn fistulas in terms of safety and efficacy. PATIENTS AND METHODS: Starting from January 10, 2007, through June 30, 2014, clinical evaluation, calculation of the Crohn disease activity index (CDAI), therapeutic management, and documentation of adverse events in 8 of the 10 patients (5 men; median age, 37 years) who had been injected locally with MSCs were prospectively recorded for 72 months. Cumulative probabilities of fistula recurrence and medical or surgical treatment were estimated using a Kaplan-Meier method, whereas differences among the pre- and post-MSC CDAI values were calculated with the Mann Whitney U test. RESULTS: Following disease remission observed after 12 months from MSC treatment (P<.001), the mean CDAI score increased significantly during the subsequent 2 years (P=.007), and was then followed by a gradual decrease, with the patients achieving remission again (P=.02) at the end of the 5-year follow-up. The probability of fistula relapse-free survival was 88% at 1 year, 50% at 2 years, and 37% during the following 4 years, and the cumulative probabilities of surgery- and medical-free survival were 100% and 88% at 1 year, 75% and 25% at 2, 3, and 4 years, and 63% and 25% at 5 and 6 years, respectively. No adverse events were recorded. CONCLUSION: Locally injected MSCs constitute a safe therapy that rescues refractory patients and regains responsiveness to drugs previously proved ineffective. PMID- 26046410 TI - Absolute Monocyte Count and Lymphocyte-Monocyte Ratio Predict Outcome in Nodular Sclerosis Hodgkin Lymphoma: Evaluation Based on Data From 1450 Patients. AB - OBJECTIVE: To verify whether absolute monocyte count (AMC) and lymphocyte- monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL). PATIENTS AND METHODS: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007. RESULTS: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm(3), and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm(3) was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3). CONCLUSION: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice. PMID- 26046411 TI - Aging and Heart Rate in Heart Failure: Clinical Implications for Long-term Mortality. AB - OBJECTIVE: To assess the relationship between resting heart rate and long-term all-cause mortality in ambulatory patients with heart failure (HF) relative to age, considering that although heart rate has been strongly associated with mortality in HF, the influence of age on target heart rate is incompletely characterized. PATIENTS AND METHODS: Consecutive patients in sinus rhythm referred to an ambulatory HF clinic of a university hospital between August 1, 2001, and March 31, 2012, were included. Unadjusted and adjusted Cox regression analyses were performed to assess heart rate as a prognostic marker, both as a continuous variable and after categorization into quintiles. Smooth spline estimates and hazard ratios (HRs) were plotted for 2 age strata (<75 years vs >=75 years) for each individual heart rate. RESULTS: A total of 1033 patients were included (766 men [74.2%]; mean age, 65.1+/-12.6 years). During a mean follow-up of 4.6+/-3.3 years (median, 3.8 years [25th-75th percentile, 1.9-6.9]), 476 patients (46.1%) died. Mortality was associated with a statistically greater heart rate in the total cohort (HR, 1.18; 95% CI, 1.11-1.26; P<.001). From a clinical viewpoint, this means an 18% increased risk for every 10-beats/min elevation in heart rate. The same characteristics were present in the relationship between heart rate assessed after 6 months and long-term mortality (HR, 1.30; 95% CI, 1.20-1.42; P<.001). Overall, the prognostic importance of heart rate in ambulatory patients with HF was largely influenced by patient age. Remarkably, in the elderly population (>=75 years), heart rate below 68 beats/min conferred an increased risk of death, whereas in younger patients, mortality exhibited a declining slope at even the lowest heart rates. CONCLUSION: Our research, if applicable to the prospective management of patients with ambulatory HF, suggests that patients aged 75 years or older have the best outcomes with target heart rates of 68 beats/min; however, younger patients may benefit from lower heart rates, even below 55 beats/min. PMID- 26046413 TI - Assessing the Existing Professional Exercise Recommendations for Hypertension: A Review and Recommendations for Future Research Priorities. AB - The Eighth Joint National Committee guideline on the management of adult hypertension was recently released. Rather than recommending specific lifestyle modifications as in the Seventh Joint National Committee guideline, the Eighth Joint National Committee endorsed the recommendations of the American Heart Association/American College of Cardiology 2013 Lifestyle Work Group. The Lifestyle Work Group report included systematic reviews and meta-analyses of randomized controlled trials or controlled clinical trials from 2001 through 2011 of "fair to good" quality. In total, 11 reviews qualified for inclusion in the report, 6 of which included blood pressure (BP) as the primary outcome. Three reviews did not find significant reductions in BP, and BP status was not reported in 5. When BP was reported, only 22% of the patients had hypertension. Yet, the group concluded with a strength of evidence categorized as "high" that aerobic exercise training reduces BP by 1 to 5 mm Hg in individuals with hypertension and that the most effective exercise interventions on average included aerobic physical activity of moderate to vigorous intensity for at least 12 weeks, 3 to 4 sessions per week lasting 40 minutes per session. The exercise prescription recommendations of the Lifestyle Work Group deviate from those of other professional organizations and committees including the Seventh Joint National Committee, another American Heart Association scientific statement, the American College of Sports Medicine, the European Society of Hypertension/European Society of Cardiology, and the Canadian Health Education Program. The purposes of this review are to present the existing exercise recommendations for hypertension, discuss reasons for differences in these recommendations, discuss gaps in the literature, and address critical future research needs regarding exercise prescription for hypertension. PMID- 26046414 TI - Diabetes and Kidney Disease in American Indians: Potential Role of Sugar Sweetened Beverages. AB - Since the early 20th century, a marked increase in obesity, diabetes, and chronic kidney disease has occurred in the American Indian population, especially the Pima Indians of the Southwest. Here, we review the current epidemic and attempt to identify remediable causes. A search was performed using PubMed and the search terms American Indian and obesity, American Indian and diabetes, American Indian and chronic kidney disease, and American Indian and sugar or fructose, Native American, Alaska Native, First Nations, Aboriginal, Amerind, and Amerindian for American Indian for articles linking American Indians with diabetes, obesity, chronic kidney disease, and sugar; additional references were identified in these publications traced to 1900 and articles were reviewed if they were directly discussing these topics. Multiple factors are involved in the increased risk for diabetes and kidney disease in the American Indian population, including poverty, overnutrition, poor health care, high intake of sugar, and genetic mechanisms. Genetic factors may be especially important in the Pima, as historical records suggest that this group was predisposed to obesity before exposure to Western culture and diet. Exposure to sugar-sweetened beverages may also be involved in the increased risk for chronic kidney disease. In these small populations in severe health crisis, we recommend further studies to investigate the role of excess added sugar, especially sugar-sweetened beverages, as a potentially remediable risk factor. PMID- 26046415 TI - 53-Year-Old Man With Hypernatremia and Encephalopathy. PMID- 26046412 TI - Motor and Nonmotor Circuitry Activation Induced by Subthalamic Nucleus Deep Brain Stimulation in Patients With Parkinson Disease: Intraoperative Functional Magnetic Resonance Imaging for Deep Brain Stimulation. AB - OBJECTIVE: To test the hypothesis suggested by previous studies that subthalamic nucleus (STN) deep brain stimulation (DBS) in patients with Parkinson disease would affect the activity of motor and nonmotor networks, we applied intraoperative functional magnetic resonance imaging (fMRI) to patients receiving DBS. PATIENTS AND METHODS: Ten patients receiving STN DBS for Parkinson disease underwent intraoperative 1.5-T fMRI during high-frequency stimulation delivered via an external pulse generator. The study was conducted between January 1, 2013, and September 30, 2014. RESULTS: We observed blood oxygen level-dependent (BOLD) signal changes (false discovery rate <0.001) in the motor circuitry (including the primary motor, premotor, and supplementary motor cortices; thalamus; pedunculopontine nucleus; and cerebellum) and in the limbic circuitry (including the cingulate and insular cortices). Activation of the motor network was observed also after applying a Bonferroni correction (P<.001) to the data set, suggesting that across patients, BOLD changes in the motor circuitry are more consistent compared with those occurring in the nonmotor network. CONCLUSION: These findings support the modulatory role of STN DBS on the activity of motor and nonmotor networks and suggest complex mechanisms as the basis of the efficacy of this treatment modality. Furthermore, these results suggest that across patients, BOLD changes in the motor circuitry are more consistent than those in the nonmotor network. With further studies combining the use of real-time intraoperative fMRI with clinical outcomes in patients treated with DBS, functional imaging techniques have the potential not only to elucidate the mechanisms of DBS functioning but also to guide and assist in the surgical treatment of patients affected by movement and neuropsychiatric disorders. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01809613. PMID- 26046416 TI - Tapering Long-term Opioid Therapy in Chronic Noncancer Pain: Evidence and Recommendations for Everyday Practice. AB - Increasing concern about the risks and limited evidence supporting the therapeutic benefit of long-term opioid therapy for chronic noncancer pain are leading prescribers to consider discontinuing the use of opioids. In addition to overt addiction or diversion, the presence of adverse effects, diminishing analgesia, reduced function and quality of life, or the absence of progress toward functional goals can justify an attempt at weaning patients from long-term opioid therapy. However, discontinuing opioid therapy is often hindered by patients' psychiatric comorbidities and poor coping skills, as well as the lack of formal guidelines for the prescribers. The aim of this article is to review the existing literature and formulate recommendations for practitioners aiming to discontinue long-term opioid therapy. Specifically, this review aims to answer the following questions: What is an optimal opioid tapering regimen? How can the risks involved in a taper be managed? What are the alternatives to an opioid taper? A PubMed literature search was conducted using the keywords chronic pain combined with opioid withdrawal, taper, wean and detoxification. Six hundred ninety-five documents were identified and screened; 117 were deemed directly relevant and are included. On the base of this literature review, this article proposes evidence-based recommendations and expert-based suggestions for clinical practice. Furthermore, areas of lack of evidence are identified, providing opportunities for further research. PMID- 26046417 TI - Systemic Mastocytosis With Decreased Bone Density and Fractures. PMID- 26046418 TI - 44-Year-Old Man With Abdominal Pain, Fever, and Bloody Diarrhea. PMID- 26046419 TI - Howard Walter Florey-Production of Penicillin. PMID- 26046421 TI - Analyses of inappropriate shocks in a Spanish ICD primary prevention population: Predictors and prognoses. AB - BACKGROUND: ICDs have been demonstrated to be highly effective in the primary prevention of sudden death, but inappropriate shocks (IS) occur frequently and represent one of the most important adverse effects of ICDs. The aim of this study was to analyze IS and identify the clinical predictors and prognostic implications of ISs in a real-world primary prevention ICD population. METHODS: This multicenter retrospective study was performed in 13 centers with experience in the field of ICD implantation (at least 30 per year) and ICD follow-up in Spain. All consecutive patients who underwent ICD implantation for primary prevention between January 2008 and May 2014 were included. RESULTS: One-thousand sixteen patients were included, and 4 (0.39%) were lost to follow-up. Two-hundred seventeen (21.4%) patients suffered from shock; 69 (6.8%) of these patients experienced IS, and 154 (15.4%) experienced appropriate shocks (AS). Age (<65 years, hazard ratio (HR) 2.588 [95% CI 1.282-5.225]; p=0.008), history of atrial fibrillation (HR 2.252 [95% CI 1.230-4.115]; p=0.009), non-ischemic myocardiopathy (HR 2.258 [95% CI 1.090-4.479]; p=0.028), and cardiac resynchronization therapy (HR 0.385 [95% CI 0.200-0.740]; p=0.004) were identified as IS predictors in a multivariate analysis. IS was not associated with rehospitalization due to heart failure, myocardial infarction, cardiovascular mortality or all-cause mortality. CONCLUSIONS: This analysis of our national registry identified the independent IS predictors of age, atrial fibrillation history and cardiac resynchronization therapy and suggests that ISs are not linked to poorer clinical endpoints. PMID- 26046422 TI - Prevalence and risk of cardiovascular risk factors and events in offspring of patients at high vascular risk and effect of location of parental vascular disease. AB - BACKGROUND: Offspring of patients with cardiovascular disease are at increased risk of developing cardiovascular events. We evaluated whether prevalence of risk factors in offspring of patients with increased cardiovascular risk is higher compared with the general population and whether the risk of cardiovascular events and prevalence of cardiovascular risk factors in offspring is dependent on parental vascular disease location. METHODS: Of 4270 patients enrolled in the SMART cohort we assessed after a follow-up of 7 years (IQR 4-8) the presence of cardiovascular risk factors and disease in their 10,572 children by questionnaire. The SMART patients had symptomatic vascular disease (coronary artery disease (CAD) (n = 1826), cerebrovascular disease (CVD) (n = 637), peripheral artery disease (PAD) (n = 275), abdominal aortic aneurysm (AAA) (n = 98), polyvascular disease (>= 2 vascular manifestations) (n = 371)) or risk factors (hypercholesterolemia, diabetes, hypertension) (n = 1063). The prevalence of risk factors in offspring was compared with the general population and stratified for parental vascular disease location. The relation between parental vascular disease location and cardiovascular events in offspring was determined by Poisson regression. RESULTS: The offspring had higher prevalence of in particular hypercholesterolemia and hypertension compared with the general population, irrespective of the parental vascular disease location. Higher risks of cardiovascular events compared with offspring of patients without manifest vascular disease were observed in offspring of patients with CAD (PR 1.8, 95%CI 0.9-3.4), CVD (PR 2.4, 95%CI 1.2-4.8), PAD (PR 2.8, 95%CI 1.3-6.4), polyvascular disease (PR 2.5, 95%CI 1.2-5.2), but not with AAA (PR 1.7, 95%CI 0.5-6.1). CONCLUSIONS: In offspring from patients with cardiovascular disease or risk factors, the prevalence of traditional risk factors was higher compared with the general population, independent of the location of vascular disease of the parent. Offspring of patients with PAD had the highest risk of developing vascular disease. PMID- 26046423 TI - Tip-of-the-tongue states reoccur because of implicit learning, but resolving them helps. AB - In six experiments, we elicited tip-of-the-tongue (TOT) states, to investigate the novel finding that TOTs on particular words tend to recur for speakers, and examine whether this effect can be attributed to implicit learning of the incorrect mapping from a lemma to phonology for that word. We elicited TOTs by asking participants to supply the word that fit a given definition, and then retested participants on those same definitions in a second test. In Experiments 1-3 we investigated the time course of learning that occurs during TOTs, and found that TOTs are likely to recur with a five-minute test-retest interval, that this error learning can still be measured following a one-week interval, and that they recur for both monolingual and bilingual speakers. We also report the novel finding that error learning can be corrected when individuals resolve their TOT, making them less likely to re-experience a TOT for that word on a later test. In Experiment 4 we showed that these learning effects are not modulated by a priori knowledge of future tests. In Experiments 5a and 5b we show that orthographic cues can help individuals resolve their TOTs, and that these cued-resolutions lead to corrective learning in much the same way as self-resolutions. In Experiment 6 we demonstrate that effortful retrieval is critical to finding differences in error learning when manipulating the duration of unresolved TOTs. We conclude that the error-repetition effect is highly robust, and is best explained by implicit learning of the erroneous state. These findings reinforce the notion that the language production system is dynamic, and continually learning from experience, even when that experience is errorful. PMID- 26046424 TI - The kind of group you want to belong to: Effects of group structure on group accuracy. AB - There has been much interest in group judgment and the so-called 'wisdom of crowds'. In many real world contexts, members of groups not only share a dependence on external sources of information, but they also communicate with one another, thus introducing correlations among their responses that can diminish collective accuracy. This has long been known, but it has-to date-not been examined to what extent different kinds of communication networks may give rise to systematically different effects on accuracy. We argue that equations that relate group accuracy, individual accuracy, and group diversity (see Hogarth, 1978; Page, 2007) are useful theoretical tools for understanding group performance in the context of research on group structure. In particular, these equations may serve to identify the kind of group structures that improve individual accuracy without thereby excessively diminishing diversity so that the net positive effect is an improvement even on the level of collective accuracy. Two experiments are reported where two structures (the complete network and a small world network) are investigated from this perspective. It is demonstrated that the more constrained network (the small world network) outperforms the network with a free flow of information. PMID- 26046425 TI - Individual differences in cognitive performance and brain structure in typically developing children. AB - Individual differences in cognitive patterning is informative in understanding one's cognitive strengths and weaknesses. However, little is known about the difference in brain structures relating to individual differences in cognitive patterning. In this study, we classified typically developing children (n=277; age range, 5-16 years) into subtypes with k-means cluster analysis along with factor index scores using the Wechsler Intelligence Scale for Children (Third Edition). We then applied voxel-based morphometry to investigate whether significant gray-matter-volume differences existed among subtypes of cognitive patterns. Depending on the level of performance and cognitive patterning, we obtained six subtypes. One subtype that generally scored below average showed larger volume in the right middle temporal gyrus than the other five. On the other hand, two subtypes that achieved average levels of performance showed reverse-patterned factor index scores (one scored higher in Verbal Comprehension and Freedom from Distractibility, and the other scored lower in these two factor index scores) and had smaller volume in the right middle temporal gyrus than the other subtypes. From these results, we concluded that cognitive discrepancy was also obvious in typically developing children and that differences in cognitive patterning are represented in brain structure. PMID- 26046426 TI - Ovarian cancer mortality and industrial pollution. AB - We investigated whether there might be excess ovarian cancer mortality among women residing near Spanish industries, according to different categories of industrial groups and toxic substances. An ecologic study was designed to examine ovarian cancer mortality at a municipal level (period 1997-2006). Population exposure to pollution was estimated by means of distance from town to facility. Using Poisson regression models, we assessed the relative risk of dying from ovarian cancer in zones around installations, and analyzed the effect of industrial groups and pollutant substances. Excess ovarian cancer mortality was detected in the vicinity of all sectors combined, and, principally, near refineries, fertilizers plants, glass production, paper production, food/beverage sector, waste treatment plants, pharmaceutical industry and ceramic. Insofar as substances were concerned, statistically significant associations were observed for installations releasing metals and polycyclic aromatic chemicals. These results support that residing near industries could be a risk factor for ovarian cancer mortality. PMID- 26046427 TI - Economic analysis of microaerobic removal of H2S from biogas in full-scale sludge digesters. AB - The application of microaerobic conditions during sludge digestion has been proven to be an efficient method for H2S removal from biogas. In this study, three microaerobic treatments were considered as an alternative to the technique of biogas desulfurization applied (FeCl3 dosing to the digesters) in a WWTP comprising three full-scale anaerobic reactors treating sewage sludge, depending on the reactant: pure O2 from cryogenic tanks, concentrated O2 from PSA generators, and air. These alternatives were compared in terms of net present value (NPV) with a fourth scenario consisting in the utilization of iron-sponge bed filter inoculated with thiobacteria. The analysis revealed that the most profitable alternative to FeCl3 addition was the injection of concentrated O2 (0.0019 ?/m(3) biogas), and this scenario presented the highest robustness towards variations in the price of FeCl3, electricity, and in the H2S concentration. PMID- 26046428 TI - Improvement of butanol production from a hardwood hemicelluloses hydrolysate by combined sugar concentration and phenols removal. AB - The feasibility of using hardwood hemicellulosic pre-hydrolysate recovered from a dissolving pulping process for Acetone-Butanol-Ethanol (ABE) fermentation has been investigated. Dilutions and detoxification methods based on flocculation and nanofiltration were tested to determine the inhibitory concentration of phenolic compounds and to evaluate the efficiency of inhibitors removal on fermentation. Flocculation carried out with ferric sulfate was the most effective method for removal of phenolics (56%) and acetic acid (80%). The impact on fermentation was significant, with an ABE production of 6.40 g/L and 4.25 g/L when using flocculation or combined nanofiltration/flocculation respectively, as compared to a non-significant production for the untreated hydrolysate. By decreasing the toxicity effect of inhibitors, this study reports for the first time that the use of these techniques is efficient to increase the inhibitory concentration threshold of phenols, from 0.3g/L in untreated hydrolysate, to 1.1g/L in flocculated and in nanofiltrated and flocculated hydrolysates. PMID- 26046430 TI - Optimum sampling time and frequency for measuring N2O emissions from a rain-fed cereal cropping system. AB - Annual cumulative nitrous oxide (N2O) emissions from soil have historically been calculated from intermittent data measured manually via the static chamber method. The temporal variability in emissions, both diurnally and between days, introduces uncertainty into the up-scaling of static chamber data. This study assessed the most appropriate time of the day to sample and the best sampling frequency to ensure reliable estimates of annual cumulative emissions. Sub-daily N2O emissions were measured using automatic gas sampling chambers over three years in a sub-tropical cereal crop system. The sub-daily dataset was divided into eight time periods per day to assess the best sampling time of the day. Daily mean N2O emissions were subsampled from the dataset to simulate different sampling frequencies, including pre-set and rainfall-based scenarios. Annual cumulative N2O emissions were calculated for these scenarios and compared to the 'actual' annual cumulative emissions. The results demonstrated that manual sampling between mid-morning (09:00) and midday (12:00), and late evening (21:00) and midnight (24:00) best approximated the daily mean N2O emission. Factoring in the need to sample during daylight hours, gas sampling from mid-morning to midday was the most appropriate sampling time. Overall, triweekly sampling provided the most accurate estimate (+/- 4% error) of annual cumulative N2O emissions, but was undesirable due to its labour intensive high sampling frequency. Weekly sampling with triweekly sampling in the two weeks following rainfall events was the most efficient sampling schedule, as it had similar accuracy (+/- 5% error) to the triweekly sampling, the smallest variability in outcomes and approximately half the sampling times of triweekly sampling. Inter-annual rainfall variability affected the accuracy and variability of estimations of annual cumulative emissions, but did not affect the overall trends in sampling frequency accuracy. This study demonstrated that intermittent samplings are capable of estimating the annual cumulative N2O emissions satisfactorily when timed appropriately. PMID- 26046429 TI - Incubation at 25 degrees C prevents acid crash and enhances alcohol production in Clostridium carboxidivorans P7. AB - Incubation of carboxydotrophs at 37 degrees C provides optimal conditions for their growth. However, a fast accumulation of organic acids, specifically acetate, during the exponential growth phase may result in low alcohol production and substrate consumption due to a phenomenon known as "acid crash". The present work investigates growth and productivity of Clostridium carboxidivorans P7 at two incubation temperatures. At 37 degrees C the culture was not able to override the "acid crash", resulting in low ethanol titers (1.56 mM). On the other hand, lower metabolic rates at 25 degrees C enhanced ethanol and butanol production (32.1 and 14.5 mM, respectively). Moreover, at low temperatures, hexanol and caproic acid were also produced at significant concentrations, 8.21 and 9.02 mM respectively, among the highest values reported for P7. Our results demonstrate that production of biofuels with longer carbon chains molecules may be enhanced incubating syngas-fermenting acetogenic bacteria at sub-optimal temperatures. PMID- 26046431 TI - Kicking Out Pathogens in Exosomes. AB - Host-pathogen interactions involve a series of attacks and counter-attacks. Miao et al. show that, although some invading bacteria can take shelter in lysosomes by neutralizing their pH, this respite is temporary, as host cells can expel them in exosomes. PMID- 26046432 TI - What's Worth the Risk? A Neural Circuit for Trade-Offs. AB - Cost-benefit analysis in decision making takes place in everyday life for animals and humans alike. In this issue, a neural circuit specific for modulating these behaviors is identified in rats and reveals elusive functional distinctions between long-mysterious anatomical features of the brain. PMID- 26046433 TI - It's a SMAD/SMAD World. AB - DPC4/SMAD4 mutations are associated with aggressive pancreatic cancer. In this issue of Cell, Whittle et al. demonstrate that Runx3 expression combined with Dpc4/Smad4 status can predict the metastatic propensity of pancreatic tumors, providing valuable guidance for personalized therapy for patients with pancreatic cancer. PMID- 26046434 TI - Dying mRNA Tells a Story of Its Life. AB - In this issue of Cell, Pelechano et al. report that sequencing of mRNA decay intermediates shows surprisingly tight coupling of a major decay pathway to the movement of the last translating ribosome, revealing stress- and starvation dependent modulation of translation elongation. PMID- 26046435 TI - Forget the Parents: Epigenetic Reprogramming in Human Germ Cells. AB - Epigenetic reprogramming in the germline resets genomic potential and erases epigenetic memory. Three studies by Gkountela et al., Guo et al., and Tang et al. analyze the transcriptional and epigenetic landscape of human primordial germ cells, revealing a unique transcriptional network and progressive and conserved global erasure of DNA methylation. PMID- 26046437 TI - PQBP1 Is a Proximal Sensor of the cGAS-Dependent Innate Response to HIV-1. AB - Dendritic cells (DCs) play a critical role in the immune response to viral infection through the facilitation of cell-intrinsic antiviral activity and the activation of adaptive immunity. HIV-1 infection of DCs triggers an IRF3 dependent innate immune response, which requires the activity of cyclic GAMP synthase (cGAS). We report the results of a targeted RNAi screen utilizing primary human monocyte-derived DCs (MDDCs) to identify immune regulators that directly interface with HIV-1-encoded features to initiate this innate response. Polyglutamine binding protein 1 (PQBP1) emerged as a strong candidate through this analysis. We found that PQBP1 directly binds to reverse-transcribed HIV-1 DNA and interacts with cGAS to initiate an IRF3-dependent innate response. MDDCs derived from Renpenning syndrome patients, who harbor mutations in the PQBP1 locus, possess a severely attenuated innate immune response to HIV-1 challenge, underscoring the role of PQBP1 as a proximal innate sensor of a HIV-1 infection. PMID- 26046438 TI - Cyclic Regulation of Sensory Perception by a Female Hormone Alters Behavior. AB - Females may display dramatically different behavior depending on their state of ovulation. This is thought to occur through sex-specific hormones acting on behavioral centers in the brain. Whether incoming sensory activity also differs across the ovulation cycle to alter behavior has not been investigated. Here, we show that female mouse vomeronasal sensory neurons (VSNs) are temporarily and specifically rendered "blind" to a subset of male-emitted pheromone ligands during diestrus yet fully detect and respond to the same ligands during estrus. VSN silencing occurs through the action of the female sex-steroid progesterone. Not all VSNs are targeted for silencing; those detecting cat ligands remain continuously active irrespective of the estrous state. We identify the signaling components that account for the capacity of progesterone to target specific subsets of male-pheromone responsive neurons for inactivation. These findings indicate that internal physiology can selectively and directly modulate sensory input to produce state-specific behavior. PAPERCLIP. PMID- 26046439 TI - Allosteric Regulation in Gating the Central Channel of the Nuclear Pore Complex. AB - The nuclear pore complex (NPC) arose in evolution as the cell's largest and most versatile transport channel. Current models for selective transport mediated by NPCs are focused on properties of intrinsically disordered regions of nucleoporins that bind transport factors. In contrast, structured regions are considered to provide static anchoring sites for the disordered regions without affecting transport factor binding. Here, we demonstrate allosteric coupling between a structured domain of a channel nucleoporin (Nup58) and its neighboring disordered domain in interaction with another channel nucleoporin (Nup54) and a transport factor (Kapbeta1). Analysis of multiple equilibria showed that multivalent interactions of Kapbeta1 with the disordered domains of Nup58 stabilize the neighboring structured domain associated with Nup54, shifting conformational equilibria from homo-oligomers to hetero-oligomers. Based on these and previous crystallographic results, a quantitative framework was established to describe constriction and dilation of the central channel as a function of transport factor occupancy. PMID- 26046436 TI - Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes. AB - Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery. PMID- 26046441 TI - Widespread Co-translational RNA Decay Reveals Ribosome Dynamics. AB - It is generally assumed that mRNAs undergoing translation are protected from decay. Here, we show that mRNAs are, in fact, co-translationally degraded. This is a widespread and conserved process affecting most genes, where 5'-3' transcript degradation follows the last translating ribosome, producing an in vivo ribosomal footprint. By sequencing the ends of 5' phosphorylated mRNA degradation intermediates, we obtain a genome-wide drug-free measurement of ribosome dynamics. We identify general translation termination pauses in both normal and stress conditions. In addition, we describe novel codon-specific ribosomal pausing sites in response to oxidative stress that are dependent on the RNase Rny1. Our approach is simple and straightforward and does not require the use of translational inhibitors or in vitro RNA footprinting that can alter ribosome protection patterns. PMID- 26046440 TI - N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. AB - N(6)-methyladenosine (m(6)A) is the most abundant internal modification in mammalian mRNA. This modification is reversible and non-stoichiometric and adds another layer to the dynamic control of mRNA metabolism. The stability of m(6)A modified mRNA is regulated by an m(6)A reader protein, human YTHDF2, which recognizes m(6)A and reduces the stability of target transcripts. Looking at additional functional roles for the modification, we find that another m(6)A reader protein, human YTHDF1, actively promotes protein synthesis by interacting with translation machinery. In a unified mechanism of m(6)A-based regulation in the cytoplasm, YTHDF2-mediated degradation controls the lifetime of target transcripts, whereas YTHDF1-mediated translation promotion increases translation efficiency, ensuring effective protein production from dynamic transcripts that are marked by m(6)A. Therefore, the m(6)A modification in mRNA endows gene expression with fast responses and controllable protein production through these mechanisms. PMID- 26046442 TI - Yeast Proteome Dynamics from Single Cell Imaging and Automated Analysis. AB - Proteomics has proved invaluable in generating large-scale quantitative data; however, the development of systems approaches for examining the proteome in vivo has lagged behind. To evaluate protein abundance and localization on a proteome scale, we exploited the yeast GFP-fusion collection in a pipeline combining automated genetics, high-throughput microscopy, and computational feature analysis. We developed an ensemble of binary classifiers to generate localization data from single-cell measurements and constructed maps of ~3,000 proteins connected to 16 localization classes. To survey proteome dynamics in response to different chemical and genetic stimuli, we measure proteome-wide abundance and localization and identified changes over time. We analyzed >20 million cells to identify dynamic proteins that redistribute among multiple localizations in hydroxyurea, rapamycin, and in an rpd3Delta background. Because our localization and abundance data are quantitative, they provide the opportunity for many types of comparative studies, single cell analyses, modeling, and prediction. VIDEO ABSTRACT. PMID- 26046443 TI - The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells. AB - Germ cells are vital for transmitting genetic information from one generation to the next and for maintaining the continuation of species. Here, we analyze the transcriptome of human primordial germ cells (PGCs) from the migrating stage to the gonadal stage at single-cell and single-base resolutions. Human PGCs show unique transcription patterns involving the simultaneous expression of both pluripotency genes and germline-specific genes, with a subset of them displaying developmental-stage-specific features. Furthermore, we analyze the DNA methylome of human PGCs and find global demethylation of their genomes. Approximately 10 to 11 weeks after gestation, the PGCs are nearly devoid of any DNA methylation, with only 7.8% and 6.0% of the median methylation levels in male and female PGCs, respectively. Our work paves the way toward deciphering the complex epigenetic reprogramming of the germline with the aim of restoring totipotency in fertilized oocytes. PMID- 26046445 TI - SnapShot: Spliceosome Dynamics I. AB - Spliceosomes are multi-megadalton RNA-protein molecular machines that carry out pre-mRNA splicing, that is, the removal of non-coding intervening sequences (introns) from eukaryotic pre-mRNAs and the ligation of neighboring coding regions (exons) to produce mature mRNA for protein biosynthesis on the ribosome. They are the prototypes of dynamic molecular machines, assembling de novo for each splicing event by the stepwise recruitment of subunits on a substrate. PMID- 26046444 TI - A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development. AB - Resetting of the epigenome in human primordial germ cells (hPGCs) is critical for development. We show that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naive pluripotency genes TFCP2L1 and KLF4. This unique gene regulatory network, established by SOX17 and BLIMP1, drives comprehensive germline DNA demethylation by repressing DNA methylation pathways and activating TET-mediated hydroxymethylation. Base resolution methylome analysis reveals progressive DNA demethylation to basal levels in week 5-7 in vivo hPGCs. Concurrently, hPGCs undergo chromatin reorganization, X reactivation, and imprint erasure. Despite global hypomethylation, evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. Remarkably, some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance that may have phenotypic consequences. We provide comprehensive insight on early human germline transcriptional network and epigenetic reprogramming that subsequently impacts human development and disease. PMID- 26046446 TI - Low MBL-associated serine protease 2 (MASP-2) levels correlate with urogenital schistosomiasis in Nigerian children. AB - OBJECTIVES: The human mannose-binding lectin (MBL) and ficolins (FCN) are involved in pathogen recognition in the first line of defence. They support activation of the complement lectin cascade in the presence of MBL-associated serine protease 2 (MASP-2), a protein that cleaves the C4 and C2 complement components. Recent studies found that distinct MBL2 and FCN2 promoter variants and their corresponding serum levels are associated with relative protection from urogenital schistosomiasis. METHODS: We investigated the contribution of MASP-2 levels and MASP2 polymorphisms in a Nigerian study group, of 163 individuals infected with Schistosoma haematobium and 183 healthy subjects. RESULTS: MASP-2 serum levels varied between younger children (<=12 years) and older children (>12 years) and adults (P = 0.0001). Younger children with a patent infection had significantly lower MASP-2 serum levels than uninfected children (P = 0.0074). Older children and adults (>12 years) with a current infection had higher serum MASP-2 levels than controls (P = 0.032). MBL serum levels correlated positively with MASP-2 serum levels (P = 0.01). MASP2 secretor haplotypes were associated with MASP-2 serum levels in healthy subjects. The heterozygous MASP2 p.P126L variant was associated with reduced serum MASP-2 levels (P = 0.01). CONCLUSIONS: The findings indicate that higher MASP-2 serum levels are associated with relative protection from urogenital schistosomiasis in Nigerian children. PMID- 26046447 TI - Probabilistic hazard assessment for skin sensitization potency by dose-response modeling using feature elimination instead of quantitative structure-activity relationships. AB - Supervised learning methods promise to improve integrated testing strategies (ITS), but must be adjusted to handle high dimensionality and dose-response data. ITS approaches are currently fueled by the increasing mechanistic understanding of adverse outcome pathways (AOP) and the development of tests reflecting these mechanisms. Simple approaches to combine skin sensitization data sets, such as weight of evidence, fail due to problems in information redundancy and high dimensionality. The problem is further amplified when potency information (dose/response) of hazards would be estimated. Skin sensitization currently serves as the foster child for AOP and ITS development, as legislative pressures combined with a very good mechanistic understanding of contact dermatitis have led to test development and relatively large high-quality data sets. We curated such a data set and combined a recursive variable selection algorithm to evaluate the information available through in silico, in chemico and in vitro assays. Chemical similarity alone could not cluster chemicals' potency, and in vitro models consistently ranked high in recursive feature elimination. This allows reducing the number of tests included in an ITS. Next, we analyzed with a hidden Markov model that takes advantage of an intrinsic inter-relationship among the local lymph node assay classes, i.e. the monotonous connection between local lymph node assay and dose. The dose-informed random forest/hidden Markov model was superior to the dose-naive random forest model on all data sets. Although balanced accuracy improvement may seem small, this obscures the actual improvement in misclassifications as the dose-informed hidden Markov model strongly reduced " false-negatives" (i.e. extreme sensitizers as non-sensitizer) on all data sets. PMID- 26046448 TI - Patients with chronic rhinosinusitis and simultaneous bronchial asthma suffer from significant extraesophageal reflux. AB - BACKGROUND: The aim of this study was to determine the severity of extraesophageal reflux (EER) in patients with various degrees of chronic rhinosinusitis (CRS), and particularly in patients with simultaneous bronchial asthma. METHODS: Patients with different severity of CRS were invited to participate in the study. Group I consisted of patients with CRS without nasal polyps or bronchial asthma; group II consisted of patients with CRS with nasal polyps but without bronchial asthma; group III consisted of patients with CRS with nasal polyps and bronchial asthma. The age, gender, Reflux Symptom Index, severity of EER evaluated using the Restech system, and number of previous functional endoscopic sinus surgeries (FESSs) were compared between groups. RESULTS: A total of 90 patients (30 in each group) were recruited for the study. Pathological EER was significantly often present in group III when compared with group I and group II in all parameters analyzed (RYAN score, number of EER episodes, total percentage of time below pH 5.5). Furthermore, patients from group III had undergone more surgeries in the past. CONCLUSION: Patients with CRS with nasal polyps and simultaneous bronchial asthma suffer from significant EER. Antireflux therapy can be recommended for these patients. However, the effect has to be confirmed in further studies. PMID- 26046449 TI - Cerebral pyogranuloma associated with systemic coronavirus infection in a ferret. AB - A 2-year-old male ferret was presented with central nervous system signs. Computed tomography (CT) of the brain revealed a well-defined contrast-enhancing lesion on the rostral forebrain that appeared extraparenchymal. Surgical excision of the mass was performed and the ferret was euthanised during the procedure. Histopathology of the excised mass showed multiple meningeal nodular lesions with infiltrates of epithelioid macrophages, occasionally centred on degenerated neutrophils and surrounded by a broad rim of plasma cells, features consistent with pyogranulomatous meningitis. The histopathological features in this ferret were similar to those in cats with feline infectious peritonitis. Definitive diagnosis was assessed by immunohistochemistry, confirming a ferret systemic coronavirus (FSCV) associated disease. This is the first case of coronavirus granuloma described on CT-scan in the central nervous system of a ferret. PMID- 26046450 TI - Anion- and Spacer-Directed Host-Guest Complexes of Bipyridine with Pyrogallol[4]arene. AB - New oval-shaped capsular and bilayer-type hydrogen-bonded arrangements of C propyl-ol-pyrogallol[4]arene (PgC3-OH) with bipyridine-type spacer complexes are reported here. These complexes are engineered by virtue of derivatization of C alkyl tails of pyrogallol[4]arene and the use of divergent spacer ligands. Complexes of PgC3-OH, PgC3-OH with bpy (4,4'-bipyridine) and PgC3-OH with bpa (1,2-bis(4-pyridyl)acetylene) have bilayer type arrangements; however, the use of hydrogen chloride causes protonation of bpy molecule, which is then entrapped flat within an offset oval-shaped dimeric hydrogen-bonded PgC3-OH nanocapsule. The presence of chloride anion in the crystal lattice controls the geometry of the resultant nanoassembly. PMID- 26046451 TI - How anthropogenic noise affects foraging. AB - The influence of human activity on the biosphere is increasing. While direct damage (e.g. habitat destruction) is relatively well understood, many activities affect wildlife in less apparent ways. Here, we investigate how anthropogenic noise impairs foraging, which has direct consequences for animal survival and reproductive success. Noise can disturb foraging via several mechanisms that may operate simultaneously, and thus, their effects could not be disentangled hitherto. We developed a diagnostic framework that can be applied to identify the potential mechanisms of disturbance in any species capable of detecting the noise. We tested this framework using Daubenton's bats, which find prey by echolocation. We found that traffic noise reduced foraging efficiency in most bats. Unexpectedly, this effect was present even if the playback noise did not overlap in frequency with the prey echoes. Neither overlapping noise nor nonoverlapping noise influenced the search effort required for a successful prey capture. Hence, noise did not mask prey echoes or reduce the attention of bats. Instead, noise acted as an aversive stimulus that caused avoidance response, thereby reducing foraging efficiency. We conclude that conservation policies may seriously underestimate numbers of species affected and the multilevel effects on animal fitness, if the mechanisms of disturbance are not considered. PMID- 26046452 TI - Hollow-fiber liquid-phase microextraction coupled with miniature capillary electrophoresis for the trace analysis of four aliphatic aldehydes in water samples. AB - An environmentally friendly method for the trace analysis of four aliphatic aldehydes as water disinfection byproducts has been developed based on hollow fiber liquid-phase microextraction followed by miniature capillary electrophoresis with amperometric detection. After derivatization with 2 thiobarbituric acid, four aliphatic aldehydes (formaldehyde, acetaldehyde, propylaldehyde, and butyraldehyde) became detectable by the amperometric detector. Under the optimum conditions, four aliphatic aldehydes can be well separated from the coexisting interferents as well as their homologs (pentanal, glyoxal, and methyl-glyoxal), and the limits of detection (S/N = 3) could reach sub-nanogram-per-milliliter level based on hollow-fiber liquid-phase microextraction. The proposed method has been applied for the analyses of above four aliphatic aldehydes in different water samples such as drinking water, tap water, and river water, and the average recoveries were in the range of 90-113%, providing an alternative to conventional and microchip capillary electrophoresis approaches. PMID- 26046453 TI - Fetal laser surgery prevents fetal death and avoids the need for neonatal sequestrectomy in cases with bronchopulmonary sequestration. PMID- 26046455 TI - Epinephrine adjuvant reduced epidural blood vessel penetration incidence in a randomized, double-blinded trial. AB - BACKGROUND: Accidental intravascular injection is a significant and potentially devastating risk of epidural block, particularly in parturients whose epidural veins are engorged and hence more easily pierced. This prospective randomized, double-blinded study determined whether the addition of epinephrine to epidural ropivacaine administered by gravity before catheter insertion was associated with fewer epidural catheter blood vessel penetrations. METHOD: Four hundred and two parturient patients receiving epidural block for elective C/S were randomly allocated to two groups; group I (n = 201) received only ropivacaine 0.75% with fentanyl 5 MUg/mL, whereas group II (n = 200) also received epinephrine 5 MUg/mL. Both groups received a total of 21 mL anesthetic solution in four increment doses of 3,5,5,5 mL by gravity into the needle through a 22 inch extension tubing before insertion of the closed-end tip catheter. An additional 3 mL of the anesthetic solution was then administered through the catheter. RESULTS: Epidural epinephrine adjuvant was associated with fewer epidural vessel penetrations (4% vs. 16.5%, P < 0.0001). The addition of epinephrine also significantly reduced catheter insertion problems (12% vs. 23.5%, P-value 0.0024) including the need for catheter readjustment (4.5% vs. 16%, P-value 0.0002) or reinsertion (2.5% vs. 9%, P-value 0.0054). The addition of epinephrine significantly reduced incidence and severity of sedation and had faster onset of surgical block. Sensory level and overall satisfaction did not differ significantly among the groups. CONCLUSION: The addition of epinephrine to ropivacaine improves the safety and quality of epidural anesthesia when administered by gravity flow via the Hustead needle for cesarean sections. PMID- 26046454 TI - Human group3 innate lymphoid cells express DR3 and respond to TL1A with enhanced IL-22 production and IL-2-dependent proliferation. AB - Death receptor 3 (DR3, TNFRSF25) is expressed by activated lymphocytes and signaling by its ligand, TL1A, enhances cytokine expression and proliferation. Recent studies show that DR3 is also present on murine type 2 innate lymphoid cells (ILC2s). Here, we show that DR3 is expressed by IL-22-producing human group 3 innate lymphoid cells (ILC3s). Stimulation of ILC3s with exogenous TL1A alone had no impact on cytokine production or proliferation. Addition of TL1A to IL 1beta + IL-23 significantly enhanced the amount IL-22 produced by ILC3s as well as the percentage IL-22- and IL-8-producing cells. Addition of TL1A to IL-1beta + IL-23 also augmented ILC3 proliferation. Mechanistically, this occurred through the upregulation of CD25 and responsiveness to IL-2 stimulation. The combination of TL1A, IL-1beta+ IL-23, and IL-2 expanded ILC3s while IL-1beta+ IL-23 did not increase proliferation above controls. After 2 weeks of expansion, ILC3s maintained their phenotype, transcription factor expression, and function (IL-22 production). These findings identify DR3 as a costimulatory molecule on ILC3s that could be exploited for ex vivo expansion and clinical use. PMID- 26046456 TI - One center's experience with complications during the Wada test. AB - This study aimed to define the number and type of complications associated with the Wada test at an academic medical center for comparison to previous reports. We performed a retrospective review of medical records for patients who underwent the Wada test at the University of Michigan between April 1991 and June 2013. Information was collected regarding the angiography procedure and the immediate postoperative period to assess for both clinical and angiographic complications. A total of 436 patients were identified who underwent the Wada procedure between April 1991 and June 2013, and 431 patients were included in the final analysis. Twenty-five patients (5.8%) had notable clinical events associated with the Wada test. Nine patients (2.1%) had clinical events meeting criteria for complication, which included seizures, status epilepticus, internal carotid artery vasospasm, inadvertent injection of anesthetic in the external carotid artery, and transient encephalopathy. No complications were associated with significant morbidity or mortality. This retrospective review of patients undergoing the Wada test found significantly fewer associated complications in comparison to previously published studies, with no patients experiencing long-term morbidity. The Wada test should be considered a safe diagnostic tool for lateralizing language and memory. PMID- 26046457 TI - When does diversity matter? Species functional diversity and ecosystem functioning across habitats and seasons in a field experiment. AB - Despite ample experimental evidence indicating that biodiversity might be an important driver of ecosystem processes, its role in the functioning of real ecosystems remains unclear. In particular, the understanding of which aspects of biodiversity are most important for ecosystem functioning, their importance relative to other biotic and abiotic drivers, and the circumstances under which biodiversity is most likely to influence functioning in nature, is limited. We conducted a field study that focussed on a guild of insect detritivores in streams, in which we quantified variation in the process of leaf decomposition across two habitats (riffles and pools) and two seasons (autumn and spring). The study was conducted in six streams, and the same locations were sampled in the two seasons. With the aid of structural equations modelling, we assessed spatiotemporal variation in the roles of three key biotic drivers in this process: functional diversity, quantified based on a species trait matrix, consumer density and biomass. Our models also accounted for variability related to different litter resources, and other sources of biotic and abiotic variability among streams. All three of our focal biotic drivers influenced leaf decomposition, but none was important in all habitats and seasons. Functional diversity had contrasting effects on decomposition between habitats and seasons. A positive relationship was observed in pool habitats in spring, associated with high trait dispersion, whereas a negative relationship was observed in riffle habitats during autumn. Our results demonstrate that functional biodiversity can be as significant for functioning in natural ecosystems as other important biotic drivers. In particular, variation in the role of functional diversity between seasons highlights the importance of fluctuations in the relative abundances of traits for ecosystem process rates in real ecosystems. PMID- 26046458 TI - Efficacy and Safety of Systemic Long-Term Treatments for Moderate-to-Severe Psoriasis: A Systematic Review and Meta-Analysis. AB - Psoriasis as a chronic inflammatory disease often requires effective long-term treatment; a comprehensive systematic evaluation of efficacy and safety of systemic long-term treatments in patients with moderate-to-severe psoriasis is lacking. Twenty-five randomized clinical trials were included. Results were pooled and quality of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). With respect to PASI 75 (psoriasis area and severity index), pooled risk ratios for infliximab (13.07, 95% confidence interval (CI): 8.60-19.87), secukinumab (11.97, 95% CI: 8.83 16.23), ustekinumab (11.39, 95% CI: 8.94-14.51), adalimumab (8.92, 95% CI: 6.33 12.57), etanercept (8.39, 95% CI: 6.74-10.45), and apremilast (5.83, 95% CI: 2.58 13.17) show superiority of biologics and apremilast in long-term therapy compared with placebo. With respect to the addressed safety parameters, no differences were seen between adalimumab, etanercept, or infliximab versus placebo. No placebo-controlled data on conventional treatments was identified. Head-to-head studies showed superior efficacy of secukinumab and infliximab versus etanercept and of infliximab versus methotrexate. A clear ranking is limited by the lack of long-term head-to-head trials. From the available evidence, infliximab, secukinumab, and ustekinumab are the most efficacious long-term treatments. Data on conventionals are insufficient. Further head-to-head comparisons and studies on safety and patient-related outcomes are needed to draw more reliable conclusions. PMID- 26046459 TI - Neonatal exposure to sevoflurane may not cause learning and memory deficits and behavioral abnormality in the childhood of Cynomolgus monkeys. AB - Results of animal studies have raised a significant concern that commonly used general anesthetics may induce neurotoxicity in children. It may be difficult to resolve this concern with human studies because randomizing children only for testing anesthetic toxicity may not be feasible. We randomized 6-day old male Cynomolgus monkeys to receive or not to receive sevoflurane anesthesia at surgical plane for 5 h. Sevoflurane is the most commonly used general anesthetic in children in the U.S.A. Here, we showed that sevoflurane anesthesia did not affect the behavior evaluated by holding cage method when the monkeys were 3 and 7 months old. However, there was an age-dependent decrease in the frequency of stress events and environmental exploration behavior during the test. Sevoflurane also did not affect the learning and memory of the monkeys when they were assessed from the age of 7 months. Finally, sevoflurane did not affect the expression of multiple neuron-specific proteins in the hippocampus and cerebral cortex of 10-month old monkeys after all behavioral and cognitive tests were completed. These results suggest that exposure of neonatal monkey to sevoflurane may not affect cognition, behavior and neuronal structures in childhood, indicating the safety of sevoflurane anesthesia in children. PMID- 26046460 TI - A minimally invasive, lentiviral based method for the rapid and sustained genetic manipulation of renal tubules. AB - The accelerated discovery of disease-related genes emerging from genomic studies has strained the capacity of traditional genetically engineered mouse models (GEMMs) to provide in-vivo validation. Direct, somatic, genetic engineering approaches allow for accelerated and flexible genetic manipulation and represent an attractive alternative to GEMMs. In this study we investigated the feasibility, safety and efficiency of a minimally invasive, lentiviral based approach for the sustained in-vivo modification of renal tubular epithelial cells. Using ultrasound guidance, reporter vectors were directly injected into the mouse renal parenchyma. We observed transgene expression confined to the renal cortex (specifically proximal and distal tubules) and sustained beyond 2 months post injection. Furthermore, we demonstrate the ability of this methodology to induce long-term, in-vivo knockdown of candidate genes either through somatic recombination of floxed alleles or by direct delivery of specific shRNA sequences. This study demonstrates that ultrasound-guided injection of lentiviral vectors provides a safe and efficient method for the genetic manipulation of renal tubules, representing a quick and versatile alternative to GEMMs for the functional characterisation of disease-related genes. PMID- 26046461 TI - Mutual Information between Discrete Variables with Many Categories using Recursive Adaptive Partitioning. AB - Mutual information, a general measure of the relatedness between two random variables, has been actively used in the analysis of biomedical data. The mutual information between two discrete variables is conventionally calculated by their joint probabilities estimated from the frequency of observed samples in each combination of variable categories. However, this conventional approach is no longer efficient for discrete variables with many categories, which can be easily found in large-scale biomedical data such as diagnosis codes, drug compounds, and genotypes. Here, we propose a method to provide stable estimations for the mutual information between discrete variables with many categories. Simulation studies showed that the proposed method reduced the estimation errors by 45 folds and improved the correlation coefficients with true values by 99 folds, compared with the conventional calculation of mutual information. The proposed method was also demonstrated through a case study for diagnostic data in electronic health records. This method is expected to be useful in the analysis of various biomedical data with discrete variables. PMID- 26046462 TI - The oncometabolite D-2-hydroxyglutarate induced by mutant IDH1 or -2 blocks osteoblast differentiation in vitro and in vivo. AB - Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are found in a somatic mosaic fashion in patients with multiple enchondromas. Enchondromas are benign cartilaginous tumors arising in the medulla of bone. The mutant IDH1/2 causes elevated levels of D-2-hydroxyglutarate (D-2-HG). Mesenchymal stem cells (MSC) are the precursor of the osteoblastic, chondrogenic and adipocytic lineage and we hypothesized that increased levels of D-2-HG cause multiple enchondromas by affecting differentiation of MSCs. Bone marrow derived MSCs from different donors were differentiated towards osteoblastic, chondrogenic and adipocytic lineage in the presence or absence of 5 mM D-2-HG. Three of four MSCs showed near complete inhibition of calcification after 3 weeks under osteogenic differentiation conditions in the presence of D-2-HG, indicating a block in osteogenic differentiation. Two of four MSCs showed an increase in differentiation towards the chondrogenic lineage. To evaluate the effect of D-2-HG in vivo we monitored bone development in zebrafish, which revealed an impaired development of vertebrate rings in the presence of D-2-HG compared to control conditions (p value < 0.0001). Our data indicate that increased levels of D-2-HG promote chondrogenic over osteogenic differentiation. Thus, mutations in IDH1/2 lead to a local block in osteogenic differentiation during skeletogenesis causing the development of benign cartilaginous tumors. PMID- 26046463 TI - Whole-exome sequencing of primary plasma cell leukemia discloses heterogeneous mutational patterns. AB - Primary plasma cell leukemia (pPCL) is a rare and aggressive form of plasma cell dyscrasia and may represent a valid model for high-risk multiple myeloma (MM). To provide novel information concerning the mutational profile of this disease, we performed the whole-exome sequencing of a prospective series of 12 pPCL cases included in a Phase II multicenter clinical trial and previously characterized at clinical and molecular levels. We identified 1, 928 coding somatic non-silent variants on 1, 643 genes, with a mean of 166 variants per sample, and only few variants and genes recurrent in two or more samples. An excess of C > T transitions and the presence of two main mutational signatures (related to APOBEC over-activity and aging) occurring in different translocation groups were observed. We identified 14 candidate cancer driver genes, mainly involved in cell matrix adhesion, cell cycle, genome stability, RNA metabolism and protein folding. Furthermore, integration of mutation data with copy number alteration profiles evidenced biallelically disrupted genes with potential tumor suppressor functions. Globally, cadherin/Wnt signaling, extracellular matrix and cell cycle checkpoint resulted the most affected functional pathways. Sequencing results were finally combined with gene expression data to better elucidate the biological relevance of mutated genes. This study represents the first whole exome sequencing screen of pPCL and evidenced a remarkable genetic heterogeneity of mutational patterns. This may provide a contribution to the comprehension of the pathogenetic mechanisms associated with this aggressive form of PC dyscrasia and potentially with high-risk MM. PMID- 26046464 TI - Expression of miR-27a-3p is an independent predictive factor for recurrence in clear cell renal cell carcinoma. AB - MicroRNAs (miRNAs) are noncoding RNAs that regulate gene expression and function in tumor development and progression. We previously identified up-regulated miRNAs in clear cell renal cell carcinoma (ccRCC) compared to matched-pair normal kidney by microarray. Here, we identify miRNAs that are up-regulated in ccRCC and are also correlated with survival and/or recurrence. Twenty-four samples from ccRCC patients who underwent nephrectomies between 2011 and 2012 were divided into two groups: one of eleven patients who experienced recurrence (Group 1), and one of thirteen patients with no evidence of disease (Group 2) 2 years after surgery. Analyzing 22 miRNAs that were up-regulated in ccRCC in our previous study, we identify five miRNAs that were statistically up-regulated in Group 1 versus Group 2 by quantitative real-time PCR. We then evaluated these miRNAs in an independent cohort of 159 frozen ccRCC samples. High levels of miR-27a-3p (p < 0.01) correlated with a worse progression-free survival rate. Multivariate analysis revealed that miR-27a-3p was an independent predictive factor for recurrence. For functional analysis, miR-27a-3p controlled cell proliferation, migration and invasion in RCC cell lines. MiR-27a-3p could act as oncogenic miRNA and may be a candidate for targeted molecular therapy in ccRCC. PMID- 26046465 TI - Analysis of the transcriptional regulation of cancer-related genes by aberrant DNA methylation of the cis-regulation sites in the promoter region during hepatocyte carcinogenesis caused by arsenic. AB - Liver is the major organ for arsenic methylation metabolism and may be the potential target of arsenic-induced cancer. In this study, normal human liver cell was treated with arsenic trioxide, and detected using DNA methylation microarray. Some oncogenes, tumor suppressor genes, transcription factors (TF), and tumor-associated genes (TAG) that have aberrant DNA methylation have been identified. However, simple functional studies of genes adjacent to aberrant methylation sites cannot well reflect the regulatory relationship between DNA methylation and gene transcription during the pathogenesis of arsenic-induced liver cancer, whereas a further analysis of the cis-regulatory elements and their trans-acting factors adjacent to DNA methylation can more precisely reflect the relationship between them. MYC and MAX (MYC associated factor X) were found to participating cell cycle through a bioinformatics analysis. Additionally, it was found that the hypomethylation of cis-regulatory sites in the MYC promoter region and the hypermethylation of cis-regulatory sites in the MAX promoter region result in the up-regulation of MYC mRNA expression and the down-regulation of MAX mRNA, which increased the hepatocyte carcinogenesis tendency. PMID- 26046467 TI - Selective Crystal Growth and Structural, Optical, and Electronic Studies of Mn3Ta2O8. AB - Mn3Ta2O8, a stable targeted material with an unusual and complex cation topology in the complicated Mn-Ta-O phase space, has been grown as a ~3-cm-long single crystal via the optical floating-zone technique. Single-crystal absorbance studies determine the band gap as 1.89 eV, which agrees with the value obtained from density functional theory electronic-band-structure calculations. The valence band consists of the hybridized Mn d-O p states, whereas the bottom of the conduction band is formed by the Ta d states. Furthermore, out of the three crystallographically distinct Mn atoms that are four-, seven-, or eight coordinate, only the former two contribute their states near the top of the valence band and hence govern the electronic transitions across the band gap. PMID- 26046466 TI - Curcumin suppresses cell growth and invasion and induces apoptosis by down regulation of Skp2 pathway in glioma cells. AB - Studies have demonstrated that curcumin exerts its tumor suppressor function in a variety of human cancers including glioma. However, the exact underlying molecular mechanisms remain obscure. Emerging evidence has revealed that Skp2 (S phase kinase associated protein 2) plays an oncogenic role in tumorigenesis. Therefore, we aim to determine whether curcumin suppresses the Skp2 expression, leading to the inhibition of cell growth, invasion, induction of apoptosis, and cell cycle arrest. To this end, we conducted multiple methods such as MTT assay, Flow cytometry, Wound healing assay, invasion assay, RT-PCR, Western blotting, and transfection to explore the functions and molecular insights of curcumin in glioma cells. We found that curcumin significantly inhibited cell growth, suppressed cell migration and invasion, induced apoptosis and cell cycle arrest in glioma cells. Furthermore, we observed that overexpression of Skp2 promoted cell growth, migration, and invasion, whereas depletion of Skp2 suppressed cell growth, migration, and invasion and triggered apoptosis in glioma cells. Mechanistically, we defined that curcumin markedly down-regulated Skp2 expression and subsequently up-regulated p57 expression. Moreover, our results demonstrated that curcumin exerts its antitumor activity through inhibition of Skp2 pathway. Collectively, our findings suggest that targeting Skp2 by curcumin could be a promising therapeutic approach for glioma prevention and therapy. PMID- 26046468 TI - Fission yeast mitochondria are distributed by dynamic microtubules in a motor independent manner. AB - The cytoskeleton plays a critical role in regulating mitochondria distribution. Similar to axonal mitochondria, the fission yeast mitochondria are distributed by the microtubule cytoskeleton, but this is regulated by a motor-independent mechanism depending on the microtubule associated protein mmb1p as the absence of mmb1p causes mitochondria aggregation. In this study, using a series of chimeric proteins to control the subcellular localization and motility of mitochondria, we show that a chimeric molecule containing a microtubule binding domain and the mitochondria outer membrane protein tom22p can restore the normal interconnected mitochondria network in mmb1-deletion (mmb1?) cells. In contrast, increasing the motility of mitochondria by using a chimeric molecule containing a kinesin motor domain and tom22p cannot rescue mitochondria aggregation defects in mmb1? cells. Intriguingly a chimeric molecule carrying an actin binding domain and tom22p results in mitochondria associated with actin filaments at the actomyosin ring during mitosis, leading to cytokinesis defects. These findings suggest that the passive motor-independent microtubule-based mechanism is the major contributor to mitochondria distribution in wild type fission yeast cells. Hence, we establish that attachment to microtubules, but not kinesin-dependent movement and the actin cytoskeleton, is required and crucial for proper mitochondria distribution in fission yeast. PMID- 26046469 TI - Resolving single molecule structures with Nitrogen-vacancy centers in diamond. AB - We present theoretical proposals for two-dimensional nuclear magnetic resonance spectroscopy protocols based on Nitrogen-vacancy (NV) centers in diamond that are strongly coupled to the target nuclei. Continuous microwave and radio-frequency driving fields together with magnetic field gradients achieve Hartmann-Hahn resonances between NV spin sensor and selected nuclei for control of nuclear spins and subsequent measurement of their polarization dynamics. The strong coupling between the NV sensor and the nuclei facilitates coherence control of nuclear spins and relaxes the requirement of nuclear spin polarization to achieve strong signals and therefore reduced measurement times. Additionally, we employ a singular value thresholding matrix completion algorithm to further reduce the amount of data required to permit the identification of key features in the spectra of strongly sub-sampled data. We illustrate the potential of this combined approach by applying the protocol to a shallowly implanted NV center addressing a small amino acid, alanine, to target specific hydrogen nuclei and to identify the corresponding peaks in their spectra. PMID- 26046470 TI - Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets in vitro. AB - MAIN PROBLEM: Islet transplantation has become a promising treatment for type 1 diabetes. However, immunosuppressive drugs used today cause islet deterioration and modification strategies are necessary. But little is known about pharmacokinetics interactions and intracellular concentrations of immunosuppressive drugs in human islets. METHODS: We determined the pharmacokinetics of tacrolimus and sirolimus in islets by measuring intracellular concentration after exposure alone or in combination at two different doses up to 48 h. A quantification technique established in our laboratory using a Micromass Quattro micro API MS/MS-instrument with electrospray ionization was used. Islets function was measured by oxygen consumption rates. Presence of drug transporters OATP1B1 and ABCB1 and metabolizing enzyme CYP3A4 in islets were quantified using real-time quantitative PCR. RESULTS: Islets incubated with tacrolimus and sirolimus had a significant decrease in intracellular concentration of sirolimus compared to sirolimus alone. Reduced intracellular sirolimus concentration was followed by increased p70S6k phosphorylation suggesting preservation of the mTOR signaling pathway. Drug transporters OATP1B1 and ABCB1 and enzyme CYP3A4 were expressed in human islets, but were not involved in the reduced sirolimus concentration by tacrolimus. CONCLUSION: These findings provide new knowledge of the drug interaction between tacrolimus and sirolimus, suggesting that tacrolimus has an inhibitory effect on the intracellular concentration of sirolimus in human islets. PMID- 26046473 TI - Development and Validation of the Simplified Chinese Version of EORTC QLQ-HCC18 for Patients with Hepatocellular Carcinoma. AB - This study aimed to develop and validate the Simplified Chinese Version of the Quality of Life Questionnaire for Hepatocellular Carcinoma (the QLQ-HCC18). It was developed by the strict translation procedure of EORTC guidelines, and the psychometrics were evaluated on a sample of 114 patients. The internal consistency Cronbach's alpha were greater than 0.60 for all domains (exception of Jaundice 0.38), and all test-retest reliability coefficients were greater than 0.80. Four out of eight domains had statistically significant changes with effect size standardized response mean (SRM) ranging from 0.31 to 0.73. The Simplified Chinese version of QLQ-HCC18 demonstrates good validity, reliability, and responsiveness. PMID- 26046471 TI - RAP: RNA-Seq Analysis Pipeline, a new cloud-based NGS web application. AB - BACKGROUND: The study of RNA has been dramatically improved by the introduction of Next Generation Sequencing platforms allowing massive and cheap sequencing of selected RNA fractions, also providing information on strand orientation (RNA Seq). The complexity of transcriptomes and of their regulative pathways make RNA Seq one of most complex field of NGS applications, addressing several aspects of the expression process (e.g. identification and quantification of expressed genes and transcripts, alternative splicing and polyadenylation, fusion genes and trans splicing, post-transcriptional events, etc.). METHODS: In order to provide researchers with an effective and friendly resource for analyzing RNA-Seq data, we present here RAP (RNA-Seq Analysis Pipeline), a cloud computing web application implementing a complete but modular analysis workflow. This pipeline integrates both state-of-the-art bioinformatics tools for RNA-Seq analysis and in house developed scripts to offer to the user a comprehensive strategy for data analysis. RAP is able to perform quality checks (adopting FastQC and NGS QC Toolkit), identify and quantify expressed genes and transcripts (with Tophat, Cufflinks and HTSeq), detect alternative splicing events (using SpliceTrap) and chimeric transcripts (with ChimeraScan). This pipeline is also able to identify splicing junctions and constitutive or alternative polyadenylation sites (implementing custom analysis modules) and call for statistically significant differences in genes and transcripts expression, splicing pattern and polyadenylation site usage (using Cuffdiff2 and DESeq). RESULTS: Through a user friendly web interface, the RAP workflow can be suitably customized by the user and it is automatically executed on our cloud computing environment. This strategy allows to access to bioinformatics tools and computational resources without specific bioinformatics and IT skills. RAP provides a set of tabular and graphical results that can be helpful to browse, filter and export analyzed data, according to the user needs. PMID- 26046475 TI - The Limits of Lamellae-Forming PS-b-PMMA Block Copolymers for Lithography. AB - We explore the lithographic limits of lamellae-forming PS-b-PMMA block copolymers by performing directed self-assembly and pattern transfer on a range of PS-b-PMMA materials having a full pitch from 27 to 18.5 nm. While directed self-assembly on chemical contrast patterns was successful with all the materials used in this study, clean removal of PMMA domains and subsequent pattern transfer could only be sustained down to 22 nm full pitch. We attribute this limitation to the width of the interface, which may represent more than half of the domain width for materials with a critical dimension below 10 nm. With the limit of pattern transfer for PS-b-PMMA set at ~11 nm, we propose an integration scheme suitable for bit patterned media for densities above 1.6 Tdot/in(2), which require features below this limit. Directed self-assembly was carried out on chemical contrast patterns made by a rotary e-beam lithography system, and pattern transfer was carried out to demonstrate fabrication of large area (up to 25 mm wide annular band of circular tracks) nanoimprint templates for bit patterned media. We also demonstrate compatibility with hard disk drive architecture by fabricating patterns with skewed radial lines with constant angular pitch and with servo patterns that are needed in hard disk drives to generate a radial positional error signal (PES). PMID- 26046474 TI - Validation of a single-stage fixed-rate step test for the prediction of maximal oxygen uptake in healthy adults. AB - Healthcare professionals with limited access to ergospirometry remain in need of valid and simple submaximal exercise tests to predict maximal oxygen uptake (VO2max ). Despite previous validation studies concerning fixed-rate step tests, accurate equations for the estimation of VO2max remain to be formulated from a large sample of healthy adults between age 18-75 years (n > 100). The aim of this study was to develop a valid equation to estimate VO2max from a fixed-rate step test in a larger sample of healthy adults. A maximal ergospirometry test, with assessment of cardiopulmonary parameters and VO2max , and a 5-min fixed-rate single-stage step test were executed in 112 healthy adults (age 18-75 years). During the step test and subsequent recovery, heart rate was monitored continuously. By linear regression analysis, an equation to predict VO2max from the step test was formulated. This equation was assessed for level of agreement by displaying Bland-Altman plots and calculation of intraclass correlations with measured VO2max . Validity further was assessed by employing a Jackknife procedure. The linear regression analysis generated the following equation to predict VO2max (l min(-1) ) from the step test: 0.054(BMI)+0.612(gender)+3.359(body height in m)+0.019(fitness index) 0.012(HRmax)-0.011(age)-3.475. This equation explained 78% of the variance in measured VO2max (F = 66.15, P<0.001). The level of agreement and intraclass correlation was high (ICC = 0.94, P<0.001) between measured and predicted VO2max . From this study, a valid fixed-rate single-stage step test equation has been developed to estimate VO2max in healthy adults. This tool could be employed by healthcare professionals with limited access to ergospirometry. PMID- 26046476 TI - Case of X-linked hypohidrotic ectodermal dysplasia with a novel EDA missense mutation. PMID- 26046477 TI - Analysis of cyclosporin A and a set of analogs as inhibitors of a T. cruzi cyclophilin by docking and molecular dynamics. AB - Cyclophilins (CyPs) are enzymes involved in protein folding. In Trypanosoma cruzi (T. cruzi), the most abundantly expressed CyP is the isoform TcCyP19. It has been shown that TcCyP19 is inhibited by the immunosuppressive drug cyclosporin A (CsA) and analogs, which also proved to have potent trypanosomicidal activity in vitro. In this work, we continue and expand a previous study on the molecular interactions of CsA, and a set of analogs modeled in complexes with TcCyP19. The modeled complexes were used to evaluate binding free energies by molecular dynamics (MD), applying the Linear Interaction Energy (LIE) method. In addition, putative binding sites were identified by molecular docking. In our analysis, the binding free energy calculations did not correlate with experimental data. The heterogeneity of the non-bonded energies and the variation in the pattern of hydrogen bonds suggest that the systems may not be suitable for the application of the LIE method. Further, the docking calculations identified two other putative binding sites with comparable scoring energies to the active site, a fact that may also explain the lack of correlation found. Kinetic experiments are needed to confirm or reject the multiple binding sites hypothesis. In the meantime, MD simulations at the alternative sites, employing other methods to compute binding free energies, might be successful at finding good correlations with the experimental data. PMID- 26046478 TI - Autophagy is a key tolerance mechanism during Staphylococcus aureus infection. AB - Defense strategies against infectious threats can be divided into resistance and tolerance mechanisms. Resistance mechanisms involve reduction of pathogen burden and include many established examples, one of them being the destruction of intracellular pathogens through autophagy (xenophagy). Tolerance mechanisms protect the host from damage caused by the pathogen or the immune response independent of pathogen load. The role of autophagy in maintaining homeostasis in response to environmental stress suggests that this pathway is involved in tolerance to a variety of infectious agents. However, demonstrating that autophagy promotes tolerance independent of its role in resistance has been a challenge, especially during infection by clinically relevant pathogens. We have found that autophagy protects against Staphylococcus aureus infection by maintaining tolerance toward a pore forming toxin secreted by the bacteria, alpha toxin. PMID- 26046479 TI - Perinatal choline deficiency delays brain development and alters metabolite concentrations in the young pig. AB - OBJECTIVES: Adequate choline supply during the perinatal period is critical for proper brain formation, when robust neurogenesis and neuronal maturation occur. Therefore, the objective of this study was to examine the impact of perinatal choline status on neurodevelopment. METHODS: Sows were fed a choline-deficient (CD) or choline-sufficient (CS) diet during the last half of the gestational period. At 2 days of age, piglets from sows within each prenatal treatment group were further stratified into postnatal treatment groups and provided either a CD or CS milk replacer, resulting in four treatment groups. At 30 days of age, piglets underwent magnetic resonance imaging (MRI) procedures to analyze structural and metabolite differences. RESULTS: Single-voxel spectroscopy (SVS) analysis revealed postnatally CS piglets had higher (P < 0.001) concentrations of glycerophosphocholine-phosphocholine than postnatally CD piglets. Volumetric analysis indicated smaller (P < 0.006) total brain volumes in prenatally CD piglets compared with prenatally CS piglets. Differences (P < 0.05) in the corpus callosum, pons, midbrain, thalamus, and right hippocampus, were observed as larger region-specific volumes proportional to total brain size in prenatally CD piglets compared with CS piglets. Diffusion tensor imaging (DTI) suggested interactions (P < 0.05) between prenatal and postnatal choline status in fractional anisotropy values of the thalamus and right hippocampus. Prenatally CS piglets had lower cerebellar radial diffusivity (P = 0.045) compared with prenatally CD piglets. DISCUSSION: This study demonstrates that prenatal choline deficiency has profound effects by delaying neurodevelopment as evidenced by structural and metabolic MRI assessments. PMID- 26046480 TI - Synthesis of Graphdiyne Nanowalls Using Acetylenic Coupling Reaction. AB - Synthesizing graphdiyne with a well-defined structure is a great challenge. We reported herein a rational approach to synthesize graphdiyne nanowalls using a modified Glaser-Hay coupling reaction. Hexaethynylbenzene and copper plate were selected as monomer and substrate, respectively. By adjusting the ratio of added organic alkali along with the amount of monomer, the proper amount of copper ions was dissolved into the solution, thus forming catalytic reaction sites. With a rapid reaction rate of Glaser-Hay coupling, graphdiyne grew vertically at these sites first, and then with more copper ions dissolved, uniform graphdiyne nanowalls formed on the surface of copper substrate. Raman spectra, UV-vis spectra, and HRTEM results confirmed the features of graphdiyne. These graphdiyne nanowalls also exhibited excellent and stable field-emission properties. PMID- 26046482 TI - Macular Thickness in Highly Myopic Children Aged 3 to 7 Years. AB - PURPOSE: To compare the macular thickness and volume of highly myopic children with healthy controls, using third generation optical coherence tomography (OCT). METHODS: OCT was performed on highly myopic (cycloplegic spherical equivalent refraction > -6.00 diopters [D]) children aged 3 to 7 years old and healthy controls (spherical equivalent refraction -2.00 to +4.00 D) between 2011 and 2013. OCT measurements of the average thicknesses of the fovea (central 1 mm) and inner (1 to 3 mm) and outer (3 to 6 mm) parafovea in superior, temporal, inferior, and nasal quadrants and total volume of the macular scan area were recorded. The differences between the two groups were tested with the Mann Whitney U test. RESULTS: There were 15 patients with high myopia and 11 controls. Foveal thickness (central 1 mm) was significantly greater in the high myopia group. The parafoveal thicknesses in all quadrants of the inner and outer circles were significantly thinner in the high myopia group. The average macular volume of the highly myopic eyes was significantly smaller than the control eyes. CONCLUSIONS: Anatomic changes in the retina occur even in young children with high myopia. Macular thickness characteristics of highly myopic children may influence the interpretation of data obtained with OCT. PMID- 26046481 TI - The transcription factor Swi4 is target for PKA regulation of cell size at the G1 to S transition in Saccharomyces cerevisiae. AB - To investigate the specific target of PKA in the regulation of cell cycle progression and cell size we developed a new approach using the yeast strain GG104 bearing a deletion in adenylate cyclase gene and permeable to cAMP ( cyr1Delta, pde2Delta, msn2Delta, msn4Delta). In this strain the PKA activity is absent and can be activated by addition of cAMP in the medium, without any other change of the growth conditions. In the present work we show that the activation of PKA by exogenous cAMP in the GG104 strain exponentially growing in glucose medium caused a marked increase of cell size and perturbation of cell cycle with a transient arrest of cells in G1, followed by an accumulation of cells in G2/M phase with a minimal change in the growth rate. Deletion of CLN1 gene, but not of CLN2, abolished the transient G1 phase arrest. Consistently we found that PKA activation caused a transcriptional repression of CLN1 gene. Transcription of CLN1 is controlled by SBF and MBF dual-regulated promoter. We found that also the deletion of SWI4 gene abolished the transient G1 arrest suggesting that Swi4 is a target responsible for PKA modulation of G1/S phase transition. We generated a SWI4 allele mutated in the consensus site for PKA (Swi4(S159A)) and we found that expression of Swi4(S159A) protein in the GG104-Swi4Delta strain did not restore the transient G1 arrest induced by PKA activation, suggesting that Swi4 phosphorylation by PKA regulates CLN1 gene expression and G1/S phase transition. PMID- 26046483 TI - Peptide to Peptoid Substitutions Increase Cell Permeability in Cyclic Hexapeptides. AB - The effect of peptide-to-peptoid substitutions on the passive membrane permeability of an N-methylated cyclic hexapeptide is examined. In general, substitutions maintained permeability but increased conformational heterogeneity. Diversification with nonproteinogenic side chains increased permeability up to 3 fold. Additionally, the conformational impact of peptoid substitutions within a beta-turn are explored. Based on these results, the strategic incorporation of peptoid residues into cyclic peptides can maintain or improve cell permeability, while increasing access to diverse side-chain functionality. PMID- 26046484 TI - Dissolution and Solubility Enhancement of the Highly Lipophilic Drug Phenytoin via Interaction with Poly(N-isopropylacrylamide-co-vinylpyrrolidone) Excipients. AB - Excipients of natural or synthetic origin play an important role in pharmaceutical performance to enhance the solubility, bioavailability, release, and stability of insoluble drugs. Herein, a series of seven excipient models was prepared by both homopolymerization and copolymerization of 1-vinyl-2-pyrrolidone (VP) and N-isopropylacrylamide (NIPAAm) by free radical polymerization yielding two homopolymers poly(VP) and poly(NIPAAm) and five copolymers of poly(NIPAAm-co VP) at difference compositions. While the VP monomer provided aqueous solubility at a variety of conditions to the excipient, the incorporation of NIPAAm into the copolymer offered additional hydrogen bond donating sites to optimize the drug polymer interactions in the system. Due to the presence of NIPAAm, the copolymers were sensitive to temperature as well. It was found that as the proportion of VP was increased (from 0 to 100%), the lower critical solution temperature (LCST) and the water solubility of the polymer models increased. To examine the role of specific drug-polymer interactions during dissolution on drug solubility and bioavailability, the polymers were formulated with the anticonvulsant drug phenytoin, which is a poorly water-soluble BCS class II drug where oral absorption is limited by the drug solubility. Amorphous solid dispersions (ASD) were prepared via spray drying of phenytoin with the polymer excipient models to contain 10% and 25% by weight drug loading. Physical characterization of the ASDs by powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) revealed that the polymers held the drug in a high-energy amorphous phase in all the formulations prepared. All ASDs exhibited improved in vitro dissolution rates compared to drug only and physical mixtures of the polymers and the drug. Drug solubility was the highest with the ASDs containing poly(NIPAAm-co-VP) 60:40 and 50:50, which showed a solubility enhancement of near 14-fold increase compared to pure drug, indicating the significance of copolymer composition to improve drug polymer interactions toward increasing bioavailability. PMID- 26046485 TI - In situ assembly of antifouling/bacterial silver nanoparticle-hydrogel composites with controlled particle release and matrix softening. AB - Controlling bacterial contamination has been a major challenge for protecting human health and welfare. In this context, hydrogels loaded with silver nanoparticles have been used to prevent biofilm formation on substrates of interest. However, such gel composites are often plagued by rapid loss of silver nanoparticles and matrix softening, and thus the gel becomes less effective for antifouling. To this end, this study demonstrates that in situ photoreaction of an aqueous mixture of silver nitrates, poly(ethylene glycol) diacrylate, and vinylpyrrolidone results in a silver nanoparticle-laden hydrogel composite with minimal nanoparticle loss and matrix softening due to enhanced binding between nanoparticles and the gel. The resulting gel composite successfully inhibits the bacterial growth in media and the bacterial adhesion to surfaces of interest. We suggest that the results of this study serve to advance quality of materials with antifouling/bacterial activities. PMID- 26046486 TI - Polymerase Chain Reaction on a Viral Nanoparticle. AB - The field of synthetic biology includes studies that aim to develop new materials and devices from biomolecules. In recent years, much work has been carried out using a range of biomolecular chassis including alpha-helical coiled coils, beta sheet amyloids and even viral particles. In this work, we show how hybrid bionanoparticles can be produced from a viral M13 bacteriophage scaffold through conjugation with DNA primers that can template a polymerase chain reaction (PCR). This unprecedented example of a PCR on a virus particle has been studied by flow aligned linear dichroism spectroscopy, which gives information on the structure of the product as well as a new protototype methodology for DNA detection. We propose that this demonstration of PCR on the surface of a bionanoparticle is a useful addition to ways in which hybrid assemblies may be constructed using synthetic biology. PMID- 26046487 TI - Prediction of work metabolism from heart rate measurements in forest work: some practical methodological issues. AB - Individual heart rate (HR) to workload relationships were determined using 93 submaximal step-tests administered to 26 healthy participants attending physical activities in a university training centre (laboratory study) and 41 experienced forest workers (field study). Predicted maximum aerobic capacity (MAC) was compared to measured MAC from a maximal treadmill test (laboratory study) to test the effect of two age-predicted maximum HR Equations (220-age and 207-0.7 * age) and two clothing insulation levels (0.4 and 0.91 clo) during the step-test. Work metabolism (WM) estimated from forest work HR was compared against concurrent work VO2 measurements while taking into account the HR thermal component. Results show that MAC and WM can be accurately predicted from work HR measurements and simple regression models developed in this study (1% group mean prediction bias and up to 25% expected prediction bias for a single individual). Clothing insulation had no impact on predicted MAC nor age-predicted maximum HR equations. Practitioner summary: This study sheds light on four practical methodological issues faced by practitioners regarding the use of HR methodology to assess WM in actual work environments. More specifically, the effect of wearing work clothes and the use of two different maximum HR prediction equations on the ability of a submaximal step-test to assess MAC are examined, as well as the accuracy of using an individual's step-test HR to workload relationship to predict WM from HR data collected during actual work in the presence of thermal stress. PMID- 26046489 TI - Effective Biomarkers and Radiation Treatment in Head and Neck Cancer. AB - CONTEXT: Radiation is a key arm in the multidisciplinary treatment of patients with head and neck squamous cell carcinoma. During the past 2 decades, significant changes in the way radiation therapy is planned and delivered have improved efficacy and decreased toxicity. Refined approaches in the application of radiation and chemoradiation have led to organ-sparing treatment regimens for laryngeal and pharyngeal cancers and have improved local and regional control rates in the postoperative, adjuvant setting. The molecular and genetic determinants of tumor cell response to radiation have been studied, and several potential biomarkers are emerging that could further improve application and efficacy of radiation treatment in head and neck squamous cell carcinoma. OBJECTIVE: To discuss the current understanding of potential biomarkers related to radiation response in head and neck squamous cell carcinoma. DATA SOURCES: Existing published literature. CONCLUSIONS: Several potential biomarkers are actively being studied as predictors and targets to improve the use and efficacy of radiation therapy to treat head and neck squamous cell carcinoma. Several promising candidates have been defined, and new markers are on the horizon. PMID- 26046488 TI - Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells. AB - Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells. PMID- 26046490 TI - Trends in Cervical Cytology Screening and Reporting Practices: Results From the College of American Pathologists 2011 PAP Education Supplemental Questionnaire. AB - CONTEXT: The College of American Pathologists periodically surveys laboratories to determine changes in cytopathology practices. We report the results of a 2011 gynecologic cytology survey. OBJECTIVE: To provide a cross-sectional survey of gynecologic cytology practices in 2010. DESIGN: In 2011, a survey was sent to 1604 laboratories participating in the College of American Pathologists gynecologic cytology interlaboratory comparison education program and proficiency testing programs requesting data from 2010 on the following topics: terminology/reporting, cytotechnologist workload, quality assurance, reagents, and ancillary testing. RESULTS: Six hundred and twenty-five laboratories (39%) replied to the survey. The nonstandard use of "low-grade squamous intraepithelial lesion cannot exclude high-grade squamous intraepithelial lesion" is used by most laboratories to report the presence of low-grade squamous intraepithelial lesion with possibility of high-grade squamous intraepithelial lesion. Most laboratories also report the presence or absence of cells from the transformation zone. Most respondents do not limit cytotechnologist screening workload during the work shift. Only about one-third of laboratories (188 of 582; 32%) use image-assisted screening devices. Rapid prescreening as a quality assurance measure is used by only 3.5% (21 of 594) of the laboratories. When used for screening, most laboratories use the imager for retrospective review of slides to detect human locator and interpretive errors. Most laboratories receive both liquid-based cytology samples (mainly ThinPrep, Hologic, Marlborough, Massachusetts) and conventional Papanicolaou tests. Expiration dates of liquid-based cytology test vials are not usually recorded. CONCLUSIONS: The field of gynecologic cytology is evolving rapidly. These survey results offer a snapshot of national gynecologic cytology practices in 2010. PMID- 26046491 TI - Mechanisms of Invasion in Head and Neck Cancer. AB - CONTEXT: The highly invasive properties demonstrated by head and neck squamous cell carcinoma (HNSCC) are often associated with locoregional recurrence and lymph node metastasis in patients and is a key factor leading to an expected 5 year survival rate of approximately 50% for patients with advanced disease. It is important to understand the features and mediators of HNSCC invasion so that new treatment approaches can be developed. OBJECTIVES: To provide an overview of the characteristics, mediators, and mechanisms of HNSCC invasion. DATA SOURCES: A literature review of peer-reviewed articles in PubMed on HNSCC invasion. CONCLUSIONS: Histologic features of HNSCC tumors can help predict prognosis and influence clinical treatment decisions. Cell surface receptors, signaling pathways, proteases, invadopodia function, epithelial-mesenchymal transition, microRNAs, and tumor microenvironment are all involved in the regulation of the invasive behavior of HNSCC cells. Identifying effective HNSCC invasion inhibitors has the potential to improve outcomes for patients by reducing the rate of spread and increasing responsiveness to chemoradiation. PMID- 26046492 TI - The Medical Home and Care Coordination in Disaster Recovery: Hypothesis for Interventions and Research. AB - In postdisaster settings, health care providers encounter secondary surges of unmet primary care and mental health needs that evolve throughout disaster recovery phases. Whatever a community's predisaster adequacy of health care, postdisaster gaps are similar to those of any underserved region. We hypothesize that existing practice and evidence supporting medical homes and care coordination in primary care for the underserved provide a favorable model for improving health in disrupted communities. Elements of medical home services can be offered by local or temporary providers from outside the region, working out of mobile clinics early in disaster recovery. As repairs and reconstruction proceed, local services are restored over weeks or years. Throughout recovery, major tasks include identifying high-risk patients relative to the disaster and underlying health conditions, assisting displaced families as they transition through housing locations, and tracking their evolving access to health care and community services as they are restored. Postdisaster sources of financial assistance for the disaster-exposed population are often temporary and evolving, requiring up-to-date information to cover costs of care until stable services and insurance coverage are restored. Evidence to support disaster recovery health care improvement will require research funding and metrics on structures, processes, and outcomes of the disaster recovery medical home and care coordination, based on adaptation of standard validated methods to crisis environments. PMID- 26046494 TI - Murine Bone Marrow-Derived Dendritic Cells Transduced by Light-Helper-Dependent Herpes Simplex Virus-1 Amplicon Vector Acquire a Mature Dendritic Cell Phenotype. AB - Dendritic cells (DCs) turn into the most potent antigen-presenting cells following a complex transforming process, which leads to their maturation. Herpes simplex virus-1 (HSV-1) amplicon vectors represent highly versatile viral vector platforms with the ability to transduce immature DCs at exceedingly high efficiencies, while the efficiency of infection of mature DCs is significantly low. However, the bacterial artificial chromosome (BAC)-dependent (BD) amplicon vectors tested so far do not result in the maturation of mouse bone marrow derived DCs (BMDCs) in vitro. In this study we investigated the effects of light helper-dependent (LHD) amplicon vectors produced with the replication-defective HSV-1 LaLDeltaJ helper virus system. First, we observed that transgene expression in BMDC cultures was equally potent between the LHD and the BD amplicon vectors. We determined that the percentage of transduced cells and the duration of transgene expression were negatively influenced by the presence of increasing levels of helper virus. Second, infection by the LHD amplicon vector as well as the helper HSV-1 LaLDeltaJ virus alone resulted in the phenotypic maturation of BMDCs and the expression of both interferon-stimulated genes and proinflammatory cytokines. Further comparisons of the gene expression of infected DCs showed that while interferon-stimulated genes such as Ifit1, Ifit3, Mx2, Isg15, and Cxcl10 were induced by both BD and LHD amplicon vectors, early proinflammatory cytokine gene expression (Tnfa, Il1a, Il1b, Il6, Il10, Il12b, Cxcl1, and Cxcl16) and DC maturation were mediated only by the LHD amplicons. PMID- 26046493 TI - Selective serotonin reuptake inhibitors for fibromyalgia syndrome. AB - BACKGROUND: Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. OBJECTIVES: The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. SELECTION CRITERIA: We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. DATA COLLECTION AND ANALYSIS: Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. MAIN RESULTS: The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together.All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional beneficial outcome (NNTB) 10, 95% CI 5 to 100; and in global improvement (proportion of patients who reported to be much or very much improved: 50/168 (29.8%) of patients with SSRIs and 26/162 (16.0%) of patients with placebo) RD 0.14, 95% CI 0.06 to 0.23; NNTB 7, 95% CI 4 to 17.SSRIs did not statistically, or clinically, significantly reduce fatigue: standard mean difference (SMD) -0.26, 95% CI -0.55 to 0.03; 7.0% absolute improvement on a 0 to 10 scale, 95% CI 14.6% relative improvement to 0.8% relative deterioration; nor sleep problems: SMD 0.03, 95 % CI -0.26 to 0.31; 0.8 % absolute deterioration on a 0 to 100 scale, 95% CI 8.3% relative deterioration to 6.9% relative improvement.SSRIs were superior to placebo in the reduction of depression: SMD 0.39, 95% CI -0.65 to -0.14; 7.6% absolute improvement on a 0 to 10 scale, 95% CI 2.7% to 13.8% relative improvement; NNTB 13, 95% CI 7 to 37. The dropout rate due to adverse events was not higher with SSRI use than with placebo use (23/146 (15.8%) of patients with SSRIs and 14/138 (10.1%) of patients with placebo) RD 0.04, 95% CI -0.06 to 0.14. There was no statistically or clinically significant difference in serious adverse events with SSRI use and placebo use (3/84 (3.6%) in patients with SSRIs and 4/84 (4.8%) and patients with placebo) RD -0.01, 95% CI -0.07 to 0.05. AUTHORS' CONCLUSIONS: There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia. The black box warning for increased suicidal tendency in young adults aged 18 to 24, with major depressive disorder, who have taken SSRIs, should be considered when appropriate. PMID- 26046496 TI - The triplet state of tanshinone I and its synergic effect on the phototherapy of cancer cells with curcumin. AB - The excited triplet state of tanshinone I (Tan I) extracted from the traditional Chinese medicine Salvia miltiorrhiza Bunge was characterized by laser flash photolysis. The synergic effect of Tan I on the phototherapy of cancer cells with curcumin (Cur) was also investigated by MTT assay because the excited energy transfer from the triplet state of Tan I ((3)Tan I(*)) to Cur occurred. At the same time, the characteristic absorption spectra of (3)Tan I(*) were recorded, and its molar absorption coefficient and rate constants for several excited energy transfers were obtained. The photo-therapeutic effect of Cur is enhanced by combination with Tan I. PMID- 26046495 TI - A new thio-Schiff base fluorophore with copper ion sensing, DNA binding and nuclease activity. AB - Copper ion recognition and DNA interaction of a newly synthesized fluorescent Schiff base (HPyETSC) were investigated using UV-vis and fluorescent spectroscopy. Examination using these two techniques revealed that the detection of copper by HPyETSC is highly sensitive and selective, with a detection limit of 0.39 MUm and the mode of interaction between HPyETSC and DNA is electrostatic, with a binding constant of 8.97*10(4) M(-1). Furthermore, gel electrophoresis studies showed that HPyETSC exhibited nuclease activity through oxidative pathway. PMID- 26046497 TI - Photophysical and photosensitizing characters of 2-phenylbenzimidazole-5-sulfonic acid. A theoretical study. AB - The sunscreen agent 2-phenylbenzimidazole-5-sulfonic acid (PBSA) has been reported to exhibit photosensitizing activity. In the present study, the photophysical and photosensitizing properties of PBSA were investigated by means of quantum chemical calculations with the aim to gain deeper insights into the underlying photosensitizing mechanisms. The results indicate that singlet oxygen may be generated spontaneously through direct energy transfer from triplet excited state PBSA to (3)O2, and superoxide anion radical is formed through electron transfer between the anion of PBSA and (3)O2. This offers some deeper insights into the photosensitizing mechanisms of PBSA. PMID- 26046498 TI - Vibrational spectroscopic studies and molecular docking study of 2-[(E)-2 phenylethenyl]quinoline-5-carboxylic acid. AB - FT-IR and FT-Raman spectra of 2-[(E)-2-phenylethenyl]quinoline-5-carboxylic acid were recorded and obtained and analyzed. The vibrational wavenumbers were computed using DFT quantum chemical calculations. The geometrical parameters (SDD) of the title compound are in agreement with that of similar derivatives. Stability of the molecule arising from the hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital analysis. From the natural and Mulliken charges, it can be concluded that electrophilic substitution of the quinoline scaffold is more preferred than nucleophilic substitution. From the MEP map it is evident that the negative regions are mainly localized over the carbonyl group and are possible sites for electrophilic attack. The title compound forms a stable complex with PknB as is evident from the binding affinity values and the molecular docking study suggests that the compound might exhibit inhibitory activity against PknB. PMID- 26046499 TI - Effects of game-based virtual reality on health-related quality of life in chronic stroke patients: A randomized, controlled study. AB - In the present study, we aimed to determine whether game-based virtual reality (VR) rehabilitation, combined with occupational therapy (OT), could improve health-related quality of life, depression, and upper extremity function. We recruited 35 patients with chronic hemiparetic stroke, and these participants were randomized into groups that underwent VR rehabilitation plus conventional OT, or the same amount of conventional OT alone, for 20 sessions over 4 weeks. Compared to baseline, the VR rehabilitation plus OT group exhibited significantly improved role limitation due to emotional problems (p=0.047). Compared to baseline, both groups also exhibited significantly improved depression (p=0.017) and upper extremity function (p=0.001), although the inter-group differences were not significant. However, a significant inter-group difference was observed for role limitation due to physical problems (p=0.031). Our results indicate that game-based VR rehabilitation has specific effects on health-related quality of life, depression, and upper extremity function among patients with chronic hemiparetic stroke. PMID- 26046500 TI - Adaptive image inversion of contrast 3D echocardiography for enabling automated analysis. AB - INTRODUCTION: Contrast 3D echocardiography (C3DE) is commonly used to enhance the visual quality of ultrasound images in comparison with non-contrast 3D echocardiography (3DE). Although the image quality in C3DE is perceived to be improved for visual analysis, however it actually deteriorates for the purpose of automatic or semi-automatic analysis due to higher speckle noise and intensity inhomogeneity. Therefore, the LV endocardial feature extraction and segmentation from the C3DE images remains a challenging problem. METHODS: To address this challenge, this work proposes an adaptive pre-processing method to invert the appearance of C3DE image. The image inversion is based on an image intensity threshold value which is automatically estimated through image histogram analysis. RESULTS: In the inverted appearance, the LV cavity appears dark while the myocardium appears bright thus making it similar in appearance to a 3DE image. Moreover, the resulting inverted image has high contrast and low noise appearance, yielding strong LV endocardium boundary and facilitating feature extraction for segmentation. CONCLUSIONS: Our results demonstrate that the inverse appearance of contrast image enables the subsequent LV segmentation. PMID- 26046501 TI - Self-help interventions for psychosis: a meta-analysis. AB - Self-help has been shown to be an effective intervention for a wide range of mental health problems. However, there is less evidence on the efficacy of self help for psychosis and, to date, there has been no systematic review. A search of bibliographic databases identified 24 relevant studies with a total sample size of N=1816. Ten studies adopted a repeated measures design and 14 an independent group design (including RCTs and quasi-experimental studies). Self-help interventions had, on average, a small-to-medium-sized effect on overall symptoms (d+=0.33, 95% CI: 0.17 to 0.48). Sub-analyses revealed that self-help interventions had a small-to-medium-sized effect on positive symptoms (d+=0.42, 95% CI: 0.13 to 0.72), a small-to-medium-sized effect on negative symptoms (d+=0.37, 95% CI: 0.07 to 0.66), and a small-sized effect on outcomes associated with the symptoms of psychosis such as quality of life (d+=0.13, 95% CI: 0.02 to 0.24). Moderation analysis identified a number of factors that influenced treatment effects including the complexity of the intervention and amount of contact time. Self-help interventions for psychosis have a lot of potential and recommendations for further research are discussed. PMID- 26046502 TI - Dual-Energy Computed Tomography: Advantages in the Acute Setting. AB - The aim of this article is to inform and update emergency radiologists in respect of the clinically relevant benefits that dual-energy computed tomography (CT) contributes over conventional single-energy CT in the emergency setting using practical imaging examples. Particular emphasis will be placed on acute gout, bone marrow edema, acute renal colic, acute cardiovascular and neurovascular emergencies aswell as characterization of abdominal incidentalomas. The relevant scientific literature will be summarized and limitations of the technique also will be emphasized to provide the reader with a rounded concept of the current state of technology. PMID- 26046503 TI - Improving Outcomes in the Patient with Polytrauma: A Review of the Role of Whole Body Computed Tomography. AB - Whole-body computed tomography (WBCT) is used for the workup of the patient with blunt polytrauma. WBCT is associated with improved patient survival and reduces the emergency department length of stay. However, randomized studies are needed to determine whether early WBCT improves survival, to clarify which patients benefit the most, and to model the costs of this technique compared with traditional workup. Advancements in modern multidetector computed tomography technology and an improved understanding of optimal protocols have enabled one to scan the entire body and achieve adequate image quality for a comprehensive trauma assessment in a short period. PMID- 26046504 TI - Pearls for Interpreting Computed Tomography of the Cervical Spine in Trauma. AB - The high morbidity and mortality associated with cervical spine injuries makes identification and classification essential. It is important to have a systematic approach to evaluation, especially in the trauma setting with other distracting injuries. Understanding the anatomy and biomechanics enables rapid and accurate interpretation of images. In severe trauma and in patients with rigid spinal disease, the classic patterns of injury may be difficult or impossible to recognize. This article provides an approach to acquiring and interpreting cervical spine images in the setting of acute trauma and reviews the classic patterns of injury. PMID- 26046506 TI - Imaging of Traumatic Brain Injury. AB - Imaging plays an important role in the management of patients with traumatic brain injury (TBI). Computed tomography (CT) is the first-line imaging technique allowing rapid detection of primary structural brain lesions that require surgical intervention. CT also detects various deleterious secondary insults allowing early medical and surgical management. Serial imaging is critical to identifying secondary injuries. MR imaging is indicated in patients with acute TBI when CT fails to explain neurologic findings. However, MR imaging is superior in patients with subacute and chronic TBI and also predicts neurocognitive outcome. PMID- 26046505 TI - Penetrating Thoracic Injury. AB - This article discusses the role of radiology in evaluating patients with penetrating injuries to the chest. Penetrating injuries to the chest encompass ballistic and nonballistic injuries and can involve superficial soft tissues of the chest wall, lungs and pleura, diaphragm, and mediastinum. The mechanism of injury in ballistic and nonballistic trauma and the impact the injury trajectory has on imaging evaluation of penetrating injuries to the chest are discussed. The article presents the broad spectrum of imaging findings a radiologist encounters with penetrating injuries to the chest, with emphasis on injuries to the lungs and pleura, diaphragm, and mediastinum. PMID- 26046507 TI - Easily Missed Fractures of the Upper Extremity. AB - Radiographs remain the mainstay for initial imaging of suspected fracture in the emergency setting. Missed fractures potentially have significant negative consequences for patients, referring physicians, and radiologists. Most missed fractures are owing to perceptual errors. In this review, we emphasize knowledge of 3 categories of pitfalls as they pertain to the upper extremity: the common but challenging; the out of mind, out of sight; and those related to satisfaction of search. For specific injuries, emphasis is placed on helpful radiographic signs and important additional radiographic views to obtain. PMID- 26046508 TI - Easily Missed Fractures in the Lower Extremity. AB - As long as radiography remains cheap and provides value in patient care, it will continue to be widely used as a front-line imaging technique. There are limitations to what a radiograph can depict, however. It is imperative to understand the limitations of radiography to avoid pitfalls owing to the overlap of numerous osseous structures. This article reminds the reader of the association between certain radiographic abnormalities and the anatomic relevance in the patient. Although interpretive errors occur in fast-paced, high-volume emergency settings, meticulous attention to changes in the cortex and medullary bone may help to keep errors to a minimum. PMID- 26046509 TI - Imaging of Pancreatic and Duodenal Trauma. AB - Pancreatic and duodenal injuries are rare but life-threatening occurrences, often occurring in association with other solid organ injuries. Findings of pancreatic and duodenal trauma on computed tomography and MR imaging are often nonspecific, and high levels of clinical suspicion and understanding of mechanism of injury are imperative. Familiarity with the grading schemes of pancreatic and duodenal injury is important because they help in assessing for key imaging findings that directly influence management. This article presents an overview of imaging of blunt and penetrating pancreatic and duodenal injuries, including pathophysiology, available imaging techniques, and variety of imaging features. PMID- 26046510 TI - Imaging of Urinary System Trauma. AB - Computed tomography (CT) imaging of the kidney, ureter, and bladder permit accurate and prompt diagnosis or exclusion of traumatic injuries, without the need to move the patient to the fluoroscopy suite. Real-time review of imaging permits selective delayed imaging, reducing time on the scanner and radiation dose for patients who do not require delays. Modifying imaging parameters to obtain thicker slices and noisier images permits detection of contrast extravasation from the kidneys, ureters, and bladder, while reducing radiation dose on the delayed or cystographic imaging. The American Association for the Surgery of Trauma grading system is discussed, along with challenges and limitations. PMID- 26046511 TI - Negative Computed Tomography for Acute Pulmonary Embolism: Important Differential Diagnosis Considerations for Acute Dyspnea. AB - Computed tomography pulmonary angiography (CTPA) is the principal means of evaluating dyspnea in the emergency department. As its use has increased, the number of studies positive for pulmonary embolism (PE) has decreased to less than 20%. Many of the negative PE studies provide an alternative explanation for dyspnea, most commonly pneumonia, pulmonary edema, pleural effusion, or atelectasis. Nonthrombotic emboli may also be suggested. Airway and obstructive lung disease may be detected on CTPA. Pleural and pericardial disease may also explain the dyspnea, but more detailed evaluation of the serosal surfaces may be limited on the arterial phase of a CTPA. PMID- 26046512 TI - Imaging Patterns and Management Algorithms in Acute Stroke: An Update for the Emergency Radiologist. AB - Neuroimaging plays a key role in the initial work-up of patients with symptoms of acute stroke. Understanding the advantages and limitations of available CT and MR imaging techniques and how to use them optimally in the emergency setting is crucial for accurately making the diagnosis of acute stroke and for rapidly determining appropriate treatment. PMID- 26046513 TI - Face and Neck Infections: What the Emergency Radiologist Needs to Know. AB - An overview of the imaging of face and neck infections is presented. Most of the imaging presented is contrast-enhanced computed tomography. The emphasis of this presentation is to enable the emergency radiologist to accurately diagnose face and neck infections, to effectively communicate the imaging findings with emergency physicians, and to function as part of a team offering the best care to patients. PMID- 26046514 TI - Imaging of Ischemia, Obstruction and Infection in the Abdomen. AB - Intestinal ischemia is a serious condition that continues to be associated with mortalities in excess of 70%. Intestinal obstruction and gastrointestinal tract sepsis are common conditions, accounting for a large proportion of patients admitted to emergency departments with acute abdominal symptoms. This article discusses the imaging methods and key findings of these entities in the emergency radiology department. The article includes imaging examples, diagnostic options, protocol selections, diagnostic criteria, and differential diagnoses. PMID- 26046516 TI - Emergency Radiology: The New Frontier of Imaging. PMID- 26046515 TI - Imaging of Nontraumatic Neuroradiology Emergencies. AB - Imaging of acute neurologic disease in the emergency department can be challenging because of the wide range of possible causes and the overlapping imaging appearance of many of these entities on nonenhanced computed tomography (CT). The key to formulating a succinct, pertinent differential diagnosis includes characterizing the pattern of abnormalities on CT and identifying key features that suggest a particular diagnosis. This article divides neurologic emergencies into 5 scenarios based on the CT findings, including subarachnoid hemorrhage, intraparenchymal hemorrhage, vasogenic edema without and with underlying mass lesion, and acute hydrocephalus. Specific common or important diagnoses in each category are discussed. PMID- 26046517 TI - The expression pattern of APC2 and APC7 in various cancer cell lines and AML patients. AB - PURPOSE: Anaphase promoting complex (APC/C) is an E3 ligase enzyme, which ubiquinates various proteins involved in the cell cycle. This protein complex may have a pivotal role in the cell cycle control affecting pathological conditions such as cancer. APC7 and APC2 subunits of the APC/C complex are involved in the substrate recognition and the catalytic reaction, respectively. MATERIALS AND METHODS: In this study, quantitative Real-time PCR was used to analyse APC2 and APC7 expression in different cancer cell lines as well as AML patient's blood cells. RESULTS: The results showed that APC2 and APC7 subunits were both over expressed in cancer cell lines (p=0.008). The mean expression ratio of APC2 and APC7 in different cancer cells were 2.60+/-0.22 and 4.83+/-0.11, respectively. An increase in expression of APC2 and APC7 was seen among 12 out of 14 AML patients (85%). There was a significant positive correlation between APC2 upregulation and the detection of splenomegaly in the patients (r=0.808, p=0.001). CONCLUSION: This was the first study suggesting that APC/C upregulation may contribute to the pathogenesis of cancer and can be used as a molecular biomarker to predict the progression and the prognosis of AML. PMID- 26046518 TI - Fully-automated synthesis of 16beta-(18)F-fluoro-5alpha-dihydrotestosterone (FDHT) on the ELIXYS radiosynthesizer. AB - Noninvasive in vivo imaging of androgen receptor (AR) levels with positron emission tomography (PET) is becoming the primary tool in prostate cancer detection and staging. Of the potential (18)F-labeled PET tracers, (18)F-FDHT has clinically shown to be of highest diagnostic value. We demonstrate the first automated synthesis of (18)F-FDHT by adapting the conventional manual synthesis onto the fully-automated ELIXYS radiosynthesizer. Clinically-relevant amounts of (18)F-FDHT were synthesized on ELIXYS in 90 min with decay-corrected radiochemical yield of 29+/-5% (n=7). The specific activity was 4.6 Ci/umol (170 GBq/umol) at end of formulation with a starting activity of 1.0 Ci (37 GBq). The formulated (18)F-FDHT yielded sufficient activity for multiple patient doses and passed all quality control tests required for routine clinical use. PMID- 26046519 TI - Identifying key surface parameters for optical photon transport in GEANT4/GATE simulations. AB - For a scintillator used for spectrometry, the generation, transport and detection of optical photons have a great impact on the energy spectrum resolution. A complete Monte Carlo model of a scintillator includes a coupled ionizing particle and optical photon transport, which can be simulated with the GEANT4 code. The GEANT4 surface parameters control the physics processes an optical photon undergoes when reaching the surface of a volume. In this work the impact of each surface parameter on the optical transport was studied by looking at the optical spectrum: the number of detected optical photons per ionizing source particle from a large plastic scintillator, i.e. the output signal. All simulations were performed using GATE v6.2 (GEANT4 Application for Tomographic Emission). The surface parameter finish (polished, ground, front-painted or back-painted) showed the greatest impact on the optical spectrum whereas the surface parameter sigma(alpha), which controls the surface roughness, had a relatively small impact. It was also shown how the surface parameters reflectivity and reflectivity types (specular spike, specular lobe, Lambertian and backscatter) changed the optical spectrum depending on the probability for reflection and the combination of reflectivity types. A change in the optical spectrum will ultimately have an impact on a simulated energy spectrum. By studying the optical spectra presented in this work, a GEANT4 user can predict the shift in an optical spectrum caused be the alteration of a specific surface parameter. PMID- 26046520 TI - Measurement of X-ray spectra using a Lu2(SiO4)O-multipixel-photon detector with changes in the pixel number. AB - To measure X-ray spectra with high count rates, we developed a detector consisting of a Lu2(SiO4)O [LSO] crystal with a decay time of 40 ns and a multipixel photon counter (MPPC). The photocurrents flowing through the MPPC are converted into voltages and amplified by a high-speed current-voltage amplifier, and event pulses from the amplifier are sent to a multichannel analyzer to measure spectra. We used three MPPCs of 100, 400 and 1600 pixels/mm(2), and the MPPCs were driven under pre-Geiger mode at a temperature of 20 degrees C. At a tube voltage of 100 kV and a tube current of 5.0 MUA, the maximum count rate was 12.8 kilo-counts per second. The event-pulse widths were 200 ns, and the energy resolution was 53% at 59.5 keV using a 100-pixel MPPC. PMID- 26046521 TI - Measurement of radiation dose with BeO dosimeters using optically stimulated luminescence technique in radiotherapy applications. AB - The radiation dose delivered to the target by using different radiotherapy applications has been measured with the help of beryllium oxide (BeO) dosimeters to be placed inside the rando phantom. Three-Dimensional Conformal Radiotherapy (3DCRT), Intensity-Modulated Radiotherapy (IMRT) and Intensity-Modulated Arc Therapy (IMAT) have been used as radiotherapy application. Individual treatment plans have been made for the three radiotherapy applications of rando phantom. The section 4 on the phantom was selected as target and 200 cGy doses were delivered. After the dosimeters placed on section 4 (target) and the sections 2 and 6 (non-target) were irradiated, the result was read through the OSL technique on the Riso TL/OSL system. This procedure was repeated three times for each radiotherapy application. The doses delivered to the target and the non-target sections as a result of the 3DCRT, IMRT and IMAT plans were analyzed. The doses received by the target were measured as 204.71 cGy, 204.76 cGy and 205.65 cGy, respectively. The dose values obtained from treatment planning system (TPS) were compared to the dose values obtained using the OSL technique. It has been concluded that, the radiation dose can be measured with the OSL technique by using BeO dosimeters in medical practices. PMID- 26046522 TI - Modifying Role of GSTP1 Polymorphism on the Association between Tea Fluoride Exposure and the Brick-Tea Type Fluorosis. AB - BACKGROUND: Brick tea type fluorosis is a public health concern in the north-west area of China. The association between SNPs of genes influencing bone mass and fluorosis has attracted attention, but the association of SNPs with the risk of brick-tea type of fluorosis has not been reported. OBJECTIVE: To investigate the modifying roles of GSTP1 rs1695 polymorphisms on this association. METHODS: A cross-sectional study was conducted. Brick-tea water was tested by the standard of GB1996-2005 (China). Urinary fluoride was tested by the standard of WS/T 89 2006 (China). Skeletal fluorosis was diagnosed by X-ray, the part we scheduled was forearm, shank, and pelvic, then diagnosed the skeletal fluorosis by the standard of WS/192-2008 (China). Gene polymorphism was tested by Sequenom MassARRAY system. RESULT: The prevalence rate in different ethnical participants was different: Tibetan individuals had the highest prevalence rate of skeletal fluorosis. There were significant differences in genotype frequencies of GSTP1 Rs1695 among different ethnical participants (p<0.001): Tibetan, Mongolian and Han subjects with homozygous wild type (GSTP1-AA) genotype were numerically higher than Kazakh and Russian subjects (p<0.001). Compared to Tibetan participants who carried homozygous A allele of GSTP1 Rs1695, Tibetan participants who carried G allele had a significantly decreased risk of skeletal fluorosis (OR = 0.558 [95% CI, 0.326-0.955]). For Kazakh participants, a decreased risk of skeletal fluorosis among carriers of the G allele was limited to non high-loaded fluoride status (OR = 0. 166 [95% CI, 0.035-0.780] vs. OR = 1.478 [95% CI, 0.866-2.552] in participants with high-loaded fluoride status). Neither SNP-IF nor SNP-age for GSTP1 Rs1695 was observed. CONCLUSION: The prevalence rate of the brick tea type fluorosis might have ethnic difference. For Tibetan individuals, who had the highest prevalence rate, G allele of GSTP1 Rs1695 might be a protective factor for brick tea type skeletal fluorosis. PMID- 26046523 TI - Pathogen-Specific T Cell Polyfunctionality Is a Correlate of T Cell Efficacy and Immune Protection. AB - INTRODUCTION: Understanding the factors that delineate the efficacy of T cell responses towards pathogens is crucial for our ability to develop potent therapies against infectious diseases. Multidimensional evaluation of T cell functionality at the single-cell level enables exhaustive analysis of combinatorial functional properties, hence polyfunctionality. We have recently invented an algorithm that quantifies polyfunctionality, the Polyfunctionality Index (Larsen et al. PLoS One 2012). Here we demonstrate that quantitative assessment of T cell polyfunctionality correlates with T cell efficacy measured as the capacity to kill target cells in vitro and control infection in vivo. METHODS: We employed the polyfunctionality index on two datasets selected for their unique ability to evaluate the polyfunctional imprint on T cell efficacy. 1) HIV-specific CD8+ T cells and 2) Leishmania major-specific CD4+ T cells were analysed for their capacity to secrete multiple effector molecules, kill target cells and control infection. Briefly, employing the Polyfunctionality Index algorithm we determined the parameter estimates resulting in optimal correlation between T cell polyfunctionality and T cell efficacy. RESULTS: T cell polyfunctionality is correlated with T cell efficacy measured as 1) target killing (r=0.807, P<0.0001) and 2) lesion size upon challenge with Leishmania major (r=-0.50, P=0.004). Contrary to an approach relying on the Polyfunctionality Index algorithm, quantitative evaluation of T cell polyfunctionality traditionally ignores the gradual contribution of more or less polyfunctional T cells. Indeed, comparing both approaches we show that optimal description of T cell efficacy is obtained when gradually integrating all levels of polyfunctionality in accordance with the Polyfunctionality Index. CONCLUSIONS: Our study presents a generalizable methodology to objectively evaluate the impact of polyfunctionality on T cell efficacy. We show that T cell polyfunctionality is a superior correlate of T cell efficacy both in vitro and in vivo as compared with response size. Therefore, future immunotherapies should aim to increase T cell polyfunctionality. PMID- 26046524 TI - Urothelial Defects from Targeted Inactivation of Exocyst Sec10 in Mice Cause Ureteropelvic Junction Obstructions. AB - Most cases of congenital obstructive nephropathy are the result of ureteropelvic junction obstructions, and despite their high prevalence, we have a poor understanding of their etiology and scarcity of genetic models. The eight-protein exocyst complex regulates polarized exocytosis of intracellular vesicles in a large variety of cell types. Here we report generation of a conditional knockout mouse for Sec10, a central component of the exocyst, which is the first conditional allele for any exocyst gene. Inactivation of Sec10 in ureteric bud derived cells using Ksp1.3-Cre mice resulted in severe bilateral hydronephrosis and complete anuria in newborns, with death occurring 6-14 hours after birth. Sec10 FL/FL;Ksp-Cre embryos developed ureteropelvic junction obstructions between E17.5 and E18.5 as a result of degeneration of the urothelium and subsequent overgrowth by surrounding mesenchymal cells. The urothelial cell layer that lines the urinary tract must maintain a hydrophobic luminal barrier again urine while remaining highly stretchable. This barrier is largely established by production of uroplakin proteins that are transported to the apical surface to establish large plaques. By E16.5, Sec10 FL/FL;Ksp-Cre ureter and pelvic urothelium showed decreased uroplakin-3 protein at the luminal surface, and complete absence of uroplakin-3 by E17.5. Affected urothelium at the UPJ showed irregular barriers that exposed the smooth muscle layer to urine, suggesting this may trigger the surrounding mesenchymal cells to overgrow the lumen. Findings from this novel mouse model show Sec10 is critical for the development of the urothelium in ureters, and provides experimental evidence that failure of this urothelial barrier may contribute to human congenital urinary tract obstructions. PMID- 26046525 TI - Increased Specific Labeling of INS-1 Pancreatic Beta-Cell by Using RIP-Driven Cre Mutants with Reduced Activity. AB - Ectopically expressed Cre recombinase in extrapancreatic tissues in RIP-Cre mice has been well documented. The objective of this study was to find a simple solution that allows for improved beta-cell specific targeting. To this end, the RIP-Cre and reporter CMV-loxP-DsRed-loxP-EGFP expression cassettes were configurated into a one-plasmid and two-plasmid systems, which labeled approximately 80% insulin-positive INS-1 cells after 48 h transfection. However, off-target labeling was robustly found in more than 15% insulin-negative Ad293 cells. When an IRES element was inserted in front of Cre to reduce the translation efficiency, the ratio of recombination between INS-1 and Ad293 cells increased 3-4-fold. Further, a series of Cre mutants were generated by site directed mutagenesis. When one of the mutants, Cre(H289P) in both configurations, was used in the experiment, the percentage of recombination dropped to background levels in a number of insulin-negative cell lines, but decreased only slightly in INS-1 cells. Consistently, DNA substrate digestion assay showed that the enzymatic activity of Cre(H289P) was reduced by 30-fold as compared to that of wild-type. In this study, we reported the generation of constructs containing RIP and Cre mutants, which enabled enhanced beta-cell specific labeling in vitro. These tools could be invaluable for beta-cell targeting and to the study of islet development. PMID- 26046526 TI - Improving In Vivo High-Resolution CT Imaging of the Tumour Vasculature in Xenograft Mouse Models through Reduction of Motion and Bone-Streak Artefacts. AB - INTRODUCTION: Preclinical in vivo CT is commonly used to visualise vessels at a macroscopic scale. However, it is prone to many artefacts which can degrade the quality of CT images significantly. Although some artefacts can be partially corrected for during image processing, they are best avoided during acquisition. Here, a novel imaging cradle and tumour holder was designed to maximise CT resolution. This approach was used to improve preclinical in vivo imaging of the tumour vasculature. PROCEDURES: A custom built cradle containing a tumour holder was developed and fix-mounted to the CT system gantry to avoid artefacts arising from scanner vibrations and out-of-field sample positioning. The tumour holder separated the tumour from bones along the axis of rotation of the CT scanner to avoid bone-streaking. It also kept the tumour stationary and insensitive to respiratory motion. System performance was evaluated in terms of tumour immobilisation and reduction of motion and bone artefacts. Pre- and post-contrast CT followed by sequential DCE-MRI of the tumour vasculature in xenograft transplanted mice was performed to confirm vessel patency and demonstrate the multimodal capacity of the new cradle. Vessel characteristics such as diameter, and branching were quantified. RESULTS: Image artefacts originating from bones and out-of-field sample positioning were avoided whilst those resulting from motions were reduced significantly, thereby maximising the resolution that can be achieved with CT imaging in vivo. Tumour vessels >= 77 MUm could be resolved and blood flow to the tumour remained functional. The diameter of each tumour vessel was determined and plotted as histograms and vessel branching maps were created. Multimodal imaging using this cradle assembly was preserved and demonstrated. CONCLUSIONS: The presented imaging workflow minimised image artefacts arising from scanner induced vibrations, respiratory motion and radiopaque structures and enabled in vivo CT imaging and quantitative analysis of the tumour vasculature at higher resolution than was possible before. Moreover, it can be applied in a multimodal setting, therefore combining anatomical and dynamic information. PMID- 26046527 TI - Quantitative Proteomics of an Amphibian Pathogen, Batrachochytrium dendrobatidis, following Exposure to Thyroid Hormone. AB - Batrachochytrium dendrobatidis (Bd), a chytrid fungus, has increasingly been implicated as a major factor in the worldwide decline of amphibian populations. The fungus causes chytridiomycosis in susceptible species leading to massive die offs of adult amphibians. Although Bd infects the keratinized mouthparts of tadpoles and negatively affects foraging behavior, these infections are non lethal. An important morphogen controlling amphibian metamorphosis is thyroid hormone (T3). Tadpoles may be infected with Bd and the fungus may be exposed to T3 during metamorphosis. We hypothesize that exposure of Bd to T3 may induce the expression of factors associated with host colonization and pathogenicity. We utilized a proteomics approach to better understand the dynamics of the Bd-T3 interaction. Using liquid chromatography-mass spectrometry (LC-MS), we generated a data set of a large number of cytoplasmic and membrane proteins following exposure of Bd to T3. From these data, we identified a total of 263 proteins whose expression was significantly changed following T3 exposure. We provide evidence for expression of an array of proteins that may play key roles in both genomic and non-genomic actions of T3 in Bd. Additionally, our proteomics study shows an increase in several proteins including proteases and a class of uncommon crinkler and crinkler-like effector proteins suggesting their importance in Bd pathogenicity as well as those involved in metabolism and energy transfer, protein fate, transport and stress responses. This approach provides insights into the mechanistic basis of the Bd-amphibian interaction following T3 exposure. PMID- 26046528 TI - An Ultrasensitive Mechanism Regulates Influenza Virus-Induced Inflammation. AB - Influenza viruses present major challenges to public health, evident by the 2009 influenza pandemic. Highly pathogenic influenza virus infections generally coincide with early, high levels of inflammatory cytokines that some studies have suggested may be regulated in a strain-dependent manner. However, a comprehensive characterization of the complex dynamics of the inflammatory response induced by virulent influenza strains is lacking. Here, we applied gene co-expression and nonlinear regression analysis to time-course, microarray data developed from influenza-infected mouse lung to create mathematical models of the host inflammatory response. We found that the dynamics of inflammation-associated gene expression are regulated by an ultrasensitive-like mechanism in which low levels of virus induce minimal gene expression but expression is strongly induced once a threshold virus titer is exceeded. Cytokine assays confirmed that the production of several key inflammatory cytokines, such as interleukin 6 and monocyte chemotactic protein 1, exhibit ultrasensitive behavior. A systematic exploration of the pathways regulating the inflammatory-associated gene response suggests that the molecular origins of this ultrasensitive response mechanism lie within the branch of the Toll-like receptor pathway that regulates STAT1 phosphorylation. This study provides the first evidence of an ultrasensitive mechanism regulating influenza virus-induced inflammation in whole lungs and provides insight into how different virus strains can induce distinct temporal inflammation response profiles. The approach developed here should facilitate the construction of gene regulatory models of other infectious diseases. PMID- 26046529 TI - The Low Proportion and Associated Factors of Involuntary Admission in the Psychiatric Emergency Service in Taiwan. AB - BACKGROUND: The involuntary admission regulated under the Mental Health Act has become an increasingly important issue in the developed countries in recent years. Most studies about the distribution and associated factors of involuntary admission were carried out in the western countries; however, the results may vary in different areas with different legal and socio-cultural backgrounds. AIMS: The aim of this study was to investigate the proportion and associated factors of involuntary admission in a psychiatric emergency service in Taiwan. METHODS: The study cohort included patients admitted from a psychiatric emergency service over a two-year period. Demographic, psychiatric emergency service utilization, and clinical variables were compared between those who were voluntarily and involuntarily admitted to explore the associated factors of involuntary admission. RESULTS: Among 2,777 admitted patients, 110 (4.0%) were involuntarily admitted. Police referrals and presenting problems as violence assessed by psychiatric nurses were found to be associated with involuntary admission. These patients were more likely to be involuntarily admitted during the night shift and stayed longer in the psychiatric emergency service. CONCLUSIONS: The proportion of involuntary admissions in Taiwan was in the lower range when compared to Western countries. Dangerous conditions evaluated by the psychiatric nurses and police rather than diagnosis made by the psychiatrists were related factors of involuntary admission. As it spent more time to admit involuntary patients, it was suggested that multidisciplinary professionals should be included in and educated for during the process of involuntary admission. PMID- 26046531 TI - Locally Confined Clonal Complexes of Mycobacterium ulcerans in Two Buruli Ulcer Endemic Regions of Cameroon. AB - BACKGROUND: Mycobacterium ulcerans is the causative agent of the necrotizing skin disease Buruli ulcer (BU), which has been reported from over 30 countries worldwide. The majority of notified patients come from West African countries, such as Cote d'Ivoire, Ghana, Benin and Cameroon. All clinical isolates of M. ulcerans from these countries are closely related and their genomes differ only in a limited number of single nucleotide polymorphisms (SNPs). METHODOLOGY/PRINCIPAL FINDINGS: We performed a molecular epidemiological study with clinical isolates from patients from two distinct BU endemic regions of Cameroon, the Nyong and the Mape river basins. Whole genome sequencing of the M. ulcerans strains from these two BU endemic areas revealed the presence of two phylogenetically distinct clonal complexes. The strains from the Nyong river basin were genetically more diverse and less closely related to the M. ulcerans strain circulating in Ghana and Benin than the strains causing BU in the Mape river basin. CONCLUSIONS: Our comparative genomic analysis revealed that M. ulcerans clones diversify locally by the accumulation of SNPs. Case isolates coming from more recently emerging BU endemic areas, such as the Mape river basin, may be less diverse than populations from longer standing disease foci, such as the Nyong river basin. Exchange of strains between distinct endemic areas seems to be rare and local clonal complexes can be easily distinguished by whole genome sequencing. PMID- 26046530 TI - Comparative Transcriptome and iTRAQ Proteome Analyses of Citrus Root Responses to Candidatus Liberibacter asiaticus Infection. AB - Root samples of 'Sanhu' red tangerine trees infected with and without Candidatus Liberibacter asiaticus (CLas) were collected at 50 days post inoculation and subjected to RNA-sequencing and isobaric tags for relative and absolute quantification (iTRAQ) to profile the differentially expressed genes (DEGs) and proteins (DEPs), respectively. Quantitative real-time PCR was subsequently used to confirm the expression of 16 selected DEGs. Results showed that a total of 3956 genes and 78 proteins were differentially regulated by HLB-infection. Among the most highly up-regulated DEPs were sperm specific protein 411, copper ion binding protein, germin-like proteins, subtilisin-like proteins and serine carboxypeptidase-like 40 proteins whose transcript levels were concomitantly up regulated as shown by RNA-seq data. Comparison between our results and those of the previously reported showed that known HLB-modulated biological pathways including cell-wall modification, protease-involved protein degradation, carbohydrate metabolism, hormone synthesis and signaling, transcription activities, and stress responses were similarly regulated by HLB infection but different or root-specific changes did exist. The root unique changes included the down-regulation in genes of ubiquitin-dependent protein degradation pathway, secondary metabolism, cytochrome P450s, UDP-glucosyl transferases and pentatricopeptide repeat containing proteins. Notably, nutrient absorption was impaired by HLB-infection as the expression of the genes involved in Fe, Zn, N and P adsorption and transportation were significantly changed. HLB-infection induced some cellular defense responses but simultaneously reduced the biosynthesis of the three major classes of secondary metabolites, many of which are known to have anti-pathogen activities. Genes involved in callose deposition were up-regulated whereas those involved in callose degradation were also up regulated, indicating that the sieve tube elements in roots were hanging on the balance of life and death at this stage. In addition, signs of carbohydrate starvation were already eminent in roots at this stage. Other interesting genes and pathways that were changed by HLB-infection were also discussed based on our findings. PMID- 26046532 TI - Liquid vs Solid Culture Medium to Evaluate Proportion and Time to Change in Management of Suspects of Tuberculosis-A Pragmatic Randomized Trial in Secondary and Tertiary Health Care Units in Brazil. AB - BACKGROUND: The use of liquid medium (MGIT960) for tuberculosis (TB) diagnosis was recommended by WHO in 2007. However, there has been no evaluation of its effectiveness on clinically important outcomes. METHODS AND FINDINGS: A pragmatic trial was carried out in a tertiary hospital and a secondary health care unit in Rio de Janeiro City, Brazil. Participants were 16 years or older, suspected of having TB. They were excluded if only cerebral spinal fluid or blood specimens were available for analysis. MGIT960 technique was compared with the Lowenstein Jensen (LJ) method for laboratory diagnosis of active TB. Primary outcome was the proportion of patients who had their initial medical management changed within 2 months after randomisation. Secondary outcomes were: mean time for changing the procedure, patient satisfaction with the overall treatment and adverse events. Data were analysed by intention-to-treat. Between April 2008 and September 2011, 693 patients were enrolled (348 to MGIT, 345 to LJ). Smear and culture results were positive for 10% and 15.7% of participants, respectively. Patients in the MGIT arm had their initial medical management changed more frequently than those in the LJ group (10.1% MGIT vs 3.8% LJ, RR 2.67 95% CI 1.44-.96, p = 0.002, NNT 16, 95% CI 10-39). Mean time for changing the initial procedure was greater in LJ group at both sites: 20.0 and 29.6 days in MGIT group and 52.2 and 64.3 in LJ group (MD 33.5, 95% CI 30.6-36.4, p = 0.0001). No other important differences were observed. CONCLUSIONS: This study suggests that opting for the MGIT960 system for TB diagnosis provides a promising case management model for improving the quality of care and control of TB. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN79888843. PMID- 26046533 TI - Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice. AB - Cognitive decline occurs during healthy aging, even in middle-aged subjects, via mechanisms that could include reduced stem cell proliferation, changed growth factor expression and/or reduced expression of synaptic plasticity genes. Although antidepressants alter these mechanisms in young rodents, their effects in older animals are unclear. In middle-aged mice, we examined the effects of a selective serotonin reuptake inhibitor (fluoxetine) and a multimodal antidepressant (vortioxetine) on cognitive and affective behaviors, brain stem cell proliferation, growth factor and gene expression. Twelve-month-old female C57BL/6 mice exhibited impaired visuospatial memory in the novel object placement (location) task associated with reduced expression of several plasticity-related genes. Chronic treatment with vortioxetine, but not fluoxetine, improved visuospatial memory and reduced depression-like behavior in the forced swim test in middle-aged mice. Vortioxetine, but not fluoxetine, increased hippocampal expression of several neuroplasticity-related genes in middle-aged mice (e.g., Nfkb1, Fos, Fmr1, Camk2a, Arc, Shank1, Nlgn2, and Rab3a). Neither drug reversed the age-associated decrease in stem cell proliferation. Hippocampal growth factor levels were not consistent with behavioral outcomes. Thus, a change in the expression of multiple genes involved in neuronal plasticity by antidepressant treatment was associated with improved cognitive function and a reduction in depression-like behavior in middle-aged mice. PMID- 26046534 TI - Historic Mining and Agriculture as Indicators of Occurrence and Abundance of Widespread Invasive Plant Species. AB - Anthropogenic disturbances often change ecological communities and provide opportunities for non-native species invasion. Understanding the impacts of disturbances on species invasion is therefore crucial for invasive species management. We used generalized linear mixed effects models to explore the influence of land-use history and distance to roads on the occurrence and abundance of two invasive plant species (Rosa multiflora and Berberis thunbergii) in a 900-ha deciduous forest in the eastern U.S.A., the Powdermill Nature Reserve. Although much of the reserve has been continuously forested since at least 1939, aerial photos revealed a variety of land-uses since then including agriculture, mining, logging, and development. By 2008, both R. multiflora and B. thunbergii were widespread throughout the reserve (occurring in 24% and 13% of 4417 10-m diameter regularly-placed vegetation plots, respectively) with occurrence and abundance of each varying significantly with land-use history. Rosa multiflora was more likely to occur in historically farmed, mined, logged or developed plots than in plots that remained forested, (log odds of 1.8 to 3.0); Berberis thunbergii was more likely to occur in plots with agricultural, mining, or logging history than in plots without disturbance (log odds of 1.4 to 2.1). Mining, logging, and agriculture increased the probability that R. multiflora had >10% cover while only past agriculture was related to cover of B. thunbergii. Proximity to roads was positively correlated with the occurrence of R. multiflora (a 0.26 increase in the log odds for every 1-m closer) but not B. thunbergii, and roads had no impact on the abundance of either species. Our results indicated that a wide variety of disturbances may aid the introduction of invasive species into new habitats, while high-impact disturbances such as agriculture and mining increase the likelihood of high abundance post-introduction. PMID- 26046535 TI - Differential Inhibition of Signal Peptide Peptidase Family Members by Established gamma-Secretase Inhibitors. AB - The signal peptide peptidases (SPPs) are biomedically important proteases implicated as therapeutic targets for hepatitis C (human SPP, (hSPP)), plasmodium (Plasmodium SPP (pSPP)), and B-cell immunomodulation and neoplasia (signal peptide peptidase like 2a, (SPPL2a)). To date, no drug-like, selective inhibitors have been reported. We use a recombinant substrate based on the amino-terminus of BRI2 fused to amyloid beta 1-25 (Abeta1-25) (FBA) to develop facile, cost effective SPP/SPPL protease assays. Co-transfection of expression plasmids expressing the FBA substrate with SPP/SPPLs were conducted to evaluate cleavage, which was monitored by ELISA, Western Blot and immunoprecipitation/MALDI-TOF Mass spectrometry (IP/MS). No cleavage is detected in the absence of SPP/SPPL overexpression. Multiple gamma-secretase inhibitors (GSIs) and (Z-LL)2 ketone differentially inhibited SPP/SPPL activity; for example, IC50 of LY-411,575 varied from 51+/-79 nM (on SPPL2a) to 5499+/-122 nM (on SPPL2b), while Compound E showed inhibition only on hSPP with IC50 of 1465+/-93 nM. Data generated were predictive of effects observed for endogenous SPPL2a cleavage of CD74 in a murine B-Cell line. Thus, it is possible to differentially inhibit SPP family members. These SPP/SPPL cleavage assays will expedite the search for selective inhibitors. The data also reinforce similarities between SPP family member cleavage and cleavage catalyzed by gamma-secretase. PMID- 26046536 TI - Restoration of Haemoglobin Level Using Hydrodynamic Gene Therapy with Erythropoietin Does Not Alleviate the Disease Progression in an Anaemic Mouse Model for TGFbeta1-Induced Chronic Kidney Disease. AB - Erythropoietin, Epo, is a 30.4 kDa glycoprotein hormone produced primarily by the fetal liver and the adult kidney. Epo exerts its haematopoietic effects by stimulating the proliferation and differentiation of erythrocytes with subsequent improved tissue oxygenation. Epo receptors are furthermore expressed in non haematopoietic tissue and today, Epo is recognised as a cytokine with many pleiotropic effects. We hypothesize that hydrodynamic gene therapy with Epo can restore haemoglobin levels in anaemic transgenic mice and that this will attenuate the extracellular matrix accumulation in the kidneys. The experiment is conducted by hydrodynamic gene transfer of a plasmid encoding murine Epo in a transgenic mouse model that overexpresses TGF-beta1 locally in the kidneys. This model develops anaemia due to chronic kidney disease characterised by thickening of the glomerular basement membrane, deposition of mesangial matrix and mild interstitial fibrosis. A group of age matched wildtype littermates are treated accordingly. After a single hydrodynamic administration of plasmid DNA containing murine EPO gene, sustained high haemoglobin levels are observed in both transgenic and wildtype mice from 7.5 +/- 0.6 mmol/L to 9.4 +/- 1.2 mmol/L and 10.7 +/- 0.3 mmol/L to 15.5 +/- 0.5 mmol/L, respectively. We did not observe any effects in the thickness of glomerular or tubular basement membrane, on the expression of different collagen types in the kidneys or in kidney function after prolonged treatment with Epo. Thus, Epo treatment in this model of chronic kidney disease normalises haemoglobin levels but has no effect on kidney fibrosis or function. PMID- 26046537 TI - Advanced Insights into Functional Brain Connectivity by Combining Tensor Decomposition and Partial Directed Coherence. AB - Quantification of functional connectivity in physiological networks is frequently performed by means of time-variant partial directed coherence (tvPDC), based on time-variant multivariate autoregressive models. The principle advantage of tvPDC lies in the combination of directionality, time variance and frequency selectivity simultaneously, offering a more differentiated view into complex brain networks. Yet the advantages specific to tvPDC also cause a large number of results, leading to serious problems in interpretability. To counter this issue, we propose the decomposition of multi-dimensional tvPDC results into a sum of rank-1 outer products. This leads to a data condensation which enables an advanced interpretation of results. Furthermore it is thereby possible to uncover inherent interaction patterns of induced neuronal subsystems by limiting the decomposition to several relevant channels, while retaining the global influence determined by the preceding multivariate AR estimation and tvPDC calculation of the entire scalp. Finally a comparison between several subjects is considerably easier, as individual tvPDC results are summarized within a comprehensive model equipped with subject-specific loading coefficients. A proof-of-principle of the approach is provided by means of simulated data; EEG data of an experiment concerning visual evoked potentials are used to demonstrate the applicability to real data. PMID- 26046538 TI - Comparing Analysis Methods in Functional Calcium Imaging of the Insect Brain. AB - We investigate four different methods for background estimation in calcium imaging of the insect brain and evaluate their performance on six data sets consisting of data recorded from two sites in two species of moths. The calcium fluorescence decay curve outside the potential response is estimated using either a low-pass filter or constant, linear or polynomial regression, and is subsequently used to calculate the magnitude, latency and duration of the response. The magnitude and variance of the responses that are obtained by the different methods are compared, and, by computing the receiver operating characteristics of a classifier based on response magnitude, we evaluate the ability of each method to detect the stimulus type and conclude that a polynomial approximation of the background gives the overall best result. PMID- 26046539 TI - Developing Molecular Signatures for Chronic Lymphocytic Leukemia. AB - Chronic lymphocytic leukemia (CLL) is a clonal malignancy of mature B cells that displays a great clinical heterogeneity, with many patients having an indolent disease that will not require intervention for many years, while others present an aggressive and symptomatic leukemia requiring immediate treatment. Although there is no cure for CLL, the disease is treatable and current standard chemotherapy regimens have been shown to prolong survival. Recent advances in our understanding of the biology of CLL have led to the identification of numerous cellular and molecular markers with potential diagnostic, prognostic and therapeutic significance. We have used the recently developed digital multiplexed gene-expression technique (DMGE) to analyze a cohort of 30 CLL patients for the presence of specific genes with known diagnostic and prognostic potential. Starting from a set of 290 genes we were able to develop a molecular signature, based on the analysis of 13 genes, which allows distinguishing CLL from normal peripheral blood and from normal B cells, and a second signature based on 24 genes, which distinguishes mutated from unmutated cases (LymphCLL Mut). A third classifier (LymphCLL Diag), based on a 44-gene signature, distinguished CLL cases from a series of other B-cell chronic lymphoproliferative disorders (n = 51). While the methodology presented here has the potential to provide a "ready to use" classification tool in routine diagnostics and clinical trials, application to larger sample numbers are still needed and should provide further insights about its robustness and utility in clinical practice. PMID- 26046540 TI - Downregulation of TNIP1 Expression Leads to Increased Proliferation of Human Keratinocytes and Severer Psoriasis-Like Conditions in an Imiquimod-Induced Mouse Model of Dermatitis. AB - Psoriasis is a chronic, inflammatory skin disease involving both environmental and genetic factors. According to genome-wide association studies (GWAS), the TNIP1 gene, which encodes the TNF-alpha-induced protein 3-interacting protein 1 (TNIP1), is strongly linked to the susceptibility of psoriasis. TNIP1 is a widely expressed ubiquitin sensor that binds to the ubiquitin-editing protein A20 and restricts TNF- and TLR-induced signals. In our study, TNIP1 expression decreased in specimens of epidermis affected by psoriasis. Based on previous studies suggesting a role for TNIP1 in modulating cancer cell growth, we investigated its role in keratinocyte proliferation, which is clearly abnormal in psoriasis. To mimic the downregulation or upregulation of TNIP1 in HaCaT cells and primary human keratinocytes (PHKs), we used a TNIP1 specific small interfering hairpin RNA (TNIP1 shRNA) lentiviral vector or a recombinant TNIP1 (rTNIP1) lentiviral vector, respectively. Blocking TNIP1 expression increased keratinocyte proliferation, while overexpression of TNIP1 decreased keratinocyte proliferation. Furthermore, we showed that TNIP1 signaling might involve extracellular signal-regulated kinase1/2 (Erk1/2) and CCAAT/enhancer-binding protein beta (C/EBPbeta) activity. Intradermal injection of TNIP1 shRNA in BALB/c mice led to exaggerated psoriatic conditions in imiquimod (IMQ)-induced psoriasis like dermatitis. These findings indicate that TNIP1 has a protective role in psoriasis and therefore could be a promising therapeutic target. PMID- 26046542 TI - Taste dysfunction in patients undergoing hematopoietic stem cell transplantation: Clinical evaluation in children. AB - The aim of this study was to determine the variability of TD in children undergoing HSCT. Cases were identified as consecutively enrolled children in the period January 2011-January 2013 among patients attending the Paediatric Department of Spedali Civili of Brescia and all candidates to HSCT. The TST was conducted in two phases: identification of threshold values and identification of perceived stimulus intensity. Sixteen sapid solutions with four flavors (sucrose, sodium chloride, citric acid, and quinine hydrochloride) at four different concentrations were administered in a random sequence. The same protocol was administered at different time intervals: before starting the conditioning therapy (T0), during the conditioning therapy (T1) (two times), and every three months (two times) after engraftment post-HSCT (T2). A p-value < 0.05 was considered statistically significant. Fifty-one children (29 female and 22 male, mean age 5.2 +/- 0.7 yr) were enrolled. Threshold value means for the four flavors increased during HSCT conditioning therapy (T1) (p < 0.01); intensity of perceived stimulus decreased during HSCT conditioning therapy (p < 0.01). At six months after engraftment (T2), both parameters had returned to starting values (T0). Changes in taste perception in children undergoing HSCT seem to occur especially during the conditioning therapy and resolve in about six months after engraftment post-HSCT. PMID- 26046543 TI - Difficulties in establishing regulations for engineered nanomaterials and considerations for policy makers: avoiding an unbalance between benefits and risks. AB - Current evidence of engineered nanomaterials' (ENM) toxicity has led to a latent concern about hazards for both humans and the environment. For this reason, some efforts have been made to suggest frameworks or other guidance to regulate ENM handling; however, the real exposure risk to humans has not been well established. The aims of this work were to analyze the difficulties in establishing regulations for ENM and to discuss some considerations that may be helpful for policy makers involved in the regulation of ENM. Difficulties in establishing regulations are based on the novel properties of ENM associated with cytotoxic effects, the insufficiency of standardized methods to test those effects and the lack of epidemiological evidence of ENM toxicity, especially in occupational settings. Nevertheless, we offer some suggestions for establishing regulations, which include frameworks oriented towards protecting personnel exposed to ENM without decreasing production. In addition, we propose an ENM data sheet to offer available information of ENM. Finally, ethical aspects should also be considered in developing ENM regulations because every person who is working around or consuming ENM has the right to be informed about the potential risk. PMID- 26046541 TI - Large-Scale Evolutionary Analysis of Genes and Supergene Clusters from Terpenoid Modular Pathways Provides Insights into Metabolic Diversification in Flowering Plants. AB - An important component of plant evolution is the plethora of pathways producing more than 200,000 biochemically diverse specialized metabolites with pharmacological, nutritional and ecological significance. To unravel dynamics underlying metabolic diversification, it is critical to determine lineage specific gene family expansion in a phylogenomics framework. However, robust functional annotation is often only available for core enzymes catalyzing committed reaction steps within few model systems. In a genome informatics approach, we extracted information from early-draft gene-space assemblies and non redundant transcriptomes to identify protein families involved in isoprenoid biosynthesis. Isoprenoids comprise terpenoids with various roles in plant environment interaction, such as pollinator attraction or pathogen defense. Combining lines of evidence provided by synteny, sequence homology and Hidden Markov-Modelling, we screened 17 genomes including 12 major crops and found evidence for 1,904 proteins associated with terpenoid biosynthesis. Our terpenoid genes set contains evidence for 840 core terpene-synthases and 338 triterpene specific synthases. We further identified 190 prenyltransferases, 39 isopentenyl diphosphate isomerases as well as 278 and 219 proteins involved in mevalonate and methylerithrol pathways, respectively. Assessing the impact of gene and genome duplication to lineage-specific terpenoid pathway expansion, we illustrated key events underlying terpenoid metabolic diversification within 250 million years of flowering plant radiation. By quantifying Angiosperm-wide versatility and phylogenetic relationships of pleiotropic gene families in terpenoid modular pathways, our analysis offers significant insight into evolutionary dynamics underlying diversification of plant secondary metabolism. Furthermore, our data provide a blueprint for future efforts to identify and more rapidly clone terpenoid biosynthetic genes from any plant species. PMID- 26046544 TI - Investigating nasal cytology as a potential tool for diagnosing occupational rhinitis in woodworkers. AB - BACKGROUND: Our primary endpoint was to use nasal cytology to compare woodworkers with unexposed subjects to see if wood dust exposure correlates with specific patterns of inflammatory or infectious rhinitis. A secondary endpoint was to identify any differences in the exposed group's nasal symptoms or nasal cytology by years of exposure or personal exposure levels. METHODS: Ninety-two woodworkers and 90 controls were assessed using a questionnaire and nasal cytology (on nasal mucosa obtained by scraping). Wood dust exposure was investigated using personal sampling methods. RESULTS: Woodworkers reported significantly more nasal symptoms than controls (p < 0.00001). The woodworkers' nasal smears revealed more neutrophils (p = 0.001) and significantly higher mean neutrophil scores (p = 0.001) than control smears. Lymphocytes were also found more often in the woodworkers' rhinocytograms (statistical trend, p = 0.06). Neutrophilic rhinitis was diagnosed more frequently in the exposed workers than in controls (chi-square = 5.97, p < 0.05). Woodworkers with lymphocytes in their nasal smears had been exposed to wood dust for longer periods of time (statistical trend; p = 0.06). No differences in nasal symptoms or cell counts emerged when woodworkers were stratified by levels of personal exposure. CONCLUSION: Nasal cytology should be further investigated in woodworkers before considering it a screening method for identifying woodworkers with chronic inflammatory rhinitis. PMID- 26046545 TI - Corrigendum. PMID- 26046546 TI - The Electronic Structure of the Al3(-) Anion: Is it Aromatic? AB - Multiconfigurational high-level electronic structure calculations show that the Al3(-) ring-like cluster anion has three close low-lying electronic states of different spin, all of them having strong multiconfigurational character. The aromaticity of the cluster has, therefore, been studied by means of total electron delocalization and normalized multicenter electron delocalization indices evaluated from the multiconfigurational wave functions of each state. The lowest-lying singlet and triplet states are found to be highly aromatic, whereas the next lowest-lying state, the quintet state, has much less, though non negligible, aromatic character. PMID- 26046547 TI - Dynamic Release of Bending Stress in Short dsDNA by Formation of a Kink and Forks. AB - Bending with high curvature is one of the major mechanical properties of double stranded DNA (dsDNA) that is essential for its biological functions. The emergence of a kink arising from local melting in the middle of dsDNA has been suggested as a mechanism of releasing the energy cost of bending. Herein, we report that strong bending induces two types of short dsDNA deformations, induced by two types of local melting, namely, a kink in the middle and forks at the ends, which we demonstrate using D-shaped DNA nanostructures. The two types of deformed dsDNA structures dynamically interconvert on a millisecond timescale. The transition from a fork to a kink is dominated by entropic contribution (anti Arrhenius behavior), while the transition from a kink to a fork is dominated by enthalpic contributions. The presence of mismatches in dsDNA accelerates kink formation, and the transition from a kink to a fork is removed when the mismatch size is three base pairs. PMID- 26046548 TI - Sperm proteome of Mytilus galloprovincialis: Insights into the evolution of fertilization proteins in marine mussels. AB - Cataloging the sperm proteome of an animal can improve our understanding of its sperm-egg interaction and speciation, but such data are available for only a few free-spawning invertebrates. This study aimed to identify the sperm proteome of Mytilus galloprovincialis, a free-spawning marine mussel. We integrated public transcriptome datasets by de novo assembly, and applied SDS-PAGE coupled LC-MS/MS analysis to profile the sperm proteome, resulting in the identification of 550 proteins. Comparing the homologous sperm protein coding genes between M. galloprovincialis and its closely related species M. edulis revealed that fertilization proteins have the highest mean nonsynonymous substitution rate (Ka/Ks = 0.62) among 11 functional groups, consistent with previous reports of positive selection of several fertilization proteins in Mytilus. Moreover, 78 sperm proteins in different functional groups have Ka/Ks values > 0.5, indicating the presence of many candidate sperm proteins for further analysis of rapid interspecific divergence. The MS data are available in ProteomeXchange with the identifier PXD001665. PMID- 26046549 TI - Do caregivers of cancer patients receiving care in home hospice services have better quality of life? An exploratory investigation in Singapore. PMID- 26046551 TI - Nordic MS Epidemiology. Introduction. PMID- 26046552 TI - Registers of multiple sclerosis in Denmark. AB - There are two nationwide population-based registers for multiple sclerosis (MS) in Denmark. The oldest register is The Danish Multiple Sclerosis Registry (DMSR), which is an epidemiological register for estimation of prevalence and incidence of MS and survival, and for identifying exposures earlier in life that may affect the risk of MS. This register has no systematic follow-up data except for survival. The DMSR has over the years published nationwide incidence- and prevalence data from Denmark and has been involved in a number of 'historical prospective' studies to elucidate the association between a number of different environmental exposures in the past and the subsequent risk of MS. Some of these studies have been able to exonerate suspected risk factors. The other register, the nationwide Danish Multiple Sclerosis Treatment Register, is a follow-up register for all patients who have received disease-modifying treatments since 1996. It has, in particular, contributed to the knowledge of the role of antibodies against the biological drugs used for the treatment of MS. PMID- 26046550 TI - Low dietary iron intake restrains the intestinal inflammatory response and pathology of enteric infection by food-borne bacterial pathogens. AB - Orally administrated iron is suspected to increase susceptibility to enteric infections among children in infection endemic regions. Here we investigated the effect of dietary iron on the pathology and local immune responses in intestinal infection models. Mice were held on iron-deficient, normal iron, or high iron diets and after 2 weeks they were orally challenged with the pathogen Citrobacter rodentium. Microbiome analysis by pyrosequencing revealed profound iron- and infection-induced shifts in microbiota composition. Fecal levels of the innate defensive molecules and markers of inflammation lipocalin-2 and calprotectin were not influenced by dietary iron intervention alone, but were markedly lower in mice on the iron-deficient diet after infection. Next, mice on the iron-deficient diet tended to gain more weight and to have a lower grade of colon pathology. Furthermore, survival of the nematode Caenorhabditis elegans infected with Salmonella enterica serovar Typhimurium was prolonged after iron deprivation. Together, these data show that iron limitation restricts disease pathology upon bacterial infection. However, our data also showed decreased intestinal inflammatory responses of mice fed on high iron diets. Thus additionally, our study indicates that the effects of iron on processes at the intestinal host pathogen interface may highly depend on host iron status, immune status, and gut microbiota composition. PMID- 26046553 TI - The Swedish MS registry - clinical support tool and scientific resource. AB - The Swedish MS registry (SMSreg) is designed to assure quality health care for patients with multiple sclerosis (MS). It has been active since 2001 and web based since 2004. It runs on government funding only and is used in all Swedish neurology departments. The SMSreg currently includes data on 14,500 of Sweden's estimated 17,500 prevalent patients with MS. One important function of SMSreg, to which participation is voluntary, is to serve as a tool for decision support and to provide an easy overview of the patient information needed at clinical visits. This is its core feature and explains why the majority of Swedish MS specialists contribute data. Another success factor for SMSreg is that entered data can be readily accessed, either through a query function into Excel format or through a set of predesigned tables and diagrams in which parameters can be selected. Recent development includes a portal allowing patients to view a summary of their registered data and to report a set of patient-reported outcomes. SMSreg data have been used in close to 100 published scientific reports. Current projects include an incidence cohort (EIMS), post-marketing cohorts of patients on novel disease-modifying drugs (IMSE), and a prevalence cohort (GEMS). As these studies combine physical sampling and questionnaire data with clinical documentation and possible linkage to other public registries, together they provide an excellent platform for integrated MS research. PMID- 26046554 TI - Role of socio-economic and reproductive factors in the risk of multiple sclerosis. AB - The incidence of multiple sclerosis is increasing in Danish women. Their risk of developing multiple sclerosis has more than doubled in 25 years while it has remained virtually unchanged for men. The explanation for these epidemiological changes should be sought in the environment as they are too rapid to be explained by gene alterations. We investigated the effect of numerous biological social physical and chemical environmental exposures in different periods of life. These data were available from population-based registries and were used in a case control approach. This study database included all multiple sclerosis cases (n = 1403) from the Danish MS Registry with clinical onset between 2000 and 2004 as well as 35,045 controls drawn by random from the Danish Civil Registration System and matched by sex year of birth and residential municipality at the reference year. Having newborn children reduced the risk of multiple sclerosis (MS) in women but not in men. Childbirths reduced the risk of MS by about 46% during the following 5 years. Even pregnancies terminated early had a protective effect on the risk of developing MS suggesting a temporary immunosuppression during pregnancy. Our data on social behaviour regarding educational level income and relationship stability did not indicate reverse causality. A greater likelihood to be exposed to common infections did not show any effect on the risk of MS neither in puberty nor in adulthood. Socio-economic status and lifestyle expressed in educational level and sanitary conditions in youth were not associated with the risk of MS. PMID- 26046555 TI - The Norwegian Multiple Sclerosis Registry and Biobank. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with unknown cause and various benefits from disease modifying therapies. Systematic recording of data into national MS registries is therefore needed to optimize treatment and define the pathogenesis of the disease. The Norwegian MS Registry and Biobank was established for systematic collection of clinical and epidemiological data, as well as biological samples. Data collection is based on informed consent from the individual patients and recordings by treating neurologists. All researchers have, by application, access to data and biological samples from the Norwegian Multiple Sclerosis Registry and Biobank. By this combined effort from both patients and healthcare personnel, the Registry and Biobank aims to facilitate research for improved understanding of disease mechanisms and improved health care in MS. PMID- 26046557 TI - Socio-economic factors and immigrant population studies of multiple sclerosis. AB - The uneven geographical distribution of multiple sclerosis (MS) and the differences in disease severity observed between different ethnic groups indicate a complex interplay between genetic and environmental risk factors involved in the disease pathogenesis. Changes in MS risk after migration suggest influence of environmental factors on disease susceptibility. Whether the risk of MS is affected by socio-economic status (SES) is still controversial. In the present review, the combined knowledge from studies of migration and SES in MS is discussed. PMID- 26046556 TI - Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades. AB - Norway has been subjected to numerous epidemiological investigations on the prevalence and incidence of multiple sclerosis (MS), dating back to 1935. The objective of this study was to review the studies on the prevalence and incidence of MS in Norway, provide an update on the prevalence of MS in Norway, and describe the time trends in the prevalence and incidence of MS in relation to risk factors, case ascertainment, and data. We performed a systematic search on PubMed and MEDLINE up to November 2014 using the search string 'multiple sclerosis prevalence in Norway' or 'multiple sclerosis incidence in Norway'. In addition, we scrutinized the reference lists of the publications identified for relevant citations. We retrieved data on the distribution of MS in Norway on December 31, 2013 from the Norwegian Multiple Sclerosis Registry and Biobank and the Norwegian Patient Registry. We identified 29 articles. From 1961 to 2014, the reported prevalence of MS increased from 20 to 203 per 100,000 inhabitants, and the incidence increased from 1.9 to 8.0 per 100,000. The nationwide crude prevalence in Norway, based on the Norwegian Patient Registry, was 208 per 100,000 on December 31, 2013. The reported prevalence of MS in Norway has increased 10-fold, with several possible causes. During eight decades, neurological health services have generally become more accessible to the population, and transforming diagnostic criteria has made the diagnosis of MS more precise and valid. There have also been changes in lifestyle behavior and known risk factors, such as vitamin D and smoking, that might have contributed to the increased incidence of MS. A possible role of increased survival in MS needs to be examined further. PMID- 26046558 TI - Does the changing sex ratio of multiple sclerosis give opportunities for intervention? AB - In several international studies, an increasing women-to-men (w/m) ratio in patients with multiple sclerosis (MS) has been reported. Such sex ratios have been analysed by year of onset or by year of birth. In a Swedish study, data from the Swedish MS register (SMSreg) were used to analyse the w/m ratio in Sweden. The sex ratio was analysed both by year of birth (8834 patients) and by year of onset (9098 patients). No increased w/m ratio was seen in this study. The age specific sex ratio did not demonstrate any significant changes. However, a new investigation of the sex ratio in Sweden, based on data from all available data sources (19,510 patients), showed a significantly increased w/m ratio of MS in Sweden from 1.70 to 2.67. Environmental factors such as cigarette smoking, hormonal factors and nutrition are of interest in this context, but the cause of the increasing w/m ratio in MS is yet not possible to explain. PMID- 26046559 TI - Multiple sclerosis and environmental factors: the role of vitamin D, parasites, and Epstein-Barr virus infection. AB - Pathogenic mechanisms underlying multiple sclerosis development have yet to be clearly identified, but considerable evidence indicates that autoimmunity plays an important role in the etiology of the disease. It is generally accepted that autoimmune diseases like MS arise from complex interactions between genetic susceptibility and environmental factors. Although environmental factors unequivocally influencing MS development have yet to be established, accumulating evidence singles out several candidates, including sunlight-UV exposure or vitamin D deficiency, viral infections, hygiene, and cigarette smoking. Vitamin D deficiency has been associated with different autoimmune diseases. Several investigations indicate 125 (OH)2 vitamin D plays a critical role in shaping T cell response and inducing T cells with immunosuppressive properties. Likewise, helminth infections represent another potential environmental factor exerting immunomodulatory properties. Both epidemiological and experimental data provide evidence to support autoimmune down-regulation secondary to parasite infections in patients with MS, through regulatory T- and B-cell action, with effects extending beyond simple response to an infectious agent. Finally, different epidemiological studies have demonstrated that Epstein-Barr virus infection confers added risk of developing MS. Proposed mechanisms responsible for this association include activation and expansion of self-reactive T and B cells, lower threshold for self-tolerance breakdown, and enhanced autoreactive B-cell survival, all to be discussed in this review. Understanding environmental factors influencing propensity to MS will lead to new and more effective approaches to prevent and treat the disease. PMID- 26046560 TI - Vitamin D and multiple sclerosis-from epidemiology to prevention. AB - In the present review, we discuss observational and experimental data suggesting a protective effect from sun exposure and/or vitamin D in multiple sclerosis (MS). These data include geographic variations in MS occurrence, temporal trends, genetics, biobank, and questionnaire data. We look more closely at the differentiation between general effects from UV exposure, and those of vitamin D per se, including plausible mechanisms of action. Finally, primary prevention is touched upon, and we suggest actions to be taken while awaiting the results from ongoing randomized controlled trials with vitamin D in MS. PMID- 26046561 TI - Hormonal and gender-related immune changes in multiple sclerosis. AB - Similarly to many other autoimmune diseases, multiple sclerosis (MS) is more common among women than men, and its incidence among women is rising. There are also qualitative differences in the disease course between men and women, with male patients experiencing increased disease progression, brain atrophy, and cognitive impairment. During pregnancy, women with MS typically have a greatly reduced relapse rate, whereas very soon after the delivery, the disease activity returns, often even at a higher level than seen in the prepregnancy year. The reasons for the increased postpartum activity are not entirely clear, but factors such as the abrupt decrease in estrogen levels immediately after the delivery and the loss of the immunosuppressive state of pregnancy are likely of importance. There is compelling evidence that estrogen, progesterone, and testosterone control MS pathology by influencing immune responses and by contributing to repair mechanisms in the nervous system. Hormones may thus offer important insights into MS disease prevention and treatment. In this review, the possible reasons for the sex bias in autoimmune diseases will be discussed. The pregnancy related alterations in MS, including the effect of pregnancy on disease activity, long-term disability accumulation, and prevalence will be reviewed, as well as the hormonal and immunological mechanisms potentially underlying these changes. Finally, the present thinking on the effect of hormones on the changing incidence of MS will be elucidated. PMID- 26046562 TI - Conclusion: National incidence and risk factor assessments may become a basis for the evaluation of prevention trials - prospects from the Third Nordic MS Symposium. AB - This symposium started with an overview of recent incidence and prevalence data from the Scandinavian national registers and continued with a critical analysis of several alleged risk factors for MS. These risk factors are constantly changing and therefore might explain current incidence changes. In addition, they may be the subject of preventive measures. PMID- 26046564 TI - Let research bloom. PMID- 26046565 TI - Updated, augmented vaccines compete with original antigenic sin. PMID- 26046563 TI - Epilepsy in children with tuberous sclerosis complex: Chance of remission and response to antiepileptic drugs. AB - OBJECTIVE: To describe treatment and outcome of epilepsy in children with tuberous sclerosis complex (TSC). METHODS: Seventy-one children with TSC and epilepsy treated at the ENCORE TSC Expertise Center between 1988 and 2014 were included. Patient characteristics and duration and effectiveness of antiepileptic treatments were extracted from our clinical database. Correlations were made between recurrence of seizures after response to treatment, and several patient characteristics. RESULTS: Median age at time of inclusion was 9.4 years (range 0.9-18.0). Seizure history showed that 55 children (77%) of 71 became seizure free for longer than 1 month, and 21 (30%) of 71 for longer than 24 months. Remission of seizures was associated with higher IQ, and a trend was observed between seizure remission and age at onset of seizures. A total of 19 antiepileptic drugs (AEDs) were used. Valproic acid, vigabatrin, levetiracetam, and carbamazepine were used most frequently. Nonpharmacologic therapies (ketogenic diet, epilepsy surgery, and vagus nerve stimulation) were used 13 times. Epilepsy surgery was most effective, with four of five children becoming seizure-free. AEDs prescribed as first and second treatment were most effective. Valproic acid was prescribed most frequently as first and second treatment, followed by vigabatrin. Thirty-one children had infantile spasms, preceded by focal seizures in 18 children (58%). Vigabatrin was used by 29 children (94%), and was first treatment in 15 (48%). Vigabatrin was more effective than other AEDs when prescribed as first treatment. SIGNIFICANCE: We showed that, although 77% of children with epilepsy due to TSC reached seizure remission, usually after their first or second AED, this was sustained for at least 24 months in only 38%. Almost half of those with 24 months of remission later had relapse of seizures. Our results support vigabatrin as first choice drug, and show the need for better treatment options for these children. PMID- 26046566 TI - New consent requirements for newborn screening raise concerns. PMID- 26046567 TI - Microbiome models, on computers and in lab dishes, see progress. PMID- 26046568 TI - Binding time--not just affinity--gains stature in drug design. PMID- 26046570 TI - Regulation of immunopathology in hepatitis B virus infection. PMID- 26046571 TI - Converting smooth muscle cells to macrophage-like cells with KLF4 in atherosclerotic plaques. PMID- 26046572 TI - Unpleasant memories: tissue-embedded T cell memory drives skin hypersensitivity. PMID- 26046573 TI - Mutant PRPS1: a new therapeutic target in relapsed acute lymphoblastic leukemia. PMID- 26046574 TI - Organic matter source and degradation as revealed by molecular biomarkers in agricultural soils of Yuanyang terrace. AB - Three soils with different tillage activities were collected and compared for their organic matter sources and degradation. Two soils (TD and TP) with human activities showed more diverse of chemicals in both free lipids and CuO oxidation products than the one (NS) without human activities. Branched alkanoic acids only accounted for less than 5% of lipids, indicating limited microbial inputs in all three investigated soils. The degradation of lignin in NS and TD was relatively higher than TP, probably because of the chemical degradation, most likely UV light-involved photodegradation. Lignin parameters obtained from CuO oxidation products confirmed that woody gymnosperm tissue (such as pine trees) may be the main source for NS, while angiosperm tissues from vascular plant may be the predominant source for the lignins in TD and TP. Analysis of BPCAs illustrated that BC in NS may be mainly originated from soot or other fossil carbon sources, whereas BC in TD and TP may be produced during corn stalk and straw burning. BC was involved in mineral interactions for TD and TP. The dynamics of organic matter needs to be extensively examined for their nonideal interactions with contaminants. PMID- 26046576 TI - L-citrulline for protection of endothelial function from ADMA-induced injury in porcine coronary artery. AB - Endogenous nitric oxide synthase (eNOS) inhibitor asymmetric dimethylarginine (ADMA) is a cardiovascular risk factor. We tested the hypothesis that L citrulline may ameliorate the endothelial function altered by ADMA in porcine coronary artery (PCA). Myograph study for vasorelaxation, electrochemical measurement for NO, RT-PCR, and Western blot analysis for expression of eNOS, argininosuccinate synthetase (ASS), and p-eNOS(ser1177) were performed. cGMP was determined by enzyme immunoassay. Superoxide anion (O2.(-)) production was detected by the lucigenin-enhanced chemiluminescence method. Compare with controls (96.03% +/- 6.2%), the maximal relaxation induced by bradykinin was significantly attenuated (61.55% +/- 4.8%, p<0.01), and significantly restored by L-citrulline (82.67 +/- 6.4%, p<0.05) after 24 hours of ADMA exposure. Expression of eNOS, p-eNOS(ser1177), and ASS in PCA significantly increased after L citrulline incubation. L-citrulline also markedly restored the NO production, and cGMP level which was reduced by ADMA. The increased O2.(-) production by ADMA was also inhibited by L-citrulline. L-citrulline restores the endothelial function in preparations treated with ADMA by preservation of NO production and suppression of O2.(-) generation. Preservation of NO is attributed to the upregulation of eNOS expression along with activation of p-eNOS(ser1177). L-citrulline improves endothelium-dependent vasodilation through NO/ cGMP pathway. PMID- 26046577 TI - d(1) Oxosulfido-Mo(V) Compounds: First Isolation and Unambiguous Characterization of an Extended Series. AB - Reaction of Tp(iPr)Mo(VI)OS(OAr) with cobaltocene in toluene results in the precipitation of brown, microcrystalline oxosulfido-Mo(V) compounds, [CoCp2][Tp(iPr)Mo(V)OS(OAr)] (Cp(-) = eta(5)-C5H5(-), Tp(iPr)(-) = hydrotris(3 isopropylpyrazol-1-yl)borate, OAr(-) = phenolate or 2-(s)Bu, 2-(t)Bu, 3-(t)Bu, 4 (s)Bu, 4-Ph, 3,5-(s)Bu2, 2-CO2Me, 2-CO2Et or 2-CO2Ph derivative thereof). The compounds are air- and water-sensitive and display nu(Mo?O) and nu(Mo[Formula: see text]S) IR absorption bands at ca. 890 and 435 cm(-1), respectively, 20-40 cm(-1) lower in energy than the corresponding bands in Tp(iPr)MoOS(OAr). They are electrochemically active and exhibit three reversible cyclovoltammetric waves (E(Mo(VI)/Mo(V)) = -0.40 to -0.66 V, E([CoCp2](+)/CoCp2) = -0.94 V and E(CoCp2/[CoCp2](-)) = -1.88 V vs SCE). Structural characterization of [CoCp2][Tp(iPr)MoOS(OC6H4CO2Et-2)].2CH2Cl2 revealed a distorted octahedral Mo(V) anion with Mo?O and Mo[Formula: see text]S distances of 1.761(5) and 2.215(2) A, respectively, longer than corresponding distances in related Tp(iPr)MoOS(OAr) compounds. The observation of strong S(1s) -> (S(3p) + Mo(4d)) S K-preedge transitions indicative of a d(1) sulfido-Mo(V) moiety and the presence of short Mo?O (ca. 1.72 A) and Mo[Formula: see text]S (ca. 2.25 A) backscattering contributions in the Mo K-edge EXAFS further support the oxosulfido-Mo(V) formulation. The compounds are EPR-active, exhibiting highly anisotropic (Deltag 0.124-0.150), rhombic, frozen-glass spectra with g1 close to the value observed for the free electron (ge = 2.0023). Spectroscopic studies are consistent with the presence of a highly covalent Mo[Formula: see text]S pi* singly occupied molecular orbital. The compounds are highly reactive, with reactions localized at the terminal sulfido ligand. For example, the compounds react with cyanide and PPh3 to produce thiocyanate and SPPh3, respectively, and various (depending on solvent) oxo-Mo(V) species. Reactions with copper reagents also generally lead to desulfurization and the formation of oxo-Mo(V) or -Mo(IV) complexes. PMID- 26046575 TI - Effects of eight weeks of aerobic interval training and of isoinertial resistance training on risk factors of cardiometabolic diseases and exercise capacity in healthy elderly subjects. AB - We investigated the effect of 8 weeks of high intensity interval training (HIT) and isoinertial resistance training (IRT) on cardiovascular fitness, muscle mass strength and risk factors of metabolic syndrome in 12 healthy older adults (68 yy +/- 4). HIT consisted in 7 two-minute repetitions at 80%-90% of VE?O2max, 3 times/w. After 4 months of recovery, subjects were treated with IRT, which included 4 sets of 7 maximal, bilateral knee extensions/flexions 3 times/w on a leg-press flywheel ergometer. HIT elicited significant: i) modifications of selected anthropometrical features; ii) improvements of cardiovascular fitness and; iii) decrease of systolic pressure. HIT and IRT induced hypertrophy of the quadriceps muscle, which, however, was paralleled by significant increases in strength only after IRT. Neither HIT nor IRT induced relevant changes in blood lipid profile, with the exception of a decrease of LDL and CHO after IRT. Physiological parameters related with aerobic fitness and selected body composition values predicting cardiovascular risk remained stable during detraining and, after IRT, they were complemented by substantial increase of muscle strength, leading to further improvements of quality of life of the subjects. PMID- 26046578 TI - Varied Probability of Staying Collapsed/Extended at the Conformational Equilibrium of Monomeric Abeta40 and Abeta42. AB - In present study, we set out to investigate the conformation dynamics of Abeta40 and Abeta42 through exploring the impact of intra-molecular interactions on conformation dynamics using equilibrium molecular dynamics simulations. Our 40 microsecond-scale simulations reveal heterogeneous conformation ensembles of Abeta40 and Abeta42 that encompass ~35% beta-strand and ~60% unstructured coils. Two conformational states were identified in both alloforms: a collapsed state (CS) that resembles the structural motif of face-to-face hydrophobic clustering in amyloid fibrils, and an extended state (ES) that features the structural characteristics of anti-parallel beta-sheets in amyloid oligomers. In Abeta40, the C-terminus remains unstructured and rarely interacts with other parts, thereof the hydrophobic clustering is in loose contact and the peptide assumes ES with high probability. In contrast, the C-terminus of Abeta42 adopts a beta strand structure that strongly interacts with segments E3-R5 and V18-A21. The active association leads to a more compact hydrophobic collapse and refrain the alloform from ES. Based on the structural characterization, we propose that the fibril and oligomer assembly pathways could respectively take off from CS and ES, and their aggregation propensity may be governed by the probability of visiting the corresponding conformational states at the equilibrium. PMID- 26046579 TI - Systemic high-mobility group box 1 administration suppresses skin inflammation by inducing an accumulation of PDGFRalpha(+) mesenchymal cells from bone marrow. AB - High-mobility group box 1 (HMGB1) mobilizes platelet-derived growth factor receptor alpha-positive (PDGFRalpha(+)) mesenchymal cells from bone marrow (BM) into circulation. However, whether HMGB1-induced endogenous PDGFRalpha(+) mesenchymal cells stimulate skin regeneration has been unclear. Here, we investigated the functions of the HMGB1/BM-PDGFRalpha(+) mesenchymal cell axis in the regeneration of mouse skin grafts. We found that intravenous HMGB1 administration induced an accumulation of endogenous BM-PDGFRalpha(+) mesenchymal cells followed by significant inflammatory suppression in the grafts. In contrast, mice with reduced BM-PDGFRalpha(+) mesenchymal cells showed massive inflammation of the grafts compared to mice that had normal levels of these cells even after HMGB1 administration, suggesting that BM-PDGFRalpha(+) mesenchymal cells contribute to the HMGB1-induced anti-inflammatory effect. We also found that intravenously administered HMGB1 augmented the local migration of BM PDGFRalpha(+) mesenchymal cells from circulation to skin graft by inducing the expression of CXCR4, an SDF-1 receptor, on these cells. Finally, we showed the therapeutic activity of the HMGB1/BM-PDGFRalpha(+) mesenchymal cell axis in an allergic contact dermatitis model. The results illustrated the contribution of the HMGB1/BM-PDGFRalpha(+) mesenchymal cell axis in suppressing the inflammation of injured/inflamed skin. These findings may provide future perspectives on the use of HMGB1-based medicines for intractable diseases. PMID- 26046581 TI - Detection of miRNA regulatory effect on triple negative breast cancer transcriptome. AB - Identifying key microRNAs (miRNAs) contributing to the genesis and development of a particular disease is a focus of many recent studies. We introduce here a rank based algorithm to detect miRNA regulatory activity in cancer-derived tissue samples which combines measurements of gene and miRNA expression levels and sequence-based target predictions. The method is designed to detect modest but coordinated changes in the expression of sequence-based predicted target genes. We applied our algorithm to a cohort of 129 tumour and healthy breast tissues and showed its effectiveness in identifying functional miRNAs possibly involved in the disease. These observations have been validated using an independent publicly available breast cancer dataset from The Cancer Genome Atlas. We focused on the triple negative breast cancer subtype to highlight potentially relevant miRNAs in this tumour subtype. For those miRNAs identified as potential regulators, we characterize the function of affected target genes by enrichment analysis. In the two independent datasets, the affected targets are not necessarily the same, but display similar enriched categories, including breast cancer related processes like cell substrate adherens junction, regulation of cell migration, nuclear pore complex and integrin pathway. The R script implementing our method together with the datasets used in the study can be downloaded here (http://bioinfo out.curie.fr/projects/targetrunningsum). PMID- 26046583 TI - Downregulation of HOXC6 in Serous Ovarian Cancer. AB - Homeobox (HOX) genes encode transcription factors critical to morphogenesis and cell differentiation. Although dysregulation of several HOX genes in ovarian cancer has been reported, little is known about HOXC6 expression in epithelial ovarian cancer. In this report, analysis of laser capture microdissected samples determined HOXC6 expression patterns in normal versus malignant serous ovarian carcinoma tissues. HOXC6 protein was quantified by ELISA in parallel serum samples and further validated in a larger cohort of serum samples collected from women with and without serous ovarian carcinoma. These data demonstrate significant downregulation of HOXC6 in serous ovarian cancer. PMID- 26046580 TI - Particle Simulation of Oxidation Induced Band 3 Clustering in Human Erythrocytes. AB - Oxidative stress mediated clustering of membrane protein band 3 plays an essential role in the clearance of damaged and aged red blood cells (RBCs) from the circulation. While a number of previous experimental studies have observed changes in band 3 distribution after oxidative treatment, the details of how these clusters are formed and how their properties change under different conditions have remained poorly understood. To address these issues, a framework that enables the simultaneous monitoring of the temporal and spatial changes following oxidation is needed. In this study, we established a novel simulation strategy that incorporates deterministic and stochastic reactions with particle reaction-diffusion processes, to model band 3 cluster formation at single molecule resolution. By integrating a kinetic model of RBC antioxidant metabolism with a model of band 3 diffusion, we developed a model that reproduces the time dependent changes of glutathione and clustered band 3 levels, as well as band 3 distribution during oxidative treatment, observed in prior studies. We predicted that cluster formation is largely dependent on fast reverse reaction rates, strong affinity between clustering molecules, and irreversible hemichrome binding. We further predicted that under repeated oxidative perturbations, clusters tended to progressively grow and shift towards an irreversible state. Application of our model to simulate oxidation in RBCs with cytoskeletal deficiency also suggested that oxidation leads to more enhanced clustering compared to healthy RBCs. Taken together, our model enables the prediction of band 3 spatio-temporal profiles under various situations, thus providing valuable insights to potentially aid understanding mechanisms for removing senescent and premature RBCs. PMID- 26046584 TI - Insights from a ten-year, prospective study of live kidney donors. PMID- 26046585 TI - The influence of water ingestion on postexercise hypotension and standing haemodynamics. AB - In young healthy adults, postexercise hypotension (PEH) occurs after a single bout of dynamic exercise due to peripheral vasodilation. Gravitational stress may further aggravate the magnitude of PEH, thus predisposing to orthostatic intolerance. As water drinking activates sympathetic vasoconstriction, it might offset PEH via enhanced alpha-adrenergic vascular responsiveness. We hypothesized that water ingestion before exercise would decrease the magnitude of PEH and improve the haemodynamic reaction to active standing postmaximal exercise. In a randomized fashion, 17 healthy adults (nine men; eight women, 21.2 +/- 1.6 years) ingested 50 and 500 ml of water before completing resting, cycle ergometer and recovery protocols on two separate days. After exercise, measurements [arterial blood pressure (BP), heart rate and spectral heart rate variability (HRV)] were taken in the seated position followed by 5 min of active standing. Compared to that seen post-50 ml of water, the 500 ml volume elicited an overall increase in BP (P < 0.05). Nevertheless, the magnitude of PEH was not different after either volume of water. There was an overall bradycardic effect of water, and this was accompanied by increased high-frequency power (P < 0.05). Finally, no BP, heart rate or HRV differences were found between conditions in response to active standing. These data suggest that, despite being well preserved after maximal exercise, the water pressor response does not affect the magnitude of PEH. They also indicate that drinking 500 ml of water does not impact the BP, heart rate or HRV response to 5 min of active standing during recovery postmaximal exercise. PMID- 26046586 TI - Accurate Location and Manipulation of Nanoscaled Objects Buried under Spin-Coated Films. AB - Detection and precise localization of nanoscale structures buried beneath spin coated films are highly valuable additions to nanofabrication technology. In principle, the topography of the final film contains information about the location of the buried features. However, it is generally believed that the relation is masked by flow effects, which lead to an upstream shift of the dry film's topography and render precise localization impossible. Here we demonstrate, theoretically and experimentally, that the flow-shift paradigm does not apply at the submicrometer scale. Specifically, we show that the resist topography is accurately obtained from a convolution operation with a symmetric Gaussian kernel whose parameters solely depend on the resist characteristics. We exploit this finding for a 3 nm precise overlay fabrication of metal contacts to an InAs nanowire with a diameter of 27 nm using thermal scanning probe lithography. PMID- 26046587 TI - All-atom molecular dynamics simulations of an artificial sodium channel in a lipid bilayer: the effect of water solvation/desolvation of the sodium ion. AB - All-atom molecular dynamics is used to investigate the transport of Na(+) across a 1,2-dioleoyl-sn-glycero-3-phosphocholine lipid bilayer facilitated by a diazacrown hydraphile. Specifically, the free energy of Na(+) passing through the bilayer is calculated using the adaptive biasing force method to study the free energy associated with the increase in Na(+) transport in the presence of the hydraphile molecule. The results show that water interaction greatly influences Na(+) transport through the lipid bilayer as water is pulled through the bilayer with Na(+) forming a water channel. The hydraphile causes a reduction in the free energy barrier for the transport of Na(+) through the head group part of the lipid bilayer since it complexes the Na(+) reducing the necessity for water to be complexed and, therefore, dragged through with Na(+), an energetically unfavorable process. The free energy associated with Na(+) being desolvated within the bilayer is significantly decreased in the presence of the hydraphile molecule; the hydraphile increases the number of solvation states of Na(+) that can be adopted, and this increase in the number of available configurations provides an entropic explanation for the success of the hydraphile. PMID- 26046588 TI - Argon Interaction with Gold Surfaces: Ab Initio-Assisted Determination of Pair Ar Au Potentials for Molecular Dynamics Simulations. AB - Global potentials for the interaction between the Ar atom and gold surfaces are investigated and Ar-Au pair potentials suitable for molecular dynamics simulations are derived. Using a periodic plane-wave representation of the electronic wave function, the nonlocal van-der-Waals vdW-DF2 and vdW-OptB86 approaches have been proved to describe better the interaction. These global interaction potentials have been decomposed to produce pair potentials. Then, the pair potentials have been compared with those derived by combining the dispersionless density functional dlDF for the repulsive part with an effective pairwise dispersion interaction. These repulsive potentials have been obtained from the decomposition of the repulsive interaction between the Ar atom and the Au2 and Au4 clusters and the dispersion coefficients have been evaluated by means of ab initio calculations on the Ar+Au2 complex using symmetry adapted perturbation theory. The pair potentials agree very well with those evaluated through periodic vdW-DF2 calculations. For benchmarking purposes, CCSD(T) calculations have also been performed for the ArAu and Ar+Au2 systems using large basis sets and extrapolations to the complete basis set limit. This work highlights that ab initio calculations using very small surface clusters can be used either as an independent cross-check to compare the performance of state-of the-art vdW-corrected periodic DFT approaches or, directly, to calculate the pair potentials necessary in further molecular dynamics calculations. PMID- 26046589 TI - Infant with generalized pustular psoriasis who responded to cyclosporin A therapy. PMID- 26046591 TI - Wiring of Photosystem II to Hydrogenase for Photoelectrochemical Water Splitting. AB - In natural photosynthesis, light is used for the production of chemical energy carriers to fuel biological activity. The re-engineering of natural photosynthetic pathways can provide inspiration for sustainable fuel production and insights for understanding the process itself. Here, we employ a semiartificial approach to study photobiological water splitting via a pathway unavailable to nature: the direct coupling of the water oxidation enzyme, photosystem II, to the H2 evolving enzyme, hydrogenase. Essential to this approach is the integration of the isolated enzymes into the artificial circuit of a photoelectrochemical cell. We therefore developed a tailor-made hierarchically structured indium-tin oxide electrode that gives rise to the excellent integration of both photosystem II and hydrogenase for performing the anodic and cathodic half-reactions, respectively. When connected together with the aid of an applied bias, the semiartificial cell demonstrated quantitative electron flow from photosystem II to the hydrogenase with the production of H2 and O2 being in the expected two-to-one ratio and a light-to-hydrogen conversion efficiency of 5.4% under low-intensity red-light irradiation. We thereby demonstrate efficient light-driven water splitting using a pathway inaccessible to biology and report on a widely applicable in vitro platform for the controlled coupling of enzymatic redox processes to meaningfully study photocatalytic reactions. PMID- 26046593 TI - beta-Decamethoxysapphyrin and Its N-Benzyl Analogue. AB - The synthesis of a highly electron-rich decamethoxysapphyrin and its 27-N-benzyl analogue is reported for the first time. The effects of beta-methoxy and 27-N benzyl substitution on structure, anion binding, absorption, and electrochemical properties were explored in detail. Upon 27-N-benzyl substitution, counteranion induced structural deformation arises in the diprotonated state, which could be clearly noticed both in solution (1)H NMR study and solid-state structural analysis. This type of anion-induced structural deformation is noted for the first time in beta-substituted sapphyrins. Further, the free base sapphyrins generate singlet oxygen with moderate efficiency (~42%); hence, they may act as good photosensitizers. PMID- 26046590 TI - Parkinsonian toxin-induced oxidative stress inhibits basal autophagy in astrocytes via NQO2/quinone oxidoreductase 2: Implications for neuroprotection. AB - Oxidative stress (OS) stimulates autophagy in different cellular systems, but it remains controversial if this rule can be generalized. We have analyzed the effect of chronic OS induced by the parkinsonian toxin paraquat (PQ) on autophagy in astrocytoma cells and primary astrocytes, which represent the first cellular target of neurotoxins in the brain. PQ decreased the basal levels of LC3-II and LC3-positive vesicles, and its colocalization with lysosomal markers, both in the absence and presence of chloroquine. This was paralleled by increased number and size of SQSTM1/p62 aggregates. Downregulation of autophagy was also observed in cells chronically exposed to hydrogen peroxide or nonlethal concentrations of PQ, and it was associated with a reduced astrocyte capability to protect dopaminergic cells from OS in co-cultures. Surprisingly, PQ treatment led to inhibition of MTOR, activation of MAPK8/JNK1 and MAPK1/ERK2-MAPK3/ERK1 and upregulation of BECN1/Beclin 1 expression, all signals typically correlating with induction of autophagy. Reduction of OS by NMDPEF, a specific NQO2 inhibitor, but not by N acetylcysteine, abrogated the inhibitory effect of PQ and restored autophagic flux. Activation of NQO2 by PQ or menadione and genetic manipulation of its expression confirmed the role of this enzyme in the inhibitory action of PQ on autophagy. PQ did not induce NFE2L2/NRF2, but when it was co-administered with NMDPEF NFE2L2 activity was enhanced in a SQSTM1-independent fashion. Thus, a prolonged OS in astrocytes inhibits LC3 lipidation and impairs autophagosome formation and autophagic flux, in spite of concomitant activation of several pro autophagic signals. These findings outline an unanticipated neuroprotective role of astrocyte autophagy and identify in NQO2 a novel pharmacological target for its positive modulation. PMID- 26046592 TI - Gating pore currents, a new pathological mechanism underlying cardiac arrhythmias associated with dilated cardiomyopathy. AB - Voltage-gated ion channels (VGIC) are transmembrane proteins responsible for the generation of electrical signals in excitable cells. VGIC were first described in 1952 by Hodgkin and Huxley, (1) and have since been associated with various physiological functions such as propagating nerve impulses, locomotion, and cardiac excitability. VGIC include channels specialized in the selective passage of K(+), Ca(2+) Na(+), or H(+). They are composed of 2 main structures: the pore domain (PD) and the voltage sensor domain (VSD). The PD ensures the physiological flow of ions and is typically composed of 8 transmembrane segments (TM). The VSD detects voltage variations and is composed of 4 TM (S1-S4). Given their crucial physiological role, VGIC dysfunctions are associated with diverse pathologies known as ion channelopathies. These dysfunctions usually affect the membrane expression of ion channels or voltage-dependent conformational changes of the pore. However, an increasing number of ion channelopathies, including periodic paralysis, dilated cardiomyopathy (DCM) associated with cardiac arrhythmias, and peripheral nerve hyperexcitability (PNH), have been linked to the appearance of a new pathological mechanism involving the creation of an alternative permeation pathway through the normally non-conductive VSD of VGIC. This permeation pathway is called the gating pore or omega pore. PMID- 26046594 TI - Shuttling of PINK1 between Mitochondrial Microcompartments Resolved by Triple Color Superresolution Microscopy. AB - The cytosolic phosphatase and tensin homologue Pten-kinase PINK1 involved in mitochondrial quality control undergoes a proteolytic process inside mitochondria. It has been suggested that the protein is not fully imported into mitochondria during this maturation. Here, we have established live cell triple color super-resolution microscopy by combining FPALM and tracking and localization microscopy (TALM) in order to unravel the spatiotemporal organization of the C-terminal kinase domain of PINK1 during this process. We find that the kinase domain is imported into active mitochondria and colocalizes with respiratory complex I at the inner mitochondrial membrane. When the processing step inside mitochondria is inhibited or mitochondria are de energized, full length PINK1 distributes between the outer and the inner mitochondrial membranes, indicating a holdup of import. These findings give the molecular base for a dual role of PINK1-inside energized mitochondria and outside of de-energized mitochondria. PMID- 26046595 TI - Colorimetric-based detection of TNT explosives using functionalized silica nanoparticles. AB - This proof-of-concept study proposes a novel sensing mechanism for selective and label-free detection of 2,4,6-trinitrotoluene (TNT). It is realized by surface chemistry functionalization of silica nanoparticles (NPs) with 3-aminopropyl triethoxysilane (APTES). The primary amine anchored to the surface of the silica nanoparticles (SiO2-NH2) acts as a capturing probe for TNT target binding to form Meisenheimer amine-TNT complexes. A colorimetric change of the self-assembled (SAM) NP samples from the initial green of a SiO2-NH2 nanoparticle film towards red was observed after successful attachment of TNT, which was confirmed as a result of the increased separation between the nanoparticles. The shift in the peak wavelength of the reflected light normal to the film surface and the associated change of the peak width were measured, and a merit function taking into account their combined effect was proposed for the detection of TNT concentrations from 10-12 to 10-4 molar. The selectivity of our sensing approach is confirmed by using TNT-bound nanoparticles incubated in AptamerX, with 2,4 dinitrotoluene (DNT) and toluene used as control and baseline, respectively. Our results show the repeatable systematic color change with the TNT concentration and the possibility to develop a robust, easy-to-use, and low-cost TNT detection method for performing a sensitive, reliable, and semi-quantitative detection in a wide detection range. PMID- 26046596 TI - A MAC protocol for medical monitoring applications of wireless body area networks. AB - Targeting the medical monitoring applications of wireless body area networks (WBANs), a hybrid medium access control protocol using an interrupt mechanism (I MAC) is proposed to improve the energy and time slot utilization efficiency and to meet the data delivery delay requirement at the same time. Unlike existing hybrid MAC protocols, a superframe structure with a longer length is adopted to avoid unnecessary beacons. The time slots are mostly allocated to nodes with periodic data sources. Short interruption slots are inserted into the superframe to convey the urgent data and to guarantee the real-time requirements of these data. During these interruption slots, the coordinator can break the running superframe and start a new superframe. A contention access period (CAP) is only activated when there are more data that need to be delivered. Experimental results show the effectiveness of the proposed MAC protocol in WBANs with low urgent traffic. PMID- 26046597 TI - Interplay between proteins and metabolic syndrome-A review. AB - Metabolic syndrome is characterized by hypertension; hyperglycemia; hypertriglyceridemia; reduced high-density lipoprotein cholesterol levels and abdominal obesity. Abundant data suggest that, compared with other people, patients meeting these diagnostic criteria have a greater risk of having substantial clinical consequences, the two most prominent of which are the development of diabetes mellitus and coronary heart disease. The metabolic syndrome is a health issue of epidemic proportions. Its prevalence in the world continues to increase, hand in hand with that of obesity. Protein, on the other hand, is the foundation of cell-building, especially in muscle tissue. The body needs protein to build not only muscle cells, but the cells of major organs, skin and red blood cells. For people with metabolic syndrome, one of the other functions of protein is to slow down the absorption of carbohydrates. When proteins are consumed with carbohydrates, it takes longer for the digestive system to break down that meal. This means that the sugar created from those carbohydrates is released at a slower rate, preventing spikes in both blood sugar and insulin. As the understanding of the metabolic syndrome evolves, it is likely that more comprehensive therapeutic options will become available. PMID- 26046598 TI - Information content in data sets for a nucleated-polymerization model. AB - We illustrate the use of statistical tools (asymptotic theories of standard error quantification using appropriate statistical models, bootstrapping, and model comparison techniques) in addition to sensitivity analysis that may be employed to determine the information content in data sets. We do this in the context of recent models [S. Prigent, A. Ballesta, F. Charles, N. Lenuzza, P. Gabriel, L.M. Tine, H. Rezaei, and M. Doumic, An efficient kinetic model for assemblies of amyloid fibrils and its application to polyglutamine aggregation, PLoS ONE 7 (2012), e43273. doi:10.1371/journal.pone.0043273.] for nucleated polymerization in proteins, about which very little is known regarding the underlying mechanisms; thus, the methodology we develop here may be of great help to experimentalists. We conclude that the investigated data sets will support with reasonable levels of uncertainty only the estimation of the parameters related to the early steps of the aggregation process. PMID- 26046599 TI - Psychological Vulnerability of Residents of Communities Affected by the Hebei Spirit Oil Spill. AB - OBJECTIVE: Psychological health is an important issue after disasters. This study aimed to investigate the prevalence of psychological symptoms among 993 residents of Taean District in South Korea after the Hebei Spirit oil spill and to examine determinants of vulnerability in residents' psychological symptoms. METHODS: Symptoms of post-traumatic stress (PTS), depression, suicidal ideation, and anxiety were assessed by questionnaires, and the responses were analyzed by using the survey analysis considering the sampling frame. RESULTS: Among the study subjects, the symptom prevalences of PTS, depression, suicidal ideation, and anxiety were 19.5%, 22.0%, 2.3%, and 4.2%, respectively, and symptoms were higher in people who were female, were older, were less educated, and had lower family income. People with fishery or related occupations compared to those with unrelated livelihoods and people residing in the vicinity of the oil band in the contaminated coastline showed additively increased symptom risks of PTS. Risk of suicidal ideation was predominantly increased in people with fishery or related occupations compared with those with unrelated livelihoods. CONCLUSIONS: Social supports, including compensation for income loss and community mental health programs, and longer follow-up studies are needed for residents in the communities affected by the Hebei Spirit oil spill. PMID- 26046600 TI - HPV One Two Three. PMID- 26046601 TI - Outcome Following Detorsion of Torsed Adnexa in Children. AB - STUDY OBJECTIVE: To examine the postoperative course and outcomes of young females with ovarian torsion treated with detorsion and ovarian preservation. The secondary objective was to determine which operative findings correlated with higher follicular counts following detorsion. DESIGN: Retrospective chart review. SETTING: Tertiary academic center. PARTICIPANTS: 29 females (mean age 10.3 +/- 4.9 y) who underwent surgery for ovarian torsion with detorsion and ovarian preservation at our institution between July 2007 and July 2010 and who had follow-up pelvic ultrasonography available for review. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Surgical findings, postoperative complications, and follicular counts on follow-up ultrasonography. RESULTS: Mean duration of abdominal pain on presentation was 77.5 +/- 78.8 h. The detorsed ovary was described as "dusky/purple" in 21 cases (72.4%), "normal" in 1 (3.4%), "necrotic" in 1 (3.4%), and not described in 6 (20.7%). All pubertal patients resumed menstrual function. No patients required reoperation for removal of the salvaged ovary. There were no instances of postoperative fever or concern for ovarian venous thrombosis. Average timing of follow-up ultrasonography was 8.1 +/- 6.7 months, with 28 patients (96.6%) showing ovarian follicles on the affected side (mean 4.6 +/- 1.9 and 4.7 +/- 3.3 follicles on the right and left ovary, respectively). No correlation was found between the side affected, gross appearance of the torsed ovary or the number of follicles found on follow-up ultrasonography. CONCLUSIONS: Detorsion with ovarian preservation is a safe and effective treatment, and should be considered the primary treatment for girls with ovarian torsion, even for those with ovaries that appear necrotic. PMID- 26046602 TI - Dietary Intake and Weight Gain Among Adolescents on Depot Medroxyprogesterone Acetate. AB - STUDY OBJECTIVE: To examine the relationship between dietary intake and weight gain among adolescent females initiating depot medroxyprogesterone acetate (DMPA). DESIGN: Prospective observational study. SETTING: Two urban Adolescent Medicine clinics. PARTICIPANTS: 45 postmenarchal females, age 12 to 21, enrolled after self-selecting to initiate DMPA. INTERVENTION: Participants received 150 mg DMPA intramuscularly every 12 weeks. Height, weight, and 24-hour dietary recall were collected at baseline, 3, 6, and 12 months. MAIN OUTCOME MEASURE: Body mass index (BMI) over time calculated as weight (kg)/height (m(2)). Associations between dietary variables and BMI were evaluated with repeated measures analysis of variance modeling. RESULTS: Mean chronological and gynecologic ages were 16.2 +/- 1.5 and 4.2 +/- 1.8 years, respectively. Mean BMI increased from 23.7 +/- 5.3 to 25.3 +/- 5.7 over 12 months. Average dietary intake included: 1781.4 +/- 554.1 total kilocalories, 228.5 g +/- 69.8 carbohydrates, 71.0 g +/- 27.3 fat, and 61.0 g +/- 20.2 protein. These diet measures were not associated with BMI over time. Dietary fiber, magnesium, and linoleic acid were inversely associated with increased BMI over time (P < .05) CONCLUSION: We found no evidence that general measures of diet (energy, carbohydrates, fat, and protein), as assessed by 24 hour recall, were predictive of weight gain on DMPA. Several nutrients abundant in foods that benefit overall health were inversely associated with increased BMI over time, suggesting that diet quality, rather than quantity, is a more important predictor of DMPA-associated weight gain. PMID- 26046603 TI - Impact of Post-visit Contact on Emergency Department Utilization for Adolescent Women with a Sexually Transmitted Infection. AB - STUDY OBJECTIVES: To understand Emergency Department (ED) utilization patterns for women who received sexually transmitted infection (STI) testing and explore the impact of post-visit telephone contact on future ED visits. DESIGN, SETTING, PARTICIPANTS: We performed a secondary analysis on a prospectively collected dataset of ED patients ages 14-21 years at a children's hospital. INTERVENTIONS AND MAIN OUTCOME MEASURES: The dataset documented initial and return visits, STI results, race, age and post-visit contact success (telephone contact <=7 days of visit). Logistic regression was performed identifying variables that predicted a return visit to the ED, a return visit with STI testing, and subsequent positive STI results. RESULTS: Of 922 women with STI testing at their initial ED visit, 216 (23%) were STI positive. One-third (315/922) returned to the ED, 15% (141/922) returned and had STI testing, and 4% (38/922) had a subsequent STI. Of 216 STI-positive women, 59% were successfully contacted. Of those who returned to the ED, age >= 18 and Black race were associated with increased STI testing at a subsequent visit. Successful contact reduced the likelihood of STI testing at a subsequent ED visit (OR 0.28, 95% CI 0.01-0.8), and ED empiric antibiotic treatment had no effect on subsequent STI testing. CONCLUSION: Contacting women with STI results and counseling them regarding safe sex behaviors may reduce the number of ED patients who return with symptoms or a new exposure necessitating STI testing. The high STI prevalence and frequent return rate suggest that ED interventions are needed. PMID- 26046605 TI - Laparoscopic Outcomes for Pelvic Pathology in Children and Adolescents among Patients Presenting to the Pediatric and Adolescent Gynecology Service. AB - STUDY OBJECTIVE: The aim of this study was to evaluate surgical indications, outcomes, and common pelvic pathologies presenting to the Pediatric and Adolescent Gynecology service in premenarcheal (PMF) and menarcheal females (MF) undergoing laparoscopic surgery. DESIGN: A retrospective chart review. SETTING: An academic children's hospital. PARTICIPANTS: Females under 21 years of age, excluding pregnant patients, who underwent laparoscopic surgery for a gynecologic indication presenting to the Pediatric and Adolescent Gynecology service at a single children's hospital between July 2007 and January 2012, identified by CPT codes. MAIN OUTCOME MEASURES: Pertinent patient demographics, indication for surgery, anesthesia time, estimated blood loss, surgical instruments used, intra operative findings, surgical pathology, complications, length of stay, and concerns at follow-up appointment. Descriptive statistics and chi-square analyses of data were performed using SAS 9.3. RESULTS: Of 158 cases meeting inclusion criteria, 33 patients were PMF (mean age 8.6 +/- 3.2 years) and 125 patients were MF (mean age 14.7 +/- 2.3 years). Acute abdominal pain was the most common surgical indication in both groups, but was significantly more likely to be the surgical indication in the PMF group (62.7% vs. 52.8%, P = .006). Adnexal torsion was more likely to be present in the PMF group than in the MF group (66.7% vs. 27.2%, P < .0001). No complications were reported in the PMF group. Two minor complications were reported in the MF group. CONCLUSION: Minimally invasive surgical techniques represent a safe and well-tolerated method for treating a wide variety of pelvic pathology in both younger children and older adolescent females. For physicians evaluating premenarcheal females with acute-onset abdominal pain, adnexal torsion should be prominent among the differential diagnoses. PMID- 26046604 TI - Hormonal State Comparison (Progesterone, Estradiol, and Leptin) of Body Fat and Body Mass Indices in Mexican Women as a Risk Factor for Neonatal Physiologic Condition. AB - STUDY OBJECTIVE: Describe the impact of teen pregnancy on later ovarian activity and metabolic hormones considering the concentration of current levels of ovarian steroids and leptin in a sample of Mexican females. DESIGN: Cross-sectional study in the maternity of the General Hospital of Atlacomulco and campus of the Autonomous University of the State of Mexico. PARTICIPANTS: 71 women between the ages of 18 and 24, and 160 neonates seen between March 2010 and June 2012. MAIN OUTCOME MEASURES: The measurements obtained included anthropometric body composition (bioelectrical impedance), serum hormone quantification of ovarian steroids and leptin (immunoassays), and the Apgar scores, height, and weight in neonates. Statistical analysis included ANOVA, Student, and chi-square for P < .05. RESULTS: Adolescent mothers showed significantly lower concentrations of estradiol (P = .001) and progesterone (P = .001). However, higher levels of leptin in adolescent mothers were not statistically different compared with older mothers (P = .84). Also, leptin was correlated with all measures of adiposity. The mean birth weights (P = .001) and Apgar scores (P = .001) were lower in neonates of adolescent mothers than in neonates of adult mothers. There was no association between maternal age with the anthropometric variables studied. CONCLUSIONS: Early reproduction represents a metabolic stress condition that modifies the long term ovarian activity and metabolic hormones, and impacts the morbidity-mortality of the mother and offspring in a later vital life cycle stage. PMID- 26046607 TI - Dysmenorrhea: Prevalence and Impact on Quality of Life among Young Adult Jordanian Females. AB - STUDY OBJECTIVE: To establish the prevalence and impact on quality of life of dysmenorrhea among young adult Jordanian females. DESIGN: Cross-sectional study based on quantitative self-reported anonymous questionnaire. SETTING: University based study. PARTICIPANTS: A total of 272 female medical students (aged 19-25 years). INTERVENTION: None. MAIN OUTCOME MEASURES: Self-reports of menstruation related pain symptoms and methods of dealing with them. RESULTS: Of study subjects 152/272 (55.8%) participants had moderate and severe dysmenorrhea. Of them, 55.8% had a family history of severe dysmenorrhea compared with 33.1% of those without dysmenorrhea (chi2 = 13.40, df = 1, P < .001). There was strong association between severity of dysmenorrhea and poor university attendance (chi(2) = 45.35, df = 2, P < .001), poor social activities (chi2 = 32.06, df = 2, P < .001), poor relationships with family (chi2 = 18.46, df = 2, P < .001) and friends (chi2 = 19.14, df = 2, P < .001), and poor sport activities (chi2 = 12.15, df = 2, P = .002). Dysmenorrhea worsens during examination periods in 50% of cases. The most common pain symptom was low back pain (60.2%). Body mass index, family monthly income and early age at menarche had no correlation with the occurrence of dysmenorrhea. Of those with dysmenorrhea, 69.4% were using analgesics. Mothers were the main source of information regarding menstruation. CONCLUSIONS: Dysmenorrhea is highly prevalent among young adult Jordanian females and seems to negatively affect quality of life, particularly as related to university attendance and performance and social relationships. PMID- 26046606 TI - Bone Density and Timing of Puberty in a Longitudinal Study of Girls. AB - STUDY OBJECTIVE: Primary: To examine the relationship between relative timing of puberty with bone mineral density (BMD) in a group of adolescent girls; Secondary: To determine if family history of breast cancer was associated with bone mineral density. DESIGN/SETTING/PARTICIPANTS: Longitudinal study of girls recruited between 6 and 7 years of age seen every 6 months for 5 years, and subsequently seen annually. BMD of the lumbar spine was measured by dual-energy X ray absorptiometry (DXA) at mean age of 12.5 years; age- and race-specific Z scores (BMDz) were calculated. Age of pubertal onset was determined by the first occurrence of breast stage 2, and participants were categorized into race specific early, on-time and late puberty onset groups. MAIN OUTCOME MEASURES: BMDz by timing of pubertal onset, and by family history of breast cancer. RESULTS: DXA scans were performed on 227 study participants, and a second scan was performed on 114 participants 2 years later. Age of onset of puberty was inversely correlated with BMDz, r = -0.31 (P < .0001). There was no association between BMDz and family history of breast cancer. CONCLUSIONS: Earlier timing of puberty was associated with higher BMD. The high shared variance of BMD and timing of pubertal onset implies an underlying biologic basis. PMID- 26046608 TI - Pediatric and Adolescent Gynecology Education through Simulation (PAGES): Development and Evaluation of a Simulation Curriculum. AB - STUDY OBJECTIVE: Develop a Pediatric and Adolescent Gynecology (PAG) curriculum, appropriate pelvic model for teaching examination skills, and an objective structured clinical examination (OSCE) for evaluation. Compare OSCE performance between residents with clinical training in PAG vs those that completed the curriculum vs those without either experience. DESIGN: Prospective cohort study. SETTING: Obstetrics and Gynecology (Ob/Gyn) residency program in an urban academic center. PARTICIPANTS: Senior Ob/Gyn residents. INTERVENTIONS: A simulation-based teaching curriculum was created to teach PAG skills. A pediatric mannequin with anatomic pre-pubertal genitalia was developed for teaching and assessment of skills. MAIN OUTCOME MEASURES: Performance on a PAG-based OSCE as assessed by 2 observers using a 40 point checklist. RESULTS: 17 residents participated in the OSCE; 5 completed the curriculum, 6 completed a clinical rotation, and 6 were controls. The teaching curriculum group had the highest median composite OSCE score (75.0%) compared to the clinical group (73.1%) and control group (55.3%). There was no statistical difference between the scores of the teaching and clinical groups, but the teaching group scored statistically higher than controls (P = .0331). Scores for each OSCE component were compared. The teaching and clinical groups outperformed controls on assessment and procedures. There was no difference in scores on history taking or physical examination. CONCLUSION: An interactive teaching curriculum incorporating simulation and a realistic pediatric pelvic model can be used to teach PAG clinical skills. Using an OSCE to evaluate skills shows that residents completing the curriculum perform as well as those with clinical experience and better than controls. PMID- 26046609 TI - Occurrence of Gonadoblastoma in Patients with 45,X/46,XY Mosaicism. AB - STUDY OBJECTIVE: To estimate the overall frequency of gonadal tumors in patients with 45,X/46,XY mosaicism who underwent gonadectomy and to determine whether the degree of external masculinization or the location of gonads were associated with the presence of gonadal tumor. DESIGN: Retrospective study of patients with karyotype of 45,X/46,XY or variant who received care at the study institution between 1995 and 2012. SETTING: University of Michigan Health System (Ann Arbor, Michigan), a tertiary care academic center. PARTICIPANTS: Sixteen patients with karyotype of 45,X/46,XY who underwent gonadectomy. INTERVENTIONS: None. MAIN OUTCOME MEASURE: Presence of pathology-confirmed gonadal tumor. RESULTS: In patients who underwent bilateral gonadectomy, gonadoblastomas were detected in 36.4% (4 of 11), and all were identified in patients with normal female external genitalia (4 of 8 [50.0%]). Abdominal gonads were associated with a nonsignificant increase in rate of gonadal tumor compared with inguinal or scrotal gonads. No malignant tumors were identified. CONCLUSION: The overall rate of gonadoblastoma was higher than previously reported. The high rate of gonadoblastoma in patients with female external genitalia and the lack of gonadal function support continuing the standard of care of practice of prophylactic gonadectomy in this patient population. PMID- 26046610 TI - The Integration of Voice and Dance Techniques in Musical Theatre: Anatomical Considerations. AB - Musical theatre performers are required to be proficient in the three artistic disciplines of dancing, singing, and acting, although in today's modern productions, there is often a requirement to incorporate other skills such as acrobatics and the playing of an instrument. This article focuses on the issues faced by performers when dancing and voicing simultaneously, as it is between these two disciplines where we see the greatest pedagogical divide in terms of breath management and muscle recruitment patterns. The traditional teaching methods of dance and voice techniques are examined, areas of conflict highlighted, and solutions proposed through an exploration of the relevant anatomy. PMID- 26046611 TI - Exploring Active and Passive Contributors to Turnout in Dancers and Non-Dancers. AB - OBJECTIVE: Lower-extremity external rotation, or turnout, is a fundamental skill in dance. Active standing turnout has previously been measured using low-friction turnout disks. Turnout is influenced by passive range of motion (ROM) and strength, with passive ROM a function of bony morphology and ligamentous/capsular restraints. PURPOSE: Our study explored the relationship between standing active turnout and femoral bony morphology, hip passive ROM, and strength among dancers and non-dancers. METHODS: Cross-sectional cohort study. Twenty-three female dancers and 13 female non-dancers aged 18 to 30 yrs were recruited. Standing active turnout on reduced-friction disks, ultrasound images of femoral version, supine passive turnout, and hip abductor and external rotator strength were collected. RESULTS: Dancers demonstrated greater standing turnout (107 degrees +/- 18 degrees ) than non-dancers (92 degrees +/- 28 degrees ), but the difference was not statistically significant (p=0.054). A significant difference was found for femoral version (p<0.001), 4.7 degrees ( +/- 2.8 degrees ) for dancers vs 12.1 degrees ( +/- 4.6 degrees ) for non-dancers. Dancers demonstrated greater supine turnout, 102.7 degrees +/-18.8 degrees , compared to non-dancers, 84.3 degrees +/- 30.4 degrees (p=0.031). Dancers were able to achieve greater peak force in turnout compared to non-dancers: 2.44 +/- 0.44 N/kg and 1.72 +/- 0.59 N/kg, respectively (p<0.0001). Supine total turnout was the best predictor of active turnout, contributing 48% of the variance (r=0.696, p<0.001). CONCLUSION: Our findings suggest supine turnout is the largest predictor for standing turnout. Investigating dancers and non-dancers independently, our finding were similar to previous studies suggesting the femoro acetabular complex may be influenced by dance training, contributing to differences in bony morphology between dancers and non-dancers. Although strength did not significantly contribute to active standing turnout, dancers demonstrated greater peak force compared to non-dancers. PMID- 26046612 TI - The Psychological Benefits from Reconceptualizing Music-Making as Mindfulness Practice. AB - While the music psychology and education literatures have devoted considerable attention to how musical instrumentalists practice their instruments, less formal scholarly attention has been given in consideration of what it means to maintain a musical "practice" over time and across context. In this paper, the practice of mindfulness meditation is used as heuristic, arguing for a view of mindfulness meditation as a formalized de-specialization of the infinite number of other activities with which people can achieve mindfulness. Sitting meditation, requiring of one to observe the contents of their mind unmediated, can serve as a useful model for the musician in understanding the phenomenology of the music making process and the "flow" states that can result from an embodied musical practice. Finally, reconceptualizing music-making as a mindfulness practice is considered with psychological and pedagogical implications relevant for developing musicians. PMID- 26046613 TI - Facial and Lingual Strength and Endurance in Skilled Trumpet Players. AB - Trumpet players produce and manipulate sound through their instrument by articulating the lips, cheeks, and tongue to create a proper airflow. These sustained muscle contractions may result in increased facial and lingual strength and endurance. The purpose of this study was to determine if adult trumpet players who practice at least 6 hrs/wk differed from adult non-trumpet-playing controls in strength and endurance of the lips, cheeks, and tongue. METHODS: This case-control study involved 16 trumpet players, 16 healthy controls balanced for age and sex, and 1 trumpet player 25 years post-Bell's palsy. Strength and endurance of lip, cheek, and tongue muscles were measured using the Iowa Oral Performance Instrument (IOPI Medical, Redmond, WA). Maximum strength was the greatest pressure value of three encouraged trials. Endurance was the length of time the participant was able to sustain 50% of maximum strength. RESULTS: The findings indicate that trumpet players had greater facial strength and endurance, which was objectively quantified using commercially available equipment. The trumpet players had greater cheek strength and greater lip endurance than controls. Tongue strength and endurance did not differ between the trumpet players and controls. Tongue strength was negatively associated with age, which is consistent with previous studies. The trumpet player with a history of Bell's palsy had decreased cheek strength and endurance on his affected side compared to his unaffected side, although this difference was comparable to the differences between right and left cheek strength in trumpet players without a history of facial nerve damage. PMID- 26046614 TI - Marching Band Camp Injury Rates at the Collegiate Level. AB - AIMS: Marching band camp injuries were recorded over the course of 1 week (10 field practices) to determine injury rate for preseason. METHODS: Members were instructed to self-report any type of injury that occurred. The collected data were coded and analyzed for total injuries and injuries per section. The injury counts, along with total practices and band members per section, were used to calculate injury rate per 1,000 exposures for total injury and injury per section. RESULTS: There were a total of 191 injuries reported in 1,540 practice exposures. The overall injury rate was 124.03/1,000 exposures. The instrument with the highest injury rate was the mellophone (220.0/1,000 exposures), followed by the trombone (190.0/1,000 exposures), and percussion (184.62/ 1,000 exposures). The instrument with the lowest injury rate was the clarinet (43.75/1,000 exposures). CONCLUSION: The findings demonstrate that marching band is a strenuous activity and deserves to be considered an area of emerging practice for athletic trainers and other health care professionals. PMID- 26046615 TI - Heart Rate Response of Professional Musicians When Playing Music. AB - OBJECTIVES: The primary aim was to determine the level of physiological stress evoked while playing music in a standing position as indicated by heart rate (HR) response. A secondary aim was to analyze the effect of music genre (classic rock, western, contemporary Christian, and metal rock) on the relative HR response. Lastly, we considered potential physiological initiators of the music-playing induced HR response. METHODS: HR response was monitored in 27 professional musicians (3 women, 24 men) between the ages of 21 and 67 yrs old during rehearsal and public performances. The percent maximal HR (%MHR) evoked was determined by taking a percentage of the age-predicted maximal HR for each musician and comparing the average %MHR in each genre during public and rehearsal events. The role of the potential initiators of these responses (e.g., number of years playing in public, event type, instrument type, tempo, etc.) was determined using multiple regression analyses. RESULTS: The overall average %MHR responses were 52 +/- 5% and 59 +/- 5% during rehearsal and public performances, respectively, with genre type having a significant effect on the HR response (p=0.01). Body mass index and tempo were each found to be significant contributors to the HR response while playing music (r2=0.506, p=0.001). CONCLUSION: Playing music professionally evokes considerable increases in HR response, with music genre influencing the level of the physiological response. We concluded that 50% of the HR response while playing music was associated with body mass index, music tempo, and instrument type. PMID- 26046616 TI - Prevalence of Musculoskeletal Injury Among Collegiate Marching Band and Color Guard Members. AB - OBJECTIVE: To investigate the prevalence of musculoskeletal injury (MSI) in collegiate marching band and color guard members and the associated factors. METHODS: An electronic survey was developed and delivered via the Qualtrics survey platform to collegiate marching band and color guard members in the United States. Information collected included demographics; years of experience; training and performance characteristics; footwear worn; instrument played/equipment used; participation in stretching/strengthening programs; injury prevalence and type; treatment sought for injury; and participation time lost due to injury. RESULTS: There were 1,379 (792 female, 587 male) members of 21 collegiate marching bands who completed the survey. Respondents had an average age of 19.8 yrs, height 171.9 cm, weight 72.3 kg, and BMI 24.4 kg/m2. Twenty-five percent of respondents reported sustaining a MSI as a result of participating in marching band or color guard. Females were 20% more likely to sustain a MSI and 87.7% of MSI involved the lower extremity. A significant difference in BMI was found between those who did and did not sustain a MSI (p=0.014). CONCLUSIONS: Members of collegiate marching band and color guard may be at risk of sustaining a MSI due to the repetitive nature of the activities performed during practice and performance. The lower extremity is more prone to injury, and a higher BMI may be a risk factor for MSI in this population. PMID- 26046617 TI - Avulsion Fracture and Myositis Ossificans in a Professional Teenage Dancer: A Case Report. AB - Fractures of the transverse processes in the lumbar vertebrae occur as the result of major forces such as direct blunt trauma, violent lateral flexion-extension forces, avulsion of the psoas muscle, or Malgaigne fractures of the pelvis. Dancers make repeated and forceful hyperextension and flexions of the spine, which may cause fractures of the transverse processes of the lumbar vertebrae. Repeated trauma of muscles in dancers may cause avulsion fractures and myositis ossificans. Herein, we report MRI and CT findings of an avulsion from the right transverse process of the L2 and L3 vertebrae in a 16-year-old professional teenage dancer, who responded to conservative treatment. PMID- 26046618 TI - The Gap Between Research and Pedagogy: Continuing the Discussion. AB - In June 2013, Dr. Ralph Manchester wrote an editorial for Medical Problems of Performing Artists examining the following question presented to him in a letter to the editor: Why haven't we used the scientific method to determine optimal piano technique? The article in this month's issue entitled "Exploring active and passive contributors to turnout in dancers and non-dancers" by Sutton-Traina et al. examines various possible contributors to turnout in dancers, and which factors may be the greatest predictors of the dancer's standing turnout. What stands out within the reported data is the recognition that professional dancers as a whole do not approach the 180 degrees of turnout that continues to be the icon of the ideal classical dancer. And so I pose the question: Why haven't we used the scientific method to determine optimal dance technique? PMID- 26046619 TI - Musicians and Dystonia: Is Sleep Part of the Problem? AB - We would like to congratulate Lee and Altenmuller for their recent study showing important findings about the characterization of a task-specific dystonia in a young professional percussionist. The authors presented in an elegant way the EMG investigation and treatment approach and the possible differential diagnoses, raising an important question about the need for physicians' awareness of this condition when considering musicians' health. We would like to add a new point of view in order to contribute with this discussion and provide critical thinking for a multidisciplinary approach to this type of dystonia, which may affect many individuals and result in severe compromise of musical technical performance. One factor that could also be potentially associated with the percussion-related dystonia is sleep. PMID- 26046620 TI - Conceptualizing and Measuring Self-Criticism as Both a Personality Trait and a Personality State. AB - Blatt's ( 2004 , 2008 ) conceptualization of self-criticism is consistent with a state-trait model that postulates meaningful variation in self-criticism both between persons (traits) and within person (states). We tested the state-trait model in a 7-day diary study with 99 college student participants. Each evening they completed a 6-item measure of self-criticism, as well as measures of perceived social support, positive and negative affect, compassionate and self image goals during interactions with others, and interpersonal behavior, including overt self-criticism and given social support. As predicted, self criticism displayed both trait-like variance between persons and daily fluctuations around individuals' mean scores for the week; slightly more than half of the total variance was between persons (ICC = .56). Numerous associations at both the between-persons and within-person levels were found between self criticism and the other variables, indicating that individuals' mean levels of self-criticism over the week, and level of self-criticism on a given day relative to their personal mean, were related to their cognitions, affect, interpersonal goals, and behavior. The results supported the construct validity of the daily self-criticism measure. Moreover, the findings were consistent with the state trait model and with Blatt's theoretical analysis of self-critical personality. PMID- 26046621 TI - Two New Species of Marine Saprotrophic Sphaeroformids in the Mesomycetozoea Isolated From the Sub-Arctic Bering Sea. AB - The genus Sphaeroforma previously encompassed organisms isolated exclusively from animal symbionts in marine systems. The first saprotrophic sphaeroformids (Mesomycetozoea) isolated from non-animal hosts are described here. Sphaeroforma sirkka and S. napiecek are also the first species in the genus possessing endogenous DNA-containing motile propagules and central vacuoles, traits that have previously guided morphological differentiation of sphaeroformids from the genus Creolimax. Phylogenetic analysis of DNA sequences from the 18S rRNA and the ITS1-5.8S--ITS2 loci firmly place S. sirkka and S. napiecek within Sphaeroforma, extending the number of known species to six within this genus. The discovery of these species increases the geographical range, cellular variation and life history complexity of the sphaeroformids. PMID- 26046622 TI - Eight weeks gait retraining in minimalist footwear has no effect on running economy. AB - PURPOSE: To evaluate the effects of an eight week combined minimalist footwear (MFW) and gait-retraining intervention on running economy (RE) and kinematics in conventional footwear runners. METHODS: Twenty-three trained male runners (age: 43 +/- 10 years, stature: 177.2 +/- 9.2 cm, body mass: 72.8 +/- 10.2 kg, VO2max: 56.5 +/- 7.0 mL min(-1) kg(-1)) were recruited. Participants were assigned to either an intervention group (n = 13) who gradually increased exposure to MFW and also implemented gait-retraining over an eight week period. RE and kinematics were measured in both MFW and conventional running shoes (CRS) at pre-tests and eight weeks, in a random order. In contrast the control group (n = 10) had no MFW exposure or gait retraining and were only tested in CRS. RESULTS: The MFW and gait re-training intervention had no effect on RE (p < .001). However, RE was significantly better in MFW (mean difference 2.72%; p = .002) at both pre and post-tests compared to CRS. Step frequency increased as a result of the intervention (+5.7 steps per minute [spm]; p < .001), and was also significantly higher in MFW vs. CRS (+7.5 spm; p < .001). CONCLUSION: Whilst a better RE in MFW was observed when compared to CRS due to shoe mass, familiarization to MFW with gait-retraining was not found to influence RE. PMID- 26046623 TI - Investigating the brain basis of facial expression perception using multi-voxel pattern analysis. AB - Humans can readily decode emotion expressions from faces and perceive them in a categorical manner. The model by Haxby and colleagues proposes a number of different brain regions with each taking over specific roles in face processing. One key question is how these regions directly compare to one another in successfully discriminating between various emotional facial expressions. To address this issue, we compared the predictive accuracy of all key regions from the Haxby model using multi-voxel pattern analysis (MVPA) of functional magnetic resonance imaging (fMRI) data. Regions of interest were extracted using independent meta-analytical data. Participants viewed four classes of facial expressions (happy, angry, fearful and neutral) in an event-related fMRI design, while performing an orthogonal gender recognition task. Activity in all regions allowed for robust above-chance predictions. When directly comparing the regions to one another, fusiform gyrus and superior temporal sulcus (STS) showed highest accuracies. These results underscore the role of the fusiform gyrus as a key region in perception of facial expressions, alongside STS. The study suggests the need for further specification of the relative role of the various brain areas involved in the perception of facial expression. Face processing appears to rely on more interactive and functionally overlapping neural mechanisms than previously conceptualised. PMID- 26046624 TI - Gender differences in adults with attention-deficit/hyperactivity disorder: A narrative review. AB - Certain characteristics of attention-deficit/hyperactivity disorder (ADHD) in children have long been known to differ by gender. What has not been as widely studied is whether gender is similarly associated with ADHD differences in adults. In this review, the relation between gender and adult ADHD prevalence, persistence, impairment, comorbidity, cognitive functioning, and treatment response was examined across 73 studies. Although gender was related to several characteristics and correlates of adult ADHD, it appeared that many of these gender differences may be at least be partially attributed to methodological artifacts or social and cultural influences, rather than fundamental differences in the expression of ADHD in men and women. We highlight how understanding the nature of the relation between gender and ADHD across the lifespan is complicated by a number of methodological difficulties, and offer recommendations for how emerging research and clinical practice can better incorporate gender into the conceptualization of ADHD in adulthood. PMID- 26046625 TI - Genome-wide analysis and expression profiling of DNA-binding with one zinc finger (Dof) transcription factor family in potato. AB - DNA-binding with one finger (Dof) domain proteins are a multigene family of plant specific transcription factors involved in numerous aspects of plant growth and development. Here, we report a genome-wide search for Solanum tuberosum Dof (StDof) genes and their expression profiles at various developmental stages and in response to various abiotic stresses. In addition, a complete overview of Dof gene family in potato is presented, including the gene structures, chromosomal locations, cis-regulatory elements, conserved protein domains, and phylogenetic inferences. Based on the genome-wide analysis, we identified 35 full-length protein-coding StDof genes, unevenly distributed on 10 chromosomes. Phylogenetic analysis with Dof members from diverse plant species showed that StDof genes can be classified into four subgroups (StDofI, II, III, and IV). qPCR expression analysis of StDof gene transcripts showed the distinct expression patterns of StDof genes in various potato organs, and tuber developmental stages analyzed. Many StDof genes were upregulated in response to drought, salinity, and ABA treatments. Overall, the StDof gene expression pattern and the number of over represented cis-acting elements in the promoter regions of the StDof genes indicate that most of the StDof genes have redundant functions. The detailed genomic information and expression profiles of the StDof gene homologs in the present study provide opportunities for functional analyses to unravel the genes' exact role in plant growth and development as well as in abiotic stress tolerance. PMID- 26046626 TI - Geographic Variation in the Association between Ambient Fine Particulate Matter (PM2.5) and Term Low Birth Weight in the United States. AB - BACKGROUND: Studies on the association between prenatal exposure to fine particulate matter <= 2.5 MUm in aerodynamic diameter (PM2.5) and term low birth weight (LBW) have resulted in inconsistent findings. Most studies were conducted in snapshots of small geographic areas and no national study exists. OBJECTIVES: We investigated geographic variation in the associations between ambient PM2.5 during pregnancy and term LBW in the contiguous United States. METHODS: A total of 3,389,450 term singleton births in 2002 (37-44 weeks gestational age and birth weight of 1,000-5,500 g) were linked to daily PM2.5 via imputed birth days. We generated average daily PM2.5 during the entire pregnancy and each trimester. Multi-level logistic regression models with county-level random effects were used to evaluate the associations between term LBW and PM2.5 during pregnancy. RESULTS: Without adjusting for covariates, the odds of term LBW increased 2% [odds ratio (OR) = 1.02; 95% CI: 1.00, 1.03] for every 5-MUg/m(3) increase in PM2.5 exposure during the second trimester only, which remained unchanged after adjusting for county-level poverty (OR = 1.02; 95% CI: 1.01, 1.04). The odds did change to null after adjusting for individual-level predictors (OR = 1.00; 95% CI: 0.99, 1.02). Multi-level analyses, stratified by census division, revealed significant positive associations of term LBW and PM2.5 exposure (during the entire pregnancy or a specific trimester) in three census divisions of the United States: Middle Atlantic, East North Central, and West North Central, and significant negative association in the Mountain division. CONCLUSIONS: Our study provided additional evidence on the associations between PM2.5 exposure during pregnancy and term LBW from a national perspective. The magnitude and direction of the estimated associations between PM2.5 exposure and term LBW varied by geographic locations in the United States. PMID- 26046627 TI - Mechanosensitive Adaptation of E-Cadherin Turnover across adherens Junctions. AB - In the natural and technological world, multi-agent systems strongly depend on how the interactions are ruled between their individual components, and the proper control of time-scales and synchronization is a key issue. This certainly applies to living tissues when multicellular assemblies such as epithelial cells achieve complex morphogenetic processes. In epithelia, because cells are known to individually generate actomyosin contractile stress, each individual intercellular adhesive junction line is subjected to the opposed stresses independently generated by its two partner cells. Contact lines should thus move unless their two partner cells mechanically match. The geometric homeostasis of mature epithelia observed at short enough time-scale thus raises the problem to understand how cells, if considered as noisy individual actuators, do adapt across individual intercellular contacts to locally balance their time-average contractile stress. Structural components of adherens junctions, cytoskeleton (F actin) and homophilic bonds (E-cadherin) are quickly renewed at steady-state. These turnovers, if they depend on forces exerted at contacts, may play a key role in the mechanical adaptation of epithelia. Here we focus on E-cadherin as a force transducer, and we study the local regulation and the mechanosensitivity of its turnover in junctions. We show that E-cadherin turnover rates match remarkably well on either side of mature intercellular contacts, despite the fact that they exhibit large fluctuations in time and variations from one junction to another. Using local mechanical and biochemical perturbations, we find faster turnover rates with increased tension, and asymmetric rates at unbalanced junctions. Together, the observations that E-cadherin turnover, and its local symmetry or asymmetry at each side of the junction, are mechanosensitive, support the hypothesis that E-cadherin turnover could be involved in mechanical homeostasis of epithelia. PMID- 26046628 TI - Cooperative Unfolding of Residual Structure in Heat Denatured Proteins by Urea and Guanidinium Chloride. AB - The denatured states of proteins have always attracted our attention due to the fact that the denatured state is the only experimentally achievable state of a protein, which can be taken as initial reference state for considering the in vitro folding and defining the native protein stability. It is known that heat and guanidinium chloride (GdmCl) give structurally different states of RNase-A, lysozyme, alpha-chymotrypsinogen A and alpha-lactalbumin. On the contrary, differential scanning calorimetric (DSC) and isothermal titration calorimetric measurements, reported in the literature, led to the conclusion that heat denatured and GdmCl denatured states are thermodynamically and structurally identical. In order to resolve this controversy, we have measured changes in the far-UV CD (circular dichroism) of these heat-denatured proteins on the addition of different concentrations of GdmCl. The observed sigmoidal curve of each protein was analyzed for Gibbs free energy change in the absence of the denaturant (DeltaG0X->D) associated with the process heat denatured (X) state <-> GdmCl denatured (D) state. To confirm that this thermodynamic property represents the property of the protein alone and is not a manifestation of salvation effect, we measured urea-induced denaturation curves of these heat denatured proteins under the same experimental condition in which GdmCl-induced denaturation was carried out. In this paper we report that (a) heat denatured proteins contain secondary structure, and GdmCl (or urea) induces a cooperative transition between X and D states, (b) for each protein at a given pH and temperature, thermodynamic cycle connects quantities, DeltaG0N->X (native (N) state <-> X state), DeltaG0X >D and DeltaG0N->D (N state <-> D state), and PMID- 26046629 TI - Effects of Choline on Meat Quality and Intramuscular Fat in Intrauterine Growth Retardation Pigs. AB - The aim of this study was to investigate the effects of choline supplementation on intramuscular fat (IMF) and lipid oxidation in IUGR pigs. Twelve normal body weight (NBW) and twelve intrauterine growth retardation (IUGR) newborn piglets were collected and distributed into 4 treatments (Normal: N, Normal+Choline: N+C, IUGR: I, and IUGR+Choline: I+C) with 6 piglets in each treatment. At 23 d of age, NBW and IUGR pigs were fed basal or choline supplemented diets. The results showed that the IUGR pigs had significantly lower (P<0.05) BW as compared with the NBW pigs at 23 d, 73 d, and 120 d of age, however, there was a slight decreased (P>0.05) in BW of IUGR pigs than the NBW pigs at 200 d. Compared with the NBW pigs, pH of meat longissimus dorsi muscle was significantly lower (P<0.05), and the meat color was improved in IUGR pigs. The malondialdehyde (MDA) levels were significantly decreased (P<0.05), while triglyceride (TG) and IMF contents were significantly higher (P<0.05) in the IUGR pigs than the NBW pigs. IUGR up-regulated the mRNA gene expression of fatty acid synthetase (FAS) and acetyl-CoA carboxylase (ACC). Dietary choline significantly increased (P<0.05) the BW at 120d of age, however, significantly decreased (P<0.05) the TG and IMF contents in both IUGR and NBW pigs. FAS and sterol regulatory element-binding proteins 1 (SREBP1) mRNA gene expressions were increased (P<0.05) while the muscle-carnitine palmityl transferase (M-CPT) and peroxisome proliferators activated receptorgamma (PPARgamma) mRNA (P<0.05) gene expressions were decreased in the muscles of the IUGR pigs by choline supplementation. Furthermore, choline supplementation significantly increased (P<0.05) the MDA content as well as the O2*- scavenging activity in meat of IUGR pigs. The results suggested that IUGR pigs showed a permanent stunting effect on the growth performance, increased fat deposition and oxidative stress in muscles. However, dietary supplementation of choline improved the fat deposition via enhancing the lipogenesis and reducing the lipolysis. PMID- 26046631 TI - The First Complete Chloroplast Genome Sequences in Actinidiaceae: Genome Structure and Comparative Analysis. AB - Actinidia chinensis is an important economic plant belonging to the basal lineage of the asterids. Availability of a complete Actinidia chloroplast genome sequence is crucial to understanding phylogenetic relationships among major lineages of angiosperms and facilitates kiwifruit genetic improvement. We report here the complete nucleotide sequences of the chloroplast genomes for Actinidia chinensis and A. chinensis var deliciosa obtained through de novo assembly of Illumina paired-end reads produced by total DNA sequencing. The total genome size ranges from 155,446 to 157,557 bp, with an inverted repeat (IR) of 24,013 to 24,391 bp, a large single copy region (LSC) of 87,984 to 88,337 bp and a small single copy region (SSC) of 20,332 to 20,336 bp. The genome encodes 113 different genes, including 79 unique protein-coding genes, 30 tRNA genes and 4 ribosomal RNA genes, with 16 duplicated in the inverted repeats, and a tRNA gene (trnfM-CAU) duplicated once in the LSC region. Comparisons of IR boundaries among four asterid species showed that IR/LSC borders were extended into the 5' portion of the psbA gene and IR contraction occurred in Actinidia. The clap gene has been lost from the chloroplast genome in Actinidia, and may have been transferred to the nucleus during chloroplast evolution. Twenty-seven polymorphic simple sequence repeat (SSR) loci were identified in the Actinidia chloroplast genome. Maximum parsimony analyses of a 72-gene, 16 taxa angiosperm dataset strongly support the placement of Actinidiaceae in Ericales within the basal asterids. PMID- 26046630 TI - Chronic Internal Exposure to Low Dose 137Cs Induces Positive Impact on the Stability of Atherosclerotic Plaques by Reducing Inflammation in ApoE-/- Mice. AB - After Chernobyl and Fukushima Dai Chi, two major nuclear accidents, large amounts of radionuclides were released in the environment, mostly caesium 137 (137Cs). Populations living in contaminated territories are chronically exposed to radionuclides by ingestion of contaminated food. However, questions still remain regarding the effects of low dose ionizing radiation exposure on the development and progression of cardiovascular diseases. We therefore investigated the effects of a chronic internal exposure to 137Cs on atherosclerosis in predisposed ApoE-/- mice. Mice were exposed daily to 0, 4, 20 or 100 kBq/l 137Cs in drinking water, corresponding to range of concentrations found in contaminated territories, for 6 or 9 months. We evaluated plaque size and phenotype, inflammatory profile, and oxidative stress status in different experimental groups. Results did not show any differences in atherosclerosis progression between mice exposed to 137Cs and unexposed controls. However, 137Cs exposed mice developed more stable plaques with decreased macrophage content, associated with reduced aortic expression of pro-inflammatory factors (CRP, TNFalpha, MCP-1, IFNgamma) and adhesion molecules (ICAM-1, VCAM-1 and E-selectin). Lesions of mice exposed to 137Cs were also characterized by enhanced collagen and smooth muscle cell content, concurrent with reduced matrix metalloproteinase MMP8 and MMP13 expression. These results suggest that low dose chronic exposure of 137Cs in ApoE-/- mice enhances atherosclerotic lesion stability by inhibiting pro-inflammatory cytokine and MMP production, resulting in collagen-rich plaques with greater smooth muscle cell and less macrophage content. PMID- 26046632 TI - Assessing environmental inequalities in ambient air pollution across urban Australia. AB - Identifying inequalities in air pollution levels across population groups can help address environmental justice concerns. We were interested in assessing these inequalities across major urban areas in Australia. We used a land-use regression model to predict ambient nitrogen dioxide (NO2) levels and sought the best socio-economic and population predictor variables. We used a generalised least squares model that accounted for spatial correlation in NO2 levels to examine the associations between the variables. We found that the best model included the index of economic resources (IER) score as a non-linear variable and the percentage of non-Indigenous persons as a linear variable. NO2 levels decreased with increasing IER scores (higher scores indicate less disadvantage) in almost all major urban areas, and NO2 also decreased slightly as the percentage of non-Indigenous persons increased. However, the magnitude of differences in NO2 levels was small and may not translate into substantive differences in health. PMID- 26046633 TI - Spatial quantile regression using INLA with applications to childhood overweight in Malawi. AB - Analyses of childhood overweight have mainly used mean regression. However, using quantile regression is more appropriate as it provides flexibility to analyse the determinants of overweight corresponding to quantiles of interest. The main objective of this study was to fit a Bayesian additive quantile regression model with structured spatial effects for childhood overweight in Malawi using the 2010 Malawi DHS data. Inference was fully Bayesian using R-INLA package. The significant determinants of childhood overweight ranged from socio-demographic factors such as type of residence to child and maternal factors such as child age and maternal BMI. We observed significant positive structured spatial effects on childhood overweight in some districts of Malawi. We recommended that the childhood malnutrition policy makers should consider timely interventions based on risk factors as identified in this paper including spatial targets of interventions. PMID- 26046634 TI - Sources of spatial animal and human health data: Casting the net wide to deal more effectively with increasingly complex disease problems. AB - During the last 30years it has become commonplace for epidemiological studies to collect locational attributes of disease data. Although this advancement was driven largely by the introduction of handheld global positioning systems (GPS), and more recently, smartphones and tablets with built-in GPS, the collection of georeferenced disease data has moved beyond the use of handheld GPS devices and there now exist numerous sources of crowdsourced georeferenced disease data such as that available from georeferencing of Google search queries or Twitter messages. In addition, cartography has moved beyond the realm of professionals to crowdsourced mapping projects that play a crucial role in disease control and surveillance of outbreaks such as the 2014 West Africa Ebola epidemic. This paper provides a comprehensive review of a range of innovative sources of spatial animal and human health data including data warehouses, mHealth, Google Earth, volunteered geographic information and mining of internet-based big data sources such as Google and Twitter. We discuss the advantages, limitations and applications of each, and highlight studies where they have been used effectively. PMID- 26046636 TI - A novel approach to mapping and calculating the rate of spread of endemic bovine tuberculosis in England and Wales. AB - A mathematical method for estimating the endemic status of bovine tuberculosis (bTB) in cattle in England and Wales has been developed. 6.25km(2) hexagonal cells were used as the base resolution. Maps were produced for overlapping two year periods spanning 2001/03 to 2009/11. Distance from a farm to the ten nearest 'Officially Tuberculosis Free status - Withdrawn' incidents within the same time period was measured. Endemic areas were defined as those hexagons containing farms where the 3rd nearest incident occurred within 7km. Temporal spread of endemic bTB was estimated by creating a contour map displaying the spread of endemic bTB over the two-year periods, and using boundary displacement to calculate the rate of spread across each hexagon. A rate was obtained for ~2300 cells and varied between 0.04km and 15.9km per year (median=3.3km per year). This work will enable further analysis of the factors associated with this expansion. PMID- 26046635 TI - Do people really know what food retailers exist in their neighborhood? Examining GIS-based and perceived presence of retail food outlets in an eight-county region of South Carolina. AB - Measures of neighborhood food environments have been linked to diet and obesity. However, the appropriate measurement methods and how people actually perceive their food environments are still unclear. In a cross-sectional study of 939 adults, the perceived presence of food outlets was compared to the geographic based presence of outlets within a participant's neighborhood, utilizing percent agreement and Kappa statistics. Perceived presence was based on survey administered questions, and geographic-based presence was characterized using 1-, 2-, 3- and 5-mile (1-mile=1.6km) Euclidean- and network-based buffers centered on each participant's residence. Analyses were also stratified by urban and non urban designations. Overall, an individual's perceived neighborhood food environment was moderately correlated with the geographic-based presence of outlets. The performance of an individual's perception was most optimal using a 2 or 3-mile geographic-based neighborhood boundary and/or when the participant lived in a non-urban neighborhood. This study has implications for how researchers measure the food environment. PMID- 26046637 TI - Optimal and Numerical Solutions for an MHD Micropolar Nanofluid between Rotating Horizontal Parallel Plates. AB - The present analysis deals with flow and heat transfer aspects of a micropolar nanofluid between two horizontal parallel plates in a rotating system. The governing partial differential equations for momentum, energy, micro rotation and nano-particles concentration are presented. Similarity transformations are utilized to convert the system of partial differential equations into system of ordinary differential equations. The reduced equations are solved analytically with the help of optimal homotopy analysis method (OHAM). Analytical solutions for velocity, temperature, micro-rotation and concentration profiles are expressed graphically against various emerging physical parameters. Physical quantities of interest such as skin friction co-efficient, local heat and local mass fluxes are also computed both analytically and numerically through mid-point integration scheme. It is found that both the solutions are in excellent agreement. Local skin friction coefficient is found to be higher for the case of strong concentration i.e. n=0, as compared to the case of weak concentration n=0.50. Influence of strong and weak concentration on Nusselt and Sherwood number appear to be similar in a quantitative sense. PMID- 26046638 TI - IRF-5-Mediated Inflammation Limits CD8+ T Cell Expansion by Inducing HIF-1alpha and Impairing Dendritic Cell Functions during Leishmania Infection. AB - Inflammation is known to be necessary for promoting, sustaining, and tuning CD8+ T cell responses. Following experimental Leishmania donovani infection, the inflammatory response is mainly induced by the transcription factor IRF-5. IRF-5 is responsible for the activation of several genes encoding key pro-inflammatory cytokines, such as IL-6 and TNF. Here, we investigate the role of IRF-5-mediated inflammation in regulating antigen-specific CD8+ T cell responses during L. donovani infection. Our data demonstrate that the inflammatory response induced by IRF-5 limits CD8+ T cell expansion and induces HIF-1alpha in dendritic cells. Ablation of HIF-1alpha in CD11c+ cells resulted into a higher frequency of short lived effector cells (SLEC), enhanced CD8+ T cell expansion, and increased IL-12 expression by splenic DCs. Moreover, mice with a targeted depletion of HIF-1alpha in CD11c+ cells had a significantly lower splenic parasite burden, suggesting that induction of HIF-1alpha may represent an immune evasive mechanism adopted by Leishmania parasites to establish persistent infections. PMID- 26046639 TI - Intra-Articular Injections of Polyphenols Protect Articular Cartilage from Inflammation-Induced Degradation: Suggesting a Potential Role in Cartilage Therapeutics. AB - Arthritic diseases, such as osteoarthritis and rheumatoid arthritis, inflict an enormous health care burden on society. Osteoarthritis, a degenerative joint disease with high prevalence among older people, and rheumatoid arthritis, an autoimmune inflammatory disease, both lead to irreversible structural and functional damage to articular cartilage. The aim of this study was to investigate the effect of polyphenols such as catechin, quercetin, epigallocatechin gallate, and tannic acid, on crosslinking type II collagen and the roles of these agents in managing in vivo articular cartilage degradation. The thermal, enzymatic, and physical stability of bovine articular cartilage explants following polyphenolic treatment were assessed for efficiency. Epigallocatechin gallate and tannic acid-treated explants showed >12 degrees C increase over native cartilage in thermal stability, thereby confirming cartilage crosslinking. Polyphenol-treated cartilage also showed a significant reduction in the percentage of collagen degradation and the release of glycosaminoglycans against collagenase digestion, indicating the increase physical integrity and resistance of polyphenol crosslinked cartilage to enzymatic digestion. To examine the in vivo cartilage protective effects, polyphenols were injected intra articularly before (prophylactic) and after (therapeutic) the induction of collagen-induced arthritis in rats. The hind paw volume and histomorphological scoring was done for cartilage damage. The intra-articular injection of epigallocatechin gallate and tannic acid did not significantly influence the time of onset or the intensity of joint inflammation. However, histomorphological scoring of the articular cartilage showed a significant reduction in cartilage degradation in prophylactic- and therapeutic-groups, indicating that intra articular injections of polyphenols bind to articular cartilage and making it resistant to degradation despite ongoing inflammation. These studies establish the value of intra-articular injections of polyphenol in stabilization of cartilage collagen against degradation and indicate the unique beneficial role of injectable polyphenols in protecting the cartilage in arthritic conditions. PMID- 26046640 TI - Glucose-Dependent Insulin Secretion in Pancreatic beta-Cell Islets from Male Rats Requires Ca2+ Release via ROS-Stimulated Ryanodine Receptors. AB - Glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells requires an increase in intracellular free Ca2+ concentration ([Ca2+]). Glucose uptake into beta-cells promotes Ca2+ influx and reactive oxygen species (ROS) generation. In other cell types, Ca2+ and ROS jointly induce Ca2+ release mediated by ryanodine receptor (RyR) channels. Therefore, we explored here if RyR mediated Ca2+ release contributes to GSIS in beta-cell islets isolated from male rats. Stimulatory glucose increased islet insulin secretion, and promoted ROS generation in islets and dissociated beta-cells. Conventional PCR assays and immunostaining confirmed that beta-cells express RyR2, the cardiac RyR isoform. Extended incubation of beta-cell islets with inhibitory ryanodine suppressed GSIS; so did the antioxidant N-acetyl cysteine (NAC), which also decreased insulin secretion induced by glucose plus caffeine. Inhibitory ryanodine or NAC did not affect insulin secretion induced by glucose plus carbachol, which engages inositol 1,4,5-trisphosphate receptors. Incubation of islets with H2O2 in basal glucose increased insulin secretion 2-fold. Inhibitory ryanodine significantly decreased H2O2-stimulated insulin secretion and prevented the 4.5-fold increase of cytoplasmic [Ca2+] produced by incubation of dissociated beta-cells with H2O2. Addition of stimulatory glucose or H2O2 (in basal glucose) to beta-cells disaggregated from islets increased RyR2 S-glutathionylation to similar levels, measured by a proximity ligation assay; in contrast, NAC significantly reduced the RyR2 S-glutathionylation increase produced by stimulatory glucose. We propose that RyR2-mediated Ca2+ release, induced by the concomitant increases in [Ca2+] and ROS produced by stimulatory glucose, is an essential step in GSIS. PMID- 26046641 TI - Antiviral Biologic Produced in DNA Vaccine/Goose Platform Protects Hamsters Against Hantavirus Pulmonary Syndrome When Administered Post-exposure. AB - Andes virus (ANDV) and ANDV-like viruses are responsible for most hantavirus pulmonary syndrome (HPS) cases in South America. Recent studies in Chile indicate that passive transfer of convalescent human plasma shows promise as a possible treatment for HPS. Unfortunately, availability of convalescent plasma from survivors of this lethal disease is very limited. We are interested in exploring the concept of using DNA vaccine technology to produce antiviral biologics, including polyclonal neutralizing antibodies for use in humans. Geese produce IgY and an alternatively spliced form, IgYDeltaFc, that can be purified at high concentrations from egg yolks. IgY lacks the properties of mammalian Fc that make antibodies produced in horses, sheep, and rabbits reactogenic in humans. Geese were vaccinated with an ANDV DNA vaccine encoding the virus envelope glycoproteins. All geese developed high-titer neutralizing antibodies after the second vaccination, and maintained high-levels of neutralizing antibodies as measured by a pseudovirion neutralization assay (PsVNA) for over 1 year. A booster vaccination resulted in extraordinarily high levels of neutralizing antibodies (i.e., PsVNA80 titers >100,000). Analysis of IgY and IgYDeltaFc by epitope mapping show these antibodies to be highly reactive to specific amino acid sequences of ANDV envelope glycoproteins. We examined the protective efficacy of the goose-derived antibody in the hamster model of lethal HPS. alpha ANDV immune sera, or IgY/IgYDeltaFc purified from eggs, were passively transferred to hamsters subcutaneously starting 5 days after an IM challenge with ANDV (25 LD50). Both immune sera, and egg-derived purified IgY/IgYDeltaFc, protected 8 of 8 and 7 of 8 hamsters, respectively. In contrast, all hamsters receiving IgY/IgYDeltaFc purified from normal geese (n=8), or no-treatment (n=8), developed lethal HPS. These findings demonstrate that the DNA vaccine/goose platform can be used to produce a candidate antiviral biological product capable of preventing a lethal disease when administered post-exposure. PMID- 26046643 TI - PKCs Sweeten Cell Metabolism by Phosphorylation of Glut1. AB - In this issue, Lee et al. (2015) show that PKC directly phosphorylates the glucose transporter Glut1, in order to promote glucose uptake in response to growth factor signaling. PMID- 26046644 TI - Rag Ubiquitination Recruits a GATOR1: Attenuation of Amino Acid-Induced mTORC1 Signaling. AB - In recent issues of Molecular Cell, two reports identify that K63-linked RagA polyubiquitination and subsequent recruitment of GATOR1, a complex with GAP activity toward RagA/B GTPases, can attenuate amino acid-induced mTORC1 signaling. PMID- 26046642 TI - Vitamin D Metabolites and Their Association with Calcium, Phosphorus, and PTH Concentrations, Severity of Illness, and Mortality in Hospitalized Equine Neonates. AB - BACKGROUND: Hypocalcemia is a frequent abnormality that has been associated with disease severity and outcome in hospitalized foals. However, the pathogenesis of equine neonatal hypocalcemia is poorly understood. Hypovitaminosis D in critically ill people has been linked to hypocalcemia and mortality; however, information on vitamin D metabolites and their association with clinical findings and outcome in critically ill foals is lacking. The goal of this study was to determine the prevalence of vitamin D deficiency (hypovitaminosis D) and its association with serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations, disease severity, and mortality in hospitalized newborn foals. METHODS AND RESULTS: One hundred newborn foals <=72 hours old divided into hospitalized (n = 83; 59 septic, 24 sick non-septic [SNS]) and healthy (n = 17) groups were included. Blood samples were collected on admission to measure serum 25-hydroxyvitamin D3 [25(OH)D3], 1,25-dihydroxyvitamin D3 [1,25(OH) 2D3], and PTH concentrations. Data were analyzed by nonparametric methods and univariate logistic regression. The prevalence of hypovitaminosis D [defined as 25(OH)D3 <9.51 ng/mL] was 63% for hospitalized, 64% for septic, and 63% for SNS foals. Serum 25(OH)D3 and 1,25(OH) 2D3 concentrations were significantly lower in septic and SNS compared to healthy foals (P<0.0001; P = 0.037). Septic foals had significantly lower calcium and higher phosphorus and PTH concentrations than healthy and SNS foals (P<0.05). In hospitalized and septic foals, low 1,25(OH)2D3 concentrations were associated with increased PTH but not with calcium or phosphorus concentrations. Septic foals with 25(OH)D3 <9.51 ng/mL and 1,25(OH) 2D3 <7.09 pmol/L were more likely to die (OR=3.62; 95% CI = 1.1-12.40; OR = 5.41; 95% CI = 1.19-24.52, respectively). CONCLUSIONS: Low 25(OH)D3 and 1,25(OH)2D3 concentrations are associated with disease severity and mortality in hospitalized foals. Vitamin D deficiency may contribute to a pro-inflammatory state in equine perinatal diseases. Hypocalcemia and hyperphosphatemia together with decreased 1,25(OH)2D3 but increased PTH concentrations in septic foals indicates that PTH resistance may be associated with the development of these abnormalities. PMID- 26046645 TI - Gear Up in Circles. AB - Two studies published in this issue of Molecular Cell (Rybak-Wolf et al., 2015) and in the April issue of Nature Neuroscience (You et al., 2015) independently report the upregulated expression of back-spliced circular RNAs (circRNAs) in brains and suggest that they have a potential to regulate synaptic function. PMID- 26046646 TI - Yearly planning meetings: individualized development plans aren't just more paperwork. AB - The National Institutes of Health (NIH) encourages trainees to make Individualized Development Plans to help them prepare for academic and nonacademic careers. We describe our approach to building an Individualized Development Plan, the reasons we find them useful and empowering for both PIs and trainees, and resources to help other labs implement them constructively. PMID- 26046647 TI - OH, the Places You'll Go! Hydroxylation, Gene Expression, and Cancer. AB - Hydroxylation is an emerging modification generally catalyzed by a family of ~70 enzymes that are dependent on oxygen, Fe(II), ascorbate, and the Kreb's cycle intermediate 2-oxoglutarate (2OG). These "2OG oxygenases" sit at the intersection of nutrient availability and metabolism where they have the potential to regulate gene expression and growth in response to changes in co-factor abundance. Characterized 2OG oxygenases regulate fundamental cellular processes by catalyzing the hydroxylation or demethylation (via hydroxylation) of DNA, RNA, or protein. As such they have been implicated in various syndromes and diseases, but particularly cancer. In this review we discuss the emerging role of 2OG oxygenases in gene expression control, examine the regulation of these unique enzymes by nutrient availability and metabolic intermediates, and describe these properties in relation to the expanding role of these enzymes in cancer. PMID- 26046649 TI - Estimating the Impact of Reducing Under-Nutrition on the Tuberculosis Epidemic in the Central Eastern States of India: A Dynamic Modeling Study. AB - BACKGROUND: Tuberculosis (TB) and under-nutrition are widespread in many low and middle-income countries. Momentum to prioritize under-nutrition has been growing at an international level, as demonstrated by the "Scaling Up Nutrition" movement. Low body mass index is an important risk factor for developing TB disease. The objective of this study was to project future trends in TB related outcomes under different scenarios for reducing under-nutrition in the adult population in the Central Eastern states of India. METHODS: A compartmental TB transmission model stratified by body mass index was parameterized using national and regional data from India. We compared TB related mortality and incidence under several scenarios that represented a range of policies and programs designed to reduce the prevalence of under-nutrition, based on the experience and observed trends in similar countries. RESULTS: The modeled nutrition intervention scenarios brought about reductions in TB incidence and TB related mortality in the Central Eastern Indian states ranging from 43% to 71% and 40% to 68% respectively, relative to the scenario of no nutritional intervention. Modest reductions in under-nutrition averted 4.8 (95% UR 0.5, 17.1) million TB cases and 1.6 (95% UR 0.5, 5.2) million TB related deaths over a period of 20 years of intervention, relative to the scenario of no nutritional intervention. Complete elimination of under-nutrition in the Central Eastern states averted 9.4 (95% UR 1.5, 30.6) million TB cases and 3.2 (95% UR 0.7-, 10.1) million TB related deaths, relative to the scenario of no nutritional intervention. CONCLUSION: Our study suggests that intervening on under-nutrition could have a substantial impact on TB incidence and mortality in areas with high prevalence of under nutrition, even if only small gains in under-nutrition can be achieved. Focusing on under-nutrition may be an effective way to reduce both rates of TB and other diseases associated with under-nutrition. PMID- 26046651 TI - Exploring the Material-Induced Transcriptional Landscape of Osteoblasts on Bone Graft Materials. AB - During the past decades, there have been major advances in the field of biomaterials, thereby generating a vast variety of materials for a broad range of tissue engineering and regeneration applications. Although gene expression profiling has been used occasionally in biomaterial research, its usefulness for understanding cell-biomaterial interactions should be further explored for it to fulfill its promise as a tool to assess and improve material properties. Here, the transcriptional landscape induced by 23 materials is explored with a variety of properties within the scope of bone regeneration. An osteoblast cell line is used to identify the gene expression profiles that can be adopted in response to biophysical and chemical cues. It is shown that TGF-beta and WNT signaling may be involved in the cellular response to osteoinductive materials along with differential cell adhesion kinetics via attenuated FAK signaling. The previously reported effect of calcium and phosphate on BMP2 and TGF-beta signaling is confirmed and the biological effect of the addition of nanohydroxyapatite in poly (d,l-lactic acid) polymer particles is studied. Together with future applications, this approach will help researchers understand cellular responses in relation to material properties, which will promote the development of more effective biomaterials for applications in tissue regeneration. PMID- 26046652 TI - Laccase-Catalyzed Surface Modification of Thermo-Mechanical Pulp (TMP) for the Production of Wood Fiber Insulation Boards Using Industrial Process Water. AB - Low-density wood fiber insulation boards are traditionally manufactured in a wet process using a closed water circuit (process water). The water of these industrial processes contains natural phenolic extractives, aside from small amounts of admixtures (e.g., binders and paraffin). The suitability of two fungal laccases and one bacterial laccase was determined by biochemical characterization considering stability and substrate spectra. In a series of laboratory scale experiments, the selected commercial laccase from Myceliophtora thermophila was used to catalyze the surface modification of thermo-mechanical pulp (TMP) using process water. The laccase catalyzed the covalent binding of the phenolic compounds of the process water onto the wood fiber surface and led to change of the surface chemistry directly via crosslinking of lignin moieties. Although a complete substitution of the binder was not accomplished by laccase, the combined use of laccase and latex significantly improved the mechanical strength properties of wood fiber boards. The enzymatically-treated TMP showed better interactions with the synthetic binder, as shown by FTIR-analysis. Moreover, the enzyme is extensively stable in the process water and the approach requires no fresh water as well as no cost-intensive mediator. By applying a second-order polynomial model in combination with the genetic algorithm (GA), the required amount of laccase and synthetic latex could be optimized enabling the reduction of the binder by 40%. PMID- 26046650 TI - Integrating mitochondriomics in children's environmental health. AB - The amount of scientific research linking environmental exposures and childhood health outcomes continues to grow; yet few studies have teased out the mechanisms involved in environmentally-induced diseases. Cells can respond to environmental stressors in many ways: inducing oxidative stress/inflammation, changes in energy production and epigenetic alterations. Mitochondria, tiny organelles that each retains their own DNA, are exquisitely sensitive to environmental insults and are thought to be central players in these pathways. While it is intuitive that mitochondria play an important role in disease processes, given that every cell of our body is dependent on energy metabolism, it is less clear how environmental exposures impact mitochondrial mechanisms that may lead to enhanced risk of disease. Many of the effects of the environment are initiated in utero and integrating mitochondriomics into children's environmental health studies is a critical priority. This review will highlight (i) the importance of exploring environmental mitochondriomics in children's environmental health, (ii) why environmental mitochondriomics is well suited to biomarker development in this context, and (iii) how molecular and epigenetic changes in mitochondria and mitochondrial DNA (mtDNA) may reflect exposures linked to childhood health outcomes. PMID- 26046653 TI - ABA-stimulated SoDOG1 expression is after-ripening inhibited during early imbibition of germinating Sisymbrium officinale seeds. AB - DELAY OF GERMINATION 1 (AtDOG1) was the first gene identified as dormancy associated, but its physiological role in germination is far from being understood. Here, an orthologue of AtDOG1 in Sisymbrium officinale (SoDOG1; KM009050) is being reported. Phylogenetically, the SoDOG1 gene is included into the dicotyledonous group together with DOG1 from Arabidopsis thaliana (EF028470), Brassica rapa (AC189537), Lepidium papillosum (JX512183, JX512185) and Lepidium sativum (GQ411192). The SoDOG1 expression peaked at the onset of the silique maturation stage and there was presence of SoDOG1-mRNA in the freshly collected viable dry seed (i.e. AR0). The SoDOG1 transcripts were also found in other organs, such as open and closed flowers and to a lesser degree in roots and stems. We have previously reported in S. officinale seeds in which sensu stricto germination is positively affected by nitrate and both testa and micropylar endosperm ruptures are temporally separated. In dry viable seeds, the SoDOG1-mRNA level in three different after-ripening (AR) status was AR0 ~ AR7 (optimal AR) < AR27 (optimal AR was almost lost). The presence of nitrate in the AR0 seed imbibition medium markedly decreased the SoDOG1 expression during sensu stricto germination. However, the nitrate stimulated the SoDOG1 expression during imbibition of AR7 compared to AR0. At the early AR0 seed imbibition (3-6 h), exogenous ABA provoked a very strong stimulation of the SoDOG1 expression. AR inhibits ABA-induced SoDOG1 expression during early germination and gibberellins (GA) can partially mimic this AR effect. A view on the integration of all found results in the sensu stricto germination of S. officinale was conducted. PMID- 26046654 TI - Mapping HA-tagged protein at the surface of living cells by atomic force microscopy. AB - Single-molecule force spectroscopy using atomic force microscopy (AFM) is more and more used to detect and map receptors, enzymes, adhesins, or any other molecules at the surface of living cells. To be specific, this technique requires antibodies or ligands covalently attached to the AFM tip that can specifically interact with the protein of interest. Unfortunately, specific antibodies are usually lacking (low affinity and specificity) or are expensive to produce (monoclonal antibodies). An alternative strategy is to tag the protein of interest with a peptide that can be recognized with high specificity and affinity with commercially available antibodies. In this context, we chose to work with the human influenza hemagglutinin (HA) tag (YPYDVPDYA) and labeled two proteins: covalently linked cell wall protein 12 (Ccw12) involved in cell wall remodeling in the yeast Saccharomyces cerevisiae and the beta2-adrenergic receptor (beta2 AR), a G protein-coupled receptor (GPCR) in higher eukaryotes. We first described the interaction between HA antibodies, immobilized on AFM tips, and HA epitopes, immobilized on epoxy glass slides. Using our system, we then investigated the distribution of Ccw12 proteins over the cell surface of the yeast S. cerevisiae. We were able to find the tagged protein on the surface of mating yeasts, at the tip of the mating projections. Finally, we could unfold multimers of beta2-AR from the membrane of living transfected chinese hamster ovary cells. This result is in agreement with GPCR oligomerization in living cell membranes and opens the door to the study of the influence of GPCR ligands on the oligomerization process. PMID- 26046655 TI - Adjustments of the Pesticide Risk Index Used in Environmental Policy in Flanders. AB - Indicators are used to quantify the pressure of pesticides on the environment. Pesticide risk indicators typically require weighting environmental exposure by a no effect concentration. An indicator based on spread equivalents (SigmaSeq) is used in environmental policy in Flanders (Belgium). The pesticide risk for aquatic life is estimated by weighting active ingredient usage by the ratio of their maximum allowable concentration and their soil halflife. Accurate estimates of total pesticide usage in the region are essential in such calculations. Up to 2012, the environmental impact of pesticides was estimated on sales figures provided by the Federal Government. Since 2013, pesticide use is calculated based on results from the Farm Accountancy Data Network (FADN). The estimation of pesticide use was supplemented with data for non-agricultural use based on sales figures of amateur use provided by industry and data obtained from public services. The Seq-indicator was modified to better reflect reality. This method was applied for the period 2009-2012 and showed differences between estimated use and sales figures of pesticides. The estimated use of pesticides based on accountancy data is more accurate compared to sales figures. This approach resulted in a better view on pesticide use and its respective environmental impact in Flanders. PMID- 26046656 TI - Novel Introner-Like Elements in fungi Are Involved in Parallel Gains of Spliceosomal Introns. AB - Spliceosomal introns are key components of the eukaryotic gene structure. Although they contributed to the emergence of eukaryotes, their origin remains elusive. In fungi, they might originate from the multiplication of invasive introns named Introner-Like Elements (ILEs). However, so far ILEs have been observed in six fungal species only, including Fulvia fulva and Dothistroma septosporum (Dothideomycetes), arguing against ILE insertion as a general mechanism for intron gain. Here, we identified novel ILEs in eight additional fungal species that are phylogenetically related to F. fulva and D. septosporum using PCR amplification with primers derived from previously identified ILEs. The ILE content appeared unique to each species, suggesting independent multiplication events. Interestingly, we identified four genes each containing two gained ILEs. By analysing intron positions in orthologues of these four genes in Ascomycota, we found that three ILEs had inserted within a 15 bp window that contains regular spliceosomal introns in other fungal species. These three positions are not the result of intron sliding because ILEs are newly gained introns. Furthermore, the alternative hypothesis of an inferred ancestral gain followed by independent losses contradicts the observed degeneration of ILEs. These observations clearly indicate three parallel intron gains in four genes that were randomly identified. Our findings suggest that parallel intron gain is a phenomenon that has been highly underestimated in ILE-containing fungi, and likely in the whole fungal kingdom. PMID- 26046657 TI - Effects of High Fat Feeding and Diabetes on Regression of Atherosclerosis Induced by Low-Density Lipoprotein Receptor Gene Therapy in LDL Receptor-Deficient Mice. AB - We tested whether a high fat diet (HFD) containing the inflammatory dietary fatty acid palmitate or insulin deficient diabetes altered the remodeling of atherosclerotic plaques in LDL receptor knockout (Ldlr-/-) mice. Cholesterol reduction was achieved by using a helper-dependent adenovirus (HDAd) carrying the gene for the low-density lipoprotein receptor (Ldlr; HDAd-LDLR). After injection of the HDAd-LDLR, mice consuming either HFD, which led to insulin resistance but not hyperglycemia, or low fat diet (LFD), showed regression compared to baseline. However there was no difference between the two groups in terms of atherosclerotic lesion size, or CD68+ cell and lipid content. Because of the lack of effects of these two diets, we then tested whether viral-mediated cholesterol reduction would lead to defective regression in mice with greater hyperglycemia. In both normoglycemic and streptozotocin (STZ)-treated hyperglycemic mice, HDAd LDLR significantly reduced plasma cholesterol levels, decreased atherosclerotic lesion size, reduced macrophage area and lipid content, and increased collagen content of plaque in the aortic sinus. However, reductions in anti-inflammatory and ER stress-related genes were less pronounced in STZ-diabetic mice compared to non-diabetic mice. In conclusion, HDAd-mediated Ldlr gene therapy is an effective and simple method to induce atherosclerosis regression in Ldlr-/- mice in different metabolic states. PMID- 26046660 TI - A Conditional Knockout Mouse Model Reveals That Calponin-3 Is Dispensable for Early B Cell Development. AB - Calponins form an evolutionary highly conserved family of actin filament associated proteins expressed in both smooth muscle and non-muscle cells. Whereas calponin-1 and calponin-2 have already been studied to some extent, little is known about the role of calponin-3 under physiological conditions due to the lack of an appropriate animal model. Here, we have used an unbiased screen to identify novel proteins implicated in signal transduction downstream of the precursor B cell receptor (pre-BCR) in B cells. We find that calponin-3 is expressed throughout early B cell development, localizes to the plasma membrane and is phosphorylated in a Syk-dependent manner, suggesting a putative role in pre-BCR signaling. To investigate this in vivo, we generated a floxed calponin-3-GFP knock-in mouse model that enables tracking of cells expressing calponin-3 from its endogenous promoter and allows its tissue-specific deletion. Using the knock in allele as a reporter, we show that calponin-3 expression is initiated in early B cells and increases with their maturation, peaking in the periphery. Surprisingly, conditional deletion of the Cnn3 revealed no gross defects in B cell development despite this regulated expression pattern and the in vitro evidence, raising the question whether other components may compensate for its loss in lymphocytes. Together, our work identifies calponin-3 as a putative novel mediator downstream of the pre-BCR. Beyond B cells, the mouse model we generated will help to increase our understanding of calponin-3 in muscle and non-muscle cells under physiological conditions. PMID- 26046661 TI - Enhancing bottom-up and top-down proteomic measurements with ion mobility separations. AB - Proteomic measurements with greater throughput, sensitivity, and structural information are essential for improving both in-depth characterization of complex mixtures and targeted studies. While LC separation coupled with MS (LC-MS) measurements have provided information on thousands of proteins in different sample types, the introduction of a separation stage that provides further component resolution and rapid structural information has many benefits in proteomic analyses. Technical advances in ion transmission and data acquisition have made ion mobility separations an opportune technology to be easily and effectively incorporated into LC-MS proteomic measurements for enhancing their information content. Herein, we report on applications illustrating increased sensitivity, throughput, and structural information by utilizing IMS-MS and LC IMS-MS measurements for both bottom-up and top-down proteomics measurements. PMID- 26046662 TI - Somatic Mutations in Catalytic Core of POLK Reported in Prostate Cancer Alter Translesion DNA Synthesis. AB - DNA polymerase kappa is a Y-family polymerase that participates to bypass the damaged DNA known as translesion synthesis (TLS) polymerase. Higher frequency of mutations in DNA polymerase kappa (POLK) recently been reported in prostate cancer. We sequenced entire exons of the POLK gene on genomic DNA from 40 prostate cancers and matched normal samples. We identified that 28% of patients have somatic mutations in the POLK gene of the prostate tumors. Mutations in these prostate cancers have somatic mutation spectra, which are dominated by C-to T transitions. In the current study, we further investigate the effect of p.E29K, p.G154E, p.F155S, p.E430K, p.L442F, and p.E449K mutations on the biochemical properties of the polymerase in vitro, using TLS assay and nucleotide incorporation fidelity, following site-directed mutagenesis bacterial expression, and purification of the respective polymerase variants. We report that following missense mutations p.E29K, p.G154E, p.F155S, p.E430K, and p.L442F significantly diminished the catalytic efficiencies of POLK with regard to the lesion bypass (AP site). POLK variants show extraordinarily low fidelity by misincorporating T, C, and G as compared to wild-type variants. Taken together, these results suggest that interfering with normal polymerase kappa function by these mutations may be involved in prostate carcinogenesis. PMID- 26046663 TI - IL-15 dependent induction of IL-18 secretion as a feedback mechanism controlling human MAIT-cell effector functions. AB - Mucosal-associated invariant T (MAIT) cells are characterized by an invariant TCRValpha7.2 chain recognizing microbial vitamin B metabolites presented by the MHC-Ib molecule MR1. They are mainly detectable in the CD8(+) and CD8(-) CD4(-) "double negative" T-cell compartments of mammals and exhibit both Th1- and Th17 associated features. As MAIT cells show a tissue-homing phenotype and operate at mucosal surfaces with myriads of pathogenic encounters, we wondered how IL-15, a multifaceted cytokine being part of the intestinal mucosal barrier, impacts on their functions. We demonstrate that in the absence of TCR cross-linking, human MAIT cells secrete IFN-gamma, increase perforin expression and switch on granzyme B production in response to IL-15. As this mechanism was dependent on the presence of CD14(+) cells and sensitive to IL-18 blockade, we identified IL-15 induced IL-18 production by monocytes as an inflammatory, STAT5-dependent feedback mechanism predominantly activating the MAIT-cell population. IL-15 equally affects TCR-mediated MAIT-cell functions since it dramatically amplifies bacteria-induced IFN-gamma secretion, granzyme production, and cytolytic activity at early time points, an effect being most pronounced under suboptimal TCR stimulation conditions. Our data reveal a new quality of IL-15 as player in an inflammatory cytokine network impacting on multiple MAIT-cell functions. PMID- 26046664 TI - Synthetic Long Peptide Influenza Vaccine Containing Conserved T and B Cell Epitopes Reduces Viral Load in Lungs of Mice and Ferrets. AB - Currently licensed influenza vaccines mainly induce antibodies against highly variable epitopes. Due to antigenic drift, protection is subtype or strain specific and regular vaccine updates are required. In case of antigenic shifts, which have caused several pandemics in the past, completely new vaccines need to be developed. We set out to develop a vaccine that provides protection against a broad range of influenza viruses. Therefore, highly conserved parts of the influenza A virus (IAV) were selected of which we constructed antibody and T cell inducing peptide-based vaccines. The B epitope vaccine consists of the highly conserved HA2 fusion peptide and M2e peptide coupled to a CD4 helper epitope. The T epitope vaccine comprises 25 overlapping synthetic long peptides of 26-34 amino acids, thereby avoiding restriction for a certain MHC haplotype. These peptides are derived from nucleoprotein (NP), polymerase basic protein 1 (PB1) and matrix protein 1 (M1). C57BL/6 mice, BALB/c mice, and ferrets were vaccinated with the B epitopes, 25 SLP or a combination of both. Vaccine-specific antibodies were detected in sera of mice and ferrets and vaccine-specific cellular responses were measured in mice. Following challenge, both mice and ferrets showed a reduction of virus titers in the lungs in response to vaccination. Summarizing, a peptide based vaccine directed against conserved parts of influenza virus containing B and T cell epitopes shows promising results for further development. Such a vaccine may reduce disease burden and virus transmission during pandemic outbreaks. PMID- 26046665 TI - Isolated Short Fetal Femur Length in the Second Trimester and the Association with Adverse Perinatal Outcome: Experiences from a Tertiary Referral Center. AB - OBJECTIVE: To determine the association between isolated mid-trimester short fetal femur length and adverse perinatal outcome. METHODS: This is a retrospective cohort study of patients with singleton gestations routinely assessed by second trimester ultrasound examination during 2006-2013. A fetal isolated short femur was defined as a femur length (FL) below the 5th percentile in a fetus with an abdominal circumference greater than the 10th percentile. Cases of aneuploidy, skeletal dysplasia and major anomalies were excluded. Primary outcomes of interest included the risk of small for gestational age neonates, low birth weight and preterm birth (PTB). Secondary outcome parameters were a 5-min Apgar score less than 7 and a neonatal intensive care unit admission. A control group of 200 fetuses with FL >= 5th percentile was used to compare primary and secondary outcome parameters within both groups. Chi-square and Student's t-tests were used where appropriate. RESULTS: Out of 608 eligible patients with a short FL, 117 met the inclusion criteria. Isolated short FL was associated with an increased risk for small for gestational age (19.7% versus 8.0%, p = 0.002) neonates, low birth weight (23.9% versus 8.5%, p<0.001), PTB (19.7% versus 6.0%, p<0.001) and neonatal intensive care unit admissions (13.7% versus 3.5%, p = 0.001). The incidence of a 5-min Apgar score less than 7 was similar in both groups. CONCLUSION: Isolated short FL is associated with a subsequent delivery of small for gestational age and Low birth weight neonates as well as an increased risk for PTB. This information should be considered when counseling patients after mid-trimester isolated short FL is diagnosed. PMID- 26046666 TI - Values of the Minimal Clinically Important Difference for the Neuropsychiatric Inventory Questionnaire in Individuals with Dementia. AB - OBJECTIVES: To estimate the minimal clinically important difference (MCID) for the Neuropsychiatric Inventory Questionnaire (NPI-Q), a widely used measure of behavioral and psychological symptoms of dementia (BPSDs) and associated caregiver stress. DESIGN: Ten registered nurses rated the severity of BPSDs and caregiver distress using the NPI-Q during six monthly assessments and an external reference, a 7-point Likert-type global rating of BPSDs change during five monthly assessments from the second to the sixth month. An anchor-based (global ratings of change) approach and a distribution-based (standard error of measurement) approach were used to determine the MCID for the NPI-Q severity and distress subscales. SETTING: Long-term care facility. PARTICIPANTS: Nonbedridden residents with dementia (n = 45) and registered nurses (n = 10). MEASUREMENTS: NPI-Q (severity and caregiver distress subscales) and global ratings of changes in BPSDs on a 7-point Likert-type scale. RESULTS: The NPI-Q MCID ranges were 2.77 to 3.18 for severity and 3.10 to 3.95 for distress. Residents in the highest NPI Q tertile at baseline had higher MCID severity (3.62) and distress (5.08) scores than those in the lowest tertile (severity (2.40), distress (3.10)). CONCLUSION: This study provides an estimate of the MCID for severity and distress subscales of the NPI-Q, which can help clinicians and researchers determine whether NPI-Q change scores within a group of individuals with dementia are beyond measurement error and are clinically important. PMID- 26046667 TI - Alanine aminotransferase and mortality in patients with type 2 diabetes (ZODIAC 38). AB - INTRODUCTION: Combined data suggest a bimodal association of alanine aminotransferase (ALT) with mortality in the general population. Little is known about the association of ALT with mortality in patients with type 2 diabetes. We therefore investigated the association of ALT with all-cause, cardiovascular and noncardiovascular mortality in patients with type 2 diabetes. DESIGN: A prospective study was performed in patients with type 2 diabetes, treated in primary care, participating in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) study. Cox regression analyses were performed to determine the associations of log2 -transformed baseline ALT with all-cause, cardiovascular and noncardiovascular mortality. RESULTS: In 1187 patients with type 2 diabetes (67 +/- 12 years, 45% female), ALT levels were 11 (8-16) U/L. During median follow-up for 11.1 (6.1-14.0) years, 553 (47%) patients died, with 238 (20%) attributable to cardiovascular causes. Overall, ALT was inversely associated with all-cause mortality (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.72-0.92), independently of potential confounders. This was less attributable to cardiovascular mortality (HR 0.87; 95% CI 0.72-1.05), than to noncardiovascular mortality (HR 0.77; 95% CI 0.65-0.90). Despite the overall inverse association of ALT with mortality, it appeared that a bimodal association with all-cause mortality was present with increasing risk for levels of ALT above normal (P = 0.003). DISCUSSION: In patients with type 2 diabetes, low levels of ALT are associated with an increased risk of all-cause mortality, in particular noncardiovascular mortality, compared to normal levels of ALT, while risk again starts to increase when levels are above normal. PMID- 26046668 TI - Printed Flexible Plastic Microchip for Viral Load Measurement through Quantitative Detection of Viruses in Plasma and Saliva. AB - We report a biosensing platform for viral load measurement through electrical sensing of viruses on a flexible plastic microchip with printed electrodes. Point of-care (POC) viral load measurement is of paramount importance with significant impact on a broad range of applications, including infectious disease diagnostics and treatment monitoring specifically in resource-constrained settings. Here, we present a broadly applicable and inexpensive biosensing technology for accurate quantification of bioagents, including viruses in biological samples, such as plasma and artificial saliva, at clinically relevant concentrations. Our microchip fabrication is simple and mass-producible as we print microelectrodes on flexible plastic substrates using conductive inks. We evaluated the microchip technology by detecting and quantifying multiple Human Immunodeficiency Virus (HIV) subtypes (A, B, C, D, E, G, and panel), Epstein-Barr Virus (EBV), and Kaposi's Sarcoma-associated Herpes Virus (KSHV) in a fingerprick volume (50 uL) of PBS, plasma, and artificial saliva samples for a broad range of virus concentrations between 10(2) copies/mL and 10(7) copies/mL. We have also evaluated the microchip platform with discarded, de-identified HIV-infected patient samples by comparing our microchip viral load measurement results with reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) as the gold standard method using Bland-Altman Analysis. PMID- 26046669 TI - Multi-dimensional TOF-SIMS analysis for effective profiling of disease-related ions from the tissue surface. AB - Time-of-flight secondary ion mass spectrometry (TOF-SIMS) emerges as a promising tool to identify the ions (small molecules) indicative of disease states from the surface of patient tissues. In TOF-SIMS analysis, an enhanced ionization of surface molecules is critical to increase the number of detected ions. Several methods have been developed to enhance ionization capability. However, how these methods improve identification of disease-related ions has not been systematically explored. Here, we present a multi-dimensional SIMS (MD-SIMS) that combines conventional TOF-SIMS and metal-assisted SIMS (MetA-SIMS). Using this approach, we analyzed cancer and adjacent normal tissues first by TOF-SIMS and subsequently by MetA-SIMS. In total, TOF- and MetA-SIMS detected 632 and 959 ions, respectively. Among them, 426 were commonly detected by both methods, while 206 and 533 were detected uniquely by TOF- and MetA-SIMS, respectively. Of the 426 commonly detected ions, 250 increased in their intensities by MetA-SIMS, whereas 176 decreased. The integrated analysis of the ions detected by the two methods resulted in an increased number of discriminatory ions leading to an enhanced separation between cancer and normal tissues. Therefore, the results show that MD-SIMS can be a useful approach to provide a comprehensive list of discriminatory ions indicative of disease states. PMID- 26046671 TI - Bessel beam CARS of axially structured samples. AB - We report about a Bessel beam CARS approach for axial profiling of multi-layer structures. This study presents an experimental implementation for the generation of CARS by Bessel beam excitation using only passive optical elements. Furthermore, an analytical expression is provided describing the generated anti Stokes field by a homogeneous sample. Based on the concept of coherent transfer functions, the underling resolving power of axially structured geometries is investigated. It is found that through the non-linearity of the CARS process in combination with the folded illumination geometry continuous phase-matching is achieved starting from homogeneous samples up to spatial sample frequencies at twice of the pumping electric field wave. The experimental and analytical findings are modeled by the implementation of the Debye Integral and scalar Green function approach. Finally, the goal of reconstructing an axially layered sample is demonstrated on the basis of the numerically simulated modulus and phase of the anti-Stokes far-field radiation pattern. PMID- 26046670 TI - BEX1 acts as a tumor suppressor in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease of the myeloid lineage. About 35% of AML patients carry an oncogenic FLT3 mutant making FLT3 an attractive target for treatment of AML. Major problems in the development of FLT3 inhibitors include lack of specificity, poor response and development of a resistant phenotype upon treatment. Further understanding of FLT3 signaling and discovery of novel regulators will therefore help to determine additional pharmacological targets in FLT3-driven AML. In this report, we identified BEX1 as a novel regulator of oncogenic FLT3-ITD-driven AML. We showed that BEX1 expression was down-regulated in a group of AML patients carrying FLT3-ITD. Loss of BEX1 expression resulted in poor overall survival (hazard ratio, HR = 2.242, p = 0.0011). Overexpression of BEX1 in mouse pro-B and myeloid cells resulted in decreased FLT3-ITD-dependent cell proliferation, colony and tumor formation, and in increased apoptosis in vitro and in vivo. BEX1 localized to the cytosolic compartment of cells and significantly decreased FLT3-ITD-induced AKT phosphorylation without affecting ERK1/2 or STAT5 phosphorylation. Our data suggest that the loss of BEX1 expression in FLT3-ITD driven AML potentiates oncogenic signaling and leads to decreased overall survival of the patients. PMID- 26046672 TI - Structural Induction Effect of a Zwitterion Pyridiniumolate for Metal-Organic Frameworks. AB - It is still an enormous challenge to obtain the metal-organic frameworks (MOFs) with specific properties by tuning their structures. Here we first reported that the structures of MOFs could be tuned by adding certain amount of zwitterion pyridiniumolate. To demonstrate the inductive effect, two series of assembly experiments were performed using different metal ions, namely, Cd(II) and Mn(II). The experimental results revealed that the zwitterion pyridiniumloate only acted as a structural induction agent (SIA), which did not exist in the aimed compounds. The SIAs could effectively tune the framework aperture or promote coordination and further tune the properties of MOFs without any removal or exchange after the synthesis. Therefore, the results could not only immensely expand the syntheses and structural diversity of MOFs with the fixed metal ions and organic ligands but also afford the possibility and effective convenience for tuning the properties of MOFs in the functional material research fields. PMID- 26046673 TI - A double-edged sword: Benefits and pitfalls of heterogeneous punishment in evolutionary inspection games. AB - As a simple model for criminal behavior, the traditional two-strategy inspection game yields counterintuitive results that fail to describe empirical data. The latter shows that crime is often recurrent, and that crime rates do not respond linearly to mitigation attempts. A more apt model entails ordinary people who neither commit nor sanction crime as the third strategy besides the criminals and punishers. Since ordinary people free-ride on the sanctioning efforts of punishers, they may introduce cyclic dominance that enables the coexistence of all three competing strategies. In this setup ordinary individuals become the biggest impediment to crime abatement. We therefore also consider heterogeneous punisher strategies, which seek to reduce their investment into fighting crime in order to attain a more competitive payoff. We show that this diversity of punishment leads to an explosion of complexity in the system, where the benefits and pitfalls of criminal behavior are revealed in the most unexpected ways. Due to the raise and fall of different alliances no less than six consecutive phase transitions occur in dependence on solely the temptation to succumb to criminal behavior, leading the population from ordinary people-dominated across punisher dominated to crime-dominated phases, yet always failing to abolish crime completely. PMID- 26046676 TI - Technical note: Development of Hemipyrellia ligurriens (Wiedemann) (Diptera: Calliphoridae) at constant temperatures: Applications in estimating postmortem interval. AB - Blowflies (Calliphoridae) are recognized as a powerful tool for estimating the minimum postmortem interval (PMImin). The times for blowflies to develop from oviposition to eclosion is mainly controlled by temperature, which can differ between even closely related species. Hemipyrellia ligurriens (Wiedemann) (Diptera: Calliphoridae) is a blowfly distributed throughout Asia and Australia. However, a systematic determination of the developmental times of H. ligurriens under constant temperature, necessary for estimating the PMImin, is lacking. Such an examination would broaden the forensic importance of the species. Thus, this study explored the growth curves of larval H. ligurriens at 7 constant temperatures (16, 19, 22, 25, 28, 31, and 34 degrees C). Isomegalen and isomorphen diagrams were successfully constructed, depicting the time of larval length or developmental event, respectively, at different temperatures. A thermal summation model was also constructed via regression analysis, by estimating the developmental threshold temperature t and thermal summation constant K. The thermal summation model indicated that t at 8.3 degrees C and K at 5747.5 degree hours ( degrees Ch) are required for complete development from oviposition to eclosion, and suggested an optimum temperature range of 16-28 degrees C for the development of H. ligurriens. These data establish for the first time the temperature-dependent developmental time of H. ligurriens for forensic entomology application. The 3 developmental models are provided. PMID- 26046674 TI - EGCG regulates the cross-talk between JWA and topoisomerase IIalpha in non-small cell lung cancer (NSCLC) cells. AB - (-)-epigallocatechin-3-gallate (EGCG) is a well-known cancer chemopreventive agent. The potential mechanisms include regulation of multiple molecules. Carcinogenesis in lung cancer is related to the imbalance of tumor suppressor and oncogene. JWA is a structurally novel microtubule-binding protein and is a potential tumor suppressor. DNA topoisomerase IIalpha is a nuclear enzyme that governs DNA topology and is usually highly expressed in many types of cancer. It serves as a target of anticancer drugs. In the current study, the regulation of JWA and topoisomerase IIalpha by EGCG, and thereafter the mutual interaction between them was investigated. The results revealed that EGCG up-regulated JWA while decreased topoisomerase IIalpha expression in both human non-small cell lung cancer (NSCLC) cells and an NSCLC xenograft mice model. There was a negative correlation between JWA and topoisomerase IIalpha in NSCLC as well as in human NSCLC tissue specimens. Topoisomerase IIalpha overexpression reduced JWA at the translational level. Meanwhile, JWA-induced topoisomerase IIalpha degradation was regulated both in the transcriptional and post-translational level. Interestingly, JWA and topoisomerase IIalpha regulated each other in the cells arrested in G2/M. Furthermore, JWA and topoisomerase IIalpha synergistically affected NCI-H460 cells invasion. These results may serve a novel mechanism for cancer prevention. PMID- 26046675 TI - Resveratrol Enhances Etoposide-Induced Cytotoxicity through Down-Regulating ERK1/2 and AKT-Mediated X-ray Repair Cross-Complement Group 1 (XRCC1) Protein Expression in Human Non-Small-Cell Lung Cancer Cells. AB - Etoposide (VP-16), a topoisomerase II inhibitor, is an effective anti-cancer drug used for the treatment of non-small-cell lung cancer (NSCLC). Resveratrol is a naturally occurring polyphenolic compound that has been proved to have anti cancer activity. XRCC1 is an important scaffold protein involved in base excision repair that is regulated by ERK1/2 and AKT signals and plays an important role in the development of lung cancer. However, the role of ERK1/2 and AKT-mediated XRCC1 expression in etoposide treatment alone or combined with resveratrol induced cytotoxicity in NSCLC cells has not been identified. In this study, etoposide treatment increased XRCC1 mRNA and protein expression through AKT and ERK1/2 activation in two NSCLC cells, H1703 and H1975. Knockdown of XRCC1 in NSCLC cells by transfection of XRCC1 siRNA or inactivation of ERK1/2 and AKT resulted in enhancing cytotoxicity and cell growth inhibition induced by etoposide. Resveratrol inhibited the expression of XRCC1 and enhanced the etoposide-induced cell death and anti-proliferation effect in NSCLC cells. Furthermore, transfection with constitutive active MKK1 or AKT vectors could rescue the XRCC1 protein level and also the cell survival suppressed by co treatment with etoposide and resveratrol. These findings suggested that down regulation of XRCC1 expression by resveratrol can enhance the chemosensitivity of etoposide in NSCLC cells. PMID- 26046677 TI - Improvement in fingerprint detection using Tb(III)-dipicolinic acid complex doped nanobeads and time resolved imaging. AB - This paper deals with the synthesis and application of lanthanide complex doped nanobeads used as a luminescent fingerprint powder. Due to their special optical properties, namely a long emission lifetime, sharp emission profiles and large Stokes shifts, luminescent lanthanide complexes are useful for discriminating against signals from background emissions. This is a big advantage because latent fingerprints placed on multicoloured fluorescent surfaces are difficult to develop with conventional powders. The complex of 2,6-dipicolinic acid (DPA) and terbium ([Tb(DPA)3](3-)) is used for this purpose. Using the Stober process, this complex is incorporated into a silica matrix forming nanosized beads (230-630nm). It is shown that the [Tb(DPA)3](3-) is successfully incorporated into the beads and that these beads exhibit the wanted optical properties of the complex. A phenyl functionalisation is applied to increase the lipophilicity of the beads and finally the beads are used to develop latent fingerprints. A device for time resolved imaging was built to improve the contrast between developed fingerprint and different background signals, whilst still detecting the long lasting luminescence of the complex. The developed fingerprint powder is therefore promising to develop fingerprints on multicoloured fluorescent surfaces. PMID- 26046678 TI - Bathtub drowning: An 11-year retrospective study in the state of Maryland. AB - A bathtub drowning is one of the leading causes of death in a bathtub. The purpose of this study was to evaluate how reliable the drowning-related signs could be for identifying a bathtub drowning in the cases of death in the bathtub. Performing a retrospective review of 92 deaths in the bathtub in Maryland, 71.7 percent were the presence of bathtub drowning and 28.3 percent were the absence of bathtub drowning. Three leading contributory causes of death were cardiovascular disease, drug/alcohol-related death, and seizure disorder in both groups. There was a statistically significant difference between the groups in relation to a history of recovery from the water (95.5% and 38.4%, p<0.001), foam in the air way (33.3% and 15.4%, p<0.05), watery fluid in the sphenoid sinuses (81.8% and 11.5%, p<0.05), hyperinflated lungs (36.4% and 3.8%, p<0.01), and watery fluid in the stomach contents (40.9% and 3.8%, p<0.01). More than triple overlapped drowning-related signs could be beneficial for the diagnosis of a bathtub drowning. A comprehensive investigation incorporating a thorough scene investigation, gathering of the victim's medical and psychosocial history, and a meticulous full autopsy is necessary to elucidate both the cause and manner of death in these cases of death in the bathtub. PMID- 26046679 TI - Detection of gene annotations and protein-protein interaction associated disorders through transitive relationships between integrated annotations. AB - BACKGROUND: Increasingly high amounts of heterogeneous and valuable controlled biomolecular annotations are available, but far from exhaustive and scattered in many databases. Several annotation integration and prediction approaches have been proposed, but these issues are still unsolved. We previously created a Genomic and Proteomic Knowledge Base (GPKB) that efficiently integrates many distributed biomolecular annotation and interaction data of several organisms, including 32,956,102 gene annotations, 273,522,470 protein annotations and 277,095 protein-protein interactions (PPIs). RESULTS: By comprehensively leveraging transitive relationships defined by the numerous association data integrated in GPKB, we developed a software procedure that effectively detects and supplement consistent biomolecular annotations not present in the integrated sources. According to some defined logic rules, it does so only when the semantic type of data and of their relationships, as well as the cardinality of the relationships, allow identifying molecular biology compliant annotations. Thanks to controlled consistency and quality enforced on data integrated in GPKB, and to the procedures used to avoid error propagation during their automatic processing, we could reliably identify many annotations, which we integrated in GPKB. They comprise 3,144 gene to pathway and 21,942 gene to biological function annotations of many organisms, and 1,027 candidate associations between 317 genetic disorders and 782 human PPIs. Overall estimated recall and precision of our approach were 90.56 % and 96.61 %, respectively. Co-functional evaluation of genes with known function showed high functional similarity between genes with new detected and known annotation to the same pathway; considering also the new detected gene functional annotations enhanced such functional similarity, which resembled the one existing between genes known to be annotated to the same pathway. Strong evidence was also found in the literature for the candidate associations detected between Cystic fibrosis disorder and the PPIs between the CFTR_HUMAN, DERL1_HUMAN, RNF5_HUMAN, AHSA1_HUMAN and GOPC_HUMAN proteins, and between the CHIP_HUMAN and HSP7C_HUMAN proteins. CONCLUSIONS: Although identified gene annotations and PPI-genetic disorder candidate associations require biological validation, our approach intrinsically provides their in silico evidence based on available data. Public availability within the GPKB (http://www.bioinformatics.deib.polimi.it/GPKB/) of all identified and integrated annotations offers a valuable resource fostering new biomedical-molecular knowledge discoveries. PMID- 26046681 TI - Salivary Immunosuppressive Cytokines IL-10 and IL-13 Are Significantly Elevated in Oral Squamous Cell Carcinoma Patients. AB - Oral squamous cell carcinoma (OSCC) is considered to be one of the most fatal diseases worldwide, owing to its late diagnosis and lack of availability of established reliable biomarkers. The aim of this study was to highlight the significance of immunosuppressive cytokines as potential biomarkers in OSCC. Whole unstimulated saliva was collected from each individual (30 OSCC patients and 33 age- and gender-matched healthy controls). Immunosuppressive cytokines, including IL-4, IL-10, IL-13, and IL-1RA, were evaluated in each sample using Luminex multianalyte profiling (xMAP) technology on BioPlex instrument. Our results showed that all the studied salivary cytokines were raised in OSCC patients as compared to controls, where IL-10 and IL-13 salivary levels showed statistically significant difference (p = .004 and p = .010, respectively). Mean levels of salivary cytokines in three histologically defined OSCC categories, compared employing one-way ANOVA, showed that salivary levels of IL-1RA were highest in patients having poorly differentiated OSCC tumors as compared to those having moderately and well-differentiated tumors (p = .000 and p = .002, respectively). Among OSCC individuals, duration of smokeless tobacco correlated positively with IL-1RA (p = .036). We conclude that salivary levels of immunosuppressive cytokines, IL-4, IL-10, IL-13, and IL-1RA, could prove to be potential biomarkers of OSCC and can be further investigated as markers of early detection and disease progression. PMID- 26046682 TI - A mutation in Escherichia coli ftsZ bypasses the requirement for the essential division gene zipA and confers resistance to FtsZ assembly inhibitors by stabilizing protofilament bundling. AB - The earliest step in Escherichia coli cell division consists of the assembly of FtsZ protein into a proto-ring structure, tethered to the cytoplasmic membrane by FtsA and ZipA. The proto-ring then recruits additional cell division proteins to form the divisome. Previously we described an ftsZ allele, ftsZL169R , which maps to the side of the FtsZ subunit and confers resistance to FtsZ assembly inhibitory factors including Kil of bacteriophage lambda. Here we further characterize this allele and its mechanism of resistance. We found that FtsZL169R permits the bypass of the normally essential ZipA, a property previously observed for FtsA gain-of-function mutants such as FtsA* or increased levels of the FtsA interacting protein FtsN. Similar to FtsA*, FtsZL169R also can partially suppress thermosensitive mutants of ftsQ or ftsK, which encode additional divisome proteins, and confers strong resistance to excess levels of FtsA, which normally inhibit FtsZ ring function. Additional genetic and biochemical assays provide further evidence that FtsZL169R enhances FtsZ protofilament bundling, thereby conferring resistance to assembly inhibitors and bypassing the normal requirement for ZipA. This work highlights the importance of FtsZ protofilament bundling during cell division and its likely role in regulating additional divisome activities. PMID- 26046684 TI - Endothelial nitric oxide synthase Glu298Asp gene polymorphism influences body composition and biochemical parameters but not the nitric oxide response to eccentric resistance exercise in elderly obese women. AB - Both endothelial nitric oxide synthase (eNOS) gene polymorphism and nitric oxide (NO) are involved in important cardiovascular, muscular and inflammatory physiological mechanisms during ageing and response to exercise. The aim of this study was to investigate the NO kinetic response following an acute eccentric resistance exercise (ERE) session and the possible effect of the Glu298Asp eNOS gene polymorphism in elderly obese women. Eighty-seven women (age 69.4 +/- 6.1 years, body weight 74.9 +/- 12.7 kg, height 151.9 +/- 6.0 cm and BMI 32.5 +/- 5.7 kg m-2 ) completed seven sets of ten eccentric repetitions at 110% of the ten repetitions maximum (10RM). NO concentrations remained elevated up to 48 h following the acute ERE session as compared with baseline, for GG and GT/TT groups (P<0.05), with no differences between genotypes. The GG genotype group had higher body weight, prevalence of obesity (BMI classification - 81% versus 56%), BMI and higher relative muscle strength, while they had significantly lower triglycerides, VLDL and urea concentrations as compared with TT/TG group. In conclusion, NO remains elevated for up to 48 h after an acute ERE session, without genotype interaction. The TT/TG genotype had a negative impact on triglycerides, VLDL and urea concentrations. Thus, T carriers should increase their attention to cardiovascular risk factor and metabolic disorders. PMID- 26046683 TI - Large-Scale Conformational Transitions and Dimerization Are Encoded in the Amino Acid Sequences of Hsp70 Chaperones. AB - Hsp70s are a class of ubiquitous and highly conserved molecular chaperones playing a central role in the regulation of proteostasis in the cell. Hsp70s assist a myriad of cellular processes by binding unfolded or misfolded substrates during a complex biochemical cycle involving large-scale structural rearrangements. Here we show that an analysis of coevolution at the residue level fully captures the characteristic large-scale conformational transitions of this protein family, and predicts an evolutionary conserved-and thus functional-homo dimeric arrangement. Furthermore, we highlight that the features encoding the Hsp70 dimer are more conserved in bacterial than in eukaryotic sequences, suggesting that the known Hsp70/Hsp110 hetero-dimer is a eukaryotic specialization built on a pre-existing template. PMID- 26046685 TI - Carbon Nanotube-Based Supercapacitors with Excellent ac Line Filtering and Rate Capability via Improved Interfacial Impedance. AB - We report the fabrication of high-performance, self-standing composite sp(2) carbon supercapacitor electrodes using single-walled carbon nanotubes (CNTs) as conductive binder. The 3-D mesoporous mesh architecture of CNT-based composite electrodes grants unimpaired ionic transport throughout relatively thick films and allows superior performance compared to graphene-based devices at an ac line frequency of 120 Hz. Metrics of 601 MUF/cm(2) with a -81 degrees phase angle and a rate capability (RC) time constant of 199 MUs are obtained for thin carbon films. The free-standing carbon films were obtained from a chlorosulfonic acid dispersion and interfaced to stainless steel current collectors with various surface treatments. CNT electrodes were able to cycle at 200 V/s and beyond, still showing a characteristic parallelepipedic cyclic votammetry shape at 1 kV/s. Current densities are measured in excess of 6400 A/g, and the electrodes retain more than 98% capacity after 1 million cycles. These promising results are attributed to a reduction of series resistance in the film through the CNT conductive network and especially to the surface treatment of the stainless steel current collector. PMID- 26046686 TI - Ab Initio Search for Global Minimum Structures of Pure and Boron Doped Silver Clusters. AB - The global minimum structures of pure and boron doped silver clusters up to 16 atoms are determined through ab initio calculations and unbiased structure searching methods. The structural and electronic properties of neutral, anionic, and cationic Ag(n)B (n <= 15) and Ag(n)B2 (n <= 14) clusters are much distinct from those of the corresponding pure silver. Considering that Ag and B possess one and three valence electrons, respectively, both the single and the double boron-atom doped silver clusters with even number of valence electrons are more stable than those with odd number of electrons, a feature also observed in the pure silver clusters. We demonstrate that the species with a valence count of 8 and 14 appear to be magic numbers with enhanced stability irrespective of component or the charged state. A new putative global minimum structure of Ag13( ) cluster, with high symmetry of C(2v), is unexpectedly observed as the ground state, which is lower in energy than the previous suggested bilayer structure. PMID- 26046688 TI - Crystalline-Amorphous Silicon Nanocomposites with Reduced Thermal Conductivity for Bulk Thermoelectrics. AB - Responding to the need for thermoelectric materials with high efficiency in both conversion and cost, we developed a nanostructured bulk silicon thermoelectric materials by sintering silicon crystal quantum dots of several nanometers in diameters synthesized by plasma-enhanced chemical vapor deposition (PECVD). The material consists of hybrid structures of nanograins of crystalline silicon and amorphous silicon oxide. The percolated nanocrystalline region gives rise to high power factor with the high doping concentration realized by PECVD, and the binding amorphous region reduces thermal conductivity. Consequently, the nondimensional figure of merit reaches 0.39 at 600 degrees C, equivalent to the best reported value for silicon thermoelectrics. The thermal conductivity of the densely packed material is as low as 5 W m(-1) K(-1) in a wide temperature range from room temperature to 1000 degrees C, which is beneficial not only for the conversion efficiency but also for material cost by requiring less material to establish certain temperature gradient. PMID- 26046687 TI - Psoriatic T cells reduce epidermal turnover time and affect cell proliferation contributed from differential gene expression. AB - Psoriasis is mediated primarily by T cells, which reduce epidermal turnover time and affect keratinocyte proliferation. We aimed to identify differentially expressed genes (DEG) in T cells from normal, five pairs of monozygotic twins concordant or discordant for psoriasis, to determine whether these DEG may account for the influence to epidermal turnover time and keratinocyte proliferation. The impact of T cells on keratinocyte proliferation and epidermal turnover time were investigated separately by immunohistochemistry and cultured with (3) H-TdR. mRNA expression patterns were investigated by RNA sequencing and verified by real-time reverse transcription polymerase chain reaction. After co culture with psoriatic T cells, the expression of Ki-67, c-Myc and p53 increased, while expression of Bcl-2 and epidermal turnover time decreased. There were 14 DEG which were found to participate in the regulation of cell proliferation or differentiation. Psoriatic T cells exhibited the ability to decrease epidermal turnover time and affect keratinocyte proliferation because of the differential expression of PPIL1, HSPH1, SENP3, NUP54, FABP5, PLEKHG3, SLC9A9 and CHCHD4. PMID- 26046689 TI - Relationship between ventricular size, white matter injury, and neurocognition in children with stable, treated hydrocephalus. AB - OBJECT: Larger-than-normal ventricles can persist in children following hydrocephalus treatment, even if they are asymptomatic and clinically well. This study aims to answer the following question: do large ventricles result in brain injuries that are detectable on diffusion tensor imaging (DTI) and/or in measurable neurocognitive deficits in children with stable, treated hydrocephalus that are not seen in children with small ventricles? METHODS: For this prospective study, we recruited 23 children (age range 8-18 years) with hydrocephalus due to aqueductal stenosis or tectal glioma who were asymptomatic following hydrocephalus treatment that had been performed at least 2 years earlier. All patients underwent detailed DTI and a full battery of neuropsychological tests. Correlation analysis was performed to assess the relationship between DTI parameters, neurocognitive tests, and ventricular size. The false-discovery rate method was used to adjust for multiple comparisons. RESULTS: The median age of these 23 children at the time of assessment was 15.0 years (interquartile range [IQR] 12.1-17.6 years), and the median age at the first hydrocephalus treatment was 5.8 years (IQR 2.2 months-12.8 years). At the time of assessment, 17 children had undergone endoscopic third ventriculostomy and 6 children had received a shunt. After adjusting for multiple comparisons, there were no significant correlations between any neurocognitive test and ventricular volume, any DTI parameter and ventricular volume, or any DTI parameter and neurocognitive test. CONCLUSIONS: Our data do not show an association between large ventricular size and additional white matter injury or worse neurocognitive deficits in asymptomatic children with stable, treated hydrocephalus caused by a discrete blockage of the cerebral aqueduct. Further investigations using larger patient samples are needed to validate these results. PMID- 26046690 TI - Baclofen pump catheter leakage after migration of the abdominal catheter in a pediatric patient with spasticity. AB - The authors report an unusual case of intrathecal baclofen withdrawal due to the perforation and subsequent leakage of a baclofen pump catheter in a patient with spastic cerebral palsy. A 15-year-old boy underwent an uncomplicated placement of an intrathecal baclofen pump for the treatment of spasticity due to cerebral palsy. After excellent control of symptoms for 3 years, the patient presented to the emergency department with increasing tremors following a refill of his baclofen pump. Initial evaluation consisted of radiographs of the pump and catheter, which appeared normal, and a successful aspiration of CSF from the pump's side port. A CT dye study revealed a portion of the catheter directly overlying the refill port and extravasation of radiopaque dye into the subfascial pocket anterior to the pump. During subsequent revision surgery, a small puncture hole in the catheter was seen to be leaking the drug. The likely cause of the puncture was an inadvertent perforation of the catheter by a needle during the refilling of the pump. This case report highlights a unique complication in a patient with an intrathecal baclofen pump. Physicians caring for these patients should be aware of this rare yet potential complication in patients presenting with baclofen withdrawal symptoms. PMID- 26046691 TI - Progressive postnatal pansynostosis: an insidious and pernicious form of craniosynostosis. AB - OBJECT Progressive postnatal pansynostosis (PPP) is a rare form of craniosynostosis that is characterized by a normal head shape, insidious decrease in percentile head circumference, and high rates of elevated intracranial pressure (ICP). This investigation describes the clinical, radiographic, and genetic features of this entity. METHODS The authors' craniofacial database for the period 1997-2013 was retrospectively culled to identify patients who had a normal or near-normal head shape and CT-confirmed multiple-suture synostosis. Patients with kleeblatt-schadel or previous craniofacial surgery were excluded. All demographic information was collected and analyzed. RESULTS Seventeen patients fit the inclusion criteria. Nine patients had a syndromic diagnosis: Crouzon syndrome (n = 4), Pfeiffer syndrome (n = 2), Saethre-Chotzen syndrome (n = 1), Apert syndrome (n = 1), and achondroplasia (n = 1). With the exception of 3 patients with mild turricephaly, all patients had a relatively normal head shape. Patients were diagnosed at an average age of 62.9 months. Nearly all patients had some combination of clinical, radiographic, or ophthalmological evidence of increased ICP. CONCLUSIONS PPP is insidious; diagnosis is typically delayed because the clinical signs are subtle and appear gradually. All normocephalic infants or children with a known or suspected craniosynostotic disorder should be carefully monitored; any decrease in percentile head circumference or signs/symptoms of increased ICP should prompt CT evaluation. PMID- 26046692 TI - In vitro 3-dimensional tumor model for radiosensitivity of HPV positive OSCC cell lines. AB - The incidence of oropharyngeal squamous cell carcinoma (OSCC) is increasing due to the rising prevalence of human papillomavirus (HPV) positive OSCC. HPV positive OSCC is associated with better outcomes than HPV negative OSCC. Our aim was to explore the possibility that this favorable prognosis is due to the enhanced radiosensitivity of HPV positive OSCC. HPV positive OSCC cell lines were generated from the primary OSCCs of 2 patients, and corresponding HPV positive cell lines generated from nodal metastases following xenografting in nude mice. Monolayer and 3 dimensional (3D) culture techniques were used to compare the radiosensitivity of HPV positive lines with that of 2 HPV negative OSCC lines. Clonogenic and protein assays were used to measure survival post radiation. Radiation induced cell cycle changes were studied using flow cytometry. In both monolayer and 3D culture, HPV positive cells exhibited a heterogeneous appearance whereas HPV negative cells tended to be homogeneous. After irradiation, HPV positive cells had a lower survival in clonogenic assays and lower total protein levels in 3D cultures than HPV negative cells. Irradiated HPV positive cells showed a high proportion of cells in G1/S phase, increased apoptosis, an increased proliferation rate, and an inability to form 3D tumor clumps. In conclusion, HPV positive OSCC cells are more radiosensitive than HPV negative OSCC cells in vitro, supporting a more radiosensitive nature of HPV positive OSCC. PMID- 26046693 TI - Mechanism of Asymmetric Hydrogenation of Aromatic Ketones Catalyzed by a Combined System of Ru(pi-CH2C(CH3)CH2)2(cod) and the Chiral sp(2)N/sp(3)NH Hybrid Linear N4 Ligand Ph-BINAN-H-Py. AB - The combination of a Goodwin-Lions-type chiral N4 ligand, (R)-Ph-BINAN-H-Py ((R) 3,3'-diphenyl-N(2),N(2')-bis((pyridin-2-yl)methyl)-1,1'-binaphthyl-2,2'-diamine; L), with Ru(pi-CH2C(CH3)CH2)2(cod) (A) (cod = 1,5-cyclooctadiene) catalyzes the hydrogenation of acetophenone (AP) to (R)-1-phenylethanol (PE) with a high enantiomer ratio (er). Almost no Ru complex forms, with A and L remaining intact throughout the reaction while generating PE quantitatively according to [PE] = k(obs)t(2). An infinitesimal amount of reactive and unstable RuH2L (B) with C2 Lambda-cis-alpha stereochemistry is very slowly and irreversibly generated from A by the action of H2 and L, which rapidly catalyzes the hydrogenation of AP via Noyori's donor-acceptor bifunctional mechanism. A CH-pi-stabilized Si-face selective transition state, CSi, gives (R)-PE together with an intermediary Ru amide, D, which is inhibited predominantly by formation of the Ru enolate of AP. The rate-determining hydrogenolysis of D completes the cycle. The time-squared term relates both to the preliminary step before the cycle and to the cycle itself, with a highly unusual eight-order difference in the generation and turnover frequency of B. This mechanism is fully supported by a series of experiments including a detailed kinetic study, rate law analysis, simulation of t/[PE] curves with fitting to the experimental observations at the initial reaction stage, X-ray crystallographic analyses of B-related octahedral metal complexes, and Hammett plot analyses of electronically different substrates and ligands in their enantioselectivities. PMID- 26046695 TI - Enantioselectivity in Catalytic Asymmetric Fischer Indolizations Hinges on the Competition of pi-Stacking and CH/pi Interactions. AB - Computational analyses of the first catalytic asymmetric Fischer indolization (J. Am. Chem. Soc. 2011, 133, 18534) reveal that enantioselectivity arises from differences in hydrogen bonding and CH/pi interactions between the substrate and catalyst in the operative transition states. This selectivity occurs despite strong pi-stacking interactions that reduce the enantioselectivity. PMID- 26046694 TI - Lead exposure induces changes in 5-hydroxymethylcytosine clusters in CpG islands in human embryonic stem cells and umbilical cord blood. AB - Prenatal exposure to neurotoxicants such as lead (Pb) may cause stable changes in the DNA methylation (5mC) profile of the fetal genome. However, few studies have examined its effect on the DNA de-methylation pathway, specifically the dynamic changes of the 5-hydroxymethylcytosine (5hmC) profile. Therefore, in this study, we investigate the relationship between Pb exposure and 5mC and 5hmC modifications during early development. To study the changes in the 5hmC profile, we use a novel modification of the InfiniumTM HumanMethylation450 assay (Illumina, Inc.), which we named HMeDIP-450K assay, in an in vitro human embryonic stem cell model of Pb exposure. We model Pb exposure-associated 5hmC changes as clusters of correlated, adjacent CpG sites, which are co-responding to Pb. We further extend our study to look at Pb-dependent changes in high density 5hmC regions in umbilical cord blood DNA from 48 mother-infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) cohort. For our study, we randomly selected umbilical cord blood from 24 male and 24 female children from the 1st and 4th quartiles of Pb levels. Our data show that Pb associated changes in the 5hmC and 5mC profiles can be divided into sex-dependent and sex-independent categories. Interestingly, differential 5mC sites are better markers of Pb-associated sex-dependent changes compared to differential 5hmC sites. In this study we identified several 5hmC and 5mC genomic loci, which we believe might have some potential as early biomarkers of prenatal Pb exposure. PMID- 26046696 TI - Asbestos exposure increases the incidence of histologically confirmed usual interstitial pneumonia. AB - AIMS: We hypothesized that asbestos exposure increases the incidence of macroscopically visible and histologically confirmed usual interstitial pneumonia (histological UIP). METHODS AND RESULTS: We retrospectively examined 1718 cases (1202 males; mean age 66.7 years) who underwent lobectomy for resection of pleuropulmonary tumours. Objective markers for asbestos exposure included: the presence of malignant pleural mesothelioma, the presence of pleural plaques (PPs) and asbestos bodies in the histological specimen. Risk factors for histological UIP were examined. Two separate groups were studied: 183 with asbestos exposure, and 239 with histological UIP. The 183 cases with asbestos exposure had higher rates of positive occupational history and histological UIP (31%) than the remaining 1535. Among the asbestos-exposed group, small numbers of asbestos bodies were found in histological specimens of 21 cases of histological UIP. PPs and asbestos bodies were more frequent in the 239 patients with histological UIP than in the remaining 1479 UIP-negative patients. Multivariate analysis showed that asbestos exposure, especially positivity for asbestos bodies, that does not meet the current criteria for asbestosis increases the risk of histological UIP (P < 0.0001). CONCLUSIONS: Asbestos exposure causes asbestosis and increases the incidence of histological UIP. PMID- 26046697 TI - One-pot reaction to obtain N,N'-disubstituted guanidines of pyrazolo[4,3 e][1,2,4]triazolo[1,5-c]pyrimidine scaffold as human A3 adenosine receptor antagonists. AB - In this paper we describe an extension SAR study of pyrazolo[4,3 e][1,2,4]triazolo[1,5-c]pyrimidine nucleus as A3AR antagonist. Our initial aim was to replace the phenylcarbamoyl moiety at the 5 position of PTP nucleus with a thiourea functionality to evaluate the contribution of new structural modification against the A3AR. The synthesized 12-25 were not characterized by the predicted side chain but by a 1,3-disubstituted guanidine and are shown to be interesting A3AR antagonists. PMID- 26046698 TI - Sparsomycin Biosynthesis Highlights Unusual Module Architecture and Processing Mechanism in Non-ribosomal Peptide Synthetase. AB - Sparsomycin is a model protein synthesis inhibitor that blocks peptide bond formation by binding to the large ribosome subunit. It is a unique dipeptidyl alcohol, consisting of a uracil acrylic acid moiety and a monooxo-dithioacetal group. To elucidate the biosynthetic logic of sparsomycin, a biosynthetic gene cluster for sparsomycin was identified from the producer Streptomyces sparsogenes by genome mining, targeted gene mutations, and heterologous expression. Both the genetic and enzymatic studies revealed a minimum set of non-ribosomal peptide synthetases needed for generating the dipeptidyl alcohol scaffold of sparsomycin, featuring unusual mechanisms in dipeptidyl assembly and off-loading. PMID- 26046699 TI - Analysis of Ergot Alkaloids. AB - The principles and application of established and newer methods for the quantitative and semi-quantitative determination of ergot alkaloids in food, feed, plant materials and animal tissues are reviewed. The techniques of sampling, extraction, clean-up, detection, quantification and validation are described. The major procedures for ergot alkaloid analysis comprise liquid chromatography with tandem mass spectrometry (LC-MS/MS) and liquid chromatography with fluorescence detection (LC-FLD). Other methods based on immunoassays are under development and variations of these and minor techniques are available for specific purposes. PMID- 26046701 TI - Microincision Hydrophobic Acrylic Aspheric Toric Intraocular Lens for Astigmatism and Cataract Correction. AB - PURPOSE: To evaluate the efficacy and safety of a new acrylic one-piece toric intraocular lens (IOL). METHODS: This prospective multicenter clinical trial included 93 eyes of 61 patients that were implanted with a hydrophobic acrylic toric IOL from 2010 to 2012 and followed for 1 year. This IOL uses the platform of a microincision one-piece aspheric IOL, the NY-60 IOL (HOYA, Tokyo, Japan), with three increments in cylindrical power (NHT15, 1.5 diopters [D]; NHT23, 2.25 D; and NHT30, 3.0 D). The inclusion criterion was preoperative corneal astigmatism from 0.75 to 3.00 D. The primary endpoint was uncorrected distance visual acuity (UDVA) of 0.0 logMAR (20/20 Snellen) or better 6 months postoperatively. In addition to UDVA, corrected distance visual acuity (CDVA), residual astigmatism, stability of the IOL alignment, need of realignment, and the rate of Nd:YAG laser capsulotomy were evaluated up to 1 year postoperatively. Errors in astigmatic correction were assessed using Alpin's vector analysis. RESULTS: The primary endpoint was achieved in 54.8% of eyes. One year postoperatively, the logMAR UDVAs were 0.02 +/- 0.13, 0.05 +/- 0.17, and 0.09 +/- 0.14 with models NHT15, NHT23, and NHT30, which corresponds to 0.96 (19/20 Snellen), 0.89 (18/20 Snellen), and 0.82 (16/20 Snellen), respectively. One year postoperatively, the residual astigmatism was 0.66 +/- 0.58 D. In each evaluation, the mean absolute change in the position of the axis mark was between 1.93 degrees and 2.32 degrees . Three eyes required repositioning of the IOL axis and 2 eyes received Nd:YAG laser capsulotomy. The correction error showed an undercorrection with against-the-rule astigmatism and overcorrection with with the-rule astigmatism. CONCLUSIONS: The new one-piece toric IOL provided desirable clinical outcomes and stability in eyes with corneal astigmatism. PMID- 26046700 TI - Exploring the Potential of Venom from Nasonia vitripennis as Therapeutic Agent with High-Throughput Screening Tools. AB - The venom from the ectoparasitoid wasp Nasonia vitripennis (Hymenoptera: Pteromalidae) contains at least 80 different proteins and possibly even more peptides or other small chemical compounds, demonstrating its appealing therapeutic application. To better understand the dynamics of the venom in mammalian cells, two high-throughput screening tools were performed. The venom induced pathways related to an early stress response and activated reporters that suggest the involvement of steroids. Whether these steroids reside from the venom itself or show an induced release/production caused by the venom, still remains unsolved. The proinflammatory cytokine IL-1beta was found to be down-regulated after venom and LPS co-treatment, confirming the anti-inflammatory action of N. vitripennis venom. When analyzing the expression levels of the NF-kappaB target genes, potentially not only the canonical but also the alternative NF-kappaB pathway can be affected, possibly explaining some counterintuitive results. It is proposed that next to an NF-kappaB binding site, the promoter of the genes tested by the PCR array may also contain binding sites for other transcription factors, resulting in a complex puzzle to connect the induced target gene with its respective transcription factor. Interestingly, Nasonia venom altered the expression of some drug targets, presenting the venom with an exciting therapeutical potential. PMID- 26046702 TI - Toric Intraocular Lens Outcomes in Patients With Glaucoma. AB - PURPOSE: To report the outcomes of toric intraocular lens implantation in patients with glaucoma and corneal astigmatism. METHODS: One hundred twenty-six eyes of 87 patients with glaucoma and corneal astigmatism that underwent cataract surgery with an AcrySof toric intraocular lens (Alcon Laboratories, Inc., Fort Worth, TX) implant were selected for this single-center, retrospective case series. Corrected distance visual acuity, intraocular pressure, and refractive astigmatism were measured in each eye preoperatively and postoperatively. Uncorrected distance visual acuity and toric alignment were measured postoperatively. RESULTS: The uncorrected distance visual acuity was 0.04 +/- 0.08 logMAR (20/22 Snellen) for all eyes. Ninety-eight percent of all eyes achieved an uncorrected distance visual acuity of 20/40 or better, with 76% achieving 20/25 or better and 47% achieving 20/20. The corrected distance visual acuity for all eyes was 0.01 +/- 0.03 logMAR (20/20.5 Snellen) postoperatively. The refractive cylinder improved from 1.47 +/- 1.10 diopters preoperatively to 0.31 +/- 0.37 diopters postoperatively. The residual refractive cylinder was 1.00 diopter or less in 97% of eyes, 0.75 diopters or less in 90% of eyes, and 0.50 diopters or less in 83% of eyes. Mean misalignment was 4.4 degrees +/- 5.1 degrees . Intraocular pressure decreased by a mean of 2.3 +/- 3.3 mm Hg following the surgery. CONCLUSION: Toric intraocular lenses can reliably reduce astigmatism and improve uncorrected vision in eyes with cataract and glaucoma. PMID- 26046703 TI - The Safety and Predictability of Implanting Autologous Lenticule Obtained by SMILE for Hyperopia. AB - PURPOSE: To evaluate the safety, effectiveness, stability, and predictability of implanting autologous lenticules obtained from small incision lenticule extraction for the treatment of hyperopia. METHODS: Five patients (10 eyes) with one myopic eye and one hyperopic eye were enrolled. The myopic eye was treated with small incision lenticule extraction; a lenticule was extracted and subsequently implanted in the hyperopic eye. Follow-up was at 1 day, 1, 3, 6, and 9 months, and 1 year postoperatively. Patients received a complete ophthalmologic examination at each visit, including uncorrected distance visual acuity, corrected distance visual acuity, anterior segment optical coherence tomography, and corneal topography. RESULTS: There were no complications in any eye during follow-up. Compared with preoperative levels, at the last follow-up visit the eyes with lenticule implantation showed mean spherical equivalent reduced by 5.53 diopters (residual spherical equivalent was +1.13 to -2.63 diopters), mean uncorrected distance visual acuity increased approximately two lines (approximately 20/63 to 20/40 Snellen), and corrected distance visual acuity in 4 (80%) eyes gained one line, 2 (40%) eyes gained two lines, and 1 (20%) eye gained more than two lines. There was no significant difference (P > .05) in spherical equivalent compared with 1 day postoperatively and the last follow-up visit. Corneal topography showed that the lenticule was uniform and located well; anterior segment optical coherence tomography images showed that the lenticule was transparent and the demarcation line was visible. CONCLUSIONS: Implanting an autologous lenticule obtained by small incision lenticule extraction for hyperopia might be safe, effective, and stable, but its predictability should be improved in the future. PMID- 26046704 TI - Accelerated Corneal Collagen Cross-linking for Postoperative LASIK Ectasia: Two Year Outcomes. AB - PURPOSE: To evaluate the effectiveness and safety of accelerated corneal collagen cross-linking for postoperative LASIK ectasia after 2 years. METHODS: A prospective, single-center case series was performed with patients treated for postoperative LASIK ectasia. All eyes underwent accelerated corneal collagen cross-linking (CCL-Vario Crosslinking; Peschke Meditrade GmbH, Zurich, Switzerland) at 9 mW/cm(2) for 10 minutes. The main outcome measures were changes in uncorrected distance visual acuity, corrected distance visual acuity, central corneal thickness, corneal topography, and endothelial cell density. These parameters were assessed at baseline and at the 6-month and 1- and 2-year follow up visit. RESULTS: The study enrolled 40 eyes of 24 patients (15 male and 9 female) with a mean age of 33.8 +/- 7.5 years (range: 24 to 52 years) that attained at least 2 years of follow-up. The surgical procedure was uneventful in all cases. All eyes stabilized after treatment without any further signs of progression and no statistically significant changes in the mean uncorrected distance visual acuity (P = .649), corrected distance visual acuity (P = .616), mean keratometry (P =.837), steep keratometry (P = .956), ultrasonic pachymetry (P = .135), slit-scanning pachymetry (P = .276), and endothelial cell density (P = .523). In addition, 72.5% of the patients presented stable or gains of Snellen lines over time. CONCLUSIONS: Accelerated corneal collagen cross-linking seems to be safe and effective in halting postoperative LASIK ectasia progression after 2 years of follow-up. However, a longer follow-up period with a larger cohort is needed to validate these findings. PMID- 26046705 TI - Accelerated Corneal Collagen Cross-Linking in Thin Keratoconic Corneas. AB - PURPOSE: To report the outcomes of accelerated corneal collagen cross-linking in patients with thin corneas (minimum corneal thickness < 400 um). METHODS: Thirty four eyes of 34 patients with a minimum corneal thickness less than 400 um were included. All patients underwent accelerated corneal collagen cross-linking (irradiance power of 30 mW/cm2 at 3 minutes with a total surface dose of 5.4 J/cm2). Uncorrected (UDVA) and corrected distance visual acuity (CDVA), manifest refraction (diopters [D]), and topography were evaluated at baseline and at the 1 , 6-, and 12-month follow-up visit. Endothelial cell density (cells/mm2) was calculated preoperatively and postoperatively at 12 months. The corneal stromal demarcation line was measured using anterior segment optical coherence tomography at 1 month postoperatively. RESULTS: The mean age of all patients (14 women and 20 men) was 23.08 +/- 3.90 years (range: 16 to 29 years). UDVA and CDVA increased but not significantly. UDVA improved from 0.67 +/- 0.32 (20/93 +/- 20/41 Snellen) to 0.56 +/- 0.28 logMAR (20/72 +/- 20/38 Snellen) (P = .033) and CDVA improved from 0.49 +/- 0.19 (20/61 +/- 20/30 Snellen) to 0.42 +/- 0.19 logMAR (20/52 +/- 20/30 Snellen) (P = .009) at the last follow-up visit. The mean spherical and cylindrical refractions did not significantly change (P = .100 and 0.139, respectively). At the last follow-up visit, the flat keratometry decreased from 47.40 +/- 2.52 to 46.95 +/- 2.48 D, steep keratometry decreased from 51.04 +/- 3.71 to 50.62 +/- 3.57 D, and apex keratometry decreased from 57.58 +/- 4.49 to 56.26 +/- 4.47 D (P = .001, = .0019, = .001, respectively) from baseline. The mean endothelial cell density changed from 2,726.02 +/- 230.21 to 2,714.58 +/- 218.26 cells/mm2 at 12 months postoperatively (P =.086). CONCLUSION: The results of this study revealed that accelerated corneal collagen cross-linking stabilized the progression of keratoconus without a significant endothelial cell density loss during the 12 months of follow-up. PMID- 26046706 TI - Intrastromal Corneal Ring Segment Explantation in Patients With Keratoconus: Causes, Technique, and Outcomes. AB - PURPOSE: To assess the causes for intrastromal corneal ring segment (Intacs; Addition Technology Inc., Lombard, IL) explantation in patients with keratoconus, and technique for explantation, long-term outcomes, and secondary procedures to correct visual acuity. METHODS: Ten eyes of 8 patients with a history of Intacs explantation between 2004 and 2012 were included in a retrospective study performed at the Bascom Palmer Eye Institute, Miami, Florida. Causes of Intacs removal, surgical technique, preoperative and postoperative corneal examination, and uncorrected and corrected distance visual acuity were documented. Additionally, corneal topography (Tomey, Nagoya, Japan) parameters such as average keratometry and corneal cylinder were assessed. RESULTS: Although the segments were well positioned, the most common cause of Intacs removal was worsening visual acuity (80%). There was no statistically significant difference between pre-Intacs placement, post-Intacs placement, and post-Intacs removal in uncorrected and corrected distance visual acuity, average keratometry, or corneal cylinder, except between 1-year post-Intacs placement corrected distance visual acuity (0.57 logMAR [20/75 Snellen]) and 1-month post-Intacs removal corrected distance visual acuity (0.25 logMAR [20/36 Snellen], P =.03). Four patients underwent penetrating keratoplasty after Intacs removal with good visual outcomes. CONCLUSION: This study demonstrates the visual and structural outcomes that returned to near baseline after Intacs explantation in keratoconic eyes. PMID- 26046707 TI - Comparison of Measurements and Clinical Outcomes After Wavefront-Guided LASEK Between iDesign and WaveScan. AB - PURPOSE: To compare the measurements of refractive errors and ocular aberrations obtained using iDesign and WaveScan (Abbott Medical Optics, Inc., Santa Ana, CA), and to compare surgical outcomes of wavefront-guided LASEK using ablation profiles based on both aberrometers. METHODS: Ninety myopic eyes of 45 normal patients were evaluated using both the iDesign and WaveScan to measure spherical and cylindrical errors, spherical equivalents, and Zernike coefficients of ocular aberrations. Wavefront-guided LASEK was performed in a different group of 59 eyes of 30 patients divided into two groups, the iDesign and Wavescan groups. The clinical outcomes between the two groups including uncorrected visual acuity, refractive errors, contrast sensitivity, and ocular aberration were compared at 1, 3, and 6 months postoperatively. RESULTS: The iDesign produced significantly higher myopic values for refractive errors than the WaveScan, as well as significantly lower levels of total higher order, third, fourth, and fifth order root mean square values and Zernike coefficients of vertical coma and spherical aberration. At postoperative 1, 3, and 6 months, there were no statistically significant differences between the two groups in terms of uncorrected visual acuity and remaining refractive errors. The percentages of patients with spherical equivalents within +/-1.00 and +/-0.50 diopters of emmetropia were 100% (29 eyes) and 75.9% (22 eyes), respectively, in the iDesign group and 96.7% (29 eyes) and 70.0% (21 eyes), respectively, in the WaveScan group. Mesopic contrast sensitivity values were significantly higher, and the change in root mean square values for spherical aberration was significantly lower in the iDesign group. CONCLUSIONS: There were significant differences between the iDesign and the WaveScan in the measurements of refraction and ocular aberrations. Wavefront guided LASEK based on an ablation profile from the iDesign demonstrated comparable refractive predictability with the WaveScan group, resulting in minimal physician adjustment and superior postoperative visual quality. PMID- 26046708 TI - Simultaneous Correction of Unilateral Rainbow Glare and Residual Astigmatism by Undersurface Flap Photoablation After Femtosecond Laser-Assisted LASIK. AB - PURPOSE: To report and document a case of successful rainbow glare correction using undersurface ablation of the LASIK flap. METHODS: A 33-year-old woman was treated bilaterally for myopia using femtosecond laser-assisted LASIK with the FS200 femtosecond laser (Alcon Laboratories, Inc., Fort Worth, TX). Postoperatively, she complained of rainbow glare in her right eye, and presented some residual myopic astigmatism. Six months after the initial LASIK procedure, the right eye flap was lifted and a toric excimer correction was delivered on its stromal side. RESULTS: Visual symptoms related to the rainbow glare disappeared immediately after the completion of the procedure and did not reoccur. Uncorrected visual acuity improved by two lines. CONCLUSIONS: Rainbow glare following femtosecond laser-assisted LASIK can be successfully corrected by undersurface ablation of the flap. PMID- 26046709 TI - Wavefront-Guided Laser Treatment Using a High-Resolution Aberrometer to Measure Irregular Corneas: A Pilot Study. AB - PURPOSE: To evaluate in a pilot study the visual, refractive, corneal topographic, and aberrometric changes after wavefront-guided LASIK or photorefractive keratectomy (PRK) using a high-resolution aberrometer to calculate the treatment for aberrated eyes. METHODS: Twenty aberrated eyes of 18 patients undergoing wavefront-guided LASIK or PRK using the VISX STARS4IR excimer laser and the iDesign aberrometer (Abbott Medical Optics, Inc., Santa Ana, CA) were enrolled in this prospective study. Three groups were differentiated: keratoconus post-CXL group including 11 keratoconic eyes (10 patients), post LASIK group including 5 eyes (5 patients) with previous decentered LASIK treatments, and post-RK group including 4 eyes (3 patients) with previous radial keratotomy. Visual, refractive, contrast sensitivity, corneal topographic, and ocular aberrometric changes were evaluated during a 6-month follow-up. RESULTS: An improvement in uncorrected (UDVA) and corrected visual acuity (CDVA) associated with a reduction in the spherical equivalent was observed in the three groups, but was only statistically significant in the keratoconus post-CXL and post-LASIK groups (P <= .04). All eyes gained one or more lines of CDVA after surgery. Improvements in contrast sensitivity were observed in the three groups, but they were only statistically significant in the keratoconus post-CXL and post LASIK groups (P <= .04). Regarding aberrations, a reduction was observed in trefoil aberrations in the keratoconus post-CXL group (P = .05) and significant reductions in higher-order and primary coma aberrations in the post-LASIK group (P = .04). CONCLUSIONS: Wavefront-guided laser enhancements using the evaluated platform seem to be safe and effective to restore the visual function in aberrated eyes. PMID- 26046710 TI - Intense Early Flattening After Corneal Collagen Cross-linking. AB - PURPOSE: To report two cases of significant flattening after corneal cross linking (CXL) for keratoconus and discuss its potential explanations and implications. METHODS: Observational case report. RESULTS: One year after standard CXL protocol (3 mW/cm(2) for 30 minutes and total energy of 5.4 J/cm(2)), a 28-year-old woman presented a flattening of greater than 14 diopters and a 14-year-old boy presented a flattening of 7 diopters. CONCLUSIONS: Although rare, a significant flattening effect may occur during the first year after CXL, probably related to intense wound healing, increase in corneal elasticity, CXL effective depth, and central cone location. These cases suggest the necessity of a patient-specific approach and a better understanding regarding the actual mechanism behind its potent effect. PMID- 26046711 TI - Total Corneal Astigmatism and Posterior Corneal Surface. PMID- 26046712 TI - Effect of Thermal and Nonthermal Processing on Textural Quality of Plant Tissues. AB - In the current fast revolving world, the consumption of processed food is increasing drastically. The population who depend on these processed foods are also cautious about the quality and safety of what they consume. This being the case, in order to satisfy the consumer it is the responsibility of the researcher and the manufacturer to check what happens to food on processing. Plant-derived foods such as fruits and vegetables are sensitive producers which are to be handled cautiously through each steps involved in processing, starting from harvest to storage, processing to package, transportation to distribution, till it reaches the consumer. During processing, the plant materials, which are made up of complex structural components such as lignin, cellulose, pectin, etc. undergo changes which has its effect on the quality attributes of the final product. Texture is an important quality parameter of all the sensory properties. The relation between the structure of the plant tissue and the texture of the final product is reviewed in this paper comprehensively. PMID- 26046713 TI - Brain-Gut Bi-Directional Axis and Hypnotic Communication. PMID- 26046714 TI - Hypnosis and Guided Imagery Treatment for Gastrointestinal Disorders: Experience With Scripted Protocols Developed at the University of North Carolina. AB - Completely scripted treatment courses for verbatim interventions are uncommon in the field of clinical hypnosis. This approach was adopted for by a North Carolina research team for treating gastrointestinal disorders 20 years ago and has been used in hypnosis treatment of irritable bowel syndrome and ulcerative colitis, as well as in guided imagery treatment for functional abdominal pain. Treatment with these scripted protocols is delivered in a fixed series of sessions over a 2- or 3-month period. They have been found efficacious for improving bowel symptoms in several clinical trials, even in patients who have been entirely unresponsive to medical treatment. Response rates in clinical trials have ranged from 53% to 94%, and the therapeutic benefits have been shown to be well maintained at 6-, 10-, or 12-month follow-ups in different studies. This article describes the development and research on these protocols and summarizes the advantages and limitations of this fully scripted treatment approach. PMID- 26046716 TI - Functional Abdominal Pain: "Get" the Function, Loose the Pain. AB - Functional abdominal pain is a mind-body, psychosocial, and self-reinforcing experience with significant consequences for the sufferer and the surrounding support network. The occurrence of unpredictable symptoms and their severity add an element of dread and feeling out-of-control to daily life and often reduce overall functioning in a downward spiral. Two clinical presentations of functional abdominal pain are offered in this article (composites to protect confidentiality) dealing with abdominal pain syndrome and abdominal migraines. The treatment demonstrates the use of hypnotic principles for self-regulation, exploration, and meaning-making. Hypnosis treatment is conducted in combination with mindfulness-based interventions and Traditional Chinese Medicine's (TCM) teachings regarding abdominal health and illness. The clinical examples illustrate medical findings that suggest children with early life stress and an early onset of gastrointestinal somatization may not simply outgrow their functional abdominal pain but may suffer into adulthood. PMID- 26046715 TI - Hypnotherapy for Esophageal Disorders. AB - Hypnotherapy is an evidence based intervention for the treatment of functional bowel disorders, particularly irritable bowel syndrome. While similar in pathophysiology, less is known about the utility of hypnotherapy in the upper gastrointestinal tract. Esophageal disorders, most of which are functional in nature, cause painful and uncomfortable symptoms that impact patient quality of life and are difficult to treat from a medical perspective. After a thorough medical workup and a failed trial of proton pump inhibitor therapy, options for treatment are significantly limited. While the pathophysiology is likely multifactorial, two critical factors are believed to drive esophageal symptoms- visceral hypersensitivity and symptom hypervigilance. The goal of esophageal directed hypnotherapy is to promote a deep state of relaxation with focused attention allowing the patient to learn to modulate physiological sensations and symptoms that are not easily addressed with conventional medical intervention. Currently, the use of hypnosis is suitable for dysphagia, globus, functional chest pain/non-cardiac chest pain, dyspepsia, and functional heartburn. In this article the authors will provide a rationale for the use of hypnosis in these disorders, presenting the science whenever available, describing their approach with these patients, and sharing a case study representing a successful outcome. PMID- 26046717 TI - Hypnosis and Therapy for a Case of Vomiting, Nausea, and Pain. AB - In this case study the author illustrates the treatment of idiopathic gastrointestinal (GI) symptoms that practitioners sometimes encounter and for which none of the usual medical explanations apply. In this case, the symptoms have deeply personal and intricate causes that are explicated for the reader. A 20-year old female was vomiting six to eight times a day, accompanied with pain and nausea, for 2 years. She had medical intervention for almost that same duration. She had numerous uneventful medical tests, her gall bladder removed, and had exhausted hope for a medical cure. Working with a resource-building approach in therapy her vomiting was stopped within 6 weeks and her nausea in the following 7th week (or 13th session). Hypnosis was used during each session along with a protocol referred to as Self-Image Thinking (Lankton & Lankton, 1983/2008, 1986/2007; Lankton, 2008) to rehearse novel experiences and behaviors that she would implement in her social environment each week. She provided yearly follow up phone contacts for 3 years and the latest contact was 1 month before this article was written. She remains symptom-free. PMID- 26046718 TI - Hypnotherapy for Inflammatory Bowel Disease Across the Lifespan. AB - Inflammatory bowel disease (IBD) is an autoimmune disorder characterized by lifelong relapsing gastrointestinal symptoms and associated with high rates of chronic pain, depression, and anxiety. In this review the author covers the existing literature including randomized controlled studies, open trials, and case reports as well as expert opinion in evaluating how hypnotherapy can be most beneficial in adolescents and adults with IBD. Hypnotherapy evidence for functional gastrointestinal disorders (FGIDs) is also reviewed as many of the gut focused hypnotherapy (GHT) approaches used in IBD trials were developed for this latter population. Collectively, the strongest evidence of use of hypnotherapy is its association with reduced IBD-related inflammation and improved health-related quality of life with mixed results in terms of its effects on psychological and pain outcomes in adults with IBD. Studies of hypnotherapy for FGID symptoms show consistently more positive results. Post-operative hypnotherapy may also be helpful based on findings in other surgical samples. Adolescents with IBD have not been as systematically studied but small case series support the use of hypnotherapy to improve inflammation and pain. Future studies are needed to better delineate the specific brain-gut pathways which are most influenced by hypnotherapy in the IBD population and to investigate the longer-term course of the positive short-term findings. PMID- 26046719 TI - Nurse-Administered, Gut-Directed Hypnotherapy in IBS: Efficacy and Factors Predicting a Positive Response. AB - Hypnotherapy is an effective treatment in irritable bowel syndrome (IBS). It is often delivered by a psychotherapist and is costly and time consuming. Nurse administered hypnotherapy could increase availability and reduce costs. In this study the authors evaluate the effectiveness of nurse-administered, gut-directed hypnotherapy and identify factors predicting treatment outcome. Eighty-five patients were included in the study. Participants received hypnotherapy by a nurse once/week for 12 weeks. Patients reported marked improvement in gastrointestinal (GI) and extra-colonic symptoms after treatment, as well as a reduction in GI-specific anxiety, general anxiety, and depression. Fifty-eight percent were responders after the 12 weeks treatment period, and of these 82% had a favorable clinical response already at week 6. Women were more likely than men to respond favorably to the treatment. Nurse-administered hypnotherapy is an effective treatment for IBS. Being female and reporting a favorable response to treatment by week 6 predicted a positive treatment response at the end of the 12 weeks treatment period. PMID- 26046720 TI - Education and Hypnosis for Treatment of Functional Gastrointestinal Disorders (FGIDs) in Pediatrics. AB - FGIDs in children and adolescents (ROME III classification) have a significant impact on the daily functioning and quality of life. Often it is the pain that is one of the main contributors to the burden of functional dyspepsia, functional abdominal pain (syndrome), and irritable bowel syndrome. Current knowledge confirms that a number of integrated networks at cortical and subcortical sites are responsible for the experience of pain. From the work of Mayer and Tillisch (2011), mainly based on structural and functional magnetic resonance imaging and positron emission tomography, it has become clear that abdominal pain syndromes are disorders of the bi-directional mind-brain-gut interactions. In this multi factorial bio-psycho-social model we recognize the importance of neurobiological processes in the mind-brain-gut interactions, leading to alterations in motility, sensation, and immune functions. Medical treatment often offers little or no relief. Until now pharmaceutical research has not succeeded in developing safe new drugs with an effect on the brain-gut axis. More recent published research shows the rationale for the use of medical hypnosis in FGID. In this article the author will illustrate her specific approach in a pediatric gastroenterology clinic with children and adolescents with FGIDs. Being a pediatric gastroenterologist, the author emphasizes the importance of a clear diagnosis, explains the rationale for educating the patient and his or her parents on the multi-factorial bio-psycho-social model and the concepts of chronic pain, discusses the specific settings and pitfalls for hypnosis treatment in children, and last but not least, provides some examples of hypnotic sessions used with FGIDs. PMID- 26046721 TI - Resilience of Nurses in the Face of Disaster. AB - OBJECTIVE: On April 27, 2011, the state of Alabama encountered a horrific day of tornados that left a trail of damage throughout the state. The city of Tuscaloosa was devastated by an EF-4 that resulted in many victims and casualties. Druid City Hospital in Tuscaloosa had a massive inflow of victims with both mild and major injuries. When disasters such as this occur, nurses must respond with efficiency and effectiveness to help as many victims as possible. However, little is known about the psychological effects of disasters on nurses and how these impact nurses both personally and professionally. Because resilience can directly impact how a nurse responds to a situation, this article aimed to examine the resilience levels of nurses working during the disaster. METHODS: This study was part of a larger study examining the needs of nurses both before and after disasters. Ten nurses were interviewed and completed a 10-item survey on resilience, the Connor-Davidson Resilience Scale (CD-RISC). The full range of scores on this scale is from 0 to 40, with higher scores reflecting greater resilience. RESULTS: In this survey of 10 nurses, the scores ranged from 33 to 40, with a mean score of 36.7. CONCLUSIONS: The nurses who were interviewed and completed the survey possessed a high level of resilience. More research should be done on the causes of increased resilience in nurses after disasters. PMID- 26046722 TI - Estimation and imaging of breast lesions using a two-layer tissue structure by ultrasound-guided optical tomography. AB - A new two-step estimation and imaging method is developed for a two-layer breast tissue structure consisting of a breast tissue layer and a chest wall underneath. First, a smaller probe with shorter distance source-detector pairs was used to collect the reflected light mainly from the breast tissue layer. Then, a larger probe with 9*14 source-detector pairs and a centrally located ultrasound transducer was used to collect reflected light from the two-layer tissue structure. The data collected from the smaller probe were used to estimate breast tissue optical properties. With more accurate estimation of the average breast tissue properties, the second layer properties can be assessed from data obtained from the larger probe. Using this approach, the unknown variables have been reduced from four to two and the estimated bulk tissue optical properties are more accurate and robust. In addition, a two-step reconstruction using a genetic algorithm and conjugate gradient method is implemented to simultaneously reconstruct the absorption and reduced scattering maps of targets inside a two layer tissue structure. Simulations and phantom experiments have been performed to validate the new reconstruction method, and a clinical example is given to demonstrate the feasibility of this approach. PMID- 26046723 TI - Effects of Theodore Millon's Teaching, Mentorship, Theory, and Scientific Contributions on Health Psychology and Behavioral Medicine Research and Practice. AB - This article summarizes the impact of Theodore Millon's work on the disciplines of health psychology and behavioral medicine over the past 5 decades spanning from the late 1960s to present. The article is written from my perspectives as a graduate student mentored by Millon on through my faculty career as a collaborator in test construction and empirical validation research. Several of the most recent entries in this summary reflect projects that were ongoing at the time of his passing, revealing the innovation and visionary spirit that he demonstrated up until the end of his life. Considering that this summary is restricted to Millon's contributions to the disciplines of health psychology and behavioral medicine, this work comprises only a small portion of his larger contribution to the field of psychology and the areas of personality theory and psychological assessment more broadly. PMID- 26046724 TI - Use of an online epilepsy diary to characterize repetitive seizures. AB - SIGNIFICANCE: Little is known about patterns of seizures that occur multiple times a day, sometimes called clusters or serial seizures. OBJECTIVE: The online diary, My Epilepsy Diary (MED), provided self-reported data from community-based patients to describe the characteristics of clusters. METHODS: We used MED data to define a population of 5098 community outpatients, including 1177 who specified time of multiple seizures in a 24-hour period. Outcomes included cluster prevalence and frequency, distribution of interseizure time intervals, as well as the types of triggers commonly reported. RESULTS: One-fourth of days with any seizures included clusters for these patients. Most days with clusters included 2 seizures, with >5 events occurring in only 10% of days. One-third of seizures occurred within 3h of the initial event and two-thirds within 6h. When more than 2 seizures occurred, the time to the next seizure decreased from an average of over 2h (to the 3rd event) to a quarter-hour (from the 4th to the 5th event). CONCLUSION: My Epilepsy Diary data have provided the first overview of cluster seizures in a large community-based population. Treatments with less than 3-hour duration of action would be bioavailable at the time of only one-third of subsequent seizures. Although limited by the self-reported and observational nature of the diary data, some general patterns emerge and can help to focus questions for future studies. PMID- 26046725 TI - The contribution of pre- and postdisaster social support to short- and long-term mental health after Hurricanes Katrina: A longitudinal study of low-income survivors. AB - A previous study of Hurricane Katrina survivors found that higher levels of predisaster social support were associated with lower psychological distress one year after the storm, and that this pathway was mediated by lower exposure to hurricane-related stressors. As a follow-up, we examined the impact of pre- and postdisaster social support on longer-term of mental health-both psychological distress and posttraumatic stress. In this three-wave longitudinal study, 492 residents in the region affected by Hurricane Katrina reported levels of perceived social support and symptoms of psychological distress prior to the storm (Wave 1). Subsequently, one year after Hurricane Katrina (Wave 2), they reported levels of exposure, perceived social support, and symptoms of psychological distress and posttraumatic stress. The latter three variables were assessed again four years after the hurricane (Wave 3). Results of mediation analysis indicated that levels of exposure to hurricane-related stressors mediated the relationship between Wave 1 perceived social support and Wave 3 psychological distress as well as postdisaster posttraumatic stress. Results of regression analyses indicated that, controlling for Wave 1 psychological distress and disaster exposure, Wave 2 perceived social support was associated with Wave 2 and Wave 3 psychological distress but not posttraumatic stress. Our results confirmed the social causation processes of social support and suggest that posttraumatic stress might not stem directly from the lack of social support. Rather, preexisting deficits in social resources might indirectly affect longer term posttraumatic stress and general psychological distress by increasing risk for disaster-related stressors. PMID- 26046726 TI - Justifying medication decisions in mental health care: Psychiatrists' accounts for treatment recommendations. AB - Psychiatric practitioners are currently encouraged to adopt a patient centered approach that emphasizes the sharing of decisions with their clients, yet recent research suggests that fully collaborative decision making is rarely actualized in practice. This paper uses the methodology of Conversation Analysis to examine how psychiatrists justify their psychiatric treatment recommendations to clients. The analysis is based on audio-recordings of interactions between clients with severe mental illnesses (such as, schizophrenia, bipolar disorders, etc.) in a long-term, outpatient intensive community treatment program and their psychiatrist. Our focus is on how practitioners design their accounts (or rationales) for recommending for or against changes in medication type and dosage and the interactional deployment of these accounts. We find that psychiatrists use two different types of accounts: they tailor their recommendations to the clients' concerns and needs (client-attentive accounts) and ground their recommendations in their professional expertise (authority-based accounts). Even though psychiatrists have the institutional mandate to prescribe medications, we show how the use of accounts displays psychiatrists' orientation to building consensus with clients in achieving medical decisions by balancing medical authority with the sensitivity to the treatment relationship. PMID- 26046727 TI - High Ambient Temperatures and Risk of Motor Vehicle Crashes in Catalonia, Spain (2000-2011): A Time-Series Analysis. AB - BACKGROUND: Experimental studies have shown a decrease in driving performance at high temperatures. The epidemiological evidence for the relationship between heat and motor vehicle crashes is not consistent. OBJECTIVES: We estimated the impact of high ambient temperatures on the daily number of motor vehicle crashes and, in particular, on crashes involving driver performance factors (namely distractions, driver error, fatigue, or sleepiness). METHODS: We performed a time-series analysis linking daily counts of motor vehicle crashes and daily temperature or occurrence of heat waves while controlling for temporal trends. All motor vehicle crashes with victims that occurred during the warm period of the years 2000-2011 in Catalonia (Spain) were included. Temperature data were obtained from 66 weather stations covering the region. Poisson regression models adjusted for precipitation, day of the week, month, year, and holiday periods were fitted to quantify the associations. RESULTS: The study included 118,489 motor vehicle crashes (an average of 64.1 per day). The estimated risk of crashes significantly increased by 2.9% [95% confidence interval (CI): 0.7%, 5.1%] during heat wave days, and this association was stronger (7.7%, 95% CI: 1.2%, 14.6%) when restricted to crashes with driver performance-associated factors. The estimated risk of crashes with driver performance factors significantly increased by 1.1% (95% CI: 0.1%, 2.1%) for each 1 degrees C increase in maximum temperature. CONCLUSIONS: Motor vehicle crashes involving driver performance-associated factors were increased in association with heat waves and increasing temperature. These findings are relevant for designing preventive plans in a context of global warming. PMID- 26046728 TI - Long-Term Risk for Aortic Complications After Aortic Valve Replacement in Patients With Bicuspid Aortic Valve Versus Marfan Syndrome. AB - BACKGROUND: Bicuspid aortic valves are associated with valve dysfunction, ascending aortic aneurysm and dissection. Management of the ascending aorta at the time of aortic valve replacement (AVR) in these patients is controversial and has been extrapolated from experience with Marfan syndrome, despite the absence of comparative long-term outcome data. OBJECTIVES: This study sought to assess whether the natural history of thoracic aortopathy after AVR in patients with bicuspid aortic valve disease is substantially different from that seen in patients with Marfan syndrome. METHODS: In this retrospective comparison, outcomes of 13,205 adults (2,079 with bicuspid aortic valves, 73 with Marfan syndrome, and 11,053 control patients with acquired aortic valve disease) who underwent primary AVR without replacement of the ascending aorta in New York State between 1995 and 2010 were compared. The median follow-up time was 6.6 years. RESULTS: The long-term incidence of thoracic aortic dissection was significantly higher in patients with Marfan syndrome (5.5 +/- 2.7%) compared with those with bicuspid valves (0.55 +/- 0.21%) and control group patients (0.41 +/- 0.08%, p < 0.001). Thoracic aortic aneurysms were significantly more likely to be diagnosed in late follow-up in patients with Marfan syndrome (10.8 +/- 4.4%) compared with those with bicuspid valves (4.8 +/- 0.8%) and control group patients (1.4 +/- 0.2%) (p < 0.001). Patients with Marfan syndrome were significantly more likely to undergo thoracic aortic surgery in late follow-up (10.4 +/- 4.3%) compared with those with bicuspid valves (2.5 +/- 0.6%) and control group patients (0.50 +/- 0.09%) (p < 0.001). CONCLUSIONS: The much higher long-term rates of aortic complications after AVR observed in patients with Marfan syndrome compared with those with bicuspid aortic valves confirm that operative management of patients with bicuspid aortic valves should not be extrapolated from Marfan syndrome and support discrete treatment algorithms for these different clinical entities. PMID- 26046729 TI - Comparison of Long-Term Risk of Thoracic Aortic Aneurysm and Dissection in Patients With Bicuspid Aortic Valve and Marfan Syndrome After Aortic Valve Replacement. PMID- 26046731 TI - Bone Marrow Mononuclear Cell Therapy and Granulocyte Colony-Stimulating Factor for Acute Myocardial Infarction: Is it Time to Reconsider? PMID- 26046730 TI - Comparison of Different Bone Marrow-Derived Stem Cell Approaches in Reperfused STEMI. A Multicenter, Prospective, Randomized, Open-Labeled TECAM Trial. AB - BACKGROUND: Stem cell-based therapy has emerged as a potential therapy in acute myocardial infarction (AMI). Although various approaches have been studied, intracoronary injection of bone marrow autologous mononuclear cells (BMMC) and the ability of granulocyte colony-stimulating factor (G-CSF) to mobilize endogenous cells have attracted the most attention. OBJECTIVES: This study compares, for the first time, the efficacy of BMMC injection, G-CSF mobilization, and the combination of both with standard treatment. METHODS: On Day 1 after primary percutaneous coronary intervention, 120 patients were randomized to a 1) intracoronary BMMC injection; 2) mobilization with G-CSF; 3) both (BMMC injection plus G-CSF); or 4) conventional treatment (control group). G-CSF, 10 MUg/kg/day subcutaneously, was started Day 1 and maintained for 5 days. BMMC injection was performed on Days 3 to 5. Our primary endpoint was absolute change in 12-month left ventricular ejection fraction (LVEF) and left ventricular end-systolic volume (LVESV) relative to baseline measured by cardiac magnetic resonance. RESULTS: The mean change in LVEF between baseline and follow-up for all patients was 4 +/- 6% (p = 0.006). Change in LVEF and LVESV over time did not differ significantly among the 4 groups. Patients actively treated with any stem cell approach showed similar changes in LVEF and LVESV versus control subjects, with a small but significant reduction in infarct area (p = 0.038). CONCLUSIONS: In our study, 3 different bone marrow-derived stem cell approaches in AMI did not result in improvement of LVEF or volumes compared with standard AMI care (Trial of Hematopoietic Stem Cells in Acute Myocardial Infarction [TECAM]; NCT00984178). PMID- 26046733 TI - Retrograde Percutaneous Coronary Intervention for Chronic Total Occlusion: Going Backward to Go Forward. PMID- 26046732 TI - Retrograde Recanalization of Chronic Total Occlusions in Europe: Procedural, In Hospital, and Long-Term Outcomes From the Multicenter ERCTO Registry. AB - BACKGROUND: A retrograde approach improves the success rate of percutaneous coronary interventions (PCIs) for chronic total occlusions (CTOs). OBJECTIVES: The authors describe the European experience with and outcomes of retrograde PCI revascularization for coronary CTOs. METHODS: Follow-up data were collected from 1,395 patients with 1,582 CTO lesions enrolled between January 2008 and December 2012 for retrograde CTO PCI at 44 European centers. Major adverse cardiac and cerebrovascular events were defined as the composite of cardiac death, myocardial infarction, stroke, and further revascularization. RESULTS: The mean patient age was 62.0 +/- 10.4 years; 88.5% were men. Procedural and clinical success rates were 75.3% and 71.2%, respectively. The mean clinical follow-up duration was 24.7 +/- 15.0 months. Compared with patients with failed retrograde PCI, successfully revascularized patients showed lower rates of cardiac death (0.6% vs. 4.3%, respectively; p < 0.001), myocardial infarction (2.3% vs. 5.4%, respectively; p = 0.001), further revascularization (8.6% vs. 23.6%, respectively; p < 0.001), and major adverse cardiac and cerebrovascular events (8.7% vs. 23.9%, respectively; p < 0.001). Female sex (hazard ratio [HR]: 2.06; 95% confidence interval [CI]: 1.33 to 3.18; p = 0.001), prior PCI (HR: 1.73; 95% CI: 1.16 to 2.60; p = 0.011), low left ventricular ejection fraction (HR: 2.43; 95% CI: 1.22 to 4.83; p = 0.011), J CTO (Multicenter CTO Registry in Japan) score >=3 (HR: 2.08; 95% CI: 1.32 to 3.27; p = 0.002), and procedural failure (HR: 2.48; 95% CI: 1.72 to 3.57; p < 0.001) were independent predictors of major adverse cardiac and cerebrovascular events at long-term follow-up. CONCLUSIONS: The number of retrograde procedures in Europe has increased, with high percents of success, low rates of major complications, and good long-term outcomes. PMID- 26046735 TI - Expanding the Roster: Developing New Inhibitors of Intravascular Thrombosis. PMID- 26046734 TI - Differential Inhibition of Human Atherosclerotic Plaque-Induced Platelet Activation by Dimeric GPVI-Fc and Anti-GPVI Antibodies: Functional and Imaging Studies. AB - BACKGROUND: Glycoprotein VI (GPVI) is the essential platelet collagen receptor in atherothrombosis, but its inhibition causes only a mild bleeding tendency. Thus, targeting this receptor has selective antithrombotic potential. OBJECTIVES: This study sought to compare compounds interfering with platelet GPVI-atherosclerotic plaque interaction to improve current antiatherothrombotic therapy. METHODS: Human atherosclerotic plaque-induced platelet aggregation was measured in anticoagulated blood under static and arterial flow conditions (550/s, 1,100/s, and 1,500/s). Inhibition by dimeric GPVI fragment crystallizable region of IgG (Fc) masking GPVI binding sites on collagen was compared with that of 3 anti-GPVI antibodies: BLO8-1, a human domain antibody; 5C4, a fragment antigen-binding (Fab fragment) of monoclonal rat immunoglobulin G; and m-Fab-F, a human recombinant sFab against GPVI dimers. RESULTS: GPVI-Fc reduced plaque-triggered platelet aggregation in static blood by 51%, BLO8-1 by 88%, and 5C4 by 93%. Under arterial flow conditions, BLO8-1 and 5C4 almost completely inhibited platelet aggregation while preserving platelet adhesion on plaque. Inhibition by GPVI-Fc, even at high concentrations, was less marked but increased with shear rate. Advanced optical imaging revealed rapid persistent GPVI-Fc binding to collagen under low and high shear flow, upstream and downstream of plaque fragments. At low shear particularly, platelets adhered in plaque flow niches to GPVI-Fc-free segments of collagen fibers and recruited other platelets onto aggregates via ADP and TxA2 release. CONCLUSIONS: Anti-GPVI antibodies inhibit atherosclerotic plaque-induced platelet aggregation under static and flow conditions more effectively than GPVI Fc. However, potent platelet inhibition by GPVI-Fc at a higher shear rate (1,500/s) suggests localized antithrombotic efficacy at denuded or fissured stenotic high-risk lesions without systemic bleeding. The compound-specific differences have relevance for clinical trials targeting GPVI-collagen interaction combined with established antiplatelet therapies in patients with spontaneous plaque rupture or intervention-associated plaque injury. PMID- 26046736 TI - Prognostic and Bioepidemiologic Implications of Papillary Fibroelastomas. AB - BACKGROUND: Papillary fibroelastomas (PFE) are benign neoplasms with little available outcome data. OBJECTIVES: This study sought to describe the frequency and clinical course of patients with surgically removed PFE and echocardiographically suspected, but unoperated, PFE. METHODS: Mayo Clinic pathology and echocardiography databases (January 1, 1995, to December 31, 2010) were queried, resulting in 511 patients: group 1 (n = 185), including patients with surgically removed, histopathologically confirmed PFE; group 1a (n = 94; 51%) with PFE removed at primary surgery; and group 1b (n = 91; 49%) with PFE removal at time of another cardiac surgery. Group 2 (n = 326) patients had echocardiographic evidence of PFE but no cardiac surgery to remove PFE. RESULTS: Group 1 had mean age of 63 +/- 14 years (116 women [63%]). During the study period, we identified 112 cardiac myxomas in the pathology database and 142 in the echocardiographic database. Mean age in group 2 was 67 +/- 14 years (162 women [50%]). PFE occurred most commonly on cardiac valves (n = 400 [78%]). In group 1, transient ischemic attack or stroke was the presenting symptom in 58 patients (32%). With surgical removal of valvular PFE, the valve was preserved in 92 (98%). Recurrence was documented in 3 patients (1.6%). Follow-up stroke risk in groups 1, 1a, and 1b at 1 year was 2%, 0%, and 4%; at 5 years, 8%, 5%, and 11%, respectively. Cerebrovascular accident risk in group 2 at 1 and 5 years was 6% and 13%. CONCLUSIONS: In patients with echocardiographically suspected PFE who do not undergo surgical removal, rates of cerebrovascular accident and mortality are increased. PMID- 26046737 TI - Papillary Fibroelastoma: Move Over Myxoma. PMID- 26046738 TI - Cardio-Pulmonary-Renal Interactions: A Multidisciplinary Approach. AB - Over the past decade, science has greatly advanced our understanding of interdependent feedback mechanisms involving the heart, lung, and kidney. Organ injury is the consequence of maladaptive neurohormonal activation, oxidative stress, abnormal immune cell signaling, and a host of other mechanisms that precipitate adverse functional and structural changes. The presentation of interorgan crosstalk may include an acute, chronic, or acute on chronic timeframe. We review the current, state-of-the-art understanding of cardio pulmonary-renal interactions and their related pathophysiology, perpetuating nature, and cycles of increased susceptibility and reciprocal progression. To this end, we present a multidisciplinary approach to frame the diverse spectrum of published observations on the topic. Assessment of organ functional reserve and use of biomarkers are valuable clinical strategies to screen and detect disease, assist in diagnosis, assess prognosis, and predict recovery or progression to chronic disease. PMID- 26046739 TI - Circulating Biomarkers of Myocardial Fibrosis: The Need for a Reappraisal. AB - Myocardial fibrosis impairs cardiac function, in addition to facilitating arrhythmias and ischemia, and thus influences the evolution and outcome of cardiac diseases. Its assessment is therefore clinically relevant. Although tissue biopsy is the gold standard for the diagnosis of myocardial fibrosis, a number of circulating biomarkers have been proposed for the noninvasive assessment of this lesion. A review of the published clinical data available on these biomarkers shows that most of them lack proof that they actually reflect the myocardial accumulation of fibrous tissue. In this "call to action" article, we propose that this absence of proof may lead to misinterpretations when considering the incremental value provided by the biomarkers with respect to traditional diagnostic tools in the clinical handling of patients. We thus argue that strategies are needed to more strictly validate whether a given circulating biomarker actually reflects histologically proven myocardial fibrosis before it is applied clinically. PMID- 26046740 TI - Industry Disclosures: More Reflective of Moral Integrity Than Rules. PMID- 26046741 TI - Social Media in Medicine: A Podium Without Boundaries. PMID- 26046742 TI - Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. PMID- 26046743 TI - Effects of Weight and Weight Change on Cardiac Remodeling Over 20 Years: The CARDIA (Coronary Artery Risk Development in Young Adults) Study. PMID- 26046744 TI - Atrial Fibrosis: An Illusion or a True Key to Successful Ablation of Atrial Fibrillation? PMID- 26046745 TI - Reply: Atrial Fibrosis: An Illusion or a True Key to Successful Ablation of Atrial Fibrillation? PMID- 26046746 TI - Atherosclerotic Burden: Complex Interplay of Anatomic, Physiologic, and Outcome Data. PMID- 26046747 TI - Reply: Atherosclerotic Burden: Complex Interplay of Anatomic, Physiologic, and Outcome Data. PMID- 26046748 TI - Synthesis, photocatalytic and antimicrobial properties of SnO2, SnS2 and SnO2/SnS2 nanostructure. AB - Nanoscale SnO2, SnS2 and SnO2/SnS2 were synthesized by hydrothermal treatment method and characterized by powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Brunauer-Emmett-Teller (BET), Barrett-Joyner-Halenda (BJH) and UV-vis spectra. The photocatalytic activity of SnO2, SnS2 and SnO2/SnS2 were tested with Enrofloxacin antibiotic. The tetragonal and hexagonal SnO2 and SnS2 phase was confirmed through XRD, respectively. The photocatalytic results indicated that the SnO2/SnS2 enhanced the photocatalytic activity and could be effectively used as photocatalyst for degradation of Enrofloxacin antibiotic pollutant. The results of antibacterial experiment under visible light irradiation demonstrate that the SnO2/SnS2 nanocomposite exhibit enhanced antibacterial efficiency compared with pure SnO2 and SnS2. The antifungal activity of the nanoscale SnO2, SnS2 and SnO2/SnS2 against Candida albicans was assessed using the disc-diffusion susceptibility tests. It was seen that the antifungal activity of SnO2/SnS2 nanocomposite is higher than the pure SnO2 and SnS2 toward pathogenic C. albicans. PMID- 26046749 TI - Preparation and characterization of injectable Mitoxantrone poly (lactic acid)/fullerene implants for in vivo chemo-photodynamic therapy. AB - Fullerene (C60) L-phenylalanine derivative attached with poly (lactic acid) (C60 phe-PLA) was developed to prepare injectable Mitoxantrone (MTX) multifunctional implants. C60-phe-PLA was self-assembled to form microspheres consisting of a hydrophilic antitumor drug (MTX) and a hydrophobic block (C60) by dispersion solvent diffusion method. The self-assembled microspheres showed sustained release pattern almost 15days in vitro release experiments. According to the tissue distribution of C57BL mice after intratumoral administration of the microspheres, the MTX mainly distributed in tumors, and rarely in heart, liver, spleen, lung, and kidney. Photodynamic antitumor efficacy of blank microsphere was realized. Microspheres afforded high antitumor efficacy without obvious toxic effects to normal organs, owing to its significantly increased MTX tumor retention time, low MTX levels in normal organs and strong photodynamic activity of PLA-phe-C60. These C60-phe-PLA microspheres may be promising for the efficacy with minimal side effects in future treatment of solid tumors. PMID- 26046750 TI - Surface protonation/deprotonation controlled instant affinity switch of nano drug vehicle (NDV) for pH triggered tumor cell targeting. AB - To realize a fast and selective capture of nano drug vehicles (NDVs) by malignant tumors, an instant affinity switchable NDV based on pH-sensitive surface protonation was prepared. This NDV is prepared from a zwitterionic polymer system with an ultra resistant poly(carboxybetaine) (pCB) shell and sulfo groups near a hydrophobic doxorubicin (DOX) loaded core. The results show that this new NDV system had an instant and sensitive affinity switch from strong resistance in physiological pH to a high affinity to tumor cell membranes in the slightly acidic extracellular pH of malignant tumors depending on if the net charge of the NDV is reversed or not. The pH of this affinity switch can be controlled by the amount of the strong acidic sulfo groups that act as the zeta potential adjustor of the NDV near the inner hydrophobic core. As a result, this CB-based NDV was captured by solid tumor tissue efficiently and thus inhibited tumor growth much more effectively than the PEGylated NDV system, while eliminating unwanted side effects in other healthy tissues. This indicates that the affinity switch caused by protein-like surface protonation of the NDV is much more efficient than the traditional charge switchable NDV approaches. PMID- 26046752 TI - Stamceller in Translation. PMID- 26046751 TI - Highly Pathogenic Porcine Reproductive and Respiratory Syndrome Virus Infection Induced Apoptosis and Autophagy in Thymi of Infected Piglets. AB - Previously, we demonstrated that the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) HuN4 strain causes obvious thymic atrophy and thymocytes apoptosis in infected piglets after birth, which is more severe than that induced by classical PRRSV. In this study, we investigated apoptosis and autophagy in the thymus of piglets infected with the HP-PRRSV HuN4 strain, and found that both apoptosis and autophagy occurred in the thymus of piglets infected with HP-PRRSV. In addition to a few virus-infected cells, CD14+ cells, the main autophagic cells in the thymus were thymic epithelial cells. These findings demonstrated that HP-PRRSV induces apoptosis in bystander cells, and induces autophagy in both infected and bystander cells in the thymus of infected piglets. Herein, we first present new data on the thymic lesions induced by HP PRRSV, and show that apoptosis and autophagy are key mechanisms involved in cell survival and determinants of the severity of thymic atrophy in infected piglets. Finally, future studies of the mechanism underlying immune responses are proposed based on our current understanding of PRRSV-host interactions. PMID- 26046753 TI - Tex10: A New Player in the Core Pluripotency Circuitry. AB - Revealing how the core pluripotency circuitry is orchestrated to maintain the ground state of embryonic stem cells (ESCs) is fundamental for understanding self renewal and early lineage specifications. In this issue of Cell Stem Cell, Ding et al. (2015) identify a new Sox2-interacting protein, Tex10, which, together with Tet1 and p300, regulate super-enhancers to sustain pluripotency. PMID- 26046754 TI - Bringing Blood Stem Cell Phenotype, Genotype, and Function Closer Together. AB - Imperfect purity, subtypes, and retrospective functional assays compromise efforts to define the molecular identity of hematopoietic stem cells (HSCs). In this issue of Cell Stem Cell, Wilson et al. (2015) use a single-cell-based bioinformatics-experimental strategy to extract a consensus molecular signature from heterogeneous HSC pools. Their data and strategy provide a powerful resource for stem cell characterization. PMID- 26046755 TI - Regenerative Medicines for Remyelination: From Aspiration to Reality. AB - Stimulating an endogenous regenerative response is a powerful approach for potential treatment of chronic demyelinating diseases such as multiple sclerosis. Recently in Nature, Najm et al. (2015) identified two clinically relevant, FDA approved compounds that promote oligodendrocyte progenitor cell differentiation and induce remyelination in demyelinating disease models. PMID- 26046756 TI - Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline? AB - The mechanisms underlying the aging process are not understood. Even tissues endowed with somatic stem cells age while the germline appears immortal. I propose that this paradox may be explained by the pervasive use of glycolysis by somatic stem cells as opposed to the predominance of mitochondrial respiration in gametes. PMID- 26046757 TI - Regulation of Muscle Satellite Cell Function in Tissue Homeostasis and Aging. AB - Age-related muscle decline is associated with functional impairment of satellite cells (SCs). Conflicting data suggest dysregulation of cell-extrinsic or intrinsic factors can independently contribute to such impairment. Here, we emphasize the importance of identifying nodes that integrate these factors into feed-forward circuits, which could provide targets for therapeutic intervention. PMID- 26046758 TI - Stem Cell Aging and Sex: Are We Missing Something? AB - Longevity differs between sexes, with females being longer-lived in most mammals, including humans. One hallmark of aging is the functional decline of stem cells. Thus, a key question is whether the aging of stem cells differs between males and females and whether this has consequences for disease and lifespan. PMID- 26046759 TI - Programming and Reprogramming Cellular Age in the Era of Induced Pluripotency. AB - The ability to reprogram adult somatic cells back to pluripotency presents a powerful tool for studying cell-fate identity and modeling human disease. However, the reversal of cellular age during reprogramming results in an embryonic-like state of induced pluripotent stem cells (iPSCs) and their derivatives, which presents specific challenges for modeling late onset disease. This age reset requires novel methods to mimic age-related changes but also offers opportunities for studying cellular rejuvenation in real time. Here, we discuss how iPSC research may transform studies of aging and enable the precise programming of cellular age in parallel to cell-fate specification. PMID- 26046760 TI - Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. AB - Aging is characterized by a decrease in genome integrity, impaired organ maintenance, and an increased risk of cancer, which coincide with clonal dominance of expanded mutant stem and progenitor cell populations in aging tissues, such as the intestinal epithelium, the hematopoietic system, and the male germline. Here we discuss possible explanations for age-associated increases in the initiation and/or progression of mutant stem/progenitor clones and highlight the roles of stem cell quiescence, replication-associated DNA damage, telomere shortening, epigenetic alterations, and metabolic challenges as determinants of stem cell mutations and clonal dominance in aging. PMID- 26046762 TI - Krt19(+)/Lgr5(-) Cells Are Radioresistant Cancer-Initiating Stem Cells in the Colon and Intestine. AB - Epithelium of the colon and intestine are renewed every 3 days. In the intestine there are at least two principal stem cell pools. The first contains rapid cycling crypt-based columnar (CBC) Lgr5(+) cells, and the second is composed of slower cycling Bmi1-expressing cells at the +4 position above the crypt base. In the colon, however, the identification of Lgr5(-) stem cell pools has proven more challenging. Here, we demonstrate that the intermediate filament keratin-19 (Krt19) marks long-lived, radiation-resistant cells above the crypt base that generate Lgr5(+) CBCs in the colon and intestine. In colorectal cancer models, Krt19(+) cancer-initiating cells are also radioresistant, while Lgr5(+) stem cells are radiosensitive. Moreover, Lgr5(+) stem cells are dispensable in both the normal and neoplastic colonic epithelium, as ablation of Lgr5(+) stem cells results in their regeneration from Krt19-expressing cells. Thus, Krt19(+) stem cells are a discrete target relevant for cancer therapy. PMID- 26046761 TI - Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease. AB - Stem cell decline is an important cellular driver of aging-associated pathophysiology in multiple tissues. Epigenetic regulation is central to establishing and maintaining stem cell function, and emerging evidence indicates that epigenetic dysregulation contributes to the altered potential of stem cells during aging. Unlike terminally differentiated cells, the impact of epigenetic dysregulation in stem cells is propagated beyond self; alterations can be heritably transmitted to differentiated progeny, in addition to being perpetuated and amplified within the stem cell pool through self-renewal divisions. This Review focuses on recent studies examining epigenetic regulation of tissue specific stem cells in homeostasis, aging, and aging-related disease. PMID- 26046763 TI - Positron Emission Tomography Imaging Reveals Auditory and Frontal Cortical Regions Involved with Speech Perception and Loudness Adaptation. AB - Considerable progress has been made in the treatment of hearing loss with auditory implants. However, there are still many implanted patients that experience hearing deficiencies, such as limited speech understanding or vanishing perception with continuous stimulation (i.e., abnormal loudness adaptation). The present study aims to identify specific patterns of cerebral cortex activity involved with such deficiencies. We performed O-15-water positron emission tomography (PET) in patients implanted with electrodes within the cochlea, brainstem, or midbrain to investigate the pattern of cortical activation in response to speech or continuous multi-tone stimuli directly inputted into the implant processor that then delivered electrical patterns through those electrodes. Statistical parametric mapping was performed on a single subject basis. Better speech understanding was correlated with a larger extent of bilateral auditory cortex activation. In contrast to speech, the continuous multi tone stimulus elicited mainly unilateral auditory cortical activity in which greater loudness adaptation corresponded to weaker activation and even deactivation. Interestingly, greater loudness adaptation was correlated with stronger activity within the ventral prefrontal cortex, which could be up regulated to suppress the irrelevant or aberrant signals into the auditory cortex. The ability to detect these specific cortical patterns and differences across patients and stimuli demonstrates the potential for using PET to diagnose auditory function or dysfunction in implant patients, which in turn could guide the development of appropriate stimulation strategies for improving hearing rehabilitation. Beyond hearing restoration, our study also reveals a potential role of the frontal cortex in suppressing irrelevant or aberrant activity within the auditory cortex, and thus may be relevant for understanding and treating tinnitus. PMID- 26046765 TI - Three-dimensional high-resolution anorectal manometry: does it allow automated analysis of sphincter defects? AB - AIM: Anorectal manometry is the most common test used to explore anorectal disorders. The recent three-dimensional high-resolution anorectal manometry (3D HRAM) technique appears to be able to provide new topographic information. Our objective was to develop an automated analysis of 3D-HRAM images to diagnose anal sphincter defects and compare the results with those of endoanal ultrasonography (EUS), which is considered to be the gold standard. METHOD: All patients being tested in our department for faecal incontinence or dyschezia by 3D-HRAM and EUS were eligible for the study. 3D-HRAM was used to record resting and squeeze pressure, reflecting internal and external anal sphincter function, respectively. A software platform was designed to automatically analyse the 3D-HRAM images and calculate a diagnostic score for any anal sphincter defect compared with EUS. RESULTS: A total of 206 (91% female) patients of mean age of 54 years were included in the study. A sphincter defect was diagnosed by EUS in 130 (63%). The diagnostic scores from the 3D-HRAM automated analysis for an internal anal sphincter defect showed a sensitivity of 65% and a specificity of 65%. For an external anal sphincter defect, the sensitivity was 43% and the specificity 87%. CONCLUSION: Our study developed a method based on 3D-HRAM to automatically diagnose sphincter defects, allowing a systematic and comprehensive analysis of the test recordings. Compared with EUS, the 3D-HRAM image analysis procedure revealed poor sensitivity and specificity. PMID- 26046764 TI - Expression of HIF-1alpha and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy. AB - INTRODUCTION: Triple negative breast cancer lacks estrogen, progesterone and epidermal growth factor receptors rendering it refractory to available targetedtherapies. TNBC is associated with central fibrosis and necrosis, both indicators of tumor hypoxia. Hypoxia inducible factor 1alpha is up-regulated under hypoxia and its expression is associated with induction of angiogenesis resulting in proliferation, aggressive tumor phenotype and metastasis. In this study we evaluate the potential use of HIF-1alpha as aTNBC-specific marker. METHODS: 62 TNBC, 64 HER2+, and 64 hormone-receptors positive breast cancer cases were evaluated for central fibrosis and necrosis, HIF-1alpha, HIF-1beta, VEGFR3, CD31 expression and microvessel density. RNA extraction from paraffin-embedded samples, followed by quantitative real-time polymerase chain reaction (qRT-PCR) evaluation of HIF-1alpha and VEGF transcripts was performed on 54 cases (18 from each subtype). RESULTS: HIF-1alpha protein was expressed in 35.5% TNBC, 45.3% HER2+and 25.0% ER+/PR+ (p = 0.055; chi2 test). PCRanalysis of subgroup of breast cancers, 84.2% expressed HIF-1alpha protein and its transcripts, while only 66.7% expressed VEGF transcripts simultaneously with the HIF-1alpha protein and its transcripts. Central fibrosis and necrosis was highest in TNBC (p = 0.015; chi2 test), while MVD was comparable among all groups (p = 0.928; chi2 test). VEGFR3 was highest in TNBC expressing HIF-1alpha. HIF-1beta protein was expressed in 32.0% of HIF-1alpha(+), and in (44.3%) of HIF-1alpha(-) breast cancer cases (p = 0.033; chi2 test). Moreover, HIF-1alpha expression in cases with central fibrosis and necrosis was highest in the HER2+ followed by the TNBC (p = 0.156; chi2 test). CONCLUSIONS: A proportion of TNBC express HIF-1alpha but not in a significantly different manner from other breast cancer subtypes. The potential of anti-HIF-1alpha targeted therapy is therefore not a candidate for exclusive use in TNBC, but should be considered in all breast cancers, especially in the setting of clinically aggressive or refractory disease. PMID- 26046766 TI - Patient Characteristics Associated with Tuberculosis Treatment Default: A Cohort Study in a High-Incidence Area of Lima, Peru. AB - BACKGROUND: Although tuberculosis (TB) is usually curable with antibiotics, poor adherence to medication can lead to increased transmission, drug resistance, and death. Prior research has shown several factors to be associated with poor adherence, but this problem remains a substantial barrier to global TB control. We studied patients in a high-incidence district of Lima, Peru to identify factors associated with premature termination of treatment (treatment default). METHODS: We conducted a prospective cohort study of adult smear-positive TB patients enrolled between January 2010 and December 2011 with no history of TB disease. Descriptive statistics and multivariable logistic regression analyses were performed to determine risk factors associated with treatment default. RESULTS: Of the 1233 patients studied, 127 (10%) defaulted from treatment. Patients who defaulted were more likely to have used illegal drugs (OR = 4.78, 95% CI: 3.05-7.49), have multidrug-resistant TB (OR = 3.04, 95% CI: 1.58-5.85), not have been tested for HIV (OR = 2.30, 95% CI: 1.50-3.54), drink alcohol at least weekly (OR = 2.22, 95% CI: 1.40-3.52), be underweight (OR = 2.08, 95% CI: 1.21-3.56), or not have completed secondary education (OR = 1.55, 95% CI: 1.03 2.33). CONCLUSIONS: Our study identified several factors associated with defaulting from treatment, suggesting a complex set of causes that might lead to default. Addressing these factors individually would be difficult, but they might help to identify certain high-risk patients for supplemental intervention prior to treatment interruption. Treatment adherence remains a barrier to successful TB care and reducing the frequency of default is important for both the patients' health and the health of the community. PMID- 26046768 TI - Circulating mir-208a fails as a biomarker of doxorubicin-induced cardiotoxicity in breast cancer patients. PMID- 26046767 TI - Identification of Reprogrammed Myeloid Cell Transcriptomes in NSCLC. AB - Lung cancer is the leading cause of cancer related mortality worldwide, with non small cell lung cancer (NSCLC) as the most prevalent form. Despite advances in treatment options including minimally invasive surgery, CT-guided radiation, novel chemotherapeutic regimens, and targeted therapeutics, prognosis remains dismal. Therefore, further molecular analysis of NSCLC is necessary to identify novel molecular targets that impact prognosis and the design of new-targeted therapies. In recent years, tumor "activated/reprogrammed" stromal cells that promote carcinogenesis have emerged as potential therapeutic targets. However, the contribution of stromal cells to NSCLC is poorly understood. Here, we show increased numbers of bone marrow (BM)-derived hematopoietic cells in the tumor parenchyma of NSCLC patients compared with matched adjacent non-neoplastic lung tissue. By sorting specific cellular fractions from lung cancer patients, we compared the transcriptomes of intratumoral myeloid compartments within the tumor bed with their counterparts within adjacent non-neoplastic tissue from NSCLC patients. The RNA sequencing of specific myeloid compartments (immature monocytic myeloid cells and polymorphonuclear neutrophils) identified differentially regulated genes and mRNA isoforms, which were inconspicuous in whole tumor analysis. Genes encoding secreted factors, including osteopontin (OPN), chemokine (C-C motif) ligand 7 (CCL7) and thrombospondin 1 (TSP1) were identified, which enhanced tumorigenic properties of lung cancer cells indicative of their potential as targets for therapy. This study demonstrates that analysis of homogeneous stromal populations isolated directly from fresh clinical specimens can detect important stromal genes of therapeutic value. PMID- 26046769 TI - Crystal Structure of USP7 Ubiquitin-like Domains with an ICP0 Peptide Reveals a Novel Mechanism Used by Viral and Cellular Proteins to Target USP7. AB - Herpes simplex virus-1 immediate-early protein ICP0 activates viral genes during early stages of infection, affects cellular levels of multiple host proteins and is crucial for effective lytic infection. Being a RING-type E3 ligase prone to auto-ubiquitination, ICP0 relies on human deubiquitinating enzyme USP7 for protection against 26S proteasomal mediated degradation. USP7 is involved in apoptosis, epigenetics, cell proliferation and is targeted by several herpesviruses. Several USP7 partners, including ICP0, GMPS, and UHRF1, interact through its C-terminal domain (CTD), which contains five ubiquitin-like (Ubl) structures. Despite the fact that USP7 has emerged as a drug target for cancer therapy, structural details of USP7 regulation and the molecular mechanism of interaction at its CTD have remained elusive. Here, we mapped the binding site between an ICP0 peptide and USP7 and determined the crystal structure of the first three Ubl domains bound to the ICP0 peptide, which showed that ICP0 binds to a loop on Ubl2. Sequences similar to the USP7-binding site in ICP0 were identified in GMPS and UHRF1 and shown to bind USP7-CTD through Ubl2. In addition, co-immunoprecipitation assays in human cells comparing binding to USP7 with and without a Ubl2 mutation, confirmed the importance of the Ubl2 binding pocket for binding ICP0, GMPS and UHRF1. Therefore we have identified a novel mechanism of USP7 recognition that is used by both viral and cellular proteins. Our structural information was used to generate a model of near full-length USP7, showing the relative position of the ICP0/GMPS/UHRF1 binding pocket and the structural basis by which it could regulate enzymatic activity. PMID- 26046770 TI - Long-Term Recency in Anterograde Amnesia. AB - Amnesia is usually described as an impairment of a long-term memory (LTM) despite an intact short-term memory (STM). The intact recency effect in amnesia had supported this view. Although dual-store models of memory have been challenged by single-store models based on interference theory, this had relatively little influence on our understanding and treatment of amnesia, perhaps because the debate has centred on experiments in the neurologically intact population. Here we tested a key prediction of single-store models for free recall in amnesia: that people with amnesia will exhibit a memory advantage for the most recent items even when all items are stored in and retrieved from LTM, an effect called long-term recency. People with amnesia and matched controls studied, and then free-recalled, word lists with a distractor task following each word, including the last (continual distractor task, CDFR). This condition was compared to an Immediate Free Recall (IFR, no distractors) and a Delayed Free Recall (DFR, end of-list distractor only) condition. People with amnesia demonstrated the full long-term recency pattern: the recency effect was attenuated in DFR and returned in CDFR. The advantage of recency over midlist items in CDFR was comparable to that of controls, confirming a key prediction of single-store models. Memory deficits appeared only after the first word recalled in each list, suggesting the impairment in amnesia may emerge only as the participant's recall sequence develops, perhaps due to increased susceptibility to output interference. Our findings suggest that interference mechanisms are preserved in amnesia despite the overall impairment to LTM, and challenge strict dual-store models of memory and their dominance in explaining amnesia. We discuss the implication of our findings for rehabilitation. PMID- 26046771 TI - Knowledge and Adherence to Medications among Palestinian Geriatrics Living with Chronic Diseases in the West Bank and East Jerusalem. AB - BACKGROUND: Adequate patient knowledge about medications is essential for appropriate drug taking behavior and patient adherence. This study aims to assess and quantify the level of knowledge and adherence to medications among Palestinian geriatrics living with chronic diseases and to investigate possible associated socio-demographic characteristics. METHODS AND FINDINGS: We conducted a cross-sectional study during June 2013 and January 2014 among Palestinian geriatrics >= 60 years old living with chronic disease in the West Bank and East Jerusalem. A stratified random sample was selected and a questionnaire-assisted interview was applied for data collection. T-test was applied for bivariate analyzing and one-way ANOVA test was applied for multivariate analyses. RESULTS: A total of 1192 Palestinian geriatrics were studied. The average age was 70.3 (SD = 8.58) years and ranged from 60-110 years. The sample comprised 659 (55.3%) females and 533 (44.7%) males. The global knowledge and global adherence scores were (67.57%) and (89.29%), respectively. Adequate levels of knowledge were 71.4%, and of adherence 75%, which were recorded for 705 (59.1%) and 1088 (91.3%) participants, respectively. Significant higher levels of global knowledge and global adherence were recorded for males, and for participants who hold a Bachelor's degree, those who live on their own, and did physical activity for more than 40 hours/week (p-value < 0.05). Furthermore, workers, participants with a higher monthly income, and non-smokers have a higher knowledge level with (p value < 0.05). We found positive correlation between participants' global adherence and global knowledge (r = 0.487 and p-value < 0.001). Negative correlation was found between participants' global knowledge and adherence with age (r = -0.236, p-value < 0.001 and r = -0.211 and p-value < 0.001, respectively. Negative correlation between global knowledge and the number of drugs taken (r = -0.130, p-value < 0.001) was predicted. CONCLUSION: We concluded that patients with a higher level of knowledge are more adherent to their medications and that better understanding of socio-demographic factors has a clear influence on the level of knowledge and adherence to medications and thus contributes to the development of guidelines for treatment and may consequently lead to favourable clinical outcomes and savings of health care costs. PMID- 26046772 TI - Culture and National Well-Being: Should Societies Emphasize Freedom or Constraint? AB - Throughout history and within numerous disciplines, there exists a perennial debate about how societies should best be organized. Should they emphasize individual freedom and autonomy or security and constraint? Contrary to proponents who tout the benefits of one over the other, we demonstrate across 32 nations that both freedom and constraint exhibit a curvilinear relationship with many indicators of societal well-being. Relative to moderate nations, very permissive and very constrained nations exhibit worse psychosocial outcomes (lower happiness, greater dysthymia, higher suicide rates), worse health outcomes (lower life expectancy, greater mortality rates from cardiovascular disease and diabetes) and poorer economic and political outcomes (lower gross domestic product per capita, greater risk for political instability). This supports the notion that a balance between freedom and constraint results in the best national outcomes. Accordingly, it is time to shift the debate away from either constraint or freedom and focus on both in moderation. PMID- 26046773 TI - Characterization of Spirometra erinaceieuropaei Plerocercoid Cysteine Protease and Potential Application for Serodiagnosis of Sparganosis. AB - BACKGROUND: Sparganosis is a neglected but important food-borne parasitic zoonosis. Clinical diagnosis of sparganosis is difficult because there are no specific manifestations. ELISA using plerocercoid crude or excretory-secretory (ES) antigens has high sensitivity but has cross-reactions with other helminthiases. The aim of this study was to characterize Spirometra erinaceieuropaei cysteine protease (SeCP) and to evaluate its potential application for serodiagnosis of sparganosis. METHODOLOGY/PRINCIPAL FINDINGS: The full length SeCP gene was cloned, and recombinant SeCP (rSeCP) was expressed and purified. Western blotting showed that rSeCP was recognized by the serum of sparganum-infected mice, and anti-rSeCP serum recognized the native SeCP protein of plerocercoid crude or ES antigens. Expression of SeCP was observed at plerocercoid stages but not at the adult and egg stages. Immunolocalization identified SeCP in plerocercoid tegument and parenchymal tissue. The rSeCP had CP activity, and the optimum pH and temperature were 5.5 and 37 degrees C, respectively. Enzymatic activity was significantly inhibited by E-64. rSeCP functions to degrade different proteins and the function was inhibited by anti rSeCP serum and E-64. Immunization of mice with rSeCP induced Th2-predominant immune responses and anti-rSeCP antibodies had the potential capabilities to kill plerocercoids in an ADCC assay. The sensitivity of rSeCP-ELISA and ES antigen ELISA was 100% when performed on sera of patients with sparganosis. The specificity of rSeCP-ELISA and ES antigen ELISA was 98.22% (166/169) and 87.57% (148/169), respectively (P<0.05). CONCLUSIONS: The rSeCP had the CP enzymatic activity and SeCP seems to be important for the survival of plerocercoids in host. The rSeCP is a potential diagnostic antigen for sparganosis. PMID- 26046774 TI - Parasympathetic Stimuli on Bronchial and Cardiovascular Systems in Humans. AB - BACKGROUND: It is not known whether parasympathetic outflow simultaneously acts on bronchial tone and cardiovascular system waxing and waning both systems in parallel, or, alternatively, whether the regulation is more dependent on local factors and therefore independent on each system. The aim of this study was to evaluate the simultaneous effect of different kinds of stimulations, all associated with parasympathetic activation, on bronchomotor tone and cardiovascular autonomic regulation. METHODS: Respiratory system resistance (Rrs, forced oscillation technique) and cardio-vascular activity (heart rate, oxygen saturation, tissue oxygenation index, blood pressure) were assessed in 13 volunteers at baseline and during a series of parasympathetic stimuli: O2 inhalation, stimulation of the carotid sinus baroreceptors by neck suction, slow breathing, and inhalation of methacholine. RESULTS: Pure cholinergic stimuli, like O2 inhalation and baroreceptors stimulation, caused an increase in Rrs and a reduction in heart rate and blood pressure. Slow breathing led to bradycardia and hypotension, without significant changes in Rrs. However slow breathing was associated with deep inhalations, and Rrs evaluated at the baseline lung volumes was significantly increased, suggesting that the large tidal volumes reversed the airways narrowing effect of parasympathetic activation. Finally inhaled methacholine caused marked airway narrowing, while the cardiovascular variables were unaffected, presumably because of the sympathetic activity triggered in response to hypoxemia. CONCLUSIONS: All parasympathetic stimuli affected bronchial tone and moderately affected also the cardiovascular system. However the response differed depending on the nature of the stimulus. Slow breathing was associated with large tidal volumes that reversed the airways narrowing effect of parasympathetic activation. PMID- 26046775 TI - Glucose- and mannose-induced stomatal closure is mediated by ROS production, Ca(2+) and water channel in Vicia faba. AB - Sugars act as vital signaling molecules that regulate plant growth, development and stress responses. However, the effects of sugars on stomatal movement have been unclear. In our study, we explored the effects of monosaccharides such as glucose and mannose on stomatal aperture. Here, we demonstrate that glucose and mannose trigger stomatal closure in a dose- and time-dependent manner in epidermal peels of broad bean (Vicia faba). Pharmacological studies revealed that glucose- and mannose-induced stomatal closure was almost completely inhibited by two reactive oxygen species (ROS) scavengers, catalase (CAT) and reduced glutathione (GSH), was significantly abolished by an NADPH oxidase inhibitor, diphenylene iodonium chloride (DPI), whereas they were hardly affected by a peroxidase inhibitor, salicylhydroxamic acid (SHAM). Furthermore, glucose- and mannose-induced stomatal closure was strongly inhibited by a Ca(2+) channel blocker, LaCl3 , a Ca(2+) chelator, ethyleneglycol-bis(beta-aminoethylether)-N,N' tetraacetic acid (EGTA) and two water channel blockers, HgCl2 and dimethyl sulfoxide (DMSO); whereas the inhibitory effects of the water channel blockers were essentially abolished by the reversing agent beta-mercaptoethanol (beta-ME). These results suggest that ROS production mainly via NADPH oxidases, Ca(2+) and water channels are involved in glucose- and mannose-induced stomatal closure. PMID- 26046777 TI - Unspecific membrane protein-lipid recognition: combination of AFM imaging, force spectroscopy, DSC and FRET measurements. AB - In this work, we will describe in quantitative terms the unspecific recognition between lactose permease (LacY) of Escherichia coli, a polytopic model membrane protein, and one of the main components of the inner membrane of this bacterium. Supported lipid bilayers of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE) and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPG) (3:1, mol/mol) in the presence of Ca(2+) display lateral phase segregation that can be distinguished by atomic force microscopy (AFM) as well as force spectroscopy. LacY shows preference for fluid (Lalpha) phases when it is reconstituted in POPE : POPG (3:1, mol/mol) proteoliposomes at a lipid-to-protein ratio of 40. When the lipid-to-protein ratio is decreased down to 0.5, two domains can be distinguished by AFM. While the upper domain is formed by self-segregated units of LacY, the lower domain is constituted only by phospholipids in gel (Lbeta) phase. On the one hand, classical differential scanning calorimetry (DSC) measurements evidenced the segregation of a population of phospholipids and point to the existence of a boundary region at the lipid-protein interface. On the other hand, Forster Resonance Energy Transfer (FRET) measurements in solution evidenced that POPE is selectively recognized by LacY. A binary pseudophase diagram of POPE : POPG built from AFM observations enables to calculate the composition of the fluid phase where LacY is inserted. These results are consistent with a model where POPE constitutes the main component of the lipid-LacY interface segregated from the fluid bulk phase where POPG predominates. PMID- 26046776 TI - Changes in Renal Function and Oxidative Status Associated with the Hypotensive Effects of Oleanolic Acid and Related Synthetic Derivatives in Experimental Animals. AB - PURPOSE: The triterpene oleanolic acid (OA) is known to possess antihypertensive actions. In the present study we to compared the effects of the triterpene on mean arterial blood pressure (MAP) and kidney function following acute administration in normotensive animals with those of its related oleanane synthetic derivatives (brominated oleanolic acid, Br-OA and oleanolic acid methyl ester, Me-OA). We also used experimental models of hypertension to further explore the effects of sub-chronic oral OA treatment and evaluated influences on oxidative status. METHODS: OA was extracted from dried flower buds of Syzygium aromaticum using a previously validated protocol in our laboratory. Me-OA and Br OA were synthesized according to a method described. Rats were supplemented with lithium chloride (12 mmol L-1) prior to experimentation in order to raise plasma lithium to allow measurements of lithium clearance and fractional excretion (FELi) as indices of proximal tubular Na+ handling. Anaesthetized animals were continuously infused via the right jugular with 0.077M NaCl. MAP was measured via a cannula inserted in the carotid artery, and urine was collected through a cannula inserted in the bladder. After a 3.5 h equilibration, MAP, urine flow, electrolyte excretion rates were determined for 4 h of 1 h control, 1.5 h treatment and 1.5 h recovery periods. OA, Me-OA and Br-OA were added to the infusate during the treatment period. We evaluated sub-chronic effects on MAP and kidney function in normotensive Wistar rats and in two animal models of hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DSS) rats, during 9-week administration of OA (p.o.). Tissue oxidative status was examined in these animals at the end of the study. Increasing evidence suggests that and renal function disturbances and oxidative stress play major roles in the pathogenesis of hypertension. RESULTS: Acute infusion OA and oleanane derivatives displayed qualitatively similar effects in decreasing MAP and increasing urinary Na+ outputs. The drugs increased the FENa and FELi without influencing GFR indicating that at least part of the overall natriuretic effect involved proximal tubular Na+ reabsorption. Sub-chronic OA administration (p.o.) also elicited hypotensive responses in Wistar, DSS and SHR rats. The MAP lowering effect was more marked in hypertensive animals and were positively correlated with increased urinary Na+ excretion. Compared with respective control rats, OA treatment reduced malondialdehyde (MDA, a marker of lipid peroxidation) and increased activities of antioxidant enzymes; superoxide dismutase and glutathione peroxidase in hepatic, cardiac and renal tissues. CONCLUSIONS: OA and oleanane derivatives have similar effects on MAP, kidney function and oxidative stress. The amelioration of oxidative stress and blood pressure lowering effects by OA are more marked in hypertensive animals and correlated with an increased urinary Na+ output. NOVELTY OF THE WORK: The results of this study are novel in that they show 1) a correlation between blood pressure reduction and increased urinary Na+ excretion by OA, 2) a more marked MAP reduction in hypertensive animals and 3) a drug-induced decrease in proximal tubule Na+ reabsorption. The results may also be clinically relevant because OA is effective via oral administration. PMID- 26046778 TI - On-farm evaluation of inundative biological control of Ostrinia nubilalis (Lepidoptera: Crambidae) by Trichogramma brassicae (Hymenoptera: Trichogrammatidae) in three European maize-producing regions. AB - BACKGROUND: A 2 year study was conducted to evaluate the efficacy of biological control with optimally timed Trichogramma brassicae releases as an integrated pest management tool against the European corn borer (ECB), Ostrinia nubilalis (Hubner), in on-farm experiments (i.e. real field conditions) in three European regions with dissimilar geoclimatic conditions and ECB pressure and conventional management (i.e. insecticide treated and untreated). RESULTS: Biological control with Trichogramma (1) provided ECB protection comparable with conventional management, (2) in all cases maintained mycotoxin levels below the EU threshold for maize raw materials destined for food products, (3) was economically sustainable in southern France and northern Italy, but not in Slovenia where it resulted in a significant decrease in gross margin, mainly owing to the cost of Trichogramma product, and (4) enabled avoidance of detrimental environmental effects of lambda-cyhalothrin use in northern Italy. CONCLUSION: Optimally timed mass release of T. brassicae could be considered a sustainable tool for IPM programmes against ECB in southern France and northern Italy. Better involvement of regional advisory services is needed for the successful dissemination and implementation of biological control. Subsidy schemes could also motivate farmers to adopt this IPM tool and compensate for high costs of Trichogramma product. PMID- 26046779 TI - Expanding the yeast protein arginine methylome. AB - Protein arginine methylation is a PTM involved in various cellular processes in eukaryotes. Recent discoveries led to a vast expansion of known sites in higher organisms, indicating that this modification is more widely spread across the proteome than previously assumed. An increased knowledge of sites in lower eukaryotes may facilitate the elucidation of its functions. In this study, we present the discovery of arginine mono-methylation sites in Saccharomyces cerevisiae by a combination of immunoaffinity enrichment and MS/MS. As detection of methylation is prone to yield false positives, we demonstrate the need for stringent measures to avoid elevated false discovery rates. To this end, we employed MethylSILAC in combination with a multistep data analysis strategy. We report 41 unambiguous methylation sites on 13 proteins. Our results indicate that, while substantially less abundant, arginine methylation follows similar patterns as in higher eukaryotes in terms of sequence context and functions of methylated proteins. The majority of sites occur on RNA-binding proteins participating in processes from transcription and splicing to translation and RNA degradation. Additionally, our data suggest a bias for localization of arginine methylation in unstructured regions of proteins, which frequently involves Arg Gly-Gly motifs or Asn-rich contexts. PMID- 26046780 TI - A Seven-microRNA Expression Signature Predicts Survival in Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth common cancer. The differential expression of microRNAs (miRNAs) has been associated with the prognosis of various cancers. However, limited information is available regarding genome-wide miRNA expression profiles in HCC to generate a tumor-specific miRNA signature of prognostic values. In this study, the miRNA profiles in 327 HCC patients, including 327 tumor and 43 adjacent non-tumor tissues, from The Cancer Genome Atlas (TCGA) Liver hepatocellular carcinoma (LIHC) were analyzed. The associations of the differentially expressed miRNAs with patient survival and other clinical characteristics were examined with t-test and Cox proportional regression model. Finally, a tumor-specific miRNA signature was generated and examined with Kaplan-Meier survival, univariate?multivariate Cox regression analyses and KEGG pathway analysis. Results showed that a total of 207 miRNAs were found differentially expressed between tumor and adjacent non-tumor HCC tissues. 78 of them were also discriminatively expressed with gender, race, tumor grade and AJCC tumor stage. Seven miRNAs were significantly associated with survival (P value <0.001). Among the seven significant miRNAs, six (hsa-mir-326, hsa-mir-3677, hsa-mir-511-1, hsa-mir-511-2, hsa-mir-9-1, and hsa-mir-9-2) were negatively associated with overall survival (OS), while the remaining one (hsa mir-30d) was positively correlated. A tumor-specific 7-miRNAs signature was generated and validated as an independent prognostic predictor. Collectively, we have identified and validated an independent prognostic model based on the expression of seven miRNAs, which can be used to assess patients' survival. Additional work is needed to translate our model into clinical practice. PMID- 26046781 TI - Automatic whole brain tract-based analysis using predefined tracts in a diffusion spectrum imaging template and an accurate registration strategy. AB - Automated tract-based analysis of diffusion MRI is an important tool for investigating tract integrity of the cerebral white matter. Current template based automatic analyses still lack a comprehensive list of tract atlas and an accurate registration method. In this study, tract-based automatic analysis (TBAA) was developed to meet the demands. Seventy-six major white matter tracts were reconstructed on a high-quality diffusion spectrum imaging (DSI) template, and an advanced two-step registration strategy was proposed by incorporating anatomical information of the gray matter from T1-weighted images in addition to microstructural information of the white matter from diffusion-weighted images. The automatic analysis was achieved by establishing a transformation between the DSI template and DSI dataset of the subject derived from the registration strategy. The tract coordinates in the template were transformed to native space in the individual's DSI dataset, and the microstructural properties of major tract bundles were sampled stepwise along the tract coordinates of the subject's DSI dataset. In a validation study of eight well-known tracts, our results showed that TBAA had high geometric agreement with manual tracts in both deep and superficial parts but significantly smaller measurement variability than manual method in functional difference. Additionally, the feasibility of the method was demonstrated by showing tracts with altered microstructural properties in patients with schizophrenia. Fifteen major tract bundles were found to have significant differences after controlling the family-wise error rate. In conclusion, the proposed TBAA method is potentially useful in brain-wise investigations of white matter tracts, particularly for a large cohort study. PMID- 26046783 TI - Errata. PMID- 26046782 TI - The Utility of Sentinel Lymph Node Biopsy in Papillary Thyroid Carcinoma with Occult Lymph Nodes. AB - BACKGROUND: The sentinel lymph node (SLN) is defined as the first draining node from the primary lesion, and it has proven to be a good indicator of the metastatic status of regional lymph nodes in solid tumors. The aim of this study was to evaluate the clinical application of SLN biopsy (SLNB) in papillary thyroid carcinoma (PTC) with occult lymph nodes. METHODS: From April 2006 to October 2012, 212 consecutive PTC patients were treated with SLNB using carbon nanoparticle suspension (CNS). Then, the stained nodes defined as SLN were collected, and prophylactic central compartment neck dissection (CCND) followed by total thyroidectomy or subtotal thyroidectomy were performed. All the samples were sent for pathological examination. RESULTS: There were 78 (36.8%) SLN metastasis (SLNM)-positive cases and 134 (63.2%) SLNM-negative cases. The sensitivity, specificity, positive and negative predictive values, and false positive and false-negative rates of SLNB were 78.8%, 100%, 100%, 84.3%, 0%, and 21.2%, respectively. The PTC patients with SLNM were more likely to be male (48.2% vs. 32.7%, p = 0.039) and exhibited multifocality (52.6% vs. 33.3%, p = 0.025) and extrathyroidal extension (56.7% vs. 33.5%, p = 0.015). A greater incidence of non-SLN metastases in the central compartment was found in patients with SLNM (41/78, 52.6%) than in those without SLNM (21/134, 15.7%; p < 0.05). However, the SLNM-negative PTC patients with non-SLN metastases were more likely to be male (37.9% vs. 9.5%, p < 0.05). CONCLUSIONS: The application of SLNB using CNS is technically feasible, safe, and useful, especially for male patients with co-existing multifocality and extrathyroidal extension. However, the sensitivity of SLNB must be improved and its false-negative rate reduced before it can be a routine procedure and replace prophylactic CCND. More attention should be paid to PTC patients (especially males) without SLNM for signs of non-SLN metastases. PMID- 26046785 TI - Correction: Expression Patterns of Bovine CD1 In Vivo and Assessment of the Specificities of the Anti-Bovine CD1 Antibodies. PMID- 26046784 TI - Multi-Acupuncture Point Injections and Their Anatomical Study in Relation to Neck and Shoulder Pain Syndrome (So-Called Katakori) in Japan. AB - Katakori is a symptom name that is unique to Japan, and refers to myofascial pain syndrome-like clinical signs in the shoulder girdle. Various methods of pain relief for katakori have been reported, but in the present study, we examined the clinical effects of multi-acupuncture point injections (MAPI) in the acupuncture points with which we empirically achieved an effect, as well as the anatomical sites affected by liquid medicine. The subjects were idiopathic katakori patients (n = 9), and three cadavers for anatomical investigation. BL-10, GB-21, LI-16, SI 14, and BL-38 as the WHO notation were selected as the acupuncture point. Injections of 1 mL of 1% w/v mepivacaine were introduced at the same time into each of these points in the patients. Assessment items were the Pain Relief Score and the therapeutic effect period. Dissections were centered at the puncture sites of cadavers. India ink was similarly injected into each point, and each site that was darkly-stained with India ink was evaluated. Katakori pain in the present study was significantly reduced by MAPI. Regardless of the presence or absence of trigger points, pain was significantly reduced in these cases. Dark staining with India ink at each of the points in the anatomical analysis was as follows: BL-10: over the rectus capitis posterior minor muscle and rectus capitis posterior major muscle fascia; GB-21: over the supraspinatus muscle fascia; LI 16: over the supraspinatus muscle fascia; SI-14: over the rhomboid muscle fascia; and BL-38: over the rhomboid muscle fascia. The anatomical study suggested that the drug effect was exerted on the muscles above and below the muscle fascia, as well as the peripheral nerves because the points of action in acupuncture were darkly-stained in the spaces between the muscle and the muscle fascia. PMID- 26046786 TI - Not sending the message: A low prevalence of strength-based exercise participation in rural and regional Central Queensland. AB - OBJECTIVE: The primary aim of this study was to determine the prevalence of current strength-based exercise in rural and regional populations of Central Queensland. The secondary aim was to examine the proportion of residents from various demographic groups who currently partake in strength-based exercise to allow for targeted strength training campaigns. DESIGN: A cross-sectional, survey based experimental design was followed. SETTING: Rural and regional Australia. PARTICIPANTS: Rural and regional community-dwelling individuals living in Central Queensland and aged 18 years and older. INTERVENTION: Survey data was collected in October and November 2010 as part of the Central Queensland University Social Survey. MAIN OUTCOME MEASURES: Strength-based exercise participation, gender, age, income, years of education, self-reported physical activity and perception of health. RESULTS: Participation in strength-based exercise was 13.2%. Women were less likely to partake in strength-based exercise than male, and >=55 year old adults were less likely to partake in strength-based exercise than 18-34 year old adults. Participation in strength-based exercise was found to increase with years of education, self-reported physical activity and self-rated health. CONCLUSION: The prevalence of adults in rural and regional Central Queensland engaging in strength-based exercise is low. Exercise physiologists, clinicians and government officials must work together to ensure that this form of exercise is acknowledged as a vital component of health in rural and regional areas. PMID- 26046788 TI - Implications of scaled delta15N fractionation for community predator-prey body mass ratio estimates in size-structured food webs. AB - Nitrogen stable isotope ratios (delta(15) N) may be used to estimate community level relationships between trophic level (TL) and body size in size-structured food webs and hence the mean predator to prey body mass ratio (PPMR). In turn, PPMR is used to estimate mean food chain length, trophic transfer efficiency and rates of change in abundance with body mass (usually reported as slopes of size spectra) and to calibrate and validate food web models. When estimating TL, researchers had assumed that fractionation of delta(15) N (Deltadelta(15) N) did not change with TL. However, a recent meta-analysis indicated that this assumption was not as well supported by data as the assumption that Deltadelta(15) N scales negatively with the delta(15) N of prey. We collated existing fish community delta(15) N-body size data for the Northeast Atlantic and tropical Western Arabian Sea with new data from the Northeast Pacific. These data were used to estimate TL-body mass relationships and PPMR under constant and scaled Deltadelta(15) N assumptions, and to assess how the scaled Deltadelta(15) N assumption affects our understanding of the structure of these food webs. Adoption of the scaled Deltadelta(15) N approach markedly reduces the previously reported differences in TL at body mass among fish communities from different regions. With scaled Deltadelta(15) N, TL-body mass relationships became more positive and PPMR fell. Results implied that realized prey size in these size structured fish communities are less variable than previously assumed and food chains potentially longer. The adoption of generic PPMR estimates for calibration and validation of size-based fish community models is better supported than hitherto assumed, but predicted slopes of community size spectra are more sensitive to a given change or error in realized PPMR when PPMR is small. PMID- 26046787 TI - The biology of circulating microRNAs in cardiovascular disease. AB - BACKGROUND: Since their first description in mammalian cells, more than 2500 microRNA molecules have been predicted or verified within human cells. Recently, extracellular microRNAs have been described, protected from degradation by specialized packaging in extracellular vesicles or RNA-binding proteins. MATERIALS AND METHODS: We will discuss recent data regarding circulating microRNAs, their potential role as novel biomarkers and intercellular communicators, as well as future challenges of studying and applying such novel biology, particularly in the cardiovascular system. RESULTS: Circulating microRNAs have been proposed as attractive candidates as both diagnostic and prognostic biomarkers in various diseases, including a spectrum of cardiovascular conditions. Moreover, consistent with our evolving appreciation of the role of exosomes and microvesicles in intercellular communication, it has been proposed that delivery of active microRNAs to recipient tissues may serve as a primary mode of intercellular communication. Indeed, the transfer of functional microRNAs has been demonstrated in in vitro models and has been reported in a few in vivo contexts. In addition, therapeutic application of extracellular microRNAs has also been explored. CONCLUSION: Over recent years, increasing attention has been paid to the role of circulating miRNAs in cardiovascular disease. As biomarkers and intercellular communicators, circulating miRNAs could play important roles in the prediction, diagnosis and tailored treatment of cardiovascular diseases in the near future. PMID- 26046789 TI - An Approach to Heterologous Expression of Membrane Proteins. The Case of Bacteriorhodopsin. AB - Heterologous overexpression of functional membrane proteins is a major bottleneck of structural biology. Bacteriorhodopsin from Halobium salinarum (bR) is a striking example of the difficulties in membrane protein overexpression. We suggest a general approach with a finite number of steps which allows one to localize the underlying problem of poor expression of a membrane protein using bR as an example. Our approach is based on constructing chimeric proteins comprising parts of a protein of interest and complementary parts of a homologous protein demonstrating advantageous expression. This complementary protein approach allowed us to increase bR expression by two orders of magnitude through the introduction of two silent mutations into bR coding DNA. For the first time the high quality crystals of bR expressed in E. Coli were obtained using the produced protein. The crystals obtained with in meso nanovolume crystallization diffracted to 1.67 A. PMID- 26046790 TI - A comparison of NBI and WLI cystoscopy in detecting non-muscle-invasive bladder cancer: A prospective, randomized and multi-center study. AB - Several single-center studies have investigated whether narrow-band imaging (NBI) cystoscopy is more effective in detecting primary and recurrent non-muscle invasive bladder cancer (NMIBC) compared with white-light imaging (WLI) cystoscopy. In this study, we further evaluated the diagnostic value of NBI cystoscopy compared with WLI cystoscopy for primary NMIBC in a multi-center study. Suspected bladder cancer patients from 8 research centers received both NBI and WLI. Two experienced doctors in each center were responsible for the NBI and WLI assessments, respectively. The number of tumors and position of each tumor were recorded, and suspicious tissues were clamped and histologically examined. The sensitivity, specificity, and false-positive rate of NBI and WLI were evaluated. Of the 384 patients, 78 had a confirmed urothelial carcinoma (UC). The sensitivities of NBI and WLI were 97.70%, and 66.67%, respectively (P < 0.0001); the specificities were 50% and 25%, respectively; and the false positive rates were 50% and 75%, respectively. Based on 300 valid biopsy specimens, the NBI and WLI sensitivities were 98.80% and 75.45%, respectively (P < 0.0001). These results suggest that NBI has a high sensitivity and has superior early bladder tumor and carcinoma in situ (CIS) detection rates compared with WLI cystoscopy. PMID- 26046791 TI - Identifying ultrasound and clinical features of breast cancer molecular subtypes by ensemble decision. AB - Breast cancer is molecularly heterogeneous and categorized into four molecular subtypes: Luminal-A, Luminal-B, HER2-amplified and Triple-negative. In this study, we aimed to apply an ensemble decision approach to identify the ultrasound and clinical features related to the molecular subtypes. We collected ultrasound and clinical features from 1,000 breast cancer patients and performed immunohistochemistry on these samples. We used the ensemble decision approach to select unique features and to construct decision models. The decision model for Luminal-A subtype was constructed based on the presence of an echogenic halo and post-acoustic shadowing or indifference. The decision model for Luminal-B subtype was constructed based on the absence of an echogenic halo and vascularity. The decision model for HER2-amplified subtype was constructed based on the presence of post-acoustic enhancement, calcification, vascularity and advanced age. The model for Triple-negative subtype followed two rules. One was based on irregular shape, lobulate margin contour, the absence of calcification and hypovascularity, whereas the other was based on oval shape, hypovascularity and micro-lobulate margin contour. The accuracies of the models were 83.8%, 77.4%, 87.9% and 92.7%, respectively. We identified specific features of each molecular subtype and expanded the scope of ultrasound for making diagnoses using these decision models. PMID- 26046792 TI - Time Related Changes of Mineral and Collagen and Their Roles in Cortical Bone Mechanics of Ovariectomized Rabbits. AB - As cortical bone has a hierarchical structure, the macroscopic bone strength may be affected by the alterations of mineral crystal and collagen, which are main components of cortical bone. Limited studies focused on the time related alterations of these two components in osteoporosis, and their contributions to bone mechanics at tissue level and whole-bone level. Therefore, the purpose of this study was to elucidate the time related changes of mineral and collagen in cortical bone of ovariectomized (OVX) rabbits, and to relate these changes to cortical bone nanomechanics and macromechanics. 40 Rabbits (7-month-old) were randomly allocated into two groups (OVX and sham). OVX group received bilateral ovariectomy operation. Sham group received sham-OVX operation. Cortical bone quality of five rabbits in each group were assessed by DXA, MUCT, nanoindentation, Fourier transform infrared (FTIR) spectroscopy and biomechanical tests (3-point bending of femoral midshaft) at pre-OVX, 4, 6, and 8 weeks after OVX. As time increased from pre-OVX to 8 weeks, the mineral to matrix ratio decreased with time, while both collagen crosslink ratio and crystallinity increased with time in OVX group. Elastic modulus and hardness measured by nanoindentation, whole-bone strength measured by biomechanical tests all decreased in OVX group with time. Bone material properties measured by FTIR correlated well with nano or whole-bone level mechanics. However, bone mineral density (BMD), structure, tissue-level and whole-bone mechanical properties did not change with age in sham group. Our study demonstrated that OVX could affect the tissue-level mechanics and bone strength of cortical bone. And this influence was attributed to the time related alterations of mineral and collagen properties, which may help us to design earlier interventions and more effective treatment strategies on osteoporosis. PMID- 26046793 TI - Identification of TAX2 peptide as a new unpredicted anti-cancer agent. AB - The multi-modular glycoprotein thrombospondin-1 (TSP-1) is considered as a key actor within the tumor microenvironment. Besides, TSP-1 binding to CD47 is widely reported to regulate cardiovascular function as it promotes vasoconstriction and angiogenesis limitation. Therefore, many studies focused on targeting TSP-1:CD47 interaction, aiming for up-regulation of physiological angiogenesis to enhance post-ischemia recovery or to facilitate engraftment. Thus, we sought to identify an innovative selective antagonist for TSP-1:CD47 interaction. Protein-protein docking and molecular dynamics simulations were conducted to design a novel CD47 derived peptide, called TAX2. TAX2 binds TSP-1 to prevent TSP-1:CD47 interaction, as revealed by ELISA and co-immunoprecipitation experiments. Unexpectedly, TAX2 inhibits in vitro and ex vivo angiogenesis features in a TSP-1-dependent manner. Consistently, our data highlighted that TAX2 promotes TSP-1 binding to CD36 containing complexes, leading to disruption of VEGFR2 activation and downstream NO signaling. Such unpredicted results prompted us to investigate TAX2 potential in tumor pathology. A multimodal imaging approach was conducted combining histopathological staining, MVD, MRI analysis and MUCT monitoring for tumor angiography longitudinal follow-up and 3D quantification. TAX2 in vivo administrations highly disturb syngeneic melanoma tumor vascularization inducing extensive tumor necrosis and strongly inhibit growth rate and vascularization of human pancreatic carcinoma xenografts in nude mice. PMID- 26046794 TI - TLR9 signaling through NF-kappaB/RELA and STAT3 promotes tumor-propagating potential of prostate cancer cells. AB - Prostate cancer progression was associated with tumorigenic signaling activated by proinflammatory mediators. However, the etiology of these events remains elusive. Here, we demonstrate that triggering of the innate immune receptor, Toll like Receptor 9 (TLR9), in androgen-independent prostate cancer cells initiates signaling cascade leading to increased tumor growth and progression. Using limited dilution/serial transplantation experiments, we show that TLR9 is essential for prostate cancer cells' potential to propagate and self-renew in vivo. Furthermore, low expression or silencing of TLR9 limits the clonogenic potential and mesenchymal stem cell-like properties of LNCaP- and PC3-derived prostate cancer cell variants. Genome-wide transcriptional analysis of prostate cancer cells isolated from xenotransplanted TLR9-positive and -negative tumors revealed a unique gene expression signature, with prominent upregulation of inflammation- and stem cell-related markers. TLR9 signaling orchestrated expression of critical stem cell-related genes such as NKX3.1, KLF-4, BMI-1 and COL1A1, at both mRNA and protein levels. Our further analysis identified that TLR9-induced NF-kappaB/RELA and STAT3 transcription factors co-regulated NKX3.1 and KLF4 gene expression by directly binding to both promoters. Finally, we demonstrated the feasibility of using TLR9-targeted siRNA delivery to block RELA- and STAT3-dependent prostate cancer cell self-renewal in vivo. The intratumoral administration of CpG-RELAsiRNA or CpG-STAT3siRNA but not control conjugates inhibited growth of established prostate tumors and reduced clonogenic potential of cancer cells. Overcoming cancer cell self-renewal and tumor-propagating potential by targeted inhibition of TLR9 signaling can provide therapeutic strategy for late-stage prostate cancer patients. PMID- 26046795 TI - Genomic instability and cellular stress in organ biopsies and peripheral blood lymphocytes from patients with colorectal cancer and predisposing pathologies. AB - Inflammatory bowel disease (IBD) and polyps, are common colorectal pathologies in western society and are risk factors for development of colorectal cancer (CRC). Genomic instability is a cancer hallmark and is connected to changes in chromosomal structure, often caused by double strand break formation (DSB), and aneuploidy. Cellular stress, may contribute to genomic instability. In colorectal biopsies and peripheral blood lymphocytes of patients with IBD, polyps and CRC, we evaluated 1) genomic instability using the gammaH2AX assay as marker of DSB and micronuclei in mononuclear lymphocytes kept under cytodieresis inhibition, and 2) cellular stress through expression and cellular localization of glutathione-S-transferase omega 1 (GSTO1). Colon biopsies showed gammaH2AX increase starting from polyps, while lymphocytes already from IBD. Micronuclei frequency began to rise in lymphocytes of subjects with polyps, suggesting a systemic genomic instability condition. Colorectal tissues lost GSTO1 expression but increased nuclear localization with pathology progression. Lymphocytes did not change GSTO1 expression and localization until CRC formation, where enzyme expression was increased. We propose that the growing genomic instability found in our patients is connected with the alteration of cellular environment. Evaluation of genomic damage and cellular stress in colorectal pathologies may facilitate prevention and management of CRC. PMID- 26046796 TI - Erlotinib is effective in pancreatic cancer with epidermal growth factor receptor mutations: a randomized, open-label, prospective trial. AB - OBJECTIVE: To analyze the efficacy of gemcitabine with or without erlotinib for pancreatic cancer, and to determine the predictive role of epidermal growth factor receptor (EGFR) and KRAS mutations in these patients. METHODS: This was a single-center, randomized, open-label, prospective trial. Eighty-eight chemotherapy-naive metastatic pancreatic cancer patients were randomized for treatment with gemcitabine or gemcitabine plus erlotinib. EGFR and KRAS mutations were analyzed, respectively. The primary endpoint was the disease control rate. RESULTS: Disease control rate (64% vs. 25%; P < 0.001), progression-free survival (median 3.8 vs. 2.4 months; P < 0.001), and overall survival (median 7.2 vs. 4.4 months; P < 0.001) were better in the gemcitabine plus erlotinib group than in the gemcitabine alone group. In the gemcitabine plus erlotinib group, disease control (85% vs. 33%; P = 0.001), progression-free survival (median 5.9 vs. 2.4 months; P = 0.004), and overall survival (median 8.7 vs. 6.0 months; P = 0.044) were better in patients with EGFR mutations than in those without EGFR mutations. KRAS mutation was not associated with treatment response or survival. CONCLUSIONS: Gemcitabine plus erlotinib is more effective than gemcitabine alone for treating metastatic pancreatic cancer patients, especially those with EGFR mutations. ClinicalTrials.gov number, NCT01608841. PMID- 26046797 TI - High RAD54B expression: an independent predictor of postoperative distant recurrence in colorectal cancer patients. AB - We recently reported a specific mechanism that RAD54B, an important factor in homologous recombination, promotes genomic instability via the degradation of p53 protein in vitro. However, clinical significance of RAD54Bin colorectal cancer (CRC) remains unclear. Thus we analyzed RAD54B geneexpression in CRC patients. Using the training set (n = 123), the optimal cut-off value for stratification was determined, and validated in another cohort (n = 89). Kaplan-Meier plots showed that distant recurrence free survival was significantly lesser in high RAD54B expression group compared with that of low expression group in both training (P = 0.0013) and validation (P = 0.024) set. Multivariate analysis using Cox proportional-hazards model showed that high RAD54B expression was an independent predictor in both training (hazard ratio, 4.31; 95% CI, 1.53-13.1; P = 0.0060) and validation (hazard ratio, 3.63; 95% CI, 1.23-10.7; P = 0.021) set. In addition, a negative significant correlation between RAD54B and CDKN1A, a target gene of p53, was partially confirmed, suggesting that RAD54B functions via the degradation of p53 protein even in clinical samples. This study first demonstrated RAD54B expression has potential to serve as a novel prognostic biomarker, particularly for distant recurrence in CRC patients. PMID- 26046799 TI - Direct Evidence for Vision-based Control of Flight Speed in Budgerigars. AB - We have investigated whether, and, if so, how birds use vision to regulate the speed of their flight. Budgerigars, Melopsittacus undulatus, were filmed in 3-D using high-speed video cameras as they flew along a 25 m tunnel in which stationary or moving vertically oriented black and white stripes were projected on the side walls. We found that the birds increased their flight speed when the stripes were moved in the birds' flight direction, but decreased it only marginally when the stripes were moved in the opposite direction. The results provide the first direct evidence that Budgerigars use cues based on optic flow, to regulate their flight speed. However, unlike the situation in flying insects, it appears that the control of flight speed in Budgerigars is direction-specific. It does not rely solely on cues derived from optic flow, but may also be determined by energy constraints. PMID- 26046798 TI - Avibirnavirus VP4 Protein Is a Phosphoprotein and Partially Contributes to the Cleavage of Intermediate Precursor VP4-VP3 Polyprotein. AB - Birnavirus-encoded viral protein 4 (VP4) utilizes a Ser/Lys catalytic dyad mechanism to process polyprotein. Here three phosphorylated amino acid residues Ser538, Tyr611 and Thr674 within the VP4 protein of the infectious bursal disease virus (IBDV), a member of the genus Avibirnavirus of the family Birnaviridae, were identified by mass spectrometry. Anti-VP4 monoclonal antibodies finely mapping to phosphorylated (p)Ser538 and the epitope motif 530PVVDGIL536 were generated and verified. Proteomic analysis showed that in IBDV-infected cells the VP4 was distributed mainly in the cytoskeletal fraction and existed with different isoelectric points and several phosphorylation modifications. Phosphorylation of VP4 did not influence the aggregation of VP4 molecules. The proteolytic activity analysis verified that the pTyr611 and pThr674 sites within VP4 are involved in the cleavage of viral intermediate precursor VP4-VP3. This study demonstrates that IBDV-encoded VP4 protein is a unique phosphoprotein and that phosphorylation of Tyr611 and Thr674 of VP4 affects its serine-protease activity. PMID- 26046800 TI - The Tie2-agonist Vasculotide rescues mice from influenza virus infection. AB - Seasonal influenza virus infections cause hundreds of thousands of deaths annually while viral mutation raises the threat of a novel pandemic strain. Antiviral drugs exhibit limited efficacy unless administered early and may induce viral resistance. Thus, targeting the host response directly has been proposed as a novel therapeutic strategy with the added potential benefit of not eliciting viral resistance. Severe influenza virus infections are complicated by respiratory failure due to the development of lung microvascular leak and acute lung injury. We hypothesized that enhancing lung endothelial barrier integrity could improve the outcome. Here we demonstrate that the Tie2-agonist tetrameric peptide Vasculotide improves survival in murine models of severe influenza, even if administered as late as 72 hours after infection; the benefit was observed using three strains of the virus and two strains of mice. The effect required Tie2, was independent of viral replication and did not impair lung neutrophil recruitment. Administration of the drug decreased lung edema, arterial hypoxemia and lung endothelial apoptosis; importantly, Vasculotide is inexpensive to produce, is chemically stable and is unrelated to any Tie2 ligands. Thus, Vasculotide may represent a novel and practical therapy for severe infections with influenza. PMID- 26046801 TI - A novel Monoclonal Antibody against Notch1 Targets Leukemia-associated Mutant Notch1 and Depletes Therapy Resistant Cancer Stem Cells in Solid Tumors. AB - Higher Notch signaling is known to be associated with hematological and solid cancers. We developed a potential immunotherapeutic monoclonal antibody (MAb) specific for the Negative Regulatory Region of Notch1 (NRR). The MAb604.107 exhibited higher affinity for the "Gain-of-function" mutants of Notch1 NRR associated with T Acute lymphoblastic Leukemia (T-ALL). Modeling of the mutant NRR with 12 amino-acid insertion demonstrated "opening" resulting in exposure of the S2-cleavage site leading to activated Notch1 signaling. The MAb, at low concentrations (1-2 MUg/ml), inhibited elevated ligand-independent Notch1 signaling of NRR mutants, augmented effect of Thapsigargin, an inhibitor of mutant Notch1, but had no effect on the wild-type Notch1. The antibody decreased proliferation of the primary T-ALL cells and depleted leukemia initiating CD34/CD44 high population. At relatively high concentrations, (10-20 MUg/ml), the MAb affected Notch1 signaling in the breast and colon cancer cell lines. The Notch-high cells sorted from solid-tumor cell lines exhibited characteristics of cancer stem cells, which were inhibited by the MAb. The antibody also increased the sensitivity to Doxorubucinirubicin. Further, the MAb impeded the growth of xenografts from breast and colon cancer cells potentiated regression of the tumors along with Doxorubucin. Thus, this antibody is potential immunotherapeutic tool for different cancers. PMID- 26046802 TI - Treatment of Community-Acquired Pneumonia in Adults: Analysis of the National Dispensing Database. AB - Crude national ambulatory antibiotic dispensing data (2007-2011) of adult patients (aged between 20 and below 65 years) with CAP were obtained and expressed as DDD per 1000 inhabitants and per day (DID). European quality indicators of antibiotic prescribing were calculated and adherence rate to the national CAP guideline was assessed. Antibiotic use for CAP in adults ranged between 0.27 and 0.30 DID in various years. The most frequently used antibacterials were levofloxacin, co-amoxiclav and clarithromycin. Antibiotic use in CAP was compliant with the European recommendations in 6.4% in 2007, which decreased to 4.9% by 2011, in contrast to the optimal compliant range of 80-100%. The consumption of fluoroquinolones mounted up to ~40% in both genders, which exceeded the recommended range (0-5%) substantially. National guideline also favoured the use of macrolides in the empiric therapy of CAP in otherwise healthy adults; hence, guideline-concordant antibiotic use ranged between 24.0-32.3%. Agents that were contra-indicated in the empiric therapy of CAP were also used in 6.5-9.0% in various years. These data reflect some worrisome figures and trends in the outpatient antibiotic treatment of adults with CAP. Clarified and updated national guidelines focusing on outpatients and incentives/regulations to increase guideline concordance are warranted. PMID- 26046804 TI - Working With the Food and Drug Administration's Center for Devices to Advance Regulatory Science and Medical Device Innovation. PMID- 26046803 TI - Photoperiod affects the cerebrospinal fluid proteome: a comparison between short day- and long day-treated ewes. AB - Photoperiod is the main physical synchronizer of seasonal functions and a key factor in the modulation of molecule access to cerebrospinal fluid (CSF) in animals. Previous work has shown that photoperiod affects the transfer rate of steroids and protein hormones from blood to CSF and modulates choroid plexus tight junction protein content. We hypothesized that the CSF proteome would also be modified by photoperiod. We tested this hypothesis by comparing CSF obtained from the third ventricle of mature, ovariectomized, estradiol-replaced ewes exposed to long day length (LD) or short day length (SD). Variations in CSF protein expression between SD- or LD-treated ewes were studied in pools of CSF collected for 48 h. Proteins were precipitated, concentrated, and included in a polyacrylamide gel without protein fractionation. After in-gel tryptic digestion of total protein samples, we analyzed the resulting peptides by nanoliquid chromatography coupled with high-resolution tandem mass spectrometry (GeLC MS/MS). Quantitative analysis was performed using 2 methods based on spectral counting and extracted ion chromatograms. Among 103 identified proteins, 41 were differentially expressed between LD and SD ewes (with P < 0.05 and at least a 1.5 fold difference). Of the 41 differentially expressed proteins, 22 were identified by both methods and 19 using extracted ion chromatograms only. Eighteen proteins were more abundant in LD ewes and 23 were more abundant in SD ewes. These proteins are involved in numerous functions including hormone transport, immune system activity, metabolism, and angiogenesis. To confirm proteomic results, 2 proteins, pigment epithelium-derived factor (PEDF) and gelsolin, for each individual sample of CSF collected under SD or LD were analyzed with Western blots. These results suggest an important photoperiod-dependent change in CSF proteome composition. Nevertheless, additional studies are required to assess the role of each protein in seasonal functions. PMID- 26046807 TI - Immunological and clinical factors associated with adverse systemic reactions during the build-up phase of honeybee venom immunotherapy. AB - BACKGROUND: Adverse systemic reactions (SRs) are more common in honeybee venom immunotherapy (VIT) than in wasp VIT. Factors that might be associated with SRs during the honeybee VIT are poorly understood. OBJECTIVE: Our aim was to evaluate risk factors for SRs during the build-up phase of honeybee venom immunotherapy. METHODS: We included 93 patients who underwent ultra-rush honeybee VIT. The adverse SRs and their severity was compared to various immunological (sIgE, tIgE, basophil CD63 response, baseline tryptase, and skin tests), patient-specific (age, sex, cardiovascular conditions and medications, and other allergic diseases), and sting-specific factors (anaphylaxis severity, time interval to onset of symptoms, and absence of cutaneous symptoms). RESULTS: Twenty-three patients (24.7%) experienced mild SRs and 13 patients (14%) severe SRs. In five patients with severe SRs, the build-up was stopped. High basophil allergen sensitivity, evaluated as dose-response curve metrics of EC15, EC50, CD-sens, AUC, or the response to submaximal 0.01 MUg/mL of venom concentration, was the most significant risk factor and only independent predictor of severe SRs and/or build-up stop. Time interval of <5 min after sting to onset of symptoms and lower specific IgEs to rApi m1 was also associated with severe SRs. There was no difference in other immunological, patient-specific, or sting-specific factors, including the baseline tryptase. None of the studied factors was associated with mild SRs. CONCLUSION AND CLINICAL RELEVANCE: High basophil allergen CD63 sensitivity phenotype was a major indicator of severe adverse SRs during the build-up phase of honeybee VIT. Possibly role was also showed for short latency to filed sting reaction and low sIgE to rApi m1. Before honeybee VIT, measurement of basophil allergen sensitivity should be used to identify patients with a high risk for severe side-effects. PMID- 26046806 TI - Neuroendocrine Function After Hypothalamic Depletion of Glucocorticoid Receptors in Male and Female Mice. AB - Glucocorticoids act rapidly at the paraventricular nucleus (PVN) to inhibit stress-excitatory neurons and limit excessive glucocorticoid secretion. The signaling mechanism underlying rapid feedback inhibition remains to be determined. The present study was designed to test the hypothesis that the canonical glucocorticoid receptors (GRs) is required for appropriate hypothalamic pituitary-adrenal (HPA) axis regulation. Local PVN GR knockdown (KD) was achieved by breeding homozygous floxed GR mice with Sim1-cre recombinase transgenic mice. This genetic approach created mice with a KD of GR primarily confined to hypothalamic cell groups, including the PVN, sparing GR expression in other HPA axis limbic regulatory regions, and the pituitary. There were no differences in circadian nadir and peak corticosterone concentrations between male PVN GR KD mice and male littermate controls. However, reduction of PVN GR increased ACTH and corticosterone responses to acute, but not chronic stress, indicating that PVN GR is critical for limiting neuroendocrine responses to acute stress in males. Loss of PVN GR induced an opposite neuroendocrine phenotype in females, characterized by increased circadian nadir corticosterone levels and suppressed ACTH responses to acute restraint stress, without a concomitant change in corticosterone responses under acute or chronic stress conditions. PVN GR deletion had no effect on depression-like behavior in either sex in the forced swim test. Overall, these findings reveal pronounced sex differences in the PVN GR dependence of acute stress feedback regulation of HPA axis function. In addition, these data further indicate that glucocorticoid control of HPA axis responses after chronic stress operates via a PVN-independent mechanism. PMID- 26046808 TI - Hemodynamic responses and energy expenditure during blood flow restriction exercise in obese population. AB - PURPOSE: The study investigated the acute effects of different initial restrictive pressures (IRP; tightness of cuffs before inflation with air) on heart rate (HR), systolic (SBP) and diastolic blood pressure (DBP), rating of perceived exertion (RPE), respiratory exchange ratio (RER) and energy expenditure (EE) during constant-load upright cycling. METHODS: In a within subject study design, 34 obese men (age = 24.3, n = 18) and women (age = 23.1, n = 16) completed three cycling sessions (two blood flow restriction and one control sessions). The cycling exercise was performed with an external load of 1kp at 50 rpm for 20 min with 1-min rest after the 10th-min. The blood flow restriction (BFR) cuffs were placed on the thigh of both legs during BFR sessions and IRP and IRP of ~40 or ~60 mmHg were applied in random order. RESULTS: There were significant condition * time interactions for HR, SBP, RPE and RER and time * gender interactions for HR and SBP. There were also significant condition and time main effects for HR, SBP, RPE and RER (P<0.01) and a significant condition effect for EE (P<0.05). CONCLUSION: The intensity of exercise with BFR was higher and affected by IRP, but the subjects perceived the effort as 'light'. Low intensity cycling with BFR shows potential to reduce the time requirement per session to elicit greater EE while placing greater demands on the circulatory system. PMID- 26046809 TI - Obsessive compulsive disorder in children and adolescents: duration of maintenance drug treatment. AB - INTRODUCTION: Obsessions or compulsions that cause personal distress or social dysfunction have been reported to affect about 3% of children and adolescents. In children, the disorder often presents at around 10 years of age. It persists in about 40% of children and adolescents at mean follow-up of 5.7 years. The disorder is disabling with adverse impact on functioning, including education and social/family life. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of maintenance drug treatment for obsessive compulsive disorder in children and adolescents? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: Two studies were included that addressed the question of maintenance drug treatment for Obsessive Compulsive Disorder (OCD) in children and adolescents. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following intervention: optimum duration of maintenance drug treatment with serotonin reuptake inhibitors (SRIs) in children and adolescents. PMID- 26046811 TI - Case of pigmented eccrine poroma macroscopically simulated a malignant neoplasm with uptake of (18) F-fluorodeoxyglucose on positron emission tomography/computed tomography. PMID- 26046810 TI - Xenotransplantation of Bone Marrow-Derived Human Mesenchymal Stem Cell Sheets Attenuates Left Ventricular Remodeling in a Porcine Ischemic Cardiomyopathy Model. AB - INTRODUCTION: Bone marrow-derived autologous human mesenchymal stem cells (MSCs) are one of the most promising cell sources for cell therapy to treat heart failure. The cell sheet technique has allowed transplantation of a large number of cells and enhanced the efficacy of cell therapy. We hypothesized that the transplantation of MSC sheets may be a feasible, safe, and effective treatment for ischemic cardiomyopathy (ICM). METHODS AND RESULTS: Human MSCs acquired from bone marrow were positive for CD73, CD90, and CD105 and negative for CD11b and CD45 by flow cytometry. Ten MSC sheets were created from a total cell number of 1*10(8) MSCs using temperature-responsive culture dishes. These were successfully transplanted over the infarct myocardium of porcine ICM models induced by placing an ameroid constrictor on the left anterior descending coronary artery without any procedural-related complications (MSC group=6: sheet transplantation; sham group=6, oral intake of tacrolimus in both groups). Premature ventricular contractions were rarely detected by Holter electrocardiogram (ECG) in the MSC group in the first week after transplantation. On echocardiography, the cardiac performance of the MSC group was significantly better than that of the sham group at 8 weeks after transplantation. On histological examination 8 weeks after transplantation, left ventricular (LV) remodeling was significantly attenuated compared with the sham group (cardiomyocyte size and interstitial fibrosis were measured). Immunohistochemistry of the von Willebrand factor showed that the vascular density in the infarct border area was significantly greater in the MSC group than the sham group. Expression of angiogenesis-related factors in the infarct border area of the MSC group was significantly greater than that of the sham group, as measured by real-time polymerase chain reaction. CONCLUSIONS: Bone marrow-derived MSC sheets improved cardiac function and attenuated LV remodeling in ICM without major complications, indicating that this strategy would be applicable in clinical settings. PMID- 26046812 TI - Fabrication of Optical Multilayer Devices from Porous Silicon Coatings with Closed Porosity by Magnetron Sputtering. AB - The fabrication of single-material photonic-multilayer devices is explored using a new methodology to produce porous silicon layers by magnetron sputtering. Our bottom-up methodology produces highly stable amorphous porous silicon films with a controlled refractive index using magnetron sputtering and incorporating a large amount of deposition gas inside the closed pores. The influence of the substrate bias on the formation of the closed porosity was explored here for the first time when He was used as the deposition gas. We successfully simulated, designed, and characterized Bragg reflectors and an optical microcavity that integrates these porous layers. The sharp interfaces between the dense and porous layers combined with the adequate control of the refractive index and thickness allowed for excellent agreement between the simulation and the experiments. The versatility of the magnetron sputtering technique allowed for the preparation of these structures for a wide range of substrates such as polymers while also taking advantage of the oblique angle deposition to prepare Bragg reflectors with a controlled lateral gradient in the stop band wavelengths. PMID- 26046813 TI - Computational Electrochemistry. Voltages of Lithium-Ion Battery Cathodes. AB - Theoretical studies on the electrode materials in lithium-ion batteries provide information on the structural changes during the charging and discharging processes. In the present study, we tested the M06-L and N12 exchange-correlation functionals on some well-studied lithium-containing materials. These functionals, which have already shown good performance for a variety of databases, outperform the widely used PBE functional for reproducing the experimental structures and averaged intercalation potentials. It is especially noteworthy that the M06-L functional gives voltages as accurate as those provided by the Heyd-Scuseria Ernzerhof (HSE06) hybrid functional, but with less computational cost. PMID- 26046814 TI - Considering too few alternatives: The mental model theory of extensional reasoning. AB - When solving a simple probabilistic problem, people tend to build an incomplete mental representation. We observe this pattern in responses to probabilistic problems over a set of premises using the conjunction, disjunction, and conditional propositional connectives. The mental model theory of extensional reasoning explains this bias towards underestimating the number of possibilities: In reckoning with different interpretations of the premises (logical rules, mental model theoretical, and, specific to conditional premises, conjunction and biconditional interpretation) the mental model theory accounts for the majority of observations. Different interpretations of a premise result in a build-up of mental models that are often incomplete. These mental models are processed using either an extensional strategy relying on proportions amongst models, or a conflict monitoring strategy. The consequence of considering too few possibilities is an erroneous probability estimate akin to that faced by decision makers who fail to generate and consider all alternatives, a characteristic of bounded rationality. We compare our results to the results published by Johnson Laird, Legrenzi, Girotto, Legrenzi, and Caverni [Johnson-Laird, P., Legrenzi, P., Girotto, V., Legrenzi, M., & Caverni, J. (1999). Naive probability: A mental model theory of extensional reasoning. Psychological Review, 106, 62-88. doi: 10. 1037/0033-295X.106.1.62], and we observe lower performance levels than those in the original article. PMID- 26046816 TI - Role of Quinones in Electron Transfer of PQQ-Glucose Dehydrogenase Anodes Mediation or Orientation Effect. AB - In this study, the influence of two quinones (1,2- and 1,4-benzoquinone) on the operation and mechanism of electron transfer in PQQ-dependent glucose dehydrogenase (PQQ-sGDH) anodes has been determined. Benzoquinones were experimentally explored as mediators present in the electrolyte. The electrochemical performance of the PQQ-sGDH anodes with and without the mediators was examined and for the first time molecular docking simulations were used to gain a fundamental understanding to explain the role of the mediator molecules in the design and operation of the enzymatic electrodes. It was proposed that the higher performance of the PQQ-sGDH anodes in the presence of 1,2- and 1,4 benzoquinones introduced in the solution is due to the shorter distance between these molecules and PQQ in the enzymatic molecule. It was also hypothesized that when 1,4-benzoquinone is adsorbed on a carbon support, it would play the dual role of a mediator and an orienting agent. At the same time, when 1,2 benzoquinone and ubiquinone are adsorbed on the electrode surface, the enzyme would transfer the electrons directly to the support, and these molecules would primarily play the role of an orienting agent. PMID- 26046815 TI - Type 1 interferons contribute to the clearance of senescent cell. AB - The major known function of cytokines that belong to type I interferons (IFN, including IFNalpha and IFNbeta) is to mount the defense against viruses. This function also protects the genetic information of host cells from alterations in the genome elicited by some of these viruses. Furthermore, recent studies demonstrated that IFN also restrict proliferation of damaged cells by inducing cell senescence. Here we investigated the subsequent role of IFN in elimination of the senescent cells. Our studies demonstrate that endogenous IFN produced by already senescent cells contribute to increased expression of the natural killer (NK) receptor ligands, including MIC-A and ULBP2. Furthermore, neutralization of endogenous IFN or genetic ablation of its receptor chain IFNAR1 compromises the recognition of senescent cells and their clearance in vitro and in vivo. We discuss the role of IFN in protecting the multi-cellular host from accumulation of damaged senescent cells and potential significance of this mechanism in human cancers. PMID- 26046817 TI - Energy Efficient Sparse Connectivity from Imbalanced Synaptic Plasticity Rules. AB - It is believed that energy efficiency is an important constraint in brain evolution. As synaptic transmission dominates energy consumption, energy can be saved by ensuring that only a few synapses are active. It is therefore likely that the formation of sparse codes and sparse connectivity are fundamental objectives of synaptic plasticity. In this work we study how sparse connectivity can result from a synaptic learning rule of excitatory synapses. Information is maximised when potentiation and depression are balanced according to the mean presynaptic activity level and the resulting fraction of zero-weight synapses is around 50%. However, an imbalance towards depression increases the fraction of zero-weight synapses without significantly affecting performance. We show that imbalanced plasticity corresponds to imposing a regularising constraint on the L1 norm of the synaptic weight vector, a procedure that is well-known to induce sparseness. Imbalanced plasticity is biophysically plausible and leads to more efficient synaptic configurations than a previously suggested approach that prunes synapses after learning. Our framework gives a novel interpretation to the high fraction of silent synapses found in brain regions like the cerebellum. PMID- 26046818 TI - Pesticide Macroscopic Recognition by a Naphthol-Appended Calix[4]arene. AB - A new naphthol-appended calix[4]arene (NOC4) has been synthesized and characterized. NOC4 is clicked onto a microstructured Au surface and exhibits selective macroscopic recognition of metolcarb (MC) via contact angle measurements. The proposed wettability sensing device displays remarkable specificity and is fast and easy to use, which should be suitable for the rapid detection of MC in environmental monitoring. PMID- 26046819 TI - Self-limited coeliac-like enteropathy: a series of 18 cases highlighting another coeliac disease mimic. AB - AIMS: To describe the clinical and pathological features of a series of patients with biopsy findings of a coeliac disease-like enteropathy in the setting of an acute illness. METHODS AND RESULTS: Eighteen cases of an abrupt-onset, self limited illness with coeliac-like enteropathy (SLCE) were collected prospectively. Medication reaction, immune disorder, food allergy and parasitic infection were excluded. Coeliac disease was excluded by the transient nature of the illness and absence of tissue transglutaminase (TTG) elevation (nine of nine) or human leucocyte antigen (HLA)-DQ2/DQ8 haplotype (eight of nine). Clinical symptoms were recorded and histopathological findings in all gastrointestinal sites were quantified. Findings in the duodenum were compared to a coeliac disease control group. In 12 cases the clinical diagnosis was infective enteritis, probably viral in type. In six cases, a definite diagnosis was not established. Histological differences from coeliac disease included intra epithelial neutrophil infiltration (P < 0.001), fewer intra-epithelial lymphocytes (P = 0.038) and uniform or crypt predominant intra-epithelial lymphocytosis in SCLE. One case displayed pan-gastrointestinal tract lymphocytosis. All resolved within 6 months. CONCLUSIONS: Histopathologists need to be aware that a coeliac disease-like enteropathy may occur in the setting of an acute gastrointestinal illness and resolve without sequelae. PMID- 26046820 TI - Chrodrimanins I and J from the Antarctic Moss-Derived Fungus Penicillium funiculosum GWT2-24. AB - Two new meroterpenoids, named chrodrimanins I and J (1 and 2), together with five known biosynthetically related chrodrimanins (3-7), were isolated from the culture of the Antarctic moss-derived fungus Penicillium funiculosum GWT2-24. Distinguished from all of the reported chrodrimanins, compounds 1 and 2 possess a unique cyclohexanone (E ring) instead of a delta-lactone ring. These structures including the absolute configurations were established on the basis of MS, NMR, and X-ray crystallographic analysis. Compounds 1-7 showed no cytotoxic or antibacterial activities, while the known compounds 3, 5, and 6 exhibited inhibitory activities against influenza virus A (H1N1), with IC50 values ranged from 21 to 57 MUM. PMID- 26046821 TI - Enhanced Adhesion of Stromal Cells to Invasive Cancer Cells Regulated by Cadherin 11. AB - Cancer-associated fibroblasts (CAFs) are known to promote tumor growth and metastasis; however their differential accumulation in invasive and noninvasive tumors is not fully understood. We hypothesized that differences in cell adhesion may contribute to this phenomenon. To test this, we analyzed the adhesion of CAF precursor fibroblasts and mesenchymal stem cells to invasive and noninvasive cancers originating from the the breast, ovaries, and prostate. In all cases, stromal cells preferentially adhered to more invasive cancer cells. Modulating integrin and cadherin binding affinities with calcium chelation revealed that adhesion was independent of integrin activity but required cadherin function. Invasive cancer cells had increased expression of mesenchymal markers cadherin 2 and 11 that localized with stromal cell cadherin 11, suggesting that these molecules are involved in stromal cell engraftment. Blockade of cadherin 11 on stromal cells inhibited adhesion and may serve as a target for metastatic disease. PMID- 26046822 TI - Spontaneous Regression of Refractory Diffuse Large B-Cell Lymphoma with Improvement in Immune Status with ART in a Patient with HIV: A Case Report and Literature Review. AB - BACKGROUND: Diffuse large B-cell lymphoma accounts for the large majority of AIDS related non-Hodgkin lymphoma. Traditionally, this lymphoma has been treated with CHOP-like regimens with the recent addition of rituximab. We report a unique case where an HIV-infected patient with diffuse large B-cell lymphoma had complete regression of the lymphoma with continued antiretroviral therapy (ART) after chemotherapy was stopped. CASE REPORT: A 55-year-old man who presented with fatigue and weight loss had initial CT findings of bilateral renal masses during his workup. Biopsy revealed diffuse large B-cell lymphoma and subsequently he was also diagnosed with HIV. He completed 6 cycles of CHOP-like (4 cycles of EPOCH-R and 2 cycles of R-CHOP) first-line therapy with significant dose delays and dose reductions due to severe adverse effects. Chemotherapy was stopped due to physical deconditioning and intolerable adverse effects. He had a FDG-PET/CT showing progression of his disease 8 weeks after completing chemotherapy. He was maintained only on ART after finishing 6 cycles of chemotherapy. With this therapy alone and with improvement in his immune status, his lymphoma regressed completely. CONCLUSIONS: There are very few reported cases in which lymphoma has regressed with treatment of HIV alone, as is regression of diffuse large B-cell lymphoma. This case emphasizes that ART can lead to immune reconstitution of HIV infected patients and can establish the anti-tumor effect, causing regression of the lymphoma. PMID- 26046823 TI - The care needs of older patients with bipolar disorder. AB - OBJECTIVES: With aging, bipolar disorder evolves into a more complex illness, with increasing cognitive impairment, somatic comorbidity, and polypharmacy. To tailor treatment of these patients, it is important to study their needs, as having more unmet needs is a strong predictor of a lower quality of life. METHOD: Seventy-eight Dutch patients with bipolar I or II disorder aged 60 years and older in contact with mental health services were interviewed using the Camberwell Assessment of Need in the Elderly (CANE) to assess met and unmet needs, both from a patient and a staff perspective. RESULTS: Patients (mean age 68 years, range 61-98) reported a mean of 4.3 needs compared to 4.4 reported by staff, of which 0.8 were unmet according to patients and 0.5 according to staff. Patients frequently rated company and daytime activities as unmet needs. More current mood symptoms were associated with a higher total number of needs. Less social participation was associated with a higher total number of needs and more unmet needs. CONCLUSION: Older bipolar patients report fewer needs and unmet needs compared to older patients with depression, schizophrenia, and dementia. A plausible explanation is that older bipolar patients had higher Global Assessment of Functioning scores, were better socially integrated, and had fewer actual mood symptoms, all of which correlated with the number of needs in this study. The results emphasize the necessity to assess the needs of bipolar patients with special attention to social functioning, as it is suggested that staff fail to recognize or anticipate these needs. PMID- 26046825 TI - HIV Testing in the Past Year Among the U.S. Household Population Aged 15-44: 2011 2013. AB - KEY FINDINGS: Overall, 19% of persons aged 15-44 in 2011-2013 had been tested for HIV in the past year, including 22% of females and 16% of males. Higher percentages of HIV testing in the past year were seen for persons aged 15-34 compared with those aged 35-44, and for non-Hispanic black persons compared with other race and ethnicity groups. Four of 10 males who had same-sex sexual contact in the past year had been tested for HIV in the past year, compared with 2 of 10 who had opposite-sex sexual contact in the past year. Levels of HIV testing in the past year were higher for persons with behaviors that increase HIV risk, including having one or more same-sex partners or higher numbers of opposite-sex sexual partners in the past year. PMID- 26046824 TI - The role of Ca(2+) influx in spontaneous Ca(2+) wave propagation in interstitial cells of Cajal from the rabbit urethra. AB - KEY POINTS: Tonic contractions of rabbit urethra are associated with spontaneous electrical slow waves that are thought to originate in pacemaker cells termed interstitial cells of Cajal (ICC). ICC pacemaker activity results from their ability to generate propagating Ca(2+) waves, although the exact mechanisms of propagation are not understood. In this study, we have identified spontaneous localised Ca(2+) events for the first time in urethral ICC; these were due to Ca(2+) release from the endoplasmic reticulum (ER) via ryanodine receptors (RyRs) and, while they often remained localised, they sometimes initiated propagating Ca(2+) waves. We show that propagation of Ca(2+) waves in urethral ICC is critically dependent upon Ca(2+) influx via reverse mode NCX. Our data provide a clearer understanding of the intracellular mechanisms involved in the generation of ICC pacemaker activity. Interstitial cells of Cajal (ICC) are putative pacemaker cells in the rabbit urethra. Pacemaker activity in ICC results from spontaneous propagating Ca(2+) waves that are modulated by [Ca(2+)]o and whose propagation is inhibited by inositol tri-phosphate receptor (IP3 R) blockers. The purpose of this study was to further examine the role of Ca(2+) influx and Ca(2+) release in the propagation of Ca(2+) waves. Intracellular Ca(2+) was measured in Fluo-4-loaded ICC using a Nipkow spinning disc confocal microscope at fast acquisition rates (50 fps). We identified previously undetected localised Ca(2+) events originating from ryanodine receptors (RyRs). Inhibiting Ca(2+) influx by removing [Ca(2+)]o or blocking reverse mode sodium-calcium exchange (NCX) with KB R 7943 or SEA-0400 abolished Ca(2+) waves, while localised Ca(2+) events persisted. Stimulating RyRs with 1 mm caffeine restored propagation. Propagation was also inhibited when Ca(2+) release sites were uncoupled by buffering intracellular Ca(2+) with EGTA-AM. This was reversed when Ca(2+) influx via NCX was increased by reducing [Na(+)]o to 13 mm. Low [Na(+)]o also increased the frequency of Ca(2+) waves and this effect was blocked by tetracaine and ryanodine but not 2-aminoethoxydiphenyl borate (2-APB). RT-PCR revealed that isolated ICC expressed both RyR2 and RyR3 subtypes. We conclude: (i) RyRs are required for the initiation of Ca(2+) waves, but wave propagation normally depends on activation of IP3 Rs; (ii) under resting conditions, propagation by IP3 Rs requires sensitisation by influx of Ca(2+) via reverse mode NCX; (iii) propagation can be maintained by RyRs if they have been sensitised to Ca(2+). PMID- 26046826 TI - Serious Psychological Distress Among Adults: United States, 2009-2013. AB - In every age group, women were more likely to have serious psychological distress than men. Among all adults, as income increased, the percentage with serious psychological distress decreased. Adults aged 18-64 with serious psychological distress were more likely to be uninsured (30.4%) than adults without serious psychological distress (20.5%). More than one-quarter of adults aged 65 and over with serious psychological distress (27.3%) had limitations in activities of daily living. Adults with serious psychological distress were more likely to have chronic obstructive pulmonary disease, heart disease, and diabetes than adults without serious psychological distress. PMID- 26046827 TI - Three Decades of Nonmarital First Births Among Fathers Aged 15-44 in the United States. AB - KEY FINDINGS: The percentage of fathers aged 15-44 whose first births were nonmarital was lower in the 2000s (36%) than in the previous 2 decades. Fathers with first births in the 2000s were more likely to be in a nonmarital cohabiting union (24%) than those in the 1980s (19%). The percentage of fathers with a nonmarital first birth over the past 3 decades has remained similar for Hispanic and non-Hispanic white men, but has declined for non-Hispanic black men (1980s, 77%; 2000s, 66%). Fathers with nonmarital first births in the 2000s were less likely to be non-Hispanic black men (21%) than Hispanic (33%) or non-Hispanic white (39%) men. Fathers with nonmarital first births in the 2000s were more likely to be older at the time of the birth (33%) than those in the previous 2 decades. PMID- 26046828 TI - Factor Structure of the Assessment of Qualitative and Structural Dimensions of Object Representations (AOR) Scale. AB - The Assessment of Qualitative and Structural Dimensions of Object Representations assessment instrument (AOR; Blatt, Chevron, Quinlan, Schaffer, & Wein, 1992 ) is one measure of parental representations used in the literature that assesses nonconscious processes while minimizing self-presentation biases. However, only 2 studies have considered the latent factor structure, with mixed findings reported that raise questions about the constructs being assessed. This study used archival data from 4 previous studies containing clinical and nonclinical samples, totaling 722 participants. Individuals were divided into 2 groups in which an exploratory factor analysis (EFA) was followed by a confirmatory factor analysis (CFA). Results of both the EFA and CFA suggested that a 3-factor solution was best, with factors that were labeled Agency, Communion, and Punitive based on previous research. The implications of these findings are explored, particularly with regard to the punitive aspect of maternal representations, as well as a possible revision to the scoring rubric. PMID- 26046829 TI - Immunity to Viruses in Immunodeficient Hosts. PMID- 26046830 TI - Hyperexpansion of Functional Viral-Specific CD8+ T Cells in Lymphopenia Associated MCMV Pneumonitis. AB - Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in immunocompromised hosts, many of whom undergo significant periods of lymphopenia. However, the impact of lymphopenia and subsequent immune reconstitution on T cell responses and pulmonary pathology are poorly understood. Using a model of primary murine CMV infection in mice treated with cyclophosphamide (CY), the relationship of CD8+ T cell reconstitution to pneumonitis pathology was studied. Female BALB/c mice were infected with murine CMV (MCMV) with/without CY on day 1 post infection. Lung pathology and viral specific T cell responses were assessed on days 7-28. T cell lymphocyte subsets, effector responses, and MCMV specificity were assessed at baseline and after in vitro stimulation of cells with immediate early peptide pp89. CY treatment of MCMV-infected mice resulted in interstitial pneumonitis not seen with MCMV alone. Compared to MCMV alone, on day 14, MCMV/CY mice had greater number of CD8+ T cells, a fourfold increase in absolute number of pp89 tetramer-specific CD8+ cells, and an eightfold increase in MCMV specific T cell effector responses (IFN-gamma; p<0.001). This expansion was preceded by transient lymphopenia, increased viral titers, and, most strikingly, a 10-fold increased proliferative capacity in MCMV/CY mice. In the setting of CY-associated lymphopenia, concurrent MCMV infection alters immune reconstitution toward a hyperexpanded MCMV-specific CD8+ effector T cell pool that correlates with significant lung immunopathology. PMID- 26046831 TI - Improvement of the Immunogenicity of Porcine Circovirus Type 2 DNA Vaccine by Recombinant ORF2 Gene and CpG Motifs. AB - Nowadays, adjuvant is still important for boosting immunity and improving resistance in animals. In order to boost the immunity of porcine circovirus type 2 (PCV2) DNA vaccine, CpG motifs were inserted. In this study, the dose-effect was studied, and the immunity of PCV2 DNA vaccines by recombinant open reading frame 2 (ORF2) gene and CpG motifs was evaluated. Three-week-old Changbai piglets were inoculated intramuscularly with 200 MUg, 400 MUg, and 800 MUg DNA vaccines containing 14 and 18 CpG motifs, respectively. Average gain and rectum temperature were recorded everyday during the experiments. Blood was collected from the piglets after vaccination to detect the changes of specific antibodies, interleukin-2, and immune cells every week. Tissues were collected for histopathology and polymerase chain reaction. The results indicated that compared to those of the control piglets, all concentrations of two DNA vaccines could induce PCV2-specific antibodies. A cellular immunity test showed that PCV2 specific lymphocytes proliferated the number of TH, TC, and CD3+ positive T-cells raised in the blood of DNA vaccine immune groups. There was no distinct pathological damage and viremia occurring in pigs that were inoculated with DNA vaccines, but there was some minor pathological damage in the control group. The results demonstrated that CpG motifs as an adjuvant could boost the humoral and cellular immunity of pigs to PCV2, especially in terms of cellular immunity. Comparing two DNA vaccines that were constructed, the one containing 18 CpG motifs was more effective. This is the first report that CpG motifs as an adjuvant insert to the PCV2 DNA vaccine could boost immunity. PMID- 26046832 TI - [Foreword]. PMID- 26046833 TI - Perfluorooctane Sulfonate Concentrations in Amniotic Fluid, Biomarkers of Fetal Leydig Cell Function, and Cryptorchidism and Hypospadias in Danish Boys (1980 1996). AB - BACKGROUND: Exposure to perfluorooctane sulfonate (PFOS) may potentially disturb fetal Leydig cell hormone production and male genital development. OBJECTIVES: We aimed to study the associations between levels of amniotic fluid PFOS, fetal steroid hormone, and insulin-like factor 3 (INSL3) and the prevalence of cryptorchidism and hypospadias. METHODS: Using the Danish National Patient Registry, we selected 270 cryptorchidism cases, 75 hypospadias cases, and 300 controls with stored maternal amniotic fluid samples available in a Danish pregnancy-screening biobank (1980-1996). We used mass spectrometry to measure PFOS in amniotic fluid from 645 persons and steroid hormones in samples from 545 persons. INSL3 was measured by immunoassay from 475 persons. Associations between PFOS concentration in amniotic fluid, hormone levels, and genital malformations were assessed by confounder-adjusted linear and logistic regression. RESULTS: The highest tertile of PFOS exposure (> 1.4 ng/mL) in amniotic fluid was associated with a 40% (95% CI: -69, -11%) lower INSL3 level and an 18% (95% CI: 7, 29%) higher testosterone level compared with the lowest tertile (< 0.8 ng/mL). Amniotic fluid PFOS concentration was not associated with cryptorchidism or hypospadias. CONCLUSIONS: Environmental PFOS exposure was associated with steroid hormone and INSL3 concentrations in amniotic fluid, but was not associated with cryptorchidism or hypospadias in our study population. Additional studies are needed to determine whether associations with fetal hormone levels may have long term implications for reproductive health. CITATION: Toft G, Jonsson BA, Bonde JP, Norgaard-Pedersen B, Hougaard DM, Cohen A, Lindh CH, Ivell R, Anand-Ivell R, Lindhard MS. 2016. Perfluorooctane sulfonate concentrations in amniotic fluid, biomarkers of fetal Leydig cell function, and cryptorchidism and hypospadias in Danish boys (1980-1996). Environ Health Perspect 124:151-156; http://dx.doi.org/10.1289/ehp.1409288. PMID- 26046834 TI - Shedding light on the effect of priority instructions during dual-task performance in younger and older adults: A fNIRS study. AB - Age-related differences in the ability to perform two tasks simultaneously (or dual-task) have become a major concern in aging neurosciences and have often been assessed with two distinct paradigms; the Psychological Refractory Period (PRP) and the Dual-Task (DT) paradigms. PRP studies assess participants when they give Priority to one task over the other (complete A then B), whereas in DT studies participants give Equal priority to both tasks (complete A and B). The Equal condition could be viewed as adding an executive control component to the task since the participants must spontaneously monitor attention between tasks. In the current study, we assessed the effect of priority instructions (Priority vs. Equal) on the dual-task performance and brain activity of younger (n = 16) and older adults (n = 19) with functional near infra-red spectroscopy (fNIRS). In younger adults, the Priority condition showed right-sided activation in the prefrontal cortex during DT execution. Older adults showed bilateral frontal activation, yet restrained to specific areas. They showed increased activation in DT vs. single task condition in the left dorsolateral prefrontal cortex (DLPFC) and the bilateral ventrolateral prefrontal cortex (VLPFC). In the Equal condition, the DT condition showed isolated left DLPFC and VLPFC activation in younger adults and widespread bilateral DLPFC activation in older adults. These results suggest that for both older and younger adults, priority effects are associated with distinct patterns of prefrontal activation. Age-related differences also exist in these patterns such that prefrontal activation seems to be more spread out at different sites in older adults when they are instructed to give Equal priority to both tasks. PMID- 26046835 TI - Proteomic analysis of anatoxin-a acute toxicity in zebrafish reveals gender specific responses and additional mechanisms of cell stress. AB - Anatoxin-a is a potent neurotoxin produced by several genera of cyanobacteria. Deaths of wild and domestic animals due to anatoxin-a exposure have been reported following a toxic response that is driven by the inhibition of the acetylcholine receptors at neuromuscular junctions. The consequent neuron depolarization results in an overstimulation of the muscle cells. In order to unravel further molecular events implicated in the toxicity of anatoxin-a, a proteomic investigation was conducted. Applying two-dimensional gel electrophoresis (2DE) and MALDI-TOF mass spectrometry, we report early proteome changes in brain and muscle of zebrafish (Danio rerio) caused by acute exposure to anatoxin-a. In this regard, the test group of male and female zebrafish received an intraperitoneal (i.p.) injection of an anatoxin-a dose of 0.8ugg(-1) of fish body weight (bw) in phosphate buffered saline solution (PBS), while the control received an i.p. injection of PBS only. Five minutes after i.p. injection, brain and muscle tissues were collected, processed and analyzed with 2DE. Qualitative and quantitative analyzes of protein abundance allowed the detection of differences in the proteome of control and exposed fish groups, and between male and female fish (gender specific responses). The altered proteins play functions in carbohydrate metabolism and energy production, ATP synthesis, cell structure maintenance, cellular transport, protein folding, stress response, detoxification and protease inhibition. These changes provide additional insights relative to the toxicity of anatoxin-a in fish. Taking into account the short time of response considered (5min of response to the toxin), the changes in the proteome observed in this work are more likely to derive from fast occurring reactions in the cells. These could occur by protein activity regulation through degradation (proteolysis) and/or post-translational modifications, than from a differential regulation of gene expression, which may require more time for proteins to be synthesized and to produce changes at the proteomic level. PMID- 26046836 TI - Main Ingredients for Success in L2 Academic Writing: Outlining, Drafting and Proofreading. AB - Spanish undergraduates of English Studies are required to submit their essays in academic English, a genre which most of them are not acquainted with. This paper aims to explore the extralinguistic side of second language (L2) academic writing, more specifically, the combination of metalinguistic items (e.g. transition and frame markers, among others) with students' writing strategies when composing an academic text in L2 English. The research sample conveys a group of 200 Spanish undergraduates of English Studies; they are in their fourth year, so they are expected to be proficient in English academic writing but their written production quality varies considerably. Results are analysed following a mixed methodology by which metalinguistic items are statistically measured, and then contrasted with semi-structured interview results; SPSS and NVivo provide quantitative and qualitative outcomes, respectively. The analyses reveal that undergraduate students who produce complex sentences and more coherent texts employ a wider range of writing strategies both prior and while writing, being able to (un)consciously structure and design their texts more successfully. These high-scoring students make more proficient use of complex transition markers for coherence and frame markers for textual cohesion; their commonly used (pre )writing strategies are drafting, outlining, and proofreading. PMID- 26046837 TI - Effects of Obesity and Metabolic Syndrome on Steroidogenesis and Folliculogenesis in the Female Ossabaw Mini-Pig. AB - The discrete effects of obesity on infertility in females remain undefined to date. To investigate obesity-induced ovarian dysfunction, we characterized metabolic parameters, steroidogenesis, and folliculogenesis in obese and lean female Ossabaw mini-pigs. Nineteen nulliparous, sexually mature female Ossabaw pigs were fed a high fat/cholesterol/fructose diet (n=10) or a control diet (n=9) for eight months. After a three-month diet-induction period, pigs remained on their respective diets and had ovarian ultrasound and blood collection conducted during a five-month study period after which ovaries were collected for histology, cell culture, and gene transcript level analysis. Blood was assayed for steroid and protein hormones. Obese pigs developed abdominal obesity and metabolic syndrome, including hyperglycemia, hypertension, insulin resistance and dyslipidemia. Obese pigs had elongated estrous cycles and hyperandrogenemia with decreased LH, increased FSH and luteal phase progesterone, and increased numbers of medium, ovulatory, and cystic follicles. Theca cells of obese, compared to control, pigs displayed androstenedione hypersecretion in response to in vitro treatment with LH, and up-regulated 3-beta-hydroxysteroid dehydrogenase 1 and 17 beta-hydroxysteroid dehydrogenase 4 transcript levels in response to in vitro treatment with LH or LH + insulin. Granulosa cells of obese pigs had increased 3 beta-hydroxysteroid dehydrogenase 1 transcript levels. In summary, obese Ossabaw pigs have increased transcript levels and function of ovarian enzymes in the delta 4 steroidogenic pathway. Alterations in LH, FSH, and progesterone, coupled with theca cell dysfunction, contribute to the hyperandrogenemia and disrupted folliculogenesis patterns observed in obese pigs. The obese Ossabaw mini-pig is a useful animal model in which to study the effects of obesity and metabolic syndrome on ovarian function and steroidogenesis. Ultimately, this animal model may be useful toward the development of therapies to improve fertility in obese and/or hyperandrogenemic females or in which to examine the effects of obesity on the maternal-fetal environment and offspring health. PMID- 26046838 TI - A Random Screen Using a Novel Reporter Assay System Reveals a Set of Sequences That Are Preferred as the TATA or TATA-Like Elements in the CYC1 Promoter of Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, the core promoters of class II genes contain either TATA or TATA-like elements to direct accurate transcriptional initiation. Genome wide analyses show that the consensus sequence of the TATA element is TATAWAWR (8 bp), whereas TATA-like elements carry one or two mismatches to this consensus. The fact that several functionally distinct TATA sequences have been identified indicates that these elements may function, at least to some extent, in a gene specific manner. The purpose of the present study was to identify functional TATA sequences enriched in one particular core promoter and compare them with the TATA or TATA-like elements that serve as the pre-initiation complex (PIC) assembly sites on the yeast genome. For this purpose, we conducted a randomized screen of the TATA element in the CYC1 promoter by using a novel reporter assay system and identified several hundreds of unique sequences that were tentatively classified into nine groups. The results indicated that the 7 bp TATA element (i.e., TATAWAD) and several sets of TATA-like sequences are preferred specifically by this promoter. Furthermore, we find that the most frequently isolated TATA-like sequence, i.e., TATTTAAA, is actually utilized as a functional core promoter element for the endogenous genes, e.g., ADE5,7 and ADE6. Collectively, these results indicate that the sequence requirements for the functional TATA or TATA like elements in one particular core promoter are not as stringent. However, the variation of these sequences differs significantly from that of the PIC assembly sites on the genome, presumably depending on promoter structures and reflecting the gene-specific function of these sequences. PMID- 26046839 TI - Prognostic Significance and Determinants of the 6-Min Walk Test in Patients With Heart Failure and Preserved Ejection Fraction. AB - OBJECTIVES: This study sought to define the prognostic significance and clinical determinants of the 6-min walk distance (6-MWD) in affected patients. BACKGROUND: Symptoms of exertional fatigue and dyspnea, as well as a reduced exercise tolerance, are cardinal features of pulmonary hypertension associated with heart failure and preserved ejection fraction (PH-HFpEF). Mechanisms limiting exercise capacity in this specific entity remain incompletely understood. METHODS: Consecutive patients with PH-HFpEF, as confirmed by right heart catheter, were enrolled in our prospective registry. Hospitalization for HF and/or death for cardiac reasons were defined as primary outcome. Multiple regression models were constructed to establish determinants of the 6-MWD. For quantification of left ventricular (LV) extracellular matrix (ECM), myocardial biopsies were taken from 18 patients. RESULTS: Between December 2010 and July 2013, 142 PH-HFpEF patients were included in the study. After a mean follow-up of 14.0 +/- 10.0 months, 43 patients (30.3%) reached the combined endpoint. The 6-MWD was found to be an independent predictor of outcome and was influenced by a variety of clinical, echocardiographic, hemodynamic, laboratory, and pulmonary parameters. There was a significant inverse correlation between the 6-MWD and the extent of ECM in the LV myocardium. CONCLUSIONS: Impaired exercise capacity in PH-HFpEF patients is explained by cardiac and noncardiac factors. The 6-MWD predicts outcome and may be a useful endpoint in clinical trials. PMID- 26046841 TI - In Search of New Targets and Endpoints in Heart Failure With Preserved Ejection Fraction. PMID- 26046840 TI - Pulmonary Arterial Capacitance Is an Important Predictor of Mortality in Heart Failure With a Preserved Ejection Fraction. AB - OBJECTIVES: The purpose of this study was to determine the predictors of mortality in patients with pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (HFpEF). BACKGROUND: PH is commonly associated with HFpEF. The predictors of mortality for patients with these conditions are not well characterized. METHODS: In a prospective cohort of patients with right heart catheterization, we identified 73 adult patients who had pulmonary hypertension due to left heart disease (PH-LHD) associated with HFpEF (left ventricular ejection fraction >=50% by echocardiography); hemodynamically defined as a mean pulmonary artery pressure >=25 mm Hg and pulmonary artery wedge pressure >15 mm Hg. PH severity was classified according to the diastolic pressure gradient (DPG). Cox proportional hazards ratios were used to estimate the associations between clinical variables and mortality. Receiver-operating characteristic curves were used to evaluate the ability of hemodynamic measurements to predict mortality. RESULTS: The mean age for study subjects was 69 +/- 12 years and 74% were female. Patients classified as having combined post-capillary PH and pre-capillary PH (DPG >=7) were not at increased risk of death as compared to patients with isolated post-capillary PH (DPG <7). A baseline pulmonary arterial capacitance (PAC) of <1.1 ml/mm Hg was 91% sensitive in predicting mortality, with better discriminatory ability than DPG, transpulmonary gradient, or pulmonary vascular resistance (area under the curve of 0.73, 0.50, 0.45, and 0.37, respectively). Fifty-seven subjects underwent acute vasoreactivity testing with inhaled nitric oxide. Acute vasodilator response by the Rich or Sitbon criteria was not associated with improved survival. CONCLUSIONS: PAC is the best predictor of mortality in our cohort and may be useful in describing phenotypic subgroups among those with PH-LHD associated with HFpEF. Acute vasodilator testing did not predict outcome in our cohort but needs to be further investigated. PMID- 26046843 TI - Time for Recognition. PMID- 26046842 TI - Relative Importance of History of Heart Failure Hospitalization and N-Terminal Pro-B-Type Natriuretic Peptide Level as Predictors of Outcomes in Patients With Heart Failure and Preserved Ejection Fraction. AB - OBJECTIVES: The aim of this study was to investigate N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and recent heart failure (HF) hospitalization as predictors of future events in heart failure - preserved ejection fraction (HF-PEF). BACKGROUND: Recently, doubt has been expressed about the value of a history of HF hospitalization as a predictor of adverse cardiovascular outcomes in patients with HF and HF-PEF. METHODS: We estimated rates and adjusted hazard ratios (HRs) for the composite endpoint of cardiovascular death or HF hospitalization, according to history of recent HF hospitalization and baseline NT-proBNP level in the I-PRESERVE (Irbesartan in Heart Failure with Preserved systolic function) trial. RESULTS: Rates of composite endpoints in patients with (n = 804) and without (n = 1,963) a recent HF hospitalization were 12.78 (95% confidence interval [CI]: 11.47 to 14.24) and 4.49 (95% CI: 4.04 to 4.99) per 100 person-years, respectively (HR: 2.71; 95% CI: 2.33 to 3.16). For patients with NT-proBNP concentrations >360 pg/ml (n = 1,299), the event rate was 11.51 (95% CI: 10.54 to 12.58) compared to 3.04 (95% CI: 2.63 to 3.52) per 100 person-years in those with a lower level of NT-proBNP (n = 1468) (HR: 3.19; 95% CI: 2.68 to 3.80). In patients with no recent HF hospitalization and NT-proBNP <=360 pg/ml (n = 1,187), the event rate was 2.43 (95% CI: 2.03 to 2.90) compared with 17.79 (95% CI: 15.77 to 20.07) per 100 person-years when both risk predictors were present (n = 523; HR: 6.18; 95% CI: 4.96 to 7.69). CONCLUSIONS: Recent hospitalization for HF or an elevated level of NT-proBNP identified patients at higher risk for cardiovascular events, and this risk was increased further when both factors were present. PMID- 26046844 TI - Effect of Cytochrome b5 Content on the Activity of Polymorphic CYP1A2, 2B6, and 2E1 in Human Liver Microsomes. AB - Human cytochrome b5 (Cyt b5) plays important roles in cytochrome P450 (CYP) mediated drug metabolism. However, the expression level of Cyt b5 in normal human liver remains largely unknown. The effect of Cyt b5 on overall CYP activity in human liver microsomes (HLM) has rarely been reported and the relationship between Cyt b5 and the activity of polymorphic CYP has not been systematically investigated. In this study, we found that the median value of Cyt b5 protein was 270.01 pmol/mg from 123 HLM samples, and 12- and 19-fold individual variation was observed in Cyt b5 mRNA and protein levels, respectively. Gender and smoking clearly influenced Cyt b5 content. In addition, we found that Cyt b5 protein levels significantly correlated with the overall activity of CYP1A2, 2B6, and 2E1 in HLM. However, when the CYP activities were sorted by single nucleotide polymorphisms (SNP), the effect of Cyt b5 protein on the kinetic parameters varied greatly. There were significant correlations between Cyt b5 content and Vmax and CLint of CYP1A2 wild-types (3860GG, 2159GG, and 5347CC) as well as homozygous mutants (163AA and 3113GG). In contrast to Vmax and CLint, the Km of CYP2B6 516GG and 785AA genotypes was inversely associated with Cyt b5 content. Correlations between Cyt b5 content and Vmax and CLint of CYP2E1 -1293GG, 1293GC, 7632TT, 7632TA, -333TT, and -352AA genotypes were also observed. In conclusion, Cyt b5 expression levels varied considerably in the Chinese cohort from this study. Cyt b5 had significant impact on the overall activity of CYP1A2, 2B6, and 2E1 in HLM and the effects of Cyt b5 protein on polymorphic CYP1A2, 2B6, and 2E1 activity were SNP-dependent. These findings suggest that Cyt b5 plays an important role in CYP-mediated activities in HLM and may possibly be a contributing factor for the individual variation observed in CYP enzyme activities. PMID- 26046846 TI - Laparoendoscopic resection of a giant sessile caecal adenoma - a video vignette. PMID- 26046845 TI - Effective Optimization of Antibody Affinity by Phage Display Integrated with High Throughput DNA Synthesis and Sequencing Technologies. AB - Phage display technology has been widely used for antibody affinity maturation for decades. The limited library sequence diversity together with excessive redundancy and labour-consuming procedure for candidate identification are two major obstacles to widespread adoption of this technology. We hereby describe a novel library generation and screening approach to address the problems. The approach started with the targeted diversification of multiple complementarity determining regions (CDRs) of a humanized anti-ErbB2 antibody, HuA21, with a small perturbation mutagenesis strategy. A combination of three degenerate codons, NWG, NWC, and NSG, were chosen for amino acid saturation mutagenesis without introducing cysteine and stop residues. In total, 7,749 degenerate oligonucleotides were synthesized on two microchips and released to construct five single-chain antibody fragment (scFv) gene libraries with 4 x 10(6) DNA sequences. Deep sequencing of the unselected and selected phage libraries using the Illumina platform allowed for an in-depth evaluation of the enrichment landscapes in CDR sequences and amino acid substitutions. Potent candidates were identified according to their high frequencies using NGS analysis, by-passing the need for the primary screening of target-binding clones. Furthermore, a subsequent library by recombination of the 10 most abundant variants from four CDRs was constructed and screened, and a mutant with 158-fold increased affinity (Kd = 25.5 pM) was obtained. These results suggest the potential application of the developed methodology for optimizing the binding properties of other antibodies and biomolecules. PMID- 26046847 TI - Identification of Novel Cetacean Poxviruses in Cetaceans Stranded in South West England. AB - Poxvirus infections in marine mammals have been mainly reported through their clinical lesions and electron microscopy (EM). Poxvirus particles in association with such lesions have been demonstrated by EM and were previously classified as two new viruses, cetacean poxvirus 1 (CePV-1) and cetacean poxvirus 2 (CePV-2). In this study, epidermal pox lesions in cetaceans stranded in South West England (Cornwall) between 2008 and 2012 were investigated by electron microscopy and molecular analysis. PCR and sequencing of a highly conserved region within the viral DNA polymerase gene ruled out both parapox- and orthopoxviruses. Moreover, phylogenetic analysis of the PCR product clustered the sequences with those previously described as cetacean poxviruses. However, taking the close genetic distance of this gene fragment across the family of poxviridae into account, it is reasonable to postulate further, novel cetacean poxvirus species. The nucleotide similarity within each cluster (tentative species) detected ranged from 98.6% to 100%, whilst the similarity between the clusters was no more than 95%. The detection of several species of poxvirus in different cetacean species confirms the likelihood of a heterogeneous cetacean poxvirus genus, comparable to the heterogeneity observed in other poxvirus genera. PMID- 26046848 TI - Gastrointestinal Fibroblasts Have Specialized, Diverse Transcriptional Phenotypes: A Comprehensive Gene Expression Analysis of Human Fibroblasts. AB - BACKGROUND: Fibroblasts are the principal stromal cells that exist in whole organs and play vital roles in many biological processes. Although the functional diversity of fibroblasts has been estimated, a comprehensive analysis of fibroblasts from the whole body has not been performed and their transcriptional diversity has not been sufficiently explored. The aim of this study was to elucidate the transcriptional diversity of human fibroblasts within the whole body. METHODS: Global gene expression analysis was performed on 63 human primary fibroblasts from 13 organs. Of these, 32 fibroblasts from gastrointestinal organs (gastrointestinal fibroblasts: GIFs) were obtained from a pair of 2 anatomical sites: the submucosal layer (submucosal fibroblasts: SMFs) and the subperitoneal layer (subperitoneal fibroblasts: SPFs). Using hierarchical clustering analysis, we elucidated identifiable subgroups of fibroblasts and analyzed the transcriptional character of each subgroup. RESULTS: In unsupervised clustering, 2 major clusters that separate GIFs and non-GIFs were observed. Organ- and anatomical site-dependent clusters within GIFs were also observed. The signature genes that discriminated GIFs from non-GIFs, SMFs from SPFs, and the fibroblasts of one organ from another organ consisted of genes associated with transcriptional regulation, signaling ligands, and extracellular matrix remodeling. CONCLUSIONS: GIFs are characteristic fibroblasts with specific gene expressions from transcriptional regulation, signaling ligands, and extracellular matrix remodeling related genes. In addition, the anatomical site- and organ dependent diversity of GIFs was also discovered. These features of GIFs contribute to their specific physiological function and homeostatic maintenance, and create a functional diversity of the gastrointestinal tract. PMID- 26046850 TI - The Annals of Thoracic Surgery: The First 50 Years. PMID- 26046849 TI - Activated Brain Endothelial Cells Cross-Present Malaria Antigen. AB - In the murine model of cerebral malaria caused by P. berghei ANKA (PbA), parasite specific CD8+ T cells directly induce pathology and have long been hypothesized to kill brain endothelial cells that have internalized PbA antigen. We previously reported that brain microvessel fragments from infected mice cross-present PbA epitopes, using reporter cells transduced with epitope-specific T cell receptors. Here, we confirm that endothelial cells are the population responsible for cross presentation in vivo, not pericytes or microglia. PbA antigen cross-presentation by primary brain endothelial cells in vitro confers susceptibility to killing by CD8+ T cells from infected mice. IFNgamma stimulation is required for brain endothelial cross-presentation in vivo and in vitro, which occurs by a proteasome and TAP-dependent mechanism. Parasite strains that do not induce cerebral malaria were phagocytosed and cross-presented less efficiently than PbA in vitro. The main source of antigen appears to be free merozoites, which were avidly phagocytosed. A human brain endothelial cell line also phagocytosed P. falciparum merozoites. Besides being the first demonstration of cross-presentation by brain endothelial cells, our results suggest that interfering with merozoite phagocytosis or antigen processing may be effective strategies for cerebral malaria intervention. PMID- 26046851 TI - Lessons Learned Regarding Myocardial Revascularization Remain True 50 Years Later: 50th Anniversary Perspective on Diethrich EB, Morris JD, Liddicoat JE, Wessinger JB. Myocardial Revascularization. Evaluation of Autogenous Vein Grafts Between Aorta and Myocardium. Ann Thorac Surg 1965;1:671-82. PMID- 26046852 TI - 50th Anniversary Landmark Commentary on Caves PK, Stinson EB, Billingham M, Shumway NE. Percutaneous transvenous endomyocardial biopsy in human heart recipients: experience with a new technique. Ann Thorac Surg 1973;16:325-36. PMID- 26046853 TI - 50th Anniversary Landmark Commentary on Oldham HN Jr, Ebert PA, Young WG, Sabiston DC Jr. Surgical Management of Congenital Coronary Artery Fistula. Ann Thorac Surg 1971;12:503-13. PMID- 26046854 TI - 50TH Anniversary Landmark Commentary on Sloan H. The Breeding and Feeding of Thoracic Surgeons. Ann Thorac Surg 1975;20:371-86. PMID- 26046855 TI - Invited Commentary. PMID- 26046856 TI - Invited Commentary. PMID- 26046857 TI - Invited Commentary. PMID- 26046858 TI - Invited Commentary. PMID- 26046859 TI - Invited Commentary. PMID- 26046860 TI - Invited Commentary. PMID- 26046861 TI - Invited Commentary. PMID- 26046862 TI - Invited Commentary. PMID- 26046863 TI - Invited Commentary. PMID- 26046864 TI - Invited Commentary. PMID- 26046865 TI - Invited Commentary. PMID- 26046866 TI - Invited Commentary. PMID- 26046868 TI - Invited Commentary. PMID- 26046867 TI - Invited Commentary. PMID- 26046869 TI - Pleural Gas Analysis for Detection of Alveolopleural Fistulae. AB - PURPOSE: Visual inspection (VI) of bubbles in the chest drainage unit does not differentiate a true leak of alveolopleural fistula (APF) from a false leak. We hypothesized that detection of elevated levels of carbon dioxide, increase in oxygen content, or both, in pleural gas upon the administration of supplemental oxygen would accurately identify APF. DESCRIPTION: Prospective study comparing pleural gas analysis (GA) with VI to detect APF after surgical lobectomy (n = 50). EVALUATION: APF was found in 22 (44%) patients at the time of analysis. VI revealed air bubbles in 31 (62%) patients, indicating the presence of APF, of whom 12 (38.7%) were false leaks. VI failed to identify APF in 3 (6%) patients that resulted in post-tube removal pneumothorax. By contrast, GA accurately demonstrated APF in 21 patients, with only one false negative and no false positives. GA demonstrated better sensitivity (95.5% vs 86.4%), specificity (100% vs 57.1%), positive predictive value (100% vs 61.3%), and negative predictive value (96.6% vs 84.2%) compared to VI. CONCLUSIONS: Pleural gas analysis is an effective technique to detect APF and can facilitate timely and safe chest tube removal. PMID- 26046870 TI - A Hybrid Tissue-Engineered Heart Valve. AB - PURPOSE: This study describes the efforts to develop and test the first hybrid tissue-engineered heart valve whose leaflets are composed of an extra-thin superelastic Nitinol mesh tightly enclosed by uniform tissue layers composed of multiple cell types. DESCRIPTION: The trileaflet Nitinol mesh scaffolds underwent three-dimensional cell culture with smooth muscle and fibroblast/myofibroblast cells enclosing the mesh, which were finally covered by an endothelial cell layer. EVALUATION: Quantitative and qualitative assays were performed to analyze the microstructure of the tissues. A tissue composition almost similar to that of natural heart valve leaflets was observed. The function of the valves and their Nitinol scaffolds were tested in a heart flow simulator that confirmed the trileaflet valves open and close robustly under physiologic flow conditions with an effective orifice area of 75%. The tissue-metal attachment of the leaflets once exposed to physiologic flow rates was tested and approved. CONCLUSIONS: Our preliminary results indicate that the novel hybrid approach with nondegradable scaffold for engineering heart valves is viable and may address the issues associated with current tissue-engineered valves developed with degradable scaffolds. PMID- 26046871 TI - A Novel Technique of Long-Segment Tracheal Repair With Extended Bronchial Flap of Right Upper and Main Bronchus Plus Tracheoplasty. AB - Long-segment tracheal resection and repair pose a great challenge. We present a successful case of long-segment tracheal defect repair with extended bronchial flap of the right upper and main bronchus, together with a tracheoplastic method. This is a novel technique for repairing a large tracheal defect with an extended pedicled bronchial flap in specific situations. PMID- 26046872 TI - Aorto-Tracheopexy in the Treatment of Hunter Syndrome. AB - Hunter syndrome is a multisystem genetic disease in which a significant proportion of morbidity and mortality arise from respiratory dysfunction. Notably, tracheal abnormalities in Hunter syndrome can compromise clinical stability, and management is primarily supportive. We describe here the first successful implementation of aorto-tracheopexy in a 19-year-old patient as a surgical strategy to resolve progressive respiratory deterioration. PMID- 26046873 TI - Pulmonary Artery Agenesis Associated With Emphysema and Multiple Invasive Non Small Cell Lung Cancers. AB - Pulmonary artery (PA) agenesis in the absence of associated cardiac abnormalities is a rare congenital abnormality. It may remain undiagnosed until adulthood when patients present with respiratory symptoms such as hemoptysis, dyspnea, repeated respiratory infections, or pulmonary hypertension. Herein we present a case of a 50-year-old woman who was found to have multiple, morphologically distinct non small cell lung cancers in association with agenesis of the PA. This instance represents the fourth reported case of such association in the English literature. PMID- 26046875 TI - Spontaneous Regression of Pulmonary Lymphoepithelioma-Like Carcinoma. AB - The spontaneous regression of lung cancer is extremely rare. We encountered a case of a 70-year-old man with pulmonary lymphoepithelioma-like carcinoma that regressed without receiving anticancer therapy. The patient had depression during tumor regression, however, and was treated with a serotonin-selective reuptake inhibitor. On histologic examination, CD3(+), CD4(+), and CD8(+) lymphocytes were found to have infiltrated around the tumor. Thus, the serotonin-selective reuptake inhibitor may have activated these lymphocytes to cause spontaneous tumor regression. PMID- 26046874 TI - Pulmonary Metastasectomy 31 Years After Surgery for Renal Cell Carcinoma. AB - An 82-year-old man underwent a left upper lobectomy for a solitary tumor on suspicion of lung cancer. Histopathologic findings of the resected specimen showed clear cell renal cell carcinoma, which was diagnosed as a metastasis from kidney cancer concealed for 31 years after nephrectomy. The Ki-67 labeling index of the metastatic tumor was high (36.1%). A few cases of recurrent renal cell carcinoma after a long interval from initial diagnosis have been seen. However, pulmonary metastasectomy more than 30 years after radical nephrectomy for renal cell carcinoma has not been reported. This remarkable case provides new and valuable clinical insights into metastatic renal cell carcinoma. PMID- 26046876 TI - Anomalous Pulmonary Venous Return of the Left Upper Lobe in a Donor Lung. AB - We report a case of partial anomalous pulmonary venous return from the left upper lobe in a donor lung discovered during lung transplantation. The upper lobe vein could be implanted successfully into the donor atrial cuff to restore physiologic venous drainage. The abnormality was retrospectively identified on the donor's chest computed tomographic scan. Cardiac magnetic resonance imaging performed in the recipient 6 months after transplantation demonstrated patent left pulmonary venous drainage. This is the third reported case of partial anomalous pulmonary venous return in a donor lung, but the first description of direct ex vivo suture into the donor cuff. PMID- 26046877 TI - Long-Term Survival After Local Resection of Cervical Esophageal Cancer. AB - Squamous cell carcinoma of the esophagus may be seen in patients with history of head and neck malignancies. Anatomic factors may limit management options. We present a case of second primary early cervical esophageal squamous cell cancer managed by local resection with reconstruction using a radial forearm flap. PMID- 26046878 TI - Mitral Valve Stenosis Progression Due to Severe Calcification on Glutaraldehyde Treated Autologous Pericardium: Word of Caution for an Attractive Repair Technique. AB - A 42-year-old woman presented with a 6-month history of palpitations and progressive dyspnea on exertion. She had undergone aortic and mitral valve repair using glutaraldehyde-treated autologous pericardium for active infective endocarditis 5 years prior. Transthoracic echocardiography showed mitral valve stenosis with limited movement of the anterior leaflet. At redo surgery, severe calcification of the glutaraldehyde-treated pericardial patch on the anterior mitral leaflet was observed. Double valve replacement was performed with pulmonary vein isolation. Pathologic examination showed calcification of the glutaraldehyde-treated autologous pericardium. The patient was discharged on postoperative day 11 with oral anticoagulant therapy. PMID- 26046879 TI - CorMatrix Extracellular Matrix Used for Valve Repair in the Adult: Is There De Novo Valvular Tissue Seen? AB - Decellularized extracellular matrix from porcine intestinal submucosa is available as an approved material for the repair of tissues including cardiac structures. Although pathologic findings of explanted CorMatrix (CorMatrix Cardiovascular, Inc, Roswell, GA) used for valvular repair have been reported in the pediatric population, there is a paucity of data in the adult population. Herein, we report the histologic changes in explanted CorMatrix from 2 adults at 10 and 18 months post-implant. PMID- 26046880 TI - Cerebral Protection During Mitral Valve Repair in a Patient With Moyamoya Syndrome. AB - In patients with moyamoya syndrome requiring heart surgery, the brain blood flow during the low perfusion state under cardiopulmonary bypass is a concern. We report on a successful mitral valve repair and tricuspid repair in a patient with moyamoya syndrome, performed using an integrated cerebral protection strategy with cerebral oxygen saturation monitoring, intraaortic balloon pumping, and cardiopulmonary bypass perfusion at a relatively high pressure. An integrated approach with a thorough discussion among cardiac surgeons, anesthesiologists, and perfusionists was invaluable to protect brain perfusion in a patient with moyamoya syndrome. PMID- 26046881 TI - Mycotic Thoracic Aortic Aneurysm After Intravesical Bacillus Calmette-Guerin Treatment. AB - Bacillus Calmette-Guerin (BCG) is widely used for the treatment of bladder cancer. We report a case of BCG-associated mycotic thoracic aortic aneurysm that was successfully treated with resection and antimycobacterial therapy. PMID- 26046882 TI - Surgical Resection of a Giant Coronary Aneurysm. AB - Coronary aneurysms are quite uncommon, and those qualifying as giant aneurysms are even more so. Currently, no standardized treatment protocol exists. We report the case of a 46-year-old man presenting with clinical signs and symptoms of acute myocardial infarction who was found to have a giant coronary aneurysm. The patient was initially evaluated with a computed tomography angiogram, which revealed a 9-cm aneurysm of the left circumflex coronary artery. Surgical resection of the aneurysm, ligation of the proximal circumflex artery, and bypass using the left internal mammary artery to vascularize the proximal circumflex artery was performed. PMID- 26046884 TI - Implantation of HeartMate II Left Ventricular Assist Device in a Single-Lung Patient. AB - The use of mechanical assist devices has been established as an effective therapy for patients with end-stage heart failure. Implantable left ventricular assist devices are becoming more common in the clinical practice of cardiac surgery. This report illustrates the use of a HeartMate II (Thoratec Pleasanton, CA) left ventricular assist device in a patient with a single lung and dilated cardiomyopathy. To our knowledge, this is the first report of a left ventricular assist device placement in a patient with a prior pneumonectomy. PMID- 26046883 TI - Acute Right Coronary Artery Occlusion After Tricuspid Valve Ring Annuloplasty. AB - A patient was submitted to mitral valve replacement and tricuspid ring annuloplasty. During immediate postoperative course, signs of inferior myocardial ischemia appeared. Acute entrapment of the right coronary artery due to tricuspid ring sutures was confirmed by coronary angiography. The patient was reoperated and a right coronary bypass graft was successfully performed. Tricuspid procedures have shown to be effective and secure with a low rate of complication. Few cases of right coronary artery occlusion have been described and the majority not treated. Exceptional cases of right coronary occlusion related to tricuspid ring annuloplasty have been reported with a favorable outcome, as the case described herein. PMID- 26046885 TI - Aortic Arch Mycotic Aneurysm Due to Scedosporium Apiospermum Reconstructed With Homografts. AB - A 39-year-old female, active parenteral drug user was diagnosed of spondylodiscitis. A computed tomography (CT) scan showed an extensive aortic arch aneurysm. A positron emission tomography (PET)-CT scan, showing significant aortic wall uptake of the tracer through the whole aortic arch and the D8-D9 intervertebral disc, allowed us to suspect an aortitis despite negative blood cultures. The aneurysm was resected and reconstructed with 2 aortic homografts. Cultures of specimens from the aortic wall were positive to the fungi Scedosporium apiospermum. A new PET-CT scan 4 months after surgery showed absence of tracer uptake both at the homografts site and intervertebral disc. PMID- 26046886 TI - Balanced Double Aortic Arch in an Older Patient. PMID- 26046887 TI - Anomalous Origin of Right Coronary Artery in Subaortic Position. PMID- 26046888 TI - Giant Right Atrial Pseudoaneurysm. PMID- 26046889 TI - Venous Collector in a Case of Partial Anomalous Pulmonary Venous Drainage. PMID- 26046890 TI - Controlled Trachea Suspension for Tracheomalacia After Resection of Large Anterior Mediastinal Mass. AB - Tracheomalacia is a disorder of the large airways that is often caused by a large anterior mediastinal mass. This study describes 7 patients who underwent controlled trachea suspension as a surgical intervention to prevent severe tracheomalacia and provide potent relief of airway symptoms. All patients recovered well. The results demonstrate this procedure may be safe and effective for resection of a large mediastinal mass compressing the trachea with collapsed segments. PMID- 26046891 TI - Chest Wall Reconstruction Using Sternal Plating in Patients With Complex Sternal Dehiscence. AB - To evaluate the effectiveness of sternal reconstruction using demineralized bone matrix in patients with complex sternal dehiscence. In this retrospective review, 14 patients with complex sternal wounds with dehiscence were evaluated after specific reconstructive methods. The steps involved ensuring sternal salvage by eradicating infection with a combination of vacuum assisted closure and antibiotic therapy. In a separate setting, patients underwent sternal reconstruction with plate fixation and local use of bone morphogenetic protein (BMP; Infuse, Medtronic, Minneapolis, MN) and demineralized bone matrix for remaining sternal defects. Pectoral myocutaneous flaps were then used to cover the sternum. Patients were evaluated daily in the immediate postoperative period for sternal wound complications and pain and were followed up at 3 and 6 months postoperatively. At 6 month after the procedure, all patients had stable chest walls with no further sternal instability and no recurrent dehiscences or wound infections. All patients returned to normal activity with complete resolution of sternal pain. Complex sternal wounds can be reconstructed and repaired effectively with a combination of bone salvage, local therapy with BMP, and flap closure, with encouraging results. PMID- 26046892 TI - Surgical Management of Caseous Calcification of the Mitral Annulus. AB - Caseous calcification of the mitral annulus is a rare variant of mitral annular calcification where liquefaction and caseation result in formation of a mass at the border of the calcified annulus. Limited reports of operative therapy for caseous calcification of the mitral annulus describe wide excision and gross debridement of the mass, a technique that can cause perioperative stroke. We present a strategy of limited incision and drainage of the liquid material, closure of the incision, and subsequent suture obliteration of the cavity and mitral valve repair or replacement. In our experience, this technique is safe and has not been associated with perioperative stroke. PMID- 26046893 TI - Anatomic Rerouting of Anomalous Left Coronary Artery From Right Coronary Sinus. AB - We herein present a new surgical technique in the treatment of an anomalous left coronary artery from the right coronary sinus in an 18-year-old patient with an intramural course of the left main coronary artery. PMID- 26046894 TI - Optimal Lung Cancer Candidates for Sublobar Resection: Prediction of Pathologic Node-Negative Clinical Stage IA NSCLC. PMID- 26046895 TI - Is There a Role for Preoperative Chemoradiation in Esophageal Signet Ring Cell Adenocarcinomas? PMID- 26046896 TI - Reply: To PMID 25193197. PMID- 26046897 TI - Robotic Resection of Accessory Mitral Valve Tissue. PMID- 26046898 TI - Subdermal Contraceptive Implant Embolism to a Pulmonary Artery. PMID- 26046899 TI - Resurrected Interest in the Rhone-Poulenc Pump for Cardiocirculatory Support. PMID- 26046900 TI - Reply: To PMID 24856794. PMID- 26046901 TI - Coronary Artery Complications After Three-Patch Repair of Supravalvar Aortic Stenosis: Recognition and Management. PMID- 26046902 TI - Reply: To PMID 25282210. PMID- 26046903 TI - Sternal Cleft and Pectus Excavatum: A Combined Approach for the Correction of a Complex Anterior Chest Wall Malformation in a Teenager. AB - Congenital sternal cleft is a rare chest wall malformation. Because of the flexibility of the chest in infants, surgical repair should be performed by primary closure in the neonatal period. In adolescents and adults, different techniques have been suggested to overcome the lack of sternal bone tissue. We describe a very rare case of an 18-year-old woman with a complete bifid sternum associated with pectus excavatum for whom a satisfactory cosmetic and functional result was obtained by adequate surgical planning, which entailed a combination of two standardized surgical techniques. PMID- 26046904 TI - Manubrioclavicular and Manubriosternal Reconstruction After Radical Resection for Chondrosarcoma of Manubriosternum: A Modified Surgical Technique. AB - Primary chondrosarcoma of the manubriosternum is a rare tumor. We describe the case of a 42 year-old man who presented with a swelling of the anterior chest wall. The computed tomography scan of the thorax showed a manubriosternal mass involving both clavicles. True-cut biopsy revealed a low-grade chondrosarcoma. The manubrium, the medial part of the clavicles, the sternum, and all costal cartilages were excised en bloc with wide, clear margins and reconstructed successfully without any residual deficit regarding the stability of the chest wall and upper arm movements. We present this rare case with a modified reconstruction technique using a methyl methacrylate Marlex mesh sandwich plate with excellent results. After 2 years' follow-up, there was no radiologic or clinical signs of recurrence. PMID- 26046905 TI - Primary Psammomatous Melanotic Schwannoma of the Spine. AB - Schwannoma is an easily identifiable and frequently diagnosed lesion of the spinal column. However, if the schwannoma contains a melanin component, the diagnosis is challenging. Our purpose in this case report is to discuss the imaging and histopathologic findings of a rarely seen psammomatous type of melanotic schwannoma diagnosed in a 31-year-old woman. PMID- 26046906 TI - Epstein-Barr Virus-Associated Pulmonary Smooth Muscle Tumor After Lung Transplantation. AB - We report an Epstein-Barr virus (EBV)-associated pulmonary posttransplant smooth muscle tumor arising in the left lung of a 71-year-old bilateral lung transplant recipient nearly 3 years after transplantation, treated with thoracoscopic wedge resection. Four previous smooth muscle tumors have been reported following lung transplantation. To our knowledge, this is the first reported case of an EBV positive posttransplant smooth muscle tumor within the transplanted lung. We describe the clinical, pathologic, and histologic diagnosis of this uncommon tumor. PMID- 26046907 TI - Adenocarcinoma of the Distal Esophagus in a Patient With a Magnetic Sphincter Augmentation Device: First of Many to Come? AB - Recently an alternative treatment option utilizing a laparoscopically placed magnetic sphincter device has been introduced for gastroesophageal reflux disease patients who are hesitant to undergo Nissen-fundoplication. Based on previous experience with similar devices, concerns have been raised about migration, and in case of a subsequently developing esophageal cancer, technical challenges during the endoscopic or surgical treatment caused by the foreign body reaction around the abdominal esophagus. In this article, we report of the first case of esophagectomy for cancer in a patient with a previously implanted magnetic sphincter augmentation device. PMID- 26046908 TI - A Hybrid Double Access for Transcatheter Mitral Valve-In-Valve Implantation. AB - We present a case of hybrid mitral valve-in valve implantation. The planned transapical approach failed due to the inability to cross the degenerated stenotic mitral bioprosthesis. An alternative strategy was performed: first, an anterograde crossing of mitral stenosis, and then, a guidewire externalization through the apex by using a snare. To our knowledge, this is the first described case of double approach mitral valve-in valve implantation. PMID- 26046909 TI - Intravenous GPIIb/IIIa Inhibitor for Secondary Prevention of Shunt Thrombosis in a Pediatric Patient. AB - Thrombosis occurs after aortopulmonary shunting in children despite the use of heparin and oral antiplatelet agents. We describe the use of an intravenous antiplatelet agent for secondary prevention of shunt thrombosis without adverse events. Platelet mapping was used to monitor the effects and demonstrated the rapid onset of platelet inhibition. PMID- 26046910 TI - Thoracoscopic Biopsy for Immunoglobulin G4-Related Coronary Periarteritis. PMID- 26046912 TI - Post-Traumatic Stress Symptoms and Post-Traumatic Growth: Evidence from a Longitudinal Study following an Earthquake Disaster. AB - OBJECTIVE: The current longitudinal study aims to examine the bidirectional relationship between post-traumatic stress symptoms (PTSS) and post-traumatic growth (PTG). METHOD: One hundred twenty-two adults in the most severely affected area were investigated by self-report questionnaires at 12 months and 18 months after the Wenchuan Earthquake occurred in China. RESULTS: The autoregressive cross-lagged structure equation analysis revealed that PTG at 12 months post earthquake could negatively predict PTSS at 18 months post-earthquake above and beyond PTSS stability, whereas PTSS at 12 months post-earthquake could not significantly predict subsequent PTG. Moreover, PTG at 12 months post-earthquake could predict fewer subsequent intrusions, numbing and hyper-arousal symptoms but not avoidance symptoms. CONCLUSION: Growth can play a role in reducing long-term post-traumatic stress symptoms, and the implication of a positive perspective in post-trauma circumstance is discussed. PMID- 26046911 TI - Optimization of a Novel Non-invasive Oral Sampling Technique for Zoonotic Pathogen Surveillance in Nonhuman Primates. AB - Free-ranging nonhuman primates are frequent sources of zoonotic pathogens due to their physiologic similarity and in many tropical regions, close contact with humans. Many high-risk disease transmission interfaces have not been monitored for zoonotic pathogens due to difficulties inherent to invasive sampling of free ranging wildlife. Non-invasive surveillance of nonhuman primates for pathogens with high potential for spillover into humans is therefore critical for understanding disease ecology of existing zoonotic pathogen burdens and identifying communities where zoonotic diseases are likely to emerge in the future. We developed a non-invasive oral sampling technique using ropes distributed to nonhuman primates to target viruses shed in the oral cavity, which through bite wounds and discarded food, could be transmitted to people. Optimization was performed by testing paired rope and oral swabs from laboratory colony rhesus macaques for rhesus cytomegalovirus (RhCMV) and simian foamy virus (SFV) and implementing the technique with free-ranging terrestrial and arboreal nonhuman primate species in Uganda and Nepal. Both ubiquitous DNA and RNA viruses, RhCMV and SFV, were detected in oral samples collected from ropes distributed to laboratory colony macaques and SFV was detected in free-ranging macaques and olive baboons. Our study describes a technique that can be used for disease surveillance in free-ranging nonhuman primates and, potentially, other wildlife species when invasive sampling techniques may not be feasible. PMID- 26046914 TI - Gene Expression Profiles of Chicken Embryo Fibroblasts in Response to Salmonella Enteritidis Infection. AB - The response of chicken to non-typhoidal Salmonella infection is becoming well characterised but the role of particular cell types in this response is still far from being understood. Therefore, in this study we characterised the response of chicken embryo fibroblasts (CEFs) to infection with two different S. Enteritidis strains by microarray analysis. The expression of chicken genes identified as significantly up- or down-regulated (>=3-fold) by microarray analysis was verified by real-time PCR followed by functional classification of the genes and prediction of interactions between the proteins using Gene Ontology and STRING Database. Finally the expression of the newly identified genes was tested in HD11 macrophages and in vivo in chickens. Altogether 19 genes were induced in CEFs after S. Enteritidis infection. Twelve of them were also induced in HD11 macrophages and thirteen in the caecum of orally infected chickens. The majority of these genes were assigned different functions in the immune response, however five of them (LOC101750351, K123, BU460569, MOBKL2C and G0S2) have not been associated with the response of chicken to Salmonella infection so far. K123 and G0S2 were the only 'non-immune' genes inducible by S. Enteritidis in fibroblasts, HD11 macrophages and in the caecum after oral infection. The function of K123 is unknown but G0S2 is involved in lipid metabolism and in beta-oxidation of fatty acids in mitochondria. PMID- 26046915 TI - In Situ OH Generation from O2- and H2O2 Plays a Critical Role in Plasma-Induced Cell Death. AB - Reactive oxygen and nitrogen species produced by cold atmospheric plasma (CAP) are considered to be the most important species for biomedical applications, including cancer treatment. However, it is not known which species exert the greatest biological effects, and the nature of their interactions with tumor cells remains ill-defined. These questions were addressed in the present study by exposing human mesenchymal stromal and LP-1 cells to reactive oxygen and nitrogen species produced by CAP and evaluating cell viability. Superoxide anion (O2-) and hydrogen peroxide (H2O2) were the two major species present in plasma, but their respective concentrations were not sufficient to cause cell death when used in isolation; however, in the presence of iron, both species enhanced the cell death inducing effects of plasma. We propose that iron containing proteins in cells catalyze O2- and H2O2 into the highly reactive OH radical that can induce cell death. The results demonstrate how reactive species are transferred to liquid and converted into the OH radical to mediate cytotoxicity and provide mechanistic insight into the molecular mechanisms underlying tumor cell death by plasma treatment. PMID- 26046913 TI - Conserved genetic pathways associated with microphthalmia, anophthalmia, and coloboma. AB - The human eye is a complex organ whose development requires extraordinary coordination of developmental processes. The conservation of ocular developmental steps in vertebrates suggests possible common genetic mechanisms. Genetic diseases involving the eye represent a leading cause of blindness in children and adults. During the last decades, there has been an exponential increase in genetic studies of ocular disorders. In this review, we summarize current success in identification of genes responsible for microphthalmia, anophthalmia, and coloboma (MAC) phenotypes, which are associated with early defects in embryonic eye development. Studies in animal models for the orthologous genes identified overlapping phenotypes for most factors, confirming the conservation of their function in vertebrate development. These animal models allow for further investigation of the mechanisms of MAC, integration of various identified genes into common developmental pathways and finally, provide an avenue for the development and testing of therapeutic interventions. PMID- 26046916 TI - Cryopreservation alters the membrane and cytoskeletal protein profile of platelet microparticles. AB - BACKGROUND: Cryopreservation of platelets (PLTs) in dimethyl sulfoxide (DMSO) and storage at -80 degrees C extends the PLT shelf life to at least 2 years, allowing greater accessibility in military and rural environments. While cryopreserved PLTs have been extensively characterized, the microparticles formed as a result of cryopreservation are yet to be fully described. STUDY DESIGN AND METHODS: Apheresis PLTs were cryopreserved at -80 degrees C with 5% DMSO and sampled before freezing and after thawing. Microparticle number, size, surface receptor phenotype, and function were assessed by microscopy, flow cytometry, dynamic light scattering, and thrombin-generating capacity. Proteomic changes were examined using two-dimensional gel electrophoresis and Western blotting. RESULTS: PLT cryopreservation resulted in a 15-fold increase in the number of microparticles compared to fresh PLTs. The surface receptor phenotype of these microparticles differed to microparticles from fresh PLTs, with more microparticles expressing glycoprotein (GP)IV, GPIIb, and the GPIb-V-IX complex. Cryopreservation drastically altered the abundance of many cytoskeletal proteins in the PLT microparticles, including actin, filamin, gelsolin, and tropomyosin. Despite these changes, PLT microparticles were functional and contributed to phosphatidylserine- and tissue factor- induced thrombin generation. CONCLUSION: This study demonstrates that PLT microparticles formed by cryopreservation are phenotypically distinct from those present before freezing. These differences may be associated with the procoagulant properties of cryopreserved PLTs. PMID- 26046918 TI - Correction: In Vitro and In Vivo Metabolism and Inhibitory Activities of Vasicine, a Potent Acetylcholinesterase and Butyrylcholinesterase Inhibitor. PMID- 26046917 TI - A Major Gene for Bovine Ovulation Rate. AB - Half-sib daughters sired by a bull believed to be a carrier of a major gene for high ovulation rate were evaluated for ovulation rate and genotyped in an effort to both test the hypothesis of segregation of a major gene and to map the gene's location. A total of 131 daughters were produced over four consecutive years at a University of Wisconsin-Madison research farm. All were evaluated for ovulation rate over an average of four estrous cycles using transrectal ultrasonography. The sire and all daughters were genotyped using a 3K SNP chip and the genotype and phenotype data were used in a linkage analysis. Subsequently, daughters recombinant within the QTL region and the sire were genotyped successively with 50K and 777K SNP chips to refine the location of the causative polymorphism. Positional candidate genes within the fine-mapped region were examined for polymorphism by Sanger sequencing of PCR amplicons encompassing coding and 5' and 3' flanking regions of the genes. Sire DNA was used as template in the PCR reactions. Strong evidence of a major gene for ovulation rate was observed (p < 1 x 10(-28)) with the gene localized to bovine chromosome 10. Fine-mapping subsequently reduced the location to a 1.2 Mb region between 13.6 and 14.8 Mb on chromosome 10. The location identified does not correspond to that for any previously identified major gene for ovulation rate. This region contains three candidate genes, SMAD3, SMAD6 and IQCH. While candidate gene screening failed to identify the causative polymorphism, three polymorphisms were identified that can be used as a haplotype to track inheritance of the high ovulation rate allele in descendants of the carrier sire. PMID- 26046919 TI - Hollow fibre liquid phase micro-extraction by facilitated anionic exchange for the determination of flavonoids in faba beans (Vicia faba L.). AB - INTRODUCTION: Flavonoids are polyphenolic compounds found ubiquitously in foods of plant origin. They are commonly extracted from plant materials with ethanol, methanol, water, their combination or even with acidified extracting solutions. The disadvantages of these methods are the use of high quantity of organic solvent, the possible loss of analytes in the different steps and the laborious process of the techniques. In addition, the complexity of the phenolic mixtures present in plant materials requires a preliminary clean-up and fractionation of the crude extracts. OBJECTIVE: To develop a hollow fibre liquid phase micro extraction (HF-LPME) method for a one step clean-up and pre-concentration of flavonoids. METHODOLOGY: Two flavonoids (catechin and rutin) has been extracted by HF-LPME and analysed by HPLC. The related driving force for the liquid membrane has been studied by means of facilitated and non-facilitated transport. Different ionic and non-ionic water insoluble compounds [trioctylamine (TOA), tributyl phosphate (TBP), trioctylphosphine oxide (TOPO) and methyltrioctylammonium chloride (aliquat 336)] were used as carriers. The liquid membrane was constituted by a solution of n-decanol in the presence or absence of carriers. RESULTS: Maximum enrichment factors were obtained with n decanol/aliquat 336 (20%) as organic liquid membrane, sodium hydroxide (NaOH) (0.1 M) as donor solution, sodium chloride (NaCl) (2 M) as acceptor solution and 3 h as extraction time. Under these conditions, good results for validation parameters were obtained [for linearity, limit of detection (LOD), limit of quantitation (LOQ) and repeatability]. CONCLUSIONS: The developed method is simple, effective and has been successfully applied to determine catechin and rutin in ethanolic extracts of faba beans. PMID- 26046920 TI - Meta-Analysis-Based Preliminary Exploration of the Connection between ATDILI and Schizophrenia by GSTM1/T1 Gene Polymorphisms. AB - Anti-tuberculosis drugs have some adverse effects such as anti-tuberculosis drug induced liver injury (ATDILI) and mental disorders. The involvement of glutathione S-transferase (GST) genes in pathogenesis of ATDILI or schizophrenia (SCZ) has been reported. Therefore, GST genes may exemplify molecular connectors between ATDILI and SCZ. However, association studies of GSTM1/T1 polymorphisms with these two diseases have yielded conflicting results. After searching case control association studies in PubMed, ISI Web of Science, EMBASE, Chinese National Knowledge Infrastructure (CNKI), and Chinese BioMedical Literature Database, we performed meta-analyses across a total of 20 published association studies on 3146 subjects for the association of GSTM1 and ATDILI, 2587 for the GSTT1-ATDILI association, 2283 for GSTM1-SCZ and 1116 for GSTT1-SCZ to test the associations of GSTM1/T1 polymorphisms with ATDILI and SCZ. The GSTM1 present genotype was significantly associated with decreased risks of ATDILI (risk ratio(RR): 0.81, 95% confidence interval (CI): 0.75-0.88, P < 0.0001) and SCZ (RR: 0.88, 95%CI: 0.80-0.96, P = 0.004) according to the fixed-effect model, while the GSTT1 present genotype was significantly associated only with a high risk of SCZ (RR: 1.17, 95%CI: 1.04-1.32, P = 0.01) according to both the random- and fixed-effect models, but not with ATDILI (P = 0.82) according to the fixed effect model. Moreover, these significant results were supported with moderate evidence according to the Venice criteria. These results indicate that GSTM1 represents a genetic connection between ATDILI and SCZ, and suggest that ATDILI and SCZ may be co-occurring for the subjects with GSTM1 null genotype. PMID- 26046921 TI - A validated HPLC-MS/MS method for the quantification of caderofloxacin in human plasma and its application to a clinical pharmacokinetic study. AB - A simple, selective and rapid HPLC-MS/MS method was developed and validated for the determination of caderofloxacin in human plasma. Sparfloxacin was used as the internal standard (IS). After precipitation with methanol and dilution with the mobile phase, the samples were injected into the HPLC-MS/MS system. The chromatographic separation was performed on a Zorbax XDB Eclipse C18 column (150 * 4.6 mm, 5 um) with a mobile phase of ammonium acetate buffer (20 mm, pH 3.0) methanol, 45:55 (v/v). The MS/MS analysis was done in positive mode. The multiple reaction monitoring transitions monitored were m/z 412.3 -> 297.1 for caderofloxacin and m/z 393.2 -> 292.2 for the IS. The calibration curve was linear over the range of 50.0-8000 ng/mL with an aliquot of 100 MUL plasma. The precision of the assay was 2.0-9.4 and 6.6-11.5% for the intra- and inter-run variability, respectively. The intra- and inter-run accuracy (relative error) was 4.4-10.0 and -1.2-4.0%. The total run time was 3.5 min. The assay was fully validated in accordance with the US Food and Drug Administration guidance. It was successfully applied to a pharmacokinetic study of caderofloxacin in healthy Chinese volunteers. PMID- 26046922 TI - Comprehensive profiling of lysine acetylation suggests the widespread function is regulated by protein acetylation in the silkworm, Bombyx mori. AB - Lysine acetylation in proteins is a dynamic and reversible PTM and plays an important role in diverse cellular processes. In this study, using lysine acetylation (Kac) peptide enrichment coupled with nano HPLC/MS/MS, we initially identified the acetylome in the silkworms. Overall, a total of 342 acetylated proteins with 667 Kac sites were identified in silkworm. Sequence motifs analysis around Kac sites revealed an enrichment of Y, F, and H in the +1 position, and F was also enriched in the +2 and -2 positions, indicating the presences of preferred amino acids around Kac sites in the silkworm. Functional analysis showed the acetylated proteins were primarily involved in some specific biological processes. Furthermore, lots of nutrient-storage proteins, such as apolipophorin, vitellogenin, storage proteins, and 30 K proteins, were highly acetylated, indicating lysine acetylation may represent a common regulatory mechanism of nutrient utilization in the silkworm. Interestingly, Ser2 proteins, the coating proteins of larval silk, were found to contain many Kac sites, suggesting lysine acetylation may be involved in the regulation of larval silk synthesis. This study is the first to identify the acetylome in a lepidoptera insect, and expands greatly the catalog of lysine acetylation substrates and sites in insects. PMID- 26046923 TI - Presence of Cardiometabolic Risk Factors Is Not Associated with Microalbuminuria in 14-to-20-Years Old Slovak Adolescents: A Cross-Sectional, Population Study. AB - INTRODUCTION: In adults, microalbuminuria indicates generalized endothelial dysfunction, and is an independent risk factor for cardiovascular and all cause mortality. Slovak adults present one of the highest cardiovascular mortality rates in Europe. Thus Slovak adolescents are on a high-risk to develop cardiovascular afflictions early, and screening for microalbuminuria might be useful in early assessment of their cardiovascular risk. We aimed to study the prevalence of microalbuminuria in Slovak adolescents, and the association of urinary albumin-to-creatinine ratio (ACR) to cardiovascular risk factors. SUBJECTS AND METHODS: Anthropometric data, blood pressure, blood count, glucose homeostasis, lipid profile, renal function, inflammatory status, concentrations of homocysteine and uric acid were determined and associated with ACR in 2 666 adolescents (49.4% boys, 51.6% girls) aged 14-to-20 years. Microalbuminuria was classified as ACR 2.5-25.0 mg/mmol in boys and 3.5-35.0 mg/mmol in girls. RESULTS: Prevalence of microalbuminuria in both genders reached 3.3%, and did not differ significantly between lean and centrally obese subjects. Girls presented higher ACR than boys (normoalbuminuric: 0.6 +/- 0.5 mg/mmol vs. 0.5 +/- 0.4 mg/mmol, p > 0.001; microalbuminuric: 9.3 +/- 7.3 mg/mmol vs. 5.0 +/- 3.8 mg/mmol; p > 0.001). Microalbuminuric adolescents and those presenting normoalbuminuria within the upper ACR quartile were slimmer than their normoalbuminuric counterparts or adolescents with normoalbuminuria within the lower quartile, respectively. No association between microalbuminuria and cardiovascular risk markers was revealed. CONCLUSION: Results obtained in this study do not support our assumption that ACR associates with cardiometabolic risk factors in apparently healthy adolescents. Follow-up studies until adulthood are needed to estimate the potential cardiometabolic risk of apparently healthy microalbuminuric adolescents. PMID- 26046924 TI - Empirical gradient threshold technique for automated segmentation across image modalities and cell lines. AB - New microscopy technologies are enabling image acquisition of terabyte-sized data sets consisting of hundreds of thousands of images. In order to retrieve and analyze the biological information in these large data sets, segmentation is needed to detect the regions containing cells or cell colonies. Our work with hundreds of large images (each 21,000*21,000 pixels) requires a segmentation method that: (1) yields high segmentation accuracy, (2) is applicable to multiple cell lines with various densities of cells and cell colonies, and several imaging modalities, (3) can process large data sets in a timely manner, (4) has a low memory footprint and (5) has a small number of user-set parameters that do not require adjustment during the segmentation of large image sets. None of the currently available segmentation methods meet all these requirements. Segmentation based on image gradient thresholding is fast and has a low memory footprint. However, existing techniques that automate the selection of the gradient image threshold do not work across image modalities, multiple cell lines, and a wide range of foreground/background densities (requirement 2) and all failed the requirement for robust parameters that do not require re adjustment with time (requirement 5). We present a novel and empirically derived image gradient threshold selection method for separating foreground and background pixels in an image that meets all the requirements listed above. We quantify the difference between our approach and existing ones in terms of accuracy, execution speed, memory usage and number of adjustable parameters on a reference data set. This reference data set consists of 501 validation images with manually determined segmentations and image sizes ranging from 0.36 Megapixels to 850 Megapixels. It includes four different cell lines and two image modalities: phase contrast and fluorescent. Our new technique, called Empirical Gradient Threshold (EGT), is derived from this reference data set with a 10-fold cross-validation method. EGT segments cells or colonies with resulting Dice accuracy index measurements above 0.92 for all cross-validation data sets. EGT results has also been visually verified on a much larger data set that includes bright field and Differential Interference Contrast (DIC) images, 16 cell lines and 61 time-sequence data sets, for a total of 17,479 images. This method is implemented as an open-source plugin to ImageJ as well as a standalone executable that can be downloaded from the following link: https://isg.nist.gov/. PMID- 26046925 TI - Genetic and Physiological Diversity in the Diatom Nitzschia inconspicua. AB - Nitzschia inconspicua is an ecologically important diatom species, which is believed to have a widespread distribution and to be tolerant to salinity and to organic or nutrient pollution. However, its identification is not straightforward and there is no information on genetic and ecophysiological diversity within the species. We used morphological, molecular (rbcL and LSU D1-D3), ecophysiological and reproductive data to investigate whether N. inconspicua constitutes a single species with a broad ecological tolerance or two or more cryptic species with shared or different ecological preferences. Molecular genetic data for clones from upstream and deltaic sites in the Ebro River basin (Catalonia, Spain) revealed seven N. inconspicua rbcL + LSU genotypes grouped into three major clades. Two of the clades were related to other Nitzschia and Denticula species, making N. inconspicua paraphyletic and suggesting the need for taxonomic revision. Most clones were observed to be automictic, exhibiting paedogamy, and so the biological species concept cannot be used to establish species boundaries. Although there were morphological differences among clones, we found no consistent differences among genotypes belonging to different clades, which are definable only through sequence data. Nevertheless, separating the genotypes could be important for ecological purposes because two different ecophysiological responses were encountered among them. PMID- 26046926 TI - Sepsis biomarkers in neutropaenic systemic inflammatory response syndrome patients on standard care wards. AB - BACKGROUND: Neutropaenic patients are at a high risk of contracting severe infections. In particular, in these patients, parameters with a high negative predictive value are desirable for excluding infection or bacteraemia. This study evaluated sepsis biomarkers in neutropaenic patients suffering from systemic inflammatory response syndrome (SIRS). Further, the predictive capacities of evaluated biomarkers in neutropaenic SIRS patients were compared to non neutropaenic SIRS patients. MATERIAL AND METHODS: In this prospective observational cohort study, patients with clinically suspected sepsis were screened. The predictive capacities of procalcitonin (PCT), C-reactive protein and lipopolysaccharide-binding protein (LBP) in neutropaenic SIRS patients were evaluated in terms of their potential to identify infection or bacteraemia and were compared to results for non-neutropaenic SIRS patients. To select an appropriate control cohort, propensity score matching was applied, balancing confounding factors between neutropaenic and non-neutropaenic SIRS patients. RESULTS: Of 3370 prospectively screened patients with suspected infection, 51 patients suffered from neutropaenic SIRS. For the identification of infection, none of the assessed biomarkers presented a clinically relevant discriminatory potency. Lipopolysaccharide-binding protein and PCT demonstrated discriminatory capacity to discriminate between nonbacteraemic and bacteraemic SIRS in patients with neutropaenia [receiver-operating characteristics-area under the curves (ROC AUCs): 0.860, 0.818]. In neutropaenic SIRS patients, LBP had a significantly better ROC-AUC than in a comparable non-neutropaenic patient cohort for identifying bacteraemia (P = 0.01). CONCLUSION: In neutropaenic SIRS patients, none of the evaluated biomarkers was able to adequately identify infection. LBP and PCT presented a good performance in identifying bacteraemia. Therefore, these markers could be used for screening purposes to increase the pretest probability of blood culture analysis. PMID- 26046927 TI - Stearoyl-CoA Desaturase-1: Is It the Link between Sulfur Amino Acids and Lipid Metabolism? AB - An association between sulfur amino acids (methionine, cysteine, homocysteine and taurine) and lipid metabolism has been described in several experimental and population-based studies. Changes in the metabolism of these amino acids influence serum lipoprotein concentrations, although the underlying mechanisms are still poorly understood. However, recent evidence has suggested that the enzyme stearoyl-CoA desaturase-1 (SCD-1) may be the link between these two metabolic pathways. SCD-1 is a key enzyme for the synthesis of monounsaturated fatty acids. Its main substrates C16:0 and C18:0 and products palmitoleic acid (C16:1) and oleic acid (C18:1) are the most abundant fatty acids in triglycerides, cholesterol esters and membrane phospholipids. A significant suppression of SCD-1 has been observed in several animal models with disrupted sulfur amino acid metabolism, and the activity of SCD-1 is also associated with the levels of these amino acids in humans. This enzyme also appears to be involved in the etiology of metabolic syndromes because its suppression results in decreased fat deposits (regardless of food intake), improved insulin sensitivity and higher basal energy expenditure. Interestingly, this anti obesogenic phenotype has also been described in humans and animals with sulfur amino acid disorders, which is consistent with the hypothesis that SCD-1 activity is influenced by these amino acids, in particularly cysteine, which is a strong and independent predictor of SCD-1 activity and fat storage. In this narrative review, we discuss the evidence linking sulfur amino acids, SCD-1 and lipid metabolism. PMID- 26046928 TI - Adult attachment style is associated with cerebral MU-opioid receptor availability in humans. AB - Human attachment behavior mediates establishment and maintenance of social relationships. Adult attachment characteristically varies on anxiety and avoidance dimensions, reflecting the tendencies to worry about the partner breaking the social bond (anxiety) and feeling uncomfortable about depending on others (avoidance). In primates and other mammals, the endogenous MU-opioid system is linked to long-term social bonding, but evidence of its role in human adult attachment remains more limited. We used in vivo positron emission tomography to reveal how variability in MU-opioid receptor (MOR) availability is associated with adult attachment in humans. We scanned 49 healthy subjects using a MOR-specific ligand [(11) C]carfentanil and measured their attachment avoidance and anxiety with the Experiences in Close Relationships-Revised scale. The avoidance dimension of attachment correlated negatively with MOR availability in the thalamus and anterior cingulate cortex, as well as the frontal cortex, amygdala, and insula. No associations were observed between MOR availability and the anxiety dimension of attachment. Our results suggest that the endogenous opioid system may underlie interindividual differences in avoidant attachment style in human adults, and that differences in MOR availability are associated with the individuals' social relationships and psychosocial well-being. PMID- 26046929 TI - Quantification of uptake and clearance of acyclovir in skin layers. AB - BACKGROUND: Quantification of drug uptake and clearance in the skin layers could provide better insight into the skin kinetics of dermatological formulations aimed for deeper skin tissues. This study assessed the skin kinetics of acyclovir in different skin layers following topical application on the abdominal region of Wistar rats. METHODS: In vivo skin pharmacokinetics parameters were determined by two different protocols such as post drug load assessment and subsequent drug load assessment following topical application of 500 mg of cream formulation containing 5% (w/w) of acyclovir. RESULTS: Topical application of acyclovir exhibited concentration gradient between the skin layers (stratum corneum > viable epidermis > dermis) which were inconsistent over the time-course of the study. The rate and extent of drug reaching target site (basal epidermis) was relatively low. The drug uptake and clearance profiles were found to be distinct in all the three skin layers suggesting no drug concentration correlation (P<0.05) between skin layers. Drug concentration in the viable epidermis continued to increase even after termination of therapy (Tmax=4 h) and then declined rapidly. The availability of acyclovir in the target was comparatively low (approximately 0.4% of the applied dose) although an order of magnitude higher percentage was determined in the stratum corneum. CONCLUSIONS: The data observed in this study demonstrates low skin uptake and rapid clearance of acyclovir in the target site. Further, the methodology employed can be useful for studying other topical antiviral agents as well as for optimizing formulations for drugs (such as acyclovir) that may enhance their efficacy. PMID- 26046930 TI - Global Spatio-temporal Patterns of Influenza in the Post-pandemic Era. AB - We study the global spatio-temporal patterns of influenza dynamics. This is achieved by analysing and modelling weekly laboratory confirmed cases of influenza A and B from 138 countries between January 2006 and January 2015. The data were obtained from FluNet, the surveillance network compiled by the the World Health Organization. We report a pattern of skip-and-resurgence behavior between the years 2011 and 2013 for influenza H1N1pdm, the strain responsible for the 2009 pandemic, in Europe and Eastern Asia. In particular, the expected H1N1pdm epidemic outbreak in 2011/12 failed to occur (or "skipped") in many countries across the globe, although an outbreak occurred in the following year. We also report a pattern of well-synchronized wave of H1N1pdm in early 2011 in the Northern Hemisphere countries, and a pattern of replacement of strain H1N1pre by H1N1pdm between the 2009 and 2012 influenza seasons. Using both a statistical and a mechanistic mathematical model, and through fitting the data of 108 countries, we discuss the mechanisms that are likely to generate these events taking into account the role of multi-strain dynamics. A basic understanding of these patterns has important public health implications and scientific significance. PMID- 26046931 TI - Pancreas-Specific Sirt1-Deficiency in Mice Compromises Beta-Cell Function without Development of Hyperglycemia. AB - AIMS/HYPOTHESIS: Sirtuin 1 (Sirt1) has been reported to be a critical positive regulator of glucose-stimulated insulin secretion in pancreatic beta-cells. The effects on islet cells and blood glucose levels when Sirt1 is deleted specifically in the pancreas are still unclear. METHODS: This study examined islet glucose responsiveness, blood glucose levels, pancreatic islet histology and gene expression in Pdx1Cre; Sirt1ex4F/F mice that have loss of function and loss of expression of Sirt1 specifically in the pancreas. RESULTS: We found that in the Pdx1Cre; Sirt1ex4F/F mice, the relative insulin positive area and the islet size distribution were unchanged. However, beta-cells were functionally impaired, presenting with lower glucose-stimulated insulin secretion. This defect was not due to a reduced expression of insulin but was associated with a decreased expression of the glucose transporter Slc2a2/Glut2 and of the Glucagon like peptide-1 receptor (Glp1r) as well as a marked down regulation of endoplasmic reticulum (ER) chaperones that participate in the Unfolded Protein Response (UPR) pathway. Counter intuitively, the Sirt1-deficient mice did not develop hyperglycemia. Pancreatic polypeptide (PP) cells were the only other islet cells affected, with reduced numbers in the Sirt1-deficient pancreas. CONCLUSIONS/INTERPRETATION: This study provides new mechanistic insights showing that beta-cell function in Sirt1-deficient pancreas is affected due to altered glucose sensing and deregulation of the UPR pathway. Interestingly, we uncovered a context in which impaired beta-cell function is not accompanied by increased glycemia. This points to a unique compensatory mechanism. Given the reduction in PP, investigation of its role in the control of blood glucose is warranted. PMID- 26046932 TI - Comparison of Biochemical Activities between High and Low Lipid-Producing Strains of Mucor circinelloides: An Explanation for the High Oleaginicity of Strain WJ11. AB - The oleaginous fungus, Mucor circinelloides, is one of few fungi that produce high amounts of gamma-linolenic acid (GLA); however, it usually only produces <25% lipid. Nevertheless, a new strain (WJ11) isolated in this laboratory can produce lipid up to 36% (w/w) cell dry weight (CDW). We have investigated the potential mechanism of high lipid accumulation in M. circinelloides WJ11 by comparative biochemical analysis with a low lipid-producing strain, M. circinelloides CBS 277.49, which accumulates less than 15% (w/w) lipid. M. circinelloides WJ11 produced more cell mass than that of strain CBS 277.49, although with slower glucose consumption. In the lipid accumulation phase, activities of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in strain WJ11 were greater than in CBS 277.49 by 46% and 17%, respectively, and therefore may provide more NADPH for fatty acid biosynthesis. The activities of NAD+:isocitrate dehydrogenase and NADP+:isocitrate dehydrogenase, however, were 43% and 54%, respectively, lower in WJ11 than in CBS 277.49 and may retard the tricarboxylic acid cycle and thereby provide more substrate for ATP:citrate lyase (ACL) to produce acetyl-CoA. Also, the activities of ACL and fatty acid synthase in the high lipid-producing strain, WJ11, were 25% and 56%, respectively, greater than in strain CBS 277.49. These enzymes may therefore cooperatively regulate the fatty acid biosynthesis in these two strains. PMID- 26046933 TI - Chromosome-level genome map provides insights into diverse defense mechanisms in the medicinal fungus Ganoderma sinense. AB - Fungi have evolved powerful genomic and chemical defense systems to protect themselves against genetic destabilization and other organisms. However, the precise molecular basis involved in fungal defense remain largely unknown in Basidiomycetes. Here the complete genome sequence, as well as DNA methylation patterns and small RNA transcriptomes, was analyzed to provide a holistic overview of secondary metabolism and defense processes in the model medicinal fungus, Ganoderma sinense. We reported the 48.96 Mb genome sequence of G. sinense, consisting of 12 chromosomes and encoding 15,688 genes. More than thirty gene clusters involved in the biosynthesis of secondary metabolites, as well as a large array of genes responsible for their transport and regulation were highlighted. In addition, components of genome defense mechanisms, namely repeat induced point mutation (RIP), DNA methylation and small RNA-mediated gene silencing, were revealed in G. sinense. Systematic bioinformatic investigation of the genome and methylome suggested that RIP and DNA methylation combinatorially maintain G. sinense genome stability by inactivating invasive genetic material and transposable elements. The elucidation of the G. sinense genome and epigenome provides an unparalleled opportunity to advance our understanding of secondary metabolism and fungal defense mechanisms. PMID- 26046934 TI - Effects of Hypergravity on Osteopontin Expression in Osteoblasts. AB - Mechanical stimuli play crucial roles in bone remodeling and resorption. Osteopontin (OPN), a marker for osteoblasts, is important in cell communication and matrix mineralization, and is known to function during mechanotransduction. Hypergravity is a convenient approach to forge mechanical stimuli on cells. It has positive effects on certain markers of osteoblast maturation, making it a possible strategy for bone tissue engineering. We investigated the effects of hypergravity on OPN expression and cell signaling in osteoblasts. Hypergravity treatment at 20 g for 24 hours upregulated OPN expression in MC3T3-E1 cells at the protein as well as mRNA level. Hypergravity promoted OPN expression by facilitating focal adhesion assembly, strengthening actin bundles, and increasing Runx2 expression. In the hypergravity-triggered OPN expression pathway, focal adhesion assembly-associated FAK phosphorylation was upstream of actin bundle assembly. PMID- 26046935 TI - Massage-like stroking boosts the immune system in mice. AB - Recent clinical evidence suggests that the therapeutic effect of massage involves the immune system and that this can be exploited as an adjunct therapy together with standard drug-based approaches. In this study, we investigated the mechanisms behind these effects exploring the immunomodulatory function of stroking as a surrogate of massage-like therapy in mice. C57/BL6 mice were stroked daily for 8 days either with a soft brush or directly with a gloved hand and then analysed for differences in their immune repertoire compared to control non-stroked mice. Our results show that hand- but not brush-stroked mice demonstrated a significant increase in thymic and splenic T cell number (p < 0.05; p < 0.01). These effects were not associated with significant changes in CD4/CD8 lineage commitment or activation profile. The boosting effects on T cell repertoire of massage-like therapy were associated with a decreased noradrenergic innervation of lymphoid organs and counteracted the immunosuppressive effect of hydrocortisone in vivo. Together our results in mice support the hypothesis that massage-like therapies might be of therapeutic value in the treatment of immunodeficiencies and related disorders and suggest a reduction of the inhibitory noradrenergic tone in lymphoid organs as one of the possible explanations for their immunomodulatory function. PMID- 26046937 TI - Correction to "transformable nanostructures of platinum-containing organosilane hybrids: non-covalent self-assembly of polyhedral oligomeric silsesquioxanes assisted by Pt...Pt and pi-pi stacking interactions of alkynylplatinum(II) terpyridine moieties". PMID- 26046936 TI - Towards Development of a Dermal Pain Model: In Vitro Activation of Rat and Human Transient Receptor Potential Ankyrin Repeat 1 and Safe Dermal Injection of o Chlorobenzylidene Malononitrile to Rat. AB - During clinical development of analgesics, it is important to have access to pharmacologically specific human pain models. o-Chlorobenzylidene malononitrile (CS) is a selective and potent agonist of the transient receptor potential ankyrin repeat 1 (TRPA1), which is a transducer molecule in nociceptors sensing reactive chemical species. While CS has been subject to extensive toxicological investigations in animals and human beings, its effects on intradermal or subcutaneous injection have not previously been reported. We have investigated the potential of CS to be used as an agonist on TRPA1 in human experimental pain studies. A calcium influx assay was used to confirm the capacity of CS to activate TRPA1 with >100,000 times the selectivity over the transient receptor potential vanilloid receptor 1. CS dose-dependently (EC50 0.9 MUM) released calcitonin gene-related peptide in rat dorsal root ganglion cultures, supporting involvement in pain signalling. In a local tolerance study, injection of a single intradermal dose of 20 mM CS to rats resulted in superficial, circular crusts at the injection sites after approximately 4 days. The histopathology evaluation revealed a mild, acute inflammatory reaction in the epidermis and dermis at the intradermal CS injection site 1 day after administration. After 14 days, the epidermal epithelium was fully restored. The symptoms were not considered to be adverse, and it is suggested that doses up to 20 MUL of 20 mM CS can be safely administered to human beings. In conclusion, our data support development of a CS human dermal pain model. PMID- 26046938 TI - Enhancing the antimicrobial activity of natural extraction using the synthetic ultrasmall metal nanoparticles. AB - The use of Catechin as an antibacterial agent is becoming ever-more common, whereas unstable and easy oxidation, have limited its application. A simple and low-energy-consuming approach to synthesize highly stable and dispersive Catechin Cu nanoparticles(NPs) has been developed, in which the stability and dispersivity of the NPs are varied greatly with the pH value and temperature of the reaction. The results demonstrate that the optimal reaction conditions are pH 11 at room temperature. As-synthesized NPs display excellent antimicrobial activity, the survival rates of bacterial cells exposed to the NPs were evaluated using live/dead Bacterial Viability Kit. The results showed that NPs at the concentration of 10 ppm and 20 ppm provided rapid and effective killing of up to 90% and 85% of S. aureus and E. coli within 3 h, respectively. After treatment with 20 ppm and 40 ppm NPs, the bacteria are killed completely. Furthermore, on the basis of assessing the antibacterial effects by SEM, TEM, and AFM, it was found the cell membrane damage of the bacteria caused by direct contact of the bacteria with the NPs was the effective mechanism in the bacterial inactivation. PMID- 26046941 TI - Transsphenoidal Approach in Endoscopic Endonasal Surgery for Skull Base Lesions: What Radiologists and Surgeons Need to Know. AB - In the last 2 decades, endoscopic endonasal transsphenoidal surgery has become the most popular choice of neurosurgeons and otolaryngologists to treat lesions of the skull base, with minimal invasiveness, lower incidence of complications, and lower morbidity and mortality rates compared with traditional approaches. The transsphenoidal route is the surgical approach of choice for most sellar tumors because of the relationship of the sphenoid bone to the nasal cavity below and the pituitary gland above. More recently, extended approaches have expanded the indications for transsphenoidal surgery by using different corridors leading to specific target areas, from the crista galli to the spinomedullary junction. Computer-assisted surgery is an evolving technology that allows real-time anatomic navigation during endoscopic surgery by linking preoperative triplanar radiologic images and intraoperative endoscopic views, thus helping the surgeon avoid damage to vital structures. Preoperative computed tomography is the preferred modality to show bone landmarks and vascular structures. Radiologists play an important role in surgical planning by reporting extension of sphenoid pneumatization, recesses and septations of the sinus, and other relevant anatomic variants. Radiologists should understand the relationships of the sphenoid bone and skull base structures, anatomic variants, and image-guided neuronavigation techniques to prevent surgical complications and allow effective treatment of skull base lesions with the endoscopic endonasal transsphenoidal approach. PMID- 26046940 TI - Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2. AB - Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29) peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2. PMID- 26046942 TI - Current and Novel Imaging Techniques in Coronary CT. AB - Multidetector coronary computed tomography (CT), which is widely performed to assess coronary artery disease noninvasively and accurately, provides excellent image quality. Use of electrocardiography (ECG)-controlled tube current modulation and low tube voltage can reduce patient exposure to nephrotoxic contrast media and carcinogenic radiation when using standard coronary CT with a retrospective ECG-gated helical scan. Various imaging techniques are expected to overcome the limitations of standard coronary CT, which also include insufficient spatial and temporal resolution, beam-hardening artifacts, limited coronary plaque characterization, and an inability to allow functional assessment of coronary stenosis. Use of a step-and-shoot scan, iterative reconstruction, and a high-pitch dual-source helical scan can further reduce radiation dose. Dual energy CT can improve contrast medium enhancement and reasonably reduce the contrast dose when combined with noise reduction with the use of iterative reconstruction. High-definition CT can improve spatial resolution and diagnostic evaluation of small or peripheral coronary vessels and coronary stents. Dual source CT and a motion correction algorithm can improve temporal resolution and reduce coronary motion artifacts. Whole-heart coverage with 320-detector CT and an intelligent boundary registration algorithm can eliminate stair-step artifacts. By decreasing beam hardening and enabling material decomposition, dual energy CT is expected to remove or reduce the depiction of coronary calcification to improve intraluminal evaluation of calcified vessels and to provide detailed analysis of coronary plaque components and accurate qualitative and quantitative assessment of myocardial perfusion. Fractional flow reserve derived from coronary CT is a state-of-the-art noninvasive technique for accurately identifying myocardial ischemia beyond coronary CT. Understanding these techniques is important to enhance the value of coronary CT for assessment of coronary artery disease. PMID- 26046943 TI - Microbiology for Radiologists: How to Minimize Infection Transmission in the Radiology Department. AB - The implementation of standardized infection control and prevention practices is increasingly relevant as modern radiology practice evolves into its more clinical role. Current Centers for Disease Control and Prevention, National Institutes of Health, and World Health Organization guidelines for the proper use of personal protective equipment, decontamination of reusable medical equipment, and appropriate management of bloodborne pathogen exposures will be reviewed. Standard precautions apply to all patients at all times and are the mainstay of infection control. Proper hand hygiene includes washing hands with soap and water when exposed to certain infectious particles, such as Clostridium difficile spores, which are not inactivated by alcohol-based hand rubs. The appropriate use of personal protective equipment in accordance with recommendations from the Centers for Disease Control and Prevention includes wearing a surgical mask during lumbar puncture. Because radiologists may perform lumbar punctures for patients with prion disease, it is important to appreciate that incineration is the most effective method of inactivating prion proteins. However, there is currently no consensus recommendation on the decontamination of prion contaminated reusable items associated with lumbar puncture, and institutional policies should be consulted for directed management. In the event of a needlestick injury, radiology staff must be able to quickly provide appropriate initial management and seek medical attention, including laboratory testing for bloodborne pathogens. PMID- 26046944 TI - The mechanism for exclusion of Pinus massoniana during the succession in subtropical forest ecosystems: light competition or stoichiometric homoeostasis? AB - Competition for light has traditionally been considered as the main mechanism for exclusion of Pinus massoniana during succession in subtropical forest ecosystems. However, both long-term inventories and a seedling cultivation experiment showed that growth of mature individuals and young seedlings of P. massoniana was not limited by available light, but was strongly influenced by stoichiometric homoeostasis. This is supported by the results of homoeostatic regulation coefficients for nitrogen (HN) and phosphorus (HP) estimated using the measured data from six transitional forests across subtropical China. Among three dominant tree species in subtropical forests, P. massoniana and Castanopsis chinensis had the lowest values of HP and HN, respectively. Therefore P. massoniana cannot survive in the advanced stage due to soil phosphorus limitation and C. chinensis cannot successfully grow in the pioneer stage due to soil nitrogen limitation. Our results support that stoichiometric homeostasis is the main reason for gradual exclusion of P. massoniana from the transitional forest and the eventual elimination from the advanced forest during the subtropical forest succession. Therefore greater attention should be paid to stoichiometric homeostasis as one of the key mechanisms for species exclusion during forest succession. PMID- 26046945 TI - Tissue Distribution, Metabolism, and Excretion of 3,3'-Dichloro-4'-sulfooxy biphenyl in the Rat. AB - Polychlorinated biphenyls (PCBs) with less chlorine atoms exhibit a greater susceptibility to metabolism than their more-chlorinated counterparts. Following initial hydroxylation of these less-chlorinated PCBs, metabolic sulfation to form PCB sulfates is increasingly recognized as an important component of their toxicology. Because procedures for the quantitative analysis of PCB sulfates in tissue samples have not been previously available, we have now developed an efficient, LC-ESI-MS/MS-based protocol for the quantitative analysis of 4-PCB 11 sulfate in biological samples. This procedure was used to determine the distribution of 4-PCB 11 sulfate in liver, kidney, lung, and brain as well as its excretion profile following its intravenous administration to male Sprague-Dawley rats. Following initial uptake of 4-PCB 11 sulfate, its concentration in these tissues and serum declined within the first hour following injection. Although biliary secretion was detected, analysis of 24 h collections of urine and feces revealed recovery of less than 4% of the administered 4-PCB 11 sulfate. High resolution LC-MS analysis of bile, urine, and feces showed metabolic products derived from 4-PCB 11 sulfate. Thus, 4-PCB 11 sulfate at this dose was not directly excreted in the urine but was instead redistributed to tissues and/or subjected to further metabolism. PMID- 26046947 TI - Corrigendum. PMID- 26046946 TI - Milk derived colloid as a novel drug delivery carrier for breast cancer. AB - Triple negative breast cancer has an extremely poor prognosis when chemotherapy is no longer effective. To overcome drug resistance, novel drug delivery systems based on nanoparticles have had remarkable success. We produced a novel nanoparticle component 'MDC' from milk-derived colloid. In order to evaluate the anti-cancer effect of MDC, we conducted in vitro and in vivo experiments on cancer cell lines and a primary tumor derived breast xenograft. Doxorubicin (Dox) conjugated to MDC (MDC-Dox) showed higher cancer cell growth inhibition than MDC alone especially in cell lines with high EGFR expression. In a mouse melanoma model, MDC-Dox significantly suppressed tumor growth when compared with free Dox. Moreover, in a primary tumor derived breast xenograft, one of the mice treated with MDC-Dox showed partial regression, while mice treated with free Dox failed to show any suppression of tumor growth. We have shown that a novel nanoparticle compound made of simple milk-derived colloid has the capability for drug conjugation, and serves as a tumor-specific carrier of anti-cancer drugs. Further research on its safety and ability to carry various anti-cancer drugs into multiple drug-resistant primary breast models is warranted. PMID- 26046948 TI - Strong Coupling between Plasmonic Gap Modes and Photonic Lattice Modes in DNA Assembled Gold Nanocube Arrays. AB - Control of both photonic and plasmonic coupling in a single optical device represents a challenge due to the distinct length scales that must be manipulated. Here, we show that optical metasurfaces with such control can be constructed using an approach that combines top-down and bottom-up processes, wherein gold nanocubes are assembled into ordered arrays via DNA hybridization events onto a gold film decorated with DNA-binding regions defined using electron beam lithography. This approach enables one to systematically tune three critical architectural parameters: (1) anisotropic metal nanoparticle shape and size, (2) the distance between nanoparticles and a metal surface, and (3) the symmetry and spacing of particles. Importantly, these parameters allow for the independent control of two distinct optical modes, a gap mode between the particle and the surface and a lattice mode that originates from cooperative scattering of many particles in an array. Through reflectivity spectroscopy and finite-difference time-domain simulation, we find that these modes can be brought into resonance and coupled strongly. The high degree of synthetic control enables the systematic study of this coupling with respect to geometry, lattice symmetry, and particle shape, which together serve as a compelling example of how nanoparticle-based optics can be useful to realize advanced nanophotonic structures that hold implications for sensing, quantum plasmonics, and tunable absorbers. PMID- 26046950 TI - Correction. PMID- 26046949 TI - The source of net ultrafiltration during hemodialysis is mostly the extracellular space regardless of hydration status. AB - Fluid shifts are common in patients undergoing chronic hemodialysis (HD) during the intradialytic periods, as several liters of fluid are removed during ultrafiltration (UF). Some patients have experienced frequent intradialytic hypotension (IDH). However, the characteristics of fluid shifts and which fluid space is affected remain controversial. Therefore, we designed this study to evaluate the fluid spaces most affected by UF and to determine whether hydration status influences the fluid shifts during HD. This was a prospective cohort study of 40 patients undergoing HD. We measured the patient's fluid spaces using a whole-body bioimpedance apparatus to evaluate the changes in the fluid spaces before HD and 1-4 hours of HD and 30 minutes after HD. UF achieved during HD by the 40 patients (age, 60.0 +/- 5.2 years; 50% men; 50% of patients with diabetes; body weight, 61.3 +/- 10.5 kg) was 2.18 +/- 0.78 L (measured fluid overload, 2.15 +/- 1.24 L). 1) Mean relative reduction of total body water and extracellular water was reduced from the start to the end of HD. 2) However, mean relative reduction of intracellular water was not reduced from the start to the end of HD. 3) No significant differences in fluid shifts were observed according to hydration status. The source of net UF during HD is mostly the extracellular space regardless of hydration status. Thus, IDH may be related to differences in the interstitial fluid shift to the vascular space. PMID- 26046951 TI - Rationally Separating the Corona and Membrane Functions of Polymer Vesicles for Enhanced T2 MRI and Drug Delivery. AB - It is an important challenge to in situ grow ultrafine super-paramagnetic iron oxide nanoparticles (SPIONs) in drug carriers such as polymer vesicles (also called polymersomes) while keeping their biodegradability for enhanced T2 weighted magnetic resonance imaging (MRI) and drug delivery. Herein, we present a new strategy by rationally separating the corona and membrane functions of polymer vesicles to solve the above problem. We designed a poly(ethylene oxide) block-poly(epsilon-caprolactone)-block-poly(acrylic acid) (PEO43-b-PCL98-b-PAA25) triblock copolymer and self-assembled it into polymer vesicle. The PAA chains in the vesicle coronas are responsible for the in situ nanoprecipitation of ultrafine SPIONs, while the vesicle membrane composed of PCL is biodegradable. The SPIONs-decorated vesicle is water-dispersible, biocompatible, and slightly cytotoxic to normal human cells. Dynamic light scattering, transmission electron microscopy, energy disperse spectroscopy, and vibrating sample magnetometer revealed the formation of ultrafine super-paramagnetic Fe3O4 nanoparticles (1.9 +/- 0.3 nm) in the coronas of polymer vesicles. Furthermore, the CCK-8 assay revealed low cytotoxicity of vesicles against normal L02 liver cells without and with Fe3O4 nanoparticles. The in vitro and in vivo MRI experiments confirmed the enhanced T2-weighted MRI sensitivity and excellent metastasis in mice. The loading and release experiments of an anticancer drug, doxorubicin hydrochloride (DOX.HCl), indicated that the Fe3O4-decorated magnetic vesicles have potential applications as a nanocarrier for anticancer drug delivery. Moreover, the polymer vesicle is degradable in the presence of enzyme such as Pseudomonas lipases, and the ultrafine Fe3O4 nanoparticles in the vesicle coronas are confirmed to be degradable under weakly acidic conditions. Overall, this decoration-in-vesicle coronas strategy provides us with a new insight for preparing water-dispersible ultrafine super-paramagnetic Fe3O4 nanoparticles with promising theranostic applications in biomedicine. PMID- 26046952 TI - Molecular phylogeny of anoplocephalid tapeworms (Cestoda: Anoplocephalidae) infecting humans and non-human primates. AB - Anoplocephalid tapeworms of the genus Bertiella Stiles and Hassall, 1902 and Anoplocephala Blanchard, 1848, found in the Asian, African and American non-human primates are presumed to sporadic ape-to-man transmissions. Variable nuclear (5.8S-ITS2; 28S rRNA) and mitochondrial genes (cox1; nad1) of isolates of anoplocephalids originating from different primates (Callicebus oenanthe, Gorilla beringei, Gorilla gorilla, Pan troglodytes and Pongo abelii) and humans from various regions (South America, Africa, South-East Asia) were sequenced. In most analyses, Bertiella formed a monophyletic group within the subfamily Anoplocephalinae, however, the 28S rRNA sequence-based analysis indicated paraphyletic relationship between Bertiella from primates and Australian marsupials and rodents, which should thus be regarded as different taxa. Moreover, isolate determined as Anoplocephala cf. gorillae from mountain gorilla clustered within the Bertiella clade from primates. This either indicates that A. gorillae deserves to be included into the genus Bertiella, or, that an unknown Bertiella species infects also mountain gorillas. The analyses allowed the genetic differentiation of the isolates, albeit with no obvious geographical or host-related patterns. The unexpected genetic diversity of the isolates studied suggests the existence of several Bertiella species in primates and human and calls for revision of the whole group, based both on molecular and morphological data. PMID- 26046953 TI - Novel mutation in LIPH in a Lebanese patient with autosomal recessive woolly hair/hypotrichosis. PMID- 26046954 TI - B2N2-Dibenzo[a,e]pentalenes: Effect of the BN Orientation Pattern on Antiaromaticity and Optoelectronic Properties. AB - Two BN units were embedded in dibenzo[a,e]pentalene with different orientation patterns, which significantly modulated its antiaromaticity and optoelectronic properties. Importantly, the vital role of the BN orientation in conjugated molecules with more than one BN unit was demonstrated for the first time. This work indicates a large potential of the BN/CC isosterism for the development of new antiaromatic systems and highlights the importance of precise control of the BN substitution patterns in conjugated materials. PMID- 26046955 TI - The Presence of the IsiA-PSI Supercomplex Leads to Enhanced Photosystem I Electron Throughput in Iron-Starved Cells of Synechococcus sp. PCC 7002. AB - Photosystem I (PS I) is highly demanding of iron, requiring 12 atoms in the bound FX, FB, and FA iron-sulfur clusters and two atoms in the mobile acceptor protein ferredoxin. When grown under iron-limiting conditions, certain cyanobacteria express IsiA, a peripheral chlorophyll a antenna protein, and IsiB, a flavodoxin that substitutes for ferredoxin. The IsiA protein forms single and double rings around PS I, presumably to increase the optical cross-section so as to compensate for fewer PS I complexes. Previous studies have shown that IsiA serves as an efficient light-harvesting structure ( Andrizhievskaya , G. G. ; et al. Biochim. Biophys. Acta 2002 , 1556 , 262 - 272 ); however, few, if any, studies have been carried out to show that the increased optical cross-section leads to an enhanced rate of electron transfer through PS I. Here, we report a more rapid transient accumulation of the A1(-) phyllosemiquinone anion radical by EPR spectroscopy in dark-adapted iron-depleted cells than in iron-replete cells after a block of intense light. A derivative-shaped optical signal in the light-minus-dark difference spectrum of PS I from an electrochromic bandshift of a carotenoid located near the A1 phylloquinones is enhanced in iron-depleted wild-type cells and in an iron-depleted isiB deletion strain, which lacks flavodoxin, but is greatly diminished in an iron-depleted isiA deletion strain, which lacks IsiA and flavodoxin. These findings indicate that the transient accumulation of electrons on A1 occurs more rapidly in the IsiA/PS I supercomplex than in the PS I complex alone. Thus, the increased absorption cross-section from the IsiA proteins translates directly to an enhanced rate of electron transfer through PS I. PMID- 26046956 TI - Total Syntheses of (-)-Spirooliganones A and B and Their Diastereoisomers: Absolute Stereochemistry and Inhibitory Activity against Coxsackie Virus B3. AB - To investigate the effects of configuration on bioactivity, spirooliganones A and B and their six diastereoisomers (1-8) were synthesized in 11 steps. The key benzopyran core was assembled by intermolecular [4 + 2] hetero-Diels-Alder cycloaddition between (-)-sabinene and o-quinone methide, which was generated from the corresponding o-hydroxybenzyl alcohol. After establishing the absolute configuration, the inhibitory activities of spirooliganones 1-8 against Coxsackie virus B3 were evaluated, and the primary structure-activity relationships were analyzed. Compound 3 was the most potent compound, with an IC50 of 0.41 MUM. PMID- 26046957 TI - Histological evaluation of a "residual" metastasis after ipilimumab therapy in a patient with advanced melanoma. PMID- 26046958 TI - Role of prophylactic central neck dissection in cN0-papillary thyroid carcinoma: results from a high-prevalence area. AB - BACKGROUND: Prophylactic, compartment-oriented central neck dissection (CND) for cN0 papillary thyroid carcinoma (PTC) is not widely practiced. We examined our results with this surgical approach. METHODS: A cohort of 158 patients operated on for the classical variant of PTC at a follow-up of 1-22 years (mean: 6.6) were enrolled. The patients with a preoperative diagnosis of cN0 PTC (group A, 59 patients) underwent total thyroidectomy (TT) + CND. In the patients with incidental postoperative diagnosis of malignancy (group B, 99 patients) a TT alone was performed. RESULTS: Ninety-six T1, 36 T2, 26 T3/T4 PTC patients were enrolled. The overall biochemical/scintigraphic recurrence rate (15 patients, 9.49%), was significantly higher in group B. Disease-free survival and need for postoperative radioiodine ablative treatment were more favorable in group A (P<0.05; P<0.001, respectively). The median radioiodine ablative treatment in the T2 cluster alone was lower in group A (P<0.001). The morbidity rate was similar in both groups. CONCLUSION: Considering the acceptable morbidity, prophylactic CND seems to be advantageous in terms of recurrence rate and need for radioiodine treatment in this variant of PTC, at least in T2 or more advanced stages. The indolent behavior of PTC does not allow for reliable prognostic evaluations. PMID- 26046959 TI - Superficial venous incompetence: low-cost outpatient minisurgery, sclerotherapy and combined procedure as a management plan. Costs and efficacy. A 20-year, follow-up registry. AB - BACKGROUND: This registry study evaluated low-cost outpatient surgery (mini-S) for venous insufficiency as an alternative to stripping. METHODS: This 20-year follow-up is focused on the recurrence of varices and on the long-term efficacy of the mini-S (group 1) in comparison with controls (2, stripping), sclerotherapy (3) or a combination of mini-S+sclerotherapy (4). Costs were compared. RESULTS: At 20-years of follow-up, considering recurrence/development of new varicose veins, 24.05% of the limbs treated with mini-S developed new varices in comparison with 64.4% in group 2, 24.1% in group 3 and 15.4% in group 4 (P<0.05). New surgical procedures were needed in 18.9% of mini-S patients vs. 58.5% in group 2, 21.9% in group 3 and 19.7% in group 4 (P<0.05 between group 2 and the other groups). Sclerotherapy (in the years following the initial treatment) was used in 37.9% of mini-S patients in comparison with 67.7% of subjects in group 2 patients, 33.1% in group 3 and 22.8% in group 4 (P<0.05 between outpatient treatment and group 2). The superficial venous system was incompetent in 21% of mini-S patients in comparison with 38.8% in group 2 (P<0.05), 20.7% in group 3 and 17.9% of group 4. At 20 years edema was present in 10.5% of limbs in group 2 in comparison with a <3% (range 2.2-2.1%) in the other groups. Edema was more significant after stripping. Ambulatory venous pressure measurements in subgroups was lower in groups 1, 3 and 4 with a lower refilling time (P<0.05). The cost of in-hospital, daily surgical treatments were ?1978 (covered by the heathcare provider). The cost of mini-S was on average ?488 per limb (covered by patients). CONCLUSIONS: Outpatients procedures, in particular the mini-S management plan, were cheaper than stripping and more effective at 20-years follow-up. They could be a model for emerging contries with restricted budgets for vein surgery. Also being cheaper more people may have benefits from treatment when/where hospital procedures are not covered by an healthcare provider. PMID- 26046960 TI - Elucidation of the Cellular Uptake Mechanisms of Polycationic HYDRAmers. AB - Dendrimers and dendrons appeared to potentially fulfill the requirements for being good and well-defined carriers in drug and gene delivery applications. We recently demonstrated that polycationic adamantane-based dendrons called HYDRAmers are easily internalized by both phagocytic and nonphagocytic cells in vitro. The aim of the present study was to investigate which of the different pathways of cellular internalization is involved in the cellular uptake of the first and second generation ammonium and guanidinium HYDRAmers. For this purpose, we have evaluated the internalization of fluorescently labeled HYDRAmers in both phagocytic murine macrophages and nonphagocytic human cervix epithelioid carcinoma cells in the presence of different well-known active uptake inhibitors. Our data revealed that the first and second generation HYDRAmers are internalized via different endocytic pathways based on the cellular type and on the type of functional groups present at the periphery of the dendrons. In particular, it was registered that the first generations were mainly internalized by clathrin mediated endocytosis and macropinocytosis while the cellular internalization of the second generations was less affected by the inhibitory conditions of the endocytic pathways. These results suggest the possibility of addressing dendrimers toward specific subcellular compartments by tuning their structure properties and, in particular, the functional groups at their periphery. PMID- 26046961 TI - Tin and Tin Compounds for Sodium Ion Battery Anodes: Phase Transformations and Performance. AB - Sodium ion batteries (NIB, NAB, SIB) are attracting interest as a potentially lower cost alternative to lithium ion batteries (LIB), with readily available and geographically democratic reserves of the metal. Tin is one of most promising SIB anode materials, which alloys with up to 3.75 Na, leading to a charge storage capacity of 847 mAh g(-1). In this Account, we outline the state-of-the-art understanding regarding the sodiation-induced phase transformations and the associated performance in a range of Sn-based systems, treating metallic Sn and its alloys, tin oxide (SnO2), tin sulfide (SnS2/SnS), and tin phosphide (Sn4P3). We first detail what is known about the sodiation sequence in metallic Sn, highlighting the most recent insight into the reactions prior to the terminal equilibrium Na15Sn4 intermetallic. We explain why researchers argue that the equilibrium (phase diagram) series of phase transitions does not occur in this system, and rather why sodiation/desodiation proceeds through a series of metastable crystalline and amorphous structures. We also outline the recent modeling-based insight regarding how this phase transition profoundly influences the mechanical properties of the alloy, progressively changing the bonding and the near neighbor arrangement from "Sn-like" to "Na-like" in the process. We then go on to discuss the sodiation reactions in SnO2. We argue that while a substantial amount of experimental work already exists where the focus is on synthesis and testing of tin oxide-based nanocomposites, the exact sodiation sequence is just beginning to be understood. Unlike in Sn and Sn alloys, where capacities near the theoretical are reached at least early during cycling, SnO2 never quite achieves anything close to the 1398 mAh g(-1) that would be possible with a combination of fully reversible conversion and alloying reactions. We highlight recent work demonstrating that contrary to general expectations, it is the Sn to Na15Sn4 alloying reaction that is incomplete and hence limits the capacity of the electrode. We also describe how the oxide conversion reaction goes through an intermediate SnO phase, and how its reversibility in a half-cell is highly dependent on the terminal anodic voltage. We then present what is known about sodiation of tin sulfide and of tin phosphide phases, including emerging microstructural evidence that may explain why both the sulfides and the phosphides are unable to achieve their highly promising theoretical capacities under conventional electrode testing conditions. Finally, we provide a broad comparison of the capacity (cycling and rate) performance for a range of Sn based anode materials, and show that there may be indeed an optimum microstructural architecture. PMID- 26046963 TI - Maternal Morbidity for Vaginal and Cesarean Deliveries, According to Previous Cesarean History: New Data From the Birth Certificate, 2013. AB - This report presents recent findings for 2013 on four maternal morbidities associated with labor and delivery-maternal transfusion, ruptured uterus, unplanned hysterectomy, and intensive care unit (ICU) admission-that are collected on birth certificates for a 41-state and District of Columbia reporting area, which represents 90% of all births in the United States. PMID- 26046962 TI - The neuromechanical adaptations to Achilles tendinosis. AB - KEY POINTS: Achilles tendinosis is a localized degenerative musculoskeletal disorder that develops over a long period of time and leads to a compliant human Achilles tendon. We demonstrate that the compliant Achilles tendon elicited a series of adaptations from different levels of the human movement control system, such as the muscle-tendon interaction, CNS control and other muscles in the lower leg. These results illustrate the human body's capacity to adapt to tendon pathology and provide the physiological basis for intervention or prevention strategies. Human movement is initiated, controlled and executed in a hierarchical system including the nervous system, muscle and tendon. If a component in the loop loses its integrity, the entire system has to adapt to that deficiency. Achilles tendon, when degenerated, exhibits lower stiffness. This local mechanical deficit may be compensated for by an alteration of motor commands from the CNS. These modulations in motor commands from the CNS may lead to altered activation of the agonist, synergist and antagonist muscles. The present study aimed to investigate the effect of tendon degeneration on its mechanical properties, the neuromechanical behaviour of the surrounding musculature and the existence of the CNS modulation accompanying tendinosis. We hypothesize that the degenerated tendon will lead to diminished tissue mechanical properties and protective muscle activation patterns, as well as an up-regulated descending drive from the CNS. Strong evidence, as reported in the present study, indicates that tendinotic tendons are more compliant compared to healthy tendons. This unilateral involvement affected the neuromuscular control on the involved side but not the non-involved side. The muscle-tendon unit on the tendinotic side exhibits a lowered temporal efficiency, which leads to altered CNS control. The altered CNS control is then expressed as an adapted muscle activation pattern in the lower leg. Taken together, the findings of the present study illustrate the co-ordinated multi-level adaptations to a mechanical lesion in a tendon caused by pathology. PMID- 26046964 TI - Glucose Metabolism in High-Risk Subjects for Type 2 Diabetes Carrying the rs7903146 TCF7L2 Gene Variant. AB - CONTEXT: The mechanisms responsible for contribution of variants in the gene TFC7L2 to the risk for type 2 diabetes (T2DM) remains far from being completely understood, and available studies have generated nonunivocal results. OBJECTIVE: We investigated the postprandial glucose metabolism in subjects at risk for T2DM carrying the TCF7L2 risk allele. DESIGN, SETTING, AND PARTICIPANTS: Twenty-three subjects carrying the risk-conferring TCF7L2 genotypes (11 TT and 12 CT at rs7901346) and 13 subjects with wild-type genotype (CC) underwent a standard mixed-meal test (MMT) in combination with stable isotope tracers. OUTCOME MEASUREMENTS: We evaluated endogenous and exogenous glucose fluxes and hormonal responses. RESULTS: Fasting plasma glucose, insulin, C-peptide, glycated hemoglobin, endogenous glucose production, and plasma glucose clearance were similar in the three groups, whereas plasma glucagon levels were lower in both CT and TT than in CC (64 +/- 20, 63 +/- 18 and 90 +/- 29 pg/mL, respectively; both P = .01). In response to the MMT, TT subjects had lower plasma glucose levels than CC subjects [mean area under the time-concentration curve (AUC) 6.1 +/- 3.9 vs 7.1 +/- 12.0 mmol/L, P = .04] and lower insulin secretion rate (mean AUC 385 +/- 95 vs 530 +/- 159 pmol/m(2) . min, P = .02). Initial (0-60 min) rate of appearance (Ra) of oral glucose was lower in TT compared with CT/CC (AUC 2.7 +/- 1.1 vs 3.8 +/- 1.2 MUmol/kg . min, P = .02) with no difference among the three groups in endogenous glucose production. The AUC0-60min for Ra of exogenous glucose (Raex) was positively correlated with the plasma glucose AUC0-60min. Total Raex AUC0-120min was correlated with total AUC0-120min of plasma glucose (r = 0.45, P < .01). Plasma glucagon-like peptide-1 and glucose-dependent insulinotropic peptide levels in response to the MMT were not affected by genotype. CONCLUSIONS: In subjects at risk for T2DM, the TCF7L2 polymorphisms were associated with reduced Raex into systemic circulation, causing reduced postprandial blood glucose increase and, in turn, lower insulin secretion rate with no impairment in beta-cell function. The reduced Raex is likely due to greater glucose retention in the splanchnic area. PMID- 26046966 TI - Radiation Safety Precautions in (131)I Therapy of Graves' Disease Based on Actual Biokinetic Measurements. AB - CONTEXT: Radiation protection is an integral part of targeted radionuclide therapy. How to offer rational radiation precautions to patients with Graves' disease (GD) undergoing (131)I therapy is still a matter of ongoing discussions. OBJECTIVE: The objective of the study was to formulate radiation precautions for GD patients undergoing (131)I therapy through actual biokinetic measurements for a particular population of patients. DESIGN: This was a prospective study. SETTING: The study was conducted at a university hospital. PATIENTS: From January 2009 through January 2012, consecutive GD patients prepared for (131)I therapy were prospectively recruited. MAIN OUTCOME MEASURES: Pretherapy thyroid radioiodine uptake and uptake ratio (4 to 24 h radioiodine uptake) were measured. Serial whole-body dose-rate measurements after therapy were performed to deduce (131)I whole-body retention. Calculations based on deduced whole-body retention and measured thyroid radioiodine biokinetics were derived to determine the thyroidal and extrathyroidal compartment uptake fractions and effective half lives. Precaution times necessary to avoid close contact with family members and the general public were derived from these parameters and regulatory dose limits. RESULTS: A total of 72 patients were eligible for the analysis. A high interpatient variability in (131)I biokinetics was observed: the mean peaking (131)I uptake (+/-1 SD) in the thyroid was 68% (+/-19%), and the range was 18% 89%; the mean effective (131)I half-life (+/-1 SD) in the remainder of the body was 5.1 (+/-0.9) hours (range 3.5-7.2 h). The mean measured initial dose rate (+/ 1 SD) at 1.0 m after (131)I administration was 0.039 (+/-0.003) MUSv.h(-1) . MBq( 1) (range 0.017-0.055 MUSv.h(-1) . MBq(-1)). The 0.3:1.0 m initial dose rate ranged from 2.9 to 7.1, which was greatly lower than the projected ratio of 11.1 by the inverse square law approximation. On the basis of the measured radioiodine biokinetics and dose rates, detailed instructions were provided to limit nearby individuals' exposure. CONCLUSION: The use of actual biokinetic measurements may remove the effect of variability errors associated with general default assumptions about the (131)I biokinetics in GD patients. The marked variability in (131)I biokinetics among GD patients reinforces the need for patient-specific iodine biokinetic measurements for radiation safety precautions. PMID- 26046965 TI - Association of Sleep Duration and Quality With Alterations in the Hypothalamic Pituitary Adrenocortical Axis: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - CONTEXT: Short sleep duration and poor sleep quality are associated with cardiovascular outcomes. One mechanism proposed to explain this association is altered diurnal cortisol secretion. OBJECTIVE: The objective of the study was to examine the associations of sleep duration and sleep quality with diurnal salivary cortisol levels. DESIGN: This was a cross-sectional analysis using data from examination 5 (2010-2012) of the Multi-Ethnic Study of Atherosclerosis. Actigraphy-based measures of sleep duration and efficiency were collected over 7 days, and salivary cortisol samples were collected over 2 days from participants aged 54-93 years (n = 600 with analyzable data). RESULTS: Shorter average sleep duration (<6 h/night) was associated with less pronounced late decline in cortisol [2.2% difference in slope; 95% confidence interval (CI) 0.8-3.7; P <= .01] and less pronounced wake-to-bed slope (2.2% difference; 95% CI 1.0-3.4; P <= .001) compared with longer sleep duration (>=6 h/night). Lower sleep efficiency (<85%) was associated with less pronounced early decline in cortisol (29.0% difference in slope; 95% CI 4.1-59.7; P < .05) compared with higher sleep efficiency (>=85%). Subjects reporting insomnia had a flatter cortisol awakening response (-16.1% difference in slope; 95% CI -34.6 to -0.1; P < .05) compared with those not reporting insomnia. CONCLUSIONS: Shorter sleep duration, lower sleep efficiency, and insomnia are associated with alterations in diurnal cortisol levels consistent with changes in hypothalamic-pituitary-adrenal regulation. PMID- 26046967 TI - The Effects of Recombinant Human Insulin-Like Growth Factor-I/Insulin-Like Growth Factor Binding Protein-3 Administration on Body Composition and Physical Fitness in Recreational Athletes. AB - CONTEXT: IGF-I is thought to mediate many of the anabolic actions of GH, and there are anecdotal reports that IGF-I is misused by elite athletes. There is no published evidence regarding the effects of IGF-I administration on athletic performance. OBJECTIVE: The objective of the study was to investigate the effects of IGF-I administration on body composition and physical fitness in recreational athletes. DESIGN AND SETTING: This was a randomized, double-blind, placebo controlled recombinant human (rh) IGF-I/rhIGF binding protein (IGFBP)-3 administration study at Southampton General Hospital (Southampton, United Kingdom). PARTICIPANTS: Fifty-six recreational athletes (30 men, 26 women) participated in the study. INTERVENTION: Participants were randomly assigned to receive placebo, low-dose rhIGF-I/rhIGFBP-3 (30 mg/d), or high dose rhIGF I/rhIGFBP-3 (60 mg/d) for 28 days. Body composition (assessed by dual energy x ray absorptiometry) and cardiorespiratory fitness (assessed by incremental treadmill test) were measured before and immediately after treatment. Within individual changes after treatment were analyzed using paired t tests. RESULTS: There were no significant changes in body fat mass or lean body mass in women or men after the administration of the rhIGF-I/rhIGFBP-3 complex. There was a significant increase in maximal oxygen consumption (VO2 max) after treatment. When women and men and low- and high-dose treatment groups were combined, mean VO2 max increased by approximately 7% (P = .001). No significant change in VO2 max was observed in the placebo group. CONCLUSIONS: rhIGF-I/rhIGFBP-3 administration for 28 days improves aerobic performance in recreational athletes, but there are no effects on body composition. PMID- 26046968 TI - IGFBP-4 Fragments as Markers of Cardiovascular Mortality in Type 1 Diabetes Patients With and Without Nephropathy. AB - CONTEXT: Type 1 diabetes (T1D) is characterized by an increased risk of macrovascular complications. Pregnancy-associated plasma protein-A (PAPP-A) generated N- and C-terminal fragments of IGF binding protein-4 (NT-IGFBP-4 and CT IGFBP-4) have been suggested as cardiac biomarkers. OBJECTIVE: The objective of the study was to investigate the prognostic value of IGFBP-4 fragments in a cohort of T1D patients. DESIGN AND PATIENTS: We prospectively followed up 178 T1D patients with diabetic nephropathy and 152 T1D patients with normoalbuminuria for 12.6 (range 0.2-12.9) years. MAIN OUTCOME MEASURES: Levels of IGF-1, IGF-2, IGFBP 1-4, NT- and CT-IGFBP-4, and PAPP-A at baseline. RESULTS: During follow-up, 15 patients with normoalbuminuria and 71 patients with nephropathy died. Of these deaths, 8 and 45 were due to fatal cardiovascular events, respectively. Using receiver-operating characteristic curve analyses, patients were divided into subgroups using cutoff values of 261 MUg/L NT-IGFBP-4, 81 MUg/L CT-IGFBP-4, or 10 mIU/L PAPP-A. All-cause mortality was significantly higher in patients with NT IGFBP-4 levels (55% vs 16%, P < .001) and CT-IGFBP-4 levels (44% vs 15%, P < .001) above vs below cutoffs. Similarly, cardiovascular mortality was elevated in patients with high NT-IGFBP-4 levels (40% vs 7.8%, P < .001) and high CT-IGFBP-4 levels (30% vs 7.4%, P < .001). After adjustments for nephropathy and traditional cardiovascular risk factors, high NT- and CT-IGFBP-4 levels remained prognostic of cardiovascular mortality with hazard ratios [95% confidence interval (CI)] of 5.81 (95% CI 2.62-12.86) (P < .001) and 2.58 (95% CI 1.10-6.10) (P = .030), respectively. After adjustments, PAPP-A was not associated with overall or cardiovascular death. All IGF protein levels were higher in patients with diabetic nephropathy (P < .001), but no variables associated with mortality. CONCLUSION: High IGFBP-4 fragment levels were associated with increased all-cause and cardiovascular mortality rates in T1D patients with and without diabetic nephropathy. PMID- 26046969 TI - Influence of Internal and External Noise on Spontaneous Visuomotor Synchronization. AB - Historically, movement noise or variability is considered to be an undesirable property of biological motor systems. In particular, noise is typically assumed to degrade the emergence and stability of rhythmic motor synchronization. Recently, however, it has been suggested that small levels of noise might actually improve the functioning of motor systems and facilitate their adaptation to environmental events. Here, the authors investigated whether noise can facilitate spontaneous rhythmic visuomotor synchronization. They examined the influence of internal noise in the rhythmic limb movements of participants and external noise in the movement of an oscillating visual stimulus on the occurrence of spontaneous synchronization. By indexing the natural frequency variability of participants and manipulating the frequency variability of the visual stimulus, the authors demonstrated that both internal and external noise degrade synchronization when the participants' and stimulus movement frequencies are similar, but can actually facilitate synchronization when the frequencies are different. Furthermore, the two kinds of noise interact with each other. Internal noise facilitates synchronization only when external noise is minimal and vice versa. Too much internal and external noise together degrades synchronization. These findings open new perspectives for better understanding the role of noise in human rhythmic coordination. PMID- 26046971 TI - Eight-year follow-up study of three individuals accidentally exposed to (60)Co radiation: Chromosome aberration and micronucleus analysis. AB - We assessed dose levels and the persistence of chromosomal aberrations and micronuclei in three individuals in the 8 year following accidental (60)Co radiation exposure. Venous blood samples were collected and used for analyses: traditional chromosome aberration (CA) measurement, G-banding, and the cytokinesis-block micronucleus (CBMN) assay. For CA analysis, we scored dicentric chromosomes (dic) and rings (r) in peripheral blood lymphocytes. The radiation doses (Gy) suffered by the individuals were estimated as: 1.79-2.43 (A), 2.36 2.86 (B), 1.58-1.82 (C), based on CA analysis; and 1.8-2.34 (A), 2.52-2.98 (B), 1.53-1.77 (C), based on CBMN frequencies. G-banding analysis was used to record translocations (t), inversions (inv), and deletions (del). Following the accident, unstable CAs reduced gradually, but stable aberrations persisted. Unstable CAs and CBMN may be valuable biomarkers for dose estimation shortly after high-dose radiation accidents, while stable aberrations may be more useful for assessing long-term effects. PMID- 26046970 TI - Protective effects of melatonin-loaded lipid-core nanocapsules on paraquat induced cytotoxicity and genotoxicity in a pulmonary cell line. AB - Many acute poisonings lack effective and specific antidotes. Due to both intentional and accidental exposures, paraquat (PQ) causes thousands of deaths annually, especially by pulmonary fibrosis. Melatonin (Mel), when incorporated into lipid-core nanocapsules (Mel-LNC), has enhanced antioxidant properties. The effects of such a formulation have not yet been studied with respect to mitigation of PQ- induced cytotoxicity and DNA damage. Here, we have tested whether Mel-LNC can ameliorate PQ-induced toxicity in the A549 alveolar epithelial cell line. Physicochemical characterization of the formulations was performed. Cellular uptake was measured using nanocapsules marked with rhodamine B. Cell viability was determined by the MTT assay and DNA damage was assessed by the comet assay. The enzyme-modified comet assay with endonuclease III (Endo III) and formamidopyrimidine glycosylase (FPG) were used to investigate oxidative DNA damage. Incubation with culture medium for 24h did not alter the granulometric profile of Mel-LNC formulations. Following treatment (3 and 24h), red fluorescence was detected around the cell nucleus, indicating internalization of the formulation. Melatonin solution (Mel), Mel-LNC, and LNC did not have significant effects on cell viability or DNA damage. Pre-treatment with Mel-LNC enhanced cell viability and showed a remarkable reduction in % DNA in tail compared to the PQ group; this was not observed in cells pre-treated with Mel. PQ induces oxidative DNA damage detected with the enzyme-modified comet assay. Mel LNC reduced this damage more effectively than did Mel. In summary, Mel-LNC is better than Mel at protecting A549 cells from the cytotoxic and genotoxic effects of PQ. PMID- 26046972 TI - Induction of cytotoxic and genotoxic responses by natural and novel quercetin glycosides. AB - The flavonoids quercetin, and its natural glycosides isoquercetin and rutin, are phytochemicals commonly consumed in plant-derived foods. Semi-synthetic water soluble isoquercetin and rutin glycosides, maltooligosyl isoquercetin, monoglucosyl rutin and maltooligosyl rutin were developed by synthetic glycosylation to overcome solubility challenges for improved incorporation in food and medicinal applications. Quercetin and its natural glycosides are known to induce genetic instability and decrease cell proliferation. Using a system of Chinese hamster ovary (CHO) cells, this study examined the differences in cytotoxic and genotoxic responses induced by natural and synthetic flavonoids. Bioactivity evaluations using poly(ADP-ribose) polymerase (PARP) ELISA showed that the synthetic flavonoids were less effective in inhibiting PARP than the natural flavonoids, where PARP inhibitory effects decreased with glycosylation of flavonoids. In the genotoxic studies, treatments with flavonoids at a concentration range of 0.2 MUM-1 mM induced significant frequencies of sister chromatid exchange (SCE) and micronuclei in CHO cells compared to spontaneous occurrences. The synthetic flavonoids monoglucosyl rutin and maltooligosyl rutin induced less genotoxic effects than the natural flavonoids. However, maltooligosyl isoquercetin induced similar responses as isoquercetin and rutin. The growth inhibition studies showed glycosylation dependent cytotoxicity in natural flavonoids. The quercetin aglycone exhibited the highest toxicity out of all the flavonoids studied. Differences in growth inhibition were not observed between the synthetic flavonoids, maltooligosyl isoquercetin and monoglucosyl rutin, and natural isoquercetin and rutin, respectively. Maltooligosyl rutin induced less cytotoxicity than rutin and monoglucosyl rutin. Our in vitro studies demonstrated that the synthetic flavonoids generally induced less genotoxic responses than their natural counterparts. PMID- 26046973 TI - A source of artifact in the lacZ reversion assay in Escherichia coli. AB - The lacZ reversion assay in Escherichia coli measures point mutations that occur by specific base substitutions and frameshift mutations. The tester strains cannot use lactose as a carbon source (Lac(-)), and revertants are easily detected by growth on lactose medium (Lac(+)). Six strains identify the six possible base substitutions, and five strains measure +G, -G, -CG, +A and -A frameshifts. Strong mutagens give dose-dependent increases in numbers of revertants per plate and revertant frequencies. Testing compounds that are arguably nonmutagens or weakly mutagenic, we often noted statistically significant dose-dependent increases in revertant frequency that were not accompanied by an absolute increase in numbers of revertants. The increase in frequency was wholly ascribable to a declining number of viable cells owing to toxicity. Analysis of the conditions revealed that the frequency of spontaneous revertants is higher when there are fewer viable cells per plate. The phenomenon resembles "adaptive" or "stress" mutagenesis, whereby lactose revertants accumulate in Lac(-) bacteria under starvation conditions in the absence of catabolite repression. Adaptive mutation is observed after long incubation and might be expected to be irrelevant in a standard assay using 48-h incubation. However, we found that elevated revertant frequencies occur under typical assay conditions when the bacterial lawn is thin, and this can cause increases in revertant frequency that mimic chemical mutagenesis when treatments are toxic but not mutagenic. Responses that resemble chemical mutagenesis were observed in the absence of mutagenic treatment in strains that revert by different frameshift mutations. The magnitude of the artifact is affected by cell density, dilution, culture age, incubation time, catabolite repression and the age and composition of media. Although the specific reversion assay is effective for quickly distinguishing classes of mutations induced by potent mutagens, its utility for discerning effects of weak mutagens may be compromised by the artifact. PMID- 26046974 TI - DNA damage in Fabry patients: An investigation of oxidative damage and repair. AB - Fabry disease (FD) is a lysosomal storage disorder associated with loss of activity of the enzyme alpha-galactosidase A. In addition to accumulation of alpha-galactosidase A substrates, other mechanisms may be involved in FD pathophysiology, such as inflammation and oxidative stress. Higher levels of oxidative damage to proteins and lipids in Fabry patients were previously reported. However, DNA damage by oxidative species in FD has not yet been studied. We investigated basal DNA damage, oxidative DNA damage, DNA repair capacity, and reactive species generation in Fabry patients and controls. To measure oxidative damage to purines and pyrimidines, the alkaline version of the comet assay was used with two endonucleases, formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (EndoIII). To evaluate DNA repair, a challenge assay with hydrogen peroxide was performed. Patients presented significantly higher levels of basal DNA damage and oxidative damage to purines. Oxidative DNA damage was induced in both DNA bases by H2O2 in patients. Fabry patients presented efficient DNA repair in both assays (with and without endonucleases) as well as significantly higher levels of oxidative species (measured by dichlorofluorescein content). Even if DNA repair be induced in Fabry patients (as a consequence of continuous exposure to oxidative species), the repair is not sufficient to reduce DNA damage to control levels. PMID- 26046975 TI - In vitro genotoxicity testing of carvacrol and thymol using the micronucleus and mouse lymphoma assays. AB - Currently, antimicrobial additives derived from essential oils (Eos) extracted from plants or spices, such as Origanum vulgare, are used in food packaging. Thymol and carvacrol, the major EO compounds of O. vulgare, have demonstrated their potential use as active additives. These new applications use high concentrations, thereby increasing the concern regarding their toxicological profile and especially their genotoxic risk. The aim of this work was to investigate the potential in vitro genotoxicity of thymol (0-250 MUM) and carvacrol (0-2500 MUM) at equivalent doses to those used in food packaging. The micronucleus (MN) test and the mouse lymphoma (MLA) assay on L5178Y/Tk(+/-) mouse lymphoma cells were used. The negative results for thymol with the MN with and without the S9 fraction and also with the MLA assay reinforce the view that this compound is not genotoxic in mammalian cells. However, carvacrol presented slight genotoxic effects, but only in the MN test at the highest concentration assayed (700 MUM) and in the absence of metabolic activation. The lack of genotoxic response in the MLA assay after 4 and 24h of exposure indicates a low genotoxic potential for carvacrol. Alternatively, the general negative findings observed in both assays suggest that the MN results of carvacrol are marginal data without biological relevance. These results can be useful to identify the appropriate concentrations of these substances to be used as additives in food packaging. PMID- 26046976 TI - Marija Alacevic (April 19, 1929-February 25, 2015). PMID- 26046977 TI - A case-control study of genotoxicity endpoints in patients with papillary thyroid cancer. AB - Thyroid cancer is one of the fastest growing cancer types worldwide. Using the cytokinesis-block micronucleus (CBMN) and comet assays, we performed a case control study of 23 untreated papillary thyroid cancer (PTC) patients and 23 healthy volunteers. PTC patients showed higher basal DNA damage in peripheral blood lymphocytes. The CBMN assay indicated that the numbers of micronuclei, nuclear buds, and nucleoplasmic bridges among the cases were 2.67-, 2.79-, and 7.72-fold higher, respectively, than among the controls (p < 0.05). Comet assay tail lengths and tail intensities were 1.20- and 1.94-fold higher, respectively (p < 0.05). In additional, 14 thyroid tissues from PTC patients were probed for Raf-B and Ret expression; all samples were positive for at least one of these proteins. PMID- 26046978 TI - A comprehensive quantification method for eicosanoids and related compounds by using liquid chromatography/mass spectrometry with high speed continuous ionization polarity switching. AB - Fatty acids and related metabolites, comprising several hundreds of molecular species, are an important target in disease metabolomics, as they are involved in various mammalian pathologies and physiologies. Selected reaction monitoring (SRM) analysis, which is capable of monitoring hundreds of compounds in a single run, has been widely used for comprehensive quantification. However, it is difficult to monitor a large number of compounds with different ionization polarity, as polarity switching requires a sub-second period per cycle in classical mass spectrometers. In the present study, we developed and evaluated a comprehensive quantification method for eicosanoids and related compounds by using LC/MS with high-speed continuous ionization polarity switching. The new method employs a fast (30ms/cycle) continuous ionization polarity switching, and differentiates 137 targets either by chromatography or by SRM transition. Polarity switching did not affect the lower limits of quantification, which ranged similarly from 0.5 to 200pg on column. Lipid extracts from mouse tissues were analyzed by this method, and 65 targets were quantitatively detected in the brain, including 6 compounds analyzed in the positive ion mode. We demonstrated that a fast continuous ionization polarity switching enables the quantification of a wide variety of lipid mediator species without compromising the sensitivity and reliability. PMID- 26046979 TI - Simple and sensitive GC/MS-method for the quantification of urinary phenol, o- and m-cresol and ethylphenols as biomarkers of exposure to industrial solvents. AB - We have developed and validated a simple and sensitive method for the determination of urinary phenol as well as the urinary metabolites of toluene and ethylbenzene in one analytical run. After enzymatic hydrolysis for the cleavage of conjugates overnight, the analytes are extracted from the matrix with a liquid liquid extraction procedure using toluene as solvent under acidic conditions. The analytes are then derivatised to volatile ethers using N,O-bis(trimethylsilyl) trifluoroacetamid (BSTFA) for cresols and ethylphenols as well as N-tert butyldimethylsilyl-N-methyltrifluoroacetamid (MTBSTFA) for the determination of phenol. Separation and detection was carried out using capillary gas chromatography with mass-selective detection (GC-MS). Deuterium-labeled o-cresol served as internal standard for the quantification of all metabolites and guaranteed good accuracy of the results. No matrix effects were observed in the quantification of the analytes. The limit of detection for o- and m-cresol and 2- and 4-ethylphenol was 10 and 20MUg/l urine and linearity ranged up to 3 and 12mg/L urine, respectively. The limit of detection for urinary phenol was 0.5mg/L with a linear range up to 200mg/L. The relative standard deviation of the within series imprecision ranged between 3.0 and 7.2% at two spiked concentrations of 60 and 400MUg/l and the relative recovery was between 84 and 104%, depending on the analyte. The method was successfully applied in proficiency testing for urinary o cresol and phenol. This method was used for the analysis of urine samples of 17 non-smoking and 13 smoking persons from the general population without known exposure to solvents. Smokers showed a significantly higher excretion of o-cresol (median: 23 vs. 33MUg/l), m-cresol (median: 43 vs. 129MUg/l) as well as 4 ethylphenol (median: 25 vs. 124MUg/l). Especially excretion of 4-ethylphenol was significantly correlated to smoking habits. The method seems to be suitable for biological monitoring of low-level solvent exposures and allows determination of background values in the general population. PMID- 26046980 TI - Burst behavior at a capillary tip: Effect of low and high surface tension. AB - Liquid retention in micron and millimeter scale devices is important for maintaining stable interfaces in various processes including bimolecular separation, phase change heat transfer, and water desalination. There have been several studies of re-entrant geometries, and very few studies on retaining low surface tension liquids such as fluorocarbon-based dielectric liquids. Here, we study retention of a liquid with very low contact angles using borosilicate glass capillary tips. We analyzed capillary tips with outer diameters ranging from 250 to 840 MUm and measured Laplace pressures up to 2.9 kPa. Experimental results agree well with a numerical model that predicts burst pressure (the maximum Laplace pressure for liquid retention), which is a function of the outer diameter (D) and capillary exit edge radius of curvature (r). PMID- 26046981 TI - Synthesis of ultrastable and multifunctional gold nanoclusters with enhanced fluorescence and potential anticancer drug delivery application. AB - The problem of stability hinders the practical applications of nanomaterials. In this research, an innovative and simple synthetic method was developed for preparing ultrastable and multifunctional gold nanoclusters (Au NCs). HS-C11-EG6 X is a class of molecules consisting of four components: a mercapto group (-SH), an alkyl chain (C11), a short chain of polyethylene glycols (EG6) and a functional group (X, X=OH, COOH, NH2, GRGD, etc). The present work demonstrated the importance of using HS-C11-EG6-X to prepare Au NCs with excellent properties and the role each component in this molecule played for synthesizing Au NCs. Au NCs with tunable surface functionalities were successfully synthesized and characterized. It was found that Au NC precursors had a fluorescent quantum yield of 0.4%; in contrast, after capping with HS-C11-EG6-X, the quantum yield significantly increased to 1.3-2.6%. The HS-C11-EG6-X capped Au NCs exhibited superior stability under various solution conditions (including extreme pH, high salt concentration, phosphate buffered saline and cell medium) for at least 6 months, even after conjugation with anticancer drug doxorubicin. Besides, we have also demonstrated that other commonly employed thiol-containing ligands failed to prepare stable fluorescent Au NCs. Moreover, the Au NCs showed negligible toxicity to A549 lung cancer cells up to 100 MUM, and the application of the ultrastable Au NCs for anticancer drug delivery has also been demonstrated. PMID- 26046982 TI - Analysis of main parameters affecting substrate/mortar contact area through tridimensional laser scanner. AB - This study assesses the influence of the granulometric composition of sand, application energy and the superficial tension of substrates on the contact area of rendering mortars. Three substrates with distinct wetting behaviors were selected and mortars were prepared with different sand compositions. Characterization tests were performed on fresh and hardened mortars, as well as the rheological characterization. Mortars were applied to substrates with two different energies. The interfacial area was then digitized with 3D scanner. Results show that variables are all of influence on the interfacial contact in the development area. Furthermore, 3D laser scanning proved to be a good method to contact area measurement. PMID- 26046983 TI - Elemental Constituents of Particulate Matter and Newborn's Size in Eight European Cohorts. AB - BACKGROUND: The health effects of suspended particulate matter (PM) may depend on its chemical composition. Associations between maternal exposure to chemical constituents of PM and newborn's size have been little examined. OBJECTIVE: We aimed to investigate the associations of exposure to elemental constituents of PM with term low birth weight (LBW; weight < 2,500 g among births after 37 weeks of gestation), mean birth weight, and head circumference, relying on standardized fine-scale exposure assessment and with extensive control for potential confounders. METHODS: We pooled data from eight European cohorts comprising 34,923 singleton births in 1994-2008. Annual average concentrations of elemental constituents of PM <= 2.5 and <= 10 MUm (PM2.5 and PM10) at maternal home addresses during pregnancy were estimated using land-use regression models. Adjusted associations between each birth measurement and concentrations of eight elements (copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc) were calculated using random-effects regression on pooled data. RESULTS: A 200 ng/m3 increase in sulfur in PM2.5 was associated with an increased risk of LBW (adjusted odds ratio = 1.36; 95% confidence interval: 1.17, 1.58). Increased nickel and zinc in PM2.5 concentrations were also associated with an increased risk of LBW. Head circumference was reduced at higher exposure to all elements except potassium. All associations with sulfur were most robust to adjustment for PM2.5 mass concentration. All results were similar for PM10. CONCLUSION: Sulfur, reflecting secondary combustion particles in this study, may adversely affect LBW and head circumference, independently of particle mass. CITATION: Pedersen M, Gehring U, Beelen R, Wang M, Giorgis-Allemand L, Andersen AM, Basagana X, Bernard C, Cirach M, Forastiere F, de Hoogh K, Grazuleviciene R, Gruzieva O, Hoek G, Jedynska A, Klumper C, Kooter IM, Kramer U, Kukkonen J, Porta D, Postma DS, Raaschou-Nielsen O, van Rossem L, Sunyer J, Sorensen M, Tsai MY, Vrijkotte TG, Wilhelm M, Nieuwenhuijsen MJ, Pershagen G, Brunekreef B, Kogevinas M, Slama R. 2016. Elemental constituents of particulate matter and newborn's size in eight European cohorts. Environ Health Perspect 124:141-150; http://dx.doi.org/10.1289/ehp.1409546. PMID- 26046985 TI - Double-Cone Coil TMS Stimulation of the Medial Cortex Inhibits Central Pain Habituation. AB - OBJECTIVE: The aim of this study was to investigate whether Transcranial Magnetic Stimulation (TMS) applied over the medial line of the scalp affects the subjective perception of continuous pain induced by means of electric stimulation. In addition, we wanted to identify the point of stimulation where this effect was maximum. METHODS: Superficial electrical stimulation was used to induce continuous pain on the dominant hand. At the beginning of the experiment we reached a pain rating of 5 on an 11-point numeric rating scale (NRS; 0 = no pain and 10 = maximum tolerable pain) for each subject by setting individually the current intensity. The TMS (five pulses at increasing intensities) was applied on 5 equidistant points (one per session) over the medial line of the scalp in 13 healthy volunteers using a double-cone coil to stimulate underlying parts of the brain cortex. In every experimental session the painful stimulation lasted 45 minutes, during which pain and distress intensities NRS were recorded continuously. We calculated the effect of adaptation and the immediate effect of the TMS stimulation for all locations. Additionally, an ALE (Activation Likelihood Estimation) meta-analysis was performed to compare our results with the neuroimaging literature on subjective pain rating. RESULTS: TMS stimulation temporarily decreased the pain ratings, and pain adaptation was suppressed when applying the TMS over the FCz site on the scalp. No effect was found for distress ratings. CONCLUSIONS: The present data suggest that the medial cortex in proximity of the cingulated gyrus has a causal role in adaptation mechanisms and in processing ongoing pain and subjective sensation of pain intensity. PMID- 26046984 TI - USP18 Sensitivity of Peptide Transporters PEPT1 and PEPT2. AB - USP18 (Ubiquitin-like specific protease 18) is an enzyme cleaving ubiquitin from target proteins. USP18 plays a pivotal role in antiviral and antibacterial immune responses. On the other hand, ubiquitination participates in the regulation of several ion channels and transporters. USP18 sensitivity of transporters has, however, never been reported. The present study thus explored, whether USP18 modifies the activity of the peptide transporters PEPT1 and PEPT2, and whether the peptide transporters are sensitive to the ubiquitin ligase Nedd4-2. To this end, cRNA encoding PEPT1 or PEPT2 was injected into Xenopus laevis oocytes without or with additional injection of cRNA encoding USP18. Electrogenic peptide (glycine-glycine) transport was determined by dual electrode voltage clamp. As a result, in Xenopus laevis oocytes injected with cRNA encoding PEPT1 or PEPT2, but not in oocytes injected with water or with USP18 alone, application of the dipeptide gly-gly (2 mM) was followed by the appearance of an inward current (Igly-gly). Coexpression of USP18 significantly increased Igly-gly in both PEPT1 and PEPT2 expressing oocytes. Kinetic analysis revealed that coexpression of USP18 increased maximal Igly-gly. Conversely, overexpression of the ubiquitin ligase Nedd4-2 decreased Igly-gly. Coexpression of USP30 similarly increased Igly gly in PEPT1 expressing oocytes. In conclusion, USP18 sensitive cellular functions include activity of the peptide transporters PEPT1 and PEPT2. PMID- 26046986 TI - Preclinical Pharmacokinetic Studies of the Tritium Labelled D-Enantiomeric Peptide D3 Developed for the Treatment of Alzheimer's Disease. AB - Targeting toxic amyloid beta (Abeta) oligomers is currently a very attractive drug development strategy for treatment of Alzheimer's disease. Using mirror image phage display against Abeta1-42, we have previously identified the fully D enantiomeric peptide D3, which is able to eliminate Abeta oligomers and has proven therapeutic potential in transgenic Alzheimer's disease animal models. However, there is little information on the pharmacokinetic behaviour of D enantiomeric peptides in general. Therefore, we conducted experiments with the tritium labelled D-peptide D3 (3H-D3) in mice with different administration routes to study its distribution in liver, kidney, brain, plasma and gastrointestinal tract, as well as its bioavailability by i.p. and p.o. administration. In addition, we investigated the metabolic stability in liver microsomes, mouse plasma, brain, liver and kidney homogenates, and estimated the plasma protein binding. Based on its high stability and long biological half life, our pharmacokinetic results support the therapeutic potential of D-peptides in general, with D3 being a new promising drug candidate for Alzheimer's disease treatment. PMID- 26046987 TI - Structural Studies of the HIV-1 Integrase Protein: Compound Screening and Characterization of a DNA-Binding Inhibitor. AB - Understanding the HIV integrase protein and mechanisms of resistance to HIV integrase inhibitors is complicated by the lack of a full length HIV integrase crystal structure. Moreover, a lentiviral integrase structure with co crystallised DNA has not been described. For these reasons, we have developed a structural method that utilizes free software to create quaternary HIV integrase homology models, based partially on available full-length prototype foamy virus integrase structures as well as several structures of truncated HIV integrase. We have tested the utility of these models in screening of small anti-integrase compounds using randomly selected molecules from the ZINC database as well as a well characterized IN:DNA binding inhibitor, FZ41, and a putative IN:DNA binding inhibitor, HDS1. Docking studies showed that the ZINC compounds that had the best binding energies bound at the IN:IN dimer interface and that the FZ41 and HDS1 compounds docked at approximately the same location in integrase, i.e. behind the DNA binding domain, although there is some overlap with the IN:IN dimer interface to which the ZINC compounds bind. Thus, we have revealed two possible locations in integrase that could potentially be targeted by allosteric integrase inhibitors, that are distinct from the binding sites of other allosteric molecules such as LEDGF inhibitors. Virological and biochemical studies confirmed that HDS1 and FZ41 share a similar activity profile and that both can inhibit each of integrase and reverse transcriptase activities. The inhibitory mechanism of HDS1 for HIV integrase seems to be at the DNA binding step and not at either of the strand transfer or 3' processing steps of the integrase reaction. Furthermore, HDS1 does not directly interact with DNA. The modeling and docking methodology described here will be useful for future screening of integrase inhibitors as well as for the generation of models for the study of integrase drug resistance. PMID- 26046988 TI - Evidence of viral dissemination and seasonality in a Mediterranean river catchment: Implications for water pollution management. AB - Conventional wastewater treatment does not completely remove and/or inactive viruses; consequently, viruses excreted by the population can be detected in the environment. This study was undertaken to investigate the distribution and seasonality of human viruses and faecal indicator bacteria (FIB) in a river catchment located in a typical Mediterranean climate region and to discuss future trends in relation to climate change. Sample matrices included river water, untreated and treated wastewater from a wastewater treatment plant within the catchment area, and seawater from potentially impacted bathing water. Five viruses were analysed in the study. Human adenovirus (HAdV) and JC polyomavirus (JCPyV) were analysed as indicators of human faecal contamination of human pathogens; both were reported in urban wastewater (mean values of 10(6) and 10(5) GC/L, respectively), river water (10(3) and 10(2) GC/L) and seawater (10(2) and 10(1) GC/L). Human Merkel Cell polyomavirus (MCPyV), which is associated with Merkel Cell carcinoma, was detected in 75% of the raw wastewater samples (31/37) and quantified by a newly developed quantitative polymerase chain reaction (qPCR) assay with mean concentrations of 10(4) GC/L. This virus is related to skin cancer in susceptible individuals and was found in 29% and 18% of river water and seawater samples, respectively. Seasonality was only observed for norovirus genogroup II (NoV GGII), which was more abundant in cold months with levels up to 10(4) GC/L in river water. Human hepatitis E virus (HEV) was detected in 13.5% of the wastewater samples when analysed by nested PCR (nPCR). Secondary biological treatment (i.e., activated sludge) and tertiary sewage disinfection including chlorination, flocculation and UV radiation removed between 2.22 and 4.52 log10 of the viral concentrations. Climate projections for the Mediterranean climate areas and the selected river catchment estimate general warming and changes in precipitation distribution. Persistent decreases in precipitation during summer can lead to a higher presence of human viruses because river and sea water present the highest viral concentrations during warmer months. In a global context, wastewater management will be the key to preventing environmental dispersion of human faecal pathogens in future climate change scenarios. PMID- 26046989 TI - Possible land management uses of common cypress to reduce wildfire initiation risk: a laboratory study. AB - Accurate determination of flammability is required in order to improve knowledge about vegetation fire risk. Study of the flammability of different plant species is essential for the Mediterranean area, where most ecosystems are adapted to natural fire but vulnerable to recurrent human-induced fires, which are the main cause of forest degradation. However, the methods used to evaluate vegetation flammability have not yet been standardized. Cupressus sempervirens is a native or naturalized forest tree species in the Mediterranean area that is able to tolerate prolonged drought and high temperatures. The aim of this study was to characterize the flammability of C. sempervirens var. horizontalis at particle level by using different bench-scale calorimetry techniques (mass loss calorimeter, epiradiator and oxygen bomb) to determine the main flammability descriptors (ignitability, sustainability, combustibility and consumability) in live crown and litter samples. Our findings indicate that this variety of cypress is relatively resistant to ignition because of the high ash content, the high critical heat flux, the high time to ignition displayed by both crown and litter samples and the ability of the leaves to maintain a high water content during the summer. We also discuss the possibility of exploiting some morphological, functional and ecological traits of the species to construct a barrier system (with selected varieties of cypress) as a promising complementary land management tool to reduce the fire spread and intensity in a Mediterranean context. PMID- 26046990 TI - Integrative Metabolic Signatures for Hepatic Radiation Injury. AB - BACKGROUND: Radiation-induced liver disease (RILD) is a dose-limiting factor in curative radiation therapy (RT) for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice. METHODS: Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI) and were contrasted to mice, which received 10 Gy whole body irradiation (WBI). Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry. RESULTS: Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate), fatty acids (lineolate, n-hexadecanoic acid) and DNA damage markers (uridine). CONCLUSIONS: We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney. PMID- 26046993 TI - Computer Navigation and Robotics for Total Knee Arthroplasty. PMID- 26046991 TI - Novel and Stress Relevant EST Derived SSR Markers Developed and Validated in Peanut. AB - With the aim to increase the number of functional markers in resource poor crop like cultivated peanut (Arachis hypogaea), large numbers of available expressed sequence tags (ESTs) in the public databases, were employed for the development of novel EST derived simple sequence repeat (SSR) markers. From 16424 unigenes, 2784 (16.95%) SSRs containing unigenes having 3373 SSR motifs were identified. Of these, 2027 (72.81%) sequences were annotated and 4124 gene ontology terms were assigned. Among different SSR motif-classes, tri-nucleotide repeats (33.86%) were the most abundant followed by di-nucleotide repeats (27.51%) while AG/CT (20.7%) and AAG/CTT (13.25%) were the most abundant repeat-motifs. A total of 2456 EST SSR novel primer pairs were designed, of which 366 unigenes having relevance to various stresses and other functions, were PCR validated using a set of 11 diverse peanut genotypes. Of these, 340 (92.62%) primer pairs yielded clear and scorable PCR products and 39 (10.66%) primer pairs exhibited polymorphisms. Overall, the number of alleles per marker ranged from 1-12 with an average of 3.77 and the PIC ranged from 0.028 to 0.375 with an average of 0.325. The identified EST-SSRs not only enriched the existing molecular markers kitty, but would also facilitate the targeted research in marker-trait association for various stresses, inter-specific studies and genetic diversity analysis in peanut. PMID- 26046992 TI - Molecular Analysis of Atypical Family 18 Chitinase from Fujian Oyster Crassostrea angulata and Its Physiological Role in the Digestive System. AB - Chitinolytic enzymes have an important physiological significance in immune and digestive systems in plants and animals, but chitinase has not been identified as having a role in the digestive system in molluscan. In our study, a novel chitinase homologue, named Ca-Chit, has been cloned and characterized as the oyster Crassostrea angulate. The 3998bp full-length cDNA of Ca-Chit consisted of 23bp 5-UTR, 3288 ORF and 688bp 3-UTR. The deduced amino acids sequence shares homologue with the chitinase of family 18. The molecular weight of the protein was predicted to be 119.389 kDa, with a pI of 6.74. The Ca-Chit protein was a modular enzyme composed of a glycosyl hydrolase family 18 domain, threonine-rich region profile and a putative membrane anchor domain. Gene expression profiles monitored by quantitative RT-PCR in different adult tissues showed that the mRNA of Ca-Chit expressed markedly higher visceral mass than any other tissues. The results of the whole mount in-situ hybridization displayed that Ca-Chit starts to express the visceral mass of D-veliger larvae and then the digestive gland forms a crystalline structure during larval development. Furthermore, the adult oysters challenged by starvation indicated that the Ca-Chit expression would be regulated by feed. All the observations made suggest that Ca-Chit plays an important role in the digestive system of the oyster, Crassostrea angulate. PMID- 26046994 TI - Rationale for Strategic Graft Placement in Anterior Cruciate Ligament Reconstruction: I.D.E.A.L. Femoral Tunnel Position. PMID- 26046995 TI - Technique for Lumbar Pedicle Subtraction Osteotomy for Sagittal Plane Deformity in Revision. AB - Pedicle subtraction osteotomies are being used with increasing frequency to treat the problem of sagittal imbalance caused by a variety of diseases. Here we describe a simple technique that assists in osteotomy closure and has proved effective and reliable in maintaining correction. PMID- 26046996 TI - Leg-Length Discrepancy After Total Hip Arthroplasty: Comparison of Robot-Assisted Posterior, Fluoroscopy-Guided Anterior, and Conventional Posterior Approaches. AB - Total hip arthroplasty (THA) effectively provides adequate pain relief and good long-term outcomes in patients with hip osteoarthritis. However, leg-length discrepancy (LLD) remains the most common cause of patient dissatisfaction and malpractice litigation in hip arthroplasty. We conducted a study to compare LLD in patients who underwent THA performed with a robot-assisted posterior approach (RTHA), a fluoroscopy-guided anterior approach (ATHA), or a conventional posterior approach (PTHA). We reviewed all RTHA, ATHA, and PTHA cases performed by Dr. Domb between September 2008 and December 2012. Patients included in the study had a primary diagnosis of hip osteoarthritis and proper postoperative anteroposterior pelvis radiographs available. Two blinded observers calibrated and measured all radiographs twice. After exclusions, 67 RTHA, 29 ATHA, and 59 PTHA cases remained in the study. There were strong interobserver and intraobserver correlations for all LLD measurements (r > 0.9; P < .001). Mean (SD) LLD was 2.7 (1.8) mm (95% CI, 2.3-3.2) in the RTHA group, 1.8 (1.6) mm (95% CI, 1.2-2.4) in the ATHA group, and 1.9 (1.6) mm (95% CI, 1.5-2.4) in the PTHA group (P = .01). When LLD of more than 3 mm was set as an outlier, percentage of outliers was 37.3% (RTHA), 17.2% (ATHA), and 22% (PTHA) (P = .06-.78). When LLD of more than 5 mm was set as an outlier, percentage of outliers was 10.4% (RTHA), 6.9% (ATHA), and 8.5% (PTHA) (P = .72 to > .99). No patient in any group had LLD of 10 mm or more. RTHA, ATHA, and PTHA did not differ in obtaining minimal LLD. All 3 techniques are effective in achieving accuracy in LLD. PMID- 26046997 TI - Targeting a New Safe Zone: A Step in the Development of Patient-Specific Component Positioning for Total Hip Arthroplasty. AB - Surgeons often target the Lewinnek zone, with its mean (SD) inclination of 40 degrees (10 degrees ) and mean (SD) anteversion of 15 degrees (10 degrees ), for acetabular orientation during total hip arthroplasty (THA). However, matching native anteversion (20 degrees -25 degrees ) may achieve optimal stability. We conducted a study in a large single-surgeon patient cohort to determine the incidence of early postoperative dislocation with increased acetabular anteversion and the accuracy of imageless navigation in achieving target acetabular position. Soft-tissue repair through a posterolateral approach was performed in 553 THAs that met the inclusion criteria. Mean (SD) target acetabular orientation was 40 degrees (10 degrees ) of inclination and 25 degrees (10 degrees ) of anteversion. Software was used to measure acetabular positioning on postoperative radiographs. Incidence of dislocation within 6 months after surgery was determined. Mean (SD) inclination was 42.2 degrees (4.9 degrees ), and mean (SD) anteversion was 23.9 degrees (6.5 degrees ). Approximately 82% of cups were placed in the target zone. Variation in anteversion accounted for 67.3% of outliers. Only body mass index was associated with inclination outside the target range (P = .017), and only female sex was associated with anteversion outside the target range (P = .030). Six THAs (1.1%) experienced early dislocation, and 3 (0.54%) of these were revised for multiple dislocations. There was no relationship between dislocation and component placement in either the Lewinnek zone (P = .224) or the target zone (P = .287). PMID- 26046998 TI - Alignment Analyses in the Varus Osteoarthritic Knee Using Computer Navigation. AB - Osteoarthritic (OA) knees with severe extension varus deformity seem to have correspondingly more severe flexion varus, especially beyond a certain tibiofemoral angle. Clinical measurement of flexion varus and fixed flexion deformity (FFD), which had been difficult to perform because of the spatial alignment of the knee in flexion, was recently made possible with computer navigation. We conducted a study to evaluate the relationship of extension and flexion varus in OA knees and to determine whether severity of FFD in the sagittal plane correlates with severity of coronal plane varus deformity. The study included 317 consecutive cases of computer-navigated total knee arthroplasty performed on OA knees with varus deformities. Three sets of values were extracted from the navigation data: varus angle at maximal knee extension, 90 degrees knee flexion, and maximal knee extension. Correlation analyses were performed for extension and flexion varus, FFD, and coronal plane deformity. OA knees with extension varus of more than 10 degrees had an incremental likelihood of more severe flexion varus. When the extension varus angle exceeded 20 degrees , probability became almost certainty. There was no correlation between FFD and coronal plane varus deformity. PMID- 26046999 TI - Hibernoma. AB - Hibernomas are rare benign soft-tissue tumors containing brown fat. Clinically, they present as slow-growing, painless soft-tissue masses. Physical examination usually reveals a palpable, solitary, soft, and rubbery mass within the subcutaneous fat, which is freely mobile and not attached to deep layers. Conventional radiography may show a radiolucent mass without internal mineralization or associated osseous abnormalities. Sonographically, hibernomas are well-circumscribed, solid, hyperechoic masses with increased internal vascular flow. Computed tomography shows internal septations and low attenuation values, between those of fat and muscle. Hibernomas are usually hyperintense to skeletal muscle on T1-weighted magnetic resonance imaging (MRI) but slightly hypointense to subcutaneous fat. On T2-weighted images, high signal intensity similar to that of subcutaneous fat is typical. Hibernomas demonstrate intense fluorine-18 fluorodeoxyglucose uptake on positron emission tomography, because, unlike other adipogenic tumors, they contain abundant mitochondria and are highly metabolically active. Complete surgical excision is the treatment of choice, and is considered curative. PMID- 26047000 TI - Co-Management Arrangements in Orthopedic Surgery. AB - A co-management arrangement (CMA) is a contractual relationship between physicians and a hospital that results in a shared-responsibility management structure for a specific service line. In orthopedic surgery, CMAs are becoming increasingly popular as stakeholders in the health care market seek increased value (ie, higher-quality care at lower costs). A CMA can significantly improve the efficiency and the outcomes of a musculoskeletal service line if it adheres to the basic principles of a focus on the patient, evidence-based decision making, physician leadership, appropriate physician compensation, transparency, reasonable and modifiable goals, and accountability. While the specifics of each CMA will vary, all CMAs have common operational elements that include the arrangement's legal structure, legal compliance, leadership and reporting structure, facilities management, personnel management, clinical data management, financial data management, and quality and effectiveness reporting. PMID- 26047001 TI - Mortality Rates Associated With Odontoid and Subaxial Cervical Spine Fractures. AB - Cervical spine fractures can lead to many devastating consequences. However, mortality rates of older individuals with odontoid or subaxial spine fractures have not been definitively established. We conducted a retrospective review of all patients who underwent computed tomography of the cervical spine in the emergency department of a level I trauma center over 9 years to compare mortality rates after odontoid and subaxial fractures in elderly persons with those of the general population. We searched the National Death Index for patient death records, and compared mortality rates at 3 months, 1 year, and 2 years to sex- and age-matched data from the general population. Odontoid fracture survival was 84.4% at 3 months, 82.2% at 1 year, and 72.9% at 2 years. Male survival was significantly worse compared with age- and sex-matched counterparts (P < .001), but female survival was not (P = .568). In subaxial fractures, survival was 87.9% at 3 months and 85.7% at 1 and 2 years. Male survival was decreased compared with age- and sex-matched counterparts (P < .0001), whereas female survival was not (P = .554). In conclusion, the mortality of men with either fracture was greater compared with age-matched men initially, but this normalized. Female survival was not affected by either fracture. PMID- 26047002 TI - Incidence and Injury Types in Motorcycle Collisions Involving Deer in Western New York. AB - Motorcycle popularity, urban sprawl, and large deer populations result in a significant number of deer-motorcycle collisions. This retrospective review of a level I trauma center in Buffalo, New York, revealed that 40 of 487 (8.2%) of patients admitted because of motorcycle crashes from May 2007 through June 2011 involved deer. There were 120 total injuries: the most common were orthopedic (39/120; 32.5%), chest (38/120; 31.7%), head (18/120; 15.0%), spine (10/120; 8.3%), facial (8/120; 6.7%), and abdominal (7/120; 5.8%). Thirty-five of 40 (87.5%) were men and were older (48.9 years, [SD, 8.9 years]) than the average for all motorcycle crashes during the study period (41.9 years, [SD, 13.9 years]). Mean (SD) injury severity score was 17.1 (9.8), reflecting the severity of encountered injuries. This study highlights the relatively common risk that deer pose to the motorcyclist and is comparable to published series in more rural Midwestern settings. PMID- 26047003 TI - Spontaneous Osteonecrosis of Knee After Arthroscopy Is Not Necessarily Related to the Procedure. AB - Reports in the literature have suggested a causal relationship between knee arthroscopy and spontaneous osteonecrosis of the knee (SONK). We conducted a study to determine if there are imaging characteristics associated with SONK and if there is a relationship between arthroscopy and SONK. In this retrospective review, we compared preoperative and postoperative findings in 11 patients (12 joints) who developed SONK after arthroscopy with findings in 11 age- and sex matched controls who did not develop SONK after arthroscopy. There were no significant preoperative radiologic differences between the SONK and control groups. All 12 SONK lesions seen on magnetic resonance imaging were in the medial femoral condyle. Six SONK knees developed the lesion after arthroscopy, and 6 had SONK lesions before arthroscopy. Eleven of the 12 SONK knees had a medial meniscal tear, compared with 8 medial meniscal tears and 3 lateral meniscal tears in the control group. Eight SONK knees and 5 control patients had medial meniscal extrusion of more than 3 mm. A causal relationship between knee arthroscopy and SONK is questionable. PMID- 26047004 TI - The Effect of Arthroscopic Rotator Interval Closure on Glenohumeral Volume. AB - The role of rotator interval in shoulder pathology and the effect of its closure are not well understood. In addition, the effect of rotator interval closure on intra-articular glenohumeral volume (GHV) remains unknown. We conducted a study to quantify the GHV reduction obtained with an arthroscopic rotator interval closure and to determine whether medial and lateral interval closures resulted in different degrees of volume reduction. We dissected 8 fresh-frozen cadaveric shoulders (mean age, 64.4 years) to the level of the rotator cuff. Volumetric measurements were taken before and after medial and lateral rotator interval closure incorporating the superior glenohumeral ligament and the upper portion of the subscapularis. Arthroscopic closure of the rotator interval with 2 sutures reduced GHV by a mean of 45%. More volume reduction resulted with use of a single lateral interval closure stitch than with use of a single medial stitch (35% vs 24%; P < .02). Arthroscopic rotator interval closure with 2 plication stitches is a powerful tool in reducing intracapsular volume of the shoulder and may be a useful adjunct in restoring glenohumeral stability. If a single plication stitch is preferred, a lateral stitch (vs a medial stitch) can be used for a significantly larger reduction in shoulder volume. PMID- 26047005 TI - Intra-Articular Dislocation of the Patella With Associated Hoffa Fracture in a Skeletally Immature Patient. AB - Since 1887, approximately 50 cases of an intra-articular patellar dislocation have been reported in the worldwide literature. The vast majority of patients required an open reduction of the patella or closed reduction under general anesthesia. This injury has never been reported in association with a coronal shear fracture of the femoral condyle. A 14-year-old boy presented to our institution with his left knee locked in flexion after a direct blow. Radiographs showed the patella rotated on its horizontal axis and lying in a transverse position within the knee joint, as well as a concomitant femoral condyle fracture. After a successful closed reduction of the patella, the patient underwent open reduction and rigid fixation of the femoral condyle fracture with countersunk interfragmentary screws. At 12 months, the patient was ambulating on the left leg and had painless motion of the knee. We present a rare injury pattern in a skeletally immature patient after a direct blow to the knee. By treating the injuries in a sequential manner and providing a stable fixation construct, the patient was able to achieve a satisfactory return to function even after sustaining a considerable injury to the knee. PMID- 26047006 TI - Knee Extensor Mechanism Reconstruction With Complete Extensor Allograft After Failure of Patellar Tendon Repair. AB - Disruptions of the extensor mechanism of the knee may be bony or tendinous in nature. The consequences of such disruptions are not favorable because they prevent normal function of the knee, which is critical for independent ambulation. We report on a 30-year-old man who underwent a successful knee extensor mechanism reconstruction with allograft after his initial tendon repair failed. PMID- 26047007 TI - Issues and challenges for pedestrian active safety systems based on real world accidents. AB - The purpose of this study was to analyze real crashes involving pedestrians in order to evaluate the potential effectiveness of autonomous emergency braking systems (AEB) in pedestrian protection. A sample of 100 real accident cases were reconstructed providing a comprehensive set of data describing the interaction between the vehicle, the environment and the pedestrian all along the scenario of the accident. A generic AEB system based on a camera sensor for pedestrian detection was modeled in order to identify the functionality of its different attributes in the timeline of each crash scenario. These attributes were assessed to determine their impact on pedestrian safety. The influence of the detection and the activation of the AEB system were explored by varying the field of view (FOV) of the sensor and the level of deceleration. A FOV of 35 degrees was estimated to be required to detect and react to the majority of crash scenarios. For the reaction of a system (from hazard detection to triggering the brakes), between 0.5 and 1s appears necessary. PMID- 26047008 TI - Three ADIPOR1 Polymorphisms and Cancer Risk: A Meta-Analysis of Case-Control Studies. AB - BACKGROUND: Studies have come to conflicting conclusions about whether polymorphisms in the adiponectin receptor 1 gene (ADIPOR1) are associated with cancer risk. To help resolve this question, we meta-analyzed case-control studies in the literature. METHODS: PubMed, EMBASE, Cochrane Library, the Chinese Biological Medical Database and the Chinese National Knowledge Infrastructure Database were systematically searched to identify all case-control studies published through February 2015 examining any ADIPOR1 polymorphisms and risk of any type of cancer. Pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated. RESULTS: A total of 13 case-control studies involving 5,750 cases and 6,762 controls were analyzed. Analysis of the entire study population revealed a significant association between rs1342387(G/A) and overall cancer risk using a homozygous model (OR 0.82, 95%CI 0.72 to 0.94), heterozygous model (OR 0.84, 95%CI 0.76 to 0.93), dominant model (OR 0.85, 95%CI 0.75 to 0.97) and allele contrast model (OR 0.88, 95%CI 0.80 to 0.97). However, subgroup analysis showed that this association was significant only for Asians in the case of colorectal cancer. No significant associations were found between rs12733285(C/T) or rs7539542(C/G) and cancer risk, either in analyses of the entire study population or in analyses of subgroups. CONCLUSIONS: Our meta analysis suggests that the ADIPOR1 rs1342387(G/A) polymorphism, but not rs12733285(C/T) or rs7539542(C/G), may be associated with cancer risk, especially risk of colorectal cancer in Asians. Large, well-designed studies are needed to verify our findings. PMID- 26047009 TI - Patterns in Leptospira Shedding in Norway Rats (Rattus norvegicus) from Brazilian Slum Communities at High Risk of Disease Transmission. AB - BACKGROUND: We address some critical but unknown parameters of individuals and populations of Norway rats (Rattus norvegicus) that influence leptospiral infection, maintenance and spirochetal loads shed in urine, which contaminates the environment ultimately leading to human infection. METHODOLOGY/PRINCIPAL FINDINGS: Our study, conducted in Salvador, Brazil, established the average load of leptospires in positive kidneys to be 5.9 x 10(6) per mL (range 3.1-8.2 x10(6)) genome equivalents (GEq), similar to the 6.1 x 10(6) per ml (range 2.2 9.4 x10(6)) average obtained from paired urines, with a significant positive correlation (R2=0.78) between the two. Based on bivariate and multivariate modeling, we found with both kidney and urine samples that leptospiral loads increased with the age of rats (based on the index of body length to mass), MAT titer and the presence of wounding/scars, and varied with site of capture. Some associations were modified by sex but trends were apparent. Combining with data on the demographic properties and prevalence of leptospiral carriage in rat populations in Salvador, we estimated that daily leptospiral loads shed in the urine of a population of 82 individuals exceeded 9.1 x 10(10) leptospires. CONCLUSIONS/SIGNIFICANCE: These factors directly influence the risk of leptospiral acquisition among humans and provide essential epidemiological information linking properties of rat populations with risk of human infection. PMID- 26047010 TI - Source-Sink Colonization as a Possible Strategy of Insects Living in Temporary Habitats. AB - Continuous colonization and re-colonization is critical for survival of insect species living in temporary habitats. When insect populations in temporary habitats are depleted, some species may escape extinction by surviving in permanent, but less suitable habitats, in which long-term population survival can be maintained only by immigration from other populations. Such situation has been repeatedly described in nature, but conditions when and how this occurs and how important this phenomenon is for insect metapopulation survival are still poorly known, mainly because it is difficult to study experimentally. Therefore, we used a simulation model to investigate, how environmental stochasticity, growth rate and the incidence of dispersal affect the positive effect of permanent but poor ("sink") habitats on the likelihood of metapopulation persistence in a network of high quality but temporary ("source") habitats. This model revealed that permanent habitats substantially increase the probability of metapopulation persistence of insect species with poor dispersal ability if the availability of temporary habitats is spatio-temporally synchronized. Addition of permanent habitats to a system sometimes enabled metapopulation persistence even in cases in which the metapopulation would otherwise go extinct, especially for species with high growth rates. For insect species with low growth rates the probability of a metapopulation persistence strongly depended on the proportions of "source" to "source" and "sink" to "source" dispersal rates. PMID- 26047011 TI - Development of Sustained Release "NanoFDC (Fixed Dose Combination)" for Hypertension - An Experimental Study. AB - OBJECTIVES: The present study was planned to formulate, characterize and evaluate the pharmacokinetics of a novel "NanoFDC" comprising three commonly prescribed anti-hypertensive drugs, hydrochlorothiazide (a diuretic), candesartan (ARB) and amlodipine (a calcium channel blocker). BASIC METHODS: The candidate drugs were loaded in Poly (DL-lactide-co-gycolide) (PLGA) by emulsion- diffusion-evaporation method. The formulations were evaluated for their size, morphology, drug loading and in vitro release individually. Single dose pharmacokinetic profiles of the nanoformulations alone and in combination, as a NanoFDC, were evaluated in Wistar rats. RESULTS: The candidate drugs encapsulated inside PLGA showed entrapment efficiencies ranging from 30%, 33.5% and 32% for hydrochlorothiazide, candesartan and amlodipine respectively. The nanoparticles ranged in size from 110 to 180 nm. In vitro release profile of the nanoformulation showed 100% release by day 6 in the physiological pH 7.4 set up with PBS (phosphate buffer saline) and by day 4-5 in the intestinal pH 1.2 and 8.0 set up SGF (simulated gastric fluid) and SIF (simulated intestinal fluid) respectively. In pharmacokinetic analysis a sustained-release for 6 days and significant increase in the mean residence time (MRT), as compared to the respective free drugs was noted [MRT of amlodipine, hydrochlorothiazide and candesartan changed from 8.9 to 80.59 hours, 11 to 69.20 hours and 9 to 101.49 hours respectively]. CONCLUSION: We have shown for the first time that encapsulating amlodipine, hydrochlorothiazide and candesartan into a single nanoformulation, to get the "NanoFDC (Fixed Dose Combination)" is a feasible strategy which aims to decrease pill burden. PMID- 26047012 TI - Three-Dimensional Mapping of Soil Organic Carbon by Combining Kriging Method with Profile Depth Function. AB - Understanding spatial variation of soil organic carbon (SOC) in three-dimensional direction is helpful for land use management. Due to the effect of profile depths and soil texture on vertical distribution of SOC, the stationary assumption for SOC cannot be met in the vertical direction. Therefore the three-dimensional (3D) ordinary kriging technique cannot be directly used to map the distribution of SOC at a regional scale. The objectives of this study were to map the 3D distribution of SOC at a regional scale by combining kriging method with the profile depth function of SOC (KPDF), and to explore the effects of soil texture and land use type on vertical distribution of SOC in a fluvial plain. A total of 605 samples were collected from 121 soil profiles (0.0 to 1.0 m, 0.20 m increment) in Quzhou County, China and SOC contents were determined for each soil sample. The KPDF method was used to obtain the 3D map of SOC at the county scale. The results showed that the exponential equation well described the vertical distribution of mean values of the SOC contents. The coefficients of determination, root mean squared error and mean prediction error between the measured and the predicted SOC contents were 0.52, 1.82 and -0.24 g kg(-1) respectively, suggesting that the KPDF method could be used to produce a 3D map of SOC content. The surface SOC contents were high in the mid-west and south regions, and low values lay in the southeast corner. The SOC contents showed significant positive correlations between the five different depths and the correlations of SOC contents were larger in adjacent layers than in non-adjacent layers. Soil texture and land use type had significant effects on the spatial distribution of SOC. The influence of land use type was more important than that of soil texture in the surface soil, and soil texture played a more important role in influencing the SOC levels for 0.2-0.4 m layer. PMID- 26047013 TI - The Prevalence of Vitamin D Deficiency among Cancer Survivors in a Nationwide Survey of the Korean Population. AB - BACKGROUND: Recent studies have shown that inadequate vitamin D levels are associated with a poor cancer prognosis, but data regarding actual vitamin D levels in cancer survivors are limited. This study investigated the vitamin D levels and prevalence of vitamin D deficiency among Korean cancer survivors compared with non-cancer controls, and identified the factors associated with vitamin D deficiency. METHODS: Using the Korea National Health and Nutrition Examination Survey (KNHANES), 915 cancer survivors and 29,694 controls without a history of cancer were selected. Serum 25(OH)D levels were measured; vitamin D deficiency was defined as 25(OH)D levels less than 20 ng/mL. Chi-square tests and multiple logistic regression analyses were used to evaluate the prevalence of vitamin D deficiency and associated factors. RESULTS: Vitamin D deficiency was observed in 62.7% of cancer survivors and 67.1% of controls. Among cancer survivors, vitamin D deficiency was most prevalent among 19-44 year olds (76.2%) and among managers, professionals, and related workers (79.3%). Multiple logistic regression analysis revealed that younger cancer survivors and those who work indoors were predisposed to vitamin D deficiency. CONCLUSION: Vitamin D deficiency was prevalent among both cancer survivors and controls in Korea. The regular evaluation and management of vitamin D levels is needed for both bone health and general health in cancer survivors. PMID- 26047014 TI - The Generation of Insulin Producing Cells from Human Mesenchymal Stem Cells by MiR-375 and Anti-MiR-9. AB - BACKGROUND: MicroRNAs (miRNAs) are a group of endogenous small non-coding RNAs that regulate gene expression at the post-transcriptional level. A number of studies have led to the notion that some miRNAs have key roles in control of pancreatic islet development and insulin secretion. Based on some studies on miRNAs pattern, the researchers in this paper investigated the pancreatic differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) by up regulation of miR-375 and down-regulation of miR-9 by lentiviruses containing miR 375 and anti-miR-9. METHODOLOGY: After 21 days of induction, islet-like clusters containing insulin producing cells (IPCs) were confirmed by dithizone (DTZ) staining. The IPCs and beta cell specific related genes and proteins were detected using qRT-PCR and immunofluorescence on days 7, 14 and 21 of differentiation. Glucose challenge test was performed at different concentrations of glucose so extracellular and intracellular insulin and C-peptide were assayed using ELISA kit. Although derived IPCs by miR-375 alone were capable to express insulin and other endocrine specific transcription factors, the cells lacked the machinery to respond to glucose. CONCLUSION: It was found that over-expression of miR-375 led to a reduction in levels of Mtpn protein in derived IPCs, while treatment with anti-miR-9 following miR-375 over-expression had synergistic effects on MSCs differentiation and insulin secretion in a glucose-regulated manner. The researchers reported that silencing of miR-9 increased OC-2 protein in IPCs that may contribute to the observed glucose-regulated insulin secretion. Although the roles of miR-375 and miR-9 are well known in pancreatic development and insulin secretion, the use of these miRNAs in transdifferentiation was never demonstrated. These findings highlight miRNAs functions in stem cells differentiation and suggest that they could be used as therapeutic tools for gene based therapy in diabetes mellitus. PMID- 26047015 TI - Nosocomial outbreak of hepatitis B virus infection in a pediatric hematology and oncology unit in South Africa: Epidemiological investigation and measures to prevent further transmission. AB - BACKGROUND: Hospital-acquired hepatitis B virus (HBV) infection has been well described and continues to occur worldwide. Recent nosocomial outbreaks have been linked to unsafe injection practices, use of multi-dose vials, and poor staff compliance with standard precautions. This report describes a nosocomial outbreak that occurred in a pediatric hematology and oncology unit of a large academic hospital, the epidemiological investigation of the outbreak, and preventive measures implemented to limit further in-hospital transmission. METHODS: Outbreak investigation including contact tracing and HBV screening were initially carried out on all patients seen by the unit during the same period as the first three cases. Routine screening for the entire patient population of the unit was initiated in February 2013 when it was realized that numerous patients may have been exposed. RESULTS: Forty-nine cases of HBV infection were confirmed in 408 patients tested between July 2011 and October 2013. Phylogenetic analysis of the HBV preC/C gene nucleotide sequences revealed that all tested outbreak strains clustered together. Most (67%) patients were HBeAg positive. The cause of transmission could not be established. Preventive measures targeted three proposed routes. HBV screening and vaccination protocols were started in the unit. CONCLUSIONS: The high number of HBeAg positive patients, together with suspected lapses in infection prevention and control measures, are believed to have played a major role in the transmission. Measures implemented to prevent further in-hospital transmission were successful. On-going HBV screening and vaccination programs in pediatric hematology and oncology units should become standard of care. PMID- 26047016 TI - Upregulated Polo-Like Kinase 1 Expression Correlates with Inferior Survival Outcomes in Rectal Cancer. AB - BACKGROUND: Human polo-like kinase 1 (PLK1) expression has been associated with inferior outcomes in colorectal cancer. Our aims were to analyse PLK1 in rectal cancer, and its association with clinicopathological variables, overall survival as well as tumour regression to neoadjuvant treatment. METHODS: PLK1 expression was quantified with immunohistochemistry in the centre and periphery (invasive front) of rectal cancers, as well as in the involved regional lymph nodes from 286 patients. Scores were based on staining intensity and percentage of positive cells, multiplied to give weighted scores from 1-12, dichotomised into low (0-5) or high (6-12). RESULTS: PLK1 scores in the tumour periphery were significantly different to adjacent normal mucosa. Survival analysis revealed that low PLK1 score in the tumour periphery had a hazard ratio of death of 0.59 in multivariate analysis. Other predictors of survival included age, tumour depth, metastatic status, vascular and perineural invasion and adjuvant chemotherapy. There was no statistically significant correlation between PLK1 score and histological tumour regression in the neoadjuvant cohort. CONCLUSION: Low PLK1 score was an independent predictor of superior overall survival, adjusting for multiple clinicopathological variables including treatment. PMID- 26047018 TI - Corrigendum for Ann. N.Y. Acad. Sci. 1048: 352-354. PMID- 26047017 TI - Robotic total proctocolectomy for ulcerative colitis - a video vignette. PMID- 26047019 TI - TaER Expression Is Associated with Transpiration Efficiency Traits and Yield in Bread Wheat. AB - ERECTA encodes a receptor-like kinase and is proposed as a candidate for determining transpiration efficiency of plants. Two genes homologous to ERECTA in Arabidopsis were identified on chromosomes 6 (TaER2) and 7 (TaER1) of bread wheat (Triticum aestivum L.), with copies of each gene on the A, B and D genomes of wheat. Similar expression patterns were observed for TaER1 and TaER2 with relatively higher expression of TaER1 in flag leaves of wheat at heading (Z55) and grain-filling (Z73) stages. Significant variations were found in the expression levels of both TaER1 and TaER2 in the flag leaves at both growth stages among 48 diverse bread wheat varieties. Based on the expression of TaER1 and TaER2, the 48 wheat varieties could be classified into three groups having high (5 varieties), medium (27 varieties) and low (16 varieties) levels of TaER expression. Significant differences were also observed between the three groups varying for TaER expression for several transpiration efficiency (TE)- related traits, including stomatal density (SD), transpiration rate, photosynthetic rate (A), instant water use efficiency (WUEi) and carbon isotope discrimination (CID), and yield traits of biomass production plant-1 (BYPP) and grain yield plant-1 (GYPP). Correlation analysis revealed that the expression of TaER1 and TaER2 at the two growth stages was significantly and negatively associated with SD (P<0.01), transpiration rate (P<0.05) and CID (P<0.01), while significantly and positively correlated with flag leaf area (FLA, P<0.01), A (P<0.05), WUEi (P<0.05), BYPP (P<0.01) and GYPP (P<0.01), with stronger correlations for TaER1 than TaER2 and at grain-filling stage than at heading stage. These combined results suggested that TaER involved in development of transpiration efficiency related traits and yield in bread wheat, implying a function for TaER in regulating leaf development of bread wheat and contributing to expression of these traits. Moreover, the results indicate that TaER could be exploitable for manipulating important agronomical traits in wheat improvement. PMID- 26047020 TI - Capsaicin reduces the metastatic burden in the transgenic adenocarcinoma of the mouse prostate model. AB - BACKGROUND: Capsaicin, the active compound in chili peppers, has demonstrated anti- carcinogenic properties in vitro in a number of malignancies, including the prostate. In the present study, we investigate the chemopreventive potential of capsaicin on prostate cancer using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The TRAMP is a murine model that resembles the progression of human disease. METHODS: Thirty-five 6-week-old TRAMP x C57BL/6 mice were randomized between treatment with capsaicin (5 mg/kg body weight) or control (saline) three times a week by oral gavage until 30 weeks of age. Body weight of animals was recorded thrice weekly. At termination, all tumors were extracted, recorded, and analyzed for histopathological analysis. To understand the effect of capsaicin on migration and invasion, in vitro experiments were carried out using PC3 cells. RESULTS: Mice in the control group expressed an overall trend of higher-grade disease with 37.5% poorly differentiated (PD), 18.75% moderately differentiated (MD), and 44% of well-differentiated (WD) adenocarcinoma, compared to the capsaicin-treated group with only 27.7% PD, 61.0% of WD, and 11.1% of intraepithelial neoplasia (PIN). The treatment group demonstrated a higher incidence of noncancerous PIN lesions compared to the control group. The capsaicin group also demonstrated a significant reduction (P < 0.05) in the metastatic burden compared to the controls, which correlated to a reduction in p27(Kip) (1) expression and neuroendocrine differentiation in prostate tumors. Furthermore, there were no differences in body weight between groups overtime, and no pathological toxicities in the liver and gastrointestinal tract with capsaicin consumption. In vitro studies revealed a dose-dependent reduction in the invasion and migration capacity of PC3 cells. CONCLUSION: The following study provides evidence supporting the safety and chemopreventive effects of capsaicin in the TRAMP model. PMID- 26047021 TI - An effective plasma membrane proteomics approach for small tissue samples. AB - Advancing the quest for new drug targets demands the development of innovative plasma membrane proteome research strategies applicable to small, functionally defined tissue samples. Biotinylation of acute tissue slices and streptavidin pull-down followed by shotgun proteomics allowed the selective extraction and identification of >1,600 proteins of which >60% are associated with the plasma membrane, including (G-protein coupled) receptors, ion channels and transporters, and this from mm(3)-scale tissue. PMID- 26047022 TI - Muscle spindle and fusimotor activity in locomotion. AB - Mammals may exhibit different forms of locomotion even within a species. A particular form of locomotion (e.g. walk, run, bound) appears to be selected by supraspinal commands, but the precise pattern, i.e. phasing of limbs and muscles, is generated within the spinal cord by so-called central pattern generators. Peripheral sense organs, particularly the muscle spindle, play a crucial role in modulating the central pattern generator output. In turn, the feedback from muscle spindles is itself modulated by static and dynamic fusimotor (gamma) neurons. The activity of muscle spindle afferents and fusimotor neurons during locomotion in the cat is reviewed here. There is evidence for some alpha-gamma co activation during locomotion involving static gamma motoneurons. However, both static and dynamic gamma motoneurons show patterns of modulation that are distinct from alpha motoneuron activity. It has been proposed that static gamma activity may drive muscle spindle secondary endings to signal the intended movement to the central nervous system. Dynamic gamma motoneuron drive appears to prime muscle spindle primary endings to signal transitions in phase of the locomotor cycle. These findings come largely from reduced animal preparations (decerebrate) and require confirmation in freely moving intact animals. PMID- 26047023 TI - Which somatic symptoms are associated with an unfavorable course in Chinese patients with major depressive disorder? AB - INTRODUCTION: This was an analysis of the impact of somatic symptoms on the severity and course of depression in Chinese patients treated for an acute episode of major depressive disorder (MDD). METHODS: Data were extracted from a 3 month prospective observational study which enrolled 909 patients with MDD in psychiatric care settings; this analysis focused on the Chinese patients (n=300). Depression severity was assessed using the Clinical Global Impression of Severity (CGI-S) and 17-item Hamilton Depression Rating Scale (HAMD-17); somatic symptoms were assessed using the patient-rated 28-item Somatic Symptom Inventory (SSI). Cluster analysis using baseline SSI scores grouped patients into three clusters with no/mild, moderate, or severe somatic symptoms. Four SSI factors (pain, autonomic symptoms, energy, and central nervous system) were defined, and regression analyses identified which factors were associated with remission at 3 months. RESULTS: More than 70% of the patients had moderate or severe somatic symptoms. Baseline depression severity (HAMD-17 and CGI-S scores) was associated with more severe somatic symptoms. Remission rates differed between clusters of patients: 84.1%, 72.0%, and 55.3% for no/mild, moderate, and severe somatic symptoms, respectively (P=0.0034). Pain symptoms were the somatic symptoms more strongly associated with lower remission rates at 3 months. DISCUSSION: Somatic symptoms are associated with greater clinical severity and lower remission rates. Among somatic symptoms, pain symptoms have the greatest prognostic value and should be taken into account when treating patients with depression. PMID- 26047026 TI - Tailor-Made Core-Shell CaO/TiO2-Al2O3 Architecture as a High-Capacity and Long Life CO2 Sorbent. AB - CaO-based sorbents are widely used for CO2 capture, steam methane reforming, and gasification enhancement, but the sorbents suffer from rapid deactivation during successive carbonation/calcination cycles. This research proposes a novel self assembly template synthesis (SATS) method to prepare a hierarchical structure CaO based sorbent, Ca-rich, Al2O3-supported, and TiO2-stabilized in a core-shell microarchitecture (CaO/TiO2-Al2O3). The cyclic CO2 capture performance of CaO/TiO2-Al2O3 is compared with those of pure CaO and CaO/Al2O3. CaO/TiO2-Al2O3 sorbent achieved superior and durable CO2 capture capacity of 0.52 g CO2/g sorbent after 20 cycles under the mild calcination condition and retained a high capacity and long-life performance of 0.44 g CO2/g sorbent after 104 cycles under the severe calcination condition, much higher than those of CaO and CaO/Al2O3. The microstructure characterization of CaO/TiO2-Al2O3 confirmed that the core shell structure of composite support effectively inhibited the reaction between active component (CaO particles) and main support (Al2O3 particles) by TiO2 addition, which contributed to its properties of high reactivity, thermal stability, mechanical strength, and resistance to agglomeration and sintering. PMID- 26047025 TI - Trophic Niche in a Raptor Species: The Relationship between Diet Diversity, Habitat Diversity and Territory Quality. AB - Recent research reports that many populations of species showing a wide trophic niche (generalists) are made up of both generalist individuals and individuals with a narrow trophic niche (specialists), suggesting trophic specializations at an individual level. If true, foraging strategies should be associated with individual quality and fitness. Optimal foraging theory predicts that individuals will select the most favourable habitats for feeding. In addition, the "landscape heterogeneity hypothesis" predicts a higher number of species in more diverse landscapes. Thus, it can be predicted that individuals with a wider realized trophic niche should have foraging territories with greater habitat diversity, suggesting that foraging strategies, territory quality and habitat diversity are inter-correlated. This was tested for a population of common kestrels Falco tinnunculus. Diet diversity, territory occupancy (as a measure of territory quality) and habitat diversity of territories were measured over an 8-year period. Our results show that: 1) territory quality was quadratically correlated with habitat diversity, with the best territories being the least and most diverse; 2) diet diversity was not correlated with territory quality; and 3) diet diversity was negatively correlated with landscape heterogeneity. Our study suggests that niche generalist foraging strategies are based on an active search for different prey species within or between habitats rather than on the selection of territories with high habitat diversity. PMID- 26047024 TI - Healthcare- and Community-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) and Fatal Pneumonia with Pediatric Deaths in Krasnoyarsk, Siberian Russia: Unique MRSA's Multiple Virulence Factors, Genome, and Stepwise Evolution. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a common multidrug resistant (MDR) pathogen. We herein discussed MRSA and its infections in Krasnoyarsk, Siberian Russia between 2007 and 2011. The incidence of MRSA in 3,662 subjects was 22.0% and 2.9% for healthcare- and community-associated MRSA (HA- and CA-MRSA), respectively. The 15-day mortality rates for MRSA hospital- and community-acquired pneumonia (HAP and CAP) were 6.5% and 50%, respectively. MRSA CAP cases included pediatric deaths; of the MRSA pneumonia episodes available, >=27.3% were associated with bacteremia. Most cases of HA-MRSA examined exhibited ST239/spa3(t037)/SCCmecIII.1.1.2 (designated as ST239Kras), while all CA-MRSA cases examined were ST8/spa1(t008)/SCCmecIV.3.1.1(IVc) (designated as ST8Kras). ST239Kras and ST8Kras strongly expressed cytolytic peptide (phenol-soluble modulin alpha, PSMalpha; and delta-hemolysin, Hld) genes, similar to CA-MRSA. ST239Kras pneumonia may have been attributed to a unique set of multiple virulence factors (MVFs): toxic shock syndrome toxin-1 (TSST-1), elevated PSMalpha/Hld expression, alpha-hemolysin, the staphylococcal enterotoxin SEK/SEQ, the immune evasion factor SCIN/SAK, and collagen adhesin. Regarding ST8Kras, SEA was included in MVFs, some of which were common to ST239Kras. The ST239Kras (strain OC3) genome contained: a completely unique phage, phiSa7-like (W), with no att repetition; S. aureus pathogenicity island SaPI2R, the first TSST-1 gene-positive (tst+) SaPI in the ST239 lineage; and a super copy of IS256 (>=22 copies/genome). ST239Kras carried the Brazilian SCCmecIII.1.1.2 and United Kingdom-type tst. ST239Kras and ST8Kras were MDR, with the same levofloxacin resistance mutations; small, but transmissible chloramphenicol resistance plasmids spread widely enough to not be ignored. These results suggest that novel MDR and MVF+ HA- and CA-MRSA (ST239Kras and ST8Kras) emerged in Siberian Russia (Krasnoyarsk) associated with fatal pneumonia, and also with ST239Kras, a new (Siberian Russian) clade of the ST239 lineage, which was created through stepwise evolution during its potential transmission route of Brazil-Europe Russia/Krasnoyarsk, thereby selective advantages from unique MVFs and the MDR. PMID- 26047027 TI - Real-time estimation of paracellular permeability of cerebral endothelial cells by capacitance sensor array. AB - Vascular integrity is important in maintaining homeostasis of brain microenvironments. In various brain diseases including Alzheimer's disease, stroke, and multiple sclerosis, increased paracellular permeability due to breakdown of blood-brain barrier is linked with initiation and progression of pathological conditions. We developed a capacitance sensor array to monitor dielectric responses of cerebral endothelial cell monolayer, which could be utilized to evaluate the integrity of brain microvasculature. Our system measured real-time capacitance values which demonstrated frequency- and time-dependent variations. With the measurement of capacitance at the frequency of 100 Hz, we could differentiate the effects of vascular endothelial growth factor (VEGF), a representative permeability-inducing factor, on endothelial cells and quantitatively analyse the normalized values. Interestingly, we showed differential capacitance values according to the status of endothelial cell monolayer, confluent or sparse, evidencing that the integrity of monolayer was associated with capacitance values. Another notable feature was that we could evaluate the expression of molecules in samples in our system with the reference of real-time capacitance values. We suggest that this dielectric spectroscopy system could be successfully implanted as a novel in vitro assay in the investigation of the roles of paracellular permeability in various brain diseases. PMID- 26047028 TI - Disease Interventions Can Interfere with One Another through Disease-Behaviour Interactions. AB - Theoretical models of disease dynamics on networks can aid our understanding of how infectious diseases spread through a population. Models that incorporate decision-making mechanisms can furthermore capture how behaviour-driven aspects of transmission such as vaccination choices and the use of non-pharmaceutical interventions (NPIs) interact with disease dynamics. However, these two interventions are usually modelled separately. Here, we construct a simulation model of influenza transmission through a contact network, where individuals can choose whether to become vaccinated and/or practice NPIs. These decisions are based on previous experience with the disease, the current state of infection amongst one's contacts, and the personal and social impacts of the choices they make. We find that the interventions interfere with one another: because of negative feedback between intervention uptake and infection prevalence, it is difficult to simultaneously increase uptake of all interventions by changing utilities or perceived risks. However, on account of vaccine efficacy being higher than NPI efficacy, measures to expand NPI practice have only a small net impact on influenza incidence due to strongly mitigating feedback from vaccinating behaviour, whereas expanding vaccine uptake causes a significant net reduction in influenza incidence, despite the reduction of NPI practice in response. As a result, measures that support expansion of only vaccination (such as reducing vaccine cost), or measures that simultaneously support vaccination and NPIs (such as emphasizing harms of influenza infection, or satisfaction from preventing infection in others through both interventions) can significantly reduce influenza incidence, whereas measures that only support expansion of NPI practice (such as making hand sanitizers more available) have little net impact on influenza incidence. (However, measures that improve NPI efficacy may fare better.) We conclude that the impact of interference on programs relying on multiple interventions should be more carefully studied, for both influenza and other infectious diseases. PMID- 26047029 TI - Computational microscopic imaging for malaria parasite detection: a systematic review. AB - Malaria, being an epidemic disease, demands its rapid and accurate diagnosis for proper intervention. Microscopic image-based characterization of erythrocytes plays an integral role in screening of malaria parasites. In practice, microscopic evaluation of blood smear image is the gold standard for malaria diagnosis; where the pathologist visually examines the stained slide under the light microscope. This visual inspection is subjective, error-prone and time consuming. In order to address such issues, computational microscopic imaging methods have been given importance in recent times in the field of digital pathology. Recently, such quantitative microscopic techniques have rapidly evolved for abnormal erythrocyte detection, segmentation and semi/fully automated classification by minimizing such diagnostic errors for computerized malaria detection. The aim of this paper is to present a review on enhancement, segmentation, microscopic feature extraction and computer-aided classification for malaria parasite detection. PMID- 26047030 TI - Convergent and invariant object representations for sight, sound, and touch. AB - We continuously perceive objects in the world through multiple sensory channels. In this study, we investigated the convergence of information from different sensory streams within the cerebral cortex. We presented volunteers with three common objects via three different modalities-sight, sound, and touch-and used multivariate pattern analysis of functional magnetic resonance imaging data to map the cortical regions containing information about the identity of the objects. We could reliably predict which of the three stimuli a subject had seen, heard, or touched from the pattern of neural activity in the corresponding early sensory cortices. Intramodal classification was also successful in large portions of the cerebral cortex beyond the primary areas, with multiple regions showing convergence of information from two or all three modalities. Using crossmodal classification, we also searched for brain regions that would represent objects in a similar fashion across different modalities of presentation. We trained a classifier to distinguish objects presented in one modality and then tested it on the same objects presented in a different modality. We detected audiovisual invariance in the right temporo-occipital junction, audiotactile invariance in the left postcentral gyrus and parietal operculum, and visuotactile invariance in the right postcentral and supramarginal gyri. Our maps of multisensory convergence and crossmodal generalization reveal the underlying organization of the association cortices, and may be related to the neural basis for mental concepts. PMID- 26047031 TI - Quantification of tannins and related polyphenols in commercial products of tormentil (Potentilla tormentilla). AB - INTRODUCTION: Potentilla tormentilla has many biological and pharmacological properties and can be used as an ingredient of some herbal medicines or beverages. OBJECTIVE: The aim of this study was to evaluate the content of individual polyphenols, especially condensed and hydrolysable tannins in commercially available tormentil rhizomes and tinctures using chromatographic methods. METHODS: A quantitative analysis (HPLC-PDA) was preceded by qualitative studies (UPLC-qTOF-MS/MS) and the isolation (CC) of the major tannin compounds. RESULTS: The tested plant material is characterised by a high content of tannins and related polyphenols, i.e. in rhizomes even at the level above 20% and in tinctures above 2%. The main components of tormentil rhizomes are procyanidin B3 (mean ~ 3.6%), procyanidin C2 (mean ~ 2.8%), agrimoniin (mean ~ 2.5%), 3-O galloylquinic acid (mean ~ 1.7%), catechin (mean ~ 1.6%), other flavan-3-ol oligomers (mean ~ 0.5-1.1) and laevigatins (mean ~ 0.2-0.6%). Free ellagic acid and glycosides of ellagic and methylellagic acids are secondary components. CONCLUSIONS: Underground parts of tormentil are a source of oligomeric proanthocyanidins and ellagitannins, but in smaller quantity of gallotannins. Monogalloylquinic acids are new identified compounds, which had not been described in Potentilla tormentilla before we started our research. In the analysed tormentil tinctures agrimoniin concentration is lower in relation to other tannins. PMID- 26047034 TI - Adult Attachment Interview differentiates adolescents with Childhood Sexual Abuse from those with clinical depression and non-clinical controls. AB - Although attachment representation is considered to be disturbed in traumatized adolescents, it is not known whether this is specific for trauma, as comparative studies with other clinical groups are lacking. Therefore, attachment representation was studied by means of the Adult Attachment Interview in adolescents with Childhood Sexual Abuse (CSA) (N = 21), clinical depression (N = 28) and non-clinical controls (N = 28). Coherence of mind and unresolved loss or trauma, as well as the disorganized attachment classification differentiated the CSA group from the clinical depression group and controls, over and above age, IQ, and psychiatric symptomatology. In the current era of sustained criticism on criteria-based classification, this may well carry substantial clinical relevance. If attachment is a general risk or vulnerability factor underlying specific psychopathology, this may guide diagnostic assessment as well as treatment. PMID- 26047032 TI - Advances and New Concepts in Alcohol-Induced Organelle Stress, Unfolded Protein Responses and Organ Damage. AB - Alcohol is a simple and consumable biomolecule yet its excessive consumption disturbs numerous biological pathways damaging nearly all organs of the human body. One of the essential biological processes affected by the harmful effects of alcohol is proteostasis, which regulates the balance between biogenesis and turnover of proteins within and outside the cell. A significant amount of published evidence indicates that alcohol and its metabolites directly or indirectly interfere with protein homeostasis in the endoplasmic reticulum (ER) causing an accumulation of unfolded or misfolded proteins, which triggers the unfolded protein response (UPR) leading to either restoration of homeostasis or cell death, inflammation and other pathologies under severe and chronic alcohol conditions. The UPR senses the abnormal protein accumulation and activates transcription factors that regulate nuclear transcription of genes related to ER function. Similarly, this kind of protein stress response can occur in other cellular organelles, which is an evolving field of interest. Here, I review recent advances in the alcohol-induced ER stress response as well as discuss new concepts on alcohol-induced mitochondrial, Golgi and lysosomal stress responses and injuries. PMID- 26047035 TI - The Evolutionary History of R2R3-MYB Proteins Across 50 Eukaryotes: New Insights Into Subfamily Classification and Expansion. AB - R2R3-MYB proteins (2R-MYBs) are one of the main transcription factor families in higher plants. Since the evolutionary history of this gene family across the eukaryotic kingdom remains unknown, we performed a comparative analysis of 2R MYBs from 50 major eukaryotic lineages, with particular emphasis on land plants. A total of 1548 candidates were identified among diverse taxonomic groups, which allowed for an updated classification of 73 highly conserved subfamilies, including many newly identified subfamilies. Our results revealed that the protein architectures, intron patterns, and sequence characteristics were remarkably conserved in each subfamily. At least four subfamilies were derived from early land plants, 10 evolved from spermatophytes, and 19 from angiosperms, demonstrating the diversity and preferential expansion of this gene family in land plants. Moreover, we determined that their remarkable expansion was mainly attributed to whole genome and segmental duplication, where duplicates were preferentially retained within certain subfamilies that shared three homologous intron patterns (a, b, and c) even though up to 12 types of patterns existed. Through our integrated distributions, sequence characteristics, and phylogenetic tree analyses, we confirm that 2R-MYBs are old and postulate that 3R-MYBs may be evolutionarily derived from 2R-MYBs via intragenic domain duplication. PMID- 26047036 TI - Emission-based estimation of lung attenuation coefficients for attenuation correction in time-of-flight PET/MR. AB - In standard segmentation-based MRI-guided attenuation correction (MRAC) of PET data on hybrid PET/MRI systems, the inter/intra-patient variability of linear attenuation coefficients (LACs) is ignored owing to the assignment of a constant LAC to each tissue class. This can lead to PET quantification errors, especially in the lung regions. In this work, we aim to derive continuous and patient specific lung LACs from time-of-flight (TOF) PET emission data using the maximum likelihood reconstruction of activity and attenuation (MLAA) algorithm. The MLAA algorithm was constrained for estimation of lung LACs only in the standard 4 class MR attenuation map using Gaussian lung tissue preference and Markov random field smoothness priors. MRAC maps were derived from segmentation of CT images of 19 TOF-PET/CT clinical studies into background air, lung, soft tissue and fat tissue classes, followed by assignment of predefined LACs of 0, 0.0224, 0.0864 and 0.0975 cm(-1), respectively. The lung LACs of the resulting attenuation maps were then estimated from emission data using the proposed MLAA algorithm. PET quantification accuracy of MRAC and MLAA methods was evaluated against the reference CT-based AC method in the lungs, lesions located in/near the lungs and neighbouring tissues. The results show that the proposed MLAA algorithm is capable of retrieving lung density gradients and compensate fairly for respiratory-phase mismatch between PET and corresponding attenuation maps. It was found that the mean of the estimated lung LACs generally follow the trend of the reference CT-based attenuation correction (CTAC) method. Quantitative analysis revealed that the MRAC method resulted in average relative errors of -5.2 +/- 7.1% and -6.1 +/- 6.7% in the lungs and lesions, respectively. These were reduced by the MLAA algorithm to -0.8 +/- 6.3% and -3.3 +/- 4.7%, respectively. In conclusion, we demonstrated the potential and capability of emission-based methods in deriving patient-specific lung LACs to improve the accuracy of attenuation correction in TOF PET/MR imaging, thus paving the way for their adaptation in the clinic. PMID- 26047037 TI - alpha-Hydroxy and alpha-Oxo Selenoamides: Synthesis via Nucleophilic Selenocarbamoylation of Carbonyl Compounds and Characterization. AB - Carbonyl compounds were added to selenocarbamoyllithiums to generate alpha hydroxy and alpha-oxo selenoamides. Their conformations were determined by X-ray analyses. These compounds adopted conformations that were almost identical to those of ordinary amides. Unlike the consistency of the chemical shifts of the C?Se groups of the selenoamides in (13)C NMR spectra and the (1)J coupling constants of the C?Se groups, the substituents far from the selenium atom influenced the chemical shifts in (77)Se NMR. PMID- 26047038 TI - Dynamics of the serologic response in vaccinated and unvaccinated mumps cases during an epidemic. AB - In the last decade, several mumps outbreaks were reported in various countries despite high vaccination coverage. In most cases, young adults were affected who have acquired immunity against mumps solely by vaccination and not by previous wild-type mumps virus infection. To investigate mumps-specific antibody levels, functionality and dynamics during a mumps epidemic, blood samples were obtained longitudinally from 23 clinical mumps cases, with or without a prior history of vaccination, and from 20 healthy persons with no serological evidence of recent mumps virus infection. Blood samples from mumps cases were taken 1-2 months and 7 10 months after onset of disease. Both vaccinated and unvaccinated mumps cases had significantly higher geomean concentrations of mumps-specific IgG (resp. 13,617 RU/ml (95% CI of 9,574-19,367 RU/ml) vs. 1,552 (445-5412) RU/ml at 1-2 months; and 6,514 (5,247-8,088) RU/ml vs. 1,143 (480-2,725) RU/ml at 7-10 months) than healthy controls (169 (135-210) RU/ml) (p = 0.001). Patterns in virus neutralizing (VN) antibody responses against the mumps vaccine virus were similar, vaccinated and unvaccinated mumps cases had significantly higher ND50 values at both time points of sampling (resp 4,695 (3,779-5,832) RU/ml vs. 1,533 (832-2,825) RU/ml at 1-2 months; 2,478 (1,968-3,122) RU/ml vs. 1,221 (1,029 1,449) RU/ml at 7-10 months) compared with (previously vaccinated) healthy controls (122 (196-76)) RU/ml) (p = 0.001) The unvaccinated mumps cases had significantly lower mumps-specific IgG and VN antibody concentrations at both sampling points compared with previously vaccinated cases, but their antibody concentrations did not differ significantly at the 2 time points. In contrast, the mumps-specific IgG and VN antibody concentrations of the previously vaccinated mumps cases were significantly higher within the first 2 months after onset of mumps and declined thereafter, characteristic for a secondary response. A moderate correlation was found between the level of mumps-specific IgG serum antibodies and VN antibodies for the mumps cases (r = 0.64; p<0.001). PMID- 26047039 TI - Computational modelling of mobile bearing TKA anterior-posterior dislocation. AB - Anterior-posterior stability in an unconstrained mobile-bearing total knee arthroplasty (TKA) and one with rotational constraints is compared in a computational model based on an ASTM test. Both TKA designs dislocate at loads greater than reported maximum in vivo forces. The posterior drawer forces (mean: 3027 N vs. 1817 N) needed to induce subluxation increase with a greater anterior jump distance (12 mm vs. 7 mm; refers to the vertical height of the anterior or posterior border of the tibial insert's articulating surface). The posterior jump distance for both tested TKA differed by 1.5 mm and had minimal effect on the magnitude of the anterior drawer forces at dislocation in mid-flexion (unconstrained vs. constrained: 445 N vs. 412 N). The unconstrained insert dislocated by means of spin-out whereas in the constrained TKA the femur dislocated from the bearing during posterior drawer and the bearing from the baseplate during anterior drawer. MCL function is an important consideration during ligament balancing since a +/- 10% variation in MCL tension affects dislocation forces by +/- 20%. The simulation platform provided the means to investigate TKA designs in terms of anterior-posterior stability as a function of knee flexion, collateral ligament function and mechanical morphology. PMID- 26047040 TI - Imaging Glaucomatous Damage Across the Temporal Raphe. AB - PURPOSE: To image and analyze anatomical differences at the temporal raphe between normal and glaucomatous eyes using adaptive optics scanning laser ophthalmoscopy (AOSLO) and optical coherence tomography (OCT), and to relate these differences to visual field measurements. METHODS: Nine glaucomatous eyes of 9 patients (age 54-78 years, mean deviation of visual field [MD] -5.03 to 0.20 dB) and 10 normal eyes of 10 controls (age 54-81, MD -1.13 to +1.39 dB) were enrolled. All the participants were imaged in a region that was centered approximately 9 degrees temporal to the fovea. The size of imaging region was at least 10 degrees vertically by 4 degrees horizontally. The raphe gap, defined as the distance between the superior and inferior retinal nerve fiber layer (RNFL) bundles, was measured. A bundle index was computed to quantify the relative reflectivity and density of the nerve fiber bundles. We also measured thickness of the ganglion cell complex (GCC) and RNFL. RESULTS: The raphe gap was larger in glaucomatous eyes than control eyes. Specifically, eight glaucomatous eyes with local averaged field loss no worse than -3.5 dB had larger raphe gaps than all control eyes. The bundle index, GCC thickness, and RNFL thickness were on average reduced in glaucomatous eyes, with the first two showing statistically significant differences between the two groups. CONCLUSIONS: Structural changes in the temporal raphe were observed and quantified even when local functional loss was mild. These techniques open the possibility of using the raphe as a site for glaucoma research and clinical assessment. PMID- 26047042 TI - Changes in Matrix Metalloproteinases in Diabetes Patients' Tears After Vitrectomy and the Relationship With Corneal Epithelial Disorder. AB - PURPOSE: Previous studies indicate involvement of matrix metalloproteinases (MMPs) in the pathogenesis of diabetic keratopathy. To evaluate MMP levels in the tears of patients with diabetes, we investigated changes in MMP levels during perioperative periods and clarify the relationship with corneal epithelial disorders following vitrectomy. METHODS: Matrix metalloproteinase levels in tears were measured by multiplex bead array in patients with or without diabetes who were scheduled for vitrectomy. Twenty-two patients with diabetes and proliferative diabetic retinopathy, and 20 patients with epiretinal membrane or macular hole (control group), were recruited. Changes in MMP levels during perioperative periods and the relationship with corneal epithelial disorders after vitrectomy were analyzed. RESULTS: The levels of MMP-2, -9, and -10 at 1 day after surgery in the diabetic group were significantly higher than in the control group. At 1 week after surgery, MMP-10 levels in the diabetic group were significantly higher than in the control group. After vitrectomy, corneal epithelial disorders occurred in six patients in the diabetic group but not in the control group. In the diabetic group, MMP-10 levels in tears of patients with corneal epithelial disorders were significantly higher than those in patients without corneal epithelial disorders. CONCLUSIONS: The MMP concentration in tears of patients with diabetes was higher than in nondiabetic patients after vitrectomy. High MMP-10 levels were observed in patients with diabetes and corneal epithelial disorders after vitrectomy. Aberrant levels of MMP-10 may cause corneal epithelial disorder after vitrectomy. PMID- 26047043 TI - Standard Automated Perimetry: Determining Spatial Summation and Its Effect on Contrast Sensitivity Across the Visual Field. AB - PURPOSE: To establish Ricco's critical area (Ac) using the 30-2 Humphrey visual field analyzer (HVFA) and thereby identify Goldmann test sizes that are within or outside complete spatial summation at all visual field testing locations. We also determined the suitability of using age normative data for different test sizes. Finally, by modifying current output measures (dB values), we provide a new method that allows comparison of contrast sensitivity when testing with different Goldmann test sizes within complete spatial summation. METHODS: We used the HVFA in full threshold mode and measured thresholds for all five Goldmann test sizes in 12 observers. Normative data of Heijl et al. were used for age transformation and comparison. RESULTS: All the data converted to a 50-year-old equivalent lie within 1 SD of expected variance for all test locations of the 30-2 paradigm. We established Ac values at all locations of the 30-2 paradigm and showed a systematic increase in Ac as a function of increased visual field eccentricity, consistent with previous studies. Age does not appear to affect Ac or the slope of partial summation for a wide range of visual field eccentricities tested using the HVFA. By equating spatial summation, we propose a new metric, dB*, that returns a uniform sensitivity value for different test sizes that are operating within complete spatial summation (i.e., follow Ricco's law). CONCLUSIONS: We established that converting to age-equivalent thresholds and application of dB* principle advantageously allows comparison of data sets across age and test size at different locations of the visual field. By identifying the Ac across the visual field, it is now possible to systematically determine threshold changes across the 30-2 locations in ocular disease and further characterize the importance of testing within complete spatial summation in standard automated perimetry. PMID- 26047041 TI - Spatiotemporally Regulated Ablation of Klf4 in Adult Mouse Corneal Epithelial Cells Results in Altered Epithelial Cell Identity and Disrupted Homeostasis. AB - PURPOSE: In previous studies, conditional disruption of Klf4 in the developing mouse ocular surface from embryonic day 10 resulted in corneal epithelial fragility, stromal edema, and loss of conjunctival goblet cells, revealing the importance of Klf4 in ocular surface maturation. Here, we use spatiotemporally regulated ablation of Klf4 to investigate its functions in maintenance of adult corneal epithelial homeostasis. METHODS: Expression of Cre was induced in ternary transgenic (Klf4(LoxP/LoxP)/Krt12(rtTA/rtTA)/Tet-O-Cre) mouse corneal epithelium by doxycycline administered through intraperitoneal injections and drinking water, to generate corneal epithelium-specific deletion of Klf4 (Klf4(Delta/DeltaCE)). Corneal epithelial barrier function was tested by fluorescein staining. Expression of selected Klf4-target genes was determined by quantitative PCR (QPCR), immunoblotting, and immunofluorescent staining. RESULTS: Klf4 was efficiently ablated within 5 days of doxycycline administration in adult Klf4(Delta/DeltaCE) corneal epithelium. The Klf4(Delta/DeltaCE) corneal epithelial barrier function was disrupted, and the basal cells were swollen and rounded after 15 days of doxycycline treatment. Increased numbers of cell layers and Ki67-positive proliferating cells suggested deregulated Klf4(Delta/DeltaCE) corneal epithelial homeostasis. Expression of tight junction proteins ZO-1 and occludin, desmosomal Dsg and Dsp, basement membrane laminin-332, and corneal epithelial-specific keratin-12 was decreased, while that of matrix metalloproteinase Mmp9 and noncorneal keratin-17 increased, suggesting altered Klf4(Delta/DeltaCE) corneal epithelial cell identity. CONCLUSIONS: Ablation of Klf4 in the adult mouse corneas resulted in the absence of characteristic corneal epithelial cell differentiation, disrupted barrier function, and squamous metaplasia, revealing that Klf4 is essential for maintenance of the adult corneal epithelial cell identity and homeostasis. PMID- 26047044 TI - Paraxial Schematic Eye Models for 7- and 14-Year-Old Chinese Children. AB - PURPOSE: To develop three-surface paraxial schematic eyes with different ages and sexes based on data for 7- and 14-year-old Chinese children from the Anyang Childhood Eye Study. METHODS: Six sets of paraxial schematic eyes, including 7 year-old eyes, 7-year-old male eyes, 7-year-old female eyes, 14-year-old eyes, 14 year-old male eyes, and 14-year-old female eyes, were developed. Both refraction dependent and emmetropic eye models were developed, with the former using linear dependence of ocular parameters on refraction. RESULTS: A total of 2059 grade 1 children (boys 58%) and 1536 grade 8 children (boys 49%) were included, with mean age of 7.1 +/- 0.4 and 13.7 +/- 0.5 years, respectively. Changes in these schematic eyes with aging are increased anterior chamber depth, decreased lens thickness, increased vitreous chamber depth, increased axial length, and decreased lens equivalent power. Male schematic eyes have deeper anterior chamber depth, longer vitreous chamber depth, longer axial length, and lower lens equivalent power than female schematic eyes. Changes in the schematic eyes with positive increase in refraction are decreased anterior chamber depth, increased lens thickness, decreased vitreous chamber depth, decreased axial length, increased corneal radius of curvature, and increased lens power. In general, the emmetropic schematic eyes have biometric parameters similar to those arising from regression fits for the refraction-dependent schematic eyes. CONCLUSIONS: The paraxial schematic eyes of Chinese children may be useful for myopia research and for facilitating comparison with other children with the same or different racial backgrounds and living in different places. PMID- 26047045 TI - Correlation Between Multimodal Microscopy, Tissue Morphology, and Enzymatic Resistance in Riboflavin-UVA Cross-Linked Human Corneas. AB - PURPOSE: To explore the utility of multimodal microscopy as a noninvasive tool to assess corneal collagen cross-linking (CXL) efficacy, we investigated the correlation between riboflavin (RF) axial profile, second harmonic generation (SHG) imaging, and histological/biochemical changes of human corneas after RF ultraviolet A (UVA)-catalyzed CXL. METHODS: De-epithelialized human corneoscleral tissues were imaged by confocal and multiphoton microscopy to study RF tissue diffusion profile and SHG-based roughness index (Rq) after CXL. We installed 0.1% RF for 5, 10, and 20 minutes, respectively, followed by UVA irradiation, while dextran drug vehicle-treated corneas served as controls. Masson's trichrome staining and collagenase digestion assay were employed to assess ultrastructural modifications of collagen lamellae and bioenzymatic strength following RF-UVA CXL. RESULTS: Stromal absorption of RF was significantly higher in 20 minutes compared with 5- and 10-minute drug instillations. The roughness index of SHG images was reduced after RF-UVA CXL at all RF instillation time points compared with dextran controls. Interestingly, correlation between axial profiles of RF dosage and Rq index was only observed in 10- and 20-minute RF instillations (R(2) = 0.13 and 0.28, respectively, all P < 0.05), but not in the 5-minute group. Masson's trichrome staining revealed collagen fibril compaction in cross-linked corneas in an RF dose-dependent manner. Collagenase digestion assay showed significantly increased biochemical strength by higher RF doses in cross-linked corneas. CONCLUSIONS: Intrastromal RF distribution profiles correlated with histological and functional property changes in RF-UVA cross-linked corneas. A riboflavin-defined threshold further determined the sensitivity of SHG imaging as a noninvasive imaging modality to assess the efficacy of RF-UVA CXL. PMID- 26047046 TI - The Role of LOX-1 in Innate Immunity to Aspergillus fumigatus in Corneal Epithelial Cells. AB - PURPOSE: To determine the role of lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) in corneal epithelial cells exposed to fungus. METHODS: Thirteen corneas with fungal keratitis composed the experimental group. Ten healthy donor corneas were the control group. Corneal epithelium was scraped and LOX-1 mRNA tested. Immunostaining was used to detect LOX-1 protein. Human corneal epithelial cells (HCECs) were treated with 75% ethanol-killed Aspergillus fumigatus. LOX-1 was detected, and CXCL1, TNF-alpha, IL-6, and dectin-1 levels were detected with or without neutralization of LOX-1. Rat fungal keratitis was established and LOX-1 was detected by PCR, immunostaining, and Western blot. Phosphorylated-p38MAPK (p-p38MAPK) protein; CXCL1, TNF-alpha, and IL-6 mRNA levels; and myeloperoxidase (MPO) were tested before and after LOX-1 neutralization. RESULTS: LOX-1 was expressed in corneal epithelium. In vitro cellular experiment showed that LOX-1 was detected in normal HCECs, and LOX-1 mRNA increased after stimulation of A. fumigatus and peaked at 8 hours; LOX-1 protein expression increased after stimulation at 24 and 48 hours. Neutralization of LOX-1 decreased expression of CXCL1, TNF-alpha, but did not change IL-6 or dectin-1 expression. Aspergillus fumigatus keratitis developed in rats activated p38MAPK and elevated the expression of CXCL1, TNF-alpha, and IL-6 through LOX-1. LOX-1 neutralization reduced MPO levels. CONCLUSIONS: LOX-1 expressed in normal corneal epithelium and HCECs and A. fumigatus elevated the expression of CXCL1 and TNF-alpha through LOX-1. Rat A. fumigatus keratitis activated p38MAPK and elevated the expression of CXCL1, TNF-alpha, and IL-6 through LOX-1. PMID- 26047047 TI - A Global Shape Index to Characterize Anterior Lamina Cribrosa Morphology and Its Determinants in Healthy Indian Eyes. AB - PURPOSE: Lamina cribrosa (LC) morphology could be implicated in the progression of glaucoma. To date, no established, quantifiable parameter to assess LC shape in vivo exists. We aim to introduce a new global shape index for the anterior LC (LC-GSI) and to identify associations with ocular factors in a healthy Indian population. METHODS: Optical coherence tomography (OCT) scans of the optic nerve head (ONH) were performed on 162 healthy subjects. Optic nerve head structures were delineated and a geometric characterization of anterior LC morphology was obtained by measuring curvature along 180 LC cross sections and representing it as LC-GSI ranging from -1 to +1. Lamina cribrosa depth and curvature were also reported. Linear regression was used to identify factors associated with LC morphology. RESULTS: The typical healthy LC had a saddle rut-like appearance, with a central ridge visible in superior-inferior cross sections. A more prominent central ridge (larger LC-GSI) was associated with shorter axial length (P < 0.001), smaller Bruch's membrane opening (BMO) area (P = 0.020), smaller vertical cup-to-disc ratio (VCDR) (P = 0.007), and larger minimum rim width (BMO MRW) (P = 0.001). A deeper LC was associated with male sex (P < 0.001), shorter axial length (P = 0.003), larger VCDR (P < 0.001), and smaller BMO-MRW (P = 0.002). Age and IOP were not significantly associated with LC morphology in healthy eyes. CONCLUSIONS: The LC-GSI is a single index that quantifies overall LC shape in an intuitive way. Ocular determinants of LC-GSI in healthy eyes included risk factors for glaucoma (axial length, VCDR, and BMO-MRW), highlighting the potential role of LC morphological characterization in the diagnosis and monitoring of glaucoma. PMID- 26047048 TI - Clinical and Echographic Features of Retinochoroidal and Optic Nerve Colobomas. AB - PURPOSE: We reported the clinical and echographic features of colobomas, prevalence of retinal detachment, and associated visual acuity in these patients. METHODS: The study is a nonrandomized consecutive case series of 140 colobomatous eyes in 98 patients (age range, 0-83 years). Coloboma depth, width, volume, and relative coloboma excavation (coloboma depth/axial length) were measured using standardized echographic images. The presence of structural and other ocular abnormalities was noted. The clinical and echographic findings present were correlated with visual acuity of the patient. In addition, these features were correlated with the presence or absence of retinal detachment. RESULTS: Increased relative coloboma excavation was significantly associated with an increased risk of retinal detachment. A relative coloboma excavation (ratio of coloboma depth to axial length) greater than 0.15 was associated with an increased risk of retinal detachment (52%), compared to those with a relative coloboma excavation less than 0.15 (23%, P = 0.014). The presence of any structural abnormality and the presence of a retrobulbar cyst were associated with increased risk of retinal detachment and severe visual impairment (worse than 20/200). Increased coloboma depth, width, volume, and relative coloboma excavation were not associated with increased risk of severe visual impairment. CONCLUSIONS: Clinical and echographic features of colobomas may be used in predicting the risk of retinal detachment. Measuring relative coloboma excavation upon presentation may alter follow-up and assist in the diagnosis of retinal detachment. PMID- 26047049 TI - Real-Time Monitoring of Suprachoroidal Space (SCS) Following SCS Injection Using Ultra-High Resolution Optical Coherence Tomography in Guinea Pig Eyes. AB - PURPOSE: To monitor the change of suprachoroidal space (SCS) using ultra high resolution-optical coherence tomography (UHR-OCT) following SCS injection with different drug formulations. METHODS: An amount of 10 or 20 MUL of saline or indocyanine green (ICG) or triamcinolone acetonide (TA) suspension (40 or 80 mg/mL) was injected suprachoroidally into the guinea pig eye with a 30-gauge needle. Immediately after injection, the eyes were imaged by UHR-OCT from 60 minutes up to 24 hours. At each time point, the SCS area on each OCT cross section was measured in pixels with Image J and the area change from the baselines was analyzed over time. RESULTS: A 20-MUL injection produced 130% to 200% SCS expansion compared to a 10-MUL injection for saline and TA suspension (P < 0.01). After SCS injection, the time that expansion persisted was formulation dependent. Thus, expansion in response to injection of TA suspension, ICG, and saline persisted for 24 hours, 180 minutes, and 60 minutes, respectively. Moreover, ICG injection produced a significantly larger area of distribution in the SCS than the TA suspension (0.626 vs. 0.275 cm(2), P < 0.0001). CONCLUSIONS: The SCS is expandable and can recover to preinjection status after injected fluid is cleared by physiological processes. The injection-induced SCS expansion is volume-dependent, and the drug/dye retained in the SCS is formulation-dependent. The current injection technique with a volume of 20 MUL or less is well tolerated in guinea pig eyes. PMID- 26047050 TI - Comprehensive Molecular Diagnosis of a Large Chinese Leber Congenital Amaurosis Cohort. AB - PURPOSE: Leber congenital amaurosis (LCA) is an inherited retinal disease that causes early-onset severe visual impairment. To evaluate the mutation spectrum in the Chinese population, we performed a mutation screen in 145 Chinese LCA families. METHODS: First, we performed direct Sanger sequencing of 7 LCA disease genes in 81 LCA families. Next, we developed a capture panel that enriches the entire coding exons and splicing sites of 163 known retinal disease genes and other candidate retinal disease genes. The capture panel allowed us to quickly identify disease-causing mutations in a large number of genes at a relatively low cost. Thus, this method was applied to the 53 LCA families that were unsolved by direct Sanger sequencing of 7 LCA disease genes and an additional 64 LCA families. Systematic next-generation sequencing (NGS) data analysis, Sanger sequencing validation, and segregation analysis were used to identify pathogenic mutations. RESULTS: Homozygous or compound heterozygous mutations were identified in 107 families, heterozygous autosomal dominant mutations were identified in 3 families and an X-linked mutation was found in 1 family, for a combined solving rate of 76.6%. In total, 136 novel pathogenic mutations were found in this study. In combination with two previous studies carried out in Chinese LCA patients, we concluded that the mutation spectrum in the Chinese population is distinct compared to that in the European population. After revisiting, we also refined the clinical diagnosis of 10 families based on their molecular diagnosis. CONCLUSIONS: Our results highlight the importance of a molecular diagnosis as an integral part of the clinical diagnostic process. PMID- 26047052 TI - Erratum to "the multiscale importance of road segments in a network disruption scenario: a risk-based approach" by Susana Freiria, Alexandre O. Tavares and Rui Pedro Juliao, in Risk Analysis, 35(3): 484-500. PMID- 26047051 TI - In vivo quantification of cochlin in glaucomatous DBA/2J mice using optical coherence tomography. AB - The expression of cochlin in the trabecular meshwork (TM) precedes the clinical glaucoma symptoms in DBA/2J mice. The ability to quantify cochlin in the local tissue (TM) offers potential diagnostic and prognostic values. We present two (spectroscopic and magnetomotive) optical coherence tomography (OCT) approaches for in vivo cochlin quantification in a periodic manner. The cochlin-antibody OCT signal remains stable for up to 24 hours as seen at 3.5 hours after injection allowing for repeated quantification in the living mouse eyes. PMID- 26047053 TI - Demonstration of quantum permutation algorithm with a single photon ququart. AB - We report an experiment to demonstrate a quantum permutation determining algorithm with linear optical system. By employing photon's polarization and spatial mode, we realize the quantum ququart states and all the essential permutation transformations. The quantum permutation determining algorithm displays the speedup of quantum algorithm by determining the parity of the permutation in only one step of evaluation compared with two for classical algorithm. This experiment is accomplished in single photon level and the method exhibits universality in high-dimensional quantum computation. PMID- 26047054 TI - Validation of Polytomella piriformis nomen nudum (Chlamydomonadaceae): a Distinct Lineage Within a Genus of Nonphotosynthetic Green Algae. AB - Polytomella strain SAG 63-10 was first described by Pringsheim (1963) as Polytomella piriformis nomen nudum. The current study validates the name Polytomella piriformis following the International Code of Nomenclature for algae, fungi, and plants (ICN). We present 18S rRNA sequences of SAG 63-10 and several other Polytomella strains, which, along with existing mitochondrial DNA sequences, clearly distinguishes P. piriformis n. sp. from other available Polytomella species. The first type material of the species is presented, as well as an illustration and micrographs. Our own observations of P. piriformis SAG 63 10 are compared to Pringsheim's description and to descriptions of other valid Polytomella spp. PMID- 26047055 TI - Gelsolin Familial Amyloidosis Peripheral Neuropathy in Canada: A Case Report. PMID- 26047056 TI - Q-Speciation and Network Structure Evolution in Invert Calcium Silicate Glasses. AB - Binary silicate glasses in the system CaO-SiO2 are synthesized over an extended composition range (42 mol % <= CaO <= 61 mol %), using container-less aerodynamic levitation techniques and CO2-laser heating. The compositional evolution of Q speciation in these glasses is quantified using (29)Si and (17)O magic angle spinning nuclear magnetic resonance spectroscopy. The results indicate progressive depolymerization of the silicate network upon addition of CaO and significant deviation of the Q speciation from the binary model. The equilibrium constants for the various Q species disproportionation reactions for these glasses are found to be similar to (much smaller than) those characteristic of Li (Mg)-silicate glasses, consistent with the corresponding trends in the field strengths of these modifier cations. Increasing CaO concentration results in an increase in the packing density and structural rigidity of these glasses and consequently in their glass transition temperature Tg. This apparent role reversal of conventional network-modifying cations in invert alkaline-earth silicate glasses are compared and contrasted with that in their alkali silicate counterparts. PMID- 26047058 TI - Correction. PMID- 26047057 TI - Fabrication of Large-Area Hierarchical Structure Array Using Siliconized Silsesquioxane as a Nanoscale Etching Barrier. AB - A material approach to fabricate a large-area hierarchical structure array is presented. The replica molding and oxygen (O2) plasma etching processes were combined to fabricate a large-area hierarchical structure array. Liquid blends consisting of siliconized silsesquioxane acrylate (Si-SSQA), ethylene glycol dimethacrylate (EGDMA), and photoinitiator are developed as a roughness amplifying material during O2 plasma etching. Microstructures composed of the Si SSQA/EGDMA mixtures are fabricated by replica molding. Nanoscale roughness on molded microstructures is realized by O2 etching. The nanoscale roughness on microstructures is efficiently controlled by varying the etching time and the weight ratio of Si-SSQA to EGDMA. The hierarchical structures fabricated by combining replica molding and O2 plasma etching showed superhydrophilicity with long-term stability, resulting in the formation of hydroxyl-terminated silicon oxide layer with the reorientation limit. On the other hand, the hierarchical structures modified with a perfluorinated monolayer showed superhydrophobicity. The increment of water contact angles is consistent with increment of the nano/microroughness of hierarchical structures and decrement of the top contact area of water/hierarchical structures. PMID- 26047059 TI - A randomized controlled trial of attention modification for social anxiety disorder. AB - Social Anxiety Disorder (SAD) models implicate social threat cue vigilance (i.e., attentional biases) in symptom development and maintenance. A modified dot-probe protocol has been shown to reduce SAD symptoms, in some but not all studies, presumably by modifying an attentional bias. The current randomized controlled trial was designed to replicate and extend such research. Participants included treatment-seeking adults (n = 108; 58% women) who met diagnostic criteria for SAD. Participants were randomly assigned to a standard (i.e., control) or modified (i.e., active) dot-probe protocol condition and to participate in-lab or at home. The protocol involved twice-weekly 15-min sessions, for 4 weeks, with questionnaires completed at baseline, post-treatment, 4-month follow-up, and 8 month follow-up. Symptom reports were assessed with repeated measures mixed hierarchical modeling. There was a main effect of time from baseline to post treatment wherein social anxiety symptoms declined significantly (p < .05) but depression and trait anxiety did not (p > .05). There were no significant interactions based on condition or participation location (ps > .05). Reductions were maintained at 8-month follow-up. Symptom reductions were not correlated with threat biases as indexed by the dot-probe task. The modified and standard protocol both produced significant sustained symptom reductions, whether administered in-lab or at home. There were no robust differences based on protocol type. As such, the mechanisms for benefits associated with modified dot probe protocols warrant additional research. PMID- 26047060 TI - Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature. AB - Interdigitating dendritic cell sarcoma is an extremely rare tumor. The diagnosis is difficult and is based on clinical, pathological and immunohistochemical evaluation. Differential diagnosis includes melanoma, mesenchymal and hematological malignancies. The mainstay of treatment is surgery for limited disease and different chemotherapy combinations have been tested for advanced disease. No evidence from prospective trials is currently available. We report the case of a 59 year-old male patient who experienced axillary lymphadenopathy with initial diagnosis of large-cell lung cancer on tumor biopsy. He underwent surgical resection with radical intent. Pathological diagnosis of interdigitating dendritic cell sarcoma was obtained on surgical samples. Nine months after radical surgery, he experienced systemic recurrence of disease and underwent chemotherapy with epirubicin and ifosfamide for 4 courses. During chemotherapy, he developed brain disease progression and underwent whole-brain radiotherapy. Systemic progression was then observed and molecular characterization was performed. B-RAF evaluation resulted positive for V600E mutation and the patient was treated with Vemurafenib according to molecular findings. He thus obtained initial clinical benefit but eventually died of brain hemorrhage. In conclusion, we report a case of B-RAF mutation detected in an interdigitating dendritic cell sarcoma patient treated with targeted therapy. B-RAF pathway could have a role in pathogenesis and evolution of this rare disease and could open new perspectives of treatment. PMID- 26047062 TI - Disseminated tuberculosis mimicking metastatic colon cancer in a hemodialysis patient. PMID- 26047061 TI - Motor units in the human medial gastrocnemius muscle are not spatially localized or functionally grouped. AB - KEY POINTS: Human medial gastrocnemius (MG) motor units (MUs) are thought to occupy small muscle territories or regions, with low-threshold units preferentially located distally. We used intramuscular recordings to measure the territory of muscle fibres from MG MUs and determine whether these MUs are grouped by recruitment threshold or joint action (ankle plantar flexion and knee flexion). The territory of MUs from the MG muscle varied from somewhat localized to highly distributed, with approximately half the MUs spanning at least half the length and width of the muscle. There was also no evidence of regional muscle activity based on MU recruitment thresholds or joint action. The CNS does not have the means to selectively activate regions of the MG muscle based on task requirements. ABSTRACT: Human medial gastrocnemius (MG) motor units (MUs) are thought to occupy small muscle territories, with low-threshold units preferentially located distally. In this study, subjects (n = 8) performed ramped and sustained isometric contractions (ankle plantar flexion and knee flexion; range: ~1-40% maximal voluntary contraction) and we measured MU territory size with spike-triggered averages from fine-wire electrodes inserted along the length (seven electrodes) or across the width (five electrodes) of the MG muscle. Of 69 MUs identified along the length of the muscle, 32 spanned at least half the muscle length (>= 6.9 cm), 11 of which spanned all recording sites (13.6-17.9 cm). Distal fibres had smaller pennation angles (P < 0.05), which were accompanied by larger territories in MUs with fibres located distally (P < 0.05). There was no distal-to-proximal pattern of muscle activation in ramp contraction (P = 0.93). Of 36 MUs identified across the width of the muscle, 24 spanned at least half the muscle width (>= 4.0 cm), 13 of which spanned all recording sites (8.0-10.8 cm). MUs were not localized (length or width) based on recruitment threshold or contraction type, nor was there a relationship between MU territory size and recruitment threshold (Spearman's rho = -0.20 and 0.13, P > 0.18). MUs in the human MG have larger territories than previously reported and are not localized based on recruitment threshold or joint action. This indicates that the CNS does not have the means to selectively activate regions of the MG muscle based on task requirements. PMID- 26047063 TI - 2-Oxo Driven Unconventional reactions: Microwave Assisted Approaches to Tetrahydrofuro[3,2-d]oxazoles and Furanones. AB - A highly efficient, novel, microwave-assisted, metal-free, diastereoselective synthesis of tetrahydrofuro[3,2-d]oxazole is disclosed. The synthesis of napthoxazoles is achieved for the first time without the aid of an external catalyst. On the contrary, our reactions generated naphthofuranones when treated in the presence of metals in microwave/thermal conditions. The unusual behavior of our reactions has further been explored in the generation of furanones from tetrahydrofuro[3,2-d]oxazole through the use of metals. PMID- 26047064 TI - Low-concentration vemurafenib induces the proliferation and invasion of human HaCaT keratinocytes through mitogen-activated protein kinase pathway activation. AB - Cutaneous squamous cell carcinomas and keratoacanthomas commonly occur in patients treated with BRAF inhibitors. We investigated the effect of the BRAF inhibitor vemurafenib on normal immortalized human HaCaT keratinocytes to explore the mechanism of hyperproliferative cutaneous neoplasia associated with the use of BRAF inhibitors. Vemurafenib induced an increase in viable cell number in BRAF wild-type cell lines (SK-MEL-2 and HaCaT) but not in BRAF mutant cell lines (SK MEL-24 and G361). In HaCaT keratinocytes, a low concentration (2 MUmol/L) of vemurafenib increased cell proliferation and activated mitogen-activated protein kinase kinase/extracellular signal-regulated kinase in a CRAF-dependent manner. Invasiveness of HaCaT cells in a Matrigel assay significantly increased upon cultivation of cells with 2 MUmol/L vemurafenib for 24 h. Gelatin zymography, reverse transcription polymerase chain reaction and western blot results revealed that 2 MUmol/L vemurafenib treatment increased matrix metalloproteinase (MMP)-2 and MMP-9 expressions and activities in HaCaT cells. These results offer additional insight into the complex mechanism of paradoxical mitogen-activated protein kinase signaling involved in hyperproliferative cutaneous neoplasias that arise after BRAF inhibition and suggest a possible role for MMP in tumor progression and invasion. PMID- 26047065 TI - Focal epithelial hyperplasia by human papillomavirus (HPV)-32 misdiagnosed as HPV 16 and treated with combination of retinoids, imiquimod and quadrivalent HPV vaccine. AB - Focal epithelial hyperplasia (FEH) or Heck's disease is a rare, benign and asymptomatic mucosal proliferation associated with human papillomavirus (HPV) infection, mainly with genotypes 13 and 32. We report a florid case of FEH in an 11-year-old Haitian girl with systemic lupus erythematosus receiving immunosuppressive therapy. Cryotherapy was previously performed on numerous occasions with no results. We decided to prescribe a non-invasive and more comfortable treatment. A combination of topical retinoid and imiquimod cream was well tolerated and led to an important improvement. The evidence of infection by HPV-16 detected by polymerase chain reaction (PCR) technique, prompted us to prescribe the quadrivalent HPV vaccine (types 6, 11,16 and 18). Subsequent PCR sequencing with generic primers GP5-GP6 and further BLAST comparative analysis confirmed that genomic viral sequence in our case truly corresponded with HPV-32. This molecular misdiagnosis can be explained by the similarity between genomic sequences of both HPV-16 and -32 genotypes. At the 1-year follow up, we observed total clinical improvement and no recurrences of the disease. Complete healing in this case may correspond to a potential action of topical retinoid, imiquimod and the cross-protection mechanism of the quadrivalent HPV vaccine. PMID- 26047066 TI - Body image, BMI, and physical activity in girls and boys aged 14-16 years. AB - The aim of this study was to investigate the relationship between body image, body mass index (BMI), and physical activity in adolescents. The study included 1702 girls and 1547 boys aged 14-16 years. Moderate-to-vigorous physical activity (MVPA) was evaluated by the Physical Activity Screening Measure. Body image was assessed using the Feelings and Attitudes Towards the Body Scale, and participants' BMI was determined based on measured height and weight. Compared to boys, girls reported more negative body image (p<.05). The results of the three way hierarchical regression revealed that body image was a statistically significant positive predictor of MVPA for adolescents, regardless of BMI. Additionally, body image was a stronger predictor of MVPA in boys than in girls. These findings suggest that body image, rather than BMI, is important in undertaking physical activity in adolescents and should be considered when preparing programs aimed at improving physical activity. PMID- 26047067 TI - On the Role of Error in Motor Learning. AB - The authors report 5 experiments that explored the role of error in motor learning. Participants practiced 4 distinct keypress sequences that varied in the amounts of advance information (i.e., choice) about which key to press next in the sequence. The amount of advance information resulted in differing levels of error during practice, which in general, was inversely related to retention performance. Although these findings support a beneficial role of error in motor learning, they also suggest that not all errors are equal in the learning process. Rather, we make a distinction between factors that induce errors that have desirable influences on learning compared to those that have undesirable effects. PMID- 26047068 TI - Music therapy as specific and complementary training for adults after cochlear implantation: A pilot study. AB - OBJECTIVES: Although cochlear implant (CI) users achieve good speech comprehension, they experience difficulty perceiving music and prosody in speech. As the provision of music training in rehabilitation is limited, a novel concept of music therapy for rehabilitation of adult CI users was developed and evaluated in this pilot study. METHODS: Twelve unilaterally implanted, postlingually deafened CI users attended ten sessions of individualized and standardized training. The training started about 6 weeks after the initial activation of the speech processor. Before and after therapy, psychological and musical tests were applied in order to evaluate the effects of music therapy. CI users completed the musical tests in two conditions: bilateral (CI + contralateral, unimplanted ear) and unilateral (CI only). RESULTS: After therapy, improvements were observed in the subjective sound quality (Hearing Implant Sound Quality Index) and the global score on the self-concept questionnaire (Multidimensional Self-Concept Scales) as well as in the musical subtests for melody recognition and for timbre identification in the unilateral condition. Discussion Preliminary results suggest improvements in subjective hearing and music perception, with an additional increase in global self-concept and enhanced daily listening capacities. CONCLUSIONS: The novel concept of individualized music therapy seems to provide an effective treatment option in the rehabilitation of adult CI users. Further investigations are necessary to evaluate effects in the area of prosody perception and to separate therapy effects from general learning effects in CI rehabilitation. PMID- 26047069 TI - Hydrogenated Graphene as a Homoepitaxial Tunnel Barrier for Spin and Charge Transport in Graphene. AB - We demonstrate that hydrogenated graphene performs as a homoepitaxial tunnel barrier on a graphene charge/spin channel. We examine the tunneling behavior through measuring the IV curves and zero bias resistance. We also fabricate hydrogenated graphene/graphene nonlocal spin valves and measure the spin lifetimes using the Hanle effect, with spintronic nonlocal spin valve operation demonstrated up to room temperature. We show that while hydrogenated graphene indeed allows for spin transport in graphene and has many advantages over oxide tunnel barriers, it does not perform as well as similar fluorinated graphene/graphene devices, possibly due to the presence of magnetic moments in the hydrogenated graphene that act as spin scatterers. PMID- 26047070 TI - Expression of expansin genes in the pulp and the dehiscence zone of ripening durian (Durio zibethinus) fruit. AB - Durian (Durio zibethinus) fruit was harvested at the commercially mature stage and stored at 25 degrees C. Durian fruit have 3-5 longitudinal dehiscence zones (DZs) in the peel, which are up to 40cm long and 2cm thick in large fruit. Dehiscence started a week after harvest, was hastened by exogenous ethylene, and delayed by 1-methylcyclopropene (1-MCP), showing that it is regulated by endogenous ethylene. Three genes encoding alpha-expansins (DzEXP1-3) were isolated. In the expression of these genes increased, prior to dehiscence. Pulp firmness decreased during storage. The decrease was hastened by ethylene and delayed by 1-methylcyclopropene (1-MCP). Exogenous ethylene promoted gene expression of DzEXP1 both in the DZs and in the pulp. It had a smaller effect on DzEXP2 in the zones and pulp, but did not affect DzEXP3 expression. 1-MCP inhibited the expression of DzEXP1 and, somewhat less, of DzEXP2, but did not affect DzEXP3 expression, both in DZs and pulp. It is concluded that the close relationship between expression of DzEXP1 and DzEXP2 and both dehiscence and fruit softening suggests that these genes are involved in both processes. PMID- 26047071 TI - Effect of short-term cadmium stress on Populus nigra L. detached leaves. AB - Pollution by toxic metals, accumulating into soils as result of human activities, is a worldwide major concern in industrial countries. Plants exhibit different degrees of tolerance to heavy metals, as a consequence of their ability to exclude or accumulate them in particular tissues, organs or sub-cellular compartments. Molecular information about cellular processes affected by heavy metals is still largely incomplete. As a fast-growing, highly tolerant perennial plant species, poplar has become a model for environmental stress response investigations. To study the short-term effects of cadmium accumulation in leaves, we analyzed photosystem II (PSII) quantum yield, hydrogen peroxide (H2O2) generation, hormone levels variation, as well as proteome profile alteration of 50MUM CdSO4 vacuum-infiltrated poplar (Populus nigra L.) detached leaves. Cadmium management brought about an early and sustained production of hydrogen peroxide, an increase of abscisic acid, ethylene and gibberellins content, as well as a decrease in cytokinins and auxin levels, whereas photosynthetic electron transport was unaffected. Proteomic analysis revealed that twenty-one proteins were differentially induced in cadmium-treated leaves. Identification of fifteen polypeptides allowed to ascertain that most of them were involved in stress response while the remaining ones were involved in photosynthetic carbon metabolism and energy production. PMID- 26047073 TI - Autonomic Imbalance as a Predictor of Metabolic Risks, Cardiovascular Disease, Diabetes, and Mortality. AB - CONTEXT: Identifying novel early predictors of metabolic disorders is essential to improving effective primary prevention. OBJECTIVES: The objectives were to examine the contribution of two measures of autonomic imbalance, resting heart rate (RHR) and heart rate variability (HRV), on the development of five metabolic risk outcomes, and on cardiovascular disease, diabetes, and early mortality. DESIGN: This study was a secondary analysis of prospective data from Offspring Cohort participants (N = 1882) in the Framingham Heart Study (FHS). PARTICIPANTS: Participants at FHS Exam 3 (1983-1987) with 1) age years 18 or older, and 2) data on RHR, HRV, and five measures of metabolic risk (blood pressure, fasting glucose, triglycerides, high-density lipoprotein [HDL] cholesterol, and body mass index [BMI]) at three follow-up visits over 12 years. We conducted a backward elimination variable selection procedure on a logistic regression model, using baseline RHR, HRV, age, sex, and smoking status to predict the odds of developing a specific metabolic risk. OUTCOMES: Measures included hyperglycemia, high blood pressure, high triglycerides, low HDL cholesterol, and high BMI over 12 years; incident diabetes, cardiovascular disease, and early mortality over 20 years. RESULTS: RHR and HRV, along with sex, age, and smoking were significant predictors of high blood pressure, hyperglycemia, and a diagnosis of diabetes within 12 years. RHR and HRV also predicted the development of cardiovascular disease and early mortality for most of the sample. CONCLUSIONS: In this community sample two measures of autonomic imbalance predicted multiple poor metabolic outcomes and mortality, making autonomic imbalance a potentially worthy target for intervention studies to reduce risks for cardiovascular disorders, diabetes, and early death. PMID- 26047076 TI - Letter to the Editor: Could Low Phosphate Level Be the Reason for High Risk of Hypertension in Normocalcemic Primary Hyperparathyroidism? PMID- 26047077 TI - Response to Letter by Dolapoglu et al. PMID- 26047078 TI - Letter to the Editor. PMID- 26047079 TI - Response to the Letter by Katiman E., et al. PMID- 26047080 TI - Letter to the Editor: The Endocrine Society Clinical Practice Guidelines on Paget's Disease: Many Recommendations Are Not Evidence Based. PMID- 26047081 TI - Response to letter by Ralston et al. PMID- 26047082 TI - Letter to the Editor: The J-shaped 25-hydroxyvitamin D concentration cardiovascular disease mortality relation is very likely due to starting vitamin D supplementation late in life. PMID- 26047083 TI - Response to the letter by Grant. PMID- 26047084 TI - Letter to the Editor: Re: Neurobehavioral Deficits, Diseases, and Associated Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union. PMID- 26047085 TI - Response to the Letter by Middlebeek and Veuger. PMID- 26047086 TI - I've got a feeling: Urban and rural indigenous children's beliefs about early life mentality. AB - This cross-cultural investigation explored children's reasoning about their mental capacities during the earliest period of human physical existence--the prenatal period. For comparison, children's reasoning about the observable period of infancy was also examined. A total of 283 5- to 12-year-olds from two distinct cultures (urban Ecuador and rural indigenous Shuar) participated. Across cultures, children distinguished the fetal period from infancy, attributing fewer capacities to fetuses. However, for both the infancy and fetal periods, children from both cultures privileged the functioning of emotions and desires over epistemic states (i.e., abilities for thought and memory). Children's justifications to questions about fetal mentality revealed that although epistemic states were generally regarded as requiring physical maturation to function, emotions and desires were seen as functioning as a de facto result of prenatal existence and in response to the prospect of future birth and being part of a social group. These results show that from early in development, children across cultures possess nuanced beliefs about the presence and functioning of mental capacities. Findings converge with recent results to suggest that there is an early arising bias to view emotions and desires as the essential inviolable core of human mentality. The current findings have implications for understanding the role that emerging cognitive biases play in shaping conceptions of human mentality across different cultures. They also speak to the cognitive foundations of moral beliefs about fetal rights. PMID- 26047087 TI - Hepatitis C virus screening to reveal a better picture of infection. AB - Antiviral therapy for hepatitis C virus (HCV) infection will be the next revolution in clinical virology. Sensible planning for treatment is needed, starting with population-screening policies ideally using the HCV core antigen. This will result in a more defined picture of the silent spread of HCV. PMID- 26047089 TI - Measuring Gestational Age in Vital Statistics Data: Transitioning to the Obstetric Estimate. AB - Beginning with the 2014 data year, the National Center for Health Statistics is transitioning to a new standard for estimating the gestational age of a newborn. The new measure, the obstetric estimate of gestation at delivery (OE), replaces the measure based on the date of the last normal menses (LMP). This transition is being made because of increasing evidence of the greater validity of the OE compared with the LMP-based measure. This report describes the relationship between the two measures. Agreement between the two measures is shown for 2013. Comparisons between the two measures for single gestational weeks and selected gestational age categories for 2013, and trends in the two measures for 2007-2013 by gestational category, focusing on preterm births, are shown for the United States and by race and Hispanic origin and state. PMID- 26047088 TI - Paired Serum and Urine Concentrations of Biomarkers of Diethyl Phthalate, Methyl Paraben, and Triclosan in Rats. AB - BACKGROUND: Exposure to environmental chemicals, including phthalates and phenols such as parabens and triclosan, is ubiquitous within the U.S. general population. OBJECTIVE: This proof-of-concept rodent study examined the relationship between oral doses of three widely used personal care product ingredients [diethyl phthalate (DEP), methyl paraben (MPB), and triclosan] and urine and serum concentrations of their respective biomarkers. METHODS: Using female Sprague Dawley rats, we carried out two rounds of experiments with oral gavage doses selected in accordance with no observed adverse effect levels (NOAELs) derived from previous studies: 1,735 (DEP), 1,050 (MPB), 50 (triclosan) mg/kg/day. Administered doses ranged from 0.005 to 173 mg/kg/day, 10-100,000 times below the NOAEL for each chemical. Controls for the MPB and triclosan experiments were animals treated with olive oil (vehicle) only; controls for the DEP serum experiments were animals treated with the lowest doses of MPB and triclosan. Doses were administered for 5 days with five rats in each treatment group. Urine and blood serum, collected on the last day of exposure, were analyzed for biomarkers. Relationships between oral dose and biomarker concentrations were assessed using linear regression. RESULTS: Biomarkers were detected in all control urine samples at parts-per-billion levels, suggesting a low endemic environmental exposure to the three chemicals that could not be controlled even with all of the precautionary measures undertaken. Among the exposed animals, urinary concentrations of all three biomarkers were orders of magnitude higher than those in serum. A consistently positive linear relationship between oral dose and urinary concentration was observed (R2 > 0.80); this relationship was inconsistent in serum. CONCLUSIONS: Our study highlights the importance of carefully considering the oral dose used in animal experiments and provides useful information in selecting doses for future studies. CITATION: Teitelbaum SL, Li Q, Lambertini L, Belpoggi F, Manservisi F, Falcioni L, Bua L, Silva MJ, Ye X, Calafat AM, Chen J. 2016. Paired serum and urine concentrations of biomarkers of diethyl phthalate, methyl paraben, and triclosan in rats. Environ Health Perspect 124:39-45; http://dx.doi.org/10.1289/ehp.1409586. PMID- 26047090 TI - Barriers to administering intravenous tissue plasminogen activator (tPA) for acute ischemic stroke in the emergency department: A cross-sectional survey of stroke centers. AB - OBJECTIVE: The logistics involved in administration of IV tPA for acute ischemic stroke patients are complex, and may contribute to variability in door-to-needle times between different hospitals. We sought to identify practice patterns in stroke centers related to IV tPA use. We hypothesized that there would be significant variability in logistics related to ancillary staff (i.e. nursing, pharmacists) processes in the emergency room setting. METHODS: A 21 question survey was distributed to attendees of the AHA/ASA Southwest Affiliate Stroke Coordinators Conference to evaluate potential barriers and delays with regards to thrombolysis for acute strokes patients in the Emergency Department setting. Answers were anonymous and aggregated to examine trends in responses. RESULTS: Responses were obtained from 37 of 67 (55%) stroke centers, which were located mainly in the Southwest United States. Logistical processes differed between facilities. Nursing and pharmacy carried stroke pagers in only 19% of the centers, and pharmacy responded to stroke alerts only one-third of centers. Insertion of Foley catheters and nasogastric tubes prior to tPA was routine in some of the sites. Other barriers to IV tPA administration included physician reluctance and inadequate communication between health care providers. CONCLUSION: Practices regarding logistics for giving IV tPA may be variable amongst different stroke centers. Given this potential variability, prospective evaluation to confirm these preliminary findings is warranted. PMID- 26047091 TI - The sociospatial diversity in the leisure activities of older people in the Netherlands. AB - Leisure activities afford an important way for old people to continue to take part in society and have a positive effect on personal wellbeing. The types and number of leisure activities in which older people participate are highly diverse. This diversity is associated not only with personal characteristics, but also with those of the environment in which old people live. Using cross sectional data selected in 2002-2003, differences are presented between regions, cities and villages, and between prosperous and deprived neighbourhoods. The characteristics of the region and of the urban or rural environment show a clear relationship wit the intrinsic orientation in leisure. The diversity is smallest among older adults who live in deprived neighbourhoods and among the very old. They take part in fewer activities (contraction), which leads to a more similar activity pattern in and around the home (convergence). PMID- 26047092 TI - Urban elders and casino gambling: Are they at risk of a gambling problem? AB - This study examined gambling among older adults and explored the critical predictors of problem gambling behaviors. Relatively unknown and understudied is the extent, or prevalence, of problem gambling behaviors among urban elders and the factors associated with problem gambling. The sample consisted of 1410 randomly selected participants, aged 60 and older, who reside in the City of Detroit. Mental health, health, demographics, social activities, senior optimism, social support network, and frequency of casino visits were examined in order to predict problem gambling behaviors among elders. The survey implemented the Lie/Bet Questionnaire for Screening Probable pathological Gamblers. The results showed that the prevalence of problem gambling behaviors was 10.4% overall, and 18% of persons reporting any casino visitation. Predictors accounted for 16% of problem gambling behaviors. The findings from this study confirmed that gambling has the potential to become a serious health problem among elders. PMID- 26047093 TI - Who now reads Parsons and Bales?: Casting a critical eye on the "gendered styles of caregiving" literature. AB - Our concern in this article is with a claim that is either explicit or implicit in much of the gerontological literature on caregiving, namely, that male caregiving is managerial and instrumental while female caregiving is intimately connected with the maintenance of family relationships. We argue that his claim can be seen as a fossilized remnant of a theoretical tradition (the Parsons/Bales argument relating to an instrumental/expressive division of labor within the nuclear family) that has increasingly gone out of fashion in other areas of sociological research. We then borrow from feminist theories relating to the ideology of intensive mothering to show why claims relating to "gendered styles of care" are problematic. Finally, we use qualitative data from interviews with the wives of caregiving husbands to suggest that the emphasis on "relationship" often found in interviews with female caregivers has less to do with the kinkeeper role typically assigned to women than with the performance of gender. PMID- 26047094 TI - Care of older persons in transnational settings. AB - The question posed in this research is: in what ways is care of older persons practiced in a transnational setting. It is answered by looking at certain transnational activities where a migrant is helping an older person living in another country. This is done by using the description of care developed by Berenice Fisher and Joan Tronto [Fisher, Berenice & Tronto, Joan. 1990. "Toward a feminist theory of caring." Pp. 35-62 in Circles of care edited by Able, E. K. & Nelson, M. Albany: State University of New York Press], where caring is seen to consist of four elements: 'caring about', 'taking care', 'caregiving' and care receiving'. Additionally the article is built around three basic elements of transnational care: distance, resources and circumstances. Distance refers to geographical distance between the migrant and the elderly person in need of care. Resources encompass a variety of resources that the migrant has or would need for the transnational caring activities. Circumstances are various determinants linked to the elderly person in need of care. Also attention is paid to the social policies involved in care-related activities. Two fundamental issues are distinctive to caring transnationally: the differing cultures of care and the two sets of social policies that have a role in this activity. PMID- 26047095 TI - "They're still in control enough to be in control": Paradox of power in dementia caregiving. AB - Based on an interview study of 26 employed women dementia caregivers, we have found that caregiving involves a complex relationship that is characterized as a paradox in which the exercise of power creates an experience of powerlessness on the part of the caregiver; that the care recipients are not powerless, but encourage as well as resist attempts at providing care; and this relationship occurs in the context of a culture that influences and controls the family through the production of knowledge that is used to shape the caregiving relationship and give direction to the caregiver's actions. The control achieved by the use of knowledge of medicine and gender is incomplete and is thus embraced yet resisted by caregivers who see the inadequacy of the knowledge for achieving the goal of loving, dignified care. PMID- 26047096 TI - The continuum of connectedness and social isolation during post stroke recovery. AB - During stroke recovery, individuals experience changes related to connectedness with others or becoming isolated from others. These experiences are an important part of the psychosocial dimensions of their health. A continuum of the major characteristics of connectedness and social isolation with others was developed from the data. Changes in connectedness for veterans post stroke were examined across 12 months following discharge home using the continuum of characteristics of connectedness and social isolation. Post-stroke, many participants were at risk of experiencing isolation. However, as a part of the recovery trajectory, many participants were able to adjust and ultimately increase their level of connectedness to others. Whether favorably or adversely, variables related to connectedness and isolation influenced the experience of participants throughout the recovery trajectory. Results suggest nearly half of stroke survivors experienced isolation post stroke; these findings are supported through participant narratives. Implications for clinical practice are discussed. PMID- 26047097 TI - Old-age pension reform and modernization pathways: Lessons for China from Latin America. AB - While numerous Western countries first experienced cultural rationalization, next economic modernization, and then faced the challenges of population aging and pension policy reform, both Latin America and China, in contrast, are dealing with these challenges in the context of much less developed economies and stronger traditional cultures. In this article we analyze old-age pension reform efforts in eight Latin American countries that have introduced funded defined contribution schemes with individual accounts. We are searching for insights about the potential success of similar reforms being implemented in China. All of these societies are organized primarily around the principles of family, reciprocity, loyalty and poverty. Our analysis suggests that these distinctive characteristics have important implications for the likely success of the reforms currently being implemented in China, particularly in four interrelated areas: coverage, compliance, transparency, and fiscal stability. PMID- 26047098 TI - A murderous ageism? Age, death and Dr. Shipman. AB - This paper examines the case of Dr. Harold Shipman, the English family doctor who is judged to have murdered over two hundred of his patients during his professional career. As nearly all of his victims were old age pensioners, his case has raised questions about the role of ageism in his committing these murders and/or in his getting away with them for so long. This paper argues that there was nothing 'ageist' about his clinical practice, nor is there reason to believe that he killed old people to 'assist' their dying (whether out of kindness or impatience). However, it was under cover of the 'naturalness' of death, that Shipman committed so many of his preventable murders. Besides any significance for understanding individual psychopathology, Shipman's case highlights how the (medico-legal) distinction between 'unlawful' and 'natural' deaths merges with the (bio-medical) distinction between 'preventable' and 'unpreventable' deaths to create a normative account of "the good death". PMID- 26047099 TI - Risk of Tuberculosis in Children with Juvenile Idiopathic Arthritis: A Nationwide Population-Based Study in Taiwan. AB - OBJECTIVE: We aimed to determine the risk of tuberculosis in children with juvenile idiopathic arthritis (JIA) in Taiwan. METHODS: We used the Taiwan National Health Insurance Research Database (NHIRD) to conduct a nested case control study. We identified a JIA cohort and matched each JIA child with non-JIA children for comparison. Methotrexate (MTX), tumor necrosis factor (TNF) inhibitor administration, and new tuberculosis cases were determined during our study period. To compare tuberculosis (TB) risk among our study groups, Cox proportional regression models were used to determine adjusted hazard ratios (aHRs). RESULTS: We identified 1495 children with JIA and 11592 non-JIA children. Majority (68.7%) children with JIA had not received MTX or TNF inhibitors; 23.9% used MTX without TNF inhibitors, and 7.4% received TNF inhibitors, irrespective of MTX administration. In total, 43 children developed tuberculosis. The overall tuberculosis infection rate for children with JIA was two times higher than that for non-JIA children. Compared with non-JIA children, children with JIA who used MTX without TNF inhibitors revealed a significantly increased of tuberculosis infection rate (aHR = 4.67; 95% CI: 1.65-13.17; P = 0.004). Children with JIA who either received TNF inhibitors or never used MTX and TNF inhibitors revealed a tuberculosis infection rate comparable to that of non-JIA children. CONCLUSIONS: Analysis of nationwide data of Taiwan suggested that children with JIA were at higher risk of tuberculosis compared with those without JIA. PMID- 26047100 TI - Characteristics and Their Clinical Relevance of Respiratory Syncytial Virus Types and Genotypes Circulating in Northern Italy in Five Consecutive Winter Seasons. AB - In order to investigate the genetic diversity and patterns of the co-circulating genotypes of respiratory syncytial virus (RSV) and their possible relationships with the severity of RSV infection, we studied all of the RSV-positive nasopharyngeal samples collected from children during five consecutive winters (2009-2010, 2010-2011, 2011-2012, 2012-2013 and 2013-2014). The RSVs were detected using the respiratory virus panel fast assay and single-tube RT-PCR, their nucleotides were sequenced, and they were tested for positive selection. Of the 165 positive samples, 131 (79.4%) carried RSV-A and 34 (20.6%) RSV-B; both groups co-circulated in all of the study periods, with RSV-A predominating in all the seasons except for winter 2010-2011, which had a predominance of RSV-B. Phylogenetic analysis of the RSV-A sequences identified genotypes NA1 and ON1, the second replacing the first during the last two years of the study period. The RSV-B belonged to genotypes BA9 and BA10. BA9 was detected in all the years of the study whereas BA only desultorily. Comparison of the subjects infected by RSV A and RSV-B types did not reveal any significant differences, but the children infected by genotype A/NA1 more frequently had lower respiratory tract infections (p<0.0001) and required hospitalisation (p = 0.007) more often than those infected by genotype A/ON1. These findings show that RSV has complex patterns of circulation characterised by the periodical replacement of the predominant genotypes, and indicate that the circulation and pathogenic role of the different RSV strains should be investigated as each may have a different impact on the host. A knowledge of the correlations between types, genotypes and disease severity may also be important in order to be able to include the more virulent strains in future vaccines. PMID- 26047101 TI - Generation of a Transcriptome in a Model Lepidopteran Pest, Heliothis virescens, Using Multiple Sequencing Strategies for Profiling Midgut Gene Expression. AB - Heliothine pests such as the tobacco budworm, Heliothis virescens (F.), pose a significant threat to production of a variety of crops and ornamental plants and are models for developmental and physiological studies. The efforts to develop new control measures for H. virescens, as well as its use as a relevant biological model, are hampered by a lack of molecular resources. The present work demonstrates the utility of next-generation sequencing technologies for rapid molecular resource generation from this species for which lacks a sequenced genome. In order to amass a de novo transcriptome for this moth, transcript sequences generated from Illumina, Roche 454, and Sanger sequencing platforms were merged into a single de novo transcriptome assembly. This pooling strategy allowed a thorough sampling of transcripts produced under diverse environmental conditions, developmental stages, tissues, and infections with entomopathogens used for biological control, to provide the most complete transcriptome to date for this species. Over 138 million reads from the three platforms were assembled into the final set of 63,648 contigs. Of these, 29,978 had significant BLAST scores indicating orthologous relationships to transcripts of other insect species, with the top-hit species being the monarch butterfly (Danaus plexippus) and silkworm (Bombyx mori). Among identified H. virescens orthologs were immune effectors, signal transduction pathways, olfactory receptors, hormone biosynthetic pathways, peptide hormones and their receptors, digestive enzymes, and insecticide resistance enzymes. As an example, we demonstrate the utility of this transcriptomic resource to study gene expression profiling of larval midguts and detect transcripts of putative Bacillus thuringiensis (Bt) Cry toxin receptors. The substantial molecular resources described in this study will facilitate development of H. virescens as a relevant biological model for functional genomics and for new biological experimentation needed to develop efficient control efforts for this and related Noctuid pest moths. PMID- 26047102 TI - De Novo Assembly of Bitter Gourd Transcriptomes: Gene Expression and Sequence Variations in Gynoecious and Monoecious Lines. AB - Bitter gourd (Momordica charantia L.) is a nutritious vegetable crop of Asian origin, used as a medicinal herb in Indian and Chinese traditional medicine. Molecular breeding in bitter gourd is in its infancy, due to limited molecular resources, particularly on functional markers for traits such as gynoecy. We performed de novo transcriptome sequencing of bitter gourd using Illumina next generation sequencer, from root, flower buds, stem and leaf samples of gynoecious line (Gy323) and a monoecious line (DRAR1). A total of 65,540 transcripts for Gy323 and 61,490 for DRAR1 were obtained. Comparisons revealed SNP and SSR variations between these lines and, identification of gene classes. Based on available transcripts we identified 80 WRKY transcription factors, several reported in responses to biotic and abiotic stresses; 56 ARF genes which play a pivotal role in auxin-regulated gene expression and development. The data presented will be useful in both functions studies and breeding programs in bitter gourd. PMID- 26047105 TI - Preface to the Special Issue: Insecticide and acaricide modes of action and their role in resistance and its management. PMID- 26047103 TI - Forward Programming of Cardiac Stem Cells by Homogeneous Transduction with MYOCD plus TBX5. AB - Adult cardiac stem cells (CSCs) express many endogenous cardiogenic transcription factors including members of the Gata, Hand, Mef2, and T-box family. Unlike its DNA-binding targets, Myocardin (Myocd)-a co-activator not only for serum response factor, but also for Gata4 and Tbx5-is not expressed in CSCs. We hypothesised that its absence was a limiting factor for reprogramming. Here, we sought to investigate the susceptibility of adult mouse Sca1+ side population CSCs to reprogramming by supplementing the triad of GATA4, MEF2C, and TBX5 (GMT), and more specifically by testing the effect of the missing co-activator, Myocd. Exogenous factors were expressed via doxycycline-inducible lentiviral vectors in various combinations. High throughput quantitative RT-PCR was used to test expression of 29 cardiac lineage markers two weeks post-induction. GMT induced more than half the analysed cardiac transcripts. However, no protein was detected for the induced sarcomeric genes Actc1, Myh6, and Myl2. Adding MYOCD to GMT affected only slightly the breadth and level of gene induction, but, importantly, triggered expression of all three proteins examined (alpha-cardiac actin, atrial natriuretic peptide, sarcomeric myosin heavy chains). MYOCD + TBX was the most effective pairwise combination in this system. In clonal derivatives homogenously expressing MYOCD + TBX at high levels, 93% of cardiac transcripts were up regulated and all five proteins tested were visualized. IN SUMMARY: (1) GMT induced cardiac genes in CSCs, but not cardiac proteins under the conditions used. (2) Complementing GMT with MYOCD induced cardiac protein expression, indicating a more complete cardiac differentiation program. (3) Homogeneous transduction with MYOCD + TBX5 facilitated the identification of differentiating cells and the validation of this combinatorial reprogramming strategy. Together, these results highlight the pivotal importance of MYOCD in driving CSCs toward a cardiac muscle fate. PMID- 26047104 TI - Calpain-1 Mediated Disorder of Pyrophosphate Metabolism Contributes to Vascular Calcification Induced by oxLDL. AB - We previously reported that oxidized low density lipoprotein (oxLDL) accelerated the calcification in aorta of rats and rat vascular smooth muscle cells (RVSMCs). However, the molecular mechanism underlying the acceleration remains poorly understood. The present study aimed to investigate the role of calpain-1, Ca2+ sensitive intracellular cysteine proteases, in the vascular calcification of rats treated with both high dose of vitamin D2 and high cholesterol diet. The results showed that calpain activity significantly increased in calcified aortic tissue of rats and RVSMCs treated with oxLDL. Specific calpain inhibitor I (CAI, 0.5mg/kg, intraperitoneal) inhibited the vascular calcification in rats with hypercholesterolemia accompanied by the increase in the level of extracellular inorganic pyrophosphate (PPi), the endogenous inhibitor of vascular calcification. In addition, CAI increased the content of adenosine triphosphate (ATP), decreased the activity, mRNA and protein expression of alkaline phosphatase (ALP) and reduced the production of superoxide anion in calcified aortic tissue. CAI also increased the activity of ATP synthase as well as protein expression of ATP5D, delta subunit of ATP synthase. In the in vitro study, suppression of calpain-1 using siRNA assay inhibited the calcium deposition, increased the levels of PPi and ATP, improved the activity of ATP synthase as well as protein expression of ATP5D in RVSMCs treated with oxLDL. Calpain-1 suppression also decreased the activity, mRNA and protein expression of ALP and reduced the mitochondrial ROS (Mito-ROS) production in RVSMCs. However, mito TEMPO, the mitochondria-targeted ROS scavenger, reduced the calcium deposition, increased the PPi in culture medium, decreased the activity, mRNA and protein expression of ALP in RVSMCs treated with oxLDL. Taken together, the results suggested that calpain-1 activation plays critical role in vascular calcification caused by oxLDL, which might be mediated by PPi metabolism disorder. The results also implied that Mito-ROS might contribute to the PPi metabolism disorder through regulation of the activity and expression of ALP. PMID- 26047107 TI - The economic importance of acaricides in the control of phytophagous mites and an update on recent acaricide mode of action research. AB - Acaricides are one of the cornerstones of an efficient control program for phytophagous mites. An analysis of the global acaricide market reveals that spider mites such as Tetranychus urticae, Panonychus citri and Panonychus ulmi are by far the most economically important species, representing more than 80% of the market. Other relevant mite groups are false spider mites (mainly Brevipalpus), rust and gall mites and tarsonemid mites. Acaricides are most frequently used in vegetables and fruits (74% of the market), including grape vines and citrus. However, their use is increasing in major crops where spider mites are becoming more important, such as soybean, cotton and corn. As revealed by a detailed case study of the Japanese market, major shifts in acaricide use are partially driven by resistance development and the commercial availability of compounds with novel mode of action. The importance of the latter cannot be underestimated, although some compounds are successfully used for more than 30 years. A review of recent developments in mode of action research is presented, as such knowledge is important for devising resistance management programs. This includes spirocyclic keto-enols as inhibitors of acetyl-CoA carboxylase, the carbazate bifenazate as a mitochondrial complex III inhibitor, a novel class of complex II inhibitors, and the mite growth inhibitors hexythiazox, clofentezine and etoxazole that interact with chitin synthase I. PMID- 26047106 TI - Development of a lateral flow test to detect metabolic resistance in Bemisia tabaci mediated by CYP6CM1, a cytochrome P450 with broad spectrum catalytic efficiency. AB - Cotton whitefly, Bemisia tabaci (Genn.) (Homoptera: Aleyrodidae) is a major sucking pest in many agricultural and horticultural cropping systems globally. The frequent use of insecticides of different mode of action classes resulted in populations resisting treatments used to keep numbers under economic damage thresholds. Recently it was shown that resistance to neonicotinoids such as imidacloprid is linked to the over-expression of CYP6CM1, a cytochrome P450 monooxygenase detoxifying imidacloprid and other neonicotinoid insecticides when recombinantly expressed in insect cells. However over-expression of CYP6CM1 is also known to confer cross-resistance to pymetrozine, an insecticide not belonging to the chemical class of neonicotinoids. In addition we were able to demonstrate by LC-MS/MS analysis the metabolisation of pyriproxyfen by recombinantly expressed CYP6CM1. Based on our results CYP6CM1 is one of the most versatile detoxification enzymes yet identified in a pest of agricultural importance, as it detoxifies a diverse range of chemical classes used to control whiteflies. Therefore we developed a field-diagnostic antibody-based lateral flow assay which detects CYP6CM1 protein at levels providing resistance to neonicotinoids and other insecticides. The ELISA based test kit can be used as a diagnostic tool to support resistance management strategies based on the alternation of different modes of action of insecticides. PMID- 26047108 TI - Novel GABA receptor pesticide targets. AB - The gamma-aminobutyric acid (GABA) receptor has four distinct but overlapping and coupled targets of pesticide action importantly associated with little or no cross-resistance. The target sites are differentiated by binding assays with specific radioligands, resistant strains, site-directed mutagenesis and molecular modeling. Three of the targets are for non-competitive antagonists (NCAs) or channel blockers of widely varied chemotypes. The target of the first generation (20th century) NCAs differs between the larger or elongated compounds (NCA-IA) including many important insecticides of the past (cyclodienes and polychlorocycloalkanes) or present (fiproles) and the smaller or compact compounds (NCA-IB) highly toxic to mammals and known as cage convulsants, rodenticides or chemical threat agents. The target of greatest current interest is designated NCA-II for the second generation (21st century) of NCAs consisting for now of isoxazolines and meta-diamides. This new and uniquely different NCA-II site apparently differs enough between insects and mammals to confer selective toxicity. The fourth target is the avermectin site (AVE) for allosteric modulators of the chloride channel. NCA pesticides vary in molecular surface area and solvent accessible volume relative to avermectin with NCA-IBs at 20-22%, NCA IAs at 40-45% and NCA-IIs at 57-60%. The same type of relationship relative to ligand-docked length is 27-43% for NCA-IBs, 63-71% for NCA-IAs and 85-105% for NCA-IIs. The four targets are compared by molecular modeling for the Drosophila melanogaster GABA-R. The principal sites of interaction are proposed to be: pore V1' and A2' for NCA-IB compounds; pore A2', L6' and T9' for NCA-IA compounds; pore T9' to S15' in proximity to M1/M3 subunit interface (or alternatively an interstitial site) for NCA-II compounds; and M1/M3, M2 interfaces for AVE. Understanding the relationships of these four binding sites is important in resistance management and in the discovery and use of safe and effective pest control agents. PMID- 26047109 TI - Flupyradifurone (SivantoTM) and its novel butenolide pharmacophore: Structural considerations. AB - Flupyradifurone (4-[(2,2-difluoroethyl)amino]-2(5H)-furanone), a member of the new class of butenolide insecticides, contains a novel bioactive scaffold as pharmacophore. It is very versatile in terms of application methods to a variety of crops, exhibits excellent and fast action against a broad spectrum of sucking pest insects including selected neonicotinoid resistant pest populations such as whiteflies and aphids expressing metabolic resistance mechanisms. As a partial agonist flupyradifurone reversibly binds to insect nicotinic acetylcholine receptors (nAChRs) and lacks metabolization by CYP6CM1, a cytochrome P450 over expressed in cotton whiteflies resistant to imidacloprid and pymetrozine. The butenolide insecticides exhibit structure-activity relationships (SAR) that are different from other nAChR agonists such as the classes of neonicotinoids and sulfoximines. The paper briefly reviews the discovery of the butenolide insecticide flupyradifurone, its SAR differentiating it from established nAChR agonists and a molecular docking approach using the binding site model of CYP6CM1vQ of Bemisia tabaci known to confer metabolic resistance to neonicotinoid insecticides. PMID- 26047110 TI - Minireview: Mode of action of meta-diamide insecticides. AB - Meta-diamides [3-benzamido-N-(4-(perfluoropropan-2-yl)phenyl)benzamides] are a distinct class of RDL GABA receptor noncompetitive antagonists showing high insecticidal activity against Spodoptera litura. The mode of action of the meta diamides was demonstrated to be distinct from that of conventional noncompetitive antagonists (NCAs) such as fipronil, picrotoxin, lindane, dieldrin, and alpha endosulfan. It was suggested that meta-diamides act at or near G336 in the M3 region of the Drosophila RDL GABA receptor. Although the site of action of the meta-diamides appears to overlap with that of macrocyclic lactones including avermectins and milbemycins, differential effects of mutations on the actions of the meta-diamides and the macrocyclic lactones were observed. Molecular modeling studies revealed that the meta-diamides may bind to an inter-subunit pocket near G336 in the Drosophila RDL GABA receptor better when in the closed state, which is distinct from the NCA-binding site, which is in a channel formed by M2s. In contrast, the macrocyclic lactones were suggested to bind to an inter-subunit pocket near G336 in the Drosophila RDL GABA receptor when in the open state. Furthermore, mechanisms underlying the high selectivity of meta-diamides are discussed. This minireview highlights the unique features of novel meta-diamide insecticides and demonstrates why meta-diamides are anticipated to become prominent insecticides that are effective against pests resistant to cyclodienes and fipronil. PMID- 26047111 TI - Probing new components (loop G and the alpha-alpha interface) of neonicotinoid binding sites on nicotinic acetylcholine receptors. AB - Neonicotinoid insecticides interact with the orthosteric site on the extracellular ligand binding domain (LBD) of nicotinic acetylcholine receptors (nAChRs), typically activating the cation permeable ion channels. In nAChRs consisting of two alpha and three non-alpha subunits, LBDs contain six loops (loops A, B and C on the alpha subunit and loops D, E and F on the non-alpha subunit) which make up the orthosteric binding site at the alpha/non-alpha subunit interfaces. Recently, an additional site (loop G) on the beta1 strand has been identified. Also, when the alpha/non-alpha subunit ratio is 3/2, another binding site is generated at the interface of two adjacent alpha subunits. Roles for loop G and the alpha-alpha interface in the interactions with neonicotinoids are discussed with reference to recent structural and physiological data. PMID- 26047112 TI - Functional characterization of glutathione S-transferases associated with insecticide resistance in Tetranychus urticae. AB - The two-spotted spider mite Tetranychus urticae is one of the most important agricultural pests world-wide. It is extremely polyphagous and develops resistance to acaricides. The overexpression of several glutathione S transferases (GSTs) has been associated with insecticide resistance. Here, we functionally expressed and characterized three GSTs, two of the delta class (TuGSTd10, TuGSTd14) and one of the mu class (TuGSTm09), which had been previously associated with striking resistance phenotypes against abamectin and other acaricides/insecticides, by transcriptional studies. Functional analysis showed that all three GSTs were capable of catalyzing the conjugation of both 1 chloro-2,4 dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzene(DCNB) to glutathione (GSH), as well as exhibiting GSH-dependent peroxidase activity toward Cumene hydroperoxide (CumOOH). The steady-state kinetics of the T. urticae GSTs for the GSH/CDNB conjugation reaction were determined and compared with other GSTs. The interaction of the three recombinant proteins with several acaricides and insecticides was also investigated. TuGSTd14 showed the highest affinity toward abamectin and a competitive type of inhibition, which suggests that the insecticide may bind to the H-site of the enzyme. The three-dimensional structure of the TuGSTd14 was predicted based on X-ray structures of delta class GSTs using molecular modeling. Structural analysis was used to identify key structural characteristics and to provide insights into the substrate specificity and the catalytic mechanism of TuGSTd14. PMID- 26047113 TI - Genotype to phenotype, the molecular and physiological dimensions of resistance in arthropods. AB - The recent accumulation of molecular studies on mutations in insects, ticks and mites conferring resistance to insecticides, acaricides and biopesticides is reviewed. Resistance is traditionally classified by physiological and biochemical criteria, such as target-site insensitivity and metabolic resistance. However, mutations are discrete molecular changes that differ in their intrinsic frequency, effects on gene dosage and fitness consequences. These attributes in turn impact the population genetics of resistance and resistance management strategies, thus calling for a molecular genetic classification. Mutations in structural genes remain the most abundantly described, mostly in genes coding for target proteins. These provide the most compelling examples of parallel mutations in response to selection. Mutations causing upregulation and downregulation of genes, both in cis (in the gene itself) and in trans (in regulatory processes) remain difficult to characterize precisely. Gene duplications and gene disruption are increasingly reported. Gene disruption appears prevalent in the case of multiple, hetero-oligomeric or redundant targets. PMID- 26047114 TI - The global status of insect resistance to neonicotinoid insecticides. AB - The first neonicotinoid insecticide, imidacloprid, was launched in 1991. Today this class of insecticides comprises at least seven major compounds with a market share of more than 25% of total global insecticide sales. Neonicotinoid insecticides are highly selective agonists of insect nicotinic acetylcholine receptors and provide farmers with invaluable, highly effective tools against some of the world's most destructive crop pests. These include sucking pests such as aphids, whiteflies, and planthoppers, and also some coleopteran, dipteran and lepidopteran species. Although many insect species are still successfully controlled by neonicotinoids, their popularity has imposed a mounting selection pressure for resistance, and in several species resistance has now reached levels that compromise the efficacy of these insecticides. Research to understand the molecular basis of neonicotinoid resistance has revealed both target-site and metabolic mechanisms conferring resistance. For target-site resistance, field evolved mutations have only been characterized in two aphid species. Metabolic resistance appears much more common, with the enhanced expression of one or more cytochrome P450s frequently reported in resistant strains. Despite the current scale of resistance, neonicotinoids remain a major component of many pest control programmes, and resistance management strategies, based on mode of action rotation, are of crucial importance in preventing resistance becoming more widespread. In this review we summarize the current status of neonicotinoid resistance, the biochemical and molecular mechanisms involved, and the implications for resistance management. PMID- 26047115 TI - Carboxylesterase-mediated insecticide resistance: Quantitative increase induces broader metabolic resistance than qualitative change. AB - Carboxylesterases are mainly involved in the mediation of metabolic resistance of many insects to organophosphate (OP) insecticides. Carboxylesterases underwent two divergent evolutionary events: (1) quantitative mechanism characterized by the overproduction of carboxylesterase protein; and (2) qualitative mechanism caused by changes in enzymatic properties because of mutation from glycine/alanine to aspartate at the 151 site (G/A151D) or from tryptophan to leucine at the 271 site (W271L), following the numbering of Drosophila melanogaster AChE. Qualitative mechanism has been observed in few species. However, whether this carboxylesterase mutation mechanism is prevalent in insects remains unclear. In this study, wild-type, G/A151D and W271L mutant carboxylesterases from Culex pipiens and Aphis gossypii were subjected to germline transformation and then transferred to D. melanogaster. These germlines were ubiquitously expressed as induced by tub-Gal4. In carboxylesterase activity assay, the introduced mutant carboxylesterase did not enhance the overall carboxylesterase activity of flies. This result indicated that G/A151D or W271L mutation disrupted the original activities of the enzyme. Less than 1.5-fold OP resistance was only observed in flies expressing A. gossypii mutant carboxylesterases compared with those expressing A. gossypii wild-type carboxylesterase. However, transgenic flies universally showed low resistance to OP insecticides compared with non-transgenic flies. The flies expressing A. gossypii W271L mutant esterase exhibited 1.5-fold resistance to deltamethrin, a pyrethroid insecticide compared with non-transgenic flies. The present transgenic Drosophila system potentially showed that a quantitative increase in carboxylesterases induced broader resistance of insects to insecticides than a qualitative change. PMID- 26047116 TI - Toxicodynamic mechanisms and monitoring of acaricide resistance in the two spotted spider mite. AB - The two-spotted spider (Tetranychus urticae) is one of the most serious pests world-wide and has developed resistance to many types of acaricides. Various mutations on acaricide target site genes have been determined to be responsible for toxicodynamic resistance, and the genotyping and frequency prediction of these mutations can be employed as an alternative resistance monitoring strategy. A quantitative sequencing (QS) protocol was reported as a population-based genotyping technique, and applied for the determination of resistance allele frequencies in T. urticae field populations. In addition, a modified glass vial bioassay method (residual contact vial bioassay, RCV) was implemented as a rapid on-site resistance monitoring tool. The QS protocol, together with the RCV, would greatly facilitate monitoring of T. urticae resistance. Recent completion of T. urticae genome analysis should facilitate the identification of additional resistance genetic markers that can be employed for molecular resistance monitoring. PMID- 26047117 TI - Isomer-specific comparisons of the hydrolysis of synthetic pyrethroids and their fluorogenic analogues by esterases from the cotton bollworm Helicoverpa armigera. AB - The low aqueous solubility and chiral complexity of synthetic pyrethroids, together with large differences between isomers in their insecticidal potency, have hindered the development of meaningful assays of their metabolism and metabolic resistance to them. To overcome these problems, Shan and Hammock (2001) [7] therefore developed fluorogenic and more water-soluble analogues of all the individual isomers of the commonly used Type 2 pyrethroids, cypermethrin and fenvalerate. The analogues have now been used in several studies of esterase based metabolism and metabolic resistance. Here we test the validity of these analogues by quantitatively comparing their hydrolysis by a battery of 22 heterologously expressed insect esterases with the hydrolysis of the corresponding pyrethroid isomers by these esterases in an HPLC assay recently developed by Teese et al. (2013) [14]. We find a strong, albeit not complete, correlation (r = 0.7) between rates for the two sets of substrates. The three most potent isomers tested were all relatively slowly degraded in both sets of data but three esterases previously associated with pyrethroid resistance in Helicoverpa armigera did not show higher activities for these isomers than did allelic enzymes derived from susceptible H. armigera. Given their amenability to continuous assays at low substrate concentrations in microplate format, and ready detection of product, we endorse the ongoing utility of the analogues in many metabolic studies of pyrethroids. PMID- 26047118 TI - RNAi validation of resistance genes and their interactions in the highly DDT resistant 91-R strain of Drosophila melanogaster. AB - 4,4'-dichlorodiphenyltrichloroethane (DDT) has been re-recommended by the World Health Organization for malaria mosquito control. Previous DDT use has resulted in resistance, and with continued use resistance will increase in terms of level and extent. Drosophila melanogaster is a model dipteran that has many available genetic tools, numerous studies done on insecticide resistance mechanisms, and is related to malaria mosquitoes allowing for extrapolation. The 91-R strain of D. melanogaster is highly resistant to DDT (>1500-fold), however, there is no mechanistic scheme that accounts for this level of resistance. Recently, reduced penetration, increased detoxification, and direct excretion have been identified as resistance mechanisms in the 91-R strain. Their interactions, however, remain unclear. Use of UAS-RNAi transgenic lines of D. melanogaster allowed for the targeted knockdown of genes putatively involved in DDT resistance and has validated the role of several cuticular proteins (Cyp4g1 and Lcp1), cytochrome P450 monooxygenases (Cyp6g1 and Cyp12d1), and ATP binding cassette transporters (Mdr50, Mdr65, and Mrp1) involved in DDT resistance. Further, increased sensitivity to DDT in the 91-R strain after intra-abdominal dsRNA injection for Mdr50, Mdr65, and Mrp1 was determined by a DDT contact bioassay, directly implicating these genes in DDT efflux and resistance. PMID- 26047120 TI - IRAC: Mode of action classification and insecticide resistance management. AB - Insecticide resistance is a long standing and expanding problem for pest arthropod control. Effective insecticide resistance management (IRM) is essential if the utility of current and future insecticides is to be preserved. Established in 1984, the Insecticide Resistance Action Committee (IRAC) is an international association of crop protection companies. IRAC serves as the Specialist Technical Group within CropLife International focused on ensuring the long term efficacy of insect, mite and tick control products through effective resistance management for sustainable agriculture and improved public health. A key function of IRAC is the continued development of the Mode of Action (MoA) classification scheme, which provides up-to-date information on the modes of action of new and established insecticides and acaricides and which serves as the basis for developing appropriate IRM strategies for crop protection and vector control. The IRAC MoA classification scheme covers more than 25 different modes of action and at least 55 different chemical classes. Diversity is the spice of resistance management by chemical means and thus it provides an approach to IRM providing a straightforward means to identify potential rotation/alternation options. PMID- 26047119 TI - Carbamate and pyrethroid resistance in the akron strain of Anopheles gambiae. AB - Insecticide resistance in the malaria vector, Anopheles gambiae, is a serious problem, epitomized by the multi-resistant Akron strain, originally isolated in the country of Benin. Here we report resistance in this strain to pyrethroids and DDT (13-fold to 35-fold compared to the susceptible G3 strain), but surprisingly little resistance to etofenprox, a compound sometimes described as a "pseudo pyrethroid." There was also strong resistance to topically-applied commercial carbamates (45-fold to 81-fold), except for the oximes aldicarb and methomyl. Biochemical assays showed enhanced cytochrome P450 monooxygenase and carboxylesterase activity, but not that of glutathione-S-transferase. A series of substituted alpha,alpha,alpha,-trifluoroacetophenone oxime methylcarbamates were evaluated for enzyme inhibition potency and toxicity against G3 and Akron mosquitoes. The compound bearing an unsubstituted phenyl ring showed the greatest toxicity to mosquitoes of both strains. Low cross resistance in Akron was retained by all analogs in the series. Kinetic analysis of acetylcholinesterase activity and its inhibition by insecticides in the G3 strain showed inactivation rate constants greater than that of propoxur, and against Akron enzyme inactivation rate constants similar to that of aldicarb. However, inactivation rate constants against recombinant human AChE were essentially identical to that of the G3 strain. Thus, the acetophenone oxime carbamates described here, though potent insecticides that control resistant Akron mosquitoes, require further structural modification to attain acceptable selectivity and human safety. PMID- 26047121 TI - Variation in P450-mediated fenvalerate resistance levels is not correlated with CYP337B3 genotype in Chinese populations of Helicoverpa armigera. AB - Metabolic resistance to synthetic pyrethroids in Helicoverpa armigera has recently been associated with the chimeric cytochrome P450 enyzme CYP337B3. One variant of the latter, CYP337B3v1, accounts for 40-50 fold resistance to fenvalerate in an Australian population while a second variant, CYP337B3v2, has been associated with ~7 fold resistance to cypermethrin in a Pakistani population. Here we show that ~250-1200 fold resistance to fenvalerate in populations of the species from northern and northwestern China is largely due to P450-based metabolism, and that CYP337B3v2 is also at high frequency in these populations but absent in a susceptible control strain. However we find little correlation between the level of resistance and CYP337B3v2 frequency, either across the resistant populations studied, or over time within them. While there is variation between populations in the levels of CYP337B3v2 expression, this is not correlated with the level of resistance either. These data suggest that much of the variation in the level of fenvalerate resistance in China is explained by P450s other than CYP337B3. We also find that both the level of resistance and CYP337B3v2 frequency decline in field populations transferred to the laboratory and remained there without fenvalerate exposure, suggesting a fitness cost to both characters in the absence of the pesticide pressure. However the declines in the two characters are not well correlated across populations, again consistent with a large contribution to the variation in resistance levels from factors other than CYP337B3. PMID- 26047122 TI - Fabrication of Biomimetic Bone Tissue Using Mesenchymal Stem Cell-Derived Three Dimensional Constructs Incorporating Endothelial Cells. AB - The development of technologies to promote vascularization of engineered tissue would drive major developments in tissue engineering and regenerative medicine. Recently, we succeeded in fabricating three-dimensional (3D) cell constructs composed of mesenchymal stem cells (MSCs). However, the majority of cells within the constructs underwent necrosis due to a lack of nutrients and oxygen. We hypothesized that incorporation of vascular endothelial cells would improve the cell survival rate and aid in the fabrication of biomimetic bone tissues in vitro. The purpose of this study was to assess the impact of endothelial cells combined with the MSC constructs (MSC/HUVEC constructs) during short- and long term culture. When human umbilical vein endothelial cells (HUVECs) were incorporated into the cell constructs, cell viability and growth factor production were increased after 7 days. Furthermore, HUVECs were observed to proliferate and self-organize into reticulate porous structures by interacting with the MSCs. After long-term culture, MSC/HUVEC constructs formed abundant mineralized matrices compared with those composed of MSCs alone. Transmission electron microscopy and qualitative analysis revealed that the mineralized matrices comprised porous cancellous bone-like tissues. These results demonstrate that highly biomimetic bone tissue can be fabricated in vitro by 3D MSC constructs incorporated with HUVECs. PMID- 26047123 TI - Oral administration of bovine milk derived extracellular vesicles attenuates arthritis in two mouse models. AB - SCOPE: This study shows the effect of bovine milk derived extracellular vesicles (BMEVs) on spontaneous polyarthritis in IL-1Ra-deficient mice and collagen induced arthritis. METHODS AND RESULTS: BMEVs were isolated from semi-skimmed milk by ultracentrifugation and the particle size was around 100 nm by dynamic light scattering and electron microscopy. BMEVs expressed exosome marker CD63, immunoregulatory microRNA's (miR-30a, -223, -92a), and milk-specific beta-casein and beta-lactoglobulin mRNA. In vitro, PKH-67-labeled BMEVs were taken up by RAW264.7, splenocytes, and intestinal cells as determined by flow cytometry and confocal microscopy. IL-1Ra(-/-) mice received BMEVs by daily oral gavage starting at wk 5 till 15 after birth and collagen-induced arthritis mice via their drinking water starting 1 wk before immunization till day 40. Macroscopically, BMEV treatment delayed the onset of arthritis and histology showed diminished cartilage pathology and bone marrow inflammation in both models. BMEV treatment also reduced the serum levels of MCP-1 and IL-6 and their production by splenic cells. BMEV treatment diminished the anticollagen IgG2a levels, which was accompanied by reduced splenic Th1 (Tbet) and Th17 (RORgammaT) mRNA. CONCLUSION: This is the first report that oral delivery of BMEVs ameliorates experimental arthritis and this warrants further research to determine whether this beneficial effect can be seen in rheumatoid arthritis patients. PMID- 26047125 TI - Trephine defunctioning loop ileostomy: a simple technique using an Alexis wound protector - a video vignette. PMID- 26047124 TI - Risk Factors Associated with Ebola and Marburg Viruses Seroprevalence in Blood Donors in the Republic of Congo. AB - BACKGROUND: Ebola and Marburg viruses (family Filoviridae, genera Ebolavirus and Marburgvirus) cause haemorrhagic fevers in humans, often associated with high mortality rates. The presence of antibodies to Ebola virus (EBOV) and Marburg virus (MARV) has been reported in some African countries in individuals without a history of haemorrhagic fever. In this study, we present a MARV and EBOV seroprevalence study conducted amongst blood donors in the Republic of Congo and the analysis of risk factors for contact with EBOV. METHODOLOGY AND FINDINGS: In 2011, we conducted a MARV and EBOV seroprevalence study amongst 809 blood donors recruited in rural (75; 9.3%) and urban (734; 90.7%) areas of the Republic of Congo. Serum titres of IgG antibodies to MARV and EBOV were assessed by indirect double-immunofluorescence microscopy. MARV seroprevalence was 0.5% (4 in 809) without any identified risk factors. Prevalence of IgG to EBOV was 2.5%, peaking at 4% in rural areas and in Pointe Noire. Independent risk factors identified by multivariate analysis were contact with bats and exposure to birds. CONCLUSIONS/SIGNIFICANCE: This MARV and EBOV serological survey performed in the Republic of Congo identifies a probable role for environmental determinants of exposure to EBOV. It highlights the requirement for extending our understanding of the ecological and epidemiological risk of bats (previously identified as a potential ecological reservoir) and birds as vectors of EBOV to humans, and characterising the protection potentially afforded by EBOV-specific antibodies as detected in blood donors. PMID- 26047127 TI - Corrigendum. PMID- 26047126 TI - BRCA Mutations Increase Fertility in Families at Hereditary Breast/Ovarian Cancer Risk. AB - BACKGROUND: Deleterious mutations in the BRCA genes are responsible for a small, but significant, proportion of breast and ovarian cancers (5 - 10 %). Proof of de novo mutations in hereditary breast/ovarian cancer (HBOC) families is rare, in contrast to founder mutations, thousands of years old, that may be carried by as much as 1 % of a population. Thus, if mutations favoring cancer survive selection pressure through time, they must provide advantages that compensate for the loss of life expectancy. METHOD: This hypothesis was tested within 2,150 HBOC families encompassing 96,325 individuals. Parameters included counts of breast/ovarian cancer, age at diagnosis, male breast cancer and other cancer locations. As expected, well-known clinical parameters discriminated between BRCA-mutated families and others: young age at breast cancer, ovarian cancer, pancreatic cancer and male breast cancer. The major fertility differences concerned men in BRCA-mutated families: they had lower first and mean age at paternity, and fewer remained childless. For women in BRCA families, the miscarriage rate was lower. In a logistic regression including clinical factors, the different miscarriage rate and men's mean age at paternity remained significant. RESULTS: Fertility advantages were confirmed in a subgroup of 746 BRCA mutation carriers and 483 non carriers from BRCA mutated families. In particular, female carriers were less often nulliparous (9.1 % of carriers versus 16.0 %, p = 0.003) and had more children (1.8 +/- 1.4 SD versus 1.5 +/- 1.3, p = 0.002) as well as male carriers (1.7 +/- 1.3 versus 1.4 +/- 1.3, p = 0.024). CONCLUSION: Although BRCA mutations shorten the reproductive period due to cancer mortality, they compensate by improving fertility both in male and female carriers. PMID- 26047128 TI - A New Approach to Segment Both Main and Peripheral Retinal Vessels Based on Gray Voting and Gaussian Mixture Model. AB - Vessel segmentation in retinal fundus images is a preliminary step to clinical diagnosis for some systemic diseases and some eye diseases. The performances of existing methods for segmenting small vessels which are usually of more importance than the main vessels in a clinical diagnosis are not satisfactory in clinical use. In this paper, we present a method for both main and peripheral vessel segmentation. A local gray-level change enhancement algorithm called gray voting is used to enhance the small vessels, while a two-dimensional Gabor wavelet is used to extract the main vessels. We fuse the gray-voting results with the 2D-Gabor filter results as pre-processing outcome. A Gaussian mixture model is then used to extract vessel clusters from the pre-processing outcome, while small vessels fragments are obtained using another gray-voting process, which complements the vessel cluster extraction already performed. At the last step, we eliminate the fragments that do not belong to the vessels based on the shape of the fragments. We evaluated the approach with two publicly available DRIVE (Staal et al., 2004) and STARE (Hoover et at., 2000) datasets with manually segmented results. For the STARE dataset, when using the second manually segmented results which include much more small vessels than the first manually segmented results as the "gold standard," this approach achieved an average sensitivity, accuracy and specificity of 65.0%, 92.1% and 97.0%, respectively. The sensitivities of this approach were much higher than those of the other existing methods, with comparable specificities; these results thus demonstrated that this approach was sensitive to detection of small vessels. PMID- 26047129 TI - Swertisin an Anti-Diabetic Compound Facilitate Islet Neogenesis from Pancreatic Stem/Progenitor Cells via p-38 MAP Kinase-SMAD Pathway: An In-Vitro and In-Vivo Study. AB - Transplanting islets serves best option for restoring lost beta cell mass and function. Small bio-chemical agents do have the potential to generate new islets mass, however lack of understanding about mechanistic action of these small molecules eventually restricts their use in cell-based therapies for diabetes. We recently reported "Swertisin" as a novel islet differentiation inducer, generating new beta cells mass more effectively. Henceforth, in the present study we attempted to investigate the molecular signals that Swertisin generate for promoting differentiation of pancreatic progenitors into islet cells. To begin with, both human pancreatic progenitors (PANC-1 cells) and primary cultured mouse intra-islet progenitor cells (mIPC) were used and tested for Swertisin induced islet neogenesis mechanism, by monitoring immunoblot profile of key transcription factors in time dependent manner. We observed Swertisin follow Activin-A mediated MEPK-TKK pathway involving role of p38 MAPK via activating Neurogenin-3 (Ngn-3) and Smad Proteins cascade. This MAP Kinase intervention in differentiation of cells was confirmed using strong pharmacological inhibitor of p38 MAPK (SB203580), which effectively abrogated this process. We further confirmed this mechanism in-vivo in partial pancreatectomised (PPx) mice model, where we could show Swertisin exerted potential increase in insulin transcript levels with persistent down-regulation of progenitor markers like Nestin, Ngn-3 and Pancreatic Duodenal Homeobox Gene-1 (PDX-1) expression, within three days post PPx. With detailed molecular investigations here in, we first time report the molecular mode of action of Swertisin for islet neogenesis mediated through MAP Kinase (MEPK-TKK) pathway involving Ngn-3 and Smad transcriptional regulation. These findings held importance for developing Swertisin as potent pharmacological drug candidate for effective and endogenous differentiation of islets in cell based therapy for diabetes. PMID- 26047131 TI - Uniform and Complementary Social Interaction: Distinct Pathways to Solidarity. AB - We examine how different forms of co-action give rise to feelings of solidarity. We propose that (a) coordinated action elicits a sense of solidarity, and (b) the process through which such solidarity emerges differs for different forms of co action. We suggest that whether solidarity within groups emerges from uniform action (e.g. synchronizing, as when people speak in unison) or from more complementary forms of action (e.g. alternating, when speaking in turns) has important consequences for the emergent position of individuals within the group. Uniform action relies on commonality, leaving little scope for individuality. In complementary action each individual makes a distinctive contribution to the group, thereby increasing a sense of personal value to the group, which should contribute to the emergence of solidarity. The predictions receive support from five studies, in which we study groups in laboratory and field settings. Results show that both complementary and uniform co-action increase a sense of solidarity compared to control conditions. However, in the complementary action condition, but not in the uniform action (or synchrony) condition, the effect on feelings of solidarity is mediated by a sense of personal value to the group. PMID- 26047130 TI - Risk of prostate cancer in African-American men: Evidence of mixed effects of dietary quercetin by serum vitamin D status. AB - BACKGROUND: African-American (AA) men experience higher rates of prostate cancer (PCa) and vitamin D (vitD) deficiency than white men. VitD is promoted for PCa prevention, but there is conflicting data on the association between vitD and PCa. We examined the association between serum vitD and dietary quercetin and their interaction with PCa risk in AA men. METHODS: Participants included 90 AA men with PCa undergoing treatment at Howard University Hospital (HUH) and 62 controls participating in HUH's free PCa screening program. We measured serum 25 hydroxy vitD [25(OH)D] and used the 98.2 item Block Brief 2000 Food Frequency Questionnaires to measure dietary intake of quercetin and other nutrients. Case and control groups were compared using a two-sample t-test for continuous risk factors and a Fisher exact test for categorical factors. Associations between risk factors and PCa risk were examined via age-adjusted logistic regression models. RESULTS: Interaction effects of dietary quercetin and serum vitD on PCa status were observed. AA men (age 40-70) with normal levels of serum vitD (>30 ng/ml) had a 71% lower risk of PCa compared to AA men with vitD deficiency (OR = 0.29, 95%CI: 0.08-1.03; P = 0.055). In individuals with vitD deficiency, increased dietary quercetin showed a tendency toward lower risk of PCa (OR = 0.91, 95%CI: 0.82-1.00; P = 0.054, age-adjusted) while men with normal vitD were at elevated risk (OR = 1.23, 95%CI: 1.04-1.45). CONCLUSION: These findings suggest that AA men who are at a higher risk of PCa may benefit more from vitD intake, and supplementation with dietary quercetin may increase the risk of PCa in AA men with normal vitD levels. Further studies with larger populations are needed to better understand the impact of the interaction between sera vitD levels and supplementation with quercetin on PCa in AA men. PMID- 26047132 TI - All-optical coherent population trapping with defect spin ensembles in silicon carbide. AB - Divacancy defects in silicon carbide have long-lived electronic spin states and sharp optical transitions. Because of the various polytypes of SiC, hundreds of unique divacancies exist, many with spin properties comparable to the nitrogen vacancy center in diamond. If ensembles of such spins can be all-optically manipulated, they make compelling candidate systems for quantum-enhanced memory, communication, and sensing applications. We report here direct all-optical addressing of basal plane-oriented divacancy spins in 4H-SiC. By means of magneto spectroscopy, we fully identify the spin triplet structure of both the ground and the excited state, and use this for tuning of transition dipole moments between particular spin levels. We also identify a role for relaxation via intersystem crossing. Building on these results, we demonstrate coherent population trapping a key effect for quantum state transfer between spins and photons- for divacancy sub-ensembles along particular crystal axes. These results, combined with the flexibility of SiC polytypes and device processing, put SiC at the forefront of quantum information science in the solid state. PMID- 26047133 TI - Prevalence and Clustering of Cardiovascular Disease Risk Factors among Tibetan Adults in China: A Population-Based Study. AB - OBJECTIVES: The prevalence of cardiovascular disease risk factors has increased worldwide. However, the prevalence and clustering of cardiovascular disease risk factors among Tibetans is currently unknown. We aimed to explore the prevalence and clustering of cardiovascular disease risk factors among Tibetan adults in China. METHODS: In 2011, 1659 Tibetan adults (aged >= 18 years) from Changdu, China were recruited to this cross-section study. The questionnaire, physical examinations and laboratory testing were completed and the prevalence of cardiovascular disease risk factors, including hypertension, diabetes, overweight/obesity, dyslipidemia, and current smoking, were counted. The association between the clustering of cardiovascular disease risk factors and demographic characteristics, and geographic altitude were assessed. RESULTS: The age-standardized prevalence of hypertension, diabetes, overweight or obesity, dyslipidemia, and current smoking were 62.4%, 6.4%, 34.3%, 42.7%, and 6.1%, respectively, and these risk factors were associated with age, gender, education level, yearly family income, altitude, occupation, and butter tea consumption (P < 0.05). Overall, the age-adjusted prevalence of clustering of >= 1, >= 2, and >= 3 cardiovascular disease risk factors were 79.4%, 47.1%, and 20.9%, respectively. There appeared higher clustering of >= 2 and >= 3 cardiovascular disease risk factors among Tibetans with higher education level and family income yearly, and those living at an altitude < 3500 m and in a township. CONCLUSIONS: The prevalence of cardiovascular disease risk factors, especially hypertension, was high in Tibetans. Moreover, there was an increased clustering of cardiovascular disease risk factors among those with higher socioeconomic status, lamas and those living at an altitude < 3500 m. These findings suggest that without the immediate implementation of an efficient policy to control these risk factors, cardiovascular disease will eventually become a major disease burden among Tibetans. PMID- 26047136 TI - Editorial: bioenergy and biorefinery - biological solution for sustainable development of human society. PMID- 26047134 TI - Sensory control of normal movement and of movement aided by neural prostheses. AB - Signals from sensory receptors in muscles and skin enter the central nervous system (CNS), where they contribute to kinaesthesia and the generation of motor commands. Many lines of evidence indicate that sensory input from skin receptors, muscle spindles and Golgi tendon organs play the predominant role in this regard. Yet in spite of over 100 years of research on this topic, some quite fundamental questions remain unresolved. How does the CNS choose to use the ability to control muscle spindle sensitivity during voluntary movements? Do spinal reflexes contribute usefully to load compensation, given that the feedback gain must be quite low to avoid instability? To what extent do signals from skin stretch receptors contribute? This article provides a brief review of various theories, past and present, that address these questions. To what extent has the knowledge gained resulted in clinical applications? Muscles paralyzed as a result of spinal cord injury or stroke can be activated by electrical stimulation delivered by neuroprostheses. In practice, at most two or three sensors can be deployed on the human body, providing only a small fraction of the information supplied by the tens of thousands of sensory receptors in animals. Most of the neuroprostheses developed so far do not provide continuous feedback control. Instead, they switch from one state to another when signals from their one or two sensors meet pre-set thresholds (finite state control). The inherent springiness of electrically activated muscle provides a crucial form of feedback control that helps smooth the resulting movements. In spite of the dissimilarities, parallels can be found between feedback control in neuroprostheses and in animals and this can provide surprising insights in both directions. PMID- 26047139 TI - Feminization of the Isopod Cylisticus convexus after Transinfection of the wVulC Wolbachia Strain of Armadillidium vulgare. AB - Reproductive parasites such as Wolbachia are able to manipulate the reproduction of their hosts by inducing parthenogenesis, male-killing, cytoplasmic incompatibility or feminization of genetic males. Despite extensive studies, no underlying molecular mechanism has been described to date. The goal of this study was to establish a system with a single Wolbachia strain that feminizes two different isopod species to enable comparative analyses aimed at elucidating the genetic basis of feminization. It was previously suggested that Wolbachia wVulC, which naturally induces feminization in Armadillidium vulgare, induces the development of female secondary sexual characters in transinfected Cylisticus convexus adult males. However, this does not demonstrate that wVulC induces feminization in C. convexus since feminization is the conversion of genetic males into functional females that occurs during development. Nevertheless, it suggests that C. convexus may represent a feminization model suitable for further development. Knowledge about C. convexus sexual differentiation is also essential for comparative analyses, as feminization is thought to take place just before or during sexual differentiation. Consequently, we first described gonad morphological differentiation of C. convexus and compared it with that of A. vulgare. Then, wVulC was injected into male and female C. convexus adult individuals. The feminizing effect was demonstrated by the combined appearance of female secondary sexual characters in transinfected adult males, as well as the presence of intersexes and female biases in progenies in which wVulC was vertically transmitted from transinfected mothers. The establishment of a new model of feminization of a Wolbachia strain in a heterologous host constitutes a useful tool towards the understanding of the molecular mechanism of feminization. PMID- 26047141 TI - Improvement of Air/Fuel Ratio Operating Window and Hydrothermal Stability for Pd Only Three-Way Catalysts through a Pd-Ce2Zr2O8 Superstructure Interaction. AB - The extremely severe and persistent haze problems in some parts of the world including China have prompted the implementation of increasingly stringent tailpipe regulations. This places increasingly higher performance requirements for three-way catalysts, and in particular a widening of the air/fuel (lambda) ratio operating window to facilitate operation of the on-board diagnostic system. A new pathway is presented here by tuning the nanostructure of TWCs to improve their lambda activities and hydrothermal stability. High-temperature reduction and a mild-temperature reoxidation treatment for alumina-modified ceria-zirconia brought about the formation of a cubic, fully oxidized, pyrochlore-like superstructure, Ce2Zr2O8. The combination of Pd and the Ce2Zr2O8 superstructure greatly improved the lambda window for Pd-only three-way catalysts. X-ray powder diffraction (XRD), temperature-programmed reduction with H2 (H2-TPR) and high resolution transmission electron microscopy (HRTEM) characterization confirmed the interaction between Pd and the Ce2Zr2O8 superstructure, which modifies the dynamic oxygen storage capacity in comparison to the conventional Pd-Ce(Zr)O2 interaction, due to higher low-temperature reducibility for the Ce2Zr2O8 superstructure than for Ce(Zr)O2. Furthermore, the retention of the Ce2Zr2O8 superstructure derived from the interaction with Pd results in superior lambda and light-off performances after hydrothermal aging treatment at 1000 degrees C for 12 h in air containing 10% H2O. PMID- 26047140 TI - IQ Motif-Containing GTPase-Activating Protein 2 (IQGAP2) Is a Novel Regulator of Colonic Inflammation in Mice. AB - IQ motif-containing GTPase-activating protein 2 (IQGAP2) is a multidomain scaffolding protein that plays a role in cytoskeleton regulation by juxtaposing Rho GTPase and Ca2+/calmodulin signals. While IQGAP2 suppresses tumorigenesis in liver, its role in pathophysiology of the gastrointestinal tract remains unexplored. Here we report that IQGAP2 is required for the inflammatory response in colon. Mice lacking Iqgap2 gene (Iqgap2-/- mice) were resistant to chemically induced colitis. Unlike wild-type controls, Iqgap2-/- mice treated with 3% dextran sulfate sodium (DSS) in water for 13 days displayed no injury to colonic epithelium. Mechanistically, resistance to colitis was associated with suppression of colonic NF-kappaB signaling and IL-6 synthesis, along with diminished neutrophil and macrophage production and recruitment in Iqgap2-/- mice. Finally, alterations in IQGAP2 expression were found in colons of patients with inflammatory bowel disease (IBD). Our findings indicate that IQGAP2 promotes inflammatory response at two distinct levels; locally, in colonic epithelium through TLR4/NF-kappaB signaling pathway, and systemically, via control of maturation and recruitment of myeloid immune cells. This work identifies a novel mechanism of colonic inflammation mediated by signal transducing scaffolding protein IQGAP2. IQGAP2 domain-specific blocking agents may represent a conceptually novel strategy for therapy of IBD and other inflammation-associated disorders, including cancer. PMID- 26047142 TI - Laser-induced thermoelastic effects can evoke tactile sensations. AB - Humans process a plethora of sensory information that is provided by various entities in the surrounding environment. Among the five major senses, technology for touch, haptics, is relatively young and has relatively limited applications largely due to its need for physical contact. In this article, we suggest a new way for non-contact haptic stimulation that uses laser, which has potential advantages such as mid-air stimulation, high spatial precision, and long working distance. We demonstrate such tactile stimulation can be enabled by laser-induced thermoelastic effects by means of physical and perceptual studies, as well as simulations. In the physical study, the mechanical effect of laser on a human skin sample is detected using low-power radiation in accordance with safety guidelines. Limited increases (< ~2.5 degrees C) in temperature at the surface of the skin, examined by both thermal camera and the Monte Carlo simulation, indicate that laser does not evoke heat-induced nociceptive sensation. In the human EEG study, brain responses to both mechanical and laser stimulation are consistent, along with subjective reports of the non-nociceptive sensation of laser stimuli. PMID- 26047143 TI - Gene Silencing and Activation of Human Papillomavirus 18 Is Modulated by Sense Promoter Associated RNA in Bidirectionally Transcribed Long Control Region. AB - BACKGROUND: Recently various studies have demonstrated the role of promoter associated non-coding RNAs (pRNA) in dsRNA induced transcriptional gene silencing and activation. However the exact mechanistic details of these processes with respect to the orientation of pRNAs are poorly defined. METHODOLOGY/PRINCIPAL FINDINGS: We have identified novel sense and antisense long control region (LCR) associated RNAs (pRNAs) in HPV18 positive cervical cancer cell lines HeLa, C-4 I and C-4 II. Using dsRNAs against these pRNAs, we were able to achieve upregulation or downregulation of the sense and antisense pRNAs and the downstream E6 and E7 oncogenes. We present evidence that knockdown of the sense pRNA is associated with reduction in E6 and E7 oncogenes and an upregulation of antisense pRNA. Conversely upregulation of sense pRNA is accompanied by an induction of the oncogenes and a concomitant reduction in antisense pRNA. Moreover, the exact role of sense and antisense pRNAs in dsRNA mediated gene modulation was confirmed by their selective degradation using antisense phosphorothioate oligodeoxynucleotides (ODN). Degradation of sense pRNA with antisense ODN led to loss of dsRNA induced silencing and activation, suggesting that dsRNA mediated gene modulation requires sense pRNA. Both processes were accompanied with congruent changes in the methylation pattern of activating and repressive histones. CONCLUSION/SIGNIFICANCE: Thus this data identifies and demonstrates the role of previously unknown important regulatory transcripts in HPV18 gene expression which can prove valuable targets in cervical cancer therapeutics. This mode of gene regulation by bidirectional transcription could be operational in other promoters as well and serve as a mechanism of regulating gene expression. PMID- 26047144 TI - Emphysema Is Common in Lungs of Cystic Fibrosis Lung Transplantation Patients: A Histopathological and Computed Tomography Study. AB - BACKGROUND: Lung disease in cystic fibrosis (CF) involves excessive inflammation, repetitive infections and development of bronchiectasis. Recently, literature on emphysema in CF has emerged, which might become an increasingly important disease component due to the increased life expectancy. The purpose of this study was to assess the presence and extent of emphysema in endstage CF lungs. METHODS: In explanted lungs of 20 CF patients emphysema was semi-quantitatively assessed on histology specimens. Also, emphysema was automatically quantified on pre transplantation computed tomography (CT) using the percentage of voxels below 950 Houndfield Units and was visually scored on CT. The relation between emphysema extent, pre-transplantation lung function and age was determined. RESULTS: All CF patients showed emphysema on histological examination: 3/20 (15%) showed mild, 15/20 (75%) moderate and 2/20 (10%) severe emphysema, defined as 0 20% emphysema, 20-50% emphysema and >50% emphysema in residual lung tissue, respectively. Visually upper lobe bullous emphysema was identified in 13/20 and more diffuse non-bullous emphysema in 18/20. Histology showed a significant correlation to quantified CT emphysema (p = 0.03) and visual emphysema score (p = 0.001). CT and visual emphysema extent were positively correlated with age (p = 0.045 and p = 0.04, respectively). CONCLUSIONS: In conclusion, this study both pathologically and radiologically confirms that emphysema is common in end-stage CF lungs, and is age related. Emphysema might become an increasingly important disease component in the aging CF population. PMID- 26047146 TI - SaDA: From Sampling to Data Analysis-An Extensible Open Source Infrastructure for Rapid, Robust and Automated Management and Analysis of Modern Ecological High Throughput Microarray Data. AB - One of the most crucial characteristics of day-to-day laboratory information management is the collection, storage and retrieval of information about research subjects and environmental or biomedical samples. An efficient link between sample data and experimental results is absolutely important for the successful outcome of a collaborative project. Currently available software solutions are largely limited to large scale, expensive commercial Laboratory Information Management Systems (LIMS). Acquiring such LIMS indeed can bring laboratory information management to a higher level, but most of the times this requires a sufficient investment of money, time and technical efforts. There is a clear need for a light weighted open source system which can easily be managed on local servers and handled by individual researchers. Here we present a software named SaDA for storing, retrieving and analyzing data originated from microorganism monitoring experiments. SaDA is fully integrated in the management of environmental samples, oligonucleotide sequences, microarray data and the subsequent downstream analysis procedures. It is simple and generic software, and can be extended and customized for various environmental and biomedical studies. PMID- 26047145 TI - The Vital Role of Blood Flow-Induced Proliferation and Migration in Capillary Network Formation in a Multiscale Model of Angiogenesis. AB - Sprouting angiogenesis and capillary network formation are tissue scale phenomena. There are also sub-scale phenomena involved in angiogenesis including at the cellular and intracellular (molecular) scales. In this work, a multiscale model of angiogenesis spanning intracellular, cellular, and tissue scales is developed in detail. The key events that are considered at the tissue scale are formation of closed flow path (that is called loop in this article) and blood flow initiation in the loop. At the cellular scale, growth, migration, and anastomosis of endothelial cells (ECs) are important. At the intracellular scale, cell phenotype determination as well as alteration due to blood flow is included, having pivotal roles in the model. The main feature of the model is to obtain the physical behavior of a closed loop at the tissue scale, relying on the events at the cellular and intracellular scales, and not by imposing physical behavior upon it. Results show that, when blood flow is considered in the loop, the anastomosed sprouts stabilize and elongate. By contrast, when the loop is modeled without consideration of blood flow, the loop collapses. The results obtained in this work show that proper determination of EC phenotype is the key for its survival. PMID- 26047147 TI - Cluster analysis of commercial samples of Bauhinia spp. using HPLC-UV/PDA and MCR ALS/PCA without peak alignment procedure. AB - INTRODUCTION: Bauhinia forficata Link. is recognised by the Brazilian Health Ministry as a treatment of hypoglycemia and diabetes. Analytical methods are useful to assess the plant identity due the similarities found in plants from Bauhinia spp. HPLC-UV/PDA in combination with chemometric tools is an alternative widely used and suitable for authentication of plant material, however, the shifts of retention times for similar compounds in different samples is a problem. OBJECTIVE: To perform comparisons between the authentic medicinal plant (Bauhinia forficata Link.) and samples commercially available in drugstores claiming to be "Bauhinia spp. to treat diabetes" and to evaluate the performance of multivariate curve resolution - alternating least squares (MCR-ALS) associated to principal component analysis (PCA) when compared to pure PCA. METHODOLOGY: HPLC-UV/PDA data obtained from extracts of leaves were evaluated employing a combination of MCR-ALS and PCA, which allowed the use of the full chromatographic and spectrometric information without the need of peak alignment procedures. RESULTS: The use of MCR-ALS/PCA showed better results than the conventional PCA using only one wavelength. Only two of nine commercial samples presented characteristics similar to the authentic Bauhinia forficata spp., considering the full HPLC-UV/PDA data. CONCLUSION: The combination of MCR-ALS and PCA is very useful when applied to a group of samples where a general alignment procedure could not be applied due to the different chromatographic profiles. This work also demonstrates the need of more strict control from the health authorities regarding herbal products available on the market. PMID- 26047148 TI - [Editorial comment: Interventional radiology, radiologic intervention]. PMID- 26047149 TI - [Revascularisation of the aorta, of the renal and of the lower limb arterial systems]. AB - Revascularisation aims to create a patent lumen in an acutely or chronically occluded or stenosed vessel. Interventional radiology has developed and used minimally invasive methods for decades concurring surgical methods and medical therapy. Innovative fields in healthcare may be handicapped since revolutionary solutions usually gain wide acceptance slowly and the results of randomized controlled trials are reported late. At present endovascular recanalization, dilatation and stent placement have achieved a well-established role in the treatment of stenosis or occlusion of the aorta, and renal and peripheral arteries. PMID- 26047150 TI - [Interventional radiology treatment of extensive pulmonary embolism and thromboembolic diseases]. AB - The authors discuss interventional radiological methods in the field of vascular interventions applied in venous system diseases. Venous diseases can be life threatening without appropriate treatment and can lead to chronic venous diseases and venous insufficiency with long-term reduction in the quality of life. In addition, recurrent clinical symptoms require additional treatments. Interventional radiology has several methods that can provide fast and complete recovery if applied in time. The authors summarize these methods hoping that they will be available for a wide range of patients through the establishment of Interventional Radiological Centres and will be a part of the daily routine of patient care. Regarding the frequency of venous diseases and its influance on life quality the authors would like to draw attention to interventional radiological techniques and modern therapeutic possibilities. PMID- 26047151 TI - [Interventional neuroradiology: current options]. AB - Modern interventional neuroradiology has a leading role in the treatment of ischemic and hemorrhagic stroke, and it provides more and more important treatment options for degenerative diseases of the vertebral column and the management of correlated pain. During the last decades interventional neuroradiology has played a primary role in the treatment of intracranial berry aneurysms due to the continuous technical improvements. Ongoing studies proved superiority of mechanical stent-thrombectomy in acute proximal occlusion of cerebral arteries. Less invasive neurointerventional methods, such as vertebroplasty, are widely used in osteoporotic and neoplastic pathologic fractures of the vertebral bodies. These treatments should be performed in a specialized center by well trained physicians. PMID- 26047152 TI - [Management of acute and subacute clinical situations by interventional radiology: non-vascular interventions and treatment for hemoptysis]. AB - Interventional radiology provides fast, straightforward and tolerable solutions for many medical problems including acute and subacute situations. Aspiration and drainage of fluid collections, biliary and endourologic interventions and gastrointestinal interventions are parts of non-vascular interventions. In addition, the authors discuss in detail interventional radiological treatment options in patients with hemoptysis. In acute cases interventions must be performed within 12-24 hours. For background, an everyday 24 hours service should be provided with well-trained personnel, high quality equipment and devices, and a reasonable financial reimbursement should be included, too. Multidisciplinary teamwork, consultations, consensus in indications and structured education should make these centers function most effectively. PMID- 26047153 TI - [From image-guided biopsies to locoregional tumour treatments]. AB - Infiltrating many traditional discipline, interventional radiology achieved a dynamic progress during the last 50 years. Collaboration with the modern, personalised, quality-sensitive oncology opened a new horizon for oncologic interventions in the early 1980s. This complex field needs multiple skills and a broadened view from the interventional radiologist. The aim of this paper is to summarize the "menu" of present and prospective therapeutic tools in oncointerventional radiology. PMID- 26047154 TI - [Interventional radiology and radiation therapy]. AB - The revolutionary role of modern cross-sectional imaging, the improved target definition in CT/MRI image guided brachytherapy, the precise topography for applicator and anatomy contribute to a better knowledge and management of tumors and critical organs. Further developments and functional imaging is expected to lead to a broad use of patient tailored therapy in the field of interventional radiation oncology. PMID- 26047156 TI - Biomechanical characteristics of adults walking forward and backward in water at different stride frequencies. AB - The aim of this study was to examine spatiotemporal characteristics and joint angles during forward and backward walking in water at low and high stride frequency. Eight healthy adults (22.1 +/- 1.1 years) walked forward and backward underwater at low (50 pulses) and high frequency (80 pulses) at the xiphoid process level with arms crossed at the chest. The main differences observed were that the participants presented a greater speed (0.58 vs. 0.85 m/s) and more asymmetry of the step length (1.24 vs. 1.48) at high frequency whilst the stride and step length (0.84 vs. 0.7 m and 0.43 vs. 0.35 m, respectively) were lower compared to low frequency (P < 0.05). Support phase duration was higher at forward walking than backward walking (61.2 vs. 59.0%). At initial contact, we showed that during forward walking, the ankle and hip presented more flexion than during backward walking (ankle: 84.0 vs. 91.8o and hip: 22.8 vs. 8.0o; P < 0.001). At final stance, the knee and hip were more flexed at low frequency than at high frequency (knee: 150.0 vs. 157.0o and hip: -12.2 vs. -14.5o; P < 0.001). The knee angle showed more flexion at forward walking (134.0o) than backward walking (173.1o) (P < 0.001). In conclusion, these results show how forward and backward walking in water at different frequencies differ and contribute to a better understanding of this activity in training and rehabilitation. PMID- 26047158 TI - Erratum. PMID- 26047157 TI - Exome Sequencing of Phenotypic Extremes Identifies CAV2 and TMC6 as Interacting Modifiers of Chronic Pseudomonas aeruginosa Infection in Cystic Fibrosis. AB - Discovery of rare or low frequency variants in exome or genome data that are associated with complex traits often will require use of very large sample sizes to achieve adequate statistical power. For a fixed sample size, sequencing of individuals sampled from the tails of a phenotype distribution (i.e., extreme phenotypes design) maximizes power and this approach was recently validated empirically with the discovery of variants in DCTN4 that influence the natural history of P. aeruginosa airway infection in persons with cystic fibrosis (CF; MIM219700). The increasing availability of large exome/genome sequence datasets that serve as proxies for population-based controls affords the opportunity to test an alternative, potentially more powerful and generalizable strategy, in which the frequency of rare variants in a single extreme phenotypic group is compared to a control group (i.e., extreme phenotype vs. control population design). As proof-of-principle, we applied this approach to search for variants associated with risk for age-of-onset of chronic P. aeruginosa airway infection among individuals with CF and identified variants in CAV2 and TMC6 that were significantly associated with group status. These results were validated using a large, prospective, longitudinal CF cohort and confirmed a significant association of a variant in CAV2 with increased age-of-onset of P. aeruginosa airway infection (hazard ratio = 0.48, 95% CI=[0.32, 0.88]) and variants in TMC6 with diminished age-of-onset of P. aeruginosa airway infection (HR = 5.4, 95% CI=[2.2, 13.5]) A strong interaction between CAV2 and TMC6 variants was observed (HR=12.1, 95% CI=[3.8, 39]) for children with the deleterious TMC6 variant and without the CAV2 protective variant. Neither gene showed a significant association using an extreme phenotypes design, and conditions for which the power of an extreme phenotype vs. control population design was greater than that for the extreme phenotypes design were explored. PMID- 26047159 TI - High throughput cross-interaction measures for human IgG1 antibodies correlate with clearance rates in mice. AB - Although improvements in technology for the isolation of potential therapeutic antibodies have made the process increasingly predictable, the development of biologically active monoclonal antibodies (mAbs) into drugs can often be impeded by developability issues such as poor expression, solubility, and promiscuous cross-reactivity. Establishing early stage developability screening assays capable of predicting late stage behavior is therefore of high value to minimize development risks. Toward this goal, we selected a panel of 16 monoclonal antibodies (mAbs) representing different developability profiles, in terms of self- and cross-interaction propensity, and examined their downstream behavior from expression titer to accelerated stability and pharmacokinetics in mice. Clearance rates showed significant rank-order correlations to 2 cross-interaction related assays, with the closest correlation to a non-specificity assay on the surface of yeast. Additionally, 2 self-association assays correlated with each other but not to mouse clearance rate. This case study suggests that combining assays capable of high throughput screening of self- and cross-interaction early in the discovery stage could significantly lower downstream development risks. PMID- 26047160 TI - Land use changes and its driving forces in hilly ecological restoration area based on gis and RS of northern China. AB - Land use change is one of the important aspects of the regional ecological restoration research. With remote sensing (RS) image in 2003, 2007 and 2012, using geographic information system (GIS) technologies, the land use pattern changes in Yimeng Mountain ecological restoration area in China and its driving force factors were studied. Results showed that: (1) Cultivated land constituted the largest area during 10 years, and followed by forest land and grass land; cultivated land and unused land were reduced by 28.43% and 44.32%, whereas forest land, water area and land for water facilities and others were increased. (2) During 2003-2007, forest land change showed the largest, followed by unused land and grass land; however, during 2008-2012, water area and land for water facilities change showed the largest, followed by grass land and unused land. (3) Land use degree was above the average level, it was in the developing period during 2003-2007 and in the degenerating period during 2008-2012. (4) Ecological Restoration Projects can greatly change the micro topography, increase vegetation coverage, and then induce significant changes in the land use distribution, which were the main driving force factors of the land use pattern change in the ecological restoration area. PMID- 26047161 TI - The Total Synthesis of Retrojusticidin B, Justicidin E, and Helioxanthin. AB - Making use of a tandem free radical cyclization process mediated by Mn(OAc)3 as a key operation, the total synthesis of retrojusticidin B, justicidin E, and helioxanthin has been concisely achieved in four or five steps in an overall yield of 45, 33 and 44%, respectively, from a common starting material 5. PMID- 26047162 TI - Dental wear estimation using a digital intra-oral optical scanner and an automated 3D computer vision method. AB - The objective of this work was to propose an automated and direct process to grade tooth wear intra-orally. Eight extracted teeth were etched with acid for different times to produce wear and scanned with an intra-oral optical scanner. Computer vision algorithms were used for alignment and comparison among models. Wear volume was estimated and visual scoring was achieved to determine reliability. Results demonstrated that it is possible to directly detect submillimeter differences in teeth surfaces with an automated method with results similar to those obtained by direct visual inspection. The investigated method proved to be reliable for comparison of measurements over time. PMID- 26047163 TI - Comparison of active-set method deconvolution and matched-filtering for derivation of an ultrasound transit time spectrum. AB - The quality of ultrasound computed tomography imaging is primarily determined by the accuracy of ultrasound transit time measurement. A major problem in analysis is the overlap of signals making it difficult to detect the correct transit time. The current standard is to apply a matched-filtering approach to the input and output signals. This study compares the matched-filtering technique with active set deconvolution to derive a transit time spectrum from a coded excitation chirp signal and the measured output signal. The ultrasound wave travels in a direct and a reflected path to the receiver, resulting in an overlap in the recorded output signal. The matched-filtering and deconvolution techniques were applied to determine the transit times associated with the two signal paths. Both techniques were able to detect the two different transit times; while matched-filtering has a better accuracy (0.13 MUs versus 0.18 MUs standard deviations), deconvolution has a 3.5 times improved side-lobe to main-lobe ratio. A higher side-lobe suppression is important to further improve image fidelity. These results suggest that a future combination of both techniques would provide improved signal detection and hence improved image fidelity. PMID- 26047164 TI - Intrinsic properties of cupric oxide nanoparticles enable effective filtration of arsenic from water. AB - The contamination of arsenic in human drinking water supplies is a serious global health concern. Despite multiple years of research, sustainable arsenic treatment technologies have yet to be developed. This study demonstrates the intrinsic abilities of cupric oxide nanoparticles (CuO-NP) towards arsenic adsorption and the development of a point-of-use filter for field application. X-ray diffraction and X-ray photoelectron spectroscopy experiments were used to examine adsorption, desorption, and readsorption of aqueous arsenite and arsenate by CuO-NP. Field experiments were conducted with a point-of-use filter, coupled with real-time arsenic monitoring, to remove arsenic from domestic groundwater samples. The CuO NP were regenerated by desorbing arsenate via increasing pH above the zero point of charge. Results suggest an effective oxidation of arsenite to arsenate on the surface of CuO-NP. Naturally occurring arsenic was effectively removed by both as prepared and regenerated CuO-NP in a field demonstration of the point-of-use filter. A sustainable arsenic mitigation model for contaminated water is proposed. PMID- 26047165 TI - Factors Affecting Interocular Differences in Retinal Nerve Fiber Layer Thickness. PMID- 26047166 TI - Relationship Between Pattern Electroretinogram, Frequency-Domain OCT, and Automated Perimetry in Chronic Papilledema From Pseudotumor Cerebri Syndrome. AB - PURPOSE: We evaluated the ability of transient pattern electroretinogram (PERG) parameters to differentiate between eyes with visual field (VF) loss and resolved papilledema from pseudotumor cerebri syndrome (PTC) and controls, to compare PERG and optical coherence tomography (OCT) with regard to discrimination ability, and to assess the correlation between PERG, frequency domain OCT (FD-OCT), and VF measurements. METHODS: The VFs and full-field stimulation PERGs based on 48 and 14-min checks were obtained from patients with PTC (n = 24, 38 eyes) and controls (n = 26, 34 eyes). In addition, FD-OCT peripapillary retinal nerve fiber layer (RNFL) and segmented macular layer measurements were obtained and correlation coefficients were determined. RESULTS: Compared to controls, PERG N95 and P50+N95 amplitude measurements with 48-minute checks were significantly reduced in eyes with resolved papilledema from PTC. Both PERG N95 amplitude and OCT parameters were able to discriminate papilledema eyes from controls with a similar performance. Significant correlations, ranging from 0.25 (P < 0.05) to 0.43 (P < 0.01) were found between PERG amplitude values and OCT-measured macular ganglion cell layer thickness, RNFL thickness, and total retinal thickness. The PERG amplitude also was significantly associated with VF sensitivity loss with correlation coefficients ranging from 0.24 (P < 0.05) and 0.35 (P < 0.01). CONCLUSIONS: The PERG measurements were able to detect neural loss in PTC eyes with resolved papilledema and were reasonably well correlated with OCT measurements and VF parameters. Thus, PERG may be a useful tool in the monitoring of retinal neural loss in eyes with active papilledema from PTC. PMID- 26047168 TI - MicroRNA Expression Profile and the Role of miR-204 in Corneal Wound Healing. AB - PURPOSE: MicroRNAs (miRNAs) are endogenous short chain (~ 22-nucleotide) noncoding RNAs that inhibit protein translation through binding to target mRNAs. Recent studies have implied that miRNAs play a regulatory role in corneal development. Here we profile their involvement in corneal epithelial renewal, develop an miRNA-target network that affects wound healing outcome, and investigate the function of miR-204 in this response. METHODS: NanoString nCounter technology and bioinformatics analyzed miRNA expression levels and their targets during mouse corneal epithelial wound healing. Real-time RT-PCR was performed to detect miR-204 expression in mouse corneal epithelium. Human corneal epithelial cells (HCECs) were transfected with miR-204 using transfection reagent. MTS (3-[4,5-dimethylthiazol-2-yl]-5-[3-carboxymethoxyphenyl]-2-[4 sulfophenyl]-2H-tetrazolium, inner salt) and a scratch wound-healing assay evaluated the effects of miR-204 expression on HCEC proliferation and migration, respectively. Cell cycle analysis was performed by flow cytometry. Expression of sirtuin 1 (SIRT1) was determined by Western blot analysis. RESULTS: Fifteen miRNAs were dramatically downregulated, whereas 14 other miRNAs were markedly upregulated during corneal wound healing. Expression of miR-204 fell the most during this process. Transfection of miR-204 into HCECs led to a significant decline in cell proliferation and induced cell cycle G1-arrest. Furthermore, in these cells, miR-204 also inhibited migration. Sirtuin 1 was confirmed as a target of miR-204. CONCLUSIONS: During mouse corneal epithelial wound healing, a complex miRNA-gene network was resolved that is modulated by changes in miR-204 expression. Downregulation of this miRNA appears to be an essential response to injury since its decline promotes human corneal epithelial cell proliferation and migration. Therefore, miR-204 could be a biomarker of this process. PMID- 26047167 TI - Prevalence of Optic Disc Hemorrhage in Korea: The Korea National Health and Nutrition Examination Survey. AB - PURPOSE: We determined the prevalence of disc hemorrhage (DH) and the associated factors of DH in a large Korean population based on the data from the nationwide cross-sectional survey, the Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: We performed a retrospective review of the KNHANES dataset covering January 2012 to December 2012. A total of 5612 subjects aged 19 years and older had completed health interviews, physical examinations, and ophthalmologic assessment, including comprehensive glaucoma evaluation. Two masked graders evaluated the fundus photography to detect DH. The prevalence of DH in each subject was defined as the presence of DH in at least one eye. RESULTS: The estimated prevalence of DH in the Korean population aged 19 years and older was 0.42% (95% confidence interval [CI], 0.26-0.67), which increased with age, 1.04-fold in 1 year and 1.54-fold in 10 years, according to Poisson regression analysis. The estimated prevalences of DH were 0.54% in subjects aged 30 years and older, 0.67% in those aged 40 years and older, and 0.71% in those aged 50 years and older. Glaucoma was diagnosed in 4.18% (95% CI, 3.58-4.88) of cases, and the prevalence of DH in glaucomatous subjects was 2.82% (95% CI, 1.53 5.14). In a multivariate analysis, the occurrence of DH was significantly associated with age (P < 0.001) and the presence of glaucoma (P < 0.001). CONCLUSIONS: The prevalences of DH among Koreans are similar to the figures reported by previous population-based studies for the same age ranges. Associated factors were age and glaucoma. The presence of DH suggested the presence of glaucoma with a positive predictive value of 41.4%. PMID- 26047169 TI - Effect of Pupil Size on Flicker ERGs Recorded With RETeval System: New Mydriasis Free Full-Field ERG System. AB - PURPOSE: We studied whether pupil size affects the flicker electroretinograms (ERGs) recorded by RETeval, a new mydriasis-free full-field flicker ERG system. METHODS: We studied 10 healthy subjects. The RETeval manufacturer claims that the system delivers a constant flash retinal illuminance by adjusting the flash luminance to compensate for changes in the pupil size. Two experiments were performed. First, the flicker ERG was recorded every 3 minutes after the instillation of mydriatics. Second, the flicker ERG was recorded while the subjects wore soft contact lenses with two different artificial pupil sizes. RESULTS: The first experiment showed that as pupil size increased, the amplitudes of the fundamental component of the flicker ERG did not change significantly, but the implicit times of the fundamental component were significantly prolonged for larger pupil sizes. There was a significant positive correlation between the pupillary area and implicit time of the fundamental component (r = 0.93, P < 0.001). The second experiment showed that the implicit times of the fundamental component in the flicker ERG were significantly longer with larger artificial pupil. CONCLUSIONS: The results suggest that the effective retinal illuminance of the stimulus delivered by the RETeval system decreases for large pupil sizes. However, in most clinical testing situations, patients' undilated pupils will likely be sufficiently small to fall within the range for which the system delivers a stimulus of constant retinal illuminance. PMID- 26047170 TI - Pathological Involvement of Astrocyte-Derived Lipocalin-2 in the Demyelinating Optic Neuritis. AB - PURPOSE: The current study was done to determine the role of lipocalin-2 (LCN2) in the pathogenesis of demyelinating optic neuritis using an experimental autoimmune optic neuritis (EAON) model. METHODS: The EAON was induced by subcutaneous immunization with an emulsified mixture of myelin oligodendrocyte glycoprotein (MOG35-55) peptide in mice. The LCN2 expression was examined in the optic nerve after MOG peptide injection. Degree of demyelination, inflammatory infiltration, glial activation, and expression profile of inflammatory mediators in the optic nerve were compared between LCN2 knockout (KO) animals and wild-type littermates by histological analysis and real-time PCR following EAON induction. Plasma levels of LCN2 in patients with optic neuritis were measured by ELISA. RESULTS: The expression of LCN2 was notably increased in the optic nerve after EAON induction. Expression of LCN2 was colocalized with reactive astrocytes. A significant reduction of demyelination, inflammatory infiltration, and gliosis was demonstrated in the optic nerve of LCN2 KO mice. The LCN2 KO mice also showed markedly reduced gene expression associated with the M1-polarized glia phenotype and toll-like receptor signaling in the optic nerve. The LCN2 levels in plasma were significantly higher in optic neuritis patients (71.6 +/- 10.6 ng/mL) compared to healthy controls (37.4 +/- 9.1 ng/mL, P = 0.0284). CONCLUSIONS: In this study, we demonstrated a significant induction of LCN2 expression in astrocytes of the optic nerve following EAON induction. Our results imply that astrocyte-derived LCN2 may have a pivotal role in the development of demyelinating optic neuritis, and LCN2 can be a therapeutic target to alleviate immune and inflammatory damage in the optic nerve. PMID- 26047171 TI - Adaptation to Laterally Displacing Prisms in Anisometropic Amblyopia. AB - PURPOSE: Using visual feedback to modify sensorimotor output in response to changes in the external environment is essential for daily function. Prism adaptation is a well-established experimental paradigm to quantify sensorimotor adaptation; that is, how the sensorimotor system adapts to an optically-altered visuospatial environment. Amblyopia is a neurodevelopmental disorder characterized by spatiotemporal deficits in vision that impacts manual and oculomotor function. This study explored the effects of anisometropic amblyopia on prism adaptation. METHODS: Eight participants with anisometropic amblyopia and 11 visually-normal adults, all right-handed, were tested. Participants pointed to visual targets and were presented with feedback of hand position near the terminus of limb movement in three blocks: baseline, adaptation, and deadaptation. Adaptation was induced by viewing with binocular 11.4 degrees (20 prism diopter [PD]) left-shifting prisms. All tasks were performed during binocular viewing. RESULTS: Participants with anisometropic amblyopia required significantly more trials (i.e., increased time constant) to adapt to prismatic optical displacement than visually-normal controls. During the rapid error correction phase of adaptation, people with anisometropic amblyopia also exhibited greater variance in motor output than visually-normal controls. CONCLUSIONS: Amblyopia impacts on the ability to adapt the sensorimotor system to an optically-displaced visual environment. The increased time constant and greater variance in motor output during the rapid error correction phase of adaptation may indicate deficits in processing of visual information as a result of degraded spatiotemporal vision in amblyopia. PMID- 26047173 TI - Femtosecond Laser-Assisted Corneal Small Incision Allogenic Intrastromal Lenticule Implantation in Monkeys: A Pilot Study. AB - PURPOSE: Lenticule implantation can be used to correct vision problems. However, it is significantly restrained by the sources of autologous lenticules. The aim of the present study was to investigate the feasibility and effects of femtosecond laser-assisted corneal small incision allogenic intrastromal lenticule implantation (AILI) in monkeys. METHODS: Six healthy adult monkeys were included in this study. Femtosecond lenticule extraction (-4.0 diopter [D] correction, 5.0-mm optical zone) was performed in one eye of two monkeys and both eyes of one monkey. Each extracted refractive lenticule was allogenically transplanted into a femtosecond laser-created corneal stromal pocket in one eye of the other two monkeys and one monkey's both eyes. Pre- and postoperative (1 or 3 days, 1 month, and 6 months) slit lamp microscopy, corneal topography, anterior segment optical coherence tomography, and in vivo confocal microscopy were performed. RESULTS: Corneal edema occurred in the early postoperative days with a large number of hyperreflective particles around the borders. Corneal tissue edema gradually decreased. Nerve fiber regeneration could be detected in the lenticule layer at 6 months. Overall, 3.27 +/- 1.2 D corneal power was increased at 6 months, accounting for 82% of the intended correction. At the same time point, corneal stroma was 69 +/- 11 MUm thicker than preoperative ones and was roughly equal to the maximum thickness of implanted lenticules. No significant complications were observed. CONCLUSIONS: The AILI technique seems to be feasible and safe for increasing corneal stromal thickness and changing corneal refractive power, which may provide a useful method for treatment of keratoectasia, presbyopia, and hyperopia. PMID- 26047172 TI - The Photopic Negative Response in Idiopathic Intracranial Hypertension. AB - PURPOSE: To evaluate the photopic negative response (PhNR) as an index of retinal ganglion cell (RGC) function in idiopathic intracranial hypertension (IIH). METHODS: Amplitude and implicit time of the PhNR, as elicited by full-field, brief-luminance flashes, was measured in IIH (n = 10) and visually normal control (n = 15) subjects. Visual function was assessed in IIH subjects using standard automated perimetry mean deviation (SAP-MD) scores. Optic nerve structure was evaluated using the Frisen papilledema grading scale (FPG). Macula ganglion cell complex volume (GCCV) was extracted from optical coherence tomography images to assess RGC loss. RESULTS: Median PhNR amplitude was significantly lower in IIH subjects compared with control subjects (P = 0.015, Mann-Whitney Rank Sum [MW]), but implicit time was similar (P = 0.54, MW). In IIH subjects, PhNR amplitude and SAP-MD were correlated (Pearson's r = 0.78, P = 0.008). Ganglion cell complex volume was correlated with both SAP-MD (r = 0.72, P = 0.019) and PhNR amplitude (r = 0.77, P = 0.009). Multivariate linear regression models demonstrated that the correlation between GCCV and PhNR amplitude was improved by accounting for FPG in the model (r = 0.94, P < 0.0001), but the correlation between GCCV and SAP MD was not (r = 0.74, P = 0.009). CONCLUSIONS: Photopic negative response amplitude, which can be decreased in IIH subjects, correlates well with a clinical measure of visual function (SAP-MD). In multivariate models, it correlated with both an imaging measure of chronic ganglion cell injury (GCCV) and a clinical measure of acute optic nerve head pathology (FPG). Further studies are needed to determine the clinical utility of PhNR as a marker for diagnosis and monitoring of IIH. PMID- 26047174 TI - Characterization of Retinal Vascular and Neural Damage in a Novel Model of Diabetic Retinopathy. AB - PURPOSE: Diabetic retinopathy (DR) is a major cause of blindness globally. Investigating the underlying mechanisms of DR would be aided by a suitable mouse model that developed key features seen in the human disease, and did so without carrying genetic modifications. This study was undertaken to produce such a model. METHODS: Our panel of Collaborative Cross strains was screened for DR-like features after induction of diabetes by intravenous injection with alloxan or streptozotocin. Both flat-mounted whole-retina and histologic sections were studied for the presence of retinal lesions. Progression of DR was also studied by histologic examination of the retinal vascular and neural structure at various time points after diabetes onset. In addition, microarray investigations were conducted on retinas from control and diabetic mice. RESULTS: Features of DR such as degenerated pericytes, acellular capillaries, minor vascular proliferation, gliosis of Muller cells, and loss of ganglion cells were noted as early as day 7 in some mice. These lesions became more evident with time. After 21 days of diabetes, severe vascular proliferation, microaneurysms, preretinal damage, increased Muller cell gliosis, and damage to the outer retina were all obvious. Microarray studies found significant differential expression of multiple genes known to be involved in DR. CONCLUSIONS: The FOT_FB strain provides a useful model to investigate the pathogenesis of DR and to develop treatments for this vision-threatening disease. PMID- 26047175 TI - Unidirectional thermal expansion in edge-sharing BO4 tetrahedra contained KZnB3O6. AB - Borates are among a class of compounds that exhibit rich structural diversity and find wide applications. The formation of edge-sharing (es-) BO4 tetrahedra is extremely unfavored according to Pauling's third and fourth rules. However, as the first and the only es-borate obtained under ambient pressure, es-KZnB3O6 shows an unexpected high thermal stability up to its melting point. The origin of this extraordinary stability is still unclear. Here, we report a novel property in KZnB3O6: unidirectional thermal expansion, which plays a role in preserving es BO4 from disassociation at elevated temperatures. It is found that this unusual thermal behavior originates from cooperative rotations of rigid groups B6O12 and Zn2O6, driven by anharmonic thermal vibrations of K atoms. Furthermore, a detailed calculation of phonon dispersion in association with this unidirectional expansion predicts the melting initiates with the breakage of the link between BO3 and es-BO4. These findings will broaden our knowledge of the relationship between structure and property and may find applications in future. PMID- 26047177 TI - Modeling the biotic and abiotic factors that describe the number of active off host Amblyomma americanum larvae. AB - Amblyomma americanum (L.) is a three-host tick that spends most of its life off host and is an important vector of pathogens in the eastern United States. Our objectives were to develop a predictive statistical model that describes the number of active, off-host larvae from 2007 to 2011 and to determine the environmental variables associated with this pattern. Data used in this study came from monitoring conducted in northeast Missouri in which off-host ticks were collected from a permanent plot in a forest and an old field habitat every other week from approximately February to December. Variables examined were day length, degree days, total precipitation prior to sampling, wind speed, saturation deficit, number of adults prior to sampling, and collection site. Of the four regression models tested, the negative binomial model was selected. Fitted candidate models were compared relative to one another using values of eight model selection criteria and model averaging was used to develop a predictive model. The residual plots indicated that the weighted average model performs well in describing the number of larvae. Of the variables considered, the number of larvae was most strongly associated with increasing degree days, the number of active adults prior to sampling, and the forested site. PMID- 26047176 TI - Emotional context facilitates cortical prediction error responses. AB - In the predictive coding framework, mismatch negativity (MMN) is regarded a correlate of the prediction error that occurs when top-down predictions conflict with bottom-up sensory inputs. Expression-related MMN is a relatively novel construct thought to reflect a prediction error specific to emotional processing, which, however, has not yet been tested directly. Our paradigm includes both neutral and emotional deviants, thereby allowing for investigating whether expression-related MMN is emotion-specific or unspecifically arises from violations of a given sequence. Twenty healthy participants completed a visual sequence oddball task where they were presented with (1) sequence deviants, (2) emotional sequence deviants, and (3) emotional deviants. Mismatch components were assessed at ventral occipitotemporal scalp sites and analyzed regarding their amplitudes, spatiotemporal profiles, and neuronal sources. Expression-related MMN could be clearly separated from its neutral counterpart in all investigated aspects. Specifically, expression-related MMN showed enhanced amplitude, shorter latency, and different neuronal sources. Our results, therefore, provide converging evidence for a quantitative specificity of expression-related MMN and seems to provide an opportunity to study prediction error during preattentive emotional processing. Our neurophysiological evidence ultimately suggests that a basic cognitive operator, the prediction error, is enhanced at the cortical level by processing of emotionally salient stimuli. PMID- 26047178 TI - Volatile semiochemical-conditioned attraction of the male yellow fever mosquito, Aedes aegypti, to human hosts. AB - We investigated the olfactory responses of male mosquitoes to kairomones of vertebrate hosts in a dual-port olfactometer. The behavioral responses of unmated and mated male and female mosquitoes from one to ten days old to human odors were compared to the odors of different human hosts. To evaluate the relationship between the age of male mosquitoes and their responses, we performed experiments with males at different ages. Unmated Ae. aegypti males, one to two days old, did not fly upwind to human odor, whereas between three and ten days old they exhibited increased flight activity. The results showed that unmated and mated females were attracted by human odor, but those mated were more attracted by human odor than when unmated. Mated males were, in general, attracted by human odor, while the unmated males were not attracted but showed increased flight activity in the presence of human odor, suggesting swarming behavior. Further studies should be carried out in order to determine the role of human odors on male Ae. aegypti behavior. PMID- 26047179 TI - Comparison of manual and semi-automatic DNA extraction protocols for the barcoding characterization of hematophagous louse flies (Diptera: Hippoboscidae). AB - The barcoding of life initiative provides a universal molecular tool to distinguish animal species based on the amplification and sequencing of a fragment of the subunit 1 of the cytochrome oxidase (COI) gene. Obtaining good quality DNA for barcoding purposes is a limiting factor, especially in studies conducted on small-sized samples or those requiring the maintenance of the organism as a voucher. In this study, we compared the number of positive amplifications and the quality of the sequences obtained using DNA extraction methods that also differ in their economic costs and time requirements and we applied them for the genetic characterization of louse flies. Four DNA extraction methods were studied: chloroform/isoamyl alcohol, HotShot procedure, Qiagen DNeasy((r)) Tissue and Blood Kit and DNA Kit Maxwell((r)) 16LEV. All the louse flies were morphologically identified as Ornithophila gestroi and a single COI based haplotype was identified. The number of positive amplifications did not differ significantly among DNA extraction procedures. However, the quality of the sequences was significantly lower for the case of the chloroform/isoamyl alcohol procedure with respect to the rest of methods tested here. These results may be useful for the genetic characterization of louse flies, leaving most of the remaining insect as a voucher. PMID- 26047181 TI - Sand fly fauna (Diptera: Psychodidae) from the Goytacazes National Forest and surrounding areas of southeastern Brazil. AB - Most studies of the sand fly fauna in southeastern Brazil are conducted in the peridomiciliary environment of leishmaniasis endemic regions. Therefore, to increase the knowledge about diversity and richness of sand fly conservation areas, we describe here the sand fly fauna from the National Forest of Goytacazes (NFG), state of Espirito Santo, Brazil, and its surroundings areas. We also used sand fly fauna records from eight conservations units within the state of Espirito Santo to understand the similarity and relationships among them. The sand flies were simultaneously collected from June, 2008 to May, 2009 in two different environments: a preserved environment represented by the NFG and a modified environment represented by a peridomicile. To establish the similarity among the conservation units, we used a method very similar to parsimony analysis of endemism. We collected 2,466 sand fly specimens belonging to 13 species. Pressatia choti and Nyssomyia intermedia were the most abundant sand fly species. Ny. intermedia is a known vector of Leishmania braziliensis and epidemiological surveillance must be conducted in the area. We discuss aspects regarding the diversity of sand flies as well as the risk of transmission of Leishmania parasites in the area. We also provide for the first time a hypothesis of similarity relationships among conservation units within the state of Espirito Santo. PMID- 26047180 TI - Phylogeny of anopheline (Diptera: Culicidae) species in southern Africa, based on nuclear and mitochondrial genes. AB - A phylogeny of anthropophilic and zoophilic anopheline mosquito species was constructed, using the nuclear internal transcribed spacer 2 (ITS2) and mitochondrial cytochrome oxidase subunit I (COI) genes. The ITS2 alignment, typically difficult due to its noncoding nature and large size variations, was aided by using predicted secondary structure, making this phylogenetically useful gene more amenable to investigation. This phylogeny is unique in explicitly including zoophilic, non-vector anopheline species in order to illustrate their relationships to malaria vectors. Two new, cryptic species, Anopheles funestus like and Anopheles rivulorum-like, were found to be present in Zambia for the first time. Sequences from the D3 region of the 28S rDNA suggest that the Zambian An. funestus-like may be a hybrid or geographical variant of An. funestus-like, previously reported in Malawi. This is the first report of An. rivulorum-like sympatric with An. rivulorum (Leeson), suggesting that these are separate species rather than geographic variants. PMID- 26047182 TI - Satellite-derived NDVI, LST, and climatic factors driving the distribution and abundance of Anopheles mosquitoes in a former malarious area in northwest Argentina. AB - Distribution and abundance of disease vectors are directly related to climatic conditions and environmental changes. Remote sensing data have been used for monitoring environmental conditions influencing spatial patterns of vector-borne diseases. The aim of this study was to analyze the effect of the Normalized Difference Vegetation Index (NDVI) and Land Surface Temperature (LST) obtained from the Moderate Resolution Imaging Spectroradiometer (MODIS), and climatic factors (temperature, humidity, wind velocity, and accumulated rainfall) on the distribution and abundance of Anopheles species in northwestern Argentina using Poisson regression analyses. Samples were collected from December, 2001 to December, 2005 at three localities, Aguas Blancas, El Oculto and San Ramon de la Nueva Oran. We collected 11,206 adult Anopheles species, with the major abundance observed at El Oculto (59.11%), followed by Aguas Blancas (22.10%) and San Ramon de la Nueva Oran (18.79%). Anopheles pseudopunctipennis was the most abundant species at El Oculto, Anopheles argyritarsis predominated in Aguas Blancas, and Anopheles strodei in San Ramon de la Nueva Oran. Samples were collected throughout the sampling period, with the highest peaks during the spring seasons. LST and mean temperature appear to be the most important variables determining the distribution patterns and major abundance of An. pseudopunctipennis and An. argyritarsis within malarious areas. PMID- 26047184 TI - Reproductive and developmental costs of deltamethrin resistance in the Chagas disease vector Triatoma infestans. AB - Effective chemical control relies on reducing vector population size. However, insecticide selection pressure is often associated with the development of resistant populations that reduce control success. In treated areas, these resistant individuals present an adaptive advantage due to enhanced survival. Resistance can also lead to negative effects when the insecticide pressure ceases. In this study, the biological effects of deltamethrin resistance were assessed in the Chagas disease vector Triatoma infestans. The length of each developmental stage and complete life cycle, mating rate, and fecundity were evaluated. Susceptible and resistant insects presented similar mating rates. A reproductive cost of resistance was expressed as a lower fecundity in the resistant colony. Developmental costs in the resistant colony were in the form of a shortening of the second and third nymph stage duration and an extension of the fifth stage. A maternal effect of deltamethrin resistance is suggested as these effects were identified in resistant females and their progeny independently of the mated male's deltamethrin response. Our results suggest the presence of pleiotropic effects of deltamethrin resistance. Possible associations of these characters to other traits such as developmental delays and behavioral resistance are discussed. PMID- 26047183 TI - New baseline environmental assessment of mosquito ecology in northern Haiti during increased urbanization. AB - The catastrophic 2010 earthquake in Port-au-Prince, Haiti, led to the large-scale displacement of over 2.3 million people, resulting in rapid and unplanned urbanization in northern Haiti. This study evaluated the impact of this unplanned urbanization on mosquito ecology and vector-borne diseases by assessing land use and change patterns. Land-use classification and change detection were carried out on remotely sensed images of the area for 2010 and 2013. Change detection identified areas that went from agricultural, forest, or bare-land pre-earthquake to newly developed and urbanized areas post-earthquake. Areas to be sampled for mosquito larvae were subsequently identified. Mosquito collections comprised five genera and ten species, with the most abundant species being Culex quinquefasciatus 35% (304/876), Aedes albopictus 27% (238/876), and Aedes aegypti 20% (174/876). All three species were more prevalent in urbanized and newly urbanized areas. Anopheles albimanus, the predominate malaria vector, accounted for less than 1% (8/876) of the collection. A set of spectral indices derived from the recently launched Landsat 8 satellite was used as covariates in a species distribution model. The indices were used to produce probability surfaces maps depicting the likelihood of presence of the three most abundant species within 30 m pixels. Our findings suggest that the rapid urbanization following the 2010 earthquake has increased the amount of area with suitable habitats for urban mosquitoes, likely influencing mosquito ecology and posing a major risk of introducing and establishing emerging vector-borne diseases. PMID- 26047185 TI - Geographic variation on biological parameters of Meccus picturatus (Usinger), 1939 (Hemiptera: Reduviidae). AB - The biological parameters related to the life cycles of three populations of Meccus picturatus (Usinger) (Hemiptera: Reduviidae), one of the main vectors of Trypanosoma cruzi Chagas (Trypanosomatida: Trypanosomatidae), were evaluated. A cohort of each of three populations from geographically isolated localities in western Mexico was maintained under similar laboratory conditions, after which all three populations were compared to each other. In each cohort, 50.9 to 72.1% of nymphs completed the cycle. The average time from N1 to adult was approximately 175 days and different for the three studied cohorts. The number of blood meals between molts varied from one to three. The hatching rates as well as the fecundity per female per day were different among the three studied populations. Our results show that the three isolated populations are statistically different in some parameters from each other, which points to the importance of studying the biological characteristics of local populations of triatomines for estimating their capacity of transmitting T. cruzi to reservoir hosts. PMID- 26047186 TI - Dengue virus detection in Aedes aegypti larvae from southeastern Brazil. AB - The transmission of dengue, the most important arthropod-borne viral disease in Brazil, has been intensified over the past decades, along with the accompanying expansion and adaptation of its Aedes vectors. In the present study, we mapped dengue vectors in Ouro Preto and Ouro Branco, Minas Gerais, by installing ovitraps in 32 public schools. The traps were examined monthly between September, 2011 through July, 2012 and November, 2012 to April, 2013. The larvae were reared until the fourth stadium and identified according to species. The presence of dengue virus was detected by real time PCR and agarose gel electrophoresis. A total of 1,945 eggs was collected during the 17 months of the study. The Ovitrap Positivity Index (OPI) ranged from 0 to 28.13% and the Eggs Density Index (EDI) ranged from 0 to 59.9. The predominant species was Aedes aegypti, with 84.9% of the hatched larvae. Although the collection was low when compared to other ovitraps studies, vertical transmission could be detected. Of the 54 pools, dengue virus was detected in four Ae. aegypti pools. PMID- 26047187 TI - Bartonella henselae in eastern Poland: the relationship between tick infection rates and the serological response of individuals occupationally exposed to tick bites. AB - To explore the potential role of Ixodes ricinus as the presumed vector of Bartonella henselae in eastern Poland, ticks collected in various geographic locations were examined for the presence of B. henselae, and the results were matched against the prevalence of anti-B. henselae antibodies in individuals occupationally exposed to tick bites. The presence of Bartonella DNA was investigated by PCR in a total of 1,603 unfed Ixodes ricinus ticks. The presence of IgG antibodies against B. henselae was investigated in serum samples from 332 people occupationally exposed to tick bites (94 farmers and 238 forestry workers). The total prevalence of B. henselae in ticks was 1.7%; the infection rates in males (3.1%) and females (2.7%) were nearly ten times greater than in nymphs (0.3%). The prevalence of seropositive results in the risk group (30.4%), farmers (27.7%) and forestry workers (31.5%), was significantly greater compared to the control group (8.9%). The results showed a weak positive correlation between the degree of infection of ticks and humans living in the same geographic region. The lack of a direct relationship indicates that exposure to tick bites is only one of the factors contributing to the significant preponderance of a seropositive response to B. henselae in the forestry workers and farmers over the control group. Other factors must be considered, such as contact with cats, which are popular domestic animals in Polish villages, and exposure to cat fleas. PMID- 26047189 TI - Seasonal dynamics and habitat specificity of mosquitoes in an English wetland: implications for UK wetland management and restoration. AB - We engaged in field studies of native mosquitoes in a Cambridgeshire Fen, investigating a) the habitat specificity and seasonal dynamics of our native fauna in an intensively managed wetland, b) the impact of water-level and ditch management, and c) their colonization of an arable reversion to flooded grassland wetland expansion project. Studies from April to October, 2010 collected 14,000 adult mosquitoes (15 species) over 292 trap-nights and ~4,000 pre-imaginal mosquitoes (11 species). Open floodwater species (Aedes caspius and Aedes cinereus, 43.3%) and wet woodland species (Aedes cantans/annulipes and Aedes rusticus, 32.4%) dominated, highlighting the major impact of seasonal water-level management on mosquito populations in an intensively managed wetland. In permanent habitats, managing marginal ditch vegetation and ditch drying significantly affect densities of pre-imaginal anophelines and culicines, respectively. This study presents the first UK field evidence of the implications of wetland expansion through arable reversion on mosquito colonization. Understanding the heterogeneity of mosquito diversity, phenology, and abundance in intensively managed UK wetlands will be crucial to mitigating nuisance and vector species through habitat management and biocidal control. PMID- 26047188 TI - Development and validation of an arthropod maceration protocol for zoonotic pathogen detection in mosquitoes and fleas. AB - Arthropod-borne diseases remain a pressing international public health concern. While progress has been made in the rapid detection of arthropod-borne pathogens via quantitative real-time (qPCR), or even hand-held detection devices, a simple and robust maceration and nucleic acid extraction method is necessary to implement biosurveillance capabilities. In this study, a comparison of maceration techniques using five types of beads followed by nucleic acid extraction and detection were tested using two morphologically disparate arthropods, the Aedes aegypti mosquito and Xenopsylla spp. flea, to detect the zoonotic diseases dengue virus serotype-1 and Yersinia pestis. Post-maceration nucleic acid extraction was carried out using the 1-2-3 Platinum-Path-Sample-Purification (PPSP) kit followed by qPCR detection using the Joint Biological Agent Identification and Diagnostic System (JBAIDS). We found that the 5mm stainless steel beads added to the beads provided in the PPSP kit were successful in macerating the exoskeleton for both Ae. aegypti and Xenopsylla spp. Replicates in the maceration/extraction/detection protocol were increased in a stepwise fashion until a final 128 replicates were obtained. For dengue virus detection there was a 99% positivity rate and for Y. pestis detection there was a 95% positive detection rate. In the examination of both pathogens, there were no significant differences between qPCR instruments, days ran, time of day ran, or operators. PMID- 26047190 TI - Investigating the relationship between environmental factors and tick abundance in a small, highly heterogeneous region. AB - The tick Ixodes ricinus (L.) is the most important vector of tick-borne zoonoses in Europe. Apart from factors related to human behavior, tick abundance is a major driver of the incidence of tick-borne diseases in a given area and related data represent critical information for promoting effective public health policies. The present study analyzed the relationship between different environmental factors and tick abundance in order to improve the understanding of I. ricinus autecology and develop spatial predictive models that can be implemented in tick-borne disease prevention strategies. Ticks were sampled in 27 sites over a four-year period and different environmental variables were studied. Five simple models were developed that explain a large part of variation in tick abundance. Precipitation seems to play the most important role, followed by temperature, woodland coverage, and solar radiation. Model equations obtained in this study may enable the spatial interpolation and extension of tick abundance predicted values to sites of the same area, in order to build regional predictive maps. They could also be useful for the validation of large-scale spatial predictive maps. PMID- 26047191 TI - Biological aspects of crosses between Triatoma recurva (Stal), 1868 (Hemiptera: Reduviidae: Triatominae) and other members of the Phyllosoma complex. AB - The degree of reproductive isolation between Triatoma recurva (Stal) (Hemiptera: Reduviidae: Triatominae) and the six species of the genus Meccus plus T. mexicana (Herrich-Schaeffer) (Hemiptera: Reduviidae) was examined. Fertility and the segregation of morphological characteristics were examined in two generations of hybrids from crosses between these species. The percentage of couples with offspring (fertile) was low in the vast majority of sets of crosses, with the exception of that between T. recurva female and M. phyllosomus male. In all studied sets of crosses, no first- (F1) or second- (F2) generation individuals were morphologically similar to T. recurva but instead shared the morphology of the other parental species. A similar phenomenon was observed in the three successful sets of backcrosses. These results indicated that different recorded levels of reproductive fitness among T. recurva and the species of Meccus involved in this study, plus T. mexicana, are present and that they were apparently influenced by differing mechanisms of isolation. The presence of some degree of reproductive compatibility between studied triatomines of distinct genera (Meccus spp. and Triatoma spp.) reinforces the need for generic revision of the tribe Triatomini. PMID- 26047192 TI - Cues used in host-seeking behavior by frog-biting midges (Corethrella spp. Coquillet). AB - We investigated the role of carbon dioxide and host temperature in host attraction in frog-biting midges (Corethrella spp). In these midges, females are known to use frog calls to localize their host, but the role of other host emitted cues has yet not been investigated. We hypothesized that carbon dioxide acts as a supplemental cue to frog calls. To test this hypothesis, we determined the responses of the midges to carbon dioxide, frog calls, and both cues. A significantly lower number of midges are attracted to carbon dioxide and silent traps than to traps broadcasting frog calls. Adding carbon dioxide to the calls does not increase the attractiveness to the midges. Instead, carbon dioxide can have deterrent effects on frog-biting midges. Temperature of calling frogs is not a cue potentially available to the midges. Contrary to our hypothesis, there was no supplemental effect of carbon dioxide when presented in conjunction to calls. Midge host-seeking behavior strongly depends on the mating calls emitted by their anuran host. Overall, non-acoustic cues such as host body temperature and carbon dioxide are not important in long-distance host location by frog-biting midges. PMID- 26047193 TI - Characteristics of Anopheles arabiensis larval habitats in Tubu village, Botswana. AB - Documented information on the ecology of larval habitats in Botswana is lacking but is critical for larval control programs. Therefore, this study determined the characteristics of these habitats and the influences of biotic and abiotic factors in Tubu village, Botswana. Eight water bodies were sampled between January and December, 2013. The aquatic vegetation and invertebrate species present were characterized. Water parameters measured were turbidity (NTU), conductivity (MUS/cm), oxygen (mg/l), and pH. Larval densities of Anopheles arabiensis mosquitoes and their correlation with abiotic factors were determined. Larval breeding was associated with 'short' aquatic vegetation, a variety of habitats fed by both rainfall and flood waters and sites with predators and competitors. The monthly mean (+/- SE(mean)) larval density was 8.16+/-1.33. The monthly mean (+/-SE(mean)) pH, conductivity, oxygen, and turbidity were 7.65+/ 0.13, 1152.834+/-69.171, 5.59+/-1.33, and 323.421+/-33.801, respectively. There was a significant negative correlation between larval density and conductivity (r = -0.839; p < 0.01), while a significant positive correlation occurred between turbidity and larval density (r = 0.685; p < 0.05). Oxygen (r = 0.140; p > 0.05) and pH (r = 0.252; p > 0.05) were not correlated with larval density. Floods and diversified breeding sites contributed to prolonged and prolific larval breeding. 'Short' aquatic vegetation and predator-infested waters offered suitable environments for larval breeding. Turbidity and conductivity were good indicators for potential breeding places and can be used as early warning indices for predicting larval production levels. PMID- 26047194 TI - Lethal ovitrap deployment for Aedes aegypti control: potential implications for non-target organisms. AB - In Australia, dengue control combines source reduction with lethal ovitraps to reduce Aedes aegypti populations during outbreaks. Lethal ovitraps are considered a sustainable and environmentally friendly method of controlling container inhabiting mosquitoes, however, to-date, this claim has not been quantified. This study assesses the potential impact of lethal ovitraps on non-target organisms when used to control Ae. aegypti in tropical Australia. For retention of specimens, we substituted standard sticky ovitraps for lethal ovitraps. We collected 988 Ae. aegypti and 44,132 non-target specimens over 13 months from 16 sites. Although Ae. aegypti comprised only 2.2% of the total collection, they were were the eighth most dominant taxa collected, on the 93(rd) percentile. Of the non-target organisms, Collembola were the dominant taxa, 44.2%, with 36.8% and 10.5% Diptera and Hymenoptera, respectively. Of the Dipterans, 61% were family Phoridae. Lethal ovitraps were visited by 90 insect or invertebrate families in total. Ovitraps are attractive to Collembola, Phoridae, Sciaridae, Formicidae, and Culicidae, with minimal attraction by Apidae and other commonly monitored non-target organisms. For container-inhabiting mosquitoes, LOs are cost effective operationally, requiring minimal staff resources for placement and retrieval. PMID- 26047195 TI - Predation by ants controls swallow bug (Hemiptera: Cimicidae: Oeciacus vicarius) infestations. AB - The swallow bug (Oeciacus vicarius) is the only known vector for Buggy Creek virus (BCRV), an alphavirus that circulates in cliff swallows (Petrochelidon pyrrhonota) and house sparrows (Passer domesticus) in North America. We discovered ants (Crematogaster lineolata and Formica spp.) preying on swallow bugs at cliff swallow colonies in western Nebraska, U.S.A. Ants reduced the numbers of visible bugs on active swallow nests by 74-90%, relative to nests in the same colony without ants. Ant predation on bugs had no effect on the reproductive success of cliff swallows inhabiting the nests where ants foraged. Ants represent an effective and presumably benign way of controlling swallow bugs at nests in some colonies. They may constitute an alternative to insecticide use at sites where ecologists wish to remove the effects of swallow bugs on cliff swallows or house sparrows. By reducing bug numbers, ant presence may also lessen BCRV transmission at the spatial foci (bird colony sites) where epizootics occur. The effect of ants on swallow bugs should be accounted for in studying variation among sites in vector abundance. PMID- 26047196 TI - Trapping biases of Culex torrentium and Culex pipiens revealed by comparison of captures in CDC traps, ovitraps, and gravid traps. AB - We evaluate three trapping methods for their effectiveness at capturing Culex pipiens and Culex torrentium, both enzootic vectors of bird-associated viruses in Europe. The comparisons, performed in two regions in Sweden, were among CDC traps baited with carbon dioxide, gravid traps, and ovitraps baited with hay infusion. The proportions of the two Culex species in a catch differed between trap types, with CDC traps catching a lower proportion of Cx. torrentium than both gravid traps and ovitraps. Between gravid traps and ovitraps, there was no difference in the proportions of the two species. The results indicate that Cx. torrentium may go undetected or underestimated compared to Cx. pipiens when using carbon dioxide baited CDC traps. The new insight of trap bias presented here adds an important dimension to consider when investigating these vectors of bird-associated viruses in the field. PMID- 26047197 TI - The effect of photoperiod on life history and blood-feeding activity in Aedes albopictus and Aedes aegypti (Diptera: Culicidae). AB - Several studies have examined how climatic variables such as temperature and precipitation may affect life history traits in mosquitoes that are important to disease transmission. Despite its importance as a seasonal cue in nature, studies investigating the influence of photoperiod on such traits are relatively few. This study aims to investigate how photoperiod alters life history traits, survival, and blood-feeding activity in Aedes albopictus (Skuse) and Aedes aegypti (Linnaeus). We performed three experiments that tested the effects of day length on female survival, development time, adult size, fecundity, adult life span, and propensity to blood feed in Ae. albopictus and Ae. aegypti. Each experiment had three photoperiod treatments: 1) short-day (10L:14D), 2) control (12L:12D), and 3) long-day (14L:10D). Aedes albopictus adult females were consistently larger in size when reared in short-day conditions. Aedes aegypti adult females from short-day treatments lived longer and were more likely to take a blood meal compared to other treatments. We discuss how species-specific responses may reflect alternative strategies evolved to increase survival during unfavorable conditions. We review the potential impacts of these responses on seasonal transmission patterns, such as potentially increasing vectorial capacity of Ae. aegypti during periods of shorter day lengths. PMID- 26047198 TI - Spatio-temporal variations of Anopheles coluzzii and An. gambiae and their Plasmodium infectivity rates in Lobito, Angola. AB - From 2003 to 2007, entomological surveys were conducted in Lobito town (Benguela Province, Angola) to determine which Anopheles species were present and to identify the vectors responsible for malaria transmission in areas where workers of the Sonamet Company live. Two types of surveys were conducted: (1) time and space surveys in the low and upper parts of Lobito during the rainy and dry periods; (2) a two-year longitudinal study in Sonamet workers' houses provided with long-lasting insecticide-treated nets (LLIN), "PermaNet," along with the neighboring community. Both species, An. coluzzii (M molecular form) and An. gambiae (S molecular form), were collected. Anopheles coluzzii was predominant during the dry season in the low part of Lobito where larvae develop in natural ponds and temporary pools. However, during the rainy season, An. gambiae was found in higher proportions in the upper part of the town where larvae were collected in domestic water tanks built near houses. Anopheles melas and An. listeri were captured in higher numbers during the dry season and in the low part of Lobito where larvae develop in stagnant brackish water pools. The infectivity rates of An. gambiae s.l. varied from 0.90% to 3.41%. PMID- 26047199 TI - Detection of Borrelia burgdorferi and Anaplasma phagocytophilum in the black legged tick, Ixodes scapularis, within southwestern Pennsylvania. AB - Prevalence studies of Borrelia burgdorferi and Anaplasma phagocytophilum have been rare for ticks from southwestern Pennsylvania. We collected 325 Ixodes scapularis ticks between 2011 and 2012 from four counties in southwestern Pennsylvania. We tested for the presence of Borrelia burgdorferi and Anaplasma phagocytophilum using PCR. Of the ticks collected from Pennsylvania, B. burgdorferi (causative agent of Lyme disease) was present in 114/325 (35%) and Anaplasma phagocytophilum (causative agent of Human Granulocytic Anaplasmosis) was present in 48/325 (15%) as determined by PCR analysis. PMID- 26047200 TI - Dengue viruses in Aedes albopictus Skuse from a pineapple plantation in Costa Rica. PMID- 26047201 TI - Colonization of bison (Bison bison) wallows in a tallgrass prairie by Culicoides spp (Diptera: Ceratopogonidae). PMID- 26047202 TI - Global potential distribution of the mosquito Aedes notoscriptus, a new alien species in the United States. PMID- 26047203 TI - Prevalence of Borrelia burgdorferi in adult female ticks (Ixodes scapularis), Wisconsin 2010-2013. PMID- 26047204 TI - Abundance and infection rates of Ixodes scapularis nymphs collected from residential properties in Lyme disease-endemic areas of Connecticut, Maryland, and New York. PMID- 26047205 TI - Attempts to feed larval Amblyomma americanum (L.) (Acari: Ixodidae) on three different arthropod hosts. PMID- 26047206 TI - Vertical stratification of sand flies (Diptera: Psychodidae) in riparian forests between the Amazon and northeast Brazil. PMID- 26047208 TI - Amorphous GeOx-Coated Reduced Graphene Oxide Balls with Sandwich Structure for Long-Life Lithium-Ion Batteries. AB - Amorphous GeOx-coated reduced graphene oxide (rGO) balls with sandwich structure are prepared via a spray-pyrolysis process using polystyrene (PS) nanobeads as sacrificial templates. This sandwich structure is formed by uniformly coating the exterior and interior of few-layer rGO with amorphous GeOx layers. X-ray photoelectron spectroscopy analysis reveals a Ge:O stoichiometry ratio of 1:1.7. The amorphous GeOx-coated rGO balls with sandwich structure have low charge transfer resistance and fast Li(+)-ion diffusion rate. For example, at a current density of 2 A g(-1), the GeOx-coated rGO balls with sandwich and filled structures and the commercial GeO2 powders exhibit initial charge capacities of 795, 651, and 634 mA h g(-1), respectively; the corresponding 700th-cycle charge capacities are 758, 579, and 361 mA h g(-1). In addition, at a current density of 5 A g(-1), the rGO balls with sandwich structure have a 1600th-cycle reversible charge capacity of 629 mA h g(-1) and a corresponding capacity retention of 90.7%, as measured from the maximum reversible capacity at the 100th cycle. PMID- 26047207 TI - Clostridium difficile Infection Among Veterans Health Administration Patients. AB - OBJECTIVE: To report on the prevalence and incidence of Clostridium difficile infection (CDI) from 2009 to 2013 among Veterans Healthcare Administration patients DESIGN: A retrospective descriptive analysis of data extracted from a large electronic medical record (EMR) database SETTING: Data were acquired from VHA healthcare records from 2009 to 2013 that included outpatient clinical visits, long-term care, and hospitalized care as well as pharmacy and laboratory information. RESULTS: In 2009, there were 10,207 CDI episodes, and in 2013, there were 12,143 CDI episodes, an increase of 19.0%. The overall CDI rate increased by 8.4% from 193 episodes per 100,000 patient years in 2009 to 209 episodes per 100,000 patient years in 2013. Of the CDI episodes identified in 2009, 58% were identified during a hospitalization, and 42% were identified in an outpatient setting. In 2013, 44% of the CDI episodes were identified in an outpatient setting. CONCLUSION: This is one of the largest studies that has utilized timely EMR data to describe the current CDI epidemiology at the VHA. Despite an aging population with greater burden of comorbidity than the general US population, our data show that VHA CDI rates stabilized between 2011 and 2013 following increases likely attributable to the introduction of the more sensitive nucleic acid amplification tests (NAATs). The findings in this report will help establish an accurate benchmark against which both current and future VA CDI prevention initiatives can be measured. PMID- 26047209 TI - Rotation of the Orientation of the Wave Function Distribution of a Charged Particle and its Utilization. AB - We describe a method for selecting and sorting particles in an ion trap with respect to charge and mass. The method exploits a so-called shortcut to adiabatic passage, specifically the fast-forward field protocol, to design an electromagnetic field that rotates the spatial orientation of the wave function of the desired ion. The electromagnetic field forces ions that have different mass and electrical charge from the desired ionic species out of the trapping potential without exciting the desired ionic species, leaving the latter undisturbed in the trap. PMID- 26047210 TI - Interaction of MYC2 and GBF1 results in functional antagonism in blue light mediated Arabidopsis seedling development. AB - Regulations of Arabidopsis seedling growth by two proteins, which belong to different classes of transcription factors, are poorly understood. MYC2 and GBF1 belong to bHLH and bZIP classes of transcription factors, respectively, and function in cryptochrome-mediated blue light signaling. Here, we have investigated the molecular and functional interrelation of MYC2 and GBF1 in blue light-mediated photomorphogenesis. Our study reveals that MYC2 and GBF1 colocalize and physically interact in the nucleus. This interaction requires the N-terminal domain of each protein. The atmyc2 gbf1 double mutant analyses and transgenic studies have revealed that MYC2 and GBF1 act antagonistically and inhibit the activity of each other to regulate hypocotyl growth and several other biological processes. This study further reveals that MYC2 and GBF1 bind to HYH promoter and inhibit each other through non-DNA binding bHLH-bZIP heterodimers. These results, taken together, provide insights into the mechanistic view on the concerted regulatory role of MYC2 and GBF1 in Arabidopsis seedling development. PMID- 26047211 TI - Glioblastoma cells induce differential glutamatergic gene expressions in human tumor-associated microglia/macrophages and monocyte-derived macrophages. AB - Glioblastoma cells produce and release high amounts of glutamate into the extracellular milieu and subsequently can trigger seizure in patients. Tumor associated microglia/macrophages (TAMs), consisting of both parenchymal microglia and monocytes-derived macrophages (MDMs) recruited from the blood, are known to populate up to 1/3 of the glioblastoma tumor environment and exhibit an alternative, tumor-promoting and supporting phenotype. However, it is unknown how TAMs respond to the excess extracellular glutamate in the glioblastoma microenvironment. We investigated the expressions of genes related to glutamate transport and metabolism in human TAMs freshly isolated from glioblastoma resections. Quantitative real-time PCR analysis showed (i) significant increases in the expressions of GRIA2 (GluA2 or AMPA receptor 2), SLC1A2 (EAAT2), SLC1A3 (EAAT1), (ii) a near-significant decrease in the expression of SLC7A11 (cystine glutamate antiporter xCT) and (iii) a remarkable increase in GLUL expression (glutamine synthetase) in these cells compared to adult primary human microglia. TAMs co-cultured with glioblastoma cells also exhibited a similar glutamatergic profile as freshly isolated TAMs except for a slight increase in SLC7A11 expression. We next analyzed these genes expressions in cultured human MDMs derived from peripheral blood monocytes for comparison. In contrast, MDMs co cultured with glioblastoma cells compared to MDMs co-cultured with normal astrocytes exhibited decreased expressions in the tested genes except for GLUL. This is the first study to demonstrate transcriptional changes in glutamatergic signaling of TAMs in a glioblastoma microenvironment, and the findings here suggest that TAMs and MDMs might potentially elicit different cellular responses in the presence of excess extracellular glutamate. PMID- 26047214 TI - Entropic Tests of Multipartite Nonlocality and State-Independent Contextuality. AB - We introduce a multipartite extension of an information-theoretic distance introduced by Zurek [Nature (London) 341, 119 (1989)]. We use it to develop a new tool for studying quantum correlations from an information-theoretic perspective. In particular, we derive entropic tests of multipartite nonlocality for three qubits and for an arbitrary even number of qubits as well as a test of state independent contextuality. In addition, we rederive the tripartite Mermin inequality and a state-independent noncontextuality inequality by Cabello [Phys. Rev. Lett. 101, 210401 (2008)]. This suggests that the information-theoretic distance approach to multipartite nonlocality and state-independent contextuality can provide a more general treatment of nonclassical correlations than the orthodox approach based on correlation functions. PMID- 26047212 TI - Kv1.2 mediates heterosynaptic modulation of direct cortical synaptic inputs in CA3 pyramidal cells. AB - KEY POINTS: We investigated the cellular mechanisms underlying mossy fibre induced heterosynaptic long-term potentiation of perforant path (PP) inputs to CA3 pyramidal cells. Here we show that this heterosynaptic potentiation is mediated by downregulation of Kv1.2 channels. The downregulation of Kv1.2 preferentially enhanced PP-evoked EPSPs which occur at distal apical dendrites. Such enhancement of PP-EPSPs required activation of dendritic Na(+) channels, and its threshold was lowered by downregulation of Kv1.2. Our results may provide new insights into the long-standing question of how mossy fibre inputs constrain the CA3 network to sparsely represent direct cortical inputs. ABSTRACT: A short high frequency stimulation of mossy fibres (MFs) induces long-term potentiation (LTP) of direct cortical or perforant path (PP) synaptic inputs in hippocampal CA3 pyramidal cells (CA3-PCs). However, the cellular mechanism underlying this heterosynaptic modulation remains elusive. Previously, we reported that repetitive somatic firing at 10 Hz downregulates Kv1.2 in the CA3-PCs. Here, we show that MF inputs induce similar somatic firing and downregulation of Kv1.2 in the CA3-PCs. The effect of Kv1.2 downregulation was specific to PP synaptic inputs that arrive at distal apical dendrites. We found that the somatodendritic expression of Kv1.2 is polarized to distal apical dendrites. Compartmental simulations based on this finding suggested that passive normalization of synaptic inputs and polarized distributions of dendritic ionic channels may facilitate the activation of dendritic Na(+) channels preferentially at distal apical dendrites. Indeed, partial block of dendritic Na(+) channels using 10 nm tetrodotoxin brought back the enhanced PP-evoked excitatory postsynaptic potentials (PP-EPSPs) to the baseline level. These results indicate that activity dependent downregulation of Kv1.2 in CA3-PCs mediates MF-induced heterosynaptic LTP of PP-EPSPs by facilitating activation of Na(+) channels at distal apical dendrites. PMID- 26047213 TI - Antimicrobial Effect of a Single Dose of Amoxicillin on the Oral Microbiota. AB - PURPOSE: Amoxicillin is commonly used in oral surgery for antimicrobial prophylaxis against surgical-site infection and bacteremia because of its effect on oral streptococci. The aim of this study was to determine whether amoxicillin reaches the break-point concentrations in saliva and has any effect on the salivary microbiota, colonizing bacteria on mucosal membranes and on the gingival crevice after a single dose of amoxicillin. MATERIAL AND METHODS: Twenty subjects received 2 g of amoxicillin, per os. The facultative and strictly anaerobic microflora, as well as the streptococcal microflora specifically, were followed from baseline and after 1, 4, and 24 hours. Samples were taken for microbial analysis from saliva, the dorsum of the tongue, and the gingival crevice, and were inoculated and cultured. Plasma samples and saliva samples were analyzed for amoxicillin concentrations (free and protein bound) using liquid chromatography and mass-spectrometry. RESULTS: Amoxicillin was detected in concentrations over the break-point (>2 MUg/mL) of amoxicillin in plasma after 1 and 4 hours but not after 24 hours. The dose had a significant effect on the streptococci in the gingival crevice. CONCLUSION: A single dose given as prophylaxis to prevent a surgical-site infection results in a significant reducing effect on the oral streptococcal microflora in the gingival crevice and may have an impact on bacteria spreading into tissues and the bacteremia of streptococci. PMID- 26047215 TI - Machine Learning for Discriminating Quantum Measurement Trajectories and Improving Readout. AB - Current methods for classifying measurement trajectories in superconducting qubit systems produce fidelities systematically lower than those predicted by experimental parameters. Here, we place current classification methods within the framework of machine learning (ML) algorithms and improve on them by investigating more sophisticated ML approaches. We find that nonlinear algorithms and clustering methods produce significantly higher assignment fidelities that help close the gap to the fidelity possible under ideal noise conditions. Clustering methods group trajectories into natural subsets within the data, which allows for the diagnosis of systematic errors. We find large clusters in the data associated with T1 processes and show these are the main source of discrepancy between our experimental and ideal fidelities. These error diagnosis techniques help provide a path forward to improve qubit measurements. PMID- 26047216 TI - High-Fidelity Single-Shot Toffoli Gate via Quantum Control. AB - A single-shot Toffoli, or controlled-controlled-not, gate is desirable for classical and quantum information processing. The Toffoli gate alone is universal for reversible computing and, accompanied by the Hadamard gate, forms a universal gate set for quantum computing. The Toffoli gate is also a key ingredient for (nontopological) quantum error correction. Currently Toffoli gates are achieved by decomposing into sequentially implemented single- and two-qubit gates, which require much longer times and yields lower overall fidelities compared to a single-shot implementation. We develop a quantum-control procedure to construct a single-shot Toffoli gate for three nearest-neighbor-coupled superconducting transmon systems such that the fidelity is 99.9% and is as fast as an entangling two-qubit gate under the same realistic conditions. The gate is achieved by a nongreedy quantum control procedure using our enhanced version of the differential evolution algorithm. PMID- 26047217 TI - Wald Entropy for Ghost-Free, Infinite Derivative Theories of Gravity. AB - In this Letter, we demonstrate that the Wald entropy for any spherically symmetric black hole within an infinite derivative theory of gravity that is quadratic in curvature is determined solely by the area law. Thus, the infrared behavior of gravity is captured by the Einstein-Hilbert term, provided that the massless graviton remains the only propagating degree of freedom in the spacetime. PMID- 26047218 TI - Black Hole Interior in Quantum Gravity. AB - We discuss the interior of a black hole in quantum gravity, in which black holes form and evaporate unitarily. The interior spacetime appears in the sense of complementarity because of special features revealed by the microscopic degrees of freedom when viewed from a semiclassical standpoint. The relation between quantum mechanics and the equivalence principle is subtle, but they are still consistent. PMID- 26047219 TI - Eightfold Classification of Hydrodynamic Dissipation. AB - We provide a complete characterization of hydrodynamic transport consistent with the second law of thermodynamics at arbitrary orders in the gradient expansion. A key ingredient in facilitating this analysis is the notion of adiabatic hydrodynamics, which enables isolation of the genuinely dissipative parts of transport. We demonstrate that most transport is adiabatic. Furthermore, in the dissipative part, only terms at the leading order in gradient expansion are constrained to be sign definite by the second law (as has been derived before). PMID- 26047220 TI - Monojetlike Searches for Top Squarks with a b Tag. AB - The LHC searches for light compressed top squarks have resulted in considerable bounds in the case where the top squark decays to a neutralino and a charm quark. However, in the case where the top squark decays to a neutralino, a bottom quark, and two fermions via an off-shell W boson, there is currently a significant unconstrained region in the top-squark-neutralino mass plane, still allowing for top squark masses in the range 90-140 GeV. In this Letter we propose a new monojetlike search for light top squarks, optimized for the four-body decay mode, in which at least one b-tagged jet is required. We show that, by using the existing 8 TeV LHC data set, such a search would cover the entire unconstrained region. Moreover, in the process of validating our tools against an ATLAS monojet search, we show that the existing limit can be extended to exclude also top squark masses below 100 GeV. PMID- 26047221 TI - Generalized Supersoft Supersymmetry Breaking and a Solution to the MU Problem. AB - We propose the framework generalized supersoft supersymmetry breaking. "Supersoft" models, with D-type supersymmetry breaking and heavy Dirac gauginos, are considerably less constrained by the LHC searches than the well studied MSSM. These models also ameliorate the supersymmetric flavor and CP problems. However, previously considered mechanisms for obtaining a natural size Higgsino mass parameter (namely, MU) in supersoft models have been relatively complicated and contrived. Obtaining a 125 GeV for the mass of the lightest Higgs boson has also been difficult. Additional issues with the supersoft scenario arise from the fact that these models contain new scalars in the adjoint representation of the standard model, which may obtain negative squared-masses, breaking color and generating too large a T parameter. In this Letter, we introduce new operators into supersoft models which can potentially solve all these issues. A novel feature of this framework is that the new MU term can give unequal masses to the up and down type Higgs fields, and the Higgsinos can be much heavier than the Higgs boson without fine-tuning. However, unequal Higgs and Higgsino masses also remove some attractive features of supersoft supersymmetry. PMID- 26047222 TI - Kinematical Correlations for Higgs Boson Plus High P_{T} Jet Production at Hadron Colliders. AB - We investigate the effect of QCD resummation to kinematical correlations in the Higgs boson plus high transverse momentum (P(T)) jet events produced at hadron colliders. We show that at the complete one-loop order, the Collins-Soper-Sterman resummation formalism can be applied to derive the Sudakov form factor. We compare the singular behavior of resummation calculation to fixed order prediction in the case that a Higgs boson and high P(T) jet are produced nearly back to back in their transverse momenta, and find perfect agreement. The phenomenological importance of the resummation effect at the LHC is also demonstrated. PMID- 26047223 TI - Constraining the Equation of State of Superhadronic Matter from Heavy-Ion Collisions. AB - The equation of state of QCD matter for temperatures near and above the quark hadron transition (~165 MeV) is inferred within a Bayesian framework through the comparison of data from the Relativistic Heavy Ion Collider and from the Large Hadron Collider to theoretical models. State-of-the-art statistical techniques are applied to simultaneously analyze multiple classes of observables while varying 14 independent model parameters. The resulting posterior distribution over possible equations of state is consistent with results from lattice gauge theory. PMID- 26047225 TI - Rotation of Quantum Impurities in the Presence of a Many-Body Environment. AB - We develop a microscopic theory describing a quantum impurity whose rotational degree of freedom is coupled to a many-particle bath. We approach the problem by introducing the concept of an "angulon"-a quantum rotor dressed by a quantum field-and reveal its quasiparticle properties using a combination of variational and diagrammatic techniques. Our theory predicts renormalization of the impurity rotational structure, such as that observed in experiments with molecules in superfluid helium droplets, in terms of a rotational Lamb shift induced by the many-particle environment. Furthermore, we discover a rich many-body-induced fine structure, emerging in rotational spectra due to a redistribution of angular momentum within the quantum many-body system. PMID- 26047224 TI - Probing the N=32 Shell Closure below the Magic Proton Number Z=20: Mass Measurements of the Exotic Isotopes ^{52,53}K. AB - The recently confirmed neutron-shell closure at N=32 has been investigated for the first time below the magic proton number Z=20 with mass measurements of the exotic isotopes (52,53)K, the latter being the shortest-lived nuclide investigated at the online mass spectrometer ISOLTRAP. The resulting two-neutron separation energies reveal a 3 MeV shell gap at N=32, slightly lower than for 52Ca, highlighting the doubly magic nature of this nuclide. Skyrme-Hartree-Fock Bogoliubov and ab initio Gorkov-Green function calculations are challenged by the new measurements but reproduce qualitatively the observed shell effect. PMID- 26047226 TI - Strongly Correlated Growth of Rydberg Aggregates in a Vapor Cell. AB - The observation of strongly interacting many-body phenomena in atomic gases typically requires ultracold samples. Here we show that the strong interaction potentials between Rydberg atoms enable the observation of many-body effects in an atomic vapor, even at room temperature. We excite Rydberg atoms in cesium vapor and observe in real time an out-of-equilibrium excitation dynamics that is consistent with an aggregation mechanism. The experimental observations show qualitative and quantitative agreement with a microscopic theoretical model. Numerical simulations reveal that the strongly correlated growth of the emerging aggregates is reminiscent of soft-matter type systems. PMID- 26047227 TI - Chiral Light-Matter Interaction in Optical Resonators. AB - The Purcell effect explains the modification of the spontaneous decay rate of quantum emitters in a resonant cavity. For quantum emitters such as chiral molecules, however, the cavity modification of the spontaneous decay rate has been little known. Here we extend Purcell's work to the chiral light-matter interaction in optical resonators and find the differential spontaneous decay rate of chiral molecules coupled to left and right circularly polarized resonator modes. We determine the chiral Purcell factor, which characterizes the ability of optical resonators to enhance chiroptical signals, by the quality factor and the chiral mode volume of a resonator, representing, respectively, the temporal confinement of light and the spatial confinement of the helicity of light. We show that the chiral Purcell effect can be applied to chiroptical spectroscopy. Specifically, we propose a realistic scheme to achieve resonator enhanced chiroptical spectroscopy that uses the double fishnet structure as a nanoscale cuvette supporting the chiral Purcell effect. PMID- 26047228 TI - Tunable Subluminal Propagation of Narrow-band X-Ray Pulses. AB - Group velocity control is demonstrated for x-ray photons of 14.4 keV energy via a direct measurement of the temporal delay imposed on spectrally narrow x-ray pulses. Subluminal light propagation is achieved by inducing a steep positive linear dispersion in the optical response of 57Fe Mossbauer nuclei embedded in a thin film planar x-ray cavity. The direct detection of the temporal pulse delay is enabled by generating frequency-tunable spectrally narrow x-ray pulses from broadband pulsed synchrotron radiation. Our theoretical model is in good agreement with the experimental data. PMID- 26047229 TI - Realization of Single-Qubit Positive-Operator-Valued Measurement via a One Dimensional Photonic Quantum Walk. AB - We perform generalized measurements of a qubit by realizing the qubit as a coin in a photonic quantum walk and subjecting the walker to projective measurements. Our experimental technique can be used to realize, photonically, any rank-1 single-qubit positive-operator-valued measure via constructing an appropriate interferometric quantum-walk network and then projectively measuring the walker's position at the final step. PMID- 26047230 TI - Continuous Solitons in a Lattice Nonlinearity. AB - We study theoretically and experimentally the propagation of optical solitons in a lattice nonlinearity, a periodic pattern that both affects and is strongly affected by the wave. Observations are carried out using spatial photorefractive solitons in a volume microstructured crystal with a built-in oscillating low frequency dielectric constant. The pattern causes an oscillating electro-optic response that induces a periodic optical nonlinearity. On-axis results in potassium-lithium-tantalate-niobate indicate the appearance of effective continuous saturated-Kerr solitons, where all spatial traces of the lattice vanish, independently of the ratio between beam width and lattice constant. Decoupling the lattice nonlinearity allows the detection of discrete delocalized and localized light distributions, demonstrating that the continuous solitons form out of the combined compensation of diffraction and of the underlying periodic volume pattern. PMID- 26047231 TI - Bubble Formation in Yield Stress Fluids Using Flow-Focusing and T-Junction Devices. AB - We study the production of bubbles inside yield stress fluids (YSFs) in axisymmetric T-junction and flow-focusing devices. Taking advantage of yield stress over capillary stress, we exhibit a robust break-up mechanism reminiscent of the geometrical operating regime in 2D flow-focusing devices for Newtonian fluids. We report that when the gas is pressure driven, the dynamics is unsteady due to hydrodynamic feedback and YSF deposition on the walls of the channels. However, the present study also identifies pathways for potential steady-state production of bubbly YSFs at large scale. PMID- 26047233 TI - Threefold Increase of the Bulk Electron Temperature of Plasma Discharges in a Magnetic Mirror Device. AB - This Letter describes plasma discharges with a high temperature of bulk electrons in the axially symmetric high-mirror-ratio (R=35) open magnetic system gas dynamic trap (GDT) in the Budker Institute (Novosibirsk). According to Thomson scattering measurements, the on-axis electron temperature averaged over a number of sequential shots is 660+/-50 eV with the plasma density being 0.7*10^{19} m^{-3}; in few shots, electron temperature exceeds 900 eV. This corresponds to at least a threefold increase with respect to previous experiments both at GDT and at other comparable machines, thus, demonstrating the highest quasistationary (about 1 ms) electron temperature achieved in open traps. The breakthrough is made possible by application of a new 0.7 MW/54.5 GHz electron cyclotron resonance heating system in addition to standard 5 MW heating by neutral beams, and application of a radial electric field to mitigate the flute instability. PMID- 26047232 TI - Observation of Wakefields and Resonances in Coherent Synchrotron Radiation. AB - We report on high resolution measurements of resonances in the spectrum of coherent synchrotron radiation (CSR) at the Canadian Light Source (CLS). The resonances permeate the spectrum at wave number intervals of 0.074 cm(-1), and are highly stable under changes in the machine setup (energy, bucket filling pattern, CSR in bursting or continuous mode). Analogous resonances were predicted long ago in an idealized theory as eigenmodes of a smooth toroidal vacuum chamber driven by a bunched beam moving on a circular orbit. A corollary of peaks in the spectrum is the presence of pulses in the wakefield of the bunch at well-defined spatial intervals. Through experiments and further calculations we elucidate the resonance and wakefield mechanisms in the CLS vacuum chamber, which has a fluted form much different from a smooth torus. The wakefield is observed directly in the 30-110 GHz range by rf diodes, and indirectly by an interferometer in the THz range. The wake pulse sequence found by diodes is less regular than in the toroidal model, and depends on the point of observation, but is accounted for in a simulation of fields in the fluted chamber. Attention is paid to polarization of the observed fields, and possible coherence of fields produced in adjacent bending magnets. Low frequency wakefield production appears to be mainly local in a single bend, but multibend effects cannot be excluded entirely, and could play a role in high frequency resonances. New simulation techniques have been developed, which should be invaluable in further work. PMID- 26047234 TI - Performance and Mix Measurements of Indirect Drive Cu-Doped Be Implosions. AB - The ablator couples energy between the driver and fusion fuel in inertial confinement fusion (ICF). Because of its low opacity, high solid density, and material properties, beryllium has long been considered an ideal ablator for ICF ignition experiments at the National Ignition Facility. We report here the first indirect drive Be implosions driven with shaped laser pulses and diagnosed with fusion yield at the OMEGA laser. The results show good performance with an average DD neutron yield of ~2*10^{9} at a convergence ratio of R_{0}/R~10 and little impact due to the growth of hydrodynamic instabilities and mix. In addition, the effect of adding an inner liner of W between the Be and DD is demonstrated. PMID- 26047235 TI - Plasmoids Formation During Simulations of Coaxial Helicity Injection in the National Spherical Torus Experiment. AB - The formation of an elongated Sweet-Parker current sheet and a transition to plasmoid instability has for the first time been predicted by simulations in a large-scale toroidal fusion plasma in the absence of any preexisting instability. Plasmoid instability is demonstrated through resistive MHD simulations of transient coaxial helicity injection experiments in the National Spherical Torus Experiment (NSTX). Consistent with the theory, fundamental characteristics of the plasmoid instability, including fast reconnection rate, have been observed in these realistic simulations. Motivated by the simulations, experimental camera images have been revisited and suggest the existence of reconnecting plasmoids in NSTX. Global, system-size plasmoid formation observed here should also have strong implications for astrophysical reconnection, such as rapid eruptive solar events. PMID- 26047236 TI - Slowing of Magnetic Reconnection Concurrent with Weakening Plasma Inflows and Increasing Collisionality in Strongly Driven Laser-Plasma Experiments. AB - An evolution of magnetic reconnection behavior, from fast jets to the slowing of reconnection and the establishment of a stable current sheet, has been observed in strongly driven, beta?20 laser-produced plasma experiments. This process has been inferred to occur alongside a slowing of plasma inflows carrying the oppositely directed magnetic fields as well as the evolution of plasma conditions from collisionless to collisional. High-resolution proton radiography has revealed unprecedented detail of the forced interaction of magnetic fields and super-Alfvenic electron jets (V_{jet}~20V_{A}) ejected from the reconnection region, indicating that two-fluid or collisionless magnetic reconnection occurs early in time. The absence of jets and the persistence of strong, stable magnetic fields at late times indicates that the reconnection process slows down, while plasma flows stagnate and plasma conditions evolve to a cooler, denser, more collisional state. These results demonstrate that powerful initial plasma flows are not sufficient to force a complete reconnection of magnetic fields, even in the strongly driven regime. PMID- 26047237 TI - Helicons in Unbounded Plasmas. AB - Helicons are whistler modes with helical phase fronts. They have been studied in solid state plasmas and in discharge tubes where boundaries and nonuniformities are ever present. The present work shows that helicons also exist in unbounded and uniform plasmas, thereby bridging the fields of laboratory and space plasma physics. First measurements of helicon field lines in three dimensional space are presented. Helicons with negative and positive mode numbers can propagate with equal amplitudes. PMID- 26047238 TI - Suppression and Revival of Weak Localization through Control of Time-Reversal Symmetry. AB - We report on the observation of suppression and revival of coherent backscattering of ultracold atoms launched in an optical disorder in a quasi-2D geometry and submitted to a short dephasing pulse, as proposed by Micklitz, Muller, and Altland [Phys. Rev. B 91, 064203 (2015)]. This observation demonstrates a novel and general method to study weak localization by manipulating time reversal symmetry in disordered systems. In future experiments, this scheme could be extended to investigate higher order localization processes at the heart of Anderson (strong) localization. PMID- 26047239 TI - Ultracold Dipolar Gas of Fermionic 23Na40 K Molecules in Their Absolute Ground State. AB - We report on the creation of an ultracold dipolar gas of fermionic 23Na40 K molecules in their absolute rovibrational and hyperfine ground state. Starting from weakly bound Feshbach molecules, we demonstrate hyperfine resolved two photon transfer into the singlet X 1Sigma+|v=0,J=0? ground state, coherently bridging a binding energy difference of 0.65 eV via stimulated rapid adiabatic passage. The spin-polarized, nearly quantum degenerate molecular gas displays a lifetime longer than 2.5 s, highlighting NaK's stability against two-body chemical reactions. A homogeneous electric field is applied to induce a dipole moment of up to 0.8 D. With these advances, the exploration of many-body physics with strongly dipolar Fermi gases of 23Na40K molecules is within experimental reach. PMID- 26047240 TI - Repulsion and Attraction between a Pair of Cracks in a Plastic Sheet. AB - We study the interaction of two collinear cracks in polymer sheets slowly growing towards each other, when submitted to uniaxial stress at a constant loading velocity. Depending on the sample's geometry-specifically, the initial distances d between the two cracks' axes and L between the cracks' tips-we observe different crack paths with, in particular, a regime where the cracks repel each other prior to being attracted. We show that the angle theta characterizing the amplitude of the repulsion-and specifically its evolution with d-depends strongly on the microscopic behavior of the material. Our results highlight the crucial role of the fracture process zone. At interaction distances larger than the process zone size, crack repulsion is controlled by the microscopic shape of the process zone tip, while at shorter distances, the overall plastic process zone screens the repulsion interaction. PMID- 26047241 TI - Evidence for a Disordered Critical Point in a Glass-Forming Liquid. AB - Using computer simulations of an atomistic glass-forming liquid, we investigate the fluctuations of the overlap between a fluid configuration and a quenched reference system. We find that large fluctuations of the overlap develop as temperature decreases, consistent with the existence of the random critical point that is predicted by effective field theories. We discuss the scaling of fluctuations near the presumed critical point, comparing the observed behavior with that of the random-field Ising model. We argue that this critical point directly reveals the existence of an interfacial tension between amorphous metastable states, a quantity relevant both for equilibrium relaxation and for nonequilibrium melting of stable glass configurations. PMID- 26047243 TI - Weyl Node and Spin Texture in Trigonal Tellurium and Selenium. AB - We study Weyl nodes in materials with broken inversion symmetry. We find based on first-principles calculations that trigonal Te and Se have multiple Weyl nodes near the Fermi level. The conduction bands have a spin splitting similar to the Rashba splitting around the H points, but unlike the Rashba splitting the spin directions are radial, forming a hedgehog spin texture around the H points, with a nonzero Pontryagin index for each spin-split conduction band. The Weyl semimetal phase, which has never been observed in real materials without inversion symmetry, is realized under pressure. The evolution of the spin texture by varying the pressure can be explained by the evolution of the Weyl nodes in k space. PMID- 26047242 TI - Rotational Spectromicroscopy: Imaging the Orbital Interaction between Molecular Hydrogen and an Adsorbed Molecule. AB - A hydrogen molecule can diffuse freely on the surface and be trapped above an adsorbed molecule within the junction of a scanning tunneling microscope. The trapped dihydrogen exhibits the properties of a free rotor. Here we show that the intermolecular interaction between dihydrogen and Mg-porphyrin (MgP) can be visualized by imaging j=0 to 2 rotational excitation of dihydrogen. The interaction leads to a weakened H-H bond and modest electron donation from the dihydrogen to the lowest unoccupied molecular orbital of MgP, a process similarly observed for the interaction between dihydrogen and an adsorbed Au atom. PMID- 26047244 TI - Entanglement Entropy of the nu=1/2 Composite Fermion Non-Fermi Liquid State. AB - The so-called "non-Fermi liquid" behavior is very common in strongly correlated systems. However, its operational definition in terms of "what it is not" is a major obstacle for the theoretical understanding of this fascinating correlated state. Recently there has been much interest in entanglement entropy as a theoretical tool to study non-Fermi liquids. So far explicit calculations have been limited to models without direct experimental realizations. Here we focus on a two-dimensional electron fluid under magnetic field and filling fraction nu=1/2, which is believed to be a non-Fermi liquid state. Using a composite fermion wave function which captures the nu=1/2 state very accurately, we compute the second Renyi entropy using the variational Monte Carlo technique. We find the entanglement entropy scales as LlogL with the length of the boundary L as it does for free fermions, but has a prefactor twice that of free fermions. PMID- 26047245 TI - Generation and Detection of Spin Currents in Semiconductor Nanostructures with Strong Spin-Orbit Interaction. AB - Storing, transmitting, and manipulating information using the electron spin resides at the heart of spintronics. Fundamental for future spintronics applications is the ability to control spin currents in solid state systems. Among the different platforms proposed so far, semiconductors with strong spin orbit interaction are especially attractive as they promise fast and scalable spin control with all-electrical protocols. Here we demonstrate both the generation and measurement of pure spin currents in semiconductor nanostructures. Generation is purely electrical and mediated by the spin dynamics in materials with a strong spin-orbit field. Measurement is accomplished using a spin-to charge conversion technique, based on the magnetic field symmetry of easily measurable electrical quantities. Calibrating the spin-to-charge conversion via the conductance of a quantum point contact, we quantitatively measure the mesoscopic spin Hall effect in a multiterminal GaAs dot. We report spin currents of 174 pA, corresponding to a spin Hall angle of 34%. PMID- 26047246 TI - Disordered Weyl Semimetals and Their Topological Family. AB - We develop a topological theory for disordered Weyl semimetals in the framework of the gauge invariance of the replica formalism and boundary-bulk correspondence of Chern insulators. An anisotropic topological theta term is analytically derived for the effective nonlinear sigma model. It is this nontrivial topological term that ensures that the bulk transverse transport of Weyl semimetals is robust against disorders. Moreover, we establish a general diagram that reveals the intrinsic relations among topological terms in the nonlinear sigma models and gauge response theories, respectively, for (2n+2)-dimensional topological insulators, (2n+1)-dimensional chiral fermions, (2n+1)-dimensional chiral semimetals, and (2n)-dimensional topological insulators with n being a positive integer. PMID- 26047248 TI - Site-Dependent Evolution of Electrical Conductance from Tunneling to Atomic Point Contact. AB - Using scanning tunneling microscopy (STM), we investigated the evolution of electrical conductance between a Pb tip and Pb(111) surface from tunneling to atomic point contact at a site that was defined with atomic precision. We found that the conductance evolution depended on the contact site, for instance, on top, bridge, or hollow (hcp and fcc) sites in the Pb lattice. In the transition from tunneling to contact regimes, the conductance measured at the on-top site was enhanced. In the point contact regime, the hollow sites had conductances larger than those of the other sites, and between the hollow sites, the hcp site had a conductance larger than that of the fcc site. We also observed the enhancement and reversal of the apparent height in atomically resolved high current STM images, consistent with the results of the conductance traces. Our results indicate the importance of atomic configuration in the conductance of atomic junctions and suggest that attractive chemical interactions have a significant role in electron transport between contacting atoms. PMID- 26047247 TI - Unidirectional Spin-Dependent Molecule-Ferromagnet Hybridized States Anisotropy in Cobalt Phthalocyanine Based Magnetic Tunnel Junctions. AB - Organic or molecular spintronics is a rising field of research at the frontier between condensed matter physics and chemistry. It aims to mix spin physics and the richness of chemistry towards designing new properties for spin electronics devices through engineering at the molecular scale. Beyond the expectation of a long spin lifetime, molecules can be also used to tailor the spin polarization of the injected current through the spin-dependent hybridization between molecules and ferromagnetic electrodes. In this Letter, we provide direct evidence of a hybrid interface spin polarization reversal due to the differing hybridization between phthalocyanine molecules and each cobalt electrode in Co/CoPc/Co magnetic tunnel junctions. Tunnel magnetoresistance and anisotropic tunnel magnetoresistance experiments show that interfacial hybridized electronic states have a unidirectional anisotropy that can be controlled by an electric field and that spin hybridization at the bottom and top interfaces differ, leading to an inverse tunnel magnetoresistance. PMID- 26047249 TI - Singlet-Triplet Excitations and Long-Range Entanglement in the Spin-Orbital Liquid Candidate FeSc2S4. AB - Theoretical models of the spin-orbital liquid (SOL) FeSc2S4 have predicted it to be in close proximity to a quantum critical point separating a spin-orbital liquid phase from a long-range ordered magnetic phase. Here, we examine the magnetic excitations of FeSc2S4 through time-domain terahertz spectroscopy under an applied magnetic field. At low temperatures an excitation emerges that we attribute to a singlet-triplet excitation from the SOL ground state. A threefold splitting of this excitation is observed as a function of applied magnetic field. As singlet-triplet excitations are typically not allowed in pure spin systems, our results demonstrate the entangled spin and orbital character of singlet ground and triplet excited states. Using experimentally obtained parameters we compare to existing theoretical models to determine FeSc2S4's proximity to the quantum critical point. In the context of these models, we estimate the characteristic length of the singlet correlations to be xi/(a/2)~8.2 (where a/2 is the nearest neighbor lattice constant), which establishes FeSc2S4 as a SOL with long-range entanglement. PMID- 26047250 TI - Interferometric phase detection at x-ray energies via Fano resonance control. AB - Modern x-ray light sources promise access to structure and dynamics of matter in largely unexplored spectral regions. However, the desired information is encoded in the light intensity and phase, whereas detectors register only the intensity. This phase problem is ubiquitous in crystallography and imaging and impedes the exploration of quantum effects at x-ray energies. Here, we demonstrate phase sensitive measurements characterizing the quantum state of a nuclear two-level system at hard x-ray energies. The nuclei are initially prepared in a superposition state. Subsequently, the relative phase of this superposition is interferometrically reconstructed from the emitted x rays. Our results form a first step towards x-ray quantum state tomography and provide new avenues for structure determination and precision metrology via x-ray Fano interference. PMID- 26047251 TI - Interfacial Structural Transition in Hydration Shells of a Polarizable Solute. AB - Electrostatics of polar solvation is typically described by harmonic free energy functionals. Polarizability contributes a negative polarization term that can make the harmonic free energy negative. The harmonic truncation fails in this regime. Simulations of polarizable ideal dipoles in water show that water's susceptibility passes through a maximum in the range of polarizabilities zeroing the harmonic term out. The microscopic origin of the nonmonotonic behavior is an interfacial structural transition involving the density collapse of the first hydration layer and enhanced number of dangling OH bonds. PMID- 26047252 TI - Volume Changes During Active Shape Fluctuations in Cells. AB - Cells modify their volume in response to changes in osmotic pressure but it is usually assumed that other active shape variations do not involve significant volume fluctuations. Here we report experiments demonstrating that water transport in and out of the cell is needed for the formation of blebs, commonly observed protrusions in the plasma membrane driven by cortex contraction. We develop and simulate a model of fluid-mediated membrane-cortex deformations and show that a permeable membrane is necessary for bleb formation which is otherwise impaired. Taken together, our experimental and theoretical results emphasize the subtle balance between hydrodynamics and elasticity in actively driven cell morphological changes. PMID- 26047253 TI - Case of food-dependent exercise-induced anaphylaxis due to Japanese apricot and peach: Detection of causative antigens. PMID- 26047254 TI - Pyoderma gangrenosum with increased levels of serum cytokines. AB - A 66-year-old woman presented after an episode of accidental trauma with a painful ulcer on her scalp which rapidly enlarged in size, accompanied by central necrosis and undermining ulceration. The patient's past history was negative for underlying systemic disease, although she had had a similar post-traumatic intractable leg ulcer 3 years prior, which was unresponsive to surgical management but successfully treated with systemic steroids. A biopsied specimen from the scalp showed marked neutrophilic infiltrates in the dermis, compatible with a diagnosis of pyoderma gangrenosum (PG). The large ulcerative lesion responded very well to oral steroid therapy, showing rapid epithelialization. Serum levels of granulocyte colony-stimulating factor and interleukin-6 were significantly elevated prior to treatment, with decrease to normal levels after treatment. Serum tumor necrosis factor (TNF)-alpha and granulocyte macrophage colony-stimulating factor levels were within normal limits. The significance and pathogenic role of cytokine burst in PG is reviewed and discussed. PMID- 26047255 TI - Dispersively Detected Pauli Spin-Blockade in a Silicon Nanowire Field-Effect Transistor. AB - We report the dispersive readout of the spin state of a double quantum dot formed at the corner states of a silicon nanowire field-effect transistor. Two face-to face top-gate electrodes allow us to independently tune the charge occupation of the quantum dot system down to the few-electron limit. We measure the charge stability of the double quantum dot in DC transport as well as dispersively via in situ gate-based radio frequency reflectometry, where one top-gate electrode is connected to a resonator. The latter removes the need for external charge sensors in quantum computing architectures and provides a compact way to readout the dispersive shift caused by changes in the quantum capacitance during inter-dot charge transitions. Here, we observe Pauli spin-blockade in the high-frequency response of the circuit at finite magnetic fields between singlet and triplet states. The blockade is lifted at higher magnetic fields when intra-dot triplet states become the ground state configuration. A line shape analysis of the dispersive phase shift reveals furthermore an intra-dot valley-orbit splitting Deltavo of 145 MUeV. Our results open up the possibility to operate compact complementary metal-oxide semiconductor (CMOS) technology as a singlet-triplet qubit and make split-gate silicon nanowire architectures an ideal candidate for the study of spin dynamics. PMID- 26047256 TI - Bi-Directional Relationship Between Self-Regulation and Improved Eating: Temporal Associations With Exercise, Reduced Fatigue, and Weight Loss. AB - Severely obese men and women (body mass index >= 35 <= 55 kg/m(2); M(age) = 44.8 years, SD = 9.3) were randomly assigned to a 6-month physical activity support treatment paired with either nutrition education (n = 83) or cognitive-behavioral nutrition (n = 82) methods for weight loss. Both groups had significant improvements in physical activity, fatigue, self-regulation for eating, and fruit and vegetable intake. Compared to those in the nutrition education group, participants in the behavioral group demonstrated greater overall increases in fruit and vegetable intake and physical activity. These group differences were associated with changes that occurred after Month 3. Increased physical activity predicted reduced fatigue, beta = -.19, p =.01. A reciprocal relationship between the mediators of that relationship, which were changes in self-regulation and fruit and vegetable intake, was identified. There was significantly greater weight loss over six months in the behavioral nutrition group when contrasted with the nutrition education group. Self-regulation for eating and fruit and vegetable intake were significant predictors of weight loss over both three and six months. Findings enabled a better understanding of psychosocial effects on temporal aspects of weight loss and may lead to more effective behavioral treatments for weight loss. PMID- 26047257 TI - The Impact of Job Insecurity on Counterproductive Work Behaviors: The Moderating Role of Honesty-Humility Personality Trait. AB - The detrimental effects of job insecurity on individual and organizational well being are well documented in recent literature. Job insecurity as a stressor is generally associated with a higher presence of negative attitudes toward the organization. In this article, the moderating role of Honesty-Humility personality trait was investigated. It was assumed that Honesty-Humility would function as a psychological moderator of the job insecurity impact on counterproductive work behaviors. Participants were 203 workers who were administered a self-reported questionnaire. Results confirmed that job insecurity was positively related to counterproductive work behaviors whereas Honesty Humility was negatively associated to them. More importantly, Honesty-Humility moderated this relationship, even after controlling for gender, age, type of contract, and the other HEXACO personality traits. For individuals with low Honesty-Humility, job insecurity was positively related to counterproductive work behaviors, whereas for individuals with high Honesty-Humility, job insecurity turned out to be unrelated to counterproductive work behaviors. PMID- 26047258 TI - Evidence for an Evolutionary Cheater Strategy--Relationships Between Primary and Secondary Psychopathy, Parenting, and Shame and Guilt. AB - In the present study, shame and guilt proneness were investigated in relation to primary and secondary psychopathy, looking at parental care as a possible mediator. A sample of 388 volunteers participated in an on-line study, completing several self-report measurements. Primary psychopathy, robust to parental care and sex of the participant, was associated with lower guilt proneness after a private transgression and lower negative self-evaluations after a public transgression. Secondary psychopathy was not associated with guilt or shame proneness. Paternal care played a mediating role between primary psychopathy and guilt, but only in male participants. High paternal care was associated with lower guilt repair in high psychopathy males, suggesting that a positive father son relationship might be essential for development of exploitive strategies in primary psychopathy. The results highlight the fundamental differences between primary and secondary psychopathy, and provide support for the idea that primary psychopathy is an evolutionary cheater-strategy. PMID- 26047259 TI - Protective effects of polyethylene oxide on the vascular and organ function of rats with severe hemorrhagic shock. AB - This study examined the effects of polyethylene oxide (PEO) on the survival rate, hemodynamics, blood gas indexes, lactic acid levels, microcirculation, and inflammatory cytokine levels in rats subjected to severe hemorrhagic shock. The shocked rats were resuscitated with either Ringer's lactate solution or 20 ppm of PEO in Ringer's lactate solution for 1 h. It was found that infusion of PEO effectively improved the survival, metabolic acidosis, oxygen delivery, hyperlactacidemia, tissue perfusion, and inflammatory responses of rats subjected to hemorrhagic shock. In addition, we found, for the first time, that PEO showed protective effects on hepatic and renal injury, as evidenced by the significant decreases in the elevated levels of alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, and creatinine caused by shock induction after infusion of PEO (p < 0.05, 60 min post-resuscitation by comparison with pre resuscitation). All of these findings indicate that PEO exhibits strong therapeutic effects under conditions of severe hemorrhagic shock,which also provides theoretical and experimental bases for the clinical use of PEO. PMID- 26047261 TI - Reproductive BioMedicine and Society Online launches at ESHRE. PMID- 26047260 TI - Realization of 13.6% Efficiency on 20 MUm Thick Si/Organic Hybrid Heterojunction Solar Cells via Advanced Nanotexturing and Surface Recombination Suppression. AB - Hybrid silicon/polymer solar cells promise to be an economically feasible alternative energy solution for various applications if ultrathin flexible crystalline silicon (c-Si) substrates are used. However, utilization of ultrathin c-Si encounters problems in light harvesting and electronic losses at surfaces, which severely degrade the performance of solar cells. Here, we developed a metal assisted chemical etching method to deliver front-side surface texturing of hierarchically bowl-like nanopores on 20 MUm c-Si, enabling an omnidirectional light harvesting over the entire solar spectrum as well as an enlarged contact area with the polymer. In addition, a back surface field was introduced on the back side of the thin c-Si to minimize the series resistance losses as well as to suppress the surface recombination by the built high-low junction. Through these improvements, a power conversion efficiency (PCE) up to 13.6% was achieved under an air mass 1.5 G irradiation for silicon/organic hybrid solar cells with the c Si thickness of only about 20 MUm. This PCE is as high as the record currently reported in hybrid solar cells constructed from bulk c-Si, suggesting a design rule for efficient silicon/organic solar cells with thinner absorbers. PMID- 26047262 TI - Costs and absence of HCV-infected employees by disease stage. AB - OBJECTIVES: Quantify the costs and absenteeism associated with stages of the Hepatitis C virus (HCV). STUDY DESIGN: Retrospective analysis of the HCMS integrated database from multiple geographically diverse, US-based employers with employee information on medical, prescription, and absenteeism claims. METHODS: Employee data were extracted from July 2001-March 2013. Employees with HCV were identified by ICD-9-CM codes and classified into disease severity cohorts using diagnosis/procedure codes assigning the first date of most severe claim as the index date. Non-HCV employees (controls) were assigned random index dates. Inclusion required 6-month pre-/post-index eligibility. Medical, prescription, and absenteeism cost and time were analyzed using two-part regression (logistic/generalized linear) models, controlling for potentially confounding factors. Costs were inflation adjusted to September 2013. RESULTS: All direct costs comparisons were statistically significant (p <= 0.05) with mean medical costs of $1813 [SE = $3] for controls (n = 727,588), $4611 [SE = $211] for non cirrhotic (n = 1007), $4646 [SE = $721] for compensated cirrhosis (CC, n = 87), $12,384 [SE = $1122] for decompensated cirrhosis (DCC, n = 256), $33,494 [SE = $11,753] for hepatocellular carcinoma (HCC, n = 17) and $97,724 [SE = $32,437] for liver transplant (LT, n = 19) cohorts. Mean short-term disability days/costs were significantly greater for the non-cirrhotic (days = 2.03 [SE = 0.36]; $299 [SE = $53]), DCC (days = 6.20 [SE = 1.36]; $763 [SE = $169]), and LT cohorts (days = 21.98 [SE = 8.21]; $2537 [SE = $972]) compared to controls (days = 1.19 [SE = 0.01]; $155 [SE = $1]). Mean sick leave costs were significantly greater for non-cirrhotic ($373 [SE = $22]) and DCC ($460 [SE = $54]) compared to controls ($327 [SE = $1]). CONCLUSIONS: Employees with HCV were shown to have greater direct and indirect costs compared to non-HCV employee controls. Costs progressively increased in the more severe HCV disease categories. Slowing or preventing disease progression may avert the costs of more severe liver disease stages and enable employees with HCV to continue as productive members of the workforce. PMID- 26047263 TI - Correction: A Text Messaging-Based Smoking Cessation Program for Adult Smokers: Randomized Controlled Trial. PMID- 26047264 TI - Structural characterisation and antimutagenic activity of a novel polysaccharide isolated from Sepiella maindroni ink. AB - A new heteropolysaccharide, named as SIP, was isolated from the ink of cuttlefish, Sepiella maindroni, by enzymolysis, anion-exchange and gel-permeation chromatography and tested for its antimutagenic activity. It was homogeneous with a molecular weight of 1.13*10(4)Da by HPSEC-MALLS analysis. SIP contained glucuronic acid, mannose, N-acetylgalactosamine, and fucose in a molar ratio of 1:1:2:2. Its structural characteristics were investigated and elucidated by methylation analysis, GLC-MS, and NMR ((1)H, (13)C, H-H COSY, HMQC, HMBC, TOCSY and NOESY). The hexasaccharide repeating unit of SIP was found to be a backbone composed of fucose, N-acetylgalactosamine and mannose in a molar ratio of 2:2:1, and with a single branch of glucuronic acid at the C-3 position of mannose. According to the micronucleus test, SIP could significantly reduce the frequency of micronucleated cells in polychromatic erythrocytes and reticulocytes induced by cyclophosphamide in tumor-bearing mice, which revealed that SIP presented strong antimutagenic activity. PMID- 26047265 TI - Comparison of phenolic compositions between common and tartary buckwheat (Fagopyrum) sprouts. AB - The phenolic compositions of non-germinated/germinated seeds and seed sprouts (at 6-10 day-old) of common (Fagopyrum esculentum Moench) and tartary (Fagopyrum tataricum Gaertn.) buckwheats were investigated. Phenolic compounds, including chlorogenic acid, four C-glycosylflavones (orientin, isoorientin vitexin, isovitexin), rutin and quercetin, were determined in the seed sprouts by high performance liquid chromatography (HPLC). In the edible parts of common buckwheat sprouts, individual phenolics significantly increased during sprout growth from 6 to 10 days after sowing (DAS), whereas in tartary buckwheat sprouts they did not. While the sum contents of phenolic compounds in the edible part (mean 24.4mg/g DW at 6-10 DAS) of tartary buckwheat sprouts were similar to those of common buckwheat sprouts, rutin contents in the non-germinated/germinated seeds (mean 14.7mg/g DW) and edible parts (mean 21.8mg/g DW) of tartary buckwheat were 49- and 5-fold, respectively, higher than those of common buckwheat. Extracts of the edible parts of both species showed very similar free radical-scavenging activities (mean 1.7MUmol trolox eq/g DW), suggesting that the overall antioxidative activity might be affected by the combination of identified phenolics and unidentified (minor) components. Therefore, buckwheat seed sprouts are recommended for their high antioxidative activity, as well as being an excellent dietary source of phenolic compounds, particularly tartary buckwheat sprouts, being rich in rutin. PMID- 26047266 TI - Effects of soaking, germination and fermentation on phytic acid, total and in vitro soluble zinc in brown rice. AB - Rice is an important staple food in Asian countries. In rural areas it is also a major source of micronutrients. Unfortunately, the bioavailability of minerals, e.g. zinc from rice, is low because it is present as an insoluble complex with food components such as phytic acid. We investigated the effects of soaking, germination and fermentation with an aim to reduce the content of phytic acid, while maintaining sufficient levels of zinc, in the expectation of increasing its bioavailability. Fermentation treatments were most effective in decreasing phytic acid (56-96% removal), followed by soaking at 10 degrees C after preheating (42 59%). Steeping of intact kernels for 24h at 25 degrees C had the least effect on phytic acid removal (<20%). With increased germination periods at 30 degrees C, phytic acid removal progressed from 4% to 60%. Most wet processing procedures, except soaking after wet preheating, caused a loss of dry mass and zinc (1-20%). In vitro solubility, as a percentage of total zinc in soaked rice, was significantly higher than in untreated brown rice while, in steeped brown rice, it was lower (p<0.05). Fermentation and germination did not have significant effects on the solubility of zinc. The expected improvement due to lower phytic acid levels was not confirmed by increasing levels of in vitro soluble zinc. This may result from zinc complexation to other food components. PMID- 26047267 TI - Pectin methylesterase in Citrus bergamia R.: purification, biochemical characterisation and sequence of the exon related to the enzyme active site. AB - Three forms of pectin methylesterase (PME) were purified, from bergamot fruit (Citrus bergamia R.), to homogeneity by ion-exchange and affinity chromatography. The isoforms, named PME I, PME II and PME III, according their elution order on a heparin-sepharose column, were characterized for their relative molecular mass, activity kinetic parameters and thermostability. The molecular mass was estimated to be 42kDa for the three forms, and the apparent Km values for citrus pectin were 0.9mg/ml for PME I and 0.5mg/ml for PME II and PME III. The optimum pH values lie within the range 6.5-9.0, depending on salt concentration. Thermal behaviours of the three PME isoforms were studied in a temperature range from 65 degrees C to 80 degrees C with the less abundant PME I isoform showing a higher heat resistance. Moreover, the complete exon 2 sequence of PME gene was acquired (GenBank accession no. DQ458770) using a PCR-based approach on well-known Citrus genomic DNA present in the NCBI database. PMID- 26047268 TI - Free and bound phenolic compounds in leaves of pak choi (Brassica campestris L. ssp. chinensis var. communis) and Chinese leaf mustard (Brassica juncea Coss). AB - Eleven pak choi cultivars and two leaf mustard cultivars grown under field conditions in China were investigated for the free polyphenol content in their outer and inner leaves, as well as in their leaf blades and leaf stalks. In most cases, there were no significant differences between the hydroxycinnamic acid derivative and flavonoid derivative contents in the outer and inner leaves for the 13 cultivars. However, the contents of blades and stalks differed: hydroxycinnamic acids and flavonoids were present in greater amounts in the leaf blade than in the leaf stalk. Trace or small amounts of flavonoids were detected in the pak choi and leaf mustard stalks. Additionally, the bound phenolic contents of two pak choi cultivars and two leaf mustard cultivars were investigated. The concentrations of cell wall-bound phenolic compounds were higher in the leaf blade than in the leaf stalk under field conditions in China. These compounds represent only a minor portion of the total phenolic contents (flavonoids and hydroxycinnamic acids) in leaf stalks (0.81-1.18%) and leaf blades (0.05-0.08%) from fresh plant material. The storage of plant samples from four Chinese cabbage cultivars resulted, in most cases, in an increase of phenolic content, within six days, at 4 degrees C and 20 degrees C. The increase might have been triggered by post-harvest plant stresses, which stimulate the biosynthesis of polyphenols. PMID- 26047269 TI - Elucidation of the mechanism of enzymatic browning inhibition by sodium chlorite. AB - Sodium chlorite (SC) is a well known anti-microbial agent and its strong inhibitory effect on enzymatic browning of fresh-cut produce has recently been identified. We investigated the effect of SC on polyphenol oxidase (PPO) and its substrate, chlorogenic acid (CA), as it relates to the mechanisms of browning inhibition by SC. Results indicate that the browning reaction of CA (1.0mM) catalyzed by PPO (33U/mL) was significantly inhibited by 1.0mM SC at pH 4.6. Two PPO isoforms were identified by native polyacrylamide gel electrophoresis, and both were inactivated by SC (3.0mM). This suggests that SC serves as a PPO inhibitor to prevent enzymatic browning. Furthermore, the effect of SC on the stability of CA in both acidic (pH 4.5) and basic conditions (pH 8.3) was studied by UV-Vis scan and LC-MS analysis. The results showed that at the presence of SC (3.0mM), CA (0.1mM) degraded to quinic acid and caffeic acid as well as other intermediates. Hence, the anti-browning property of SC can be attributed to the two modes of action: the inactivation of polyphenol oxidase directly and the oxidative degradation of phenolic substrates. PMID- 26047270 TI - Phenolic content and antioxidative capacity of green and white tea extracts depending on extraction conditions and the solvent used. AB - The efficiencies of different solvents in the extraction of phenolics from bagged and loose leaves of white and green tea, after different extraction times, as well as the antioxidative capacity of the obtained extracts, were investigated. The developed HPLC method has the potential to separate and determinate 17 phenolics widely distributed in plants, but in investigated tea extracts only four catechins and traces of three flavonols and one flavone were separated and detected based on comparison with authentic standards. The extraction efficiency of phenolics depended strongly on the time of extraction and the solvents used. The extraction of catechins from green tea was significantly affected by the form (bagged or loose) of the tea, whereas this effect was shown not to be statistically significant for white tea. Green tea was a richer source of phenolics than was white tea. The extraction of phenolics from white tea by water could be accelerated by the addition of lemon juice. Aqueous ethanol (40%) was most effective in the prolonged extraction of catechins. The antioxidative capacity of the investigated tea extracts correlated with their phenolic content. PMID- 26047271 TI - In vitro antimicrobial activities against cariogenic streptococci and their antioxidant capacities: A comparative study of green tea versus different herbs. AB - The antimicrobial activity against cariogenic bacteria, total antioxidant capacity and phenolic constituents of methanolic extracts from 11 herbs were investigated and compared with those of green tea (Camellia sinensis). Among the 12 tested herbs, eight herbal extracts could inhibit the growth of Streptococcus sanguinis. Jasmine, jiaogulan, and lemongrass were the most potent, with minimum inhibitory concentrations (MIC) of 1mg/ml, while green tea was less effective, with a MIC of 4mg/ml. Among them, only rosemary could inhibit the growth of S. mutans at a MIC of 4mg/ml. Total antioxidant capacities of herbal extracts were analyzed by three different assays, including 2,2-diphenyl-1-picrylhydrazyl (DPPH.) radical scavenging activity, trolox equivalent antioxidant capacity (TEAC) and oxygen radical absorbance capacity (ORAC). Regardless of the assays used, green tea exhibited the highest antioxidant capacity, followed by osmanthus. Wide variations in total phenolics and total flavonoids of herbal tea extracts were observed. Chlorogenic acid was detected in high amount in honeysuckle and duzhong. These data suggest that rosemary is a potent inhibitor of oral streptococci, and green tea and osmanthus may be effective potential sources of natural antioxidants. PMID- 26047272 TI - The effect of different enzymes on the quality of high-fibre enriched brewer's spent grain breads. AB - The brewing industry produces large quantities of waste co-products. There is increasing pressure to ensure total utilisation of such products to address economic and environmental concerns. Brewer's spent grain (BSG) the main by product of the brewing industry is rich in dietary fibre and has a strong potential to be recycled. The overall objective of this study was to incorporate BSG into wheat flour breads together with a range of different enzymes (Maxlife 85, Lipopan Extra, Pentopan Mono BG and Celluclast) and evaluate the bread quality. A number of nutritional and textural properties of the finished product were studied. The incorporation of BSG significantly (P<0.0001) improved the dietary fibre but the major difficulty encounted was to achieve a good structure and high loaf volume. Increasing the level of dietary fibre significantly (P<0.001) increased dough development time, dough stability and crumb firmness but decreased the degree of softening and loaf volume. It was found that addition of Lipopan Extra (LE), Pentopan Mono (PE) and a mixture of Pentopan Mono and Celluclast (PCE) enzymes improved the texture, loaf volume and shelf life while Maxlife 85 enzyme (ME) was not significantly different from control samples (wheat flour breads containing 0%, 10%, 20% and 30% BSG). Image analysis of the bread structure obtained from the C-cell analyzer showed that the most significantly (P<0.001) open network was obtained using LE, followed by PE and PCE. PMID- 26047273 TI - Pigment profile and colour of monovarietal virgin olive oils from Arbequina cultivar obtained during two consecutive crop seasons. AB - Monovarietal virgin olive oils are labelled with the olive varieties giving them their distinctive character. There are numerous studies focussed on the characterisation and quantification of the minor fractions of virgin olive oils that have generated databases on varietal olive oils. However, few studies have focussed on the components of the pigment fraction of virgin olive oils. The aim of this work was to quantify the components of the chlorophyll and carotenoid fractions of the monovarietal virgin olive oils from the Arbequina cultivar, growing in the Spanish area of Catalonia, during two consecutive crop seasons. Additionally the pigment changes occurring during 24 months of oil storage were evaluated. The results of this study showed minor qualitative differences between monovarietal virgin olive oils from two consecutive seasons. The quantitative differences could be attributed to the harvest period in each season rather than to the year's weather conditions. Storage of the monovarietal virgin olive oils probably caused an important loss of the chlorophyll fraction, mainly chlorophyll a, during the first 6 months of storage. On the other hand, the carotenoid fraction was very stable and the retention of provitamin A was close to 80%, even after 24 months of storage. PMID- 26047274 TI - Phenolic contents and antioxidant activities of bitter gourd (Momordica charantia L.) leaf, stem and fruit fraction extracts in vitro. AB - Bitter gourd (Momordica charantia L.) has long been regarded as a food and medicinal plant. We investigated the antioxidant activity of the water extract of leaf, stem and fruit fractions by several in vitro systems of assay, namely DPPH radical-scavenging activity, hydroxyl radical-scavenging activity, beta-carotene linoleate bleaching assay, ferric reducing/antioxidant power (FRAP) assay and total antioxidant capacity. Total phenolic content was measured by Folin Ciocalteu reagent. Identification of phenolic compounds was achieved using HPLC with the UV-diode array detection. The extracts of different fractions were found to have different levels of antioxidant activity in the systems tested. The leaf extract showed the highest value of antioxidant activity, based on DPPH radical scavenging activity and ferric reducing power, while the green fruit extract showed the highest value of antioxidant activity, based on hydroxyl radical scavenging activity, beta-carotene-linoleate bleaching assay and total antioxidant capacity. The predominant phenolic compounds were gallic acid, followed by caffeic acid and catechin. The present study demonstrated that the water extract fractions of bitter gourd have different responses with different antioxidant methods. Total phenol content was shown to provide the highest association with FRAP assay in this present study (R(2)=0.948). PMID- 26047275 TI - Changes in fatty acid composition and electrolyte leakage of 'Hayward' kiwifruit during storage at different temperatures. AB - Exposure to low storage temperature induces changes in electrolyte leakage and fatty acids composition, in a way depending on the plant tissue. Those changes alter the response of the fruit to storage conditions. The influence of storage temperature on ripening, fatty acids composition and electrolyte leakage of 'Hayward' kiwifruit were investigated. Harvested fruit were stored at 0, 5, 10, 15 and 20 degrees C for 5, 12 and 17 days. Measurements of SSC, firmness, flesh colour, fatty acid composition and electrolyte leakage were performed during the experiment. Kiwifruit did not fully ripen during the 17 days storage at any temperature. The major fatty acid component in 'Hayward' kiwifruit consisted of linolenic, followed by oleic, palmitic, linoleic and stearic acid. Membrane permeability and unsaturated/saturated fatty acid ratio increased during storage in all treatments. The highest increase was during the first 5 days and at the lowest temperatures. The increase in unsaturated/saturated fatty acid ratio was caused mainly by a decrease in palmitic and an increase in oleic acids. Stearic, linoleic and linolenic acids had insignificant changes during storage. The main increase in electrolyte leakage and unsaturated/saturated fatty acid ratio occurred during the first storage days and at lower temperatures, probably as a response of the tissue to an adaptation to the new stress storage conditions. PMID- 26047276 TI - Release of beta-casomorphins 5 and 7 during simulated gastro-intestinal digestion of bovine beta-casein variants and milk-based infant formulas. AB - The release of beta-casomorphin-5 (BCM5) and beta-casomorphin-7 (BCM7) was investigated during simulated gastro-intestinal digestion (SGID) of bovine beta casein variants (n=3), commercial milk-based infant formulas (n=6) and experimental infant formulas (n=3). SGID included pepsin digestion at pH 2.0, 3.0 and 4.0 and further hydrolysis with Corolase PPTM. beta-Casein (beta-CN) variants were extracted from raw milks coming from cows of Holstein-Friesian and Jersey breeds. Genomic DNA was isolated from milk and the beta-CN genotype was determined by a PCR-based method. Phenotype at protein level was determined by capillary zone electrophoresis in order to ascertain the level of gene expression. Recognition and quantification of BCMs involved HPLC coupled to tandem MS. Regardless of the pH, BCM7 generated from variants A1 and B of beta-CN (5-176mmol/mol casein) the highest amount being released during SGID of form B. As expected, the peptide was not released from variant A2 at any steps of SGID. BCM5 was not formed in hydrolysates irrespective of either the genetic variant or the pH value during SGID. Variants A1, A2 and B of beta-CN were present in all the commercial infant formulae (IFs) submitted to SGID. Accordingly, 16-297nmol BCM7 were released from 800ml IF, i.e. the daily recommended intake for infant. Industrial indirect-UHT treatments (156 degrees C*6-9s) did not modify release of BCM7 and, during SGID, comparable peptide amounts formed in raw formulation and final heat-treated IFs. PMID- 26047277 TI - Heat denaturation of Brazil nut allergen Ber e 1 in relation to food processing. AB - Ber e 1, a major allergen from Brazil nuts, is very stable to in vitro peptic digestion. As heat-induced denaturation may affect protein digestibility, the denaturation behaviour of Ber e 1 was investigated. The denaturation temperature of Ber e 1 varies from approximately 80-110 degrees C, depending on the pH. Upon heating above its denaturation temperature at pH 7.0, the protein partly forms insoluble aggregates and partly dissociates into its polypeptides, whereas heating at pH 5.0 does neither induce aggregation, nor dissociation of the protein. The denaturation temperature of approximately 110 degrees C at pH values corresponding to the general pH values of foods (pH 5-7) is very high and is expected to be even higher in Brazil nuts themselves. As a result, it is unlikely that heat processing causes the denaturation of all Ber e 1 present in food products. Consequently, the allergen is assumed to be consumed (mainly) in its native form, having a high stability towards pepsin digestion. PMID- 26047278 TI - The role of gluten in a pound cake system: A model approach based on gluten starch blends. AB - In order to evaluate the role of gluten in cake-making, gluten-starch (GS) blends with different ratios of gluten to starch were tested in a research pound cake formula. The viscosities of batters made from commercial GS blends in the otherwise standardised formula increased with their gluten content. High viscosities during heating provide the batters with the capacity to retain expanding air nuclei, and thereby led to desired product volumes. In line with the above, increasing gluten levels in the cake recipes led to a more extended oven spring period. Cakes with a starch content exceeding 92.5% in the GS blend suffered from substantial collapse during cooling. They had a coarse crumb with a solid gummy layer at the bottom. Image analysis showed statistical differences in numbers of cells per cm(2), cell to total area ratio and mean cell area (p<0.05). Both density and mean cell area were related to gluten level. Moreover, mean cell area and cell to total area ratio were the highest for cakes with the lowest density and highest gluten levels. Relative sodium dodecyl sulfate (SDS, 2.0%) buffer (pH 6.8) extractabilities of protein from cakes baked with the different GS blends decreased with gluten content and were strongly correlated with the intensity of collapse. Taken together, the results teach that protein gives the cakes resistance to collapse, resulting in desirable volumes and an optimal grain structure with uniform cell distribution. PMID- 26047279 TI - Impact of parboiling conditions on Maillard precursors and indicators in long grain rice cultivars. AB - The effect of steaming conditions (mild, intermediate and severe) during parboiling of five different long-grain rice cultivars (brown rice cultivars Puntal, Cocodrie, XL8 and Jacinto, and a red rice) on rice colour, and Maillard precursors and indicators was investigated. Rice colour increased with severity of parboiling conditions. Redness increased more than yellowness when parboiling brown rice. Parboiling turned red rice black. It changed the levels of glucose, fructose, sucrose, and maltose. Losses of the non-reducing sugar, sucrose were caused by both leaching into the soaking water and enzymic conversion, rather than by thermal degradation during steaming. Concentrations of the reducing sugars, glucose and fructose, in intermediately parboiled rice were higher than those of mildly parboiled rice. After severe parboiling, glucose levels were lower than those of intermediately parboiled rice, while fructose levels were higher. These changes were ascribed to the sum of losses in the Maillard reaction (MR), formations as a result of starch degradation and isomerisation of glucose into fructose. It was clear that the epsilon-amino group of protein-bound lysine was more affected by parboiling conditions and loss in MRs, than that of free lysine. Low values of the MR indicators furosine and free 5-hydroxymethyl-2 furaldehyde (HMF) in processed brown and red rices were related to mild parboiling, whereas high furosine and low free HMF levels were indicative of rices being subjected to intermediate processing conditions. High furosine and high free HMF contents corresponded to severe hydrothermal treatments. The strong correlation (r=0.89) between the free HMF levels and the increase in redness of parboiled brown rices suggested that Maillard browning was reflected more in the red than in the yellow colour. PMID- 26047280 TI - Influence of hyaluronidase addition on the production of hyaluronic acid by batch culture of Streptococcuszooepidemicus. AB - Enhancement of hyaluronic acid (HA) production by Streptococcus zooepidemicus through increasing oxygen transfer rate via degradation of HA by hyaluronidase was investigated. Dissolved oxygen (DO) level became a limiting factor for HA production during 8-16h, and thus hyaluronidase (0.05, 0.10, 0.15, 0.20, 0.25g/l) was added at 8h to degrade HA. Oxygen transfer rate coefficient and DO level during 8-16h increased with increased hyaluronidase concentration. Compared to 5.0+/-0.1g/l of the control without hyaluronidase addition, HA production was increased from 5.0+/-0.1g/l to 6.0+/-0.1g/l when hyaluronidase concentration was 0.15g/l. Further increase of hyaluronidase concentration had no effect on HA production. The molecular weight of HA decreased with the increased hyaluronidase concentration and decreased to 21kDa when hyaluronidase concentration was 0.25g/l from 1300kDa of the control. The prepared low molecular weight HA (LMW-HA) could function as potential anti-angiogenic substances, antiviral and anti-tumor agents to possibly be used as functional food ingredients. PMID- 26047281 TI - Essential oil composition and antibacterial activity of Thymus caramanicus at different phenological stages. AB - Thymus species are well known as medicinal plants because of their biological and pharmacological properties. Thymus caramanicus is an endemic species grown in Iran. Variation in the quantity and quality of the essential oil of wild population of T. caramanicus at different phenological stages including vegetative, floral budding, flowering and seed set are reported. The oils of air dried samples were obtained by hydrodistillation. The yields of oils (w/w%) at different stages were in the order of: flowering (2.5%), floral budding (2.1%), seed set (2.0%) and vegetative (1.9%). The oils were analyzed by GC and GC-MS. In total 37, 37, 29 and 35 components were identified and quantified in vegetative, floral budding, full flowering and seed set, representing 99.3, 98.6, 99.2 and 97.8% of the oil, respectively. Carvacrol was the major compound in all samples. The ranges of major constituents were as follow: carvacrol (58.9-68.9%), p-cymene (3.0-8.9%), gamma-terpinene (4.3-8.0%), thymol (2.4-6.0%) and borneol (2.3-4.0%). Antibacterial activity of the oils and their main compounds were tested against seven Gram-positive and Gram-negative bacteria by disc diffusion method and determining their minimum inhibitory concentration (MIC) values. The inhibition zones (IZ) and MIC values for bacterial strains, which were sensitive to the essential oil of T. caramanicus, were in the range of 15-36mm and 0.5-15.0mg/ml, respectively. The oils of various phenological stages showed high activity against all tested bacteria, of which Bacillus subtilis and Pseudomonas aeruginosa were the most sensitive and resistant strains, respectively. Thus, they represent an inexpensive source of natural antibacterial substances that exhibited potential for use in pathogenic systems. PMID- 26047283 TI - Functional properties and in vitro trypsin digestibility of red kidney bean (Phaseolus vulgaris L.) protein isolate: Effect of high-pressure treatment. AB - The effects of high-pressure (HP) treatment at 200-600MPa, prior to freeze drying, on some functional properties and in vitro trypsin digestibility of vicilin-rich red kidney bean (Phaseolus vulgaris L.) protein isolate (KPI) were investigated. Surface hydrophobicity and free sulfhydryl (SH) and disulfide bond (SS) contents were also evaluated. HP treatment resulted in gradual unfolding of protein structure, as evidenced by gradual increases in fluorescence strength and SS formation from SH groups, and decrease in denaturation enthalpy change. The protein solubility of KPI was significantly improved at pressures of 400MPa or higher, possibly due to formation of soluble aggregate from insoluble precipitate. HP treatment at 200 and 400MPa significantly increased emulsifying activity index (EAI) and emulsion stability index (ESI); however, EAI was significantly decreased at 600MPa (relative to untreated KPI). The thermal stability of the vicilin component was not affected by HP treatment. Additionally, in vitro trypsin digestibility of KPI was decreased only at a pressure above 200MPa and for long incubation time (e.g., 120min). The data suggest that some physiochemical and functional properties of vicilin-rich kidney proteins can be improved by means of high-pressure treatment. PMID- 26047282 TI - Inhibitors of lactic acid fermentation in Spanish-style green olive brines of the Manzanilla variety. AB - Frequently, a delay or lack of lactic acid fermentation occurs during the processing of Spanish-style green olives, in particular of the Manzanilla variety. Many variables can affect the progress of fermentation such as temperature, nutrients, salt concentration, antimicrobials in brines, and others. In this study, it was demonstrated that an inappropriate alkaline treatment (low NaOH strength and insufficient alkali penetration) allowed for the presence of several antimicrobial compounds in brines, which inhibited the growth of Lactobacillus pentosus. These substances were the dialdehydic form of decarboxymethyl elenolic acid either free or linked to hydroxytyrosol and an isomer of oleoside 11-methyl ester. Olive brines, from olives treated with a NaOH solution of low concentration up to 1/2 the distance to the pit, contained these antimicrobials, and no lactic acid fermentation took place in them. By contrast, a more intense alkaline treatment (2/3 lye depth penetration) gave rise to an abundant growth of lactic acid bacteria without any antimicrobial in brines. Therefore, the precise cause of stuck fermentation in Manzanilla olive brines was demonstrated for the first time and this finding will contribute to better understand the table olive fermentation process. PMID- 26047284 TI - Interfacial composition and stability of emulsions made with mixtures of commercial sodium caseinate and whey protein concentrate. AB - The interfacial composition and the stability of oil-in-water emulsion droplets (30% soya oil, pH 7.0) made with mixtures of sodium caseinate and whey protein concentrate (WPC) (1:1 by protein weight) at various total protein concentrations were examined. The average volume-surface diameter (d32) and the total surface protein concentration of emulsion droplets were similar to those of emulsions made with both sodium caseinate alone and WPC alone. Whey proteins were adsorbed in preference to caseins at low protein concentrations (<3%), whereas caseins were adsorbed in preference to whey proteins at high protein concentrations. The creaming stability of the emulsions decreased markedly as the total protein concentration of the system was increased above 2% (sodium caseinate >1%). This was attributed to depletion flocculation caused by the sodium caseinate in these emulsions. Whey proteins did not retard this instability in the emulsions made with mixtures of sodium caseinate and WPC. PMID- 26047286 TI - New source of alpha-d-galactosidase: Germinating coffee beans. AB - Enzyme activities of alpha-Gal from dormant and germinating coffee beans (Coffea arabica) were studied and compared to develop one new source of alpha-d galactosidase (alpha-Gal). During the germination, enzyme activity showed a continuous improvement: it increased slowly within 25 days and then rapidly increased. At the beginning of the germination, enzyme activity was lower than that from dormant coffee beans (DCB). It became higher than the latter around the 30th day, and rose to a maximum at the 35th day. The partially purified enzymes from germinating coffee beans (GCB) and DCB were obtained through ammonium sulphate precipitation, acetone precipitation and DEAE Sepharose ion exchange chromatography. The results showed that enzyme activity of purified alpha-Gal from GCB was 1.73 times greater than that from DCB. It was most stable for six weeks at its optimal pH (4.8) during the storage. GCB could become a new source of alpha-Gal instead of DCB. PMID- 26047285 TI - Inflorescences of Brassicacea species as source of bioactive compounds: A comparative study. AB - Two Brassica oleracea varieties (B. oleracea L. var. costata DC and B. oleracea L. var. acephala) and Brassica rapa L. var. rapa inflorescences were studied for their chemical composition and antioxidant capacity. Phenolic compounds and organic acids profiles were determined by HPLC-DAD and HPLC-UV, respectively. B. oleracea var. costata and B. oleracea L. var. acephala inflorescences presented a similar qualitative phenolic composition, exhibiting several complex kaempferol derivatives and 3-p-coumaroylquinic acid, while B. rapa var. rapa was characterized by kaempferol and isorhamnetin glycosides and several phenolic acids derivatives. B. oleracea L. var. costata and B. rapa var. rapa showed the highest phenolics content. The three Brassica exhibited the same six organic acids (aconitic, citric, pyruvic, malic, shikimic and fumaric acids), but B. oleracea L. var. acephala presented a considerably higher amount. Each inflorescence was investigated for its capacity to act as a scavenger of DPPH radical and reactive oxygen species (superoxide radical, hydroxyl radical and hypochlorous acid), exhibiting antioxidant capacity in a concentration dependent manner against all radicals. These samples were also studied for its antimicrobial potential against Gram-positive and Gram-negative bacteria and fungi, displaying antimicrobial capacity only against Gram-positive bacteria. PMID- 26047287 TI - Effect of gamma irradiation on the extraction yield, total phenolic content and free radical-scavenging activity of Nigella staiva seed. AB - In the present study, the radiation processing of Nigella sativa seed samples was carried out at dose levels of 2, 4, 8, 10, 12 and 16kGy. The extraction yield, total phenolic content and 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity of both control and irradiated samples extracted in acetone, methanol and water were assessed. The results showed that the extraction yields increased with an increase in radiation dose for all the test solvents. At 16kGy the increases were 3.7%, 4.2%, 5.6% and 9.0% for hexane, acetone, water and methanol extracts, respectively. The phenolic content in the acetone extract was found to be increased from 3.7 for the control sample to 3.8mg/g for the 16kGy radiation-processed sample. No significant change was observed for the phenolic content of the methanolic extract, while the aqueous extract showed a decrease at dose levels of 12 and 16kGy. In the control samples, the DPPH radical-scavenging activity was 79.4%, 79.1% and 92.0% for water, acetone and methanol extracts, respectively, at 5mg/ml concentration. Gamma irradiation enhanced the scavenging activity in acetone and methanol extracts by 10.6% and 5.4%, respectively, at 16kGy. In summary, gamma irradiation increased the extraction yield and total phenolic content, as well as enhancing the free radical-scavenging activity. In addition, the type of solvent used for extraction also affected the impact of irradiation on antioxidant activity and total phenolic content of N. sativa seed. PMID- 26047288 TI - Flavouring reduced fat high fibre cheese products with enzyme modified cheeses (EMCs). AB - Medium (13%) and low (2%) fat imitation cheeses (pH 6 or 5.5) were flavoured with 5% w/w EMC containing 16%, 28% or 47% total free fatty acids (low to high levels of hydrolysis, respectively) and were examined by a sensory panel. Aroma active short-chain free fatty acids were monitored using gas chromatographic techniques. Regardless of cheese pH or EMC composition, panellists ranked all medium-fat cheeses similarly. Low-fat cheeses flavoured (pH 6 or 5.5) with low or medium lipolysis EMC were described as 'well-balanced' and 'cheesy' and were significantly more preferred to cheeses containing high hydrolysis EMCs. Low-fat cheeses were least preferred of all cheeses because of 'very intense' bursts of off-flavours. Lower pH cheeses were softer and less melting. Higher fat levels in imitation cheese modulated a greater retention of fat-based flavour compounds and improved their release during consumption more than did lower fat levels. PMID- 26047289 TI - Biochemical characterisation of a glycogen branching enzyme from Streptococcus mutans: Enzymatic modification of starch. AB - A gene encoding a putative glycogen branching enzyme (SmGBE) in Streptococcus mutans was expressed in Escherichia coli and purified. The biochemical properties of the purified enzyme were examined relative to its branching specificity for amylose and starch. The activity of the approximately 75kDa enzyme was optimal at pH 5.0, and stable up to 40 degrees C. The enzyme predominantly transferred short maltooligosyl chains with a degree of polymerization (dp) of 6 and 7 throughout the branching process for amylose. When incubated with rice starch, the enzyme modified its optimal branch chain-length from dp 12 to 6 with large reductions in the longer chains, and simultaneously increased its branching points. The results indicate that SmGBE can make a modified starch with much shorter branches and a more branched structure than to native starch. In addition, starch retrogradation due to low temperature storage was significantly retarded along with the enzyme reaction. PMID- 26047290 TI - Comparison between free radical scavenging capacity and oxidative stability of nut oils. AB - Several works have measured free radical scavenging capacity of nut oils, since they may become a significant source of dietary fat. However, they have not considered kinetic parameters, what was the first aim of this work. Also, it was studied the possible relation between values of free radical scavenging capacity DPPH and oxidative stability (Rancimat method) in different nut (hazelnut, peanut, pistachio, walnut and almond) oils. The ranking of antioxidant capacity of nut oils, by both assays, was: pistachio>hazelnut>walnut>almond>peanut. A significant correlation was found between DPPH and Rancimat methods assays. Tocopherols appear to be the responsible compounds of this antioxidant capacity being neglictible the contribution of polyphenols. An interference effect of phospholipids, present in methanolic fraction of nut oils, was observed in the determination of polyphenols in nut oils by Folin and ortho-diphenols assays. PMID- 26047291 TI - Non-nutritive functional agents in rattan-shoots, a food consumed by native people in the Philippines. AB - The tender shoots of Calamus ornatus, one of the food items consumed by the native people, Kanawan Aytas, in the Bataan region of the Philippines, have not been studied before. A bioassay-guided investigation of its methanolic extract afforded non-nutritive functional agents (NFAs), steroidal saponins 1-3, along with its aglycone (4). The NFAs 1-4 inhibited cyclooxygenase enzymes, COX-1 and 2, by 47%, 43%, 33%, and 53% and 71%, 75%, 78%, and 73%, respectively, at 28.2, 24.2, 21.2 and 60.4MUM. Treatment of breast (MCF-7), CNS (SF-268), lung (NCI H460), colon (HCT-116) and gastric (AGS) cancer cell lines with the extract at 100MUg/ml reduced cell proliferation. Similarly, the pure NFAs 2 and 3 reduced the cell viability of breast, CNS, lung, colon and gastric cancer cell lines by 37.5%, 22.4%, 53.3%, 58.2%, 40.3% and 29.8%, 21.3%, 45.6%, 37.1%, 25.0%, respectively, at 24.2 and 21.2MUM. The 50% reduction in cell viability (IC50) concentrations of 2 and 3 against these cancer cell lines were 8.8, 6.1, 7.5, 23.8, 12.1 and 3.8, 7.1, 3.3, 14.3, 12.1MUM, respectively. This is the first report on the isolation of steroidal saponins from C. ornatus shoots and their antiinflammatory and tumor cell proliferation inhibitory activities. Therefore, our results suggest that the Kanawan Aytas may yield health benefits from rattan shoots in their diet. PMID- 26047292 TI - Phenolic glucosides in bread containing flaxseed. AB - Three phenolic glucosides, secoisolariciresinol diglucoside, p-coumaric acid glucoside and ferulic acid glucoside, were analyzed in commercial breads containing flaxseed. The total phenolic glucoside content ranged from 15 to 157mg/100g dry bread. Secoisolariciresinol diglucoside was the dominating phenolic glucoside with an average relative content of 62%, followed by p coumaric acid glucoside (20%) and ferulic acid glucoside (18%). Strong positive correlations between the phenolic glucosides were found, indicating no major effect of raw material or bread-making process on the relative content of the phenolic glucosides in flaxseed. PMID- 26047293 TI - Square wave voltammetry for analytical determination of paraquat at carbon paste electrode modified with fluoroapatite. AB - This paper describes the construction of a carbon paste electrode (CPE) impregnated with fluoroapatite (FAP). The new electrode (FAP-CPE) was revealed an interesting determination of paraquat. The latter was accumulated on the surface of the modified electrode by adsorbing onto fluoroapatite and reduced in 0.1molL( 1) K2SO4 electrolyte at -0.70 and -1.0V for peaks 1 and 2, respectively. Experimental conditions were optimized by varying the accumulation time, FAP loading and measuring solution pH. Under the optimized working conditions, calibration graphs were linear in the concentration ranging from 5*10(-8) to 7*10(-5)molL(-1) with detection limits (DL,3sigma) of 3.5*10(-9) and 7.4*10( 9)molL(-1), respectively, for peaks 1 and 2. Fluoroapatite was characterized by X ray diffraction XRD analysis; Fourier-transform infrared spectroscopy FT-IR and inductively coupled plasma-atomic emission spectrometry (ICP-AES) analysis. PMID- 26047294 TI - Extraction and determination of ellagic acid contentin chestnut bark and fruit. AB - Chestnuts are an important economic resource in the chestnut growing regions, not only for the fruit, but also for the wood. The content of ellagic acid (EA), a naturally occurring inhibitor of carcinogenesis, was determined in chestnut fruits and bark. EA was extracted with methanol and free ellagic acid was determined by HPLC with UV detection, both in the crude extract and after hydrolysis. The concentration of EA was generally increased after hydrolysis due to the presence of ellagitannins in the crude extract. The concentration varied between 0.71 and 21.6mgg(-1) (d.w.) in un-hydrolyzed samples, and between 2.83 and 18.4mgg(-1) (d.w.) in hydrolyzed samples. In chestnut fruits, traces of EA were present in the seed, with higher concentrations in the pellicle and pericarp. However, all fruit tissues had lower concentrations of EA than had the bark. The concentration of EA in the hydrolyzed samples showed a non-linear correlation with the concentration in the unhydrolyzed extracts. PMID- 26047295 TI - Use of thiolysis hyphenated to RP-HPLC-ESI(-)-MS/MS for the analysis of flavanoids in fresh lager beers. AB - Proanthocyanidins are well known for their involvement in haze and colour development during beer ageing. New methodologies are needed, however, to understand what happens to them in the bottled beer. For the first time in the brewing field, thiolysis was hyphenated to RP-HPLC-ESI(-)-MS/MS to investigate these flavanoids. Thirty minutes at 40 degrees C followed by 10h at room temperature emerged as the best conditions for complete depolymerisation. NP-HPLC ESI(-)-MS/MS was used to quantify and isolate fractions from monomers to trimers in a Sephadex LH20 acetone/water (70/30, v/v) beer extract. Unsurprisingly, a lower dimer/monomer ratio was evidenced in PVPP-treated beers than in silica gel filtered beers. Most beer dimers are procyanidins B3 (two catechin units) whilst most trimers are prodelphinidins (catechin in terminal units and gallocatechins or catechins in extension units). Gallocatechin appeared to come mainly from malt. Despite the absence of chromatographic peaks corresponding to oligomers above trimers, an apparent degree of polymerisation close to six was calculated in the total LH20 extract. Still higher mean degrees of polymerisation (mDPs) were calculated for malt and hop, indicating selective extraction or depolymerisation from raw materials to beer. The main part of beer polyphenols is composed of complex undefined structures not degraded by toluene-alpha-thiol. PMID- 26047296 TI - A comparison of three amperometric phenoloxidase-Sonogel-Carbon based biosensors for determination of polyphenols in beers. AB - Three phenoloxidases based biosensors were successfully developed using as electrochemical transducer a new type of electrode recently developed by our group: the "Sonogel-Carbon electrode". The employed enzymes were Trametes versicolor laccase (Lac), Mushroom tyrosinase (Tyr), and Horseradish peroxidase (HRP). Immobilization step was accomplished by doping the electrode surface with a mixture of the individual enzyme and Nafion ion exchanger as additive protective. The biosensor responses, optimized in beer real samples, were evaluated for five individual polyphenols. It was found that the developed biosensors were sensitive to nanomolar concentrations of the tested polyphenols. As example, the limit of detection, sensitivity, and response linear range for caffeic acid for Nafion-Lac/Sonogel-Carbon biosensor were 0.06MUmolL(-1), 99.6nAMUmol(-1)L, and 0.04-2MUmolL(-1), respectively. The stability and reproducibility of the biosensors were evaluated by applying them directly to beer real samples. It has been demonstrated that the Nafion-Lac/Sonogel-Carbon system is the more stable with a relative standard deviation of 3.3% (n=10), maintaining 84% of its stable response for at least three weeks. Estimation of polyphenol index in eight lager beers and a comparison of the results with those obtained by a classical method was carried out. PMID- 26047297 TI - Comparison of different methods for total lipid quantification in meat and meat products. AB - This study was aimed to evaluate the efficiency of six extraction methods for the quantification of total lipid content in meat and meat products: standard Soxhlet method (with and without previous acid hydrolysis), continuous Soxhlet method (with and without previous acid hydrolysis), and those methods based in the use of a mixture of chloroform and methanol, and described by Folch, Less, and Sloane (1957) and Bligh and Dyer (1959). Lipid content was determined in nine different meat products with different fat contents and physico-chemical features: cooked turkey breast, fresh pork loin, cooked ham, dry-cured ham, mortadella, beef burger, fresh sausage, dry-cured sausage and salami. The most effective methods for determining fat content in the studied meat products were the method described by Folch et al. (1957) and the Soxhlet with previous acid hydrolysis method. The Soxhlet method without previous acid hydrolysis adequately extracted lipids only in those meat products with very high fat content. The use of the method described by Bligh and Dyer (1959) gave rise to the lowest lipid contents in all the studied meat products. PMID- 26047298 TI - Fast simultaneous analysis of caffeine, trigonelline, nicotinic acid and sucrose in coffee by liquid chromatography-mass spectrometry. AB - A rapid liquid chromatography-mass spectrometry method for the simultaneous quantification of caffeine, trigonelline, nicotinic acid and sucrose in coffee was developed and validated. The method involved extraction with hot water, clarification with basic lead acetate and membrane filtration, followed by chromatographic separation using a Spherisorb((r)) S5 ODS2, 5MUm chromatographic column and gradient elution with 0.3% aqueous formic acid/methanol at a flow rate of 0.2mL/min. The electrospray ionization source was operated in the negative mode to generate sucrose ions and in the positive mode to generate caffeine, trigonelline and nicotinic acid ions. Ionization suppression of all analytes was found due to matrix effect. Calibrations curves prepared in green and roasted coffee extracts were linear with r(2)>0.999. Roasted coffee was spiked and recoveries ranged from 93.0% to 105.1% for caffeine, from 85.2% to 116.2% for trigonelline, from 89.6% to 113.5% for nicotinic acid and from 94.1% to 109.7% for sucrose. Good repeatibilities (RSD<5%) were found for all analytes in the matrix. The limit of detection (LOD), calculated on the basis of signal-to-noise ratios of 3:1, was 11.9, 36.4, 18.5 and 5.0ng/mL for caffeine, trigonelline, nicotinic acid and sucrose, respectively. Analysis of 11 coffee samples (regular or decaffeinated green, ground roasted and instant) gave results in agreement with the literature. The method showed to be suitable for different types of coffee available in the market thus appearing as a fast and reliable alternative method to be used for routine coffee analysis. PMID- 26047299 TI - Effect of gamma irradiation on the stability of anthocyanins and shelf-life of various pomegranate juices. AB - Food irradiation is a process which exposing food to ionizing radiations and it can improve the safety of food. The pomegranate juice contained considerable anthocyanins and has become a new functional food available for dieting and health. In the present study, the effects of gamma irradiation (0-10kGy) on the stability of anthocyanins and inhibition of microbial growth in pomegranate juice during storage were investigated. Results indicated that the irradiation at all applied doses, significantly reduced total and individual anthocyanins. Moreover, irradiation with higher dosages (3.5-10kGy) had undesirable effect on the total content of anthocyanins. However, irradiation at 2.0kGy had effectively diminished the total bacteria and fungi count and retarding microbial growth during storage. Based on adverse effect of gamma irradiation on ACs content of studied juices, it is not recommended to irradiate pomegranate juice with dosage higher than 2.0kGy. PMID- 26047300 TI - Identification and quantification of polyphenolic compounds from okra seeds and skins. AB - The aims of the present work were to identify and quantify the polyphenolic profile of okra (Abelmoschus esculentus), a vegetable almost worldwide consumed. Since the knowledge about the okra polyphenolic compounds is limited, the seeds and the skins of okra were separately analyzed. The seeds, which represent the 17% of the vegetable and are richer in phenolic compounds, were mainly composed by oligomeric catechins (2.5mg/g of seeds) and flavonol derivatives (3.4mg/g of seeds). The skins polyphenolic profile was composed principally by hydroxycinnamic and quercetin derivatives (0.2 and 0.3mg/g of skins). These findings in associations with the high content of okra in carbohydrates and proteins enhance the importance of this foodstuff in the human diet. PMID- 26047301 TI - Optimization of the determination of tocopherols in Agaricus sp. edible mushrooms by a normal phase liquid chromatographic method. AB - Individual tocopherol profile of five Agaricus mushroom species, widely consumed in Portugal, was obtained by a normal-phase high-performance liquid chromatography (NP-HPLC). It was used a simple solid-liquid extraction procedure without saponification step and the chromatographic separation was achieved using a YMC-Pack Polyamine II column using an isocratic elution with hexane/ethyl acetate (70:30, v/v) at a flow rate of 1.0mL/min. The effluent was monitored by a fluorescence detector. All the compounds were separated in a period of time of 30min. The method proved to be sensitive, reproducible and accurate, allowing the determination of tocopherols. PMID- 26047302 TI - Novel surface-active ionic liquids used as solubilizers for water-insoluble pesticides. AB - Three surface active ionic liquids (ILs) containing organic anions but no halides were used as solubilizers for water insoluble pesticides and as well as alternates for similar ILs with halide anions, which have been increasingly popular in the agricultural practice. The solubilities of five pesticides (fluazifop-P, clethodim, pyrethrin, fosthiazate, and prochloraz) in three aqueous micellar systems, each containing 1-octyl-3-methylimidazolium--tartrate ([OMIM][Tart]), 1-octyl-3-methylimidazolium-l-proline ([OMIM][Prol]), 1-octyl-3 methylimidazolium-l-lactate ([OMIM][lact]), respectively, were measured. The solubilities of all five pesticides were found to increase with the increasing concentrations of ILs solubilzers The enhancements in solubilities were related to surface activities of these SAILs, as indicated in the results of the measurements of their corresponding critical aggregation concentration (CAC), lowest surface tension (gammacac), maximum surface excess concentration (Gammamax) and minimum area per molecule (Amin) of aqueous solutions of ILs. When comparing with similar ILs with halides as counter anions, we found that these ILs with organic counterions are at least comparable, often more effective solubilizers for all of the five very different pesticides we tested. We conclude that these novel SAILs with organic counterions would serve as at least similarly effective and more environmentally-friendly solubilizers over the more traditional ones with halides. PMID- 26047303 TI - The new paradigm: from 'bench to bedside' to the translational research 'valleys of death'. PMID- 26047304 TI - Exposure to socioeconomic adversity in early life and risk of depression at 18 years: The mediating role of locus of control. AB - BACKGROUND: Previous studies have linked exposure to early socioeconomic adversity to depression, but the mechanisms of this association are not well understood. Locus of control (LoC), an individual's control-related beliefs, has been implicated as a possible mechanism, however, longitudinal evidence to support this is lacking. METHODS: The study sample comprised 8803 participants from a UK cohort, the Avon Longitudinal Study of Parents and Children (ALSPAC). Indicators of early socioeconomic adversity were collected from the antenatal period to 5 years and modelled as a latent factor. Depression was assessed using the Clinical Interview Schedule-Revised (CIS-R) at 18 years. LoC was assessed with the Nowicki-Strickland Internal-External (CNSIE) scale at 16 years. RESULTS: Using structural equation modelling, we found that 34% of the total estimated association between early socioeconomic adversity and depression at 18 years was explained by external LoC at 16 years. There was weak evidence of a direct pathway from early socioeconomic adversity to depression after accounting for the indirect effect via external locus of control. Socioeconomic adversity was associated with more external LoC, which, in turn, was associated with depression. LIMITATIONS: Attrition may have led to an underestimation of the direct and indirect effect sizes in the complete case analysis. CONCLUSIONS: Results suggest that external LoC in adolescence is one of the factors mediating the link between early adversity and depression at 18 years. Cognitive interventions that seek to modify maladaptive control beliefs in adolescence may be effective in reducing risk of depression following early life adversity. PMID- 26047305 TI - An association study of the m6A genes with major depressive disorder in Chinese Han population. AB - BACKGROUND: Major depressive disorder (MDD) is a common, chronic and recurrent mental disease but the precise mechanism behind this disorder remains unknown. FTO is one of the N6-methyladenosine (m6A) modification genes and has recently been found to be associated with depression. N6-methyladenosine (m6A) is the most abundant internal modification on RNA, which is highly enriched within the brain. There are five genes involved in m6A modification including FTO, but whether these m6A modification genes could confer a risk of MDD is still unclear. This study aimed to investigate the genetic influence of the m6A modification genes on risk of MDD. METHODS: We genotyped 23 SNPs in 5 modification genes among 738 patients with MDD and 1098 controls. The UNPHASED program was applied to analyze the genotyping data for allelic and genotypic association with MDD. RESULTS: Of the 23 SNPs selected, rs12936694 from the m6A demethylase gene ALKBH5 showed allelic association (chi(2)=11.19, p=0.0008, OR=1.491, 95%CI 1.179-1.887) and genotypic association (chi(2)=12.26, df=2, p=0.0022) with MDD. LIMITATIONS: Replication and functional study are required to draw a firm conclusion. CONCLUSIONS: The ALKBH5 gene may play a role in conferring risk of MDD in the Chinese population. PMID- 26047306 TI - Neurotrophic factors in depression in response to treatment. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF) have been suggested to play a role in the pathophysiology of depression. The neurotrophic model of depression hypothesises that the serum level of e.g. BDNF is decreased during depression and increased in response to treatment. The aim of the present study was to investigate BDNF and VEGF as potential predictors of response to antidepressant treatment. METHODS: We investigated the longitudinal associations between depression scores and serum levels of these neurotrophic factors during antidepressant treatment in 90 individuals with depression of at least moderate severity. Serum levels were measured at baseline and after 8 and 12 weeks of treatment with nortriptyline or escitalopram. RESULTS: No baseline or longitudinal correlations between depression scores and serum levels of BDNF and VEGF were found, and the baseline serum levels did not predict the MADRS depression score after 12 weeks of treatment or the improvement in depression scores. Interestingly, we observed a significant baseline and longitudinal correlation between serum levels of BDNF and VEGF. The two classes of antidepressant treatment did not affect the results differently. LIMITATIONS: Information on potential factors influencing the serum levels is missing. CONCLUSION: Our results do not support the neurotrophic model of depression, since a significant decrease in serum BDNF and VEGF levels after 12 weeks of antidepressant treatment was observed. Our study encourages future studies with large sample sizes, more observations and a longer follow-up period. PMID- 26047307 TI - Genetic variants in the promoters of let-7 family are associated with an increased risk of major depressive disorder. AB - BACKGROUND: Let-7 family plays a critical role in the pathogenesis of major depressive disorder (MDD). Genetic polymorphisms in the promoters of miRNA may influence individual's susceptibility to diseases. The purpose of this study was to investigate the association between rs10877887 and rs13293512 polymorphisms in the promoters of let-7 family and the risk of MDD. METHOD: Polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing assays were used to analyze the rs10877887 and rs13293512 polymorphisms in 237 MDD patients and 296 controls. RESULTS: We found that the rs10877887 CC genotype was associated with an increased risk of MDD (CC vs. TT: OR=1.73, 95% CI, 1.04-2.86, P=0.03, and CC vs. TT/TC: OR=1.74, 95% CI, 1.08-2.80, P=0.02, respectively). Similarly increased risk was also observed for the rs13293512 (CC vs. TT: OR=1.83, 95% CI, 1.12-2.99, P=0.015; CC vs. TT/TC: OR=1.84, 95% CI, 1.20-2.81, P=0.005; and C vs. T: OR=1.32, 95% CI, 1.03-1.68, P=0.03, respectively). Stratification analysis showed that patients with the rs13293512 TC and CC genotypes had a 2.29 and 2.56-fold increased risk of MDD recurrence after treatment (TC vs. TT: 95% CI, 1.23-4.25, P=0.008; CC vs. TT: 95% CI, 1.25-5.23, P=0.009, respectively). LIMITATIONS: Relatively small sample size and hospital based study design may influence the results. CONCLUSIONS: Our findings suggest that the rs10877887 and rs13293512 polymorphisms may be related to the development of MDD. PMID- 26047308 TI - Cognitive reactivity, self-depressed associations, and the recurrence of depression. AB - BACKGROUND: Mixed evidence exists regarding the role of cognitive reactivity (CR; cognitive responsivity to a negative mood) as a risk factor for recurrences of depression. One explanation for the mixed evidence may lie in the number of previous depressive episodes. Heightened CR may be especially relevant as a risk factor for the development of multiple depressive episodes and less so for a single depressive episode. In addition, it is theoretically plausible but not yet tested that the relationship between CR and number of episodes is moderated by the strength of automatic depression-related self-associations. AIM: To investigate (i) the strength of CR in remitted depressed individuals with a history of a single vs. multiple episodes, and (ii) the potentially moderating role of automatic negative self-associations in the relationship between the number of episodes and CR. METHOD: Cross-sectional analysis of data obtained in a cohort study (Study 1) and during baseline assessments in two clinical trials (Study 2). Study 1 used data from the Netherlands Study of Depression and Anxiety (NESDA) and compared never-depressed participants (n=901) with remitted participants with either a single (n=336) or at least 2 previous episodes (n=273). Study 2 included only remitted participants with at least two previous episodes (n=273). The Leiden Index of Depression Sensitivity Revised (LEIDS-R) was used to index CR and an Implicit Association Test (IAT) to measure implicit self-associations. RESULTS: In Study 1, remitted depressed participants with multiple episodes had significantly higher CR than those with a single or no previous episode. The remitted individuals with multiple episodes of Study 2 had even higher CR scores than those of Study 1. Within the group of individuals with multiple episodes, CR was not heightened as a function of the number of episodes, even if individual differences in automatic negative self-associations were taken into account. LIMITATIONS: The study employed a cross-sectional design, which precludes a firm conclusion with regard to the direction of this relationship. CONCLUSIONS: The findings are consistent with the view that high CR puts people at risk for recurrent depression and is less relevant for the development of an incidental depressive episode. This suggests that CR is an important target for interventions that aim to prevent the recurrence of depression. PMID- 26047309 TI - Dynamic nuclear polarization properties of nitroxyl radical in high viscous liquid using Overhauser-enhanced Magnetic Resonance Imaging (OMRI). AB - The dynamic nuclear polarization (DNP) studies were carried out for (15)N labeled carbamoyl-PROXYL in pure water and pure water/glycerol mixtures of different viscosities (1.8cP, 7cP and 14cP). The dependence of DNP parameters was demonstrated over a range of agent concentration, viscosities, RF power levels and ESR irradiation time. DNP spectra were also recorded for 2mM concentration of (15)N labeled carbamoyl-PROXYL in pure water and pure water/glycerol mixtures of different viscosities. The DNP factors were measured as a function of ESR irradiation time, which increases linearly up to 2mM agent concentration in pure water and pure water/glycerol mixtures of different viscosities. The DNP factor started declining in the higher concentration region (~3mM), which is due to the ESR line width broadening. The water proton spin-lattice relaxation time was measured at very low Zeeman field (14.529mT). The increased DNP factor (35%) was observed for solvent 2 (eta=1.8cP) compared with solvent 1 (eta=1cP). The increase in the DNP factor was brought about by the shortening of water proton spin-lattice relaxation time of solvent 2. The decreased DNP factors (30% and 53%) were observed for solvent 3 (eta=7cP) and solvent 4 (eta=14cP) compared with solvent 2, which is mainly due to the low value of coupling parameter in high viscous liquid samples. The longitudinal relaxivity, leakage factor and coupling parameter were estimated. The coupling parameter values reveal that the dipolar interaction as the major mechanism. The longitudinal relaxivity increases with the increasing viscosity of pure water/glycerol mixtures. The leakage factor showed an asymptotic increase with the increasing agent concentration. It is envisaged that the results reported here may provide guidelines for the design of new viscosity prone nitroxyl radicals, suited to the biological applications of DNP. PMID- 26047310 TI - A multi-method laboratory investigation of emotional reactivity and emotion regulation abilities in borderline personality disorder. AB - BACKGROUND AND OBJECTIVES: Borderline personality disorder (BPD) is conceptualized as a disorder of heightened emotional reactivity and difficulties with emotion regulation. However, findings regarding emotional reactivity in BPD are mixed and there are limited studies examining emotion regulation capabilities in this population. METHODS: Twenty-five individuals with BPD and 30 healthy controls (HCs) engaged in a baseline assessment followed by the presentation of neutral and BPD-relevant negative images. Participants were instructed to react as they naturally would to the image, or to use a mindfulness-based or distraction-based strategy to feel less negative. Self-reported and physiological (i.e., heart rate, electrodermal activity, and respiratory sinus arrhythmia) measures were collected. RESULTS: Compared with the HCs, the BPD group exhibited elevated heart rate and reduced respiratory sinus arrhythmia at baseline. However, there were no differences in emotional reactivity in self-report or physiological indices between the two groups. In addition, the BPD group did not exhibit deficits in the ability to implement either emotion regulation strategy, with the exception that the BPD group reported less positive emotions while distracting compared with the HCs. LIMITATIONS: This study is limited by a small sample size and the inclusion of a medicated BPD sample. CONCLUSIONS: Emotion dysregulation in BPD might be better accounted for by abnormal baseline emotional functioning rather than heightened emotional reactivity or deficits in emotion regulation. Treatments for BPD might be enhanced by directly targeting resting state emotional functioning rather than emotional reactions or regulatory attempts. PMID- 26047311 TI - Microglial HO-1 induction by curcumin provides antioxidant, antineuroinflammatory, and glioprotective effects. AB - SCOPE: We have studied if curcumin can protect glial cells under an oxidative stress and inflammatory environment, which is known to be deleterious in neurodegeneration. METHODS AND RESULTS: Primary rat glial cultures exposed to the combination of an oxidative (rotenone/oligomycin A) and a proinflammatory LPS stimuli reduced by 50% glial viability. Under these experimental conditions, curcumin afforded significant glial protection and reduction of reactive oxygen species; these effects were blocked by the HO-1 inhibitor tin protoporphyrin-IX (SnPP). These findings correlate with the observation that curcumin induced the antioxidative protein HO-1. Most interesting was the observation that the glial protective effects related to HO-1 induction were microglial specific as shown in glial cultures from LysM(Cre) Hmox(?/?) mice where curcumin lost its protective effect. Under LPS conditions, curcumin reduced the microglial proinflammatory markers iNOS and tumor necrosis factor, but increased the anti-inflammatory cytokine IL4. Analysis of the microglial phenotype showed that curcumin favored a ramified morphology toward a microglial alternative activated state against LPS insult also by a HO-1-dependent mechanism. CONCLUSION: The curry constituent curcumin protects glial cells and promotes a microglial anti-inflammatory phenotype by a mechanism that implicates HO-1 induction; these effects may have impact on brain protection under oxidative and inflammatory conditions. PMID- 26047313 TI - Corrigendum. PMID- 26047312 TI - In Vitro Interaction of the Housekeeping SecA1 with the Accessory SecA2 Protein of Mycobacterium tuberculosis. AB - The majority of proteins that are secreted across the bacterial cytoplasmic membrane leave the cell via the Sec pathway, which in its minimal form consists of the dimeric ATP-driven motor protein SecA that associates with the protein conducting membrane pore SecYEG. Some Gram-positive bacteria contain two homologues of SecA, termed SecA1 and SecA2. SecA1 is the essential housekeeping protein, whereas SecA2 is not essential but is involved in the translocation of a subset of proteins, including various virulence factors. Some SecA2 containing bacteria also harbor a homologous SecY2 protein that may form a separate translocase. Interestingly, mycobacteria contain only one SecY protein and thus both SecA1 and SecA2 are required to interact with SecYEG, either individually or together as a heterodimer. In order to address whether SecA1 and SecA2 cooperate during secretion of SecA2 dependent proteins, we examined the oligomeric state of SecA1 and SecA2 of Mycobacterium tuberculosis and their interactions with SecA2 and the cognate SecA1, respectively. We conclude that both SecA1 and SecA2 individually form homodimers in solution but when both proteins are present simultaneously, they form dissociable heterodimers. PMID- 26047314 TI - Leaf hydraulic conductance varies with vein anatomy across Arabidopsis thaliana wild-type and leaf vein mutants. AB - Leaf venation is diverse across plant species and has practical applications from paleobotany to modern agriculture. However, the impact of vein traits on plant performance has not yet been tested in a model system such as Arabidopsis thaliana. Previous studies analysed cotyledons of A. thaliana vein mutants and identified visible differences in their vein systems from the wild type (WT). We measured leaf hydraulic conductance (Kleaf ), vein traits, and xylem and mesophyll anatomy for A. thaliana WT (Col-0) and four vein mutants (dot3-111 and dot3-134, and cvp1-3 and cvp2-1). Mutant true leaves did not possess the qualitative venation anomalies previously shown in the cotyledons, but varied quantitatively in vein traits and leaf anatomy across genotypes. The WT had significantly higher mean Kleaf . Across all genotypes, there was a strong correlation of Kleaf with traits related to hydraulic conductance across the bundle sheath, as influenced by the number and radial diameter of bundle sheath cells and vein length per area. These findings support the hypothesis that vein traits influence Kleaf , indicating the usefulness of this mutant system for testing theory that was primarily established comparatively across species, and supports a strong role for the bundle sheath in influencing Kleaf . PMID- 26047315 TI - Unpacking of a Crumpled Wire from Two-Dimensional Cavities. AB - The physics of tightly packed structures of a wire and other threadlike materials confined in cavities has been explored in recent years in connection with crumpled systems and a number of topics ranging from applications to DNA packing in viral capsids and surgical interventions with catheter to analogies with the electron gas at finite temperature and with theories of two-dimensional quantum gravity. When a long piece of wire is injected into two-dimensional cavities, it bends and originates in the jammed limit a series of closed structures that we call loops. In this work we study the extraction of a crumpled tightly packed wire from a circular cavity aiming to remove loops individually. The size of each removed loop, the maximum value of the force needed to unpack each loop, and the total length of the extracted wire were measured and related to an exponential growth and a mean field model consistent with the literature of crumpled wires. Scaling laws for this process are reported and the relationship between the processes of packing and unpacking of wire is commented upon. PMID- 26047316 TI - Hyperpigmentation Results in Aberrant Immune Development in Silky Fowl (Gallus gallus domesticus Brisson). AB - The Silky Fowl (SF) is known for its special phenotypes and atypical distribution of melanocytes among internal organs. Although the genes associated with melanocyte migration have been investigated substantially, there is little information on the postnatal distribution of melanocytes in inner organs and the effect of hyperpigmentation on the development of SF. Here, we analyzed melanocyte distribution in 26 tissues or organs on postnatal day 1 and weeks 2, 3, 4, 6, 10, and 23. Except for the liver, pancreas, pituitary gland, and adrenal gland, melanocytes were distributed throughout the body, primarily around blood vessels. Interaction between melanocytes and the tissue cells was observed, and melanin was transported by filopodia delivery through engulfed and internalized membrane-encapsulated melanosomes. SFs less than 10 weeks old have lower indices of spleen, thymus, and bursa of Fabricius than White Leghorns (WLs). The expression levels of interferon-gamma and interlukin-4 genes in the spleen, and serum antibody levels against H5N1 and infectious bursal disease virus were lower in SF than in WL. We also found immune organ developmental difference between Black-boned and non-Black- boned chickens from SFs and WLs hybrid F2 population. However, degeneration of the thymus and bursa of Fabricius occurred later in SF than in WL after sexual maturity. Analysis of apoptotic cells and apoptosis associated Bax and Bcl-2 proteins indicated that apoptosis is involved in degeneration of the thymus and bursa of Fabricius. Therefore, these results suggest that hyperpigmentation in SF may have a close relationship with immune development in SF, which can provide an important animal model to investigate the roles of melanocyte. PMID- 26047317 TI - Lack of the Lysosomal Membrane Protein, GLMP, in Mice Results in Metabolic Dysregulation in Liver. AB - Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU G1) has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmp gt/gt mice (formerly known as Ncu-g1gt/gt mice) were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmp gt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmp gt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmp gt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmp gt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmp gt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmp gt/gt liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmp gt/gt liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury. PMID- 26047318 TI - Quantitative Analyses of Force-Induced Amyloid Formation in Candida albicans Als5p: Activation by Standard Laboratory Procedures. AB - Candida albicans adhesins have amyloid-forming sequences. In Als5p, these amyloid sequences cluster cell surface adhesins to create high avidity surface adhesion nanodomains. Such nanodomains form after force is applied to the cell surface by atomic force microscopy or laminar flow. Here we report centrifuging and resuspending S. cerevisiae cells expressing Als5p led to 1.7-fold increase in initial rate of adhesion to ligand coated beads. Furthermore, mechanical stress from vortex-mixing of Als5p cells or C. albicans cells also induced additional formation of amyloid nanodomains and consequent activation of adhesion. Vortex mixing for 60 seconds increased the initial rate of adhesion 1.6-fold. The effects of vortex-mixing were replicated in heat-killed cells as well. Activation was accompanied by increases in thioflavin T cell surface fluorescence measured by flow cytometry or by confocal microscopy. There was no adhesion activation in cells expressing amyloid-impaired Als5pV326N or in cells incubated with inhibitory concentrations of anti-amyloid dyes. Together these results demonstrated the activation of cell surface amyloid nanodomains in yeast expressing Als adhesins, and further delineate the forces that can activate adhesion in vivo. Consequently there is quantitative support for the hypothesis that amyloid forming adhesins act as both force sensors and effectors. PMID- 26047319 TI - Variation in genes involved in the immune response and prostate cancer risk in the placebo arm of the Prostate Cancer Prevention Trial. AB - BACKGROUND: We previously found that inflammation in benign prostate tissue is associated with an increased odds of prostate cancer, especially higher-grade disease. Since part of this link may be due to genetics, we evaluated the association between single nucleotide polymorphisms (SNPs) in immune response genes and prostate cancer in the placebo arm of the Prostate Cancer Prevention Trial. METHODS: We genotyped 16 candidate SNPs in IL1beta, IL2, IL4, IL6, IL8, IL10, IL12(p40), IFNG, MSR1, RNASEL, TLR4, and TNFA and seven tagSNPs in IL10 in 881 prostate cancer cases and 848 controls negative for cancer on an end-of-study biopsy. Cases and controls were non-Hispanic white and frequency matched on age and family history. We classified cases as lower (Gleason sum <7; N = 674) and higher (7-10; N = 172) grade, and used logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age and family history. RESULTS: The minor allele (C) of rs3212227 in IL12(p40) was associated with an increased risk of total (log additive: OR = 1.30, 95%CI 1.10-1.53; P trend = 0.0017) and lower-grade (OR = 1.36, 95%CI 1.15-1.62; P-trend = 0.0004) prostate cancer. The minor allele (A) of rs4073 in IL8 was possibly associated with a decreased risk of higher-grade (OR = 0.81, 95%CI 0.64-1.02; P-trend = 0.07), but not total disease. None of the other candidates was associated with risk. The minor alleles of IL10 tagSNPs rs1800890 (A; OR = 0.87, 95%CI: 0.75 0.99; P-trend = 0.04) and rs3021094 (C; OR = 1.31, 95%CI 1.03-1.66, P-trend = 0.03) were associated with risk; the latter also with lower- (P-trend = 0.04) and possibly higher- (P-trend = 0.06) grade disease. These patterns were similar among men with PSA <2 ng/ml at biopsy. CONCLUSION: Variation in some immune response genes may be associated with prostate cancer risk. These associations were not fully explained by PSA-associated detection bias. Our findings generally support the role of inflammation in the etiology of prostate cancer. PMID- 26047320 TI - Phenotypic diversity within a Pseudomonas aeruginosa population infecting an adult with cystic fibrosis. AB - Chronic airway infections caused by Pseudomonas aeruginosa contribute to the progression of pulmonary disease in individuals with cystic fibrosis (CF). In the setting of CF, within-patient adaptation of a P. aeruginosa strain generates phenotypic diversity that can complicate microbiological analysis of patient samples. We investigated within- and between- sample diversity of 34 phenotypes among 235 P. aeruginosa isolates cultured from sputum samples collected from a single CF patient over the span of one year, and assessed colony morphology as a screening tool for predicting phenotypes, including antimicrobial susceptibilities. We identified 15 distinct colony morphotypes that varied significantly in abundance both within and between sputum samples. Substantial within sample phenotypic heterogeneity was also noted in other phenotypes, with morphotypes being unreliable predictors of antimicrobial susceptibility and other phenotypes. Emergence of isolates with reduced susceptibility to beta-lactams was observed during periods of clinical therapy with aztreonam. Our findings confirm that the P. aeruginosa population in chronic CF lung infections is highly dynamic, and that intra-sample phenotypic diversity is underestimated if only one or few colonies are analyzed per sample. PMID- 26047321 TI - Septic Shock in Advanced Age: Transcriptome Analysis Reveals Altered Molecular Signatures in Neutrophil Granulocytes. AB - Sepsis is one of the highest causes of mortality in hospitalized people and a common complication in both surgical and clinical patients admitted to hospital for non-infectious reasons. Sepsis is especially common in older people and its incidence is likely to increase substantially as a population ages. Despite its increased prevalence and mortality in older people, immune responses in the elderly during septic shock appear similar to that in younger patients. The purpose of this study was to conduct a genome-wide gene expression analysis of circulating neutrophils from old and young septic patients to better understand how aged individuals respond to severe infectious insult. We detected several genes whose expression could be used to differentiate immune responses of the elderly from those of young people, including genes related to oxidative phosphorylation, mitochondrial dysfunction and TGF-beta signaling, among others. Our results identify major molecular pathways that are particularly affected in the elderly during sepsis, which might have a pivotal role in worsening clinical outcomes compared with young people with sepsis. PMID- 26047322 TI - A Network-Based Target Overlap Score for Characterizing Drug Combinations: High Correlation with Cancer Clinical Trial Results. AB - Drug combinations are highly efficient in systemic treatment of complex multigene diseases such as cancer, diabetes, arthritis and hypertension. Most currently used combinations were found in empirical ways, which limits the speed of discovery for new and more effective combinations. Therefore, there is a substantial need for efficient and fast computational methods. Here, we present a principle that is based on the assumption that perturbations generated by multiple pharmaceutical agents propagate through an interaction network and can cause unexpected amplification at targets not immediately affected by the original drugs. In order to capture this phenomenon, we introduce a novel Target Overlap Score (TOS) that is defined for two pharmaceutical agents as the number of jointly perturbed targets divided by the number of all targets potentially affected by the two agents. We show that this measure is correlated with the known effects of beneficial and deleterious drug combinations taken from the DCDB, TTD and Drugs.com databases. We demonstrate the utility of TOS by correlating the score to the outcome of recent clinical trials evaluating trastuzumab, an effective anticancer agent utilized in combination with anthracycline- and taxane- based systemic chemotherapy in HER2-receptor (erb-b2 receptor tyrosine kinase 2) positive breast cancer. PMID- 26047323 TI - Stability and removal of atorvastatin, rosuvastatin and simvastatin from wastewater. AB - Atorvastatin (ATO), rosuvastatin (RST) and simvastatin (SIM) are commonly used drugs that belong to the statin family (lowering human blood cholesterol levels) and have been detected as contaminants in natural waters. Stability and removal of ATO, RST and SIM from spiked wastewater produced at the Al-Quds University campus were investigated. All three statins were found to undergo degradation in wastewater (activated sludge). The degradation reactions of the three drugs in wastewater at room temperature follow first-order kinetics with rate constants of 2.2 * 10-7 s-1 (ATO), 1.8 * 10-7 s-1 (RST) and 1.8 * 10-6 s-1 (SIM), which are larger than those obtained in pure water under the same conditions, 1.9 * 10-8 s 1 (ATO), 2.2 * 10-8 s-1 (RST) and 6.2 * 10-7 s-1 (SIM). Degradation products were identified by LC-MS and LC/MS/MS. The overall performance of the wastewater treatment plant (WWTP) installed in the Al-Quds University campus towards the removal of these drugs was assessed showing that more than 90% of spiked ATO, RST and SIM were removed. In order to evaluate the efficiency of alternative removal methods to replace ultra-filtration membranes, adsorption isotherms for the three statins were investigated using both activated carbon and clay-micelle complex as adsorbents. The batch adsorption isotherms for the three statins were found to fit the Langmuir equation, with a larger number of adsorption sites and binding affinity for micelle-clay composite compared with activated carbon and filtration experiments of the three statins and their corresponding metabolites demonstrated a more efficient removal by micelle-clay filters. PMID- 26047324 TI - Complex impairment of IA muscle proprioceptors following traumatic or neurotoxic injury. AB - The health of primary sensory afferents supplying muscle has to be a first consideration in assessing deficits in proprioception and related motor functions. Here we discuss the role of a particular proprioceptor, the IA muscle spindle proprioceptor in causing movement disorders in response to either regeneration of a sectioned peripheral nerve or damage from neurotoxic chemotherapy. For each condition, there is a single preferred and widely repeated explanation for disability of movements associated with proprioceptive function. We present a mix of published and preliminary findings from our laboratory, largely from in vivo electrophysiological study of treated rats to demonstrate newly discovered IA afferent defects that seem likely to make important contributions to movement disorders. First, we argue that reconnection of regenerated IA afferents with inappropriate targets, although often repeated as the reason for lost stretch-reflex contraction, is not a complete explanation. We present evidence that despite successful recovery of stretch-evoked sensory signaling, peripherally regenerated IA afferents retract synapses made with motoneurons in the spinal cord. Second, we point to evidence that movement disability suffered by human subjects months after discontinuation of oxaliplatin (OX) chemotherapy for some is not accompanied by peripheral neuropathy, which is the acknowledged primary cause of disability. Our studies of OX-treated rats suggest a novel additional explanation in showing the loss of sustained repetitive firing of IA afferents during static muscle stretch. Newly extended investigation reproduces this effect in normal rats with drugs that block Na(+) channels apparently involved in encoding static IA afferent firing. Overall, these findings highlight multiplicity in IA afferent deficits that must be taken into account in understanding proprioceptive disability, and that present new avenues and possible advantages for developing effective treatment. Extending the study of IA afferent deficits yielded the additional benefit of elucidating normal processes in IA afferent mechanosensory function. PMID- 26047325 TI - Cohorting Dengue Patients Improves the Quality of Care and Clinical Outcome. AB - INTRODUCTION: The increasing incidence of dengue among adults in Malaysia and other countries has important implications for health services. Before 2004, in order to cope with the surge in adult dengue admissions, each of the six medical wards in a university hospital took turns daily to admit and manage patients with dengue. Despite regular in-house training, the implementation of the WHO 1997 dengue case management guidelines by the multiple medical teams was piecemeal and resulted in high variability of care. A restructuring of adult dengue inpatient service in 2004 resulted in all patients being admitted to one ward under the care of the infectious disease unit. Hospital and Intensive Care Unit admission criteria, discharge criteria and clinical laboratory testing were maintained unchanged throughout the study period. OBJECTIVES: To evaluate the impact of cohorting adult dengue patients on the quality of care and the clinical outcome in a university hospital in Malaysia. METHODS: A pre (2003) and post-intervention (2005-6) retrospective study was undertaken. INTERVENTION: Cohorting all dengue patients under the care of the Infectious Disease team in a designated ward in 2004. RESULTS: The number of patients enrolled was 352 in 2003, 785 in 2005 and 1158 in 2006. The evaluation and detection of haemorrhage remained high (>90%) and unchanged throughout the study period. The evaluation of plasma leakage increased from 35.4% pre-intervention to 78.8% post-intervention (p = <0.001) while its detection increased from 11.4% to 41.6% (p = <0.001). Examination for peripheral perfusion was undertaken in only 13.1% of patients pre-intervention, with a significant increase post-intervention, 18.6% and 34.2% respectively, p = <0.001. Pre-intervention, more patients had hypotension (21.5%) than detected peripheral hypoperfusion (11.4%), indicating that clinicians recognised shock only when patients developed hypotension. In contrast, post-intervention, clinicians recognised peripheral hypoperfusion as an early sign of shock. The highest haematocrit was significantly higher post-intervention but the lowest total white cell counts and platelet counts remained unchanged. A significant and progressive reduction in the use of platelet transfusions occurred, from 21.7% pre-intervention to 14.6% in 2005 and 5.2% in 2006 post-intervention, p<0.001. Likewise, the use of plasma transfusion decreased significantly from 6.1% pre intervention to 4.0% and 1.6% in the post-intervention years of 2005 and 2006 respectively, p<0.001. The duration of intravenous fluid therapy decreased from 3 days pre-intervention to 2.5 days (p<0.001) post-intervention; the length of hospital stay reduced from 4 days pre- to 3 days (p<0.001) post-intervention and the rate of intensive care admission from 5.8% pre to 2.6% and 2.5% post intervention, p = 0.005. CONCLUSION: Cohorting adult dengue patients under a dedicated and trained team of doctors and nurses led to a substantial improvement in quality of care and clinical outcome. PMID- 26047326 TI - All-Trans Retinoic Acid Activity in Acute Myeloid Leukemia: Role of Cytochrome P450 Enzyme Expression by the Microenvironment. AB - Differentiation therapy with all-trans retinoic acid (atRA) has markedly improved outcome in acute promyelocytic leukemia (APL) but has had little clinical impact in other AML sub-types. Cell intrinsic mechanisms of resistance have been previously reported, yet the majority of AML blasts are sensitive to atRA in vitro. Even in APL, single agent atRA induces remission without cure. The microenvironment expression of cytochrome P450 (CYP)26, a retinoid-metabolizing enzyme was shown to determine normal hematopoietic stem cell fate. Accordingly, we hypothesized that the bone marrow (BM) microenvironment is responsible for difference between in vitro sensitivity and in vivo resistance of AML to atRA induced differentiation. We observed that the pro-differentiation effects of atRA on APL and non-APL AML cells as well as on leukemia stem cells from clinical specimens were blocked by BM stroma. In addition, BM stroma produced a precipitous drop in atRA levels. Inhibition of CYP26 rescued atRA levels and AML cell sensitivity in the presence of stroma. Our data suggest that stromal CYP26 activity creates retinoid low sanctuaries in the BM that protect AML cells from systemic atRA therapy. Inhibition of CYP26 provides new opportunities to expand the clinical activity of atRA in both APL and non-APL AML. PMID- 26047327 TI - Fasting Plasma Insulin at 5 Years of Age Predicted Subsequent Weight Increase in Early Childhood over a 5-Year Period-The Da Qing Children Cohort Study. AB - BACKGROUND: The association between hyperinsulinemia and obesity is well known. However, it is uncertain especially in childhood obesity, if initial fasting hyperinsulinemia predicts obesity, or obesity leads to hyperinsulinemia through insulin resistance. OBJECTIVE: To investigate the predictive effect of fasting plasma insulin on subsequent weight change after a 5-year interval in childhood. METHODS: 424 Children from Da Qing city, China, were recruited at 5 years of age and followed up for 5 years. Blood pressure, anthropometric measurements, fasting plasma insulin, glucose and triglycerides were measured at baseline and 5 years later. RESULTS: Fasting plasma insulin at 5 years of age was significantly correlated with change of weight from 5 to 10 years (DeltaWeight). Children in the lowest insulin quartile had DeltaWeight of 13.08+/-0.73 kg compare to 18.39+/ 0.86 in the highest insulin quartile (P<0.0001) in boys, and similarly 12.03+/ 0.71 vs 15.80+/-0.60 kg (P<0.0001) in girls. Multivariate analysis showed that the predictive effect of insulin at 5 years of age on subsequent weight gain over 5 years remained statistically significant even after the adjustment for age, sex, birth weight, TV-viewing time and weight (or body mass index) at baseline. By contrast, the initial weight at 5 years of age did not predict subsequent changes in insulin level 5 years later. Children who had both higher fasting insulin and weight at 5 years of age showed much higher levels of systolic blood pressures, fasting plasma glucose, the homeostasis model assessment for insulin resistance (HOMA-IR) and triglycerides at 10 years of age. CONCLUSIONS: Fasting plasma insulin at 5 years of age predicts weight gain and cardiovascular risk factors 5 year later in Chinese children of early childhood, but the absolute weight at 5 years of age did not predict subsequent change in fasting insulin. PMID- 26047330 TI - Effects of Humic and Fulvic Acids on Silver Nanoparticle Stability, Dissolution, and Toxicity. AB - The colloidal stability of silver nanoparticles (AgNPs) in natural aquatic environments influences their transport and environmental persistence, while their dissolution to Ag(+) influences their toxicity to organisms. Here, we characterize the colloidal stability, dissolution behavior, and toxicity of two industrially relevant classes of AgNPs (i.e., AgNPs stabilized by citrate or polyvinylpyrrolidone) after exposure to natural organic matter (NOM, i.e., Suwannee River Humic and Fulvic Acid Standards and Pony Lake Fulvic Acid Reference). We show that NOM interaction with the nanoparticle surface depends on (i) the NOM's chemical composition, where sulfur- and nitrogen-rich NOM more significantly increases colloidal stability, and (ii) the affinity of the capping agent for the AgNP surface, where nanoparticles with loosely bound capping agents are more effectively stabilized by NOM. Adsorption of NOM is shown to have little effect on AgNP dissolution under most experimental conditions, the exception being when the NOM is rich in sulfur and nitrogen. Similarly, the toxicity of AgNPs to a bacterial model (Shewanella oneidensis MR-1) decreases most significantly in the presence of sulfur- and nitrogen-rich NOM. Our data suggest that the rate of AgNP aggregation and dissolution in aquatic environments containing NOM will depend on the chemical composition of the NOM, and that the toxicity of AgNPs to aquatic microorganisms is controlled primarily by the extent of nanoparticle dissolution. PMID- 26047331 TI - Energy Spectral Behaviors of Communication Networks of Open-Source Communities. AB - Large-scale online collaborative production activities in open-source communities must be accompanied by large-scale communication activities. Nowadays, the production activities of open-source communities, especially their communication activities, have been more and more concerned. Take CodePlex C # community for example, this paper constructs the complex network models of 12 periods of communication structures of the community based on real data; then discusses the basic concepts of quantum mapping of complex networks, and points out that the purpose of the mapping is to study the structures of complex networks according to the idea of quantum mechanism in studying the structures of large molecules; finally, according to this idea, analyzes and compares the fractal features of the spectra in different quantum mappings of the networks, and concludes that there are multiple self-similarity and criticality in the communication structures of the community. In addition, this paper discusses the insights and application conditions of different quantum mappings in revealing the characteristics of the structures. The proposed quantum mapping method can also be applied to the structural studies of other large-scale organizations. PMID- 26047332 TI - Better you lose than I do: neural networks involved in winning and losing in a real time strictly competitive game. AB - Many situations in daily life require competing with others for the same goal. In this case, the joy of winning is tied to the fact that the rival suffers. In this fMRI study participants played a competitive game against another player, in which every trial had opposite consequences for the two players (i.e., if one player won, the other lost, or vice versa). Our main aim was to disentangle brain activation for two different types of winning. Participants could either win a trial in a way that it increased their payoff; or they could win a trial in a way that it incurred a monetary loss to their opponent. Two distinct brain networks were engaged in these two types of winning. Wins with a monetary gain activated the ventromedial prefrontal cortex, an area associated with the processing of rewards. In contrast, avoidance of loss/other-related monetary loss evoked activation in areas related to mentalizing, such as the temporo-parietal junction and precuneus. However, both types of winnings shared activation in the striatum. Our findings extend recent evidence from neuroeconomics by suggesting that we consider our conspecifics' payoff even when we directly compete with them. PMID- 26047334 TI - ERRATA. AB - Comparison of Height, Weight, and Body Mass Index Data From State-Mandated School Physical Fitness Testing and a Districtwide Surveillance Project. This errata corrects the following errors, which were originally published in Khaokham et al.[1]Affiliation Section. First author Christina B. Khaokham's affiliation, Scimetrika, LLC 3851 Rosecrans Street (MS-P572), San Diego, CA 92110, has been corrected to Scimetrika, LLC, CDC Health Systems Integration Program, 3851 Rosecrans Street (MS-P572), San Diego, CA 92110. Address Correspondence. Address correspondence has been changed from Christina B. Khaokham, Epidemiologist, (christinakhaokham@gmail.com), Scimetrika, LLC 3851 Rosecrans Street (MS-P572), San Diego, CA 92110, to Shaila Serpas, Associate Program Director, (serpas.shaila@scrippshealth.org), Scripps Mercy Family Medicine Residency Program, 499 H Street, Chula Vista, CA 91910. The above errors, as well as other previously omitted adjustments in phrasing and formatting, have been corrected in the online version of the article. We apologize for these errors. PMID- 26047333 TI - Iridovirus CARD Protein Inhibits Apoptosis through Intrinsic and Extrinsic Pathways. AB - Grouper iridovirus (GIV) belongs to the genus Ranavirus of the family Iridoviridae; the genomes of such viruses contain an anti-apoptotic caspase recruitment domain (CARD) gene. The GIV-CARD gene encodes a protein of 91 amino acids with a molecular mass of 10,505 Daltons, and shows high similarity to other viral CARD genes and human ICEBERG. In this study, we used Northern blot to demonstrate that GIV-CARD transcription begins at 4 h post-infection; furthermore, we report that its transcription is completely inhibited by cycloheximide but not by aphidicolin, indicating that GIV-CARD is an early gene. GIV-CARD-EGFP and GIV-CARD-FLAG recombinant proteins were observed to translocate from the cytoplasm into the nucleus, but no obvious nuclear localization sequence was observed within GIV-CARD. RNA interference-mediated knockdown of GIV-CARD in GK cells infected with GIV inhibited expression of GIV-CARD and five other viral genes during the early stages of infection, and also reduced GIV infection ability. Immunostaining was performed to show that apoptosis was effectively inhibited in cells expressing GIV-CARD. HeLa cells irradiated with UV or treated with anti-Fas antibody will undergo apoptosis through the intrinsic and extrinsic pathways, respectively. However, over-expression of recombinant GIV-CARD protein in HeLa cells inhibited apoptosis induced by mitochondrial and death receptor signaling. Finally, we report that expression of GIV-CARD in HeLa cells significantly reduced the activities of caspase-8 and -9 following apoptosis triggered by anti-Fas antibody. Taken together, these results demonstrate that GIV-CARD inhibits apoptosis through both intrinsic and extrinsic pathways. PMID- 26047335 TI - Bioinformatic Amplicon Read Processing Strategies Strongly Affect Eukaryotic Diversity and the Taxonomic Composition of Communities. AB - Amplicon read sequencing has revolutionized the field of microbial diversity studies. The technique has been developed for bacterial assemblages and has undergone rigorous testing with mock communities. However, due to the great complexity of eukaryotes and the numbers of different rDNA copies, analyzing eukaryotic diversity is more demanding than analyzing bacterial or mock communities, so studies are needed that test the methods of analyses on taxonomically diverse natural communities. In this study, we used 20 samples collected from the Baltic Sea ice, slush and under-ice water to investigate three program packages (UPARSE, mothur and QIIME) and 18 different bioinformatic strategies implemented in them. Our aim was to assess the impact of the initial steps of bioinformatic strategies on the results when analyzing natural eukaryotic communities. We found significant differences among the strategies in resulting read length, number of OTUs and estimates of diversity as well as clear differences in the taxonomic composition of communities. The differences arose mainly because of the variable number of chimeric reads that passed the pre processing steps. Singleton removal and denoising substantially lowered the number of errors. Our study showed that the initial steps of the bioinformatic amplicon read processing strategies require careful consideration before applying them to eukaryotic communities. PMID- 26047337 TI - Production of Galactooligosaccharides Using beta-Galactosidase Immobilized on Chitosan-Coated Magnetic Nanoparticles with Tris(hydroxymethyl)phosphine as an Optional Coupling Agent. AB - beta-Galactosidase was immobilized on chitosan-coated magnetic Fe3O4 nanoparticles and was used to produce galactooligosaccharides (GOS) from lactose. Immobilized enzyme was prepared with or without the coupling agent, tris(hydroxymethyl)phosphine (THP). The two immobilized systems and the free enzyme achieved their maximum activity at pH 6.0 with an optimal temperature of 50 degrees C. The immobilized enzymes showed higher activities at a wider range of temperatures and pH. Furthermore, the immobilized enzyme coupled with THP showed higher thermal stability than that without THP. However, activity retention of batchwise reactions was similar for both immobilized systems. All the three enzyme systems produced GOS compound with similar concentration profiles, with a maximum GOS yield of 50.5% from 36% (w . v(-1)) lactose on a dry weight basis. The chitosan-coated magnetic Fe3O4 nanoparticles can be regenerated using a desorption/re-adsorption process described in this study. PMID- 26047336 TI - Urotensin II Protects Cardiomyocytes from Apoptosis Induced by Oxidative Stress through the CSE/H2S Pathway. AB - Plasma urotensin II (UII) has been observed to be raised in patients with acute myocardial infarction; suggesting a possible cardiac protective role for this peptide. However, the molecular mechanism is unclear. Here, we treated cultured cardiomyocytes with H2O2 to induce oxidative stress; observed the effect of UII on H2O2-induced apoptosis and explored potential mechanisms. UII pretreatment significantly reduced the number of apoptotic cardiomyocytes induced by H2O2; and it partly abolished the increase of pro-apoptotic protein Bax and the decrease of anti-apoptotic protein Bcl-2 in cardiomyocytes induced by H2O2. SiRNA targeted to the urotensin II receptor (UT) greatly inhibited these effects. Further analysis revealed that UII increased the production of hydrogen sulfide (H2S) and the level of cystathionine-gamma-lyase (CSE) by activating the ERK signaling in H2O2 treated-cardiomyocytes. Si-CSE or ERK inhibitor not only greatly inhibited the increase in CSE level or the phosphorylation of ERK induced by UII but also reversed anti-apoptosis of UII in H2O2-treated-cadiomyocytes. In conclusion, UII rapidly promoted the phosphorylation of ERK and upregulated CSE level and H2S production, which in turn activated ERK signaling to protect cardiomyocytes from apoptosis under oxidative stress. These results suggest that increased plasma UII level may protect cardiomyocytes at the early-phase of acute myocardial infarction in patients. PMID- 26047338 TI - Selection of Reliable Reference Genes for Gene Expression Studies of a Promising Oilseed Crop, Plukenetia volubilis, by Real-Time Quantitative PCR. AB - Real-time quantitative PCR (RT-qPCR) is a reliable and widely used method for gene expression analysis. The accuracy of the determination of a target gene expression level by RT-qPCR demands the use of appropriate reference genes to normalize the mRNA levels among different samples. However, suitable reference genes for RT-qPCR have not been identified in Sacha inchi (Plukenetia volubilis), a promising oilseed crop known for its polyunsaturated fatty acid (PUFA)-rich seeds. In this study, using RT-qPCR, twelve candidate reference genes were examined in seedlings and adult plants, during flower and seed development and for the entire growth cycle of Sacha inchi. Four statistical algorithms (delta cycle threshold (DeltaCt), BestKeeper, geNorm, and NormFinder) were used to assess the expression stabilities of the candidate genes. The results showed that ubiquitin-conjugating enzyme (UCE), actin (ACT) and phospholipase A22 (PLA) were the most stable genes in Sacha inchi seedlings. For roots, stems, leaves, flowers, and seeds from adult plants, 30S ribosomal protein S13 (RPS13), cyclophilin (CYC) and elongation factor-1alpha (EF1alpha) were recommended as reference genes for RT-qPCR. During the development of reproductive organs, PLA, ACT and UCE were the optimal reference genes for flower development, whereas UCE, RPS13 and RNA polymerase II subunit (RPII) were optimal for seed development. Considering the entire growth cycle of Sacha inchi, UCE, ACT and EF1alpha were sufficient for the purpose of normalization. Our results provide useful guidelines for the selection of reliable reference genes for the normalization of RT-qPCR data for seedlings and adult plants, for reproductive organs, and for the entire growth cycle of Sacha inchi. PMID- 26047339 TI - 25-Hydroxyvitamin D3 Levels, BsmI Polymorphism and Insulin Resistance in Brazilian Amazonian Children. AB - Vitamin D is associated with a wide range of other functions beyond bone development. We evaluated the factors associated with 25-hydroxyvitamin D levels in 974 children aged <= 10 years and the impact of BsmI polymorphism of the vitamin D receptor (VDR) gene (rs1544410) on metabolic parameters in a subsample (n: 430) with a follow-up 2 years later from the initial population-based cross sectional study. Multiple linear regression models were used in the analyses. The prevalence (95% CI) of vitamin D deficiency, insufficiency and sufficiency of children was 11.1% (9.2-13.2), 21.8% (19.2-24.5) and 67.2% (64.1-70.1), respectively. Overall, 23% of the variation in serum 25-hydroxyvitamin D concentrations was accounted for by BsmI polymorphism beta = -0.053 (95% CI) ( 0.100, -0.006), maternal schooling (>= 9 years) beta = 0.100 (0.039, 0.161), serum vitamin E beta = 0.478 (0.381, 0.574), total cholesterol concentration beta = 0.232 (0.072, 0.393) and serum folate beta = 0.064 (0.013, 0.115). BsmI polymorphism was positively associated with HOMA-IR beta = 0.122 (0.002, 0.243) and fasting glucose concentration beta = 1.696 (0.259, 3.133). In conclusion, variables related to socioeconomic level, the presence of the allele risk for BsmI and other nutrient concentrations were associated with serum 25 hydroxyvitamin D concentrations. Our results suggest that BsmI polymorphism is correlated with metabolic outcomes. PMID- 26047340 TI - Hydrothermal Synthesis Au-Bi2Te3 Nanocomposite Thermoelectric Film with a Hierarchical Sub-Micron Antireflection Quasi-Periodic Structure. AB - In this work, Au-Bi(2)Te(3) nanocomposite thermoelectric film with a hierarchical sub-micron antireflection quasi-periodic structure was synthesized via a low temperature chemical route using Troides helena (Linnaeus) forewing (T_FW) as the biomimetic template. This method combines chemosynthesis with biomimetic techniques, without the requirement of expensive equipment and energy intensive processes. The microstructure and the morphology of the Au-Bi(2)Te(3) nanocomposite thermoelectric film was analyzed by X-ray diffraction (XRD), field emission scanning-electron microscopy (FESEM), and transmission electron microscopy (TEM). Coupled the plasmon resonances of the Au nanoparticles with the hierarchical sub-micron antireflection quasi-periodic structure, the Au Bi(2)Te(3) nanocomposite thermoelectric film possesses an effective infrared absorption and infrared photothermal conversion performance. Based on the finite difference time domain method and the Joule effect, the heat generation and the heat source density distribution of the Au-Bi(2)Te(3) nanocomposite thermoelectric film were studied. The heterogeneity of heat source density distribution of the Au-Bi(2)Te(3) nanocomposite thermoelectric film opens up a novel promising technique for generating thermoelectric power under illumination. PMID- 26047342 TI - Quantitative and qualitative investigations of pharmacopoeial plant material polygoni avicularis herba by UHPLC-CAD and UHPLC-ESI-MS methods. AB - INTRODUCTION: Polygonum aviculare L. also known as common knotgrass is an annual herbaceous weed occurring all over the world in the temperate regions. Recent studies report that flavonol glucuronides are major constituents of common knotgrass. There is no comprehensive analytical procedure for the standardisation of Polygoni Avicularis Herba available on the European market. OBJECTIVE: To develop a method for the proper authentication and standardisation of Polygoni Avicularis Herba and to preliminary evaluate variability in qualitative and quantitative composition among commercial samples and samples from wild harvesting defined as Polygonum aviculare sensu lato. METHODOLOGY: The UHPLC ESI(+)-MS method was used for the qualitative screening of nine independent samples of Polygonum aviculare herb. The UHPLC-CAD method was developed for the quantitation of the major compounds in an extract using quercetin-3-O-glucuronide as a standard. RESULTS: Twenty-five major constituents were detected and characterised. Among them three new natural products were tentatively identified. Twelve compounds were quantitated using a validated UHPLC-CAD method. In all nine samples flavonol glucuronides were confirmed as major compounds. The total flavonoid content was estimated for all samples and varied from 0.70 to 2.20%. CONCLUSION: The developed procedure may be used for the routine standardisation of common knotgrass. The results indicate that the pharmacopoeial approach to the authentication and standardisation of Polygonum aviculare herb should be revised. PMID- 26047343 TI - Cervical disc arthroplasty: nonconstrained versus semiconstrained. PMID- 26047341 TI - Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter. AB - Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine beta-synthase and cystathionine gamma-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF alpha and IL-1beta in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-alpha and IL-1beta in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages. PMID- 26047344 TI - Evaluation of mobility and stability in the Discover artificial disc: an in vivo motion study using high-accuracy 3D CT data. AB - OBJECT: Artificial disc replacement (ADR) devices are unlike implants used in cervical fusion in that they are continuously exposed to stress not only within the implant site but also at their site of attachment to the adjacent vertebra. An imaging technique with higher accuracy than plain radiography and with the possibility of 3D visualization would provide more detailed information about the motion quality and stability of the implant in relation to the vertebrae. Such high-accuracy studies have previously been conducted with radiostereometric analysis (RSA), which requires implantation of tantalum markers in the adjacent vertebrae. The aim of this study was to evaluate in vivo motion and stability of implanted artificial discs. A noninvasive analysis was performed with CT, with an accuracy higher than that of plain radiographs and almost as high as RSA in cervical spine. METHODS: Twenty-eight patients with ADR were included from a larger cohort of a randomized controlled trial comparing treatment of cervical radiculopathy with ADR or anterior cervical decompression and fusion. Surgical levels included C4-7; 18 patients had 1-level surgery and 10 patients had 2-level surgery. Follow-up time ranged from 19 to 50 months, with an average of 40 months. Two CT volumes of the cervical spine, 1 in flexion and 1 in extension, were obtained in each patient and then spatially registered using a customized imaging tool, previously used and validated for the cervical spine. Motion between the components in the artificial disc, as well as motion between the components and adjacent vertebrae, were calculated in 3 planes. Intraclass correlation (ICC) between independent observers and repeatability of the method were also calculated. RESULTS: Intrinsic motion, expressed as degrees in rotation and millimeters in translation, was detectable in a majority of the ADRs. In the sagittal plane, in which the flexion/extension was performed, sagittal rotation ranged between 0.2 degrees and 15.8 degrees and translation between 0.0 and 5.5 mm. Eight percent of the ADRs were classified as unstable, as motion between at least 1 of the components and the adjacent vertebra was detected. Five percent were classified as ankylotic, with no detectable motion, and another 8% showed very limited motion due to heterotopic ossification. Repeatability for the motion in the sagittal plane was calculated to be 1.30 degrees for rotation and 1.29 mm for translation (95% confidence level), ICC 0.99 and 0.84, respectively. All 3 patients with unstable devices had undergone 1-level ADRs at C5-6. They all underwent revision surgery due to increased neck pain, and instability was established during the surgery. CONCLUSIONS: The majority of the artificial discs in this study showed intrinsic mobility several years after implantation and were also shown to be properly attached. Implant instability was detected in 8% of patients and, as all of these patients underwent revision surgery due to increasing neck pain, this might be a more serious problem than heterotopic bone formation. PMID- 26047345 TI - Comparison of best versus worst clinical outcomes for adult spinal deformity surgery: a retrospective review of a prospectively collected, multicenter database with 2-year follow-up. AB - OBJECT: Although recent studies suggest that average clinical outcomes are improved following surgery for selected adult spinal deformity (ASD) patients, these outcomes span a broad range. Few studies have specifically addressed factors that may predict favorable clinical outcomes. The objective of this study was to compare patients with ASD with best versus worst clinical outcomes following surgical treatment to identify distinguishing factors that may prove useful for patient counseling and optimization of clinical outcomes. METHODS: This is a retrospective review of a prospectively collected, multicenter, database of consecutively enrolled patients with ASD who were treated operatively. Inclusion criteria were age > 18 years and ASD. For patients with a minimum of 2-year follow-up, those with best versus worst outcomes were compared separately based on Scoliosis Research Society-22 (SRS-22) and Oswestry Disability Index (ODI) scores. Only patients with a baseline SRS-22 <= 3.5 or ODI >= 30 were included to minimize ceiling/floor effects. Best and worst outcomes were defined for SRS-22 (>= 4.5 and <= 2.5, respectively) and ODI (<= 15 and >= 50, respectively). RESULTS: Of 257 patients who met the inclusion criteria, 227 (88%) had complete baseline and 2-year follow-up SRS-22 and ODI outcomes scores and radiographic imaging and were analyzed in the present study. Of these 227 patients, 187 had baseline SRS-22 scores <= 3.5, and 162 had baseline ODI scores >= 30. Forthe SRS-22, best and worst outcomes criteria were met at follow-up for 25 and 27 patients, respectively. For the ODI, best and worst outcomes criteria were met at follow-up for 43 and 51 patients, respectively. With respect to the SRS-22, compared with best outcome patients, those with worst outcomes had higher baseline SRS-22 scores (p < 0.0001), higher prevalence of baseline depression (p < 0.001), more comorbidities (p = 0.012), greater prevalence of prior surgery (p = 0.007), a higher complication rate (p = 0.012), and worse baseline deformity (sagittal vertical axis [SVA], p = 0.045; pelvic incidence [PI] and lumbar lordosis [LL] mismatch, p = 0.034). The best-fit multivariate model for SRS-22 included baseline SRS-22 (p = 0.033), baseline depression (p = 0.012), and complications (p = 0.030). With respect to the ODI, compared with best outcome patients, those with worst outcomes had greater baseline ODI scores (p < 0.001), greater baseline body mass index (BMI; p = 0.002), higher prevalence of baseline depression (p < 0.028), greater baseline SVA (p = 0.016), a higher complication rate (p = 0.02), and greater 2-year SVA (p < 0.001) and PI-LL mismatch (p = 0.042). The best-fit multivariate model for ODI included baseline ODI score (p < 0.001), 2-year SVA (p = 0.014) and baseline BMI (p = 0.037). Age did not distinguish best versus worst outcomes for SRS-22 or ODI (p > 0.1). CONCLUSIONS: Few studies have specifically addressed factors that distinguish between the best versus worst clinical outcomes for ASD surgery. In this study, baseline and perioperative factors distinguishing between the best and worst outcomes for ASD surgery included several patient factors (baseline depression, BMI, comorbidities, and disability), as well as residual deformity (SVA), and occurrence of complications. These findings suggest factors that may warrant greater awareness among clinicians to achieve optimal surgical outcomes for patients with ASD. PMID- 26047346 TI - Brief intraoperative heparinization and blood loss in anterior lumbar spine surgery. AB - OBJECT: The anterior approach to the lumbar spine may be associated with iliac artery thrombosis. Intraoperative heparin can be administered to prevent thrombosis; however, there is a concern that this will increase the procedural blood loss. The aim of this study was to examine whether intraoperative heparin can be administered without increasing blood loss in anterior lumbar spine surgery. METHODS: A prospective study of consecutive anterior approaches for lumbar spine surgery was performed between January 2009 and June 2014 by a single vascular surgeon and a single spine surgeon. Patients underwent an anterior lumbar interbody fusion (ALIF) at L4-5 and/or L5-S1, a total disc replacement (TDR) at L4-5 and/or L5-S1, or a hybrid procedure with a TDR at L4-5 and an ALIF at L5-S1. Heparin was administered intravenously when arterial flow to the lower limbs was interrupted during the procedure. Heparin was usually reversed on removal of the causative retraction. RESULTS: The cohort consisted of 188 patients with a mean age of 41.7 years; 96 (51.1%) were male. Eighty-four patients (44.7%) had an ALIF, 57 (30.3%) had a TDR, and 47 (25.0%) had a hybrid operation with a TDR at L4-5 and an ALIF at L5-S1. One hundred thirty-four patients (71.3%) underwent a single-level procedure (26.9% L4-5 and 73.1% L5-S1) and 54 (28.7%) underwent a 2-level procedure (L4-5 and L5-S1). Seventy-two patients (38.3%) received heparinization intraoperatively. Heparin was predominantly administered during hybrid operations (68.1%), 2-level procedures (70.4%), and procedures involving the L4-5 level (80.6%). There were no intraoperative ischemic vascular complications reported in this series. There was 1 postoperative deep venous thrombosis. The overall mean estimated blood loss (EBL) for the heparin group (389.7 ml) was significantly higher than for the nonheparin group (160.5 ml) (p < 0.0001). However, when all variables were analyzed with multiple linear regression, only the prosthesis used and level treated were found to be significant in blood loss (p < 0.05). The highest blood loss occurred in hybrid procedures (448.1 ml), followed by TDR (302.5 ml) and ALIF (99.7 ml). There were statistically significant differences between the EBL during ALIF compared with TDR and hybrid (p < 0.0001), but not between TDR and hybrid. The L4-5 level was associated with significantly higher blood loss (384.9 ml) compared with L5-S1 (111.4 ml) (p < 0.0001). CONCLUSIONS: During an anterior exposure for lumbar spine surgery, the administration of heparin does not significantly increase blood loss. The prosthesis used and level treated were found to significantly increase blood loss, with TDR and the L4-5 level having greater blood loss compared with ALIF and L5-S1, respectively. Heparin can be administered safely to help prevent thrombotic intraoperative vascular complications without increasing blood loss. PMID- 26047347 TI - Choosing a Future for Epidemiology. 1996. PMID- 26047349 TI - Guiding Classical Biological Control of an Invasive Mealybug Using Integrative Taxonomy. AB - Delottococcus aberiae De Lotto (Hemiptera: Pseudococcidae) is a mealybug of Southern African origin that has recently been introduced into Eastern Spain. It causes severe distortions on young citrus fruits and represents a growing threat to Mediterranean citrus production. So far, biological control has proven unsatisfactory due to the absence of efficient natural enemies in Spain. Hence, the management of this pest currently relies only on chemical control. The introduction of natural enemies of D. aberiae from the native area of the pest represents a sustainable and economically viable alternative to reduce the risks linked to pesticide applications. Since biological control of mealybugs has been traditionally challenged by taxonomic misidentification, an intensive survey of Delottococcus spp. and their associated parasitoids in South Africa was required as a first step towards a classical biological control programme. Combining morphological and molecular characterization (integrative taxonomy) a total of nine mealybug species were identified in this study, including three species of Delottococcus. Different populations of D. aberiae were found on wild olive trees, in citrus orchards and on plants of Chrysanthemoides monilifera, showing intra-specific divergences according to their host plants. Interestingly, the invasive mealybug populations from Spanish orchards clustered together with the population on citrus from Limpopo Province (South Africa), sharing COI haplotypes. This result pointed to an optimum location to collect natural enemies against the invasive mealybug. A total of 14 parasitoid species were recovered from Delottococcus spp. and identified to genus and species level, by integrating morphological and molecular data. A parasitoid belonging to the genus Anagyrus, collected from D. aberiae in citrus orchards in Limpopo, is proposed here as a good biological control agent to be introduced into Spain. PMID- 26047350 TI - Parturition Signaling by Visual Cues in Female Marmosets (Callithrix jacchus). AB - New World monkeys have polymorphic color vision, in which all males and some females are dichromats, while most females are trichromats. There is little consensus about which selective pressures fashioned primate color vision, although detection of food, mates and predators has been hypothesized. Behavioral evidence shows that males from different species of Neotropical primates seem to perceive the timing of female conception and gestation, although, no signals fulfilling this function have been identified. Therefore, we used visual models to test the hypothesis that female marmosets show chromatic and/or achromatic cues that may indicate the time of parturition for male and female conspecifics. By recording the reflectance spectra of female marmosets' (Callithrix jacchus) sexual skin, and running chromatic and achromatic discrimination models, we found that both variables fluctuate during the weeks that precede and succeed parturition, forming "U" and inverted "U" patterns for chromatic and achromatic contrast, respectively. We suggest that variation in skin chroma and luminance might be used by female helpers and dominant females to identify the timing of birth, while achromatic variations may be used as clues by potential fathers to identify pregnancy stage in females and prepare for paternal burdens as well as to detect oestrus in the early post-partum period. PMID- 26047351 TI - Erratum. PMID- 26047352 TI - Structure-guided residence time optimization of a dabigatran reversal agent. AB - Novel oral anticoagulants are effective and safe alternatives to vitamin-K antagonists for anticoagulation therapy. However, anticoagulation therapy in general is associated with an elevated risk of bleeding. Idarucizumab is a reversal agent for the direct thrombin inhibitor, dabigatran etexilate (Pradaxa(r)) and is currently in Phase 3 studies. Here, we report data on the antibody fragment aDabi-Fab2, a putative backup molecule for idarucizumab. Although aDabi-Fab2 completely reversed effects of dabigatran in a rat model in vivo, we observed significantly reduced duration of action compared to idarucizumab. Rational protein engineering, based on the X-ray structure of aDabi Fab2, led to the identification of mutant Y103W. The mutant had optimized shape complementarity to dabigatran while maintaining an energetically favored hydrogen bond. It displayed increased affinity for dabigatran, mainly driven by a slower off-rate. Interestingly, the increased residence time translated into longer duration of action in vivo. It was thus possible to further enhance the efficacy of aDabi-Fab2 based on rational design, giving it the potential to serve as a back-up candidate for idarucizumab. PMID- 26047353 TI - Characterization of Adelphocoris suturalis (Hemiptera: Miridae) Transcriptome from Different Developmental Stages. AB - Adelphocoris suturalis is one of the most serious pest insects of Bt cotton in China, however its molecular genetics, biochemistry and physiology are poorly understood. We used high throughput sequencing platform to perform de novo transcriptome assembly and gene expression analyses across different developmental stages (eggs, 2(nd) and 5(th) instar nymphs, female and male adults). We obtained 20 GB of clean data and revealed 88,614 unigenes, including 23,830 clusters and 64,784 singletons. These unigene sequences were annotated and classified by Gene Ontology, Clusters of Orthologous Groups, and Kyoto Encyclopedia of Genes and Genomes databases. A large number of differentially expressed genes were discovered through pairwise comparisons between these developmental stages. Gene expression profiles were dramatically different between life stage transitions, with some of these most differentially expressed genes being associated with sex difference, metabolism and development. Quantitative real-time PCR results confirm deep-sequencing findings based on relative expression levels of nine randomly selected genes. Furthermore, over 791,390 single nucleotide polymorphisms and 2,682 potential simple sequence repeats were identified. Our study provided comprehensive transcriptional gene expression information for A. suturalis that will form the basis to better understanding of development pathways, hormone biosynthesis, sex differences and wing formation in mirid bugs. PMID- 26047354 TI - Natural Mutations in Streptococcus agalactiae Resulting in Abrogation of beta Antigen Production. AB - Streptococcus agalactiae genome encodes 21 two-component systems (TCS) and a variety of regulatory proteins in order to control gene expression. One of the TCS, BgrRS, comprising the BgrR DNA-binding regulatory protein and BgrS sensor histidine kinase, was discovered within a putative virulence island. BgrRS influences cell metabolism and positively control the expression of bac gene, coding for beta antigen at transcriptional level. Inactivation of bgrR abrogated bac gene expression and increased virulence properties of S. agalactiae. In this study, a total of 140 strains were screened for the presence of bac gene, and the TCS bgrR and bgrS genes. A total of 53 strains carried the bac, bgrR and bgrS genes. Most of them (48 strains) expressed beta antigen, while five strains did not express beta antigen. Three strains, in which bac gene sequence was intact, while bgrR and/or bgrS genes had mutations, and expression of beta antigen was absent, were complemented with a constructed plasmid pBgrRS(P) encoding functionally active bgrR and bgrS gene alleles. This procedure restored expression of beta antigen indicating the crucial regulatory role of TCS BgrRS. The complemented strain A49V/BgrRS demonstrated attenuated virulence in intraperitoneal mice model of S. agalactiae infection compared to parental strain A49V. In conclusion we showed that disruption of beta antigen expression is associated with: i) insertion of ISSa4 upstream the bac gene just after the ribosomal binding site; ii) point mutation G342A resulting a stop codon TGA within the bac gene and a truncated form of beta antigen; iii) single deletion (G) in position 439 of the bgrR gene resulting in a frameshift and the loss of DNA-binding domain of the BgrR protein, and iv) single base substitutions in bgrR and bgrS genes causing single amino acid substitutions in BgrR (Arg187Lys) and BgrS (Arg252Gln). The fact that BgrRS negatively controls virulent properties of S. agalactiae gives a novel clue for understanding of S. agalactiae adaptation to the human. PMID- 26047355 TI - Expression Levels of miR-30a-5p in Papillary Thyroid Carcinoma: A Comparison Between Serum and Fine Needle Aspiration Biopsy Samples. AB - BACKGROUND: Fine needle aspiration biopsy (FNAB) is a useful tool in the diagnosis of thyroid nodules. However, some limitations exist as approximately 25% of the cases cannot be distinguished with this method. Therefore, identification of novel diagnostic markers is very important in improving the papillary thyroid carcinoma (PTC) diagnosis. microRNAs (miRNAs) are small regulatory RNA molecules that have been involved in a variety of biological processes, including tumorigenesis. Moreover, determination of miRNAs with prognostic, diagnostic, and therapeutic potential is of a great interest today. AIMS: In the present study, we evaluated the expression level of miR-30a-5p in serum and FNAB samples of PTC patients. METHODS: A total of 60 cases were included in the study, with the patients subdivided into four groups; benign, atypical cells of undetermined significance (ACUS), malignant group, including Hurthle cell PTC (HC-PTC), and malignant without Hurthle cell PTC (non-HC-PTC). Peripheral blood and FNAB samples of the cases were collected. The serum and FNAB expression levels of miR-30a-5p among the groups were compared. The miR-30a-5p expression level was determined using real-time polymerase chain reaction (RT PCR). RESULTS: According to both pre- and postoperative pathological diagnosis, miR-30a-5p levels were significantly increased in both serum and FNAB samples of HC-PTC and non-HC-PTC groups compared to other groups. This increase was more evident in the non-HC-PTC group (p=0.0245 for FNAB, p=0.0166 for serum). CONCLUSIONS: The results of this study suggest that miR-30a-5p might be a novel diagnostic marker candidate in PTC. Further studies are required to investigate this possibility. PMID- 26047357 TI - Quantum Coherent Feedback Control for Generation System of Optical Entangled State. AB - The non-measurement based coherent feedback control (CFC) is a control method without introducing any backaction noise into the controlled system, thus is specially suitable to manipulate various quantum optical systems for preparing nonclassical states of light. By simply tuning the transmissivity of an optical controller in a CFC loop attached to a non-degenerate optical parametric amplifier (NOPA), the quantum entanglement degree of the output optical entangled state of the system is improved. At the same time, the threshold pump power of the NOPA is reduced also. The experimental results are in reasonable agreement with the theoretical expectation. PMID- 26047356 TI - Loss and Gain of Tolerance to Pancreatic Glycoprotein 2 in Celiac Disease. AB - BACKGROUND: Autoantibodies against pancreatic secretory-granule membrane glycoprotein 2 (GP2) have been demonstrated in patients with Crohn's disease but recently also with celiac disease (CD). Both entities are characterized by intestinal barrier impairment with increased gut permeability. Pathophysiological hallmark of CD is a permanent loss of tolerance to alimentary gliadin and a transient loss of tolerance to the autoantigen human tissue transglutaminase (tTG). Therefore, we explored the behavior of loss of tolerance to GP2 reported in CD. METHODS: We assessed prevalences and levels of autoantibodies against GP2, CD-specific antibodies to endomysial antigens and tTG as well as Crohn's disease specific anti-Saccharomyces cerevisiae antibodies in sera of 174 patients with active CD, 84 patients under gluten-free diet (GFD) and 129 controls. Furthermore, we looked for an association between anti-GP2 antibody positivity and degree of mucosal damage in CD. RESULTS: We found significantly elevated anti GP2 IgA positivity in active CD patients (19.5%) compared to CD patients under GFD (0.0%) and controls (5.4%, p < 0.001, respectively). Anti-GP2 IgA levels correlated significantly with CD-specific antibodies (p < 0.001). Anti-GP2 autoantibody positivity disappeared under GFD similarly to CD-specific autoantibodies against tTG and endomysial antigens. For the first time, IgA antibody levels to GP2 are demonstrated to be associated with degree of villous atrophy according to Marsh classification. CONCLUSIONS: Anti-GP2 IgA seems to be associated with disease activity in a distinct subgroup of patients with CD. The observed loss of tolerance to GP2 in a subset of patients with CD is transient and disappears under GFD. PMID- 26047358 TI - Differences in Fine-Root Biomass of Trees and Understory Vegetation among Stand Types in Subtropical Forests. AB - Variation of total fine-root biomass among types of tree stands has previously been attributed to the characteristics of the stand layers. The effects of the understory vegetation on total fine-root biomass are less well studied. We examined the variation of total fine-root biomass in subtropical tree stands at two sites of Datian and Huitong in China. The two sites have similar humid monsoon climate but different soil organic carbon. One examination compared two categories of basal areas (high vs. low basal area) in stands of single species. A second examination compared single-species and mixed stands with comparable basal areas. Low basal area did not correlate with low total fine-root biomass in the single-species stands. The increase in seedling density but decrease in stem density for the low basal area stands at Datian and the quite similar stand structures for the basal-area contrast at Huitong helped in the lack of association between basal area and total fine-root biomass at the two sites, respectively. The mixed stands also did not yield higher total fine-root biomasses. In addition to the lack of niche complementarity between tree species, the differences in stem and seedling densities and the belowground competition between the tree and non-tree species also contributed to the similarity of the total fine-root biomasses in the mixed and single-species stands. Across stand types, the more fertile site Datian yielded higher tree, non-tree and total fine root biomasses than Huitong. However, the contribution of non-tree fine-root biomass to the total fine-root biomass was higher at Huitong (29.4%) than that at Datian (16.7%). This study suggests that the variation of total fine-root biomass across stand types not only was associated with the characteristics of trees, but also may be highly dependent on the understory layer. PMID- 26047359 TI - Effects of spatial cues on color-change detection in humans. AB - Studies of covert spatial attention have largely used motion, orientation, and contrast stimuli as these features are fundamental components of vision. The feature dimension of color is also fundamental to visual perception, particularly for catarrhine primates, and yet very little is known about the effects of spatial attention on color perception. Here we present results using novel dynamic color stimuli in both discrimination and color-change detection tasks. We find that our stimuli yield comparable discrimination thresholds to those obtained with static stimuli. Further, we find that an informative spatial cue improves performance and speeds response time in a color-change detection task compared with an uncued condition, similar to what has been demonstrated for motion, orientation, and contrast stimuli. Our results demonstrate the use of dynamic color stimuli for an established psychophysical task and show that color stimuli are well suited to the study of spatial attention. PMID- 26047360 TI - Targeted disruption of a single sex pheromone receptor gene completely abolishes in vivo pheromone response in the silkmoth. AB - Male moths use species-specific sex pheromones to identify and orientate toward conspecific females. Odorant receptors (ORs) for sex pheromone substances have been identified as sex pheromone receptors in various moth species. However, direct in vivo evidence linking the functional role of these ORs with behavioural responses is lacking. In the silkmoth, Bombyx mori, female moths emit two sex pheromone components, bombykol and bombykal, but only bombykol elicits sexual behaviour in male moths. A sex pheromone receptor BmOR1 is specifically tuned to bombykol and is expressed in specialized olfactory receptor neurons (ORNs) in the pheromone sensitive long sensilla trichodea of male silkmoth antennae. Here, we show that disruption of the BmOR1 gene, mediated by transcription activator-like effector nucleases (TALENs), completely removes ORN sensitivity to bombykol and corresponding pheromone-source searching behaviour in male moths. Furthermore, transgenic rescue of BmOR1 restored normal behavioural responses to bombykol. Our results demonstrate that BmOR1 is required for the physiological and behavioural response to bombykol, demonstrating that it is the receptor that mediates sex pheromone responses in male silkmoths. This study provides the first direct evidence that a member of the sex pheromone receptor family in moth species mediates conspecific sex pheromone information for sexual behaviour. PMID- 26047361 TI - The DnaA Protein Is Not the Limiting Factor for Initiation of Replication in Escherichia coli. AB - The bacterial replication cycle is driven by the DnaA protein which cycles between the active ATP-bound form and the inactive ADP-bound form. It has been suggested that DnaA also is the main controller of initiation frequency. Initiation is thought to occur when enough ATP-DnaA has accumulated. In this work we have performed cell cycle analysis of cells that contain a surplus of ATP-DnaA and asked whether initiation then occurs earlier. It does not. Cells with more than a 50% increase in the concentration of ATP-DnaA showed no changes in timing of replication. We suggest that although ATP-DnaA is the main actor in initiation of replication, its accumulation does not control the time of initiation. ATP DnaA is the motor that drives the initiation process, but other factors will be required for the exact timing of initiation in response to the cell's environment. We also investigated the in vivo roles of datA dependent DnaA inactivation (DDAH) and the DnaA-binding protein DiaA. Loss of DDAH affected the cell cycle machinery only during slow growth and made it sensitive to the concentration of DiaA protein. The result indicates that compromised cell cycle machines perform in a less robust manner. PMID- 26047362 TI - DEPRESSION MEDIATES THE RELATION OF INSOMNIA SEVERITY WITH SUICIDE RISK IN THREE CLINICAL SAMPLES OF U.S. MILITARY PERSONNEL. AB - BACKGROUND: A growing body of empirical research suggests insomnia severity is directly related to suicide ideation, attempts, and death in nonmilitary samples, even when controlling for depression and other suicide risk factors. Few studies have explored this relationship in U.S. military personnel. METHODS: The present study entailed secondary data analyses examining the associations of insomnia severity with suicide ideation and attempts in three clinical samples: Air Force psychiatric outpatients (n = 158), recently discharged Army psychiatric inpatients (n = 168), and Army psychiatric outpatients (n = 54). Participants completed the Beck Scale for Suicide Ideation, the Beck Depression Inventory-II or Patient Health Questionnaire-9, the Insomnia Severity Index, and the Posttraumatic Stress Disorder Checklist at baseline; two samples also completed these measures during follow-up. RESULTS: Sleep disturbance was associated with concurrent (beta's > 0.21; P's < 0.059) and prospective (beta's > 0.39; P's < 0.001) suicide ideation in all three samples. When adjusting for age, gender, depression, and posttraumatic stress, insomnia severity was no longer directly associated with suicide ideation either concurrently (beta's < 0.19; P's > 0.200) or prospectively (beta's < 0.26; P's > 0.063), but depression was (beta's > 0.22; P's < 0.012). Results of a latent difference score mediation model indicated that depression mediated the relation of insomnia severity with suicide ideation. CONCLUSIONS: Across three clinical samples of military personnel, depression explained the relationship between insomnia severity and suicide risk. PMID- 26047363 TI - Beneficial Therapeutic Effects of Spinal Cord Stimulation in Advanced Cases of Parkinson's Disease With Intractable Chronic Pain: A Case Series. AB - OBJECTIVES: Pain is one of the common symptoms in patients with Parkinson's disease (PD), with a prevalence of approximately 40-85%. These symptoms affect the quality of life of PD patients. We evaluated the effect of spinal cord stimulation (SCS) to chronic pain and motor symptoms of PD. MATERIALS AND METHODS: Three PD patients were treated with SCS to relieve their persistent and intractable pain. One patient had failed back surgery syndrome and the other two had lumbar canal stenosis. All patients had a stooped posture and pain that was resistant to analgesics. We evaluated motor symptoms using Hoehn and Yahr scale and the Unified Parkinson's Disease Rating Scale (UPDRS), and evaluated pain using visual analog scale and widespread pain index, before and after SCS. RESULTS: After SCS insertion, chronic pain in the patients decreased in both the lower back and limbs. Moreover, SCS ameliorated the symptoms of PD. One-year follow-up after SCS showed that UPDRS part III scores, rigidity, and tremor were improved without large alterations in levodopa dosage. Dementia and activities of daily living did not improve after SCS. DISCUSSION AND CONCLUSION: Our results indicate that SCS may be a treatment option for both motor symptoms and chronic pain in PD, especially in cases complicated with lumbar canal stenosis or disc herniation. Further studies are needed to evaluate the efficacy of SCS in PD patients. PMID- 26047364 TI - Impact of Contact Isolation Precautions on Multi-Drug Resistant Acinetobacter baumannii in the Pediatric Intensive Care Unit. PMID- 26047365 TI - Molecular Recognition of PPARgamma by Kinase Cdk5/p25: Insights from a Combination of Protein-Protein Docking and Adaptive Biasing Force Simulations. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) is an important transcription factor that plays a major role in the regulation of glucose and lipid metabolisms and has, therefore, many implications in modern-life metabolic disorders such as diabetes, obesity, and cardiovascular diseases. Phosphorylation of PPARgamma by the cyclin-dependent kinase 5 (Cdk5) has been recently proved to promote obesity and loss of insulin sensitivity. The inhibition of this reaction is currently being pursued to develop PPARgamma ligands for type 2 diabetes treatments. The knowledge of the protein-protein interactions between Cdk5/p25 and PPARgamma can be an important asset for better understanding of the molecular basis of the Cdk5-meditated phosphorylation of PPARgamma and its inhibition. By means of a computational approach that combines protein-protein docking and adaptive biasing force molecular dynamics simulations, we obtained PPARgamma Cdk5/p25 structural models that are consistent with the mechanism of the enzymatic reaction and with overall structural features of the full length PPARgamma-RXRalpha heterodimer bound to DNA. In addition to the active site, our model shows that the interacting regions between the two proteins should involve two distal docking sites, comprising the PPARgamma Omega-loop and Cdk5 N-terminal lobe and the PPARgamma beta-sheet and Cdk5 C-terminal lobe. These sites are related to PPARgamma transactivation and directly interact with PPARgamma ligands. Our results suggest that beta-sheets and Omega-loop stabilization promoted by PPARgamma agonists could be important to inhibit Cdk5-mediated phosphorylation. PMID- 26047366 TI - Understanding receptivity to informal supportive cancer care in regional and rural Australia: a Heideggerian analysis. AB - The concept of receptivity is a new way of understanding the personal and social factors that affect a person living with and beyond cancer, and how these factors influence access to formal supportive care service provision and planning. This article contributes to new knowledge through applying the concept of receptivity to informal supportive cancer care in regional Australia. Literature indicates that a cancer diagnosis is a life-changing experience, particularly in regional communities, where survival rates are lower and there are significant barriers to accessing services. Heideggerian phenomenology informed the design of the study and allowed for a rich and nuanced understanding of participants lived experiences of informal supportive cancer care. These experiences were captured using in-depth interviews, which were subsequently thematically analysed. Nineteen participants were recruited from across regional Victoria, Australia. Participants self-reported a range of stages and types of cancer. Significantly, findings revealed that most participants were not referred to, and did not seek, formal supportive care. Instead, they were receptive to informal supportive care. Understanding receptivity and the role of anxiety and fear of death has implications for partners, family, community members, as well as professionals working with people with living with and beyond cancer. PMID- 26047367 TI - Photoinduced Anisotropic Assembly of Conjugated Polymers in Insulating Polymer Blends. AB - Low-dose UV irradiation of poly(3-hexylthiophene) (P3HT)-insulating polymer (polystyrene (PS) or polyisobutylene (PIB)) blend solutions led to the formation of highly ordered P3HT nanofibrillar structures in solidified thin films. The P3HT nanofibers were effectively interconnected through P3HT islands phase separated from insulating polymer regions in blend films comprising a relatively low fraction of P3HT. Films prepared with a P3HT content as low as 5 wt % exhibited excellent macroscopic charge transport characteristics. The impact of PS on P3HT intramolecular and intermolecular interactions was systematically investigated. The presence of PS chains appeared to assist in the UV irradiation process of the blend solutions to facilitate molecular interactions of the semiconductor component, and to enhance P3HT chain interactions during spin coating because of relatively unfavorable P3HT-PS chain interactions. However, P3HT lamellar packing was hindered in the presence of PS chains, because of favorable hydrophobic interactions between the P3HT hexyl substituents and the PS chains. As a result, the lamellar packing d-spacing increased, and the coherence length corresponding to the lamellar packing decreased, as the amount of PS in the blend films increased. PMID- 26047368 TI - Correlation of CEA but not CA 19-9 as serum biomarkers of disease activity in a case of metastatic rectal adenocarcinoma. AB - We present the case of a 62-year-old-man with moderately differentiated adenocarcinoma of the rectum. This patient underwent neoadjuvant chemoradiation and surgical resection followed by adjuvant chemotherapy. After completing therapy, this patient had 2 instances of CEA elevation, both of which preceded the discovery of recurrent disease. While on treatment for these recurrences, CA 19-9 increased rapidly to 4,405. This CA 19-9 elevation persisted for approximately 4 months in the absence of clinical, radiographic or additional serologic evidence of progressive disease before returning to baseline. Shortly after this tumor marker normalized, a small area of locally recurrent disease was discovered. This case highlights the utility and pitfalls of colorectal cancer disease monitoring with CEA and CA 19-9. The differential diagnosis of CA 19-9 elevation is discussed in this report. PMID- 26047370 TI - Apolipoprotein B and Insulin Resistance in Hypertensive Compared With Normotensive Patients: An Epidemiological Study. PMID- 26047369 TI - Human psychophysics and rodent spinal neurones exhibit peripheral and central mechanisms of inflammatory pain in the UVB and UVB heat rekindling models. AB - Translational research is key to bridging the gaps between preclinical findings and the patients, and a translational model of inflammatory pain will ideally induce both peripheral and central sensitisation, more effectively mimicking clinical pathophysiology in some chronic inflammatory conditions. We conducted a parallel investigation of two models of inflammatory pain, using ultraviolet B (UVB) irradiation alone and UVB irradiation with heat rekindling. We used rodent electrophysiology and human quantitative sensory testing to characterise nociceptive processing in the peripheral and central nervous systems in both models. In both species, UVB irradiation produces peripheral sensitisation measured as augmented evoked activity of rat dorsal horn neurones and increased perceptual responses of human subjects to mechanical and thermal stimuli. In both species, UVB with heat rekindling produces central sensitisation. UVB irradiation alone and UVB with heat rekindling are translational models of inflammation that produce peripheral and central sensitisation, respectively. The predictive value of laboratory models for human pain processing is crucial for improving translational research. The discrepancy between peripheral and central mechanisms of pain is an important consideration for drug targets, and here we describe two models of inflammatory pain that involve ultraviolet B (UVB) irradiation, which can employ peripheral and central sensitisation to produce mechanical and thermal hyperalgesia in rats and humans. We use electrophysiology in rats to measure the mechanically- and thermally-evoked activity of rat spinal neurones and quantitative sensory testing to assess human psychophysical responses to mechanical and thermal stimulation in a model of UVB irradiation and in a model of UVB irradiation with heat rekindling. Our results demonstrate peripheral sensitisation in both species driven by UVB irradiation, with a clear mechanical and thermal hypersensitivity of rat dorsal horn neurones and enhanced perceptual responses of human subjects to both mechanical and thermal stimulation. Additional heat rekindling produces markers of central sensitisation in both species, including enhanced receptive field sizes. Importantly, we also showed a correlation in the evoked activity of rat spinal neurones to human thermal pain thresholds. The parallel results in rats and humans validate the translational use of both models and the potential for such models for preclinical assessment of prospective analgesics in inflammatory pain states. PMID- 26047371 TI - Photocontrol of Elicitor Activity of PIP-1 to Investigate Temporal Factors Involved in Phytoalexin Biosynthesis. AB - The peptide elicitor PIP-1 can induce various immune responses in tobacco cells. Previously, we showed that types of responses induced by PIP-1 are different depending on its stimulation periods; short-term stimulation induces weak responses, whereas long-term stimulation leads to strong responses including production of the phytoalexin capsidiol. However, key components that directly regulate the initiation of capsidiol biosynthesis in response to continuous stimulation with PIP-1 remain unclear. In this study, we designed a photocleavable PIP-1 analog containing 3-amino-3-(2-nitrophenyl)propionic acid as a photocleavable residue. The activity of the analog can be "switched off" using ultraviolet (UV) irradiation without undesired side effects. This analog induced a significant level of capsidiol production unless UV-irradiated, whereas no capsidiol production was observed when tobacco cells were UV-irradiated 1 h after treatment. Using this analog, we found that the elicitor-inducible 3-hydroxy-3 methylglutaryl-CoA reductase activity is regulated based on the duration of the stimulation with PIP-1, which could be associated with the initiation of capsidiol biosynthesis. PMID- 26047372 TI - Heat treatment inhibits skeletal muscle atrophy of glucocorticoid-induced myopathy in rats. AB - The purpose of this study was to investigate the influence of heat treatment on glucocorticoid (GC)-induced myopathy. Eight-week-old Wistar rats were randomly assigned to the control, Dex, and Dex + Heat groups. Dexamethasone (2 mg/kg) was injected subcutaneously 6 days per week for 2 weeks in the Dex and Dex + Heat group. In the Dex + Heat group, heat treatment was performed by immersing hindlimbs in water at 42 degrees C for 60 min, once every 3 days for 2 weeks. The extensor digitorum longus muscle was extracted following 2 weeks of experimentation. In the Dex + Heat group, muscle fiber diameter, capillary/muscle fiber ratio, and level of heat shock protein 72 were significantly higher and atrogene expression levels were significantly lower than in the Dex group. Our results suggest that heat treatment inhibits the development of GC-induced myopathy by decreasing atrogene expression and increasing angiogenesis. PMID- 26047373 TI - CARM1 modulators affect epigenome of stem cells and change morphology of nucleoli. AB - CARM1 interacts with numerous transcription factors to mediate cellular processes, especially gene expression. This is important for the maintenance of ESC pluripotency or intervention to tumorigenesis. Here, we studied epigenomic effects of two potential CARM1 modulators: an activator (EML159) and an inhibitor (ellagic acid dihydrate, EA). We examined nuclear morphology in human and mouse embryonic stem cells (hESCs, mESCs), as well as in iPS cells. The CARM1 modulators did not function similarly in all cell types. EA decreased the levels of the pluripotency markers, OCT4 and NANOG, particularly in iPSCs, whereas the levels of these proteins increased after EML159 treatment. EML159 treatment of mouse ESCs led to decreased levels of OCT4 and NANOG, which was accompanied by an increased level of Endo-A. The same trend was observed for NANOG and Endo-A in hESCs affected by EML159. Interestingly, EA mainly changed epigenetic features of nucleoli because a high level of arginine asymmetric di-methylation in the nucleoli of hESCs was reduced after EA treatment. ChIP-PCR of ribosomal genes confirmed significantly reduced levels of H3R17me2a, in both the promoter region of ribosomal genes and rDNA encoding 28S rRNA, after EA addition. Moreover, EA treatment changed the nuclear pattern of AgNORs (silver-stained nucleolus organizer regions) in all cell types studied. In EA-treated ESCs, AgNOR pattern was similar to the pattern of AgNORs after inhibition of RNA pol I by actinomycin D. Together, inhibitory effect of EA on arginine methylation and effect on related morphological parameters was especially observed in compartment of nucleoli. PMID- 26047374 TI - One-year results from cryopreserved mitral allograft transplantation into the tricuspid position in a sheep experimental model. AB - Mitral allografts are still used only exceptionally in the mitral or tricuspid position. The main indication remains infectious endocarditis of atrioventricular valves for its flexibility and low risk of infection. The aim of our study was to evaluate 1-year results of mitral allografts transplantation into the tricuspid position in a sheep model. Mitral allografts were processed, cryopreserved, and transplanted into the tricuspid position anatomically (Group I - 11 animals) or antianatomically (Group II - 8 animals). All survivors (4 from Group I, and 3 from Group II) were checked at 3, 6, and 12 months by echocardiography with the exception of one survivor from Group II (which was examinated only visually). Examination throughout follow-up included for mitral allograft regurgitation and annuli dilatation. At postmortem, the papillary muscles were healed and firmly anchored to the right ventricular wall in all subjects. Transventricular fixation of the papillary muscles with buttressed sutures was proven to be a stable, reproducible, and safe method for anchoring mitral allograft leaflets. There were no significant differences between the two implantation methods. Annulus support of mitral allografts might be very useful in this type of operation and could prevent annular dilatation. PMID- 26047376 TI - The relationship between antioxidant enzymes and lipid peroxidation in senescent rat erythrocytes. AB - The aim of this study was to gain more complete information about the relationships between some endogenous antioxidants and the malondialdehyde (MDA) as a marker of lipid peroxidation, during D-galactose induced senescence. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and the concentrations of uric acid (UA) in plasma and MDA in erythrocyte's hemolysate, were determined in 15 D-galactose (D-gal), treated rats and compared with 15 placebo. The activity of the erythrocyte's CAT was found significantly increased due to the senescence. The ratio of the activities of antioxidant enzymes R=SOD/(GPx+CAT) was significantly decreased due to the senescence and negatively correlated with the MDA (rho=-0.524, p=0.045). The antioxidant enzymes SOD and GPx negatively correlated with the MDA, while CAT displayed no correlation. Further, the UA positively correlated with the ratio of activities of the antioxidant enzymes R=SOD/(GPx+CAT), (rho=0.564, p=0.029 for senescent rats). Obtained results may contribute to better understanding of the process of D-gal induced senescence in the erythrocytes. PMID- 26047377 TI - Is ionized oxygen negatively or positively charged more effective for carboxyhemoglobin reduction compare to medical oxygen at atmospheric pressure? AB - Carbon monoxide (CO) reversibly binds to hemoglobin forming carboxyhemoglobin (COHb). CO competes with O(2) for binding place in hemoglobin leading to tissue hypoxia. Already 30 % saturation of COHb can be deadly. Medical oxygen at atmospheric pressure as a therapy is not enough effective. Therefore hyperbaric oxygen O(2) inhalation is recommended. There was a question if partially ionized oxygen can be a better treatment at atmospheric pressure. In present study we evaluated effect of partially ionized oxygen produced by device Oxygen Ion 3000 by Dr. Engler in elimination of COHb in vitro experiments and in smokers. Diluted blood with different content of CO was purged with 5 l/min of either medicinal oxygen O(2), negatively ionized O(2) or positively ionized O(2) for 15 min, then the COHb content was checked. In vivo study, 15 smokers inhaled of either medicinal oxygen O(2) or negatively ionized O(2), than we compared CO levels in expired air before and after inhalation. In both studies we found the highest elimination of CO when we used negatively ionized O(2). These results confirmed the benefit of short inhalation of negatively ionized O(2), in frame of Ionized Oxygen Therapy (I O(2)Th/Engler) which could be used in smokers for decreasing of COHb in blood. PMID- 26047375 TI - Inhibition of soluble epoxide hydrolase does not improve the course of congestive heart failure and the development of renal dysfunction in rats with volume overload induced by aorto-caval fistula. AB - The detailed mechanisms determining the course of congestive heart failure (CHF) and associated renal dysfunction remain unclear. In a volume overload model of CHF induced by creation of aorto-caval fistula (ACF) in Hannover Sprague-Dawley (HanSD) rats we explored the putative pathogenetic contribution of epoxyeicosatrienoic acids (EETs), active products of CYP-450 dependent epoxygenase pathway of arachidonic acid metabolism, and compared it with the role of the renin-angiotensin system (RAS). Chronic treatment with cis-4-[4-(3 adamantan-1-yl-ureido) cyclohexyloxy]benzoic acid (c-AUCB, 3 mg/l in drinking water), an inhibitor of soluble epoxide hydrolase (sEH) which normally degrades EETs, increased intrarenal and myocardial EETs to levels observed in sham operated HanSD rats, but did not improve the survival or renal function impairment. In contrast, chronic angiotensin-converting enzyme inhibition (ACEi, trandolapril, 6 mg/l in drinking water) increased renal blood flow, fractional sodium excretion and markedly improved survival, without affecting left ventricular structure and performance. Hence, renal dysfunction rather than cardiac remodeling determines long-term mortality in advanced stage of CHF due to volume overload. Strong protective actions of ACEi were associated with suppression of the vasoconstrictor/sodium retaining axis and activation of vasodilatory/natriuretic axis of the renin-angiotensin system in the circulating blood and kidney tissue. PMID- 26047378 TI - Acetaldehyde at clinically relevant concentrations inhibits inward rectifier potassium current I(K1) in rat ventricular myocytes. AB - Considering the effects of alcohol on cardiac electrical behavior as well as the important role of the inward rectifier potassium current I(K1) in arrhythmogenesis, this study was aimed at the effect of acetaldehyde, the primary metabolite of ethanol, on I(K1) in rat ventricular myocytes. Acetaldehyde induced a reversible inhibition of I(K1) with IC(50) = 53.7+/-7.7 microM at -110 mV; a significant inhibition was documented even at clinically-relevant concentrations (at 3 microM by 13.1+/-3.0 %). The inhibition was voltage-independent at physiological voltages above -90 mV. The I(K1) changes under acetaldehyde may contribute to alcohol-induced alterations of cardiac electrophysiology, especially in individuals with a genetic defect of aldehyde dehydrogenase where the acetaldehyde level may be elevated. PMID- 26047379 TI - The skin remodeling in type 1 diabetes and insulin resistance animal models. AB - The skin matrix metalloproteinase 3, tissue inhibitors of matrix metalloproteinase 2 and collagen III content changes in type 1 diabetes and insulin resistance treated with insulin and metformin were studied. Healthy adult male Wistar rats were obtained from experimental animal house, Department of Experimental Pharmacology, Medical University in Bialystok. The rats were divided randomly into five groups of 8 rats each. Control rats were injected intraperitoneally by NaCl. Type IDDM was induced by a single injection of Streptozocin. Insulin resistance was induced by a high-fat diet. The chosen groups of rats were also treated with insulin or metformin. ELISA Kits (USCN Life Science, China) were used to measure content of matrix metallo-proteinase 3 (ELISA Kit for Matrix Metalloproteinase 3 - MMP3), tissue inhibitor of matrix metalloproteinase 2 (ELISA Kit for Tissue Inhibitors of Metalloproteinase 2 - TIMP2) and content of collagen type 3 (ELISA Kit for Collagen Type III - COL3). The results were reported as a median. The statistical significance was defined as p<0.05. Type 1 diabetes and insulin resistance have significantly reduced the quality of the skin, shown by the increase in content of matrix metalloproteinase 3 and the decrease in content of tissue inhibitors of matrix metalloproteinase 2. Type 1 diabetes and insulin resistance have reduced the quality of the skin expressed by type III collagen content decrease but for future studies it is recommend to determine rat interstitial collagenase, MMP-13, as well. Insulin and metformin treatment improved the quality of the diabetic skin, demonstrated by the type III collagen content increase. PMID- 26047380 TI - Melanocortin-4 receptor gene mutations in obese Slovak children. AB - The most common etiology of non-syndromic monogenic obesity are mutations in gene for the Melanocortin-4 receptor (MC485) with variable prevalence in different countries (1.2-6.3 % of obese children). The aim of our study was 1) to search for MC4R mutations in obese children in Slovakia and compare their prevalence with other European countries, and 2) to describe the phenotype of the mutation carriers. DNA analysis by direct Sanger sequencing of the coding exons and intron/exon boundaries of the MC4R gene was performed in 268 unrelated Slovak children and adolescents with body mass index above the 97(th) percentile for age and sex and obesity onset up to 11 years (mean 4.3+/-2.8 years). Two different previously described heterozygous loss of function MC4R variants (i.e. p.Ser19Alafs*34, p.Ser127Leu) were identified in two obese probands, and one obese (p.Ser19Alafs*34), and one lean (p.Ser127Leu) adult family relatives. No loss of function variants were found in lean controls. The prevalence of loss-of function MC4R variants in obese Slovak children was 0.7 %, what is one of the lowest frequencies in Europe. PMID- 26047381 TI - proBDNF is a major product of bdnf gene expressed in the perinatal rat cortex. AB - In the developing brain, mature brain derived neurotrophic factor (mBDNF) and its precursor (proBDNF) exhibit prosurvival and proapoptotic functions, respectively. However, it is still unknown whether mBDNF or proBDNF is a major form of neurotrophin expressed in the immature brain, as well as if the level of active caspase-3 correlates with the levels of BDNF forms during normal brain development. Here we found that both proBDNF and mBDNF were expressed abundantly in the rat brainstem, hippocampus and cerebellum between embryonic day 20 and postnatal day 8. The levels of mature neurotrophin as well as mBDNF to proBDNF ratios negatively correlated with the expression of active caspase-3 across brain regions. The immature cortex was the only structure, in which proBDNF was the major product of bdnf gene, especially in the cortical layers 2-3. And only in the cortex, the expression of BDNF precursor positively correlated with the levels of active caspase-3. These findings suggest that proBDNF alone may play an important role in the regulation of naturally occurring cell death during cortical development. PMID- 26047382 TI - Impact of high intensity exercise on muscle morphology in EAE rats. AB - The impact of high-intensity exercise on disease progression and muscle contractile properties in experimental autoimmune encephalomyelitis (EAE) remains unclear. Control (CON) and EAE rats were divided into sedentary and exercise groups. Before onset (experiment 1, n=40) and after hindquarter paralysis (experiment 2, n=40), isokinetic foot extensor strength, cross sectional area (CSA) of tibialis anterior (TA), extensor digitorum longus (EDL) and soleus (SOL) and brain-derived neurotrophic factor (BDNF) levels were assessed. EAE reduced muscle fiber CSA of TA, EDL and SOL. In general, exercise was not able to affect CSA, whereas it delayed hindquarter paralysis peak. CON muscle work peaked and declined, while it remained stable in EAE. BDNF-responses were not affected by EAE or exercise. In conclusion, EAE affected CSA-properties of TA, EDL and SOL, which could, partly, explain the absence of peak work during isokinetic muscle performance in EAE-animals. However, exercise was not able to prevent muscle fiber atrophy. PMID- 26047383 TI - The VO(2)-on kinetics in constant load exercise sub-anaerobic threshold reflects endothelial function and dysfunction in muscle microcirculation. AB - To propose a test to evaluate endothelial function, based on VO(2) on-transition kinetics in sub-anaerobic threshold (AT) constant load exercise, we tested healthy subjects and patients with ischemic-hypertensive cardiopathy by two cardiopulmonary tests on a cycle ergometer endowed with an electric motor to overcome initial inertia: a pre-test and, after at least 24 h, one 6 min constant load exercise at 90 % AT. We measured net phase 3 VO(2)-on kinetics and, by phase 2 time constant (tau), valued endothelial dysfunction. We found shorter tau in repeated tests, shorter time between first and second test, by persisting endothelium-dependent arteriolar vasodilatation and/or several other mechanisms. Reducing load to 80 % and 90 % AT did not produce significant changes in tau of healthy volunteers, while in heart patients an AT load of 70 %, compared to 80 % AT, shortened tau (delta=4.38+/-1.65 s, p=0.013). In heart patients, no correlation was found between NYHA class, ejection fraction (EF), and the two variables derived from incremental cycle cardio-pulmonary exercise, as well as between EF and tau; while NYHA class groups were well correlated with tau duration (r=0.92, p=0.0001). Doxazosin and tadalafil also significantly reduced tau. In conclusion, the O(2) consumption kinetics during the on-transition of constant load exercise below the anaerobic threshold are highly sensitive to endothelial function in muscular microcirculation, and constitute a marker for the evaluation of endothelial dysfunction. PMID- 26047384 TI - Neonatal rat hearts cannot be protected by ischemic postconditioning. AB - Although there are abundant data on ischemic postconditioning (IPoC) in the adult myocardium, this phenomenon has not yet been investigated in neonatal hearts. To examine possible protective effects of IPoC, rat hearts isolated on days 1, 4, 7 and 10 of postnatal life were perfused according to Langendorff. Developed force (DF) of contraction was measured by an isometric force transducer. Hearts were exposed to 40 or 60 min of global ischemia followed by reperfusion up to the maximum recovery of DF. IPoC was induced by three cycles of 10, 30 or 60 s periods of global ischemia/reperfusion. To further determine the extent of ischemic injury, lactate dehydrogenase (LDH) release was measured in the coronary effluent. Tolerance to ischemia did not change from day 1 to day 4 but decreased to days 7 and 10. None of the postconditioning protocols tested led to significant protection on the day 10. Prolonging the period of sustained ischemia to 60 min on day 10 did not lead to better protection. The 3x30 s protocol was then evaluated on days 1, 4 and 7 without any significant effects. There were no significant differences in LDH release between postconditioned and control groups. It can be concluded that neonatal hearts cannot be protected by ischemic postconditioning during first 10 days of postnatal life. PMID- 26047385 TI - A comparison of portal vein embolization with poly(2-hydroxyethylmethacrylate) and a histoacryl/lipiodol mixture in patients scheduled for extended right hepatectomy. AB - To determine whether PHEMA [poly(2-hydroxyethylmethacrylate)] is suitable for portal vein embolization in patients scheduled to right hepatectomy and whether it is as effective as the currently used agent (a histoacryl/lipiodol mixture). Two groups of nine patients each scheduled for extended right hepatectomy for primary or secondary hepatic tumor, had right portal vein embolization in an effort to induce future liver remnant (FLR) hypertrophy. One group had embolization with PHEMA, the other one with the histoacryl/lipiodol mixture. In all patients, embolization was performed using the right retrograde transhepatic access. Embolization was technically successful in all 18 patients, with no complication related to the embolization agent. Eight patients of either group developed FLR hypertrophy allowing extended right hepatectomy. Likewise, one patient in each group had recanalization of a portal vein branch. Histology showed that both embolization agents reach the periphery of portal vein branches, with PHEMA penetrating somewhat deeper into the periphery. PHEMA has been shown to be an agent suitable for embolization in the portal venous system comparable with existing embolization agent (histoacryl/lipiodol mixture). PMID- 26047386 TI - Dielectric Genome of van der Waals Heterostructures. AB - Vertical stacking of two-dimensional (2D) crystals, such as graphene and hexagonal boron nitride, has recently lead to a new class of materials known as van der Waals heterostructures (vdWHs) with unique and highly tunable electronic properties. Ab initio calculations should in principle provide a powerful tool for modeling and guiding the design of vdWHs, but in their traditional form such calculations are only feasible for commensurable structures with a few layers. Here we show that the dielectric properties of realistic, incommensurable vdWHs comprising hundreds of layers can be efficiently calculated using a multiscale approach where the dielectric functions of the individual layers (the dielectric building blocks) are computed ab initio and coupled together via the long-range Coulomb interaction. We use the method to illustrate the 2D-3D transition of the dielectric function of multilayer MoS2 crystals, the hybridization of quantum plasmons in thick graphene/hBN heterostructures, and to demonstrate the intricate effect of substrate screening on the non-Rydberg exciton series in supported WS2. The dielectric building blocks for a variety of 2D crystals are available in an open database together with the software for solving the coupled electrodynamic equations. PMID- 26047387 TI - Case report of aquagenic wrinkling of the palms associated with impaired stratum corneum function. PMID- 26047388 TI - Outcomes of allogeneic stem cell transplantation in hepatosplenic T-cell lymphoma. PMID- 26047389 TI - Osteoprotegerin is a significant prognostic factor for overall survival in patients with primary systemic amyloidosis independent of the Mayo staging. AB - Bone metabolism has not been systematically studied in primary (AL) amyloidosis. Thus we prospectively evaluated bone remodeling indices in 102 patients with newly diagnosed AL amyloidosis, 35 healthy controls, 35 newly diagnosed myeloma and 40 monoclonal gammopathy of undetermined significance patients. Bone resorption markers (C-telopeptide of type-1 collagen, N-telopeptide of type-1 collagen) and osteoclast regulators (soluble receptor activator of nuclear factor kappaB ligand (sRANKL), osteoprotegerin (OPG)) were increased in AL patients compared with controls (P<0.01), but bone formation was unaffected. Myeloma patients had increased bone resorption and decreased bone formation compared with AL patients, while sRANKL/OPG ratio was markedly decreased in AL, due to elevated OPG in AL (P<0.001). OPG correlated with N-terminal pro-brain natriuretic peptide (P<0.001) and was higher in patients with cardiac involvement (P=0.028) and advanced Mayo stage (P=0.001). OPG levels above the upper value of healthy controls was associated with shorter survival (34 versus 91 months; P=0.026), while AL patients with OPG levels in the top quartile had very short survival (12 versus 58 months; P=0.024). In Mayo stage 1 disease, OPG identified patients with poor survival (12 versus >60 months; P=0.012). We conclude that increased OPG in AL is not only a compensation to osteoclast activation but may also reflect early cardiac damage and may identify patients at increased risk of death within those with earlier Mayo stage. PMID- 26047390 TI - Inhibition of brain retinoic acid catabolism: a mechanism for minocycline's pleiotropic actions? AB - OBJECTIVES: Minocycline is a tetracycline antibiotic increasingly recognized in psychiatry for its pleiotropic anti-inflammatory and neuroprotective potential. While underlying mechanisms are still incompletely understood, several lines of evidence suggest a relevant functional overlap with retinoic acid (RA), a highly potent small molecule exhibiting a great variety of anti-inflammatory and neuroprotective properties in the adult central nervous system (CNS). RA homeostasis in the adult CNS is tightly controlled through local RA synthesis and cytochrome P450 (CYP450)-mediated inactivation of RA. Here, we hypothesized that minocycline may directly affect RA homeostasis in the CNS via altering local RA degradation. METHODS: We used in vitro RA metabolism assays with metabolically competent synaptosomal preparations from murine brain and human SH-SY5Y neuronal cells as well as viable human SH-SY5Y neuroblastoma cell cultures. RESULTS: We revealed that minocycline potently blocks RA degradation as measured by reversed phase high-performance liquid chromatography and in a viable RA reporter cell line, even at low micromolar levels of minocycline. CONCLUSIONS: Our findings provide evidence for enhanced RA signalling to be involved in minocycline's pleiotropic mode of action in the CNS. This novel mode of action of minocycline may help in developing more specific and effective strategies in the treatment of neuroinflammatory or neurodegenerative disorders. PMID- 26047391 TI - Allele frequencies of 20 autosomal STR in the population from Rio Grande do Sul Southern Brazil. PMID- 26047392 TI - Effect of nefopam- versus fentanyl-based patient-controlled analgesia on postoperative nausea and vomiting in patients undergoing gynecological laparoscopic surgery: a prospective double-blind randomized controlled trial. AB - OBJECTIVE: This study comparatively evaluated the effect of patient-controlled analgesia (PCA) regimens using equipotent doses of nefopam or fentanyl during laparoscopic gynecological surgery on postoperative nausea and vomiting (PONV). RESEARCH DESIGN AND METHODS: Patients undergoing gynecological laparoscopic surgery were randomly allocated to receive either nefopam- (non-opioid; N group) or fentanyl-based (F group) PCA. PONV and postoperative pain were assessed during the 72 hours following discharge from the post-anesthetic care unit (PACU). The adverse effects of nefopam were also evaluated. CLINICAL TRIAL REGISTRATION: Cris.nih.go.kr ID KCT0000783. RESULTS: In total, 94 patients were included in the final analysis. The PONV incidence and scale and the Rhodes index scores were significantly lower in the N group than the F group at all measured times. The N group exhibited a significantly lower incidence of PONV (15/47 [31.9%] vs. 27/47 [57.4%], respectively; P = 0.022) and severity of PONV (0 [1] vs. 1 [2], respectively; P = 0.005) 24 hours after PACU discharge and a significantly lower Rhodes index score (0 [3] vs. 5 [9], respectively; P = 0.002) from 30 minutes after PACU arrival to 24 hours after PACU discharge than did the F group. There was no significant difference in postoperative pain at any time between the two groups. Dry mouth on PACU arrival was significantly more frequent in the N group. However, the frequency of dry mouth decreased after PACU arrival in the N group, resulting in a significantly lower incidence 24 hours after PACU discharge. CONCLUSIONS: Use of a PCA regimen with nefopam for analgesia was associated with a similar degree of pain control and superior PONV outcomes 24 hours after PACU discharge and no adverse events compared with a PCA regimen using an equipotent dose of fentanyl. PMID- 26047393 TI - Three-Dimensional Bicontinuous Graphene Monolith from Polymer Templates. AB - The two-dimensional single-layer and few-layered graphene exhibit many attractive properties such as large specific surface area and high charge carrier mobility. However, graphene sheets tend to stack together and form aggregates, which do not possess the desirable properties associated with graphene. Herein, we report a method to fabricate three-dimensional (3D), bicontinuous graphene monolith through a versatile hollow nickel (Ni) template derived from polymer blends. The poly(styrene)/poly(ethylene oxide) were used to fabricate a bicontinuous gyroid template using controlled phase separation. The Ni template was formed by electroless metal depositing on the polymer followed by removing the polymer phase. The resulting hollow Ni structure was highly porous (95.2%). Graphene was then synthesized from this hollow Ni template using chemical vapor deposition and the free-standing bicontinuous graphene monolith was obtained in high-throughput process. Finally, the bicontinuous graphene monolith was used directly as binder free electrode in supercapacitor applications. The supercapacitor devices exhibited excellent stability. PMID- 26047394 TI - What's Right With Radiology. PMID- 26047395 TI - Speaking of Language. PMID- 26047396 TI - Avoid Jargon Terms for Normal. PMID- 26047397 TI - The Vermont Retreat. PMID- 26047398 TI - Cost and Morbidity Analysis of Chest Port Insertion: Interventional Radiology Suite Versus Operating Room. AB - PURPOSE: To compare complications and cost, from a hospital perspective, of chest port insertions performed in an interventional radiology (IR) suite versus in surgery in an operating room (OR). METHODS: This study was approved by an institutional review board and is HIPAA compliant. Medical records were retrospectively searched on consecutive chest port placement procedures, in the IR suite and the OR, between October 22, 2010 and February 26, 2013, to determine patients' demographic information and chest port-related complications and/or infections. A total of 478 charts were reviewed (age range: 21-85 years; 309 women, 169 men). Univariate and bivariate analyses were performed to identify risk factors associated with an increased complication rate. Cost data on 149 consecutive Medicare outpatients (100 treated in the IR suite; 49 treated in the OR) who had isolated chest port insertions between March 2012 and February 2013 were obtained for both the operative services and pharmacy. Nonparametric tests for heterogeneity were performed using the Kruskal-Wallis method. RESULTS: Early complications occurred in 9.2% (22 of 239) of the IR patients versus 13.4% (32 of 239) of the OR patients. Of the 478 implanted chest ports, 9 placed in IR and 18 placed in surgery required early removal. Infections from the ports placed in IR versus the OR were 0.25 versus 0.18 infections per 1000 catheters, respectively. Overall mean costs for chest port insertion were significantly higher in the OR, for both room and pharmacy costs (P < .0001). Overall average cost to place chest ports in an OR setting was almost twice that of placement in the IR suite. CONCLUSIONS: Hospital costs to place a chest port were significantly lower in the IR suite than in the OR, whereas radiology and surgery patients did not show a significantly different rate of complications and/or infections. PMID- 26047399 TI - Access to Radiology Reports via an Online Patient Portal: Experiences of Referring Physicians and Patients. AB - PURPOSE: Few organizations have reported providing radiology reports to patients via an electronic health record patient portal. The authors describe the process of manual release of reports made by referring physicians, and patients' and referring physicians' experiences during the first year that release through the portal was available. METHODS: A survey of 508 patients assessed perceived accessibility and importance of portal-released radiology reports, and communications with referring physicians before and after the release. A survey of 48 referring physicians and a group interview assessed the utility of releasing reports, preferences regarding automatic release, and workload impact. Data were analyzed using descriptive statistics and qualitative methods. RESULTS: A total of 74% (377) of patients found reports easy to access, and 88% (446) reported that the ability to do so was important. In all, 49% (250) of patients were contacted by their referring physician before report release, and 25% (156) contacted their physician for more information after viewing a report. Of the referring physicians, 88% (42) found that releasing reports to patients was useful. Auto-release of x-ray reports, with a 1-week delay, was preferred by 58% (28), but they were more reluctant to auto-release CT and MRI reports. A total of 86% (41) of referring physicians reported that follow-up emails, telephone calls, and office visits were unchanged or had decreased. CONCLUSIONS: Referring physician release of radiology reports via the online portal is important to patients, useful to referring physicians, and does not affect referring-physician workloads. A delay between reporting results to referring physicians and releasing them to patients allows time for needed physician-patient communication. PMID- 26047400 TI - Imaging Appropriateness and Implementation of Clinical Decision Support. PMID- 26047401 TI - Performance Quality Improvement in Community Practice. PMID- 26047402 TI - CT Dose Reduction Workshop: An Active Educational Experience. AB - PURPOSE: Improving patient safety by minimizing CT radiation dose, while maintaining diagnostic image quality, has become an important skill in diagnostic radiology. The aim of this study was to examine the value of an educational workshop for optimizing CT protocols in an academic department, and to assess its impact on resident education. METHODS: The CT Dose Reduction Workshop met monthly for 1 year, to teach and implement dose reduction strategies. Changes were made to CT protocols through group consensus while participants kept up to date with current literature. A survey was sent to 48 radiology residents and 32 attending radiologists in the department, including both participants and nonparticipants, after completion of the workshop, to assess its utility. The survey used a 5 point Likert-type scale. Average doses for a specific CT protocol before and after the workshop were compared. RESULTS: About 80% of respondents agreed or strongly agreed that the workshop was essential. Workshop participants expressed greater confidence in their knowledge of dose reduction techniques, with a mean score of 3.74 (95% confidence interval, 3.35-4.13), compared with nonparticipants, who had a mean score of 3.00 (95% confidence interval, 2.64 3.36) (P < .01). Dose reductions were established across numerous CT protocols. For instance, the average total dose-length product in renal mass protocol CT examinations decreased by 54% (P < .0001). CONCLUSIONS: A CT dose reduction workshop increases participants' confidence in knowledge of dose reduction techniques, fosters a culture of safety and quality improvement in the department, and reduces radiation dose to patients. PMID- 26047403 TI - Monitoring Patient Exposure During Fluoroscopic Procedures: How We Do It. PMID- 26047404 TI - Midcareer Transition in Radiology: Threat or Opportunity? AB - Midcareer job transitions are occurring for many reasons other than individual radiologists' professional performance quality, affability, and desire for geographic change. New causes seem to be related to the present health care environment. All radiologists should be aware of this disruptive change to the profession and of the resources available to help job seekers find new positions. PMID- 26047405 TI - 15 Practical Ways to Add Value in Daily Practice: An Imaging 3.0 Primer for Trainees. PMID- 26047406 TI - Restrictive Covenants. PMID- 26047407 TI - Highly selective anti-cancer properties of ester functionalized enantiopure dinuclear gold(I)-diphosphine. AB - Two chiral (-)-diphosphine-digold(I) complexes containing mono- and di methylester substituted diphosphine ligands have been prepared and structurally characterized. Both complexes are highly potent against breast cancer cell line MDA-MB-231 but showed much lower cytotoxicity against the normal human breast epithelial cells MCF10A. When compared with its mono-substituted analogue, the di methylester substituted complex caused markedly lower and relatively insignificant damage to the normal breast cells. The analogous mono- and di ethylester substituted complexes with the same stereochemistry exhibited similar anti-cancer properties but with noticeably higher cytotoxicity against the MCF10A cells. The enantiomeric complex (+)-diphosphine-digold(I) complexes containing the di-methylester substituted diphosphine ligand exhibited clearly different biological properties from its (-)-enantiomer. Furthermore, a structurally similar diphosphine-digold(I) complex but in the absence of an ester substituent, killed both the cancerous and the healthy cells indiscriminately. The current study thus revealed that the introduction of multi-esters, particularly methylesters, is an efficient approach to suppress the side-effects and to improve the efficiency of potential gold-based anti-cancer reagents. When combined with the biological observations, the chirality of gold complexes may serve as a sensitive probe for the future mechanistic studies. PMID- 26047408 TI - Preservation of multidimensional quality of life after endoscopic pituitary adenoma resection. AB - OBJECT: Pituitary adenomas are well suited to resection by a minimal-access endoscopic technique. Validation of this approach requires prospective outcome studies to determine the impact on quality of life (QOL). This study aims to assess the effect of endoscopic pituitary adenoma resection on site-specific and sinonasal-related QOL before and after endoscopic surgery using validated instruments. METHODS: Consecutive adult patients undergoing endoscopic endonasal resection of pituitary adenoma were prospectively enrolled from a single tertiary care center. All patients completed the Anterior Skull Base Questionnaire (ASBQ) and the 22-Item Sino-Nasal Outcome Test (SNOT-22) preoperatively and then at regular intervals after surgery to assess their perceived QOL with regard to hormonal, surgical, and anatomical factors. RESULTS: Eighty-one of 114 patients were eligible for study; median follow-up was 16 months. This cohort included 24 (29.6%) nonsecreting macroadenomas and 57 (70.4%) hypersecreting tumors. There was significant improvement in the mean ASBQ score at 12 weeks, 6 months, and 1 year after surgery (p < 0.05), while postoperative SNOT-22 scores, at the same time points, showed no significant difference from preoperative scores. Both ASBQ and SNOT-22 scores showed transient worsening at 3 weeks postoperatively. Subtotal resection correlated with worse QOL, both overall and among patients with hypersecreting tumors (p < 0.05). Extrasellar tumor extension, intraoperative CSF leakage, and a reconstruction technique during surgery did not impact postoperative QOL. Visual disturbances did not significantly alter QOL. There were no postoperative CSF leaks in this series. CONCLUSIONS: Endoscopic resection of pituitary adenoma is associated with long-term improvements in site specific QOL and stability in sinonasal QOL when assessed pre- and postoperatively with validated instruments. Subtotal resection was the only factor that negatively impacted postoperative QOL. Therefore, gross-total resection should be attempted for all patients to optimize QOL after surgery. PMID- 26047409 TI - Operative complications and differences in outcome after clipping and coiling of ruptured intracranial aneurysms. AB - OBJECT: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with substantial morbidity and mortality, with better outcomes reported following endovascular coiling compared with neurosurgical clipping of the aneurysm. The authors evaluated the contribution of perioperative complications and neurological decline to patient outcomes after both aneurysm-securing procedures. METHODS: A post hoc analysis of perioperative complications from the Clazosentan to Overcome Neurological iSChemia and Infarction Occurring after Subarachnoid hemorrhage (CONSCIOUS-1) study was performed. Glasgow Coma Scale (GCS) scores for patients who underwent neurosurgical clipping and endovascular coiling were analyzed preoperatively and each day following the procedure. Complications associated with a decline in postoperative GCS scores were identified for both cohorts. Because patients were not randomized to the aneurysm-securing procedures, propensity-score matching was performed to balance selected covariates between the 2 cohorts. Using a multivariate logistic regression, the authors evaluated whether a perioperative decline in GCS scores was associated with long-term outcomes on the extended Glasgow Outcome Scale (eGOS). RESULTS: Among all enrolled subjects, as well as the propensity-matched cohort, patients who underwent clipping had a significantly greater decline in their GCS scores postoperatively than patients who underwent coiling (p = 0.0024). Multivariate analysis revealed that intraoperative hypertension (p = 0.011) and intraoperative induction of hypotension (p = 0.0044) were associated with a decline in GCS scores for patients undergoing clipping. Perioperative thromboembolism was associated with postoperative GCS decline for patients undergoing coiling (p = 0.03). On multivariate logistic regression, postoperative neurological deterioration was strongly associated with a poor eGOS score at 3 months (OR 0.86, 95% CI 0.78-0.95, p = 0.0032). CONCLUSIONS: Neurosurgical clipping following aSAH is associated with a greater perioperative decline in GCS scores than endovascular coiling, which is in turn associated with poorer long-term outcomes. These findings provide novel insight into putative mechanisms of improved outcomes following coiling, highlighting the potential importance of perioperative factors when comparing outcomes between clipping and coiling and the need to mitigate the morbidity of surgical strategies following aSAH. PMID- 26047410 TI - Patency of the anterior choroidal artery covered with a flow-diverter stent. AB - OBJECT: The concept of the flow-diverter stent (FDS) is to induce aneurysmal thrombosis while preserving the patency of the parent vessel and any covered branches. In some circumstances, it is impossible to avoid dangerously covering small branches, such as the anterior choroidal artery (AChA), with the stent. In this paper, the authors describe the clinical and angiographic effects of covering the AChA with an FDS. METHODS: Between April 2011 and July 2013, 92 patients with intracranial aneurysms were treated with the use of FDSs in the authors' institution. For 20 consecutive patients (21.7%) retrospectively included in this study, this involved the unavoidable covering of the AChA with a single FDS during endovascular therapy. AChAs feeding the choroid plexus were classified as the long-course group (14 cases), and those not feeding the choroid plexus were classified as the short-course group (6 cases). Clinical symptoms and the angiographic aspect of the AChA were evaluated immediately after stent delivery and during follow-up. Neurological examinations were performed to rule out hemiparesis, hemihypesthesia, hemianopsia, and other cortical signs. RESULTS: FDS placement had no immediate effect on AChA blood flow. Data were obtained from 1-month clinical follow-up in all patients and from midterm angiographic follow up in 17 patients (85.0%), with a mean length of 9.8 +/- 5.4 months. No patient in either group complained of transient or permanent symptoms related to an AChA occlusion. In all cases, the AChA remained patent without any flow changes. CONCLUSIONS: The results of this study suggest that when impossible to avoid, the AChA may be safely covered with a single FDS during intracranial aneurysm treatment, irrespective of anatomy and anastomoses. PMID- 26047411 TI - Trigeminal neuralgia without neurovascular compression presents earlier than trigeminal neuralgia with neurovascular compression. AB - OBJECT: Trigeminal neuralgia (TN) occurs and recurs in the absence of neurovascular compression (NVC). To characterize what may be distinct patient populations, the authors examined age at onset in patients with TN with and without NVC. METHODS: A retrospective review of patients undergoing posterior fossa surgery for Type I TN at Oregon Health & Science University from 2009 to 2013 was undertaken. Charts were reviewed, and imaging and operative data were collected for patients with and without NVC. Mean, median, and the empirical cumulative distribution of onset age were determined. Statistical analysis was performed using Student t-test, Wilcoxon and Kolmogorov-Smirnoff tests, and Kaplan-Meier analysis. Multivariate analysis was performed using a Cox proportional hazards model. RESULTS: The charts of 219 patients with TN were reviewed. There were 156 patients who underwent posterior fossa exploration and microvascular decompression or internal neurolysis: 129 patients with NVC and 27 without NVC. Mean age at symptoms onset for patients with and without NVC was 51.1 and 42.6 years, respectively. This difference (8.4 years) was significant (t test: p = 0.007), with sufficient power to detect an effect size of 8.2 years. Median age between groups with and without NVC was 53.25 and 41.2 years, respectively (p = 0.003). Histogram analysis revealed a bimodal age at onset in patients without NVC, and cumulative distribution of age at onset revealed an earlier presentation of symptoms (p = 0.003) in patients without NVC. Chi-square analysis revealed a trend toward female predominance in patients without NVC, which was not significant (p = 0.08). Multivariate analysis revealed that age at onset was related to NVC but not sex, symptom side or distribution, or patient response to medical treatment. CONCLUSIONS: NVC is neither sufficient nor necessary for the development of TN. Patients with TN without NVC may represent a distinct population of younger, predominantly female patients. Further research into the pathophysiology underlying this debilitating disease is needed. PMID- 26047412 TI - Intraoperative subcortical motor evoked potential stimulation: how close is the corticospinal tract? AB - OBJECT: Subcortical stimulation is a method used to evaluate the distance from the stimulation site to the corticospinal tract (CST) and to decide whether the resection of an adjacent lesion should be terminated to prevent damage to the CST. However, the correlation between stimulation intensity and distance to the CST has not yet been clearly assessed. The objective of this study was to investigate the appropriate correlation between the subcortical stimulation pattern and the distance to the CST. METHODS: Monopolar subcortical motor evoked potential (MEP) mapping was performed in addition to continuous MEP monitoring in 37 consecutive patients with lesions located in motor-eloquent locations. The proximity of the resection cavity to the CST was identified by subcortical MEP mapping. At the end of resection, the point at which an MEP response was still measurable with minimal subcortical MEP intensity was marked with a titanium clip. At this location, different stimulation paradigms were executed with cathodal or anodal stimulation at 0.3-, 0.5-, and 0.7-msec pulse durations. Postoperatively, the distance between the CST as defined by postoperative diffusion tensor imaging fiber tracking and the titanium clip was measured. The correlation between this distance and the subcortical MEP electrical charge was calculated. RESULTS: Subcortical MEP mapping was successful in all patients. There were no new permanent motor deficits. Transient new postoperative motor deficits were observed in 14% (5/36) of cases. Gross-total resection was achieved in 75% (27/36) and subtotal resection (> 80% of tumor mass) in 25% (9/36) of cases. Stimulation intensity with various pulse durations as well as current intensity was plotted against the measured distance between the CST and the titanium clip on postoperative MRI using diffusion-weighted imaging fiberitracking tractography. Correlational and regression analyses showed a nonlinear correlation between stimulation intensity and the distance to the CST. Cathodal stimulation appeared better suited for subcortical stimulation. CONCLUSIONS: Subcortical MEP mapping is an excellent intraoperative method to determine the distance to the CST during resection of motor-eloquent lesions and is highly capable of further reducing the risk of a new neurological deficit. PMID- 26047413 TI - Correlation of high delta-like ligand 4 expression with peritumoral brain edema and its prediction of poor prognosis in patients with primary high-grade gliomas. AB - OBJECT: Peritumoral brain edema (PTBE) is a common phenomenon associated with high-grade gliomas (HGGs). In this study, the authors investigated the expression of Notch delta-like ligand 4 (DLL4) and its correlation with PTBE and prognosis in patients with an HGG. METHODS: Tumors from 99 patients with HGG were analyzed for DLL4 expression using immunohistochemistry. PTBE on preoperative MR images and the relationship between PTBE and DLL4 expression were evaluated. The effect of DLL4 on patient prognosis was assessed by using Kaplan-Meier survival and Cox proportional hazard models. RESULTS: Immunohistochemistry results revealed that the expression of DLL4 was distributed primarily within the cytoplasm of tumor vascular endothelial cells and seldom detected in tumor cells. DLL4 expression was correlated positively with the degree of edema (r = 0.845 and p < 0.001, Spearman's test). In addition, DLL4 was an independent predictor of prognosis in patients with HGGs (p = 0.001). CONCLUSIONS: DLL4 expression was correlated positively with the degree of PTBE and was an independent unfavorable prognostic indicator in patients with HGG. PMID- 26047414 TI - Real-time ultrasound-guided endoscopic surgery for putaminal hemorrhage. AB - OBJECT: Endoscopic surgery plays a significant role in the treatment of intracerebral hemorrhage. However, the residual hematoma cannot be measured intraoperatively from the endoscopic view, and it is difficult to determine the precise location of the endoscope within the hematoma cavity. The authors attempted to develop real-time ultrasound-guided endoscopic surgery using a bur hole-type probe. METHODS: From November 2012 to March 2014, patients with hypertensive putaminal hemorrhage who underwent endoscopic hematoma removal were enrolled in this study. Real-time ultrasound guidance was performed with a bur hole-type probe that was advanced via a second bur hole, which was placed in the temporal region. Ultrasound was used to guide insertion of the endoscope sheath as well as to provide information regarding the location of the hematoma during surgical evacuation. Finally, the cavity was irrigated with artificial cerebrospinal fluid and was observed as a low-echoic space, which facilitated detection of residual hematoma. RESULTS: Ten patients with putaminal hemorrhage>30 cm3 were included in this study. Their mean age (+/-SD) was 60.9+/ 8.6 years, and the mean preoperative hematoma volume was 65.2+/-37.1 cm3. The mean percentage of hematoma that was evacuated was 96%+/-3%. None of the patients exhibited rebleeding after surgery. CONCLUSIONS: This navigation method was effective in demonstrating both the real-time location of the endoscope and real time viewing of the residual hematoma. Use of ultrasound guidance minimized the occurrence of brain injury due to hematoma evacuation. PMID- 26047415 TI - Unilateral contrast-enhancing pontomedullary lesion due to an intracranial dural arteriovenous fistula with perimedullary spinal venous drainage: the exception that proves the rule. AB - A large spectrum of possible diagnoses must be taken into consideration when a contrast-enhancing lesion of the pontomedullary region is found on MRI. Among these diagnoses are neoplastic, inflammatory, and infectious, as well as vascular pathologies. The authors report a rare case of an intracranial dural arteriovenous fistula (DAVF) with perimedullary spinal venous drainage (Cognard Type V) that initially presented as a unilateral contrast-enhancing pontomedullary lesion mimicking a brainstem neoplasm in a 76-year-old man. Following occlusion of the DAVF by transarterial embolization that resulted in clinical and radiological improvement, the fistula recurred 10 months later and was finally cured by a combined endovascularand surgical approach that resulted in complete occlusion. Clinical symptoms and MRI findings gradually improved following this treatment. A literature review on the MRI findings of Cognard Type V DAVF was performed. Centrally located medullary or pontomedullary edema represents the typical imaging finding, while unilateral edema as seen in the authors' patient is exceptionally rare. The hallmark imaging finding suggestive of DAVF consisting of perimedullary engorged vessels may not always be present or may only be very subtly visible. Therefore, the authors suggest performing contrast-enhanced MR angiography or even digital subtraction angiography in the presence of an unclear edematous brainstem lesion before scheduling stereotactic biopsy. PMID- 26047416 TI - An unusual complication of atrial fibrillation ablation: case report. AB - The authors report a complication of catheter ablation that, to their knowledge, has never been previously reported. A 63-year-old man had undergone successful transvenous catheter thermoablation for atrial fibrillation. The patient remained well until 3 days prior to further admission when he noticed itching in the right frontal area of his scalp. On palpating his scalp, he discovered a metallic body projecting out of it and he proceeded to extract 20 cm of wire from his head. The following day a progressive left hemiplegia developed, and the patient experienced a deteriorating level of consciousness. A CT scan of the brain showed a right frontotemporal intraparenchymal hemorrhage and revealed a metallic structure in the middle of the hematoma. The hematoma was evacuated and a decompressive craniotomy was performed. The guidewire was identified, but it was only possible to extract part of it. It was covered by fibrous tissue, secondary to inflammatory reaction. To the authors' knowledge, this is the first report of guidewire-induced brain hemorrhage. The guidewire apparently had not been removed and had spontaneously migrated from the heart to the brain and beyond to the scalp where it then exited the patient's head. The patient had been well before he attempted to pull out the wire. Earlier identification of the iatrogenic complication of a retained guidewire might have prevented the fatal outcome in this case. PMID- 26047417 TI - Posterior callosotomy using a parietooccipital interhemispheric approach in the semi-prone park-bench position. AB - A 2-stage corpus callosotomy is accepted as a palliative procedure for patients older than 16 years with, in particular, medically intractable generalized epilepsy and drop attack seizures and is preferable for a lower risk of disconnection syndrome. Although the methods by which a previously performed craniotomy can be reopened for posterior callosotomy have already been reported, posterior corpus callosotomy using a parietooccipital interhemispheric approach with the patient in a semi-prone park-bench position has not been described in the literature. Here, the authors present a surgical technique for posterior callosotomy using a parietooccipital interhemispheric approach with a semi-prone park-bench position as a second surgery. Although this procedure requires an additional skin incision in the parietooccipital region, it makes the 2-stage callosotomy safer and easier to perform because of reduced intracranial adhesion, less bleeding, and an easier approach to the splenium of the corpus callosum. PMID- 26047418 TI - Pure neuritic leprosy presenting as ulnar nerve neuropathy: a case report of electrodiagnostic, radiographic, and histopathological findings. AB - Hansen's disease, or leprosy, is a chronic infectious disease with many manifestations. Though still a major health concern and leading cause of peripheral neuropathy in the developing world, it is rare in the United States, with only about 150 cases reported each year. Nevertheless, it is imperative that neurosurgeons consider it in the differential diagnosis of neuropathy. The causative organism is Mycobacterium leprae, which infects and damages Schwann cells in the peripheral nervous system, leading first to sensory and then to motor deficits. A rare presentation of Hansen's disease is pure neuritic leprosy. It is characterized by nerve involvement without the characteristic cutaneous stigmata. The authors of this report describe a case of pure neuritic leprosy presenting as ulnar nerve neuropathy with corresponding radiographic, electrodiagnostic, and histopathological data. This 11-year-old, otherwise healthy male presented with progressive right-hand weakness and numbness with no cutaneous abnormalities. Physical examination and electrodiagnostic testing revealed findings consistent with a severe ulnar neuropathy at the elbow. Magnetic resonance imaging revealed diffuse thickening and enhancement of the ulnar nerve and narrowing at the cubital tunnel. The patient underwent ulnar nerve decompression with biopsy. Pathology revealed acid-fast organisms within the nerve, which was pathognomonic for Hansen's disease. He was started on antibiotic therapy, and on follow-up he had improved strength and sensation in the ulnar nerve distribution. Pure neuritic leprosy, though rare in the United States, should be considered in the differential diagnosis of those presenting with peripheral neuropathy and a history of travel to leprosy-endemic areas. The long incubation period of M. leprae, the ability of leprosy to mimic other conditions, and the low sensitivity of serological tests make clinical, electrodiagnostic, and radiographic evaluation necessary for diagnosis. Prompt diagnosis and treatment is imperative to prevent permanent neurological injury. PMID- 26047419 TI - Editorial: More on the clip versus coil controversy. PMID- 26047420 TI - Longitudinal evaluation of corticospinal tract in patients with resected brainstem cavernous malformations using high-definition fiber tractography and diffusion connectometry analysis: preliminary experience. AB - OBJECT: Brainstem cavernous malformations (CMs) are challenging due to a higher symptomatic hemorrhage rate and potential morbidity associated with their resection. The authors aimed to preoperatively define the relationship of CMs to the perilesional corticospinal tracts (CSTs) by obtaining qualitative and quantitative data using high-definition fiber tractography. These data were examined postoperatively by using longitudinal scans and in relation to patients' symptomatology. The extent of involvement of the CST was further evaluated longitudinally using the automated "diffusion connectometry" analysis. METHODS: Fiber tractography was performed with DSI Studio using a quantitative anisotropy (QA)-based generalized deterministic tracking algorithm. Qualitatively, CST was classified as being "disrupted" and/or "displaced." Quantitative analysis involved obtaining mean QA values for the CST and its perilesional and nonperilesional segments. The contralateral CST was used for comparison. Diffusion connectometry analysis included comparison of patients' data with a template from 90 normal subjects. RESULTS: Three patients (mean age 22 years) with symptomatic pontomesencephalic hemorrhagic CMs and varying degrees of hemiparesis were identified. The mean follow-up period was 37.3 months. Qualitatively, CST was partially disrupted and displaced in all. Direction of the displacement was different in each case and progressively improved corresponding with the patient's neurological status. No patient experienced neurological decline related to the resection. The perilesional mean QA percentage decreases supported tract disruption and decreased further over the follow-up period (Case 1, 26%-49%; Case 2, 35%-66%; and Case 3, 63%-78%). Diffusion connectometry demonstrated rostrocaudal involvement of the CST consistent with the quantitative data. CONCLUSIONS: Hemorrhagic brainstem CMs can disrupt and displace perilesional white matter tracts with the latter occurring in unpredictable directions. This requires the use of tractography to accurately define their orientation to optimize surgical entry point, minimize morbidity, and enhance neurological outcomes. Observed anisotropy decreases in the perilesional segments are consistent with neural injury following hemorrhagic insults. A model using these values in different CST segments can be used to longitudinally monitor its craniocaudal integrity. Diffusion connectometry is a complementary approach providing longitudinal information on the rostrocaudal involvement of the CST. PMID- 26047421 TI - Early noninvasive brain stimulation after severe TBI. PMID- 26047422 TI - Obesity and hypogonadism are associated with an increased risk of predominant Gleason 4 pattern on radical prostatectomy specimen. AB - PURPOSE: To compare histological features of prostate cancer according to both obesity, defined by a body mass index (BMI) >=30 kg/m2, and androgenic status in patients who underwent radical prostatectomy. MATERIALS AND METHODS: Between March 2007 and September 2013, clinical, pathological and biological data were prospectively collected for patients referred for radical prostatectomy in a single European center. Preoperative total testosterone (TT) and bioavailable testosterone (bioT) serum determinations were performed. The threshold for hypogonadism was set at TT <3 ng/mL. The preoperative PSA value was registered. Gleason score (GS) and predominant Gleason pattern (PrdGP) were determined in prostate tissue specimens, and crosschecked by two uro-pathologists. Statistical analyzes were done for PrdGP4 risk assessment. RESULTS: A total of 937 consecutive patients were included. One hundred and thirty-five filled the criterion for obesity (14.4%), out of which 42 had TT <3 ng/mL (31.1%), while in non-obese patients, only 97 had TT <3 ng/mL (12.0%). In prostate specimens, mean GS was 6.8+/-0.5: 291 patients (31.1%) had a PrdGP4. The incidence of PrdGP4 was higher (p<0.001) in the 135 obese patients [50% when hypogonadal (p<0.02) or 42% when eugonadal (p<0.005)] than in non-obese patients (28.9% and 27.1%, respectively). In multivariable analyzis for PrdGP4 risk, obesity, TT <3 ng/mL, PSA, and age were independent risk factors. CONCLUSIONS: Both obesity and hypogonadism are independent risk factors for PrdGP4 in patients who underwent radical prostatectomy and should be taken into account in localized prostate cancer management, to improve the therapeutic choice, especially when prostate sparing approach is considered. PMID- 26047423 TI - Chemical composition and functional properties of raw and roasted Nigerian benniseed (Sesamum indicum) and bambara groundnut (Vigna subterranean). AB - Benniseed and bambara groundnut seeds were roasted at 80 and 120 degrees C for 10 60min. For both flours, the effects of roasting temperature and time on selected functional properties and chemical composition were determined, as were the effects of pH on the emulsification capacity and nitrogen solubility. The chemical constituents of the raw flours were present at higher concentrations than those of the roasted flours except for fat and ash. Protein concentrates of both flours contained 80.5-81.5% crude protein as the major constituent. Nitrogen solubility was lowest at pH 4.0 for raw and roasted benniseed flour and pH 5.0 for raw and roasted bambara groundnut flour. Roasting generally lowered the nitrogen solubility and increased the water and oil absorption capacities while decreasing the foaming capacity and emulsification capacity of both flours. PMID- 26047424 TI - Lactulose production from milk concentration permeate using calcium carbonate based catalysts. AB - Milk concentration permeate (MCP), a low-value by-product of ultrafiltration plants and calcium carbonate-based catalysts were used for lactulose production. The results obtained show the effectiveness of oyster shell powder and limestone for lactose isomerisation as a replacement for egg shell powder. With the reaction conditions of 12mg/ml catalyst loading, reflux time of 120min at 96 degrees C, a maximum yield of 18-21% lactulose was achievable at a cost of <50% of original lactose degradation (measured by HPLC). De-proteination of MCP by acidification prior to isomerisation helped lactulose formation in the earlier stages, but did not significantly increase the yield. The resulting lactulose MCP (40 degrees B) incorporated at the rate of 3-4% was effective in enhancing the growth rate and acid production of Lactobacillus acidophilus (LA-5) in probiotic products. PMID- 26047425 TI - Enzymatic preparation of chitooligosaccharides by commercial lipase. AB - The effect of a commercial lipase on chitosan degradation was investigated. When four chitosans with various degrees of deacetylation were used as substrates, the lipase showed higher optimal pH toward chitosan with higher DD (degree of deacetylation). The optimal temperature of the lipase was 55 degrees C for all chitosans. The enzyme exhibited higher activity to chitosans which were 82.8% and 73.2% deacetylated. Kinetics experiments show that chitosans with DD of 82.8% and 73.2% which resulted in lower Km values had stronger affinity for the lipase. The chitosan hydrolysis carried out at 37 degrees C produced larger quantity of COS (chitooligosaccharides) than that at 55 degrees C when the reaction time was longer than 6h, and COS yield of 24h hydrolysis at 37 degrees C was 93.8%. Products analysis results demonstrate that the enzyme produced glucosamine and chitooligosaccharides with DP (degree of polymerization) of 2-6 and above, and it acted on chitosan in both exo- and endo-hydrolytic manner. PMID- 26047426 TI - Collagen from common minke whale (Balaenoptera acutorostrata) unesu. AB - Collagen was prepared from common minke whale unesu and characterised. The yield of collagen was high, about 28.4% on a wet weight basis. By SDS-PAGE and CM Toyopearl 650M column chromatography, the collagen was classified as type I collagen. The denaturation temperature of the collagen was 31.5 degrees C, about 6-7 degrees C lower than that of porcine collagen. Attenuated total reflectance FTIR analysis indicated that acid-soluble collagen from common minke whale unesu held its triple helical structure well, but the structures of porcine skin collagen and pepsin-solubilized collagen from common minke whale unesu were changed slightly, due to the loss of N- and C-terminus domains. PMID- 26047427 TI - Purification and identification of a ACE inhibitory peptide from oyster proteins hydrolysate and the antihypertensive effect of hydrolysate in spontaneously hypertensive rats. AB - Oyster (Crassostrea talienwhanensis Crosse) proteins were produced from fresh oyster and subsequently digested with pepsin. The separations were performed with a Sephadex LH-20 gel filtration chromatography and a RP-HPLC. A purified peptide with sequence Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe (VVYPWTQRF) was firstly isolated and characterized from oyster protein hydrolysate and its ACE inhibitory activity was determined with IC50 value of 66MUmol/L in vitro. Stability study for ACE inhibitory activity showed that the isolated nonapeptide had the good heat and pH stability and strong enzyme-resistant properties against gastrointestinal proteases. Kinetic experiments demonstrated that inhibitory kinetic mechanism of this peptide was non-competitive and its Km and Ki values were calculated. The yield of this peptide from oyster proteins was 8.5%. Furthermore, the oyster protein hydrolysate (fraction II), prepared by pepsin treatment firstly exhibited antihypertensive activity when it was orally administered to spontaneously hypertensive rat (SHR) at a dose of 20mg/kg. These results demonstrated that the hydrolysate from oyster proteins prepared by pepsin treatment could serve as a source of peptides with antihypertensive activity. PMID- 26047428 TI - Study of the effect of 'Ataulfo' mango (Mangifera indica L.) intake on mammary carcinogenesis and antioxidant capacity in plasma of N-methyl-N-nitrosourea (MNU) treated rats. AB - The effect of 'Ataulfo' mango consumption on chemically induced mammary carcinogenesis and plasma antioxidant capacity in rats treated with N-methyl-N nitrosourea (MNU) was studied. Mango was administered in the drinking water (0.02 0.06g/mL) during both short-term and long-term (LT) periods to rats treated or not with MNU. Rats treated with MNU showed no differences in mammary carcinogenesis or in plasma antioxidant capacity measured by both ferric reducing/antioxidant power (FRAP) and total oxyradical scavenging capacity assays. However, in animals not treated with MNU but with a LT intake of mango the plasma antioxidant capacity as measured by the FRAP assay tended to increase in a dose-dependent manner. This suggests that mango consumption by healthy subjects may increase antioxidants in plasma. PMID- 26047429 TI - In vitro starch digestibility, expected glycemic index, and thermal and pasting properties of flours from pea, lentil and chickpea cultivars. AB - In vitro starch digestibility, expected glycemic index (eGI), and thermal and pasting properties of flours from pea, lentil and chickpea grown in Canada under identical environmental conditions were investigated. The protein content and gelatinization transition temperatures of lentil flour were higher than those of pea and chickpea flours. Chickpea flour showed a lower amylose content (10.8 13.5%) but higher free lipid content (6.5-7.1%) and amylose-lipid complex melting enthalpy (0.7-0.8J/g). Significant differences among cultivars within the same species were observed with respect to swelling power, gelatinization properties, pasting properties and in vitro starch digestibility, especially chickpea flour from desi (Myles) and kabuli type (FLIP 97-101C and 97-Indian2-11). Lentil flour was hydrolyzed more slowly and to a lesser extent than pea and chickpea flours. The amount of slowly digestible starch (SDS) in chickpea flour was the highest among the pulse flours, but the resistant starch (RS) content was the lowest. The eGI of lentil flour was the lowest among the pulse flours. PMID- 26047430 TI - Comparative study on volatile compounds from Tunisian and Sicilian monovarietal virgin olive oils. AB - The effects of ripening degree of olives on volatile profile of monovarietal virgin olive oils (VOO) from Tunisian and Sicilian cultivars were investigated. Fruits obtained from Tunisia (Chetoui and Chemlali) and Italy (Nocellara del Belice, Biancolilla and Cerasuola) were picked at three different stages of ripeness and then immediately processed. Moreover, the changes in volatile composition were evaluated in Chetoui variety as a function of the irrigation regime versus the rain-fed control. Using headspace-solid-phase microextraction (HS-SPME) technique coupled to GC-MS and GC-FID, the volatile compounds of the monovarietal virgin olive oils were identified and quantitatively analyzed. The proportions of different classes of volatiles of oils showed significant differences throughout the maturity process. The results suggest that adding to the genetic factor; agronomic conditions affect the volatile formation and therefore the organoleptic properties of VOO. PMID- 26047431 TI - Effects of -1.5 degrees C Super-chilling on quality of Atlantic salmon (Salmo salar) pre-rigor Fillets: Cathepsin activity, muscle histology, texture and liquid leakage. AB - The aim of this study was to evaluate the impact of super-chilling on the quality of Atlantic salmon (Salmo salar) pre-rigor fillets. The fillets were kept for 45min in a super-chilling tunnel at -25 degrees C with an air speed in the tunnel at 2.5m/s, to reach a fillet core temperature of -1.5 degrees C, prior to ice storage in a cold room for 4 weeks. Super-chilling seemed to form intra- and extracellular ice crystals in the upper layer of the fillets and prevent myofibre contraction. Lysosome breakages followed by release of cathepsin B and L during storage and myofibre-myofibre detachments were accelerated in the super-chilled fillets. Super-chilling resulted in higher liquid leakage and increased myofibre breakages in the fillets, while texture values of fillets measured instrumentally were not affected by super-chilling one week after treatment. Optimisation of the super-chilling technique is needed to avoid the formation of ice crystals, which may cause irreversible destruction of the myofibres, in order to obtain high quality products. PMID- 26047432 TI - Optimization of the production of Momordica charantia L. Var. abbreviata Ser. protein hydrolysates with hypoglycemic effect using Alcalase. AB - Momordica charantia L. Var. abbreviata Ser. protein was hydrolyzed using six different proteases. The results showed Alcalase 2.4L to have the best hydrolyzing capacity, followed by Pancreatin. In addition, Alcalase hydrolysate had stronger hypoglycemic effect than that of Pancreatin hydrolysate at the same dose. Alcalase was chosen to produce M. charantia L. Var. abbreviata Ser. protein hydrolysates (MCPHs) with hypoglycemic effect. Response surface methodology (RSM) was applied to optimize the hydrolysis conditions using Alcalase. Model equation was proposed with regard to the effect of enzyme/substrate ratio, pH and temperature. The optimum values for enzyme/substrate ratio, pH and temperature were found to be 2.37%, 9.2 and 57 degrees C respectively. PMID- 26047433 TI - Purification and characterisation of multiple forms of polygalacturonase from mango (Mangifera indica cv. Dashehari) fruit. AB - Three multiple forms of polygalacturonase (PG) namely PGI, PGII and PGIII were isolated, purified and characterized from ripe mango (Mangifera indica cv. Dashehari) fruit. Native molecular weights of PGI, PGII and PGIII were found to be 120, 105 and 65kDa, respectively. On SDS-PAGE analysis, PGI was found to be a homodimer of subunit size 60kDa each while those of PGII and PGIII were found to be heterodimers of 70, 35 and 38, 27kDa subunit size each, respectively. Three isoforms of PG differed with respect to the effect of pH, metals, reducing agents and their susceptibility towards heat. PG isoforms also differed with respect to the effect of substrate concentration on enzyme activity. PGI and PGIII exhibited inhibition at high substrate concentration while PGII did not. Km for polygalacturonic acid was found to be 0.02% for PGI. PMID- 26047434 TI - Angiotensin I-converting enzyme (ACE) inhibitory activities of sardinelle (Sardinella aurita) by-products protein hydrolysates obtained by treatment with microbial and visceral fish serine proteases. AB - The angiotensin I-converting enzyme (ACE) inhibitory activities of protein hydrolysates prepared from heads and viscera of sardinelle (Sardinella aurita) by treatment with various proteases were investigated. Protein hydrolysates were obtained by treatment with Alcalase((r)), chymotrypsin, crude enzyme preparations from Bacillus licheniformis NH1 and Aspergillus clavatus ES1, and crude enzyme extract from sardine (Sardina pilchardus) viscera. All hydrolysates exhibited inhibitory activity towards ACE. The alkaline protease extract from the viscera of sardine produced hydrolysate with the highest ACE inhibitory activity (63.2+/ 1.5% at 2mg/ml). Further, the degrees of hydrolysis and the inhibitory activities of ACE increased with increasing proteolysis time. The protein hydrolysate generated with alkaline proteases from the viscera of sardine was then fractionated by size exclusion chromatography on a Sephadex G-25 into eight major fractions (P1-P8). Biological functions of all fractions were assayed, and P4 was found to display a high ACE inhibitory activity. The IC50 values for ACE inhibitory activities of sardinelle by-products protein hydrolysates and fraction P4 were 1.2+/-0.09 and 0.81+/-0.013mg/ml, respectively. Further, P4 showed resistance to in vitro digestion by gastrointestinal proteases. The amino acid analysis by GC/MS showed that P4 was rich in phenylalanine, arginine, glycine, leucine, methionine, histidine and tyrosine. The added-value of sardinelle by products may be improved by enzymatic treatment with visceral serine proteases from sardine. PMID- 26047435 TI - Characterisation and immunostimulatory activity of an alpha-(1->6)-d-glucan from the cultured Armillariella tabescens mycelia. AB - IPS-B2, an intracellular polysaccharide with anti-tumor effect, was isolated from cultured Armillariella tabescens mycelia by hot water extraction, anion-exchange and gel chromatography. Based on the results of paper chromatography (PC), gas chromatography (GC), infra-red (IR) spectroscopy and (13)C NMR, IPS-B2 was characterized as an alpha-(1->6)-d-glucan with a molecular weight of 49.5kDa. The effects of IPS-B2 on murine peritoneal macrophages were further investigated. The results demonstrated that IPS-B2 induced nitric oxide (NO) and cytokines (TNF alpha, IL-1beta and IL-6) production in macrophages. The outcomes of real-time reverse transcription-polymerase chain reaction (RT-PCR) proved that the transcribing level of inducible NO synthase (iNOS), TNF-alpha, IL-1beta and IL-6 mRNA in the peritoneal macrophages have been augmented by IPS-B2. These data suggest that the anti-tumor activity of the polysaccharide from A. tabescens may due to activation of macrophage. PMID- 26047436 TI - Attenuated effects of peptides derived from porcine plasma albumin on in vitro lipid peroxidation in the liver homogenate of mice. AB - Porcine plasma albumin was hydrolyzed with alcalase available for industrial application, and attenuated effects of peptides were evaluated using 4 Nitroquiunoline 1-oxide (4-NQO) as an inducing reagent. 4-NQO is a potent oral carcinogen, which has been found to induce lipid peroxidation in vivo and in vitro. Our results indicated that addition of 4-NQO resulted in increase of hydroxyl and superoxide radicals, glutathione peroxidase (GPx) activity and levels of malondialdehyde (MDA), and decrease in activities of superoxide dismutase (SOD) and catalase (CAT) and levels of glutathione (GSH). Simultaneous addition of peptides significantly attenuated lipid peroxidation. The lowermost molecular weight (MW) peptide fractions (<3kDa) had the highest activity. This study also demonstrated that the attenuated effects of peptides might be due to the protective interactions between cells and peptides rather than the direct inhibition of 4-NQO by peptides. The results of this study showed the potential of utilizing porcine plasma albumin as a source of functional peptides. PMID- 26047437 TI - Antioxidant activity of peptides isolated from alfalfa leaf protein hydrolysate. AB - Alfalfa leaf protein, a potential source of high quality protein for human consumption, was hydrolyzed with protease. Alfalfa leaf protein hydrolysate was fractionated by ultrafiltration and the obtained peptides were purified by dynamical adsorption. The antioxidant activity of alfalfa leaf peptides (ALPs) was investigated and compared with that of a native antioxidant, reduced glutathione (GSH), which was used as a reference. The reducing power of ALPs was 0.69 at 2.00mg/mL. ALPs at 1.60mg/mL and 0.90mg/mL exhibited 79.71% and 67.00% of scavenging activities on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical and superoxide radical, respectively. In addition, ALPs showed 65.15% chelating effect on ferrous ion at 0.50mg/mL. The molecular weight of the peptides was determined and 67.86% of the total amount was below 1000Da. Combined with the result of the amino acid profiles, ALPs was believed to have high nutritive value in addition to antioxidant activity. PMID- 26047438 TI - The effect of thawing methods on the quality of eels (Anguilla anguilla). AB - Physical (colour), chemical (pH, total volatile basic nitrogen (TVB-N), thiobarbituric acid values (TBA)) and microbiological (total aerobic mesophylic bacteria, salmonella, coliform, yeast and mould counts) analyses were carried out on thawed European eel (Anguilla anguilla). Different thawing treatments were used (in a refrigerator, in water, in air at ambient temperature and in a microwave oven). The results obtained were compared statistically with those of fresh fish. pH, TBA and a(*) values of thawed samples usually decreased significantly (P<0.05) when compared to the fresh control. Salmonella was not detected in any of the samples. Coliform and mould counts of fresh control and thawed samples were <1CFU/g. Total aerobic mesophylic bacteria count of all thawed fish decreased. However, the yeast count of the refrigerator-thawed samples increased. The lowest total aerobic mesophylic bacteria and yeast counts were determined in water-thawed samples. Water thawing is therefore suitable for frozen eel. PMID- 26047439 TI - Influence of mussels (Mytilus galloprovincialis) from polluted and non-polluted areas on some atherosclerosis indices in rats fed cholesterol. AB - The influence of diets supplemented with mussels, from polluted (MPoll) and non polluted (MNPoll) areas, on some atherosclerosis indices in rats fed cholesterol (Chol) were studied. According to the results of our investigation in vitro, mussels from polluted areas had higher contents of proteins, metals and antioxidant compounds, mostly phenolics and higher antioxidant capacities. 28 male Wistar rats were divided into 4 groups of 7 and named Control, Chol, Chol/MPoll and Chol/MNPoll. The rats of the Control group received basal diet (BD) only, and the diets of the other 3 groups were supplemented with 1% of non oxidized cholesterol (NOC), 1% of NOC and 5.6% of mussel dry matter (DM) from polluted and 1% of NOC and 5.6% of mussel DM from non-polluted areas for Chol, Chol/MPoll and Chol/MNPoll, respectively. The histology of the aorta and brain in rats fed cholesterol did not show any signs of atherosclerosis. Some differences were registered in the electrophoretic protein patterns of plasma in rats, with mussel-supplemented diets. In full plasma electrophoretic patterns of the Chol/MPoll diet group more proteins were detected than in both Chol and Control groups, and the differences were significant. In conclusion, in groups of rats fed cholesterol with mussels supplementation, a significant hindering in the rise of plasma lipid levels and also hindering in the decrease of plasma antioxidant activity were registered. PMID- 26047440 TI - Influence of pre- and post-harvest factors and processing on the levels of furocoumarins in grapefruits (Citrus paradisi Macfed.). AB - The changes in the levels of three furocoumarins such as dihydroxybergamottin (DHB), paradisin A and bergamottin in Rio Red and Marsh White cultivars of grapefruits were monitored from November to May. The levels of DHB and bergamottin in both varieties of grapefruits decreased as the season progressed except for the bergamottin in Marsh White grapefruit. Influence of growing location, processing and storage on the levels of these compounds were also evaluated. Among the varieties the highest levels of DHB (2.266MUg/ml) and bergamottin (2.411MUg/ml) were found in Flame grapefruit grown in Florida. The highest level of paradisin A was found in Rio Red grapefruit grown in California and the lowest levels were observed in Rio Red grapefruit grown organically in Texas. Hand squeezed juice contained 1.98, 1.06 and 3.03-fold more DHB, paradisin A and bergamottin, respectively as compared to processed juice. The levels of furocoumarins showed a decreasing trend in all the juices with progress of storage. Levels of furocoumarins were more in cartons container than the cans and cardboard container juices. PMID- 26047441 TI - Organic acids composition of Cydonia oblonga Miller leaf. AB - Organic acid profiles of 36 Cydonia oblonga Miller leaf samples, from three different geographical origins of northern (Braganca and Carrazeda de Ansiaes) and central Portugal (Covilha), harvested in three collection months (June, August and October of 2006), were determined by HPLC/UV (214nm). Quince leaves presented a common organic acid profile, composed of six constituents: oxalic, citric, malic, quinic, shikimic and fumaric acids. C. oblonga leaves total organic acid content varied from 1.6 to 25.8g/kg dry matter (mean value of 10.5g/kg dry matter). Quinic acid was the major compound (72.2%), followed by citric acid (13.6%). Significant differences were found in malic and quinic acids relative abundances and total organic acid contents according to collection time, which indicates a possible use of these compounds as maturity markers. Between June and August seems to be the best period to harvest quince leaves for preparation of decoctions or infusions, since organic acids total content is higher in this season. PMID- 26047442 TI - Antioxidant activity and proline content of leaf extracts from Dorystoechas hastata. AB - Dorystoechas hastata (D. hastata) is a monotypic plant endemic to Antalya province of Turkey. D. hastata leaves are used to make a tea locally called "calba tea". Diethyl ether (E), ethanol (A), and water (W) were used for the sequential preparation of extracts from dried D. hastata leaves. A hot water extract (S) was also prepared by directly boiling the powdered plant in water. The antioxidant activities of the extracts were tested by ferric thiocyanate (FTC) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging methods. E extract exhibited the greatest antioxidant activity with FTC method, whereas S extract exhibited the lowest IC50 value (6.17+/-0.53MUg/ml) for DPPH radical scavenging activity. Total phenolic contents of the extracts were estimated by Folin-Ciocalteu method and S extract was found to contain the highest amount (554.17+/-20.83mg GAE/g extract) of phenolics. Extract A contained highest flavonoid content and there was a inverse linear correlation (R(2)=0.926) between IC50 values for DPPH radical scavenging activity and flavonoid contents of all extracts. Reducing power of extracts increased in a concentration-dependent manner. S extract was found to possess higher reducing power than equivalent amount of ascorbic acid at 20 and 25MUg/ml concentrations. Linear correlation between reducing power and concentration of E, A, and W extracts (R(2)>0.95) was observed. A, W, and S extracts contained relatively high levels of proline. The results presented suggest that D. hastata may provide a natural source of antioxidants and proline. PMID- 26047443 TI - The novel trypsin Y from Atlantic cod (Gadus morhua) - isolation, purification and characterisation. AB - This report describes the isolation and partial characterization of the novel group III trypsin Y from the pyloric caeca of Atlantic cod. Other Atlantic cod trypsins have been used as food processing aids with good results. Trypsin Y was purified by p-aminobenzamidine affinity chromatography and characterized by SDS PAGE and western blot analysis, as well as by activity measurements towards synthetic substrates. Identification of trypsin Y was done with polyclonal antibodies raised towards the recombinant form of the enzyme and by MALDI-TOF mass spectrometry. Trypsin Y is the only group III trypsin isolated from its native source and characterized by biochemical methods. In accordance with the r trypsin Y, the native enzyme shows dual substrate specificity, i.e. towards trypsin and chymotrypsin specific substrates. This, along with the high cold adapted character of trypsin Y, may be valuable for its use as a processing aid for sensitive products such as seafood. PMID- 26047444 TI - Purification and characterisation of a hypoglycemic peptide from Momordica Charantia L. Var. abbreviata Ser. AB - A water-soluble peptide MC2-1-5 from Momordica charantia L. Var. Abbreviata Ser., with hypoglycemic effect, was purified by ultrafiltration, gel filtration chromatography and reverse-phase high performance liquid chromatography (RP HPLC). The infrared (IR) spectra showed characteristic absorption peaks and the molecular mass of MC2-1-5 was found to be 3405.5174Da by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The sequence of its first 10 N-terminal amino acids was GHPYYSIKKS as determined by a protein sequencer. MC2-1-5 reduced the blood glucose level in alloxan-induced diabetic mice by 61.70% and 69.18% at 2 and 4h, respectively, after oral administration at a dose of 2mg/kg. The oral glucose tolerance test (OGTT) showed MC2-1-5 produced a reduction of 25.50%, 39.62% and 41.74% in blood glucose level after 1, 2 and 3h, respectively, of oral administration compared with a diabetic control. PMID- 26047445 TI - Antioxidant activity of minor components of tree nut oils. AB - The antioxidative components of tree nut oils were extracted using a solvent stripping process. Tree nut oil extracts contained phospholipids, sphingolipids, sterols and tocopherols. The chloroform/methanol extracted oils had higher amounts of phenolic compounds than their hexane extracted counterparts. The antioxidant activity of tree nut oil minor component extracts were assessed using the 2,2-azino-bis (3-ethylbenzthiazoline sulphonate) (ABTS) radical scavenging activity, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging capacity, beta carotene bleaching test, oxygen radical absorbance capacity (ORAC) and photochemiluminescence inhibition assays. Results of these studies demonstrated that extracts of chloroform/methanol extracted oils possessed higher antioxidant activities than extracts of their hexane extracted counterparts. Meanwhile the extract of chloroform/methanol extracted pecan oil possessed the highest antioxidant activity. PMID- 26047446 TI - Purification, antitumor and antioxidant activities in vitro of polysaccharides from the brown seaweed Sargassum pallidum. AB - Supercritical CO2 extraction, ultrasonic-aid extraction and membrane separation technology were applied to prepare Sargassum pallidum polysaccharides (SP). Three main fractions, SP-1, SP-2 and SP-3, were obtained by membranes of 1.0*10(-4)mm pore size and normal molecular-weight cut-off of 50kDa. The resulting three preparations were further purified by DEAE Cellulose-52 chromatography to afford seven polysaccharide fractions. Furthermore, the antitumor and antioxidant activities, in vitro, of the polysaccharide fractions were evaluated by MTT (3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay and DPPH (2,2 diphenyl-1-picrylhydrazyl) free radical-scavenging assay, respectively. SP-3-1 and SP-3-2 showed significantly higher antitumor activity against the HepG2 cells, A549 cells, and MGC-803 cells. SP-3 had the highest sulfate content (22.6%). These results indicate that the higher antitumor activity of SP-3-1 and SP-3-2 from SP-3 with lower molecular weights may be related to their molecular weights and sulfate contents. The antioxidant activities of SP-1, SP-2 and SP-3 were low at the tested concentration. PMID- 26047447 TI - Antibacterial and anti-PAF activity of lipid extracts from sea bass (Dicentrarchus labrax) and gilthead sea bream (Sparus aurata). AB - The anti-PAF and the antibacterial activities of lipid extracts obtained from cultured sea bass (Dicentrarchus labrax) and cultured gilthead sea bream (Sparus aurata) were evaluated. Total lipids of sea bass and gilthead sea bream exerted PAF-like activity while, in higher amounts they inhibited this PAF activity. Neutral lipids of both sea bass and gilthead sea bream contained only PAF antagonists while the polar lipid fractions contained both PAF antagonists and agonists. Total lipids of sea bass exhibited stronger PAF-like activity than did those of gilthead sea bream; however, neutral lipids of sea bass contained stronger PAF antagonists than did gilthead sea bream. Total lipids of both sea bass and gilthead sea bream exhibited antibacterial activity only towards Staphylococcus aureus (S. aureus) with those of sea bass being more potent. Subsequently, neutral lipids of both sea bass and gilthead sea bream also showed antibacterial activity against S. aureus and less so towards Escherichia coli (E. coli), while only neutral lipids of sea bass showed antibacterial activity against Enterococcusfaecalis (E. faecalis). Sea bass neutral lipids were more active against S. aureus than were those of gilthead sea bream, while their activity towards E. coli was similar. Polar lipids of both sea bass and gilthead sea bream showed antibacterial activity against all bacteria strains. Sea bass polar lipids were more active towards S. aureus than were those of gilthead sea bream, while their activities against E. faecalis and E. coli were the same. The detected antibacterial activities of the lipid extracts isolated from sea bass and gilthead sea bream were observed in amounts equal to those that exerted either PAF inhibition or PAF-like activity, suggesting that PAF antagonists and agonists of fish lipids may be responsible for the antibacterial activity. PMID- 26047448 TI - Thermal stability of fish natural actomyosin affects reactivity to cross-linking by microbial and fish transglutaminases. AB - Natural actomyosin (NAM) from Pacific whiting (PW) showed thermal transition temperatures by circular dichroism at 31.8 and 43.1 degrees C, which were lower than those of threadfin bream (TB) NAM, 35.0 and 49.3 degrees C. Endothermic transitions of PW-NAM by differential scanning calorimetry were at 31.8, 42.1 and 75.3 degrees C, compared to 36.1, 50.9 and 78.4 degrees C for TB-NAM. Based on surface hydrophobicity, alpha-helical content, and solubility, PW-NAM unfolded to a greater extent than did TB-NAM when incubated at 25 degrees C for 4h and 40 degrees C for 2h, suggesting its lower thermal stability. Transglutaminase generally catalyzed more extensive cross-linking of PW-myosin heavy chain (MHC) than TB-MHC, and the MHC cross-linking mediated by microbial transglutaminase (MTG) was greater than by fish transglutaminase (FTG). Textural properties of PW NAM gels increased approximately 3.6-6.1-fold and 1.3-1.5-fold in the presence of MTG and FTG, respectively. PMID- 26047449 TI - Role of lees in wine production: A review. AB - The sometimes contradictory role attributed by scientists to lees in wine production is discussed in this review. Studies dealing with the importance of lees in the natural removal of undesirable compounds from wine, the effect of lees-wine contact on the volatile fraction of wines, the key influence of lees on biogenic amine contents in wines, the interactions between lees and phenolic compounds, and the importance of mannoproteins and lipids released by lees have been critically reviewed. Finally, the present exploitation of lees is also outlined. PMID- 26047450 TI - Authentication of "Cereza del Jerte" sweet cherry varieties by free zone capillary electrophoresis (FZCE). AB - The purpose of this work was to develop a procedure based on protein analysis by free zone capillary electrophoresis (FZCE) that can be used as an alternative to other methods in the determination of sweet cherry varieties for the authentication of "Cereza del Jerte". Two autochthonous varieties of sweet cherry type "Picota", 'Ambrunes' and 'Pico Negro', and the foreign variety 'Sweetheart' were used in the study. Two protocols for extracting the methanol-soluble proteins were tested. On the basis of the results, direct evaporation with nitrogen of a methanol extract was included in the extraction protocol for routine analysis. This method was found to give excellent repeatability of the corrected migration time (CMT), and showed greater effectiveness in discriminating sweet cherry varieties than the SDS-PAGE technique. Three peaks found in the FZCE electropherograms were investigated as a basis for discriminating between varieties. In addition, the FZCE analysis of methanol soluble proteins provides information about the physico-chemical parameters relevant to the sensorial quality of the sweet cherries. PMID- 26047451 TI - Determination of biogenic diamines with a vaporisation derivatisation approach using solid-phase microextraction gas chromatography-mass spectrometry. AB - A gas-phase on-fibre derivatisation method for the determination of putrescine and cadaverine by gas chromatography/mass spectrometry using trifluoroacetylacetone (TFAA) has been studied and optimised. Small amounts (2MUl) of putrescine, cadaverine and TFAA standards were vaporised at high temperature in a 20cm(3) closed SPME vial. The subsequent derivatives were recovered from the headspace of the vial using a PDMS/DVB fibre. The optimised mole ratio for [TFAA]/[Putrescine+Cadaverine] reaction was 22.3/1 with a derivatisation and extraction temperature of 120(o)C and an extraction time of 20min. The retention times for the derivatised putrescine and cadaverine were 20.5 and 22.2min, respectively on a capillary column, CP-Sil 8CB; 30m length*0.25mmi.d.*0.25MUm film thickness. The correlation coefficients (R(2)) of calibration curves for putrescine and cadaverine were 0.999 and 0.997, respectively over a range of sample masses of 20-350ng, using nonadecane as an internal standard. Putrescine and cadaverine recoveries were determined to be 93.9% and 103.3%, respectively. The method was found to be a straightforward single step procedure that was unaffected by complex sample matrices and was successfully tested on samples of meat, vegetables and cheese. PMID- 26047452 TI - Rapid analytical method for the determination of organic and inorganic species in tomato samples through HPLC-ICP-AES coupling. AB - A HPLC-inductively coupled plasma atomic emission spectrometer (ICP-AES) hyphenation technique was used to determine the concentration of some organic (i.e., carbohydrates, carboxylic acids) as well as inorganic (metals and anions) compounds in tomato samples. A high efficiency nebulizer (HEN) coupled to a low inner volume cyclonic spray chamber (Cinnabar) was used to interface both techniques. The HPLC-ICP-AES chromatograms for organic compounds were obtained by plotting the 193.03nm carbon emission intensity versus time. In the present work, it was also possible to obtain information about the concentration of several metals in foodstuffs. Finally, by registering the intensity at the sulphur and phosphorous emission wavelengths, the content of anions such as sulphate and phosphate was determined. In general terms, the results obtained with HPLC-ICP AES did not differ significantly from those found with a refractive index detector. Due to the huge amount of information provided by this hyphenation, it was possible to apply it to the discrimination among different samples of native tomato cultivars. PMID- 26047453 TI - Viability of an enzymatic mannitol method to predict sugarcane deterioration at factories. AB - The delivery of consignments of deteriorated sugarcane to factories can detrimentally affect multiple process units, and even lead to a factory shut down. An enzymatic factory method was used to measure mannitol, a major degradation product of sugarcane Leuconostoc deterioration in the US, in press (consignment) and crusher juices collected across the 2004 processing season at a Louisiana factory. Weather conditions varied markedly across the season causing periods of the delivery of deteriorated sugarcane to the factory. A strong polynomial relationship existed between mannitol and haze dextran (R(2)=0.912) in press and crusher juices. Mannitol concentrations were usually higher than haze and monoclonal antibody dextran concentrations, which indicates: (i) the usefulness and higher sensitivity of mannitol to better predict sugarcane deterioration from Leuconostoc and other bacteria than dextran, and (ii) the underestimation by sugar industry personnel of the relatively large amounts of mannitol present in deteriorated sugarcane that can affect processing. Greater than ~2500ppm/%Brix mannitol in juice predicts downstream processing problems. The enzymatic method is quantitative and could be used in a sugarcane payment formula. Approximately >300ppm/%Brix haze dextran in raw sugar indicated that the majority of the crystals were elongated. Approximately >600ppm/%Brix antibody dextran indicated when elongated crystals were predominant in the raw sugar. The enzymatic mannitol method underestimates mannitol in raw sugars. PMID- 26047454 TI - Estimation of the percentage of transgenic Bt maize in maize flour mixtures using perfusion and monolithic reversed-phase high-performance liquid chromatography and chemometric tools. AB - The estimation of the percentage of transgenic Bt maize in maize flour mixtures has been achieved in this work by high-performance liquid chromatography using perfusion and monolithic columns and chemometric analysis. Principal component analysis allowed a preliminary study of the data structure. Then, linear discriminant analysis was used to develop decision rules to classify samples in the established categories (percentages of transgenic Bt maize). Finally, linear regression (LR) and multivariate regression models (namely, principal component analysis regression (PCR), partial least squares regression (PLS-1), and multiple linear regression (MLR)) were assayed for the prediction of the percentages of transgenic Bt maize present in a maize flour mixture. Using the relative areas of the protein peaks, MLR provided the best models and was able to predict the percentage of transgenic Bt maize in flour mixtures with an error of +/-5.3%, +/ 2.3%, and +/-3.8% in the predictions of Aristis Bt, DKC6575, and PR33P67, respectively. PMID- 26047455 TI - Chemical characterisation of non-defective and defective green arabica and robusta coffees by electrospray ionization-mass spectrometry (ESI-MS). AB - The coffee roasted in Brazil is considered to be of low quality, due to the presence of defective coffee beans that depreciate the beverage quality. These beans, although being separated from the non-defective ones prior to roasting, are still commercialized in the coffee trading market. Thus, it was the aim of this work to verify the feasibility of employing ESI-MS to identify chemical characteristics that will allow the discrimination of Arabica and Robusta species and also of defective and non-defective coffees. Aqueous extracts of green (raw) defective and non-defective coffee beans were analyzed by direct infusion electrospray ionization mass spectrometry (ESI-MS) and this technique provided characteristic fingerprinting mass spectra that not only allowed for discrimination of species but also between defective and non-defective coffee beans. ESI-MS profiles in the positive mode (ESI(+)-MS) provided separation between defective and non-defective coffees within a given species, whereas ESI MS profiles in the negative mode (ESI(-)-MS) provided separation between Arabica and Robusta coffees. PMID- 26047456 TI - Chemiluminescence screening assay for diethylstilbestrol in meat. AB - A simple, rapid, and sensitive flow injection method with chemiluminescence detection was developed for the screening of meat samples containing diethylstilbestrol, based on the enhancement by diethylstilbestrol of the cerium(IV)-rhodamine 6G chemiluminescence system in sulfuric acid medium. Under the optimal conditions, the chemiluminescence intensity was linear for the diethylstilbestrol concentration in four types of meat (chicken, beef, mutton, and pork) matrix, with the linear ranges of CL detection more than three orders of magnitude and the detection limits (3sigma) in the range 0.75-1.12pg/mL. The relative standard deviations for intra-day and inter-day precision were less than 3.0%. The proposed method was found to be highly reliable for screening purpose and successfully applied to the screening of diethylstilbestrol residue in four types of meat samples, with the good quantitative recoveries for the different concentration levels varied from 93.1% to 104.5%. The mechanism of this chemiluminescence reaction has also been proposed. PMID- 26047457 TI - Determination of physicochemical properties of sulphated fucans from sporophyll of Undaria pinnatifida using light scattering technique. AB - The weight average molecular weight (Mw) of the intact sulphated fucans extracted with water from the sporophyll of Undaria pinnatifida without acid treatment was determined using the high performance size exclusion chromatography coupled to multiangle laser light scattering and refractive index detection (HPSEC-MALLS-RI) system. The effects of different heating conditions on the determination of Mw were investigated. The extracted intact fucoidans mostly consisted of carbohydrates (54.9%) and sulphate (41.5%) with monosaccharide composition of 78.8% fucose and 21.2% galactose. The Mw of the intact fucoidans was reduced from 23,600 to 5200kDa when heated in boiling water for 1-15min. Microwave heating for 30s decreased the Mw of fucoidans to 2400kDa despite no significant polymer degradation. The results indicate that the 30s-microwave heating yielded a more accurate Mw value of the intact fucoidans than any other heat treatments used in this study. PMID- 26047458 TI - Enzyme assisted extraction of luteolin and apigenin from pigeonpea [Cajanuscajan (L.) Millsp.] leaves. AB - Luteolin and apigenin are naturally occurring flavones with a wide spectrum of pharmacological properties. In the present study, enzyme assisted extraction of luteolin and apigenin from pigeonpea leaves using commercial plant cell wall degrading enzyme preparations including cellulase, beta-glucosidase and pectinase were examined. We found that pectinase offered a better performance in enhancement of the extraction yields of luteolin and apigenin than cellulase and beta-glucosidase. The pectinase assisted extraction process was further optimized by varying different parameters such as pectinase concentration, time of incubation, pH of pectinase solution, and incubation temperature. The optimum parameters were obtained as follows: 0.4mg/ml pectinase, incubation for 18h at 30 35 degrees C, pH of pectinase solution 3.5-4. Under the optimum conditions, the extraction yields of luteolin and apigenin achieved 0.268 and 0.132mg/g in pectinase treated sample, which increased 248% and 239%, respectively, compared with the untreated ones. PMID- 26047459 TI - The profile of volatile compounds and polyphenols in wines produced from dessert varieties of apples. AB - The aim of this study was to determine the influence of apple variety (Sampion, Idared and Gloster) on the polyphenol profile, volatile composition and sensory characteristics of apple wines. Apples were harvested from the orchard in Garlica Murowana (Poland) and the experiments were conducted on a laboratory scale. Statistically significant differences were detected in the chemical composition of the analyzed wines. The highest antioxidant activity was found in Sampion wines, which was associated with a relatively high concentration of chlorogenic acid and procyanidins. These samples also contained high amounts of acetaldehyde, ethyl acetate and methanol. Idared wines showed a similar polyphenol profile, but they had lower antioxidant capacity and were characterized by a high level of butanol and acetic acid. Gloster wines were distinguished from other samples by a lower concentration of polyphenols and higher concentration of fusel alcohols. During sensory evaluation, wines produced from Idared apples scored the highest value for overall quality. PMID- 26047460 TI - Determination of certain micro and macroelements in plant stimulants and their infusions. AB - The quantitative analysis of Al, B, Cu, Fe, Mn, P and Zn by inductively coupled plasma optical emission spectrometry (ICP-OES) and Ca, K and Mg by atomic absorption spectrometry (AAS) has been carried out in both the raw material and infusions from 31 samples of traditional plant stimulants (tea and coffee) and mate, rooibos, honeybush and chamomile. The results were discussed with respect to differences to the beverage quality and their role in the human diet. The levels of elements not significantly differ between tea types (black, green, oolong, white), and between Arabica and Robusta coffee. In comparison with tea, coffee was found to be a poor source of elements with the exception of Ca and Fe. High levels of B, Ca, Cu, Mn, Mg and Zn were found in mate (mainly green type) and of B, Ca, Cu, Fe and P in chamomile, whereas the amounts of all elements in rooibos and honeybush infusions were low (except of Ca). Apart from tea, other stimulants appeared to not represent important sources of potentially harmful amounts of Al for the human diet. PMID- 26047461 TI - Simultaneous characterisation and quantitation of flavonol glycosides and aglycones in noni leaves using a validated HPLC-UV/MS method. AB - The leaves of Morinda citrifolia L. (noni) have been utilized in a variety of commercial products marketed for their health benefits. This paper reports on a rapid and selective HPLC method for simultaneous characterization and quantitation of four flavonols in an ethanolic extract of noni leaves by using dual detectors of UV (365nm) and ESI-MS (negative mode). The limits of detection and quantitation were between 0.012 and 0.165MUg/mL. The intra- and inter-assay precisions, in terms of percent relative standard deviation, are less than 4.38% and 3.50%, respectively. The accuracy, in terms of recovery percentage, ranged from 96.66% to 100.03%. Good linearity (correlation coefficient >0.999) for each calibration curve of standards was achieved in the range investigated. The contents of four flavonoids in the noni leaves varied from 1.16 to 371.6mg/100g dry weight. PMID- 26047462 TI - Dynamic regulation of transcription factors by nucleosome remodeling. AB - The chromatin landscape and promoter architecture are dominated by the interplay of nucleosome and transcription factor (TF) binding to crucial DNA sequence elements. However, it remains unclear whether nucleosomes mobilized by chromatin remodelers can influence TFs that are already present on the DNA template. In this study, we investigated the interplay between nucleosome remodeling, by either yeast ISW1a or SWI/SNF, and a bound TF. We found that a TF serves as a major barrier to ISW1a remodeling, and acts as a boundary for nucleosome repositioning. In contrast, SWI/SNF was able to slide a nucleosome past a TF, with concurrent eviction of the TF from the DNA, and the TF did not significantly impact the nucleosome positioning. Our results provide direct evidence for a novel mechanism for both nucleosome positioning regulation by bound TFs and TF regulation via dynamic repositioning of nucleosomes. PMID- 26047464 TI - Synthesis and affinities of C3-symmetric thioglycoside-containing trimannosides. AB - Thioglycoside-containing trimannose analogs were designed and prepared to mimic the natural N-glycan core trisaccharide alpha-d-Man-(1->3)-[alpha-d-Man-(1->6)]-d Man. (1->6)-S-Linked trimannoside 1 and its trivalent cluster 2 were synthesized in 11 and 15 steps, respectively, taking advantages of the armed mannopyranosyl trichloroacetimidate as glycosyl donor. Hemagglutination inhibition of the two new thiomannotriose analogs was preliminarily examined. Comparing to the parent trimannoside alpha-d-Man-(1->3)-[alpha-d-Man-(1->6)]-d-Man-OMe, the cluster mannotrioside 2 presented a comparable binding affinity to Con A, while the monomer 6-S-trimannoside 1 exhibited a slightly lower inhibition ability. PMID- 26047465 TI - High-performance liquid chromatography with fluorescence detection for the rapid analysis of pheophytins and pyropheophytins in virgin olive oil. AB - Pheophytins and pyropheophytin are degradation products of chlorophyll pigments, and their ratios can be used as a sensitive indicator of stress during the manufacturing and storage of olive oil. They increase over time depending on the storage condition and if the oil is exposed to heat treatments during the refining process. The traditional analysis method includes solvent- and time consuming steps of solid-phase extraction followed by analysis by high performance liquid chromatography with ultraviolet detection. We developed an improved dilute/fluorescence method where multi-step sample preparation was replaced by a simple isopropanol dilution before the high-performance liquid chromatography injection. A quaternary solvent gradient method was used to include a fourth strong solvent wash on a quaternary gradient pump, which avoided the need to premix any solvents and greatly reduced the oil residues on the column from previous analysis. This new method not only reduces analysis cost and time but shows reliability, repeatability, and improved sensitivity, especially important for low-level samples. PMID- 26047463 TI - Evidence that synthetic lethality underlies the mutual exclusivity of oncogenic KRAS and EGFR mutations in lung adenocarcinoma. AB - Human lung adenocarcinomas (LUAD) contain mutations in EGFR in ~15% of cases and in KRAS in ~30%, yet no individual adenocarcinoma appears to carry activating mutations in both genes, a finding we have confirmed by re-analysis of data from over 600 LUAD. Here we provide evidence that co-occurrence of mutations in these two genes is deleterious. In transgenic mice programmed to express both mutant oncogenes in the lung epithelium, the resulting tumors express only one oncogene. We also show that forced expression of a second oncogene in human cancer cell lines with an endogenous mutated oncogene is deleterious. The most prominent features accompanying loss of cell viability were vacuolization, other changes in cell morphology, and increased macropinocytosis. Activation of ERK, p38 and JNK in the dying cells suggests that an overly active MAPK signaling pathway may mediate the phenotype. Together, our findings indicate that mutual exclusivity of oncogenic mutations may reveal unexpected vulnerabilities and therapeutic possibilities. PMID- 26047466 TI - On the Formation of Nanobubbles in Vycor Porous Glass during the Desorption of Halogenated Hydrocarbons. AB - Vycor porous glass has long served as a model mesoporous material. During the physical adsorption of halogenated hydrocarbon vapours, such as dibromomethane, the adsorption isotherm exhibits an hysteresis loop; a gradual ascent is observed at higher pressures during adsorption, and a sharp drop is observed at lower pressures during desorption. For fully wetting fluids, an early hypothesis attributed the hysteresis to mechanistic differences between capillary condensation (adsorption) and evaporation (desorption) processes occurring in the wide bodies and narrow necks, respectively, of 'ink-bottle' pores. This was later recognized as oversimplified when the role of network percolation was included. For the first time, we present in-situ small angle x-ray scattering measurements on the hysteresis effect which indicate nanobubble formation during desorption, and support an extended picture of network percolation. The desorption pattern can indeed result from network percolation; but this can sometimes be initiated by a local cavitation process without pore blocking, which is preceded by the temporary, heterogeneous formation of nanobubbles involving a change in wetting states. The capacity of the system to sustain such metastable states is governed by the steepness of the desorption boundary. PMID- 26047467 TI - The Evolutionary History of MAPL (Mitochondria-Associated Protein Ligase) and Other Eukaryotic BAM/GIDE Domain Proteins. AB - MAPL (mitochondria-associated protein ligase, also called MULAN/GIDE/MUL1) is a multifunctional mitochondrial outer membrane protein found in human cells that contains a unique BAM (beside a membrane) domain and a C-terminal RING-finger domain. MAPL has been implicated in several processes that occur in animal cells such as NF-kB activation, innate immunity and antiviral signaling, suppression of PINK1/parkin defects, mitophagy in skeletal muscle, and caspase-dependent apoptosis. Previous studies demonstrated that the BAM domain is present in diverse organisms in which most of these processes do not occur, including plants, archaea, and bacteria. Thus the conserved function of MAPL and its BAM domain remains an open question. In order to gain insight into its conserved function, we investigated the evolutionary origins of MAPL by searching for homologues in predicted proteomes of diverse eukaryotes. We show that MAPL proteins with a conserved BAM-RING architecture are present in most animals, protists closely related to animals, a single species of fungus, and several multicellular plants and related green algae. Phylogenetic analysis demonstrated that eukaryotic MAPL proteins originate from a common ancestor and not from independent horizontal gene transfers from bacteria. We also determined that two independent duplications of MAPL occurred, one at the base of multicellular plants and another at the base of vertebrates. Although no other eukaryote genome examined contained a verifiable MAPL orthologue, BAM domain-containing proteins were identified in the protists Bigelowiella natans and Ectocarpus siliculosis. Phylogenetic analyses demonstrated that these proteins are more closely related to prokaryotic BAM proteins and therefore likely arose from independent horizontal gene transfers from bacteria. We conclude that MAPL proteins with BAM RING architectures have been present in the holozoan and viridiplantae lineages since their very beginnings. Our work paves the way for future studies into MAPL function in alternative model organisms like Capsaspora owczarzaki and Chlamydomonas reinhardtii that will help to answer the question of MAPL's ancestral function in ways that cannot be answered by studying animal cells alone. PMID- 26047468 TI - Abdominal Functional Electrical Stimulation to Assist Ventilator Weaning in Acute Tetraplegia: A Cohort Study. AB - BACKGROUND: Severe impairment of the major respiratory muscles resulting from tetraplegia reduces respiratory function, causing many people with tetraplegia to require mechanical ventilation during the acute stage of injury. Abdominal Functional Electrical Stimulation (AFES) can improve respiratory function in non ventilated patients with sub-acute and chronic tetraplegia. The aim of this study was to investigate the clinical feasibility of using an AFES training program to improve respiratory function and assist ventilator weaning in acute tetraplegia. METHODS: AFES was applied for between 20 and 40 minutes per day, five times per week on four alternate weeks, with 10 acute ventilator dependent tetraplegic participants. Each participant was matched retrospectively with a ventilator dependent tetraplegic control, based on injury level, age and sex. Tidal Volume (VT) and Vital Capacity (VC) were measured weekly, with weaning progress compared to the controls. RESULTS: Compliance to training sessions was 96.7%. Stimulated VT was significantly greater than unstimulated VT. VT and VC increased throughout the study, with mean VC increasing significantly (VT: 6.2 mL/kg to 7.8 mL/kg VC: 12.6 mL/kg to 18.7 mL/kg). Intervention participants weaned from mechanical ventilation on average 11 (sd: +/- 23) days faster than their matched controls. CONCLUSION: The results of this study indicate that AFES is a clinically feasible technique for acute ventilator dependent tetraplegic patients and that this intervention may improve respiratory function and enable faster weaning from mechanical ventilation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02200393. PMID- 26047470 TI - Metabolic syndrome is common and persistent in youth-onset type 2 diabetes: Results from the TODAY clinical trial. AB - OBJECTIVE: To examine the prevalence of metabolic syndrome (MetS) in youth-onset type 2 diabetes in the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study. METHODS: Prevalence of MetS (ATP III definition) was compared at baseline (n = 679) and at 6 (n = 625) and 24 months (n = 545) using chi-square tests. Laboratory data were examined between MetS classifications at each time point using ANOVA. RESULTS: Baseline prevalence of MetS was 75.8% and did not differ by treatment group or change over time. MetS was more common in females (83.1%) than males (62.3%; P < 0.0001) at baseline; this difference persisted over 24 months. Prevalence of MetS was similar between ethnic groups at baseline but greater in Hispanics (82.7%) vs. non-Hispanic Whites (67.5%; P = 0.0017) and non-Hispanic Blacks (72.7%; P = 0.0164) at 24 months. Although MetS was common in participants with hemoglobin A1c < 7.0% (74.4% at baseline; no significant change over 24 months), it was more common in those who did not maintain glycemic control at 6 months (80.3%; P = 0.0081). Elevated C-reactive protein, ALT, IL-6, and PAI-1 levels were more frequent with MetS. CONCLUSIONS: Persistent high prevalence of MetS in youth-onset diabetes, even with excellent glycemic control, is of concern given the associated increased cardiovascular risk. PMID- 26047469 TI - Serotype M3 and M28 Group A Streptococci Have Distinct Capacities to Evade Neutrophil and TNF-alpha Responses and to Invade Soft Tissues. AB - The M3 Serotype of Group A Streptococcus (GAS) is one of the three most frequent serotypes associated with severe invasive GAS infections, such as necrotizing fasciitis, in the United States and other industrialized countries. The basis for this association and hypervirulence of invasive serotype M3 GAS is not fully understood. In this study, the sequenced serotype M3 strain, MGAS315, and serotype M28 strain, MGAS6180, were characterized in parallel to determine whether contemporary M3 GAS has a higher capacity to invade soft tissues than M28 GAS. In subcutaneous infection, MGAS315 invaded almost the whole skin, inhibited neutrophil recruitment and TNF-alpha production, and was lethal in subcutaneous infection of mice, whereas MGAS6180 did not invade skin, induced robust neutrophil infiltration and TNF-alpha production, and failed to kill mice. In contrast to MGAS6180, MGAS315 had covS G1370T mutation. Either replacement of the covS1370T gene with wild-type covS in MGAS315 chromosome or in trans expression of wild-type covS in MGAS315 reduced expression of CovRS-controlled virulence genes hasA, spyCEP, and sse by >10 fold. MGAS315 covSwt lost the capacity to extensively invade skin and to inhibit neutrophil recruitment and had attenuated virulence, indicating that the covS G1370T mutation critically contribute to the hypervirulence of MGAS315. Under the background of functional CovRS, MGAS315 covSwt still caused greater lesions than MGAS6180, and, consistently under the background of covS deletion, MGAS6180 DeltacovS caused smaller lesions than MGAS315 DeltacovS. Thus, contemporary invasive M3 GAS has a higher capacity to evade neutrophil and TNF-alpha responses and to invade soft tissue than M28 GAS and that this skin-invading capacity of M3 GAS is maximized by natural CovRS mutations. These findings enhance our understanding of the basis for the frequent association of M3 GAS with necrotizing fasciitis. PMID- 26047471 TI - Structural Bases for the Regulation of CO Binding in the Archaeal Protoglobin from Methanosarcina acetivorans. AB - Studies of CO ligand binding revealed that two protein states with different ligand affinities exist in the protoglobin from Methanosarcina acetivorans (in MaPgb*, residue Cys(E20)101 was mutated to Ser). The switch between the two states occurs upon the ligation of MaPgb*. In this work, site-directed mutagenesis was used to explore the role of selected amino acids in ligand sensing and stabilization and in affecting the equilibrium between the "more reactive" and "less reactive" conformational states of MaPgb*. A combination of experimental data obtained from electronic and resonance Raman absorption spectra, CO ligand-binding kinetics, and X-ray crystallography was employed. Three amino acids were assigned a critical role: Trp(60)B9, Tyr(61)B10, and Phe(93)E11. Trp(60)B9 and Tyr(61)B10 are involved in ligand stabilization in the distal heme pocket; the strength of their interaction was reflected by the spectra of the CO-ligated MaPgb* and by the CO dissociation rate constants. In contrast, Phe(93)E11 is a key player in sensing the heme-bound ligand and promotes the rotation of the Trp(60)B9 side chain, thus favoring ligand stabilization. Although the structural bases of the fast CO binding rate constant of MaPgb* are still unclear, Trp(60)B9, Tyr(61)B10, and Phe(93)E11 play a role in regulating heme/ligand affinity. PMID- 26047472 TI - How Has the Free Obstetric Care Policy Impacted Unmet Obstetric Need in a Rural Health District in Guinea? AB - INTRODUCTION: In 2010, the Ministry of Health (MoH) of Guinea introduced a free emergency obstetric care policy in all the public health facilities of the country. This included antenatal checks, normal delivery and Caesarean section. OBJECTIVE: This study aims at assessing the changes in coverage of obstetric care according to the Unmet Obstetric Need concept before (2008) and after (2012) the implementation of the free emergency obstetric care policy in a rural health district in Guinea. METHODS: We carried out a descriptive cross-sectional study involving the retrospective review of routine programme data during the period April to June 2014. RESULTS: No statistical difference was observed in women's sociodemographic characteristics and indications (absolute maternal indications versus non-absolute maternal indications) before and after the implementation of the policy. Compared to referrals from health centers of patients, direct admissions at hospital significantly increased from 49% to 66% between 2008 and 2012 (p = 0.001). In rural areas, this increase concerned all maternal complications regardless of their severity, while in urban areas it mainly affected very severe complications. Compared to 2008, there were significantly more Major Obstetric Interventions for Maternal Absolute Indications in 2012 (p < 0.001). Maternal deaths decreased between 2008 and 2012 from 1.5% to 1.1% while neonatal death increased from 12% in 2008 to 15% in 2012. CONCLUSION: The implementation of the free obstetric care policy led to a significant decrease in unmet obstetric need between 2008 and 2012 in the health district of Kissidougou. However, more research is needed to allow comparisons with other health districts in the country and to analyse the trends. PMID- 26047473 TI - Is Beauty in the Eyes of the Beholder? Aesthetic Quality versus Technical Skill in Movement Evaluation of Tai Chi. AB - The aim of this study was to compare experts to naive practitioners in rating the beauty and the technical quality of a Tai Chi sequence observed in video-clips (of high and middle level performances). Our hypothesis are: i) movement evaluation will correlate with the level of skill expressed in the kinematics of the observed action but ii) only experts will be able to unravel the technical component from the aesthetic component of the observed action. The judgments delivered indicate that both expert and non-expert observers are able to discern a good from a mediocre performance; however, as expected, only experts discriminate the technical from the aesthetic component of the action evaluated and do this independently of the level of skill shown by the model (high or middle level performances). Furthermore, the judgments delivered were strongly related to the kinematic variables measured in the observed model, indicating that observers rely on specific movement kinematics (e.g. movement amplitude, jerk and duration) for action evaluation. These results provide evidence of the complementary functional role of visual and motor action representation in movement evaluation and underline the role of expertise in judging the aesthetic quality of movements. PMID- 26047474 TI - Large expansion of CTG*CAG repeats is exacerbated by MutSbeta in human cells. AB - Trinucleotide repeat expansion disorders (TRED) are caused by genomic expansions of trinucleotide repeats, such as CTG and CAG. These expanded repeats are unstable in germline and somatic cells, with potential consequences for disease severity. Previous studies have demonstrated the involvement of DNA repair proteins in repeat instability, although the key factors affecting large repeat expansion and contraction are unclear. Here we investigated these factors in a human cell model harboring 800 CTG*CAG repeats by individually knocking down various DNA repair proteins using short interfering RNA. Knockdown of MSH2 and MSH3, which form the MutSbeta heterodimer and function in mismatch repair, suppressed large repeat expansions, whereas knockdown of MSH6, which forms the MutSalpha heterodimer with MSH2, promoted large expansions exceeding 200 repeats by compensatory increases in MSH3 and the MutSbeta complex. Knockdown of topoisomerase 1 (TOP1) and TDP1, which are involved in single-strand break repair, enhanced large repeat contractions. Furthermore, knockdown of senataxin, an RNA/DNA helicase which affects DNA:RNA hybrid formation and transcription coupled nucleotide excision repair, exacerbated repeat instability in both directions. These results indicate that DNA repair factors, such as MutSbeta play important roles in large repeat expansion and contraction, and can be an excellent therapeutic target for TRED. PMID- 26047475 TI - The Plastid Genome of the Cryptomonad Teleaulax amphioxeia. AB - Teleaulax amphioxeia is a photosynthetic unicellular cryptophyte alga that is distributed throughout marine habitats worldwide. This alga is an important plastid donor to the dinoflagellate Dinophysis caudata through the ciliate Mesodinium rubrum in the marine food web. To better understand the genomic characteristics of T. amphioxeia, we have sequenced and analyzed its plastid genome. The plastid genome sequence of T. amphioxeia is similar to that of Rhodomonas salina, and they share significant synteny. This sequence exhibits less similarity to that of Guillardia theta, the representative plastid genome of photosynthetic cryptophytes. The gene content and order of the three photosynthetic cryptomonad plastid genomes studied is highly conserved. The plastid genome of T. amphioxeia is composed of 129,772 bp and includes 143 protein-coding genes, 2 rRNA operons and 30 tRNA sequences. The DNA polymerase III gene (dnaX) was most likely acquired via lateral gene transfer (LGT) from a firmicute bacterium, identical to what occurred in R. salina. On the other hand, the psbN gene was independently encoded by the plastid genome without a reverse transcriptase gene as an intron. To clarify the phylogenetic relationships of the algae with red-algal derived plastids, phylogenetic analyses of 32 taxa were performed, including three previously sequenced cryptophyte plastid genomes containing 93 protein-coding genes. The stramenopiles were found to have branched out from the Chromista taxa (cryptophytes, haptophytes, and stramenopiles), while the cryptophytes and haptophytes were consistently grouped into sister relationships with high resolution. PMID- 26047476 TI - HIV-TB coinfection impairs CD8(+) T-cell differentiation and function while dehydroepiandrosterone improves cytotoxic antitubercular immune responses. AB - Tuberculosis (TB) is the leading cause of death among HIV-positive patients. The decreasing frequencies of terminal effector (TTE ) CD8(+) T cells may increase reactivation risk in persons latently infected with Mycobacterium tuberculosis (Mtb). We have previously shown that dehydroepiandrosterone (DHEA) increases the protective antitubercular immune responses in HIV-TB patients. Here, we aimed to study Mtb-specific cytotoxicity, IFN-gamma secretion, memory status of CD8(+) T cells, and their modulation by DHEA during HIV-TB coinfection. CD8(+) T cells from HIV-TB patients showed a more differentiated phenotype with diminished naive and higher effector memory and TTE T-cell frequencies compared to healthy donors both in total and Mtb-specific CD8(+) T cells. Notably, CD8(+) T cells from HIV TB patients displayed higher Terminal Effector (TTE ) CD45RA(dim) proportions with lower CD45RA expression levels, suggesting a not fully differentiated phenotype. Also, PD-1 expression levels on CD8(+) T cells from HIV-TB patients increased although restricted to the CD27(+) population. Interestingly, DHEA plasma levels positively correlated with TTE in CD8(+) T cells and in vitro DHEA treatment enhanced Mtb-specific cytotoxic responses and terminal differentiation in CD8(+) T cells from HIV-TB patients. Our data suggest that HIV-TB coinfection promotes a deficient CD8(+) T-cell differentiation, whereas DHEA may contribute to improving antitubercular immunity by enhancing CD8(+) T-cell functions during HIV-TB coinfection. PMID- 26047477 TI - Tumor-Targeting Salmonella typhimurium A1-R in Combination with Trastuzumab Eradicates HER-2-Positive Cervical Cancer Cells in Patient-Derived Mouse Models. AB - We have previously developed mouse models of HER-2-positive cervical cancer. Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer. We have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination. In the current study, we determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer. Mice were randomized to 5 groups and treated as follows: (1) no treatment; (2) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (3) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (4) S. typhimurium A1-R (5 * 107 CFU/body, ip, weekly, 5 weeks); (5) S. typhimurium A1-R (5 * 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks). All regimens had significant efficacy compared to the untreated mice. The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039). No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021). Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab. The results of the present study suggest that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer. PMID- 26047478 TI - MONSTER v1.1: a tool to extract and search for RNA non-branching structures. AB - BACKGROUND: Detection of RNA structure similarities is still one of the major computational problems in the discovery of RNA functions. A case in point is the study of the new appreciated long non-coding RNAs (lncRNAs), emerging as new players involved in many cellular processes and molecular interactions. Among several mechanisms of action, some lncRNAs show specific substructures that are likely to be instrumental for their functioning. For instance, it has been reported in literature that some lncRNAs have a guiding or scaffolding role by binding chromatin-modifying protein complexes. Thus, a functionally characterized lncRNA (reference) can be used to infer the function of others that are functionally unknown (target), based on shared structural motifs. METHODS: In our previous work we presented a tool, MONSTER v1.0, able to identify structural motifs shared between two full-length RNAs. Our procedure is mainly composed of two ad-hoc developed algorithms: nbRSSP_extractor for characterizing the folding of an RNA sequence by means of a sequence-structure descriptor (i.e., an array of non-overlapping substructures located on the RNA sequence and coded by dot bracket notation); and SSD_finder, to enable an effective search engine for groups of matches (i.e., chains) common to the reference and target RNA based on a dynamic programming approach with a new score function. Here, we present an updated version of the previous one (MONSTER v1.1) accounting for the peculiar feature of lncRNAs that are not expected to have a unique fold, but appear to fluctuate among a large number of equally-stable folds. In particular, we improved our SSD_finder algorithm in order to take into account all the alternative equally-stable structures. RESULTS: We present an application of MONSTER v1.1 on lincRNAs, which are a specific class of lncRNAs located in genomic regions which do not overlap protein-coding genes. In particular, we provide reliable predictions of the shared chains between HOTAIR, ANRIL and COLDAIR. The latter are lincRNAs which interact with the same protein complexes of the Polycomb group and hence they are expected to share structural motifs. PMID- 26047479 TI - Adaptive Potential of Hybridization among Malaria Vectors: Introgression at the Immune Locus TEP1 between Anopheles coluzzii and A. gambiae in 'Far-West' Africa. AB - "Far-West" Africa is known to be a secondary contact zone between the two major malaria vectors Anopheles coluzzii and A. gambiae. We investigated gene-flow and potentially adaptive introgression between these species along a west-to-east transect in Guinea Bissau, the putative core of this hybrid zone. To evaluate the extent and direction of gene flow, we genotyped site 702 in Intron-1 of the para Voltage-Gated Sodium Channel gene, a species-diagnostic nucleotide position throughout most of A. coluzzii and A. gambiae sympatric range. We also analyzed polymorphism in the thioester-binding domain (TED) of the innate immunity-linked thioester-containing protein 1 (TEP1) to investigate whether elevated hybridization might facilitate the exchange of variants linked to adaptive immunity and Plasmodium refractoriness. Our results confirm asymmetric introgression of genetic material from A. coluzzii to A. gambiae and disruption of linkage between the centromeric "genomic islands" of inter-specific divergence. We report that A. gambiae from the Guinean hybrid zone possesses an introgressed TEP1 resistant allelic class, found exclusively in A. coluzzii elsewhere and apparently swept to fixation in West Africa (i.e. Mali and Burkina Faso). However, no detectable fixation of this allele was found in Guinea Bissau, which may suggest that ecological pressures driving segregation between the two species in larval habitats in this region may be different from those experienced in northern and more arid parts of the species' range. Finally, our results also suggest a genetic subdivision between coastal and inland A. gambiae Guinean populations and provide clues on the importance of ecological factors in intra specific differentiation processes. PMID- 26047480 TI - Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile. AB - Dillenia suffruticosa, which is locally known as Simpoh air, has been traditionally used to treat cancerous growth. The ethyl acetate extract of D. suffruticosa (EADs) has been shown to induce apoptosis in MCF-7 breast cancer cells in our previous study. The present study aimed to elucidate the molecular mechanisms involved in EADs-induced apoptosis and to identify the major compounds in the extract. EADs was found to promote oxidative stress in MCF-7 cells that led to cell death because the pre-treatment with antioxidants alpha-tocopherol and ascorbic acid significantly reduced the cytotoxicity of the extract (P<0.05). DCFH-DA assay revealed that treatment with EADs attenuated the generation of intracellular ROS. Apoptosis induced by EADs was not inhibited by the use of caspase-inhibitor Z-VAD-FMK, suggesting that the cell death is caspase independent. The use of JC-1 dye reflected that EADs caused disruption in the mitochondrial membrane potential. The related molecular pathways involved in EADs induced apoptosis were determined by GeXP multiplex system and Western blot analysis. EADs is postulated to induce cell cycle arrest that is p53- and p21 dependent based on the upregulated expression of p53 and p21 (P<0.05). The expression of Bax was upregulated with downregulation of Bcl-2 following treatment with EADs. The elevated Bax/Bcl-2 ratio and the depolarization of mitochondrial membrane potential suggest that EADs-induced apoptosis is mitochondria-dependent. The expression of oxidative stress-related AKT, p-AKT, ERK, and p-ERK was downregulated with upregulation of JNK and p-JNK. The data indicate that induction of oxidative-stress related apoptosis by EADs was mediated by inhibition of AKT and ERK, and activation of JNK. The isolation of compounds in EADs was carried out using column chromatography and elucidated using the nuclear resonance magnetic analysis producing a total of six compounds including 3-epimaslinic acid, kaempferol, kaempferide, protocatechuic acid, gallic acid and beta-sitosterol-3-O-beta-D-glucopyranoside. The cytotoxicity of the isolated compounds was determined using MTT assay. Gallic acid was found to be most cytotoxic against MCF-7 cell line compared to others, with IC50 of 36 +/- 1.7 MUg/mL (P<0.05). In summary, EADs generated oxidative stress, induced cell cycle arrest and apoptosis in MCF-7 cells by regulating numerous genes and proteins that are involved in the apoptotic signal transduction pathway. Therefore, EADs has the potential to be developed as an anti-cancer agent against breast cancer. PMID- 26047481 TI - Fucoidan Suppresses Hypoxia-Induced Lymphangiogenesis and Lymphatic Metastasis in Mouse Hepatocarcinoma. AB - Metastasis, the greatest clinical challenge associated with cancer, is closely connected to multiple biological processes, including invasion and adhesion. The hypoxic environment in tumors is an important factor that causes tumor metastasis by activating HIF-1alpha. Fucoidan, extracted from brown algae, is a sulfated polysaccharide and, as a novel marine biological material, has been used to treat various disorders in China, Korea, Japan and other countries. In the present study, we demonstrated that fucoidan derived from Undaria pinnatifida sporophylls significantly inhibits the hypoxia-induced expression, nuclear translocation and activity of HIF-1alpha, the synthesis and secretion of VEGF-C and HGF, cell invasion and lymphatic metastasis in a mouse hepatocarcinoma Hca-F cell line. Fucoidan also suppressed lymphangiogenesis in vitro and in vivo. In addition, accompanied by a reduction in the HIF-1alpha nuclear translocation and activity, fucoidan significantly reduced the levels of p-PI3K, p-Akt, p-mTOR, p-ERK, NF kappaB, MMP-2 and MMP-9, but increased TIMP-1 levels. These results indicate strongly that the anti-metastasis and anti-lymphangiogenesis activities of fucoidan are mediated by suppressing HIF-1alpha/VEGF-C, which attenuates the PI3K/Akt/mTOR signaling pathways. PMID- 26047483 TI - Iron homeostasis and its disruption in mouse lung in iron deficiency and overload. AB - NEW FINDINGS: What is the central question of this study? The aim was to explore the role and hitherto unclear mechanisms of action of iron proteins in protecting the lung against the harmful effects of iron accumulation and the ability of pulmonary cells to mobilize iron in iron deficiency. What is the main finding and its importance? We show that pulmonary hepcidin appears not to modify cellular iron mobilization in the lung. We propose pathways for supplying iron to the lung in iron deficiency and for protecting the lung against iron excess in iron overload, mediated by the co-ordinated action of iron proteins, such as divalent metal transporter 1, ZRT-IRE-like-protein 14, transferrin receptor, ferritin, haemochromatosis-associated protein and ferroportin. Iron dyshomeostasis is associated with several forms of chronic lung disease, but its mechanisms of action remain to be elucidated. The aim of the present study was to determine the role of the lung in whole-animal models with iron deficiency and iron overload, studying the divalent metal transporter 1 (DMT1), ZRT-IRE-like protein 14 (ZIP14), transferrin receptor (TfR), haemochromatosis-associated protein (HFE), hepcidin, ferritin and ferroportin (FPN) expression. In each model, adult CF1 mice were divided into the following groups (six mice per group): (i) iron overload model, iron saccharate i.p. and control group (iron adequate), 0.9% NaCl i.p.; and (ii) iron-deficiency model, induced by repeated bleeding, and control group (sham operated). Proteins were assessed by immunohistochemistry and Western blot. In control mice, DMT1 was localized in the cytoplasm of airway cells, and in iron deficiency and overload it was in the apical membrane. Divalent metal transporter 1 and TfR increased in iron deficiency, without changes in iron overload. ZRT-IRE-like protein 14 decreased in airway cells in iron deficiency and increased in iron overload. In iron deficiency, HFE and FPN were immunolocalized close to the apical membrane. Ferroportin increased in iron overload. Prohepcidin was present in control groups, with no changes in iron deficiency and iron overload. In iron overload, ferritin showed intracytoplasmic localization close to the apical membrane of airway cells and intense immunostaining in macrophage-like cells. The results show that pulmonary hepcidin does not appear to modify cellular iron mobilization in the lung. We propose the following two novel pathways in the lung: (i) for supplying iron in iron deficiency, mediated principally by DMT1 and TfR and regulated by the action of FPN and HFE; and (ii) for iron detoxification in order to protect the lung against iron overload, facilitated by the action of DMT1, ZIP14, FPN and ferritin. PMID- 26047482 TI - Biological Activities and Chemical Composition of Methanolic Extracts of Selected Autochthonous Microalgae Strains from the Red Sea. AB - Four lipid-rich microalgal species from the Red Sea belonging to three different genera (Nannochloris, Picochlorum and Desmochloris), previously isolated as novel biodiesel feedstocks, were bioprospected for high-value, bioactive molecules. Methanol extracts were thus prepared from freeze-dried biomass and screened for different biological activities. Nannochloris sp. SBL1 and Desmochloris sp. SBL3 had the highest radical scavenging activity against 1,1-diphenyl-2 picrylhydrazyl, and the best copper and iron chelating activities. All species had potent butyrylcholinesterase inhibitory activity (>50%) and mildly inhibited tyrosinase. Picochlorum sp. SBL2 and Nannochloris sp. SBL4 extracts significantly reduced the viability of tumoral (HepG2 and HeLa) cells with lower toxicity against the non-tumoral murine stromal (S17) cells. Nannochloris sp. SBL1 significantly reduced the viability of Leishmania infantum down to 62% (250 ug/mL). Picochlorum sp. SBL2 had the highest total phenolic content, the major phenolic compounds identified being salicylic, coumaric and gallic acids. Neoxanthin, violaxanthin, zeaxanthin, lutein and beta-carotene were identified in the extracts of all strains, while canthaxanthin was only identified in Picochlorum sp. SBL2. Taken together, these results strongly suggest that the microalgae included in this work could be used as sources of added-value products that could be used to upgrade the final biomass value. PMID- 26047484 TI - Biogeography of Anurans from the Poorly Known and Threatened Coastal Sandplains of Eastern Brazil. AB - The east coast of Brazil comprises an extensive area inserted in the Tropical Atlantic Domain and is represented by sandy plains of beach ridges commonly known as Restingas. The coastal environments are unique and house a rich amphibian fauna, the geographical distribution patterns of which are incipient. Biogeographical studies can explain the current distributional patterns and provide the identification of natural biogeographical units. These areas are important in elucidating the evolutionary history of the taxa and the areas where they occur. The aim of this study was to seek natural biogeographical units in the Brazilian sandy plains of beach ridges by means of distribution data of amphibians and to test the main predictions of the vicariance model to explain the patterns found. We revised and georeferenced data on the geographical distribution of 63 anuran species. We performed a search for latitudinal distribution patterns along the sandy coastal plains of Brazil using the non metric multidimensional scaling method (NMDS) and the biotic element analysis to identify natural biogeographical units. The results showed a monotonic variation in anuran species composition along the latitudinal gradient with a break in the clinal pattern from 23 degrees S to 25 degrees S latitude (states of Rio de Janeiro to Sao Paulo). The major predictions of the vicariance model were corroborated by the detection of four biotic elements with significantly clustered distribution and by the presence of congeneric species distributed in distinct biotic elements. The results support the hypothesis that vicariance could be one of the factors responsible for the distribution patterns of the anuran communities along the sandy coastal plains of eastern Brazil. The results of the clusters are also congruent with the predictions of paleoclimatic models made for the Last Glacial Maximum of the Pleistocene, such as the presence of historical forest refugia and biogeographical patterns already detected for amphibians in the Atlantic Rainforest. PMID- 26047486 TI - Structural color printing based on plasmonic metasurfaces of perfect light absorption. AB - Subwavelength structural color filtering and printing technologies employing plasmonic nanostructures have recently been recognized as an important and beneficial complement to the traditional colorant-based pigmentation. However, the color saturation, brightness and incident angle tolerance of structural color printing need to be improved to meet the application requirement. Here we demonstrate a structural color printing method based on plasmonic metasurfaces of perfect light absorption to improve color performances such as saturation and brightness. Thin-layer perfect absorbers with periodic hole arrays are designed at visible frequencies and the absorption peaks are tuned by simply adjusting the hole size and periodicity. Near perfect light absorption with high quality factors are obtained to realize high-resolution, angle-insensitive plasmonic color printing with high color saturation and brightness. Moreover, the fabricated metasurfaces can be protected with a protective coating for ambient use without degrading performances. The demonstrated structural color printing platform offers great potential for applications ranging from security marking to information storage. PMID- 26047485 TI - Vitamin D Deficiency and Insufficiency in Hospitalized COPD Patients. AB - INTRODUCTION: 31-77% of patients with COPD have vitamin D deficiency and insufficiency, with results being highly variable between studies. Vitamin D may also correlate with disease characteristics. AIM: To find out the prevalence of vitamin D deficiency and insufficiency in patients with COPD admitted for exacerbation and a risk factors for lower vitamin D levels among comorbidities and COPD characteristics. METHODS: 152 patients were studied for vitamin D serum levels (25(OH)D). All of them were also assessed for diabetes mellitus (DM) and metabolic syndrome (MS). Data were gathered also for smoking status and exacerbations in last year. All patients completed CAT and mMRC questionnaires and underwent spirometry. RESULTS: A total of 83,6% of patients have reduced levels of vitamin D. 42,8% (65/152) have vitamin D insufficiency (defined as 25 50 nmol/L) and 40,8% (62/152) have vitamin D deficiency (<25 nmol/L). The mean level of 25(OH)D for all patients is 31,97 nmol/L (95%CI 29,12-34,68). Vitamin D deficiency and insufficiency are more prevalent in females vs. males (97,7 vs 77,8%; p = 0.003). The prevalence and severity of vitamin D deficiency and insufficiency in this study is significantly higher when compared to an unselected Bulgarian population (prevalence 75,8%; mean level 38,75 nmol/L). Vitamin D levels correlate with quality of life (measured by the mMRC scale) and lung function (FVC, FEV1, FEV6, FEF2575, FEV3, but not with FEV1/FVC ratio and PEF), it does not correlate with the presence of arterial hypertension, DM, MS and number of moderate, severe and total exacerbations. Vitamin D deficiency is a risk factor for longer hospital stay. CONCLUSIONS: The patients with COPD admitted for exacerbation are a risk group for vitamin D deficiency and insufficiency, which is associated with worse disease characteristics. PMID- 26047487 TI - Using Tournament Angler Data to Rapidly Assess the Invasion Status of Alien Sport Fishes (Micropterus spp.) in Southern Africa. AB - Fishes are one of the most commonly introduced aquatic taxa worldwide, and invasive fish species pose threats to biodiversity and ecosystem function in recipient waters. Considerable research efforts have focused on predicting the invasibility of different fish taxa; however, accurate records detailing the establishment and spread of invasive fishes are lacking for large numbers of fish around the globe. In response to these data limitations, a low-cost method of cataloging and quantifying the temporal and spatial status of fish invasions was explored. Specifically, angler catch data derived from competitive bass angling tournaments was used to document the distribution of 66 non-native populations of black bass (Micropterus spp.) in southern Africa. Additionally, catch data from standardized tournament events were used to assess the abundance and growth of non-native bass populations in southern Africa relative to their native distribution (southern and eastern United States). Differences in metrics of catch per unit effort (average number of fish retained per angler per day), daily bag weights (the average weight of fish retained per angler), and average fish weight were assessed using catch data from 14,890 angler days of tournament fishing (11,045 days from South Africa and Zimbabwe; 3,845 days from the United States). No significant differences were found between catch rates, average daily bag weight, or the average fish weight between countries, suggesting that bass populations in southern Africa reach comparable sizes and numbers relative to waters in their native distribution. Given the minimal cost associated with data collection (i.e. records are collected by tournament organizers), the standardized nature of the events, and consistent bias (i.e. selection for the biggest fish in a population), the use of angler catch data represents a novel approach to infer the status and distribution of invasive sport fish. PMID- 26047488 TI - Evidence for Autoinduction and Quorum Sensing in White Band Disease-Causing Microbes on Acropora cervicornis. AB - Coral reefs have entered a state of global decline party due to an increasing incidence of coral disease. However, the diversity and complexity of coral associated bacterial communities has made identifying the mechanisms underlying disease transmission and progression extremely difficult. This study explores the effects of coral cell-free culture fluid (CFCF) and autoinducer (a quorum sensing signaling molecule) on coral-associated bacterial growth and on coral tissue loss respectively. All experiments were conducted using the endangered Caribbean coral Acropora cervicornis. Coral-associated microbes were grown on selective media infused with CFCF derived from healthy and white band disease-infected A. cervicornis. Exposure to diseased CFCF increased proliferation of Cytophaga Flavobacterium spp. while exposure to healthy CFCF inhibited growth of this group. Exposure to either CFCF did not significantly affect Vibrio spp. growth. In order to test whether disease symptoms can be induced in healthy corals, A. cervicornis was exposed to bacterial assemblages supplemented with exogenous, purified autoinducer. Incubation with autoinducer resulted in complete tissue loss in all corals tested in less than one week. These findings indicate that white band disease in A. cervicornis may be caused by opportunistic pathogenesis of resident microbes. PMID- 26047489 TI - A new strategy for controlling invasive weeds: selecting valuable native plants to defeat them. AB - To explore replacement control of the invasive weed Ipomoea cairica, we studied the competitive effects of two valuable natives, Pueraria lobata and Paederia scandens, on growth and photosynthetic characteristics of I. cairica, in pot and field experiments. When I. cairica was planted in pots with P. lobata or P. scandens, its total biomass decreased by 68.7% and 45.8%, and its stem length by 33.3% and 34.1%, respectively. The two natives depressed growth of the weed by their strong effects on its photosynthetic characteristics, including suppression of leaf biomass and the abundance of the CO2-fixing enzyme RUBISCO. The field experiment demonstrated that sowing seeds of P. lobata or P. scandens in plots where the weed had been largely cleared produced 11.8-fold or 2.5-fold as much leaf biomass of the two natives, respectively, as the weed. Replacement control by valuable native species is potentially a feasible and sustainable means of suppressing I. cairica. PMID- 26047490 TI - Occupational exposures and sick leave during pregnancy: results from a Danish cohort study. AB - OBJECTIVE: This study aimed to investigate associations between work postures, lifting at work, shift work, work hours, and job strain and the risk of sick leave during pregnancy from 10-29 completed pregnancy weeks in a large cohort of Danish pregnant women. METHODS: Data from 51 874 pregnancies in the Danish National Birth Cohort collected between 1996-2002 were linked to the Danish Register for Evaluation of Marginalization. Exposure information was based on telephone interviews. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated by Cox regression analysis, using time of first episode of sick leave as the primary outcome. RESULTS: We found statistically significant associations between all the predictors and risk of sick leave; for non-sitting work postures (HRrange 1.55-2.79), cumulative lifting HRtrend 1.29, 95% CI 1.26 1.31, shift work (HRevening 1.90, 95% CI 1.73-2.09, HRnight 1.52, 95% CI 1.15 2.01), monthly night shifts HRtrend 1.12, 95% CI 1.11-1.14, increasing weekly work hours HRtrend 0.93, 95% CI 0.91-0.95 and high job strain HR 1.52, 95% CI 1.42-1.63. Some exposures influenced HR in either a positive or negative time dependent way. CONCLUSION: Our results support previous findings and suggest that initiatives to prevent sick leave during pregnancy could be based on work conditions. Preventive measures may have important implications for pregnant women and workplaces. PMID- 26047491 TI - Microclimatic Divergence in a Mediterranean Canyon Affects Richness, Composition, and Body Size in Saproxylic Beetle Assemblages. AB - Large valleys with opposing slopes may act as a model system with which the effects of strong climatic gradients on biodiversity can be evaluated. The advantage of such comparisons is that the impact of a change of climate can be studied on the same species pool without the need to consider regional differences. The aim of this study was to compare the assemblage of saproxylic beetles on such opposing slopes at Lower Nahal Oren, Mt. Carmel, Israel (also known as "Evolution Canyon") with a 200-800% higher solar radiation on the south facing (SFS) compared to the north-facing slope (NFS). We tested specific hypotheses of species richness patterns, assemblage structure, and body size resulting from interslope differences in microclimate. Fifteen flight interception traps per slope were distributed over three elevation levels ranging from 50 to 100 m a.s.l. Richness of saproxylic beetles was on average 34% higher on the SFS compared with the NFS, with no detected influence of elevation levels. Both assemblage structure and average body size were determined by slope aspect, with more small-bodied beetles found on the SFS. Both the increase in species richness and the higher prevalence of small species on the SFS reflect ecological rules present on larger spatial grain (species-energy hypothesis and community body size shift hypothesis), and both can be explained by the metabolic theory of ecology. This is encouraging for the complementary use of micro- and macroclimatic gradients to study impacts of climate warming on biodiversity. PMID- 26047492 TI - SLEEP DURATION AND DEPRESSION AMONG ADULTS: A META-ANALYSIS OF PROSPECTIVE STUDIES. AB - BACKGROUND: Results from longitudinal studies on sleep duration and incidence of depression remain controversial. METHODS: PubMed and Web of Science updated on October 22, 2014 were searched for eligible publications. Pooled relative risks (RRs) with 95% confidence interval (CI) were calculated using a random-effects model. RESULTS: Seven prospective studies were included, involving 25,271 participants for short sleep duration and 23,663 participants for long sleep duration. Compared with the normal sleep duration, the pooled RR for depression was 1.31 (95% CI, 1.04-1.64; I(2) = 0%) for the short sleep duration overall. For long sleep duration, the pooled RR was 1.42 (95% CI, 1.04-1.92; I(2) = 0%). The associations between short or long sleep duration and risk of depression did not substantially change in sensitivity and subgroup analyses. No evidence of publication bias was found. CONCLUSION: This meta-analysis indicates that short and long sleep duration was significantly associated with increased risk of depression in adults. PMID- 26047493 TI - Diorcinol D Exerts Fungicidal Action against Candida albicans through Cytoplasm Membrane Destruction and ROS Accumulation. AB - Candida albicans, which is the most common human fungal pathogen, causes high mortality among immunocompromised patients. Antifungal drug resistance becomes a major challenge for the management of Candida infection. Diorcinol D (DD), a diphenyl ether derivative isolated from an endolichenic fungus, exerted fungicidal action against Candida species. In this study, we investigated the possible mechanism of its antifungal activity. The change of membrane dynamics and permeability suggested that the cell membrane was disrupted by the treatment of DD. This was further supported by the evidences of intracellular glycerol accumulation, alteration of cell ultrastructure, and down-regulation of genes involved in cell membrane synthesis. In addition, the treatment of C. albicans with DD resulted in the elevation of reactive oxygen species (ROS), which caused the dysfunction of mitochondria. These altogether suggested that DD exerted its antifungal activity through cytoplasmic membrane destruction and ROS accumulation. This finding is helpful to uncover the underlying mechanisms for the diphenyl ether derivatives and provides a potential application in fighting clinical fungal infections. PMID- 26047494 TI - Bed Net Durability Assessments: Exploring a Composite Measure of Net Damage. AB - BACKGROUND: The durability of Long Lasting Insecticidal Nets (LLINs) in field conditions is of great importance for malaria prevention and control efforts; however, the physical integrity of the net fabric is not well understood making it challenging to determine overall effectiveness of nets as they age. The 2011 World Health Organization Pesticide Evaluation Scheme (WHOPES) guidelines provide a simple, standardized method using a proportional hole index (PHI) for assessing net damage with the intent to provide national malaria control programs with guidelines to assess the useful life of LLINS and estimate the rate of replacement. METHODS: We evaluated the utility of the PHI measure using 409 LLINs collected over three years in Nampula Province, Mozambique following a mass distribution campaign in 2008. For each LLIN the diameter and distance from the bottom of the net were recorded for every hole. Holes were classified into four size categories and a PHI was calculated following WHOPES guidelines. We investigate how the size, shape, and location of holes influence the PHI. The areas of the WHOPES defined categories were compared to circular and elliptical areas based on approximate shape and actual measured axes of each hole and the PHI was compared to cumulative damaged surface area of the LLIN. RESULTS: The damaged area of small, medium, large, and extra-large holes was overestimated using the WHOPES categories compared to elliptical areas using the actual measured axes. Similar results were found when comparing to circular areas except for extra-large holes which were underestimated. (Wilcoxon signed rank test of differences p< 0.0001 for all sizes). Approximating holes as circular overestimated hole surface area by 1.5 to 2 times or more. There was a significant difference in the mean number of holes < 0.5 cm by brand and there were more holes of all sizes on the bottom of nets than the top. For a range of hypothetical PHI thresholds used to designate a "failed LLIN", roughly 75 to 80% of failed LLINs were detected by considering large and extra-large holes alone, but sensitivity varied by brand. CONCLUSIONS: Future studies may refine the PHI to better approximate overall damaged surface area. Furthermore, research is needed to identify whether or not appropriate PHI thresholds can be used to deem a net no longer protective. Once a cutoff is selected, simpler methods of determining the effective lifespan of LLINs can help guide replacement strategies for malaria control programs. PMID- 26047495 TI - Motor skills of 5-year-old children who underwent early cardiac surgery. AB - Aims To describe the motor proficiency of 5-year-old children who underwent early infant cardiac surgery and had atypical infant gross motor development. To identify risk factors for motor dysfunction at 5 years of age. METHODS: A total of 33 children (80.5% participation rate) were re-assessed by a physiotherapist blinded to the diagnosis and previous clinical course, using standardised motor assessment tools. RESULTS: Motor proficiency was categorised as below average or well below average in 41% of the study patients. Approximately 30% of the cohort had balance deficits. Motor abilities at 4 months and 2 years of age were associated with motor proficiency at age 5; however, atypical motor development in infancy was not predictive of below-average or well below-average scores at age 5. Risk factors associated with motor ability at age 5 included respiratory support and intensive care length of stay in the 1st year of life, asymmetrical crawling in infancy, and cyanotic CHD at age 5. CONCLUSIONS: Despite differences from other reported studies in terms of cohort diagnoses and age at surgery, the rate of motor dysfunction was similar, with rates much higher than expected in typical children. Further assessment is needed in later childhood to determine the significance of these findings. PMID- 26047496 TI - Histomorphological and Immunophenotypic Features of Pill-Induced Esophagitis. AB - The aim of this study was to investigate histomorphological and immunophenotypic features in pill-induced esophagitis. We comparatively evaluated the histomorphological, immunophenotypic features of pill-induced esophagitis vs. reflux esophagitis, as well as clinical information and endoscopic findings. Fifty-two tissue pieces from 22 cases of pill-induced esophagitis, 46 pieces from 20 reflux esophagitis, and 16 pieces from 14 control samples were subjected to immunohistochemistry for inflammatory infiltrates (CD3 for T lymphocyte, CD20 for B lymphocyte, CD56 for NK cell, CD68 for macrophage, CD117 for mast cell) and eosinophil chemotaxis-associated proteins (Erk, leptin, leptin receptor, pSTAT3, phospho-mTOR). As a result, Histomorphology showed that a diffuse pattern of dilated intercellular spaces was more frequently observed in pill-induced esophagitis, while reactive atypia and subepithelial papillary elongation were more often found in reflux esophagitis (P < 0.05, respectively). Interestingly, intraepithelial eosinophilic microabscess, intraepithelial pustule and diffuse pattern of dilated intercellular spaces were observed in 14% (3 cases), 9% (2 cases) and 32% (7 cases) of pill-induced esophagitis, respectively, but in no cases of reflux esophagitis. Regarding intraepithelial inflammatory infiltrates in pill-induced esophagitis, T lymphocytes were the most common cells, followed by eosinophil; 11 and 7 in one x400 power field, respectively. Intraepithelial pSTAT3-positive pattern was more frequently observed in pill-induced esophagitis than in reflux esophagitis, at 45% (10 cases) versus 10% (2 cases), respectively (P < 0.05). Considering the distal esophageal lesion only, intraepithelial pustule, diffuse dilated intercellular spaces and stromal macrophages were more frequently found in distal pill-induced esophagitis, whereas reactive atypia and intraepithelial mast cells in reflux esophagitis (P < 0.05, respectively). In conclusion, diffuse dilated intercellular spaces, intraepithelial eosinophil microabscess, pustule, T lymphocytes, eosinophils, and pSTAT3 positivity can be added to histopathological features of pill-induced esophagitis, other than non specific ulcer. Besides, distal pill-induced esophagitis may be histopathologically differentiated from reflux esophagitis. PMID- 26047497 TI - Loss of Homogentisate 1,2-Dioxygenase Activity in Bacillus anthracis Results in Accumulation of Protective Pigment. AB - Melanin production is important to the pathogenicity and survival of some bacterial pathogens. In Bacillus anthracis, loss of hmgA, encoding homogentisate 1,2-dioxygenase, results in accumulation of a melanin-like pigment called pyomelanin. Pyomelanin is produced in the mutant as a byproduct of disrupted catabolism of L-tyrosine and L-phenylalanine. Accumulation of pyomelanin protects B. anthracis cells from UV damage but not from oxidative damage. Neither loss of hmgA nor accumulation of pyomelanin alter virulence gene expression, sporulation or germination. This is the first investigation of homogentisate 1,2-dioxygenase activity in the Gram-positive bacteria, and these results provide insight into a conserved aspect of bacterial physiology. PMID- 26047499 TI - Integron, Plasmid and Host Strain Characteristics of Escherichia coli from Humans and Food Included in the Norwegian Antimicrobial Resistance Monitoring Programs. AB - Antimicrobial resistant Escherichia coli (n=331) isolates from humans with bloodstream infections were investigated for the presence of class 1 and class 2 integrons. The integron cassettes arrays were characterized and the findings were compared with data from similar investigations on resistant E. coli from meat and meat products (n=241) produced during the same time period. All isolates were obtained from the Norwegian monitoring programs for antimicrobial resistance in human pathogens and in the veterinary sector. Methods used included PCR, sequencing, conjugation experiments, plasmid replicon typing and subtyping, pulsed-field-gel-electrophoresis and serotyping. Integrons of class 1 and 2 occurred significantly more frequently among human isolates; 45.4% (95% CI: 39.9 50.9) than among isolates from meat; 18% (95% CI: 13.2 -23.3), (p<0.01, Chi square test). Identical cassette arrays including dfrA1-aadA1, aadA1, dfrA12-orfF aadA2, oxa-30-aadA1 (class 1 integrons) and dfrA1-sat1-aadA1 (class 2 integrons) were detected from both humans and meat. However, the most prevalent cassette array in human isolates, dfrA17-aadA5, did not occur in isolates from meat, suggesting a possible linkage between this class 1 integron and a subpopulation of E. coli adapted to a human host. The drfA1-aadA1 and aadA1 class 1 integrons were found frequently in both human and meat isolates. These isolates were subjected to further studies to investigate similarities with regard to transferability, plasmid and host strain characteristics. We detected incF plasmids with pMLST profile F24:A-:B1 carrying drfA1-aadA1 integrons in isolates from pork and in a more distantly related E. coli strain from a human with septicaemia. Furthermore, we showed that most of the class 1 integrons with aadA1 were located on incF plasmids with pMLST profile F51:A-:B10 in human isolates. The plasmid was present in unrelated as well as closely related host strains, demonstrating that dissemination of this integron also could be attributed to clonal spread. In conclusion, among the systematically collected isolates from two different sources, some significant differences concerning integron prevalence and integron variants were observed. However, closely related plasmids as vehicles for specific class 1 integrons in isolates from meat and from a human with bloodstream infection were found. The occurrence of similar multi-resistance plasmids in bacteria from a food source and from a human clinical sample highlights the possible role of meat as a source of resistance elements for pathogenic bacteria. PMID- 26047498 TI - Directed Evolution of RecA Variants with Enhanced Capacity for Conjugational Recombination. AB - The recombination activity of Escherichia coli (E. coli) RecA protein reflects an evolutionary balance between the positive and potentially deleterious effects of recombination. We have perturbed that balance, generating RecA variants exhibiting improved recombination functionality via random mutagenesis followed by directed evolution for enhanced function in conjugation. A recA gene segment encoding a 59 residue segment of the protein (Val79-Ala137), encompassing an extensive subunit-subunit interface region, was subjected to degenerate oligonucleotide-mediated mutagenesis. An iterative selection process generated at least 18 recA gene variants capable of producing a higher yield of transconjugants. Three of the variant proteins, RecA I102L, RecA V79L and RecA E86G/C90G were characterized based on their prominence. Relative to wild type RecA, the selected RecA variants exhibited faster rates of ATP hydrolysis, more rapid displacement of SSB, decreased inhibition by the RecX regulator protein, and in general displayed a greater persistence on DNA. The enhancement in conjugational function comes at the price of a measurable RecA-mediated cellular growth deficiency. Persistent DNA binding represents a barrier to other processes of DNA metabolism in vivo. The growth deficiency is alleviated by expression of the functionally robust RecX protein from Neisseria gonorrhoeae. RecA filaments can be a barrier to processes like replication and transcription. RecA regulation by RecX protein is important in maintaining an optimal balance between recombination and other aspects of DNA metabolism. PMID- 26047500 TI - Characterization of the Kallikrein-Kinin System Post Chemical Neuronal Injury: An In Vitro Biochemical and Neuroproteomics Assessment. AB - Traumatic Brain Injury (TBI) is the result of a mechanical impact on the brain provoking mild, moderate or severe symptoms. It is acknowledged that TBI leads to apoptotic and necrotic cell death; however, the exact mechanism by which brain trauma leads to neural injury is not fully elucidated. Some studies have highlighted the pivotal role of the Kallikrein-Kinin System (KKS) in brain trauma but the results are still controversial and inconclusive. In this study, we investigated both the expression and the role of Bradykinin 1 and 2 receptors (B1R and B2R), in mediating neuronal injury under chemical neurotoxicity paradigm in PC12 cell lines. The neuronal cell line PC12 was treated with the apoptotic drug Staurosporine (STS) to induce cell death. Intracellular calcium release was evaluated by Fluo 4-AM staining and showed that inhibition of the B2R prevented calcium release following STS treatment. Differential analyses utilizing immunofluorescence, Western blot and Real-time Polymerase Chain Reaction revealed an upregulation of both bradykinin receptors occurring at 3h and 12h post-STS treatment, but with a higher induction of B2R compared to B1R. This implies that STS-mediated apoptosis in PC12 cells is mainly conducted through B2R and partly via B1R. Finally, a neuroproteomics approach was conducted to find relevant proteins associated to STS and KKS in PC12 cells. Neuroproteomics results confirmed the presence of an inflammatory response leading to cell death during apoptosis-mediated STS treatment; however, a "survival" capacity was shown following inhibition of B2R coupled with STS treatment. Our data suggest that B2R is a key player in the inflammatory pathway following STS-mediated apoptosis in PC12 cells and its inhibition may represent a potential therapeutic tool in TBI. PMID- 26047501 TI - Mobility and International Collaboration: Case of the Mexican Scientific Diaspora. AB - We use a data set of Mexican researchers working abroad that are included in the Mexican National System of Researchers (SNI). Our diaspora sample includes 479 researchers, most of them holding postdoctoral positions in mainly seven countries: USA, Great Britain, Germany, France, Spain, Canada and Brazil. Their research output and impact is explored in order to determine their patterns of production, mobility and scientific collaboration as compared with previous studies of the SNI researchers in the periods 1991-2001 and 2003-2009. Our findings confirm that mobility has a strong impact on their international scientific collaboration. We found no substantial influence among the researchers that got their PhD degrees abroad from those trained in Mexican universities. There are significant differences among the areas of knowledge studied: biological sciences, physics and engineering have better production and impact rates than mathematics, geosciences, medicine, agrosciences, chemistry, social sciences and humanities. We found a slight gender difference in research production but Mexican female scientists are underrepresented in our diaspora sample. These findings would have policy implications for the recently established program that will open new academic positions for young Mexican scientists. PMID- 26047502 TI - Dissemination of NDM-1-Producing Enterobacteriaceae Mediated by the IncX3-Type Plasmid. AB - The emergence and spread of NDM-1-producing Enterobacteriaceae have resulted in a worldwide public health risk that has affected some provinces of China. China is an exceptionally large country, and there is a crucial need to investigate the epidemic of blaNDM-1-positive Enterobacteriaceae in our province. A total of 186 carbapenem-resistant Enterobacteriaceae isolates (CRE) were collected in a grade 3 hospital in Zhejiang province. Carbapenem-resistant genes, including blaKPC, blaIMP, blaVIM, blaOXA-48 and blaNDM-1 were screened and sequenced. Ninety isolates were identified as harboring the blaKPC-2 genes, and five blaNDM-1 positive isolates were uncovered. XbaI-PFGE revealed that three blaNDM-1-positive K. pneumoniae isolates belonged to two different clones. S1-PFGE and southern blot suggested that the blaNDM-1 genes were located on IncX3-type plasmids with two different sizes ranging from 33.3 to 54.7 kb (n=4) and 104.5 to 138.9 kb (n=1), respectively, all of which could easily transfer to Escherichia coli by conjugation and electrotransformation. The high-throughput sequencing of two plasmids was performed leading to the identification of a smaller 54-kb plasmid, which had high sequence similarity with a previously reported pCFNDM-CN, and a larger plasmid in which only a 7.8-kb sequence of a common gene environment around blaNDM-1 (blaNDM-1-trpF- dsbC-cutA1-groEL-DeltaInsE,) was detected. PCR mapping and sequencing demonstrated that four smaller blaNDM-1 plasmids contained a common gene environment around blaNDM-1 (IS5-blaNDM-1-trpF- dsbC-cutA1-groEL). We monitored the CRE epidemic in our hospital and determined that KPC-2 carbapenemase was a major risk to patient health and the IncX3-type plasmid played a vital role in the spread of the blaNDM-1 gene among the CRE. PMID- 26047503 TI - Characterisation of 20S Proteasome in Tritrichomonas foetus and Its Role during the Cell Cycle and Transformation into Endoflagellar Form. AB - Proteasomes are intracellular complexes that control selective protein degradation in organisms ranging from Archaea to higher eukaryotes. These structures have multiple proteolytic activities that are required for cell differentiation, replication and maintaining cellular homeostasis. Here, we document the presence of the 20S proteasome in the protist parasite Tritrichomonas foetus. Complementary techniques, such as a combination of whole genome sequencing technologies, bioinformatics algorithms, cell fractionation and biochemistry and microscopy approaches were used to characterise the 20S proteasome of T. foetus. The 14 homologues of the typical eukaryotic proteasome subunits were identified in the T. foetus genome. Alignment analyses showed that the main regulatory and catalytic domains of the proteasome were conserved in the predicted amino acid sequences from T. foetus-proteasome subunits. Immunofluorescence assays using an anti-proteasome antibody revealed a labelling distributed throughout the cytosol as punctate cytoplasmic structures and in the perinuclear region. Electron microscopy of a T. foetus-proteasome-enriched fraction confirmed the presence of particles that resembled the typical eukaryotic 20S proteasome. Fluorogenic assays using specific peptidyl substrates detected presence of the three typical peptidase activities of eukaryotic proteasomes in T. foetus. As expected, these peptidase activities were inhibited by lactacystin, a well-known specific proteasome inhibitor, and were not affected by inhibitors of serine or cysteine proteases. During the transformation of T. foetus to endoflagellar form (EFF), also known as pseudocyst, we observed correlations between the EFF formation rates, increases in the proteasome activities and reduced levels of ubiquitin-protein conjugates. The growth, cell cycle and EFF transformation of T. foetus were inhibited after treatment with lactacystin in a dose-dependent manner. Lactacystin treatment also resulted in an accumulation of ubiquitinated proteins and caused increase in the amount of endoplasmic reticulum membranes in the parasite. Taken together, our results suggest that the ubiquitin-proteasome pathway is required for cell cycle and EFF transformation in T. foetus. PMID- 26047504 TI - Hyperglycemia and Diabetes Downregulate the Functional Expression of TRPV4 Channels in Retinal Microvascular Endothelium. AB - Retinal endothelial cell dysfunction is believed to play a key role in the etiology and pathogenesis of diabetic retinopathy. Numerous studies have shown that TRPV4 channels are critically involved in maintaining normal endothelial cell function. In the current paper, we demonstrate that TRPV4 is functionally expressed in the endothelium of the retinal microcirculation and that both channel expression and activity is downregulated by hyperglycaemia. Quantitative PCR and immunostaining demonstrated molecular expression of TRPV4 in cultured bovine retinal microvascular endothelial cells (RMECs). Functional TRPV4 activity was assessed in cultured RMECs from endothelial Ca2+-responses recorded using fura-2 microfluorimetry and electrophysiological recordings of membrane currents. The TRPV4 agonist 4alpha-phorbol 12,13-didecanoate (4-alphaPDD) increased [Ca2+]i in RMECs and this response was largely abolished using siRNA targeted against TRPV4. These Ca2+-signals were completely inhibited by removal of extracellular Ca2+, confirming their dependence on influx of extracellular Ca2+. The 4-alphaPDD Ca2+-response recorded in the presence of cyclopiazonic acid (CPA), which depletes the intracellular stores preventing any signal amplification through store release, was used as a measure of Ca2+-influx across the cell membrane. This response was blocked by HC067047, a TRPV4 antagonist. Under voltage clamp conditions, the TRPV4 agonist GSK1016790A stimulated a membrane current, which was again inhibited by HC067047. Following incubation with 25 mM D-glucose TRPV4 expression was reduced in comparison with RMECs cultured under control conditions, as were 4alphaPDD-induced Ca2+-responses in the presence of CPA and ion currents evoked by GSK1016790A. Molecular expression of TRPV4 in the retinal vascular endothelium of 3 months' streptozotocin-induced diabetic rats was also reduced in comparison with that in age-matched controls. We conclude that hyperglycaemia and diabetes reduce the molecular and functional expression of TRPV4 channels in retinal microvascular endothelial cells. These changes may contribute to diabetes induced endothelial dysfunction and retinopathy. PMID- 26047505 TI - Determinants of Sexual Activity and Pregnancy among Unmarried Young Women in Urban Kenya: A Cross-Sectional Study. AB - OBJECTIVES: With age of marriage rising in Kenya, the period between onset of puberty and first marriage has increased, resulting in higher rates of premarital sexual activity and pregnancy. We assessed the determinants of sexual activity and pregnancy among young unmarried women in urban Kenya. METHODS: Baseline data from five urban areas in Kenya (Nairobi, Mombasa, Kisumu, Machakos, and Kakamega) collected in 2010 by the Measurement, Learning & Evaluation project were used. Women aged 15-24 years, who had never been married, and were not living with a male partner at the time of survey (weighted n = 2020) were included. Using weighted, multivariate Cox proportional hazard regression and logistic regression analyses, we assessed factors associated with three outcome measures: time to first sex, time to first pregnancy, and teenage pregnancy. RESULTS: One-half of our sample had ever had sex; the mean age at first sex among the sexually experienced was 17.7 (+/- 2.6) years. About 15% had ever been pregnant; mean age at first pregnancy was 18.3 (+/- 2.2) years. Approximately 11% had a teenage pregnancy. Three-quarters (76%) of those who had ever been pregnant (weighted n = 306) reported the pregnancy was unwanted at the time. Having secondary education was associated with a later time to first sex and first pregnancy. In addition, religion, religiosity, and employment status were associated with time to first sex while city of residence, household size, characteristics of household head, family planning knowledge and misconceptions, and early sexual debut were significantly associated with time to first pregnancy. Education, city of residence, household wealth, early sexual debut, and contraceptive use at sexual debut were associated with teenage pregnancy for those 20-24 years. CONCLUSION: Understanding risk and protective factors of youth sexual and reproductive health can inform programs to improve young people's long-term potential by avoiding early and unintended pregnancies. PMID- 26047506 TI - The Orphan G Protein-Coupled Receptor Gene GPR178 Is Evolutionary Conserved and Altered in Response to Acute Changes in Food Intake. AB - G protein-coupled receptors (GPCRs) are a class of integral membrane proteins mediating physiological functions fundamental for survival, including energy homeostasis. A few years ago, an amino acid sequence of a novel GPCR gene was identified and named GPR178. In this study, we provide new insights regarding the biological significance of Gpr178 protein, investigating its evolutionary history and tissue distribution as well as examining the relationship between its expression level and feeding status. Our phylogenetic analysis indicated that GPR178 is highly conserved among all animal species investigated, and that GPR178 is not a member of a protein family. Real-time PCR and in situ hybridization revealed wide expression of Gpr178 mRNA in both the brain and periphery, with high expression density in the hypothalamus and brainstem, areas involved in the regulation of food intake. Hence, changes in receptor expression were assessed following several feeding paradigms including starvation and overfeeding. Short term starvation (12-48h) or food restriction resulted in upregulation of Gpr178 mRNA expression in the brainstem, hypothalamus and prefrontal cortex. Conversely, short-term (48h) exposure to sucrose or Intralipid solutions downregulated Gpr178 mRNA in the brainstem; long-term exposure (10 days) to a palatable high-fat and high-sugar diet resulted in a downregulation of Gpr178 in the amygdala but not in the hypothalamus. Our results indicate that hypothalamic Gpr178 gene expression is altered during acute exposure to starvation or acute exposure to palatable food. Changes in gene expression following palatable diet consumption suggest a possible involvement of Gpr178 in the complex mechanisms of feeding reward. PMID- 26047508 TI - Identifying Pathways for Improving Household Food Self-Sufficiency Outcomes in the Hills of Nepal. AB - Maintaining and improving household food self-sufficiency (FSS) in mountain regions is an ongoing challenge. There are many facets to the issue, including comparatively high levels of land fragmentation, challenging terrain and transportation bottlenecks, declining labor availability due to out-migration, and low technical knowledge, among others. Using a nonparametric multivariate approach, we quantified primary associations underlying current levels of FSS in the mid-hills of Nepal. A needs assessment survey was administered to 77 households in Lungaun (Baglung District), Pang (Parbat District), and Pathlekhet (Myagdi District), with a total of 80 variables covering five performance areas; resulting data were analyzed using Classification and Regression Trees. The most parsimonious statistical model for household FSS highlighted associations with agronomic management, including yields of maize and fingermillet within a relay cropping system and adoption of improved crop cultivars. Secondary analyses of the variables retained in the first model again focused primarily on crop and livestock management. It thus appears that continued emphasis on technical agricultural improvements is warranted, independent of factors such as land holding size that, in any case, are very difficult to change through development interventions. Initiatives to increase household FSS in the mid-hills of Nepal will benefit from placing a primary focus on methods of agricultural intensification to improve crop yields and effective technology transfer to increase adoption of these methods. PMID- 26047507 TI - Macular Microcysts in Mitochondrial Optic Neuropathies: Prevalence and Retinal Layer Thickness Measurements. AB - PURPOSE: To investigate the thickness of the retinal layers and to assess the prevalence of macular microcysts (MM) in the inner nuclear layer (INL) of patients with mitochondrial optic neuropathies (MON). METHODS: All patients with molecularly confirmed MON, i.e. Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), referred between 2010 and 2012 were enrolled. Eight patients with MM were compared with two control groups: MON patients without MM matched by age, peripapillary retinal nerve fiber layer (RNFL) thickness, and visual acuity, as well as age-matched controls. Retinal segmentation was performed using specific Optical coherence tomography (OCT) software (Carl Zeiss Meditec). Macular segmentation thickness values of the three groups were compared by one-way analysis of variance with Bonferroni post hoc corrections. RESULTS: MM were identified in 5/90 (5.6%) patients with LHON and 3/58 (5.2%) with DOA. The INL was thicker in patients with MON compared to controls regardless of the presence of MM [133.1+/-7MUm vs 122.3+/-9MUm in MM patients (p<0.01) and 128.5+/ 8MUm vs. 122.3+/-9MUm in no-MM patients (p<0.05)], however the outer nuclear layer (ONL) was thicker in patients with MM (101.4+/-1mMU) compared to patients without MM [77.5+/-8mMU (p<0.001)] and controls [78.4+/-7mMU (p<0.001)]. ONL thickness did not significantly differ between patients without MM and controls. CONCLUSION: The prevalence of MM in MON is low (5-6%), but associated with ONL thickening. We speculate that in MON patients with MM, vitreo-retinal traction contributes to the thickening of ONL as well as to the production of cystic spaces. PMID- 26047509 TI - Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response. AB - Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM) and CD27 IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naive/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation. PMID- 26047510 TI - Factors Associated with Unplanned Dialysis Starts in Patients followed by Nephrologists: A Retropective Cohort Study. AB - The number of patients starting dialysis is increasing world wide. Unplanned dialysis starts (patients urgently starting dialysis in hospital) is associated with increased costs and high morbidity and mortality. Risk factors for starting dialysis urgently in hospital have not been well studied. The primary objective of this study was to identify risk factors for unplanned dialysis starts in patients followed in a multidisciplinary chronic kidney disease (CKD) clinic. We performed a retrospective cohort study of 649 advanced CKD patients followed in a multidisciplinary CKD clinic at a tertiary care hospital from January 01, 2010 to April 30, 2013. Patients were classified as unplanned start (in hospital) or elective start. Multivariable logistic regression was used to identify variables associated with unplanned dialysis initiation. 184 patients (28.4%) initiated dialysis, of which 76 patients (41.3%) initiated dialysis in an unplanned fashion and 108 (58.7%) starting electively. Unplanned start patients were more likely to have diabetes (68.4% versus 51.9%; p = 0.04), CAD (42.1% versus 24.1%; p = 0.02), congestive heart failure (36.8% versus 17.6%; p = 0.01), and were less likely to receive modality education (64.5% vs 89.8%; p < 0.01) or be assessed by a surgeon for access creation (40.8% vesrus 78.7% p < 0.01). On multivariable analysis, higher body mass index (OR 1.07, 95% CI 1.02, 1.13), and a history of congestive heart failure (OR 2.41, 95% CI 1.09, 5.41) were independently associated with an unplanned start. Unplanned dialysis initiation is common among advanced CKD patients, even if they are followed in a multidisciplinary chronic kidney disease clinic. Timely education and access creation in patients at risk may lead to lower costs and less morbidity and mortality. PMID- 26047511 TI - Effects of Aggregation on Blood Sedimentation and Conductivity. AB - The erythrocyte sedimentation rate (ESR) test has been used for over a century. The Westergren method is routinely used in a variety of clinics. However, the mechanism of erythrocyte sedimentation remains unclear, and the 60 min required for the test seems excessive. We investigated the effects of cell aggregation during blood sedimentation and electrical conductivity at different hematocrits. A sample of blood was drop cast into a small chamber with two planar electrodes placed on the bottom. The measured blood conductivity increased slightly during the first minute and decreased thereafter. We explored various methods of enhancing or retarding the erythrocyte aggregation. Using experimental measurements and theoretical calculations, we show that the initial increase in blood conductivity was indeed caused by aggregation, while the subsequent decrease in conductivity resulted from the deposition of erythrocytes. We present a method for calculating blood conductivity based on effective medium theory. Erythrocytes are modeled as conducting spheroids surrounded by a thin insulating membrane. A digital camera was used to investigate the erythrocyte sedimentation behavior and the distribution of the cell volume fraction in a capillary tube. Experimental observations and theoretical estimations of the settling velocity are provided. We experimentally demonstrate that the disaggregated cells settle much slower than the aggregated cells. We show that our method of measuring the electrical conductivity credibly reflected the ESR. The method was very sensitive to the initial stage of aggregation and sedimentation, while the sedimentation curve for the Westergren ESR test has a very mild slope in the initial time. We tested our method for rapid estimation of the Westergren ESR. We show a correlation between our method of measuring changes in blood conductivity and standard Westergren ESR method. In the future, our method could be examined as a potential means of accelerating ESR tests in clinical practice. PMID- 26047512 TI - Perceived Stigma towards Leprosy among Community Members Living Close to Nonsomboon Leprosy Colony in Thailand. AB - BACKGROUND: Interpretation of Leprosy as a sickness differs among society. The set of beliefs, knowledge and perceptions towards a disease play a vital role in the construction of stigma towards a disease. The main purpose of this study was to explore the extent and correlates of the perceived stigma towards leprosy in the community living close to the leprosy colony in Non Somboon region of Khon Kaen Province of Thailand. METHODS: A cross-sectional study was conducted among 257 leprosy unaffected community participants, above the age of 18 who were living close to the Leprosy colony in Non Somboon region of Thailand. Each participant was asked a questionnaire containing characteristics of the participants in terms of socio-demographic background and knowledge regarding the disease. In addition perceived stigma towards leprosy was measured using EMIC (Explanatory Model Interview Catalogue) questionnaire. RESULTS: Among EMIC items, shame or embarrassment in the community due to leprosy was felt by 54.5%, dislike to buy food from leprosy affected persons were 49.8% and difficulty to find work for leprosy affected persons were perceived by 47.1%. Higher total EMIC score was found in participants age 61 years or older (p = 0.021), staying longer in the community (p = 0.005), attending fewer years of education (p = 0.024) and who were unemployed (p = 0.08). Similarly, perceptions about leprosy such as difficult to treat (p = 0.015), severe disease (p = 0.004) and punishment by God (p = 0.011) were significantly associated with higher perceived stigma. CONCLUSIONS: Perceived stigma towards leprosy was found highest among participants with age 61 years or older, longer duration of stay in community close to the leprosy colony, lower duration of education and participants who were unemployed had higher perceived stigma. Similarly, participants with perceptions of leprosy such as difficult to treat, severe disease and punishment by God had higher perceived stigma towards leprosy. There is an urgent need of stigma reduction strategies focused on education and awareness concerning leprosy. PMID- 26047513 TI - Quorum Sensing Controls Swarming Motility of Burkholderia glumae through Regulation of Rhamnolipids. AB - Burkholderia glumae is a plant pathogenic bacterium that uses an acyl-homoserine lactone-mediated quorum sensing system to regulate protein secretion, oxalate production and major virulence determinants such as toxoflavin and flagella. B. glumae also releases surface-active rhamnolipids. In Pseudomonas aeruginosa and Burkholderia thailandensis, rhamnolipids, along with flagella, are required for the social behavior called swarming motility. In the present study, we demonstrate that quorum sensing positively regulates the production of rhamnolipids in B. glumae and that rhamnolipids are necessary for swarming motility also in this species. We show that a rhlA- mutant, which is unable to produce rhamnolipids, loses its ability to swarm, and that this can be complemented by providing exogenous rhamnolipids. Impaired rhamnolipid production in a quorum sensing-deficient B. glumae mutant is the main factor responsible for its defective swarming motility behaviour. PMID- 26047515 TI - Effect of Pore Size and Porosity on the Biomechanical Properties and Cytocompatibility of Porous NiTi Alloys. AB - Five types of porous Nickel-Titanium (NiTi) alloy samples of different porosities and pore sizes were fabricated. According to compressive and fracture strengths, three groups of porous NiTi alloy samples underwent further cytocompatibility experiments. Porous NiTi alloys exhibited a lower Young's modulus (2.0 GPa ~ 0.8 GPa). Both compressive strength (108.8 MPa ~ 56.2 MPa) and fracture strength (64.6 MPa ~ 41.6 MPa) decreased gradually with increasing mean pore size (MPS). Cells grew and spread well on all porous NiTi alloy samples. Cells attached more strongly on control group and blank group than on all porous NiTi alloy samples (p < 0.05). Cell adhesion on porous NiTi alloys was correlated negatively to MPS (277.2 MUm ~ 566.5 MUm; p < 0.05). More cells proliferated on control group and blank group than on all porous NiTi alloy samples (p < 0.05). Cellular ALP activity on all porous NiTi alloy samples was higher than on control group and blank group (p < 0.05). The porous NiTi alloys with optimized pore size could be a potential orthopedic material. PMID- 26047517 TI - R.I.P. SGR. AB - Medicine's united voice was instrumental in successfully repealing the flawed Medicare Sustainable Growth Rate (SGR) formula--a payment design enacted in 1997 to sustain Medicare with lower costs but that instead threatened physicians with unsustainable payment cuts every year since 2003. Doctors say the elimination of SGR frees medicine to advocate for other lingering issues affecting Medicare. PMID- 26047516 TI - Classification of Epidermal Growth Factor Receptor Gene Mutation Status Using Serum Proteomic Profiling Predicts Tumor Response in Patients with Stage IIIB or IV Non-Small-Cell Lung Cancer. AB - OBJECTIVES: Epidermal growth factor receptor (EGFR) gene mutations in tumors predict tumor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non small-cell lung cancer (NSCLC). However, obtaining tumor tissue for mutation analysis is challenging. Here, we aimed to detect serum peptides/proteins associated with EGFR gene mutation status, and test whether a classification algorithm based on serum proteomic profiling could be developed to analyze EGFR gene mutation status to aid therapeutic decision-making. PATIENTS AND METHODS: Serum collected from 223 stage IIIB or IV NSCLC patients with known EGFR gene mutation status in their tumors prior to therapy was analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) and ClinProTools software. Differences in serum peptides/proteins between patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes were detected in a training group of 100 patients; based on this analysis, a serum proteomic classification algorithm was developed to classify EGFR gene mutation status and tested in an independent validation group of 123 patients. The correlation between EGFR gene mutation status, as identified with the serum proteomic classifier and response to EGFR-TKIs was analyzed. RESULTS: Nine peptide/protein peaks were significantly different between NSCLC patients with EGFR gene TKI sensitive mutations and wild-type EGFR genes in the training group. A genetic algorithm model consisting of five peptides/proteins (m/z 4092.4, 4585.05, 1365.1, 4643.49 and 4438.43) was developed from the training group to separate patients with EGFR gene TKI-sensitive mutations and wild-type EGFR genes. The classifier exhibited a sensitivity of 84.6% and a specificity of 77.5% in the validation group. In the 81 patients from the validation group treated with EGFR TKIs, 28 (59.6%) of 47 patients whose matched samples were labeled as "mutant" by the classifier and 3 (8.8%) of 34 patients whose matched samples were labeled as "wild" achieved an objective response (p<0.0001). Patients whose matched samples were labeled as "mutant" by the classifier had a significantly longer progression free survival (PFS) than patients whose matched samples were labeled as "wild" (p=0.001). CONCLUSION: Peptides/proteins related to EGFR gene mutation status were found in the serum. Classification of EGFR gene mutation status using the serum proteomic classifier established in the present study in patients with stage IIIB or IV NSCLC is feasible and may predict tumor response to EGFR-TKIs. PMID- 26047514 TI - The Use of Chemical-Chemical Interaction and Chemical Structure to Identify New Candidate Chemicals Related to Lung Cancer. AB - Lung cancer causes over one million deaths every year worldwide. However, prevention and treatment methods for this serious disease are limited. The identification of new chemicals related to lung cancer may aid in disease prevention and the design of more effective treatments. This study employed a weighted network, constructed using chemical-chemical interaction information, to identify new chemicals related to two types of lung cancer: non-small lung cancer and small-cell lung cancer. Then, a randomization test as well as chemical chemical interaction and chemical structure information were utilized to make further selections. A final analysis of these new chemicals in the context of the current literature indicates that several chemicals are strongly linked to lung cancer. PMID- 26047518 TI - Saving 1 Million Lives. AB - The Million Hearts initiative aims to get physicians, health systems, patients, and public and private partners on board to prevent 1 million heart attacks and strokes by 2017. PMID- 26047519 TI - Who Really Owns Knapp Medical Center? AB - The sale of Knapp Medical Center in Weslaco to Prime Healthcare Foundation raised questions regarding the validity of the transaction and prompted the City of Weslaco to sue Prime and other parties. PMID- 26047520 TI - A Heavy Burden. AB - A Texas Health and Human Services Commission report reveals gestational diabetes mellitus (GDM) and obese mothers take a toll on the state's Medicaid program. According to the report, in Medicaid, the excess medical and drug costs among women with GDM and their babies totaled $10 million. Women with pregestational diabetes cost Medicaid $60 million more than nondiabetic, normal-weight women. Much of the cost associated with diabetes and obesity comes from more frequent hospitalizations for the mother and a higher likelihood the infant will be admitted into the neonatal intensive care unit. PMID- 26047521 TI - Read the Fine Print. AB - Physicians in private practice must negotiate contracts with vendors for various services. Many contracts often come with fine print that's worth taking some time to examine. PMID- 26047522 TI - Commercial Tanning Bed Use as a Medical Therapy. AB - An anonymous 9-question survey was composed and distributed to members of the Texas Dermatological Society to evaluate dermatologists' prescription of commercial tanning beds for treatment of certain dermatologic and other medical conditions and to seek opinions on whether commercial tanning beds are a legitimate medical therapy. Results show that although dermatologists agree recreational tanning should always be discouraged, some Texas dermatologists do occasionally recommend commercial tanning bed use for some conditions in patients who cannot afford traditional in-office phototherapy because they lack insurance or have high copays or for those patients who live in regions with limited access to in-office phototherapy or have significant barriers to coming into the clinic. Conditions for which patients are referred to commercial tanning beds include psoriasis, renal prurigo, atopic dermatitis, and mycosis fungoides. PMID- 26047523 TI - Differential effects of massed and spaced training on place and response learning: A memory systems perspective. AB - Studies employing brain lesion or intracerebral drug infusions in rats have demonstrated a double dissociation between the roles of the hippocampus and dorsolateral striatum in place and response learning. The hippocampus mediates a rapid cognitive learning process underlying place learning, whereas the dorsolateral striatum mediates a relatively slower learning process in which stimulus-response habits underlying response learning are acquired in an incremental fashion. One potential implication of these findings is that hippocampus-dependent learning may benefit from a relative massing of training trials, whereas dorsal striatum-dependent learning may benefit from a relative distribution of training trials. In order to examine this hypothesis, the present study compared the effects of massed (30s inter-trial interval; ITI) or spaced (30min ITI) training on acquisition of a hippocampus-dependent place learning task, and a dorsolateral striatum-dependent response task in a plus-maze. In the place task rats swam from varying start points (N or S) to a hidden escape platform located in a consistent spatial location (W). In the response task rats swam from varying start points (N or S) to a hidden escape platform located in the maze arm consistent with a body-turn response (left). In the place task, rats trained with the massed trial schedule acquired the task quicker than rats trained with the spaced trial schedule. In the response task, rats trained with the spaced trial schedule acquired the task quicker than rats trained with the massed trial schedule. The double dissociation observed suggests that the reinforcement parameters most conducive to effective learning in hippocampus dependent and dorsolateral striatum-dependent learning may have differential temporal characteristics. PMID- 26047524 TI - PD-1/PD-L1 inhibitors. AB - Tumors may adopt normal physiologic checkpoints for immunomodulation leading to an imbalance between tumor growth and host surveillance. Antibodies targeting the PD-1/PD-L1 checkpoint have shown dynamic and durable tumor regressions, suggesting a rebalancing of the host-tumor interaction. Nivolumab and pembrolizumab are the anti-PD-1 antibodies that are currently the furthest in clinical development, and anti-PD-L1 agents under investigation include MPDL3280A, MEDI4736, and BMS-936559. These agents have been used to treat advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer and Hodgkin lymphoma, amongst other tumor types. In this article, we review the updated response results for early clinical trials, note recent FDA actions regarding this class of agents, and summarize results across trials looking at PD-L1 status as a predictor of response to anti-PD-1/PD-L1. PMID- 26047525 TI - A polyvinyl alcohol-functionalized sorbent for extraction and determination of aminoglycoside antibiotics in honey. AB - A novel highly hydrophilic sorbent simply prepared by coating polyvinyl alcohol (PVA) onto silica gel was used for extraction and determination of aminoglycoside antibiotics (AAs). The fabricated PVA coating is aimed to effectively protect core silica gel inside and offers good hydrophilic property. In combination of hydrophilic interaction chromatography tandem mass spectrometry, the performance of the sorbent was evaluated by selecting four model AAs (dihydrostreptomycin, streptomycin, kanamycin, spectinomycin). The sorbent was found to have effective adsorption ability to hydrophilic AAs, which was superior or comparable to those of commercial ones. Good recoveries (84-112%) of model AAs spiked in honey were obtained with good precision (<12.4%) and the limit of quantitation for the proposed method was in the range of 7.8-19.4ng/mL. PMID- 26047526 TI - Co-expression of vacuolar Na(+)/H(+) antiporter and H(+)-pyrophosphatase with an IRES-mediated dicistronic vector improves salinity tolerance and enhances potassium biofortification of tomato. AB - Potassium (K) deficiency is a worldwide problem. Thus, the K biofortification of crops is needed to enhance human nutrition. Tomato represents an ideal candidate for such biofortification programs thanks to its widespread distribution and its easy growth on a commercial scale. However, although tomato is moderately tolerant to abiotic stresses, the crop losses due to salinity can be severe. In this study, we generated transgenic tomato plants over-expressing a Na(+) K(+)/H(+) exchanger gene (TNHXS1), singly or with H(+)-pyrophosphatase (H(+) PPiase) gene using a bicistronic construct. Transgenic tomato lines co-expressing both genes (LNV) significantly showed higher salinity tolerance than the wild type (WT) plans or those expressing the TNHXS1 gene alone (LN). Indeed, under salt stress conditions, double transgenic plants produced higher biomass and retained more chlorophyll and catalase (CAT) activity. In addition, they showed earlier flowering and produced more fruits. To address K deficiencies in humans, an increase of 50% in K content of vegetable products was proposed. In this study, ion content analysis revealed that, under salt stress, fruits from double transgenic plants accumulated 5 times more potassium and 9 times less sodium than WT counterparts. Interestingly, the ionomic analysis of tomato fruits also revealed that LNV had a distinct profile compared to WT and to LN plants. Indeed, LNV fruits accumulated less Fe(2+), Ca(2+), Mg(2+) and Zn(2+), but more Mn(2+). This study demonstrates the effectiveness of bicistronic constructs as an important tool for the enhancement of biofortification and salt stress tolerance in crops. PMID- 26047527 TI - Exploring Fluorous Affinity by Liquid Chromatography. AB - Terms such as "fluorous affinity" and "fluorophilicity" have been used to describe the unique partition and sorption properties often exhibited by highly fluorinated organic compounds, that is molecules rich in sp(3) carbon-fluorine bonds. In this work, we made use of a highly fluorinated stationary phase and a series of benzene derivatives to study the effect of one single perfluorinated carbon on the chromatographic behavior and adsorption properties of molecules. For this purpose, the adsorption equilibria of alpha,alpha,alpha trifluorotoluene, toluene, and other alkylbenzenes have been studied by means of nonlinear chromatography in a variety of acetonitrile/water eluents. Our results reveal that one single perfluorinated carbon is already enough to induce a drastic change in the adsorption properties of molecules on the perfluorinated stationary phase. In particular, it has been found that adsorption is monolayer if the perfluoroalkyl carbon is present but that, when this unit is missing, molecules arrange as multilayer stack structures. These findings can contribute to the understanding of molecular mechanisms of fluorous affinity. PMID- 26047528 TI - A versatile salicyl hydrazonic ligand and its metal complexes as antiviral agents. AB - Acylhydrazones are very versatile ligands and their coordination properties can be easily tuned, giving rise to metal complexes with different nuclearities. In the last few years, we have been looking for new pharmacophores able to coordinate simultaneously two metal ions, because many enzymes have two metal ions in the active site and their coordination can be a successful strategy to inhibit the activity of the metalloenzyme. As a part of this ongoing research, we synthesized the acylhydrazone H2L and its complexes with Mg(II), Mn(II), Co(II), Ni(II), Cu(II) and Zn(II). Their characterization, both in solution--also by means of potentiometric studies--and in the solid state, evidenced the ability of the o-vanillin hydrazone scaffold to give rise to different types of metal complexes, depending on the metal and the reaction conditions. Furthermore, we evaluated both the free ligand and its metal complexes in in vitro studies against a panel of diverse DNA- and RNA-viruses. In particular, the Mg(II), Mn(II), Ni(II) and Zn(II) complexes had EC50 values in the low micromolar range, with a pronounced activity against vaccinia virus. PMID- 26047529 TI - Vitamin D and uterine leiomyoma among a sample of US women: Findings from NHANES, 2001-2006. AB - Scientific understanding of the etiology of uterine leiomyomata (UL) remains incomplete, but recent investigations have suggested an association between low Vitamin D and UL risk. In this study, we conducted a cross-sectional analysis of Vitamin D exposure, measured using serum levels of 25(OH)D (a Vitamin D metabolite), and self-reported UL diagnosis among 3590 women aged 20-54 in the National Health and Nutrition Examination Survey (NHANES 2001-2006). Multivariate logistic regression models comparing each quartile of 25(OH)D to the lowest quartile indicated no relationship between 25(OH)D and odds of UL in the whole population (Ptrend=0.37), or in sensitivity analyses. However, a probabilistic analysis correcting outcome misclassification indicated that insufficient 25(OH)D was associated with UL in white (Odds ratio (OR) median estimate: 2.17; 2.5, 97.5 percentiles: (1.26, 23.47)), but not black women (OR median estimate: 1.70; 2.5, 97.5 percentiles: (0.89, 3.51)), suggesting misclassification may have driven some of the null findings. PMID- 26047530 TI - Feasibility of Handcycle Training During Inpatient Rehabilitation in Persons With Spinal Cord Injury. AB - OBJECTIVE: To assess the feasibility of a handcycle training program during inpatient rehabilitation and the changes in physical capacity in persons with subacute spinal cord injury (SCI). DESIGN: Before-after trial. SETTING: Rehabilitation centers. PARTICIPANTS: Persons with subacute SCI in regular rehabilitation (N=45). INTERVENTIONS: A structured handcycle interval training program during the last 8 weeks of inpatient rehabilitation. Training was scheduled 3 times per week (24 sessions total), with an intended frequency of >=2 times per week. Intended intensity was a Borg score of 4 to 7 on a 10-point scale. MAIN OUTCOME MEASURES: Feasibility was assessed, and participant satisfaction was evaluated (n=30). A maximal handcycling test was performed 8 weeks prior to discharge and at discharge to determine peak power output and peak oxygen uptake (VO2peak) (n=23). RESULTS: Of the participants, 91% completed the handcycle training, and no adverse events were reported. Mean training frequency was 1.8+/-0.5 times per week, and mean Borg score was 6.2+/-1.4. Persons with complete lesions demonstrated lower training feasibility. Most participants were satisfied with the handcycle training. Peak power output and VO2peak improved significantly after the training period (P<.01) by 36.4% and 9.6%, respectively. CONCLUSIONS: Overall, handcycle training during inpatient rehabilitation in persons with SCI was feasible except for the training frequency. Persons with complete lesions likely need extra attention to benefit optimally from handcycling training. Because the improvements in physical capacity were larger than those known to occur in persons with paraplegia receiving regular rehabilitation, the results suggest that the addition of handcycle training may result in larger increases in physical capacity compared with regular rehabilitation only. PMID- 26047531 TI - Frequency of Dietary Recalls, Nutritional Assessment, and Body Composition Assessment in Men With Chronic Spinal Cord Injury. AB - OBJECTIVES: To assess different frequencies of dietary recalls while evaluating caloric intake and the percentage of macronutrients in men with spinal cord injury (SCI) and to examine the relations between caloric intake or percentage of macronutrients and assessment of whole and regional body composition using dual energy x-ray absorptiometry. DESIGN: Cross-sectional and longitudinal. SETTING: Laboratory and hospital. PARTICIPANTS: Men with chronic (>1 y postinjury) motor complete SCI (N=16). INTERVENTIONS: Participants were asked to turn in a 5-day dietary recall on a weekly basis for 4 weeks. The averages of 5-, 3-, and 1-day dietary recalls for caloric intake and percentage of macronutrients (carbohydrates, fat, protein) were calculated. Body composition was evaluated using whole-body dual-energy x-ray absorptiometry. After overnight fast, basal metabolic rate (BMR) was evaluated using indirect calorimetry and total energy expenditure (TEE) was estimated. MAIN OUTCOME MEASURES: Caloric intake, percentage of macronutrients, BMR, and body composition. RESULTS: Caloric intake and percentage of macronutrients were not different after using 5-, 3-, and 1-day dietary recalls (P>.05). Caloric intake was significantly lower than TEE (P<.05). The percentage of fat accounted for 29% to 34% of the whole and regional body fat mass (P=.037 and P=.022). The percentage of carbohydrates was positively related to the percentage of whole-body lean mass (r=.54; P=.037) and negatively related to the percentage of fat mass. CONCLUSIONS: The frequency of dietary recalls does not vary while evaluating caloric intake and macronutrients. Total caloric intake was significantly lower than the measured BMR and TEE. Percentages of dietary fat and carbohydrates are related to changes in body composition after SCI. PMID- 26047532 TI - Risk factors for depressive symptoms in glaucoma patients: a nationwide case control study. AB - PURPOSE: The purpose was to investigate the risk factors for depressive symptoms in glaucoma patients. METHODS: From the Longitudinal Health Insurance Database in Taiwan, we included 1190 glaucoma patients with subsequent depression diagnoses in the case group and randomly selected 4673 glaucoma patients without depression diagnoses as the control group, matched by age, sex, and time of glaucoma diagnosis. The age-adjusted Charlson comorbidity index (ACCI) score was used to compute the burden of comorbidity for each patient. Current use (past 6 months) of topical antiglaucoma medications and systemic medications was identified. Multivariate regression was used to analyze the risk factors for depression. RESULTS: The mean age for glaucoma patients was 61.88 years. Patients with depressive symptoms had significantly higher ACCI scores (P < .0001). The current use of any topical antiglaucoma medications was not associated with an increased risk for depression. However, higher ACCI scores (P < .0001), cerebrovascular diseases (odds ratio [OR] = 1.324, 95 % confidence interval [CI] = 1.118--1.568), dementia (OR = 2.647, 95 % CI = 2.142-3.270), thyroid diseases (OR = 1.720, 95 % CI = 1.366-2.165), headaches (OR = 1.299, 95 % CI = 1.112-1.518), and current use of systemic beta-blockers (OR = 1.782, 95 % CI = 1.538-2.065) and calcium channel blockers (OR = 1.396, 95 % CI, 1.197-1.629) were found to increase the risk of depression in glaucoma patients. CONCLUSIONS: In this study, a comorbidity burden was a significant risk factor for depression in glaucoma patients, particularly for those currently using systemic beta-blockers and calcium channel blockers. PMID- 26047533 TI - Enhanced-depth optical coherence tomography for imaging horizontal rectus muscles in Graves' orbitopathy. AB - PURPOSE: Graves' orbitopathy (GO) is an extraocular eye disease with symptoms ranging from minor discomfort from dry eyes to strabismus and visual loss. One of the hallmarks of active GO is visible hyperemia at the insertion of the extraocular muscles. The aim of the present study was to evaluate the use of enhanced-depth imaging spectral domain anterior segment optical coherence tomography (EDI SD AS-OCT) for detecting pathological changes in horizontal recti muscles of patients with GO. METHODS: Prospective cross sectional study of 27 eyes. Only women were included. EDI AS-OCT was used to measure the thickness of the tendons of the horizontal recti muscles in a predefined area in patients with GO and healthy controls. RESULTS: EDI AS-OCT was able to image the tendons of the horizontal recti muscles in both healthy controls and patients suffering from GO. The mean thickness of the medial rectus muscle (MR) tendon was 256.4 MUm [+/ 17.13 MUm standard deviation (SD)] in the GO group and, therefore, significantly thicker (p = 0.046) than in the healthy group which had a mean thickness of 214.7 MUm (+/-5.516 MUm SD). There was no significant difference in the mean thickness of the tendon of the lateral recti muscles (LRs) between these groups. CONCLUSION: This is the first report showing that EDI AS-OCT is suitable to detect swelling at the insertion site of the MR muscle in GO. MR tendon thickness may be a useful parameter to monitor activity in these patients. PMID- 26047534 TI - Antifibrotic effects of pirfenidone on Tenon's fibroblasts in glaucomatous eyes: comparison with mitomycin C and 5-fluorouracil. AB - PURPOSE: The purpose of this study was to evaluate the antifibrotic effects of pirfenidone (PFD) on primary cultured human Tenon's fibroblasts (HTFs) from primary open-angle glaucoma (POAG) eyes, compared to mitomicin C (MMC) and 5 fluorouracil (5-FU). MATERIALS AND METHODS: Samples of human Tenon's capsule were obtained during respective surgeries from three groups of patients: patients with cataract (CAT group), patients with POAG who underwent glaucoma filtration surgery (GFS) (POAG1 group), and patients with POAG who underwent GFS due to failed bleb of previous GFS (POAG2 group). Cell toxicity, cell migration, and the expression level of alpha-smooth muscle actin (alpha-SMA) protein were evaluated in primary cultured HTFs from the three patient groups after treatment (PFD, MMC, or 5-FU). RESULTS: Overall, cell viability after PFD treatment was higher compared to MMC treatment (82.3 +/- 5.1 % vs 56.7 +/- 3.8 %; p = 0.001) and comparable to 5-FU treatment (82.3 +/- 5.1 % vs 85.7 +/- 10.7 %, p = 0.214) at the same concentration (0.4 mg/ml). Both 0.3 mg/ml PFD and 0.1 mg/ml MMC inhibited cell migration compared to control (without treatment) cells (p = 0.014 and 0.005, respectively), while 0.2 mg/ml 5-FU showed the highest degree of cell migration among the three agents in the POAG1 group (PFD vs MMC vs 5-FU; 29.5 +/- 2.1 % vs 34.5 +/- 0.7 % vs 76.0 +/- 8.5 %, PFD vs MMC; p = 1.000, PFD vs 5-FU; p = 0.008, MMC vs 5-FU; p = 0.011). PFD (0.1 or 0.3 mg/ml) and MMC (0.05 and 0.1 mg/ml) treatment significantly reduced the protein expression level of alpha-SMA in the POAG 1 group (all p < 0.05), and the alpha-SMA protein level following treatment with 0.3 mg/ml PFD was lower than that of 0.1 mg/ml MMC (p = 0.040). CONCLUSION: PFD showed less cytotoxicity compared to MMC. PFD and MMC inhibited cell migration and reduced alpha-SMA protein expression levels, while 5-FU showed neither inhibition of cell migration nor reduction in alpha-SMA expression level. These findings indicate PFD as a potential adjunctive antifibrotic agent to prevent bleb failure during GFS. PMID- 26047535 TI - The use of human cornea organotypic cultures to study herpes simplex virus type 1 (HSV-1)-induced inflammation. AB - PURPOSE: To determine the utility of human organotypic cornea cultures as a model to study herpes simplex virus type 1 (HSV-1)-induced inflammation and neovascularization. METHODS: Human organotypic cornea cultures were established from corneas with an intact limbus that were retrieved from donated whole globes. One cornea culture was infected with HSV-1 (10(4) plaque-forming units), while the other cornea from the same donor was mock-infected. Supernatants were collected at intervals post-culture with and without infection to determine viral titer (by plaque assay) and pro-angiogenic and proinflammatory cytokine concentration by suspension array analysis. In some experiments, the cultured corneas were collected and evaluated for HSV-1 antigens by immunohistochemical means. Another set of experiments measured susceptibility of human three dimensional cornea fibroblast constructs, in the presence and absence of TGF beta1, to HSV-1 infection in terms of viral replication and the inflammatory response to infection as a comparison to the organotypic cornea cultures. RESULTS: Organotypic cornea cultures and three-dimensional fibroblast constructs exhibited varying degrees of susceptibility to HSV-1. Fibroblast constructs were more susceptible to infection in terms of infectious virus recovered in a shorter period of time. There were changes in the levels of select pro-angiogenic or proinflammatory cytokines that were dictated as much by the cultures producing them as by whether they were infected with HSV-1 or treated with TGF-beta1. CONCLUSION: Organotypic cornea and three-dimensional fibroblast cultures are likely useful for the identification and short-term study of novel antiviral compounds and virus replication, but are limited in the study of the local immune response to infection. PMID- 26047536 TI - Long-term effects of intracameral moxifloxacin. PMID- 26047537 TI - Application of water-assisted pulsed light treatment to decontaminate raspberries and blueberries from Salmonella. AB - We developed and evaluated a small scaled-up water-assisted pulsed light (WPL) system, in which berries were washed in a flume washer while being irradiated by pulsed light (PL). Hydrogen peroxide (H2O2) was used in combination with PL as an advanced oxidation process and chlorine wash was used as a control. The effects of organic load, water turbidity, berry type and PL energy output on the inactivation of Salmonella using the WPL system were investigated. The combination of WPL and 1% H2O2 (WPL-H2O2) was the most effective treatment which reduced Salmonella on raspberries and blueberries by 4.0 and >5.6logCFU/g, respectively, in clear water. When high organic load and SiO2, as a soil simulator, were added in wash water, the free chlorine level in chlorinated water decreased significantly (P<0.05); however, no significant difference (P>0.05) was observed for the decontamination efficacy of 1-min WPL-H2O2 treatment. Even in the presence of high organic load and water turbidity, no viable bacterial cells were recovered from the wash water, which showed that WPL-H2O2 could effectively prevent the risk of cross-contamination during treatment. Taken together, 1-min WPL treatment without H2O2 could provide a chemical free alternative to chlorine washing with similar and in some cases significantly higher bactericidal efficacy. Compared with chlorine washing, the combination of WPL and H2O2 resulted in significantly higher (P<0.05) reduction of Salmonella on berries, providing a novel intervention for processing of small berries intended for fresh cut and frozen berry products. PMID- 26047538 TI - Fertility analysis from a life course perspective. AB - In the past decades, the life course approach has gained importance in studies on the timing and incidence of childbirth. It allows a complex analysis of fertility. Following this approach, family formation and parenthood are perceived as instrumental goals of individual welfare production over the life course. In addition, the analysis of fertility has to take into account three kinds of essential interdependence: time dependence of the life course, multilevel structure of the life course and multidimensionality of the life course. As a consequence future fertility research should emphasize more on pre-decisional individual dispositions and behavioral intentions, should take into account more seriously that fertility takes place in the context of interdependent social relationships and social groups, and address changes in the cultural and institutional environment. The aim of this special issue is to present a series of empirical studies touching upon some of these aspects and therefore substantially contributing to progress in contemporary longitudinal fertility research. The twelve contributions deal with childbearing intentions and outcomes in multidimensional life courses; dyadic decision-making and social influences on fertility; and the interdependence of spatial mobility, regional context, culture, and fertility. PMID- 26047539 TI - Educational differences in fertility desires, intentions and behaviour: A life course perspective. AB - Despite a long tradition of studying the relationship between education and fertility outcomes less is known about how educational differences in fertility intentions are formed and translated into achieved births over the life course. This paper provides new insights using data from a large cohort study and Miller's Traits-Desires-Intentions-Behaviour framework for understanding childbearing. We examine how parental aspirations for education, educational ability in childhood, and educational attainment in young adulthood relate to: males' and females' fertility desires in adolescence; fertility intentions in early adulthood; and educational differences in the achievement of fertility intentions. We conclude that family building preferences expressed in adolescence, especially those for the timing of entry into parenthood are shaped by parental socio-economic background, mediated through educational ability and parental expectations for education. In young adulthood, no clear, consistent educational gradient in intended family size is found. However, there is a negative educational gradient in the likelihood of achieving intended births by age 46, especially for women. The findings indicate the importance of educational differences in employment and partnership behaviour in mediating these relationships. PMID- 26047541 TI - Compensating dissatisfaction in the job by turning to the family? The impact of current occupation on timing of first births in Germany. AB - The current study analyses the impact of occupational activity on the timing of first births in Germany. Empirical evidence on the topic in a country with a standardized education system and a credential labor market is still rather limited, despite several recent studies. Moreover, previous research usually lacks the theoretical explanation of why women working in certain occupations are more likely to give birth. This study aims to close these gaps. Using the German Life History Study, occupations are grouped according to characteristics deduced from theoretical considerations using a cluster analysis. In the next step, exponential rate models are estimated to investigate the effect of the clusters on fertility timing. The estimations reveal an accelerated transition to parenthood for women and men working in occupations with unfavorable working conditions. Individuals thus seem to compensate for dissatisfaction with the job by turning to the family. However, for women these occupational differences can completely be explained by differences in educational level, while the effects remain if we look at men. PMID- 26047540 TI - On the positive correlation between education and fertility intentions in Europe: Individual- and country-level evidence. AB - Increasing shares of European women are making large investments in their human capital. Whether and to what extent these investments are in conflict with reproductive behaviour are issues that have repercussions for fertility levels. Using two Eurobarometer survey data (2006 and 2011) on individuals clustered in the 27 EU countries, I investigate the relationship between women's education and lifetime fertility intentions. Results suggest that a positive association between women's level of education and lifetime fertility intentions exists at both the individual and country levels, as well as in a micro-macro integrated framework. The main explanation for these findings--which remains to be proven by future research--is that, in institutional contexts allowing highly educated women to have large families, women of reproductive ages are more prone to make investments in both human capital and family size, because these choices are not seen as incompatible alternatives. PMID- 26047542 TI - Socioeconomic differences in the unemployment and fertility nexus: Evidence from Denmark and Germany. AB - Studies that have investigated the role of unemployment in childbearing decisions have often shown no or only barely significant results. We argue that many of these "non-findings" may be attributed to a neglect of group-specific differences in behavior. In this study, we examine how the association of unemployment and fertility varies by socio-demographic subgroups using data from the German Socio Economic Panel (GSOEP) and from Danish population registers. We find that male unemployment is related to a postponement of first and second childbearing in both countries. The role of female unemployment is less clear at these two parities. Both male and female unemployment is positively correlated with third birth risks. More importantly, our results show that there are strong educational gradients in the unemployment and fertility nexus, and that the relationship between unemployment and fertility varies by socioeconomic group. Fertility tends to be lower during periods of unemployment among highly educated women and men, but not among their less educated counterparts. PMID- 26047543 TI - Unintended pregnancy in the life-course perspective. AB - OBJECTIVE: In this contribution unintended pregnancies are studied as a multidimensional concept from a life-course perspective. Standardized data on the prevalence of unwanted pregnancies in different stages of women's life course are combined with a qualitative analysis of the subjective meaning of "unwanted" and of subjective explanations of getting pregnant unintentionally. METHODS: The study "frauen leben 3" on family planning in the life course of 20-44 year old women was conducted on behalf of the Federal Centre for Health Education (BZgA) from 2011 until 2014 in four federal states in Germany. A standardized questionnaire was used to collect retrospective information on 4794 pregnancies (including induced abortions), and biographical in-depth interviews provide qualitative information on 103 unwanted pregnancies. The standardized data were analyzed with bivariate methods and multivariate logistic regression models. The qualitative procedure to construct typologies of subjective meanings consisted of contrasting cases according to the generative approach of Grounded Theory. MAIN RESULTS: In contrast to unwanted pregnancies, mistimed pregnancies are characterized to a greater extent by negligence in the use of contraceptives, by a positive reaction to the pregnancy and by a more general desire to have a child. Four different subjective meanings of "unwanted" are constructed in qualitative analysis. The logistic regressions show that the selected factors that increase the likelihood of an unwanted pregnancy vary according to age and stage in the life course. The quantitative analysis reveals furthermore that relationship with a partner had a significant effect in all stages of the life course. The qualitative interviews specify the age- and life course-related aspects of these effects. PMID- 26047544 TI - Dyadic fertility decisions in a life course perspective. AB - This paper focuses on how couples arrive at joint decisions with regard to fertility behaviour. We build upon previous work on decision rules that couples might apply as heuristics in order to arrive at joint action in cases in which partners' fertility preferences differ. Previous research found either stronger effects of women's desires or symmetrical effects of both spouses' desires and net benefits associated with (further) children on proceptive behaviour. The latter finding is in line with the notion of household utility maximisation, in which both partners' preferences enter into a joint utility function with equal weight. On the other hand, some evidence indicates that one partner can exercise a 'veto' if he or she anticipates individual utility losses from a further child (due to opportunity costs arising in other life domains). We now enhance previous research by applying a life-course perspective. Our analysis makes use of variation in initial conditions due to previous births: couples decide on fertility in different situations as they find themselves in different life course stages and have had certain experiences. Parity-specific differences affect not only fertility outcomes but also the decision-making process itself. Our findings show that the decision to have a first child is made jointly, and each partner may exercise a veto. On the other hand, women appear to dominate decisions on higher parity births, not per se, but because they are (still) the ones more affected by the concomitant housework. PMID- 26047545 TI - Fertility after repartnering in the Netherlands: Parenthood or commitment? AB - In this paper, we focus on childbearing after the dissolution of the first marital union. The discussion of what drives fertility decisions after dissolution has been largely dominated by the arguments that: (a) people want to have a child as a way to achieve the adult status of parenthood (the "parenthood hypothesis"), and that (b) a shared child can signal the partners' commitment to each other (the "commitment hypothesis"). Earlier studies have reported mixed findings for these hypotheses. We used couple data from several Dutch surveys (N = 8094 couples of which 10.2% included a repartnering partner) and utilized a new analytical approach to test the commitment proposition in particular. Our main findings lend support to the parenthood hypothesis when it comes to men's transition to a union-specific birth and to the commitment hypothesis when considering women's transition. Whereas for men, children from a prior union decrease the likelihood of transitioning to a union-specific birth, for women children from a prior union do not matter. That is, women would find it important to confirm the union as a family despite the presence of children. Additional support for the commitment hypothesis for women is that being in a second union rather than first union increases chances of parity progression. PMID- 26047546 TI - Fertility and social interaction at the workplace: Does childbearing spread among colleagues? AB - This research investigates whether colleagues' fertility influences women's transitions to parenthood. We draw on Linked-Employer-Employee data (1993-2007) from the German Institute for Employment Research comprising 33,119 female co workers in 6579 firms. Results from discrete-time hazard models reveal social interaction effects on fertility among women employed in the same firm. In the year after a colleague gave birth, transition rates to first pregnancy double. This effect declines over time and vanishes after two years. Further analyses suggest that the influence of colleagues' fertility is mediated by social learning. PMID- 26047547 TI - Is fertility contagious? Using panel data to disentangle mechanisms of social network influences on fertility decisions. AB - Using panel data (N = 1.679 married and cohabiting couples), this paper investigates the presence and causal mechanisms of social contagion processes regarding first births. Results confirmed the hypothesized positive association between the number of network members (friends, acquaintances, siblings) with young children and the respondents' transition rate into parenthood, particularly among younger couples. Several potential intervening mechanisms underlying this social contagion effect were tested. First, evidence was found for observational learning processes in which Ego obtained information on the joys and challenges of parenthood from network members with children. Second, childless respondents tended to feel pressured from couples with children in the network to start a family. Third, results supported the notion of social opportunity costs in that the anticipated loss of social ties after becoming a parent was more likely the fewer parents there were in the network. All three mechanisms exerted a positive impact on both fertility intentions and behavior. Panel regression models relying on intraindividual change scores showed that social learning was the most robust mechanism. An additional indirect test for causality suggested that the findings were unlikely to merely reflect parental status homophily (i.e., selection effects). PMID- 26047548 TI - Value of children and fertility: Results from a cross-cultural comparative survey in eighteen areas in Asia, Africa, Europe and America. AB - For explaining cross-cultural differences in fertility behavior, this paper conjoins three complementary approaches: the 'demand'-based economic theory of fertility (ETF), a revised version of the 'supply'-based 'value-of-children' (VOC)-approach as a special theory of the general social theory of social production functions and the framing theory of variable rationality. A comprehensive model is specified that encompasses the variable efficiency of having children for the optimization of physical well-being and of social esteem of (potential) parents; it also accounts for the variable rationality of fertility decisions. The model is tested with a data set that comprises information on VOC and fertility of women within the social settings of 18 areas (Peoples Republic of China, North and South India, Indonesia, Palestine, Israel, Turkey, Ghana, South Africa, East and West Germany, the Czech Republic, France, Russia, Poland, Estonia, the United States and Jamaica). Latent class analysis is used to establish a measurement model for the costs and benefits of children and to analyze area differences by a two-level multinomial-model. Two-level Cox regressions are used to estimate the effects of perceived costs and benefits of children, individual resources and context opportunities, with births of different parity as dependents. This simultaneous test in a cross-cultural context goes beyond the current state of fertility research and provides evidence about the cross-cultural validity of the model, the systematic effects of VOC on fertility and the changing rationality of fertility decisions during demographic transition and socio-economic change. PMID- 26047549 TI - Geographical variations in fertility and transition to second and third birth in Britain. AB - Geographical variations in fertility have been observed within several countries in Northern Europe, with higher fertility in rural areas, smaller settlements and city suburbs. However, the processes underlying such fertility variations across residential contexts are not well understood. This paper contributes to the on going debate by looking at local variations in fertility in Britain. It aims to disentangle the relative contribution of a number of factors, including the socio economic characteristics of individuals, housing conditions, patterns of residential relocation and lastly, contextual factors stricto sensu. In addition, it seeks to identify those aspects of reproductive behaviour which are more likely to be associated with the observed spatial differences, and to distinguish between those that may be influenced by local context and those that respond to social influences at different scales. The focus is on local fertility contexts which, we argue, have the potential to influence the fertility behaviour of individuals through processes of social learning. Individual level data from the British Household Panel Survey and methods of event history analysis are used to explore women's transitions to second and third order births in Britain in the early 21st century. Our findings indicate that individual reproductive life paths respond to a variety of social processes acting at various scales, and that these influences vary by birth order. Most interestingly, local fertility contexts influence transition to first birth but not transition to higher order births, which are mainly associated with individual characteristics of women and their partners. Dominant spacing effects, however, suggest that local contexts have an indirect impact on second and third births through age at the onset of childbearing. The study demonstrates the importance of considering social interaction theories, and their extension to scale-sensitive spatial contexts in which these interactions take place, when analysing geographical variations in fertility. Future research seeking to explain subnational fertility variations must recognize the importance of developing theoretical understandings to inform empirical work. PMID- 26047550 TI - Residential context, migration and fertility in a modern urban society. AB - This study examines fertility variation by residential context in Britain. While there is a large literature on fertility trends and determinants in industrialised countries, to date longitudinal research on spatial fertility variation has been restricted to the Nordic countries. We study fertility variation across regions of different sizes, and within urban regions by distinguishing between central cities and suburbs. We use vital statistics and longitudinal data and apply event history analysis. We investigate the extent to which the socio-economic characteristics of couples and selective migrations explain fertility variation between residential contexts, and the extent to which contextual factors potentially play a role. Our analysis shows that fertility levels decline as the size of an urban area increases; within urban regions suburbs have significantly higher fertility levels than city centres. Differences in fertility by residential context persist when we control for the effect of population composition and selective migrations. PMID- 26047551 TI - Green Tea and Bone Marrow Transplantation: From Antioxidant Activity to Enzymatic and Multidrug-resistance Modulation. AB - Epigallocatechin-3-gallate (EGCG), the main flavonoid of green tea (GT), could play an active role in the prevention of oxidative-stress-related diseases, such as hematologic malignancies. Some effects of EGCG are not imputable to antioxidant activity, but involve modulation of antioxidant enzymes and uric acid (UA) levels. The latter is the major factor responsible of the plasma non enzymatic antioxidant capacity (NEAC). However, hyperuricemia is a frequent clinical feature caused by tumor lysis syndrome or cyclosporine side effects, both before and after bone marrow transplantation (BMT). Besides this, food-drug interactions could be associated with GT consumption and could have clinical implications. The molecular mechanisms involved in the redox and drug metabolizing/transporting pathways were discussed, with particular reference to the potential role of GT and EGCG in BMT. Moreover, on reviewing data on NEAC, isoprostanes, uric acid, and various enzymes from human studies on GT, its extract, or EGCG, an increase in NEAC, without effect on isoprostanes, and contrasting results on UA and enzymes were observed. Currently, few and contrasting available evidences suggest caution for GT consumption in BMT patients and more studies are needed to better understand the potential impact of EGCG on oxidative stress and metabolizing/transporting systems. PMID- 26047552 TI - [Home care for acute pulmonary embolism: Feasibility and general practitioner acceptability]. AB - BACKGROUND: In France, initial management of pulmonary embolism (PE) is performed in the hospital setting. The latest international guidelines suggest that PE at low risk of mortality can be treated in the ambulatory care setting. This means that ambulatory care pathways and general practitioner (GP) opinions concerning such a change in practice need to be determined. OBJECTIVES: To determine: (1) rate of patients eligible for an ambulatory management of their PE and reasons for hospitalization of PE at low risk of mortality; (2) acceptability for GPs of PE home care and patient's desired care pathway. METHODS: Two-part prospective observational study conducted in Montpellier University Hospital from May 2012 to August 2013: (1) in-hospital study including all consecutive patients with non hospital acquired PE; (2) telephonic survey on PE patient's ambulatory care pathway conducted among GPs. RESULTS: In-hospital study: 99.1% (n=211) of included patients were hospitalized and only 14.1% (n=30) had all criteria for home care. Patient's pathway survey: 68.3% (n=112) of GPs, particularly those aged 40-54 years and those who had already managed patients alone after hospital discharge, were in favour of home care for PE. One hundred and thirty-nine (84.8%) GPs wanted a collaborative management with an expert thrombosis physician and an outpatient follow-up visit at one week. CONCLUSION: Few patients managed at Montpellier University Hospital are eligible for ambulatory management of their PE. GPs have a favorable opinion of home care for PE if it is conducted in collaboration with an expert thrombosis physician. PMID- 26047553 TI - Valorization of fatty acids-containing wastes and byproducts into short- and medium-chain length polyhydroxyalkanoates. AB - Olive oil distillate (OOD), biodiesel fatty acids-byproduct (FAB) and used cooking oil (UCO) were tested as inexpensive carbon sources for the production of polyhydroxyalkanoates (PHA) with different composition using twelve bacterial strains. OOD and FAB were exploited for the first time as alternative substrates for PHA production. UCO, OOD and FAB were used by Cupriavidus necator and Pseudomonas oleovorans to synthesize the homopolymer poly-3-hydroxybutyrate, while Pseudomonas resinovorans and Pseudomonas citronellolis produced mcl-PHA polymers mainly composed of hydroxyoctanoate and hydroxydecanoate monomers. The highest polymer content in the biomass was obtained for C. necator (62 wt.%) cultivated on OOD. Relatively high mcl-PHA content (28-31 wt.%) was reached by P. resinovorans cultivated in OOD. This study shows, for the first time, that OOD is a promising substrate for PHA production since it gives high polymer yields and allows for the synthesis of different polymers (scl- or mcl-PHA) by selection of the adequate strains. PMID- 26047554 TI - Vitamin D treatment protects against and reverses oxidative stress induced muscle proteolysis. AB - Vitamin D is known to have a biological role in many extra skeletal tissues in the body including muscle. Vitamin D deficiency has been associated with preferential atrophy of type II fibres in human muscle. Vitamin D at physiological concentrations is known to protect cells against oxidative damage. In this study we examined whether vitamin D deficiency induces muscle oxidative stress in a rat model and further if pre or post treatment of C2C12 muscle cells with vitamin D offers protection against oxidative stress induced muscle proteolysis. Protein carbonylation as a marker of protein oxidation was increased in both the deficient muscle and vehicle-treated C2C12 cells. Vitamin D deficiency led to an increase in activities of the glutathione-dependent enzymes and decrease in SOD and catalase enzymes in the rat muscle. Higher nitrate levels indicative of nitrosative stress were observed in the deficient muscle compared to control muscle. Rehabilitation with vitamin D could reverse the alterations in oxidative and nitrosative stress parameters. Increase in total protein degradation, 20S proteasomal enzyme activity, muscle atrophy gene markers and expression of proteasome subunit genes induced by oxidative stress were corrected both by pre/post treatment of C2C12 muscle cells with vitamin D. Increase in SOD activity in the presence of vitamin D indicates antioxidant potential of vitamin D in the muscle. The data presented indicates that vitamin D deficiency leads to mild oxidative stress in the muscle which may act as a trigger for increased proteolysis in the vitamin D deficient muscle. PMID- 26047555 TI - Measurement of amniotic fluid steroids of midgestation via LC-MS/MS. AB - INTRODUCTION: Analysis of steroids by mass spectrometry (MS) has evolved into a reliable tool for the simultaneous detection of multiple steroids. As amniotic fluid (AF) and fetal serum composition of early pregnancy are closely related, the analysis of AF can yield information on the physiological status of the developing fetus. We evaluated the use of liquid-chromatography tandem mass spectrometry (LC-MS/MS) for AF steroid analysis, including the analysis of its sensitivity and accuracy for gender verification in healthy subjects. MATERIALS AND METHODS: AF of 78 male and 94 female healthy newborns was analyzed by LC MS/MS at 16 weeks of gestation. The levels of androstenedione, corticosterone, cortisol, cortisone, deoxycorticosterone, 11-deoxycortisol, dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), 17 hydroxyprogesterone, progesterone (17-OHP) and testosterone were measured. Steroid levels were compared to RIA and GC-MS levels of midgestation from the literature. Cross-validated logistic regression was used to obtain statistical predictions of gender at birth from testosterone and the above steroids. RESULTS: LC-MS/MS analysis of AF steroids yielded comparable results with published GC-MS data. Gender specific differences were found for androstenedione and testosterone concentrations with higher levels in the male fetus. In contrast to published RIA data no gender specific differences were observed for 17-hydroxyprogesterone and dehydroepiandrosterone AF concentrations. Testosterone concentrations yielded highly accurate predictions for male gender at birth. Additional analysis of further steroids did neither increase the accuracy, sensitivity nor specificity of this prediction. The estimated optimal cut-off value for amniotic testosterone level was 0.074 MUg/L for healthy male newborns. CONCLUSIONS: LC-MS/MS is a reliable method for the determination of steroids in amniotic fluid. The determination of testosterone in amniotic fluid by LC-MS/MS in early pregnancy of healthy subjects can be used to offer a reliable prediction of fetal gender at birth. PMID- 26047557 TI - Genomics spurs rapid advances in our understanding of the biology of vascular wilt pathogens in the genus Verticillium. AB - The availability of genomic sequences of several Verticillium species triggered an explosion of genome-scale investigations of mechanisms fundamental to the Verticillium life cycle and disease process. Comparative genomics studies have revealed evolutionary mechanisms, such as hybridization and interchromosomal rearrangements, that have shaped these genomes. Functional analyses of a diverse group of genes encoding virulence factors indicate that successful host xylem colonization relies on specific Verticillium responses to various stresses, including nutrient deficiency and host defense-derived oxidative stress. Regulatory pathways that control responses to changes in nutrient availability also appear to positively control resting structure development. Conversely, resting structure development seems to be repressed by pathways, such as those involving effector secretion, which promote responses to host defenses. The genomics-enabled functional characterization of responses to the challenges presented by the xylem environment, accompanied by identification of novel virulence factors, has rapidly expanded our understanding of niche adaptation in Verticillium species. PMID- 26047558 TI - Identification of viruses and viroids by next-generation sequencing and homology dependent and homology-independent algorithms. AB - A fast, accurate, and full indexing of viruses and viroids in a sample for the inspection and quarantine services and disease management is desirable but was unrealistic until recently. This article reviews the rapid and exciting recent progress in the use of next-generation sequencing (NGS) technologies for the identification of viruses and viroids in plants. A total of four viroids/viroid like RNAs and 49 new plant RNA and DNA viruses from 18 known or unassigned virus families have been identified from plants since 2009. A comparison of enrichment strategies reveals that full indexing of RNA and DNA viruses as well as viroids in a plant sample at single-nucleotide resolution is made possible by one NGS run of total small RNAs, followed by data mining with homology-dependent and homology independent computational algorithms. Major challenges in the application of NGS technologies to pathogen discovery are discussed. PMID- 26047556 TI - The next 150 years of congenital adrenal hyperplasia. AB - Congenital adrenal hyperplasias (CAH) are a group of autosomal recessive defects in cortisol biosynthesis. Substantial progress has been made since the description of the first report, 150 years ago. This article reviews some of the recent advances in the genetics, diagnosis and treatment of CAH. In addition, we underline the aspects where further progress is required, including, among others, better diagnostic modalities for the mild phenotype and for some of the rare forms of disease, elucidation of epigenetic factors that lead to different phenotypes in patients with identical genotype and expending on treatment options for controlling the adrenal androgen excess. PMID- 26047559 TI - Sharka epidemiology and worldwide management strategies: learning lessons to optimize disease control in perennial plants. AB - Many plant epidemics that cause major economic losses cannot be controlled with pesticides. Among them, sharka epidemics severely affect prunus trees worldwide. Its causal agent, Plum pox virus (PPV; genus Potyvirus), has been classified as a quarantine pathogen in numerous countries. As a result, various management strategies have been implemented in different regions of the world, depending on the epidemiological context and on the objective (i.e., eradication, suppression, containment, or resilience). These strategies have exploited virus-free planting material, varietal improvement, surveillance and removal of trees in orchards, and statistical models. Variations on these management options lead to contrasted outcomes, from successful eradication to widespread presence of PPV in orchards. Here, we present management strategies in the light of sharka epidemiology to gain insights from this worldwide experience. Although focused on sharka, this review highlights more general levers and promising approaches to optimize disease control in perennial plants. PMID- 26047560 TI - Landscape-scale disease risk quantification and prediction. AB - The study of plant disease epidemics at a landscape scale can be extended to allow for predictions about disease occurrence at this scale. Examined within the context of the disease triangle, systems developed to incorporate information primarily about the pathogen and conditions conducive to the infection process. Parametric methods can be used to relate environmental conditions to disease, and specifically relate environment to the inoculum production, the resulting infection process, or both. Aspects relating to the presence or absence of the host plant within the landscape, or patterns of the host within the landscape, are much rarer in disease prediction, although analyses incorporating these factors have been conducted. Predictive systems at the landscape scale may concentrate only on the conditions for infection or possible migratory paths of pathogen propagules. Incorporation of all components of the disease triangle may be one way to improve these systems. PMID- 26047561 TI - Highways in the sky: scales of atmospheric transport of plant pathogens. AB - Many high-risk plant pathogens are transported over long distances (hundreds of meters to thousands of kilometers) in the atmosphere. The ability to track the movement of these pathogens in the atmosphere is essential for forecasting disease spread and establishing effective quarantine measures. Here, we discuss the scales of atmospheric dispersal of plant pathogens along a transport continuum (pathogen scale, farm scale, regional scale, and continental scale). Growers can use risk information at each of these dispersal scales to assist in making plant disease management decisions, such as the timely application of appropriate pesticides. Regional- and continental-scale atmospheric features known as Lagrangian coherent structures (LCSs) may shuffle plant pathogens along highways in the sky. A promising new method relying on overlapping turbulent back trajectories of pathogen-laden parcels of air may assist in localizing potential inoculum sources, informing local and/or regional management efforts such as conservation tillage. The emergence of unmanned aircraft systems (UASs, or drones) to sample plant pathogens in the lower atmosphere, coupled with source localization efforts, could aid in mitigating the spread of high-risk plant pathogens. PMID- 26047562 TI - Lipochitooligosaccharides modulate plant host immunity to enable endosymbioses. AB - Symbiotic nitrogen-fixing rhizobium bacteria and arbuscular mycorrhizal fungi use lipochitooligosaccharide (LCO) signals to communicate with potential host plants. Upon a compatible match, an intimate relation is established during which the microsymbiont is allowed to enter root (-derived) cells. Plants perceive microbial LCO molecules by specific LysM-domain-containing receptor-like kinases. These do not only activate a common symbiosis signaling pathway that is shared in both symbioses but also modulate innate immune responses. Recent studies revealed that symbiotic LCO receptors are closely related to chitin innate immune receptors, and some of these receptors even function in symbiosis as well as immunity. This raises questions about how plants manage to translate structurally very similar microbial signals into different outputs. Here, we describe the current view on chitin and LCO perception in innate immunity and endosymbiosis and question how LCOs might modulate the immune system. Furthermore, we discuss what it takes to become an endosymbiont. PMID- 26047563 TI - Quantitative resistance to biotrophic filamentous plant pathogens: concepts, misconceptions, and mechanisms. AB - Quantitative resistance (QR) refers to a resistance that is phenotypically incomplete and is based on the joined effect of several genes, each contributing quantitatively to the level of plant defense. Often, QR remains durably effective, which is the primary driver behind the interest in it. The various terms that are used to refer to QR, such as field resistance, adult plant resistance, and basal resistance, reflect the many properties attributed to it. In this article, we discuss aspects connected to those attributions, in particular the hypothesis that much of the QR to biotrophic filamentous pathogens is basal resistance, i.e., poor suppression of PAMP-triggered defense by effectors. We discuss what role effectors play in suppressing defense or improving access to nutrients. Based on the functions of the few plant proteins identified as involved in QR, vesicle trafficking and protein/metabolite transportation are likely to be common physiological processes relevant to QR. PMID- 26047564 TI - Understanding plant immunity as a surveillance system to detect invasion. AB - Various conceptual models to describe the plant immune system have been presented. The most recent paradigm to gain wide acceptance in the field is often referred to as the zigzag model, which reconciles the previously formulated gene for-gene hypothesis with the recognition of general elicitors in a single model. This review focuses on the limitations of the current paradigm of molecular plant microbe interactions and how it too narrowly defines the plant immune system. As such, we discuss an alternative view of plant innate immunity as a system that evolves to detect invasion. This view accommodates the range from mutualistic to parasitic symbioses that plants form with diverse organisms, as well as the spectrum of ligands that the plant immune system perceives. Finally, how this view can contribute to the current practice of resistance breeding is discussed. PMID- 26047565 TI - Range-expanding pests and pathogens in a warming world. AB - Crop pests and pathogens (CPPs) present a growing threat to food security and ecosystem management. The interactions between plants and their natural enemies are influenced by environmental conditions and thus global warming and climate change could affect CPP ranges and impact. Observations of changing CPP distributions over the twentieth century suggest that growing agricultural production and trade have been most important in disseminating CPPs, but there is some evidence for a latitudinal bias in range shifts that indicates a global warming signal. Species distribution models using climatic variables as drivers suggest that ranges will shift latitudinally in the future. The rapid spread of the Colorado potato beetle across Eurasia illustrates the importance of evolutionary adaptation, host distribution, and migration patterns in affecting the predictions of climate-based species distribution models. Understanding species range shifts in the framework of ecological niche theory may help to direct future research needs. PMID- 26047566 TI - Leaf rust of cultivated barley: pathology and control. AB - Leaf rust of barley is caused by the macrocyclic, heteroecious rust pathogen Puccinia hordei, with aecia reported from selected species of the genera Ornithogalum, Leopoldia, and Dipcadi, and uredinia and telia occurring on Hordeum vulgare, H. vulgare ssp. spontaneum, Hordeum bulbosum, and Hordeum murinum, on which distinct parasitic specialization occurs. Although Puccinia hordei is sporadic in its occurrence, it is probably the most common and widely distributed rust disease of barley. Leaf rust has increased in importance in recent decades in temperate barley-growing regions, presumably because of more intensive agricultural practices. Although total crop loss does not occur, under epidemic conditions yield reductions of up to 62% have been reported in susceptible varieties. Leaf rust is primarily controlled by the use of resistant cultivars, and, to date, 21 seedling resistance genes and two adult plant resistance (APR) genes have been identified. Virulence has been detected for most seedling resistance genes but is unknown for the APR genes Rph20 and Rph23. Other potentially new sources of APR have been reported, and additivity has been described for some of these resistances. Approaches to achieving durable resistance to leaf rust in barley are discussed. PMID- 26047568 TI - Identifying and naming plant-pathogenic fungi: past, present, and future. AB - Scientific names are crucial in communicating knowledge about fungi. In plant pathology, they link information regarding the biology, host range, distribution, and potential risk. Our understanding of fungal biodiversity and fungal systematics has undergone an exponential leap, incorporating genomics, web-based systems, and DNA data for rapid identification to link species to metadata. The impact of our ability to recognize hitherto unknown organisms on plant pathology and trade is enormous and continues to grow. Major challenges for phytomycology are intertwined with the Genera of Fungi project, which adds DNA barcodes to known biodiversity and corrects the application of old, established names via epi or neotypification. Implementing the one fungus-one name system and linking names to validated type specimens, cultures, and reference sequences will provide the foundation on which the future of plant pathology and the communication of names of plant pathogens will rest. PMID- 26047567 TI - Torradoviruses. AB - Torradoviruses are an example of a group of recently discovered plant viruses. The first description of Tomato torrado virus, now the type member of the newly established genus Torradovirus within the family Secoviridae, was published in 2007 and was quickly followed by findings of other torradoviruses, initially all on tomato. Their characterization led to the development of tools that allowed recognition of still other torradoviruses, only very recently found on non-tomato crops, which indicates these viruses have a much wider host range and diversity than previously believed. This review describes the characteristics of this newly emerged group of plant viruses. It looks in detail at taxonomic relationships and specific characteristics in their genomes and encoded proteins. Furthermore, it discusses their epidemiology, including host range, semipersistent transmission by whitefly vectors, and impact on diverse cropping systems. PMID- 26047569 TI - Evolution of plant parasitism in the phylum Nematoda. AB - Within the species-rich and trophically diverse phylum Nematoda, at least four independent major lineages of plant parasites have evolved, and in at least one of these major lineages plant parasitism arose independently multiple times. Ribosomal DNA data, sequence information from nematode-produced, plant cell wall modifying enzymes, and the morphology and origin of the style(t), a protrusible piercing device used to penetrate the plant cell wall, all suggest that facultative and obligate plant parasites originate from fungivorous ancestors. Data on the nature and diversification of plant cell wall-modifying enzymes point at multiple horizontal gene transfer events from soil bacteria to bacterivorous nematodes resulting in several distinct lineages of fungal or oomycete-feeding nematodes. Ribosomal DNA frameworks with sequence data from more than 2,700 nematode taxa combined with detailed morphological information allow for explicit hypotheses on the origin of agronomically important plant parasites, such as root knot, cyst, and lesion nematodes. PMID- 26047570 TI - Towards an improved understanding of processes controlling absorption efficiency and biomagnification of organic chemicals by fish. AB - Dietary exposure is considered the dominant pathway for fish exposed to persistent, hydrophobic chemicals in the environment. Here we present a dynamic, fugacity-based three-compartment bioaccumulation model that describes the fish body as one compartment and the gastrointestinal tract (GIT) as two compartments. The model simulates uptake from the GIT by passive diffusion and micelle-mediated diffusion, and chemical degradation in the fish and the GIT compartments. We applied the model to a consistent measured dietary uptake and depuration dataset for rainbow trout (n=215) that is comprised of chlorinated benzenes, biphenyls, dioxins, diphenyl ethers, and polycyclic aromatic hydrocarbons (PAHs). Model performance relative to the measured data is statistically similar regardless of whether micelle-mediated diffusion is included; however, there are considerable uncertainties in modeling this process. When degradation in the GIT is assumed to be negligible, modeled chemical elimination rates are similar to measured rates; however, predicted concentrations of the PAHs are consistently higher than measurements by up to a factor of 20. Introducing a kinetic limit on chemical transport from the fish compartment to the GIT and increasing the rate constant for degradation of PAHs in tissues of the liver and/or GIT are required to achieve good agreement between the modelled and measured concentrations for PAHs. Our results indicate that the apparent low absorption efficiency of PAHs relative to the chemicals with similar hydrophobicity is attributable to biotransformation in the liver and/or the GIT. Our results provide process-level insights about controls on the extent of bioaccumulation of chemicals. PMID- 26047571 TI - Theta response in schizophrenia is indifferent to perceptual illusion. AB - OBJECTIVE: Patients with schizophrenia are impaired in maintaining coherent perceptual experiences. This is reflected in the oscillatory theta response and can be investigated by visual illusions. Ambiguous stimuli elicit illusory perceptual switches while the stimulus remains unchanged. METHODS: Theta responses elicited by an ambiguous and unambiguous control stimulus were measured using the EEG during time periods of perceptual switching and perceptual stability (non-switching). RESULTS: For the ambiguous task, theta activity increased during perceptual switching in healthy controls only. For the unambiguous task, the switching-related increase of theta activity was larger in controls than in patients. This reduced modulation of the theta response seems not to be related to a general decrease of theta activity in patients. CONCLUSIONS: These findings may be related to disturbances in the spatio-temporal integration of neural activity in patients. Reporting ambiguous and unambiguous perceptual switches seems to be more demanding for patients with schizophrenia than healthy controls. SIGNIFICANCE: This is one of the first studies on the neurophysiologic correlates of illusory perception in schizophrenia. Focussing on the relation between different brain states (such as switching and non-switching) might integrate different findings about altered theta oscillations in schizophrenia. PMID- 26047572 TI - Arbuscular mycorrhizal colonization in field-collected terrestrial cordate gametophytes of pre-polypod leptosporangiate ferns (Osmundaceae, Gleicheniaceae, Plagiogyriaceae, Cyatheaceae). AB - To determine the mycorrhizal status of pteridophyte gametophytes in diverse taxa, the mycorrhizal colonization of wild gametophytes was investigated in terrestrial cordate gametophytes of pre-polypod leptosporangiate ferns, i.e., one species of Osmundaceae (Osmunda banksiifolia), two species of Gleicheniaceae (Diplopterygium glaucum, Dicranopteris linearis), and four species of Cyatheales including tree ferns (Plagiogyriaceae: Plagiogyria japonica, Plagiogyria euphlebia; Cyatheaceae: Cyathea podophylla, Cyathea lepifera). Microscopic observations revealed that 58 to 97% of gametophytes in all species were colonized with arbuscular mycorrhizal (AM) fungi. Fungal colonization was limited to the multilayered midrib (cushion) tissue in all gametophytes examined. Molecular identification using fungal SSU rDNA sequences indicated that the AM fungi in gametophytes primarily belonged to the Glomeraceae, but also included the Claroideoglomeraceae, Gigasporaceae, Acaulosporaceae, and Archaeosporales. This study provides the first evidence for AM fungal colonization of wild gametophytes in the Plagiogyriaceae and Cyatheaceae. Taxonomically divergent photosynthetic gametophytes are similarly colonized by AM fungi, suggesting that mycorrhizal associations with AM fungi could widely occur in terrestrial pteridophyte gametophytes. PMID- 26047573 TI - Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/beta-catenin signaling pathway. AB - The canonical Wnt/beta-catenin signaling pathway has been shown to promote the epithelial-mesenchymal transition (EMT), which is a crucial process in multiple embryonic developmental processes and the progression of carcinomas. We recently provided evidence that leucine-rich repeat flightless-1-interacting protein 1 (LRRFIP1) promotes cancer metastasis and invasion. In the present study, we identified the signaling elements targeted by LRRFIP1 for promotion of the EMT in pancreatic and lung cancer. LRRFIP1 silencing reversed the EMT, as shown by increased expression of E-cadherin (an epithelial marker) and decreased expression of vimentin (a mesenchymal marker). Silencing of LRRFIP1 up-regulated phosphorylation of beta-catenin and decreased its nuclear localization by targeting the beta-catenin destruction complex. The expression of beta-catenin and E-cadherin in the plasma membrane fraction was increased in LRRFIP1 silenced cancer cells, and the migration and invasion capabilities were strongly inhibited. In addition, this protein was highly expressed at the invasion front of malignant tissue collected from pancreatic cancer patients. Consequently, our data strongly suggested that LRRFIP1 played an important role in the invasion of carcinoma cells. Our data provide experimental evidence that LRRFIP1 is an attractive candidate for targeted therapy in human cancers. PMID- 26047575 TI - Professional Ethics of Software Engineers: An Ethical Framework. AB - The purpose of this article is to propose an ethical framework for software engineers that connects software developers' ethical responsibilities directly to their professional standards. The implementation of such an ethical framework can overcome the traditional dichotomy between professional skills and ethical skills, which plagues the engineering professions, by proposing an approach to the fundamental tasks of the practitioner, i.e., software development, in which the professional standards are intrinsically connected to the ethical responsibilities. In so doing, the ethical framework improves the practitioner's professionalism and ethics. We call this approach Ethical-Driven Software Development (EDSD), as an approach to software development. EDSD manifests the advantages of an ethical framework as an alternative to the all too familiar approach in professional ethics that advocates "stand-alone codes of ethics". We believe that one outcome of this synergy between professional and ethical skills is simply better engineers. Moreover, since there are often different software solutions, which the engineer can provide to an issue at stake, the ethical framework provides a guiding principle, within the process of software development, that helps the engineer evaluate the advantages and disadvantages of different software solutions. It does not and cannot affect the end-product in and of-itself. However, it can and should, make the software engineer more conscious and aware of the ethical ramifications of certain engineering decisions within the process. PMID- 26047574 TI - Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice. AB - Loop diuretics are used for fluid control in patients with heart failure. Furosemide and torasemide may exert differential effects on myocardial fibrosis. Here, we studied the effects of torasemide and furosemide on atrial fibrosis and remodeling during atrial fibrillation. In primary neonatal cardiac fibroblasts, torasemide (50MUM, 24h) but not furosemide (50MUM, 24h) reduced the expression of connective tissue growth factor (CTGF; 65+/-6%) and the pro-fibrotic miR-21 (44+/ 23%), as well as the expression of lysyl oxidase (LOX; 57+/-8%), a regulator of collagen crosslinking. Mineralocorticoid receptor (MR) expression and activity were not altered. Torasemide but not furosemide inhibited human aldosterone synthase (CYP11B2) activity in transfected lung fibroblasts (V79MZ cells) by 75+/ 1.8%. The selective CYP11B2 inhibitor SL242 mimicked the torasemide effects. Mice with cardiac overexpression of Rac1 GTPase (RacET), which develop atrial fibrosis and spontaneous AF with aging, were treated long-term (8months) with torasemide (10mg/kg/day), furosemide (40mg/kg/day) or vehicle. Treatment with torasemide but not furosemide prevented atrial fibrosis in RacET as well as the up-regulation of CTGF, LOX, and miR-2, whereas MR expression and activity remained unaffected. These effects correlated with a reduced prevalence of atrial fibrillation (33% RacET+Tora vs. 80% RacET). Torasemide but not furosemide inhibits CYP11B2 activity and reduces the expression of CTGF, LOX, and miR-21. These effects are associated with prevention of atrial fibrosis and a reduced prevalence of atrial fibrillation in mice. PMID- 26047576 TI - Thermomyces lanuginosus lipase-catalyzed hydrolysis of the lipid cubic liquid crystalline nanoparticles. AB - In this study well-ordered glycerol monooleate (GMO)-based cubic liquid crystalline nanoparticles (LCNPs) have been used as substrates for Thermomyces lanuginosus lipase in order to establish the relation between the catalytic activity, measured by pH-stat titration, and the change in morphology and nanostructure determined by cryogenic transmission electron microscopy and synchrotron small angle X-ray diffraction. The initial lipase catalyzed LCNP hydrolysis rate is approximately 25% higher for large 350nm nanoparticles compared to the small 190nm particles, which is attributed to the increased number of structural defects on the particle surface. At pH 8.0 and 8.4 bicontinuous Im3m cubic LCNPs transform into "sponge"-like assemblies and disordered multilamellar onion-like structures upon exposure to lipase. At pH 6.5 and 7.5 lipolysis induced phase transitions of the inner core of the particles, following the sequence Im3m cubic -> reversed hexagonal -> reversed micellar Fd3m cubic -> reversed micelles. These transitions to the liquid crystalline phases with higher negative curvature of the lipid/water interface were found to trigger protonation of the oleic acid produced during lipase catalyzed reaction. The increase curvature of the reversed discrete micellar cubic phase was suggested to cause an increase in the oleic acid pKa to a larger value observed by pH-stat titration. PMID- 26047577 TI - Systematic review of effects of pregnancy on breast and abdominal contour after TRAM/DIEP breast reconstruction in breast cancer survivors. AB - Transverse rectus abdominis myocutaneous (TRAM) and its derivatives are the most commonly performed autologous breast reconstruction procedures. These procedures were not recommended in the past for those who planned for subsequent childbearing because of the transposition of portions of the abdominal wall during the procedure into the anatomic position of the breast, implying possible adverse effects over the contour of these manipulated areas during pregnancy and delivery. We conducted a systematic review to assess the literature on esthetic or functional consequences of childbearing over the breast and abdomen after these procedures in patients that were affected by breast cancer. A comprehensive literature search in databases and citation indexes was conducted from February 2014 to April 2015. Any paper on pregnancy after breast reconstruction by TRAM or its derivatives and modifications, written in English or French, were included. The search results underwent a first screening to exclude duplicate and irrelevant papers. Full texts were then reviewed as to the criteria for inclusion, and data were extracted into data extraction forms from eligible papers. The initial search yielded 5132 articles. After screening and review, overall 17 papers met all criteria for inclusion in this review. Our work revealed that uneventful pregnancy and delivery can be anticipated in breast cancer survivors who had undergone breast reconstruction via TRAM or its derivatives with minor negative effects on either the breast or the abdomen. PMID- 26047578 TI - Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer. AB - OBJECTIVES: Lung cancer is the leading cause of cancer-related death in the USA. Regulatory T cells (Tregs) normally function to temper immune responses and decrease inflammation. Previous research has demonstrated different subsets of Tregs with contrasting anti- or pro-inflammatory properties. This study aimed to determine Treg subset distributions and characteristics present in non-small cell lung cancer (NSCLC) patients. METHODS: Peripheral blood was collected from healthy controls (HC) and NSCLC patients preceding surgical resection, and mononuclear cells were isolated, stained, and analyzed by flow cytometry. Tregs were defined by expression of CD4 and CD25 and classified into CD45RA(+)Foxp3(int) (naive, Fr. I) or CD45RA(-)Foxp3(hi) (activated Fr. II). Activated conventional T cells were CD4(+)CD45RA(-)Foxp3(int) (Fr. III). RESULTS: Samples from 23 HC and 26 NSCLC patients were collected. Tregs isolated from patients with NSCLC were found to have enhanced suppressive function on naive T cells. Cancer patients had significantly increased frequencies of activated Tregs (fraction II: FrII), 17.5 versus 3.2% (P < 0.001). FrII Tregs demonstrated increased RORgammat and IL17 expression and decreased IL10 expression compared to Tregs from HC, indicating pro-inflammatory characteristics. CONCLUSIONS: This study demonstrates that a novel subset of Tregs with pro-inflammatory characteristics preferentially expand in NSCLC patients. This Treg subset appears identical to previously reported pro-inflammatory Tregs in human colon cancer patients and in mouse models of polyposis. We expect the pro-inflammatory Tregs in lung cancer to contribute to the immune pathogenesis of disease and propose that targeting this Treg subset may have protective benefits in NSCLC. PMID- 26047579 TI - Intragingival injection of Porphyromonas gingivalis-derived lipopolysaccharide induces a transient increase in gingival tumour necrosis factor-alpha, but not interleukin-6, in anaesthetised rats. AB - This study used in vivo microdialysis to examine the effects of intragingival application of lipopolysaccharide (LPS) derived from Porphyromonas gingivalis (Pg LPS) on gingival tumour necrosis factor (TNF)-alpha and interleukin (IL)-6 levels in rats. A microdialysis probe with an injection needle attached to the surface of the dialysis membrane was implanted into the gingiva of the upper incisor. For comparison, the effects of LPS derived from Escherichia coli (Ec-LPS) on IL-6 and TNF-alpha levels were also analysed. Pg-LPS (1 MUg/1 MUL) or Ec-LPS (1 or 6 MUg/1 MUL) was applied by microsyringe, with gingival dialysates collected every hour. Enzyme-linked immunosorbent assay (ELISA) revealed that gingival dialysates contained approximately 389 pg.mL-1 of IL-6 basally; basal TNF-alpha levels were lower than the detection limit of the ELISA. Pg-LPS failed to alter IL-6 levels but markedly increased TNF-alpha levels, which remained elevated for 2 h after treatment. Neither IL-6 nor TNF-alpha were affected by Ec-LPS. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that the gingiva expresses Toll-like receptor (TLR) 2 and TLR4 mRNA. Immunohistochemical examination showed that TLR2 and TLR4 are expressed by gingival epithelial cells. The present study provides in vivo evidence that locally applied Pg-LPS, but not Ec-LPS, into the gingiva transiently increases gingival TNF-alpha without affecting IL-6. The present results suggest that TLR2 but not TLR4 expressed on gingival epithelial cells may mediate the Pg-LPS-induced increase in gingival TNF alpha in rats. PMID- 26047581 TI - A plea for uniform terminology for patients with urothelial carcinoma treated with chemotherapy prior to radical cystectomy: induction versus neoadjuvant chemotherapy. PMID- 26047580 TI - Bone morphogenetic protein 2-induced human dental pulp cell differentiation involves p38 mitogen-activated protein kinase-activated canonical WNT pathway. AB - Both bone morphogenetic protein 2 (BMP2) and the wingless-type MMTV integration site (WNT)/beta-catenin signalling pathway play important roles in odontoblast differentiation and dentinogenesis. Cross-talk between BMP2 and WNT/beta-catenin in osteoblast differentiation and bone formation has been identified. However, the roles and mechanisms of the canonical WNT pathway in the regulation of BMP2 in dental pulp injury and repair remain largely unknown. Here, we demonstrate that BMP2 promotes the differentiation of human dental pulp cells (HDPCs) by activating WNT/beta-catenin signalling, which is further mediated by p38 mitogen activated protein kinase (MAPK) in vitro. BMP2 stimulation upregulated the expression of beta-catenin in HDPCs, which was abolished by SB203580 but not by Noggin or LDN193189. Furthermore, BMP2 enhanced cell differentiation, which was not fully inhibited by Noggin or LDN193189. Instead, SB203580 partially blocked BMP2-induced beta-catenin expression and cell differentiation. Taken together, these data suggest a possible mechanism by which the elevation of beta-catenin resulting from BMP2 stimulation is mediated by the p38 MAPK pathway, which sheds light on the molecular mechanisms of BMP2-mediated pulp reparative dentin formation. PMID- 26047582 TI - Probing gelation ability for a library of dipeptide gelators. AB - Functionalised dipeptides are a class of interesting and useful low molecular weight hydrogelators. Here, we report a significantly expanded library of materials, including dipeptides conjugated to carbazole, phenanthracene, anthracene, pyrene and substituted naphthalenes. We assess the effect of using two different gelation methods; a pH-switch and a solvent switch on the gelation behaviour and properties of the dipeptides. Importantly, we investigate the relationship between the structure of these dipeptides and their ability to form gels. From an analysis of the gelation ability of all these dipeptides, it is clear that those containing a phenylalanine as either of the constituent amino acids are much more likely to lead to a gelator being formed as opposed to using non-aromatic amino acids only. PMID- 26047584 TI - Oral anaerobes in health and disease. PMID- 26047583 TI - Down-regulation of hsa-miR-1264 contributes to DNMT1-mediated silencing of SOCS3. AB - Previously we found decreased expression of SOCS3 in neointimal hyperplastic region following balloon angioplasty in atherosclerotic micro swine. In our recent in vitro studies using human coronary artery smooth muscle cells (HCASMC), we observed the inhibition of SOCS3 expression in the presence of both TNF-alpha and IGF-1, correlating with the in vivo findings in microswine. We also reported that two independent mechanisms, JAK/STAT3/NFkappaB and promoter methylation of SOCS3 were responsible for TNF-alpha and IGF-1 induced SOCS3 inhibition. In this study, using miRNA array and gene expression approaches, we explored the molecular mechanisms involved in the above SOCS3 repression and identified several miRNAs that are associated with the regulation of SOCS3 expression. Our miRNA expression profiling revealed profound down-regulation of two specific miRNAs, hsa-miR-758 and hsa-miR-1264, whose expression levels were decreased by 8 10 folds in HCASMCs that were treated with both TNF-alpha and IGF-1. This was accompanied with a significant up-regulation of three specific miRNAs, hsa-miR 155, hsa-miR-146b-5p and hsa-miR-146a, which showed about 3-7 fold increases in their expression levels. Importantly, we also found that the miRNA hsa-miR-1264 targets DNA methyltransferase-1 (DNMT1) transcripts by binding to its 3'UTR region to affect its expression. Expression of hsa-miR-1264 in HCASMCs not only resulted in decreased DNMT1 mRNA transcripts but it also increased SOCS3 expression. The treatment with TNF-alpha and IGF-1 resulted in drastic decrease in hsa-miR-1264 levels with no change in the expression of DNMT1. Consequently, the DNMT1 activity caused hypermethylation in the CpG island of the SOCS3 promoter region and inhibited its expression. This could be a causative epigenetic mechanism associated with TNF-alpha and IGF-1 induced smooth muscle cell proliferation involved in the pathogenesis of coronary artery hyperplasia and restenosis. PMID- 26047585 TI - Skin response to sustained loading: A clinical explorative study. AB - BACKGROUND: Severe illness, disability and immobility increase the risk of pressure ulcer development. Pressure ulcers are localized injuries to the skin and/or underlying tissue as a result of long enduring pressure and shear. Little is known about the role of the stratum corneum and the upper skin layers in superficial pressure ulcer development. OBJECTIVES: To investigate possible effects of long enduring loading on the skin barrier function under clinical conditions at two pressure ulcer predilection sites. METHODS: Under controlled conditions 20 healthy females (mean age 69.9 (3.4) years) followed a standardized immobilization protocol of 90 and 150 min in supine position wearing hospital nightshirts on a standard hospital mattress. Before and immediately after the loading periods skin surface temperature, stratum corneum hydration, transepidermal water loss and erythema were measured at the sacral and heel skin. RESULTS: Prolonged loading caused increases of skin surface temperature and erythema at the sacral and heel skin. Stratum corneum hydration remained stable. Transepidermal water loss increased substantially after loading at the heel but not at the sacral skin. CONCLUSIONS: Skin functions change during prolonged loading at the sacral and heel skin in aged individuals. Accumulation of heat and hyperaemia seem to be primarily responsible for increasing skin temperature and erythema which are associated with pressure ulcer development. Increased transepidermal water loss at the heels indicate subclinical damages of the stratum corneum at the heel but not at the sacral skin during loading indicating distinct pathways of pressure ulcer development at both skin areas. PMID- 26047586 TI - Small RNA profiles of wild-type and silencing suppressor-deficient tomato spotted wilt virus infected Nicotiana benthamiana. AB - Tospoviruses are plant-infecting viruses belonging to the family Bunyaviridae. We used a collection of wild-type, phylogenetically distinct tomato spotted wilt virus isolates and related silencing-suppressor defective mutants to study the effects on the small RNA (sRNA) accumulation during infection of Nicotiana benthamiana. Our data showed that absence of a functional silencing suppressor determined a marked increase of the total amount of viral sRNAs (vsRNAs), and specifically of the 21 nt class. We observed a common under-representation of vsRNAs mapping to the intergenic region of S and M genomic segments, and preferential mapping of the reads against the viral sense open reading frames, with the exception of the NSs gene. The NSs-mutant strains showed enrichment of NSm-derived vsRNA compared to the expected amount based on gene size. Analysis of 5' terminal nucleotide preference evidenced a significant enrichment in U for the 21 nt- and in A for 24 nt-long endogenous sRNAs in all the samples. Hotspot analysis revealed a common abundant accumulation of reads at the 5' end of the L segment, mostly in the antiviral sense, for the NSs-defective isolates, suggesting that absence of the silencing suppressor can influence preferential targeting of the viral genome. PMID- 26047588 TI - To Befriend or Not: Naturally Developing Friendships Amongst a Clinical Group of Adolescents with Chronic Pain. AB - Adolescents with chronic pain frequently perceive a lack of support from friends. Support from a peer with a shared experience has been found to provide emotional, informational, and appraisal support. We sought to quantify the frequency with which adolescents with chronic pain want to befriend other adolescents with chronic pain, and to describe the features of these friendships. Adolescents with chronic pain who had attended a 10-week structured self-management program from 3 sites were invited to complete an online survey. Forty teens participated, 95% (n = 38) were girls; 32% (n = 13) befriended another; 52% (n = 21) were interested in befriending another but did not; 15% (n = 6) were not interested in befriending anyone. Over half (62%) of the friendships lasted at least 1 year (n = 8), but only 2 intermingled these with their regular friendships. Pain was discussed frequently during interactions. The most common reasons for not forming friendships were no time to exchange contact information during group and not having things in common. Reasons for not being interested in forming a friendship also included not having anything in common apart from pain. The majority of participants were interested in befriending another. Emotional support, by feeling understood and discussing pain without fear that the other is disinterested, was the main peer support provided. Without common interests, this form of friendship may not last and is at risk for being overly solicitous by focusing on pain. It remains unclear whether the benefits of peer support translate into improved function. PMID- 26047587 TI - Characterization and comparative analysis of a simian foamy virus complete genome isolated from Brazilian capuchin monkeys. AB - Foamy viruses infect a wide range of placental mammals, including primates. However, despite of great diversity of New World primates, only three strains of neotropical simian foamy viruses (SFV) have been described. Only after 40 years since serological characterization, the complete sequence of an SFVcap strain infecting a family of six capuchin monkeys (Sapajus xanthosternos) was obtained. Co-culture of primate peripheral blood mononuclear cells with Cf2Th canine cells was established and monitored for the appearance of cytopathic effects, PCR amplification of integrated SFV proviral genome and viral reverse transcriptase activity. The novel SFVcap was fully sequenced through a next-generation sequencing protocol. Phylogenetic analysis of the complete genome grouped SFVcap and SFVmar, both infecting primate species of the Cebidae family with a genetic similarity of approximately 85%. Similar ORF sizes were observed among SFV from neotropical primates, and env and pol genes were the most conserved. Neotropical SFV presented the smallest LTRs among exogenous mammalians. The novel SFVcap strain provides a valuable research tool for the FV community. PMID- 26047589 TI - Registered Nurses' Knowledge about Adverse Effects of Analgesics when Treating Postoperative Pain in Patients with Dementia. AB - Registered nurses (RNs) play a pivotal role in treating pain and preventing and recognizing the adverse effects (AEs) of analgesics in patients with dementia. The purpose of this study was to determine RNs' knowledge of potentially clinically relevant AEs of analgesics. A descriptive, cross-sectional study design was used. In all, 267 RNs treating orthopedic patients, including patients with dementia, in 7 university hospitals and 10 central hospitals in Finland, completed a questionnaire. Analgesics were defined according to the Anatomic Therapeutic Classification as strong opioids, weak opioids, nonsteroidal anti inflammatory analgesics (NSAIDs), and paracetamol. Definitions of AEs were based on the literature. Logistic regression analysis was applied to analyze which variables predicted nurses' knowledge. The RNs had a clear understanding of the AEs of paracetamol and strong opioids. However, the AEs of NSAIDs, especially renal and cardiovascular AEs, were less well known. The median percentage of correct answers was 87% when asked about strong opioids, 73% for weak opioids, and 60% for NSAIDs. Younger RNs had better knowledge of opioid-related AEs (odds ratio [OR] per 1-year increase, 0.97; 95% confidence interval [CI], 0.94-1.00) and weak opioids (OR, 0.96; 95% CI, 0.93-0.99). This study provides evidence of a deficiency in RNs' knowledge, especially regarding the adverse renal and cardiovascular effects of NSAIDs. Such lack of knowledge indicates that hospitals may need to update the knowledge of older RNs, especially those who treat vulnerable patients with dementia. PMID- 26047590 TI - Visual annotation display (VLAD): a tool for finding functional themes in lists of genes. AB - Experiments that employ genome scale technology platforms frequently result in lists of tens to thousands of genes with potential significance to a specific biological process or disease. Searching for biologically relevant connections among the genes or gene products in these lists is a common data analysis task. We have implemented a software application for uncovering functional themes in sets of genes based on their annotations to bio-ontologies, such as the gene ontology and the mammalian phenotype ontology. The application, called VisuaL Annotation Display (VLAD), performs a statistical analysis to test for the enrichment of ontology terms in a set of genes submitted by a researcher. The results for each analysis using VLAD includes a table of ontology terms, sorted in decreasing order of significance. Each row contains the term, statistics such as the number of annotated terms, the p value, etc., and the symbols of annotated genes. An accompanying graphical display shows portions of the ontology hierarchy, where node sizes are scaled based on p values. Although numerous ontology term enrichment programs already exist, VLAD is unique in that it allows users to upload their own annotation files and ontologies for customized term enrichment analyses, supports the analysis of multiple gene sets at once, provides interfaces to customize graphical output, and is tightly integrated with functional and biological details about mouse genes in the Mouse Genome Informatics (MGI) database. VLAD is available as a web-based application from the MGI web site (http://proto.informatics.jax.org/prototypes/vlad/). PMID- 26047591 TI - Fatal gestational trophoblastic neoplasia: An analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. AB - OBJECTIVE: To determine clinical factors that contributed to death from gestational trophoblastic neoplasia (GTN) at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. METHODS: Nineteen women who died of GTN from 1979-2012 were retrospectively identified and compared to 45 women previously reported on who died of GTN from 1962-1978. Clinical factors analyzed included demographics, pretreatment human chorionic gonadotropin (hCG) level, duration of disease, antecedent pregnancy, number and sites of metastases, FIGO stage and score, treatment, and cause of death. RESULTS: Death from GTN occurred in 19 (4%) of 483 patients treated from 1979-2012 compared to 45 (11%) of 396 patients treated from 1962-1978 (P<0.001). Pretreatment hCG level >100,000 mIU/mL, time from pregnancy event to treatment >4 months, nonmolar antecedent pregnancy and use of surgery to control metastatic disease were similar between the two treatment eras. Patients in the recent series were more likely to have presented with FIGO IV disease or brain metastasis, been initially treated with multiagent chemotherapy, and received treatment before referral to our center compared to the earlier series. The most common causes of death from 1979-2012 and 1962-1978 were hemorrhage from one or more metastatic sites (11% vs. 42%), respiratory failure (37% vs. 31%), and multiorgan failure due to widespread chemoresistant disease (42% vs. 8%), respectively. CONCLUSIONS: Our overall survival rate in patients with gestational trophoblastic neoplasia improved from 89% in 1962-1978 to 96% in 1979-2012. More patients treated between 1979-2012 died from widespread chemoresistant disease rather than hemorrhagic complications. PMID- 26047592 TI - Sentinel lymph node procedure in endometrial cancer: A systematic review and proposal for standardization of future research. AB - OBJECTIVES: Sentinel lymph node (SLN) procedure could be an attractive solution to the debate on lymphadenectomy in endometrial cancer; however challenges to interpreting the literature include marked heterogeneity across studies, a wide variety of injection techniques and a lack of uniformly accepted definitions for important outcomes. We aim to critically appraise the published literature and streamline terminology and methodology for future studies in this field. METHODS: We conducted a PubMed search and included all original research of endometrial cancer patients having undergone SLN procedure with an n>30. Data collected included injection technique, unilateral, bilateral, and para-aortic detection rates, and ultrastaging results. When different definitions were used for reporting outcomes, we recalculated the original study results according to our proposed definitions. Data was analyzed using descriptive statistics. RESULTS: Seventeen studies met our inclusion criteria. Injection sites were categorized into cervical versus corporeal. Overall detection rates ranged from 60 to 100%; studies with n>100 all had overall detection rates of >80%. Bilateral detection rates were higher with a combination of two injection agents. Para-aortic mapping was most frequent after corporeal injection techniques (39%), and was higher after deep vs. standard cervical injection (17% vs. 2%). The proportion of metastatic lymph nodes diagnosed through ultrastaging was high (around 40%) and ultrastaging of SLN upstaged approximately 5% of patients. Retrospectively applying a surgical algorithm revealed a sensitivity of 95%, a negative predictive value of 99%, and a false negative rate of 5% (with only 9 false negative cases remaining in total). CONCLUSION: Results of SLN research for endometrial cancer are promising. We believe that in future studies, uniform reporting is needed to improve our understanding of the safety and feasibility of SLN in EC. We propose 2 strategies: a checklist of elements to include in future reports and the standardization of key definitions. PMID- 26047593 TI - Chemical characterization of milk oligosaccharides of the eastern quoll (Dasyurus viverrinus). AB - Structural characterizations of marsupial milk oligosaccharides have been performed in four species to date: the tammar wallaby (Macropus eugenii), the red kangaroo (Macropus rufus), the koala (Phascolarctos cinereus) and the common brushtail possum (Trichosurus vulpecula). To clarify the homology and heterogeneity of milk oligosaccharides among marsupials, the oligosaccharides in the carbohydrate fraction of eastern quoll milk were characterized in this study. Neutral and acidic oligosaccharides were separated and characterized by (1)H nuclear magnetic resonance spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The structures of the neutral oligosaccharides were Gal(beta1-3)Gal(beta1-4)Glc (3'-galactosyllactose), Gal(beta1-3)Gal(beta1-3)Gal(beta1-4)Glc (3",3'-digalactosyllactose), Gal(beta1 3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (lacto-N-novopentaose I), Gal(beta1-3)Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (galactosyl lacto-N-novopentaose I), Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1 3)Gal(beta1-4)Glc (galactosyl lacto-N-novopentaose II), Gal(beta1-3)[Gal(beta1 3)Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (galactosyl lacto-N-novopentaose III) and Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-3)[Gal(beta1 4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (lacto-N-novooctaose). The structures of the acidic oligosaccharides detected are Neu5Ac(alpha2-3)Gal(beta1-4)Glc (3' sialyllactose), Gal(beta1-3)(O-3-sulfate)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1 4)Glc (lacto-N-novopentaose I sulfate a), Gal(beta1-3)[Gal(beta1-4)(O-3 sulfate)GlcNAc(beta1-6)]Gal(beta1-4)Glc (lacto-N-novopentaose I sulfate b), Neu5Ac(alpha2-3)Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-4)Glc (sialyl lacto-N-novopentaose a), Gal(beta1-3)[Neu5Ac(alpha2-3)Gal(beta1-4)GlcNAc(beta1 6)]Gal(beta1-4)Glc (sialyl lacto-N-novopentaose c), Neu5Ac(alpha2-3) Gal(beta1 3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1 4)Glc, and Gal(beta1-3)[Gal(beta1-4)GlcNAc(beta1-6)]Gal(beta1-3)[Gal(beta1 4)GlcNAc(beta1-6)]Gal(beta1-4)Glc with an alpha(2-3) Neu5Ac linked to beta(1 4)Gal residue of either branch of Gal(beta1-4)GlcNAc(beta1-6) units. The most predominant oligosaccharides in the carbohydrate fraction of mid-lactation milk were found to be lacto-N-novopentaose I and lacto-N-novooctaose, i.e., branched oligosaccharides that contain N-acetylglucosamine. The predominance of these branched oligosaccharides, rather than of a series of linear beta(1-3) linked galacto oligosaccharides, appears to be the main feature of the eastern quoll milk oligosaccharides that differentiates them from those of the tammar wallaby and the brushtail possum. PMID- 26047594 TI - N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-kappaB signaling. AB - OBJECTIVE: N-methyl pyrrolidone (NMP), a small bioactive molecule, stimulates bone formation and inhibits osteoclast differentiation and bone resorption. The present study was aimed to evaluate the anti-inflammatory potentials of NMP on the inflammatory process and the underlying molecular mechanisms in RAW264.7 macrophages. MATERIALS AND METHODS: RAW264.7 macrophages and mouse primary bone marrow macrophages (mBMMs) were used as an in vitro model to investigate inflammatory processes. Cells were pre-treated with or without NMP and then stimulated with lipopolysaccharides (LPS). The productions of cytokines and NO were determined by proteome profiler method and nitrite analysis, respectively. The expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were measured by Western blotting and/or qPCR. Western blot, ELISA-base reporter assay, and immunofluorescence were used to evaluate the activation of MAP kinases and NF-kappaB. RESULTS: LPS-induced mRNA expressions of TNF-alpha, IL-1beta, IL 6, iNOS, and COX-2 were inhibited by NMP in a dose-dependent manner. NMP also suppressed the LPS-increased productions of iNOS and NO. The proteome profiler array showed that several cytokines and chemokines involved in inflammation and up-regulated by LPS stimulation were significantly down-regulated by NMP. Additionally, this study shows that the effect of NMP is mediated through down regulation of NFkappaB pathway. CONCLUSIONS: Our results show that NMP inhibits the inflammatory mediators in macrophages by an NFkappaB-dependent mechanism, based on the epigenetical activity of NMP as bromodomain inhibitor. In the light of its action on osteoblast and osteoclast differentiation process and its anti inflammatory potential, NMP might be used in inflammation-related bone loss. PMID- 26047595 TI - TNF-alpha-mediated suppression of Leydig cell steroidogenesis involves DAX-1. AB - OBJECTIVE AND DESIGN: The proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) has an inhibitory role in gonadal functions particularly in the steroidogenesis of Leydig cells. A detailed understanding of the mechanisms by which TNF-alpha regulates testicular steroidogenesis will be helpful in the design of novel clinical interventions for the treatment and prevention of male reproductive disorders. Here, we report that TNF-alpha-mediated activation of DAX 1 (dosage-sensitive sex reversal adrenal hypoplasia congenital critical region on X chromosome, gene 1) is involved in the inhibition of Leydig cell steroidogenesis. MATERIALS AND METHODS: Rat testis Leydig tumor cells (LC-540) were treated with TNF-alpha (10 ng/ml) for different time intervals. To elucidate the pathways of intracellular signal transduction that regulate DAX-1 expression, we utilized specific inhibitors. The siRNA transfection of DAX-1 into LC-540 cells was performed by electroporation. The mRNA and protein levels were determined by RT-PCR and Western blotting, respectively. RESULTS: We found that the mRNA and protein levels of DAX-1 were increased by threefold approximately in TNF-alpha-treated cells when compared to controls. Staurosporine, JNK inhibitor SP600125 and ERK inhibitor PD98059 significantly decreased DAX-1 expression in TNF-alpha-treated Leydig cells when compared to their respective controls. Further, a siRNA-mediated knockdown of DAX-1 restores the expression of steroidogenic proteins in TNF-alpha-treated Leydig cells. CONCLUSIONS: These findings provide valuable information that TNF-alpha activates DAX-1 through JNK/ERK MAP kinase pathway which regulates the expression of steroidogenic enzyme genes in Leydig cells. PMID- 26047597 TI - Field Safety Notes in Product Problems of Medical Devices for Use in Pulmonology. AB - The current European system for medical devices is governed by three EC directives: the Medical Device Directive 93/42/EEC, the In-Vitro Diagnostic Directive 98/79/EC and the Active Implantable Medical Device Directive 90/385/EEC and regulates marketing and post-market surveillance of medical devices in the European Economic Area. In cases of incidents and field safety corrective actions (FSCA) manufacturers have to inform the responsible Competent Authority, which is the Federal Institute for Drugs and Medical Devices (BfArM) and the public by field safety notices (FSN). In this study we analyzed FSN of medical devices exclusively serving for diagnostics or treatment in pulmonology (e.g. nebulizers, oxygen concentrators, pulse oximeters, lung function analyzers, and non-active devices for treatment). FSCA and FSN publicized by BfArM in 2005-2013 were analyzed in respect to the MEDDEV 2.12-1 rev 8. In total 41 FSCA were publicized for the included products. German and English FSN were found in 36/35 cases, respectively. FSN were clearly characterized as FSN in 22/20 cases and declaration of the type of action was found in 27/26 cases, respectively. Product names were provided in all cases. Lot numbers or other information for product characterization were available in 7/8 and 26/24 cases, respectively. Detailed information regarding FSCA and product malfunction were found in 27/33 and 36/35 cases, respectively. Information on product related risks with previous use of the affected product was provided in 24/23 cases. In 34/34 cases manufacturers provided information to mitigate product related risks. Requests to pass FSN to persons needing awareness were found in 10/14 cases. Contact data were provided in 30/30 cases. Confirmation that the Competent Authority was informed was found in 12/14 cases and in 19/18 cases a customer confirmation was included. The obtained data suggest that there is an increasing annual number of FSCA and most FSN fulfill the criteria of MEDDEV 2.12-1 rev 8. However, there are differences between German and English FSN, e.g. regarding the distribution to persons needing awareness, missing statement that the Competent Authority was informed and missing customer confirmation. Due to the importance of FSN for reduction of product related risks in FSCA type and content of FSN should be further improved. PMID- 26047596 TI - Correlation between arterial stiffness and inflammatory markers in autosomal dominant polycystic kidney disease patients with preserved renal function. AB - AIM: To evaluate the association between arterial stiffness and inflammatory markers including C-reactive protein (CRP), pentraxin 3 (PTX3) and neutrophil-to lymphocyte ratio (NLR) in autosomal dominant polycystic kidney disease (ADPKD) patients with preserved renal function. METHODS: A total of 52 ADPKD patients [mean (SD) age 38.2 (12.8) years, 69.2 % were females] with preserved renal function and 25 healthy volunteers [mean (SD) age 35.5 (6.5) years, 48.0 % were females] were included. Data on patient characteristics, blood biochemistry, inflammatory markers [PTX3 (pg/mL), CRP (mg/dL) and NLR] and arterial stiffness [large artery elasticity index (LAEI) (mL/mmHg * 10) and small artery elasticity index (SAEI) (mL/mmHg * 100)] were recorded in patient and control groups. Correlation between inflammatory markers and arterial stiffness parameters was analysed in patients. RESULTS: Overall, 42.3 % of ADPKD patients were hypertensive and 44.4 % were receiving renin-angiotensin-aldosterone system (RAAS) blockade therapy. Median levels for PTX3 [442.0 (20.0-4140.0) pg/mL vs. 220.5 (14.7-393.0) pg/mL, p < 0.001] and SAEI [4.90 (1.60-11.80) mL/mmHg * 100 vs. 6.45 (2.80-15.70) mL/mmHg * 10, p = 0.013] were significantly higher in ADPKD patients than in controls. PTX3 and CRP were not correlated with arterial elasticity, while NLR was significantly correlated with LAEI negatively (Rho = 0.278, p = 0.042). CONCLUSION: In conclusion, our findings revealed increased PTX3 levels and reduced SAEI in patients as compared with controls, while no correlation between inflammatory markers studied and the small artery elasticity. PMID- 26047598 TI - Clinical Characteristics of Intracranial Reversed Vertebral Artery Flow Evaluated by Transcranial Color Flow Imaging. AB - BACKGROUND: Carotid duplex ultrasonography (CUS) has been used to identify reversed vertebral artery flow (RVAF) at the extracranial cervical artery in some patients with subclavian steal syndrome. However, the characteristics of intracranial RVAF as evaluated by transcranial color flow imaging (TC-CFI), which can examine intracranial hemodynamics in a real-time and noninvasive fashion, remain unclear. The goal of this study was to analyze the prevalence of intracranial RVAF and its associated clinical characteristics. METHODS: Subjects were consecutive patients who underwent TC-CFI and CUS. We evaluated blood flow in both intracranial vertebral arteries (VAs) from the suboccipital echo window using TC-CFI. RVAF was defined as a flow signal directed toward the probe. We calculated the prevalence of intracranial RVAF in our subjects. Then, we investigated vascular condition (ie, site of lesion, stenosis, occlusion, and dissection) using magnetic resonance angiography, computed tomography angiography , and CUS in patients with intracranial RVAF. RESULTS: Seven hundred twenty patients (508 men; median age, 73 years) were included in this study from September 2007 to March 2013. Intracranial RVAF was seen in 12 patients (1.7%; 11 men; median age, 61 years). Among the 12 patients with intracranial RVAF, 8 patients (67%) had ischemia of the vertebrobasilar territory with distal VA occlusion, according to CUS. Of those patients, 6 (75%) had dissection of the VA. CONCLUSIONS: TC-CFI detected intracranial RVAF in 1.7% of consecutive examinations in our facility. In vertebrobasilar territory stroke patients with intracranial RVAF, VA dissection may contribute to the development of stroke. PMID- 26047599 TI - HMGB1 Level in Cerebrospinal Fluid as a Marker of Treatment Outcome in Patients with Acute Hydrocephalus Following Aneurysmal Subarachnoid Hemorrhage. AB - BACKGROUND: Attempts to clarify mechanisms of early brain injury in subarachnoid hemorrhage (SAH) revealed a high-mobility group box 1 (HMGB1) protein involvement in sterile inflammation initiated by aneurysm rupture. This study aims at assessing the prognostic value of HMGB1 in comparison with traditional biomarkers. METHODS: Ten patients with Fisher grade 4 SAH and acute hydrocephalus underwent endovascular coiling and ventriculostomy. HMGB1 level was measured in cerebrospinal fluid (CSF) samples collected on first, fifth, and 10th day. HMGB1 level in first sample was correlated with treatment outcome assessed in Glasgow outcome scale (GOS) at 3 months. Obtained results were compared with plasma inflammatory markers, clinical grading scales, and imaging grading scales. HMGB1 level in consecutive samples was analyzed in search of concentration trends correlating with patients' outcome. RESULTS: HMGB1 level in CSF of SAH patients, in contrast to control group, is significantly elevated (P < .001). Good (GOS > 3) and poor (GOS <= 3) outcome patients differ significantly in HMGB1 level on admission (P < .01). The strongest correlation to patients' outcome was found for Hunt and Hess scale (R = -.887, P < .01), HMGB1 level (R = -.859, P < .01), and World Federation of Neurological Surgeons scale (R = -.832, P < .01). Constant and high HMGB1 level of 10 ng/mL or more in consecutive CSF samples identifies nonsurvivors. CONCLUSIONS: HMGB1 protein is elevated in SAH patients. Changes in the concentration of HMGB1 in consecutive samples of the CSF correlate with outcome. Our results encourage further proteomic investigation. PMID- 26047600 TI - A national study of paramedic and nursing students' readiness for interprofessional learning (IPL): Results from nine universities. AB - BACKGROUND: The development of successful and functional interprofessional practice is best achieved through interprofessional learning (IPL). Given that many paramedic programmes still take an isolative uni-professional educational approach to their undergraduate courses, it is unclear on their preparedness for students' IPL. Therefore, the objective of this study was to assess the attitudes of undergraduate paramedic and nursing/paramedic students from nine Australian universities towards IPL over a two year period. METHODS: Using a convenience sample of paramedic and nursing/paramedic students-attitudes towards IPL was measured using the Readiness for Interprofessional Learning Scale (RIPLS) 5-point Likert-scale (1=strongly disagree and 5=strongly agree). RESULTS: A total of 1264 students participated (n=303 in 2011 and n=961 in 2012) in this study, consistent with a 43% response rate. Surveyed students were predominantly first year n=506 (40.03%), female n=748 (59.2%) and undertaking single paramedic degrees n=948 (75.0%). Nursing/paramedic students demonstrated significantly lower Negative Professional Identity (M=6.26, p=0.004) and Roles and Responsibilities means (M=6.87, p<0.0001) and higher Positive Professional Identity means (M=15.68, p=0.011) compared with paramedic students. CONCLUSIONS: The impact of nursing/paramedic education was shown to significantly enhance student attitudes towards interprofessionalism and the individual universities involved in this study generated students at varying stages of IPL preparedness. Students' year level appeared to influence IPL readiness, yet there are compelling paradoxical arguments for both earlier and later inclusion of IPL within curricula. PMID- 26047601 TI - Thai nursing students' experiences when attending real life situations involving cardiac life support: A Phenomenological study. AB - BACKGROUND: During the last few years, manikin simulations have been used for cardiac life support training procedures in medical and nursing education. However, some nursing students have experienced attending real events involving cardiac life support during their clinical practice. OBJECTIVE: This study aims to describe the meaning of experience of Thai nursing students when attending real situations of cardiac life support. METHODS: A hermeneutic phenomenological study was used. Third and fourth year bachelor of nursing students at a university in the southern region of Thailand who had the experience of attending real situation of cardiac life support were purposely selected as the informants. The data were generated from individual in-depth interviews with eighteen nursing students. Van Manen's approach was used to analyze the data. Trustworthiness was established using the criteria set out by Lincoln and Guba. RESULTS: Essential themes situated in the context of the four existential grounds of body, time, space, and relation emerged. These were: being worried and fearful while desiring to participate in cardiac life support procedures; enhancing self value; knowing each moment is meaningful for one's life; having time to understand the reality of life; being in a small corner; appreciating such opportunities and the encouragement given by nurses and the healthcare team; and feeling empathy. CONCLUSIONS: Besides learning in classrooms and practicing in labs, experiencing real situations is beneficial for nursing students in learning cardiac life support. This study provides information that can be used for clinical teaching management in the topics relating to cardiac life support. PMID- 26047602 TI - Comparison of standardized patients with high-fidelity simulators for managing stress and improving performance in clinical deterioration: A mixed methods study. AB - BACKGROUND: The use of standardized patients in deteriorating patient simulations adds realism that can be valuable for preparing nurse trainees for stress and enhancing their performance during actual patient deterioration. Emotional engagement resulting from increased fidelity can provide additional stress for student nurses with limited exposure to real patients. To determine the presence of increased stress with the standardized patient modality, this study compared the use of standardized patients (SP) with the use of high-fidelity simulators (HFS) during deteriorating patient simulations. Performance in managing deteriorating patients was also compared. It also explored student nurses' insights on the use of standardized patients and patient simulators in deteriorating patient simulations as preparation for clinical placement. METHODS: Fifty-seven student nurses participated in a randomized controlled design study with pre- and post-tests to evaluate stress and performance in deteriorating patient simulations. Performance was assessed using the Rescuing A Patient in Deteriorating Situations (RAPIDS) rating tool. Stress was measured using salivary alpha-amylase levels. Fourteen participants who joined the randomized controlled component then participated in focus group discussions that elicited their insights on SP use in patient deterioration simulations. RESULTS: Analysis of covariance (ANCOVA) results showed no significant difference (p=0.744) between the performance scores of the SP and HFS groups in managing deteriorating patients. Amylase levels were also not significantly different (p=0.317) between the two groups. Stress in simulation, awareness of patient interactions, and realism were the main themes that resulted from the thematic analysis. CONCLUSIONS: Performance and stress in deteriorating patient simulations with standardized patients did not vary from similar simulations using high-fidelity patient simulators. Data from focus group interviews, however, suggested that the use of standardized patients was perceived to be valuable in preparing students for actual patient deterioration management. PMID- 26047603 TI - The use of pre-existing video in the clinical environment. PMID- 26047604 TI - The relationship between telomere length and clinicopathologic characteristics in colorectal cancers among Tunisian patients. AB - Alterations in telomere dynamics have emerged as having a causative role in carcinogenesis. Both the telomere attrition contribute to tumor initiation via increasing chromosomal instability and that the telomere elongation induces cell immortalization and leads to tumor progression. The objectives of this study are to investigate the dynamics of telomere length in colorectal cancer (CRC) and the clinicopathological parameters implicated. We measured the relative telomere length (RTL) in cancerous tissues and in corresponding peripheral blood leukocytes (PBL) using quantitative PCR (Q-PCR) from 94 patients with CRC. Telomere length correlated significantly in cancer tissues and corresponding PBL (r = 0.705). Overall, cancer tissue had shorter telomeres than PBL (p = 0.033). In both cancer tissue and PBL, the RTL was significantly correlated with age groups (p = 0.008 and p = 0.012, respectively). The RTL in cancer tissue was significantly longer in rectal tumors (p = 0.04) and in the late stage of tumors (p = 0.01). In PBL, the RTL was significantly correlated with the macroscopic aspect of tumors (p = 0.02). In addition, the telomere-length ratio of cancer to corresponding PBL increased significantly with late-stage groups. Shortening of the telomere was detected in 44.7%, elongation in 36.2%, and telomeres were unchanged in 19.1% of 94 tumors. Telomere shortening occurred more frequently in the early stage of tumors (p = 0.01). This study suggests that the telomere length in PBL is affected by the macroscopic aspect of tumors and that telomere length in cancer tissues is a marker for progression of CRC and depends on tumor origin site. PMID- 26047605 TI - MiR-503 inhibited cell proliferation of human breast cancer cells by suppressing CCND1 expression. AB - Breast cancer is one of the most common malignancies and a major cause of cancer related mortality all over the world. A growing body of reports revealed that microRNAs play essential roles in the progression of cancers. Aberrant expression of miR-503 has been reported in several kinds of cancer. The aim of the current study was to elucidate the role of miR-503 in the pathogenesis of breast cancer. In the present study, our results suggested that miR-503 expression was markedly downregulated in breast cancer tissues and cells. Overexpression of miR-503 in breast cancer cell lines reduced cell proliferation through inducing G0/G1 cell cycle arrest by targeting CCND1. Together, our findings provide new knowledge regarding the role of miR-503 in the progression of breast cancer and indicate the role of miR-503 as a tumor suppressor microRNA (miRNA) in breast cancer. PMID- 26047606 TI - Extracorporeal membranous oxygenation (ECMO) in polytrauma: what the radiologist needs to know. AB - The purpose of this article is to review the spectrum of severe traumatic injuries treatable with ECMO and their imaging features, considerations for cannula placement, and complications that may arise in polytraumatized patients on extracorporeal life support. Recent major advances in miniaturization and biocompatibility of ECMO devices have dramatically increased their safety profile and expanded the application of ECMO to patients with severe polytrauma. PMID- 26047607 TI - Novosphingobium endophyticum sp. nov. isolated from roots of Glycyrrhiza uralensis. AB - A novel Gram-staining-negative, non-motile, rod-shaped and aerobic bacterial strain, designated EGI 60015(T), was isolated from healthy roots of Glycyrrhiza uralensis F. collected from Yili County, Xinjiang Province, Northwest China. The 16S rRNA gene sequence of strain EGI 60015(T) was found to show 97.6% sequence similarity with Novosphingobium pentaromativorans US6-1(T). The phylogenetic analysis based on 16S rRNA gene sequences showed that the strain formed a clade with N. pentaromativorans US6-1(T) in the neighbor-joining tree. Q-10 was identified as the respiratory quinone of strain EGI 60015(T). The major fatty acids were summed feature 8 (C18:1 omega6c and/or C18:1 omega7c; 55.04%), summed feature 4 (C17:1 anteiso B and/or iso I; 18.34%) and summed feature 3 (C16:1 omega6c and/or C16:1 omega7c; 8.53%). The polar lipids detected were phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, phosphatidylcholine and sphingoglycolipids. The DNA G+C content of strain EGI 60015(T) was determined to be 66.6 mol%. The genomic DNA relatedness value between EGI 60015(T) and N. pentaromativorans US6-1(T) (54%) was below the 70% limit for species identification. Based on the result of the molecular studies supported by its morphological, physiological, chemotaxonomic and other differentiating phenotypic characteristics, strain EGI 60015(T) was considered to represent a novel species within the genus Novosphingobium, for which the name Novosphingobium endophyticum sp. nov. is proposed. The type strain is EGI 60015(T) (=CGMCC 1.15095(T) = KCTC 42486(T) = DSM 29948(T)). PMID- 26047608 TI - Angioleiomyoma of the Sinonasal Tract: Analysis of 16 Cases and Review of the Literature. AB - Angioleiomyoma (ALM; synonyms: angiomyoma, vascular leiomyoma) is an uncommon benign tumor of skin and subcutaneous tissue. Most arise in the extremities (90 %). Head and neck ALMs are uncommon (~10 % of all ALMs) and those arising beneath the sinonasal tract mucosa are very rare (<1 %) with 38 cases reported so far. We herein analyzed 16 cases identified from our routine and consultation files. Patients included seven females and nine males aged 25-82 years (mean 58; median 62). Symptoms were intermittent nasal obstruction, sinusitis, recurrent epistaxis, and a slow-growing mass. Fifteen lesions originated within different regions of the nasal cavity and one lesion was detected incidentally in an ethmoid sinus sample. Size range was 6-25 mm (mean 11). Histologically, all lesions were well circumscribed but non-encapsulated and most (12/16) were of the compact solid type superficially mimicking conventional leiomyoma but contained numerous compressed muscular veins. The remainder were of venous (2) and cavernous (2) type. Variable amounts of mature fat were observed in four cases (25 %). Atypia, necrosis, and mitotic activity were absent. Immunohistochemistry showed consistent expression of smooth muscle actin (12/12), h-caldesmon (9/9), muscle-specific actin (4/4), variable expression of desmin (11/14) and CD56 (4/6), and absence of HMB45 expression (0/11). The covering mucosa was ulcerated in 6 cases and showed squamous metaplasia in one case. There were no recurrences after local excision. Submucosal sinonasal ALMs are rare benign tumors similar to their reported cutaneous counterparts with frequent adipocytic differentiation. They should be distinguished from renal-type angiomyolipoma. Simple excision is curative. PMID- 26047609 TI - Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach. AB - BACKGROUND: Extreme constitution "Prakriti" types of Ayurveda exhibit systemic physiological attributes. Our earlier genetic study has revealed differences in EGLN1, key modulator of hypoxia axis between Prakriti types. This was associated with differences in high altitude adaptation and susceptibility to high altitude pulmonary edema (HAPE). In this study we investigate other molecular differences that contribute to systemic attributes of Prakriti that would be relevant in predictive marker discovery. METHODS: Genotyping of 96 individuals of the earlier cohort was carried out in a panel of 2,800 common genic SNPs represented in Indian Genomic Variation Consortium (IGVC) panel from 24 diverse populations. Frequency distribution patterns of Prakriti differentiating variations (FDR correction P < 0.05) was studied in IGVC and 55 global populations (HGDP-CEPH) panels. Genotypic interactions between VWF, identified from the present analysis, and EGLN1 was analyzed using multinomial logistic regression in Prakriti and Indian populations from contrasting altitudes. Spearman's Rank correlation was used to study this genotypic interaction with respect to altitude in HGDP-CEPH panel. Validation of functional link between EGLN1 and VWF was carried out in a mouse model using chemical inhibition and siRNA studies. RESULT: Significant differences in allele frequencies were observed in seven genes (SPTA1, VWF, OLR1, UCP2, OR6K3, LEPR, and OR10Z1) after FDR correction (P < 0.05). A non synonymous variation (C/T, rs1063856) associated with thrombosis/bleeding susceptibility respectively, differed significantly between Kapha (C-allele) and Pitta (T allele) constitution types. A combination of derived EGLN1 allele (HAPE associated) and ancestral VWF allele (thrombosis associated) was significantly high in Kapha group compared to Pitta (p < 10(-5)). The combination of risk associated Kapha alleles was nearly absent in natives of high altitude. Inhibition of EGLN1 using (DHB) and an EGLN1 specific siRNA in a mouse model lead to a marked increase in vWF levels as well as pro-thrombotic phenotype viz. reduced bleeding time and enhanced platelet count and activation. CONCLUSION: We demonstrate for the first time a genetic link between EGLN1 and VWF in a constitution specific manner which could modulate thrombosis/bleeding susceptibility and outcomes of hypoxia. Integration of Prakriti in population stratification may help assemble common variations in key physiological axes that confers differences in disease occurrence and patho-phenotypic outcomes. PMID- 26047610 TI - A cross-sectional survey to investigate the quality of care in Tuscan (Italy) nursing homes: the structural, process and outcome indicators of nutritional care. AB - BACKGROUND: Previous studies have investigated process and structure indicators of nutritional care as well as their use in nursing homes (NHs), but the relative weight of these indicators in predicting the risk of malnutrition remains unclear. Aims of the present study are to describe the quality indicators of nutritional care in older residents in a sample of NHs in Tuscany, Italy, and to evaluate the predictors of protein-energy malnutrition risk. METHODS: A cross sectional survey was conducted in 67 NHs. Information was collected to evaluate quality indicators of nutritional care and the individual risk factors for malnutrition, which was assessed using the Malnutrition Universal Screening Tool. A multilevel model was used to analyse the association between risk and predictors. RESULTS: Out of 2395 participants, 23.7 % were at high, 11 % at medium, and 65.3 % at low risk for malnutrition. Forty-two percent of the NHs had only a personal scale to weigh residents; 88 % did not routinely use a screening test/tool for malnutrition; 60 % used some standardized approach for weight measurement; 43 % did not assess the severity of dysphagia; 12 % were not staffed with dietitians. Patients living in NHs where a chair or platform scale was available had a significantly lower risk of malnutrition (OR = 0.73; 95 % CI = 0.56-0.94). None of the other structural or process quality indicators showed a statistically significant association with malnutrition risk. CONCLUSIONS: Of all the process and structural indicators considered, only the absence of an adequate scale to weigh residents predicted the risk of malnutrition, after adjusting for case mix. These findings prompt the conduction of further investigations on the effectiveness of structural and process indicators that are used to describe quality of nutritional care in NHs. PMID- 26047611 TI - Prevalence of hepatitis C virus (HCV) variants resistant to NS5A inhibitors in naive patients infected with HCV genotype 1 in Tunisia. AB - BACKGROUND: Hepatitis C virus (HCV) non-structural protein 5A (NS5A) inhibitors have been recently developed to inhibit NS5A activities and have been approved for the treatment of HCV infection. However the drawback of these direct acting antivirals (DAAs) is the emergence of resistance mutations. The prevalence of such mutations conferring resistance to HCV-NS5A inhibitors before treatment has not been investigated so far in the Tunisian population. The aim of this study was to detect HCV variants resistant to HCV-NS5A inhibitors in hepatitis C patients infected with HCV genotype 1 before any treatment with NS5A inhibitors. METHODS: Amplification and direct sequencing of the HCV NS5A region was carried out on 112 samples from 149 untreated patients. RESULTS: In genotype 1a strains, amino acid substitutions conferring resistance to NS5A inhibitors (M28V) were detected in 1/7 (14.2 %) HCV NS5A sequences analyzed. In genotype 1b, resistance mutations in the NS5A region (R30Q; L31M; P58S and Y93H) were observed in 17/105 (16.2 %) HCV NS5A sequences analyzed. R30Q and Y93H (n = 6; 5.7 %) predominated over P58S (n = 4; 3.8 %) and L31M (n = 3; 2.8 %). CONCLUSIONS: Mutations conferring resistance to HCV NS5A inhibitors are frequent in treatment-naive Tunisian patients infected with HCV genotype 1b. Their influence in the context of DAA therapies has not been fully investigated and should be taken into consideration. PMID- 26047613 TI - Associations between childhood maltreatment and emotion processing biases in major depression: results from a dot-probe task. AB - BACKGROUND: Childhood maltreatment is considered an important risk factor for the development of major depression. Research indicates an association between childhood adversity and altered emotion processing. Depression is characterized by mood-congruent cognitive biases, which play a crucial role in symptom persistence and recurrence. However, whether attentional biases in adult major depression are associated with experienced childhood neglect or abuse remains unclear. METHODS: A sample of 45 patients suffering from major depression were recruited to examine correlations between maltreatment experienced during childhood and attentional biases to sad and happy facial expressions. Attention allocation was assessed using the dot-probe task and a history of childhood maltreatment was measured by means of the 25-item Childhood Trauma Questionnaire (CTQ). RESULTS: Our results indicate an association between childhood maltreatment and sustained attention toward sad facial expressions. This relationship was not confounded by severity of symptoms, age, verbal intelligence or more recent stressful experiences. CONCLUSIONS: Our findings confirm the hypothesis that a mood-congruent bias in emotion processing observed in major depression is related to early traumatic experiences. PMID- 26047612 TI - Differential connectivity of splicing activators and repressors to the human spliceosome. AB - BACKGROUND: During spliceosome assembly, protein-protein interactions (PPI) are sequentially formed and disrupted to accommodate the spatial requirements of pre mRNA substrate recognition and catalysis. Splicing activators and repressors, such as SR proteins and hnRNPs, modulate spliceosome assembly and regulate alternative splicing. However, it remains unclear how they differentially interact with the core spliceosome to perform their functions. RESULTS: Here, we investigate the protein connectivity of SR and hnRNP proteins to the core spliceosome using probabilistic network reconstruction based on the integration of interactome and gene expression data. We validate our model by immunoprecipitation and mass spectrometry of the prototypical splicing factors SRSF1 and hnRNPA1. Network analysis reveals that a factor's properties as an activator or repressor can be predicted from its overall connectivity to the rest of the spliceosome. In addition, we discover and experimentally validate PPIs between the oncoprotein SRSF1 and members of the anti-tumor drug target SF3 complex. Our findings suggest that activators promote the formation of PPIs between spliceosomal sub-complexes, whereas repressors mostly operate through protein-RNA interactions. CONCLUSIONS: This study demonstrates that combining in silico modeling with biochemistry can significantly advance the understanding of structure and function relationships in the human spliceosome. PMID- 26047614 TI - Serum fibroblast growth factor 21 levels are related to subclinical atherosclerosis in patients with type 2 diabetes. AB - BACKGROUND: Fibroblast growth factor 21 (FGF21), a glucose and lipid metabolic regulator, has recently been demonstrated to be associated with cardiovascular diseases (CVD) such as carotid atherosclerosis, coronary heart disease and carotid artery plaques. However, the relationship between circulating FGF21 and subclinical atherosclerosis or atherosclerosis of other arteries such as the femoral and iliac artery remains unclear. In this study, we evaluated the association of serum FGF21 with intima-media thickness (IMT) and subclinical atherosclerosis in type 2 diabetic patients. METHODS: Serum FGF21 levels were detected by enzyme-linked immunosorbent assay in 212 newly diagnosed type 2 diabetic patients without clinical symptoms of atherosclerosis or cardiovascular diseases. IMT of the carotid, femoral, and iliac arteries were measured by high resolution B-mode ultrasound to determine the presence of subclinical atherosclerosis, which was defined as having an IMT > 1.0 mm and/or plaque on one or more of the three arteries without any clinical manifestations. The relationship between serum FGF21 levels and subclinical atherosclerosis was analyzed. RESULTS: Serum FGF21 levels were significantly higher in patients with subclinical atherosclerosis compared to those without [261.3 (135.1-396.4) versus 144.9 (95.9-223.0) ng/L, P < 0.001]. These differences were also observed in both men and women with subclinical atherosclerosis compared to their respective groups without [men: 243.2 (107.6-337.0) versus 136.8 (83.6-212.8) ng/L, P = 0.048; women: 292.4 (174.2-419.9) versus 160.4 (115.3-258.5) ng/L, P = 0.001]. Moreover, serum FGF21 levels showed a significantly positive correlation with carotid IMT in women (r = 0.23, P = 0.018) and with iliac IMT in both genders (women: r = 0.27, P = 0.005; men: r = 0.22, P = 0.024). Multiple logistic regression analysis further showed that serum FGF21 was an independent impact factor for subclinical atherosclerosis in patients with type 2 diabetes. CONCLUSIONS: Serum FGF21 is elevated in newly diagnosed type 2 diabetes, and positively correlates with carotid and iliac lesions in patients with subclinical atherosclerosis, especially in women. High levels of FGF21 may be a compensatory reaction to offset atherosclerosis. PMID- 26047615 TI - Eurythmy therapy increases specific oscillations of heart rate variability. AB - BACKGROUND: Mind-body therapies are beneficial for several diseases (e.g. chronic pain, arterial hypertension, mood disorders). Eurythmy therapy (EYT) is a mind body therapy from Anthroposophic Medicine. In each EYT exercise a short sequence of body movements and simultaneous guided imagery is repeated several times. In this study, the simultaneous effects of two different EYT exercises on cardiac autonomic regulation as assessed by spectral analysis of heart rate variability (HRV) were investigated. METHODS: Twenty healthy subjects (age: 29.1 +/- 9.3 years, 13 female) performed two different EYT exercises (EYT-A and EYT-B) for 8 min. Each EYT exercise was compared against two matched control exercises: control exercise 1 (CE1-A and CE1-B) consisted of a repetition of the body movements of the EYT exercise but without guided imagery, control exercise 2 consisted of walking on the spot (CE2-A and CE2-B). Spectral power of HRV during each exercise was quantified on the basis of Holter ECG recordings. RESULTS: During EYT-A the frequency of the peak oscillation in the very low frequency (VLF) band matched the repetition rate of the sequence of body movements (0.02 Hz). Low frequency (LF) oscillations were augmented when compared to the control exercises (EYT-A: 7.31 +/- 0.84, CE1-A: 6.98 +/- 0.90, CE2-A: 6.52 +/- 0.87 ln ms(2), p < 0.05). They showed a peak frequency at 0.08 Hz indicating that the body postures had an impact in HRV. Performing EYT-B increased VLF oscillations when compared to the control exercises (EYT-B: 9.32 +/- 0.82, CE1-B: 6.31 +/- 0.75, CE2-B: 6.04 +/- 0.80 ln ms(2), p < 0.05). The frequency of the peak oscillation again matched the repetition rate of the sequence of body movements (0.028 Hz). CONCLUSIONS: The repetition of the sequence of body movements of both EYT exercises clearly affected cardiac autonomic regulation in a rhythmic manner according to the stimulus of the specific body movements of each EYT exercise. These results offer a physiological basis to develop a rationale for specific clinical indications of these EYT exercises such as stress reduction or prevention of hypertension. TRIAL REGISTRATION: CLINICAL TRIALS REGISTRATION NUMBER: DRKS00006760 (registered on 10/10/2014, i.e. retrospective registration); view details at http://www.drks.de/DRKS00006760. PMID- 26047616 TI - Clinical features, outcome and risk factors in cervical cancer patients after surgery for chronic radiation enteropathy. AB - BACKGROUND: Radical hysterectomy and radiotherapy have long been mainstays of cervical cancer treatment. Early stage cervical cancer (FIGO stage IB1-IIA) is traditionally treated using radical surgery combined with radiotherapy, while locally advanced cervical cancer is treated using radiotherapy alone or chemoradiotherapy. In this retrospective study, we describe and analyse the presenting clinical features and outcomes in our cohort and evaluate possible risk factors for postoperative morbidity in women who underwent surgery for chronic radiation enteropathy (CRE). METHODS: One hundred sixty-six eligible cervical cancer patients who underwent surgery for CRE were retrospectively identified between September 2003 and July 2014 in a prospectively maintained database. Among them, 46 patients received radical radiotherapy (RRT) and 120 received radical surgery plus radiotherapy (RS + RT). Clinical features, postoperative morbidity and mortality, and risk factors for postoperative morbidity were analysed. RESULTS: RS + RT group patients were more likely to present with RTOG/EORTC grade III late morbidity (76.1 % vs 92.5 %; p = 0.004), while RRT group patients tended to show RTOG/EORTC grade IV late morbidity (23.9 % vs 7.5 %; p = 0.004). One hundred forty patients (84.3 %) were treated with aggressive resection (anastomosis 57.8 % and stoma 26.5 %). Overall and major morbidity, mortality and incidence of reoperation in the RRT and RS + RT groups did not differ significantly (63 % vs 64.2 % [p = 1.000], 21.7 % vs 11.7 % [p = 0.137], 6.5 % vs 0.8 % [p = 0.065] and 6.5 % vs 3.3 % [p = 0.360], respectively). However, incidence of permanent stoma and mortality during follow-up was higher in the RRT group than in the RS + RT group (44.2 % vs 12.6 % [p = 0.000] and 16.3 % vs 3.4 % [p = 0.004], respectively). In multivariate analysis, preoperative anaemia was significantly associated with overall morbidity (p = 0.015), while severe intra-abdominal adhesion (p = 0.017), ASA grades III-V (P = 0.022), and RTOG grade IV morbidity (P = 0.018) were predicators of major morbidity. CONCLUSIONS: Radiation-induced late morbidity tended to be severe in the RRT group with more patients suffering RTOG/EORTC grade IV morbidity, while there were no significant differences in postoperative morbidity, mortality and reoperation. Aggressive resection was feasible with acceptable postoperative outcomes. Severe intra-abdominal adhesion, ASA grades III-V and RTOG/EORTC grade IV late morbidity contributed significantly to major postoperative morbidity. PMID- 26047617 TI - Genome-wide analysis of the ATP-binding cassette (ABC) transporter gene family in sea lamprey and Japanese lamprey. AB - BACKGROUND: Lampreys are extant representatives of the jawless vertebrate lineage that diverged from jawed vertebrates around 500 million years ago. Lamprey genomes contain information crucial for understanding the evolution of gene families in vertebrates. The ATP-binding cassette (ABC) gene family is found from prokaryotes to eukaryotes. The recent availability of two lamprey draft genomes from sea lamprey Petromyzon marinus and Japanese lamprey Lethenteron japonicum presents an opportunity to infer early evolutionary events of ABC genes in vertebrates. RESULTS: We conducted a genome-wide survey of the ABC gene family in two lamprey draft genomes. A total of 37 ABC transporters were identified and classified into seven subfamilies; namely seven ABCA genes, 10 ABCB genes, 10 ABCC genes, three ABCD genes, one ABCE gene, three ABCF genes, and three ABCG genes. The ABCA subfamily has expanded from three genes in sea squirts, seven and nine in lampreys and zebrafish, to 13 and 16 in human and mouse. Conversely, the multiple copies of ABCB1-, ABCG1-, and ABCG2-like genes found in sea squirts have contracted in the other species examined. ABCB2 and ABCB3 seem to be new additions in gnathostomes (not in sea squirts or lampreys), which coincides with the emergence of the gnathostome-specific adaptive immune system. All the genes in the ABCD, ABCE and ABCF subfamilies were conserved and had undergone limited duplication and loss events. In the sea lamprey transcriptomes, the ABCE and ABCF gene subfamilies were ubiquitously and highly expressed in all tissues while the members in other gene subfamilies were differentially expressed. CONCLUSIONS: Thirteen more lamprey ABC transporter genes were identified in this study compared with a previous study. By concatenating the same gene sequences from the two lampreys, more full length sequences were obtained, which significantly improved both the assignment of gene names and the phylogenetic trees compared with a previous analysis using partial sequences. The ABC gene subfamilies in chordates have undergone obvious expansion or contraction. The ABCA subfamily showed the highest gene expansion rate during chordate evolution. The evolution of ABC transporters in lampreys requires further evaluation because the present results are based on a draft genome. PMID- 26047618 TI - The short-term association of selected components of fine particulate matter and mortality in the Denver Aerosol Sources and Health (DASH) study. AB - BACKGROUND: Associations of short-term exposure to fine particulate matter (PM2.5) with daily mortality may be due to specific PM2.5 chemical components. Daily concentrations of PM2.5 components were measured over five years in Denver to investigate whether specific PM2.5 components are associated with daily mortality. METHODS: Daily counts of total and cause-specific deaths were obtained for the 5-county Denver metropolitan region from 2003 through 2007. Daily 24-hour concentrations of PM2.5, elemental carbon (EC), organic carbon (OC), sulfate and nitrate were measured at a central residential monitoring site. Using generalized additive models, we estimated relative risks (RRs) of daily death counts for daily PM2.5 and four PM2.5 component concentrations at single and distributed lags between the current and three previous days, while controlling for longer term time trend and meteorology. RESULTS: RR of total non-accidental mortality for an inter-quartile increase of 4.55 MUg/m(3) in PM2.5 distributed over 4 days was 1.012 (95 % confidence interval: 0.999, 1.025); RRs for EC and OC were larger (1.024 [1.005, 1.043] and 1.020 [1.000, 1.040] for 0.33 and 1.67 MUg/m(3) increases, respectively) than those for sulfate and nitrate. We generally did not observe associations with cardiovascular and respiratory mortality except for associations with ischemic heart disease mortality at lags 3 and 0-3 depending on the component. In addition, there were associations with cancer mortality, particularly for EC and OC, possibly reflecting advanced deaths of a frail population. CONCLUSIONS: PM2.5 components possibly from combustion-related sources are more strongly associated with daily mortality than are secondary inorganic aerosols. PMID- 26047619 TI - Applying knowledge translation tools to inform policy: the case of mental health in Lebanon. AB - BACKGROUND: Many reform efforts in health systems fall short because the use of research evidence to inform policy remains scarce. In Lebanon, one in four adults suffers from a mental illness, yet access to mental healthcare services in primary healthcare (PHC) settings is limited. Using an "integrated" knowledge framework to link research to action, this study examines the process of influencing the mental health agenda in Lebanon through the application of Knowledge Translation (KT) tools and the use of a KT Platform (KTP) as an intermediary between researchers and policymakers. METHODS: This study employed the following KT tools: 1) development of a policy brief to address the lack of access to mental health services in PHC centres, 2) semi-structured interviews with 10 policymakers and key informants, 3) convening of a national policy dialogue, 4) evaluation of the policy brief and dialogue, and 5) a post-dialogue survey. RESULTS: Findings from the key informant interviews and a comprehensive synthesis of evidence were used to develop a policy brief which defined the problem and presented three elements of a policy approach to address it. This policy brief was circulated to 24 participants prior to the dialogue to inform the discussion. The policy dialogue validated the evidence synthesized in the brief, whereby integrating mental health into PHC services was the element most supported by evidence as well as participants. The post-dialogue survey showed that, in the following 6 months, several implementation steps were taken by stakeholders, including establishing national taskforce, training PHC staff, and updating the national essential drug list to include psychiatric medications. Relationships among policymakers, researchers, and stakeholders were strengthened as they conducted their own workshops and meetings after the dialogue to further discuss implementation, and their awareness about and demand for KT tools increased. CONCLUSIONS: This case study showed that the use of KT tools in Lebanon to help generate evidence-informed programs is promising. This experience provided insights into the most helpful features of the tools. The role of the KTP in engaging stakeholders, particularly policymakers, prior to the dialogue and linking them with researchers was vital in securing their support for the KT process and uptake of the research evidence. PMID- 26047620 TI - What do haematological cancer survivors want help with? A cross-sectional investigation of unmet supportive care needs. AB - BACKGROUND: This study aimed to identify the most prevalent unmet needs of haematological cancer survivors. METHODS: Haematological cancer survivors aged 18 80 years at time of recruitment were selected from four Australian state cancer registries. Survivors completed the Survivor Unmet Needs Survey. The most frequently reported "high/very high" unmet needs items were identified, as well as characteristics associated with the three most prevalent "high/very high" unmet needs reported by haematological cancer survivors. RESULTS: A total of 715 eligible survivors returned a completed survey. "Dealing with feeling tired" (17%), was the most frequently endorsed "high/very high" unmet need. Seven out of the ten most frequently endorsed unmet needs related to emotional health. Higher levels of psychological distress (e.g., anxiety, depression and stress) and indicators of financial burden as a result of cancer (e.g., having used up savings and trouble meeting day-to-day expenses due to cancer) were consistently identified as characteristics associated with the three most prevalent "high/very high" unmet needs. CONCLUSIONS: A minority of haematological cancer survivors endorsed a "high/very high" unmet need on individual items. Additional emotional support may be needed by a minority of survivors. Survivors reporting high levels of psychological distress or those who experience increased financial burden as a result of their cancer diagnosis may be at risk of experiencing the most prevalent "high/very high" unmet needs identified by this study. PMID- 26047621 TI - Pathology and function of conduction tissue in Fabry disease cardiomyopathy. AB - BACKGROUND: Cardiac arrhythmias are common in Fabry disease (FD) and may occur in prehypertrophic cardiomyopathy suggesting an early compromise of conduction tissue (CT). Therefore, FD X-linked and CT may be variously involved in male and female patients with FD cardiomyopathy, affecting CT function. METHODS AND RESULTS: Among 74 patients with endomyocardial biopsy diagnosis of FD cardiomyopathy, 13 (6 men; 7 women; mean age, 50.1+/-13.5 years; maximal wall thickness, 16.7+/-3.7 mm) had CT included in histological specimens and 6 also at electron microscopy. CT glycolipid infiltration was defined as focal, moderate, extensive, or massive, if involved <=30%, <=50%, >50%, or 100% of cells; identified as loosely arranged small myocytes positive to HCN4 immunostaining, supplied by a centrally placed thick-walled arteriole. CT involvement was correlated with age, sex, and alpha-Gal gene mutation. CT function was evaluated by electrophysiological study and arrhythmias at Holter registration. CT infiltration was focal/moderate in 4 women with no arrhythmias and normal electrophysiological study, extensive in 3 women with atrial or ventricular arrhythmias and short HV interval, and massive in 6 men with atrial fibrillation or ventricular arrhythmias and short HV. Short PR/AH with increased refractoriness was additionally found in 3 patients with extensive/massive CT infiltration. A male patient with the shortest HV presented infra-Hissian block during decremental atrial stimulation. There was no correlation with age, maximal wall thickness, and type of gene mutation. CONCLUSIONS: CT infiltration in FD cardiomyopathy is constant in men and variable in women because of skewed X chromosome inactivation; its extensive/massive involvement causes accelerated conduction with prolonged refractoriness and electric instability. PMID- 26047622 TI - EGFR mutant allelic-specific imbalance assessment in routine samples of non-small cell lung cancer. AB - In non-small cell lung cancer (NSCLC), the epidermal growth factor receptor (EGFR) gene may undergo both mutations and copy number gains. EGFR mutant allele specific imbalance (MASI) occurs when the ratio of mutant-to-wild-type alleles increases significantly. In this study, by using a previously validated microfluidic-chip-based technology, EGFR-MASI occurred in 25/67 mutant cases (37%), being more frequently associated with EGFR exon 19 deletions (p=0.033). In a subset of 49 treated patients, we assessed whether MASI is a modifier of anti EGFR treatment benefit. The difference in progression-free survival and overall survival between EGFR-MASI-positive and EGFR-MASI-negative groups of patients did not show a statistical significance. In conclusion, EGFR-MASI is a significant event in NSCLC, specifically associated with EGFR exon 19 deletions. However, EGFR-MASI does not seem to play a role in predicting the response to first generation EGFR small molecules inhibitors. PMID- 26047624 TI - Comfortable in their bodies: the rise of transgender care. PMID- 26047623 TI - Salvinorin-A Induces Intense Dissociative Effects, Blocking External Sensory Perception and Modulating Interoception and Sense of Body Ownership in Humans. AB - BACKGROUND: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception, but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profiles of subjective effects of increasing doses of salvinorin-A in healthy volunteers, with a special emphasis on interoception. METHODS: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included, among others, the Hallucinogen Rating Scale, the Altered States of Consciousness, and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness. RESULTS: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the highest dose led to a sense of a complete loss of contact with the body. CONCLUSIONS: Salvinorin-A induced intense psychotropic effects characterized by a dose dependent gating of external audio-visual information and an inverted-U dose response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception, and the sense of body ownership in humans. PMID- 26047626 TI - Even low levels of air pollution are linked to more deaths in over 65s, study finds. PMID- 26047627 TI - Diabetes self-management education and support in type 2 diabetes: a joint position statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. PMID- 26047628 TI - The Cost of Dengue Vector Control Activities in Malaysia by Different Service Providers. AB - We examined variations in dengue vector control costs and resource consumption between the District Health Departments (DHDs) and Local Authorities (LAs) to assist informed decision making as to the future roles of these agencies in the delivery of dengue vector control services in Malaysia. Data were collected from the vector control units of DHDs and LAs in 8 selected districts. We captured costs and resource consumption in 2010 for premise inspection for mosquito breeding sites, fogging to destroy adult mosquitoes and larviciding of potential breeding sites. Overall, DHDs spent US$5.62 million or US$679 per case and LAs spent US$2.61 million or US$499 per case. The highest expenditure for both agencies was for fogging, 51.0% and 45.8% of costs for DHDs and LAs, respectively. The DHDs had higher resource costs for human personnel, vehicles, pesticides, and equipment. The findings provide some evidence to rationalize delivery of dengue vector control services in Malaysia. PMID- 26047625 TI - Lanreotide Autogel 120 mg at extended dosing intervals in patients with acromegaly biochemically controlled with octreotide LAR: the LEAD study. AB - OBJECTIVE: To evaluate extended dosing intervals (EDIs) with lanreotide Autogel 120 mg in patients with acromegaly previously biochemically controlled with octreotide LAR 10 or 20 mg. DESIGN AND METHODS: Patients with acromegaly had received octreotide LAR 10 or 20 mg/4 weeks for >= 6 months and had normal IGF1 levels. Lanreotide Autogel 120 mg was administered every 6 weeks for 24 weeks (phase 1); depending on week-24 IGF1 levels, treatment was then administered every 4, 6 or 8 weeks for a further 24 weeks (phase 2). Hormone levels, patient reported outcomes and adverse events were assessed. PRIMARY ENDPOINT: proportion of patients on 6- or 8-week EDIs with normal IGF1 levels at week 48 (study end). RESULTS: 107/124 patients completed the study (15 withdrew from phase 1 and two from phase 2). Of 124 patients enrolled, 77.4% were allocated to 6- or 8-week EDIs in phase 2 and 75.8% (95% CI: 68.3-83.3) had normal IGF1 levels at week 48 with the EDI (primary analysis). A total of 88.7% (83.1-94.3) had normal IGF1 levels after 24 weeks with 6-weekly dosing. GH levels were <= 2.5 MUg/l in > 90% of patients after 24 and 48 weeks. Patient preferences for lanreotide Autogel 120 mg every 4, 6 or 8 weeks over octreotide LAR every 4 weeks were high. CONCLUSIONS: Patients with acromegaly achieving biochemical control with octreotide LAR 10 or 20 mg/4 weeks are possible candidates for lanreotide Autogel 120 mg EDIs. EDIs are effective and well received among such patients. PMID- 26047629 TI - Adverse Childhood Experiences and the Health of University Students in Eight Provinces of Vietnam. AB - Recent systematic reviews have emphasized the need for more research into the health and social impacts of adverse childhood experiences (ACEs) in the Asia Pacific region. This cross-sectional study was conducted with 2099 young adult students in 8 medical universities throughout Vietnam. An anonymous, self-report questionnaire included the World Health Organization ACE-International Questionnaire and standardized measures of mental and physical health. Three quarters (76%) of the students reported at least one exposure to ACEs; 21% had 4 or more ACEs. The most commonly reported adversities were emotional abuse, physical abuse, and witnessing a household member being treated violently (42.3%, 39.9%, and 34.6%, respectively). Co-occurrence of ACEs had dose-response relationships with poor mental health, suicidal ideation, and low physical health related quality of life. This first multisite study of ACEs among Vietnamese university students provided evidence that childhood adversity is common and is significantly linked with impaired health and well-being into the early adult years. PMID- 26047630 TI - Shelf life extension of fresh fruit and vegetables by chitosan treatment. AB - Among alternatives that are currently under investigation to replace the use of synthetic fungicides to control postharvest diseases in fresh produce and to extend their shelf life, chitosan application has shown promising disease control, at both preharvest and postharvest stages. Chitosan shows a dual mode of action, on the pathogen and on the plant, as it reduces the growth of decay causing fungi and foodborne pathogens and induces resistance responses in the host tissues. Chitosan coating forms a semipermeable film on the surface of fruit and vegetables, thereby delaying the rate of respiration, decreasing weight loss, maintaining the overall quality, and prolonging the shelf life. Moreover, the coating can provide a substrate for incorporation of other functional food additives, such as minerals, vitamins, or other drugs or nutraceutical compounds that can be used to enhance the beneficial properties of fresh commodities, or in some cases the antimicrobial activity of chitosan. Chitosan coating has been approved as GRAS substance by USFDA, and its application is safe for the consumer and the environment. This review summarizes the most relevant and recent knowledge in the application of chitosan in postharvest disease control and maintenance of overall fruit and vegetable quality during postharvest storage. PMID- 26047631 TI - Selecting a strategy for prevention of contrast-induced nephropathy in clinical practice: an evaluation of different clinical practice guidelines using the AGREE tool. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is a potential complication of radio-contrast investigations. Many organisations have published guidance documents on the prevention of CI-AKI. Our aim is to explore the scope, content, consistency, practicality in clinical practice and reasons for eventual underlying discrepancies of these documents. METHODS: We searched the literature for guidance documents developed to guide prevention of CI-AKI up to 09/2014. Four reviewers appraised guideline quality using the 23-item AGREE-II instrument, which rates reporting of the guidance development process across six domains: scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, applicability and editorial independence. Total scores were calculated as standardised averages by domain. RESULTS: Twenty-four guidance documents were evaluated. The guidance documents were produced by radiologists (N = 7), intensivists (N = 2), nephrologists (N = 6) or multidisciplinary teams (N = 9). One document did not mention the background of the authors. Only guidance documents (N = 15) that were not mere adaptations of existing guidelines were evaluated more in depth, using the AGREE tool. Overall, quality was mixed: only one clinical practice guidance document obtained an average score of >50% for all domains. The evidence was rated in a systematic way in only 11, and only 7 graded the strength of the recommendations. The Kidney Diseases Improving Global Outcomes guideline was the only one recommended without adaptions by all assessors. The guidance documents agreed in recommending pre-hydration as the main preventive measure, but there was difference in recommended total volumes, composition, rate and duration of the infused solutions. There was no consensus on the use of NaHCO3, with eight recommending it, six considering it and one not. Five guidance documents mentioned oral pre-hydration as a possibility, and none recommended N-acetylcysteine as solitary preventive measure. More recent guidance documents recommend avoiding hypertonic contrast media, but did not recommend preference of iso-osmolar over low-osmolar contrast media. Most guidance documents recognised pre-existing chronic kidney disease, diabetes, age and cardiovascular comorbidity as risk factors. CONCLUSIONS: There seems to be a relative consensus on the need for adequate pre-hydration to avoid CI-AKI, but recommendations to define at-risk populations for whom these measures should be applied and how they should be implemented differ substantially. Based on accumulating evidence, more recent guidelines do not recommend iso-osmolar over low-osmolar contrast media, whereas all recommend avoiding hypertonic agents. PMID- 26047632 TI - Clinical decision support system for end-stage kidney disease risk estimation in IgA nephropathy patients. AB - BACKGROUND: The progression of IgA nephropathy (IgAN) to end-stage kidney disease (ESKD) depends on several factors that are not quite clear and tangle the risk assessment. We aimed at developing a clinical decision support system (CDSS) for a quantitative risk assessment of ESKD and its timing using available clinical data at the time of renal biopsy. METHODS: We included a total of 1040 biopsy proven IgAN patients with long-term follow-up from Italy (N = 546), Norway (N = 441) and Japan (N = 53). Of these, 241 patients reached ESKD: 104 Italian [median time to ESKD = 5 (3-9) years], 134 Norwegian [median time to ESKD = 6 (2-11) years] and 3 Japanese [median time to ESKD = 3 (2-12) years]. We independently trained and validated two cooperating artificial neural networks (ANNs) for predicting first the ESKD status and then the time to ESKD (defined as three categories: <= 3 years, between > 3 and 8 years and over 8 years). As inputs we used gender, age, histological grading, serum creatinine, 24-h proteinuria and hypertension at the time of renal biopsy. RESULTS: The ANNs demonstrated high performance for both the prediction of ESKD (with an AUC of 89.9, 93.3 and 100% in the Italian, Norwegian and Japanese IgAN population, respectively) and its timing (f-measure of 90.7% in the cohort from Italy and 70.8% in the one from Norway). We embedded the two ANNs in a CDSS available online (www.igan.net). Entering the clinical parameters at the time of renal biopsy, the CDSS returns as output the estimated risk and timing of ESKD for the patient. CONCLUSIONS: This CDSS provides useful additional information for identifying 'high-risk' IgAN patients and may help stratify them in the context of a personalized medicine approach. PMID- 26047634 TI - Comparison of Clock Test Deficits Between Elderly Patients With Early and Late Onset Depression. AB - To compare clock test deficits in elderly patients with early onset depression (EOD) and late onset depression (LOD), we assessed 32 elderly healthy controls (HCs), 26 patients with EOD, and 27 patients with LOD with the clock drawing test (CDT), clock setting test, clock reading test, and the Tubingen Clock Questionnaire testing semantic memory about clock times. There was no significant difference in depression severity between patients with EOD and LOD. Patients with LOD had significantly lower scores on the CDT than patients with EOD and HCs. Semantic memory impairment concerning minute hand functionality was highly correlated with CDT performance and was significantly different between the EOD and the LOD groups. It can be suggested that significant differences in cognitive impairment severity between patients with EOD and LOD can be detected with CDT. Semantic memory impairment concerning minute hand functionality might affect CDT test results in elderly patients with depression. PMID- 26047633 TI - Children of a lesser god or miracles? An emotional and behavioural profile of children born to mothers on dialysis in Italy: a multicentre nationwide study 2000-12. AB - BACKGROUND: Pregnancy on dialysis is increasingly being reported. This study evaluates the behavioural profile of the children of mothers on dialysis and the parental stress their mothers undergo when compared with a group of mothers affected by a different chronic disease (microcythaemia) and a group of healthy control mothers. METHODS: Between 2000 and 2012, 23 on-dialysis mothers gave birth to 24 live-born children in Italy (23 pregnancies, 1 twin pregnancy, one of the twins deceased soon after delivery); of these, 16 mothers and 1 father (whose wife died before the inquiry) were included in the study (1 mother had died and the father was unavailable; 2 were not asked to participate because their children had died and 3 were unavailable; children: median age: 8.5, min-max: 2 13 years). Twenty-three mothers affected by transfusion-dependent microcythaemia or drepanocitosis (31 pregnancies, 32 children) and 35 healthy mothers (35 pregnancies, 35 children; median age of the children: 7, min-max: 1-13 years) were recruited as controls. All filled in the validated questionnaires: 'Child Behaviour Checklist' (CBCL) and the 'Parental Stress Index-Short Form' (PSI-SF). RESULTS: The results of the CBCL questionnaire were similar for mothers on dialysis and healthy controls except for pervasive developmental problems, which were significantly higher in the dialysis group, while microcythaemia mothers reported higher emotional and behavioural problems in their children in 8 CBCL sub-scales. Two/16 children in the dialysis and 3/32 in the microcythaemia group had pathological profiles, as assessed by T-scores (p: ns). PSI-SF indicated a normal degree of parental stress in microcythaemia subjects and healthy controls, while mothers on dialysis declared significantly lower stress, suggesting a defensive response in order to minimize problems, stress or negativity in their relationship with their child. CONCLUSIONS: According to the present analysis, the emotional and behavioural outcome is normal in most of the children from on dialysis mothers. A 'positive defence' in the dialysis mothers should be kept in mind when tailoring psychological support for this medical miracle. PMID- 26047635 TI - A Pilot Study of a Cognitive-Behavioral Treatment for Anxiety and Depression in Patients With Parkinson Disease. AB - Anxiety and depression often remain unrecognized or inadequately treated in patients with Parkinson disease (PD). Cognitive-behavioral therapy (CBT) is effective, but limited evidence supports its use for anxiety and depression in patients with PD. Sixteen patients with PD having significant anxiety and/or depressive symptoms were assigned to CBT or enhanced usual care. Assessments occurred at baseline, posttreatment, and 1-month follow-up. The CBT intervention included tools for anxiety, depression, and healthy living with PD symptoms. Individual sessions were delivered by telephone or in person, based on patient preference. Treatment was feasible with participants choosing 67% of sessions by telephone and 80% completed treatment. The between-group effect sizes for change scores from baseline to posttreatment and baseline to 1-month follow-up were large (posttreatment: d = 1.49 for depression and 1.44 for anxiety; 1-month follow-up: d = .73 for depression and 1.24 for anxiety), although only the posttreatment effect size for depression was significant. This pilot CBT program is feasible for treatment of anxiety and depression in patients with PD. PMID- 26047636 TI - Symptom Assessment for a Palliative Care Approach in People With Dementia Admitted to Acute Hospitals: Results From a National Audit. AB - CONTEXT: As the prevalence of dementia increases, more people will need dementia palliative and end-of-life (EOL) care in acute hospitals. Published literature suggests that good quality care is not always provided. OBJECTIVE: To evaluate the prescription of antipsychotics and performance of multidisciplinary assessments relevant to palliative care for people with dementia, including those at EOL, during hospital admission. METHOD: As part of a national audit of dementia care, 660 case notes were reviewed across 35 acute hospitals. RESULTS: In the entire cohort, many assessments essential to dementia palliative care were not performed. Of the total sample, 76 patients died, were documented to be receiving EOL care, and/or were referred for specialist palliative care. In this cohort, even less symptom assessment was performed (eg, no pain assessment in 27%, no delirium screening in 68%, and no mood or behavioral and psychological symptoms of dementia in 93%). In all, 37% had antipsychotic drugs during their admission and 71% of these received a new prescription in hospital, most commonly for "agitation." CONCLUSION: This study suggests a picture of poor symptom assessment and possible inappropriate prescription of antipsychotic medication, including at EOL, hindering the planning and delivery of effective dementia palliative care in acute hospitals. PMID- 26047637 TI - Text mining facilitates database curation - extraction of mutation-disease associations from Bio-medical literature. AB - BACKGROUND: Advances in the next generation sequencing technology has accelerated the pace of individualized medicine (IM), which aims to incorporate genetic/genomic information into medicine. One immediate need in interpreting sequencing data is the assembly of information about genetic variants and their corresponding associations with other entities (e.g., diseases or medications). Even with dedicated effort to capture such information in biological databases, much of this information remains 'locked' in the unstructured text of biomedical publications. There is a substantial lag between the publication and the subsequent abstraction of such information into databases. Multiple text mining systems have been developed, but most of them focus on the sentence level association extraction with performance evaluation based on gold standard text annotations specifically prepared for text mining systems. RESULTS: We developed and evaluated a text mining system, MutD, which extracts protein mutation-disease associations from MEDLINE abstracts by incorporating discourse level analysis, using a benchmark data set extracted from curated database records. MutD achieves an F-measure of 64.3% for reconstructing protein mutation disease associations in curated database records. Discourse level analysis component of MutD contributed to a gain of more than 10% in F-measure when compared against the sentence level association extraction. Our error analysis indicates that 23 of the 64 precision errors are true associations that were not captured by database curators and 68 of the 113 recall errors are caused by the absence of associated disease entities in the abstract. After adjusting for the defects in the curated database, the revised F-measure of MutD in association detection reaches 81.5%. CONCLUSIONS: Our quantitative analysis reveals that MutD can effectively extract protein mutation disease associations when benchmarking based on curated database records. The analysis also demonstrates that incorporating discourse level analysis significantly improved the performance of extracting the protein mutation-disease association. Future work includes the extension of MutD for full text articles. PMID- 26047638 TI - Catalyst-Dependent Stereodivergent and Regioselective Synthesis of Indole-Fused Heterocycles through Formal Cycloadditions of Indolyl-Allenes. AB - Stereo- and regioselective construction of poly-heterocycles, especially those with several contiguous stereocenters, is still a challenge. In this paper, catalyst-dependent stereodivergent and regioselective synthesis of indole-fused heterocycles through formal cycloadditions of indolyl-allenes has been developed. The reaction features total reversion of an all-carbon quaternary stereocenter when a gold or platinum complex was employed as the catalyst through [3 + 2] cycloaddition of allene with indole, affording different diazabenzo[a]cyclopenta[cd]azulenes as epimers, respectively. In addition, in the presence of IPrAuCl and AgNTf2, highly regioselective exo-type [2 + 2] cycloaddition was observed, in which allene served as a 2C synthon. This methodology provides a simple and straightforward approach for the construction of indole-fused tricyclic systems under mild conditions in an atom-economical way. PMID- 26047639 TI - Moraxella catarrhalis induces an immune response in the murine lung that is independent of human CEACAM5 expression and long-term smoke exposure. AB - In patients with chronic obstructive pulmonary disease (COPD), Moraxella catarrhalis infection of the lower airways is associated with chronic colonization and inflammation during stable disease and acute exacerbations. Chronic smoke exposure induces chronic inflammation and impairs mucociliary clearance, thus contributing to bacterial colonization of the lower airways in COPD patients. The human-specific carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5, expressed in human airways, has been shown to contribute to epithelial colonization of CEACAM-binding pathogens. To investigate the impact of CEACAM5 expression on pulmonary M. catarrhalis colonization, we infected mice transgenic for human CEACAM5 (hCEACAM5) and wild type mice intratracheally with M. catarrhalis with or without preceding smoke exposure and analyzed bacterial colonization and local and systemic inflammation. Our results show that airway infection with M. catarrhalis accelerated acute local but not systemic inflammation, albeit independent of hCEACAM5 expression. Long-term smoke exposure alone or prior to M. catarrhalis infection did not contribute to increased local or systemic inflammation. No difference was found in pulmonary clearance of M. catarrhalis in hCEACAM5-transgenic mice compared with wild-type mice. Smoke exposure neither altered time nor extent of persistence of M. catarrhalis in the lungs of both genotypes. In conclusion, M. catarrhalis induced a local acute immune response in murine airways. Neither hCEACAM5 expression nor chronic smoke exposure nor a combination of both was sufficient as prerequisites for the establishment of chronic M. catarrhalis colonization. Our results demonstrate the difficulties in mirroring conditions of chronic airways colonization of M. catarrhalis in a murine model. PMID- 26047640 TI - EG-VEGF, BV8, and their receptor expression in human bronchi and their modification in cystic fibrosis: Impact of CFTR mutation (delF508). AB - Enhanced lung angiogenesis has been reported in cystic fibrosis (CF). Recently, two highly homologous ligands, endocrine gland vascular endothelial growth factor (EG-VEGF) and mammalian Bv8, have been described as new angiogenic factors. Both ligands bind and activate two closely related G protein-coupled receptors, the prokineticin receptor (PROKR) 1 and 2. Yet, the expression, regulation, and potential role of EG-VEGF, BV8, and their receptors in normal and CF lung are still unknown. The expression of the receptors and their ligands was examined using molecular, biochemical, and immunocytochemistry analyses in lungs obtained from CF patients vs. control and in normal and CF bronchial epithelial cells. Cystic fibrosis transmembrane conductance regulator (CFTR) activity was evaluated in relation to both ligands, and concentrations of EG-VEGF were measured by ELISA. At the mRNA level, EG-VEGF, BV8, and PROKR2 gene expression was, respectively, approximately five, four, and two times higher in CF lungs compared with the controls. At the cellular level, both the ligands and their receptors showed elevated expressions in the CF condition. Similar results were observed at the protein level. The EG-VEGF secretion was apical and was approximately two times higher in CF compared with the normal epithelial cells. This secretion was increased following the inhibition of CFTR chloride channel activity. More importantly, EG-VEGF and BV8 increased the intracellular concentration of Ca(2+) and cAMP and stimulated CFTR-chloride channel activity. Altogether, these data suggest local roles for epithelial BV8 and EG-VEGF in the CF airway peribronchial vascular remodeling and highlighted the role of CFTR activity in both ligand biosynthesis and secretion. PMID- 26047641 TI - Metformin attenuates hyperoxia-induced lung injury in neonatal rats by reducing the inflammatory response. AB - Because therapeutic options are lacking for bronchopulmonary dysplasia (BPD), there is an urgent medical need to discover novel targets/drugs to treat this neonatal chronic lung disease. Metformin, a drug commonly used to lower blood glucose in type 2 diabetes patients, may be a novel therapeutic option for BPD by reducing pulmonary inflammation and fibrosis and improving vascularization. We investigated the therapeutic potential of daily treatment with 25 and 100 mg/kg metformin, injected subcutaneously in neonatal Wistar rats with severe experimental BPD, induced by continuous exposure to 100% oxygen for 10 days. Parameters investigated included survival, lung and heart histopathology, pulmonary fibrin and collagen deposition, vascular leakage, right ventricular hypertrophy, and differential mRNA expression in the lungs of key genes involved in BPD pathogenesis, including inflammation, coagulation, and alveolar development. After daily metformin treatment rat pups with experimental BPD had reduced mortality, alveolar septum thickness, lung inflammation, and fibrosis, demonstrated by a reduced influx of macrophages and neutrophils and hyperoxia induced collagen III and fibrin deposition (25 mg/kg), as well as improved vascularization (100 mg/kg) compared with control treatment. However, metformin did not ameliorate alveolar enlargement, small arteriole wall thickening, vascular alveolar leakage, and right ventricular hypertrophy. In conclusion metformin prolongs survival and attenuates pulmonary injury by reducing pulmonary inflammation, coagulation, and fibrosis but does not affect alveolar development or prevent pulmonary arterial hypertension and right ventricular hypertrophy in neonatal rats with severe hyperoxia-induced experimental BPD. PMID- 26047642 TI - Human airway smooth muscle cells secrete amphiregulin via bradykinin/COX-2/PGE2, inducing COX-2, CXCL8, and VEGF expression in airway epithelial cells. AB - Human airway smooth muscle cells (HASMC) contribute to asthma pathophysiology through an increased smooth muscle mass and elevated cytokine/chemokine output. Little is known about how HASMC and the airway epithelium interact to regulate chronic airway inflammation and remodeling. Amphiregulin is a member of the family of epidermal growth factor receptor (EGFR) agonists with cell growth and proinflammatory roles and increased expression in the lungs of asthma patients. Here we show that bradykinin (BK) stimulation of HASMC increases amphiregulin secretion in a mechanism dependent on BK-induced COX-2 expression, increased PGE2 output, and the stimulation of HASMC EP2 and EP4 receptors. Conditioned medium from BK treated HASMC induced CXCL8, VEGF, and COX-2 mRNA and protein accumulation in airway epithelial cells, which were blocked by anti-amphiregulin antibodies and amphiregulin siRNA, suggesting a paracrine effect of HASMC-derived amphiregulin on airway epithelial cells. Consistent with this, recombinant amphiregulin induced CXCL8, VEGF, and COX-2 in airway epithelial cells. Finally, we found that conditioned media from amphiregulin-stimulated airway epithelial cells induced amphiregulin expression in HASMC and that this was dependent on airway epithelial cell COX-2 activity. Our study provides evidence of a dynamic axis of interaction between HASMC and epithelial cells that amplifies CXCL8, VEGF, COX-2, and amphiregulin production. PMID- 26047643 TI - Effect of unilateral knee extensor fatigue on force and balance of the contralateral limb. AB - PURPOSE: Fatigue in one limb can decrease force production in the homologous muscle as well as other muscles of the non-fatigued limb affecting balance. The objective of the study was to examine the effect of unilateral knee extensor fatigue on the non-fatigued limb's standing balance, muscle force and activation. METHOD: Sixteen healthy male subjects performed pre-fatigue balance trials, warm up exercises, maximum voluntary isometric contractions, a knee extensors fatigue protocol, and post-fatigue balance trials. The fatigue protocol consisted of sets of 15 consecutive isometric contractions of 16 s each with 4 s recovery between repetitions, which were performed at 30% peak force for the dominant knee extensor muscles. Additional sets of contractions continued until a 50% decrease in MVIC knee extensor force was observed. Pre- and post-fatigue balance assessment consisted of transition from double to single leg standing and also single leg standing trials, which were performed bilaterally and in randomized order. RESULT: The peak force and F100 were significantly decreased by 44.8% (ES = 2.54) and 39.9% (ES = 0.59), respectively, for the fatigued limb post-fatigue. There were no significant changes in the non-fatigued limb's muscle force, activation, muscle onset timing or postural stability parameters. CONCLUSION: While the lack of change in non-fatigued limb force production is in agreement with some of the previous literature in this area, the lack of effect on postural measures directly contradicts earlier work. It is hypothesized that discrepancies in the duration and the intensity of the fatigue protocol may have accounted for this discrepancy. PMID- 26047644 TI - Fat intake after prostate cancer diagnosis and mortality in the Physicians' Health Study. AB - PURPOSE: Diet after prostate cancer diagnosis may impact disease progression. We hypothesized that consuming saturated fat after prostate cancer diagnosis would increase risk of mortality, and consuming vegetable fat after diagnosis would lower the risk of mortality. METHODS: This was a prospective study among 926 men with non-metastatic prostate cancer in the Physicians' Health Study who completed a food frequency questionnaire a median of 5 years after diagnosis and were followed for a median of 10 years after the questionnaire. We examined post diagnostic saturated, monounsaturated, polyunsaturated, and trans fat, as well as animal and vegetable fat, intake in relation to all-cause and prostate cancer specific mortality. Hazard ratios (HR) and 95 % confidence intervals (CI) were estimated using multivariate Cox proportional hazards regression. RESULTS: We observed 333 deaths (56 prostate cancer deaths) during follow-up. Men who obtained 5 % more of their daily calories from saturated fat and 5 % less of their daily calories from carbohydrate after diagnosis had a 1.8-fold increased risk of all-cause mortality (HR 1.81; 95 % CI 1.20, 2.74; p value 0.005) and a 2.8-fold increased risk of prostate cancer-specific mortality (HR 2.78; 95 % CI 1.01, 7.64; p value 0.05). Men who obtained 10 % more of their daily calories from vegetable fats and 10 % less of their daily calories from carbohydrates had a 33 % lower risk of all-cause mortality (HR 0.67; 95 % CI 0.47, 0.96; p value 0.03). CONCLUSIONS: Among men with non-metastatic prostate cancer, saturated fat intake may increase risk of death and vegetable fat intake may lower risk of death. PMID- 26047645 TI - The Knee Society Short Form Reduces Respondent Burden in the Assessment of Patient-reported Outcomes. AB - BACKGROUND: The patient's own evaluation of function and satisfaction is a fundamental component of assessing outcomes after total knee arthroplasty (TKA). The new Knee Society Knee Score was introduced in 2012 and has been shown to be a valid and reliable instrument for measuring the outcome of TKA. This score combines an objective, physician-derived component and a patient-reported component to characterize the expectations, satisfaction, and functional activities of diverse lifestyles of contemporary patients undergoing TKA. However, in the routine clinical setting, the administration and scoring of outcome measures is often resource-intensive, as the expenditure of time and budget for outcome measurement increase with the length and complexity of the instrument used, and so a short-form assessment can help to reduce the burden the assessment of outcomes. QUESTIONS/PURPOSES: The purposes of this study were (1) to develop a short-form version of the new Knee Society Knee Score; (2) to validate the short form against the full Knee Society Knee Score; and (3) to evaluate the responsiveness to treatment (TKA) of the new Knee Society short-form assessment. METHODS: To develop the short form, data from the sample of 497 patients recruited during validation of the original long form the new Knee Society Knee Score were used. The multicenter study was approved by the institutional review boards at 15 participating medical institutions within the United States and Canada. An analytic item reduction approach was applied simultaneously but separately to preoperative and postoperative patient-reported data to select a subset of items from the original form that had good measurement properties and closely reflected the scores obtained using the original form. RESULTS: Expectations and satisfaction were reflected by a single item in the newly developed short form compared with a total of five satisfaction and three expectation items in the long form. The functional activities subscale was reduced from 17 to six items. An excellent correlation was demonstrated between function scores derived from the functional activities subscale of the original long-form score (17 items) and the six-item short form (r = 0.97; p < 0.01). The sample mean difference between the two scores was less than 4 points with a SD of 6.7 points. The short form was capable of discriminating clinically different groups of patients before and after TKA with virtually the same estimated effect size as the original functional activities subscale of the new Knee Society Knee Score. CONCLUSIONS: The Knee Society Knee Score long form is still recommended for research studies and for more sensitive measurement of the outcomes of individual patients. However, for general clinical use with large patient populations, the short form is expected to improve the rate of patient completion while also being easier to administer. In this study, we found the short-form version of the Knee Society Knee Score to be practical, valid, reliable, and responsive for assessing the functional outcome of TKA. PMID- 26047646 TI - Posterior Soft Tissue Repair After Primary THA is Durable at Mid-term Followup: A Prospective MRI Study. AB - BACKGROUND: The enhanced posterior soft tissue repair has reduced the frequency of dislocation after primary THA performed through the posterolateral approach. However, the long-term integrity of the repair is unknown and could influence surgeon choice regarding surgical technique and THA approach. QUESTIONS/PURPOSES: We asked: (1) What is the durability of the enhanced posterior soft tissue repair at a minimum of 49 months using MRI to evaluate soft tissue to bone integrity? (2) How does the appearance of the posterior soft tissues change during this time? (3) Are there patient characteristics associated with the long-term imaging appearance of the posterior repair? METHODS: All patients without a contraindication for MRI who were undergoing unilateral primary uncemented THA through a posterior approach between February and May 2005 were eligible for inclusion. Ninety percent consented to participate (36 of 40 patients), and 30 patients were followed prospectively with MRI postoperatively and again at 3 months; of those, 22 (73%; 12 men, 10 women) completed the study by having another MRI study at a minimum of 49 months (mean, 51 months; range, 49-59 months). Each patient underwent metal-artifact-reduction sequence MRI to evaluate the integrity of the posterior soft tissues, which had been repaired anatomically during primary THA at a minimum of 4 years earlier. The results were compared with those of prior MR images obtained immediately after surgery and at 3 months postoperatively. All patients were given a self-reported modified Harris hip score at the time of the most recent MRI study (maximum score = 81). RESULTS: At latest followup, 21 of 22 (96%) patients had a posterior capsule in contact with bone, and 21 of 22 (96%) had an intact quadratus femoris. Twenty-one patients (96%) had soft tissue or a scar from the piriformis and conjoined tendons in continuity with bone. In these cases, the interface between the piriformis and conjoined tendons and the greater trochanter observed immediately postoperatively and at 3 months postoperatively became filled with hypointense tissue, with signal characteristics similar to tendon. Time from surgery was most associated with changes in native tendon-to-bone distances (p < 0.001) and MRI signal intensity of the repair (p < 0.001). CONCLUSIONS: At followup of just more than 4 years, the posterior capsule and quadratus femoris most often were healed to bone. In the majority of patients, scar tissue between the piriformis and conjoined tendons and bone matured to achieve orientation and signal intensity resembling native tendon. We believe the enhanced posterior soft tissue repair facilitates this process. Our results provide a plausible explanation for improved postoperative stability observed in patients receiving an enhanced soft tissue repair compared with those in whom a repair is not performed. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 26047647 TI - Success of Pavlik Harness Treatment Decreases in Patients >= 4 Months and in Ultrasonographically Dislocated Hips in Developmental Dysplasia of the Hip. AB - BACKGROUND: Treatment of developmental dysplasia of the hip (DDH) using the Pavlik harness has been a widely used method in patients between 0 and 6 months of age for many years. However, the factors influencing the success rate of this treatment modality have still not exactly been determined as a result of the limited number of clinical studies with higher level of evidence. QUESTIONS/PURPOSES: We, therefore, asked whether (1) patient-related variables such as age, gender, and laterality; coexisting risk factors including family history, breech presentation, intrauterine packing, first-born girl, oligohydroamnios, and swaddling; and (2) the severity of hip dysplasia, defined by ultrasonography, are associated with differences in the success rate of Pavlik harness treatment in infants with DDH. METHODS: Between 2012 and 2014, we treated 153 children (<= 6 months of age) with DDH using the Pavlik harness. Hip dysplasia apart from coexisting neuromuscular disorders, congenital abnormalities, or syndromes was our inclusion criteria. Of patients thus treated, 130 (85%) were available for the evaluation of patient- and hip-related variables against the success of Pavlik harness treatment. Mean age of these patients on day of diagnosis and initiation of treatment was 108 days. The diagnostic and followup examinations of the hips were made by ultrasonography using Graf's method. Pavlik harness treatment was initiated in Graf Type IIa- and worse hips and treatment was considered "successful" when a Graf Type I hip was achieved. Pavlik harness treatment was successful in 92 (71%) patients (130 of 181 hips [72%]). RESULTS: Age was the only patient-related variable influencing the success rate of the treatment; the mean age of children in whom Pavlik harness treatment succeeded (97 +/- 38 days; 95% confidence interval [CI], 90-112) was lower than the age of those who failed (135 +/- 37 days; 95% CI, 123-147; p < 0.001). The highest success rate was obtained in children younger than age 3 months (37 of 40 [93%]) and the lowest one older than age 5 months (nine of 24 [37%]) (p < 0.001). The threshold age value related to an increased risk of failure was found to be 4 months and older, which had a sensitivity of 66% and a specificity of 77% (p < 0.001). A higher initial alpha angle was observed in the hips in which the treatment succeeded (53 degrees +/- 6 degrees ; 95% CI, 51 degrees -53 degrees ) than in those that failed (47 degrees +/- 7 degrees ; 95% CI, 45 degrees -50 degrees ; p < 0.001). The threshold alpha angle value related to an increased risk of treatment failure was 46 degrees and less, which had a sensitivity of 47% and a specificity of 86% (p < 0.001). Dislocated hips (Graf Type III and IV hips) had the lowest rate of treatment success (five of 19 [26%] and two of four [50%], respectively), whereas Graf Type IIa- hips had the highest (27 of 29 [93%]) (p < 0.001). CONCLUSIONS: We conclude that Pavlik harness treatment is less effective in children at and over the age of 4 months at the time the harness is first applied as well as in hips with complete dislocations and hips with severely deficient acetabular bony roofs. In such older patients and worse hip types, the use of initial Pavlik harness treatment needs to be revisited. Future studies, comparing the outcomes of the Pavlik harness treatment and other types of interventions in such patients and hip types, are needed. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 26047648 TI - Description and prevalence of a putative novel mycovirus within the conifer pathogen Gremmeniella abietina. AB - The European race of Gremmeniella abietina (Lagerberg) Morelet is the causal agent of stem canker and shoot blight on numerous conifers in Europe and North America. It comprises different species and biotypes in which the presence of mycoviruses has been determined. In this report, we describe the full-length sequence of the RNA-dependent RNA polymerase (RdRp) of a putative novel virus, Gremmeniella abietina RNA virus 6 (GaRV6), with 2165 nt and a GC content of 54.7 %. A BLASTp search using the deduced RdRp amino acid sequence confirmed GaRV6 to be related to members of a still unassigned virus taxon, which includes, e.g., Fusarium graminearum dsRNA mycovirus 4 (FgV-4) and the mutualistic Curvularia thermal tolerance virus (CThTV). The prevalence and genetic diversity of GaRV6 was also studied within the European race of G. abietina. We examined 162 isolates originating from Canada, the Czech Republic, Finland, Italy, Montenegro, Serbia, Spain, Switzerland, Turkey and the United States. According to direct specific reverse transcription (RT) PCR screening based on the RdRp sequence, the virus appears to be present only in Spain, where it is relatively abundant but genetically highly uniform. PMID- 26047649 TI - Sasa quelpaertensis Nakai extract suppresses porcine reproductive and respiratory syndrome virus replication and modulates virus-induced cytokine production. AB - Although Sasa quelpaertensis Nakai, a dwarf bamboo, is known to exert a variety of beneficial effects on health, its antiviral effect remains to be elucidated. Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating viral pathogens of swine and has a substantial economic impact on the global pork industry. Therefore, the present study was conducted to determine whether Sasa quelpaertensis Nakai extract (SQE) inhibits PRRSV infection in cultured porcine alveolar macrophages (PAMs). Our results demonstrated that SQE treatment suppressed the replication of PRRSV in a dose-dependent manner. The antiviral activity of SQE on PRRSV replication was found to be primarily exerted at early times postinfection. Treatment with SQE resulted in marked reduction of viral genomic and subgenomic RNA synthesis, viral protein expression, and progeny virus production. Notably, pro-inflammatory cytokine production in PAM cells infected with PRRSV was shown to be modulated in the presence of SQE. Taken together, our data indicate that SQE has potential as a therapeutic agent against PRRSV. PMID- 26047650 TI - Expression of porcine Mx1 with FMDV IRES enhances the antiviral activity against foot-and-mouth disease virus in PK-15 cells. AB - Foot-and-mouth disease virus (FMDV) is the most contagious pathogen in cloven hoofed (two-toed) animals. Due to the rapid replication and spread of FMDV, novel therapeutic strategies are greatly needed to reduce or block FMDV shedding in cases of disease outbreak. Here, we generated an IRES-Mx1 construct in which the internal ribosome entry site (IRES) of FMDV was inserted between the promoter and open reading frame (ORF) of porcine myxovirus resistance protein 1 (poMx1). This construct provides more powerful protection against FMDV infection than the IRES IFN construct that was previously generated by our group. The results indicate that this IRES-Mx1 construct was able to express poMx1 12 h after transfection and induce a robust immune response. In contrast to the control, the proliferation of virus in transfected cells was significantly inhibited, as evaluated by morphology monitoring, real-time RT-PCR, virus titration and Western blot. In addition, we also found that the antiviral activity in cells transfected with pc-IRES-Mx1 was abolished when the JAK/STAT pathway was repressed, which indicates that the antiviral mechanism of poMx1 is JAK/STAT pathway dependent. Taken together, our data suggest that the antiviral activity of poMx1 is possibly produced by affecting the host cells themselves, instead of interacting with the virus directly. The new construct reported here could be used as a novel effective therapy against FMDV infection. PMID- 26047651 TI - Modified STOP-BANG questionnaire to predict obesity hypoventilation syndrome in obese subjects with obstructive sleep apnea. AB - PURPOSE: The STOP-BANG questionnaire (SBQ) has never been studied in the context of its ability to predict obesity hypoventilation syndrome (OHS). Our aim was to evaluate the predictive performance of the original and modified SBQs for OHS in obese subjects with obstructive sleep apnea (OSA). METHODS: Demographics, polysomnographic data, body mass index (BMI), Epworth Sleepiness Scale (ESS) scores, arterial blood gases, spirometric measurements, and SBQ scores were recorded. The modified SBQ was created by dividing BMI into ranges and adding the serum bicarbonate ranges. RESULTS: The study included 196 obese subjects, of whom 17 had normal polysomnography. Of the remaining subjects, 105 had pure OSA and 74 had OHS with OSA. Both the original and modified SBQs scores were higher for the OHS subjects than for those with pure OSA (p < 0.001). An original SBQ score of >=6 gave a satisfactory discrimination for OHS diagnosis (sensitivity 71.6 %, specificity 59.1 %, positive predictive value (PPV) 55.2 %, and negative predictive value (NPV) 74.7 %). The diagnostic OR for an original SBQ score of >=6 for predicting OHS was 3.7. The sensitivity and NPV were increased for the modified SBQ (sensitivity 89.2 %, specificity 47.6 %, PPV 54.6 %, NPV 86.2 %), and the OR was 7.5. Both the original and modified SBQ scores were moderately correlated with ESS, AHI, ODI, lowest SpO2, and sleep time spent with SpO2 <90 %. CONCLUSIONS: The modified SBQ can be used to screen for OHS in obese subjects. PMID- 26047652 TI - Final pathohistology after radical prostatectomy in patients eligible for active surveillance (AS). AB - PURPOSE: The aim of the current study was to determine in retrospect how many of a group of patients who underwent radical prostatectomy were correctly classified with an insignificant prostate carcinoma by means of preoperative diagnostics. Furthermore, we are aiming at finding preoperative parameters which predict an insignificant prostate carcinoma with higher accuracy. The current inclusion parameters of AS will be verified with regard to their reliability, and we will discuss the possibility of improving their prediction accuracy. METHODS: We examined the data of 308 consecutive patients who were diagnosed with a clinically insignificant prostate carcinoma and therefore would be suited for AS, but opted for a radical prostatectomy. According to the literature(1), the following inclusion criteria were chosen for our evaluation: a proven prostate carcinoma, detected by either ultrasonically guided transrectal core needle biopsy (cT1c) with at least six obtained samples and with a maximum of two positive samples on one side and a less than a 50 % tumor rate per sample, or a 5 % or lower tumor rate found in the tissue obtained by transurethral prostate resection (cT1a). The PSA value in all cases was below 10 ng/ml and the Gleason Score <=6. The probability of a preoperative "undergrading" or "understaging" was determined as a function of preoperative parameters like Gleason Score, PSA value, the number of collected samples and positive samples obtained by core needle biopsy, prostate volume, and PSA density. Based on the available preoperative data, we developed and tested several regression models for the identification of independent factors for upgrading and upstaging. RESULTS: Within the examined patient population, 232 of 308 patients (75 %) were, according to their final prostate histology, diagnosed with a stage >=pT2b prostate carcinoma. Eight percentage of the patients who had undergone surgery had a stage >=pT3a carcinoma, and 118 of 308 (38 %) had a Gleason Score of 6 or higher. Positive lymph nodes and an infiltration of the seminal vesicle each occurred in 1 % of the cases. Histopathologic positive margins of resection existed in 33 of 308 patients (11 %). Independent factors for upgrading and upstaging a prostate volume of <50 ml and a preoperative Gleason Score of <=6 were identified. CONCLUSION: The presented results show that the current inclusion criteria for AS are insufficient. For many patients, the beginning of the necessary therapy is delayed. According to our data, the prostate volume, the preoperative Gleason Score, and the number of positive samples obtained by transrectal core needle biopsy have the highest predictive power with regard to aggressiveness and expansion of the tumor. Despite the consideration of all these preoperative parameters, the differentiation of the prostate carcinomas was underrated in a third of all cases. The expansion of the tumor within the prostate was underrated even in three fourths of the cases. PMID- 26047653 TI - Comparison of renal function detriments after local tumor ablation or partial nephrectomy for renal cell carcinoma. AB - PURPOSE: Local tumor ablation (LTA) and partial nephrectomy (PN) represent treatment alternatives for patients diagnosed with small renal mass and both may result in renal function detriments. The aim of the study was to compare renal function detriments after LTA or PN. METHODS: A Surveillance epidemiology and End Results-Medicare-linked retrospective cohort of 2850 T1 kidney cancer patients who underwent LTA or PN was abstracted. Short-term outcomes consisted of 30-day acute kidney injury (AKI) and 30-day dialysis rates. Long-term outcomes consisted of episodes of AKI, mild and moderate-severe chronic kidney disease (CKD), end stage renal disease, hemodialysis and anemia in CKD. Analyses consisted of propensity score matching, logistic and Cox regression. RESULTS: After propensity score matching, 1122 patients remained. The 30-day incidence of AKI was 4.6 % after LTA and 9.4 % after PN. In multivariable analyses (MVAs), LTA was associated with a lower AKI rate (OR 0.42; p = 0.001). The 30-day incidence of any dialysis was <2 % after either LTA or PN. In MVA, LTA was not associated with a lower rate of any dialysis (OR 0.43; p = 0.2). At long-term assessment, both the unadjusted and adjusted rates of all six examined end points were not different between LTA and PN (all p > 0.5). CONCLUSIONS: LTA offers short-term protective effect from AKI. The short-term rates of any dialysis treatment are similar after either LTA or PN. At long-term assessment, LTA and PN renal function detriment rates are not different. Concern for long-term functional outcomes should not be a barrier for PN. PMID- 26047654 TI - Validation of TNM classification for metastatic prostatic cancer treated using primary androgen deprivation therapy. AB - PURPOSE: The current tumor-node-metastasis (TNM) classification system has been used for many years. The prognosis of patients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification. METHODS: A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan-Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model. RESULTS: The 5 year OS, CSS, and PFS were 76.0, 83.2, and 38.8% in N1M0, 57.5, 69.0, and 23.0% in M1a, 54.0, 63.1, and 23.0% in M1b, and 40.0, 51.5, and 16.6% in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score >=8 and that combined androgen blockade (CAB) treatment provided better OS than non CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen >100 ng/ml only in M1b. CONCLUSIONS: Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics. PMID- 26047655 TI - Observations and outcomes of urethroplasty for bulbomembranous stenosis after radiation therapy for prostate cancer. AB - PURPOSE: Bulbomembranous stenosis is a significant complication of radiotherapy for prostate cancer. Our purpose is to report outcomes of urethroplasty for radiation-induced bulbomembranous urethral stenoses. METHODS: Thirty-five patients underwent urethroplasty for refractory radiation-induced bulbomembranous stenoses from January 2004 to November 2013. Patients had a minimum follow-up of 12 months with routine cystoscopy at 6 and 12 months. Primary outcome was urethral patency, and secondary outcomes were 90-day complications, de novo incontinence, de novo erectile dysfunction and bothersome LUTS. Outcomes were compared using Fisher's exact test. RESULTS: Of the 35 patients, 20 and 15 had stenosis related to external beam radiation therapy and brachytherapy, respectively. Mean stricture length was 3.5 cm. Reconstruction was performed using anastomotic urethroplasty in 23 patients (65.7 %), while 12 required tissue transfer as a buccal mucosa graft (20.0 %) or penile island flap (14.3 %). With 50.5 months of follow-up, thirty patients (85.7 %) achieved cystoscopic patency with no significant difference between techniques (p = 0.32). A 90-day complication rate of 31.4 % was observed (all Clavien 1-2) with no difference between techniques (p = 1.00). Adverse change in continence occurred in 25.7 % of patients (13.3 % in those without previous TURP). Postoperatively, persisting storage LUTS occurred in 40.0 and 30.4 % described adverse change in erectile function (exclusively in the anastomotic urethroplasty group). CONCLUSIONS: Reconstruction of radiation-induced bulbomembranous stenosis yields satisfying patency rates. However, radiation-induced urethral stenosis is not an isolated problem as many patients suffer from storage symptoms, erectile dysfunction or incontinence as a consequence of treatment either before or after urethroplasty. PMID- 26047656 TI - Should we repair nonunion of the lateral humeral condyle in children? AB - PURPOSE: Patients with nonunion of the lateral humeral condyle often present with pain, instability, progressive cubitus valgus and tardy ulnar nerve palsy. At present repairing of this nonunion is still controversial due to previous reported complications such as stiffness and avascular necrosis (AVN). This study reported the outcomes of treatment in nonunion of the lateral humeral condyle in children. METHODS: We evaluated 17 patients with nonunion of the lateral humeral condyle after repair. Corrective osteotomy was done in patients with valgus deformity of more than 30 degrees and anterior ulnar nerve transposition in patients with ulnar nerve symptoms. Evaluations were performed with the use of radiographic examination, clinical assessment and also evaluated using Mayo Elbow Performance score by interview and physical examination interpreted as excellent (>= 90 points), good (75-89 points), fair (60-74 points), and poor (<60 points). RESULTS: Nine patients were male, and eight were female. The mean age at presentation was 6.5 years. The average interval from the injury to the presentation of the symptoms was 31.5 months. The average duration of follow-up was 48.6 months. The range of flexion was 130-145 degrees (average 130 degrees ). The Mayo elbow performance score was excellent in 11 patients and good in six patients. Mean Mayo elbow performance score was 94. Osseous union was achieved after the initial operation in 16 patients. One patient had re-operation using local bone graft and healed nicely. Determination of correlation coefficients found good correlation between neglected time and Mayo performance score <89 ( 0.741), age of patient was fairly well correlated with Mayo performance score <89 (-0.635) and ROC curve show that neglected lateral condyle fracture in children more than 28 months will reduce the Mayo score. CONCLUSION: (1) We support osteosynthesis for children, not only for those who have pain but also for those who are less symptomatic. Good and excellent results by Mayo elbow performance score were found in all patients, and all nonunions were united with good range of motion. (2) Neglecting lateral condyle fracture in children more than 28 months will reduce Mayo performance score to below 89 points. (3) Cases presenting with AVN pre-operatively can still have good results and remodeling potential with congruency of the joint. PMID- 26047657 TI - PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas. AB - Internal ribosomal entry site (IRES)-mediated translation initiation is constitutively activated during stress conditions such as tumorigenesis and hypoxia. The RNA editing enzyme ADAR1 plays an important role in physiology and pathology. Initially, we found that the ADAR1 p150 or p110 transcript levels were decreased in glioma cells compared with normal astrocyte cells. In contrast, protein levels of ADAR1 p110 were significantly upregulated in glioma tissues and cells. This expression pattern indicated translationally controlled regulation. We identified an 885-nt sequence that was located between AUG1 and AUG2 within the ADAR1 mRNA that exhibited IRES-like activity. Furthermore, we confirmed that the translational mode of ADAR1 p110 was mediated by PTBP1 in glioma cells. The protein levels of PTBP1 and ADAR1 were cooperatively expressed in glioma tissues and cells. Knocking down ADAR1 p110 significantly decreased cell proliferation in three types of glioma cells (T98G, U87MG and A172). The removal of a minimal IRES like sequence in a p150-overexpression construct could effectively abolish p110 induction and resulted in the slight suppression of cell proliferation compared with ADAR1-p150 overexpression in siPTBP1-treated T98G cells. In summary, our study revealed a mechanism whereby ADAR1 p110 can be activated by PTBP1 through an IRES-like element in glioma cells, and ADAR1 is essential for the maintenance of gliomagenesis. PMID- 26047660 TI - 10th Annual meeting of the Mediterranean Society of Pelvic Floor Disorders, Cairo, Egypt, 9th-11th April, 2015, Chairman: Ali A. Shafik, MD. PMID- 26047659 TI - Efficient inhibition of infectious prions multiplication and release by targeting the exosomal pathway. AB - Exosomes are secreted membrane vesicles of endosomal origin present in biological fluids. Exosomes may serve as shuttles for amyloidogenic proteins, notably infectious prions, and may participate in their spreading in vivo. To explore the significance of the exosome pathway on prion infectivity and release, we investigated the role of the endosomal sorting complex required for transport (ESCRT) machinery and the need for ceramide, both involved in exosome biogenesis. Silencing of HRS-ESCRT-0 subunit drastically impairs the formation of cellular infectious prion due to an altered trafficking of cholesterol. Depletion of Tsg101-ESCRT-I subunit or impairment of the production of ceramide significantly strongly decreases infectious prion release. Together, our data reveal that ESCRT dependent and -independent pathways can concomitantly regulate the exosomal secretion of infectious prion, showing that both pathways operate for the exosomal trafficking of a particular cargo. These data open up a new avenue to regulate prion release and propagation. PMID- 26047658 TI - The function of RNA-binding proteins at the synapse: implications for neurodegeneration. AB - The loss of synapses is a central event in neurodegenerative diseases. Synaptic proteins are often associated with disease neuropathology, but their role in synaptic loss is not fully understood. Of the many processes involved in sustaining the integrity of synapses, local protein translation can directly impact synaptic formation, communication, and maintenance. RNA-binding proteins and their association with RNA granules serve to regulate mRNA transportation and translation at synapses and in turn regulate the synapse. Genetic mutations in RNA-binding proteins FUS and TDP-43 have been linked with causing neurodegenerative diseases: amyotrophic lateral sclerosis and frontotemporal dementia. The observation that mutations in FUS and TDP-43 coincide with changes in RNA granules provides evidence that dysfunction of RNA metabolism may underlie the mechanism of synaptic loss in these diseases. However, we do not know how mutations in RNA-binding proteins would affect RNA granule dynamics and local translation, or if these alterations would cause neurodegeneration. Further investigation into this area will lead to important insights into how disruption of RNA metabolism and local translation at synapses can cause neurodegenerative diseases. PMID- 26047661 TI - Descending perineum syndrome: new perspectives. AB - The classical clinical profile of descending perineum syndrome (DPS) has been replaced by new pathophysiological, diagnostic, and therapeutic acquisitions. This paper will focus on trigger factors ranging from dyssynergic defecation to excessive straining, fecal incontinence against the backdrop of obstructed defecation, attendant rectal diseases, and therapy tailored to evolving stages of DPS. PMID- 26047662 TI - The brain's Geppetto-microbes as puppeteers of neural function and behaviour? AB - Research on the microbiome and its interaction with various host organs, including the brain, is increasingly gaining momentum. With more evidence establishing a comprehensive microbiota-gut-brain axis, questions have been raised as to the extent to which microbes influence brain physiology and behaviour. In parallel, there is a growing literature showing active behavioural manipulation in favour of the microbe for certain parasites. However, it seems unclear where the hidden majority of microbes are localised on the parasitism mutualism spectrum. A long evolutionary history intimately connects host and microbiota, which complicates this classification. In this conceptual minireview, we discuss current hypotheses on host-microbe interaction and argue that novel experimental approaches and theoretical concepts, such as the hologenome theory, are necessary to incorporate transgenerational epigenetic inheritance of the microbiome into evolutionary theories. PMID- 26047663 TI - Physical exercise affects slow cycling cells in the rat heart and reveals a new potential niche area in the atrioventricular junction. AB - Physical exercise has several beneficial effects on the heart. In other tissues it has been shown to activate endogenous stem cells. There is however a lack of knowledge how exercise affects the distribution of progenitor cells as well as overall cell turnover within the heart. Therefore, proliferating cells were identified using BrdU DNA labeling in a rat exercise model. Slow cycling cells were identified by label retention. BrdU+ nuclei were counted in apex, ventricle and atrioventricular junction (AV junction), as well as in skin tissue where label retaining cells (LRC) have been described previously. After 13 weeks of chasing, the cells with the highest intensity were identified and considered as LRC. Heart tissue showed slower proliferation compared to skin. The highest number of BrdU+ cells was found in the AV junction. Here, a sub region in close proximity to the valvular insertion point was observed, where density of BrdU+ cells was high at all time points. Physical exercise increased proliferation in AV junction at the early stage. Furthermore, the sub region was found to harbor a significant higher number of LRC compared to other regions of the heart in the exercised animals. Progenitor markers MDR1 and Sca-1 were detected in the same area by immunohistochemistry. In conclusions, our data shows that physical exercise affects cell turnover and distribution of LRC in the heart. Furthermore, it reveals a region within the AV junction of the heart that shows features of a stem cell niche. PMID- 26047664 TI - Procedural Learning and Memory Rehabilitation in Korsakoff's Syndrome - a Review of the Literature. AB - Korsakoff's syndrome (KS) is a chronic neuropsychiatric disorder caused by alcohol abuse and thiamine deficiency. Patients with KS show restricted autonomy due to their severe declarative amnesia and executive disorders. Recently, it has been suggested that procedural learning and memory are relatively preserved in KS and can effectively support autonomy in KS. In the present review we describe the available evidence on procedural learning and memory in KS and highlight advances in memory rehabilitation that have been demonstrated to support procedural memory. The specific purpose of this review was to increase insights in the available tools for successful memory rehabilitation and give suggestions how to apply these tools in clinical practice to increase procedural learning in KS. Current evidence suggests that when memory rehabilitation is adjusted to the specific needs of KS patients, this will increase their ability to learn procedures and their typically compromised autonomy gets enhanced. PMID- 26047666 TI - Extended evaluation on the ES-D3 cell differentiation assay combined with the BeWo transport model, to predict relative developmental toxicity of triazole compounds. AB - The mouse embryonic stem D3 (ES-D3) cell differentiation assay is based on the morphometric measurement of cardiomyocyte differentiation and is a promising tool to detect developmental toxicity of compounds. The BeWo transport model, consisting of BeWo b30 cells grown on transwell inserts and mimicking the placental barrier, is useful to determine relative placental transport velocities of compounds. We have previously demonstrated the usefulness of the ES-D3 cell differentiation assay in combination with the in vitro BeWo transport model to predict the relative in vivo developmental toxicity potencies of a set of reference azole compounds. To further evaluate this combined in vitro toxicokinetic and toxicodynamic approach, we combined ES-D3 cell differentiation data of six novel triazoles with relative transport rates obtained from the BeWo model and compared the obtained ranking to the developmental toxicity ranking as derived from in vivo data. The data show that the combined in vitro approach provided a correct prediction for in vivo developmental toxicity, whereas the ES D3 cell differentiation assay as stand-alone did not. In conclusion, we have validated the combined in vitro approach for developmental toxicity, which we have previously developed with a set of reference azoles, for a set of six novel triazoles. We suggest that this combined model, which takes both toxicodynamic and toxicokinetic aspects into account, should be further validated for other chemical classes of developmental toxicants. PMID- 26047665 TI - Interactions between mitochondrial reactive oxygen species and cellular glucose metabolism. AB - Mitochondrial reactive oxygen species (ROS) production and detoxification are tightly balanced. Shifting this balance enables ROS to activate intracellular signaling and/or induce cellular damage and cell death. Increased mitochondrial ROS production is observed in a number of pathological conditions characterized by mitochondrial dysfunction. One important hallmark of these diseases is enhanced glycolytic activity and low or impaired oxidative phosphorylation. This suggests that ROS is involved in glycolysis (dys)regulation and vice versa. Here we focus on the bidirectional link between ROS and the regulation of glucose metabolism. To this end, we provide a basic introduction into mitochondrial energy metabolism, ROS generation and redox homeostasis. Next, we discuss the interactions between cellular glucose metabolism and ROS. ROS-stimulated cellular glucose uptake can stimulate both ROS production and scavenging. When glucose stimulated ROS production, leading to further glucose uptake, is not adequately counterbalanced by (glucose-stimulated) ROS scavenging systems, a toxic cycle is triggered, ultimately leading to cell death. Here we inventoried the various cellular regulatory mechanisms and negative feedback loops that prevent this cycle from occurring. It is concluded that more insight in these processes is required to understand why they are (un)able to prevent excessive ROS production during various pathological conditions in humans. PMID- 26047668 TI - The Curse of Curves: Sex Differences in the Associations Between Body Shape and Pain Expression. AB - This study examines the associations between objective and subjective measurements and impressions of body shape and cold pressor pain reporting in healthy adults. On the basis of sexual selection theory (SST), we hypothesized that body characteristics that are universally preferred by the opposite sex specifically, lower waist-to-hip ratios (WHR) in women and higher shoulder-to-hip ratios (SHR) in men-and characteristics (e.g., proportion of body fat in women) that infer attractiveness differently across cultures will correspond to higher experimental pain reporting in women and lower pain reporting in males. A convenience sample of young adults (n = 96, 58 females, 18-24 years; mean age = 19.4) was measured for body mass index (BMI), WHR, SHR, and subjective body impressions (SBI), along with cold pressor pain reporting. The findings showed that BMI was positively associated with WHR and less-positive SBI in both sexes. Consistent with SST, however, only BMI and WHR predicted variability in pain expression in women, whereas only SHR predicted variability in men. Subjective body impressions were positively associated with SHR among males and unrelated to WHR among females, yet only females showed a positive association between SBI and higher pain reporting. The findings suggest that sexually selected physical characteristics (WHR and SHR) and culturally influenced somatic (BMI) and psychological (SBI) indicators of attractiveness correspond with variability in pain reporting, potentially reflecting the general tendency for people to express clusters of sexually selected and culturally influenced traits that may include differential pain perception. PMID- 26047669 TI - Meta-analysis of the influence of dietary glycine and serine, with consideration of methionine and cysteine, on growth and feed conversion of broilers. AB - The existing literature is inconsistent with respect to optimal dietary concentrations of glycine (Gly) and serine (Ser) in broiler feed. Therefore, we conducted a meta-analysis to investigate the response of broilers to dietary levels of Gly using a full quadratic model based on mixed model methodology. Response was measured as ADG (g/d), ADFI (g/d), and G:F (g/g). In addition, the influence of other dietary constituents was evaluated. This meta-analysis was based on a data set comprising a total of 9,626 broilers in 10 peer-reviewed papers that investigated the response of broilers to different dietary concentrations of Gly, achieved by addition of free Gly. The fitted quadratic model, with either Gly+Ser or the calculated glycine equivalent (Glyequi) of both amino acids as the independent variable, revealed that all model terms were significant (P <= 0.05), and hence proved a curvilinear relationship between these independent variables and response traits. The R(2) value and root MS error confirmed a strong relationship between observed and predicted traits. A comparison of the influence of Gly+Ser and Glyequi on response traits revealed that both approaches produced similar results. Because Glyequi should meet the physiological values of a diet better than Gly+Ser, models with 2 independent variables were conducted using Glyequi. The second independent variables were methionine (Met):TSAA ratio and the concentrations of cysteine (Cys) and CP. In models with one or 2 independent variables, the impact of dietary Gly on ADFI was low. By contrast, G:F was markedly influenced by dietary Gly; this effect intensified at lower Met:TSAA ratios and higher Cys and CP levels. ADG was also a function of Glyequi and the second independent variables. For ADG, an optimal Met:TSAA ratio of 0.655 and Cys concentration of 0.302% was calculated. Following the nonlinear nature of relationship, generally applicable replacement values could not be calculated. However, it was concluded that consideration of dietary Cys can diminish the requirement for Glyequi, and therefore, enable a reduction in the CP of broiler diets without limiting growth performance. PMID- 26047670 TI - Effects of color temperatures (Kelvin) of LED bulbs on blood physiological variables of broilers grown to heavy weights. AB - Light-emitting diode (LED) lighting is being used in the poultry industry to reduce energy usage in broiler production facilities. However, limited data are available comparing efficacy of different spectral distribution of LED bulbs on blood physiological variables of broilers grown to heavy weights (>3 kg). The present study evaluated the effects of color temperature (Kelvin) of LED bulbs on blood physiological variables of heavy broilers in 2 trials with 4 replicates/trial. The study was a randomized complete block design. Four light treatments consisted of 3 LED light bulbs [2,700 K, (Warm-LED); 5,000 K, (Cool LED-#1); 5,000 K, (Cool-LED-#2)] and incandescent light (ICD, standard) from 1 to 56 d age. A total of 960 1-day-old Ross * Ross 708 chicks (30 males/room 30 females/room) were equally and randomly distributed among 16 environmentally controlled rooms at 50% RH. Each of the 4 treatments was represented by 4 rooms. Feed and water were provided ad libitum. All treatment groups were provided the same diet. Venous blood samples were collected on d 21, 28, 42, and 56 for immediate analysis of selected physiological variables and plasma collection. In comparison with ICD, Cool-LED-#1 had greater (P < 0.05) effects on pH, partial pressure of CO2(pCO2), partial pressure of O2(pO2), saturated O2(sO2), and K+. However, all these acid-base changes remained within the normal venous acid-base homeostasis and physiological ranges. In addition, no effect of treatments was observed on HCO(3)(-), hematocrit (Hct), hemoglobin (Hb), Na+, Ca2+, Cl-, mean corpuscular hemoglobin concentration (McHc), osmolality, and anion gap. Moreover, blood glucose concentrations were not affected by treatments. This study shows that the 3 LED light bulbs evaluated in this study may be suitable for replacement of ICD light sources in commercial poultry facilities to reduce energy cost and optimize production efficiency without inducing physiological stress on broilers grown to heavy weights. PMID- 26047671 TI - On-farm comparisons of different cleaning protocols in broiler houses. AB - The present study evaluated the effectiveness of 4 cleaning protocols designed to reduce the bacteriological infection pressure on broiler farms and prevent food borne zoonoses. Additionally, difficult to clean locations and possible sources of infection were identified. Cleaning and disinfection rounds were evaluated in 12 broiler houses on 5 farms through microbiological analyses and adenosine triphosphate hygiene monitoring. Samples were taken at 3 different times: before cleaning, after cleaning, and after disinfection. At each sampling time, swabs were taken from various locations for enumeration of the total aerobic flora and Enterococcus species pluralis ( SPP:). In addition, before cleaning and after disinfection, testing for Escherichia coli and Salmonella was carried out. Finally, adenosine triphosphate swabs and agar contact plates for total aerobic flora counts were taken after cleaning and disinfection, respectively. Total aerobic flora and Enterococcus spp. counts on the swab samples showed that cleaning protocols which were preceded by an overnight soaking with water caused a higher bacterial reduction compared to protocols without a preceding soaking step. Moreover, soaking of broiler houses leads to less water consumption and reduced working time during high pressure cleaning. No differences were found between protocols using cold or warm water during cleaning. Drinking cups, drain holes, and floor cracks were identified as critical locations for cleaning and disinfection in broiler houses. PMID- 26047672 TI - Assessment of enzyme supplementation on growth performance and apparent nutrient digestibility in diets containing undecorticated sunflower seed meal in layer chicks. AB - Six hundred and forty one-day-old layer chicks were used to investigate the effect of replacing soybean meal with undecorticated sunflower seed meal protein for protein at 0, 25, 50, and 75% levels. Diets were without enzyme supplementation or with enzyme supplementation with four replications of twenty birds. Growth performance and nutrient utilization were determined. Proximate composition of the undecorticated sunflower seed meal used revealed that undecorticated sunflower seed meal contained 925.9, 204.5, 336.2, 215.1, 52.0 and 192.2g/kg dry matter, crude protein, ether extract, crude fibre, ash and soluble carbohydrates, respectively. Results showed that the final weight of 484.4 g/bird was obtained for birds on 75% undecorticated sunflower seed meal diet, while the lowest value of 472.2g/bird was obtained for birds on 25% undecorticated sunflower seed meal diet. Weight gain per bird per day was not significantly (P > 0.05) affected as the level of undecorticated sunflower seed meal increased in the diets. Feed intake per bird per day increased (P < 0.05) across the treatment as a result of increased undecorticated sunflower seed meal inclusion in the diet. However, enzyme supplementation of the diets showed marked (P < 0.05) improvements in feed intake, weight gain, and final weight as well as the feed to gain ratio. Survivability was not affected by the treatments imposed. Dry matter digestibility were significantly (P < 0.05) reduced due to high undecorticated sunflower seed meal inclusion in the diet while crude protein digestibility progressively reduced (P < 0.05) as the level of undecorticated sunflower seed meal increased in the diet. Ash digestibility values were, however, increased (P < 0.05) as the level of undecorticated sunflower seed meal increased in the diets. Birds on enzyme-supplemented diets consistently showed superior (P < 0.05) digestibility values than those on diets without enzyme supplementation. However ether extract digestibility was not affected by enzyme supplementation. The results indicated that higher inclusion levels of undecorticated sunflower seed meal in the diets of layer chicks showed a similar body weight gain/bird/day with the control. Undecorticated sunflower seed meal used in this study is a good source of crude protein, ether extract, and amino acids and had the potential to serve as feeding stuffs as replacement for soybeans. The nutritive value of undecorticated sunflower seed meal was improved for layer chicks with exogenous enzyme supplementation. PMID- 26047673 TI - Bioefficacy comparison of organic manganese with inorganic manganese for eggshell quality in Hy-Line Brown laying hens. AB - This study was aimed at investigating the bioefficacy of organic compared with inorganic manganese (Mn) for eggshell quality. An amino acid-Mn complex or Mn sulfate monohydrate was used as the organic or inorganic Mn source. A total of six hundred forty-eight 50-wk-old layers (Hy-Line Brown) were divided into 9 groups; each group consisted of 6 replicates with 12 layers each. The feeding trial lasted 12 wk. During the first 4 wk of the feeding trial, the groups were fed a basal diet, which met the nutrient requirements of the layers, except for Mn. During the following 8 wk, 9 levels of Mn (inorganic Mn: 0, 25, 50, 100, and 200 mg/kg; organic Mn: 25, 50, 100, and 200 mg/kg) were used to supplement, respectively, in the basal diet on an equimolar basis. An exponential regression model was applied to calculate the bioefficacy of organic Mn compared with the inorganic Mn. Dietary supplementation with either organic or inorganic Mn did not influence egg production and feed efficiency of (P > 0.05), and eggshell quality did not exhibit a significant response to dietary supplementation with Mn sources at 56 and 58 wk (P > 0.05). Dietary supplementation with either organic Mn or inorganic Mn significantly enhanced the thickness, breaking strength, and elastic modulus of the eggshells compared with the control group at the end of 62 wk (P < 0.05). At the end of 62 wk, the bioefficacy of organic Mn was 357% (shell thickness), 406% (breaking strength), 458% (elastic modulus), and 470% (eggshell Mn), as efficacious as inorganic Mn at equimolar levels. This study suggests that organic Mn enhances eggshell quality in aged laying hens compared with inorganic Mn. PMID- 26047667 TI - Experimental models of liver fibrosis. AB - Hepatic fibrosis is a wound healing response to insults and as such affects the entire world population. In industrialized countries, the main causes of liver fibrosis include alcohol abuse, chronic hepatitis virus infection and non alcoholic steatohepatitis. A central event in liver fibrosis is the activation of hepatic stellate cells, which is triggered by a plethora of signaling pathways. Liver fibrosis can progress into more severe stages, known as cirrhosis, when liver acini are substituted by nodules, and further to hepatocellular carcinoma. Considerable efforts are currently devoted to liver fibrosis research, not only with the goal of further elucidating the molecular mechanisms that drive this disease, but equally in view of establishing effective diagnostic and therapeutic strategies. The present paper provides a state-of-the-art overview of in vivo and in vitro models used in the field of experimental liver fibrosis research. PMID- 26047674 TI - Impact of a drug-free program on broiler chicken growth performances, gut health, Clostridium perfringens and Campylobacter jejuni occurrences at the farm level. AB - The use of antimicrobial agents as feed additives in poultry production is a public health concern due to the overall increase in antimicrobial resistance. Although some alternative products are commercially available, little is known on their potential impact on flock health and productivity. A prospective study involving 1.55 million birds was conducted on eight commercial broiler farms in Quebec, Canada, to evaluate the impact of replacing antibiotic growth promoters and anticoccidial drugs by a drug-free program including improved brooding conditions, anticoccidial vaccination, essential oil-based feed additives, and water acidification. Various productivity and health parameters were compared between barns allocated to the conventional and the drug-free program. Zootechnical performances were monitored as productivity criteria. Clinical necrotic enteritis and subclinical enteritis occurrences, litter and fecal moistures content were measured, and microscopic gut health was evaluated. Clostridium perfringens and Campylobacter spp. strains were recovered from fecal samples collected during farm visits. Clostridium perfringens counts were used as poultry health indicators and Campylobacter prevalence was noted as well. The drug-free program was associated with a significant increase in feed conversion ratio and a decrease in mean live weight at slaughter and in daily weight gain. An increased incidence of necrotic enteritis outbreaks and subclinical enteritis cases, as well as an increase in litter moisture content at the end of the rearing period were also observed for this program. Mean microscopic intestinal lesion scores and prevalence of Campylobacter colonization were not statistically different between the two groups but the drug-free program was associated with higher Clostridium perfringens isolation rates. According to the current study design, the results suggest that substitution of antibiotic growth promoters and anticoccidial drugs by a drug-free program impacts various broiler chicken production parameters and Clostridium perfringens carriage levels. PMID- 26047675 TI - The Spanish FRAX((r)) fits better in the prediction of femoral fractures than in the rest of osteoporotic fractures. Preliminary results of the FRODOS study. PMID- 26047676 TI - Sudden onset of facial diplegia and aphagia. PMID- 26047678 TI - Marital conflict and parental responses to infant negative emotions: Relations with toddler emotional regulation. AB - According to family systems theory, children's emotional development is likely to be influenced by family interactions at multiple levels, including marital, mother-child, and father-child interactions, as well as by interrelations between these levels. The purpose of the present study was to examine parents' marital conflict and mothers' and fathers' distressed responses to their infant's negative emotions, assessed when their child was 8 and 24 months old, in addition to interactions between parents' marital conflict and their distressed responses, as predictors of their toddler's negative and flat/withdrawn affect at 24 months. Higher marital conflict during infancy and toddlerhood predicted both increased negative and increased flat/withdrawn affect during toddlerhood. In addition, toddlers' negative (but not flat) affect was related to mothers' distressed responses, but was only related to father's distressed responses when martial conflict was high. Implications of this study for parent education and family intervention were discussed. PMID- 26047677 TI - Changes in N-terminal pro-B-type natriuretic peptide and incidence of diabetes: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - AIMS: This study looked at whether the inverse association of circulating N terminal pro-B-type natriuretic peptide (NT-proBNP) with incident diabetes is modified by changes in NT-proBNP (DeltaNT-proBNP) levels. METHODS: Plasma NT proBNP was assayed at baseline and 3.2 years later (visit 3) in the Multi-Ethnic Study of Atherosclerosis (MESA). DeltaNT-proBNP was calculated as NT-proBNP visit3-NT-proBNP baseline. A Poisson distribution was fitted to determine the incidence density of diabetes, adjusted for age, race, gender, educational attainment, antihypertensive medication, total intentional exercise and plasma IL 6 levels. In the primary analysis (n=3236 without diabetes up to visit 3, followed for a mean of 6.3 years), incidence density was regressed for the following categories of baseline NT-proBNP: (1)<54.4 pg/mL; (2) 54.4-85.9 pg/mL; and (3) 86-54.2 pg/mL. This was crossed with categories of DeltaNT-proBNP as medians (ranges): (1) -6.2 (-131-11.7) pg/mL; (2) 19.8 (11.8-30.1) pg/mL; (3) 44.0 (30.2-67.9) pg/mL; and (4) 111.2 (68.0-3749.9) pg/mL. RESULTS: The incidence density of diabetes followed a U-shaped association across categories of DeltaNT proBNP within categories of baseline NT-proBNP after adjusting for other covariates (P=0.02). At each level of baseline NT-proBNP, the incidence density of diabetes was lowest for small-to-moderate increases in NT-proBNP. CONCLUSION: This analysis suggests that NT-proBNP has a biphasic association with diabetes in which the risk of incident diabetes decreases within a 'physiological range' of DeltaNT-proBNP, and plateaus or increases as NT-proBNP concentrations increase, probably in response to pathophysiological conditions leading to high levels of NT-proBNP. PMID- 26047679 TI - miRNA-584-5p exerts tumor suppressive functions in human neuroblastoma through repressing transcription of matrix metalloproteinase 14. AB - Matrix metalloproteinase 14 (MMP-14) is a membrane-anchored MMP crucial for tumorigenesis and aggressiveness, and is highly expressed in neuroblastoma (NB), the most common extracranial solid tumor in childhood. Recent evidence shows the emerging roles of endogenous promoter-targeting microRNAs (miRNAs) in regulating gene transcription. However, the roles of miRNAs in the transcription of MMP-14 still remain largely unknown. In this study, through mining computational algorithm program and Argonaute-chromosome interaction dataset, we identified one binding site of miRNA-584-5p (miR-584-5p) within the MMP-14 promoter. In NB tissues, miR-584-5p was under-expressed and inversely correlated with MMP-14 expression, and was an independent prognostic factor for favorable outcome of patients. miR-584-5p precursor attenuated the expression of MMP-14 in a Dicer dependent manner, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines. In addition, miR-584-5p suppressed the promoter activity of MMP-14, and mutation of miR-584-5p binding site abolished these effects. Mechanistically, miR-584-5p recruited Argonaute 2 to facilitate the enrichment of enhancer of zeste homolog 2, histone H3 lysine 27 trimethylation, and histone H3 lysine 9 dimethylation on MMP-14 promoter in NB cells, which was abolished by repressing the miR-584-5p-promoter interaction. Gain- and loss-of-function studies demonstrated that miR-584-5p suppressed the growth, invasion, metastasis, and angiogenesis of NB cells in vitro and in vivo. Moreover, restoration of MMP-14 expression rescued the NB cells from changes in these biological features. Taken together, these results indicate that promoter targeting miR-584-5p exerts tumor suppressive functions in NB through repressing the transcription of MMP-14. PMID- 26047680 TI - Gliadin-mediated production of polyamines by RAW264.7 macrophages modulates intestinal epithelial permeability in vitro. AB - Celiac disease (CD) is an immune-mediated enteropathy sustained by dietary gluten in susceptible individuals, and characterized by a complex interplay between adaptive and innate responses against gluten peptides (PTG). In a recent contribution we have demonstrated that the treatment with PTG induces the expression and activity of arginase in both murine macrophages and human monocytes from healthy subjects, thus suggesting a role for arginine and its metabolites in gluten-triggered response of these cells. Here we further explore this field, by addressing the effects of PTG on polyamine synthesis and release in murine RAW264.7 macrophages, and how they affect epithelial permeability of Caco-2 monolayers. Results obtained show a massive production and release of putrescine by macrophages upon incubation with gluten peptides; this, in turn, causes a decrease in TEER in epithelial cells, indicating that PTG-driven secretion of polyamines by macrophages has a role in the modulation of intestinal permeability in vitro. At a molecular level, putrescine production appears referable to the activation of C/EBPbeta transcription factor, which is known to be responsible for arginase induction in activated macrophages and is a crucial mediator of inflammation. Whether these pathways are stimulated also in vivo deserves to be further investigated, as well as their role in gluten-driven cellular and intestinal defects typical of CD patients. PMID- 26047681 TI - Coefficient of variation of R-R interval closely correlates with glycemic variability assessed by continuous glucose monitoring in insulin-depleted patients with type 1 diabetes. AB - AIMS: In type 1 diabetic patients, insulin secretory capacity, meals and physical activity correlate with glycemic variability. Autonomic function associated with gastrointestinal motility and counterregulatory hormone secretion is another candidate which correlates with glucose variability. The aim of this study is to clarify a new clinical parameter associated with glycemic variability in insulin depleted patients with type 1 diabetes. METHODS: We studied 31 inpatients with type 1 diabetes. We evaluated glycemic variability calculated by continuous glucose monitoring, clinical parameters and the coefficient of variation of R-R interval (CVR-R). Glycemic variability was also assessed during the daytime and nighttime. RESULTS: The CVR-R showed a significant negative correlation with the whole-day standard deviation (SD) (r = -0.50, p = 0.007), mean amplitude of glycemic excursions (MAGE) (r = -0.47, p=0.011), M-value (r = -0.38, p = 0.048) and mean of daily differences (MODD) (r = -0.59, p = 0.001). The CVR-R also showed a significant negative correlation with the nighttime SD (r = -0.59, p = 0.001), MAGE (r = -0.47, p=0.011), M-value (r = -0.53, p = 0.004) and MODD (r = 0.65, p = 0.0003). And furthermore, the CVR-R also showed a significant negative correlation with the daytime SD (r = -0.44, p = 0.019) and MAGE (r = -0.50, p = 0.006), but not with the daytime M-value or MODD. The nighttime SD was significantly higher in patients with diabetic polyneuropathy than in patients without it (p = 0.016), while the CVR-R was significantly lower in patients with polyneuropathy than in patients without it (p = 0.009). CONCLUSIONS: CVR-R is closely correlated with glycemic variability, especially during nighttime, in insulin-depleted patients with type 1 diabetes. Measuring CVR-R may help us to presume the degree of glycemic variability in those patients. PMID- 26047682 TI - Volume-dependent effect of supervised exercise training on fatty liver and visceral adiposity index in subjects with type 2 diabetes The Italian Diabetes Exercise Study (IDES). AB - AIMS: This study evaluated the effect of supervised exercise training on liver enzymes and two surrogate measures of non-alcoholic fatty liver disease (NAFLD) in subjects with type 2 diabetes. METHODS: Sedentary patients from 22 outpatient diabetes clinics were randomized by center, age and treatment to twice-a-week supervised aerobic and resistance training plus structured exercise counseling (exercise group, EXE; n=303) versus counseling alone (control group, CON; n=303) for 12 months. EXE participants were further randomized to low-to-moderate (n=142) or moderate-to-high (n=161) intensity training of equal energy cost. Baseline and end-of-study levels of liver enzymes, fatty liver index (FLI) and visceral adiposity index (VAI) were obtained. RESULTS: Enzyme levels did not change, whereas FLI and VAI decreased significantly in EXE, but not CON participants. Physical activity (PA) volume was an independent predictor of both FLI and VAI reductions, the extent of which increased from the 1st to the 4th quintile of PA volume and baseline to end-of-study changes in fitness parameters. Differences in the effect of LI versus HI training were negligible. CONCLUSIONS: Data from this large cohort of subjects with type 2 diabetes indicate that FLI and VAI decrease with supervised training in a volume-dependent manner. PMID- 26047684 TI - Accuracy of the Diagnosis of Bronchopulmonary Dysplasia in a Referral-Based Health Care System. AB - OBJECTIVE: To evaluate the accuracy of the diagnosis of bronchopulmonary dysplasia (BPD) in a national database of a referral-based health care system, where preterm infants are often transferred back to regional hospitals before 36 weeks postmenstrual age (PMA). STUDY DESIGN: We evaluated preterm infants <32 weeks, born between 2004 and 2008 in the Academic Medical Center in Amsterdam with a high-risk profile for BPD. In addition to patient characteristics and outcomes, we collected data on respiratory support at 36 weeks PMA. True incidence of BPD, defined as needing supplemental oxygen and/or positive pressure support at 36 weeks PMA, was compared with the diagnosis registered in the National Perinatal Registry. Two imputation algorithms for patients transferred before 36 weeks PMA were validated. RESULTS: We identified 243 preterm infants with a high-risk BPD profile. Sixty-seven percent of these infants had a correct BPD diagnosis recorded in the National Perinatal Registry, 2% had a false positive, and 31% a false negative diagnosis. Infants with a false negative diagnosis of BPD were twice as often transferred to a regional hospital before 36 weeks PMA compared with a true positive diagnosis. Imputation algorithms did not improve the accuracy of BPD registration. CONCLUSIONS: Registration of the diagnosis BPD in a national database in countries with a referral-based health care system may not be accurate. Optimizing data collection and monitoring data entry is necessary to improve BPD registration before data can be used for national and international benchmarking. PMID- 26047683 TI - Prenatal Lead Exposure Modifies the Impact of Maternal Self-Esteem on Children's Inattention Behavior. AB - OBJECTIVE: To prospectively evaluate the association of maternal self-esteem measured when their offspring were toddlers with the subsequent development of attention deficit hyperactivity disorder (ADHD)-like behavior in their school-age offspring and the potential modifying effects of prenatal lead exposure. STUDY DESIGN: We evaluated a subsample of 192 mother-child pairs from a long-running birth-cohort project that enrolled mothers in Mexico from 1994-2011. Prenatal lead exposure was assessed using cord blood lead and maternal bone lead around delivery (tibia and patella lead, measured by K-x-ray-fluorescence). When children were 2 years old, maternal self-esteem was measured using the Coopersmith Self-Esteem Inventory. When children were 7-15 years old, children's blood lead levels and ADHD symptoms were assessed, and Conners' Parent Rating Scale-Revised and Behavior Rating Inventory of Executive Function-Parent Form were used as measures of ADHD-like behavior. RESULTS: Adjusting for family economic status, marital status, maternal education and age, child's age and sex, and children's current blood lead levels, increased maternal self-esteem was associated with reduced child inattention behavior. Compared with those among high prenatal lead exposure (P25-P100), this association was stronger among low prenatal lead exposure groups (P1-P25, P values for the interaction effects between prenatal lead exposure and maternal self-esteem levels of <.10). Each 1 point increase in maternal self-esteem scores was associated with 0.6- to 1.3 point decrease in Conners' Parent Rating Scale-Revised and Behavior Rating Inventory of Executive Function-Parent Form T-scores among groups with low cord blood lead and patella lead (P1-P25). CONCLUSIONS: Children experiencing high maternal self-esteem during toddlerhood were less likely to develop inattention behavior at school age. Prenatal lead exposure may play a role in attenuating this protective effect. PMID- 26047685 TI - The evolutionary origins of Southeast Asian Ovalocytosis. AB - Southeast Asian Ovalocytosis (SAO) is a common red blood cell disorder that is maintained as a balanced polymorphism in human populations. In individuals heterozygous for the SAO-causing mutation there are minimal detrimental effects and well-documented protection from severe malaria caused by Plasmodium vivax and Plasmodium falciparum; however, the SAO-causing mutation is fully lethal in utero when homozygous. The present-day high frequency of SAO in Island Southeast Asia indicates the trait is maintained by strong heterozygote advantage. Our study elucidates the evolutionary origin of SAO by characterizing DNA sequence variation in a 9.5 kilobase region surrounding the causal mutation in the SLC4A1 gene. We find substantial haplotype diversity among SAO chromosomes and estimate the age of the trait to be approximately 10,005 years (95% CI: 4930-23,200 years). This date is far older than any other human malaria-resistance trait examined previously in Southeast Asia, and considerably pre-dates the widespread adoption of agriculture associated with the spread of speakers of Austronesian languages some 4000 years ago. Using a genealogy-based method we find no evidence of historical positive selection acting on SAO (s=0.0, 95% CI: 0.0-0.03), in sharp contrast to the strong present-day selection coefficient (e.g., 0.09) estimated from the frequency of this recessively lethal trait. This discrepancy may be due to a recent increase in malaria-driven selection pressure following the spread of agriculture, with SAO targeted as a standing variant by positive selection in malarial populations. PMID- 26047686 TI - Audit of carbapenem prescriptions comparing 2 assessment periods. AB - OBJECTIVE: The emergence of extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae has resulted in the increase of carbapenem prescriptions. The objective of our study was to determine the appropriateness of carbapenem prescriptions from initiation to reassessment of treatment, between 2009 and 2011. PATIENTS AND METHOD: A questionnaire drafted by infectious diseases specialists (IDS) and microbiologists was used to collect clinical and microbiological data concerning carbapenem prescriptions in 2009 and 2011. An IDS then compared the results to assess carbapenem prescription compliance with our hospital's local recommendations. RESULTS: Seventy-one prescriptions were included in 2009 and 32 in 2011. The carbapenem treatment had been most frequently probabilistic to treat nosocomial infections. The microbiological data revealed that the number of multidrug-resistant (MDR) infections had increased between 2009 and 2011, especially infections involving ESBL-producing Enterobacteriaceae. At treatment reassessment, in 2009 and 2011, 15 (21%) and 12 (38%) carbapenem prescriptions were appropriate and continued. Overall, when comparing the 2 periods, prescriptions complied with local guidelines from initiation to reassessment of treatment without any statistically significant difference (68% in 2009 and 75% in 2011). CONCLUSION: Our study results showed that MDR infections had increased and especially infections due to ESBL-producing Enterobacteriaceae; this was consistent with epidemiological data. We also proved that most carbapenem prescriptions were compliant with recommendations. The increased mobile IDS interventions in medical and surgical departments helped reach this rate of compliance. Carbapenem stewardship may be promoted even in a difficult epidemiological context, especially with IDS interventions for the duration of treatment or at treatment reassessment. PMID- 26047687 TI - Explaining patterns in the school-to-work transition: An analysis using optimal matching. AB - This paper studies the school to work transition in the UK with the aim of achieving a richer understanding of individuals' trajectories in the five years after reaching school leaving age. By applying the technique of 'optimal matching' on data from 1991 to 2008, we group individuals' trajectories post-16, and identify a small number of distinct transition patterns. Our results suggest that while 9 out of 10 young people have generally positive experiences post-16, the remaining individuals exhibit a variety of histories that might warrant policy attention. We assess the extent to which characteristics at age 16 can predict which type of trajectory a young person will follow. Our analysis shows that, despite the apparent heterogeneity, virtually all at-risk trajectories are associated with a relatively small set of key 'risk factors': early pregnancy; low educational attainment and self-confidence; and disadvantaged family background. These characteristics are known to be strongly correlated across individuals and raise concerns about the degree of socio-economic polarisation in the transition from school to work. PMID- 26047688 TI - Parents' health and children's help. AB - The paper uses 'within-parent' variation to study how changes in British parents' health, marital status and financial resources affect receipt of help from their children. The analysis considers two measures of children's help (one enumerating specific activities and another reporting assistance with particular difficulties) and two measures of parents' health: self-reported assessments of overall health and enumeration of difficulties with activities of daily living. It uses three longitudinal data sets from Britain: the British Household Panel Study, Understanding Society and the English Longitudinal Study of Ageing. The primary finding is that children's help is highly responsive to problems arising from a parent's health that limit a parent's mobility or their ability to live independently in a community. But it is not responsive to severe difficulties requiring daily care. The estimates of responsiveness that are based fully or partially on between-individual variation overstate the impact of parent's health on help. PMID- 26047689 TI - Life course transitions and racial and ethnic differences in smoking prevalence. AB - This study aims to: (1) describe trajectories in the likelihood of smoking by racial or ethnic group across the transition to adulthood, (2) identify the influence of achieved socioeconomic status (SES) and the nature and timing of adult role transitions, and (3) determine the extent to which achieved SES and adult roles mediate the effects of race and ethnicity on smoking. The analyses use U.S. longitudinal data from the National Longitudinal Study of Adolescent Health (Add Health), which follows a representative national sample over four waves and from ages 11-17 in 1994/95 to 26-34 in 2007/08. Growth curve models compare trajectories of smoking likelihood for white, black, Hispanic, Asian/Pacific Islander, and American Indian/Alaska Native individuals. While whites have higher rates of smoking than blacks and Hispanics during their teen years and 20s, blacks and Hispanics lose their advantage relative to whites as they approach and enter their 30s. American Indian/Alaska Natives show high rates of smoking at earlier ages and an increasing likelihood to smoke. Although life course transitions are influential for smoking prevalence in the overall U.S. population, SES and the nature and timing of adult role transitions account for little of the gap between whites and black, Hispanic, and American Indian/Alaska Native individuals. Racial and ethnic disparities in adult smoking are independent of SES and life transitions, pointing to explanations such as culturally specific normative environments or experiences of discrimination. PMID- 26047690 TI - Multi-partner fertility is associated with lower grandparental investment from in laws in Finland. AB - Divorce and remarriage influence family relations, yet few studies explore changes in grandparenting due to family recomposition. We study variations in grandparental investment when the parents have children from several unions. Using nationally representative data of younger adults from the Generational Transmissions in Finland survey conducted in 2012 (sample n = 760 parents), we compare the grandchild care that parents report having received from their parents and parents-in-law. Results show that multipartner fertility is not associated with the amount of grandparental investment a parent receives from his or her own parents, but is associated with the investment received from mother's parents-in-law. Mother's parents-in-law are less likely to invest in grandchild sets which include step-grandchildren, compared to grandchildren living with their original parents. Fully biological grandchildren are 31% more likely to receive grandparental care compared to grandchild sets including step grandchildren. Thus the reduction in grandparental investment associated with step-grandchildren may also affect children from the new union. PMID- 26047691 TI - Economic hardship in childhood and adult health trajectories: An alternative approach to investigating life-course processes. AB - In this study, we advance existing research on health as a life course process by conceptualizing and measuring both childhood disadvantage and health as dynamic processes in order to investigate the relationship between trajectories of early life socioeconomic conditions and trajectories of health in midlife. We utilize a trajectory-based analysis that takes a disaggregated, person-centered approach to understand dynamic trajectories of health as latent variables that reflect the timing, duration and change in health conditions experienced by respondents over a period of 10 years in midlife as a function of stability and change in exposure to economic hardship in early life. Results from repeated-measures latent class analysis of longitudinal data from the Panel Study of Income Dynamics indicate that economic hardship in childhood has long-term, negative consequences for health both among individuals beginning life and remaining in poverty as well as those moving into poverty. In contrast, adults with more advantaged early life experiences, or who moved out of poverty during the period of observation, were at a lower risk of experiencing health trajectories characterized by the early onset or increasing risk of disease. We argue that a person-centered, disaggregated approach to the study of the relationship between socioeconomic status and health across the life course holds potential for the study of health inequality and that a greater focus on trajectory-based analysis is needed. PMID- 26047692 TI - Trajectories of intimate partnerships, sexual attitudes, desire and satisfaction. AB - This research addresses the interrelations existing between trajectories of intimate partnerships and attitudes toward sexuality, sexual desire, and sexual satisfaction. It is based on a dataset of 600 adults aged 25-46 living in Geneva (Switzerland) and uses innovative multivariate techniques for clustering life trajectories. The results emphasize the diversity of men's and women's trajectories of intimate partnerships. Trajectories with frequent and short-term partnerships are associated with recreational attitudes and higher solitary and dyadic sexual desire. In contrast, trajectories featuring few or no intimate partnerships are associated with traditional sexual attitudes and less sexual desire. Women's attitudes toward sexuality are more strongly associated with their intimate trajectories than men's. This suggests that men and women do not develop their sexuality in the same relation with intimacy. The results are referred to the gendered master status hypothesis. PMID- 26047693 TI - Early Anatomical Injury Patterns Predict Epilepsy in Head Cooled Neonates With Hypoxic-Ischemic Encephalopathy. AB - BACKGROUND: Our aim was to determine whether early anatomical injury patterns on magnetic resonance imaging-correlate with the development of postneonatal epilepsy in infants treated with selective head cooling for hypoxic-ischemic encephalopathy. METHODS: We retrospectively analyzed infants >=35 weeks' gestation born between 2008 and 2013 and followed for at least one year at Northwestern University. All had brain magnetic resonance imaging scans at days 4 5 and electroencephalographs during rewarming and at 3 to 6 months of age. RESULTS: Outcome was favorable for our cohort of 73 individuals with a mean follow-up of 41 (+/-7) months. The majority (66%) survived with no seizure recurrence, whereas 13 (18%) developed postneonatal epilepsy, including eight who had infantile spasms. Twelve infants (16%) died. The most common magnetic resonance imaging pattern was diffuse brain injury involving both cortical and subcortical gray matter (26/73, 35%), followed by cortical and subcortical white matter injury (18/73, 25%) and normal magnetic resonance imaging (16/73, 22%). In 13 infants (18%), the brainstem was involved in addition to cortical and subcortical gray matter; nine died and all four surviving infants developed infantile spasms. All 18 infants with cortical and subcortical white matter injury survived and none developed postneonatal epilepsy. The risk of postneonatal epilepsy was associated with injury involving subcortical regions (basal ganglia, thalamus +/- brainstem) (12/39 versus 1/34, P < 0.003). CONCLUSIONS: Brainstem injury was highly predictive of infantile spasms, whereas cortical injury alone predicted low risk for short-term postneonatal epilepsy. Location of anatomical injury on magnetic resonance imaging can be an early predictive factor for development of infantile spasms and inform prognostic decisions in newborns treated with selective head cooling for hypoxic-ischemic encephalopathy. PMID- 26047694 TI - Pediatric Neurology 2014 Trainee Publication Award Winner: Dr. Mitchel T. Williams. PMID- 26047695 TI - Novel transport function of adherens junction revealed by live imaging in Drosophila. AB - Adherens junctions are known for their role in mediating cell-cell adhesion. DE cadherin and Echinoid are the principle adhesion molecules of adherens junctions in Drosophila epithelia. Here, using live imaging to trace the movement of endocytosed Echinoid vesicles in the epithelial cells of Drosophila embryos, we demonstrate that Echinoid vesicles co-localize and move with Rab5-or Rab11 positive endosomes. Surprisingly, these Echinoid-containing endosomes undergo directional cell-to-cell movement, through adherens junctions. Consistent with this, cell-to-cell movement of Echinoid vesicles requires the presence of DE cadherin at adherens junctions. Live imaging further revealed that Echinoid vesicles move along adherens junction-associated microtubules into adjacent cells, a process requiring a kinesin motor. Importantly, DE-cadherin- and EGFR containing vesicles also exhibit intercellular movement. Together, our results unveil a transport function of adherens junctions. Furthermore, this adherens junctions-based intercellular transport provides a platform for the exchange of junctional proteins and signaling receptors between neighboring cells. PMID- 26047697 TI - The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1(-/-) murine model of ovarian cancer. AB - Familial breast and ovarian cancer are often caused by inherited mutations of BRCA1. While current prognoses for such patients are rather poor, inhibition of poly-ADP ribose polymerase 1 (PARP1) induces synthetic lethality in cells that are defective in homologous recombination. BMN 673 is a potent PARP1 inhibitor that is being clinically evaluated for treatment of BRCA-mutant cancers. Using the Brca1-deficient murine epithelial ovarian cancer cell line BR5FVB1-Akt, we investigated whether the antitumor effects of BMN 673 extend beyond its known pro apoptotic function. Administration of modest amounts of BMN 673 greatly improved the survival of mice bearing subcutaneous or intraperitoneal tumors. We thus hypothesized that BMN 673 may influence the composition and function of immune cells in the tumor microenvironment. Indeed, BMN 673 significantly increases the number of peritoneal CD8(+) T cells and NK cells as well as their production of IFN-gamma and TNF-alpha. These data suggest that the cell stress caused by BMN 673 induces not only cancer cell-intrinsic apoptosis but also cancer cell extrinsic antitumor immune effects in a syngeneic murine model of ovarian cancer. BMN 673 may therefore serve as a promising adjuvant therapy to immunotherapy to achieve durable responses among patients whose tumors harbor defects in homologous recombination. PMID- 26047696 TI - ABA-induced CCCH tandem zinc finger protein OsC3H47 decreases ABA sensitivity and promotes drought tolerance in Oryza sativa. AB - Water deficit causes multiple negative impacts on plants, such as reactive oxygen species (ROS) accumulation, abscisic acid (ABA) induction, stomatal closure, and decreased photosynthesis. Here, we characterized OsC3H47, which belongs to CCCH zinc-finger families, as a drought-stress response gene. It can be strongly induced by NaCl, PEG, ABA, and drought conditions. Overexpression of OsC3H47 significantly enhanced tolerance to drought and salt stresses in rice seedlings, which indicates that OsC3H47 plays important roles in post-stress recovery. However, overexpression of OsC3H47 reduced the ABA sensitivity of rice seedlings. This suggests that OsC3H47 is a newly discovered gene that can control rice drought-stress response, and it may play an important role in ABA feedback and post-transcription processes. PMID- 26047698 TI - Innate immune evasion by hepatitis B virus-mediated downregulation of TRIF. AB - Hepatocytes are the target host cells during hepatitis B virus (HBV) infection. Recent studies indicate that the innate immune response of hepatocytes plays an important role in inhibiting HBV replication. TIR-domain-containing adaptor inducing interferon-beta (TRIF) is a key component in innate immune signaling pathways. In this study, we found that the TRIF protein was downregulated in human hepatoma cell lines and liver tissue samples harboring HBV. Hepatitis B virus X protein (HBX) reduced TRIF protein expression in a dose-dependent manner via the proteasomal pathway. HBX appeared to not directly interact with TRIF as these proteins failed to co-immunoprecipitate when overexpressed in hepatoma cells. TRIF upregulation in hepatoma cell lines dramatically inhibited HBV transcription and expression of its viral proteins. Cellular apoptosis induced by TRIF was also confirmed in hepatoma cell lines. Taken together, these findings reveal a new mechanism for HBV evasion of the cellular innate immunity by HBX mediated degradation of TRIF protein in hepatocytes. PMID- 26047699 TI - Disruption of beta-catenin binding to parathyroid hormone (PTH) receptor inhibits PTH-stimulated ERK1/2 activation. AB - The type I parathyroid hormone receptor (PTH1R) mediates PTH and PTH-related protein (PTHrP) actions on extracellular mineral ion homeostasis and bone remodeling. These effects depend in part on the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). Sequences located within or at the carboxyl-terminus of PTH1R control its activation and trafficking. beta-catenin regulates PTH1R signaling and promotes chondrocyte hypertrophy through binding to the intracellular carboxyl-terminal region of the receptor. How the interaction of PTH1R with beta-catenin affects PTH-stimulated ERK1/2 is unknown. In the present study, human embryonic kidney 293 (HEK293) cells, which do not express the PTH1R, were used to investigate whether the disruption of beta-catenin binding to PTH1R affects PTH-stimulated ERK1/2 activation. We demonstrated that beta-catenin interacted with wild-type PTH1R but this interaction was markedly reduced with mutant PTH1R (L584A/L585A). PTH stimulated less cAMP formation and increased more intracellular calcium in HEK293 cells transfected with wild-type PTH1R compared with mutant PTH1R, indicating beta-catenin switches PTH1R signaling from Galphas activation to Galphaq signaling. In addition, ERK1/2 activation in HEK293 cells transfected with PTH1R exhibited time and concentration dependence. PTH-stimulated ERK1/2 activation was mostly mediated through Galphaq/PLC signaling pathway. Importantly, transfection of mutant PTH1R decreased PTH-induced ERK1/2 activation by inhibiting Galphaq-mediated signaling. This study shows for the first time that the interference of beta-catenin binding to PTH1R inhibits PTH-stimulated ERK1/2 phosphorylation. PMID- 26047700 TI - Identification of miR-2400 gene as a novel regulator in skeletal muscle satellite cells proliferation by targeting MYOG gene. AB - MicroRNAs play critical roles in skeletal muscle development as well as in regulation of muscle cell proliferation and differentiation. Previous study in our laboratory showed that the expression level of miR-2400, a novel and unique miRNA from bovine, had significantly changed in skeletal muscle-derived satellite cells (MDSCs) during differentiation, however, the function and expression pattern for miR-2400 in MDSCs has not been fully understood. In this report, we firstly identified that the expression levels of miR-2400 were down-regulated during MDSCs differentiation by stem-loop RT-PCR. Over-expression and inhibition studies demonstrated that miR-2400 promoted MDSCs proliferation by EdU (5-ethynyl 2' deoxyuridine) incorporation assay and immunofluorescence staining of Proliferating cell nuclear antigen (PCNA). Luciferase reporter assays showed that miR-2400 directly targeted the 3' untranslated regions (UTRs) of myogenin (MYOG) mRNA. These data suggested that miR-2400 could promote MDSCs proliferation through targeting MYOG. Furthermore, we found that miR-2400, which was located within the eighth intron of the Wolf-Hirschhorn syndrome candidate 1-like 1 (WHSC1L1) gene, was down-regulated in MDSCs in a direct correlation with the WHSC1L1 transcript by Clustered regularly interspaced palindromic repeats interference (CRISPRi). In addition, these observations not only provided supporting evidence for the codependent expression of intronic miRNAs and their host genes in vitro, but also gave insight into the role of miR-2400 in MDSCs proliferation. PMID- 26047701 TI - Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL 33 secreted from impaired vessels in the skin compared to fractionated irradiation. AB - We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm(2) fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C-C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA sequencing using 30 Gy-irradiated mouse skin and functional assays in a co culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-beta, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil mediated fibrosis in high-dose-per fraction irradiated skin. PMID- 26047702 TI - Hepassocin is required for hepatic outgrowth during zebrafish hepatogenesis. AB - BACKGROUND & AIMS: Hepassocin (HPS) is a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage. In this paper, zebrafish were used to investigate the role of HPS in liver development. METHODS AND RESULTS: During zebrafish development, HPS expression is enriched in liver throughout hepatogenesis. Knockdown of HPS using its specific morpholino leads to a smaller liver phenotype. Further results showed that the HPS knockdown has no effect on the expression of the early endoderm marker gata6 and early hepatic marker hhex. In addition, results showed that the smaller-liver phenotype in HPS morphants was caused by suppression of cell proliferation, not induction of cell apoptosis. CONCLUSIONS: Current findings indicated that HPS is essential to the later stages of development in vertebrate liver organogenesis. PMID- 26047703 TI - Suppression of death-associated protein kinase 2 by interaction with 14-3-3 proteins. AB - Death-associated protein kinase 2 (DAPK2), a Ca(2+)/calmodulin-regulated serine/threonine kinase, induces apoptosis. However, the signaling mechanisms involved in this process are unknown. Using a proteomic approach, we identified 14-3-3 proteins as novel DAPK2-interacting proteins. The 14-3-3 family has the ability to bind to phosphorylated proteins via recognition of three conserved amino acid motifs (mode 1-3 motifs), and DAPK2 contains the mode 3 motif ((pS/pT)X1-2-COOH). The interaction of 14-3-3 proteins with DAPK2 was dependent on the phosphorylation of Thr(369), and effectively suppressed DAPK2 kinase activity and DAPK2-induced apoptosis. Furthermore, we revealed that the 14-3-3 binding site Thr(369) of DAPK2 was phosphorylated by the survival kinase Akt. Our findings suggest that DAPK2-induced apoptosis is negatively regulated by Akt and 14-3-3 proteins. PMID- 26047704 TI - Isopentenyl pyrophosphate secreted from Zoledronate-stimulated myeloma cells, activates the chemotaxis of gammadeltaT cells. AB - gammadeltaT cell receptor (TCR)-positive T cells, which control the innate immune system, display anti-tumor immunity as well as other non-immune-mediated anti cancer effects. gammadeltaT cells expanded ex vivo by nitrogen-containing bisphosphonate (N-BP) treatment can kill tumor cells. N-BP inhibits farnesyl pyrophosphate synthase in the mevalonate pathway, resulting in the accumulation of isopentenyl pyrophosphate (IPP), which is a stimulatory antigen for gammadeltaT cells. We have previously observed that as they get closer, migrating gammadeltaT cells increase in speed toward target multiple myeloma (MM) cells. In the present study, we investigated the gammadeltaT cell chemotactic factors involving using a micro total analysis system-based microfluidic cellular analysis device. The addition of supernatant from RPMI8226 MM cells treated with the N-BP zoledronic acid (ZOL) or the addition of IPP to the device induced chemotaxis of gammadeltaT cells and increased the speed of migration compared to controls. Analysis of the ZOL-treated RPMI8226 cell supernatant revealed that it contained IPP secreted in a ZOL-dose-dependent manner. These observations indicate that IPP activates the chemotaxis of gammadeltaT cells toward target MM cells treated with ZOL. PMID- 26047705 TI - Ascorbic acid promotes the direct conversion of mouse fibroblasts into beating cardiomyocytes. AB - Recent advances in the direct conversion of fibroblasts to cardiomyocytes suggest this process as a novel promising approach for cardiac cell-based therapies. Here, by screening the effects of 10 candidate small molecules along with transient overexpression of Yamanaka factors, we show ascorbic acid (AA), also known as vitamin C, enhances reprogramming of mouse fibroblasts into beating cardiomyocytes. Immunostaining and gene expression analyses for pluripotency and cardiac lineage markers confirmed beating patches were derived from non-cardiac lineage cells without passing through a pluripotent intermediate. Further analysis revealed that AA also increased the size of the beating areas and the number of cardiac progenitors. Immunostaining for cardiac markers, as well as electrophysiological analysis confirmed the functionality of directly converted cardiomyocytes. These results illustrate the importance of AA in direct conversion of fibroblasts to cardiomyocytes and may open new insights into future biomedical applications for induced cardiomyocytes. PMID- 26047706 TI - Seminal characteristics and cryopreservation of sperm from the squirrel monkey, Saimiri collinsi. AB - The Neotropical nonhuman primate squirrel monkey (Saimiri sp.) is one of the most commonly used species in research in several areas of knowledge. However, little progress has been reported in respect to techniques for preservation of their gametes. Thus, the main objectives of this study were (1) to describe testicular and seminal aspects of a new species, Saimiri collinsi, (2) to preserve semen of this species by cooling or freezing using ACP-118 (powdered coconut water), and (3) to test two glycerol (GLY) concentrations (1.5% or 3%) for semen freezing in the presence of ACP-118. The experimental group started with 14 captive males, but only 11 were suitable to collect ejaculates containing sperm. After anesthesia, both testes were evaluated: length, width, height, and testicular circumference. Semen was collected by electroejaculation and evaluated, followed by dilution, cooling, and freezing. Seminal parameters and sperm motility, vigor, plasma membrane integrity, and normal morphology were evaluated after each step; functionality was also checked in fresh and frozen-thawed sperm. Sperm motility, plasma membrane integrity, and normal sperm in cooled semen (n = 11) were 44.1 +/ 34.0, 63.1 +/- 15.6, and 73.8 +/- 19.8, respectively, with vigor ranging of 2 to 3. Sperm motility, plasma membrane integrity, normal and functional sperm in frozen semen (n = 5) were 0.6 +/- 1.3 (1.5% and 3% GLY); 4.4 +/- 4.9 (1.5% GLY) and 6.6 +/- 7.2 (3% GLY); 86.8 +/- 3.0 (1.5% GLY) and 88.8 +/- 5.1 (3% GLY); 13.3 +/- 11.9 (1.5% GLY) and 14.3 +/- 13.5 (3% GLY), respectively, and vigor 0 for both 1.5% and 3% GLY. No significant difference between GLY concentrations was observed. We concluded that electroejaculation was efficient for semen collection of S collinsi and tested the cooling protocol that allowed to recover a satisfactory percentage (63%) of membrane intact sperm. However, the freezing protocol was not appropriate to sperm preservation. PMID- 26047707 TI - Heat shock protein A8 stabilizes the bull sperm plasma membrane during cryopreservation: Effects of breed, protein concentration, and mode of use. AB - Heat shock protein A8 (HSPA8) is a highly conserved member of the Hsp70 family, which is expressed in oviductal cells, translocated into oviductal fluid, and becomes attached to the sperm surface during sperm transport. Previous research has shown that HSPA8 supports mammalian sperm viability during in vitro incubation at both 5 degrees C and body temperature. The present series of experiments was designed to explore the possibility that bovine recombinant HSPA8 might therefore protect bull spermatozoa during cryopreservation through its beneficial effects on the sperm plasma membrane. Soy-based cryopreservation media were used in these experiments. The effects of HSPA8 addition before freezing were examined at concentrations ranging from 0.2 to 6.4 MUg/mL, whereas the effects of postthaw HSPA8 addition were tested between 0.2 and 12.8 MUg/mL. When bull spermatozoa (from beef and dairy breeds) were frozen in the presence of HSPA8, beneficial but complex effects on postthaw viability were observed. Low HSPA8 concentrations (0.2 and 0.4 MUg/mL) resulted in significantly reduced postthaw sperm viability, but concentrations above 0.8 MUg/mL improved plasma membrane integrity. If HSPA8 was added to spermatozoa after thawing, outcomes were also biphasic and beneficial effects on viability were only seen if the HSPA8 concentration exceeded 3.2 MUg/mL. Beneficial effects were significantly more apparent with beef rather than dairy breeds. When HSPA8 was used in combination with cholesterol-loaded cyclodextrin, spermatozoa from the beef breeds showed significantly lower apoptotic effects. This was not observed with the dairy breeds. PMID- 26047708 TI - Effect of zinc on in vitro development of porcine embryos. AB - This study aimed to investigate the effect of zinc on in vitro development of porcine embryos. We evaluated the effects of zinc on blastocysts formation and investigated gene expression at zinc-deficient and supplemented conditions. Zinc deficient in vitro condition was induced by 10-MUM N,N,N',N'-tetrakis-(2 pyridylmethyl)-ethylendiamine (TPEN) (zinc chelator) treatment during IVC. On parthenogenetic activated embryos, this treatment significantly decreased cleavage rate and blastocyst formation compared with the control (0.0% and 0.0% vs. 69.0% and 36.0%, respectively). And time effect of the zinc deficiency exposure is observed. Blastocyst formation rate was significantly decreased as zinc-deficient time increases (54.1%, 31.0%, 9.0%, and 1.2% for zinc deficiency during 0, 3, 5, and 7 hours). However, zinc supplementation during IVC supported in vitro embryonic development. On parthenogenetic activated embryos, supplementation of 0.8 MUg/mL of zinc during IVC significantly increased blastocyst formation compared with other groups (43.9%, 57.8%, 67.1%, 51.4%, and 52.6% for zinc supplementation of 0, 0.4, 0.8, 1.2, and 1.6 MUg/mL). In vitro fertilized (IVF) embryos showed similar results. The blastocyst formation rate was significantly higher in the 0.8 MUg/mL of zinc-supplemented group than in the other groups (21.3%, 24.1%, 36.1%, 25.9%, and 25.2% for zinc supplementation of 0, 0.4, 0.8, 1.2, and 1.6 MUg/mL). PCNA, POU5F1, and Bcl2 messenger RNA expressions were unregulated in IVF-derived blastocysts in the 0.8 MUg/mL of zinc supplemented group compared with the control. These results suggest that zinc is required for embryonic development, and supplementation with adequate zinc concentrations during IVC improved the viability of porcine embryos, possibly by increasing PCNA, POU5F1, and Bcl2 gene expression of embryos. PMID- 26047709 TI - Oral Squamous Cell Carcinoma Presenting in a Patient Receiving Adalimumab for Rheumatoid Arthritis. AB - The efficacy of biologic agents in the treatment of inflammatory immune-mediated conditions has been clearly shown, but there also are numerous reports of adverse effects. Most reported adverse effects have been associated with tumor necrosis factor-alpha (TNF-alpha) inhibitors and include a possible increased risk of malignancy. There have been some reported cases of oral cancer developing in patients treated with TNF-alpha inhibitors. This case report describes a patient who was taking adalimumab for rheumatoid arthritis and who presented with a squamous cell carcinoma (SCC) in the mandible. Diagnosis was complicated because the clinical appearance was of a nonhealing extraction socket and the patient had a history of bisphosphonate therapy. An initial diagnosis of bisphosphonate related osteonecrosis of the jaws was made, which delayed the commencement of appropriate treatment. This case highlights the importance of ruling out SCC in patients taking biological agents with unusual symptoms. PMID- 26047710 TI - Hypotensive Anesthesia Is Associated With Shortened Length of Hospital Stay Following Orthognathic Surgery. AB - PURPOSE: To evaluate the impact of induced hypotensive anesthesia on length of hospital stay (LOS) for patients undergoing maxillary Le Fort I osteotomy in isolation or in combination with mandibular orthognathic surgery. MATERIALS AND METHODS: A retrospective cohort study design was implemented and patients undergoing a Le Fort I osteotomy as a component of orthognathic surgery at the Mayo Clinic from 2010 through 2014 were identified. The primary predictor variable was the presence of induced hypotensive anesthesia during orthognathic surgery. Hypotensive anesthesia was defined as at least 10 consecutive minutes of a mean arterial pressure no higher than 60 mmHg documented within the anesthetic record. The primary outcome variable was LOS in hours after completion of orthognathic surgery. The secondary outcome variable was the duration of surgery in hours. Multiple covariates also abstracted included patient age, patient gender, American Society of Anesthesiologists score, complexity of surgical procedure, and volume of intraoperative fluids administered during surgery. Univariable and multivariable models were developed to evaluate associations between the primary predictor variable and covariates relative to the primary and secondary outcome variables. RESULTS: A total of 117 patients were identified undergoing Le Fort I orthognathic surgery in isolation or in combination with mandibular surgery. Induced hypotensive anesthesia was significantly associated with shortened LOS (odds ratio [OR] = 0.33; 95% confidence interval [CI], 0.12 0.88; P = .026) relative to patients with normotensive regimens. This association between hypotensive anesthesia and LOS remained statistically significant in a subgroup analysis of 47 patients in whom isolated Le Fort I surgery was performed (OR = 0.13; 95% CI, 0.03-0.62; P = .010). Induced hypotensive anesthesia was not statistically associated with shorter duration of surgery. CONCLUSION: Induced hypotensive anesthesia represents a potential factor that minimizes postoperative LOS for patients undergoing routine maxillary orthognathic surgery alone or in combination with mandibular procedures. Hypotensive anesthesia does not appear to be effective in minimizing the duration of surgery within this same patient population. PMID- 26047711 TI - Primary Malignant Melanoma of the Lip: A Report of 48 Cases. AB - PURPOSE: Lip melanoma (LM) is a rare malignant tumor and well-established treatment protocols for it are in short supply. The objective of this study was to evaluate the outcome of treatment modalities and explore the prognostic factors. PATIENTS AND METHODS: A retrospective chart review was performed on 48 patients with primary LM treated in the authors' hospital from January 1992 to November 2013. The clinical characteristics and treatment modalities were identified and correlated with the outcomes. RESULTS: The 5-year overall survival (OS) rate was 56.1%, and the rate of cervical lymph node (CLN) metastasis was 46% (22 of 48). A tumor of at least 4 cm (P = .001), nodular types (P = .003), and CLN (P < .0001) were independent prognostic factors for OS. Twenty-five patients died during follow-up, mainly from to neck recurrence (14 of 25). Chemotherapy significantly improved the 5-year OS rate in patients with stage IV LM (P = .03), but not in those with stage III (P = .8). CONCLUSIONS: LM has a lower CLN and distant metastasis rate and a better prognosis than other oral mucosal melanomas. A long history of melanin pigmentation is a dangerous sign for all patients, and smoking seems to be associated with LM in male patients. Tumor size (>=4 cm), nodular type, and CLN positivity are poor prognostic factors. A wide excision with close observation is advocated as the primary treatment for stage III LM. Adjuvant chemotherapy is useful for patients with stage IV cancer, but not for those with stage III. PMID- 26047712 TI - iTRAQ-facilitated proteomic profiling of anthers from a photosensitive male sterile mutant and wild-type cotton (Gossypium hirsutum L.). AB - Male sterility is a common phenomenon in flowering plants, and it has been successfully developed in several crops by taking advantage of heterosis. Cotton (Gossypium hirsutum L.) is an important economic crop, used mainly for the production of textile fiber. Using a space mutation breeding technique, a novel photosensitive genetic male sterile mutant CCRI9106 was isolated from the wild type upland cotton cultivar CCRI040029. To use CCRI9106 in cotton hybrid breeding, it is of great importance to study the molecular mechanisms of its male sterility. Here, histological and iTRAQ-facilitated proteomic analyses of anthers were performed to explore male sterility mechanisms of the mutant. Scanning and transmission electron microscopy of the anthers showed that the development of pollen wall in CCRI9106 was severely defective with a lack of exine formation. At the protein level, 6121 high-confidence proteins were identified and 325 of them showed differential expression patterns between mutant and wild-type anthers. The proteins up- or down-regulated in MT anthers were mainly involved in exine formation, protein degradation, calcium ion binding,etc. These findings provide valuable information on the proteins involved in anther and pollen development, and contribute to elucidate the mechanism of male sterility in upland cotton. PMID- 26047713 TI - Comparative proteomic analysis of Populus trichocarpa early stem from primary to secondary growth. AB - Wood is derived from the secondary growth of tree stems. In this study, we investigated the global changes of protein abundance in Populus early stems using a proteomic approach. Morphological and histochemical analyses revealed three typical stages during Populus early stems, which were the primary growth stage, the transition stage from primary to secondary growth and the secondary growth stage. A total of 231 spots were differentially abundant during various growth stages of Populus early stems. During Populus early stem lignifications, 87 differential spots continuously increased, while 49 spots continuously decreased. These two categories encompass 58.9% of all differential spots, which suggests significant molecular changes from primary to secondary growth. Among 231 spots, 165 unique proteins were identified using LC-ESI-Q-TOF-MS, which were classified into 14 biological function groups. The proteomic characteristics indicated that carbohydrate metabolism, oxido-reduction, protein degradation and secondary cell wall metabolism were the dominantly occurring biochemical processes during Populus early stem development. This study helps in elucidating biochemical processes and identifies potential wood formation-related proteins during tree early stem development. It is a comprehensive proteomic investigation on tree early stem development that, for the first time, reveals the overall molecular networks that occur during Populus early stem lignifications. PMID- 26047714 TI - Heat differentiated complement factor profiling. AB - Complement components and their cascade of reactions are important defense mechanisms within both innate and adaptive immunity. Many complement deficient patients still remain undiagnosed because of a lack of high throughput screening tools. Aiming towards neonatal proteome screening for immunodeficiencies, we used a multiplex profiling approach with antibody bead arrays to measure 9 complement proteins in serum and dried blood spots. Several complement components have been described as heat sensitive, thus their heat-dependent detectability was investigated. Using sera from 16 patients with complement deficiencies and 23 controls, we confirmed that the proteins C1q, C2, C3, C6, C9 and factor H were positively affected by heating, thus the identification of deficient patients was improved when preheating samples. Measurements of C7, C8 and factor I were negatively affected by heating and non-heated samples should be used in analysis of these components. In addition, a proof of concept study demonstrated the feasibility of labeling eluates from dried blood spots to perform a subsequent correct classification of C2-deficiencies. Our study demonstrates the potential of using multiplexed single binder assays for screening of complement components that open possibilities to expand such analysis to other forms of deficiencies. PMID- 26047715 TI - Venomics of the beaked sea snake, Hydrophis schistosus: A minimalist toxin arsenal and its cross-neutralization by heterologous antivenoms. AB - The venom proteome of Hydrophis schistosus (syn: Enhydrina schistosa) captured in Malaysian waters was investigated using reverse-phase HPLC, SDS-PAGE and high resolution liquid chromatography-tandem mass spectrometry. The findings revealed a minimalist profile with only 18 venom proteins. These proteins belong to 5 toxin families: three-finger toxin (3FTx), phospholipase A2 (PLA2), cysteine-rich secretory protein (CRISP), snake venom metalloprotease (SVMP) and L-amino acid oxidase (LAAO). The 3FTxs (3 short neurotoxins and 4 long neurotoxins) constitute 70.5% of total venom protein, 55.8% being short neurotoxins and 14.7% long neurotoxins. The PLA2 family consists of four basic (21.4%) and three acidic (6.1%) isoforms. The minor proteins include one CRISP (1.3%), two SVMPs (0.5%) and one LAAO (0.2%). This is the first report of the presence of long neurotoxins, CRISP and LAAO in H. schistosus venom. The neurotoxins and the basic PLA2 are highly lethal in mice with an intravenous median lethal dose of <0.2 MUg/g. Cross-neutralization by heterologous elapid antivenoms (Naja kaouthia monovalent antivenom and Neuro polyvalent antivenom) was moderate against the long neurotoxin and basic PLA2, but weak against the short neurotoxin, indicating that the latter is the limiting factor to be overcome for improving the antivenom cross-neutralization efficacy. PMID- 26047716 TI - Distributed and interactive visual analysis of omics data. AB - The amount of publicly shared proteomics data has grown exponentially over the last decade as the solutions for sharing and storing the data have improved. However, the use of the data is often limited by the manner of which it is made available. There are two main approaches: download and inspect the proteomics data locally, or interact with the data via one or more web pages. The first is limited by having to download the data and thus requires local computational skills and resources, while the latter most often is limited in terms of interactivity and the analysis options available. A solution is to develop web based systems supporting distributed and fully interactive visual analysis of proteomics data. The use of a distributed architecture makes it possible to perform the computational analysis at the server, while the results of the analysis can be displayed via a web browser without the need to download the whole dataset. Here the challenges related to developing such systems for omics data will be discussed. Especially how this allows for multiple connected interactive visual displays of omics dataset in a web-based setting, and the benefits this provide for computational analysis of proteomics data.This article is part of a Special Issue entitled: Computational Proteomics. PMID- 26047717 TI - Targeted release and fractionation reveal glucuronylated and sulphated N- and O glycans in larvae of dipteran insects. AB - Mosquitoes are important vectors of parasitic and viral diseases with Anopheles gambiae transmitting malaria and Aedes aegypti spreading yellow and Dengue fevers. Using two different approaches (solid-phase extraction and reversed-phase or hydrophilic interaction HPLC fractionation followed by MALDI-TOF MS or permethylation followed by NSI-MS), we examined the N-glycans of both A. gambiae and A. aegypti larvae and demonstrate the presence of a range of paucimannosidic glycans as well as bi- and tri-antennary glycans, some of which are modified with fucose or with sulphate or glucuronic acid residues; the latter anionic modifications were also found on N-glycans of larvae from another dipteran species (Drosophila melanogaster). The sulphate groups are attached primarily to core alpha-mannose residues (especially the alpha1,6-linked mannose), whereas the glucuronic acid residues are linked to non-reducing beta1,3-galactose. Also, O glycans were found to possess glucuronic acid and sulphate as well as phosphoethanolamine modifications. The presence of sulphated and glucuronylated N glycans is a novel feature in dipteran glycomes; these structures have the potential to act as additional anionic glycan ligands involved in parasite interactions with the vector host. PMID- 26047718 TI - Benchmark study of automatic annotation of MALDI-TOF N-glycan profiles. AB - Human experts can annotate peaks in MALDI-TOF profiles of detached N-glycans with some degree of accuracy. Even though MALDI-TOF profiles give only intact masses without any fragmentation information, expert knowledge of the most common glycans and biosynthetic pathways in the biological system can point to a small set of most likely glycan structures at the "cartoon" level of detail. Cartoonist is a recently developed, fully automatic annotation tool for MALDI-TOF glycan profiles. Here we benchmark Cartoonist's automatic annotations against human expert annotations on human and mouse N-glycan data from the Consortium for Functional Glycomics. We find that Cartoonist and expert annotations largely agree, but the expert tends to annotate more specifically, meaning fewer suggested structures per peak, and Cartoonist more comprehensively, meaning more annotated peaks. On peaks for which both Cartoonist and the expert give unique cartoons, the two cartoons agree in over 90% of all cases. This article is part of a Special Issue entitled: Computational Proteomics. PMID- 26047719 TI - The roles of puberty and age in explaining the diminished effectiveness of parental buffering of HPA reactivity and recovery in adolescence. AB - Parental support is a powerful regulator of stress and fear responses for infants and children, but recent evidence suggests it may be an ineffective stress buffer for adolescents. The mechanisms underlying this developmental shift are not well understood. The goal of the present study was to examine the independent and joint contributions of pubertal status and chronological age in explaining this shift. A sample of 75 typically developing youth (M age=12.95 years, SD=0.70, range=11.7-14.6 years; 37 females) was recruited to complete a modified Trier Social Stress Test (TSST-M) in the laboratory. Participants were recruited in such a way as to disentangle pubertal stage and chronological age by phone screening for markers of pubertal stage and then recruiting roughly equal numbers of younger and older, pre/early and mid/late pubertal youth who were then randomly assigned within groups to condition. The TSST-M was used as the stressor and youth prepared either with their parent or stranger (parent condition: N=39). Pubertal stage was confirmed by the Petersen Pubertal Development Scale at the time of testing and treated, along with chronological age, as a continuous variable in the analyses. The results revealed an interaction of pubertal stage and support condition for cortisol reactivity to the TSST-M such that preparing for the speech with the parent became a less potent buffer of the HPA axis as pubertal stage increased. Age did not interact with condition in predicting cortisol reactivity. In contrast, the parent's presence during speech preparation decreased in its effectiveness to hasten recovery of the HPA axis as children got older, but pubertal stage was not predictive of recovery rate. These patterns were specific to cortisol and were not observed with salivary alpha-amylase levels or subjective stress ratings for the task. These analyses suggest that the switch away from using parents as social buffers may be the result of neurobiological mechanisms associated with puberty. PMID- 26047720 TI - Concentrations of arsenic and other elements in groundwater of Bangladesh and West Bengal, India: potential cancer risk. AB - We investigated the concentrations of 23 elements in groundwater from arsenic (As) contaminated areas of Bangladesh and West Bengal, India to determine the potential human exposure to metals and metalloids. Elevated concentrations of As was found in all five study areas that exceeded the World Health Organization (WHO) guideline value of 10MUg/L. The mean As concentrations in groundwater of Noakhali, Jalangi and Domkal, Dasdia Nonaghata, Deganga and Baruipur were 297MUg/L, 262MUg/L, 115MUg/L, 161MUg/L and 349MUg/L, respectively. Elevated concentrations of Mn were also detected in all areas with mean concentrations were 139MUg/L, 807MUg/L, 341MUg/L, 579MUg/L and 584MUg/L for Noakhali, Jalangi and Domkal, Dasdia Nonaghata, Deganga and Baruipur, respectively. Daily As intakes from drinking water for adults and the potential cancer risk for all areas was also estimated. Results suggest that mitigation activities such as water treatment should not only be focused on As but must also consider other elements including Mn, B and Ba. The groundwater used for public drinking purposes needs to be tested periodically for As and other elements to ensure the quality of drinking water is within the prescribed national guidelines. PMID- 26047721 TI - DAMGO depresses inhibitory synaptic transmission via different downstream pathways of MU opioid receptors in ventral tegmental area and periaqueductal gray. AB - Opioid-induced rewarding and motorstimulant effects are mediated by an increased activity of the ventral tegmental area (VTA) dopamine (DA) neurons. The excitatory mechanism of opioids on VTA-DA neurons has been proposed to be due to the depression of GABAergic synaptic transmission in VTA-DA neurons. However, how opioids depress GABAergic synaptic transmission in VTA-DA neurons remain to be studied. In the present study, we explored the mechanism of the inhibitory effect of [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO) on GABAergic synaptic transmission in VTA-DA neurons using multiple approaches and techniques. Our results showed that (1) DAMGO inhibits GABAergic inputs in VTA-DA neurons at presynaptic sites; (2) effect of DAMGO on GABAergic inputs in VTA-DA neurons is inhibited by potassium channel blocker 4-aminopyridine (4-AP) and Gi protein inhibitor N-ethylmaleimide (NEM); (3) phospholipase A2 (PLA2) does not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons, but mediates it in the periaqueductal gray (PAG); (4) multiple downstream signaling molecules of MU receptors do not mediate the effect of DAMGO on GABAergic inputs in VTA-DA neurons. These results suggest that DAMGO depresses inhibitory synaptic transmission via MU receptor-Gi protein-Kv channel pathway in VTA-DA neurons, but via MU receptor-PLA2 pathway in PAG neurons. PMID- 26047722 TI - Methylxanthine-evoked perturbation of spontaneous and evoked activities in isolated newborn rat hippocampal networks. AB - Treatment of apnea of prematurity with methylxanthines like caffeine, aminophylline or theophylline can evoke hippocampal seizures. However, it is unknown at which interstitial brain concentrations methylxanthines promote such neonatal seizures or interfere with physiological 'early network oscillations' (ENOs) that are considered as pivotal for maturation of hippocampal neural networks. We studied theophylline and caffeine effects on ENOs in CA3 neurons (CA3-ENOs) and CA3 electrical stimulation-evoked monosynaptic CA1 field potentials (CA1-FPs) in sliced and intact hippocampi, respectively, from 8 to 10 days-old rats. Submillimolar doses of theophylline and caffeine, blocking adenosine receptors and phosphodiesterase-4 (PDE4), did not affect CA3-ENOs, ENO associated cytosolic Ca(2+) transients or CA1-FPs nor did they provoke seizure like discharges. Low millimolar doses of theophylline (?1mM) or caffeine (?5mM), blocking GABAA and glycine receptors plus sarcoplasmic-endoplasmic reticulum Ca(2+) ATPase (SERCA)-type Ca(2+) ATPases, evoked seizure-like discharges with no indication of cytosolic Ca(2+) dysregulation. Inhibiting PDE4 with rolipram or glycine receptors with strychnine had no effect on CA3-ENOs and did not occlude seizure-like events as tested with theophylline. GABAA receptor blockade induced seizure-like discharges and occluded theophylline-evoked seizure-like discharges in the slices, but not in the intact hippocampi. In summary, submillimolar methylxanthine concentrations do not acutely affect spontaneous CA3-ENOs or electrically evoked synaptic activities and low millimolar doses are needed to evoke seizure-like discharges in isolated developing hippocampal neural networks. We conclude that mechanisms of methylxanthine-related seizure-like discharges do not involve SERCA inhibition-related neuronal Ca(2+) dysregulation, PDE4 blockade or adenosine and glycine receptor inhibition, whereas GABA(A) receptor blockade may contribute partially. PMID- 26047723 TI - Repeated forced swim stress prior to complete Freund's adjuvant injection enhances mechanical hyperalgesia and attenuates the expression of pCREB and DeltaFosB and the acetylation of histone H3 in the insular cortex of rat. AB - Exposure to stressors causes substantial effects on the perception and response to pain. In several animal models, chronic stress produces hyperalgesia. The insular (IC) and anterior cingulate cortices (ACC) are the regions exhibiting most reliable pain-related activity. And the IC and ACC play an important role in pain modulation via descending pain modulatory system. In the present study we examined the expression of phospho-cAMP response element-binding protein (pCREB) and DeltaFosB and the acetylation of histone H3 in the IC and ACC after forced swim stress (FS) and complete Freund's adjuvant (CFA) injection to clarify changes in the cerebral cortices that affect the activity of the descending pain modulatory system in rats with stress-induced hyperalgesia. CFA injection into the hindpaw or FS (day 1, 10min; days 2-3, 20min) induced a significant increase in the expression of pCREB and DeltaFosB and the acetylation of histone H3 in the IC. Quantitative image analysis showed that the numbers of DeltaFosB immunoreactivity (IR) cells in the bilateral anterior and posterior IC (AIC and PIC) were significantly higher in the CFA group (AIC R, 548.0+/-98.6; AIC L, 433.5+/-89.4; PIC R, 546.1+/-72.8; PIC L, 415.5+/-53.5) than those in the naive group (AIC R, 86.6+/-14.8; AIC L, 85.5+/-24.7; PIC R, 124.5+/-29.9; PIC L, 107.0+/-19.8, p<0.01). However the FS prior to the CFA injection enhanced the mechanical hyperalgesia and attenuated the expression of pCREB and DeltaFosB and the acetylation of histone H3 in the IC. There was no significant difference in the numbers of DeltaFosB-IR cells in the bilateral PIC between the FS+CFA and naive groups. These findings suggest neuroplasticity in the IC after the FS, which may be involved in the enhancement of CFA-induced mechanical hyperalgesia through dysfunction of the descending pain modulatory system. PMID- 26047724 TI - The potential role of melatonin on sleep deprivation-induced cognitive impairments: implication of FMRP on cognitive function. AB - While prolonged sleep deprivation (SD) could lead to profound negative health consequences, such as impairments in vital biological functions of immunity and cognition, melatonin possesses powerful ameliorating effects against those harmful insults. Melatonin has strong antioxidant and anti-inflammatory effects that help to restore body's immune and cognitive functions. In this study, we investigated the possible role of melatonin in reversing cognitive dysfunction induced by SD in rats. Our experimental results revealed that sleep-deprived animals exhibited spatial memory impairment in the Morris water maze tasks compared with the control groups. Furthermore, there was an increased glial activation most prominent in the hippocampal region of the SD group compared to the normal control (NC) group. Additionally, markers of oxidative stress such as 4-hydroxynonenal (4-HNE) and 7,8-dihydro-8-oxo-deoxyguanine (8-oxo-dG) were significantly increased, while fragile X-mental retardation protein (FMRP) expression was decreased in the SD group. Interestingly, melatonin treatment normalized these events to control levels following SD. Our data demonstrate that SD induces oxidative stress through glial activation and decreases FMRP expression in the neurons. Furthermore, our results suggest the efficacy of melatonin for the treatment of sleep-related neuronal dysfunction, which occurs in neurological disorders such as Alzheimer's disease and autism. PMID- 26047725 TI - Serotonin, a possible intermediate between disturbed circadian rhythms and metabolic disease. AB - It is evident that eating in misalignment with the biological clock (such as in shift work, eating late at night and skipping breakfast) is associated with increased risk for obesity and diabetes. The biological clock located in the suprachiasmatic nucleus dictates energy balance including feeding behavior and glucose metabolism. Besides eating and sleeping patterns, glucose metabolism also exhibits clear diurnal variations with higher blood glucose concentrations, glucose tolerance and insulin sensitivity prior to waking up. The daily variation in plasma glucose concentrations in rats, is independent of the rhythm in feeding behavior. On the other hand, feeding itself has profound effects on glucose metabolism, but differential effects occur depending on the time of the day. We here review data showing that a disturbed diurnal eating pattern results in alterations in glucose metabolism induced by a disrupted circadian clock. We first describe the role of central serotonin on feeding behavior and glucose metabolism and subsequently describe the effects of central serotonin on the circadian system. We next explore the interaction between the serotonergic system and the circadian clock in conditions of disrupted diurnal rhythms in feeding and how this might be involved in the metabolic dysregulation that occurs with chronodisruption. PMID- 26047726 TI - Inhibition of prolactin with bromocriptine for 28days increases blood-brain barrier permeability in the rat. AB - The blood-brain barrier (BBB) is necessary for the proper function of the brain. Its maintenance is regulated by endogenous factors. Recent evidences suggest prolactin (PRL) regulates the BBB properties in vitro, nevertheless no evidence of these effects have been reported in vivo. The aim of this study was to evaluate the role of PRL in the maintenance of the BBB in the rat. Male Wistar rats were treated with Bromocriptine (Bromo) to inhibit PRL production for 28days in the absence or presence of lipopolysaccharide (LPS). BBB permeability was evaluated through the Evans Blue dye and fluorescein-dextran extravasation as well as through edema formation. The expression of claudin-5, occludin, glial fibrillary acidic protein (GFAP) and the PRL receptor (PRLR) was evaluated through western blot. Bromo reduced the physiological levels of PRL at 28days. At the same time, Bromo increased BBB permeability and edema formation associated with a decrement in claudin-5 and occludin and potentiated the increase in BBB permeability induced by LPS. However, no neuroinflammation was detected, since the expression of GFAP was unchanged, as well as the expression of the PRLR. These data provide the first evidence that inhibition of PRL with Bromo affects the maintenance of the BBB through modulating the expression of tight junction proteins in vivo. PMID- 26047727 TI - Persistent hindlimb inflammation induces changes in activation properties of hyperpolarization-activated current (Ih) in rat C-fiber nociceptors in vivo. AB - A hallmark of chronic inflammation is hypersensitivity to noxious and innocuous stimuli. This inflammatory pain hypersensitivity results partly from hyperexcitability of nociceptive dorsal root ganglion (DRG) neurons innervating inflamed tissue, although the underlying ionic mechanisms are not fully understood. However, we have previously shown that the nociceptor hyperexcitability is associated with increased expression of hyperpolarization activated cyclic nucleotide-gated channel 2 (HCN2) protein and hyperpolarization activated current (Ih) in C-nociceptors. Here we used in vivo voltage-clamp and current-clamp recordings, in deeply anesthetized rats, to determine whether activation properties of Ih in these C-nociceptors also change following persistent (not acute) hindlimb inflammation induced by complete Freund's adjuvant (CFA). Recordings were made from lumbar (L4/L5) C-nociceptive DRG neurons. Behavioral sensory testing was performed 5-7days after CFA treatment, and all the CFA-treated group showed significant behavioral signs of mechanical and heat hypersensitivity, but not spontaneous pain. Compared with control, C nociceptors recorded 5-7days after CFA showed: (a) a significant increase in the incidence of spontaneous activity (from ~5% to 26%) albeit at low rate (0.14+/ 0.08Hz (Mean+/-SEM); range, 0.01-0.29Hz), (b) a significant increase in the percentage of neurons expressing Ih (from 35%, n=43-84%, n=50) based on the presence of voltage "sag" of >10%, and (c) a significant increase in the conductance (Gh) of the somatic channels conducting Ih along with the corresponding Ih,Ih, activation rate, but not voltage dependence, in C nociceptors. Given that activation of Ih depolarizes the neuronal membrane toward the threshold of action potential generation, these changes in Ih kinetics in CFA C-nociceptors may contribute to their hyperexcitability and thus to pain hypersensitivity associated with persistent inflammation. PMID- 26047728 TI - The timing of neuronal loss across adolescence in the medial prefrontal cortex of male and female rats. AB - Adolescence is a critical period of brain maturation characterized by the reorganization of interacting neural networks. In particular the prefrontal cortex (PFC), a region involved in executive function, undergoes synaptic and neuronal pruning during this time in both humans and rats. Our laboratory has previously shown that rats lose neurons in the medial prefrontal cortex (mPFC) and there is an increase in white matter under the frontal cortex between adolescence and adulthood. Female rats lose more neurons during this period, and ovarian hormones may play a role as ovariectomy before adolescence prevents neuronal loss. However, little is known regarding the timing of neuroanatomical changes that occur between early adolescence and adulthood. In the present study, we quantified the number of neurons and glia in the male and female mPFC at multiple time points from preadolescence through adulthood (postnatal days 25, 35, 45, 60 and 90). Females, but not males, lost a significant number of neurons in the mPFC between days 35 and 45, coinciding with the onset of puberty. Counts of GABA immunoreactive cell bodies indicated that the neurons lost were not primarily GABAergic. These results suggest that in females, pubertal hormones may exert temporally specific changes in PFC anatomy. As expected, both males and females gained white matter under the PFC throughout adolescence, though these gains in females were diminished after day 35, but not in males. The differences in cell loss in males and females may lead to differential vulnerability to external influences and dysfunctions of the PFC that manifest in adolescence. PMID- 26047729 TI - Catecholamine secretion by chemical hypoxia in guinea-pig, but not rat, adrenal medullary cells: differences in mitochondria. AB - The effects of mitochondrial inhibitors (CN(-), a complex IV inhibitor and CCCP, protonophore) on catecholamine (CA) secretion and mitochondrial function were explored functionally and biochemically in rat and guinea-pig adrenal chromaffin cells. Guinea-pig chromaffin cells conspicuously secreted CA in response to CN(-) or CCCP, but rat cells showed a little, if any, secretory response to either of them. The resting metabolic rates in rat adrenal medullae did not differ from those in guinea-pig adrenal medullae. On the other hand, the time course of depolarization of the mitochondrial membrane potential (DeltaPsim) in guinea-pig chromaffin cells in response to CN(-) was slower than that in rat chromaffin cells, and this difference was abolished by oligomycin, an F1F0-ATPase inhibitor. The extent of CCCP-induced decrease in cellular ATP in guinea-pig chromaffin cells, which was indirectly measured using a Mg(2+) indicator, was smaller than that in rat chromaffin cells. Relative expression levels of F1F0-ATPase inhibitor factor in guinea-pig adrenal medullae were smaller than in rat adrenal medullae, and the opposite was true for F1F0-ATPase alpha subunit. The present results indicate that guinea-pig chromaffin cells secrete more CA in response to a mitochondrial inhibitor than rat chromaffin cells and this higher susceptibility in the former is accounted for by a larger extent of reversed operation of F1F0 ATPase with the consequent decrease in ATP under conditions where DeltaPsim is depolarized. PMID- 26047730 TI - Probenecid protects against cerebral ischemia/reperfusion injury by inhibiting lysosomal and inflammatory damage in rats. AB - Probenecid has been used for decades to treat gout, and recent studies have revealed it is also a specific inhibitor of the pannexin-1 channel. It has been reported that the pannexin-1 channel is involved in ischemic injury. Here, we investigated the neuroprotective effect and the possible mechanisms of action of probenecid in global cerebral ischemia/reperfusion (I/R) injury in rats. Twenty minutes of transient global cerebral I/R injury was induced using the four-vessel occlusion (4-VO) method in male Sprague-Dawley rats. Different doses of probenecid were administered intravenously, intraperitoneally, or by gavage before or after reperfusion. Probenecid via all three routes protected against CA1 neuronal death when given before reperfusion. This protective effect continued when probenecid was given at 2h after reperfusion, but not at 6h. Interestingly, the protective effect regained if probenecid was given continuously for 7days after reperfusion. The release of cathepsin B and overexpression of calpain-1 after reperfusion were inhibited, while the upregulation of Hsp70 was strengthened by probenecid pre-treatment. Furthermore, the activation and proliferation of microglia and astrocytes after I/R injury were suppressed by continuous given for 7days, but only partly by a single dose at 6h of reperfusion. Thus, our data indicate that probenecid protects against transient global cerebral I/R injury probably by inhibiting calpain-cathepsin pathway and the inflammatory reaction. PMID- 26047731 TI - Evaluation of established human iPSC-derived neurons to model neurodegenerative diseases. AB - Neurodegenerative diseases are difficult to study due to unavailability of human neurons. Cell culture systems and primary rodent cultures have shown to be indispensable to clarify disease mechanisms and provide insights into gene functions. Nevertheless, it is hard to translate new findings into new medicines. The discovery of human induced pluripotent stem cells (iPSC) might partially overcome this problem. Commercially available human iPSC-derived neurons, when thoroughly characterized and suitable for viral transduction, might represent a faster model for drugs screening than the time-consuming derivation and differentiation of iPSC from patient samples. In this study we show that iCell(r) neurons are primarily immature GABAergic neurons within the tested time frame. Addition of C6 glioma conditioned medium improved the bursting frequency of cells without further maturation or evidence for glutamatergic responses. Furthermore, cells were suitable for lentiviral transduction within the tested time frame. Altogether, iCell(r) neurons might be useful to model neurodegenerative diseases in which young GABAergic subtypes are affected. PMID- 26047732 TI - Neural control of movement stability: Lessons from studies of neurological patients. AB - The concept of synergy provides a theoretical framework for movement stability resulting from the neural organization of multiple elements (digits, muscles, etc.) that all contribute to salient performance variables. Although stability of performance is obviously important for steady-state tasks leading to high synergy indices, a feed-forward drop in synergy indices is seen in preparation to a quick action (i.e., anticipatory synergy adjustments, ASAs). We review recent studies of multi-finger and multi-muscle synergies that show decreased indices of synergies and ASAs in patients with Parkinson's disease (PD) or multisystem atrophy. In PD, the impairments in synergies and ASAs are partially reversed by dopaminergic drugs, and changes in synergy indices are present even in PD patients at earliest diagnosis. Taken together, these results point at subcortical structures that are crucial for proper control of movement stability. It is timely to introduce the concept of impaired control of stability as an objective, quantifiable, and theory-based clinical descriptor of movement disorders that can increase our understanding of the neural control of movement with all of its implications for clinical practice. PMID- 26047734 TI - Impairment of insulin receptor substrate 1 signaling by insulin resistance inhibits neurite outgrowth and aggravates neuronal cell death. AB - In the central nervous system (CNS), insulin resistance (I/R) can cause defective neurite outgrowth and neuronal cell death, which can eventually lead to cognitive deficits. Recent research has focused on the relationship between I/R and the cognitive impairment caused by dementia, with the goal of developing treatments for dementia. Insulin signal transduction mediated by insulin receptor substrate (IRS-1) has been thoroughly studied in the CNS of patients with I/R. In the present study, we investigated whether the impairment of IRS-1-mediated insulin signaling contributes to neurite outgrowth and neuronal loss, both in mice fed a high-fat diet and in mouse neuroblastoma (Neuro2A) cells. To investigate the changes caused by the inhibition of IRS-1-mediated insulin signaling in the brain, we performed Cresyl Violet staining and immunochemical analysis. To investigate the changes caused by the inhibition of IRS-1-mediated insulin signaling in neuroblastoma cells, we performed Western blot analysis, reverse transcription-PCR, and immunochemical analysis. We show that the deactivation of IRS-1-mediated insulin signaling can inhibit neuronal outgrowth and aggravate neuronal cell death in the insulin-resistant CNS. Thus, IRS-1-mediated insulin signal transduction may be an important factor in the treatment of cognitive decline induced by I/R. PMID- 26047733 TI - Methylene blue-induced neuronal protective mechanism against hypoxia reoxygenation stress. AB - Brain ischemia and reperfusion (I/R) injury occurs in various pathological conditions, but there is no effective treatment currently available in clinical practice. Methylene blue (MB) is a century-old drug with a newly discovered protective function in the ischemic stroke model. In the current investigation we studied the MB-induced neuroprotective mechanism focusing on stabilization and activation of hypoxia-inducible factor-1alpha (HIF-1alpha) in an in vitro oxygen and glucose deprivation (OGD)-reoxygenation model. METHODS: HT22 cells were exposed to OGD (0.1% O2, 6h) and reoxygenation (21% O2, 24h). Cell viability was determined with the calcein AM assay. The dynamic change of intracellular O2 concentration was monitored by fluorescence lifetime imaging microscopy (FLTIM). Glucose uptake was quantified using the 2-[N-(7-Nitrobenz-2-Oxa-1,3-Diazol-4 yl)Amino]-2-Deoxy-d-Glucose (2-NBDG) assay. ATP concentration and glycolytic enzyme activity were examined by spectrophotometry. Protein content changes were measured by immunoblot: HIF-1alpha, prolyl hydroxylase 2 (PHD2), erythropoietin (EPO), Akt, mTOR, and PIP5K. The contribution of HIF-1alpha activation in the MB induced neuroprotective mechanism was confirmed by blocking HIF-1alpha activation with 2-methoxyestradiol-2 (2-MeOE2) and by transiently transfecting constitutively active HIF-1alpha. RESULTS: MB increases cell viability by about 50% vs. OGD control. Compared to the corresponding control, MB increases intracellular O2 concentration and glucose uptake as well as the activities of hexokinase and G-6-PDH, and ATP concentration. MB activates the EPO signaling pathway with a corresponding increase in HIF-1alpha. Phosphorylation of Akt was significantly increased with MB treatment followed by activation of the mTOR pathway. Importantly, we observed, MB increased nuclear translocation of HIF 1alpha vs. control (about three folds), which was shown by a ratio of nuclear:cytoplasmic HIF-1alpha protein content. CONCLUSION: We conclude that MB protects the hippocampus-derived neuronal cells against OGD-reoxygenation injury by enhancing energy metabolism and increasing HIF-1alpha protein content accompanied by an activation of the EPO signaling pathway. PMID- 26047736 TI - Effect of separation distance on the growth and differentiation of mouse embryoid bodies in micropatterned cultures. AB - Embryoid body (EB) culture has been widely used for in vitro differentiation of embryonic stem (ES) cells. Micropatterning of cultures is a promising technique for regulating EB development, because it allows for controlling the EB size and the distance between neighboring EBs. In this study, we examined the relationship of EB separation distance to their growth and differentiation using a micropatterned chip. The basic chip design consisted of 91 gelatin spots (300 MUm in diameter) in a hexagonal arrangement on a glass substrate that served as the cell adhesion area; the region without gelatin spots was modified with polyethylene glycol to create the non-adhesion area. Two similar chips were fabricated with distances between gelatin spots of 500 and 1500 MUm. Mouse ES cells adhered on the gelatin spots and then proliferated to form EBs. When the EB EB distance was at 1500 MUm, their size and the expression of developmental gene markers were almost the same for all EBs on the chip. This indicated that interference between neighboring EBs was avoided. In contrast, when the EB-EB distance was at 500 MUm, the size of EBs located in the inside region of the chip was smaller than that in the outside region. Additionally, in the inside region, hepatic differentiation of EB cells was increased over cardiac and vascular differentiation. These results indicate that the distance between EBs is an important factor in the regulation of their growth and differentiation. PMID- 26047738 TI - [Reflecting on biomedical ethics: Conviction and responsibility]. PMID- 26047735 TI - Anti-PolyQ Antibodies Recognize a Short PolyQ Stretch in Both Normal and Mutant Huntingtin Exon 1. AB - Huntington's disease is caused by expansion of a polyglutamine (polyQ) repeat in the huntingtin protein. A structural basis for the apparent transition between normal and disease-causing expanded polyQ repeats of huntingtin is unknown. The "linear lattice" model proposed random-coil structures for both normal and expanded polyQ in the preaggregation state. Consistent with this model, the affinity and stoichiometry of the anti-polyQ antibody MW1 increased with the number of glutamines. An opposing "structural toxic threshold" model proposed a conformational change above the pathogenic polyQ threshold resulting in a specific toxic conformation for expanded polyQ. Support for this model was provided by the anti-polyQ antibody 3B5H10, which was reported to specifically recognize a distinct pathologic conformation of soluble expanded polyQ. To distinguish between these models, we directly compared binding of MW1 and 3B5H10 to normal and expanded polyQ repeats within huntingtin exon 1 fusion proteins. We found similar binding characteristics for both antibodies. First, both antibodies bound to normal, as well as expanded, polyQ in huntingtin exon 1 fusion proteins. Second, an expanded polyQ tract contained multiple epitopes for fragments antigen binding (Fabs) of both antibodies, demonstrating that 3B5H10 does not recognize a single epitope specific to expanded polyQ. Finally, small-angle X-ray scattering and dynamic light scattering revealed similar binding modes for MW1 and 3B5H10 Fab-huntingtin exon 1 complexes. Together, these results support the linear lattice model for polyQ binding proteins, suggesting that the hypothesized pathologic conformation of soluble expanded polyQ is not a valid target for drug design. PMID- 26047739 TI - [Anterior transolecranon fracture-dislocations of the elbow in children: A case report and review of the literature]. AB - Anterior transolecranon fracture-dislocations of the elbow are rare in children and the literature is poor in recommendations for the management of these lesions. We report a new case with a type of lesion that has not been described previously and discuss this pathology. Based on a literature review, we propose a classification into four types of anterior transolecranon fracture-dislocations of the elbow in children, thereby guiding surgical indications. We recommend reduction and synthesis using a figure-eight tension-band wire in avulsions and transverse type I and II fractures. The bone plate is the best indication in type III oblique fractures in older children. PMID- 26047740 TI - [Bronchiectasis revealing triple A syndrome]. AB - We report on the case of a 3-year-old child presenting bilateral bronchiectasis due to recurrent pneumonia with esophageal achalasia. The final diagnosis was triple A syndrome. This presentation is particularly atypical and rare at this age. PMID- 26047742 TI - [Pediatric post-traumatic limb pseudoaneurysm: Case report and literature review]. AB - INTRODUCTION: Pediatric post-traumatic pseudoaneurysms are a rare complication of arterial limb injuries. Management modalities in children are poorly defined. We report on a case of post-traumatic pseudoaneurysm of the right anterior tibial artery after minimal penetrating trauma, treated with surgery. CASE REPORT: A 14 year-old boy presented in consultation with a limp and right calf pain 3 months after a penetrating trauma. On physical examination, a painful mass in the middle third of the right leg was found, without inflammatory signs, but with a pulsatile character and a palpable thrill. Ultrasonography revealed a hypoechoic cystic structure, adjacent to the anterior tibial artery with a characteristic ying-yang flow on color Doppler, suggesting a post-traumatic pseudoaneurysm. The diagnosis was confirmed by CT angiography. The treatment was surgical, including flattening of the pseudoaneurysm and interposition of an autologous graft. CONCLUSION: Management of pediatric post-traumatic pseudoaneurysm of the limbs is surgical. Currently however, new alternatives exist: endovascular techniques, ultrasound-guided compression, and embolization by thrombin injection. PMID- 26047741 TI - [Clowns in the pediatric intensive care unit in France]. AB - INTRODUCTION: In recent years, in children's hospitals, clowns are involved in pediatric intensive care units (PICUs), at the bedside of the most severely ill children. This study is the first that addresses the work of professional clowns in the PICU. Its aim is to describe this practice in French hospitals. METHODS: This study is a descriptive and prospective study conducted in December 2013 involving all the pediatric PICUs in French hospitals. A survey was emailed to all the PICU department heads in France. RESULTS: Questionnaires were sent to 32 PICUs (21 pediatric and neonatal intensive care units and 11 pediatric intensive care units). The response rate was 81.2% (26 questionnaires completed). Among the 26 units that responded to the survey, clowns intervened in 13 of them (50%). Eight had an exclusive pediatric activity and five had both pediatric and neonatal activities. The clown visit was twice a week in six units and once in seven (missing data: one unit). The head doctor was satisfied or very satisfied in 92.3% of the cases (n=12/13). Medical clowns were trained and professional artists in all of the units. They worked in duo in most units (n=12/13) and solo in one unit. The clown rounds were preceded by a meeting with a healthcare worker in 12 of the 13 PICUs in which the clowns worked. They dialogued with a doctor in four and a nurse (or head nurse) in eight. DISCUSSION: Prior to implementation, the clowns' work should be understood, accepted, and supported by each PICU team, to be validated in the overall care plan for each child. CONCLUSION: Despite the severity of the situations met in the PICU, the instability of patients and the technical environment, clowning in PICUs appears to be a common and worthwhile practice in most French pediatric hospitals. PMID- 26047743 TI - [Neurological symptoms due to Mycoplasma pneumoniae infection in nine children]. AB - Mycoplasma pneumoniae infection is common in children. Extrapulmonary symptoms usually reveal as neurological symptoms, mainly as encephalitis with significant morbidity and mortality. Various other neurological presentations have also been reported. We describe a cohort of nine children with neurological manifestations due to M. pneumoniae infection, including five cases of encephalitis, one of polyradiculoneuritis, one of ophthalmoplegia, one of optic neuritis, and one of myositis. Progression was variable from ad integrum recovery to severe brain damage. Diagnosis is usually confirmed by PCR and/or serological follow-up, but the latter is still insufficiently used in practice to systematically affirm the diagnosis. Therapeutic management is not clearly defined and long-term progression can be uncertain despite early antibiotic and/or anti-inflammatory treatments. PMID- 26047744 TI - [A surgical approach of severe obesity in adolescents]. PMID- 26047745 TI - [Significance of the urine strip test in case of stunted growth]. AB - Observation of stunted growth in children usually leads the general practitioner to refer the patient to endocrinologists or gastroenterologists. In most cases, after a complementary check-up, the diagnosis is made and treatment is initiated. However, certain cases remain undiagnosed, particularly renal etiologies, such as proximal tubulopathy. The urine strip test at the initial check-up would be an easy and inexpensive test to avoid delayed diagnosis. The aim of the present paper is to increase general physicians' and pediatricians' awareness of the significance of questioning the parents and using the urine strip test for any child presenting stunted growth. We report a patient case of a 20-month-old child admitted to the emergency department for severe dehydration. He had displayed stunted growth since the age of 5 months and showed a negative etiologic check-up at 9 months of age. Clinical examination at admission confirmed stunted growth with loss of 2 standard deviations and signs of dehydration with persistent diuresis. Skin paleness, ash-blond hair, and signs of rickets were also observed and the urine strip test showed positive pads for glycosuria and proteinuria. Polyuria and polydipsia were also revealed following parents' questioning, suggesting proximal tubulopathy (Fanconi syndrome). Association of stunted growth, rickets, polyuria and polydipsia, glycosuria (without ketonuria and normal glycemia), and proteinuria suggest nephropathic cystinosis. Ophthalmic examination showed cystine deposits in the cornea. The semiotic diagnosis of nephropathic cystinosis was confirmed by leukocyte cystine concentrations and genetic investigations. This case report clearly illustrates the significance of the urine strip test to easily and quickly concentrate the diagnosis of stunted growth on a renal etiology (glycosuria, proteinuria), especially on proximal tubulopathy for which the most frequent cause is nephropathic cystinosis. Specificity of nephropathic cystinosis treatment is that the age of treatment initiation is crucial and determinant for the prognosis of the disease and the onset of final stage renal failure. Therefore, the urine strip test should be included in the systematic check-up of stunted growth to identify any renal etiology. PMID- 26047746 TI - [Congenital hemangiomas: Report on ten patients]. AB - INTRODUCTION: Congenital hemangiomas (CHs) are rare congenital vascular tumors seldom mentioned in the literature. MATERIALS AND METHODS: We carried out a retrospective study of all the cases of CH diagnosed and treated at Besancon Hospital from 2008 to 2014. The clinical, radiological, and histological data of each case were collected. All the children were seen again in 2014. RESULTS: Ten CHs (seven rapidly involuting CHs, RICH and three non-involuting CH, NICH), predominantly full-term eutrophic male infants, were enrolled. RICHs were located on the head (n=2), trunk (n=2), and lower limbs (n=3), and NICHs were found on the hands. Diagnosis was clinical for all ten infants. All CHs resembled "tumor" congenital lesions: single, oval-shaped, nonpulsatile, and well delimited, and their size did not increase after birth. Two RICHs were warm, one had phlebolites, and two had draining veins at the first visit. The mean age of the RICH involution onset was 1.7 months and the mean time to complete involution was 10.4 months. One CH was classified as a PICH (partially involuting CH) due to partial regression, two RICHs were still in the involution process at the age of 10 and 15 months, and one regressed very quickly within 7 days. No complications were observed in the NICH. Two RICHs presented benign complications (ulcerations and bleeding). Two RICHs regressed entirely, and five regressed with sequelae: lipoatrophy (n=3), cutaneous excess (n=2), dysplastic veins (n=3), a pigmented area (n=1), and an anemic halo (n=2). DISCUSSION: The small number of patients in our cohort, in spite of the length of the study, confirms the rarity of CH. The sex-ratio in favor of male infants and the location of NICH on the hands have not been reported. The most discriminating element remained the follow-up over 1 year. The initial clinical aspect of the NICH and the progression of one RICH into a NICH suggested possible overlapping forms between RICH and NICH. Some CHs, including one PICH, presented clinical and radiological criteria similar to those of vascular malformations (warm lesion, dysplastic veins, and echo-Doppler results in favor of vascular malformation). RICH regressed with sequelae in most cases. CONCLUSION: This study reveals a polymorphous clinical presentation of CH and provides a thorough description of their progression. It underlines the existence of overlapping phenomena between RICH and NICH, and between CH and vascular malformations, thus suggesting a possible link between proliferation and malformation phenomena at the origin of these lesions. PMID- 26047747 TI - [Extensive ulcerations in children: The difficulty diagnosing pyoderma gangrenosum]. AB - Pyoderma gangrenosum is an amicrobial neutrophilic dermatosis of unknown cause with a chronic course. We report a case in a 30-month-old child who presented with progressive and painful skin ulcers. Lesions were quickly extensive, refractory to local and systemic antibiotic therapy. Histopathology of the skin biopsies confirmed the diagnosis of ulcerative pyoderma gangrenosum. Only 4% of the cases reported in the literature are in children below the age of 4 years. This neutrophilic dermatosis is associated in half of the cases with a systemic disease. The treatment is based on corticosteroids. Immunosuppressant drugs such as tacrolimus, cyclosporine, and mycophenolate mofetil may be effective for pyoderma gangrenosum refractory to corticosteroids. Currently, anti-TNF is a promising treatment for refractory PG. PMID- 26047748 TI - [Thrombosed scapular intramuscular venous malformation: A pediatric case report]. AB - Venous malformation (VM) is a frequent soft tissue mass in children that should not be confused with vascular tumors. We report the case of a 10-year-old boy with a bulky thrombosed VM of the shoulder with functional disability. D-dimer levels were high. Pathognomonic phleboliths were demonstrated on conventional x rays. Echo-doppler confirmed the venous nature of the lesion and areas without flow suspicious for thrombosis. MRI provides the deep extension and can show non calcified thrombi that are difficult to see with ultrasound. Localized intravascular coagulopathy is often associated with thrombosis phenomena and has to be confirmed by measurement of D-dimer levels in order to initiate anticoagulation quickly with low-molecular-weight heparin. Follow-up includes measurement of D-dimer levels and potentially MRI to evaluate the anticoagulation efficacy and tailor treatment duration. PMID- 26047749 TI - [Bluish swelling of the scalp. Sinus pericranii: A rare vascular anomaly ]. PMID- 26047750 TI - [Early type 2 neurofibromatosis and congenital retinal hamartoma]. AB - Neurofibromatosis type 2 (NF2) is a heritable syndrome characterized by multifocal proliferation of neural crest-derived cells. It has long been regarded as an adolescent- and adult-onset disease. We report here on a case of a 6-year old girl with infantile-onset clinical signs. The girl, who had a history of amblyopia and congenital retinal hamartoma, presented with rough dimness of visual acuity. Cerebral magnetic resonance imaging found a left voluminous fronto temporal tumor including the chiasma and optical nerves. Vestibular and cervical nerve schwannomas were also found. She underwent a first neurosurgical partial excision and histopathology revealed meningioma. Postoperative radiotherapy was necessary due to a secondary increase of the tumor size. Subsequent molecular testing revealed a NF2 gene abnormality. NF2 can become evident in infancy but clinical early symptomatology is often different: ocular symptoms and neurological problems are common. There is no consensus on the treatment of tumors involving the central and peripheral nervous system, abstention being usual. In case of severe signs, surgery and radiotherapy can be proposed. The diagnosis of a hamartoma must lead to multidisciplinary follow-up. PMID- 26047751 TI - [Biliary peritonitis after traumatic rupture of a choledochal cyst]. AB - Choledochal cysts are rare congenital malformations of the biliary tract. Traumatic rupture of a choledochal cyst can be misleading. An 11-year-old boy was admitted for peritonitis and intestinal occlusion after blunt abdominal trauma, evolving over 48 h. Laparotomy revealed bile ascites and a suspected duodenal perforation. After referral to our center, a CT scan showed a perforated choledochal cyst. Six months later, a complete excision of the cyst was successfully performed. This treatment is mandatory because of the risk of further complications such as lithiasis, pancreatitis, cholangitis, biliary cirrhosis, and malignant transformation (cholangiocarcinoma). PMID- 26047752 TI - [Pediatric liver tumor: What to do?]. AB - Two-thirds of pediatric liver tumors are malignant, but pseudotumors such as abscesses or hematoma can simulate a tumor. The pediatrician is often the first to discover a hepatic mass in a child. The diagnostic gamut varies depending on the child's age. Before the age of three years, the main diagnoses are hepatoblastoma and hemangioma, while after the age of three, hepatocarcinoma, sarcoma, focal nodular hyperplasia, and adenoma are more frequent. The laboratory findings to search for are alpha-fetoprotein whatever the age (increased in hepatoblastoma and hepatocarcinoma), beta-hCG, and urinary catecholamines in infants. Liver function is usually normal. Ultrasonography is the first-line examination to request. It confirms the hepatic location of the mass, differentiates solid from cystic tumors (cystic mesenchymal hamartoma and undifferentiated sarcoma), hypervascular findings (hemangioma in the infant, focal nodular hyperplasia in the older child), portal or hepatic thrombosis suggesting a malignant tumor, and findings of portacaval fistula predisposing to focal nodular hyperplasia and adenoma. At the end of this clinical, biological, and ultrasound examination, the pediatrician will refer the patient to a specialized center for further investigation and management, which are at best performed by pediatric oncologists, surgeons, and radiologists. Diagnostic confirmation and extension work-up will require CT or MRI depending on the patient's age and clinical state and the availability of equipment. PMID- 26047753 TI - Muscle recovery after ACL reconstruction with 4-strand semitendinosus graft harvested through either a posterior or anterior incision: a preliminary study. AB - INTRODUCTION: Harvesting of a 4-strand semitendinosis (ST4) graft during anterior cruciate ligament (ACL) reconstruction can be performed through either a posterior or anterior approach. The objective of this study was to evaluate the recovery of the quadriceps and hamstring muscles as a function of the graft harvesting method. We hypothesized that posterior harvesting (PH) would lead to better recovery in hamstring strength than anterior harvesting (AH). METHODS: In this prospective study, the semitendinosus was harvested through an anterior incision in the first group of patients and through a posterior one in the second group of patients. The patients were enrolled consecutively, without randomization. Isokinetic muscle testing was performed three and six months postoperative to determine the strength deficit in the quadriceps and hamstring muscles of the operated leg relative to the uninjured contralateral leg. RESULTS: Thirty-nine patients were included: 20 in the AH group and 19 in the PH group. The mean quadriceps strength deficit after three and six months was 42% and 26% for AH and 29% and 19% for the PH, respectively (P=0.01 after three months and P=0.16 after six months). The mean hamstring strength deficit after three and six months was 31% and 17% for AH and 23% and 15% for the PH, respectively (P=0.09 after three months and P=0.45 after six months). After three months, the PH group had recovered 12% more quadriceps muscle strength than the AH group (P=0.03). CONCLUSION: Our hypothesis was not confirmed. Harvesting of a ST4 graft for ACL reconstruction using a posterior approach led to better muscle strength recovery in the quadriceps only after three months. CASE CONTROL STUDY: Level 3. PMID- 26047754 TI - Is knee function better with contemporary modular bicompartmental arthroplasty compared to total knee arthroplasty? Short-term outcomes of a prospective matched study including 68 cases. AB - BACKGROUND: Bicompartmental knee arthroplasty (BKA) was developed to treat medial tibiofemoral and patellofemoral osteoarthritis while preserving the anterior cruciate ligament to optimise knee kinematics. Our objective here was to compare the probability of achieving forgotten knee status and the functional outcomes at least two years after BKA versus total knee arthroplasty (TKA). We hypothesised that contemporary modular BKA produced better functional outcomes than TKA after at least two years, for patients with similar pre-operative osteoarthritic lesions. MATERIAL AND METHODS: We conducted a two-centre prospective controlled study of 34consecutive patients who underwent BKA between January 2008 and January 2011. Each patient was matched on age, gender, body mass index, preoperative range of knee flexion, centre, and surgeon to a patient treated with TKA. An independent observer evaluated all 68 patients after six and 12months then once a year. Forgotten knee status was defined as a 100/100 value of the Forgotten Joint Score (FJS-12) and each of the five KOOS subscales. We also compared the two groups for knee range of motion, Knee Society Scores (KSSs), Timed Up-and-Go test (TUG), and UCLA Activity Score. RESULTS: At a mean follow-up of 3.8+/-1.7 years, the probability of forgotten knee status was significantly higher in the BKA group (odds ratio, 4.64; 95% confidence interval, 1.63-13.21; P=0.007, Chi(2) test). Mean post-operative extension was not significantly different between the groups, whereas mean range of knee flexion was significantly greater in the BKA group (130 degrees +/-6 degrees vs. 125 degrees +/-8 degrees after TKA; P=0.03). The BKA group had significantly higher mean values for the knee and function KSSs, TUG test, and UCLA score (P<0.04 for all four comparisons). CONCLUSION: After at least two years, contemporary unlinked BKA was associated with greater comfort during everyday activities (forgotten knee) and better functional outcomes, compared to TKA. These short-term results require validation in randomised trials with longer follow-ups. LEVEL OF EVIDENCE: III, case-control study. PMID- 26047755 TI - Endoluminal minimally invasive surgery for chronic exertional compartment syndrome: a new technique. AB - INTRODUCTION: Fasciotomy is the usual treatment for chronic exertional compartment syndrome of the lower limb. For esthetic reasons, minimally invasive techniques have been developed but can generate complications. Herein, we report the use of the KnifeLight during minimally invasive anterior and lateral compartment release in view of reducing these complications, within a feasibility study. MATERIAL AND METHODS: This study was conducted on four cadavers (eight legs) and then an athletic patient (two legs). RESULTS: The technique was carried out on all cases with no complications. The patient's result was excellent. DISCUSSION: The KnifeLight can be used to perform a fasciotomy of the leg's anterior and lateral compartments. It seems to provide the operator with additional safety compared to other minimally invasive techniques. CONCLUSION: This is a simple, reliable, and reproducible technique that deserves to be better known. PMID- 26047756 TI - Low SOD activity is associated with overproduction of peroxynitrite and nitric oxide in patients with acute coronary syndrome. AB - OBJECTIVE: The present study was undertaken to evaluate the variation of the oxidative/nitrosative stress status in a population of subjects; with acute coronary syndrome (ACS), and examine its possible implication in plaque rupture which is the main mechanism in the pathophysiology of ACS. PATIENTS AND METHODS: We made this study on 50 men with ACS and 50 age and sex matched healthy controls. Nitrosative/oxidative stress markers including; nitric oxide, superoxide anion levels, superoxide dismutase (SOD) activity and peroxynitrite levels were evaluated in blood samples of patients and controls. RESULTS: Compared with healthy subjects, coronary patients had significantly higher nitric oxide, peroxynitrite and superoxide anion concentrations in both plasma and erythrocytes associated to significant decrease of SOD activity. Erythrocytes peroxynitrite concentration was negatively correlated with the antioxidant enzyme activity (SOD). CONCLUSION: Our results show a significant accumulation of both intracellular and plasma pro-oxidants with a concomitant decrease in the SOD scavenging activity in ACS patients. Both seem to be associated with plaque rupture and ischemia observed in ACS. PMID- 26047757 TI - Core muscle activity in a series of balance exercises with different stability conditions. AB - Literature that provides progression models based on core muscle activity and postural manipulations is scarce. The purpose of this study was to investigate the core muscle activity in a series of balance exercises with different stability levels and additional elastic resistance. A descriptive study of electromyography (EMG) was performed with forty-four healthy subjects that completed 12 exercises in a random order. Exercises were performed unipedally or bipedally with or without elastic tubing as resistance on various unstable (uncontrolled multiaxial and uniaxial movement) and stable surfaces. Surface EMG on the lumbar multifidus spinae (LM), thoracic multifidus spinae (TM), lumbar erector spinae (LE), thoracic erector spinae (TE) and gluteus maximus (GM), on the dominant side of the body were collected to quantify the amount of muscle activity and were expressed as a % of the maximum voluntary isometric contraction (MVIC). Significant differences (p<.001) were found between exercises. The three unipedal standing exercises with additional elastic resistance generated the greatest EMG values, ranging from 19% MVIC to 30% MVIC. Postural manipulations with additional elastic resistance and/or unstable devices increase core muscle activity. An adequate exercise progression based on global core EMG could start with seated positions, progressing to bipedal standing stance (i.e., from either multiaxial or stable surface to uniaxial surface). Following this, unipedal standing positions may be performed (i.e., from either multiaxial or stable surface to uniaxial surface) and finally, elastic resistance must be added in order to increase EMG levels (i.e., from stable surface progressing to any of the used unstable surfaces). PMID- 26047758 TI - Recent approaches for reducing hemolytic activity of chemotherapeutic agents. AB - Drug induced hemolysis is a frequent complication associated with chemotherapy. It results from interaction of drug with erythrocyte membrane and leads to cell lysis. In recent past, various approaches were made to reduce drug-induced hemolysis, which includes drug polymer conjugation, drug delivery via colloidal carriers and hydrogels, co-administration of botanical agents and modification in molecular chemistry of drug molecules. The basic concept behind these strategies is to protect the red blood cells from membrane damaging effects of drugs. There are several examples of drug polymer conjugate that either are approved by Food and Drug Administration or are under clinical trial for delivering drugs with reduced toxicities. Likewise, colloidal carriers are also used successfully nowadays for the delivery of various chemotherapeutic agents like gemcitabine and amphotericin B with remarkable decrease in their hemolytic activity. Similarly, co-administration of botanical agents with drugs works as secondary system proving protection and strength to erythrocyte membranes. In addition to the above statement, interaction hindrance between RBC and drug molecule by molecular modification plays an important role in reducing hemolysis. This review predominantly describes the above recent approaches explored to achieve the reduced hemolytic activity of drugs especially chemotherapeutic agents. PMID- 26047759 TI - Targeting microbubbles-carrying TGFbeta1 inhibitor combined with ultrasound sonication induce BBB/BTB disruption to enhance nanomedicine treatment for brain tumors. AB - The clinical application of chemotherapy for brain cancer tumors remains a challenge due to difficulties in the transport of therapeutic agents across the blood-brain barrier/blood-tumor barrier (BBB/BTB). In this study, we developed des-octanoyl ghrelin-conjugated microbubbles (GMB) loaded with TGFbeta1 inhibitor (LY364947) (GMBL) to induce BBB/BTB disruption for ultrasound (US) sonication with GMBL. The in-vitro stability study showed that GMB was pretty stable over one month. The in-vivo study showed that the accumulation of superparamagnetic iron oxide nanoparticles (SPION) in the sonicated tumor was significantly higher for focused US sonication in the presence of GMBL, indicating that GMBL/US can locally disrupt BBB/BTB to promote vascular permeability of nanoparticles. In addition, the combination of folate-conjugated polymersomal doxorubicin (FPD) and GMBL/US (FPD+GMBL/US) achieved the best anti-glioma effect and significant improvement in the overall survival time for brain tumor-bearing mice. When combined with focused US, GMBL facilitated local BBB/BTB disruption and simultaneously released LY364947 to decrease the pericyte coverage of the endothelium at the targeted brain tumor sites, resulting in enhanced accumulation and antitumor activity of FPD. The overall results indicate that GMBL/US owns a great potential for non-invasive targeting delivery of nanomedicine across the BBB to treat central nervous system (CNS) diseases. PMID- 26047760 TI - Definition of Readmission in 3,041 Patients Undergoing Hepatectomy. AB - BACKGROUND: Readmission rates of 9.7% to 15.5% after hepatectomy have been reported. These rates are difficult to interpret due to variability in the time interval used to monitor readmission. The aim of this study was to refine the definition of readmission after hepatectomy. STUDY DESIGN: A prospectively maintained database of 3,041 patients who underwent hepatectomy from 1998 through 2013 was merged with the hospital registry to identify readmissions. Area under the curve (AUC) analysis was used to determine the time interval that best captured unplanned readmission. RESULTS: Readmission rates at 30 days, 90 days, and 1 year after discharge were 10.7% (n = 326), 17.3% (n = 526), and 31.9% (n = 971) respectively. The time interval that best accounted for unplanned readmissions was 45 days after discharge (AUC, 0.956; p < 0.001), during which 389 patients (12.8%) were readmitted (unplanned: n = 312 [10.3%]; planned: n = 77 [2.5%]). In comparison, the 30 days after surgery interval (used in the ACS-NSQIP database) omitted 65 (26.3%) unplanned readmissions. Multivariate analysis revealed the following risk factors for unplanned readmission: diabetes (odds ratio [OR] 1.6; p = 0.024), right hepatectomy (OR 2.1; p = 0.034), bile duct resection (OR 1.9; p = 0.034), abdominal complication (OR 1.8; p = 0.010), and a major postoperative complication (OR 2.4; p < 0.001). Neither index hospitalization > 7 days nor postoperative hepatobiliary complications were independently associated with readmission. CONCLUSIONS: To accurately assess readmission after hepatectomy, patients should be monitored 45 days after discharge. PMID- 26047761 TI - Predictors of Hospital Readmission after Bariatric Surgery. AB - BACKGROUND: Identification of factors that might predict readmission after bariatric surgery could help surgeons target high-risk patients. The purpose of this study was to identify comorbidities, surgical variables, and postoperative complications associated with readmission. STUDY DESIGN: Patients with bariatric surgery as their primary procedure were identified from the 2012 American College of Surgeons (ACS) NSQIP database. Patient variables, operative times, and major postoperative complications were analyzed for predictors of readmission. The ACS NSQIP estimated probability of morbidity (MORBPROB) was also considered. Chi square tests and Poisson regression were used for statistical analysis to identify significant predictors. RESULTS: There were 18,186 patients who met inclusion criteria. There were 1,819 who had a laparoscopic gastric band, 9,613 who had laparoscopic Roux-en-Y gastric bypass (RYGB), 6,439 who had gastroplasties (vertical banded gastroplasty and sleeve), and 315 who had open RYGB. Age, sex, BMI, American Society of Anesthesiologists (ASA) class, diabetes, hypertension, steroid use, type of procedure, and operative time all were significantly associated with readmission within 30 days of operation. All major postoperative complications were significant predictors of readmission. Patients expected to be at high risk based on the ACS NSQIP MORBPROB had a significantly higher rate of readmissions. The overall readmission rate for patients undergoing bariatric surgery was 5%. The readmission rate among patients with any major complication was 31%. CONCLUSIONS: Bariatric surgery is a low-risk procedure. Complexity of operation, ASA class, prolonged operative time, and major postoperative complications are important determinants of high risk for readmission. The ACS NSQIP MORBPROB may be a useful tool to identify and target patients at risk for readmission. PMID- 26047762 TI - Use of Magnetic Resonance Cholangiopancreatography in Clinical Practice: Not as Good as We Once Thought. AB - BACKGROUND: Magnetic resonance cholangiopancreatography (MRCP) is believed to be a useful tool to evaluate the biliary tree and pancreas for stones, tumors, or injuries to the ductile system. The purpose of this study was to compare the accuracy of MRCP to the gold standard, endoscopic retrograde cholangiopancreatography (ERCP), in our institution. STUDY DESIGN: We performed a retrospective review of all MRCP followed by ERCP (follow-on ERCP) at a single institution over a 6-year period. Exam findings from MRCP were compared with findings on the follow-on ERCP and compared. Studies were grouped into 2 main classifications: tests being performed for patients with suspected choledocholithiasis (stone disease) and tests being performed for concerns of malignant strictures or duct injuries (non-stone disease). RESULTS: A total of 81 patients had MRCPs and follow-on ERCPs in this time period. Thirty-six patients had positive findings on MRCP and ERCP for stones in the common duct system, and 14 patients had positive findings on MRCP and subsequent ERCP for masses and strictures of the common duct. Three patients had positive MRCP and ERCP findings for pancreatic duct abnormalities. The specificity and positive predictive value of MRCP were 94% and 98%, respectively. However, 13 of 28 patients had lesions identified on ERCP after a normal MRCP. The sensitivity and negative predictive value were 80% and 54%, respectively. CONCLUSIONS: Magnetic resonance cholangiopancreatography was not useful in the management algorithm of either stone or non-stone disease of the biliary tree or pancreas. It should be abandoned as a diagnostic tool for work-up of biliary duct pathology. PMID- 26047763 TI - Variation in Contralateral Prophylactic Mastectomy Rates According to Racial Groups in Young Women with Breast Cancer, 1998 to 2011: A Report from the National Cancer Data Base. AB - BACKGROUND: The rate of contralateral prophylactic mastectomy (CPM) for unilateral breast cancer has increased over the past decade, particularly for young women. This study investigates the impact of race and socioeconomic status (SES) on use of CPM. STUDY DESIGN: Using the National Cancer Data Base (NCDB), we selected 1,781,409 stage 0 to II unilateral breast cancer patients between 1998 and 2011. Trends in use of CPM by race and SES were analyzed using chi-square tests and logistic regression models. RESULTS: For women of all ages, rates of CPM increased, from 1.9% in 1998 to 10.2% in 2011 (p < 0.001), with higher rates in women <=45 years old, rising from 3.7% in 1998 to 26.2% in 2011 (p < 0.001). Among young women, white women had the greatest increase in CPM from 4.3% in 1998 to 30.2% in 2011 (p < 0.001). In 2011, CPM rates were 30.2% for white, 18.5% for Hispanic, 16.5% for black, and 15.2% for Asian patients (p < 0.001). The gap in CPM use between white and minority patients persisted in every SES classification, geographic region, and facility type. On multivariate analysis, minority women were 50% less likely to undergo CPM than white women were. CONCLUSIONS: Young, white, breast cancer patients are twice as likely to undergo CPM compared with women in other racial groups, even after accounting for pathologic, patient, and facility factors. Variations in shared decision-making processes between women of different backgrounds may contribute to these trends, supporting the need for future studies investigating decision-making processes and decisional aids. PMID- 26047764 TI - Development and Evolution of Self-Retaining Retractors in Surgery: The Example of the Bookwalter Retractor. PMID- 26047765 TI - Contributions of Public Hospitals to Surgery in the United States. PMID- 26047766 TI - Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: & aims: Few clinical trials have addressed the potential benefits of omega-3 polyunsaturated fatty acids (PUFAs) on non-alcoholic steatohepatitis (NASH). We evaluated the effects of supplementation with omega-3 PUFAs from flaxseed and fish oils in patients with biopsy-proven NASH. METHODS: Patients received three capsules daily, each containing 0.315 g of omega-3 PUFAs (64% alpha-linolenic [ALA], 16% eicosapentaenoic [EPA], and 21% docosahexaenoic [DHA] acids; n-3 group, n = 27) or mineral oil (placebo group, n = 23). Liver biopsies were evaluated histopathologically by the NASH activity score (NAS). Plasma levels of omega-3 PUFAs were assessed as a marker of intake at baseline and after 6 months of treatment. Secondary endpoints included changes in plasma biochemical markers of lipid metabolism, inflammation, and liver function at baseline and after 3 and 6 months of treatment. RESULTS: At baseline, NAS was comparable between the groups (p = 0.98). After intervention with omega-3 PUFAs, plasma ALA and EPA levels increased (p <= 0.05). However in the placebo group, we also observed increased EPA and DHA (p <= 0.05), suggesting an off-protocol intake of PUFAs. NAS improvement/stabilization was correlated with increased ALA in the n-3 group (p = 0.02) and with increased EPA (p = 0.04) and DHA (p = 0.05) in the placebo group. Triglycerides were reduced after 3 months in the n-3 group compared to baseline (p = 0.01). CONCLUSIONS: In NASH patients, the supplementation of omega-3 PUFA from flaxseed and fish oils significantly impacts on plasma lipid profile of patients with NASH. Plasma increase of these PUFAs was associated with better liver histology. (ID 01992809). PMID- 26047767 TI - The Evolving Role of the Laboratory Professional in the Age of Genome Sequencing: A Vision of the Association for Molecular Pathology. AB - In conclusion, to maximize the benefit of the genomic era, the molecular laboratory director will continue to be essential in the generation, analysis, and interpretation of patient results, which now include genomic data obtained through NGS approaches. That includes integrating this information as part of the complete care of the patient and communicating and interacting with professionals across disciplines. In addition, the molecular laboratory director must continue to provide training and education to current and future colleagues, within and outside of molecular pathology and molecular genetics. Professionalism includes volunteerism in professional organizations and education and advocacy to policy makers, health administrators, payers, and the public. It also includes efforts to increase visibility of the profession to our colleagues from other medical disciplines and the public at large. Thus, the role of the molecular laboratory professional is multifaceted, but, above all, it is to ensure the access to and quality of molecular pathology testing, the responsible implementation of expanded test modalities such as genome sequencing, and the interpretation thereof to aid the clinician in the medical management of the patient and ultimately to benefit the society by providing precision patient care. PMID- 26047768 TI - Nanotechnology -New Lifeline For Food Industry. AB - Nanotechnology is an enable technology that has the potential to revolutionize agriculture and food systems. Food nanotechnology is an area of emerging interest and opens up a whole universe of new possibilities for the food industry. The basic categories of nanotechnology applications and functionalities currently in the development of food packaging include: the improvement of plastic materials barriers, the incorporation of active components that can deliver functional attributes beyond those of conventional active packaging, and the sensing and signaling of relevant information. Nano food packaging materials may extend food life, improve food safety, alert consumers that food is contaminated or spoiled, repair tears in packaging, and even release preservatives to extend the life of the food in the package. Nanotechnology applications in the food industry can be utilized to detect bacteria in packaging, or produce stronger flavors and color quality, and safety by increasing the barrier properties. Nanotechnology holds great promise to provide benefits not just within food products but also around food products. In fact, nanotechnology introduces new chances for innovation in the food industry at immense speed, but uncertainty and health concerns are also emerging. PMID- 26047770 TI - Conformational Properties of Sodium Polystyrenesulfonate in Water: Insights from a Coarse-Grained Model with Explicit Solvent. AB - Polymer solutions present a significant computational challenge because chemical realism on small length scales can be important, but the polymer molecules are very large. In polyelectrolyte solutions, there is often the additional complexity that the molecules consist of hydrophobic and charged groups, which makes an accurate treatment of the solvent, water, crucial. One route to achieve this balance is through coarse-grained models where several atoms on a monomer are grouped into one interaction site. In this work, we develop a coarse grained (CG) model for sodium polystyrenesulfonate (NaPSS) in water using a methodology consistent with the MARTINI coarse-graining philosophy, where four heavy atoms are grouped into one CG site. We consider two models for water: polarizable MARTINI (POL) and big multipole water (BMW). In each case, interaction parameters for the polymer sites are obtained by matching the potential of mean force between two monomers to results of atomistic simulations. The force field based on the POL water provides a more reasonable description of polymer properties than that based on the BMW water. We study the properties of single chains using the POL force field. Fully sulfonated chains are rodlike (i.e., the root-mean square radius of gyration, Rg, scales linearly with degree of polymerization, N). When the fraction of sulfonation, f, is 0.25 or less, the chain collapses into a cylindrical globule. For f = 0.5, pearl-necklace conformations are observed when every second monomer is sulfonated. The lifetime of a counterion around a polymer is on the order of 100 ps, suggesting that there is no counterion condensation. The model is computationally feasible and should allow one to study the effect of local chemistry on the properties of polymers in aqueous solution. PMID- 26047769 TI - The effect of the antipsychotic drug quetiapine and its metabolite norquetiapine on acute inflammation, memory and anhedonia. AB - The atypical antipsychotic drug, quetiapine, has recently been suggested to not only show efficacy in schizophrenia, bipolar, major depressive and general anxiety disorders, but to also have a possible anti-inflammatory effect, which could be important in the treatment of the inflammatory aspects of psychiatric diseases. Male C57BL/6 mice were given either quetiapine (i.p. 10mg/kg), its main active metabolite norquetiapine (i.p. 10mg/kg), or saline as a vehicle control, once a day for 14days. On the 14th day, this dose was followed by a single dose of either LPS (i.p. 1mg/kg) or saline. 24h post LPS short-term recognition memory and anhedonia behaviour were measured using the Y-maze and saccharin preference test respectively. Immediately following behavioural testing, mice were culled before serum, prefrontal cortex and hippocampal analysis of cytokine levels was conducted. It was found that LPS challenge led to increased serum and brain cytokine levels as well as anhedonia, with no significant effect on recognition memory. Quetiapine and norquetiapine both increased levels of the anti inflammatory cytokine IL-10 and decreased levels of the pro-inflammatory cytokine IFN-gamma in serum 4h post LPS. Within the brain, a similar pattern was seen in gene expression in the hippocampus at 4h for Il-10 and Ifn-gamma, however norquetiapine led to an increase in Il-1beta expression in the PFC at 4h, while both drugs attenuated the increased Il-10 in different regions of the brain at 24h. These effects in the serum and brain, however, had no effect on the observed LPS induced changes in behaviour. Both quetiapine and its metabolite norquetiapine appear to have a partial anti-inflammatory effect on IL-10 and IFN gamma following acute LPS challenge in serum and brain, however these effects did not translate into behavioural changes. PMID- 26047771 TI - Assessment of the relationships between myocardial contractility and infarct tissue revealed by serial magnetic resonance imaging in patients with acute myocardial infarction. AB - Imaging changes in left ventricular (LV) volumes during the cardiac cycle and LV ejection fraction do not provide information on regional contractility. Displacement ENcoding with Stimulated Echoes (DENSE) is a strain-encoded cardiac magnetic resonance (CMR) technique that measures strain directly. We investigated the relationships between strain revealed by DENSE and the presence and extent of infarction in patients with recent myocardial infarction (MI). 50 male subjects were invited to undergo serial CMR within 7 days of MI (baseline) and after 6 months (follow-up; n = 47). DENSE and late gadolinium enhancement (LGE) images were acquired to enable localised regional quantification of peak circumferential strain (Ecc) and the extent of infarction, respectively. We assessed: (1) receiver operating characteristic (ROC) analysis for the classification of LGE, (2) strain differences according to LGE status (remote, adjacent, infarcted) and (3) changes in strain revealed between baseline and follow-up. 300 and 258 myocardial segments were available for analysis at baseline and follow-up respectively. LGE was present in 130/300 (43%) and 97/258 (38%) segments, respectively. ROC analysis revealed moderately high values for peak Ecc at baseline [threshold 12.8%; area-under-curve (AUC) 0.88, sensitivity 84%, specificity 78%] and at follow-up (threshold 15.8%; AUC 0.76, sensitivity 85%, specificity 64%). Differences were observed between remote, adjacent and infarcted segments. Between baseline and follow-up, increases in peak Ecc were observed in infarcted segments (median difference of 5.6%) and in adjacent segments (1.5%). Peak Ecc at baseline was indicative of the change in LGE status between baseline and follow-up. Strain-encoded CMR with DENSE has the potential to provide clinically useful information on contractility and its recovery over time in patients with MI. PMID- 26047773 TI - Isolated right ventricular infiltrating tumour: metastatic hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) with intracavitary metastasis to the heart is rare. The incidence of HCC with right atrial metastasis is less than 6% at autopsy. Reports of HCC with right ventricular metastasis without inferior vena cava and right atrial metastasis are rarer. The diagnosis of metastasis of HCC into the cardiac cavity might be overlooked because the symptoms are neither apparent nor specific. Here, we report a patient with metastasis of HCC into the right ventricle cavity. The patient was in a disease-free status and experienced lower limbs oedema and gradual shortness of breath. PMID- 26047772 TI - Feasibility and influence of hTEE monitoring on postoperative management in cardiac surgery patients. AB - Monoplane hemodynamic TEE (hTEE) monitoring (ImaCor((r)) ClariTEE((r))) might be a useful alternative to continuously evaluate cardiovascular function and we aimed to investigate the feasibility and influence of hTEE monitoring on postoperative management in cardiac surgery patients. After IRB approval we reviewed the electronic data of cardiac surgery patients admitted to our intensive care between 01/01/2012 and 30/06/2013 in a case-controlled matched pairs design. Patients were eligible for the study when they presented a sustained hemodynamic instability postoperatively with the clinical need of an extended hemodynamic monitoring: (a) hTEE (hTEE group, n = 18), or (b) transpulmonary thermodilution (control group, n = 18). hTEE was performed by ICU residents after receiving an approximately 6-h hTEE training session. For hTEE guided hemodynamic optimization an institutional algorithm was used. The hTEE probe was blindly inserted at the first attempt in all patients and image quality was at least judged to be adequate. The frequency of hemodynamic examinations was higher (ten complete hTEE examinations every 2.6 h) in contrast to the control group (one examination every 8 h). hTEE findings, including five unexpected right heart failure and one pericardial tamponade, led to a change of current therapy in 89% of patients. The cumulative dose of epinephrine was significantly reduced (p = 0.034) and levosimendan administration was significantly increased (p = 0.047) in the hTEE group. hTEE was non-inferior to the control group in guiding norepinephrine treatment (p = 0.038). hTEE monitoring performed by ICU residents was feasible and beneficially influenced the postoperative management of cardiac surgery patients. PMID- 26047774 TI - The homogeneous mutation status of a 22 gene panel justifies the use of serial sections of colorectal cancer tissue for external quality assessment. AB - Testing for treatment related biomarkers in clinical care, like Ras mutation status in colorectal cancer (CRC), has increased drastically over recent years. Reliable testing of these markers is pivotal for optimal treatment of patients. Participation in external quality assessment (EQA) programs is an important element in quality management and often obligatory to comply with regulations or for accreditation. Formalin-fixed paraffin-embedded (FFPE) clinical specimens would ideally form the basis for these assessments, as they represent the most common starting material for molecular testing. However, molecular heterogeneity of a lesion in a FFPE tissue block could potentially affect test results of participating laboratories, which might compromise reliability of the quality assessment results. To assess the actual impact of this potential problem, we determined the mutation status of 22 genes commonly mutated in colon cancer in four levels covering 360 MUm of 30 FFPE tissue blocks, by Next Generation Sequencing. In each block, the genotype of these genes was identical at all four levels, with only little variation in mutation load. This result shows that the mutation status of the selected 22 genes in CRC specimens is homogeneous within a 360 MUm segment of the tumor. These data justify the use of serial sections, within a defined segment of a CRC tissue block, for external quality assessment of mutation analysis. PMID- 26047775 TI - Clinical effectiveness of the systematic use of the GRACE scoring system (in addition to clinical assessment) for ischaemic outcomes and bleeding complications in the management of NSTEMI compared with clinical assessment alone: a prospective study. AB - We assessed the interest of systematically using the GRACE scoring system (in addition to clinical assessment) for in- hospital outcomes and bleeding complications in the management of NSTEMI compared with clinical assessments alone. Multicentre, randomized study that included 572 consecutive NSTEMI patients, randomized 1:1, into group A: clinical stratification alone and group B: clinical+ GRACE score stratification. MAIN OUTCOME MEASURES: in-hospital outcomes and bleeding complications. There was no significant difference between the two groups for baseline data or for in-hospital MACE. In multivariate analysis, only a GRACE >140 (OR: 3.5, 95 % CI: 1.8-6.6, p < 0.001) and PCI (OR: 0.55, 95 % CI: 0.3-1.0; p = 0.05) were independent predictors of in-hospital MACE. The sub-analysis of group B showed that 56 patients (20 %) were given a compliance score of 0, showing that diagnostic angiography was performed later than as recommended by the guidelines. Interestingly, 91 % had a GRACE score >140, and these patients were significantly older, and were more likely to have a history of diabetes, stroke and renal failure, together with symptoms of heart failure. After multivariate analysis, the independent predictors of a lack of compliance with guideline delays were a GRACE score >140 (OR: 9.2; CI: 4.2-20.3, p < 0.001) and secondary referral from a non-PCI cardiology department (OR: 2.7; CI: 1.4-5.2, p = 0.003). In a real-world setting of patients admitted with NSTEMI, the systematic use of the GRACE scoring system at admission in the PCI centre does not improve in-hospital outcomes and bleeding complications. PMID- 26047776 TI - Inferential revision in narrative texts: An ERP study. AB - We evaluated the process of inferential revision during text comprehension in adults. Participants with high or low working memory read short texts, in which the introduction supported two plausible concepts (e.g., 'guitar/violin'), although one was more probable ('guitar'). There were three possible continuations: a neutral sentence, which did not refer back to either concept; a no-revise sentence, which referred to a general property consistent with either concept (e.g., '...beautiful curved body'); and a revise sentence, which referred to a property that was consistent with only the less likely concept (e.g., '...matching bow'). Readers took longer to read the sentence in the revise condition, indicating that they were able to evaluate their comprehension and detect a mismatch. In a final sentence, a target noun referred to the alternative concept supported in the revise condition (e.g., 'violin'). ERPs indicated that both working memory groups were able to evaluate their comprehension of the text (P3a), but only high working memory readers were able to revise their initial incorrect interpretation (P3b) and integrate the new information (N400) when reading the revise sentence. Low working memory readers had difficulties inhibiting the no-longer-relevant interpretation and thus failed to revise their situation model, and they experienced problems integrating semantically related information into an accurate memory representation. PMID- 26047777 TI - A mixture approach to investigate interstitial growth in engineering scaffolds. AB - Controlling biological growth within a cell-laden polymeric scaffold is a critical challenge in the tissue engineering community. Indeed, construct growth must often be balanced with scaffold degradation and is often coupled to varying degrees of deformation that originate from swelling, external forces and the effects of confinement. These factors have been shown to affect growth in many ways, but to date, our understanding is mostly qualitative. While cell sensing, molecular transport and scaffold/tissue interactions are believed to be important players, it will be critical to quantify, predict and control these effects in order to eventually optimize tissue growth in the laboratory. The aim of this paper was thus to provide a theoretical framework to better understand how the scaffold-mediated mechanisms of transport, deposition (and possibly degradation) and elasticity affect the overall growth of a tissue subjected to finite deformations. We propose a formulation in which the macroscopic evolutions in tissue size, density as well as the appearance of residual stresses can be directly related to changes in internal composition by considering three fundamental principles: mechanical equilibrium, chemical equilibrium and molecular incompressibility. The resulting model allows us to pay particular attention to features that are critical to the interaction between growth and deformation: osmotic pressure and swelling, the strain mismatch between old and newly deposited material as well as the mechano-sensitive cell-mediated production. We show that all of these phenomena may indeed strongly affect the overall growth of a construct under finite deformations. PMID- 26047780 TI - Beta adrenergic modulation of spontaneous microcontractions and electrical field stimulated contractions in isolated strips of rat urinary bladder from normal animals and animals with partial bladder outflow obstruction. AB - Spontaneous microcontractions and electrical field stimulation (EFS)-evoked contractions in isolated rat bladder strips from normal and from 6 weeks partial bladder outflow obstruction (pBOO) animals were studied to identify the potential site of action for the beta3-adrenoceptor (AR) agonist mirabegron in detrusor overactivity in rats. For this, effects of the beta-AR agonist isoprenaline and mirabegron were tested in presence or absence of selective antagonists for beta AR subtypes, namely CGP-20712A for beta1-AR, ICI-118,551 for beta2-AR, and L 748,337 for beta3-AR. In detrusor strips from both normal and obstructed animals, EFS-induced contractions were weakly affected by isoprenaline and even less so by mirabegron. In contrast, microcontraction activity was more potently reduced by isoprenaline (pIC50 7.3; Emax +/-85 %), whereas mirabegron showed a small effect. In pBOO strips, concentration response curves for isoprenaline and mirabegron at inhibition of EFS and spontaneous microcontractions were similar to those in normal strips. Isoprenaline-induced inhibition of microcontractions and EFS was antagonized by the beta1-AR antagonist, but not by the beta2- and beta3-AR antagonists. In the context of beta3-AR-mediated bladder functions for mirabegron in other experiments, the current data question a role for effects at spontaneous microcontractions, or neurogenic detrusor stimulation in the mode of action for mirabegron in vivo, since functional bladder effects for mirabegron are reported to occur at much lower concentrations. PMID- 26047782 TI - MRI in axial spondyloarthritis: From light to shadow? PMID- 26047781 TI - Gunshot-induced fractures of the extremities: a review of antibiotic and debridement practices. AB - The use of antibiotic prophylaxis and debridement is controversial when treating low- and high-velocity gunshot-induced fractures, and established treatment guidelines are currently unavailable. The purpose of this review was to evaluate the literature for the prophylactic antibiotic and debridement policies for (1) low-velocity gunshot fractures of the extremities, joints, and pelvis and (2) high-velocity gunshot fractures of the extremities. Low-velocity gunshot fractures of the extremities were subcategorized into operative and non-operative cases, whereas low-velocity gunshot fractures of the joints and pelvis were evaluated based on the presence or absence of concomitant bowel injury. In the absence of surgical necessity for fracture care such as concomitant absence of gross wound contamination, vascular injury, large soft-tissue defect, or associated compartment syndrome, the literature suggests that superficial debridement for low-velocity ballistic fractures with administration of antibiotics is a satisfactory alternative to extensive operative irrigation and debridement. In operative cases or those involving bowel injuries secondary to pelvic fractures, the literature provides support for and against extensive debridement but does suggest the use of intravenous antibiotics. For high velocity ballistic injuries, the literature points towards the practice of extensive immediate debridement with prophylactic intravenous antibiotics. Our systematic review demonstrates weak evidence for superficial debridement of low velocity ballistic fractures, extensive debridement for high-velocity ballistic injuries, and antibiotic use for both types of injury. Intra-articular fractures seem to warrant debridement, while pelvic fractures with bowel injury have conflicting evidence for debridement but stronger evidence for antibiotic use. Given a relatively low number of studies on this subject, we recommend that further high-quality research on the debridement and antibiotic use for gunshot induced fractures of the extremities should be conducted before definitive recommendations and guidelines are developed. PMID- 26047779 TI - Development of Rous sarcoma Virus-like Particles Displaying hCC49 scFv for Specific Targeted Drug Delivery to Human Colon Carcinoma Cells. AB - PURPOSE: Virus-like particles (VLPs) have been used as drug carriers for drug delivery systems. In this study, hCC49 single chain fragment variable (scFv) displaying Rous sarcoma virus-like particles (RSV VLPs) were produced in silkworm larvae to be a specific carrier of an anti-cancer drug. METHOD: RSV VLPs displaying hCC49 scFv were created by the fusion of the transmembrane and cytoplasmic domains of hemagglutinin from influenza A (H1N1) virus and produced in silkworm larvae. The display of hCC49 scFv on the surface of RSV VLPs was confirmed by enzyme-linked immunosorbent assay using tumor-associated glycoprotein-72 (TAG-72), fluorescent microscopy, and immunoelectron microscopy. Fluorescein isothiocyanate (FITC) or doxorubicin (DOX) was incorporated into hCC49 scFv-displaying RSV VLPs by electroporation and specific targeting of these VLPs was investigated by fluorescent microscopy and cytotoxicity assay using LS174T cells. RESULTS: FITC was delivered to LS174T human colon adenocarcinoma cells by hCC49 scFv-displaying RSV VLPs, but not by RSV VLPs. This indicated that hCC49 scFv allowed FITC-loaded RSV VLPs to be delivered to LS174T cells. DOX, which is an anti-cancer drug with intrinsic red fluorescence, was also loaded into hCC49 scFv-displaying RSV VLPs by electroporation; the DOX-loaded hCC49 scFv displaying RSV VLPs killed LS174T cells via the specific delivery of DOX that was mediated by hCC49 scFv. HEK293 cells were alive even though in the presence of DOX-loaded hCC49 scFv-displaying RSV VLPs. CONCLUSION: These results showed that hCC49 scFv-displaying RSV VLPs from silkworm larvae offered specific drug delivery to colon carcinoma cells in vitro. This scFv-displaying enveloped VLP system could be applied to drug and gene delivery to other target cells. PMID- 26047783 TI - Evolution of the profile of patients hospitalized for gout in a tertiary rheumatology unit. PMID- 26047784 TI - Include patient education in daily practice: Promoting the patient-centered care approach. PMID- 26047785 TI - MRI aspect of intradural extramedullary lipoma. PMID- 26047786 TI - Deciphering the underlying mechanisms of oxidation-state dependent cytotoxicity of graphene oxide on mammalian cells. AB - The promising broad applications of graphene oxide (GO) derivatives in biomedicine have raised concerns about their safety on biological organisms. However, correlations between the physicochemical properties, especially oxidation degree of GOs and their toxicity, and the underlying mechanisms are not well understood. Herein, we evaluated the cytotoxicity of three GO samples with various oxidation degrees on mouse embryo fibroblasts (MEFs). Three samples can be internalized by MEFs observed via transmission electron microscopy (TEM), and were well tolerant by MEFs at lower doses (below 25MUg/ml) but significantly toxic at 50 and 100MUg/ml via Cytell Imaging System. More importantly, as the oxidation degree decreased, GO derivatives led to a higher degree of cytotoxicity and apoptosis. Meanwhile, three GOs stimulated dramatic enhancement in reactive oxygen species (ROS) production in MEFs, where the less oxidized GO produced a higher level of ROS, suggesting the major role of oxidative stress in the oxidation-degree dependent toxicity of GOs. Results from electron spin resonance (ESR) spectrometry showed a strong association of the lower oxidation degree of GOs with their stronger indirect oxidative damage through facilitating H2O2 decomposition into OH and higher direct oxidative abilities on cells. The theoretical simulation revealed the key contributions of carboxyl groups and aromatic domain size of nanosheets to varying the energy barrier of H2O2 decomposition reaction. These systematic explorations in the chemical mechanisms unravel the key physicochemical properties that would lead to the diverse toxic profiles of the GO nanosheets with different oxygenation levels, and offer us new clues in the molecular design of carbon nanomaterials for their safe applications in biomedicine. PMID- 26047787 TI - Particulate matter (PM10) induces metalloprotease activity and invasion in airway epithelial cells. AB - Airborne particulate matter with an aerodynamic diameter <= 10 MUm (PM10) is a risk factor for the development of lung diseases and cancer. The aim of this work was to identify alterations in airway epithelial (A549) cells induced by PM10 that could explain how subtoxic exposure (10 MUg/cm(2)) promotes a more aggressive in vitro phenotype. Our results showed that cells exposed to PM10 from an industrial zone (IZ) and an urban commercial zone (CZ) induced an increase in protease activity and invasiveness; however, the cell mechanism is different, as only PM10 from CZ up-regulated the activity of metalloproteases MMP-2 and MMP-9 and disrupted E-cadherin/beta-catenin expression after 48 h of exposure. These in vitro findings are relevant in terms of the mechanism action of PM10 in lung epithelial cells, which could be helpful in understanding the pathogenesis of some human illness associated with highly polluted cities. PMID- 26047788 TI - Urine Metabolite Profiles Predictive of Human Kidney Allograft Status. AB - Noninvasive diagnosis and prognostication of acute cellular rejection in the kidney allograft may help realize the full benefits of kidney transplantation. To investigate whether urine metabolites predict kidney allograft status, we determined levels of 749 metabolites in 1516 urine samples from 241 kidney graft recipients enrolled in the prospective multicenter Clinical Trials in Organ Transplantation-04 study. A metabolite signature of the ratio of 3-sialyllactose to xanthosine in biopsy specimen-matched urine supernatants best discriminated acute cellular rejection biopsy specimens from specimens without rejection. For clinical application, we developed a high-throughput mass spectrometry-based assay that enabled absolute and rapid quantification of the 3-sialyllactose-to xanthosine ratio in urine samples. A composite signature of ratios of 3 sialyllactose to xanthosine and quinolinate to X-16397 and our previously reported urinary cell mRNA signature of 18S ribosomal RNA, CD3epsilon mRNA, and interferon-inducible protein-10 mRNA outperformed the metabolite signatures and the mRNA signature. The area under the receiver operating characteristics curve for the composite metabolite-mRNA signature was 0.93, and the signature was diagnostic of acute cellular rejection with a specificity of 84% and a sensitivity of 90%. The composite signature, developed using solely biopsy specimen-matched urine samples, predicted future acute cellular rejection when applied to pristine samples taken days to weeks before biopsy. We conclude that metabolite profiling of urine offers a noninvasive means of diagnosing and prognosticating acute cellular rejection in the human kidney allograft, and that the combined metabolite and mRNA signature is diagnostic and prognostic of acute cellular rejection with very high accuracy. PMID- 26047789 TI - Efficacy of Targeted Complement Inhibition in Experimental C3 Glomerulopathy. AB - C3 glomerulopathy refers to renal disorders characterized by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which includes functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of a recombinant mouse protein composed of domains from complement receptor 2 (CR2) and FH (CR2-FH) in two models of C3 glomerulopathy with either preexisting or triggered C3 deposition along the GBM. FH-deficient mice spontaneously develop renal pathology associated with abnormal C3 accumulation along the GBM and secondary plasma C3 deficiency. CR2-FH partially restored plasma C3 levels in FH-deficient mice 2 hours after intravenous injection. CR2-FH specifically targeted glomerular C3 deposits, reduced the linear C3 reactivity assessed with anti-C3 and anti-C3b/iC3b/C3c antibodies, and prevented further spontaneous accumulation of C3 fragments along the GBM. Reduction in glomerular C3d and C9/C5b-9 reactivity was observed after daily administration of CR2-FH for 1 week. In a second mouse model with combined deficiency of FH and complement factor I, CR2-FH prevented de novo C3 deposition along the GBM. These data show that CR2-FH protects the GBM from both spontaneous and triggered C3 deposition in vivo and indicate that this approach should be tested in C3 glomerulopathy. PMID- 26047790 TI - Renal Clearance of Mineral Metabolism Biomarkers. AB - CKD leads to disturbances in multiple interrelated hormones that regulate bone and mineral metabolism. The renal handling of mineral metabolism hormones in humans is incompletely understood. We determined the single-pass renal clearance of parathyroid hormone, fibroblast growth factor 23, vitamin D metabolites, and phosphate from paired blood samples collected from the abdominal aorta and renal vein in 17 participants undergoing simultaneous right and left heart catheterization and estimated associations of eGFR with the renal elimination of metabolites. The mean age +/-SD of the study population was 71.4+/-10.0 years and 11 participants (65%) were male. We found a relatively large mean+/-SD single pass renal extraction of parathyroid hormone (44.2%+/-10.3%) that exceeded the extraction of creatinine (22.1%+/-7.9%). The proportionate renal extraction of parathyroid hormone correlated with eGFR. The renal extraction of fibroblast growth factor 23 was, on average, lower than that of parathyroid hormone with greater variability across individuals (17.1%+/-19.5%). There were no differences in the mean concentrations of vitamin D metabolites across the renal vein and artery. In summary, we demonstrate substantial single-pass renal extraction of parathyroid hormone at a rate that exceeds glomerular filtration. Impaired renal clearance of parathyroid hormone may contribute to secondary hyperparathyroidism in CKD. PMID- 26047792 TI - Myeloperoxidase Peptide-Based Nasal Tolerance in Experimental ANCA-Associated GN. AB - Less toxic treatment options for patients with myeloperoxidase (MPO)-ANCA associated GN are needed. Using an established murine model of focal necrotizing GN mediated by autoimmunity to MPO (autoimmune anti-MPO GN), we assessed the capacity for nasal tolerance induced by nasal insufflation of the immunodominant nephritogenic MPO peptide (MPO409-428) to attenuate this disease. Compared with mice that received an irrelevant immunodominant ovalbumin (OVA) peptide, OVA323 339, mice that received MPO409-428 were protected from the development of humoral and cell-mediated autoimmunity to full-length MPO and the development of GN. In mice with established anti-MPO autoimmunity, nasal insufflation of MPO409-428 as a therapeutic attenuated anti-MPO GN. To investigate the nature of this induced tolerance, we isolated CD4(+) T cells from the upper airway draining lymph nodes of both OVA323-339- and MPO409-428-tolerized mice. Adoptive transfer of CD4(+) T cells from MPO409-428- but not OVA323-339-tolerized mice to animals with established anti-MPO autoimmunity attenuated the subsequent development of GN, confirming that the immunosuppression induced by these T cells is antigen specific. Ex vivo studies showed that nasal tolerance to MPO is mediated by both conventional and induced T regulatory cells. The strong homology between the pathogenic human MPO B cell epitope recognized by ANCA in patients with acute vasculitis and the nephritogenic murine T cell MPO epitope emphasizes the clinical relevance of this study. PMID- 26047791 TI - N-Acetyl-beta-D-Glucosaminidase Does Not Enhance Prediction of Cardiovascular or All-Cause Mortality by Albuminuria in a Low-Risk Population. AB - Albuminuria is a well known risk factor for cardiovascular disease and mortality, but focus on renal tubular dysfunction as a potential risk factor is growing also. The association between the urinary activity of N-acetyl-beta-D glucosaminidase (NAG) and cardiovascular risk has been assessed mostly in cross sectional studies. We studied the cross-sectional associations between urinary NAG and cardiovascular risk factors and the longitudinal associations between NAG, cardiovascular disease, and all-cause mortality in a general population. Urinary NAG/creatinine ratio (NAG ratio) and albumin/creatinine ratio (ACR) were measured in 6834 participants of the Tromso Study in 1994-1995. During the median 17.5 years of follow-up, 958 myocardial infarctions, 726 ischemic strokes, and 2358 deaths were registered. In multivariable analyses adjusted for albuminuria and cardiovascular risk factors, a baseline NAG ratio in the highest quartile was associated with an increased risk of myocardial infarction (hazard ratio [HR], 1.43; 95% confidence interval [95% CI], 1.16 to 1.76), ischemic stroke (HR, 1.41; 95% CI, 1.10 to 1.80), and all-cause mortality (HR, 1.60; 95% CI, 1.39 to 1.84). Combined, ACR and NAG ratio above median associated with a 48%-80% increased risk for the three end points. However, the NAG ratio did not add significantly to the baseline risk-prediction models when assessed by area under the receiver operating characteristics curve or net reclassification improvement. In conclusion, the nonsignificant improvement of risk prediction does not support the clinical use of NAG ratio in cardiovascular risk assessment in a low-risk group. PMID- 26047793 TI - Non-Complement-Binding De Novo Donor-Specific Anti-HLA Antibodies and Kidney Allograft Survival. AB - C1q-binding ability may indicate the clinical relevance of de novo donor-specific anti-HLA antibodies (DSA). This study investigated the incidence and risk factors for the appearance of C1q-binding de novo DSA and their long-term impact. Using Luminex Single Antigen Flow Bead assays, 346 pretransplant nonsensitized kidney recipients were screened at 2 and 5 years after transplantation for de novo DSA, which was followed when positive by a C1q Luminex assay. At 2 and 5 years, 12 (3.5%) and eight (2.5%) patients, respectively, had C1q-binding de novo DSA. De novo DSA mean fluorescence intensity >6237 and >10,000 at 2 and 5 years, respectively, predicted C1q binding. HLA mismatches and cyclosporine A were independently associated with increased risk of C1q-binding de novo DSA. When de novo DSA were analyzed at 2 years, the 5-year death-censored graft survival was similar between patients with C1q-nonbinding de novo DSA and those without de novo DSA, but was lower for patients with C1q-binding de novo DSA (P=0.003). When de novo DSA were analyzed at 2 and 5 years, the 10-year death-censored graft survival was lower for patients with C1q-nonbinding de novo DSA detected at both 2 and 5 years (P<0.001) and for patients with C1q-binding de novo DSA (P=0.002) than for patients without de novo DSA. These results were partially confirmed in two validation cohorts. In conclusion, C1q-binding de novo DSA are associated with graft loss occurring quickly after their appearance. However, the long-term persistence of C1q-nonbinding de novo DSA could lead to lower graft survival. PMID- 26047796 TI - Current and next generation influenza vaccines: Formulation and production strategies. AB - Vaccination is the most effective method to prevent influenza infection. However, current influenza vaccines have several limitations. Relatively long production times, limited vaccine capacity, moderate efficacy in certain populations and lack of cross-reactivity are important issues that need to be addressed. We give an overview of the current status and novel developments in the landscape of influenza vaccines from an interdisciplinary point of view. The feasibility of novel vaccine concepts not only depends on immunological or clinical outcomes, but also depends on biotechnological aspects, such as formulation and production methods, which are frequently overlooked. Furthermore, the next generation of influenza vaccines is addressed, which hopefully will bring cross-reactive influenza vaccines. These developments indicate that an exciting future lies ahead in the influenza vaccine field. PMID- 26047795 TI - LDL Receptor-Related Protein 6 Modulates Ret Proto-Oncogene Signaling in Renal Development and Cystic Dysplasia. AB - Hypoplastic and/or cystic kidneys have been found in both LDL receptor-related protein 6 (Lrp6)- and beta-catenin-mutant mouse embryos, and these proteins are key molecules for Wnt signaling. However, the underlying mechanisms of Lrp6/beta catenin signaling in renal development and cystic formation remain poorly understood. In this study, we found evidence that diminished cell proliferation and increased apoptosis occur before cystic dysplasia in the renal primordia of Lrp6-deficient mouse embryos. The expression of Ret proto-oncogene (Ret), a critical receptor for the growth factor glial cell line-derived neurotrophic factor (GDNF), which is required for early nephrogenesis, was dramatically diminished in the mutant renal primordia. The activities of other representative nephrogenic genes, including Lim1, Pax2, Pax8, GDNF, and Wnt11, were subsequently diminished in the mutant renal primordia. Molecular biology experiments demonstrated that Ret is a novel transcriptional target of Wnt/beta-catenin signaling. Wnt agonist lithium promoted Ret expression in vitro and in vivo. Furthermore, Lrp6-knockdown or lithium treatment in vitro led to downregulation or upregulation, respectively, of the phosphorylated mitogen-activated protein kinases 1 and 3, which act downstream of GDNF/Ret signaling. Mice with single and double mutations of Lrp6 and Ret were perinatal lethal and demonstrated gene dosage-dependent effects on the severity of renal hypoplasia during embryogenesis. Taken together, these results suggest that Lrp6-mediated Wnt/beta catenin signaling modulates or interacts with a signaling network consisting of Ret cascades and related nephrogenic factors for renal development, and the disruption of these genes or signaling activities may cause a spectrum of hypoplastic and cystic kidney disorders. PMID- 26047797 TI - Mechanistic analysis of PLGA/HPMC-based in-situ forming implants for periodontitis treatment. AB - In-situ forming implant formulations based on poly(lactic-co-glycolic acid) (PLGA), acetyltributyl citrate (ATBC), minocycline HCl, N-methyl pyrrolidone (NMP) and optionally hydroxypropyl methylcellulose (HPMC) were prepared and thoroughly characterized in vitro. This includes electron paramagnetic resonance (EPR), nuclear magnetic resonance ((1)H NMR), mass change and drug release measurements under different conditions, optical microscopy, size exclusion chromatography (SEC) as well as antibacterial activity tests using gingival crevicular fluid samples from periodontal pockets of periodontitis patients. Based on these results, deeper insight into the physico-chemical phenomena involved in implant formation and the control of drug release could be gained. For instance, the effects of adding HPMC to the formulations, resulting in improved implant adherence and reduced swelling, could be explained. Importantly, the in-situ formed implants effectively hindered the growth of bacteria present in the patients' periodontal pockets. Interestingly, the systems were more effectively hindering the growth of pathogenic bacterial strains (e.g., Fusobacterium nucleatum) than that of strains with a lower pathogenic potential (e.g., Streptococcus salivarius). In vivo, such a preferential action against the pathogenic bacteria can be expected to give a chance to the healthy flora to re colonize the periodontal pockets. PMID- 26047794 TI - Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia. AB - Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24 hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24 hydroxylase) defects appears critical for targeted therapy in patients with IIH. PMID- 26047798 TI - Intimate partner violence education for medical students in the USA, Vietnam and China. AB - OBJECTIVES: While intimate partner violence (IPV) is a global concern for women's health, there are few comparative studies of IPV training in medical schools. The aim of this study was to investigate medical students' knowledge of, and training in, IPV in the USA, Vietnam and China. STUDY DESIGN: Cross-national, cross sectional study. METHODS: US (n = 60), Vietnamese (n = 232) and Chinese (n = 174) medical students participated in a cross-sectional self-administered survey that included demographic characteristics; opinions, training and knowledge regarding IPV against women; and personal experience with IPV victims. RESULTS: Attitudes, knowledge and training about IPV among medical students varied between the three countries. US participants reported higher levels of knowledge of IPV, were more likely to believe that IPV was a serious problem, and were more likely to consider IPV to be a healthcare problem compared with Vietnamese and Chinese participants. Chinese participants, in particular, did not appear to appreciate the importance of addressing IPV. Differences were found between the Vietnamese and Chinese students. CONCLUSIONS: While most medical schools in the USA include IPV training within their core medical curricula, education throughout medical school seems to be necessary to improve medical education regarding treatment of patients with a history of IPV. Vietnamese and Chinese medical schools should consider including IPV education in the training of their future physicians to improve the health of women who have experienced IPV. Practical opportunities for medical students to interact with women who have experienced IPV are essential to develop effective IPV education. PMID- 26047799 TI - Fracture resistance of compromised endodontically treated teeth restored with bonded post and cores: An in vitro study. AB - STATEMENT OF PROBLEM: It is unclear which post and core system performs best when bonded to severely compromised endodontically treated teeth. PURPOSE: The purpose of this study was to investigate the fracture resistance and mode of failure of severely compromised teeth restored with 3 different adhesively bonded post and core systems. MATERIAL AND METHODS: Thirty extracted endodontically treated maxillary anterior teeth were randomly divided into 3 groups, CPC, gold cast post and core; TPC, titanium prefabricated post/composite resin core; and FPC, quartz fiber reinforced post/composite resin core. All posts were adhesively cemented. All cores resembled a central incisor preparation with no remaining tooth structure above the finish line. Cast gold crowns were fabricated and cemented adhesively. The specimens were aged with thermocycling and cyclic loading. Two specimens per group were randomly selected for micro-computed tomographic imaging before and after aging. Failure was induced with a universal testing machine. The mode of failure was characterized by the interface separation. Data were analyzed with 1-way ANOVA (alpha=.05) followed by post hoc tests (Bonferroni). RESULTS: A statistically significant difference was found among the 3 groups (P=.002). CPC was significantly different than TPC (P=.008) or FPC (P=.003). The primary mode of failure for CPC and TPC was root fracture, and for FPC post debonding. CONCLUSIONS: Severely compromised endodontically treated teeth restored with bonded gold cast post and cores showed significantly higher fracture resistance. PMID- 26047800 TI - Digital versus analog complete-arch impressions for single-unit premolar implant crowns: Operating time and patient preference. AB - STATEMENT OF PROBLEM: Digital impression-making techniques are supposedly more patient friendly and less time-consuming than analog techniques, but evidence is lacking to substantiate this assumption. PURPOSE: The purpose of this in vivo within-subject comparison study was to examine patient perception and time consumption for 2 complete-arch impression-making methods: a digital and an analog technique. MATERIAL AND METHODS: Fifty participants with a single missing premolar were included. Treatment consisted of implant therapy. Three months after implant placement, complete-arch digital (Cerec Omnicam; Sirona) and analog impressions (semi-individual tray, Impregum; 3M ESPE) were made, and the participant's opinion was evaluated with a standard questionnaire addressing several domains (inconvenience, shortness of breath, fear of repeating the impression, and feelings of helplessness during the procedure) with the visual analog scale. All participants were asked which procedure they preferred. Operating time was measured with a stopwatch. The differences between impressions made for maxillary and mandibular implants were also compared. The data were analyzed with paired and independent sample t tests, and effect sizes were calculated. RESULTS: Statistically significant differences were found in favor of the digital procedure regarding all subjective domains (P<.001), with medium to large effect sizes. Of all the participants, over 80% preferred the digital procedure to the analog procedure. The mean duration of digital impression making was 6 minutes and 39 seconds (SD=1:51) versus 12 minutes and 13 seconds (SD=1:24) for the analog impression (P<.001, effect size=2.7). CONCLUSIONS: Digital impression making for the restoration of a single implant crown takes less time than analog impression making. Furthermore, participants preferred the digital scan and reported less inconvenience, less shortness of breath, less fear of repeating the impression, and fewer feelings of helplessness during the procedure. PMID- 26047801 TI - Alternative technique for handling indirect restorations during evaluation and cementation. PMID- 26047802 TI - Cost-effective, expedient, and time-saving surface texturing technique for facial prostheses. AB - This article describes a cost-effective, expedient, and time-saving technique for surface texturing a facial prosthesis with fine sand mixed in resin adhesive glue. PMID- 26047803 TI - Crestal bone loss and periimplant inflammatory parameters around zirconia implants: A systematic review. AB - STATEMENT OF PROBLEM: Zirconia implants have been used for oral rehabilitation; however, evidence of their ability to maintain crestal bone and periimplant soft tissue health is not clear. PURPOSE: The purpose of this systematic review was to evaluate crestal bone loss (CBL) around zirconia dental implants and clinical periimplant inflammatory parameters. MATERIAL AND METHODS: The focus question addressed was, "Do zirconia implants maintain crestal bone levels and periimplant soft tissue health?" Databases were searched for articles from 1977 through September 2014 with different combinations of the following MeSH terms: "dental implants," "zirconium," "alveolar bone loss," "periodontal attachment loss," "periodontal pocket," "periodontal index." Letters to the editor, case reports, commentaries, review articles, and articles published in languages other than English were excluded. RESULTS: Thirteen clinical studies were included. In 8 of the studies, the CBL around zirconia implants was comparable between baseline and follow-up. In the other 5 studies, the CBL around zirconia implants was significantly higher at follow-up. Among the studies that used titanium implants as controls, 2 studies showed significantly higher CBL around zirconia implants, and in 1 study, the CBL around zirconia and titanium implants was comparable. The reported implant survival rates for zirconia implants ranged between 67.6% and 100%. Eleven studies selectively reported the periimplant inflammatory parameters. CONCLUSIONS: Because of the variations in study design and methodology, it was difficult to reach a consensus regarding the efficacy of zirconia implants in maintaining crestal bone levels and periimplant soft tissue health. PMID- 26047804 TI - Color-to-grayscale conversion using a smart phone camera for value comparison. PMID- 26047805 TI - Cone-beam tomography assessment of the condylar position in asymptomatic and symptomatic young individuals. AB - STATEMENT OF PROBLEM: Studies of the condyle-mandibular fossa relationship are common, although the role of this relationship in the development of a temporomandibular disorder remains controversial. PURPOSE: The purpose of this study was to quantitatively evaluate the condyle-mandibular fossa relationship in young individuals with intact dentitions and compare it to that between individuals with and without symptoms of temporomandibular disorder. MATERIAL AND METHODS: Volunteers were classified as asymptomatic (n=20) or symptomatic (n=20) according to research diagnostic criteria for temporomandibular disorders. Each participant underwent 2 cone beam-computed tomography scans of the middle and lower third of the face: 1 scan of the maximum intercuspation position and 1 of the centric relationship position. The distance between the condyle and mandibular fossa was measured on frontal and lateral images of the temporomandibular joint. The condylar position was compared across groups (asymptomatic, symptomatic) by using the Mann-Whitney U test (alpha=.05). Within each group, the condylar position was compared across maximum intercuspation and centric relationship positions by using the Mann-Whitney U test (alpha=.05). RESULTS: No statistically significant differences were found in condylar positions between centric relationships and maximum intercuspation in either asymptomatic or symptomatic young adults, and no significant differences were found between asymptomatic and symptomatic young adults. CONCLUSIONS: The condyle mandibular fossa relationships of these young adults were similar in the centric relationships and maximum intercuspation positions when evaluated by computed tomography. The presence or absence of temporomandibular disorder was not correlated with the condyle position in the temporomandibular joint. PMID- 26047806 TI - Effect of a zirconia primer on the push-out bond strength of zirconia ceramic posts to root canal dentin. AB - STATEMENT OF PROBLEM: The retention of zirconia ceramic posts to root canal dentin with resin-based luting cements is relatively poor. PURPOSE: The purpose of this in vitro study was to evaluate the effect of a new zirconia primer, a mixture of organophosphate and carboxylic acid monomers, on the push-out bond strength of zirconia posts to root canal dentin. MATERIAL AND METHODS: The root canals of 40 extracted human maxillary central incisors were endodontically treated and the post spaces were prepared. Zirconia posts were luted with 2 different resin luting agents (Panavia F and Clearfil SA luting cements) with and without the zirconia primer (Z-Prime Plus; Bisco). Three segments, each 2 mm high, were cut perpendicular to the post from each root. Bond strength was determined by pushing out the post with a universal testing machine. Three-way ANOVA and the Tukey HSD test was used to assess the effects of the zirconia primer, the 2 different resin luting cements, and different thirds of the root canal (alpha=.05). RESULTS: The zirconia primer significantly increased the push out bond strength of zirconia posts to root canal dentin. Clearfil SA luting cement provided significantly higher bond strength than did Panavia F. For all experimental groups combined, bond strength decreased from the coronal to the apical section. CONCLUSIONS: A zirconia primer based on organophosphate/carboxylic acid monomers increased the bond strength of zirconia posts to root canal dentin bonded with both resin luting cements. PMID- 26047807 TI - Scalable microfluidics for single-cell RNA printing and sequencing. AB - Many important biological questions demand single-cell transcriptomics on a large scale. Hence, new tools are urgently needed for efficient, inexpensive manipulation of RNA from individual cells. We report a simple platform for trapping single-cell lysates in sealed, picoliter microwells capable of printing RNA on glass or capturing RNA on beads. We then develop a scalable technology for genome-wide, single-cell RNA-Seq. Our device generates pooled libraries from hundreds of individual cells with consumable costs of $0.10-$0.20 per cell and includes five lanes for simultaneous experiments. We anticipate that this system will serve as a general platform for single-cell imaging and sequencing. PMID- 26047808 TI - An exploratory randomised controlled trial of a web-based integrated bipolar parenting intervention (IBPI) for bipolar parents of young children (aged 3-10). AB - BACKGROUND: Communication, impulse control and motivation can all be affected by Bipolar Disorder (BD) making consistent parenting more difficult than for parents without mental health problems. Children of parents with BD (CPB) are at significantly increased risk of a range of mental health issues including Attention Deficit Hyperactivity Disorder (ADHD), anxiety, depression, substance use, and sleep disorders. Furthermore, CPB are also at elevated risk for BD compared to the general population. This paper describes the rationale and protocol for a pilot randomised controlled trial (RCT) designed to assess the feasibility and acceptability of a new online intervention providing interactive psychoeducational information and parenting support for parents with BD. METHODS AND DESIGN: This article describes a single-blind randomised controlled trial comparing an Integrated Bipolar Parenting Intervention (IBPI) in addition to treatment as usual (TAU) with TAU alone. Participants will be recruited from across the UK from mental health services and through self-referral. The primary outcome of the study is the feasibility and acceptability of IBPI as indicated by recruitment to target, use of the intervention site, and retention to follow-up. Parents with BD allocated to the IBPI condition will have access to the intervention for 16 weeks. Effect size estimates will be obtained with respect to child behaviour, parenting skills and measures of parental mental health using measures taken at baseline (0), and at 16, 24, 36, and 48 weeks post randomization. DISCUSSION: This is the first randomised controlled trial of an integrated bipolar disorder parenting intervention. The benefits and challenges of delivering this online intervention, and evaluation using online RCT methodology are discussed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN75279027 Registered 12 August 2013. PMID- 26047809 TI - Prognostic significance of c-Met in breast cancer: a meta-analysis of 6010 cases. AB - BACKGROUND: The prognostic value of c-Met in breast cancer remains controversial. A meta-analysis of the impact of c-Met in breast cancer was performed by searching published data. METHODS: Published studies analyzing overall survival (OS) or relapse free survival (RFS) according to c-Met expression were searched. The principal outcome measures were hazard ratios (HRs) for RFS or OS according to c-Met expression. Combined HRs were calculated using fixed- or random- effects models according to the heterogeneity. RESULTS: Twenty-one studies involving 6,010 patients met our selection criteria. The impact of c-Met on RFS and OS was investigated in 12 and 17 studies, respectively. The meta-analysis results showed that c-Met overexpression significantly predicted poor RFS and OS in unselected breast cancer. Subgroup analysis indicated that c-Met overexpression was correlated with poor RFS and OS in Western patients, but was not associated with RFS or OS in Asian patients. C-Met was associated with poor OS in lymph node negative breast cancer and with poor RFS in hormone-receptor positive and triple negative breast cancer, but was not associated with prognosis in human epidermal growth factor receptor (HER)-2 positive breast cancer. CONCLUSIONS: C-Met overexpression is an adverse prognostic marker in breast cancer, except among Asian and HER-2 positive patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1869780799156041. PMID- 26047811 TI - Implementing administrative evidence based practices: lessons from the field in six local health departments across the United States. AB - BACKGROUND: Administrative evidence based practices (A-EBPs) are agency level structures and activities positively associated with performance measures (e.g., achieving core public health functions, carrying out evidence-based interventions). The objectives of this study were to examine the contextual conditions and explore differences in local health department (LHD) characteristics that influence the implementation of A-EBPs. METHODS: Qualitative case studies were conducted based on data from 35 practitioners in six LHDs across the United States. The sample was chosen using an A-EBP score from our 2012 national survey and was linked to secondary data from the National Public Health Performance Standards Program. Three LHDs that scored high and three LHDs that scored low on both measures were selected as case study sites. The 37 question interview guide explored LHD use of an evidence based decision making process, including A-EBPs and evidence-based programs and policies. Each interview took 30-60 min. Standard qualitative methodology was used for data coding and analysis using NVivo software. RESULTS: As might be expected, high capacity LHDs were more likely to have strong leadership, partnerships, financial flexibility, workforce development activities, and an organizational culture supportive of evidence based decision making and implementation of A-EBPs. They were also more likely to describe having strong or important relationships with universities and other educational resources, increasing their access to resources and allowing them to more easily share knowledge and expertise. CONCLUSIONS: Differences between high- and low-capacity LHDs in A-EBP domains highlight the importance of investments in these areas and the potential those investments have to contribute to overall efficiency and performance. Further research may identify avenues to enhance resources in these domains to create an organizational culture supportive of A-EBPs. PMID- 26047810 TI - Using Gene Ontology to describe the role of the neurexin-neuroligin-SHANK complex in human, mouse and rat and its relevance to autism. AB - BACKGROUND: People with an autistic spectrum disorder (ASD) display a variety of characteristic behavioral traits, including impaired social interaction, communication difficulties and repetitive behavior. This complex neurodevelopment disorder is known to be associated with a combination of genetic and environmental factors. Neurexins and neuroligins play a key role in synaptogenesis and neurexin-neuroligin adhesion is one of several processes that have been implicated in autism spectrum disorders. RESULTS: In this report we describe the manual annotation of a selection of gene products known to be associated with autism and/or the neurexin-neuroligin-SHANK complex and demonstrate how a focused annotation approach leads to the creation of more descriptive Gene Ontology (GO) terms, as well as an increase in both the number of gene product annotations and their granularity, thus improving the data available in the GO database. CONCLUSIONS: The manual annotations we describe will impact on the functional analysis of a variety of future autism-relevant datasets. Comprehensive gene annotation is an essential aspect of genomic and proteomic studies, as the quality of gene annotations incorporated into statistical analysis tools affects the effective interpretation of data obtained through genome wide association studies, next generation sequencing, proteomic and transcriptomic datasets. PMID- 26047812 TI - Embolization of the first diagonal branch of the left anterior descending coronary artery as a porcine model of chronic trans-mural myocardial infarction. AB - BACKGROUND: Although the incidence of acute death related to coronary artery disease has decreased with the advent of new interventional therapies, myocardial infarction remains one of the leading causes of death in the US. Current animal models developed to replicate this phenomenon have been associated with unacceptably high morbidity and mortality. A new model utilizing the first diagonal branch of the left anterior descending artery (D1-LAD) was developed to provide a clinically relevant lesion, while attempting to minimize the incidence of adverse complications associated with infarct creation. METHODS: Eight Yucatan miniature pigs underwent percutaneous embolization of the D1-LAD via injection of 90 um polystyrene micro-spheres. Cardiac structure and function were monitored at baseline, immediately post-operatively, and at 8-weeks post-infarct using transthoracic echocardiography. Post-mortem histopathology and biochemical analyses were performed to evaluate for changes in myocardial structure and extracellular matrix (ECM) composition respectively. Echocardiographic data were evaluated using a repeated measures analysis of variance followed by Tukey's HSD post hoc test. Biochemical analyses of infarcted to non-infarcted myocardium were compared using analysis of variance. RESULTS: All eight pigs successfully underwent echocardiography prior to catheterization. Overall procedural survival rate was 83% (5/6) with one pig excluded due to failure of infarction and another due to deviation from protocol. Ejection fraction significantly decreased from 69.7 +/- 7.8% prior to infarction to 50.6 +/- 14.7% immediately post-infarction, and progressed to 48.7 +/- 8.9% after 8-weeks (p = 0.011). Left ventricular diameter in systole significantly increased from 22.6 +/- 3.8 mm pre-operatively to 30.9 +/- 5.0 mm at 8 weeks (p = 0.016). Histopathology showed the presence of disorganized fibrosis on hematoxylin and eosin and Picro Sirius red stains. Collagen I and sulfated glycosaminoglycan content were significantly greater in the infarcted region than in normal myocardium (p = 0.007 and p = 0.018, respectively); however, pyridinoline crosslink content per collagen I content in the infarcted region was significantly less than normal myocardium (p = 0.048). CONCLUSION: Systolic dysfunction and changes in ECM composition induced via embolization of the D1-LAD closely mimic those found in individuals with chronic myocardial infarction (MI), and represents a location visible without the need for anesthesia. As a result, this method represents a useful model for studying chronic MI. PMID- 26047813 TI - Human African trypanosomiasis in the Democratic Republic of the Congo: disease distribution and risk. AB - BACKGROUND: For the past three decades, the Democratic Republic of the Congo (DRC) has been the country reporting the highest number of cases of human African trypanosomiasis (HAT). In 2012, DRC continued to bear the heaviest burden of gambiense HAT, accounting for 84 % of all cases reported at the continental level (i.e., 5,968/7,106). This paper reviews the status of sleeping sickness in DRC between 2000 and 2012, with a focus on spatio-temporal patterns. Epidemiological trends at the national and provincial level are presented. RESULTS: The number of HAT cases reported yearly from DRC decreased by 65 % from 2000 to 2012, i.e., from 16,951 to 5,968. At the provincial level a more complex picture emerges. Whilst HAT control in the Equateur province has had a spectacular impact on the number of cases (97 % reduction), the disease has proved more difficult to tackle in other provinces, most notably in Bandundu and Kasai, where, despite substantial progress, HAT remains entrenched. HAT prevalence presents its highest values in the northern part of the Province Orientale, where a number of constraints hinder surveillance and control. Significant coordinated efforts by the National Sleeping Sickness Control Programme and the World Health Organization in data collection, reporting, management and mapping, culminating in the Atlas of HAT, have enabled HAT distribution and risk in DRC to be known with more accuracy than ever before. Over 18,000 locations of epidemiological interest have been geo-referenced (average accuracy ~ 1.7 km), corresponding to 93.6 % of reported cases (period 2000-2012). The population at risk of contracting sleeping sickness has been calculated for two five-year periods (2003 2007 and 2008-2012), resulting in estimates of 33 and 37 million people respectively. CONCLUSIONS: The progressive decrease in HAT cases reported since 2000 in DRC is likely to reflect a real decline in disease incidence. If this result is to be sustained, and if further progress is to be made towards the goal of HAT elimination, the ongoing integration of HAT control and surveillance into the health system is to be closely monitored and evaluated, and active case finding activities are to be maintained, especially in those areas where the risk of infection remains high and where resurgence could occur. PMID- 26047814 TI - Malaysian endophytic fungal extracts-induced anti-inflammation in Lipopolysaccharide-activated BV-2 microglia is associated with attenuation of NO production and, IL-6 and TNF-alpha expression. AB - BACKGROUND: Excessive production of inflammatory mediators such as nitric oxide (NO) and proinflammatory cytokines like tumour necrosis factor-alpha (TNF-alpha) from activated microglia contributes to uncontrolled inflammation in neurodegenerative diseases. This study investigated the protective role of five endophytic extracts (HAB16R12, HAB16R13, HAB16R14, HAB16R18 and HAB8R24) against LPS-induced inflammatory events in vitro. These endophytic extracts were previously found to exhibit potent neuroprotective effect against LPS-challenged microglial cells. METHODS: The effects of these fungal endophytic extracts against nitric oxide (NO), CD40 phenotype and, pro- and anti-inflammatory cytokine production in lipopolysaccharide (LPS)-stimulated BV2 microglia cells were examined using commercially available assay kits, immunophenotyping and flow cytometry, respectively. RESULTS: Microglia pre-treated with the five endophytic extracts (0.1 mg/mL) reduced NO production without compromising cell viability. Whilst CD40 expression in LPS-stimulated microglia was not significantly different with or without the influence of endophytic extracts, expression of the proinflammatory cytokines, IL-6 and TNF-alpha in LPS-stimulated microglia was significantly (P < 0.05) inhibited by these endophytic extracts. CONCLUSIONS: The outcomes suggest that the neuroprotective effect of the fungal endophytic extracts is likely mediated through supression of neuroinflammation. To our knowledge, this is the first report of the effect of a fungal endophytic extract in controlling inflammation in BV2 microglia cells. PMID- 26047815 TI - Galectin-3 deficiency exacerbates hyperglycemia and the endothelial response to diabetes. AB - BACKGROUND: Diabetes promotes maladaptive changes in the endothelium that lead to its dysfunction and contribute to the vascular pathology of diabetes. We have previously reported the up-regulation of galectin-3, a beta-galactoside-binding lectin, in the endothelium and sera of diabetic mice, implicating this molecule in diabetic vasculopathy and suggesting its potential as a biomarker of the disease. Therefore, we sought to assess the role of galectin-3 in the vascular pathology of diabetes. METHODS: Galectin-3 knockout mice (KO) and wild-type mice (WT) were fed either a high-fat diet (HFD) (60 % fat calories) to produce insulin resistant diabetes, or standard chow (12 % fat calories), and their metabolic and endothelial responses were measured. After 8 weeks, the aortic and skeletal muscle endothelia were isolated by fluorescence sorting of CD105(+)/CD45(-) cells and comprehensive transcriptional analyses were performed. Transcripts differentially dysregulated by HFD in KO endothelium compared to WT were confirmed by semi-quantitative RT-PCR, and protein expression was determined by immunofluorescence of aortic and muscle tissue. Ingenuity(r) Pathway Analysis was used to identify pathways up-regulated by HFD in the KO, such as the coagulation cascade, and measurements of blood clotting activity were performed to confirm these results. RESULTS: KO mice demonstrate greater hyperglycemia and impaired glucose tolerance but lower insulin levels on HFD compared to WT. KO mice demonstrate a more robust transcriptional response to HFD in the vascular endothelium compared to WT. Transcripts dysregulated in the KO endothelium after HFD are involved in glucose uptake and insulin signaling, vasoregulation, coagulation, and atherogenesis. One of the most down-regulated transcripts in the endothelium of the KO after HFD was the glucose transporter, Glut4/Slc2a4. GLUT4 immunofluorescence confirmed lower protein abundance in the endothelium and muscle of the HFD-fed KO. Prothrombin time was decreased in the diabetic KO indicating increased coagulation activity. CONCLUSIONS: Galectin-3 deficiency leads to exacerbated metabolic derangement and endothelial dysfunction. The impaired tissue uptake of glucose in KO mice can be attributed to the reduced expression of GLUT4. Enhanced coagulation activity in the diabetic KO suggests a protective role for galectin-3 against thrombosis. These studies demonstrate that galectin-3 deficiency contributes both to the pathogenesis of diabetes and the associated vasculopathy. PMID- 26047816 TI - Clarithromycin and dexamethasone show similar anti-inflammatory effects on distinct phenotypic chronic rhinosinusitis: an explant model study. AB - BACKGROUND: Phenotype of chronic rhinosinusitis (CRS) may be an important determining factor of the efficacy of anti-inflammatory treatments. Although both glucocorticoids and macrolide antibiotics have been recommended for the treatment of CRS, whether they have different anti-inflammatory functions for distinct phenotypic CRS has not been completely understood. The aim of this study is to compare the anti-inflammatory effects of clarithromycin and dexamethasone on sinonasal mucosal explants from different phenotypic CRS ex vivo. METHODS: Ethmoid mucosal tissues from CRSsNP patients (n = 15), and polyp tissues from eosinophilic (n = 13) and non-eosinophilic (n = 12) CRSwNP patients were cultured in an ex vivo explant model with or without dexamethasone or clarithromycin treatment for 24 h. After culture, the production and/or expression of anti inflammatory molecules, epithelial-derived cytokines, pro-inflammatory cytokines, T helper (Th)1, Th2 and Th17 cytokines, chemokines, dendritic cell relevant markers, pattern recognition receptors (PRRs), and tissue remodeling factors were detected in tissue explants or culture supernatants by RT-PCR or ELISA, respectively. RESULTS: We found that both clarithromycin and dexamethasone up regulated the production of anti-inflammatory mediators (Clara cell 10-kDa protein and interleukin (IL)-10), whereas down-regulated the production of Th2 response and eosinophilia promoting molecules (thymic stromal lymphopoietin, IL 25, IL-33, CD80, CD86, OX40 ligand, programmed cell death ligand 1, CCL17, CCL22, CCL11, CCL5, IL-5, IL-13, and eosinophilic cationic protein) and Th1 response and neutrophilia promoting molecules (CXCL8, CXCL5, CXCL10, CXCL9, interferon-gamma, and IL-12), from sinonasal mucosa from distinct phenotypic CRS. In contrast, they had no effect on IL-17A production. The expression of PRRs (Toll-like receptors and melanoma differentiation-associated gene 5) was induced, and the production of tissue remodeling factors (transforming growth factor-beta1, epidermal growth factor, basic fibroblast growth factor, platelet derived growth factor, vascular endothelial growth factor, and matrix metalloproteinase 9) was suppressed, in different phenotypic CRS by dexamethasone and clarithromycin in comparable extent. CONCLUSIONS: Out of our expectation, our explant model study discovered herein that glucocorticoids and macrolides likely exerted similar regulatory actions on CRS and most of their effects did not vary by the phenotypes of CRS. PMID- 26047817 TI - Hematological parameters in the early phase of influenza A virus infection in differentially susceptible inbred mouse strains. AB - BACKGROUND: Hematological parameters have not received much attention in small animal models of infection, particularly at very early time points. We therefore studied changes in leukocyte and thrombocyte numbers in a mouse model of influenza A virus (IAV) infection, including measurements within the first 24 h after infection, and also assessing effects, if any, of the infection/anesthesia procedure on these parameters. METHODS: DBA/2J and C57BL/6J mice (n = 5-8 per observation) were evaluated in a time course experiment of IAV infection, focusing on early time points. After anesthesia with ketamine/xylazine, a suspension of 2 * 10(3) focus forming units of the mouse-adapted IAV strain A/Puerto Rico/8/1934 (H1N1) in 20 ul sterile PBS, or 20 ul sterile PBS only ("mock treatment"), were instilled intranasally. Weight loss was assessed daily, and eight common hematological parameters and viral hemagglutinin (HA) mRNA expression were determined after 6, 12, 18, 24, 48 and 120 h. RESULTS: Hematological differences between the strains were apparent even in untreated mice. Infection-dependent changes, in particular increased granulocyte and decreased lymphocyte counts, were first detectable after 18 h in DBA/2J, were fully manifest in both strains at 48 h, and were usually more pronounced in the DBA/2J mice. In this strain, relative granulocyte and lymphocyte counts and the granulocyte/lymphocyte ratio correlated with viral HA mRNA expression and weight loss. In C57BL/6J, hematological parameters did not correlate with weight loss, but HA mRNA expression correlated weakly with total leukocyte counts, granulocyte/lymphocyte ratio, relative and absolute granulocyte counts, and relative lymphocyte counts. Significant changes due to mock treatment were mild and were detected only in C57BL/6J. CONCLUSION: This study underscores the value of hematological parameters in monitoring disease evolution in the early phase of IAV infection, and likely other pathogens. The hematological response to infection may differ significantly among inbred mouse strains. PMID- 26047818 TI - The impact of a community-based HIV and sexual reproductive health program on sexual and healthcare-seeking behaviors of female entertainment workers in Cambodia. AB - BACKGROUND: In Cambodia, despite great successes in the fight against HIV, challenges remain to eliminating new HIV infections and addressing sexual reproductive health (SRH) issues in key populations including female entertainment workers (FEWs). To address these issues, the Sustainable Action against HIV and AIDS in Communities (SAHACOM) project has been implemented since late 2009 using a community-based approach to integrate HIV and SRH services. This study evaluates the impact of the SAHACOM on sexual and healthcare-seeking behaviors among FEWs in Cambodia. METHODS: A midterm and endpoint comparison design was utilized. Midterm data were collected in early 2012, and endpoint data were collected in early 2014. A two-stage cluster sampling method was used to randomly select 450 women at midterm and 556 women at endpoint for face-to-face interviews. RESULTS: Compared to women at midterm, women at endpoint were significantly less likely to report having sexual intercourse in exchange for money or gifts in the past three months (OR = 2.1, 95 % CI = 1.6-2.7). The average number of commercial sexual partners in the past three months also decreased significantly from 5.5 (SD = 13.3) at midterm to 3.6 (SD = 13.9) at endpoint (p = 0.03). However, women at endpoint were significantly less likely to report always using condom when having sexual intercourse with clients in exchange for money or gifts (OR = 2.6, 95 % CI = 1.5-4.5). Regarding sexually transmitted infections (STIs), women at endpoint were significantly less likely to report having an STI symptom in the past three months (OR = 1.8, 95 % CI = 1.4 2.3) and more likely to seek treatment for the most recent STI symptom (OR = 1.6, 95 % CI = 1.1-1.9). Furthermore, women at endpoint were significantly more likely to be currently using a contraceptive method (OR = 1.4, 95 % CI = 1.1-1.8) and less likely to report having an induced abortion (OR = 1.4, 95 % CI = 1.1-1.7) during the time working as a FEW. CONCLUSIONS: The overall findings of the study indicate that the SAHACOM is effective in reducing sexual risk behaviors and improving the access to SRH care services among FEWs in Cambodia. However, several unfavorable findings merit attention. PMID- 26047819 TI - The vapor-phase multi-stage CMD test for characterizing contaminant mass discharge associated with VOC sources in the vadose zone: Application to three sites in different lifecycle stages of SVE operations. AB - Vapor-phase multi-stage contaminant mass discharge (CMD) tests were conducted at three field sites to measure mass discharge associated with contaminant sources located in the vadose zone. The three sites represent the three primary stages of the soil vapor extraction (SVE) operations lifecycle-pre/initial-SVE, mid lifecycle, and near-closure. A CMD of 32g/d was obtained for a site at which soil vapor SVE has been in operation for approximately 6years, and for which mass removal is currently in the asymptotic stage. The contaminant removal behavior exhibited for the vapor extractions conducted at this site suggests that there is unlikely to be a significant mass of non-vapor-phase contaminant (e.g., DNAPL, sorbed phase) remaining in the advective domains, and that most remaining mass is likely located in poorly accessible domains. Given the conditions for this site, this remaining mass is hypothesized to be associated with the low-permeability (and higher water saturation) region in the vicinity of the saturated zone and capillary fringe. A CMD of 25g/d was obtained for a site wherein SVE has been in operation for several years but concentrations and mass-removal rates are still relatively high. A CMD of 270g/d was obtained for a site for which there were no prior SVE operations. The behavior exhibited for the vapor extractions conducted at this site suggest that non-vapor-phase contaminant mass (e.g., DNAPL) may be present in the advective domains. Hence, the asymptotic conditions observed for this site most likely derive from a combination of rate-limited mass transfer from DNAPL (and sorbed) phases present in the advective domain as well as mass residing in lower-permeability ("non-advective") regions. The CMD values obtained from the tests were used in conjunction with a recently developed vapor-discharge tool to evaluate the impact of the measured CMDs on groundwater quality. PMID- 26047820 TI - Liver fat quantification: Comparison of dual-echo and triple-echo chemical shift MRI to MR spectroscopy. AB - PURPOSE: To assess the diagnostic value of MRI using dual-echo (2PD) and triple echo (3PD) chemical shift imaging for liver fat quantification against multi-echo T2 corrected MR spectroscopy (MRS) used as the reference standard, and examine the effect of T2(*) imaging on accuracy of MRI for fat quantification. MATERIALS AND METHODS: Patients who underwent 1.5T liver MRI that incorporated 2PD, 3PD, multi-echo T2(*) and MRS were included in this IRB approved prospective study. Regions of interest were placed in the liver to measure fat fraction (FF) with 2PD and 3PD and compared with MRS-FF. A random subset of 25 patients with a wide range of MRS-FF was analyzed with an advanced FF calculation method, to prove concordance with the 3PD. The statistical analysis included correlation stratified according to T2(*), Bland-Altman analysis, and calculation of diagnostic accuracy for detection of MRS-FF>6.25%. RESULTS: 220 MRI studies were identified in 217 patients (mean BMI 28.0+/-5.6). 57/217 (26.2%) patients demonstrated liver steatosis (MRS-FF>6.25%). Bland-Altman analysis revealed strong agreement between 3PD and MRS (mean+/-1.96 SD: -0.5%+/-4.6%) and weaker agreement between 2PD and MRS (4.7%+/-16.0%). Sensitivity of 3PD for diagnosing FF> 6.25% was higher than that of 2PD. 3PD-FF showed minor discrepancies (coefficient of variation <10%) from FF measured with the advanced method. CONCLUSION: Our large series study validates the use of 3PD chemical shift sequence for detection of liver fat in the clinical environment, even in the presence of T2(*) shortening. PMID- 26047821 TI - CT and MR imaging of non-cavernous cranial dural arteriovenous fistulas: Findings associated with cortical venous reflux. AB - PURPOSE: To compare the conventional CT and MR findings of DAVFs in relation to the venous drainage pattern on digital subtraction angiography (DSA). MATERIALS AND METHODS: Cross-sectional imaging findings (CT and/or MR) in 92 patients were compared to the presence of cortical venous reflux (CVR) on DSA. RESULTS: Imaging features significantly more prevalent in patients with CVR included: abnormally dilated and tortuous leptomeningeal vessels (92% vs. 4%, p<0.001) or medullary vessels (69% vs. 0%, p<0.001), venous ectasias (45% vs. 0%, p<0.001) and focal vasogenic edema (38% vs. 0%, p<0.001). The following findings trended towards association but did not reach the p value established following Bonferroni correction: dilated external carotid artery branches (71% vs. 38%, p=0.005), cluster of vessels surrounding dural venous sinus (50% vs. 19%, p=0.009), presence of hemorrhage (33 vs. 12%, p=0.040), and parenchymal enhancement (21% vs. 0%, p=0.030). CONCLUSION: In the appropriate clinical setting, recognition of ancillary signs presumably related to venous arterialization and congestion as well as arterial feeder hypertrophy should prompt DSA confirmation to identify DAVFs associated with CVR. PMID- 26047822 TI - Prevalence and clinical significance of extravascular incidental findings in patients undergoing CT cervico-cerebral angiography. AB - INTRODUCTION: CT cervico-cerebral angiography (CTCCA) is now the first line diagnostic imaging modality for the majority of vascular pathologies of the head and neck with diagnostic value comparable to or better than traditional angiographic techniques. The aim of this study was to assess the prevalence, clinical significance and management of extravascular incidental findings detected on CTCCA. MATERIALS AND METHODS: A retrospective review of the CTCCA reports of 302 consecutive patients from 2009 to 2013 was undertaken. Extravascular incidental findings were classified, according to an adaptation of the CT colonography data and reporting system (CRADS), as EV1-EV4. EV1=no incidental findings, EV2=clinically insignificant incidental finding, EV3=incidental finding of intermediate clinical significance, EV4=highly clinically significant finding. Follow up of the electronic medical records of patients with EV3 or EV4 findings was undertaken to determine subsequent management. RESULTS: Potentially clinically significant findings were demonstrated in 14.2% of patients with 8.6% of patients having a highly clinically significant finding. 4 incidental findings were confirmed to be malignant lesions and 5 required acute intervention. In addition 19% of patients with highly clinically significant incidental findings did not receive appropriate follow up. DISCUSSION: This study has demonstrated the presence of clinically important incidental findings in a significant proportion of patients undergoing CTCCA with a significant minority of these patients not receiving follow up. A standardised method of reporting incidental findings, such as that used in this paper, would aid radiologists and referring physicians in recording and communicating these findings. PMID- 26047823 TI - Enabling minimal invasive parathyroidectomy for patients with primary hyperparathyroidism using Tc-99m-sestamibi SPECT-CT, ultrasound and first results of (18)F-fluorocholine PET-CT. AB - OBJECTIVE: Assessment of the diagnostic value of ultrasound (US), single photon emission computed tomography-computed tomography (SPECT-CT) and (18)F fluorocholine (FCH) PET-CT for preoperative localization of hyper-functioning parathyroid(s) in order to create a more efficient diagnostic pathway and enable minimal invasive parathyroidectomy (MIP) in patients with biochemical proven non familial primary hyperparathyroidism (pHPT). METHODS: A single-institution retrospective study of 63 consecutive patients with a biochemical diagnosis of non-familial pHPT who received a Tc-99m-sestamibi SPECT-CT and neck ultrasound. Surgical findings were used in calculating the sensitivity and the positive predictive value (PPV) of both imaging modalities. Furthermore we present 5 cases who received additional FCH PET-CT. RESULTS: A total of 42 (66.7%) patients underwent MIP. The PPV and sensitivity of SPECT-CT, 93.0% and 80.3%, were significantly higher than those of US with 78.3% and 63.2%, respectively. Adding US to SPECT-CT for initial pre-operative localization did not significantly increase sensitivity but did significantly decrease PPV. Performance of US was significantly better when performed after SPECT-CT. (18)F-fluorocholine PET-CT localized the hyper-functioning parathyroid gland in 4/5 cases with discordant conventional imaging, enabling MIP. CONCLUSION: SPECT-CT is the imaging modality of choice for initial pre-operative localization of hyper-functioning parathyroid gland(s) in patients with biochemical pHPT. Ultrasound should be performed after SPECT-CT for confirmation of positive SPECT-CT findings and for pre-operative marking allowing MIP. In cases with negative or discordant imaging additional FCH PET-CT should be considered since this might enable the surgeon to perform MIP. PMID- 26047824 TI - Quantitative circumferential strain analysis using adenosine triphosphate stress/rest 3-T tagged magnetic resonance to evaluate regional contractile dysfunction in ischemic heart disease. AB - PURPOSE: We evaluated whether a quantitative circumferential strain (CS) analysis using adenosine triphosphate (ATP)-stress/rest 3-T tagged magnetic resonance (MR) imaging can depict myocardial ischemia as contractile dysfunction during stress in patients with suspected coronary artery disease (CAD). We evaluated whether it can differentiate between non-ischemia, myocardial ischemia, and infarction. We assessed its diagnostic performance in comparison with ATP-stress myocardial perfusion MR and late gadolinium enhancement (LGE)-MR imaging. METHODS: In 38 patients suspected of having CAD, myocardial segments were categorized as non ischemic (n=485), ischemic (n=74), or infarcted (n=49) from the results of perfusion MR and LGE-MR. The peak negative CS value, peak circumferential systolic strain rate (CSR), and time-to-peak CS were measured in 16 segments. RESULTS: A cutoff value of -12.0% for CS at rest allowed differentiation between infarcted and other segments with a sensitivity of 79%, specificity of 76%, accuracy of 76%, and an area under the curve (AUC) of 0.81. Additionally, a cutoff value of 477.3ms for time-to-peak CS at rest allowed differentiation between infarcted and other segments with a sensitivity of 61%, specificity of 91%, accuracy of 88%, and an AUC of 0.75. The differences in CS values between ATP-stress and rest conditions (DeltaCS) in non-ischemic segments (median [first quartile, third quartile] -1.7 [-3.2, -0.1] %) were smaller than in segments with ischemia (+1.1 [+0.3, +2.3] %, p<0.001). A cutoff value of +0.3% for the DeltaCS value could differentiate segments with ischemia from non-ischemic segments with a sensitivity of 75%, a specificity of 82%, an accuracy of 82%, and an AUC of 0.86. CONCLUSIONS: Circumferential strain analysis using tagged MR can quantitatively assess contractile dysfunction in ischemic and infarcted myocardium. PMID- 26047826 TI - GMC proposes single test for all doctors wishing to work in UK. PMID- 26047825 TI - Coronary Artery Calcium Improves Risk Assessment in Adults With a Family History of Premature Coronary Heart Disease: Results From Multiethnic Study of Atherosclerosis. AB - BACKGROUND: The prognostic value of coronary artery calcium (CAC) or carotid intima-media thickness (CIMT) among asymptomatic adults with a family history (FH) of premature coronary heart disease is unclear. METHODS AND RESULTS: Multiethnic Study of Atherosclerosis enrolled 6814 adults without known atherosclerotic cardiovascular disease (ASCVD). Hard ASCVD events were ascertained over a median follow-up of 10.2 years. We estimated adjusted-hazard ratios for CAC and CIMT categories using Cox regression, both within and across FH status groups. Improvement in discrimination with CAC or CIMT added to variables from the ASCVD pooled cohort equation was also evaluated using receiver operating characteristic curve and likelihood ratio analysis. Of 6125 individuals (62+/-10 years; 47% men) who reported information on FH, 1262 (21%) had an FH of premature coronary heart disease. Among these, 104 hard ASCVD events occurred. Crude incidence rates (per 1000 person-years) for hard ASCVD were 4.4 for CAC, 0 (n=574; 46% of the sample); 8.8 for CAC, 1 to 99 (n=368); 14.9 for CAC, 100 to 399 (n=178); and 20.8 for CAC, >=400 (n=142). Relative to CAC=0, adjusted hard ASCVD hazard ratios for each CAC category among persons with an FH were 1.64 (95% confidence interval, 0.94-2.87), 2.45 (1.31-4.58), and 2.80 (1.44-5.43), respectively. However, there was no increased adjusted hazard for hard ASCVD in high versus low CIMT categories. In participants with an FH of premature coronary heart disease, CAC improved discrimination of hard ASCVD events (P<0.001). However, CIMT did not discriminate ASCVD (P=0.70). CONCLUSIONS: Nearly half of individuals reporting FH have zero CAC and may receive less net benefit from aspirin or statin therapy. Among persons with an FH, CAC is a robust marker of absolute and relative risk of ASCVD, whereas CIMT is not. PMID- 26047827 TI - Influence of a Suggestive Placebo Intervention on Psychobiological Responses to Social Stress: A Randomized Controlled Trial. AB - We tested the hypothesis that a suggestive placebo intervention can reduce the subjective and neurobiological stress response to psychosocial stress. Fifty-four healthy male subjects with elevated levels of trait anxiety were randomly assigned in a 4:4:1 fashion to receive either no treatment (n = 24), a placebo pill (n = 24), or a herbal drug (n = 6) before undergoing a stress test. We repeatedly measured psychological variables as well as salivary cortisol, alpha amylase, and heart rate variability prior to and following the stress test. The stressor increased subjective stress and anxiety, salivary cortisol, and alpha amylase, and decreased heart rate variability (all P < .001). However, no significant differences between subjects receiving placebo or no treatment were found. Subjects receiving placebo showed increased wakefulness during the stress test compared with no-treatment controls (P < .001). Thus, the suggestive placebo intervention increased alertness, but modulated neither subjective stress and anxiety nor the physiological response to psychosocial stress. PMID- 26047828 TI - Family interventions in traumatized immigrants and refugees: A systematic review. AB - The importance of the family as a unit in the aftermath of trauma necessitates the use of family interventions among immigrants and refugees. While abundant clinical material suggests that family-based trauma interventions are applicable across cultures, very little is known about the extent to which family treatment modalities are effective for immigrants and refugees. We conducted a systematic review of intervention studies that have been designed or modified specifically for traumatized immigrant and refugee families. The terms "trauma," "family," and "immigrants/refugees/culture" were used along with different terms for "intervention." Studies with no research methodology were excluded. Only 6 experimental studies met our inclusion criteria; 4 of them describe school-based interventions and 2 present multifamily support groups. The shortage of research in this area does not allow clear conclusions about the effectiveness of family interventions for traumatized immigrants or refugees. The complexity of employing methodologically rigorous research in small communities is discussed. Future trials should go beyond the individualistic approach and focus on posttraumatic stress disorder to address family-level processes, such as family relationship, communication, and resilience. PMID- 26047830 TI - Preparedness explains some differences between Haiti and Nepal's response to earthquake. PMID- 26047829 TI - The effects of acute hyperinsulinemia on bone metabolism. AB - Insulin signaling in bone-forming osteoblasts stimulates bone formation and promotes the release of osteocalcin (OC) in mice. Only a few studies have assessed the direct effect of insulin on bone metabolism in humans. Here, we studied markers of bone metabolism in response to acute hyperinsulinemia in men and women. Thirty-three subjects from three separate cohorts (n=8, n=12 and n=13) participated in a euglycaemic hyperinsulinemic clamp study. Blood samples were collected before and at the end of infusions to determine the markers of bone formation (PINP, total OC, uncarboxylated form of OC (ucOC)) and resorption (CTX, TRAcP5b). During 4 h insulin infusion (40 mU/m(2) per min, low insulin), CTX level decreased by 11% (P<0.05). High insulin infusion rate (72 mU/m(2) per min) for 4 h resulted in more pronounced decrease (-32%, P<0.01) whereas shorter insulin exposure (40 mU/m(2) per min for 2 h) had no effect (P=0.61). Markers of osteoblast activity remained unchanged during 4 h insulin, but the ratio of uncarboxylated-to-total OC decreased in response to insulin (P<0.05 and P<0.01 for low and high insulin for 4 h respectively). During 2 h low insulin infusion, both total OC and ucOC decreased significantly (P<0.01 for both). In conclusion, insulin decreases bone resorption and circulating levels of total OC and ucOC. Insulin has direct effects on bone metabolism in humans and changes in the circulating levels of bone markers can be seen within a few hours after administration of insulin. PMID- 26047831 TI - Inequalities in non-small cell lung cancer treatment and mortality. AB - BACKGROUND: Non-small cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, and surgery is the preferred treatment for patients. The National Health Service established Primary Care Trusts (PCTs) in 2002 to manage local health needs. We investigate whether PCTs with a lower uptake of surgical treatment are those with above-average mortality 1 year after diagnosis. The applied methods can be used to monitor the performance of any administrative bodies responsible for the management of patients with cancer. METHODS: All adults diagnosed with NSCLC lung cancer during 1998-2006 in England were identified. We fitted mixed effect logistic models to predict surgical treatment within 6 months after diagnosis, and mortality within 1 year of diagnosis. RESULTS: Around 10% of the NCSLC patients received curative surgery. Older deprived patients and those who did not receive surgery had much higher odds of death 1 year after being diagnosed with cancer. In total, 69% of the PCTs were below the lower control limit of surgery and have predicted random intercepts above the mean value of zero of the random effect for mortality, whereas 40% were above the upper control limit of mortality within 1 year. CONCLUSIONS: Our main results suggest the presence of clear geographical variation in the use of surgical treatment of NSCLC and mortality. Mixed-effects models combined with the funnel plot approach were useful for assessing the performance of PCTs that were above average in mortality and below average in surgery. PMID- 26047832 TI - The Use of the Internet for Prevention of Binge Drinking Among the College Population: A Systematic Review of Evidence. AB - AIMS: There are many consequences of binge drinking compared with light or moderate drinking behaviors. The prevalence rate and intensity of binge drinking is highest among the college-aged population. Given the popularity and high use of the Internet among college students, a novel approach for programming is through Internet-based interventions. The purpose of this study was to conduct a systematic review of Internet-based interventions targeting binge drinking among the college population. METHODS: Eligibility criteria included peer-reviewed articles evaluating Internet-based interventions for binge drinking prevention among college students published between 2000 and 2014. Only English language articles were included. Review articles and articles only explaining intervention pedagogies were not included. After a systematic screening process, a total of 14 articles were included for the final review. Each article was read thoroughly in order to extract the following variables: study design and sample size, average age of participants, underpinning theoretical framework, and intervention description and duration. This review also synthesized a methodological assessment with variables such as outcome measures, sample size justification, number of measurements and use of process evaluations. RESULTS: All studies but one reported a significant reduction in the frequency and quantity of alcohol consumption and problems related with heavy drinking. Furthermore, Internet-based interventions appeared to be more effective than traditional print-based interventions; however, face-to-face interventions were typically more effective. CONCLUSIONS: This review supports using the Internet as a brief intervention approach that can effectively support efforts to reduce binge drinking among college students. PMID- 26047833 TI - Novice drivers' individual trajectories of driver behavior over the first three years of driving. AB - Identifying the changes in driving behavior that underlie the decrease in crash risk over the first few months of driving is key to efforts to reduce injury and fatality risk in novice drivers. This study represented a secondary data analysis of 1148 drivers who participated in the UK Cohort II study. The Driver Behavior Questionnaire was completed at 6 months and 1, 2 and 3 years after licensure. Linear latent growth models indicated significant increases across development in all four dimensions of aberrant driving behavior under scrutiny: aggressive violations, ordinary violations, errors and slips. Unconditional and conditional latent growth class analyses showed that the observed heterogeneity in individual trajectories was explained by the presence of multiple homogeneous groups of drivers, each exhibiting specific trajectories of aberrant driver behavior. Initial levels of aberrant driver behavior were important in identifying sub groups of drivers. All classes showed positive slopes; there was no evidence of a group of drivers whose aberrant behavior decreased over time that might explain the decrease in crash involvement observed over this period. Male gender and younger age predicted membership of trajectories with higher levels of aberrant behavior. These findings highlight the importance of early intervention for improving road safety. We discuss the implications of our findings for understanding the behavioral underpinnings of the decrease in crash involvement observed in the early months of driving. PMID- 26047834 TI - Differential activation of kiss receptors by Kiss1 and Kiss2 peptides in the sea bass. AB - Two forms of kiss gene (kiss1 and kiss2) have been described in the teleost sea bass. This study assesses the cloning and characterization of two Kiss receptor genes, namely kissr2 and kissr3 (known as gpr54-1b and gpr54-2b, respectively), and their signal transduction pathways in response to Kiss1 and Kiss2 peptides. Phylogenetic and synteny analyses indicate that these paralogs originated by duplication of an ancestral gene before teleost specific duplication. The kissr2 and kissr3 mRNAs encode proteins of 368 and 378 amino acids, respectively, and share 53.1% similarity in amino acid sequences. In silico analysis of the putative promoter regions of the sea bass Kiss receptor genes revealed conserved flanking regulatory sequences among teleosts. Both kissr2 and kissr3 are predominantly expressed in brain and gonads of sea bass, medaka and zebrafish. In the testis, the expression levels of sea bass kisspeptins and Kiss receptors point to a significant variation during the reproductive cycle. In vitro functional analyses revealed that sea bass Kiss receptor signals are transduced both via the protein kinase C and protein kinase A pathway. Synthetic sea bass Kiss1-15 and Kiss2-12 peptides activated Kiss receptors with different potencies, indicating a differential ligand selectivity. Our data suggest that Kissr2 and Kissr3 have a preference for Kiss1 and Kiss2 peptides, respectively, thus providing the basis for future studies aimed at establishing their physiologic roles in sea bass. PMID- 26047835 TI - Protective effect of porcine placenta in a menopausal ovariectomized mouse. AB - Menopause is a significant physiological phase that occurs as women's ovaries stop producing ovum and the production of estrogen declines. Human placenta and some amino acids are known to improve menopausal symptoms. In this study, we investigated that porcine placenta extract (PPE) and arginine (Arg), a main amino acid of PPE, would have estrogenic activities in ovariectomized (OVX) mice as a menopause mouse model, human breast cancer cell line (MCF-7) cells, and human osteoblast cell line (MG-63) cells. PPE or Arg significantly inhibited the body weight and increased the vagina weight compared to the OVX mice. PPE or Arg ameliorated the vaginal atrophy in the OVX mice. The levels of 17beta-estradiol and the activities of alkaline phosphatase (ALP) were significantly increased by PPE or Arg in the serum of OVX mice. Trabecular bone parameters such as bone mineral density and porosity were also improved by PPE or Arg in the OVX mice. In the MCF-7 and MG-63 cells, PPE or Arg significantly increased the cell proliferation, estrogen receptor beta mRNA expression, and estrogen-response elements luciferase activity. Finally, PPE or Arg increased the activations of ALP and extracellular signal-regulated kinase 1/2 in the MG-63 cells. These results indicate that PPE or Arg would have estrogenic and osteoblastic activity. Therefore, PPE or Arg may be useful as new pharmacological tools for treating menopausal symptoms including osteoporosis. Free Korean abstract: A Korean translation of this abstract is freely available at http://www.reproduction online.org/content/150/3/173/suppl/DC1. PMID- 26047836 TI - Individual variables related to craving reduction in cue exposure treatment. AB - INTRODUCTION: Although extensive research has demonstrated that cigarette craving can be effectively attenuated, very few studies have explored associations between individual variables and craving reduction. This study explored whether individual characteristics predict craving decreases during virtual reality cue exposure treatment (VR-CET). METHOD: Participants were 41 treatment-seeking smokers (73% women) with a mean age of 39.4 (SD=13.2), who had been smoking 15.0 (SD=7.1) cigarettes per day for 20.0 (SD=10.7) years. Their mean score on the Fagerstrom Test of Nicotine Dependence (FTND) was 4.8 (SD=2.3). Participants completed five cue exposure sessions using virtual reality for smoking cessation over a five-week period. The percentage of reduction in craving was calculated by comparing self-reported craving after the first and last exposure sessions. Sociodemographic characteristics (gender, age, years of education and marital status), tobacco-related [duration of daily smoking, cigarettes per day, FTND and Nicotine Dependence Syndrome Scale (NDSS)] and psychological characteristics [depressive symptoms (Beck's Depression Inventory-Second Edition, BDI-II), impulsiveness (delay discounting) and anxiety (State-Trait Anxiety Inventory, STAI)] were examined as possible predictors for craving reductions. RESULTS: Multiple regression revealed that greater decreases in craving were associated with younger age (beta=-.30, p=.043), cigarettes smoked per day (beta=.30, p=.042), higher values on delay discounting (beta=.34, p=.020) and higher BDI-II scores (beta=.30, p=.035). CONCLUSION: These findings suggest that smokers with certain individual characteristics may benefit most from interventions aimed at reducing craving through VR-CET. PMID- 26047837 TI - Reconsidering adulthood: Relative constructions of adult identity during the transition to adulthood. AB - This article explores how peers influence the process of adult identity development during the transition to adulthood. The influence of peers leads to similar individuals adopting differing definitions of adulthood. Utilizing data from interviews with 60 young adults who are all exactly 30 years old, findings indicate that peer groups can partly explain variation in self-perceived definitions of adulthood. Respondents described how peers influence the transition to adulthood in two ways. First, they measure the timing of their transitions relative to their peers. Second, they assess the nature of their transitions relative to what they perceive to be the normative nature of that transition within their peer group. While this process was reported by respondents across gender and education level, the outcomes varied between individuals who are demographically similar. Variation in self-perceived status is due in part to the differences between peer groups, as the reference point for each individual varies from one peer group to another. These findings suggest that norms about adulthood are perceived at the group level, which can explain why differing feelings of adulthood exist among individuals who have completed comparable transitions and share similar status characteristics. As previous research has focused on adulthood norms that exist primarily at the societal level, this study expands on that work by suggesting that salient adulthood norms may be developed and referenced at multiple levels. PMID- 26047838 TI - Fertility intentions and outcomes: Implementing the Theory of Planned Behavior with graphical models. AB - This paper studies fertility intentions and their outcomes, analyzing the complete path leading to fertility behavior according to the social psychological model of Theory Planned Behavior (TPB). We move beyond existing research using graphical models to have a precise understanding, and a formal description, of the developmental fertility decision-making process. Our findings yield new results for the Italian case which are empirically robust and theoretically coherent, adding important insights to the effectiveness of the TPB for fertility research. In line with TPB, all intentions' primary antecedents are found to be determinants of the level of fertility intentions, but do not affect fertility outcomes, being pre-filtered by fertility intentions. Nevertheless, in contrast with TPB, background factors are not fully mediated by intentions' primary antecedents, influencing directly fertility intentions and even fertility behaviors. PMID- 26047839 TI - Self-esteem growth trajectory from adolescence to mid-adulthood and its predictors in adolescence. AB - The present study examined the trajectory of self-esteem from adolescence to mid adulthood and its predictors in adolescence in a prospective cohort sample with a 26-year follow-up. Participants of a Finnish cohort study in 1983 at 16 years (N = 2194) were followed up at ages 22 (N = 1656), 32 (N = 1471) and 42 (N = 1334) years. Self-esteem development was analyzed using latent growth curve models with parental socioeconomic status (SES), parental divorce, school achievement, daily smoking, and heavy drinking as time invariant covariates. Self-esteem grew linearly from 16 to 32 years, but stabilized after that with no growth between 32 and 42 years. Males had significantly higher self-esteem throughout the follow up, although females had a faster growth rate. Better school performance and higher parental SES were associated with a higher initial level of self-esteem among both genders, while parental divorce among females and daily smoking among males were associated with a lower initial level of self-esteem. Among females the growth rate of self-esteem was practically unaffected by the studied covariates. Among males, however, the initial differences in self-esteem favouring those from a higher SES background were indicated to diminish, while the differences between non-smokers and smokers were indicated to increase. The studied adolescent covariates combined had only limited predictive value for the later self-esteem development. However, the effects of any covariate on the level and slope of the self-esteem trajectory, even if small, should be assessed in combination in order to identify whether they lead to converging, diverging or constantly equidistant self-esteem trajectories. The findings highlight the variety of roles that adolescent behaviours and social environments may have in the developmental process of self-esteem from adolescence into mid-adulthood. PMID- 26047840 TI - Moving and union formation in the transition to adulthood in the United States. AB - Although previous research has paid attention to profound changes in union formation among young adults, few studies have incorporated moving events in the estimation of union formation. Moreover, less attention has been given to detailed moving experiences in young adults' life course. Using panel data from the National Longitudinal Survey of Youth 1997, we examine the relationship between moving and first union formation of young adults in the United States. Moving events are aggregated by distance moved, economic conditions in origin and destination places (i.e. moving within the same county, moving to new counties with better or the same economic conditions, and moving to new counties with worse economic conditions) and the time since a move. Our findings suggest that moving events, regardless of type, are significantly related to first union formation for females while the time since a move is important to union formation of males. PMID- 26047841 TI - Intergenerational cohesiveness and later geographic distance to parents in the Netherlands. AB - Although spatial proximity no doubt facilitates interaction and assistance, no research to date has addressed the extent to which children who are emotionally closer to parents choose to live nearby. Using the Netherlands Kinship Panel Study (N = 1055), this research evaluates the relationship between parent-child cohesion at age 15 (measured retrospectively among individuals 18-35 in 2002 2004) and later geographic distance between young adults and their parents in 2006-2007. Importantly, this research is the first to consider the relationship between intergenerational solidarity and young adult's later geographic proximity to parents, proximity known to contribute to exchanges of support between the generations. For both mothers and fathers, each model yielded qualified evidence of the cohesion-proximity relationship. These findings highlight a potential selection issue related to intergenerational support and contact as it is facilitated by geographic proximity. PMID- 26047843 TI - Romantic relationship formation, maintenance and changes in personal networks. AB - According to the social withdrawal hypothesis, a personal network becomes smaller when a person starts dating, cohabitates and marries. This phenomenon is widely established in the literature. However, these studies were usually done with cross-sectional data. As a consequence, it is still unclear whether or how personal networks actually change after the formation of a romantic relationship (i.e. dating), after starting cohabitation and after getting married. It is also unclear how long and to what extent social withdrawal continues. To overcome these shortcomings, we examine how the size and composition of personal networks change after relationship formation. We use two waves of the PAIRFAM dataset (2008 and 2011), which include information about 6640 Germans who were between 16 and 39 years of age at the time of the second interview in 2008. Results from fixed effects regression models underscore that the association between romantic relationships and changes in personal networks is more dynamic than previous studies suggested. For example, after the formation of a romantic relationship people show a decrease in non-kin contacts, while an increase in non-kin contacts is observed after two years of dating, as well as after two years of cohabitation. These network changes suggest that people adapt their social networks to the demands and constraints of each phase of a romantic relationship. Because the decline in network size after dating is not stable, there is no need to be afraid that those who have a romantic partner remain isolated from other relationships. PMID- 26047842 TI - Racial/ethnic disparities in midlife depressive symptoms: The role of cumulative disadvantage across the life course. AB - This study examines the role of cumulative disadvantage mechanisms across the life course in the production of racial and ethnic disparities in depressive symptoms at midlife, including the early life exposure to health risk factors, the persistent exposure to health risk factors, and varying mental health returns to health risk factors across racial and ethnic groups. Using data from the over 40 health module of the National Longitudinal Study of Youth (NLSY) 1979 cohort, this study uses regression decomposition techniques to attend to differences in the composition of health risk factors across racial and ethnic groups, differences by race and ethnicity in the association between depressive symptoms and health risk factors, and how these differences combine within racial and ethnic groups to produce group-specific levels of--and disparities in--depressive symptoms at midlife. While the results vary depending on the groups being compared across race/ethnicity and gender, the study documents how racial and ethnic mental health disparities at midlife stem from life course processes of cumulative disadvantage through both unequal distribution and unequal associations across racial and ethnic groups. PMID- 26047844 TI - Sense of coherence changes with aging over the second half of life. AB - Sense of coherence (SOC), a concept reflecting meaningfulness, comprehensibility, and manageability of life, has been demonstrated to have strong connections to positive outcomes such as good health. However, less is known about how SOC changes over the second half of life as age-related deficits accumulate. We used longitudinal samples of mature adults that included the oldest-old to track change in SOC from age 55 to 101. Growth curves using an accelerated longitudinal design were estimated for 1809 individuals who contributed 4072 observations from five national Swedish surveys between 1991 and 2010/11. Results indicated that deficits in health and social resources were largely responsible for the precipitous decline in SOC after age 70. When controlling for these deficits, SOC increased continuously into advanced old age. We conclude that the capacity to comprehend, manage, and find meaning in life--the component elements of SOC- strengthens over the last years of life, suggesting a positive ontogenic development that runs parallel but opposite to the negative impact of health and social decline. PMID- 26047845 TI - Polymorphism Analysis Reveals Reduced Negative Selection and Elevated Rate of Insertions and Deletions in Intrinsically Disordered Protein Regions. AB - Intrinsically disordered protein regions are abundant in eukaryotic proteins and lack stable tertiary structures and enzymatic functions. Previous studies of disordered region evolution based on interspecific alignments have revealed an increased propensity for indels and rapid rates of amino acid substitution. How disordered regions are maintained at high abundance in the proteome and across taxa, despite apparently weak evolutionary constraints, remains unclear. Here, we use single nucleotide and indel polymorphism data in yeast and human populations to survey the population variation within disordered regions. First, we show that single nucleotide polymorphisms in disordered regions are under weaker negative selection compared with more structured protein regions and have a higher proportion of neutral non-synonymous sites. We also confirm previous findings that nonframeshifting indels are much more abundant in disordered regions relative to structured regions. We find that the rate of nonframeshifting indel polymorphism in intrinsically disordered regions resembles that of noncoding DNA and pseudogenes, and that large indels segregate in disordered regions in the human population. Our survey of polymorphism confirms patterns of evolution in disordered regions inferred based on longer evolutionary comparisons. PMID- 26047846 TI - Comparison of the Venom Peptides and Their Expression in Closely Related Conus Species: Insights into Adaptive Post-speciation Evolution of Conus Exogenomes. AB - Genes that encode products with exogenous targets, which comprise an organism's "exogenome," typically exhibit high rates of evolution. The genes encoding the venom peptides (conotoxins or conopeptides) in Conus sensu lato exemplify this class of genes. Their rapid diversification has been established and is believed to be linked to the high speciation rate in this genus. However, the molecular mechanisms that underlie venom peptide diversification and ultimately emergence of new species remain poorly understood. In this study, the sequences and expression levels of conotoxins from several specimens of two closely related worm-hunting species, Conus tribblei and Conus lenavati, were compared through transcriptome analysis. Majority of the identified putative conopeptides were novel, and their diversity, even in each specimen, was remarkably high suggesting a wide range of prey targets for these species. Comparison of the interspecific expression patterns of conopeptides at the superfamily level resulted in the discovery of both conserved as well as species-specific expression patterns, indicating divergence in the regulatory network affecting conotoxin gene expression. Comparison of the transcriptomes of the individual snails revealed that each specimen produces a distinct set of highly expressed conopeptides, reflecting the capability of individual snails to fine-tune the composition of their venoms. These observations reflect the role of sequence divergence and divergence in the control of expression for specific conopeptides in the evolution of the exogenome and hence venom composition in Conus. PMID- 26047847 TI - Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2. AB - Divalent metal transporter-1 (SLC11A2/DMT1) uses the H(+) electrochemical gradient as the driving force to transport divalent metal ions such as Fe(2+), Mn(2+) and others metals into mammalian cells. DMT1 is ubiquitously expressed, most notably in proximal duodenum, immature erythroid cells, brain and kidney. This transporter mediates H(+)-coupled transport of ferrous iron across the apical membrane of enterocytes. In addition, in cells such as to erythroid precursors, following transferrin receptor (TfR) mediated endocytosis; it mediates H(+)-coupled exit of ferrous iron from endocytic vesicles into the cytosol. Dysfunction of human DMT1 is associated with several pathologies such as iron deficiency anemia hemochromatosis, Parkinson's disease and Alzheimer's disease, as well as colorectal cancer and esophageal adenocarcinoma, making DMT1 an attractive target for drug discovery. In the present study, we performed a ligand-based virtual screening of the Princeton database (700,000 commercially available compounds) to search for pharmacophore shape analogs of recently reported DMT1 inhibitors. We discovered a new compound, named pyrimidinone 8, which mediates a reversible linear non-competitive inhibition of human DMT1 (hDMT1) transport activity with a Ki of ~20MUM. This compound does not affect hDMT1 cell surface expression and shows no dependence on extracellular pH. To our knowledge, this is the first experimental evidence that hDMT1 can be allosterically modulated by pharmacological agents. Pyrimidinone 8 represents a novel versatile tool compound and it may serve as a lead structure for the development of therapeutic compounds for pre-clinical assessment. PMID- 26047848 TI - Activation of AMPK by chitosan oligosaccharide in intestinal epithelial cells: Mechanism of action and potential applications in intestinal disorders. AB - Chitosan oligosaccharide (COS), a biomaterial derived from chitin, is absorbed by intestinal epithelia without degradation and has diverse biological activities including intestinal epithelial function. However, the mode of action is still unclear. This study aimed to investigate the effect of COS on AMP-activated protein kinase (AMPK) in intestinal epithelial cells (IEC) and its potential applications in the intestinal diseases benefited from AMPK activation. COS with molecular weights (MW) from 5,000Da to 14,000Da induced AMPK activation in T84 cells. That with MW of 5,000-Da was the most potent polymer and was used in the subsequent experiments. COS also activated AMPK in other IEC including HT-29 and Caco-2 cells. Mechanism of COS-induced AMPK activation in T84 cells involves calcium-sensing receptor (CaSR)-phospholipase C (PLC)-IP3 receptor channel mediated calcium release from endoplasmic reticulum (ER). In addition, COS promoted tight junction assembly in T84 cells in an AMPK-dependent manner. COS also inhibited NF-kappaB transcriptional activity and NF-kappaB-mediated inflammatory response and barrier disruption via AMPK-independent mechanisms. Interestingly, luminal exposure to COS suppressed cholera toxin-induced intestinal fluid secretion by ~30% concurrent with AMPK activation in a mouse closed loop model. Importantly, oral administration of COS prevented the development of aberrant crypt foci in a mouse model of colitis-associated colorectal cancer (CRC) via a mechanism involving AMPK activation-induced beta catenin suppression and caspase-3 activation. Collectively, this study reveals a novel action of COS in activating AMPK via CaSR-PLC-IP3 receptor channel-mediated calcium release from ER. COS may be beneficial in the treatment of secretory diarrheas and CRC chemoprevention. PMID- 26047849 TI - Identification of snake bradykinin-potentiating peptides (BPPs)-simile sequences in rat brain--Potential BPP-like precursor protein? AB - Bradykinin-potentiating peptides (BPPs) from the South American pit viper snake venom were the first natural inhibitors of the human angiotensin I-converting enzyme (ACE) described. The pioneer characterization of the BPPs precursor from the snake venom glands by our group showed for the first time the presence of the C-type natriuretic peptide (CNP) in this same viper precursor protein. The confirmation of the BPP/CNP expression in snake brain regions correlated with neuroendocrine functions stimulated us to pursue the physiological correlates of these vasoactive peptides in mammals. Notably, several snake toxins were shown to have endogenous physiological correlates in mammals. In the present work, we expressed in bacteria the BPPs domain of the snake venom gland precursor protein, and this purified recombinant protein was used to raise specific polyclonal anti BPPs antibodies. The correspondent single protein band immune-recognized in adult rat brain cytosol was isolated by 2D-SDS/PAGE and/or HPLC, before characterization by MS fingerprint analysis, which identified this protein as superoxide dismutase (SOD, EC 1.15.1.1), a classically known enzyme with antioxidant activity and important roles in the blood pressure modulation. In silico analysis showed the exposition of the BPP-like peptide sequences on the surface of the 3D structure of rat SOD. These peptides were chemically synthesized to show the BPP-like biological activities in ex vivo and in vivo pharmacological bioassays. Taken together, our data suggest that SOD protein have the potential to be a source for putative BPP-like bioactive peptides, which once released may contribute to the blood pressure control in mammals. PMID- 26047850 TI - Sulfur amino acid metabolism in Zucker diabetic fatty rats. AB - The present study was aimed to investigate the metabolomics of sulfur amino acids in Zucker diabetic fatty (ZDF) rats, an obese type 2 diabetic animal model. Plasma levels of total cysteine, homocysteine and methionine, but not glutathione (GSH) were markedly decreased in ZDF rats. Hepatic methionine, homocysteine, cysteine, betaine, taurine, spermidine and spermine were also decreased. There are no significant difference in hepatic S-adenosylmethionine, S adenosylhomocysteine, GSH, GSH disulfide, hypotaurine and putrescine between control and ZDF rats. Hepatic SAH hydrolase, betaine-homocysteine methyltransferase and methylene tetrahydrofolate reductase were up-regulated while activities of gamma-glutamylcysteine ligase and methionine synthase were decreased. The area under the curve (AUC) of methionine and methionine-d4 was not significantly different in control and ZDF rats treated with a mixture of methionine (60mg/kg) and methionine-d4 (20mg/kg). Moreover, the AUC of the increase in plasma total homocysteine was comparable between two groups, although the homocysteine concentration curve was shifted leftward in ZDF rats, suggesting that the plasma total homocysteine after the methionine loading was rapidly increased and normalized in ZDF rats. These results show that the AUC of plasma homocysteine is not responsive to the up-regulation of hepatic BHMT in ZDF rats. The present study suggests that the decrease in hepatic methionine may be responsible for the decreases in its metabolites, such as homocysteine, cysteine, and taurine in liver and consequently decreased plasma homocysteine levels. PMID- 26047851 TI - Incomplete penetrance: The role of stochasticity in developmental cell colonization. AB - Cell colonization during embryonic development involves cells migrating and proliferating over growing tissues. Unsuccessful colonization, resulting from genetic causes, can result in various birth defects. However not all individuals with the same mutation show the disease. This is termed incomplete penetrance, and it even extends to discordancy in monozygotic (identical) twins. A one dimensional agent-based model of cell migration and proliferation within a growing tissue is presented, where the position of every cell is recorded at any time. We develop a new model that approximates this agent-based process - rather than requiring the precise configuration of cells within the tissue, the new model records the total number of cells, the position of the most advanced cell, and then invokes an approximation for how the cells are distributed. The probability mass function (PMF) for the most advanced cell is obtained for both the agent-based model and its approximation. The two PMFs compare extremely well, but using the approximation is computationally faster. Success or failure of colonization is probabilistic. For example for sufficiently high proliferation rate the colonization is assured. However, if the proliferation rate is sufficiently low, there will be a lower, say 50%, chance of success. These results provide insights into the puzzle of incomplete penetrance of a disease phenotype, especially in monozygotic twins. Indeed, stochastic cell behavior (amplified by disease-causing mutations) within the colonization process may play a key role in incomplete penetrance, rather than differences in genes, their expression or environmental conditions. PMID- 26047852 TI - Theoretical lessons for increasing algal biofuel: Evolution of oil accumulation to avert carbon starvation in microalgae. AB - Microalgae-derived oil is considered as a feasible alternative to fossil-derived oil. To produce more algal biomass, both algal population size and oil accumulation in algae must be maximized. Most of the previous studies have concentrated on only one of these issues, and relatively little attention has been devoted to considering the tradeoff between them. In this paper, we first theoretically investigated evolutionary reasons for oil accumulation and then by coupling population and evolutionary dynamics, we searched for conditions that may provide better yields. Using our model, we assume that algae allocate assimilated carbon to growth, maintenance, and carbon accumulation as biofuel and that the amount of essential materials (carbon and nitrate) are strongly linked in fixed proportions. Such stoichiometrically explicit models showed that (i) algae with more oil show slower population growth; therefore, the use of such algae results in lower total yields of biofuel and (ii) oil accumulation in algae is caused by carbon and not nitrate starvation. The latter can be interpreted as a strategy for avoiding the risk of increased death rate by carbon starvation. Our model also showed that both strong carbon starvation and moderately limited nitrate will promote total biofuel production. Our results highlight considering the life-history traits for a higher total yields of biofuel, which leads to insight into both establishing a prolonged culture and collection of desired strains from a natural environment. PMID- 26047853 TI - Mathematical model for alopecia areata. AB - Alopecia areata (AA) is an autoimmune disease, and its clinical phenotype is characterized by the formation of distinct hairless patterns on the scalp or other parts of the body. In most cases hair falls out in round patches. A well established hypothesis for the pathogenesis of AA states that collapse of hair follicle immune privilege is one of the essential elements in disease development. To investigate the dynamics of alopecia areata, we develop a mathematical model that incorporates immune system components and hair follicle immune privilege agents whose involvement in AA has been confirmed in clinical studies and experimentally. We perform parameter sensitivity analysis in order to determine which inputs have the greatest effect on outcome variables. Our findings suggest that, among all processes reflected in the model, immune privilege guardians and the pro-inflammatory cytokine interferon-gamma govern disease dynamics. These results agree with the immune privilege collapse hypothesis for the development of AA. PMID- 26047854 TI - Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. AB - The water-soluble prodrug MCB3837 is rapidly converted to MCB3681, active against Gram-positive bacterial species, after intravenous infusion. The aim of this study was to prove the principle that MCB3681 is efficacious in vivo by demonstrating its effect on the resident microflora or colonizers of the human skin, nose, oropharynx and intestine. MCB3837 was infused at a daily dose of 6 mg/kg for 5 days. MCB3681 was active against clostridia, bifidobacteria, lactobacilli, enterococci and Staphylococcus aureus, thus proving the principle that MCB3681 is antibacterially efficacious in vivo without affecting the Gram negative microflora. PMID- 26047855 TI - A CFD modeling study in an urban street canyon for ultrafine particles and population exposure: The intake fraction approach. AB - Air quality in street canyons is of major importance, since the highest pollution levels are often encountered in these microenvironments. The canyon effect (reduced natural ventilation) makes them "hot spots" for particulate pollution contributing to adverse health effects for the exposed population. In this study we tried to characterize the influence of UFP (ultrafine particle) emissions from traffic on population exposure in an urban street canyon, by applying the intake fraction (iF) approach. One month long measurements of UFP levels have been monitored and used for the need of this study. We applied a three dimensional computational fluid dynamic (CFD) model based on real measurements for the simulation of UFP levels. We used infiltration factors, evaluated on a daily basis for the under study area, to estimate the indoor UFP levels. As a result the intake fraction for the pedestrians, residents and office workers is in the range of (1E-5)-(1E-4). The street canyon is mostly residential justifying partially the higher value of intake fraction for residents (1E-4). The above iF value is on the same order of magnitude with the corresponding one evaluated in a relative street canyon study. The total iF value in this microenvironment is one order of magnitude higher than ours, explained partially by the different use and activities. Two specific applications of iF to assess prioritization among emission sources and environmental justice issues are also examined. We ran a scenario with diesel and gasoline cars and diesel fueled vehicle seems to be a target source to improve overall iF. Our application focus on a small residential area, typical of urban central Athens, in order to evaluate high resolution iF. The significance of source-exposure relationship study in a micro scale is emphasized by recent research. PMID- 26047856 TI - Ecological impacts of long-term application of biosolids to a radiata pine plantation. AB - Assessment of the ecological impact of applying biosolids is important for determining both the risks and benefits. This study investigated the impact on soil physical, chemical and biological properties, tree nutrition and growth of long-term biosolids applications to a radiata pine (Pinus radiata D. Don) plantation growing on a Sandy Raw Soil in New Zealand. Biosolids were applied to the trial site every 3 years from tree age 6 to 19 years at three application rates: 0 (Control), 300 (Standard) and 600 (High) kg nitrogen (N) ha(-1), equivalent to 0, 3 and 6 Mg ha(-1) of dry biosolids, respectively. Tree nutrition status and growth have been monitored annually. Soil samples were collected 13 years after the first biosolids application to assess the soil properties and functioning. Both the Standard and High biosolids treatments significantly increased soil (0-50 cm depth) total carbon (C), N, and phosphorus (P), Olsen P and cation exchange capacity (CEC), reduced soil pH, but had no significant effects on soil (0-20 cm depth) physical properties including bulk density, total porosity and unsaturated hydraulic conductivity. The High biosolids treatment also increased concentrations of soil total cadmium (Cd), chromium (Cr), copper (Cu) and lead (Pb) at 25-50 cm depth, but these concentrations were still considered very low for a soil. Ecotoxicological assessment showed no significant adverse effects of biosolids application on either the reproduction of springtails (Folsomia candida) or substrate utilisation ability of the soil microbial community, indicating no negative ecological impact of bisolids-derived heavy metals or triclosan. This study demonstrated that repeated application of biosolids to a plantation forest on a poor sandy soil could significantly improve soil fertility, tree nutrition and pine productivity. However, the long-term fate of biosolids-derived N, P and litter-retained heavy metals needs to be further monitored in the receiving environment. PMID- 26047857 TI - Inhibition or promotion of biodegradation of nitrate by Paracoccus sp. in the presence of nanoscale zero-valent iron. AB - To investigate the effect of nanoscale zero-valent iron (nZVI) on the growth of Paracoccus sp. strain and biodenitrification under aerobic conditions, specific factors were studied, pH, concentration of nitrate, Fe (II) and carbon dioxide. Low concentration of nZVI (50mg/L) promoted both cell growth and biodegradation of nitrate which rose from 69.91% to 76.16%, while nitrate removal fell to 67.10% in the presence of high nZVI concentration (1000 mg/L). This may be attributed to the ions produced in nZVI corrosion being used as an electron source for the biodegradation of nitrate. However, the excess uptake of Fe (II) causes oxidative damage to the cells. To confirm this, nitrate was completely removed after 20 h when 100mg/L Fe (II) was added to the solution, which is much faster than the control (86.05%, without adding Fe (II)). However, nitrate removal reached only 45.64% after 20 h, with low cell density (OD 600=0.62) in the presence of 300 mg/L Fe (II). Characterization techniques indicated that nZVI adhered to microorganism cell membranes. These findings confirmed that nZVI could affect the activity of the strain and consequently change the biodenitrification. PMID- 26047858 TI - A client-server software for the identification of groundwater vulnerability to pesticides at regional level. AB - The groundwater VULnerability to PESticide software system (VULPES) is a user friendly, GIS-based and client-server software developed to identify vulnerable areas to pesticides at regional level making use of pesticide fate models. It is a Decision Support System aimed to assist the public policy makers to investigate areas sensitive to specific substances and to propose limitations of use or mitigation measures. VULPES identify the so-called Uniform Geographical Unit (UGU) which are areas characterised by the same agro-environmental conditions. In each UGU it applies the PELMO model obtaining the 80th percentile of the substance concentration at 1 metre depth; then VULPES creates a vulnerability map in shapefile format which classifies the outputs comparing them with the lower threshold set to the legal limit concentration in groundwater (0.1 MUg/l). This paper describes the software structure in details and a case study with the application of the terbuthylazine herbicide on the Lombardy region territory. Three zones with different degrees of vulnerabilities has been identified and described. PMID- 26047859 TI - Influence of walking route choice on primary school children's exposure to air pollution--A proof of concept study using simulation. AB - This study developed a walking network for the Greater Manchester area (UK). The walking network allows routes to be calculated either based on the shortest duration or based on the lowest cumulative nitrogen dioxide (NO2) or particulate matter (PM10) exposure. The aim of this study was to analyse the costs and benefits of faster routes versus lower pollution exposure for walking routes to primary schools. Random samples of primary schools and residential addresses were used to generate 100,000 hypothetical school routes. For 60% (59,992) and 40% (40,460) an alternative low NO2 and PM10 route was found, respectively. The median change in travel time (NO2: 4.5s, PM10: 0.5s) and average route exposure (NO2: -0.40 MUg/m(3), PM10: -0.03 MUg/m(3)) was small. However, quantile regression analysis indicated that for 50% of routes a 1% increase in travel time was associated with a 1.5% decrease in NO2 and PM10 exposure. The results of this study suggest that the relative decrease in pollution exposure on low pollution routes tends to be greater than the relative increase in route length. This supports the idea that a route planning tool identifying less polluted routes to primary schools could help deliver potential health benefits for children. PMID- 26047860 TI - The effects of the presence of Bt-transgenic oilseed rape in wild mustard populations on the rhizosphere nematode and microbial communities. AB - The adventitious presence of transgenic crops in wild plant populations is of ecological and regulatory concern. In this context, their effects on non-target, below-ground organisms are not well understood. Here, we introduced, at various frequencies, Bt-transgenic oilseed rape (OSR, Brassica napus) into wild mustard (Brassica juncea) populations in the presence and absence of the target herbivore (Plutella xylostella). The impacts on soil nematode and microbial communities were assessed in this system. There were no significant changes on the number of nematode genera and abundance in proportions of OSR with mustard. Nonetheless, the Shannon-Wiener and Pielou evenness index was lowest in plant stands containing 50% of Bt-transgenic OSR. Among treatments, there was no significant variation for culturable soil microbes. There was a positive association between foliar herbivory and the abundance of plant parasitic (PP) and cp-3 nematodes, whereas there was no association between herbivory and soil microbial populations. There was no direct effects of the presence of Bt-transgenic OSR in wild mustard populations on the rhizosphere nematode and microbial communities, whereas its indirect effects via aboveground herbivory might be important to consider for biosafety assessments. PMID- 26047861 TI - Geochemical controls of high fluoride groundwater in Umarkot Sub-District, Thar Desert, Pakistan. AB - Groundwater samples (n=152) were collected in the Thar Desert of the Umarkot Sub District, Pakistan to evaluate the geochemical controls on the occurrence of high fluoride (F(-)) levels within the study area. Fluoride concentrations range from 0.06 to 44.4 mg/L, with mean and median values of 5.22 and 4.09 mg/L, respectively; and roughly 84% of the samples contain fluoride concentrations that exceed the 1.5mg/L drinking water standard set by WHO. The overall groundwater quality reflects the influences of silicate mineral weathering and evaporation. Fluoride originates from the weathering of minerals derived from Type-A granite and possibly anion exchange (OH(-) for F(-)) on clays and weathered micas under high pH conditions. High fluoride levels are associated with Na-HCO3 type water produced by calcite precipitation and/or base ion exchange. Depleted calcium levels in groundwater allow higher fluoride concentrations to occur before the solubility limit for fluoride is reached. PMID- 26047862 TI - Variation in stream diatom communities in relation to water quality and catchment variables in a boreal, urbanized region. AB - Intensive anthropogenic land use such as urbanization alters the hydrological cycle, water chemistry and physical habitat characteristics, thus impairing stream physicochemical and biological quality. Diatoms are widely used to assess stream water quality as they integrate water chemistry temporally and reflect the joint influence of multiple stressors on stream biota. However, knowledge of the major community patterns of diatoms in urban streams remains limited especially in boreal regions. The aim of this study was to examine the effects of water chemistry and catchment characteristics on stream diatom communities, and to test the performance of the Index of Pollution Sensitivity (IPS) as a stream water quality indicator across an urban-to-rural gradient in southern Finland. Diatom community structure and species richness were related to local-scale variables such as water temperature, aluminium concentration, and electrical conductivity, which were in turn influenced by patterns in catchment land use and land cover. Diatoms reflected the intensity of human activities as more intensive land use increased the occurrence of pollution-tolerant species. The change in community structure along the land use intensity gradient was accompanied by a distinct decline in species richness. On the contrary, the IPS index failed to indicate differences in water quality along the urban-to-rural gradient as no consistent differences in the IPS values were found. Our results highlight the joint influence of multifaceted factors that underlie diatom patterns, and show that diatom biodiversity can be used as cost-effective metric indicating urban stream conditions. However, the IPS index turned out to be an unsuitable tool for assessing water quality among these streams. PMID- 26047864 TI - Farmers' willingness to pay for less health risks by pesticide use: A case study from the cotton belt of Punjab, Pakistan. AB - The amount of pesticides used in crop production in Pakistan has increased rapidly in the last decades, whereas farmers in many areas of the country show little knowledge of safe and efficient use of pesticides. The level of willingness to pay (WTP) for avoiding health risks by pesticides was studied among 318 randomly selected cotton farmers from two districts of the area of Punjab (i.e., Vehari and Lodhran) in Pakistan, using the contingent valuation method. Most farmers felt that pesticide use is a prerequisite for successful cotton production, whereas at the same time they were well aware of pesticide health risks, which they considered minor. The majority of the farmers (77%) showed varying levels of WTP some fee up to 20% of the current pesticide expenditures for avoiding pesticide health risks, but few were willing to pay a fee over 20%. The mean WTP per farmer was low, reaching 5.8 $US on an annual basis. By contrast, a considerable proportion of the farmers (23%) were not willing to pay any fee for avoiding pesticide health risks. These individuals were mostly poor small-scale farmers with limited or no education. High levels of risk perception about pesticides, past experience of pesticide intoxication, high levels of education, and high income were associated with high farmers' WTP for less health risks by pesticides. Farmers who perceived major health risks by pesticides appeared to be highly willing to pay a premium for safe pesticides. Elderly farmers appeared more likely to pay some premium for safe pesticides as a result of higher farming experience and higher income than young farmers. Well educated farmers were more likely to pay a high premium for safe pesticides. Large farm size was a significant predictor of positive WTP, which was interpreted as an indicator of farmers' wealth. PMID- 26047863 TI - The emissions of monoaromatic hydrocarbons from small polymeric toys placed in chocolate food products. AB - The article presents findings on the emissions of selected monoaromatic hydrocarbons from children's toys placed in chocolate food products. The emission test system involved the application of a new type of microscale stationary emission chamber, MU-CTETM 250. In order to determine the type of the applied polymer in the manufacture of the tested toys, Fourier transform infrared spectroscopy and thermogravimetric analysis coupled with differential scanning calorimetry were used. It was found that the tested toy components or the whole toys (figurines) are made of two main types of polymers: polyamide and acrylonitrile-butadiene-styrene copolymer. Total number of studied small polymeric toys was 52. The average emissions of selected monoaromatic hydrocarbons from studied toys made of polyamide were as follows: benzene: 0.45 +/- 0.33 ng/g; toluene: 3.3 +/- 2.6 ng/g; ethylbenzene: 1.4 +/- 1.4 ng/g; p,m xylene: 2.5 +/- 4.5 ng/g; and styrene: 8.2 +/- 9.9 ng/g. In the case of studied toys made of acrylonitrile-butadiene-styrene copolymer the average emissions of benzene, toluene, ethylbeznene, p,m-xylene and styrene were: 0.31 +/- 0.29 ng/g; 2.5 +/- 1.4 ng/g; 4.6 +/- 8.9 ng/g; 1.4 +/- 1.1 ng/g; and 36 +/- 44 ng/g, respectively. PMID- 26047865 TI - Ambient air quality and emission characteristics in and around a non-recovery type coke oven using high sulphur coal. AB - The objective of this study is to determine the concentrations of gaseous species and aerosols in and around a non-recovery type coke making oven using high sulphur coals. In this paper, physico-chemical properties of the feed coal sample are reported along with the collection and measurement of the emitted gases (SO2, NO2, and NH3) and aerosol particles (PM2.5, PM10) during the coal carbonization in the oven. The coals used are from northeast India and they are high sulphur in nature. The concentrations of the gases e.g., SO2, NO2 and NH3 emitted are observed to be within the limit of National Ambient Air Quality Standard for 24h. The mean PM10 and PM2.5 concentrations are found to be 125.4 MUg/m(3) and 48.6 MUg/m(3) respectively, as measured during three days of coke oven operations. About 99% of the SO2 in flue gases is captured by using an alkali treatment during the coke oven operation. A Principal Component Analysis (PCA) after Centred Log Ratio (clr) transformation is also performed to know the positive and negative correlation among the coal properties and the emission parameters. PMID- 26047866 TI - Behaviour and recovery of human adenovirus from tropical sediment under simulated conditions. AB - This study assessed the contributions of pH and organic matter (OM) on the recovery of infectious human adenovirus 5 (HAdV-5) and genome copies (GCs) in waters that were artificially contaminated with tropical soil. The use of a mathematical equation was proposed based on the flocculation index of clay to assess the recovery of total GCs in these controlled assays. The results suggest that solids in the water reduced the viral genome copy loads per millilitre (GC . mL(-1)) and viral infectivity. OM did not influence the GC . mL(-1) recovery rate (p > 0.05) but led to a 99% (2 log10) reduction in plaque-forming unit counts per millilitre (PFU/mL), which indicates that infectivity and gene integrity were non related parameters. Our findings also suggest that acidic pH levels hinder viral inactivation and that clay is the main factor responsible for the interactions of HAdV-5 with soil. These findings may be useful for future eco-epidemiological investigations and studies of viral inactivation or even as parameters for future research into water quality analysis and water treatment. PMID- 26047867 TI - Stream macroinvertebrate communities across a gradient of natural gas development in the Fayetteville Shale. AB - Oil and gas extraction in shale plays expanded rapidly in the U.S. and is projected to expand globally in the coming decades. Arkansas has doubled the number of gas wells in the state since 2005 mostly by extracting gas from the Fayetteville Shale with activity concentrated in mixed pasture-deciduous forests. Concentrated well pads in close proximity to streams could have adverse effects on stream water quality and biota if sedimentation associated with developing infrastructure or contamination from fracturing fluid and waste occurs. Cumulative effects of gas activity and local habitat conditions on macroinvertebrate communities were investigated across a gradient of gas well activity (0.2-3.6 wells per km(2)) in ten stream catchments in spring 2010 and 2011. In 2010, macroinvertebrate density was positively related to well pad inverse flowpath distance from streams (r=0.84, p<0.001). Relatively tolerant mayflies Baetis and Caenis (r=0.64, p=0.04), filtering hydropsychid caddisflies (r=0.73, p=0.01), and chironomid midge densities (r=0.79, p=0.008) also increased in streams where more well pads were closer to stream channels. Macroinvertebrate trophic structure reflected environmental conditions with greater sediment and primary production in streams with more gas activity close to streams. However, stream water turbidity (r=0.69, p=0.02) and chlorophyll a (r=0.89, p<0.001) were the only in-stream variables correlated with gas well activities. In 2011, a year with record spring flooding, a different pattern emerged where mayfly density (p=0.74, p=0.01) and mayfly, stonefly, and caddisfly richness (r=0.78, p=0.008) increased in streams with greater well density and less silt cover. Hydrology and well pad placement in a catchment may interact to result in different relationships between biota and catchment activity between the two sample years. Our data show evidence of different macroinvertebrate communities expressed in catchments with different levels of gas activity that reinforce the need for more quantitative analyses of cumulative freshwater-effects from oil and gas development. PMID- 26047868 TI - The tumor necrosis factor-alpha-238 polymorphism and digestive system cancer risk: a meta-analysis. AB - Many studies have reported the association between tumor necrosis factor-alpha (TNF-alpha)-238 polymorphism and digestive system cancer susceptibility, but the results were inconclusive. We performed a meta-analysis to derive a more precise estimation of the relationship between TNF-alpha-238 G/A polymorphism and digestive system cancer risk. Pooled analysis for the TNF-alpha-238 G/A polymorphism contained 26 studies with a total of 4849 cases and 8567 controls. The meta-analysis observed a significant association between TNF-alpha-238 G/A polymorphism and digestive system cancer risk in the overall population (GA vs GG: OR 1.19, 95 % CI 1.00-1.40, P heterpgeneity = 0.016; A vs G: OR 1.19, 95 % CI 1.03-1.39, P heterpgeneity = 0.015; dominant model: OR 1.20, 95 % CI 1.02-1.41, P heterpgeneity = 0.012). In the analysis of the ethnic subgroups, however, similar results were observed only in the Asian population, but not in the Caucasian population. Therefore, this meta-analysis suggests that TNF-alpha-238 G/A polymorphism is associated with a significantly increased risk of digestive system cancer. Further large and well-designed studies are needed to confirm these findings. PMID- 26047870 TI - [Development and evaluation of ExSel Test to screen for excess salt intake in hypertensive subjects]. AB - OBJECTIVE: Development of a test to screen excess salt intake (ESI) in hypertensive patients. METHODS: Hypertensive subjects living in Paris area have been included. A 24-hour urinary sodium collection has been performed the day before the visit for a day hospital. A food diary was completed on the day of the urine collection and validated after an interview with a dietetician. An ESI was defined by a urinary sodium >= 200mmol/d. Clinical or food characteristics associated to an ESI were retained for the ExSel Test variables. A ROC curve was performed to determine the optimal score for the ExSel Test in detection of ESI in hypertensive patients. RESULTS: One hundred and forty-eight hypertensive patients have been included living in the Ile-de-France area. ESI was observed in 19% with a higher frequency in men. Seven major determinants of ESI have been identified and are the questions that constitute the ExSel Test. A positive response assigns points: man (1); BMI > 30 (2); bread 4 or 5 pieces per day (1) or more than 6 pieces; cheese at least 1 time per day (2); charcuterie at least 2 times per week (2); use of processed broth or pilaf (1); food rich in hidden salt (pizza, cheeseburger, quiche, shrimp, potato chips, smoked fish, olive) at least 2 times per week (1). The ROC curve analysis shows that a score of 5 or more has the best Youden index with a sensitivity of 0.63, specificity of 0.95, PPV of 0.75, NPV of 0.92. CONCLUSIONS: In hypertensive subjects, an excessive salt intake can be detected by the realization of the ExSel Test based only on a simple food-questionnaire and some clinical parameters. For a clinical use of the ExSel Test, an electronic version is available on http://www.comitehta.org. PMID- 26047869 TI - Human adipose-derived stem cells stimulate neuroregeneration. AB - Traumatic brain injuries and degenerative neurological disorders such as Alzheimer's dementia, Parkinson's disease, amyotrophic lateral sclerosis and many others are characterized by loss of brain cells and supporting structures. Restoring microanatomy and function using stem cells is a promising therapeutic approach. Among the many various sources, adipose-derived stem cells (ADSCs) are one of the most easily harvested alternatives, they multiply rapidly, and they demonstrate low immunogenicity with an ability to differentiate into several cell types. The objective of this study was to evaluate the effect of xenotransplanted human ADSCs on post-traumatic regeneration of rat sciatic nerve. Peripheral reconstruction following complete sciatic transection and autonerve grafting was complemented by intra-operative injection of hADSCs into the proximal and distal stumps. The injury caused gliosis and apoptosis of sensory neurons in the lumbar 5 (L5) ganglia in the control rodents; however, animals treated with hADSCs demonstrated a smaller amount of cellular loss. Formation of amputation neuroma, which hinders axonal repair, was less prominent in the experimental group, and immunohistochemical analysis of myelin basic protein showed good myelination 65 days after surgery. At this point, control groups still exhibited high levels of microglia/macrophage-specific marker Iba-1 and proliferating cell nuclear antigen, the mark of an ongoing inflammation and incomplete axonal growth 2 months after the injury. This report demonstrates that hADSCs promote neuronal survival in the spinal ganglion, fuel axonal repair and stimulate the regeneration of peripheral nerves. PMID- 26047871 TI - [Factors associated with medication non-adherence in uncontrolled hypertensive males and females: ODACE study]. AB - OBJECTIVES: The aim of this study was (1) to measure adherence in males and females with uncontrolled hypertension, and (2) to identify factors associated with non-adherence to antihypertensive medication. PATIENTS AND METHODS: Each general practitioner (GP) should include the first two male and the first two female patients with uncontrolled treated hypertension. Adherence to antihypertensive treatment was estimated by the GP and using the French League Against High blood pressure (FLAH) self-administered questionnaire. A stepwise logistic regression analysis was used to identify factors associated with non adherence on the FLAH scale, independently in males and in females. RESULTS: A total of 1630 males and 1612 females were included in the analysis. Adherence to treatment was significantly better in females or when estimated by the GP. Lack of motivation was the first factor associated with poor adherence in both sexes. Considering hypertension as a simple anomaly and not a disease that can lead to cardiac or cerebral disorders was the second common parameter in both sexes. Other common factors were: having monthly periods of financial difficulties in facing his/her needs and absence of regular screening for colon cancer. CONCLUSION: Adherence to treatment is better in uncontrolled hypertensive females. Poor adherence is mainly associated with non-clinical factors. The lack of motivation is the most important element. PMID- 26047872 TI - [Short-term impact of an ambulatory cardiac rehabilitation program on arterial rigidity]. AB - BACKGROUND: If the positive impact of cardiac rehabilitation on metabolic profile and exercise tolerance is well documented in the literature, very few studies evaluated the impact of these rehabilitation programs on arterial rigidity. PURPOSE: The main objective of this study was to determine if a short and intense 4-week cardiac rehabilitation program could yield a positive impact on arterial rigidity. METHOD: A cohort study was performed on Leopold Bellan Foundation. All patients referred for cardiac rehabilitation program after an acute event (surgery, technical gesture or acute decompensate heart failure) were included in this study. Our CR program consists of four sessions per week for five weeks (total of 20 sessions) and includes both exercise and health and nutrition education sessions. In addition to clinical and therapeutic data collection, biochemical analysis for carbohydrate and lipid metabolism and exercise capacity measurements, carotid femoral pulse wave velocity (PWV) were measured in a quiet room in the morning of their first and last day prior to any exercise. RESULTS: One hundred and ninety-eight cardiac patients have participated in this study, of which 79% were male, mean age 60 +/- 10, 50 (25%) were diabetic, 103 (52%) were hypertensive, 60 (30%) were current smokers, 98 (50%) had dyslipidemia, and 140 (71%) were referred for cardiac rehabilitation after acute coronary syndrome. Arterial stiffness is defined by a VPWV value greater or equal to 10. At the beginning, 59% of our patients have rigid arteries. After 20 sessions of cardiac rehabilitation, this number is significantly reduced to 51% (P=0.12). Patients with arterial stiffness have accumulated more major cardiovascular risk factors, and have had less exercise capacity than others. However they benefit similarly from the cardiovascular rehabilitation program. CONCLUSION: In the present study, we observed that arterial stiffness, as reflected by the PWV, tends to decrease after short-term ambulatory cardiac rehabilitation program. PMID- 26047873 TI - [Assessment at distance of a self-measurement of blood pressure education program: The PEA]. AB - Current recommendations advocate self-measurement of blood pressure (SMBP) for the diagnosis and monitoring of high blood pressure (HBP). The "PEA" is an education program of the HTA GWAD network. Its mission is to train hypertensive patients with SMBP. The objective of this study is to evaluate between 6 months to 1 year after the efficiency of this program on the theoretical and practical knowledge of patients, as well as their behavior towards hypertension. Hundred and twenty patients were included in the study. In an interview, their knowledge was assessed using a questionnaire. The acquisition of the technique, reading and figures transcription, purchase of a SMBP device were also evaluated. The average questionnaire score was 5.7/13 (sigma=2.7) before the educational session, 9.5/13 (sigma=1.9) 1 week after the educational session. This improvement persisted over time with 8.9/13 (sigma=2.9) correct answers 6 months to 1 year later. Exactly 73.3% (n=88/120) had a self-measurement device. Among them, 44.3% (n=39/88) practiced SMBP before medical consultations and 10% systematically did it before each medical consultation. A number of 84.2% (n=101/120) mastered the technique and 76.7% (n=92/120) of patients knew how to transcribe figures. Reading and understanding figures were acquired by 61.7% (n=74/120) of patients. A high level of education was correlated with a high level of practice. PEA is a sustainable solid and stable education program. However, the practice of SMBP is not yet systematic and remains to be encouraged in some patients. Given this situation, the network offers improvements in its program: highlighting of objectives, calendar reminder, "coaching" nurse. PMID- 26047874 TI - [Physical activity level and home blood pressure measurement: Pilot study "Acti HTA"]. AB - While physical activity (PA) is recommended for high blood pressure management, the level of PA practice of hypertensive patients remains unclear. We aimed to assess the association between the level of both PA and blood pressure of individuals consulting in 9 hypertension specialist centres. Eighty-five hypertensive patients were included (59 +/- 14 years, 61% men, 12% smokers, 29% with diabetes). Following their consultation, they performed home blood pressure measurement (HBPM) over 7 days (2 in the morning+2 in the evening), they wrote in a dedicated form their daily activities to estimate the additional caloric expenditure using Acti-MET device (built from International physical Activity Questionnaire [IPAQ]). Thus, patients completed a self-administered questionnaire "score of Dijon" (distinguishing active subjects with a score>20/30, from sedentary<10/30). Subjects with normal HBPM value (<135/85 mm Hg) (55% of them) compared to those with high HBPM were older, had a non-significant trend towards higher weekly caloric expenditure (4959 +/- 5045 kcal/week vs. 4048 +/- 4199 kcal/week, P=0.3755) and score of Dijon (19.44 +/- 5.81 vs. 18.00 +/- 4.32, P=0.2094) with a higher proportion of "active" subjects (48.9% vs. 34.2%, P=0.1773). In conclusion, our results demonstrate a "tendency" to a higher level of reported PA for subjects whose hypertension was controlled. This encourages us to continue with a study that would include more subjects, which would assess PA level using an objective method such as wearing an accelerometer sensor. PMID- 26047875 TI - [A multicenter study on profile of hypertension in focal segmental glomerulosclerosis in Tunisia]. AB - Hypertension in focal segmental glomerulosclerosis is frequent and responsible for the progression of the disease. It could be a circumstance of the diagnosis of FSG or a complication of the nephrotic syndrome. PURPOSE: To determine the prevalence of hypertension among patients with FSG diagnosed in Tunisia and to describe the profile of patients with FSG having hypertension in contrast with who do not. PATIENTS AND METHODS: It was a retrospective multicentric study based on 116 patient files having FSG located in 5 specialized centers in Tunisia. RESULTS: The prevalence of hypertension among our patients was 41%, with a feminine predominance, their mean age was 36.34 +/- 15.71 years. The systolic blood pressure among the patients with hypertension was 153.18 mmHg. The nephrotic syndrome was impure due to hypertension in 14.5% of the cases. The patients affected by hypertension were more obese. Proteinuria was higher among those not having hypertension than those with it, who score an average value of 5.67 +/- 4.51 g/24h, with an insignificant difference. Serum creatinine at presentation was significantly higher among patients with hypertension. Vascular lesions were present at the renal biopsy among 39.45% of patients affected by hypertension, associated with renal failure in 58.50% of patients. The etiopathogenic treatment of FSG was essentially based on steroids full dose. CONCLUSION: Hypertension is often present in FSG and its' treatment must be as soon as possible in order to slow the progression of kidney chronic disease. PMID- 26047876 TI - [Hypertension and cardiovascular risk associated with obstructive sleep apnea in adult in Guadeloupe (French West Indies)]. AB - BACKGROUND AND PURPOSE: In Guadeloupe, data on the relationships between arterial hypertension and obstructive sleep apnea are unavailable. The aim of this study was: to assess the frequency of hypertension and non-dipper pattern evaluated by 48-hour ambulatory blood pressure monitoring in an adult population identified obstructive sleep apnea/non-obstructive sleep apnea during overnight polygraphy ; to determine the cardio-metabolic factors associated with obstructive sleep apnea. DESIGN AND METHOD: A cross-sectional study was realized at Pointe-a-Pitre Hospital. Patients were referred for suspected sleep apnea to sleep specialist and performed a nocturnal polygraphy. Diagnosis was confirmed if the apnea hypopnea index was >= 5. We obtained two groups: sleep apnea/non-sleep apnea. All patients underwent 48-hour ambulatory blood pressure monitoring. The cardio metabolic factors were identified and assessed (fasten level of hs-CRP and Homa IR index). RESULTS: A total of 204 patients were included. Mean age at diagnosis was 54 +/- 10 years, 63% were women. OSA was present in 69.6% with a higher frequency in men than in women. Difference was not significant between the two groups for hypertension frequency (84.5% vs 77%; P=0.22), non-dipper pattern (77.5% vs 76%; P=0.79) and hs-CRP. Differences for age, snoring, body max index, mean waist circumference, Homa-IR index, obesity, dyslipidemia, and type 2 diabetes were significant. CONCLUSIONS: Our data highlight raised frequency of cardiovascular metabolic factors in patients with obstructive sleep apnea and confirm their high cardiovascular risk. PMID- 26047877 TI - [Vascular age and cardiovascular risk in patients suffering from stroke]. AB - AIMS: To determine the vascular age of patients suffering from stroke and their cardiovascular risk at 10 years and to compare their vascular age to their real age. MATERIAL AND METHODS: It was about a descriptive and retrospective study carried up from 1st January 2012 to 31st December 2013 at the neurologic clinic of the University teaching hospital Sylvanus Olympio of Lome from patients' files with a confirmed diagnostic of stroke according to the clinical examination and the scanner data. RESULTS: One hundred and ninety-four patients were related to our study. They were shared-out into 101 men and 93 women equal to a sex-ratio (man/woman) of 1.08. The average real age was of 57.6 +/- 13.7 years. High blood pressure was the main risk factor with a prevailing rate of 86.6%, followed by the total hypercholesterolemia (54.3%), the hypocholesterolemia HDL (22.7%), diabetes (10.8%) and nicotinism addiction (4.1%). The average vascular age for all patients was of 68.23 years. The average difference between the real age and the vascular age was of 10 years. The average cardiovascular risk at 10 years in our study was of 13.2%. CONCLUSION: The vascular age of patients suffering from stroke at the University teaching hospital Sylvanus Olympio of Lome is 10 years higher than their real age. This condition considerably increases their risk of cardiovascular diseases. The screening and the early care about vascular risk factors appear therefore of utmost importance. PMID- 26047878 TI - [Relationship between blood pressure, heart rate and cardiac autonomic dysfunction in non-diabetic obese patients]. AB - RATIONALE: Some studies suggest that a high heart rate (HR) would be predictive of the incidence of an elevated blood pressure (BP). Cardiac autonomic dysfunction (CAD) affects a high proportion of obese patients. CAD could be involved in BP increase. Our aim was to examine the relationship between CAD, HR and BP in obese patients without known diabetes. PATIENTS AND METHODS: We included 428 overweight or obese patients. CAD was assessed by analyzing HR variations during three standard tests (Valsalva, deep breathing, lying-to standing), which are mostly dependent on vagal control. An oral load in glucose was performed and the Matsuda index was calculated. RESULTS: The population was separated in 4 groups according to the grade of CAD (no or only one abnormal test, 2 or 3 abnormal tests) and HR (< or >= 75 bpm). Age was similar in the four groups. Systolic (P=0.05), diastolic (P<0.005) and mean BP (P<0.001) differed significantly between the 4 groups, and was the highest in the group of patients who had 2 or 3 abnormal tests and HR >= 75 bpm. Matsuda index differed across the groups (P=0.018) and was the lowest in this group. CONCLUSION: These data indicate that among overweight or obese patients with a defect in cardiac vagal activity BP is elevated only in those with a high heart rate, which is indicative of a more marked insulin resistance and probably an excess in sympathetic activity. PMID- 26047879 TI - [Post-denervation renal artery stenosis - a matter of concern?]. AB - Renal denervation, an invasive technique indicated in resistant hypertension patients insufficiently controlled by antihypertensive drugs, has a good safety profile. However, an increasing number of post-denervation renal artery stenosis cases has recently been reported. We describe the case of a 49-year-old woman with resistant hypertension who was referred to our university hypertension center for renal sympathetic denervation. Her daily treatment included six antihypertensive drugs. CT angiography prior to denervation showed no renal artery stenosis or vessel wall lesions. A standard renal denervation procedure using the St Jude protocol was performed. After an initial improvement in blood pressure profile, she presented with a blood pressure impairment at 3 months after renal denervation leading to the diagnosis of a severe right renal artery stenosis. PMID- 26047880 TI - Comparative studies of the in vitro dissolution and in vivo pharmacokinetics for different formulation strategies (solid dispersion, micronization, and nanocrystals) for poorly water-soluble drugs: A case study for lacidipine. AB - Different formulation strategies have been proposed for poorly water-soluble drugs. The objective of this study is to give an in vitro and in vivo comparison of a solid dispersion, micronization, and nanocrystals, with lacidipine as a model substance. Micronized lacidipine was obtained by jet milling, and nanocrystals were prepared by bead milling. The d50 for the microcrystals (11,200 nm) was about 20 times larger than that for nanocrystals (623 nm). Both colloidal dispersions maintained a crystalline state after milling. Lacipil((r)), lacidipine solid dispersion, was purchased from GlaxoSmithKline. It exhibited a much higher in vitro dissolution profile than both the micronized and nanonized tablets while the micronized and nanonized tablets showed approximately a 1.30- and 2.05-fold increase in AUC(0-24 h) compared with Lacipil((r)), respectively. Among the three formulation approaches, Lacipil((r)) (solid dispersion) exhibited highest dissolution profile, while nanocrystals produced the greatest increase in oral bioavailability. PMID- 26047778 TI - Observation of the rare B(s)(0) ->u+u- decay from the combined analysis of CMS and LHCb data. AB - The standard model of particle physics describes the fundamental particles and their interactions via the strong, electromagnetic and weak forces. It provides precise predictions for measurable quantities that can be tested experimentally. The probabilities, or branching fractions, of the strange B meson (B(s)(0)) and the B0 meson decaying into two oppositely charged muons (MU+ and MU-) are especially interesting because of their sensitivity to theories that extend the standard model. The standard model predicts that the B(s)(0) ->u+u- and B(0) >u+u- decays are very rare, with about four of the former occurring for every billion mesons produced, and one of the latter occurring for every ten billion B0 mesons. A difference in the observed branching fractions with respect to the predictions of the standard model would provide a direction in which the standard model should be extended. Before the Large Hadron Collider (LHC) at CERN started operating, no evidence for either decay mode had been found. Upper limits on the branching fractions were an order of magnitude above the standard model predictions. The CMS (Compact Muon Solenoid) and LHCb (Large Hadron Collider beauty) collaborations have performed a joint analysis of the data from proton proton collisions that they collected in 2011 at a centre-of-mass energy of seven teraelectronvolts and in 2012 at eight teraelectronvolts. Here we report the first observation of the B(s)(0) -> u+u- decay, with a statistical significance exceeding six standard deviations, and the best measurement so far of its branching fraction. Furthermore, we obtained evidence for the B(0) -> u+u- decay with a statistical significance of three standard deviations. Both measurements are statistically compatible with standard model predictions and allow stringent constraints to be placed on theories beyond the standard model. The LHC experiments will resume taking data in 2015, recording proton-proton collisions at a centre-of-mass energy of 13 teraelectronvolts, which will approximately double the production rates of B(s)(0) and B0 mesons and lead to further improvements in the precision of these crucial tests of the standard model. PMID- 26047881 TI - Preparation and properties of PLGA nanofiber membranes reinforced with cellulose nanocrystals. AB - Although extensively used in the fields of drug-carrier and tissue engineering, the biocompatibility and mechanical properties of polylactide-polyglycolide (PLGA) nanofiber membranes still limit their applications. The objective of this study was to improve their utility by introducing cellulose nanocrystals (CNCs) into PLGA nanofiber membranes. PLGA and PLGA/CNC composite nanofiber membranes were prepared via electrospinning, and the morphology and thermodynamic and mechanical properties of these nanofiber membranes were characterized by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and dynamic mechanical analysis (DMA). The cytocompatibility and cellular responses of the nanofiber membranes were also studied by WST-1 assay, SEM, and confocal laser scanning microscopy (CLSM). Incorporation of CNCs (1, 3, 5, and 7 wt.%) increased the average fiber diameter of the prepared nanofiber membranes from 100 nm (neat PLGA) to ~400 nm (PLGA/7 wt.% CNC) and improved the thermal stability of the nanofiber membranes. Among the PLGA/CNC composite nanofiber membranes, those loaded with 7 wt.% CNC nanofiber membranes had the best mechanical properties, which were similar to those of human skin. Cell culture results showed that the PLGA/CNC composite nanofiber membranes had better cytocompatibility and facilitated fibroblast adhesion, spreading, and proliferation compared with neat PLGA nanofiber membranes. These preliminary results suggest that PLGA/CNC composite nanofiber membranes are promising new materials for the field of skin tissue engineering. PMID- 26047882 TI - Stimuli-responsive polyamine-DNA blend nanogels for co-delivery in cancer therapy. AB - Polyamine plasmid DNA (pDNA) hydrogels have been synthesized by an original approach which conjugates pDNA condensation by polyamines and cross-linking reaction with ethylene glycol diglycidyl ether. In an attempt to design more sophisticated vectors with enhanced transfection efficiency and targeting ability, the cell-binding ligand transferrin has been incorporated into polyethylenimine formulations. All systems are photodegradable which allows for the controlled release of different plasmids (pVAX1-LacZ and pcDNA3-FLAG-p53) and anticancer drugs (doxorubicin, epirubicin and paclitaxel). The tumoral treatment through the combined action of pcDNA3-FLAG-p53 gene and an anticancer drug has a stronger potential to suppress the development of cancer cells. The effect is greatly improved when transferrin is encapsulated into the carriers. This study is a relevant contribution for the design of novel generation of plasmid biopharmaceuticals for progresses in gene cancer therapy, feeding the hope of cancer cure. PMID- 26047883 TI - Investigation of cell behaviors on thermo-responsive PNIPAM microgel films. AB - The use of poly(N-isopropylacrylamide) (PNIPAM) as building blocks for engineering responsive coatings and their potential use as switchable substrates such as biosensors have attracted great attention in recent years. However, few studies have been conducted regarding the cell behaviors and the related mechanism on thermos-responsive surfaces consisting of PNIPAM microgel particles. In this work, monodisperse PNIPAM microgels were synthesized and used to prepare PINPAM microgel films. Uniform microgel surfaces can be fabricated by drop coating with the precoating of a polyethylenimine (PEI) layer. Cell experiments indicate that unlike PNIPAM polymer brushes reported with controllable detachment ability, HepG2, which is a human liver carcinoma cell line, remains adherent on the microgel films upon cooling. Surface plasmon resonance (SPR) experiments show an irreversible adsorption of serum proteins on the microgel surface upon cooling, whose adsorption is a prerequisite of cell adhesion during cell culture. This fact may account for the irreversible adhesion of HepG2 cells. PMID- 26047888 TI - HORMONE MEASUREMENT GUIDELINES: Tracing lipid metabolism: the value of stable isotopes. AB - Labelling molecules with stable isotopes to create tracers has become a gold standard method to study the metabolism of lipids and lipoproteins in humans. There are a range of techniques which use stable isotopes to measure fatty acid flux and oxidation, hepatic fatty synthesis, cholesterol absorption and synthesis and lipoprotein metabolism in humans. Stable isotope tracers are safe to use, enabling repeated studies to be undertaken and allowing studies to be undertaken in children and pregnant women. This review provides details of the most appropriate tracers to use, the techniques which have been developed and validated for measuring different aspects of lipid metabolism and some of the limitations of the methodology. PMID- 26047887 TI - Helping Patients to Help Themselves after Breast Cancer Treatment. AB - There is a rise in the number of women living with the long-term consequences of cancer and continuing to suffer unmet need as breast cancer survival improves. This paper includes an introduction to self-management and a discussion of the evidence around the effectiveness of the key intervention types that could help patients to help themselves after treatment. Self-management interventions are particularly beneficial in reducing bother from symptoms, without patients having to take on the additional burden of more unwanted side-effects frequently seen with pharmacological interventions. There is a need to prioritise the funding of these financially viable self-management strategies to ensure equity of access and that these interventions are available for those in need. PMID- 26047886 TI - Biointerface dynamics--Multi scale modeling considerations. AB - Irreversible nature of matrix structural changes around the immobilized cell aggregates caused by cell expansion is considered within the Ca-alginate microbeads. It is related to various effects: (1) cell-bulk surface effects (cell polymer mechanical interactions) and cell surface-polymer surface effects (cell polymer electrostatic interactions) at the bio-interface, (2) polymer-bulk volume effects (polymer-polymer mechanical and electrostatic interactions) within the perturbed boundary layers around the cell aggregates, (3) cumulative surface and volume effects within the parts of the microbead, and (4) macroscopic effects within the microbead as a whole based on multi scale modeling approaches. All modeling levels are discussed at two time scales i.e. long time scale (cell growth time) and short time scale (cell rearrangement time). Matrix structural changes results in the resistance stress generation which have the feedback impact on: (1) single and collective cell migrations, (2) cell deformation and orientation, (3) decrease of cell-to-cell separation distances, and (4) cell growth. Herein, an attempt is made to discuss and connect various multi scale modeling approaches on a range of time and space scales which have been proposed in the literature in order to shed further light to this complex course consequence phenomenon which induces the anomalous nature of energy dissipation during the structural changes of cell aggregates and matrix quantified by the damping coefficients (the orders of the fractional derivatives). Deeper insight into the matrix partial disintegration within the boundary layers is useful for understanding and minimizing the polymer matrix resistance stress generation within the interface and on that base optimizing cell growth. PMID- 26047889 TI - Response to Dr Rahul Katyal's commentary. PMID- 26047891 TI - Obstructive apnea with pseudo-Cheyne-Stokes breathing. PMID- 26047884 TI - 45S5Bioglass(r)-based scaffolds coated with selenium nanoparticles or with poly(lactide-co-glycolide)/selenium particles: Processing, evaluation and antibacterial activity. AB - In the bone tissue engineering field, there is a growing interest in the application of bioactive glass scaffolds (45S5Bioglass((r))) due to their bone bonding ability, osteoconductivity and osteoinductivity. However, such scaffolds still lack some of the required functionalities to enable the successful formation of new bone, e.g. effective antibacterial properties. A large number of studies suggest that selenium (Se) has significant role in antioxidant protection, enhanced immune surveillance and modulation of cell proliferation. Selenium nanoparticles (SeNp) have also been reported to possess antibacterial as well as antiviral activities. In this investigation, uniform, stable, amorphous SeNp have been synthesized and additionally immobilized within spherical PLGA particles (PLGA/SeNp). These particles were used to coat bioactive glass-based scaffolds synthesized by the foam replica method. Samples were characterized by X ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and transmission electron microscopy (TEM). SeNp, 45S5Bioglass((r))/SeNp and 45S5Bioglass((r))/PLGA/SeNp showed a considerable antibacterial activity against Gram positive bacteria, Staphylococcus aureus and Staphylococcus epidermidis, one of the main causative agents of orthopedic infections. The functionalized Se coated bioactive glass scaffolds represent a new family of bioactive, antibacterial scaffolds for bone tissue engineering applications. PMID- 26047885 TI - Wheat germ agglutinin anchored chitosan microspheres of reduced brominated derivative of noscapine ameliorated acute inflammation in experimental colitis. AB - Reduced brominated derivative of noscapine (Red-Br-Nos, EM012), has potent anti inflammatory property. However, physicochemical limitations of Red-Br-Nos like low aqueous solubility (0.43*10(-3) g/mL), high lipophilicity (logP~2.94) and ionization at acidic pH greatly encumber the scale-up of oral drug delivery systems for the management of colitis. Therefore, in present investigation, chitosan microspheres bearing Red-Br-Nos (CTS-MS-Red-Br-Nos) were prepared by emulsion polymerization method and later coated with wheat germ agglutinin (WGA CTS-MS-Red-Br-Nos) to boost the bioadhesive property. The mean particle size and zeta-potential of CTS-MS-Red-Br-Nos were measured to be 10.5+/-5.4 MUm and 8.1+/ 2.2 mV, significantly (P<0.05) lesser than, 30.2+/-3.2 MUm and 19.2+/-2.3 mV of WGA-CTS-MS-Red-Br-Nos. Furthermore, various spectral techniques like SEM, FT-IR, DSC and PXRD substantiated that Red-Br-Nos was molecularly dispersed in tailored microspheres in amorphous state. Surface bioadhesive property of WGA-CTS-MS-Red Br-Nos promoted the affinity toward colon mucin cells in simulated colonic fluid (SCF, pH~7.2). In vitro release studies carried out on WGA-CTS-MS-Red-Br-Nos and CTS-MS-Red-Br-Nos indicated that SCF with colitis milieu (pH~4.7) favored the controlled release of Red-Br-Nos, owing to solubilization at acidic pH. Consistently, in vivo investigation also demonstrated the utility of WGA-CTS-MS Red-Br-Nos, which remarkably attenuated the DSS encouraged neutrophil infiltration, myeloperoxidase activity, and pro-inflammatory cytokine production in C57BL6J mice, as compared to CTS-MS-Red-Br-Nos and Red-Br-Nos suspension. The noteworthy anti-inflammatory activity of WGA-CTS-MS-Red-Br-Nos against acute colitis may be attributed to enhanced drug delivery, affinity and utmost drug exposure at inflamed mucosal layers of colon. In conclusion, WGA-CTS-MS-Red-Br Nos warrants further in-depth in vitro and in vivo investigations to scale-up the technology for clinical translation. PMID- 26047890 TI - Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a 2-week randomized outpatient trial. AB - BACKGROUND: Esmirtazapine (Org 50081), a high-affinity antagonist at 5-HT2A and H1 receptors, was assessed for its hypnotic efficacy. METHODS: In this double blind, randomized study, non-elderly patients with primary insomnia (but otherwise healthy) were treated with esmirtazapine (1.5, 3.0, or 4.5 mg) or placebo for two weeks. The primary end point was patient-reported total sleep time (TST); other patient-reported end points included sleep latency (SL), wake time after sleep onset (WASO), number of awakenings, sleep quality, and satisfaction with sleep duration. Measures to assess the potential adverse effects of treatment included morning alertness, daytime function/napping, and rebound insomnia during a single-blind placebo run-out week after treatment ended. Adverse events (AEs) were also assessed. RESULTS: Overall, 526 patients were randomized and 463 (88%) completed treatment. All esmirtazapine doses significantly improved TST, SL, sleep quality, and satisfaction with sleep duration versus placebo. Relative to placebo, TST was increased by 30-40 min and SL decreased by ~12 min for all doses. The highest dose (4.5 mg) also significantly reduced WASO and number of awakenings. Across doses, AEs occurred in 25.5-32.8% of patients, compared with 20.7% with placebo. The most common AE was somnolence (~10% for esmirtazapine and 2% for placebo). The incidence of AEs leading to discontinuation was low (<=7%), and there were no serious drug-related AEs. Finally, there was no evidence of a rebound insomnia after discontinuation of esmirtazapine. CONCLUSIONS: Two weeks of treatment with esmirtazapine consistently and significantly improved patient-reported sleep parameters, and it was well tolerated in patients with primary insomnia. PMID- 26047892 TI - Esmirtazapine in non-elderly adult patients with primary insomnia: efficacy and safety from a randomized, 6-week sleep laboratory trial. AB - OBJECTIVE: Esmirtazapine (Org 50081), a medication that binds with high affinity to serotonin 5-HT2A and histamine-1 receptors, was evaluated as a potential treatment for insomnia. METHODS: Adults with primary insomnia were treated with esmirtazapine (3.0 or 4.5 mg) or placebo in this 6-week, double-blind, randomized, polysomnography (PSG) study. The end points included wake time after sleep onset (WASO) (primary), latency to persistent sleep, and total sleep time. Patient-reported parameters were also evaluated, including sleep quality and satisfaction with sleep duration. Residual daytime effects and rebound insomnia (sleep parameters during the single-blind placebo run-out week after treatment ended) were also assessed. RESULTS: Overall, 419 patients were randomized and 366 (87%) completed treatment. The median decrease in PSG WASO (double-blind average) was 20.5 min for placebo, and 52.0 min and 53.6 min for the 3.0- and 4.5-mg esmirtazapine groups, respectively (P < 0.0001 vs. placebo for both doses). Changes in the other PSG parameters and in all patient-reported parameters were also statistically significant with both doses versus placebo. Overall, 35-42% of esmirtazapine-treated patients had adverse events (AEs) versus 29% in the placebo group. AEs were mild or moderate in most esmirtazapine-treated patients. Furthermore, the incidence of AEs leading to discontinuation was low (<8%). CONCLUSIONS: Six weeks of treatment with esmirtazapine was associated with consistent improvements in objective and patient-reported parameters of sleep onset, maintenance, and duration. It was generally well tolerated, and residual daytime effects were minimal and no rebound insomnia was observed. PMID- 26047893 TI - Poly(ADP-ribosyl)ation enhances H-RAS protein stability and causes abnormal cell cycle progression in human TK6 lymphoblastoid cells treated with hydroquinone. AB - Hydroquinone (HQ), one of the most important benzene-derived metabolites, can induce aberrant cell cycle progression; however, the mechanism of this induction remains unclear. Poly(ADP-ribosyl)ation (PARylation), which is catalysed primarily by poly(ADP-ribose) polymerase-1 (PARP-1), participates in various biological processes, including cell cycle control. The results of the present study show an accumulation in G1 phase versus S phase of TK6 human lymphoblast cells treated with HQ for 48h compared with PBS-treated cells; after 72h of HQ treatment, the cells transitioned from G1 arrest to S phase arrest. We examined the expression of six genes related to the cell cycle or leukaemia to further explore the reason for this phenomenon. Among these genes, H-RAS was found to be associated with this phenomenon because its mRNA and protein expression decreased at 48h and increased at 72h. Experiments for PARP activity induction and inhibition revealed that the observed PARylation was positively associated with H RAS expression. Moreover, in cells treated with HQ in conjunction with PARP-1 knockdown, expression of the H-RAS protein decreased and the number of cells in G1 phase increased. The degree of poly(ADP-ribosyl) modification of the H-RAS protein increased in cells treated with HQ for 72h, further supporting that changes in PARylation contributed to the rapid alteration of H-RAS protein expression, followed by abnormal progression of the cell cycle. Co immunoprecipitation (co-IP) assays were employed to determine whether protein complexes were formed by PARP-1 and H-RAS proteins, and the direct interaction between these proteins indicated that PARylation regulated H-RAS expression. As detected by confocal microscopy, the H-RAS protein was found in the nucleus and cytoplasm. To our knowledge, this study is the first to reveal that H-RAS protein can be modified by PARylation. PMID- 26047894 TI - Glucuronic acid in Arabidopsis thaliana xylans carries a novel pentose substituent. AB - Glucuronic acids in Arabidopsis thaliana xylans exist in 4-O-methylated (MeGlcA) and non-methylated (GlcA) forms at a ratio of about 3:2. The matrix-assisted laser desorption/ionization mass spectrometry analysis of the endoxylanase liberated acidic oligosaccharides from the Arabidopsis inflorescence stem showed that two peaks with GlcA (GlcA-Xyl4Ac1 and GlcA-Xyl5Ac2) had abnormally high intensities, as well as different tandem mass spectra, than their 4-O-methylated counterparts. These peaks were interestingly enriched in the xylan biosynthesis mutant irx7 and irx9-1. Multi-stages fragmentation analysis using negative ion electrospray-ion trap mass spectrometry indicated that this GlcA was further carrying a pentose residue in the glucuronoxylan-derived oligosaccharide from irx9-1. The structure was also identified in Arabidopsis wild type. The results prove evidence of a new pentose substitution on the GlcA residue of Arabidopsis GX, which is likely present in the primary walls. PMID- 26047895 TI - Sources of marine superoxide dismutases: Characteristics and applications. AB - The ability of marine organism to cope with oxidative stress is one of the main factors that influence its survival in the marine environment, when senescence conditions prevail. The antioxidative defense system includes enzymatic and non enzymatic components. Among the enzymatic system, superoxide dismutases are the first and most important of the antioxidant metalloenzymes. Four different types of metal centers have been detected in SODs, dividing this family into Cu/Zn, Ni, Mn and Fe-SODs. Its use was limited to non-drug applications in humans (include: cosmetic, food, agriculture, and chemical industries) and drug applications in animals. This paper is a review of the recent literatures on sources of marine SODs, the need for SOD and different applications in industry, covering the last decades. The most recent paper, patents and reviews on characterization and application are reviewed. PMID- 26047896 TI - Influence of chitosan and its derivatives on cell development and physiology of Ustilago maydis. AB - Ustilago maydis, a dimorphic fungus causing corn smut disease, serves as an excellent model to study different aspects of cell development. This study shows the influence of chitosan, oligochitosan and glycol chitosan on cell growth and physiology of U. maydis. These biological macromolecules affected the cell growth of U. maydis. In particular, it was found that chitosan completely inhibited U. maydis growth at 1mg/mL concentration. Microscopic studies revealed swellings on the surface of the cells treated with the polymers, and chitosan caused complete destruction of the membrane and formation of vesicles on the periphery of the cell. Oligochitosan and chitosan caused changes in oxygen consumption, K(+) efflux and H(+)-ATPase activity. Oligochitosan induced a faster consumption of oxygen in the cells, while glycol chitosan provoked slower oxygen consumption. It is noteworthy that chitosan completely inhibited the fungal respiratory activity. The strongest effects were exhibited by chitosan in all evaluated aspects. These findings showed high sensitivity of U. maydis to chitosan and provided evidence for antifungal effects of chitosan derivatives. To our knowledge, this is a first report showing that chitosan and its derivatives affect the cell morphology and physiological processes in U. maydis. PMID- 26047897 TI - Fabrication and durable antibacterial properties of electrospun chitosan nanofibers with silver nanoparticles. AB - Non-precipitation chitosan/silver nanoparticles (AgNPs) in 1% acetic acid aqueous solution was prepared from chitosan colloidal gel with various contents of silver nitrate via electron beam irradiation (EBI). Electrospun chitosan-based nanofibers decorated with AgNPs were successfully performed by blending poly(vinyl alcohol). The morphology of as-prepared nanofibers and the size of AgNPs in the nanofibers were investigated by field emission scanning electron microscopy (FESEM) and transmission electron microscopy (TEM). The presence of AgNPs in as-obtained nanofibers was also confirmed by ultraviolet-visible spectroscopy (UV), Fourier transform infrared (FT-IR) spectroscopy, EDX spectrum and metal mapping. Silver ion release behavior indicated that these hybrid nanofibers continually release adequate silver to exhibit antibacterial activity over 16 days. These biocomposite nanofibers showed pronounced antibacterial activity against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). PMID- 26047898 TI - Production of poly-beta-hydroxybutyrate by Bacillus cereus PS 10 using biphasic acid-pretreated rice straw. AB - Poly-beta-hydroxybutyrate (PHB) has attracted a great deal of attention in recent years due to its potential use for production of fully degradable bioplastics, however, high cost of PHB production is the major bottleneck for its wide range industrial applications. In the current study rice straw hydrolysate (RSH) was employed as a cost-effective substrate for PHB production. RSH was prepared based on biphasic acid-pretreatment of rice straw i.e. first phase treatment with 1% sulphuric acid at 121 degrees C for 45 min, followed by second phase treatment using 5% sulphuric acid at 121 degrees C for 60 min (solid:liquid ratio, 1:10). RSH turned out be an efficient substrate for PHB production from a recently isolated Bacillus cereus PS 10, and yielded higher PHB amount than that obtained with glucose (8.6g/L in glucose based medium vs 10.61 g/L in RSH based medium) after response surface methodology (RSM) based optimization. Design of experiments based on RSM was used to optimize three process variables i.e. amount of RSH and NH4Cl, and medium pH, and enhanced PHB yield (23.3%) was obtained. PHB produced was investigated by differential scanning calorimetry and X-ray diffraction powder analysis. PMID- 26047899 TI - Protective effects of Ginkgo biloba leaf polysaccharide on nonalcoholic fatty liver disease and its mechanisms. AB - A water-soluble polysaccharide fraction extracted from the leaf of Ginkgo biloba was named GBLP. The protective effect of GBLP on nonalcoholic fatty liver disease (NAFLD) was observed and underlying mechanism was explored. Wistar male rats were randomly divided into five groups, namely, normal control group, model control group and GBLP groups (100, 200 and 400 mg/kg/d). A rat model of NAFLD was established in male Wistar rats by feeding with high-fat diet (HFD) for 8 weeks. On day 57, the intragastric administration of GBLP started once daily for 4 weeks. The results showed that GBLP supplementation significantly and dose dependently lowered the weight gain of body, liver index and serum lipid parameters in HFD-fed rat. Meanwhile, GBLP attenuated HFD-induced liver injury through reducing hepatic steatosis, TG accumulation, serum ALT, AST and ALP levels. GBLP had a positive effect on obesity-associated insulin resistance (IR) via reducing serum glucose and insulin levels. Furthermore, GBLP enhanced the activities of antioxidant enzymes and reduced MDA levels in serum and liver. These results indicate that GBLP can play a certain protective role against HFD induced NAFLD, and the protective effects may be associated with attenuating IR, preserving liver function, enhancing antioxidant defense system, and reducing lipid peroxidation. PMID- 26047900 TI - Montmorillonite/graphene oxide/chitosan composite: Synthesis, characterization and properties. AB - The present work reports the successful preparation, thermal and mechanical characterization of high performance films of Na(+) montmorillonite (MMT)/graphene oxide (GO)/chitosan (CS) composite using simple solution mixing evaporation method. The formations of films were verified by Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), X-ray diffraction (XRD) and Raman spectroscopy. The thermal stability and mechanical properties of these films were investigated by thermogravimetric analysis (TGA) and mechanical testing (Instron 8871). The results obtained from these studies revealed that the composites of chitosan, MMT, and graphene oxide were homogeneous in nature. A synergistic effect of MMT and GO reinforcing on chitosan matrix was observed for the first time, in case of 5 wt.% MMT and 1 wt.% GO. The tensile strength of (5 wt.%) MMT/(1 wt.%) GO/CS composite was formed 9+/-0.23% and 27+/-0.25% higher than that of the (1 wt.%) GO/CS composite and chitosan, respectively. PMID- 26047901 TI - (1->3)-alpha-D-Glucan hydrolases in dental biofilm prevention and control: A review. AB - Dental plaque is a highly diverse biofilm, which has an important function in maintenance of oral and systemic health but in some conditions becomes a cause of oral diseases. In addition to mechanical plaque removal, current methods of dental plaque control involve the use of chemical agents against biofilm pathogens, which however, given the complexity of the oral microbiome, is not sufficiently effective. Hence, there is a need for development of new anti biofilm approaches. Polysaccharides, especially (1->3),(1->6)-alpha-D-glucans, which are key structural and functional constituents of the biofilm matrix, seem to be a good target for future therapeutic strategies. In this review, we have focused on (1->3)-alpha-glucanases, which can limit the cariogenic properties of the dental plaque extracellular polysaccharides. These enzymes are not widely known and have not been exhaustively described in literature. PMID- 26047902 TI - Discrepancy between early neurological course and mid-term outcome in older stroke patients after mechanical thrombectomy. AB - BACKGROUND: Stroke in aged patients has a relatively poor prognosis, even after recanalizing therapy. Potential reasons include mechanisms that relate directly to the extent of brain tissue damage, but also age-dependent factors which are not, or only indirectly, stroke-related, such as pre-existing functional deficits, comorbidities, and post-stroke complications (eg, infections). OBJECTIVE: To compare early neurological course with subsequent functional outcome in older (>=80 years) and younger stroke patients in order to estimate the relative impact of these factors. Specifically, to examine if the strong age dependency of modified Rankin Scale (mRS) outcome scores in stroke patients after mechanical thrombectomy is paralleled by a similar age dependency of early postinterventional National Institute of Health Stroke Scale (NIHSS) scores-a more specific measure of stroke-induced brain damage. METHODS: We evaluated technical results, pre- and postinterventional NIHSS scores, mid-term mRS scores and early and overall mortality and their relation to age in 125 patients, 40 of them >=80 years, with acute middle cerebral artery occlusion, treated by mechanical thrombectomy. RESULTS: Technical success, pre- and postinterventional NIHSS scores and early mortality were age-independent. Early neurological improvement depended on successful recanalization, but not on age. Nevertheless, good mRS outcome (mRS 0-2) was much rarer, and overall mortality almost threefold higher in aged patients. CONCLUSIONS: Older patients exhibit a similar early neurological course and responsiveness to mechanical thrombectomy as younger patients, but this is not reflected in mid-term functional outcome scores. This indicates that post-stroke complications and other factors that are not, or only indirectly, related to the brain tissue damage induced by the incident stroke have a dominant role in their poor prognosis. PMID- 26047903 TI - Accuracy of flat panel detector CT with integrated navigational software with and without MR fusion for single-pass needle placement. AB - PURPOSE: Fluoroscopic systems in modern interventional suites have the ability to perform flat panel detector CT (FDCT) with navigational guidance. Fusion with MR allows navigational guidance towards FDCT occult targets. We aim to evaluate the accuracy of this system using single-pass needle placement in a deep brain stimulation (DBS) phantom. MATERIALS AND METHODS: MR was performed on a head phantom with DBS lead targets. The head phantom was placed into fixation and FDCT was performed. FDCT and MR datasets were automatically fused using the integrated guidance system (iGuide, Siemens). A DBS target was selected on the MR dataset. A 10 cm, 19 G needle was advanced by hand in a single pass using laser crosshair guidance. Radial error was visually assessed against measurement markers on the target and by a second FDCT. Ten needles were placed using CT-MR fusion and 10 needles were placed without MR fusion, with targeting based solely on FDCT and fusion steps repeated for every pass. RESULTS: Mean radial error was 2.75+/-1.39 mm as defined by visual assessment to the centre of the DBS target and 2.80+/ 1.43 mm as defined by FDCT to the centre of the selected target point. There were no statistically significant differences in error between MR fusion and non-MR guided series. CONCLUSIONS: Single pass needle placement in a DBS phantom using FDCT guidance is associated with a radial error of approximately 2.5-3.0 mm at a depth of approximately 80 mm. This system could accurately target sub-centimetre intracranial lesions defined on MR. PMID- 26047904 TI - Targeted epidural patch with n-butyl cyanoacrylate (n-BCA) through a single catheter access site for treatment of a cerebral spinal fluid leak causing spontaneous intracranial hypotension. AB - Spontaneous intracranial hypotension (SIH) usually occurs in the setting of a spontaneous cerebral spinal fluid (CSF) leak. We report the first description of a case of SIH caused by a CSF leak which improved after a targeted epidural patch with n-butyl cyanoacrylate (n-BCA) at the right T1-T2 level. An 81-year-old woman presented with an orthostatic headache for 6 days. MRI of the brain with contrast demonstrated low lying cerebellar tonsils, an engorged transverse sinus flow void, bifrontal small subdural fluid collections, and diffuse dural enhancement. CT myelography showed extravasation of intrathecal contrast at the right T1-T2 level. A targeted epidural patch was performed by injection of n-BCA through a catheter at the right T1-T2 level. After treatment, the patient's symptoms immediately improved and she was without a headache at 1-year follow-up. PMID- 26047905 TI - Get Up and Go. PMID- 26047906 TI - Quality Control of Widely Used Therapeutic Recombinant Proteins by a Novel Real Time PCR Approach. AB - BACKGROUND: Existence of bacterial host-cell DNA contamination in biopharmaceutical products is a potential risk factor for patients receiving these drugs. Hence, the quantity of contamination must be controlled under the regulatory standards. Although different methods such as hybridization assays have been employed to determine DNA impurities, these methods are labor intensive and rather expensive. In this study, a rapid real-time PCR test was served as a method of choice to quantify the E. coli host- cell DNA contamination in widely used recombinant streptokinase (rSK) , and alpha interferon (IFN-alpha) preparations. METHODS: A specific primer pair was designed to amplify a sequence inside the E. coli 16S rRNA gene. Serial dilutions of DNA extracted from E. coli host cells, along with DNA extracted from Active Pharmaceutical Ingredients of rSK, and IFN-alpha samples were subjected to an optimized real-time PCR assay based on SYBR Green chemistry. RESULTS: The test enabled us to detect a small quantity of genomic DNA contamination as low as 0.0002 pg in recombinant protein based drugs. For the first time, this study showed that DNA contamination in rSK and IFN-alpha preparation manufactured in Pasteur Institute of Iran is much lower than the safety limit suggested by the US FDA. CONCLUSION: Real-time PCR is a reliable test for rapid detection of host-cell DNA contamination, which is a major impurity of therapeutic recombinant proteins to keep manufacturers' minds on refining drugs, and provides consumers with safer biopharmaceuticals. PMID- 26047907 TI - QR Codes: Outlook for Food Science and Nutrition. AB - QR codes opens up the possibility to develop simple-to-use, cost-effective-cost, and functional systems based on the optical recognition of inexpensive tags attached to physical objects. These systems, combined with Web platforms, can provide us with advanced services that are already currently broadly used on many contexts of the common life. Due to its philosophy, based on the automatic recognition of messages embedded on simple graphics by means of common devices such as mobile phones, QR codes are very convenient for the average user. Regretfully, its potential has not yet been fully exploited in the domains of food science and nutrition. This paper points out some applications to make the most of this technology for these domains in a straightforward manner. For its characteristics, we are addressing systems with low barriers to entry and high scalability for its deployment. Therefore, its launching among professional and final users is quite simple. The paper also provides high-level indications for the evaluation of the technological frame required to implement the identified possibilities of use. PMID- 26047909 TI - Conjugation of D-glucosamine to bovine trypsin increases thermal stability and alters functional properties. AB - D-Glucosamine was conjugated to bovine trypsin by carbodiimide chemistry, involving a water-soluble carbodiimide and a succinimide ester, with the latter being to increase the yield of the conjugation. Mass spectrometric data suggested that several glycoforms were formed, with around 12 D-glucosamine moieties coupled to each trypsin molecule on average. The moieties were probably coupled to eight carboxyl groups (of glutamyl and aspartyl residues) and to four tyrosyl residues on the surface of the enzyme. The glycated trypsin possessed increased thermal stability. When compared with its unmodified counterpart, T50% was increased by 7 degrees C, thermal inactivation of the first step was increased 34%, and long-term stability assay revealed 71-times higher residual activity at 25 degrees C (without stabilizing Ca(2+) ions in aqueous buffer) after 67 days. Furthermore, resistance against autolysis was increased almost two-fold. Altered functional properties of the glycated trypsin were also observed. The glycated trypsin was found to become increasingly basophilic, and was found to be slightly structurally altered. This was indicated by 1.2 times higher catalytic efficiency (k(cat)/K(m)) than unmodified trypsin against the substrate N-alpha-benzoyl-L arginine-p-nitroanilide. Circular dichroism spectropolarimetry suggested a minor change in spatial arrangement of alpha-helix/helices, resulting in an increased affinity of the glycated trypsin for this small synthetic substrate. PMID- 26047908 TI - Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. PMID- 26047910 TI - Mechanism of papain-catalyzed synthesis of oligo-tyrosine peptides. AB - Di-, tri-, and tetra-tyrosine peptides with angiotensin I-converting enzyme inhibitory activity were synthesized by papain-catalyzed polymerization of L tyrosine ethyl ester in aqueous media at 30 degrees C. Varying the reaction pH from 6.0 to 7.5 and the initial concentration of the ester substrate from 25 to 100 mM, the highest yield of oligo-tyrosine peptides (79% on a substrate basis) was produced at pH 6.5 and 75 mM, respectively. In the reaction initiated with 100 mM of the substrate, approx. 50% yield of insoluble, highly polymerized peptides accumulated. At less than 15 mM, the reaction proceeded poorly; however, from 30 mM to 120 mM a dose-dependent increase in the consumption rate of the substrate was observed with a sigmoidal curve. Meanwhile, each of the tri- and tetra-tyrosine peptides, even at approx. 5mM, was consumed effectively by papain but was not elongated to insoluble polymers. For deacylation of the acyl-papain intermediate through which a new peptide bond is made, L-tyrosine ethyl ester, even at 5mM, showed higher nucleophilic activity than di- and tri-tyrosine. These results indicate that the mechanism through which papain polymerizes L-tyrosine ethyl ester is as follows: the first interaction between papain and the ester substrate is a rate-limiting step; oligo-tyrosine peptides produced early in the reaction period are preferentially used as acyl donors, while the initial ester substrate strongly contributes as a nucleophile to the elongation of the peptide product; and the balance between hydrolytic fragmentation and further elongation of oligo-tyrosine peptides is dependent on the surrounding concentration of the ester substrate. PMID- 26047911 TI - Enzymatic synthesis of gamma-L-glutamyl-S-allyl-L-cysteine, a naturally occurring organosulfur compound from garlic, by Bacillus licheniformis gamma glutamyltranspeptidase. AB - In the practical application of Bacillus licheniformis gamma glutamyltranspeptidase (BlGGT), we describe a straightforward enzymatic synthesis of gamma-L-glutamyl-S-allyl-L-cysteine (GSAC), a naturally occurring organosulfur compound found in garlic, based on a transpeptidation reaction involving glutamine as the gamma-glutamyl donor and S-allyl-L-cysteine as the acceptor. With the help of thin layer chromatography technique and computer-assisted image analysis, we performed the quantitative determination of GSAC. The optimum conditions for a biocatalyzed synthesis of GSAC were 200 mM glutamine, 200 mM S allyl-L-cysteine, 50 mM Tris-HCl buffer (pH 9.0), and BlGGT at a final concentration of 1.0 U/mL. After a 15-h incubation of the reaction mixture at 60 degrees C, the GSAC yield for the free and immobilized enzymes was 19.3% and 18.3%, respectively. The enzymatic synthesis of GSAC was repeated under optimal conditions at 1-mmol preparative level. The reaction products together with the commercially available GSAC were further subjected to an ESI-MS/MS analysis. A significant signal with m/z of 291.1 and the protonated fragments at m/z of 73.0, 130.1, 145.0, and 162.1 were observed in the positive ESI-MS/MS spectrum, which is consistent with those of the standard compound. These results confirm the successful synthesis of GSAC from glutamine and S-allyl-L-cysteine by BlGGT. PMID- 26047912 TI - A new generation of flowerlike horseradish peroxides as a nanobiocatalyst for superior enzymatic activity. AB - Although various supports including nanomaterials have been widely utilized as platforms for enzymes immobilization in order to enhance their catalytic activities, most of immobilized enzymes exhibited reduced activities compared to free enzymes. In this study, for the first time, we used iron ions (Fe(2+)) and horseradish peroxidase (HRP) enzyme together to synthesize flowerlike hybrid nanostructures with greatly enhanced activity and stability and reported an explanation of the enhancements in both catalytic activity and stability. We demonstrated that Fe(2+)-HRP hybrid nanoflower (HNF) showed catalytic activity of ~ 512% and ~ 710%, respectively when stored at +4 degrees C and room temperature (RT = 20 degrees C) compared to free HRP. In addition, the HNF stored at +4 degrees C lost only 2.9% of its original activity within 30 days while the HNF stored at RT lost approximately 10% of its original activity. However, under the same conditions, free HRP enzymes stored at +4 degrees C and RT lost 68% and 91% of their activities, respectively. We claim that the drastic increases in activities of HNF are associated with to high local HRP concentration in nanoscale dimension, appropriate HRP conformation, less mass transfer limitations, and role of Fe(2+) ion as an activator for HRP. Further biosensors studies based on enhanced activity and stability of HNF are currently underway. PMID- 26047914 TI - Galactose-limited fed-batch cultivation of Escherichia coli for the production of lacto-N-tetraose. AB - Lacto-N-tetraose (Gal(beta1-3)GlcNAc(beta1-3)Gal(beta1-4)Glc) is one of the most abundant oligosaccharide structures in human milk. We recently described the synthesis of lacto-N-tetraose by a whole-cell biotransformation with recombinant Escherichia coli cells. However, only about 5% of the lactose was converted into lacto-N-tetraose by this approach. The major product obtained was the intermediate lacto-N-triose II (GlcNAc(beta1-3)Gal(beta1-4)Glc). In order to improve the bioconversion of lactose to lacto-N-tetraose, we have investigated the influence of the carbon source on the formation of lacto-N-tetraose and on the intracellular availability of the glycosyltransferase substrates, UDP-N acetylglucosamine and UDP-galactose. By growth of the recombinant E. coli cells on D-galactose, the yield of lacto-N-tetraose (810.8 mg L(-1) culture) was 3.6 times higher compared to cultivation on D-glucose. Using fed-batch cultivation with galactose as sole energy and carbon source, a large-scale synthesis of lacto N-tetraose was demonstrated. During the 26 h feeding phase the growth rate (MU = 0.05) was maintained by an exponential galactose feed. In total, 16 g L(-1) lactose were fed and resulted in final yields of 12.72 +/- 0.21 g L(-1) lacto-N tetraose and 13.70 +/- 0.10 g L(-1) lacto-N-triose II. In total, 173 g of lacto-N tetraose were produced with a space-time yield of 0.37 g L(-1) h(-1). PMID- 26047913 TI - Scaling-up the synthesis of myristate glucose ester catalyzed by a CALB displaying Pichia pastoris whole-cell biocatalyst. AB - The novel whole-cell biocatalyst Candida antarctica lipase B displaying-Pichia pastoris (Pp-CALB) is characterized by its low preparation cost and could be an alternative to the commercial immobilized Candida antarctica lipase B (CALB). This study addresses the feasibility of using Pp-CALB in large scale glucose fatty acid esters production. 1,2-O-Isopropylidene-alpha-D-glucofuranose (IpGlc) was used as the acyl acceptor to overcome the low solubility of glucose in an organic solvent and to avoid the addition of toxic co-solvents. IpGlc significantly improved the Pp-CALB catalyzing esterification efficiency when using long chain fatty acids as the acyl donor. Under the preferred operating conditions (50 degrees C, 40 g/L molecular sieve dosage and 200 rpm mixing intensity), 60.5% of IpGlc converted to 6-O-myristate-1, 2-O-isopropylidene-alpha D-glucofuranose (C14-IpGlc) after a 96-h reaction in a 2-L stirred reactor. In a 5-L pilot scale test, Pp-CALB also showed a similar substrate conversion rate of 55.4% and excellent operational stability. After C14-IpGlc was collected, 70% trifluoroacetic acid was adopted to hydrolyze C14-IpGlc to myristate glucose ester (C14-Glc) with a high yield of 95.3%. In conclusion, Pp-CALB is a powerful biocatalyst available for industrial synthesis, and this study describes an applicable and economical process for the large scale production of myristate glucose ester. PMID- 26047915 TI - Cell lysis induced by membrane-damaging detergent saponins from Quillaja saponaria. AB - This paper presents the results of a study to determine the effect of Quillaja saponaria saponins on the lysis of industrial yeast strains. Cell lysis induced by saponin from Q. saponaria combined with the plasmolysing effect of 5% NaCl for Saccharomyces cerevisiae, Kluyveromyces marxianus yeasts biomass was conducted at 50 degrees C for 24-48 h. Membrane permeability and integrity of the yeast cells were monitored using fluorescent techniques and concentrations of proteins, free amino nitrogen (FAN) and free amino acids in resulting lysates were analyzed. Protein release was significantly higher in the case of yeast cell lysis promoted with 0.008% Q. saponaria and 5% NaCl in comparison to plasmolysis triggered by NaCl only. PMID- 26047916 TI - Characterization and application of a novel class II thermophilic peroxidase from Myceliophthora thermophila in biosynthesis of polycatechol. AB - A peroxidase from the thermophilic fungus Myceliophthora thermophila that belongs to ascomycete Class II based on PeroxiBase classification was functionally expressed in methylotrophic yeast Pichia pastoris. The putative peroxidase from the genomic DNA was successfully cloned in P. pastoris X-33 under the transcriptional control of the alcohol oxidase (AOX1) promoter. The heterologous production was greatly enhanced by the addition of hemin with a titer of 0.41 U mL(-1) peroxidase activity at the second day of incubation. The recombinant enzyme was purified to homogeneity (50 kDa) and characterized using a series of phenolic substrates that indicated similar characteristics with those of generic peroxidases. In addition, the enzyme was found thermostable, retaining its activity for temperatures up to 60 degrees C after eight hours incubation. Moreover, the enzyme displayed remarkable H2O2 stability, retaining more than 80% of its initial activity after 24h incubation in 5000-fold molar excess of H2O2. The ability of the peroxidase to polymerize catechol at high superoxide concentrations, together with its high thermostability and substrate specificity, indicate a potential commercial significance of the enzyme. PMID- 26047917 TI - Exploring codon context bias for synthetic gene design of a thermostable invertase in Escherichia coli. AB - Various isoforms of invertases from prokaryotes, fungi, and higher plants has been expressed in Escherichia coli, and codon optimisation is a widely-adopted strategy for improvement of heterologous enzyme expression. Successful synthetic gene design for recombinant protein expression can be done by matching its translational elongation rate against heterologous host organisms via codon optimization. Amongst the various design parameters considered for the gene synthesis, codon context bias has been relatively overlooked compared to individual codon usage which is commonly adopted in most of codon optimization tools. In addition, matching the rates of transcription and translation based on secondary structure may lead to enhanced protein folding. In this study, we evaluated codon context fitness as design criterion for improving the expression of thermostable invertase from Thermotoga maritima in Escherichia coli and explored the relevance of secondary structure regions for folding and expression. We designed three coding sequences by using (1) a commercial vendor optimized gene algorithm, (2) codon context for the whole gene, and (3) codon context based on the secondary structure regions. Then, the codon optimized sequences were transformed and expressed in E. coli. From the resultant enzyme activities and protein yield data, codon context fitness proved to have the highest activity as compared to the wild-type control and other criteria while secondary structure based strategy is comparable to the control. Codon context bias was shown to be a relevant parameter for enhancing enzyme production in Escherichia coli by codon optimization. Thus, we can effectively design synthetic genes within heterologous host organisms using this criterion. PMID- 26047918 TI - Constitutive expression of Campylobacter jejuni truncated hemoglobin CtrHb improves the growth of Escherichia coli cell under aerobic and anaerobic conditions. AB - Bacteria hemoglobin could bind to the oxygen, transfer it from the intracellular microenvironment to the respiration process and sustain the energy for the metabolism and reproduction of cells. Heterologous expression of bacteria hemoglobin gene could improve the capacity of the host on oxygen-capturing and allow it to grow even under microaerophilic condition. To develop a system based on hemoglobin to help bacteria cells overcome the oxygen shortage in fermentation, in this study, Campylobacter jejuni truncated hemoglobin (CtrHb) gene was synthesized and expressed under the control of constitutive expression promoters P2 and P(SPO1-II) in Escherichia coli. As showed by the growth curves of the two recombinants P2-CtrHb and P(SPO1-II)-CtrHb, constitutive expression of CtrHb improved cell growth under aerobic shaking-flasks, anaerobic capped-bottles and bioreactor conditions. According to the NMR analysis, this improvement might come from the expression of hemoglobin which could boost the metabolism of cells by supplying more oxygen to the respiratory chain processes. Through semi quantitative RT-PCR and CO differential spectrum assays, we further discussed the connection between the growth patterns of the recombinants, the expression level of CtrHb and oxygen binding capacity of CtrHb in cells. Based on the growth patterns of these recombinants in bioreactor, a possible choice on different type of recombinants under specific fermentation conditions was also suggested in this study. PMID- 26047919 TI - A Novel Configuration of Pipeline Embolization Device for Internal Carotid Bifurcation Region Aneurysms: Horizontal Deployment. AB - PURPOSE: To describe a novel configuration of pipeline embolization device for internal carotid bifurcation region aneurysm, named horizontal stenting. CLINICAL PRESENTATION: A 64-year-old woman, with visual deficit, harboring a large wide necked aneurysm located at the junction between left internal carotid artery and left A1 segment of anterior cerebral artery, was submitted to endovascular treatment. As she had pre-existing occlusion of left internal carotid, approach from the contralateral internal carotid was used to advance the pipeline embolization device through the anterior communicating artery and place the flow diverter horizontally across the neck (from M1 to A1). Coil embolization was also performed through a microcatheter navigated via posterior communicating artery. The intervention was uneventful, with total aneurysm occlusion. Patient presented with visual improvement on follow-up. CONCLUSION: Horizontal deployment of pipeline embolization device appears to be an acceptable and feasible alternative to treat internal carotid bifurcation aneurysms. Long-term follow-up and a greater number of cases are mandatory to establish the safety of this strategy. PMID- 26047920 TI - Visualization of the Abducens Nerve in its Petroclival Segment Using Contrast Enhanced FIESTA MRI: The Size of the Petroclival Venous Confluence Affects Detectability. AB - PURPOSE: Visualization of the abducens nerve in its petroclival segment still remains challenging. We aimed to investigate the detectability of the petroclival segment of the abducens nerve and to evaluate the role of the size of the petroclival venous confluence (PVC) in the visibility of the nerve using contrast enhanced fast imaging employing steady-state acquisition (FIESTA) magnetic resonance imaging (MRI). METHODS: We retrospectively evaluated the contrast enhanced FIESTA images of 237 patients (female/male: 127/110; mean age: 49.0 +/- 14.7). Two radiologists divided the imaging findings of the petroclival segments of the abducens nerves into three groups: 0 (not visualized), 1 (partially visualized), and 2 (completely visualized). Another radiologist measured the anteroposterior diameter of the PVC from the clival bony surface to the inner layer of dura at the dural entrance level of the abducens nerve. One-way analysis of variance, Tukey's test, and receiving operating curve analysis were performed. RESULTS: Among 474 abducens nerves, 76 were classified as group 0 (76/474, 16.03 %), 100 were classified as group 1 (100/474, 21.10 %), and 298 were classified as group 2 (298/474, 62.87 %). There was significant difference in mean anteroposterior diameters of the PVC for each group (group 0, 0.95 mm; group 1, 1.80 mm; group 2, 2.51 mm). The cut-off values for the differentiation of group 0 from group 1 and group 1 from group 2 were found to be 1.35 and 2.09 mm, respectively. CONCLUSIONS: Abducens nerve in its petroclival segment can be reliably identified using contrast-enhanced FIESTA MRI especially in those with a greater anteroposterior diameter of the PVC. PMID- 26047921 TI - How to Avoid Earlobe Deformation in Face Lift. AB - BACKGROUND: During the postoperative period following a facelift, caudal extension of the earlobe secondary to pulling of the submandibular tissues can occur. This earlobe shape, often termed "pixie ear", is unnatural, and patients often request its repair. The objective of this study was to design a modified facelift technique that provides natural, aesthetically acceptable, and long lasting results. METHODS: In patients with pixie ear secondary to classical rhytidectomy, we omitted the incision around the earlobe; instead, we interrupted it in front of the earlobe and finished it behind the earlobe, without fully dissecting the earlobe from its base. We then performed all required stages of the facelift: detachment of the cellulocutaneous flap, manipulation of the superficial musculoaponeurotic system, establishment of homeostasis, lifting of the cutaneous flap, and finally suturing of the retained edges of the skin onto the cartilage matrix of the pinna. RESULTS: The above-described operative technique was used in 24 patients from October 2008 to January 2014. Long-lasting projected results were achieved in each case. CONCLUSIONS: The modified facelift technique described herein can be used to perform facelifts with a pre-existing pixie ear, as well as to prevent the development of pixie ear. PMID- 26047922 TI - Leukotriene B4-Neutrophil Elastase Axis Drives Neutrophil Reverse Transendothelial Cell Migration In Vivo. AB - Breaching endothelial cells (ECs) is a decisive step in the migration of leukocytes from the vascular lumen to the extravascular tissue, but fundamental aspects of this response remain largely unknown. We have previously shown that neutrophils can exhibit abluminal-to-luminal migration through EC junctions within mouse cremasteric venules and that this response is elicited following reduced expression and/or functionality of the EC junctional adhesion molecule-C (JAM-C). Here we demonstrate that the lipid chemoattractant leukotriene B4 (LTB4) was efficacious at causing loss of venular JAM-C and promoting neutrophil reverse transendothelial cell migration (rTEM) in vivo. Local proteolytic cleavage of EC JAM-C by neutrophil elastase (NE) drove this cascade of events as supported by presentation of NE to JAM-C via the neutrophil adhesion molecule Mac-1. The results identify local LTB4-NE axis as a promoter of neutrophil rTEM and provide evidence that this pathway can propagate a local sterile inflammatory response to become systemic. PMID- 26047923 TI - The Docosanoid Neuroprotectin D1 Induces TH-Positive Neuronal Survival in a Cellular Model of Parkinson's Disease. AB - Parkinson's disease (PD) does not manifest clinically until 80 % of striatal dopamine is reduced, thus most neuronal damage takes place before the patient presents clinical symptoms. Therefore, it is important to develop preventive strategies for this disease. In the experimental models of PD, 1-methyl-4 phenylpyridinium ion (MPP+) and rotenone induce toxicity in dopaminergic neurons. Neuroprotectin D1 (NPD1) displays neuroprotection in cells undergoing proteotoxic and oxidative stress. In the present report, we established an in vitro model using a primary neuronal culture from mesencephalic embryonic mouse tissue in which 17-20 % of neurons were TH-positive when differentiated in vitro. NPD1 (100 nM) rescued cells from apoptosis induced by MPP+ and rotenone, and the dendritic arbor of surviving neurons was examined using Sholl analysis. Rotenone, as well as MPP+ and its precursor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), severely promoted retraction of dendritic arbor distal segments, thus decreasing the maximum branch order reached. On average, NPD1 counteracted the effects of MPP+ on the dendritic arborization, but failed to do so in the rotenone-treated neurons. However, rotenone did decrease the Sholl intersection number from radii 25 to 125 um, and NPD1 did restore the pattern to control levels. Similarly, NPD1 partially reverted the dendrite retraction caused by MPP+ and MPTP. These results suggest that the apoptosis occurring in mesencephalic TH-positive neurons is not a direct consequence of mitochondrial dysfunction alone and that NPD1 signaling may be counteracting this damage. These findings lay the groundwork for the use of the in vitro model developed for future studies and for the search of specific molecular events that NPD1 targets to prevent early neurodegeneration in PD. PMID- 26047924 TI - When the tendon autograft is dropped accidently on the floor: A study about bacterial contamination and antiseptic efficacy. AB - BACKGROUND: Inadvertent contamination of the autograft can occur during anterior cruciate ligament (ACL) reconstruction if the autograft is dropped on the floor during surgery. A study was undertaken to determine the incidence of contamination when a graft is dropped on the operating room floor and the efficacy of antimicrobial solutions to decontaminate it. METHODS: Samples from 25 patients undergoing ACL reconstruction with a hamstring tendon were sectioned and dropped onto the floor. Cultures were taken after immersion in antiseptic solutions (a chlorhexidine gluconate solution (group 1), a povidone-iodine solution (group 2), and a sodium hypochlorite solution (group 3)). A fourth piece (group 0) was cultured without being exposed to any solution. Cultures of a floor swab were taken at the same time. RESULTS: The floor swab cultures were positive in 96% of cases. The rate of contamination was 40% in group 0, 8% in group 1, 4% in group 2, and 16% in group 3. There was a significant difference between groups 1 and 2 and group 0 (p<0.05) but not between groups 3 and 0. CONCLUSIONS: Immersing a graft dropped on the floor during surgery in a chlorhexidine gluconate solution or povidone-iodine solution significantly reduces contamination of the graft. Soaking of the hamstring autograft in one of these solutions is recommended in the case of inadvertent contamination. CLINICAL RELEVANCE: Laboratory investigation (level 2). PMID- 26047925 TI - The magnetic resonance aspect of a polyurethane meniscal scaffold is worse in advanced cartilage defects without deterioration of clinical outcomes after a minimum two-year follow-up. AB - BACKGROUND: Meniscal scaffolding is thought to provide functional improvement and to prevent cartilage degeneration. Advanced chondral injuries might damage the scaffold structural properties. OBJECTIVE: To evaluate the influence of different degrees of articular chondral injuries on the imaging aspect of a polyurethane meniscal scaffold (Actifit(r)). METHODS: Fifty-four patients operated on with an Actifit(r) were studied. The status of the articular cartilage in the involved compartment was classified according to ICRS. The characteristics of the implant were evaluated in MRI with the Genovese score. Functional scores included WOMET, IKDC and Kujala scores. The Genovese score was correlated with the degree of chondral injury and functional results. RESULTS: The mean follow-up was 39 months (range 25-63). Additional procedures were performed in 69.5%. There were 19 patients without chondral injuries and 14 with grade 1, 10 with grade 3 and eight with grade 4 chondral lesions. The morphology and size of the implant on MRI scanning were worse with a higher degree of chondral injury (p=0.023). WOMET, IKDC and Kujala improved from 36.2SD +/-7.6, 32.3SD +/-13.5 and 39.2SD +/-8.1 to 75.8SD +/-12.9 (p=0.02), 75.5SD +/-15.4 (p=0.03) and 85.6SD +/-13.4 (0.042), respectively. There was no relationship between the severity of chondral injury and functional scores. CONCLUSIONS: Patients without chondral injuries showed a better MRI aspect of the polyurethane scaffold in terms of size and morphology. By optimizing biomechanics, in particular the implantation of a meniscal substitute, significant pain relief and functional improvement were observed after a minimum two-year follow-up. LEVEL OF EVIDENCE: Therapeutic case series; level 4. PMID- 26047926 TI - Migrants' perceptions of aging in Denmark and attitudes towards remigration: findings from a qualitative study. AB - BACKGROUND: The increasing number of elderly migrants in Europe poses challenges for the organisation of healthcare and social services if these migrants do not remigrate to their countries of birth at old age. More insight into perceptions of aging among migrant women is needed to inform service delivery for culturally and linguistic diverse populations, yet few studies have explored this field. The aim of this study is to explore perceptions of aging among middle-aged migrant women, with emphasis on identifying factors shaping their decisions on whether to remigrate or stay in Denmark during old age. METHODS: The study is based on 14 semi-structured interviews including a total of 29 migrant women residing in Copenhagen, Denmark. The women were born in Somalia, Turkey, India, Iran, Pakistan, or Middle Eastern countries. The majority of participants were middle aged and had one or more chronic illnesses. The analysis was inspired by phenomenological methods and guided by theory on access to services, social relations, and belonging. RESULTS: The results showed that the existence of chronic conditions requiring frequent use of medical care and the availability of high-quality healthcare in Denmark were important factors for the decision to spend one's old age in Denmark rather than to remigrate to one's country of origin. Similarly, availability of social services providing financial and tangible support for the elderly was perceived to be important during old age. For these middle-aged women, social ties to children and grandchildren in Denmark and feelings of belonging further nourished a wish to stay in Denmark rather than remigrating. CONCLUSIONS: Since the study suggests that elderly migrants will be utilising healthcare and social services in Denmark rather than returning to their countries of birth, these services should prepare for increased cultural and linguistic diversity among users. This could entail provision of translators, specific outreach programmes, and culturally adapted services to meet elderly from diverse linguistic, religious, and cultural backgrounds. PMID- 26047927 TI - Influence of leg-length discrepancy on anterior acetabular coverage using false profile image. AB - BACKGROUND: Leg-length discrepancy (LLD) occurs commonly in patients with osteoarthritis (OA) of the hip. Although some investigators argue that LLD in a weight-bearing position may influence lateral acetabular coverage, there have been no reports on the influence of LLD on anterior acetabular coverage and the relationship between LLD and vertical center anterior margin (VCA) angle before and after LLD correction. Anterior acetabular coverage is an important index for diagnosis, treatment, and surgery for OA of the hip. Therefore, we investigated the influence of LLD in a weight-bearing position on VCA angle. METHODS: There were 154 patients with LLD in OA of the hip and 146 healthy individuals without LLD. The sole of the short-leg side in patients was adjusted with an acrylic plate, and the LLD revision value was calculated in the anteroposterior (AP) view in a weight-bearing position. Calculated revision value was applied to individuals and VCA angles in false profile images before and after correction was measured. For healthy individuals, we corrected the sole of the nonexamined side with an acrylic plate to artificially increase LLD and then measured VCA angles in false profile images before and after correction. RESULTS: Significant difference was found in VCA angles between before and after LLD correction in patients and healthy individuals (p < 0.05). Difference in VCA angles before and after LLD correction in both patients and health individuals highly correlated with LLD level in both short- and long-leg sides. CONCLUSIONS: This study clarified that LLD in a weight-bearing position influenced VCA angle. Results suggested that comparison of images before and after correction increases diagnostic accuracy. Assessing anterior acetabular coverage before and after LLD correction is valuable in evaluating the need for surgery, suitable correction of osteotomized acetabular fragments in periacetabular osteotomy, and determining acetabular cup angle in artificial joint replacement. PMID- 26047928 TI - Integration of Quercetin-Iron Complexes into Phosphatidylcholine or Phosphatidylethanolamine Liposomes. AB - It is well known that flavonoids can chelate transition metals. Flavonoid-metal complexes exhibit a high antioxidative and therapeutic potential. However, the complexes are frequently hydrophobic ones and low soluble in water, which restricts their medical applications. Integration of these complexes into liposomes may increase their bioavailability and therapeutic effect. Here, we studied the interaction of quercetin-iron complexes with dimyristoylphosphatidylcholine (DMPC) or palmitoyl-oleoyl phosphatidylethanolamine (POPE) multilamellar liposomes. Differential scanning calorimetry (DSC) and freeze-fracture electron microscopy revealed that quercetin iron complexes did not interact with liposomes. Quercetin however could penetrate lipid bilayers, when added to liposomes at a temperature above lipid melting. Iron cations added later penetrated into the lipid bilayers and produced complexes with quercetin in the liposomes. The quercetin-iron entry in POPE liposomes was improved when the suspension was heated above the temperature of the bilayer-hexagonal HII phase transition of the lipid. The approach proposed facilitates the integration of quercetin-iron complexes into liposomes and may promote their use in medicine. PMID- 26047929 TI - IL-17A Autoantibody Induced by Recombinant Mycobacterium smegmatis Expressing Ag85A-IL-17A Fusion Protein. AB - Interleukin-17A is a newly described proinflammatory cytokine, which plays important roles in autoimmune diseases as well as asthma. In current work, we constructed a recombinant plasmid pMFA42S-Ag85a-IL-17a by inserting fusion gene Ag85a-IL-17a into shuttle vector pMFA42S, which was transformed to Mycobacterium smegmatis by electroporation to obtain recombinant M. smegmatis named rMS-Ag85a IL-17a. The comparison of growth pattern between M. smegmatis and rMS-Ag85a-IL 17a suggested fusion gene had no significant influence on the growth of strains, and rMS-Ag85a-IL-17a expressed fusion protein Ag85A-IL-17A which had good immunogenicity revealed by Western blot. M. smegmatis and rMS-Ag85a-IL-17a were performed to intranasally immunize mice; then, antibody response in sera was detected by enzyme-linked immunosorbent assay. Our findings demonstrated that rMS Ag85a-IL-17a could induce specific IL-17A autoantibody in mice, which laid the foundation for further study. PMID- 26047930 TI - Influence of Altered NADH Metabolic Pathway on the Respiratory-deficient Mutant of Rhizopus oryzae and its L-lactate Production. AB - Respiratory-deficient mutants of Rhizopus oryzae (R. oryzae) AS 3.3461 were acquired by ultraviolet (UV) irradiation to investigate changes in intracellular NADH metabolic pathway and its influence on the fermentation characteristics of the strain. Compared with R. oryzae AS 3.3461, the intracellular ATP level of the respiratory-deficient strain UV-1 decreased by 52.7 % and the glucose utilization rate rose by 8.9 %; When incubated for 36 h, the activities of phosphofructokinase (PFK), hexokinase (HK), and pyruvate kinase (PK) in the mutant rose by 74.2, 7.2, and 12.0 %, respectively; when incubated for 48 h, the intracellular NADH/NAD(+) ratio of the mutant rose by 14.6 %; when a mixed carbon source with a glucose/gluconic acid ratio of 1:1 was substituted to culture the mutant, the NADH/NAD(+) ratio decreased by 4.6 %; the ATP content dropped by 27.6 %; the lactate dehydrogenase (LDH) activity rose by 22.7 %; and the lactate yield rose by 11.6 %. These results indicated that changes to the NADH metabolic pathway under a low-energy charge level can effectively increase the glycolytic rate and further improve the yield of L-lactate of R. oryzae. PMID- 26047931 TI - Construction of Synthetic Promoter-Based Expression Cassettes for the Production of Cadaverine in Recombinant Corynebacterium glutamicum. AB - Corynebacterium glutamicum is an important microorganism in the biochemical industry for the production of various platform chemicals. However, despite its importance, a limited number of studies have been conducted on how to constitute gene expression cassettes in engineered C. glutamicum to obtain desired amounts of the target products. Therefore, in this study, six expression cassettes for the expression of the second lysine decarboxylase of Escherichia coli, LdcC, were constructed using six synthetic promoters with different strengths and were examined in C. glutamicum for the production of cadaverine. Among six expression cassettes, the expression of the E. coli ldcC gene under the PH30 promoter supported the highest production of cadaverine in flask and fed-batch cultivations. A fed-batch fermentation of recombinant C. glutamicum expressing E. coli ldcC gene under the PH30 promoter resulted in the production of 40.91 g/L of cadaverine in 64 h. This report is expected to contribute toward developing engineered C. glutamicum strains to have desired features. PMID- 26047932 TI - Involvement of sulfates from cruzipain, a major antigen of Trypanosoma cruzi, in the interaction with immunomodulatory molecule Siglec-E. AB - In order to investigate the involvement of sulfated groups in the Trypanosoma cruzi host-parasite relationship, we studied the interaction between the major cysteine proteinase of T. cruzi, cruzipain (Cz), a sulfate-containing sialylated molecule and the sialic acid-binding immunoglobulin like lectin-E (Siglec-E). To this aim, ELISA, indirect immunofluorescence assays and flow cytometry, using mouse Siglec-E-Fc fusion molecules and glycoproteins of parasites, were performed. Competition assays verified that the lectins, Maackia amurensis II (Mal II) and Siglec-E-Fc, compete for the same binding sites. Taking into account that Mal II binding remains unaltered by sulfation, we established this lectin as sialylation degree control. Proteins of an enriched microsomal fraction showed the highest binding to Siglec-E as compared with those from the other parasite subcellular fractions. ELISA assays and the affinity purification of Cz by a Siglec-E column confirmed the interaction between both molecules. The significant decrease in binding of Siglec-E-Fc to Cz and to its C-terminal domain (C-T) after desulfation of these molecules suggests that sulfates contribute to the interaction between Siglec-E-Fc and these glycoproteins. Competitive ELISA assays confirmed the involvement of sulfated epitopes in the affinity between Siglec-E and Cz, probably modified by natural protein environment. Interestingly, data from flow cytometry of untreated and chlorate-treated parasites suggested that sulfates are not primary receptors, but enhance the binding of Siglec-E to trypomastigotic forms. Altogether, our findings support the notion that sulfate containing sialylated glycoproteins interact with Siglec-E, an ortholog protein of human Siglec-9, and might modulate the immune response of the host, favoring parasitemia and persistence of the parasite. PMID- 26047934 TI - The NAtional randomised controlled Trial of Tonsillectomy IN Adults (NATTINA): a clinical and cost-effectiveness study: study protocol for a randomised control trial. AB - BACKGROUND: The role of tonsillectomy in the management of adult tonsillitis remains uncertain and UK regional variation in tonsillectomy rates persists. Patients, doctors and health policy makers wish to know the costs and benefits of tonsillectomy against conservative management and whether therapy can be better targeted to maximise benefits and minimise risks of surgery, hence maximising cost-effective use of resources. NATTINA incorporates the first attempt to map current NHS referral criteria against other metrics of tonsil disease severity. METHODS/DESIGN: A UK multi-centre, randomised, controlled trial for adults with recurrent tonsillitis to compare the clinical and cost-effectiveness of tonsillectomy versus conservative management. An initial feasibility study comprises qualitative interviews to investigate the practicality of the protocol, including willingness to randomise and be randomised. Approximately 20 otolaryngology staff, 10 GPs and 15 ENT patients will be recruited over 5 months in all 9 proposed main trial participating sites. A 6-month internal pilot will then recruit 72 patients across 6 of the 9 sites. Participants will be adults with recurrent acute tonsillitis referred by a GP to secondary care. Randomisation between tonsillectomy and conservative management will be according to a blocked allocation method in a 1:1 ratio stratified by centre and baseline disease severity. If the pilot is successful, the main trial will recruit a further 528 patients over 18 months in all 9 participating sites. All participants will be followed up for a total of 24 months, throughout which both primary and secondary outcome data will be collected. The primary outcome is the number of sore throat days experienced over the 24-month follow-up. The pilot and main trials include an embedded qualitative process evaluation. DISCUSSION: NATTINA is designed to evaluate the relative effectiveness and efficiency of tonsillectomy versus conservative management in patients with recurrent sore throat who are eligible for surgery. Most adult tonsil disease and surgery has an impact on economically active age groups, with individual and societal costs through loss of earnings and productivity. Avoidance of unnecessary operations and prioritisation of those individuals likely to gain most from tonsillectomy would reduce costs to the NHS and society. TRIAL REGISTRATION: ISRCTN55284102, Date of Registration: 4 August 2014. PMID- 26047935 TI - The Deserving Poor, the Family, and the U.S. Welfare System. AB - Contrary to the popular view that the U.S. welfare system has been in a contractionary phase after the expansions of the welfare state in the 1960s, welfare spending resumed steady growth after a pause in the 1970s. However, although aggregate spending is higher than ever, there have been redistributions away from non-elderly and nondisabled families to families with older adults and to families with recipients of disability programs; from non-elderly, nondisabled single-parent families to married-parent families; and from the poorest families to those with higher incomes. These redistributions likely reflect long-standing, and perhaps increasing, conceptualizations by U.S. society of which poor are deserving and which are not. PMID- 26047933 TI - The genetics of Leishmania virulence. AB - The ability of Leishmania parasites to infect and persist in the antigen presenting cell population of their mammalian hosts is dependent on their ability to gain entry to their host and host cells, to survive the mammalian cell environment, and to suppress or evade the protective immune response mechanisms of their hosts. A multitude of genes and their products have been implicated in each of these virulence-enhancing strategies to date, and we present an overview of the nature and known function of such virulence genes. PMID- 26047936 TI - Outcomes of tricuspid annuloplasty with and without prosthetic rings: a retrospective follow-up study. AB - BACKGROUND: The efficacies of tricuspid valve repair, risk factors for treatment failure and postoperative quality of life have not been thoroughly evaluated in patients with tricuspid insufficiency associated with rheumatic heart disease (RHD). We therefore reviewed our experience with ring and non-ring tricuspid annuloplasty for the treatment of functional tricuspid insufficiency (TI) in RHD. METHODS: This retrospective, follow-up study involved 74 RHD patients who underwent either non-ring annuloplasty (De Vega procedure; 34 patients, 45.95 %) or ring annuloplasty (40 patients, 54.05 %) along with concurrent mitral or/and aortic valve replacement. Operation time, cardiopulmonary bypass time, aortic clamping time, intensive care unit stay and extubation time were recorded. Echocardiographic findings and Short Form (SF)-36 scores were compared between the two groups. RESULTS: In hospital mortality and complications were similar in the two study groups (P = 0.6755). At 1 week, 1 month, 6 months, 1 year, 2 years and even longer after the operation, the Kaplan-Meier curve of freedom from mild and above recurrent TI showed significantly better efficacy in the ring annuloplasty group than the De Vega procedure group (log rank P = 0.0377). Risk factors for recurrent TI included high pulmonary artery systolic pressure (PASP) and non-ring annuloplasty (PASP: hazard ratio = 1.52; non-ring: hazard ratio = 1.42). The mental component summary score at 1 year after the operation did not significantly differ between the two groups (P = 0.6446), but the physical component summary score was significantly better in the ring annuloplasty group (P = 0.0037). CONCLUSION: Compared with non-ring annuloplasty, ring annuloplasty was associated with improved survival, decreased TI recurrence and higher quality of life in RHD patients undergoing tricuspid valve repair combined with mitral and/or aortic valve replacement. PMID- 26047937 TI - Identification of outer membrane Porin D as a vitronectin-binding factor in cystic fibrosis clinical isolates of Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is a pathogen that frequently colonizes patients with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Several pathogens are known to bind vitronectin to increase their virulence. Vitronectin has been shown to enhance P. aeruginosa adhesion to host epithelial cells. METHODS: We screened clinical isolates from the airways of CF patients and from the bloodstream of patients with bacteremia for binding of vitronectin. Two-dimensional SDS-PAGE and a proteomic approach were used to identify vitronectin-receptors in P. aeruginosa. RESULTS: P. aeruginosa from the airways of CF patients (n=27) bound more vitronectin than bacteremic isolates (n=15, p=0.025). Porin D (OprD) was identified as a vitronectin-binding protein. A P. aeruginosa oprD transposon insertion mutant had a decreased binding to soluble and immobilized vitronectin (p<=0.001). CONCLUSIONS: P. aeruginosa isolates obtained from CF patients significantly bound vitronectin. Porin D was defined as a novel P. aeruginosa vitronectin-receptor, and we postulate that the Porin D-dependent interaction with vitronectin may be important for colonization. PMID- 26047938 TI - Multiple thyroid nodules in the lung: metastasis or ectopia? AB - BACKGROUND: Intrapulmonary thyroid tissue with no malignant history of the thyroid gland is extremely rare. Usually, it is interpreted as ectopic thyroid tissue. Here we describe a case of bilateral pulmonary thyroid nodules with a history of multinodular thyroid goiter. HISTORY: A 37-year-old female had recurrent multinodular thyroid goiter and showed bilateral pulmonary nodules on CT scan. Video-assisted thoracic surgery (VATS) was performed for the largest nodule biopsy. Pathological and molecular examinations were done after biopsy, and both were shown the characters of benign thyroid tissues. To eliminate the possibility of thyroid carcinoma metastases, total thyroidectomy with modified radical neck dissection was performed, and there were no malignant pathological findings. After surgery, this patient accepted adjuvant radiometabolic treatment for ablation of the remaining intrapulmonary nodules. Her thyroglobulin level decreased to an undetectable level, and she has currently survived for 24 months after surgery. CLINICAL SIGNIFICANCE: In this case, pulmonary ectopic thyroid and metastasizing thyroid carcinoma should both be considered, but the metastatic pattern and benign pathological characters were inconsistent with any of the corresponding diagnosis. Ultimately, this patient accepted postoperative treatment of thyroid carcinoma metastasis. CONCLUSIONS: This is a rare thyroid disease with malignant behavior but no pathological evidence. Careful diagnosis and postoprative follow-up should be carried out whenever such nodules are encountered in clinical practice. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1255194331453728 . PMID- 26047939 TI - Association of insulin resistance and coronary artery remodeling: an intravascular ultrasound study. AB - BACKGROUND: There are few studies that investigated the correlation between insulin resistance (IR) and the coronary artery remodeling. The aim of the study is to investigate the association of IR measured by homeostasis model assessment of insulin resistance (HOMA-IR) and coronary artery remodeling evaluated by intravascular ultrasound (IVUS). METHODS: A total of 298 consecutive patients who received percutaneous coronary interventions under IVUS guidance were retrospectively enrolled. The value of HOMA-IR more than 2.5 was considered as IR positive. Metabolic syndrome was classified according to NCEP ATP III guidelines. The remodeling index was defined as the ratio of the external elastic membrane (EEM) area at the lesion site to the EEM area at the proximal reference site. RESULTS: A total of 369 lesions were analyzed (161 lesions in HOMA-IR positive and 208 lesions in HOMA-IR negative). Remodeling index was significantly higher in the HOMA-IR positive group compared with the negative group (HOMA-IR positive vs. negative: 1.074 +/- 0.109 vs. 1.042 +/- 0.131, p = 0.013). There was a significant positive correlation between remodeling index and HOMA-IR (p = 0.010). Analysis of HOMA-IR according to remodeling groups showed increasing tendency of HOMA-IR, and it was statistically significant (p = 0.045). Multivariate analysis revealed that only HOMA-IR was an independent predictor of remodeling index (r = 0.166, p = 0.018). CONCLUSION: Increased IR estimated by HOMA-IR was significantly associated with a higher remodeling index and positive coronary artery remodeling. PMID- 26047941 TI - Views and experiences of healthcare professionals towards the use of African traditional, complementary and alternative medicines among patients with HIV infection: the case of eThekwini health district, South Africa. AB - BACKGROUND: Many patients with human immunodeficiency virus infection use traditional, complementary, and alternative medicines and other practices to combat the disease, with some also using prescribed antiretroviral therapy provided by the public health sector. This study aimed to establish the awareness of public sector biomedical health care providers on the use of traditional, complementary and alternative medicines by HIV-infected patients who also used highly active antiretroviral therapy, and to determine whether this was based on patients seen or cases being reported to them. Potential risks of interactions between the prescribed antiretroviral and non-prescribed medication therapies may pose safety and effectiveness issues in patients using both types of treatment. METHODS: A descriptive cross-sectional study, using a researcher administered semi-structured questionnaire, was conducted from June to August 2013 at ten public sector antiretroviral clinics in five regional, three specialised and two district hospitals in eThekwini Health District, South Africa. Questionnaires were administered through face-to face interview to 120 eligible participants consisting of doctors, nurses, pharmacists and post-basic pharmacist assistants in HIV clinical practice. The results are presented as percent or proportion with standard error (SE), or as frequency. RESULTS: Ninety-four respondents completed the questionnaire, yielding a response rate of 78.3 %. Almost half (48/94) were aware of patients using African traditional herbal medicines, over-the-counter supplements, unnamed complementary Ayurveda medicines and acupuncture. Twenty three of the 94 respondents (24.4 %) said they had consulted patients who were using both antiretroviral therapy and certain types of non-prescribed medication in the previous three months. CONCLUSIONS: Awareness among healthcare providers on patient use of traditional, complementary and alternative medicines was relatively high. Few respondents had seen patients who used mostly African traditional medicines, over-the counter supplements, and negligible complementary Ayurveda medicines and acupuncture, with caution being advised in the interpretation of the former. Further research is needed to investigate communication between healthcare providers and patients in this regard, and levels of acceptance of traditional, complementary and alternative medicines by biomedical health care workers in HIV public sector practice. PMID- 26047940 TI - Effects of hydrogen-rich saline on early acute kidney injury in severely burned rats by suppressing oxidative stress induced apoptosis and inflammation. AB - BACKGROUND: Early acute kidney injury (AKI) in severely burned patients predicts a high mortality that is multi-factorial. Hydrogen has been reported to alleviate organ injury via selective quenching of reactive oxygen species. This study investigated the potential protective effects of hydrogen against severe burn induced early AKI in rats. METHODS: Severe burn were induced via immersing the shaved back of rats into a 100 degrees C bath for 15 s. Fifty-six Sprague-Dawley rats were randomly divided into Sham, Burn + saline, and Burn + hydrogen-rich saline (HS) groups, and renal function and the apoptotic index were measured. Kidney histopathology and immunofluorescence staining, quantitative real-time PCR, ELISA and western blotting were performed on the sera or renal tissues of burned rats to explore the underlying effects and mechanisms at varying time points post burn. RESULTS: Renal function and tubular apoptosis were improved by HS treatment. In addition, the oxidation-reduction potential and malondialdehyde levels were markedly reduced with HS treatment, whereas endogenous antioxidant enzyme activities were significantly increased. HS also decreased the myeloperoxidase levels and influenced the release of inflammatory mediators in the sera and renal tissues of the burned rats. The regulatory effects of HS included the inhibition of p38, JNK, ERK and NF-kappaB activation, and an increase in Akt phosphorylation. CONCLUSION: Hydrogen can attenuate severe burn induced early AKI; the mechanisms of protection include the inhibition of oxidative stress induced apoptosis and inflammation, which may be mediated by regulation of the MAPKs, Akt and NF-kappaB signalling pathways. PMID- 26047942 TI - Meta-analysis of the efficacy and safety of sofosbuvir for the treatment of hepatitis C virus infection. AB - BACKGROUND: Hepatitis C virus infection is a worldwide health problem and one of the leading causes of cirrhosis and hepatocellular carcinoma. Recently, sofosbuvir was introduced to the therapeutic arsenal against this virus, thereby paving the way for all-oral regimen. Aims of the review This study aimed to systematically analyze the efficacy and safety of sofosbuvir for the treatment of hepatitis C virus infection. METHOD: PubMed and EMBASE database searches were conducted using "sofosbuvir" as the search term. Phase III clinical studies retrieved from the two databases and resources posted on the Drug@FDA and ClinicalTrials.gov websites were evaluated with regard to outcomes of the efficacy and safety analyses of the drug. RESULTS: Eight Phase III clinical studies compared the efficacy and safety of sofosbuvir. When sofosbuvir replaced peginterferon which was used in the previous standard regimen, a superior sustained virologic response, as defined by a viral RNA load less than the lower limit of quantification 12 weeks after cessation of therapy, was obtained (74.3 vs. 66.7%, p < 0.05). The response improved even more (90.8 vs. 66.7%, p < 0.0001) when sofosbuvir was used as an add-on therapy to the standard regimen. The overall odds ratio to achieve the response in the sofosbuvir-containing arm of the eight clinical studies was 3.66 times greater (95% CI 3.00-4.46) than that of the standard regimen arm. During the eight clinical studies, adverse events were observed in 83.61 and 87.22% of the patients in the sofosbuvir and non sofosbuvir arms, respectively, with the most frequent events being mild central nervous system symptoms such as fatigue, headache, and asthenia. CONCLUSIONS: Sofosbuvir was safe and effective in the treatment of hepatitis C virus genotype 1, 2, 3, or 4 infections. However, the lack of persistence of the sustained virologic response beyond the study duration and long-term safety concerns need to be addressed in future studies. PMID- 26047943 TI - Potential drug-related problems detected by electronic expert support system: physicians' views on clinical relevance. AB - BACKGROUND: Drug-related problems cause suffering for patients and substantial costs. Multi-dose drug dispensing is a service in which patients receive their medication packed in bags with one unit for each dose occasion. The electronic expert support system (EES) is a clinical decision support system that provides alerts if potential drug-related problems are detected among a patients' current prescriptions, including drug-drug interactions, therapy duplications, high doses, drug-disease interactions, drug gender warnings, and inappropriate drugs and doses for geriatric or pediatric patients. OBJECTIVE: The aim of the study was to explore physicians' views on the clinical relevance of alerts provided by EES. Furthermore we investigated if physicians performed any changes in drug treatment following the alerts and if there were any differences in perceived relevance and performed changes between different types of alerts and drugs. SETTING: Two geriatric clinics and three primary care units in Sweden. METHOD: Prescribed medications for patients (n = 254) with multi-dose drug dispensing were analyzed for potential drug-related problems using EES. For each alert, a physician assessed clinical relevance and indicated any intended action. A total of 15 physicians took part in the study. Changes in drug treatment following the alerts were later measured. The relationship between variables was analyzed using Chi square test. MAIN OUTCOME MEASURE: Physicians' perceived clinical relevance of each alert, and changes in drug treatment following the alerts. RESULTS: Physicians perceived 68% (502/740) of EES alerts as clinically relevant and 11% of all alerts were followed by a change in drug treatment. Clinical relevance and likelihood to make changes in drug treatment was related to the alert category and substances involved in the alert. CONCLUSION: In most patients with multi dose drug dispensing, EES detected potential drug-related problems, with the majority of the alerts regarded as clinically relevant and some followed by measurable changes in drug treatment. PMID- 26047944 TI - Older peoples' attitudes regarding polypharmacy, statin use and willingness to have statins deprescribed in Australia. AB - BACKGROUND: Deprescribing is the process of medication withdrawal with the aims of reducing the harms of potentially inappropriate medication use and improving patient outcomes. Deprescribing of statins may be indicated for some older people, because the evidence for benefit in primary prevention of cardiovascular disease is limited and there is an increased risk of side effects in old age. OBJECTIVE: To determine older peoples' attitudes and beliefs regarding medication use and their willingness to have regular medications, particularly statins, deprescribed. Setting An Australian acute-care hospital. METHOD: A cross sectional study of patients admitted to a teaching hospital in Sydney, Australia, aged >=65 years and taking a statin was conducted. Attitudes and beliefs regarding medication use and willingness to have medications or statins deprescribed were captured using the validated Patients' Attitudes Towards Deprescribing questionnaire, supplemented with additional statin-specific questions. MAIN OUTCOME MEASURES: Older inpatients' attitudes and perspectives towards stopping medications, in particular statins. RESULTS: Overall, 180 participants were recruited, with a median age of 78 years, (interquartile range 71-85). Eighty-nine percent (95% CI 84.4-93.6) of participants reported that they would be willing to stop one or more of their regular medications if their doctor said it was possible. Ninety-five percent (95% CI 91.8-98.2) agreed that they would be willing to have a statin deprescribed. Moreover, 94% (95% CI 90.5-97.5) of participants expressed concern regarding the potential side effects of taking a statin. CONCLUSION: The majority of older inpatients using statins are willing to have one or more of their current medications, including statins, deprescribed. These findings can be used to inform clinical practice and interventional statin deprescribing studies to optimise medication use in older adults. PMID- 26047945 TI - The chemokine receptor CCR6 facilitates the onset of mammary neoplasia in the MMTV-PyMT mouse model via recruitment of tumor-promoting macrophages. AB - BACKGROUND: The expression of the chemokine receptor CCR6 has been previously correlated with higher grades and stages of breast cancer and decreased relapse free survival. Also, its cognate chemokine ligand CCL20 has been reported to induce proliferation of cultured human breast epithelial cells. METHODS: To establish if CCR6 plays a functional role in mammary tumorigenesis, a bigenic MMTV-PyMT CCR6-null mouse was generated and mammary tumor development was assessed. Levels of tumor-infiltrating immune cells within tumor-bearing mammary glands from MMTV-PyMT Ccr6 (WT) and Ccr6 (-/-) mice were also analyzed. RESULTS: Deletion of CCR6 delayed tumor onset, significantly reduced the extent of initial hyperplastic outgrowth, and decreased tumor incidence in PyMT transgenic mice. CCR6 was then shown to promote the recruitment of pro-tumorigenic macrophages to the tumor site, facilitating the onset of neoplasia. CONCLUSIONS: This study delineated for the first time a role for CCR6 in the development of breast cancer, and demonstrated a critical function for this receptor in maintaining the pro-tumorigenic cancer microenvironment. PMID- 26047946 TI - Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B. AB - BACKGROUND: Activins are members of the TGF-beta family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease. RESULTS: In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6. CONCLUSIONS: We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling. PMID- 26047947 TI - Posterior fossa ependymoma in childhood: 60 years event-free survival after partial resection-a case report. AB - A 13-year-old boy with severe clinical symptoms and signs underwent surgery for a posterior fossa ependymoma in 1954. The tumor was adjacent to the floor of the fourth ventricle, and surgery was complicated by profound bleeding. Therefore, only a partial resection was performed. Postoperative radiotherapy was given to the posterior fossa. The recovery was uneventful, and he has been in full-time work until the age of 62 years and is now 74 years old. Repeated MRI scans demonstrate a stable residual fourth ventricular tumor. PMID- 26047948 TI - CCR5 Blockade Suppresses Melanoma Development Through Inhibition of IL-6-Stat3 Pathway via Upregulation of SOCS3. AB - In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, we found that chemokine receptor 5 (CCR5) neutralization resulted in reduced melanoma tumor size, decreased percentage of CD11b+ Gr-1(+) myeloid-derived suppressor cells (MDSCs), and increased proportion of cluster of differentiation (CD)3+ T cells in tumor tissues. Suppressive activity of MDSCs on CD4+ T cells and CD8+ T cell proliferation is significantly inhibited by anti-CCR5 antibody. CCR5 blockade also suppresses interleukin (IL)-6 induction, which in turn deactivates signal transducer and activator of transcription 3 (Stat3) in tumors. Furthermore, the suppressed B16 tumor growth induced by CCR5 blockade is abolished with additional administration of recombinant IL-6. CCR5 blockade also induces suppressor of cytokine signaling 3 (SOCS3) upregulations, and anti-CCR5 antibody fails to suppress expression of phospho-Stat3 (p-Stat3), matrix metallopeptidase 9 (MMP9), and IL-6 in cells transfected with SOCS3 short-interfering RNA (SiRNA). All these data suggest that CCR5 blockade suppresses melanoma development through inhibition of IL-6-Stat3 pathway via upregulation of SOCS3. PMID- 26047950 TI - Early years interventions to improve child health and wellbeing: what works, for whom and in what circumstances? Protocol for a realist review. AB - BACKGROUND: Child health and wellbeing is influenced by multiple factors, all of which can impact on early childhood development. Adverse early life experiences can have lasting effects across the life course, sustaining inequalities and resulting in negative consequences for the health and wellbeing of individuals and society. The potential to influence future outcomes via early intervention is widely accepted; there are numerous policy initiatives, programmes and interventions clustered around the early years theme, resulting in a broad and disparate evidence base. Existing reviews have addressed the effectiveness of early years interventions, yet there is a knowledge gap regarding the mechanisms underlying why interventions work in given contexts. METHODS/DESIGN: This realist review seeks to address the question 'what works, for whom and in what circumstances?' in terms of early years interventions to improve child health and wellbeing. The review will be conducted following Pawson's five-stage iterative realist methodology: (1) clarify scope, (2) search for evidence, (3) appraise primary studies and extract data, (4) synthesise evidence and draw conclusions and (5) disseminate findings. The reviewers will work with stakeholders in the early stages to refine the focus of the review, create a review framework and build programme theory. Searches for primary evidence will be conducted iteratively. Data will be extracted and tested against the programme theory. A review collaboration group will oversee the review process. DISCUSSION: The review will demonstrate how early years interventions do or do not work in different contexts and with what outcomes and effects. Review findings will be written up following the RAMESES guidelines and will be disseminated via a report, presentations and peer-reviewed publications. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015017832. PMID- 26047949 TI - Rosiglitazone, a Peroxisome Proliferator-Activated Receptor (PPAR)-gamma Agonist, Attenuates Inflammation Via NF-kappaB Inhibition in Lipopolysaccharide-Induced Peritonitis. AB - We assessed the anti-inflammatory effect of peroxisome proliferator-activated receptor (PPAR)-gamma agonist, rosiglitazone, in a lipopolysaccharide (LPS) induced peritonitis rat model. LPS was intraperitoneally injected into rats to establish peritonitis model. Male Sprague-Dawley (SD) rats were assigned to normal saline (the solvent of LPS), LPS, rosiglitazone plus LPS, and rosiglitazone alone. A simple peritoneal equilibrium test was performed with 20 ml 4.25 % peritoneal dialysis fluid. We measured the leukocyte count in dialysate and ultrafiltration volume. Peritoneal membrane histochemical staining was performed, and peritoneal thickness was assessed. CD40 and intercellular adhesion molecule-1 messenger RNA (ICAM-1 mRNA) levels in rat visceral peritoneum were detected by reverse transcription (RT)-PCR. IL-6 in rat peritoneal dialysis effluent was measured using enzyme-linked immunosorbent assay. The phosphorylation of NF-kappaB-p65 and IkappaBalpha was analyzed by Western blot. LPS administration resulted in increased peritoneal thickness and decreased ultrafiltration volume. Rosiglitazone pretreatment significantly decreased peritoneal thickness. In addition to CD40 and ICAM-1 mRNA expression, the IL-6, p p65, and p-IkappaBalpha protein expressions were enhanced in LPS-administered animals. Rosiglitazone pretreatment significantly decreased ICAM-1 mRNA upregulation, secretion of IL-6 protein, and phosphorylation of NF-kappaB-p65 and IkappaBalpha without decreasing CD40 mRNA expression. Rosiglitazone has a protective effect in peritonitis, simultaneously decreasing NF-kappaB phosphorylation, suggesting that NF-kappaB signaling pathway mediated peritoneal inflammation induced by LPS. PPAR-gamma might be considered a potential therapeutic target against peritonitis. PMID- 26047951 TI - Surface-Functionalized Biodegradable Nanoparticles Consisting of Amphiphilic Graft Polymers Prepared by Radical Copolymerization of 2-Methylene-1,3-Dioxepane and Macromonomers. AB - Biodegradable polyester-based nanoparticles were prepared by the precipitation of amphiphilic graft copolymers, which were prepared by the ring-opening radical copolymerization of 2-methylene-1,3-dioxepane (MDO) and amphiphilic macromonomers. The diameter of the nanoparticles was controlled by the degree of grafting and the molecular weight of the grafting oligomer. PMDO-g-poly(ethylene glycol) nanoparticles were degraded by the alkaline hydrolysis of the polyester backbone. Although the colloidal stability of nanoparticles was retained due to the reorientation of the PEG chains during hydrolysis, the size of the nanoparticles decreased with increasing hydrolysis time. We also prepared PMDO-g poly(N-isopropylacrylamide) nanoparticles, which show aggregation in response to increasing temperature. PMID- 26047952 TI - DeCoaD: determining correlations among diseases using protein interaction networks. AB - BACKGROUND: Disease-disease similarities can be investigated from multiple perspectives. Identifying similar diseases based on the underlying biomolecular interactions can be especially useful, because it may shed light on the common causes of the diseases and therefore may provide clues for possible treatments. Here we introduce DeCoaD, a web-based program that uses a novel method to assign pair-wise similarity scores, called correlations, to genetic diseases. FINDINGS: DeCoaD uses a random walk to model the flow of information in a network within which nodes are either diseases or proteins and links signify either protein protein interactions or disease-protein associations. For each protein node, the total number of visits by the random walker is called the weight of that node. Using a disease as both the starting and the terminating points of the random walks, a corresponding vector, whose elements are the weights associated with the proteins, can be constructed. The similarity between two diseases is defined as the cosine of the angle between their associated vectors. For a user-specified disease, DeCoaD outputs a list of similar diseases (with their corresponding correlations), and a graphical representation of the disease families that they belong to. Based on a probabilistic clustering algorithm, DeCoaD also outputs the clusters that the disease of interest is a member of, and the corresponding probabilities. The program also provides an interface to run enrichment analysis for the given disease or for any of the clusters that contains it. CONCLUSIONS: DeCoaD uses a novel algorithm to suggest non-trivial similarities between diseases with known gene associations, and also clusters the diseases based on their similarity scores. DeCoaD is available at http://www.ncbi.nlm.nih.gov/CBBresearch/Yu/mn/DeCoaD/. PMID- 26047953 TI - Evaluation of Microscopic Observation Drug Susceptibility (MODS) and the string test for rapid diagnosis of pulmonary tuberculosis in HIV/AIDS patients in Bolivia. AB - BACKGROUND: Tuberculosis (TB) is the most common opportunistic infection and the leading cause of death in HIV-positive people worldwide. Diagnosing TB is difficult, and is more challenging in resource-scarce settings where culture based diagnostic methods rely on poorly sensitive smear microscopy by Ziehl Neelsen stain (ZN). METHODS: We performed a cross-sectional study examining the diagnostic utility of Microscopic Observation Drug Susceptibility liquid culture (MODS) versus traditional Ziehl-Neelsen staining (ZN) and Lowenstein Jensen culture (LJ) of pulmonary tuberculosis (TB) and multidrug-resistant tuberculosis (MDRTB) in HIV-infected patients in Bolivia. For sputum scarce individuals we assessed the value of the string test and induced sputum for TB diagnosis. The presence of Mycobacterium tuberculosis (Mtb) in the sputum of 107 HIV-positive patients was evaluated by ZN, LJ, and MODS. Gastric secretion samples obtained by the string test were evaluated by MODS in 102 patients. RESULTS: The TB-HIV co infection rate of HIV patients with respiratory symptoms by sputum sample was 45 % (48/107); 46/48 (96 %) were positive by MODS, 38/48 (79 %) by LJ, and 30/48 (63 %) by ZN. The rate of MDRTB was 9 % (4/48). Median time to positive culture was 10 days by MODS versus 34 days by LJ (p < 0.0001). In smear-negative patients, MODS detected TB in 17/18 patients, compared to 11/18 by LJ (94.4 % vs 61.0 %, p = 0.03 %). In patients unable to produce a sputum sample without induction, the string test cultured by MODS yielded Mtb in of 9/11 (82 %) TB positive patients compared to 11/11 (100 %) with induced sputum. Of the 10 patients unable to produce a sputum sample, 4 were TB-positive by string test. CONCLUSION: MODS was faster and had a higher Mtb detection yield compared to LJ, with a greater difference in yield between the two in smear-negative patients. The string test is a valuable diagnostic technique for HIV sputum-scarce or sputum-absent patients, and should be considered as an alternative test to induced sputum to obtain sample for Mtb in resource-limited settings. Nine percent of our TB+ patients had MDRTB, which reinforces the need for rapid detection with direct drug susceptibility testing in HIV patients in Bolivia. PMID- 26047955 TI - Differences in illness perceptions between patients with non-epileptic seizures and functional limb weakness. AB - OBJECTIVES: Illness perceptions play an important role in the onset and maintenance of symptoms in functional neurological symptom disorder (conversion disorder). There has, however, been little work examining differences between subtypes of this disorder. We therefore aimed to compare illness perceptions of patients with non-epileptic seizures (NES) and those with functional weakness (FW) with matching neurological disease controls to examine their specificity. METHODS: The Illness Perception Questionnaire Revised (IPQ-R) was completed by patients with functional limb weakness, non-epileptic seizures and patients with neurological disease causing limb weakness and epilepsy in two separate case control studies. RESULTS: Patients with FW (n=107), NES (=40), Epilepsy (n=34) and neurological disease causing limb weakness (NDLW) (n=46) were included in the analysis. Both FW and NES patients reported a low level of personal control, understanding of their symptoms and a tendency to reject a psychological causation of their symptoms. However NES patients rejected psychological causes less strongly than FW patients (P<.01). Patients with NES were also more likely to consider their treatment to be more effective (P<.01). None of these differences appeared in a similar comparison between patients with epilepsy and patients with NDLW. CONCLUSION: Although patients with NES tended, as a group, to reject psychological factors as relevant to their symptoms, they did so less strongly than patients with functional limb weakness in these cohorts. This has implications for both the way in which these symptoms are grouped together but also the way in which treatment is approached. PMID- 26047954 TI - Identification of genes essential for pellicle formation in Acinetobacter baumannii. AB - BACKGROUND: Acinetobacter baumannii is an opportunistic pathogen, which has the ability to persist in the clinical environment, causing acute and chronic infections. A possible mechanism contributing to survival of A. baumannii is its ability to form a biofilm-like structure at the air/liquid interface, known as a pellicle. This study aimed to identify and characterise the molecular mechanisms required for pellicle formation in A. baumannii and to assess a broad range of clinical A. baumannii strains for their ability to form these multicellular structures. RESULTS: Random transposon mutagenesis was undertaken on a previously identified hyper-motile variant of A. baumannii ATCC 17978 designated 17978hm. In total three genes critical for pellicle formation were identified; cpdA, a phosphodiesterase required for degradation of cyclic adenosine monophosphate (cAMP), and A1S_0112 and A1S_0115 which are involved in the production of a secondary metabolite. While motility of the A1S_0112::Tn and A1S_0115::Tn mutant strains was abolished, the cpdA::Tn mutant strain displayed a minor alteration in its motility pattern. Determination of cAMP levels in the cpdA::Tn strain revealed a ~24-fold increase in cellular cAMP, confirming the role CpdA plays in catabolising this secondary messenger molecule. Interestingly, transcriptional analysis of the cpdA::Tn strain showed significant down-regulation of the operon harboring the A1S_0112 and A1S_0115 genes, revealing a link between these three genes and pellicle formation. Examination of our collection of 54 clinical A. baumannii strains revealed that eight formed a measurable pellicle; all of these strains were motile. CONCLUSIONS: This study shows that pellicle formation is a rare trait in A. baumannii and that a limited number of genes are essential for the expression of this phenotype. Additionally, an association between pellicle formation and motility was identified. The level of the signalling molecule cAMP was found to be controlled, in part, by the cpdA gene product, in addition to playing a critical role in pellicle formation, cellular hydrophobicity and motility. Furthermore, cAMP was identified as a novel regulator of the operon A1S_0112-0118. PMID- 26047956 TI - Analysis of gene expression during aging of CGNs in culture: implication of SLIT2 and NPY in senescence. AB - Senescence is the major key factor that leads to the loss of neurons throughout aging. Cellular senescence is not the consequence of single cause, but there are multiple aspects which may induce senescence in a cell. Various causes such as gene expression, molecular interactions and protein processing and chromatin organization are described as causal factor for senescence. It is well known that the damage to the nuclear or mitochondrial DNA contributes to the aging either directly by inducing the apoptosis/cellular senescence or indirectly by altering cellular functions. The significant nuclear DNA damage with the age is directly associated with the continuous declining in DNA repair. The continuous decline in expression of topoisomerase 2 beta (Topo IIbeta) in cultured cerebellar granule neurons over time indicated the decline in the repair of damage DNA. DNA Topo IIbeta is an enzyme that is crucial for solving topological problems of DNA and thus has an important role in DNA repair. The enzyme is predominantly present in non-proliferating cells such as neurons. In this paper, we have studied the genes which were differentially expressed over time in cultured cerebellar granule neurons (CGNs) and identified potential genes associated with the senescence. Our results showed that the two genes neuropeptide Y (Npy) and Slit homolog 2 (Drosophila) (Slit2) gradually increase during aging, and upon suppression of these two genes, there was gradual increase in cell viability along with restoration of the expression of Topo IIbeta and potential repair proteins. PMID- 26047957 TI - Chronic resistance training does not affect post-exercise blood pressure in normotensive older women: a randomized controlled trial. AB - Resistance training has been recommended for maintenance or improvement of the functional health of older adults, but its effect on acute cardiovascular responses remains unclear. Thus, the purpose of this study was to analyze the effect of 12 weeks of resistance training on post-exercise blood pressure (BP) in normotensive older women. Twenty-eight normotensive and physically inactive women (>= 60 years) were randomly assigned to a training group (TG) or a control group (CG). The TG underwent a resistance training program (12 weeks, 8 exercises, 2 sets, 10-15 repetitions, 3 days/week), while the CG performed stretching exercises (12 weeks, 2 sets, 20 s each, 2 days/week). At baseline and after the intervention, participants were randomly submitted to two experimental sessions: a resistance exercise session (7 exercises, 2 sets, 10-15 repetitions) and a control session. BP was obtained pre- and post-sessions (90 min), through auscultation. Post-exercise hypotension was observed for systolic, diastolic, and mean BP in the TG (-6.1, -3.4, and -4.3 mmHg, respectively; P < 0.05) and in the CG (-4.1, -0.7, and -1.8 mmHg, respectively; P < 0.05). After the intervention period, the magnitude and pattern of this phenomenon for systolic, diastolic, and mean BP were similar between groups (TG -8.8, -4.1, and -5.7 mmHg, respectively; P < 0.05 vs CG -11.1, -5.8, and -7.6 mmHg, respectively; P < 0.05). These results indicate that a single session of resistance exercise promotes reduction in post exercise BP and 12 weeks of resistance training program do not change the occurrence or magnitude of this hypotension. (ClinicalTrial.gov: NCT02346981). PMID- 26047958 TI - Polygenic risk scores in bipolar disorder subgroups. AB - BACKGROUND: Bipolar disorder (BD) is a genetically and clinically heterogeneous disorder. Current classifications of BD rely on clinical presentations without any validating biomarkers, making homogenous and valid subtypes warranted. This study aims at investigating whether a BD polygenic risk score (PGRS) can validate BD subtypes including diagnostic sub-categories (BD-I versus BD-II), patients with and without psychotic symptoms, polarity of first presenting episode and age at onset based groups. We also wanted to investigate whether illness severity indicators were associated with a higher polygenic risk for BD. METHODS: Analyze differences in BD PGRS scores between suggested subtypes of BD and between healthy controls (CTR) and BD in a sample of N=669 (255 BD and 414 CTR). RESULTS: The BD PGRS significantly discriminates between BD and CTR (p<0.001). There were no differences in BD PGRS between groups defined by diagnostic sub-categories, presenting polarity and age at onset. Patients with psychotic BD had nominally significantly higher BD PGRS than patients with non-psychotic BD after controlling for diagnostic sub-category (p=0.019). These findings remained trend level significant after Bonferroni corrections (p=0.079). LIMITATIONS: The low explained variance of the current PGRS method could lead to type II errors. CONCLUSIONS: There are nominally significant differences in BD PGRS scores between patients with and without psychotic symptoms, indicating that these two forms of BD might represent distinct subtypes of BD based in its polygenic architecture and a division between BD with and without psychotic symptoms could represent a more valid subclassification of BD than current diagnostic sub categories. If replicated, this finding could affect future research, diagnostics and clinical practice. PMID- 26047959 TI - Correlates of bullying in Quebec high school students: The vulnerability of sexual-minority youth. AB - PURPOSE: Bullying has become a significant public health issue, particularly among youth. This study documents cyberbullying, homophobic bullying and bullying at school or elsewhere and their correlates among both heterosexual and sexual minority high school students in Quebec (Canada). METHOD: A representative sample of 8194 students aged 14-20 years was recruited in Quebec (Canada) high schools. We assessed cyberbullying, homophobic bullying and bullying at school or elsewhere in the past 12 months and their association with current self-esteem and psychological distress as well as suicidal ideations. RESULTS: Bullying at school or elsewhere was the most common form of bullying (26.1%), followed by cyberbullying (22.9%) and homophobic bullying (3.6%). Overall, girls and sexual minority youth were more likely to experience cyberbullying and other forms of bullying as well as psychological distress, low self-esteem and suicidal ideations. The three forms of bullying were significantly and independently associated with all mental health outcomes. CONCLUSIONS: The results underscore the relevance of taking into account gender and sexual orientation variations in efforts to prevent bullying experience and its consequences. PMID- 26047960 TI - Mental disorders in motherhood according to prepregnancy BMI and pregnancy related weight changes--A Danish cohort study. AB - BACKGROUND: Previous studies have shown an association between prepregnancy BMI and postpartum depression, but little is known about this association beyond one year postpartum and the influence of postpartum weight retention (PPWR). METHODS: We used data from 70355 mothers from the Danish National Birth Cohort to estimate the associations between maternal prepregnancy BMI and PPWR, respectively, and incident depression/anxiety disorders until six years postpartum. Outcome was depression or anxiety diagnosed clinically or filling a prescription for an antidepressant. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Follow-up started at the day of delivery. For the analysis regarding PPWR, follow-up started six months postpartum. RESULTS: Underweight, overweight and obesity were associated with depression and/or anxiety disorders when compared to normal-weight, though the associations were attenuated after adjustments (HR 1.24 [95% CI 1.06-1.45], 1.05 [95% CI 0.96-1.15] and 1.07 [95% CI 0.95-1.21] for underweight, overweight and obese, respectively). Compared to mothers who had returned to their prepregnancy BMI, risk of depression/anxiety disorders was increased for mothers, who from prepregnancy to 6 months postpartum experienced either weight loss >1 BMI unit (HR 1.19 [95% CI 1.06-1.25]), weight gain of 2-3 BMI units (HR 1.23 [95% CI 1.08-1.40]), or weight gain of >=3 BMI units (HR 1.21 [95% CI 1.05-1.40]). LIMITATION: Causal direction and mechanisms behind the associations are largely unknown. CONCLUSIONS: Low prepregnancy body weight and postpartum weight gain or loss are associated with occurrence of depression and anxiety disorders. PMID- 26047961 TI - Parenting strategies for reducing the risk of childhood depression and anxiety disorders: A Delphi consensus study. AB - BACKGROUND: Substantial evidence that some modifiable parental factors are associated with childhood depression and anxiety indicates that parents can play a crucial role in the prevention of these disorders in their children. However, more effective translation of research evidence is required. METHODS: This study employed the Delphi methodology to establish expert consensus on parenting strategies that are important for preventing depression or anxiety disorders in children aged 5-11 years. A literature search identified 289 recommendations for parents. These were presented to a panel of 44 international experts over three survey rounds, who rated their preventive importance. RESULTS: 171 strategies were endorsed as important or essential for preventing childhood depression or anxiety disorders by >=90% of the panel. These were written into a parenting guidelines document, with 11 subheadings: Establish and maintain a good relationship with your child, Be involved and support increasing autonomy, Encourage supportive relationships, Establish family rules and consequences, Encourage good health habits, Minimise conflict in the home, Help your child to manage emotions, Help your child to set goals and solve problems, Support your child when something is bothering them, Help your child to manage anxiety, and Encourage professional help seeking when needed. LIMITATIONS: This study relied on experts from Western countries; hence the strategies identified may not be relevant for all ethnic groups. CONCLUSIONS: This study produced new parenting guidelines that are supported by research evidence and/or international experts, which can now be promoted in Western English-speaking communities to help parents protect their children from depression and anxiety disorders. PMID- 26047962 TI - Design of a novel crosslinked HEC-PAA porous hydrogel composite for dissolution rate and solubility enhancement of efavirenz. AB - The purpose of this research was to synthesize, characterize and evaluate a Crosslinked Hydrogel Composite (CHC) as a new carrier for improving the solubility of the anti-HIV drug, efavirenz. The CHC was prepared by physical blending of hydroxyethylcellulose (HEC) with poly(acrylic acid) (PAA) (1:1) in the presence of poly(vinyl alcohol) (PVA) (as a crosslinker) (1:5) under lyophilization. Efavirenz was loaded in situ into the CHC in varying proportions (200-600 mg). The CHC demonstrated impressive rheological properties (dynamic viscosity=6053 mPa; 500 s(-1)) and tensile strength (2.5 mPa) compared with the native polymers (HEC and PAA). The physicochemical and thermal behavior also confirmed that the CHC was compatible with efavirenz. The incorporation of efavirenz in the CHC increased the surface area (4.4489-8.4948 m(2)/g) and pore volume (469.547-776.916A) of the hydrogel system which was confirmed by SEM imagery and BET surface area measurements. The solubility of efavirenz was significantly enhanced (150 times) in a sustained release manner over 24h as affirmed by the in vitro drug release studies. The hydration medium provided by the CHC network played a pivotal role in improving the efavirenz solubility via increasing hydrogen bonding as proved by the zeta potential measurements (-18.0 to +0.10). The CHC may be a promising alternative as an oral formulation for the delivery of efavirenz with enhanced solubility. PMID- 26047963 TI - The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial. AB - RATIONALE: There has recently been increasing interest in the potential of flavanols, plant-derived compounds found in foods such as fruit and vegetables, to ameliorate age-related cognitive decline. Research suggests that cocoa flavanols improve memory and learning, possibly as a result of their anti inflammatory and neuroprotective effects. These effects may be mediated by increased cerebral blood flow (CBF), thus, stimulating neuronal function. OBJECTIVES: The present study employed arterial spin labelling functional magnetic resonance imaging to explore the effect of a single acute dose of cocoa flavanols on regional CBF. METHODS: CBF was measured pre- and post-consumption of low (23 mg) or high (494 mg) 330 ml equicaloric flavanol drinks matched for caffeine, theobromine, taste and appearance according to a randomized counterbalanced crossover double-blind design in eight males and ten females, aged 50-65 years. Changes in perfusion from pre- to post-consumption were calculated as a function of each drink. RESULTS: Significant increases in regional perfusion across the brain were observed following consumption of the high flavanol drink relative to the low flavanol drink, particularly in the anterior cingulate cortex and the central opercular cortex of the parietal lobe. CONCLUSIONS: Consumption of cocoa flavanol improves regional cerebral perfusion in older adults. This provides evidence for a possible acute mechanism by which cocoa flavanols are associated with benefits for cognitive performance. PMID- 26047965 TI - Neuroleptic malignant syndrome and catatonia overlapping: 2 case reports. PMID- 26047966 TI - India is declared free of maternal and neonatal tetanus. PMID- 26047964 TI - Diet-induced obesity and diet-resistant rats: differences in the rewarding and anorectic effects of D-amphetamine. AB - RATIONALE: Obesity is a leading public health problem worldwide. Multiple lines of evidence associate deficits in the brain reward circuit with obesity. OBJECTIVE: Whether alterations in brain reward sensitivity precede or are a consequence of obesity is unknown. This study aimed to investigate both innate and obesity-induced differences in the sensitivity to the effects of an indirect dopaminergic agonist. METHODS: Rats genetically prone to diet-induced obesity (DIO) and their counterpart diet-resistant (DR) were fed a chow diet, and their response to D-amphetamine on intracranial self-stimulation and food intake were assessed. The same variables were then evaluated after exposing the rats to a high-fat diet, after DIO rats selectively developed obesity. Finally, gene expression levels of dopamine receptors 1 and 2 as well as tyrosine hydroxylase were measured in reward-related brain regions. RESULTS: In a pre-obesity state, DIO rats showed innate decreased sensitivity to the reward-enhancing and anorectic effects of D-amphetamine, as compared to DR rats. In a diet-induced obese state, the insensitivity to the potentiating effects of D-amphetamine on intracranial self-stimulation (ICSS) threshold persisted and became more marked in DIO rats, while the anorectic effects were comparable between genotypes. Finally, innate and obesity-induced differences in the gene expression of dopamine receptors were observed. CONCLUSIONS: Our results demonstrate that brain reward deficits antedate the development of obesity and worsen after obesity is fully developed, suggesting that these alterations represent vulnerability factors for its development. Moreover, our data suggests that the reward enhancing and anorectic effects of D-amphetamine are dissociable in the context of obesity. PMID- 26047967 TI - Regulatory Forum Commentary* Counterpoint: Dose Selection for Tg.rasH2 Mouse Carcinogenicity Studies. AB - High-dose selection for 6-month carcinogenicity studies of pharmaceutical candidates in Tg.rasH2-transgenic mice currently primarily relies on (1) estimation of a maximum tolerated dose (MTD) from the results of a 1-month range finding study, (2) determination of the maximum dose administrable to the animals (maximum feasible dose [MFD]), (3) demonstration of a plateau in systemic exposure, and (4) use of a limit dose of 1,500 mg/kg/day for products with human daily doses not exceeding 500 mg. Eleven 6-month Tg.rasH2 carcinogenicity studies and their corresponding 1-month range-finding studies conducted at Merck were reviewed. High doses were set by estimation of the MTD in 6, by plateau of exposure in 3, and by MFD in 2 cases. For 4 of 6 studies where MTD was used for high-dose selection, the 1-month study accurately predicted the 6-month study tolerability whereas in the remaining 2 studies the high doses showed poorer tolerability than expected. The use of 3 or more drug-treated dose levels proved useful to ensure that a study would successfully and unambiguously demonstrate that a drug candidate was adequately evaluated for carcinogenicity at a minimally toxic high dose level, especially when the high dose may be found to exceed the MTD. PMID- 26047968 TI - [Cardiac tamponade by pneumopericardium due to stab injury]. PMID- 26047969 TI - [Treatment of vulvar intra-epithelial neoplasias with Imiquimod]. AB - The incidence of vulvar intra-epithelial neoplasia (VIN) is increasing in the developed countries especially in young women. There is little consensus regarding the optimal management. Surgery used to be the gold standard. Alternatives to surgery are now needed for the treatment of VIN. Many studies investigated the effectiveness of Imiquimod 5% cream in this pathology. We present a literature review of the results published on the subject. PMID- 26047970 TI - South Korea scrambles to contain MERS virus. PMID- 26047971 TI - Bilateral In-Office Injection Laryngoplasty as an Adjunctive Treatment for Recalcitrant Puberphonia: A Case Report and Review of the Literature. AB - Puberphonia or mutational falsetto is a voice disorder seen in male adolescents. It is defined as the failure of the voice to change from the high pitch of early childhood to the low pitch of adulthood. Puberphonia is usually treated with voice therapy (with or without adjunctive laryngeal manipulation) and psychological counseling. Small series of surgical treatments have also been described. We present the first report of bilateral in-office injection laryngoplasty with hyaluronic acid with voice therapy to treat a 22-year-old male with puberphonia that had not responded to voice therapy. The subject presented with a speaking fundamental frequency of 152 Hz, which decreased to 102 Hz immediately after bilateral injection laryngoplasty and has been maintained at 108 Hz after 24 months. PMID- 26047972 TI - A Survey of Equipment in the Singing Voice Studio and Its Perceived Effectiveness by Vocologists and Student Singers. AB - OBJECTIVES: Speech-language pathologists have long used technology for the clinical measurement of the speaking voice, but present research shows that vocal pedagogues and voice students are becoming more accepting of technology in the studio. As a result, the equipment and technology used in singing voice studios by speech-language pathologists and vocal pedagogues are changing. Although guides exist regarding equipment and technology necessary for developing a voice laboratory and private voice studio, there are no data documenting the current implementation of these items and their perceived effectiveness. This study seeks to document current trends in equipment used in voice laboratories and studios. METHODS: Two separate surveys were distributed to 60 vocologists and approximately 300 student singers representative of the general singing student population. The surveys contained questions about the inventory of items found in voice studios and perceived effectiveness of these items. Data were analyzed using descriptive analyses and statistical analyses when applicable. RESULTS/CONCLUSIONS: Twenty-six of 60 potential vocologists responded, and 66 student singers responded. The vocologists reported highly uniform inventories and ratings of studio items. There were wide-ranging differences between the inventories reported by the vocologist and student singer groups. Statistically significant differences between ratings of effectiveness of studio items were found for 11 of the 17 items. In all significant cases, vocologists rated usefulness to be higher than student singers. Although the order of rankings of vocologists and student singers was similar, a much higher percentage of vocologists report the items as being efficient and effective than students. The historically typical studio items, including the keyboard and mirror, were ranked as most effective by both vocologists and student singers. PMID- 26047973 TI - From hands to feet: Abstract response representations in distractor-response bindings. AB - Evidence suggests that, when people respond to target stimuli, distractors that accompany the target become integrated with the response, and can thus subsequently serve as a retrieval cue of that response-an example of distractor response binding. In two experiments, we investigated whether the response codes that become part of such distractor-response bindings are effector-specific or abstract. In a prime-probe design, participants gave left and right responses with their hands or their feet. The required effector set was systematically varied between prime and probe responses. If participants executed each response immediately, effects of distractor-response binding were only observed for effector repetitions but not for effector changes. However, distractor-response binding was observed in effector-change trials if participants were keeping the prime-action plan active during probe-response execution. These results indicate that it is rather abstract response codes that are integrated with distractor stimuli and retrieved upon distractor repetition. PMID- 26047975 TI - Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. AB - BACKGROUND: Dyslipidaemia remains a significant risk factor for cardiovascular disease and additional lipid-modifying treatments are warranted to further decrease the cardiovascular disease burden. We assessed the safety, tolerability and efficacy of a novel cholesterol esterase transfer protein (CETP) inhibitor TA 8995 in patients with mild dyslipidaemia. METHODS: In this randomised, double blind, placebo-controlled, parallel-group phase 2 trial, we recruited patients (aged 18-75 years) from 17 sites (hospitals and independent clinical research organisations) in the Netherlands and Denmark with fasting LDL cholesterol levels between 2.5 mmol/L and 4.5 mmol/L, HDL cholesterol levels between 0.8 and 1.8 mmol/L and triglyceride levels below 4.5 mmol/L after washout of lipid-lowering treatments. Patients were randomly allocated (1:1) by a computer-generated randomisation schedule to receive one of the following nine treatments: a once a day dose of 1 mg, 2.5 mg, 5 mg, or 10 mg TA-8995 or matching placebo; 10 mg TA 8995 plus 20 mg atorvastatin; 10 mg TA-8995 plus 10 mg rosuvastatin or 20 mg atorvastatin or 10 mg rosuvastatin alone. We overencapsulated statins to achieve masking. The primary outcome was percentage change in LDL cholesterol and HDL cholesterol from baseline at week 12, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01970215. FINDINGS: Between Aug 15, 2013, and Jan 10, 2014, 364 patients were enrolled. At week 12, LDL cholesterol levels were reduced by 27.4% in patients assigned to the 1 mg dose, 32.7% in patients given the 2.5 mg dose, 45.3% in those given the 5 mg dose, and 45.3% in those given the 10 mg dose (p<0.0001). LDL cholesterol levels were reduced by 68.2% in patients given 10 mg TA-8995 plus atorvastatin, and by 63.3% in patients given rosuvastatin plus 10 mg TA-8995 (p<0.0001). A daily dose of 1 mg TA-8995 increased HDL cholesterol levels by 75.8%, 2.5 mg by 124.3%, 5 mg by 157.1%, and 10 mg dose by 179.0% (p<0.0001). In patients receiving 10 mg TA-8995 and 20 mg atorvastatin HDL cholesterol levels increased by 152.1% and in patients receiving 10 mg TA-8995 and 10 mg rosuvastatin by 157.5%. We recorded no serious adverse events or signs of liver or muscle toxic effects. INTERPRETATION: TA 8995, a novel CETP inhibitor, is well tolerated and has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidaemia. A cardiovascular disease outcome trial is needed to translate these effects into a reduction of cardiovascular disease events. FUNDING: Dezima. PMID- 26047976 TI - The evolving role of CETP inhibition: beyond HDL cholesterol. PMID- 26047974 TI - Pavement cells: a model system for non-transcriptional auxin signalling and crosstalks. AB - Auxin (indole acetic acid) is a multifunctional phytohormone controlling various developmental patterns, morphogenetic processes, and growth behaviours in plants. The transcription-based pathway activated by the nuclear TRANSPORT INHIBITOR RESISTANT 1/auxin-related F-box auxin receptors is well established, but the long sought molecular mechanisms of non-transcriptional auxin signalling remained enigmatic until very recently. Along with the establishment of the Arabidopsis leaf epidermal pavement cell (PC) as an exciting and amenable model system in the past decade, we began to gain insight into non-transcriptional auxin signalling. The puzzle-piece shape of PCs forms from intercalated or interdigitated cell growth, requiring local intra- and inter-cellular coordination of lobe and indent formation. Precise coordination of this interdigitated pattern requires auxin and an extracellular auxin sensing system that activates plasma membrane-associated Rho GTPases from plants and subsequent downstream events regulating cytoskeletal reorganization and PIN polarization. Apart from auxin, mechanical stress and cytokinin have been shown to affect PC interdigitation, possibly by interacting with auxin signals. This review focuses upon signalling mechanisms for cell polarity formation in PCs, with an emphasis on non-transcriptional auxin signalling in polarized cell expansion and pattern formation and how different auxin pathways interplay with each other and with other signals. PMID- 26047977 TI - Effect of dietary amylose/amylopectin ratio on growth performance, carcass traits, and meat quality in finishing pigs. AB - The present study was conducted to evaluate the effect of dietary amylose/amylopectin ratio (DAR) on body health and meat quality in finishing pigs. A total of forty-eight DLY pigs (initial body weight of 74.9+/-5.0kg) were randomly allotted to two treatments, and fed either with LR (DAR: 12/88) or HR (DAR: 30/70) diet. Results showed that ingestion of a HR diet not only decreased the triacylglycerol and cholesterol concentrations in plasma (P<0.05), but also reduced the lipid contents in liver (P<0.05). Interestingly, ingestion of a HR diet tended to reduce the intramuscular fat content (P=0.06), and significantly increased the firmness (P<0.05) and loin-eye area (P<0.01). Moreover, ingestion of a HR diet significantly decreased the levels of MyHC I (P<0.05), and elevated the levels of MyHCIIb (P<0.05) gene expression in longissimus dorsi. Ingestion of a HR diet has resulted in down-regulation of the FAS3 gene in liver and longissimus dorsi (P<0.05). These findings suggested that a HR diet is helpful to reduce the lipogenesis both in liver and muscle. PMID- 26047978 TI - Effect of dietary inclusion of a herbal extract mixture and different oils on pig performance and meat quality. AB - The aim of the study was to evaluate the effect of a herbal extract mixture on pig performance and meat quality. The experiment was performed on 60 fatteners (60+/-0.5-112+/-2.0kg). Group I (control) was fed with standard feed; groups II and III received the same feed supplemented with 150mg BHT or 500mg of a herbal extract mixture (sage, nettle, lemon balm and coneflower) per kg of feed, respectively. In each group, half of the animals received 4% rapeseed oil, the other half soybean oil. The herbal extracts had no effect on animal performance but significantly improved meat oxidative stability, lowered cholesterol and TI index and increased PUFA content in meat. Slight differences between animals fed with rapeseed or soybean oils were observed. Gilt meat had significantly better (P<=0.01) AI, TI, and h/H indices than barrow meat. It was concluded that herbal extracts have a beneficial effect on pork health-promoting properties due to changes in lipid fraction. PMID- 26047979 TI - Preliminary study of FMO1, FMO5, CYP21, ESR1, PLIN2 and SULT2A1 as candidate gene for compounds related to boar taint. AB - An association study between polymorphisms of six genes and boar taint related compounds androstenone, skatole and indole was performed in a boar population (n=370). Significant association (P<0.05) was detected for SNP of FMO5 (g.494A>G) with all boar taint compounds, SNP of CYP21 (g.3911T>C) with skatole and indole, and SNP of ESR1 (g.672C>T) with androstenone and indole. mRNA expression of CYP21 and ESR1 was higher in CAB (castrated boar) compared to non-castrated boars; whereas, the expression of FMO5 and ESR1 was higher in LBT (low boar taint) compared to HBT (high boar taint) in liver tissue. FMO5, CYP21 and ESR1 proteins were less detectable in HBT compared with LBT and CAB in liver tissues. These findings suggest that FMO5, CYP21 and ESR1 gene variants might have effects on the boar taint compounds. PMID- 26047980 TI - Horse-meat for human consumption - Current research and future opportunities. AB - The consumption of horse-meat is currently not popular in most countries, but because of its availability and recognized nutritional value consumption is slowly increasing in several western European countries based on claims that it could be an alternative red meat. In this review, horse-meat production, trade and supply values have been summarized. In addition, the advantage of horse production is noted because of its lower methane emissions and increased uptake, particularly of n-3 polyunsaturated fatty acids (PUFAs), which is based on its digestive physiology. Of particular interest in this review is the unique fatty acid composition of horse-meat with its high level of the nutritionally desirable PUFAs in both the adipose and muscle fat. Because of its large frame size and digestive physiology, the horse can be considered an alternative to bovine meat, with large advantages regarding the maintenance of less favored mountain grazing areas and its facility to transfer PUFA from feed to meat. PMID- 26047981 TI - The influence of maternal dietary fat on the fatty acid composition and lipid metabolism in the subcutaneous fat of progeny pigs. AB - To investigate the influence of maternal dietary fat intake on the fatty acid composition and lipid metabolism of progeny subcutaneous fat (SQ), fourteen sows were randomly assigned to a control or high fat (HF) group which received a diet containing 8% corn oil starting seven days before farrowing until weaning. The results showed the fatty acid composition in progeny SQ at weaning age generally demonstrated a similar pattern with the sow milk. However, this pattern was not observed at the finishing stage. The stearoyl-CoA desaturase 1 mRNA and protein levels in the progeny SQ of the HF group decreased at both sampling stages when compared with controls. The study demonstrated that maternal dietary fat during lactation significantly affected the fatty acid composition of progeny SQ at the weaning stage, yet no obvious lasting effect was observed in progeny SQ at the finishing stage. PMID- 26047982 TI - Histopathological Validation of the Surface-Intermediate-Base Margin Score for Standardized Reporting of Resection Technique during Nephron Sparing Surgery. AB - PURPOSE: The surface-intermediate-base margin score is a novel standardized reporting system of resection techniques during nephron sparing surgery. We validated the surgeon assessed surface-intermediate-base score with microscopic histopathological assessment of partial nephrectomy specimens. MATERIALS AND METHODS: Between June and August 2014 data were prospectively collected from 40 consecutive patients undergoing nephron sparing surgery. The surface-intermediate base score was assigned to all cases. The score specific areas were color coded with tissue margin ink and sectioned for histological evaluation of healthy renal margin thickness. Maximum, minimum and mean thickness of healthy renal margin for each score specific area grade (surface [S] = 0, S = 1 ; intermediate [I] or base [B] = 0, I or B = 1, I or B = 2) was reported. The Mann-Whitney U and Kruskal Wallis tests were used to compare the thickness of healthy renal margin in S = 0 vs 1 and I or B = 0 vs 1 vs 2 grades, respectively. RESULTS: Maximum, minimum and mean thickness of healthy renal margin was significantly different among score specific area grades S = 0 vs 1, and I or B = 0 vs 1, 0 vs 2 and 1 vs 2 (p <0.001). The main limitations of the study are the low number of the I or B = 1 and I or B = 2 samples and the assumption that each microscopic slide reflects the entire score specific area for histological analysis. CONCLUSIONS: The surface-intermediate-base scoring method can be readily harnessed in real-world clinical practice and accurately mirrors histopathological analysis for quantification and reporting of healthy renal margin thickness removed during tumor excision. PMID- 26047983 TI - Targeting HER2 with T-DM1, an Antibody Cytotoxic Drug Conjugate, is Effective in HER2 Over Expressing Bladder Cancer. AB - PURPOSE: Systemic therapy for advanced bladder cancer has not changed substantially in more than 2 decades and mortality rates remain high. The recognition of HER2 over expression in bladder cancer has made HER2 a promising therapeutic target. T-DM1, a new drug consisting of the HER2 antibody trastuzumab conjugated with a cytotoxic agent, has been shown in breast cancer to be superior to trastuzumab. We tested T-DM1 in preclinical models of bladder cancer. MATERIALS AND METHODS: We evaluated the effect of T-DM1 compared to trastuzumab in different in vitro and in vivo models of HER2 over expressing bladder cancer. RESULTS: RT4V6 was the highest HER2 expressing bladder cancer cell line and it showed higher growth inhibition with T-DM1 compared to trastuzumab. T-DM1 but not trastuzumab induced apoptosis of RT4V6 cells after G2/M arrest on cell cycle analysis. HER2 expression was higher in cell lines with acquired cisplatin resistance compared to the corresponding parental cell lines. Resistant cells showed higher sensitivity to T-DM1 by the induction of apoptosis. In addition, cells cultured in anchorage independent conditions increased HER2 expression compared to cells cultured in adherent conditions and T-DM1 significantly inhibited colony formation in soft agar compared to trastuzumab. In an orthotopic bladder cancer xenograft model tumor growth of cisplatin resistant RT112 was significantly inhibited by T-DM1 via the induction of apoptosis compared to treatment with control IgG or trastuzumab. CONCLUSIONS: T-DM1 has promising antitumor effects in preclinical models of HER2 over expressing bladder cancer. PMID- 26047985 TI - Beyond Mannheim: Conceptualising how people 'talk' and 'do' generations in contemporary society. AB - In the 1920s, Karl Mannheim developed the concept of generation in a treatise entitled 'The Problem of Generations' (1952/1928). His conceptualisation pertained to what Pilcher (1994) calls 'social generations', that is, cohort members who have similar attitudes, worldview and beliefs grounded in their shared context and experiences accumulated over time. It is often argued that social generation has been hollowed out as a sociological concept, yet it continues to feature prominently in policy debates, media, academic literature and everyday talk. This article develops a grounded conceptual framework of how the notion of 'generation' is employed by 'ordinary people'. We induct the meaning of 'generation' from how people use the term and the meaning they attribute to it. We contribute to the current scholarship engaging with Mannheim to explore how people's portrayals of their 'performance' of generation can help to develop further the concept of social generation. We draw on qualitative primary data collected in the Changing Generations project, a Grounded Theory study of intergenerational relations in Ireland. Far from outdated or redundant, generation emerges as a still-relevant concept that reflects perceptions of how material resources, period effects and the welfare state context shape lives in contemporary societies. Generation is a conceptual device used to 'perform' several tasks: to apportion blame, to express pity, concern and solidarity, to highlight unfairness and inequity, and to depict differential degrees of agency. Because the concept performs such a wide range of important communicative and symbolic functions, sociologists should approach generations (as discursive formations) as a concept and practice that calls for deeper understanding, not least because powerful political actors have been quicker than sociologists to recognise the potential of the concept to generate new societal cleavages. PMID- 26047986 TI - Inter-generational contact from a network perspective. AB - Pathways for resource--or other--exchanges within families have long been known to be dependent on the structure of relations between generations (Agree et al., 2005; Fuller-Thomson et al., 1997; Silverstein, 2011; Treas & Marcum, 2011). Much life course research has theorized models of inter-generational exchange- including, the 'sandwich generation' (Miller, 1981) and the 'skipped generation' pathways (Chalfie, 1994)--but there is little work relating these theories to relevant network mechanisms such as liaison brokerage (Gould & Fernandez, 1989) and other triadic configurations (Davis & Leinhardt, 1972; Wasserman & Faust, 1994). To address this, a survey of models of resource allocation between members of inter-generational households from a network perspective is introduced in this paper. Exemplary data come from health discussion networks among Mexican-origin multi-generational households. PMID- 26047984 TI - Midbrain dopamine neurons in Parkinson's disease exhibit a dysregulated miRNA and target-gene network. AB - The degeneration of substantia nigra (SN) dopamine (DA) neurons in sporadic Parkinson's disease (PD) is characterized by disturbed gene expression networks. Micro(mi)RNAs are post-transcriptional regulators of gene expression and we recently provided evidence that these molecules may play a functional role in the pathogenesis of PD. Here, we document a comprehensive analysis of miRNAs in SN DA neurons and PD, including sex differences. Our data show that miRNAs are dysregulated in disease-affected neurons and differentially expressed between male and female samples with a trend of more up-regulated miRNAs in males and more down-regulated miRNAs in females. Unbiased Ingenuity Pathway Analysis (IPA) revealed a network of miRNA/target-gene associations that is consistent with dysfunctional gene and signaling pathways in PD pathology. Our study provides evidence for a general association of miRNAs with the cellular function and identity of SN DA neurons, and with deregulated gene expression networks and signaling pathways related to PD pathogenesis that may be sex-specific. PMID- 26047987 TI - Informal caring in England and Wales--Stability and transition between 2001 and 2011. AB - Informal caring is of significant and increasing importance in the context of an ageing population, growing pressures on public finances, and increasing life expectancy at older ages. A growing body of research has examined the characteristics associated with informal care provision, as well as the impact of caring for the carer's physical and mental health, and their economic activity. However, only a relatively small body of literature has focused on the study of 'repeat' or continuous caring over time, and the factors associated with such trajectories. In 2001, for the first time, the United Kingdom census asked about provision of informal care, enabling identification of the prevalence of informal caregiving at a national level. This paper follows up informal carers from the 2001 Census in order to examine their characteristics and circumstances 10 years later using a nationally representative 1% sample of linked census data for England and Wales, the Office for National Statistics Longitudinal Study. The analysis classifies the range of possible combinations of caring and non-caring roles between 2001 and 2011, focusing on the characteristics of those who were providing care at one, or both, time points. Among other results, the analysis identified that, among those who were carers in 2001, caring again in, or continuing to care until, 2011 was associated with being female, aged between 45 and 54 years in 2011, looking after the home, and providing care for 50 hours or more per week in 2001. Such results contribute to our understanding of a particular group of informal carers and provide a more nuanced picture of informal care provision at different stages of the life course. PMID- 26047988 TI - Realization of fertility intentions by different time frames. AB - This paper focuses on the realization of positive fertility intentions with different time frames. The analyses are based on a unique combination of survey data and information from Norwegian administrative registers on childbearing in the years following the complete selected sample. Guided by the theoretical and empirical framework of the Theory of Planned Behavior (TPB), the results suggest that a fertility intention's time frame is relevant for childbearing behaviour, but the patterns are somewhat different for respondents who were childless at the time of the interview compared to those who already had children. Overall, childless were less likely to realize their fertility intentions than parents. Following the TPB, childless may underestimate the difficulty of acting on their intentions and therefore have more difficulty realizing their intentions, versus parents who take into account their ability to manage another child. The results also show that childless with an immediate fertility intention are more likely to succeed than those with a longer-term intention. Likewise, parents with an immediate fertility intention are more likely to realize their intention during the two first years after the interview, but after four years the childbearing rate was higher among those with longer-term fertility intentions. PMID- 26047989 TI - Within-couple specialisation in paid work: A long-term pattern? A dual trajectory approach to linking lives. AB - Research on the division of labour has mainly focussed on transitions between individuals' labour market states during the first years of parenthood. A common conclusion has been that couples specialize--women in unpaid and men in paid work -either due to gender ideologies or a comparative advantage in the labour market. But what happens later in life? The German Socio-Economic Panel now provides researchers with a continuous measure of working hours across decades of couples' lives, enabling a dual trajectory analysis to explore couples' long-term specialisation patterns. I focus on the career trajectories of West German couples, and specifically, due to the relatively low institutional and normative support for female employment during its members' early years, on the 1956-65 female birth cohort. Even in this setting and with a conservative estimate, a surprisingly small number of couples--only a fifth--adopt full specialisation in later life. A sizable proportion--a third--moves into dual full-time employment. This trend is even more common among highly educated couples: half of those couples move into dual full-time employment. I find that highly educated women are not only less likely to permanently specialise but also more likely to try working full-time, possibly because their partners' comparative advantages are lower. But despite high opportunity costs, 45% of highly educated parents never try to pursue a dual career either because of a satiation of material wants or because of low societal support for maternal employment. The latter phenomenon is further underscored by the finding that many couples' increase in working hours occurs only when a youngest child is a teenager. PMID- 26047990 TI - Assessing the relationships among race, religion, humility, and self-forgiveness: A longitudinal investigation. AB - Social and behavioral scientists have shown a growing interest in the study of virtues due, in part, to the influence of positive psychology. The underlying premise in this research is that adopting key virtues promotes a better quality of life. Consistent with this orientation, the purpose of this study is to assess the relationship between humility and self-forgiveness over time. The analyses are organized around three issues. First, it is proposed that older Blacks will be more humble than older Whites and older Blacks will be more likely to forgive themselves than older Whites. Second, it is hypothesized that, over time, more humble older people are more likely to forgive themselves than individuals who are less humble. Third, it is proposed that greater involvement in religion is associated with greater humility and greater self-forgiveness. Data from a nationwide longitudinal survey of older adults provides support for all these hypotheses. PMID- 26047991 TI - Survival on treatment with second-line biologic therapy: a cohort study comparing cycling and swap strategies. PMID- 26047992 TI - Association between acute kidney injury and in-hospital mortality in patients undergoing percutaneous coronary interventions. AB - BACKGROUND: Acute kidney injury (AKI) post percutaneous coronary intervention (PCI) is associated with increased mortality but both death and AKI share common risk factors. Moreover, the effect of a high contrast dose, a known modifiable risk factor for AKI, on mortality is unknown. The aim of our study was to analyze the association between AKI and in-hospital mortality post PCI after adjustment for confounding by common risk factors. METHODS AND RESULTS: This study was performed using a regional registry of all patients undergoing PCI in Michigan. Primary end points were AKI (serum creatinine increase >0.5 mg/dL) and all-cause in-hospital mortality. Propensity matching was performed, with each AKI patient matched to 4 controls. Attributable risk fraction and the exposed index number of AKI for mortality were calculated within the propensity-matched cohort. Between 2010 and 2013, 92 317 patients underwent PCI, of whom 2141 (2.3%) developed AKI. We matched 1371/2141 patients with AKI to 5484 controls. AKI was strongly associated with mortality (odds ratio=12.52, 95% confidence interval 9.29-16.86) in the propensity-matched cohort. The attributable risk fraction for mortality of AKI was 31.4% (95% confidence interval 26.8%-37.5%), and one death could be prevented for every 9 cases of AKI successfully avoided. The independent impact of a high contrast dose at time of PCI on in-hospital mortality risk was weak (adjusted odds ratio 1.19, 95% confidence interval 0.97-1.45). CONCLUSIONS: Nearly one-third of the in-hospital mortality post PCI is attributable to AKI. Preventing 9 cases of AKI could potentially prevent one death. These study findings stress the need for developing effective AKI preventive strategies beyond minimization of contrast dose. PMID- 26047993 TI - Comparison of zotarolimus- and everolimus-eluting coronary stents: final 5-year report of the RESOLUTE all-comers trial. AB - BACKGROUND: Newer-generation drug-eluting stents that release zotarolimus or everolimus have been shown to be superior to the first-generation drug-eluting stents. However, data comparing long-term safety and efficacy of zotarolimus- (ZES) and everolimus-eluting stents (EES) are limited. RESOLUTE all-comers (Randomized Comparison of a Zotarolimus-Eluting Stent With an Everolimus-Eluting Stent for Percutaneous Coronary Intervention) trial compared these 2 stents and has shown that ZES was noninferior to EES at 12-month for the primary end point of target lesion failure. We report the secondary clinical outcomes at the final 5-year follow-up of this trial. METHODS AND RESULTS: RESOLUTE all-comer clinical study is a prospective, multicentre, randomized, 2-arm, open-label, noninferiority trial with minimal exclusion criteria. Patients (n=2292) were randomly assigned to treatment with either ZES (n=1140) or EES (n=1152). Patient oriented composite end point (combination of all-cause mortality, myocardial infarction, and any revascularizations), device-oriented composite end point (combination of cardiac death, target vessel myocardial infarction, and clinically indicated target lesion revascularization), and major adverse cardiac events (combination of all-cause death, all myocardial infarction, emergent coronary bypass surgery, or clinically indicated target lesion revascularization) were analyzed at 5-year follow-up. The 2 groups were well-matched at baseline. Five-year follow-up data were available for 98% patients. There were no differences in patient-oriented composite end point (ZES 35.3% versus EES 32.0%, P=0.11), device-oriented composite end point (ZES 17.0% versus EES 16.2%, P=0.61), major adverse cardiac events (ZES 21.9% versus EES 21.6%, P=0.88), and definite/probable stent thrombosis (ZES 2.8% versus EES 1.8%, P=0.12). CONCLUSIONS: At 5-year follow-up, ZES and EES had similar efficacy and safety in a population of patients who had minimal exclusion criteria. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00617084. PMID- 26047994 TI - Late Electrical and Mechanical Remodeling After Atrial Septal Defect Closure in Children: Surgical Versus Percutaneous Approach. AB - BACKGROUND: Conflicting data were reported about normalization of sizes of right chambers, systolic and diastolic function and prevalence of arrhythmias after ostium secundum atrial septal defect closure. We sought to compare surgical and percutaneous approaches in terms of arrhythmias, right chamber volumes, and function at long-term follow-up. METHODS: In all, 107 patients were enrolled, all corrected at pediatric age. Forty-four of them were treated surgically with a right thoracotomy approach and 63 were treated percutaneously. All patients underwent a standard echocardiogram and electrocardiographic Holter examinations. RESULTS: No difference was detected between the two groups regarding right atrial or ventricular volumes. The global right ventricular function assessed by fractional area change was similar between the two groups. However, the longitudinal function and the diastolic function were significantly impaired in the surgical group (tricuspid annulus peak systolic excursion 23.7 +/- 4.5 mm versus 18.7 +/- 3.5 mm, p < 0.001; S' wave 13.7 +/- 3.1 cm/s versus 9.8 +/- 2.4 cm/s, p < 0.001; E/E' 4.7 +/- 1.7 versus 7.1 +/- 2.9, p < 0.001). There was a low incidence of supraventricular couples or runs, but slightly higher in the surgical group (6.8% versus 1.6%), although not statistically significant. No echocardiographic variable related to ventricular or supraventricular arrhythmic events. CONCLUSIONS: Either surgical or percutaneous closure of atrial septal defect have a similar efficacy on the volume normalization of the right chamber. Modern surgical techniques have a limited impact on the systolic and diastolic function as well as on the arrhythmic risk; however, the right ventricular longitudinal and diastolic function seems to be better preserved in the percutaneous group. PMID- 26047995 TI - Higher Versus Standard Preoperative Radiation in the Trimodality Treatment of Stage IIIa Lung Cancer. AB - BACKGROUND: The management of potentially resectable stage III non-small cell lung carcinoma (NSCLC) is controversial. Options include induction chemotherapy or induction chemoradiation followed by resection, or chemoradiation without surgery. No trial has compared the outcomes of induction chemoradiation using different radiation doses. We reviewed our experience involving patients with clinical stage III disease treated with trimodality therapy involving two radiation strategies to determine the response rates, operative results, recurrence patterns, and long-term survival. METHODS: A retrospective review was made of consecutive stage III NSCLC patients treated from 2004 to 2011. RESULTS: Fifty-two patients with clinical stage IIIa NSCLC were treated with trimodality therapy. Eighteen patients were treated to doses of 60 Gy or higher, and 34 to lower doses (45, 50, or 54 Gy). There were significantly more postoperative complications in the higher radiation group (p < 0.001). Pathologic complete response (50% versus 15%, p = 0.016) and mediastinal nodal clearance (75% versus 42%, p = 0.254) rates were also higher in the high-dose group. That did not, however, translate into better disease-free and overall survival rates. Importantly, long-term noncancer mortality was significantly higher after higher dose preoperative radiation therapy. CONCLUSIONS: In this series of patients with clinical stage IIIa NSCLC treated with trimodality therapy, a higher dose of preoperative radiation therapy resulted in better response rates but that did not translate to better cancer-specific survival. Of significance, we observed a notably higher delayed noncancer mortality in the high-dose group. PMID- 26047996 TI - Rhf1 gene is involved in the fruiting body production of Cordyceps militaris fungus. AB - Cordyceps militaris is an important medicinal fungus. Commercialization of this fungus needs to improve the fruiting body production by molecular engineering. An improved Agrobacterium tumefaciens-mediated transformation (ATMT) method was used to select an insertional mutant (g38) which exhibited fast stromatal differentiation and increased yield. The Rhf1 gene encoding filamentation protein was destroyed by a single T-DNA and no Rhf1 transcription was detected in mutant g38. To verify the function of the Rhf1 gene, RNA interference plasmid and overexpression vector of the Rhf1 gene were constructed and transferred to the wild-type JM4 by ATMT. Fast stromatal differentiation and larger fruiting bodies were found in the RNAi-Rhf1 mutants (JM-iRhf1). In the overexpression mutants (JM OERhf1), neither stromata nor fruiting bodies appeared. The rescued strain (38 OERhf1) showed similar growth characteristics as JM4. These results indicated that the Rhf1 gene was involved in the stromatal differentiation and the shape formation of fruiting bodies. PMID- 26047997 TI - Quantitative blood group typing using surface plasmon resonance. AB - The accurate and reliable typing of blood groups is essential prior to blood transfusion. While current blood typing methods are well established, results are subjective and heavily reliant on analysis by trained personnel. Techniques for quantifying blood group antibody-antigen interactions are also very limited. Many biosensing systems rely on surface plasmon resonance (SPR) detection to quantify biomolecular interactions. While SPR has been widely used for characterizing antibody-antigen interactions, measuring antibody interactions with whole cells is significantly less common. Previous studies utilized SPR for blood group antigen detection, however, showed poor regeneration causing loss of functionality after a single use. In this study, a fully regenerable, multi functional platform for quantitative blood group typing via SPR detection is achieved by immobilizing anti-human IgG antibody to the sensor surface, which binds to the Fc region of human IgG antibodies. The surface becomes an interchangeable platform capable of quantifying the blood group interactions between red blood cells (RBCs) and IgG antibodies. As with indirect antiglobulin tests (IAT), which use IgG antibodies for detection, IgG antibodies are initially incubated with RBCs. This facilitates binding to the immobilized monolayer and allows for quantitative blood group detection. Using the D-antigen as an example, a clear distinction between positive (>500 RU) and negative (<100 RU) RBCs is achieved using anti-D IgG. Complete regeneration of the anti-human IgG surface is also successful, showing negligible degradation of the surface after more than 100 regenerations. This novel approach is validated with human-sourced whole blood samples to demonstrate an interesting alternative for quantitative blood grouping using SPR analysis. PMID- 26047998 TI - A multi-walled carbon nanotubes-poly(L-lysine) modified enantioselective immunosensor for ofloxacin by using multi-enzyme-labeled gold nanoflower as signal enhancer. AB - The enantioselective detection of trace amounts of ofloxacin is very important in many fields. In this work, an enantioselective and sensitive electrochemical immunosensor was constructed for the detection of chiral antibiotic ofloxacin based on a dual amplification strategy using multiwall carbon nanotubes-poly(L lysine) as a matrix to immobilize the antigen and multi-enzyme-antibody functionalized gold nanoflowers as an electrochemical detection label. The fabrication process of the dual-amplified immunosensor was characterized by scanning electron microscopy, cyclic voltammogram and electrochemical impedance spectroscopy, respectively. After the optimization of the experimental conditions, a competitive immunoassay, i.e., the association ability with the corresponding antibody between the captured antigen and free S-OFL or R-OFL in the solution, showed that the immunosensor exhibited a sensitive response to S OFL in the range from 0.26 to 25.6 ng/mL with a detection limit of 0.15 ng/mL as well as a sensitive response to R-OFL in the range from 0.37 to 12.8 ng/mL with a detection limit of 0.30 ng/mL. Along with the acceptable sensitivity and stability, the S-OFL or R-OFL immunosensor showed selective ability to its corresponding enantiomer, suggesting this amplification strategy may hold a potential application in the detection of OFL in food or environment. PMID- 26047999 TI - [Phosphodiesterase-5 inhibitors for the treatment of pulmonary arterial hypertension]. AB - In experimental and clinical cardiology, phosphodiesterase type 5 (PDE-5) inhibitors have brought scientific interest as a therapeutic tool in pulmonary arterial hypertension (PAH) management in recent years. Phosphodiesterases are a superfamily of enzymes that inactivate cyclic adenosine monophosphate and cyclic guanosine monophosphate, the second messengers of prostacyclin and nitric oxide. The rationale for the use of PDE-5 inhibitors in PAH is based on their capacity to overexpresss the nitric oxide pathway pursued inhibition of cyclic guanosine monophosphate hydrolysis. By increasing cyclic guanosine monophosphate levels it promotes vasodilation, antiproliferative and pro-apoptotic effects that may reverse pulmonary vascular remodeling. There is also evidence that these drugs may directly enhance right ventricular contractility through an increase in cyclic adenosine monophosphate mediated by the inhibition of the cyclic guanosine monophosphate -sensitive PDE-3. Sildenafil, tadalafil and vardenafil are 3 specific PDE-5 inhibitors in current clinical use, which share similar mechanisms of action but present some significant differences regarding potency, selectivity for PDE-5 and pharmacokinetic properties. Sildenafil received approval in 2005 by the Food and Drug Administration and the European Medicines Agency and tadalafil in 2009 by the Food and Drug Administration and the European Medicines Agency for the treatment of PAH in patients classified as NYHA/WHO functional class II and III. In Mexico, sildenafil and tadalafil were approved by Comision Federal de Proteccion contra Riesgos Sanitarios for this indication in 2010 and 2011, respectively. PMID- 26048000 TI - Pre-existing diabetes and risks of morbidity and mortality after liver transplantation: A nationwide database study in an Asian population. AB - BACKGROUND: Whether diabetes mellitus (DM) is associated with a higher risk of perioperative mortality and mortality after liver transplantation (LTx) remains unclear. METHODS: We compared the risk of postoperative mortality and morbidity in DM and non-DM patients undergoing LTx. We enrolled 558 DM patients who underwent LTx from 2000 to 2010. RESULTS: DM was associated with elevated 90-day risk of post-LTx stroke. Otherwise, the DM cohort did not exhibit significantly higher risks of postoperative morbidities, such as septicemia, pneumonia, and wound infection, than the non-DM cohort. Cox proportional hazards regression model showed that patients with DM with coexisting renal manifestations were at a significantly high risk of 30-day and 90-day postoperative mortality. Further comorbidity stratification analysis showed that DM cohort exhibited higher risk of mortality than the non-DM cohort if the patients had liver cancer, or did not have hypertension, ischemic heart disease, and chronic obstructive pulmonary disease. CONCLUSION: DM is associated with elevated risk of 90-day post-LTx. Moreover, DM patients with coexisting renal manifestations exhibited an increased postoperative risk of mortality after LTx. PMID- 26048001 TI - Adolescent nicotine induces persisting changes in development of neural connectivity. AB - Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part through D1DR receptors, in a network activated by nicotine. The adolescent nicotine effects reviewed here suggest that modification of late CNS development constitutes a hazard of adolescent nicotine use. PMID- 26048002 TI - Molecular delineation of a caspase 10 homolog from black rockfish (Sebastes schlegelii) and its transcriptional regulation in response to pathogenic stress. AB - Caspase 10 is an initiator caspase in death cascades of death receptor mediated apoptotic signaling. We identified and molecularly characterized a novel homolog of caspase 10 from black rockfish (Sebastes schlegelii) and designated as RfCasp10. The complete coding region of RfCasp10 was found to consist of 1659 bps, encoding a 553 amino acid protein with a predicted molecular mass of 61.7 kDa. The characteristic caspase family domain architecture, including death effecter domains (DEDs), was clearly identified in RfCasp10. Moreover, the RfCasp10 gene was found to contain 13 exons. Our pairwise sequence alignment confirmed the prominent sequence similarity of RfCasp10 with its fish homologs, and phylogenetic reconstruction affirmed its homology and substantial evolutionary relationship with known caspases 10 similitudes, in particular with those of teleosts. As detected by qPCR, RfCasp10 was markedly expressed in blood tissues under physiological conditions, whereas its expression was found to be upregulated under pathogenic stress, elicited by Streptococcus iniae and polyinosinic:polycytidylic acid in blood, liver, and spleen tissues. Collectively, our study suggests the plausible elicitation of RfCasp10 mediated apoptosis in immune relevant tissues of black rockfish as a host immune response to a bacterial or viral infection. PMID- 26048004 TI - Effects of awareness that food intake is being measured by a universal eating monitor on the consumption of a pasta lunch and a cookie snack in healthy female volunteers. AB - To date, there have been no studies that have explicitly examined the effect of awareness on the consumption of food from a Universal Eating Monitor (UEM - hidden balance interfaced to a computer which covertly records eating behaviour). We tested whether awareness of a UEM affected consumption of a pasta lunch and a cookie snack. 39 female participants were randomly assigned to either an aware or unaware condition. After being informed of the presence of the UEM (aware) or not being told about its presence (unaware), participants consumed ad-libitum a pasta lunch from the UEM followed by a cookie snack. Awareness of the UEM did not significantly affect the amount of pasta or cookies eaten. However, awareness significantly reduced the rate of cookie consumption. These results suggest that awareness of being monitored by the UEM has no effect on the consumption of a pasta meal, but does influence the consumption of a cookie snack in the absence of hunger. Hence, energy dense snack foods consumed after a meal may be more susceptible to awareness of monitoring than staple food items. PMID- 26048003 TI - Structure Principles of CRISPR-Cas Surveillance and Effector Complexes. AB - The pathway of CRISPR-Cas immunity redefines the roles of RNA in the flow of genetic information and ignites excitement for next-generation gene therapy tools. CRISPR-Cas machineries offer a fascinating set of new enzyme assemblies from which one can learn principles of molecular interactions and chemical activities. The interference step of the CRISPR-Cas immunity pathway congregates proteins, RNA, and DNA into a single molecular entity that selectively destroys invading nucleic acids. Although much remains to be discovered, a picture of how the interference process takes place is emerging. This review focuses on the current structural data for the three known types of RNA-guided nucleic acid interference mechanisms. In it, we describe key features of individual complexes and we emphasize comparisons across types and along functional stages. We aim to provide readers with a set of core principles learned from the three types of interference complexes and a deep appreciation of the diversity among them. PMID- 26048005 TI - Quantifying consumer portion control practices. A cross-sectional study. AB - The use of portion control practices has rarely been quantified. The present study aimed to: (1) explore which portion control practices are actually used by the general population and their association with cognitive restraint, demographic background and general health interest (GHI), and (2) examine how the usage of portion control practices predicts the estimated consumption of an energy dense food (i.e. pizza). Twenty-two portion control practices were rated in terms of their frequency of use from 'never' to 'very often' by a representative sample of 1012 consumers from the island of Ireland. Three factors were extracted and named: measurement-strategy scale, eating-strategy scale, and purchasing-strategy scale. The eating-strategy scale score was the highest, while the measurement-strategy scale carried the lowest frequency score. For each strategy scale score, the strongest predictor was GHI, followed by gender. Having higher GHI and being female were independently associated with more frequent portion control. Both the eating-strategy scale score and the purchasing-strategy scale score were negatively associated with pizza portion size consumption estimates. In conclusion, while this study demonstrates that the reported use of portion control practices is low, the findings provide preliminary evidence for their validity. Further studies are needed to explore how portion control practices are used in different kinds of portion size decisions and what their contribution is to the intake of food over an extended period of time. PMID- 26048006 TI - The weight management strategies inventory (WMSI). Development of a new measurement instrument, construct validation, and association with dieting success. AB - In an obesogenic environment, people have to adopt effective weight management strategies to successfully gain or maintain normal body weight. Little is known about the strategies used by the general population in daily life. Due to the lack of a comprehensive measurement instrument to assess conceptually different strategies with various scales, we developed the weight management strategies inventory (WMSI). In study 1, we collected 19 weight management strategies from research on self-regulation of food intake and successful weight loss and maintenance, as well as from expert interviews. We classified them under the five main categories of health self-regulation strategies - goal setting and monitoring, prospection and planning, automating behavior, construal, and inhibition. We formulated 93 items. In study 2, we developed the WMSI in a random sample from the general population (N = 658), using reliability and exploratory factor analysis. This resulted in 19 factors with 63 items, representing the 19 strategies. In study 3, we tested the 19-factor structure in a quota (age, gender) sample from the general population (N = 616), using confirmatory factor analysis. A good model fit (CFI = .918; RMSEA = .043) was revealed. Reliabilities and construct validity were high. Positive correlations of most strategies with dieting success and negative correlations of some strategies with body mass index were found among dieters (N = 292). Study 4 (N = 162) revealed a good test-retest reliability. The WMSI assesses theoretically derived, evidence-based, and conceptually different weight management strategies with different scales that have good psychometric characteristics. The scales can also be used for pre- and post measures in intervention studies. The scales provide insights into the general population's weight management strategies and facilitate tailoring and evaluating health communication. PMID- 26048007 TI - Molecular diversity and pleiotropic role of the mitochondrial calcium uniporter. AB - The long awaited molecular identification of the mitochondrial calcium uniporter (MCU) in 2011 has opened an exciting phase in the study of mitochondrial calcium homeostasis. On the one hand, MCU proved to be the core of a complex signaling system, composed of a channel moiety (MCU itself and the related MCUb protein) and a family of essential regulators (the MICUs, MCUR, EMRE). On the other hand, the availability of molecular information and tools opened the possibility of directly altering mitochondrial calcium homeostasis in cell cultures or intact organisms, thus obtaining new insight into its role in physiological and pathological events. We will review here these exciting advancements, summarizing the current knowledge of the molecular composition of the MCU complex and of its role in shaping mitochondrial and cytosolic [Ca(2+)] signals. PMID- 26048008 TI - [Complications in hepatopancreatobiliary surgery: The complexity necessitates close interdisciplinary cooperation]. PMID- 26048009 TI - Deletion of the DNA Ligase IV Gene in Candida glabrata Significantly Increases Gene-Targeting Efficiency. AB - Candida glabrata is reported as the second most prevalent human opportunistic fungal pathogen in the United States. Over the last decades, its incidence increased, whereas that of Candida albicans decreased slightly. One of the main reasons for this shift is attributed to the inherent tolerance of C. glabrata toward the commonly used azole antifungal drugs. Despite a close phylogenetic distance to Saccharomyces cerevisiae, homologous recombination works with poor efficiency in C. glabrata compared to baker's yeast, in fact limiting targeted genetic alterations of the pathogen's genome. It has been shown that nonhomologous DNA end joining is dominant over specific gene targeting in C. glabrata. To improve the homologous recombination efficiency, we have generated a strain in which the LIG4 gene has been deleted, which resulted in a significant increase in correct gene targeting. The very specific function of Lig4 in mediating nonhomologous end joining is the reason for the absence of clear side effects, some of which affect the ku80 mutant, another mutant with reduced nonhomologous end joining. We also generated a LIG4 reintegration cassette. Our results show that the lig4 mutant strain may be a valuable tool for the C. glabrata research community. PMID- 26048010 TI - Evidence for Extracellular ATP as a Stress Signal in a Single-Celled Organism. AB - ATP is omnipresent in biology and acts as an extracellular signaling molecule in mammals. Information regarding the signaling function of extracellular ATP in single-celled eukaryotes is lacking. Here, we explore the role of extracellular ATP in cell volume recovery during osmotic swelling in the amoeba Dictyostelium. Release of micromolar ATP could be detected during cell swelling and regulatory cell volume decrease (RVD) phases during hypotonic challenge. Scavenging ATP with apyrase caused profound cell swelling and loss of RVD. Apyrase-induced swelling could be rescued by 100 MUM betagamma-imidoATP. N-Ethylmalemide (NEM), an inhibitor of vesicular exocytosis, caused heightened cell swelling, loss of RVD, and inhibition of ATP release. Amoebas with impaired contractile vacuole (CV) fusion (drainin knockout [KO] cells) displayed increased swelling but intact ATP release. One hundred micromolar Gd(3+) caused cell swelling while blocking any recovery by betagamma-imidoATP. ATP release was 4-fold higher in the presence of Gd(3+). Cell swelling was associated with an increase in intracellular nitric oxide (NO), with NO-scavenging agents causing cell swelling. Swelling-induced NO production was inhibited by both apyrase and Gd(3+), while NO donors rescued apyrase- and Gd(3+)-induced swelling. These data suggest extracellular ATP released during cell swelling is an important signal that elicits RVD. Though the cell surface receptor for ATP in Dictyostelium remains elusive, we suggest ATP operates through a Gd(3+)-sensitive receptor that is coupled with intracellular NO production. PMID- 26048012 TI - Application of computational models to estimate organ radiation dose in rainbow trout from uptake of molybdenum-99 with comparison to iodine-131. AB - This study compares three anatomical phantoms for rainbow trout (Oncorhynchus mykiss) for the purpose of estimating organ radiation dose and dose rates from molybdenum-99 ((99)Mo) uptake in the liver and GI tract. Model comparison and refinement is important to the process of determining accurate doses and dose rates to the whole body and the various organs. Accurate and consistent dosimetry is crucial to the determination of appropriate dose-effect relationships for use in environmental risk assessment. The computational phantoms considered are (1) a geometrically defined model employing anatomically relevant organ size and location, (2) voxel reconstruction of internal anatomy obtained from CT imaging, and (3) a new model utilizing NURBS surfaces to refine the model in (2). Dose Conversion Factors (DCFs) for whole body as well as selected organs of O. mykiss were computed using Monte Carlo modeling and combined with empirical models for predicting activity concentration to estimate dose rates and ultimately determine cumulative radiation dose (MUGy) to selected organs after several half-lives of (99)Mo. The computational models provided similar results, especially for organs that were both the source and target of radiation (less than 30% difference between all models). Values in the empirical model as well as the 14 day cumulative organ doses determined from (99)Mo uptake are compared to similar models developed previously for (131)I. Finally, consideration is given to treating the GI tract as a solid organ compared to partitioning it into gut contents and GI wall, which resulted in an order of magnitude difference in estimated dose for most organs. PMID- 26048011 TI - The N-Linked Outer Chain Mannans and the Dfg5p and Dcw1p Endo-alpha-1,6 Mannanases Are Needed for Incorporation of Candida albicans Glycoproteins into the Cell Wall. AB - A biochemical pathway for the incorporation of cell wall protein into the cell wall of Neurospora crassa was recently proposed. In this pathway, the DFG-5 and DCW-1 endo-alpha-1,6-mannanases function to covalently cross-link cell wall protein-associated N-linked galactomannans, which are structurally related to the yeast outer chain mannans, into the cell wall glucan-chitin matrix. In this report, we demonstrate that the mannosyltransferase enzyme Och1p, which is needed for the synthesis of the N-linked outer chain mannan, is essential for the incorporation of cell wall glycoproteins into the Candida albicans cell wall. Using endoglycosidases, we show that C. albicans cell wall proteins are cross linked into the cell wall via their N-linked outer chain mannans. We further demonstrate that the Dfg5p and Dcw1p alpha-1,6-mannanases are needed for the incorporation of cell wall glycoproteins into the C. albicans cell wall. Our results support the hypothesis that the Dfg5p and Dcw1p alpha-1,6-mannanases incorporate cell wall glycoproteins into the C. albicans cell wall by cross linking outer chain mannans into the cell wall glucan-chitin matrix. PMID- 26048013 TI - Spontaneous Hemoperitoneum in Pregnancy Treated with Transarterial Embolization of the Uterine Artery. PMID- 26048014 TI - Percutaneous Augmented Peripheral Osteoplasty in Long Bones of Oncologic Patients for Pain Reduction and Prevention of Impeding Pathologic Fracture: The Rebar Concept. AB - PURPOSE: To evaluate clinical efficacy/safety of augmented peripheral osteoplasty in oncologic patients with long-term follow-up. MATERIALS AND METHODS: Percutaneous augmented peripheral osteoplasty was performed in 12 patients suffering from symptomatic lesions of long bones. Under extensive local sterility measures, anesthesiology care, and fluoroscopic guidance, direct access to lesion was obtained and coaxially a metallic mesh consisting of 25-50 medical grade stainless steel micro-needles (22 G, 2-6 cm length) was inserted. PMMA for vertebroplasty was finally injected under fluoroscopic control. CT assessed implant position 24-h post-treatment. RESULTS: Clinical evaluation included immediate and delayed follow-up studies of patient's general condition, NVS pain score, and neurological status. Imaging assessed implant's long-term stability. Mean follow-up was 16.17 +/- 10.93 months (range 2-36 months). Comparing patients' scores prior (8.33 +/- 1.67 NVS units) and post (1.42 +/- 1.62 NVS units) augmented peripheral osteoplasty, there was a mean decrease of 6.92 +/- 1.51 NVS units. Overall mobility improved in 12/12 patients. No complication was observed. CONCLUSION: Percutaneous augmented peripheral osteoplasty (rebar concept) for symptomatic malignant lesions in long bones seems to be a possible new technique for bone stabilization. This combination seems to provide necessary stability against shearing forces applied in long bones during weight bearing. PMID- 26048015 TI - Ultrasound-Guided Percutaneous Nephrostomy Performed on Neonates and Infants Using a "14-4" (Trocar and Cannula) Technique. AB - PURPOSE: Percutaneous nephrostomy (PCN) catheters are placed under combined ultrasound and fluoroscopic guidance in the interventional radiology suite and present unique challenges in neonates and infants. The purpose of this study was to demonstrate feasibility of PCN using a "14-4" (trocar and cannula) technique on neonates and infants. MATERIALS AND METHODS: Between September 2009 and June 2014, data for 27 kidneys from consecutive 22 neonates or infants who underwent PCN catheter placement using the "14-4" technique were retrospectively analyzed. The median age at the time of placement of the PCN catheters was 11 days (range 5 300 days). There were 18 males and 4 females. All procedures were performed in the interventional radiology suite but without using fluoroscopy. RESULTS: Unilateral PCN was performed on 17 out of 22 patients, while bilateral drainage was performed on five patients. The technical success rate was 100%. The median duration of PCN catheter was 75 days (range 10-138 days). Minor macroscopic hematuria not requiring blood transfusion was present in two of the patients in which the hematuria lasted in 2 days. CONCLUSION: Placement of PCN catheters using a "14-4" technique with ultrasound as the sole imaging modality is a technically feasible and desirable option for neonates or infants. The technique obviates the need for ionizing radiation and potentially could be performed in the ultrasound room or even at the bedside. PMID- 26048016 TI - Closure of Nonmalignant Tracheoesophageal Fistula Using an Atrial Septal Defect Occluder: Case Report and Review of the Literature. AB - Tracheoesophageal fistula (TEF) is a life-threatening condition for which there are several management techniques. We present a case of nonmalignant TEF closure using an atrial septal defect (ASD) occluder. A 53-year-old man with a severe TEF was admitted to our hospital for TEF caused by stenting of an esophagogastric anastomotic stricture. He was successfully treated with closure of the TEF using an endotracheal ASD occluder. Three hundred and eighteen days after placement of the occluder, he suddenly developed a severe cough after dilatation of the esophagogastric anastomosis and spontaneously coughed out the occluder. The fistula was repaired and complete closure that was confirmed on esophagography. He had no recurrence of fistula during the follow-up period of 13 months. PMID- 26048017 TI - Inferior Mesenteric Artery Rendezvous for Revascularization of Aorto-iliac Occlusive Disease. PMID- 26048018 TI - Reconstruction of Genome Ancestry Blocks in Multiparental Populations. AB - We present a general hidden Markov model framework called R: econstructing A: ncestry B: locks BIT: by bit (RABBIT) for reconstructing genome ancestry blocks from single-nucleotide polymorphism (SNP) array data, a required step for quantitative trait locus (QTL) mapping. The framework can be applied to a wide range of mapping populations such as the Arabidopsis multiparent advanced generation intercross (MAGIC), the mouse Collaborative Cross (CC), and the diversity outcross (DO) for both autosomes and X chromosomes if they exist. The model underlying RABBIT accounts for the joint pattern of recombination breakpoints between two homologous chromosomes and missing data and allelic typing errors in the genotype data of both sampled individuals and founders. Studies on simulated data of the MAGIC and the CC and real data of the MAGIC, the DO, and the CC demonstrate that RABBIT is more robust and accurate in reconstructing recombination bin maps than some commonly used methods. PMID- 26048019 TI - Control of mRNA Stability in Fungi by NMD, EJC and CBC Factors Through 3'UTR Introns. AB - In higher eukaryotes the accelerated degradation of mRNAs harboring premature termination codons is controlled by nonsense-mediated mRNA decay (NMD), exon junction complex (EJC), and nuclear cap-binding complex (CBC) factors, but the mechanistic basis for this quality-control system and the specific roles of the individual factors remain unclear. Using Neurospora crassa as a model system, we analyzed the mechanisms by which NMD is induced by spliced 3'-UTR introns or upstream open reading frames and observed that the former requires NMD, EJC, and CBC factors whereas the latter requires only the NMD factors. The transcripts for EJC components eIF4A3 and Y14, and translation termination factor eRF1, contain spliced 3'-UTR introns and each was stabilized in NMD, EJC, and CBC mutants. Reporter mRNAs containing spliced 3'-UTR introns, but not matched intronless controls, were stabilized in these mutants and were enriched in mRNPs immunopurified from wild-type cells with antibody directed against human Y14, demonstrating a direct role for spliced 3'-UTR introns in triggering EJC-mediated NMD. These results demonstrate conclusively that NMD, EJC, and CBC factors have essential roles in controlling mRNA stability and that, based on differential requirements for these factors, there are branched mechanisms for NMD. They demonstrate for the first time autoregulatory control of expression at the level of mRNA stability through the EJC/CBC branch of NMD for EJC core components, eIF4A3 and Y14, and for eRF1, which recognizes termination codons. Finally, these results show that EJC-mediated NMD occurs in fungi and thus is an evolutionarily conserved quality-control mechanism. PMID- 26048020 TI - Lysyl Oxidase Is Predictive of Unfavorable Outcomes and Essential for Regulation of Vascular Endothelial Growth Factor in Hepatocellular Carcinoma. AB - BACKGROUND: Lysyl oxidase (LOX) is frequently overexpressed in a variety of malignancies and involved in tumor invasion and metastasis. Furthermore, it has been shown that LOX is closely related to vascular endothelial growth factor (VEGF). AIMS: In this study, we aimed to investigate the exact role of LOX and the correlation between LOX and VEGF in hepatocellular carcinoma (HCC). METHODS: The expression levels of LOX in HCC tissue and adjacent noncancerous tissue were evaluated by quantitative reverse transcription polymerase chain reaction and immunohistochemical analysis. The effect of LOX knockdown on cell proliferation, migration, and invasion was investigated in vitro. The role of LOX in the regulation of VEGF was further characterized in HCC cells that had been treated with transforming growth factor beta (TGF-beta). RESULTS: Our study showed that LOX was up-regulated in HCC cell lines and tissue. HCC patients with elevated expression of LOX had relatively shorter disease-free survival and overall survival. Knockdown of LOX reduced the proliferation, migration, and invasion of HCC cells. Additionally, the expression level of LOX positively correlated with that of VEGF. After treatment with TGF-beta, the levels of LOX and VEGF were both up-regulated in a dose-dependent manner. In the cells treated with siRNA of LOX, levels of VEGF and phosphorylated p38 were significantly decreased and could not be up-regulated by TGF-beta. Inhibition of p38 MAPK signaling abrogated TGF-beta mediated up-regulation of VGEF but did not affect LOX expression. CONCLUSIONS: LOX appears to be a predictor of less favorable outcomes and may regulate the expression of VEGF via p38 MAPK signaling. PMID- 26048021 TI - Impact of Bowel Preparation Quality on Adenoma Identification During Colonoscopy and Optimal Timing of Surveillance. AB - BACKGROUND: All present guidelines regarding surveillance intervals after index colonoscopy are based on optimal bowel preparation. However, the appropriate timing of repeat colonoscopy after suboptimal bowel preparation is not clear. AIMS: To determine the appropriate timing of repeat colonoscopy following index colonoscopy with suboptimal bowel preparation. METHODS: The medical records of patients who underwent colonoscopy over 5 years were retrospectively analyzed. Index colonoscopy was defined as the first colonoscopy in patients who underwent the procedure at least twice during the study period. Bowel preparation quality was classified as optimal, fair, or poor. RESULTS: The overall adenoma detection rate was 39.1% (95% confidence interval [CI], 38.0-40.1%), but the detection rate depended significantly on bowel preparation quality (p < 0.001). The adenoma miss rate (AMR) was significant after poor (69.6%) than after optimal (27.3%) and fair (48.1%) preparation (p < 0.001). At surveillance intervals <=2 years, the odds ratio (OR) for AMR was significantly higher for poor (OR 6.25; 95% CI, 3.76 11.83) and fair (OR 3.67; 95% CI, 2.19-6.16) preparation relative to optimal preparation; however, no difference was observed at surveillance intervals >2 years. CONCLUSIONS: Bowel preparation quality significantly affects AMR. Colonoscopy should be repeated within 2 years in patients with suboptimal bowel preparation at index colonoscopy. PMID- 26048022 TI - Association of tcdA+/tcdB+ Clostridium difficile Genotype with Emergence of Multidrug-Resistant Strains Conferring Metronidazole Resistant Phenotype. AB - BACKGROUND: Reduced susceptibility of Clostridium difficile to antibiotics is problematic in clinical settings. There is new evidence indicating the cotransfer of toxin-encoding genes and conjugative transposons encoding resistance to antibiotics among different C. difficile strains. To analyze this association, in the current study, we evaluated the frequency of toxigenic C. difficile among the strains with different multidrug-resistant (MDR) profiles in Iran. METHODS: Antimicrobial susceptibility patterns and minimal inhibitory concentrations (MIC) of the isolates were determined against metronidazole, imipenem, ceftazidime, amikacin, and ciprofloxacin by agar dilution method. The association of the resistance profiles and toxigenicity of the strains were studied by PCR targeting tcdA and tcdB genes. RESULTS: Among 86 characterized strains, the highest and lowest resistance rates were related to ciprofloxacin (97%) and metronidazole (5%), respectively. The frequency of resistance to other antibiotics was as follow: imipenem (48%), ceftazidime (76%), and amikacin (76.5%). Among the resistant strains, double drug resistance and MDR phenotypes were detected in the frequencies of 10.4% and 66.2%, respectively. All of the metronidazole-resistant strains belonged to tcdA +/tcdB + genotype with triple or quintuple drug resistance phenotypes. MIC50 and MIC90 for this antibiotic was equally <= 8 MUg/ml. CONCLUSION: These results proposed the association of tcdA +/tcdB + genotype of C. difficile and the emergence of resistance strains to broad spectrum antibiotics and metronidazole. PMID- 26048023 TI - Synthesis and bioactivity of a Goralatide analog with antileukemic activity. AB - Natural tetrapeptide Goralatide (AcSDKP) is a selective inhibitor of primitive haematopoietic cell proliferation. It is not stable in vivo and decomposes within 4.5min when applied to live cells. In this work we developed an analog of Goralatide that exhibits cytotoxicity towards human myeloid HL-60, HEL, Nalm-6 leukemia cells, endothelial HUVEC, glioblastoma U251 and transformed kidney 293T cells. The Goralatide analog showed significant stability in organic solution with no tendency to degrade oxidatively. PMID- 26048024 TI - Design and synthesis of benzothiazole-6-sulfonamides acting as highly potent inhibitors of carbonic anhydrase isoforms I, II, IX and XII. AB - A series of novel 2-aminobenzothiazole derivatives bearing sulfonamide at position 6 was designed, synthesized and investigated as inhibitors of four isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), the cytosolic CA I and II, and the tumor-associated isozymes CA IX and XII. Docking and binding energy studies were carried out to reveal details regarding the favorable interactions between the scaffolds of these new inhibitors and the active sites of the investigated CA isoforms. Most of the novel compounds were acting as highly potent inhibitors of the tumor-associated hCA IX and hCA XII with KIs in the nanomolar range. The ubiquitous and dominant rapid cytosolic isozyme hCA II was also inhibited with KIs ranging from 3.5 to 45.4 nM. The favorable interactions between some of the new compounds and the active site of different CA isoforms were delineated by using molecular docking which may be useful for designing compounds with high affinity and selectivity for some CAs with biomedical applications. PMID- 26048025 TI - Plasmid DNA delivery using fluorescein-labeled arginine-rich peptides. AB - Arginine (Arg)-rich peptides exhibit an effective cell-penetrating ability and deliver membrane-impermeable compounds into cells. In the present study, three types of Arg-rich peptides, R9 containing nine Arg residues, (RRG)3 containing six Arg and three glycine (Gly) residues, and (RRU)3 containing six Arg and three alpha-aminoisobutyric acid (Aib) residues, were evaluated for their plasmid DNA (pDNA) delivery and cell-penetrating abilities. The transfection efficiency of R9/pDNA complexes was much higher than those of (RRG)3 and (RRU)3/pDNA complexes, and was derived from the enhanced cellular uptake of R9/pDNA complexes. The replacement of three Arg residues with the neutral amino acid Gly and hydrophobic amino acid Aib drastically changed the cell-penetrating ability and physicochemical properties of peptide/pDNA complexes, resulting in markedly reduced transfection efficiency. A comparison of the R9 peptide administration forms between a peptide alone and peptide/pDNA complex revealed that the uptake of R9 peptides was more efficient for the complex than the peptide alone, but occurred through the same internalization mechanism. The results of the present study will contribute to the design of novel Arg-rich cell-penetrating peptides for pDNA delivery. PMID- 26048026 TI - Optimization of histone deacetylase inhibitor activity in non-secosteroidal vitamin D-receptor agonist hybrids. AB - The combination of (1alpha,25)-dihydroxyvitamin D3 (1,25D) and histone deacetylase inhibitor (HDACi) trichostatin A is highly antiproliferative in numerous cancer cell lines. We have previously prepared novel non-secosteroidal hybrid molecules which simultaneously act as both vitamin D receptor (VDR) agonists and HDACi. These molecules function as cytostatic and cytotoxic agents in 1,25D-resistant SCC4 squamous carcinoma cells. Here we have extended the scope of the hybrids by making several modifications to the diarylpentane core and to the aliphatic spacer unit to develop molecules with increased potency towards HDACs while maintaining VDR agonist activity. Notably, hybrid DK-366 (33a), a direct analog of first-generation hybrids but lacking a methyl group on one aryl ring possesses low micromolar potency for HDAC3 and HDAC6 and is a highly effective antiproliferative agent in SCC4 cells. Chain extended hybrids such as DK-367 (33c) possess even greater HDAC potency and are also highly antiproliferative. These results show that we can optimize HDACi potency in hybrid molecules without sacrificing VDR agonism. PMID- 26048027 TI - Synthesis, molecular docking and biological evaluation of 3-arylfuran-2(5H)-ones as anti-gastric ulcer agent. AB - 3-Arylfuran-2(5H)-one derivatives show good antibacterial activity and were determined as tyrosyl-tRNA synthetase (TyrRS) inhibitors. In a systematic medicinal chemistry exploration, we demonstrated chemical opportunities to treat infections caused by Helicobacter pylori. Twenty 3-arylfuran-2(5H)-ones were synthesized and evaluated for anti-H. pylori, antioxidant and anti-urease activities which are closely interconnected with H. pylori infection. The results displayed that some of the compounds show excellent antioxidant activity, and good anti-H. pylori and urease inhibitory activities. Out of these compounds, 3 (3-methylphenyl)furan-2(5H)-one (b9) showed the most potent antioxidant activity (IC50=8.2 MUM) and good anti-H. pylori activity (MIC50=2.6 MUg/mL), and it can be used as a good candidate for discovering novel anti-gastric ulcer agent. PMID- 26048029 TI - Small cell neuroendocrine carcinoma of the ethmoid sinus revealed by syndrome of inappropriate antidiuretic hormone secretion. PMID- 26048028 TI - Subjective cognitive concerns, amyloid-beta, and neurodegeneration in clinically normal elderly. AB - OBJECTIVE: To determine whether neuroimaging biomarkers of amyloid-beta (Abeta) and neurodegeneration (ND) are associated with greater self-reported subjective cognitive concerns (SCC) in clinically normal older individuals. METHODS: A total of 257 participants underwent Pittsburgh compound B PET, PET with fluorodeoxyglucose (18)F, and structural MRI, as well as a battery of neuropsychological measures including several questionnaires regarding SCC. Individuals were classified into 4 biomarker groups: biomarker negative (Abeta /ND-), amyloidosis alone (Abeta+/ND-), amyloidosis plus ND (Abeta+/ND+), and ND alone (Abeta-/ND+). RESULTS: Both Abeta and ND were independently associated with greater SCC controlling for objective memory performance. By contrast, neither Abeta nor ND was associated with objective memory performance controlling for SCC. Further examination revealed greater SCC in individuals with Abeta or ND positivity compared to biomarker-negative individuals. In addition, greater SCC predicted Abeta positivity when controlling for ND status. CONCLUSIONS: When individuals were grouped by biomarker status, those who were positive on Abeta or ND had the highest report of SCC compared to biomarker-negative individuals. Findings were consistent when SCC was used to predict Abeta positivity. Taken together, results suggest that both Abeta and ND are associated with SCC, independent of objective memory performance. Enrichment of individuals with SCC may increase likelihood of Abeta and ND markers in potential participants for secondary prevention trials. PMID- 26048030 TI - Expression patterns of immune genes in long-term cultured dental stem cells. AB - BACKGROUND AND OBJECTIVES: Long-term culture system is used to prevent the impediment of insufficient cells and is good for low starting materials such as dental pulp or periodontal ligament. In general, although cell viability and functionality are the most common aspects taken into consideration in culturing cells for a long term, they may not truly represent the biological state of the cells. Hence, we explored the behaviour of another important aspect which is the immune properties in long-term cultured cells. METHODS: Dental pulp stem cells from deciduous (SHED; n = 3) and permanent (DPSCs; n = 3) teeth as well as periodontal ligament stem cells (PDLSCs; n = 3) were cultured under identical culture condition. The immune properties of each cell lines were profiled at passage 2 [P2] and passage 9 [P9] as early and late passages, respectively. This was further validated at the protein level using the Luminex platform. RESULTS: A major shift of genes was noticed at P9 with SHED being the highest. SHED cultured at P9 displayed many genes representing pathogen recognition (P < 0.001), immune signalling (P < 0.001, pro-inflammatory (P < 0.001), anti-inflammatory (P < 0.001) and immune-related growth and stimulation factor (P < 0.001) as compared to DPSCs and PDLSCs. Surprisingly, SHED also expressed many cytotoxicity genes (P < 0.001). CONCLUSIONS: Communally, instabilities of immune genes from our findings suggest that long-term cultured cells may not be feasible for transplantation purposes. CLINICAL RELEVANCE: A complete biological characterization covering all major aspects including immune properties should be made as prerequisite criteria prior to the use of long-term cultured stem cells in clinical settings. PMID- 26048032 TI - Isolated meningeal inflammatory myofibroblastic tumor: an enigmatic tumor. PMID- 26048031 TI - Androgens enhance the glycolytic metabolism and lactate export in prostate cancer cells by modulating the expression of GLUT1, GLUT3, PFK, LDH and MCT4 genes. AB - PURPOSE: The present study aims to investigate the role of androgens in controlling the glycolytic metabolism and lactate efflux in prostate cancer (PCa) cells. METHODS: Androgen-responsive LNCaP cells were treated with 5alpha dihydrotestosterone (DHT, 10 nM) for 12-48 h, and their glycolytic metabolism, lactate production and viability were analyzed. Intracellular and extracellular levels of glucose and lactate were determined spectrophotometrically, and the expression of glucose transporters (GLUT1/GLUT3), phosphofructokinase 1, lactate dehydrogenase (LDH) and monocarboxylate transporter (MCT4) was analyzed by real time PCR and Western blot. The enzymatic activity of LDH was determined by means of a colorimetric assay. Experiments were reproduced in androgen-non-responsive DU145 and PC3 cells. RESULTS: Androgens stimulated glucose consumption in LNCaP cells by increasing the expression of GLUT3, GLUT1 and PFK, which was underpinned by increased cell viability. Accordingly, lactate production by LNCaP cells was enhanced upon DHT stimulation as evidenced by the increased levels of lactate found in cell culture medium. Although LDH enzymatic activity decreased in LNCaP cells treated with DHT, the expression of MCT4 was significantly increased with androgenic treatment, which sustains the increase on lactate export. Glucose consumption and the expression of GLUTs and PFK remained unchanged in DHT-treated DU145 and PC3 cells. CONCLUSIONS: The results obtained establish androgens as modulators of glycolytic metabolism in PCa cells by stimulating glucose consumption, as well as the production and export of lactate, which may represent a crucial issue-driven prostate tumor development. These findings also highlight the importance of PCa therapies targeting AR and metabolism-related proteins. PMID- 26048033 TI - A model to estimate the cost of the National Essential Public Health Services Package in Beijing, China. AB - BACKGROUND: In order to address several health challenges, the Chinese government issued the National Essential Public Health Services Package (NEPHSP) in 2009. In China's large cities, the lack of funding for community health centers and consequent lack of comprehensive services and high quality care has become a major challenge. However, no study has been carried out to estimate the cost of delivering the services in the package. This project was to develop a cost estimation approach appropriate to the context and use it to calculate the cost of the NEPHSP in Beijing in 2011. METHODS: By adjusting models of cost analysis of primary health care and workload indicators of staffing need developed by the World Health Organization, a model was developed to estimate the cost of the services in the package through an intensive interactive process. A total of 17 community health centers from eight administrative districts in Beijing were selected. Their service volume and expenditure data in 2010 were used to evaluate the costs of providing the NEPHSP in Beijing based on the applied model. RESULTS: The total workload of all types of primary health care in 17 sample centers was equivalent to the workload requirement for 14,056,402 standard clinic visits. The total expenditure of the 17 sample centers was 26,329,357.62 USD in 2010. The cost of the workload requirement of one standard clinic visit was 1.87 USD. The workload of the NEPHSP was equivalent to 5,514,777 standard clinic visits (39.23 % of the total workload). The model suggests that the cost of the package in Beijing was 7.95 USD per capita in 2010. The cost of the NEPHSP in urban areas was lower than suburban areas: 7.31 and 8.65 USD respectively. CONCLUSIONS: The average investment of 3.97 USD per capita in NEPHSP was lower than the amount needed to meet its running costs. NEPHSP in Beijing is therefore underfunded. Additional investment is needed, and a dynamic cost estimate mechanism should be introduced to ensure services remain adequately funded. PMID- 26048035 TI - Anti-inflammatory and anticholinesterase activity of six flavonoids isolated from Polygonum and Dorstenia species. AB - This study was aimed at investigating the anti-inflammatory and anticholinesterase activity of six naturally occurring flavonoids: (-) pinostrobin (1), 2',4'-dihydroxy-3',6'-dimethoxychalcone (2), 6-8 diprenyleriodictyol (3), isobavachalcone (4), 4-hydroxylonchocarpin (5) and 6 prenylapigenin (6). These compounds were isolated from Dorstenia and Polygonum species used traditionally to treat pain. The anti-inflammatory activity was determined by using the Griess assay and the 15-lipoxygenase inhibitory activity was determined with the ferrous oxidation-xylenol orange assay. Acetylcholinesterase inhibition was determined by the Ellman's method. At the lowest concentration tested (3.12 ug/ml), compounds 2, 3 and 4 had significant NO inhibitory activity with 90.71, 84.65 and 79.57 % inhibition respectively compared to the positive control quercetin (67.93 %). At this concentration there was no significant cytotoxicity against macrophages with 91.67, 72.86 and 70.86 % cell viability respectively, compared to 73.1 % for quercetin. Compound 4 had the most potent lipoxygenase inhibitory activity (IC50 of 25.92 ug/ml). With the exception of (-) pinostrobin (1), all the flavonoids had selective anticholinesterase activity with IC50 values ranging between 5.93 and 8.76 ug/ml compared to the IC50 4.94 ug/ml of eserine the positive control. These results indicate that the studied flavonoids especially isobavachalcone are potential anti-inflammatory natural products that may have the potential to be developed as therapeutic agents against inflammatory conditions and even Alzheimer's disease. PMID- 26048034 TI - Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation. AB - BACKGROUND: Alpha-mannosidosis is caused by mutations in MAN2B1, leading to loss of lysosomal alpha-mannosidase activity. Symptoms include intellectual disabilities, hearing impairment, motor function disturbances, facial coarsening and musculoskeletal abnormalities. METHODS: To study the genotype-phenotype relationship for alpha-mannosidosis 66 patients were included. Based on the predicted effect of the mutations and the subcellular localisation of mutant MAN2B1 in cultured cells, the patients were divided into three subgroups. Clinical and biochemical data were collected. Correlation analyses between each of the three subgroups of genotype/subcellular localisation and the clinical and biochemical data were done to investigate the potential relationship between genotype and phenotype in alpha-mannosidosis. Statistical analyses were performed using the SPSS software. Analyses of covariance were performed to describe the genotype-phenotype correlations. The phenotype parameters were modelled by the mutation group and age as a covariate. P values of <0.05 were considered as statistically significant. RESULTS: Complete MAN2B1 genotypes were established for all patients. We found significantly higher scores in the Leiter-R test, lower concentrations of CSF-oligosaccharides, higher point scores in the Bruininks-Oseretsky Test of Motor Proficiency subtests (BOT-2); Upper limb coordination and Balance, and a higher FVC% in patients in subgroup 3, harbouring at least one variant that allows localisation of the mutant MAN2B1 protein to the lysosomes compared to subgrou 2 and/or subgroup 1 with no lysosomal localization of the mutant MAN2B1 protein. CONCLUSION: Our results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. This correlation depends on the subcellular localisation of the mutant MAN2B1 protein. PMID- 26048036 TI - Synthesis and anticancer activity of 4-aza-daurinol derivatives. AB - Daurinol, a natural aryl naphthalene lactone, has been reported to have antiproliferative activity against various cell lines, and has also been shown to be efficacious in an in vivo xenograft mouse model. In this study, we tried to discover a new scaffold that enables both rapid structure-activity relationship study of daurinol and scalable synthesis of active compounds. 4-Aza-daurinol, a bioisosterism-based scaffold of daurinol, was designed and 17 analogues were synthesized and evaluated against five representative cancer cell lines. Among them, the 2,3-dihydrobenzo[b][1,4]dioxinyl derivative was found to be the most potent and showed similar activity and tendency as daurinol. PMID- 26048038 TI - Socio-cultural profile of Bapedi traditional healers as indigenous knowledge custodians and conservation partners in the Blouberg area, Limpopo Province, South Africa. AB - BACKGROUND: Bapedi traditional healers of Blouberg are custodians of indigenous knowledge on medicinal plants of this region. They provide primary health care to a large number of people in the Blouberg area of South Africa. There is concern that this profession is dying out, which may be detrimental to the Blouberg community and to biodiversity conservation in the area. METHODS: Thirty two healers and 30 community members were interviewed between March 2011 and July 2013 around Blouberg Mountain in the Blouberg Municipality. A semi-structured questionnaire was used to elucidate socio-cultural and demographic variables and healing customs of practicing healers. Attitudes to sustainable management of medicinal plants were captured. A second semi-structured questionnaire was used to gather information on community members' views of traditional healers and their practices. RESULTS: Sixty seven percent of interviewed community members visited traditional healers. Female traditional healers dominated (80%) the profession. Sixty four percent of the healers have no formal education, with only 4% having secondary school education. Seventy nine percent of healers see between 15 and 20 patients per month. Clinics and a hospital in the vicinity have resulted in a shift by the community from using tradition-based healing to that of allopathic health care. Most interviewed traditional healers (71%) are in favour of conservation actions to prevent over-harvesting, as 86% believe that indiscriminate collecting is compromising the flora of the area. Most (93%) are willing to use cultivated plants. CONCLUSIONS: State health care has negatively influenced the practice of traditional healing as patients now first consult government health centres before turning to traditional healers. In the past, traditional healing has been ignored because, as an oral history, it could not be included in school curricula or government policy documents. Those traditional healers who learn to write will have the skills to document and safeguard their own knowledge. This can help to prevent the erosion of knowledge around Blouberg's medicinal plants and support the conservation of natural resources in the area. Adult learning programmes might therefore be worth implementing amongst healers. PMID- 26048039 TI - Water intake: validity of population assessment and recommendations. AB - Good hydration is vital for good health and well-being. Until recently, there was little interest in collecting data on water and drink and beverage intake. However, there is increasing evidence that a low water intake or mild dehydration may be linked with the risk of chronic diseases. Accurate estimates of intake in populations are essential to explore these relationships. This will enable the identification of specific populations at the risk of low water intake and allow exposure assessment of potential contaminates and specific nutrients present in drinks and beverages. In addition, data from these population studies are used as the basis of national and international recommendations on water intake and to set and evaluate national health policies. For example, EFSA based their recommendations on data from population studies from 13 European countries. The range of intakes varied from 720 to 2621 mL/day; this diversity cannot be explained by environmental differences alone. However, this variability may, at least partially, be explained by the inconsistency in methodologies used as none of surveys used a dietary assessment tool validated for total water intake or beverage and drink intake. It is reasonable to suggest that this may result in incomplete data collection and it raises questions on the validity of the recommendations. The relationship between water consumption and health warrants further investigation, and robust methodologies are essential to ensure that these data are accurate and useful for setting public health priorities and policies. PMID- 26048037 TI - Identification of ICE1 as a negative regulator of ABA-dependent pathways in seeds and seedlings of Arabidopsis. AB - Inducer of CBF expression 1 (ICE1) mediates the cold stress signal via an abscisic acid (ABA)-independent pathway. A possible role of ICE1 in ABA-dependent pathways was examined in this study. Seedling growth was severely reduced in a T DNA insertion mutant of ICE1, ice1-2, when grown on 1/2 MS medium lacking sugars, but was restored to wild-type (WT) levels by supplementation with 56 mM glucose. In addition to this sugar-dependent phenotype, germination and establishment of ice1-2 were more sensitive to high glucose concentrations than in the WT. Hypersensitivity to ABA was also observed in ice1-2, suggesting its sensitivity to glucose might be mediated through the ABA signaling pathway. Glucose and ABA induced much higher expression of two genes related to ABA signal transduction, ABA-INSENSITIVE 3 (ABI3) and ABA-INSENSITIVE 4 (ABI4), in ice1-2 than in the WT during establishment. In summary, in addition to its known roles in regulating cold responses, stomatal development, and endosperm breakdown, ICE1 is a negative regulator of ABA-dependent responses. PMID- 26048040 TI - Autism spectrum disorder symptoms among children enrolled in the Study to Explore Early Development (SEED). AB - This study examined the phenotypic profiles of children aged 30-68 months in the Study to Explore Early Development (SEED). Children classified as autism spectrum disorder (ASD), developmental delay (DD) with ASD symptoms, DD without ASD symptoms, and population comparison (POP) differed significantly from each other on cognitive, adaptive, behavioral, and social functioning and the presence of parent-reported conditions. Children with ASD and DD with ASD symptoms had mild to severe ASD risk on several measures compared to children with other DD and POP who had little ASD risk across measures. We conclude that children in SEED have varying degrees of ASD impairment and associated deficits. SEED thus provides a valuable sample to explore ASD phenotypes and inform risk factor analyses. PMID- 26048041 TI - Low but increasing prevalence of autism spectrum disorders in a French area from register-based data. AB - Register-based prevalence rates of childhood autism (CA), Asperger's syndrome (AS) and other autism spectrum disorders (ASD) were calculated among children aged 7 years old of the 1997-2003 birth cohorts, living in four counties in France. The proportion of children presenting comorbidities was reported. 1123 children with ASD were recorded (M/F ratio: 4.1), representing an overall prevalence rate of 36.5/10,000 children (95 % CI 34.4-38.7): 8.8/10,000 for CA (95 % CI 7.8-9.9), 1.7/10,000 for AS (95 % CI 1.3-2.3) and 25.9/10,000 for other ASD (95 % CI 24.2-27.8). ASD prevalence significantly increased (p < 0.0001) during the period under study. The proportion of children with an intellectual disability was 47.3 %, all other comorbidities were present in less than 5 % of the cases. PMID- 26048042 TI - Is grammar spared in autism spectrum disorder? Data from judgments of verb argument structure overgeneralization errors. AB - Children with Autism Spectrum Disorder (ASD) aged 11-13 (N = 16) and an IQ matched typically developing (TD) group aged 7-12 (N = 16) completed a graded grammaticality judgment task, as well as a standardized test of cognitive function. In a departure from previous studies, the judgment task involved verb argument structure overgeneralization errors (e.g., *Lisa fell the cup off the shelf) of the type sometimes observed amongst typically developing children, as well as grammatical control sentences with the same verbs (e.g., The cup fell off the shelf). The ASD group showed a smaller dispreference for ungrammatical sentences (relative to the control sentences) than did the TD group. These findings are indicative of a subtle grammatical impairment in even relatively high-functioning children with ASD. PMID- 26048043 TI - Patterned Threadlike Micelles and DNA-Tethered Nanoparticles: A Structural Study of PEGylated Cationic Liposome-DNA Assemblies. AB - The self-assembly of oppositely charged biomacromolecules has been extensively studied due to its pertinence in the design of functional nanomaterials. Using cryo electron microscopy (cryo-EM), optical light scattering, and fluorescence microscopy, we investigated the structure and phase behavior of PEGylated (PEG: poly(ethylene glycol)) cationic liposome-DNA nanoparticles (CL-DNA NPs) as a function of DNA length, topology (linear and circular), and rho(chg) (the molar charge ratio of cationic lipid to anionic DNA). Although all NPs studied exhibited lamellar internal nanostructure, NPs formed with short (~2 kbps), linear, polydisperse DNA were defect-rich and contained smaller domains. Unexpectedly, we found distinctly different equilibrium structures away from the isoelectric point. At rho(chg) > 1, in the excess cationic lipid regime, threadlike micelles rich in PEG-lipid were found to coexist with NPs, cationic liposomes, and spherical micelles. At high concentrations these PEGylated threadlike micelles formed a well-ordered, patterned morphology with highly uniform intermicellar spacing. At rho(chg) < 1, in the excess DNA regime and with no added salt, individual NPs were tethered together via long, linear DNA (48 kbps lambda-phage DNA) into a biopolymer-mediated floc. Our results provide insight into what equilibrium nanostructures can form when oppositely charged macromolecules self-assemble in aqueous media. Self-assembled, well-ordered threadlike micelles and tethered nanoparticles may have a broad range of applications in bionanotechnology, including nanoscale lithograpy and the development of lipid-based multifunctional nanoparticle networks. PMID- 26048044 TI - Long-term kidney survival analyses in IgA nephropathy patients under steroids therapy: a case control study. AB - BACKGROUND: Corticosteroids are preferred to treat patients with active IgA nephropathy (IgAN), and beneficial effects from the short-term use of corticosteroids have been confirmed. However, a large number of patients will progress to end-stage renal disease after a long time follow-up. This study aimed to evaluate kidney disease progression and risk factors on kidney survival in IgAN patients receiving steroids treatment. METHODS: Two hundred biopsy-proven IgAN patients who received corticosteroid therapy were enrolled and followed for a median period of 63.33 months. Risk factors on kidney survival were retrospectively investigated by the Cox proportional hazards model. RESULTS: Of the two hundred patients, twenty patients showed progression of renal impairment at the end of follow-up. The median and interquartile range values for initial serum creatinine were 89.2 and 68.08-121.35 umol/L, respectively. Multivariate Cox regression analyses revealed that relapse, non-remission, time-averaged eGFR (TA-eGFR), and time-averaged serum albumin (TA-ALB) were independently associated with the kidney progression. Those with TA-ALB levels <35 g/L and TA-eGFR levels <60 mL/min/1.73 m(2) were less likely to recover from kidney progression. Patients were more likely to show kidney function deterioration, when they had non-remission or relapse after corticosteroids treatment. CONCLUSION: This study demonstrated that relapse, non-remission, TA-eGFR, and TA-ALB could serve as independent predictors of long term prognosis of IgAN patients receiving corticosteroid therapy. PMID- 26048045 TI - Frequency and co-prescription pattern of Chinese herbal products for hypertension in Taiwan: a Cohort study. AB - BACKGROUND: Chinese herbal products (CHPs) have been frequently used among patients with chronic diseases including hypertension; however, the co prescription pattern of herbal formulae and single herbs remain uncharacterized. Thus, this large-scale pharmacoepidemiological study evaluated the frequency and co-prescription pattern of CHPs for treating hypertension in Taiwan from 2003 to 2009. METHODS: The database of traditional Chinese medicine (TCM) outpatient claims was obtained from the National Health Insurance in Taiwan. Patients with hypertension during study period were defined according to diagnostic codes in the International Classification of Disease Ninth Revision, Clinical Modification. The frequencies and percentages of herbal formula and single herb prescriptions for hypertension were analyzed. We also applied association rules to evaluate the CHPs co-prescription patterns. RESULTS: The hypertension cohort included 154,083 patients, 123,240 patients of which (approximately 80 %) had used TCM at least once. In total, 81,582 visits involving CHP prescriptions were hypertension related; Tian-Ma-Gou-Teng-Yin and Dan Shen (Radix Salvia Miltiorrhizae) were the most frequently prescribed herbal formula and single herb, respectively, for treating hypertension. CONCLUSIONS: This study elucidated the utilization pattern of CHPs for treating hypertension. Future studies on the efficacy and safety of these CHPs and on drug-herb interactions are warranted. PMID- 26048046 TI - The Pathogenesis and Therapy of Muscular Dystrophies. AB - Current molecular genomic approaches to human genetic disorders have led to an explosion in the identification of the genes and their encoded proteins responsible for these disorders. The identification of the gene altered by mutations in Duchenne and Becker muscular dystrophy was one of the earliest examples of this paradigm. The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them. The identification of the protein dystrophin has led to a new understanding of the muscle cell membrane and the proteins involved in membrane stability, as well as new candidate genes for additional forms of muscular dystrophy. Animal models identified with naturally occurring mutations and developed by genetic manipulation have furthered the understanding of disease progression and underlying pathology. The biochemistry and molecular analysis of patient samples have led to the different dystrophin-dependent and -independent therapies that are currently close to or in human clinical trials. The lessons learned from decades of research on dystrophin have benefited the field of human genetics. PMID- 26048047 TI - Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease. AB - Freezing of Gait (FOG) is a frequent and disabling feature of Parkinson disease (PD). Gait rehabilitation assisted by electromechanical devices, such as training on treadmill associated with sensory cues or assisted by gait orthosis have been shown to improve FOG. Overground robot assisted gait training (RGT) has been recently tested in patients with PD with improvement of several gait parameters. We here evaluated the effectiveness of RGT on FOG severity and gait abnormalities in PD patients. Eighteen patients with FOG resistant to dopaminergic medications were treated with 15 sessions of RGT and underwent an extensive clinical evaluation before and after treatment. The main outcome measures were FOG questionnaire (FOGQ) global score and specific tasks for gait assessment, namely 10 meter walking test (10 MWT), Timed Up and Go test (TUG) and 360 degrees narrow turns (360 NT). Balance was also evaluated through Fear of Falling Efficacy Scale (FFES), assessing self perceived stability and Berg Balance Scale (BBS), for objective examination. After treatment, FOGQ score was significantly reduced (P=0.023). We also found a significant reduction of time needed to complete TUG, 10 MWT, and 360 NT (P=0.009, 0.004 and 0.04, respectively). By contrast the number of steps and the number of freezing episodes recorded at each gait task did not change. FFES and BBS scores also improved, with positive repercussions on performance on daily activity and quality of life. Our results indicate that RGT is a useful strategy for the treatment of drug refractory FOG. PMID- 26048048 TI - Rare brainstem oligodendroglioma in an adult patient: Presentation, molecular characteristics and treatment response. PMID- 26048049 TI - Prevalence and determinants of diabetic polyneuropathy in a sub-Saharan African referral hospital. AB - BACKGROUND: Diabetic peripheral neuropathy is the commonest complication of diabetes mellitus, and a major cause of limb amputations. In general however, the magnitude of diabetic neuropathy in sub-Saharan Africans with diabetes has been less reliably quantified. We assessed the prevalence and determinants of diabetic polyneuropathy in hospital settings in Cameroon. METHODS: We conducted a cross sectional survey at the Douala Laquintinie Hospital, which is one of the main reference hospital in the economic capital of Cameroon (3 million populations). Participants included all patients with type 1 (T1DM) or type 2 (T2DM) diabetes who reported to the hospital regardless of the reason, during a 5-month recruitment period. Polyneuropathy was defined as diabetic in a patient with a Diabetic Neuropathy Examination score of >3/16 and/or a monofilament score of <5/9. RESULTS: A total of 306 patients were recruited, including 196 women (64%) and 294 (96%) with T2DM. The mean (standard deviation) values were 59.8 (11.2) years for age and 8.4 (8.2) years for diabetes duration. Clinical signs of polyneuropathy were present in 102 (crude prevalence rate: 33.3%) patients. The polyneuropathy was symptomatic in 79/102 (77.4%) patients. Determinants of polyneuropathy were urban residence (p=0.02), infection with hepatitis C virus (p=0.002), infection with HIV (p=0.012) and presence of albuminuria (p=0.0001). CONCLUSION: About one in three patients with diabetes reporting to the hospital in our setting has prevalent diabetes related polyneuropathy. This emphasizes the importance of routine implementation of therapeutic education and other measures to limit the complications. PMID- 26048050 TI - Asymptomatic tracheal MALT lymphoma discovered on spirometric findings presenting with elevated respiratory resistance. AB - BACKGROUND: Central airway obstruction (CAO) may be caused by various etiologies. However, conventional chest X-rays are rarely diagnostic for patients with CAO. CASE PRESENTATION: We here described a 64-year-old asymptomatic female with tracheal mucosa-associated lymphoid tissue lymphoma discovered on spirometric findings during a complete physical examination. The plateau of forced expiratory flow was consistent with CAO. A decreased peak expiratory flow rate was noted at least 3 years before the diagnosis, and was attributed to an insufficient effort by the patient. Impulse oscillometric measurements, which were taken during quiet breathing and were effort-independent, suggested elevated respiratory resistance. These abnormalities completely disappeared after radiation therapy. CONCLUSION: The addition of impulse oscillometry to spirometry may be useful for screening CAO in routine health examinations. PMID- 26048052 TI - Histological characteristics of the myometrium in the postpartum hemorrhage of unknown etiology: a possible involvement of local immune reactions. AB - The aim of this study was to evaluate the histological characteristics of the myometrium obtained in postpartum hemorrhage (PPH) of unknown etiology secondary to uterine atony. These characteristics were selected from among registered cases of clinically suspected amniotic fluid embolism (AFE) and classified as PPH of unknown etiology because of no obvious cause of PPH at Hamamatsu University School of Medicine, a registration center for clinical AFE in Japan. Immunohistochemical studies were performed on myometrium using anti-mast cell tryptase, anti-neutrophil elastase, anti-CD68, anti-CD88, anti-CD3, and anti-ZnCP 1 antibodies. Massive infiltrations of inflammatory cells with mast cell degranulation within the myometrium secondary to complement activation were observed in PPH of unknown etiology (n=34), but not in control pregnant women (n=15) or after delivery in women without PPH (n=18). The concomitant immunohistochemical detection of meconium in myometrium suggests that amniotic fluids or fetal materials are one of the candidates for inducing maternal local immune activation in the PPH of unknown etiology. Postpartum acute myometritis in the absence of an infective etiology may be a histological characteristic of PPH of unknown etiology. PMID- 26048051 TI - Quantitative analysis of BKV-specific CD4+ T cells before and after kidney transplantation. AB - BACKGROUND: BK virus (BKV) is the main infectious cause of renal allograft dysfunction. Although recent studies showed an inverse correlation between BKV specific T-cell responses and viral load after transplantation, the importance of pre-transplant response in the process of virus reactivation has only been studied once. In this study, we aimed to determine whether pre-transplant CD4+ T cell response can be used for prediction of BKV reactivation and BKV nephropathy (BKVN), by a method that can practically be used in routine patient monitoring. METHODS: BKV-specific CD4+ T-cell responses of 31 kidney recipients (all from live donors) were measured by an IFN-gamma-enzyme-linked-immunospot (ELISPOT) method using mixture of peptides, at day 0 and +1, +3, and +6 months posttransplant. Additionally, seven other reactivation patients as another group were also analyzed. BKV viral loads in plasma were measured by real-time polymerase chain reaction (PCR). Responses of 10 healthy people were also included as controls in the analysis. RESULTS: All but one patient and all of the controls had detectable CD4+ T-cell responses. Reactivation occurred in 8 out of 31 patients. There was no significant association between pretransplant BKV specific CD4+ T-cell responses and BKV reactivation and between BKV DNA levels and CD4+ T-cell responses. In the additional group consisting of reactivation patients, four patients who had BKVN showed negative correlation between BKV-DNA levels and BKV-specific CD4+ T-cell responses (p<0.05). One patient who developed BKVN, however, was not able to mount a similar CD4+ T-cell response to viral reactivation despite immunosuppressive reduction. CONCLUSION: Even though our cohort is small, our results may suggest that pre-transplant measurement of BKV specific CD4+ T-cell response may not be necessary, and that post-transplant monitoring, particularly during reactivation, may be more helpful in the management of the infection. PMID- 26048053 TI - Violacein induces cell death by triggering mitochondrial membrane hyperpolarization in vitro. AB - BACKGROUND: Violacein is a purple pigment from Chromobacterium violaceum that possesses diverse biological and pharmacological properties. Among these, pro oxidant and antioxidant activities have been suggested. However, the cytotoxic mechanisms induced by violacein are poorly understood and the improvement in knowledge regarding these cell death mechanisms will be useful to develop new therapeutic approaches. Considering this, in our work, we investigated the pro oxidant effects of violacein in non-tumor (CHO-K1 and MRC-5) and tumor (HeLa) cell lines, searching for a better understanding of reactive oxygen species (ROS) production and cell death induction. RESULTS: Cytotoxicity induced by violacein was observed in the three cell lines; however, MRC-5 and HeLa cells were shown to be more sensitive to violacein treatment. Although punctual alterations in the antioxidant apparatus and increase in oxidative stress biomarkers was observed in some violacein concentrations, no association was found between increased oxidative stress and induction of cell death. However, the increase of mitochondrial membrane potential was observed. CONCLUSIONS: In fact, the increase of mitochondrial membrane potential in MRC-5 and HeLa cells suggests that mitochondrial membrane hyperpolarization might be the main cause of cell death triggered by violacein. PMID- 26048055 TI - Sensitive gluten determination in gluten-free foods by an electrochemical aptamer based assay. AB - Enzyme immunoassays are currently the methods of choice for gluten control in foods labelled as gluten free, providing a mechanism for assessing food safety for consumption by coeliac and other allergic patients. However, their limitations, many of them associated to the reactivity of the different antibodies used and their degree of specificity, have prevented the establishment of a standardised method of analysis. We explore new methods for quantitatively determining gluten content in foods based on the use of two recently described aptamers, raised against a 33-mer peptide recognised as the immunodominant fragment from alpha2-gliadin. The assays use the target peptide immobilised onto streptavidin-coated magnetic beads in combination with a limited amount of biotin aptamer in a competitive format, followed by streptavidin-peroxidase labelling of the aptamer that remains bound to the magnetic beads. The enzyme activity onto the beads, measured by chronoamperometry in disposable screen-printed electrodes, is inversely related to the target concentration in the test solution. We find that while the assay using the aptamer with the highest affinity towards the target (Gli 4) achieves low detection limits (~0.5 ppm) and excellent analytical performance, when challenged in samples containing the intact protein, gliadin, it fails in detecting the peptide in solution. This problem is circumvented by employing another aptamer (Gli 1), the most abundant one in the SELEX pool, as a receptor. The proposed assays allow the convenient detection of the allergen in different kinds of food samples, including heat-treated and hydrolysed ones. The obtained results correlate with those of commercially available antibody-based assays, providing an alternative for ensuring the safety and quality of nominally gluten-free foods. Graphical Abstract Electrochemical magnetoassay for gluten determination using biotin-aptamers as receptors. PMID- 26048054 TI - Perturbation training to promote safe independent mobility post-stroke: study protocol for a randomized controlled trial. AB - BACKGROUND: Falls are one of the most common medical complications post-stroke. Physical exercise, particularly exercise that challenges balance, reduces the risk of falls among healthy and frail older adults. However, exercise has not proven effective for preventing falls post-stroke. Falls ultimately occur when an individual fails to recover from a loss of balance. Thus, training to specifically improve reactive balance control could prevent falls. Perturbation training aims to improve reactive balance control by repeatedly exposing participants to postural perturbations. There is emerging evidence that perturbation training reduces fall rates among individuals with neurological conditions, such as Parkinson disease. The primary aim of this work is to determine if perturbation-based balance training can reduce occurrence of falls in daily life among individuals with chronic stroke. Secondary objectives are to determine the effect of perturbation training on balance confidence and activity restriction, and functional balance and mobility. METHODS/DESIGN: Individuals with chronic stroke will be recruited. Participants will be randomly assigned to one of two groups: 1) perturbation training, or 2) 'traditional' balance training. Perturbation training will involve both manual perturbations (e.g., a push or pull from a physiotherapist), and rapid voluntary movements to cause a loss of balance. Training will occur twice per week for 6 weeks. Participants will record falls and activity for 12 months following completion of the training program. Standardized clinical tools will be used to assess functional balance and mobility, and balance confidence before and after training. DISCUSSION: Falls are a significant problem for those with stroke. Despite the large body of work demonstrating effective interventions, such as exercise, for preventing falls in other populations, there is little evidence for interventions that prevent falls post-stroke. The proposed study will investigate a novel and promising intervention: perturbation training. If effective, this training has the potential to not only prevent falls, but to also improve safe independent mobility and engagement in daily activities for those with stroke. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN05434601 . PMID- 26048056 TI - Intraspecific variations in Conus purpurascens injected venom using LC/MALDI-TOF MS and LC-ESI-TripleTOF-MS. AB - The venom of cone snails is composed of highly modified peptides (conopeptides) that target a variety of ion channels and receptors. The venom of these marine gastropods represents a largely untapped resource of bioactive compounds of potential pharmaceutical value. Here, we use a combination of bioanalytical techniques to uncover the extent of venom expression variability in Conus purpurascens, a fish-hunting cone snail species. The injected venom of nine specimens of C. purpurascens was separated by reversed-phase high-performance liquid chromatography (RP-HPLC), and fractions were analyzed using matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) in parallel with liquid chromatography-electrospray ionization (LC-ESI) TripleTOF-MS to compare standard analytical protocols used in preparative bioassay-guided fractionations with a deeper peptidomic analysis. Here, we show that C. purpurascens exhibits pronounced intraspecific venom variability. RP-HPLC fractionation followed by MALDI-TOF-MS analysis of the injected venom of these nine specimens identified 463 distinct masses, with none common to all specimens. Using LC-ESI-TripleTOF-MS, the injected venom of these nine specimens yielded a total of 5517 unique masses. We also compare the injected venom of two specimens with their corresponding dissected venom. We found 2566 and 1990 unique masses for the dissected venom compared to 941 and 1959 masses in their corresponding injected venom. Of these, 742 and 1004 masses overlapped between the dissected and injected venom, respectively. The results indicate that larger conopeptide libraries can be assessed by studying multiple individuals of a given cone snail species. This expanded library of conopeptides enhances the opportunities for discovery of molecular modulators with direct relevance to human therapeutics. Graphical Abstract The venom of cone snails are extraordinarily complex mixtures of highly modified peptides. Venom analysis requires separation through RP-HPLC followed by MALDI-TOF mass spectrometry or direct analysis using LC-ESI-TripleTOF MS. Using these techniques, venom intraspecific variability and comparison between injected and dissected were assessed. PMID- 26048057 TI - A novel two-dimensional liquid-chromatography method for online prediction of the toxicity of transformation products of benzophenones after water chlorination. AB - Benzophenone-type UV filters (BPs) are ubiquitous in the environment. Transformation products (TPs) of BPs with suspected toxicity are likely to be produced during disinfection of water by chlorination. To quickly predict the toxicity of TPs, in this study, a novel two-dimensional liquid-chromatography (2D LC) method was established in which the objective of the first dimension was to separate the multiple components of the BPs sample after chlorination, using a reversed-phase liquid-chromatography mode. A biochromatographic system, i.e. bio partitioning micellar chromatography with the polyoxyethylene (23) lauryl ether aqueous solution as the mobile phase, served as the second dimension to predict the toxicity of the fraction from the first dimension on the basis of the quantitative retention-activity relationships (QRARs) model. Six BPs, namely 2,4 dihydroxybenzophenone, oxybenzone, 4-hydroxybenzophenone, 2-hydroxy-4 methoxybenzophenone-5-sulfonic acid, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone and 2,2'-dihydroxy-4-methoxybenzophenone, were the target analytes subjected to chlorination. The products of these BPs after chlorination were directly injected to the 2D-LC system for analysis. The results indicated that most TPs may be less toxic than their parent chemicals, but some may be more toxic, and that intestinal toxicity of TPs may be more obvious than blood toxicity. The proposed method is time-saving, high-throughput, and reliable, and has great potential for predicting toxicity or bioactivity of unknown and/or known components in a complex sample. Graphical Abstract The scheme for the 2D-LC online prediction of toxicity of the transformation products of benzophenone-type UV filters after chlorination. PMID- 26048058 TI - Optimization of ultrasonic-assisted extraction for determination of polycyclic aromatic hydrocarbons in biochar-based fertilizer by gas chromatography-mass spectrometry. AB - Application of biochar-based fertilizers is increasingly being considered for its potential agronomic and environmental benefits. However, biochar may contain residues of polycyclic aromatic hydrocarbons (PAHs) as a result of its production by pyrolysis. The strong adsorption of PAHs to biochar makes extraction and analysis of biochar-based fertilizers difficult. This study optimizes the extraction of PAHs in biochar-based fertilizer samples by using an ultrasonic bath for quantification by gas chromatography-mass spectrometry. Among 12 solvents, acetone-cyclohexane (1:1) mixture was selected as the optimum solvent for extraction. Three variables affecting the extraction were studied by Box Behnken design. The optimum conditions were 57 degrees C extraction temperature, 81 min extraction time, and two extraction cycles, which were validated by assessing the linearity of analysis, LOD, LOQ, recovery, and levels of PAHs in real biochar-based fertilizer samples. Results revealed that the 16 U.S. EPA PAHs had good linearity, with squared correlation coefficients greater than 0.99. LODs were low, ranging from 2.2 ng g(-1) (acenaphthene) to 23.55 ng g(-1) (indeno[1,2,3-cd]perylene), and LOQs varied from 7.51 ng g(-1) to 78.49 ng g(-1). The recoveries of 16 individual PAHs from the three biochar-based fertilizer samples were 81.8-109.4 %. Graphical Abstract Use of RSM to optimize UAE for extraction of the PAHs in biochar-based fertilizer. PMID- 26048059 TI - Physico-chemical studies in the removal of Sr(II) from aqueous solutions using activated sericite. AB - Sericite, a mica based natural clay, was annealed at 800 degrees C for 4 h followed by acid activation using 3.0 mol/L of HCl at 100 degrees C in order to obtain activated sericite (AS). The activation of sericite causes a significant increase in specific surface area. Further, SEM images of the AS showed a disordered and heterogeneous surface structure with mesopores on its surface whereas the pristine sericite possessed a compact layered structure. The materials were further employed in the removal of Sr(II) from aqueous solutions in a batch reactor system. Removal of Sr(II) was studied as a function of pH, concentration of adsorbate, contact time, background electrolyte concentrations and dose of adsorbents using pristine sericite and AS. The removal of Sr(II) was favoured increasing the pH of the solution and the extent of Sr(II) removal was increased with increasing the sorbate concentration. Equilibrium sorption data obtained with pristine sericite were fitted well to Langmuir adsorption isotherm whereas the sorption data collected using AS better fitted to the Freundlich adsorption isotherm. The time dependence sorption data showed that the uptake of Sr(II) was very rapid and an apparent sorption equilibrium was achieved within 30 min and 60 min of contact for sericite and AS, respectively. The kinetic data were modelled to the pseudo-first order and pseudo-second order rate kinetics and sorption capacities as well as rate constants were evaluated. Increase in background electrolyte concentrations NaNO3 (0.001-0.1 mol/L) indicated that the presence of NaNO3 caused to decrease the percent removal of Sr(II) by sericite and AS. Furthermore, fixed-bed column reactor operations were performed to obtain the breakthrough data. The breakthrough data were fitted well to the non-linear Thomas equation. Therefore, the present study suggested that AS can be adequately applied for the removal of Sr(II) from the aquatic environment. PMID- 26048060 TI - The microbial impact on the sorption behaviour of selenite in an acidic, nutrient poor boreal bog. AB - (79)Se is among the most important long lived radionuclides in spent nuclear fuel and selenite, SeO3(2-), is its typical form in intermediate redox potential. The sorption behaviour of selenite and the bacterial impact on the selenite sorption in a 7-m-deep profile of a nutrient-poor boreal bog was studied using batch sorption experiments. The batch distribution coefficient (Kd) values of selenite decreased as a function of sampling depth and highest Kd values, 6600 L/kg dry weight (DW), were observed in the surface moss and the lowest in the bottom clay at 1700 L/kg DW. The overall maximum sorption was observed at pH between 3 and 4 and the Kd values were significantly higher in unsterilized compared to sterilized samples. The removal of selenite from solution by Pseudomonas sp., Burkholderia sp., Rhodococcus sp. and Paenibacillus sp. strains isolated from the bog was affected by incubation temperature and time. In addition, the incubation of sterilized surface moss, subsurface peat and gyttja samples with added bacteria effectively removed selenite from the solution and on average 65% of selenite was removed when Pseudomonas sp. or Burkholderia sp. strains were used. Our results demonstrate the important role of bacteria for the removal of selenite from the solution phase in the bog environment, having a high organic matter content and a low pH. PMID- 26048061 TI - T-cell clonality assessment by next-generation sequencing improves detection sensitivity in mycosis fungoides. AB - BACKGROUND: T-cell receptor (TCR) clonality assessment is a principal diagnostic test in the management of mycosis fungoides (MF). However, current polymerase chain reaction-based methods may produce ambiguous results, often because of low abundance of clonal T lymphocytes, resulting in weak clonal peaks that cannot be size-resolved by contemporary capillary electrophoresis (CE). OBJECTIVE: We sought to determine if next-generation sequencing (NGS)-based detection has increased sensitivity for T-cell clonality over CE-based detection in MF. METHODS: Clonality was determined by an NGS-based method in which the TCR-gamma variable region was polymerase chain reaction amplified and the products sequenced to establish the identity of rearranged variable and joining regions. RESULTS: Of the 35 MF cases tested, 29 (85%) showed a clonal T-cell rearrangement by NGS, compared with 15 (44%) by standard CE detection. Three patients with MF had follow-up testing that showed identical, clonal TCR sequences in subsequent skin biopsy specimens. LIMITATIONS: Clonal T-cell populations have been described in benign conditions; evidence of clonality alone, by any method, is not sufficient for diagnosis. CONCLUSION: TCR clonality assessment by NGS has superior sensitivity compared with CE-based detection. Further, NGS enables tracking of specific clones across multiple time points for more accurate identification of recurrent MF. PMID- 26048062 TI - First determination of azole resistance in Aspergillus fumigatus strains carrying the TR34/L98H mutations in Turkey. AB - Aspergillus fumigatus is the most important etiological agent of invasive aspergillosis. Recently, an increasing number of azole-resistant A. fumigatus isolates have been described in various countries. The prevalence of azole resistance was investigated in this study using our culture collection of A. fumigatus isolates collected between 1999 and 2012 from clinical specimens. Seven hundred and forty-six A. fumigatus isolates, collected from 419 patients, were investigated. First, all isolates were screened for resistance to itraconazole by subculturing on Sabouraud dextrose agar that contained 4 mg/L itraconazole. For isolates that grew on the itraconazole containing agar, the in vitro activities of amphotericin B, itraconazole, voriconazole and posaconazole were determined using the Clinical and Laboratory Standards Institute (CLSI) M38-A reference method. After PCR amplification, the full sequence of the cyp51A gene and its promoter region was determined for all in vitro azole-resistant isolates. Itraconazole resistance was found in 10.2% of the A. fumigatus isolates. From 2000 onwards, patients were observed annually with an itraconazole-resistant isolate. According to in vitro susceptibility tests, amphotericin B exhibited good activity against all isolates whereas the azoles were resistant. Sequence analysis of the promoter region and CYP51A gene indicated the presence of TR34/L98H in 86.8% (n = 66) of isolates. This initial analysis of the resistance mechanism of A. fumigatus from Turkey revealed a common TR34/L98H mutation in the cyp51A gene. PMID- 26048063 TI - Advanced stage of chronic kidney disease is risk of poor treatment outcome for smear-positive pulmonary tuberculosis. AB - Chronic kidney disease (CKD) is an increased risk for the development of active tuberculosis, but few studies have analyzed the treatment outcome of pulmonary tuberculosis among CKD patients. A retrospective cohort study was conducted at Chiba-East Hospital in Chiba, Japan. Our study estimated the treatment outcomes in smear-positive pulmonary tuberculosis in relation to CKD and its stages. Total subjects were 759 patients (12-99 years) hospitalized between 2007 and 2012. Patients suffering from multi-drug-resistant tuberculosis were excluded. Patients with CKD were 19.3% aged <65 years (n = 384), and 49.6% aged >= 65 years, respectively (P < 0.001). Successful treatment was 52.7% in CKD (n = 260) and 67.3% in non-CKD (n = 499) (P < 0.001). Death was 25.4% in CKD and 12.4% in non CKD (P < 0.001). Treatment outcome was especially poor in patients with low estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m(2), as successful treatment was 20.0%, and death was 50.0%, significantly lower than in other CKD and non-CKD patients. After multivariate logistic regression analysis, eGFR<30 ml/min/1.73 m(2) was an independent factor affecting successful treatment and death, and its adjusted odds ratios (aOR) were 0.20 (95% confidence interval (CI) 0.07-0.50) and 2.99 (95%CI 1.20-7.51), respectively. Other factors affecting successful treatment were serum albumin <3.0 mg/dl, steroid therapy for underlying disease and cardiovascular disease, with aOR (95%CI) of 0.28 (0.20 0.39), 0.32 (0.16-0.63) and 0.49 (0.28-0.86), respectively. Several factors were associated with poor treatment outcome of smear-positive pulmonary tuberculosis. Advanced stage of CKD with eGFR of <30 ml/min/1.73 m(2) was a risk factor for poor treatment outcome. PMID- 26048064 TI - Dart-Splint: An innovative orthosis that can be integrated into a scapho-lunate and palmar midcarpal instability re-education protocol. AB - The Authors describe a novel hinged orthosis that permits selective midcarpal mobilization along the plane of the dart throwing motion. This orthotic device can be used to assist rehabilitation protocols aimed to limit radiocarpal joint mobility and scapho-lunate ligament overload and to accelerate wrist functional recovery after ligamentous injuries around the proximal carpal row. - VictoriaW. Priganc, PhD, OTR, CHT, CLT, Practice Forum Editor. PMID- 26048065 TI - Untangling attention bias modification from emotion: A double-blind randomized experiment with individuals with social anxiety disorder. AB - BACKGROUND: Uncertainty abounds regarding the putative mechanisms of attention bias modification (ABM). Although early studies showed that ABM reduced anxiety proneness more than control procedures lacking a contingency between cues and probes, recent work suggests that the latter performed just as well as the former did. In this experiment, we investigated a non-emotional mechanism that may play a role in ABM. METHODS: We randomly assigned 62 individuals with a DSM-IV diagnosis of social anxiety disorder to a single-session of a non-emotional contingency training, non-emotional no-contingency training, or control condition controlling for potential practice effects. Working memory capacity and anxiety reactivity to a speech challenge were assessed before and after training. RESULTS: Consistent with the hypothesis of a practice effect, the three groups likewise reported indistinguishably significant improvement in self-report and behavioral measures of speech anxiety as well as in working memory. Repeating the speech task twice may have had anxiolytic benefits. LIMITATIONS: The temporal separation between baseline and post-training assessment as well as the scope of the training sessions could be extended. CONCLUSIONS: The current findings are at odds with the hypothesis that the presence of visuospatial contingency between non-emotional cues and probes produces anxiolytic benefits. They also show the importance of including a credible additional condition controlling for practice effects. PMID- 26048066 TI - A Method for Delineation of Bone Surfaces in Photoacoustic Computed Tomography of the Finger. AB - Photoacoustic (PA) imaging of interphalangeal peripheral joints is of interest in the context of using the synovial membrane as a surrogate marker of rheumatoid arthritis. Previous work has shown that ultrasound (US) produced by absorption of light at the epidermis reflects on the bone surfaces within the finger. When the reflected signals are backprojected in the region of interest, artifacts are produced, confounding interpretation of the images. In this work, we present an approach where the PA signals known to originate from the epidermis are treated as virtual US transmitters, and a separate reconstruction is performed as in US reflection imaging. This allows us to identify the bone surfaces. Furthermore, the identification of the joint space is important as this provides a landmark to localize a region-of-interest in seeking the inflamed synovial membrane. The ability to delineate bone surfaces allows us to identify not only the artifacts but also the interphalangeal joint space without recourse to new US hardware or a new measurement. We test the approach on phantoms and on a healthy human finger. PMID- 26048067 TI - Acute Medical Diagnoses Are Common in "Found Down" Adult Patients Presenting to the Emergency Department as Trauma. AB - BACKGROUND: Patients often present to the emergency department (ED) as "found down," with limited history to suggest a primary traumatic or medical etiology. OBJECTIVE: The study objective was to describe the characteristics of "found down" adult patients presenting to the ED as trauma, specifically the incidence of acute medical diagnoses and major trauma. METHODS: Using an institutional trauma registry, we reviewed trauma activations with the cause of injury "found down" between January 2008 and December 2012. We excluded patients with cardiac arrest, transfers from other hospitals, and patients with a more than likely (>50%) traumatic or medical etiology on initial ED presentation. Inclusion and exclusion criteria were reviewed by two independent abstractors. We abstracted demographic, clinical, injury severity, and outcomes variables. Major trauma was defined as Injury Severity Score >= 16. RESULTS: There were 659 patients identified with the cause of injury "found down." A total of 207 (31%) patients met inclusion criteria; median age was 67 years (interquartile range 50-82 years), and 110 (53%) were male. Among the included patients, 137 (66%, 95% confidence interval [Cl] 59-73%) had a discharge diagnosis of an acute medical condition, 14 (7%, 95% Cl 4-11%) with major trauma alone, 21 (10%, 95% Cl 6-15) with both an acute medical condition and major trauma, and 35 (17%, 95% Cl 12 23%) with minor trauma. The most common acute medical diagnoses were toxicological (56 patients, 35%; 95% Cl 28-43%) and infectious (32 patients, 20%; 95% Cl 14-27%). CONCLUSION: Acute medical diagnoses were common in undifferentiated ED patients "found down" in an institutional trauma registry. Clinicians should maintain a broad differential diagnosis in the workup of the undifferentiated "found down" patient. PMID- 26048068 TI - A Randomized Controlled Trial of Intravenous Haloperidol vs. Intravenous Metoclopramide for Acute Migraine Therapy in the Emergency Department. AB - BACKGROUND: Emergency Department (ED) headache patients are commonly treated with neuroleptic antiemetics like metoclopramide. Haloperidol has been shown to be effective for migraine treatment. STUDY OBJECTIVE: Our study compared the use of metoclopramide vs. haloperidol to treat ED migraine patients. METHODS: A prospective, double-blinded, randomized control trial of 64 adults aged 18-50 years with migraine headache and no recognized risks for QT-prolongation. Haloperidol 5 mg or metoclopramide 10 mg was given intravenously after 25 mg diphenhydramine. Pain, nausea, restlessness (akathisia), and sedation were assessed with 100-mm visual analog scales (VAS) at baseline and every 20 min, to a maximum of 80 min. The need for rescue medications, side effects, and subject satisfaction were recorded. QTc intervals were measured prior to and after treatment. Follow-up calls after 48 h assessed satisfaction and recurrent or persistent symptoms. RESULTS: Thirty-one subjects received haloperidol, 33 metoclopramide. The groups were similar on all VAS measurements, side effects, and in their satisfaction with therapy. Pain relief averaged 53 mm VAS over both groups, with equal times to maximum improvement. Subjects receiving haloperidol required rescue medication significantly less often (3% vs. 24%, p < 0.02). Mean QTcs were equal and normal in the two groups and did not change after treatment. In telephone follow-up, 90% of subjects contacted were "happy with the medication" they had received, with haloperidol-treated subjects experiencing more restlessness (43% vs. 10%). CONCLUSIONS: Intravenous haloperidol is as safe and effective as metoclopramide for the ED treatment of migraine headaches, with less frequent need for rescue medications. PMID- 26048069 TI - Double-blind, Randomized, Placebo-controlled Study Evaluating the Use of Platelet rich Plasma Therapy (PRP) for Acute Ankle Sprains in the Emergency Department. AB - BACKGROUND: Over 23,000 people per day require treatment for ankle sprains. Platelet-rich plasma (PRP) is an autologous concentration of platelets that is thought to improve healing by promoting inflammation through growth factor and cytokine release. Studies to date have shown mixed results, with few randomized trials. OBJECTIVES: To determine patient function among patients randomized to receive standard therapy plus PRP, compared to patients who receive standard therapy plus sham injection (placebo). METHODS: Prospective, randomized, double blinded, placebo-controlled trial. Patients with severe ankle sprains were randomized. Severity was graded on degree of swelling, ecchymosis, and ability to bear weight. PRP with lidocaine and bupivacaine was injected at the point of maximum tenderness by a blinded physician under ultrasound guidance. The control group was injected in a similar fashion with sterile 0.9% saline. Both groups had visual analog scale (VAS) pain scores and Lower Extremity Functional Scale (LEFS) on days 0, 3, and 8. LEFS and a numeric pain score were obtained via phone call on day 30. All participants were splinted, given crutches, and instructed to not bear weight for 3 days; at this time patients were reevaluated. RESULTS: There were 1156 patients screened and 37 were enrolled. Four withdrew before PRP injection was complete; 18 were randomized to PRP and 15 to placebo. There was no statistically significant difference in VAS and LEFS scores between groups. CONCLUSION: In this small study, PRP did not provide benefit in either pain control or function over placebo. PMID- 26048070 TI - Metastatic Obstruction of the Small Bowel Revealing Squamous-Cell Lung Cancer with Incidental Myocardial Metastasis. PMID- 26048071 TI - Breast virtual special issue. PMID- 26048072 TI - Nicotine stimulation increases proliferation and matrix metalloproteinases-2 and 28 expression in human dental pulp cells. AB - AIMS: Dental pulp is the specialized tissue responsible for maintaining tooth viability. When tooth mineralized matrix is damaged, pulp is exposed to a plethora of environmental stimuli. In particular, in smokers, pulp become exposed to very high concentrations of nicotine. The aim of this study was to investigate the effect of direct nicotine stimulation on human dental pulp cell proliferation. Moreover, as it is known that nicotine could upregulate the expression of matrix metalloproteinases (MMPs), enzymes involved in pulpal inflammation, the effects of nicotine stimulation on MMP-2 and MMP-28 gene expression have also been investigated. MAIN METHODS: Human dental pulp cells were extracted from impacted third molars obtained from healthy patients undergoing routine orthodontic treatments. Such cells were treated with growing concentrations of nicotine in the presence or absence of a nicotine antagonist (hexamethonium chloride) or of a MEK signaling inhibitor (PD98059). Cell proliferation was evaluated by cell counting, while nicotine effects on MMP expression were evaluated by PCR. KEY FINDINGS: The data obtained indicate that nicotine is able to increase human dental pulp cell proliferation by acting through nicotinic cholinergic receptors and downstream MAPK signaling pathway. Moreover, it is also able to increase both MMP-2 and MMP-28 gene expression. SIGNIFICANCE: In summary these results highlight that direct exposure of human dental pulp cells to nicotine results in an inflammatory response, that could have a role in pulpal inflammation onset, a pathological condition that, when ignored, could eventually spread to the surrounding alveolar bone and progress to pulp necrosis. PMID- 26048073 TI - FDA committee recommends approval for "female Viagra". PMID- 26048074 TI - Oxalic acid capped iron oxide nanorods as a sensing platform. AB - A label free impedimetric immunosensor has been fabricated using protein bovine serum albumin (BSA) and monoclonal antibodies against Vibrio cholerae (Ab) functionalized oxalic acid (OA) capped iron oxide (Fe3O4) nanorods for V. cholerae detection. The structural and morphological studies of Fe3O4 and OA Fe3O4, were characterized by X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy and dynamic light scattering (DLS) techniques. The average crystalline size of Fe3O4, OA Fe3O4 nanorods were obtained as about 29+/-1 and 39+/-1nm, respectively. The hydrodynamic radius of nanorods is found as 116nm (OA-Fe3O4) and 77nm (Fe3O4) by DLS measurement. Cytotoxicity of Fe3O4 and OA-Fe3O4 nanorods has been investigated in the presence of human epithelial kidney (HEK) cell line 293 using MTT assay. The cell viability and proliferation studies reveal that the OA-Fe3O4 nanorods facilitate cell growth. The results of electrochemical response studies of the fabricated BSA/Ab/OA-Fe2O3/ITO immunosensor exhibits good linearity in the range of 12.5-500ng mL(-1) with low detection limit of 0.5ng mL(-1), sensitivity 0.1Omegang(-1)ml(-1)cm(-2) and reproducibility more than 11 times. PMID- 26048075 TI - A Scalable Framework to Detect Personal Health Mentions on Twitter. AB - BACKGROUND: Biomedical research has traditionally been conducted via surveys and the analysis of medical records. However, these resources are limited in their content, such that non-traditional domains (eg, online forums and social media) have an opportunity to supplement the view of an individual's health. OBJECTIVE: The objective of this study was to develop a scalable framework to detect personal health status mentions on Twitter and assess the extent to which such information is disclosed. METHODS: We collected more than 250 million tweets via the Twitter streaming API over a 2-month period in 2014. The corpus was filtered down to approximately 250,000 tweets, stratified across 34 high-impact health issues, based on guidance from the Medical Expenditure Panel Survey. We created a labeled corpus of several thousand tweets via a survey, administered over Amazon Mechanical Turk, that documents when terms correspond to mentions of personal health issues or an alternative (eg, a metaphor). We engineered a scalable classifier for personal health mentions via feature selection and assessed its potential over the health issues. We further investigated the utility of the tweets by determining the extent to which Twitter users disclose personal health status. RESULTS: Our investigation yielded several notable findings. First, we find that tweets from a small subset of the health issues can train a scalable classifier to detect health mentions. Specifically, training on 2000 tweets from four health issues (cancer, depression, hypertension, and leukemia) yielded a classifier with precision of 0.77 on all 34 health issues. Second, Twitter users disclosed personal health status for all health issues. Notably, personal health status was disclosed over 50% of the time for 11 out of 34 (33%) investigated health issues. Third, the disclosure rate was dependent on the health issue in a statistically significant manner (P<.001). For instance, more than 80% of the tweets about migraines (83/100) and allergies (85/100) communicated personal health status, while only around 10% of the tweets about obesity (13/100) and heart attack (12/100) did so. Fourth, the likelihood that people disclose their own versus other people's health status was dependent on health issue in a statistically significant manner as well (P<.001). For example, 69% (69/100) of the insomnia tweets disclosed the author's status, while only 1% (1/100) disclosed another person's status. By contrast, 1% (1/100) of the Down syndrome tweets disclosed the author's status, while 21% (21/100) disclosed another person's status. CONCLUSIONS: It is possible to automatically detect personal health status mentions on Twitter in a scalable manner. These mentions correspond to the health issues of the Twitter users themselves, but also other individuals. Though this study did not investigate the veracity of such statements, we anticipate such information may be useful in supplementing traditional health related sources for research purposes. PMID- 26048076 TI - Summarizing and visualizing structural changes during the evolution of biomedical ontologies using a Diff Abstraction Network. AB - Biomedical ontologies are a critical component in biomedical research and practice. As an ontology evolves, its structure and content change in response to additions, deletions and updates. When editing a biomedical ontology, small local updates may affect large portions of the ontology, leading to unintended and potentially erroneous changes. Such unwanted side effects often go unnoticed since biomedical ontologies are large and complex knowledge structures. Abstraction networks, which provide compact summaries of an ontology's content and structure, have been used to uncover structural irregularities, inconsistencies and errors in ontologies. In this paper, we introduce Diff Abstraction Networks ("Diff AbNs"), compact networks that summarize and visualize global structural changes due to ontology editing operations that result in a new ontology release. A Diff AbN can be used to support curators in identifying unintended and unwanted ontology changes. The derivation of two Diff AbNs, the Diff Area Taxonomy and the Diff Partial-area Taxonomy, is explained and Diff Partial-area Taxonomies are derived and analyzed for the Ontology of Clinical Research, Sleep Domain Ontology, and eagle-i Research Resource Ontology. Diff Taxonomy usage for identifying unintended erroneous consequences of quality assurance and ontology merging are demonstrated. PMID- 26048078 TI - The Arabidopsis epitranscriptome. AB - The most prevalent internal modification of plant messenger RNAs, N(6) methyladenosine (m(6)A), was first discovered in the 1970s, then largely forgotten. However, the impact of modifications to eukaryote mRNA, collectively known as the epitranscriptome, has recently attracted renewed attention. mRNA methylation is required for normal Arabidopsis development and the first methylation maps reveal that thousands of Arabidopsis mRNAs are methylated. Arabidopsis is likely to be a model of wide utility in understanding the biological impacts of the epitranscriptome. We review recent progress and look ahead with questions awaiting answers to reveal an entire layer of gene regulation that has until recently been overlooked. PMID- 26048077 TI - Predicting censored survival data based on the interactions between meta dimensional omics data in breast cancer. AB - Evaluation of survival models to predict cancer patient prognosis is one of the most important areas of emphasis in cancer research. A binary classification approach has difficulty directly predicting survival due to the characteristics of censored observations and the fact that the predictive power depends on the threshold used to set two classes. In contrast, the traditional Cox regression approach has some drawbacks in the sense that it does not allow for the identification of interactions between genomic features, which could have key roles associated with cancer prognosis. In addition, data integration is regarded as one of the important issues in improving the predictive power of survival models since cancer could be caused by multiple alterations through meta dimensional genomic data including genome, epigenome, transcriptome, and proteome. Here we have proposed a new integrative framework designed to perform these three functions simultaneously: (1) predicting censored survival data; (2) integrating meta-dimensional omics data; (3) identifying interactions within/between meta-dimensional genomic features associated with survival. In order to predict censored survival time, martingale residuals were calculated as a new continuous outcome and a new fitness function used by the grammatical evolution neural network (GENN) based on mean absolute difference of martingale residuals was implemented. To test the utility of the proposed framework, a simulation study was conducted, followed by an analysis of meta-dimensional omics data including copy number, gene expression, DNA methylation, and protein expression data in breast cancer retrieved from The Cancer Genome Atlas (TCGA). On the basis of the results from breast cancer dataset, we were able to identify interactions not only within a single dimension of genomic data but also between meta-dimensional omics data that are associated with survival. Notably, the predictive power of our best meta-dimensional model was 73% which outperformed all of the other models conducted based on a single dimension of genomic data. Breast cancer is an extremely heterogeneous disease and the high levels of genomic diversity within/between breast tumors could affect the risk of therapeutic responses and disease progression. Thus, identifying interactions within/between meta-dimensional omics data associated with survival in breast cancer is expected to deliver direction for improved meta-dimensional prognostic biomarkers and therapeutic targets. PMID- 26048079 TI - Refining the nuclear auxin response pathway through structural biology. AB - Auxin is a key regulator of plant growth and development. Classical molecular and genetic techniques employed over the past 20 years identified the major players in auxin-mediated gene expression and suggest a canonical auxin response pathway. In recent years, structural and biophysical studies clarified the molecular details of auxin perception, the recognition of DNA by auxin transcription factors, and the interaction of auxin transcription factors with repressor proteins. These studies refine the auxin signal transduction model and raise new questions that increase the complexity of auxin signaling. PMID- 26048080 TI - Deontological guilt and obsessive compulsive disorder. AB - BACKGROUND AND OBJECTIVES: The emotion of guilt plays a pivotal role in the genesis and maintenance of Obsessive-Compulsive Disorder (OCD). But what kind of guilt do OC patients want to prevent? Several studies suggest the existence of two different types of guilt emotions, namely deontological and altruistic guilt. This research suggests that the former, more than the latter, is involved in OCD. Studies in which people must hypothetically choose between killing one person to save a few (consequentialist choice) or take no action and allow things to take their course (omission choice), have found that the latter is consistent with the "Do not play God" moral principle whereas the former is consistent with altruistic motivations. This paper is aimed at verifying whether both OC patients, with no induction, and nonclinical participants, after the induction of deontological guilt prefer omission more often than a consequentialist option. It is hypothesized that people with OCD will be motivated to avoid feeling deontological guilt and thus will be more likely to opt for omission. Similarly, nonclinical participants who receive a deontological guilt induction will also be more likely to choose omission. METHOD: In two studies participants were given seven scenarios (four moral dilemmas, three control scenarios). Twenty patients with OCD, 20 anxious controls, and 20 healthy participants took part in study 1. In study 2, we recruited 70 healthy participants who were randomly assigned to receive a deontological guilt or a control induction. RESULTS: Consistent with hypotheses, in Study 1 OC patients preferred omission, instead of the consequentialist option, moreso than did the clinical and nonclinical controls. In Study 2, the group receiving the deontological guilt induction preferred omission to a greater extent than did the altruistic group. LIMITATIONS: The present study cannot establish that the goal of preventing or neutralizing deontological guilt actually drives obsessions and compulsions. CONCLUSIONS: These results provide further evidence that people with OCD are more sensitive to deontological guilt, compared to other people. They thus contribute to improve the moral appraisal theory of OCD. PMID- 26048081 TI - Fear reactions to snakes in naive mouse lemurs and pig-tailed macaques. AB - Primates have been predated on by snakes throughout their evolution and as a result, antipredator responses accompanied by signs of fear are often witnessed in the wild. In captivity, however, the fear of snakes is less clear, as experiments with naive nonhuman primates have given inconsistent results. In this study, we present evidence that naive mouse lemurs (Microcebus murinus) and putatively naive pig-tailed macaques (Macaca nemestrina) do exhibit fear of snakes, even though the apparent reactions are mild. In an experiment with control- or snake-odoured boxes, mouse lemurs clearly avoided feeding in the latter. When the latency of touching rubber models was measured, pig-tailed macaques took longer to touch a toy snake compared with a toy lizard. Our findings that fear of snakes is shown by naive individuals support the hypothesis that it is innate in primates. PMID- 26048082 TI - Pleural neoplastic pathology. AB - BACKGROUND/PURPOSE: Malignant pleural effusion is a frequent situation in pulmonary medicine. However, it is sometimes difficult to recognize the underlying etiology. The aim of this review is to provide the key characteristics of primary and metastatic pleural neoplasms. METHODS: A review of the recent literature regarding pleural neoplasia is provided. RESULTS: Malignant pleural mesothelioma (MPM) is the commonest primary pleural epithelial tumor showing remarkable histological heterogeneity often with prognostic significance. Various genetic alterations like changes in INK4 locus, NF2, BAP1 but also epigenetic changes are present in MPM. It should be distinguished from atypical mesothelial hyperplasia, mainly through morphological and clinical criteria, and from other rare primary and metastatic tumors, for which immunohistochemistry is rather important. Solitary fibrous tumor, the commonest primary pleural mesenchymal tumor is characterized by STAT6 overexpression. Other primary tumors, like adenomatoid tumor, well-differentiated papillary mesothelioma, synovial sarcoma, vascular tumors, various other sarcomas, thymic tumors and tumors of uncertain histogenesis are rarely encountered in the pleura. In contrast, metastatic disease is the commonest neoplasia of the pleura, and especially lung, breast and lymphoid malignancies. CONCLUSION: The basic pathological, immunohistochemical and molecular characteristics of these entities are provided in the current review, along with their differential diagnosis. PMID- 26048083 TI - Extended analysis of exhaled and nasal nitric oxide for the evaluation of chronic cough. AB - INTRODUCTION: Chronic cough is usually defined as a cough that lasts for eight weeks or longer. Its etiological diagnosis is not always straightforward, and the measurement of exhaled nitric oxide (FeNO) has been proposed in patients' evaluation. No studies have assessed the usefulness of extended exhaled NO measurement for the evaluation of chronic cough. Therefore, we aimed at evaluating the usefulness of an extended exhaled NO measurement and nasal NO for an initial evaluation of chronic cough. METHODS: We studied 52 non-smoker patients with prolonged cough lasting more than eight weeks. Etiologies of cough were identified. Nasal NO and FeNO were assessed using multiple single-breath NO analysis at different constant expiratory flow-rates. From the fractional NO concentration measured at each flow-rate, the total NO flux between tissue and gas phase in the bronchial lumen (J'awNO), and the alveolar NO concentration (Cano) were extrapolated. RESULTS: The patients were classified in four categories: cough variant asthma (CVA), nonasthmatic eosinophilic bronchitis (NAEB), upper airway cough syndrome (UACS) and gastro-esophageal reflux disease (GERD). Compared with UACS and GERD, both exhaled NO and J'awNO were higher in CVA and NAEB, and no differences were found in Cano and nasal NO level among the four groups. CONCLUSIONS: Our study suggests a potentially useful role for FeNO measurement in the etiological diagnosis of chronic cough. We did not find any additive value of performing exhaled NO at multiple flow-rates and nasal NO measurements. PMID- 26048084 TI - Fate of beta-hexachlorocyclohexane in the mixed microbial cultures (MMCs) three stage polyhydroxyalkanoates (PHA) production process from cheese whey. AB - This work aimed to study the fate and effect of beta-hexachlorocyclohexane (beta HCH) during several steps of PHA production and purification, by using an artificially contaminated cheese whey (CW) as the feedstock. Most of beta-HCH (around 90%) was adsorbed on CW solids and it was removed after the acidogenic fermentation step, when residual CW solids are separated along with anaerobic biomass from the liquid-phase. Purification steps also contributed strongly to the removal of residual beta-HCH; overall, the PHA production process removed about 99.9% of initial beta-HCH content. Moreover, it has been shown that beta HCH has neither detrimental effect on acidogenic fermentation nor on PHA accumulation, that were performed by using unacclimated mixed microbial cultures. PMID- 26048085 TI - Effect of pyrolysis temperature on polycyclic aromatic hydrocarbons toxicity and sorption behaviour of biochars prepared by pyrolysis of paper mill effluent treatment plant sludge. AB - The polycyclic aromatic hydrocarbons (PAHs) toxicity and sorption behaviour of biochars prepared from pyrolysis of paper mill effluent treatment plant (ETP) sludge in temperature range 200-700 degrees C was studied. The sorption behaviour was found to depend on the degree of carbonization where the fractions of carbonized and uncarbonized organic content in the biochar act as an adsorption media and partition media, respectively. The sorption and partition fractions were quantified by isotherm separation method and isotherm parameters were correlated with biochar properties (aromaticity, polarity, surface area, pore volume and ash content). The risk assessment for the 16 priority EPA PAHs present in the biochar matrix was performed and it was found that the concentrations of the PAHs in the biochar were within the permissible limits prescribed by US EPA (except BC400 and BC500 for high molecular weight PAHs). PMID- 26048086 TI - Apitoxin protects rat pups brain from propionic acid-induced oxidative stress: The expression pattern of Bcl-2 and Caspase-3 apoptotic genes. AB - The primary aim of this study was to determine the potential modulatory role of the apitoxin (bee venom; BV) against propionic acid (PPA)-induced neurotoxicity. The biochemical responses to PPA exposure in rat pups were assayed, including changes in the antioxidant barrier systems and lipid peroxidation and protein oxidation biomarkers in the brain tissue. DNA damage was measured by single-cell gel electrophoresis and differences in Bcl-2 and Caspase-3 mRNA expression were assessed using real-time PCR. Changes in amygdala complex ultrastructure were visually assessed using electron microscopy. Sixty rat pups were assigned into six groups: a control group, a PPA-treated group, a BV-treated group, a protective co-treated group, a therapeutic co-treated group, and a protective/therapeutic co-treated group. The results indicate that PPA induced a pronounced increase (64.6%) in malondialdehyde (MDA), and in DNA damage (73.3%) with three-fold increase in protein carbonyl concentration. A significant reduction was observed in the enzyme activities of superoxide dismutase (SOD) (48.7%) and catalase (CAT) (74.8%) and reduced glutathione (GSH) level (52.6%). BV significantly neutralized the PPA-induced oxidative stress effects, especially in the BV protective/therapeutic co-treated group. In this group, GSH levels were restored to 64.5%, and MDA, protein carbonyl levels and tail moment % were diminished by 69.5, 21.1 and 18.8% relative to the control, respectively. Furthermore, while PPA induced significant apoptotic neural cell death, BV markedly inhibited apoptosis by promoting Bcl-2 expression and blocking Caspase-3 expression. BV markedly restored the normal ultrastructural morphology of the amygdala complex neurons. These results conclusively demonstrate that BV administration provides both protective and therapeutic effects in response to the PPA-induced deleterious effects, including oxidative stress, DNA damage, and neuronal death in the brains of rat pups. PMID- 26048087 TI - Economic Evaluations of Everolimus Versus Other Hormonal Therapies in the Treatment of HR+/HER2- Advanced Breast Cancer From a US Payer Perspective. AB - INTRODUCTION: The objective of the study was to assess the cost-effectiveness of EVE+EXE versus endocrine monotherapies in the treatment of postmenopausal women with HR(+), HER2(-) ABC after failure of treatment with nonsteroidal aromatase inhibitors from a US third-party payer perspective. MATERIALS AND METHODS: A Markov model was developed to evaluate the costs and effectiveness associated with EVE+EXE, exemestane (EXE), fulvestrant (FUL), and tamoxifen (TAM) over a 10 year time horizon. The model included 3 health states: responsive/stable disease, progression, or death. Monthly transition probabilities were estimated based on the BOLERO-2 (Breast cancer trials of OraL EveROlimus-2) data and network meta analyses. Costs included drug acquisition and administration costs, medical costs associated health states, and costs for managing adverse events (AEs). Utilities for each health state and disutilities for AEs were derived from the literature. Incremental costs per quality-adjusted life year (QALY) were estimated by comparing EVE+EXE with each endocrine monotherapy. One-way and probabilistic sensitivity analyses were performed. RESULTS: In the base case, EVE+EXE was associated with 1.99 QALYs and total direct costs of $258,648 over 10 years. The incremental cost per QALY of EVE+EXE was $139,740 compared with EXE, $157,749 compared with FUL, and $115,624 compared with TAM. At a willingness-to-pay threshold of $130,000/QALY or above, EVE+EXE appeared to be the most cost effective treatment among all drugs. CONCLUSIONS: Everolimus with EXE demonstrated QALY improvements compared with 3 other endocrine monotherapies. Benchmarked by the economic value of other novel cancer therapies, EVE+EXE might be considered a cost-effective option compared with endocrine therapies for HR(+)/HER2(-) ABC. PMID- 26048088 TI - Wear testing of total hip replacements under severe conditions. AB - Controlled wear testing of total hip replacements in hip joint simulators is a well-established and powerful method, giving an extensive prediction of the long term clinical performance. To understand the wear behavior of a bearing and its limits under in vivo conditions, testing scenarios should be designed as physiologically as possible. Currently, the ISO standard protocol 14242 is the most common preclinical testing procedure for total hip replacements, based on a simplified gait cycle for normal walking conditions. However, in recent years, wear patterns have increasingly been observed on retrievals that cannot be replicated by the current standard. The purpose of this study is to review the severe testing conditions that enable the generation of clinically relevant wear rates and phenomena. These conditions include changes in loading and activity, third-body wear, surface topography, edge wear and the role of aging of the bearing materials. PMID- 26048089 TI - Antimicrobial peptides: Possible anti-infective agents. AB - Multidrug-resistant bacterial, fungal, viral, and parasitic infections are major health threats. The Infectious Diseases Society of America has expressed concern on the decrease of pharmaceutical companies working on antibiotic research and development. However, small companies, along with academic research institutes, are stepping forward to develop novel therapeutic methods to overcome the present healthcare situation. Among the leading alternatives to current drugs are antimicrobial peptides (AMPs), which are abundantly distributed in nature. AMPs exhibit broad-spectrum activity against a wide variety of bacteria, fungi, viruses, and parasites, and even cancerous cells. They also show potential immunomodulatory properties, and are highly responsive to infectious agents and innate immuno-stimulatory molecules. In recent years, many AMPs have undergone or are undergoing clinical development, and a few are commercially available for topical and other applications. In this review, we outline selected anion and cationic AMPs which are at various stages of development, from preliminary analysis to clinical drug development. Moreover, we also consider current production methods and delivery tools for AMPs, which must be improved for the effective use of these agents. PMID- 26048090 TI - Stability, toxicity and intestinal permeation enhancement of two food-derived antihypertensive tripeptides, Ile-Pro-Pro and Leu-Lys-Pro. AB - Two food-derived ACE inhibitory peptides, Ile-Pro-Pro (IPP) and Leu-Lys-Pro (LKP), may have potential as alternative treatments for treatment of mild- or pre hypertension. Lack of stability to secretory and intracellular peptidases and poor permeability across intestinal epithelia are typical limiting factors of oral delivery of peptides. The stability of IPP and LKP was confirmed in vitro in rat intestinal washes, and intestinal and liver homogenates over 60min. A positive protein control for peptidases, insulin, was significantly digested in each format over the same period. Neither tripeptide showed cytotoxic activity on Caco-2 and Hep G2 cells using the 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, even after chronic exposure. The basal Papp of fluorescein isothiocyanate (FITC)-labeled IPP and FITC-LKP across isolated rat jejunal and colonic mucosae were low, but were significantly increased in each tissue type by the medium chain fatty acids (MCFA) permeation enhancers, sodium caprate (C10) and the sodium salt of 10 undecylenic acid (uC11). IPP and LKP were therefore stable against intestinal and liver peptidases and were non-cytotoxic; their Papp values across rat intestinal mucosae were low, but could be increased by MCFA. There is potential to make on oral dosage form once in vivo pharmacology is confirmed. PMID- 26048091 TI - Important species differences regarding lymph contribution to gut hormone responses. AB - INTRODUCTION: GLP-1 is secreted from the gut upon nutrient intake and stimulates insulin secretion. The lymph draining the intestine may transport high levels of GLP-1 to the systemic circulation before it is metabolized by DPP-4. The aims of this study were to investigate to what extent the lymphatic system might contribute to the final level(s) of systemic circulating intact GLP-1 and, in addition, whether secretory profiles in intestinal lymph might reflect lamina propria levels of GLP-1 i.e. before capillary uptake and degradation by endothelial dipeptidyl peptidase-4 (DPP-4). METHOD: 7 pigs of the YDL-strain were catheterized in the portal vein, carotid artery and cisterna chyli (lymph). Neuromedin C (NC) was infused through an ear vein catheter, before and after injection of a selective DPP-4 inhibitor (vildagliptin). Total and intact GLP-1 levels were measured throughout the 150min experiments using specific sandwich ELISAs. DPP-4 activity was measured spectrophotometrically. RESULTS: Concentrations of both total and intact GLP-1 were markedly lower in lymph compared to plasma samples, and did not increase significantly in response to stimulation with NC in the absence/presence of vildagliptin. In contrast, total and intact GLP-1 levels increased significantly in the portal vein and carotid artery. DPP-4 activity was lower in lymph than plasma, and was reduced further by vildagliptin. CONCLUSION: Our observations indicate that the lymphatic system does not transport high levels of intact GLP-1 to the systemic circulation, and that GLP-1 levels in cisternal lymph do not reflect the hormone levels in the intestinal lamina propria. PMID- 26048092 TI - QTL mapping in multiple populations and development stages reveals dynamic quantitative trait loci for fruit size in cucumbers of different market classes. AB - KEY MESSAGE: QTL analysis in multi-development stages with different QTL models identified 12 consensus QTLs underlying fruit elongation and radial growth presenting a dynamic view of genetic control of cucumber fruit development. Fruit size is an important quality trait in cucumber (Cucumis sativus L.) of different market classes. However, the genetic and molecular basis of fruit size variations in cucumber is not well understood. In this study, we conducted QTL mapping of fruit size in cucumber using F2, F2-derived F3 families and recombinant inbred lines (RILs) from a cross between two inbred lines Gy14 (North American picking cucumber) and 9930 (North China fresh market cucumber). Phenotypic data of fruit length and diameter were collected at three development stages (anthesis, immature and mature fruits) in six environments over 4 years. QTL analysis was performed with three QTL models including composite interval mapping (CIM), Bayesian interval mapping (BIM), and multiple QTL mapping (MQM). Twenty-nine consistent and distinct QTLs were detected for nine traits from multiple mapping populations and QTL models. Synthesis of information from available fruit size QTLs allowed establishment of 12 consensus QTLs underlying fruit elongation and radial growth, which presented a dynamic view of genetic control of cucumber fruit development. Results from this study highlighted the benefits of QTL analysis with multiple QTL models and different mapping populations in improving the power of QTL detection. Discussion was presented in the context of domestication and diversifying selection of fruit length and diameter, marker assisted selection of fruit size, as well as identification of candidate genes for fruit size QTLs in cucumber. PMID- 26048093 TI - Dissemination of Chest Compression-Only Cardiopulmonary Resuscitation and Survival After Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: The best cardiopulmonary resuscitation (CPR) technique for survival after out-of-hospital cardiac arrests (OHCAs) has been intensively discussed in the recent few years. However, most analyses focused on comparison at the individual level. How well the dissemination of bystander-initiated chest compression-only CPR (CCCPR) increases survival after OHCAs at the population level remains unclear. We therefore evaluated the impact of nationwide dissemination of bystander-initiated CCCPR on survival after OHCA. METHODS AND RESULTS: A nationwide, prospective, population-based, observational study covering the whole population of Japan and involving consecutive OHCA patients with resuscitation attempts was conducted from January 2005 through December 2012. The main outcome measure was 1-month survival with favorable neurological outcome. The incidence of survival with favorable neurological outcome attributed to types of bystander CPR (CCCPR and conventional CPR with rescue breathing) was estimated. Among 816 385 people experiencing OHCAs before emergency medical services arrival, 249 970 (30.6%) received CCCPR, 100 469 (12.3%) received conventional CPR, and 465 946 (57.1%) received no CPR. The proportion of OHCA patients receiving CCCPR or any CPR (either CCCPR or conventional CPR) by bystanders increased from 17.4% to 39.3% (P for trend <0.001) and from 34.6% to 47.3% (P for trend <0.001), respectively. The incidence of survival with favorable neurological outcome attributed to CCCPR per 10 million population significantly increased from 0.6 to 28.3 (P for trend=0.010), and that by any bystander-initiated CPR significantly increased from 9.0 to 43.6 (P for trend=0.003). CONCLUSION: Nationwide dissemination of CCCPR for lay-rescuers was associated with the increase in the incidence of survival with favorable neurological outcome after OHCAs in Japan. PMID- 26048094 TI - Circulating Very-Long-Chain Saturated Fatty Acids and Incident Coronary Heart Disease in US Men and Women. AB - BACKGROUND: Circulating very-long-chain saturated fatty acids (VLCSFAs) may play an active role in the origin of cardiometabolic diseases. METHODS AND RESULTS: We measured 3 VLCSFAs (C20:0, C22:0, and C24:0) in plasma and erythrocytes using gas liquid chromatography among 794 incident coronary heart disease (CHD) cases who were prospectively identified and confirmed among women in the Nurses' Health Study (NHS; 1990-2006) and among men in the Health Professionals Follow-Up Study (HPFS; 1994-2008). A total of 1233 CHD-free controls were randomly selected and matched to cases in these 2 cohorts. Conditional logistic regression was used to estimate hazard ratios and 95% confidence intervals. Plasma VLCSFAs were correlated with favorable profiles of blood lipids, C-reactive protein, and adiponectin in the NHS and HPFS and with fasting insulin and C-peptide levels in a nationally representative US comparison population. After multivariate adjustment for lifestyle factors, body mass index, diet, and long-chain n-3 and trans fatty acids, total VLCSFAs in plasma were associated with a 52% decreased risk of CHD (pooled hazard ratio, 0.48; 95% confidence interval, 0.32-0.72, comparing extreme quintiles; Ptrend<0.0001). For VLCSFAs in erythrocytes, a nonsignificant inverse trend with CHD risk was observed (pooled hazard ratio, 0.66; 95% confidence interval, 0.41-1.06, comparing extreme quintiles; Ptrend=0.16). CONCLUSIONS: In US men and women, plasma VLCSFAs were independently associated with favorable profiles of blood lipids and other cardiovascular disease risk markers and a lower risk of CHD. Erythrocyte VLCSFAs were associated with nonsignificant trends of lower CHD risk. Future studies are warranted to elucidate the underlying biological mechanisms. PMID- 26048095 TI - Pressure effects on the nose by an in-flight oxygen mask during simulated flight conditions. AB - BACKGROUND: Dutch F-16 fighter pilots experience oxygen mask inflicted nasal trauma, including discomfort, pain, skin abrasions, bruises and bone remodelling. Pressure and shear forces on the nose might contribute to causing these adverse effects. In this study, it was evaluated how flight conditions affected the exerted pressure, and whether shear forces were present. METHODS: The pressure exerted by the oxygen mask was measured in 20 volunteers by placing pressure sensors on the nose and chin underneath the mask. In the human centrifuge, the effects on the exerted pressure during different flight conditions were evaluated (+3Gz, +6Gz, +9Gz, protocolised head movements, mounted visor or night vision goggles, NVG). The runs were recorded to evaluate if the mask's position changed during the run, which would confirm the presence of shear forces. RESULTS: Head movements increased the median pressure on the nose by 50 mm Hg and on the chin by 37 mm Hg. NVG, a visor and accelerative forces also increased the median pressure on the nose. Pressure drops on the nose were also observed, during mounted NVG (-63 mm Hg). The recordings showed the mask slid downwards, especially during the acceleration phase of the centrifuge run, signifying the presence of shear forces. CONCLUSIONS: The exerted pressure by the oxygen mask changes during different flight conditions. Exposure to changing pressures and to shear forces probably contributes to mask-inflicted nasal trauma. PMID- 26048096 TI - Investigation of the impact of hepatic impairment on the pharmacokinetics of dacomitinib. AB - Dacomitinib (PF-00299804) is a small-molecule inhibitor of the tyrosine kinases human epidermal growth factor receptor-1 (HER1; epidermal growth factor receptor, EGFR), HER2, and HER4 currently being developed for the treatment of lung cancer with sensitizing mutations in EGFR or refractory to EGFR-directed treatment. Dacomitinib is largely metabolized by the liver through oxidative and conjugative metabolism; therefore, determination of the impact of varying degrees of hepatic impairment on the pharmacokinetics (PK) of dacomitinib was warranted to ensure patient safety. In this phase I, open-label, parallel-group study, a single dose of dacomitinib was administered to healthy volunteers and to subjects with mild or moderate liver dysfunction, as determined by Child-Pugh classification. The primary goal of this study was to evaluate the effects of mild and moderate hepatic impairment on the single-dose PK profile of dacomitinib, as well as to assess the safety and tolerability in these subjects. Plasma protein binding and impact of hepatic function on the PK of the active metabolite PF-05199265 was also investigated. Twenty-five male subjects received dacomitinib 30 mg, with 8 subjects in the healthy- and mild-impairment cohorts and 9 subjects in the moderate-impairment cohort. Compared with healthy volunteers, there was no significant change in dacomitinib exposure in subjects with mild or moderate liver dysfunction and no observed alteration in plasma protein binding. No serious treatment-related adverse events were reported in any group, and dacomitinib was well tolerated. A dose adjustment does not appear necessary when administering dacomitinib to patients with mild or moderate hepatic impairment. PMID- 26048097 TI - One miniplate compared with two in the fixation of isolated fractures of the mandibular angle. AB - The purpose of this study was to compare one miniplate with two in the management of isolated fractures of the mandibular angle as regards wound healing, failure of hardware, scarring, weakness of the facial nerve, and overall morbidity, by making a systematic review with a meta-analysis. I made a comprehensive electronic search with no date or language restrictions in October 2014. The inclusion criteria were studies in humans, including randomised or quasirandomised controlled trials (RCT), controlled clinical trials (CCT), and retrospective studies that compared the morbidity after treatment of such fractures with one and two miniplates. Ten publications were included: three RCT, three CCT, and four retrospective studies. Three studies showed a low, and seven a moderate, risk of bias. There was a significant difference between one and two miniplates in the incidence of wound healing, failure of hardware, weakness of the facial nerve, and overall complications (p=0.04, p =0.05, p=0.002, and p=0.05, respectively). The result of the meta-analysis showed that one miniplate placed on the external oblique ridge provided a significant reduction in the incidence of wound infection and dehiscence, failure of hardware, and overall complications, compared with two miniplates, one placed on the external oblique ridge and one placed on to the ventral surface of mandible to fix the fracture. PMID- 26048098 TI - Sialolithiasis of an accessory parotid gland: an unusual case. AB - We report a rare case of sialolithiasis of an accessory parotid gland, which was located anteromedial to the masseter muscle and isolated from the main parotid gland. The calculus developed from this accessory gland, and the main gland was free of lithiasis and inflammation. To our knowledge, there is no reported case of 14 stones in an accessory parotid salivary gland. The calculus was removed through a standard incision without injury to the facial nerve or a salivary fistula. PMID- 26048099 TI - Laser scanner compared with stereophotogrammetry for measurements of area on nasal plaster casts. PMID- 26048100 TI - Re: Efficacy of antibiotic prophylaxis on postoperative inflammatory complications in Chinese patients having impacted mandibular third molars removed: a split-mouth, double-blind, self-controlled, clinical trial. Br J Oral Maxillofac Surg 2015 May;53(5):416-20. PMID- 26048101 TI - Contrast imaging study of the horseshoe kidney for transplantation. AB - In the surgical setting, horseshoe kidneys (HKs) may be a cause for confusion because of their complicated morphology, especially in the vicinity of the vascular and urinary collecting systems around the isthmus of the HK. In the patients with HK, analysis of the anatomical structure of the isthmus is both useful and necessary. The aim of this study is to observe the vascular and collecting system of the HK using anatomical and contrast imaging technique, then make use of the knowledge for clinical anatomy. A HK voluntarily donated post mortem to our department in 2013 by an 80-year-old woman was dissected. The gross anatomy of this HK was reported. In this study, we additionally analyzed this kidney using micro-computed tomography with both colored and colorless contrast media after the kidney was made transparent. Contrast imaging clearly revealed that each of the five renal arteries, including the three surplus renal arteries, entering the HK distributed blood to different regions. Neither side of the urinary collecting system crossed the midline of the isthmus. Two surplus renal veins emerged from the HK and two ureters descended dorsal to the isthmus. These observations show that gross anatomical observation and contrast imaging of the HK can provide very important surgical information. Our results can contribute to both better understanding of fundamental knowledge and progress in the surgery of HKs such as in the setting of biopsy and transplantation. PMID- 26048102 TI - Erratum to: Weapon carrying and psychopathic-like features in a population-based sample of Finnish adolescents. PMID- 26048104 TI - Histogram analysis of diffusion kurtosis magnetic resonance imaging in differentiation of pathologic Gleason grade of prostate cancer. AB - OBJECTIVE: To investigate diagnostic performance of diffusion kurtosis imaging with histogram analysis for stratifying pathologic Gleason grade of prostate cancer (PCa). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and written informed consent was waived. A total of 110 patients pathologically confirmed as having PCa (diameter>0.5 cm) underwent preoperative diffusion-weighted magnetic resonance imaging (b value of 0-2,100 s/mm(2)) at 3T. Data were postprocessed by monoexponential and diffusion kurtosis models for quantitation of apparent diffusion coefficients (ADCs), apparent diffusion for Gaussian distribution (D(app)), and apparent kurtosis coefficient (K(app)). The measurement was based on an entire-tumor histogram analysis approach. The ability of imaging indices for differentiating low-grade (LG) PCa (Gleason score [GS]<=6) from intermediate-/high-grade (HG: GS>6) PCa was analyzed by receiver operating characteristic regression. RESULTS: There were 49 LG tumors and 77 HG tumors at pathologic findings. HG-PCa had significantly lower ADCs, lower diffusion kurtosis diffusivity (D(app)), and higher kurtosis coefficient (K(app)) in mean, median, 10th, and 90th percentile, with higher D(app) in skewness and kurtosis than LG-PCa (P< 0.05). The 10th ADCs, the 10th D(app), and the 90th K(app) showed relatively higher area under receiver operating characteristic curve (Az), Youden index, and positive likelihood ratio in stratifying aggressiveness of PCa against other indices. The 90th K(app) showed relatively higher correlation (rho>0.6) with ordinal GS of PCa; significantly higher Az, sensitivity, and specificity (0.889, 74.1%, and 93.9%, respectively) than the 10th D(app) did (0.765, 61.0%, and 79.6%, respectively; P<0.05); and higher Az and specificity than the 10th ADCs did (0.738 and 71.4%, respectively; P<0.05) in differentiating LG-PCa from HG-PCa. CONCLUSIONS: It demonstrated a good reliability of histogram diffusion kurtosis imaging for stratifying pathologic GS of PCa. The 90th K(app) had better diagnostic performance in differentiating LG-PCa from HG-PCa. PMID- 26048103 TI - Emotional face recognition in adolescent suicide attempters and adolescents engaging in non-suicidal self-injury. AB - Little is known about the bio-behavioral mechanisms underlying and differentiating suicide attempts from non-suicidal self-injury (NSSI) in adolescents. Adolescents who attempt suicide or engage in NSSI often report significant interpersonal and social difficulties. Emotional face recognition ability is a fundamental skill required for successful social interactions, and deficits in this ability may provide insight into the unique brain-behavior interactions underlying suicide attempts versus NSSI in adolescents. Therefore, we examined emotional face recognition ability among three mutually exclusive groups: (1) inpatient adolescents who attempted suicide (SA, n = 30); (2) inpatient adolescents engaged in NSSI (NSSI, n = 30); and (3) typically developing controls (TDC, n = 30) without psychiatric illness. Participants included adolescents aged 13-17 years, matched on age, gender and full-scale IQ. Emotional face recognition was evaluated using the diagnostic assessment of nonverbal accuracy (DANVA-2). Compared to TDC youth, adolescents with NSSI made more errors on child fearful and adult sad face recognition while controlling for psychopathology and medication status (ps < 0.05). No differences were found on emotional face recognition between NSSI and SA groups. Secondary analyses showed that compared to inpatients without major depression, those with major depression made fewer errors on adult sad face recognition even when controlling for group status (p < 0.05). Further, compared to inpatients without generalized anxiety, those with generalized anxiety made fewer recognition errors on adult happy faces even when controlling for group status (p < 0.05). Adolescent inpatients engaged in NSSI showed greater deficits in emotional face recognition than TDC, but not inpatient adolescents who attempted suicide. Further results suggest the importance of psychopathology in emotional face recognition. Replication of these preliminary results and examination of the role of context-dependent emotional processing are needed moving forward. PMID- 26048105 TI - The relation between lymphocyte-monocyte ratio and renal cell carcinoma. PMID- 26048107 TI - Evaluation of the role of autogenous bone-marrow-derived mesenchymal stem cell transplantation for the repair of mandibular bone defects in rabbits. AB - The repair of craniofacial bony defects by traditional grafting techniques requires substantial time and effort, with associated morbidity. Tissue engineering has therefore become a novel approach targeting application for bone regeneration. This study used the rabbit model for radiographic and histological evaluation of bone bioengineering for mandibular defects reconstruction using only beta-tricalcium phosphate (beta-TCP) and, when loaded with autogenous; bone marrow-derived undifferentiated mesenchymal stem cells (BM-MSCs). Critical-sized defects (10 * 15 mm) were created unilaterally in the mandibular body region of each rabbit (n = 16), to be filled with the BM-MSCs/beta-TCP constructs for the study group (group I) (n1 = 8) and with scaffold devoid of cells for the control group (group II) (n2 = 8). Two rabbits from each group were sacrificed after healing periods of 2, 4, 12, and 24 weeks. The results revealed that the BM-MSCs endowed beta-TCP scaffold with a better and more rapid bone regenerating potential: since the first evaluation period of 2 weeks, the regenerated bone tissue in group I was more mature, denser and homogeneously distributed. From these findings we could infer that the bone regeneration process was jump-started within the study group cases, which led to better quality of regenerated bone. PMID- 26048106 TI - Spectral heterogeneity and carotenoid-to-bacteriochlorophyll energy transfer in LH2 light-harvesting complexes from Allochromatium vinosum. AB - Photosynthetic organisms produce a vast array of spectral forms of antenna pigment-protein complexes to harvest solar energy and also to adapt to growth under the variable environmental conditions of light intensity, temperature, and nutrient availability. This behavior is exemplified by Allochromatium (Alc.) vinosum, a photosynthetic purple sulfur bacterium that produces different types of LH2 light-harvesting complexes in response to variations in growth conditions. In the present work, three different spectral forms of LH2 from Alc. vinosum, B800-820, B800-840, and B800-850, were isolated, purified, and examined using steady-state absorption and fluorescence spectroscopy, and ultrafast time resolved absorption spectroscopy. The pigment composition of the LH2 complexes was analyzed by high-performance liquid chromatography, and all were found to contain five carotenoids: lycopene, anhydrorhodovibrin, spirilloxanthin, rhodopin, and rhodovibrin. Spectral reconstructions of the absorption and fluorescence excitation spectra based on the pigment composition revealed significantly more spectral heterogeneity in these systems compared to LH2 complexes isolated from other species of purple bacteria. The data also revealed the individual carotenoid-to-bacteriochlorophyll energy transfer efficiencies which were correlated with the kinetic data from the ultrafast transient absorption spectroscopic experiments. This series of LH2 complexes allows a systematic exploration of the factors that determine the spectral properties of the bound pigments and control the rate and efficiency of carotenoid-to bacteriochlorophyll energy transfer. PMID- 26048108 TI - [In Process Citation]. PMID- 26048110 TI - [In Process Citation]. PMID- 26048111 TI - [In Process Citation]. PMID- 26048112 TI - [In Process Citation]. PMID- 26048113 TI - [In Process Citation]. PMID- 26048114 TI - [In Process Citation]. PMID- 26048115 TI - [In Process Citation]. PMID- 26048116 TI - [In Process Citation]. PMID- 26048117 TI - [In Process Citation]. PMID- 26048118 TI - [In Process Citation]. PMID- 26048119 TI - [In Process Citation]. PMID- 26048120 TI - [In Process Citation]. PMID- 26048121 TI - [In Process Citation]. PMID- 26048122 TI - [In Process Citation]. PMID- 26048123 TI - [In Process Citation]. PMID- 26048124 TI - [In Process Citation]. PMID- 26048125 TI - [In Process Citation]. PMID- 26048126 TI - [In Process Citation]. PMID- 26048127 TI - [In Process Citation]. PMID- 26048128 TI - [In Process Citation]. PMID- 26048129 TI - A low-pungency S3212 genotype of Capsicum frutescens caused by a mutation in the putative aminotransferase (p-AMT) gene. AB - The purpose of this study was to identify the genetic mechanism underlying capsinoid biosynthesis in S3212, a low-pungency genotype of Capsicum frutescens. Screening of C. frutescens accessions for capsaicinoid and capsiate contents by high-performance liquid chromatography revealed that low-pungency S3212 contained high levels of capsiate but no capsaicin. Comparison of DNA coding sequences of pungent (T1 and Bird Eye) and low-pungency (S3212) genotypes uncovered a significant 12-bp deletion mutation in exon 7 of the p-AMT gene of S3212. In addition, p-AMT gene transcript levels in placental tissue were positively correlated with the degree of pungency. S3212, the low-pungency genotype, exhibited no significant p-AMT transcript levels, whereas T1, one of the pungent genotypes, displayed high transcript levels of this gene. We therefore conclude that the deletion mutation in the p-AMT gene is related to the loss of pungency in placental tissue and has given rise to the low-pungency S3212 C. frutescens genotype. C. frutescens S3212 represents a good natural source of capsinoids. Finally, our basic characterization of the uncovered p-AMT gene mutation should contribute to future studies of capsinoid biosynthesis in Capsicum. PMID- 26048131 TI - Evaluating clinical trial design: systematic review of randomized vehicle controlled trials for determining efficacy of benzoyl peroxide topical therapy for acne. AB - Determined efficacies of benzoyl peroxide may be affected by study design, implementation, and vehicle effects. We sought to elucidate areas that may allow improvement in determining accurate treatment efficacies by determining rates of active treatment and vehicle responders in randomized controlled trials assessing the efficacy of topical benzoyl peroxide to treat acne. We conducted a systematic review of randomized vehicle-controlled trials evaluating the efficacy of topical benzoyl peroxide for the treatment of acne. We compared response rates of vehicle treatment arms versus those in benzoyl peroxide arms. Twelve trials met inclusion criteria with 2818 patients receiving benzoyl peroxide monotherapy treatment and 2004 receiving vehicle treatment. The average percent reduction in total number of acne lesions was 44.3 (SD = 9.2) and 27.8 (SD = 21.0) for the active and vehicle treatment groups, respectively. The average reduction in non-inflammatory lesions was 41.5 % (SD = 9.4) in the active treatment group and 27.0 % (SD = 20.9) in the vehicle group. The average percent decrease in inflammatory lesions was 52.1 (SD = 10.4) in the benzoyl peroxide group and 34.7 (SD = 22.7) in the vehicle group. The average percentage of participants achieving success per designated study outcomes was 28.6 (SD = 17.3) and 15.2 (SD = 9.5) in the active treatment and vehicle groups, respectively. Patient responses in randomized controlled trials evaluating topical acne therapies may be affected by clinical trial design, implementation, the biologic effects of vehicles, and natural disease progression. "No treatment" groups may facilitate determination of accurate treatment efficacies. PMID- 26048130 TI - Association between left atrial low-voltage area, serum apoptosis, and fibrosis biomarkers and incidence of silent cerebral events after catheter ablation of atrial fibrillation. AB - BACKGROUND: Silent cerebral events (SCE) have been identified on cerebral diffusion-weighted cerebral magnetic resonance imaging (DE-MRI) after catheter ablation (CA) of atrial fibrillation (AF). The purpose of this study was to investigate the impact of atrial remodeling on the incidence of SCE after AF CA. METHODS: Forty patients (67.8 +/- 10 years, 47.5 % women) with symptomatic paroxysmal (n = 11, 27.5 %) or persistent AF undergoing AF CA were prospectively enrolled. LA fibrosis was estimated by intraprocedural bipolar voltage mapping in sinus rhythm. Apoptosis-stimulating fragment (Fas-Ligand) and amino terminal peptide from collagen III (PIIINP) concentrations were analyzed of LA and femoral vein blood. Cerebral DE-MRI was performed 1 to 2 days after CA of AF for detection of SCE. In nine patients (22.5 %), new SCE were detected on DE-MRI after AF CA. RESULTS: Patients with SCE had higher CHA2DS2-VASc score, larger left atrial diameter (LADmax), and higher surface area of left atrial low-voltage (24 +/- 11.2 vs 3.5 +/- 4.2 %, p < 0.0001). Concentrations of peripheral PIIINP (103.7 +/- 25.9 vs 81.8 +/- 16.7 pg/ml, p < 0.01) and Fas-Ligand (124.1 +/- 22.4 vs 87.6 +/- 19.4 pg/ml, p < 0.01) were significantly higher in patients with SCE and correlated to low-voltage surface area (p < 0.01). Multivariable logistic regression analysis revealed peripheral Fas-Ligand, LADmax, CHA2DS2-Vasc score, and LA low-voltage area proportion to be independent predictors for the development of SCE. CONCLUSIONS: LA remodeling, estimated by LADmax and LA low voltage area, has significant relationship with the risk of SCE after AF ablation. Moreover, Fas-Ligand may act as an independent predictor for SCE in the context of AF CA. PMID- 26048132 TI - Neuroleptic malignant syndrome in trauma patient. AB - In recent years, there has been an increased use of neuroleptic agents in the unit care in trauma patients. There is a lack of prospective data, and most of the information is obtained from related cases. It is needed to have a high index of suspicion with regard to excluding neuroleptic malignant syndrome (NMS) in patients taking neuroleptics and presenting with hyperthermia, because of the potentially fatal consequences. It is a rare syndrome in the burn patient with a lack of proven treatments, and high morbidity and mortality are related. In the actual literature there are few related cases of NMS in the polytrauma patient, particularly in association with psychiatric conditions. In burn NMS is a rare complication with difficult diagnosis, because of the similar symptoms that can occur either in patients in the Burn Unit Care with other fatal conditions that are present in the acute phase response. Actually, there is no marker for the NMS, which difficult the early diagnosis and prognosis. The treatment still is based on case reports, with lack of clinical trials, but remain as standard and universally accepted. Besides that, the neural signaling of the NMS indicates possibilities for better understanding of the pathophysiology treatment protocol. PMID- 26048133 TI - Decellularized human amniotic membrane: more is needed for an efficient dressing for protection of burns against antibiotic-resistant bacteria isolated from burn patients. AB - Human amniotic membranes (HAMs) have attracted the attention of burn surgeons for decades due to favorable properties such as their antibacterial activity and promising support of cell proliferation. On the other hand, as a major implication in the health of burn patients, the prevalence of bacteria resistant to multiple antibiotics is increasing due to overuse of antibiotics. The aim of this study was to investigate whether HAMs (both fresh and acellular) are an effective antibacterial agent against antibiotic-resistant bacteria isolated from burn patients. Therefore, a HAM was decellularized and tested for its antibacterial activity. Decellularization of the tissue was confirmed by hematoxylin and eosin (H&E) and 4,6-diamidino-2-phenylindole (DAPI) staining. In addition, the cyto-biocompatibility of the acellular HAM was proven by the cell viability test (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, MTT) and scanning electron microscopy (SEM). The resistant bacteria were isolated from burns, identified, and tested for their susceptibility to antibiotics using both the antibiogram and polymerase chain reaction (PCR) techniques. Among the isolated bacteria, three blaIMP gene-positive Pseudomonas aeruginosa strains were chosen for their high resistance to the tested antibiotics. The antibacterial activity of the HAM was also tested for Klebsiella pneumoniae (American Type Culture Collection (ATCC) 700603) as a resistant ATCC bacterium; Staphylococcus aureus (mecA positive); and three standard strains of ATCC bacteria including Escherichia coli (ATCC 25922), Pseudomonas aeruginosa (ATCC 27833), and S. aureus (ATCC 25923). Antibacterial assay revealed that only the latter three bacteria were susceptible to the HAM. All the data obtained from this study suggest that an alternative strategy is required to complement HAM grafting in order to fully protect burns from nosocomial infections. PMID- 26048134 TI - Effect of Food on the Pharmacokinetics of Olaparib after Oral Dosing of the Capsule Formulation in Patients with Advanced Solid Tumors. AB - BACKGROUND: The oral, potent poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, is well tolerated at doses of <=400 mg twice daily (BID) (administered as capsules), and has shown efficacy in patients with advanced BRCA-mutated ovarian and breast cancer. METHODS: This Phase I, open-label, randomized trial investigates the effect of food on the pharmacokinetics of olaparib in patients with refractory/resistant advanced solid tumors. In Part A, a three-period crossover study, patients received a single oral dose of olaparib 400 mg (8 * 50 mg capsules) in three prandial states: fasted, a high-fat meal or a standard meal (with a 5-14 day washout). Blood samples for pharmacokinetic (PK) assessments were taken pre-dose and up to 72 h post-dose. After completing Part A, patients could enter Part B, where they would receive olaparib 400 mg BID. RESULTS: 32 patients were randomized; 31 contributed to the PK statistical analysis and entered Part B. The presence of food slowed the rate of absorption (time to maximal plasma concentration [t max] was delayed by ~2 h). Maximum plasma concentration (C max) was increased by 10% following a standard meal and was unchanged with a high-fat meal (ratio of geometric means [90% confidence interval (CI)]: 1.10 [1.02-1.20] for standard and 1.00 [0.92-1.09] for high-fat meal). The extent of olaparib absorption (AUC) was increased by ~20% in the fed state (ratio of geometric means: 1.21 [1.10-1.33] for standard and 1.19 [1.08-1.31] for high fat meal). CONCLUSIONS: The presence of food decreased the rate and increased the extent of absorption of olaparib following oral dosing of the capsule formulation. However, the effects of food on olaparib PK were not deemed clinically important, according to predefined criteria. Safety data were consistent with the known safety profile of olaparib. FUNDING: AstraZeneca. PMID- 26048135 TI - Migration-related detention centers: the challenges of an ecological perspective with a focus on justice. AB - BACKGROUND: In recent years, border control and migration-related detention have become increasingly widespread practices affecting the lives of undocumented migrants, their families, and communities at large. In spite of the concern within academia, few studies have directly witnessed the life and experiences of people confined to migration-related detention centers. In the medical and psychological fields, a considerable body of research has demonstrated the pathogenic nature of detention in terms of mental health, showing an association between length of detention and severity of distress. Nevertheless, it was limited to the assessment of individuals' clinical consequences, mainly focusing on asylum seekers. There currently exists a need to adopt an ecological perspective from which to study detained migrants' experiences as context dependent, and influenced by power inequalities. This paper addresses this gap. DISCUSSION: Drawing upon advances in community psychology, we illustrate an ecological framework for the study of migration-related detention contexts, and their effects on the lives of detained migrants and all people exposed to them. Making use of existing literature, Kelly's four principles (interdependence, cycling of resources, adaptation, succession) are analyzed at multiple ecological levels (personal, interpersonal, organizational, communal), highlighting implications for future research in this field. A focus on justice, as a key dimension of analysis, is also discussed. Wellbeing is acknowledged as a multilevel, dynamic, and value-dependent phenomenon. SUMMARY: In presenting this alternative framework, the potential for studying migration-related detention through an ecological lens is highlighted, pointing the way for future fields of study. We argue that ecological multilevel analyses, conceptualized in terms of interdependent systems and with a focus on justice, can enhance the comprehension of the dynamics at play in migration-related detention centers, providing an effective tool to address the multi-level challenges of doing research within them. Furthermore, they can contribute to the development of policies and practices concerned with health, equality, and human rights of all people exposed to migration-related detention. Consistent with these assumptions, empirical studies adopting such a framework are strongly encouraged. These studies should use mixed and multi-method culturally situated designs, based on the development of collaborative and empowering relationships with participants. Ethnographic approaches are recommended. PMID- 26048136 TI - The Cytosolic Sensor cGAS Detects Mycobacterium tuberculosis DNA to Induce Type I Interferons and Activate Autophagy. AB - Type I interferons (IFNs) are critical mediators of antiviral defense, but their elicitation by bacterial pathogens can be detrimental to hosts. Many intracellular bacterial pathogens, including Mycobacterium tuberculosis, induce type I IFNs following phagosomal membrane perturbations. Cytosolic M. tuberculosis DNA has been implicated as a trigger for IFN production, but the mechanisms remain obscure. We report that the cytosolic DNA sensor, cyclic GMP AMP synthase (cGAS), is required for activating IFN production via the STING/TBK1/IRF3 pathway during M. tuberculosis and L. pneumophila infection of macrophages, whereas L. monocytogenes short-circuits this pathway by producing the STING agonist, c-di-AMP. Upon sensing cytosolic DNA, cGAS also activates cell intrinsic antibacterial defenses, promoting autophagic targeting of M. tuberculosis. Importantly, we show that cGAS binds M. tuberculosis DNA during infection, providing direct evidence that this unique host-pathogen interaction occurs in vivo. These data uncover a mechanism by which IFN is likely elicited during active human infections. PMID- 26048138 TI - Mycobacterium tuberculosis Differentially Activates cGAS- and Inflammasome Dependent Intracellular Immune Responses through ESX-1. AB - Cytosolic detection of microbial products is essential for the initiation of an innate immune response against intracellular pathogens such as Mycobacterium tuberculosis (Mtb). During Mtb infection of macrophages, activation of cytosolic surveillance pathways is dependent on the mycobacterial ESX-1 secretion system and leads to type I interferon (IFN) and interleukin-1beta (IL-1beta) production. Whereas the inflammasome regulates IL-1beta secretion, the receptor(s) responsible for the activation of type I IFNs has remained elusive. We demonstrate that the cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) is essential for initiating an IFN response to Mtb infection. cGAS associates with Mtb DNA in the cytosol to stimulate cyclic GAMP (cGAMP) synthesis. Notably, activation of cGAS-dependent cytosolic host responses can be uncoupled from inflammasome activation by modulating the secretion of ESX-1 substrates. Our findings identify cGAS as an innate sensor of Mtb and provide insight into how ESX-1 controls the activation of specific intracellular recognition pathways. PMID- 26048137 TI - Cyclic GMP-AMP Synthase Is an Innate Immune DNA Sensor for Mycobacterium tuberculosis. AB - Activation of the DNA-dependent cytosolic surveillance pathway in response to Mycobacterium tuberculosis infection stimulates ubiquitin-dependent autophagy and inflammatory cytokine production, and plays an important role in host defense against M. tuberculosis. However, the identity of the host sensor for M. tuberculosis DNA is unknown. Here we show that M. tuberculosis activated cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) in macrophages to produce cGAMP, a second messenger that activates the adaptor protein stimulator of interferon genes (STING) to induce type I interferons and other cytokines. cGAS localized with M. tuberculosis in mouse and human cells and in human tuberculosis lesions. Knockdown or knockout of cGAS in human or mouse macrophages blocked cytokine production and induction of autophagy. Mice deficient in cGAS were more susceptible to lethality caused by infection with M. tuberculosis. These results demonstrate that cGAS is a vital innate immune sensor of M. tuberculosis infection. PMID- 26048139 TI - Carboxybetaine Modified Interface for Electrochemical Glycoprofiling of Antibodies Isolated from Human Serum. AB - Impedimetric lectin biosensors capable of recognizing two different carbohydrates (galactose and sialic acid) in glycans attached to antibodies isolated from human serum were prepared. The first step entailed the modification of a gold surface by a self-assembled monolayer (SAM) deposited from a solution containing a carboxybetaine-terminated thiol applied to the subsequent covalent immobilization of lectins and to resist nonspecific protein adsorption. In the next step, Sambucus nigra agglutinin (SNA) or Ricinus communis agglutinin (RCA) was covalently attached to the SAM, and the whole process of building a bioreceptive layer was optimized and characterized using a diverse range of techniques including electrochemical impedance spectroscopy, cyclic voltammetry, quartz crystal microbalance, contact angle measurements, zeta-potential assays, X-ray photoelectron spectroscopy, and atomic force microscopy. In addition, the application of the SNA-based lectin biosensor in the glycoprofiling of antibodies isolated from the human sera of healthy individuals and of patients suffering from rheumatoid arthritis (RA) was successfully validated using an SNA-based lectin microarray. The results showed that the SNA lectin, in particular, is capable of discriminating between the antibodies isolated from healthy individuals and those from RA patients based on changes in the amount of sialic acid present in the antibodies. In addition, the results obtained by the application of RCA and SNA biosensors indicate that the abundance of galactose and sialic acid in antibodies isolated from healthy individuals is age-related. PMID- 26048140 TI - Perceived social support disparities among children affected by HIV/AIDS in Ghana: a cross-sectional survey. AB - BACKGROUND: The study investigated whether perceived social support varied among children who have lost their parents to AIDS, those who have lost their parents to other causes, those who are living with HIV/AIDS-infected caregivers and children from intact families (comparison group). METHOD: This study employed cross-sectional, quantitative survey that involved 291 children aged 10-18 years in the Lower Manya Krobo District of Ghana and examined their social support disparities. RESULTS: Multivariate linear regressions indicate that children living with HIV/AIDS-infected caregivers reported significantly lower levels of social support compared with AIDS-orphaned children, other-orphaned children and non-orphaned children independent of socio-demographic covariates. Children who have lost their parents to other causes and other-orphaned children reported similar levels of social support. In terms of sources of support, all children orphans and vulnerable children were more likely to draw support from friends and significant others rather than from the family. CONCLUSION: The findings indicate a need to develop interventions that can increase levels of social support for orphaned and vulnerable children within the context of HIV/AIDS in Ghana, particularly networks that include the family. PMID- 26048142 TI - Inactivation of the ubiquitin-specific protease 19 deubiquitinating enzyme protects against muscle wasting. AB - The ubiquitin system plays a critical role in muscle wasting. Previous work has focused on the roles of ubiquitination. However, a role for deubiquitination in this process has not been established. Because ubiquitin-specific protease (USP)19 deubiquitinating enzyme is induced in skeletal muscle in many catabolic conditions, we generated USP19 knockout (KO) mice. These mice lost less muscle mass than wild-type (WT) animals in response to glucocorticoids, a common systemic cause of muscle atrophy as well as in response to denervation, a model of disuse atrophy. KO mice retained more strength and had less myofiber atrophy with both type I and type IIb fibers being protected. Rates of muscle protein synthesis were similar in WT and KO mice, suggesting that the sparing of atrophy was attributed to suppressed protein degradation. Consistent with this, expression of the ubiquitin ligases MuRF1 and MAFbx/atrogin-1 as well as several autophagy genes was decreased in the muscles of catabolic KO mice. Expression of USP19 correlates with that of MuRF1 and MAFbx/atrogin-1 in skeletal muscles from patients with lung cancer or gastrointestinal cancer, suggesting that USP19 is involved in human muscle wasting. Inhibition of USP19 may be a useful approach to the treatment of many muscle-wasting conditions. PMID- 26048141 TI - Actin-bundling protein plastin 3 is a regulator of ectoplasmic specialization dynamics during spermatogenesis in the rat testis. AB - Ectoplasmic specialization (ES) is an actin-rich adherens junction in the seminiferous epithelium of adult mammalian testes. ES is restricted to the Sertoli-spermatid (apical ES) interface, as well as the Sertoli cell-cell (basal ES) interface at the blood-testis barrier (BTB). ES is typified by the presence of an array of bundles of actin microfilaments near the Sertoli cell plasma membrane. These actin microfilament bundles require rapid debundling to convert them from a bundled to branched/unbundled configuration and vice versa to confer plasticity to support the transport of 1) spermatids in the adluminal compartment and 2) preleptotene spermatocytes at the BTB while maintaining cell adhesion. Plastin 3 is one of the plastin family members abundantly found in yeast, plant and animal cells that confers actin microfilaments their bundled configuration. Herein, plastin 3 was shown to be a component of the apical and basal ES in the rat testis, displaying spatiotemporal expression during the epithelial cycle. A knockdown (KD) of plastin 3 in Sertoli cells by RNA interference using an in vitro model to study BTB function showed that a transient loss of plastin 3 perturbed the Sertoli cell tight junction-permeability barrier, mediated by changes in the localization of basal ES proteins N-cadherin and beta-catenin. More importantly, these changes were the result of an alteration of the actin microfilaments, converting from their bundled to branched configuration when examined microscopically, and validated by biochemical assays that quantified actin-bundling and polymerization activity. Moreover, these changes were confirmed by studies in vivo by plastin 3 KD in the testis in which mis localization of N-cadherin and beta-catenin was also detected at the BTB, concomitant with defects in the transport of spermatids and phagosomes and a disruption of cell adhesion most notably in elongated spermatids due to a loss of actin-bundling capability at the apical ES, which in turn affected localization of adhesion protein complexes at the site. In summary, plastin 3 is a regulator of actin microfilament bundles at the ES in which it dictates the configuration of the filamentous actin network by assuming either a bundled or unbundled/branched configuration via changes in its spatiotemporal expression during the epithelial cycle. PMID- 26048143 TI - A standard cytogenetic map of Culex quinquefasciatus polytene chromosomes in application for fine-scale physical mapping. AB - BACKGROUND: Southern house mosquito Culex quinquefasciatus belongs to the C. pipiens cryptic species complex, with global distribution and unclear taxonomy. Mosquitoes of the complex can transmit human and animal pathogens, such as filarial worm, West Nile virus and avian malarial Plasmodium. Physical gene mapping is crucial to understanding genome organization, function, and systematic relationships of cryptic species, and is a basis for developing new vector control strategies. However, physical mapping was not established previously for Culex due to the lack of well-structured polytene chromosomes. METHODS: Inbreeding was used to diminish inversion polymorphism and asynapsis of chromosomal homologs. Identification of larvae of the same developmental stage using the shape of imaginal discs allowed achievement of uniformity in chromosomal banding pattern. This together with high-resolution phase-contrast photography enabled the development of a cytogenetic map. Fluorescent in situ hybridization was used for gene mapping. RESULTS: A detailed cytogenetic map of C. quinquefasciatus polytene chromosomes was produced. Landmarks for chromosome recognition and cytological boundaries for two inversions were identified. Locations of 23 genes belonging to 16 genomic supercontigs, and 2 cDNA were established. Six supercontigs were oriented and one was found putatively misassembled. The cytogenetic map was linked to the previously developed genetic linkage groups by corresponding positions of 2 genetic markers and 10 supercontigs carrying genetic markers. Polytene chromosomes were numbered according to the genetic linkage groups. CONCLUSIONS: This study developed a new standard cytogenetic photomap of the polytene chromosomes for C. quinquefasciatus and was applied for the fine-scale physical mapping. It allowed us to infer chromosomal position of 1333 of annotated genes belonging to 16 genomic supercontigs and find orientation of 6 of these supercontigs; the new cytogenetic and previously developed genetic linkage maps were integrated based on 12 matches. The map will further assist in finding chromosomal position of the medically important and other genes, contributing into improvement of the genome assembly. Better assembled C. quinquefasciatus genome can serve as a reference for studying other vector species of C. pipiens complex and will help to resolve their taxonomic relationships. This, in turn, will contribute into future development of vector and disease control strategies. PMID- 26048144 TI - Multifarious immunotherapeutic approaches to cure HIV-1 infection. AB - Immunotherapy in the context of treated HIV-1 infection aims to improve immune responses to achieve better control of the virus. To date, multifaceted immunotherapeutic approaches have been shown to reduce immune activation and increase CD4 T-lymphocyte counts, further to the effects of antiretroviral therapy alone, in addition to improving HIV-1-specific T-cell responses. While sterilizing cure of HIV-1 would involve elimination of all replication-competent virus, a functional cure in which the host has long-lasting control of viral replication may be more feasible. In this commentary, we discuss novel strategies aimed at targeting the latent viral reservoir with cure of HIV-1 infection being the ultimate goal, an achievement that would have considerable impact on worldwide HIV-1 infection. PMID- 26048145 TI - The Role of Transanal Surgery in the Management of T1 Rectal Cancers. AB - The management of T1 rectal cancers is based on finding the balance between optimal oncologic outcomes and acceptable functional results for the patient. While radical resection involving a proctectomy is considered the most oncologically adequate option, its adverse effects on patient reported outcomes makes this a less than ideal choice in certain circumstances. While local excision can circumvent some of the adverse functional outcomes, its inadequacy in assessing metastatic lymph node disease and the subsequent negative impact of untreated positive lymph nodes on patient prognosis is a cause for concern. As a result, the therapeutic strategy has to be based on patient and disease-related factors in order to identify the best treatment choice that maximizes survival benefit and preserves health-related quality of life. After adequate preoperative staging work up, in selected patients with favorable pathological features, local excision can be considered. These cancers can be removed by transanal local excision or transanal endoscopic microsurgery, depending on the location of the cancer and expertise available. While perioperative morbidity is minimal, close postoperative follow-up is essential. PMID- 26048146 TI - Attenuation of Cardiac Dysfunction in Polymicrobial Sepsis by MicroRNA-146a Is Mediated via Targeting of IRAK1 and TRAF6 Expression. AB - Cardiac dysfunction is a major consequence of sepsis/septic shock and contributes to the high mortality of sepsis. Innate and inflammatory responses mediated by TLRs play a critical role in sepsis-induced cardiac dysfunction. MicroRNA-146 (miR-146) was first identified as a negative regulator in innate immune and inflammatory responses induced by LPS. This study examined whether miR-146a will have a protective effect on sepsis-induced cardiac dysfunction. Lentivirus expressing miR-146a (LmiR-146a) or lentivirus-expressing scrambled miR (LmiR control) was delivered into the myocardium via the right carotid artery. Seven days after transfection, mice were subjected to cecal ligation and puncture (CLP). Untransfected mice were also subjected to CLP-induced sepsis. Cardiac function was examined by echocardiography before and 6 h after CLP. In vitro studies showed that increased miR-146a levels suppress LPS-induced IkappaBalpha phosphorylation and inflammatory cytokine production in both H9C2 cardiomyocytes and J774 macrophages. In vivo transfection of LmiR-146a attenuated sepsis-induced cardiac dysfunction. The values for percent ejection fraction and percent fractional shortening in LmiR-146a-transfected CLP mice were significantly greater than in untransfected CLP control. LmiR-146a transfection prevented sepsis-induced NF-kappaB activity, suppressed IRAK and TRAF6 expression in the myocardium, and attenuated sepsis-induced inflammatory cytokine production in both plasma and peritoneal fluid. In addition, LmiR-146a transfection decreased sepsis-induced infiltration of neutrophils and macrophages into the myocardium. LmiR-146a can also transfect macrophages in the periphery. We conclude that miR 146a attenuates sepsis-induced cardiac dysfunction by preventing NF-kappaB activation, inflammatory cell infiltration, and inflammatory cytokine production via targeting of IRAK and TRAF6 in both cardiomyocytes and inflammatory monocytic cells. PMID- 26048147 TI - HY-Specific Induced Regulatory T Cells Display High Specificity and Efficacy in the Prevention of Acute Graft-versus-Host Disease. AB - Naturally derived regulatory T cells (Tregs) may prevent graft-versus-host disease (GVHD) while preserving graft-versus-leukemia (GVL) activity. However, clinical application of naturally derived regulatory T cells has been severely hampered by their scarce availability and nonselectivity. To overcome these limitations, we took alternative approaches to generate Ag-specific induced Tregs (iTregs) and tested their efficacy and selectivity in the prevention of GVHD in preclinical models of bone marrow transplantation. We selected HY as a target Ag because it is a naturally processed, ubiquitously expressed minor histocompatibility Ag (miHAg) with a proven role in GVHD and GVL effect. We generated HY-specific iTregs (HY-iTregs) from resting CD4 T cells derived from TCR transgenic mice, in which CD4 cells specifically recognize HY peptide. We found that HY-iTregs were highly effective in preventing GVHD in male (HY(+)) but not female (HY(-)) recipients using MHC II-mismatched, parent->F1, and miHAg mismatched murine bone marrow transplantation models. Interestingly, the expression of target Ag (HY) on the hematopoietic or nonhematopoietic compartment alone was sufficient for iTregs to prevent GVHD. Furthermore, treatment with HY iTregs still preserved the GVL effect even against pre-established leukemia. We found that HY-iTregs were more stable in male than in female recipients. Furthermore, HY-iTregs expanded extensively in male but not female recipients, which in turn significantly reduced donor effector T cell expansion, activation, and migration into GVHD target organs, resulting in effective prevention of GVHD. This study demonstrates that iTregs specific for HY miHAgs are highly effective in controlling GVHD in an Ag-dependent manner while sparing the GVL effect. PMID- 26048148 TI - Cutting Edge: PD-1 Regulates Imiquimod-Induced Psoriasiform Dermatitis through Inhibition of IL-17A Expression by Innate gammadelta-Low T Cells. AB - Programmed cell death 1 (PD-1) is a key regulatory molecule that has been targeted in human cancers, including melanoma. In clinical testing, Abs against PD-1 have resulted in psoriasiform dermatitis (PsD). To determine whether PD-1 regulates PsD, we compared skin responses of PD-1-deficient (PD-1KO) mice and wild-type (WT) controls in an imiquimod (IMQ)-induced murine model of psoriasis. PD-1KO mice showed severe epidermal hyperplasia, greater neutrophilic infiltration, and higher expression of Th17 cytokines (versus WT mice). IMQ exposure increased PD-1 expression by skin gammadelta-low (GDL) T cells and enhanced expression of PD-L1 by keratinocytes. Three-fold increases in the percentage of IL-17A(+) GDL T cells were observed in skin cell suspensions derived from IMQ-treated PD-1KO mice (versus WT controls), suggesting that the lack of PD-1 has a functional effect not only on alphabeta T cells, but also on GDL T cells, and that PD-1 may play a regulatory role in PsD. PMID- 26048150 TI - Evaluation of quantitative polymerase chain reaction markers for the detection of breast cancer cells in ovarian tissue stored for fertility preservation. AB - OBJECTIVE: To develop molecular tools increasing the sensitivity of breast cancer micrometastases detection within ovarian tissue cryopreserved for fertility preservation. DESIGN: Expression of breast markers was evaluated by quantitative polymerase chain reaction in ovarian tissue from patients with benign or cancerous diseases. Suspected tissues were long-term xenografted into mice. SETTING: Academic research institute. PATIENT(S): Patients undergoing a fertility preservation procedure. INTERVENTION(S): Ovarian tissue was processed for RNA extraction and quantitative polymerase chain reaction analysis. Cryopreserved ovarian cortex from patients with breast cancer or benign disease was grafted for 6 months into severe combined immunodeficiency mice. MAIN OUTCOMES MEASURE(S): Predictive values of mammaglobin 1 (MGB-1), gross cystic disease fluid protein-15 (GCDFP-15), small breast epithelial mucine (SBEM), and mammaglobin 2 (MGB-2) to detect breast cancer cells in ovarian tissue, and the potential development of cancerous disease after xenograft of ovarian cortex from breast cancer patients. RESULT(S): MGB-1 and GCDFP-15 presented the highest predictive values to detect breast cancer micrometastases in the ovarian cortex, with an efficiency reaching 100% and 77%, respectively. The MGB-2 assay resulted in a high false-positive rate (47%) in the ovarian cortex but could be used to detect breast cancer cells in ovarian medulla. MGB-1 was detected in three of five ovarian cortex samples from early-stage breast cancer patients but not in the ovarian tissue from advanced breast cancer patients (none of 10). None of the mice grafted with ovarian tissue expressing these markers developed cancerous disease. CONCLUSION(S): MGB-1, GCDFP-15, and MGB-2 can serve as molecular markers for the detection of breast cancer micrometastases within the ovarian tissue of breast cancer patients. However, the clinical relevance of such a highly sensitive assay must be further investigated. PMID- 26048149 TI - Metabolomic Endotype of Asthma. AB - Metabolomics, the quantification of small biochemicals in plasma and tissues, can provide insight into complex biochemical processes and enable the identification of biomarkers that may serve as therapeutic targets. We hypothesized that the plasma metabolome of asthma would reveal metabolic consequences of the specific immune and inflammatory responses unique to endotypes of asthma. The plasma metabolomic profiles of 20 asthmatic subjects and 10 healthy controls were examined using an untargeted global and focused metabolomic analysis. Individuals were classified based on clinical definitions of asthma severity or by levels of fraction of exhaled NO (FENO), a biomarker of airway inflammation. Of the 293 biochemicals identified in the plasma, 25 were significantly different among asthma and healthy controls (p < 0.05). Plasma levels of taurine, lathosterol, bile acids (taurocholate and glycodeoxycholate), nicotinamide, and adenosine-5 phosphate were significantly higher in asthmatics compared with healthy controls. Severe asthmatics had biochemical changes related to steroid and amino acid/protein metabolism. Asthmatics with high FENO, compared with those with low FENO, had higher levels of plasma branched-chain amino acids and bile acids. Asthmatics have a unique plasma metabolome that distinguishes them from healthy controls and points to activation of inflammatory and immune pathways. The severe asthmatic and high FENO asthmatic have unique endotypes that suggest changes in NO-associated taurine transport and bile acid metabolism. PMID- 26048151 TI - Fellowship training and board certification in reproductive endocrinology and infertility. AB - Reproductive endocrinology and infertility (REI) is one of the original officially recognized subspecialties in obstetrics and gynecology and among the earlier subspecialties in medicine. Recognized by the American Board of Obstetrics and Gynecology in 1972, fellowship programs are now 3 years in length following an obstetrics and gynecology residency. Originally focused on endocrine problems related to reproductive function, the assisted reproductive technologies (ART) have recently become the larger part of training during REI fellowships. It is likely that the subspecialty of REI strengthens the specialty of obstetrics and gynecology and enhances the educational experience of residents in the field. The value of training and certification in REI is most evident in the remarkable and consistent improvement in the success of ART procedures, particularly in vitro fertilization. The requirement for documented research activity during REI fellowships is likely to stimulate a more rapid adoption (translation) of newer research findings into clinical care after training. Although mandatory reporting of outcomes has been proposed as a reason for this improvement the rapid translation of reproductive research into clinical practice is likely to be a major cause. Looking forward, REI training should emphasize and strengthen education and research into the endocrine, environmental, and genetic aspects of female and male reproduction to improve the reproductive health and fertility of all women. PMID- 26048152 TI - Differences in the seminal plasma proteome are associated with oxidative stress levels in men with normal semen parameters. AB - OBJECTIVE: To study the seminal plasma proteome in association with semen lipid peroxidation levels in men with normal semen parameters. DESIGN: Cross-sectional study. SETTING: University andrology and research laboratories. PATIENT(S): A total of 156 normozoospermic men. INTERVENTION(S): Seminal lipid peroxidation levels were assessed in individual samples through thiobarbituric acid reactive substances quantification. Subsequently, lipid peroxidation data were used to divide the samples into the experimental groups: low lipid peroxidation levels (control group, bottom 15%, n = 23) and high lipid peroxidation levels (study group, top 15%, n = 23). Seminal plasma proteins from these groups were pooled (four pools per group, with biological variation between the pools) and used for a shotgun proteomic analysis using a liquid chromatography-tandem mass spectrometry approach. Quantitative data were used for univariate (unpaired Student's t test) and multivariate (partial least-squares discriminant analysis, logistic regression, and discriminant analyses) statistical analyses. Significant proteins were also used for functional enrichment analysis. MAIN OUTCOME MEASURE(S): Seminal plasma protein profile and postgenomic pathways of seminal plasma are associated with seminal lipid peroxidation levels. RESULT(S): In total, 629 proteins were quantified in seminal plasma. Of these, 23 proteins were absent or underexpressed and 71 were exclusive or overexpressed in the study group. The main enriched functions in association with seminal lipid peroxidation were unsaturated fatty acids biosynthesis, oxidants and antioxidants activity, cellular response to heat stress, and immune response. Moreover, we suggested mucin-5B as a potential biomarker of semen oxidative stress. CONCLUSION(S): The seminal plasma proteome does reflect semen lipid peroxidation status and, thus, oxidative stress. PMID- 26048153 TI - When treatment appears futile: the role of the mental health professional and end of-treatment counseling. AB - The end of treatment, whether initiated by the medical team or by the patient, represents a difficult transition for the patient. The mental health professional, as part of a multidisciplinary team, can offer important assistance and support to the patient as they move through the end of their infertility treatment. A description of the topics covered in exit counseling is provided, as well as indications for referral. PMID- 26048154 TI - Subspecialty training in andrology. AB - The field of andrology has evolved significantly in both Europe and the United States over the past 30 years. Although andrology fellowship training programs in these two regions share some common aspects, there are substantial differences as well. Andrology is a broader field in Europe, with andrology fellowship training incorporating topics such as prostate disease, testicular cancer, and genitourinary infection/inflammation. In the United States, these issues are more commonly taught during urology residency, with andrology fellowship training focusing more commonly on male sexual and reproductive health. Finally, European and American fellowship training is compared and contrasted in terms of certification and accreditation procedures, with a look toward the future in each region. PMID- 26048155 TI - Infertility counseling (or the lack thereof) of the forgotten male partner. AB - Men with infertility represent a significant percentage of the infertile population. However, public awareness of this fact is limited at best. Literature and other media have neglected the male component of reproduction other than its sexual nature. Men's emotional reactions to a diagnosis of infertility have been studied far less than those of women. However, there is a growing body of research indicating that men do feel the loss associated with a failure to conceive and have unique methods of adapting. At the same time resources available for infertile men are limited or underutilized. Several factors contribute to the underutilization, including narrow awareness, lack of high visibility individuals willing to speak about the problem, and male avoidance of mental health services. Suggestions for improving this situation are offered. PMID- 26048156 TI - Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington's disease. AB - Huntington's disease (HD) is caused by an expansion of glutamine repeats in the huntingtin protein (mHtt) that invokes early and prominent damage of the striatum, a region that controls motor behaviors. Despite its ubiquitous expression, why certain brain regions, such as the cerebellum, are relatively spared from neuronal loss by mHtt remains unclear. Previously, we implicated the striatal-enriched GTPase, Rhes (Ras homolog enriched in the striatum), which binds and SUMOylates mHtt and increases its solubility and cellular cytotoxicity, as the cause for striatal toxicity in HD. Here, we report that Rhes deletion in HD mice (N171-82Q), which express the N-terminal fragment of human Htt with 82 glutamines (Rhes(-/-)/N171-82Q), display markedly reduced HD-related behavioral deficits, and absence of lateral ventricle dilatation (secondary to striatal atrophy), compared to control HD mice (N171-82Q). To further validate the role of GTPase Rhes in HD, we tested whether ectopic Rhes expression would elicit a pathology in a brain region normally less affected in HD. Remarkably, ectopic expression of Rhes in the cerebellum of N171-82Q mice, during the asymptomatic period led to an exacerbation of motor deficits, including loss of balance and motor incoordination with ataxia-like features, not apparent in control-injected N171-82Q mice or Rhes injected wild-type mice. Pathological and biochemical analysis of Rhes-injected N171-82Q mice revealed a cerebellar lesion with marked loss of Purkinje neuron layer parvalbumin-immunoreactivity, induction of caspase 3 activation, and enhanced soluble forms of mHtt. Similarly reintroducing Rhes into the striatum of Rhes deleted Rhes(-/-)Hdh(150Q/150Q) knock-in mice, elicited a progressive HD-associated rotarod deficit. Overall, these studies establish that Rhes plays a pivotal role in vivo for the selective toxicity of mHtt in HD. PMID- 26048157 TI - Prevalence and modes of complementary and alternative medicine use among peasant farmers with musculoskeletal pain in a rural community in South-Western Nigeria. AB - BACKGROUND: Anecdotally, use of Complementary and Alternative Medicine (CAM) for Musculoskeletal Pain (MSP) is common in Nigeria; however, there seems to be a dearth of empirical data on its prevalence and mode of use. This study investigated the prevalence and modes of use of CAM for MSP among farmers in a rural community in South-western Nigeria. METHODS: This cross-sectional survey employed multistage sampling technique guidelines for conducting community survey by the World Health Organization among rural community farmers in Gudugbu village, Oyo State, Nigeria. A questionnaire developed from previous studies and validated by expert reviews was used to assess prevalence and modes of CAM use. Data was analyzed using descriptive and inferential statistics. Alpha level was set at p < 0.05. RESULTS: A total of 230 consenting rural farmers volunteered for this study with a valid response rate of 93.9 % (n = 216). The lifetime, 12-month and point prevalence of CAM for MSP was 96.8 % respectively. Herbal therapy and massage were the predominant types of CAM therapies among previous (83.8 and 80.1 %) and current CAM users (37.5 and 37.5 %). CAM was largely used as sole therapy for MSP (75.5 %) and also in combination with orthodox medicine (23.6 %), and it is consumed on daily basis (21.8 %). CAM was perceived to be very good in maintaining a healthy life (87.1 %) and has less side effects (74 %) and more healthy than taking doctors' prescriptions (63.4 %). CONCLUSION: There is a high prevalence of CAM among Nigerian rural farmers. The most commonly employed CAM for MSP were herbal remedies and massage which are attributable to beliefs on their perceived efficacy. PMID- 26048158 TI - Asymmetric saccade reaction times to smooth pursuit. AB - Before initiating a saccade to a moving target, the brain must take into account the target's eccentricity as well as its movement direction and speed. We tested how the kinematic characteristics of the target influence the time course of this oculomotor response. Participants performed a step-ramp task in which the target object stepped from a central to an eccentric position and moved at constant velocity either to the fixation position (foveopetal) or further to the periphery (foveofugal). The step size and target speed were varied. Of particular interest were trials that exhibited an initial saccade prior to a smooth pursuit eye movement. Measured saccade reaction times were longer in the foveopetal than in the foveofugal condition. In the foveopetal (but not the foveofugal) condition, the occurrence of an initial saccade, its reaction time as well as the strength of the pre-saccadic pursuit response depended on both the target's speed and the step size. A common explanation for these results may be found in the neural mechanisms that select between oculomotor response alternatives, i.e., a saccadic or smooth response. PMID- 26048159 TI - Position sense at the human forearm after conditioning elbow muscles with isometric contractions. AB - These experiments were designed to test the idea that, in a forearm position matching task, it is the difference in afferent signals coming from the antagonist muscles of the forearm that determines the perceived position of the arm. In one experiment, flexor and then extensor muscles of the reference arm were conditioned by isometric voluntary contractions while the arm was held at the test angle, approximately 45 degrees from the horizontal. At the same time, indicator arm flexor muscles were contracted while the arm was flexed, or extensors were contracted while it was extended. After an indicator flexor contraction, during matching, subjects made large errors in the direction of flexion, by 9.3 degrees relative to the reference arm and after an indicator extensor contraction by 7.4 degrees in the direction of extension. In the second experiment, with reference muscles conditioned as before, slack was introduced in indicator muscles by a combination of muscle contraction and stretch. This was expected to lower levels of afferent activity in indicator muscles. The subsequent matching experiment yielded much smaller errors than before, 1.4 degrees in the direction of flexion. In both experiments, signal levels coming from the reference arm remained the same and what changed was the level of indicator signal. The fact that matching errors were small when slack was introduced in indicator muscles supported the view that the signal coming from reference muscles was also small. It was concluded that the brain is concerned with the signal difference from the antagonist pair of each arm and with the total signal difference between the two arms. PMID- 26048160 TI - Modulation of soleus corticospinal excitability during Achilles tendon vibration. AB - Soleus (SOL) corticospinal excitability has been reported to increase during Achilles tendon vibration. The aim of the present study was to further investigate SOL corticospinal excitability and elucidate the changes to intracortical mechanisms during Achilles tendon vibration. Motor-evoked potentials (MEPs) were elicited in the SOL by transcranial magnetic stimulation (TMS) of the corresponding motor cortical area of the leg with and without 50-Hz Achilles tendon vibration. SOL input-output curves were determined. Paired-pulse protocols were also performed to investigate short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) by conditioning test TMS pulses with sub-threshold TMS pulses at inter-stimulus intervals of 3 and 13 ms, respectively. During Achilles tendon vibration, motor threshold was lower than in the control condition (43 +/- 13 vs. 49 +/- 11 % of maximal stimulator output; p = 0.008). Input-output curves were also influenced by vibration, i.e. there was increased maximal MEP amplitude (0.694 +/- 0.347 vs. 0.268 +/- 0.167 mV; p < 0.001), decreased TMS intensity to elicit a MEP of half the maximal MEP amplitude (100 +/- 13 vs. 109 +/- 9 % motor threshold; p = 0.009) and a strong tendency for decreased slope constant (0.076 +/- 0.04 vs. 0.117 +/- 0.04; p = 0.068). Vibration reduced ICF (98 +/- 61 vs. 170 +/- 105 % of test MEP amplitude; p = 0.05), but had no effect on SICI (53 +/- 26 vs. 48 +/- 22 % of test MEP amplitude; p = 0.68). The present results further document the increased vibration-induced corticospinal excitability in the soleus muscle and suggest that this increase is not mediated by changes in SICI or ICF. PMID- 26048161 TI - Neural correlates underlying insight problem solving: Evidence from EEG alpha oscillations. AB - Previous studies on insight problem solving using Chinese logogriphs as insight problems only investigated the time- and phase-locked changes of electrocortical responses triggered by Chinese logogriphs, but did not focus on what kind of brain state facilitates individuals to solve insight problems. To investigate this, we focused on participants' alpha activities (8-12 Hz) that closely correlates with insight problem solving and defocused attention while they were solving Chinese logogriphs. Results indicated that in the time window of 800-1400 ms after the presentation of target logogriphs, alpha power over parieto-central electrodes decreased relative to the reference interval in both the successful and unsuccessful logogriphs solving conditions. However, alpha power increased at parieto-occipital electrode sites in successful conditions compared with that in unsuccessful condition. The decrease in alpha activity in both conditions may reflect the cognitive demands in solving the target logogriphs. Furthermore, difference in alpha power between the successful and unsuccessful conditions at parieto-occipital electrode sites is associated with the process of heuristic information. Alpha synchronization observed in the successful condition compared to the unsuccessful condition might reflect a state of defocused attention that facilitates insight problem solving. PMID- 26048162 TI - School-aged children can benefit from audiovisual semantic congruency during memory encoding. AB - Although we live in a multisensory world, children's memory has been usually studied concentrating on only one sensory modality at a time. In this study, we investigated how audiovisual encoding affects recognition memory. Children (n = 114) from three age groups (8, 10 and 12 years) memorized auditory or visual stimuli presented with a semantically congruent, incongruent or non-semantic stimulus in the other modality during encoding. Subsequent recognition memory performance was better for auditory or visual stimuli initially presented together with a semantically congruent stimulus in the other modality than for stimuli accompanied by a non-semantic stimulus in the other modality. This congruency effect was observed for pictures presented with sounds, for sounds presented with pictures, for spoken words presented with pictures and for written words presented with spoken words. The present results show that semantically congruent multisensory experiences during encoding can improve memory performance in school-aged children. PMID- 26048164 TI - For the Boys in the Family: An Investigation Into the Relationship Between "Honor"-Based Violence and Endogamy. AB - Germaine Tillion's classic work of ethnology My Cousin, My Husband related so called "honor"-based violence (HBV) to the institution of cousin marriage as a response to women's entitlement to inheritance within the Greater Mediterranean Region. This article will scrutinize Tillion's position using original survey data gathered in the Kurdistan region of Iraq, finding that although there is a correlation between HBV and cousin marriage, Tillion's association of this with inheritance laws is inadequate. An alternative position is proposed, in which the relationship between HBV and cousin marriage is situated in coercion around marriage, intergenerational tensions, and in-group exclusivity, exacerbated by the contemporary politics of nationalist neopatrimonialism and an economy based in oil rentierism. PMID- 26048165 TI - Evaluating factors and interventions that influence help-seeking and mental health service utilization among suicidal individuals: A review of the literature. AB - Connecting suicidal individuals to appropriate mental health care services is a key component of suicide prevention efforts. This review aims to critically discuss the extant literature on help-seeking and mental health service utilization among individuals at elevated risk for suicide, as well as to outline challenges and future directions for research in this area. Across studies, the rate of mental health service use for those with past-year suicide ideation, plans, and/or attempts was approximately 29.5% based on weighted averages, with a lack of perceived need for services, preference for self-management, fear of hospitalization, and structural factors (e.g., time, finances) identified as key barriers to care. Studies also revealed facilitators to care, which include mental health literacy, positive views of services, and encouragement from family or friends to seek support. To address these low rates of help-seeking and barriers to care, a number of interventions have been developed, including psychoeducation-based programs, peer and gatekeeper training, and screening-based approaches. Despite these efforts, it appears that work is still needed to gauge the impact of these interventions on behavioral outcomes and to more rigorously test their effectiveness. Additional implications for future research on help seeking among suicidal individuals are discussed. PMID- 26048163 TI - Temporal changes of light-induced proteins in the SCN following treatment with the serotonin mixed agonist/antagonist BMY7378. AB - The 5-HT1A mixed agonist/antagonist BMY7378 has been shown to greatly potentiate photic phase advances in hamsters. The underlying mechanism and intracellular changes in the suprachiasmatic nucleus (SCN) by which this potentiation is accomplished have yet to be fully determined. Here, we examine the effect of BMY7378 on temporal activation patterns of a number of proteins and enzymes in the SCN following light exposure in the late subjective night. BMY7378 administration increased the amount of several photo-inducible proteins in the SCN at specific time points following light exposure in the late subjective night. Relative to animals given saline before a light pulse, the number of cells immunoreactive for cFos, JunB and PER1 was all significantly greater 360 min following the light pulse in BMY7378 pretreated animals, indicating an extended action of these light-induced proteins in the SCN following BMY7378 pretreatment. Aside from a modest, nonsignificant increase in P-ERK levels at 60 min, BMY7378 did not affect light-induced P-ERK levels. The levels of light-induced P-CREB were similarly unaffected by BMY7378. Also unaffected by BMY7378 treatment were cFos expression and JunB expression at 120 and 180 min following light exposure. These findings suggest that BMY7378 may potentiate photic phase shifts at least partly by prolonging the activity of some, but not all, light-induced proteins and biochemical pathways involved in coupling the light signal to the output of the circadian clock, particularly those which are active many hours after the light signal reaches the SCN. PMID- 26048166 TI - The creation of a healthy eating motivation score and its association with food choice and physical activity in a cross sectional sample of Irish adults. AB - BACKGROUND: This study aimed to develop a healthy eating motivation score and to determine if dietary, lifestyle and activity behaviours vary across levels of motivation to eat a healthy diet with a view to informing health promotion interventions. METHODS: A cross-sectional survey of food intake, physical activity, lifestyles and food choice attitudes was conducted in a nationally representative sample of 1262 adults in the Republic of Ireland aged 18 years and over. RESULTS: Increasing score for health motivation was significantly and positively related to healthy eating and exercise. Women, increasing age, normal BMI, regular exercise and increasing intakes of fruit and vegetables were associated with a higher odds ratio (OR) for having a high healthy eating motivation score. However, despite a high motivation score only 31% of consumers in the strong motivation group achieved the recommendations for daily fruit and vegetable consumption, while 57% achieved the fat recommendation. A higher intake of calorie dense foods from the top shelf of the food pyramid and increased time spent watching T.V. was associated with a decreased OR for positive motivation towards healthy eating. CONCLUSIONS: Healthy eating promotions directed at women and older adults should focus on supporting people's motivations to attain a healthy diet by addressing issues such as dietary self-control and self regulation. For men and younger adults, healthy eating promotions will need to address the issues underlying their weak attitudes towards healthy eating. PMID- 26048167 TI - Analgesic use in a Norwegian general population: change over time and high-risk use--The Tromso Study. AB - BACKGROUND: Increased use of analgesics in the population is a cause for concern in terms of drug safety. There is a paucity of population-based studies monitoring the change in use over time of both non-prescription (OTC) analgesics and prescription (Rx) analgesics. Although much is known about the risks associated with analgesic use, we are lacking knowledge on high-risk use at a population level. The purpose of this study was to estimate the prevalence of non prescription and prescription analgesic use, change over time and the prevalence in the presence of potential contraindications and drug interactions in a general population. METHODS: A repeated cross-sectional study with data from participants (30-89 years) of the Tromso Study in 2001-02 (Tromso 5; N = 8039) and in 2007-08 (Tromso 6; N = 12,981). Participants reported use of OTC and Rx analgesics and regular use of all drugs in the preceding four weeks. Change over the time period was analyzed with generalized estimating equations. The prevalence of regular analgesic use in persons with or without a clinically significant contraindication or drug interaction was determined in the Tromso 6 population, and differences were tested with logistic regression. RESULTS: Analgesic use increased from 54 to 60% in women (OR = 1.24, 95% CI 1.15-1.32) and from 29 to 37% in men (OR = 1.39, 95% CI 1.27-1.52) in the time period; the increase was due to sporadic use of OTC analgesics. There was substantial regular use of analgesics in several of the contraindication categories examined; the prevalence of non-steroidal anti-inflammatory drugs was more than eight per cent among persons with chronic kidney disease, gastrointestinal ulcers, or high primary cardiovascular risk. About four per cent of the study population demonstrated at least one potential drug interaction with an analgesic drug. CONCLUSIONS: The use of analgesics increased in the time period due to an increase in the use of OTC analgesics. Analgesic exposure in the presence of contraindications or drug interactions may put patients at risk. Public and prescriber awareness about clinically relevant contraindications and drug interactions with analgesics need to be increased. PMID- 26048168 TI - Evaluating Nicotine Craving, Withdrawal, and Substance Use as Mediators of Smoking Cessation in Cocaine- and Methamphetamine-Dependent Patients. AB - INTRODUCTION: Smoking is highly prevalent in substance dependence, but smoking cessation treatment (SCT) is more challenging in this population. To increase the success of smoking cessation services, it is important to understand potential therapeutic targets like nicotine craving that have meaningful but highly variable relationships with smoking outcomes. This study characterized the presence, magnitude, and specificity of nicotine craving as a mediator of the relationship between SCT and smoking abstinence in the context of stimulant dependence treatment. METHODS: This study was a secondary analysis of a randomized, 10-week trial conducted at 12 outpatient SUD treatment programs. Adults with cocaine and/or methamphetamine dependence (N = 538) were randomized to SUD treatment as usual (TAU) or TAU+SCT. Participants reported nicotine craving, nicotine withdrawal symptoms, and substance use in the week following a uniform quit attempt of the TAU+SCT group, and self-reported smoking 7-day point prevalence abstinence (verified by carbon monoxide) at end-of-treatment. RESULTS: Bootstrapped regression models indicated that, as expected, nicotine craving following a quit attempt mediated the relationship between SCT and end-of treatment smoking point prevalence abstinence (mediation effect = 0.09, 95% CI = 0.04% to 0.14%, P < .05, 14% of total effect). Nicotine withdrawal symptoms and substance use were not significant mediators (Ps > .05, <1% of total effect). This pattern held for separate examinations of cocaine and methamphetamine dependence. CONCLUSIONS: Nicotine craving accounts for a small but meaningful portion of the relationship between smoking-cessation treatment and smoking abstinence during SUD treatment. Nicotine craving following a quit attempt may be a useful therapeutic target for increasing the effectiveness of smoking-cessation treatment in substance dependence. PMID- 26048169 TI - Prevalence of spondyloarthritis in Serbia: a EULAR endorsed study. PMID- 26048172 TI - Finite element simulation of core inspection in helicopter rotor blades using guided waves. AB - This paper extends the work presented earlier on inspection of helicopter rotor blades using guided Lamb modes by focusing on inspecting the spar-core bond. In particular, this research focuses on structures which employ high stiffness, high density core materials. Wave propagation in such structures deviate from the generic Lamb wave propagation in sandwich panels. To understand the various mode conversions, finite element models of a generalized helicopter rotor blade were created and subjected to transient analysis using a commercial finite element code; ANSYS. Numerical simulations showed that a Lamb wave excited in the spar section of the blade gets converted into Rayleigh wave which travels across the spar-core section and mode converts back into Lamb wave. Dispersion of Rayleigh waves in multi-layered half-space was also explored. Damage was modeled in the form of a notch in the core section to simulate a cracked core, and delamination was modeled between the spar and core material to simulate spar-core disbond. Mode conversions under these damaged conditions were examined numerically. The numerical models help in assessing the difficulty of using nondestructive evaluation for complex structures and also highlight the physics behind the mode conversions which occur at various discontinuities. PMID- 26048171 TI - Spontaneous thoracic ventral spinal subdural hematoma mimicking a tumoral lesion: a case report. AB - INTRODUCTION: Spinal subdural hematoma is rare and can cause serious neurological symptoms. Sometimes, idiopathic spinal subdural hematoma can spontaneously occur without any identifiable underlying etiologies. In this report, we present such an uncommon case of paraplegia caused by idiopathic spinal subdural hematoma that was successfully managed by laminectomy. CASE PRESENTATION: A 45-year-old Chinese woman presented with sudden onset of progressive asthenia and numbness in both lower extremities, accompanied by difficulty in micturition. An initial non contrast spinal magnetic resonance imaging at a local hospital suggested a spinal subdural tumoral hematoma at the T9 level. She was referred to our hospital and an emergency laminectomy from T8 to T10 was performed 22 hours after onset of her initial symptoms. However, nothing but a hematoma was identified during the operation, and a final diagnosis of spontaneous acute spinal subdural hematoma was concluded. She had partial return of sensations and voluntary movement after the operation. CONCLUSIONS: On imaging findings, spinal subdural hematoma could manifest as focal and independent from the dura matter, and, therefore, it should be included in the differential diagnosis of medullary compressive lesions. PMID- 26048173 TI - Transient analysis of leaky Lamb waves with a semi-analytical finite element method. AB - We previously formulated a semi-analytical finite element technique for Lamb waves in a plate surrounded by fluids and investigated the dispersion curves and wave structures for leaky Lamb waves. Herein, this technique is extended to the calculation of transient responses both in a plate and in fluids for dynamic loading on the plate surface. To gain fundamental insights into guided wave inspection for a water-filled pipe or tank, guided waves generated upon transient loading of a flat plate water-loaded on one side were analyzed. The results show that a quasi-Scholte mode propagating at the plate-water interface is useful for the long-range inspection of a water-loaded plate because of its non-attenuation and minimal dispersion; moreover, this mode has superior generation efficiency in the low-frequency range, while it is localized near the plate-water interface at higher frequencies. PMID- 26048170 TI - Predictive risk factors of serious infections in patients with rheumatoid arthritis treated with abatacept in common practice: results from the Orencia and Rheumatoid Arthritis (ORA) registry. AB - OBJECTIVES: Little data are available regarding the rate and predicting factors of serious infections in patients with rheumatoid arthritis (RA) treated with abatacept (ABA) in daily practice. We therefore addressed this issue using real life data from the Orencia and Rheumatoid Arthritis (ORA) registry. METHODS: ORA is an independent 5-year prospective registry promoted by the French Society of Rheumatology that includes patients with RA treated with ABA. At baseline, 3 months, 6 months and every 6 months or at disease relapse, during 5 years, standardised information is prospectively collected by trained clinical nurses. A serious infection was defined as an infection occurring during treatment with ABA or during the 3 months following withdrawal of ABA without any initiation of a new biologic and requiring hospitalisation and/or intravenous antibiotics and/or resulting in death. RESULTS: Baseline characteristics and comorbidities: among the 976 patients included with a follow-up of at least 3 months (total follow-up of 1903 patient-years), 78 serious infections occurred in 69 patients (4.1/100 patient-years). Predicting factors of serious infections: on univariate analysis, an older age, history of previous serious or recurrent infections, diabetes and a lower number of previous anti-tumour necrosis factor were associated with a higher risk of serious infections. On multivariate analysis, only age (HR per 10 year increase 1.44, 95% CI 1.17 to 1.76, p=0.001) and history of previous serious or recurrent infections (HR 1.94, 95% CI 1.18 to 3.20, p=0.009) were significantly associated with a higher risk of serious infections. CONCLUSIONS: In common practice, patients treated with ABA had more comorbidities than in clinical trials and serious infections were slightly more frequently observed. In the ORA registry, predictive risk factors of serious infections include age and history of serious infections. PMID- 26048174 TI - Combined effect of ultrasound/SonoVue microbubble on CD4(+)CD25(+) regulatory T cells viability and optimized parameters for its transfection. AB - The purpose of this study was to investigate the combined effect of ultrasound and SonoVue microbubble on CD4(+)CD25(+) regulatory T cells (Tregs) viability and to explore the appropriate parameters for Tregs transfection. Tregs were separated from peripheral venous blood of patients with hepatocellular carcinoma and seeded in 96-well plates. The optimal ultrasound exposure time and optimal SonoVue microbubble concentration for Tregs were measured by mechanical index (MI) of 1.2 or 1.4, exposure time of 0, 30, 60, 90, 120, 150, 180s, and 0, 10, 20, 30, 40, 50MUL/100MUL microbubble per well, respectively. In addition, the combined effect of ultrasound and microbubble on Tregs viability was evaluated according to the following parameters: MI 1.2/1.4+exposure time of 120, 150, 180s+0, 10, 20, 30, 40, 50MUL/100MUL microbubble per well. Tregs viability investigations were performed in order to explore the optimal transfection condition. The efficiency of plasmid transfer was determined by detection of luciferase activity on the microscopic examinations. The proliferation of Tregs could be promoted by ultrasound exposures, while being decreased with the increasing concentration of microbubbles. Under the current experimental conditions, the optimal ultrasound parameters were MI=1.4 and exposure time=150/180s. The optimal microbubble concentration was 10MUL/100MUL. Compared with treatment with ultrasound or microbubbles alone, the transfection efficiency of Tregs improved 50% by combining ultrasound and microbubble. The results indicate that both ultrasound and microbubble could affect the Tregs proliferation and the optimal Treg transfection rate was obtained by treating with 10% microbubbles and ultrasound exposure for 150/180s under ultrasound MI of 1.4. PMID- 26048175 TI - Review of magnetostrictive patch transducers and applications in ultrasonic nondestructive testing of waveguides. AB - A magnetostrictive patch transducer (MPT) is a transducer that exploits the magnetostrictive phenomena representing interactions between mechanical and magnetic fields in ferromagnetic materials. Since MPT technology was mainly developed and applied for nondestructive ultrasonic testing in waveguides such as pipes and plates, this paper will accordingly review advances of this technology in such a context. An MPT consists of a magnetic circuit composed of permanent magnets and coils, and a thin magnetostrictive patch that works as a sensing and actuating element which is bonded onto or coupled with a test waveguide. The configurations of the circuit and magnetostrictive patch therefore critically affect the performance of an MPT as well as the excited and measured wave modes in a waveguide. In this paper, a variety of state-of-the-art MPT configurations and their applications will be reviewed along with the working principle of this transducer type. The use of MPTs in wave experiments involving phononic crystals and elastic metamaterials is also briefly introduced. PMID- 26048176 TI - Mindfulness meditation training alters stress-related amygdala resting state functional connectivity: a randomized controlled trial. AB - Recent studies indicate that mindfulness meditation training interventions reduce stress and improve stress-related health outcomes, but the neural pathways for these effects are unknown. The present research evaluates whether mindfulness meditation training alters resting state functional connectivity (rsFC) of the amygdala, a region known to coordinate stress processing and physiological stress responses. We show in an initial discovery study that higher perceived stress over the past month is associated with greater bilateral amygdala-subgenual anterior cingulate cortex (sgACC) rsFC in a sample of community adults (n = 130). A follow-up, single-blind randomized controlled trial shows that a 3-day intensive mindfulness meditation training intervention (relative to a well matched 3-day relaxation training intervention without a mindfulness component) reduced right amygdala-sgACC rsFC in a sample of stressed unemployed community adults (n = 35). Although stress may increase amygdala-sgACC rsFC, brief training in mindfulness meditation could reverse these effects. This work provides an initial indication that mindfulness meditation training promotes functional neuroplastic changes, suggesting an amygdala-sgACC pathway for stress reduction effects. PMID- 26048177 TI - Delay of gratification in childhood linked to cortical interactions with the nucleus accumbens. AB - Delay of gratification (DG) is the ability to forego immediate temptations in the service of obtaining larger, delayed rewards. An extensive body of behavioral research has revealed that DG ability in childhood is associated with a host of important outcomes throughout development, and that attentional focus away from temptations underlies this ability. In this study, we conducted a functional magnetic resonance imaging study to identify the neural underpinnings of individual differences in DG among children. We observed a relationship between behavior during the classic DG task, a well-studied and ecologically valid measure, and functional connectivity during a modified version of this task in the scanner. Specifically, greater attentional focus away from temptations was associated with stronger functional coupling between the nucleus accumbens, a brain region that supports approach behavior, and several regions within prefrontal and parietal cortex that support self-control. These results shed light on the network interactions that contribute to DG and that account for individual differences in this capacity. PMID- 26048178 TI - Narcissism is associated with weakened frontostriatal connectivity: a DTI study. AB - Narcissism is characterized by the search for affirmation and admiration from others. Might this motivation to find external sources of acclaim exist to compensate for neurostructural deficits that link the self with reward? Greater structural connectivity between brain areas that process self-relevant stimuli (i.e. the medial prefrontal cortex) and reward (i.e. the ventral striatum) is associated with fundamentally positive self-views. We predicted that narcissism would be associated with less integrity of this frontostriatal pathway. We used diffusion tensor imaging to assess the frontostriatal structural connectivity among 50 healthy undergraduates (32 females, 18 males) who also completed a measure of grandiose narcissism. White matter integrity in the frontostriatal pathway was negatively associated with narcissism. Our findings, while purely correlational, suggest that narcissism arises, in part, from a neural disconnect between the self and reward. The exhibitionism and immodesty of narcissists may then be a regulatory strategy to compensate for this neural deficit. PMID- 26048180 TI - Healthcare students' and workers' knowledge about epidemiology and symptoms of Ebola in one city of Colombia. PMID- 26048179 TI - Fear extinction, persistent disruptive behavior and psychopathic traits: fMRI in late adolescence. AB - Children diagnosed with a Disruptive Behavior Disorder (DBD, i.e. Oppositional Defiant Disorder or Conduct Disorder), especially those with psychopathic traits, are at risk of developing persistent and severe antisocial behavior. Reduced fear conditioning has been proposed to underlie persistent antisocial development. However, we have recently shown that both DBD persisters and desisters are characterized by increased fear conditioning compared with healthy controls (HCs). In this study, we investigated whether brain function during fear extinction is associated with DBD subgroup-membership and psychopathic traits. Adolescents from a childhood arrestee cohort (mean age 17.6 years, s.d. 1.4) who met criteria for a DBD diagnosis during previous assessments were re-assessed and categorized as persistent DBD (n = 25) or desistent DBD (n = 25). Functional MRI during the extinction phase of a classical fear-conditioning task was used to compare regional brain function between these subgroups and 25 matched controls. Both DBD persisters and desisters showed hyperreactivity during fear extinction, when compared with HCs. Impulsive-irresponsible psychopathic traits were positively associated with responses in the fear neurocircuitry and mediated the association between neural activation and group membership. These results suggest that fear acquisition and fear extinction deficits may provide an endophenotype for an emotionally hyperreactive subtype of antisocial development. PMID- 26048181 TI - Rupture of massive coronary artery aneurysm resulting in cardiac tamponade. AB - Coronary artery aneurysm is a fairly uncommon clinical entity, which is defined by a characteristic dilatation that exceeds 1.5 times the width of normal adjacent coronary artery segments. In the present report, we describe a case of rupture of a massive coronary artery aneurysm. A man in his 40s was found dead in his bed. The pericardial cavity contained 270mL of blood with 428.2g of coagulation. Two true aneurysms of the right coronary artery were identified. A proximal aneurysm, adjacent to the right auricle, had ruptured on the right. A distal unruptured aneurysm was identified 5.1cm distal to the proximal ruptured aneurysm. Atherosclerosis of the coronary arteries and aorta was severe. The heart weighed 799.1g and showed concentric ventricular hypertrophy, myocardial thinning, and patchy fibrosis. Histological analysis showed that both aneurysms were purely atherosclerotic true aneurysms without considerable inflammation. The cause of death was determined as cardiac tamponade due to rupture of a giant coronary atherosclerotic aneurysm. PMID- 26048183 TI - Sinus floor elevation with a crestal approach using a press-fit bone block: a case series. AB - This prospective study aimed to provide detailed clinical information on a sinus augmentation procedure, i.e., transcrestal sinus floor elevation with a bone block using the press-fit technique. A bone block is harvested with a trephine burr to obtain a cylinder. This block is inserted into the antrum via a crestal approach after creation of a circular crestal window. Thirty-three patients were treated with a fixed prosthesis supported by implants placed on 70 cylindrical bone blocks. The mean bone augmentation was 6.08+/-2.87 mm, ranging from 0 to 12.7 mm. Only one graft failed before implant placement. During surgery and the subsequent observation period, no complications were recorded, one implant was lost, and no infection or inflammation was observed. This proof-of-concept study suggests that the use of a bone block inserted into the sinus cavity via a crestal approach can be an alternative to the sinus lift procedure with the creation of a lateral window. It reduces the duration of surgery, cost of treatment, and overall discomfort. PMID- 26048182 TI - Polyelectrolyte-mediated increase of biofilm mass formation. AB - BACKGROUND: Biofilm formation is associated with various aspects of bacterial and fungal infection. This study was designed to assess the impact of diverse natural polyelectrolytes, such as DNA, F-actin, neurofilaments (NFs), vimentin and purified Pf1 bacteriophage on biofilm formation and swarming motility of select pathogens including Pseudomonas aeruginosa associated with lung infections in CF patients. RESULTS: The bacteriophage Pf1 (1 mg/ml) significantly increased biofilm mass produced by Pseudomonas aeruginosa P14, Escherichia coli RS218 and Bacillus subtilis ATCC6051. DNA, F-actin, NFs and Pf1 also increased biofilm mass of the fungal C. albicans 1409 strain. Addition of F-actin, DNA or Pf1 bacteriophage to 0.5% agar plates increased swarming motility of Pseudomonas aeruginosa Xen5. CONCLUSIONS: The presence of polyelectrolytes at infection sites is likely to promote biofilm growth and bacterial swarming. PMID- 26048184 TI - Structure of the O-specific polysaccharide from a marine bacterium Cellulophaga tyrosinoxydans. AB - The O-polysaccharide was isolated from the lipopolysaccharide of Cellulophaga tyrosinoxydans and studied by chemical analyses along with (1)H and (13)C NMR spectroscopy, including 2D (1)H, (1)H COSY, TOCSY, ROESY, (1)N, (13)S HSQC, HMBC and H2BC experiments. The following new structure of the O-polysaccharide of C. tyrosinoxydans containing l-fucose (Fuc), N-acetyl-d-glucosamine (GlcNAc), 4 acetamido-4,6-dideoxy-d-glucose (Qui4NAc) and two l-rhamnose residues (Rha) was established:. PMID- 26048185 TI - Bioequivalence, Food Effect, and Steady-State Assessment of Dapagliflozin/Metformin Extended-release Fixed-dose Combination Tablets Relative to Single-component Dapagliflozin and Metformin Extended-release Tablets in Healthy Subjects. AB - PURPOSE: Simplification of therapeutic regimens for patients with type 2 diabetes mellitus can provide convenience that leads to improved compliance. Dapagliflozin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the convenience of once-daily dosing. Two pharmacokinetic (PK) studies were conducted to establish bioequivalence for 2 doses of dapagliflozin/metformin XR FDC versus the same dosage of the individual component (IC) tablets in healthy adults. METHODS: Two open-label, randomized, 4-period, 4 arm crossover studies were conducted to assess the bioequivalence and PK properties of dapagliflozin and metformin FDCs in healthy subjects under fed and fasting conditions. Participants received single oral doses or once-daily dosing of dapagliflozin/metformin XR (5 mg/500 mg [study 1] or 10 mg/1000 mg [study 2]) for 4 days in an FDC formulation or corresponding strengths of IC tablets. FINDINGS: For both of the studies, dapagliflozin and metformin 5 mg/500 mg or 10 mg/1000 mg FDC tablets were bioequivalent to the respective IC tablets. The 90% CIs of the ratio of the adjusted geometric means for all key PK parameters (Cmax, AUC0-T, and AUC0-infinity) were contained within the predefined 0.80 to 1.25 range to conclude bioequivalence for both dapagliflozin and metformin. Once-daily dosing to steady state of each FDC tablet had no effect on the PK properties of dapagliflozin or metformin. When the FDCs were administered with a light-fat meal, there was no effect on metformin PK values and only a modest, nonclinically meaningful effect on dapagliflozin PK values. There were no safety or tolerability concerns. IMPLICATIONS: Bioequivalence of the FDCs of dapagliflozin/metformin XR and the ICs was established, and no safety issues of clinical concern were raised. PMID- 26048186 TI - Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Canagliflozin in Healthy Chinese Subjects. AB - PURPOSE: Canagliflozin, an orally active sodium-glucose cotransporter 2 inhibitor, is approved in many countries as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The recommended dose of canagliflozin is 100 or 300 mg once daily. This Phase I study was conducted to evaluate the pharmacokinetics, pharmacodynamics, and safety profile of canagliflozin in healthy Chinese subjects. METHODS: In this double-blind, single-dose, 3-way crossover study, 15 healthy subjects were randomized (1:1:1) to receive single oral doses of canagliflozin 100 mg, canagliflozin 300 mg, or placebo. Pharmacokinetic, pharmacodynamic, and safety assessments were made at prespecified time points. FINDINGS: All participants are healthy Chinese adults. Mean AUC and Cmax of canagliflozin increased in a dose-dependent manner after single-dose administration (AUC0-infinity, 10,521 ng . h/mL for 100 mg, 33,583 ng . h/mL for 300 mg; Cmax, 1178 ng/mL for 100 mg, 4113 ng/mL for 300 mg). The mean apparent t1/2 and the median Tmax of canagliflozin were independent of dose (t1/2, 16.0 hours for 100 mg, 16.2 hours for 300 mg; Tmax, ~1 hour). Mean CL/F and renal clearance of canagliflozin were comparable between the 2 doses. Mean plasma metabolite to parent molar ratios for Cmax and AUC0-infinity were similar with both doses. Canagliflozin decreased the 24-hour mean renal threshold for glucose, calculated by using measured creatinine clearance to estimate the glomerular filtration rate (67.9 and 60.7 mg/dL for canagliflozin 100 and 300 mg, respectively) and 24-hour increased urinary glucose excretion (33.8 and 42.9 g for canagliflozin 100 and 300 mg, respectively) in a dose-dependent manner; the 24-hour plasma glucose profile remained largely unchanged. No deaths, hypoglycemic events, or discontinuations due to adverse events were observed. IMPLICATIONS: Pharmacokinetics (AUC and Cmax) of canagliflozin increased in a dose-dependent manner after single oral doses of canagliflozin (100 and 300 mg) in these healthy Chinese subjects. Tmax and t1/2 of canagliflozin were independent of the dose. Canagliflozin decreased the 24-hour mean renal threshold for glucose and increased urinary glucose excretion in a dose-dependent manner; these results are consistent with those observed in other patient populations. Canagliflozin was generally safe and well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01707316. PMID- 26048187 TI - A Retrospective Evaluation of Inpatient Transfer from High-Dose Methadone to Buprenorphine Substitution Therapy. AB - The product license of buprenorphine/naloxone for opioid substitution therapy indicates reducing methadone concentrations to 30 mg or less per day for a minimum of 1 week before transferring patients to buprenorphine and no sooner than 24 hours after the last methadone dose, because of the risk of precipitated withdrawal and a corresponding high risk of relapse to opioid use. There are few studies describing high-dose methadone transfers. This retrospective case review assessed the feasibility of transferring patients on methadone doses above 30 mg/day to buprenorphine or buprenorphine/naloxone in the inpatient setting. Six of seven patients on 60-120 mg/day of methadone successfully completed the transfer, and four cases tested negative for opiates at long-term follow-up (6-15 months). This suggests that methadone transfer to buprenorphine can be performed rapidly without the need to taper methadone doses in patients indicated for a therapeutic switch. This small study is hypothesis-generating; larger, well designed trials are needed to define a protocol that can be used routinely to improve and widen transfers to buprenorphine when indicated. PMID- 26048188 TI - Determining six cardiac conductivities from realistically large datasets. AB - Simulation studies of cardiac electrophysiological behaviour that use the bidomain model require accurate values for the bidomain extracellular and intracellular conductivities to produce useful results. This work considers an inversion algorithm, which has previously been shown, using simulated data, to be capable of retrieving six bidomain conductivities and the fibre rotation angle from measurements of electric potential made in the heart. The aim here is to see whether it is possible to improve the accuracy of the retrieved parameters. The scenario of retrieving only conductivities and not fibre rotation is examined but this does not lead to a worthwhile improvement in retrieval accuracy. It is also found that it is possible to retrieve the bidomain conductivities using not two but just one pass of the algorithm, made on a 'widely-spaced' electrode set. This appears to work because the algorithm is still very sensitive to the extracellular conductivities. However, the single-pass method is not recommended because the intracellular conductivities that are retrieved are not as accurate as those that are retrieved in the usual two-pass method, particularly for higher values of added noise. The second part of this work considers retrieving the six conductivities and fibre rotation from realistically large sets of potential measurements and identifies the best data analysis method. It is found that, even with added noise of up to 40%, the extracellular conductivities can still be retrieved extremely accurately (relative errors of around 2% on average) and so can the intracellular longitudinal conductivities and fibre rotation (errors less than 8% on average). The remaining intracellular conductivities have errors that are generally less than twice the added noise, particularly for the higher noise values. PMID- 26048189 TI - Numerical computation of an Evans function for travelling waves. AB - We demonstrate a geometrically inspired technique for computing Evans functions for the linearised operators about travelling waves. Using the examples of the F KPP equation and a Keller-Segel model of bacterial chemotaxis, we produce an Evans function which is computable through several orders of magnitude in the spectral parameter and show how such a function can naturally be extended into the continuous spectrum. In both examples, we use this function to numerically verify the absence of eigenvalues in a large region of the right half of the spectral plane. We also include a new proof of spectral stability in the appropriate weighted space of travelling waves of speed c>=2?delta in the F-KPP equation. PMID- 26048190 TI - Annexin A4 and cancer. AB - Annexin A4 (Anxa4) is one of the Ca(2+)-regulated and phospholipid-binding annexin superfamily proteins. Anxa4 has a potential role in diagnosis, prognosis, and treatment of certain cancers. Studies indicate that Anxa4 up-regulation promotes the progression of tumor and chemoresistance of colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), endometrial carcinoma (EC), gastric cancer (GC), chemoresistant lung cancer (LC), malignant mesothelioma (MM), renal cell carcinoma (RCC), ovarian clear cell carcinoma (OCCC), cholangiocarcinoma, hepatocellular carcinoma (HCC), breast cancer (BC), and laryngeal cancer. Interestingly, Anxa4 also might specifically function as a tumor suppressor for prostate cancer (PCa) and have a paradoxical role for pancreatic cancer (PCC). Differential expression of Anxa4 may distinguish major salivary gland tumor (MSGT) from thyroid cancer. In addition, its differential expression was linked to Sirt1-induced cisplatin resistance of oral squamous cell carcinoma (OSCC) and miR-7-induced migration and invasion inhibition of glioma. This current review summarizes and discusses the clinical significance of Anxa4 in cancer as well as its potential mechanisms of action. It may provide new integrative understanding for future studies on the exact role of Anxa4 in cancer. PMID- 26048191 TI - Increased plasma corin levels in patients with atrial fibrillation. AB - BACKGROUND: NPPA mutations/polymorphisms were associated with atrial fibrillation (AF), and plasma proatrial natriuretic peptide (proANP) concentrations were increased in AF patients. Corin, as a transmembrane protease that processes proANP in the heart, may play a potential role in AF. METHODS: To test whether corin concentrations are altered in AF patients, we used ELISA to measure corin and N-terminal proANP (NT-proANP) concentrations in plasma samples from control (n=127) and AF patients (n=141), including paroxysmal AF (PAF, n=83) and persistent AF (PeAF, n=58). RESULTS: In patients with AF, plasma corin concentrations were 1209+/-510pg/ml, which were significantly higher than in the controls (973+/-528pg/ml, P<0.001). The increased plasma corin concentrations were found in both male and female patients. Plasma NT-proANP concentrations in AF patients were 3.1+/-2.42nmol/l, which were higher than in the controls (1.77+/ 1.04nmol/l, P<0.001). Gender (P=0.003), weight (P=0.016) and PR interval (P=0.028) were independent predictors of plasma corin concentrations in AF patients. A positive correlation was found between corin concentrations and left atrial diameter/PR interval in AF patients. CONCLUSION: High plasma corin concentrations in AF patients suggest that corin may play an important role in the pathology of AF. PMID- 26048192 TI - Candidate genes for Parkinson disease: Lessons from pathogenesis. AB - Parkinson disease (PD) is a multifactorial neurodegenerative disease characterized by the progressive loss of specific neuronal populations and accumulation of Lewy bodies in the brain, leading to motor and non-motor symptoms. In a small subset of patients, PD is dominantly or recessively inherited, while a number of susceptibility genetic loci have been identified through genome wide association studies. The discovery of genes mutated in PD and functional studies on their protein products have provided new insights into the molecular events leading to neurodegeneration, suggesting that few interconnected molecular pathways may be deranged in all forms of PD, triggering neuronal loss. Here, we summarize the most relevant findings implicating the main PD-related proteins in biological processes such as mitochondrial dysfunction, misfolded protein damage, alteration of cellular clearance systems, abnormal calcium handling and altered inflammatory response, which represent key targets for neuroprotection. PMID- 26048194 TI - Prominent R wave in ECG lead V1 predicts improvement of left ventricular ejection fraction after cardiac resynchronization therapy in patients with or without left bundle branch block. AB - BACKGROUND: QRS morphology on postprocedural ECG indicating posterolateral left ventricular pacing may be predictive of response to cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to assess whether a positive vector in V1 and/or negative vector in lead I on the first postprocedural ECG, suggesting posterolateral capture from CRT, correlates with improvement in left ventricular ejection fraction (LVEF). METHODS: A retrospective chart review was conducted on all patients who underwent CRT implantation at our institution between April 2008 and December 2011. Biventricular (BiV) paced QRS morphology was defined as R/S >=1 in V1 and/or R/S <= 1 in lead I. The primary outcome was improvement of LVEF >=7.5%. The chi(2) and t tests were used for analysis. RESULTS: Of 68 patients, 49 (72%) met our BiV paced QRS morphology criteria. Thirty-four of these 49 patients (69%) had improvement in LVEF. Of the 19 patients who did not meet our criteria, 17 (89%) did not have an improvement in LVEF (sensitivity 94%, specificity 53%, chi(2) = 19.04, P < .0001). The average LVEF improvement in patients who met our BiV paced QRS morphology criteria was significantly greater than in those who did not (14.27% vs 2.63%, P = .0001). Preprocedural left bundle branch block was not a predictor of echocardiographic response. CONCLUSION: Our results highlight the importance of periprocedural ECG analysis to optimize response to CRT. Moreover, patients without left bundle branch block still benefited from CRT if they met our BiV paced morphology criteria. This suggests that postprocedural left ventricular activation as reflected on the ECG may supersede the baseline conduction delay. PMID- 26048193 TI - Computerized Cognitive Behavior Therapy for Anxiety and Depression in Rural Areas: A Systematic Review. AB - BACKGROUND: People living in rural and remote communities have greater difficulty accessing mental health services and evidence-based therapies, such as cognitive behavior therapy (CBT), than their urban counterparts. Computerized CBT (CCBT) can be used to effectively treat depression and anxiety and may be particularly useful in rural settings where there are a lack of suitably trained practitioners. OBJECTIVE: To systematically review the global evidence regarding the clinical effectiveness and acceptability of CCBT interventions for anxiety and/or depression for people living in rural and remote locations. METHODS: We searched seven online databases: Medline, Embase Classic and Embase, PsycINFO, CINAHL, Web of Science, Scopus, and the Cochrane Library. We also hand searched reference lists, Internet search engines, and trial protocols. Two stages of selection were undertaken. In the first, the three authors screened citations. Studies were retained if they reported the efficacy, effectiveness or acceptability of CCBT for depression and/or anxiety disorders, were peer reviewed, and written in English. The qualitative data analysis software, NVivo 10, was then used to run automated text searches for the word "rural," its synonyms, and stemmed words. All studies identified were read in full and were included in the study if they measured or meaningfully discussed the efficacy or acceptability of CCBT among rural participants. RESULTS: A total of 2594 studies were identified, of which 11 met the selection criteria and were included in the review. The studies that disaggregated efficacy data by location of participant reported that CCBT was equally effective for rural and urban participants. Rural location was found to both positively and negatively predict adherence across studies. CCBT may be more acceptable among rural than urban participants-studies to date showed that rural participants were less likely to want more face-to-face contact with a practitioner and found that computerized delivery addressed confidentiality concerns. CONCLUSIONS: CCBT can be effective for addressing depression and anxiety and is acceptable among rural participants. Further work is required to confirm these results across a wider range of countries, and to determine the most feasible model of CCBT delivery, in partnership with people who live and work in rural and remote communities. PMID- 26048195 TI - Effect of radiofrequency energy delivery in proximity to metallic medical device components. AB - BACKGROUND: Radiofrequency (RF) ablation of cardiac arrhythmias is often performed in the presence of metallic materials in the heart. OBJECTIVES: We hypothesize that metal objects in proximity to an RF ablation source can lead to ohmic heating of surrounding tissue. Furthermore, we hypothesize that insulation of the metal can mitigate this RF effect. METHODS: A model consisting of viable bovine myocardium or thermochromic liquid crystal medium, a circulating saline bath at 37 degrees C, and a load cell was used. A 4-mm RF ablation catheter was positioned with 10 g of force over bovine myocardium and placed in proximity to a copper wire, a defibrillator lead, and a circular mapping catheter. RF was applied at 30 W, and tissue temperatures were measured. Ablation near insulated and noninsulated esophageal temperature probes was also performed. RESULTS: Ablation in proximity to metal resulted in higher temperatures. Average maximum distances for observed thermal changes to >45 degrees C for the +/- lead were 5.2 +/- 0.3 mm and 5.7 +/- 0.4 mm when metal was interposed between the catheter and the ground electrode. Presence of an esophageal temperature probe increased temperatures in tissues adjacent to the probe and caused lesions remote to the ablation site. Esophageal probe insulation prevented these tissue temperature increases and injury to nontargeted tissues. CONCLUSION: Effects of RF ablation are potentiated near metallic components of medical devices, leading to significant tissue heating. Further research is needed to assess the safety impact of RF in the myocardium near metallic objects, particularly esophageal temperature probes. PMID- 26048196 TI - Metagenomics of extreme environments. AB - Whether they are exposed to extremes of heat or cold, or buried deep beneath the Earth's surface, microorganisms have an uncanny ability to survive under these conditions. This ability to survive has fascinated scientists for nearly a century, but the recent development of metagenomics and 'omics' tools has allowed us to make huge leaps in understanding the remarkable complexity and versatility of extremophile communities. Here, in the context of the recently developed metagenomic tools, we discuss recent research on the community composition, adaptive strategies and biological functions of extremophiles. PMID- 26048197 TI - Hospital treatment targets have been simplified. PMID- 26048198 TI - Mechanical Properties of Porcine Brain Tissue in the Coronal Plane: Interregional Variations of the Corona Radiata. AB - Most biomechanical models that aim to investigate traumatic brain injury consider the corona radiata as a homogeneous structure. To verify this, indentation relaxation tests using a custom-designed indentation device were performed on the anterior, superior, and posterior region of the corona radiata in the coronal plane of the porcine brain. Using Boltzmann hereditary integral, a linear viscoelastic model with a Prony series approximation was fitted to the time dependent shear modulus for different regions of the corona radiata, and the fit parameters were generated. The posterior region was the stiffest and the anterior region was the least stiff. A statistical analysis revealed a significant difference in biomedical properties between the anterior and superior regions, as well as between the anterior and posterior regions in the short time scale. However, the results showed that these differences faded away as the tissue approached equilibrium. No significant difference was observed between the superior and posterior regions along the total time history of relaxation. This is the first demonstration of the regional biomechanical heterogeneity of the corona radiata, and these results will improve future biomedical models of the porcine brain. PMID- 26048199 TI - "Positive Attitude": A multilevel model analysis of the effectiveness of a Social and Emotional Learning Program for Portuguese middle school students. AB - This study investigated the impact, reported by students and their teachers, of a universal, school-based, social-emotional learning program, implemented in three school years on the social-emotional competencies of middle school students (7th to 9th grade). It also analyzes, at post-test and follow-up, the differential results by gender and among students with lower levels of competence. There were 1091 participants, 855 students received the treatment condition (i.e., Project Attitude) and 236 students the control condition. Self-reports identified positive intervention results in social awareness, self-control, self-esteem, social isolation and social anxiety, teachers reported gains in all dimensions. These positive effects were stably effective along the three cohorts. Self reports also identified bigger gains for girls in social awareness and for boys in social anxiety, self-esteem and leadership. Students with initial lower levels of competence benefited more from the intervention, especially at follow-up. These results support the effectiveness of social-emotional learning programs. PMID- 26048200 TI - Metabolomic profiles illuminate the efficacy of Chinese herbal Da-Cheng-Qi decoction on acute pancreatitis in rats. AB - BACKGROUND AND OBJECTIVES: Chinese herbal drug Da-Cheng-Qi decoction (DCQD) has been widely used for decades to treat acute pancreatitis (AP). Previous trials are mostly designed to state the potential mechanisms of the therapeutic effects rather than to detect its whole effect on metabolism. This study aimed to investigate the efficacy of DCQD on metabolism in AP. METHODS: Twenty-two male adult Sprague-Dawley rats were randomized into three groups. AP was induced by retrograde ductal infusion of 3.5% sodium taurocholate solution in DCQD and AP group, while 0.9% saline solution was used in sham operation (SO) group. Blood samples were obtained 12 h after drug administration and a 600 MHz superconducting Nuclear Magnetic Resonance (NMR) spectrometer was used to detected plasma metabolites. Principal Components Analysis (PCA) and Partial Least Squares-Discriminant Analysis after Orthogonal Signal Correction (OSC-PLS DA) were applied to analyze the Longitudinal Eddy-delay (LED) and Carr-Purcell Meiboom-Gill (CPMG) spectra. RESULTS: Differences in concentrations of metabolites among the three groups were detected by OSC-PLS-DA of 1HNMR spectra (both LED and CPMG). Compared with SO group, DCQD group had higher levels of plasma glycerol, glutamic acid, low density lipoprotein (LDL), saturated fatty acid (FA) and lower levels of alanine and glutamine, while the metabolic changes were reversed in the AP group. CONCLUSIONS: Our results demonstrated that DCQD was capable of altering the changed concentrations of metabolites in rats with AP and 1HNMR-based metabolomic approach provided a new methodological cue for systematically investigating the efficacies and mechanisms of DCQD in treating AP. PMID- 26048201 TI - Decaffeinated green tea extract rich in epigallocatechin-3-gallate improves insulin resistance and metabolic profiles in normolipidic diet--but not high-fat diet-fed mice. AB - Supplementation with epigallocatechin-3-gallate (EGCG), which restores metabolic profiles, has been proposed as an option for preventing and treating obesity. We investigated whether decaffeinated green tea extract rich in EGCG, attenuates high-fat diet (HFD)-induced metabolic alterations in Swiss mice. The mice were maintained on either a control diet (CD) or HFD for 8 weeks and supplemented with either a placebo or EGCG (50mg/kg/day). Body weight, serum lipid profiles, cytokine protein expression, and content in epididymal (EPI) and retroperitoneal (RET) adipose tissues, and adipocyte area were measured. The body weights of HFD + placebo-fed mice were increased compared with those of HFD + EGCG-fed mice (28 and 21%, respectively), whereas the body weights of CD + EGCG-fed mice were decreased 16% compared with those of the CD + placebo group. Serum triglyceride levels were decreased 32% in the CD + EGCG group compared with the CD + placebo group. Compared with the CD + placebo group, increased phosphorylation of AMPK and hormone-sensitive lipase in EPI and RET, respectively, was found in the CD + EGCG group. Increased acetyl-CoA carboxylase phosphorylation was observed in both adipose tissues. In addition, TNF-alpha and IL-10 levels in EPI and adiponectin levels were higher in the CD + EGCG group than in the CD + placebo group. TNF alpha levels were lower in the HFD + EGCG group than in the HFD + placebo group. Furthermore, the CD + EGCG group exhibited a lower adipocyte area than the CD + placebo group. These indicate that the effects of decaffeinated green tea extract on body mass may be related to the crosstalk between lipolytic and inflammatory pathways in normolipidic diet-fed mice but not in HFD-fed mice. PMID- 26048202 TI - Necrotizing soft tissue infections after injection therapy: Higher mortality and worse outcome compared to other entry mechanisms. AB - OBJECTIVES: Necrotizing Soft Tissue Infections represent a rare entity of infection associated with a high mortality. The aim of this retrospective study was to analyze patients with an iatrogenic etiology of injection or infiltration to compare the outcome with other etiologies. METHODS: The study group consisted of 21 patients treated with a Necrotizing Fasciitis caused by injection or infiltration. Risk factors and outcome were compared to 134 patients with a Necrotizing Fasciitis caused by other entry mechanisms. RESULTS: Overall mortality in our study group was 14 of 21 (67%) with an amputation rate of 11 of 15 (73%) if an extremity was involved. The survival rate was significantly worse after injection or infiltration (p < 0.001) as was the amputation rate (p = 0.013), the percentage of patients requiring intensive care (100% vs. 83%, p = 0.038) and vasopressors (81% vs. 54%, p = 0.02). Injection or infiltration therapy proved to be the strongest prognostic factor (p = 0.003) besides the known risk factors obesity (0.007) and renal insufficiency (0.025). CONCLUSIONS: Our results demonstrate that patients with a Necrotizing Soft Tissue Infection after injection or infiltration therapy have a significantly worse prognosis. PMID- 26048203 TI - Decreased microbiota diversity associated with urinary tract infection in a trial of bacterial interference. AB - BACKGROUND: Patients with long-term indwelling catheters are at high risk of catheter-associated urinary tract infection (CAUTI). We hypothesized that colonizing the bladder with a benign Escherichia coli strain (E. coli HU2117, a derivative of E. coli 83972) would prevent CAUTI in older, catheterized adults. MATERIALS AND METHODS: Adults with chronic, indwelling urinary catheters received study catheters that had been pre-coated with E. coli HU2117. We monitored the cultivatable organisms in the bladder for 28 days or until loss of E. coli HU2117. Urine from 4 subjects was collected longitudinally for 16S rRNA gene profiling. RESULTS: Eight of the ten subjects (average age 70.9 years) became colonized with E. coli HU2117, with a mean duration of 57.7 days (median: 28.5, range 0-266). All subjects also remained colonized by uropathogens. Five subjects suffered invasive UTI, 3 febrile UTI and 2 urosepsis/bacteremia, all associated with overgrowth of a urinary pathogen. Colonization with E. coli HU2117 did not impact bacterial bladder diversity, but subjects who developed infections had less diverse bladder microbiota. CONCLUSIONS: Colonization with E. coli HU2117 did not prevent bladder colonization or subsequent invasive disease by uropathogens. Microbial diversity may play a protective role against invasive infection of the catheterized bladder. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00554996 http://clinicaltrials.gov/ct2/show/NCT00554996. PMID- 26048204 TI - Markers of endothelial cell activation and immune activation are increased in patients with severe leptospirosis and associated with disease severity. AB - OBJECTIVES: Previous studies concluded that haemorrhage is one of the most accurate prognostic factors of mortality in leptospirosis. Therefore, endothelial cell activation was investigated in relation to disease severity in severe leptospirosis. METHODS: Prospective cohort study of severe leptospirosis patients. Plasma levels of sE-selectin and Von Willebrand factor (VWF) were determined. Consequently, an in vitro endothelial cell model was used to assess endothelial activation after exposure to virulent Leptospira. Finally, immune activation, as a potential contributing factor to endothelial cell activation, was determined by soluble IL2-receptor (sIL-2r) and soluble Fas-ligand (sFasL) levels. RESULTS: Plasma levels of sE-selectin and VWF strongly increased in patients compared to healthy controls. Furthermore, sE-selectin was significantly elevated (203 ng/ml vs. 157 ng/ml, p < 0.05) in survivors compared to non survivors. Endothelial cells exposed to virulent Leptospira showed increased VWF expression. E-selectin and ICAM-1 expression did not change. Immunohistochemistry revealed the presence of intracellular Leptospira and qPCR suggested replication. In vivo analysis showed that increased levels of sFasL and sIL-2r were both strongly associated with mortality. Furthermore sIL-2r levels were increased in patients that developed bleeding and significantly correlated to duration of hospital stay. DISCUSSION: Markers of endothelial activation and immune activation were associated with disease severity in leptospirosis patients. PMID- 26048205 TI - Association of pneumococcal conjugate vaccination with rates of ventilation tube insertion in Denmark: population-based register study. AB - OBJECTIVE: To examine if the introduction of pneumococcal conjugate vaccine (PCV) in Denmark was associated with a decrease in the rate of ventilation tube (VT) insertions performed by office-based practising ear, nose and throat (ENT) specialists. DESIGN: Population-based register study based on prospectively collected data. SETTING: Central Denmark Region. Data on VT insertions performed by any office-based practising ENT specialist in the region were collected from the National Health Service Registry. PARTICIPANTS: All children below the age of 2 years with a first-time VT insertion from 2001 through 2011. MAIN OUTCOME MEASURES: Age-stratified and gender-stratified standardised incidence rates of first-time VT insertion, and incidence rate ratio for PCV period 2008-2011 compared with pre-PCV period 2001-2007. RESULTS: The annual incidence rate of first-time VT insertion in small children increased steadily from 64/1000 person years in 2001 to 100/1000 person-years in 2011. The incidence rate ratio was 1.27 (95% CI 1.24 to 1.30) in the PCV period compared with the pre-PCV period. CONCLUSIONS: The introduction of PCV into the Danish childhood immunisation programme in 2007 was not associated with a subsequent decrease in the rate of VT insertions among children below the age of 2 years. Instead, the rate continued to rise, as before the introduction of PCV. TRIAL REGISTRATION NUMBER: Danish Data Protection Agency: 2007-58-0010. PMID- 26048206 TI - Young people's perceptions of tobacco packaging: a comparison of EU Tobacco Products Directive & Ireland's Standardisation of Tobacco Act. AB - OBJECTIVES: To measure young people's perceptions of tobacco packaging according to two current pieces of legislation: The EU Tobacco Products Directive (TPD) and Ireland's Public Health (Standardisation of Tobacco Products) Act. DESIGN: Within subject experimental cross-sectional survey of a representative sample of secondary school students. School-based pen and paper survey. SETTING: 27 secondary schools across Ireland, randomly stratified for size, geographic location, gender, religious affiliation and school-level socioeconomic status. Data were collected between March and May 2014. PARTICIPANTS: 1378 fifth year secondary school students aged 16-17 in Ireland. MAIN OUTCOME MEASURES: Young people's perceptions of attractiveness, health risk and smoker characteristics of packs according to EU and Irish branding and packaging guidelines. RESULTS: Packs with more branding elements were thought to be healthier than standardised packs for Silk Cut (chi(2)=158.58, p<0.001), Marlboro (chi(2)=113.65, p<0.001), and Benson and Hedges (chi(2)=137.95, p<0.001) brands. Generalized estimating equation binary regressions found that gender was a significant predictor of pack attractiveness for Silk Cut, with females being more likely to find the EU packs attractive (beta=-0.45, p=0.007). Gender was a significant predictor for females with regards to the perceived popularity of the Silk Cut brand (beta=-0.37, p=0.03). CONCLUSIONS: The removal of brand identifiers, including colour, font and embossing, reduces the perceived appeal of cigarette packs for young people across all three tested brands. Packs standardised according to Irish legislation are perceived as less attractive, less healthy and smoked by less popular people than packs which conform to the EU TPD 2014 guidelines. PMID- 26048207 TI - Changing adherence-related beliefs about ICS maintenance treatment for asthma: feasibility study of an intervention delivered by asthma nurse specialists. AB - OBJECTIVES: The Necessity-Concerns Framework (NCF) posits that non-adherence to inhaled corticosteroids (ICS) in asthma is influenced by doubts about the necessity for ICS and concerns about their potential adverse effects. This feasibility study examined whether these beliefs could be changed by briefing asthma nurse specialists on ways of addressing necessity beliefs and concerns within consultations. DESIGN: Pre-post intervention study. SETTING: Secondary care. PARTICIPANTS: Patients with a diagnosis of moderate to severe asthma who were prescribed daily ICS were recruited to either a hospital care group (n=79; 71.0% female) or intervention group (n=57; 66.7% female). INTERVENTION: Asthma nurse specialists attended a 1.5-day NCF briefing. PRIMARY AND SECONDARY OUTCOME MEASURES: Beliefs about ICS (primary outcome) and self-reported adherence were measured preconsultation and 1 month postconsultation. Participants also rated their satisfaction with their consultations immediately after the consultation. Consultation recordings were coded to assess intervention delivery. RESULTS: After the NCF briefing, nurse specialists elicited and addressed beliefs about medicine more frequently. The frequency of using the NCF remained low, for example, open questions eliciting adherence were used in 0/59 hospital care versus 14/49 (28.6%) intervention consultations. Doubts about personal necessity for, and concerns about, ICS were reduced at 1 month postbriefing (p<0.05), but the intervention was not applied extensively enough to improve adherence. CONCLUSIONS: The intervention changed nurse consultations, but not sufficiently enough to fully address non-adherence or adherence-related ICS beliefs (necessity and concerns). More effective techniques are needed to support nurse specialists and other practitioners to apply the intervention in hospital asthma review consultations. PMID- 26048208 TI - Acupuncture for psoriasis: protocol for a systematic review. AB - INTRODUCTION: The described systematic review aims to assess the effectiveness and safety of acupuncture for psoriasis. METHODS AND ANALYSIS: We will electronically search for randomised controlled trials in the following databases from inception to 31 March 2015: OVID MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Chinese Biomedical Literature Database, Chinese Medical Current Content, Chinese Scientific Journal Database (VIP database), Wan-Fang Database and China National Knowledge Infrastructure. We will also try to obtain literature by manually searching reference lists, conference proceedings and registers of clinical trials (eg, the Meta Register of Controlled Trials and the Chinese Clinical Trial Registry). Changes in disease status as evaluated by clinical signs or any available tool will be measured as the primary outcome. Global changes as well as changes in participant status (as evaluated by quality of life), safety (as measured by the prevalence and severity of adverse effects or adverse events) and costs (if available) will be measured as secondary outcomes. Two researchers will independently undertake selection of studies, data extraction and assessment of the quality of included studies. Data synthesis and subgroup analyses will be performed using special software (Review Manager). Data will be combined with a random effect model. Results will be presented as risk ratios for dichotomous data and the standardised mean difference for continuous data. ETHICS AND DISSEMINATION: Ethical approval will not be required as this is a protocol for a systematic review. The systematic review will evaluate the current evidence regarding acupuncture therapy for psoriasis. Findings will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: PROSPERO CRD 42014013695. PMID- 26048209 TI - Comparative efficacy and safety of approved treatments for macular oedema secondary to branch retinal vein occlusion: a network meta-analysis. AB - OBJECTIVE: To compare the efficacy and safety of approved treatments for macular oedema secondary to branch retinal vein occlusion (BRVO). DESIGN: Randomised controlled trials (RCTs) evaluating the efficacy and safety of approved treatments for macular oedema secondary to BRVO were identified from an updated systematic review. SETTING: A Bayesian network meta-analysis of RCTs of treatments for macular oedema secondary to BRVO. INTERVENTIONS: Ranibizumab 0.5 mg pro re nata, aflibercept 2 mg monthly (2q4), dexamethasone 0.7 mg implant, laser photocoagulation, ranibizumab+laser, or sham intervention. Bevacizumab and triamcinolone were excluded. OUTCOME MEASURES: Efficacy outcomes were mean change in best corrected visual acuity (Early Treatment Diabetic Retinopathy Study scale) and the percentage of patients gaining >= 15 letters. Safety outcome was the percentage of patients with increased intraocular pressure (IOP)/ocular hypertension (OH). RESULTS: 8 RCTs were identified for inclusion with 1743 adult patients. The probability of being the most efficacious treatment at month 6 or 12 based on letters gained was 54% for ranibizumab monotherapy, 30% for aflibercept, 16% for ranibizumab plus laser (adjunctive or prompt), and 0% for dexamethasone implant, laser or sham. The probability of being the most efficacious treatment for patients gaining >= 15 letters was 39% for aflibercept, 35% for ranibizumab monotherapy, 24% for ranibizumab plus laser, 2% for dexamethasone implant, and less than 1% for laser or sham. There was no statistical difference between ranibizumab monotherapy and aflibercept for letters gained (+1.4 letters for ranibizumab vs aflibercept with 95% credible interval (CrI) of -5.2 to +8.5 letters) or the OR for gaining >= 15 letters: 1.06 (95% CrI 0.16 to 8.94)). Dexamethasone implant was associated with significantly higher IOP/OH than antivascular endothelial growth factor agents (OR 13.1 (95% CrI 1.7 to 116.9)). CONCLUSIONS: There was no statistically significant difference between ranibizumab and aflibercept. PMID- 26048211 TI - Hospitalisation for heart failure and mortality associated with dipeptidyl peptidase 4 (DPP-4) inhibitor use in an unselected population of subjects with type 2 diabetes: a nested case-control study. AB - OBJECTIVE: The SAVOR TIMI-53 study reported a significant increase in the risk of hospitalisation for heart failure (HF) in patients treated with a DPP-4 inhibitor (DPP-4i) in comparison with placebo. A recent case-control study in part confirmed this risk signal. Our aim was to compare the occurrence of HF in relation to DPP-4i use versus any antidiabetic treatment. DESIGN: Population based matched case-control study conducted using administrative data. SETTING: The Italian Region of Piedmont (4.4 million inhabitants). PARTICIPANTS: From a database of 282,000 patients treated with antidiabetic drugs, we identified 14,613 hospitalisations for HF, 7212 incident cases, and 1727 hospital re admissions between 2008 and 2012; each case was matched for gender, age and antidiabetic therapy with 10 controls; cases and controls were compared for exposure to DPP-4i. OUTCOME MEASURES: ORs and 95% CIs were calculated by fitting a conditional logistic model. All analyses were adjusted for available risk factors for HF. RESULTS: We found no increased risk of hospitalisation for HF associated with the use of DPP-4i (OR for admission for HF 1.00 (0.94 to 1.07), incident HF1.01 (0.92 to 1.11), recurrent HF 1.02 (0.84 to 1.22)). All-cause mortality was 6% lower in DPP-4i users (p<0.001), whereas insulin users showed an excess of risk for any type of hospital admission (19%) and death (20%) (p<0.001). CONCLUSIONS: Our findings suggest that, in an unselected population of diabetic patients, the use of DPP-4i is not associated with an increased risk of HF. The favourable impact on all-cause mortality should be viewed with caution and also other explanations investigated. PMID- 26048210 TI - Impact of ethnicity on progress of glycaemic control in 131,935 newly diagnosed patients with type 2 diabetes: a nationwide observational study from the Swedish National Diabetes Register. AB - OBJECTIVES: Studies on ethnic disparities in glycaemic control have been contradictory, and compromised by excessively broad categories of ethnicity and inadequate adjustment for socioeconomic differences. We aimed to study the effect of ethnicity on glycaemic control in a large cohort of patients with type 2 diabetes. SETTING: We used nationwide data (mainly from primary care) from the Swedish National Diabetes Register (2002-2011) to identify patients with newly diagnosed (within 12 months) type 2 diabetes. PARTICIPANTS: We included 131,935 patients (with 713,495 appointments), representing 10 ethnic groups, who were followed up to 10 years. PRIMARY AND SECONDARY OUTCOME MEASURES: Progress of glycated haemoglobin (HbA1c) for up to 10 years was examined. Mixed models were used to correlate ethnicity with HbA1c (mmol/mol). The effect of glycaemic disparities was examined by assessing the risk of developing albuminuria. The impact of ethnicity was compared to that of income, education and physical activity. RESULTS: Immigrants, particularly those of non-Western origin, received glucose-lowering therapy earlier, had 30% more appointments but displayed poorer glycaemic control (2-5 mmol/mol higher HbA1c than native Swedes). Probability of therapy failure was 28-111% higher for non-Western groups than for native Swedes. High-income Western groups remained below the target-level of HbA1c for 4-5 years, whereas non-Western populations never reached the target level. These disparities translated into 51-92% higher risk of developing albuminuria. The impact of ethnicity was greater than the effect of income and education, and equal to the effect of physical activity. CONCLUSIONS: Despite earlier pharmacological treatment and more frequent appointments, immigrants of non Western origin display poorer glycaemic control and this is mirrored in a higher risk of developing albuminuria. PMID- 26048212 TI - A comparison of the recording of comorbidity in primary and secondary care by using the Charlson Index to predict short-term and long-term survival in a routine linked data cohort. AB - OBJECTIVE: Hospital admission records provide snapshots of clinical histories for a subset of the population admitted to hospital. In contrast, primary care records provide continuous clinical histories for complete populations, but might lack detail about inpatient stays. Therefore, combining primary and secondary care records should improve the ability of comorbidity scores to predict survival in population-based studies, and provide better adjustment for case-mix differences when assessing mortality outcomes. DESIGN: Cohort study. SETTING: English primary and secondary care 1 January 2005 to 1 January 2010. PARTICIPANTS: All patients 20 years and older registered to a primary care practice contributing to the linked Clinical Practice Research Datalink from England. OUTCOME: The performance of the Charlson index with mortality was compared when derived from either primary or secondary care data or both. This was assessed in relation to short-term and long-term survival, age, consultation rate, and specific acute and chronic diseases. RESULTS: 657,264 people were followed up from 1 January 2005. Although primary care recorded more comorbidity than secondary care, the resulting C statistics for the Charlson index remained similar: 0.86 and 0.87, respectively. Higher consultation rates and restricted age bands reduced the performance of the Charlson index, but the index's excellent performance persisted over longer follow-up; the C statistic was 0.87 over 1 year, and 0.85 over all 5 years of follow-up. The Charlson index derived from secondary care comorbidity had a greater effect than primary care comorbidity in reducing the association of upper gastrointestinal bleeding with mortality. However, they had a similar effect in reducing the association of diabetes with mortality. CONCLUSIONS: These findings support the use of the Charlson index from linked data and show that secondary care comorbidity coding performed at least as well as that derived from primary care in predicting survival. PMID- 26048213 TI - Background Predictors and Event-Specific Characteristics of Sexual Aggression Incidents: The Roles of Alcohol and Other Factors. AB - Sexual assault in the United States is an important public health concern. Using prospective longitudinal methods and responses from 217 community men, we examined whether background characteristics predicted subsequent sexual aggression (SA) perpetration during a 3-month follow-up period. We also examined event-specific characteristics of reported SA occurrences. Consistent with predictions, SA perpetration history, aggressive and impulsive personality traits, rape myth attitudes, and alcohol expectancies predicted SA (both non- and alcohol-involved) at follow-up. In addition, alcohol-involved assaults occurred more often with casual (vs. steady) partners but were more likely to involve condom use with casual (vs. steady) partners. Results suggest important avenues for future research and SA prevention efforts. PMID- 26048214 TI - Using Experimental Paradigms to Examine Alcohol's Role in Men's Sexual Aggression: Opportunities and Challenges in Proxy Development. AB - The goals of this article are to review the major findings from alcohol administration studies that use sexual aggression proxies and to encourage additional experimental research that evaluates hypotheses about the role of alcohol in the etiology of men's sexual aggression. Experiments allow participants to be randomly assigned to drink conditions, therefore ensuring that any differences between drinkers and nondrinkers can be attributed to their alcohol consumption. One of the biggest challenges faced by experimental researchers is the identification of valid operationalizations of key constructs. The tension between internal and external validity is particularly problematic for violence researchers because they cannot allow participants to engage in the target behavior in the laboratory. The strengths and limitations associated with written vignettes, audiotapes, videotapes, and confederate proxies for sexual aggression are described. Suggestions are made for future research to broaden the generalizability of the findings from experimental research. PMID- 26048215 TI - Narrow QRS systolic heart failure: is there a target for cardiac resynchronization? AB - Cardiac resynchronization therapy has revolutionized the management of systolic heart failure in patients with prolonged QRS during the past 20 years. Initially, the use of this treatment in patients with shorter QRS durations showed promising results, which have since been opposed by larger randomized controlled trials. Despite this, some questions remain, such as, whether correction of mechanical dyssynchrony is the therapeutic target by which biventricular pacing may confer benefit in this group, or are there other mechanisms that need consideration? In addition, novel techniques of cardiac resynchronization therapy delivery such as endocardial and multisite pacing may reduce potential detrimental effects of biventricular pacing, thereby improving the benefit/harm balance of this therapy in some patients. PMID- 26048216 TI - Non-animal photosafety screening for complex cosmetic ingredients with photochemical and photobiochemical assessment tools. AB - Previously, a non-animal screening approach was proposed for evaluating photosafety of cosmetic ingredients by means of in vitro photochemical and photobiochemical assays; however, complex cosmetic ingredients, such as plant extracts and polymers, could not be evaluated because their molecular weight is often poorly defined and so their molar concentration cannot be calculated. The aim of the present investigation was to establish a photosafety screen for complex cosmetic ingredients by using appropriately modified in vitro photosafety assays. Twenty plant extracts were selected as model materials on the basis of photosafety information, and their phototoxic potentials were assessed by means of ultraviolet (UV)/visible light (VIS) spectral analysis, reactive oxygen species (ROS)/micellar ROS (mROS) assays, and 3T3 neutral red uptake phototoxicity testing (3T3 NRU PT). The maximum UV/VIS absorption value was employed as a judgment factor for evaluating photoexcitability of samples, and the value of 1.0 was adopted as a tentative criterion for photosafety identification. The ROS/mROS assays were conducted at 50 MUg/mL, and no false negative prediction was obtained. Furthermore, the ROS/mROS assays at 50 MUg/mL had a similar predictive capacity to the ROS/mROS assays in the previous study. A systematic tiered approach for simple and rapid non-animal photosafety evaluation of complex cosmetic ingredients can be constructed using these modified in vitro photochemical assays. PMID- 26048217 TI - Pullulan: Microbial sources, production and applications. AB - Pullulan is a water-soluble glucan gum produced aerobically by growing a yeast like fungus Aureobasidium pullulans. It is a regularly repeating copolymer with the chemical structure {->6)-alpha-d-glucopyranosyl-(1->4)-alpha-d-glucopyranosyl (1->4)-alpha-d-glucopyranosyl-(1->}n. Thus the polysaccharide is viewed as a succession of alpha-(1->6)-linked (1->4)-alpha-d-triglucosides i.e. maltotriose (G3). Pullulan have a wide range of commercial and industrial applications in many fields like food science, health care, pharmacy and even in lithography. Due to its strictly linear structure, pullulan is also very valuable in basic research as well as a well-defined model substance. This review attempts to critically appraise the current literature on fungal exopolysaccharide (EPS) 'pullulan' considering its microbial sources, structural geometry, upstream processing, downstream processing, peculiar characteristics and applications. PMID- 26048218 TI - Effects of protein on crosslinking of normal maize, waxy maize, and potato starches. AB - Channels of maize starch granules are lined with proteins and phospholipids. Therefore, when they are treated with reagents that react at or near the surfaces of channels, three types of crosslinks could be produced: protein-protein, protein-starch, starch-starch. To determine which of these may be occurring and the effect(s) of channel proteins (and their removal) on crosslinking, normal and waxy maize starches were treated with a proteinase (thermolysin, which is known to remove protein from channels) before and after crosslinking, and the properties of the products were compared to those of a control (crosslinking without proteinase treatment). After establishing that treatment of starch with thermolysin alone had no effect on the RVA trace, three reaction sequences were used: crosslinking alone (CL), proteinase treatment before crosslinking (Enz-CL), proteinase treatment after crosslinking (CL-Enz). Two crosslinking reagents were used: phosphoryl chloride (POCl3), which is known to react at or near channel surfaces; STMP, which is believed to react throughout the granule matrix. Three concentrations of POCl3 (based on the weight of starch) were used. For both normal maize starch (NMS) and waxy maize starch (WMS) reacted with POCl3, the trends were generally the same, with apparent relative degrees of crosslinking indicated to be CL-Enz=CL>Enz-CL, but the effects were greater with NMS and there were differences when different concentrations of reagent were used. The basic trends were the same when potato starch was used in the same experiments. Crosslinking with STMP was done both in the presence and the absence of sodium sulfate (SS). Both with and without SS and with both NMS and WMS, the order of indicated crosslinking was generally the same as found after reaction with POCl3, with the indicated swelling inhibition being greater when SS was present in the reaction mixture. Examination of the maize starches with a protein stain indicated that channel protein was removed by treatment with thermolysin when the proteinase treatment occurred before crosslinking with either POCl3 or STMP, but only incompletely or not at all if the treatment with the proteinase occurred after crosslinking. Because the crosslinking reactions were less effective when the protein was removed, the results are tentatively interpreted as indicating that they involved protein molecules, although there may not be a direct relationship. PMID- 26048219 TI - Antifungal effects of chitosan with different molecular weights on in vitro development of Rhizopus stolonifer (Ehrenb.:Fr.) Vuill. AB - Determination of the molecular weight of three types of chitosan was carried out by HPSEC-RI. The effect of low, medium and high molecular weight chitosan was evaluated on development of three isolates of Rhizopus stolonifer. Image analysis and electronic microscopy observations were done in spores of this fungus. Germination of R. stolonifer in potato dextrose broth with chitosan was also evaluated. Results pointed out that the low molecular weight chitosan was more effective for inhibition of mycelial growth while the high molecular weight chitosan affected spore shape, sporulation and germination. Studies of scanning and transmission electron microscopy revealed numerous and deeper ridge ornamentations of the chitosan-treated spore. PMID- 26048220 TI - Structural investigation and thermal stability of new extruded wheat flour based polymeric materials. AB - In this study, we compare physical properties of wheat starch and wheat-flour based materials. The comparison has been done using thermogravimetric, calorimetric, X-ray diffraction, mechanic and morphologic experiments conducted on a series of wheat-flour extruded materials. The wheat flour used here can be understood as a by-product of the farm-produce wheat flour. All data obtained by means of these experimental methods allow us to conclude that, basically no significant difference exists between our wheat-flour based and wheat-starch based materials. Only one clear difference occurs for the strain to break value which decreases by about 30% for wheat-flour based materials. PMID- 26048221 TI - Orthogonal test design for optimization of the extraction of polysaccharides from Phascolosoma esulenta and evaluation of its immunity activity. AB - Yield of polysaccharides from Phascolosoma esulenta obtained by phosphate buffer extraction through an orthogonal experiment (L9(3)(4)) were investigated to get the best extraction conditions. The results showed that extraction temperature, ratio of phosphate buffer to raw material, extraction time, and ratio of trypsinase to raw material were the main four variables that influenced the yields of extracts. The highest yield was obtained when extraction temperature, ratio of phosphate buffer to raw material, extraction time and ratio of trypsinase to raw material were 40 degrees C, 2, 5.5h and 1.6, respectively. The immunity-stimulating method showed that polysaccharides from P. esulenta could significantly raise liver, spleen and thymus index of mice and enhance Con A stimulated mouse spleen cells proliferation. These results indicate that polysaccharides from P. esulenta had significantly higher immunity-stimulating activities. PMID- 26048222 TI - Structural characterization of an acidic exoheteropolysaccharide produced by the nitrogen-fixing bacterium Burkholderia tropica. AB - An acidic exopolysaccharide (EPS) produced by the diazotrophic bacterium Burkholderia tropica, strain Ppe8, was isolated from the culture supernatant of bacteria grown in a synthetic liquid medium containing mannitol and glutamate. Monosaccharide composition showed Rha, Glc and GlcA in a 2.0:2.0:1.0 molar ratio, respectively. Further structural characterization was performed by a combination of NMR, mass spectrometry and chemical methods. Partial acid hydrolysis of EPS provided a mixture of acidic oligosaccharides that were characterized by ESI-MS, giving rise to ions with m/z 193 (GlcA-H)(-), 339 (GlcA,Rha-H)(-), 501 (GlcA,Rha,Glc-H)(-), 647 (GlcA,Rha2,Glc,-H)(-), 809 (GlcA,Rha2,Glc2,-H)(-) and 851 (GlcA,Rha2,Glc2,OAc-H)(-). Carboxyreduced EPS (EPS-CR) had Glc and Rha in a 3:2 ratio, present as d- and l-enantiomers, respectively. Methylation and NMR analysis of EPS and EPS-CR showed a main chain containing 2,4-di-O-Rhap, 3-O-Rhap and 4-O-Glcp. A GlcA side chain unit was found in the acidic EPS, substituting O 4 of alpha-l-Rhap units. This was observed as a non-reducing end unit of glucopyranose in the EPS-CR. Acetyl esters occured at O-2 of beta-l-Rhap units. From the combined results herein, we determined the structure of the exocellular polysaccharide produced by B. tropica, Ppe8, as being a pentasaccharide repeating unit as shown. PMID- 26048223 TI - Film forming capacity of chemically modified corn starches. AB - Native starch can be chemically modified to improve its functionality and to expand its uses. Modified starches were characterized and the rheological behavior of filmogenic suspensions was analyzed. The film forming capacity of different chemical modified corn starches was evaluated. Acetylated starch was selected by the characteristics of the resulted films; its optimum concentration was 5% w/w since their films exhibited the lowest water vapor permeability (WVP, 1.26*10(-10)g/msPa). The effect of glycerol as plasticizer on film properties depend on its concentration, being 1.5% w/w those that allows to obtain the lowest WVP value (1.64*10(-11)g/msPa), low film solubility in water and a more compact structure than those of unplasticized films. Mechanical behavior of plasticized acetylated starch films depends on glycerol concentration, being rigid and brittle the unplasticized ones, ductile those containing 1.5% w/w of glycerol and very flexible those with a higher plasticizer content. PMID- 26048224 TI - Preparation and characterization of the graft copolymer of chitosan with poly[rosin-(2-acryloyloxy)ethyl ester]. AB - Graft copolymerization of rosin-(2-acryloyloxy)ethyl ester (RAEE) onto chitosan (Cts) was carried out under microwave irradiation using potassium persulfate as an initiator. The structures, morphology, and thermal properties of the Cts graft copolymer (Cts-g-PRAEE) were characterized by means of FT-IR, XRD, SEM, and TG. Also, Cts and Cts-g-PRAEE copolymer were used as carriers of fenoprofen calcium (FC), and their controlled release behavior in artificial intestinal juice were studied. The results show that the rate of release of fenoprofen calcium from the carrier of Cts-g-PRAEE copolymer becomes very slower than that of Cts in artificial intestinal juice. PMID- 26048225 TI - Influence of different sugars on pullulan production and activities of alpha phosphoglucose mutase, UDPG-pyrophosphorylase and glucosyltransferase involved in pullulan synthesis in Aureobasidium pullulans Y68. AB - Effects of different sugars on pullulan production, UDP-glucose level, and activities of alpha-phosphoglucose mutase, UDPG-pyrophosphorylase and glucosyltransferase in Aureobasidium pullulans Y68 were examined. It was found that more pullulan was produced when the yeast strain was grown in the medium containing glucose than when it was cultivated in the medium supplementing other sugars. Our results demonstrate that when more pullulan was synthesized, less UDP glucose was left in the cells of A. pullulans Y68. However, it was observed that more pullulan was synthesized, the cells had higher activities of alpha phosphoglucose mutase, UDPG-pyrophosphorylase and glycosyltransferase. Therefore, high pullulan yield is related to high activities of alpha-phosphoglucose mutase, UDPG-pyrophosphorylase and glucosyltransferase in A. pullulans Y68 grown on different sugars. A pathway of pullulan biosynthesis in A. pullulan Y68 was proposed based on the results of this study and those from other researchers. This study will be helpful to metabolism-engineer the yeast strain to further enhance pullulan yield. PMID- 26048226 TI - The system of sulfated galactans from the red seaweed Gymnogongrus torulosus (Phyllophoraceae, Rhodophyta): Location and structural analysis. AB - Sulfated polysaccharides were localized in the cuticle, cortex and medulla of the gametophyte thallus, being more concentrated in the intercellular matrix than in the cell walls. During the water extraction sequence, a small percentage of galactan sulfates (5.1% of dry seaweed) with average low Mr (6-11.4kDa) were extracted at room temperature without disturbing the cellular arrangement, while sulfated galactans of average medium Mr (18-45kDa) were obtained by further hot water extractions (52.4% of dry seaweed), with diorganization of the tissue. The residue (40.0% of dry seaweed) still contained carrageenan-type (major) and agaran-type (minor) galactans. Part of these galactans was extracted with 8.4% LiCl solution in DMSO, from which "pure" kappa/iota-carrageenans were isolated. Carrageenans and agarans were extracted in a ratio 1:0.5, showing the highest amount of agaran-structures for a carrageenophyte. The galactans comprise alternating 4-sulfated (major) and non-sulfated (minor) 3-linked beta-d galactopyranose units, and 4-linked alpha-galactopyranose units with the following substitutions: (i) non-sulfated and 2-sulfated 3,6-anhydro-alpha-d galactopyranose residues in the carrageenan-structures, which belong to the kappa family (kappa/iota-carrageenans); (ii) 3-sulfated alpha-l-galactopyranose units and 2-sulfated 3,6-anhydro-alpha-l-galactopyranose residues in the agaran structures. Alkaline treatment and alkaline dialysis of the main extracts gave "pure" kappa/iota-carrageenans, showing that carrageenan molecules are extracted together with low Mr agarans or agaran-dl-hybrids. PMID- 26048227 TI - Crosslinking of alginic acid/chitosan matrices using polycarboxylic acids and their utilization for sodium diclofenac release. AB - Three different ratios of alginic acid/chitosan matrices of ratios 3/1, 1/1 and 1/2, respectively, were crosslinked in their dry state using citric acid (CA)/sodium hypophosphite (SHP) at different conditions controlling the crosslinking process such as citric acid concentration, citric acid/sodium hypophosphite molar ratio as well as time and temperature of reaction. Results indicate that such matrices were crosslinked efficiently on curing at 180 degrees C for 9min in presence of CA/SHP ratio 1 and the citric acid concentration of 0.6 based on the weight of any matrices. The crosslinked matrices were characterized by investigating their swelling properties, FT-IR and thermalgravimetric analysis. Furthermore, such crosslinked matrices were tested as drug release for sodium diclofenac. PMID- 26048228 TI - Rapid esterification of wheat straw hemicelluloses induced by microwave irradiation. AB - Esterification of wheat straw hemicelluloses with acetyl chloride, propionyl chloride, n-octanoyl chloride, lauroyl chloride, palmitoyl chloride, stearoyl chloride, and oleoyl chloride, respectively, using N-bromosuccinimide (NBS) as a catalyst was achieved in DMF/LICl medium by microwave irradiation. The effects of various acyl chlorides and the molar ratios of xylose units in hemicelluloses/acyl chloride on the degree of substitution (DS) were investigated and DS reached up to 1.34 by a few minutes. (13)C NMR studies showed that the esterification occurred preferentially at the C-3 and C-2 positions. On the other hand, microwave irradiation brought a partial degradation of the polymer, and therefore resulted in a slight decrease in thermal stability of the hemicellulosic derivatives in comparison with conventional heating technique. PMID- 26048229 TI - Sequential solvent extraction and structural characterization of polysaccharides from the endosperm cell walls of barley grown in different environments. AB - The objective of this study was to examine the composition and molecular structure of the endosperm cell walls (CW) derived from barley grain grown in three environments in Canada, and differing in grain hardness, protein, and total beta-glucan contents. The endosperm CW were isolated from barley, cv. Metcalfe, grown in Davidson, SK (Sample A), Hythe, AB (sample B), and Hamiota, MB (sample C). The CW were sequentially extracted with water at 65(o)C, saturated Ba(OH)2, again with water at 25(o)C, and 1M NaOH, resulting in fractions designated WE65, BaE, Ba/WE, and NaE, respectively. The monosaccharide analysis indicated the presence of beta-glucans, arabinoxylans, and small amounts of arabinogalactans, glucomannans, and xyloglucans. Cellulose was detected in the CW remnants. The CW of sample A, exhibiting a lower grain hardness than sample B, contained the lowest amount of beta-glucans, but the highest amount of arabinoxylans and the mannose-containing polysaccharides. The CW of sample C, characterized by very high protein content in the grain, contained the highest amount of beta-glucans and the lowest amount of other polysaccharides. Polysaccharides in the CW of sample B, exhibiting the highest grain hardness, were characterized by the highest weight average molecular weights (Mw). beta-Glucans in the CW of Sample B showed the highest ratio of DP3/DP4 and the longest cellulosic fragments in the polymeric chains. Of the three barley samples, arabinoxylans in the endosperm CW of sample A exhibited the lowest degree of branching, the highest amount of unsubstituted Xyl residues, and the highest ratio of singly to doubly substituted Xylp. The highest water solubility of the CW of sample C was associated with the highest concentration of beta-glucans, the lowest DP3/DP4 ratio, and the lowest Mw of the polymeric constituents. Arabinoxylans with the lowest amount of doubly substituted but the highest amount of unsubstituted xylose residues and long sequences of unsubstituted xylan regions were found in the NaE fractions. The NaE fractions showed a high ratio of ->4)-Glcp-(1-> to ->3)-Glcp-(1-> linkages and some ->4)-Manp-(1-> linkages, indicating a high level of long cellulosic regions in beta-glucan chains and the presence of glucomannans. PMID- 26048230 TI - Effect of microwave irradiation on the molecular and structural properties of hyaluronan. AB - Hyaluronan (Na(+) salt of hyaluronic acid, HA) was extensively depolymerised by HCl-catalyzed hydrolysis at pH 3 for up to 500min under temperature-controlled microwave irradiation. The effects of microwave heating on the hydrodynamic properties of the polysaccharide were determined by SEC-MALLS and viscometry. The weight-average molecular mass (Mw) of HA decreased from 1.44*10(6) to ~5000, reaching the region of higher oligosaccharides. The scission of HA chains was found to proceed randomly during the whole degradation process. Treatment of the Mw and intrinsic viscosity data according to the Mark-Houwink equation, [eta]=k*Mw(alpha) suggested three relationships with alpha1=0.46 for Mw>500,000, alpha2=0.84 for Mw between 500,000 and 50,000, and alpha3=1.13 for Mw<50,000. The results revealed that HA with Mw>10,000 adopts a stiffish coil conformation in solution. As monitored by FT-IR and NMR spectroscopic techniques, the primary structure of the HA chains was maintained during the microwave-assisted hydrolysis at pH 3 at 105 degrees C. At reaction times larger than 240min, uv spectroscopy suggested the depolymerisation of HA was accompanied by formation of by-products produced by side reaction. PMID- 26048231 TI - Preparation of cassava starch grafted with polystyrene by suspension polymerization. AB - Cassava starch grafted with polystyrene (PS-g-starch) copolymer was synthesized via free-radical polymerization of styrene by using suspension polymerization technique. Potassium persulfate (PPS) was used as an initiator and water was used as a medium. The graft copolymer was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, thermal gravimetric analysis, X ray diffraction and scanning electron microscopy. The sub-micron spherical beads of PS were observed on the surface of starch granules. SEM micrographs showed porous patches of PS adhering on the starch granules after Soxhlet extraction. FTIR spectra also indicated the presence of PS-g-starch copolymer. XRD analysis exhibited insignificant changes in crystalline structure and degree of crystallinity. The effects of starch:styrene weight ratio, amount of PPS, reaction time and reaction temperature on the percentage of grafting - G (%), were investigated. G (%) increased with increasing starch content. Other variables showed their own individual optimal values. The optimum condition yielding 31.47% of G (%) was derived when the component ratio was 1:3 and reaction temperature and time were 50 degrees C and 2h, respectively. Graft copolymerization did not change granular shape and crystallinity of starch. This study demonstrated the capability of polymerization of styrene monomer on the granular starch without emulsifier and the synthesis of graft copolymer without gelatinization of starch. PMID- 26048232 TI - Kinetics and mechanisms of depolymerization of alginate and chitosan in aqueous solution. AB - The kinetics and mechanisms of depolymerization of aqueous chitosan and alginate solutions at elevated temperatures have been investigated. Chitosan salts of different degree of acetylation (FA), type of counterions (-glutamate, -chloride) and degree of purity were studied. One commercially available highly purified sodium alginate sample with high content of guluronic acid (G) was also studied. Furthermore, the influence of oxygen, H(+) and OH(-) ions on the initial depolymerization rates was investigated. Depolymerization kinetics was followed by measuring the time courses of the apparent viscosity and the intrinsic viscosity. The initial rate constants for depolymerization were determined from the intrinsic viscosity data converted to a quantity proportional to the fraction of bonds broken. The activation energies of the chitosan chloride and chitosan glutamate solutions with pH close to 5 and the same degree of acetylation, FA=0.14, were determined from the initial rate constants to be 76+/-13kJ/mol and 80+/-11kJ/mol, respectively. The results reported herein suggest that the stability of aqueous chitosan and alginate solutions at pH values 5-8 will be influenced by oxidative-reductive depolymerization (ORD) as the primary mechanism as long as transition metal ions are presented in the samples. Acid - and alkaline depolymerization will be the primary mechanisms for highly purified samples. PMID- 26048233 TI - Factors influencing production of cationic starches. AB - The main factors - the amount of catalyst NaOH, the temperature and composition of reaction mixture - influencing the effectiveness of starch cationization with glycidyltrimethylammonium chloride (GTAC) were investigated. It was found that cationic or cross-linked cationic starches with preserved microgranules, a degree of substitution from 0.2 to 0.85 and reaction efficiency from 82% to 93% could be obtained during etherification of starch or cross-linked starch with a mixture containing GTAC, "free" water and 0.04-0.08mol/AGU sodium hydroxide in heterogeneous condition. The activation energy of the GTAC main reaction is lower than that of the side reactions, thus starch cationization at a lower temperature proceeds with higher reaction efficiency. The amount of NaOH in the cationization mixture has a great influence on the rate of the main and side reactions of GTAC. Only the main reaction - cationization of starch - proceeds when all the NaOH present in the reaction mixture is adsorbed from the liquid phase by the starch. The duration of this "first reaction stage" decreases with increasing reaction temperature and the amount of NaOH in the reaction mixture. NaOH present in the liquid phase of the reaction mixture catalyzes the side reactions of GTAC and changes their character. PMID- 26048235 TI - Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJ db/db mice. AB - AIMS/HYPOTHESIS: GIP(6-30)Cex-K(40)[Pal] has been characterised as a fatty-acid derived gastric inhibitory polypeptide (GIP) inhibitor that can induce pancreatic beta cell rest by diminishing the incretin effect. We investigated its therapeutic efficacy with and without the glucagon-like peptide-1 (GLP-1) beta cell cytotropic agent liraglutide. METHODS: The therapeutic efficacy of GIP(6 30)Cex-K(40)[Pal] alone, and in combination with liraglutide, was determined in C57BL/KsJ db/db mice using a sequential 12 h administration schedule. RESULTS: GIP(6-30)Cex-K(40)[Pal] was devoid of cAMP-generating or insulin-secretory activity, and inhibited GIP-induced cAMP production and insulin secretion. GIP(6 30)Cex-K(40)[Pal] also inhibited GIP-induced glucose-lowering and insulin releasing actions in mice. Dose- and time-dependent studies in mice revealed that 2.5 nmol/kg GIP(6-30)Cex-K(40)[Pal], and 0.25 nmol/kg liraglutide, imparted distinct biological effects for 8-12 h post administration. When GIP(6-30)Cex K(40)[Pal] (2.5 nmol/kg) and liraglutide (0.25 nmol/kg) were administered sequentially at 12 h intervals (at 08:00 and 20:00 hours) to db/db mice for 28 days, mice treated with GIP(6-30)Cex-K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours) displayed pronounced reductions in circulating glucose and insulin. Both oral and intraperitoneal glucose tolerance and glucose-stimulated plasma insulin concentrations were improved together with enhanced insulin sensitivity. The expression of genes involved in adipocyte lipid deposition was generally decreased. The other treatment modalities, including GIP(6-30)Cex-K(40)[Pal] (08:00 and 20:00 hours), liraglutide (08:00 and 20:00 hours) and liraglutide (08:00 hours) combined with GIP(6-30)Cex-K(40)[Pal] (20:00 hours), also imparted beneficial effects but these were not as prominent as those of GIP(6-30)Cex K(40)[Pal] (08:00 hours) and liraglutide (20:00 hours). CONCLUSION/INTERPRETATION: These data demonstrate that periods of beta cell rest combined with intervals of beta cell stimulation benefit diabetes control and should be further evaluated as a potential treatment option for type 2 diabetes. PMID- 26048234 TI - Effects of exogenous glucagon-like peptide-1 on blood pressure, heart rate, gastric emptying, mesenteric blood flow and glycaemic responses to oral glucose in older individuals with normal glucose tolerance or type 2 diabetes. AB - AIMS/HYPOTHESIS: A postprandial fall in BP occurs frequently in older individuals and in patients with type 2 diabetes. The magnitude of this decrease in BP is related to the rate of gastric emptying (GE). Intravenous administration of glucagon-like peptide-1 (GLP-1) attenuates the hypotensive response to intraduodenal glucose in healthy older individuals. We sought to determine the effects of exogenous GLP-1 on BP, GE, superior mesenteric artery (SMA) flow and glycaemic response to oral ingestion of glucose in healthy older individuals and patients with type 2 diabetes. METHODS: Fourteen older volunteers (six men, eight women; age 72.1 +/- 1.1 years) and ten patients with type 2 diabetes (six men, four women; age 68.7 +/- 3.4 years; HbA1c 6.6 +/- 0.2% [48.5 +/- 2.0 mmol/mol]; nine with blood glucose managed with metformin, two with a sulfonylurea and one with a dipeptidyl-peptidase 4 inhibitor) received an i.v. infusion of GLP-1 (0.9 pmol kg(-1) min(-1)) or saline (154 mmol/l NaCl) for 150 min (t = -30 min to t = 120 min) in randomised order. At t = 0 min, volunteers consumed a radiolabelled 75 g glucose drink. BP was assessed with an automated device, GE by scintigraphy and SMA flow by ultrasonography. Blood glucose and serum insulin were measured. RESULTS: GLP-1 attenuated the fall in diastolic BP after the glucose drink in older individuals (p < 0.05) and attenuated the fall in systolic and diastolic BP in patients with type 2 diabetes (p < 0.05). GE was faster in patients with type 2 diabetes than in healthy individuals (p < 0.05). In both groups, individuals had slower GE (p < 0.001), decreased SMA flow (p < 0.05) and a lower degree of glycaemia (p < 0.001) when receiving GLP-1. CONCLUSIONS/INTERPRETATION: Intravenous GLP-1 attenuates the hypotensive response to orally administered glucose and decreases SMA flow, probably by slowing GE. GLP-1 and 'short-acting' GLP-1 agonists may be useful in the management of postprandial hypotension. PMID- 26048236 TI - Markers of autophagy are adapted to hyperglycaemia in skeletal muscle in type 2 diabetes. AB - AIMS/HYPOTHESIS: Autophagy is a catabolic process that maintains cellular homeostasis by degradation of protein aggregates and selective removal of damaged organelles, e.g. mitochondria (mitophagy). Insulin resistance in skeletal muscle has been linked to mitochondrial dysfunction and altered protein metabolism. Here, we investigated whether abnormalities in autophagy are present in human muscle in obesity and type 2 diabetes. METHODS: Using a case-control design, skeletal muscle biopsies obtained in the basal and insulin-stimulated states from patients with type 2 diabetes during both euglycaemia and hyperglycaemia, and from glucose-tolerant lean and obese individuals during euglycaemia, were used for analysis of mRNA levels, protein abundance and phosphorylation of autophagy related proteins. RESULTS: Muscle transcript levels of autophagy-related genes (ULK1, BECN1, PIK3C3, ATG5, ATG7, ATG12, GABARAPL1, MAP1LC3B, SQSTM1, TP53INP2 and FOXO3A [also known as FOXO3]), including some specific for mitophagy (BNIP3, BNIP3L and MUL1), and protein abundance of autophagy-related gene (ATG)7 and Bcl 2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), as well as content and phosphorylation of forkhead box O3A (FOXO3A) were similar among the groups. Insulin reduced lipidation of microtubule-associated protein light chain 3 (LC3)B I to LC3B-II, a marker of autophagosome formation, with no effect on p62/sequestosome 1 (SQSTM1) content in muscle of lean and obese individuals. In diabetic patients, insulin action on LC3B was absent and p62/SQSTM1 content increased when studied under euglycaemia, whereas the responses of LC3B and p62/SQSTM1 to insulin were normalised during hyperglycaemia. CONCLUSIONS/INTERPRETATION: Our results demonstrate that the levels of autophagy related genes and proteins in muscle are normal in obesity and type 2 diabetes. This suggests that muscle autophagy in type 2 diabetes has adapted to hyperglycaemia, which may contribute to preserve muscle mass. PMID- 26048237 TI - Sugar intake is associated with progression from islet autoimmunity to type 1 diabetes: the Diabetes Autoimmunity Study in the Young. AB - AIMS/HYPOTHESIS: Dietary sugar intake may increase insulin production, stress the beta cells and increase the risk for islet autoimmunity (IA) and subsequent type 1 diabetes. METHODS: Since 1993, the Diabetes Autoimmunity Study in the Young (DAISY) has followed children at increased genetic risk for type 1 diabetes for the development of IA (autoantibodies to insulin, GAD or protein tyrosine phosphatase-like protein [IA2] twice or more in succession) and progression to type 1 diabetes. Information on intake of fructose, sucrose, total sugars, sugar sweetened beverages, beverages with non-nutritive sweetener and juice was collected prospectively throughout childhood via food frequency questionnaires (FFQs). We examined diet records for 1,893 children (mean age at last follow-up 10.2 years); 142 developed IA and 42 progressed to type 1 diabetes. HLA genotype was dichotomised as high risk (HLA-DR3/4,DQB1*0302) or not. All Cox regression models were adjusted for total energy, FFQ type, type 1 diabetes family history, HLA genotype and ethnicity. RESULTS: In children with IA, progression to type 1 diabetes was significantly associated with intake of total sugars (HR 1.75, 95% CI 1.07-2.85). Progression to type 1 diabetes was also associated with increased intake of sugar-sweetened beverages in those with the high-risk HLA genotype (HR 1.84, 95% CI 1.25-2.71), but not in children without it (interaction p value = 0.02). No sugar variables were associated with IA risk. CONCLUSIONS/INTERPRETATION: Sugar intake may exacerbate the later stage of type 1 diabetes development; sugar-sweetened beverages may be especially detrimental to children with the highest genetic risk of developing type 1 diabetes. PMID- 26048238 TI - Correlations between cyanobacterial density and bacterial transformation to the viable but nonculturable (VBNC) state in four freshwater water bodies. AB - Nutrient concentrations, phytoplankton density and community composition, and the viable but nonculturable (VBNC) state of heterotrophic bacteria were investigated in three connected reservoirs and a small isolated lake in South China to study the relationship between biotic and abiotic factors and the VBNC state in bacteria. Nutrient concentrations in the reservoirs increased in the direction of water flow, whereas Wenshan Lake was more eutrophic. Cyanobacterial blooms occurred in all four water bodies, with differing seasonal trends and dominant species. In Xili and Tiegang Reservoirs, the VBNC ratio (percent of VBNC state bacteria over total viable bacteria) was high for most of the year and negatively correlated with cyanobacterial density. Laboratory co-culture experiments were performed with four heterotrophic bacterial species isolated from Wenshan Lake (Escherichia coli, Klebsiella peneumoniae, Bacillus megaterium and Bacillus cereus) and the dominant cyanobacterial species (Microcystis aeruginosa). For the first three bacterial species, the presence of M. aeruginosa induced the VBNC state and the VBNC ratio was positively correlated with M. aeruginosa density. However, B. cereus inhibited M. aeruginosa growth. These results demonstrate that cyanobacteria could potentially regulate the transformation to the VBNC state of waterborne bacteria, and suggest a role for bacteria in cyanobacterial bloom initiation and termination. PMID- 26048239 TI - Family-portraits for daphnids: scanning living individuals and populations to measure body length. AB - A method has been developed and tested to determine the body length of living daphnids. The purpose of the method was the simple, accurate, repeatable, quick, and to the living organism, harmless measurement of body length of all individuals in a population to enhance the capability of observing population development over time. Generally, organisms are transferred to a petri dish and temporarily fixed by removing access medium. A picture of the petri dish is taken using an ordinary flatbed scanner. Pictures are manually analysed with purposely developed software. We found no significant impact of the method on either individual performance (growth and reproduction) or population development (abundance and structure) of daphnids in comparison to the previously used method for data gathering (sieving, counting and length measurement of a subsample via microscopy). The disadvantage of our method, an increased demand in time for picture analysis, is negligible compared to the advantages this method has. Data generated with the new method do represent the population structure more accurately than those data generated with the previously used method. Scanning organisms does also allow a retrospective quality control for generated data as pictures can securely be stored. The quality of the pictures is furthermore sufficient to include additional endpoints to the analysis (e.g., number and size of aborts, number and size of eggs in the brood pouch, spine length). Here, we present, test and discuss an alternative approach to automated image analysis for data gathering in single and multiple individual and species experiments. PMID- 26048240 TI - Responses of bacterial communities in seagrass sediments to polycyclic aromatic hydrocarbon-induced stress. AB - The seagrass meadows represent one of the highest productive marine ecosystems, and have the great ecological and economic values. Bacteria play important roles in energy flow, nutrient biogeochemical cycle and organic matter turnover in marine ecosystems. The seagrass meadows are experiencing a world-wide decline, and the pollution is one of the main reasons. Polycyclic aromatic hydrocarbons (PAHs) are thought be the most common. Bacterial communities in the seagrass Enhalus acoroides sediments were analyzed for their responses to PAHs induced stress. Dynamics of the composition and abundance of bacterial communities during the incubation period were explored by polymerase chain reaction denaturing gradient gel electrophoresis (PCR-DGGE) and quantitative PCR assay, respectively. Both the incubation time and the PAHs concentration played significant roles in determining the microbial diversity, as reflected by the detected DGGE bands. Analysis of sequencing results showed that the Gammaproteobacteria were dominant in the seagrass sediments, accounting for 61.29 % of all sequenced bands. As PAHs could be used as carbon source for microbes, the species and diversity of the PAH added groups (group 1 and 2) presented higher Shannon Wiener index than the group CK, with the group 1 showing the highest values almost through the same incubation stage. Patterns of changes in abundance of the three groups over the experiment time were quite different. The bacterial abundance of the group CK and group 2 decreased sharply from 4.15 * 10(11) and 6.37 * 10(11) to 1.17 * 10(10) and 1.07 * 10(10) copies/g from day 2 to 35, respectively while bacterial abundance of group 1 increased significantly from 1.59 * 10(11) copies/g at day 2 to 8.80 * 10(11) copies/g at day 7, and then dropped from day 14 till the end of the incubation. Statistical analysis (UMPGA and PCA) results suggested that the bacterial community were more likely to be affected by the incubation time than the concentration of the PAHs. This study provided the important information about dynamics of bacterial community under the PAHs stress and revealed the high bacterial diversity in sediments of E. acoroides. Investigation results also indicated that microbial community structure in the seagrass sediment were sensible to the PAHs induced stress, and may be used as potential indicators for the PAHs contamination. PMID- 26048241 TI - Tensile properties of the transverse carpal ligament and carpal tunnel complex. AB - BACKGROUND: A new sophisticated method that uses video analysis techniques together with a Maillon Rapide Delta to determine the tensile properties of the transverse carpal ligament-carpal tunnel complex has been developed. METHODS: Six embalmed cadaveric specimens amputated at the mid-forearm and aged (mean (SD)): 82 (6.29) years were tested. The six hands were from three males (four hands) and one female (two hands). Using trigonometry and geometry the elongation and strain of the transverse carpal ligament and carpal arch were calculated. The cross sectional area of the transverse carpal ligament was determined. Tensile properties of the transverse carpal ligament-carpal tunnel complex and Load Displacement data were also obtained. Descriptive statistics, one-way ANOVA together with a post-hoc analysis (Tukey) and t-tests were incorporated. FINDINGS: A transverse carpal ligament-carpal tunnel complex novel testing method has been developed. The results suggest that there were no significant differences between the original transverse carpal ligament width and transverse carpal ligament at peak elongation (P=0.108). There were significant differences between the original carpal arch width and carpal arch width at peak elongation (P=0.002). The transverse carpal ligament failed either at the mid-substance or at their bony attachments. At maximum deformation the peak load and maximum transverse carpal ligament displacements ranged from 285.74N to 1369.66N and 7.09mm to 18.55mm respectively. The transverse carpal ligament cross-sectional area mean (SD) was 27.21 (3.41)mm(2). INTERPRETATION: Using this method the results provide useful biomechanical information and data about the tensile properties of the transverse carpal ligament-carpal tunnel complex. PMID- 26048242 TI - Comparison of knee kinematics between meniscal tear and normal control during a step-down task. AB - BACKGROUND: Difficulty descending stairs is a common functional complaint reported by patients with meniscal tears. Abnormal knee movement patterns, such as dynamic valgus of the knee or decreased knee flexion during step down, have been reported by clinicians, but 3D knee kinematics descending stairs has never been described in this population. OBJECTIVE: The objective of this study is to compare 3D knee kinematics of individuals with a meniscal tear to that of control individuals during a step-down task. METHODS: Ten participants (6 men and 4 women) diagnosed with a meniscal tear and eleven healthy participants (3 men and 8 women) were recruited. Three-dimensional knee kinematic data were recorded during five step-down task trials with a VICONTM motion analysis system. The following parameters were extracted from the stance phase period only: maximum angle, minimum knee angle, and range of motion (maximum minus minimum) values for sagittal, frontal, and transverse planes. A group comparison was performed by ANOVA using the velocity of the step-down task as the control variable. FINDINGS: Significant reductions in the mean maximum knee flexion angle, knee flexion/extension range of motion, and knee abduction/adduction were observed among the participants with a meniscal tear compared to the control group (mean differences and P values were 4.7 degrees , P=0.02; 5.4 degrees , P=0.02 and 1.6 degrees , P=0.03 respectively). Differences in rotation movement were not significant. INTERPRETATION: This study is the first to describe and compare 3D knee kinematics of persons with a meniscal tear during a step-down task. These findings support that significant kinematic changes occur in the sagittal and frontal plane in individuals with a meniscal tear compared to normal controls. PMID- 26048243 TI - Repurposing medicinal compounds for blood cancer treatment. AB - Drug development is being continuously scrutinised for its lack of productivity. Novel drug development is associated with high costs, high failure rates and lengthy development process. These downfalls combined with a huge demand in blood cancer for new therapeutic treatments have led many to consider the method of drug repurposing. Finding new therapeutic indications for already established drug substances is known as redirecting, repositioning, reprofiling, or repurposing of drugs. Off-patent and on-patent drugs can be screened for additional targets and new indications thus bringing them to clinical trials at a faster pace. This approach offers smaller research groups, such as those that are academic based, into the drug development industry. Drug repurposing can make use of previously published data concerning dosage, toxicology and mechanism of activity. PMID- 26048244 TI - Localized LECT2 amyloidosis of the adrenal gland with coexisting MGUS: a diagnostic challenge. PMID- 26048245 TI - High-throughput gene targeting and phenotyping in zebrafish using CRISPR/Cas9. AB - The use of CRISPR/Cas9 as a genome-editing tool in various model organisms has radically changed targeted mutagenesis. Here, we present a high-throughput targeted mutagenesis pipeline using CRISPR/Cas9 technology in zebrafish that will make possible both saturation mutagenesis of the genome and large-scale phenotyping efforts. We describe a cloning-free single-guide RNA (sgRNA) synthesis, coupled with streamlined mutant identification methods utilizing fluorescent PCR and multiplexed, high-throughput sequencing. We report germline transmission data from 162 loci targeting 83 genes in the zebrafish genome, in which we obtained a 99% success rate for generating mutations and an average germline transmission rate of 28%. We verified 678 unique alleles from 58 genes by high-throughput sequencing. We demonstrate that our method can be used for efficient multiplexed gene targeting. We also demonstrate that phenotyping can be done in the F1 generation by inbreeding two injected founder fish, significantly reducing animal husbandry and time. This study compares germline transmission data from CRISPR/Cas9 with those of TALENs and ZFNs and shows that efficiency of CRISPR/Cas9 is sixfold more efficient than other techniques. We show that the majority of published "rules" for efficient sgRNA design do not effectively predict germline transmission rates in zebrafish, with the exception of a GG or GA dinucleotide genomic match at the 5' end of the sgRNA. Finally, we show that predicted off-target mutagenesis is of low concern for in vivo genetic studies. PMID- 26048246 TI - The sea lamprey meiotic map improves resolution of ancient vertebrate genome duplications. AB - It is generally accepted that many genes present in vertebrate genomes owe their origin to two whole-genome duplications that occurred deep in the ancestry of the vertebrate lineage. However, details regarding the timing and outcome of these duplications are not well resolved. We present high-density meiotic and comparative genomic maps for the sea lamprey (Petromyzon marinus), a representative of an ancient lineage that diverged from all other vertebrates ~550 million years ago. Linkage analyses yielded a total of 95 linkage groups, similar to the estimated number of germline chromosomes (1n ~ 99), spanning a total of 5570.25 cM. Comparative mapping data yield strong support for the hypothesis that a single whole-genome duplication occurred in the basal vertebrate lineage, but do not strongly support a hypothetical second event. Rather, these comparative maps reveal several evolutionarily independent segmental duplications occurring over the last 600+ million years of chordate evolution. This refined history of vertebrate genome duplication should permit more precise investigations of vertebrate evolution. PMID- 26048248 TI - Specific distributions of anions and cations of an ionic liquid through confinement between graphene sheets. AB - This work was aimed to investigate the behavior, morphology, structure, and dynamical properties of pure ionic liquid (IL) 1-ethyl-3-methylimidazolium tetrafluoroborate ([emim][BF4]) confined between two parallel and flat graphene sheets at different interwall distances, H. Thus, molecular dynamic (MD) simulations were performed for different interwall distances including (10, 14, 16, 20, 23, and 28) A at seven temperatures from 278 to 308 K. These results showed that the distribution and orientation of cations and anions on the graphene sheets depended on H. At the shortest H, a dense monolayer of the anions and cations was formed between two graphene sheets. The number of these layers increased as H increased. The potential energy diagram as a function of H demonstrated a minimum potential energy at H = 16 A. Also, there was a minimum overlap between the density profiles of the cations and anions at H = 16 A. Diffusion coefficients of the cations and anions increased as temperature and H increased. Moreover, slope of the plot of the diffusion coefficients of the cations and anions versus H significantly changed at H = 16 A. Orientation functions revealed that most of the cations oriented parallel to the graphene sheets. PMID- 26048247 TI - Regulation of the ESC transcriptome by nuclear long noncoding RNAs. AB - Long noncoding (lnc)RNAs have recently emerged as key regulators of gene expression. Here, we performed high-depth poly(A)(+) RNA sequencing across multiple clonal populations of mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs) to comprehensively identify differentially regulated lncRNAs. We establish a biologically robust profile of lncRNA expression in these two cell types and further confirm that the majority of these lncRNAs are enriched in the nucleus. Applying weighted gene coexpression network analysis, we define a group of lncRNAs that are tightly associated with the pluripotent state of ESCs. Among these, we show that acute depletion of Platr14 using antisense oligonucleotides impacts the differentiation- and development-associated gene expression program of ESCs. Furthermore, we demonstrate that Firre, a lncRNA highly enriched in the nucleoplasm and previously reported to mediate chromosomal contacts in ESCs, controls a network of genes related to RNA processing. Together, we provide a comprehensive, up-to-date, and high resolution compilation of lncRNA expression in ESCs and NPCs and show that nuclear lncRNAs are tightly integrated into the regulation of ESC gene expression. PMID- 26048249 TI - Omalizumab in chronic spontaneous urticaria: patient-tailored tapering or planned discontinuation? PMID- 26048250 TI - Fatal Coxsackie meningoencephalitis in a patient with B-cell lymphopenia and hypogammaglobulinemia following rituximab therapy. PMID- 26048251 TI - Cone-like resection, fistulectomy and mucosal rectal sleeve partial endorectal pull-through in paediatric Crohn's disease with perianal complex fistula. AB - BACKGROUND: Perianal abscesses and fistulae have been reported in approximately 15% of patients with paediatric Crohn's disease and they are associated with poor quality of life. Several surgical techniques were proposed for the treatment of perianal Crohn's disease, characterized by an elevated incidence of failure, incontinence, and relapse. Aim of our study was to present the technical details and results of our surgical technique in case of recurrent, persistent, complex perianal ano-rectal destroying Crohn's disease not responding to medical treatment. METHODS: Data of patients who underwent surgical treatment (cone-like resection, fistulectomy, sphincter reconstruction, endorectal advancement sleeve flaps like in Soave endorectal pull-through) for complicated high-level trans, inter or suprasphincteric fistulae between January 2009 and June 2014 were retrospectively reviewed. RESULTS: 20 surgical procedures were performed in 11 patients (males 72.7%) with transsphincteric (n=5), intersphincteric (n=4) and suprasphincteric (n=2) fistulae. Three patients needed a second treatment. Two patients needed more than 2 surgeries and one temporary colostomy. No patient presented anal incontinence at 15 months' median follow-up. CONCLUSIONS: Although several procedures may be required to obtain a complete remission of perianal lesions, in our series the proposed surgical technique seemed effective and safe, preserving anal continence in all treated cases and reducing the need of faecal diversion. PMID- 26048252 TI - Telomere dysfunction in peripheral blood lymphocytes from patients with primary sclerosing cholangitis and inflammatory bowel disease. AB - BACKGROUND AND AIMS: Primary sclerosing cholangitis and inflammatory bowel disease are two associated, chronic inflammatory, pre-malignant conditions. We hypothesized that patients with these disorders may harbour telomere dysfunction as a marker of chromosomal instability. The aim of our study was to compare parameters of the telomere-telomerase system in these cohorts. METHODS: In this prospective study, peripheral blood was withdrawn from patients with primary sclerosing cholangitis (N=20), inflammatory bowel disease (N=20) and healthy controls (N=20), and lymphocytes were isolated. Telomere length was quantified as a function of the signal intensity and telomere number. Random aneuploidy and telomere capture were determined by fluorescence in situ hybridization technique with specific probes. RESULTS: Patients with inflammatory bowel disease had higher measures of intestinal disease activity than patients with primary sclerosing cholangitis. Despite this, shorter telomere length and telomere aggregates, especially the fusion of 2-5 telomeres, were observed at significantly higher rate in patients with primary sclerosing cholangitis relative to inflammatory bowel disease or healthy controls. Rates of aneuploidy and telomere capture were higher in the two probes in both diseases compared to controls (p<0.001). CONCLUSION: Dysfunction of telomeres was demonstrated in primary sclerosing cholangitis patients more than inflammatory bowel disease and healthy controls patients, which attests to genetic instability and immunosenescence. TRIAL REGISTRATION NUMBER: NCT02247622. PMID- 26048253 TI - Yield of second surveillance colonoscopy to predict adenomas with high-risk characteristics. AB - BACKGROUND AND AIMS: The yield of surveillance colonoscopies for patients with a history of polyps is well established for first surveillance, but limited for second surveillance. The aim of this study was to evaluate the proportion of high risk adenomas at second surveillance colonoscopy based on findings of previous colonoscopies. METHODS: This retrospective cohort study was conducted in a tertiary hospital and patients who had undergone three colonoscopies were included. Based on the findings at index colonoscopy, patients were categorized into three groups: high-risk adenoma (n=252), low-risk adenoma (n=158) or no adenoma (n=318). Findings of subsequent high-risk adenoma, low-risk adenoma and no adenoma at surveillance colonoscopies were documented in each group. RESULTS: Among patients with high-risk adenoma at index and first surveillance colonoscopies, significantly higher rates of high-risk findings were found at second surveillance, compared with patients who had low-risk or no-adenoma at index colonoscopy and high-risk adenoma at first surveillance colonoscopy (58%, 33% and 10%, respectively, p<0.001). CONCLUSIONS: Both index colonoscopy and first surveillance high-risk adenoma have an impact on incidence high-risk findings at second surveillance colonoscopy and these subjects need close surveillance. PMID- 26048254 TI - Early Academic Achievement Among American Low-Income Black Students from Immigrant and Non-Immigrant Families. AB - At least half of the well-documented achievement gap for low-income Black children is already present in kindergarten, due in part to limited opportunities for acquiring foundational skills necessary for school success. There is some evidence that low-income minority children from immigrant families have more positive outcomes than their non-immigrant counterparts, although little is known about how the immigrant paradox may manifest in young children. This study examines foundational school readiness skills (academic and social-emotional learning) at entry into pre-kindergarten (pre-k) and achievement in kindergarten and second grade among Black children from low-income immigrant and non-immigrant families (N = 299). Immigrant and non-immigrant children entered pre-k with comparable readiness scores; in both groups, reading scores decreased significantly from kindergarten to second grade and math scores decreased significantly for non-immigrant children and marginally for immigrant children. Regardless of immigrant status, pre-k school readiness and pre-k classroom quality were associated with elementary school achievement. However, declines in achievement scores were not as steep for immigrant children and several predictive associations were moderated by immigrant status, such that among those with lower pre-k school readiness or in lower quality classrooms, immigrant children had higher achievement test scores than children from non-immigrant families. Findings suggest that immigrant status provides young Black students with some protection against individual- and classroom-level risk factors for early underachievement in elementary school. PMID- 26048255 TI - Strategies to optimize photosensitizers for photodynamic inactivation of bacteria. AB - The Infectious Diseases Society of America (IDSA) highlights that over the past several years, the number of new antibacterial drugs approved continues to decrease (Boucher et al., 2009) [1]. Bacteria are very good in developing resistance against antibiotics in a short time. Therefore new approaches like antibacterial photodynamic inactivation of bacteria (aPDI) will become more important in the future as antimicrobial resistance is expected to continue to increase. This review summarises the potential of the susceptibility of bacteria to aPDI and the strategies to optimize leading photosensitizers which are useful for aPDI. The most appropriate photosensitizers belonging to the chemical classes of phenothiazinium, porphyrine, fullerene and perinaphthenone. They all share the following characteristics: positively-charged, water-soluble and photostable. Taken together the most promising clinical applications of aPDI are (i) decolonization of pathogens on skin, (ii) treatments of the oral cavity like periodontitis and root canal infection and (iii) superinfected burn wounds, because these are relatively accessible for photosensitizer application and illumination. PMID- 26048256 TI - Risk factors and prognosis of vertebral compressive fracture in pyogenic vertebral osteomyelitis. AB - OBJECTIVES: To analyse the clinical, microbiological and radiological characteristics, and to identify risk factors of vertebral compressive fracture (VF) in spontaneous pyogenic vertebral osteomyelitis (VO). METHODS: A retrospective clinical study and blinded radiological review of adult patients with VO. RESULTS: Eighty-eight patients were included: 57 (65%) had a definitive diagnosis of VO (positive microbiology), and 31 (35%) had a probable diagnosis of VO. Of these, 27 (30.7%) presented with VF at diagnosis of VO, and 4 afterwards (total 31, 35.2%). Patients with VF were considered to be at higher risk of osteopenia--they were older (74 vs 66 years, p = 0.013), and included high percentage of women (33 vs 41%, NS)--; and presented more dorsal involvement (56 vs 21%; p < 0.007). Causal microorganisms were similar between groups (VF, no VF). The time to diagnosis of VO was longer in the presence of VF (65 vs 23 days, p = 0.001), and also in cases with no isolated organisms. All patients received antibiotics, and just one patient required spinal stabilisation (VF). After 357 median days of follow-up, all patients were cured. Clinical improvement (residual pain, functional recovery) tended to be slower in patients with VF (log-rank 0.19 and 0.15, respectively), but clinical symptoms were similar in most patients at the last follow-up (VF, no VF). CONCLUSIONS: VF is a common complication in pyogenic VO that causes slower clinical recovery. Risk factors of VF are: osteopenia, a delayed diagnosis and dorsal involvement. Conservative management is probably appropriate for most cases, but spinal stabilisation should be considered in some specific cases. PMID- 26048257 TI - Refractory chyluria due to filariasis. PMID- 26048258 TI - Modeling auditory coding: from sound to spikes. AB - Models are valuable tools to assess how deeply we understand complex systems: only if we are able to replicate the output of a system based on the function of its subcomponents can we assume that we have probably grasped its principles of operation. On the other hand, discrepancies between model results and measurements reveal gaps in our current knowledge, which can in turn be targeted by matched experiments. Models of the auditory periphery have improved greatly during the last decades, and account for many phenomena observed in experiments. While the cochlea is only partly accessible in experiments, models can extrapolate its behavior without gap from base to apex and with arbitrary input signals. With models we can for example evaluate speech coding with large speech databases, which is not possible experimentally, and models have been tuned to replicate features of the human hearing organ, for which practically no invasive electrophysiological measurements are available. Auditory models have become instrumental in evaluating models of neuronal sound processing in the auditory brainstem and even at higher levels, where they are used to provide realistic input, and finally, models can be used to illustrate how such a complicated system as the inner ear works by visualizing its responses. The big advantage there is that intermediate steps in various domains (mechanical, electrical, and chemical) are available, such that a consistent picture of the evolvement of its output can be drawn. However, it must be kept in mind that no model is able to replicate all physiological characteristics (yet) and therefore it is critical to choose the most appropriate model-or models-for every research question. To facilitate this task, this paper not only reviews three recent auditory models, it also introduces a framework that allows researchers to easily switch between models. It also provides uniform evaluation and visualization scripts, which allow for direct comparisons between models. PMID- 26048259 TI - Heterogeneous vascular permeability and alternative diffusion barrier in sensory circumventricular organs of adult mouse brain. AB - Fenestrated capillaries of the sensory circumventricular organs (CVOs), including the organum vasculosum of the lamina terminalis, the subfornical organ and the area postrema, lack completeness of the blood-brain barrier (BBB) to sense a variety of blood-derived molecules and to convey the information into other brain regions. We examine the vascular permeability of blood-derived molecules and the expression of tight-junction proteins in sensory CVOs. The present tracer assays revealed that blood-derived dextran 10 k (Dex10k) having a molecular weight (MW) of 10,000 remained in the perivascular space between the inner and outer basement membranes, but fluorescein isothiocyanate (FITC; MW: 389) and Dex3k (MW: 3000) diffused into the parenchyma. The vascular permeability of FITC was higher at central subdivisions than at distal subdivisions. Neither FITC nor Dex3k diffused beyond the dense network of glial fibrillar acidic protein (GFAP)-positive astrocytes/tanycytes. The expression of tight-junction proteins such as occludin, claudin-5 and zonula occludens-1 (ZO-1) was undetectable at the central subdivisions of the sensory CVOs but some was expressed at the distal subdivisions. Electron microscopic observation showed that capillaries were surrounded with numerous layers of astrocyte processes and dendrites. The expression of occludin and ZO-1 was also observed as puncta on GFAP-positive astrocytes/tanycytes of the sensory CVOs. Our study thus demonstrates the heterogeneity of vascular permeability and expression of tight-junction proteins and indicates that the outer basement membrane and dense astrocyte/tanycyte connection are possible alternative mechanisms for a diffusion barrier of blood derived molecules, instead of the BBB. PMID- 26048260 TI - Disseminated Mycobacterium kansasii disease in complete DiGeorge syndrome. AB - PURPOSE: Complete DiGeorge syndrome (cDGS) describes a subset of patients with DiGeorge syndrome that have thymic aplasia, and thus are at risk for severe opportunistic infections. Patients with cDGS and mycobacterial infection have not previously been described. We present this case to illustrate that patients with cDGS are at risk for nontuberculous mycobacterial infections and to discuss further antimicrobial prophylaxis prior to thymic transplantation. METHODS: A 13 month old male was identified as T cell deficient by the T cell receptor excision circle (TREC) assay on newborn screening, and was subsequently confirmed to have cDGS. He presented with fever and cough, and was treated for chronic aspiration pneumonia as well as Pneumocystis jirovecii infection without significant improvement. It was only after biopsy of mediastinal lymph nodes seen on CT that the diagnosis of disseminated Mycobacterium kansasii was made. We reviewed the literature regarding atypical mycobacterial infections and prophylaxis used in other immunocompromised patients, as well as the current data regarding cDGS detection through TREC newborn screening. RESULTS: Multiple cases of cDGS have been diagnosed via TREC newborn screening, however this is the first patient with cDGS and disseminated mycobacterial infection to be reported in literature. Thymic transplantation is the definitive treatment of choice for cDGS. Prophylaxis with either clarithromycin or azithromycin has been shown to reduce mycobacterial infections in children with advanced human immunodeficiency virus infection. CONCLUSIONS: Children with cDGS should receive thymic transplantion as soon as possible, but prior to this are at risk for nontuberculous mycobacterial infections. Severe, opportunistic infections may require invasive testing for diagnosis in patients with cDGS. Antimicrobial prophylaxis should be considered to prevent disseminated mycobacterial infection in these patients. PMID- 26048261 TI - Anticoagulant management of pregnant women with mechanical heart valve replacement during perioperative period. AB - OBJECTIVE: To investigate the morbidity of complications and pregnancy outcomes in women with mechanical heart valve replacement who received low-dose oral anticoagulation treatment with warfarin throughout the pregnancy, compare the prognosis and complications of patients who were treated with single oral warfarin treatment or the "bridging" therapy treatment, investigate the influence of using vitamin K1 before emergency cesarean section delivery on postoperative warfarin anticoagulant effect and to explore an appropriate anticoagulant regimen during perioperative period for pregnant women with mechanical heart valve replacement. METHOD: 46 pregnant women with mechanical heart valve replacement who received low-dose oral anticoagulation treatment from October 2008 to October 2014 treated at West China Women's and Children's Hospital were retrospectively reviewed. Eight patients received emergency cesarean section (CS), while 38 patients received selective CS, in which 17 patients received single oral warfarin and 21 patients received "bridging" anticoagulation treatment during postoperative period. Morbidity of complications and the time to achieve the target INR after operation were compared. RESULTS: The mechanical valves were at the mitral position in 35 (76.09 %) patients, at the aortic position in 2 (4.35 %) patient and at both the mitral and aortic position in 9 (19.57 %) patients. 46 full-term healthy babies were delivered and no maternal thromboembolic was observed during pregnancy. There was no significant difference of the amount of uterine bleeding between single oral warfarin group and "bridging" treatment group during postpartum period. In single oral warfarin group, one valve thrombosis was observed and led to sudden death. No periphery thrombosis, hematoma, general hemorrhage or other sign of over-anticoagulation was observed. The INR increased more slowly in the group who received emergency CS with preoperative application of vitamin K1 than other two groups. CONCLUSION: The use of vitamin K1 preoperatively might result in warfarin resistance and discontinuation of warfarin therapy before selective CS might be more appropriate than application of vitamin K1. The "bridging" anticoagulation treatment which combines oral warfarin and subcutaneous LMWH might be more effective and safer than single oral warfarin therapy for patients with mechanical heart valve replacement during postoperative period, no matter selective or emergency CS. The safety of low-dose oral warfarin therapy throughout pregnancy is still under controversy. PMID- 26048262 TI - Reply to: Continuous versus cyclic oral contraceptives for endometriosis: any conclusive evidence? PMID- 26048263 TI - Moral reasoning in disaster scenarios. PMID- 26048264 TI - Does diastolic dysfunction precede systolic dysfunction in trastuzumab-induced cardiotoxicity? Assessment with multigated radionuclide angiography (MUGA). AB - BACKGROUND: Trastuzumab is successfully used for the treatment of HER2-positive breast cancer. Because of its association with cardiotoxicity, LVEF is monitored by MUGA, though this is a relatively late measure of cardiac function. Diastolic dysfunction (DD) is believed to be an early predictor of cardiac impairment. We evaluate the merit of MUGA-derived diastolic function parameters in the early detection of trastuzumab-induced cardiotoxicity (TIC). METHODS AND RESULTS: 77 trastuzumab-treated patients with normal baseline systolic and diastolic function were retrospectively selected (n = 77). All serial MUGA examinations were re analyzed for systolic and diastolic function parameters. 36 patients (47%) developed SD and 45 patients (58%) DD during treatment. Both systolic and diastolic parameters significantly decreased. Of the patients with SD, 24 (67%) also developed DD. DD developed prior to systolic impairment in 54% of cases, in 42% vice versa, while time to occurrence did not differ significantly (P = .52). This also applied to the subgroup of advanced stage breast cancer patients (P = .1). CONCLUSIONS: Trastzumab-induced SD and DD can be detected by MUGA. An impairment of MUGA-derived diastolic parameters does not occur prior to SD and therefore cannot be used as earlier predictors of TIC. PMID- 26048265 TI - Dependence of left ventricular functional parameters on image acquisition time in cardiac-gated myocardial perfusion SPECT. AB - BACKGROUND: Reduction of image acquisition time in single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) examinations has been considered. However, association between left ventricular (LV) functional parameters and acquisition time is unclear. METHODS: Twenty-four patients referred to one-day stress/rest SPECT MPI examinations were imaged at rest with dual-headed gamma camera. List-mode emission data were processed into sets of cardiac-gated images corresponding to different acquisition times: 20%, 30%, 40%, 50%, 60%, 80%, and 100% of total acquisition time (30 seconds per projection). Image quality was quantitatively evaluated by computing contrast-to-noise ratio. LV volumes, wall motion, wall thickening, and mechanical dyssynchrony were quantified with automatic clinical software (QGS; Cedars-Sinai Medical Center). RESULTS: A significant negative dependence was found between phase analysis parameter values and image acquisition time. Differences in LV volume parameters were small but statistically significant at relative acquisition times of less than 50%. LV wall motion and wall thickening were found to be robust to the increase of noise. CONCLUSIONS: Image acquisition time of gated SPECT MPI examination can be reduced to 15 seconds per projection without significantly affecting LV volumes, wall motion, or wall thickening. However, reduction of acquisition time has a significant effect on phase analysis results. PMID- 26048267 TI - Determining the competences of community based workers for disability-inclusive development in rural areas of South Africa, Botswana and Malawi. AB - INTRODUCTION: Persons with disabilities and their families still live with stigma and a high degree of social exclusion especially in rural areas, which are often poorly resourced and serviced. Community-based workers in health and social development are in an ideal position to assist in providing critical support for some of those most at risk of neglect in these areas. This article analyses the work of community disability workers (CDWs) in three southern African countries to demonstrate the competencies that these workers acquired to make a contribution to social justice for persons with disabilities and their families. It points to some gaps and then argues that these competencies should be consolidated and strengthened in curricula, training and policy. The article explores local experiences and practices of CDWs so as to understand and demonstrate their professional competencies and capacity to deliver disability inclusive services in rural areas, ways that make all information, activities and programs offered accessible and available to persons with disabilities. METHODS: A qualitative interpretive approach was adopted, informed by a life history approach. Purposive sampling was used to select 16 CDWs who had at least 5 years experience of disability-related work in a rural area. In-depth interviews with CDWs were conducted by postgraduate students in Disability Studies. An inductive and interpretative phenomenological approach was used to analyse data. RESULTS: Three main themes with sub-categories emerged demonstrating the competencies of CDWs. First, integrated management of health conditions and impairments within a family focus comprised 'focus on the functional abilities' and 'communication, information gathering and sharing'. Second, negotiating for disability-inclusive community development included four sub-categories, namely 'mobilising families and community leaders', 'finding local solutions with local resources', 'negotiating retention and transitions through the education system' and 'promoting participation in economic activities'. Third, coordinated and efficient intersectoral management systems involved 'gaining community and professional recognition' and the ability to coordinate efforts ('it's not a one man show'). The CDWs spoke of their commitment to fighting the inequities and social injustices that persons with disabilities experienced. They facilitate change and manage the multiple transitions experienced by the families at different stages of the disabled person's development. CONCLUSIONS: Disability inclusive development embraces a philosophy of social inclusion and a set of values that seeks to protect the human dignity and rights of persons with disabilities. It requires a workforce equipped with skills to work intersectorally and in a cross-disciplinary manner in order to operationalise the community-based rehabilitation guidelines that are designed to promote delivery of services in remote and rural areas. CDWs potentially have a unique set of competencies that enables them to facilitate disability-inclusive community development in rural areas. The themes reveal how the CDWs contribute to building relationships that restore the humanity and dignity of persons with disabilities in their family and community. These competencies draw from different disciplines which necessitates recognition of the CDWs as a cross-disciplinary profession. PMID- 26048266 TI - Off-Label Uses of Omalizumab. AB - The off-label use of medicines is a common and extensive clinical practice. Omalizumab has been licensed for use in severe allergic asthma and chronic urticaria. Omalizumab dosing was based on body weight and baseline serum IgE concentration. All patients are required to have a baseline IgE between 30 and 700 IU/ml and body weight not more than 150 kg. The use of off-label drugs may lead to several problems including adverse effects and an increased risk/benefit balance. In this article, there are summarized off-label uses of omalizumab in the last recent years in diseases in which IgE maybe or certainly has a corner role such as allergic rhinitis, allergic bronchopulmonary aspergillosis, anaphylaxis, keratoconjunctivitis, food allergy, drug allergy, urticaria, angioedema, non-atopic asthma, atopic dermatitis, nasal polyps, Churg-Strauss syndrome, eosinophilic otitis media, chronic rhinosinusitis, bullous pemphigoid, contact dermatitis, and others. Use in pregnancy asthmatic women and pre-co administration with specific immunotherapy will also be revised. PMID- 26048268 TI - A fully human monoclonal antibody with novel binding epitope and excellent neutralizing activity to multiple human IFN-alpha subtypes: A candidate therapy for systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease short of effective therapeutic agents. A multitude of studies of SLE in the last decade have accentuated a central role of the interferon alpha (IFN-alpha) pathway in SLE pathogenesis. We report here a candidate therapeutic neutralizing antibody, AIA22, with a different binding epitope and discrepant neutralizing profile from the anti-multiple IFN-alpha subtype antibodies currently in clinical trials. AIA22 specifically interacts with multiple IFN-alpha subtypes, binds to the type I IFN receptor 2 (IFNAR2) recognition region of IFN-alpha (considered a novel antigen epitope), and effectively neutralizes the activity of almost all of the IFN-alpha subtypes (with the exception of IFN-alpha7) both in vitro and in vivo. Concurrently, structural modeling and computational design yielded a mutational antibody of AIA22, AIAmut, which exhibited substantially improved neutralizing activity to multiple IFN-alpha subtypes. PMID- 26048269 TI - A ruptured pulmonary arteriovenous fistula. PMID- 26048270 TI - Transapical valve-in-valve implantation to treat a regurgitant mitral bioprothesis in a child with failing Fontan circulation. PMID- 26048271 TI - Long-term outcomes after surgical repair of complete atrioventricular septal defect. AB - OBJECTIVE: Survival after surgical repair for complete atrioventricular septal defect (CAVSD) has improved, but patients are at risk for reoperation to address left atrioventricular valve regurgitation and left ventricular outflow tract obstruction. We examined the long-term survival, need for reoperation, and associated risk factors after CAVSD repair at our institution. METHODS: Between 1974 and 2000, a total of 198 patients underwent surgical repair for CAVSD. Of these, 178 patients survived to hospital discharge, of whom 153 (86%) had available follow-up data at a median postoperative time point of 17.2 years (range: 2 months to 38.1 years). RESULTS: Overall perioperative mortality was 10.1%, with a significant decrease to 2.9% in the late surgical era: 1991 to 2000 (P < .001). The overall estimated survival for the entire cohort was 85% at 10 years, 82% at 20 years, and 71% at 30 years after initial CAVSD repair. Requiring a reoperation after initial CAVSD repair was a risk factor for late mortality (P = .04). The estimated freedom from reoperation was 88% at 10 years, 83% at 20 years, and 78% at 30 years after initial CAVSD repair. Indications for reoperation included left atrioventricular valve regurgitation in 14 patients (7.1%) and left ventricular outflow obstruction in 7 patients (3.5%). CONCLUSIONS: Long-term survival after repair of CAVSD remains good. However, the need for reoperation is common and affects long-term survival after CAVSD repair. PMID- 26048272 TI - Delayed sternal closure after total artificial heart implantation. PMID- 26048273 TI - First surgical implantation of a sutureless valve in the pulmonary outflow tract. PMID- 26048274 TI - Another off-label novel oral anticoagulant to HIT cardiac surgery patients. PMID- 26048275 TI - Evaluating a Model to Predict Primary Care Physician-Defined Complexity in a Large Academic Primary Care Practice-Based Research Network. AB - BACKGROUND: Improving the ability to risk-stratify patients is critical for efficiently allocating resources within healthcare systems. OBJECTIVE: The purpose of this study was to evaluate a physician-defined complexity prediction model against outpatient Charlson score (OCS) and a commercial risk predictor (CRP). DESIGN: Using a cohort in which primary care physicians reviewed 4302 of their adult patients, we developed a predictive model for estimated physician defined complexity (ePDC) and categorized our population using ePDC, OCS and CRP. PARTICIPANTS: 143,372 primary care patients in a practice-based research network participated in the study. MAIN MEASURES: For all patients categorized as complex in 2007 by one or more risk-stratification method, we calculated the percentage of total person time from 2008-2011 for which eligible cancer screening was incomplete, HbA1c was >= 9 %, and LDL was >= 130 mg/dl (in patients with cardiovascular disease). We also calculated the number of emergency department (ED) visits and hospital admissions per person year (ppy). KEY RESULTS: There was modest agreement among individuals classified as complex using ePDC compared with OCS (36.7 %) and CRP (39.6 %). Over 4 follow-up years, eligible ePDC-complex patients had higher proportions (p < 0.001) of time with: incomplete cervical (17.8 % vs. 13.3 % for OCS; 19.4 % vs. 11.2 % for CRP), breast (21.4 % vs. 14.9 % for OCS; 22.7 % vs. 15.0 % for CRP), and colon (25.9 % vs. 18.7 % for OCS; 27.0 % vs. 18.2 % for CRP) cancer screening; HbA1c >= 9 % (15.6 % vs. 8.1 % for OCS; 15.9 % vs. 6.9 % for CRP); and LDL >= 130 mg/dl (12.4 % vs. 7.9 % for OCS; 11.8 % vs 9.0 % for CRP). ePDC-complex patients had higher rates (p < 0.003) of: ED visits (0.21 vs. 0.11 ppy for OCS; 0.17 vs. 0.15 ppy for CRP), and admissions in patients 45-64 and >= 65 years old (0.11 vs. 0.10 ppy AND 0.24 vs. 0.21 ppy for OCS). CONCLUSION: Our measure for estimated physician-defined complexity compared favorably to commonly used risk-prediction approaches in identifying future suboptimal quality and utilization outcomes. PMID- 26048276 TI - Bovine TLR2 and TLR4 mediate Cryptosporidium parvum recognition in bovine intestinal epithelial cells. AB - Cryptosporidium parvum (C. parvum) is an intestinal parasite that causes diarrhea in neonatal calves. It results in significant morbidity of neonatal calves and economic losses for producers worldwide. Innate resistance against C. parvum is thought to depend on engagement of pattern recognition receptors. However, the role of innate responses to C. parvum has not been elucidated in bovine. The aim of this study was to evaluate the role of TLRs in host-cell responses during C. parvum infection of cultured bovine intestinal epithelial cells. The expressions of TLRs in bovine intestinal epithelial cells were detected by qRT-PCR. To determine which, if any, TLRs may play a role in the response of bovine intestinal epithelial cells to C. parvum, the cells were stimulated with C. parvum and the expression of TLRs were tested by qRT-PCR. The expression of NF kappaB was detected by western blotting. Further analyses were carried out in bovine TLRs transfected HEK293 cells and by TLRs-DN transfected bovine intestinal epithelial cells. The results showed that bovine intestinal epithelial cells expressed all known TLRs. The expression of TLR2 and TLR4 were up-regulated when bovine intestinal epithelial cells were treated with C. parvum. Meanwhile, C. parvum induced IL-8 production in TLR2 or TLR4/MD-2 transfected HEK293 cells. Moreover, C. parvum induced NF-kappaB activation and cytokine expression in bovine intestinal epithelial cells. The induction of NF-kappaB activation and cytokine expression by C. parvum were reduced in TLR2-DN and TLR4-DN transfected cells. The results showed that bovine intestinal epithelial cells expressed all known TLRs, and bovine intestinal epithelial cells recognized and responded to C. parvum via TLR2 and TLR4. PMID- 26048277 TI - FDA Approval Summary: Ramucirumab for Gastric Cancer. AB - The FDA approved ramucirumab (CYRAMZA; Eli Lilly and Company) for previously treated patients with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma initially as monotherapy (April 21, 2014) and subsequently as combination therapy with paclitaxel (November 5, 2014). In the monotherapy trial, 355 patients in the indicated population were randomly allocated (2:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks. In the combination trial, 665 patients were randomly allocated (1:1) to receive ramucirumab or placebo, 8 mg/kg intravenously every 2 weeks, in combination with paclitaxel, 80 mg/m(2) on days 1, 8, and 15 of 28-day cycles. Overall survival (OS) was increased in patients who received ramucirumab in both the monotherapy [HR, 0.78; 95% confidence interval (CI), 0.60-0.998; log rank P = 0.047] and combination trials (HR, 0.81; 95% CI, 0.68-0.96; P = 0.017). The most common adverse reactions were hypertension and diarrhea in the monotherapy trial and fatigue, neutropenia, diarrhea, and epistaxis in the combination trial. Because of concerns about the robustness of the monotherapy trial results, FDA approved the original application after receiving the results of the combination trial confirming the OS effect. Based on exploratory exposure-response analyses, there is residual uncertainty regarding the optimal dose of ramucirumab. PMID- 26048278 TI - Using CellMiner 1.6 for Systems Pharmacology and Genomic Analysis of the NCI-60. AB - The NCI-60 cancer cell line panel provides a premier model for data integration, and systems pharmacology being the largest publicly available database of anticancer drug activity, genomic, molecular, and phenotypic data. It comprises gene expression (25,722 transcripts), microRNAs (360 miRNAs), whole-genome DNA copy number (23,413 genes), whole-exome sequencing (variants for 16,568 genes), protein levels (94 genes), and cytotoxic activity (20,861 compounds). Included are 158 FDA-approved drugs and 79 that are in clinical trials. To improve data accessibility to bioinformaticists and non-bioinformaticists alike, we have developed the CellMiner web-based tools. Here, we describe the newest CellMiner version, including integration of novel databases and tools associated with whole exome sequencing and protein expression, and review the tools. Included are (i) "Cell line signature" for DNA, RNA, protein, and drugs; (ii) "Cross correlations" for up to 150 input genes, microRNAs, and compounds in a single query; (iii) "Pattern comparison" to identify connections among drugs, gene expression, genomic variants, microRNA, and protein expressions; (iv) "Genetic variation versus drug visualization" to identify potential new drug:gene DNA variant relationships; and (v) "Genetic variant summation" designed to provide a synopsis of mutational burden on any pathway or gene group for up to 150 genes. Together, these tools allow users to flexibly query the NCI-60 data for potential relationships between genomic, molecular, and pharmacologic parameters in a manner specific to the user's area of expertise. Examples for both gain- (RAS) and loss-of-function (PTEN) alterations are provided. PMID- 26048279 TI - Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action. AB - Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1alpha, growth hormone/insulin like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified. PMID- 26048280 TI - Hypothesis: Cryptosporidium genetic diversity mirrors national disease notification rate. AB - BACKGROUND: Cryptosporidiosis is a gastrointestinal disease affecting many people worldwide. Disease incidence is often unknown and surveillance of human cryptosporidiosis is installed in only a handful of developed countries. A genetic marker that mirrors disease incidence is potentially a powerful tool for monitoring the two primary human infected species of Cryptosporidium. METHODS: We used the molecular epidemiological database with Cryptosporidium isolates from ZoopNet, which currently contains more than 1400 records with their sampling nations, and the names of the host species from which the isolates were obtained. Based on 296 C. hominis and 195 C. parvum GP60 sequences from human origin, the genetic diversities of Cryptosporidium was estimated for several nations. Notified cases of human cryptosporidiosis were collected from statistics databases for only four nations. RESULTS: Genetic diversities of C. hominis were estimated in 10 nations in 5 continents, and that of C. parvum of human origin were estimated in 15 nations. Correlation with reported incidence of human cryptosporidiosis in four nations (the Netherlands, United States, United Kingdom and Australia) was positive and significant. A linear model for testing the relationship between the genetic diversity and incidence produced a significantly positive estimate for the slope (P-value < 0.05). CONCLUSIONS: The hypothesis that genetic diversity at GP60 locus mirrors notification rates of human cryptosporidiosis was not rejected based on the data presented. Genetic diversity of C. hominis and C. parvum may therefore be an independent and complementary measure for quantifying disease incidence, for which only a moderate number of stool samples from each nation are sufficient data input. PMID- 26048281 TI - Factors affecting costs for on-farm control of salmonella in Swedish dairy herds. AB - BACKGROUND: The Swedish control program for salmonella includes restrictions and on-farm control measures when salmonella is detected in a herd. Required control measures are subsidised by the government. This provides an opportunity to study costs for on-farm salmonella control. The aim of this study was to describe the costs for on-farm salmonella control in Swedish cattle herds and to investigate the effects of herd factors on these costs in dairy herds. RESULTS: During the 15 years studied there had been a total of 124 restriction periods in 118 cattle herds; 89 dairy herds, 28 specialised fattening herds and three suckler herds. The average costs per herd for on-farm salmonella control was 4.60 million SEK with a median of 1.06 million SEK corresponding to approximately 490 000 and 110 000 EUR. The range was 0.01 to 41 million SEK corresponding to 1080 EUR to 4.44 million EUR per farm. The costs cover measures required in herd-specific control plans, generally measures improving herd hygiene. A mixed linear model was used to investigate associations between herd factors and costs for on-farm salmonella control in dairy herds. Herd size and length of the restriction period were both significantly associated with costs for on-farm control of salmonella with larger herds and longer periods of restrictions leading to higher costs. Serotype detected and administrative changes in the Swedish Board of Agriculture aiming at reducing costs were not associated with costs for on-farm salmonella control. CONCLUSIONS: On-farm control of salmonella in Swedish cattle herds incurred high costs but the costs also varied largely between herds. Larger herds and longer restriction periods increased the costs for on-farm control of salmonella in Swedish dairy herds. This causes concern for future costs for the Swedish salmonella control program as herd sizes are increasing. PMID- 26048283 TI - Attenuation of Antiresorptive Action in Withdrawal of Minodronic Acid for Three Months After Treatment for Twelve Months in Ovariectomized Rats. AB - The purpose of this study was to evaluate the effects of withdrawal of minodronic acid (MIN) for 3 months after 12 months of treatment in ovariectomized (OVX) rat. OVX rats were orally treated with MIN (6, 30, and 150 ug/kg/day) for 12 months and necropsied on the day after the last dosing or following 3 months of withdrawal. Lumbar and femoral BMD were decreased in OVX controls. MIN dose dependently increased BMD. Withdrawal eliminated the effect of MIN on BMD loss after treatment at 6 ug/kg, but not after treatment at 30 and 150 ug/kg. In MIN treated rats, trabecular thinning occurred during withdrawal after treatment at 6 ug/kg, but the trabecular microstructure was maintained at 30 and 150 ug/kg. In a mechanical test of the femoral diaphysis, stiffness of in OVX controls was decreased but ultimate load was similar to that in sham after withdrawal. MIN increased ultimate load and stiffness, but endosteal length decreased after withdrawal. Suppression of bone turnover by MIN based on bone turnover markers and histomorphometric indices was attenuated by withdrawal after treatment at 6 and 30 ug/kg and partially at 150 ug/kg. The MIN concentration in the humerus decreased during withdrawal, and half-life at 30 ug/kg was shorter than that at 150 ug/kg. These results show that the antiresorptive action of MIN was dose dependently attenuated by 3-month withdrawal in a rat OVX model. An absence of BMD increase was only observed at a low dose but decreases in antiresorptive activity occurred over a wide dose range. PMID- 26048282 TI - Do Non-collagenous Proteins Affect Skeletal Mechanical Properties? AB - The remarkable mechanical behavior of bone is attributed to its complex nanocomposite structure that, in addition to mineral and collagen, comprises a variety of non-collagenous matrix proteins or NCPs. Traditionally, NCPs have been studied as signaling molecules in biological processes including bone formation, resorption, and turnover. Limited attention has been given to their role in determining the mechanical properties of bone. Recent studies have highlighted that NCPs can indeed be lost or modified with aging, diseases, and drug therapies. Homozygous and heterozygous mice models of key NCP provide a useful approach to determine the impact of NCPs on bone morphology as well as matrix quality, and to carry out detailed mechanical analysis for elucidating the pathway by which NCPs can affect the mechanical properties of bone. In this article, we present a systematic analysis of a large cohort of NCPs on bone's structural and material hierarchy, and identify three principal pathways by which they determine bone's mechanical properties. These pathways include alterations of bone morphological parameters crucial for bone's structural competency, bone quality changes in key matrix parameters (mineral and collagen), and a direct role as load-bearing structural proteins. PMID- 26048284 TI - High diversity of skin-associated bacterial communities of marine fishes is promoted by their high variability among body parts, individuals and species. AB - Animal-associated microbiotas form complex communities, which are suspected to play crucial functions for their host fitness. However, the biodiversity of these communities, including their differences between host species and individuals, has been scarcely studied, especially in case of skin-associated communities. In addition, the intraindividual variability (i.e. between body parts) has never been assessed to date. The objective of this study was to characterize skin bacterial communities of two teleostean fish species, namely the European seabass (Dicentrarchus labrax) and gilthead seabream (Sparus aurata), using a high throughput DNA sequencing method. In order to focus on intrinsic factors of host associated bacterial community variability, individuals of the two species were raised in controlled conditions. Bacterial diversity was assessed using a set of four complementary indices, describing the taxonomic and phylogenetic facets of biodiversity and their respective composition (based on presence/absence data) and structure (based on species relative abundances) components. Variability of bacterial diversity was quantified at the interspecific, interindividual and intraindividual scales. We demonstrated that fish surfaces host highly diverse bacterial communities, whose composition was very different from that of surrounding bacterioplankton. This high total biodiversity of skin-associated communities was supported by the important variability, between host species, individuals and the different body parts (dorsal, anal, pectoral and caudal fins). PMID- 26048285 TI - Curcumin prophylaxis mitigates the incidence of hypobaric hypoxia-induced altered ion channels expression and impaired tight junction proteins integrity in rat brain. AB - BACKGROUND: The present study was proposed to elucidate the prophylactic role of curcumin in the prevention of hypoxia-induced cerebral edema (HACE). METHODS: Rats were exposed to simulated hypobaric hypoxia at 7620 m for 24 h at 25 +/- 1 degrees C. Transvascular leakage, expression of transcriptional factors (nuclear factor-kappa B (NF-kappaB) and hypoxia inducible factor 1 alpha (Hif-1alpha) and also the genes regulated by these transcriptional factors, sodium potassium adenosine triphosphatase (Na(+)/K(+)-ATPase) and endothelial sodium channel (ENaC) levels and brain tight junction (TJ) proteins like ZO-1, junctional adhesion molecule C (JAMC), claudin 4 and claudin 5 levels were determined in the brain of rats under hypoxia by Western blotting, electro mobility shift assay, ELISA, immunohistochemistry, and histopathology along with haematological parameters. Simultaneously, to rule out the fact that inflammation causes impaired Na(+)/K(+)-ATPase and ENaC functions and disturbing the TJ integrity leading to cerebral edema, the rats were pre-treated with curcumin (100 mg/kg body weight) 1 h prior to 24-h hypoxia. RESULTS: Curcumin administration to rats, under hypoxia showed a significant decrease (p < 0.001) in brain water content (3.53 +/- 0.58 wet-to-dry-weight (W/D) ratio) and transvascular leakage (136.2 +/ 13.24 relative fluorescence units per gram (r.f.u./g)) in the brain of rats compared to control (24-h hypoxia) (7.1 +/- 1.0 W/D ratio and 262.42 +/- 24.67 r.f.u./g, respectively). Curcumin prophylaxis significantly attenuated the upregulation of NF-kappaB (p < 0.001), thereby leading to concomitant downregulation of pro-inflammatory cytokine levels (?IL-1, IL-2, IL-18 and TNF alpha), cell adhesion molecules (?P-selectin and E-selectin) and increased anti inflammatory cytokine (?IL-10). Curcumin stabilized the brain HIF-1alpha levels followed by maintaining VEGF levels along with upregulated Na(+)/K(+)-ATPase and ENaC levels (p < 0.001) under hypoxia. Curcumin restored the brain ZO-1, JAMC, claudin 4 and claudin 5 levels (p < 0.001) under hypoxia. Histopathological observations revealed the absence of edema and inflammation in the brain of rats supplemented with curcumin. CONCLUSIONS: These results indicate that curcumin is a potent drug in amelioration of HACE as it effectively attenuated inflammation as well as fluid influx by maintaining the tight junction proteins integrity with increased ion channels expression in the brain of rats under hypoxia. PMID- 26048286 TI - Validation of ethnopharmacological uses of Heliotropium strigosum Willd. as spasmolytic, bronchodilator and vasorelaxant remedy. AB - BACKGROUND: Heliotropium strigosum is used in traditional medicine to manage gastrointestinal pain, respiratory distress and vascular disorders. The present study was undertaken to provide scientific evidences for these folkloric uses by in vitro experimental settings. METHODS: A crude methanol extract of the Heliotropium strigosum (Hs.Cr) was tested in vitro on isolated rabbit jejunum preparations to detect the possible presence of spasmolytic activity. Moreover, isolated rabbit tracheal and aorta preparations were used to ascertain the relaxant effects of the extract. RESULTS: The Hs.Cr exhibited relaxant effects in rabbit jejunum in a concentration dependent manner (0.01-3.0 mg/ml). The Hs.Cr also relaxed K(+) (80 mM)-induced spastic contractions in rabbit jejunum and shifted the Ca(2+) concentration response curves towards right. The extract relaxed carbachol (1 MUM)- as well as K(+) (80 mM)-induced contractions in rabbit trachea at concentrations ranging from 0.01 to 10 mg/ml. Moreover, Hs.Cr. also relaxed (0.01-3.0 mg/ml) the phenylephrine (1 MUM)- and K(+) (80 mM)-induced contractions in isolated rabbit aorta. CONCLUSIONS: The Hs.Cr was found to exhibit spasmolytic, bronchodilator and vasorelaxant activities on isolated rabbit jejunum, trachea and aorta preparations, likely mediated through Ca(2+) channel blockade. This finding may provide a scientific basis for the folkloric uses of the plant. PMID- 26048287 TI - A review of the effect of omega-3 polyunsaturated fatty acids on blood triacylglycerol levels in normolipidemic and borderline hyperlipidemic individuals. AB - Circulating levels of triacylglycerol (TG) is a recognized risk factor for developing cardiovascular disease, a leading cause of death worldwide. The Institute of Medicine and the American Heart Association both recommend the consumption of n-3 polyunsaturated fatty acids (PUFA), specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), to reduce serum TG in hyperlipidemic individuals. Additionally, a number of systematic reviews have shown that individuals with any degree of dyslipidemia, elevated serum TG and/or cholesterol, may benefit from a 20-30% reduction in serum TG after consuming n-3 PUFA derived from marine sources. Given that individuals with serum lipid levels ranging from healthy to borderline dyslipidemic constitute a large portion of the population, the focus of this review was to assess the potential for n-3 PUFA consumption to reduce serum TG in such individuals. A total of 1341 studies were retrieved and 38 clinical intervention studies, assessing 2270 individuals, were identified for inclusion in the current review. In summary, a 9-26% reduction in circulating TG was demonstrated in studies where >= 4 g/day of n-3 PUFA were consumed from either marine or EPA/DHA-enriched food sources, while a 4-51% reduction was found in studies where 1-5 g/day of EPA and/or DHA was consumed through supplements. Overall, this review summarizes the current evidence with regards to the beneficial effect of n-3 PUFA on circulating TG levels in normolipidemic to borderline hyperlipidemic, otherwise healthy, individuals. Thus demonstrating that n-3 PUFA may play an important role in the maintenance of cardiovascular health and disease prevention. PMID- 26048289 TI - The Nevada Rural Ozone Initiative: A framework for developing an understanding of factors contributing to elevated ozone concentrations in rural and remote environments. PMID- 26048288 TI - Anti-CII antibody as a novel indicator to assess disease activity in systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects a variety of organ systems. Anti-dsDNA Abs and complement factors have been used as indicators of lupus activity for more than 50 years. A novel indicator of activation in SLE is reported in this paper. Anti-collagen type II (CII) Ab was obviously elevated in patients with SLE compared to those patients with ankylosing spondylitis (AS) and healthy controls (HCs). Anti-CII-Ab-positive patients with SLE showed significantly higher levels of serum IgG and higher titers of ANA but lower levels of C3 and C4 than controls. A positive correlation was demonstrated between anti-CII Ab and serum IgG in SLE patients (r = 0.50, p < 0.0001). The negative correlations of anti-CII Ab with C3 and C4 were observed in SLE patients (r = -0.36, p = 0.0013; r = -0.37, p = 0.0006, respectively). The reduced anti-CII Ab level was accompanied by decreased level of serum IgG and increased levels of C3 and C4 after regular treatment. Therefore, anti-CII Ab could be a novel indicator for monitoring activity of SLE. PMID- 26048290 TI - Modeling dry and wet deposition of sulfate, nitrate, and ammonium ions in Jiuzhaigou National Nature Reserve, China using a source-oriented CMAQ model: Part I. Base case model results. AB - A source-oriented Community Multiscale Air Quality (CMAQ) model driven by the meteorological fields generated by the Weather Research and Forecasting (WRF) model was used to study the dry and wet deposition of nitrate (NO3(-)), sulfate (SO4(2-)), and ammonium (NH4(+)) ions in the Jiuzhaigou National Nature Reserve (JNNR), China from June to August 2010 and to identify the contributions of different emission sectors and source regions that were responsible for the deposition fluxes. The model performance is evaluated in this paper and the source contribution analyses are presented in a companion paper. The results show that WRF is capable of reproducing the observed precipitation rates with a Mean Normalized Gross Error (MNGE) of 8.1%. Predicted wet deposition fluxes of SO4(2-) and NO3(-) at the Long Lake (LL) site (3100 m a.s.l.) during the three-month episode are 2.75 and 0.34 kg S(N) ha(-1), which agree well with the observed wet deposition fluxes of 2.42 and 0.39 kg S(N) ha(-1), respectively. Temporal variations in the weekly deposition fluxes at LL are also well predicted. Wet deposition flux of NH4(+) at LL is over-predicted by approximately a factor of 3 (1.60 kg N ha(-1)vs. 0.56 kg N ha(-1)), likely due to missing alkaline earth cations such as Ca(2+) in the current CMAQ simulations. Predicted wet deposition fluxes are also in general agreement with observations at four Acid Deposition Monitoring Network in East Asia (EANET) sites in western China. Predicted dry deposition fluxes of SO4(2-) (including gas deposition of SO2) and NO3(-) (including gas deposition of HNO3) are 0.12 and 0.12 kg S(N) h a(-1) at LL and 0.07 and 0.08 kg S(N) ha(-1) at Jiuzhaigou Bureau (JB) in JNNR, respectively, which are much lower than the corresponding wet deposition fluxes. Dry deposition flux of NH4(+) (including gas deposition of NH3) is 0.21 kg N ha(-1) at LL, and is also much lower than the predicted wet deposition flux. For both dry and wet deposition fluxes, predictions from the 12-km resolution nested domain are similar to those from the 36-km resolution parent domain. PMID- 26048291 TI - Weight-loss talks: what works (and what doesn't). AB - BACKGROUND: In primary care encounters, it is unknown whether physician advice on weight-related matters leads to patient weight loss. To examine this issue, we analyzed physician weight loss advice and measured corresponding changes in patients' dietary intake, physical activity, and weight. METHODS: Using audio recorded primary care encounters between 40 physicians and 461 of their overweight or obese patients, we coded weight-related advice as nonspecific, specific nutritional, specific exercise, or specific weight. Physicians and patients were told the study was about preventive health, not weight. We used mixed models (SAS ProcMixed), controlled for physician clustering and baseline covariates, to assess changes in diet, exercise, and measured weight, both pre encounter and 3 months post-encounter. RESULTS: When discussing weight, physicians typically provided a combination of specific weight, nutrition, and physical activity advice to their patients (34%). Combined advice resulted in patients reducing their dietary fat intake (P=.02). However, when physicians provided physical activity advice only, patients were significantly (P=.02) more likely to gain weight (+1.41 kg) compared with those who received no advice. CONCLUSION: When giving weight-related advice, most physicians provided a combination of lifestyle recommendations. Combining advice may help patients reduce their fat intake. Physical activity advice alone may not be particularly helpful. PMID- 26048292 TI - A comparison of the low temperature transcriptomes of two tomato genotypes that differ in freezing tolerance: Solanum lycopersicum and Solanum habrochaites. AB - BACKGROUND: Solanum lycopersicum and Solanum habrochaites are closely related plant species; however, their cold tolerance capacities are different. The wild species S. habrochaites is more cold tolerant than the cultivated species S. lycopersicum. RESULTS: The transcriptomes of S. lycopersicum and S. habrochaites leaf tissues under cold stress were studied using Illumina high-throughput RNA sequencing. The results showed that more than 200 million reads could be mapped to identify genes, microRNAs (miRNAs), and alternative splicing (AS) events to confirm the transcript abundance under cold stress. The results indicated that 21% and 23% of genes were differentially expressed in the cultivated and wild tomato species, respectively, and a series of changes in S. lycopersicum and S. habrochaites transcriptomes occur when plants are moved from warm to cold conditions. Moreover, the gene expression patterns for S. lycopersicum and S. habrochaites were dissimilar; however, there were some overlapping genes that were regulated by low temperature in both tomato species. An AS analysis identified 75,885 novel splice junctions among 172,910 total splice junctions, which suggested that the relative abundance of alternative intron isoforms in S. lycopersicum and S. habrochaites shifted significantly under cold stress. In addition, we identified 89 miRNA sequences that may regulate relevant target genes. Our data indicated that some miRNAs (e.g., miR159, miR319, and miR6022) play roles in the response to cold stress. CONCLUSIONS: Differences in gene expression, AS events, and miRNAs under cold stress may contribute to the observed differences in cold tolerance of these two tomato species. PMID- 26048293 TI - Metabotropic glutamate receptor 5, and its trafficking molecules Norbin and Tamalin, are increased in the CA1 hippocampal region of subjects with schizophrenia. AB - Metabotropic glutamate receptor 5 (mGluR5) is involved in hippocampal-dependent learning and memory, which are processes disrupted in schizophrenia. Recent evidence from human genetic and animal studies suggests that the regulation of mGluR5, including its interaction with trafficking molecules, may be altered in the disorder. However there have been no investigations of hippocampal mGluR5 or mGluR5 trafficking molecules in the postmortem schizophrenia brain to confirm this. In the present study, we investigated whether protein expression of mGluR5, as well as Norbin and Tamalin (modulators of mGluR5 signalling and trafficking), might be altered in the schizophrenia brain, using postmortem samples from the hippocampal CA1 region of schizophrenia subjects and matched controls (n=20/group). Protein levels of mGluR5 (total: 42%, p<0.001; monomer: 25%, p=0.011; dimer: 52%, p<0.001) and mGluR5 trafficking molecules (Norbin: 47%, p<0.001; Tamalin: 34%, p=0.009) were significantly higher in schizophrenia subjects compared to controls. To determine any influence of antipsychotic drug treatment, all proteins were also correlated with lifetime chlorpromazine equivalents in patients, and separately measured in the hippocampus of rats exposed to haloperidol or olanzapine treatment. mGluR5 was negatively correlated with lifetime antipsychotic drug exposure in schizophrenia patients, suggesting antipsychotic drugs could reduce mGluR5 protein in schizophrenia subjects. In contrast, mGluR5 and mGluR5 trafficking molecules were not altered in the hippocampus of antipsychotic drug treated rats. This investigation provides strong support for the hypothesis that mGluR5 is involved in the pathology of schizophrenia, and that alterations to mGluR5 trafficking might contribute to the hippocampal-dependent cognitive dysfunctions associated with this disorder. PMID- 26048296 TI - Feasibility and validity of monitoring subarachnoid hemorrhage by a noninvasive MRI imaging perfusion technique: Pulsed Arterial Spin Labeling (PASL). AB - BACKGROUND AND PURPOSE: To evaluate the validity of pulsed arterial spin labeling (PASL) imaging with cerebral blood flow (CBF) quantification for monitoring subarachnoid hemorrhage (SAH); to describe changes in the perfusion signal in the absence of or following several classic complications. MATERIALS AND METHODS: Fifteen patients and 14 healthy volunteers were assigned to SAH and control populations, respectively. ASL imaging was performed three times: between Day 0 (D0, i.e., day of onset of SAH symptoms) and D3, between D7 and D9 and between D12 and D14. ASL points were classified as complicated (symptomatic vasospasm, intraparenchymal hematoma or severe intracranial hypertension) or uncomplicated. Perfusion and CBF maps were generated after automated processing. The inversion time (TI) was fixed at 1800 ms. RESULTS: CBF mean value of Day0-3 uncomplicated SAH patients (47 +/- 11.7 mL/min/100g) was significantly higher than that of the volunteers (36.5 +/- 7.6 mL/min/100g; P=0.014). In a case-by-case analysis, we observed a global or regional hypoperfusion pattern when SAH was complicated by vasospasm or severe intracranial hypertension, particularly at the junctional areas. Furthermore, we have faced major vascular artefacts, visible as serpiginous high signals and related to the retention of labeled protons in arteries concerning by angiographic vasospasm. CONCLUSION: PASL is an interesting perfusion technique to non-invasively highlight perfusion changes in complicated SAH and can provide a new element in the decision to perform urgent endovascular treatment. However, the increase in arterial transit time makes the Buxton quantification model inapplicable and leads to false high CBF values in the single-TI PASL technique. PMID- 26048295 TI - Trends and predictors of outcomes after surgery for hepatocellular carcinoma: A nationwide population-based study in Taiwan. AB - BACKGROUND: Despite the huge and growing global burden of hepatocellular carcinoma (HCC), high-quality population-based studies of HCC prevalence and outcomes are scarce. PURPOSE: To analyze trends and predictors of hospital resource utilization and mortality rates in a population of patients who had received HCC surgery. PATIENTS AND MATERIALS: This population-based patient cohort study retrospectively analyzed 23,107 patients who had received surgical treatment for HCC from 1998 to 2009. RESULTS: The prevalence rate of surgical treatment in HCC patients significantly increased by 167.4% from 4.857 per 100,000 persons in 1998 to 12.989 per 100,000 persons in 2009 (P < 0.001). Age, gender, Deyo-Charlson co-morbidity index score, hospital volume, surgeon volume, digestive system disease, hepatitis type and liver cirrhosis were significantly associated with HCC surgical outcomes (P < 0.05). Over the 12-year period analyzed, the estimated mean hospital treatment cost increased 9.4% whereas mean length of stay (LOS) decreased 25.3%. The estimated mean overall survival time after HCC surgery was 40.9 months (SD 1.2 months), and the overall in-hospital 1 , 3-, and 5-year survival rates were 97.2%, 79.9%, 61.1%, and 54.6%, respectively. CONCLUSIONS: These population-based data reveal that the prevalence of HCC has increased, especially in older patients. Additionally, hospital treatment costs for HCC have increased despite decreases in LOS. These analytical results should be applicable to most countries with relatively small populations. Additionally, healthcare providers and patients should recognize that attributes of both the patient and the hospital may affect outcomes. PMID- 26048297 TI - Privileged versus shared knowledge about object identity in real-time referential processing. AB - A central claim in research on interactive conversation is that listeners use the knowledge assumed to be shared with a conversational partner to guide their understanding of utterances from the earliest moments of processing. In the present study we investigated whether this claim extends to cases where shared vs. private knowledge is discrepant in terms of the identity assigned to a mutually seen object that could be misidentified on the basis of its appearance. Eye movement measures were used to evaluate listeners' ability to integrate a speaker's perspective as they identified the referent for an unfolding expression. The results reconfirmed previous findings showing that listeners can rapidly take into account a speaker's awareness of the existence/presence of a referential object. In contrast, however, listeners showed strong consideration of their private knowledge about the identity of an object during referential processing. Strikingly, this tendency was found even when speaker-produced discourse reinforced the way in which the speaker's understanding of the object's identity differed from that of the listener. Together, the results reveal clear and important differences in the way in which distinct types of perspective-based cues are integrated in real-time communicative interaction. PMID- 26048298 TI - From Imaging the Brain to Imaging the Retina: Optical Coherence Tomography (OCT) in Schizophrenia. AB - Optical Coherence Tomography (OCT) is a noninvasive imaging method, which provides an in vivo image of the retina. It allows for quantitative measurements of retinal and macular thickness, including single-layer analysis. Because the retinal nerve fibre layer comprises the first axons of the visual pathway and is unmyelinated, it can be considered a unique anatomical model, which may provide insight into the pathophysiological processes of diseases with a neurodegenerative character. In fact, past OCT studies have emphasized the role of the visual pathway as an ideal structure for exploring neurodegeneration and have demonstrated the potential of the method as an instrument for longitudinally monitoring structural changes in neurological disorders such as multiple sclerosis. Progress in signal processing and advancements to the OCT technique enables the illustration of structural changes in the retinal layers in a quick, reproducible, and objective manner with a spatial resolution comparable to those of histological slices.Findings from computer-based magnetic resonance imaging analyses and neuropathological studies support the hypothesis of a degenerative component of certain psychiatric disorders such as schizophrenia. Studies in schizophrenia incorporating OCT are currently rare and have yielded further heterogeneous results. This article elucidates the method of OCT and the retina's role as a "window to the brain". Furthermore, in delineating the degenerative components of schizophrenia, we discuss the possible applications of OCT in the schizophrenia population. PMID- 26048294 TI - In vivo imaging of neuroinflammation in schizophrenia. AB - In recent years evidence has accumulated to suggest that neuroinflammation might be an early pathology of schizophrenia that later leads to neurodegeneration, yet the exact role in the etiology, as well as the source of neuroinflammation, are still not known. The hypothesis of neuroinflammation involvement in schizophrenia is quickly gaining popularity, and thus it is imperative that we have reliable and reproducible tools and measures that are both sensitive, and, most importantly, specific to neuroinflammation. The development and use of appropriate human in vivo imaging methods can help in our understanding of the location and extent of neuroinflammation in different stages of the disorder, its natural time-course, and its relation to neurodegeneration. Thus far, there is little in vivo evidence derived from neuroimaging methods. This is likely the case because the methods that are specific and sensitive to neuroinflammation are relatively new or only just being developed. This paper provides a methodological review of both existing and emerging positron emission tomography and magnetic resonance imaging techniques that identify and characterize neuroinflammation. We describe ?how these methods have been used in schizophrenia research. We also outline the shortcomings of existing methods, and we highlight promising future techniques that will likely improve state-of-the-art neuroimaging as a more refined approach for investigating neuroinflammation in schizophrenia. PMID- 26048300 TI - Vagal mediation of GLP-1's effects on food intake and glycemia. AB - Nutrient stimulation of the enteroendocrine L-cells induces the release of the glucagon-like peptide-1 (GLP-1), an incretin and satiating peptide. Due to its short half-life, meal-induced GLP-1's effects on food intake and glycemia are likely to be mediated in part by a paracrine signaling mechanism near the site of release. Early and recent findings from vagus nerve lesion studies scrutinized in this review strongly support an important role of the vagus nerve in mediating GLP-1's effects. Peripheral GLP-1 or GLP-1R agonist treatment failed to elicit the full satiating effects and maintain glucose homeostasis in various lesion models. The potential mechanisms underlying the vagal GLP-1R mediated satiation and glycemic control presumably involve the activation of caudal brainstem neurons via glutamatergic signaling, which activate a vagal reflex loop or/and relay the information to higher brain centers. Recent studies also presented here, however, diminish the relevance of the vagus nerve for the pharmacological intervention of obesity and diabetes with chronic GLP-1R agonist treatments, suggesting that endogenous intestinal GLP-1 and GLP-1R agonists may activate different GLP-1R populations. Finally, lesion-based approaches are limited and new technical approaches are discussed to improve the understanding of vagal GLP 1R functions in maintaining normal energy balance and its relevance in pharmacological interventions. PMID- 26048299 TI - Maternal nicotine exposure during lactation alters food preference, anxiety-like behavior and the brain dopaminergic reward system in the adult rat offspring. AB - The mesolimbic reward pathway is activated by drugs of abuse and palatable food, causing a sense of pleasure, which promotes further consumption of these substances. Children whose parents smoke are more vulnerable to present addictive like behavior to drugs and food.We evaluated the association between maternal nicotine exposure during lactation with changes in feeding, behavior and in the dopaminergic reward system. On postnatal day (PN) 2,Wistar rat dams were implanted with minipumps releasing nicotine (N; 6 mg/kg/day, s.c.) or saline (C) for 14 days. On PN150 and PN160, offspring were divided into 4 groups for a food challenge: N and C that received standard chow(SC); and N and C that could freely self-select (SSD) between high-fat and high-sugar diets (HFD and HSD, respectively). Offspring were tested in the elevated plus maze (EPM) and open field (OF) arena on PN152-153. On PN170, offspring were euthanized for central dopaminergic analysis. SSD animals showed an increased food intake compared to SC ones and a preference for HFD. However, N-SSD animals consumed relatively more HSD than C-SSD ones. Regarding behavior, N animals showed an increase in the time spent in the EPM center and a reduction in relative activity in the OF center. N offspring presented lower dopamine receptor (D2R) and transporter (DAT) contents in the nucleus accumbens, and lower D2R in the arcuate nucleus. Postnatal exposure to nicotine increases preference for sugar and anxiety levels in the adult progeny possibly due to a decrease in dopaminergic action in the nucleus accumbens and arcuate nucleus. PMID- 26048301 TI - A comparison of heart rate variability in women at the third trimester of pregnancy and during low-risk labour. AB - Heart rate variability (HRV) has been recognised as a non-invasive method for assessing cardiac autonomic regulation. Aiming to characterize HRV changes at labour in women, we studied 10 minute ECG recordings from young mothers (n=30) at the third trimester of pregnancy (P) or during augmentation of labour (L) (n=30). Data of the L group were collected when no-contractions (L-NC) or the contractile activity (L-C) was manifested. Accordingly, the inter-beat interval (IBI) time series were processed to estimate relevant parameters of HRV such as the mean IBI (IBI-), the mean heart rate HR-, the root mean square of successive differences (RMSSD) in IBIs, the natural logarithm of high-frequency component (LnHF), the short-term scaling parameters from detrended fluctuation and magnitude and sign analyses such as (alpha1, alpha1(MAG), alpha1(SIGN)), and the sample entropy (SampEn). We found statistical differences (p<0.05) for RMSSD among P and L-NC/L C groups (25 +/- 13 vs. 36 +/- 14/34 +/- 16 ms) and for LnHF between P and L-NC (5.37 +/- 1.15 vs. 6.05 +/- 0.86 ms(2)). Likewise, we identified statistical differences (p<0.05) for alpha1(SIGN) among P and L-NC/L-C groups (0.19 +/- 0.20 vs. 0.32 +/- 0.17/0.39 +/- 0.13). By contrast, L-NC and L-C groups showed statistical differences (p<0.05) in alpha1(MAG) (0.67 +/- 0.12 vs. 0.79 +/- 0.12), and SampEn (1.62 +/- 0.26 vs. 1.20 +/- 0.44). These results suggest that during labour, despite preserving a concomitant non-linear influence, the maternal short-term cardiac autonomic regulation becomes weakly anticorrelated (as indicated by alpha1(SIGN)); furthermore, an increased vagally mediated activity is observed (as indicated by RMSSD and LnHF), which may reflect a cholinergic pathway activation owing to the use of oxytocin or the anti inflammatory cholinergic response triggered during labour. PMID- 26048302 TI - Agonistic sounds signal male quality in the Lusitanian toadfish. AB - Acoustic communication during agonistic behaviour is widespread in fishes. Yet, compared to other taxa, little is known on the information content of fish agonistic calls and their effect on territorial defence. Lusitanian toadfish males (Halobatrachus didactylus) are highly territorial during the breeding season and use sounds (boatwhistles, BW) to defend nests from intruders. BW present most energy in either the fundamental frequency, set by the contraction rate of the sonic muscles attached to the swimbladder, or in the harmonics, which are multiples of the fundamental frequency. Here we investigated if temporal and spectral features of BW produced during territorial defence reflect aspects of male quality that may be important in resolving disputes. We found that higher mean pulse period (i.e. lower fundamental frequency) reflected higher levels of 11-ketotestosterone (11KT), the main teleost androgen which, in turn, was significantly related with male condition (relative body mass and glycogen content). BW dominant harmonic mean and variability decreased with sonic muscle lipid content. We found no association between BW duration and male quality. Taken together, these results suggest that the spectral content of fish agonistic sounds may signal male features that are key in fight outcome. PMID- 26048303 TI - Deletion of Melanin Concentrating Hormone Receptor-1 disrupts overeating in the presence of food cues. AB - Exposure to environmental cues associated with food can evoke eating behavior in the absence of hunger. This capacity for reward cues to promote feeding behaviors under sated conditions can be examined in the laboratory using cue-potentiated feeding (CPF). The orexigenic neuropeptide Melanin Concentrating Hormone (MCH) is expressed throughout brain circuitry critical for CPF. We examined whether deletion of the MCH receptor, MCH-1R, would in KO mice disrupt overeating in the presence of a Pavlovian CS+ associated with sucrose delivery. While both wild type controls and KO mice showed comparable food magazine approach responses during the CPF test, MCH-1R deletion significantly impaired the ability of the CS+ to evoke overeating of sucrose under satiety. Through the use of a refined analysis of meal intake, it was revealed that this disruption to overeating behavior in KO mice reflected a reduction in the capacity for the CS+ to initiate and maintain bursts of licking behavior. These findings suggest that overeating during CPF requires intact MCH-1R signaling and may be due to an influence of the CS+ on the palatability of food and on regulatory mechanisms of peripheral control. Thus, disruptions to MCH-1R signaling may be a useful pharmacological tool to inhibit this form of overeating behavior. PMID- 26048304 TI - Effects of a high protein diet on cognition and brain metabolism in cirrhotic rats. AB - Hepatic encephalopathy (HE) is a neurological complication observed in patients with liver disease. Patients who suffer from HE present neuropsychiatric, neuromuscular and behavioral symptoms. Animal models proposed to study HE resulting from cirrhosis mimic the clinical characteristics of cirrhosis and portal hypertension, and require the administration of hepatotoxins such as thioacetamide (TAA). The aim of this study was to assess the effects of a high protein diet on motor function, anxiety and memory processes in a model of cirrhosis induced by TAA administration. In addition, we used cytochrome c oxidase (COx) histochemistry to assess the metabolic activity of the limbic system regions. Male rats were distributed into groups: control, animals with cirrhosis, Control rats receiving a high protein diet, and animals with cirrhosis receiving a high protein diet. Results showed preserved motor function and normal anxiety levels in all the groups. The animals with cirrhosis showed an impairment in active avoidance behavior and spatial memory, regardless of the diet they received. However, the animals with cirrhosis and a high protein diet showed longer escape latencies on the spatial memory task. The model of cirrhosis presented an under-activation of the dentate gyrus and CA3 hippocampal subfields and the medial part of the medial mammillary nucleus. The results suggest that a high protein intake worsens spatial memory deficits shown by the TAA-induced model of cirrhosis. However, high protein ingestion has no influence on the COx hypoactivity associated with the model. PMID- 26048306 TI - Changes of the hindgut microbiota due to high-starch diet can be associated with behavioral stress response in horses. AB - The digestive system of horses is adapted to a high-fiber diet consumed in small amounts over a long time. However, during training, high-starch and low-fiber diets are usually fed which may induce hindgut microbial disturbances and intestinal pain. These diets can be described as alimentary stress. The aim of the present study was to investigate to what extent changes in behavior are associated with alimentary stress and microbial composition changes of the cecal or colonic ecosystem. Six fistulated horses were used. The alimentary stress was a modification of diet from a high-fiber diet (100% hay) to a progressive low fiber and high-starch diet (from 90% hay and 10% barley to 57% hay and 43% barley in 5 days). Cecal and colonic total anaerobic, cellulolytic, amylolytic and lactate-utilizing bacteria were enumerated three times (twice on high-fiber diet and once on 57% hay and 43% barley diet). The behavior of horses was assessed from continuous video recording over an 18-h time period. In addition two personality traits were measured: neophobia (assessed from the reaction to the presence of a novel object placed near a feeder in a test arena) and sociability (assessed from the reaction to an unfamiliar horse in a stall). Video recordings were analyzed by scan sampling every 10 min using the following behavioral categories: lying, resting, feeding and being vigilant. In addition, we recorded time spent feeding and time spent in vigilance during the neophobia test, and time spent in vigilance and time spent in interactions with the unfamiliar horse during the sociability test. The alimentary stress induced significant increases of colonic total anaerobic bacteria, lactate-utilizing bacteria and amylolytic bacteria concentrations. When horses were fed the 57% hay-43% barley diet, time spent in vigilance tended to be positively correlated with cecal and colonic amylolytic bacteria concentrations during the sociability test and with cecal lactate-utilizing and colonic amylolytic bacteria concentrations during the neophobia test. These correlations suggested that dietary-induced modulation of the microbiota may affect horse behavior and that behavioral cues may be used as non-invasive indicators of alimentary stress. It might prove useful to prevent intestinal pain of horses on farms. PMID- 26048307 TI - Biochemical characterization of smoothened receptor antagonists by binding kinetics against drug-resistant mutant. AB - Hedgehog (Hh) signaling critical for development, differentiation, and cell growth is involved in several cancers, including medulloblastoma and basal cell carcinoma. Although antagonism of the smoothened receptor (SMO), which mediates Hh signaling, is an attractive therapeutic target, a drug-resistant mutation in SMO (SMO-D473H) was identified in a clinical trial of the approved drug vismodegib. TAK-441 potently inhibits SMO-D473H, unlike vismodegib and another SMO antagonist, cyclopamine, whereas the differences in binding modes between these antagonists remain unknown. Here we report the biochemical characterization of TAK-441, vismodegib, and cyclopamine by binding kinetics. The association (kon) and dissociation (koff) rates were determined by kinetic binding studies using [(3)H]TAK-441, and dissociation was confirmed by label-free affinity selection-mass spectrometry (AS-MS). In the [(3)H]TAK-441 competition assay, TAK 441 but not vismodegib and cyclopamine showed time-dependent inhibition. Quantitative kinetic binding analysis revealed that koff of TAK-441 was >10-fold smaller than those of vismodegib and cyclopamine. To further assess the binding mode of antagonists, kinetic binding analysis was performed against SMO-D473H. The D473H mutation affected koff of TAK-441 but not kon. In contrast, only kon was changed by the D473H mutation in the case of vismodegib and cyclopamine. These results suggest that the difference in antagonist efficacy against D473H is associated with the binding mode of antagonists. These findings provide a new insight into the drug action of SMO antagonists and help develop potential therapeutics for drug-resistant mutants. PMID- 26048305 TI - Physiological mechanisms by which non-nutritive sweeteners may impact body weight and metabolism. AB - Evidence linking sugar-sweetened beverage (SSB) consumption to weight gain and other negative health outcomes has prompted many individuals to resort to artificial, non-nutritive sweetener (NNS) substitutes as a means of reducing SSB intake. However, there is a great deal of controversy regarding the biological consequences of NNS use, with accumulating evidence suggesting that NNS consumption may influence feeding and metabolism via a variety of peripheral and central mechanisms. Here we argue that NNSs are not physiologically inert compounds and consider the potential biological mechanisms by which NNS consumption may impact energy balance and metabolic function, including actions on oral and extra-oral sweet taste receptors, and effects on metabolic hormone secretion, cognitive processes (e.g. reward learning, memory, and taste perception), and gut microbiota. PMID- 26048308 TI - Impact of fexofenadine, osthole and histamine on peripheral blood mononuclear cell proliferation and cytokine secretion. AB - This paper compares results of peripheral blood mononuclear cell (PBMC) incubation with fexofenadine (FXF) and osthole. FXF is a third-generation antihistamine drug and osthole is assumed a natural antihistamine alternative. To our best knowledge, this is the first comparative study on FXF, osthole and histamine cytokine secretion and cytotoxicity in PBMC in vitro cultures using cell proliferation ELISA BrdU. The cultures were treated 12, 42, 48 and 72h with FXF and osthole at 150, 300 and 450ng/ml concentrations and histamine at 50, 100 and 200ng/ml. Our study results confirm that FXF, osthole and histamine exert no cytotoxic effect on PBMCs and that IL-6, IL-10 and TNF-alpha cytokine secretion following osthole cell stimulation was similar to that by FXF stimulation.This confirms our hypothesis that osthole is a natural histamine antagonist, and can therefore be beneficially applied in antihistamine treatment. PMID- 26048309 TI - Vitamin B complex attenuated heat hyperalgesia following infraorbital nerve constriction in rats and reduced capsaicin in vivo and in vitro effects. AB - Vitamins of the B complex attenuate some neuropathic pain sensory aspects in various animal models and in patients, but the mechanisms underlying their effects remain to be elucidated. Herein it was investigated if the treatment with a vitamin B complex (VBC) reduces heat hyperalgesia in rats submitted to infraorbital nerve constriction and the possibility that TRPV1 receptors represent a target for B vitamins. In the present study, the VBC refers to a combination of vitamins B1, B6 and B12 at low- (18, 18 and 1.8mg/kg, respectively) or high- (180, 180 and 18mg/kg, respectively) doses. Acute treatment of rats with either the low- or the high-doses combination reduced heat hyperalgesia after nerve injury, but the high-doses combination resulted in a long-lasting effect. Repeated treatment with the low-dose combination reduced heat hyperalgesia on day four after nerve injury and showed a synergist effect with a single injection of carbamazepine (3 or 10mg/kg), which per se failed to modify the heat threshold. In naive rats, acute treatment with the high-dose of VBC or B1 and B12 vitamins independently reduced heat hyperalgesia evoked by capsaicin (3ug into the upper lip). Moreover, the VBC, as well as, each one of the B vitamins independently reduced the capsaicin-induced calcium responses in HEK 293 cells transiently transfected with the human TRPV1 channels. Altogether, these results indicate that B vitamins can be useful to control heat hyperalgesia associated with trigeminal neuropathic pain and that modulation of TRPV1 receptors may contribute to their anti-hyperalgesic effects. PMID- 26048310 TI - Aloe-emodin exerts a potent anticancer and immunomodulatory activity on BRAF mutated human melanoma cells. AB - Aim of this study was to extend the knowledge on the antineoplastic effect of aloe-emodin (AE), a natural hydroxyanthraquinone compound, both in metastatic human melanoma cell lines and in primary stem-like cells (melanospheres). Treatment with AE caused reduction of cell proliferation and induction of SK-MEL 28 and A375 cells differentiation, characterized by a marked increase of transamidating activity of transglutaminase whose expression remained unmodified. In vitro antimetastatic property of AE was evaluated by adhesion and Boyden chamber invasion assays. The effect of AE on melanoma cytokines/chemokines production was determined by a multiplex assay: interestingly AE showed an immunomodulatory activity through GM-CSF and IFN-gamma production. We report also that AE significantly reduced the proliferation, stemness and invasive potential of melanospheres. Moreover, AE treatment significantly enhanced dabrafenib (a BRAF inhibitor) antiproliferative activity in BRAF mutant cell lines. Our results confirm that AE possesses remarkable antineoplastic properties against melanoma cells, indicating this anthraquinone as a promising agent for differentiation therapy of cancer, or as adjuvant in chemotherapy and targeted therapy. Further, its mechanisms of action support a potential efficacy of AE treatment to counteract resistance of BRAF-mutated melanoma cells to target therapy. PMID- 26048311 TI - Synergistic interaction between tapentadol and flupirtine in the rat orafacial formalin test. AB - Combination therapy with two or more analgesics is widely used for conditions associated with moderate to severe pain. Combinations of diverse analgesics with different modes of action can improve the risk-benefit ratio of analgesic treatments. The aim of this study is to evaluate the antinociceptive effect of tapentadol (TAP) and flupirtine (FLP), when administered separately or in combination, as well as their synergistic interaction in the orofacial formalin test in rats. After i.p. injection of TAP at different doses (2, 5, 10 and 15mg/kg), the biphasic nociceptive behavior was reduced in a dose-dependent manner in both phase I and II. Conversely, i.p. injection of FLP at different doses (0.6, 1.6, 3.3, 6.6, 16.6 and 22.2mg/kg) induced a dose-dependent antinociceptive effect in phase II only. TAP was found to be more effective than FLP. The interaction between TAP and FLP was synergistic in phase II with an interaction index (gamma) of 0.50+/-0.24. The data reported in this study indicate that FLP enhances the antinociceptive effect of TAP and this drug combination might be potentially useful in the treatment of chronic pain. PMID- 26048312 TI - Orlistat limits cholesterol intestinal absorption by Niemann-pick C1-like 1 (NPC1L1) inhibition. AB - The known mechanism by which orlistat decreases the absorption of dietary cholesterol is by inhibition of intestinal lipases. The aim of this study was to investigate the ability of orlistat to limit cholesterol absorption by inhibition of the cholesterol transport protein Niemann-Pick C1-like 1 (NPC1L1) as another mechanism of action. In situ rat intestinal perfusion studies were conducted to study the effect of orlistat on jejunal cholesterol absorption. Inhibition kinetic parameters were calculated from in vitro inhibition studies using Caco2 and NPC1L1 transfected cell lines. The in situ studies demonstrated that intestinal perfusion of orlistat (100uM) was able to reduce cholesterol absorption by three-fold when compared to control (i.e. in the absence of orlistat, P<0.01). In vitro studies using Caco2 cells demonstrated orlistat to reduce the cellular uptake of cholesterol by 30%. Additionally, orlistat reduced the cellular uptake of cholesterol in dose dependent manner in NPC1L1 transfected cell line with an IC50=1.2uM. Lineweaver-Burk plot indicated a noncompetitive inhibition of NPC1L1 by orlistat. Beside the already established mechanism by which orlistat reduces the absorption of cholesterol, we demonstrated for the first time that orlistat limits cholesterol absorption by the inhibition of NPC1L1 transport protein. PMID- 26048313 TI - Development and Pilot Testing of the Eating4two Mobile Phone App to Monitor Gestational Weight Gain. AB - BACKGROUND: The number of pregnant women with a body mass index (BMI) of 30kg/m(2) or more is increasing, which has important implications for antenatal care. Various resource-intensive interventions have attempted to assist women in managing their weight gain during pregnancy with limited success. A mobile phone app has been proposed as a convenient and cost-effective alternative to face-to face interventions. OBJECTIVE: This paper describes the process of developing and pilot testing the Eating4Two app, which aims to provide women with a simple gestational weight gain (GWG) calculator, general dietary information, and the motivation to achieve a healthy weight gain during pregnancy. METHODS: The project involved the development of app components, including a graphing function that allows the user to record their weight throughout the pregnancy and to receive real-time feedback on weight gain progress and general information on antenatal nutrition. Stakeholder consultation was used to inform development. The app was pilot tested with 10 pregnant women using a mixed method approach via an online survey, 2 focus groups, and 1 individual interview. RESULTS: The Eating4Two app took 7 months to develop and evaluate. It involved several disciplines--including nutrition and dietetics, midwifery, public health, and information technology--at the University of Canberra. Participants found the Eating4Two app to be a motivational tool but would have liked scales or other markers on the graph that demonstrated exact weight gain. They also liked the nutrition information; however, many felt it should be formatted in a more user friendly way. CONCLUSIONS: The Eating4Two app was viewed by participants in our study as an innovative support system to help motivate healthy behaviors during pregnancy and as a credible resource for accessing nutrition-focused information. The feedback provided by participants will assist with refining the current prototype for use in a clinical intervention trial. PMID- 26048314 TI - Kocuria dechangensis sp. nov., an actinobacterium isolated from saline and alkaline soils. AB - A Gram-stain positive, strictly aerobic, non-motile and coccus-shaped actinobacterium, designated strain NEAU-ST5-33(T), was isolated from saline and alkaline soils in Dechang Township, Zhaodong City, PR China. It formed beige yellow colonies and grew at NaCl concentrations of 0-5% (w/v) (optimum 0%), at pH 6.0-9.0 (optimum pH 7.0) and over a temperature range of 4-50 degrees C (optimum 35 degrees C). Based on 16S rRNA gene sequence analysis, strain NEAU-ST5-33(T) was phylogenetically closely related to the type strains of species of the genus Kocuria, Kocuria polaris CMS 76or(T), Kocuria rosea DSM 20447(T), Kocuria turfanensis HO-9042(T), Kocuria aegyptia YIM 70003(T), Kocuria himachalensis K07 05(T) and Kocuria flava HO-9041(T), with respective sequence similarities of 98.8%, 98.8%, 98.3%, 98.1%, 98.1% and 97.9%. DNA-DNA hybridization relatedness values of strain NEAU-ST5-33(T) with type strains of the closely related species ranged from 54 +/- 1% to 34 +/- 1%. The DNA G+C content was 61.2 mol%. The major fatty acids (>5%) were C15 : 0 anteiso, C15 : 0 iso and C16 : 1omega7c and/or C16 : 1omega6c. The major menaquinone detected was MK-8 (H2), and the polar lipids consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, one unknown aminolipid and one unknown lipid. On the basis of the genotypic, chemotaxonomic and phenotypic data, we propose that strain NEAU ST5-33(T) represents a novel species of the genus Kocuria, with the name Kocuria dechangensis sp. nov. The type strain is NEAU-ST5-33(T) ( = CGMCC 1.12187(T) = DSM 25872(T)). PMID- 26048315 TI - Enhanced Achilles tendon healing by fibromodulin gene transfer. AB - Tendon injury is a major musculoskeletal disorder with a high public health impact. We propose a non-viral based strategy of gene therapy for the treatment of tendon injuries using histidylated vectors. Gene delivery of fibromodulin, a proteoglycan involved in collagen assembly was found to promote rat Achilles tendon repair in vivo and in vitro. In vivo liposome-based transfection of fibromodulin led to a better healing after surgical injury, biomechanical properties were better restored compared to untransfected control. These measures were confirmed by histological observations and scoring. To get better understandings of the mechanisms underlying fibromodulin transfection, an in vitro tendon healing model was developed. In vitro, polymer-based transfection of fibromodulin led to the best wound enclosure speed and a pronounced migration of tenocytes primary cultures was observed. These results suggest that fibromodulin non-viral gene therapy could be proposed as a new therapeutic strategy to accelerate tendon healing. FROM THE CLINICAL EDITOR: Tendon injury is relatively common and healing remains unsatisfactory. In this study, the effects of liposomal-based delivery of fibromodulin gene were investigated in a rat Achilles tendon injury model. The positive results observed would provide a new therapeutic strategy in clinical setting in the future. PMID- 26048316 TI - From the blood to the brain: avenues of eukaryotic pathogen dissemination to the central nervous system. AB - Infection of the central nervous system (CNS) is a significant cause of morbidity and mortality, and treatments available to combat the highly debilitating symptoms of CNS infection are limited. The mechanisms by which pathogens in the circulation overcome host immunity and breach the blood-brain barrier are active areas of investigation. In this review, we discuss recent work that has significantly advanced our understanding of the avenues of pathogen dissemination to the CNS for four eukaryotic pathogens of global health importance: Toxoplasma gondii, Plasmodium falciparum, Trypanosoma brucei, and Cryptococcus neoformans. These studies highlight the remarkable diversity of pathogen strategies for trafficking to the brain and will ultimately contribute to an improved ability to combat life-threatening CNS disease. PMID- 26048317 TI - Effect of Intracoronary Plus Low-Dose Intravenous Tirofiban in Elderly Patients with Acute Myocardial Infarction. AB - BACKGROUND: To investigate the efficacy and safety of low-dose tirofiban in elderly patients undergoing primary percutaneous coronary intervention (PPCI) for acute myocardial infarction (AMI). METHODS: One hundred and four patients aged 70 years and above undergoing PPCI for AMI were divided into control (n=52) and study (n=52) groups. All patients received bolus intracoronary injection of tirofiban (10MUg/kg), which was followed by intravenous infusion at 0.15MUg/kg/min in the control group and at 0.075MUg/kg/min in the study group for 24h. RESULTS: There was no statistically significant difference between the study group and the control group in patients with complete ST segment resolution (84.2% vs. 85.7%, P=0.851), peak high-sensitive cardiac troponin T level (5.1+/ 1.9 vs. 5.8+/-2.6MUg/L, P=0.123), scores of thrombus in the infarct-related artery (0.98+/-0.51 vs. 1.12+/-0.59, P=0.214), and patients with TIMI grade 3 flow (86.0% vs. 88.2%, P=0.737) after PPCI. There were no statistically significant differences between the two groups in left ventricular ejection fraction (57.1+/-6.3 vs. 57.7+/-6.1, P=0.611) and composite major adverse cardiovascular events rate (P =0.778) at 90 days after PCI. The total bleeding rate in the study group was lower than in the control group (P=0.048). CONCLUSION: In elderly patients with AMI undergoing primary PCI, low and standard dose of tirofiban exerts similar effects on platelet aggregation, coronary flow, infarct size, left ventricular systolic function and short-term clinical outcomes. Low dose regimen is associated with a lower bleeding rate than the standard dose. PMID- 26048318 TI - Paravalvular Leak Leading to Severe Aortic Valve Regurgitation after TAVI: Percutaneous Closure Strategy. AB - Regurgitation due to a paravalvular leak (PVL) is a complication that may affect patients undergoing surgical mechanical or bioprosthetic heart valve replacement. PVL can also occur after transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis and is associated with significantly worse outcomes. We report a case in which different closure strategies and devices were attempted and required to percutaneously close a severe PVL after TAVI in a patient with prohibitive surgical risk. PMID- 26048319 TI - An Absolute Risk Prediction Model to Determine Unplanned Cardiovascular Readmissions for Adults with Chronic Heart Failure. AB - BACKGROUND: Frequent readmissions are a hallmark of chronic heart failure (CHF). We sought to develop an absolute risk prediction model for unplanned cardiovascular readmissions following hospitalisation for CHF. METHODS: An inception cohort was obtained from the WHICH? trial, a prospective, multi-centre randomised controlled trial which was a head-to-head comparison of the efficacy of a home-based intervention versus clinic-based intervention for adults with CHF. A Cox's proportional hazards model (taking into account the competing risk of death) was used to develop a prediction model. Bootstrap methods were used to identify factors for the final model. Based on these data a nomogram was developed. RESULTS: Of the 280 participants in the WHICH? trial 37 (13%) were readmitted for a cardiovascular event (including CHF) within 28 days, and a further 149 (53%) were readmitted within 18 months for a cardiovascular event. In the proposed competing risk model, factors associated with an increased risk of hospitalisation for CHF were: age (HR 1.07, 95% CI 0.90-1.26) for each 10-year increase in age; living alone (HR 1.09, 95% CI 0.74-1.59); those with a sedentary lifestyle (HR 1.44, 95% CI, 0.92-2.25) and the presence of multiple co-morbid conditions (HR 1.69, 95% CI 0.38-7.58) for five or more co-morbid conditions (compared to individuals with one documented co-morbidity). The C-statistic of the final model was 0.80. CONCLUSION: We have developed a practical model for individualising the risk of short-term readmission for CHF. This model may provide additional information for targeting and tailoring interventions and requires future prospective evaluation. PMID- 26048320 TI - Refractory hypoxaemia following inferior ST-segment elevation myocardial infarction: case report of an unusual complication and review of treatment strategies. AB - Right ventricular (RV) infarction is not an uncommon complication of acute left ventricular infarction. It has been established that RV dysfunction post myocardial infarction (MI) is associated with increased mortality and morbidity. When RV infarction occurs in a patient with previously dormant patent foramen ovale (PFO), an unusual presentation of persistent refractory hypoxaemia ensues. We present a case of new RV infarction in a patient with underlying ischaemic cardiomyopathy, which was complicated by acute right-to-left shunting through the PFO. He was treated with percutaneous coronary intervention (PCI) and subsequent percutaneous PFO closure. We will also review the existing literature with regards to diagnostic and management strategies for patients with this unusual sequelae of MI. PMID- 26048321 TI - Same Day Discharge after PCI can also be Safe in High Risk Patients and Acute Coronary Syndrome. PMID- 26048322 TI - Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant recipients. AB - Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are >5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients. PMID- 26048323 TI - A portable shield for a neutron howitzer used for instructional and research purposes. AB - Neutron howitzers are routinely used in universities to activate samples for instructional laboratory experiments on radioactivity. They are also a convenient source of neutrons and gammas for research purposes, but they must be used with caution. This paper describes the modeling, design, construction, and testing of a portable, economical shield for a 1.0 Curie neutron howitzer. The Monte Carlo N Particle Transport Code (MCNP5) has been used to model the (239)PuBe source and the howitzer and to design the external neutron and gamma shield. PMID- 26048324 TI - Estimation of eye lens doses received by pediatric interventional cardiologists. AB - Maximum Hp(0.07) dose to the eye lens received in a year by the pediatric interventional cardiologists has been estimated. Optically stimulated luminescence dosimeters were placed on the eyes of an anthropomorphic phantom, whose position in the room simulates the most common irradiation conditions. Maximum workload was considered with data collected from procedures performed in the Hospital. None of the maximum values obtained exceed the dose limit of 20 mSv recommended by ICRP. PMID- 26048325 TI - Measurement of (222)Rn concentration levels in drinking water and the associated health effects in the Southern part of West Bank - Palestine. AB - Radon concentration and annual effective doses were measured in drinking water in the Southern Part of West Bank - Palestine, by using both passive and active techniques. 184 samples were collected from various sources i.e. tap water, groundwater, rain waters and mineral waters. It is found that the annual effective dose resulting from inhalation and ingestion of radon emanated from all types of drinking water is negligible compared to the total annual effective dose from indoor radon in the region. Results reveal that there is no significant public health risk from radon ingested and inhalation with drinking water in the study region. PMID- 26048326 TI - US initiatives to boost organ donation have had little effect, study finds. PMID- 26048328 TI - Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties. AB - Several recent studies have demonstrated that TAT and other arginine-rich cell penetrating peptides (CPPs) have intrinsic neuroprotective properties in their own right. Examples, we have demonstrated that in addition to TAT, poly-arginine peptides (R8 to R18; containing 8-18 arginine residues) as well as some other arginine-rich peptides are neuroprotective in vitro (in neurons exposed to glutamic acid excitotoxicity and oxygen glucose deprivation) and in the case of R9 in vivo (after permanent middle cerebral artery occlusion in the rat). Based on several lines of evidence, we propose that this neuroprotection is related to the peptide's endocytosis-inducing properties, with peptide charge and arginine residues being critical factors. Specifically, we propose that during peptide endocytosis neuronal cell surface structures such as ion channels and transporters are internalised, thereby reducing calcium influx associated with excitotoxicity and other receptor-mediated neurodamaging signalling pathways. We also hypothesise that a peptide cargo can act synergistically with TAT and other arginine-rich CPPs due to potentiation of the CPPs endocytic traits rather than by the cargo-peptide acting directly on its supposedly intended intracellular target. In this review, we systematically consider a number of studies that have used CPPs to deliver neuroprotective peptides to the central nervous system (CNS) following stroke and other neurological disorders. Consequently, we critically review evidence that supports our hypothesis that neuroprotection is mediated by carrier peptide endocytosis. In conclusion, we believe that there are strong grounds to regard arginine-rich peptides as a new class of neuroprotective molecules for the treatment of a range of neurological disorders. PMID- 26048329 TI - Allergic reaction to polyethylene glycol in a painter. AB - We report a case of a male painter who visited our outpatient clinic after developing a distinct skin reaction 15 min after the ingestion of a laxative solution containing polyethylene glycol (PEG) prior to colonoscopy. He described suffering from the same skin reaction when he was previously exposed to paints that contained PEG-4000. An exposure challenge test with pure PEG-4000, simulating his workplace conditions, elicited a generalized urticarial reaction. Allergy to PEG should be considered in painters who develop urticarial or other systemic symptoms after handling PEG-containing products. PMID- 26048327 TI - Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein. AB - Nucleocytoplasmic trafficking of proteins/RNAs is essential to normal cellular function. Indeed, accumulating evidence suggests that cancer cells escape anti neoplastic mechanisms and benefit from pro-survival signals via the dysregulation of this system. The nuclear exporter chromosome region maintenance 1 (CRM1) protein is the only protein in the karyopherin-beta protein family that contributes to the trafficking of numerous proteins and RNAs from the nucleus. It is considered to be an oncogenic, anti-apoptotic protein in transformed cells, since it reportedly functions as a gatekeeper for cell survival, including affecting p53 function, and ribosomal biogenesis. Furthermore, abnormally high expression of CRM1 is correlated with poor patient prognosis in various malignancies. Therapeutic targeting of CRM1 has emerged as a novel cancer treatment strategy, starting with a clinical trial with leptomycin B, the original specific inhibitor of CRM1, followed by development of several next generation small molecules. KPT-330, a novel member of the CRM1-selective inhibitors of nuclear export (SINE) class of compounds, is currently undergoing clinical evaluation for the therapy of various malignancies. Results from these trials suggest that SINE compounds may be particularly useful against hematological malignancies, which often become refractory to standard chemotherapeutic agents. PMID- 26048330 TI - Impact of peer review audit on occupational health report quality. AB - BACKGROUND: In a previous report, we described the implementation of a formal process for peer review of occupational health (OH) reports and a method of assessment of the outcomes of this process. The initial audit identified that 27% of OH reports required modifications. AIMS: To assess formally, following implementation of this process, if changes in practice had occurred, i.e. whether fewer deficiencies were being identified in reports. METHODS: We repeated a prospective internal audit of all peer reviewed OH reports between September and November 2011. We used an abbreviated assessment form, based on questions 4-8 and 10-12 of the modified SAIL (Sheffield Assessment Instrument for Letters), with four possible outcomes: no action, no changes made to report following discussion with author, changes made without discussion with author and changes made following discussion with author. RESULTS: One hundred seventy-three reports by 10 clinicians were audited. The audit identified a 13% reduction in OH reports requiring modifications (from 27 to 14%) compared with the previous cycle. Where modifications were required, 8% of these were related to minor typographical, spelling and grammar errors and 6% were for more complex reasons. Implementation of this process also produced a reduction in clinical complaints about OH reports from customers, from three in the preceding year to none 2 years later. CONCLUSIONS: Peer review improved the standard of OH reports and was associated with a reduction in customer complaints about reports. PMID- 26048331 TI - Occupational stress, anxiety and coping strategies in police officers. AB - BACKGROUND: Studies on occupational stress have shown that police officers are exposed to stressful events more often than other workers and this can result in impaired psychosocial well-being and physical health. AIMS: To measure the level of stress experienced, the consequences in terms of anxiety and the coping strategies adopted in a sample of police officers working in a large city in northern Italy. METHODS: We used the Police Stress Questionnaire and the Distress Thermometer to measure occupational stress, the State-Trait Anxiety Inventory to measure anxiety and the Brief COPE questionnaire to measure coping strategies. RESULTS: Six hundred seventeen police officers completed the questionnaire, a response rate of 34%. Differences between genders, sectors and roles emerged, but overall the study population generally demonstrated good use of positive coping strategies. Women in all operational service roles were more vulnerable to both organizational and operational stressors than men (P < 0.001), while in the interior department, men were more vulnerable to organizational stressors (P < 0.05). CONCLUSIONS: Our results suggest that for Italian police officers, training courses and support in dealing with occupational stress should take into account gender, role and type of work. Tailored training courses and support programmes could be useful and effective tools for preventing stress before it becomes chronic. PMID- 26048332 TI - Contraceptive Vaginal Rings: Do They Pose an Increased Risk of Venous Thromboembolism in Aesthetic Surgery? AB - Nuvaring (Organon, Kenilworth, NJ) is a vaginal contraception ring inserted by the patient. It was approved by the Food and Drug Administration in 2001 for the prevention of pregnancy. The intent of this paper is to increase the awareness of Nuvaring among plastic surgeons, and to explore the risks associated with its use. We report the cases of two cosmetic surgery patients. These patients developed deep venous thrombosis and pulmonary emboli in the postoperative period while using Nuvaring. The very advantages of the Nuvaring-the ease of use, the avoidance of daily administration, and the insertion and removal of the device by the patient-may lead to the failure of patients to recollect being on a vaginal ring for contraception. LEVEL OF EVIDENCE: 4 Risk. PMID- 26048333 TI - Framing the Breast. PMID- 26048334 TI - Monitoring ankylosing spondylitis: clinically useful markers and prediction of clinical outcomes. AB - Patient assessment in axial spondyloarthritis (axSpA) is multidimensional, and monitoring of disease activity, function and radiographic progression is complex. There is no simple 'gold standard' for measuring disease activity in all individual patients, as disease activity in axSpA is the sum of many different aspects and a complexity that cannot be represented by a single variable. Limited spinal mobility is a cardinal sign of ankylosing spondylitis and loss of spinal mobility has been reported to be a prognostic factor and most often evaluated with the Bath Ankylosing Spondylitis Functional Index. Imaging of the spine and assessment of safety aspects plays an important role in the monitoring of patients with axSpA. The timeframe for collecting information regarding disease activity, function and radiographic progression are recommended on an individual basis. PMID- 26048336 TI - Vasopressin induces endolymphatic hydrops in mouse inner ear, as evaluated with repeated 9.4 T MRI. AB - From histopathological specimens, endolymphatic hydrops has been demonstrated in association with inner ear disorders. Recent studies have observed findings suggestive of hydrops using MRI in humans. Previous studies suggest that vasopressin may play a critical role in endolymph homeostasis and may be involved in the development of Meniere's disease. In this study we evaluate the effect of vasopressin administration in vivo in longitudinal studies using two mouse strains. High resolution MRI at 9.4 T in combination with intraperitoneally delivered Gadolinium contrast, was performed before and after chronic subcutaneous administration of vasopressin via mini-osmotic pumps in the same mouse. A development of endolymphatic hydrops over time could be demonstrated in C57BL6 mice (5 mice, 2 and 4 weeks of administration) as well as in CBA/J mice (4 mice, 2 weeks of administration; 6 mice, 3 and 4 weeks of administration). In most C57BL6 mice hydrops developed first after more than 2 weeks while CBA/J mice had an earlier response. These results may suggest an in vivo model for studying endolymphatic hydrops and corroborates the future use of MRI as a tool in the diagnosis and treatment of inner ear diseases, such as Meniere's disease. MRI may also be developed as a critical tool in evaluating inner ear homeostasis in genetically modified mice, to augment the understanding of human disease. PMID- 26048335 TI - Sound localization in the alligator. AB - In early tetrapods, it is assumed that the tympana were acoustically coupled through the pharynx and therefore inherently directional, acting as pressure difference receivers. The later closure of the middle ear cavity in turtles, archosaurs, and mammals is a derived condition, and would have changed the ear by decoupling the tympana. Isolation of the middle ears would then have led to selection for structural and neural strategies to compute sound source localization in both archosaurs and mammalian ancestors. In the archosaurs (birds and crocodilians) the presence of air spaces in the skull provided connections between the ears that have been exploited to improve directional hearing, while neural circuits mediating sound localization are well developed. In this review, we will focus primarily on directional hearing in crocodilians, where vocalization and sound localization are thought to be ecologically important, and indicate important issues still awaiting resolution. PMID- 26048337 TI - Selective activation of the trace amine-associated receptor 1 decreases cocaine's reinforcing efficacy and prevents cocaine-induced changes in brain reward thresholds. AB - The newly discovered trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in stimulant addiction due to its ability to regulate dopamine (DA) function and modulate stimulants' effects. Recent findings indicate that TAAR1 activation blocks some of the abuse-related physiological and behavioral effects of cocaine. However, findings from existing self-administration studies are inconclusive due to the very limited range of cocaine unit doses tested. Here, in order to shed light on the influence of TAAR1 on cocaine's reward and reinforcement, we studied the effects of partial and full activation of TAAR1on (1) the dose-response curve for cocaine self-administration and (2) cocaine-induced changes in intracranial self-stimulation (ICSS). In the first experiment, we examined the effects of the selective full and partial TAAR1 agonists, RO5256390 and RO5203648, on self-administration of five unit-injection doses of cocaine (0.03, 0.1, 0.2, 0.45, and 1mg/kg/infusion). Both agonists induced dose-dependent downward shifts in the cocaine dose-response curve, indicating that both partial and full TAAR1 activation decrease cocaine, reinforcing efficacy. In the second experiment, RO5256390 and the partial agonist, RO5263397, dose-dependently prevented cocaine-induced lowering of ICSS thresholds. Taken together, these data demonstrated that TAAR1 stimulation effectively suppresses the rewarding and reinforcing effects of cocaine in self administration and ICSS models, supporting the candidacy of TAAR1 as a drug discovery target for cocaine addiction. PMID- 26048339 TI - Polyvictimization, income, and ethnic differences in trauma-related mental health during adolescence. AB - PURPOSE: The purpose of the present study was to investigate ethnic differences in trauma-related mental health symptoms among adolescents, and test the mediating and moderating effects of polyvictimization (i.e., number of types of traumas/victimizations experienced by an individual) and household income, respectively. METHODS: Data were drawn from the first wave of the National Survey of Adolescents-replication study (NSA-R), which took place in the US in 2005 and utilized random digit dialing to administer a telephone survey to adolescents ages 12-17. Participants included in the current analyses were 3312 adolescents (50.2 % female; mean age 14.67 years) from the original sample of 3614 who identified as non-Hispanic White (n = 2346, 70.8 %), non-Hispanic Black (n = 557, 16.8 %), or Hispanic (n = 409, 12.3 %). Structural equation modeling was utilized to test hypothesized models. RESULTS: Non-Hispanic Black and Hispanic participants reported higher levels of polyvictimization and trauma-related mental health symptoms (symptoms of posttraumatic stress and depression) compared to non-Hispanic Whites, though the effect sizes were small (gamma <= 0.07). Polyvictimization fully accounted for the differences in mental health symptoms between non-Hispanic Blacks and non-Hispanic Whites, and partially accounted for the differences between Hispanics and non-Hispanic Whites. The relation between polyvictimization and trauma-related mental health symptoms was higher for low income youth than for high-income youth. CONCLUSIONS: Disparities in trauma exposure largely accounted for racial/ethnic disparities in trauma-related mental health. Children from low-income family environments appear to be at greater risk of negative mental health outcomes following trauma exposure compared to adolescents from high-income families. PMID- 26048340 TI - Species-Level Phylogeny and Polyploid Relationships in Hordeum (Poaceae) Inferred by Next-Generation Sequencing and In Silico Cloning of Multiple Nuclear Loci. AB - Polyploidization is an important speciation mechanism in the barley genus Hordeum. To analyze evolutionary changes after allopolyploidization, knowledge of parental relationships is essential. One chloroplast and 12 nuclear single-copy loci were amplified by polymerase chain reaction (PCR) in all Hordeum plus six out-group species. Amplicons from each of 96 individuals were pooled, sheared, labeled with individual-specific barcodes and sequenced in a single run on a 454 platform. Reference sequences were obtained by cloning and Sanger sequencing of all loci for nine supplementary individuals. The 454 reads were assembled into contigs representing the 13 loci and, for polyploids, also homoeologues. Phylogenetic analyses were conducted for all loci separately and for a concatenated data matrix of all loci. For diploid taxa, a Bayesian concordance analysis and a coalescent-based dated species tree was inferred from all gene trees. Chloroplast matK was used to determine the maternal parent in allopolyploid taxa. The relative performance of different multilocus analyses in the presence of incomplete lineage sorting and hybridization was also assessed. The resulting multilocus phylogeny reveals for the first time species phylogeny and progenitor-derivative relationships of all di- and polyploid Hordeum taxa within a single analysis. Our study proves that it is possible to obtain a multilocus species-level phylogeny for di- and polyploid taxa by combining PCR with next-generation sequencing, without cloning and without creating a heavy load of sequence data. PMID- 26048341 TI - Characteristics, sources and health risk assessment of toxic heavy metals in PM2.5 at a megacity of southwest China. AB - Twenty trace elements in fine particulate matters (i.e., PM2.5) at urban Chengdu, a southwest megacity of China, were determined to study the characteristics, sources and human health risk of particulate toxic heavy metals. This work mainly focused on eight toxic heavy metal elements (As, Cd, Cr, Cu, Mn, Ni, Pb and Zn). The average concentration of PM2.5 was 165.1 +/- 84.7 ug m(-3) during the study period, significantly exceeding the National Ambient Air Quality Standard (35 ug m(-3) in annual average). The particulate heavy metal pollution was very serious in which Cd and As concentrations in PM2.5 significantly surpassed the WHO standard. The enrichment factor values of heavy metals were typically higher than 10, suggesting that they were mainly influenced by anthropogenic sources. More specifically, the Cr, Mn and Ni were slightly enriched, Cu was highly enriched, while As, Cd, Pb and Zn were severely enriched. The results of correlation analysis showed that Cd may come from metallurgy and mechanical manufacturing emissions, and the other metals were predominately influenced by traffic emissions and coal combustion. The results of health risk assessment indicated that As, Mn and Cd would pose a significant non-carcinogenic health risk to both children and adults, while Cr would cause carcinogenic risk. Other toxic heavy metals were within a safe level. PMID- 26048342 TI - Schisandra chinensis fruit modulates the gut microbiota composition in association with metabolic markers in obese women: a randomized, double-blind placebo-controlled study. AB - Schisandra chinensis fruit (SCF) is known to have beneficial effects on metabolic diseases, including obesity, and to affect gut microbiota in in vivo studies. However, in human research, there have been a few studies in terms of its clinical roles in lipid metabolism and modulation of gut microbiota. A double blind, placebo-controlled study with 28 obese women with SCF or placebo was conducted for 12 weeks. Anthropometry and blood and fecal sampling were performed before and after treatment. Analysis of the gut microbiota in feces was performed using denaturing gradient gel electrophoresis and quantitative polymerase chain reaction. Although the values did not differ significantly between the 2 groups, the SCF group tended to show a greater decrease in waist circumference, fat mass, fasting blood glucose, triglycerides, aspartate aminotransferase, and alanine aminotransferase than the placebo group. Clustering of the denaturing gradient gel electrophoresis fingerprints for total bacteria before and after treatment indicated more separate clustering in SCF group than placebo. In correlation analysis, Bacteroides and Bacteroidetes (both increased by SCF) showed significant negative correlation with fat mass, aspartate aminotransferase, and/or alanine aminotransferase, respectively. Ruminococcus (decreased by SCF) showed negative correlation with high-density lipoprotein cholesterol and fasting blood glucose. In conclusion, administration of SCF for 12 weeks resulted in modulation of the gut microbiota composition in Korean obese women, and significant correlations with some bacterial genera and metabolic parameters were noted. However, in general, SCF was not sufficient to induce significant changes in obesity-related parameters compared with placebo. PMID- 26048343 TI - Rapana venosa consumption improves the lipid profiles and antioxidant capacities in serum of rats fed an atherogenic diet. AB - In the recent years, the consumption of seafood has increased. There are no results on the studies of Rapana venosa (Rv) as a supplementation to the diets. We hypothesized that Rv would increase antioxidant capacity and reduce blood lipids, based on the composition of bioactive compounds and fatty acids. Therefore, the aim of this investigation was to evaluate in vitro and in vivo actions of Rv from contaminated (C) and non-C (NC) regions of collection on lipid profiles, antioxidant capacity, and enzyme activities in serum of rats fed an atherogenic diet. Twenty-four male Wistar rats were divided into 4 groups of 6 each and named control, cholesterol (Chol), Chol/RvC and Chol/RvNC. Rats of all 4 groups were fed the basal diet, which included wheat starch, casein, soybean oil, cellulose, vitamin (American Institute of Nutrition for laboratory animals vitamin mixtures), and mineral mixtures (American Institute of Nutrition for laboratory animals mineral mixtures). During 28 days of the experiment, the rats of the control group received the basal diet only, and the diets of the other 3 groups were supplemented with 1% of Chol, 1% of Chol, and 5% of Rv dry matter from C and NC areas. Dry matter from C and NC areas supplemented diets slightly hindered the rise in serum lipids vs. Chol group: total Chol, 13.18% and 11.63% and low-density lipoprotein Chol, 13.57% and 15.08%, respectively. Cholesterol significantly decreased the value of total antioxidant capacity. The supplementation of Rv to the Chol diet significantly affected the increase of antioxidant capacity in serum of rats, expressed by the 2,2'-azinobis (3 ethylbenzothiazoline-6-sulfonic acid) method. The water extracts of Rv exhibited high binding properties with bovine serum albumin in comparison with quercetin. In conclusion, atherogenic diets supplemented with Rv from C and NC areas hindered both the rise in serum lipids levels and the decrease in the antioxidant capacity. Based on fluorescence and electrospray-ionization mass spectrometry profiles and in vivo studies, changes in the intensity of the found peaks were estimated in the serum samples after supplemented diets. These findings indicate that the supplementation of Rv to the atherogenic diets improve the lipid profiles and the antioxidant status in serum of rats. PMID- 26048344 TI - Elemental diet moderates 5-fluorouracil-induced gastrointestinal mucositis through mucus barrier alteration. AB - PURPOSE: There are reports that elemental diet (ED) ameliorates oral mucositis caused by antineoplastic chemotherapy. Although this effectiveness may be partly due to high nutrient absorption, the effects of chemotherapy on mucosal defense mechanisms remain unclear. We investigated the effects of oral supplementation with ED on mucin in 5-fluorouracil (5-FU)-induced intestinal mucositis. METHODS: 5-FU was administered to rats orally once daily, and ED was supplied orally twice daily for 5 days. The severity of mucositis was assessed by length, dry tissue weight, and villus height of the intestinal tract. Using anti-mucin monoclonal antibody, we compared the immunoreactivity in the gastrointestinal (GI) tract and mucin content by histological and biochemical examinations. RESULTS: Oral supplementation with ED reduced histological damage and loss of length, dry tissue weight, and villus height induced by 5-FU administration. ED markedly altered PGM34 antibody immunoreactivity and mucin contents in the small intestine of rats with 5-FU-induced mucositis. CONCLUSIONS: ED may possibly be more effective for the prevention of antineoplastic chemotherapy-induced mucositis through the activation of GI mucus cells. PMID- 26048345 TI - Positive predictive value of clinical diagnosis of head and neck non-melanoma skin malignancies. How accurate are we? AB - ?: The purpose of the current study was to determine the accuracy of the clinical diagnosis in non-melanoma skin malignancy as confirmed by histopathological examination of the specimen. Positive predictive value (PPV) was selected as a reliable measure of diagnostic accuracy. METHODS: Clinical diagnosis was made in the outpatient clinic by a consultant oral and maxillofacial surgeon. We reviewed the electronic charts of 210 patients with non-melanoma skin malignant tumours and calculated the positive predictive value of the initial clinical diagnosis. Histological confirmation for each lesion was compared with the provisional clinical diagnosis made in the clinic. RESULTS: Of the 147 lesions provisionally diagnosed as basal cell carcinomas, 133 lesions were histologically confirmed to be basal cell carcinomas (BCC) (PPV 90.4 %). Of the 63 lesions provisionally thought to be squamous cell carcinomas, 47 lesions were histologically confirmed as squamous cell carcinomas (SCC) (PPV 74.6 %). The difference between the PPVs for the two types of malignancy in our study was not significant (p = 0.39). Statistics between our results for BCC and SCC and those reported from two other cancer institutes revealed no significant difference (p = 0.58 and 0.07). CONCLUSIONS: The present study supports that relying on clinical diagnosis with the purpose to formalise a treatment plan for head and neck non-melanoma skin cancer is safe and efficient. This is more reliable in cases of basal cell carcinoma in comparison to suspected squamous cell carcinomas. Although positive predictive value represents a reliable measure of diagnostic accuracy, it is increased when populations with higher prevalence of the disease are studied. PMID- 26048346 TI - Dynamic weight-bearing assessment of pain in knee osteoarthritis: a reliability and agreement study. AB - PURPOSE: To evaluate the reliability, agreement and smallest detectable change in a measurement instrument for pain and function in knee osteoarthritis; the Dynamic weight-bearing Assessment of Pain (DAP). METHODS: The sample size was set to 20 persons, recruited from the outpatient osteoarthritis clinic at Frederiksberg Hospital, Copenhagen. Two physiotherapists tested all participants during two visits; at the first visit, one single DAP (including four scores) was conducted by rater one; at the second visit, DAP was conducted by both raters one and two in randomized order with concealed allocation. The time interval was approximately 1.5 h. Measurement error was estimated by standard error of measurement (SEM). The intra- and inter-rater reliability was estimated by Intra class Correlation Coefficients for agreement based on a two-way ANOVA with random effects (single measures ICC 2.1). Smallest detectable change (SDC) and limits of agreement were calculated. RESULTS: The pain score showed excellent reliability in terms of ICC (intra-rater 0.93, CI 0.83-0.97, inter-rater 0.91, CI 0.78-0.96), low SEM (intra-rater 0.70, inter-rater 0.86, on a scale from 0 to 10), and acceptable SDC for intra-rater test (1.95). The three knee bend scores all had ICC above 0.50, showing fair-to-good reliability. None of the knee bend scores showed acceptable SEM and SDC. CONCLUSIONS: The reproducibility of the DAP pain score meets the demands for use in clinical practice and research. The total knee bend could be useful for motivational purpose in clinical use. Testing of other psychometric properties of the DAP is pending. PMID- 26048347 TI - Meaning-focused coping, pain, and affect: a diary study of hospitalized women with rheumatoid arthritis. AB - PURPOSE: The aim of the study was to investigate the relationship between affective state, pain, and coping in hospitalized women with rheumatoid arthritis, including both between- and within-person perspectives. METHODS: Participants were 95 female patients between 24 and 82 years of age (M = 50.91; SD = 13.80). For three consecutive days, they rated each night their state affect (positive and negative), pain level, and coping strategies (emotion-, problem- and meaning-focused ones). Relations among variables were tested with a multilevel approach with time included as a covariate. RESULTS: Within-person meaning-focused coping suppressed the negative pain effect on emotional state, but only for positive affect (Sobel's z = 2.07, p = .04). Moderators of the pain affect relationship were between-person differences in pain level (B = -.23, SE = .08, t = -2.884, p = .004) and in meaning-focused coping (B = -.63, SE = .20, t = -2.097, p = .04). Specifically, suppression was significant only for patients who reported lower than sample average pain levels and for patients who reported lower than sample average use of meaning-focused strategies. CONCLUSIONS: Findings indicated that meaning-focused coping can be a crucial strategy for keeping daily positive affect in the face of chronic pain and how this effect is modified by interindividual differences. Even if restricted to the specific context, it may inform an intervention for hospitalized women with rheumatoid arthritis. PMID- 26048349 TI - Trigeminal Nerve Injuries: Avoidance and Management of Iatrogenic Injury. AB - Iatrogenic injury to the trigeminal nerve can remain a source of concern and litigation even for the most experienced oral and maxillofacial surgeons. This article provides the most up-to-date evidence-based recommendations for identification, prevention, and management of these injuries to help clinicians provide the highest level of patient care. PMID- 26048348 TI - Psychometric properties of the EQ-5D-5L in Thai patients with chronic diseases. AB - PURPOSE: Due to the problem of high ceiling effects of the EQ-5D-3L, the EQ-5D-5L was developed. However, little was known about the full psychometric properties of the EQ-5D-5L. Thus, this study aimed to evaluate its practicality, reliability, validity, and responsiveness in Thai patients with chronic diseases. METHODS: One thousand one hundred and fifty-six adults taking a medicine at least 3 months were identified from three university hospitals in Bangkok, Thailand, between July 2014 and March 2015. Practicality was evaluated by administration times and ceiling effects. Test-retest reliability was assessed using weighted kappa and intraclass correlation coefficients (ICCs). Validity was tested with correlations between the EQ-5D-5L and WHOQoL-BREF and SF-12v2, and known-groups validity. Responsiveness was measured with standardized effect sizes (SES). RESULTS: The mean administration time was approximately 2 min, and the ceiling effect of the EQ-5D-5L index was 13.6 %. The weighted kappa values and ICC of the EQ-5D-5L were 0.48-0.61 and 0.82, respectively. Similar dimensions of the EQ-5D 5L had higher correlations with those of WHOQoL-BREF and SF-12v2. As expected, elderly, female, low-educated, unemployed, higher number of comorbidities and medicines, patients' perception of poor disease control, and having an adverse drug reaction tended to have poorer EQ-5D-5L scores. The SES of EQ-5D-5L index and EQ-VAS were considered small (0.33-0.42) for the improved group. For the worsened group, the SES of the EQ-5D-5L index were considered small (-0.29) but that of the EQ-VAS considered large (-0.82). CONCLUSIONS: The EQ-5D-5L was practical, reliable, valid, and responsive in Thai patients with chronic diseases. PMID- 26048350 TI - Current Concepts of Periapical Surgery. AB - Preoperative decision-making is vital to determine potential success of periapical surgery. Adequate exposure of the root apical region is best approached via a sulcular-type incision. Surgical procedures include resection of 2 to 3 mm of the apical portion along with root end preparation and seal. The surgeon must decide if submission of periapical tissues to pathology is indicated. PMID- 26048351 TI - Root depth and morphology in response to soil drought: comparing ecological groups along the secondary succession in a tropical dry forest. AB - Root growth and morphology may play a core role in species-niche partitioning in highly diverse communities, especially along gradients of drought risk, such as that created along the secondary succession of tropical dry forests. We experimentally tested whether root foraging capacity, especially at depth, decreases from early successional species to old-growth forest species. We also tested for a trade-off between two mechanisms for delaying desiccation, the capacity to forage deeper in the soil and the capacity to store water in tissues, and explored whether successional groups separate along such a trade-off. We examined the growth and morphology of roots in response to a controlled-vertical gradient of soil water, among seedlings of 23 woody species dominant along the secondary succession in a tropical dry forest of Mexico. As predicted, successional species developed deeper and longer root systems than old-growth forest species in response to soil drought. In addition, shallow root systems were associated with high plant water storage and high water content per unit of tissue in stems and roots, while deep roots exhibited the opposite traits, suggesting a trade-off between the capacities for vertical foraging and water storage. Our results suggest that an increased capacity of roots to forage deeper for water is a trait that enables successional species to establish under the warm-dry conditions of the secondary succession, while shallow roots, associated with a higher water storage capacity, are restricted to the old-growth forest. Overall, we found evidence that the root depth-water storage trade-off may constrain tree species distribution along secondary succession. PMID- 26048352 TI - Pre-eclampsia Diagnosis and Treatment Options: A Review of Published Economic Assessments. AB - BACKGROUND: Pre-eclampsia is a pregnancy complication affecting both mother and fetus. Although there is no proven effective method to prevent pre-eclampsia, early identification of women at risk of pre-eclampsia could enhance appropriate application of antenatal care, management and treatment. Very little is known about the cost effectiveness of these and other tests for pre-eclampsia, mainly because there is no clear treatment path. The aim of this study was to provide a comprehensive overview of the existing evidence on the health economics of screening, diagnosis and treatment options in pre-eclampsia. METHODS: We searched three electronic databases (PubMed, EMBASE and the Cochrane Library) for studies on screening, diagnosis, treatment or prevention of pre-eclampsia, published between 1994 and 2014. Only full papers written in English containing complete economic assessments in pre-eclampsia were included. RESULTS: From an initial total of 138 references, six papers fulfilled the inclusion criteria. Three studies were on the cost effectiveness of treatment of pre-eclampsia, two of which evaluated magnesium sulphate for prevention of seizures and the third evaluated the cost effectiveness of induction of labour versus expectant monitoring. The other three studies were aimed at screening and diagnosis, in combination with subsequent preventive measures. The two studies on magnesium sulphate were equivocal on the cost effectiveness in non-severe cases, and the other study suggested that induction of labour in term pre-eclampsia was more cost effective than expectant monitoring. The screening studies were quite diverse in their objectives as well as in their conclusions. One study concluded that screening is probably not worthwhile, while two other studies stated that in certain scenarios it may be cost effective to screen all pregnant women and prophylactically treat those who are found to be at high risk of developing pre eclampsia. DISCUSSION: This study is the first to provide a comprehensive overview on the economic aspects of pre-eclampsia in its broadest sense, ranging from screening to treatment options. The main limitation of the present study lies in the variety of topics in combination with the limited number of papers that could be included; this restricted the comparisons that could be made. In conclusion, novel biomarkers in screening for and diagnosing pre-eclampsia show promise, but their accuracy is a major driver of cost effectiveness, as is prevalence. Universal screening for pre-eclampsia, using a biomarker, will be feasible only when accuracy is significantly increased. PMID- 26048353 TI - Disinvestment and Value-Based Purchasing Strategies for Pharmaceuticals: An International Review. AB - Pharmaceutical expenditure has increased rapidly across many Organisation for Economic Cooperation and Development (OECD) countries over the past three decades. This growth is an increasing concern for governments and other third party payers seeking to provide equitable and comprehensive healthcare within sustainable budgets. In order to create headroom for increasing utilisation, and to fund new high-cost therapies, there is an active push to 'disinvest' from low value drugs. The aim of this article is to review how reimbursement policy decision makers have sought to partially or completely disinvest from drugs in a range of OECD countries (UK, France, Canada, Australia and New Zealand) where they are publicly funded or subsidised. We employed a systematic literature search strategy and the incorporation of grey literature known to the authorship team. We canvass key policy instruments from each country to outline key approaches to the identification of candidate drugs for disinvestment assessment (passive approaches vs. more active approaches); methods of disinvestment and value-based purchasing (de-listing, restricting treatment, price or reimbursement rate reductions, encouraging generic prescribing); lessons learnt from the various approaches; the potential role of coverage with evidence development; and the need for careful stakeholder management. Dedicated sections are provided with detailed coverage of policy approaches (with drug examples) from each country. Historically, countries have relied on 'passive disinvestment'; however, due to (1) the availability of new cost-effectiveness evidence, or (2) 'leakage' in drug utilisation, or (3) market failure in terms of price competition, there is an increasing focus towards 'active disinvestment'. Isolating low-value drugs that would create headroom for innovative new products to enter the market is also motivating disinvestment efforts by multiple parties, including industry. Historically, disinvestment has mainly taken the form of price reductions, especially when market failures are perceived to exist, and restricting treatment to subpopulations, particularly when a drug is no longer considered value for money. There is considerable experimentation internationally in mechanisms for disinvestment and the opportunity for countries to learn from each other. Ongoing evaluation of disinvestment strategies is essential, and ought to be reported in the peer-reviewed literature. PMID- 26048354 TI - Assessing the Economics of Dengue: Results from a Systematic Review of the Literature and Expert Survey. AB - BACKGROUND: The economics of dengue is complex and multifaceted. OBJECTIVES: We performed a systematic review of the literature to provide a critical overview of the issues related to dengue economics research and to form a background with which to address the question of cost. METHODS: Three literature databases were searched [PubMed, Embase and Latin American and Caribbean Health Sciences Literature (LILACS)], covering a period from 1980 to 2013, to identify papers meeting preset inclusion criteria. Studies were reviewed for methodological quality on the basis of a quality checklist developed for this purpose. An expert survey was designed to identify priority areas in dengue economics research and to identify gaps between the methodology and actual practice. Survey responses were combined with the literature review findings to determine stakeholder priorities in dengue economics research. RESULTS: The review identified over 700 papers. Forty-two of these papers met the selection criteria. The studies that were reviewed presented results from 32 dengue-endemic countries, underscoring the importance of dengue as a global public health problem. Cost analyses were the most common, with 21 papers, followed by nine cost-effectiveness analyses and seven cost-of-illness studies, indicating a relatively strong mix of methodologies. Dengue annual overall costs (in 2010 values) ranged from US$13.5 million (in Nicaragua) to $56 million (in Malaysia), showing cost variations across countries. Little consistency exists in the way costs were estimated and dengue interventions evaluated, making generalizations around costs difficult. CONCLUSIONS: The current evidence suggests that dengue costs are substantial because of the cost of hospital care and lost earnings. Further research in this area will broaden our understanding of the true economic impact of dengue. PMID- 26048355 TI - Supra-thyroid alar cartilage approach for the complete resection of laryngeal submucosal tumors and postoperative voice quality. AB - Various surgical approaches for the treatment of laryngeal submucosal tumors have been reported. Endoscopic excision is indicated for small lesions, while external approaches are recommended for larger tumors. This report introduces a supra thyroid alar cartilage approach (STACA), which has strong advantages for the preservation of the laryngeal framework and voice recovery after surgery. Case series with chart review. Four patients with laryngeal submucosal tumors in the paraglottic space underwent complete tumor removal through STACA. Medical charts were reviewed to evaluate patient background, major complaints, tumor type, tumor size, the time period from operation to tracheostomy closure, tumor recurrence, and the difference between pre- and postoperative voice quality. Voice quality was assessed using the GRBAS score, maximum phonation time (MPT) and Voice Handicap Index-10 (VHI-10) 6 months after surgery. All patients were females between 43 and 67 years of age. Two patients had schwannoma, one laryngocele, and one lipoma. Mean tumor size was 3.4 cm. The main complaints were hoarseness in all patients, and dyspnea in one. The periods of time from surgery to oral intake and tracheostomy closure were 3.5 and 7 days, respectively. No patient developed recurrence during a minimum follow-up period of 2 years. The postoperative GRBAS scores, MPT and VHI-10 improved in all patients. STACA has advantages including minimal trauma, no deformity to the laryngeal framework, and good voice qualities after the resection of laryngeal submucosal tumors. PMID- 26048356 TI - Endoscopic endonasal multilayer repair of traumatic CSF rhinorrhea. AB - The incidence of traumatic CSF has increased in recent years due to increased incidence of road traffic accidents (RTA) as well the increasing number of endoscopic sinus surgeries (ESS). The objective of this study is to present our experience in management of traumatic CSF leaks using the endoscopic multilayer repair technique. Forty-two patients (aged 10-75 years, 30 males and 12 females) presenting with confirmed post-traumatic CSF rhinorrhea were operated upon between January 2007 and December 2013. The endoscopic multilayer technique was used in all cases. Electromagnetic navigation was used in some cases. All cases presented with intermittent watery rhinorrhea. The duration of the rhinorrhea ranged from 3 days to 1 year before repair. One case presented after 10 years from the causative trauma. Ten cases had a history of meningitis. Nine cases had more than one defect. Iatrogenic defects were larger than defects following accidental trauma. Two cases, following RTA, developed pseudo-aneurysm of internal carotid artery. Ten cases had associated pneumocephalus. The mean duration of postoperative hospitalization was 6 days (range 4-8 days). The mean follow-up duration was 31.2 +/- 11.4 months (range 16-48 months). None of our patient developed serious intra- or postoperative complications. Only one case required another surgery to repair a missed second defect. Post-traumatic CSF leaks can be successfully managed via the endonasal endoscopic route using the multilayer repair technique. It is important to look for multiple defects in these cases. CT angiography is recommended for traumatic leaks involving the lateral wall of the sphenoid sinus to diagnose or exclude the development of pseudo-aneurysm of the internal carotid artery. PMID- 26048357 TI - Issues in Lung Cancer Screening Among Asian American Immigrants. PMID- 26048358 TI - The Impact of Acculturation Style and Acculturative Hassles on the Mental Health of Somali Adolescent Refugees. AB - Refugee adolescents often immigrate to a new society because of experiences of persecution and trauma, which can have profound effects on their mental health. Once they immigrate, many refugees experience stressors related to resettlement and acculturation in the new society. The current study examined relationships among acculturation styles and hassles and the well-being of young refugees as well as the role of gender. Data were collected from 135 young refugees (M age = 15.39, SD = 2.2; 62 % male) from Somalia resettled in the United States The findings from our study indicate that in addition to trauma history, acculturative hassles and acculturation style impact the wellbeing of Somali refugee adolescents. These findings indicate the need to understand both past experiences as well as current challenges. Potential areas for intervention are discussed. PMID- 26048359 TI - Early antipsychotic intervention and schizophrenia. AB - Schizophrenia is a major mental disorder in which patients' cognitive functions gradually deteriorate. Pharmacological intervention with antipsychotics has proven effective, yet it is still debatable whether to initiate treatment in patients' premorbid stage. Based on the developmental origins of schizophrenia, we hypothesize that for those who are at high risk for schizophrenia, particularly with gating problems, an early pharmacological intervention would be beneficial. We performed a pilot rodent study to evaluate this hypothesis. Our results demonstrated that isolation rearing-induced sensorimotor gating dysfunction could be reversed by a chronic risperidone regimen initiated at different age time points. As expected, interventions that we initiated earlier (in adolescent stage) appeared to have better efficacy than interventions initiated four weeks later (in young adult stage). Our hypothesis may contribute new insight for both prevention and treatment of schizophrenia. PMID- 26048360 TI - Effect of absent bilateral radial arteries on the accuracy of continuous real time noninvasive blood pressure monitoring with the NexfinTM system. PMID- 26048361 TI - Restoration of Normal Cerebral Oxygen Consumption with Rapamycin Treatment in a Rat Model of Autism-Tuberous Sclerosis. AB - Tuberous sclerosis (TSC) is associated with autism spectrum disorders and has been linked to metabolic dysfunction and unrestrained signaling of the mammalian target of rapamycin (mTOR). Inhibition of mTOR by rapamycin can mitigate some of the phenotypic abnormalities associated with TSC and autism, but whether this is due to the mTOR-related function in energy metabolism remains to be elucidated. In young Eker rats, an animal model of TSC and autism, which harbors a germ line heterozygous Tsc2 mutation, we previously reported that cerebral oxygen consumption was pronouncedly elevated. Young (4 weeks) male control Long-Evans and Eker rats were divided into control and rapamycin-treated (20 mg/kg once daily for 2 days) animals. Cerebral regional blood flow ((14)C-iodoantipyrine) and O2 consumption (cryomicrospectrophotometry) were determined in isoflurane anesthetized rats. We found significantly increased basal O2 consumption in the cortex (8.7 +/- 1.5 ml O2/min/100 g Eker vs. 2.7 +/- 0.2 control), hippocampus, pons and cerebellum. Regional cerebral blood flow and cerebral O2 extractions were also elevated in all brain regions. Rapamycin had no significant effect on O2 consumption in any brain region of the control rats, but significantly reduced consumption in the cortex (4.1 +/- 0.3) and all other examined regions of the Eker rats. Phosphorylation of mTOR and S6K1 was similar in the two groups and equally reduced by rapamycin. Thus, a rapamycin-sensitive, mTOR-dependent but S6K1-independent, signal led to enhanced oxidative metabolism in the Eker brain. We found decreased Akt phosphorylation in Eker but not Long-Evans rat brains, suggesting that this may be related to the increased cerebral O2 consumption in the Eker rat. Our findings suggest that rapamycin targeting of Akt to restore normal cerebral metabolism could have therapeutic potential in tuberous sclerosis and autism. PMID- 26048365 TI - Laparoscopic Conversion of a Sleeve Gastrectomy to the Roux-en-Y Gastric Bypass. AB - After the failure of sleeve gastrectomy (SG), three options are available as a second intervention: the conversion into a biliopancreatic diversion with duodenal switch, the Roux-en-Y gastric bypass (RYGBP), and more recently, a re-SG consisting in the refashioning of a dilated gastric tube. We describe two different approaches for the conversion. The conversion to RYGBP remains a technically challenging operation but feasible and effective, and it should be reserved to specialized centers. PMID- 26048366 TI - Calorie restriction does not restore brain mitochondrial function in P301L tau mice, but it does decrease mitochondrial F0F1-ATPase activity. AB - Calorie restriction (CR) has been shown to increase lifespan and delay aging phenotypes in many diverse eukaryotic species. In mouse models of Alzheimer's disease (AD), CR has been shown to decrease amyloid-beta and hyperphosphorylated tau levels and preserve cognitive function. Overexpression of human mutant tau protein has been shown to induce deficits in mitochondrial electron transport chain complex I activity. Therefore, experiments were performed to determine the effects of 4-month CR on brain mitochondrial function in Tg4510 mice, which express human P301L tau. Expression of mutant tau led to decreased ADP-stimulated respiratory rates, but not uncoupler-stimulated respiratory rates. The membrane potential was also slightly higher in mitochondria from the P301L tau mice. As shown previously, tau expression decreased mitochondrial complex I activity. The decreased complex I activity, decreased ADP-stimulated respiratory rate, and increased mitochondrial membrane potential occurring in mitochondria from Tg4510 mice were not restored by CR. However, the CR diet did result in a genotype independent decrease in mitochondrial F0F1-ATPase activity. This decrease in F0F1 ATPase activity was not due to lowered levels of the alpha or beta subunits of F0F1-ATPase. The possible mechanisms through which CR reduces the F0F1-ATPase activity in brain mitochondria are discussed. PMID- 26048362 TI - Synergistic combinations of antifungals and anti-virulence agents to fight against Candida albicans. AB - Candida albicans, one of the pathogenic Candida species, causes high mortality rate in immunocompromised and high-risk surgical patients. In the last decade, only one new class of antifungal drug echinocandin was applied. The increased therapy failures, such as the one caused by multi-drug resistance, demand innovative strategies for new effective antifungal drugs. Synergistic combinations of antifungals and anti-virulence agents highlight the pragmatic strategy to reduce the development of drug resistant and potentially repurpose known antifungals, which bypass the costly and time-consuming pipeline of new drug development. Anti-virulence and synergistic combination provide new options for antifungal drug discovery by counteracting the difficulty or failure of traditional therapy for fungal infections. PMID- 26048367 TI - Dental wear patterns in early modern humans from Skhul and Qafzeh: A response to Sarig and Tillier. AB - The use of teeth as tools for manipulating objects and simple food-processing methods was common among prehistoric and modern hunter-gatherer human populations. Paramasticatory uses of teeth frequently produce enamel chipping and distinctive types of dental wear that can readily be related to specific tool functions. In particular, the presence of unusual occlusal wear areas (named para facets) on maxillary teeth of prehistoric, historic and modern hunter-gatherers has been associated with cultural habits involving extensive use of teeth (Fiorenza et al., 2011; Fiorenza and Kullmer, 2013). However, Sarig and Tillier (2014) believe that this wear had been caused by pathological occlusal relationships rather than by the use of teeth as tools. In this contribution, we show how occlusal contacts are created and how it is possible to distinguish between masticatory and non-masticatory wear facets by using an innovative digital approach called Occlusal Fingerprint Analysis. Statistical results from the analysis of comparative modern samples clearly demonstrate that described para-facets in Skhul and Qafzeh could not have been produced by dental occlusal anomalies such as malocclusions and crossbites. Moreover, dental pathologies in prehistoric humans were extremely rare. Only with the adoption of the modern lifestyle between 18th and 19th centuries, did the emergence of malocclusions become significantly more common. Because more than 50% of the Skhul and Qafzeh individuals analysed in our study are characterised by this distinctive type of wear, it is highly unlikely that their para-facets occurred as a result of dental pathologies. PMID- 26048368 TI - Evidence of probable tuberculosis in Lithuanian mummies. AB - Tuberculosis has affected Europe for millennia and continues to be a burden upon modern society. It is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis, the causative agent of this condition. Despite the introduction of control strategies, the disease continues to be one of the most common causes of death globally. Within the framework of the Lithuanian Mummy Project, seven spontaneously mummified human bodies from a church crypt in Vilnius, dating from the 18th and 19th century, were CT-scanned to assess the presence of tuberculosis or other lung diseases. We encountered pulmonary lesions suggestive of cases of pulmonary tuberculosis. In addition, one case might have been affected by extra-pulmonary tuberculosis. This report replicates the image findings from previous studies on ancient mummies that provided evidence of tuberculosis in soft tissues, thus helping reconstruct the history of this disease over time. PMID- 26048369 TI - The outlook of physician histories: J. Marion Sims and 'The Discovery of Anaesthesia'. AB - The fact that doctors have a long tradition of writing medical history to interpret and direct their profession is well established. But readers (particularly modern physician readers) can also understand physician-authored histories as offering commentary and analysis of the world beyond medicine. In this essay, we offer a reading (perhaps a modern one) of J. Marion Sims's 1877 article, 'The Discovery of Anaesthesia' which exemplifies the stance of looking both inward and outward from the medical field. We begin by discussing Sims, including the complicated legacy he left as a physician. Next, we review late 19th-century history with a focus on Reconstruction. Finally, we show how the modern reader can use Sims's article both to trace the first use of ether and nitrous oxide for surgical anaesthesia and to provide a window into the 19th century medical profession and the post-Civil War period. Through this study, we hope to show how to read both medicine and the world around it in physician histories. PMID- 26048370 TI - Supratidal Extremophiles--Cyanobacterial Diversity in the Rock Pools of the Croatian Adria. AB - Hardly any molecular studies have been done on euendoliths of marine coastal environments, especially along the supratidal ranges of carbonate coasts. In our study, we provide a comparative sequence analysis using 454 pyrosequencing of the 16S ribosomal RNA (rRNA) gene combined with extensive microscopy of the endolithic community from rock pools of the Croatian Adria. Molecular diversity indices and richness estimates showed high level of diversity, particularly in high-salinity samples. The most common cyanobacteria belong to the order Pleurocapsales, similar to observations on limestone coasts in other parts of the world. Using single-cell amplification sequences of Hormathonema spp., Hyella caespitosa, and Kyrtuthrix dalmatica was for the first time introduced to the public GenBank.Microscopic investigations did not show qualitative variances in diversity among sites with different salinity but clear differences in prevalent organisms from similar environments suggesting that most of them are adapted to inhabit extreme, marine endolithic habitats and that similar species inhabit geographically separated but ecologically similar environments. This is a remarkable concordance rather seldom seen in molecular community studies in support of the hypothesis that endolithic ecosystems are seeded from a global meta-community.The relative diversity of the community is greater than those described from harsh endolithic habitats of cold and hot deserts. The maximum likelihood phylogenetic tree consisting of 166 operational taxonomic units (OTUs) at 96 % sequence similarity revealed 11 distinct clusters. Three clusters contained only epilithic or endolithic taxa, and five clusters contained mixed epilithic and endolithic taxa. Organisms clustered according to their taxonomic affiliations and not to their preferences to salt concentrations. PMID- 26048371 TI - Risk of tuberculosis in patients with diabetes: population based cohort study using the UK Clinical Practice Research Datalink. AB - BACKGROUND: Previous cohort studies demonstrate diabetes as a risk factor for tuberculosis (TB) disease. Public Health England has identified improved TB control as a priority area and has proposed a primary care-based screening program for latent TB. We investigated the association between diabetes and risk of tuberculosis in a UK General Practice cohort in order to identify potential high-risk groups appropriate for latent TB screening. METHODS: Using data from the UK Clinical Practice Research Datalink we constructed a cohort of patients with incident diabetes. We included 222,731 patients with diabetes diagnosed from 1990-2013 and 1,218,616 controls without diabetes at index date who were matched for age, sex and general practice. The effect of diabetes was explored using a Poisson analysis adjusted for age, ethnicity, body mass index, socioeconomic status, alcohol intake and smoking. We explored the effects of age, diabetes duration and severity. The effects of diabetes on risk of incident TB were explored across strata of chronic disease care defined by cholesterol and blood pressure measurement and influenza vaccination rates. RESULTS: During just under 7 million person-years of follow-up, 969 cases of TB were identified. The incidence of TB was higher amongst patients with diabetes compared with the unexposed group: 16.2 and 13.5 cases per 100,000 person-years, respectively. After adjustment for potential confounders the association between diabetes and TB remained (adjusted RR 1.30, 95 % CI 1.01 to 1.67, P = 0.04). There was no evidence that age, time since diagnosis and severity of diabetes affected the association between diabetes and TB. Diabetes patients with the lowest and highest rates of chronic disease management had a higher risk of TB (P <0.001 for all comparisons). CONCLUSIONS: Diabetes as an independent risk factor is associated with only a modest overall increased risk of TB in our UK General Practice cohort and is unlikely to be sufficient cause to screen for latent TB. Across different consulting patterns, diabetes patients accessing the least amount of chronic disease care are at highest risk for TB. PMID- 26048372 TI - Erratum: Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer's disease donor as a model for investigating AD-associated gene regulatory networks. PMID- 26048373 TI - Eco-epidemiology of Borrelia miyamotoi and Lyme borreliosis spirochetes in a popular hunting and recreational forest area in Hungary. AB - BACKGROUND: Borrelia miyamotoi, the newly discovered human pathogenic relapsing fever spirochete, and Borrelia burgdorferi sensu lato are maintained in natural rodent populations. The aim of this study was to investigate the natural cycle of B. miyamotoi and B. burgdorferi s.l. in a forest habitat with intensive hunting, forestry work and recreational activity in Southern Hungary. METHODS: We collected rodents with modified Sherman-traps during 2010-2013 and questing ticks with flagging in 2012. Small mammals were euthanized, tissue samples were collected and all ectoparasites were removed and stored. Samples were screened for pathogens with multiplex quantitative real-time polymerase chain reaction (qPCR) targeting a part of flagellin gene, then analysed with conventional PCRs and sequencing. RESULTS: 177 spleen and 348 skin samples of six rodent species were individually analysed. Prevalence in rodent tissue samples was 0.2 % (skin) and 0.5 % (spleen) for B. miyamotoi and 6.6 % (skin) and 2.2 % (spleen) for B. burgdorferi s.l. Relapsing fever spirochetes were detected in Apodemus flavicollis males, B. burgdorferi s.l. in Apodemus spp. and Myodes glareolus samples. Borrelia miyamotoi was detected in one questing Ixodes ricinus nymph and B. burgdorferi s.l in nymphs and adults. In the ticks removed from rodents DNA amplification of both pathogens was successful from I. ricinus larvae (B. miyamotoi 5.6 %, B. burgdorferi s.l. 11.1 %) and one out of five nymphs while from Ixodes acuminatus larvae, and nymph only B. burgdorferi s.l. DNA was amplified. Sequencing revealed B. lusitaniae in a questing I. ricinus nymph and altogether 17 B. afzelii were identified in other samples. Two Dermacentor marginatus engorged larva pools originating from uninfected hosts were also infected with B. afzelii. CONCLUSIONS: This is the first report of B. miyamotoi occurrence in a natural population of A. flavicollis as well as in Hungary. We provide new data about circulation of B. burgdorferi s.l. in rodent and tick communities including the role of I. acuminatus ticks in the endophilic pathogen cycle. Our results highlight the possible risk of infection with relapsing fever and Lyme borreliosis spirochetes in forest habitats especially in the high-risk groups of hunters, forestry workers and hikers. PMID- 26048375 TI - Placing HPS2-THRIVE in context using Bayesian analysis. PMID- 26048376 TI - Sensitivity and specificity of the subcutaneous implantable cardioverter defibrillator pre-implant screening tool. AB - BACKGROUND: The sensitivity and specificity of the subcutaneous implantable cardioverter defibrillator (S-ICD) pre-implant screening tool required clinical evaluation. METHODS: Bipolar vectors were derived from electrodes positioned at locations similar to those employed for S-ICD sensing and pre-implant screening electrodes, and recordings collected through 80-electrode PRIME(r)-ECGs, in six different postures, from 40 subjects (10 healthy controls, and 30 patients with complex congenital heart disease (CCHD); 10 with Tetralogy of Fallot (TOF), 10 with single ventricle physiology (SVP), and 10 with transposition of great arteries (TGA)). The resulting vectors were analysed using the S-ICD pre-implant screening tool (Boston Scientific) and processed through the sensing algorithm of S-ICD (Boston Scientific). The data were then evaluated using 2 * 2 contingency tables. Fisher exact and McNemar tests were used for a comparison of the different categories of CCHD, and p < 0.05 vs. controls considered to be statistically significant. RESULTS: 57% of patients were male, mean age of 36.3 years. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the S-ICD screening tool were 95%, 79%, 59% and 98%, respectively, for controls, and 84%, 79%, 76% and 86%, respectively, in patients with CCHD (p = 0.0001). CONCLUSION: The S-ICD screening tool was comparatively more sensitive in normal controls but less specific in both CCHD patients and controls; a possible explanation for the reported high incidence of inappropriate S-ICD shocks. Thus, we propose a pre-implant screening device using the S-ICD sensing algorithm to minimise false exclusion and selection, and hence minimise potentially inappropriate shocks. PMID- 26048374 TI - Targeting Wnt pathway in mantle cell lymphoma-initiating cells. AB - BACKGROUND: Mantle cell lymphoma (MCL) is an aggressive and incurable form of non Hodgkin's lymphoma. Despite initial intense chemotherapy, up to 50% of cases of MCL relapse often in a chemoresistant form. We hypothesized that the recently identified MCL-initiating cells (MCL-ICs) are the main reason for relapse and chemoresistance of MCL. Cancer stem cell-related pathways such as Wnt could be responsible for their maintenance and survival. METHODS: We isolated MCL-ICs from primary MCL cells on the basis of a defined marker expression pattern (CD34-CD3 CD45+CD19-) and investigated Wnt pathway expression. We also tested the potential of Wnt pathway inhibitors in elimination of MCL-ICs. RESULTS: We showed that MCL ICs are resistant to genotoxic agents vincristine, doxorubicin, and the newly approved Burton tyrosine kinase (BTK) inhibitor ibrutinib. We confirmed the differential up-regulation of Wnt pathway in MCL-ICs. Indeed, MCL-ICs were particularly sensitive to Wnt pathway inhibitors. Targeting beta-catenin-TCF4 interaction with CCT036477, iCRT14, or PKF118-310 preferentially eliminated the MCL-ICs. CONCLUSIONS: Our results suggest that Wnt signaling is critical for the maintenance and survival of MCL-ICs, and effective MCL therapy should aim to eliminate MCL-ICs through Wnt signaling inhibitors. PMID- 26048377 TI - New-onset atrial fibrillation in patients with elevated troponin I levels in the acute phase of stroke. PMID- 26048378 TI - Antihyperlipidemic therapies targeting PCSK9: Novel therapeutic agents for lowering low-density lipoprotein cholesterol. PMID- 26048379 TI - Delving into the issue of life-threatening arrhythmias in patients with Takotsubo syndrome. PMID- 26048380 TI - A new method of applying randomised control study data to the individual patient: A novel quantitative patient-centred approach to interpreting composite end points. AB - BACKGROUND: Modern randomised controlled trials typically use composite endpoints. This is only valid if each endpoint is equally important to patients but few trials document patient preference and seek the relative importance of components of combined endpoints. If patients weigh endpoints differentially, our interpretation of trial data needs to be refined. METHODS AND RESULTS: We derive a quantitative, structured tool to determine the relative importance of each endpoint to patients. We then apply this tool to data comparing angioplasty with drug-eluting stents to bypass surgery. The survey was administered to patients undergoing cardiac catheterisation. A meta-analysis comparing coronary artery bypass grafting (CABG) to percutaneous coronary interventuin (PCI) was then performed using (a) standard MACE and (b) patient-centred MACE. Patients considered stroke worse than death (stroke 102.3 +/- 19.6%, p < 0.01), and MI and repeat revascularisation less severe than death (61.9 +/- 26.8% and 41.9 +/- 25.4% respectively p < 0.01 for both). 7 RCTs (5251 patients) were eligible. Meta analysis demonstrated that standard MACE occurs more frequently with PCI than surgery (OR 1.44; 95% CI 1.10 to 1.87; p = 0.007). Re-analysis using patient centred MACE found no significant difference between PCI and CABG (OR 1.22, 95% CI 0.97 to 1.53; p = 0.10). CONCLUSIONS: Patients do not consider the constituent endpoints of MACE equal. We derive a novel patient-centred metric that recognises and quantifies the differences attributed to each endpoint. When patient preference data are applied to contemporary trial results, there is no significant difference between PCI and CABG. Responses from individual patients in clinic could be used to give individual patients a recommendation that is truly personalised. PMID- 26048381 TI - Acute pulmonary embolism (PE) as the most serious clinical presentation of venous thromboembolism (VTE). PMID- 26048382 TI - Continuous intravenous infusion of nicorandil for 4 hours before and 24 hours after percutaneous coronary intervention protects against contrast-induced nephropathy in patients with poor renal function. AB - BACKGROUND: We conducted a prospective randomized trial to assess the protective effect of continuous intravenous infusion of nicorandil against contrast-induced nephropathy (CIN) in patients with poor renal function. METHODS AND RESULTS: We randomly assigned 213 patients who would subsequently undergo elective percutaneous coronary intervention (PCI) and who had a high serum cystatin C level to a saline group (n=107) or a nicorandil group (n=106, nicorandil infused in addition to saline for 4h before and 24h after PCI). There were no significant differences in baseline characteristics between the two groups. However, the average percent increases in serum creatinine and cystatin C following PCI were significantly smaller in the nicorandil group than the saline group. Likewise, the average percent decline in the estimated glomerular filtration rate was smaller in the nicorandil group. Correspondingly, the incidence of CIN was dramatically lower in the nicorandil group than the saline group (2.0% vs. 10.7%, p<0.02). Univariate regression analysis revealed nicorandil treatment to be the only significant predictor of CIN development (odds ratio: 0.173, 95% confidence interval: 0.037-0.812, p=0.026). CONCLUSIONS: Nicorandil strongly prevents CIN in patients with poor renal function undergoing PCI. PMID- 26048383 TI - Patent foramen ovale closure and migraine time course: Clues for positive interaction. PMID- 26048384 TI - The CHADS2 and CHA2DS2-VASc scores for predicting ischemic stroke among East Asian patients with atrial fibrillation: A systemic review and meta-analysis. AB - BACKGROUND: Both the CHADS2 and CHA2DS2-VASc scores are well-validated in Western populations for predicting risk of stroke among patients with atrial fibrillation (AF). There is some uncertainty as to which risk score is best to guide optimal anticoagulant therapy among Asian populations with AF. METHODS: A systemic literature search of Cochrane library, Scopus, and PubMed databases was conducted using search terms: atrial fibrillation, CHADS2 and CHA2DS2-VASc. Stroke/thromboembolism (TE) outcome events at low, moderate, and high risk groups were compared in relation to both scores. Statistical analyses were performed using Revman 5.3 software. RESULTS: 493 records were retrieved, of which 6 cohort studies focusing on patients from Asian regions were finally appraised and included. Absolute event rates were usually lower when patients were categorized as CHA2DS2-VASc of 0-1, rather than CHADS2 of 0-1, respectively. Meta-analysis revealed that when compared with the CHA2DS2-VASc score, there was a 1.71-fold elevated risk of stroke when patients were stratified as 'low risk' using a CHADS2 score = 0, or a 1.40-fold increase with a CHADS2 score = 1. A 1.19-fold elevated event rate was observed among CHADS2 score >= 2 compared to CHA2DS2 VASc, but the total stroke/TE events were numerically higher in patients categorized as CHA2DS2-VASc >= 2. CONCLUSION: The CHA2DS2-VASc score is superior to the CHADS2 score in identifying 'low risk' East Asian AF patients. Rather than a categorical approach, Asian guidelines should adopt a 2 step approach, by initially identifying the truly low risk patients, following which effective stroke prevention can be offered to those with >= 1 additional stroke risk factors. PMID- 26048385 TI - Immunohistochemical analysis of estrogen and progesterone receptor expression in cardiac myxomas. PMID- 26048386 TI - Out-of-hospital cardiac arrest after acute cocaine intoxication associated with Brugada ECG patterns: Insights into physiopathologic mechanisms and implications for therapy. PMID- 26048387 TI - Projected morbidity and mortality from missed diagnoses of coronary artery disease in the United States. PMID- 26048388 TI - Pulmonary vein measurements on pre-procedural CT/MR imaging can predict difficult pulmonary vein isolation and phrenic nerve injury during cryoballoon ablation for paroxysmal atrial fibrillation. AB - OBJECTIVE: We tested the hypothesis that pulmonary vein (PV) measurements on pre procedural CT/MR imaging can predict difficulty in isolation and phrenic nerve (PN) injury during cryoballoon ablation for paroxysmal atrial fibrillation (AF). METHODS: Consecutive patients with paroxysmal AF who had pre-procedural CT/MRI and underwent cryoballoon ablation as part of a randomized trial were studied. Imaging was anonymized for blinded analysis of: (1) maximum ostial diameter, (2) minimum ostial diameter, (3) ostial area and (4) ratio of maximum over minimum ostial diameter (eccentricity index). Veins that required more than 2 freezes of at least 200 s duration to isolate or not isolated were defined as difficult to isolate. Loss of PN pacing during right-sided ablation was defined as PN injury. Logistic regression was used to analyze the predictive effect of the measurements on the 2 outcomes. RESULTS: 148 PVs in 38 patients (aged 60 +/- 11 years, 76% male) were analyzed. Left inferior PV (LIPV) was most difficult to isolate with 23 out of 37 PVs (62%), and PN injury occurred in 3 of 38 (8%) right superior PV (RSPV). Greater eccentricity index predicted difficulty in isolating LIPV, OR 40.33 (95% CI 1.40 to 1160, p = 0.03) and smaller eccentricity index predicted PN injury in RSPV, OR 0.01 (95% CI 0.01-0.16, p = 0.001). CONCLUSIONS: Eccentricity index measured from pre-procedural CT/MR imaging can predict difficulty of PV isolation and PN injury during cryoballoon ablation for paroxysmal AF. PMID- 26048389 TI - Long-term survival of elderly patients undergoing percutaneous coronary intervention for myocardial infarction complicated by cardiogenic shock. AB - BACKGROUND: The long-term benefit of early percutaneous coronary intervention (PCI) for cardiogenic shock (CS) in elderly patients remains unclear. We sought to assess the long-term survival of elderly patients (age >= 75 years) with myocardial infarction (MI) complicated by CS undergoing PCI. METHODS: We analyzed baseline characteristics, early outcomes, and long-term survival in 421 consecutive patients presenting with MI and CS who underwent PCI from the Melbourne Interventional Group registry from 2004 to 2011. Mean follow-up of patients who survived to hospital discharge was 3.0 +/- 1.8 years. RESULTS: Of the 421 consecutive patients, 122 patients were elderly (>= 75 years) and 299 patients were younger (< 75 years). The elderly cohort had significantly more females, peripheral and cerebrovascular disease, renal impairment, heart failure (HF) and prior MI (all p < 0.05). Procedural success was lower in the elderly (83% vs. 92%, p < 0.01). Long-term mortality was significantly higher in the elderly (p < 0.01), driven by high in-hospital mortality (48% vs. 36%, p < 0.05). However, in a landmark analysis of hospital survivors in the elderly group, long term mortality rates stabilized, approximating younger patients with CS (p = 0.22). Unsuccessful procedure, renal impairment, HF and diabetes mellitus were independent predictors of long-term mortality. However, age >= 75 was not a significant predictor (HR 1.2; 95% CI 0.9-1.7; p = 0.2). CONCLUSIONS: Elderly patients with MI and CS have lower procedural success and higher in-hospital mortality compared to younger patients. However, comparable long-term survival can be achieved, especially in patients who survive to hospital discharge with the selective use of early revascularization. PMID- 26048390 TI - Relationships between positive psychological constructs and health outcomes in patients with cardiovascular disease: A systematic review. AB - Depression and anxiety are well-known to be associated with adverse health outcomes in cardiac patients. However, there has been less work synthesizing the effects of positive psychological constructs (e.g., optimism) on health-related outcomes in cardiac patients. We completed a systematic review of prospective observational studies using established guidelines. A search of PubMed and PsycINFO databases from inception to January 2014 was used to identify articles. To be eligible, studies were required to assess effects of a positive psychological construct on subsequent health-related outcomes (including mortality, rehospitalizations, self-reported health status) in patients with established heart disease. Exploratory random effects' meta-analyses were performed on the subset of studies examining mortality or rehospitalizations. Seventy-seven analyses from 30 eligible studies (N=14,624) were identified. Among studies with 100 or more participants, 65.0% of all analyses and 64.7% of analyses adjusting for one or more covariates reported a significant (p<.05) association between positive psychological constructs and subsequent health outcomes. An exploratory meta-analysis of 11 studies showed that positive constructs were associated with reduced rates of rehospitalization or mortality in unadjusted (odds ratio=.87; 95% confidence interval [.83, .92]; p<.001) and adjusted analyses (odds ratio=.89; 95% confidence interval [.84, .91]; p<.001); there was little suggestion of publication bias. Among cardiac patients, positive psychological constructs appear to be prospectively associated with health outcomes in most but not all studies. Additional work is needed to identify which constructs are most important to cardiac health, and whether interventions can cultivate positive attributes and improve clinical outcomes. PMID- 26048391 TI - The anti-allergic activity of Cymbopogon citratus is mediated via inhibition of nuclear factor kappa B (Nf-Kappab) activation. AB - BACKGROUND: The prevalence of allergic diseases such as asthma has significantly increased worldwide, making it a public health concern. There is an urgent need for new anti-inflammatory agents with selective pharmacology and lower toxicity. Plant extracts have been used for centuries in traditional medicine to alleviate inflammatory diseases. In this work, we evaluated the anti-allergic activity of Cymbopogon citratus (Cy), a medicinal herb used by folk medicine to treat asthma. METHODS: We used a murine model of respiratory allergy to the mite Blomia tropicalis (Bt) and evaluated certain parameters known to be altered in this model. A/J mice were sensitized (100 MUg/animal s.c.) and challenged (10 MUg/animal i.n.) with Bt mite extract and treated with 60, 120 or 180 mg/kg of Cy standardized hexane extract. The parameters evaluated included: cellular infiltrate in bronchoalveolar lavage (BAL); eosinophil peroxidase activity (EPO); histopathological examination of the lung; serum levels of specific IgE, IgG1 and IgG2a; Th2 cytokine concentrations in BAL and expression of NF-kappaB. RESULTS: Our results showed that oral administration of a Cy hexane extract (especially 180 mg/Kg) reduced the numbers of leukocytes/eosinophils in BAL; the eosinophil peroxidase activity in BAL; the infiltration of leukocytes in lung tissue; the production of mucus in the respiratory tract; the level of IL-4 in BAL and the nuclear expression of NF-kappaB. CONCLUSIONS: The results presented demonstrate the potential of the Cy hexane extract to modulate allergic asthma; this extract may be an alternative future approach to treat this pathology. PMID- 26048393 TI - Physical activity in people with asbestos related pleural disease and dust related interstitial lung disease: An observational study. AB - This study aimed to measure the levels of physical activity (PA) in people with dust-related pleural and interstitial lung diseases and to compare these levels of PA to a healthy population. There is limited data on PA in this patient population and no previous studies have compared PA in people with dust-related respiratory diseases to a healthy control group. Participants with a diagnosis of a dust-related respiratory disease including asbestosis and asbestos related pleural disease (ARPD) and a healthy age- and gender-matched population wore the SenseWear((r)) Pro3 armband for 9 days. Six-minute walk distance, Medical Outcomes Study 36-item short-form health survey and the Hospital Anxiety and Depression Scale were also measured. Fifty participants were recruited and 46 completed the study; 22 with ARPD, 10 with dust-related interstitial lung disease (ILD) and 14 healthy age-matched participants. The mean (standard deviation) steps/day were 6097 (1939) steps/day for dust-related ILD, 9150 (3392) steps/day for ARPD and 10,630 (3465) steps/day for healthy participants. Compared with the healthy participants, dust-related ILD participants were significantly less active as measured by steps/day ((mean difference 4533 steps/day (95% confidence interval (CI): 1888-7178)) and energy expenditure, ((mean difference 512 calories (95% CI: 196-827)) and spent significantly less time engaging in moderate, vigorous or very vigorous activities (i.e. >3 metabolic equivalents; mean difference 1.2 hours/day (95% CI: 0.4-2.0)). There were no differences in levels of PA between healthy participants and those with ARPD. PA was reduced in people with dust-related ILD but not those with ARPD when compared with healthy age and gender-matched individuals. PMID- 26048392 TI - Identification and characterization of long non-coding RNAs involved in osmotic and salt stress in Medicago truncatula using genome-wide high-throughput sequencing. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have been shown to play crucially regulatory roles in diverse biological processes involving complex mechanisms. However, information regarding the number, sequences, characteristics and potential functions of lncRNAs in plants is so far overly limited. RESULTS: Using high-throughput sequencing and bioinformatics analysis, we identified a total of 23,324 putative lncRNAs from control, osmotic stress- and salt stress-treated leaf and root samples of Medicago truncatula, a model legume species. Out of these lncRNAs, 7,863 and 5,561 lncRNAs were identified from osmotic stress treated leaf and root samples, respectively. While, 7,361 and 7,874 lncRNAs were identified from salt stress-treated leaf and root samples, respectively. To reveal their potential functions, we analyzed Gene Ontology (GO) terms of genes that overlap with or are neighbors of the stress-responsive lncRNAs. Enrichments in GO terms in biological processes such as signal transduction, energy synthesis, molecule metabolism, detoxification, transcription and translation were found. CONCLUSIONS: LncRNAs are likely involved in regulating plant's responses and adaptation to osmotic and salt stresses in complex regulatory networks with protein-coding genes. These findings are of importance for our understanding of the potential roles of lncRNAs in responses of plants in general and M. truncatula in particular to abiotic stresses. PMID- 26048394 TI - Enhanced sludge properties and distribution study of sludge components in electrically-enhanced membrane bioreactor. AB - This study investigated the impact of electric field on the physicochemical and biological characteristics of sludge wasted from an electrically-enhanced membrane bioreactor treating medium-strength raw wastewater. This method offers a chemical-free electrokinetic technique to enhance sludge properties and remove heavy metals. For example, sludge volume index (SVI), time-to-filter (TTF), mean sludge particle diameter (PSD), viscosity, and oxidation-reduction potential (ORP) of 21.7 mL/g, 7 min, 40.2 MUm, 3.22 mPa s, and -4.9 mV were reported, respectively. Also, X-ray fluorescence (XRF) and X-ray diffraction (XRD) analyses provided mechanisms for heavy metal removal so as to establish relevant pathways for nutrient recovery. Furthermore, variations in dissolved oxygen (DO), conductivity, viscosity, ORP, total suspended solids (MLSS), and volatile suspended solids (MLVSS) were interrelated to evaluate the quality of wasted sludge. A pathway study on the transport and chemical distribution of nutrients and metals in sludge showed great potential for metal removal and nutrient recovery. PMID- 26048395 TI - Biochar application to a contaminated soil reduces the availability and plant uptake of zinc, lead and cadmium. AB - Heavy metals in soil are naturally occurring but may be enhanced by anthropogenic activities such as mining. Bio-accumulation of heavy metals in the food chain, following their uptake to plants can increase the ecotoxicological risks associated with remediation of contaminated soils using plants. In the current experiment sugar cane straw-derived biochar (BC), produced at 700 degrees C, was applied to a heavy metal contaminated mine soil at 1.5%, 3.0% and 5.0% (w/w). Jack bean (Canavalia ensiformis) and Mucuna aterrima were grown in pots containing soil and biochar mixtures, and control pots without biochar. Pore water was sampled from each pot to confirm the effects of biochar on metal solubility, whilst soils were analyzed by DTPA extraction to confirm available metal concentrations. Leaves were sampled for SEM analysis to detect possible morphological and anatomical changes. The application of BC decreased the available concentrations of Cd, Pb and Zn in 56, 50 and 54% respectively, in the mine contaminated soil leading to a consistent reduction in the concentration of Zn in the pore water (1st collect: 99 to 39 MUg L(-1), 2nd: 97 to 57 MUg L(-1) and 3rd: 71 to 12 MUg L(-1)). The application of BC reduced the uptake of Cd, Pb and Zn by plants with the jack bean translocating high proportions of metals (especially Cd) to shoots. Metals were also taken up by Mucuna aterrima but translocation to shoot was more limited than for jack bean. There were no differences in the internal structures of leaves observed by scanning electron microscopy. This study indicates that biochar application during mine soil remediation reduce plant concentrations of potential toxic metals. PMID- 26048397 TI - Wide variation in price paid for basic supplies means NHS wastes millions. PMID- 26048396 TI - Effectiveness and relevant factors of 2% rebamipide ophthalmic suspension treatment in dry eye. AB - BACKGROUND: Rebamipide with mucin secretagogue activity was recently approved for the treatment of dry eye. The efficacy and safety in the treatment of rebamipide were shown in two pivotal clinical trials. It was the aim of this study to evaluate the effect of 2% rebamipide ophthalmic suspension in patients with dry eye and analyze relevant factors for favorable effects of rebamipide in clinical practice. METHODS: This was a retrospective cohort study of 48 eyes from 24 patients with dry eye treated with 2% rebamipide ophthalmic suspension. Dry eye related symptom score, tear film break-up time (TBUT), fluorescein ocular surface staining score (FOS) and the Schirmer test were used to collect the data from patients at baseline, and at 2, 4, 8, and 12 week visits. To determine the relevant factors, multiple regression analyses were then performed. RESULTS: Mean dry eye-related symptom score showed a significant improvement from the baseline (14.5 points) at 2, 4, 8 and 12 weeks (9.80, 7.04, 7.04 and 7.83 points, corrected P value < 0.001, respectively). Median FOS showed a significant improvement from the baseline (3.0 points) at 2, 4, 8 and 12 weeks (2.0, 2.0, 1.0 and 1.0 points, corrected P value < 0.001, respectively). TBUT and Schirmer test values were not significantly improved after the treatment. For ocular symptoms, three parameters (foreign body sensation, dry eye sensation and ocular discomfort) showed significant improvements at all visits. The multiple regression analyses showed that the fluorescein conjunctiva staining score was significantly correlated with the changes of dry eye-related symptom score at 12 weeks (P value = 0.017) and dry eye-related symptom score was significantly correlated with independent variables for the changes of FOS at 12 weeks (P value = 0.0097). CONCLUSIONS: Two percent rebamipide ophthalmic suspension was an effective therapy for dry eye patients. Moreover the fluorescein conjunctiva staining score and dry eye-related symptom score might be good relevant factors for favorable effects of rebamipide. PMID- 26048398 TI - Adverse reaction to benzathine benzylpenicillin due to soy allergy: a case report. AB - INTRODUCTION: Soybean allergy is one of the most common food allergies especially among children. The Food Allergen Labeling and Consumer Protection Act (FALCPA) in the US requires the labeling of soy lecithin because it is derived from soybeans and may contain a number of IgE-binding proteins, possibly representing a source of hidden allergens. Here we describe a pediatric case of soy allergy misunderstood as drug allergy. CASE PRESENTATION: An 11-year-old Caucasian girl was referred to our Allergy Unit because of the delayed appearance of an itching papular rash at the site of an injection of benzathine benzylpenicillin delivered by prefilled syringe. A skin test with benzathine benzylpenicillin and detection of serum-specific IgE to penicilloyl V, penicilloyl G, ampicillin and amoxicillin were negative. From her past medical history we know that, at the age of three years, she presented with edema of the lips and difficulty in breathing after eating a soy ice-cream. For that reason, she underwent a skin prick test with soybean that was negative and a serum-specific IgE to soybean test that was weakly positive (0.21KU/L). She underwent an oral provocation test with soy milk that yielded a positive result. CONCLUSIONS: We describe a case of a patient with a delayed reaction to soy as a hidden allergen in a benzathine benzylpenicillin prefilled syringe. This case shows that lecithin contaminated by soy proteins and used as an excipient in drugs can cause reactions in patients with soy allergy. For that reason, the source of lecithin should always be specified among the constituents of drugs to avoid a source of hidden allergens and difficulties in the allergy work-up. PMID- 26048399 TI - Denser plasma clot formation and impaired fibrinolysis in paroxysmal and persistent atrial fibrillation while on sinus rhythm: association with thrombin generation, endothelial injury and platelet activation. AB - INTRODUCTION: Formation of compact and poorly lysable fibrin clots have been demonstrated in patients following ischemic stroke. Recently, it has been shown that denser fibrin networks and impaired fibrinolysis occurs in subjects with permanent atrial fibrillation (AF). Fibrin clot phenotype in other types of AF remains to be established. We evaluated fibrin clot properties in paroxysmal (PAF) and persistent AF (PsAF). MATERIAL AND METHODS: We studied 88 non anticoagulated patients with AF on sinus rhythm and free of stroke (41 with PAF, 47 with PsAF) versus 50 controls. Ex-vivo plasma fibrin clot permeability (Ks) and clot lysis time (CLT) were evaluated along with von Willebrand factor (vWF), peak thrombin generation (TG), platelet factor 4 (PF4) and fibrinolytic proteins. RESULTS: Compared with control subjects, clots obtained from plasma of patients with PAF and PsAF had similarly lower Ks (-7.7%, P=0.01; -8.6%, P=0.005, respectively) and prolonged CLT (+10.8%, P=0.006; +7.8% P=0.04, respectively). No associations of Ks and CLT with CHA2DS2-VASc and HAS-BLED score were observed. Patients with AF had higher TG, vWF, PF4 and plasminogen activator inhibitor-1 (PAI-1) antigen compared with controls. Multiple linear regression adjusted for age, gender, body mass index and fibrinogen showed that TG (beta=-0.41), vWF (beta=-0.29) and PF4 (beta=-0.28) are the independent predictors of Ks (R(2)=0.78), while CLT was independently predicted by TG (beta=0.37), PAI-1 antigen (beta=0.29) and vWF (beta=0.26) in the AF group (R(2)=0.39). CONCLUSIONS: Patients with PAF and PsAF while on sinus rhythm display unfavorably altered fibrin clot properties, which might contribute to thromboembolic complications. PMID- 26048400 TI - The temporal pattern of postoperative coagulation status in patients undergoing major liver surgery. AB - INTRODUCTION: After major liver surgery, there are risks of both postoperative bleeding and thrombosis. Routine coagulation monitoring is indicated, but may not provide adequate clinical guidance. Thus, we described the clotting status in a pilot study using broader coagulation testing. We analysed the temporal pattern of coagulation tests to assess whether thromboelastometry (ROTEM(r)) would improve the quality of the postoperative monitoring of the coagulation status in patients undergoing major hepatic resections. MATERIAL AND METHODS: Sixteen patients undergoing major liver resections were examined prior to surgery, on postoperative day 1, and subsequently, every three postoperative days during hospitalization. At the same time, the clinical signs of bleeding and thrombotic complications were monitored. RESULTS: On postoperative day 1, increases in bilirubin, PT-INR, APTT, and D-dimers were observed, together with concomitant decreases in fibrinogen, platelet count, antithrombin (AT), protein C and protein S compared to preoperative values. On postoperative days 4 and 7, all of the variables had returned to the normal range except for D-dimers, AT and protein C. The ROTEM(r) median values remained within the normal range. There were no significant episodes of postoperative bleeding. Two patients were diagnosed with a pulmonary embolism. CONCLUSION: Despite the abnormalities observed in routine coagulation monitoring, thromboelastometry indicated a balanced coagulation status following major hepatic surgery. The levels of both pro- and anticoagulant proteins changed over time during this period. The exact clinical role for thromboelastometry in major hepatic surgery remains to be established. PMID- 26048401 TI - A primer on precision medicine informatics. AB - In this review, we describe key components of a computational infrastructure for a precision medicine program that is based on clinical-grade genomic sequencing. Specific aspects covered in this review include software components and hardware infrastructure, reporting, integration into Electronic Health Records for routine clinical use and regulatory aspects. We emphasize informatics components related to reproducibility and reliability in genomic testing, regulatory compliance, traceability and documentation of processes, integration into clinical workflows, privacy requirements, prioritization and interpretation of results to report based on clinical needs, rapidly evolving knowledge base of genomic alterations and clinical treatments and return of results in a timely and predictable fashion. We also seek to differentiate between the use of precision medicine in germline and cancer. PMID- 26048402 TI - CD8(+) T cell response to adenovirus vaccination and subsequent suppression of tumor growth: modeling, simulation and analysis. AB - BACKGROUND: Using immune checkpoint modulators in the clinic to increase the number and activity of cytotoxic T lymphocytes that recognize tumor antigens can prolong survival for metastatic melanoma. Yet, only a fraction of the patient population receives clinical benefit. In short, these clinical trials demonstrate proof-of-principle but optimizing the specific therapeutic strategies remains a challenge. In many fields, CAD (computer-aided design) is a tool used to optimize integrated system behavior using a mechanistic model that is based upon knowledge of constitutive elements. The objective of this study was to develop a predictive simulation platform for optimizing anti-tumor immunity using different treatment strategies. METHODS: To better understand the therapeutic role that cytotoxic CD8(+) T cells can play in controlling tumor growth, we developed a multi-scale mechanistic model of the biology using impulsive differential equations and calibrated it to a self-consistent data set. RESULTS: The multi-scale model captures the activation and differentiation of naive CD8(+) T cells into effector cytotoxic T cells in the lymph node following adenovirus-mediated vaccination against a tumor antigen, the trafficking of the resulting cytotoxic T cells into blood and tumor microenvironment, the production of cytokines within the tumor microenvironment, and the interactions between tumor cells, T cells and cytokines that control tumor growth. The calibrated model captures the modest suppression of tumor cell growth observed in the B16F10 model, a transplantable mouse model for metastatic melanoma, and was used to explore the impact of multiple vaccinations on controlling tumor growth. CONCLUSIONS: Using the calibrated mechanistic model, we found that the cytotoxic CD8(+) T cell response was prolonged by multiple adenovirus vaccinations. However, the strength of the immune response cannot be improved enough by multiple adenovirus vaccinations to reduce tumor burden if the cytotoxic activity or local proliferation of cytotoxic T cells in response to tumor antigens is not greatly enhanced. Overall, this study illustrates how mechanistic models can be used for in silico screening of the optimal therapeutic dosage and timing in cancer treatment. PMID- 26048403 TI - Copy number alterations and allelic ratio in relation to recurrence of rectal cancer. AB - BACKGROUND: In rectal cancer, total mesorectal excision surgery combined with preoperative (chemo)radiotherapy reduces local recurrence rates but does not improve overall patient survival, a result that may be due to the harmful side effects and/or co-morbidity of preoperative treatment. New biomarkers are needed to facilitate identification of rectal cancer patients at high risk for local recurrent disease. This would allow for preoperative (chemo)radiotherapy to be restricted to high-risk patients, thereby reducing overtreatment and allowing personalized treatment protocols. We analyzed genome-wide DNA copy number (CN) and allelic alterations in 112 tumors from preoperatively untreated rectal cancer patients. Sixty-six patients with local and/or distant recurrent disease were compared to matched controls without recurrence. Results were validated in a second cohort of tumors from 95 matched rectal cancer patients. Additionally, we performed a meta-analysis that included 42 studies reporting on CN alterations in colorectal cancer and compared results to our own data. RESULTS: The genomic profiles in our study were comparable to other rectal cancer studies. Results of the meta-analysis supported the hypothesis that colon cancer and rectal cancer may be distinct disease entities. In our discovery patient study cohort, allelic retention of chromosome 7 was significantly associated with local recurrent disease. Data from the validation cohort were supportive, albeit not statistically significant, of this finding. CONCLUSIONS: We showed that retention of heterozygosity on chromosome 7 may be associated with local recurrence in rectal cancer. Further research is warranted to elucidate the mechanisms and effect of retention of chromosome 7 on the development of local recurrent disease in rectal cancer. PMID- 26048405 TI - Designing optimal food intake patterns to achieve nutritional goals for Japanese adults through the use of linear programming optimization models. AB - BACKGROUND: Simultaneous dietary achievement of a full set of nutritional recommendations is difficult. Diet optimization model using linear programming is a useful mathematical means of translating nutrient-based recommendations into realistic nutritionally-optimal food combinations incorporating local and culture specific foods. We used this approach to explore optimal food intake patterns that meet the nutrient recommendations of the Dietary Reference Intakes (DRIs) while incorporating typical Japanese food selections. METHODS: As observed intake values, we used the food and nutrient intake data of 92 women aged 31-69 years and 82 men aged 32-69 years living in three regions of Japan. Dietary data were collected with semi-weighed dietary record on four non-consecutive days in each season of the year (16 days total). The linear programming models were constructed to minimize the differences between observed and optimized food intake patterns while also meeting the DRIs for a set of 28 nutrients, setting energy equal to estimated requirements, and not exceeding typical quantities of each food consumed by each age (30-49 or 50-69 years) and gender group. RESULTS: We successfully developed mathematically optimized food intake patterns that met the DRIs for all 28 nutrients studied in each sex and age group. Achieving nutritional goals required minor modifications of existing diets in older groups, particularly women, while major modifications were required to increase intake of fruit and vegetables in younger groups of both sexes. Across all sex and age groups, optimized food intake patterns demanded greatly increased intake of whole grains and reduced-fat dairy products in place of intake of refined grains and full-fat dairy products. Salt intake goals were the most difficult to achieve, requiring marked reduction of salt-containing seasoning (65-80%) in all sex and age groups. CONCLUSION: Using a linear programming model, we identified optimal food intake patterns providing practical food choices and meeting nutritional recommendations for Japanese populations. Dietary modifications from current eating habits required to fulfil nutritional goals differed by age: more marked increases in food volume were required in younger groups. PMID- 26048406 TI - Decreased miR-154 expression and its clinical significance in human colorectal cancer. AB - BACKGROUND: miRNA-154 (miR-154) has been identified as a tumor suppressor in several types of human cancers. However, its clinical significance in colorectal cancer (CRC) is still unclear. The aim of this study was to analyze the association of miR-154 expression with clinicopathologic features and prognosis in CRC patients. METHODS: Quantitative RT-PCR was performed to evaluate miR-154 levels in 169 pairs of CRC specimens and adjacent noncancerous tissues. Then, the associations of miR-154 expression with clinicopathological factors or survival of patients suffering CRC were determined. RESULTS: The expression levels of miR 154 in CRC tissues were significantly lower than those in corresponding noncancerous tissues (P < 0.001). Decreased miR-154 expression was significantly associated with large tumor size, positive lymph node metastasis, and advanced clinical stage. Moreover, the univariate analysis demonstrated that CRC patients with low miR-154 expression had poorer overall survival (P = 0.006). The multivariate analysis identified low miR-154 expression as an independent predictor of poor survival. CONCLUSIONS: These findings suggested that miR-154 downregulation may be associated with tumor progression of CRC, and that this miR may be an independent prognostic marker for CRC patients. PMID- 26048404 TI - Characteristics of COPD in never-smokers and ever-smokers in the general population: results from the CanCOLD study. AB - BACKGROUND: There is limited data on the risk factors and phenotypical characteristics associated with spirometrically confirmed COPD in never-smokers in the general population. AIMS: To compare the characteristics associated with COPD by gender and by severity of airway obstruction in never-smokers and in ever smokers. METHOD: We analysed the data from 5176 adults aged 40 years and older who participated in the initial cross-sectional phase of the population-based, prospective, multisite Canadian Cohort of Obstructive Lung Disease study. Never smokers were defined as those with a lifetime exposure of <1/20 pack year. Logistic regressions were constructed to evaluate associations for 'mild' and 'moderate-severe' COPD defined by FEV1/FVC <5th centile (lower limits of normal). Analyses were performed using SAS V.9.1 (SAS Institute, Cary, North Carolina, USA). RESULTS: The prevalence of COPD (FEV1/FVCT polymorphism in the transforming growth factor-beta1 (TGFB1) gene correlates with increased risk of urinary bladder cancer. AB - TGF-beta1 is a pleiotropic cytokine, which plays a dual role in tumor development. In the early stages, it inhibits the growth of tumor while in the late stages of carcinoma, it promotes tumor growth. The purpose of this study was to analyze the distribution of the TGFB1 gene polymorphisms between cases and controls so as to assess their correlation with bladder cancer risk. This study included 237 cases of urinary bladder cancer and 290 age matched controls from the same ethnic background. Three polymorphisms in the TGFB1 gene, c.29C>T (rs 1800470), c.74G>C (rs-1800471) and +140A>G (rs-13447341), were analyzed by direct DNA sequencing. Statistical analyses revealed no significant differences in the demographical data, except that the frequencies of smokers and non-vegetarians were higher in the cases. Eighty percent of the bladder cancer patients had superficial transitional cell carcinoma, and 53.16% and 26.31% of the patients were in grade I and grade II, respectively. We found that c.29C>T substitution increased the risk of bladder cancer significantly and recessive model of analysis was the best fitted model (p=0.004; OR=1.72 95% CI 1.18-2.50). A significantly higher risk in the recessive form was also suggested by co-dominant analysis showing that the homozygous form (TT) was a significant risk factor in comparison to CC and CT genotypes. The other two polymorphisms, c.74G>C (p=0.18, OR=0.67 95% CI 0.37-1.21) and +140A>G (p=0.416, OR=0.77 95% CI 0.41-1.45) did not affect the risk of urinary bladder cancer. In conclusion, we found that the TGFB1 c.29C>T substitution increases the risk of bladder cancer significantly while c.74G>C and +140A>G polymorphisms do not affect the risk. PMID- 26048436 TI - Caring for continence in stroke care settings: a qualitative study of patients' and staff perspectives on the implementation of a new continence care intervention. AB - OBJECTIVES: Investigate the perspectives of patients and nursing staff on the implementation of an augmented continence care intervention after stroke. DESIGN: Qualitative data were elicited during semi-structured interviews with patients (n = 15) and staff (14 nurses; nine nursing assistants) and analysed using thematic analysis. SETTING: Mixed acute and rehabilitation stroke ward. PARTICIPANTS: Stroke patients and nursing staff that experienced an enhanced continence care intervention. RESULTS: Four themes emerged from patients' interviews describing: (a) challenges communicating about continence (initiating conversations and information exchange); (b) mixed perceptions of continence care; (c) ambiguity of focus between mobility and continence issues; and (d) inconsistent involvement in continence care decision making. Patients' perceptions reflected the severity of their urinary incontinence. Staff described changes in: (i) knowledge as a consequence of specialist training; (ii) continence interventions (including the development of nurse-led initiatives to reduce the incidence of unnecessary catheterisation among patients admitted to their ward); (iii) changes in attitude towards continence from containment approaches to continence rehabilitation; and (iv) the challenges of providing continence care within a stroke care context including limitations in access to continence care equipment or products, and institutional attitudes towards continence. CONCLUSION: Patients (particularly those with severe urinary incontinence) described challenges communicating about and involvement in continence care decisions. In contrast, nurses described improved continence knowledge, attitudes and confidence alongside a shift from containment to rehabilitative approaches. Contextual components including care from point of hospital admission, equipment accessibility and interdisciplinary approaches were perceived as important factors to enhancing continence care. PMID- 26048437 TI - Comparisons of the efficacy of glucose control, lipid profile, and beta-cell function between DPP-4 inhibitors and AGI treatment in type 2 diabetes patients: a meta-analysis. AB - The aim of this study is to compare the efficacy of dipeptidyl peptidase-4 (DPP 4) inhibitor treatment with alpha-glucosidase inhibitor (AGI) treatment in patients with type 2 diabetes through a meta-analysis. Studies were identified by a literature search of Medline, Embase, and others from the time that recording commenced until December 2014. The meta-analysis was performed by computing the weighted mean difference (WMD) and 95 % confidence interval (CI) for a change from baseline to the study endpoint for DPP-4 inhibitors versus AGIs. Nine randomized controlled trial were judged to be appropriate for inclusion in the meta-analysis. One thousand and forty-six patients were treated with a DPP-4 inhibitor, while 929 patients were treated with AGI treatment; the groups had a comparable baseline body mass index of 25.5 +/- 1.3 kg/m(2) and mean baseline HbA1c of 7.83 +/- 0.53 %. Treatment with DPP-4 inhibitors led to a significantly greater change from baseline in the HbA1c levels (WMD -0.30 %; 95 % CI -0.47 to 0.13 %, p < 0.001) and fasting plasma glucose levels (WMD -0.50 mmol/L; 95 % CI 0.89 to -0.11 mmol/L, p = 0.01) compared with AGI treatment. Compared with AGIs, treatment with DPP-4 inhibitors was associated with a significantly greater increase in the weight change from baseline (WMD 0.89 kg; 95 % CI 0.53-1.25, p < 0.001). Treatment with DPP-4 inhibitors was associated with a significantly greater increase in the fasting insulin level from baseline (WMD 0.63 uU/mL; 95 % CI 0.35-0.90 uU/mL, p < 0.001). DPP-4 inhibitors significantly improved homeostatic model assessment for beta-cell function in type 2 diabetes patients compared with AGI treatment (WMD 5.43; 95 % CI 1.01-9.85, p = 0.02). DPP-4 inhibitors were associated with a significantly greater decrease in the cholesterol (CHO) level (WMD -0.19 mmol/L; 95 % CI -0.19 to -0.19 mmol/L, p < 0.001) and a significantly greater decrease in the low-density lipoprotein cholesterol (LDL-C) level (WMD -0.16 mmol/L; 95 % CI -0.26 to -0.05 mmol/L, p = 0.003). Compared with AGIs (813 participants), treatment with DPP-4 inhibitors (1031 participants) was associated with a significantly lower incidence of drug related adverse event (OR 0.48; 95 % CI 0.36-0.64, p < 0.0001). The efficacy of glucose control and improvement of beta-cell function, as well as total CHO and LDL-C decreases, in DPP-4 inhibitor treatment were superior to those with AGI treatment, and there was a lower incidence of drug-related AE. PMID- 26048438 TI - Biochemical Adaptations in Zea mays Roots to Short-Term Pb(2+) Exposure: ROS Generation and Metabolism. AB - The present study investigated the effect of lead (0, 16, 40 and 80 mg L(-1) Pb2+) exposure for 3, 12 and 24 h on root biochemistry in hydroponically grown Zea mays (maize). Pb2+ exposure (80 mg L(-1)) enhanced malondialdehyde content (239%-427%), reactive carbonyl groups (425%-512%) and H2O2 (129%-294%) accumulation during 3-24 h of treatment, thereby indicating cellular peroxidation and oxidative damage. The quantitative estimations were in accordance with in situ detection of ROS generation (using 2',7'-dichlorodihydrofluorescein diacetate dye) and H2O2 accumulation. Pb2+ treatment significantly reduced ascorbate and glutathione content during 3-24 h of exposure. On the contrary, levels of non-protein thiols were enhanced by 3-11.8 time over control in response to 16-80 mg L(-1) Pb2+ treatment, after 24 h. A dose-dependent induction in ascorbate peroxidase and lipoxygenase enzyme activity was observed in Z. mays roots. The activities of ascorbate-recycling enzymes (dehydroascorbate reductase and monodehydroascorbate reductase) were significantly increased in relation to concentration and duration of Pb2+ treatment. The study concludes that Pb2+ exposure induces ROS-mediated oxidative damage during early period of exposure despite the upregulation of enzymes of ascorbate-glutathione cycle. PMID- 26048439 TI - Effect of Pre-emergence Herbicides on Microbial Biomass and Biochemical Processes in a Typic Fluvaquent Soil Amended with Farm Yard Manure. AB - Application of thiobencarb, pendimethalin and pretilachlor at rates of 7.5, 10.0 and 2.5 kg a.i. ha(-1), respectively, under laboratory conditions, significantly increased microbial biomass C, N and P, resulting in greater availability of C, N and P in soil amended with farm yard manure. Application of thiobencarb highly induced microbial biomass C (46.3 %) and N (40.6 %), while pretilachlor and thiobencarb augmented microbial biomass P to the extent of 14.9 % and 14.1 %, respectively. Application of pendimethalin retained the highest amount of total N (19.9 %), soluble NO3 (-) (56 %) and available P (69.5 %) in soil. A similar trend was recorded with thiobencarb for oxidizable organic C (18.1 %) and with pretilachlor for exchangeable NH4 (+) (65.8 %). At the end of the experiment, the highest stimulation of bacteria was recorded with thiobencarb (29.6 %), while pretilachlor harboured the maximum number of actinomycetes (37.2 %) and fungi (40 %) in soil compared to the untreated control. PMID- 26048440 TI - Dissemination of the chromosomally encoded CMY-2 cephalosporinase gene in Escherichia coli isolated from animals. AB - In this study, 619 individual Escherichia coli isolates from food-producing and companion animals were analysed to determine the prevalence of the cephalosporinase gene blaCMY-2. In total, 18 CMY-2-producers (2.9%) were detected and exhibited multidrug-resistant phenotypes. One of the CMY-2-producers was found to possess a novel blaCMY-2-like allele, blaCMY-130. The isolates belonged to distinct pulsotypes, suggesting that the blaCMY-2 gene was not disseminated by clonal expansion of blaCMY-2-positive strains. The blaCMY-2 genes were located on IncA/C-, IncHI2- or IncX-type plasmids in 9 (50%) of the 18 E. coli isolates. However, in the other nine isolates I-CeuI-PFGE and hybridisation analyses revealed that the blaCMY-2 gene was chromosomally located. A CMY gene-containing region composed of five open reading frames (ORFs) (ISEcp1-blaCMY-2-blc-sugE DeltaencR) was observed in plasmids from eight strains. A CMY gene-containing region composed of ten ORFs was observed in all of the nine chromosomally encoded blaCMY-2 genes, including a putative IS66-like element inserted in this conserved CMY genetic region in three strains. This conserved CMY genetic region was also found to be inserted into the oriVgamma (putative gamma origin), part of the IncX plasmid backbone, by a complete transposition unit flanked by 5-bp DRs (direct repeat sequence) in pS62T. These results demonstrate the high prevalence of the chromosomally encoded blaCMY-2 gene in E. coli. This is the first study reporting a chromosomally encoded blaCMY-2 gene in E. coli. Chromosomally encoded blaCMY-2 might be a source of some plasmid-mediated blaCMY-2 genes and this probably facilitates the spread of cephalosporin-resistant strains. PMID- 26048441 TI - Identifying Quality Indicators Used by Patients to Choose Secondary Health Care Providers: A Mixed Methods Approach. AB - BACKGROUND: Patients in health systems across the world can now choose between different health care providers. Patients are increasingly using websites and apps to compare the quality of health care services available in order to make a choice of provider. In keeping with many patient-facing platforms, most services currently providing comparative information on different providers do not take account of end-user requirements or the available evidence base. OBJECTIVE: To investigate what factors were considered most important when choosing nonemergency secondary health care providers in the United Kingdom with the purpose of translating these insights into a ratings platform delivered through a consumer mHealth app. METHODS: A mixed methods approach was used to identify key indicators incorporating a literature review to identify and categorize existing quality indicators, a questionnaire survey to formulate a ranked list of performance indicators, and focus groups to explore rationales behind the rankings. Findings from qualitative and quantitative methodologies were mapped onto each other under the four categories identified by the literature review. RESULTS: Quality indicators were divided into four categories. Hospital access was the least important category. The mean differences between the other three categories hospital statistics, hospital staff, and hospital facilities, were not statistically significant. Staff competence was the most important indicator in the hospital staff category; cleanliness and up-to-date facilities were equally important in hospital facilities; ease of travel to the hospital was found to be most important in hospital access. All quality indicators within the hospital statistics category were equally important. Focus groups elaborated that users find it difficult to judge staff competence despite its importance. CONCLUSIONS: A mixed methods approach is presented, which supported a patient-centered development and evaluation of a hospital ratings mobile app. Where possible, mHealth developers should use systematic research methods in order to more closely meet the needs of the end user and add credibility to their platform. PMID- 26048442 TI - Early life exposure to bisphenol A investigated in mouse models of airway allergy, food allergy and oral tolerance. AB - The impact of early life exposure to bisphenol A (BPA) through drinking water was investigated in mouse models of respiratory allergy, food allergy and oral tolerance. Balb/c mice were exposed to BPA (0, 10 or 100 MUg/ml), and the offspring were intranasally exposed to the allergen ovalbumin (OVA). C3H/HeJ offspring were sensitized with the food allergen lupin by intragastric gavage, after exposure to BPA (0, 1, 10 or 100 MUg/ml). In separate offspring, oral tolerance was induced by gavage of 5 mg lupin one week before entering the protocol for the food allergy induction. In the airway allergy model, BPA (100 MUg/ml) caused increased eosinophil numbers in bronchoalveolar lavage fluid (BALF) and a trend of increased OVA-specific IgE levels. In the food allergy and tolerance models, BPA did not alter the clinical anaphylaxis or antibody responses, but induced alterations in splenocyte cytokines and decreased mouse mast cell protease (MMCP)-1 serum levels. In conclusion, early life exposure to BPA through drinking water modestly augmented allergic responses in a mouse model of airway allergy only at high doses, and not in mouse models for food allergy and tolerance. Thus, our data do not support that BPA promotes allergy development at exposure levels relevant for humans. PMID- 26048443 TI - Association between kidney function, rehabilitation outcome, and survival in older patients discharged from inpatient rehabilitation. AB - BACKGROUND: Chronic kidney disease (CKD) is common in older people, but it is unclear if it affects survival and rehabilitation outcomes independent of comorbid conditions and physical function in this population. STUDY DESIGN: Cohort analysis of prospective, routinely collected, linked clinical data sets. SETTING & PARTICIPANTS: Patients discharged from a single inpatient geriatric rehabilitation center over a 12-year period. PREDICTORS: Admission estimated glomerular filtration rate (eGFR) category as a predictor of improvement in the 20-point Barthel score (activities of daily living measure) during rehabilitation; discharge eGFR category and Barthel score as predictors of survival postdischarge. OUTCOMES: Survival postdischarge was modeled using Cox regression analyses, unadjusted and adjusted for age, sex, morbidities (ischemic heart disease, chronic obstructive pulmonary disease, stroke, diabetes, and heart failure), Barthel score and eGFR category on discharge, and serum calcium, hemoglobin, and albumin levels. The effect of admission eGFR category on change in Barthel score during admission was modeled using analysis of covariance, adjusted for admission, Barthel score, and comorbid conditions. RESULTS: 3,012 patients were included; mean age, 84 years. 2,394 patients died during a mean follow-up of 8.3 years. Compared with patients with eGFR of 60 to 89mL/min/1.73m(2), adjusted HRs for death were 1.26 (95% CI, 1.13-1.40), 1.45 (95% CI, 1.29-1.63), and 1.68 (95% CI, 1.42-1.99) for eGFR categories of 45 to 59, 30 to 44, and <30mL/min/1.73m(2), respectively. The relationship between discharge Barthel score and survival was similar within each discharge eGFR category (HRs of 0.95, 0.93, 0.92, 0.95, and 0.90 per Barthel score point within eGFR categories of >=90, 60-89, 45-59, 30-44, and <30mL/min/1.73m(2); P for interaction = 0.2). Similar improvements in Barthel score between admission and discharge were seen for each admission eGFR category. LIMITATIONS: Single-center study using routinely collected clinical data. CONCLUSIONS: eGFR category and Barthel score are independent risk markers for survival in older rehabilitation patients, but advanced CKD does not preclude successful rehabilitation. PMID- 26048444 TI - Influence of a survivin suppressor YM155 on the chemoresistance of canine histiocytic sarcoma cells. AB - Histiocytic sarcoma (HS) in dogs exhibits aggressive biological behaviors and currently few effective treatments are available. Survivin could serve as a potential therapeutic target in several cancers. Sepantronium bromide (YM155) is a potential novel survivin-targeting agent and in this study the influence of survivin expression on clinical outcomes and the effects of YM155 on biological activities in HS cells were investigated. Specimens of HS dogs (n = 30) and four canine HS cell lines were used. The correlation between survivin expression and clinical outcome in the HS dogs was retrospectively assessed using quantitative PCR. Following YM155 treatment of cell lines, apoptosis, cell viability, and drug transporter activities were evaluated using annexin V staining, methylthiazole tetrazolium assays, and Hoechst-33342 staining, respectively. Elevated survivin expression in the HS dogs corresponded with reduced disease-free intervals and survival time, and increased chemoresistance, which led to poor clinical outcomes. Furthermore, YM155 treatment suppressed cell-growth and resistance to lomustine in HS cells by inhibiting the activity of ATP-binding cassette transporters. The evidence presented here supports favorable preclinical evaluation and indicates that survivin-targeted therapies might be effective against HS dogs. PMID- 26048445 TI - Acute phase proteins for diagnosis of diseases in dairy cattle. PMID- 26048446 TI - Resveratrol ameliorates depressive-like behavior in repeated corticosterone induced depression in mice. AB - A mouse model of depression has been recently developed by exogenous corticosterone (CORT) administration, which has shown to mimic HPA-axis induced depression-like state in animals. The present study aimed to examine the antidepressant-like effect and the possible mechanisms of resveratrol, a naturally occurring polyphenol of phytoalexin family, on depressive-like behavior induced by repeated corticosterone injections in mice. Mice were injected subcutaneously (s.c.) with 40mg/kg corticosterone (CORT) chronically for 21days. Resveratrol and fluoxetine were administered 30min prior to the CORT injection. After 21-days treatment with respective drugs, behavioral and biochemical parameters were estimated. Since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant activity of many drugs, we also evaluated the effect of resveratrol on BDNF in the hippocampus. Three weeks of CORT injections in mice resulted in depressive-like behavior, as indicated by the significant decrease in sucrose consumption and increase in immobility time in the forced swim test and tail suspension test. Further, there was a significant increase in serum corticosterone level and a significant decrease in hippocampus BDNF level in CORT-treated mice. Treatment of mice with resveratrol significantly ameliorated all the behavioral and biochemical changes induced by corticosterone. These results suggest that resveratrol produces an antidepressant-like effect in CORT-induced depression in mice, which is possibly mediated by rectifying the stress-based hypothalamic-pituitary-adrenal (HPA) axis dysfunction paradigm and upregulation of hippocampal BDNF levels. PMID- 26048447 TI - C21 steroidal glycosides from the roots of Cynanchum saccatum. AB - Eight new C21 steroidal glycosides, named cynsaccatols A-H (1-8), along with two known analogs (9-10), were isolated from the roots of Cynanchum saccatum. Their structures were determined on the basis of detailed spectroscopic analysis, as well as HRESIMS. All compounds (1-10) were tested for their cytotoxicity in vitro using three human cancer cell lines (HepG2, Hela and U251), and compounds 1, 4, 5, 9, 10 showed weak inhibitory activities against different cell lines, respectively. PMID- 26048448 TI - Application of palladium-catalyzed carboxyl anhydride-boronic acid cross coupling in the synthesis of novel bile acids analogs with modified side chains. AB - Palladium-catalyzed cross coupling of 4-methoxycarbonyl phenyboronic acid with acetylated bile acids in which the carboxyl functions was activated by formation of a mixed anhydride with pivalic anhydride afforded the cross coupled compounds, which were converted in novel side chain modified bile acids by one pot carbonyl reduction/removal of the protecting acetyl groups by Wolff-Kishner reduction. Unambiguous assignments of the NMR signals and crystal characterization of the heretofore unknown compounds are provided. PMID- 26048449 TI - NIH Clinical Center closes its pharmacy after contamination found. PMID- 26048450 TI - Obsessive-compulsive symptom severity in schizophrenia: a Janus Bifrons effect on functioning. AB - The impact of obsessive-compulsive symptoms on functioning in schizophrenia is still debated. This study investigated the relationship between OC symptoms and functioning along a severity gradient of obsessive-compulsive dimension. Sixty patients affected by schizophrenia completed the SCID-IV, the Positive and Negative Syndrome Scale, the Yale-Brown Obsessive-Compulsive Scale and the Social and Occupational Functioning Assessment Scale. The relationship between functioning and obsessive-compulsive dimension was described by a reverse U shaped curve; functioning was positively related to the presence of mild obsessive-compulsive symptoms and inversely related to moderate and severe symptoms, after controlling for the severity of positive, negative, disorganization and general psychopathological symptoms. The role of obsessive compulsive symptoms on social functioning in schizophrenia occurs along a severity continuum with a gradual transition from a positive correlation (from absent to mild symptoms) to an inverse correlation (for symptoms ranging from moderate to severe) and independently from schizophrenia symptom dimensions. PMID- 26048451 TI - CACNA1C risk variant is associated with increased amygdala volume. AB - Genome-wide association studies suggest that genetic variation within L-type calcium channel subunits confer risk to psychosis. The single nucleotide polymorphism at rs1006737 in CACNA1C has been associated with both schizophrenia and bipolar disorder and with several intermediate phenotypes that may serve as neurobiological antecedents, linking psychosis to genetic aetiology. Amongst others, it has been implicated in alterations in amygdala structure and function. In the present study, we show that the risk allele (A) is associated with increased amygdala volume in healthy individuals (n = 258). This observation reinforces a hypothesis that genetic variation may confer risk to psychosis via alterations in limbic structures. Further study of CACNA1C using intermediate phenotypes for psychosis will determine the mechanisms by which variation in this gene confers risk. PMID- 26048452 TI - Recognition of activities of daily living in healthy subjects using two ad-hoc classifiers. AB - BACKGROUND: Activities of daily living (ADL) are important for quality of life. They are indicators of cognitive health status and their assessment is a measure of independence in everyday living. ADL are difficult to reliably assess using questionnaires due to self-reporting biases. Various sensor-based (wearable, in home, intrusive) systems have been proposed to successfully recognize and quantify ADL without relying on self-reporting. New classifiers required to classify sensor data are on the rise. We propose two ad-hoc classifiers that are based only on non-intrusive sensor data. METHODS: A wireless sensor system with ten sensor boxes was installed in the home of ten healthy subjects to collect ambient data over a duration of 20 consecutive days. A handheld protocol device and a paper logbook were also provided to the subjects. Eight ADL were selected for recognition. We developed two ad-hoc ADL classifiers, namely the rule based forward chaining inference engine (RBI) classifier and the circadian activity rhythm (CAR) classifier. The RBI classifier finds facts in data and matches them against the rules. The CAR classifier works within a framework to automatically rate routine activities to detect regular repeating patterns of behavior. For comparison, two state-of-the-art [Naives Bayes (NB), Random Forest (RF)] classifiers have also been used. All classifiers were validated with the collected data sets for classification and recognition of the eight specific ADL. RESULTS: Out of a total of 1,373 ADL, the RBI classifier correctly determined 1,264, while missing 109 and the CAR determined 1,305 while missing 68 ADL. The RBI and CAR classifier recognized activities with an average sensitivity of 91.27 and 94.36%, respectively, outperforming both RF and NB. CONCLUSIONS: The performance of the classifiers varied significantly and shows that the classifier plays an important role in ADL recognition. Both RBI and CAR classifier performed better than existing state-of-the-art (NB, RF) on all ADL. Of the two ad-hoc classifiers, the CAR classifier was more accurate and is likely to be better suited than the RBI for distinguishing and recognizing complex ADL. PMID- 26048453 TI - Lipid-free Apolipoprotein A-I Structure: Insights into HDL Formation and Atherosclerosis Development. AB - Apolipoprotein A-I is the major protein in high-density lipoprotein (HDL) and plays an important role during the process of reverse cholesterol transport (RCT). Knowledge of the high-resolution structure of full-length apoA-I is vital for a molecular understanding of the function of HDL at the various steps of the RCT pathway. Due to the flexible nature of apoA-I and aggregation properties, the structure of full-length lipid-free apoA-I has evaded description for over three decades. Sequence analysis of apoA-I suggested that the amphipathic alpha-helix is the structural motif of exchangeable apolipoprotein, and NMR, X-ray and MD simulation studies have confirmed this. Different laboratories have used different methods to probe the secondary structure distribution and organization of both the lipid-free and lipid-bound apoA-I structure. Mutation analysis, synthetic peptide models, surface chemistry and crystal structures have converged on the lipid-free apoA-I domain structure and function: the N-terminal domain [1 184] forms a helix bundle while the C-terminal domain [185-243] mostly lacks defined structure and is responsible for initiating lipid-binding, aggregation and is also involved in cholesterol efflux. The first 43 residues of apoA-I are essential to stabilize the lipid-free structure. In addition, the crystal structure of C-terminally truncated apoA-I suggests a monomer-dimer conversation mechanism mediated through helix 5 reorganization and dimerization during the formation of HDL. Based on previous research, we have proposed a structural model for full-length monomeric apoA-I in solution and updated the HDL formation mechanism through three states. Mapping the known natural mutations on the full length monomeric apoA-I model provides insight into atherosclerosis development through disruption of the N-terminal helix bundle or deletion of the C-terminal lipid-binding domain. PMID- 26048455 TI - A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate resistant prostate cancer. AB - BACKGROUND: Bicalutamide blocks androgen action and is frequently used in men with non-metastatic, castration-resistant prostate cancer (CRPC). By reducing intracellular dihydrotestosterone, dutasteride (dual 5-alpha reductase inhibitor) could increase the effectiveness of bicalutamide in this setting. The objective of the study is therefore to prospectively evaluate dutasteride plus bicalutamide in men with asymptomatic, non-metastatic CRPC with rising prostate-specific antigen (PSA). METHODS: Prostate cancer patients with rising PSA whilst on first line androgen deprivation therapy (ADT) were randomised (1:1) in a double-blind trial to receive bicalutamide 50mg plus placebo or bicalutamide 50mg plus dutasteride 3.5mg once daily for 18 months. Randomisation was stratified by centre; treatment assignments were generated using GlaxoSmithKline's RandAll System. Subjects who completed 18 months could participate in the 2-year extension. Central laboratory and study sites/monitors remained treatment blinded. Primary end-point was time to disease progression (TDP) up to 42 months (defined as PSA progression from baseline or nadir, radiographic disease progression, death from prostate cancer or receipt of rescue medication). FINDINGS: There was no statistically significant difference in TDP in 127 men treated with bicalutamide/dutasteride (n=62) compared with bicalutamide/placebo (n=65) (hazard ratio (HR)=0.94 [95% confidence interval (CI) 0.61, 1.46]; p=0.79). The estimated median TDP was 425 days (95% CI 302, 858) in the bicalutamide/placebo group and 623 days (95% CI 369, 730) in the bicalutamide/dutasteride group. There was no statistically significant difference between the treatment groups for any secondary efficacy end-points, including time to treatment failure or PSA response. In the multivariate analysis, age, non White race, higher baseline testosterone and lower baseline PSA were associated with longer TDP. Adverse events were comparable between treatment groups. INTERPRETATION: In men with non-metastatic CRPC, adding dutasteride to bicalutamide did not significantly prolong TDP. Prospective data are provided concerning the common practice of using bicalutamide in this setting. PMID- 26048454 TI - LRP receptor family member associated bone disease. AB - A dozen years ago the identification of causal mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene involved in two rare bone disorders propelled research in the bone field in totally new directions. Since then, there have been an explosion in the number of reports that highlight the role of the Wnt/beta-catenin pathway in the regulation of bone homeostasis. In this review we discuss some of the most recent reports (in the past 2 years) highlighting the involvement of the members of the LRP family (LRP5, LRP6, LRP4, and more recently LRP8) in the maintenance of bone and their implications in bone diseases. These reports include records of new single nucleotides polymorphisms (SNPs) and haplotypes that suggest variants in these genes can contribute to subtle variation in bone traits to mutations that give rise to extreme bone phenotypes. All of these serve to further support and reinforce the importance of this tightly regulated pathway in bone. Furthermore, we discuss provocative reports suggesting novel approaches through inhibitors of this pathway to treat rarer diseases such as Osteoporosis-Pseudoglioma Syndrome (OPPG), Osteogenesis Imperfecta (OI), and Sclerosteosis/Van Buchem disease. It is hoped that by understanding the role of each component of the pathway and their involvement in bone diseases that this knowledge will allow us to develop new, more effective therapeutic approaches for more common diseases such as post-menopausal osteoporosis, osteoarthritis, and rheumatoid arthritis as well as these rarer bone diseases. PMID- 26048456 TI - Baseline caspase activity predicts progression free survival of temsirolimus treated head neck cancer patients. AB - Squamous cell cancer of the head and neck (SCCHN) is a frequent aggressive malignancy with limited therapeutic options. Increasing evidence suggests that mammalian target of rapamycin (mTOR)-inhibitors might be effective in advanced SCCHN. However, non-invasive biomarkers for early prediction of treatment efficacy are not established in SCCHN. Highly proliferating tumours are characterised by enhanced cell turnover which is associated with enhanced apoptosis. During apoptosis of epithelial cells caspases cleave cytokeratin (CK) 18 can be detected in the blood. In this study we analysed sera from patients with relapsed or metastatic SCCHN patients who have been treated with temsirolimus for caspase-cleaved and total (caspase-cleaved and uncleaved) CK-18 by enzyme-linked immunosorbent assays (ELISAs). In addition, caspase-3 activity was detected by luminometric substrate assay. SCCHN patients revealed higher serum levels of those biomarkers compared to healthy controls. Importantly, patients with short progression-free survival (PFS) showed higher serum levels of caspase-3 activity compared to patients with longer PFS (? 2months). Caspase-3 activity is inversely correlated with PFS. A cut-off value for caspase-3 activity was determined that correctly predicted PFS <2months with a sensitivity of 86% and a specificity of 67%. These data demonstrate that detection of serum caspase 3 activity might be a useful non-invasive biomarker for early identification of SCCHN patients not responding to treatment with novel targeted therapies such as mTOR-inhibitors. PMID- 26048457 TI - Training Psychiatry Addiction Fellows in Acupuncture. AB - OBJECTIVE: Acupuncture has been studied as an adjunct for addiction treatments. Because many hospitals, outpatient clinics, and facilities are integrating acupuncture treatment, it is important that psychiatrists remain informed about this treatment. This manuscript describes the National Acupuncture Detoxification Association (NADA) protocol and its inclusion as part of the curriculum for psychiatry addictions fellows. METHODS: Psychiatry and psychology fellows completed the NADA training (n = 20) and reported on their satisfaction with the training. RESULTS: Overall, participants stated that they found the training beneficial and many were integrating acupuncture within their current practice. CONCLUSIONS: Results support the acceptability of acupuncture training among psychiatry fellows in this program. PMID- 26048458 TI - General Medicine Training in Psychiatry Residency. AB - With growing awareness of the need for integrated health care settings, psychiatrists may be required to provide clinical care at the primary care and behavioral health interface. This article discusses the curricular changes that could enhance the development of psychiatrists as leaders in integrated primary and behavioral health care. Psychiatrists may be called upon to provide enhanced collaborative care services at primary care or behavioral health settings. This article focuses on the provision of integrated care in behavioral health settings, especially in the public sector. The authors review the additional training in general medicine that would facilitate these skills. They outline the principles and goals to be considered in building such a curriculum. They examine the curricular building blocks of such training and also discuss challenges in implementing these curricular changes. Finally, they discuss the implications of incorporating integrated health care training on the future of psychiatric practice. PMID- 26048459 TI - Teaching Integrated Care. PMID- 26048461 TI - The Many Dimensions of Quality. PMID- 26048462 TI - Taking a Seat at the Quality Assurance Table. AB - Quality assurance and performance improvement are here, and pharmacists need to have a place at the table. This requires understanding the principles of quality improvement, how to track and analyze data effectively, conduct root-cause analyses, and work with the interdisciplinary team to make systems and process changes that improve quality and prevent recurrence of problems and incidences. PMID- 26048460 TI - Career Development Institute with Enhanced Mentoring: A Revisit. AB - OBJECTIVE: The need for innovative methods to promote training, advancement, and retention of clinical and translational investigators in order to build a pipeline of trainees to focus on mental health-relevant research careers is pressing. The specific aim of the Career Development Institute for Psychiatry is to provide the necessary skill set and support to a nationally selected broad based group of young psychiatrists and PhD researchers to launch and maintain successful research careers in academic psychiatry. The program targets such career skills as writing, negotiating, time management, juggling multiple demanding responsibilities, networking, project management, responsible conduct of research, and career goal setting. The current program builds on the previous program by adding a longitudinal, long-distance, virtual mentoring, and training program, seen as integral components to sustaining these career skills. METHODS: Career development activities occur in four phases over a 24-month period for each annual class of up to 18 participants: online baseline career and skills self-assessment and goal setting, preparations for 4-day in-person workshop, long distance structured mentoring and online continued learning, peer-mentoring activities, and post-program career progress and process evaluation. Program instructors and mentors consist of faculty from the University of Pittsburgh and Stanford University as well as successful past program graduates from other universities as peer mentors. A comprehensive website facilitates long-distance activities to occur online. Continued training occurs via webinars every other month by experts discussing topics selected for the needs of each particular class. Personally assigned mentors meet individually bimonthly with participants via a secure web-based "mentor center" that allows mentor dyads to collaborate, share, review, and discuss career goals and research activities. RESULTS: Preliminary results after the first 24 months are favorable. Almost uniformly, participants felt the program was very helpful. They had regular contact with their long-distance mentor at least every 2 months over the 2-year period. At the end of the 2-year period, the majority of participants had full-time faculty appointments with K-award support and very few were doing primarily clinical work. CONCLUSIONS: The longitudinal program of education, training, mentoring, peer support, and communications for individuals making the transition to academic research should increase the number of scientists committed to research careers in mental health. PMID- 26048463 TI - ASCP Forum Radical Changes Needed in Post-Acute Care. PMID- 26048464 TI - New Oral Anticoagulants: Clinical Parameters and Uses in Practice. AB - OBJECTIVE: This article serves as a resource for health care professionals by providing a summary of primary literature and guidelines for use of the available oral anticoagulant agents. The cost vs. efficacy aspects and reversibility of these medications are also addressed. DATA SOURCES, STUDY SELECTION, AND DATA SYNTHESIS: A PubMed search and Cochrane database review were conducted between June 15 and June 30, 2014, to find appropriate primary literature on each of the new oral anticoagulants. All phase 3 trials for apixaban, rivaroxaban, dabigatran, and edoxaban for the treatment of stroke prevention in atrial fibrillation (AF) and venous thromboembolism (VTE) were included. The American College of Chest Physicians guideline recommendations for stroke prevention in AF and VTE treatment, and the American Heart Association/American College of Cardiology guidelines for AF were reviewed, and pertinent information regarding the new anticoagulants from these guidelines is included in this review. A PubMed search was also used to identify cost-efficacy references and articles on reversibility of bleeding discussed in this paper. For all these articles, no further data analysis was performed; rather summaries and discussions of all of the articles included are provided in this review. CONCLUSION: The new oral anticoagulant agents have great potential in becoming standard therapy in both VTE and stroke prevention with AF. Initial clinical evidence proves they are clinically effective and potentially cost-effective for patients searching for an alternative for warfarin. Once reversal agents are developed and long-term use data become available, these agents will likely become common in many clinical practices. PMID- 26048465 TI - Relationship Between Nonsteroidal Anti-inflammatory Drugs and Fall Risk in Older Adults. AB - Approximately 20% to 30% of older adults use nonsteroidal anti-inflammatory drugs (NSAIDs) daily. While some NSAIDs are known to cause adverse central nervous system effects, the risk of falls associated with NSAID use in older adults has not been as closely scrutinized as it has with other pain medications. This article reviews 16 studies evaluating NSAID use by older adults and subsequent fall risk. In the majority of evaluated studies, geriatric patients using NSAIDs had a higher occurrence of falls compared with those not takinG NSAIDS. It is important for pharmacists to understand this potential hazard of NSAID use by older adults to minimize the risk of falls by providing patient education, adjusting dosages, discontinuing medications, and closely monitoring patients. PMID- 26048466 TI - Death with Dignity: The Developing Debate Among Health Care Professionals. AB - The right-to-die movement-known variously as death with dignity, physician assisted suicide, or aid in dying-remains controversial. The recently publicized death of 29-year-old Brittany Maynard, who chose to end her life through physician-assisted suicide, forced many health care professionals to evaluate or re-evaluate their stance on the issue. Currently, only five states have aid-in dying laws, but many others have bills under consideration. The legalized process for physician-assisted suicide has a strict set of procedures that physicians and patients must follow to ensure the competency and safety of all parties involved. Opposition against legalizing physician-assisted suicide encompasses more than simply moral, religious, or ethical differences. While some individuals believe that physician-assisted suicide gives patients autonomy in their end-of-life care, health care professionals also may have reservations about the liability of the situation. Pharmacists, in particular, play a pertinent role in the dispensing of, and counseling about, the medications used to assist patients in hastening their death. It is imperative that pharmacists be aware of the intended use of the particular medication so that they can make informed decisions about their participation and ensure that they perform all the necessary steps required to remain compliant with the laws or statutes in their jurisdiction. This practice places an increased burden on pharmacists to evaluate their opinion on the concept of death with dignity and whether or not they want to participate. PMID- 26048467 TI - The Impact of a Student-Run Journal Club on Pharmacy Students' Self-Assessment of Critical Appraisal Skills. AB - After attending an educational session on hosting journal clubs at the 2013 Annual Meeting & Exhibition, American Society of Consultant Pharmacists, Seattle, Washington, two third-year professional pharmacy students created a student-run journal club through the University of Rhode Island's ASCP student chapter. Three journal club sessions were held during the spring semester and were open to all pharmacy students. Students completed an anonymous pre- and post-survey to assess confidence in evaluating medical literature. Of the 18 participants, 5 were lost to follow-up. Significant improvements were found among all participants in their confidence in critically evaluating clinical research, interpreting statistical methods, and completing a journal club during Advanced Pharmacy Practice Experience rotations. This activity can be replicated in academic settings as well as workplace environments where pharmacy students are involved. PMID- 26048468 TI - GAO Report Focuses on Antipsychotic Use in the Community. PMID- 26048469 TI - Conditional survival of pancreatic ductal adenocarcinoma in surgical and nonsurgical patients: a retrospective analysis report from a single institution in China. AB - BACKGROUND: Conditional survival (CS) could offer reliable prognostic information for patients who survived beyond a specified time since diagnosis when the impact of late effects have the greatest influence on prognosis. We aim to investigate CS for pancreatic ductal adenocarcinoma (PDAC) patients with surgery and nonsurgery. METHODS: Chinese PDAC patients between January 2002 and September 2012 were reviewed for analyses. CS rates were calculated for survivors after surgery and nonsurgery at different time points. RESULTS: Several clinicopathologic features were associated with overall survival (OS) in each subgroup including curative resection, palliative surgery, and nonsurgery. Both univariate and multivariate analyses showed that chemotherapy was a critical predictor for OS regardless of treatment status. CS rates were higher in the curative resected patients than other cases at the same time points. Importantly, stratification of 1-year CS by carcinoembryonic antigen (CEA), (carbohydrate antigen) CA19-9, and tumor stage showed lower CEA, CA19-9, and tumor stage associated with favorable 1-year CS over time (P = 0.016, 0.009 and 0.003). CONCLUSIONS: Dynamic CS estimates could be an accurate assessment for the prognosis of PDAC patients, allowing patients and clinicians to project subsequent survival based on time change. PMID- 26048470 TI - Expression and purification of recombinant human neuritin from Pichia pastoris and a partial analysis of its neurobiological activity in vitro. AB - Neuritin (also known as candidate plasticity gene 15 (cpg15)) is a neurotrophic factor that was recently discovered in a screen aimed at identifying genes involved in activity-dependent synaptic plasticity. Neuritin plays multiple roles in both neural development (Chen et al. Zhonghua Yan Ke Za Zhi 46:978-983 2010; Corriveau et al. J Neurosci 19:7999-8008 1999; Lee and Nedivi J Neurosci 22:1807 1815 2002) and synaptic plasticity (Fujino et al. Gene Dev 25:2674-2685 2011; Leslie and Nedivi Prog 14 Neurobiol 94:223-237 2011; Loebrich and Nedivi Physiol Rev 89:1079 2009). In this study, to produce bioactive, soluble recombinant human neuritin protein, a portion of NRN1 was cloned into the Pichia pastoris expression vector pPIC9K. The recombinant vector was then transformed into the methylotrophic yeast strain P. pastoris GS115, and a shaking flask method and His tag purification strategy were utilized to express and purify neuritin protein. The resulting protein had a molecular mass of approximately 11 kDa, and subsequent functional analyses indicated that the purified neuritin promoted neurite outgrowth from embryonic chicken dorsal root ganglions, while also prolonging the survival of these ganglions, and from PC12 cells. These findings suggest that neuritin was expressed effectively in vitro and that this protein may play a role in stimulating neurite outgrowth of both dorsal root ganglions and PC12 cells. This study provides a novel strategy for the large-scale production of bioactive neuritin, which will enable further study of the biological function of this protein. PMID- 26048471 TI - Evaluation of the radioactive contamination in fungi genus Boletus in the region of Europe and Yunnan Province in China. AB - Numerous species of wild-grown mushrooms are among the most vulnerable organisms for contamination with radiocesium released from a radioactive fallout. A comparison was made on radiocesium as well as the natural gamma ray-emitting radionuclide ((40)K) activity concentrations in the fruiting bodies of several valued edible Boletus mushrooms collected from the region of Europe and Yunnan Province in China. Data available for the first time for Boletus edulis collected in Yunnan, China, showed a very weak contamination with (137)Cs. Radiocesium concentration activity of B. edulis samples that were collected between 2011 and 2014 in Yunnan ranged from 5.2 +/- 1.7 to 10 +/- 1 Bq kg(-1) dry matter for caps and from 4.7 +/- 1.3 to 5.5 +/- 1.0 Bq kg(-1) dry matter for stipes. The mushrooms Boletus badius, B. edulis, Boletus impolitus, Boletus luridus, Boletus pinophilus, and Boletus reticulatus collected from the European locations between 1995 and 2010 showed two to four orders of magnitude greater radioactivity from (137)Cs compared to B. edulis from Yunnan. The nuclide (40)K in B. badius was equally distributed between the caps and stipes, while for B. edulis, B. impolitus, B. luridus, B. pinophilus, and B. reticulatus, the caps were richer, and for each mushroom, activity concentration seemed to be more or less species specific. PMID- 26048472 TI - DNA vaccine prime and recombinant FPV vaccine boost: an important candidate immunization strategy to control bluetongue virus type 1. AB - Bluetongue virus (BTV) is the causative agent of bluetongue (BT), an important sheep disease that caused great economic loss to the sheep industry. There are 26 BTV serotypes based on the outer protein VP2. However, the serotypes BTV-1 and BTV-16 are the two most prevalent serotypes in China. Vaccination is the most effective method of preventing viral infections. Therefore, the need for an effective vaccine against BTV is urgent. In this study, DNA vaccines and recombinant fowlpox virus (rFPV) vaccines expressing VP2 alone or VP2 in combination with VP5 or co-expressing the VP2 and VP5 proteins of BTV-1 were evaluated in both mice and sheep. Several strategies were tested in mice, including DNA vaccine prime and boost, rFPV vaccine prime and boost, and DNA vaccine prime and rFPV vaccine boost. We then determined the best vaccine strategy in sheep. Our results indicated that a strategy combining a DNA vaccine prime (co-expressing VP2 and VP5) followed by an rFPV vaccine boost (co expressing VP2 and VP5) induced a high titer of neutralizing antibodies in sheep. Therefore, our data suggest that a DNA vaccine consisting of a pCAG-(VP2+VP5) prime and an rFPV-(VP2+VP5) boost is an important candidate for the design of a novel vaccine against BTV-1. PMID- 26048473 TI - Quantifying viable Vibrio parahaemolyticus and Listeria monocytogenes simultaneously in raw shrimp. AB - A novel TaqMan-based multiplex real-time PCR method combined with propidium monoazide (PMA) treatment was firstly developed for the simultaneous quantification of viable Vibrio parahaemolyticus and Listeria monocytogenes in raw shrimp. The optimization of PMA concentration showed that 100 MUM was considered optimal to effectively inhibit 10(8) CFU/mL dead cells of both bacteria. The high specificity of this method was confirmed on tests using 96 target and non-target strains. The optimized assay could detect as low as 10(1) 10(2) CFU/g of each strain on the artificially contaminated shrimp, and its amplification efficiencies were up to 100 and 106 % for V. parahaemolyticus and L. monocytogenes, respectively. Furthermore, this assay has been successfully applied to describe the behavior of these two pathogens in raw shrimps stored at 4 degrees C. In conclusion, this PMA TaqMan-based multiplex real-time PCR technique, where the whole procedure takes less than 5 h, provides an effective and rapid tool for monitoring contamination of viable V. parahaemolyticus and L. monocytogenes in seafood, improving seafood safety and protecting public health. PMID- 26048474 TI - Insights into the surface topology of polyhydroxyalkanoate synthase: self assembly of functionalized inclusions. AB - The polyhydroxyalkanoate (PHA) synthase catalyzes the synthesis of PHA and remains attached to the hydrophobic PHA inclusions it creates. Although this feature is actively exploited to generate functionalized biobeads via protein engineering, little is known about the structure of the PHA synthase. Here, the surface topology of Ralstonia eutropha PHA synthase was probed to inform rational protein engineering toward the production of functionalized PHA beads. Surface exposed residues were detected by conjugating biotin to inclusion-bound PHA synthase and identifying the biotin-conjugated lysine and cysteine residues using peptide fingerprinting analysis. The identified sites (K77, K90, K139, C382, C459, and K518) were investigated as insertion sites for the generation of new protein fusions. Insertions of FLAG epitopes into exposed sites K77, K90, K139, and K518 were tolerated, retaining >65 % of in vivo activity. Sites K90, K139, and K518 were also tested by insertion of the immunoglobulin G (IgG)-binding domain (ZZ), successfully producing PHA inclusions able to bind human IgG in vitro. Although simultaneous insertions of the ZZ domain into two sites was permissive, insertion at all three lysine sites inactivated the synthase. The K90/K139 double ZZ insertion had the optimum IgG-binding capacity of 16 mg IgG/g wet PHA beads and could selectively purify the IgG fraction from human serum. Overall, this study identified surface-exposed flexible regions of the PHA synthase which either tolerate protein/peptide insertions or are critical for protein function. This further elucidates the structure and function of PHA synthase and provides new opportunities for generating functionalized PHA biobeads. PMID- 26048476 TI - Plate reader-based cell viability assays for glioprotection using primary rat optic nerve head astrocytes. AB - Optic nerve head astrocytes (ONHAs) are the major glia cell type in the non myelinated optic nerve head where they contribute critically to extracellular matrix synthesis during development and throughout life. In glaucoma, and in related disorders affecting the optic nerve and the optic nerve head, pathological changes include altered astrocyte gene and protein expression resulting in their activation and extracellular matrix remodeling. ONHAs are highly sensitive to mechanical and oxidative stress resulting in the initiation of axon damage early during pathogenesis. Furthermore, ONHAs are crucial for the maintenance of retinal ganglion cell physiology and function. Therefore, glioprotective strategies with the goal to preserve and/or restore the structural and functional viability of ONHA in order to slow glaucoma and related pathologies are of high clinical relevance. Herein, we describe the development of standardized methods that will allow for the systematic advancement of such glioprotective strategies. These include isolation, purification and culture of primary adult rat ONHAs, optimized immunocytochemical protocols for cell type validation, as well as plate reader-based assays determining cellular viability, proliferation and the intracellular redox state. We validated and standardized our protocols by performing a glioprotection study using primary ONHAs. Specifically, we measured protection against exogenously-applied oxidative stress using tert-butylhydroperoxide (tBHP) as a model of disease-mediated oxidative stress in the retina and optic nerve head by the prototypic antioxidant, 6 hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Levels of oxidative stress were increased in the response to exogenously applied tBHP and were assessed by 6-carboxy-2', 7' dichlorodihydrofluorescein diacetate (DCFDA) fluorescence. Normalized DCFDA fluorescence showed a maximal 5.1-fold increase; the half-maximal effect (EC50) for tBHP was 212 +/- 25 MUM. This was paralleled very effectively in the assays measuring cell death and cell viability with half maximal effects of 241 +/- 20 MUM and 194 +/- 5 MUM for tBHP in the lactate dehydrogenase (LDH) release and the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) conversion assays, respectively. Pre-treatment with 100 MUM Trolox decreased the sensitivity of ONHAs to tBHP. Half-maximal effects increased to 396 +/- 12 MUM tBHP in the LDH release assay and to 383 +/- 3 MUM tBHP in the MTT assay. Vehicle treatment (0.1% v/v ethanol) did not significantly affect cellular responses to tBHP. Antioxidant treatment increases ONHA viability and reduces the deleterious effects of oxidative stress. Our experiments provide important feasibility data for utilizing primary rat ONHAs in plate reader-based assays assessing novel therapeutics for glioprotection of the optic nerve and the optic nerve head in glaucoma and related disorders. Furthermore, our novel, standardized protocols have the potential to be readily adapted to high-throughput and high-content testing strategies. PMID- 26048478 TI - Identification of aldehyde reductase catalyzing the terminal step for conversion of xylose to butanetriol in engineered Escherichia coli. AB - Biosynthetic pathways for the production of biofuels often rely on inherent aldehyde reductases (ALRs) of the microbial host. These native ALRs play vital roles in the success of the microbial production of 1,3-propanediol, 1,4 butanediol, and isobutanol. In the present study, the main ALR for 1,2,4 butanetriol (BT) production in Escherichia coli was identified. Results of real time PCR analysis for ALRs in EWBT305 revealed the increased expression of adhP, fucO, adhE, and yqhD genes during BT production. The highest increase of expression was observed up to four times in yqhD. Singular deletion of adhP, fucO, or adhE gene showed marginal differences in BT production compared to that of the parent strain, EWBT305. Remarkably, yqhD gene deletion (KBTA4 strain) almost completely abolished BT production while its re-introduction (wild-type gene with its native promoter) on a low copy plasmid restored 75 % of BT production (KBTA4-2 strain). This suggests that yqhD gene is the main ALR of the BT pathway. In addition, KBTA4 showed almost no NADPH-dependent ALR activity, but was also restored upon re-introduction of the yqhD gene (KBTA4-2 strain). Therefore, the required ALR activity to complete the BT pathway was mainly contributed by YqhD. Increased gene expression and promiscuity of YqhD were both found essential factors to render YqhD as the key ALR for the BT pathway. PMID- 26048477 TI - Photoacoustic tomography imaging and estimation of oxygen saturation of hemoglobin in ocular tissue of rabbits. AB - This study evaluated in vivo imaging capabilities and safety of qualitative monitoring of oxygen saturation of hemoglobin (sO2) of rabbit ciliary body tissues obtained with acoustic resolution (AR) photoacoustic tomography (PAT). AR PAT was used to collect trans-scleral images from ciliary body vasculature of seven New Zealand White rabbits. The PAT sO2 measurements were obtained under the following conditions: when systemic sO2 as measured by pulse oximetry was between 100% and 99% (level 1); systemic sO2 as measured by pulse oximetry was between 98% and 90% (level 2); and systemic sO2 as measured by pulse oximetry was less than 90% (level 3). Following imaging, histological analysis of ocular tissue was conducted to evaluate for possible structural damage caused by the AR PAT imaging. AR PAT was able to resolve anatomical structures of the anterior segment of the eye, viewed through the cornea or anterior sclera. Histological studies revealed no ocular damage. On average, sO2 values (%) obtained with AR PAT were lower than sO2 values obtained with pulse oximetry (all p < 0.001): 86.28 +/- 4.16 versus 99.25 +/- 0.28, 84.09 +/- 1.81 vs. 95.3 +/- 2.6, and 64.49 +/- 7.27 vs. 71.15 +/- 10.21 for levels 1, 2 and 3 respectively. AR PAT imaging modality is capable of qualitative monitoring for deep tissue sO2 in rabbits. Further studies are needed to validate and modify the AR PAT modality specifically for use in human eyes. Having a safe, non-invasive method of in vivo imaging of sO2 in the anterior segment is important to studies evaluating the role of oxidative damage, hypoxia and ischemia in pathogenesis of ocular diseases. PMID- 26048479 TI - Evaluation of the osteoinductive potential of a bio-inspired scaffold mimicking the osteogenic niche for bone augmentation. AB - Augmentation of regenerative osteogenesis represents a premier clinical need, as hundreds of thousands of patients are left with insufficient healing of bony defects related to a host of insults ranging from congenital abnormalities to traumatic injury to surgically-induced deficits. A synthetic material that closely mimics the composition and structure of the human osteogenic niche represents great potential to successfully address this high demand. In this study, a magnesium-doped hydroxyapatite/type I collagen scaffold was fabricated through a biologically-inspired mineralization process and designed to mimic human trabecular bone. The composition of the scaffold was fully characterized by XRD, FTIR, ICP and TGA, and compared to human bone. Also, the scaffold microstructure was evaluated by SEM, while its nano-structure and nano-mechanical properties were evaluated by AFM. Human bone marrow-derived mesenchymal stem cells were used to test the in vitro capability of the scaffold to promote osteogenic differentiation. The cell/scaffold constructs were cultured up to 7 days and the adhesion, organization and proliferation of the cells were evaluated. The ability of the scaffold to induce osteogenic differentiation of the cells was assessed over 3 weeks and the correlate gene expression for classic genes of osteogenesis was assessed. Finally, when tested in an ectopic model in rabbit, the scaffold produced a large volume of trabecular bone in only two weeks, that subsequently underwent maturation over time as expected, with increased mature cortical bone formation, supporting its ability to promote bone regeneration in clinically-relevant scenarios. Altogether, these results confirm a high level of structural mimicry by the scaffold to the composition and structure of human osteogenic niche that translated to faster and more efficient osteoinduction in vivo--features that suggest such a biomaterial may have great utility in future clinical applications where bone regeneration is required. PMID- 26048480 TI - The Great Diadema antillarum Die-Off: 30 Years Later. AB - In 1983-1984, the sea urchin Diadema antillarum suffered mass mortality throughout the Caribbean, Florida, and Bermuda. The demise of this herbivore contributed to a phase shift of Caribbean reefs from coral-dominated to alga dominated communities. A compilation of published data of D. antillarum population densities shows that there has been moderate recovery since 1983, with the highest rates on islands of the eastern Caribbean. On the average the current population densities are approximately 12% of those before the die-off, apparently because of recruitment limitation, but the exact factors that are constraining the recovery are unclear. Scattered D. antillarum cohorts in some localities and aggregation of settled individuals in shallow water have created zones of higher herbivory in which juvenile coral recruitment, survivorship, and growth are higher than they are in alga-dominated areas. Unlike other stressors on Caribbean coral reefs, recent changes in D. antillarum populations progress toward aiding the recovery of coral cover. PMID- 26048475 TI - In vivo imaging methods to assess glaucomatous optic neuropathy. AB - The goal of this review is to summarize the most common imaging methods currently applied for in vivo assessment of ocular structure in animal models of experimental glaucoma with an emphasis on translational relevance to clinical studies of the human disease. The most common techniques in current use include optical coherence tomography and scanning laser ophthalmoscopy. In reviewing the application of these and other imaging modalities to study glaucomatous optic neuropathy, this article is organized into three major sections: 1) imaging the optic nerve head, 2) imaging the retinal nerve fiber layer and 3) imaging retinal ganglion cell soma and dendrites. The article concludes with a brief section on possible future directions. PMID- 26048481 TI - Mapping protein structural changes by quantitative cross-linking. AB - Chemical cross-linking is a promising technology for protein tertiary structure determination. Though the data has low spatial resolution, it is possible to obtain it at physiological conditions on proteins that are not amenable to standard high resolution techniques such as X-ray, NMR analysis and cryo-EM. Here we demonstrate the utilization of isotopically labeled chemical cross-linking to visualize protein conformation rearrangements. Since calmodulin exists in two distinct conformations (calcium-free and calcium-containing forms), we selected this protein for testing the potential and the limits of a new technique. After cross-linking of both calmodulin forms, the calcium-free and calcium-containing forms were mixed together and digested under different conditions and the products of proteolysis were monitored using high resolution mass spectrometry. Finally, the ratios of heavy/light cross-links were calculated by mMass open source platform. PMID- 26048482 TI - Sexual agreements and perception of HIV prevalence among an online sample of partnered men who have sex with men. AB - Stemming from recent evidence that between one- and two-thirds of new HIV transmissions among men who have sex with men (MSM) occur within main partnerships, research and programmatic efforts have begun to recognize the role of the male-male dyad in shaping HIV risk. Central to this new focus has been studies detailing the presence of sexual agreements, which provide guidelines governing permissions around sex with partners outside of the relationship. Using a Facebook-recruited sample of US-partnered MSM (n = 454), this study examines the associations between reporting of sexual agreements and perceptions of HIV prevalence among male sex partners, friends, and local and national MSM populations. Men who perceived that 10-20 % (OR 6.18, 95 % CI 1.28-29.77) and >20 % of their male sex partners were HIV positive (OR 2.68, 95 % CI 1.02-7.08) had significantly higher odds of reporting having an open agreement with their current main partner than men who perceived that less than 10 % of their male sex partners were HIV positive. Partnered men with open sexual agreements may have more sexual partners than those who report monogamy, possibly leading to heightened perceptions of HIV risk, which may result in reporting of perceptions of greater local HIV prevalence. Additionally, men who have made agreements with their partners may have done so due to concerns about HIV risks, and may also be more aware of increased risks of HIV infection, or may have greater knowledge of HIV prevalence through discussions of serostatus with sex partners. Attention is needed to develop prevention efforts, such as toolkits and resources that enable men to form sexual agreements that are based on comprehensive knowledge of the potential risks for acquisition of HIV. PMID- 26048483 TI - Stability of Self-Reported Same-Sex and Both-Sex Attraction from Adolescence to Young Adulthood. AB - This study examined how sexual attraction varied across age, gender of participant, and gender of romantic partner, from adolescence to early adulthood. Comparisons between same-sex and both-sex attracted individuals were of particular interest. Using the National Longitudinal Study of Adolescent Health (AddHealth), we examined the responses of participants who reported experiencing same-sex attractions or both-sex attractions at least once within four waves (n = 1889). Results indicated that same-sex attractions became more stable over time, whereas both-sex attraction remained unstable even into adulthood. Compared with males, females were less stable in same-sex attraction, but more stable in both sex attraction. The majority of people who reported same-sex attraction did not report having a same-sex romantic partner before they entered adulthood, and those who reported a same-sex romantic partner were more likely to maintain their same-sex attraction than those who did not. As males got older, the gender of their romantic partner tended to become more consistent with their sexual attraction. However, for females, the consistency between the gender of their romantic partner and sexual attraction did not change over time. PMID- 26048484 TI - Production of Sophorolipid from an Identified Current Yeast, Lachancea thermotolerans BBMCZ7FA20, Isolated from Honey Bee. AB - Biosurfactants are a family of diverse amphipathic molecules that are produced by several microorganisms such as bacteria, molds, and yeasts. These surface active agents have several applications in agriculture, oil processing, food, and pharmaceutical industries. In this research using YMG and YUG culture media, a native yeast strain, HG5, was isolated from honey bee. The oil spread test as a screening method was used to evaluate biosurfactant production by the yeast HG5 isolate. The 5.8s-rDNA analysis confirmed that the isolated yeast was related to Lachancea thermotolerans. We named this strain Lachancea thermotolerans strain BBMCZ7FA20 and its 5.8s-rDNA sequence was deposited in GenBank, NCBI under accession number of KM042082.1. The best precursor of biosurfactant production was canola oil and the sophorolipid amount was measured for 24.2 g/l. The thin layer chromatography and Fourier Transform Infrared Spectroscopy analysis showed that the extracted biosurfactant from Lachancea thermotolerans was sophorolipid. In conclusion, this is the first report of sophorolipid production by a native yeast Lachancea thermotolerans BBMCZ7FA20 we isolated from the honey bee gut collected from an apiary farm in Saman, Chaharmahal Bakhtiari province, Iran. We suggested that some cost-effective supplements such as canola oil, sunflower oil, and corn oils could be applied for increasing the sophorolipid production by this native yeast strain. According to several applications of biosurfactants in today world, the production of sophorolipid by Lachancea thermotolerans could be considered as a potential in the current industrial microbiology and modern microbial biotechnology. PMID- 26048485 TI - Relative Expression of Low Molecular Weight Protein, Tyrosine Phosphatase (Wzb Gene) of Herbaspirillum sp. GW103 Toward Arsenic Stress and Molecular Modeling. AB - This study investigated the expression rate and molecular modeling of Wzb gene, a low molecular weight protein tyrosine phosphatase, under As stress in Herbaspirillum sp. GW103. Expression of Wzb gene was quantified at transcriptional level through real-time quantitative PCR. The results showed up- and down-regulations of Wzb gene in the presence of As (50 and 100 mg/L). The maximum Wzb transcript expression was 1.2-fold after 72 h exposure to 50 mg/L of As. However, the minimum expression was 0.1-fold after 48 h exposure to 100 mg/L of As. The Wzb protein sequence was retrieved from NCBI sequence database and was used for in silico analysis. 3D structure of Wzb gene was predicted by comparative modeling using modeler 9v9. Further, the model was validated for its quality by Ramachandran plot, ERRAT, Verify 3D, and SAVES server which revealed structure and quality of the Wzb gene model. PMID- 26048486 TI - The context of host competence: a role for plasticity in host-parasite dynamics. AB - Even apparently similar hosts can respond differently to the same parasites. Some individuals or specific groups of individuals disproportionately affect disease dynamics. Understanding the sources of among-host heterogeneity in the ability to transmit parasites would improve disease management. A major source of host variation might be phenotypic plasticity - the tendency for phenotypes to change across different environments. Plasticity might be as important as, or even more important than, genetic change, especially in light of human modifications of the environment, because it can occur on a more rapid timescale than evolution. We argue that variation in phenotypic plasticity among and within species strongly contributes to epidemiological dynamics when parasites are shared among multiple hosts, which is often the case. PMID- 26048487 TI - Distinction between forensic evidence and dermatological findings. AB - The external examination after death requires knowledge in forensics/pathology, dermatology, as well as associated diseases and age-related alterations of the skin. This article highlights some findings with forensic evidence versus dermatological findings. The lectures in forensic medicine should be structured interdisciplinarily, especially to dermatology, internal medicine, surgery, pathology, and toxicology in order to train the overlapping skills required for external and internal postmortem examinations. PMID- 26048488 TI - Outdoor post-mortem bite injuries by Tapinoma nigerrimum (Hymenoptera, Formicidae) on a human corpse: Case report. AB - Ants are among the insects that colonize exposed human and animal corpses during the early stage of decomposition. In Calabria, Italy (as well as in other countries), Formicidae have been observed preying on immature stages of Diptera and other insects, as well as causing irregular scalloped areas of superficial skin loss on human corpses and animal carcasses. We present a case of injuries on a human corpse caused by ant feeding. The macroscopic appearance is described and the results of a histochemical investigation of the skin lesions caused by worker ants are reported for the first time. The investigation was carried out on the fresh corpse of a 53-year-old man discovered in a rural area of Cosenza province (Calabria, southern Italy). Numerous irregular areas of superficial skin loss caused by the ant Tapinoma nigerrimum (Nylander 1856) (Hymenoptera, Formicidae) were observed on the body surface, inflicted very early in the post-mortem period. Because the classification of lesions is of crucial importance for forensic investigations, the macroscopic appearance and distribution pattern of the lesions on the corpse are illustrated. The histochemical investigation of the damaged skin explains, for the first time, the mechanism of production of the lesions. PMID- 26048489 TI - Reliability of mandibular canine and mandibular canine index in sex determination: A study using Uyghur population. AB - Sex determination is a key process that is required to establish the forensic profile of an individual. Mandibular canine index (MCI) method yields fairly positive results for sex determination. However, this method has been challenged by a few authors. This study aimed to examine the reliability of MCI in Chinese Uyghur population and to establish its normal value for this ethnic group. Dental casts of 216 students (117 males and 119 females) from the College of Stomatology of Xinjiang Medical University in China were used to determine the sexing accuracy of MCI. The mesiodistal (MD) dimension of mandibular canine crowns, the inter-canine distance, and the MCI were calculated. The accuracy of the standard MCI derived from the current data was compared with that of the standard MCIs derived from previous data. Results were statistically described using the independent-samples t-test. The MD dimension of mandibular crown, the inter canine distance, and the MCI exhibited statistically significant sexual dimorphism. Sex determination using the MCI derived from the current data revealed fairly reliable results. Therefore, MCI is a reliable method for sex determination for Uyghur population, with 0.248 as standard MCI value. PMID- 26048490 TI - Sex determination from the talus in a contemporary Greek population using discriminant function analysis. AB - The determination of sex is an important part of building the biological profile for unknown human remains. Many of the bones traditionally used for the determination of sex are often found fragmented or incomplete in forensic and archaeological cases. The goal of the present research was to derive discriminant function equations from the talus, a preservationally favoured bone, for sexing skeletons from a contemporary Greek population. Nine parameters were measured on 182 individuals (96 males and 86 females) from the University of Athens Human Skeletal Reference Collection. The individuals ranged in age from 20 to 99 years old. The statistical analyses showed that all measured parameters were sexually dimorphic. Discriminant function score equations were generated for use in sex determination. The average accuracy of sex classification ranged from 65.2% to 93.4% for the univariate analysis, 90%-96.5% for the direct method and 86.7% for the stepwise method. Comparisons to other populations were made. Overall, the cross-validated accuracies ranged from 65.5% to 83.2% and males were most often correctly identified. The talus was shown to be useful for sex determination in the modern Greek population. PMID- 26048491 TI - Physician liability for procedure related injury: Focused on central venous catheterization. AB - Central venous catheterization (CVC) is one of essential procedures in critical care medicine. CVC is relatively safe when performed by experienced physicians. Complications may occur due to various risk factors. Although the incidence of CVC-related complications is not high, a serious risk may ensue in cases of such complications. Procedure related complications could lead to civil and criminal lawsuits. This study reviewed the occurrence patterns and rulings of the courts related to CVC in South Korea and tried to find pitfalls that medical professionals should keep in mind before, during and after medical procedures. Various patterns of CVC-related lawsuits have been raised. During the procedure, physicians should perform their duty considering risk factors such as patients' underlying diseases and age. In addition, before the procedure, physicians must obtain written consent for CVC from patients or their legal guardians including explanation of rare complications that could be lethal. After the completion of CVC, surveillance of anticipated complications including chest radiographs should be conducted for the immediate management of any possible complications. PMID- 26048492 TI - Comparative analysis of hospital and forensic laboratory ethanol concentrations: A 15 month investigation of antemortem specimens. AB - Quantitative serum alcohol concentrations from regional hospitals (from specimens collected at time of hospital admission) were compared to results from whole blood (from specimens collected at the time of hospital admission) concentrations measured at the San Diego County Medical Examiner's Office (SDCMEO). Over a 15 month period (January 2012 to March 2013), the postmortem forensic toxicology laboratory analyzed a total of 2,321 cases. Of these, 280 were hospital cases (antemortem) representing 12% of the overall Medical Examiner toxicology casework. 59 of the 280 hospital cases (or 21%) screened positive for alcohol (ethanol). 39 of these 59 cases were included in the study based on available specimens for quantitative analyses. This investigation indicated that serum hospital ethanol concentrations correlated well (R(2) = 0.942) with ethanol values determined at SDCMEO (generally measured in whole blood). There was an observed negative bias with an average of -14.1%. A paired t-test was applied to the data and it was shown that this observed bias is statistically significant. These differences in ethanol concentrations could result from differences in specimen, analytical techniques, and/or calibration. The potential for specimen contamination is also discussed. PMID- 26048493 TI - Analysis of organophosphorus pesticides in whole blood by GC-MS-MUECD with forensic purposes. AB - In the present work, two multi-residue methods for the determination of ten organophosphorus pesticides (OPs), namely chlorfenvinphos, chlorpyrifos, diazinon, dimethoate, fenthion, malathion, parathion, phosalone, pirimiphos methyl and quinalphos, in post-mortem whole blood samples are presented. The adopted procedure uses GC-MS for screening and quantitation, and GC-MUECD (electron capture detector) for compound confirmation. Three different Solid Phase Extraction (SPE) procedures for OPs with Oasis((r)) hydrophilic lipophilic balanced (HLB) and Sep-Pak((r)) C18 cartridges were tested, and followed by GC MUECD and GC-MS analysis. The Sep-Pak((r)) C18 cartridges extraction procedure was selected since it generated analytical signals 5 times higher than those obtained with the two different Oasis((r)) HLB cartridges extraction procedures. The method has shown to be selective for the isolation of selected OPs as well as to the chosen internal standard (ethion) in postmortem blood samples. Calibration curves between 50 and 5000 ng/mL were prepared using weighted linear regression models (1/x(2)). It was not possible to establish a working range for fenthion by GC-MUECD due to the lower sensitivity of the detector to this compound, whereas for pirimiphos-methyl it was set between 500 and 5000 ng/mL. The limit of quantitation was established at 50 ng/mL for all analytes, except for pirimiphos methyl by GC-MUECD analysis (500 ng/mL). The average extraction efficiency ranged from 72 to 102%. The developed methods were considered robust and fit for the purpose, and had already been adopted in the laboratory routine analysis. PMID- 26048494 TI - Clinico-epidemiological study of near-hanging cases - An investigation from Nepal. AB - Hanging is one of the commonest methods of suicide. Epidemiological data of near hanging patients from Nepal is limited. The present research from Nepal attempts to review the clinico-epidemiological profile of near-hanging patients. A retrospective review of case records was done for the near hanging patients admitted to a tertiary care teaching hospital in Nepal, between August 2012 and August 2014. Details regarding socio-demographic profile, circumstances of hanging, clinical details, and outcome etc. were obtained and examined. During the study period, 10 near hanging patients were admitted to the hospital. The majority of the patients were below 30 years. Mean age of the study group was 28.8 years. The GCS on arrival ranged between 5/15 and 15/15 with the mean GCS being 9.5/15. Hypoxic encephalopathy and cerebral edema were the only noted complications. None of the patient had a cervical spinal injury. All the patients survived the near hanging episode. The mean ICU and hospital stay were 3.9 days and 6.2 days respectively. Prompt resuscitation, active interventions and intensive care support favors a good prognosis. Psychiatric evaluation and support to the patients and their relatives is the key to preventing such attempts in future. PMID- 26048495 TI - Injuries associated with resuscitation - An overview. AB - External cardiopulmonary resuscitation is a potentially lifesaving intervention aimed at preserving the cerebral function of a person in cardiac arrest. However, certain injuries can be caused by the various techniques employed. Although these are seldom consequential, they may complicate the forensic evaluation of cases. Fractures of the ribs and sternum are the most common internal injuries and are frequently acknowledged as a consequence of resuscitation. Nonethlesss, the recognition that less common fractures such as of the larynx or injuries involving the stomach, spleen, heart and liver can occur due to resuscitation will assist the forensic examiner assess the significance of these findings when they present in cases of sudden death. PMID- 26048496 TI - Suicidal hanging in Istanbul, Turkey: 1979-2012 Autopsy results. AB - A retrospective study was carried out on 4549 which is the total number of hanging cases autopsied at Forensic Medicine Institute in Istanbul, Turkey. 4502 hanging cases of suicidal origin were detected and evaluated in terms of demographic features, the type of hanging material used for ligature, internal findings in neck organs, toxicological findings and microscopic findings. Of these suicides, 3295 (73.2%) were males and 1207 (26.8%) were females. The average age of the victims was 37.8 (SD 1.6). Crude suicidal hanging rate is approximately two-fold increase in women, while it is about five-to six-fold increase in men during 33 years. 1424 of the victims committed suicide by hanging themselves at home, and 441 of them in prison and indoor areas. The alcohol in the blood of all autopsy victims was tested and results were positive for 687 people. A drug active agent was detected in 108 (2.4%) victims: 70 (1.5%) of them were antidepressants, 20 (0.5%) of them were analgesic/anti-inflammatory/anti histaminic and 18 (0.4%) of them were antipsychotic. In the examination of the psychoactive substances in blood and urine, any of such substances was not detected in 4146 of the victims. However, victims' blood and urine contained a sedative-hypnotic-anxiolytic with 74 (1.6%), a cannabinoid with 16 (0.4%) and an opioid with 12 (0.3%). Psychoactive substance examination was not carried out for 243 victims. Of these cases, 4060 (90.2%), ecchymosis in soft tissues and 2800 (62.1%) fracture in neck organs was found. PMID- 26048497 TI - Police shootings against civilians in Portugal: Contextual, forensic medical and judicial characterization. AB - The aim of this study was to analyse the circumstances, the forensic assessment and the legal assessment of police shootings of civilians, according to the severity of the victim's injuries. Sixty-nine cases tried in Portuguese criminal courts were analysed. Of the 32 cases that resulted in death, 16 were on the public thoroughfare and 13 were in the victim's vehicle or in third-party vehicles. The majority of the lethal cases occurred when the region of the body hit was the thorax/abdomen. The firearm most frequently used was a semi-automatic 9 mm pistol. In cases resulting in death police officers involved were convicted whilst those involved in non-lethal cases were acquitted. The results of this study can be taken into account by Portuguese authorities for the implementation of policies that will allow the restriction of firearms use by police officers to situations of imminent danger of death or serious injury and that will make it possible to avoid shooting at fleeing civilians. PMID- 26048498 TI - Analysis of methanol and its derivatives in illegally produced alcoholic beverages. AB - INTRODUCTION: Illegal alcohol production remains as a common issue worldwide. Methanol poisoning mostly occurs because of the methanol used in production of counterfeit alcohol instead of ethyl alcohol due to its low price or by drinking the liquids containing methyl alcohol. Pectolytic enzymes results in an increase of methanol levels in many fermentation products such as ciders or wines. Methanol poisonings are infrequently encountered in forensic medicine practice. However, sporadic cases due to methanol intoxication as well as epidemic cases have been reported. In this study, we aimed to identify existence of methanol and its metabolites in illegally produced alcoholic beverages used in Antakya region. MATERIAL AND METHODS: Twelve legally produced alcohol samples and Fifty-six different illegally produced alcohol samples were collected from the markets and local producers. Existence of methanol, formic acid, methyl amine, methyl formate and trioxan were determined using GC-MS method in these samples. RESULTS: Fifty six different illegal alcohol samples were analyzed in this study and methanol was detected in 39 (75%) of samples. Formic acid was detected in 3, formamide in 1, methyl amine in 6, methyl formate in 10 and trioxan in 2 samples. CONCLUSION: Overwhelming majority of illegal alcoholic beverages was detected to contain methanol. Interestingly this study also revealed the presence of trioxane, which has not previously reported among toxic agents in illegal alcohol samples. PMID- 26048499 TI - Diagnostic yield of hair and urine toxicology testing in potential child abuse cases. AB - Detection of drugs in a child may be the first objective finding that can be reported in cases of suspected child abuse. Hair and urine toxicology testing, when performed as part of the initial clinical evaluation for suspected child abuse or maltreatment, may serve to facilitate the identification of at-risk children. Furthermore, significant environmental exposure to a drug (considered by law to constitute child abuse in some states) may be identified by toxicology testing of unwashed hair specimens. In order to determine the clinical utility of hair and urine toxicology testing in this population we performed a retrospective chart review on all children for whom hair toxicology testing was ordered at our academic medical center between January 2004 and April 2014. The medical records of 616 children aged 0-17.5 years were reviewed for injury history, previous medication and illicit drug use by caregiver(s), urine drug screen result (if performed), hair toxicology result, medication list, and outcome of any child abuse evaluation. Hair toxicology testing was positive for at least one compound in 106 cases (17.2%), with unexplained drugs in 82 cases (13.3%). Of these, there were 48 cases in which multiple compounds (including combination of parent drugs and/or metabolites within the same drug class) were identified in the sample of one patient. The compounds most frequently identified in the hair of our study population included cocaine, benzoylecgonine, native (unmetabolized) tetrahydrocannabinol, and methamphetamine. There were 68 instances in which a parent drug was identified in the hair without any of its potential metabolites, suggesting environmental exposure. Among the 82 cases in which hair toxicology testing was positive for unexplained drugs, a change in clinical outcome was noted in 71 cases (86.5%). Urine drug screens (UDS) were performed in 457 of the 616 reviewed cases. Of these, over 95% of positive UDS results could be explained by iatrogenic drug administration. There were no cases in which a urine drug screen alone altered the outcome of a case. In summary, hair toxicology testing proved clinically useful in the evaluation of a child for suspected abuse; in contrast, urine drug testing showed low clinical yield. PMID- 26048500 TI - Fatal tiger shark, Galeocerdo cuvier attack in New Caledonia erroneously ascribed to great white shark, Carcharodon carcharias. AB - To understand the causes and patterns of shark attacks on humans, accurate identification of the shark species involved is necessary. Often, the only reliable evidence for this comes from the characteristics of the wounds exhibited by the victim. The present case report is intended as a reappraisal of the Luengoni, 2007 case (International Shark Attack File no. 4299) where a single shark bite provoked the death of a swimmer by haemorrhagic shock. Our examination of the wounds on the body of the victim, here documented by so-far unpublished photographic evidence, determined that the shark possessed large and homodontous jaws. This demonstrates that the attacker was a tiger shark, not a great white shark as previously published. PMID- 26048501 TI - Homicide by hanging: A case report and its forensic-medical aspects. AB - We report a rare case of homicide by hanging. The postmortem examination resulted in a verdict of death by suicidal hanging and the Public Prosecutor's Office released the body for burial. After intervention by the relatives police investigations were resumed. Based on evidence impossible to reconcile with the results of the postmortem examination and requiring further clarification, an autopsy was ordered. The results of the postmortem could not be brought in line with a suicidal hanging and were further substantiated by DNA analysis. The scenario put forward by the defense claiming a secondary transfer of trace evidence onto the ligature and the victim's clothes was excluded because of the distribution pattern and the trace evidence ratio. The defendant was sentenced to 20 years of prison for homicide. The verdict was confirmed by the Supreme Court and commuted to 18 years. PMID- 26048502 TI - The utilization of a commercial gloss spray in stabilization of incinerated dental structures. AB - PURPOSE: Incinerated human remains may require dental comparison to establish identity. The remains are often fragile and minor forces can damage teeth and facial bones, disrupting anatomical relationships, and impairing the ability to compare with antemortem records. This study evaluated the ability of a commercially available gloss spray to stabilize teeth in incinerated remains. METHODS: Lower anterior teeth of scavenged sheep mandibles were incinerated in a furnace at a temperature of 500 degrees C for 35 min. Before a series of vibration tests, the left side of each sample was treated with the spray, with the right side acting as a control. RESULTS: Significant retention of dental data was achieved utilizing the spray in comparison to the non-stabilized sides. CONCLUSION: This study showed that a commercial clear gloss spray did not affect the ability to document or perform radiographic assessment of restorations, and statistically improved the stability and anatomical relationships of incinerated dental remains in scavenged sheep mandibles. Commercial products, such as the one tested in this study, are readily available and could be deployed at a mass disaster situation. However, the spray should not be used if there is any suspicion that accelerants might be involved at the scene. PMID- 26048503 TI - Response to "Letter to the Editor from Fieuws et al. J For Leg Med [29 (2015) 24]". PMID- 26048504 TI - Post-mortem toxicology: A pilot study to evaluate the use of a Bayesian network to assess the likelihood of fatality. AB - The challenge of interpreting post-mortem drug concentrations is well documented and relies on appropriate sample collection, knowledge of case circumstances as well as reference to published tables of data, whilst taking into account the known issues of post-mortem drug redistribution and tolerance. Existing published data has evolved from simple data tables to those now including sample origin and single to poly drug use, but additional information tends to be specific to those reported in individual case studies. We have developed a Bayesian network framework to assign a likelihood of fatality based on the contribution of drug concentrations whilst taking into account the pathological findings. This expert system has been tested against casework within the coronial jurisdiction of Sunderland, UK. We demonstrate in this pilot study that the Bayesian network can be used to proffer a degree of confidence in how deaths may be reported in cases when drugs are implicated. It has also highlighted the potential for deaths to be reported according to the pathological states at post-mortem when drugs have a significant contribution that may have an impact on mortality statistics. The Bayesian network could be used as complementary approach to assist in the interpretation of post-mortem drug concentrations. PMID- 26048505 TI - Review of the medical and legal literature on restraint chairs. AB - Use of restraint chairs by law enforcement for violent individuals has generated controversy and a source of litigation because of reported injuries and deaths of restrained subjects. The purpose of this study is to review the available medical and legal literature and to allow the development of evidence-based, best practice recommendations to inform the further development of restraint chair policies. This is a structured literature review of four databases, two medical and two legal. The medical review focus was on the restraint chair with additional review of materials regarding other restraint methods and options. The legal review focused on litigation cases involving the restraint chair. The review of the medical literature revealed 21 peer-reviewed studies investigating the physiological or psychological effects of using a restraint chair on humans or primates. Of these studies, 20 were performed on primates. The single human study revealed no clinically significant effects from the restraint chair on test subjects. The legal literature review revealed very few cases where the restraint chair was either a major or minor focus. The overall issues relating to the restraint chair cases involved deviations from set protocols and rarely involved issues with the chair itself. The available medical literature reveals that the restraint chair poses little to no medical risk. Additionally, when used appropriately, the restraint chair alone carries little legal liability. With proper monitoring and adherence to set protocols, the restraint chair is a safe and appropriate device for use in restraining violent individuals. PMID- 26048506 TI - An overhung mute suspect died during restraint - Is this a case of positional asphyxia? AB - Positional asphyxia is a specific type of suffocation that results from the body being forced and fixed in a particular position causing death by suffocation. The body exhibits obvious general characteristics of death by suffocation. We report a case of custody death that may have been caused by positional asphyxia. The mute criminal suspect died in a detention room after arrest. The suspect was found unconscious and died following placement in a hanging position for 8 h. We reviewed the case with respect to the autopsy findings, pathological changes, and specific scene where the death occurred as well as the circumstantial correlation of the investigation. PMID- 26048507 TI - Pathological changes in anabolic androgenic steroid users. AB - Several classes of recreational and prescription drugs have additional effects on the heart and vasculature, which may significantly contribute to morbidity and mortality in chronic users. The study presented herein focuses on pathological changes involving the heart possibly due to anabolic androgenic steroid use. The role these hormones may play in their occurrence of sudden cardiac death is also investigated. 98 medico-legal cases including 6 anabolic androgenic steroid users were retrospectively reviewed. Autopsies, histology, immunohistochemistry, biochemistry and toxicology were performed in all cases. Pathological changes consisted of various degrees of interstitial and perivascular fibrosis as well as fibroadipous metaplasia and perineural fibrosis within the myocardium of the left ventricle. Within the limits of the small number of investigated cases, our results appear to confirm former observations on this topic and suggest anabolic androgenic steroid's potential causative role in the pathogenesis of sudden cardiac deaths in chronic users. PMID- 26048508 TI - The challenges of accurately estimating time of long bone injury in children. AB - The ability to determine the time an injury occurred can be of crucial significance in forensic medicine and holds special relevance to the investigation of child abuse. However, dating paediatric long bone injury, including fractures, is nuanced by complexities specific to the paediatric population. These challenges include the ability to identify bone injury in a growing or only partially-calcified skeleton, different injury patterns seen within the spectrum of the paediatric population, the effects of bone growth on healing as a separate entity from injury, differential healing rates seen at different ages, and the relative scarcity of information regarding healing rates in children, especially the very young. The challenges posed by these factors are compounded by a lack of consistency in defining and categorizing healing parameters. This paper sets out the primary limitations of existing knowledge regarding estimating timing of paediatric bone injury. Consideration and understanding of the multitude of factors affecting bone injury and healing in children will assist those providing opinion in the medical-legal forum. PMID- 26048509 TI - Age estimation among Brazilians: Younger or older than 18? AB - The age estimation of living or dead individuals is an important part of forensic science because it can be used in various situations, including mass disasters, or for civil or criminal reasons, such as adoption or asylum. Teeth play a major role in this context because they are more resistant than bones in extreme environmental conditions and their development is hardly affected by exogenous or endogenous factors. Because the third molars (3rdM) are still in development from the age of 14, they are useful for determining whether an individual has reached the legal age of 18 years. This study aims to verify the method of Cameriere et al. (2008) in Brazil to discriminate whether an individual is under or over 18 years from the maturity index of the 3rdM (I3m). The analysis of 444 panoramic radiographs resulted in a sensitivity of 78.3%, a specificity of 85.1% and a correct classification of 87%. Significant differences in sexual dimorphism in the early mineralization of males were found only for the average age with I3m >= 0.08, except for the range (0.7, 0.9). Due to the high miscegenation ratio of the Brazilian population the ancestry was not one of the studied variables. The method is suitable for estimating adulthood for forensic purposes in Brazil, although it must be applied carefully and judiciously. We recommend a combination of several methods that are available to increase accuracy as well as the establishment of different parameters that are likely to determine whether a person is more or less than 18 years of age, depending on the different legal requirements, whether civil or criminal. PMID- 26048510 TI - Marks caused by the scavenging activity of Necrobia rufipes (Coleoptera: Cleridae) under laboratory conditions. AB - Insects are an important group involved in carrion consumption and are thus of forensic interest. In the laboratory we studied the taphonomic marks that Necrobia rufipes (Cleridae) can produce. Pig trotters were exposed to adult beetles at 21 +/- 3 degrees C and 12:12 h day/night cycle. We made observations and took photographs every 4-5 days for 12 months. Marks were noted after a month. We found scratches, pits, holes, and tunnels in several kinds of tissue such as integumental, connective and muscular. This work contributes preliminary data of significant application in biology, ecology, anthropology and forensics. Until now, no study has provided taphonomic information with N. rufipes. PMID- 26048511 TI - Statement on virginity testing. AB - Virginity testing (virginity examination) is a gynecological examination that is intended to correlate the status and appearance of the hymen with previous sexual contact to determine whether a female has had or is habituated to sexual intercourse. Virginity examinations are practiced in many countries, often forcibly, including in detention places; on women who allege rape or are accused of prostitution; and as part of public or social policies to control sexuality. The Independent Forensic Expert Group (IFEG) - thirty-five preeminent independent forensic experts from eighteen countries specialized in evaluating and documenting the physical and psychological effects of torture and ill-treatment - released a statement on the practice in December 2014. In its statement, the IFEG outlines the physical and psychological effects of forcibly conducting virginity examinations on females based on its collective experience. The Group assesses whether, based on the effects, forcibly conducted virginity examinations constitute cruel, inhuman, or degrading treatment or torture. Finally, the IFEG addresses the medical interpretation, relevance, and ethical implications of such examinations. The IFEG concludes that virginity examinations are medically unreliable and have no clinical or scientific value. These examinations are inherently discriminatory and, in almost all instances, when conducted forcibly, result in significant physical and mental pain and suffering, thereby constituting cruel, inhuman and degrading treatment or torture. When virginity examinations are forcibly conducted and involve vaginal penetration, the examination should be considered as sexual assault and rape. Involvement of health professionals in these examinations violates the basic standards and ethics of the professions. PMID- 26048512 TI - Application of the microwave digestion-vacuum filtration-automated scanning electron microscopy method for diatom detection in the diagnosis of drowning. AB - The cause of death for the decomposed corpses recovered from water is still a difficult issue in current forensic practice. In this article, we present two cases of bodies recovered from water with no positive findings to indicate the cause of their death. We apply both conventional acid digestion method as well as the microwave digestion-vacuum filtration-automated scanning electron microscopy method (MD-VF-Auto SEM) for diatom detection in different organs of both bodies. Our results indicate that MD-VF-Auto SEM method provide more accurate information and match further police investigation. This novel method would be a useful technique in assessing cause of death for body found in water. PMID- 26048513 TI - Feasibility and outcomes of laparoscopic sleeve gastrectomy after solid organ transplantation. AB - BACKGROUND: Obesity is common after solid organ transplantation and is associated with worse transplantation-related outcomes. Laparoscopic sleeve gastrectomy (LSG) may be the preferred bariatric operation in transplantation patients over other techniques, such as gastric bypass, given the concerns about medication absorption. However, little is known about LSG outcomes in post-transplantation patients. OBJECTIVES: We report the outcomes in 10 consecutive patients who underwent solid organ transplantation followed by LSG. SETTING: An academic medical center. METHODS: Primary outcomes studied were weight loss, perioperative complications, resolution or improvement of obesity-related co-morbidities, and markers of graft function following LSG. RESULTS: The types of transplantation before LSG were as follows: liver = 5, kidney = 4, and heart = 1. Mean body mass index (BMI) at LSG was 44.7 +/- 1.7 kg/m(2). All patients had hypertension, and 6 had type 2 diabetes. Perioperative complications occurred in 2 patients, and there were no deaths. Excess weight loss at 12 and 24 months after LSG was 45.7% and 42.5%, respectively. At 1 year after LSG, there was a significant reduction in the number of antihypertensive medications (2.4 to 1.5; P = .02). Three patients achieved complete remission of type 2 diabetes, and the other 3 significantly reduced their dosages of insulin. Graft function remained preserved in liver transplantation patients; left ventricular ejection fraction (LVEF) increased by 10% in the heart transplantation subject, and the estimated glomerular filtration rate (eGFR) increased significantly in kidney transplantation patients (53 +/- 3 to 82 +/- 3 mL/min; P = .03). CONCLUSIONS: We concluded that LSG, in selected patients with severe obesity after solid organ transplantation, results in significant weight loss, improvement or resolution of obesity-related conditions, and preservation or improvement of graft function. Larger studies are needed to determine tolerability standards. PMID- 26048514 TI - Detailed characterization of incretin cell distribution along the human small intestine. AB - BACKGROUND: Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are physiologic stimulants of insulin release that have been implicated in diabetes remission after bariatric surgery. The detailed distribution of incretin cells along the human small gut, so far unknown, is of utmost importance for the understanding of the metabolic changes observed after bariatric surgery because diabetes remission rate varies according to the type of anatomic rearrangement. OBJECTIVE: To characterize the distribution of incretin producing cells along the human jejunum-ileum. SETTING: Academic public institution. METHODS: Small intestines (n = 30) from autopsies were sampled every 20 cm along their entire length and tissue microarrays were constructed. The percentage of immunohistochemistry-stained cell areas for GLP-1, GIP, and chromogranin A at each segment length was quantified using a computer aided analysis tool. RESULTS: The percentage of stained area for GLP-1 immunoreactive cells was found to be significantly higher from 200 cm from Treitz ligament onward compared with the first 80 cm of the small intestine, whereas GIP immunoreactive cells were predominant expressed in the first 80 cm. In contrast, chromogranin A expression was constant along the entire jejunum-ileum. CONCLUSION: The uneven distribution of GLP-1-expressing cells, with a higher density from 200 cm of the jejunum-ileum, could contribute to explain the improvement of glycemic profile of diabetic patients observed after anatomic rearrangement of the intestinal tract, in particular when subjected to gastric bypass with longer biliopancreatic limbs. PMID- 26048515 TI - Chronic gastrointestinal bleeding from an internal hernia after Roux-en-Y gastric bypass causing superior mesenteric venous obstruction with associated intestinal varices. PMID- 26048516 TI - The effects of weight loss surgery on blood rheology in severely obese patients. AB - BACKGROUND: The effects of dieting on blood rheology in obese individuals suggest that improving the rheologic profiles depends on the amount of weight lost and its long-term maintenance. The aim of this study was to evaluate the effects of weight loss after surgery on blood rheology at 12-month follow-up. METHODS: We studied 38 obese patients who underwent laparoscopic weight loss surgery, 22 of whom had sleeve gastrectomy (SG) and 16 of whom had gastric banding (LAGB). We evaluated rheologic parameters such as blood viscosity, plasma viscosity, and erythrocyte deformability (as measured by elongation index [EI]) preoperatively and 12 months after surgery. RESULTS: Whole blood viscosity at 150 s(-1) shear rate (P<.01) and 300 s(-1) shear rate (P<.05), blood viscosity corrected to a standard hematocrit at both shear rates (P<.0005 and P<.005, respectively), and plasma viscosity (P<.005) were significantly reduced after surgery. EI evaluated at different shear stresses (18.49-60.03 Pa) decreased (P<.005) 12 months after surgery. There were significantly decreased EI and blood viscosity corrected to a standard hematocrit after SG (P<.005 and P<.05) and LAGB (P = .0621 and P<.05), but plasma viscosity significantly decreased only after SG (P<.005). Blood viscosity at both shear rates correlated with plasma viscosity (r = .51, P<.005 and r = .5, P<.005). Plasma viscosity correlated positively with body mass index (r = .57; P<.0005) and negatively with percentage of excess weight lost (r = .56; P< .005). CONCLUSIONS: This study found that weight loss after bariatric surgery induced improvement in blood rheology in obese patients at 12 months after surgery. The increased red blood cell rigidity after surgery requires further study because the physiologic importance of this change has not yet been established. PMID- 26048517 TI - Single-anastomosis duodenoileal bypass with sleeve gastrectomy (SADI-S) for obese diabetic patients. AB - BACKGROUND: Bariatric operations achieve a high remission rate of type 2 diabetes in patients with morbid obesity. Malabsorptive operations usually are followed by a higher rate of metabolic improvement, though complications and secondary effects of these operations are usually higher. OBJECTIVES: Analyze the results of a simplified duodenal switch, the single-anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) on patients with obesity and type 2 diabetes mellitus (T2 DM). SETTING: University Hospital, Madrid, Spain. METHODS: Ninety-seven T2 DM patients with a mean body mass index (BMI) of 44.3 kg/m(2) were included. Mean preoperative glycated hemoglobin was 7.6%, and mean duration of the disease was 8.5 years. Forty patients were under insulin treatment. SADI-S was completed with a sleeve gastrectomy performed over a 54 French bougie and a 200 cm common limb in 28 cases and 250 cm in 69. RESULTS: Follow up was possible for 86 patients (95.5%) in the first postoperative year, 74 (92.5%) in the second, 66 (91.6%) in the third, 46 (86.7%) in the fourth and 25 out of 32 (78%) in the fifht postoperative year. Mean glycemia and glycated hemoglobin decreased immediately. Control of the disease, with HbA1c below 6%, was obtained in 70 to 84% in the long term, depending on the initial antidiabetic therapy. Most patients abandoned antidiabetic therapy after the operation. Absolute remission rate was higher for patients under oral therapy than for those under initial insulin therapy, 92.5% versus 47% in the first postoperative year, 96.4% versus 56% in the third and 75% versus 38.4% in the fifth. A short diabetes history and no need for insulin were related to a higher remission rate. Three patients had to be reoperated for recurrent hypoproteinemia. CONCLUSION: SADI-S is an effective therapeutic option for obese patients with diabetes mellitus. PMID- 26048518 TI - Revised sleeve gastrectomy (re-sleeve). AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) has rapidly become increasingly popular in bariatric surgery. However, in the long-term follow-up, weight loss failure and intractable severe reflux after primary LSG can necessitate further surgical interventions. OBJECTIVES: To evaluate the safety and the efficiency of revisional sleeve gastrectomy (ReSG). SETTING: Private hospital. METHODS: From October 2008 to October 2014, 61 patients underwent ReSG. All patients with failure after primary LSG underwent radiologic evaluation, and an algorithm of treatment was proposed. RESULTS: Sixty-one patients (54 women, 7 men; mean age 40.8 yr) with a body mass index (BMI) of 39.4 kg/m2 underwent ReSG. The primary LSG was performed for mean BMI of 46.2 kg/m2 (range 35.4-77.9). The mean interval time from the primary LSG to ReSG was of 37.5 months (9-80 mo). The indication for ReSG was insufficient weight loss in 28 patients (45.9%), weight regain in 29 patients (47.5%), and gastroesophageal reflux disease (GERD) in 4 patients. In 42 patients the gastrografin swallow results were interpreted as primary dilation and in the remaining 19 cases as secondary dilation. The computed tomography (CT) scan volumetry was obtained in 38 patients with mean gastric volume of 436.3 cc (275-1056 cc). All cases were completed by laparoscopy with no intraoperative incidents. The mean operative time was 39 minutes (range 29-70 min) and the mean hospital stay was 3.5 days (range 3-16 d). One perigastric hematoma and 2 cases of gastric stenosis were recorded. The mean BMI decreased to 29.2 kg/m(2) (range 20.2-37.5); the mean percentage of excess weight loss (%EWL) was 58.5% (+/-25.3) (P<.0004) for a mean follow-up of 20 months (range 6-56 mo). CONCLUSION: The ReSG may be a valid option for failure of primary LSG. Further prospective clinical trials are required to compare the outcomes of ReSG with those of laparoscopic Roux-en-Y gastric bypass or duodenal switch for weight loss failure after LSG. PMID- 26048520 TI - Effect of sleeve gastrectomy on type 2 diabetes as an alternative to Roux-en-Y gastric bypass: a better long-term strategy. PMID- 26048519 TI - Reduction of surgical site infections after laparoscopic gastric bypass with circular stapled gastrojejunostomy. AB - BACKGROUND: Circular stapled gastrojejunostomy (GJ) is favored by many surgeons during laparoscopic Roux-en-Y gastric bypass (LRYGB). However, it has been associated with higher rates of surgical site infection (SSI). OBJECTIVES: To study the impact of introducing standard technical modifications (intervention) on the incidence of SSI after LRYGB with circular stapled GJ. SETTING: Tertiary academic medical center. METHODS: Consecutive patients who underwent primary LRYGB between May 2010 and September 2014 were separated into preintervention and postintervention cohorts. The intervention consisted of the use of a stapler cover, wound irrigation, antibiotic application to the wound, and primary wound closure. Predictor variables studied included patient demographic characteristics, the intervention, and other operative and perioperative factors. The primary outcome studied was SSI. Univariate and multivariate analyses were used to determine factors independently associated with SSI. RESULTS: Three hundred thirty patients underwent LRYGB (preintervention n = 200, postintervention n = 130). Patients' characteristics were similar in both groups. A 21-mm stapler and chlorhexidine-based skin preparation were more frequently used in the postintervention group. SSI rate decreased from 15% to 3.8% (P<.01) after the intervention. On multivariate analysis, the intervention (OR .28, 95% CI .09-0.86, P = .026), use of chlorhexidine-based prep (OR .37, 95%CI .15-.93, P = .034), and maintenance of patient temperature (OR .47 95%CI .26-0.85, P = .012) were independently associated with reduced SSI rates. CONCLUSION: Use of a stapler cover, wound irrigation, wound antibiotic application, and primary wound closure were associated with a significantly lower wound infection rate after LRYGB with the circular stapled GJ. The observed SSI rates after our intervention are similar to those reported after hand-sewn and linear stapled techniques. In addition, other factors associated with decreasing the likelihood of developing SSI were use of chlorhexidine-based prep and maintaining intraoperative normothermia. PMID- 26048521 TI - Bariatric surgery results: reporting clinical characteristics and adverse outcomes from an integrated healthcare delivery system. AB - BACKGROUND: Limited data have been reported on bariatric surgery within a large, high-volume regional multicenter integrated healthcare delivery system. OBJECTIVES: Review clinical characteristics and short- and intermediate-term outcomes and adverse events from a bariatric surgery program within an integrated healthcare delivery system. SETTING: Single high-volume, multicenter regional integrated healthcare delivery system. METHODS: Adult patients who underwent primary bariatric surgery during 2010-2011 were reviewed. Clinical characteristics, outcomes, and weight loss results were extracted from the electronic medical record. RESULTS: A total of 2399 patients were identified within the study period. The 30-day rates of clinical outcomes for Roux-en-Y gastric bypass (RYGB; n = 1313) and sleeve gastrectomy (SG; n = 1018) were 2.9% for readmission, 3.0% for major complications, .8% for reoperation, and 0% for mortality. One-year and 2-year weight loss results were as follows: percent weight loss (%WL) was 31.4 (+/-SD 8.5) and 34.2+/-12.0% for SG and 34.1+/-9.3 and 39.1+/-11.9 for RYGB; percent excess weight loss (%EBWL) was 64.2+/-18.0 and 69.8+/-23.7 for SG and 68.0+/-19.3 and 77.8+/-23.7 for RYGB; percent excess body mass index loss (%EBMIL) was 72.9+/-21.0 and 77.7+/-22.4 for SG and 76.6+/-22.1% and 85.6+/-21.6 for RYGB. Follow-up for each procedure at 1 year was 76% for SG (n = 778) and 80% for RYGB (n = 1052) and at 2 years was 65% for SG (n = 659) and 67% for RYGB (n = 875). CONCLUSIONS: A large regional high-volume multicenter bariatric program within an integrated healthcare delivery system can produce excellent short-term results with low rates of short- and intermediate-term adverse outcomes. PMID- 26048522 TI - Differences in open versus laparoscopic gastric bypass mortality risk using the Obesity Surgery Mortality Risk Score (OS-MRS). AB - BACKGROUND: The Obesity Surgery Mortality Risk Score (OS-MRS) was developed to ascertain preoperative mortality risk of patients having bariatric surgery. To date there has not been a comparison between open and laparoscopic operations using the OS-MRS. OBJECTIVE: To determine whether there are differences in mortality risk between open and laparoscopic Roux-en-Y Gastric Bypass (RYGB) using the OS-MRS. SETTING: Three university-affiliated hospitals. METHODS: The 90 day mortality of 2467 consecutive patients who had primary open (1574) or laparoscopic (893) RYGB performed by one surgeon was determined. Univariate and multivariate analysis using 5 OS-MRS risk factors including body mass index (BMI) gender, age>45, presence of hypertension and preoperative deep vein thrombosis (DVT) risk was performed in each group. Each patient was placed in 1 of 3 OS-MRS risk classes based on the number of risks: A (0-1), B (2-3), and C (4-5). RESULTS: Preoperative BMI and DVT risk factors were significantly greater in the open group (OG). Preoperative age was significantly greater in the laparoscopic group (LG). There were significantly more class B and C patients in LG. Ninety day mortality rates for OG and LG patients were 1.0% and .9%, respectively. Pulmonary embolism was the most common cause of death. All deaths in LG occurred during first 4 years of that experience. Mortality rate by class was A = .1%; B = 1.5%; C = 2.3%. The difference in mortality between class B and C patients was not significant. Univariate analysis in the OG indicated that BMI, age, gender, and DVT risk were significant predictors of mortality. In the LG only BMI and DVT were significant predictors of death. Presence of hypertension was not a significant predictor in either group. Multivariate analysis excluding hypertension found that age was predictive of mortality in the OG while BMI (P = .057) and gender (P = .065) approached statistical significance. Conversely, only BMI was predictive of mortality in the LG with age approaching significance (P = .058). In multivariate analysis DVT risk was not predictive of mortality in either group. CONCLUSIONS: There are significant differences in the predictive value of the OS-MRS between open and laparoscopic RYGB. Although laparoscopic patients were significantly older versus the open patients, age was not predictive of mortality after laparoscopic RYGB. BMI trended toward increased mortality risk in both groups. Changes in technique and protocol likely contributed toward no mortality during the last 6 years of our laparoscopic experience. PMID- 26048523 TI - The association between sleeve gastrectomy and histopathologic changes consistent with esophagitis in a rodent model. AB - BACKGROUND: As the association between sleeve gastrectomy (SG) and gastroesophageal reflux disease remains unclear, the aim of this study was to evaluate whether performance of SG impacts the development and severity of esophagitis in a rodent model. SETTING: University Hospital. METHODS: Wistar rats (Charles River Institute, Wilmington, MA) were fed a high fat diet (HFD) for 4 months and then were divided into 3 cohorts of nearly equal mean weight: HFD only (n = 25), sham operation+HFD (n = 29), and SG+HFD (n = 19). Animals were euthanized at 12 weeks. The esophagus was harvested en-bloc and processed for histologic assessment by a board certified pathologist, blinded to the animal treatment group. Reflux was graded by severity and defined as the presence of inflammation in the esophageal squamous mucosa. RESULTS: Rats who underwent SG had significantly increased reflux severity, compared with sham and HFD alone (21.1% versus 0% versus 4.5%, P = .02), respectively. No difference was demonstrated in negative, mild, or moderate esophagitis between the control, sham, and sleeve groups. Using nonparametric ANOVA, the mean severity score for severe esophagitis was significantly increased in the SG group versus sham or HFD group (1.5 versus .81 versus 1.36, P = .0202) respectively. Following multinomial logistic regression to assess for confounding variables to the severity scores, final weight, and change in weight, had no effect on severity of esophagitis between the 3 groups (P > .373). CONCLUSIONS: SG is independently associated with histopathologic changes consistent with severe esophagitis in an animal model, likely secondary to gastroesophageal reflux. PMID- 26048524 TI - Bariatric surgery in cancer survivorship: does a history of cancer affect weight loss outcomes? AB - BACKGROUND: Weight loss is recommended for obese cancer survivors who are at increased risk of recurrence and non-cancer-related mortality. It remains unknown if this vulnerable population benefits from bariatric surgery to the same extent as those without a history of cancer. METHODS: A retrospective chart review of 1013 patients identified 29 bariatric surgery patients with a history of cancer who were then matched to patients without a history of cancer. RESULTS: At 1-year postsurgical follow-up, individuals with a history of cancer had lost less weight than those without a history of cancer (14.2 versus 14.8); however, this difference was not significant (P = .76). CONCLUSION: Cancer survivors appear to draw similar benefit from bariatric surgery as those without a history of cancer, although a larger study with greater statistical power to detect differences is needed to confirm these results. These preliminary results are encouraging in light of the increasing focus on weight loss among this population. PMID- 26048525 TI - Spectroscopic study on the interaction of resveratrol and pterostilbene with human serum albumin. AB - The interaction of human serum albumin (HSA) with two stilbene compounds, resveratrol and pterostilbene was investigated using fluorescence, UV-visible absorption, Fourier transform infrared spectroscopic methods and molecular modeling technique. The intrinsic fluorescence of HSA was quenched significantly by resveratrol and pterostilbene. Analysis of fluorescence quenching data of HSA by the two compounds using Stern-Volmer and modified Stern-Volmer methods showed the formation of ground state complexes of HSA with resveratrol and pterostilbene. The binding analysis showed that the binding constant for resveratrol as 4.47*10(6) and 0.299*10(2)M(-1)s(-1) for pterostilbene revealing the high binding affinity of resveratrol to HSA. The conformational changes of HSA were investigated using synchronous fluorescence and Fourier transform infrared spectroscopy. The efficiency of energy transfer and the distance between HSA and resveratrol/pterostilbene were calculated. The binding of resveratrol/pterostilbene was modeled by molecular docking, which is in accordance with the experimental data. PMID- 26048526 TI - Inhibitory effect of silver nanoparticle fabricated urinary catheter on colonization efficiency of Coagulase Negative Staphylococci. AB - Multiple antibiotic resistance and diverse mechanisms for biofilm formation make Coagulase Negative Staphylococci (CoNS) to cause infections associated with insertion of medical devices. As the infectious life style of CoNS pose difficult to treat conditions, materials with multitargeted antimicrobial effect can offer promising ways to modify the surface of devices to limit microbial growth. The broad spectrum of antimicrobial properties shown by silver nanoparticles (AgNPs) make it as an excellent candidate to act on device surface as persistent antimicrobial structures. In the current study, AgNPs assembled by soil bacteria under visible light at room temperature were analysed for its physical properties by UV-Vis spectroscopy, FTIR, SEM, HR-TEM and EDS and they also showed significant antimicrobial and antibiofilm properties against selected members of CoNS like Staphylococcus epidermidis and Staphylococcus haemolyticus. Very interestingly, further analysis on antibacterial mechanism of AgNPs showed their remarkable ability to cause disorganization of bacterial cell membrane. Further, surface engineering application of AgNPs on urinary catheter showed its excellent potential to prevent the attachment and colonization of CoNS which make result of study with significantly novel medical applications. PMID- 26048527 TI - Structural, optical, photoluminescence and antibacterial properties of copper doped silver sulfide nanoparticles. AB - The Ag2S and Cu doped Ag2S nanoparticles were prepared by simple chemical co precipitation method and characterized by XRD, SEM, EDX, TEM, PL and UV-vis spectra. The photocatalytic activity of Ag2S and Cu doped Ag2S nanoparticles were investigated with Ofloxacin antibiotic, which is part of the fluoroquinolone family. The morphological study indicated that the products were spherical shape in with diameter size of 30nm. The photocatalytic results demonstrated that the Cu doping increased the photocatalytic efficiency of Ag2S nanoparticles. The outcome of antibacterial experiment under visible light irradiation indicate that the Cu doped Ag2S nanoparticles represent increased antibacterial performance compared with un-doped Ag2S nanoparticles. PMID- 26048528 TI - A DTI tractography study in pre-readers at risk for dyslexia. AB - In adults and school-aged children, phonological aspects of reading seem to be sustained by left dorsal regions, while ventral regions seem to be involved in orthographic word recognition. Yet, given that the brain reorganises during reading acquisition, it is unknown when and how these reading routes emerge and whether neural deficits in dyslexia predate reading onset. Using diffusion MRI in 36 pre-readers with a family risk for dyslexia (FRD(+)) and 35 well matched pre readers without a family risk (FRD(-)), our results show that phonological predictors of reading are sustained bilaterally by both ventral and dorsal tracts. This suggests that a dorsal and left-hemispheric specialisation for phonological aspects of reading, as observed in adults, is presumably gradually formed throughout reading development. Second, our results indicate that FRD(+) pre-readers display mainly white matter differences in left ventral tracts. This suggests that atypical white matter organisation previously found in dyslexic adults may be causal rather than resulting from a lifetime of reading difficulties, and that the location of such a deficit may vary throughout development. While this study forms an important starting point, longitudinal follow-up of these children will allow further investigation of the dynamics between emerging literacy development and white matter connections. PMID- 26048529 TI - Bystander Action in Situations of Dating and Sexual Aggression: A Mixed Methodological Study of High School Youth. AB - Bystander action is a critical component of dating and sexual aggression prevention; however, little is known about barriers and facilitators of bystander action among high school youth and in what situations youth are willing to engage in bystander action. The current study examined bystander action in situations of dating and sexual aggression using a mixed methodological design. Participants included primarily Caucasian (83.0%, n = 181) male (54.6%, n = 119) and female (44.5%, n = 97) high school youth (N = 218). Most (93.6%) students had the opportunity to take action during the past year in situations of dating or sexual aggression; being female and histories of dating and sexual aggression related to bystander action. Thematic analysis of the focus group data identified barriers (e.g., the aggression not meeting a certain threshold, anticipated negative consequences) to bystander action, as well as insight on promising forms of action (e.g., verbally telling the perpetrator to stop, getting a teacher); problematic intervention methods (e.g., threatening or using physical violence to stop the perpetrator) were also noted. Implications for programming are discussed. PMID- 26048530 TI - Cryptococcosis mimicking lung cancer with brain metastasis. PMID- 26048531 TI - Intraoperative ultrasound in low-grade glioma surgery. PMID- 26048532 TI - Disparities in the Availability and Price of Low-Fat and Higher-Fat Milk in US Food Stores by Community Characteristics. AB - BACKGROUND: National surveillance data identify disparities in low-fat milk consumption by race/ethnicity and income. Some localized studies have shown disparities in access to low-fat milk by community characteristics. OBJECTIVE: Our aim was to assess the availability and price of low-fat and higher-fat milk in food stores throughout the United States and examine associations with community characteristics. DESIGN: We conducted a cross-sectional study involving observational data collection in 2010, 2011, and 2012. PARTICIPANTS/SETTINGS: The study included 8,959 food stores in 468 communities where nationally representative samples of students attending traditional public middle and high schools resided. MAIN OUTCOME MEASURES: We studied the availability and price of whole, 2%, 1%, and skim milk. STATISTICAL ANALYSES PERFORMED: Multivariate logistic regression and ordinary least squares regression analyses were performed. Models included store type, race/ethnicity, median household income, urbanicity, US Census division, and year of data collection. RESULTS: Less than half of all stores carried 1% and skim milk, and more than three-quarters of stores carried whole and 2% milk. Regression results indicated that the odds of carrying any type of milk were 31% to 67% lower in stores in majority black and 26% to 45% lower in other/mixed race compared with majority white communities. The odds of carrying specifically low-fat milk were 50% to 58% lower in majority Hispanic compared with majority white communities, and 32% to 44% lower in low income compared with high-income communities. Some significant differences in milk prices by community characteristics were observed in grocery and limited service stores. On average, low-fat milk options were more expensive in grocery stores in majority black and rural and suburban communities compared with such stores in majority white and urban communities. CONCLUSIONS: This is the first nationwide study to examine the availability and price of low-fat and higher-fat milk in food stores and show disparities in access by community characteristics. Policies and programs can play a role in increasing accessibility of low-fat milk in stores in nonwhite and low-income communities. PMID- 26048533 TI - Are the Recommended Dietary Allowances for Vitamins Appropriate for Elderly People? AB - BACKGROUND: An adequate vitamin intake is essential for a good nutritional status, especially in older women, who are more sensitive to nutritional deficiencies. The American, European and Italian Recommended Dietary Allowances (RDAs) derive mainly from studies on adults, and it is not clear whether they also apply to elderly people. Comparing the RDAs with the actual vitamin intake of a group of healthy older women could help to clarify the real needs of elderly people. OBJECTIVE: Our aim was to compare the American, European, and Italian RDAs with the actual vitamin intake of a group of healthy older women. DESIGN: This was a cross-sectional study. PARTICIPANTS: The study included 286 healthy women aged older than 65 years. MAIN OUTCOME MEASURES: For each micronutrient, the 50th percentile of the distribution of its intake was considered as the average requirement, and the corresponding calculated RDA for our sample was the average requirement*1.2, as recommended by the US Food and Nutrition Board. This calculated RDA was then compared with the American, European, and Italian RDAs. STATISTICAL ANALYSES PERFORMED: Student's t test or the Mann-Whitney test (after checking the normal distribution of the micronutrient) for continuous variables; the chi(2) test for categorical variables. RESULTS: The calculated RDA were 2,230 MUg retinol equivalents for vitamin A, 2.8 MUg for vitamin B-12, 0.9 mg for thiamin, 1.4 mg for riboflavin, 3.6 mg for pantothenic acid, 1.4 mg for vitamin B 6, 320 MUg for folic acid, and 115 mg for vitamin C. CONCLUSIONS: Our findings suggest that the current RDAs are adequate for older women's intake of riboflavin, vitamin B-6, and folic acid, but should be raised for vitamin B-12 and for vitamin C. PMID- 26048534 TI - Over-nutrient environment during both prenatal and postnatal development increases severity of islet injury, hyperglycemia, and metabolic disorders in the offspring. AB - Prenatal and postnatal over-nutrition has emerged as a new health issue contributing to metabolic disorders in early development of the offspring. Accumulating evidence has suggested that adverse prenatal and postnatal environments gave rise to the predisposition to metabolic syndromes including hyperglycemia, obesity, and diabetes. However, little research has concentrated on the effects of exposures to both adverse conditions before and after birth of the offspring. In this study, we aimed to investigate whether prenatal and postnatal over-nutrition is able to cause metabolic disorders to female mice feed on high-fat/fructose diet (HFFD) as well as their offspring. Female mice were fed on either HFFD or a normal chow diet (NC), while their offspring were divided into four experimental groups as NC/NC, HFFD/NC, NC/HFFD, and HFFD/HFFD (prenatal/postnatal diet order), respectively. Both NC/HFFD and HFFD/HFFD offspring exhibited obvious body weight and fat content gain, hyperglycemia, and severe insulin resistance. Interestingly, when compared to NC/HFFD offspring, the HFFD/HFFD offspring exhibited more severe alterations in their metabolism and dysfunctions on pancreatic beta-cells, suggesting a potential impact of prenatal HFFD on the programming of pancreatic beta-cell deficiency in the fetus. Meanwhile, the results from HFFD/NC mice indicated that a balance diet after birth partially compensated the adverse prenatal HFFD impact. In conclusion, this study demonstrated that prenatal and postnatal over-nutrition increases severity of islet injury, hyperglycemia, and metabolic disorders in the offspring. PMID- 26048535 TI - [Vitamin D deficiency in a cohort of patients over 69 years with femoral fracture admitted to an Acute Geriatric Unit of Hospital Igualada]. PMID- 26048537 TI - Emergency department management of falls in the elderly: A clinical audit and suggestions for improvement. AB - INTRODUCTION: Falls are a major source of injury in the elderly and their incomplete management is a cause for concern by health systems. The present study looks at the current state of managing fall victims in Iran and offers suggestions for improvement. METHODS: This was a clinical care audit comparing the state of current care with an institutionally approved optimum. Patients aged 60 years and over presenting with a fall were evaluated and deficiencies in their care were recorded and categorized. These were presented to an expert panel, where the Delphi method was used to come up with a list of actions to address the deficiencies. Furthermore an educational program was implemented based on these suggestions. Chi-squared and t-test were used to evaluate the efficacy of this program in improving treatment. Linear regression analysis was used to find factors affecting care. RESULTS: Overall 431 cases were reviewed. The most common errors during clinical examination were: not performing Romberg test (92.75%) and lack of physiotherapy consultation (82.75%). The educational program had a modest effect on improving the clinical audit processes (beta = 3.79; P < 0.001) and medical interventions (beta = 2.004; P = 0.002); however, performing the correct diagnostic tests was worse after the program (beta = -1.21; P = 0.008). CONCLUSION: There is a wide gap between the care services delivered in the management of falls and international standards. Therefore, measures should be adopted to close this gap. Education may have a modest positive effect in this regard. PMID- 26048536 TI - Growth hormone therapy and risk of recurrence/progression in intracranial tumors: a meta-analysis. AB - Growth hormone deficiency is common in intracranial tumors, which is usually treated with surgery and radiotherapy. A number of previous studies have investigated the relationship between the growth hormone replacement therapy (GHRT) and risk of tumor recurrence/progression; however, the evidence remains controversial. We conducted a meta-analysis of published studies to estimate the potential relation between GHRT and intracranial tumors recurrence/progression. Three comprehensive databases, PUBMED, EMBASE, and Cochrane Library, were researched with no limitations, covering all published studies till the end of July, 2014. Reference lists from identified studies were also screened for additional database. The summary relative risks (RR) and 95% confidence intervals (CI) were calculated by fixed-effects models for estimation. Fifteen eligible studies, involving more than 2232 cases and 3606 controls, were included in our meta-analysis. The results indicated that intracranial tumors recurrence/progression was not associated with GHRT (RR 0.48, 95% CI 0.39-0.56), and for children, the pooled RR was 0.44 and 95% CI was 0.34-0.54. In subgroup analysis, risks of recurrence/progression were decreased for craniopharyngioma, medulloblastoma, astrocytoma, glioma, but not for pituitary adenomas, and non functioning pituitary adenoma (NFPA), ependymoma. Results from our analysis indicate that GHRT decreases the risk of recurrence/progression in children with intracranial tumors, craniopharyngioma, medulloblastoma, astrocytoma, or glioma. However, GHRT for pituitary adenomas, NFPA, and ependymoma was not associated with the recurrence/progression of the tumors. GH replacement seems safe from the aspect of risk of tumor progression. PMID- 26048538 TI - 61st International Congress of Meat Science and Technology. PMID- 26048539 TI - [Mesalamine-induced myocarditis]. PMID- 26048540 TI - [Cystatin C, many answers but some unmet questions]. PMID- 26048541 TI - [Thoughts on use of statins in geriatric patients]. PMID- 26048542 TI - [Medical errors and the apology laws, do we need them?]. PMID- 26048543 TI - [Carotid-cavernous fistula successfully treated with carotid compression]. PMID- 26048544 TI - [Granulomatous reaction in a patient with eyebrows tattoo]. PMID- 26048545 TI - [Therapeutic holidays in osteoporosis: Long-term strategy of treatment with bisphosphonates]. AB - Oral bisphosphonates (BF) are drugs widely used in the treatment of osteoporosis and placed as first-line treatment for osteoporosis in most clinical guidelines. BF are effective drugs that reduce the incidence of fractures and even reduce mortality. Because of their great affinity for bone, BF have shown that even when they are discontinued still offer a latent protective effect on bone mineral density, maintaining their anti-fracture effect. However, prolonged use for years has been linked to the gradual emergence of complications such as osteonecrosis of the jaw or atypical femur fractures, which have raised questions as when to hold and when to make a final or temporary break, recognized as periods of rest or "therapeutic holidays" of these drugs. Thus, in patients treated with BF for a period of 3-5 years with a low risk of fracture, the drug should be discontinued and restarted when there is an indication for treatment. In contrast, in patients with moderate risk, therapeutic holidays are advised, while reassessing after 2-3 years for restarting purposes. Finally, in patients with high risk of fracture, treatment with BF should not be withdrawn. PMID- 26048546 TI - Social-ecological correlates of physical activity in kidney cancer survivors. AB - PURPOSE: Previous studies in cancer survivors have examined behavioral correlates of physical activity (PA), but no study to date has adopted a broader social ecological framework in understanding PA. This study examined the associations among demographic, medical, social-cognitive, and environmental correlates of meeting PA guidelines among kidney cancer survivors (KCS). METHODS: All 1985 KCS diagnosed between 1996 and 2010 identified through a Canadian provincial registry were mailed a survey that consisted of medical, demographic, and social-cognitive measures, as well as PA as measured by the Godin Leisure Time Exercise Questionnaire. Environmental constructs were also assessed for both self-report and objective measures using geographic information systems (GIS). A series of binary logistic regression analyses were conducted in this cross-sectional study. RESULTS: Completed surveys with geographical information were received from 432 KCS with M age = 64.4 +/- 11.1 years, 63.2 % male, and 82.2 % having localized kidney cancer. In the final multivariate model, meeting PA guidelines was associated with disease stage (OR = 0.25, p = .005), having drug therapy (OR = 3.98, p = .009), higher levels of instrumental attitudes (OR = 1.66, p = .053), higher levels of intention (OR = 1.72, p = .002), and the perceived presence of many retail shops in the neighborhood (OR = 1.37, p = .032). CONCLUSIONS: Meeting PA guidelines in KCS were associated with various aspects of the social ecological model. IMPLICATIONS FOR CANCER SURVIVORS: Understanding the social ecological correlates for PA can provide insight into future interventions designed to increase PA in KCS. Prime targets for PA promotion should consider treatment-related factors, promote the benefits of PA, and enhance positive perceptions of the built environment. PMID- 26048547 TI - Longevity Is Linked to Mitochondrial Mutation Rates in Rockfish: A Test Using Poisson Regression. AB - The mitochondrial theory of ageing proposes that the cumulative effect of biochemical damage in mitochondria causes mitochondrial mutations and plays a key role in ageing. Numerous studies have applied comparative approaches to test one of the predictions of the theory: That the rate of mitochondrial mutations is negatively correlated with longevity. Comparative studies face three challenges in detecting correlates of mutation rate: Covariation of mutation rates between species due to ancestry, covariation between life-history traits, and difficulty obtaining accurate estimates of mutation rate. We address these challenges using a novel Poisson regression method to examine the link between mutation rate and lifespan in rockfish (Sebastes). This method has better performance than traditional sister-species comparisons when sister species are too recently diverged to give reliable estimates of mutation rate. Rockfish are an ideal model system: They have long life spans with indeterminate growth and little evidence of senescence, which minimizes the confounding tradeoffs between lifespan and fecundity. We show that lifespan in rockfish is negatively correlated to rate of mitochondrial mutation, but not the rate of nuclear mutation. The life history of rockfish allows us to conclude that this relationship is unlikely to be driven by the tradeoffs between longevity and fecundity, or by the frequency of DNA replications in the germline. Instead, the relationship is compatible with the hypothesis that mutation rates are reduced by selection in long-lived taxa to reduce the chance of mitochondrial damage over its lifespan, consistent with the mitochondrial theory of ageing. PMID- 26048548 TI - Proposal of a Twin Arginine Translocator System-Mediated Constraint against Loss of ATP Synthase Genes from Nonphotosynthetic Plastid Genomes. [Corrected]. AB - Organisms with nonphotosynthetic plastids often retain genomes; their gene contents provide clues as to the functions of these organelles. Yet the functional roles of some retained genes-such as those coding for ATP synthase remain mysterious. In this study, we report the complete plastid genome and transcriptome data of a nonphotosynthetic diatom and propose that its ATP synthase genes may function in ATP hydrolysis to maintain a proton gradient between thylakoids and stroma, required by the twin arginine translocator (Tat) system for translocation of particular proteins into thylakoids. Given the correlated retention of ATP synthase genes and genes for the Tat system in distantly related nonphotosynthetic plastids, we suggest that this Tat-related role for ATP synthase was a key constraint during parallel loss of photosynthesis in multiple independent lineages of algae/plants. PMID- 26048549 TI - Iontronics. AB - Iontronics is an emerging technology based on sophisticated control of ions as signal carriers that bridges solid-state electronics and biological system. It is found in nature, e.g., information transduction and processing of brain in which neurons are dynamically polarized or depolarized by ion transport across cell membranes. It suggests the operating principle of aqueous circuits made of predesigned structures and functional materials that characteristically interact with ions of various charge, mobility, and affinity. Working in aqueous environments, iontronic devices offer profound implications for biocompatible or biodegradable logic circuits for sensing, ecofriendly monitoring, and brain machine interfacing. Furthermore, iontronics based on multi-ionic carriers sheds light on futuristic biomimic information processing. In this review, we overview the historical achievements and the current state of iontronics with regard to theory, fabrication, integration, and applications, concluding with comments on where the technology may advance. PMID- 26048550 TI - Carbon Substrates: A Stable Foundation for Biomolecular Arrays. AB - Since their advent in the early 1990s, microarray technologies have developed into a powerful and ubiquitous platform for biomolecular analysis. Microarrays consist of three major elements: the substrate upon which they are constructed, the chemistry employed to attach biomolecules, and the biomolecules themselves. Although glass substrates and silane-based attachment chemistries are used for the vast majority of current microarray platforms, these materials suffer from severe limitations in stability, due to hydrolysis of both the substrate material itself and of the silyl ether linkages employed for attachment. These limitations in stability compromise assay performance and render impossible many potential microarray applications. We describe here a suite of alternative carbon-based substrates and associated attachment chemistries for microarray fabrication. The substrates themselves, as well as the carbon-carbon bond-based attachment chemistries, offer greatly increased chemical stability, enabling a myriad of novel applications. PMID- 26048551 TI - Single-Molecule Electronics: Chemical and Analytical Perspectives. AB - It is now possible to measure the electrical properties of single molecules using a variety of techniques including scanning probe microcopies and mechanically controlled break junctions. Such measurements can be made across a wide range of environments including ambient conditions, organic liquids, ionic liquids, aqueous solutions, electrolytes, and ultra high vacuum. This has given new insights into charge transport across molecule electrical junctions, and these experimental methods have been complemented with increasingly sophisticated theory. This article reviews progress in single-molecule electronics from a chemical perspective and discusses topics such as the molecule-surface coupling in electrical junctions, chemical control, and supramolecular interactions in junctions and gating charge transport. The article concludes with an outlook regarding chemical analysis based on single-molecule conductance. PMID- 26048553 TI - Electronic Biosensors Based on III-Nitride Semiconductors. AB - We review recent advances of AlGaN/GaN high-electron-mobility transistor (HEMT) based electronic biosensors. We discuss properties and fabrication of III-nitride based biosensors. Because of their superior biocompatibility and aqueous stability, GaN-based devices are ready to be implemented as next-generation biosensors. We review surface properties, cleaning, and passivation as well as different pathways toward functionalization, and critically analyze III-nitride based biosensors demonstrated in the literature, including those detecting DNA, bacteria, cancer antibodies, and toxins. We also discuss the high potential of these biosensors for monitoring living cardiac, fibroblast, and nerve cells. Finally, we report on current developments of covalent chemical functionalization of III-nitride devices. Our review concludes with a short outlook on future challenges and projected implementation directions of GaN-based HEMT biosensors. PMID- 26048554 TI - Late Infection of an Atrial Septal Defect Closure Device: A Possible Complication. AB - Atrial septal defect is a common congenital heart defect. In the late 1990s, percutaneous closure became available and eventually the treatment of choice. The procedure is considered safe because of its low incidence of complications. Infection rate is extremely low and occurs typically early after device implantation. Herein we present a case of late and dramatic infection of an Amplatzer Septal Occluder (St Jude Medical). This case illustrates that infection remains possible a long time after atrial septal defect occlusion despite theoretical device endothelialization. PMID- 26048552 TI - Analytical Aspects of Hydrogen Exchange Mass Spectrometry. AB - This article reviews the analytical aspects of measuring hydrogen exchange by mass spectrometry (HX MS). We describe the nature of analytical selectivity in hydrogen exchange, then review the analytical tools required to accomplish fragmentation, separation, and the mass spectrometry measurements under restrictive exchange quench conditions. In contrast to analytical quantitation that relies on measurements of peak intensity or area, quantitation in HX MS depends on measuring a mass change with respect to an undeuterated or deuterated control, resulting in a value between zero and the maximum amount of deuterium that can be incorporated. Reliable quantitation is a function of experimental fidelity and to achieve high measurement reproducibility, a large number of experimental variables must be controlled during sample preparation and analysis. The method also reports on important qualitative aspects of the sample, including conformational heterogeneity and population dynamics. PMID- 26048555 TI - How do third sector organisations use research and other knowledge? A systematic scoping review. AB - BACKGROUND: Third sector organisations (TSOs) are a well-established component of health care provision in the UK's NHS and other health systems, but little is known about how they use research and other forms of knowledge in their work. There is an emerging body of evidence exploring these issues but there is no review of this literature. This scoping review summarises what is known about how health and social care TSOs use research and other forms of knowledge in their work. METHODS: A systematic search of electronic databases was carried out with initial exploratory searching of knowledge mobilisation websites, contacting authors, and hand searching of journals. The literature was narratively summarised to describe how TSOs use knowledge in decision making. RESULTS: Ten qualitative and mixed methods studies were retrieved. They show that TSOs wish to be "evidence-informed" in their decision making, and organisational context influences the kinds of research and knowledge they prefer, as well as how they use it. Barriers to research use include time, staff skill, resources and the acontextual nature of some academic research. Appropriate approaches to knowledge mobilisation may include using research intermediaries, involving TSOs in research, and better description of interventions and contexts in academic publications to aid applying it in the multi-disciplinary contexts of TSOs. TSOs identified specific benefits of using research, such as confidence that services were good quality, ability to negotiate with stakeholders and funders, and saving time and resources through implementing interventions shown to be effective. The small number of included studies means the findings need further confirmation through primary research. CONCLUSIONS: As the contribution of health and social care TSOs to service delivery is growing, the need to understand how they mobilise research and other forms of knowledge will continue. The research community could 1) develop relationships with TSOs to support the design and development of research projects, 2) use a range of methods to evaluate interventions to facilitate TSOs applying them to their organisational contexts and 3) improve our understanding of how TSOs use knowledge, through the use of complementary research methods, such as a realist review or ethnography. PMID- 26048556 TI - Proteome-scale identification and characterization of mitochondria targeting proteins of Mycobacterium avium subspecies paratuberculosis: Potential virulence factors modulating host mitochondrial function. AB - Mycobacterium avium subsp. paratuberculosis is the etiological agent of Johne's Disease among ruminants. During the course of infection, it expresses a number of proteins for its successful persistence inside the host that cause variety of physiological abnormalities in the host. Mitochondrion is one of the attractive targets for pathogenic bacteria. Employing a proteome-wide sequence and structural signature based approach we have identified 46 M. avium subsp. paratuberculosis proteins as potential targets for the host mitochondrial targeting. These may act as virulence factors modulating mitochondrial physiology for bacterial survival and immune evasion inside the host cells. PMID- 26048557 TI - A protective effect of the laminated layer on Echinococcus granulosus survival dependent on upregulation of host arginase. AB - The role of nitric oxide (NO) in host defense against Echinococcus granulosus larvae was previously reported. However, NO production by NOS2 (inducible NO synthase) is counteracted by the expression of Arginase. In the present study, our aim is to evaluate the involvement of the laminated layer (external layer of parasitic cyst) in Arginase induction and the protoscoleces (living and infective part of the cyst) survival. Our in vitro results indicate that this cystic compound increases the Arginase activity in macrophages. Moreover, C-type lectin receptors (CLRs) with specificity for mannan and the TGF-beta are implicated in this effect as shown after adding Mannan and Anti-TGFbeta. Interestingly, the laminated layer increases protoscoleces survival in macrophages-parasite co cultures. Our results indicate that the laminated layer protects E. granulosus against the NOS2 protective response through Arginase pathway, a hallmark of M2 macrophages. PMID- 26048558 TI - A global map of suitability for coastal Vibrio cholerae under current and future climate conditions. AB - Vibrio cholerae is a globally distributed water-borne pathogen that causes severe diarrheal disease and mortality, with current outbreaks as part of the seventh pandemic. Further understanding of the role of environmental factors in potential pathogen distribution and corresponding V. cholerae disease transmission over time and space is urgently needed to target surveillance of cholera and other climate and water-sensitive diseases. We used an ecological niche model (ENM) to identify environmental variables associated with V. cholerae presence in marine environments, to project a global model of V. cholerae distribution in ocean waters under current and future climate scenarios. We generated an ENM using published reports of V. cholerae in seawater and freely available remotely sensed imagery. Models indicated that factors associated with V. cholerae presence included chlorophyll-a, pH, and sea surface temperature (SST), with chlorophyll-a demonstrating the greatest explanatory power from variables selected for model calibration. We identified specific geographic areas for potential V. cholerae distribution. Coastal Bangladesh, where cholera is endemic, was found to be environmentally similar to coastal areas in Latin America. In a conservative climate change scenario, we observed a predicted increase in areas with environmental conditions suitable for V. cholerae. Findings highlight the potential for vulnerability maps to inform cholera surveillance, early warning systems, and disease prevention and control. PMID- 26048559 TI - Determination of sucrose in date fruits (Phoenix dactylifera L.) growing in the Sultanate of Oman by NIR spectroscopy and multivariate calibration. AB - A Near Infrared (NIR) spectroscopic method combined with multivariate calibration was developed for the determination of the amount of sucrose in date fruits growing in the Sultanate of Oman. In this study two groups of samples were used: one group of 48 sucrose standard solutions in the concentration range from 0.01% to 50% (w/v) and another group of 54 date fruit samples of 18 different varieties. The sucrose standard samples were split in two sets, i.e. one training set of 31 samples and one test set of 17 samples. All samples were measured with a NIR spectrophotometer in the wavelength range from 700 to 2500 nm. The spectra collected were preprocessed using baseline correction and Savitzky-Golay 1st derivative. Partial least-squares regression (PLSR) was used to build the regression model with the training set of 31 samples. This model was then validated by using random leave-one-out cross-validation. Later, the PLS regression model was externally validated by using the test set of 17 samples of known sucrose concentration. The root mean squared error of prediction (RMSEP) was found to be of 1.5%, which shows a good prediction ability of the model. Finally, the PLS model was applied to the spectra of 54 date fruit samples to quantify their sucrose amount. It was found that the Khalas, Barnia Nizwi, Ajwa Almadina, Maan, and Khunizi varieties contain high amounts of sucrose, i.e. ranging from 36% to 60%, while Naghal, Fardh, Nashu and Qash Tabaq varieties contain the least amount of sucrose, ranging from 3.5% to 8.1%. PMID- 26048560 TI - In situ study of water uptake by the seeds, endosperm and husk of barley using infrared spectroscopy. AB - Variations in the amount and rates of water uptake influence the seed hydration as well as the modification of the endosperm for industrial uses (e.g., malting). The aim of this study was to investigate and interpret absorption frequencies in the mid infrared (MIR) region associated with water uptake in whole seeds, husk and endosperm of barley seeds during the initial period of soaking in water. Partial least squares (PLS) regression models for the prediction of water uptake in the set of samples yield a coefficient of determination (R(2)) and a standard error in cross validation of 0.75 and 2.57 (% w/w), respectively. The biological implications of this study are that the first stages of germination can be monitored using the information derived from the MIR spectra. These results also demonstrated that whole seeds, endosperm and husk derived from the same variety or genotype have different patterns in the MIR region. PMID- 26048562 TI - A Search for Parent-of-Origin Effects on Honey Bee Gene Expression. AB - Parent-specific gene expression (PSGE) is little known outside of mammals and plants. PSGE occurs when the expression level of a gene depends on whether an allele was inherited from the mother or the father. Kin selection theory predicts that there should be extensive PSGE in social insects because social insect parents can gain inclusive fitness benefits by silencing parental alleles in female offspring. We searched for evidence of PSGE in honey bees using transcriptomes from reciprocal crosses between European and Africanized strains. We found 46 transcripts with significant parent-of-origin effects on gene expression, many of which overexpressed the maternal allele. Interestingly, we also found a large proportion of genes showing a bias toward maternal alleles in only one of the reciprocal crosses. These results indicate that PSGE may occur in social insects. The nonreciprocal effects could be largely driven by hybrid incompatibility between these strains. Future work will help to determine if these are indeed parent-of-origin effects that can modulate inclusive fitness benefits. PMID- 26048563 TI - CYCLoPs: A Comprehensive Database Constructed from Automated Analysis of Protein Abundance and Subcellular Localization Patterns in Saccharomyces cerevisiae. AB - Changes in protein subcellular localization and abundance are central to biological regulation in eukaryotic cells. Quantitative measures of protein dynamics in vivo are therefore highly useful for elucidating specific regulatory pathways. Using a combinatorial approach of yeast synthetic genetic array technology, high-content screening, and machine learning classifiers, we developed an automated platform to characterize protein localization and abundance patterns from images of log phase cells from the open-reading frame green fluorescent protein collection in the budding yeast, Saccharomyces cerevisiae. For each protein, we produced quantitative profiles of localization scores for 16 subcellular compartments at single-cell resolution to trace proteome-wide relocalization in conditions over time. We generated a collection of ~300,000 micrographs, comprising more than 20 million cells and ~9 billion quantitative measurements. The images depict the localization and abundance dynamics of more than 4000 proteins under two chemical treatments and in a selected mutant background. Here, we describe CYCLoPs (Collection of Yeast Cells Localization Patterns), a web database resource that provides a central platform for housing and analyzing our yeast proteome dynamics datasets at the single cell level. CYCLoPs version 1.0 is available at http://cyclops.ccbr.utoronto.ca. CYCLoPs will provide a valuable resource for the yeast and eukaryotic cell biology communities and will be updated as new experiments become available. PMID- 26048565 TI - Horizontal gene transfer in schistosomes: A critical assessment. AB - Horizontal gene transfer (HGT), the movement of genetic material between distinct evolutionary lineages, has long been known as a principal force of diversification and adaptation of prokaryotes. More recently, genomic and transcriptomic datasets have suggested gene transfers among various eukaryotic taxa (e.g., Porifera, Cnidaria, Nematoda, Arthropoda, Rotifera, Craniata, and Plantae). Although the exact mechanism of eukaryotic HGT is often unknown, host parasite interactions may provide ample opportunities for HGT. Schistosomes are trematode blood parasites with complex life cycles that have been repeatedly implicated in HGT. We employed molecular, bioinformatic and phylogenetic approaches to critically analyze 13 published reports of direct HGTs between schistosomes and their hosts to better understand host-parasite co-evolution. Our research suggests that reported cases of schistosome-associated HGT may be due to technical artifacts as opposed to biological reality as we were unable to substantiate them. HGT clearly occurs in eukaryotic organisms, but the burden of proof is high and we emphasize the importance of multiple lines of evidence to conclusively document HGT. PMID- 26048564 TI - Evidence for a Common Origin of Homomorphic and Heteromorphic Sex Chromosomes in Distinct Spinacia Species. AB - The dioecious genus Spinacia is thought to include two wild relatives (S. turkestanica Ilj. and S. tetrandra Stev.) of cultivated spinach (S. oleracea L.). In this study, nuclear and chloroplast sequences from 21 accessions of Spinacia germplasm and six spinach cultivars or lines were subjected to phylogenetic analysis to define the relationships among the three species. Maximum-likelihood sequence analysis suggested that the Spinacia plant samples could be classified into two monophyletic groups (Group 1 and Group 2): Group 1 consisted of all accessions, cultivars, and lines of S. oleracea L. and S. turkestanica Ilj. and two of five S. tetrandra Stev. accessions, whereas Group 2 was composed of the three remaining S. tetrandra Stev. accessions. By using flow cytometry, we detected a distinct difference in nuclear genome size between the groups. Group 2 also was characterized by a sexual dimorphism in inflorescence structure, which was not observed in Group 1. Interspecific crosses between the groups produced hybrids with drastically reduced pollen fertility and showed that the male is the heterogametic sex (XY) in Group 2, as is the case in S. oleracea L. (Group 1). Cytogenetic and DNA marker analyses suggested that Group 1 and Group 2 have homomorphic and heteromorphic sex chromosome pairs (XY), respectively, and that the sex chromosome pairs of the two groups evolved from a common ancestral pair. Our data suggest that the Spinacia genus may serve as a good model for investigation of evolutionary mechanisms underlying the emergence of heteromorphic sex chromosome pairs from ancestral homomorphic pairs. PMID- 26048561 TI - Identification of Wnt Pathway Target Genes Regulating the Division and Differentiation of Larval Seam Cells and Vulval Precursor Cells in Caenorhabditis elegans. AB - The evolutionarily conserved Wnt/beta-catenin signaling pathway plays a fundamental role during metazoan development, regulating numerous processes including cell fate specification, cell migration, and stem cell renewal. Wnt ligand binding leads to stabilization of the transcriptional effector beta catenin and upregulation of target gene expression to mediate a cellular response. During larval development of the nematode Caenorhabditis elegans, Wnt/beta-catenin pathways act in fate specification of two hypodermal cell types, the ventral vulval precursor cells (VPCs) and the lateral seam cells. Because little is known about targets of the Wnt signaling pathways acting during larval VPC and seam cell differentiation, we sought to identify genes regulated by Wnt signaling in these two hypodermal cell types. We conditionally activated Wnt signaling in larval animals and performed cell type-specific "mRNA tagging" to enrich for VPC and seam cell-specific mRNAs, and then used microarray analysis to examine gene expression compared to control animals. Two hundred thirty-nine genes activated in response to Wnt signaling were identified, and we characterized 50 genes further. The majority of these genes are expressed in seam and/or vulval lineages during normal development, and reduction of function for nine genes caused defects in the proper division, fate specification, fate execution, or differentiation of seam cells and vulval cells. Therefore, the combination of these techniques was successful at identifying potential cell type specific Wnt pathway target genes from a small number of cells and at increasing our knowledge of the specification and behavior of these C. elegans larval hypodermal cells. PMID- 26048566 TI - The role of muscle mass and body fat on disability among older adults: A cross national analysis. AB - BACKGROUND: The aim of this study was to evaluate the association of sarcopenia and sarcopenic obesity with disability among older adults (>=65years old) in nine high-, middle- and low-income countries from Asia, Africa, Europe, and Latin America. METHODS: Data were available for 53,289 people aged >=18years who participated in the Collaborative Research on Ageing in Europe (COURAGE) survey conducted in Finland, Poland, and Spain, and the WHO Study on global AGEing and adult health (SAGE) survey conducted in China, Ghana, India, Mexico, Russia, and South Africa, between 2007 and 2012. Skeletal muscle mass, skeletal muscle mass index, and percent body fat were calculated with specific population formulas. Sarcopenia and sarcopenic obesity were defined by specific cut-offs used in previous studies. Disability was assessed with the WHODAS 2.0 score (range 0-100) with higher scores corresponding to higher levels of disability. Multivariable linear regression analysis was conducted with disability as the outcome. RESULTS: The analytical sample consisted of 18,363 people (males; n=8116, females; n=10247) aged >=65years with mean (SD) age 72.9 (11.1) years. In the fully adjusted overall analysis, sarcopenic obesity was associated with greater levels of disability [b-coefficient 3.01 (95% CI 1.14-4.88)]. In terms of country-wise analyses, sarcopenia was associated with higher WHODAS 2.0 scores in China [b coefficient 4.56 (95% CI: 3.25-5.87)], Poland [b-coefficient 6.66 (95% CI: 2.17 11.14)], Russia [b-coefficient 5.60 (95% CI: 2.03-9.16)], and South Africa [b coefficient 7.75 (95% CI: 1.56-13.94)]. CONCLUSIONS: Prevention of muscle mass decline may contribute to reducing the global burden of disability. PMID- 26048567 TI - Effect of age on mean platelet volume: Does it exist? PMID- 26048568 TI - Different trends in trauma care - The Turkish perspective. PMID- 26048569 TI - [Modification to stapled mucosectomy technique with PPH. Experience of a surgical group]. AB - BACKGROUND: Haemorrhoidal disease is a common disorder. Surgical treatment is indicated in cases of advanced disease. However, postoperative pain, operative time, and technical difficulties have prompted the search for new procedures and improve the existing ones. A modification is proposed to the technique of PPH (Procedure for Prolapse and Haemorrhoids) stapled haemorrhoidectomy that facilitates and standardises the procedure without altering its benefits. OBJECTIVE: To describe the postoperative results and short-term evolution of patients with internal haemorrhoidal disease, who underwent stapled mucosectomy with PPH with a modified technique. MATERIAL AND METHODS: This is a retrospective review of 35 patients who underwent stapled haemorrhoidectomy with a modified technique by the same surgical team. RESULTS: Twenty-five patients were men (71%) and 10 women (29%). Sixteen patients had grade III internal haemorrhoid disease (46%) and 19 grade IV (54%). The mean operative time was 31 minutes. Six patients had acute urinary retention. There were no cases of severe pain, bleeding, haematoma, stenosis, incontinence, thrombosis, or re-operation. The median hospital stay was 1 day. CONCLUSIONS: The proposed modification of PPH haemorrhoidectomy is performed with greater technical ease without increased morbidity, preserving the advantages of the original technique. PMID- 26048570 TI - [Dermoscopy in cutaneous melanoma]. AB - BACKGROUND: The mortality of cutaneous melanoma has not declined over the past 50 years. The only interventions that can reduce mortality are primary prevention and early diagnosis, and the dermoscopic evaluation is essential to achieve this. Dermoscopy identifies characteristics of melanoma that would go unnoticed to the naked eye. The aim of this paper is to report the most frequent dermoscopic findings in patients diagnosed with in situ and invasive melanoma. MATERIAL AND METHODS: An observational and retrospective study of contact dermoscopy was performed using LED DermliteTM and camera DermliteTM dermoscope. The findings evaluated were: asymmetry in two axes, association of colours, lack of pigment, irregular points, atypical network, pseudopods, blue veil, ulceration, and peri lesional pink ring. These dermoscopic findings were compared with the histological diagnosis. RESULTS: The study included 65 patients with cutaneous melanoma; 10 in situ, and 55 invasive. The mean Breslow in invasive melanoma was 3 mm. Most patients (35) had localization in extremities. In all patients, the most frequent dermoscopic finding was asymmetry in two axes, followed by association of two or more colours; in melanoma in situ, asymmetry was the most frequent, followed by atypical-irregular points. In invasive melanoma asymmetry in two axes, the association of two or more colours, and pseudopods, were the most frequent findings. CONCLUSION: Asymmetry in two axes is the most common dermoscopic finding in in situ and invasive melanoma. The presence of two or more colours in a pigmented lesion should be suspected in an invasive melanoma. PMID- 26048571 TI - Specialised lipid mediators and their targets. AB - Inflammation is a complex process governed by the interaction of multiple cell types of the innate immune system and secreted mediators. Such mediators may act in a paracrine or autocrine fashion on target effector cells. An appropriate inflammatory response is characterised by dynamically regulated initiation, propagation and eventual resolution and restoration of tissue homeostasis. Dysregulation of any of these processes may underlie chronic inflammatory conditions such as atherosclerosis, diabetes and arthritis. Our growing understanding of the active processes underlying the resolution of inflammation suggest novel therapeutic paradigms. Here we review specialised lipid mediators and their targets which regulate such innate processes. PMID- 26048572 TI - The LIM-domain only protein 4 contributes to lung epithelial cell proliferation but is not essential for tumor progression. AB - BACKGROUND: The lung is constantly exposed to environmental challenges and must rapidly respond to external insults. Mechanisms involved in the repair of the damaged lung involve expansion of different epithelial cells to repopulate the injured cellular compartment. However, factors regulating cell proliferation following lung injury remain poorly understood. Here we studied the role of the transcriptional regulator Lmo4 during lung development, in the regulation of adult lung epithelial cell proliferation following lung damage and in the context of oncogenic transformation. METHODS: To study the role of Lmo4 in embryonic lung development, lung repair and tumorigenesis, we used conditional knock-out mice to delete Lmo4 in lung epithelial cells from the first stages of lung development. The role of Lmo4 in lung repair was evaluated using two experimental models of lung damage involving chemical and viral injury. The role of Lmo4 in lung tumorigenesis was measured using a mouse model of lung adenocarcinoma in which the oncogenic K-Ras protein has been knocked into the K-Ras locus. Overall survival difference between genotypes was tested by log rank test. Difference between means was tested using one-way ANOVA after assuring that assumptions of normality and equality of variance were satisfied. RESULTS: We found that Lmo4 was not required for normal embryonic lung morphogenesis. In the adult lung, loss of Lmo4 reduced epithelial cell proliferation and delayed repair of the lung following naphthalene or flu-mediated injury, suggesting that Lmo4 participates in the regulation of epithelial cell expansion in response to cellular damage. In the context of K-Ras(G12D)-driven lung tumor formation, Lmo4 loss did not alter overall survival but delayed initiation of lung hyperplasia in K-Ras(G12D) mice sensitized by naphthalene injury. Finally, we evaluated the expression of LMO4 in tissue microarrays of early stage non-small cell lung cancer and observed that LMO4 is more highly expressed in lung squamous cell carcinoma compared to adenocarcinoma. CONCLUSIONS: Together these results show that the transcriptional regulator Lmo4 participates in the regulation of lung epithelial cell proliferation in the context of injury and oncogenic transformation but that Lmo4 depletion is not sufficient to prevent lung repair or tumour formation. PMID- 26048573 TI - Whole genome capture of vector-borne pathogens from mixed DNA samples: a case study of Borrelia burgdorferi. AB - BACKGROUND: Rapid and accurate retrieval of whole genome sequences of human pathogens from disease vectors or animal reservoirs will enable fine-resolution studies of pathogen epidemiological and evolutionary dynamics. However, next generation sequencing technologies have not yet been fully harnessed for the study of vector-borne and zoonotic pathogens, due to the difficulty of obtaining high-quality pathogen sequence data directly from field specimens with a high ratio of host to pathogen DNA. RESULTS: We addressed this challenge by using custom probes for multiplexed hybrid capture to enrich for and sequence 30 Borrelia burgdorferi genomes from field samples of its arthropod vector. Hybrid capture enabled sequencing of nearly the complete genome (~99.5 %) of the Borrelia burgdorferi pathogen with 132-fold coverage, and identification of up to 12,291 single nucleotide polymorphisms per genome. CONCLUSIONS: The proprosed culture-independent method enables efficient whole genome capture and sequencing of pathogens directly from arthropod vectors, thus making population genomic study of vector-borne and zoonotic infectious diseases economically feasible and scalable. Furthermore, given the similarities of invertebrate field specimens to other mixed DNA templates characterized by a high ratio of host to pathogen DNA, we discuss the potential applicabilty of hybrid capture for genomic study across diverse study systems. PMID- 26048574 TI - Difficult intubation and outcome after out-of-hospital cardiac arrest: a registry based analysis. AB - BACKGROUND: Airway management during resuscitation attempts is pivotal for treating hypoxia, and endotracheal intubation is the standard procedure. This German Resuscitation Registry analysis investigates the influence of airway management on primary outcomes after out-of-hospital cardiac arrest, in a physician-based emergency system. METHODS: A total of 8512 patients recorded in the German Resuscitation Registry (2007-2011) were analyzed. The Return of Spontaneous Circulation After Cardiac Arrest (RACA) score was used to compare observed return of spontaneous circulation (ROSC) rates with the ROSC predicted by the score and to analyze factors influencing the primary outcome. Patients were classified into three groups: difficult intubation, impossible intubation, and a control group with normal airways. RESULTS: The observed ROSC matched the predicted ROSC in the group with difficult airways. The impossible intubation group had lower ROSC rates (31.3% vs. 40.5%; P < 0.05). Impossible intubation was more frequent in men (OR 2.28; 95% CI, 1.43-3.63; P = 0.001), young patients (OR 2.18; 95% CI, 1.26-3.76; P = 0.005) and those with trauma (OR 2.22; 95% CI, 1.01 4.85; P = 0.046). Fewer impossible intubations were reported when the emergency physicians were anesthesiologists (OR 0.65; 95% CI, 0.44-0.96; P = 0.028). If a supraglottic airway device was not used in the impossible intubation group, the observed ROSC (18.0%; 95% CI, 7.4-28.6%) was poorer than predicted (38.2%) (P < 0.05). CONCLUSIONS: Outcomes after resuscitation attempts are poorer when endotracheal intubation is not possible. Predictive factors for impossible intubation are male gender, younger age, and trauma. Supraglottic airway devices should be used at an early stage whenever these negative factors are present. PMID- 26048575 TI - Melanoma Induces, and Adenosine Suppresses, CXCR3-Cognate Chemokine Production and T-cell Infiltration of Lungs Bearing Metastatic-like Disease. AB - Despite immunogenicity, melanoma-specific vaccines have demonstrated minimal clinical efficacy in patients with established disease but enhanced survival when administered in the adjuvant setting. Therefore, we hypothesized that organs bearing metastatic-like melanoma may differentially produce T-cell chemotactic proteins over the course of tumor development. Using an established model of metastatic-like melanoma in lungs, we assessed the production of specific cytokines and chemokines over a time course of tumor growth, and we correlated chemokine production with chemokine receptor-specific T-cell infiltration. We observed that the interferon (IFN)-inducible CXCR3-cognate chemokines (CXCL9 and CXCL10) were significantly increased in lungs bearing minimal metastatic lesions, but chemokine production was at or below basal levels in lungs with substantial disease. Chemokine production was correlated with infiltration of the organ compartment by adoptively transferred CD8(+) tumor antigen-specific T cells in a CXCR3- and host IFNgamma-dependent manner. Adenosine signaling in the tumor microenvironment (TME) suppressed chemokine production and T-cell infiltration in the advanced metastatic lesions, and this suppression could be partially reversed by administration of the adenosine receptor antagonist aminophylline. Collectively, our data demonstrate that CXCR3-cognate ligand expression is required for efficient T-cell access of tumor-infiltrated lungs, and these ligands are expressed in a temporally restricted pattern that is governed, in part, by adenosine. Therefore, pharmacologic modulation of adenosine activity in the TME could impart therapeutic efficacy to immunogenic but clinically ineffective vaccine platforms. PMID- 26048576 TI - A Paracrine Role for IL6 in Prostate Cancer Patients: Lack of Production by Primary or Metastatic Tumor Cells. AB - Correlative human studies suggest that the pleiotropic cytokine IL6 contributes to the development and/or progression of prostate cancer. However, the source of IL6 production in the prostate microenvironment in patients has yet to be determined. The cellular origin of IL6 in primary and metastatic prostate cancer was examined in formalin-fixed, paraffin-embedded tissues using a highly sensitive and specific chromogenic in situ hybridization (CISH) assay that underwent extensive analytical validation. Quantitative RT-PCR showed that benign prostate tissues often had higher expression of IL6 mRNA than matched tumor specimens. CISH analysis further indicated that both primary and metastatic prostate adenocarcinoma cells do not express IL6 mRNA. IL6 expression was highly heterogeneous across specimens and was nearly exclusively restricted to the prostate stromal compartment--including endothelial cells and macrophages, among other cell types. The number of IL6-expressing cells correlated positively with the presence of acute inflammation. In metastatic disease, tumor cells were negative in all lesions examined, and IL6 expression was restricted to endothelial cells within the vasculature of bone metastases. Finally, IL6 was not detected in any cells in soft tissue metastases. These data suggest that, in prostate cancer patients, paracrine rather than autocrine IL6 production is likely associated with any role for the cytokine in disease progression. PMID- 26048577 TI - Exome Sequencing to Predict Neoantigens in Melanoma. AB - The ability to use circulating peripheral blood cells and matched tumor sequencing data as a basis for neoantigen prediction has exciting possibilities for application in the personalized treatment of cancer patients. We have used a high-throughput screening approach, combining whole-exome sequence data, mRNA microarrays, and publicly available epitope prediction algorithm output to identify mutated proteins processed and displayed by patient tumors and recognized by circulating immune cells. Matched autologous melanoma cell lines and peripheral blood mononuclear cells were used to create mixed lymphocyte tumor cell cultures, resulting in an expansion of tumor-reactive T cells to use for mutated peptide screening. Five patients were investigated, three of whom had a durable complete response (CR; 15+ years) in an autologous melanoma-pulsed dendritic cell clinical trial. We identified seven mutated antigens in total that stimulated T-effector memory cells in two of the five patients. While the procedure did not result in clinically applicable neoantigens for all patients, those identified were likely important in tumor clearance, leading to durable CR. The nature of the screening process allows results to be obtained rapidly and is easily applicable to a wide variety of different tumor types. PMID- 26048578 TI - Systemic inflammation and microglial activation: systematic review of animal experiments. AB - BACKGROUND: Animal studies show that peripheral inflammatory stimuli may activate microglial cells in the brain implicating an important role for microglia in sepsis-associated delirium. We systematically reviewed animal experiments related to the effects of systemic inflammation on the microglial and inflammatory response in the brain. METHODS: We searched PubMed between January 1, 1950 and December 1, 2013 and Embase between January 1, 1988 and December 1, 2013 for animal studies on the influence of peripheral inflammatory stimuli on microglia and the brain. Identified studies were systematically scored on methodological quality. Two investigators extracted independently data on animal species, gender, age, and genetic background; number of animals; infectious stimulus; microglial cells; and other inflammatory parameters in the brain, including methods, time points after inoculation, and brain regions. RESULTS: Fifty-one studies were identified of which the majority was performed in mice (n = 30) or in rats (n = 19). Lipopolysaccharide (LPS) (dose ranging between 0.33 and 200 mg/kg) was used as a peripheral infectious stimulus in 39 studies (76 %), and live or heat-killed pathogens were used in 12 studies (24 %). Information about animal characteristics such as species, strain, sex, age, and weight were defined in 41 studies (80 %), and complete methods of the disease model were described in 35 studies (68 %). Studies were also heterogeneous with respect to methods used to assess microglial activation; markers used mostly were the ionized calcium binding adaptor molecule-1 (Iba-1), cluster of differentiation 68 (CD68), and CD11b. After LPS challenge microglial activation was seen 6 h after challenge and remained present for at least 3 days. Live Escherichia coli resulted in microglial activation after 2 days, and heat-killed bacteria after 2 weeks. Concomitant with microglial response, inflammatory parameters in the brain were reviewed in 23 of 51 studies (45 %). Microglial activation was associated with an increase in Toll-like receptor (TLR-2 and TLR-4), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 beta (IL-1beta) messenger ribonucleic acid (mRNA) expression or protein levels. INTERPRETATION: Animal experiments robustly showed that peripheral inflammatory stimuli cause microglial activation. We observed distinct differences in microglial activation between systemic stimulation with (supranatural doses) LPS and live or heat-killed bacteria. PMID- 26048579 TI - Pneumococcal polysaccharide vaccination in adults undergoing immunosuppressive treatment for inflammatory diseases--a longitudinal study. AB - INTRODUCTION: Patients undergoing immunosuppressive therapy are at increased risk of infection. Community-acquired pneumonia and invasive pneumococcal disease account for substantial morbidity and mortality in this population and may be prevented by vaccination. Ideally, immunization to pneumococcal antigens should take place before the start of immunosuppressive treatment. Often, however, the treatment cannot be delayed. Little is known about the efficacy of pneumococcal vaccines during immunosuppressive treatment. The objectives of this study were to determine the percentage of vaccine-naive, immunosuppressed adults with inflammatory diseases seroprotected against Streptococcus pneumoniae and to assess factors associated with the immunogenicity, clinical impact and safety of 23-valent pneumococcal polysaccharide vaccine (PPV) in seronegative subjects. METHODS: This observational study included patients 18 years of age and older who were receiving prednisone >=20 mg/day or other immunosuppressive drugs. Exclusion criteria were PPV administration in the previous 5 years, intravenous immunoglobulins and pregnancy. Serum immunoglobulin G (IgG) antibody levels against six pneumococcal serotypes were measured. Seropositivity was defined as IgG of 0.5 MUg/ml or greater for at least four of six serotypes. Seronegative patients received PPV, and seropositive patients were included as a comparison group. Vaccine response and tolerance were assessed after 4-8 weeks. Disease activity was evaluated on the basis of the Physician Global Assessment scores. Serology was repeated after 1 year, and information on any kind of infection needing medical attention was collected. Outcomes were the proportion of seropositivity and infections between vaccinated and unvaccinated patients. RESULTS: Of 201 included patients, 35 received high-dose corticosteroids and 181 were given immunosuppressive drugs. Baseline seronegativity in 60 (30%) patients was associated with corticotherapy and lower total IgG. After PPV, disease activity remained unchanged or decreased in 81% of patients, and 87% became seropositive. After 1 year, 67% of vaccinated compared with 90% of observed patients were seropositive (p < 0.001), whereas the rate of infections did not differ between groups. Those still taking prednisone >=10 mg/day tended to have poorer serological responses and had significantly more infections. CONCLUSIONS: PPV was safe and moderately effective based on serological response. Seropositivity to pneumococcal antigens significantly reduced the risk of infections. Sustained high-dose corticosteroids were associated with poor vaccine response and more infections. PMID- 26048580 TI - High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial. AB - Previous randomized, placebo-controlled trials (RCTs) assessing the efficacy of the selective gamma-aminobutyric acid (GABA)-B receptor agonist baclofen in the treatment of alcohol dependence have reported divergent results, possibly related to the low to medium dosages of baclofen used in these studies (30-80mg/d). Based on preclinical observations of a dose-dependent effect and positive case reports in alcohol-dependent patients, the present RCT aimed to assess the efficacy and safety of individually titrated high-dose baclofen for the treatment of alcohol dependence. Out of 93 alcohol-dependent patients initially screened, 56 were randomly assigned to a double-blind treatment with individually titrated baclofen or placebo using dosages of 30-270mg/d. The multiple primary outcome measures were (1) total abstinence and (2) cumulative abstinence duration during a 12-week high-dose phase. More patients of the baclofen group maintained total abstinence during the high-dose phase than those receiving placebo (15/22, 68.2% vs. 5/21, 23.8%, p=0.014). Cumulative abstinence duration was significantly higher in patients given baclofen compared to patients of the placebo group (mean 67.8 (SD 30) vs. 51.8 (SD 29.6) days, p=0.047). No drug-related serious adverse events were observed during the trial. Individually titrated high-dose baclofen effectively supported alcohol-dependent patients in maintaining alcohol abstinence and showed a high tolerability, even in the event of relapse. These results provide further evidence for the potential of baclofen, thereby possibly extending the current pharmacological treatment options in alcohol dependence. PMID- 26048581 TI - Effective Strategies to Recruit Young Adults Into the TXT2BFiT mHealth Randomized Controlled Trial for Weight Gain Prevention. AB - BACKGROUND: Younger adults are difficult to engage in preventive health, yet in Australia they are gaining more weight and increasing in waist circumference faster than middle-to-older adults. A further challenge to engaging 18- to 35 year-olds in interventions is the limited reporting of outcomes of recruitment strategies. OBJECTIVE: This paper describes the outcomes of strategies used to recruit young adults to a randomized controlled trial (RCT), healthy lifestyle mHealth program, TXT2BFiT, for prevention of weight gain. The progression from enquiry through eligibility check to randomization into the trial and the costs of recruitment strategies are reported. Factors associated with nonparticipation are explored. METHODS: Participants were recruited either via letters of invitation from general practitioners (GPs) or via electronic or print advertisements, including Facebook and Google-social media and advertising university electronic newsletters, printed posters, mailbox drops, and newspapers. Participants recruited from GP invitation letters had an appointment booked with their GP for eligibility screening. Those recruited from other methods were sent an information pack to seek approval to participate from their own GP. The total number and source of enquiries were categorized according to eligibility and subsequent completion of steps to enrolment. Cost data and details of recruitment strategies were recorded. RESULTS: From 1181 enquiries in total from all strategies, 250 (21.17%) participants were randomized. A total of 5311 invitation letters were sent from 12 GP practices-16 participating GPs. A total of 131 patients enquired with 68 participants randomized (68/74 of those eligible, 92%). The other recruitment methods yielded the remaining 182 randomized participants. Enrolment from print media was 26% of enquiries, from electronic media was 20%, and from other methods was 3%. Across all strategies the average cost of recruitment was Australian Dollar (AUD) $139 per person. The least expensive modality was electronic (AUD $37), largely due to a free feature story on one university Web home page, despite Facebook advertising costing AUD $945 per enrolment. The most expensive was print media at AUD $213 and GP letters at AUD $145 per enrolment. CONCLUSIONS: The research indicated that free electronic media was the most cost-effective strategy, with GP letters the least expensive of the paid strategies in comparison to the other strategies. This study is an important contribution for future research into efficacy, translation, and implementation of cost-effective programs for the prevention of weight gain in young adults. Procedural frameworks for recruitment protocols are required, along with systematic reporting of recruitment strategies to reduce unnecessary expenditure and allow for valuable public health prevention programs to go beyond the research setting. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12612000924853; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=362872 (Archived by WebCite at http://www.webcitation.org/6YpNfv1gI). PMID- 26048582 TI - Expanding the chemical space of polyketides through structure-guided mutagenesis of Vitis vinifera stilbene synthase. AB - Several natural polyketides (PKs) have been associated with important pharmaceutical properties. Type III polyketide synthases (PKS) that generate aromatic PK polyketides have been studied extensively for their substrate promiscuity and product diversity. Stilbene synthase-like (STS) enzymes are unique in the type III PKS class as they possess a hydrogen bonding network, furnishing them with thioesterase-like properties, resulting in aldol condensation of the polyketide intermediates formed. Chalcone synthases (CHS) in contrast, lack this hydrogen-bonding network, resulting primarily in the Claisen condensation of the polyketide intermediates formed. We have attempted to expand the chemical space of this interesting class of compounds generated by creating structure-guided mutants of Vitis vinifera STS. Further, we have utilized a previously established workflow to quickly compare the wild-type reaction products to those generated by the mutants and identify novel PKs formed by using XCMS analysis of LC-MS and LC-MS/MS data. Based on this approach, we were able to generate 15 previously unreported PK molecules by exploring the substrate promiscuity of the wild-type enzyme and all mutants using unnatural substrates. These structures were specific to STSs and cannot be formed by their closely related CHS-like counterparts. PMID- 26048583 TI - Physical constraint as psychological holding: Mental-health treatment for difficult and violent adolescents in France. AB - The phrase "Contraindre est therapeutique"--constraining is therapeutic- underpins the principle of numerous interventions within the field of mental health in France, ranging from traditional psychiatric units to the courthouse to violence management and prevention of dangerousness. The treatment of violence in "difficult and violent adolescents" provides a paradigmatic and revealing example of this tendency. The aim of this article is to understand how the clinical category--contenir, or "to contain"--was formed and is used. The perspective taken is that of the political anthropology of mental health and the article combines a genealogical approach of the notion with a multisite ethnographical study (conducted between September 2008 and June 2012 in three facilities for adolescent care). This study will show how "psychological holding" is used to justify "physical constraint" in the treatment of adolescent crisis and violence. Furthermore, we will see how this "dirty work", delegated to front-line professionals (educators, social workers, nurses), is used within a moral economy of suffering that promotes care and control measures in a population largely from immigrant backgrounds, judged to be both potentially vulnerable and dangerous. PMID- 26048584 TI - Lung inflammation biomarkers and lung function in children chronically exposed to arsenic. AB - Evidence suggests that exposure to arsenic in drinking water during early childhood or in utero has been associated with an increase in respiratory symptoms or diseases in the adulthood, however only a few studies have been carried out during those sensitive windows of exposure. Recently our group demonstrated that the exposure to arsenic during early childhood or in utero in children was associated with impairment in the lung function and suggested that this adverse effect could be due to a chronic inflammation response to the metalloid. Therefore, we designed this cross-sectional study in a cohort of children associating lung inflammatory biomarkers and lung function with urinary As levels. A total of 275 healthy children were partitioned into four study groups according with their arsenic urinary levels. Inflammation biomarkers were measured in sputum by ELISA and the lung function was evaluated by spirometry. Fifty eight percent of the studied children were found to have a restrictive spirometric pattern. In the two highest exposed groups, the soluble receptor for advanced glycation end products' (sRAGE) sputum level was significantly lower and matrix metalloproteinase-9 (MMP-9) concentration was higher. When the biomarkers were correlated to the urinary arsenic species, negative associations were found between dimethylarsinic (DMA), monomethylarsonic percentage (%MMA) and dimethylarsinic percentage (%DMA) with sRAGE and positive associations between %DMA with MMP-9 and with the MMP-9/tissue inhibitor of metalloproteinase (TIMP-1) ratio. In conclusion, chronic arsenic exposure of children negatively correlates with sRAGE, and positively correlated with MMP-9 and MMP-9/TIMP-1 levels, and increases the frequency of an abnormal spirometric pattern. Arsenic-induced alterations in inflammatory biomarkers may contribute to the development of restrictive lung diseases. PMID- 26048585 TI - Safety evaluation of intravenously administered mono-thioated aptamer against E selectin in mice. AB - The medical applications of aptamers have recently emerged. We developed an antagonistic thioaptamer (ESTA) against E-selectin. Previously, we showed that a single injection of ESTA at a dose of 100MUg inhibits breast cancer metastasis in mice through the functional blockade of E-selectin. In the present study, we evaluated the safety of different doses of intravenously administered ESTA in single-dose acute and repeat-dose subacute studies in ICR mice. Our data indicated that intravenous administration of up to 500MUg ESTA did not result in hematologic abnormality in either study. Additionally, intravenous injection of ESTA did not affect the levels of plasma cytokines (IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, GM-CSF, IFN-gamma, and TNF-alpha) or complement split products (C3a and C5a) in either study. However, repeated injections of ESTA slightly increased plasma ALT and AST activities, in accordance with the appearance of small necrotic areas in the liver. In conclusion, our data demonstrated that intravenous administration of ESTA does not cause overt hematologic, organs, and immunologic responses under the experimental conditions. PMID- 26048586 TI - Risk of death from cardiovascular disease associated with low-level arsenic exposure among long-term smokers in a US population-based study. AB - High levels of arsenic exposure have been associated with increases in cardiovascular disease risk. However, studies of arsenic's effects at lower exposure levels are limited and few prospective studies exist in the United States using long-term arsenic exposure biomarkers. We conducted a prospective analysis of the association between toenail arsenic and cardiovascular disease mortality using longitudinal data collected on 3939 participants in the New Hampshire Skin Cancer Study. Using Cox proportional hazard models adjusted for potential confounders, we estimated hazard ratios and 95% confidence intervals associated with the risk of death from any cardiovascular disease, ischemic heart disease, and stroke, in relation to natural-log transformed toenail arsenic concentrations. In this US population, although we observed no overall association, arsenic exposure measured from toenail clipping samples was related to an increased risk of ischemic heart disease mortality among long-term smokers (as reported at baseline), with increased hazard ratios among individuals with >= 31 total smoking years (HR: 1.52, 95% CI: 1.02, 2.27), >= 30 pack-years (HR: 1.66, 95% CI: 1.12, 2.45), and among current smokers (HR: 1.69, 95% CI: 1.04, 2.75). These results are consistent with evidence from more highly exposed populations suggesting a synergistic relationship between arsenic exposure and smoking on health outcomes and support a role for lower-level arsenic exposure in ischemic heart disease mortality. PMID- 26048587 TI - Seasonal concentrations, contamination levels, and health risk assessment of arsenic and heavy metals in the suspended particulate matter from an urban household environment in a metropolitan city, Beijing, China. AB - The levels and health risks of arsenic and heavy metals (As, Ba, Cd, Co, Cr, Cu, Mn, Ni, Pb, and Zn) in the suspended particulate matter (SPM) collected from an urban household environment in Beijing of China for 12 months were investigated. The mean concentrations of the studied toxic elements were higher and lower than crustal abundance and PM2.5 in the urban outdoors of Beijing. The concentrations of the studied elements displayed significant seasonality. The highest concentrations of the total elements occurred in winter, followed by autumn, while the lowest concentrations were recorded in summer. Based on the calculated values of enrichment factor (EF) and geoaccumulation index (Igeo), the levels for As and Cu were heavily contaminated, while those for Cd, Pb, and Zn were extremely contaminated. As and Pb might pose risks to children and adults via ingestion exposure. The accumulative risks of multi-elements resulted from dermal contact and inhalation exposures were not negligible. More attention should be paid to reducing the non-carcinogenic and carcinogenic health risks posed by the toxic elements bound to urban household SPM particles via ingestion, inhalation, and dermal contact exposure. PMID- 26048588 TI - Anatomic Feasibility Study of Posterior Arthroscopic Tibiotalar Arthrodesis. AB - BACKGROUND: Operative indications for an anterior arthroscopic tibiotalar arthrodesis are well defined. A posterior approach with the patient in a prone position may be indicated when the anterior approach is precluded by the soft tissue condition or for a 1-step procedure associated with posterior approach subtalar fusion. METHODS: An anatomic study assessed the feasibility of posterior arthroscopic tibiotalar fusion and sought to determine arthroscopy entry points, mortise cartilage freshening quality, and the risk of osseous, tendinous, vascular, and neural complications. Twenty-two zones of the fibular tibiotalar mortise were mapped from 10 specimens. Medial and lateral para-Achilles arthroscopic portals were used with a 4 mm 30-degree arthroscope. Chondral resection was performed with a motorized burr, curette, and osteotome. RESULTS: The entire plafond of the tibia could be debrided in all cases, whereas the talar dome was debrided in its entirety in 20% of cases; in 80%, only the posterior two thirds could be treated with the anterior portion approaching the neck of the talus being poorly accessible. More than 50% of the area of the malleolar grooves was debrided. There was 1 medial malleolar fracture and 1 peroneal artery lesion. CONCLUSION: The technique was shown to be feasible if there was no frontal hindfoot deformity or tibiotalar equinus preventing satisfactory resection of the posterior and anterior talar cartilage. CLINICAL RELEVANCE: This study demonstrated that a posterior approach arthroscopic ankle fusion would lead to adequate joint preparation. This procedure reduces the risk of nerve damage. PMID- 26048589 TI - The ultrastructure of mono- and holocentric plant centromeres: an immunological investigation by structured illumination microscopy and scanning electron microscopy. AB - The spatial distribution of the three centromere-associated proteins alpha tubulin, CENH3, and phosphorylated histone H2A (at threonine 120, H2AThr120ph) was analysed by indirect immunodetection at monocentric cereal chromosomes and at the holocentric chromosomes of Luzula elegans by super-resolution light microscopy and scanning electron microscopy (SEM). Using structured illumination microscopy (SIM) as the super-resolution technique on squashed specimens and SEM on uncoated isolated specimens, the three-dimensional (3D) distribution of the proteins was visualized at the centromeres. Technical aspects of 3D SEM are explained in detail. We show that CENH3 forms curved "pads" mainly around the lateral centromeric region in the primary constriction of metacentric chromosomes. H2AThr120ph is present in both the primary constriction and in the pericentromere. alpha-tubulin-labeled microtubule bundles attach to CENH3 containing chromatin structures, either in single bundles with a V-shaped attachment to the centromere or in split bundles to bordering pericentromeric flanks. In holocentric L. elegans chromosomes, H2AThr120ph is located predominantly in the centromeric groove of each chromatid as proven by subsequent FIB/FESEM ablation and 3D reconstruction. alpha-tubulin localizes to the edges of the groove. In both holocentric and monocentric chromosomes, no additional intermediate structures between microtubules and the centromere were observed. We established models of the distribution of CENH3, H2AThr120ph and the attachment sites of microtubules for metacentric and holocentric plant chromosomes. PMID- 26048590 TI - Giant primary mediastinal liposarcoma: A rare cause of atrial flutter. AB - We report the case of a 68-year-old man who presented with atrial flutter and was observed radiologically to have a large mass in the posterior mediastinum. During surgical removal, spontaneous recovery of sinus rhythm occurred. There was no late recurrence of arrhythmia. The diagnosis was mediastinal liposarcoma of mixed type (extremely rare). Supraventricular arrhythmia associated with mediastinal tumors is exceptional. Surgery appears to be the only potentially curative treatment for these tumors. In cases like ours presenting with arrhythmia, surgery is considered essential for control of the arrhythmia. PMID- 26048591 TI - Adenocarcinoma in pulmonary sequestration: A case report and literature review. AB - A 67-year-old male smoker presented with hemoptysis. Chest computed tomography showed an emphysematous cyst and air-fluid levels in the left lower lobe of the lung. A lobectomy was performed. Intraoperatively, the lesion was found to be an intralobar sequestration. Histopathology showed adenocarcinoma within the sequestrated lobe. This case suggests the need for criteria for a thorough diagnostic work-up in patients diagnosed with pulmonary sequestration, to rule out carcinoma as a distinct clinicopathological entity. PMID- 26048592 TI - Giant cavernous hemangioma of rib: A rare presentation. PMID- 26048594 TI - Commentary: Estimating the undeniable, not denying the immeasurable. PMID- 26048593 TI - Lessons from mouse chimaera experiments with a reiterated transgene marker: revised marker criteria and a review of chimaera markers. AB - Recent reports of a new generation of ubiquitous transgenic chimaera markers prompted us to consider the criteria used to evaluate new chimaera markers and develop more objective assessment methods. To investigate this experimentally we used several series of fetal and adult chimaeras, carrying an older, multi-copy transgenic marker. We used two additional independent markers and objective, quantitative criteria for cell selection and cell mixing to investigate quantitative and spatial aspects of developmental neutrality. We also suggest how the quantitative analysis we used could be simplified for future use with other markers. As a result, we recommend a five-step procedure for investigators to evaluate new chimaera markers based partly on criteria proposed previously but with a greater emphasis on examining the developmental neutrality of prospective new markers. These five steps comprise (1) review of published information, (2) evaluation of marker detection, (3) genetic crosses to check for effects on viability and growth, (4) comparisons of chimaeras with and without the marker and (5) analysis of chimaeras with both cell populations labelled. Finally, we review a number of different chimaera markers and evaluate them using the extended set of criteria. These comparisons indicate that, although the new generation of ubiquitous fluorescent markers are the best of those currently available and fulfil most of the criteria required of a chimaera marker, further work is required to determine whether they are developmentally neutral. PMID- 26048595 TI - Coagulation parameters and platelet function analysis in patients with acromegaly. AB - OBJECTIVE: Acromegaly is associated with increased cardiovascular morbidity and mortality. The data about the evaluation of coagulation and fibrinolysis in acromegalic patients are very limited and to our knowledge, platelet function analysis has never been investigated. So, we aimed to investigate the levels of protein C, protein S, fibrinogen, antithrombin 3 and platelet function analysis in patients with acromegaly. METHODS: Thirty-nine patients with active acromegaly and 35 healthy subjects were included in the study. Plasma glucose and lipid profile, fibrinogen levels, GH and IGF-1 levels and protein C, protein S and antithrombin III activities were measured in all study subjects. Also, platelet function analysis was evaluated with collagen/ADP and collagen-epinephrine closure times. RESULTS: Demographic characteristics of the patient and the control were similar. As expected, fasting blood glucose levels and serum GH and IGF-1 levels were significantly higher in the patient group compared with the control group (pglc: 0.002, pGH: 0.006, pIGF-1: 0.001, respectively). But lipid parameters were similar between the two groups. While serum fibrinogen and antithrombin III levels were found to be significantly higher in acromegaly group (p fibrinogen: 0.005 and pantithrombin III: 0.001), protein S and protein C activity values were significantly lower in the patient group (p protein S: 0.001, p protein C: 0.001). Also significantly enhanced platelet function (measured by collagen/ADP- and collagen/epinephrine-closure times) was demonstrated in acromegaly (p col-ADP: 0.002, p col-epinephrine: 0.002). The results did not change, when we excluded six patients with type 2 diabetes in the acromegaly group. There was a negative correlation between serum GH levels and protein S (r: -0.25, p: 0.04)) and protein C (r: -0.26, p: 0.04) values. Likewise, there was a negative correlation between IGF-1 levels and protein C values (r: -0.39, p: 0.002), protein S values (r: -0.39, p: 0.001), collagen/ADP closure times (r: -0.28, p: 0.02) and collagen/epinephrine-closure times (r: 0.26, p: 0.04). Also, we observed a positive correlation between IGF-1 levels and fibrinogen levels (r: 0.31, p: 0.01). CONCLUSION: Acromegaly was found to be associated with increased tendency to coagulation and enhanced platelet activity. This hypercoagulable state might increase the risk for cardiovascular and cerebrovascular events in acromegaly. PMID- 26048596 TI - Parathyroid hormone response to two levels of vitamin D deficiency is associated with high risk of medical problems during hospitalization in patients with hip fracture. AB - BACKGROUND: Vitamin D and the parathyroid hormone (PTH) response play an important role in hip fracture patients. This study was carried out to determine the factors associated with the PTH response to different levels of vitamin D deficiency during hospitalization. METHODS: This was a cross-sectional study of patients over 64 years of age admitted with an acute fragility hip fracture between March 1st 2009 and November 30th 2012. Demographic, clinical, functional, and cognitive function were evaluated at admission and during hospitalization. Levels of 25-hydroxyvitamin D (25-OHD) and PTH were analyzed. Two 25-OHD cut-off points were considered, <12 ng/ml and 12-20 ng/ml. Multivariate logistic regression analysis was used. RESULTS: Mean age of the 607 patients included was 84.7 years (SD 7.10), and 81.9 % were women. The mean 25-OHD level in the total sample was 13.2 (SD 11.1) ng/ml. Levels of 25-OHD <12 ng/ml were present in 347 patients (57.2 %), of whom 158 (45.5 %) had secondary hyperparathyroidism (SHPT) (PTH >65 pg/ml). 25-OHD levels of 12-20 ng/ml were present in 168 (27.7 %) patients, of whom 47 (28 %) had SHPT. Following logistic regression, SHPT was associated in both groups (25-OHD <12 and 12-20 ng/ml) with a greater number of medical problems during hospitalization. In the 25-OHD group <12 ng/ml, SHPT was also associated with poorer glomerular filtration rates. CONCLUSION: The PTH response to vitamin D deficiency in hip fracture patients may be a marker for patients with higher risk of developing multiple medical problems, both when considering severe (<12 ng/ml) and moderate (12-20 ng/ml) vitamin D deficiency. PMID- 26048597 TI - Endocrinology and art. Maddalena Ventura: an impressive case of hirsutism in a painting of Jusepe De Ribera (1631). PMID- 26048598 TI - CCLasso: correlation inference for compositional data through Lasso. AB - MOTIVATION: Direct analysis of microbial communities in the environment and human body has become more convenient and reliable owing to the advancements of high throughput sequencing techniques for 16S rRNA gene profiling. Inferring the correlation relationship among members of microbial communities is of fundamental importance for genomic survey study. Traditional Pearson correlation analysis treating the observed data as absolute abundances of the microbes may lead to spurious results because the data only represent relative abundances. Special care and appropriate methods are required prior to correlation analysis for these compositional data. RESULTS: In this article, we first discuss the correlation definition of latent variables for compositional data. We then propose a novel method called CCLasso based on least squares with [Formula: see text] penalty to infer the correlation network for latent variables of compositional data from metagenomic data. An effective alternating direction algorithm from augmented Lagrangian method is used to solve the optimization problem. The simulation results show that CCLasso outperforms existing methods, e.g. SparCC, in edge recovery for compositional data. It also compares well with SparCC in estimating correlation network of microbe species from the Human Microbiome Project. AVAILABILITY AND IMPLEMENTATION: CCLasso is open source and freely available from https://github.com/huayingfang/CCLasso under GNU LGPL v3. CONTACT: dengmh@pku.edu.cn SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26048599 TI - Sparse multi-view matrix factorization: a multivariate approach to multiple tissue comparisons. AB - MOTIVATION: Within any given tissue, gene expression levels can vary extensively among individuals. Such heterogeneity can be caused by genetic and epigenetic variability and may contribute to disease. The abundance of experimental data now enables the identification of features of gene expression profiles that are shared across tissues and those that are tissue-specific. While most current research is concerned with characterizing differential expression by comparing mean expression profiles across tissues, it is believed that a significant difference in a gene expression's variance across tissues may also be associated with molecular mechanisms that are important for tissue development and function. RESULTS: We propose a sparse multi-view matrix factorization (sMVMF) algorithm to jointly analyse gene expression measurements in multiple tissues, where each tissue provides a different 'view' of the underlying organism. The proposed methodology can be interpreted as an extension of principal component analysis in that it provides the means to decompose the total sample variance in each tissue into the sum of two components: one capturing the variance that is shared across tissues and one isolating the tissue-specific variances. sMVMF has been used to jointly model mRNA expression profiles in three tissues obtained from a large and well-phenotyped twins cohort, TwinsUK. Using sMVMF, we are able to prioritize genes based on whether their variation patterns are specific to each tissue. Furthermore, using DNA methylation profiles available, we provide supporting evidence that adipose-specific gene expression patterns may be driven by epigenetic effects. AVAILABILITY AND IMPLEMENTATION: Python code is available at http://wwwf.imperial.ac.uk/~gmontana/. CONTACT: giovanni.montana@kcl.ac.uk SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26048600 TI - Quantitative frame analysis and the annotation of GC-rich (and other) prokaryotic genomes. An application to Anaeromyxobacter dehalogenans. AB - MOTIVATION: Graphical representations of contrasts in GC usage among codon frame positions (frame analysis) provide evidence of genes missing from the annotations of prokaryotic genomes of high GC content but the qualitative approach of visual frame analysis prevents its applicability on a genomic scale. RESULTS: We developed two quantitative methods for the identification and statistical characterization in sequence regions of three-base periodicity (hits) associated with open reading frame structures. The methods were implemented in the N-Profile Analysis Computational Tool (NPACT), which highlights in graphical representations inconsistencies between newly identified ORFs and pre-existing annotations of coding-regions. We applied the NPACT procedures to two recently annotated strains of the deltaproteobacterium Anaeromyxobacter dehalogenans, identifying in both genomes numerous conserved ORFs not included in the published annotation of coding regions. AVAILABILITY AND IMPLEMENTATION: NPACT is available as a web-based service and for download at http://genome.ufl.edu/npact. CONTACT: lucianob@ufl.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26048601 TI - "Thickened" ligamentum flavum caused by laminectomy. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of a laminectomy on the adjacent ligamentum flavum (LF) by measuring LF thickness using magnetic resonance imaging (MRI). MATERIALS AND METHODS: A total of 78 patients (31 man, 47 woman) with laminectomy were included in our study. After determination of laminectomy level, measurements were done from the thickest parts of the bilateral LF at the upper level of the laminectomy where bilateral facet joints were evident at the slice. RESULTS: Ipsilateral ligamentum flavum with laminectomy was significantly thicker than the contralateral ligamentum flavum with laminectomy. CONCLUSION: Laminectomy cause thickening of ligamentum flavum. Therefore we assume that it should kept in mind that LFH may develop at the adjacent level to the laminectomy and careful clinical and radiological assessments' should be done to exclude LFH in cases who complain about the recurrence of complaints during the post-operative period after laminectomy. PMID- 26048602 TI - The effect of differential training-based occupational therapy on hand and arm function in patients after stroke: Results of the pilot study. AB - OBJECTIVE: The aim of this study was to evaluate the effect of differential training-based occupational therapy on the recovery of arm function and to compare these data with the results obtained after conventional occupational therapy. METHODS: A total of 27 patients who had suffered a cerebral infarction in the left brain hemisphere were recruited for the study. There were 9 men (33.33%) and 18 women (66.67%). All the patients had paresis of the right arm. The patients were divided into 2 groups: the control group comprised 15 patients who were given conventional occupational therapy (5 times per week) and the study group consisted of 12 patients who underwent conventional occupational therapy (3 times per week) along with occupational therapy based on differential training (2 times per week). RESULTS: In the control group, the mean performance time of only 2 tasks, i.e., flip cards and fold towel, improved significantly (P<0.05), while significant deterioration in the mean performance time of the task "lift can" was observed (P<0.05). In the study group, the mean performance time of all the tasks except for forearm to box (side), hand to box (front), and lift paperclip improved significantly (P<0.05), and no deterioration in arm function was observed. CONCLUSION: Both patients' groups improved arm function after occupational therapy sessions, but the patients who underwent conventional occupational therapy along with differential training-based occupational therapy recovered their arm function more effectively than their counterparts after conventional occupational therapy. PMID- 26048603 TI - Non-paraganglioma tumors of the jugular foramen - Growth patterns, radiological presentation, differential diagnosis. AB - OBJECTIVE: Most common tumors of the jugular foramen are paragangliomas. However, other lesions, also malignant, may involve the jugular foramen and mimic radiographic presentation of paragangliomas. Therefore, a correct preoperative diagnosis is crucial for best treatment planning. This study analyzes imaging characteristics of non-paraganglioma neoplasms involving the jugular foramen, with attention given to features helpful in differential diagnosis. STUDY DESIGN: A retrospective chart search. SETTING: Teritary referral university centre. SUBJECTS AND METHODS: During the years 1997-2010, 11 cases of jugular foramen tumors other than paragangliomas, with available imaging studies, were identified. Histopathology revealed: 3 schwannomas, 1 malignant schwannoma, 2 meningiomas, 1 hemangiopericytoma, 1 ependymoma, 1 endolymphatic sac carcinoma (ELST) and 2 nasopharyngeal carcinoma metastases. CT, MRI and angiography were assessed to determine tumor growth directions, bone involvement, tumor morphology and vascular composition. RESULTS: Schwannomas were characterized by parapharyngeal space involvement, jugular foramen expansion, preservation of cortical margins, irregular contrast enhancement. Meningiomas presented diffuse bone infiltration, sclerotic changes, erosion of the cortical bone. Ependymoma showed diffuse skull base infiltration, permeative erosion, heterogeneity, abundant vascularization. Hemangiopericytoma radiologically imitated paraganglioma. ELST showed permeative/geographic bony destruction, heterogeneity, intratumoral bony fragments. Metastases were lytic, solid lesions characterized by circumferential growth, internal carotid artery encasement and stenosis. CONCLUSIONS: A combination of certain radiological features including tumor epicenter, growth vectors, skull base infiltration, bony changes and tumor morphology help establish correct preoperative diagnosis and differentiate less common jugular foramen tumors, from most common paragangliomas. Hemangiopericytoma may radiologically mimic paraganglioma. PMID- 26048604 TI - Peripheral nerve involvement in myotonic dystrophy type 2 - similar or different than in myotonic dystrophy type 1? AB - INTRODUCTION: Multisystem manifestations of myotonic dystrophies type 1 (DM1) and 2 (DM2) are well known. Peripheral nerve involvement has been reported in DM1 but not in genetically confirmed DM2. The aim of our study was to assess peripheral nerve involvement in DM2 using nerve conduction studies and to compare these results with findings in DM1. METHODS: We prospectively studied patients with genetically confirmed DM2 (n=30) and DM1 (n=32). All patients underwent detailed neurological examination and nerve conduction studies. RESULTS: Abnormalities in electrophysiological studies were found in 26.67% of patients with DM2 and in 28.13% of patients with DM1 but the criteria of polyneuropathy were fulfilled in only 13.33% of patients with DM2 and 12.5% of patients with DM1. The polyneuropathy was subclinical, and no correlation was found between its presence and patient age or disease duration. CONCLUSIONS: Peripheral nerves are quite frequently involved in DM2, but abnormalities meeting the criteria of polyneuropathy are rarely found. The incidence of peripheral nerve involvement is similar in both types of myotonic dystrophy. PMID- 26048605 TI - Intracranial bleedings in patients on long-term anticoagulant treatment: Benefits from oral thrombin and factor Xa inhibitors in clinical practice. AB - Dabigatran, a direct thrombin inhibitor and activated factor X inhibitors, rivaroxaban and apixaban, used in the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation (AF), have several advantages over vitamin K antagonists (VKAs). The non-vitamin K oral anticoagulants (NOACs) have been shown to reduce the risk of intracranial bleedings by 50%. The current review summarizes the available data on the epidemiology, mechanisms and treatment of intracranial bleedings observed on oral anticoagulation with the focus on the specificity of NOACs in this context. PMID- 26048606 TI - Rivaroxaban 10mg/d in severe renal failure does not prevent ischemic events in premorbid neurologic disease. AB - BACKGRUND: The direct oral anticoagulants (DOAC) are increasingly used for primary and secondary stroke prophylaxis in atrial fibrillation, although their use in patients with renal failure is problematic. CASE REPORT: In an 82-years old female with recurrent strokes and atrial fibrillation, the vitamin-K antagonist was changed to rivaroxaban because of "unstable international normalized ratio (INR) values". Because of renal failure with a creatinine clearance of 32ml/min, a dosage of rivaroxaban 10mg/d was chosen. Eleven days after initiation of rivaroxaban, she was re-hospitalized because of acute onset of right-sided weakness of the upper and lower limbs. CONCLUSIONS: In cases of stroke, renal failure and inadequate anticoagulation it is not useful to change from vitamin-K-antagonists to "low dose" DOAC. Diligent investigations for the cause of INR-instability and continuation of vitamin-K-antagonist therapy seem to be more effective and safer since there is the opportunity of monitoring therapy and to avoid under- as well as over-dosage. PMID- 26048607 TI - Non-classical presentation of congenital cholesteatoma as cerebrospinal fluid rhinorrhea - Case report and systematic review of the literature. AB - OBJECTIVE: Congenital cholesteatoma (CC) becomes clinically apparent as a cholesteatoma usually during childhood. Nontraumatic otogenic cerebrospinal fluid (CSF) rhinorrhea with an intact tympanic membrane is a very rare symptom. METHODS: The review of recent literature and case report of the 60-year old patient - a trumpeter presented with nontraumatic otogenic CSF rhinorrhea, intact tympanic membrane on microotoscopy, and besides colorless fluid in right nasal cavity, normal finding on nasal endoscopy examination. RESULTS: CSF rhinorrhea was caused by CC in the petrous bone apex. Early diagnosis was facilitated by computed tomography scanning. Complete cholesteatoma removal was accomplished using a middle fossa craniotomy and an open non-radical antromastoidectomy. CONCLUSION: The diagnosis of otogenic cerebrospinal fluid (CSF) rhinorrhea is challenging and it can easily be misdiagnosed. Congenital cholesteatoma is a rare entity. We present a non-classical presentation of CC in an adult male, with a previously unreported symptom of CSF rhinorrhea. Symptomatic improvement occurred after surgical treatment of the disease. PMID- 26048608 TI - A blackhole over brain: Interdural hematoma - A challenging diagnosis. AB - Hematoma in between two dura leaves, named as 'interdural hematoma', is a very rare entity in adulthood. Interdural hematoma may emerge spontaneously or secondary to coagulopathies. A 61-year-old male patient, who had a medical history of alcoholic cirrhosis, presented with interdural hematoma. The case has been discussed with a literature review about diagnostic and therapeutic approaches in this pathology. PMID- 26048609 TI - Hemorrhagic stroke, cerebral amyloid angiopathy, Down syndrome and the Boston criteria. AB - A stroke, or a cerebrovascular accident (CVA) is a life-threatening condition which often results in permanent or significant disability in the adult population. Several classifications of CVAs exist, one of them being based on the mechanism of injury of brain tissue: ischemic (85-90%) and hemorrhagic (10-15%). In a hemorrhagic stroke an intercranial bleeding occurs, leading to the formation of a focal hematoma typically located in the basal ganglia of the brain (approx. 45% of cases). A common yet underestimated cause of intracerebral hemorrhage is cerebral small vessel disease with microhemorrhages, including the cerebral amyloid angiopathy (CAA). This condition is associated with the deposition of amyloid-beta in arterial walls (in soft meninges, subcortical areas and the cerebral cortex). Research has shown that causes of hemorrhagic changes in the brain include genetic disorders, such as Down syndrome. The association is caused by the so-called 'gene dosage effect', as the gene for the precursor protein for amyloid-beta is located in chromosome 21. We wish to present the case of a 60 year old patient with Down syndrome who suffered a hemorrhagic stroke without antecedent hypertension. Based on the history taken, diagnostic imaging and the source literature, a diagnosis of cerebral amyloid angiopathy as the source of the bleeding was made (however it must be noted that without a full post-mortem examination, the Boston criteria allow only for a 'probable cerebral amyloid angiopathy' diagnosis to be made). The authors hereby also report the need to modify the Boston criteria for cerebral amyloid angiopathy. PMID- 26048610 TI - A patient with acute aortic dissection presenting with bilateral stroke - A rare experience. AB - Acute aortic dissection is a rare, life-threatening condition requiring early recognition and proper treatment. Although chest pain remains the most frequent initial symptom, clinical manifestation of aortic dissection varies. Rarely aortic dissection starts with neurological symptoms such as ischemic stroke, which is usually right-sided. A danger of performing thrombolytic therapy in these patients exists if aortic dissection is overlooked. Herein, we present a case of a patient with acute aortic dissection without typical chest pain whose initial manifestation was bilateral stroke. The uncommon presentation which masked the underlying condition delayed implementation of appropriate management. Moreover, the late admission to hospital prevented the patient from administration of recombined tissue plasminogen activator that would certainly decrease chances of survival. Presented case highlights the need for thorough physical examination at admission to hospital in all patients with acute stroke and points out the necessity of proper clinical work-up including adequate aorta imaging modalities of patients with acute stroke and suggestive findings of aortic dissection. PMID- 26048611 TI - An unusual radiological presentation of posterior reversible encephalopathy syndrome. PMID- 26048612 TI - DNA damage in blood lymphocytes in patients after (177)Lu peptide receptor radionuclide therapy. AB - PURPOSE: The aim of the study was to investigate DNA double strand break (DSB) formation and its correlation with the absorbed dose to the blood lymphocytes of patients undergoing their first peptide receptor radionuclide therapy (PRRT) with (177)Lu-labelled DOTATATE/DOTATOC. METHODS: The study group comprised 16 patients receiving their first PRRT. At least six peripheral blood samples were obtained before, and between 0.5 h and 48 h after radionuclide administration. From the time-activity curves of the blood and the whole body, residence times for blood self-irradiation and whole-body irradiation were determined. Peripheral blood lymphocytes were isolated, fixed with ethanol and subjected to immunofluorescence staining for colocalizing gamma-H2AX/53BP1 DSB-marking foci. The average number of DSB foci per cell per patient sample was determined as a function of the absorbed dose to the blood and compared with an in vitro calibration curve established in our laboratory with (131)I and (177)Lu. RESULTS: The average number of radiation-induced foci (RIF) per cell increased over the first 5 h after radionuclide administration and decreased thereafter. A linear fit from 0 to 5 h as a function of the absorbed dose to the blood agreed with our in vitro calibration curve. At later time-points the number of RIF decreased, indicating progression of DNA repair. CONCLUSION: Measurements of RIF and the absorbed dose to the blood after systemic administration of (177)Lu may be used to obtain data on the individual dose-response relationships in vivo. Individual patient data were characterized by a linear dose-dependent increase and an exponential decay function describing repair. PMID- 26048613 TI - HMGB1 and RAGE in skeletal muscle inflammation: Implications for protein accumulation in inclusion body myositis. AB - Inflammation is associated with protein accumulation in IBM, but precise mechanisms are elusive. The "alarmin" HMGB1 is upregulated in muscle inflammation. Its receptor RAGE is crucial for beta-amyloid-associated neurodegeneration. Relevant signaling via HMGB1/RAGE is expected in IBM pathology. By real-time-PCR, mRNA-expression levels of HMGB1 and RAGE were upregulated in muscle biopsies of patients with IBM and PM, but not in muscular dystrophy or non-myopathic controls. By immunohistochemistry, both molecules displayed the highest signal in IBM, where they distinctly co-localized to intra fiber accumulations of beta-amyloid and neurofilament/tau. In these fibers, identification of phosphorylated Erk suggested that relevant downstream activation is present upon HMGB1 signaling via RAGE. Protein expressions of HMGB1, RAGE, Erk and phosphorylated Erk were confirmed by Western blot. In a well established cell-culture model for pro-inflammatory cell-stress, exposure of human muscle-cells to IL-1beta+IFN-gamma induced cytoplasmic translocation of HMGB1 and subsequent release as evidenced by ELISA. Upregulation of RAGE on the cell surface was demonstrated by immunocytochemistry and flow-cytometry. Recombinant HMGB1 was equally potent as IL-1beta+IFN-gamma in causing amyloid accumulation and cell-death, and both were abrogated by the HMGB1-blocker BoxA. The findings strengthen the concept of unique interactions between degenerative and inflammatory mechanisms and suggest that HMGB1/RAGE signaling is a critical pathway in IBM pathology. PMID- 26048614 TI - Cerebral Vascular Injury in Traumatic Brain Injury. AB - Traumatic cerebral vascular injury (TCVI) is a very frequent, if not universal, feature after traumatic brain injury (TBI). It is likely responsible, at least in part, for functional deficits and TBI-related chronic disability. Because there are multiple pharmacologic and non-pharmacologic therapies that promote vascular health, TCVI is an attractive target for therapeutic intervention after TBI. The cerebral microvasculature is a component of the neurovascular unit (NVU) coupling neuronal metabolism with local cerebral blood flow. The NVU participates in the pathogenesis of TBI, either directly from physical trauma or as part of the cascade of secondary injury that occurs after TBI. Pathologically, there is extensive cerebral microvascular injury in humans and experimental animal, identified with either conventional light microscopy or ultrastructural examination. It is seen in acute and chronic TBI, and even described in chronic traumatic encephalopathy (CTE). Non-invasive, physiologic measures of cerebral microvascular function show dysfunction after TBI in humans and experimental animal models of TBI. These include imaging sequences (MRI-ASL), Transcranial Doppler (TCD), and Near InfraRed Spectroscopy (NIRS). Understanding the pathophysiology of TCVI, a relatively under-studied component of TBI, has promise for the development of novel therapies for TBI. PMID- 26048615 TI - The Effect of Bolus Consistency on Hyoid Velocity in Healthy Swallowing. AB - The aim of this study was to determine whether measures of hyoid velocity increase when swallowing liquids of thicker consistency at a constant volume. A gender-balanced sample of 20 healthy young participants (mean age 31.5) each swallowed 3 boluses of 5 ml volume in 3 consistencies (ultrathin, thin, and nectar-thick barium). Using frame-by-frame tracking of hyoid position, we identified the onset and peak of the hyoid movement and derived measures of velocity (i.e., distance in anatomically normalized units, i.e., % of the C2-4 vertebral distance, divided by duration in ms) for the X, Y, and XY movement directions. Peak hyoid velocity was also identified for each movement direction. Where significant differences were identified, the component measures of hyoid movement distance and duration were further explored to determine the strategies used to alter velocity. The results showed increased velocities and higher peak velocities with the nectar-thick stimuli compared to thin and ultrathin stimuli. This was achieved by a primary strategy of larger hyoid movement distances per unit of time when swallowing nectar-thick liquids. These results point to one mechanism by which thickened liquids may contribute to improved airway protection by facilitating more timely laryngeal vestibule closure. PMID- 26048616 TI - How an urban Aboriginal and Torres Strait Islander primary health care service improved access to mental health care. AB - INTRODUCTION: Aboriginal and Torres Strait Islander people experience higher levels of psychological distress and mental ill health than their non-Indigenous counterparts, but underuse mental health services. Interventions are required to address the structural and functional access barriers that cause this underuse. In 2012, the Southern Queensland Centre of Excellence in Aboriginal and Torres Strait Islander Primary Health Care employed a psychologist and a social worker to integrate mental health care into its primary health care services. This research study examines the impact of this innovation. METHODS: A mixed-method research design was used whereby a series of qualitative open-ended interviews were conducted with 7 psychology clients, 5 social work clients, the practice dietician, and the social worker and psychologist. General practitioners, practice nurses, Aboriginal Health Workers and receptionists participated in 4 focus groups. Key themes were identified, discussed, refined and agreed upon by the research team. Occasions of service by the psychologist and social worker were reviewed and quantitative data presented. RESULTS: Clients and staff were overwhelmingly positive about the inclusion of a psychologist and a social worker as core members of a primary health care team. In one-year, the psychologist and social worker recorded 537 and 447 occasions of service respectively, and referrals to a psychologist, psychiatrist, mental health worker or counsellor increased from 17% of mental health clients in 2010 to 51% in 2012. Increased access by Aboriginal and Torres Strait Islander people to mental health care was related to three main themes: (1) Responsiveness to community needs; (2) Trusted relationships; and (3) Shared cultural background and understanding. The holistic nature and cultural safety of the primary health care service, its close proximity to where most people lived and the existing trusted relationships were identified as key factors in decreasing barriers to access. CONCLUSIONS: Improving social and emotional well-being is critical to addressing the health inequalities experienced by Aboriginal and Torres Strait Islander peoples. This study demonstrates the benefits for clients and health professionals of integrating culturally safe mental health services into primary health care. PMID- 26048617 TI - Association between tumour necrosis factor-alpha inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study. AB - OBJECTIVE: To investigate whether people with inflammatory bowel disease treated with tumour necrosis factor-alpha (TNF-alpha) inhibitors are at increased risk of serious infections. DESIGN: Nationwide register based propensity score matched cohort study. SETTING: Denmark, 2002-12. PARTICIPANTS: The background cohort eligible for matching comprised 52,392 people with inflammatory bowel disease, aged 15 to 75 years, of whom 4300 were treated with TNF-alpha inhibitors. To limit confounding, a two stage matching method was applied; firstly matching on age, sex, disease duration, and inflammatory bowel disease subtype, and secondly matching on propensity scores (1:1 ratio); this yielded 1543 people treated with TNF-alpha inhibitors and 1543 untreated to be included in the analyses. MAIN OUTCOME MEASURES: The main outcome was any serious infection, defined as a diagnosis of infection associated with hospital admission. Cox regression was used to estimate hazard ratios for two risk periods (90 and 365 days after the start of TNF-alpha inhibitor treatment). Hazard ratios of site specific serious infections were obtained solely for the 365 days risk period. RESULTS: Within the 90 days risk period, 51 cases of infection were observed in users of TNF-alpha inhibitors (incidence rate 14/100 person years), compared with 33 cases in non users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12). CONCLUSIONS: This nationwide propensity score matched cohort study suggests an increased risk of serious infections associated with use of TNF-alpha inhibitors within the first 90 days of starting treatment and a subsequent decline in risk. This calls for increased clinical awareness of potential infectious complications among people with inflammatory bowel disease using these drugs, especially early in the course of treatment. PMID- 26048618 TI - OpenfMRI: Open sharing of task fMRI data. AB - OpenfMRI is a repository for the open sharing of task-based fMRI data. Here we outline its goals, architecture, and current status of the repository, as well as outlining future plans for the project. PMID- 26048619 TI - Inversion of hierarchical Bayesian models using Gaussian processes. AB - Over the past decade, computational approaches to neuroimaging have increasingly made use of hierarchical Bayesian models (HBMs), either for inferring on physiological mechanisms underlying fMRI data (e.g., dynamic causal modelling, DCM) or for deriving computational trajectories (from behavioural data) which serve as regressors in general linear models. However, an unresolved problem is that standard methods for inverting the hierarchical Bayesian model are either very slow, e.g. Markov Chain Monte Carlo Methods (MCMC), or are vulnerable to local minima in non-convex optimisation problems, such as variational Bayes (VB). This article considers Gaussian process optimisation (GPO) as an alternative approach for global optimisation of sufficiently smooth and efficiently evaluable objective functions. GPO avoids being trapped in local extrema and can be computationally much more efficient than MCMC. Here, we examine the benefits of GPO for inverting HBMs commonly used in neuroimaging, including DCM for fMRI and the Hierarchical Gaussian Filter (HGF). Importantly, to achieve computational efficiency despite high-dimensional optimisation problems, we introduce a novel combination of GPO and local gradient-based search methods. The utility of this GPO implementation for DCM and HGF is evaluated against MCMC and VB, using both synthetic data from simulations and empirical data. Our results demonstrate that GPO provides parameter estimates with equivalent or better accuracy than the other techniques, but at a fraction of the computational cost required for MCMC. We anticipate that GPO will prove useful for robust and efficient inversion of high-dimensional and nonlinear models of neuroimaging data. PMID- 26048620 TI - Differences in the neural signature of remembering schema-congruent and schema incongruent events. AB - New experiences are remembered in relation to one's existing world knowledge or schema. Recent research suggests that the medial prefrontal cortex (mPFC) supports the retrieval of schema-congruent information. However, the neural mechanisms supporting memory for information violating a schema have remained elusive, presumably because incongruity is inherently ambiguous in tasks that rely on world knowledge. We present a novel paradigm that experimentally induces hierarchically structured knowledge to directly contrast neural correlates that contribute to the successful retrieval of schema-congruent versus schema incongruent information. We hypothesize that remembering incongruent events engages source memory networks including the lateral PFC. In a sample of young adults, we observed enhanced activity in the dorsolateral PFC (DLPFC), in the posterior parietal cortex, and in the striatum when successfully retrieving incongruent events, along with enhanced connectivity between DLPFC and striatum. In addition, we found enhanced mPFC activity for successfully retrieved events that are congruent with the induced schema, presumably reflecting a role of the mPFC in biasing retrieval towards schema-congruent episodes. We conclude that medial and lateral PFC contributions to memory retrieval differ by schema congruency, and highlight the utility of the new experimental paradigm for addressing developmental research questions. PMID- 26048621 TI - Solving the EEG inverse problem based on space-time-frequency structured sparsity constraints. AB - We introduce STOUT (spatio-temporal unifying tomography), a novel method for the source analysis of electroencephalograpic (EEG) recordings, which is based on a physiologically-motivated source representation. Our method assumes that only a small number of brain sources are active throughout a measurement, where each of the sources exhibits focal (smooth but localized) characteristics in space, time and frequency. This structure is enforced through an expansion of the source current density into appropriate spatio-temporal basis functions in combination with sparsity constraints. This approach combines the main strengths of two existing methods, namely Sparse Basis Field Expansions (Haufe et al., 2011) and Time-Frequency Mixed-Norm Estimates (Gramfort et al., 2013). By adjusting the ratio between two regularization terms, STOUT is capable of trading temporal for spatial reconstruction accuracy and vice versa, depending on the requirements of specific analyses and the provided data. Due to allowing for non-stationary source activations, STOUT is particularly suited for the localization of event related potentials (ERP) and other evoked brain activity. We demonstrate its performance on simulated ERP data for varying signal-to-noise ratios and numbers of active sources. Our analysis of the generators of visual and auditory evoked N200 potentials reveals that the most active sources originate in the temporal and occipital lobes, in line with the literature on sensory processing. PMID- 26048622 TI - The diffusion tensor imaging (DTI) component of the NIH MRI study of normal brain development (PedsDTI). AB - The NIH MRI Study of normal brain development sought to characterize typical brain development in a population of infants, toddlers, children and adolescents/young adults, covering the socio-economic and ethnic diversity of the population of the United States. The study began in 1999 with data collection commencing in 2001 and concluding in 2007. The study was designed with the final goal of providing a controlled-access database; open to qualified researchers and clinicians, which could serve as a powerful tool for elucidating typical brain development and identifying deviations associated with brain-based disorders and diseases, and as a resource for developing computational methods and image processing tools. This paper focuses on the DTI component of the NIH MRI study of normal brain development. In this work, we describe the DTI data acquisition protocols, data processing steps, quality assessment procedures, and data included in the database, along with database access requirements. For more details, visit http://www.pediatricmri.nih.gov. This longitudinal DTI dataset includes raw and processed diffusion data from 498 low resolution (3 mm) DTI datasets from 274 unique subjects, and 193 high resolution (2.5 mm) DTI datasets from 152 unique subjects. Subjects range in age from 10 days (from date of birth) through 22 years. Additionally, a set of age-specific DTI templates are included. This forms one component of the larger NIH MRI study of normal brain development which also includes T1-, T2-, proton density-weighted, and proton magnetic resonance spectroscopy (MRS) imaging data, and demographic, clinical and behavioral data. PMID- 26048624 TI - MicroRNAs Signature in IL-2-Induced CD4+ T Cells and Their Potential Targets. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs regulated gene expression at the post-transcriptional level. Many studies have investigated role of miRNAs in the biological processes such as proliferation, apoptosis, differentiation, and development. To evaluate role of miRNAs in proliferation and death of T cell, we performed miRNA profiling in activated CD4+ T cells after IL-2 induction and depletion. Proliferation rate of IL-2-induced cells was measured by MTT assay. Then quantitative RT-PCR arrays on 739 miRNAs revealed up- and down-regulation of 170 miRNAs in IL-2-induced CD4+ T cells relative to IL-2-depleted ones. In addition, in silico analysis predicted miRNA's potential targets in pathways such as JAK/STAT and PI3K pathways. JAK1 expression, a potential target of modulated miRNAs, was decreased in IL-2-depleted cells. This study suggests that clonal expansion is regulated by miRNAs in the absence or presence of IL-2 by targeting genes implicated in JAK/STAT and PI3K pathways. PMID- 26048623 TI - Social exclusion modulates event-related frontal theta and tracks ostracism distress in children. AB - Social exclusion is a potent elicitor of distress. Previous studies have shown that medial frontal theta oscillations are modulated by the experience of social exclusion. Using the Cyberball paradigm, we examined event-related dynamics of theta power in the EEG at medial frontal sites while children aged 8-12 years were exposed to conditions of fair play and social exclusion. Using an event related design, we found that medial frontal theta oscillations (4-8Hz) increase during both early (i.e., 200-400ms) and late (i.e., 400-800ms) processing of rejection events during social exclusion relative to perceptually identical "not my turn" events during inclusion. Importantly, we show that only for the later time window (400-800ms) slow-wave theta power tracks self-reported ostracism distress. Specifically, greater theta power at medial frontal sites to "rejection" events predicted higher levels of ostracism distress. Alpha and beta oscillations for rejection events were unrelated to ostracism distress at either 200-400ms or 400-800ms time windows. Our findings extend previous studies by showing that medial frontal theta oscillations for rejection events are a neural signature of social exclusion, linked to experienced distress in middle childhood. PMID- 26048625 TI - The impact of concomitant diffuse idiopathic skeletal hyperostosis on the achievement of minimal disease activity in subjects with psoriatic arthritis. AB - Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of different entheses. Psoriatic arthritis (PsA) is a seronegative spondyloarthritis associated with psoriasis. Given the possible overlap of the two diseases, we assessed whether DISH presence may affect PsA clinical outcomes. Also, predictors of DISH presence in the cohort were investigated. Consecutive PsA patients from two Italian Rheumatology Research Units were enrolled. Subjects were splitted into two groups, according to the current treatment (TNF-alpha blockers or traditional DMARDs). All patients underwent a rheumatologic examination, blood sample collections and spine radiographs. Information about traditional vascular risk factors was recorded. In each patient, the presence of minimal disease activity was evaluated and the presence of DISH was established according to the Resnick and Niwayama criteria. Among the 80 enrolled subjects (57.5 % men, mean age 56.5 +/- 11.1 years), the overall prevalence of DISH was 30.0 %. Patients with DISH were older, with higher BMI and waist circumference. DISH subjects showed worsen BASMI, HAQ and ESR. In a multivariate regression model, BASMI was a significant predictor of DISH presence (OR 3.027, 95 % CI 1.449-6.325, p = 0.003). The prevalence of MDA was lower in DISH patients than in no-DISH (16.7 vs 41.1 %, p = 0.041), and the presence of DISH was a predictor of not achieving MDA (OR 3.485, 95 % CI 1.051-11.550, p = 0.041). PsA subjects with DISH showed worsen indices of spine mobility and articular function and lower prevalence of minimal disease activity than no-DISH patients. PMID- 26048626 TI - Canakinumab efficacy and long-term tocilizumab administration in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). AB - Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominantly inherited autoinflammatory disease caused by mutations in the TNFRSF1A gene. Treatment is aimed at preventing acute disease attacks, improving quality of life, and preventing long-term complications such as systemic reactive amyloidosis. Biologic agents have significantly improved TRAPS management. In particular, interleukin 1 (IL-1) inhibition either with the recombinant IL-1 receptor antagonist anakinra or with the human IgG1 anti-IL 1beta monoclonal antibody canakinumab has recently shown to induce a prompt and stable disease remission. Conversely, the successful experience with IL-6 inhibition is nowadays limited to a single patient. Anyway, introduction of new treatment options for patients requiring a lifelong therapy is desirable. We describe two TRAPS patients (son and father) successfully treated with canakinumab and tocilizumab, respectively. In particular, we highlight the clinical and laboratory efficacy as well as the good safety profile of tocilizumab during a 42-month follow-up period. PMID- 26048628 TI - Automated Tests for Telephone Telepathy Using Mobile Phones. AB - OBJECTIVE: To carry out automated experiments on mobile phones to test for telepathy in connection with telephone calls. STUDY METHOD: Subjects, aged from 10 to 83, registered online with the names and mobile telephone numbers of three or two senders. A computer selected a sender at random, and asked him to call the subject via the computer. The computer then asked the subject to guess the caller's name, and connected the caller and the subject after receiving the guess. A test consisted of six trials. INTERACTIONS EVALUATED: The effects of subjects' sex and age and the effects of time delays on guesses. MAIN OUTCOME MEASURE: The proportion of correct guesses of the caller's name, compared with the 33.3% or 50% mean chance expectations. MAIN RESULTS: In 2080 trials with three callers there were 869 hits (41.8%), above the 33.3% chance level (P < 1 * 10(-15)). The hit rate in incomplete tests was 43.8% (P = .00003) showing that optional stopping could not explain the positive results. In 745 trials with two callers, there were 411 hits (55.2%), above the 50% chance level (P = .003). An analysis of the data made it very unlikely that cheating could explain the positive results. These experiments showed that automated tests for telephone telepathy can be carried out using mobile phones. PMID- 26048627 TI - The presence of a galactosamine substituent on the arabinogalactan of Mycobacterium tuberculosis abrogates full maturation of human peripheral blood monocyte-derived dendritic cells and increases secretion of IL-10. AB - Slow-growing and pathogenic Mycobacterium spp. are characterized by the presence of galactosamine (GalN) that modifies the interior branched arabinosyl residues of the arabinogalactan (AG) that is a major heteropolysaccharide cell wall component. The availability of null mutants of the polyprenyl-phospho-N acetylgalactosaminyl synthase (Rv3631, PpgS) and the (N-acetyl-) galactosaminyl transferase (Rv3779) of Mycobacterium tuberculosis (Mtb) has provided a means to elucidate the role of the GalN substituent of AG in terms of host-pathogen interactions. Comparisons of treating human peripheral blood monocyte-derived dendritic cells (hPMC-DCs) with wild-type, Rv3631 and Rv3779 mutant strains of Mtb revealed increased expression of DC maturation markers, decreased affinity for a soluble DC-SIGN probe, reduced IL-10 secretion and increased TLR-2-mediated NF-kappaB activation among GalN-deficient Mtb strains compared to GalN-producing strains. Analysis of surface expression of a panel of defined or putative DC-SIGN ligands on both WT strains or either Rv3631 or Rv3779 mutant did not show significant differences suggesting that the role of the GalN substituent of AG may be to modulate access of the bacilli to immunologically-relevant receptor domains on DCs or contribute to higher ordered pathogen associated molecular pattern (PAMP)/pattern recognition receptor (PRR) interactions rather than the GalN-AG components having a direct immunological effect per se. PMID- 26048629 TI - Transoral endoscopic thyroidectomy: A case report. AB - INTRODUCTION: Endoscopic thyroidectomy, initially an experimental procedure, is now being performed in increasing frequency. It aims to provide patients undergoing thyroidectomy with a 'scar-free' surgery. Transoral endoscopic thyroidectomy is one such novel procedure that is based on the principles of natural orifice translumenal surgery (NOTES) and allows for a truly scar-free surgery with minimal dissection. PRESENTATION OF CASE: A 21-year-old female presented with a swelling over the left side of her neck. Ultrasound revealed a solitary nodule and FNAC showed features suggestive of a follicular adenoma. DISCUSSION: The patient underwent transoral endoscopic hemi-thyroidectomy. The procedure lasted for 2h and is one of the few documented cases of transoral endoscopic thyroidectomy performed on live patients. CONCLUSION: Transoral endoscopic thyroidectomy is proving to be a feasible technique with little or no complications as compared to other endoscopic thyroid surgeries. It provides surgeons with easy access to the thyroid gland and patients with aesthetically pleasing results. PMID- 26048630 TI - Malignant melanoma revealed by testicular metastasi. AB - We report the case of an 83 years old man supported for painless indurated and nodular lesion of the left testicle. Histological analysis identified a primary cutaneous melanoma metastasis although it has never been found on physical examination. The discovery of a testicular mass should suggest first a germ cell tumor, despite in some populations (age over 60 years), other diagnosis are more frequent, including metastasis. Due to rapid disease progression and high mortality rate within a short interval, a complete staging looking for other secondary locations must be done and a multidisciplinary care and palliative involvement must also be initiated in the context of metastatic melanoma. PMID- 26048631 TI - CO2 removal: Is a new simplified device could extended the indications? PMID- 26048632 TI - African American Patients' Psychosocial Support Needs and Barriers to Treatment: Patient Needs Assessment. AB - This study assessed adult patient's psychosocial support needs and treatment barriers in an urban diverse cancer center. A needs assessment was conducted with a convenience sample of adult oncology patients (n = 113; 71.7 % African American). Most patients were parenting school-age children and worried about them (96 %); 86.7 % would attend a family support program. Among patients who were married or partnered (68 %), 63.7 % were concerned about communication, coping, and emotional support; 53.9 % would attend a couple support program. Patients identified similar treatment barriers: transportation, babysitting for younger children, convenience of time/place, and refreshments. Findings suggest that behavioral health care providers should be available to screen cancer patients and improve access to appropriate psychosocial oncology support programs. PMID- 26048633 TI - [Is management of analgesia correct in terminally ill patients?]. PMID- 26048634 TI - Fluoroquinolone-based antimicrobial prophylaxis in patients undergoing transrectal ultrasound-guided prostate biopsy. AB - The aim of this study was to establish the prevalence of resistance to fluoroquinolones in Escherichia coli strains isolated from patients undergoing transrectal ultrasound-guided prostate biopsy (TRUS-Bx) and to evaluate the incidence of possible infectious complications associated with this procedure. One hundred and four patients undergoing a TRUS-Bx in a single medical centre were prospectively enrolled in this study. In all patients, pre-biopsy rectal swabs were obtained. The analysis determined the antimicrobial susceptibility of E. coli strains to levofloxacin, ciprofloxacin and a panel of other antibiotics. Before biopsy, each of the men received a levofloxacin-based prophylaxis. Telephone follow-up was used to identify patients who had complications after TRUS-Bx. Fluoroquinolone-resistant strains were isolated from 9.62 % of the patients. In all cases, there were related to E. coli and all those strains were resistant to both levofloxacin and ciprofloxacin. Fluoroquinolones showed greater antimicrobial activity against E. coli (p < 0.05) than ampicillin, amoxicillin/clavulanate and cephalothin. Minor infectious complications occurred in three patients (2.91 %). The relation between the resistance of E. coli to fluoroquinolones and the risk of readmission, as well as infectious complications, was statistically significant (p < 0.05). Despite recent reports of increasing prevalence of fluoroquinolone-resistant E. coli and the associated increase of severe infectious complications, the presented results have not confirmed this phenomenon. Resistance to fluoroquinolones of E. coli strains isolated from rectal swab cultures prior to TRUS-Bx is the risk factor for readmission and infectious complications after this procedure. PMID- 26048635 TI - Pulmonary edema secondary to a cardiac schwannoma in a dog. AB - A 4-year-old castrated labrador retriever presented for cardiac evaluation to determine the etiology of cardiogenic pulmonary edema diagnosed 1 month prior. A large pedunculated mass involving the ventral aspect of the mural mitral valve leaflet and the endocardial surface of the left ventricular free wall, resulting in severe mitral regurgitation, was identified on echocardiogram. Histopathology and immunohistochemistry of this mass and other endocardial masses identified at necropsy for S-100 protein were consistent with a diagnosis of schwannoma. To the authors' knowledge, this is the first case of a benign intracardiac schwannoma described in the left heart of a dog. PMID- 26048636 TI - Effects of chronic binge-like ethanol consumption on cocaine self-administration in rhesus monkeys. AB - BACKGROUND: Most cocaine abusers also abuse alcohol, but little is known about interactions that promote co-abuse. These experiments in rhesus monkeys determined the effects of >8 weeks of ethanol (EtOH) consumption on cocaine self administration (n=6), effects of dopamine (DA) receptor antagonists on cocaine reinforcement (n=3-4 per drug) and the ability of the D2-like DA receptor agonist quinpirole to elicit yawning (n=3). METHODS: Monkeys self-administered cocaine (0.0-1.0mg/kg/injection, i.v.) under a 300-s fixed-interval schedule and the above-listed variables were measured before EtOH exposure. Next, monkeys consumed a sweetened, 4% EtOH solution in the home cage under binge-like conditions: 1h, 5 days/week with daily intake equaling 2.0g/kg EtOH. After approximately 8 weeks, measures were re-determined, then EtOH drinking was discontinued. Finally, acute effects of EtOH on cocaine self-administration were determined by infusing EtOH (0.0-1.0g/kg. i.v.) prior to cocaine self-administration sessions (n=4). RESULTS: In five of six monkeys, EtOH drinking increased self-administration of low cocaine doses but did not alter reinforcing effects of higher doses. Self administration returned to baseline after EtOH access was terminated (n=3). Effects of DA receptor antagonists on cocaine self-administration were not consistently altered after EtOH consumption, but the ability of quinpirole to induce yawning was enhanced in two of three monkeys. Acute EtOH infusions only decreased self-administration of lower cocaine doses. CONCLUSIONS: Taken together, the data suggest that long-term EtOH exposure can increase sensitivity to cocaine, possibly by increasing D3 receptor sensitivity. Data do not support a role for acute pharmacological interactions in promoting cocaine/EtOH co-abuse. PMID- 26048637 TI - A single dose of kudzu extract reduces alcohol consumption in a binge drinking paradigm. AB - BACKGROUND: Overconsumption of alcohol has significant negative effects on an individual's health and contributes to an enormous economic impact on society as a whole. Pharmacotherapies to curb excessive drinking are important for treating alcohol use disorders. METHODS: Twenty (20) men participated in a placebo controlled, double-blind, between subjects design experiment (n=10/group) that tested the effects of kudzu extract (Alkontrol-HerbalTM) for its ability to alter alcohol consumption in a natural settings laboratory. A single dose of kudzu extract (2g total with an active isoflavone content of 520mg) or placebo was administered 2.5h before the onset of a 90min afternoon drinking session during which participants had the opportunity to drink up to 6 beers ad libitum; water and juice were always available as alternative beverages. RESULTS: During the baseline session, the placebo-randomized group consumed 2.7+/-0.78 beers before treatment and increased consumption to 3.4+/-1.1 beers after treatment. The kudzu group significantly reduced consumption from 3.0+/-1.7 at baseline to 1.9+/-1.3 beers after treatment. The placebo-treated group opened 33 beers during baseline conditions and 38 following treatment whereas the kudzu-treated group opened 32 beers during baseline conditions and only 21 following treatment. Additionally, kudzu-treated participants drank slower. CONCLUSION: This is the first demonstration that a single dose of kudzu extract quickly reduces alcohol consumption in a binge drinking paradigm. These data add to the mounting clinical evidence that kudzu extract may be a safe and effective adjunctive pharmacotherapy for alcohol abuse and dependence. PMID- 26048638 TI - Hepatitis C virus infection and pain sensitivity in patients on methadone or buprenorphine maintenance therapy for opioid use disorders. AB - BACKGROUND: Patients with opioid use disorders on opioid agonist therapy (OAT) have lower pain tolerance compared to controls. While chronic viral infections such as HCV and HIV have been associated with chronic pain in this population, no studies have examined their impact on pain sensitivity. METHODS: We recruited 106 adults (41 uninfected controls; 40 HCV mono-infected; and 25 HCV/HIV co-infected) on buprenorphine or methadone to assess whether HCV infection (with or without HIV) was associated with increased experimental pain sensitivity and self reported pain. The primary outcome was cold pain tolerance assessed by cold pressor test. Secondary outcomes were cold pain thresholds, wind-up ratios to repetitive mechanical stimulation (i.e., temporal summation) and acute and chronic pain. Multivariable regression models evaluated associations between viral infection status and outcomes, adjusting for other factors. RESULTS: No significant differences were detected across groups for primary or secondary outcomes. Adjusted mean cold pain tolerance was 25.7 (uninfected controls) vs. 26.8 (HCV mono-infection) vs. 25.3 (HCV/HIV co-infection) seconds (global p value=0.93). Current pain appeared more prevalent among HCV mono-infected (93%) compared to HCV/HIV co-infected participants (76%) and uninfected controls (80%), as did chronic pain (77% vs. 64% vs. 61%, respectively). However, differences were not statistically significant in multivariable models. CONCLUSION: This study did not detect an association between HCV infection and increased sensitivity to pain among adults with and without HIV who were treated with buprenorphine or methadone for opioid use disorders. Results reinforce that pain and hyperalgesia are common problems in this population. PMID- 26048639 TI - Application of programmable bio-nano-chip system for the quantitative detection of drugs of abuse in oral fluids. AB - OBJECTIVE: There is currently a gap in on-site drug of abuse monitoring. Current detection methods involve invasive sampling of blood and urine specimens, or collection of oral fluid, followed by qualitative screening tests using immunochromatographic cartridges. While remote laboratories then may provide confirmation and quantitative assessment of a presumptive positive, this instrumentation is expensive and decoupled from the initial sampling making the current drug-screening program inefficient and costly. The authors applied a noninvasive oral fluid sampling approach integrated with the in-development chip based Programmable bio-nano-chip (p-BNC) platform for the detection of drugs of abuse. METHOD: The p-BNC assay methodology was applied for the detection of tetrahydrocannabinol, morphine, amphetamine, methamphetamine, cocaine, methadone and benzodiazepines, initially using spiked buffered samples and, ultimately, using oral fluid specimen collected from consented volunteers. RESULTS: Rapid (~10min), sensitive detection (~ng/mL) and quantitation of 12 drugs of abuse was demonstrated on the p-BNC platform. Furthermore, the system provided visibility to time-course of select drug and metabolite profiles in oral fluids; for the drug cocaine, three regions of slope were observed that, when combined with concentration measurements from this and prior impairment studies, information about cocaine-induced impairment may be revealed. CONCLUSIONS: This chip-based p BNC detection modality has significant potential to be used in the future by law enforcement officers for roadside drug testing and to serve a variety of other settings, including outpatient and inpatient drug rehabilitation centers, emergency rooms, prisons, schools, and in the workplace. PMID- 26048640 TI - Discrepancies in addressing overdose prevention through prescription monitoring programs. AB - BACKGROUND: State prescription monitoring programs (PMPs) purport to address the prescription opioid epidemic, but have evidenced limited effect on reducing opioid-related mortality. METHODS: We systematically reviewed publicly available, PMP web-based materials from December, 2012 to October, 2013, to assess the degree to which overdose prevention was articulated in state PMP goals, mission statement, and accessible educational materials. The sites and available resources of 47 state PMPs with a web presence were reviewed by two independent coders for use of "overdose" and related terms. Website materials were further coded to capture five general thematic orientations: supply reduction therapeutic, supply reduction-punitive, demand reduction, public health/research, and harm reduction oriented in content. RESULTS: Twenty-nine of 47 (62%) PMPs did not address overdose or related terms in available online materials; six (12.8%) contained overdose-oriented messaging; and two included specific overdose prevention tools for providers. There were a median of three thematic orientations represented on the 18 state PMP websites mentioning only the term overdose, compared with a median of 4.5 thematic domains on the six PMP websites with overdose-oriented content. CONCLUSIONS: A more comprehensive, public health orientation for PMPs that explicitly and publicly articulates their application and role in overdose prevention may increase PMP effectiveness and use. PMID- 26048641 TI - Inter-observer reliability of DSM-5 substance use disorders. AB - AIMS: Although studies have examined the impact of changes made in DSM-5 on the estimated prevalence of substance use disorder (SUD) diagnoses, there is limited evidence concerning the reliability of DSM-5 SUDs. We evaluated the inter observer reliability of four DSM-5 SUDs in a sample in which we had previously evaluated the reliability of DSM-IV diagnoses, allowing us to compare the two systems. METHODS: Two different interviewers each assessed 173 subjects over a 2 week period using the Semi-Structured Assessment for Drug Dependence and Alcoholism (SSADDA). Using the percent agreement and kappa (kappa) coefficient, we examined the reliability of DSM-5 lifetime alcohol, opioid, cocaine, and cannabis use disorders, which we compared to that of SSADDA-derived DSM-IV SUD diagnoses. We also assessed the effect of additional lifetime SUD and lifetime mood or anxiety disorder diagnoses on the reliability of the DSM-5 SUD diagnoses. RESULTS: Reliability was good to excellent for the four disorders, with kappa values ranging from 0.65 to 0.94. Agreement was consistently lower for SUDs of mild severity than for moderate or severe disorders. DSM-5 SUD diagnoses showed greater reliability than DSM-IV diagnoses of abuse or dependence or dependence only. Co-occurring SUD and lifetime mood or anxiety disorders exerted a modest effect on the reliability of the DSM-5 SUD diagnoses. CONCLUSIONS: For alcohol, opioid, cocaine and cannabis use disorders, DSM-5 criteria and diagnoses are at least as reliable as those of DSM-IV. PMID- 26048643 TI - The use of neuroimaging in dementia by Irish general practitioners. AB - BACKGROUND: More than 48,000 people in Ireland are living with dementia, and the number is likely to rise to 130,000 by 2041. Dementia frequently remains undiagnosed, depriving many of early interventions and the opportunity to plan for the future. Neuroimaging is helpful in the diagnosis of dementia, yet it is often insufficiently utilised. General practitioners (GPs) often decide which patients should be referred on for specialist assessment and as such play a crucial role in dementia diagnosis. AIMS: To establish the accessibility of neuroimaging in dementia by GPs, current referral patterns, confidence in referral and opinions on radiology reports. METHODS: The research design was a postal survey among GPs in single and group practices in urban, rural and semi rural areas in the east and southeast of Ireland. GPs were identified from the Irish Medical Directory and posted individual anonymous questionnaires. RESULTS: A third of participants reported that they had no direct access to neuroimaging. Access differed between public and private patients. GPs primarily referred to computed tomography and magnetic resonance imaging, but only 14.6 % based these referrals on published guidelines. A total of 47.8 % of participants were not very confident in their ability to choose the most appropriate modality. CONCLUSION: Access to neuroimaging investigations for suspected cases of dementia varies between locations and public and private systems. To improve diagnostic rates and ensure appropriate utilisation of imaging resources, GPs require access to clinical and referral guidelines to ensure appropriate use of neuroimaging and the best possible patient outcomes. PMID- 26048642 TI - Assessing contributions of nucleus accumbens shell subregions to reward-seeking behavior. AB - BACKGROUND: The nucleus accumbens (NAc) plays a key role in brain reward processes including drug seeking and reinstatement. Several anatomical, behavioral, and neurochemical studies discriminate between the limbic-associated shell and the motor-associated core regions. Less studied is the fact that the shell can be further subdivided into a dorsomedial shell (NAcDMS) and an intermediate zone (NAcINT) based on differential expression of transient c-Fos and long-acting immediate-early gene DeltaFosB upon cocaine sensitization. These disparate expression patterns suggest that NAc shell subregions may play distinct roles in reward-seeking behavior. In this study, we examined potential differences in the contributions of the NAcDMS and the NAcINT to reinstatement of reward-seeking behavior after extinction. METHODS: Rats were trained to intravenously self-administer cocaine, extinguished, and subjected to a reinstatement test session consisting of an intracranial microinfusion of either amphetamine or vehicle targeted to the NAcDMS or the NAcINT. RESULTS: Small amphetamine microinfusions targeted to the NAcDMS resulted in statistically significant reinstatement of lever pressing, whereas no significant difference was observed for microinfusions targeted to the NAcINT. No significant difference was found for vehicle microinfusions in either case. CONCLUSION: These results suggest heterogeneity in the behavioral relevance of NAc shell subregions, a possibility that can be tested in specific neuronal populations in the future with recently developed techniques including optogenetics. PMID- 26048644 TI - An extremely rare mass of bladder: lipoma in the bladder. PMID- 26048645 TI - Functional Characteristics of Milk Protein Concentrates and Their Modification. AB - A major deterrent to the usage of milk protein concentrate (MPC), a high-protein milk product with increasing demand as a food and sports drink ingredient, has been its poor functional characteristics when compared with other milk protein products such as whey protein concentrate and sodium caseinates. This review discusses the recent research on functional properties of MPC, focusing on factors that may contribute to the poor functional characteristics before, during, and after production. Current research, methods employed, and new understanding on the causes of poor solubility of MPC at mild temperatures (about 20 degrees C) has been presented, including loss of solubility during storage as these areas have received unprecedented attention over the past decade, and also affects other useful functional properties of MPC, such as emulsifying properties, gelation, and foaming. Processing methods, which include heat treatment, high-pressure application, microwave heating, ultrasound application, and enzyme and salts modification, have been used or have potential to modify or improve the functional properties of MPCs. Future research on the effects of these processing methods on the functional properties, including effects of enzyme hydrolysis on bitterness and bioactivity, has also been discussed. PMID- 26048646 TI - Enhancing Care Coordination Through Patient- and Family-Initiated Telephone Encounters: A Quality Improvement Project. AB - Telehealth activities are often conducted by ambulatory nurses to assist with care coordination; these activities are especially important for children with complex, chronic conditions. This quality-improvement project examines specific components of nursing care delivered to children on the neurology and gastroenterology services through patient-initiated telephone encounters. Metrics and nurse-sensitive indicators explored include the type of services requested, the nurses' ability to resolve patients' concerns while eliminating otherwise unnecessary care, and associated costs with providing this care. The usefulness of a standardized instrument, the care coordination management tool, used in this project is discussed. PMID- 26048647 TI - MEF13 Requires MORF3 and MORF8 for RNA Editing at Eight Targets in Mitochondrial mRNAs in Arabidopsis thaliana. AB - RNA editing sites in plant mitochondria and plastids are addressed by pentatricopeptide repeat (PPR) proteins with E or E and DYW domains, which recognize a specific nucleotide motif upstream of the edited nucleotide. In addition, some sites require MORF proteins for efficient RNA editing. Here, we assign the novel E domain-containing PPR protein, MEF13, as being required for editing at eight sites in Arabidopsis thaliana. A SNP in ecotype C24 altering the editing level at only one of the eight target sites was located by genomic mapping. An EMS mutant allele of the gene for MEF13 was identified in a SNaPshot screen of a mutated plant population. At all eight target sites of MEF13, editing levels are reduced in both morf3 and morf8 mutants, but at only one site in morf1 mutants, suggesting that specific MEF13-MORF interactions are required. Yeast two hybrid analyses detect solid connections of MEF13 with MORF1 and weak contact with MORF3 proteins. Yeast three-hybrid (Y3H) analysis shows that the presence of MORF8 enhances the connection between MEF13 and MORF3, suggesting that a MORF3 MORF8 heteromer may form stably or transiently to establish interaction with MEF13. PMID- 26048648 TI - High-quality RNA extraction from small cardamom tissues rich in polysaccharides and polyphenols. AB - Due to the presence of a diverse array of metabolites, no standard method of RNA isolation is available for plants. We noted that polysaccharide and polyphenol contents of cardamom tissues critically hinder the RNA extraction procedure. Hence, we attempted several methods for obtaining intact mRNA and small RNA from various cardamom tissues. It was found that protocols involving a combination of commercial kits and conventional CTAB (cetyl trimethylammonium bromide) methods yielded RNA with good purity, higher yield, and good integrity. The total RNA isolated through this approach was found to be amenable for transcriptome and small RNA analysis through next-generation sequencing platforms. PMID- 26048649 TI - Selection of phage-displayed peptides for the detection of imidacloprid in water and soil. AB - Imidacloprid is the most widely used neonicotinoid insecticide in the world and shows widespread environment and human exposures. A phage clone designated L7-1 that selectively binds to imidacloprid was selected from a commercial phage display library containing linear 7-mer randomized amino acid residues. Using the clone L7-1, a competitive enzyme-linked immunosorbent assay (ELISA) for imidacloprid was developed. The half-maximum signal inhibition concentration (IC50) and the limit of detection (LOD) of the phage ELISA for imidacloprid were 96 and 2.3 ng ml(-1), respectively. This phage ELISA showed relatively low cross reactivity with all of the tested compounds structurally similar to imidacloprid, less than 2% with the exception of 6-chloronicotinic acid, a metabolite of imidacloprid that showed 11.5%. The average recoveries of the phage ELISA for imidacloprid in water and soil samples were in the ranges of 74.6 to 86.3% and 72.5 to 93.6%, respectively. The results of the competitive phage ELISA for imidacloprid in the fortified samples agreed well with those of a high performance liquid chromatography (HPLC) method. The simple phage-displayed peptide technology has been proven to be a convenient and efficient method for the development of an alternative format of ELISA for small molecules. PMID- 26048650 TI - A Dose-Response Modeling Approach Shows That Effects From Mixture Exposure to the Skin Sensitizers Isoeugenol and Cinnamal Are in Line With Dose Addition and Not With Synergism. AB - Currently, hazard characterization of skin sensitizers is based on data obtained from studies examining single chemicals. Many consumer products, however, contain mixtures of sensitizers that might interact in such a way that the response induced by a substance is higher than predicted in the hazard assessment. To assess interaction of skin sensitizers in a mixture, a dose-response modeling approach is applied. With this approach, it is possible to assess whether or not responses from mixtures of sensitizers can be predicted from the dose-response information obtained from individual chemicals using dose addition. We selected the skin sensitizers isoeugenol and cinnamal, frequently occurring together in consumer products, to be examined in an adjusted local lymph node assay (LLNA). Cell number and cytokine production (IL-10 and IFN-gamma) of the auricular lymph nodes were measured as hallmarks of the skin sensitization response. We found that dose addition for these 2 skin sensitizers closely predicted the effects from mixtures of both chemicals across the broad dose range tested. Hence, isoeugenol and cinnamal show no synergistic effects in the LLNA. Therefore, hazard assessment and risk assessment of these substances can be performed without taking into account mixture exposure. PMID- 26048651 TI - A Single Aspiration of Rod-like Carbon Nanotubes Induces Asbestos-like Pulmonary Inflammation Mediated in Part by the IL-1 Receptor. AB - Carbon nanotubes (CNT) have been eagerly studied because of their multiple applications in product development and potential risks on health. We investigated the difference of two different CNT and asbestos in inducing proinflammatory reactions in C57BL/6 mice after single pharyngeal aspiration exposure. We used long tangled and long rod-like CNT, as well as crocidolite asbestos at a dose of 10 or 40 ug/mouse. The mice were sacrificed 4 and 16 h or 7, 14, and 28 days after the exposure. To find out the importance of a major inflammatory marker IL-1beta in CNT-induced pulmonary inflammation, we used etanercept and anakinra as antagonists as well as Interleukin 1 (IL-1) receptor (IL-1R-/-) mice. The results showed that rod-like CNT, and asbestos in lesser extent, induced strong pulmonary neutrophilia accompanied by the proinflammatory cytokines and chemokines 16 h after the exposure. Seven days after the exposure, neutrophilia had essentially disappeared but strong pulmonary eosinophilia peaked in rod-like CNT and asbestos-exposed groups. After 28 days, pulmonary granulomas, goblet cell hyperplasia, and Charcot-Leyden-like crystals containing acidophilic macrophages were observed especially in rod-like CNT-exposed mice. IL-1R-/- mice and antagonists-treated mice exhibited a significant decrease in neutrophilia and messenger ribonucleic acid (mRNA) levels of proinflammatory cytokines at 16 h. However, rod-like CNT-induced Th2-type inflammation evidenced by the expression of IL-13 and mucus production was unaffected in IL-1R-/- mice at 28 days. This study provides knowledge about the pulmonary effects induced by a single exposure to the CNT and contributes to hazard assessment of carbon nanomaterials on airway exposure. PMID- 26048652 TI - Nanoparticles Made From Xyloglucan-Block-Polycaprolactone Copolymers: Safety Assessment for Drug Delivery. AB - Xyloglucan-block-polycaprolactone (XGO-PCL) copolymer nanoparticles have been proposed as nanocarriers for drug delivery. However, the possible harmful effects of exposure to nanoparticles still remain a concern. Therefore, the aim of this study is to evaluate the potential toxicity of XGO-PCL nanoparticles using in vitro and in vivo assays. Cytotoxicity and genotoxicity studies were conducted on MRC-5 human fetal lung fibroblast cells upon exposure to XGO-PCL nanoparticles. No significant reduction in the cell viability and no DNA damage were observed at the different concentrations tested. Erythrocyte toxicity was assessed by the incubation of nanoparticles with human blood. XGO-PCL nanoparticles induced a hemolytic ratio of less than 1%, indicating good blood compatibility. Finally, the subacute toxicity of XGO-PCL nanoparticles (10 mg/kg/day) was evaluated in BALB/c mice when administered orally or intraperitoneally for 14 days. Results of the in vivo toxicity study showed no clinical signs of toxicity, mortality, weight loss, or hematological and biochemical alterations after treatment with nanoparticles. Also, microscopic analysis of the major organs revealed no histopathological abnormalities, corroborating the previous results. Thus, it can be concluded that XGO-PCL nanoparticles induced no effect indicative of toxicity, indicating their potential use as drug delivery systems. PMID- 26048653 TI - Phytoestrogen beta-Ecdysterone Protects PC12 Cells Against MPP+-Induced Neurotoxicity In Vitro: Involvement of PI3K-Nrf2-Regulated Pathway. AB - Epidemiological studies have strongly linked postmenopausal estrogens uptake with a reduced risk of developing Parkinson's disease (PD) in women. Estrogen replacement therapy may be beneficial in early PD. The aim of this study is to evaluate the hypothesis that the neuroprotective effects of phytoestrogen beta ecdysterone (beta-Ecd) might mainly result from its antioxidant capability by the activation of the phosphoinositide-3-kinase (PI3K)-nuclear factor E2-related factor 2 (Nrf2)-regulated signaling pathway. We found that beta-Ecd is able to protect MPP(+)-induced oxidative stress and apoptosis in PC12 cells in a concentration-dependent manner. beta-Ecd increased the Akt kinase activity and the Akt signaling pathways, including glycogen synthase kinase 3-beta inactivation, nuclear translocation of Nrf2, upregulation of HO-1 expression, but without affecting activity of both NF-kappaB and calpain. Enhancement of antioxidant response element (ARE) promoter-driven luciferase activity by beta Ecd correlated with the blockade of oxidative stress. Antioxidative effects of beta-Ecd could be blocked by pharmacologic inhibition of the PI3K pathways with LY294002 or Nrf2 pathway with shRNA-mediated knockdown of Nrf2 but not by SP600125 (JNK inhibitor), SB203580 (p38-MAPK inhibitor), or PD98059 (ERK1/2 inhibitor). Together, our results indicate that the inducible effect of beta-Ecd on HO-1 expression might be mediated, at least in part, by activating Akt kinase pathway and subsequent enhancement of Nrf2/ARE signaling pathway. In concert, these data suggest that beta-Ecd may be a potential candidate for further preclinical study aimed at the treatment of PD. PMID- 26048655 TI - Statistical inference for extended or shortened phase II studies based on Simon's two-stage designs. AB - BACKGROUND: Simon's two-stage designs are popular choices for conducting phase II clinical trials, especially in the oncology trials to reduce the number of patients placed on ineffective experimental therapies. Recently Koyama and Chen (2008) discussed how to conduct proper inference for such studies because they found that inference procedures used with Simon's designs almost always ignore the actual sampling plan used. In particular, they proposed an inference method for studies when the actual second stage sample sizes differ from planned ones. METHODS: We consider an alternative inference method based on likelihood ratio. In particular, we order permissible sample paths under Simon's two-stage designs using their corresponding conditional likelihood. In this way, we can calculate p values using the common definition: the probability of obtaining a test statistic value at least as extreme as that observed under the null hypothesis. RESULTS: In addition to providing inference for a couple of scenarios where Koyama and Chen's method can be difficult to apply, the resulting estimate based on our method appears to have certain advantage in terms of inference properties in many numerical simulations. It generally led to smaller biases and narrower confidence intervals while maintaining similar coverages. We also illustrated the two methods in a real data setting. CONCLUSIONS: Inference procedures used with Simon's designs almost always ignore the actual sampling plan. Reported P-values, point estimates and confidence intervals for the response rate are not usually adjusted for the design's adaptiveness. Proper statistical inference procedures should be used. PMID- 26048654 TI - Triclosan Induces Thymic Stromal Lymphopoietin in Skin Promoting Th2 Allergic Responses. AB - Triclosan is an antimicrobial chemical incorporated into many personal, medical and household products. Approximately, 75% of the U.S. population has detectable levels of triclosan in their urine, and although it is not typically considered a contact sensitizer, recent studies have begun to link triclosan exposure with augmented allergic disease. We examined the effects of dermal triclosan exposure on the skin and lymph nodes of mice and in a human skin model to identify mechanisms for augmenting allergic responses. Triclosan (0%-3%) was applied topically at 24-h intervals to the ear pinnae of OVA-sensitized BALB/c mice. Skin and draining lymph nodes were evaluated for cellular responses and cytokine expression over time. The effects of triclosan (0%-0.75%) on cytokine expression in a human skin tissue model were also examined. Exposure to triclosan increased the expression of TSLP, IL-1beta, and TNF-alpha in the skin with concomitant decreases in IL-25, IL-33, and IL-1alpha. Similar changes in TSLP, IL1B, and IL33 expression occurred in human skin. Topical application of triclosan also increased draining lymph node cellularity consisting of activated CD86(+)GL-7(+) B cells, CD80(+)CD86(+) dendritic cells, GATA-3(+)OX-40(+)IL-4(+)IL-13(+) Th2 cells and IL-17 A(+) CD4 T cells. In vivo antibody blockade of TSLP reduced skin irritation, IL-1beta expression, lymph node cellularity, and Th2 responses augmented by triclosan. Repeated dermal exposure to triclosan induces TSLP expression in skin tissue as a potential mechanism for augmenting allergic responses. PMID- 26048656 TI - A reliable phenotypic assay for detection of ESBLs and AmpCs in MBL-producing gram-negative bacteria with the use of aminophenylboronic acid, dipicolinic acid and cloxacillin. AB - ESBLs and AmpCs may escape detection when they coexist with metallo-beta lactamases such as New Delhi Metallo-beta-lactamases-1. In this study a combination disk assay was established using cefotaxime, cefotaxime/clavulanic acid, cefotaxime/clavulanic acid/cloxacillin, cefoxitin and cefoxitin/phenylboronic acid/cloxacillin on Mueller Hinton agar supplemented with dipicolinic acid for determination of beta-lactamases in the presence of NDM-1. PMID- 26048657 TI - Spatiotemporal psychopathology I: No rest for the brain's resting state activity in depression? Spatiotemporal psychopathology of depressive symptoms. AB - Despite intense neurobiological investigation in psychiatric disorders like major depressive disorder (MDD), the basic disturbance that underlies the psychopathological symptoms of MDD remains, nevertheless, unclear. Neuroimaging has focused mainly on the brain's extrinsic activity, specifically task-evoked or stimulus-induced activity, as related to the various sensorimotor, affective, cognitive, and social functions. Recently, the focus has shifted to the brain's intrinsic activity, otherwise known as its resting state activity. While various abnormalities have been observed during this activity, their meaning and significance for depression, along with its various psychopathological symptoms, are yet to be defined. Based on findings in healthy brain resting state activity and its particular spatial and temporal structure - defined in a functional and physiological sense rather than anatomical and structural - I claim that the various depressive symptoms are spatiotemporal disturbances of the resting state activity and its spatiotemporal structure. This is supported by recent findings that link ruminations and increased self-focus in depression to abnormal spatial organization of resting state activity. Analogously, affective and cognitive symptoms like anhedonia, suicidal ideation, and thought disorder can be traced to an increased focus on the past, increased past-focus as basic temporal disturbance o the resting state. Based on these findings, I conclude that the various depressive symptoms must be conceived as spatiotemporal disturbances of the brain's resting state's activity and its spatiotemporal structure. Importantly, this entails a new form of psychopathology, "Spatiotemporal Psychopathology" that directly links the brain and psyche, therefore having major diagnostic and therapeutic implications for clinical practice. PMID- 26048658 TI - Prediction in speech and language processing. PMID- 26048659 TI - Bilingual advantages in executive functioning either do not exist or are restricted to very specific and undetermined circumstances. AB - The hypothesis that managing two languages enhances general executive functioning is examined. More than 80% of the tests for bilingual advantages conducted after 2011 yield null results and those resulting in significant bilingual advantages tend to have small sample sizes. Some published studies reporting significant bilingual advantages arguably produce no group differences if more appropriate tests of the critical interaction or more appropriate baselines are used. Some positive findings are likely to have been caused by failures to match on demographic factors and others have yielded significant differences only with a questionable use of the analysis-of-covariance to "control" for these factors. Although direct replications are under-utilized, when they are, the results of seminal studies cannot be reproduced. Furthermore, most studies testing for bilingual advantages use measures and tasks that do not have demonstrated convergent validity and any significant differences in performance may reflect task-specific mechanism and not domain-free executive functions (EF) abilities. Brain imaging studies have made only a modest contribution to evaluating the bilingual-advantage hypothesis, principally because the neural differences do not align with the behavioral differences and also because the neural measures are often ambiguous with respect to whether greater magnitudes should cause increases or decreases in performance. The cumulative effect of confirmation biases and common research practices has either created a belief in a phenomenon that does not exist or has inflated the frequency and effect size of a genuine phenomenon that is likely to emerge only infrequently and in restricted and undetermined circumstances. PMID- 26048660 TI - Contact lens induced Pseudomonas keratitis following descemet stripping automated endothelial keratoplasty. AB - To report a case of bandage contact lens induced infectious keratitis caused by Pseudomonas aeruginosa following DSAEK. CASE REPORT: A 56-year-old female who underwent DSAEK at our institute for pseudophakic bullous keratopathy, developed contact lens induced keratitis in the fifth post operative week. Best corrected visual acuity (BCVA) reduced to perception of light in the left eye. Slit lamp examination revealed an epithelial ulcer measuring 4.7mm*6mm with surrounding infiltrates in the anterior stroma with hypopyon. The interface was clear. The corneoscleral rim culture of the donor tissue showed no growth on bacterial and fungal culture ruling out the possibility of donor-to-host transmission of infection. Microbiological evaluation identified the causative agent to be Pseudomonas aeruginosa. Based on culture and sensitivity report patient was started on hourly instillation of topical polymyxin B 20,000IU and fortified ceftazidime 5%. A response to treatment was noted and there was a complete resolution of keratitis with residual scarring. DISCUSSION: There have been case reports suggesting a host to donor transmission of infection which manifests during the postoperative period. To the best of our knowledge there are no reports of bandage contact lens associated Pseudomonas keratitis in a case that has undergone DSAEK. The prolonged use of bandage contact lens, lens contamination, stagnation of tear film behind the lens, compromised ocular surface and post operative use of topical steroids can contribute to infectious keratitis in DSAEK cases. PMID- 26048661 TI - Reply to "Corneal biomechanics in steroid induced ocular hypertension" by Yulek et al. PMID- 26048662 TI - Central corneal thickness evaluation in healthy eyes with three different optical devices. AB - PURPOSE: To compare corneal pachymetry values measured by three different optical devices: Orbscan II, Pentacam HR and Sirius in healthy eyes. METHODS: The central corneal thickness (CCT) of 102 eyes of 102 healthy subjects (mean age of 33.09 +/ 8.72 years and mean refractive defect -4.11 +/- 4.74 D) was measured by three different physicians using Orbscan II, Pentacam HR and Sirius. The normality of the distribution was evaluated by with Kolmogorov-Smirnov test. The correlations between CCT obtained from each device and refractive defect and age were evaluated using the Pearson test. The differences were evaluated by the Student paired t-test using SPSS 18.0 (IBM Corp. Armonk, New York). RESULTS: Orbscan II provided significant (p < 0.0001) lower CCT measurements then both Pentacam HR ( 13.66 +/- 16.53 MUm) and Sirius (-15.18 +/- 17.16 MUm); Sirius showed values slightly higher than Oculus Pentacam HR (+1.52 +/- 6.21 MUm) that appeared to be statistically significant (p < 0.015). CONCLUSIONS: The measurement of CCT by Sirius and Pentacam HR provides similar results. By contrast, the results obtained by Orbscan II are different from those obtained from both Sirius and Pentacam HR. PMID- 26048663 TI - Level of compliance in contact lens wearing medical doctors in Nepal. AB - PURPOSES: To determine the level of compliance and major non-compliant behaviors in contact lens (CL) wearing medical doctors (MDs) and to compare it with age matched CL wearing normal subjects with no medical background (NS). METHODS: Thirty-nine current CL wearing MDs, who were prescribed CLs in Nepal Eye Hospital, Kathmandu, Nepal, between 2007 and 2011, were interviewed on ten modifiable compliant behaviors regarding lens care and maintenance. The level of compliance and the rate of non-compliance for each behavior were determined and compared with NS. RESULTS: Level of compliance was good, average and poor in 35.9%, 48.7% and 15.4% of MDs, respectively. There was no significant difference in compliance between MDs and NS (p=0.209). Level of compliance was not associated with age, gender and duration of lens wear (p>0.05). Compliance rate varied according to different behaviors, achieving a good compliance level of 95% for hand hygiene, avoidance of water contact and not sleeping with lenses. There was poor compliance for topping up solution (53.8%) and lens case replacement (15.4%). CONCLUSION: About one third of MDs had a good level of compliance. Level of compliance and compliance rate of different behaviors were similar in MDs and NS. Periodic lens case replacement was the most neglected behavior in CL wearers for this region. PMID- 26048664 TI - Skin test evaluation of a novel peptide carrier-based vaccine, BM32, in grass pollen-allergic patients. PMID- 26048665 TI - Do human rhinovirus infections and food allergy modify grass pollen-induced asthma hospital admissions in children? PMID- 26048666 TI - Development of a simple and sensitive HPLC-UV method for the simultaneous determination of cannabidiol and Delta(9)-tetrahydrocannabinol in rat plasma. AB - There has been increased interest in the medical use of cannabinoids in recent years, particularly in the predominant natural cannabinoids, cannabidiol (CBD) and Delta(9)-tetrahydrocannabinol (THC). The aim of the current study was to develop a sensitive and reliable method for the quantification of CBD and THC in rat plasma. A combination of protein precipitation using cold acetonitrile and liquid-liquid extraction using n-hexane was utilised to extract CBD and THC from rat plasma. Samples were then evaporated and reconstituted in acetonitrile and 30 MUL was injected into an HPLC system. Separation was achieved using an ACE C18 PFP 150 mm * 4.6 mm, 3 MUm column at 55 degrees C with isocratic elution using a mobile phase consisting of acetonitrile-water (62:38, v/v) at 1 mL/min for 20 min. Both cannabinoids, as well as the internal standard (4,4 dichlorodiphenyltrichloroethane, DDT) were detected at 220 nm. Our new method showed linearity in the range of 10-10,000 ng/mL and a lower limit of quantification (LLOQ) of 10 ng/mL for both cannabinoids, which is comparable to previously reported LC-MS/MS methods. Inter- and intra-day precision and accuracy were below 15% RSD and RE, respectively. To demonstrate the suitability of the method for in vivo studies in rats, the assay was applied to a preliminary pharmacokinetic study following IV bolus administration of 5 mg/kg CBD or THC. In conclusion, a simple, sensitive, and cost-efficient HPLC-UV method for the simultaneous determination of CBD and THC has been successfully developed, validated and applied to a pharmacokinetic study in rats. PMID- 26048668 TI - Identification and characterization of related substances in pomalidomide by hyphenated LC-MS techniques. AB - The current study dealt with the separation, identification and characterization of related substances in pomalidomide by hyphenated techniques. Complete separation was obtained with an Inertsil ODS-SP column (250 mm * 4.6 mm, 5 MUm) by linear gradient elution using a mobile phase consisting of 0.1% formic acid solution and acetonitrile. They were characterized by hyphenated chromatographic techniques with the accurate mass determination using high resolution LC-TOF-MS methods as well as the product MS spectra determination and elucidation. The degradation behaviors of pomalidomide under ICH prescribed stress conditions were also conducted. Pomalidomide was found to be labile to degrade under acid, alkaline, oxidative and thermal stress conditions, while it was relatively stable to photolytic stress. 13 related substances were detected and identified to be 10 degradation products and three process related substances. The hyphenated LC-MS method with high resolution accurate mass determination facilitated the qualitative analysis of the unknown compounds than that of the conventional HPLC UV. The related compounds identified are valuable for pomalidomide manufacturing process optimization and quality control. PMID- 26048667 TI - Comparative pharmacokinetic and tissue distribution profiles of four major bioactive components in normal and hepatic fibrosis rats after oral administration of Fuzheng Huayu recipe. AB - Fuzheng Huayu recipe (FZHY) is a herbal product for the treatment of liver fibrosis approved by the Chinese State Food and Drug Administration (SFDA), but its pharmacokinetics and tissue distribution had not been investigated. In this study, the liver fibrotic model was induced with intraperitoneal injection of dimethylnitrosamine (DMN), and FZHY was given orally to the model and normal rats. The plasma pharmacokinetics and tissue distribution profiles of four major bioactive components from FZHY were analyzed in the normal and fibrotic rat groups using an ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method. Results revealed that the bioavailabilities of danshensu (DSS), salvianolic acid B (SAB) and rosmarinic acid (ROS) in liver fibrotic rats increased 1.49, 3.31 and 2.37-fold, respectively, compared to normal rats. There was no obvious difference in the pharmacokinetics of amygdalin (AMY) between the normal and fibrotic rats. The tissue distribution of DSS, SAB, and AMY trended to be mostly in the kidney and lung. The distribution of DSS, SAB, and AMY in liver tissue of the model rats was significantly decreased compared to the normal rats. Significant differences in the pharmacokinetics and tissue distribution profiles of DSS, ROS, SAB and AMY were observed in rats with hepatic fibrosis after oral administration of FZHY. These results provide a meaningful basis for developing a clinical dosage regimen in the treatment of hepatic fibrosis by FZHY. PMID- 26048669 TI - Opposite Dysregulation of Fragile-X Mental Retardation Protein and Heteronuclear Ribonucleoprotein C Protein Associates with Enhanced APP Translation in Alzheimer Disease. AB - Amyloid precursor protein (APP) is overexpressed in familiar and sporadic Alzheimer Disease (AD) patients suggesting that, in addition to abnormalities in APP cleavage, enhanced levels of APP full length might contribute to the pathology. Based on data showing that the two RNA binding proteins (RBPs), Fragile-X Mental Retardation Protein (FMRP) and heteronuclear Ribonucleoprotein C (hnRNP C), exert an opposite control on APP translation, we have analyzed whether expression and translation of these two RBPs vary in relation to changes in APP protein and mRNA levels in the AD brain at 1, 3, and 6 months of age. Here, we show that, as expected, human APP is overexpressed in hippocampal total extract from Tg2576 mice at all age points. APP overexpression, however, is not stable over time but reaches its maximal level in 1-month-old mutants in association with the stronger (i) reduction of FMRP and (ii) augmentation of hnRNP C. APP levels then decrease progressively as a function of age in close relationship with the gradual normalization of FMRP and hnRNP C levels. Consistent with the mouse data, expression of FMRP and hnRNP C are, respectively, decreased and increased in hippocampal synaptosomes from sporadic AD patients. Our findings identify two RBP targets that might be manipulated for reducing abnormally elevated levels of APP in the AD brain, with the hypothesis that acting upstream of amyloidogenic processing might contribute to attenuate the amyloid burden. PMID- 26048670 TI - Early Exposure to General Anesthesia Disrupts Spatial Organization of Presynaptic Vesicles in Nerve Terminals of the Developing Rat Subiculum. AB - Exposure to general anesthesia (GA) during critical stages of brain development induces widespread neuronal apoptosis and causes long-lasting behavioral deficits in numerous animal species. Although several studies have focused on the morphological fate of neurons dying acutely by GA-induced developmental neuroapoptosis, the effects of an early exposure to GA on the surviving synapses remain unclear. The aim of this study is to study whether exposure to GA disrupts the fine regulation of the dynamic spatial organization and trafficking of synaptic vesicles in presynaptic terminals. We exposed postnatal day 7 (PND7) rat pups to a clinically relevant anesthetic combination of midazolam, nitrous oxide, and isoflurane and performed a detailed ultrastructural analysis of the synaptic vesicle architecture at presynaptic terminals in the subiculum of rats at PND 12. In addition to a significant decrease in the density of presynaptic vesicles, we observed a reduction of docked vesicles, as well as a reduction of vesicles located within 100 nm from the active zone, in animals 5 days after an initial exposure to GA. We also found that the synaptic vesicles of animals exposed to GA are located more distally with respect to the plasma membrane than those of sham control animals and that the distance between presynaptic vesicles is increased in GA-exposed animals compared to sham controls. We report that exposure of immature rats to GA during critical stages of brain development causes significant disruption of the strategic topography of presynaptic vesicles within the nerve terminals of the subiculum. PMID- 26048671 TI - Early Exposure to General Anesthesia with Isoflurane Downregulates Inhibitory Synaptic Neurotransmission in the Rat Thalamus. AB - Recent evidence supports the idea that common general anesthetics (GAs) such as isoflurane (Iso) and nitrous oxide (N2O; laughing gas) are neurotoxic and may harm the developing mammalian brain, including the thalamus; however, to date very little is known about how developmental exposure to GAs may affect synaptic transmission in the thalamus which, in turn, controls the function of thalamocortical circuitry. To address this issue we used in vitro patch-clamp recordings of evoked inhibitory postsynaptic currents (eIPSCs) from intact neurons of the nucleus reticularis thalami (nRT) in brain slices from rat pups (postnatal age P10-P18) exposed at age of P7 to clinically relevant GA combinations of Iso and N2O. We found that rats exposed to a combination of 0.75 % Iso and 75 % N2O display lasting reduction in the amplitude and faster decays of eIPSCs. Exposure to sub-anesthetic concentrations of 75 % N2O alone or 0.75 % Iso alone at P7 did not affect the amplitude of eIPSCs; however, Iso alone, but not N2O, significantly accelerated decay of eIPSCs. Anesthesia with 1.5 % Iso alone decreased amplitudes, caused faster decay and decreased the paired-pulse ratio of eIPSCs. We conclude that anesthesia at P7 with Iso alone or in combination with N2O causes plasticity of eIPSCs in nRT neurons by both presynaptic and postsynaptic mechanisms. We hypothesize that changes in inhibitory synaptic transmission in the thalamus induced by GAs may contribute to altered neuronal excitability and consequently abnormal thalamocortical oscillations later in life. PMID- 26048673 TI - HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. AB - At least 250 million people worldwide are chronically infected with HBV, a small hepatotropic DNA virus that replicates through reverse transcription. Chronic infection greatly increases the risk for terminal liver disease. Current therapies rarely achieve a cure due to the refractory nature of an intracellular viral replication intermediate termed covalently closed circular (ccc) DNA. Upon infection, cccDNA is generated as a plasmid-like episome in the host cell nucleus from the protein-linked relaxed circular (RC) DNA genome in incoming virions. Its fundamental role is that as template for all viral RNAs, and in consequence new virions. Biosynthesis of RC-DNA by reverse transcription of the viral pregenomic RNA is now understood in considerable detail, yet conversion of RC-DNA to cccDNA is still obscure, foremostly due to the lack of feasible, cccDNA-dependent assay systems. Conceptual and recent experimental data link cccDNA formation to cellular DNA repair, which is increasingly appreciated as a critical interface between cells and viruses. Together with new in vitro HBV infection systems, based on the identification of the bile acid transporter sodium taurocholate cotransporting polypeptide as an HBV entry receptor, this offers novel opportunities to decipher, and eventually interfere with, formation of the HBV persistence reservoir. After a brief overview of the role of cccDNA in the HBV infectious cycle, this review aims to summarise current knowledge on cccDNA molecular biology, to highlight the experimental restrictions that have hitherto hampered faster progress and to discuss cccDNA as target for new, potentially curative therapies of chronic hepatitis B. PMID- 26048674 TI - Thoracolumbar fascia injury associated with residual back pain after percutaneous vertebroplasty: a compelling study. PMID- 26048675 TI - Two-year adherence to treatment and associated factors in a fracture liaison service in Spain. AB - A fracture liaison service in Spain is able to maintain 73 % of the patients on antiresorptive 2 years after the fracture. INTRODUCTION: The purpose of this study was to evaluate the 2-year effectiveness of a program for the secondary prevention of fractures. METHODS: Fragility fractures in patients over 50 attending the emergency room in our centre are captured by the recruitment system of a secondary prevention program. The unit is attended by a nurse, coordinated by two rheumatologists and with the collaboration of primary care consisted of a training program and annual meetings. The outcome of the program was analysed 2 years after implementation, including: (1) percentage of attendees/eligible; (2) percentage of attendees who start treatment with antiresorptive; (3) percentage of patients who retain treatment after 6, 12, 18 and 24 months; and (4) factors associated to adherence. RESULTS: After 2 years of implementation, the program detected 1674 patients with fracture, of whom 759 finally entered the program (57 % of eligible). After 3 months, 82 % of patients prescribed an antiresorptive started treatment. After a year, 52 % of the patients in the program, 72 % of those of a prescribed treatment, were taking antiresorptives. Adherence at 24 months among those who had prescribed anti-fracture drugs was 73 %. Factors associated with adherence at 12 months were female sex (76 vs 45 %; p = 0.01) and previous treatment with antiresorptive (86 vs 68 %; p = 0.02). CONCLUSIONS: In Spain, a program designed to prevent secondary fragility fractures based on the collaboration between primary care and rheumatology seems effective in terms of recruitment of patients and adherence to treatment in the mid/long-term. PMID- 26048676 TI - Diagnosis of vertebral fractures using a low-dose biplanar imaging system. AB - Vertebral fractures (VFs) are independent risk factors for new fractures. However, spine radiographs cannot be used as a screening method. EOS(r) has a good diagnostic value for the diagnosis of VF with a better legibility of upper thoracic spine and a higher concordance between readers compared to vertebral fracture assessment (VFA). INTRODUCTION: Vertebral fractures (VFs) are risk factors for new fractures. However, spine radiographs cannot be used as a screening method for both cost and radiation concerns. EOS(r) X-ray imaging system which allows the acquisition of biplane images in an upright weight bearing position with low radiation dose was used. The objective of this study was to compare EOS(r) to VFA for the diagnosis of VF. METHODS: We conducted a cross-sectional study in subjects aged above 50 years with indication for spine imaging. EOS(r) and VFA of the spine were performed the same day. Sensitivity (Se), specificity (Sp), negative predictive value (NPV), and the interobserver precision of EOS(r) were compared to VFA for the diagnosis of VF. RESULTS: Two hundred patients (mean age 66.2 years) were included. At the vertebral level, 2.4 and 3.6 % of vertebrae were not legible using EOS(r) and VFA, respectively (p = 0.0007). The legibility of spine was significantly affected by scoliosis (odds ratio (OR) = 2.8, p < 0.0001, for EOS(r), and OR = 1.8, p = 0.0041, for VFA). Sixty-six patients (33.0 %) and 69 (34.5 %) had at least one VF using VFA and EOS(r), respectively. At patient level, Se, Sp, and NPV for the diagnosis of VF of EOS(r) were 79.7, 91.6, and 99 %, respectively. Concordance between both observers was very good for EOS(r) (kappa-score = 0.89), higher than for VFA (kappa = 0.67). CONCLUSIONS: This study shows that EOS(r) has a good diagnostic value for the diagnosis of VF with a better legibility of upper thoracic spine and a higher concordance between readers compared to VFA. PMID- 26048677 TI - Nocturnal hypoxia and the success rate of standard atrial fibrillation treatment: a case report. AB - INTRODUCTION: Sleep apnea-hypopnea syndrome (SAHS) is one of the extracardiac reasons of atrial fibrillation (AF), and the prevalence of AF is high in SAHS diagnosed patients. Nocturnal hypoxemia is associated with AF, pulmonary hypertension, and nocturnal death. The rate of AF recurrence is high in untreated SAHS-diagnosed patients after cardioversion (CV). In this study, we present a patient whose SAHS was diagnosed with an apnea test performed in the intensive care unit (ICU) and who did not develop recurrent AF after the administration of standard AF treatment and bi-level positive airway pressure (BiPAP). CASE PRESENTATION: A 57-year-old male hypertensive Caucasian patient who was on medical treatment for 1.5 months for non-organic AF was admitted to the ICU because of high-ventricular response AF (170 per minute), and sinus rhythm was maintained during the CV that was performed two times every second day. The results of the apnea test performed in the ICU on the same night after the second CV were as follows: apnea-hypopnea index (AHI) of 71 per hour, minimum peripheral oxygen saturation (SpO2) of 67%, and desaturation period (SpO2 of less than 90%) of 28 minutes. The patient was discharged with medical treatment and nocturnal BiPAP treatment. The results of the apnea test performed under BiPAP on the sixth month were as follows: AHI of 1 per hour, desaturation period of 1 minute, and minimum SpO2 of 87%. No recurrent AF developed in the patient, and his medical treatment was reduced within 6 months. After gastric bypass surgery on the 12th month, nocturnal hypoxia and AF did not re-occur. Thus, BiPAP and medical treatments were ended. CONCLUSIONS: SAHS can be diagnosed by performing an apnea test in the ICU. SAHS should be investigated in patients developing recurrent AF after CV. Recovery of nocturnal hypoxia may increase the success rate of standard AF treatment. PMID- 26048672 TI - Platelet-Rich Plasma Promotes Axon Regeneration, Wound Healing, and Pain Reduction: Fact or Fiction. AB - Platelet-rich plasma (PRP) has been tested in vitro, in animal models, and clinically for its efficacy in enhancing the rate of wound healing, reducing pain associated with injuries, and promoting axon regeneration. Although extensive data indicate that PRP-released factors induce these effects, the claims are often weakened because many studies were not rigorous or controlled, the data were limited, and other studies yielded contrary results. Critical to assessing whether PRP is effective are the large number of variables in these studies, including the method of PRP preparation, which influences the composition of PRP; type of application; type of wounds; target tissues; and diverse animal models and clinical studies. All these variables raise the question of whether one can anticipate consistent influences and raise the possibility that most of the results are correct under the circumstances where PRP was tested. This review examines evidence on the potential influences of PRP and whether PRP-released factors could induce the reported influences and concludes that the preponderance of evidence suggests that PRP has the capacity to induce all the claimed influences, although this position cannot be definitively argued. Well-defined and rigorously controlled studies of the potential influences of PRP are required in which PRP is isolated and applied using consistent techniques, protocols, and models. Finally, it is concluded that, because of the purported benefits of PRP administration and the lack of adverse events, further animal and clinical studies should be performed to explore the potential influences of PRP. PMID- 26048678 TI - Capillary nano-immunoassays: advancing quantitative proteomics analysis, biomarker assessment, and molecular diagnostics. AB - There is an emerging demand for the use of molecular profiling to facilitate biomarker identification and development, and to stratify patients for more efficient treatment decisions with reduced adverse effects. In the past decade, great strides have been made to advance genomic, transcriptomic and proteomic approaches to address these demands. While there has been much progress with these large scale approaches, profiling at the protein level still faces challenges due to limitations in clinical sample size, poor reproducibility, unreliable quantitation, and lack of assay robustness. A novel automated capillary nano-immunoassay (CNIA) technology has been developed. This technology offers precise and accurate measurement of proteins and their post-translational modifications using either charge-based or size-based separation formats. The system not only uses ultralow nanogram levels of protein but also allows multi analyte analysis using a parallel single-analyte format for increased sensitivity and specificity. The high sensitivity and excellent reproducibility of this technology make it particularly powerful for analysis of clinical samples. Furthermore, the system can distinguish and detect specific protein post translational modifications that conventional Western blot and other immunoassays cannot easily capture. This review will summarize and evaluate the latest progress to optimize the CNIA system for comprehensive, quantitative protein and signaling event characterization. It will also discuss how the technology has been successfully applied in both discovery research and clinical studies, for signaling pathway dissection, proteomic biomarker assessment, targeted treatment evaluation and quantitative proteomic analysis. Lastly, a comparison of this novel system with other conventional immuno-assay platforms is performed. PMID- 26048679 TI - Depression history as a moderator of relations between cortisol and shame responses to social-evaluative threat in young adults. AB - Changes in cortisol and shame are commonly elicited by psychosocial stressors involving social-evaluative threat. According to social self preservation theory, this coordinated psychobiological response is adaptive. Individuals with a history of depression, however, may exhibit diminished cortisol reactivity to acute stressors, which could interfere with coordinated cortisol and shame responses. The present study examined temporal relations between cortisol and shame responses to a psychosocial stress task in young adults who varied in their history of depression (56 remitted-depressed, 46 never-depressed). Lagged effects multilevel models revealed that depression history moderated relations between cortisol levels and shame ratings 25-55min later. The pattern of these interactions was similar: whereas higher cortisol levels predicted increases in shame in never-depressed individuals, cortisol levels were unrelated to shame responses in remitted-depressed individuals. Findings suggest a dissociation between cortisol and shame responses to stress in individuals with a history of depression. PMID- 26048681 TI - "It scares me to know that we might not have been there!": a qualitative study into the experiences of parents of seriously ill children participating in ethical case discussions. AB - BACKGROUND: All hospital trusts in Norway have clinical ethics committees (CEC). Some of them invite next of kin/patients to be present during the discussion of their case. This study looks closer at how parents of seriously ill children have experienced being involved in CEC discussions. METHODS: Ten next of kin of six seriously ill children were interviewed. Their cases were discussed in two CECs between April of 2011 and March of 2014. The main ethical dilemma was limitation of life-prolonging treatment. Health care personnel who could elucidate the case were also present in the discussion. The interviewer observed each discussion and then interviewed the next of kin shortly after the meeting, following a structured interview guide. RESULTS: All next of kin emphasized that it had been important for them to be present. They stressed the important role of the CEC chair and appreciated that their case was discussed in a systematic way. Some next of kin appreciated that the child's impending death was discussed openly, and believed that this would facilitate their future grieving. Having had an opportunity to hear all the arguments behind the decision to be made would probably help them to accept the road ahead. All of them felt that they were taken seriously and listened to. They felt that they had added vital information to the discussion. All but one couple did not want any decision-making responsibility, some of them even worried that they might have influenced the discussion too much. CONCLUSIONS: None of the next of kin felt that being present during the CEC discussion had been too heavy a burden. On the contrary, they claimed that their presence in a CEC discussion may add vital information to the discussion and may improve the quality of the decision. It is important that the CEC's role is explained to them so they are well prepared for what to expect. They need to be followed up after the discussion. PMID- 26048680 TI - Identification of Oncogenic and Drug-Sensitizing Mutations in the Extracellular Domain of FGFR2. AB - The discovery of oncogenic driver mutations and the subsequent developments in targeted therapies have led to improved outcomes for subsets of lung cancer patients. The identification of additional oncogenic and drug-sensitive alterations may similarly lead to new therapeutic approaches for lung cancer. We identify and characterize novel FGFR2 extracellular domain insertion mutations and demonstrate that they are both oncogenic and sensitive to inhibition by FGFR kinase inhibitors. We demonstrate that the mechanism of FGFR2 activation and subsequent transformation is mediated by ligand-independent dimerization and activation of FGFR2 kinase activity. Both FGFR2-mutant forms are predominantly located in the endoplasmic reticulum and Golgi but nevertheless can activate downstream signaling pathways through their interactions with fibroblast growth factor receptor substrate 2 (FRS2). Our findings provide a rationale for therapeutically targeting this unique subset of FGFR2-mutant cancers as well as insight into their oncogenic mechanisms. PMID- 26048682 TI - Development of a 3D optical scanner for evaluating patient-specific dose distributions. AB - PURPOSE: This paper describes the hardware and software characteristics of a 3D optical scanner (P3DS) developed in-house. The P3DS consists of an LED light source, diffuse screen, step motor, CCD camera, and scanner management software with 3D reconstructed software. MATERIALS AND METHOD: We performed optical simulation, 2D and 3D reconstruction image testing, and pre-clinical testing for the P3DS. We developed the optical scanner with three key characteristics in mind. First, we developed a continuous scanning method to expand possible clinical applications. Second, we manufactured a collimator to improve image quality by reducing scattering from the light source. Third, we developed an optical scanner with changeable camera positioning to enable acquisition of optimal images according to the size of the gel dosimeter. RESULTS: We confirmed ray-tracing in P3DS with optic simulation and found that 2D projection and 3D reconstructed images were qualitatively similar to the phantom images. For pre clinical tests, the dose distribution and profile showed good agreement among RTP, optical CT, and external beam radiotherapy film data for the axial and coronal views. The P3DS has shown that it can scan and reconstruct for evaluation of the gel dosimeter within 1 min. We confirmed that the P3DS system is a useful tool for the measurement of 3D dose distributions for 3D radiation therapy QA. Further experiments are needed to investigate quantitative analysis for 3D dose distribution. PMID- 26048683 TI - Repeat physical activity measurement by accelerometry among colorectal cancer patients--feasibility and minimal number of days of monitoring. AB - BACKGROUND: Physical activity plays an important role in colorectal cancer and accelerometry is more frequently used to measure physical activity. The aim of this study was to evaluate feasibility of physical activity measurement by accelerometry in colorectal cancer patients under free-living conditions at 6, 12 and 24 months after surgery, to evaluate the appropriate wear time and to compare results to pedometry. METHODS: Colorectal cancer patients (stage 0/I-IV) from the ColoCare study were asked to optionally wear an accelerometer and a pedometer for ten consecutive days 6, 12 and 24 months post-surgery. Participants completed a feedback questionnaire about the accelerometer measurement. The course of moderate-to-vigorous physical activity over the 10 days was investigated. Additionally, daily step counts from accelerometers and pedometers were compared. RESULTS: In total, there were 317 individual time points, at which 198 participants were asked to wear an accelerometer. Fifty-nine% initially agreed to participate and of these, 83% (n = 156) completed the assessment with at least 4 days of data. Twenty-one% more consents were obtained when participants were asked on a face-to-face basis compared to recruitment by telephone (P = 0.0002). There were no significant differences in time spent in moderate-to-vigorous physical activity between different wear-time lengths of accelerometry. Both Spearman and intraclass correlation coefficients showed strong correlations (0.92 0.99 and 0.84-0.99, respectively) of moderate-to-vigorous physical activity across 3, 4, 7 and 10 days measurement. Step counts measured by accelerometry and pedometry were strongly correlated (rho = 0.91, P < 0.0001). CONCLUSION: This study suggest that accelerometry is a feasible method to assess physical activity in free-living colorectal cancer patients and that three valid days of physical activity measurement are sufficient for an accurate assessment. PMID- 26048684 TI - Word length and frequency effects on children's eye movements during silent reading. AB - In the present study we measured the eye movements of a large sample of 2nd grade German speaking children and a control group of adults during a silent reading task. To be able to directly investigate the interaction of word length and frequency effects we employed controlled sentence frames with embedded target words in an experimental design in which length and frequency were manipulated independently of one another. Unlike previous studies which have investigated the interaction of word length and frequency effects in children, we used age appropriate word frequencies for children. We found significant effects of word length and frequency for both children and adults while effects were generally greater for children. The interaction of word length and frequency was significant for children in gaze duration and total viewing time eye movement measures but not for adults. Our results suggest that children rely on sublexical decoding of infrequent words, leading to greater length effects for infrequent than frequent words while adults do not show this effect when reading children's reading materials. PMID- 26048685 TI - Effects of visual expertise on a novel eye-size illusion: implications for holistic face processing. AB - We examined the effect of visual experience on the magnitude of a novel eye-size illusion: when the size of a face's frame is increased or decreased but eye size is unchanged, observers judge the size of the eyes to be different from that in the original face frame. In the current study, we asked Chinese and Caucasian participants to judge eye size in different pairs of faces and measured the magnitude of the illusion when the faces were own- or other-age (adult vs. infant faces) and when the faces were own- or other-race (Chinese vs. Caucasian faces). We found an other-age effect and an other-race effect with the eye-size illusion: The illusion was more pronounced with own-race and own-age faces than with other race and other-age faces. These findings taken together suggest that visual experience with faces influences the magnitude of this novel illusion. Extensive experience with certain face categories strengthens the illusion in the context of these categories, but lack of it reduces the magnitude of the illusion. Our results further imply that holistic processing may play an important role in engendering the eye-size illusion. PMID- 26048686 TI - Unchanged gastric emptying and visceral perception in early Parkinson's disease after a high caloric test meal. AB - Delayed gastric emptying (GE) is a frequent non-motor feature in Parkinson's disease (PD). This prospective study (clinicaltrials.gov Identifier NCT01518751) investigated GE and visceral perception in early motor phase PD patients in comparison to age-matched and younger controls. In addition, the effect of Levodopa on GE was assessed in healthy aged controls. 16 PD patients (Hoehn & Yahr 2), 11 sex-/age-matched Ctrl1 and 10 young, male Ctrl2 subjects were subjected to a high caloric (428 kcal) (13)C-Sodium Octanoate breath test strictly OFF dopaminergic medication. Visceral appetite sensation was monitored using visual analogue scales (VAS). GE was similarly studied in 7 controls ON/OFF oral Levodopa. GE was not altered in PD patients compared to age-/sex-matched and younger controls (p = 0.76). Subjective appetite perception was not altered in the PD group in comparison to Ctrl1, but was significantly higher in Ctrl2 subjects (p = 0.02). 100 mg oral Levodopa/25 mg Benserazide significantly slowed GE by 18% among healthy controls (p = 0.04). In early motor stage PD OFF dopaminergic medication, there was no GE slowing after a high caloric test meal. Levodopa, however, caused a robust GE slowing in healthy aged individuals. Our data indicate that clinically relevant GE slowing in early PD is related to the iatrogenic effect of dopamine treatment. Subjective appetite perception is not affected in this disease stage. This data add to the understanding of gastrointestinal symptoms in early motor stage PD and highlight the influence of dopaminergic medication. PMID- 26048687 TI - Charcot-Marie-Tooth disease type 2C and scapuloperoneal muscular atrophy overlap syndrome in a patient with the R232C TRPV4 mutation. PMID- 26048688 TI - Tatsuji Inouye (1881-1976). PMID- 26048689 TI - Robert Marcus Gunn (1850-1909). PMID- 26048690 TI - Impulsive aggressive obsessions following cerebellar strokes: a case study. PMID- 26048691 TI - Follicular variant of papillary thyroid cancer in Alstrom syndrome. AB - Alstrom syndrome (AS) is an autosomal recessive disorder, characterized by cone rod dystrophy, sensorineural hearing loss, obesity, hyperinsulinemia with insulin resistance, type 2 diabetes mellitus and progressive pulmonary, hepatic and renal dysfunction. AS is caused by mutations in the ALMS1 gene, located on the short arm of chromosome 2. We report a 35-year-old woman with known history of AS, who developed a follicular variant of papillary thyroid carcinoma. To our knowledge this is the first association of AS with thyroid malignancy, among the approximately 450 cases reported since the first description of the syndrome. We conclude that papillary thyroid carcinoma should be considered in the differential diagnosis of thyroid nodules in patients with AS. PMID- 26048692 TI - Role of extracellular polymeric substances in improvement of sludge dewaterability through peroxidation. AB - Extracellular polymeric substances (EPS) was believed to be the primary factor determining the sludge dewaterability due to its ability to bind with water. Conventionally, several different mechanisms were proposed for the enhanced dewaterability. This study firstly clarified the correlation between EPS structure/property changes and improved sludge dewaterability. The characteristics of both extracted EPS from waste activated sludge and the sludge itself before and after the treatment with the Fe(II) activated peroxidation process, i.e. Fenton's conditioning, were investigated. The treatment with Fenton's reagent improved sludge dewaterability, with the EPS structure changed as well. It was found that both EPS and cells were solubilized by comparing the release of protein and polysaccharide from extracted EPS and sludge itself after peroxidation. The increased dewaterability was thus likely achieved through the destruction of both EPS (including loosely-bound and tightly-bound EPS) and cells by Fenton's conditioning while other mechanisms (i.e. flocculation/oxidization) played a secondary role. PMID- 26048693 TI - Technologies that affect the weaning rate in beef cattle production systems. AB - We investigated the differences between weaning rates and technologies adopted by farmers in cow-calf production systems in Rio Grande do Sul State, Brazil. Interviews were carried out with 73 farmers about 48 technologies that could affect reproductive performance. Data were analyzed by multivariate analysis using a non-hierarchical cluster method. The level of significance was set at P < 0.05. Three distinct clusters of farmers were created (R (2) = 0.90), named as low (LWR), intermediate (IWR), and high (HWR) weaning rate, with 100, 91, and 96 % of the farmers identified within their respective groups and average weaning rates of 59, 72, and 83 %, respectively. IWR and HWR farmers used more improved natural pasture, fixed-time artificial insemination, selection for birth weight, and proteinated salt compared to LWR. HWR farmers used more stocking rate control, and IWR farmers used more ultrasound to evaluate reproductive performance compared to the LWR group. IWR and HWR adopted more technologies related to nutrition and reproductive aspects of the herd in comparison to LWR. We concluded that farmers with higher technology use on farm had higher weaning rates which could be used to benefit less efficient farmers. PMID- 26048695 TI - The medical diagnostic approaches with phylogenetic analysis for rare Brucella spp. diagnosis in Taiwan. AB - Brucellosis is a bacterial zoonotic disease which can be easy to misdiagnose in clinical microbiology laboratories. In the present study, we have tried to improve the current clinical method for detecting Brucella spp. and its antibiotic characteristics. Our method begins with detecting the clinical isolate through traditional biochemical methods and automatic identification systems. Then, we move on to editing the sequence for BLAST allows us to compare 16s rRNA sequences with sequences from other species, allowing the gene level to be determined. Next, the phylogenetic analysis of multiple genetic loci is able to determine the evolutionary relationships between our bacteria strain and those from other locations. Finally, an anti-microbial susceptibility test hones in on the level of antibacterial activity that the bacteria displays. Employing these four steps in concert is extremely effective in identifying rare bacteria. Thus, when attempting to determine the identity of rare bacteria such as Brucella, utilizing these four steps from our research should be highly effective and ultimately prevent further identification errors and misdiagnoses. The standards we have suggested to identify rare bacteria strains is applicable not only to Brucella, but also to other rarely encountered bacteria. PMID- 26048694 TI - Impact of cholesterol on disease progression. AB - Cholesterol-rich microdomains (also called lipid rafts), where platforms for signaling are provided and thought to be associated with microbe-induced pathogenesis and lead to cancer progression. After treatment of cells with cholesterol disrupting or usurping agents, raft-associated proteins and lipids can be dissociated, and this renders the cell structure nonfunctional and therefore mitigates disease severity. This review focuses on the role of cholesterol in disease progression including cancer development and infectious diseases. Understanding the molecular mechanisms of cholesterol in these diseases may provide insight into the development of novel strategies for controlling these diseases in clinical scenarios. PMID- 26048696 TI - P-coumaric acid regulates exon 12 splicing of the ATP7B gene by modulating hnRNP A1 protein expressions. AB - BACKGROUND: Wilson's disease (WD) is a genetic disorder involving the metabolism of copper. WD patients exhibit a wide range of disease phenotypes, including Kayser-Fleischer rings in the cornea, predominant progressive hepatic disease, neurological diseases, and/or psychiatric illnesses, among others. Patients with exon12 mutations of the ATP7B gene have progressive hepatic disease. An ATP7B gene that lacks exon12 retains 80% of its copper transport activities, suggesting that alternative splicing of ATP7B gene may provide alternative therapeutic ways for patients with inherited sequence variants and mutations of this gene. PURPOSE: We aimed to search for possible Chinese herbs and related compounds for modulating ATP7B premRNA splicing. METHODS: We used an ATP7B exon11-12-13 mini gene vector as a model and screened 18 Chinese herbal extracts and four compounds from Schizonepeta to determine their effects on ATP7B pre-mRNA splicing in vitro. RESULTS: We found that Schizonepeta demonstrated the greatest potential for alternative splicing activity. Specifically, we found that p-coumaric acid from this herb enhanced ATP7B exon12 exclusion through the down-regulation of heterogeneous ribonucleoprotein (hnRNP) A1 protein expressions. CONCLUSION: These results suggest that there are herbs or herb-related compounds that could modify the alternative splicing of the ATP7B gene via a mechanism that regulates pre mRNA splicing. PMID- 26048697 TI - Low-tube voltage 100 kVp MDCT in screening of cocaine body packing: image quality and radiation dose compared to 120 kVp MDCT. AB - PURPOSE: The aim of this study was to evaluate the impact of a reduced tube potential (100 kVp) for non-enhanced abdominal low-dose CT on radiation dose and image quality (IQ) in the detection of body packing. METHODS: This retrospective study was approved by the local research ethics committee of our clinic. From March 2012 to July 2014, 99 subjects were referred to our institute with suspected body packing. 50 CT scans were performed using a 120 kVp protocol (group A), and 49 CTs were performed using a low-dose protocol with a tube voltage of 100 kVp (group B). Subjective and objective IQ were assessed. DLP and CTDIvol were analyzed. RESULTS: All examinations were of diagnostic IQ. Objective IQ was not significantly different between the 120 kVp and 100 kVp protocol. Mean density of solid and liquid body packets was 210 +/- 60.2 HU at 120 kVp and 250.6 +/- 29.7 HU at 100 kVp. Radiation dose was significantly lower in group B as compared to group A (p < 0.05). In group A, body packs were detected in 16 (32%) of the 50 patients. In group B, packets were observed in 15 (31%) of 49 patients. Laboratory analysis detected cocaine in all smuggled body packs. CONCLUSIONS: Low tube voltage 100 kVp MDCT with automated tube current modulation in screening of illegal drugs leads to a diagnostic IQ and significant dose reduction compared to 120 kVp low-tube voltage protocols. Despite lower radiation dose, liquid and solid cocaine containers retain high attenuation and are easily detected. PMID- 26048698 TI - The influence of anti-TNF therapy on the magnetic resonance enterographic parameters of Crohn's disease activity. AB - PURPOSE: Magnetic resonance enterography (MRE) is a useful tool in assessing the transmural and extraintestinal lesions in Crohn's disease (CD). However, the influence of anti-tumor necrosis factor (anti-TNF) therapy on MRE features of CD severity remains unknown. The purpose of the study was to assess the short- and long-term changes in MRE features of CD activity in relation to CD clinical course in patients treated with anti-TNF antibodies. METHODS: The influence on the most important parameters of CD activity seen in MRE was assessed retrospectively using a validated score. Patients were treated with anti-TNF agents and the clinical, laboratory, and MRE CD activity was estimated at baseline, after the induction therapy and after 1 year of treatment. RESULTS: 71 patients were enrolled in a study. The change in CD clinical activity correlated significantly with fluctuations in MRE activity score (P < 0.0001, r = 0.5 for induction; P = 0.004, r = 0.7 for maintenance anti-TNF therapy, respectively). Bowel wall thickening, mesenteric lymphadenopathy, and fat wrapping with vascular proliferation were MRE parameters which changed significantly both after the induction and maintenance treatment in patients responding to the therapy. The change in MRE activity score was mostly pronounced during the first 3 months of treatment, when compared to the continuation of the therapy till week 52-54 (-6 points vs. -2 points, respectively; P = 0.0008). CONCLUSIONS: Transmural and extraintestinal healing seen in MRE correlates with changes in CD clinical activity during anti-TNF therapy, thus MRE seems to be a useful tool in monitoring the efficacy of biological agents. PMID- 26048699 TI - Suburothelial and extrinsic lesions of the urinary bladder: radiologic and pathologic features with emphasis on MR imaging. AB - OBJECTIVE: The purpose of this article is to present a contemporary review of the imaging appearance of diseases which affect the deeper layers of the urinary bladder, including both suburothelial and extrinsic pathologies, using radiologic pathologic correlation. CONCLUSION: Compared to the more common urothelial lesions, at cystoscopy, suburothelial and extrinsic diseases of the urinary bladder wall often have a non-specific appearance or may be occult. Cross sectional imaging, in particular MRI, plays an integral role in diagnosis. Mesenchymal tumors have distinct imaging features on MRI. Leiomyomas are characteristically low signal intensity on T2-weighted (T2W) imaging and progressively enhance. Lipomas and lipomatous hypertrophy are diagnosed by the presence of macroscopic fat. Neurofibromas, hemangiomas, and paragangliomas are hyperintense on T2W sequences and hypervascular. Reactive lesions occur in the setting of chronic inflammation and include: nephrogenic adenoma, cystitis cystica, and cystitis glandularis. Imaging findings are commonly non-specific; however, a mass with internal cystic spaces in association with pelvic lipomatosis is suggestive of cystitis glandularis. Urachal anomalies may be complicated by infection or malignancy. Urachal mucinous adenocarcinoma has a poor prognosis and may present as a T2-hyperintense suburothelial/extrinsic mass centered in the bladder dome. Other diseases may extrinsically involve the urinary bladder by hematogenous and peritoneal spread, including infection, endometriosis, and malignancy. A familiarity with suburothelial and extrinsic pathologies of the urinary bladder is critical for the radiologist, who may be the first to suggest these diagnoses. PMID- 26048700 TI - The difference between energy consumption and energy cost: Modelling energy tariff structures for water resource recovery facilities. AB - The objective of this paper is to demonstrate the importance of incorporating more realistic energy cost models (based on current energy tariff structures) into existing water resource recovery facilities (WRRFs) process models when evaluating technologies and cost-saving control strategies. In this paper, we first introduce a systematic framework to model energy usage at WRRFs and a generalized structure to describe energy tariffs including the most common billing terms. Secondly, this paper introduces a detailed energy cost model based on a Spanish energy tariff structure coupled with a WRRF process model to evaluate several control strategies and provide insights into the selection of the contracted power structure. The results for a 1-year evaluation on a 115,000 population-equivalent WRRF showed monthly cost differences ranging from 7 to 30% when comparing the detailed energy cost model to an average energy price. The evaluation of different aeration control strategies also showed that using average energy prices and neglecting energy tariff structures may lead to biased conclusions when selecting operating strategies or comparing technologies or equipment. The proposed framework demonstrated that for cost minimization, control strategies should be paired with a specific optimal contracted power. Hence, the design of operational and control strategies must take into account the local energy tariff. PMID- 26048701 TI - Characterization of the quinones in purple sulfur bacterium Thermochromatium tepidum. AB - Quinone distributions in the thermophilic purple sulfur bacterium Thermochromatium tepidum have been investigated at different levels of the photosynthetic apparatus. Here we show that, on average, the intracytoplasmic membrane contains 18 ubiquinones (UQ) and 4 menaquinones (MQ) per reaction center (RC). About one-third of the quinones are retained in the light-harvesting reaction center core complex (LH1-RC) with a similar ratio of UQ to MQ. The numbers of quinones essentially remains unchanged during crystallization of the LH1-RC. There are 1-2 UQ and 1 MQ associated with the RC-only complex in the purified solution sample. Our results suggest that a large proportion of the quinones are confined to the core complex and at least five UQs remain invisible in the current LH1-RC crystal structure. PMID- 26048702 TI - Transpiration of urban trees and its cooling effect in a high latitude city. AB - An important ecosystem service provided by urban trees is the cooling effect caused by their transpiration. The aim of this study was to quantify the magnitude of daytime and night-time transpiration of common urban tree species in a high latitude city (Gothenburg, Sweden), to analyse the influence of weather conditions and surface permeability on the tree transpiration, and to find out whether tree transpiration contributed to daytime or nocturnal cooling. Stomatal conductance and leaf transpiration at day and night were measured on mature street and park trees of seven common tree species in Gothenburg: Tilia europaea, Quercus robur, Betula pendula, Acer platanoides, Aesculus hippocastanum, Fagus sylvatica and Prunus serrulata. Transpiration increased with vapour pressure deficit and photosynthetically active radiation. Midday rates of sunlit leaves ranged from less than 1 mmol m(-2) s(-1) (B. pendula) to over 3 mmol m(-2) s(-1) (Q. robur). Daytime stomatal conductance was positively related to the fraction of permeable surfaces within the vertically projected crown area. A simple estimate of available rainwater, comprising of precipitation sum and fractional surface permeability within the crown area, was found to explain 68% of variation in midday stomatal conductance. Night-time transpiration was observed in all studied species and amounted to 7 and 20% of midday transpiration of sunlit and shaded leaves, respectively. With an estimated night-time latent heat flux of 24 W m(-2), tree transpiration significantly increased the cooling rate around and shortly after sunset, but not later in the night. Despite a strong midday latent heat flux of 206 W m(-2), a cooling effect of tree transpiration was not observed during the day. PMID- 26048704 TI - Root of Dictyostelia based on 213 universal proteins. AB - Dictyostelia are common soil microbes that can aggregate when starved to form multicellular fruiting bodies, a characteristic that has also led to their long history of study and widespread use as model systems. Ribosomal RNA phylogeny of Dictyostelia identified four major divisions (Groups 1-4), none of which correspond to traditional genera. Group 1 was also tentatively identified as sister lineage to the other three Groups, although not consistently or with strong support. We tested the dictyostelid root using universal protein-coding genes identified by exhaustive comparison of six completely sequenced dictyostelid genomes, which include representatives of all four major molecular Groups. A set of 213 genes are low-copy number in all genomes, present in at least one amoebozoan outgroup taxon (Acanthamoeba castellanii or Physarum polycephalum), and phylogenetically congruent. Phylogenetic analysis of a concatenation of the deduced protein sequences produces a single topology dividing Dictyostelia into two major divisions: Groups 1+2 and Groups 3+4. All clades in the tree are fully supported by maximum likelihood and Bayesian inference, and all alternative roots are unambiguously rejected by the approximately unbiased (AU) test. The 1+2, 3+4 root is also fully supported even after deleting clusters with strong individual support for this root, or concatenating all clusters with low support for alternative roots. The 213 putatively ancestral amoebozoan proteins encode a wide variety of functions including 21 KOG categories out of a total of 25. These comprehensive analyses and consistent results indicate that it is time for full taxonomic revision of Dictyostelia, which will also enable more effective exploitation of its unique potential as an evolutionary model system. PMID- 26048705 TI - Origin and evolution of fleshy fruit in woody bamboos. AB - Several hypotheses have been suggested to explain the origin of fleshy fruit in monocots. One is that they originated in the understory of tropical regions and another is that fleshy fruit originated in tropical rainforests where high year round rainfall implies that seasonality is not a limiting factor. Here we identify the time of origin and ecological preferences of woody bamboos to understand the evolution of the fleshy fruit known as the bacoid caryopsis. Bayesian Inference, Maximum Likelihood and molecular dating analyses were run based on eight plastid and two nuclear regions for 68 bamboo species. Climate data and soil parameters were gathered for 464 localities for these species. The ancestral type of caryopsis was reconstructed by parsimony. According to these analyses the bacoid caryopsis may have evolved independently seven times from the Late Miocene to the Early Pliocene and Mid-Pliocene to Mid-Pleistocene via convergent evolution. Our results suggest that in bamboos neither current climatic variables nor soil parameters were significantly correlated with the appearance of this type of fruit, nor do they have a phylogenetic signal. It is remarkable, however, that the first appearance of the bacoid caryopsis in bamboos might be associated with historical preferences for warmer and wetter climate during the Miocene. Further research is needed to identify whether other factors, such as vivipary or dispersal by small animals, rather than climate, could be responsible for the evolution of this trait in woody bamboos. PMID- 26048703 TI - Stable Isotope Ratios as Biomarkers of Diet for Health Research. AB - Diet is a leading modifiable risk factor for chronic disease, but it remains difficult to measure accurately due to the error and bias inherent in self reported methods of diet assessment. Consequently, there is a pressing need for more objective biomarkers of diet for use in health research. The stable isotope ratios of light elements are a promising set of candidate biomarkers because they vary naturally and reproducibly among foods, and those variations are captured in molecules and tissues with high fidelity. Recent studies have identified valid isotopic measures of short- and long-term sugar intake, meat intake, and fish intake in specific populations. These studies provide a strong foundation for validating stable isotopic biomarkers in the general US population. Approaches to improve specificity for specific foods are needed; for example, by modeling intake using multiple stable isotope ratios or by isolating and measuring specific molecules linked to foods of interest. PMID- 26048706 TI - Outcomes following 'mini' percutaneous nephrolithotomy for renal calculi in children. A single-centre study. AB - INTRODUCTION: This retrospective review was undertaken to identify the postoperative outcomes of children undergoing 'mini' percutaneous nephrolithotomy (MPCNL) at a single institution. OBJECTIVE: Outcomes measured included: percentage of stone clearance, postoperative analgesia requirements, the need for intraoperative or postoperative blood transfusion, length of stay and morbidity. STUDY DESIGN: A total of 46 patients were reviewed over a two-and-a-half-year period; the mean age was 7.3 years (range: 1-16 years). The MPCNL was performed with a radiological-guided peripheral puncture, followed by dilatation of the nephrostomy tract to a maximum Amplatz sheath size of 16-French; an 11-French nephroscope was used. Stone disintegration was achieved either with pneumatic or laser lithotripsy. RESULTS: Complete stone clearance was achieved in 35/46 children (76%). The remaining 11 children had a stone clearance rate of over 80%. No patients required intraoperative/postoperative blood transfusion. A total of 39% of patients were managed on simple/non-opiate based analgesia, with 54% requiring opioid analgesia postoperatively for less than 24 h. There were no procedure-related complications and no mortalities. The mean length of stay was 2.24 days. DISCUSSION: The management of urolithiasis can be challenging in children. The use of percutaneous nephrolithotomy, is becoming increasingly popular in the treatment of paediatric urolithiasis. The stone clearance rate in children undergoing standard PCNL, has been reported to be 50-98% in the literature [1,2,3,4]. Samad et al. [2] in 2006, reported their experience in 188 consecutive PCNLs, using a 17Fr or 26Fr nephroscope. Their largest sub group included children aged >5-16 yrs. Within this group, 57% were treated with a 17Fr nephroscope and 43% with the 26Fr nephroscope, achieving stone clearance of only 47% with PCNL monotherapy. In this group the transfusion rate was 3% [2]. Badawy et al., reported their experience of 60 children in 1999, using a 26 or 28Fr Amplatz sheath. They reported an 83.3% stone clearance with single session PCNL, with only one procedure being abandoned due to intraoperative bleeding requiring blood transfusion [3]. In 2007, Bilen et al. reported their experience and compared the use of 26Fr, 20Fr and 14Fr (mini) PCNL. Stone size, previous surgery and the mean haemoglobin drop postoperatively did not change between the groups, however the blood transfusion rate was higher in the 26Fr and 20Fr Amplatz sheath groups. The stone clearance was highest in the 'mini PCNL' group at 90%, compared to 69.5% in the 26Fr and 80% in the 20Fr group [4]. MPCNL has become increasingly popular over recent years, with stone clearance reported as 80-85% [5-7] following a single session of MPCNL as monotherapy. In 2012, Yan et al. reported 85.2% stone clearance with mini PCNL monotherapy (tract size 14-16Fr), with no children requiring blood transfusion [6]. Zeng et al. reported their experience of 331 renal units in children, with stone clearance rates reaching 80.4% and a blood transfusion rate of 3.1% [8]. In our centre, we do not perform postoperative haemoglobin levels as a matter of routine and any investigations are performed on an intention to treat principle. Bilen et al. reported no blood transfusions being required in their cohort of patients undergoing MPCNL [4] and this is supported by Yan et al. [6]. CONCLUSION: Mini PCNL is an effective and safe procedure for the treatment of paediatric renal stones. In the present series, all children achieved greater than 80% stone clearance, none received a blood transfusion (intra/postoperatively) and there were no mortalities. Postoperative pain was managed with simple analgesia in 39%; however, the majority required opiate analgesia for less than 24 hours. PMID- 26048707 TI - Caregiving and bereavement research: Bridges over the gap. PMID- 26048708 TI - Rhino-orbito-cerebral mucormycosis. Management strategies to avoid or limit intracraneal affection and improve survival. AB - Mucormycosis is a rare opportunistic infection. The aim of the study was to review the cases presented in our department with rhino-orbital mucormycosis and to describe the clinical protocol, diagnosis and therapy used in these patients. We conducted a retrospective, longitudinal, descriptive study, in which we evaluated the records of patients with rhino-orbital mucormycosis in the period from January to October 2013. We found 5 cases. Pterigomaxillary fossa disease was found in 100% of our patients. Medical and surgical treatment performed early by extensive endoscopic debridement (including debridement and resection of pterygomaxillary fossa) and orbital exenteration in patients presenting with orbitary apex syndrome in conjunction with the ophthalmology department of our hospital, with excellent results in the survival of our patients (all patients survived). PMID- 26048709 TI - EU report shows massive increase in legal highs. PMID- 26048710 TI - Developing a framework of care for opioid medication misuse in community pharmacy. AB - BACKGROUND: Prescription opioid misuse is a major public health concern in the US. Few resources exist to support community pharmacists engaging patients who misuse or are at risk for misuse. OBJECTIVES: This report describes the results of the execution of the ADAPT-ITT model (a model for modifying evidence-based behavioral interventions to new populations and service settings) to guide the development of a behavioral health framework for opioid medication misuse in the community pharmacy setting. METHODS: Pharmacy, addiction, intervention, and treatment experts were convened to attend a one-day meeting to review the empirical knowledgebase and discuss adapting the screening, brief intervention, and referral to treatment (SBIRT) protocol for addressing opioid medication misuse in community pharmacy. Qualitative data gathered from the meeting were analyzed by 2 independent coders in a 2-cycle process using objective coding schemes. Percentage of agreement and Cohen's Kappa were calculated to assess coder agreement. RESULTS: First-cycle coding identified 4 distinct themes, with coder percentage of agreement ranging from 93.5 to 99.6% and with Kappa values between 0.81 and 0.93. Second-cycle coding identified 10 sub-themes, with coder percentage of agreement ranging from 83 to 99.8% and with Kappa values between 0.58 and 0.93. Identified themes and sub-themes encompassed patient identification, intervention, prevention, and referral to treatment. CONCLUSIONS: Focus of screening efforts in the emerging model should capitalize on pharmacists' knowledge of medication management. Screening likewise should be multidimensional in order to facilitate patient-centered interventions that activate additional disciplines able to interface with patients at risk or involved in medication misuse. PMID- 26048711 TI - Factors influencing nurse and pharmacist willingness to take or not take responsibility for non-medical prescribing. AB - BACKGROUND: In the UK, the majority of non-medical prescribers (NMPs) are nurses or pharmacists working in community or primary care. However, little is known about what influences their decisions to prescribe, unlike with medical prescribing. It is also unclear whether the medical findings can be extrapolated, given their very different prescribing training. OBJECTIVES: To explore the factors influencing whether nurse and pharmacist NMPs in community and primary care settings take responsibility for prescribing. METHODS: Initially, 20 NMPs (15 nurses and 5 pharmacists) were purposively selected and interviewed using the critical incident technique about situations where they felt it was inappropriate for them to take responsibility for prescribing or where they were uneasy about doing so. In addition, more general factors influencing their decision to take or not take prescribing responsibility were discussed. Subsequently, the themes from the interview analysis were validated in three focus groups with a total of 10 nurse NMPs. All data were analyzed using a constant comparison approach. RESULTS: Fifty-two critical incidents were recorded--12 from pharmacist NMPs and 40 from nurse NMPs. Participants experienced situations where they were reluctant to accept responsibility for prescribing. Perceptions of competency, role and risk influenced their decision to prescribe. Workarounds such as delaying the prescribing decision or refer the patient to a doctor were used. CONCLUSIONS: For NMPs to feel more confident about taking responsibility for prescribing, these issues of competency, role and perceived risk need to be addressed. Roles of NMPs must be clear to colleagues, doctors and patients. Training and support must be provided to enable professional development and increasing competence of NMPs. PMID- 26048712 TI - A lupane-triterpene isolated from Combretum leprosum Mart. fruit extracts that interferes with the intracellular development of Leishmania (L.) amazonensis in vitro. AB - BACKGROUND: 3beta,6beta,16beta-trihydroxylup-20(29)-ene is a lupane triterpene isolated from Combretum leprosum fruit. The lupane group has been extensively used in studies on anticancer effects; however, its possible activity against protozoa parasites is yet poorly known. The high toxicity of the compounds currently used in leishmaniasis chemotherapy stimulates the investigation of new molecules and drug targets for antileishmanial therapy. METHODS: The activity of 3beta,6beta,16beta-trihydroxylup-20(29)-ene was evaluated against Leishmania (L.) amazonensis by determining the cytotoxicity of the compound on murine peritoneal macrophages, as well as its effects on parasite survival inside host cells. To evaluate the effect of this compound on intracellular amastigotes, cultures of infected macrophages were treated for 24, 48 and 96 h and the percentage of infected macrophages and the number of intracellular parasites was scored using light microscopy. RESULTS: Lupane showed significant activity against the intracellular amastigotes of L. (L.) amazonensis. The treatment with 109 MUM for 96 h reduced in 80 % the survival index of parasites in BALB/c peritoneal macrophages. At this concentration, the triterpene caused no cytotoxic effects against mouse peritoneal macrophages. Ultrastructural analyses of L. (L.) amazonensis intracellular amastigotes showed that lupane induced some morphological changes in parasites, such as cytosolic vacuolization, lipid body formation and mitochondrial swelling. Bioinformatic analyses through molecular docking suggest that this lupane has high-affinity binding with DNA topoisomerase. CONCLUSION: Taken together, our results have showed that the lupane triterpene from C. leprosum interferes with L. (L.) amazonensis amastigote replication and survival inside vertebrate host cells and bioinformatics analyses strongly indicate that this molecule may be a potential inhibitor of topoisomerase IB. Moreover, this study opens major prospects for the development of novel chemotherapeutic agents with leishmanicidal activity. PMID- 26048713 TI - The effect of different ranges of motion on local dynamic stability of the elbow during unloaded repetitive flexion-extension movements. AB - Local dynamic stability (LDS) of movement is controlled primarily by active muscles, and is known to be influenced by factors such as movement speed and inertial load. Other factors such as muscle length, the length of the target trajectory, and the resistance of passive tissues through ranges of motion (ROM) may also influence LDS. This study was designed to examine the effect of ROM, which impacts each of the aforementioned factors, on LDS of the elbow. 16 participants performed 30 unloaded, repetitive, flexion-extension movements of the elbow with varying (1) angular displacement magnitudes: 40 degrees and 80 degrees ; (2) locations of ROM: mid-range, flexion end-range, extension end range; and (3) rotated positions of the forearm: pronated and supinated. LDS was calculated using a finite time Lyapunov analysis of angular elbow flexion extension kinematic data. EMG-based muscle activation and co-contraction data were also examined for possible mechanisms of stabilization. Results showed no changes in LDS with any movement condition; however, there were significant effects on muscle activation with ROM location and forearm rotated position. This suggests that a consistent level of LDS of the elbow through varying ROMs is maintained, at least in part, by the active control of the elbow flexor and extensor muscles. PMID- 26048714 TI - Kaempferol inhibits vascular smooth muscle cell migration by modulating BMP mediated miR-21 expression. AB - Bioflavonoids are known to induce cardioprotective effects by inhibiting vascular smooth muscle cell (VSMC) proliferation and migration. Kaempferol has been shown to inhibit VSMC proliferation. However, little is known about the effect of kaempferol on VSMC migration and the underlying molecular mechanisms. Our studies provide the first evidence that kaempferol inhibits VSMC migration by modulating the BMP4 signaling pathway and microRNA expression levels. Kaempferol activates the BMP signaling pathway, induces miR-21 expression and downregulates DOCK4, 5, and 7, leading to inhibition of cell migration. Moreover, kaempferol antagonizes the PDGF-mediated pro-migratory effect. Therefore, our study uncovers a novel regulatory mechanism of VSMC migration by kaempferol and suggests that miRNA modulation by kaempferol is a potential therapy for cardiovascular diseases. PMID- 26048715 TI - Punicalagin attenuates osteoclast differentiation by impairing NFATc1 expression and blocking Akt- and JNK-dependent pathways. AB - Punicalagin is a bioactive polyphenol that is classified as an ellagitannin. Although punicalagin has been shown to have various pharmacological effects, such as anti-oxidative, anti-inflammatory, and anti-tumor effects, no studies have reported the effects of punicalagin on osteoclasts (OCLs). In this study, we investigated the effects of punicalagin on OCL differentiation by receptor activator of nuclear factor kappa-B ligand in the murine monocytic RAW-D cell line and bone marrow-derived macrophages (BMMs). Treatment with punicalagin significantly inhibited OCL formation from RAW-D cells and BMMs and prevented bone resorption of BMM-derived OCLs. Moreover, punicalagin impaired multinucleation and actin-ring formation in OCLs, and decreased the protein levels of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), which is a master regulator of OCL differentiation, and concomitantly reduced the expression levels of Src and cathepsin K, which are transcriptionally regulated by NFATc1. The effects of punicalagin on intracellular signaling during the OCL differentiation of BMMs indicated that punicalagin-treated OCLs displayed markedly reduced phosphorylation of Jun N-terminal kinase and Akt, and partially impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen activated protein kinase, and inhibitor of nuclear factor kappa-B alpha compared with untreated OCLs. Thus, punicalagin may affect bone metabolism by inhibiting OCL differentiation. PMID- 26048716 TI - Rosiglitazone suppresses HIV-1 Tat-induced vascular inflammation via Akt signaling. AB - Peroxisome proliferator-activated receptor gamma (PPARGamma) contributes to human immunodeficiency virus (HIV)-1-induced dysfunction of brain endothelial cells. The aim of the present study was to evaluate the protection mechanism of PPARGamma against Tat-induced responses of adhesion molecules. We measured the protein expressions of intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 in human brain microvascular endothelial cells (hCMEC/D3) and C57BL/6J mouse brain microvessels with Western blotting and immunofluorescent labeling. The mRNA levels of ICAM-1 and VCAM-1 were determined by real-time reverse-transcriptase polymerase chain reaction. HIV-1 Tat induced overexpression of ICAM-1 but not VCAM-1 in both hCMEC/D3 and brain microvessels, this response was attenuated by treatment with the PPARGamma agonist rosiglitazone. Tat-mediated upregulation of ICAM-1 and VCAM-1 levels were abolished by the addition of PPARGamma antagonist GW9662 and the Akt inhibitor KP3721, indicating that Akt signaling is involved in the PPARGamma-mediated protection of Tat-induced adhesion molecule upregulation. These results show that Akt signaling plays a key role in PPARGamma's vascular inflammatory effects that contribute to blood-brain barrier damage. PMID- 26048717 TI - Effect of estrogen on expression of prohibitin in white adipose tissue and liver of diet-induced obese rats. AB - Prohibitin (PHB) is a ubiquitously expressed and highly conserved protein that participates in diverse cellular processes, and its functions are linked to a variety of diseases. In the present study, to explore transcriptional activation and signaling pathways involved in PHB regulation in response to sex hormone treatment, we investigated the effects of estrogen (17-beta-estradiol, E2) on regulation of PHB in several metabolic tissues from male and female rats. Elevated expression of PHB was prominent in white adipose tissue (WAT) and the liver, and E2 stimulated PHB expression in both ND and HFD-fed rats. To further confirm the expression of PHB which was increased in WAT and the liver, we analyzed PHB expression levels in 3T3-L1 and C9 cells after the treatment of E2. Transcription and protein levels of PHB were dose-dependently increased by E2 treatment in both cell types, supporting our in vivo data. To further evaluate the possible role of E2 in elevation of PHB via estrogen receptors (ER), the potent ER inhibitor fulvestrant was treated to 3T3-L1 and C9 cells. Fulvestrant markedly suppressed both transcription and protein levels of PHB, suggesting that PHB expression in both tissues may be regulated through ERs. GeneMANIA, a predictive web interface, was used to show that Phb is regulated via the intracellular steroid hormone receptor signaling pathway, suggesting a role for ERs in expression of Phb as well as other metabolically important genes. Based on these results, we expect that targeting PHB would be a useful therapeutic approach for treatment of obesity. PMID- 26048719 TI - An assessment of image distortion and CT number accuracy within a wide-bore CT extended field of view. AB - Although wide bore computed tomography (CT) scanners provide increased space for patients, the scan field of view (sFOV) remains considerably smaller than the bore size. Consequently, patient anatomy which spans beyond the sFOV is truncated and the information is lost. As a solution, some manufacturers provide the capacity to reconstruct CT images from a partial dataset at an extended field of view (eFOV). To assess spatial distortion within this eFOV three phantoms were considered a 30 * 30 * 20 cm(3) slab of solid water, the Gammex electron density CT phantom and a female anthropomorphic phantom. For each phantom, scans were taken centrally within the sFOV as a reference image and with the phantom edge extended at 1 cm intervals from 0 to 5 cm beyond the sFOV into the eFOV. To assess CT number accuracy various tissue equivalent materials were scanned in the eFOV and resulting CT numbers were compared to inserts scanned within the sFOV. For all phantom geometries, objects within the eFOV were geometrically overestimated with elongation of phantom shapes into the eFOV. The percentage increase in size ranged from 0.22 to 15.94 % over all phantoms considered. The difference between eFOV and sFOV CT numbers was dependent upon insert density. The eFOV underestimated CT numbers in the range of -127 to -230 HU for soft tissue densities and -278 to -640 for bone densities. This trend reversed for low tissue densities with the CT numbers in the eFOV being overestimated by 100-130 HU for lung equivalent inserts. Initial correlation between eFOV and sFOV CT numbers was seen and a correction function was successfully applied to better estimate the CT number representative of that seen within the sFOV. PMID- 26048718 TI - Cellular therapy in combination with cytokines improves survival in a xenograft mouse model of ovarian cancer. AB - Studies have shown enhanced survival of ovarian cancer patients in which the tumors are infiltrated with tumor infiltrating lymphocytes and natural killer cells showing the importance of immune surveillance and recognition in ovarian cancer. Therefore, in this study, we tested cellular immunotherapy and varying combinations of cytokines (IL-2 and/or pegylated-IFNalpha-2b) in a xenograft mouse model of ovarian cancer. SKOV3-AF2 ovarian cancer cells were injected intra peritoneally (IP) into athymic nude mice. On day 7 post-tumor cell injection, mice were injected IP with peripheral blood mononuclear cells (PBMC; 5 * 10(6) PBMC) and cytokine combinations [IL-2 +/- pegylated-IFNalpha-2b (IFN)]. Cytokine injections were continued weekly for IFN (12,000 U/injection) and thrice weekly for IL-2 (4000 U/injection). Mice were euthanized when they became moribund due to tumor burden at which time tumor and ascitic fluid were measured and collected. Treatment efficacy was measured by improved survival at 8 weeks and overall survival by Kaplan-Meier analysis. We observed that the mice tolerated all treatment combinations without significant weight loss or other apparent illness. Mice receiving PBMC plus IL-2 showed improved median survival (7.3 weeks) compared to mice with no treatment (4.2 weeks), IL-2 (3.5 weeks), PBMC (4.0 weeks), or PBMC plus IL-2 and IFN (4.3 weeks), although PBMC plus IL-2 was not statistically different than PBMC plus IFN (5.5 weeks, p > 0.05). We demonstrate that cytokine-stimulated cellular immune therapy with PBMC and IL-2 was well tolerated and resulted in survival advantage compared to untreated controls and other cytokine combinations in the nude-mouse model. PMID- 26048720 TI - [Spread of genetically related methicillin-susceptible Staphylococcus aureus belonging to CC45, in healthy nasal carriers in Child Day Care Centers of Medellin, Colombia]. AB - INTRODUCTION: Colonization plays a major role in the epidemiology and pathogenesis of Staphylococcus aureus infections. The child population is one of the most susceptible to colonization; however, community and children studies are limited in Colombia. OBJECTIVE: To assess the clonal relationship of S.aureus strains isolated from colonized children in eight day care centers (DCCs) from Medellin and to determine the presence of epidemiological characteristics in these populations. METHODS: An observational cross-sectional study was conducted on a sample of 200 children aged from 6 months to 5 years attending eight DCCs in Medellin, Colombia, during 2011. Nasal samples were collected from each nostril. The isolates species and methicillin resistance were molecularly confirmed using nuc and mec genes. Genotypic analysis included SCCmec typing, spa typing, PFGE and MLST. Epidemiological information was obtained from the parents and analyzed using the statistics program SPSS 21.0 RESULTS: The colonization frequency in DCCs ranged from 16.7% (n=3) to 53.6% (n=15). Genetically related isolates were identified inside four DCCs. Half (50%) of the isolates were grouped in 3 clusters, which belonged to the clonal complexes CC45, CC30, and CC121. CONCLUSION: Molecular typing of isolates from colonized children and comparison among DCCs showed the spread of colonizing strains inside DCCs in Medellin; predominantly the CC45 clone, a successful child colonizer. PMID- 26048721 TI - Evaluation of wavelength-dependent hair growth effects on low-level laser therapy: an experimental animal study. AB - In this study, we aimed to investigate the wavelength-dependent effects of hair growth on the shaven backs of Sprague-Dawley rats using laser diodes with wavelengths of 632, 670, 785, and 830 nm. Each wavelength was selected by choosing four peak wavelengths from an action spectrum in the range 580 to 860 nm. The laser treatment was performed on alternating days over a 2-week period. The energy density was set to 1.27 J/cm(2) for the first four treatments and 1.91 J/cm(2) for the last four treatments. At the end of the experiment, both photographic and histological examinations were performed to evaluate the effect of laser wavelength on hair growth. Overall, the results indicated that low-level laser therapy (LLLT) with a 830-nm wavelength resulted in greater stimulation of hair growth than the other wavelengths examined and 785 nm also showed a significant effect on hair growth. PMID- 26048722 TI - Why weight for happiness? Correlates of BMI and SWB in Australia. AB - Despite our best medical and behavioural strategies, the physical and mental health of the overweight and obese remains compromised. In an effort to improve treatment outcomes, research has begun to focus on (1) specific BMI categories, and (2) subjective well-being (SWB), a broad construct exploring how we evaluate and experience our lives. Positive psychology is concerned with SWB, through the application of variables associated with health, happiness and optimal functioning. To date, research exploring the relationship between BMI categories and SWB is lacking for community based Australians. This study employed a cross sectional design using an online survey method (n=260). SWB and related variables were assessed over five BMI categories including normal, overweight, and obese classes one, two and three. Main findings suggest the class two and three obese demonstrated significantly lower scores on flourishing in comparison with the normal and overweight. The class three obese also demonstrated higher depression, and lower scores on agency and positive affect in comparison with the normal and overweight. Furthermore class two and three obese reported lower scores on pathways thinking than the overweight. Results provide preliminary support for the hypothesis that a lack of SWB may contribute to or maintain atypical BMI. Implications for treatment interventions are discussed. PMID- 26048723 TI - The construction of professional identity by physiotherapists: a qualitative study. AB - The U.K. Frances Report and increasing societal expectations of healthcare have challenged physiotherapists to reconsider professionalism. Physiotherapy has viewed identity as a fixed entity emphasising coherence, continuity and distinctiveness. Socialisation has required the acquisition of a professional identity as one necessary 'asset' for novices. Yet how do physiotherapists come to be the physiotherapists they are? DESIGN: Qualitative study using Collective Memory Work. Eight physiotherapists in South West England met for two hours, once a fortnight, for six months. Seventeen hours of group discussions were recorded and transcribed. Data were managed via the creation of crafted dialogues and analysed using narrative analysis. RESULTS: Participants shared ethical dilemmas: successes and unresolved anxiety about the limits of personal actions in social situations. These included matters of authenticity, role strain, morality, diversity. Participants made claims about their identity; claims made to support an attitude, belief, motivation or value. CONCLUSIONS: Professional identity in physiotherapy is more complex than traditionally thought; fluid across time and place, co-constructed within changing communities of practice. An ongoing and dynamic process, physiotherapists make sense and (re)interpret their professional self-concept based on evolving attributes, beliefs, values, and motives. Participants co-constructed the meaning of being a physiotherapist within intra professional and inter-professional communities of practice. Patients informed this, and it was mediated by workplace and institutional discourses, boundaries and hierarchies, through an unfolding career and the contingencies of a life story. More empirical data are required to understand how physiotherapists negotiate the dilemmas they face and enact the values the profession espouses. PMID- 26048724 TI - Experimental investigation on the use of highly charged nanoparticles to improve the stability of weakly charged colloidal system. AB - The present work highlighted on the implementation of a unique concept for stabilizing colloids at their incipiently low charge potential. A highly charged nanoparticle was introduced within a coagulated prone colloidal system, serving as stabilizer to resist otherwise rapid flocculation and sedimentation process. A low size asymmetry of nanoparticle/colloid serves as the new topic of investigation in addition to the well-established large size ratio nanoparticle/microparticle study. Highly charged Al2O3 nanoparticles were used within the present research context to stabilize TiO2 and Fe3O4 based colloids via the formation of composite structures. It was believed, based on the experimental evidence, that Al2O3 nanoparticle interact with the weakly charged TiO2 and Fe3O4 colloids within the binary system via absorption and/or haloing modes to increase the overall charge potential of the respective colloids, thus preventing further surface contact via van der Waal's attraction. Series of experimental results strongly suggest the presence of weakly charged colloids in the studied bimodal system where, in the absence of highly charged nanoparticle, experience rapid instability. Absorbance measurement indicated that the colloidal stability drops in accordance to the highly charged nanoparticle sedimentation rate, suggesting the dominant influence of nanoparticles to attain a well dispersed binary system. Further, it was found that the level of colloidal stability was enhanced with increasing nanoparticle fraction within the mixture. Rheological observation revealed that each hybrid complexes demonstrated behavior reminiscence to water with negligible increase in viscosity which serves as highly favorable condition particularly in thermal transport applications. PMID- 26048726 TI - Editorial 52.2. PMID- 26048725 TI - Niacin Therapy, HDL Cholesterol, and Cardiovascular Disease: Is the HDL Hypothesis Defunct? AB - High-density lipoprotein cholesterol (HDL-C) has been shown in epidemiologic studies to be associated with cardiovascular (CV) risk and thus significant efforts have been focused on HDL-C modulation. Multiple pharmaceutical agents have been developed with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by up to 25 % and was shown in multiple surrogate end point studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects. Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. While these findings have cast doubt upon the importance of HDL-C modulation on CV risk, it is becoming increasingly clear that HDL function related measures may be better targets for CV risk reduction. Increasing ApoA-I, the primary apolipoprotein associated with HDL, correlates with reduced risk of events, and HDL particle concentration (HDL-P) inversely associates with incident CV events adjusted for HDL-C and LDL particle measures. Cholesterol efflux, the mechanism by which macrophages in vessel walls secrete cholesterol outside cells, correlates with both surrogate end points and clinical events. The effects of niacin on these alternate measures of HDL have been conflicting. Further studies should determine if modulation of these HDL function markers translates to clinical benefits. Although the HDL cholesterol hypothesis may be defunct, the HDL function hypothesis is now poised to be rigorously tested. PMID- 26048727 TI - Edible lipids modification processes: A review. AB - Lipid is the general name given to fats and oils, which are the basic components of cooking oils, shortening, ghee, margarine, and other edible fats. The chosen term depends on the physical state at ambient temperature; fats are solids and oils are liquids. The chemical properties of the lipids, including degree of saturation, fatty acid chain length, and acylglycerol molecule composition are the basic determinants of physical characteristics such as melting point, cloud point, solid fat content, and thermal behavior. This review will discuss the major lipid modification strategies, hydrogenation, and chemical and enzymatic interesterification, describing the catalysts used mechanisms, kinetics, and impacts on the health-related properties of the final products. Enzymatic interesterification will be emphasized as method that produces a final product with good taste, zero trans fatty acids, and a low number of calories, requires less contact with chemicals, and is cost efficient. PMID- 26048728 TI - A Current Review of Mechanical Compression and Its Role in Venous Thromboembolic Prophylaxis in Total Knee and Total Hip Arthroplasty. AB - Interest in mechanical compression for venous thromboembolic disease prophylaxis has increased over the last several years because of concerns related to bleeding complications associated with chemoprophylaxis. However, the research evaluating compression is clearly not definitive. Therefore, this review aims to: (1) summarize methods of compression; (2) compare AAOS, ACCP, and SCIP guidelines; and (3) make recommendations regarding usage. Below-the-knee devices have demonstrated the most efficacy with multiple guidelines recommending usage. Efficacy and compliance may be improved with the use of mobile devices. PMID- 26048729 TI - In Vivo Oxidative Stability Changes of Highly Cross-Linked Polyethylene Bearings: An Ex Vivo Investigation. AB - The development of highly cross-linked UHMWPEs focused on stabilizing radiation induced free radicals as the sole precursor to oxidative degradation. However, secondary in vivo oxidation mechanisms have been discovered. After a preliminary post-operative analysis, we subjected highly cross-linked retrievals with 1-4 years in vivo durations and never-implanted controls to accelerated aging to predict the extent to which their oxidative stability was compromised in vivo. Lipid absorption, oxidation, and hydroperoxides were measured using infrared spectroscopy. Gravimetric swelling was used to measure cross-link density. After aging, all retrievals, except vitamin E-stabilized components, regardless of initial lipid levels or oxidation, showed significant oxidative degradation, demonstrated by subsurface oxidative peaks, increased hydroperoxides and decreased cross-link density, compared to their post-operative material properties and never-implanted counterparts, confirming oxidative stability changes. PMID- 26048730 TI - Safety and efficacy of intra-articular tranexamic acid injection without drainage on blood loss in total knee arthroplasty: A randomized clinical trial. AB - BACKGROUND: Major blood loss is unavoidable after primary total knee arthroplasty (TKA). The aim of this study was to determine if tranexamic acid (TXA) can reduce major blood loss following TKA. METHODS: In this double-blind, randomized, placebo-control trial, 60 patients treated with unilateral primary cement TKA between August 1st 2013 and September 30th 2013 were randomized into TXA 500 mg intra-articular injection without drainage (test group, 30 knees) and 30 patients with saline intra-articular injection (control group, 30 knees). RESULTS: There was a significant reduction in mean blood loss (560.55 mL) between the groups at postoperative day (POD) 5 (999.22 mL vs. 1559.77 mL, P = 0.001). The maximum hemoglobin drop was identified at POD 3 (10.51 g/dL vs. 9.10 g/dL, mean difference = 1.41 g/dL). Also, there was a significant reduction in red blood cell and hematocrit loss (P = 0.001). The transfusion rates (0% vs. 23.3%, P = 0.011) and average amount transfused (0.00 +/- 0.00 units vs. 0.53 +/- 1.04 units, P = 0.009) were significantly lower in the TXA group compared with control group. No significant difference in coagulation marker changes were found between TXA and control groups (P > 0.05), but the D-dimer levels at 3 and 5 days post TKA were statistically lower in the TXA group (P < 0.05). No significant changes in the rate of symptomatic deep venous thrombosis, pulmonary embolism, or wound healing problems were noted. CONCLUSIONS: TXA treatment without drainage during TKA reduces the amount of blood transfusions required without increasing the rate of adverse events. PMID- 26048731 TI - Enzymatic characterization of a class II lysyl-tRNA synthetase, LysS, from Myxococcus xanthus. AB - Lysyl-tRNA synthetases efficiently produce diadenosine tetraphosphate (Ap4A) from lysyl-AMP with ATP in the absence of tRNA. We characterized recombinant class II lysyl-tRNA synthetase (LysS) from Myxococcus xanthus and found that it is monomeric and requires Mn(2+) for the synthesis of Ap4A. Surprisingly, Zn(2+) inhibited enzyme activity in the presence of Mn(2+). When incubated with ATP, Mn(2+), lysine, and inorganic pyrophosphatase, LysS first produced Ap4A and ADP, then converted Ap4A to diadenosine triphosphate (Ap3A), and finally converted Ap3A to ADP, the end product of the reaction. Recombinant LysS retained Ap4A synthase activity without lysine addition. Additionally, when incubated with Ap4A (minus pyrophosphatase), LysS converted Ap4A mainly ATP and AMP, or ADP in the presence or absence of lysine, respectively. These results demonstrate that M. xanthus LysS has different enzymatic properties from class II lysyl-tRNA synthetases previously reported. PMID- 26048732 TI - Roles of active site residues in LodA, a cysteine tryptophylquinone dependent epsilon-lysine oxidase. AB - Site-directed mutagenesis identified residues in the substrate channel of LodA that play multiple roles in regulating Km values of substrates, kcat and the extent of biosynthesis of the protein-derived cysteine tryptophylquinone (CTQ) cofactor. Mutations of Cys448 increase Km values for lysine and O2, with the larger effect on Klysine. Tyr211 resides within a mobile loop and is seen in the crystal structure of LodA to form a hydrogen bond with Lys530 that appears to stabilize its position in the channel. Y211F LodA had reduced levels of CTQ but near normal levels of kcat. K530A and K530R variants exhibited diminished levels of CTQ but significantly increased kcat. The Y211F, K530A and K530R mutations each caused large increases in the Km values for lysine and O2. These effects of the mutations of Tyr211 and Lys530 suggest that when these residues are hydrogen bonded they may form a gate that controls entry and exit of substrates and products from the active site. Y211A and Y211E variants had the highest level of CTQ but exhibited no activity. These results highlight the different evolutionary factors that must be considered for enzymes which possess protein-derived cofactors, in which the catalytic cofactor must be generated by posttranslational modifications. PMID- 26048733 TI - High variability in quorum quenching and growth inhibition by furanone C-30 in Pseudomonas aeruginosa clinical isolates from cystic fibrosis patients. AB - Pseudomonas aeruginosa colonizes the lungs of cystic fibrosis patients causing severe damage. This bacterium is intrinsically resistant to antibiotics and shows resistance against new antimicrobials and its virulence is controlled by the quorum-sensing response. Thus, attenuating its virulence by quorum quenching instead of inhibiting its growth has been proposed to minimize resistance; however, resistance against the canonical quorum quencher furanone C-30 can be achieved by mutations leading to increased efflux. In the present work, the effect of C-30 in the attenuation of the QS-controlled virulence factors elastase and pyocyanin was investigated in 50 isolates from cystic fibrosis patients. The results demonstrate that there is a high variability in the expression of both elastase and pyocyanin and that there are many naturally resistant C-30 strains. We report that the main mechanism of C-30 resistance in these strains was not due to enhanced efflux but a lack of permeability. Moreover, C-30 strongly inhibited the growth of several of the isolates studied, thus imposing high selective pressure for the generation of resistance. PMID- 26048735 TI - Pharmacological diversity among drugs that inhibit bone resorption. AB - Drugs that inhibit bone resorption ('anti-resorptives') continue to dominate the therapy of bone diseases characterized by enhanced bone destruction, including Paget's disease, osteoporosis and cancers. The historic use of oestrogens for osteoporosis led on to SERMs (Selective Estrogen Receptor Modulators, e.g. raloxifene and bazedoxifene). Currently the mainstay of treatment worldwide is still with bisphosphonates, as used clinically for over 40 years. The more recently introduced anti-RANK-ligand antibody, denosumab, is also very effective in reducing vertebral, non-vertebral and hip fractures. Odanacatib is the only cathepsin K inhibitor likely to be registered for clinical use. The pharmacological basis for the action of each of these drug classes is different, enabling choices to be made to ensure their optimal use in clinical practice. PMID- 26048734 TI - Validation of the Simplified Palliative Prognostic Index Using a Single Item From the Communication Capacity Scale. AB - CONTEXT: Although the Palliative Prognostic Index (PPI) is a reliable and validated tool to predict the survival of terminally ill cancer patients, all clinicians cannot always precisely diagnose delirium. OBJECTIVES: The primary aim of this study was to examine the predictive value of a simplified PPI. In the simplified PPI, a single item from the Communication Capacity Scale was substituted for the delirium item of the original. METHODS: This multicenter prospective cohort study was conducted in Japan from September 2012 through April 2014 and involved 16 palliative care units, 19 hospital-based palliative care teams, and 23 home-based palliative care services. Palliative care physicians recorded clinical variables at the first assessment and followed up patients six months later. RESULTS: A total of 2425 subjects were recruited; 2343 had analyzable data. The C-statistics of the original and simplified PPIs were 0.801 and 0.800 for three week and 0.800 and 0.781 for six-week survival predictions, respectively. The sensitivity and specificity for survival predictions using the simplified PPI were 72.9% and 67.6% (for three week) and 80.3% and 61.8% (for six week), respectively. CONCLUSION: The simplified PPI showed essentially the same predictive value as the original PPI and is an alternative when clinicians have difficulties in diagnosing delirium. PMID- 26048736 TI - Regulation of cough by neuronal Na(+)-K(+) ATPases. AB - The Na(+)-K(+) ATPases play an essential role in establishing the sodium gradients in excitable cells. Multiple isoforms of the sodium pumps have been identified, with tissue and cell specific expression patterns. Because the vagal afferent nerves regulating cough must be activated at sustained high frequencies of action potential patterning to achieve cough initiation thresholds, it is a certainty that sodium pump function is essential to maintaining cough reflex sensitivities in health and in disease. The mechanisms by which Na(+)-K(+) ATPases regulate bronchopulmonary vagal afferent nerve excitability are reviewed as are potential therapeutic strategies targeting the sodium pumps in cough. PMID- 26048737 TI - Altered characteristic of brain networks in mild cognitive impairment during a selective attention task: An EEG study. AB - The present study evaluated the topological properties of whole brain networks using graph theoretical concepts and investigated the time-evolution characteristic of brain network in mild cognitive impairment patients during a selective attention task. Electroencephalography (EEG) activities were recorded in 10 MCI patients and 17 healthy subjects when they performed a color match task. We calculated the phase synchrony index between each possible pairs of EEG channels in alpha and beta frequency bands and analyzed the local interconnectedness, overall connectedness and small-world characteristic of brain network in different degree for two groups. Relative to healthy normal controls, the properties of cortical networks in MCI patients tend to be a shift of randomization. Lower sigma of MCI had suggested that patients had a further loss of small-world attribute both during active and resting states. Our results provide evidence for the functional disconnection of brain regions in MCI. Furthermore, we found the properties of cortical networks could reflect the processing of conflict information in the selective attention task. The human brain tends to be a more regular and efficient neural architecture in the late stage of information processing. In addition, the processing of conflict information needs stronger information integration and transfer between cortical areas. PMID- 26048738 TI - Can a health information exchange save healthcare costs? Evidence from a pilot program in South Korea. AB - OBJECTIVE: Governments and institutions across the world have made efforts to adopt and diffuse the health information exchange (HIE) technology with the expectation that the technology would improve the quality and efficiency of care by allowing providers online access to healthcare information generated by other providers at the point of care. However, evidence concerning the effectiveness of the technology is limited hindering the wide adoption of a HIE. The objective of this study was to assess impacts of a HIE on healthcare utilization and costs of patient episodes at a tertiary care hospital following referrals by clinic physicians. MATERIAL/METHODS: We studied 1265 HIE and 2702 non-HIE episodes after physicians referred patients from 35 HIE and 59 non-HIE clinics to Seoul National University Bundang Hospital (SNUBH) during a 17-month period from June 2009. We examined 9 measures of healthcare utilization and the magnitude of clinical information exchanged in 4 categories. We estimated the savings resulting from HIE use through linear regression models with dummy variables for HIE participation and patient classification codes controlling the case-mix differences between HIE and non-HIE cases. RESULTS: The total charges incurred by the HIE group during episodes at SNUBH were approximately 13% lower (P<0.001), and the charges for clinical laboratory tests, pathological diagnosis, function tests, and diagnostic imaging were 54% (P<0.001), 76% (P<0.001), 73% (P<0.001), and 80% (P<0.001) lower for the HIE group than for the non-HIE group. SNUBH physicians had access to more clinical information for HIE than for non-HIE patients. CONCLUSIONS: HIE technology improved physicians' access to past clinical information, which appeared to reduce diagnostic test utilization and healthcare costs. The payer was the major beneficiary of HIE cost savings whereas providers paid for the technology. Fair allocation of benefits and costs among stakeholders is needed for wide HIE adoption. PMID- 26048740 TI - Continuous Processing for Production of Biotech Therapeutics. PMID- 26048739 TI - What device should be used for telementoring? Randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: The paper analyzes behavioral patterns of mentors while using different mentoring devices to demonstrate the feasibility of multi platform mentoring. The fundamental differences of devices supporting telementoring create threats for the perception and interpretation of the transmitted video, highlighting the necessity of exploring hardware usability aspects in a safety critical surgical mentoring scenario. MATERIALS AND METHODS: Three types of devices, based on the screen size, formed the arms for the randomized controlled trial. Streaming video recordings of a laparoscopic procedure to the mentors imitated the mentoring scenario. User preferences and response times were recorded while participating in a session performed on all devices. RESULTS: Median response to a mentoring request times were similar for mobile platforms; expected durations were considerably longer for stationary computer. Ability to perceive and identify anatomical structures was insignificantly lower on small sized devices. Stationary and tablet platforms were nearly equally preferred by the most of participants as default telementoring hardware. DISCUSSION: As a side effect, incompatibility of daily duties of the surgeons in the hospital and telementoring responsibilities while implementing systems locally was identified. Scaling up the use of the service in combination with the organizational changes of clinical staff looks like a promising solution. CONCLUSION: The trial demonstrated the feasibility of using all three types of devices for the purpose of mentoring, allowing users to choose the preferred platform. The paper provided initial results on the quality assurance of telementoring systems imposed by the regulatory documents. PMID- 26048741 TI - Risk-based Strategy to Determine Testing Requirement for the Removal of Residual Process Reagents as Process-related Impurities in Bioprocesses. AB - The purpose of this article is to recommend a risk-based strategy for determining clearance testing requirements of the process reagents used in manufacturing biopharmaceutical products. The strategy takes account of four risk factors. Firstly, the process reagents are classified into two categories according to their safety profile and history of use: generally recognized as safe (GRAS) and potential safety concern (PSC) reagents. The clearance testing of GRAS reagents can be eliminated because of their safe use historically and process capability to remove these reagents. An estimated safety margin (Se) value, a ratio of the exposure limit to the estimated maximum reagent amount, is then used to evaluate the necessity for testing the PSC reagents at an early development stage. The Se value is calculated from two risk factors, the starting PSC reagent amount per maximum product dose (Me), and the exposure limit (Le). A worst-case scenario is assumed to estimate the Me value, that is common. The PSC reagent of interest is co-purified with the product and no clearance occurs throughout the entire purification process. No clearance testing is required for this PSC reagent if its Se value is >=1; otherwise clearance testing is needed. Finally, the point of the process reagent introduction to the process is also considered in determining the necessity of the clearance testing for process reagents. How to use the measured safety margin as a criterion for determining PSC reagent testing at process characterization, process validation, and commercial production stages are also described. LAY ABSTRACT: A large number of process reagents are used in the biopharmaceutical manufacturing to control the process performance. Clearance testing for all of the process reagents will be an enormous analytical task. In this article, a risk-based strategy is described to eliminate unnecessary clearance testing for majority of the process reagents using four risk factors. The risk factors included in the strategy are (i) safety profile of the reagents, (ii) the starting amount of the process reagents used in the manufacturing process, (iii) the maximum dose of the product, and (iv) the point of introduction of the process reagents in the process. The implementation of the risk-based strategy can eliminate clearance testing for approximately 90% of the process reagents used in the manufacturing processes. This science-based strategy allows us to ensure patient safety and meet regulatory agency expectations throughout the product development life cycle. PMID- 26048742 TI - Physicochemical Stability of Emulsions and Admixtures for Parenteral Nutrition during Irradiation by Glass-Filtered Daylight at Standardized Conditions. AB - Commercially available parenteral emulsions (n = 4) and admixtures for parenteral nutrition (n = 2) were exposed to UVA and visible irradiation (320-800 nm) at standardized, validated conditions according to the ICH Guideline Q1B (Option 1, to an endpoint corresponding to 1.2 * 10(6) lux h in the range 400-800 nm). Physical stability was evaluated as changes in emulsion droplet size measured by photon correlation spectroscopy, and emulsion droplet zeta potential measured by micro-electrophoresis. Chemical stability was evaluated by detection of lipid peroxidation according to the thiobarbituric acid test and changes in pH. The results are valid for samples stored up to 24 h after exposure. The preparations remained physically stable, even though exposed to UVA (489 W h/m(2)) and visible radiation (1.2 * 10(6) lux h) that correspond to as much as 2-4 days exposure on a sunny window sill. This was the case also when vitamins and trace metals were added. Spiking of the samples with the highly efficient photosensitizer 5 hydroxymethyl furfural (5-HMF), a thermal degradation product of glucose commonly present in steam-sterilized glucose infusions, did not reduce physical stability. Hence, the lipid peroxidation and changes in pH and color induced by irradiation of certain preparations did obviously not influence their physical stability. LAY ABSTRACT: Parenteral preparations are commonly exposed to optical radiation during storage and administration. Exposure to visible light and UVA radiation indoors, or additionally UVB radiation outdoors, may lead to degradation of active pharmaceutical ingredients and drug formulations. Clear plastic and glass containers commonly used for parenteral preparations do not protect the contents from exposure to radiation, even in the UVB region. The investigated parenteral emulsions and admixtures of emulsions, glucose, and amino acids are physically stable during exposure to optical radiation corresponding to indoor conditions (i.e., glass-filtered daylight). They can be considered physically stable under normal in-use conditions. PMID- 26048743 TI - Microscopic Characterization of Brevundimonas diminuta in the Hydrated State. AB - Brevundimonas diminuta is the organism most commonly used for challenge testing of sterilizing-grade filter membranes. ASTM F838-05 and PDA Technical Report 26 rely on B. diminuta ATCC #19146 for standard challenge tests used to designate sterilizing-grade filter performance. Despite the importance and widespread use of B. diminuta in filter testing and validation, information about this microorganism in its native hydrated state is limited. In this work, we measure, for the first time, the mechanical property of modulus for B. diminuta cultured in saline lactose broth (as described in ASTM F838-05) via wet atomic force microscopy. For comparison, we also imaged B. diminuta by the traditional method of electron microscopy after capture on a filter and chemical fixation. The modulus of hydrated B. diminuta cells was ~193 mPa. To put this result into context, a simple model for pore penetration that correlates the role of the Young's modulus of hydrated cells to the penetration of sterilizing-grade filters is proposed. The model confirms the industry experience that pore size is an essential parameter in preventing the penetration of B. diminuta into sterilizing grade filters. LAY ABSTRACT: The small microorganism Brevundimonas diminuta is used to characterize the performance of sterilizing-grade filter membranes used in the manufacturing of sterile drug products. Little is known about the size, shape, or elasticity of living bacterial cells, as it is easier to characterize bacteria after chemical fixation in a dry state. In this work, we use atomic force microscopy to determine the size, shape, and deformability of this important microorganism while it is alive and fully hydrated. Additionally, we compare the physical and mechanical properties of B. diminuta measured in wet and dry states. This information can be used to advance our understanding of how filter membranes remove these organisms from fluid streams. PMID- 26048744 TI - A Means of Establishing and Justifying Binary Ethanol/Water Mixtures as Simulating Solvents in Extractables Studies. AB - Ethanol/water mixtures are frequently used as simulating solvents in extractables studies. However, the basis for determining and justifying the right ethanol proportion in a simulating solvent for a particular drug product or solution has not been previously established.A solvent strength model has been developed in this study, based on the correlation between the levels of a model compound, di (2-ethylhexyl) phthalate (DEHP), extracted from a reference source material, plasticized poly-(vinyl chloride) (PVC) resin, and the proportion of ethanol in ethanol/water extractions solvents. This model was established by experimentally investigating DEHP leaching and takes the form: [Formula: see text] If the level of DEHP extracted from the standard source PVC resin by a drug product is measured, then the level can be input into the above equation and the proper ethanol content of the appropriate simulating solvent can be determined.The model has been applied to certain drug products and additives used in drug products, and the proper ethanol/simulating solvents for these products have been established. Additionally, the leaching behavior revealed in this study has been established to be consistent with previously published research and a mechanism for the observed behavior has been proposed. LAY ABSTRACT: Although ethanol/water mixtures are frequently used as simulating solvents in extractables studies, it is difficult to establish and justify what the right proportion of ethanol is for a particular drug product. A solvent strength model has been developed based on the leaching behavior of a model compound, di-(2-ethylhexyl) phthalate (DEHP), from a reference source material, plasticized poly-(vinyl chloride) (PVC). By measuring the level of DEHP leached into a drug product from the reference source material, one can use the model to calculate the correct ethanol proportion in the simulating solvent.Using this approach, ethanol/water proportions have been obtained for certain drug products. Additionally, the leaching profiles for DEHP obtained in this study were noted to be consistent with such profiles for other extractables from the PVC reference source material and with other investigations of ethanol/water as model stimulants. PMID- 26048745 TI - Comparison of Different Calculation Approaches for Defining Microbiological Control Levels Based on Historical Data. AB - In the present work we compared different calculation approaches for their ability to accurately define microbiological control levels based on historical data. To that end, real microbiological data were used for simulation experiments. The results of our study confirmed that assuming a normal distribution is not appropriate for that purpose. In addition, assumption of a Poisson distribution generally underestimated the control level, and the predictive power for future values was highly insufficient. The non-parametric Excel percentile strongly predicted future values in our simulation experiments (although not as good as some of the parametric models). With the limited amount of data used in the simulations, the calculated control levels for the upper percentiles were on average higher and more variable compared to the parametric models. This was due to the fact that the largest observed value was generally defined as the control level. Accordingly, the Excel percentile is less robust towards outliers and requires more data to accurately define control levels as compared to parametric models. The negative binomial as well as the zero-inflated negative binomial distribution, both parametric models, had good predictive power for future values. Nonetheless, on basis of our simulation experiments, we saw no evidence to generally prefer the zero-inflated model over the non-inflated one. Finally, with our data, the gamma distribution on average had at least as good predictive power as the negative binomial distribution and zero-inflated negative binomial distribution for percentiles >=98%, indicating that it may represent a viable option for calculating microbiological control levels at high percentiles. Presumably, this was based on the fact that the gamma distribution fitted the upper end of the distribution better than other models. Since in general microbiological control levels would be based on the upper percentiles, microbiologists may exclusively rely on the gamma distribution for calculation of their control levels. As the gamma distribution can conveniently be calculated in standard office calculation software, it may represent a superior alternative to the widely used percentile functions or other distribution models. LAY ABSTRACT: During the manufacturing of pharmaceutical drug products, the counts of microorganisms are monitored in the cleanroom environment, water, the product's raw materials, and the final product. This enables manufacturers to ensure that high numbers of microorganisms that may impair the product's microbiological quality are detected before the product is released to the patient. Microbiological control levels must be set to determine at which number a count is considered too high. Exceeding such levels may require an investigation to determine the root cause explaining why such high numbers of microorganisms occurred, and a set of actions should be performed with the aim of eliminating this root cause. In order to really differentiate higher-than-usual counts, microbiological control levels should be based on historical data. In the present work we analyzed different calculation approaches towards that purpose. We used real microbiological data and performed simulation experiments to determine which statistical method could calculate the most realistic control levels that would provide the best prediction for future routine testing. Better predictions would ensure that only significant contaminations lead to an excursion of the microbiological control level, which would avoid wasting resources by investigating non-issues or normal/controlled conditions. PMID- 26048746 TI - Stability Studies of a Freeze-Dried Recombinant Human Epidermal Growth Factor Formulation for Wound Healing. AB - We report on the stability assessment of a recombinant human epidermal growth factor (rhEGF) freeze-dried formulation for wound healing by intra-lesional injections. The suitability of packaging material for the light protection of finished dried powder was evaluated after stressed exposure conditions. Degradation kinetics of powder for injection was investigated at concentrations of 25-250 MUg/vial and temperatures of 45, 60, and 70 degrees C. The long-term stability was evaluated after storage at 25 +/- 2 degrees C/60 +/- 5% relative humidity (6 months) and 2-8 degrees C (24 months) in the dark and analyzed at several time points. The stability after reconstitution with various diluents was also assessed after 24 h storage at 2-8 degrees C. The rhEGF samples were analyzed for structural integrity by reversed-phase high-performance liquid chromatography (RP-HPLC), size-exclusion HPLC, and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Biological activity was investigated by measuring the cell proliferation in a murine fibroblast cell line. Results show that freeze-dried rhEGF in primary packaging only was photosensitive, as degradation by RP-HPLC that was completely suppressed by the secondary carton package was revealed. An increase in freeze-dried rhEGF stability was observed with the increase in protein concentration from 25 to 250 MUg/vial. The long-term stability study showed no significant rhEGF degradation or physical change within the freeze-dried formulations containing 25 or 250 MUg/vial of rhEGF. No physical, chemical or biological changes were observed for rhEGF after reconstitution in water for injection or 0.9% sodium chloride during the storage conditions studied. LAY ABSTRACT: The stability of a recombinant human epidermal growth factor (rhEGF) freeze-dried formulation for wound healing by intra-lesional injections was assessed. The suitability of packaging material for the light protection of finished dried powder was evaluated after stressed exposure conditions. Degradation kinetics of powder for injection was investigated at concentrations of 25-250 MUg/vial and temperatures of 45, 60, and 70 degrees C. The accelerated, long-term, and reconstitution stabilities were examined according to ICH guidelines for their utility time. The stability of rhEGF samples was analyzed by different chemical, physical, and biological activity assays. Results show that freeze-dried rhEGF in primary packaging only was photosensitive, as degradation by reversed-phase high performance liquid chromatography that was completely suppressed by the secondary carton package was revealed. An increase in freeze-dried rhEGF stability was observed with the increase in protein concentration. No significant rhEGF degradation or physical changes were observed within the freeze-dried formulations after 6 months storage at 25 +/- 2 degrees C/60 +/- 5% relative humidity or 24 months storage at 2-8 degrees C. No physical, chemical, or biological changes were observed for rhEGF after reconstitution in water for injection or 0.9% sodium chloride after 24 h storage at 2-8 degrees C. PMID- 26048747 TI - Filling of High-Concentration Monoclonal Antibody Formulations into Pre-filled Syringes: Investigating Formulation-Nozzle Interactions To Minimize Nozzle Clogging. AB - Syringe filling of high-concentration/viscosity monoclonal antibody formulations is a complex process that is not fully understood. This study, which builds on a previous investigation that used a bench-top syringe filling unit to examine formulation drying at the filling nozzle tip and subsequent nozzle clogging, further explores the impact of formulation-nozzle material interactions on formulation drying and nozzle clogging. Syringe-filling nozzles made of glass, stainless steel, or plastic (polypropylene, silicone, and Teflon(r)), which represent a full range of materials with hydrophilic and hydrophobic properties as quantified by contact angle measurements, were used to fill liquids of different viscosity, including a high-concentration monoclonal antibody formulation. Compared with hydrophilic nozzles, hydrophobic nozzles offered two unique features that discouraged formulation drying and nozzle clogging: (1) the liquid formulation is more likely to be withdrawn into the hydrophobic nozzle under the same suck-back conditions, and (2) the residual liquid film left on the nozzle wall when using high suck-back settings settles to form a liquid plug away from the hydrophobic nozzle tip. Making the tip of the nozzle hydrophobic (silicone-coating on glass and Teflon-coating stainless steel) could achieve the same suck-back performance as plastic nozzles. This study demonstrated that using hydrophobic nozzles are most effective in reducing the risk of nozzle clogging by drying of high-concentration monoclonal antibody formulation during extended nozzle idle time in a large-scale filling facility and environment. LAY ABSTRACT: Syringe filling is a well-established manufacturing process and has been implemented by numerous contract manufacturing organizations and biopharmaceutical companies. However, its technical details and associated critical process parameters are rarely published. Information on high concentration/viscosity formulation filling is particularly lacking. This study is the continuation of a previous investigation with a focus on understanding the impact of nozzle material on the suck-back function of liquid formulations. The findings identified the most critical parameter-nozzle material hydrophobicity-in alleviating formulation drying at the nozzle tip and eventually limiting the occurrence of nozzle clogging during the filling process. The outcomes of this study will benefit scientists and engineers who develop pre-filled syringe products by providing a better understanding of high-concentration formulation filling principles and challenges. PMID- 26048748 TI - Practical Considerations for Detection and Characterization of Sub-Micron Particles in Protein Solutions by Nanoparticle Tracking Analysis. AB - Nanoparticle Tracking Analysis (NTA) is an emerging analytical technique developed for detection, sizing, and counting of sub-micron particles in liquid media. Its feasibility for use in biopharmaceutical development was evaluated with particle standards and recombinant protein solutions. Measurements of aqueous suspensions of NIST-traceable polystyrene particle standards showed accurate particle concentration detection between 2 * 10(7) and 5 * 10(9) particles/mL. Sizing was accurate for particle standards up to 200 nm. Smaller than nominal value sizes were detected by NTA for the 300-900 nm particles. Measurements of protein solutions showed that NTA performance is solution specific. Reduced sensitivity, especially in opalescent solutions, was observed. Measurements in such solutions may require sample dilution; however, common sample manipulations, such as dilution and filtration, may result in particle formation. Dilution and filtration case studies are presented to further illustrate such behavior. To benchmark general performance, NTA was compared against asymmetric flow field flow fractionation coupled with multi-angle light scattering (aF4-MALS) and dynamic light scattering, which are other techniques for sub-micron particles. Data shows that all three methods have limitations and may not work equally well under certain conditions. Nevertheless, the ability of NTA to directly detect and count sub-micron particles is a feature not matched by aF4-MALS or dynamic light scattering. LAY ABSTRACT: Thorough characterization of particulate matter present in protein therapeutics is limited by the lack of analytical methods for particles in the sub-micron size range. Emerging techniques are being developed to bridge this analytical gap. In this study, Nanoparticle Tracking Analysis is evaluated as a potential tool for biologics development. Our results indicate that method performance is molecule-specific and may not work as well under all solution conditions, especially when testing opalescent solutions. Advantages and disadvantages of Nanoparticle Tracking Analysis are discussed in comparison to other analytical techniques for particles in the sub-micron size range. PMID- 26048750 TI - Introduction to BioPhorum Operations Group (BPOG) Special Section Editorials. PMID- 26048749 TI - Achieving a Successful Scale-Down Model and Optimized Economics through Parvovirus Filter Validation using Purified TrueSpikeTM Viruses. AB - This article describes a four virus panel validation of EMD Millipore's (Bedford, MA) small virus-retentive filter, Viresolve(r) Pro, using TrueSpike(TM) viruses for a Biogen Idec process intermediate. The study was performed at Charles River Labs in King of Prussia, PA. Greater than 900 L/m(2) filter throughput was achieved with the approximately 8 g/L monoclonal antibody feed. No viruses were detected in any filtrate samples. All virus log reduction values were between >=3.66 and >=5.60. The use of TrueSpike(TM) at Charles River Labs allowed Biogen Idec to achieve a more representative scaled-down model and potentially reduce the cost of its virus filtration step and the overall cost of goods. The body of data presented here is an example of the benefits of following the guidance from the PDA Technical Report 47, The Preparation of Virus Spikes Used for Viral Clearance Studies. LAY ABSTRACT: The safety of biopharmaceuticals is assured through the use of multiple steps in the purification process that are capable of virus clearance, including filtration with virus-retentive filters. The amount of virus present at the downstream stages in the process is expected to be and is typically low. The viral clearance capability of the filtration step is assessed in a validation study. The study utilizes a small version of the larger manufacturing size filter, and a large, known amount of virus is added to the feed prior to filtration. Viral assay before and after filtration allows the virus log reduction value to be quantified. The representativeness of the small scale model is supported by comparing large-scale filter performance to small scale filter performance. The large-scale and small-scale filtration runs are performed using the same operating conditions. If the filter performance at both scales is comparable, it supports the applicability of the virus log reduction value obtained with the small-scale filter to the large-scale manufacturing process. However, the virus preparation used to spike the feed material often contains impurities that contribute adversely to virus filter performance in the small-scale model. The added impurities from the virus spike, which are not present at manufacturing scale, compromise the scale-down model and put into question the direct applicability of the virus clearance results. Another consequence of decreased filter performance due to virus spike impurities is the unnecessary over-sizing of the manufacturing system to match the low filter capacity observed in the scale-down model. This article describes how improvements in mammalian virus spike purity ensure the validity of the log reduction value obtained with the scale-down model and support economically optimized filter usage. PMID- 26048751 TI - Microbial Monitoring For Biological Drug Substance Manufacturing: An Industry Perspective. PMID- 26048752 TI - White Paper: Container Closure Integrity Control versus Integrity Testing during Routine Manufacturing. PMID- 26048753 TI - Mechanisms of pinon pine mortality after severe drought: a retrospective study of mature trees. AB - Conifers have incurred high mortality during recent global-change-type drought(s) in the western USA. Mechanisms of drought-related tree mortality need to be resolved to support predictions of the impacts of future increases in aridity on vegetation. Hydraulic failure, carbon starvation and lethal biotic agents are three potentially interrelated mechanisms of tree mortality during drought. Our study compared a suite of measurements related to these mechanisms between 49 mature pinon pine (Pinus edulis Engelm.) trees that survived severe drought in 2002 (live trees) and 49 trees that died during the drought (dead trees) over three sites in Arizona and New Mexico. Results were consistent over all sites indicating common mortality mechanisms over a wide region rather than site specific mechanisms. We found evidence for an interactive role of hydraulic failure, carbon starvation and biotic agents in tree death. For the decade prior to the mortality event, dead trees had twofold greater sapwood cavitation based on frequency of aspirated tracheid pits observed with scanning electron microscopy (SEM), smaller inter-tracheid pit diameter measured by SEM, greater diffusional constraints to photosynthesis based on higher wood delta(13)C, smaller xylem resin ducts, lower radial growth and more bark beetle (Coleoptera: Curculionidae) attacks than live trees. Results suggest that sapwood cavitation, low carbon assimilation and low resin defense predispose pinon pine trees to bark beetle attacks and mortality during severe drought. Our novel approach is an important step forward to yield new insights into how trees die via retrospective analysis. PMID- 26048755 TI - Gene expression profiling of laterally spreading tumors. AB - BACKGROUND: Laterally spreading tumors (LSTs) are generally defined as lesions >10 mm in diameter, are characterized by lateral expansion along the luminal wall with a low vertical axis. In contrast to other forms of tumor, LSTs are generally considered to have a superficial growth pattern and the potential for malignancy. We focused on this morphological character of LSTs, and analyzed the gene expression profile of LSTs. METHODS: The expression of 168 genes in 41 colorectal tumor samples (17 LST-adenoma, 12 LST-carcinoma, 12 Ip [pedunculated type of the Paris classification)-adenoma, all of which were 10 mm or more in diameter] was analyzed by PCR array. Based on the results, we investigated the expression levels of genes up-regulated in LST-adenoma, compared to Ip-adenoma, by hierarchical and K-means clustering. To confirm the results of the array analysis, using an additional 60 samples (38 LST-adenoma, 22 Ip-adenoma), we determined the localization of the gene product by immunohistochemical staining. RESULT: The expression of 129 genes differed in colorectal tumors from normal mucosa by PCR array analysis. As a result of K-means clustering, the expression levels of five genes, AKT1, BCL2L1, ERBB2, MTA2 and TNFRSF25, were found to be significantly up-regulated (p < 0.05) in LST-adenoma, compared to Ip-adenoma. Immunohistochemical analysis showed that the BCL2L1 protein was significantly and meaningfully up-regulated in LST-adenoma compared to Ip-adenoma (p = 0.010). With respect to apoptosis status in LST-Adenoma, it assumes that BCL2L1 is anti apoptotic protein, the samples such as BCL2L1 positive and TUNEL negative, or BCL2L1 negative and TUNEL positive are consistent with the assumption. 63.2 % LST adenoma samples were consistent with the assumption. CONCLUSIONS: LSTs have an unusual profile of gene expression compared to other tumors and BCL2L1 might be concerned in the organization of LSTs. PMID- 26048756 TI - Female Condoms=Missed Opportunities: Lessons Learned from Promotion-centered Interventions. AB - INTRODUCTION: The female condom is a barrier contraceptive device that is underutilized despite its effectiveness at preventing both unintended pregnancy and sexually transmitted infections (STIs). Prior research has highlighted that the underuse of the female condom as a contraceptive option is owing in large part to social stigma, and lacking or incorrect information about the product. METHODS: In an attempt to better understand the discrepancy between the female condom's documented effectiveness and its general lack of uptake, we conducted a systematic search and qualitatively reviewed 20 published intervention studies that focus on efforts to promote the female condom. The strategies that each intervention used were coded and carefully examined. We obtained information regarding relevant characteristics of the studies, including intervention setting, sampling strategy, participant demographics, and methodology used. RESULTS: We found that the majority of the studies had significant positive findings concerning the female condom, for example, many were effective at demonstrating participant uptake as well as increasing the number of protected sex acts. Additionally, perceived ability to use the device was a significant predictor of female condom use in multiple studies. Finally, the studies tended to include younger women; only 10.0% (n=2) reported having participants with a mean age older than 30), meaning that older women generally have not been well served by previous efforts to promote the use of the female condom. CONCLUSIONS: We offer guidelines for improving female condom uptake and recommendations for future research that seeks to establish and utilize best practice promotional strategies for female condoms. PMID- 26048754 TI - Increased survival with the combination of stereotactic radiosurgery and gefitinib for non-small cell lung cancer brain metastasis patients: a nationwide study in Taiwan. AB - PURPOSE: Whole brain irradiation (WBRT) either with or without resection has historically been the treatment for brain metastases from non-small cell lung cancer (NSCLC). The effect of gamma knife (GK) radiosurgery, chemotherapy, or the combination remains incompletely defined. In this study, we assessed the outcome of brain metastases from non-small cell lung cancer treated by WBRT followed by GK, gefitinib, or the combination of GK and gefitinib. MATERIAL AND METHODS: We retrieved the records of NSCLC patients with brain metastases from the National Health Insurance Research Database (NHIRD) of Taiwan from 2004 to 2010. WBRT either with or without resection was the first line treatment for nearly all patients. The decision to add GK and/or gefitinib treatment was at the discretion of the treating physician and based upon a patient's medical records and imaging data. These patients were classified into four groups including WBRT, WBRT + gefitinib, WBRT + GK, WBRT + gefitinib + GK. These data was evaluated for difference in survival and factors that portended an extended survival from the time of brain metastasis diagnosis. RESULTS: Of the 60194 patients with newly diagnosed NSCLC, 23874 (39.6 %) developed brain metastases. The distribution of patients for the groups was WBRT for 20241, WBRT + gefitinib for 3379, WBRT + GK for 155, and WBRT+ gefitinib + GK for 99 patients. The median survival for the time of brain metastasis diagnosis for WBRT, WBRT+ gefitinib, WBRT+ GK, WBRT+ gefitinib + GK groups was 0.53, 1.01, 1.46, and 2.25 years, respectively (p < 0.0001). The hazard ratio (95 % CI) for survival was 1, 0.56, 0.43, and 0.40, respectively (p < 0.001). The adjusted hazard ratio (95 % CI) by age, sex and Charlson comorbidity index (CCI) was 1, 0.73, 0.49, and 0.42, respectively (p < 0.001). CONCLUSION: Patients with brain metastases from NSCLC receiving GK or gefitinib demonstrated extended survival. The improved survival seen with GK and gefitinib suggests a survival benefit in selected patients receiving the combined treatment. Further Phase II study should be conducted to assessment these influence. PMID- 26048757 TI - Association of Restraint and Disinhibition to Gestational Weight Gain among Pregnant Former Smokers. AB - INTRODUCTION: Gaining excessive weight during pregnancy is associated with immediate maternal and fetal complications as well as longer term obesity. Prepregnancy body mass index, age, and smoking cessation have been related to gestational weight gain (GWG); however, less is known about how eating behaviors, that may be amenable to modification and have been related to weight gain outside of pregnancy, affect GWG. METHODS: The present study evaluated the relationship of dietary restraint and disinhibition to GWG in a sample of women (n=248) who quit smoking before or early in pregnancy. Women self-reported height and prepregnancy weight during their third trimester. GWG was calculated by subtracting prepregnancy weight from third trimester weight. The Three-Factor Eating Questionnaire assessed restraint and disinhibition. RESULTS: Average GWG was 14.60 (+/-7.64) kg and 47% of women had a GWG greater than the Institute of Medicine recommendations. Linear regression models were used to examine restraint and disinhibition as correlates of GWG, and multinomial logistic regressions were utilized to determine whether eating behaviors were associated with inadequate or excessive GWG. Restraint was associated positively with total GWG, but disinhibition was not associated with GWG. Thus, conscious attempts to restrict intake were associated with GWG beyond the influence of covariates. CONCLUSION: These findings highlight the potential influence of modifiable eating behaviors on GWG and demonstrate the need for additional research to determine how these behaviors relate to GWG over the course of pregnancy. PMID- 26048758 TI - Barriers to Immediate Post-placental Intrauterine Devices among Attending Level Educators. AB - OBJECTIVE: To determine whether barriers to immediate post-placental intrauterine device (PPIUD) placement exist at the provider level. STUDY DESIGN: Obstetrics providers at seven academic teaching hospitals in Massachusetts were asked to complete an electronic survey regarding their knowledge, experience, and opinions about immediate PPIUDs. RESULTS: Eighty-two providers, including obstetricians, family medicine physicians, and midwives, completed the survey. Thirty-five (42.7%) reported experience placing an immediate PPIUD with the majority of them having placed three to five PPIUDs. Of participants who had never placed a PPIUD, the reason cited most frequently was inadequate training. Fewer than one-half (43.4%) correctly identified the PPIUD expulsion rate, whereas 75.9% knew the correct expulsion rate for interval IUD placement. The majority of providers responded that PPIUDs are acceptable in certain clinical scenarios. CONCLUSIONS: Overall, knowledge and experience with PPIUD placement is relatively low. As increasing numbers of states amend Medicaid policy to include reimbursement for immediate postpartum IUDs, additional education and training opportunities are needed. PMID- 26048759 TI - Change is a Constant. AB - In 2015, Henry P. Hackett, Managing Editor, Arthroscopy, retires, and Edward A. Goss, Executive Director, Arthroscopy Association of North America (AANA), retires. Association is a positive constant, in a time of change. With change comes a need for continuing education, research, and sharing of ideas. While the quality of education at AANA and ISAKOS is superior and most relevant, the unique reason to travel and meet is the opportunity to interact with innovative colleagues. Personal interaction best stimulates new ideas to improve patient care, research, and teaching. Through our network, we best create innovation. PMID- 26048760 TI - Lamina-Specific Double-Row Fixation of Rotator Cuff Tears. PMID- 26048761 TI - Authors' Reply. PMID- 26048762 TI - The New Microfracture: All Things Considered. PMID- 26048763 TI - Comments on Complications After Arthroscopic Coracoclavicular Reconstruction Using a Single Adjustable Loop Length Suspensory Fixation Device. PMID- 26048764 TI - Authors' Reply. PMID- 26048765 TI - Causes and Predictors of 30-Day Readmission After Shoulder and Knee Arthroscopy: An Analysis of 15,167 Cases. AB - PURPOSE: To evaluate the incidence, causes, and risk factors for unplanned 30-day readmission after shoulder and knee arthroscopy. METHODS: A multicenter, prospective clinic registry, the American College of Surgeons National Surgical Quality Improvement Program, was queried for Current Procedural Terminology codes representing the most common shoulder and knee arthroscopic procedures. Unplanned readmissions within 30 days were evaluated dichotomously, and causes of readmission were identified. Univariate and multivariate logistic regression analyses were used to identify variables predictive of readmission. RESULTS: In total, we identified 15,167 patients who underwent shoulder and knee arthroscopic procedures in 2012. Overall, 136 (0.90%) were readmitted within 30 days, and the rates were similar after shoulder (0.86%) and knee (0.92%) procedures. Readmissions were most common after arthroscopic debridement of the knee (1.56%) and lowest after rotator cuff and labral repairs (0.68%) and cruciate reconstructions (0.78%). The most common causes of readmission were surgical-site infections (37.1%), deep venous thrombosis and pulmonary embolism (17.1%), and postoperative pain (7.1%). Multivariate analysis identified age older than 80 years (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.5 to 8.1), chronic steroid use (OR, 3.3; 95% CI, 1.5 to 7.2), and elevated American Society of Anesthesiologists class (OR, 4.2; 95% CI, 1.4 to 12.0) as independent risk factors for readmission. CONCLUSIONS: The rate of unplanned readmissions within 30 days of shoulder and knee arthroscopic procedures is low, at 0.92%, with wound related complications being the most common cause. In patients with advanced age, with chronic steroid use, and with chronic systemic disease, the risk of readmission may be higher. These findings may aid in the informed-consent process, patient optimization, and the quality-reporting risk-adjustment process. LEVEL OF EVIDENCE: Level III, prognostic study. PMID- 26048766 TI - Editorial Commentary: Shoulder Arthroscopy, Shoulder Hemiarthroplasty, and Total Shoulder Arthroplasty for Glenohumeral Osteoarthritis. AB - Shoulder arthroscopy offers a safe, effective, and less invasive alternative to arthroplasty in patients under 60 years of age with glenohumeral arthritis. However, indications include joint space of greater than 2 mm. For patients who do not meet arthroscopic indications, total shoulder arthroplasty is more effective than hemiarthroplasty. Performance and publication bias may effect generalizability of these findings. Biologic treatment options seem on the horizon. PMID- 26048767 TI - Editorial Commentary: Hamstring Tendon Regeneration After Autograft Harvest. AB - While radiographic and histologic data show features of hamstring tendon regeneration after harvest for ligament reconstruction, we remain skeptical that hamstring regeneration is clinically meaningful. We cannot recommend reharvest for revision surgery. PMID- 26048768 TI - Editorial Commentary: ACL Reconstruction: Single-Bundle Versus Double-Bundle. AB - Double-bundle ACL reconstruction results in statistically significant, but not clinically significant improvement in knee anteroposterior stability, and improved rotational stability, according to the pivot-shift test, which is subjective. However, double-bundle does not improve clinical outcomes, does not reduce graft failure rates, and is more complex, more expensive, takes longer, and is harder to revise. As a result, for now, we prefer single-bundle ACL reconstruction. PMID- 26048769 TI - Editorial Commentary: Hip Imaging Studies Suggest Significant Pathology in Asymptomatic Individuals. AB - Hip imaging studies suggest significant pathology in asymptomatic individuals. We use the term suggest, because if the patient is asymptomatic, perhaps reported findings should not be labeled pathologic. Hip imaging researchers may need to reconsider what represents an abnormal radiologic sign. And, while we introduce that knee and shoulder imaging is of greater diagnostic value, on reflection, we realize that knee and shoulder imaging researchers may also need to reconsider what represents abnormal. PMID- 26048770 TI - Editorial Commentary: Operative Treatment of Primary Patellar Dislocation. AB - Systematic review of the literature does not support operative treatment of primary patellar dislocation, as the results of nonoperative treatment are similar. However, surgery is indicated for recurrent patellar dislocation, and in the future, we anticipate that contemporary medial patellofemoral ligament reconstruction outcomes for primary patellar dislocation will prove superior to nonoperative treatment. PMID- 26048771 TI - Biodegradable thermosensitive polymer gel for sustained BMP-2 delivery. PMID- 26048772 TI - Stable oxyntomodulin analogues exert positive effects on hippocampal neurogenesis and gene expression as well as improving glucose homeostasis in high fat fed mice. AB - The weight-lowering and gluco-regulatory actions of oxyntomodulin (Oxm) have been well-documented however potential actions of this peptide in brain regions associated with learning and memory have not yet been evaluated. The present study examined the long-term actions of a stable acylated analogue of Oxm, (dS(2))Oxm(K-gamma-glu-Pal), together with parent (dS(2))Oxm peptide, on hippocampal neurogenesis, gene expression and metabolic control in high fat (HF) mice. Groups of HF mice (n = 12) received twice-daily injections of Oxm analogues (both at 25 nmol/kg body weight) or saline vehicle (0.9% wt/vol) over 28 days. Hippocampal gene expression and histology were assessed together with evaluation of energy intake, body weight, non-fasting glucose and insulin, glucose tolerance, insulin sensitivity and lipids. Oxm analogues significantly reduced body weight, improved glucose tolerance, glucose-mediated insulin secretion, insulin sensitivity, islet architecture and lipid profile. Analysis of brain histology revealed significant reduction in hippocampal oxidative damage (8 oxoguanine), enhanced hippocampal neurogenesis (doublecortin) and improved hippocampal and cortical synaptogenesis (synaptophysin) following treatment. Furthermore, Oxm analogues up-regulated hippocampal mRNA expression of MASH1, Synaptophysin, SIRT1, GLUT4 and IRS1, and down-regulated expression of LDL-R and GSK3beta. These data demonstrate potential of stable Oxm analogues, and particularly (dS(2))Oxm(K-gamma-glu-Pal) to improve metabolic function and enhance neurogenesis, synaptic plasticity, insulin signalling and exert protective effects against oxidative damage in hippocampus and cortex brain regions in HF mice. PMID- 26048773 TI - [The importance of ultrasound in primary care]. PMID- 26048774 TI - Hepatitis E virus chronic infection of swine co-infected with Porcine Reproductive and Respiratory Syndrome Virus. AB - In developed countries, most of hepatitis E human cases are of zoonotic origin. Swine is a major hepatitis E virus (HEV) reservoir and foodborne transmissions after pork product consumption have been described. The risk for HEV-containing pig livers at slaughter time is related to the age at infection and to the virus shedding duration. Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) is a virus that impairs the immune response; it is highly prevalent in pig production areas and suspected to influence HEV infection dynamics. The impact of PRRSV on the features of HEV infections was studied through an experimental HEV/PRRSV co-infection of specific-pathogen-free (SPF) pigs. The follow-up of the co-infected animals showed that HEV shedding was delayed by a factor of 1.9 in co infected pigs compared to HEV-only infected pigs and specific immune response was delayed by a factor of 1.6. HEV shedding was significantly increased with co infection and dramatically extended (48.6 versus 9.7 days for HEV only). The long term HEV shedding was significantly correlated with the delayed humoral response in co-infected pigs. Direct transmission rate was estimated to be 4.7 times higher in case of co-infection than in HEV only infected pigs (0.70 and 0.15 per day respectively). HEV infection susceptibility was increased by a factor of 3.3, showing the major impact of PRRSV infection on HEV dynamics. Finally, HEV/PRRSV co-infection - frequently observed in pig herds - may lead to chronic HEV infection which may dramatically increase the risk of pig livers containing HEV at slaughter time. PMID- 26048775 TI - Measurement of myocardial perfusion and infarction size using computer-aided diagnosis system for myocardial contrast echocardiography. AB - Proper evaluation of myocardial microvascular perfusion and assessment of infarct size is critical for clinicians. We have developed a novel computer-aided diagnosis (CAD) approach for myocardial contrast echocardiography (MCE) to measure myocardial perfusion and infarct size. Rabbits underwent 15 min of coronary occlusion followed by reperfusion (group I, n = 15) or 60 min of coronary occlusion followed by reperfusion (group II, n = 15). Myocardial contrast echocardiography was performed before and 7 d after ischemia/reperfusion, and images were analyzed with the CAD system on the basis of eliminating particle swarm optimization clustering analysis. The myocardium was quickly and accurately detected using contrast-enhanced images, myocardial perfusion was quantitatively calibrated and a color-coded map calibrated by contrast intensity and automatically produced by the CAD system was used to outline the infarction region. Calibrated contrast intensity was significantly lower in infarct regions than in non-infarct regions, allowing differentiation of abnormal and normal myocardial perfusion. Receiver operating characteristic curve analysis documented that -54-pixel contrast intensity was an optimal cutoff point for the identification of infarcted myocardium with a sensitivity of 95.45% and specificity of 87.50%. Infarct sizes obtained using myocardial perfusion defect analysis of original contrast images and the contrast intensity-based color-coded map in computerized images were compared with infarct sizes measured using triphenyltetrazolium chloride staining. Use of the proposed CAD approach provided observers with more information. The infarct sizes obtained with myocardial perfusion defect analysis, the contrast intensity-based color-coded map and triphenyltetrazolium chloride staining were 23.72 +/- 8.41%, 21.77 +/- 7.8% and 18.21 +/- 4.40% (% left ventricle) respectively (p > 0.05), indicating that computerized myocardial contrast echocardiography can accurately measure infarct size. On the basis of the results, we believe the CAD method can quickly and automatically measure myocardial perfusion and infarct size and will, it is hoped, be very helpful in clinical therapeutics. PMID- 26048776 TI - Helix mimetics: Recent developments. AB - The development of protein-protein interaction (PPIs) inhibitors represents a challenging goal in chemical biology and drug discovery. PPIs are problematic targets because they involve large surfaces with less well defined features and recognition motifs that are less amenable to conventional experimental and computational ligand discovery methodologies. alpha-Helix mediated PPIs represent a sub group with a clearly defined interface and thus may be more amenable to the development of generic ligand discovery methods. Indeed, this is borne out in numerous studies using peptides covalently constrained into a helical conformation resulting in improvement of myriad biophysical and cellular properties. It is however desirable to have small molecule alternatives: a helix mimetic (proteomimetic) is a generic small molecule scaffold that projects functional groups in a similar spatial orientation so as to mimic the presentation of key amino acid side chains from the helix that mediates the PPI. The first true example of a helix mimetic was described over a decade ago however this approach has not yet been elaborated to the extent that it receives similar levels of attention to constrained peptides. This review explores recent significant developments in the area of small molecule alpha-helix mimetics and provides a critical overview of success stories, potential limitations of the approach, and areas for future development. PMID- 26048777 TI - Recovery of a human natural antibody against the noncollagenous-1 domain of type IV collagen using humanized models. AB - BACKGROUND: Anti-glomerular basement membrane nephritis and Goodpasture syndrome result from autoantibody (Ab)-mediated destruction of kidney and lung. Ab target the noncollagenous 1 (NC1) domain of alpha3(IV) collagen, but little is known about Ab origins or structure. This ignorance is due in part to the inability to recover monoclonal Ab by transformation of patients' blood cells. The aim of this study was to assess the suitability of two humanized models for this purpose. METHODS: NOD-scid-gamma immunodeficient mice were engrafted either with human CD34+ hematopoietic stem cells (HSC) (Hu-HSC mice) and immunized with alpha3(IV)NC1 collagen containing the Goodpasture epitopes or with nephritis patients' peripheral blood leukocytes (PBL) (Hu-PBL mice). After in vivo immune cell development and/or expansion, recovered human B cells were Epstein Barr virus (EBV)-transformed, screened for antigen (Ag) binding, electrofused with a mouse-human heterohybridoma, subcloned, and human Ab RNA sequenced by PCR after reverse transcription to cDNA. Flow cytometry was used to assess human B cell markers and differentiation in Hu-PBL mice. RESULTS: Sequence analysis of a human Ab derived from an immunized Hu-HSC mouse and reactive with alpha3(IV)NC1 collagen reveals that it is encoded by unmutated heavy and light chain genes. The heavy chain complementarity determining region 3, a major determinant of Ag binding, contains uncommon motifs, including an N-region somatically-introduced highly hydrophobic tetrapeptide and dual cysteines encoded by a uniquely human IGHD2-2 Ab gene segment that lacks a murine counterpart. Comparison of human and mouse autoantibodies suggests that structurally similar murine Ab may arise by convergent selection. In contrast to the Hu-HSC model, transformed human B cells are rarely recovered from Hu-PBL mice, in which human B cells terminally differentiate and lose expression of EBV receptor CD21, thus precluding their transformation and recovery. CONCLUSIONS: Hu-HSC mice reveal that potentially pathogenic B cells bearing unmutated Ig receptors reactive with the NC1 domain on alpha3(IV) collagen can be generated in, and not purged from, the human preimmune repertoire. Uniquely human gene elements are recruited to generate the antigen binding site in at least a subset of these autoantibodies, indicating that humanized models may provide insights inaccessible using conventional mouse models. PMID- 26048778 TI - Vaccination against Staphylococcus aureus experimental endocarditis using recombinant Lactococcus lactis expressing ClfA or FnbpA. AB - Staphylococcus aureus is a major cause of serious infections in humans and animals and a vaccine is becoming a necessity. Lactococcus lactis is a non pathogenic bacterium that can be used as a vector for the delivery of antigens. We investigated the ability of non-living L. lactis heterologously expressing S. aureus clumping factor A (ClfA) and fibronectin-binding protein A (FnbpA), alone or together, to elicit an immune response in rats and protect them from S. aureus experimental infective endocarditis (IE). L. lactis ClfA was used for immunization against S. aureus Newman (expressing ClfA but not FnbpA), while L. lactis ClfA, L. lactis FnbpA, as well as L. lactis ClfA/FnbpA, were used against S. aureus P8 (expressing ClfA and FnbpA). Vaccination of rats with L. lactis ClfA elicited antibodies that inhibited binding of S. aureus Newman to fibrinogen, triggered the production of IL-17A and conferred protection to 13/19 (68%) of the animals from IE (P<0.05). Immunization with L. lactis ClfA, L. lactis FnbpA or L. lactis ClfA/FnbpA also produced antibodies against the target proteins, but these did not prevent binding of S. aureus P8 to fibrinogen or fibronectin and did not protect animals against S. aureus P8 IE. Moreover, immunization with constructs containing FnbpA did not increase IL-17A production. These results indicate that L. lactis is a valuable antigen delivery system able to elicit efficient humoral and cellular responses. However, the most appropriate antigens affording protection against S. aureus IE are yet to be elucidated. PMID- 26048779 TI - Market implementation of the MVA platform for pre-pandemic and pandemic influenza vaccines: A quantitative key opinion leader analysis. AB - A quantitative method is presented to rank strengths, weaknesses, opportunities, and threats (SWOT) of modified vaccinia virus Ankara (MVA) as a platform for pre pandemic and pandemic influenza vaccines. Analytic hierarchy process (AHP) was applied to achieve pairwise comparisons among SWOT factors in order to prioritize them. Key opinion leaders (KOLs) in the influenza vaccine field were interviewed to collect a unique dataset to evaluate the market potential of this platform. The purpose of this study, to evaluate commercial potential of the MVA platform for the development of novel generation pandemic influenza vaccines, is accomplished by using a SWOT and AHP combined analytic method. Application of the SWOT-AHP model indicates that its strengths are considered more important by KOLs than its weaknesses, opportunities, and threats. Particularly, the inherent immunogenicity capability of MVA without the requirement of an adjuvant is the most important factor to increase commercial attractiveness of this platform. Concerns regarding vector vaccines and anti-vector immunity are considered its most important weakness, which might lower public health value of this platform. Furthermore, evaluation of the results of this study emphasizes equally important role that threats and opportunities of this platform play. This study further highlights unmet needs in the influenza vaccine market, which could be addressed by the implementation of the MVA platform. Broad use of MVA in clinical trials shows great promise for this vector as vaccine platform for pre-pandemic and pandemic influenza and threats by other respiratory viruses. Moreover, from the results of the clinical trials seem that MVA is particularly attractive for development of vaccines against pathogens for which no, or only insufficiently effective vaccines, are available. PMID- 26048780 TI - The tuberculosis vaccine H4:IC31 is safe and induces a persistent polyfunctional CD4 T cell response in South African adults: A randomized controlled trial. AB - BACKGROUND: New, more effective vaccines to prevent tuberculosis (TB) disease are needed urgently. H4:IC31 is an investigational vaccine that contains a fusion protein of the immunodominant antigens TB10.4 and Ag85B, formulated in IC31 adjuvant. We assessed the safety and immunogenicity of H4:IC31 in South African adults from a TB endemic setting. METHODS: In this double blind, placebo controlled, phase I trial, Mycobacterium tuberculosis-uninfected, HIV-uninfected, healthy adults with a history of childhood BCG vaccination were randomly allocated to two intramuscular vaccinations with 5, 15, 50 or 150 MUg H4 formulated in 500nmol IC31, two months apart. Vaccinees were followed for six months to assess safety; immunogenicity was measured by ELISpot and intracellular cytokine staining assays. RESULTS: Thirty-two participants received H4:IC31 and 8 received placebo. Injection site adverse events were common but mild; mild fatigue was the most common systemic adverse event. Frequencies of adverse events did not differ between dosage groups. Detectable antigen-specific CD4 T cell responses were induced by all doses of H4:IC31, but doses below 50 MUg induced the highest frequencies of CD4 T cells, comprised predominantly of IFN gamma(+)TNF-alpha(+)IL-2(+) or TNF-alpha(+)IL-2(+) cells. These memory responses persisted up to the end of follow up, on study day 182. CONCLUSIONS: H4:IC31 demonstrated an acceptable safety profile and was immunogenic in South African adults. In this trial, the 15 MUg dose appeared to induce the most optimal immune response. PMID- 26048781 TI - Immune response triggered by Brucella abortus following infection or vaccination. AB - Brucella abortus live vaccines have been used successfully to control bovine brucellosis worldwide for decades. However, due to some limitations of these live vaccines, efforts are being made for the development of new safer and more effective vaccines that could also be used in other susceptible species. In this context, understanding the protective immune responses triggered by B. abortus is critical for the development of new vaccines. Such understandings will enhance our knowledge of the host/pathogen interactions and enable to develop methods to evaluate potential vaccines and innovative treatments for animals or humans. At present, almost all the knowledge regarding B. abortus specific immunological responses comes from studies in mice. Active participation of macrophages, dendritic cells, IFN-gamma producing CD4(+) T-cells and cytotoxic CD8(+) T-cells are vital to overcome the infection. In this review, we discuss the characteristics of the immune responses triggered by vaccination versus infection by B. abortus, in different hosts. PMID- 26048782 TI - (18)F-Fluorodeoxyglucamines: Reductive amination of hydrophilic (18)F-fluoro-2 deoxyglucose with lipophilic amines for the development of potential PET imaging agents. AB - Maillard reaction of (18)F-FDG with biological amines results in the formation of (18)F-fluorodeoxyglycosylamines ((18)F-FDGly) as pseudo-Amadori products. To increase in vivo stability, we report the reductive amination of FDGly to provide reduced fluorodeoxyglucamines (FDGlu). (18)F-Fluorodeoxyglucamines ((18)F-FDGlu), resulting from linking (18)F-FDG (hydrophilic) to lipophilic molecules containing amine group may be useful as positron emission tomography (PET) imaging agents. Two amine derivatives, 7-chloro-8-hydroxy-3-methyl-l-(3'-aminophenyl)-2,3,4,5 tetrahydro-lH-3-benzazepine (SCH 38548 for dopamine D1 receptors) and BTA-0 (for Abeta amyloid) were reacted with FDG under reductive amination conditions to yield stable products, FDGluSCH and FDGluBTA. FDGluSCH had high binding affinity to rat brain dopamine D1 receptors with a Ki of 19.5 nM while FDGluBTA had micromolar affinity for human frontal cortex Abeta plaques. (18)F-FDGluSCH was prepared in low to modest radiochemical yields and preliminary results showed binding to the rat striatum in brain slices. In vivo stability of(18)F-FDGluSCH needs to be determined. Our results suggest that (18)F-FDG is a useful 'radioactive synthon' for PET radiotracer development. Its usefulness will have to be determined on the basis of the structure-activity relationship of the target molecule. PMID- 26048783 TI - Suppression of CSN5 promotes the apoptosis of gastric cancer cells through regulating p53-related apoptotic pathways. AB - As one of the COP9 signalosome complex, CSN5 (also known as Jab1) has been confirmed overexpression in many human cancers and affected multiple pathways associating with cell proliferation and apoptosis. Correlation of CSN5 overexpression with poor prognosis for cancer provides evidence that it is involved in the tumorigenesis. However, little is known about the functional role and the underlying mechanism of CSN5 in gastric cancer progression. In the current study, the effect of CSN5 siRNA (small-interfering RNA) on the proliferation and apoptosis of human gastric cancer cells (AGS and MKN45) were examined. Our results showed that knockdown of CSN5 could inhibit proliferation and promote apoptosis of gastric cancer cells. Additionally, suppression of CSN5 expression contributed to the increased expression levels of p53 and Bax. In conclusion, CSN5 overexpression is significantly correlated with gastric cancer progression, and CSN5 could be a novel target in gastric cancer therapy. PMID- 26048784 TI - Alternative synthesis of 3-acetyl, 3-epoxy, and 3-formyl chlorins from a 3-vinyl chlorin, methyl pyropheophorbide-a, via iodination. AB - We developed novel methods to convert the C3-vinyl group of a chlorophyll derivative, methyl pyropheophorbide-a, into an acetyl group, an epoxy group, and a formyl group via iodination with I2 and phenyliodine(III) bis(trifluoroacetate). Reaction of the iodinated intermediate with ethylene glycol and subsequent treatment with base led to formation of the C3-acetyl chlorin. Reaction of the iodinated intermediate with ethylenediamine afforded the C3-oxiranyl chlorin. The C3-formyl chlorin was readily derived from the epoxide without hazardous reagents such as OsO4. These reactions were facile and useful alternatives to the previous methods. PMID- 26048785 TI - Meridianin derivatives as potent Dyrk1A inhibitors and neuroprotective agents. AB - Meridianins are a group of marine-derived indole alkaloids which are reported to possess kinase inhibitory activities. In the present Letter, we report synthesis of N1-substituted and C-ring modified meridianin derivatives and their evaluation as Dyrk1A inhibitors and neuroprotective agents. Among the library of 52 compounds screened, morpholinoyl linked derivative 26b and 2-nitro-4 trifluoromethyl phenyl sulfonyl derivative 29v displayed potent inhibition of Dyrk1A with IC50 values of 0.5 and 0.53 MUM, respectively. The derivative 26b also inhibited Dyrk2 and Dyrk3 with IC50 values of 1.4 and 2.2 MUM, respectively showing 2.2 and 4.4 fold selectivity for Dyrk1A with respect to Dyrk2 and Dyrk3. The compound 26b was not cytotoxic to human neuroblastoma SH-SY5Y cells (IC50>100 MUM) and it displayed significant neuroprotection against glutamate-induced neurotoxicity in these cells at 10 MUM. Molecular modelling studies of compound 26b led to identification of key interactions in the binding site of Dyrk1A and the possible reasons for observed Dyrk1A selectivity over Dyrk2. PMID- 26048786 TI - Synthesis and biological evaluation of curcumin derivatives containing NSAIDs for their anti-inflammatory activity. AB - Oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) was frequently associated with serious adverse effects. Inspired by curcumin-a naturally traditional Chinese medicine, a series of curcumin derivatives containing NSAIDs, used for transdermal application, were synthesized and screened for their anti-inflammatory activities in vitro and in vivo. Compared with curcumin and parent NSAID (salicylic acid and salsalate), topical application of A11 and B13 onto mouse ear edema, prior to TPA treatment markedly suppressed the expression of IL-1beta, IL-6 and TNF-alpha, respectively. Mechanistically, A11 and B13 blocked the phosphorylation of IkappaBalpha and suppressed the activation of p65 and IkappaBalpha. It was found that A11 and B13 may be potent anti-inflammatory agents for the treatment of inflammatory diseases. PMID- 26048787 TI - Synthesis of chemically-tethered amyloid-beta segment trimer possessing amyloidogenic properties. AB - As amyloid-beta (Abeta) undergoes dynamic aggregation, it is impossible to isolate ('hook') the transient Abeta oligomer in an assembly state-pure form (e.g., sole Abeta dimer, trimer, tetramer, etc.). Obtaining such a pure Abeta oligomer would allow us to establish an in vitro system to perform a more detailed investigation of the pathogenic properties of the oligomer. A chemically tethered Abeta oligomer, constructed only by covalent bonds, could satisfy this demand. Here we designed a chemically-tethered trimer of a pathogenic Abeta fragment (Abeta25-35) (1) and successfully generated it in situ from its precursor (4), a water-soluble and non-aggregative O-acyl isopeptide of 1, in neutral aqueous media. Chemically-tethered 1 possessed stronger amyloidogenic properties, that is, potential for beta-sheet structure, fibril formation, and cytotoxicity, than the corresponding monomer Abeta25-35 (6). Trimerization of Abeta25-35 sequence might affect both the aggregative properties and cytotoxicity, based on the present results. This work opens the door for chemical synthesis of oligomers bigger than trimers in an assembly state-pure form, allowing for identification of the most toxic Abeta oligomer. PMID- 26048788 TI - Design, synthesis and biological evaluation of paralleled Aza resveratrol chalcone compounds as potential anti-inflammatory agents for the treatment of acute lung injury. AB - Acute lung injury (ALI) is a major cause of acute respiratory failure in critically-ill patients. It has been reported that both resveratrol and chalcone derivatives could ameliorate lung injury induced by inflammation. A series of paralleled Aza resveratrol-chalcone compounds (5a-5m, 6a-6i) were designed, synthesized and screened for anti-inflammatory activity. A majority showed potent inhibition on the IL-6 and TNF-alpha expression-stimulated by LPS in macrophages, of which compound 6b is the most potent analog by inhibition of LPS-induced IL-6 release in a dose-dependent manner. Moreover, 6b exhibited protection against LPS induced acute lung injury in vivo. These results offer further insight into the use of Aza resveratrol-chalcone compounds for the treatment of inflammatory diseases, and the use of compound 6b as a lead compound for the development of anti-ALI agents. PMID- 26048789 TI - Discovery of novel pyrazole-containing benzamides as potent RORgamma inverse agonists. AB - The nuclear receptor RORgamma plays a central role in controlling a pro inflammatory gene expression program in several lymphocyte lineages including TH17 cells. RORgamma-dependent inflammation has been implicated in the pathogenesis of several major autoimmune diseases and thus RORgamma is an attractive target for therapeutic intervention in these diseases. Starting from a lead biaryl compound 4a, replacement of the head phenyl moiety with a substituted aminopyrazole group resulted in a series with improved physical properties. Further SAR exploration led to analogues (e.g., 4j and 5m) as potent RORgamma inverse agonists. PMID- 26048790 TI - New anti-trypanosomal active tetracyclic iridoid isolated from Morinda lucida Benth. AB - Human African trypanosomiasis (HAT), commonly known as sleeping sickness has remained a serious health problem in many African countries with thousands of new infected cases annually. Chemotherapy, which is the main form of control against HAT has been characterized lately by the viewpoints of toxicity and drug resistance issues. Recently, there have been a lot of emphases on the use of medicinal plants world-wide. Morinda lucida Benth. is one of the most popular medicinal plants widely distributed in Africa and several groups have reported on its anti-protozoa activities. In this study, we have isolated one novel tetracyclic iridoid, named as molucidin, from the CHCl3 fraction of the M. lucida leaves by bioassay-guided fractionation and purification. Molucidin was structurally elucidated by (1)H and (13)C NMR including HMQC, HMBC, H-H COSY and NOESY resulting in tetracyclic iridoid skeleton, and its absolute configuration was determined. We have further demonstrated that molucidin presented a strong anti-trypanosomal activity, indicating an IC50 value of 1.27 MUM. The cytotoxicity study using human normal and cancer cell lines indicated that molucidin exhibited selectivity index (SI) against two normal fibroblasts greater than 4.73. Furthermore, structure-activity relationship (SAR) study was undertaken with molucidin and oregonin, which is identical to anti-trypanosomal active components of Alnus japonica. Overlapping analysis of the lowest energy conformation of molucidin with oregonin suggested a certain similarities of aromatic rings of both oregonin and molucidin. These results contribute to the future drug design studies for HAT. PMID- 26048791 TI - Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series. AB - The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models. PMID- 26048792 TI - Identification of 3,5,6-substituted indolin-2-one's inhibitors of Aurora B by development of a luminescent kinase assay. AB - Aurora B kinase plays an important role in the cell normal mitosis and overexpresses in a variety of tumors. Inhibition of Aurora B kinase resulted in an apoptosis of cancer cells, which prevented tumor growth in xenograft models. In this Letter, we developed a luminescent kinase assay to perform high throughput screening for identification of small molecule Aurora B inhibitors. Two 3,5,6-substituted indolin-2-one derivatives were identified within an in house compound library. Their new derivatives were then designed and synthesized that resulting two new inhibitors of Aurora B kinase with improved potency. Docking simulation further demonstrated the proposed binding modes between indolin-2-one inhibitor and Aurora B. PMID- 26048793 TI - Discovery of imidazo[1,5-a]pyridines and -pyrimidines as potent and selective RORc inverse agonists. AB - The nuclear receptor (NR) retinoic acid receptor-related orphan receptor gamma (RORgamma, RORc, or NR1F3) is a promising target for the treatment of autoimmune diseases. RORc is a critical regulator in the production of the pro-inflammatory cytokine interleukin-17. We discovered a series of potent and selective imidazo[1,5-a]pyridine and -pyrimidine RORc inverse agonists. The most potent compounds displayed >300-fold selectivity for RORc over the other ROR family members, PPARgamma, and NRs in our cellular selectivity panel. The favorable potency, selectivity, and physiochemical properties of GNE-0946 (9) and GNE-6468 (28), in addition to their potent suppression of IL-17 production in human primary cells, support their use as chemical biology tools to further explore the role of RORc in human biology. PMID- 26048794 TI - Synthesis and characterization of novel oxazines and demonstration that they specifically target cyclooxygenase 2. AB - In the present study, we used solution combustion synthesis-bismuth oxide (Bi2O3) as catalyst for the simple and efficient synthesis of 1,2-oxazine based derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazoles, 1-arylpiperazine and carbazoles. (4aR,8aR)-4-(4-Methoxyphenyl)-3-((4-(4-methoxyphenyl)piperazin-1 yl)methyl)-4a,5,6,7,8,8a-hexahydro-4H-benzo[e][1,2]oxazine was found to be the most potent compound with a high degree of selectivity in inhibition towards COX2 (1.7 MUM) over COX1 (40.4 MUM) demonstrating the significance of 1,2-oxazine derivatives in developing COX2 specific inhibitors. Molecular docking analyses demonstrated that an isoleucine residue in the active site of COX1 is responsible for lower affinity to COX1 and increased potency towards COX2. Overall, our study reveals that the new 1,2-oxazine-based small molecules qualify as lead structures in developing COX2-specific inhibitors for anti-inflammatory therapy. PMID- 26048795 TI - Investigation on the sucrose binding pocket of HIV-1 Integrase by molecular dynamics and synergy experiments. AB - Enzymes whose catalytic activity depends on multimeric assembly are targets for inhibitors that perturb the interactions between the protein subunits such as the HIV-1 Integrase (IN). Sucrose has been recently crystallized in complex with IN revealing an allosteric binding pocket at the monomer-monomer interface. Herein, molecular dynamics were applied to theoretically test the effect of this small ligand on IN. As a result, such a compound increases the mutual free energy of binding between the two interacting monomers. Biological experiments confirmed the computational forecast. PMID- 26048796 TI - Structure-activity relationship study of E6 as a novel necroptosis inducer. AB - Necroptosis inducers represent a promising potential treatment for drug-resistant cancer. We herein describe the structure modification of E6, which was identified recently as a potent and selective necroptosis inducer. The studies described herein demonstrate for the first time that functionalized biphenyl derivatives possess necroptosis inducer activity. Furthermore, these studies have led to the identification of two promising compounds (5h and 5j) that can be used for further optimization studies as well as mechanism of action investigations. PMID- 26048797 TI - Polymerase incorporation of a 2'-deoxynucleoside-5'-triphosphate bearing a 4 hydroxy-2-mercaptobenzimidazole nucleobase analogue. AB - Here, we describe the enzymatic construction of a new larger base pair formed between adenine (A) and a 4-hydroxy-2-mercaptobenzimidazole (SB) nucleobase analogue. We investigated the enzymatic incorporation of 2'-deoxynucleoside-5' triphosphate bearing a SB nucleobase analogue (dSBTP) into oligonucleotides (ONs) by DNA polymerases. dSBTP could be effectively incorporated at the site opposite a dA in a DNA template by several B family DNA polymerases. These findings provide new insights into various aspects of biotechnology, including the design of non-natural base pairs. PMID- 26048798 TI - Naltrindole derivatives with fluorinated ethyl substituents on the 17-nitrogen as delta opioid receptor inverse agonists. AB - We synthesized derivatives of the delta opioid receptor (DOR) antagonists naltrindole (NTI) and compound 1 that were modified with small alkyl or fluorinated ethyl substituents on the 17-nitrogen. Although the derivatives showed decreased binding affinities for the opioid receptors, their selectivities for the DOR were higher than the parent compounds NTI and compound 1. Surprisingly, 17-fluoroethyl NTI derivatives exerted DOR inverse agonistic activities. The DOR inverse agonism of compounds 4c-e was less efficacious but significant, as compared with a standard DOR inverse agonist ICI-174864. On the other hand, compound 1 and its derivatives with small alkyl or monofluoroethyl substituents were partial agonists, but the derivatives having di- or trifluoroethyl group showed neither agonistic nor inverse agonistic activities. PMID- 26048799 TI - Synthesis, molecular docking and anticancer studies of peptides and iso-peptides. AB - Chiral peptides and iso-peptides were synthesized in excellent yield by using benzotriazole mediated solution phase synthesis. Benzotriazole acted both as activating and leaving group, eliminating frequent use of protection and subsequent deprotection. The procedure was based on the hypothesis that epimerization should be suppressed in solution due to a faster coupling rate than SPPS. All the synthesized peptides complied with Lipinski's Ro5 except for the rotatable bonds. Inhibition of cell proliferation of cancer cell lines is one of the most commonly used methods to study the effectiveness of any anticancer agents. Synthesized peptides and iso-peptides were tested against three cancer cell lines (MCF-7, MDA-MB 231) to determine their anti-proliferative potential. NFkB was also determined. Molecular docking studies were also carried out to complement the experimental results. PMID- 26048800 TI - Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors. AB - Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection. PMID- 26048801 TI - An efficient synthesis and in vitro antibacterial evaluation of ruthenium quinolinol complexes. AB - A series of ruthenium-quinolinol complexes were synthesized using a simple and effective pathway and their in vitro antibacterial activity against various resistant gram-positive and gram-negative bacteria were evaluated. It was established that compound [(eta6-pcymene)RuCl(kappa2-O,N-5,7-dibromo-HyQ)].Cl (3b) & [(eta6-pcymene)RuCl(kappa2-O,N-5,7-dibromo-HyQ)].Cl (3e) were significantly active against Staphylococcus aureus, Escherichia coli, Bacillus subtilis &Salmonella sp. The structures of the new compounds were elucidated by the analysis of spectroscopic data. The stability of complex [(eta6 pcymene)RuCl(kappa2-O,N-5,7-dibromo-HyQ)].Cl (3b) was measured by UV spectroscopy & time dependent NMR spectroscopy. Compound 3b also shows remarkable fluorescence. PMID- 26048802 TI - Design, synthesis and biological evaluation of 4-(alkyloxy)-6-methyl-2H-pyran-2 one derivatives as quorum sensing inhibitors. AB - Novel pyrone-derived quorum sensing (QS) ligands to inhibit the binding of OdDHL to the LasR of Pseudomonas aeruginosa were designed, synthesized and evaluated. Among the analogs, the most potent compound 8 exhibited strong in vitro inhibitory activities against biofilm formation and down-regulated OdDHL/LasR associated genes by 35-67%. The binding mode of 8 in silico was highly similar to that of the crystal ligand OdDHL in the active site of LasR. PMID- 26048803 TI - Discovery of substituted 1,4-dihydroquinolines as novel promising class of P glycoprotein inhibitors: First structure-activity relationships and bioanalytical studies. AB - Multidrug resistance (mdr) is the most important problem in the therapeutical treatment of cancer. One central problem in the resistance proceeding is the expression of transmembrane efflux pumps which transport drugs out of the cells. We developed novel substituted 1,4-dihydroquinolines as inhibitors of the transmembrane efflux pump P-glycoprotein. Structure-activity relationships are discussed for this first series. Promising active inhibitors have been identified and first bioanalytical studies have been carried out to address questions of cellular toxicity, P-gp substrate as well as mdr reversal properties. PMID- 26048804 TI - Use of molecular modeling aided design to dial out hERG liability in adenosine A(2A) receptor antagonists. AB - Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile. PMID- 26048805 TI - Fully automated synthesis of [(18)F]T807, a PET tau tracer for Alzheimer's disease. AB - The authentic standard T807 and its nitro-precursor T807P as well as t-Boc protected T807P precursor for radiolabeling were synthesized from (4 bromophenyl)boronic acid, 3-bromo-4-nitropyridine and 3-bromo-6-nitropyridine with overall chemical yield 27% in three steps, 4-7% in three to five steps, and 3-8% in four to five steps, respectively. [(18)F]T807 was synthesized from T807P by the nucleophilic [(18)F]fluorination with K[(18)F]F/Kryptofix 2.2.2 in DMSO at 140 degrees C followed by reduction with Fe powder/HCOOH through manual synthesis with 5-10% decay corrected radiochemical yield in two steps. [(18)F]T807 was also synthesized from t-Boc-protected T807P by a concurrent [(18)F]fluorination and deprotection with K[(18)F]F/Kryptofix 2.2.2 in DMSO at 140 degrees C and purified by HPLC-SPE method in a home-built automated [(18)F]radiosynthesis module with 20-30% decay corrected radiochemical yield in one step. The specific activity of [(18)F]T807 at end of bombardment (EOB) was 37 370 GBq/MUmol. PMID- 26048806 TI - Discovery of biaryl carboxylamides as potent RORgamma inverse agonists. AB - RORgammat is a pivotal regulator of a pro-inflammatory gene expression program implicated in the pathology of several major human immune-mediated diseases. Evidence from mouse models demonstrates that genetic or pharmacological inhibition of RORgamma activity can block the production of pathogenic cytokines, including IL-17, and convey therapeutic benefit. We have identified and developed a biaryl-carboxylamide series of RORgamma inverse agonists via a structure based design approach. Co-crystal structures of compounds 16 and 48 supported the design approach and confirmed the key interactions with RORgamma protein; the hydrogen bonding with His479 was key to the significant improvement in inverse agonist effect. The results have shown this is a class of potent and selective RORgamma inverse agonists, with demonstrated oral bioavailability in rodents. PMID- 26048807 TI - Synthesis and antimicrobial evaluation of 5-aryl-1,2,4-triazole-3-thione derivatives containing a rhodanine moiety. AB - Three series of 5-aryl-1,2,4-triazole-3-thione derivatives containing a rhodanine moiety (5a-k, 6a-i, and 7a-i) have been synthesized, characterized and evaluated for their antibacterial activity. Some of these displayed potent antibacterial activity against several Gram-positive and Gram-negative bacterial strains (including multidrug-resistant clinical isolates) with minimum inhibitory concentration (MIC) values in the range of 4-64 MUg/mL and minimum bactericidal concentration (MBC) values in the range of 8-256 MUg/mL. Compared with previously reported rhodanine derivatives, these compounds exhibited a broad spectrum of antibacterial activity by means of introducing 4-amino-5-aryl-1,2,4-triazole-3 thione moiety. Notably, compound 5f exhibited good antibacterial activity against Staphylococcus aureus RN 4220, S. aureus 209, S. aureus 503, Gram-negative bacteria (Escherichia coli 1924), and Candida albicans 7535 with MBC values of 8 or 16 MUg/ml. All of the compounds synthesized in the current Letter were characterized by (1)H NMR, (13)C NMR, infrared and mass spectroscopy. PMID- 26048808 TI - Synthesis and evaluation of novel fluorinated pyrazolo-1,2,3-triazole hybrids as antimycobacterial agents. AB - A library of novel 3-trifluoromethyl pyrazolo-1,2,3-triazole hybrids (5-7) were accomplished starting from 5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-amine (1) via key intermediate 2-azido-N-(5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4 yl)acetamide (3) through click chemistry approach. Thus obtained compounds in 5-7 series were evaluated for in vitro antimycobacterial activity against Mycobacterium smegmatis (MC(2) 155) and also verified the cytotoxicity. These studies engendered promising lead compounds 5q, 7b and 7c with MIC (MUg/mL) values 15.34, 16.18 and 16.60, respectively. Amongst these three compounds, 2-(4 (4-methoxybenzoyl)-1H-1,2,3-triazol-1-yl)-N-(5-phenyl-3-(trifluoromethyl)-1H pyrazol-4-yl) acetamide (5q) emerged as the most promising antitubercular agent with lowest cytotoxicity against the A549 cancer cell line. This is the first report to demonstrate the pyrazolo triazole hybrids as potential antimycobacterial agents. PMID- 26048809 TI - Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity. AB - A series of doubly flexible nucleoside analogues were designed based on the acyclic sugar scaffold of acyclovir and the flex-base moiety found in the fleximers. The target compounds were evaluated for their antiviral potential and found to inhibit several coronaviruses. Significantly, compound 2 displayed selective antiviral activity (CC50 >3* EC50) towards human coronavirus (HCoV) NL63 and Middle East respiratory syndrome-coronavirus, but not severe acute respiratory syndrome-coronavirus. In the case of HCoV-NL63 the activity was highly promising with an EC50 <10 MUM and a CC50 >100 MUM. As such, these doubly flexible nucleoside analogues are viewed as a novel new class of drug candidates with potential for potent inhibition of coronaviruses. PMID- 26048810 TI - Synthesis of novel amide functionalized 2H-chromene derivatives by Ritter amidation of primary alcohol using HBF4.OEt2 as a mild and versatile reagent and evaluation of their antimicrobial and anti-biofilm activities. AB - A series of novel amide functionalized 2H-chromene derivatives 3 were prepared starting from ethyl-2-hydroxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate 1 via sodium borohydride reduction followed by Ritter amidation using HBF4.OEt2 as a mild and versatile reagent. All the products 3 were screened for antimicrobial activity against various Gram-positive, Gram-negative bacteria and fungal strain. The promising derivatives such as 3f, 3g, 3k, 3l, 3m, 3n and 3o were further screened for minimum bactericidal concentration and bio-film inhibition activity and identified the potential ones. Among all the promising, compound 3g was more potent for antimicrobial, MBC and anti bio-film activities. The structure verses activity relationship of 3g revealed that the presence of two bromine atoms at sixth and R position promotes high activity. PMID- 26048811 TI - Women with comorbid substance dependence and psychiatric disorders in Sweden: a longitudinal study of hospital care utilization and costs. AB - BACKGROUND: Substance use disorders are regarded as one of the most prevalent, deadly and costly of health problems. Research has consistently found that the prevalence of other psychiatric disorders among those with substance related disorders is substantial. Combined, these disorders lead to considerable disability and health years lost worldwide as well as extraordinary societal costs. Relatively little of the literature on substance dependence and its impact on healthcare utilization and associated costs has focused specifically on chronic drug users, adolescents or women. In addition, the research that has been conducted relies largely on self-reported data and does not provide long-term estimates of hospital care utilization. The purpose of this study is to describe the long-term (24-32 year) healthcare utilization and it's associated costs for a nationally representative cohort of chronic substance abusing women (adults and adolescents) remanded to compulsory care between 1997-2000 (index episode). As such, this is the first study investigating healthcare costs for women in compulsory treatment in Sweden. METHODS: Women (n = 227) remanded to compulsory care for substance abuse were assessed at intake and their hospital care utilization was retrieved 5-years post compulsory care from national records. Unit costs for ICD-10 diagnoses were applied to all hospital care used from 1975 2006. Attempts are made to estimate productivity losses associated with hospitalization and premature death. RESULTS: Upon clinical assessment it was found that a majority of these women had a comorbid psychiatric disorder (primarily personality disorder). The women followed in this study were admitted to hospital five to six times that of the general population and had stays six to eight times that of the general population. Total direct healthcare costs per person over the study period averaged approximately $173,000 and was primarily the result of psychiatric department visits (71 %) and inpatient treatment (98.5 %; detoxification and short-term rehabilitation). CONCLUSIONS: Women placed in compulsory care use more hospital resources than that of the general Swedish population and when compared to international research of hospital care use and substance abuse. Direct hospital costs vary greatly over the life course. Effective services can have significant economic benefit. PMID- 26048812 TI - Optimizing stimulation parameters in functional electrical stimulation of denervated muscles: a cross-sectional study. AB - BACKGROUND: To counteract denervation atrophy long-term electrical stimulation with a high number of muscle contractions has to be applied. This may lead to discomfort of the patient and negative side effects like burns. A functional effective muscle contraction induced by the lowest possible stimulation intensity is desirable. In clinical practice a selective stimulation of denervated muscles with triangular pulses is used. The aim of the study was to evaluate the influence of polarity and pulse duration on the stimulation intensity of triangular pulses in denervated muscles in patients with peripheral nerve lesions. METHODS: Twenty-four patients with denervated extensor digitorum communis muscle and twenty-four patients with denervated tibialis anterior muscle due to peripheral nerve lesions were included. Four different combinations of triangular pulses with various duration and polarity were delivered randomly to the denervated muscles. The threshold intensity to induce a functional effective muscle contraction was noted. One-way within subject ANOVA was used to assess changes in intensity. An alpha level of p less than or equal to 0.05 was the criterion for statistical significance. RESULTS: Patients with a denervated tibialis anterior muscle presented significant lower intensities inducing a functional effective muscle contraction in favor of the stimulation with a duration of 200 ms and a polarity with the cathode proximally applied. No significant differences could be shown between the different stimulation protocols in case of denervated extensor digitorum communis muscle. CONCLUSIONS: We recommend electrical stimulation of the denervated tibialis anterior muscle with triangular current with a duration of 200 ms and a polarity with the cathode proximally applied. PMID- 26048813 TI - Failure of a numerical quality assessment scale to identify potential risk of bias in a systematic review: a comparison study. AB - BACKGROUND: Assessing methodological quality of primary studies is an essential component of systematic reviews. Following a systematic review which used a domain based system [United States Preventative Services Task Force (USPSTF)] to assess methodological quality, a commonly used numerical rating scale (Downs and Black) was also used to evaluate the included studies and comparisons were made between quality ratings assigned using the two different methods. Both tools were used to assess the 20 randomized and quasi-randomized controlled trials examining an exercise intervention for chronic musculoskeletal pain which were included in the review. Inter-rater reliability and levels of agreement were determined using intraclass correlation coefficients (ICC). Influence of quality on pooled effect size was examined by calculating the between group standardized mean difference (SMD). RESULTS: Inter-rater reliability indicated at least substantial levels of agreement for the USPSTF system (ICC 0.85; 95% CI 0.66, 0.94) and Downs and Black scale (ICC 0.94; 95% CI 0.84, 0.97). Overall level of agreement between tools (ICC 0.80; 95% CI 0.57, 0.92) was also good. However, the USPSTF system identified a number of studies (n = 3/20) as "poor" due to potential risks of bias. Analysis revealed substantially greater pooled effect sizes in these studies (SMD -2.51; 95% CI -4.21, -0.82) compared to those rated as "fair" (SMD 0.45; 95% CI -0.65, -0.25) or "good" (SMD -0.38; 95% CI -0.69, -0.08). CONCLUSIONS: In this example, use of a numerical rating scale failed to identify studies at increased risk of bias, and could have potentially led to imprecise estimates of treatment effect. Although based on a small number of included studies within an existing systematic review, we found the domain based system provided a more structured framework by which qualitative decisions concerning overall quality could be made, and was useful for detecting potential sources of bias in the available evidence. PMID- 26048814 TI - Biodegradation of polycyclic aromatic hydrocarbons (PAHs) by laccase from Trametes versicolor covalently immobilized on amino-functionalized SBA-15. AB - A covalent immobilization method based on glutaraldehyde and amino-functionalized SBA-15 supports has been successfully applied to covalently and stably immobilize laccase from Trametes versicolor. The resultant biocatalysts displayed high incorporation yields of enzyme and led to excellent biodegradation rates of selected HPAs models, i.e. naphthalene, phenanthrene and anthracene, in water. The nature of the hydrocarbon chain accompanying the amino group has been shown as determinant for the immobilization as well as for the activity and reusability of the materials. Thus, alkyl moieties displayed higher enzyme loadings than phenyl moieties, being more adequate the larger n-butyl tethering residue likely due to its higher mobility. Using the aminobutyl-based laccase-SBA-15, 82%, 73%, and 55% conversion of naphthalene, phenanthrene and anthracene, respectively, were achieved after 48 h, very close to the values obtained with free laccase under the same reaction conditions. On the other hand, aminopropyl-based laccase SBA-15 biocatalysts displayed the best reusability properties, retaining higher activity after four repeated uses than the corresponding aminobutyl-based materials. PMID- 26048815 TI - Conductive diamond electrochemical oxidation of caffeine-intensified biologically treated urban wastewater. AB - In this work, the usefulness of Conductive Diamond Electrochemical Oxidation (CDEO) to degrade caffeine in real urban wastewater matrixes was assessed. The oxidation of actual wastewater intensified with caffeine (from 1 to 100 mg L(-1)) was studied, paying particular attention to the influence of the initial load of caffeine and the differences observed during the treatment of caffeine in synthetic wastewater. The results showed that CDEO is a technology that is capable of efficiently degrading this compound even at very low concentrations and that it can even be completely depleted. Profiles of the ionic species of S (SO4(2-)), N (NH4(+), NO3(-)) and Cl (ClO(-), ClO3(-) and ClO4(-)) were monitored and explained for plausible oxidation mechanisms. It was observed that the efficiency achieved is higher in the treatment of real wastewater than in the oxidation of synthetic wastewater because of the contribution of electrogenerated oxidant species such as hypochlorite. The formation of chlorate and perchlorate during electrochemical processes was observed, and a combined strategy to prevent this important drawback was successfully tested based on the application of low current densities with the simultaneous dosing of hydrogen peroxide. PMID- 26048816 TI - Polyethyleneimine-grafted boronate affinity materials for selective enrichment of cis-diol-containing compounds. AB - Polyethyleneimine (PEI)-grafted and 3-acrylamidophenylboronic acid (AAPBA) functionalized SiO2 boronate affinity materials were synthesized for the selective enrichment of cis-diol-containing compounds. Characterization results of scanning electron microscopy, Fourier transform infrared spectroscopy, elemental analysis, zeta potential, and X-ray photoelectron spectroscopy indicated the successful fabrication of SiO2@PEI-AAPBA materials. Chromatographic separation of test mixtures reveals that SiO2@PEI-AAPBA has high selective enrichment ability for cis-diol-containing compounds. The binding pH between SiO2@PEI-AAPBA and catechol was found to be as low as pH 4.5, while that between SiO2@PEI-AAPBA and adenosine was only ~7.5. This difference might be attributed to the strong electrostatic repulsion between the solid phase and analytes at a low pH. Furthermore, a diphasic separation column was fabricated based on boronate affinity chromatography, C18-reversed-phase chromatography and applied in pressurized capillary electrochromatography (pCEC). Results showed that four polar nucleosides could be well captured by the boronate affinity chromatography (BAC) section and separated by reversed phase pCEC. Finally, SiO2@PEI600-AAPBA based solid-phase extraction technology was applied to the purification of ribonucleosides in real urine samples, and results of UHPLC-MS/MS revealed that the intensities of the extracted ions (a neutral mass loss of m/z 132.04 Da) of the ribonucleosides were significantly enhanced after the enrichment. PMID- 26048817 TI - Gas phase ion chemistry of an ion mobility spectrometry based explosive trace detector elucidated by tandem mass spectrometry. AB - The gas phase ion chemistry for an ion mobility spectrometer (IMS) based explosive detector has been elucidated using tandem mass spectrometry. The IMS system, which is operated with hexachloroethane and isobutyramide reagent gases and an ion shutter type gating scheme, is connected to the atmospheric pressure interface of a triple quadrupole mass spectrometer (MS/MS). Product ion masses, daughter ion masses, and reduced mobility values for a collection of nitro, nitrate, and peroxide explosives measured with the IMS/MS/MS instrument are reported. The mass and mobility data together with targeted isotopic labeling experiments and information about sample composition and reaction environment are leveraged to propose molecular formulas, structures, and ionization pathways for the various product ions. The major product ions are identified as [DNT-H](-) for DNT, [TNT-H](-) for TNT, [RDX+Cl](-) and [RDX+NO2](-) for RDX, [HMX+Cl](-) and [HMX+NO2](-) for HMX, [NO3](-) for EGDN, [NG+Cl](-) and [NG+NO3](-) for NG, [PETN+Cl](-) and [PETN+NO3](-) for PETN, [HNO3+NO3](-) for NH4NO3, [NO2](-) for DMNB, [HMTD-NC3H6O3+H+Cl](-) and [HMTD+H-CH2O-H2O2](+) for HMTD, and [(CH3)3CO2](+) for TATP. In general, the product ions identified for the IMS system studied here are consistent with the product ions reported previously for an ion trap mobility spectrometer (ITMS) based explosive trace detector, which is operated with dichloromethane and ammonia reagent gases and an ion trap type gating scheme. Differences between the explosive trace detectors include the [NG+Cl](-) and [PETN+Cl](-) product ions being major ions in the IMS system compared to minor ions in the ITMS system as well as the major product ion for TATP being [(CH3)3CO2](+) for the IMS system and [(CH3)2CNH2](+) for the ITMS system. PMID- 26048818 TI - Determination of lead isotopes in a new Greenland deep ice core at the sub picogram per gram level by thermal ionization mass spectrometry using an improved decontamination method. AB - An improved decontamination method and ultraclean analytical procedures have been developed to minimize Pb contamination of processed glacial ice cores and to achieve reliable determination of Pb isotopes in North Greenland Eemian Ice Drilling (NEEM) deep ice core sections with concentrations at the sub-picogram per gram level. A PL-7 (Fuso Chemical) silica-gel activator has replaced the previously used colloidal silica activator produced by Merck and has been shown to provide sufficiently enhanced ion beam intensity for Pb isotope analysis for a few tens of picograms of Pb. Considering the quantities of Pb contained in the NEEM Greenland ice core and a sample weight of 10 g used for the analysis, the blank contribution from the sample treatment was observed to be negligible. The decontamination and analysis of the artificial ice cores and selected NEEM Greenland ice core sections confirmed the cleanliness and effectiveness of the overall analytical process. PMID- 26048819 TI - Facile synthesis of polyaniline-coated SiO2 nanofiber and its application in enrichment of fluoroquinolones from honey samples. AB - In this study, polyaniline coated SiO2 nanofibers (PANI/SiO2) was prepared by combining electrospinning technique with in-situ polymerization. The proposed strategy for the preparation of PANI/SiO2 can eliminate the aggregation of PANI and the yield of PANI/SiO2 was high. Scanning electron microscopy (SEM) images showed that PANI nanoparticles were uniformly coated on the surface of SiO2 nanofibers. The as-prepared PANI/SiO2 nanofibers were then applied as the sorbent for in-syringe dispersive solid-phase extraction (dSPE) for the extraction of fluoroquinolones (FQs) from honey samples. The influence of SiO2 amount on the formation of PANI/SiO2 and several parameters that affect the extraction efficiency were investigated. Under optimized conditions, a rapid, simple and effective method for the determination of FQs in honey sample was developed by coupling with liquid chromatography-fluorescence detector (LC-FLD) analysis. Due to the fast extraction equilibrium, the whole sample pretreatment process could be accomplished within 4 min. The limits of detection (LODs) for the target FQs were found to be 0.1-1.3 ng/g. The recoveries in honey sample were in the range of 81.4-118.1% with the RSDs of 0.8-14.4% (intra-day) and 1.4-14.9% (inter-day). This study offers a new strategy for the preparation of functional SiO2 nanofibers using post-electrospinning modification by in-situ polymerization, which could be generally applied in the preparation of various separation materials with electrospun nanofibers. PMID- 26048820 TI - Quantification of caffeine in human saliva by Nuclear Magnetic Resonance as an alternative method for cytochrome CYP1A2 phenotyping. AB - The first step in caffeine metabolism is mediated for over 95% by the CYP1A2 isoform of cytochrome P450. Therefore, CYP1A2 activity is most conveniently measured through the determination of caffeine clearance. The HPLC quantification of caffeine is fully validated and is the most widely used method. It can be performed on saliva, which is gaining importance as a diagnostic biofluid and permits easy and low invasive sampling. Here, we present a quantitative (1)H nuclear magnetic resonance (NMR) method to determine caffeine in human saliva. The procedure is simple because it involves only an ultra-filtration step and a direct extraction in a deuterated solvent, yielding a matrix that is then analyzed. The reliability of this NMR method was demonstrated in terms of linearity, accuracy, recovery, and limits of detection (LoD). Good precision (relative standard deviation, RSD <4%), a recovery of >95% and LoD of 6.8.10(-7) mol L(-1) were obtained. The method was applied to samples collected from different volunteers over 24h following a single oral dose of about 100mg of caffeine administered with either coffee beverage or a capsule. PMID- 26048821 TI - Fully automated photocolorimetric method for dissolved silica in oil well water rich in sulfide and bicarbonate. AB - A fully automated photocolorimetric method for dissolved silica in oil well water rich in sulfide and bicarbonate is proposed; the method is based on yellow silicomolybdic heteropolyacid. To eliminate the interference of sulfide a treatment with bromate is utilized. The analytical range is 1-30 mg L(-1); with the automatically performed dilution it extends up to 300 mg L(-1), RSD 5.5%. PMID- 26048822 TI - A novel mixed-mode solid phase extraction coupled with LC-MS/MS for the re evaluation of free 3-nitrotyrosine in human plasma as an oxidative stress biomarker. AB - 3-Nitrotyrosine (3-NT) has been widely adopted as a biomarker of oxidative stress. However, an enormous range of reported concentrations of 3-NT in biological matrices indicated an underlying methodological problem. Consequently, our understanding of tyrosine nitration in vivo and its significance as a biomarker may have been confounded. Here we report a fast, specific and sensitive LC-MS/MS method to accurately quantify free 3-NT in human plasma. For the first time, a single-step solid phase extraction of 3-NT using mixed-mode sorbent in a 96-well plate was developed after significant optimization. Complete chromatographic separation of 3-NT from other tyrosine analogs was achieved on a PFPP column (150 mm, 2.1 mm, 3 MUm) with a cycle time of 10 min. The developed method was validated in terms of linearity, sensitivity, specificity, precision, accuracy, matrix effect, carryover, analyte stability and reference interval. The lower limit of quantification of the method was 5 pg/ml for plasma 3-NT, which represents a significant sensitivity improvement over reported methods. No artifactual 3-NT formation was observed, and the assay was not affected by 40 likely interferences. The average intra- and inter-assay variances were 3.4% and 3.7%, respectively. Of note, the reference interval for a healthy population was established to be 2.0-40.1 pg/ml (8.8-177 pM) with a mean of 11.1 pg/ml (49 pM). The mean value is at least 13-fold lower than previously reported mean values. Furthermore, the method was applied to the investigation of biological variation (n=15) over a three week period and no statistical differences were found. The solid phase extraction in a 96-well format and a fast LC-MS/MS delivered a practical, precise and accurate tool well-suited to quantify free plasma 3-NT in a large number of biological samples. PMID- 26048823 TI - A rapid LC-MS/MS method for quantitative profiling of fatty acids, sterols, glycerolipids, glycerophospholipids and sphingolipids in grapes. AB - The abundance of lipids in plants is influenced by genotype and phenotype. Despite being a very important class of plant metabolites, knowledge of grape lipids is still very limited to date, with the exception of those located in seeds. Few investigations of grape lipids have shown that their profile depends on grape maturity, the variety and their location in the berry. Recent advances in liquid chromatography coupled to mass spectrometry have paved the way for faster analysis of lipids with minimal sample preparation. Here we describe a validation method for the extraction, identification and quantification of different classes of grape lipids: fatty acids, sterols, glycerolipids, glycerophospholipids and sphingolipids using liquid chromatographic electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). The method was validated for 33 lipids, with linearity range (R(2)=0.95-1.00), LOQ (0.003-14.88 ng mL(-1)) and intraday and interday repeatability being evaluated for each lipid. The lipid profiling method developed was successfully applied to the analysis of 18 grape samples (10 red grape and 8 white grape varieties) from 4 different genetic groups: Vitis vinifera, Vitis non-vinifera, Muscat and hybrid; 33 lipids were identified and quantified. This method, which can be easily expanded to include further compounds and other plant tissues, is the starting point for analysis of the lipid profile in different grape tissues, an essential goal for better understanding the role of lipids in grape physiology. PMID- 26048824 TI - Development and validation of LC-MS/MS method for quantification of bisphenol A and estrogens in human plasma and seminal fluid. AB - Bisphenol A (BPA) is a widely known endocrine disruptor with estrogenic, antiestrogenic or antiandrogenic properties. BPA could interfere with estrogen metabolism as well with receptor-mediated estrogen actions. Both environmental BPA and estrogens may be traced in body fluids, of which, besides the blood plasma, the seminal fluid is of particular interest regarding their possible interactions in the testis. The method for simultaneously determining BPA and estrogens is then needed, taking into account that their concentrations in these body fluid may differ. Here the method was developed and validated for measurements of BPA, estrone (E1), estradiol (E2) and estriol (E3) in blood plasma and seminal plasma using liquid chromatography-tandem mass spectrometry. Due to the phenolic moiety of all compounds, dansyl chloride derivatization could be used. The analytical criteria of the method with respect to expected concentration of the analytes were satisfactory. The lower limits of quantifications (LLOQ) amounted to 43.5, 4.0, 12.7, 6.7 pg/mL for plasma BPA, E1, E2 and E3, and 28.9, 4.9, 4.5, 3.4 pg/mL for seminal BPA, E1, E2 and E3, respectively. The concentrations of individual steroids differed between body fluids. To the best of our knowledge, this is the first method that enabled the measurement of estrogens and BPA together in one run. The concentrations of E1, E2 and for the first time also of E3 in seminal plasma in normospermic men are reported. PMID- 26048825 TI - Molecularly imprinted hollow spheres for the solid phase extraction of estrogens. AB - Solid phase extraction (SPE) is widely used in many different areas, such as environmental, biological, and food analysis, where cleaning and pre concentration of samples are key steps in the analytical protocol. New materials have significant impact on the development of solid phase extraction. In this paper, mono-dispersed molecularly imprinted hollow spheres (MIHSs) of beta estradiol (E2) were synthesized using silica nanospheres particles as the sacrificial matrix. Compared to the corresponding non-imprinted hollow spheres (NIHSs), the MIHSs with uniform size of 290 nm have outstanding affinity in aqueous solution. Static saturation adsorption required only 15min to achieve equilibrium, with a binding capacity (Qmax) of 44.5 MUmol g(-1). The extraction of E2, ethinyl estradiol (EE), diethylstilbestrol (DES), ethisterone (ES) and estrone (E1) from water samples by MIHSs was also investigated. In the spiked samples of tap water, Qinghe river water and Zhanjiang river water, more than 90.42% of E2, but less than 79% of EE, DES, ES and E1 were recovered. The limits of detection (LOD) ranged from 0.1 to 0.26 umol L(-1) after solid phase extraction by MIHSs and HPLC-UV analysis. The adsorption capacity of the MIHSs showed no significant deterioration after six rounds of regeneration. PMID- 26048826 TI - Development of a simple method for determination of NO2 in air using digital scanner images. AB - Nitrogen dioxide (NO2) is an important indicator of atmospheric pollution that is mainly derived from combustion processes. The gas is often present at undesirable levels in both open and closed environments worldwide, requiring monitoring under a variety of different conditions. This work describes the development of a sensitive, selective, and inexpensive method for the determination of NO2 in gaseous samples. The method is based on the processing of digital images of the product of the Griess-Saltzman (GS) colorimetric reaction. NO2 was collected and pre-concentrated using C-18 cartridges impregnated with triethanolamine, followed by elution with 5% methanol solution. The reaction for formation of the colored product only required 300 MUL volumes of sample containing reagent, minimizing the generation of chemical wastes. Calibrations using standard atmospheres showed that it was possible to measure NO2 in a concentration range from 5.1 to 100.0 ppb (9.4-188.0 ug m(-3)), using a sampling flow rate of 0.50 L min(-1) and a collection time of 60 min. The limit of detection achieved with a solution volume of 300 MUL was 5.0 ppb (9.6 ug m(-3)), with a relative error of 2% and a coefficient of variation of 1.6%. PMID- 26048827 TI - Development and comparison of two multi-residue methods for the analysis of select pesticides in honey bees, pollen, and wax by gas chromatography-quadrupole mass spectrometry. AB - One of the hypotheses that may help explain the loss of honey bee colonies worldwide is the increasing potential for exposure of honey bees to complex mixtures of pesticides. To better understand this phenomenon, two multi-residue methods based on different extraction and cleanup procedures have been developed, and compared for the determination of 11 relevant pesticides in honey bees, pollen, and wax by gas chromatography-quadrupole mass spectrometry. Sample preparatory methods included solvent extraction followed by gel permeation chromatography (GPC) cleanup and cleanup using a dispersive solid-phase extraction with zirconium-based sorbents (Z-Sep). Matrix effects, method detection limits, recoveries, and reproducibility were evaluated and compared. Method detection limits (MDL) of the pesticides for the GPC method in honey bees, pollen, and wax ranged from 0.65 to 5.92 ng/g dw, 0.56 to 6.61 ng/g dw, and 0.40 to 8.30 ng/g dw, respectively, while MDLs for the Z-Sep method were from 0.33 to 4.47 ng/g dw, 0.42 to 5.37 ng/g dw, and 0.51 to 5.34 ng/g dw, respectively. The mean recoveries in all matrices and at three spiking concentrations ranged from 64.4% to 149.5% and 71.9% to 126.2% for the GPC and Z-Sep methods, with relative standard deviation between 1.5-25.3% and 1.3-15.9%, respectively. The results showed that the Z-Sep method was more suitable for the determination of the target pesticides, especially chlorothalonil, in bee hive samples. The Z-Sep method was then validated using a series of field-collected bee hive samples taken from honey bee colonies in Virginia. PMID- 26048828 TI - An easy way to realize SPR aptasensor: A multimode plastic optical fiber platform for cancer biomarkers detection. AB - The introduction of new compact systems for sensitive, fast and simplified analysis is currently playing a substantial role in the development of point-of care solutions aimed to assist both prognosis and diagnosis. Here we report a simple and low cost biosensor based on Surface Plasmon Resonance (SPR) taking advantage of a plastic optical fiber (POF) for the detection of Vascular endothelial growth factor (VEGF), selected as a circulating protein potentially associated with cancer. Our system is based onto two crucial aspects. By one hand, the functional layer which allows the transduction signal is based on DNA aptamers, short oligonucleotide sequences that bind to non-nucleic acid targets with high affinity and specificity. By the other hand, the light guiding structure is based on a POF with a planar gold layer as the sensing region, which is particularly suitable for bioreceptors implementation. The sensor revealed to be really useful in the interface characterization. The developed system is relatively easy to realize and could well address the development of a rapid, portable and low cost diagnostic platform, with a sensitivity in the nanomolar range. PMID- 26048829 TI - One-step electrochemical detection of cholesterol in the presence of suitable K3Fe(CN)6/phosphate buffer mediator by an electrochemical approach. AB - One-step approach of cholesterol biosensor was fabricated onto smart micro-chips based on cholesterol oxidase (ChOx) co-immobilized thioglycolic acid self assembled monolayer (TGA-SAM) for biomedical applications. The selective cholesterol biosensor was investigated with modified tiny micro-chip (Au/SAM/ChOx) by the facile and reliable cyclic voltammetric (CV) method in a K3Fe(CN)6/phosphate buffer (PB) system. The modified micro-chip displayed a large dynamic range (1.0 nmol L(-1) to 1.0 mmol L(-1)), lower detection limit (~0.49 nmol L(-1), based on S/N~3), higher sensitivity (~93.75 uA umol L(-2) cm(-2)), good linearity (correlation coefficient r(2), 0.9995), lower sample volume (<50.0 MUL), and good stability as well as reproducibility. The Au/TGA system was implemented for a facile and simple approach to the immobilization of ChOx onto micro-chip, which can offer analytical access to a large group of enzymes for a wide range of bio-molecule applications in health-care and biomedical fields. This integrated microchip provides a promising low-cost platform for the sensitive and rapid detection of biomolecules using miniatured samples. PMID- 26048830 TI - Sensitive and selective determination of polycyclic aromatic hydrocarbons in mainstream cigarette smoke using a graphene-coated solid-phase microextraction fiber prior to GC/MS. AB - A simple method has been developed for the simultaneous determination of 16 polycyclic aromatic hydrocarbons (PAHs) in mainstream cigarette smoke. The procedure is based on employing a homemade graphene-coated solid-phase microextraction (SPME) fiber for extraction prior to GC/MS. In comparison to commercial 100-MUm poly(dimethyl siloxane) (PDMS) fiber, the graphene-coated SPME fiber exhibits advantageous cleanup and preconcentration efficiencies. By collecting the particulate phase 5 cigarettes, the LODs and LOQs of 16 target PAHs were 0.02-0.07 and 0.07-0.22 ng/cigarette, respectively, and all of the linear correlation efficiencies were larger than 0.995. The validation results also indicate that the method has good repeatability (RSD between 4.2% and 9.5%) and accuracy (spiked recoveries between 80% and 110%). The developed method was applied to analyze two Kentucky reference cigarettes (1R5F and 3R4F) and six Chinese brands of cigarettes. In addition, the PAH concentrations in the particulate phase of the smoke from the 1R5F Kentucky cigarettes were in good agreement with recently reported results. Due to easy operation and good validation results, this SPME-GC/MS method may be an excellent alternative for trace analysis of PAHs in cigarette smoke. PMID- 26048831 TI - Multiphoton ionization mass spectrometry of nitrated polycyclic aromatic hydrocarbons. AB - In order to suppress the fragmentation and improve the sensitivity for determination of nitrated polycyclic aromatic hydrocarbons (NPAHs), the mechanism of multiphoton ionization was studied for the following representative NPAHs, 9 nitroanthracene, 3-nitrofluoranthene, and 1-nitropyrene. The analytes were extracted from the PM2.5 on the sampling filter ultrasonically, and were measured using gas chromatography/multiphoton ionization/time-of-flight mass spectrometry with a femtosecond tunable laser in the range from 267 to 405 nm. As a result, a molecular ion was observed as the major ion and fragmentation was suppressed at wavelengths longer than 345 nm. Furthermore, the detection limit measured at 345 nm was measured to be the subpicogram level. The organic compounds were extracted from a 2.19 mg sample of particulate matter 2.5 (PM2.5), and the extract was subjected to multiphoton ionization mass spectrometry after gas chromatograph separation. The background signals were drastically suppressed at 345 nm, and the target NPAHs, including 9-nitroanthracene and 1-nitropyrene, were detected, and their concentrations were determined to be 5 and 3 pg/m(3), respectively. PMID- 26048832 TI - Development, validation, and application of an ultra-performance liquid chromatography-sector field inductively coupled plasma mass spectrometry method for simultaneous determination of six organotin compounds in human serum. AB - Organotin compounds (OTCs) are heavily employed by industry for a wide variety of applications, including the production of plastics and as biocides. Reports of environmental prevalence, differential toxicity between OTCs, and poorly characterized human exposure have fueled the demand for sensitive, selective speciation methods. The objective of this investigation was to develop and validate a rapid, sensitive, and selective analytical method for the simultaneous determination of a suite of organotin compounds, including butyl (mono-, di-, and tri-substituted) and phenyl (mono-, di-, and tri-substituted) species in human serum. The analytical method utilized ultra-performance liquid chromatography (UPLC) coupled with sector field inductively coupled plasma mass spectrometry (SF ICP-MS). The small (sub-2 um) particle size of the UPLC column stationary phase and the sensitivity of the SF-ICP-MS enabled separation and sensitive determination of the analyte suite with a runtime of approximately 3 min. Validation activities included demonstration of method linearity over the concentration range of approximately 0.250-13.661 ng mL(-1), depending on the species; intraday precision of less than 21%, interday precision of less than 18%, intraday accuracy of -5.3% to 19%, and interday accuracy of -14% to 15% for all species; specificity, and matrix impact. In addition, sensitivity, and analyte stability under different storage scenarios were evaluated. Analyte stability was found to be limited for most species in freezer, refrigerator, and freeze-thaw conditions. The validated method was then applied for the determination of the OTCs in human serum samples from women participating in the Snart-Foraeldre/MiljO (Soon-Parents/Environment) Study. The concentration of each OTC ranged from below the experimental limit of quantitation to 10.929 ng tin (Sn) mL(-1) serum. Speciation values were confirmed by a total Sn analysis. PMID- 26048833 TI - Sensitive electrochemical detection of Salmonella with chitosan-gold nanoparticles composite film. AB - An ultrasensitive electrochemical immunosensor for detection of Salmonella has been developed based on using high density gold nanoparticles (GNPs) well dispersed in chitosan hydrogel and modified glassy carbon electrode. The composite film has been oxidized in NaCl solution and used as a platform for the immobilization of capture antibody (Ab1) for biorecognition. After incubation in Salmonella suspension and horseradish peroxidase (HRP) conjugated secondary antibody (Ab2) solution, a sandwich electrochemical immunosensor has been constructed. The electrochemical signal was obtained and improved by comparing the composite film with chitosan film. The result has shown that the constructed sensor provides a wide linear range from 10 to 10(5) CFU/mL with a low detection limit of 5 CFU/mL (at the ratio of signal to noise, S/N=3:1). Furthermore, the proposed immunosensor has demonstrated good selectivity and reproducibility, which indicates its potential in the clinical diagnosis of Salmonella contaminations. PMID- 26048834 TI - Carbon dots derived from rose flowers for tetracycline sensing. AB - Herein, an innovative and simple method for synthesizing carbon dots (CDs) with satisfactory fluorescence has been successfully established while rose flowers served as carbon source for the first time. Meanwhile, the fluorescence (FL) mechanism of current CDs was elucidated in detail by fluorescence, UV-vis, HR TEM, and FTIR-based analyses. Subsequently, this type of CDs was employed for detecting tetracycline (TC) on the basis of the interactions between TC and CDs, and allowed quenching their fluorescence. Moreover, the proposed analytical strategy permitted detecting TC in a linear range of 1.0*10(-8)-1.0*10(-4) mol/L with a detection limit of 3.3*10(-9) mol/L at a signal-to-noise ratio of 3. Significantly, the CDs described here were further applied for fluorescent coding, demonstrating their promising future towards various applications in analytic science. PMID- 26048835 TI - Use of ethyl lactate to extract bioactive compounds from Cytisus scoparius: Comparison of pressurized liquid extraction and medium scale ambient temperature systems. AB - An important trend in the extraction of chemical compounds is the application of new environmentally friendly, food grade solvents. Ethyl lactate (ethyl 2 hydroxypropanoate), produced by fermentation of carbohydrates, is miscible with both hydrophilic and hydrophobic compounds being a potentially good solvent for bioactive compounds. Despite its relatively wide use as a general solvent, the utilization of ethyl lactate as an extraction solvent has only recently been considered. Here, we evaluate the possible use of ethyl lactate to extract phenolic compounds from wild plants belonging to Cytisus scoparius, and we compare the characteristics of the extracts obtained by Pressurized Solvent Extraction (the total phenolics content, the antioxidant activity and the concentration of the major polyphenols) with those of other extracts obtained with methanol. In order to explore the industrial production of the ethyl lactate Cytisus extract, we also evaluate medium scale ambient temperature setups. The whole plant and the different parts (flowers, branches, and seed pods) were evaluated separately as potential sources of polyphenols. All extracts were analyzed by LC-MS/MS for accurate identification of the major polyphenols. Similar phenolic profiles were obtained when using ethyl lactate or methanol. The main bioactives found in the Cytisus extract were the non-flavonoid phenolic compounds caffeic and protocatechuic acids and 3,4-dihydroxybenzaldehyde; the flavonoids rutin, kaempferol and quercetin; the flavones chrysin, orientin and apigenin; and the alkaloid lupanine. Regarding the comparison of the extraction systems, although the performance of the PLE was much better than that of the ambient-temperature columns, the energy consumption was also much higher. Ethyl lactate has resulted an efficient extraction solvent for polyphenols from C. scoparius, yielding extracts with high levels of plant phenolics and antioxidant activity. The antimicrobial activity of these extracts was also tested, showing antibacterial activity against Gram +ve bacteria. Qualitatively similar extracts were obtained either by using PLE or medium-scale-ambient-temperature systems, these last rendering larger volumes of extract with lower energy cost. Good results have been obtained with whole plant extracts; nevertheless, extracts enriched in a particular polyphenol can be obtained from different parts of the plant. PMID- 26048836 TI - Sensitive detection of carcinoembryonic antigen using surface plasmon resonance biosensor with gold nanoparticles signal amplification. AB - A new method for real-time detection of carcinoembryonic antigen (CEA) in human serum with high sensitivity and selectivity using surface plasmon resonance (SPR) biosensor was developed. Two kinds of antibodies were used to recognize CEA at different epitopes with high affinity and specificity. Gold nanoparticles (GNPs) modified with streptavidin (SA) were used to further enhance signal specifically via biotin-streptavidin interaction. The binding capacity of the streptavidin modified gold nanoparticles (SA-GNPs) for ligand biotin was quantified by titration with biotin (5-fluorescein) conjugate to be 10.54 biotin binding sites per 100 nm(2). The developed GNPs enhanced sandwich SPR biosensor successfully fulfilled the sensitive detection of CEA in the range of 1-60 ng/mL with a detection limit of 1.0 ng/mL. Compared to the direct assay format, sandwich format without GNPs and SA-GNPs enhanced sandwich format led to 4.2-fold and 13.8 fold in the sensitivity, respectively. This sensor also showed good selectivity for CEA in the interference study. The results demonstrated that the proposed method could provide a high sensitivity and selectivity in the detection of CEA and offer a promising alternative for cancer biomarker than traditional clinical examinations. PMID- 26048837 TI - 1H NMR and HPLC/DAD for Cannabis sativa L. chemotype distinction, extract profiling and specification. AB - The medicinal use of different chemovars and extracts of Cannabis sativa L. requires standardization beyond ?9-tetrahydrocannabinol (THC) with complementing methods. We investigated the suitability of (1)H NMR key signals for distinction of four chemotypes measured in deuterated dimethylsulfoxide together with two new validated HPLC/DAD methods used for identification and extract profiling based on the main pattern of cannabinoids and other phenolics alongside the assayed content of THC, cannabidiol (CBD), cannabigerol (CBG) their acidic counterparts (THCA, CBDA, CBGA), cannabinol (CBN) and cannflavin A and B. Effects on cell viability (MTT assay, HeLa) were tested. The dominant cannabinoid pairs allowed chemotype recognition via assignment of selective proton signals and via HPLC even in cannabinoid-low extracts from the THC, CBD and CBG type. Substantial concentrations of cannabinoid acids in non-heated extracts suggest their consideration for total values in chemotype distinction and specifications of herbal drugs and extracts. Cannflavin A/B are extracted and detected together with cannabinoids but always subordinated, while other phenolics can be accumulated via fractionation and detected in a wide fingerprint but may equally serve as qualitative marker only. Cell viability reduction in HeLa was more determined by the total cannabinoid content than by the specific cannabinoid profile. Therefore the analysis and labeling of total cannabinoids together with the content of THC and 2-4 lead cannabinoids are considered essential. The suitability of analytical methods and the range of compound groups summarized in group and ratio markers are discussed regarding plant classification and pharmaceutical specification. PMID- 26048838 TI - Hybrid silica monolith for microextraction by packed sorbent to determine drugs from plasma samples by liquid chromatography-tandem mass spectrometry. AB - The present study (1) reports on the synthesis of two hybrid silica monoliths functionalized with aminopropyl or cyanopropyl groups by the sol-gel process; (2) evaluates these monoliths as selective stationary phase for microextraction by packed sorbent (MEPS) to determine drugs in plasma samples via liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the multiple reactions monitoring (MRM) mode; and (3) discusses important factors related to the optimization of MEPS efficiency as well as the carryover effect. The prepared hybrid silica monoliths consisted of a uniform, porous, and continuous silica monolithic network. The structure of the aminopropyl hybrid silica monolith was more compact than the structure of the cyanopropyl hybrid silica monolith. The Fourier-transform infrared spectroscopy (FTIR) spectra of the hybrid silica monoliths displayed readily identifiable peaks, characteristic of the cyanopropyl and aminopropyl groups. Compared with the aminopropyl hybrid silica phase, the cyanopropyl hybrid silica phase exhibited higher binding capacity for most of the target drugs. The developed method afforded adequate linearity at concentrations ranging from the lower limit of quantification (0.05-1.00 ng mL(-1)) to the upper limit of quantification (40-10,500 ng mL(-1)); the coefficients of determination (r(2)) were higher than 0.9955. The precision of the method presented coefficients of variation (CV) lower than 14%; the relative standard error (RSE) of the accuracy ranged from -12% to 14%. The developed method allowed for simultaneous analysis of five antipsychotics (olanzapine, quetiapine, clozapine, haloperidol, and chlorpromazine) in combination with seven antidepressants (mirtazapine, paroxetine, citalopram, sertraline, imipramine, clomipramine, fluoxetine), two anticonvulsants (carbamazepine and lamotrigine), and two anxiolytics (diazepam and clonazepam) in plasma samples from schizophrenic patients, which should be valuable for therapeutic drug monitoring purposes. PMID- 26048839 TI - Establishment of a finite element model for extracting chemical reaction kinetics in a micro-flow injection system with high throughput sampling. AB - Numerical simulation can provide valuable insights for complex microfluidic phenomena coupling mixing and diffusion processes. Herein, a novel finite element model (FEM) has been established to extract chemical reaction kinetics in a microfluidic flow injection analysis (micro-FIA) system using high throughput sample introduction. To reduce the computation burden, the finite element mesh generation is performed with different scales based on the different geometric sizes of micro-FIA. In order to study the contribution of chemical reaction kinetics under non-equilibrium condition, a pseudo-first-order chemical kinetics equation is adopted in the numerical simulations. The effect of reactants diffusion on reaction products is evaluated, and the results demonstrate that the Taylor dispersion plays a determining role in the micro-FIA system. In addition, the effects of flow velocity and injection volume on the reaction product are also simulated. The simulated results agree well with the ones from experiments. Although gravity driven flow is used to the numerical model in the present study, the FEM model also can be applied into the systems with other driving forces such as pressure. Therefore, the established FEM model will facilitate the understanding of reaction mechanism in micro-FIA systems and help us to optimize the manifold of micro-FIA systems. PMID- 26048840 TI - Chemiluminescence immunoassay using magnetic nanoparticles with targeted inhibition for the determination of ochratoxin A. AB - In this work, a chemiluminescence (CL) immunoassay with targeted inhibition was developed for the determination of toxins in food products. For sample treatment, amine-functionalized magnetic nanoparticles (MNPs) were synthesized to extract target molecules, and horseradish peroxidase (HRP) tagged on an antibody was used as a label for CL reaction. In particular, amine-targeted inhibition using aldehyde, i.e., specifically capping the amine with an alkyl group, was developed for a non-specific extraction platform to lower background and improve signal-to background ratio. For demonstration, ochratoxin A (OTA) was determined in rice using a lab-built drop-type chemiluminescence (DCL) system with luminol-H2O2 reagent. The obtained limit of detection was 1.39 pg mL(-1), which was about 7.3 times better than that of ELISA. Recovery of the method in the range of 87-99% was observed, which was compared with ELISA. PMID- 26048841 TI - Selective and trace determination of monochloramine in river water by chemical derivatization and liquid chromatography/tandem mass spectrometry analysis. AB - Monochloramine (MCA) may enter the aquatic environment through three main sources: wastewater treatment plant effluents, industrial effluents and thermal power plant wastes. Up to date, there are no available data about the concentration levels of this chemical in river water due to lack of appropriate analytical methods. Therefore, sensitive and selective analytical methods for monochloramine analysis in river water are required to evaluate its environmental fate and its effects on aquatic ecosystems. Thus, in this study we describe a highly specific and sensitive method for monochloramine determination in river water. This method combines chemical derivatization of monochloramine into indophenol followed by liquid chromatography coupled to electrospray ionisation tandem mass spectrometry (LC-ESI-MS/MS) analysis. Two precursor-to-product ion transitions were monitored (200->127 and 200->154) in positive ionisation mode, fulfilling the criteria of selectivity, in accordance with the European Legislation requirements (decision 2002/657/EC). Ion structures and fragmentation mechanisms have been proposed to explain the selected transitions. Linearity range, accuracy and precision of the method have been assessed according to the French method validation standard NF T90-210. Detecting the derivatized monochloramine (indophenol) in Multiple Reaction Monitoring (MRM) mode provided a limit of quantification of 40 ng L(-1) equivalent monochloramine. Applied to Loire river water (France), the developed method occasionally detected monochloramine at concentrations less than 300 ng L(-1), which could be explained by punctual discharges of water containing active chlorine upstream of the sampling point. Indeed, it is widely reported in the literature that the addition of chlorine to water containing ammonia (e.g., wastewater effluents and river water) may result in the instantaneous formation of monochloramine. The proposed method is a powerful tool that can be used in environmental research (e.g., assessment of environmental fate and generating of ecotoxicological data) as well as in research studies concerning the evaluation of water disinfection efficiency; but it is not currently appropriate for routine use in industrial applications given the complexity of the procedure, the instability of indophenol and the use of certain toxic reagents. PMID- 26048842 TI - Synthesis of silver nanoparticle at a gas/liquid interface in the presence of silver seeds and its application for electrochemical sensing. AB - Silver nanoparticles were synthesized by reducing [Ag(NH3)2](+) at a gas/liquid interface in the presence of silver seeds. Transmission electron microscopy (TEM) observations reveal that the size of these silver nanoparticles is around 35-40 nm with the average particle size of 37 nm. The silver nanoparticles were applied for the electrochemical sensor and electrochemical investigations indicate that the nanoparticles possess an excellent performance toward H2O2. The linear range is estimated to be from 5.0 MUM to 4.0 mM with a low detection limit of 1.7 MUM, a sensitivity of 166.7 MUA mM(-1) cm(-2) and a response time of 3 s. Additionally, the sensor exhibits good anti-interference. PMID- 26048843 TI - Simultaneous enzymatic and SERS properties of bifunctional chitosan-modified popcorn-like Au-Ag nanoparticles for high sensitive detection of melamine in milk powder. AB - In this work, we suggest a chitosan-modified popcorn-like Au-Ag nanoparticles (CSPNPs) based assay for high sensitive detection of melamine, in which CSPNPs not only provide with an intrinsic peroxidase-like activity but also act as surface enhanced Raman scattering (SERS) substrates. CSPNPs can catalyze the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 to the charge transfer complex (CTC), which contributes to a tremendous surface-enhanced resonant Raman scattering (SERRS) signals with 632.8 nm laser excitation. The target molecule melamine can generate an additional compound with H2O2, which means the available amount of H2O2 for the oxidation of TMB reduced. Correspondingly, the SERRS intensity of CTC is decreased. The decreased Raman intensity is proportional to the concentration of melamine over a wide range from 10 nM to 50 MUM (R(2)=0.989), with a limit of detection (LOD) of 8.51 nM. Moreover, the proposed highly selective method is fully capable of rapid, separation-free detection of melamine in milk powder. PMID- 26048844 TI - A sensitive protein-based sensor for quantifying histone acetylation levels. AB - H3K14ac (acetylation of lysine 14 of histone H3) is one of the most important epigenetic modifications in cells. Aberrant changes in H3K14ac are commonly found in various types of cancers and neurological disorders. Current detection approaches for histone modifications, however, require either tedious sample pre treatments or lack the quantitative accuracy required for biochemical and biomedical applications. In this study, we engineered a protein sensor using the amino acid sequences derived from the bromodomain of human polybromo-1 (PB1). The protein sensor was conjugated to a fluorescent dye for sensitive detection of H3K14ac. Different detection conditions, such as additive concentrations and probe concentrations, were optimally selected by balancing signal strength (I(Rel)) and signal-to-noise ratio (SNR). The protein sensor was verified using histone H3 peptides containing different H3K14 acetylation levels. The detection signal was found to be linearly dependent on acetylation levels of H3K14 ranging from 5% to 100%. The designed platform can be used for screening epigienetic drugs regulating H3K14 acetylation levels as well as monitoring H3K14 acetylation level of circulating nucleosomes for disease progression. PMID- 26048845 TI - Bare conical nanopore embedded in polymer membrane for Cr(III) sensing. AB - In this article, we propose a nanopore-based approach to detect metal ions without any external functionalization. In detection of the biologically and environmentally relevant Cr(3+) ion as a prototypical example to prove our strategy, both selectivity and sensitivity were individually achieved. In contrast to mainstream research based on receptor-functionalized nanopores, we report a method for easy regeneration of the nanopore surface that allows elimination of the tedious functionalization steps. Besides, with the assistance of a strong chelator (EDTA), the asymmetric nanopore becomes highly resistant to the interference of the metal-ions matrix, and shows significant specificity towards Cr(3+). The detection limit of this sensor was 16 nM (signal-to-noise ratio=3), which was comparable to reported values. By virtue of the reusability of the polymer surface, metal ion sensors based on asymmetric nanopores can be applied universally in combination with chelators sensitive to specific metal ions. PMID- 26048846 TI - Talanta. Editorial. PMID- 26048847 TI - Fruit- and Vegetable-Focused Grocery Store Tour Training Kit to Promote Peer-on Peer Nutrition Education Utilizing Nutrition and Dietetics Students. PMID- 26048848 TI - Safety of gadoxetate disodium: results from six clinical phase IV studies in 8194 patients. AB - Background Safety data on routine clinical use of gadoxetate disodium for liver magnetic resonance imaging (MRI) is not reported yet. Purpose To assess the safety profile of gadoxetate disodium for liver MRI in the routine clinical setting. Material and Methods Six multicenter studies were performed in Europe, USA, Australia, and Asia to evaluate the safety and efficacy of gadoxetate disodium (Primovist(r)/Eovist(r)) enhanced liver MRI. Patients received a single intravenous bolus injection of the standard approved dose of 0.025 mmol/kg body weight (0.1 mL/kg). The number of patients, the characteristics of adverse events, related adverse events, and serious adverse events were analyzed. Results A total of 8194 patients were included in the database. A total of 141 patients (1.7%) reported 230 AEs of which 129 were considered being related to the use of gadoxetate disodium by the investigators. None of the AEs in the pediatric population ( n = 52) were related. The most frequent AEs independent of relationship to the drug included dyspnea (25/0.31%), nausea (22/0.27%), liver disorders (13/0.16%), and renal disorders (9/0.11%). Nine related SAEs were recorded. No patient died during the studies. Conclusion Gadoxetate disodium for liver MRI is safe and well tolerated in the routine clinical setting. PMID- 26048849 TI - Functionality of alternative protein in gluten-free product development. AB - Celiac disease is an immune-mediated disease triggered in genetically susceptible individuals by ingested gluten from wheat, rye, barley, and other closely related cereal grains. The current treatment for celiac disease is life-long adherence to a strict gluten-exclusion diet. The replacement of gluten presents a significant technological challenge, as it is an essential structure-building protein, which is necessary for formulating high-quality baked goods. A major limitation in the production of gluten-free products is the lack of protein functionality in non wheat cereals. Additionally, commercial gluten-free mixes usually contain only carbohydrates, which may significantly limit the amount of protein in the diet. In the recent past, various approaches are attempted to incorporate protein-based ingredients and to modify the functional properties for gluten-free product development. This review aims to the highlight functionality of the alternative protein-based ingredients, which can be utilized for gluten-free product development both functionally as well as nutritionally. PMID- 26048850 TI - Complex Disease, Partial Revascularization, and Adverse Outcomes in Patients Treated With Long-Term Warfarin Therapy Who Underwent Percutaneous Coronary Intervention. AB - Patients treated with warfarin who undergo percutaneous coronary intervention (PCI) present a difficult therapeutic problem. Their baseline demographics, procedural characteristics, and 12-month outcomes are poorly defined. We conducted a retrospective analysis of all patients who underwent PCI at a major UK Cardiac Center from 2012 to 2013. Of the 2,675 patients who underwent PCI, 155 were on long-term warfarin treatment (5.8%). Patients on warfarin were older and more likely to have significant co-morbidity than those not on warfarin. The modified Mehran bleed score was higher in patients treated with warfarin versus those not treated (19.0 +/- 5.8 vs 15.4 +/- 8.0, p = 0.004). Baseline SYNTAX scores were higher in the patients treated with warfarin (18.5 +/- 9.1 vs 12.4 +/ 3.8, p = 0.0006) as were residual SYNTAX scores (8.3 +/- 1.1 vs 3.8 +/- 5.9, p = 0.001). Bare metal stents were more frequently used in warfarin-treated patients than those not treated (44.8% vs 26.3%, p <0.0001). Antiplatelet monotherapy was prescribed after PCI in 14.4% of patients treated with warfarin and 0.7% of non warfarin (p <0.0001), whereas average dual anti-platelet therapy duration was also significantly shorter (4.3 vs 10.7 months, p <0.0001). At 1-year follow-up, target-vessel revascularization (6.5% vs 3.3%, p <0.05), stent thrombosis (5.0% vs 2.6%, p = 0.14), death (10.1% vs 4.6%, p <0.01), and target-vessel revascularization/stent thrombosis/death (21.6% vs 10.5%, p = 0.004) were all more common in the warfarin cohort. In conclusion, patients treated with warfarin who need PCI are a complex cohort, more likely to receive incomplete revascularization, less intense, and shorter durations of antiplatelet therapy, and have adverse 1-year outcomes. More trials of both current DES and newer DES technologies in warfarin-treated patients are needed. PMID- 26048852 TI - Prevalence and Prognostic Value of Right Ventricular Systolic Dysfunction in Patients With Constrictive Pericarditis Who Underwent Pericardiectomy. AB - Impaired right ventricular systolic function (RVSF) may complicate the treatment of constrictive pericarditis (CP) by pericardiectomy, which is a procedure that remains with significant morbidity and mortality. We evaluated RVSF in patients with CP who underwent pericardiectomy to determine the prognostic value of RVSF. RVSF was assessed by measuring Tricuspid Annular Plane Systolic Excursion (TAPSE) in 35 patients (mean age 52 +/- 15.4 years) who underwent pericardiectomy. Thirty one patients (88.6%) had reduced RVSF (TAPSE <=1.8 cm). Eight patients (23%) had postoperative events (heart failure 3 and hospital mortality 5). Logistic regression showed that concomitant coronary artery bypass grafting (CABG) (p = 0.052), left ventricular ejection fraction (p = 0.059), left atrial diameter (p = 0.028), and TAPSE (p = 0.016) were borderline or significant univariate predictors of events. TAPSE (p = 0.018, odds ratio = 0.605 [0.40 to 0.92]) and CABG (p = 0.033, odds ratio = 20 [1.26 to 315]) were independent predictors of events on multivariate analysis. Stepwise analysis showed that TAPSE provided incremental prognostic value (p = 0.029, chi-square increase 11.6 to 16.3) to the combination of CABG, ejection fraction, and left atrial diameter. Receiver operating characteristic curve analysis showed an area under the curve of 0.815 for TAPSE. TAPSE of 1.38 cm had a sensitivity of 88% and specificity of 67% for identifying patients with events. TAPSE was also inversely related to the length of hospital stay after pericardiectomy (p = 0.02, R = -0.424). Hence, our study showed that RVSF is frequently reduced in patients with CP who underwent pericardiectomy. In conclusion, TAPSE is an independent predictor of events and provides incremental prognostic value to other clinical and echocardiographic variables. PMID- 26048851 TI - Effect of Cardiac Resynchronization Therapy in Patients With Insulin-Treated Diabetes Mellitus. AB - Diabetes mellitus (DM) modify outcome in patients with heart failure (HF). We aimed to analyze the risk for death, HF alone, combined end point HF/death, and ventricular tachycardia/ventricular fibrillation (VT/VF) in patients with mild HF without DM and in those with DM, further stratified by the presence of insulin treatment. We determined whether cardiac resynchronization therapy with defibrillator (CRT-D) versus implantable cardioverter defibrillator improves clinical outcomes in these 3 subgroups. Cox proportional hazards regression models were used to analyze 1,278 patients with left bundle branch block in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy trial. Treatment with CRT-D versus implantable cardioverter defibrillator was associated with 76% risk reduction in all-cause mortality (hazard ratio 0.24; 95% confidence interval 0.08 to 0.74, p = 0.012) in subgroup of diabetic patients treated with insulin only (interaction p = 0.043). Significant risk reduction in HF alone, HF/death, and the VT/VF after CRT-D was observed across investigated groups and similar left ventricular reverse remodeling to CRT-D. In conclusion, patients with mild HF with DM treated with insulin derive significant risk reduction in mortality, in HF, and VT/VF after implantation of CRT-D. Diabetic patients not receiving insulin benefit from CRT-D by reduction of HF events. PMID- 26048853 TI - Event Rates in Randomized Clinical Trials Evaluating Cardiovascular Interventions and Devices. AB - Randomized clinical trials (RCTs) are considered the gold standard for evidence based medicine. However, an accurate estimation of the event rate is crucial for their ability to test clinical hypotheses. Overestimation of event rates reduces the required sample size but can compromise the statistical power of the RCT. Little is known about the prevalence, extent, and impact of overestimation of event rates. The latest RCTs on 10 preselected topics in the field of cardiovascular interventions and devices were selected, and actual primary event rates in the control group were compared with their respective event rate estimations. We also assessed what proportion of the nonsignificant RCTs was truly able to exclude a relevant treatment effect. A total of 27 RCTs randomizing 19,436 patients were included. The primary event rate in the control group was overestimated in 20 of the 27 RCTs (74.1%) resulting in a substantial relative difference between observed and estimated event rates (mean -22.9%, 95% confidence interval -33.5% to -12.2%; median -16.3%, 95% confidence interval 30.3% to -6.5%). Event rates were particularly overestimated in RCTs on biodegradable polymer drug-eluting coronary stents and renal artery stenting. Of the 14 single end point superiority trials with nonsignificant results, only 3 (21.4%) actually resulted in truly negative conclusions. In conclusion, event rates in RCTs evaluating cardiovascular interventions and devices are frequently overestimated. This under-reported phenomenon has fundamental impact on the design of RCTs and can have an adverse impact on the statistical power of these trials to answer important questions about therapeutic strategies. PMID- 26048854 TI - Usefulness of Rabbit Anti-thymocyte Globulin in Patients With Giant Cell Myocarditis. AB - Giant cell myocarditis (GCM) is an aggressive inflammatory myocardial disease. Immunosuppression is an effective treatment for some cases. However, the duration of action of agents such as muromonab CD3 is short and others such as the calcineurin inhibitors may lead to renal failure. Here we describe the outcome of a novel approach to treatment using rabbit anti-thymocyte globulin (RATG). A retrospective analysis of 6 patients treated with RATG for GCM was performed. Diagnosis was confirmed by endomyocardial biopsy, and RATG was administered with a high dose of corticosteroids. None of the patients had cytokine release syndrome or leukopenia, and 5 had thrombocytopenia (2 of them severe). Only 1 had a serious bleeding event that occurred after implantation of mechanical circulatory support. None developed impaired renal function after the treatment. Five were successfully discharged home with an increase in global left ventricular ejection fraction of 29%. Four are currently alive without recurrent disease, 1 of them after heart transplantation, with a mean follow-up of 970 days (423 to 1,875 days), left ventricular ejection fraction of 53%, and all in current New York Heart Association Classification class <=II. Only 1 case had GCM recurrence. There were 2 deaths: one because of intracranial bleeding after mechanical circulatory support implantation and the other caused by primary graft dysfunction. In conclusion, patients with GCM can be successfully immunosuppressed with RATG and corticosteroids, thereby avoiding renal impairment. Early thrombocytopenia is the main adverse event. Larger cohorts of patients are necessary to compare the different immunosuppressant strategies available for GCM in a randomized fashion. PMID- 26048855 TI - Restless Legs Syndrome-An Emerging Potential Side Effect of Enzalutamide: Report of 2 Cases. PMID- 26048856 TI - Retrospective reversal of extinction of conditioned fear by instruction. AB - In the present study, we examined the impact of verbal instruction during extinction of human fear-conditioning. We extended the study of Raes, De Houwer, Verschuere, and De Raedt (2011) by controlling for context conditioning and recording unconditioned stimulus expectancy online in a within-subject design. We informed participants of an alternative reason for the absence of the aversive unconditioned stimulus after extinction had been carried out, to see if such instruction could induce retrospective protection from extinction. The results demonstrated that both the expectancy of an aversive outcome and conditioned skin conductance were significantly increased for the conditioned stimulus targeted by the instruction. Thus extinction was reversed by the concurrent presence of an alternative cause for the absence of the unconditioned stimulus. PMID- 26048857 TI - Re: Cytoreductive Radical Prostatectomy in Patients with Prostate Cancer and Low Volume Skeletal Metastases: Results of a Feasibility and Case-Control Study: A. Heidenreich, D. Pfister and D. Porres J Urol 2015;193:832-838. PMID- 26048859 TI - Power Heightens Sensitivity to Unfairness Against the Self. AB - Power is accompanied by a sense of entitlement, which shapes reactions to self relevant injustices. We propose that powerful people more strongly expect to be treated fairly and are faster to perceive unjust treatment that violates these expectations. After preliminary data demonstrated that power leads people to expect fair outcomes for themselves, we conducted four experiments. Participants primed with high (vs. low) power were faster to identify violations of distributive justice in which they were victims (Study 1). This effect was specific to self-relevant injustices (Study 2) and generalized to violations of interpersonal justice (Study 3). Finally, participants primed with high power were more likely to take action against unfair treatment (Study 4). These findings suggest a process by which hierarchies may be maintained: Whereas the powerless are comparatively less sensitive to unfair treatment, the powerful may retain their social standing by quickly perceiving and responding to self relevant injustices. PMID- 26048860 TI - A prospective audit of the impact of additional staff on the care of diabetic patients in a community podiatry service. AB - OBJECTIVE: The purpose of this study was to evaluate the impact of the employment of additional podiatry staff on patients with diabetes attending a community based podiatry service. METHODS: An audit was conducted to evaluate the intervention of two additional podiatry staff. All patients with diabetes referred to and attending community podiatry services in a specified area in the Republic of Ireland between June 2011 and June 2012 were included. The service was benchmarked against the UK gold standard outlined in the 'Guidelines on prevention & management of foot problems in Type 2 Diabetes' by the National Institute of Clinical Excellence (NICE). Process of care measures addressed were the number of patients with diabetes receiving treatment and the waiting times of patients with diabetes from referral to initial review. RESULTS: An increase in the number of patients with diabetes receiving treatment was seen in all risk categories (ranging from low risk to the emergency foot). Waiting times for patients with diabetes decreased post-intervention but did not reach the targets outlined in the NICE guidelines. The average time from referral to initial review of patients with an emergency diabetic foot was 37 weeks post-intervention. NICE guidelines recommend that these patients are seen within 24 hours. DISCUSSION: During the life cycle of this audit, increased numbers of patients were treated and waiting times for patients with diabetes were reduced. An internal re organisation of the services coincided with the commencement of the additional staff. The improvements observed were due to the effects of a combination of additional staff and service re-organisation. Efficient organisation of services is key to optimal performance. Continued efforts to improve services are required to reach the standards outlined in the NICE guidelines. PMID- 26048861 TI - Alcohol--who is paying the price? PMID- 26048862 TI - Fatal Clostridium perfringens septicemia suggested by postmortem computed tomography: A medico-legal autopsy case report. AB - We report a fatal case of suspected Clostridium (Cl.) perfringens septicemia in a previously healthy woman in her eighties. At first, she presented at the hospital complaining of upper abdominal discomfort and vomiting, and was discharged the next day after ruling out any fatal conditions. However, her condition deteriorated approximately 10h after discharge and she died shortly after. The postmortem computed tomography (PMCT) performed 29h postmortem revealed an excessive systemic gas accumulation compared with the postmortem external appearance and time elapsed since her death, which suggested the presence of a gas-forming infection. Histopathological examination showed diffuse proliferation of Gram-positive bacilli in almost all the organ tissues, especially in blood vessels. Along with these findings, hyperthermia 3h postmortem, and severe anemia and thrombocytopenia without an obvious site of hemorrhage suggested hemolysis due to Cl. perfringens septicemia. These findings suggested the diagnosis before performing the conventional autopsy. To the best of our knowledge, this is the first case report to describe PMCT findings of gas-forming infection and septicemia in contrast with the external appearance and histopathological findings in a medico-legal autopsy setting. PMID- 26048863 TI - Relevance of discrete traits in forensic anthropology: From the first cervical vertebra to the pelvic girdle. AB - In forensic anthropology, identification begins by determining the sex, age, ancestry and stature of the individuals. Asymptomatic variations present on the skeleton, known as discrete traits, can be useful to identify individuals, or at least contribute to complete their biological profile. We decided to focus our work on the upper part of the skeleton, from the first vertebra to the pelvic girdle, and we chose to present 8 discrete traits (spina bifida occulta, butterfly vertebra, supraclavicular nerve foramen, coracoclavicular joint, os acromiale, suprascapular foramen, manubrium foramen and pubic spine), because they show a frequency lower than 10%. We examined 502 anonymous CT scans from polytraumatized individuals, aged 15 to 65 years, in order to detect the selected discrete traits. Age and sex were known for each subject. Thin sections in the axial, coronal and sagittal planes and 3D volume rendering images were created and examined for the visualization of the selected discrete traits. Supraclavicular foramina were found only in males and only on the left clavicle. Coracoclavicular joints were observed only in males. The majority of individuals with a suprascapular foramen were older than 50 years of age. Pubic spines were observed mostly in females. Other traits did not present significant association with sex, age and laterality. No association between traits was highlighted. Better knowledge of human skeletal variations will help anthropologists come closer to a positive identification, especially if these variations are rare, therefore making them more discriminant. PMID- 26048864 TI - Sudden death due to coronary artery dissection associated with fibromuscular dysplasia revealed by postmortem selective computed tomography coronary angiography: A case report. AB - We present an autopsy case of sudden death due to coronary artery dissection associated with fibromuscular dysplasia (FMD) in a young female patient. Postmortem selective coronary artery computed tomography (CT) angiography revealed dissections of the left anterior descending and left circumflex arteries. These findings were confirmed by subsequent autopsy. Histopathological examination revealed coronary artery FMD, which is considered a risk factor for dissection. To the best of our knowledge, this is the first postmortem radiology pathology correlation of coronary artery dissection associated with FMD. PMID- 26048865 TI - Translating primary into 'positive' prevention for adolescents in Eastern Africa. AB - There is an urgent need to develop positive prevention interventions for adolescents living with HIV in high endemic regions. Adapting existing evidence based interventions for resource-constrained settings is effective when the intervention's theoretical core elements are preserved while achieving cultural relevance. We describe the process of adapting a primary prevention to a secondary/positive prevention programme for adolescents living with HIV in Kenya and Uganda. The systematic adaptation was guided by the Centers for Diseases Control's map for the adaptation process, describing an iterative process. The procedure included: assessing the target positive prevention group's needs (safer sex; fertility-related issues), identifying the potential interventions through a literature review, conducting qualitative adaptation research to identify areas for adaptation by ensuring cultural relevance (revising the intervention logic by adding topics such as adherence; HIV-related stigma; HIV-disclosure; safer sex), pilot-testing the adapted programme and conducting a process evaluation of its first implementation. Areas added onto the original intervention's logic framework, based on social cognitive theory, the theories of reasoned action and planned behaviour were information and skills building on sexual relationships and protection behaviour, prevention of vertical HIV transmission, contraception, HIV-disclosure, HIV-related stigma, HIV-treatment and adherence. The process evaluation using mixed methods showed that we delivered a feasible and acceptable intervention for HIV-positive adolescents aged 13-17 years. The systematic approach adopted facilitated the development of a contextualized and developmentally appropriate (i.e. age-specific) intervention for adolescents living with HIV. PMID- 26048866 TI - HIV risk and sexual health among female migrants in China. AB - Sexual behavior is the dominant mode of HIV transmission in China, and young female migrants are among the populations at highest risk. This article examines how HIV-related risk behaviors among female migrants might vary according to workplace settings. Participants were young female migrants recruited from three workplace settings-factories, restaurants and entertainment venues. In a cross sectional survey, we assessed 457 participants' sociodemographic characteristics, HIV/AIDS-related knowledge, condom use knowledge, sexual behaviors, condom use behavior and reproductive health factors. Participants working in entertainment venues were significantly more likely than those working in factories and restaurants to report sexual behavior, unprotected sex, multiple pregnancy terminations and sexually transmitted infections (STI). However, participants working in factories and restaurants reported significantly lower levels of HIV/AIDS knowledge, condom use knowledge, condom use self-efficacy and history of HIV/AIDS counseling and testing. Independent correlates of unprotected sex included employment in an entertainment venue, abortion history and sexual self efficacy. Independent correlates of STI or genitourinary tract infection included employment in an entertainment venue, abortion history, recent migration and recent unprotected sex. These findings indicate a need for sexual and reproductive health interventions prioritizing young female migrants, and call for programs that can be incorporated into different workplace settings. PMID- 26048867 TI - Does social capital protect mental health among migrants in Sweden? AB - Poor mental health is common among migrants. This has been explained by migration related and socio-economic factors. Weak social capital has also been related to poor mental health. Few studies have explored factors that protect mental health of migrants in the post-migration phase. Such knowledge could be useful for health promotion purposes. Therefore, this study aimed to analyse associations between financial difficulties, housing problems and experience of discrimination and poor mental health; and to detect possible effect modification by social capital, among recently settled Iraqi migrants in Sweden. A postal questionnaire in Arabic was sent to recently settled Iraqi citizens. The response rate was 51% (n = 617). Mental health was measured by the GHQ-12 instrument and social capital was defined as social participation and trust in others. Data were analysed by means of logistic regression. Poor mental health was associated with experience of discrimination (OR 2.88, 95% CI 1.73-4.79), housing problems (OR 2.79, 95% CI 1.84-4.22), and financial difficulties (OR 2.14, 95% CI 1.44-3.19), after adjustments. Trust in others seemed to have a protective effect for mental health when exposed to these factors. Social participation had a protective effect when exposed to experience of discrimination. Social determinants and social capital in the host country play important roles in the mental health of migrants. Social capital modifies the effect of risk factors and might be a fruitful way to promote resilience to factors harmful to mental health among migrants, but must be combined with policy efforts to reduce social inequities. PMID- 26048868 TI - Overcoming disparities in organized physical activity: findings from Australian community strategies. AB - Organized physical activity through sport and recreational activities is beneficial for physical and psychosocial well-being and community connectedness. However, many who could gain significantly from this have lower participation, especially the socioeconomically disadvantaged, Indigenous people, culturally diverse communities and people with a disability. This study examined barriers to participation by these underserved groups and the success of strategies for overcoming these used in 22 community projects over 3 years in the VicHealth Participation in Community Sport and Recreation Program, in Victoria, Australia. Each year, in-depth interviews were undertaken with 50-60 activity providers and 30-40 project partners. Major barriers to participation were cost, lack of transport, cultural differences, the environment of sporting groups and inaccessible facilities for people with disabilities. Projects that overcame these selected one or two priority groups, put significant effort into communication and building partnerships with community organizations, provided training to staff and volunteers and created new or modified forms of activity. Strategies were put in place to reduce cost and provide transport, but these did not appear to be sustainable. Many organizations found engaging the underserved was more difficult than anticipated and require information and support about how to develop acceptable, accessible and flexible opportunities for disadvantaged groups. Cost and lack of transport are persistent barriers to participation that need to be addressed by the sport and recreation sector and policy-makers. PMID- 26048870 TI - Albendazole-induced cirrhosis decompensation and pancytopenia. PMID- 26048869 TI - Involvement of Arabidopsis Hexokinase1 in Cell Death Mediated by Myo-Inositol Accumulation. AB - Programmed cell death (PCD) is essential for several aspects of plant life, including development and stress responses. We recently identified the mips1 mutant of Arabidopsis thaliana, which is deficient for the enzyme catalyzing the limiting step of myo-inositol (MI) synthesis. One of the most striking features of mips1 is the light-dependent formation of lesions on leaves due to salicylic acid (SA)-dependent PCD. Here, we identified a suppressor of PCD by screening for mutations that abolish the mips1 cell death phenotype. Our screen identified the hxk1 mutant, mutated in the gene encoding the hexokinase1 (HXK1) enzyme that catalyzes sugar phosphorylation and acts as a genuine glucose sensor. We show that HXK1 is required for lesion formation in mips1 due to alterations in MI content, via SA-dependant signaling. Using two catalytically inactive HXK1 mutants, we also show that hexokinase catalytic activity is necessary for the establishment of lesions in mips1. Gas chromatography-mass spectrometry analyses revealed a restoration of the MI content in mips1 hxk1 that it is due to the activity of the MIPS2 isoform, while MIPS3 is not involved. Our work defines a pathway of HXK1-mediated cell death in plants and demonstrates that two MIPS enzymes act cooperatively under a particular metabolic status, highlighting a novel checkpoint of MI homeostasis in plants. PMID- 26048871 TI - Direct detection of Burkholderia pseudomallei and biological factors in soil. AB - BACKGROUND: Burkholderia pseudomallei, a Gram-negative saprophytic bacillus, is a severe infectious agent that causes melioidosis and soil is the most important reservoir. METHODS: One hundred and forty soil samples were tested for pH, moisture content and total C and N measurements and used for DNA extraction and culture for B. pseudomallei. The quantitative real-time PCR (qPCR) targeting wcbG, a putative capsular polysaccharide biosynthesis protein gene of B. pseudomallei, was developed to detect the bacterium, and random amplified polymorphic DNA (RAPD) was used to detect the microbial diversity in soil. RESULTS: The acidic pH was correlated with the presence of the bacterium. Forty four soil sites (44/140, 31.4%) were positive for B. pseudomallei by qPCR, of which 21 were positive by culture. The limit of detection is 32 fg of DNA (about 4 genomes). The RAPD method could classify the soil samples into low diversity (LD) and high diversity (HD) sites. The trend of LD was found with B. pseudomallei positive soil sites. CONCLUSIONS: The acidity of the soil or metabolites from organisms in the sites may contribute to the presence of the bacterium. Further investigation of microbes by a more robust method should elucidate biological factors that promote the presence of B. pseudomallei and may be used for controlling the bacterium in the environment. PMID- 26048872 TI - Risk factors for hospital admission of Brazilian children with non-rotavirus diarrhoea: a case control-study. AB - BACKGROUND: Rotavirus has been the leading cause of severe cases of acute diarrhoea (AD) among children worldwide; however, in the same areas, a large reduction in AD related to rotavirus has been observed after the introduction of the rotavirus vaccine. In Brazil, where there is a high rotavirus vaccine coverage, AD caused by pathogens other than rotavirus is still a frequent cause of outpatient visits and hospitalisations among children under 5 years. METHODS: A hospital-based case-control study enrolled children aged 4 to 24 months admitted to 10 hospitals from all five Brazilian Regions. Cases (n=1178) were children admitted with diarrhoea who tested negative for rotavirus in a stool sample. Controls (n=2515) were children admitted without diarrhoea, frequency matched to cases by sex and age group. We estimated odds ratios using logistic regression, in a hierarchical approach according to a previously defined conceptual framework. Population-attributable fractions (PAF) were estimated for each variable, each block and for all significant variables in the latter model adjusted. RESULTS: The factors studied accounted for 41% of the non-rotavirus AD hospital admissions and the main risk factors included lack of adequate excreta disposal (PAF=12%), untreated drinking water (PAF=11%) and a history of previous hospitalization due to AD (PAF=21%). Low socio-economic conditions, no public water supply, crowding and low weight-for-age made smaller contributions. CONCLUSIONS: These findings further our knowledge of risk factors associated with severe AD in the post-rotavirus vaccination era. We recommend further increase in coverage of basic sanitation, improvements in water quality and further expansion of primary healthcare coverage to reduce the occurrence of non-rotavirus severe diarrhoea and subsequent hospitalization of Brazilian children. PMID- 26048873 TI - Development of Leishmania vaccines in the era of visceral leishmaniasis elimination. AB - A visceral leishmaniasis (VL) elimination target set for the Indian subcontinent in 2005 is being met in many endemic areas without a vaccine. This begs a question: is a VL vaccine needed if elimination targets can be met with current control programs? Here, we argue that a vaccine will be critical if the success of recent VL control efforts are to be sustained. However, not only do we require a safe and effective vaccine, but we also need to know how this should be used for maximum impact. In particular, identifying appropriate target populations to vaccinate will be crucial. PMID- 26048874 TI - Long-Term Muscle Fatigue After Standing Work. AB - OBJECTIVE: The aims of this study were to determine long-term fatigue effects in the lower limbs associated with standing work and to estimate possible age and gender influences. BACKGROUND: The progressive accumulation of muscle fatigue effects is assumed to lead to musculoskeletal disorders, as fatigue generated by sustained low-level exertions exhibits long-lasting effects. However, these effects have received little attention in the lower limbs. METHOD: Fourteen men and 12 women from two different age groups simulated standing work for 5 hr including 5-min seated rest breaks and a 30-min lunch. The younger group was also tested in a control day. Muscle fatigue was quantified by electrically induced muscle twitches (muscle twitch force [MTF]), postural stability, and subjective evaluation of discomfort. RESULTS: MTF showed a significant fatigue effect after standing work that persisted beyond 30 min after the end of the workday. MTF was not affected on the control day. The center of pressure displacement speed increased significantly over time after standing work but was also affected on the control day. Subjective evaluations of discomfort indicated a significant increase in perception of fatigue immediately after the end of standing work; however, this perception did not persist 30 min after. Age and gender did not influence fatigue. CONCLUSION: Objective measures show the long-term effects of muscle fatigue after 5 hr of standing work; however, this fatigue is no longer perceived after 30 min of rest postwork. APPLICATION: The present results suggest that occupational activities requiring prolonged standing are likely to contribute to lower-extremity and/or back disorders. PMID- 26048875 TI - Mechanisms of Identity Conflict: Uncertainty, Anxiety, and the Behavioral Inhibition System. AB - Social identities are associated with normative standards for thought and action, profoundly influencing the behavioral choices of individual group members. These social norms provide frameworks for identifying the most appropriate actions in any situation. Given the increasing complexity of the social world, however, individuals are more and more likely to identify strongly with multiple social groups simultaneously. When these groups provide divergent behavioral norms, individuals can experience social identity conflict. The current manuscript examines the nature and consequences of this socially conflicted state, drawing upon advances in our understanding of the neuropsychology of conflict and uncertainty. Identity conflicts are proposed to involve activity in the Behavioral Inhibition System, which in turn produces high levels of anxiety and stress. Building upon this framework, four strategies for resolving identity conflict are reviewed. PMID- 26048876 TI - Clonal diversity, virulence patterns and antimicrobial and biocide susceptibility among human, animal and environmental MRSA in Portugal. AB - OBJECTIVES: The objective of this study was to identify the Staphylococcus aureus clonal types currently circulating in animals, humans in contact with animals and the environment in Portugal based on genetic relatedness, virulence potential and antimicrobial/biocide susceptibility. METHODS: Seventy-four S. aureus isolates from pets, livestock, the environment and humans in contact with animals were characterized by SCCmec typing, spa typing, PFGE and CC398-specific PCR, by antimicrobial and biocide susceptibility testing and by detection of resistance genes and genes for efflux pumps. Representative strains were analysed by DNA microarray and MLST. RESULTS: The S. aureus isolates represented 13 spa types and 3 SCCmec types and belonged to three clonal complexes (CC5, CC22 and CC398). Most of the isolates were multiresistant and harboured the resistance genes that explained the resistance phenotype. The qacG and qacJ genes for biocide resistance were detected in 14 isolates (all MRSA CC398), while 4 isolates (3 CC5 and 1 CC22) had insertions in the -10 motif of the norA promoter. Isolates of the clonal lineages associated with pets (CC5 and CC22) harboured specific sets of virulence genes and often a lower number of resistance genes than isolates of the clonal lineage associated with livestock animals (CC398). CONCLUSIONS: We found, for the first time in animals in Portugal, four strains belonging to CC5, including ST105-II, a lineage that has been previously reported as vancomycin resistant S. aureus in Portugal. Moreover, for the first time the qacG and qacJ genes were detected in MRSA CC398 strains. Active surveillance programmes detecting MRSA not only in livestock animals but also in companion animals are urgently needed. PMID- 26048877 TI - Relationship of cerebral blood flow to aortic-to-pulmonary collateral/shunt flow in single ventricles. AB - OBJECTIVE: Patients with single ventricle can develop aortic-to-pulmonary collaterals (APCs). Along with systemic-to-pulmonary artery shunts, these structures represent a direct pathway from systemic to pulmonary circulations, and may limit cerebral blood flow (CBF). This study investigated the relationship between CBF and APC flow on room air and in hypercarbia, which increases CBF in patients with single ventricle. METHODS: 106 consecutive patients with single ventricle underwent 118 cardiac magnetic resonance (CMR) scans in this cross sectional study; 34 prior to bidirectional Glenn (BDG) (0.50+/-0.30 years old), 50 prior to Fontan (3.19+/-1.03 years old) and 34 3-9 months after Fontan (3.98+/ 1.39 years old). Velocity mapping measured flows in the aorta, cavae and jugular veins. Analysis of variance (ANOVA) and multiple linear regression were used. Significance was p<0.05. RESULTS: A strong inverse correlation was noted between CBF and APC/shunt both on room air and with hypercarbia whether CBF was indexed to aortic flow or body surface area, independent of age, cardiopulmonary bypass time, Po2 and Pco2 (R=-0.67--0.70 for all patients on room air, p<0.01 and R= 0.49--0.90 in hypercarbia, p<0.01). Correlations were not different between surgical stages. CBF was lower, and APCs/shunt flow was higher prior to BDG than in other stages. CONCLUSIONS: There is a strong inverse relationship between CBF and APC/shunt flow in patients with single ventricle throughout surgical reconstruction on room air and in hypercarbia independent of other factors. We speculate that APC/shunt flow may have a negative impact on cerebral development and neurodevelopmental outcome. Interventions on APC may modify CBF, holding out the prospect for improving neurodevelopmental trajectory. TRIAL REGISTRATION NUMBER: NCT02135081. PMID- 26048879 TI - Meta-Analysis of Case-Control and Family-Based Associations Between the 5-HTTLPR L/S Polymorphism and Susceptibility to ADHD. AB - OBJECTIVE: The aim of this study was to determine whether the serotonin transporter-linked polymorphic region (5-HTTLPR) L (long)/S (short) polymorphism is associated with susceptibility to ADHD. METHOD: We conducted a meta-analysis of case-control associations and the transmission disequilibrium test (TDT) between the 5-HTTLPR L/S polymorphism and ADHD. RESULTS: A total of 19 comparison studies were included in this meta-analysis. Our meta-analysis of the case control studies showed no association between ADHD and the 5-HTTLPR S allele, for all study participants (odds ratio [OR] = 1.075, 95% confidence interval [CI] = [0.990, 1.167], p = .085), or for the European or Asian population. The TDT indicated no association between ADHD and the 5-HTTLPR S allele, for all study participants (OR = 1.078, 95% CI = [0.962, 1.207], p = .196). CONCLUSION: This meta-analysis of case-control studies and TDT showed a lack of association between the 5-HTTLPR L/S polymorphism and ADHD. PMID- 26048878 TI - Prevalence of cerebral and pulmonary thrombosis in patients with cyanotic congenital heart disease. AB - BACKGROUND: Patients with cyanotic congenital heart disease (CCHD) have a high prevalence of thrombosis, the most frequently described locations being the cerebral and pulmonary vessels. The reported prevalence of both cerebral infarction and pulmonary thrombosis has been highly variable. The aim of this study was to examine the prevalence of both cerebral and pulmonary thrombosis in CCHD according to medical history and imaging. In addition, the role of known erythrocytosis and haemostatic abnormalities as risk factors was evaluated. METHODS AND RESULTS: A cross-sectional descriptive study examining 98 stable adult patients with CCHD with a medical questionnaire, blood samples, MRI of the cerebrum (n=72), multidetector CT imaging (MDCT) of the thorax (n=76) and pulmonary scintigraphy (ventilation/perfusion/single-photon emission computerised tomography/CT) (n=66). The prevalence of cerebral infarction and pulmonary thrombosis according to imaging were 47% and 31%, respectively. Comparing the findings with previous medical history revealed a large under-reporting of thrombosis with only 22% of the patients having a clinical history of stroke and 25% of pulmonary thrombosis. There was no association between the degree of erythrocytosis or haemostatic abnormalities and the prevalence of thrombosis. CONCLUSIONS: Patients with CCHD have a prevalence of both cerebral and pulmonary thrombosis of around 30%-40%, which is much higher than that reported previously. Furthermore, there is a large discrepancy between clinical history and imaging findings, suggesting a high prevalence of silent thrombotic events. Neither erythrocytosis nor haemostatic abnormalities were associated with the prevalence of thrombosis in patients with CCHD. TRIAL REGISTRATION NUMBER: http://www.cvk.sum.dk/CVK/Home/English.aspx (H-KF-2006-4068). PMID- 26048880 TI - Inattention Symptoms Are Associated With Academic Achievement Mostly Through Variance Shared With Intrinsic Motivation and Behavioral Engagement. AB - OBJECTIVE: The main goal of the current study is to investigate whether intrinsic motivation and behavioral engagement mediate the association between inattention symptoms and academic achievement (reading, writing, and mathematics), as well as to document the extent to which inattention symptoms contribute to academic achievement due to variance overlapping with intrinsic motivation and behavioral engagement. METHOD: Participants were 92 children (Grades 1-4). Data were gathered using a combination of parent and teacher reports as well as objective assessments. RESULTS: Results did not support the mediating role of intrinsic motivation and behavioral engagement. A commonality analysis showed that 77.44% to 82.10% of the variance explained in each academic achievement domains was due to variance shared by inattention symptoms, intrinsic motivation, and behavioral engagement. CONCLUSION: These results suggest more commonality than differences between inattention symptoms, intrinsic motivation, and behavioral engagement with regard to their association with academic achievement. The implications of these findings are discussed. PMID- 26048881 TI - Loss of FERULATE 5-HYDROXYLASE Leads to Mediator-Dependent Inhibition of Soluble Phenylpropanoid Biosynthesis in Arabidopsis. AB - Phenylpropanoids are phenylalanine-derived specialized metabolites and include important structural components of plant cell walls, such as lignin and hydroxycinnamic acids, as well as ultraviolet and visible light-absorbing pigments, such as hydroxycinnamate esters (HCEs) and anthocyanins. Previous work has revealed a remarkable degree of plasticity in HCE biosynthesis, such that most Arabidopsis (Arabidopsis thaliana) mutants with blockages in the pathway simply redirect carbon flux to atypical HCEs. In contrast, the ferulic acid hydroxylase1 (fah1) mutant accumulates greatly reduced levels of HCEs, suggesting that phenylpropanoid biosynthesis may be repressed in response to the loss of FERULATE 5-HYDROXYLASE (F5H) activity. Here, we show that in fah1 mutant plants, the activity of HCE biosynthetic enzymes is not limiting for HCE accumulation, nor is phenylpropanoid flux diverted to the synthesis of cell wall components or flavonol glycosides. We further show that anthocyanin accumulation is also repressed in fah1 mutants and that this repression is specific to tissues in which F5H is normally expressed. Finally, we show that repression of both HCE and anthocyanin biosynthesis in fah1 mutants is dependent on the MED5a/5b subunits of the transcriptional coregulatory complex Mediator, which are similarly required for the repression of lignin biosynthesis and the stunted growth of the phenylpropanoid pathway mutant reduced epidermal fluorescence8. Taken together, these observations show that the synthesis of HCEs and anthocyanins is actively repressed in a MEDIATOR-dependent manner in Arabidopsis fah1 mutants and support an emerging model in which MED5a/5b act as central players in the homeostatic repression of phenylpropanoid metabolism. PMID- 26048882 TI - Chlorophyll Synthase under Epigenetic Surveillance Is Critical for Vitamin E Synthesis, and Altered Expression Affects Tocopherol Levels in Arabidopsis. AB - Chlorophyll synthase catalyzes the final step in chlorophyll biosynthesis: the esterification of chlorophyllide with either geranylgeranyl diphosphate or phytyl diphosphate (PDP). Recent studies have pointed to the involvement of chlorophyll linked reduction of geranylgeranyl by geranylgeranyl reductase as a major pathway for the synthesis of the PDP precursor of tocopherols. This indirect pathway of PDP synthesis suggests a key role of chlorophyll synthase in tocopherol production to generate the geranylgeranyl-chlorophyll substrate for geranylgeranyl reductase. In this study, contributions of chlorophyll synthase to tocopherol formation in Arabidopsis (Arabidopsis thaliana) were explored by disrupting and altering expression of the corresponding gene CHLOROPHYLL SYNTHASE (CHLSYN; At3g51820). Leaves from the homozygous chlysyn1-1 null mutant were nearly devoid of tocopherols, whereas seeds contained only approximately 25% of wild-type tocopherol levels. Leaves of RNA interference lines with partial suppression of CHLSYN displayed marked reductions in chlorophyll but up to a 2 fold increase in tocopherol concentrations. Cauliflower mosaic virus35S-mediated overexpression of CHLSYN unexpectedly caused a cosuppression phenotype at high frequencies accompanied by strongly reduced chlorophyll content and increased tocopherol levels. This phenotype and the associated detection of CHLSYN-derived small interfering RNAs were reversed with CHLSYN overexpression in rna-directed rna polymerase6 (rdr6), which is defective in RNA-dependent RNA polymerase6, a key enzyme in sense transgene-induced small interfering RNA production. CHLSYN overexpression in rdr6 had little effect on chlorophyll content but resulted in up to a 30% reduction in tocopherol levels in leaves. These findings show that altered CHLSYN expression impacts tocopherol levels and also, show a strong epigenetic surveillance of CHLSYN to control chlorophyll and tocopherol synthesis. PMID- 26048884 TI - Preferential host switching and its relation with Hantavirus diversification in South America. AB - In recent years, the notion of co-speciation between Hantavirus species and their hosts was discarded in favour of a more likely explanation: preferential host switching. However, the relative importance of this last process in shaping the evolutionary history of hantaviruses remains uncertain, given the present limited knowledge not only of virus-host relationships but also of the pathogen and reservoir phylogenies. In South America, more than 25 hantavirus genotypes were detected; several of them act as aetiological agents of hantavirus pulmonary syndrome (HPS). An understanding of the diversity of hantaviruses and of the processes underlying host switching is critical since human cases of HPS are almost exclusively the result of human-host interactions. In this study, we tested if preferential host switching is the main process driving hantavirus diversification in South America, by performing a co-phylogenetic analysis of the viruses and their primary hosts. We also suggest a new level of amino acid divergence to define virus species in the group. Our results indicate that preferential host switching would not be the main process driving virus diversification. The historical geographical proximity among rodent hosts emerges as an alternative hypothesis to be tested. PMID- 26048885 TI - Comparative analysis of the gene-inactivating potential of retroviral restriction factors APOBEC3F and APOBEC3G. AB - APOBEC3 (A3) proteins are host-encoded restriction factors that inhibit retrovirus infection by mutagenic deamination of cytosines in minus-strand DNA replication intermediates. APOBEC3F (A3F) and APOBEC3G (A3G) are two of the most potent A3 enzymes in humans with each having a different target DNA specificity. A3G prefers to deaminate cytosines preceded by a cytosine (5'-CC), whereas A3F preferentially targets cytosines preceded by a thymine (5'-TC). Here we performed a detailed comparative analysis of retrovirus-encoded gene sequences edited by A3F and A3G, with the aim of correlating the context and intensity of the mutations with their effects on gene function. Our results revealed that, when there are few (TGG) tryptophan codons in the sequence, both enzymes alter gene function with a similar efficiency when given equal opportunities to deaminate in their preferred target DNA context. In contrast, tryptophan-rich genes are efficiently inactivated in the presence of a low mutational burden, through termination codon generation by A3G but not A3F. Overall, our results clearly demonstrated that the target DNA specificity of an A3 enzyme along with the intensity of the mutational burden and the tryptophan content of the gene being targeted are the factors that have the most forceful influence on whether A3 induced mutations will favour either terminal inactivation or genetic diversification of a retrovirus. PMID- 26048883 TI - Subfamily-Specific Fluorescent Probes for Cysteine Proteases Display Dynamic Protease Activities during Seed Germination. AB - Cysteine proteases are an important class of enzymes implicated in both developmental and defense-related programmed cell death and other biological processes in plants. Because there are dozens of cysteine proteases that are posttranslationally regulated by processing, environmental conditions, and inhibitors, new methodologies are required to study these pivotal enzymes individually. Here, we introduce fluorescence activity-based probes that specifically target three distinct cysteine protease subfamilies: aleurain-like proteases, cathepsin B-like proteases, and vacuolar processing enzymes. We applied protease activity profiling with these new probes on Arabidopsis (Arabidopsis thaliana) protease knockout lines and agroinfiltrated leaves to identify the probe targets and on other plant species to demonstrate their broad applicability. These probes revealed that most commercially available protease inhibitors target unexpected proteases in plants. When applied on germinating seeds, these probes reveal dynamic activities of aleurain-like proteases, cathepsin B-like proteases, and vacuolar processing enzymes, coinciding with the remobilization of seed storage proteins. PMID- 26048886 TI - In vitro growth, pathogenicity and serological characteristics of the Japanese encephalitis virus genotype V Muar strain. AB - The characteristics of genotype V Japanese encephalitis virus (GV JEV) remain poorly understood as only two strains have been isolated to date. In this study, we examined the effects of the GV JEV Muar strain on in vitro growth and pathogenicity in mice; we also evaluated the efficacy of inactivated JEV vaccines against the Muar strain. Although growth of the Muar strain in mouse neuroblastoma N18 cells was clearly worse than that of the GIII Beijing-1 and GI Mie/41/2002 strains, neuroinvasiveness of the Muar strain was similar to that of the Beijing-1 strain and significantly higher than that of the Mie/41/2002 strain. The results of a plaque reduction neutralization test suggested that the neutralization ability of the JEV vaccines against the Muar strain was reduced compared with the GI and GIII strains. However, the protection potency of the JEV vaccine against the Muar strain was similar to that for the Beijing-1 strain in mice. Our data indicate that GV JEV has unique growth, virulence and antigenicity features. PMID- 26048887 TI - The Contribution of Early Communication Quality to Low-Income Children's Language Success. AB - The disparity in the amount and quality of language that low-income children hear relative to their more-affluent peers is often referred to as the 30-million-word gap. Here, we expand the literature about this disparity by reporting the relative contributions of the quality of early parent-child communication and the quantity of language input in 60 low-income families. Including both successful and struggling language learners from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development, we noted wide variation in the quality of nonverbal and verbal interactions (symbol-infused joint engagement, routines and rituals, fluent and connected communication) at 24 months, which accounted for 27% of the variance in expressive language 1 year later. These indicators of quality were considerably more potent predictors of later language ability than was the quantity of mothers' words during the interaction or sensitive parenting. Bridging the word gap requires attention to how caregivers and children establish a communication foundation within low income families. PMID- 26048888 TI - Variability Modifies Life Satisfaction's Association With Mortality Risk in Older Adults. AB - Greater life satisfaction is associated with greater longevity, but its variability across time has not been examined relative to longevity. We investigated whether mean life satisfaction across time, variability in life satisfaction across time, and their interaction were associated with mortality over 9 years of follow-up. Participants were 4,458 Australians initially at least 50 years old. During the follow-up, 546 people died. After we adjusted for age, greater mean life satisfaction was associated with a reduction in mortality risk, and greater variability in life satisfaction was associated with an increase in mortality risk. These findings were qualified by a significant interaction such that individuals with low mean satisfaction and high variability in satisfaction had the greatest risk of mortality over the follow-up period. In combination with mean life satisfaction, variability in life satisfaction is relevant for mortality risk among older adults. Considering intraindividual variability provides additional insight into associations between psychological characteristics and health. PMID- 26048889 TI - Object Persistence Enhances Spatial Navigation: A Case Study in Smartphone Vision Science. AB - Violations of spatiotemporal continuity disrupt performance in many tasks involving attention and working memory, but experiments on this topic have been limited to the study of moment-by-moment on-line perception, typically assessed by passive monitoring tasks. We tested whether persisting object representations also serve as underlying units of longer-term memory and active spatial navigation, using a novel paradigm inspired by the visual interfaces common to many smartphones. Participants used key presses to navigate through simple visual environments consisting of grids of icons (depicting real-world objects), only one of which was visible at a time through a static virtual window. Participants found target icons faster when navigation involved persistence cues (via sliding animations) than when persistence was disrupted (e.g., via temporally matched fading animations), with all transitions inspired by smartphone interfaces. Moreover, this difference occurred even after explicit memorization of the relevant information, which demonstrates that object persistence enhances spatial navigation in an automatic and irresistible fashion. PMID- 26048890 TI - Effect of Neutral-pH, Low-Glucose Degradation Product Peritoneal Dialysis Solutions on Residual Renal Function, Urine Volume, and Ultrafiltration: A Systematic Review and Meta-Analysis. AB - BACKGROUND AND OBJECTIVES: Neutral-pH, low-glucose degradation products solutions were developed in an attempt to lessen the adverse effects of conventional peritoneal dialysis solutions. A systematic review was performed evaluating the effect of these solutions on residual renal function, urine volume, peritoneal ultrafiltration, and peritoneal small-solute transport (dialysate to plasma creatinine ratio) over time. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Multiple electronic databases were searched from January of 1995 to January of 2013. Randomized trials reporting on any of four prespecified outcomes were selected by consensus among multiple reviewers. RESULTS: Eleven trials of 643 patients were included. Trials were generally of poor quality. The meta-analysis was performed using a random effects model. The use of neutral-pH, low-glucose degradation products solutions resulted in better preserved residual renal function at various study durations, including >1 year (combined analysis: 11 studies; 643 patients; standardized mean difference =0.17 ml/min; 95% confidence interval, 0.01 to 0.32), and greater urine volumes (eight studies; 598 patients; mean difference =128 ml/d; 95% confidence interval, 58 to 198). There was no significant difference in peritoneal ultrafiltration (seven studies; 571 patients; mean difference =-110; 95% confidence interval, -312 to 91) or dialysate to plasma creatinine ratio (six studies; 432 patients; mean difference =0.03; 95% confidence interval, 0.00 to 0.06). CONCLUSIONS: The use of neutral pH, low-glucose degradation products solutions results in better preservation of residual renal function and greater urine volumes. The effect on residual renal function occurred early and persisted beyond 12 months. Additional studies are required to evaluate the use of neutral-pH, low-glucose degradation products solutions on hard clinical outcomes. PMID- 26048892 TI - A Perspective on the Future of High-Throughput RNAi Screening: Will CRISPR Cut Out the Competition or Can RNAi Help Guide the Way? AB - For more than a decade, RNA interference (RNAi) has brought about an entirely new approach to functional genomics screening. Enabling high-throughput loss-of function (LOF) screens against the human genome, identifying new drug targets, and significantly advancing experimental biology, RNAi is a fast, flexible technology that is compatible with existing high-throughput systems and processes; however, the recent advent of clustered regularly interspaced palindromic repeats (CRISPR)-Cas, a powerful new precise genome-editing (PGE) technology, has opened up vast possibilities for functional genomics. CRISPR-Cas is novel in its simplicity: one piece of easily engineered guide RNA (gRNA) is used to target a gene sequence, and Cas9 expression is required in the cells. The targeted double-strand break introduced by the gRNA-Cas9 complex is highly effective at removing gene expression compared to RNAi. Together with the reduced cost and complexity of CRISPR-Cas, there is the realistic opportunity to use PGE to screen for phenotypic effects in a total gene knockout background. This review summarizes the exciting development of CRISPR-Cas as a high-throughput screening tool, comparing its future potential to that of well-established RNAi screening techniques, and highlighting future challenges and opportunities within these disciplines. We conclude that the two technologies actually complement rather than compete with each other, enabling greater understanding of the genome in relation to drug discovery. PMID- 26048891 TI - Biomarker Enhanced Risk Prediction for Adverse Outcomes in Critically Ill Patients Receiving RRT. AB - BACKGROUND AND OBJECTIVES: Higher plasma concentrations of inflammatory and apoptosis markers in critically ill patients receiving RRT are associated with RRT dependence and death. This study objective was to examine whether plasma inflammatory (IL-6, -8, -10, and -18; macrophage migration inhibitory factor) and apoptosis (death receptor-5, tumor necrosis factor receptor I and II) biomarkers augment risk prediction of renal recovery and mortality compared with clinical models. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Biologic Markers of Recovery for the Kidney study (n=817) was a prospective, nested, observational cohort study conducted as an ancillary to the Veterans Affairs/National Institutes of Health Acute renal failure Trial Network study, a randomized trial of intensive versus less intensive RRT in critically ill patients with AKI conducted between November 2003 and July 2007 at 27 Veterans Affairs- and university-affiliated centers. Primary outcomes of interest were renal recovery and mortality at day 60. RESULTS: A parsimonious clinical model consisting of only four variables (age, mean arterial pressure, mechanical ventilation, and bilirubin) predicted renal recovery (area under the receiver-operating characteristic curve [AUROC], 0.73; 95% confidence interval [95% CI], 0.68 to 0.78) and mortality (AUROC, 0.74; 95% CI, 0.69 to 0.78). By contrast, individual biomarkers were only modestly predictive of renal recovery (AUROC range, 0.55 0.63) and mortality (AUROC range, 0.54-0.68). Adding plasma IL-8 to a parsimonious model augmented prediction of recovery (AUROC, 0.76; 95% CI, 0.71 to 0.81; P=0.04) and mortality (AUROC, 0.78; 95% CI, 0.73 to 0.82; P<0.01) compared with the clinical model alone. CONCLUSIONS: This study suggests that a simple four-variable clinical model with plasma IL-8 had predictive value for renal recovery and mortality. These findings require external validation but could easily be used by clinicians. PMID- 26048893 TI - ABC transporter Cdr1p harbors charged residues in the intracellular loop and nucleotide-binding domain critical for protein trafficking and drug resistance. AB - The ABC transporter Cdr1 protein of Candida albicans, which plays a major role in antifungal resistance, has two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs). The 12 transmembrane helices of TMDs that are interconnected by extracellular and intracellular loops (ICLs) mainly harbor substrate recognition sites where drugs bind while cytoplasmic NBDs hydrolyze ATP which powers drug efflux. The coupling of ATP hydrolysis to drug transport requires proper communication between NBDs and TMDs typically accomplished by ICLs. This study examines the role of cytoplasmic ICLs of Cdr1p by rationally predicting the critical residues on the basis of their interatomic distances. Among nine pairs that fall within a proximity of <4 A, an ion pair between K577 of ICL1 and E315 of NBD1 was found to be critical. The substitution, swapping and changing of the length or charge of K577 or E315 by directed mutagenesis led to a misfolded, non-rescuable protein entrapped in intracellular structures. Furthermore, the equipositional ionic pair-forming residues from ICL3 and NBD2 (R1260 and E1014) did not impact protein trafficking. These results point to a new role for ICL/NBD interacting residues in PDR ABC transporters in protein folding and trafficking. PMID- 26048895 TI - Coach's eye. PMID- 26048894 TI - Response of yeast cells to high glucose involves molecular and physiological differences when compared to other osmostress conditions. AB - Yeast cells can be affected by several causes of osmotic stress, such as high salt, sorbitol or glucose concentrations. The last condition is particularly interesting during natural processes where this microorganism participates. Response to osmostress requires the HOG (High Osmolarity Glycerol) pathway and several transcription factors, including Hot1, which plays a key role in high glucose concentrations. In this work, we describe how the yeast response to osmotic stress shows differences in accordance with the stress agent responsible for it. Compared with other conditions, under high glucose stress, delocalization of MAPK (Mitogen-Activated Protein Kinase) Hog1 is slower, induction of HOT1 expression is higher and Msn2/4 transcription factors are involved to a lesser extent. The transcriptomic analyses carried out with samples incubated for 30 min in the presence of high glucose or sorbitol reveal the presence of two functional categories with a differential expression between these conditions: glycogen biosynthesis and mobilization, and membrane-anchored proteins. We present data to demonstrate that the cells treated with 20% (w/v) (1.11 M) glucose contain higher chitin levels and are more sensitive to calcofluor white and ethanol. PMID- 26048896 TI - Return to sports after anterior cruciate ligament injury: neither surgery nor rehabilitation alone guarantees success--it is much more complicated. PMID- 26048897 TI - Clarifying concussion in youth rugby: recognise and remove. PMID- 26048898 TI - Disease prevention: what's really important? PMID- 26048899 TI - Should patients reach certain knee function benchmarks before anterior cruciate ligament reconstruction? Does intense 'prehabilitation' before anterior cruciate ligament reconstruction influence outcome and return to sports? PMID- 26048900 TI - Deaf Adolescents' Learning of Cardiovascular Health Information: Sources and Access Challenges. AB - Deaf individuals have more cardiovascular risks than the general population that are believed to be related to their cardiovascular health knowledge disparities. This phenomenological study describes where 20 deaf sign language-using adolescents from Rochester, New York, many who possess many positive characteristics to support their health literacy, learn cardiovascular health information and their lived experiences accessing health information. The goal is to ultimately use this information to improve the delivery of cardiovascular health education to this population and other deaf adolescents at a higher risk for weak health literacy. Deaf bilingual researchers interviewed deaf adolescents, transcribed and coded the data, and described the findings. Five major sources of cardiovascular health information were identified including family, health education teachers, healthcare providers, printed materials, and informal sources. Despite possessing advantageous characteristics contributing to stronger health literacy, study participants described significant challenges with accessing health information from each source. They also demonstrated inconsistencies in their cardiovascular health knowledge, especially regarding heart attack, stroke, and cholesterol. These findings suggest a great need for additional public funding to research deaf adolescents' informal health-related learning, develop accessible and culturally appropriate health surveys and health education programming, improve interpreter education, and disseminate information through social media. PMID- 26048901 TI - Validation of the dorsal approach for the blockade of the femoral nerve using ultrasound and nerve electrolocation in cats. AB - OBJECTIVES: This study was conducted to validate the dorsal approach for femoral nerve (FN) blockade in cats and to verify the efficacy of the sole use of peripheral nerve electrolocation (PNE) or ultrasound (US)-guided technique to achieve the block. METHODS: This study was carried out in two phases. In phase 1, five adult experimental cats were used to validate the approach. In each cat, one FN was located by US and the accuracy of this location confirmed by PNE. Then, 2 mg/kg lidocaine 2% (diluted in saline to a final volume of 1 ml) was injected around the target nerve and the success of the blockade was evaluated. In phase 2, four adult experimental cats were included in two groups to verify the reliability of this approach to block eight FNs by the sole use of PNE (group 1) or US-guided technique (group 2). Evidence of motor blockade, time required to perform the blockade, onset time and duration of the blockades were determined. RESULTS: The FN was successfully located by US in all cats enrolled in phase 1, as confirmed by PNE in all cases. The success rate was clinically higher in group 2 (87.5%) than in group 1 (75.0%). The US-guided technique required less time to perform and produced blocks of longer duration. Recovery was uneventful in all cases. CONCLUSIONS AND RELEVANCE: The combined use of PNE and US-guided technique enabled validation of the dorsal approach for the FN blockade as it provided a successful FN blockade in all cases. The sole use of a US-guided technique may offer some advantages over the use of a sole PNE-guided technique to perform these blocks. PMID- 26048902 TI - Decision-theoretic designs for small trials and pilot studies: A review. AB - Pilot studies and other small clinical trials are often conducted but serve a variety of purposes and there is little consensus on their design. One paradigm that has been suggested for the design of such studies is Bayesian decision theory. In this article, we review the literature with the aim of summarizing current methodological developments in this area. We find that decision-theoretic methods have been applied to the design of small clinical trials in a number of areas. We divide our discussion of published methods into those for trials conducted in a single stage, those for multi-stage trials in which decisions are made through the course of the trial at a number of interim analyses, and those that attempt to design a series of clinical trials or a drug development programme. In all three cases, a number of methods have been proposed, depending on the decision maker's perspective being considered and the details of utility functions that are used to construct the optimal design. PMID- 26048903 TI - A new framework of statistical inferences based on the valid joint sampling distribution of the observed counts in an incomplete contingency table. AB - Some existing confidence interval methods and hypothesis testing methods in the analysis of a contingency table with incomplete observations in both margins entirely depend on an underlying assumption that the sampling distribution of the observed counts is a product of independent multinomial/binomial distributions for complete and incomplete counts. However, it can be shown that this independency assumption is incorrect and can result in unreliable conclusions because of the under-estimation of the uncertainty. Therefore, the first objective of this paper is to derive the valid joint sampling distribution of the observed counts in a contingency table with incomplete observations in both margins. The second objective is to provide a new framework for analyzing incomplete contingency tables based on the derived joint sampling distribution of the observed counts by developing a Fisher scoring algorithm to calculate maximum likelihood estimates of parameters of interest, the bootstrap confidence interval methods, and the bootstrap testing hypothesis methods. We compare the differences between the valid sampling distribution and the sampling distribution under the independency assumption. Simulation studies showed that average/expected confidence-interval widths of parameters based on the sampling distribution under the independency assumption are shorter than those based on the new sampling distribution, yielding unrealistic results. A real data set is analyzed to illustrate the application of the new sampling distribution for incomplete contingency tables and the analysis results again confirm the conclusions obtained from the simulation studies. PMID- 26048904 TI - Diabetes Self-management Education and Support in Type 2 Diabetes: A Joint Position Statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. PMID- 26048905 TI - Transgenic songbirds with suppressed or enhanced activity of CREB transcription factor. AB - Songbirds postnatally develop their skill to utter and to perceive a vocal signal for communication. How genetic and environmental influences act in concert to regulate the development of such skill is not fully understood. Here, we report the phenotype of transgenic songbirds with altered intrinsic activity of cAMP response element-binding protein (CREB) transcription factor. By viral vector mediated modification of genomic DNA, we established germ line-transmitted lines of zebra finches, which exhibited enhanced or suppressed activity of CREB. Although intrinsically acquired vocalizations or their hearing ability were not affected, the transgenic birds showed reduced vocal learning quality of their own songs and impaired audio-memory formation against conspecific songs. These results thus demonstrate that appropriate activity of CREB is necessary for the postnatal acquisition of learned behavior in songbirds, and the CREB transgenic birds offer a unique opportunity to separately manipulate both genetic and environmental factors that impinge on the postnatal song learning. PMID- 26048906 TI - Reevaluating carbon fluxes in subduction zones, what goes down, mostly comes up. AB - Carbon fluxes in subduction zones can be better constrained by including new estimates of carbon concentration in subducting mantle peridotites, consideration of carbonate solubility in aqueous fluid along subduction geotherms, and diapirism of carbon-bearing metasediments. Whereas previous studies concluded that about half the subducting carbon is returned to the convecting mantle, we find that relatively little carbon may be recycled. If so, input from subduction zones into the overlying plate is larger than output from arc volcanoes plus diffuse venting, and substantial quantities of carbon are stored in the mantle lithosphere and crust. Also, if the subduction zone carbon cycle is nearly closed on time scales of 5-10 Ma, then the carbon content of the mantle lithosphere + crust + ocean + atmosphere must be increasing. Such an increase is consistent with inferences from noble gas data. Carbon in diamonds, which may have been recycled into the convecting mantle, is a small fraction of the global carbon inventory. PMID- 26048907 TI - Reply to Szuwalski and Hilborn: Forage fish require an ecosystem approach. PMID- 26048908 TI - Environment drives forage fish productivity. PMID- 26048909 TI - Consequences of Intermodality Registration Errors for Intramodality 3D Ultrasound IGRT. AB - Intramodality ultrasound image-guided radiotherapy systems compare daily ultrasound to reference ultrasound images. Nevertheless, because the actual treatment planning is based on a reference computed tomography image, and not on a reference ultrasound image, their accuracy depends partially on the correct intermodality registration of the reference ultrasound and computed tomography images for treatment planning. The error propagation in daily patient positioning due to potential registration errors at the planning stage was assessed in this work. Five different scenarios were simulated involving shifts or rotations of ultrasound or computed tomography images. The consequences of several workflow procedures were tested with a phantom setup. As long as the reference ultrasound and computed tomography images are made to match, the patient will be in the correct treatment position. In an example with a phantom measurement, the accuracy of the performed manual fusion was found to be <=2 mm. In clinical practice, manual registration of patient images is expected to be more difficult. Uncorrected mismatches will lead to a systematically incorrect final patient position because there will be no indication that there was a misregistration between the computed tomography and reference ultrasound images. In the treatment room, the fusion with the computed tomography image will not be visible and based on the ultrasound images the patient position seems correct. PMID- 26048910 TI - Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis. AB - Therapy for childhood acute lymphoblastic leukemia (ALL) is associated with 5 year survival rates of ~90% even after largely eliminating cranial radiation. This meta-analysis assesses the long-term neurocognitive functioning after chemotherapy-only regimens among survivors of childhood ALL. We conducted a systematic review to identify studies that evaluated long-term neurocognitive functioning following treatment of ALL by searching MEDLINE/PubMed, Database of Abstracts of Reviews of Effects, and secondary sources. Studies were included if ALL survivors were in continuous first remission, did not receive any radiation, were at least >=2 years off therapy or >=5 years since diagnosis, and were compared with a healthy control group. Weighted mean differences with 95% confidence intervals (CIs) were calculated. Ten nonexperimental studies met all eligibility criteria and included 509 patients and 555 controls. Meta-analysis demonstrated statistically significant moderate impairment across multiple neurocognitive domains evaluated, with intelligence most affected. Significant differences in standard deviation (SD) scores were found for Full Scale intelligence quotient (IQ) (-0.52 SD; 95% CI, -0.68 to -0.37), Verbal IQ (-0.54 SD; 95% CI, -0.69 to -0.40), and Performance IQ (-0.41 SD; 95% CI, -0.56 to 0.27); these SD scores correspond to changes in IQ of 6 to 8 points. Working memory, information processing speed, and fine motor domains were moderately, but statistically significantly, impaired. Meta-analysis of ALL survivors treated without cranial radiation demonstrated significant impairment in IQ and other neurocognitive domains. Patients and their families should be informed about these potential negative effects to encourage surveillance and educational planning. Both preventive and intervention strategies are needed. PMID- 26048912 TI - Danazol Inhibits Cytochrome P450 2J2 Activity in a Substrate-independent Manner. AB - Cytochrome P450 2J2 (CYP2J2) is an enzyme responsible for the metabolism of endogenous substrates including arachidonic acid, as well as therapeutic drugs such as albendazole, astemizole, ebastine, and terfenadine. Selective inhibitors of CYP2J2 are essential for P450 reaction phenotyping studies. To find representative CYP2J2 index inhibitors, we evaluated the inhibitory potential of danazol, hydroxyebastine, telmisartan, and terfenadone against CYP2J2 activity for four representative CYP2J2 substrates (albendazole, astemizole, ebastine, and terfenadine) using recombinant CYP2J2. Of these four CYP2J2 inhibitors, danazol strongly inhibited CYP2J2-mediated albendazole, astemizole, ebastine, and terfenadine metabolism in a substrate-independent manner, with IC50 values of 0.05, 0.07, 0.18, and 0.34 MUM, respectively. Danazol noncompetitively inhibited CYP2J2-mediated astemizole O-demethylation activities with a Ki value of 0.06 MUM. Terfenadone strongly inhibited CYP2J2-mediated albendazole, astemizole, and terfenadine metabolism (IC50 < 0.21 MUM), whereas it showed weak inhibition against CYP2J2-catalyzed ebastine hydroxylase activity (IC50 = 6.04 MUM). Telmisartan had no inhibitory effect on CYP2J2-mediated ebastine and terfenadine hydroxylation (IC50 > 20 MUM). Taken together, these data suggest that danazol may be used as a CYP2J2 index inhibitor in reaction phenotyping studies. PMID- 26048911 TI - Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53 inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL. PMID- 26048913 TI - The phenotypic diversity in per-follicle anti-Mullerian hormone production in polycystic ovary syndrome. AB - STUDY QUESTION: Is intrinsic dysregulation of granulosa cells (GC) and consequent increases in the per-follicle production of anti-Mullerian hormone (AMH), correlated with the phenotypic presentation of women with polycystic ovaries? SUMMARY ANSWER: Involvement of intrinsic GC dysregulation in oligo-anovulation associated with polycystic ovary syndrome (PCOS) is likely because among women with PCOS, those with oligo-amenorrhea have higher per-follicle AMH production than those who ovulate normally, irrespective of their androgen and/or metabolic status. WHAT IS KNOWN ALREADY: Women with PCOS have higher serum AMH level than non-PCOS women due to an increased follicle number and excessive AMH production per follicle, the latter reflecting a putative GC dysfunction that may vary between PCOS phenotypes. STUDY DESIGN, SIZE, DURATION: This is a retrospective analysis of data collected from 1021 women undergoing infertility evaluation from March 2011 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included women with polycystic ovarian morphology (PCOM) who met the Rotterdam criteria for PCOS (n = 272), women with PCOM only (n = 168) and controls (n = 581). MAIN RESULTS AND THE ROLE OF CHANCE: We used serum AMH to antral follicle count (AFC) ratio (AMH/AFC) as a marker of per-follicle AMH production and checked whether this ratio was associated with the PCOS phenotype and to the menstrual, androgen and metabolic status in women with PCOS, women with PCOM only and in controls. AMH/AFC was significantly higher in oligo-amenorrheic women with PCOS than in eumenorrheic women with PCOS or PCOM (P < 0.001) but also in the latter group compared with controls (P < 0.001) regardless of androgen status. Stepwise discriminant analysis yielded a significant score for the menstrual status with a discriminant power of 26.5% (P < 0.001). This score included AFC, AMH/AFC, waist circumference and LH with partial R(2) of 0.172, 0.042, 0.024 and 0.023, respectively. LIMITATIONS, REASONS FOR CAUTION: The AMH to AFC ratio as a surrogate marker for average AMH may be subject to error because follicles below the sensitivity limit of the ultrasonography used may also contribute to serum AMH concentration and secondly, AFC can be subjective. WIDER IMPLICATIONS OF THE FINDINGS: The higher AMH/AFC in women with PCOM only than in controls suggests that isolated PCOM may represent a PCOS-like phenotype in which an inherent dysfunction of GC exists but is too mild to affect the ovulatory process. STUDY FUNDING/COMPETING INTERESTS: No funding was obtained for this study. There are no conflicts of interest to be declared. TRIAL REGISTRATION NUMBER: Non-applicable. PMID- 26048914 TI - The transthyretin amyloidoses: advances in therapy. AB - There are two forms of transthyretin (TTR) amyloidosis: non-hereditary and hereditary. The non-hereditary form (ATTRwt) is caused by native or wild-type TTR and was previously referred to as senile systemic amyloidosis. The hereditary form (ATTRm) is caused by variant TTR which results from a genetic mutation of TTR. The predominant effect of ATTRwt amyloidosis is on the heart, with patients having a greater left ventricular wall thickness at presentation than the devastating form which is light chain (AL) amyloidosis. ATTRm amyloidosis is broadly split into two categories: a type that predominantly affects the nervous system (often called familial amyloid polyneuropathy (FAP)) and one with a predilection for the heart (often called familial amyloid cardiomyopathy (FAC)). Approximately half of all TTR mutations known to express a clinical phenotype cause a cardiomyopathy. Since the introduction of orthotopic liver transplantation for ATTRm amyloidosis in 1991, several additional therapies have been developed. These therapies aim to provide a reduction or elimination of TTR from the plasma (through genetic approaches), stabilisation of the TTR molecule (to prevent deposition) and dissolution of the amyloid matrix. We describe the latest developments in these approaches to management, many of which are also applicable to wild-type amyloidosis. PMID- 26048915 TI - Allergy myths lead to underdiagnosis and overdiagnosis, say specialists. PMID- 26048916 TI - Quantitative assessment of CD30+ lymphocytes and eosinophils for the histopathological differential diagnosis of inflammatory bowel disease. AB - BACKGROUND AND AIMS: The histopathological discrimination of Crohn's disease [CD] and ulcerative colitis [UC] can be challenging. The aim of this study was to evaluate if quantification of CD30(+) lymphocytes and eosinophils in histopathological material improves the accuracy of diagnosis of inflammatory bowel disease. METHODS: A total of 156 patients were diagnosed with IBD by a gastroenterologist and corroborated by 5 years of follow-up. Patients were treatment naive at the time of biopsy. Samples were taken from diseased areas of the colon and examined by a gastrointestinal pathologist. RESULTS: The median number of eosinophils in biopsies from affected segments was 42/high power field [hpf] [25.5-63.5] in CD and 98/hpf [67-123] in UC [p < 0.001]. Biopsies containing >= 70 eosinophils/hpf field had a sensitivity of 78.3% and a specificity of 71% for the diagnosis of UC ({area under the receiver operating characteristic (ROC) curve 0.767 (95% confidence interval [CI] 0.696-0.838)}. There was a median of three CD30(+) cells/hpf [range 2-6] in diseased CD biopsies and 33 cells/hpf [24-52] in diseased UC biopsies [p < 0.001]. The cut-off determined by the ROC curve was 15 (sensitivity 97.4%, specificity 97.4%, positive likelihood ratio (PLR) 17.1, Negative likelihood ratio (NLR) 0.03, area under the curve [AUC]: 0.978; 95% CI 0.95310.999). CONCLUSIONS: Routine histopathological assessment with quantification of CD30+ cells is highly accurate at discriminating CD and UC. All the measured parameters are easy to perform, low-cost, and available in most pathological laboratories. PMID- 26048917 TI - Aggravation of Established Colitis in Specific Pathogen-free IL-10 Knockout Mice by Restraint Stress Is Not Mediated by Increased Colonic Permeability. AB - BACKGROUND: Pathogenic mechanisms responsible for the undulating symptom pattern, or indeed causative agents for the development, of inflammatory bowel diseases [IBD] are largely unknown. Many physicians and most patients are convinced that stress affects the course of IBD. As with most factors that contribute to IBD, it is unclear whether stress merely exacerbates established disease or indeed contributes to the development of disease. We designed this study to investigate whether stress induces or aggravates colitis in interkeukin-10 knockout [IL-10 ko] mice and to determine the role of intestinal permeability in this model of stress-related colitis. METHODS: The study was divided into two experiments depending on the age of the animals. Stress was induced by placing 5-week old disease-free mice or 8-week-old mice (IL-10ko and wild type [wt]) with mild colitis in movement restrainers for 2h twice daily for 7 days. The development of colitis was assessed clinically [weight and faecal pellet production], histologically [haematoxylin and eosin staining], and biochemically [colonic IL 2, IL-4, IL-6, IL-12p40, TNFalpha, and IFNgamma]. Permeability was measured in Ussing chambers. RESULTS: Faecal pellet production increased significantly in all stressed animals compared with control animals, indicating successful application of stress. Stressed 8-week old mice lost weight [p < 0.001] and stressed IL-10(-/ ) mice showed a significantly increased histological score compared with non stressed or wt mice [p < 0.001]. There was no appreciable difference in cytokine production. Stress did not alter intestinal permeability. CONCLUSIONS: Restraint stress aggravates experimental colitis in 8-week old IL-10ko mice but cannot induce colitis in disease-free younger mice. This is not mediated by an increased intestinal permeability. PMID- 26048924 TI - Adaptive Evolution of Thermotoga maritima Reveals Plasticity of the ABC Transporter Network. AB - Thermotoga maritima is a hyperthermophilic anaerobe that utilizes a vast network of ABC transporters to efficiently metabolize a variety of carbon sources to produce hydrogen. For unknown reasons, this organism does not metabolize glucose as readily as it does glucose di- and polysaccharides. The leading hypothesis implicates the thermolability of glucose at the physiological temperatures at which T. maritima lives. After a 25-day laboratory evolution, phenotypes were observed with growth rates up to 1.4 times higher than and glucose utilization rates exceeding 50% those of the wild type. Genome resequencing revealed mutations in evolved cultures related to glucose-responsive ABC transporters. The native glucose ABC transporter, GluEFK, has more abundant transcripts either as a result of gene duplication-amplification or through mutations to the operator sequence regulating this operon. Conversely, BglEFGKL, a transporter of beta glucosides, is substantially downregulated due to a nonsense mutation to the solute binding protein or due to a deletion of the upstream promoter. Analysis of the ABC2 uptake porter families for carbohydrate and peptide transport revealed that the solute binding protein, often among the transcripts detected at the highest levels, is predominantly downregulated in the evolved cultures, while the membrane-spanning domain and nucleotide binding components are less varied. Similar trends were observed in evolved strains grown on glycerol, a substrate that is not dependent on ABC transporters. Therefore, improved growth on glucose is achieved through mutations favoring GluEFK expression over BglEFGKL, and in lieu of carbon catabolite repression, the ABC transporter network is modulated to achieve improved growth fitness. PMID- 26048925 TI - Three New Cutinases from the Yeast Arxula adeninivorans That Are Suitable for Biotechnological Applications. AB - The genes ACUT1, ACUT2, and ACUT3, encoding cutinases, were selected from the genomic DNA of Arxula adeninivorans LS3. The alignment of the amino acid sequences of these cutinases with those of other cutinases or cutinase-like enzymes from different fungi showed that they all had a catalytic S-D-H triad with a conserved G-Y-S-Q-G domain. All three genes were overexpressed in A. adeninivorans using the strong constitutive TEF1 promoter. Recombinant 6* His (6h)-tagged cutinase 1 protein (p) from A. adeninivorans LS3 (Acut1-6hp), Acut2 6hp, and Acut3-6hp were produced and purified by immobilized-metal ion affinity chromatography and biochemically characterized using p-nitrophenyl butyrate as the substrate for standard activity tests. All three enzymes from A. adeninivorans were active from pH 4.5 to 6.5 and from 20 to 30 degrees C. They were shown to be unstable under optimal reaction conditions but could be stabilized using organic solvents, such as polyethylene glycol 200 (PEG 200), isopropanol, ethanol, or acetone. PEG 200 (50%, vol/vol) was found to be the best stabilizing agent for all of the cutinases, and acetone greatly increased the half-life and enzyme activity (up to 300% for Acut3-6hp). The substrate spectra for Acut1-6hp, Acut2-6hp, and Acut3-6hp were quite similar, with the highest activity being for short-chain fatty acid esters of p-nitrophenol and glycerol. Additionally, they were found to have polycaprolactone degradation activity and cutinolytic activity against cutin from apple peel. The activity was compared with that of the 6* His-tagged cutinase from Fusarium solani f. sp. pisi (FsCut 6hp), also expressed in A. adeninivorans, as a positive control. A fed-batch cultivation of the best Acut2-6hp-producing strain, A. adeninivorans G1212/YRC102 ACUT2-6H, was performed and showed that very high activities of 1,064 U ml(-1) could be achieved even with a nonoptimized cultivation procedure. PMID- 26048926 TI - Treatment of Alkaline Cr(VI)-Contaminated Leachate with an Alkaliphilic Metal Reducing Bacterium. AB - Chromium in its toxic Cr(VI) valence state is a common contaminant particularly associated with alkaline environments. A well-publicized case of this occurred in Glasgow, United Kingdom, where poorly controlled disposal of a cementitious industrial by-product, chromite ore processing residue (COPR), has resulted in extensive contamination by Cr(VI)-contaminated alkaline leachates. In the search for viable bioremediation treatments for Cr(VI), a variety of bacteria that are capable of reduction of the toxic and highly soluble Cr(VI) to the relatively nontoxic and less mobile Cr(III) oxidation state, predominantly under circumneutral pH conditions, have been isolated. Recently, however, alkaliphilic bacteria that have the potential to reduce Cr(VI) under alkaline conditions have been identified. This study focuses on the application of a metal-reducing bacterium to the remediation of alkaline Cr(VI)-contaminated leachates from COPR. This bacterium, belonging to the Halomonas genus, was found to exhibit growth concomitant to Cr(VI) reduction under alkaline conditions (pH 10). Bacterial cells were able to rapidly remove high concentrations of aqueous Cr(VI) (2.5 mM) under anaerobic conditions, up to a starting pH of 11. Cr(VI) reduction rates were controlled by pH, with slower removal observed at pH 11, compared to pH 10, while no removal was observed at pH 12. The reduction of aqueous Cr(VI) resulted in the precipitation of Cr(III) biominerals, which were characterized using transmission electron microscopy and energy-dispersive X-ray analysis (TEM-EDX) and X-ray photoelectron spectroscopy (XPS). The effectiveness of this haloalkaliphilic bacterium for Cr(VI) reduction at high pH suggests potential for its use as an in situ treatment of COPR and other alkaline Cr(VI)-contaminated environments. PMID- 26048927 TI - Anaerobic Oxidation of Methane Coupled to Nitrite Reduction by Halophilic Marine NC10 Bacteria. AB - Anaerobic oxidation of methane (AOM) coupled to nitrite reduction is a novel AOM process that is mediated by denitrifying methanotrophs. To date, enrichments of these denitrifying methanotrophs have been confined to freshwater systems; however, the recent findings of 16S rRNA and pmoA gene sequences in marine sediments suggest a possible occurrence of AOM coupled to nitrite reduction in marine systems. In this research, a marine denitrifying methanotrophic culture was obtained after 20 months of enrichment. Activity testing and quantitative PCR (qPCR) analysis were then conducted and showed that the methane oxidation activity and the number of NC10 bacteria increased correlatively during the enrichment period. 16S rRNA gene sequencing indicated that only bacteria in group A of the NC10 phylum were enriched and responsible for the resulting methane oxidation activity, although a diverse community of NC10 bacteria was harbored in the inoculum. Fluorescence in situ hybridization showed that NC10 bacteria were dominant in the enrichment culture after 20 months. The effect of salinity on the marine denitrifying methanotrophic culture was investigated, and the apparent optimal salinity was 20.50/00, which suggested that halophilic bacterial AOM coupled to nitrite reduction was obtained. Moreover, the apparent substrate affinity coefficients of the halophilic denitrifying methanotrophs were determined to be 9.8 +/- 2.2 MUM for methane and 8.7 +/- 1.5 MUM for nitrite. PMID- 26048928 TI - Microbial Infections Are Associated with Embryo Mortality in Arctic-Nesting Geese. AB - To address the role of bacterial infection in hatching failure of wild geese, we monitored embryo development in a breeding population of Greater white-fronted geese (Anser albifrons) on the Arctic Coastal Plain of Alaska. During 2013, we observed mortality of normally developing embryos and collected 36 addled eggs for analysis. We also collected 17 infertile eggs for comparison. Using standard culture methods and gene sequencing to identify bacteria within collected eggs, we identified a potentially novel species of Neisseria in 33 eggs, Macrococcus caseolyticus in 6 eggs, and Streptococcus uberis and Rothia nasimurium in 4 eggs each. We detected seven other bacterial species at lower frequencies. Sequences of the 16S rRNA genes from the Neisseria isolates most closely matched sequences from N. animaloris and N. canis (96 to 97% identity), but phylogenetic analysis suggested substantial genetic differentiation between egg isolates and known Neisseria species. Although definitive sources of the bacteria remain unknown, we detected Neisseria DNA from swabs of eggshells, nest contents, and cloacae of nesting females. To assess the pathogenicity of bacteria identified in contents of addled eggs, we inoculated isolates of Neisseria, Macrococcus, Streptococcus, and Rothia at various concentrations into developing chicken eggs. Seven-day mortality rates varied from 70 to 100%, depending on the bacterial species and inoculation dose. Our results suggest that bacterial infections are a source of embryo mortality in wild geese in the Arctic. PMID- 26048929 TI - Prevalence of Antimicrobial Resistance and Transfer of Tetracycline Resistance Genes in Escherichia coli Isolates from Beef Cattle. AB - The aim of this study was to investigate the prevalence and transferability of resistance in tetracycline-resistant Escherichia coli isolates recovered from beef cattle in South Korea. A total of 155 E. coli isolates were collected from feces in South Korea, and 146 were confirmed to be resistant to tetracycline. The tetracycline resistance gene tet(A) (46.5%) was the most prevalent, followed by tet(B) (45.1%) and tet(C) (5.8%). Strains carrying tet(A) plus tet(B) and tet(B) plus tet(C) were detected in two isolates each. In terms of phylogenetic grouping, 101 (65.2%) isolates were classified as phylogenetic group B1, followed in decreasing order by D (17.4%), A (14.2%), and B2 (3.2%). Ninety-one (62.3%) isolates were determined to be multidrug resistant by the disk diffusion method. MIC testing using the principal tetracyclines, namely, tetracycline, chlortetracycline, oxytetracycline, doxycycline, and minocycline, revealed that isolates carrying tet(B) had higher MIC values than isolates carrying tet(A). Conjugation assays showed that 121 (82.9%) isolates could transfer a tetracycline resistance gene to a recipient via the IncFIB replicon (65.1%). This study suggests that the high prevalence of tetracycline-resistant E. coli isolates in beef cattle is due to the transferability of tetracycline resistance genes between E. coli populations which have survived the selective pressure caused by the use of antimicrobial agents. PMID- 26048930 TI - Novel Route for Agmatine Catabolism in Aspergillus niger Involves 4 Guanidinobutyrase. AB - Agmatine, a significant polyamine in bacteria and plants, mostly arises from the decarboxylation of arginine. The functional importance of agmatine in fungi is poorly understood. The metabolism of agmatine and related guanidinium group containing compounds in Aspergillus niger was explored through growth, metabolite, and enzyme studies. The fungus was able to metabolize and grow on l arginine, agmatine, or 4-guanidinobutyrate as the sole nitrogen source. Whereas arginase defined the only route for arginine catabolism, biochemical and bioinformatics approaches suggested the absence of arginine decarboxylase in A. niger. Efficient utilization by the parent strain and also by its arginase knockout implied an arginase-independent catabolic route for agmatine. Urea and 4 guanidinobutyrate were detected in the spent medium during growth on agmatine. The agmatine-grown A. niger mycelia contained significant levels of amine oxidase, 4-guanidinobutyraldehyde dehydrogenase, 4-guanidinobutyrase (GBase), and succinic semialdehyde dehydrogenase, but no agmatinase activity was detected. Taken together, the results support a novel route for agmatine utilization in A. niger. The catabolism of agmatine by way of 4-guanidinobutyrate to 4 aminobutyrate into the Krebs cycle is the first report of such a pathway in any organism. A. niger GBase peptide fragments were identified by tandem mass spectrometry analysis. The corresponding open reading frame from the A. niger NCIM 565 genome was located and cloned. Subsequent expression of GBase in both Escherichia coli and A. niger along with its disruption in A. niger functionally defined the GBase locus (gbu) in the A. niger genome. PMID- 26048931 TI - Facultative Anaerobe Caldibacillus debilis GB1: Characterization and Use in a Designed Aerotolerant, Cellulose-Degrading Coculture with Clostridium thermocellum. AB - Development of a designed coculture that can achieve aerotolerant ethanogenic biofuel production from cellulose can reduce the costs of maintaining anaerobic conditions during industrial consolidated bioprocessing (CBP). To this end, a strain of Caldibacillus debilis isolated from an air-tolerant cellulolytic consortium which included a Clostridium thermocellum strain was characterized and compared with the C. debilis type strain. Characterization of isolate C. debilis GB1 and comparisons with the type strain of C. debilis revealed significant physiological differences, including (i) the absence of anaerobic metabolism in the type strain and (ii) different end product synthesis profiles under the experimental conditions used. The designed cocultures displayed unique responses to oxidative conditions, including an increase in lactate production. We show here that when the two species were cultured together, the noncellulolytic facultative anaerobe C. debilis GB1 provided respiratory protection for C. thermocellum, allowing the synergistic utilization of cellulose even under an aerobic atmosphere. PMID- 26048932 TI - Acromyrmex Leaf-Cutting Ants Have Simple Gut Microbiota with Nitrogen-Fixing Potential. AB - Ants and termites have independently evolved obligate fungus-farming mutualisms, but their gardening procedures are fundamentally different, as the termites predigest their plant substrate whereas the ants deposit it directly on the fungus garden. Fungus-growing termites retained diverse gut microbiota, but bacterial gut communities in fungus-growing leaf-cutting ants have not been investigated, so it is unknown whether and how they are specialized on an exclusively fungal diet. Here we characterized the gut bacterial community of Panamanian Acromyrmex species, which are dominated by only four bacterial taxa: Wolbachia, Rhizobiales, and two Entomoplasmatales taxa. We show that the Entomoplasmatales can be both intracellular and extracellular across different gut tissues, Wolbachia is mainly but not exclusively intracellular, and the Rhizobiales species is strictly extracellular and confined to the gut lumen, where it forms biofilms along the hindgut cuticle supported by an adhesive matrix of polysaccharides. Tetracycline diets eliminated the Entomoplasmatales symbionts but hardly affected Wolbachia and only moderately reduced the Rhizobiales, suggesting that the latter are protected by the biofilm matrix. We show that the Rhizobiales symbiont produces bacterial NifH proteins that have been associated with the fixation of nitrogen, suggesting that these compartmentalized hindgut symbionts alleviate nutritional constraints emanating from an exclusive fungus garden diet reared on a substrate of leaves. PMID- 26048934 TI - Survival and Competitiveness of Bradyrhizobium japonicum Strains 20 Years after Introduction into Field Locations in Poland. AB - It was previously demonstrated that there are no indigenous strains of Bradyrhizobium japonicum forming nitrogen-fixing root nodule symbioses with soybean plants in arable field soils in Poland. However, bacteria currently classified within this species are present (together with Bradyrhizobium canariense) as indigenous populations of strains specific for nodulation of legumes in the Genisteae tribe. These rhizobia, infecting legumes such as lupins, are well established in Polish soils. The studies described here were based on soybean nodulation field experiments, established at the Poznan University of Life Sciences Experiment Station in Gorzyn, Poland, and initiated in the spring of 1994. Long-term research was then conducted in order to study the relation between B. japonicum USDA 110 and USDA 123, introduced together into the same location, where no soybean rhizobia were earlier detected, and nodulation and competitive success were followed over time. Here we report the extra-long-term saprophytic survival of B. japonicum strains nodulating soybeans that were introduced as inoculants 20 years earlier and where soybeans were not grown for the next 17 years. The strains remained viable and symbiotically competent, and molecular and immunochemical methods showed that the strains were undistinguishable from the original inoculum strains USDA 110 and USDA 123. We also show that the strains had balanced numbers and their mobility in soil was low. To our knowledge, this is the first report showing the extra-long-term persistence of soybean-nodulating strains introduced into Polish soils and the first analyzing the long-term competitive relations of USDA 110 and USDA 123 after the two strains, neither of which was native, were introduced into the environment almost 2 decades ago. PMID- 26048933 TI - Physiological and Transcriptional Responses of Different Industrial Microbes at Near-Zero Specific Growth Rates. AB - The current knowledge of the physiology and gene expression of industrially relevant microorganisms is largely based on laboratory studies under conditions of rapid growth and high metabolic activity. However, in natural ecosystems and industrial processes, microbes frequently encounter severe calorie restriction. As a consequence, microbial growth rates in such settings can be extremely slow and even approach zero. Furthermore, uncoupling microbial growth from product formation, while cellular integrity and activity are maintained, offers perspectives that are economically highly interesting. Retentostat cultures have been employed to investigate microbial physiology at (near-)zero growth rates. This minireview compares information from recent physiological and gene expression studies on retentostat cultures of the industrially relevant microorganisms Lactobacillus plantarum, Lactococcus lactis, Bacillus subtilis, Saccharomyces cerevisiae, and Aspergillus niger. Shared responses of these organisms to (near-)zero growth rates include increased stress tolerance and a downregulation of genes involved in protein synthesis. Other adaptations, such as changes in morphology and (secondary) metabolite production, were species specific. This comparison underlines the industrial and scientific significance of further research on microbial (near-)zero growth physiology. PMID- 26048935 TI - Screening of Chlamydomonas reinhardtii Populations with Single-Cell Resolution by Using a High-Throughput Microscale Sample Preparation for Matrix-Assisted Laser Desorption Ionization Mass Spectrometry. AB - The consequences of cellular heterogeneity, such as biocide persistence, can only be tackled by studying each individual in a cell population. Fluorescent tags provide tools for the high-throughput analysis of genomes, RNA transcripts, or proteins on the single-cell level. However, the analysis of lower-molecular weight compounds that elude tagging is still a great challenge. Here, we describe a novel high-throughput microscale sample preparation technique for single cells that allows a mass spectrum to be obtained for each individual cell within a microbial population. The approach presented includes spotting Chlamydomonas reinhardtii cells, using a noncontact microarrayer, onto a specialized slide and controlled lysis of cells separated on the slide. Throughout the sample preparation, analytes were traced and individual steps optimized using autofluorescence detection of chlorophyll. The lysates of isolated cells are subjected to a direct, label-free analysis using matrix-assisted laser desorption ionization mass spectrometry. Thus, we were able to differentiate individual cells of two Chlamydomonas reinhardtii strains based on single-cell mass spectra. Furthermore, we showed that only population profiles with real single-cell resolution render a nondistorted picture of the phenotypes contained in a population. PMID- 26048936 TI - Identification of a Chemoreceptor for C2 and C3 Carboxylic Acids. AB - Chemoreceptors are at the beginnings of chemosensory signaling cascades that mediate chemotaxis. Most bacterial chemoreceptors are functionally unannotated and are characterized by a diversity in the structure of their ligand binding domains (LBDs). The data available indicate that there are two major chemoreceptor families at the functional level, namely, those that respond to amino acids or to Krebs cycle intermediates. Since pseudomonads show chemotaxis to many different compounds and possess different types of chemoreceptors, they are model organisms to establish relationships between chemoreceptor structure and function. Here, we identify PP2861 (termed McpP) of Pseudomonas putida KT2440 as a chemoreceptor with a novel ligand profile. We show that the recombinant McpP LBD recognizes acetate, pyruvate, propionate, and l-lactate, with KD (equilibrium dissociation constant) values ranging from 34 to 107 MUM. Deletion of the mcpP gene resulted in a dramatic reduction in chemotaxis toward these ligands, and complementation restored a native-like phenotype, indicating that McpP is the major chemoreceptor for these compounds. McpP has a CACHE-type LBD, and we present data indicating that CACHE-containing chemoreceptors of other species also mediate taxis to C2 and C3 carboxylic acids. In addition, the LBD of NbaY of Pseudomonas fluorescens, an McpP homologue mediating chemotaxis to 2 nitrobenzoate, bound neither nitrobenzoates nor the McpP ligands. This work provides further insight into receptor structure-function relationships and will be helpful to annotate chemoreceptors of other bacteria. PMID- 26048937 TI - Correlation of Lactobacillus rhamnosus Genotypes and Carbohydrate Utilization Signatures Determined by Phenotype Profiling. AB - Lactobacillus rhamnosus is a bacterial species commonly colonizing the gastrointestinal (GI) tract of humans and also frequently used in food products. While some strains have been studied extensively, physiological variability among isolates of the species found in healthy humans or their diet is largely unexplored. The aim of this study was to characterize the diversity of carbohydrate utilization capabilities of human isolates and food-derived strains of L. rhamnosus in relation to their niche of isolation and genotype. We investigated the genotypic and phenotypic diversity of 25 out of 65 L. rhamnosus strains from various niches, mainly human feces and fermented dairy products. Genetic fingerprinting of the strains by amplified fragment length polymorphism (AFLP) identified 11 distinct subgroups at 70% similarity and suggested niche enrichment within particular genetic clades. High-resolution carbohydrate utilization profiling (OmniLog) identified 14 carbon sources that could be used by all of the strains tested for growth, while the utilization of 58 carbon sources differed significantly between strains, enabling the stratification of L. rhamnosus strains into three metabolic clusters that partially correlate with the genotypic clades but appear uncorrelated with the strain's origin of isolation. Draft genome sequences of 8 strains were generated and employed in a gene-trait matching (GTM) analysis together with the publicly available genomes of L. rhamnosus GG (ATCC 53103) and HN001 for several carbohydrates that were distinct for the different metabolic clusters: l-rhamnose, cellobiose, l-sorbose, and alpha-methyl-d-glucoside. From the analysis, candidate genes were identified that correlate with l-sorbose and alpha-methyl-d-glucoside utilization, and the proposed function of these genes could be confirmed by heterologous expression in a strain lacking the genes. This study expands our insight into the phenotypic and genotypic diversity of the species L. rhamnosus and explores the relationships between specific carbohydrate utilization capacities and genotype and/or niche adaptation of this species. PMID- 26048938 TI - Ecology, Virulence, and Phylogeny of Blastulidium paedophthorum, a Widespread Brood Parasite of Daphnia spp. AB - Parasitism is now recognized as a major factor impacting the ecology and evolution of plankton, including Daphnia. Parasites that attack the developing embryos of daphniids, known as brood parasites, were first described in the early 1900s but have received relatively little study. Here, we link previous morphological descriptions of the oomycete brood parasite Blastulidium paedophthorum with information on its phylogenetic placement, ecology, and virulence. Based on the morphology and phylogenetic relationship with other members of the Leptomitales, we show that a brood parasite observed in daphniids in the Midwestern United States is B. paedophthorum. We used morphology, DNA sequences, and laboratory infection experiments to show that B. paedophthorum is a multihost parasite that can be transmitted between species and genera. A field survey of six hosts in 15 lakes revealed that B. paedophthorum is common in all six host taxa (present on 38.3% of our host species-lake-sampling date combinations; the maximum infection prevalences were 8.7% of the population and 20% of the asexual adult female population). Although B. paedophthorum was observed in all 15 lakes, presence and infection prevalence varied among lakes. Infection with B. paedophthorum did not reduce host life span but significantly impacted host fecundity. Theory predicts that parasites that affect host fecundity without affecting host life span should have the strongest impact on host population dynamics. Based on its virulence and commonness in natural populations and on the central role of daphniids in freshwater food webs, we predict that B. paedophthorum will influence daphniid ecology and evolution, as well as the larger food web. PMID- 26048939 TI - Implications of Genome-Based Discrimination between Clostridium botulinum Group I and Clostridium sporogenes Strains for Bacterial Taxonomy. AB - Taxonomic classification of Clostridium botulinum is based on the production of botulinum neurotoxin (BoNT), while closely related, nontoxic organisms are classified as Clostridium sporogenes. However, this taxonomic organization does not accurately mirror phylogenetic relationships between these species. A phylogenetic reconstruction using 2,016 orthologous genes shared among strains of C. botulinum group I and C. sporogenes clearly separated these two species into discrete clades which showed ~93% average nucleotide identity (ANI) between them. Clustering of strains based on the presence of variable orthologs revealed 143 C. sporogenes clade-specific genetic signatures, a subset of which were further evaluated for their ability to correctly classify a panel of presumptive C. sporogenes strains by PCR. Genome sequencing of several C. sporogenes strains lacking these signatures confirmed that they clustered with C. botulinum strains in a core genome phylogenetic tree. Our analysis also identified C. botulinum strains that contained C. sporogenes clade-specific signatures and phylogenetically clustered with C. sporogenes strains. The genome sequences of two bont/B2-containing strains belonging to the C. sporogenes clade contained regions with similarity to a bont-bearing plasmid (pCLD), while two different strains belonging to the C. botulinum clade carried bont/B2 on the chromosome. These results indicate that bont/B2 was likely acquired by C. sporogenes strains through horizontal gene transfer. The genome-based classification of these species used to identify candidate genes for the development of rapid assays for molecular identification may be applicable to additional bacterial species that are challenging with respect to their classification. PMID- 26048940 TI - Enhanced Alcaligenes faecalis Denitrification Rate with Electrodes as the Electron Donor. AB - The utilization by Alcaligenes faecalis of electrodes as the electron donor for denitrification was investigated in this study. The denitrification rate of A. faecalis with a poised potential was greatly enhanced compared with that of the controls without poised potentials. For nitrate reduction, although A. faecalis could not reduce nitrate, at three poised potentials of +0.06, -0.06, and -0.15 V (versus normal hydrogen electrode [NHE]), the nitrate was partially reduced with 0.15- and -0.06-V potentials at rates of 17.3 and 28.5 mg/liter/day, respectively. The percentages of reduction for -0.15 and -0.06 V were 52.4 and 30.4%, respectively. Meanwhile, for nitrite reduction, the poised potentials greatly enhanced the nitrite reduction. The nitrite reduction rates for three poised potentials (-0.06, -0.15, and -0.30 V) were 1.98, 4.37, and 3.91 mg/liter/h, respectively. When the potentials were cut off, the nitrite reduction rate was maintained for 1.5 h (from 2.3 to 2.25 mg/liter/h) and then greatly decreased, and the reduction rate (0.38 mg/liter/h) was about 1/6 compared with the rate (2.3 mg/liter/h) when potential was on. Then the potentials resumed, but the reduction rate did not resume and was only 2 times higher than the rate when the potential was off. PMID- 26048941 TI - Paenibacillus larvae-Directed Bacteriophage HB10c2 and Its Application in American Foulbrood-Affected Honey Bee Larvae. AB - Paenibacillus larvae is the causative agent of American foulbrood (AFB), the most serious honey bee brood bacterial disease. We isolated and characterized P. larvae-directed bacteriophages and developed criteria for safe phage therapy. Whole-genome analysis of a highly lytic virus of the family Siphoviridae (HB10c2) provided a detailed safety profile and uncovered its lysogenic nature and a putative beta-lactamase-like protein. To rate its antagonistic activity against the pathogens targeted and to specify potentially harmful effects on the bee population and the environment, P. larvae genotypes ERIC I to IV, representatives of the bee gut microbiota, and a broad panel of members of the order Bacillales were analyzed for phage HB10c2-induced lysis. Breeding assays with infected bee larvae revealed that the in vitro phage activity observed was not predictive of the real-life scenario and therapeutic efficacy. On the basis of the disclosed P. larvae-bacteriophage coevolution, we discuss the future prospects of AFB phage therapy. PMID- 26048942 TI - Genotyping and Source Tracking of Cronobacter sakazakii and C. malonaticus Isolates from Powdered Infant Formula and an Infant Formula Production Factory in China. AB - Cronobacter spp. (formerly defined as Enterobacter sakazakii) are opportunistic bacterial pathogens of both infants and adults. In this study, we analyzed 70 Cronobacter isolates from powdered infant formula (PIF) and an infant formula production facility in China to determine possible contamination routes. The strains were profiled by multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE), PCR-based O-antigen serotyping, and ompA and rpoB sequence analyses. The isolates were primarily Cronobacter sakazakii (66/70) or Cronobacter malonaticus (4/70). The strains were divided into 38 pulsotypes (PTs) using PFGE and 19 sequence types (STs) by MLST. In contrast, rpoB and ompA sequence analyses divided the strains into 10 overlapping clusters each. PCR serotyping of the 66 C. sakazakii and 4 C. malonaticus strains resulted in the identification of four C. sakazakii serotypes (O1, O2, O4, and O7) and a single C. malonaticus serotype, O2. The dominant C. sakazakii sequence types from PIF and an infant formula production factory in China were C. sakazakii clonal complex 4 (CC4) (n = 19), ST1 (n = 14), and ST64 (n = 11). C. sakazakii CC4 is a clonal lineage strongly associated with neonatal meningitis. In the process of manufacturing PIF, the spray-drying, fluidized-bed-drying, and packing areas were the main areas with Cronobacter contamination. C. sakazakii strains with the same pulsotypes (PT3 and PT2) and sequence types (ST1 and ST64) were isolated both from processing equipment and from the PIF finished product. PMID- 26048943 TI - Extracellular Glycoside Hydrolase Activities in the Human Oral Cavity. AB - Carbohydrate availability shifts when bacteria attach to a surface and form biofilm. When salivary planktonic bacteria form an oral biofilm, a variety of polysaccharides and glycoproteins are the primary carbon sources; however, simple sugar availabilities are limited due to low diffusion from saliva to biofilm. We hypothesized that bacterial glycoside hydrolase (GH) activities would be higher in a biofilm than in saliva in order to maintain metabolism in a low-sugar, high glycoprotein environment. Salivary bacteria from 13 healthy individuals were used to grow in vitro biofilm using two separate media, one with sucrose and the other limiting carbon sources to a complex carbohydrate. All six GHs measured were higher in vitro when grown in the medium with complex carbohydrate as the sole carbon source. We then collected saliva and overnight dental plaque samples from the same individuals and measured ex vivo activities for the same six enzymes to determine how oral microbial utilization of glycoconjugates shifts between the planktonic phase in saliva and the biofilm phase in overnight dental plaque. Overall higher GH activities were observed in plaque samples, in agreement with in vitro observation. A similar pattern was observed in GH activity profiles between in vitro and ex vivo data. 16S rRNA gene analysis showed that plaque samples had a higher abundance of microorganisms with larger number of GH gene sequences. These results suggest differences in sugar catabolism between the oral bacteria located in the biofilm and those in saliva. PMID- 26048946 TI - pSW2, a Novel Low-Temperature-Inducible Gene Expression Vector Based on a Filamentous Phage of the Deep-Sea Bacterium Shewanella piezotolerans WP3. AB - A low-temperature-inducible protein expression vector (pSW2) based on a filamentous phage (SW1) of the deep-sea bacterium Shewanella piezotolerans WP3 was constructed. This vector replicated stably in Escherichia coli and Shewanella species, and its copy number increased at low temperatures. The pSW2 vector can be utilized as a complementation plasmid in WP3, and it can also be used for the production of complex cytochromes with multiple heme groups, which has the potential for application for metal ion recovery or bioremediation. Promoters of low-temperature-inducible genes in WP3 were fused into the vector to construct a series of vectors for enhancing protein expression at low temperature. The maximum green fluorescent protein intensity was obtained when the promoter for the hfq gene was used. The WP3/pSW2 system can efficiently produce a patatin-like protein (PLP) from a metagenomic library that tends to form inclusion bodies in E. coli. The yields of PLP in the soluble fraction were 8.3 mg/liter and 4.7 mg/liter of culture at 4 degrees C and 20 degrees C, respectively. Moreover, the pSW2 vector can be broadly utilized in other Shewanella species, such as S. oneidensis and S. psychrophila. PMID- 26048945 TI - Physiology, Genomics, and Pathway Engineering of an Ethanol-Tolerant Strain of Clostridium phytofermentans. AB - Novel processing strategies for hydrolysis and fermentation of lignocellulosic biomass in a single reactor offer large potential cost savings for production of biocommodities and biofuels. One critical challenge is retaining high enzyme production in the presence of elevated product titers. Toward this goal, the cellulolytic, ethanol-producing bacterium Clostridium phytofermentans was adapted to increased ethanol concentrations. The resulting ethanol-tolerant (ET) strain has nearly doubled ethanol tolerance relative to the wild-type level but also reduced ethanol yield and growth at low ethanol concentrations. The genome of the ET strain has coding changes in proteins involved in membrane biosynthesis, the Rnf complex, cation homeostasis, gene regulation, and ethanol production. In particular, purification of the mutant bifunctional acetaldehyde coenzyme A (CoA)/alcohol dehydrogenase showed that a G609D variant abolished its activities, including ethanol formation. Heterologous expression of Zymomonas mobilis pyruvate decarboxylase and alcohol dehydrogenase in the ET strain increased cellulose consumption and restored ethanol production, demonstrating how metabolic engineering can be used to overcome disadvantageous mutations incurred during adaptation to ethanol. We discuss how genetic changes in the ET strain reveal novel potential strategies for improving microbial solvent tolerance. PMID- 26048947 TI - The Effect of Creatine Kinase Inhibition on Contractile Properties of Human Resistance Arteries. AB - BACKGROUND: Creatine kinase (CK) is a main predictor of blood pressure, and this is thought to largely depend on high resistance artery contractility. We previously reported an association between vascular contractility and CK in normotensive pregnancy, but pregnancy is a strong CK inducer, and data on human hypertension are lacking. Therefore, we further explored CK-dependency of vascular contractility outside the context of pregnancy in normotensive and hypertensive women. METHODS AND RESULTS: Nineteen consecutive women, mean age 42 years (SE 1.3), mean systolic/diastolic blood pressure respectively 142.6 (SE 5.9)/85.6 (3.4) mm Hg (9 hypertensive), donated an omental fat sample during abdominal surgery. We compared vasodilation after the specific CK inhibitor 2,4 dinitro-1-fluorobenzene (DNFB; 10(-6) mol/l) to sodium nitroprusside (10(-6) mol/l) in isolated resistance arteries using a wire myograph. Additionally, we assessed predictors of vasoconstrictive force. DNFB reduced vascular contractility to 24.3% (SE 4.4), P < 0.001, compared to baseline. Sodium nitroprusside reduced contractility to 89.8% (SE 2.3). Maximum contractile force correlated with DNFB effect as a measure of CK (r = 0.8), and with vessel diameter (r = 0.7). The increase in contractile force was 16.5 mN [9.1-23.9] per unit DNFB effect in univariable and 10.35 mN [2.10-18.60] in multivariable regression analysis. CONCLUSION: This study extends on our previous findings in pregnant normotensive women of CK-dependent microvascular contractility, indicating that CK contributes significantly to resistance artery contractility across human normotension and primary hypertension outside the context of pregnancy. Further studies should explore the effect of CK inhibitors on clinical blood pressure. PMID- 26048950 TI - Corrigendum. Results of anterior facial nerve rerouting procedures for removing skull base tumors. PMID- 26048944 TI - Phylogenetic and Variable-Number Tandem-Repeat Analyses Identify Nonpathogenic Xanthomonas arboricola Lineages Lacking the Canonical Type III Secretion System. AB - Xanthomonas arboricola is conventionally known as a taxon of plant-pathogenic bacteria that includes seven pathovars. This study showed that X. arboricola also encompasses nonpathogenic bacteria that cause no apparent disease symptoms on their hosts. The aim of this study was to assess the X. arboricola population structure associated with walnut, including nonpathogenic strains, in order to gain a better understanding of the role of nonpathogenic xanthomonads in walnut microbiota. A multilocus sequence analysis (MLSA) was performed on a collection of 100 X. arboricola strains, including 27 nonpathogenic strains isolated from walnut. Nonpathogenic strains grouped outside clusters defined by pathovars and formed separate genetic lineages. A multilocus variable-number tandem-repeat analysis (MLVA) conducted on a collection of X. arboricola strains isolated from walnut showed that nonpathogenic strains clustered separately from clonal complexes containing Xanthomonas arboricola pv. juglandis strains. Some nonpathogenic strains of X. arboricola did not contain the canonical type III secretion system (T3SS) and harbored only one to three type III effector (T3E) genes. In the nonpathogenic strains CFBP 7640 and CFBP 7653, neither T3SS genes nor any of the analyzed T3E genes were detected. This finding raises a question about the origin of nonpathogenic strains and the evolution of plant pathogenicity in X. arboricola. T3E genes that were not detected in any nonpathogenic isolates studied represent excellent candidates to be those responsible for pathogenicity in X. arboricola. PMID- 26048951 TI - A Diffusion MRI Tractography Connectome of the Mouse Brain and Comparison with Neuronal Tracer Data. AB - Interest in structural brain connectivity has grown with the understanding that abnormal neural connections may play a role in neurologic and psychiatric diseases. Small animal connectivity mapping techniques are particularly important for identifying aberrant connectivity in disease models. Diffusion magnetic resonance imaging tractography can provide nondestructive, 3D, brain-wide connectivity maps, but has historically been limited by low spatial resolution, low signal-to-noise ratio, and the difficulty in estimating multiple fiber orientations within a single image voxel. Small animal diffusion tractography can be substantially improved through the combination of ex vivo MRI with exogenous contrast agents, advanced diffusion acquisition and reconstruction techniques, and probabilistic fiber tracking. Here, we present a comprehensive, probabilistic tractography connectome of the mouse brain at microscopic resolution, and a comparison of these data with a neuronal tracer-based connectivity data from the Allen Brain Atlas. This work serves as a reference database for future tractography studies in the mouse brain, and demonstrates the fundamental differences between tractography and neuronal tracer data. PMID- 26048952 TI - Brain Mechanisms for Processing Affective (and Nonaffective) Touch Are Atypical in Autism. AB - C-tactile (CT) afferents encode caress-like touch that supports social-emotional development, and stimulation of the CT system engages the insula and cortical circuitry involved in social-emotional processing. Very few neuroimaging studies have investigated the neural mechanisms of touch processing in people with autism spectrum disorder (ASD), who often exhibit atypical responses to touch. Using functional magnetic resonance imaging, we evaluated the hypothesis that children and adolescents with ASD would exhibit atypical brain responses to CT-targeted touch. Children and adolescents with ASD, relative to typically developing (TD) participants, exhibited reduced activity in response to CT-targeted (arm) versus non-CT-targeted (palm) touch in a network of brain regions known to be involved in social-emotional information processing including bilateral insula and insular operculum, the right posterior superior temporal sulcus, bilateral temporoparietal junction extending into the inferior parietal lobule, right fusiform gyrus, right amygdala, and bilateral ventrolateral prefrontal cortex including the inferior frontal and precentral gyri, suggesting atypical social brain hypoactivation. Individuals with ASD (vs. TD) showed an enhanced response to non-CT-targeted versus CT-targeted touch in the primary somatosensory cortex, suggesting atypical sensory cortical hyper-reactivity. PMID- 26048953 TI - Evidence for a Specific Integrative Mechanism for Episodic Memory Mediated by AMPA/kainate Receptors in a Circuit Involving Medial Prefrontal Cortex and Hippocampal CA3 Region. AB - We asked whether episodic-like memory requires neural mechanisms independent of those that mediate its component memories for "what," "when," and "where," and if neuronal connectivity between the medial prefrontal cortex (mPFC) and the hippocampus (HPC) CA3 subregion is essential for episodic-like memory. Unilateral lesion of the mPFC was combined with unilateral lesion of the CA3 in the ipsi- or contralateral hemispheres in rats. Episodic-like memory was tested using a task, which assesses the integration of memories for "what, where, and when" concomitantly. Tests for novel object recognition (what), object place (where), and temporal order memory (when) were also applied. Bilateral disconnection of the mPFC-CA3 circuit by N-methyl-d-aspartate (NMDA) lesions disrupted episodic like memory, but left the component memories for object, place, and temporal order, per se, intact. Furthermore, unilateral NMDA lesion of the CA3 plus injection of (6-cyano-7-nitroquinoxaline-2,3-dione) (CNQX) (AMPA/kainate receptor antagonist), but not AP-5 (NMDA receptor antagonist), into the contralateral mPFC also disrupted episodic-like memory, indicating the mPFC AMPA/kainate receptors as critical for this circuit. These results argue for a selective neural system that specifically subserves episodic memory, as it is not critically involved in the control of its component memories for object, place, and time. PMID- 26048954 TI - Functional Organization of Social Perception and Cognition in the Superior Temporal Sulcus. AB - The superior temporal sulcus (STS) is considered a hub for social perception and cognition, including the perception of faces and human motion, as well as understanding others' actions, mental states, and language. However, the functional organization of the STS remains debated: Is this broad region composed of multiple functionally distinct modules, each specialized for a different process, or are STS subregions multifunctional, contributing to multiple processes? Is the STS spatially organized, and if so, what are the dominant features of this organization? We address these questions by measuring STS responses to a range of social and linguistic stimuli in the same set of human participants, using fMRI. We find a number of STS subregions that respond selectively to certain types of social input, organized along a posterior-to anterior axis. We also identify regions of overlapping response to multiple contrasts, including regions responsive to both language and theory of mind, faces and voices, and faces and biological motion. Thus, the human STS contains both relatively domain-specific areas, and regions that respond to multiple types of social information. PMID- 26048955 TI - Deprivation and Recovery of Sleep in Succession Enhances Reflexive Motor Behavior. AB - Sleep deprivation impairs inhibitory control over reflexive behavior, and this impairment is commonly assumed to dissipate after recovery sleep. Contrary to this belief, here we show that fast reflexive behaviors, when practiced during sleep deprivation, is consolidated across recovery sleep and, thereby, becomes preserved. As a model for the study of sleep effects on prefrontal cortex mediated inhibitory control in humans, we examined reflexive saccadic eye movements (express saccades), as well as speeded 2-choice finger motor responses. Different groups of subjects were trained on a standard prosaccade gap paradigm before periods of nocturnal sleep and sleep deprivation. Saccade performance was retested in the next morning and again 24 h later. The rate of express saccades was not affected by sleep after training, but slightly increased after sleep deprivation. Surprisingly, this increase augmented even further after recovery sleep and was still present 4 weeks later. Additional experiments revealed that the short testing after sleep deprivation was sufficient to increase express saccades across recovery sleep. An increase in speeded responses across recovery sleep was likewise found for finger motor responses. Our findings indicate that recovery sleep can consolidate motor disinhibition for behaviors practiced during prior sleep deprivation, thereby persistently enhancing response automatization. PMID- 26048956 TI - Purely Translational Realignment in Grid Cell Firing Patterns Following Nonmetric Context Change. AB - Grid cells in entorhinal and parahippocampal cortices contribute to a network, centered on the hippocampal place cell system, that constructs a representation of spatial context for use in navigation and memory. In doing so, they use metric cues such as the distance and direction of nearby boundaries to position and orient their firing field arrays (grids). The present study investigated whether they also use purely nonmetric "context" information such as color and odor of the environment. We found that, indeed, purely nonmetric cues--sufficiently salient to cause changes in place cell firing patterns--can regulate grid positioning; they do so independently of orientation, and thus interact with linear but not directional spatial inputs. Grid cells responded homogeneously to context changes. We suggest that the grid and place cell networks receive context information directly and also from each other; the information is used by place cells to compute the final decision of the spatial system about which context the animal is in, and by grid cells to help inform the system about where the animal is within it. PMID- 26048958 TI - Biphasic Effects of Ingenol 3,20-Dibenzoate on the Erythropoietin Receptor: Synergism at Low Doses and Antagonism at High Doses. AB - Although ingenol 3,20-dibenzoate (IDB) is known as a selective novel protein kinase C (PKC) agonist, its biologic actions and underlying mechanisms remain incompletely understood. In this study, we identified IDB as a proliferative agent for an erythropoietin (EPO)-dependent cell line, UT-7/EPO, through the screening of a natural compound library. To clarify the underlying mechanism of IDB's EPO-like activities, we thoroughly analyzed the mutual relation between EPO and IDB in terms of in vitro and in vivo activities, signaling molecules, and a cellular receptor. IDB substantially induced the proliferation of UT-7/EPO cells, but not as much as EPO. IDB also lessened the anemia induced by 5-fluorouracil in an in vivo mouse model. Interestingly, IDB showed a synergistic effect on EPO at low concentration, but an antagonistic effect at higher concentration. Physical interaction and activation of PKCs by IDB- and EPO-competitive binding of IDB to EPO receptor (EPOR) explain these synergistic and antagonistic activities, respectively. Importantly, we addressed IDB's mechanism of action by demonstrating the direct binding of IDB to PKCs, and by identifying EPOR as a novel molecular target of IDB. Based on these dual targeting properties, IDB holds promise as a new small molecule modulator of EPO-related pathologic conditions. PMID- 26048959 TI - The RAD52-like protein ODB1 is required for the efficient excision of two mitochondrial introns spliced via first-step hydrolysis. AB - Transcript splicing in plant mitochondria involves numerous nucleus-encoded factors, most of which are of eukaryotic origin. Some of these belong to protein families initially characterised to perform unrelated functions. The RAD52-like ODB1 protein has been reported to have roles in homologous recombination dependent DNA repair in the nuclear and mitochondrial compartments in Arabidopsis thaliana. We show that it is additionally involved in splicing and facilitates the excision of two cis-spliced group II introns, nad1 intron 2 and nad2 intron 1, in Arabidopsis mitochondria. odb1 mutants lacking detectable amounts of ODB1 protein over-accumulated incompletely spliced nad1 and nad2 transcripts. The two ODB1-dependent introns were both found to splice via first-step hydrolysis and to be released as linear or circular molecules instead of lariats. Our systematic analysis of the structures of excised introns in Arabidopsis mitochondria revealed several other hydrolytically spliced group II introns in addition to nad1 intron 2 and nad2 intron 1, indicating that ODB1 is not a general determinant of the hydrolytic splicing pathway. PMID- 26048960 TI - R3D-2-MSA: the RNA 3D structure-to-multiple sequence alignment server. AB - The RNA 3D Structure-to-Multiple Sequence Alignment Server (R3D-2-MSA) is a new web service that seamlessly links RNA three-dimensional (3D) structures to high quality RNA multiple sequence alignments (MSAs) from diverse biological sources. In this first release, R3D-2-MSA provides manual and programmatic access to curated, representative ribosomal RNA sequence alignments from bacterial, archaeal, eukaryal and organellar ribosomes, using nucleotide numbers from representative atomic-resolution 3D structures. A web-based front end is available for manual entry and an Application Program Interface for programmatic access. Users can specify up to five ranges of nucleotides and 50 nucleotide positions per range. The R3D-2-MSA server maps these ranges to the appropriate columns of the corresponding MSA and returns the contents of the columns, either for display in a web browser or in JSON format for subsequent programmatic use. The browser output page provides a 3D interactive display of the query, a full list of sequence variants with taxonomic information and a statistical summary of distinct sequence variants found. The output can be filtered and sorted in the browser. Previous user queries can be viewed at any time by resubmitting the output URL, which encodes the search and re-generates the results. The service is freely available with no login requirement at http://rna.bgsu.edu/r3d-2-msa. PMID- 26048961 TI - Treatment of Disseminated Leishmaniasis With Liposomal Amphotericin B. AB - BACKGROUND: Disseminated leishmaniasis (DL) is a severe and emerging form of American tegumentary leishmaniasis, associated primarily with infection by Leishmania brasiliensis. DL is defined by the presence of >=10 mixed-type lesions such as inflammatory papules and ulcers, located in >=2 body parts. Most patients have hundreds of lesions all over the body, and mucosal involvement is detected in up to 44% of cases. DL is a difficult to cure disease and pentavalent antimony (Sb(v)) is used as standard treatment, its highest dosage being 20 mg/kg/day, for 30 days. However, less than 25% of DL cases will be cured after standard therapy, and the majority of cases will require more than one course of Sb(v) for a cure. In this context, new therapies are needed that offer a higher cure rate and a better safety profile, with convenience in drug administration. METHODS: We have evaluated liposomal amphotericin B in 20 patients with DL in an open clinical trial. The total dose ranged from 17 to 37 mg/kg, used in 7 to 14 days of treatment. RESULTS: Cure rate at 3 months after therapy was 70%. One relapse was documented 4 months after treatment, producing a final cure rate of 65%. Although liposomal amphotericin B was considered well tolerated, mild adverse events were documented in 75% of the patients. CONCLUSIONS: Liposomal amphotericin B is an effective therapy for DL, with a higher final cure rate of 75% observed when used in a total dose above 30 mg/kg. CLINICAL TRIALS REGISTRATION: NCT02025491. PMID- 26048963 TI - AMIA--Setting the Standard. PMID- 26048962 TI - A journal's role in resource sharing and reproducibility. PMID- 26048964 TI - J. Donald Capra, M.D. (1937-2015). PMID- 26048965 TI - Nouvelle cuisine: platelets served with inflammation. AB - Platelets are small cellular fragments with the primary physiological role of maintaining hemostasis. In addition to this well-described classical function, it is becoming increasingly clear that platelets have an intimate connection with infection and inflammation. This stems from several platelet characteristics, including their ability to bind infectious agents and secrete many immunomodulatory cytokines and chemokines, as well as their expression of receptors for various immune effector and regulatory functions, such as TLRs, which allow them to sense pathogen-associated molecular patterns. Furthermore, platelets contain RNA that can be nascently translated under different environmental stresses, and they are able to release membrane microparticles that can transport inflammatory cargo to inflammatory cells. Interestingly, acute infections can also result in platelet breakdown and thrombocytopenia. This report highlights these relatively new aspects of platelets and, thus, their nonhemostatic nature in an inflammatory setting. PMID- 26048967 TI - Retraction: Pregnancy-associated exosomes and their modulation of T cell signaling. PMID- 26048966 TI - Intestinal fucose as a mediator of host-microbe symbiosis. AB - Fucose is an L-configuration sugar found abundantly in the mammalian gut. It has long been known to be induced there by the presence of bacteria, but only recently have some of the molecular mechanisms behind this process been uncovered. New work suggests that fucose can have a protective role in both gut centered and systemic infection and inflammation. This review highlights recent studies showing that, in addition to acting as a food source for beneficial gut symbionts, host fucose can suppress the virulence of pathogens and pathobionts. The relevance of gut fucosylation to human diseases also is discussed. PMID- 26048968 TI - Correction: Repression of Ccr9 transcription in mouse T lymphocyte progenitors by the notch signaling pathway. PMID- 26048969 TI - Correction: Viral MHC class I-like molecule allows evasion of NK cell effector responses in vivo. PMID- 26048970 TI - Correction: Extracellular vesicles derived from gram-negative bacteria, such as Escherichia coli, induce emphysema mainly via IL-17A-mediated neutrophilic inflammation. PMID- 26048971 TI - Parallel Epidemics of Community-Associated Methicillin-Resistant Staphylococcus aureus USA300 Infection in North and South America. AB - BACKGROUND: The community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) epidemic in the United States is attributed to the spread of the USA300 clone. An epidemic of CA-MRSA closely related to USA300 has occurred in northern South America (USA300 Latin-American variant, USA300-LV). Using phylogenomic analysis, we aimed to understand the relationships between these 2 epidemics. METHODS: We sequenced the genomes of 51 MRSA clinical isolates collected between 1999 and 2012 from the United States, Colombia, Venezuela, and Ecuador. Phylogenetic analysis was used to infer the relationships and times since the divergence of the major clades. RESULTS: Phylogenetic analyses revealed 2 dominant clades that segregated by geographical region, had a putative common ancestor in 1975, and originated in 1989, in North America, and in 1985, in South America. Emergence of these parallel epidemics coincides with the independent acquisition of the arginine catabolic mobile element (ACME) in North American isolates and a novel copper and mercury resistance (COMER) mobile element in South American isolates. CONCLUSIONS: Our results reveal the existence of 2 parallel USA300 epidemics that shared a recent common ancestor. The simultaneous rapid dissemination of these 2 epidemic clades suggests the presence of shared, potentially convergent adaptations that enhance fitness and ability to spread. PMID- 26048972 TI - What can we learn about treating heart failure from the heart's response to acute exercise? Focus on the coronary microcirculation. AB - Coronary microvascular function and cardiac function are closely related in that proper cardiac function requires adequate oxygen delivery through the coronary microvasculature. Because of the close proximity of cardiomyocytes and coronary microvascular endothelium, cardiomyocytes not only communicate their metabolic needs to the coronary microvasculature, but endothelium-derived factors also directly modulate cardiac function. This review summarizes evidence that the myocardial oxygen balance is disturbed in the failing heart because of increased extravascular compressive forces and coronary microvascular dysfunction. The perturbations in myocardial oxygen balance are exaggerated during exercise and are due to alterations in neurohumoral influences, endothelial function, and oxidative stress. Although there is some evidence from animal studies that the myocardial oxygen balance can partly be restored by exercise training, it is largely unknown to what extent the beneficial effects of exercise training include improvements in endothelial function and/or oxidative stress in the coronary microvasculature and how these improvements are impacted by risk factors such as diabetes, obesity, and hypercholesterolemia. PMID- 26048973 TI - Blunted hypertrophic response in aged skeletal muscle is associated with decreased ribosome biogenesis. AB - The ability of skeletal muscle to hypertrophy in response to a growth stimulus is known to be compromised in older individuals. We hypothesized that a change in the expression of protein-encoding genes in response to a hypertrophic stimulus contributes to the blunted hypertrophy observed with aging. To test this hypothesis, we determined gene expression by microarray analysis of plantaris muscle from 5- and 25-mo-old mice subjected to 1, 3, 5, 7, 10, and 14 days of synergist ablation to induce hypertrophy. Overall, 1,607 genes were identified as being differentially expressed across the time course between young and old groups; however, the difference in gene expression was modest, with cluster analysis showing a similar pattern of expression between the two groups. Despite ribosome protein gene expression being higher in the aged group, ribosome biogenesis was significantly blunted in the skeletal muscle of aged mice compared with mice young in response to the hypertrophic stimulus (50% vs. 2.5-fold, respectively). The failure to upregulate pre-47S ribosomal RNA (rRNA) expression in muscle undergoing hypertrophy of old mice indicated that rDNA transcription by RNA polymerase I was impaired. Contrary to our hypothesis, the findings of the study suggest that impaired ribosome biogenesis was a primary factor underlying the blunted hypertrophic response observed in skeletal muscle of old mice rather than dramatic differences in the expression of protein-encoding genes. The diminished increase in total RNA, pre-47S rRNA, and 28S rRNA expression in aged muscle suggest that the primary dysfunction in ribosome biogenesis occurs at the level of rRNA transcription and processing. PMID- 26048974 TI - Separating the roles of nitrogen and oxygen in high pressure-induced blood-borne microparticle elevations, neutrophil activation, and vascular injury in mice. AB - An elevation in levels of circulating microparticles (MPs) due to high air pressure exposure and the associated inflammatory changes and vascular injury that occur with it may be due to oxidative stress. We hypothesized that these responses arise due to elevated partial pressures of N2 and not because of high pressure O2. A comparison was made among high-pressure air, normoxic high pressure N2, and high-pressure O2 in causing an elevation in circulating annexin V-positive MPs, neutrophil activation, and vascular injury by assessing the leakage of high-molecular-weight dextran in a murine model. After mice were exposed for 2 h to 790 kPa air, there were over 3-fold elevations in total circulating MPs as well as subgroups bearing Ly6G, CD41, Ter119, CD31, and CD142 surface proteins-evidence of neutrophil activation; platelet-neutrophil interaction; and vascular injury to brain, omentum, psoas, and skeletal muscles. Similar changes were found in mice exposed to high-pressure N2 using a gas mixture so that O2 partial pressure was the same as that of ambient air, whereas none of these changes occurred after exposures to 166 kPa O2, the same partial pressure that occurs during high-pressure air exposures. We conclude that N2 plays a central role in intra- and perivascular changes associated with exposure to high air pressure and that these responses appear to be a novel form of oxidative stress. PMID- 26048975 TI - The effect of increased lung volume in chronic obstructive pulmonary disease on upper airway obstruction during sleep. AB - Patients with chronic obstructive pulmonary disease (COPD) exhibit increases in lung volume due to expiratory airflow limitation. Increases in lung volumes may affect upper airway patency and compensatory responses to inspiratory flow limitation (IFL) during sleep. We hypothesized that COPD patients have less collapsible airways inversely proportional to their lung volumes, and that the presence of expiratory airflow limitation limits duty cycle responses to defend ventilation in the presence of IFL. We enrolled 18 COPD patients and 18 controls, matched by age, body mass index, sex, and obstructive sleep apnea disease severity. Sleep studies, including quantitative assessment of airflow at various nasal pressure levels, were conducted to determine upper airway mechanical properties [passive critical closing pressure (Pcrit)] and for quantifying respiratory timing responses to experimentally induced IFL. COPD patients had lower passive Pcrit than their matched controls (COPD: -2.8 +/- 0.9 cmH2O; controls: -0.5 +/- 0.5 cmH2O, P = 0.03), and there was an inverse relationship of subject's functional residual capacity and passive Pcrit (-1.7 cmH2O/l increase in functional residual capacity, r(2) = 0.27, P = 0.002). In response to IFL, inspiratory duty cycle increased more (P = 0.03) in COPD patients (0.40 to 0.54) than in controls (0.41 to 0.51) and led to a marked reduction in expiratory time from 2.5 to 1.5 s (P < 0.01). COPD patients have a less collapsible airway and a greater, not reduced, compensatory timing response during upper airway obstruction. While these timing responses may reduce hypoventilation, it may also increase the risk for developing dynamic hyperinflation due to a marked reduction in expiratory time. PMID- 26048977 TI - Soothing the sleeping giant: improving skeletal muscle oxygen kinetics and exercise intolerance in HFpEF. AB - Patients with heart failure with preserved ejection fraction (HFpEF) have similar degrees of exercise intolerance and dyspnea as patients with heart failure with reduced EF (HFrEF). The underlying pathophysiology leading to impaired exertional ability in the HFpEF syndrome is not completely understood, and a growing body of evidence suggests "peripheral," i.e., noncardiac, factors may play an important role. Changes in skeletal muscle function (decreased muscle mass, capillary density, mitochondrial volume, and phosphorylative capacity) are common findings in HFrEF. While cardiac failure and decreased cardiac reserve account for a large proportion of the decline in oxygen consumption in HFrEF, impaired oxygen diffusion and decreased skeletal muscle oxidative capacity can also hinder aerobic performance, functional capacity and oxygen consumption (Vo2) kinetics. The impact of skeletal muscle dysfunction and abnormal oxidative capacity may be even more pronounced in HFpEF, a disease predominantly affecting the elderly and women, two demographic groups with a high prevalence of sarcopenia. In this review, we 1) describe the basic concepts of skeletal muscle oxygen kinetics and 2) evaluate evidence suggesting limitations in aerobic performance and functional capacity in HFpEF subjects may, in part, be due to alterations in skeletal muscle oxygen delivery and utilization. Improving oxygen kinetics with specific training regimens may improve exercise efficiency and reduce the tremendous burden imposed by skeletal muscle upon the cardiovascular system. PMID- 26048976 TI - Independent effect of type 2 diabetes beyond characteristic comorbidities and medications on immediate but not continued knee extensor exercise hyperemia. AB - We tested the hypothesis that type 2 diabetes (T2D), when present in the characteristic constellation of comorbidities (obesity, hypertension, dyslipidemia) and medications, slows the dynamic adjustment of exercising muscle perfusion and blunts the steady state relative to that of controls matched for age, body mass index, fitness, comorbidities, and non-T2D medications. Thirteen persons with T2D and 11 who served as controls performed rhythmic single-leg isometric quadriceps exercise (rest-to-6 kg and 6-to-12 kg transitions, 5 min at each intensity). Measurements included leg blood flow (LBF, femoral artery ultrasound), mean arterial pressure (MAP, finger photoplethysmography), and leg vascular conductance (LVK, calculated). Dynamics were quantified using mean response time (MRT). Measures of amplitude were also used to compare response adjustment: the change from baseline to 1) the peak initial response (greatest 1 s average in the first 10 s; DeltaLBFPIR, DeltaLVKPIR) and 2) the on-transient (average from curve fit at 15, 45, and 75 s; DeltaLBFON, DeltaLVKON). DeltaLBFPIR was significantly blunted in T2D vs. control individuals (P = 0.037); this was due to a tendency for reduced DeltaLVKPIR (P = 0.063). In contrast, the overall response speed was not different between groups (MRT P = 0.856, DeltaLBFON P = 0.150) nor was the change from baseline to steady state (P = 0.204). DeltaLBFPIR, DeltaLBFON, and LBF MRT did not differ between rest-to-6 kg and 6-to-12 kg workload transitions (all P > 0.05). Despite a transient amplitude impairment at the onset of exercise, there is no robust or consistent effect of T2D on top of the comorbidities and medications typical of this population on the overall dynamic adjustment of LBF, or the steady-state levels achieved during low- or moderate-intensity exercise. PMID- 26048978 TI - The generation of macrophages with anti-inflammatory activity in the absence of STAT6 signaling. AB - Macrophages readily change their phenotype in response to exogenous stimuli. In this work, macrophages were stimulated under a variety of experimental conditions, and phenotypic alterations were correlated with changes in gene expression. We identified 3 transcriptionally related populations of macrophages with immunoregulatory activity. They were generated by stimulating cells with TLR ligands in the presence of 3 different "reprogramming" signals: high-density ICs, PGE2, or Ado. All 3 of these cell populations produced high levels of transcripts for IL-10 and growth and angiogenic factors. They also secreted reduced levels of inflammatory cytokines IL-1beta, IL-6, and IL-12. All 3 macrophage phenotypes could partially rescue mice from lethal endotoxemia, and therefore, we consider each to have anti-inflammatory activity. This ability to regulate innate-immune responses occurred equally well in macrophages from STAT6-deficient mice. The lack of STAT6 did not affect the ability of macrophages to change cytokine production reciprocally or to rescue mice from lethal endotoxemia. Furthermore, treatment of macrophages with IL-4 failed to induce similar phenotypic or transcriptional alterations. This work demonstrates that there are multiple ways to generate macrophages with immunoregulatory activity. These anti-inflammatory macrophages are transcriptionally and functionally related to each other and are quite distinct from macrophages treated with IL-4. PMID- 26048980 TI - AIM/CD5L: a key protein in the control of immune homeostasis and inflammatory disease. AB - CD5L, a soluble protein belonging to the SRCR superfamily, is expressed mostly by macrophages in lymphoid and inflamed tissues. The expression of this protein is transcriptionally controlled by LXRs, members of the nuclear receptor family that play major roles in lipid homeostasis. Research undertaken over the last decade has uncovered critical roles of CD5L as a PRR of bacterial and fungal components and in the control of key mechanisms in inflammatory responses, with involvement in processes, such as infection, atherosclerosis, and cancer. In this review, we summarize the current knowledge of CD5L, its roles at the intersection between lipid homeostasis and immune response, and its potential use as a diagnostic biomarker in a variety of diseases, such as TB and liver cirrhosis. PMID- 26048981 TI - Editorial: NK cell reaping of Tfh cells: reckless slaughter or sensible pruning? PMID- 26048982 TI - Recessive DEAF1 mutation associates with autism, intellectual disability, basal ganglia dysfunction and epilepsy. AB - BACKGROUND: Various genetic defects cause autism associated with intellectual disability and epilepsy. Here, we set out to identify the genetic defect in a consanguineous Omani family with three affected children in whom mutations in known candidate genes had been excluded beforehand. METHODS: For mutation screening, we combined autozygosity mapping and whole exome sequencing. Segregation of potential disease variants with the phenotype was verified by Sanger sequencing. A splice-site mutation was confirmed and quantified by qPCR. RESULTS: We found an autosomal recessive splice acceptor mutation in DEAF1 (c.997+4A>C, p.G292Pfs*) in all affected individuals, which led to exon skipping, and reduced the normal full-length mRNA copy number in the patients to 5% of the wild-type level. Besides intellectual disability and autism, two of three affected siblings suffered from severe epilepsy. All patients exhibited dyskinesia of the limbs coinciding with symmetric T2 hyperintensities of the basal ganglia on cranial MRI. CONCLUSIONS: A recent report has shown dominant DEAF1 mutations to occur de novo in patients with intellectual disability. Here, we demonstrate that a DEAF1-associated disorder can also be inherited as an autosomal recessive trait with heterozygous individuals being entirely healthy. Our findings expand the clinical and genetic spectrum of DEAF1 mutations to comprise epilepsy and extrapyramidal symptoms. PMID- 26048979 TI - Salt, chloride, bleach, and innate host defense. AB - Salt provides 2 life-essential elements: sodium and chlorine. Chloride, the ionic form of chlorine, derived exclusively from dietary absorption and constituting the most abundant anion in the human body, plays critical roles in many vital physiologic functions, from fluid retention and secretion to osmotic maintenance and pH balance. However, an often overlooked role of chloride is its function in innate host defense against infection. Chloride serves as a substrate for the generation of the potent microbicide chlorine bleach by stimulated neutrophils and also contributes to regulation of ionic homeostasis for optimal antimicrobial activity within phagosomes. An inadequate supply of chloride to phagocytes and their phagosomes, such as in CF disease and other chloride channel disorders, severely compromises host defense against infection. We provide an overview of the roles that chloride plays in normal innate immunity, highlighting specific links between defective chloride channel function and failures in host defense. PMID- 26048983 TI - Quantitative analysis of angle-selective backscattering electron image of iron oxide and steel. AB - The contrasts in backscattered electron (BSE) images, such as topographic, channeling and mean atomic number (Z) contrasts, were investigated quantitatively from the cross section of a heat-treated steel sheet using a scanning electron microscope (SEM). High primary electron energy (EP) enhances Z contrast, whereas low EP improves channeling contrast. A high take-off angle (theta; measured from the specimen surface) also enhances Z contrast, whereas low theta improves channeling contrast. When theta becomes very low, topographic information is enhanced and superimposed on channeling contrast due to the tilt effect of BSE. The relationship of the behaviors of the Z contrast and the channeling contrast can be understood by the detection ratio of low-loss electrons (LLEs) to the inelastic BSE components emitted from the sample surface; LLEs contribute to channeling contrast, and their ratio increases with decreasing EP and theta. The systematic results obtained in this study are useful for controlling SEM conditions in order to enhance the target information in BSE images for practical materials of interest. PMID- 26048984 TI - Epidermal Growth Factor-dependent Activation of the Extracellular Signal regulated Kinase Pathway by DJ-1 Protein through Its Direct Binding to c-Raf Protein. AB - DJ-1 is an oncogene and also a causative gene for familial Parkinson disease. DJ 1 has various functions, and the oxidative status of cysteine at position 106 (Cys-106) is crucial for determination of the activation level of DJ-1. Although DJ-1 requires activated Ras for its oncogenic activity and although it activates the extracellular signal-regulated kinase (ERK) pathway, a cell growth pathway downstream of Ras, the precise mechanism underlying activation of the ERK pathway by DJ-1 is still not known. In this study, we found that DJ-1 directly bound to the kinase domain of c-Raf but not to Ras and that Cys-106 mutant DJ-1 bound to c Raf more weakly than did wild-type DJ-1. Co-localization of DJ-1 with c-Raf in the cytoplasm was enhanced in epidermal growth factor (EGF)-treated cells. Knockdown of DJ-1 expression attenuated the phosphorylation level of c-Raf in EGF treated cells, resulting in reduced activation of MEK and ERK1/2. Although EGF treated DJ-1 knock-out cells also showed attenuated c-Raf activation, reintroduction of wild-type DJ-1, but not C106S DJ-1, into DJ-1 knock-out cells restored c-Raf activation in a DJ-1 binding activity in a c-Raf-dependent manner. DJ-1 was not responsible for activation of c-Raf in phorbol myristate acetate treated cells. Furthermore, DJ-1 stimulated self-phosphorylation activity of c Raf in vitro, but DJ-1 was not a target for Raf kinase. Oxidation of Cys-106 in DJ-1 was not affected by EGF treatment. These findings showed that DJ-1 is a positive regulator of the EGF/Ras/ERK pathway through targeting c-Raf. PMID- 26048985 TI - Salt-inducible Kinase 3 Signaling Is Important for the Gluconeogenic Programs in Mouse Hepatocytes. AB - Salt-inducible kinases (SIKs), members of the 5'-AMP-activated protein kinase (AMPK) family, are proposed to be important suppressors of gluconeogenic programs in the liver via the phosphorylation-dependent inactivation of the CREB-specific coactivator CRTC2. Although a dramatic phenotype for glucose metabolism has been found in SIK3-KO mice, additional complex phenotypes, dysregulation of bile acids, cholesterol, and fat homeostasis can render it difficult to discuss the hepatic functions of SIK3. The aim of this study was to examine the cell autonomous actions of SIK3 in hepatocytes. To eliminate systemic effects, we prepared primary hepatocytes and screened the small compounds suppressing SIK3 signaling cascades. SIK3-KO primary hepatocytes produced glucose more quickly after treatment with the cAMP agonist forskolin than the WT hepatocytes, which was accompanied by enhanced gluconeogenic gene expression and CRTC2 dephosphorylation. Reporter-based screening identified pterosin B as a SIK3 signaling-specific inhibitor. Pterosin B suppressed SIK3 downstream cascades by up-regulating the phosphorylation levels in the SIK3 C-terminal regulatory domain. When pterosin B promoted glucose production by up-regulating gluconeogenic gene expression in mouse hepatoma AML-12 cells, it decreased the glycogen content and stimulated an association between the glycogen phosphorylase kinase gamma subunit (PHKG2) and SIK3. PHKG2 phosphorylated the peptides with sequences of the C-terminal domain of SIK3. Here we found that the levels of active AMPK were higher both in the SIK3-KO hepatocytes and in pterosin B-treated AML-12 cells than in their controls. These results suggest that SIK3, rather than SIK1, SIK2, or AMPKs, acts as the predominant suppressor in gluconeogenic gene expression in the hepatocytes. PMID- 26048986 TI - Pregnancy and Smoothelin-like Protein 1 (SMTNL1) Deletion Promote the Switching of Skeletal Muscle to a Glycolytic Phenotype in Human and Mice. AB - Pregnancy promotes physiological adaptations throughout the body, mediated by the female sex hormones progesterone and estrogen. Changes in the metabolic properties of skeletal muscle enable the female body to cope with the physiological challenges of pregnancy and may also be linked to the development of insulin resistance. We conducted global microarray, proteomic, and metabolic analyses to study the role of the progesterone receptor and its transcriptional regulator, smoothelin-like protein 1 (SMTNL1) in the adaptation of skeletal muscle to pregnancy. We demonstrate that pregnancy promotes fiber-type changes from an oxidative to glycolytic isoform in skeletal muscle. This phenomenon is regulated through an interaction between SMTNL1 and progesterone receptor, which alters the expression of contractile and metabolic proteins. smtnl1(-/-) mice are metabolically less efficient and show impaired glucose tolerance. Pregnancy antagonizes these effects by inducing metabolic activity and increasing glucose tolerance. Our results suggest that SMTNL1 has a role in mediating the actions of steroid hormones to promote fiber switching in skeletal muscle during pregnancy. Our findings also bear on the management of gestational diabetes that develops as a complication of pregnancy in ~4% of women. PMID- 26048988 TI - Dopamine Transporter Activity Is Modulated by alpha-synuclein. AB - The duration and strength of the dopaminergic signal is regulated by the dopamine transporter (DAT). Drug addiction, neurodegenerative and neuropsychiatric diseases have all been associated with altered DAT activity. The membrane localization and the activity of DAT are regulated by a number of intracellular proteins. alpha-synuclein, a protein partner of DAT, is implicated in neurodegenerative disease and drug addiction. Little is known about the regulatory mechanisms of the interaction between DAT and alpha-synuclein, the cellular location of this interaction, and the functional consequences of this interaction on the basal, amphetamine (AMPH) induced DAT-meditated DA efflux and membrane microdomain distribution of the transporter. Here, we found that the majority of DAT/alpha-synuclein protein complexes are found at the plasma membrane of dopaminergic neurons or mammalian cells, and that AMPH-mediated increase in DAT activity enhances the association of these proteins at the plasma membrane. Further examination of the interaction of DAT and alpha-synuclein revealed a transient interaction between these two proteins at the plasma membrane. Additionally, we found DAT-induced membrane depolarization enhances plasma membrane localization of alpha-synuclein, which in turn increases DA efflux and enhances DAT localization in cholesterol rich membrane microdomains. PMID- 26048987 TI - Deciphering the BRCA1 Tumor Suppressor Network. AB - The BRCA1 tumor suppressor protein is a central constituent of several distinct macromolecular protein complexes that execute homology-directed DNA damage repair and cell cycle checkpoints. Recent years have borne witness to an exciting phase of discovery at the basic molecular level for how this network of DNA repair proteins acts to maintain genome stability and suppress cancer. The clinical dividends of this investment are now being realized with the approval of first-in class BRCA-targeted therapies for ovarian cancer and identification of molecular events that determine responsiveness to these agents. Further delineation of the basic science underlying BRCA network function holds promise to maximally exploit genome instability for hereditary and sporadic cancer therapy. PMID- 26048989 TI - Differences in ATP Generation Via Glycolysis and Oxidative Phosphorylation and Relationships with Sperm Motility in Mouse Species. AB - Mouse sperm produce enough ATP to sustain motility by anaerobic glycolysis and respiration. However, previous studies indicated that an active glycolytic pathway is required to achieve normal sperm function and identified glycolysis as the main source of ATP to fuel the motility of mouse sperm. All the available evidence has been gathered from the studies performed using the laboratory mouse. However, comparative studies of closely related mouse species have revealed a wide range of variation in sperm motility and ATP production and that the laboratory mouse has comparatively low values in these traits. In this study, we compared the relative reliance on the usage of glycolysis or oxidative phosphorylation as ATP sources for sperm motility between mouse species that exhibit significantly different sperm performance parameters. We found that the sperm of species with higher oxygen consumption/lactate excretion rate ratios were able to produce higher amounts of ATP, achieving higher swimming velocities. Additionally, we show that the species with higher respiration/glycolysis ratios have a higher degree of dependence upon active oxidative phosphorylation. Moreover, we characterize for the first time two mouse species in which sperm depend on functional oxidative phosphorylation to achieve normal performance. Finally, we discuss that sexual selection could promote adaptations in sperm energetic metabolism tending to increase the usage of a more efficient pathway for the generation of ATP (and faster sperm). PMID- 26048990 TI - Ctr9, a Protein in the Transcription Complex Paf1, Regulates Dopamine Transporter Activity at the Plasma Membrane. AB - Dopamine (DA) is a major regulator of sensorimotor and cognitive functions. The DA transporter (DAT) is the key protein that regulates the spatial and temporal activity of DA release into the synaptic cleft via the rapid reuptake of DA into presynaptic termini. Several lines of evidence have suggested that transporter interacting proteins may play a role in DAT function and regulation. Here, we identified the tetratricopeptide repeat domain-containing protein Ctr9 as a novel DAT binding partner using a yeast two-hybrid system. We showed that Ctr9 is expressed in dopaminergic neurons and forms a stable complex with DAT in vivo via GST pulldown and co-immunoprecipitation assays. In mammalian cells co-expressing both proteins, Ctr9 partially colocalizes with DAT at the plasma membrane. This interaction between DAT and Ctr9 results in a dramatic enhancement of DAT mediated DA uptake due to an increased number of DAT transporters at the plasma membrane. We determined that the binding of Ctr9 to DAT requires residues YKF in the first half of the DAT C terminus. In addition, we characterized Ctr9, providing new insight into this protein. Using three-dimensional modeling, we identified three novel tetratricopeptide repeat domains in the Ctr9 sequence, and based on deletion mutation experiments, we demonstrated the role of the SH2 domain of Ctr9 in nuclear localization. Our results demonstrate that Ctr9 localization is not restricted to the nucleus, as previously described for the transcription complex Paf1. Taken together, our data provide evidence that Ctr9 modulates DAT function by regulating its trafficking. PMID- 26048991 TI - Hydroxyproline-induced Helical Disruption in Conantokin Rl-B Affects Subunit selective Antagonistic Activities toward Ion Channels of N-Methyl-d-aspartate Receptors. AB - Conantokins are ~20-amino acid peptides present in predatory marine snail venoms that function as allosteric antagonists of ion channels of the N-methyl-d aspartate receptor (NMDAR). These peptides possess a high percentage of post-/co translationally modified amino acids, particularly gamma-carboxyglutamate (Gla). Appropriately spaced Gla residues allow binding of functional divalent cations, which induces end-to-end alpha-helices in many conantokins. A smaller number of these peptides additionally contain 4-hydroxyproline (Hyp). Hyp should prevent adoption of the metal ion-induced full alpha-helix, with unknown functional consequences. To address this disparity, as well as the role of Hyp in conantokins, we have solved the high resolution three-dimensional solution structure of a Gla/Hyp-containing 18-residue conantokin, conRl-B, by high field NMR spectroscopy. We show that Hyp(10) disrupts only a small region of the alpha helix of the Mn(2+).peptide complex, which displays cation-induced alpha-helices on each terminus of the peptide. The function of conRl-B was examined by measuring its inhibition of NMDA/Gly-mediated current through NMDAR ion channels in mouse cortical neurons. The conRl-B displays high inhibitory selectivity for subclasses of NMDARs that contain the functionally important GluN2B subunit. Replacement of Hyp(10) with N(8)Q results in a Mg(2+)-complexed end-to-end alpha helix, accompanied by attenuation of NMDAR inhibitory activity. However, replacement of Hyp(10) with Pro(10) allowed the resulting peptide to retain its inhibitory property but diminished its GluN2B specificity. Thus, these modified amino acids, in specific peptide backbones, play critical roles in their subunit selective inhibition of NMDAR ion channels, a finding that can be employed to design NMDAR antagonists that function at ion channels of distinct NMDAR subclasses. PMID- 26048992 TI - AMP-activated Protein Kinase Suppresses Biosynthesis of Glucosylceramide by Reducing Intracellular Sugar Nucleotides. AB - The membrane glycolipid glucosylceramide (GlcCer) plays a critical role in cellular homeostasis. Its intracellular levels are thought to be tightly regulated. How cells regulate GlcCer levels remains to be clarified. AMP activated protein kinase (AMPK), which is a crucial cellular energy sensor, regulates glucose and lipid metabolism to maintain energy homeostasis. Here, we investigated whether AMPK affects GlcCer metabolism. AMPK activators (5 aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside and metformin) decreased intracellular GlcCer levels and synthase activity in mouse fibroblasts. AMPK inhibitors or AMPK siRNA reversed these effects, suggesting that GlcCer synthesis is negatively regulated by an AMPK-dependent mechanism. Although AMPK did not affect the phosphorylation or expression of GlcCer synthase, the amount of UDP glucose, an activated form of glucose required for GlcCer synthesis, decreased under AMPK-activating conditions. Importantly, the UDP-glucose pyrophosphatase Nudt14, which degrades UDP-glucose, generating UMP and glucose 1-phosphate, was phosphorylated and activated by AMPK. On the other hand, suppression of Nudt14 by siRNA had little effect on UDP-glucose levels, indicating that mammalian cells have an alternative UDP-glucose pyrophosphatase that mainly contributes to the reduction of UDP-glucose under AMPK-activating conditions. Because AMPK activators are capable of reducing GlcCer levels in cells from Gaucher disease patients, our findings suggest that reducing GlcCer through AMPK activation may lead to a new strategy for treating diseases caused by abnormal accumulation of GlcCer. PMID- 26048994 TI - RE: Aspirin and COX-2 Inhibitor Use in Patients With Stage III Colon Cancer. PMID- 26048993 TI - Lysophosphatidylcholine Acyltransferase 1 (LPCAT1) Specifically Interacts with Phospholipid Transfer Protein StarD10 to Facilitate Surfactant Phospholipid Trafficking in Alveolar Type II Cells. AB - Pulmonary surfactant, a mixture of proteins and phospholipids, plays an important role in facilitating gas exchange by maintaining alveolar stability. Saturated phosphatidylcholine (SatPC), the major component of surfactant, is synthesized both de novo and by the remodeling of unsaturated phosphatidylcholine (PC) by lyso-PC acyltransferase 1 (LPCAT1). After synthesis in the endoplasmic reticulum, SatPC is routed to lamellar bodies (LBs) for storage prior to secretion. The mechanism by which SatPC is transported to LB is not understood. The specificity of LPCAT1 for lyso-PC as an acyl acceptor suggests that formation of SatPC via LPCAT1 reacylation is a final step in SatPC synthesis prior to transport. We hypothesized that LPCAT1 forms a transient complex with SatPC and specific phospholipid transport protein(s) to initiate trafficking of SatPC from the endoplasmic reticulum to the LB. Herein we have assessed the ability of different StarD proteins to interact with LPCAT1. We found that LPCAT1 interacts with StarD10, that this interaction is direct, and that amino acids 79-271 of LPCAT1 and the steroidogenic acute regulatory protein-related lipid transfer (START) domain of START domain-containing protein 10 (StarD10) are sufficient for this interaction. The role of StarD10 in trafficking of phospholipid to LB was confirmed by the observation that knockdown of StarD10 significantly reduced transport of phospholipid to LB. LPCAT1 also interacted with one isoform of StarD7 but showed no interaction with StarD2/PC transfer protein. PMID- 26048995 TI - Response. PMID- 26048996 TI - Short term exposure of beta cells to low concentrations of interleukin-1beta improves insulin secretion through focal adhesion and actin remodeling and regulation of gene expression. PMID- 26048997 TI - YidC occupies the lateral gate of the SecYEG translocon and is sequentially displaced by a nascent membrane protein. PMID- 26048998 TI - The Down syndrome cell adhesion molecule (DSCAM) interacts with and activates Pak. PMID- 26048999 TI - Fatty acid binding into the highest affinity site of human serum albumin observed in molecular dynamics simulation. AB - Multiple molecular dynamics simulations were performed to investigate the association of stearic acid into the highest affinity binding site of human serum albumin. All binding events ended with a rapid (<10 ps) lock-in of the fatty acid due to formation of a hydrogen bond with Tyr401. The kinetics and energetics of the penetration process both depended linearly on the positional shift of the fatty acid, with an average insertion time and free energy reduction of, respectively, 32 +/- 20 ps and 0.70 +/- 0.15 kcal/mol per methylene group absorbed. Binding events of longer duration (tbind>1 ns) were characterized by a slow exploration of the pocket entry and, frequently, of a nearby protein crevice corresponding to a metastable state along the route to the binding site. Taken all together, these findings reconstruct the following pathway for the binding process of stearic acid: (i) contact with the protein surface, possibly facilitated by the presence of an intermediate location, (ii) probing of the site entry, (iii) insertion into the protein, and (iv) lock-in at the final position. This general description may also apply to other long-chain fatty acids binding into any of the high-affinity sites of albumin, or to specific sites of other lipid-binding proteins. PMID- 26049000 TI - Renalase does not catalyze the oxidation of catecholamines. AB - It is widely accepted that the function of human renalase is to oxidize catecholamines in blood. However, this belief is based on experiments that did not account for slow, facile catecholamine autoxidation reactions. Recent evidence has shown that renalase has substrates with which it reacts rapidly. The reaction catalyzed defines renalase as an oxidase, one that harvests two electrons from either 2-dihydroNAD(P) or 6-dihydroNAD(P) to form beta-NAD(P)(+) and hydrogen peroxide. The apparent metabolic purpose of such a reaction is to avoid inhibition of primary dehydrogenase enzymes by these beta-NAD(P)H isomers. This article demonstrates that renalase does not catalyze the oxidation of neurotransmitter catecholamines. Using high-performance liquid chromatography we show that there is no evidence of consumption of epinephrine by renalase. Using time-dependent spectrophotometry we show that the renalase FAD cofactor spectrum is unresponsive to added catecholamines, that adrenochromes are not observed to accumulate in the presence of renalase and that the kinetics of single turnover reactions with 6-dihydroNAD are unaltered by the addition of catecholamines. Lastly we show using an oxygen electrode assay that plasma renalase activity is below the level of detection and only when exogenous renalase and 6-dihydroNAD are added can dioxygen be observed to be consumed. PMID- 26049001 TI - Impact of membrane-associated hydrogenases on the F0F1-ATPase in Escherichia coli during glycerol and mixed carbon fermentation: ATPase activity and its inhibition by N,N'-dicyclohexylcarbodiimide in the mutants lacking hydrogenases. AB - Escherichia coli is able to ferment glycerol and to produce molecular hydrogen (H2) by four membrane-associated hydrogenases (Hyd) changing activity in response to different conditions. In this study, overall ATPase activity of glycerol alone and mixed carbon sources (glucose and glycerol) fermented E. coli wild type and different Hyd mutants and its inhibition by N,N'-dicyclohexylcarbodiimide (DCCD) were first investigated. ATPase activity was higher in glycerol fermented wild type cells at pH 7.5 compared to pH 6.5 and pH 5.5; DCCD inhibited markedly ATPase activity at pH 7.5. The ATPase activity at pH 7.5, compared with wild type, was lower in selC and less in hypF single mutants, suppressed in hyaB hybC selC triple mutant. Moreover, total ATPase activity of mixed carbon fermented wild type cells was maximal at pH 7.5 and lowered at pH 5.5. The ATPase activities of hypF and hyaB hybC selC mutants were higher at pH 5.5, compared with wild type; DCCD inhibited markedly ATPase activity of hypF mutant. These results demonstrate that in E. coli during glycerol fermentation the membrane proton-translocating FOF1-ATPase has major input in overall ATPase activity and alkaline pH is more optimal for the FOF1-ATPase operation. Hyd-1 and Hyd-2 are required for the FOF1-ATPase activity upon anaerobic fermentation of glycerol. The impact of Hyd-1 and Hyd-2 on the FOF1-ATPase is more obvious during mixed carbon fermentation at slightly acidic pH. PMID- 26049002 TI - A lipidated form of the extracellular domain of influenza M2 protein as a self adjuvanting vaccine candidate. AB - The highly conserved extracellular domain of Matrix protein 2 (M2e) of influenza A virus has been previously investigated as a potential target for an universal influenza vaccine. In this study we prepared four lipopeptide influenza vaccine candidates in which the TLR2 agonist S-[2,3-bis(palmitoyloxy)propyl] cysteine, (Pam2Cys) was attached to either the N- or C-terminus of the M2e consensus sequence SLLTEVETPIRNEWGCRCNDSSDP and its analogue sequence with the two cysteine residues replaced with serine residues. The results of animal study show that each of these lipopeptides induced strong M2e-specific antibody responses in the absence of extraneous T helper cell epitope(s) which are normally incorporated in the previous studies or addition of extraneous adjuvant and that these antibodies are protective against lethal challenge with influenza virus. Comparison of different routes of inoculation demonstrated that intranasal administration of M2e lipopeptide induced higher titers of IgA and IgG2b antibodies in the bronchoalveolar lavage than did subcutaneous vaccination and was better at mitigating the severity of viral challenge. Finally, we show that anti-M2e antibody specificities absent from the antibody repertoire elicited by a commercially available influenza vaccine and by virus infection can be introduced by immunization with M2e-lipopeptide and boosted by viral challenge. Immunization with this lipidated form of the M2e epitope therefore offers a means of using a widely conserved epitope to generate protective antibodies which are not otherwise induced. PMID- 26049003 TI - High resolution identity testing of inactivated poliovirus vaccines. AB - BACKGROUND: Definitive identification of poliovirus strains in vaccines is essential for quality control, particularly where multiple wild-type and Sabin strains are produced in the same facility. Sequence-based identification provides the ultimate in identity testing and would offer several advantages over serological methods. METHODS: We employed random RT-PCR and high throughput sequencing to recover full-length genome sequences from monovalent and trivalent poliovirus vaccine products at various stages of the manufacturing process. RESULTS: All expected strains were detected in previously characterised products and the method permitted identification of strains comprising as little as 0.1% of sequence reads. Highly similar Mahoney and Sabin 1 strains were readily discriminated on the basis of specific variant positions. Analysis of a product known to contain incorrect strains demonstrated that the method correctly identified the contaminants. CONCLUSION: Random RT-PCR and shotgun sequencing provided high resolution identification of vaccine components. In addition to the recovery of full-length genome sequences, the method could also be easily adapted to the characterisation of minor variant frequencies and distinction of closely related products on the basis of distinguishing consensus and low frequency polymorphisms. PMID- 26049004 TI - Pigs immunized with Chinese highly pathogenic PRRS virus modified live vaccine are protected from challenge with North American PRRSV strain NADC-20. AB - Modified live virus (MLV) vaccines developed to protect against PRRSV circulating in North America (NA) offer limited protection to highly pathogenic (HP) PRRSV strains that are emerging in Asia. MLV vaccines specific to HP-PRRSV strains commercially available in China provide protection to HP-PRRSV; however, the efficacy of these HP-PRRSV vaccines to current circulating NA PRRS viruses has not been reported. The aim of this study is to investigate whether pigs vaccinated with attenuated Chinese HP-PRRSV vaccine (JXA1-R) are protected from infection by NA PRRSV strain NADC-20. We found that pigs vaccinated with JXA1-R were protected from challenges with HV-PRRSV or NADC-20 as shown by fewer days of clinical fever, reduced lung pathology scores, and lower PRRS virus load in the blood. PRRSV-specific antibodies, as measured by IDEXX ELISA, appeared one week after vaccination and virus neutralizing antibodies were detected four weeks post vaccination. Pigs vaccinated with JXA1-R developed broadly neutralizing antibodies with high titers to NADC-20, JXA1-R, and HV-PRRSV. In addition, we also found that IFN-alpha and IFN-beta occurred at higher levels in the lungs of pigs vaccinated with JXA1-R. Taken together, our studies provide the first evidence that JXA1-R can confer protection in pigs against the heterologous NA PRRSV strain NADC-20. PMID- 26049005 TI - Analysis of pregnancy and infant health outcomes among women in the National Smallpox Vaccine in Pregnancy Registry who received Anthrax Vaccine Adsorbed. AB - The National Smallpox Vaccine in Pregnancy Registry (NSVIPR) actively follows women inadvertently vaccinated with smallpox vaccine during or shortly before pregnancy to evaluate their reproductive health outcomes. Approximately 65% of NSVIPR participants also inadvertently received Anthrax Vaccine Adsorbed (AVA) while pregnant, providing a ready opportunity to evaluate pregnancy and infant health outcomes among these women. AVA-exposed pregnancies were ascertained using NSVIPR and electronic healthcare data. Rates of pregnancy loss and infant health outcomes, including major birth defects, were compared between AVA-exposed and AVA-unexposed pregnancies. Analyses included AVA-exposed and AVA-unexposed pregnant women who also received smallpox vaccine 28 days prior to or during pregnancy. Rates of adverse outcomes among the AVA-exposed group were similar to or lower than expected when compared with published reference rates and the AVA unexposed population. The findings provide reassurance of the safety of AVA when inadvertently received by a relatively young and healthy population during pregnancy. PMID- 26049006 TI - Altered expression of microRNAs in the neuronal differentiation of human Wharton's Jelly mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have the capacity to generate multiple tissues of mesodermal origin, and also have the potential to trans-differentiate into neurons. We isolated MSCs from the Wharton's jelly of the human umbilical cord (WJ-MSCs), and efficiently induced WJ-MSCs into neuron-like cells using a modified method. After neuronal induction for 12 days, most of WJ-MSCs expressed mature neuronal marker MAP2 (83 +/- 7%), and meanwhile some adopted neuronal morphology. WJ-MSCs also expressed Nestin (34 +/- 6%), NSE (30 +/- 5%), and GFAP (12 +/- 3%). Moreover, we used miRNA microarray to analyze the differentially expressed miRNAs in neuronal differentiation of WJ-MSCs. Microarray analysis revealed discrepant miRNA profiles in the uninduced WJ-MSCs and WJ-MSCs derived neurons. Six miRNAs were chosen for further qRT-PCR validation. Among these 6 miRNAs, four miRNAs (miR-1290, miR-26b, miR-194, and miR-124a) were up-regulated and 2 miRNAs (miR-4521 and miR-543) were down-regulated in the WJ-MSCs derived neurons. In conclusion, WJ-MSCs could be efficiently induced into neuron-like cells. More importantly, our findings suggested that miRNAs might play important roles in the neuronal differentiation of WJ-MSCs. PMID- 26049007 TI - Neuroanatomical deficits correlate with executive dysfunction in boys with attention deficit hyperactivity disorder. AB - Previous structural imaging studies have revealed gray matter volume abnormalities to reflect the etiology of attention deficit hyperactivity disorder (ADHD), however, which are confounded by age, medication and comorbidity and also ignore the core feature of brain structure in the executive impairments of ADHD. In the present study, we explored gray matter volume abnormalities in male children and adolescents with ADHD who were drug-naive and without comorbidities, and tried to connect structural data and behavioral executive dysfunction to provide more information regarding the brain-behavior relationships in ADHD. Seventy-two male subjects (37 patients and 35 controls) underwent three dimensional high-resolution structural magnetic resonance imaging and executive function assessments, including the Stroop Color-Word Test and Wisconsin Card Sorting Test (WCST). Voxel-based morphometry with diffeomorphic anatomical registration through exponentiated Lie algebra was used to identify gray matter volume differences between the ADHD and controls. Correlation analyses were performed to identify neuroanatomical deficits that were associated with executive dysfunctions. Significantly reduced gray matter volumes were identified in the right orbitofrontal cortex, right primary motor/premotor cortex, left anterior cingulate cortex and left posterior midcingulate cortex of ADHD patients compared with controls (P<0.05, corrected for family-wise errors). In patients group, the gray matter volumes of the right orbitofrontal cortex and left posterior midcingulate cortex were positively correlated with the completed categories on the WCST, and the gray matter volume of the left posterior midcingulate cortex was negatively correlated with the total and non perseverative errors on the WCST (P<0.05). The present findings show gray matter volume reductions in motor regions as well as the orbitofrontal and cingulate cortex; this evidence supports theories that suggest frontal abnormalities in children and adolescents with ADHD at early illness stage. The correlations between structural abnormalities and executive dysfunction suggest that neuroanatomical substrate deficits are implicated in the pathophysiology of ADHD. PMID- 26049008 TI - Antibody/receptor protein immunocomplex in human and mouse cortical nerve endings amplifies complement-induced glutamate release. AB - Previous studies have demonstrated that complement alone releases glutamate from human and mouse cortical terminals in an antibody-independent manner. In order to expand our knowledge on complement-mediated effects, we investigated whether the presence of an antigen-antibody complex in synaptosomal plasmamembranes could also trigger complement-induced functional responses that might affect neurotransmitter release. To this aim, we focused on the chemokine 5 receptor (CCR5) expressed in human and mouse cortical glutamate terminals, whose activation by CCL5 elicits [(3)H]D-aspartate ([(3)H]D-ASP) release. Preincubating synaptosomes with an antibody recognizing the NH2 terminus of the CCR5 protein (anti-NH2-CCR5 antibody) abolished the CCL5-induced [(3)H]D-ASP release. Similarly, enriching synaptosomes with an antibody recognizing the COOH terminus of CCR5 (anti-COOH-CCR5 antibody) prevented the CCL5-induced [(3)H]D-ASP release. The antagonist-like activity of the anti-NH2-CCR5 antibody turned to facilitation when anti-NH2-CCR5-treated synaptosomes were exposed to complement. In these terminals, the releasing effect was significantly higher than that elicited by complement in untreated synaptosomes. On the contrary, the complement-induced [(3)H]D-ASP release from anti-COOH-CCR5 antibody-entrapped synaptosomes did not differ from that from untreated synaptosomes. Preincubating synaptosomes with anti-beta tubulin III antibody, used as negative control, neither prevented the CCL5-induced releasing effect nor it amplified the complement-induced [(3)H]D-ASP release. Finally, serum lacking the C1q protein, i.e. the protein essential to promote the antibody-mediated activation of complement, elicited a comparable [(3)H]D-ASP release from both untreated and anti-NH2-CCR5 antibody-treated synaptosomes. Thus, we propose that antibodies raised against the outer sequence of a receptor protein can trigger the activation of the complement through the classic, C1q-mediated antibody-dependent pathway, which results in an abnormal release of glutamate that could be deleterious to central nervous system. PMID- 26049009 TI - Pinocembrin inhibits lipopolysaccharide-induced inflammatory mediators production in BV2 microglial cells through suppression of PI3K/Akt/NF-kappaB pathway. AB - Pinocembrin, one of the primary flavonoids from Pinus heartwood and Eucalyptus, has been reported to have anti-inflammatory and antioxidant activity. This study was designed to evaluate the inhibitory effects of pinocembrin on inflammatory mediators production in LPS-stimulated BV2 microglial cells. The results showed that pinocembrin dose-dependently inhibited LPS-induced inflammatory mediators TNF-alpha, IL-1beta, NO and PGE2 production. Pinocembrin also inhibited LPS induced iNOS and COX-2 expression. Moreover, pinocembrin inhibited LPS-induced PI3K, Akt phosphorylation, and NF-kappaB activation, which were required for inflammatory mediators production. Furthermore, treatment of pinocembrin induced nuclear translocation of Nrf2 and expression of HO-1. In conclusion, our data indicated that pinocembrin inhibited LPS-induced inflammatory mediators production by suppressing PI3K/Akt/NF-kappaB signaling pathway. PMID- 26049010 TI - AMP-activated protein kinase is activated by non-steroidal anti-inflammatory drugs. AB - AMP-activated kinase (AMPK) is a cellular energy sensor, which is activated in stages of increased adenosine triphosphate (ATP) consumption. Its activation has been associated with a number of beneficial effects such as decrease of inflammatory processes and inhibition of disease progression of diabetes and obesity. A recent study suggested that salicylate, the active metabolite of the non-steroidal anti-inflammatory drug (NSAID) acetyl-salicylic acid (aspirin), is able to activate AMPK pharmacologically. This observation raised the question whether or not other NSAIDs might also act as AMPK activators and whether this action might contribute to their cyclooxygenase (COX)-independent anti inflammatory properties. In this study, we investigated mouse and human neuronal cells and liver tissue of mice after treatment with various NSAIDs. Our results showed that the non-selective acidic NSAIDs ibuprofen and diclofenac induced AMPK activation similar to aspirin while the COX-2 selective drug etoricoxib and the non-opioid analgesic paracetamol, both drugs have no acidic structure, failed to activate AMPK. In conclusion, our results revealed that AMPK can be activated by specific non-steroidal anti-inflammatory drugs such as salicylic acid, ibuprofen or diclofenac possibly depending on the acidic structure of the drugs. AMPK might therefore contribute to their antinociceptive and anti-inflammatory properties. PMID- 26049011 TI - Mechanisms underlying the vasorelaxation of human internal mammary artery induced by (-)-epicatechin. AB - Evidences have suggested that flavanol compound (-)-epicatechin is associated with reduced risk of cardiovascular diseases. One of the mechanisms of its cardioprotective effect is vasodilation. However, the exact mechanisms by which ( )-epicatechin causes vasodilation are not yet clearly defined. The aims of the present study were to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human internal mammary artery (HIMA) and to determine the mechanisms underlying its vasorelaxation. Our results showed that (-)-epicatechin induced a concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Among the K(+) channel blockers, 4-aminopyridine (4-AP) and margatoxin, blockers of voltage-gated K(+) (KV) channels, and glibenclamide, a selective ATP-sensitive K(+) (KATP) channels blocker, partly inhibited the (-)-epicatechin-induced relaxation of HIMA, while iberiotoxin, a most selective blocker of large conductance Ca(2+)-activated K(+) channels (BKCa), almost completely inhibited the relaxation. In rings pre-contracted by 80mM K(+), (-)-epicatechin induced partial relaxation of HIMA, whereas in Ca(2+)-free medium, (-)-epicatechin completely relaxed HIMA rings pre-contracted by phenylephrine and caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, slightly antagonized (-)-epicatechin-induced relaxation of HIMA pre-contracted by phenylephrine. These results suggest that (-)-epicatechin induces strong endothelium-independent relaxation of HIMA pre-contracted by phenylephrine whilst 4-AP- and margatoxin-sensitive KV channels, as well as BKCa and KATP channels, located in vascular smooth muscle, mediate this relaxation. In addition, it seems that (-)-epicatechin could inhibit influx of extracellular Ca(2+), interfere with intracellular Ca(2+) release and re-uptake by the sarcoplasmic reticulum. PMID- 26049012 TI - Inhibition of cholesteryl ester transfer protein increases cholesteryl ester content of large HDL independently of HDL-to-HDL homotypic transfer: in vitro vs in vivo comparison using anacetrapib and dalcetrapib. AB - The increase in high density lipoprotein (HDL)-cholesterol observed with cholesteryl ester transfer protein (CETP) inhibition is commonly attributed to blockade of cholesteryl ester (CE) transfer from HDL to low density lipoprotein particles. In vitro, it has been observed that CETP can mediate transfer of CE between HDL particles ("homotypic transfer"), and it is postulated that this contributes to HDL remodeling and generation of anti-atherogenic pre-beta HDL. Inhibition of CETP could limit this beneficial remodeling and reduce pre-beta HDL levels. We observed that anacetrapib does not reduce pre-beta HDL in vivo, but the role of HDL homotypic transfer was not examined. This study evaluated the effects of anacetrapib on homotypic transfer from HDL3 to HDL2 in vivo using deuterium-labeled HDL3, and compared this to in vitro settings, where homotypic transfer was previously described. In vitro, both anacetrapib and dalcetrapib inhibited transfer of CE from HDL3 to HDL2 particles. In CETP transgenic mice, anacetrapib did not inhibit the appearance of labeled CE derived from HDL3 in HDL2 particles, but rather promoted the appearance of labeled CE in HDL2. We concluded that inhibition of CETP by anacetrapib promoted HDL particle remodeling, and does not impair the flux of cholesterol ester into larger HDL particles when studied in vivo, which is not consistent with in vitro observations. We further conclude, therefore, that the in vitro conditions used to examine HDL-to-HDL homotypic transfer may not recapitulate the in vivo condition, where multiple mechanisms contribute to cholesteryl ester flux into and out of the HDL pool. PMID- 26049013 TI - Allicin improves endoplasmic reticulum stress-related cognitive deficits via PERK/Nrf2 antioxidative signaling pathway. AB - Endoplasmic reticulum (ER) stress is involved in neurodegenerative diseases including Alzheimer's disease (AD), in which dysregulation of double-stranded RNA dependent protein kinase (PKR)-like ER-resident kinase (PERK) is considered to play a critical role. Allicin, a garlic extract, has been demonstrated a protective role in AD model. The present study was designed to investigate the possible protective effect of allicin on ER stress-induced cognitive deficits and underlying mechanisms in rats. In this study, 72h of lateral ventricular infusion of tunicamycin (TM), an ER stress stimulator, induced significant cognitive deficits. TM increased tau phosphorylation, Abeta42 deposit, and oxidative stress, and reduced antioxidative enzymes activity in the hippocampus. TM moderately elevated the expression of PERK and its downstream substrate nuclear factor erythroid-derived 2-like 2 (Nrf2) in the hippocampus. All these impaired changes by TM were significantly improved by allicin pretreatment. Allicin markedly increased PERK and Nrf2 expression in the hippocampus. Thus, our data demonstrate the protective role of allicin in ER stress-related cognitive deficits, and suggest that PERK/Nrf2 antioxidative signaling pathway underlies the action mechanism. PMID- 26049014 TI - Oseltamivir produces hypothermic and neuromuscular effects by inhibition of nicotinic acetylcholine receptor functions: comparison to procaine and bupropion. AB - Oseltamivir, an anti-influenza virus drug, induces marked hypothermia in normal mice. We have proposed that the hypothermic effect arises from inhibition of the nicotinic acetylcholine receptor function of sympathetic ganglion neurons which innervate the brown adipose tissue (a heat generator). It has been reported that local anesthetics inhibit nicotinic acetylcholine receptor function by acting on its ionic channels, and that bupropion, a nicotinic antagonist, induces hypothermia. In this study, we compared the effects of oseltamivir, procaine and bupropion on body temperature, cardiovascular function and neuromuscular transmission. Intraperitoneal administration of oseltamivir (100mg/kg), procaine (86.6mg/kg) and bupropion (86.7mg/kg) lowered the core body temperature of normal mice. At lower doses (10-30mg/kg oseltamivir, 8.7-26mg/kg procaine and bupropion), when administered subcutaneously, the three drugs antagonized the hypothermia induced by intraperitoneal injection of nicotine (1mg/kg). In anesthetized rats, intravenous oseltamivir (30-100mg/kg), procaine (10mg/kg) and bupropion (10mg/kg) induced hypotension and bradycardia. Oseltamivir alone (100mg/kg) did not inhibit neuromuscular twitch contraction of rats, but at 3 30mg/kg it augmented the muscle-relaxing effect of d-tubocurarine. Similar effects were observed when lower doses of procaine (10-30mg/kg) and bupropion (3 10mg/kg) were administered, suggesting that systemic administration of oseltamivir inhibits muscular nicotinic acetylcholine receptors. These results support the idea that the hypothermic effect of oseltamivir is due to its effects on sympathetic ganglia which innervate the brown adipose tissue, and suggest that oseltamivir may exert non-selective ion channel blocking effects like those of ester-type local anesthetics. PMID- 26049015 TI - Oligomerization of the UapA Purine Transporter Is Critical for ER-Exit, Plasma Membrane Localization and Turnover. AB - Central to the process of transmembrane cargo trafficking is the successful folding and exit from the ER (endoplasmic reticulum) through packaging in COPII vesicles. Here, we use the UapA purine transporter of Aspergillus nidulans to investigate the role of cargo oligomerization in membrane trafficking. We show that UapA oligomerizes (at least dimerizes) and that oligomerization persists upon UapA endocytosis and vacuolar sorting. Using a validated bimolecular fluorescence complementation assay, we provide evidence that a UapA oligomerization is associated with ER-exit and turnover, as ER-retained mutants due to either modification of a Tyr-based N-terminal motif or partial misfolding physically associate but do not associate properly. Co-expression of ER-retained mutants with wild-type UapA leads to in trans plasma membrane localization of the former, confirming that oligomerization initiates in the ER. Genetic suppression of an N-terminal mutation in the Tyr motif and mutational analysis suggest that transmembrane alpha-helix 7 affects the oligomerization interface. Our results reveal that transporter oligomerization is essential for membrane trafficking and turnover and is a common theme in fungi and mammalian cells. PMID- 26049016 TI - Immunotoxin therapy for hematologic malignancies: where are we heading? AB - The identification of numerous unique targets in recent years has led to the development of various immunotoxins (ITs) for treating hematological malignancies. Some of these ITs have advanced to clinical trials and have resulted in a high response rate against leukemia. Newer targets with improve specificity are also being identified for targeting several leukemias. Currently, several modified versions of ITs with increased efficacy are being constructed and evaluated for cytotoxicity in vitro as well as in vivo. Here, we summarize recent advances in preclinical and clinical studies of recombinant ITs targeting diverse surface receptors. PMID- 26049017 TI - Behavioural and neurotoxic effects of ayahuasca infusion (Banisteriopsis caapi and Psychotria viridis) in female Wistar rat. AB - Ayahuasca, a psychoactive beverage used by indigenous and religious groups, is generally prepared by the coction of Psychotria viridis and Banisteriopsis caapi plants containing N,N-dimethyltryptamine (DMT) and beta-carboline alkaloids, respectively. To investigate the acute toxicity of ayahuasca, the infusion was administered by gavage to female Wistar rats at doses of 30X and 50X the dose taken during a religious ritual, and the animals observed for 14 days. Behavioural functions were investigated one hour after dosing at 15X and 30X using the open field, elevated plus maze, and forced swimming tests. Neuronal activation (c-fos marked neurons) and toxicity (Fluoro-Jade B and Nissl/Cresyl staining) were investigated in the dorsal raphe nuclei (DRN), amygdaloid nucleus, and hippocampal formation brain areas of rats treated with a 30X ayahuasca dose. The actual lethal oral dose in female Wistar rats could not be determined in this study, but was shown to be higher than the 50X (which corresponds to 15.1mg/kg bw DMT). The ayahuasca and fluoxetine treated groups showed a significant decrease in locomotion in the open field and elevated plus-maze tests compared to controls. In the forced swimming test, ayahuasca treated animals swam more than controls, a behaviour that was not significant in the fluoxetine group. Treated animals showed higher neuronal activation in all brain areas involved in serotoninergic neurotransmission. Although this led to some brain injury, no permanent damage was detected. These results suggest that ayahuasca has antidepressant properties in Wistar female at high doses, an effect that should be further investigated. PMID- 26049018 TI - Design, characterization and skin permeating potential of Fluocinolone acetonide loaded nanostructured lipid carriers for topical treatment of psoriasis. AB - The aim of the current study was to develop and optimize Fluocinolone acetonide (FA) loaded nanostructured lipid carriers (NLC) and to evaluate its potential as topical delivery system for management of psoriasis. FA loaded NLCs were successfully developed by modified microemulsion method and optimized using 3 level Box-Behnken design. NLCs were evaluated for particle size, polydispersity index, zeta potential, drug entrapment efficiency and drug loading. Further X-ray diffraction (XRD) and Differential scanning calorimetry (DSC), in vitro release, in vitro skin distribution and stability study were also performed. Transmission electron microscopy confirmed spherical shape of prepared NLCs. Complete encapsulation of drug in the nanoparticles was confirmed by XRD and DSC. Release study showed prolonged drug release from the NLCs following Higuchi release kinetics and Zero order release kinetics, whereas pure FA suspension exhibited faster drug release following Zero order release kinetics with R(2) value of 0.995. Stability study confirmed that NLCs were stable for 3months at 4 degrees C. Furthermore, in vitro skin distribution studies showed presence of significant amount of FA in the epidermal and dermal layer of skin when treated with FA loaded NLCs suspension while plain FA suspension showed significantly lesser amount of FA in the epidermis and dermis. Moreover, selective retention of FA in the epidermis might eliminate adverse side effects associated with systemic exposure. Thus FA loaded NLCs could be a potential system for psoriasis treatment but to create clinical value of the present system further studies are needed in clinically relevant models. PMID- 26049019 TI - Intake at a single, palatable buffet test meal is associated with total body fat and regional fat distribution in children. AB - Previous studies testing the relationship between short-term, ad libitum test meal intake and body composition in children have shown inconsistent relationships. The objective of this study was to determine whether children's intake at a palatable, buffet meal was associated with body composition, assessed by dual-energy X-ray absorptiometry (DXA). A sample of 71 children (4-6 years) participated in 4 sessions where ad libitum food intake was measured. Children's intake at two of the test-meals was retained for the present analysis: a baseline meal consisting of moderately palatable foods and a highly palatable buffet including sweets, sweet-fats, and savory-fats. On the last visit, anthropometrics and DXA were assessed to determine child body composition. Children consumed significantly more calories at the palatable buffet compared to the baseline test meal. Children's total fat-free mass was positively associated with intake at both the baseline meal and the palatable buffet meal. Total energy intake at both meals and intake of savory-fats at the palatable buffet were positively associated with children's total fat mass, total percent body fat, and percent android fat. Intake of sweet-fats was associated with child fat-free mass index. Intake of sweets was not correlated with body composition. Children's intake at a palatable test-meal, particularly of savory-fat foods, was associated with measures of total and regional body fat. PMID- 26049020 TI - Glioma initiating cells contribute to malignant transformation of host glial cells during tumor tissue remodeling via PDGF signaling. AB - INTRODUCTION: Glioma initiating cells (GICs) play important roles in tumor initiation and progression. However, interactions between tumor cells and host cells of local tumor microenvironment are kept largely unknown. Besides GICs and their progeny cells, whether adjacent normal glial cells contribute to tumorigenesis during glioma tissue remodeling deserves further investigation. METHODS: Red fluorescence protein (RFP) gene was stably transfected into human GIC cells lines SU3 and U87, then were transplanted intracerebrally into athymic nude mice with whole-body green fluorescence protein (GFP) expression. The interactions between GICs and host cells in vivo were observed during tissue remodeling processes initiated by hGICs. The biological characteristics of host glial cells with high proliferation capability cloned from the xenograft were further assayed. RESULTS: In a SU3 initiated dual-fluorescence xenograft glioma model, part of host cells cloned from the intracerebral tumors were found acquiring the capability of unlimited proliferation. PCR and FISH results indicated that malignant transformed cells were derived from host cells; cell surface marker analysis showed these cells expressed murine oligodendrocyte specific marker CNP, and oligodendrocyte progenitor cells (OPCs) specific markers PDGFR-alpha and NG2. Chromosomal analysis showed these cells were super tetraploid. In vivo studies showed they behaved with high invasiveness activity and nearly 100% tumorigenic ratio. Compared with SU3 cells with higher PDGF-B expression, GICs derived from U87 cells with low level of PDGF-B expression failed to induce host cell transformation. CONCLUSIONS: Primary high invasive GICs SU3 contribute to transformation of adjacent normal host glial cells in local tumor microenvironment possibly via PDGF/PDGFR signaling activation, which deserved further investigation. PMID- 26049021 TI - IDH1, a CHOP and C/EBPbeta-responsive gene under ER stress, sensitizes human melanoma cells to hypoxia-induced apoptosis. AB - Isocitrate dehydrogenase1 (IDH1) is of great importance in cell metabolism and energy conversion. However, alterations in IDH1 in response to stress and excise regulated mechanisms are not well described. Here we investigated gene expression profiles under ER stress in melanoma cells and found that IDH1 was dramatically increased with ER stress induced by tunicamycin. Elevated IDH1 subsequently sensitized human melanoma cells to hypoxia-induced apoptosis and promoted HIF 1alpha degradation. In addition, we revealed that CHOP and C/EBPbeta were involved in hypoxia-induced apoptosis via transcriptional regulation of IDH1 expression. Our data indicate that IDH1, regulated by CHOP and C/EBPbeta in response to ER stress treatment, inhibits survival of melanoma cells under hypoxia and promotes HIF-1alpha degradation. Therefore, we propose that IDH1 may serve as a valuable target for melanoma therapy. PMID- 26049022 TI - BCL6 induces EMT by promoting the ZEB1-mediated transcription repression of E cadherin in breast cancer cells. AB - B-cell CLL/lymphoma 6 (BCL6), a transcriptional repressor, is involved in the development and progression of breast cancers with uncertain mechanism. The purpose of this study is to investigate the potential effect and mechanism of BCL6 in the regulation of epithelial-mesenchymal transition (EMT), a critical cellular process for controlling the development and progression of breast cancers. We found that BCL6 promoted invasion, migration and growth by stimulating EMT in breast cancer cells. BCL6 induced EMT by enhancing the expression of transcriptional repressor ZEB1 which bound to the E-cadherin promoter and repressing the E-cadherin transcription. Deletion of ZEB1 protected against the pro-EMT roles of BCL6 by restoring the expression of E-cadherin in these cells. Moreover, inhibition of BCL6 with BCL6 inhibitor 79-6 suppressed these functions of BCL6 in breast cancer cells. These findings indicate that BCL6 promotes EMT via enhancing the ZEB1-mediated transcriptional repression of E cadherin in breast cancer cells. Targeting BCL6 has therapeutic potential against the development and progression of breast cancer. PMID- 26049023 TI - c-Met targeting in advanced gastric cancer: An open challenge. AB - Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC) remains poor. Because of molecular heterogeneity, it is essential to classify tumors based on the underlying oncogenic pathways and to develop targeted therapies acting on individual tumors. High-quality research and advances in technology have contributed to the elucidation of molecular pathways underlying disease progression and have stimulated many clinical studies testing target therapies in an advanced disease setting. In particular, strong preclinical evidence for the aberrant activation of the HGF/c-Met signaling pathways in GC cancers exists. This review will cover the c-Met pathway, the mechanisms of c-Met activation and the different strategies of its inhibition. Next, we will focus on the current state of the art in the clinical evaluation of c-Met-targeted therapies and the description of ongoing randomized trials with the idea that in this disease, high quality translational research to identify and validate biomarkers is a priority task. PMID- 26049024 TI - Differential zinc permeation and blockade of L-type Ca2+ channel isoforms Cav1.2 and Cav1.3. AB - Certain voltage-activated Ca2+ channels have been reported to act as potential zinc entry routes. However, it remains to be determined whether zinc can permeate individual Ca2+ channel isoforms. We expressed recombinant Ca2+ channel isoforms in Xenopus oocytes and attempted to record zinc currents from them using a two electrode voltage clamp method. We found that, in an extracellular zinc solution, inward currents arising from zinc permeation could be recorded from Xenopus oocytes expressing L-type Cav1.2 or Cav1.3 isoforms, but not from oocytes expressing Cav2.2, Cav2.3, Cav3.1, or Cav3.2. Zinc currents through Cav1.2 and Cav1.3 were blocked by nimodipine, but enhanced by (+/-)Bay K8644, supporting the finding that zinc can permeate both L-type Cav1.2 and Cav1.3 channel isoforms. We also examined the blocking effects of low concentrations of zinc on Ca2+ currents through the L-type channel isoforms. Low micro-molar zinc potently blocked Ca2+ currents through Cav1.2 and Cav1.3 with different sensitivities (IC50 for Cav1.2 and Cav1.3=18.4 and 34.1 MUM) and de-accelerated the activation and inactivation kinetics in a concentration-dependent manner. Notably, mild acidifications of the external zinc solution increased zinc currents through Cav1.2 and Cav1.3, with the increment level for Cav1.3 being greater than that for Cav1.2. In overall, we provide evidence that Cav1.2 and Cav1.3 isoforms are capable of potentially functioning as zinc permeation routes, through which zinc entry can be differentially augmented by mild acidifications. PMID- 26049026 TI - Immunofluorescence vs immunochemiluminescent methods: AIA 2000 vs Immulite 2000. AB - The aim of this study was to evaluate the measurement of C-peptide, insulin, sex hormone binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEAS), tests of specific clinical value that are not frequently measured in routine clinical laboratories, carried out using an automated system, AIA 2000 (Tosoh). The obtained data demonstrated that the evaluated system, characterized by fluorescence system detector provides satisfactory analytical performance comparable to those of different instrument that use the well known and widely diffused chemiluminescent principle (Immulite 2000). These characteristics allow an excellent comparability between methods for the measurement of same specific hormones not frequently used in clinical practice. PMID- 26049027 TI - Lactobacillus sakei K040706 evokes immunostimulatory effects on macrophages through TLR 2-mediated activation. AB - Lactobacillus sakei K040706 is the most populous lactic acid bacteria (LAB) in over ripened Doenjang, a traditional Korean fermented soybean paste. In this study, we investigated the immunostimulating effects of L. sakei K040706 (K040706) in macrophages and in cyclophosphamide-induced immunosuppressed mice. Upon exposure to K040706, significant increases in phagocytic activity and in the productions of nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were observed in rIFN-gamma-primed RAW 264.7 macrophages. K040706 also increased the expressions of inducible nitric oxide synthase (iNOS) at the protein and promoter binding levels, and the expressions of iNOS, TNF alpha, and IL-6, at the mRNA level. In addition, K040706 significantly increased the transcriptional activities and DNA binding of nuclear factor-kappaB (NF kappaB), which was accompanied by parallel enhancement of the nuclear translocation of p65 via the phosphorylations inhibitory kappa B-alpha (IkappaB alpha) and IkappaB-kinase (IKK). On the other hand, pretreatment with NF-kappaB inhibitors reduced K040706-induced NO production in IFN-gamma-primed RAW 264.7 macrophages. Furthermore, K040706 induced-NO production was completely abolished by anti-Toll-like receptor 2 (TLR2) antibody. In our cyclophosphamide-induced immunosuppressed mouse model, administration of K040706 restored thymus and spleen indices. Taken together, our findings suggest that K040706 improves immune function by regulating immunological parameters, such as, the productions of NO, TNF-alpha, and IL-6 via NF-kappaB activation, and by activating TLR2 in rIFN gamma-primed macrophages. In parallel, K040706 restored immunological parameters in cyclophosphamide-induced immunosuppressed mice and may warrant further evaluations as potential immunomodulatory agent. PMID- 26049028 TI - Paeoniflorin down-regulates ATP-induced inflammatory cytokine production and P2X7R expression on peripheral blood mononuclear cells from patients with primary Sjogren's syndrome. AB - This study determined the effects of paeoniflorin (PF) on the expression of purinergic receptor P2X ligand-gated ion channel 7 (P2X7R) expressed on peripheral blood mononuclear cells (PBMCs) and production of ATP-induced pro inflammatory cytokines released by PBMCs in patients with primary Sjogren's syndrome (pSS). The pharmacological functions and cytotoxic effects of PF were dose dependent in PBMCs from 20 newly diagnosed pSS patients and 20 normal individuals. The optimum dose of PF was 100MUM. PF significantly down-regulated the production of interleukin (IL)-1beta and IL-6 from pSS PBMCs, and significantly inhibited ATP-induced expression of P2X7R, that might contribute to reduced IL-1beta and IL-6. mRNA and protein levels of P2X7R on pSS PBMCs were significantly higher than in normal individuals (p=0.03, p<0.001). When PBMCs from subjects were stimulated in vitro with ATP in the presence of PF, P2X7R mRNA and protein levels were decreased significantly (p<0.001, p<0.001, respectively versus ATP group) in the pSS. Supernatant IL-1beta and IL-6 levels were significantly lower in the PF group compared with ATP group (p<0.001, p<0.001). We show for the first time that PF-mediated reduction of IL-1beta and IL-6 was due in part to the reduced expression and activation of the ATP sensor P2X7R on pSS PBMCs, indicating that PF might be useful for the management of pSS via down regulating P2X7R expression. Thus, PF may provide a new therapeutic approach to regulate P2X7R-mediated pathologic responses of pSS. PMID- 26049029 TI - Tryptase and protease-activated receptor-2 stimulate scratching behavior in a murine model of ovalbumin-induced atopic-like dermatitis. AB - The aim of the current study was to investigate the involvement of tryptase and protease-activated receptor-2 (PAR2) in the pathogenesis of itch using a recently developed murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). We also examined whether tacrolimus exerts an antipruritic effect. Epicutaneous sensitization of BALB/c mice with OVA led to a significant increase in the number of scratches. Notably, PAR2 mRNA and protein levels as well as cutaneous levels of tryptase were significantly enhanced in epicutaneously sensitized mice. Pretreatment with the protease inhibitor, leupeptin, PAR2 antibody, and tacrolimus significantly reduced the number of degranulated mast cells and tryptase content, and consequently alleviated scratching behavior. Cetirizine (10mg/kg) exerted a significant inhibitory effect on the scratching behavior of mice, but did not affect the number of degranulated mast cells and induction of tryptase. Our results collectively suggest that tryptase and PAR2 are involved in OVA allergy-induced scratching behavior. PMID- 26049030 TI - Acetylcholine enhances keratocyte proliferation through muscarinic receptor activation. AB - Acetylcholine (ACh), a classical neurotransmitter, has been shown to be present in various non-neuronal cells, including cells of the eye, such as corneal epithelium and endothelium, and to have widespread physiological effects such as cytoskeleton reorganization, cellular proliferation, differentiation, and apoptosis. The aim of this study was to investigate the effect of ACh on corneal keratocyte proliferation, and the underlying mechanisms, in order to explore its possible effect in corneal wound healing. Primary culture of human keratocytes was established from donated corneas. Cell viability and fraction of proliferating cells were detected by MTS assay and BrdU incorporation ELISA, respectively. Expression of proliferative markers, PCNA and Ki-67, was detected by western blot and immunocytochemistry. Activation of the MAPK/Erk signaling pathway and its involvement in ACh-enhanced proliferation was determined by western blot analysis, MTS, and BrdU ELISA. We found that ACh enhanced keratocyte proliferation even at low concentrations. Stimulation of proliferation was mediated through activation of muscarinic ACh receptors (mAChRs). Western blot analysis revealed that ACh stimulation of keratocytes upregulated the expression of PCNA and Ki-67, and Ki-67 immunocytochemistry showed that ACh-treated cells were in an active phase of the cell cycle. ACh activated MAPK signaling, and this step was crucial for the ACh-enhanced proliferation, as inhibition of the MAPK pathway resulted in ACh having no proliferative effect. In conclusion, ACh enhances keratocyte proliferation and might thus play a role in proper corneal wound healing. PMID- 26049031 TI - Quantitative proteomics provides new insights into chicken eggshell matrix protein functions during the primary events of mineralisation and the active calcification phase. AB - Eggshell is a bioceramic composed of 95% calcium carbonate mineral and 3.5% organic matrix. Its structural organisation is controlled by its organic matrix. We have used quantitative proteomics to study four key stages of shell mineralisation: 1) widespread deposition of amorphous calcium carbonate (ACC), 2) ACC transformation into crystalline calcite aggregates, 3) formation of larger calcite crystal units and 4) development of a columnar structure with preferential calcite crystal orientation. This approach explored the distribution of 216 shell matrix proteins found at the four stages. Variations in abundance according to these calcification events were observed for 175 proteins. A putative function related to the mineralisation process was predicted by bioinformatics for 77 of them and was further characterised. We confirmed the important role of lysozyme, ovotransferrin, ovocleidin-17 and ovocleidin-116 for shell calcification process, characterised major calcium binding proteins (EDIL3, ALB, MFGE8, NUCB2), and described novel proteoglycans core proteins (GPC4, HAPLN3). We suggest that OVAL and OC-17 play a role in the stabilisation of ACC. Finally, we report proteins involved in the regulation of proteins driving the mineralisation. They correspond to numerous molecular chaperones including CLU, PPIB and OCX21, protease and protease inhibitors including OVM and CST3, and regulators of phosphorylation. PMID- 26049032 TI - DNA adenine hypomethylation leads to metabolic rewiring in Deinococcus radiodurans. AB - The protein encoded by DR_0643 gene from Deinococcus radiodurans was shown to be an active N-6 adenine-specific DNA methyltransferase (Dam). Deletion of corresponding protein reduced adenine methylation in the genome by 60% and resulted in slow-growth phenotype. Proteomic changes induced by DNA adenine hypomethylation were mapped by two-dimensional protein electrophoresis coupled with mass spectrometry. As compared to wild type D. radiodurans cells, at least 54 proteins were differentially expressed in Deltadam mutant. Among these, 39 metabolic enzymes were differentially expressed in Deltadam mutant. The most prominent change was DNA adenine hypomethylation induced de-repression of pyruvate dehydrogenase complex, E1 component (aceE) gene resulting in 10 fold increase in the abundance of corresponding protein. The observed differential expression profile of metabolic enzymes included increased abundance of enzymes involved in fatty acid and amino acid degradation to replenish acetyl Co-A and TCA cycle intermediates and diversion of phosphoenolpyruvate and pyruvate into amino acid biosynthesis, a metabolic rewiring attempt by Deltadam mutant to restore energy generation via glycolysis-TCA cycle axis. This is the first report of DNA adenine hypomethylation mediated rewiring of metabolic pathways in prokaryotes. PMID- 26049033 TI - SIRT1 is a regulator of autophagy: Implications in gastric cancer progression and treatment. AB - Silent mating type information regulation 1 (SIRT1) is implicated in tumorigenesis through its effect on autophagy. In gastric cancer (GC), SIRT1 is a marker for prognosis and is involved in cell invasion, proliferation, epithelial mesenchymal transition (EMT) and drug resistance. Autophagy can function as a cell-survival mechanism or lead to cell death during the genesis and treatment of GC. This functionality is determined by factors including the stage of the tumor, cellular context and stress levels. Interestingly, SIRT1 can regulate autophagy through the deacetylation of autophagy-related genes (ATGs) and mediators of autophagy. Taken together, these findings support the need for continued research efforts to understand the mechanisms mediating the development of gastric cancer and unveil new strategies to eradicate this disease. PMID- 26049035 TI - Small saccades versus microsaccades: Experimental distinction and model-based unification. AB - Natural vision is characterized by alternating sequences of rapid gaze shifts (saccades) and fixations. During fixations, microsaccades and slower drift movements occur spontaneously, so that the eye is never motionless. Theoretical models of fixational eye movements predict that microsaccades are dynamically coupled to slower drift movements generated immediately before microsaccades, which might be used as a criterion to distinguish microsaccades from small voluntary saccades. Here we investigate a sequential scanning task, where participants generate goal-directed saccades and microsaccades with overlapping amplitude distributions. We show that properties of microsaccades are correlated with precursory drift motion, while amplitudes of goal-directed saccades do not dependent on previous drift epochs. We develop and test a mathematical model that integrates goal-directed and fixational eye movements, including microsaccades. Using model simulations, we reproduce the experimental finding of correlations within fixational eye movement components (i.e., between physiological drift and microsaccades) but not between goal-directed saccades and fixational drift motion. These results lend support to a functional difference between microsaccades and goal-directed saccades, while, at the same time, both types of behavior may be part of an oculomotor continuum that is quantitatively described by our mathematical model. PMID- 26049025 TI - Emergence of sex differences in the development of substance use and abuse during adolescence. AB - Substance use and abuse begin during adolescence. Male and female adolescent humans initiate use at comparable rates, but males increase use faster. In adulthood, more men than women use and abuse addictive drugs. However, some women progress more rapidly from initiation of use to entry into treatment. In animal models, adolescent males and females consume addictive drugs similarly. However, reproductively mature females acquire self-administration faster, and in some models, escalate use more. Sex/gender differences exist in neurobiologic factors mediating both reinforcement (dopamine, opioids) and aversiveness (CRF, dynorphin), as well as intrinsic factors (personality, psychiatric co morbidities) and extrinsic factors (history of abuse, environment especially peers and family) which influence the progression from initial use to abuse. Many of these important differences emerge during adolescence, and are moderated by sexual differentiation of the brain. Estradiol effects which enhance both dopaminergic and CRF-mediated processes contribute to the female vulnerability to substance use and abuse. Testosterone enhances impulsivity and sensation seeking in both males and females. Several protective factors in females also influence initiation and progression of substance use including hormonal changes of pregnancy as well as greater capacity for self-regulation and lower peak levels of impulsivity/sensation seeking. Same sex peers represent a risk factor more for males than females during adolescence, while romantic partners increase risk for women during this developmental epoch. In summary, biologic factors, psychiatric co-morbidities as well as personality and environment present sex/gender-specific risks as adolescents begin to initiate substance use. PMID- 26049034 TI - Neuropsychiatric symptoms in Alzheimer's disease: What might be associated brain circuits? AB - Neuropsychiatric symptoms (NPS) are very common in Alzheimer's disease (AD), particularly agitation, apathy, depression, and delusions. Brain networks or circuits underlying these symptoms are just starting to be understood, and there is a growing imaging and neurochemical evidence base for understanding potential mechanisms for NPS. We offer a synthetic review of the recent literature and offer hypotheses for potential networks/circuits underlying these NPS, particularly agitation, apathy, and delusions. Agitation in AD appears to be associated with deficits in structure and function of frontal cortex, anterior cingulate cortex, posterior cingulate cortex, amygdala, and hippocampus, and may be associated with mechanisms underlying misinterpretation of threats and affective regulation. Apathy in AD is associated with frontal cortex, anterior cingulate cortex, posterior cingulate cortex, as well as orbitofrontal cortex, and inferior temporal cortex, and may be associated with mechanisms underlying avoidance behaviors. PMID- 26049036 TI - Opponent backgrounds reduce discrimination sensitivity to competing motions: effects of different vertical motions on horizontal motion perception. AB - We examined the relationship between two distinct motion phenomena. First, locally balanced stimuli in which opposing motion signals are presented spatially near one another fail to cause a robust firing pattern in brain area MT. The brain's response to this motion is effectively suppressed, a phenomenon known as opponency. Second, past research has found that discrimination sensitivity to a target motion is negatively affected by a superimposed irrelevant motion signal - a process we call "perceptual suppression." In the current study, we examined how opponency affects the strength of perceptual suppression. We found unexpected results: a target motion embedded within an opponent background was harder to discriminate than a target motion embedded within a non-opponent background. We argue that this pattern of results runs contrary to the clear prediction stemming from the current understanding of the role of opponency in motion processing and tentatively offer an explanation based on recent MT physiology. PMID- 26049038 TI - The effect of occlusion therapy on motion perception deficits in amblyopia. AB - There is growing evidence for deficits in motion perception in amblyopia, but these are rarely assessed clinically. In this prospective study we examined the effect of occlusion therapy on motion-defined form perception and multiple-object tracking. Participants included children (3-10years old) with unilateral anisometropic and/or strabismic amblyopia who were currently undergoing occlusion therapy and age-matched control children with normal vision. At the start of the study, deficits in motion-defined form perception were present in at least one eye in 69% of the children with amblyopia. These deficits were still present at the end of the study in 55% of the amblyopia group. For multiple-object tracking, deficits were present initially in 64% and finally in 55% of the children with amblyopia, even after completion of occlusion therapy. Many of these deficits persisted in spite of an improvement in amblyopic eye visual acuity in response to occlusion therapy. The prevalence of motion perception deficits in amblyopia as well as their resistance to occlusion therapy, support the need for new approaches to amblyopia treatment. PMID- 26049039 TI - The uncatchable smile in Leonardo da Vinci's La Bella Principessa portrait. AB - A portrait of uncertain origin recently came to light which, after extensive research and examination, was shown to be that rarest of things: a newly discovered Leonardo da Vinci painting entitled La Bella Principessa. This research presents a new illusion which is similar to that identified in the Mona Lisa; La Bella Principessa's mouth appears to change slant depending on both the Viewing Distance and the Level of Blur applied to a digital version of the portrait. Through a series of psychophysics experiments, it was found that a perceived change in the slant of the La Bella Principessa's mouth influences her expression of contentment thus generating an illusion that we have coined the "uncatchable smile". The elusive quality of the Mona Lisa's smile has been previously reported (Science, 290 (2000) 1299) and so the existence of a similar illusion in a portrait painted prior to the Mona Lisa becomes more interesting. The question remains whether Leonardo da Vinci intended this illusion. In any case, it can be argued that the ambiguity created adds to the portrait's allure. PMID- 26049040 TI - Spatial properties of non-retinotopic reference frames in human vision. AB - Many visual attributes of a target stimulus are computed according to dynamic, non-retinotopic reference frames. For example, the motion trajectory of a reflector on a bicycle wheel is perceived as orbital, even though it is in fact cycloidal in retinal, as well as spatial coordinates. We cannot perceive the cycloidal motion because the linear motion of the bike is discounted for. In other words, the linear motion common to all bicycle components serves as a non retinotopic reference frame, with respect to which the residual (orbital) motion of the reflector is computed. Very little is known about the underlying mechanisms involved in formation and operation of non-retinotopic reference frames. Here, we investigate spatial properties of non-retinotopic reference frames. We show that reference frames are not restricted within the boundaries of moving stimuli but extend over space. By using a variation of the Ternus-Pikler paradigm, we show that the spatial extent of a non-retinotopic reference frame is independent of the size of the inducing elements and the target position near the object boundary. While dynamic reference-frames interact with each other significantly, a static reference-frame has no effect on a dynamic one. The magnitude of interactions between two neighboring dynamic reference-frames increases as the distance between them reduces. Finally, our results indicate that the reference-frame strength is significantly attenuated if the locus of attention is shifted to the elements of the neighboring reference instead of the main reference. We suggest that these results can be conceptualized as reference frames that act and interact as fields. PMID- 26049037 TI - Micro and regular saccades across the lifespan during a visual search of "Where's Waldo" puzzles. AB - Despite the fact that different aspects of visual-motor control mature at different rates and aging is associated with declines in both sensory and motor function, little is known about the relationship between microsaccades and either development or aging. Using a sample of 343 individuals ranging in age from 4 to 66 and a task that has been shown to elicit a high frequency of microsaccades (solving Where's Waldo puzzles), we explored microsaccade frequency and kinematics (main sequence curves) as a function of age. Taking advantage of the large size of our dataset (183,893 saccades), we also address (a) the saccade amplitude limit at which video eye trackers are able to accurately measure microsaccades and (b) the degree and consistency of saccade kinematics at varying amplitudes and directions. Using a modification of the Engbert-Mergenthaler saccade detector, we found that even the smallest amplitude movements (0.25-0.5 degrees ) demonstrate basic saccade kinematics. With regard to development and aging, both microsaccade and regular saccade frequency exhibited a very small increase across the life span. Visual search ability, as per many other aspects of visual performance, exhibited a U-shaped function over the lifespan. Finally, both large horizontal and moderate vertical directional biases were detected for all saccade sizes. PMID- 26049041 TI - Unraveling the evolutionary history of the Chilostoma Fitzinger, 1833 (Mollusca, Gastropoda, Pulmonata) lineages in Greece. AB - The land snails of the genus Chilostoma Fitzinger, 1833 that includes, in Greece, the (sub)genera Cattania, Josephinella and Thiessea, are highly diversified and present high levels of endemism. However, their evolutionary history is unknown and their taxonomy is complex and continuously revised. The aim of this study is to investigate the phylogenetic relationships of the lineages of the genus Chilostoma distributed in Greece based on partial DNA sequences of two mitochondrial DNA (16S rRNA and COI) genes. Complete sequences of one nuclear gene (ITS1) representing the major mitochondrial lineages were also analyzed. The phylogenetic trees revealed three distinct major clades that correspond to the three (sub)genera. Several taxonomical incongruencies were made obvious, thus, raising questions about the "true" number of species in each clade, while rendering a taxonomic re-evaluation necessary. From a phylogeographic point of view, it seems that the three major phylogenetic clades were separated in the late Miocene. They started differentiating into distinct species during the Pliocene and Pleistocene through several vicariance and dispersal events. PMID- 26049042 TI - Phylogenetic framework of the systematically confused Anteholosticha-Holosticha complex (Ciliophora, Hypotrichia) based on multigene analysis. AB - The Anteholosticha-Holosticha complex is an extremely divergent group within the urostylids, especially because the genus characterization lacks suitable synapomorphies. Previous studies have shown that morphological classification of species within this group often conflicts with SSU-rDNA data, that is this complex is not recovered as a monophyletic group and Anteholosticha spp. are widely dispersed throughout the urostylid assemblage in SSU-rDNA trees. In this study, we provided 38 new sequences (including the type species of Anteholosticha) of SSU-rDNA, ITS1-5.8S-ITS2 and LSU-rDNA genes to infer molecular phylogenies of all available taxa in the Anteholosticha-Holosticha complex. The results show that: (1) Holosticha is monophyletic in all trees, suggesting it is a well-defined genus; (2) Anteholosticha is polyphyletic and distinctly separated from Holosticha in all single-gene based and concatenated phylogenies; (3) the monophyly of Arcuseries, a recently established genus split from Anteholosticha, is strongly supported by all molecular data; (4) Anteholosticha multicirrata, Anteholosticha manca, Anteholosticha paramanca and Bakuella subtropica may share a most recent common ancestor; (5) multi-gene analyses receive higher support values than the single-gene analyses. PMID- 26049043 TI - Re-evaluating the phylogeny of allopolyploid Gossypium L. AB - The formation of allopolyploid cotton precipitated a rapid diversification and colonization of dry coastal American tropical and subtropical regions. Previous phylogenetic analyses, combined with molecular divergence analyses, have offered a temporal framework for this radiation, but provide only weak support for some of the resolved branches. Moreover, these earlier analyses did not include the recently recognized sixth polyploid species, G. ekmanianum Wittmack. Here we use targeted sequence capture of multiple loci in conjunction with both concatenated and Bayesian concordance analyses to reevaluate the phylogeny of allopolyploid cotton species. Although phylogenetic resolution afforded by individual genes is often low, sufficient signal was attained both through the concatenated and concordance analyses to provide robust support for the Gossypium polyploid clade, which is reported here. PMID- 26049044 TI - Evolutionary trajectories and diagnostic challenges of potentially zoonotic avian influenza viruses H5N1 and H9N2 co-circulating in Egypt. AB - In Egypt, since 2006, descendants of the highly pathogenic avian influenza virus (HP AIV) H5N1 of clade 2.2 continue to cause sharp losses in poultry production and seriously threaten public health. Potentially zoonotic H9N2 viruses established an endemic status in poultry in Egypt as well and co-circulate with HP AIV H5N1 rising concerns of reassortments between H9N2 and H5N1 viruses along with an increase of mixed infections of poultry. Nucleotide sequences of whole genomes of 15 different isolates (H5N1: 7; H9N2: 8), and of the hemagglutinin (HA) and neuraminidase (NA) encoding segments of nine further clinical samples (H5N1: 2; H9N2: 7) from 2013 and 2014 were generated and analysed. The HA of H5N1 viruses clustered with clade 2.2.1 while the H9 HA formed three distinguishable subgroups within cluster B viruses. BEAST analysis revealed that H9N2 viruses are likely present in Egypt since 2009. Several previously undescribed substituting mutations putatively associated with host tropism and virulence modulation were detected in different proteins of the analysed H9N2 and H5N1 viruses. Reassortment between HP AIV H5N1 and H9N2 is anticipated in Egypt, and timely detection of such events is of public health concern. As a rapid tool for detection of such reassortants discriminative SYBR-Green reverse transcription real-time PCR assays (SG-RT-qPCR), targeting the internal genes of the Egyptian H5N1 and H9N2 viruses were developed for the rapid screening of viral RNAs from both virus isolates and clinical samples. However, in accordance to Sanger sequencing, no reassortants were found by SG-RT-qPCR. Nevertheless, the complex epidemiology of avian influenza in poultry in Egypt will require sustained close observation. Further development and continuing adaptation of rapid and cost effective screening assays such as the SG-RT-qPCR protocol developed here are at the basis of efforts for improvement the currently critical situation. PMID- 26049046 TI - PcFKH1, a novel regulatory factor from the forkhead family, controls the biosynthesis of penicillin in Penicillium chrysogenum. AB - Penicillin biosynthesis in Penicillium chrysogenum (re-identified as Penicillium rubens) is a good example of a biological process subjected to complex global regulatory networks and serves as a model to study fungal secondary metabolism. The winged-helix family of transcription factors recently described, which includes the forkhead type of proteins, is a key type of regulatory proteins involved in this process. In yeasts and humans, forkhead transcription factors are involved in different processes (cell cycle regulation, cell death control, pre-mRNA processing and morphogenesis); one member of this family of proteins has been identified in the P. chrysogenum genome (Pc18g00430). In this work, we have characterized this novel transcription factor (named PcFKH1) by generating knock down mutants and overexpression strains. Results clearly indicate that PcFKH1 positively controls antibiotic biosynthesis through the specific interaction with the promoter region of the penDE gene, thus regulating penDE mRNA levels. PcFKH1 also binds to the pcbC promoter, but with low affinity. In addition, it also controls other ancillary genes of the penicillin biosynthetic process, such as phlA (encoding phenylacetyl CoA ligase) and ppt (encoding phosphopantetheinyl transferase). PcFKH1 also plays a role in conidiation and spore pigmentation, but it does not seem to be involved in hyphal morphology or cell division in the improved laboratory reference strain Wisconsin 54-1255. A genome-wide analysis of processes putatively coregulated by PcFKH1 and PcRFX1 (another winged-helix transcription factor) in P. chrysogenum provided evidence of the global effect of these transcription factors in P. chrysogenum metabolism. PMID- 26049045 TI - The phenotype of a knockout mouse identifies flavin-containing monooxygenase 5 (FMO5) as a regulator of metabolic ageing. AB - We report the production and metabolic phenotype of a mouse line in which the Fmo5 gene is disrupted. In comparison with wild-type (WT) mice, Fmo5(-/-) mice exhibit a lean phenotype, which is age-related, becoming apparent after 20 weeks of age. Despite greater food intake, Fmo5(-/-) mice weigh less, store less fat in white adipose tissue (WAT), have lower plasma glucose and cholesterol concentrations and enhanced whole-body energy expenditure, due mostly to increased resting energy expenditure, with no increase in physical activity. An increase in respiratory exchange ratio during the dark phase, the period in which the mice are active, indicates a switch from fat to carbohydrate oxidation. In comparison with WT mice, the rate of fatty acid oxidation in Fmo5(-/-) mice is higher in WAT, which would contribute to depletion of lipid stores in this tissue, and lower in skeletal muscle. Five proteins were down regulated in the liver of Fmo5(-/-) mice: aldolase B, ketohexokinase and cytosolic glycerol 3 phosphate dehydrogenase (GPD1) are involved in glucose or fructose metabolism and GPD1 also in production of glycerol 3-phosphate, a precursor of triglyceride biosynthesis; HMG-CoA synthase 1 is involved in cholesterol biosynthesis; and malic enzyme 1 catalyzes the oxidative decarboxylation of malate to pyruvate, in the process producing NADPH for use in lipid and cholesterol biosynthesis. Down regulation of these proteins provides a potential explanation for the reduced fat deposits and lower plasma cholesterol characteristic of Fmo5(-/-) mice. Our results indicate that disruption of the Fmo5 gene slows metabolic ageing via pleiotropic effects. PMID- 26049047 TI - Leukocyte telomere length is associated with advanced age-related macular degeneration in the Han Chinese population. AB - Telomeres located at the ends of chromosomes are involved in genomic stability and play a key role in various cancers and age-related diseases. Age-related macular degeneration (AMD) is a late-onset, age-associated progressive neurodegenerative disease, which includes the geographic atrophy (GA) subtype and the choroidal neovascularization (CNV) subtype. To better understand how leukocyte telomere length (LTL) is related to AMD, we conducted an association study in 197 AMD patients and 259 healthy controls using the established quantitative PCR technique. Logistic regression was performed to evaluate the association of LTL and AMD with the age-adjusted ratio of the telomere length to the copy number of a single-copy gene (T/S). Notably, we found a significant association between AMD and LTL (OR=2.24; 95% CI=1.68-3.07; P=0.0001) after adjusting for age and sex. Furthermore, the results showed a strongly significant association between the GA subtype and the LTL (OR=4.81; 95% CI=3.15-7.82; P=0.0001) after adjusting for age and sex. Our findings provide evidence of the role that LTL plays in the pathological mechanisms of AMD, mainly in the GA subgroup but not the CNV subgroup. PMID- 26049048 TI - Clinical safety of the Iforia implantable cardioverter-defibrillator system in patients subjected to thoracic spine and cardiac 1.5-T magnetic resonance imaging scanning conditions. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are generally considered a contraindication to magnetic resonance imaging (MRI). OBJECTIVE: The purpose of the ProMRI Phase C study, a multicenter, prospective, single-arm, nonrandomized study, was to evaluate the clinical safety of the Biotronik ProMRI Iforia ICD system during MRI. METHODS: Patients were enrolled after ICD implantation, with either a dual-chamber DR-T or single-lead VR-T DX system. Study-defined, nondiagnostic cardiac or thoracic spine MRI was performed at least 1 week after enrollment. ICDs were placed into MRI mode with ventricular fibrillation (VF) detection/therapy programmed "off" before scan and restored to non-MRI mode after scan. Interrogation was performed before, immediately after, and 1 month post-MRI. The primary end-points were (1) ventricular pacing threshold increase >0.5 V from pre-MRI to 1 month post-MRI; (2) R-wave amplitude decrease >50% from pre-MRI to 1 month post-MRI or R-wave amplitude <5 mV at 1 month post-MRI; and (3) MRI and ICD system-related serious adverse device effects. RESULTS: One hundred seventy patients were enrolled at 39 US centers. One hundred fifty-three patients underwent MRI (25.7% cardiac, 74.3% thoracic spine) and completed follow-up. Freedom from the primary end-points was met in all but 1 subject, in whom reduced R-wave amplitude was detected 1 month post MRI. No serious adverse device effects occurred during the course of the study. CONCLUSION: These results demonstrate the clinical safety and efficacy of the ProMRI ICD system in patients subjected to thoracic spine and cardiac MRI imaging in 1.5-T scanners. PMID- 26049049 TI - Management of patients with implantable cardioverter-defibrillators and pacemakers who require radiation therapy. AB - BACKGROUND: Radiation therapy (RT) may pose acute and long-term risks for patients with cardiac implantable electronic devices (CIEDs), including pacemakers (PMs) and implantable cardioverter-defibrillators (ICDs). However, the frequency of these problems has not been accurately defined. OBJECTIVE: The purpose of this study was to determine the prevalence of CIEDs among patients requiring RT and report the common CIED-related problems when patients are managed according to a standard clinical care path. METHODS: In a single tertiary care center, we prospectively screened all patients requiring RT and identified patients with ICDs or PMs. We collected clinical data about their cancer, RT treatment plan, and CIED. Radiation dose to the device was estimated in all patients, and any device malfunction during RT was documented. RESULTS: Of the 34,706 consecutive patients receiving RT, 261 patients (0.8%, mean age 77.9 +/- 9.4 years) had an implantable cardiac device: 54 (20.7%) ICDs and 207 (79.3%) PMs. The site of RT was head and neck (27.4%), chest (30.0%), and abdomen/pelvis (32.6%). Using our care path, 63.2% of patients required continuous cardiac monitoring, 14.6% required device reprogramming, 18.8% required magnet application during RT, and 3.4% required device repositioning to the contralateral side before RT. Four patients (1.5%) had inappropriate device function during RT: 3 experienced hemodynamically tolerated ventricular pacing at the maximum sensor rate, and 1 experienced a device power-on-reset. No patient died or suffered permanent device failure. CONCLUSION: Nearly 1% of patients receiving RT in this series has a PM or ICD. However, with a systematic policy of risk assessment and patient management, significant device-related complications are rare. PMID- 26049050 TI - History of hyperthyroidism and long-term outcome of catheter ablation of drug refractory atrial fibrillation. AB - BACKGROUND: Hyperthyroidism is a known reversible cause of atrial fibrillation (AF). However, some patients remain in AF despite restoration of euthyroid status. OBJECTIVE: The purpose of this study was to compare the electrophysiologic characteristics and long-term ablation outcome in AF patients with and without history of hyperthyroidism. METHODS: The study enrolled 717 consecutive patients with AF who underwent first AF ablation, which involved pulmonary vein (PV) isolation in paroxysmal AF and additional substrate modification in nonparoxysmal AF patients. Eighty-four patients (12%) with hyperthyroidism history were compared to those without. Euthyroid status was achieved for >=3 months before ablation in hyperthyroid patients. RESULTS: Patients with hyperthyroid history were associated with older age, more female gender, lower mean right atrial voltage, higher number of PV ectopic foci (1.3 +/ 0.4 vs 1.0 +/- 0.2, P < .01), and higher prevalence of non-PV foci (42% vs 23%, P < .01). Ectopic foci from ligament of Marshall were demonstrated more often in hyperthyroid patients (7.1% vs 1.6%, P < .01) in whom alcohol ablations were required. After propensity score matching for potential covariates, history of hyperthyroidism was an independent predictor of AF recurrence after single procedure (hazard ratio 2.07, 95% confidence interval 1.27-3.38). AF recurrence rates after multiple procedures were not different between patients with and those without hyperthyroid history. CONCLUSION: Patients with hyperthyroid history had a significantly higher number of PV ectopies and higher prevalence of non-PV ectopic foci compared to euthyroid patients, which resulted in a higher AF recurrence rate after a single procedure. PMID- 26049051 TI - Coenzyme Q-dependent mitochondrial respiratory chain activity in granulosa cells is reduced with aging. AB - OBJECTIVE: To examine coenzyme Q10 (CoQ10)-dependent mitochondrial respiratory chain (MRC) activity in granulosa cells (GC) with aging and examine the effect of in vitro CoQ supplementation. DESIGN: Experimental study. SETTING: Hospital laboratory. PATIENT(S): Ten younger (<32 years) and 10 older (>39 years) patients undergoing in vitro fertilization (IVF) treatment. INTERVENTION(S): Measurement of succinate-cytochrome c reductase (MRC complex II + III) activity in the presence and absence of CoQ1 (a soluble CoQ analog). MAIN OUTCOME MEASURE(S): MRC enzymatic activity in human GC via complex II + III measured in GC homogenate by spectrophotometry and compared with CoQ in dependent MRC complex II and citrate synthase (CS). RESULT(S): Complex II + III activity was 1.9 times higher in young patients compared with older patients (18.3 +/- 5.8 and 9.6 +/- 3 nmol/min/mg, respectively) whereas II and CS were not statistically significantly different. Increased II + III activity in the presence CoQ1 was observed in both groups but was statistically significantly higher in the older patients, reaching similar levels. Compared with baseline (II + III + Q/II + III), the increase was 2.47 times higher in older patients compared with young patients (6.5 +/- 2.0 and 2.62 +/- 0.83, respectively). CONCLUSION(S): Coenzyme Q10-dependent MRC activity in GC reduces with aging. This reduction is diminished upon in vitro CoQ1 supplementation, indicating that CoQ10 deficit is the underlying cause for the mitochondrial dysfunction. The results show that functional CoQ10 status can be assessed by measuring complex II + III activity in GC and might provide a useful monitoring tool for future clinical studies of oral CoQ10 supplementation to older patients undergoing IVF treatment. PMID- 26049052 TI - Who are we? A perspective on the reproductive endocrinologist and infertility specialist in the 21st century. PMID- 26049053 TI - Invasion process of induced deep nodular endometriosis in an experimental baboon model: similarities with collective cell migration? AB - OBJECTIVE: To determine the implications of collective cell migration in the invasion phenomenon observed in deep endometriotic lesions induced in a baboon model. DESIGN: Study of morphology and collective cell migration markers in invasive and noninvasive deep endometriotic lesions induced in a baboon model. Invasive lesions were defined as the presence of endometrial glands and stroma in surrounding organs, and a distinction was made between the center of the lesion (glands present in the main lesion) and the invasion front (glands present in surrounding organs). SETTING: Academic research unit. ANIMAL(S): Ten female baboons (Papio anubis). INTERVENTION(S): Recovery of induced deep nodular endometriotic nodules. MAIN OUTCOME MEASURE(S): Evaluation of the morphology of glands by analysis of noninvasive and invasive lesions (center of the lesion and invasion front); staining with specific antibodies (Ki67, E-cadherin, beta catenin) for immunohistochemical study of mitotic activity and cell-cell junctions. RESULT(S): Glands from invasive lesions, particularly from the invasion front, showed a significantly lower thickness coefficient, higher mitotic activity, and lower expression of E-cadherin and beta-catenin than glands from noninvasive lesions and the center of invasive lesions. CONCLUSION(S): We report altered morphology, increased mitotic activity, and fewer adhesion molecules in invasive glands present in induced nodular endometriosis, particularly along the invasion front, suggesting that collective cell migration is involved in the invasion process of deep endometriotic lesions induced in a baboon model. PMID- 26049054 TI - Infertility, fertility treatment, and risk of hypertension. AB - OBJECTIVE: To evaluate the association between infertility and fertility treatments on subsequent risk of hypertension. DESIGN: Cohort study. SETTING: Not applicable. PATIENT(S): A total of 116,430 female nurses, followed from 1993 to June 2011, as part of the Nurses' Health Study II cohort. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Self-reported, physician-diagnosed hypertension. RESULT(S): Compared with women who have never reported infertility, infertile women were at no greater risk of hypertension (multivariable adjusted relative risk (RR) = 1.01, with 95% confidence interval [CI] [0.94-1.07]). Infertility due to tubal disease was associated with a higher risk of hypertension (RR = 1.15 [1.01-1.31]), but no other diagnoses were associated with hypertension risk, compared with women who did not report infertility (ovulatory disorder: RR = 1.03 [0.94-1.13]; cervical: RR = 0.88 [0.70-1.10]; male factor: RR = 1.05 [0.95-1.15]; other reason: RR = 1.02 [0.94-1.11]; reason not found: RR = 1.02 [0.95-1.10]). Infertile women collectively had 5,070 cases of hypertension. No clear pattern between use of fertility treatment and hypertension was found among infertile women (clomiphene citrate: RR = 0.97 [0.90-1.04]; gonadotropin alone: RR = 0.97 [0.87-1.08]; intrauterine insemination: RR = 0.86 [0.71-1.03]; in vitro fertilization: RR = 0.86 [0.73-1.01]). CONCLUSION(S): Among this relatively young cohort of women, no apparent increase occurred in hypertension risk among infertile women, or among women who had undergone fertility treatment previously. PMID- 26049055 TI - Value of transferring embryos that show no evidence of fertilization at the time of fertilization assessment. AB - OBJECTIVE: To determine the value of transferring embryos formed from nonpronuclear (0PN) zygotes. DESIGN: A case-control study. SETTING: Not applicable. PATIENT(S): The current study was a retrospective analysis of embryo transfers of just 0PN embryos using fresh cleavage-stage embryos (0PN cleavage fresh), frozen-thawed cleavage-stage 0PN embryos (0PN cleavage frozen), and frozen 0PN blastocyst-stage embryos (0PN blast frozen). INTERVENTION(S): To study the effect of 0PN transfer, comparison groups were used: fresh cycles of 2PN (2PN cleavage fresh-C) and frozen-thawed cycles cleavage-stage (2PN cleavage frozen-C) and blastocyst-stage (2PN blast frozen-C). Comparison groups were matched for cycle and patient characteristics to the 0PN group. MAIN OUTCOME MEASURE(S): Implantation rate (IR), pregnancy rate, and transferable embryo rate. RESULT(S): For fresh cycles, the IR in the 0PN cleavage fresh was lower than that in the 2PN cleavage fresh-C (8.04% vs. 19.50%, respectively). For frozen-thawed cycles, the IR in the 0PN cleavage frozen was lower than that in the 2PN cleavage frozen-C (15.38% vs. 28.24%, respectively), but the IR in 0PN blast frozen was comparable to that of 2PN blast frozen-C (39.56% vs. 48.18%, respectively). CONCLUSION(S): Transfer of 0PN embryos from fresh or frozen-thawed cycles results in pregnancies and live births. Nonpronuclear embryos have a lower IR than 2PN embryos, but if the embryos are cultured to the blastocyst stage and then are frozen, their IRs approach that of 2PN embryos in subsequent frozen-thawed cycles. The culture of 0PN embryos to the blastocyst stage may select for embryos with a near-normal IR. PMID- 26049056 TI - Racial disparities in in vitro fertilization outcomes. AB - OBJECTIVE: To evaluate the impact of race on in vitro fertilization (IVF) outcomes. DESIGN: Retrospective analysis. SETTING: Private practice. PATIENT(S): All women who underwent a first autologous IVF cycle at Fertility Centers of Illinois from January 2010 to December 2012. INTERVENTION(S): Information was collected on baseline characteristics, cycle parameters, and outcomes. Race was self-reported. MAIN OUTCOME MEASURE(S): Clinical intrauterine pregnancy and live birth rates. RESULT(S): A total of 4,045 women were included: 3,003 white (74.2%), 213 black (5.3%), 541 Asian (13.4%), and 288 Hispanic women (7.1%). A multivariable logistic regression was performed to control for confounders. Compared with white women, the adjusted odds ratio for clinical intrauterine pregnancy was 0.63 (95% confidence interval [CI] 0.44-0.88) in black women, 0.73 (95% CI 0.60-0.90) in Asian women, and 0.82 (95% CI 0.62-1.07) in Hispanic women. The adjusted odds ratio for live birth was 0.50 (95% CI 0.33-0.72) in black women, 0.64 (95% CI 0.51-0.80) in Asian women, and 0.80 (95% CI 0.60-1.06) in Hispanic women compared with white women. The spontaneous abortion rate was 14.6% in white women versus 28.9% in black women, 20.6% in Asian women, and 15.3% in Hispanic women. CONCLUSION(S): Black and Asian women had lower odds of clinical intrauterine pregnancy and live birth and higher rates of spontaneous abortion compared with white women. Further research is needed to better characterize the mechanisms associated with this racial disparity and to improve treatment options for black and Asian women. PMID- 26049057 TI - Diminished ovarian reserve in the United States assisted reproductive technology population: diagnostic trends among 181,536 cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. AB - OBJECTIVE: To evaluate trends in diminished ovarian reserve (DOR) assignment in the Society for Assisted Reproductive Technology (SART) Clinic Outcomes Reporting System database and to evaluate its accuracy in predicting poor ovarian response (POR) as defined in European Society of Human Reproduction and Embryology's Bologna criteria (2011). DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): A total of 181,536 fresh, autologous ART cycles reported to SART by U.S. clinics in 2004 and 2011 (earliest and most recent available reporting years). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): DOR assignment was the primary exposure. POR, defined as cycle cancellation for poor response or less than 4 oocytes retrieved after conventional gonadotropin stimulation (>149 IU FSH daily), was the primary outcome. Secondary outcomes were live birth and number of oocytes retrieved. DOR prevalence, power of DOR and FSH (=12 mIU/mL) to predict POR, and live birth in POR cycles were also calculated. RESULT(S): DOR prevalence increased from 19% to 26% from 2004 to 2011. Among cycles clinically assigned as DOR, incidence of POR decreased from 32% to 30%, and live birth improved from 15% to 17%. Comparing basal FSH >=12 versus clinical assignment of DOR, basal FSH had a higher specificity (92.2% vs. 81.6%) and positive predictive value (38.3% vs. 30.9%) for predicting POR. Live birth among POR cycles was 4%. CONCLUSION(S): DOR diagnosis is increasing, and accuracy remains poor, despite the availability of additional diagnostic parameters such as antral follicle count and antimullerian hormone. POR entailed poor outcomes, but the majority of patients clinically assigned as DOR did not experience POR. Development and use of more accurate predictors of POR are needed to minimize patient distress resulting from overdiagnosis. PMID- 26049059 TI - Predictability and context determine differences in conflict monitoring between adolescence and adulthood. AB - The ability to link contextual information to actions is an important aspect of conflict monitoring and response selection. These mechanisms depend on medial prefrontal networks. Although these areas undergo a protracted development from adolescence to adulthood, it has remained elusive how the influence of contextual information on conflict monitoring is modulated between adolescence and adulthood. Using event-related potentials (ERPs) and source localization techniques we show that the ability to link contextual information to actions is altered and that the predictability of upcoming events is an important factor to consider in this context. In adolescents, conflict monitoring functions are not as much modulated by predictability factors as in adults. It seems that adults exhibit a stronger anticipation of upcoming events than adolescents. This results in disadvantages for adults when the upcoming context is not predictable. In adolescents, problems to predict upcoming events therefore turn out to be beneficial. Two cognitive-neurophysiological factors are important for this: The first factor is related to altered conflict monitoring functions associated with modulations of neural activity in the medial frontal cortex. The second factor is related to altered perceptual processing of target stimuli associated with modulations of neural activity in parieto-occipital areas. PMID- 26049058 TI - Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep. AB - Recent evidence suggests that blockade of the hypocretin receptor 1 may act as a useful pharmacotherapy for cocaine abuse. Here we investigated the extent to which various doses of a hypocretin receptor 1 antagonist, SB-334867, affect cocaine self-administration at varying doses of cocaine and across a range of effort requirements, and tested if these SB-334867 doses produce sedative effects. First, we trained animals to self-administer one of three doses of cocaine on a progressive ratio schedule, and then tested the effects of three doses of SB-334867. Responding for cocaine was then analyzed to segregate features of relatively high and low effort requirements across the progressive ratio session. In another set of experiments, we tested potential sleep-promoting effects of the same doses of SB-334867. Our data indicate that blockade of hypocretin receptor 1 preferentially reduces high effort responding for cocaine at levels that do not promote sedation. PMID- 26049060 TI - Antagonism of kappa opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence. AB - The association between morphine withdrawal and depressive-like symptoms is well documented, however, the role of dynorphin/kappa opioid receptor system and the underlying neural substrates have not been fully understood. In the present study, we found that four weeks morphine abstinence after a chronic escalating morphine regimen significantly induced depressive-like behaviors in mice. Prodynorphin mRNA and protein levels were increased in the nucleus accumbens (NAc) after four weeks of morphine withdrawal. Local injection of kappa opioid receptor antagonist nor-Binaltorphimine (norBNI) in the NAc significantly blocked the expression of depressive-like behaviors without influencing general locomotor activity. Thus, the present study extends previous findings by showing that prolonged morphine withdrawal-induced depressive-like behaviors are regulated by dynorphin/kappa opioid receptor system, and shed light on the kappa opioid receptor antagonists as potential therapeutic agents for the treatment of depressive-like behaviors induced by opiate withdrawal. PMID- 26049061 TI - Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments. AB - Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60-70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle. PMID- 26049062 TI - Assessment of learning, memory and attention in developmental neurotoxicity regulatory studies: Introduction. AB - There are a variety of chemicals, including pharmaceuticals, that alter neurobehavior following developmental exposure and guidelines for the conduct of studies to detect such effects by statute in the United States and Europe. Guidelines for Developmental Neurotoxicity Testing (DNT) studies issued by the U.S. Environmental Protection Agency (EPA) under prevailing law and European Organization for Economic Cooperation and Development (OECD) recommendations to member countries provide that such studies include a series of neurobehavioral and neuropathological assessments. Among these are assessment of cognitive function, specifically learning and memory. After reviewing 69 DNT studies submitted to the EPA, tests of learning and memory were noted to have detected the lowest observed adverse effect level (LOAELs) less frequently than behavioral tests of locomotor activity and acoustic/auditory startle, but slightly more than for the developmental Functional Observational Battery (devFOB; which is less extensive than the full FOB), but the reasons for the lower LOAEL detection rate for learning and memory assessment could not be determined. A major concern identified in the review, however, was the adequacy of the methods employed in these studies rather than on the importance of learning and memory to the proper assessment of brain function. Accordingly, a symposium was conducted to consider how the guidelines for tests of learning and memory might be improved. Four laboratories with established histories investigating the effects of chemical exposures during development on learning, memory, and attention, were invited to review the topic and offer recommendations, both theoretical and practical, on approaches to improve the assessment of these vital CNS functions. Reviewers were asked to recommend methods that are grounded in functional importance to CNS integrity, well-validated, reliable, and amenable to the context of regulatory studies as well as to basic research on the underlying processes they measure. This Introduction sets the stage for the reviews by providing the background and regulatory context for improved tests for learning and memory in DNT and other regulatory studies, such as single- or multi-generational studies where similar methods are incorporated. PMID- 26049063 TI - A novel multi-domain C1qDC protein from Zhikong scallop Chlamys farreri provides new insights into the function of invertebrate C1qDC proteins. AB - The C1q domain containing (C1qDC) proteins are a family of proteins possessing globular C1q (gC1q) domains, and they rely on this domain to recognize various ligands such as PAMPs, immunoglobulins, ligands on apoptotic cell. In the present study, a novel multi-domain C1qDC protein (CfC1qDC-2) was identified from scallop Chlamys farreri, and its full length cDNA was composed of 1648 bp, encoding a signal peptide and three typical gC1q domains. BLAST analysis revealed significant sequence similarity between CfC1qDC-2 and C1qDC proteins from mollusks. Three gC1q domains were predicted in its tertiary structure to form a tightly packed bell-shaped trimer, and each one adopted a typical 10-stranded sandwich fold with a jelly-roll topology and contained six aromatic amino acids forming the hydrophobic core. The mRNA transcripts of CfC1qDC-2 were mainly detected in the tissues of hepatopancreas and gonad of adult scallops, and the expression level was up-regulated in hemocytes after stimulated by LPS, PGN and beta-glucan. During the embryonic development of scallop, the mRNA transcripts of CfC1qDC-2 were presented in all the detected stages, and the expression level was up-regulated from D-hinged larvae and reached the highest at eye-spot larvae. The recombinant protein of MBP-CfC1qDC-2 (rCfC1qDC-2) could bind various PAMPs including LPS, PGN, LTA, beta-glucan, mannan as well as polyI:C, and different microorganisms including three Gram-negative bacteria, three Gram-positive bacteria and two yeasts, as well as scallop apoptotic cells. Meanwhile, rCfC1qDC 2 could interact with human heat-aggregated IgG and IgM, and inhibit the C1q dependent hemolysis of rabbit serum. All these results indicated that CfC1qDC-2 could recognize not only PAMPs as a PRR, but also the apoptotic cells. Moreover, the similar structures and functions shared by CfC1qDC-2 and complement C1q provided a new insight into the evolution of C1qDC proteins in complement system. PMID- 26049064 TI - Debridement with prosthesis retention and antibiotherapy vs. two-stage revision for periprosthetic knee infection within 3 months after arthroplasty: a case control study. AB - Sixty-four patients with periprosthetic infection within 3 months of index arthroplasty, of whom 39 underwent debridement with prosthesis retention and antibiotherapy (DPRA), and 25 underwent two-stage revision (2SR), were compared regarding control of infection and functional outcomes by use of Knee Society scores. Failure was defined as the need for subsequent surgery to control infection. The failure rate after DPRA was 61.5%, and that after 2SR was 12.0% (p 0.001). The failure risk was not significantly associated with the duration of symptoms (<=4 weeks). The only predictor of failure was isolation of Staphylococcus aureus or Staphylococcus epidermidis. Treatment with 2SR required fewer surgical operations, a shorter duration of hospitalization, and a shorter duration of treatment. All patients who required a second debridement ultimately underwent prosthesis removal. The functional outcome was significantly better for 2SR at the last follow-up. PMID- 26049066 TI - Prediction of Esophageal Variceal Bleeding in Liver Cirrhosis: Is There a Role for Hemostatic Factors? AB - Variceal bleeding is a frequent and ominous complication of liver cirrhosis. Fortunately, primary prophylaxis with beta blockers or esophageal band ligation effectively reduces the risk of variceal bleeding and its associated mortality. Periodic endoscopic surveillance of esophageal varices (EV) is currently recommended in every patient with cirrhosis for early detection of EV and initiation of primary variceal bleeding prophylaxis is indicated for high-risk patients. During the last decades several noninvasive tests have emerged, aiming to facilitate access, reduce cost, and avoid unnecessary risk associated with endoscopic EV surveillance. In addition, several hemostatic abnormalities have been described in cirrhosis, and their role in variceal bleeding pathogenesis is yet to be defined. In this article, we review and critically analyze the accuracy of noninvasive EV predictors and utility of hemostatic factors to predict individual variceal bleeding risk. In addition, we summarize available data regarding the therapeutic role of hemostatic factors in primary prevention of variceal bleeding and early recurrence after an initial episode of variceal hemorrhage. PMID- 26049065 TI - Past Tense Production in Children With and Without Specific Language Impairment Across Germanic Languages: A Meta-Analysis. AB - PURPOSE: This study examined the extent to which children with specific language impairment (SLI) across Germanic languages differ from their typically developing (TD) peers in the use of past tense morphology. METHOD: A systematic literature search identified empirical studies examining regular and/or irregular past tense production by English and non-English Germanic-speaking children with SLI and their TD peers. Data from qualifying studies were extracted and converted to Hedges's g effect sizes. RESULTS: Seventeen English and 8 non-English Germanic studies met inclusionary criteria. Comparing children with SLI and their TD age matched (TDA) peers resulted in large combined effect sizes for English and non English Germanic regular and irregular past tense production. Comparisons between children with SLI and their TD younger (TDY) peers also revealed large combined effect sizes for English and non-English Germanic regular past tense production. Effect sizes for studies comparing SLI and TDY irregular past tense production were large for non-English Germanic-speaking children and moderate for English speaking children. CONCLUSIONS: Results suggest that children with SLI across Germanic languages do indeed have more difficulty marking verbs for past tense than TDA and TDY peers. The findings suggest that the potential value of past tense production as a clinical marker of SLI may well extend beyond English. PMID- 26049067 TI - Platelet Dysfunction: Status of Thrombopoietin in Thrombocytopenia Associated with Chronic Liver Failure. AB - Thrombocytopenia is a common hematological abnormality in patients with chronic liver disease, and its prevalence is higher in patients with liver failure. Although the presence of thrombocytopenia has historically been associated with portal hypertension, the characterization of thrombopoietin has improved our understanding of the determinants of platelet count in patients with liver disease. In particular, the association between thrombopoietin levels and residual liver function helped disclose the multifaceted pathophysiology of thrombocytopenia in patients with chronic liver failure. In this regard, important results were provided by studies performed in patients with chronic viral hepatitis that assessed the complex interplay between thrombocytopenia induced by the myelosuppressive effect of interferon-based treatment and thrombopoietin pathophysiology. These studies showed that successful antiviral therapy is accompanied by improved hepatic thrombopoietin production. Moreover, studies that evaluated thrombopoietin and platelet count dynamics before and after liver transplantation were instrumental in describing how restoration of liver function determines a normalization of the thrombopoietin-platelet count feedback that is deranged in patients with end-stage liver disease. PMID- 26049068 TI - Coagulation in Liver Disease. AB - The liver plays a key role in hemostasis as the site of synthesis of many of the proteins involved in the coagulation, antithrombotic and fibrinolytic systems that interact to both establish hemostasis, and preventing thrombosis. The common laboratory tests, prothrombin time (PT) and activated partial thromboplastin time (aPTT), evolved from studies of plasma clotting in test tubes. Such studies laid the basis for the coagulation cascade model of hemostasis. However, thought has evolved to place a greater emphasis on the active roles of cells in localizing and regulating hemostasis. The PT and aPTT do not reflect the roles of cellular elements in hemostasis, nor do they reflect the crucial roles of antithrombotic and fibrinolytic systems. Thus, though the PT may indeed reflect the synthetic capacity of the liver, it does not accurately reflect the risk of bleeding or thrombosis in patients with liver failure. PMID- 26049069 TI - Anticoagulant Therapy in Patients with Cirrhosis. AB - Recent studies have greatly expanded our understanding of the coagulopathy of cirrhosis. It is clear that cirrhosis patients are at a risk of both bleeding and thrombosis. While prediction of these events remains challenging, cirrhosis patients are not protected from the development of venous and arterial thrombosis. In fact, studies show that hypercoagulability may promote hepatic decompensation and development of fibrosis. Anticoagulation for thrombosis is now becoming a common prospect in many clinical situations. Our understanding of the efficacy and safety of commonly used therapeutics is only beginning to emerge and the risks and benefits remain unclear in this unique population. In this review, we discuss the role of anticoagulation in the treatment and prevention peripheral and splanchnic thrombosis in patients with cirrhosis, as well as examine the potential role of anticoagulants in altering the progression of chronic liver disease. PMID- 26049070 TI - The Fibrinolytic Status in Liver Diseases. AB - The liver is the main site of synthesis and/or clearance of proteins involved in fibrinolysis. Therefore, chronic liver disease, including cirrhosis, leads to altered plasma levels of fibrinolytic proteins. Historical studies using in vitro clot lysis assays suggested that patients with chronic liver disease had accelerated fibrinolysis. Subsequent studies measured levels of individual pro- and antifibrinolytic proteins and showed that levels of tissue-type plasminogen activator are elevated. Plasma levels of plasminogen activator inhibitor-1 may also be altered, which leads to a shift in balance in the fibrinolytic system. Despite the fact that a more recent study using a plasma clot lysis assay challenged the existence of hyperfibrinolysis, other recent studies detected hyperfibrinolysis in a considerable number of patients with cirrhosis. Therefore, it is now recognized that hyperfibrinolysis may occur in 30 to 50% of patients with end-stage liver disease. A causal role of hyperfibrinolysis in bleeding is difficult to establish because also other concomitant changes in hemostasis occur. Treatment of hyperfibrinolysis consists of the use of fibrinolysis inhibitors, such as tranexamic acid. In this review we summarize current insights of the role of the liver in fibrinolysis, changes in fibrinolytic proteins, the potential clinical implications, and management of hyperfibrinolysis in liver disease. PMID- 26049071 TI - Rebalanced Hemostasis in Patients with Acute Liver Failure. AB - Patients with acute liver failure (ALF) have substantial alterations in their hemostatic system. Since an international normalized ratio of >= 1.5 is part of the definition of the syndrome, it has long been believed that patients with ALF had a hemostasis-related bleeding tendency. Recent data, however, show that spontaneous bleeding in ALF is rare. In addition, thrombotic complications may be more common than spontaneous bleeding complications. Laboratory studies have suggested that patients with ALF may be in hemostatic balance as a result of a commensurate decline in pro- and anti-hemostatic factors. The unstable nature of the hemostatic balance in ALF may explain the occurrence of both bleeding and thrombotic complications. The hemostatic profile of patients with ALF includes hypercoagulable features, including von Willebrand factor/a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 unbalance, elevated levels of highly procoagulant, platelet-derived microparticles, and a profound hypofibrinolytic status. These hypercoagulable features may contribute to systemic thrombotic complications, but may also drive intrahepatic clot formation. Studies in experimental animal models of ALF have demonstrated that intrahepatic clot formation contributes to disease progression. The clinical consequences of these new insights in the hemostatic system of patients with ALF will be discussed in this review. PMID- 26049072 TI - Clinical Utility of Viscoelastic Tests of Coagulation (TEG/ROTEM) in Patients with Liver Disease and during Liver Transplantation. AB - The concept that patients with stable liver disease are at an increased risk of bleeding, based solely on abnormalities of conventional coagulation tests such as prothrombin time (PT) and international normalized ratio (INR), is now recognized to be an overly simplistic interpretation of an extremely complex situation. These tests are in fact very poor predictors of bleeding in patients with liver disease who undergo invasive or surgical procedures. Commercially available whole blood viscoelastic tests (thromboelastography [TEG] and thromboelastometry [ROTEM]) evaluate the kinetics of coagulation from initial clot formation to final clot strength. These dynamic tests provide a composite picture reflecting the interaction of plasma, blood cells, and platelets, and more closely reflect the situation in vivo than do PT/INR, which are performed on plasma samples and measure isolated end points. Despite prolonged PT/INR and low platelet counts, viscoelastic tests are within normal range in many patients with both acute and chronic liver disease, commensurate with the concept of rebalanced hemostasis, and in keeping with the fact that an increasing number of these patients undergo liver transplantation without the need for blood or blood products. In addition, these tests reveal important additional information, such as the presence of hypercoagulability and a prothrombotic state, and also information about the presence of endogenous heparinoids associated with vascular endothelial damage, due to sepsis or acute inflammation. This review provides an overview of the current literature on the potential clinical utility of viscoelastic tests of coagulation in patients with liver disease. PMID- 26049073 TI - Vascular Disease in Patients with Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is increasingly being diagnosed and is considered to be the most frequent chronic liver disorder in Western countries. It represents a histopathological spectrum ranging from simple hepatic steatosis to steatohepatitis and finally cirrhosis. NAFLD is considered as the hepatic manifestation of the metabolic syndrome and is associated with increased mortality. Increasing evidence now suggests that NAFLD is also associated with higher cardiovascular disease (CVD) morbidity and mortality independent of conventional cardiometabolic risk factors (such as obesity, insulin resistance, and diabetes mellitus). The exact mechanisms linking NAFLD to increased CVD risk are still incompletely understood and likely reflect multiple coexisting pathways. Recent evidence suggests a contributive effect of an altered hemostasis in patients with NAFLD. For example, patients with NAFLD have higher levels of prothrombotic factors (e.g., von Willebrand factor, fibrinogen, factor VII activity, and plasminogen activator inhibitor-1), which correlate with underlying histological severity of the disease. The current review focuses on these hemostatic abnormalities in NAFLD and the link with increased CVD risk. PMID- 26049074 TI - Preferential sites for intramolecular glucosepane cross-link formation in type I collagen: A thermodynamic study. AB - The extracellular matrix (ECM) undergoes progressive age-related stiffening and loss of proteolytic digestibility due to an increase in concentration of advanced glycation end products (AGEs). The most abundant AGE, glucosepane, accumulates in collagen with concentrations over 100 times greater than all other AGEs. Detrimental collagen stiffening properties are believed to play a significant role in several age-related diseases such as osteoporosis and cardiovascular disease. Currently little is known of the potential location of covalently cross linked glucosepane formation within collagen molecules; neither are there reports on how the respective cross-link sites affect the physical and biochemical properties of collagen. Using fully atomistic molecular dynamics simulations (MD) we have identified six sites where the formation of a covalent intra-molecular glucosepane cross-link within a single collagen molecule in a fibrillar environment is energetically favourable. Identification of these favourable sites enables us to align collagen cross-linking with experimentally observed changes to the ECM. For example, formation of glucosepane was found to be energetically favourable within close proximity of the Matrix Metalloproteinase-1 (MMP1) binding site, which could potentially disrupt collagen degradation. PMID- 26049075 TI - Design, characterisation, and bioefficiency of insulin-chitosan nanoparticles after stabilisation by freeze-drying or cross-linking. AB - Insulin delivery by oral route would be ideal, but has no effect, due to the harsh conditions of the gastrointestinal tract. Protection of insulin using encapsulation in self-assembled particles is a promising approach. However, the lack of stability of this kind of particles in biological environments induces a low bioavailability of encapsulated insulin after oral administration. The objective of this work was to evaluate the effect of two stabilisation strategies alone or combined, freeze-drying and cross-linking, on insulin-loaded chitosan NPs, and to determine their bioefficiency in vitro and in vivo. NPs were prepared by complex coacervation between insulin and chitosan, stabilised either by cross linking with sodium tripolyphosphate solution (TPP), by freeze-drying or both treatments. In vitro bioefficiency NP uptake was evaluated by flow cytometry on epithelial models (Caco-2/RevHT29MTX (mucus secreting cells)). In vivo, NPs were injected via catheter in the peritoneum or duodenum on insulinopenic rats. Freeze drying increased in size and charge (+15% vs control 412 +/- 7 nm; + 36 +/- 0.3 mV) in comparison with cross linking which decreased NP size (-25%) without impacting the NP charge. When combined the consecutive treatments reduced NPs size and increased charges as compared to standard level. Freeze drying is necessary to prevent the destruction of NP in intestinal environment in comparison with no freeze dryed one where 60% of NP were destroyed after 2h. Additionally freeze drying combined with cross linking treatments improved bioefficiency of NP with uptake in cell increased when mucus is present. Combination of both treatment showed a protection of insulin in vivo, with a reduction of glycemia when NPs were administrated. This work showed that the combination of freeze drying and cross linking treatment is necessary to stabilize (freeze-drying) and increase bioefficiency (cross-linking) of self assembled NP in the delivery of insulin in vitro and in vivo. PMID- 26049076 TI - A Randomized Controlled Trial of Two Syntactic Treatment Procedures With Cantonese-Speaking, School-Age Children With Language Disorders. AB - PURPOSE: In this study, we aimed to evaluate the efficacy of sentence-combining (SC) and narrative-based (NAR) intervention approaches to syntax intervention using a randomized-controlled-trial design. METHOD: Fifty-two Cantonese-speaking, school-age children with language impairment were assigned randomly to either the SC or the NAR treatment arm. Seven children did not receive treatment as assigned. Intervention in both arms targeted the same complex syntactical structures. The SC group focused on sentence combination training, whereas the NAR group made use of narratives in which the target structures were embedded. Pretest and posttest performances measured using a standardized language assessment were subjected to analyses of covariance mixed-effect-model analyses of variance. RESULTS: Children in both treatment arms demonstrated significant growth after 4 months of intervention. The main effect between treatment arms and time was not significant after controlling the pretest performance, suggesting that both treatment approaches showed similar effects. The main effect of time was significant. CONCLUSIONS: This study provided evidence to support language intervention in the school years in Cantonese-speaking children. However, neither approach was shown to be more efficacious than the other. Future researchers could examine the effects of a longer treatment period and include functional outcome measures. PMID- 26049077 TI - Directly reconstructing principal components of heterogeneous particles from cryo EM images. AB - Structural heterogeneity of particles can be investigated by their three dimensional principal components. This paper addresses the question of whether, and with what algorithm, the three-dimensional principal components can be directly recovered from cryo-EM images. The first part of the paper extends the Fourier slice theorem to covariance functions showing that the three-dimensional covariance, and hence the principal components, of a heterogeneous particle can indeed be recovered from two-dimensional cryo-EM images. The second part of the paper proposes a practical algorithm for reconstructing the principal components directly from cryo-EM images without the intermediate step of calculating covariances. This algorithm is based on maximizing the posterior likelihood using the Expectation-Maximization algorithm. The last part of the paper applies this algorithm to simulated data and to two real cryo-EM data sets: a data set of the 70S ribosome with and without Elongation Factor-G (EF-G), and a data set of the influenza virus RNA dependent RNA Polymerase (RdRP). The first principal component of the 70S ribosome data set reveals the expected conformational changes of the ribosome as the EF-G binds and unbinds. The first principal component of the RdRP data set reveals a conformational change in the two dimers of the RdRP. PMID- 26049078 TI - Tissue-specific sequence and structural environments of lysine acetylation sites. AB - Lysine acetylation is a widespread reversible post-translational modification that regulates a broad spectrum of biological activities across various cellular compartments, cell types, tissues, and disease states. While compartment-specific trends in lysine acetylation have recently been investigated, its tissue-specific preferences remain unexplored. Here we present a comprehensive tissue-based analysis of sequence and structural features of lysine acetylation sites (LASs) based on the recent experimental data of Lundby et al. (2012). We show that acetylated substrates are characterized by tissue-specific motifs both in linear amino acid sequence and in spatial environments. We further demonstrate that the general tendency of LASs to reside in ordered regions and, specifically, in alpha helices, is also subject to tissue specific variation. In line with previous findings we show that LASs are generally more evolutionarily conserved than non LASs, especially in proteins with known function and in structurally regular regions. On the other hand, as revealed by metabolic pathway analysis, LASs have diverse cellular functions in different tissues and are frequently associated with tissue-specific protein domains. These findings may imply the existence of tissue-specific lysine acetyltransferases (KATs) and lysine deacetylases (KDACs). PMID- 26049080 TI - Characterization of the TolB-Pal trans-envelope complex from Xylella fastidiosa reveals a dynamic and coordinated protein expression profile during the biofilm development process. AB - The intriguing roles of the bacterial Tol-Pal trans-envelope protein complex range from maintenance of cell envelope integrity to potential participation in the process of cell division. In this study, we report the characterization of the XfTolB and XfPal proteins of the Tol-Pal complex of Xylella fastidiosa. X. fastidiosa is a major plant pathogen that forms biofilms inside xylem vessels, triggering the development of diseases in important cultivable plants around the word. Based on functional complementation experiments in Escherichia coli tolB and pal mutant strains, we confirmed the role of xftolB and xfpal in outer membrane integrity. In addition, we observed a dynamic and coordinated protein expression profile during the X. fastidiosa biofilm development process. Using small-angle X-ray scattering (SAXS), the low-resolution structure of the isolated XfTolB-XfPal complex in solution was solved for the first time. Finally, the localization of the XfTolB and XfPal polar ends was visualized via immunofluorescence labeling in vivo during bacterial cell growth. Our results highlight the major role of the components of the cell envelope, particularly the TolB-Pal complex, during the different phases of bacterial biofilm development. PMID- 26049079 TI - Crystallins and neuroinflammation: The glial side of the story. AB - BACKGROUND: There is an abundance of evidence to support the association of damaging neuroinflammation and neurodegeneration across a multitude of diseases. One of the links between these pathological phenomena is the role of chaperone proteins as both neuroprotective and immune-regulatory agents. SCOPE OF REVIEW: Chaperone proteins are highly expressed at sites of neuroinflammation both in glial cells and in the injured neurons that initiate the immune response. For this reason, the use of chaperones as treatment for various diseases associated with neuroinflammation is a highly active area of investigation. This review explores the various ways that the small heat shock protein chaperones, alpha crystallins, can affect glial cell function with a specific focus on their implication in the inflammatory response associated with neurodegenerative disorders, and their potential as therapeutic treatment. MAJOR CONCLUSIONS: Although the mechanisms are still under investigation, a clear link has now been established between alpha-crystallins and neuroinflammation, especially through their roles in microglial and macroglial cells. Interestingly, similar to inflammation in itself, crystallins can have a beneficial or detrimental impact on the CNS based on the context and duration of the condition. GENERAL SIGNIFICANCE: Overall this review points out the novel roles that chaperones such as alpha-crystallins can play outside of the classical protein folding pathways, and their potential in the development of new therapies for the treatment of neuroinflammatory/neurodegenerative diseases. This article is part of a Special Issue entitled Crystallin Biochemistry in Health and Disease. PMID- 26049081 TI - Time-series analysis of the transcriptome and proteome of Escherichia coli upon glucose repression. AB - Time-series transcript- and protein-profiles were measured upon initiation of carbon catabolite repression in Escherichia coli, in order to investigate the extent of post-transcriptional control in this prototypical response. A glucose limited chemostat culture was used as the CCR-free reference condition. Stopping the pump and simultaneously adding a pulse of glucose, that saturated the cells for at least 1h, was used to initiate the glucose response. Samples were collected and subjected to quantitative time-series analysis of both the transcriptome (using microarray analysis) and the proteome (through a combination of 15N-metabolic labeling and mass spectrometry). Changes in the transcriptome and corresponding proteome were analyzed using statistical procedures designed specifically for time-series data. By comparison of the two sets of data, a total of 96 genes were identified that are post-transcriptionally regulated. This gene list provides candidates for future in-depth investigation of the molecular mechanisms involved in post-transcriptional regulation during carbon catabolite repression in E. coli, like the involvement of small RNAs. PMID- 26049082 TI - Taking the Role of the Family Seriously in Treating Chinese Psychiatric Patients: A Confucian Familist Review of China's First Mental Health Act. AB - This essay argues that the Chinese Mental Health Act of 2013 is overly individualistic and fails to give proper moral weight to the role of Chinese families in directing the process of decision-making for hospitalizing and treating the mentally ill patients. We present three types of reactions within the medical community to the Act, each illustrated with a case and discussion. In the first two types of cases, we argue that these reactions are problematic either because they comply with the law but undermine the patient's interests by refusing the family's request to have the patient hospitalized, or violate the law by hospitalizing patients in response to the real concerns of their families. In the third type of situation, psychiatrists inappropriately encourage families to produce evidence of the patient's behavior that is harmful to self or others in order legally to commit the patient. Each of these problems, we conclude, should be tackled by supplementing Article 30 of the Act with the stipulation that a psychiatrist may authorize the involuntary hospitalization of a patient, who is not at risk of causing physical harm to self or others, with the consent of all major family members. Drawing on the deeply culturally embedded moral traditions of Confucian medical familism, this proposal would facilitate the proper treatment of a significant number of Chinese mentally ill patients under the care of their families. PMID- 26049083 TI - Impaired Activation in Cognitive Control Regions Predicts Reversal Learning in Schizophrenia. AB - Reinforcement learning deficits have been associated with schizophrenia (SZ). However, the pathophysiology that gives rise to these abnormalities remains unclear. To address this question, SZ patients (N = 58) and controls (CN; N = 36) completed a probabilistic reversal-learning paradigm during functional magnetic resonance imaging scanning. During the task, participants choose between 2 stimuli. Initially, 1 stimulus was frequently rewarded (80%); the other was infrequently rewarded (20%). The reward contingencies reversed periodically because the participant learned the more rewarded stimulus. The results indicated that SZ patients achieved fewer reversals than CN, and demonstrated decreased winstay-loseshift decision-making behavior. On loseshift compared to winstay trials, SZ patients showed reduced Blood Oxygen Level Dependent activation compared to CN in a network of brain regions widely associated with cognitive control, and striatal regions. Importantly, relationships between group membership and behavior were mediated by alterations in the activity of cognitive control regions, but not striatum. These findings indicate an important role for the cognitive control network in mediating the use and updating of value representations in SZ. Such results provide biological targets for further inquiry because researchers attempt to better characterize decision-making neural circuitry in SZ as a means to discover new pathways for interventions. PMID- 26049084 TI - Association of Mineralocorticoid Receptor Polymorphism I180V With Left Ventricular Hypertrophy in Resistant Hypertension. AB - OBJECTIVES: Genetic polymorphisms on mineralocorticoid receptor gene (NC3C2) are associated with variability of mineralocorticoid receptor (MR) function and cardiovascular implications. We sought to investigate whether I180V (rs5522) and MRc.-2G_C (rs2070951) polymorphisms in NR3C2 gene are associated with resistance to antihypertensive treatment and target-organ damage in resistant hypertensive (RHTN) patients. METHODS: One hundred and eighty-one RHTN and 122 mild to moderate hypertensive (HTN) patients were enrolled in this study. Genotypes were obtained by allelic discrimination assay using real-time polymerase chain reaction. We determined pulse wave velocity (PWV), microalbuminuria, and left ventricular mass index to assess target-organ damage. We compared clinical and laboratorial characteristics of AA vs. G carriers for rs5522 and AC vs. GG vs. CG for rs2070951. RESULTS: We did not found differences in allele, genotype, and haplotype frequencies for both polymorphisms between HTN and RHTN subjects. We found increased levels of aldosterone and ambulatory blood pressure (BP) in G carriers only for rs5522. Left ventricular hypertrophy (LVH) was more prevalent in G carriers than AA homozygous for rs5522 but not for rs2070951 in RHTN. On the other hand, microalbuminuria and PWV were similar among genotypes for both polymorphisms. No differences were observed between the haplotypes, except for higher aldosterone concentration in GG compared to AG and AC haplotypes. CONCLUSION: Our study suggests that rs5522 polymorphism might affect cardiac remodeling and aldosterone levels in RHTN subjects. PMID- 26049085 TI - Do antenatal care visits always contribute to facility-based delivery in Tanzania? A study of repeated cross-sectional data. AB - There is a known high disparity in access to perinatal care services between urban and rural areas in Tanzania. This study analysed repeated cross-sectional (RCS) data from Tanzania to explore the relationship between antenatal care (ANC) visits, facility-based delivery and the reasons for home births in women who had made ANC visits. We used data from RCS Demographic and Health Surveys spanning 20 years and a cluster sample of 30 830 women from ~52 districts of Tanzania. The relationship between the number of ANC visits (up to four) and facility delivery in the latest pregnancy was explored. Regional changes in facility delivery and related variables over time in urban and rural areas were analysed using linear mixed models. To explore the disconnect between ANC visits and facility deliveries, reasons for home delivery were analysed. In the analytic model with other regional-level covariates, a higher proportion of ANC (>2-4 visits) and exposure to media related to an increased facility delivery rate in urban areas. For rural women, there was no significant relationship between the number of visits and facility delivery rate. According to the fifth wave result (2009-10), the most frequent reason for home delivery was 'physical distance to facility', and a significantly higher proportion of rural women reported that they were 'not allowed to deliver in facility'. The disconnect between ANC visits and facility delivery in rural areas may be attributable to physical, cultural or familial barriers, and quality of care in health facilities. This suggests that improving access to ANC may not be enough to motivate facility-based delivery, especially in rural areas. PMID- 26049086 TI - Relation between stress-precipitated seizures and the stress response in childhood epilepsy. AB - The majority of patients with epilepsy report that seizures are sometimes triggered or provoked. Stress is the most frequently self-reported seizure precipitant. The mechanisms underlying stress-sensitivity of seizures are currently unresolved. We hypothesized that stress-sensitivity of seizures relates to alteration of the stress response, which could affect neuronal excitability and hence trigger seizures. To study this, children with epilepsy between 6 and 17 years of age and healthy controls, with similar age, sex and intelligence, were exposed to a standardized acute psychosocial stressor (the Trier Social Stress Test for Children), during which salivary cortisol and sympathetic parameters were measured. Beforehand, the relation between stress and seizures in children with epilepsy was assessed by (i) a retrospective questionnaire; and (ii) a prospective 6-week diary on stress and seizure occurrence. Sixty-four children with epilepsy and 40 control subjects were included in the study. Of all children with epilepsy, 49% reported that seizures were precipitated by acute stress. Diary analysis showed a positive association between acute stress and seizures in 62% of children who experienced at least one seizure during the diary period. The acute social stress test was completed by 56 children with epilepsy and 37 control subjects. Children with sensitivity of seizures for acute stress, either determined by the questionnaire or by the prospective diary, showed a blunted cortisol response to stress compared with patients without acute stress precipitated seizures and healthy controls (questionnaire-based F = 2.74, P = 0.018; diary-based F = 4.40, P = 0.007). No baseline differences in cortisol were observed, nor differences in sympathetic stress response. The relation between acute stress-sensitivity of seizures and the cortisol response to stress remained significant in multivariable analysis (beta = -0.30, P = 0.03). Other variables associated with the acute stress response were the number of anti-epileptic drugs (beta = -0.27, P = 0.05) and sleep quality (beta = 0.30, P = 0.03). In conclusion, we show that children with acute stress-sensitive seizures have a decreased cortisol response to stress. These results support our hypothesis that stress-sensitivity of seizures is associated with alterations of the stress response, thereby providing a first step in unravelling the mechanisms behind the seizure-precipitating effects of stress. Increased knowledge of the relation between stress and seizures in childhood epilepsy might benefit our understanding of the fundamental processes underlying epilepsy and ictogenesis in general, and provide valuable clues to direct the development of new therapeutic strategies for epilepsy. PMID- 26049088 TI - Physical Activity Measurement Accuracy in Individuals With Chronic Lung Disease: A Systematic Review With Meta-Analysis of Method Comparison Studies. AB - OBJECTIVE: To investigate the accuracy of physical activity measurement strategies in adults with chronic lung disease. DATA SOURCES: MEDLINE, Embase, and CINAHL databases were searched from inception to September 30, 2014. STUDY SELECTION: Studies reporting validity data for devices measuring energy expenditure in comparison with indirect calorimetry or doubly labeled water measurements in chronic lung disease were included. Nine publications in chronic obstructive pulmonary disease (COPD) or cystic fibrosis (CF) from 2294 studies were identified. DATA EXTRACTION: Two reviewers evaluated studies for quality using a modified version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) checklist and extracted data relating to population, setting, devices, activity protocols, and energy expenditure. Disagreements were resolved by consensus. DATA SYNTHESIS: Studies were of high quality, with 8 studies scoring at least 9 out of 11 on the QUADAS checklist. In laboratory-based settings, the SenseWear multisensor accurately estimated energy expenditure during walking compared with indirect calorimetry (pooled mean difference, -0.7 kcal/min; 95% confidence interval [CI], -2.5 to 1.1) in COPD, but overestimated it in CF. However, 2 studies in COPD and CF showed the SenseWear multisensor accurately estimated energy expenditure during lifestyle tasks compared with indirect calorimetry (pooled mean difference, .18 kcal/min; 95% CI, -.13 to .49). The Digi Walker pedometer underestimated energy expenditure compared with indirect calorimetry in COPD (mean difference walking, -2.4 kcal/min; 95% CI -3.4 to -1.1; mean difference lifestyle tasks, -2.3 kcal/min; 95% CI, -2.8 to -1.8). In free living settings, the ActiReg multisensor accurately measured energy expenditure in COPD (mean difference, -21 kcal/d; 95% CI, -133.9 to 91.9), whereas the Flex Heart Rate Method underestimated energy expenditure in CF (mean difference, 454.1 kcal/d; 95% CI, -727 to -181.2). CONCLUSIONS: Energy expenditure estimation was accurate from the SenseWear and ActiReg multisensors during laboratory-based and free-living testing. Future studies warrant investigation of activity measures in other lung diseases and in specific ranges of lung disease severity. PMID- 26049087 TI - Therapeutic effects of glatiramer acetate and grafted CD115+ monocytes in a mouse model of Alzheimer's disease. AB - Weekly glatiramer acetate immunization of transgenic mice modelling Alzheimer's disease resulted in retained cognition (Morris water maze test), decreased amyloid-beta plaque burden, and regulation of local inflammation through a mechanism involving enhanced recruitment of monocytes. Ablation of bone marrow derived myeloid cells exacerbated plaque pathology, whereas weekly administration of glatiramer acetate enhanced cerebral recruitment of innate immune cells, which dampened the pathology. Here, we assessed the therapeutic potential of grafted CD115(+) monocytes, injected once monthly into the peripheral blood of transgenic APPSWE/PS1DeltaE9 Alzheimer's disease mouse models, with and without weekly immunization of glatiramer acetate, as compared to glatiramer acetate alone. All immune-modulation treatment groups were compared with age-matched phosphate buffered saline-injected control transgenic and untreated non-transgenic mouse groups. Two independent cohorts of mice were assessed for behavioural performance (6-8 mice/group); treatments started in 10-month-old symptomatic mice and spanned a total of 2 months. For all three treatments, our data suggest a substantial decrease in cognitive deficit as assessed by the Barnes maze test (P < 0.0001 0.001). Improved cognitive function was associated with synaptic preservation and reduction in cerebral amyloid-beta protein levels and astrogliosis (P < 0.001 and P < 0.0001), with no apparent additive effects for the combined treatment. The peripherally grafted, green fluorescent protein-labelled and endogenous monocytes, homed to cerebral amyloid plaques and directly engulfed amyloid-beta; their recruitment was further enhanced by glatiramer acetate. In glatiramer acetate-immunized mice and, moreover, in the combined treatment group, monocyte recruitment to the brain was coupled with greater elevation of the regulatory cytokine IL10 surrounding amyloid-beta plaques. All treated transgenic mice had increased cerebral levels of MMP9 protein (P < 0.05), an enzyme capable of degrading amyloid-beta, which was highly expressed by the infiltrating monocytes. In vitro studies using primary cultures of bone marrow monocyte-derived macrophages, demonstrated that glatiramer acetate enhanced the ability of macrophages to phagocytose preformed fibrillar amyloid-beta1-42 (P < 0.0001). These glatiramer acetate-treated macrophages exhibited increased expression of the scavenger receptors CD36 and SCARA1 (encoded by MSR1), which can facilitate amyloid-beta phagocytosis, and the amyloid-beta-degrading enzyme MMP9 (P < 0.0001 0.001). Overall, our studies indicate that increased cerebral infiltration of monocytes, either by enrichment of their levels in the circulation or by weekly immunization with glatiramer acetate, resulted in substantial attenuation of disease progression in murine Alzheimer's models by mechanisms that involved enhanced cellular uptake and enzymatic degradation of toxic amyloid-beta as well as regulation of brain inflammation. PMID- 26049089 TI - Freezing tolerance of sea urchin embryonic cells: Differentiation commitment and cytoskeletal disturbances in culture. AB - This study focuses on the freezing tolerance of sea urchin embryonic cells. To significantly reduce the loss of physiological activity of these cells that occurs after cryopreservation and to study the effects of ultra-low temperatures on sea urchin embryonic cells, we tested the ability of the cells to differentiate into spiculogenic or pigment directions in culture, including an evaluation of the expression of some genes involved in pigment differentiation. A morphological analysis of cytoskeletal disturbances after freezing in a combination of penetrating (dimethyl sulfoxide and ethylene glycol) and non penetrating (trehalose and polyvinylpyrrolidone) cryoprotectants revealed that the distribution pattern of filamentous actin and tubulin was similar to that in the control cultures. In contrast, very rare spreading cells and a small number of cells with filamentous actin and tubulin were detected after freezing in the presence of only non-penetrating cryoprotectants. The largest number of pigment cells was found in cultures frozen with trehalose or trehalose and dimethyl sulfoxide. The ability to induce the spicule formation was lost in the cells frozen only with non-penetrating cryoprotectants, while it was maximal in cultures frozen in a cryoprotective mixture containing both non-penetrating and penetrating cryoprotectants (particularly, when ethylene glycol was present). Using different markers for cell state assessment, an effective cryopreservation protocol for sea urchin cells was developed: three-step freezing with a low cooling rate (1-2 degrees C/min) and a combination of non-penetrating and penetrating cryoprotectants made it possible to obtain a high level of cell viability (up to 65-80%). PMID- 26049090 TI - A confocal microscopy-based atlas of tissue architecture in the tapeworm Hymenolepis diminuta. AB - Tapeworms are pervasive and globally distributed parasites that infect millions of humans and livestock every year, and are the causative agents of two of the 17 neglected tropical diseases prioritized by the World Health Organization. Studies of tapeworm biology and pathology are often encumbered by the complex life cycles of disease-relevant tapeworm species that infect hosts such as foxes, dogs, cattle, pigs, and humans. Thus, studies of laboratory models can help overcome the practical, ethical, and cost-related difficulties faced by tapeworm parasitologists. The rat intestinal tapeworm Hymenolepis diminuta is easily reared in the laboratory and has the potential to enable modern molecular-based experiments that will greatly contribute to our understanding of multiple aspects of tapeworm biology, such as growth and reproduction. As part of our efforts to develop molecular tools for experiments on H. diminuta, we have characterized a battery of lectins, antibodies, and common stains that label different tapeworm tissues and organ structures. Using confocal microscopy, we have assembled an "atlas" of H. diminuta organ architecture that will be a useful resource for helminthologists. The methodologies we describe will facilitate characterization of loss-of-function perturbations using H. diminuta. This toolkit will enable a greater understanding of fundamental tapeworm biology that may elucidate new therapeutic targets toward the eradication of these parasites. PMID- 26049091 TI - The right insula contributes to memory awareness in cognitively diverse older adults. AB - Unawareness of memory loss is a challenging characteristic of Alzheimer's disease (AD) and other age-related neurodegenerative conditions at their earliest stages, adversely affecting important outcomes such as patient decision making and safety. The basis of this metacognitive disturbance has been elusive; however it is almost certainly determined in part by compromise to brain regions critical for self-assessment. The subjectivity of traditional measurements of self awareness in dementia has likely limited the rigor with which its neuroanatomic correlates can be established. Here we objectively measure memory awareness (metamemory) using a Feeling of Knowing (FOK) task in a group of cognitively diverse older adults, including 14 with mild AD and 20 cognitively healthy older adults. Performance on the metamemory task was examined in relation to the structural integrity of 14 bilateral neuroanatomic regions hypothesized to support self-awareness. Less accurate metamemory was associated only with reduced right insular volume (r=.41, p=.019). Implications of the current findings for models of metacognitive aging are discussed, with attention to the role of the insula in the conscious detection of errors. PMID- 26049092 TI - Formalize clinical processes into electronic health information systems: Modelling a screening service for diabetic retinopathy. AB - Most healthcare services use information and communication technologies to reduce and redistribute the workload associated with follow-up of chronic conditions. However, the lack of normalization of the information handled in and exchanged between such services hinders the scalability and extendibility. The use of medical standards for modelling and exchanging information, especially dual-model based approaches, can enhance the features of screening services. Hence, the approach of this paper is twofold. First, this article presents a generic methodology to model patient-centered clinical processes. Second, a proof of concept of the proposed methodology was conducted within the diabetic retinopathy (DR) screening service of the Health Service of Navarre (Spain) in compliance with a specific dual-model norm (openEHR). As a result, a set of elements required for deploying a model-driven DR screening service has been established, namely: clinical concepts, archetypes, termsets, templates, guideline definition rules, and user interface definitions. This model fosters reusability, because those elements are available to be downloaded and integrated in any healthcare service, and interoperability, since from then on such services can share information seamlessly. PMID- 26049093 TI - Promoter hypermethylation of let-7a-3 is relevant to its down-expression in diabetic nephropathy by targeting UHRF1. AB - Diabetic nephropathy (DN) is one of the most serious complications of diabetes mellitus (DM). Recent researches show that DNA methylation plays a role in DN. However, the exact mechanism is not fully understood. MicroRNAs (miRNAs) are a group of endogenous non-coding small RNAs that are involved in the regulation of the development of DN. We have previously demonstrated that let-7a was down expressed in DN by microarray, but the mechanism is unclear. In this study, let 7a-3 was found to be the only gene with the CpG island in the promoter region among the three let-7a members (let-7a-1, let-7a-2 and let-7a-3) by bioinformatic methods. Also, the expression levels of three homologues of let-7a were tested by real-time PCR, and DNA methylation of the let-7a-3 gene in the promoter region was analyzed by quantitative methylation-specific PCR (qMSP) in 60 individuals, with 20 cases in the control (CON), DM and DN groups respectively. Additionally, the target gene of let-7a-UHRF1 was proved by bioinformatic analysis and dual luciferase reporter assay. Results showed that let-7a-3 was down-regulated in DN patients. Moreover, qMSP data showed that the average methylation ratio of the let-7a-3 promoter in the DN group was significantly higher than that in the CON and DM groups (P<0.05). Data also showed that let-7a negatively regulated the mRNA and protein expressions of methylation-related gene-UHRF1 through UHRF1 3'UTR. And the expressions of UHRF1 and DNMT1 were increased in DN patients. Therefore, we concluded that promoter hypermethylation and down-expression of let 7a-3 may play a role in DN by targeting UHRF1. PMID- 26049094 TI - Association of common eNOS/NOS3 polymorphisms with preeclampsia in Tunisian Arabs. AB - We investigated the association of endothelial nitric oxide synthase (NOS3) polymorphisms -786T>C, 27-bp repeat 4b/4a, and Glu298Asp with preeclampsia (PE). This was a case-control study involving 345 unrelated Tunisian women with PE and 289 unrelated age- and ethnically matched control women. The -786C allele was significantly increased in PA patients when compared to healthy controls (P=0.015). In contrast, MAF of Glu298Asp (P=0.103) and 4b/4a (P=0.168) were not significantly different between the study groups. Higher frequencies of heterozygous Glu298/298Asp and homozygous -786T/-786T genotypes were seen in PE cases compared to healthy subjects. The combination of genotypes 221 (-786T>C, Glu298Asp, 4a/4a) was more in PE cases compared with control women (17.68% vs. 8.36%; P=0.029). Multivariate regression analysis confirmed this association. Genetic variation at the NOS3 locus represents a genetic risk factor for increased susceptibility to PE. PMID- 26049095 TI - Transcriptome analysis of the adult rumen fluke Paramphistomum cervi following next generation sequencing. AB - Rumen flukes are parasitic trematodes (Platyhelminthes: Digenea) of major socioeconomic importance in many countries. Key representatives, such as Paramphistomum cervi, can cause "Rumen fluke disease" or paramphistomosis and undermine economic animal productivity and welfare. P. cervi is primarily a problem in sheep, goat and buffalo production as a consequence of reduced weight gain and milk production, clinical disease or death. Recent technological advances in genomics and bioinformatics now provide unique opportunities for the identification and pre-validation of drug targets and vaccines through improved understanding of the biology of pathogens such as P. cervi and their relationship with their hosts at the molecular level. Here, we report next generation transcriptome sequencing analysis for P. cervi. RNAseq libraries were generated from RNA extracted from 15 adult P. cervi parasites sampled from each of three different host species (sheep, goat and buffalo) and a reference transcriptome was generated by assembly of all Ion Torrent PGM sequencing data. Raw reads (7,433,721 in total) were initially filtered for host nucleotide contamination and ribosomal RNAs and the remaining reads were assembled into 43,753 high confidence transcript contigs. In excess of 50% of the assembled transcripts were annotated with domain- or protein sequence similarity derived functional information. The reference adult P. cervi transcriptome will serve as a basis for future work on the biology of this important parasite. Using the widely investigated trematode virulence factor and vaccine candidate Cathepsin L as an example, the epitope GPISIAINA was found to be conserved in P. cervi isolated from three different host species supporting its candidacy for vaccine development and illustrating the utility of the adult P. cervi transcriptome. PMID- 26049096 TI - Molecular characterization and expression analysis of the duck viperin gene. AB - Viperin is well known as one of the interferon-stimulated genes involved in innate immunity. Recent studies showed that this gene is mainly responsible for antiviral response to a large variety of viral infections. In this study, we successfully cloned and characterized the complete coding sequence of duck viperin gene. The duck viperin gene encodes 363 amino acids (aa) and is highly similar to viperins from other species. Moreover, secondary and 3D structures were predicted, and these structures showed two main domains, one signal peptide, and one radical S-adenosyl methionine (SAM) domain. Additionally, the duck viperin expression was analyzed in vitro and in vivo, and analysis results indicated that the duck viperin can be strongly up-regulated by poly(I:C) and Newcastle disease virus in primary duck embryo fibroblast cells. Results also demonstrated that Newcastle disease virus significantly induced duck viperin expression in the spleen, kidneys, liver, brain, and blood. Our findings will contribute to future studies on the detailed functions and potential underlying mechanisms of this novel protein in innate immunity. PMID- 26049097 TI - An enhanced chimeric firefly luciferase-inspired enzyme for ATP detection and bioluminescence reporter and imaging applications. AB - Firefly luciferases, which emit visible light in a highly specific ATP-dependent process, have been adapted for a variety of applications, including gene reporter assays, whole-cell biosensor measurements, and in vivo imaging. We previously reported the approximately 2-fold enhanced activity and 1.4-fold greater bioluminescence quantum yield properties of a chimeric enzyme that contains the N domain of Photinus pyralis luciferase joined to the C-domain of Luciola italica luciferase. Subsequently, we identified 5 amino acid changes based on L. italica that are the main determinants of the improved bioluminescence properties. Further engineering to enhance thermal and pH stability produced a novel luciferase called PLG2. We present here a systematic comparison of the spectral and physical properties of the new protein with P. pyralis luciferase and demonstrate the potential of PLG2 for use in assays based on the detection of femtomole levels of ATP. In addition, we compared the performance of a mammalian codon-optimized version of the cDNA for PLG2 with the luc2 gene in HEK293T cells. Using an optimized low-cost assay system, PLG2 activity can be monitored in mammalian cell lysates and living cells with 4.4-fold and approximately 3.0-fold greater sensitivity, respectively. PLG2 could be an improved alternative to Promega's luc2 for reporter and imaging applications. PMID- 26049098 TI - The development of mitochondrial membrane affinity chromatography columns for the study of mitochondrial transmembrane proteins. AB - Mitochondrial membrane fragments from U-87 MG (U87MG) and HEK-293 cells were successfully immobilized onto immobilized artificial membrane (IAM) chromatographic support and surface of activated open tubular (OT) silica capillary, resulting in mitochondrial membrane affinity chromatography (MMAC) columns. Translocator protein (TSPO), located in mitochondrial outer membrane as well as sulfonylurea and mitochondrial permeability transition pore (mPTP) receptors, localized to the inner membrane, were characterized. Frontal displacement experiments with multiple concentrations of dipyridamole (DIPY) and PK-11195 were run on MMAC (U87MG) column, and the binding affinities (Kd) determined were 1.08+/-0.49 and 0.0086+/-0.0006MUM, respectively, consistent with previously reported values. Furthermore, binding affinities (Ki) for DIPY binding site were determined for TSPO ligands, PK-11195, mesoporphyrin IX, protoporphyrin IX, and rotenone. In addition, the relative ranking of these TSPO ligands based on single displacement studies using DIPY as marker on MMAC (U87MG) was consistent with the obtained Ki values. The immobilization of mitochondrial membrane fragments was also confirmed by confocal microscopy. PMID- 26049099 TI - Optimized luciferase assay for cell-penetrating peptide-mediated delivery of short oligonucleotides. AB - An improved assay for screening for the intracellular delivery efficacy of short oligonucleotides using cell-penetrating peptides is suggested. This assay is an improvement over previous assays that use luciferase reporters for cell penetrating peptides because it has been scaled up from a 24-well format to a 96 well format and no longer relies on a luciferin reagent that has been commercially sourced. In addition, the homemade luciferin reagent is useful in multiple cell lines and in different assays that rely on altering the expression of luciferase. To establish a new protocol, the composition of the luciferin reagent was optimized for both signal strength and longevity by multiple two factorial experiments varying the concentrations of adenosine triphosphate, luciferin, coenzyme A, and dithiothreitol. In addition, the optimal conditions with respect to cell number and time of transfection for both short interfering RNA (siRNA) and splice-correcting oligonucleotides (SCOs) are established. Optimal transfection of siRNA and SCOs was achieved using the reverse transfection method where the oligonucleotide complexes are already present in the wells before the cells are plated. Z' scores were 0.73 for the siRNA assay and 0.71 for the SCO assay, indicating that both assays are suitable for high throughput screening. PMID- 26049100 TI - Fluorescence melting curve analysis using self-quenching dual-labeled peptide nucleic acid probes for simultaneously identifying multiple DNA sequences. AB - Previous fluorescence melting curve analysis (FMCA) used intercalating dyes, and this method has restricted application. Therefore, FMCA methods such as probe based FMCA and molecular beacons were studied. However, the usual dual-labeled probes do not possess adequate fluorescence quenching ability and sufficient specificity, and molecular beacons with the necessary stem structures are hard to design. Therefore, we have developed a peptide nucleic acid (PNA)-based FMCA method. PNA oligonucleotide can have a much higher melting temperature (Tm) value than DNA. Therefore, short PNA probes can have adequate Tm values for FMCA, and short probes can have higher specificity and accuracy in FMCA. Moreover, dual labeled PNA probes have self-quenching ability via single-strand base stacking, which makes PNA more favorable. In addition, this method can facilitate simultaneous identification of multiple DNA templates. In conventional real-time polymerase chain reaction (PCR), one fluorescence channel can identify only one DNA template. However, this method uses two fluorescence channels to detect three types of DNA. Experiments were performed with one to three different DNA sequences mixed in a single tube. This method can be used to identify multiple DNA sequences in a single tube with high specificity and high clarity. PMID- 26049102 TI - Coordinated induction of GST and MRP2 by cAMP in Caco-2 cells: Role of protein kinase A signaling pathway and toxicological relevance. AB - The cAMP pathway is a universal signaling pathway regulating many cellular processes including metabolic routes, growth and differentiation. However, its effects on xenobiotic biotransformation and transport systems are poorly characterized. The effect of cAMP on expression and activity of GST and MRP2 was evaluated in Caco-2 cells, a model of intestinal epithelium. Cells incubated with the cAMP permeable analog dibutyryl cyclic AMP (db-cAMP: 1,10,100 MUM) for 48 h exhibited a dose-response increase in GST class alpha and MRP2 protein expression. Incubation with forskolin, an activator of adenylyl cyclase, confirmed the association between intracellular cAMP and upregulation of MRP2. Consistent with increased expression of GSTalpha and MRP2, db-cAMP enhanced their activities, as well as cytoprotection against the common substrate 1-chloro-2,4 dinitrobenzene. Pretreatment with protein kinase A (PKA) inhibitors totally abolished upregulation of MRP2 and GSTalpha induced by db-cAMP. In silico analysis together with experiments consisting of treatment with db-cAMP of Caco-2 cells transfected with a reporter construct containing CRE and AP-1 sites evidenced participation of these sites in MRP2 upregulation. Further studies involving the transcription factors CREB and AP-1 (c-JUN, c-FOS and ATF2) demonstrated increased levels of total c-JUN and phosphorylation of c-JUN and ATF2 by db-cAMP, which were suppressed by a PKA inhibitor. Co-immunoprecipitation and ChIP assay studies demonstrated that db-cAMP increased c-JUN/ATF2 interaction, with further recruitment to the region of the MRP2 promoter containing CRE and AP-1 sites. We conclude that cAMP induces GSTalpha and MRP2 expression and activity in Caco-2 cells via the PKA pathway, thus regulating detoxification of specific xenobiotics. PMID- 26049101 TI - Cytochrome P450 1b1 in polycyclic aromatic hydrocarbon (PAH)-induced skin carcinogenesis: Tumorigenicity of individual PAHs and coal-tar extract, DNA adduction and expression of select genes in the Cyp1b1 knockout mouse. AB - FVB/N mice wild-type, heterozygous or null for Cyp 1b1 were used in a two-stage skin tumor study comparing PAH, benzo[a]pyrene (BaP), dibenzo[def,p]chrysene (DBC), and coal tar extract (CTE, SRM 1597a). Following 20 weeks of promotion with TPA the Cyp 1b1 null mice, initiated with DBC, exhibited reductions in incidence, multiplicity, and progression. None of these effects were observed with BaP or CTE. The mechanism of Cyp 1b1-dependent alteration of DBC skin carcinogenesis was further investigated by determining expression of select genes in skin from DBC-treated mice 2, 4 and 8h post-initiation. A significant reduction in levels of Cyp 1a1, Nqo1 at 8h and Akr 1c14 mRNA was observed in Cyp 1b1 null (but not wt or het) mice, whereas no impact was observed in Gst a1, Nqo 1 at 2 and 4h or Akr 1c19 at any time point. Cyp 1b1 mRNA was not elevated by DBC. The major covalent DNA adducts, dibenzo[def,p]chrysene-(+/-)-11,12 dihydrodiol-cis and trans-13,14-epoxide-deoxyadenosine (DBCDE-dA) were quantified by UHPLC-MS/MS 8h post-initiation. Loss of Cyp1 b1 expression reduced DBCDE-dA adducts in the skin but not to a statistically significant degree. The ratio of cis- to trans-DBCDE-dA adducts was higher in the skin than other target tissues such as the spleen, lung and liver (oral dosing). These results document that Cyp 1b1 plays a significant role in bioactivation and carcinogenesis of DBC in a two stage mouse skin tumor model and that loss of Cyp 1b1 has little impact on tumor response with BaP or CTE as initiators. PMID- 26049103 TI - Solubility shift and SUMOylaltion of promyelocytic leukemia (PML) protein in response to arsenic(III) and fate of the SUMOylated PML. AB - Promyelocytic leukemia (PML), which is a tumor suppressor protein that nevertheless plays an important role in the maintenance of leukemia initiating cells, is known to be biochemically modified by As(3+). We recently developed a simple method to evaluate the modification of PML by As(3+) resulting in a change in solubility and the covalent binding of small ubiquitin-like modifier (SUMO). Here we semi-quantitatively investigated the SUMOylation of PML using HEK293 cells which were stably transfected with PML-VI (HEK-PML). Western blot analyses indicated that PML became insoluble in cold RadioImmunoPrecipitation Assay (RIPA) lysis buffer and was SUMOylated by both SUMO2/3 and SUMO1 by As(3+). Surprisingly SUMO1 monomers were completely utilized for the SUMOylation of PML. Antimony (Sb(3+)) but not bismuth (Bi(3+)), Cu(2+), or Cd(2+) biochemically modified PML similarly. SUMOylated PML decreased after removal of As(3+) from the culture medium. However, unSUMOylated PML was still recovered in the RIPA-insoluble fraction, suggesting that SUMOylation is not requisite for changing the RIPA soluble PML into the RIPA-insoluble form. Immunofluorescence staining of As(3+) exposed cells indicated that SUMO2/3 was co-localized with PML in the nuclear bodies. However, some PML protein was present in peri-nuclear regions without SUMO2/3. Functional Really Interesting New Gene (RING)-deleted mutant PML neither formed PML nuclear bodies nor was biochemically modified by As(3+). Conjugation with intracellular glutathione may explain the accessibility of As(3+) and Sb(3+) to PML in the nuclear region evading chelation and entrapping by cytoplasmic proteins such as metallothioneins. PMID- 26049104 TI - Sameness: The regulatory crux with nanomaterial identity and grouping schemes for hazard assessment. AB - Regulators and industry need clear rules for identification and grouping of nanomaterials for a streamlined quantitative hazard evaluation. Therefore, we provide convincing reasons for (i) why to introduce pragmatic definition of identities for nanomaterials, (ii) how to combine them into entities, and ultimately (iii) how the entities might be evaluated with testing strategies based on clouds of similar nanomaterials. PMID- 26049105 TI - Structural characterization of dioicin 1 from Phytolacca dioica L. gains novel insights into phylogenetic relationships of Phytolaccaceae type 1 RIPs. AB - Ribosome-inactivating proteins are plant cytotoxic enzymes, also present in fungi, algae and bacteria, mainly known for their ability to inhibit protein synthesis. We previously purified and structurally characterized three type 1 RIPs (PD-S1-3) from Phytolacca dioica seeds and four type 1 RIPs (PD-L1-4) from adult plant leaves. Two additional RIPs, named dioicin 1 and dioicin 2, were isolated from leaves of young plants and developing leaves of adult plants. The evidence that P. dioica synthesizes and accumulates these RIPs isoforms suggests that these proteins have been conserved during evolution. Though several aspects of P. dioica type 1 RIP characterization have been studied, some important questions remain to be answered especially with respect to Phytolaccaceae RIP evolution. One of the major problems encountered in approaching RIPs phylogeny concerns the availability of their sequences. In this study, we report the characterization of biological and structural properties of dioicin 1, including the determination of its primary structure by using a combined approach based on Edman degradation, de novo sequencing by ESI-Q-TOF-MS/MS and peptide mapping by MALDI-TOF MS. Knowledge of dioicin 1 primary structure provide us a mean to deepen Phytolaccaceae's RIPs phylogeny. We speculate that both dioicins 1 and 2 share common ancestors with PAP-II and PAP icos-II and that dioicin 1 is not closely related to other members of this clade, thus shedding lights on evolutionary relationships among type 1 RIPs from Phytolaccaceae. PMID- 26049106 TI - Transmembrane protein 139 (TMEM139) interacts with human kidney isoform of anion exchanger 1 (kAE1). AB - Human kidney anion exchanger 1 (kAE1) mediates Cl(-)/HCO3(-) exchanges at the basolateral membrane of the acid-secreting alpha-intercalated cells. Mutations in SLC4A1 gene encoding kAE1 are associated with distal renal tubular acidosis (dRTA). Several studies have shown that impaired trafficking of the mutant kAE1 is an important molecular mechanism underlying the pathogenesis of dRTA. Proteins involved in kAE1 trafficking were identified but the mechanism resulting in dRTA remained unclear. Thus, this study attempted to search for additional proteins interacting with C-terminal of kAE1 (Ct-kAE1) and involved in kAE1 trafficking to cell membrane. Transmembrane protein 139 (TMEM139) was identified as a protein interacting with Ct-kAE1 by yeast two-hybrid screening. The interaction between kAE1 and TMEM139 was confirmed by affinity co-purification, co immunoprecipitation (co-IP) and yellow fluorescent protein (YFP)-based protein fragment complementation assay (PCA). In addition, flow cytometry results showed that suppression of endogenous TMEM139 by small interfering RNA (siRNA) and over expression of TMEM139 in HEK293T cells could reduce and increase membrane localization of kAE1, respectively. The presented data demonstrate that TMEM139 interacts with kAE1 and promotes its intracellular trafficking. PMID- 26049107 TI - Differential binding of prohibitin-2 to estrogen receptor alpha and to drug resistant ERalpha mutants. AB - Endocrine resistance is one of the most challenging problems in estrogen receptor alpha (ERalpha)-positive breast cancer. The transcriptional activity of ERalpha is controlled by several coregulators, including prohibitin-2 (PHB2). Because of its ability to repress the transcriptional activity of activated ERalpha, PHB2 is a promising antiproliferative agent. In this study, were analyzed the interaction of PHB2 with ERalpha and three mutants (Y537S, D538G, and E380Q) that are frequently associated with a lack of sensitivity to hormonal treatments, to help advance novel drug discovery. PHB2 bound to ERalpha wild-type (WT), Y537S, and D538G, but did not bind to E380Q. The binding thermodynamics of Y537S and D538G to PHB2 were favorably altered entropically compared with those of WT to PHB2. Our results show that PHB2 binds to the ligand binding domain of ERalpha with a conformational change in the helix 12 of ERalpha. PMID- 26049108 TI - Constitutive activation of Drosophila CncC transcription factor reduces lipid formation in the fat body. AB - Accumulating evidence indicates that the vertebrate stress-response transcription factors Nrf1 and Nrf2 are involved in hepatic lipid metabolism. However, the underlying molecular mechanisms of Nrf1-and Nrf2-mediated lipid metabolism remain unclear. To elucidate the precise roles of Nrfs in this process, we analyzed the physiological role of CncC in lipid metabolism as a Drosophila model for vertebrate Nrf1 and Nrf2. We first examined whether CncC activity is repressed under physiological conditions through a species-conserved NHB1 (N-terminal homology box 1) domain, similar to that observed for Nrf1. Deletion of the NHB1 domain (CncCDeltaN) led to CncC-mediated rough-eye phenotypes and the induced expression of the CncC target gene gstD1 both in vivo and in vitro. Thus, we decided to explore how CncCDeltaN overexpression affects the formation of the fat body, which is the major lipid storage organ. Intriguingly, CncCDeltaN caused a significant reduction in lipid droplet size and triglyceride (TG) levels in the fat body compared to wild type. We found that CncCDeltaN induced a number of genes related to innate immunity that might have an effect on the regulation of cellular lipid storage. Our study provides new insights into the regulatory mechanism of CncC and its role in lipid homeostasis. PMID- 26049109 TI - Effect of different N7 substitution of dinucleotide cap analogs on the hydrolytic susceptibility towards scavenger decapping enzymes (DcpS). AB - Scavenger decapping enzymes (DcpS) are involved in eukaryotic mRNA degradation process. They catalyze the cleavage of residual cap structure m(7)GpppN and/or short capped oligonucleotides resulting from exosom-mediated the 3' to 5' digestion. For the specific cap recognition and efficient degradation by DcpS, the positive charge at N7 position of guanine moiety is required. Here we examine the role the N7 substitution within the cap structure on the interactions with DcpS (human, Caenorhabditis elegans and Ascaris suum) comparing the hydrolysis rates of dinucleotide cap analogs (m(7)GpppG, et(7)GpppG, but(7)GpppG, bn(7)GpppG) and the binding affinities of hydrolysis products (m(7)GMP, et(7)GMP, but(7)GMP, bn(7)GMP). Our results show the conformational flexibility of the region within DcpS cap-binding pocket involved in the interaction with N7 substituted guanine, which enables accommodation of substrates with differently sized N7 substituents. PMID- 26049110 TI - ICOS promotes group 2 innate lymphoid cell activation in lungs. AB - Group 2 innate lymphoid cells (ILC2s) are newly identified, potent producers of type 2 cytokines, such as IL-5 and IL-13, and contribute to the development of allergic lung inflammation induced by cysteine proteases. Although it has been shown that inducible costimulator (ICOS), a costimulatory molecule, is expressed on ILC2s, the role of ICOS in ILC2 responses is largely unknown. In the present study, we investigated whether the interaction of ICOS with its ligand B7-related protein-1 (B7RP-1) can promote ILC2 activation. Cytokine production in ILC2s purified from mouse lungs was significantly increased by coculture with B7RP-1 transfected cells, and increased cytokine production was inhibited by monoclonal antibody-mediated blocking of the ICOS/B7RP-1 interaction. ILC2 expansion and eosinophil influx induced by papain, a cysteine protease antigen, in mouse lungs were significantly abrogated by blocking the ICOS/B7RP-1 interaction. Dendritic cells (DCs) in the lungs expressed B7RP-1 and the number of DCs markedly increased with papain administration. B7RP-1 expression on lung DCs was reduced after papain administration. This downregulation of B7RP-1 expression may be an indication of ICOS/B7RP-1 binding. These results indicate that ILC2s might interact with B7RP-1-expressing DCs in allergic inflammatory lung, and ICOS signaling can positively regulate the protease allergen-induced ILC2 activation followed by eosinophil infiltration into the lungs. PMID- 26049111 TI - A transparent epidural electrode array for use in conjunction with optical imaging. AB - BACKGROUND: Combining optical imaging and direct cortical stimulation can be a powerful technique for high-resolution functional mapping of the cortex. However, stimulating electrodes often obstruct the field of view, resulting in a lack of functional images behind the electrodes. NEW METHOD: To overcome this problem, we developed a transparent electrode array with 16-contact grids for epidural cortical stimulation. Using a commercially available indium tin oxide (ITO) coated polyethylene terephthalate (PET) sheet, the electrode array was fabricated using a photolithography process. Because a complete circuit pattern, including the electrode contact itself, was formed in the transparent metal ITO layer, our electrode array was completely transparent and therefore could be used with optical imaging. RESULTS: Cortical stimulation was performed using the transparent electrode array. Evoked neural activity was successfully monitored through the array using a voltage-sensitive dye and optical imaging. The newly developed electrode array made it possible to detect optical signals from directly below the stimulating electrode. The electrode array could also be used for epidural recording of somatosensory evoked potentials. COMPARISON WITH EXISTING METHODS: A variety of surface electrodes for cortical recording and stimulation exist. However, this study aimed to make electrodes as transparent as possible. We provided a simple and low-cost fabrication process for producing the transparent electrode arrays. CONCLUSIONS: Our transparent epidural electrode can be used for both stimulation and recordings without interfering with the detection of optical signals from the underlying cortex. PMID- 26049112 TI - Association of heat shock protein 90 with the developmental competence of immature oocytes following Cryotop and solid surface vitrification in yaks (Bos grunniens). AB - The correlation between the 90 kDa heat-shock protein (HSP90) and the developmental competence of yak (Bos grunniens) oocytes following the process of vitrification has not been studied clearly. In the present study, we compare the efficacies of Cryotop (CT) and solid surface vitrification (SSV) methods for the cryopreservation of immature yak oocytes. Yak cumulus oocyte complexes were randomly allocated into three groups: (1) controls, (2) CT vitrification, and (3) SSV vitrification. Oocytes were vitrified and in vitro maturated and fertilized. The percentages of nuclear maturation and in vitro development were evaluated. The vitrified-warmed oocytes were evaluated for mRNA and protein expression levels of HSP90 using quantitative real-time PCR and western blotting at various stages: matured oocytes, 2-8 cells embryos and blastocysts. No difference was found in the percentages of nuclear maturation, cleavage or blastocyst in the two vitrified groups; however, the rates of maturation were significantly lower than those in the control group. Among the three groups, the maturation rates in CT: 51.14+/-0.86% and SSV: 50.82+/-1.34% were less than those of the controls: 69.65+/-1.13%; the cleavage rates in CT: 39.16+/-1.01% and SSV: 39.08+/-0.92%, were less than those of the controls: 58.14+/-0.76%; but the blastocysts rates and total cell number in the blastocysts were similar: CT: 32.20+/-0.73% and 104.6+/-3.72; SSV: 32.35+/-0.81% and 102.4+/-1.34; and controls: 34.38+/-1.32% and 103.8+/-4.13, respectively. The HSP90 expression level in the matured oocytes and 2-8 cell embryos of the control group was significantly higher than that in the two vitrified groups; there was not significant difference in the blastocysts in the three groups. We thus conclude that CT and SSV perform equally in the vitrification of immature yak oocytes during the process of cryopreservation, and their influence on oocytes mainly occured from the maturation to cleavage stages. The HSP90 levels in the blastocysts of the vitrified groups increased is associated with the developmental competence of the embryo. PMID- 26049113 TI - Morphological characterization and conservation of bovine spermatogenic cells by refrigeration at 4 degrees C and freezing using different cryoprotective molecules. AB - The objectives of this study were study a practical method to characterize bovine spermatogenic cells and test the efficiency cells conservation by refrigeration at 4 degrees C and cryopreservation in different solutions using two cooling curves. Cellular identification was performing by analysis of shape, size and morphology, associated with nucleus positioning and nuclear-cytoplasm ratio (NCR). Cellular samples were kept at 4 degrees C for a period of 96 h in refrigeration solution and every 24h plasma membrane and DNA integrity were evaluated. Cryopreservation of cells was carried out using solutions containing 10% Dimethyl sulfoxide, 5% Dimethylformamide, 7% Glycerol and 7% Ethylene glycol, using a controlled and non-controlled cooling curve. Results of cellular characterization demonstrated that spermatocytes II presented a cylindrical shape, NCR of 1:1.5 and diameter ranging from 14.5 to 17.5 MUm. Round spermatids presented diameter ranging from 7.6 to 13.4 MUm, acrosomal cap and NCR of 1:2. Elongation and elongated spermatids showed to marked divergence in shape. There was a daily significant loss of viability of cooled cells until third day of storage, however they presented 72.77+/-5.16% viability after 4 days of storage at 4 degrees C. There was no difference among the cryoprotectant solutions and cooling curves. In conclusion we demonstrated that association of microscopes and staining was a practical method to identify bovine spermatogenic cells. Furthermore, refrigeration at 4 degrees C is an important strategy to preserve over 70% of viable cells after 4 days and cryopreservation, regardless of cryoprotectant solution or cooling curve used, can maintain over 50% of cells viable. PMID- 26049114 TI - The Risk of Getting Worse: Predictors of Deterioration After Decompressive Surgery for Lumbar Spinal Stenosis: A Multicenter Observational Study. AB - OBJECTIVE: To investigate the frequency and predictors of deterioration after decompressive surgery for single and 2-level lumbar spinal stenosis. METHODS: Prospectively collected data were retrieved from the Norwegian Registry for Spine Surgery. Clinically significant deterioration was defined as an 8-point increase in Oswestry disability index (ODI) between baseline and 12 months' follow-up. RESULTS: There were 2181 patients enrolled in the study. Of 1735 patients with complete 12 months follow-up, 151 (8.7%) patients reported deterioration. The following variables were significantly associated with deterioration at 12 months' follow-up; decreasing age (odds ratio [OR] 1.02, 95% confidence interval [95% CI] 1.00-1.04, P = 0.046), tobacco smoking (OR 2.10, 95% CI 1.42-3.22, P = 0.000), American Society of Anesthesiologists grade >=3 (OR 1.80, 95% CI 1.07 2.94, P = 0.025), decreasing preoperative ODI (OR 1.05, 95% CI 1.02-1.07, P = 0.000), previous surgery at the same level (OR 2.00, 95% CI 1.18-3.27, P = 0.009), and previous surgery at other lumbar levels (OR 2.10, 95% CI 1.19-3.53, P = 0.009). CONCLUSIONS: Overall risk of clinically significant deterioration in patient-reported pain and disability after decompressive surgery for lumbar spinal stenosis is approximately 9%. Predictors for deterioration are decreasing age, current tobacco smoking, American Society of Anesthesiologists grade >=3, decreasing preoperative ODI, and previous surgery at same or different lumbar level. We suggest that these predictors should be emphasized and discussed with the patients before surgery. PMID- 26049115 TI - Osteopontin: A major player on hypertension-induced vascular remodeling. PMID- 26049116 TI - Isolation, characterization, interaction of a thiazolekinase (Plasmodium falciparum) with silver nanoparticles. AB - Malaria, a mosquito-borne infectious disease, is caused by the Plasmodium genus, and remains one of the greatest health challenges worldwide. The malarial parasite possess a biosynthetic pathway for the B-group vitamin incorporating the thiamine metabolizing enzymes; humans on the other hand cannot synthesize the vitamin and require it from within their diet. The vitamin B1 biosynthetic enzyme 5-(2-hydroxyethyl)-4-methylthioazolekinase [EC. 2.7.1.50] from Plasmodium (PfThzK) is particularly attractive as a biomedical target since any inhibition of this enzyme may lead to an effective treatment for malaria. In the present study, PfThzK was recombinantly produced as a 6* His fusion protein in Escherichia coli BL21(DE3) and purified using nickel affinity and size exclusion chromatography. The enzyme was monomeric with a molecular mass of 34 kDa, a specific activity of 295.04 nmol min(-1) mg(-1) and showed an optimum temperature and pH of 37 degrees C and 7.5, respectively. The purified PfThzK was non competitively inhibited (79%) by silver nanoparticles (2-6 nm); Ki=6.45 MUM. A mechanism is suggested for the interaction of the silver nanoparticle with PfThzK through two sulphur bearing amino acids (Met(1), Cys(206)) on the surface of each subunit of the enzyme. PMID- 26049117 TI - Cooperativity and evolution of Tetrahymena two-domain arginine kinase. AB - Tetrahymena pyriformis contains two arginine kinases, a 40-kDa enzyme (AK1) with a myristoylation signal sequence at the N-terminus and a two-domain 80-kDa enzyme (AK2). The former is localized mainly in cilia and the latter is in the cytoplasm. AK1 was successfully synthesized using an insect cell-free protein synthesis system and subjected to peptide mass fingerprinting (PMF) analysis. The masses corresponding to unmodified N-terminal tryptic peptide or N-terminal myristoylated peptide were not observed, suggesting that N-terminal peptides were not ionized in this analysis. We performed PMF analyses for two other phosphagen kinases (PKs) with myristoylation signals, an AK from Nematostella vectensis and a PK from Ectocarpus siliculosus. In both cases, the myristoylated, N-terminal peptides were clearly identified. The differences between the experimental and theoretical masses were within 0.0165-0.0583 Da, supporting the accuracy of the identification. Domains 1 and 2 of Tetrahymena two-domain AK2 were expressed separately in Escherichia coli and the extent of cooperativity was estimated on the basis of their kinetic constants. The results suggested that each of the domains functions independently, namely no cooperativity is displayed between the two domains. This is in sharp contrast to the two-domain AK from Anthopleura. PMID- 26049118 TI - Chameleon 'aggregation-prone' segments of apoA-I: A model of amyloid fibrils formed in apoA-I amyloidosis. AB - Apolipoprotein A-I (apoA-I) is the major component of high density lipoproteins and plays a vital role in reverse cholesterol transport. Lipid-free apoA-I is the main constituent of amyloid deposits found in atherosclerotic plaques, an acquired type of amyloidosis, whereas its N-terminal fragments have been associated with a hereditary form, known as familial apoA-I amyloidosis. Here, we identified and verified four "aggregation-prone" segments of apoA-I with amyloidogenic properties, utilizing electron microscopy, X-ray fiber diffraction, ATR FT-IR spectroscopy and polarized light microscopy. These segments may act as conformational switches, possibly controlling the transition of the alpha-helical apoA-I content into the "cross-beta" architecture of amyloid fibrils. A structural model illuminating the structure of amyloid fibrils formed by the N terminal fragments of apoA-I is proposed, indicating that two of the identified chameleon segments may play a vital part in the formation of amyloid fibrils in familial apoA-I amyloidosis. PMID- 26049119 TI - What Our Hands Say: Exploring Gesture Use in Subgroups of Children With Language Delay. AB - PURPOSE: The aim of this study was to investigate whether children with receptive expressive language delay (R/ELD) and expressive-only language delay (ELD) differ in their use of gesture; to examine relationships between their use of gesture, symbolic comprehension, and language; to consider implications for assessment and for the nature of problems underlying different profiles of early language delay. METHOD: Twelve children with ELD (8 boys, 4 girls) and 10 children with R/ELD (8 boys, 2 girls), aged 2-3 years, were assessed on measures of gesture use and symbolic comprehension. RESULTS: Performance of the R/ELD group was significantly poorer than performance of the ELD group on measures of gesture and symbolic comprehension. Gesture use and symbolic comprehension were significantly associated with receptive language, but associations with expressive language were not significant. CONCLUSIONS: Findings of this study support previous research pointing to links between gesture and language development, and more specifically, between delays in gesture, symbolic understanding, and receptive rather than expressive language. Given potentially important implications for the nature of problems underlying ELD and R/ELD, and for assessment of children with language delay, this preliminary study invites further investigation comparing the use of different gesture types in samples of children matched on age and nonverbal IQ. PMID- 26049120 TI - A Computational Model Quantifies the Effect of Anatomical Variability on Velopharyngeal Function. AB - PURPOSE: This study predicted the effects of velopharyngeal (VP) anatomical parameters on VP function to provide a greater understanding of speech mechanics and aid in the treatment of speech disorders. METHOD: We created a computational model of the VP mechanism using dimensions obtained from magnetic resonance imaging measurements of 10 healthy adults. The model components included the levator veli palatini (LVP), the velum, and the posterior pharyngeal wall, and the simulations were based on material parameters from the literature. The outcome metrics were the VP closure force and LVP muscle activation required to achieve VP closure. RESULTS: Our average model compared favorably with experimental data from the literature. Simulations of 1,000 random anatomies reflected the large variability in closure forces observed experimentally. VP distance had the greatest effect on both outcome metrics when considering the observed anatomic variability. Other anatomical parameters were ranked by their predicted influences on the outcome metrics. CONCLUSIONS: Our results support the implication that interventions for VP dysfunction that decrease anterior to posterior VP portal distance, increase velar length, and/or increase LVP cross sectional area may be very effective. Future modeling studies will help to further our understanding of speech mechanics and optimize treatment of speech disorders. PMID- 26049121 TI - Immunological changes in the ascites of cancer patients after intraperitoneal administration of the bispecific antibody catumaxomab (anti-EpCAM*anti-CD3). AB - OBJECTIVE: To explore the effects of intraperitoneal (i.p.) infusion of catumaxomab, a bispecific monoclonal antibody (anti-EpCAM*anti-CD3), on T cells, NK cells and macrophages in ascites of cancer patients and to understand how ascitic immune cells can be activated despite the pervasive immunosuppressive ability of ascites microenvironment. METHODS: Six patients with malignant ascites received i.p. catumaxomab infusion. Ascitic immune cells were profiled by flow cytometry and gene expression at baseline and after i.p. catumaxomab infusion. In vitro experiments enabled investigations on the adverse effect of ascites microenvironment on catumaxomab-stimulated immune cells. RESULTS: I.p. catumaxomab infusion enhanced the expression of the CD69 and CD38 activation molecules in CD4(+) and CD8(+) T cells, NK cells and macrophages, and favoured CD8(+) T cell accumulation into the peritoneal cavity. An analogous immune cell activation as well as IFN-gamma and IL-2 production were induced by catumaxomab in vitro. In vitro experiments showed that the immunosuppressive milieu of ascites abrogated all the immunostimulatory activities of catumaxomab. Adding EpCAM(+) tumour cells to the culture permitted both catumaxomab Fab regions to engage cognate antigens and restored immunostimulatory catumaxomab activity. CONCLUSIONS: This is the first demonstration in a clinical setting that i.p. catumaxomab infusion activates NK cells and macrophages in addition to T cells in ascites and favours CD8(+) T cell accumulation into the peritoneal cavity. Moreover, our findings indicate that the concomitant binding of both catumaxomab Fab regions delivers an activation signal that is strong enough to activate immune cells despite the prevailing immunosuppressive environment of malignant ascites. PMID- 26049122 TI - Transdiaphragmatic cardiophrenic lymph node resection for Stage IV ovarian cancer. PMID- 26049123 TI - Phase II study of weekly paclitaxel/carboplatin in combination with prophylactic G-CSF in the treatment of gynecologic cancers: A study in 108 patients by the Belgian Gynaecological Oncology Group. AB - OBJECTIVE: To investigate the addition of prophylactic G-CSF to each weekly paclitaxel/carboplatin course in patients with recurrent platinum-resistant ovarian (OC), or recurrent or advanced endometrial (EC) or cervical carcinoma (CC). METHODS: 108 patients were enrolled i.e. 36 in each cohort. Eighteen courses of paclitaxel (60 mg/m(2)) and carboplatin (AUC 2.7) were administered weekly. G-CSF (filgrastim) was given to all patients on day 5 (and if needed on day 6). RESULTS: For patients with OC, 91% had platinum-resistant and 9% platinum refractory disease. Median number of prior chemotherapy lines was 3 for OC, 1 for EC, and 1 for CC. Grade 3-4 neutropenia was observed in 34% of patients (95% CI: 26%-44%, P<0,0001) (OC 29%, EC 36%, CC 38%). This is lower compared to historical data in all cohorts (84%). Confirmed sepsis was observed in 5%, grade 3-4 thrombocytopenia in 41%, grade 2-3 peripheral neuropathy in 17% of patients. In 71% of patients dose was delayed. Dose reduction was necessary for carboplatin in 47% and paclitaxel in 18% of patients. ORR was 51% (OC 48%, EC 45%, CC 58%). Median (95% CI) PFS and OS was 7.1 (5.1-8.1) and 12.7 (10.2-16.3) months, respectively (OC 7 and 13, EC 6 and 19, CC 6 and 14). CONCLUSION: Weekly paclitaxel/carboplatin with G-CSF is an effective treatment with acceptable toxicity in patients with platinum-resistant or platinum-refractory OC, advanced or recurrent EC and CC. The incidence of grade 3-4 neutropenia is lower with the addition of weekly G-CSF compared with earlier studies without routine use of prophylactic G-CSF. PMID- 26049124 TI - Too much, too late: Aggressive measures and the timing of end of life care discussions in women with gynecologic malignancies. AB - OBJECTIVE: This study describes the patterns of end of life (EOL) discussions and their impact on the use of aggressive measures in women with terminal gynecologic malignancies at a single institution. METHODS: An IRB-approved retrospective chart review identified 136 patients who died of gynecologic cancer between 2010 and 2012 with at least one interaction with their oncologists in the last 6 months of life. Aggressive measures were defined as chemotherapy within the last 14 days of life, emergency department (ED) visits, hospital and intensive care unit (ICU) admissions within the last 30 days of life, and inpatient deaths. The frequency and timing of EOL conversations were recorded. Utilization of hospice care was also described. RESULTS: In the last 30 days of life, 54 (40%) patients were evaluated in the ED, 67 (49%) were admitted into hospital, and 16 (12%) were admitted to the ICU. Thirteen patients (10%) had chemotherapy in the last 14 days of life. Ninety-seven (71%) patients had a documented EOL conversation, eighteen (19%) as outpatients, and 79 (81%) as inpatients. Thirty (22%) patients died in the hospital. At the time of death, 55 (40%) patients were enrolled in outpatient hospice care. The mean amount of time in hospice was 28 days. CONCLUSIONS: End of life care discussions rarely occurred in the outpatient setting or >30 days before death. Inpatient encounters led to discussions about hospice and code status. Evaluation in the ED frequently resulted in escalation of care. Earlier EOL care discussions resulted in less aggressive measures. PMID- 26049125 TI - Characterization and distribution of mating-type genes of the turfgrass pathogen Sclerotinia homoeocarpa on a global scale. AB - Sclerotinia homoeocarpa F.T. Bennett is a filamentous member of Ascomycota that causes dollar spot, the most economically important disease of turfgrass worldwide. We sequenced and characterized the mating-type (MAT) locus of four recently-collected contemporary strains causing dollar spot, four historical type strains used to describe the fungus, and three species of Rutstroemiaceae. Moreover, we developed a multiplex PCR assay to screen 1019 contemporary isolates for mating-type. The organization of the MAT loci of all strains examined could be classified into one of four categories: (1) putatively heterothallic, as exemplified by all contemporary strains and three of four historical type strains; (2) putatively heterothallic with a deleted putative gene in the MAT1-2 idiomorph, as detected in strains from two recently-collected populations in the United Kingdom that show more similarity to historical strains; (3) putatively homothallic with close physical linkage between MAT1-1-1 and MAT1-2-1, as found in one historical type strain of S. homoeocarpa and two strains of Rutstroemia cuniculi; and (4) an unresolved but apparently homothallic organization in which strains contained both MAT1-1-1 and MAT1-2-1 but linkage between these genes and between the two flanking genes could not be confirmed, as identified in R. paludosa and Poculum henningsianum. In contemporary S. homoeocarpa populations there was no significant difference in the frequency of the two mating types in clone-corrected samples when analyzed on regional and local scales, suggesting sex may be possible in this pathogen. However, two isolates from Italy and twenty from California were heterokaryotic for both complete heterothallic MAT idiomorphs. Results from this study contribute to knowledge about mating systems in filamentous fungi and enhance our understanding of the evolution and biology of an important plant pathogen. PMID- 26049126 TI - Cognitive behaviour therapy reduces dyspnoea ratings in patients with chronic obstructive pulmonary disease (COPD). AB - There is evidence that psychological factors contribute to the perception of increased difficulty of breathing in patients with chronic obstructive pulmonary disease (COPD), and increase morbidity. We tested the hypothesis that cognitive behaviour therapy (CBT) decreases ratings of perceived dyspnoea in response to resistive loading in patients with COPD. From 31 patients with COPD, 18 were randomised to four sessions of specifically targeted CBT and 13 to routine care. Prior to randomisation, participants were tested with an inspiratory external resistive load protocol (loads between 5 and 45cmH2O/L/s). Six months later, we re-measured perceived dyspnoea in response to the same inspiratory resistive loads and compared results to measurements prior to randomisation. There was a significant 17% reduction in dyspnoea ratings across the loads for the CBT group, and no reduction for the routine care group. The decrease in ratings of dyspnoea suggests that CBT to alleviate breathing discomfort may have a role in the routine treatment of people with COPD. PMID- 26049128 TI - Erythropoietin attenuates Alzheimer-like memory impairments and pathological changes induced by amyloid beta42 in mice. AB - Amyloid beta (Abeta) is a key molecule in the neurodegenerative progression of Alzheimer's disease (AD). It is critical to develop a treatment that can arrest the Abeta-induced pathologic progression of AD. Erythropoietin (EPO) has various protective effects in the nervous system. However, the effect of EPO on Abeta induced Alzheimer-like cognitive deficits and pathological changes remains unclear. In the present study, we observed that the treatment of mice with EPO (1000 IU/kg) attenuated Abeta42-induced cognitive deficits and tau hyperphosphorylation at multiple AD-related sites through the regulation of glycogen synthase kinase-3beta (GSK-3beta). We also observed that EPO attenuated the Abeta42-induced mitochondrial dysfunction and apoptosis in brain. These results indicate a potential role for EPO in AD therapy. PMID- 26049127 TI - Adolescent olanzapine sensitization is correlated with hippocampal stem cell proliferation in a maternal immune activation rat model of schizophrenia. AB - Previous work established that repeated olanzapine (OLZ) administration in normal adolescent rats induces a sensitization effect (i.e. increased behavioral responsiveness to drug re-exposure) in the conditioned avoidance response (CAR) model. However, it is unclear whether the same phenomenon can be detected in animal models of schizophrenia. The present study explored the generalizability of OLZ sensitization from healthy animals to a preclinical neuroinflammatory model of schizophrenia in the CAR. Maternal immune activation (MIA) was induced via polyinosinic:polycytidylic acid (PolyI:C) administration into pregnant dams. Behavioral assessments of offspring first identified decreased maternal separation-induced pup ultrasonic vocalizations and increased amphetamine-induced hyperlocomotion in animals prenatally exposed to PolyI:C. In addition, repeated adolescent OLZ administration confirmed the generalizability of the sensitization phenomenon. Using the CAR test, adolescent MIA animals displayed a similar increase in behavioral responsiveness after repeated OLZ exposure during both the repeated drug test days as well as a subsequent challenge test. Neurobiologically, few studies examining the relationship between hippocampal cell proliferation and survival and either antipsychotic exposure or MIA have incorporated concurrent behavioral changes. Thus, the current study also sought to reveal the correlation between OLZ behavioral sensitization in the CAR and hippocampal cell proliferation and survival. 5'-bromodeoxyuridine immunohistochemistry identified a positive correlation between the magnitude of OLZ sensitization (i.e. change in avoidance suppression induced by OLZ across days) and hippocampal cell proliferation. The implications of the relationship between behavioral and neurobiological results are discussed. PMID- 26049129 TI - Neuroprotective mechanisms activated in non-seizing rats exposed to sarin. AB - Exposure to organophosphate (OP) nerve agents, such as sarin, may lead to uncontrolled seizures and irreversible brain injury and neuropathology. In rat studies, a median lethal dose of sarin leads to approximately half of the animals developing seizures. Whereas previous studies analyzed transcriptomic effects associated with seizing sarin-exposed rats, our study focused on the cohort of sarin-exposed rats that did not develop seizures. We analyzed the genomic changes occurring in sarin-exposed, non-seizing rats and compared differentially expressed genes and pathway activation to those of seizing rats. At the earliest time point (0.25 h) and in multiple sarin-sensitive brain regions, defense response genes were commonly expressed in both groups of animals as compared to the control groups. All sarin-exposed animals activated the MAPK signaling pathway, but only the seizing rats activated the apoptotic-associated JNK and p38 MAPK signaling sub-pathway. A unique phenotype of the non-seizing rats was the altered expression levels of genes that generally suppress inflammation or apoptosis. Importantly, the early transcriptional response for inflammation- and apoptosis-related genes in the thalamus showed opposite trends, with significantly down-regulated genes being up-regulated, and vice versa, between the seizing and non-seizing rats. These observations lend support to the hypothesis that regulation of anti-inflammatory genes might be part of an active and sufficient response in the non-seizing group to protect against the onset of seizures. As such, stimulating or activating these responses via pretreatment strategies could boost resilience against nerve agent exposures. PMID- 26049131 TI - Neurological outcome prediction in the new era of targeted temperature management: Is 36 degrees C different from 33 degrees C? PMID- 26049130 TI - Paeoniflorin attenuates Abeta1-42-induced inflammation and chemotaxis of microglia in vitro and inhibits NF-kappaB- and VEGF/Flt-1 signaling pathways. AB - Alzheimer's disease (AD) is a neurodegenerative disease with elusive pathogenesis, which accounts for most cases of dementia in the aged population. It has been reported that persistent inflammatory responses and excessive chemotaxis of microglia stimulated by beta-amyloid (Abeta) oligomers in the brain may accelerate the progression of AD. The present study was conducted to explore whether paeoniflorin (PF), a water-soluble monoterpene glycoside isolated from the root of Paeonia lactiflora Pallas, could attenuate Abeta1-42-induced toxic effects on primary and BV-2 microglial cells in vitro. Our data showed that PF pretreatment inhibited Abeta1-42-induced production of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 in rodent microglia. Also, the nuclear translocation of nuclear factor kappa B (NF-kappaB) subunit p65 and the phosphorylation of NF-kappaB inhibitor alpha (IkappaBalpha) in Abeta1-42 stimulated microglial cells were suppressed by PF administration. Moreover, PF treatment reduced the release of chemokine (C-X-C motif) ligand 1 (CXCL1) and chemokine (C-C motif) ligand 2 (CCL-2) from Abeta1-42-stimulated microglia. Additionally, application of PF inhibited the increases in vascular endothelial growth factor (VEGF) and VEGF receptor 1 (Flt-1) triggered by Abeta1-42, and resulted in a concomitant reduction in microglial chemotaxis. Restoration of VEGF was noted to counteract the inhibitory effect of PF, suggesting that PF mitigated Abeta1-42-elicited microglial migration at least partly by suppressing the VEGF/Flt-1 axis. In summary, in presence of Abeta1-42, PF pretreatment inhibited the excessive microglial activation and chemotaxis. PMID- 26049132 TI - Prehospital endovascular occlusion of the aorta is now a technically feasible strategy for improving haemodynamics in CPR. PMID- 26049133 TI - Nanoengineering of vaccines using natural polysaccharides. AB - Currently, there are over 70 licensed vaccines, which prevent the pathogenesis of around 30 viruses and bacteria. Nevertheless, there are still important challenges in this area, which include the development of more active, non invasive, and thermo-resistant vaccines. Important biotechnological advances have led to safer subunit antigens, such as proteins, peptides, and nucleic acids. However, their limited immunogenicity has demanded potent adjuvants that can strengthen the immune response. Particulate nanocarriers hold a high potential as adjuvants in vaccination. Due to their pathogen-like size and structure, they can enhance immune responses by mimicking the natural infection process. Additionally, they can be tailored for non-invasive mucosal administration (needle-free vaccination), and control the delivery of the associated antigens to a specific location and for prolonged times, opening room for single-dose vaccination. Moreover, they allow co-association of immunostimulatory molecules to improve the overall adjuvant capacity. The natural and ubiquitous character of polysaccharides, together with their intrinsic immunomodulating properties, their biocompatibility, and biodegradability, justify their interest in the engineering of nanovaccines. In this review, we aim to provide a state-of-the-art overview regarding the application of nanotechnology in vaccine delivery, with a focus on the most recent advances in the development and application of polysaccharide based antigen nanocarriers. PMID- 26049134 TI - Biological assessment of self-assembled polymeric micelles for pulmonary administration of insulin. AB - Pulmonary delivery of drugs for both local and systemic action has gained new attention over the last decades. In this work, different amphiphilic polymers (Soluplus(r), Pluronic(r) F68, Pluronic(r) F108 and Pluronic(r) F127) were used to produce lyophilized formulations for inhalation of insulin. Development of stimuli-responsive, namely glucose-sensitive, formulations was also attempted with the addition of phenylboronic acid (PBA). Despite influencing the in vitro release of insulin from micelles, PBA did not confer glucose-sensitive properties to formulations. Lyophilized powders with aerodynamic diameter (<6 MUm) compatible with good deposition in the lungs did not present significant in vitro toxicity for respiratory cell lines. Additionally, some formulations, in particular Pluronic(r) F127-based formulations, enhanced the permeation of insulin through pulmonary epithelial models and underwent minimal internalization by macrophages in vitro. Overall, formulations based on polymeric micelles presenting promising characteristics were developed for the delivery of insulin by inhalation. FROM THE CLINICAL EDITOR: The ability to deliver other systemic drugs via inhalation has received renewed interests in the clinical setting. This is especially true for drugs which usually require injections for delivery, like insulin. In this article, the authors investigated their previously developed amphiphilic polymers for inhalation of insulin in an in vitro model. The results should provide basis for future in vivo studies. PMID- 26049135 TI - IV fluid choices in children: have we found the solution? PMID- 26049136 TI - Relationship between obesity, negative affect and basal heart rate in predicting heart rate reactivity to psychological stress among adolescents. AB - Reduced cardiovascular responses to psychological stressors have been found to be associated with both obesity and negative affect in adults, but have been less well studied in children and adolescent populations. These findings have most often been interpreted as reflecting reduced sympathetic nervous system response, perhaps associated with heightened baseline sympathetic activation among the obese and those manifesting negative affect. However, obesity and negative affect may themselves be correlated, raising the question of whether they both independently affect cardiovascular reactivity. The present study thus examined the separate effects of obesity and negative affect on both cardiovascular and skin conductance responses to stress (e.g., during a serial subtraction math task) in adolescents, while controlling for baseline levels of autonomic activity during rest. Both obesity and negative affect had independent and negative associations with cardiovascular reactivity, such that reduced stress responses were apparent for obese adolescents and those with high levels of negative affect. In contrast, neither obesity nor negative affect was related to skin conductance responses to stress, implicating specifically noradrenergic mechanisms rather than sympathetic mechanisms generally as being deficient. Moreover, baseline heart rate was unrelated to obesity in this sample, which suggests that heightened baseline of sympathetic activity is not necessary for the reduced cardiovascular reactivity to stress. PMID- 26049137 TI - Down-regulation of Wt1 activates Wnt/beta-catenin signaling through modulating endocytic route of LRP6 in podocyte dysfunction in vitro. AB - Podocyte dysfunction plays important roles in the pathogenesis of chronic kidney disease, and Wt1 has long been considered to be a marker of podocyte, whereas its roles and mechanisms in podocyte injury are still unclear though Wt1 mutations are reported to be involved in the development of glomerular disease in human and mice. Here we show that down-regulation of Wt1 could induce podocyte dysfunction and apoptosis through activating Wnt/beta-catenin signaling. Podocytes treated with adriamycin demonstrated decreased expression of Wt1, coupled with activated Wnt/beta-catenin signaling in vitro. Reduced expression of Wt1 in podocytes transfected with Wt1 siRNA is correlated with activated Wnt/beta-catenin signaling, increased podocyte apoptosis, as well as suppressed expression of nephrin. Blockade of Wnt/beta-catenin signaling with Dickkopf-1 ameliorated podocyte injury and apoptosis induced by Wt1 siRNA. We also found that membrane LRP6 was increased dramatically in podocytes transfected with Wt1 siRNA compared with control siRNA, while no significant change was found in total LRP6. Caveolin and clathrin-dependent endocytosis were both involved in the regulation of beta catenin signaling. And we found that down-regulation of Wt1 in podocytes mediates activation of Wnt/beta-catenin signaling by recruiting LRP6 to the caveolin mediated endocytosis route, thereby sequestering it from clathrin-dependent endocytosis. As a result, we concluded that Wt1 expression levels in podocytes regulate Wnt/beta-catenin signaling through modulating the endocytic fate of LRP6, and this indicates a potential target for the therapy of CKD. PMID- 26049138 TI - Mycobacterial load affects adenosine deaminase 2 levels of tuberculous pleural effusion. PMID- 26049139 TI - Progressive multifocal leukoencephalopathy with immune reconstitution inflammatory syndrome misdiagnosed as cerebral toxoplasmosis in an HIV-infected woman. PMID- 26049140 TI - A WNT1-regulated developmental gene cascade prevents dopaminergic neurodegeneration in adult En1(+/-) mice. AB - The protracted and age-dependent degeneration of dopamine (DA)-producing neurons of the Substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in the mammalian midbrain is a hallmark of human Parkinson's Disease (PD) and of certain genetic mouse models of PD, such as mice heterozygous for the homeodomain transcription factor Engrailed 1 (En1(+/-) mice). Neurotoxin-based animal models of PD, in contrast, are characterized by the fast and partly reversible degeneration of the SNc and VTA DA neurons. The secreted protein WNT1 was previously shown to be strongly induced in the neurotoxin-injured adult ventral midbrain (VM), and to protect the SNc and VTA DA neurons from cell death in this context. We demonstrate here that the sustained and ectopic expression of Wnt1 in the SNc and VTA DA neurons of En1(+/Wnt1) mice also protected these genetically affected En1 heterozygote (En1(+/-)) neurons from their premature degeneration in the adult mouse VM. We identified a developmental gene cascade that is up regulated in the adult En1(+/Wnt1) VM, including the direct WNT1/beta-catenin signaling targets Lef1, Lmx1a, Fgf20 and Dkk3, as well as the indirect targets Pitx3 (activated by LMX1A) and Bdnf (activated by PITX3). We also show that the secreted neurotrophin BDNF and the secreted WNT modulator DKK3, but not the secreted growth factor FGF20, increased the survival of En1 mutant dopaminergic neurons in vitro. The WNT1-mediated signaling pathway and its downstream targets BDNF and DKK3 might thus provide a useful means to treat certain genetic and environmental (neurotoxic) forms of human PD. PMID- 26049141 TI - The tip-link molecular complex of the auditory mechano-electrical transduction machinery. AB - Sound waves are converted into electrical signals by a process of mechano electrical transduction (MET), which takes place in the hair bundle of cochlear hair cells. In response to the mechanical stimulus of the hair bundle, the tip links, key components of the MET machinery, are tensioned and the MET channels open, which results in the generation of the cell receptor potential. Tip-links are composed of cadherin-23 (Cdh23) and protocadherin-15 (Pcdh15), both non conventional cadherins, that form the upper and the lower part of these links, respectively. Here, we review the various Pcdh15 isoforms present in the organ of Corti, their localization in the auditory hair bundles, their involvement in the molecular complex forming the tip-link, and their interactions with transmembrane molecules that are components of the lower MET machinery. PMID- 26049142 TI - Neuronal hypoxia disrupts mitochondrial fusion. AB - Brain ischemia/reperfusion injury results in death of vulnerable neurons and extensive brain damage. It is well known that mitochondrial release of cytochrome c (cyto c) is a hallmark of neuronal death, however the molecular events underlying this release are largely unknown. We tested the hypothesis that cyto c release is regulated by breakdown of the cristae architecture maintenance protein, optic atrophy 1 (OPA1), located in the inner mitochondrial membrane. We simulated ischemia/reperfusion in isolated primary rat neurons and interrogated OPA1 release from the mitochondria, OPA1 oligomeric breakdown, and concomitant dysfunction of mitochondrial dynamic state. We found that ischemia/reperfusion induces cyto c release and cell death that corresponds to multiple changes in OPA1, including: (i) translocation of the mitochondrial fusion protein OPA1 from the mitochondria to the cytosol, (ii) increase in the short isoform of OPA1, suggestive of proteolytic processing, (iii) breakdown of OPA1 oligomers in the mitochondria, and (iv) increased mitochondrial fission. Thus, we present novel evidence of a connection between release of cyto c from mitochondria and disruption of the mitochondrial fusion. PMID- 26049143 TI - Disruption of 5-HT1A function in adolescence but not early adulthood leads to sustained increases of anxiety. AB - Current evidence suggests that anxiety disorders have developmental origins. Early insults to the circuits that sub-serve emotional regulation are thought to cause disease later in life. Evidence from studies in mice demonstrate that the serotonergic system in general, and serotonin 1A (5-HT1A) receptors in particular, are critical during the early postnatal period for the normal development of circuits that subserve anxious behavior. However, little is known about the role of serotonin signaling through 5-HT1A receptors between the emergence of normal anxiety behavior after weaning, and the mature adult phenotype. Here, we use both transgenic and pharmacological approaches in male mice, to identify a sensitive period for 5-HT1A function in the stabilization of circuits mediating anxious behavior during adolescence. Using a transgenic approach we show that suppression of 5-HT1A receptor expression beginning in early adolescence results in an anxiety-like phenotype in the open field test. We further demonstrate that treatment with the 5-HT1A antagonist WAY 100,635 between postnatal day (P)35 and P50, but not at later timepoints, results in altered anxiety in ethologically based conflict tests like the open field test and elevated plus maze. This change in anxiety behavior occurs without impacting behavior in the more depression-related sucrose preference test or forced swim test. The treatment with WAY 100,635 does not affect adult 5-HT1A expression levels, but leads to increased expression of the serotonin transporter in the raphe, along with enhanced serotonin levels in both the prefrontal cortex and raphe that correlate with the behavioral changes observed in adult mice. This work demonstrates that signaling through 5-HT1A receptors during adolescence (a time when pathological anxiety emerges), but not early adulthood, is critical in regulating anxiety setpoints. These data suggest the possibility that brief interventions in the serotonergic system during adolescence could lead to profound and enduring changes in physiology and behavior. PMID- 26049144 TI - Induction of long-term oscillations in the gamma frequency band by nAChR activation in rat hippocampal CA3 area. AB - The hippocampal neuronal network oscillation at gamma frequency band (gamma oscillation) is generated by the precise interaction between interneurons and principle cells. gamma oscillation is associated with attention, learning and memory and is impaired in the diseased conditions such as Alzheimer's disease (AD) and schizophrenia. Nicotinic acetylcholine receptor (nAChR) plays an important role in the regulation of hippocampal neurotransmission and network activity. It is not known whether nicotine modulates plasticity of network activity at gamma oscillations in the hippocampus. In this study we investigated the effects of nicotine on the long-term changes of KA-induced gamma oscillations. We found that hippocampal gamma oscillations can be enhanced by a low concentration of nicotine (1MUM), such an enhancement lasts for hours after washing out of nicotine, suggesting a form of synaptic plasticity, named as long term oscillation at gamma frequency band (LTOgamma). Nicotine-induced LTOgamma was mimicked by the selective alpha4beta2 but not by alpha7 nAChR agonist and was involved in N-methyl-d-aspartate (NMDA) receptor activation as well as depended on excitatory and inhibitory neurotransmission. Our results indicate that nAChR activation induced plasticity in gamma oscillation, which may be beneficial for the improvement of cognitive deficiency in AD and schizophrenia. PMID- 26049145 TI - Complementary roles of cortical oscillations in automatic and controlled processing during rapid serial tasks. AB - Cognitive control may involve adjusting behaviour by inhibiting or altering habitual actions, requiring rapid communication between sensory, cognitive, and motor systems of the brain. Cognitive control may be achieved using top-down processing from frontal areas to inhibit prepared responses, likely mediated through frontal theta (4-8 Hz) oscillations. However there is conflicting evidence for mechanisms of response inhibition, where global and selective inhibition are either considered separate processes, or frontal areas maintain and execute goal-directed actions, including inhibition. In the current study we measured neuromagnetic oscillatory brain activity in twelve adults responding to rapidly presented visual cues. We used two tasks in the same subjects that required inhibition of a habitual "go" response. Presentation of infrequent "target" cues required subjects to completely inhibit responding (go/no-go task) or to perform an alternate response (go/switch task). Source analysis of oscillatory brain activity was compared for correct no-go and switch trials as well as error trials ("go" responses to targets). Frontal theta activity was similar in cortical location, amplitude and time course for correct no-go and switch responses reflecting an equivalent role in both global and selective response inhibition. Error-related frontal theta activity was also observed but was different in source location (errors vs correct, both tasks: p<0.005) and power (go/switch>go/no-go error, correct switch power, p=0.01). We additionally observed sensorimotor high gamma (60-90 Hz) activity accompanying motor responses, which was markedly stronger for correct switch and error responses compared with go responses, and was delayed for errors (p<0.01). These results suggest that gamma signals in the motor cortex may function to integrate inhibitory signals with sensorimotor processing, and may represent a mechanism for the overriding of habitual behaviours, as errors were predicted by a delay in gamma onset. This study supports a role for frontal areas in maintaining and executing goal-directed actions, and demonstrates that frontal theta activity and sensorimotor gamma oscillations have distinct yet complementary functional roles in monitoring and modifying habitual motor plans. PMID- 26049146 TI - Effects of lesions on synchrony and metastability in cortical networks. AB - At the macroscopic scale, the human brain can be described as a complex network of white matter tracts integrating grey matter assemblies - the human connectome. The structure of the connectome, which is often described using graph theoretic approaches, can be used to model macroscopic brain function at low computational cost. Here, we use the Kuramoto model of coupled oscillators with time-delays, calibrated with respect to empirical functional MRI data, to study the relation between the structure of the connectome and two aspects of functional brain dynamics - synchrony, a measure of general coherence, and metastability, a measure of dynamical flexibility. Specifically, we investigate the relationship between the local structure of the connectome, quantified using graph theory, and the synchrony and metastability of the model's dynamics. By removing individual nodes and all of their connections from the model, we study the effect of lesions on both global and local dynamics. Of the nine nodal graph-theoretical properties tested, two were able to predict effects of node lesion on the global dynamics. The removal of nodes with high eigenvector centrality leads to decreases in global synchrony and increases in global metastability, as does the removal of hub nodes joining topologically segregated network modules. At the level of local dynamics in the neighbourhood of the lesioned node, structural properties of the lesioned nodes hold more predictive power, as five nodal graph theoretical measures are related to changes in local dynamics following node lesions. We discuss these results in the context of empirical studies of stroke and functional brain dynamics. PMID- 26049147 TI - Sharing data in the global alzheimer's association interactive network. AB - The Global Alzheimer's Association Interactive Network (GAAIN) aims to be a shared network of research data, analysis tools, and computational resources for studying the causes of Alzheimer's disease. Central to its design are policies that honor data ownership, prevent unauthorized data distribution, and respect the boundaries of contributing institutions. The results of data queries are displayed in graphs and summary tables, which protects data ownership while providing sufficient information to view trends in aggregated data and discover new data sets. In this article we report on our progress in sharing data through the integration of geographically-separated and independently-operated Alzheimer's disease research studies around the world. PMID- 26049148 TI - Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations. AB - We investigated fluctuations in brain volume throughout the day using statistical modeling of magnetic resonance imaging (MRI) from large populations. We applied fully automated image analysis software to measure the brain parenchymal fraction (BPF), defined as the ratio of the brain parenchymal volume and intracranial volume, thus accounting for variations in head size. The MRI data came from serial scans of multiple sclerosis (MS) patients in clinical trials (n=755, 3269 scans) and from subjects participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n=834, 6114 scans). The percent change in BPF was modeled with a linear mixed effect (LME) model, and the model was applied separately to the MS and ADNI datasets. The LME model for the MS datasets included random subject effects (intercept and slope over time) and fixed effects for the time-of-day, time from the baseline scan, and trial, which accounted for trial-related effects (for example, different inclusion criteria and imaging protocol). The model for ADNI additionally included the demographics (baseline age, sex, subject type [normal, mild cognitive impairment, or Alzheimer's disease], and interaction between subject type and time from baseline). There was a statistically significant effect of time-of-day on the BPF change in MS clinical trial datasets (-0.180 per day, that is, 0.180% of intracranial volume, p=0.019) as well as the ADNI dataset (-0.438 per day, that is, 0.438% of intracranial volume, p<0.0001), showing that the brain volume is greater in the morning. Linearly correcting the BPF values with the time-of-day reduced the required sample size to detect a 25% treatment effect (80% power and 0.05 significance level) on change in brain volume from 2 time-points over a period of 1year by 2.6%. Our results have significant implications for future brain volumetric studies, suggesting that there is a potential acquisition time bias that should be randomized or statistically controlled to account for the day-to-day brain volume fluctuations. PMID- 26049149 TI - What makes your brain suggestible? Hypnotizability is associated with differential brain activity during attention outside hypnosis. AB - Theoretical models of hypnosis have emphasized the importance of attentional processes in accounting for hypnotic phenomena but their exact nature and brain substrates remain unresolved. Individuals vary in their susceptibility to hypnosis, a variability often attributed to differences in attentional functioning such as greater ability to filter irrelevant information and inhibit prepotent responses. However, behavioral studies of attentional performance outside the hypnotic state have provided conflicting results. We used fMRI to investigate the recruitment of attentional networks during a modified flanker task in High and Low hypnotizable participants. The task was performed in a normal (no hypnotized) state. While behavioral performance did not reliably differ between groups, components of the fronto-parietal executive network implicated in monitoring (anterior cingulate cortex; ACC), adjustment (lateral prefrontal cortex; latPFC), and implementation of attentional control (intraparietal sulcus; IPS) were differently activated depending on the hypnotizability of the subjects: the right inferior frontal gyrus (rIFG) was more recruited, whereas IPS and ACC were less recruited by High susceptible individuals compared to Low. Our results demonstrate that susceptibility to hypnosis is associated with particular executive control capabilities allowing efficient attentional focusing, and point to specific neural substrates in right prefrontal cortex. SIGNIFICANCE STATEMENT: We demonstrated that outside hypnosis, low hypnotizable subjects recruited more parietal cortex and anterior cingulate regions during selective attention conditions suggesting a better detection and implementation of conflict. However, outside hypnosis the right inferior frontal gyrus (rIFG) was more recruited by highly hypnotizable subjects during selective attention conditions suggesting a better control of conflict. Furthermore, in highly hypnotizable subjects this region was more connected to the default mode network suggesting a tight dialogue between internally and externally driven processes that may permit higher flexibility in attention and underlie a greater ability to dissociate. PMID- 26049150 TI - T2 quantification from only proton density and T2-weighted MRI by modelling actual refocusing angles. AB - Proton density and transverse relaxation (T2)-weighted fast spin echo images are frequently acquired. T2 quantification is commonly performed by applying an exponential fit to these two images, despite recent evidence that an exponential fit is insufficient to correctly quantify T2 in the presence of imperfect RF refocusing due to standard 2D slice selection or use of reduced refocusing angles. Here we examine the feasibility of accurate two echo fitting using standard proton density and T2-weighted images by utilizing Bloch equation simulations and prior knowledge of refocusing angles. This method is demonstrated in simulation, phantom, and human brain experiments, in comparison to the exponential approach, and to a 32 echo multiple-echo spin echo approach. Comparison to single spin echo is also performed in phantom experiments. The two echo method, which compensates for indirect and stimulated echoes, enables accurate quantitative T2 over a wide range of flip angle and T2 values using standard MRI methods, provided there is adequate SNR and flip angle knowledge. PMID- 26049151 TI - Imaging collagen packing dynamics during mineralization of engineered bone tissue. AB - The structure and organization of the Type I collagen microfibrils during mineral nanoparticle formation appear as the key factor for a deeper understanding of the biomineralization mechanism and for governing the bone tissue physical properties. In this work we investigated the dynamics of collagen packing during ex-vivo mineralization of ceramic porous hydroxyapatite implant scaffolds using synchrotron high resolution X-ray phase contrast micro-tomography (XPCMUT) and synchrotron scanning micro X-ray diffraction (SMUXRD). While XPCMUT provides the direct 3D image of the collagen fibers network organization with micrometer spatial resolution, SMUXRD allows to probe the structural statistical fluctuations of the collagen fibrils at nanoscale. In particular we imaged the lateral spacing and orientation of collagen fibrils during the anisotropic growth of mineral nanocrystals. Beyond throwing light on the bone regeneration multiscale process, this approach can provide important information in the characterization of tissue in health, aging and degeneration conditions. STATEMENT OF SIGNIFICANCE: BONE grafts are the most common transplants after the blood transfusions. This makes the bone-tissue regeneration research of pressing scientific and social impact. Bone is a complex hierarchical structure, where the interplay of organic and inorganic mineral phases at different length scale (from micron to atomic scale) affect its functionality and health. Thus, the understanding of bone tissue regeneration requires to image its spatial-temporal evolution (i) with high spatial resolution and (ii) at different length scale. We exploited high spatial resolution X-ray Phase Contrast micro Tomography and Scanning micro X-ray Diffraction in order to get new insight on the engineered tissue formation mechanisms. This approach could open novel routes for the early detection of different degenerative conditions of tissue. PMID- 26049152 TI - Time-dependent bladder tissue regeneration using bilayer bladder acellular matrix graft-silk fibroin scaffolds in a rat bladder augmentation model. AB - With advances in tissue engineering, various synthetic and natural biomaterials have been widely used in tissue regeneration of the urinary bladder in rat models. However, reconstructive procedures remain insufficient due to the lack of appropriate scaffolding, which should provide a waterproof barrier function and support the needs of various cell types. To address these problems, we have developed a bilayer scaffold comprising a porous network (silk fibroin [SF]) and an underlying natural acellular matrix (bladder acellular matrix graft [BAMG]) and evaluated its feasibility and potential for bladder regeneration in a rat bladder augmentation model. Histological (hematoxylin and eosin and Masson's trichrome staining) and immunohistochemical analyses demonstrated that the bilayer BAMG-SF scaffold promoted smooth muscle, blood vessel, and nerve regeneration in a time-dependent manner. At 12weeks after implantation, bladders reconstructed with the BAMG-SF matrix displayed superior structural and functional properties without significant local tissue responses or systemic toxicity. These results demonstrated that the bilayer BAMG-SF scaffold may be a promising scaffold with good biocompatibility for bladder regeneration in the rat bladder augmentation model. PMID- 26049153 TI - Bisphenol A exposure inhibits germ cell nest breakdown by reducing apoptosis in cultured neonatal mouse ovaries. AB - Bisphenol A is a known endocrine disrupting chemical and reproductive toxicant. Previous studies indicate that in utero BPA exposure increases the percentage of germ cells in nests and decreases the percentage of primordial follicles. However, the mechanism by which BPA affects germ cell nest breakdown is unknown. Thus, we hypothesized that BPA inhibits germ cell nest breakdown by interfering with oxidative stress and apoptosis pathways. To test our hypothesis, ovaries from newborn mice were collected and cultured with vehicle (dimethyl sulfoxide, DMSO) or different doses of BPA (0.1, 1, 5, and 10MUg/mL). Ovaries then were subjected to histological evaluation of germ cell nests and primordial follicles or to measurements of factors that regulate oxidative stress and apoptosis. Our results indicate that in vitro BPA exposure significantly inhibits germ cell nest breakdown by altering the expression of key ovarian apoptotic genes, but not by interfering with the oxidative stress pathway. PMID- 26049154 TI - TPP and TCEP induce oxidative stress and alter steroidogenesis in TM3 Leydig cells. AB - Effects of triphenyl phosphate (TPP) and tris-(2-chloroethyl) phosphate (TCEP) exposure on induction of oxidative stress and endocrine disruption were investigated in TM3 cells. After 24h exposure, cell growth declined and morphology changed in TPP and TCEP treated groups with high dosages. Significant increases in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione S-transferase (GST) activities and their respective gene expressions in a dose-dependent and/or time-dependent manner in TPP or TCEP groups. Moreover, the expression of main genes related to testosterone (T) synthesis including cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc), cytochrome P450 17alpha-hydroxysteroid dehydrogenase (P450-17alpha), 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) were dramatically reduced by TPP and TCEP treatments, especially with the high dosage for 24h. TPP and TCEP treatments for 24h caused significant decreases in T levels in the medium. Furthermore, co-treatments of hCG with TPP or TCEP could inhibit hCG-induced changes in the expression of P450scc, P450-17alpha and 17beta-HSD and T levels. Taken together, TPP and TCEP could induce oxidative stress and endocrine disruption in TM3 cells. PMID- 26049156 TI - Strategy for stochastic dose-rate induced enhanced elimination of malignant tumour without dose escalation. AB - The efficacy of radiation therapy, a primary modality of cancer treatment, depends in general upon the total radiation dose administered to the tumour during the course of therapy. Nevertheless, the delivered radiation also irradiates normal tissues and dose escalation procedure often increases the elimination of normal tissue as well. In this article, we have developed theoretical frameworks under the premise of linear-quadratic-linear (LQL) model using stochastic differential equation and Jensen's inequality for exploring the possibility of attending to the two therapeutic performance objectives in contraposition-increasing the elimination of prostate tumour cells and enhancing the relative sparing of normal tissue in fractionated radiation therapy, within a prescribed limit of total radiation dose. Our study predicts that stochastic temporal modulation in radiation dose-rate appreciably enhances prostate tumour cell elimination, without needing dose escalation in radiation therapy. However, constant higher dose-rate can also enhance the elimination of tumour cells. In this context, we have shown that the sparing of normal tissue with stochastic dose-rate is considerably more than the sparing of normal tissue with the equivalent constant higher dose-rate. Further, by contrasting the stochastic dose rate effects under LQL and linear-quadratic (LQ) models, we have also shown that the LQ model over-estimates stochastic dose-rate effect in tumour and under estimates the stochastic dose-rate effect in normal tissue. Our study indicates the possibility of utilizing stochastic modulation of radiation dose-rate for designing enhanced radiation therapy protocol for cancer. PMID- 26049155 TI - WNT10A exonic variant increases the risk of keratoconus by decreasing corneal thickness. AB - Keratoconus is a degenerative eye condition which results from thinning of the cornea and causes vision distortion. Treatments such as ultraviolet (UV) cross linking have proved effective for management of keratoconus when performed in early stages of the disease. The central corneal thickness (CCT) is a highly heritable endophenotype of keratoconus, and it is estimated that up to 95% of its phenotypic variance is due to genetics. Genome-wide association efforts of CCT have identified common variants (i.e. minor allele frequency (MAF) >5%). However, these studies typically ignore the large set of exonic variants whose MAF is usually low. In this study, we performed a CCT exome-wide association analysis in a sample of 1029 individuals from a population-based study in Western Australia. We identified a genome-wide significant exonic variant rs121908120 (P = 6.63 * 10(-10)) in WNT10A. This gene is 437 kb from a gene previously associated with CCT (USP37). We showed in a conditional analysis that the WNT10A variant completely accounts for the signal previously seen at USP37. We replicated our finding in independent samples from the Brisbane Adolescent Twin Study, Twin Eye Study in Tasmania and the Rotterdam Study. Further, we genotyped rs121908120 in 621 keratoconus cases and compared the frequency to a sample of 1680 unscreened controls from the Queensland Twin Registry. We found that rs121908120 increases the risk of keratoconus two times (odds ratio 2.03, P = 5.41 * 10(-5)). PMID- 26049157 TI - Novel methodologies for biomarker discovery in atherosclerosis. AB - Identification of subjects at increased risk for cardiovascular events plays a central role in the worldwide efforts to improve prevention, prediction, diagnosis, and prognosis of cardiovascular disease and to decrease the related costs. Despite their high predictive value on population level, traditional risk factors fail to fully predict individual risk. This position paper provides a summary of current vascular biomarkers other than the traditional risk factors with a special focus on the emerging -omics technologies. The definition of biomarkers and the identification and use of classical biomarkers are introduced, and we discuss the limitations of current biomarkers such as high sensitivity C reactive protein (hsCRP) or N-terminal pro-brain natriuretic peptide (NT-proBNP). This is complemented by circulating plasma biomarkers, including high-density lipoprotein (HDL), and the conceptual shift from HDL cholesterol levels to HDL composition/function for cardiovascular risk assessment. Novel sources for plasma derived markers include microparticles, microvesicles, and exosomes and their use for current omics-based analytics. Measurement of circulating micro-RNAs, short RNA sequences regulating gene expression, has attracted major interest in the search for novel biomarkers. Also, mass spectrometry and nuclear magnetic resonance spectroscopy have become key complementary technologies in the search for new biomarkers, such as proteomic searches or identification and quantification of small metabolites including lipids (metabolomics and lipidomics). In particular, pro-inflammatory lipid metabolites have gained much interest in the cardiovascular field. Our consensus statement concludes on leads and needs in biomarker research for the near future to improve individual cardiovascular risk prediction. PMID- 26049158 TI - Comparison of in vitro and in vivo clastogenic potency based on benchmark dose analysis of flow cytometric micronucleus data. AB - The application of flow cytometry as a scoring platform for both in vivo and in vitro micronucleus (MN) studies has enabled the efficient generation of high quality datasets suitable for comprehensive assessment of dose-response. Using this information, it is possible to obtain precise estimates of the clastogenic potency of chemicals. We illustrate this by estimating the in vivo and the in vitro potencies of seven model clastogenic agents (melphalan, chlorambucil, thiotepa, 1,3-propane sultone, hydroxyurea, azathioprine and methyl methanesulfonate) by deriving BMDs using freely available BMD software (PROAST). After exposing male rats for 3 days with up to nine dose levels of each individual chemical, peripheral blood samples were collected on Day 4. These chemicals were also evaluated for in vitro MN induction by treating TK6 cells with up to 20 concentrations in quadruplicate. In vitro MN frequencies were determined via flow cytometry using a 96-well plate autosampler. The estimated in vitro and in vivo BMDs were found to correlate to each other. The correlation showed considerable scatter, as may be expected given the complexity of the whole animal model versus the simplicity of the cell culture system. Even so, the existence of the correlation suggests that information on the clastogenic potency of a compound can be derived from either whole animal studies or cell culture based models of chromosomal damage. We also show that the choice of the benchmark response, i.e. the effect size associated with the BMD, is not essential in establishing the correlation between both systems. Our results support the concept that datasets derived from comprehensive genotoxicity studies can provide quantitative dose-response metrics. Such investigational studies, when supported by additional data, might then contribute directly to product safety investigations, regulatory decision-making and human risk assessment. PMID- 26049159 TI - Effect of lipo-chitooligosaccharide on early growth of C4 grass seedlings. AB - Although lipo-chitooligosaccharides (LCOs) are important signal molecules for plant-symbiont interactions, a number of reports suggest that LCOs can directly impact plant growth and development, separate from any role in plant symbioses. In order to investigate this more closely, maize and Setaria seedlings were treated with LCO and their growth was evaluated. The data indicate that LCO treatment significantly enhanced root growth. RNA-seq transcriptomic analysis of LCO-treated maize roots identified a number of genes whose expression was significantly affected by the treatment. Among these genes, some LCO-up-regulated genes are likely involved in root growth promotion. Interestingly, some stress related genes were down-regulated after LCO treatment, which might indicate reallocation of resources from defense responses to plant growth. The promoter activity of several LCO-up-regulated genes using a beta-glucuronidase reporter system was further analysed. The results showed that the promoters were activated by LCO treatment. The data indicate that LCO can directly impact maize root growth and gene expression. PMID- 26049160 TI - Identification and characterization of Arabidopsis AtNUDX9 as a GDP-d-mannose pyrophosphohydrolase: its involvement in root growth inhibition in response to ammonium. AB - GDP-d-mannose (GDP-d-Man) is an important intermediate in ascorbic acid (AsA) synthesis, cell wall synthesis, protein N-glycosylation, and glycosylphosphatidylinositol-anchoring in plants. Thus, the modulation of intracellular levels of GDP-d-Man could be important for maintaining various cellular processes. Here an Arabidopsis GDP-d-Man pyrophosphohydrolase, AtNUDX9 (AtNUDT9; At3g46200), which hydrolysed GDP-d-Man to GMP and mannose 1-phosphate, was identified. The K m and V max values for GDP-d-Man of AtNUDX9 were 376+/-24 MUM and 1.61+/-0.15 MUmol min(-1) mg(-1) protein, respectively. Among various tissues, the expression levels of AtNUDX9 and the total activity of GDP-d-Man pyrophosphohydrolase were the highest in the roots. The GDP-d-Man pyrophosphohydrolase activity was increased in the root of plants grown in the presence of ammonium. No difference was observed in the levels of AsA in the leaf and root tissues of the wild-type and knockout-nudx9 (KO-nudx9) plants, whereas a marked increase in N-glycoprotein levels and enhanced growth were detected in the roots of KO-nudx9 plants in the presence of ammonium. These results suggest that AtNUDX9 is involved in the regulation of GDP-d-Man levels affecting ammonium sensitivity via modulation of protein N-glycosylation in the roots. PMID- 26049161 TI - GeIST: a pipeline for mapping integrated DNA elements. AB - There are several experimental contexts in which it is important to identify DNA integration sites, such as insertional mutagenesis screens, gene and enhancer trap applications, and gene therapy. We previously developed an assay to identify millions of integrations in multiplexed barcoded samples at base-pair resolution. The sheer amount of data produced by this approach makes the mapping of individual sites non-trivial without bioinformatics support. This article presents the Genomic Integration Site Tracker (GeIST), a command-line pipeline designed to map the integration sites produced by this assay and identify the samples from which they came. GeIST version 2.1.0, a more adaptable version of our original pipeline, can identify integrations of murine leukemia virus, adeno associated virus, Tol2 transposons or Ac/Ds transposons, and can be adapted for other inserted elements. It has been tested on experimental data for each of these delivery vectors and fine-tuned to account for sequencing and cloning artifacts. AVAILABILITY AND IMPLEMENTATION: GeIST uses a combination of Bash shell scripting and Perl. GeIST is available at http://research.nhgri.nih.gov/software/GeIST/. CONTACT: burgess@mail.nih.gov. PMID- 26049167 TI - Lipopolysaccharide stimulation upregulated Toll-like receptor 4 expression in chicken cerebellum. AB - Toll-like receptors (TLRs) play crucial roles in innate and adaptive immune responses to invading pathogens. TLR4 is responsible for the recognition of bacterial lipopolysaccharide (LPS) in different parts of central nervous system of many vertebrates. To better understand the functions of TLR4 in cerebellum of chicken, present study was designed to identify the cell types that express TLR4 during postnatal stages as well as the changes in its expression in response to LPS challenge. For this purpose, cerebella were collected from chicken aged 1, 14 and 40 days (n=7 in each group) to analyze TLR4 distribution pattern. The cerebella from 14 chickens injected with LPS or sterilizing saline were also collected at Day 14 (n=7 in each group) to investigate changes in TLR4 expression. This expression was analyzed by immunohistochemistry using an anti TLR4 antibody. TLR4 was constitutively expressed in the Purkinje cell layer, pia mater, neurons in medulla and blood vessels in the cerebellum and LPS stimulation significantly up-regulated TLR4 expression on Day 14 in the chicken cerebellum. This study provides evidence that neurons in chicken cerebellum can express TLR4 in vivo and suggests that these neurons may play an important role in initiating a defense reaction via activation of TLR4. PMID- 26049162 TI - The pervasiveness and plasticity of circadian oscillations: the coupled circadian oscillators framework. AB - MOTIVATION: Circadian oscillations have been observed in animals, plants, fungi and cyanobacteria and play a fundamental role in coordinating the homeostasis and behavior of biological systems. Genetically encoded molecular clocks found in nearly every cell, based on negative transcription/translation feedback loops and involving only a dozen genes, play a central role in maintaining these oscillations. However, high-throughput gene expression experiments reveal that in a typical tissue, a much larger fraction ([Formula: see text]) of all transcripts oscillate with the day-night cycle and the oscillating species vary with tissue type suggesting that perhaps a much larger fraction of all transcripts, and perhaps also other molecular species, may bear the potential for circadian oscillations. RESULTS: To better quantify the pervasiveness and plasticity of circadian oscillations, we conduct the first large-scale analysis aggregating the results of 18 circadian transcriptomic studies and 10 circadian metabolomic studies conducted in mice using different tissues and under different conditions. We find that over half of protein coding genes in the cell can produce transcripts that are circadian in at least one set of conditions and similarly for measured metabolites. Genetic or environmental perturbations can disrupt existing oscillations by changing their amplitudes and phases, suppressing them or giving rise to novel circadian oscillations. The oscillating species and their oscillations provide a characteristic signature of the physiological state of the corresponding cell/tissue. Molecular networks comprise many oscillator loops that have been sculpted by evolution over two trillion day-night cycles to have intrinsic circadian frequency. These oscillating loops are coupled by shared nodes in a large network of coupled circadian oscillators where the clock genes form a major hub. Cells can program and re-program their circadian repertoire through epigenetic and other mechanisms. AVAILABILITY AND IMPLEMENTATION: High resolution and tissue/condition specific circadian data and networks available at http://circadiomics.igb.uci.edu. CONTACT: pfbaldi@ics.uci.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26049168 TI - The complex bacterial ecosystem of the human gastrointestinal tract. Foreword. PMID- 26049169 TI - Tannic acid modulates NFkappaB signaling pathway and skin inflammation in NC/Nga mice through PPARgamma expression. AB - Polyphenolic compound tannic acid, which is mainly found in grapes and green tea, is a potent antioxidant with anticarcinogenic activities. In this present study, we hypothesized that tannic acid could inhibit nuclear factor (NF)kappaB signaling and inflammation in atopic dermatitis (AD) NC/Nga mice. We have analyzed the effects of tannic acid on dermatitis severity, histopathology and expression of inflammatory signaling proteins in house dust mite extract induced AD mouse skin. In addition, serum levels of T helper (Th) cytokines (interferon (IFN)gamma, interleukin (IL)-4) were measured by enzyme-linked immunosorbent assay. Treatment with tannic acid ameliorated the development of AD-like clinical symptoms and effectively inhibited hyperkeratosis, parakeratosis, acanthosis, mast cells and infiltration of inflammatory cells in the AD mouse skin. Serum levels of IFNgamma and IL-4 were significantly down-regulated by tannic acid. Furthermore, tannic acid treatment inhibited DfE induced tumor necrosis factor (TNF)alpha, high mobility group protein (HMG)B1, receptor for advanced glycation end products (RAGE), extracellular signal-regulated kinase (ERK)1/2, NFkappaB, cyclooxygenase (COX)2, IL-1beta and increased the protein expression of peroxisome proliferator-activated receptor (PPAR)gamma. Taken together, our results demonstrate that, DfE induced skin inflammation might be mediated through NFkappaB signaling and tannic acid may be a potential therapeutic agent for AD, which may possibly act via induction of PPARgamma protein. PMID- 26049170 TI - Inhibitory effects of harpagoside on TNF-alpha-induced pro-inflammatory adipokine expression through PPAR-gamma activation in 3T3-L1 adipocytes. AB - Obesity is closely associated with increased production of pro-inflammatory adipokines, including interleukin (IL)-6, plasminogen activator inhibitor (PAI) 1, and adipose-tissue-derived monocyte chemoattractant protein (MCP)-1, which contribute to chronic and low-grade inflammation in adipose tissue. Harpagoside, a major iridoid glycoside present in devil's claw, has been reported to show anti inflammatory activities by suppression of lipopolysaccharide (LPS)-induced production of inflammatory cytokines in murine macrophages. The present study is aimed to investigate the effects of harpagoside on both tumor necrosis factor (TNF)-alpha-induced inflammatory adipokine expression and its underlying signaling pathways in differentiated 3T3-L1 cells. Harpagoside significantly inhibited TNF-alpha-induced mRNA synthesis and protein production of the atherogenic adipokines including IL-6, PAI-1, and MCP-1. Further investigation of the molecular mechanism revealed that pretreatment with harpagoside activated peroxisome proliferator-activated receptor (PPAR)-gamma. These findings suggest that the clinical application of medicinal plants which contain harpagoside may lead to a partial prevention of obesity-induced atherosclerosis by attenuating inflammatory responses. PMID- 26049171 TI - Role of plasma high mobility group box-1 in disseminated intravascular coagulation with leukemia. AB - INTRODUCTION: High mobility group box 1(HMGB1) is a DNA-binding protein which can act as a proinflammatory cytokine when released by necrotic cells, monocytes or macrophages. It also plays a role in the coagulation activation and several tumors including leukemia. The objective of this study was to investigate the role of HMGB1 in the diagnosis of DIC with leukemia. METHODS: 89 subjects with leukemia in Wuhan Union Hospital were prospectively recruited. Among them, 83 cases were suspected of DIC, while the other 6 were the negative controls. Their clinical data, laboratory tests and plasma samples were collected or measured respectively. Accordingly, we made scores for these subjects by the Japanese Ministry of Health and Welfare (JMHW) criteria. RESULTS: This study demonstrated that the plasma levels of HMGB1 were higher in the DIC group than non-DIC (115.16 ng/ml vs. 63.94 ng/ml, p=0.003). The similar results were achieved in infected or non-infected groups. And along with the increase of DIC scores, the levels of HMGB1 increased gradually (p=0.006). In addition, HMGB1 was an independent factor in the diagnosis of DIC with leukemia(p<0.05). The diagnostic sensitivity of HMGB1 was high (Se=90.32%), and there was a tendency of increased HMGB1 levels in the pre-DIC patients. Three of these six pre-DIC patients were diagnosed as DIC by the new revised scoring system which contained HMGB1. Finally, the HMGB1 levels were significantly higher in patients with organ failures (SOFA>=2) than those without (118.76 vs. 72.75, p=0.032). CONCLUSION: The increased plasma levels of HMGB1 were related tightly to the diagnosis and severity of DIC in leukemia patients. Furthermore, the diagnostic sensitivity of HMGB1 was high. So HMGB1 in plasma is a helpful molecular marker, and can be added in the scoring system for the early diagnosis of DIC with leukemia. PMID- 26049172 TI - Nerve conduction studies in diabetics presymptomatic and symptomatic for diabetic polyneuropathy. AB - OBJECTIVE: We performed nerve conduction studies (NCS) on diabetics with and without symptoms of diabetic polyneuropathy (DPN) and evaluated correlations with glycaemic control and clinical features. METHODS: Consecutive patients were recruited in three groups: "normals" (nondiabetics without peripheral nerve disease); "presymptomatic diabetics" (diabetes without DPN); and "symptomatic diabetics". Clinical questionnaire and neurological examination were administered, and NCS were performed using standard techniques. RESULTS: 153 patients were recruited (51 normals, 50 presymptomatic diabetics, 52 symptomatic). Glycosylated haemoglobin and duration of DM were higher in symptomatic diabetics, with symptoms present for 1-60 months (mean 14.5). Alterations in NCS included prolonged latencies, lowered amplitudes and slowed conduction velocities, following a pattern of initially reduced sensory amplitudes and slowed motor velocities, with later reduced motor and sensory amplitudes and prolonged motor latencies. Neuropathic pain, clinical signs and glycosylated haemoglobin correlated with these changes. CONCLUSIONS: Even in asymptomatic patients, NCS show diffuse changes, in a predictable pattern. Electrophysiological parameters correlate with neuropathic pain, physical findings and glycosylated haemoglobin levels. SIGNIFICANCE: We demonstrate that NCS changes in DPN follow a predictable pattern, correlating with clinical features and long-term glycaemic control. PMID- 26049173 TI - Haemophilia gene therapy: Progress and challenges. AB - Current treatment for haemophilia entails life-long intravenous infusion of clotting factor concentrates. This is highly effective at controlling and preventing haemorrhage and its associated complications. Clotting factor replacement therapy is, however, demanding, exceedingly expensive and not curative. In contrast, gene therapy for haemophilia offers the potential of a cure as a result of continuous endogenous expression of biologically active factor VIII (FVIII) or factor IX (FIX) proteins following stable transfer of a normal copy of the respective gene. Our group has recently established the first clear proof-of-concept for a gene therapy approach to the treatment of severe haemophilia B. This entails a single intravenous administration of an adeno associated virus vector encoding an optimised FIX gene, resulting in a long-term (>4 years) dose dependent increase in plasma FIX levels at therapeutic levels without persistent or late toxicity. Gene therapy therefore has the potential to change the treatment paradigm for haemophilia but several hurdles need to be overcome before this can happen. This review provides a summary of the progress made to date and discusses the remaining changes. PMID- 26049174 TI - BK channel beta1-subunit deficiency exacerbates vascular fibrosis and remodelling but does not promote hypertension in high-fat fed obesity in mice. AB - OBJECTIVE: Reduced expression or increased degradation of BK (large conductance Ca-activated K) channel beta1-subunits has been associated with increased vascular tone and hypertension in some metabolic diseases. The contribution of BK channel function to control of blood pressure (BP), heart rate (HR) and vascular function/structure was determined in wild-type and BK channel beta1-subunit knockout mice fed a high-fat or control diet. METHODS AND RESULTS: After 24 weeks of high-fat diet, wild-type and BK beta1-knockout mice were obese, diabetic, but normotensive. High-fat-BK beta1-knockout mice had decreased HR, while high-fat wild-type mice had increased HR compared with mice on the control diet. Ganglion blockade caused a greater fall in BP and HR in mice on a high-fat diet than in mice on the control diet. beta1-adrenergic receptor blockade reduced BP and HR equally in all groups. alpha1-adrenergic receptor blockade decreased BP in high fat-BK beta1-knockout mice only. Echocardiographic evaluation revealed left ventricular hypertrophy in high-fat-BK beta1-knockout mice. Although under anaesthesia, mice on a high-fat diet had higher absolute stroke volume and cardiac output, these measures were similar to control mice when adjusted for body weight. Mesenteric arteries from high-fat-BK beta1-knockout mice had higher norepinephrine reactivity, greater wall thickness and collagen accumulation than high-fat-wild-type mesenteric arteries. Compared with control-wild-type mesenteric arteries, high-fat-wild-type mesenteric arteries had blunted contractile responses to a BK channel blocker, although BK alpha-subunit (protein) and beta1-subunit (mRNA) expression were unchanged. CONCLUSION: BK channel deficiency promotes increased sympathetic control of BP, and vascular dysfunction, remodelling and fibrosis, but does not cause hypertension in high fat fed mice. PMID- 26049176 TI - [Chinese guidelines for management of severe sepsis and septic shock 2014]. PMID- 26049175 TI - [Bibliometric analysis of the Spanish scientific production in Infectious Diseases and Microbiology]. AB - INTRODUCTION: The bibliometric analysis of production and impact of documents by knowledge area is a quantitative and qualitative indicator of research activity in this field. The aim of this article is to determine the contribution of Spanish research institutions in Infectious Diseases and Microbiology in recent years. MATERIAL AND METHODS: Documents published in the journals included in the categories "Infectious Diseases" and "Microbiology" of the Web of Science (Science Citation Index Expanded) of the ISI Web of Knowledge from the year 2000 2013 were analysed. RESULTS: In Infectious Diseases, Spain ranked fourth worldwide, and contributed 5.7% of the 233,771 documents published in this specialty. In Microbiology, Spain was in sixth place with a production rate of 5.8% of the 149,269 documents of this category. The Spanish production increased over the study period, both in Infectious Diseases and Microbiology, from 325 and 619 documents in 2000 to 756 and 1245 documents in 2013, with a growth rate of 131% and 45.8%, respectively. The journal with the largest number of documents published was Enfermedades Infecciosas y Microbiologia Clinica, with 8.6% and 8.2% of papers published in the categories of Infectious Diseases and Microbiology, respectively, and was the result of international collaborations, especially with institutions in the United States. The "index h" was 116 and 139 in Infectious Diseases and Microbiology, placing Spain in fifth place in both categories within countries of the European Union. CONCLUSIONS: In recent years, Spanish research in Infectious Diseases and Microbiology has reached a good level of production and international visibility, reaching a global leadership position. PMID- 26049177 TI - [The "guidance of sepsis" leads us to ponder over some problems]. PMID- 26049178 TI - [Interpretation of the section of Chinese herb medicine in "Chinese guidelines for management of severe sepsis and septic shock 2014"]. PMID- 26049179 TI - [The immune response and inflammation in sepsis]. PMID- 26049180 TI - [The effects of early goal-directed therapy on mortality rate in patients with severe sepsis and septic shock: a systematic literature review and Meta analysis]. AB - OBJECTIVE: To investigate whether early goal-directed therapy (EGDT) could lower the mortality rate in patients with severe sepsis and septic shock. METHODS: Articles with items sepsis, severe sepsis, septic shock, EGDT were retrieved from MEDLINE, EMBASE, Cochrane, Wanfang Data and CNKI. Inclusion criteria included randomized controlled trial, subjects concerning patients with severe sepsis or septic shock, endpoints with short-term mortality [ in-hospital, intensive care unit (ICU) or 28-day] and long-term mortality (60-day or 90-day). Related risk (RR) and 95% confidence interval (95%CI) were used as indices to judge the difference in mortality rate between EGDT group and standard treatment group. RevMan 5.2 software was used for Meta analysis. RESULTS: There were 8 studies meeting inclusive criteria with a total of 4,853 patients. For patients with severe sepsis and septic shock, compared with the group with routine treatment, EGDT showed a decrease in the short-term mortality (RR=0.74, 95%CI=0.66-0.82, P<0.00001), but did not decrease the long-term mortality (RR=0.99, 95%CI=0.92 1.06, P=0.81). CONCLUSIONS: EGDT strategy may decrease the short-term mortality in patients with severe sepsis and septic shock, but it showed no influence on the long-term mortality. PMID- 26049181 TI - [The impacts of low-dose corticosteroids infusion given in different manners on refractory septic shock patients]. AB - OBJECTIVE: To discuss the influence of different ways of low-dose corticosteroids infusion on hemodynamics, changes in blood glucose level and prognosis in patients with refractory septic shock. METHODS: A prospective single-blind randomized controlled trial was conducted. Refractory septic shock patients admitted to the Department of Critical Care Medicine of Jiangxi Provincial People's Hospital from April 1st, 2013 to October 31st, 2014 were enrolled for the study. The patients were divided into control group and research group by random number table. Besides conventional treatment for septic shock, patients in control group were given 200 mg/d hydrocortisone intravenous infusion lasting for 2 hours, while those of research group were given 8.33 mg/h hydrocortisone per hour with an intravenous pump. Treatment lasted for 5 continuous days for both groups. The changes in heart rate (HR), mean arterial pressure (MAP), central venous pressure (CVP) and arterial blood lactic acid in both groups were observed at the time of enroldment and 6 hours, 24 hours, 48 hours, and 5 days after the treatment. With a dynamic blood glucose monitor, mean blood glucose (MBG) level, largest amplitude of glycemic excursions (LAGE), glucose variability (GV), and the ratio of hyperglycaemia time were recorded. The duration of shock, length of intensive care unit (ICU) stay, total length of hospital stay, and 28-day mortality of both groups were recorded. RESULTS: Seventy-nine septic shock patients were assigned to the treatment, with 41 in control group, and 38 in research group. Compared with control group, 6-hour MAP in research group was obviously lowered [mmHg (1 mmHg=0.133 kPa): 66.31+/-4.38 vs. 68.58+/-4.86, t=1.062, P=0.033], but there were no significant differences in HR, MAP, CVP, lactic acid clearance and norepinephrine (NE) utilization rates at other time points between two groups. No significant difference in MBG was found between research group and control group (mmol/L: 8.69+/-2.14 vs. 9.95+/-3.87, t=1.771, P=0.080), but LAGE, GV, the ratio of hyperglycemia time in research group were significantly lower than those of the control group [LAGE (mmol/L): 17.18+/-8.97 vs. 22.71+/-11.80, t=2.331, P=0.022; GV (mmol/L): 2.57+/-1.05 vs. 3.16+/-1.37, t=2.136, P=0.036; the ratio of hyperglycemia time: (43.1+/-11.7)% vs. (49.4+/ 15.3)%, t=2.044, P=0.044]. There was no statistical difference in the following features between research group and control group, such as the duration of shock (days: 3.47+/-0.98 vs. 3.61+/-1.07, t=0.605, P=0.547), length of ICU stay (days: 8.74+/-3.12 vs. 9.97+/-3.37, t=1.543, P=0.120), total length of hospital stay (days: 18.34+/-9.27 vs. 19.58+/-9.83, t=0.576, P=0.566) and 28-day mortality rate (23.68% vs. 26.83%, chi2=0.103, P=0.748). CONCLUSIONS: Compared with slow intravenous infusion, a continuous intravenous supplementation of small amount of hydrocortisone to patients with refractory septic shock could stabilize blood glucose levels and maintain metabolic balance efficiently. However, in both groups there was no significant difference in the efficiency in stabilizing hemodynamics, shortening shock duration, reducing ICU or hospital days and decreasing 28-day mortality. PMID- 26049182 TI - [Analysis of correlation between inflammatory parameters and severity of sepsis caused by bacterial bloodstream infection in septic patients]. AB - OBJECTIVE: To discuss the differences of inflammatory parameters such as procalcitonin (PCT), C-reactive protein (CRP), endotoxin, white blood cell (WBC), neutrophil ratio (Neut%) in blood of septic patients caused by bacterial bloodstream infection, and their correlation with the severity of disease. METHODS: 292 septic patients with positive blood culture were enrolled in Beijing Shijitan Hospital Affiliated to Capital Medical University from February 2012 to March 2015, and their gender, age, acute physiology and chronic health evaluation II (APACHEII) score, bacterial species and other general information were retrospectively collected. The differences in inflammatory parameters (PCT, CRP, endotoxin, WBC, Neut%) in septic patients caused by bacterial bloodstream infection were compared, their correlations with APACHEII scores within 24 hours were analyzed, and their diagnostic efficacies were also analyzed. RESULTS: (1) It was shown by Pearson correlation coefficients that positively statistical correlation was found between PCT (r=0.638), CRP (r=0.620), endotoxin (r=0.284), WBC (r=0.209) and APACHE II score (all P=0.000) in bacterial bloodstream infective patients (n=292), and positively statistical correlation was found between PCT (r=0.626), CRP (r=0.616), Neut% (r=0.297) and APACHE II score (all P<0.01 ) in Gram positive bacterial (G+) group (n=86), and positively statistical correlation was shown between PCT (r=0.631), CRP (r=0.616), endotoxin (r=0.301), WBC (r=0.226 ) and APACHE II score (all P<0.01) in Gram negative bacterial (G-) group (n=206). (2) It was shown that PCT and CRP of both G+/G- bacterial severe sepsis and septic shock subgroup were significantly higher than those of sepsis subgroup, respectively [G+ group: PCT (MUg/L):0.92 (0.38, 4.75) vs. 0.43 (0.22, 1.00), CRP (mg/L): 118.45+/-62.60 vs. 57.97+/-32.41; G- group: PCT (MUg/L):6.92 (1.94, 25.90) vs. 1.28 (0.27, 4.12), CRP (mg/L): 130.99+/-60.18 vs. 49.18+/ 26.87, all P<0.01], and the endotoxin and WBC in G- bacterial severe sepsis and septic shock subgroup were significantly higher than those of sepsis subgroup [endotoxin (ng/L): 19.40 (9.62, 33.87) vs. 10.00 (5.00, 18.52), WBC (*10(9)/L): 12.13+/-6.72 vs. 9.61+/-5.01, both P<0.01]. The PCT and endotoxin in G- bacterial severe sepsis and septic shock subgroup were significantly higher than those in G+ severe sepsis and septic shock subgroup [PCT (MUg/L): 6.92 (1.94, 25.90) vs. 0.92 (0.38, 4.75), endotoxin (ng/L): 19.40 (9.62, 33.87) vs. 2.56 (1.11, 4.01), both P<0.01]. (3) The diagnostic efficacy of inflammatory parameters for severe sepsis and septic shock subgroup were: PCT area under receiver operating characteristic (ROC) curve (AUC)=0.683, the cut-off point=0.55 MUg/L, sensitivity 63.2%, specificity 69.0%; CRP AUC=0.802, the cut-off point=92.25 mg/L, sensitivity 73.7%, specificity 86.2%; WBC AUC=0.614, the cut-off point=7.35*10(9)/L, sensitivity 75.4%, specificity 48.3%; Neut% AUC=0.622, the cut-off point=0.882, sensitivity 43.9%, specificity 79.3% in G+ group. At the same time, it was shown that PCT AUC=0.780, the cut-off point=6.80 MUg/L, sensitivity 51.0%, specificity 93.9%; CRP AUC=0.907, the cut-off point=90.10 mg/L, sensitivity 73.2%, specificity 95.9%; endotoxin AUC=0.694, the cut-off point=17.54 ng/L, sensitivity 57.3%, specificity 75.5%; WBC AUC=0.611, the cut off point=10.54*10(9)/L, sensitivity 54.1%, specificity 69.4%; Neut% AUC=0.621, the cut-off point=0.843, sensitivity 65.6%, specificity 61.2% in G- group. CONCLUSIONS: The plasma PCT and CRP have the best correlation between inflammatory parameters and severity of disease in bloodstream infective sepsis patients. CRP has the best diagnostic effect in severe sepsis/septic shock patients with bloodstream infection. PMID- 26049183 TI - [Comparison of simplified acute physiology score III and other scoring systems in prediction of 28-day prognosis in patients with severe sepsis]. AB - OBJECTIVE: To investigate the power of the simplified acute physiology score III (SAPSIII) for prediction of outcome for patients with severe sepsis admitted to the intensive care unit (ICU). METHODS: A retrospective study was conducted. 677 severe sepsis patients with age>=18 years old and the survival time in emergency ICU>=24 hours admitted to the emergency ICU of Beijing Chaoyang Hospital Affiliated to Capital Medical University from January 2008 to December 2011 were enrolled. The acute physiology and chronic health evaluation II (APACHEII), sequential organ failure assessment (SOFA), SAPSII, SAPSIII, and mortality in emergency department sepsis (MEDS) scores were recorded based on the poorest value within 24 hours of ICU admission. The 28-day result as denoted as survival or death was considered as the end point of the study. The ability to predict mortality by the score systems was assessed by using receiver operating characteristic (ROC) curve analysis and binary logistic regression models. RESULTS: Among the 677 patients with severe sepsis, 284 cases died within 28 days after admission, and the mortality rate was 41.9%. Compared with survivors, the patients in non-survival group was older with higher APACHEII, SOFA, SAPSII, SAPSIII, and MEDS scores and higher ratio of underlying diseases, such as primary hypertension and renal dysfunction, and they had more organ injury, higher ratio of lung infection and bacterial infection (P<0.05 or P<0.01). It was identified by logistic regression that the APACHEII, SOFA, SAPSII, SAPSIII and MEDS scores were significantly independent factors in 28-day death prediction in patients with severe sepsis (all P=0.000). The rank of areas under the ROC curve (AUC) from high to low were MEDS (0.970), APACHEII (0.893), SAPSIII (0.875), SOFA (0.871), and SAPSII (0.860), respectively. SAPSIII score and APACHEII, SOFA, SAPSII scores were found to have an equivalent capacity in predicting the prognosis (all P>0.05). The MEDS score in predicting the prognosis was obviously better than that of APACHEII, SOFA, SAPSII, and SAPSIII scores (all P<0.05 ). The MEDS score showed the best sensitivity (91.5%), and specificity (89.1%). The 28 day mortality in cases of MEDS>=11 was 85.8%. CONCLUSIONS: (1) For patients with severe sepsis who were admitted to ICU, MEDS was superior to APACHEII, SOFA, SAPSII, and SAPSIII scores in predicting prognosis. MEDS>=11 may indicate a higher mortality rate. (2) SAPSIII score has comparable predictive capability with APACHEII, SOFA and SAPSII scores may be recommended for prediction of the prognosis of patients with severe sepsis in ICU. But the SAPSIII score is unsuitable for predicting the prognosis of patients with acute sepsis in ICU options, and it is not superior to that of SAPSIII score in predicting prognosis of patients with sepsis in the emergency ICU than other score systems. PMID- 26049184 TI - [Value of interleukin-27 as a diagnostic biomarker of sepsis in critically ill adults]. AB - OBJECTIVE: To evaluate interleukin-27 (IL-27) as a sepsis diagnostic biomarker in critically ill adults with sepsis. METHODS: A retrospetive study was conducted. A total of 176 systemic inflammatory response syndrome (SIRS) patients in Department of Critical Care Medicine of Xinxiang Medical College First Affiliated Hospital from March to November in 2014 were enrolled. The patients were divided into no sepsis group (n=66), pulmonary originated sepsis group (n=65), and non pulmonary originated sepsis group (n=45). Plasma IL-27 and procalcitonin (PCT) were determined with enzyme linked immunosorbent assay (ELISA). Receiver operating characteristic curve (ROC) and classification and regression tree methodology was used to evaluate diagnostic biomarker performance. RESULTS: The proportion of patients in pulmonary original sepsis group whose body temperature in line with SIRS criteria was significantly higher than no sepsis group (66.2% vs. 44.5%, P<0.05), and they were easy to suffer from tumor (44.6% vs. 22.7%, P<0.05). The proportion of patients in non-pulmonary originated sepsis group whose white blood cell count in line with SIRS criteria was significantly higher than no sepsis group (68.9% vs. 42.7%, P<0.05). It indicated that patients in pulmonary originated sepsis group and non-pulmonary originated sepsis group were more in line with SIRS criteria compared with no sepsis group. It was shown by ROC curve that IL-27 and PCT was not effective in discriminating sepsis among unselected patients showing symptoms and signs of SIRS. The area under the curve (AUC) was 0.59 [95% confidence interval (95%CI)=0.49-0.65] and 0.61 (95%CI=0.55 0.71). According to the further analysis from different infection sources, the highest AUC was 0.71 (95%CI=0.59-0.79) for IL-27 in patients with a non-pulmonary originated sepsis. A decision tree incorporating IL-27, PCT, and age had an AUC of 0.78 (95%CI=0.71-0.87) in patients with a non-pulmonary originated sepsis, which was higher than IL-27 [0.71(95%CI=0.59-0.79)] or PCT [0.65 (95%CI=0.57 0.78)]. Compared to that of pediatric cohort with sepsis, lower expression of IL 27 was found in adult patients. CONCLUSIONS: IL-27 performed overall poorly as a sepsis diagnostic biomarker in adults. IL-27 may be a more reliable diagnostic biomarker for sepsis in children than in adults. The combination of IL-27 and PCT can reasonably estimate the risk of sepsis in subjects with a non-pulmonary originated sepsis. PMID- 26049185 TI - [A prospective multicenter clinical study of Xuebijing injection in the treatment of sepsis and multiple organ dysfunction syndrome]. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of Xuebijing injection in treatment of sepsis and multiple organ dysfunction syndrome (MODS). METHODS: A prospective multicenter clinical study was conducted. The patients with sepsis, severe sepsis, or MODS admitted to Department of Emergency and Critical Care Medicine of 70 hospitals across the country during 2006 to 2008 were enrolled. All of the patients received the basis treatment of conventional therapy, plus Xuebijing injection of 50-100 mL, 2-3 times a day for 5-7 days, and the dose might be increased in serious cases. The vital signs, 24-hour urine output, Glasgow coma score (GCS), white blood cell count (WBC), platelet count (PLT), Marshall score, gastrointestinal function score, syndrome of traditional Chinese medicine (TCM), blood lactate (Lac), blood glucose, serum creatinine (SCr), and total bilirubin (TBil) were observed before treatment, 1, 3, and 5 days after treatment, and at the end of the treatment. The results of above mentioned parameters after the treatment were compared with that before treatment in each patient. At the same time, the occurrence and the degree of adverse reactions were recorded to evaluate the safety of Xuebijing injection. RESULTS: A total of 2,574 patients were enrolled, and in 2,509 cases the treatment was completed in, with a drop of 65 cases. 704 cases were diagnosed to have sepsis, 768 with severe sepsis, and 1,037 with MODS. According to TCM, in 1,951 cases syndrome of stasis toxin in the interior, and in 558 syndrome of excessive exuberance of heat-toxic in the interior were diagnosed. After the treatment of Xuebijing injection combined with conventional therapy, the temperature, heart rate, respiration rate, blood pressure, WBC, PLT, GCS, 24-hour urine output, blood glucose, Lac, SCr, TBil, Marshall score, gastrointestinal function score, as well as the symptoms, signs and TCM tongue condition and pulse condition, and TCM scores were significantly improved in all patients as well as the patients with sepsis, severe sepsis, or MODS (P<0.05 or P<0.01). The effective rate of all patients and the patients with sepsis, severe sepsis, or MODS was 89.20% (2,238/2,509), 92.76% (653/704), 91.54% (703/768), 85.05% (882/1,037), respectively, and the 28-day survival rate was 93.90% (2,356/2,509), 98.01% (690/704), 96.35% (740/768), 89.30% (926/1,037), respectively. In 3 patients with MODS adverse events (0.12%) occurred, including 2 cases of stress ulcer and 1 case of Adams-Stokes syndrome. After clinical evaluation, the adverse events were found to be unrelated with the study medication, and Xuebijing injection was continued till the end of treatment. CONCLUSIONS: Xuebijing injection combined with conventional therapy may effectively ameliorate systemic inflammatory response, protect organ function, alleviate the symptoms, improve organ functions, and elevate the clinical cure rate. Adverse events occur occasionally. Xuebijing injection is found to be safe. PMID- 26049186 TI - [Dynamic monitoring of the neutrophil/lymphocyte ratio could predict the prognosis of patients with bloodstream infection]. AB - OBJECTIVE: To explore the value of dynamic monitoring of the neutrophils/lymphocyte ratio (NLR) in peripheral blood for the prognosis of patients with bloodstream infection (BSI). METHODS: A retrospective study was conducted. 205 patients who were >=18 years old, their length of hospital stay>24 hours, and they were treated in the China-Japanese Friendship Hospital from January 2013 to October 2014 were enrolled. According to the 28-day survival, the patients were divided into survival group (n=160) and death group (n=45). The white blood cell (WBC), neutrophils count (NEU), neutrophils ratio (Neut%), lymphocyte count (LYM), lymphocyte ratio (Lym%), and NLR in peripheral blood were recorded at 1, 3, 7 days after admission. Receiver-operating characteristic curve (ROC) was plotted for evaluating the value of these factors on the 28-day prognosis, and logistic regression analysis was used to evaluate the risk factors for predicting the outcome. RESULTS: (1) On the 1st day, WBC, NEU, Neut%, NLR, and procalcitonin (PCT) in the death group were significantly higher than those in the survival group [WBC (*10(9)/L): 15.28+/-8.23 vs. 11.58+/-6.55, NEU (*10(9)/L): 13.34+/-7.53 vs. 10.03+/-5.31, Neut%: 0.886+/-0.076 vs. 0.845+/ 0.102, NLR: 21.20 ( 13.10, 28.80) vs. 12.08 (6.81, 20.47), PCT (MUg/L): 3.13 (0.85, 10.12) vs. 1.34 (0.36, 5.81), P<0.05 or P<0.01], while hemoglobin (Hb), platelet count (PLT), albumin (ALB) content were significantly lower than those of the survival group [Hb (g/L): 86.09+/-19.83 vs. 107.89+/-22.82, PLT (*10(9)/L): 157.51+/-117.81 vs. 195.44+/-97.28, ALB (g/L): 24.11+/-6.94 vs. 31.99+/-6.89, P<0.05 or P<0.01]. On the 3rd day and 7th day, WBC, NEU and NLR in the death group were significantly higher than those of the survival group [WBC (*10(9)/L): 16.61+/-10.25 vs. 8.91+/-4.93, 16.05+/-9.46 vs. 8.79+/-4.45; NEU (*10(9)/L): 14.15+/-9.98 vs. 6.97+/-4.64, 14.36+/-9.03 vs. 6.59+/-4.07; NLR: 24.13 (8.49, 38.26) vs. 5.52 (3.58, 8.87), 17.74 (10.74, 32.85) vs. 4.35 (2.78, 7.27), all P<0.01 ], and the LYM and Lym% were significantly lower than those in the survival group [LYM (*10(9)/L): 0.61 (0.38, 1.04) vs. 1.05 (0.78, 1.43), 0.69 (0.35, 0.92) vs. 1.37 (0.93, 1.76); Lym%: 0.039 (0.024, 0.101) vs. 0.135 (0.094, 0.186), 0.056 (0.033, 0.082) vs. 0.170 (0.108, 0.237), all P<0.01]. (2) It was shown by ROC curve that the maximum area under the ROC curve (AUC) of WBC, NEU, Neut%, LYM, Lym%, and NLR about prognosis of BSI were observed on 7 days (0.777, 0.819, 0.905, 0.755, 0.880, 0.887). Based on Neut%>0.855 on the 7th day as a predictor of cut-off value of death in 28 days, the sensitivity was 78.8%, specificity 89.1%, respectively. When Lym%<0.088 on the 7th day as a predictor of cut-off value of death on 28 days, the sensitivity was 89.5%, and specificity was 83.9%. When NLR>10.34 on the 7th day as a predictor of cut-off value of death in 28 days, the sensitivity was 81.8%, and specificity was 91.0%. (3) Survival analysis showed that the 28-day survival rate in the patients with 7-day NLR<10.34 was significantly higher than that in those with 7-day NLR>10.34 (95.0% vs. 34.1%, chi2=82.650, P=0.000). (4) It was shown by multi-factor logistic regression analysis that the levels of 1-day Hb and 7-day NLR were the independent prognostic predictors of 28-day mortality [Hb: odds ratio (OR)=0.946, 95% confidence interval (95%CI)=0.913-0.981, P=0.003; 7-day NLR: OR=34.941, 95%CI=8.728-139.884, P=0.000]. CONCLUSIONS: The trend of changes in NEU, LYM and NLR as shown by repeated routine blood examinations contributes to prediction of the outcome of patients with BSI. The levels of 1-day Hb and 7-day NLR are the independent prognostic predictors for 28-day mortality. PMID- 26049187 TI - [Diagnostic value of serum procalcitonin for infection in the immunocompromised critically ill patients with suspected infection]. AB - OBJECTIVE: To evaluate the diagnostic and prognostic value of the serum procalcitonin (PCT) level in the non-acquired immune deficiency syndrome (AIDS) immunocompromised critically ill patients suspected to have infection. METHODS: A retrospective study was conducted in the non-AIDS immunocompromised patients who were admitted to Department of Critical Care Medicine of Xiangya Hospital, Central South University during January 2011 to December 2014. Demographic characteristics, underlying disease, acute physiology and chronic health evaluation II (APACHEII) score at admission, and clinical records including baseline and peak levels of temperature, white blood count (WBC), PCT, and survival rate within 28 days, infection focus, infectious agents (bacterial, fungi or mixed infection), and the severity of infection (sepsis, severe sepsis, or septic shock) were recorded. Receiver operating characteristic (ROC) curve was plotted, and the diagnostic and protective value of above parameters was evaluated. RESULTS: A total of 98 patients (43 male and 55 female) were enrolled in the study with a median age of 44 (28, 52) years old and a median APACHEII score of 17 (11, 20); 47 with malignant hematological tumor, 45 with autoimmune diseases, and 6 post solid organ transplantation. Among them 53 patients (54.1%) died within 28 days. Twenty-seven patients were diagnosed as systemic inflammatory response syndrome (SIRS) without infection. Among 71 patients with infection, 45 were diagnosed as bacterial infection, 10 with fungal infection, and 16 with mixed infection. Sepsis was diagnosed in 7 patients, severe sepsis in 32 patients, and septic shock in 32 patients. (1) There was no statistical significance in the baseline and peak levels of PCT and WBC, or baseline level of temperature between the groups of SIRS patients without infection and infected patients. The peak level of temperature was significantly higher in the patients with infection as compared with that of the SIRS without infection patients [centigrade: 39.4 (38.9, 40.0) vs. 38.8 (37.8, 39.2), Z=-3.268, P=0.001]. It was showed by subgroup analysis that in patients with hematological malignant disease or autoimmune diseases, higher level of body temperature was found in infection group compared with non-infection SIRS group [centigrade: 39.5 (39.0, 40.0) vs. 39.0 (38.4, 39.4), Z=-2.349, P=0.019; 39.0 (38.4, 39.5) vs. 38.2 (37.0, 38.9), Z= 2.221, P=0.026]. (2) The baseline level of PCT (MUg/L) were 0.54 (0.20, 4.19), 2.78 (0.50, 9.54), 1.00 (0.45, 6.89), and 0.22 (0.07, 1.86) in non-infection SIRS patients or the patients with bacterial, fungal, and mixed infection, respectively. The peak level of PCT (MUg/L) were 4.19 (1.95, 13.42), 12.37 (3.82, 45.89), 1.82 (0.49, 17.86), and 5.14 (2.66, 12.62), respectively, in each subgroup. When the comparison was conducted among the patients with different infectious agent, the baseline level of PCT in patients with bacterial infection was significantly higher than that in SIRS patients without infection (P=0.026) and mixed infection patients (P=0.001), and the peak level of PCT was significantly higher than that in the SIRS patients without infection (P=0.009) and the patients with fungal infection (P=0.016). ROC curve showed that the higher value was found in the baseline and peak levels of PCT for diagnosis of septic shock in all patients [ area under ROC curve (AUC) of baseline level=0.681+/-0.054, P=0.001; AUC of peak level=0.690+/-0.054, P=0.002], and the same value was also found in the baseline and peak levels of PCT for diagnosis of bacterial infection in the patients with malignant hematological tumor (AUC of baseline level=0.687+/-0.080, P=0.008; AUC of peak level=0.697+/-0.079, P=0.021). (3) The peak level of PCT (MUg/L) were 4.05 (0.53, 31.22), 5.78 (2.14, 16.68), and 11.64 (2.94, 58.14) in subgroup of patients with sepsis, severe sepsis and septic shock, respectively, and they showed no statistical significance among subgroups (P>0.05). A high serum level of peak PCT strongly indicated the presence of septic shock (AUC=0.646+/-0.060, P=0.019), especially in the subgroup of patients with systemic autoimmune disease (AUC=0.689+/-0.081, P=0.035). (4) The peak level of PCT (MUg/L) in the APACHEII>18 group (38 cases) was significantly higher than that of APACHEII<=18 group [ 60 cases, PCT (MUg/L): 11.64 (3.36, 39.39) vs. 4.42 (1.32, 14.70), P=0.016]; there was a certain correlation between the peak level of PCT and the severity of the disease. (5) The peak level of PCT in death group was significantly higher than that of the survival group [MUg/L: 9.07 (3.05, 33.09) vs. 4.19 (1.26, 14.61), P=0.043]. ROC curve showed that the peak level of PCT might be valuable in predicting the prognosis in immunocompromised patients (AUC=0.619+/-0.057, P=0.043). CONCLUSIONS: The serum level of PCT is found to be a reliable marker for the diagnosis of bacterial infection in immunocompromised critical patients, especially in those with hematologic malignancy. Additionally, PCT provides a useful tool for evaluating the severity of infection and the prognosis of critically ill patients. PMID- 26049188 TI - [Effect of selective gut decontamination in regulation of inflammatory reaction in patients with systemic inflammatory response syndrome]. AB - OBJECTIVE: To explore the effect of selective gut decontamination in regulation of inflammatory reaction compared with rhubarb and glycerine enema for catharsis in patients with systemic inflammatory response syndrome ( SIRS ), and to discuss its mechanisms. METHODS: A prospective randomized controlled trial was conducted. Fifty-seven patients with SIRS admitted to Department of General Surgery of Aviation General Hospital from June 2009 to June 2014 were enrolled. The patients were randomly divided into rhubarb decontaminate group, traditional decontaminate group and blank control group, with 19 cases in each group. Besides the treatment for primary disease, including anti-infection, operation, alleviate pain, nutritional support, and maintaining water and electrolyte balance, the patients in rhubarb decontaminate group received aqueous extract from rhubarb 15-20 g by gastric tube, enema, or peros, twice a day; and those in traditional decontaminate group received glycerine enema or glycerol enema, twice a day; while no gavage or enema was prescribed in blank control group. Peripheral blood was collected before and 72 hours after treatment. Enzyme linked immunosorbent assay (ELISA) was used to determine the concentration of lipopolysaccharide (LPS) and inflammatory mediators. RESULTS: Compared with blank control group and traditional decontaminate group, the levels of interleukins (IL-1, IL-8), LPS, platelet activating factor (PAF), tumor necrosis factor-alpha (TNF-alpha), and gamma- interferon (IFN-gamma) before treatment was similar to that of rhubarb decontaminate group [IL-1 (ng/L): 53.154+/-5.783, 50.564+/-5.771, 51.082+/-6.403, F=0.994, P=0.377; IL-8 (ng/L): 70.492+/-6.146, 68.376+/-6.112, 68.673+/-8.384, F=0.514, P=0.601; LPS (MUg/L): 11.630+/-2.449, 10.858+/-2.307, 10.463+/-2.145, F=1.261, P=0.291; PAF (MUg/L): 4.173+/-0.395, 4.051+/-0.362, 4.078+/-0.487, F=0.446, P=0.642; TNF-alpha (ng/L): 132.498+/-10.772, 129.735+/-12.881, 127.207+/ 11.514, F=0.963, P=0.388; IFN-gamma (MUg/L): 45.645+/-4.558, 43.692+/-5.578, 43.767+/-5.028, F=0.904, P=0.411]. The above parameters after treatment were significantly lower than those before treatment in three groups. The effect on the LPS and pro-inflammatory factors of the rhubarb decontaminate group was more obvious than that of the blank control group and traditional decontaminate group [LPS(MUg/L): 7.571+/-1.113 vs. 9.008+/-1.904, 8.874+/-1.808, F=4.416, P=0.017; IL 1 (ng/L): 45.309+/-3.563 vs. 48.731+/-4.466, 46.112+/-4.322, F=3.557, P=0.035; IL 8 (ng/L): 60.492+/-5.346 vs. 65.553+/-5.384, 63.437+/-5.462, F=4.213, P=0.020; PAF (MUg/L): 3.519+/-0.250 vs. 3.832+/-0.356, 3.766+/-0.309, F=5.450, P=0.007; TNF-alpha (ng/L): 114.988+/-8.772 vs. 123.230+/-10.433, 118.534+/-9.519, F=3.525, P=0.036; IFN-gamma (MUg/L): 38.683+/-3.190 vs. 41.831+/-4.122, 39.161+/-3.972, F=3.820, P=0.028]. CONCLUSIONS: The usage of selective gut decontamination can inhibit the release of endotoxin and inflammatory mediators in patients with SIRS, and it will get a better effect using rhubarb, and the mechanism may be related to the protection of intestinal mucosal barrier function. PMID- 26049189 TI - [The value of differential time to positivity of blood cultures in diagnosis of catheter-related bloodstream infection in patients with solid tumors in intensive care unit]. AB - OBJECTIVE: To determine the value of differential time to positivity (DTTP) of blood culture for the diagnosis of catheter-related bloodstream infection (CRBSI) in patients with solid tumors in intensive care unit (ICU). METHODS: A retrospective study was conducted. 615 pairs of peripheral vein blood cultures and instantaneous catheter tip blood culture of 615 patients admitted to ICU of Tianjin Medical University Cancer Institute and Hospital were collected from August 2011 to March 2014. The DTTP method and (or) semi quantitative culture of catheter tip were compared. CRBSI was diagnosed when both cultures were positive for the same microorganism and DTTP>=2 hours (120 minutes). The result of this procedure was compared with that of organism obtained using the semi quantitative culture of blood at catheter tip with >=15 cfu. Based on the clinical diagnosis, the reliability of two kinds of laboratory examination was compared for the diagnosis of CRBSI by plotting receiver operator characteristic curve (ROC curve). RESULTS: The result of 615 cases suspected of having CRBSI were analyzed during the study period. Of these, 440 episodes were excluded because cultures were negative for blood obtained through peripheral vein and central vein. Eight episodes were excluded because only peripheral vein blood culture was positive and 57 episodes were excluded because of only central vein blood culture was positive, 68 pairs of blood cultures were excluded due to the presence of multiple catheters and repeated blood withdrawals. Two cases of polymicrobial cultures were excluded from the final analysis due to the difficulty in determining the time of positive result for each individual microorganism. Ten cases in 42 cases of suspected cases of CRBSI were excluded from analysis because catheter was not removed, therefore culture from catheter tip could not be obtained. Using the DTTP method, 14 out of 17 CRBSI cases were diagnosed with DTTP>=120 minutes, while 3 cases were missed; the semi quantitative catheter tip culture was positive in 13 cases, and in 4 cases it was neglected. In 2 cases of CRBSI it was missed by both methods. The area under the ROC curve (AUC) of DTTP, catheter tip culture and the combination method was 0.912, 0.882 and 0.941 for diagnosis of CRBSI, respectively. Validity values for the diagnosis of CRBSI for DTTP were: sensitivity 82.35%, specificity 92.31%, positive predictive value 93.33% and negative predictive value 80.00%, and they were higher than those of the catheter tip culture method only (76.47%, 84.62%, 86.67% and 73.33%). The specificity and positive predictive CRBSI combination of the two methods in the diagnosis value were up to 100%, the sensitivity (88.24%) and negative predictive value (86.67%) was also increased, but no significant differences were found with DTTP method (chi2=0.00, P=1.00; chi2=0.00, P=0.98; chi2=0.00, P=0.98; chi2=0.00, P=0.98). CONCLUSIONS: DTTP can be a valid method recommended for CRBSI diagnosis in critically ill patients with acceptable sensitivity, good specificity as well as positive predictive value. DTTP combined with other clinical symptoms can not only avoid unnecessary catheter withdrawal, but it also can help obtain the optimal treatment time and strategy. PMID- 26049190 TI - [Modulation of endothelial progenitor cells by tumor necrosis factor-alpha in multiple organ dysfunction syndrome in swine]. AB - OBJECTIVE: To study the modulation in number and function of endothelial progenitor cell (EPC) in multiple organ dysfunction syndrome (MODS) after trauma in swine, and to investigate its pathogenesis. METHODS: Forty pigs were divided into sham group and MODS group (each, n=20). The model of MODS of "two-hit" injury, namely hemorrhagic shock and endotoxemia, was reproduced. The peripheral blood was collected before hemorrhage (T1) and endotoxin injection (T2), and 1 hour (T3), 24 hours (T4), 48 hours (T5) after endotoxin injection. Phosphorylation of p38 mitogen-activated protein kinase (p-p38MAPK ) in mononuclear cell was determined by Western Blot, the content of tumor necrosis factor-alpha (TNF-alpha) was determined with enzyme linked immunosorbent assay (ELISA), and the number of EPC was determined with flow cytometry. RESULTS: Model of MODS was successfully reproduced in 17 pigs. In model group, the expression of p-p38MAPK (A value) peaked at T3 (4.83+/-0.52), and gradually declined at T4 and T5 (4.36+/-0.43, 1.93+/-0.33), and the expression of p-p38MAPK at T3-T5 was significantly higher than that at T1 (1.00+/-0.22, all P<0.01). The plasma concentration of TNF-alpha (ng/L) at T3 in MODS group was obviously elevated compared with that of sham group (532.43+/-52.17 vs. 129.03+/-20.45, t=31.163, P<0.001), and it peaked at T3, it then gradually lowered, and it was significantly higher at T4 and T5 than that in sham group (T4: 398.93+/-35.75 vs. 131.12+/-29.53, t=26.562, P<0.001; T5: 287.48+/-27.26 vs. 126.44+/-26.96, t=17.861, P<0.001). The number of EPC (*10(7)/L) was apparently increased in MODS group at T3 compared with sham group (4.832+/-0.624 vs. 3.545+/-0.363, t=9.542, P<0.001), and it peaked at T3, then gradually decreased, and the number of EPC at T4 and T5 was significantly lower than that in sham group (T4: 2.628+/-0.627 vs. 3.442+/-0.325, t=5.043, P<0.001; T5: 2.203+/-0.711 vs. 3.471+/-0.323, t=2.972, P<0.001). CONCLUSIONS: Phosphorylation of p38MAPK could increase the plasma concentration of TNF-alphaand decrease the quantity of EPC in MODS,which may be one of the mechanisms of MODS. PMID- 26049191 TI - [Effects of hydrogen inhalation on serum pro-inflammatory factors and intestinal injury in mice with severe sepsis]. AB - OBJECTIVE: To investigate the effects and mechanisms of hydrogen inhalation on serum levels of pro-inflammatory factors and intestinal injury in severe septic mice. METHODS: 176 male ICR mice were randomly divided into four groups: sham operation group, hydrogen control group (sham+hydrogen inhalation), model group (severe sepsis model) and hydrogen treatment group (severe sepsis model+hydrogen inhalation), with 44 mice in each group. Severe sepsis model was reproduced by cecal ligation and puncture (CLP). 2% hydrogen inhalation was given for 1 hour at 1 hour and 6 hours after sham or CLP operation. Twenty animals in each group were selected and observed for 7-day survival rate. Six animals in each group were selected and sacrificed at 6, 12, 24 and 48 hours after sham or CLP, the concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukins (IL-6, IL 10) and high mobility group box 1 (HMGB1) in serum were determined, the intestinal histopathological changes and scores were evaluated by light microscopy, and the activities of myeloperoxidase (MPO) and caspase-3 were determined. RESULTS: The 7-day survival rate of severe sepsis mice was 0; the 7 day survival rate was increased to 60% in hydrogen treatment group, with statistical significance in variables compared with model group (P<0.05). Compared with sham operation group, the serum concentrations of TNF-alpha, IL-6, IL-10 and HMGB1 were obviously increased, the intestine were heavily injured along with higher histopathological scores, and the intestinal MPO and caspase-3 activities were significantly enhanced at different time points after CLP in model group (all P<0.05). Compared with model group, the serum concentrations of TNF-alpha, IL-6 and HMGB1 were significantly decreased [ TNF-alpha (ng/L): 6 hours: 110.34+/-9.28 vs. 440.55+/-25.78, 12 hours: 82.29+/-8.43 vs. 448.36+/ 32.54, 24 hours: 79.68+/-9.04 vs. 346.42+/-22.24, 48 hours: 80.79+/-10.06 vs. 368.94+/-31.58; IL-6 (ng/L): 12 hours: 58.68+/-8.55 vs. 158.28+/-16.73, 24 hours: 46.98+/-7.58 vs. 146.74+/-18.02, 48 hours: 38.67+/-8.22 vs. 136.45+/-15.45; HMGB1 (MUg/L): 6 hours: 15.75+/-4.32 vs. 55.56+/-10.04, 12 hours: 32.02+/-9.33 vs. 89.65+/-15.65, 24 hours: 35.87+/-8.54 vs. 86.44+/-20.33, 48 hours: 23.85+/-9.83 vs. 98.33+/-18.88, all P<0.05], the serum concentrations of IL-10 (ng/L) at 24 hours and 48 hours after CLP were obviously increased (24 hours: 135.44+/-16.43 vs. 79.22+/-12.03, 48 hours: 110.92+/-12.54 vs. 74.47+/-11.18, both P<0.05), the intestinal injury were ameliorated with decreased histopathological scores (12 hours: 1.70+/-0.06 vs. 3.23+/-0.44, 24 hours: 2.12+/-0.31 vs. 4.51+/-0.58, 48 hours: 2.03+/-0.42 vs. 4.27+/-0.58, all P<0.05), and the intestinal MPO and caspase-3 activities were significantly decreased [MPO (U/g): 6 hours: 13.75+/ 4.21 vs. 25.56+/-5.34, 12 hours: 14.72+/-4.22 vs. 30.53+/-6.87, 24 hours: 11.62+/ 3.14 vs. 33.58+/-7.24, 48 hours: 11.33+/-4.03 vs. 38.57+/-8.12; caspase-3 (fluorescence intensity): 6 hours: 0.37+/-0.07 vs. 0.69+/-0.23, 12 hours: 0.42+/ 0.07 vs. 0.86+/-0.13, 24 hours: 0.53+/-0.11 vs. 1.36+/-0.23, 48 hours: 0.50+/ 0.08 vs. 1.48+/-0.15, all P<0.05] in hydrogen treatment group. CONCLUSIONS: Hydrogen inhalation can down-regulate the systemic inflammatory response to ameliorate the intestinal injury, and it may improve the septic process and increase the survival rate of mice with severe sepsis. PMID- 26049192 TI - [Apoptosis of interstitial cells of Cajal in deep muscular layer of small intestine in rats with multiple organ dysfunction syndrome]. AB - OBJECTIVE: To observe the apoptosis of interstitial cells of Cajal in deep muscular layer (ICC-DMP) of small intestine in rats with multiple organ dysfunction syndrome (MODS) as a result of bacterial peritonitis, and the expression of c-kit (an ICC phenotype marker) and Bax/Bcl-2, in order to investigate the mechanism of gastrointestinal motility dysfunction in MODS. METHODS: According to the random number table, 40 Wistar rats were randomly divided into two groups: control group (n=20) and MODS group (n=20). The MODS model in rats was reproduced by intraperitoneal injection of 8*10(8) cfu/mL Escherichia coli suspension 1 mL, and the control group was given the same amount of normal saline. After 24 hours, the upper small intestine was harvested for examination. Ultrastructure of ICC-DMP was observed using electron microscope. The network structure of ICC-DMP and the expression of c-kit and Bax/Bcl-2 were observed and determined with immunofluorescence and laser scanning confocal microscope. RESULTS: Macroscopic observation revealed that the gastrointestinal motility of rats was normal in the control group. Compared with the control group, gastro intestine was significantly expanded with parulytic ileus in MODS group. It was shown by transmission electron microscopy that intermediate filament structure of ICC-DMP was clear without swelling of mitochondria; chromatin distributed uniformly with small amounts of heterochromatin aggregated in perinuclear. Compared with the control group, intermediate filament structure of ICC-DMP was fuzzy, and mitochondria were swollen obviously in MODS group; chromatin was assembled in nucleus centre. It was shown by laser scanning confocal microscope that the network structure of ICC-DMP was clear, the expression of c-kit and Bcl-2 was strongly and overlapping; the expression of Bax was weak and scatter distributed. Compared with control group, ICC-DMP quantity in MODS group was significantly reduced (cells/HP: 15.80+/-2.30 vs. 25.70+/-3.97, t=6.819, P=0.000 ), and ICC network was incomplete. The expression of c-kit and Bcl-2 was significantly decreased as compared with control group [ c-kit (fluorescence intensity): 129.56+/-36.90 vs. 307.23+/-40.07, t=10.314, P=0.000; Bcl-2 (fluorescence intensity): 103.23+/-25.19 vs. 378.92+/-43.79, t=17.259, P=0.000], whereas, the expression of Bax was significantly increased (fluorescence intensity: 270.94+/-36.98 vs. 92.57+/-20.92, t=-13.277, P=0.000 ). CONCLUSIONS: The mechanism of gastrointestinal motility dysfunction in MODS maybe closely related to ultrastructural damage of ICC-DMP, changes of c-kit phenotypic and activation of mitochondrial apoptosis pathway. PMID- 26049193 TI - [Protective effects of vagus nerve stimulation on rats with sepsis-associated encephalopathy]. AB - OBJECTIVE: To observe the effects of electrical stimulation of the vagus nerve on sepsis-associated encephalopathy, and to explore its possible mechanism. METHODS: Forty adult male Sprague-Dawley (SD) rats were randomly divided into sham group, model group, vagotomy group (VGX group), vagus nerve stimulation group (VNS group), with 10 rats in each group. The rat model of sepsis was reproduced by injecting lipopolysaccharide (LPS) through femoral vein, and rats of sham group were given the same volume of normal saline. The left cervical vagotomy was performed 30 minutes before LPS administration in VGX group, electrical stimulation of the left vagus nerve was initiated 30 minutes after LPS administration in VNS group. The rats in sham group were sacrificed after receiving electroencephalogram (EEG) examinations, and brain specimens were taken. The changes in EEG in the other three groups were monitored at 2, 4 and 6 hours after LPS administration, and the alpha wave activity percentage was calculated. The blood was collected from abdominal aorta 6 hours after LPS administration, the rats were sacrificed and brain tissue was harvested. The concentrations of tumor necrosis factor-alpha (TNF-alpha) in plasma and brain were measured with enzyme-linked immunosorbent assay (ELISA). The histology and ultrastructure changes in the prefrontal cortex in the rats were observed with both light microscope and transmission electron microscope. RESULTS: Compared with sham group, the percentage of alpha wave on EEG was significantly increased at 2, 4 and 6 hours after LPS administration in model group [(14.52+/-0.50)%, (16.70+/-0.85)%, (17.35+/-0.36)% vs. (12.60+/-0.46)%, all P<0.01]. It could be deduced that early brain dysfunction occurred in septic rats. Compared with model group, percentage of alpha wave on EEG was significantly reduced at 2, 4, and 6 hours in VNS group [(13.10+/-0.24)% vs. (14.52+/-0.50)%, (12.81+/-0.53)% vs. (16.70+/-0.85)%, (12.61+/-0.37)% vs. (17.35+/-0.36)%, all P<0.01], while there was no such effect in the VGX group. Compared with sham group, the concentrations of TNF-alpha in plasma and brain were all increased in model group [ plasma TNF alpha(ng/L): 120.11+/-5.10 vs. 24.37+/-1.85, brain TNF-alpha(ng/L): 165.20+/-6.31 vs. 14.89+/-0.83, both P<0.01]. Compared with model group, the concentrations of TNF-alpha in plasma and brain were all significantly decreased in VNS group [ plasma TNF-alpha(ng/L): 46.72+/-4.90 vs. 120.11+/-5.10, brain TNF-alpha(ng/L): 107.95+/-1.83 vs. 165.20+/-6.31, both P<0.01], while there was no such effect in the VGX group. Light microscope and transmission electron microscope showed that the damage of brain tissue and neurons in model group and VGX group was more obvious, while that in the VNS group was less severe, though not completely disappeared. CONCLUSIONS: LPS can lead to sepsis-associated encephalopathy in rats. It was shown that electrical stimulation of the vagus nerve can activate anti-inflammatory effect through cholinergic pathway, and improve the cerebral function, and inhibit the development of sepsis-associated encephalopathy by reducing systemic and cerebral inflammatory reaction. PMID- 26049194 TI - [Role of endothelial progenitor cell transplantation in rats with sepsis]. AB - OBJECTIVE: To investigate the role of endothelial progenitor cells (EPCs) transplantation in rats with sepsis induced by endotoxin (lipopolysaccharides, LPS). METHODS: Sixty clean grade Sprague-Dawley (SD) rats with genetic background were divided into three groups according to random number table method: control group, model group, and EPCs transplantation group, with 20 rats in each group. The sepsis model was reproduced by intravenous delivery of LPS 5 mg/kg. Rats in control group were injected with the same amount of normal saline. EPCs were isolated, and cultured and identified were fluorescently labeled with the green fluorescent protein (GFP) adenoviral transfection method. The EPC transplantation group was injected with LPS, then a fluorescently labeled EPCs suspension was injected via the tail vein 1 hour later. The expression of fluorescent markers of EPCs was detected with both small animal in vivo imaging instrument and frozen section. Seven days after transplantation, abdominal aorta blood was collected to determine interleukins (IL-6 and IL-10) in peripheral blood with enzyme linked immunosorbent assay (ELISA), and the lung, liver, and kidney tissues were harvested, the wet/dry ratio of the lung (W/D) was calculated, and hematoxylin and eosin (HE) staining was performed to observe, the change in histopathology. Toll-like receptor 4 (TLR4) mRNA expression in lung, liver, and kidney tissues was determined with real-time reverse transcription-polymerase chain reaction (RT PCR). RESULTS: The positive rate of EPCs cells with double marking of CD133 and CD34 was 99.0% at the 5th generation of subculture by using flow cytometry. After the transplantation of EPCs labeled with the green fluorescent protein, the appearance of fluorescence indicated that EPCs were mainly localized in the chest, and a stronger fluorescence was observed near the blood vessels. EPCs transplantation could significantly reduce the inflammatory cell infiltration and cell damage in lung, liver, and kidney tissue in septic rats. Compared with control group, the expression of IL-6 and IL-10 in the peripheral blood, W/D ratio, and TLR4 mRNA in lung, liver, and kidney were increased significantly in the model group. Compared with model group, the expressions of IL-6 and IL-10 in the peripheral blood were significantly reduced after EPCs transplantation [IL-6 (MUg/L): 2.127+/-0.118 vs. 2.664+/-0.438, IL-10 (ng/L): 24.5+/-3.9 vs. 31.5+/ 3.8, both P<0.01]. EPCs transplantation reduced the W/D ratio of lung, liver and kidney tissues (lung: 4.68+/-0.24 vs. 5.48+/-0.15, liver: 3.33+/-0.11 vs. 3.94+/ 0.09, kidney: 4.08+/-0.20 vs. 4.84+/-0.21, all P<0.05], and down-regulated the expression of TLR4 mRNA (*10(3), lung: 782+/-131 vs. 1 136+/-126, liver: 39.1+/ 14.0 vs. 69.2+/-8.7, kidney: 52.2+/-15.2 vs. 83.5+/-17.1, all P<0.01). CONCLUSIONS: EPCs can enter the lung, liver and kidney tissues of the rat successfully after transplantation of EPCs via vein. EPCs transplantation can down-regulate pro-inflammatory process, help to recover the balance of pro- and anti-inflammatory processes, alleviate the damage to the lung, liver, and kidney tissue significantly. PMID- 26049195 TI - [The role of peroxisome proliferator-activated receptor-gamma/nuclear factor KappaB transduction pathway on coagulation disorders induced by sepsis]. AB - OBJECTIVE: To determine the role of activated status of peroxisome proliferator activated receptorgamma/nuclear factor-KappaB (PPAR-gamma/NF-KappaB ) in coagulation disorders induced by sepsis. METHODS: Forty male Sprague-Dawley (SD) rats were randomly divided into four groups, n=10 in each group: control group, lipopolysaccharide (LPS) challenged group, rosiglitazone (ROSI, selective agonist of PPAR-gamma) pretreatment group, and GW9662 (PPAR-gamma antagonist) pretreatment group. The sepsis model was reproduced by injection of 6 mg/kg LPS via sublingual vein, and the rats in control group were injected with 2 mL/kg normal saline. The rats in ROSI pretreatment group were given 0.3 mg/kg ROSI by sublingual venous injection followed by injection of LPS 30 minutes later; and in GW9662 pretreatment group rats were given 0.3 mg/kg GW9662 by sublingual venous injection followed by 0.3 mg/kg ROSI 15 minutes later, followed by injection of LPS 30 minutes later. Blood was collected at 4 hours after LPS administration, and the expressions of PPAR-gamma and NF-KappaBp65 in peripheral blood mononuclear cell (PBMC) were determined with immunocytocheminal technique and graph analysis. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-dimer were determined simultaneously. RESULTS: (1) PPAR-gamma/NF-KappaB pathway: the expressions of PPAR-gamma and NF KappaBp65 were lowered in control group, and they were expressed in cytoplasm. In LPS challenged group the expression of PPAR-gamma (gray value) was slightly increased but with no significant difference as compared with control group (111.01+/-4.06 vs. 98.46+/-5.99, P>0.05). In ROSI pretreatment group the expression of PPAR-gamma (gray value) was significantly higher than that in LPS challenged group (214.38+/-5.79 vs. 111.01+/-4.06, P<0.01), with dislocation into nuclei. In GW9662 pretreatment group the expression of PPAR-gamma (gray value) was lowered but without significant difference compared with that of control group (44.21+/-2.64 vs. 98.46+/-5.99, P>0.05). In LPS challenged group the expression of NF-KappaBp65 (gray value) was significantly higher than that in control group (249.48+/-6.86 vs. 105.81+/-10.19, P<0.01), and it was translocated into the nuclei. In ROSI pretreatment group the expression of NF-KappaBp65 (gray value) was significantly lower than that in LPS challenged group (102.47+/-8.05 vs. 249.48+/-6.86, P<0.01), and it lied in cytoplasm. In GW9662 pretreatment group the expression of NF-KappaBp65 (gray value) showed no significant difference as compared with that of LPS challenged group (214.84+/-7.91 vs. 249.48+/-6.86, P>0.05). (2) Coagulation: compared with control group, PT and APTT were significantly prolonged, FIB was significantly decreased, and D-dimer was significantly increased in LPS challenged group [PT (s): 18.32+/-2.03 vs. 12.22+/ 1.38, APTT (s): 40.05+/-2.72 vs. 26.64+/-2.73, FIB (g/L): 1.65+/-0.51 vs. 3.60+/ 0.37, D-dimer (mg/L): 2.58+/-0.73 vs. 0.37+/-0.06, all P<0.01]. Compared with LPS challenged group, APTT and PT were significantly shortened, FIB was significantly increased, and D-dimer was significantly lowered in ROSI pretreatment group [PT (s): 13.93+/-1.67 vs. 18.32+/-2.03, APTT (s): 30.29+/-0.86 vs. 40.05+/-2.72, FIB (g/L): 3.18+/-0.69 vs 1.65+/-0.51, D-dimer (mg/L): 0.40+/-0.12 vs. 2.58+/-0.73, all P<0.01]. All parameters in GW9662 pretreatment group showed no significant difference as compared with those of LPS challenged group. CONCLUSIONS: PPAR gamma agonist ROSI may ameliorate coagulation disorders in septic rats. PPAR gamma/NF-KappaB transduction pathway plays an important role in septic coagulopathy. PMID- 26049196 TI - [A sensitive method for detection of Clostridium difficile in diarrheal patients]. PMID- 26049197 TI - [Research progress regarding autophagy in inflammatory diseases]. PMID- 26049198 TI - [The latest advance in treatment of sepsis with soluble CD14-ST]. PMID- 26049199 TI - [The metabolic change in citrulline and its use in sepsis]. PMID- 26049200 TI - [Incompatibility with vancomycin hydrochloride and ambroxol hydrochloride injection]. PMID- 26049201 TI - [Evaluation of biomarkers for early diagnosis of sepsis]. PMID- 26049202 TI - [Roles of aveolae and caveolin 1 in sepsis]. PMID- 26049203 TI - Assessing the environmental impact of energy production from hydrochar generated via hydrothermal carbonization of food wastes. AB - Although there are numerous studies suggesting hydrothermal carbonization is an environmentally advantageous process for transformation of wastes to value-added products, a systems level evaluation of the environmental impacts associated with hydrothermal carbonization and subsequent hydrochar combustion has not been conducted. The specific objectives of this work are to use a life cycle assessment approach to evaluate the environmental impacts associated with the HTC of food wastes and the subsequent combustion of the generated solid product (hydrochar) for energy production, and to understand how parameters and/or components associated with food waste carbonization and subsequent hydrochar combustion influence system environmental impact. Results from this analysis indicate that HTC process water emissions and hydrochar combustion most significantly influence system environmental impact, with a net negative GWP impact resulting for all evaluated substituted energy-sources except biomass. These results illustrate the importance of electricity production from hydrochar particularly when it is used to offset coal-based energy sources. HTC process water emissions result in a net impact to the environment, indicating a need for developing appropriate management strategies. Results from this analysis also highlight a need for additional exploration of liquid and gas-phase composition, a better understanding of how changes in carbonization conditions (e.g., reaction time and temperature) influence metal and nutrient fate, and the exploration of liquid-phase treatment. PMID- 26049204 TI - Health Care Waste generation rates and patterns: The case of Lebanon. AB - The objective of this study is to analyze Infectious Health Care Waste generation rates and patterns in Lebanon. Therefore, the quantities generated during five years by 57 hospitals from a total of 163 in the country have been analyzed. The seasonal evolution of Infectious Health Care Waste production and the evolution of the evaluation of the trends over years have been studied. Besides, the generation per capita have been estimated and compared to other countries. The variance between categories and the correlation between number of beds and Infectious Health Care Waste generation have been analyzed. The obtained results showed that the large private hospitals (over 200 beds) are characterized by their high generation rate: an average of 2.45kg per occupied bed(-1)day(-1), whereas the average generation rate for other categories is 0.94kg per occupied bed(-1)day(-1). The weighted mean is 1.14 per occupied kgbed(-1)day(-1). Small public hospitals (i.e. less than 100 beds) have the smallest standard deviation: 0.13, whereas large private hospitals (i.e. over than 200 beds) have the highest standard deviation: 0.40. Infectious Health Care Waste generation has been estimated to 1.42kg/capita/year. The correlation between the numbers of hospitals beds in hospitals and the generation rate per bed is weak. The correlation between Infectious Health Care Waste generation per day and beds number is stronger. The total quantity produced by hospitals has increased over the five past years. These results suggest that the quantities of medical waste are not well controlled, and that hospitals have a defective monitoring management system of their waste. Annual peaks are observed in June, July, and December. Thus, this study, for the first time in Lebanon, has provided information on the infectious waste generation, allowing benchmarking between hospitals and between countries. PMID- 26049205 TI - Commonly used stimulants: Sleep problems, dependence and psychological distress. AB - BACKGROUND: Caffeine and nicotine are commonly used stimulants that enhance alertness and mood. Discontinuation of both stimulants is associated with withdrawal symptoms including sleep and mood disturbances, which may differ in males and females. The present study examines changes in sleep quality, daytime sleepiness and psychological distress associated with use and dependence on caffeine and nicotine. METHODS: An online survey comprising validated tools to assess sleep quality, excessive daytime sleepiness and psychological distress was completed by 166 participants (74 males, 96 females) with a mean age of 28 years. Participants completed the study in their own time, and were not offered any inducements to participate. RESULTS: Sleep quality was poorer in those dependent upon caffeine or nicotine, and there were also significant interaction effects with gender whereby females reported poorer sleep despite males reporting higher use of both stimulants. Caffeine dependence was associated with poorer sleep quality, increased daytime dysfunction, and increased levels of night time disturbance, while nicotine dependence was associated with poorer sleep quality and increased use of sleep medication and sleep disturbances. There were strong links between poor sleep and diminished affect, with psychological distress found to co-occur in the context of disturbed sleep. CONCLUSIONS: Stimulants are widely used to promote vigilance and mood; however, dependence on commonly used drugs including caffeine and nicotine is associated with decrements in sleep quality and increased psychological distress, which may be compounded in female dependent users. PMID- 26049206 TI - A multi-level analysis of the impact of neighborhood structural and social factors on adolescent substance use. AB - BACKGROUND: This paper examined the effects of neighborhood structural (i.e., economic disadvantage, immigrant concentration, residential stability) and social (e.g., collective efficacy, social network interactions, intolerance of drug use, legal cynicism) factors on the likelihood of any adolescent tobacco, alcohol, and marijuana use. METHODS: Analyses drew upon information from the Project on Human Development in Chicago Neighborhoods (PHDCN). Data were obtained from a survey of adult residents of 79 Chicago neighborhoods, two waves of interviews with 1657 to 1664 care-givers and youth aged 8 to 16 years, and information from the 1990 U.S. Census Bureau. Hierarchical Bernoulli regression models estimated the impact of neighborhood factors on substance use controlling for individual-level demographic characteristics and psycho-social risk factors. RESULTS: Few neighborhood factors had statistically significant direct effects on adolescent tobacco, alcohol or marijuana use, although youth living in neighborhoods with greater levels of immigrant concentration were less likely to report any drinking. CONCLUSION: Additional theorizing and more empirical research are needed to better understand the ways in which contextual influences affect adolescent substance use and delinquency. PMID- 26049207 TI - Intranasal Oxytocin: Myths and Delusions. AB - Despite widespread reports that intranasal application of oxytocin has a variety of behavioral effects, very little of the huge amounts applied intranasally appears to reach the cerebrospinal fluid. However, peripheral concentrations are increased to supraphysiologic levels, with likely effects on diverse targets including the gastrointestinal tract, heart, and reproductive tract. The wish to believe in the effectiveness of intranasal oxytocin appears to be widespread and needs to be guarded against with scepticism and rigor. Preregistering trials, declaring primary and secondary outcomes in advance, specifying the statistical methods to be applied, and making all data openly available should minimize problems of publication bias and questionable post hoc analyses. Effects of intranasal oxytocin also need proper dose-response studies, and such studies need to include control subjects for peripheral effects, by administering oxytocin peripherally and by blocking peripheral actions with antagonists. Reports in the literature of oxytocin measurements include many that have been made with discredited methodology. Claims that peripheral measurements of oxytocin reflect central release are questionable at best. PMID- 26049208 TI - Effort cost computation in schizophrenia: a commentary on the recent literature. AB - The cognitive and affective factors implicated in the motivational impairments seen in many people with schizophrenia remain poorly understood. Many research groups have done studies in the past 2 years examining the role of effort-cost computations driven by the hypothesis that overestimation of the cost of effort involved in volitional behavior might underlie the reduction in goal-directed behavior seen in some people with schizophrenia. The goal of this review is to assess the available evidence and the interpretative ambiguities that remain to be addressed by further studies. There is a clear preponderance of evidence suggesting that people with schizophrenia demonstrate altered effort allocation by failing to make high-effort response choices to maximize reward. The evidence relating altered effort allocation to the severity of negative symptoms is mixed. It remains for future work to determine the precise mechanisms implicated in altered effort allocation with two prominent possibilities: that patients 1) overestimate the cost of effort or 2) underestimate the value of potential awards. Other mechanisms that need to be investigated include the potential contributions of other impairments associated with the illness that increase the cost of effort. Furthermore, it is possible that accurate value representations fail to invigorate behavior. Although questions remain, evidence available to date suggests that the study of cost/benefit decision making may shed new light on the motivational impairments seen in many people with schizophrenia. PMID- 26049210 TI - Ethics in perinatal medicine: A global perspective. AB - This article describes the professional responsibility model of perinatal ethics, which requires the perinatologist in all cases to identify and balance beneficence-based and autonomy-based obligations to the pregnant patient, beneficence-based obligations to the fetal patient, and beneficence-based obligations to the neonatal patient. We explain how this model avoids the clinical failure of both fetal and maternal rights-based reductionism, i.e., insistence either on unlimited fetal rights or on unlimited maternal rights, respectively. The professional responsibility model of perinatal ethics provides the basis for the transnational clinical ethical concept of healthcare justice, which requires that beneficence-based obligations to all patients be routinely fulfilled by providing them with an evidence-based standard of care. We then show how healthcare justice can be used to identify and address ethically unacceptable allocation of healthcare resources. The professional responsibility model of perinatal ethics creates an important role for the perinatologist as responsible advocate for pregnant, fetal, and neonatal patients. PMID- 26049209 TI - Naltrexone Facilitates Learning and Delays Extinction by Increasing AMPA Receptor Phosphorylation and Membrane Insertion. AB - BACKGROUND: The opioid antagonists naloxone/naltrexone are involved in improving learning and memory, but their cellular and molecular mechanisms remain unknown. We investigated the effect of naloxone/naltrexone on hippocampal alpha-amino-3 hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) trafficking, a molecular substrate of learning and memory, as a probable mechanism for the antagonists activity. METHODS: To measure naloxone/naltrexone-regulated AMPAR trafficking, pHluorin-GluA1 imaging and biochemical analyses were performed on primary hippocampal neurons. To establish the in vivo role of GluA1-Serine 845 (S845) phosphorylation on the behavioral effect induced by inhibition of the endogenous MU-opioid receptor (MOR) by naltrexone, MOR knockout, and GluA1-S845A mutant (in which Ser(845) was mutated to Ala) mice were tested in a water maze after chronic naltrexone administration. Behavioral responses and GluA1 levels in the hippocampal postsynaptic density in wild-type and GluA1-S845A mutant mice were compared using western blot analysis. RESULTS: In vitro prolonged naloxone/naltrexone exposure significantly increased synaptic and extrasynaptic GluA1 membrane expression as well as GluA1-S845 phosphorylation. In the MOR knockout and GluA1-S845A mutant mice, naltrexone did not improve learning, which suggests that naltrexone acts via inhibition of endogenous MOR action and alteration of GluA1 phosphorylation. Naltrexone-treated wild-type mice had significantly increased phosphorylated GluA1-S845 and GluA1 levels in their hippocampal postsynaptic density on the third day of acquisition, which is the time when naltrexone significantly improved learning. CONCLUSIONS: The beneficial effect of naltrexone on spatial learning and memory under normal conditions appears to be the result of increasing GluA1-S845 phosphorylation-dependent AMPAR trafficking. These results can be further explored in a mouse model of memory loss. PMID- 26049211 TI - Ventilation with facial mask in the prone position for radiotherapy procedures in children. AB - OBJECTIVES: Ventilation of patients undergoing procedures in the prone position represents a challenge for the anesthesiologist, especially when trying to avoid tracheal intubation. This study aimed to test the effectiveness and safety of a prototype designed for pediatric facial mask ventilation in the prone position. MATERIAL AND METHODS: A prospective descriptive study was conducted on 105 sedations performed in 3 children scheduled for radiotherapy treatment of posterior fossa desmoplastic medulloblastoma (6 and 4 y.o. males), and neuroblastoma in temporal area (4 y.o. male). Induction and maintenance of sedation were conducted with sevoflurane in oxygen, maintaining spontaneous ventilation. After achieving loss of consciousness and immobility, the patients were placed in the prone position. Their heads were fixed with the forehead and face supported by a prototype made with a cast of expanded polystyrene (EPS), which held the facial mask (connected to a Mapleson D circuit), and the back of the head immobilized with a layer of thermoplastic material. Time variables and complications were recorded. RESULTS: All sedations were performed according to the planned protocol. All patients maintained oxygen saturation levels above 95%, and no complications were reported. Daily hospital length of stay including the procedure and post anesthetic recovery was 54.4+/-7.9 min (mean+/-SD). CONCLUSIONS: The prototype and the sedation technique with face mask in the prone position employed were effective and safe, allowing the completion of the radiotherapy sessions and securing the airway in a minimally invasive way, maintaining adequate ventilation, light sedation and enabling early hospital discharge. PMID- 26049212 TI - Implementation of a patient blood management program in pediatric scoliosis surgery. AB - OBJECTIVES: To determine whether the implementation of a blood conservation program, and the adoption and progressive association of different methods, reduces transfusion requirements in pediatric patients undergoing scoliosis surgery of different origins. MATERIAL AND METHOD: Quasi-experimental, nonrandomized, descriptive study, approved by the Ethics Committee for Research of our institution. 50 pediatric patients (ASA I-III) aged 5 to 18 years, undergoing scoliosis surgery of any etiology by a single posterior or double approach (anterior and posterior) were included. A historical group with no alternatives to transfusion: Group No ahorro=15 patients (retrospective data collection) was compared with another 3 prospective study groups: Group HNA (acute normovolemic hemodilution)=9 patients; Group HNA+Rec (intraoperative blood salvage)=14 patients, and Group EPO (HNA+Rec+erythropoietin+/-preoperative donation)=12 patients; according with the implementation schedule of the transfusion alternatives in our institution. RESULTS: The rate of transfusion in different groups (No ahorro, HNA, HNA+Rec, EPO) was 100, 66, 57, and 0% of the patients, respectively, with a mean+/-SD of 3.40+/-1.59; 1.33+/-1.41; 1.43+/ 1.50; 0+/-0 RBC units transfused per patient, respectively. Statistically significant differences (P<.001) were found in both the transfusion rate and number of RBC units. CONCLUSIONS: The application of a multimodal blood transfusion alternatives program, individualized for each pediatric patient undergoing scoliosis surgery can avoid transfusion in all cases. PMID- 26049213 TI - Standards for ambulatory blood pressure monitoring clinical reporting in daily practice: recommendations from the Italian Society of Hypertension. AB - This paper aims to provide practical indications to healthcare professionals and manufacturers of ambulatory blood pressure monitoring (ABPM) devices on the characteristics and minimum required contents of a standard ABPM report to be used in the clinical practice. Such indications will help make ABPM reports more easily interpretable and independent from the ABPM device and software used. The first important and unavoidable step of ABPM reporting is a quality assessment: if a recording does not meet the minimum requirements for quality criteria, the reporting physician should advise the patient to repeat the test and should not further proceed to a diagnostic evaluation and interpretation of the recording. A basic clinical report must contain the list of each single reading, the graphical display of individual readings and hourly average values, the mean, minimum and maximum values, and SDs of blood pressure and heart rate values for the 24 h, daytime and night-time, day-night differences, and blood pressure loads. The final medical report should be prepared in a quite logically structured way, considering the following: (i) a judgment on the overall quality of the 24 h recording; (ii) an indication of whether average 24 h, daytime and night-time systolic, and diastolic blood pressure values are within or above the normal limits; and (iii) a description of the 24 h pattern of blood pressure fluctuations. A final general statement on the normotensive or hypertensive status and on the degree of blood pressure control in case of treated patients should also be provided. PMID- 26049214 TI - Distracted Driving in Teens With and Without Attention-Deficit/Hyperactivity Disorder. AB - OBJECTIVE: This study is among the first to examine the effect of talking on a cell phone or text messaging while driving in teens with and without attention deficit/hyperactivity disorder (ADHD). METHOD: Teens (average age 17years) with a diagnosis of ADHD (N=16) were matched with typically developing controls (N=18). All participants operated a driving simulator while (1) conversing on a cell phone, (2) text messaging, and (3) with no distraction during a baseline condition. Six indicators of driving performance were recorded: (a) time to complete the drive; (b) lane deviations; (c) variability in lane position (i.e., root mean square [RMS]); (d) reaction time; (e) motor vehicle collisions; and, (f) speed fluctuation. RESULTS: Significantly greater variation in lane position occurred in the texting task compared to no task and the cell phone task. While texting, in particular, teens with ADHD took significantly less time to complete the scenario. No significant main effects of group were found. CONCLUSIONS: Generally, those with ADHD did not differ in regard to driving performance, when compared to controls, with the exception of one outcome: time to complete scenario. These findings suggest that distracted driving impairs driving performance of teen drivers, regardless of ADHD status. Texting while driving had the greatest negative impact on driving performance, particularly with regard to variability in lane position (i.e., RMS). This study sheds light on key issues regarding injury prevention, with the intent of providing pediatric care providers with the knowledge to inform teen drivers of risks associated with distracted driving which will ultimately result in reduced rates of motor vehicle crashes and concomitant injuries. PMID- 26049215 TI - Theory of mind impairments in patients with first-episode schizophrenia and their unaffected siblings. AB - BACKGROUND: Theory of mind (ToM) impairment has been consistently demonstrated in patients with schizophrenia, but whether ToM impairments exist in unaffected siblings of patients with schizophrenia remains unclear. Few studies have examined the affective and cognitive components of ToM in schizophrenia. This study aimed to examine whether ToM impairments exist in patients with first episode schizophrenia and their unaffected siblings, and whether there is any dissociation between the affective and cognitive components of ToM. METHOD: We adopted a family-based case-control design. Participants were 41 patients with first-episode schizophrenia, 43 unaffected siblings, and 42 healthy controls. The Yoni Task which measures the participants' ability to understand first- and second-order affective versus cognitive ToM and the Faux Pas Task which taps into integration of the affective and cognitive components of ToM were administered. Multivariate and univariate ANCOVAs were used to examine the group differences in ToM, while controlling for other neurocognitive functions. RESULTS: Compared with controls, patients with schizophrenia and their unaffected siblings performed poorer on the Faux Pas Task (p<0.001), with siblings having intermediate performance between patients and controls. Patients with schizophrenia performed worse than controls on second-order affective condition of the Yoni Task (p=0.004), but their unaffected siblings did not (p=0.063). We did not find any significant Group-by-Condition interaction in the Yoni Task (p=0.358). CONCLUSION: Patients with first-episode schizophrenia and their unaffected siblings exhibit ToM impairments, but no dissociation between affective and cognitive component of ToM was found. Our findings support the notion that ToM deficit may be a trait marker of schizophrenia. PMID- 26049216 TI - Pyostomatitis vegetans: An oral manifestation of inflammatory bowel disease. PMID- 26049217 TI - Changes of intramuscular phospholipids and free fatty acids during the processing of Nanjing dry-cured duck. AB - In this study, changes of intramuscular phospholipids and free fatty acids were tracked during the processing of Nanjing dry-cured duck. Phospholipids were identified and quantified by high performance liquid chromatography combined with UV and evaporative light scattering detectors. The types and quantities of free fatty acids and fatty acids derived from phospholipids were analyzed by capillary gas chromatography. The results showed that raw duck meat had high quantities of phosphatidylethanolamine, and phosphatidylcholine (37.95% and 54.07% of total phospholipids, respectively), which contained high percentages of polysaturated fatty acids. The percentages of total phospholipids, phosphatidylethanolamine, and phosphatidylcholine decreased during processing, with a concomitant increase in quantities of free fatty acids. The lipolysis of phospholipids, especially phosphatidylethanolamine is the main contributor to the increase of free fatty acids. PMID- 26049218 TI - Quality changes in yogurt during storage in different packaging materials. AB - The influence of packaging polymers (polypropylene or polystyrene) on the sensory and physicochemical characteristics of flavoured stirred yogurts with either 0% or 4%-fat content was investigated during the 28 days of storage at 4 degrees C. Regardless of the packaging type, complex viscosity and thickness perception increased during storage due to exopolysaccharide production, whereas the pH of yogurts decreased. Packaging type had a greater impact on 0%-fat yogurts than on 4%-fat yogurts for both sensory and physicochemical characteristics. During storage, 0%-fat yogurt conditioned in glass displayed the lowest aroma quantity decrease of the three types of packaging, in accordance with the olfactory properties. However, between the two polymer types, polystyrene packaging seemed to be preferable for limiting aroma compound losses and subsequent fruity note intensities, and for avoiding the development of odour and aroma defects. Less significant packaging effect was observed for 4%-fat yogurts. PMID- 26049219 TI - Optimization of tyrosinase inhibition activity of ultrasonic-extracted polysaccharides from longan fruit pericarp. AB - Various ultrasonic conditions were employed to prepare polysaccharides from longan fruit pericarp (PLFP) and the Lineweaver-Burk equation was then used to determine the effect of PLFP on inhibition of tyrosinase activity. This result showed that PLFP acted as a non-competitive inhibitor of tyrosinase. The highest slope was observed for ultrasonic extraction, followed by the hot-water extraction, suggesting that the ultrasonic treatment of PLFP increased the inhibition of tyrosinase activity. Furthermore, a multilayer feed-forward neural network trained with an error back-propagation algorithm was used to evaluate the effects of ultrasonic power, time and temperature on the slope value. The trained network gave a regression coefficient (R(2)) of 0.98 and a mean squared error (MSE) of 0.58, implying a good agreement between the predicted value and the actual value of the slope, and confirmed a good generalization of the network. Based on the artificial neural network-genetic algorithm, the optimal ultrasonic extraction conditions to obtain the highest slope value (154.1) were determined to be 120W, 12min and 57 degrees C. Application of response surface plots showed the slope value as a function of every two factors under various ultrasonic extraction conditions, which can be observed directly. Therefore, the artificial neural network provided a model with high performance and indicated the non linear nature of the relation between ultrasonic conditions and slope value. PMID- 26049220 TI - Trace element content of fish feed and bluegill sunfish (Lepomis macrochirus) from aquaculture and wild source in Missouri. AB - Trace element content of fish feed and bluegill sunfish muscles (Lepomis macrochirus) from aquaculture and natural pond in Missouri were determined using the inductively coupled-plasma optical emission spectrometer (ICP-OES) and the direct mercury analyzer (DMA). Dietary intake rates of trace elements were estimated. Dogfish muscle (DORM-2) and lobster hepatopancreas (TORT-2) reference standards were used in trace element recovery and method validations. The average elemental concentrations (mg/kg diet, dry wt.) of fish feed were: As 1.81, Cd 2.37, Co 0.10, Cr 1.42, Cu 8.0, Fe 404, Mn 35.9, Ni 0.51, Pb 9.16, Se 1.71, Sn 20.7, V 0.09, Zn 118 and Hg 0.07. The mean elemental concentrations (MUg/kg wet wt.) in bluegill muscles from both aquaculture and wild (in parenthesis) sources were: As 0.36 (0.06), Cd 0.28 (0.01), Co 0.0 (0.0), Cr 0.52 (0.05), Cu 0.38 (0.18), Fe 17.5 (2.43), Mn 0.18 (0.24), Ni 0.18 (0.04), Pb 1.03 (0.04), Se 0.34 (0.30), Sn 0.66 (0.42), V 0.02 (0.01), Zn 6.97 (9.13) and Hg 0.06 (0.24). Kruskal Wallis chi square indicated significant differences in As, Cd, Co, Cr, Cu, Fe, Ni, Pb, Sn, V, Zn and Hg (P<0.001), Se (P<0.01) and Mn (P<0.05) across the sampling locations. Dietary intake rates, estimated from weekly consumption of 228g of aquaculture and wild bluegills, posed no health risks for approximately 85% of all samples. PMID- 26049221 TI - Isolation of cathepsin B from the muscle of silver carp (Hypophthalmichthys molitrix) and comparison of cathepsins B and L actions on surimi gel softening. AB - Cathepsin B from silver carp muscle was purified to 263-fold by acid treatment, ammonium sulfate fractionation, followed by a series of chromatographic separations. The molecular mass of the purified enzyme was 29kDa as determined by SDS-PAGE and immunoblotting. The purified enzyme was activated by dithiothreitol and cysteine while it was substantially inhibited by E-64, suggesting the purified enzyme belongs to the cysteine proteinase family. Optimal pH and temperature were 5.5 and 35 degrees C, respectively. The enzyme catalyzed the hydrolysis of Z-Arg-Arg-MCA with a parameter of Km (90MUM) and Kcat (20.3s(-1)), but hardly hydrolyzed Arg-MCA. Analysis of surimi gel strength and microstructure showed that cathepsins B and L were capable of destroying the network structure of silver carp surimi gels, consequently causing gel softening. Cathepsin L might play an important role in the modori effect. PMID- 26049222 TI - Antioxidative properties of Pandanus amaryllifolius leaf extracts in accelerated oxidation and deep frying studies. AB - The potential uses of Pandanus amaryllifolius leaf extract as a natural antioxidant were evaluated in refined, bleached and deodorized (RBD) palm olein, using accelerated oxidation and deep frying studies at 180 degrees C from 0 to 40h. The extracts (optimum concentration 0.2%) significantly retarded oil oxidation and deterioration (P<0.05), comparably to 0.02% BHT in tests such as peroxide value, anisidine value, iodine value, free fatty acid, oxidative stability index (OSI), polar and polymer compound contents. In sensory evaluation studies, different batches of French fries were not significantly different (P<0.05) from one another for oiliness, crispiness, taste and overall acceptability when the same oil was used for up to the 40th hour of frying. P. amaryllifolius leaf extract, which had a polyphenol content of 102mg/g, exhibited an excellent heat-stable antioxidant property and may be a good natural alternative to existing synthetic antioxidants in the food industry. PMID- 26049223 TI - Purification and kinetic characterization of polyphenol oxidase from Barbados cherry (Malpighia glabra L.). AB - Polyphenol oxidase (PPO) of Barbados cherry was extracted and purified through ammonium sulfate precipitation, gel filtration, and affinity chromatography. The purification factor for PPO was 60% with 8.3% yield. The enzyme was characterized for thermal stability, pH and kinetic parameters. The molecular mass of PPO was approximately the sum of 52 and 38kDa estimated by SDS-PAGE. The purity was checked by native PAGE, showing a single prominent band. The optimum pH was 7.2. The enzyme had a temperature optimum at 40 degrees C and was relatively stable at 60 degrees C, with 55% loss of activity. Sodium diethyl dithiocarbamate (SDDC), l cysteine and ascorbate significantly inhibited PPO activity. 4-Methyl catechol and catechol were found to be efficient diphenolic substrates for cherry PPO, considering the Vmax/Km ratio. The data obtained in this study may help to understand cherry fruit browning. PMID- 26049224 TI - The effect of pulsed electric fields on the inactivation and structure of lysozyme. AB - The effect of pulsed electric fields (PEF) on the activity and structure of lysozyme selected as a model enzyme was investigated. The inactivation of lysozyme in phosphate buffer was a function of electric field strength, treatment time, electrical conductivity, and enzyme concentration. No significant (p>0.05) change in the activity of PEF-treated lysozyme was found after storage for 12, 24 and 48h at 4 degrees C. The effect of PEF on tertiary structure of lysozyme was demonstrated by second-derivative UV spectra and intrinsic fluorescence. The results indicated that the unfolding of tertiary structure was induced by PEF treatment at 35kV/cm for 1200MUs, and more tyrosine residues were buried inside the protein after PEF treatment, accompanied by the exposure of more tryptophan residues. CD spectra suggested that the inactivation of lysozyme by PEF was closely related to the loss of alpha-helix of secondary structure. PMID- 26049225 TI - Formation of new stable pigments from condensation reaction between malvidin 3 glucoside and (-)-epicatechin mediated by acetaldehyde: Effect of tartaric acid concentration. AB - The objective of this work was to study the effect of tartaric acid concentration on the condensation reaction between malvidin 3-glucoside (Mv-glc) and flavanols mediated by acetaldehyde in the model solution. The model wine solutions were prepared by 12% ethanol in water (v/v) with two different l-tartaric acid concentrations (5g/l and 25g/l, respectively) and at two different pH values (3.2 and 1.7, respectively). Four new pigments were detected in model wine solutions containing Mv-glc, (-)-epicatechin and acetaldehyde. By reverse-phase HPLC-DAD, ESI-MS and MS(n) fragmentation analysis, the four new pigments were tentatively identified as four isomers of hydroxyethyl malvidin-3-glucoside-ethyl-flavanol. The decrease in the concentration of Mv-glc and (-)-epicatechin and the increase in the concentration of the new identified pigments were more pronounced at higher tartaric acid concentration. At pH 1.7, although the two well-recognized ethyl-linked Mv-glc-flavanol isomers were quantitatively the major pigmented products in the reaction solution throughout the assay period, they appeared less stable than the four new pigments. At pH 3.2, the rate of formation of ethyl linked Mv-glc-flavanol pigments was much slower than at pH 1.7, whereas the four new pigments were quantitatively the predominant pigmented products at the latter stage of the reaction. PMID- 26049226 TI - Purification and characterisation of trypsins from the pyloric caeca of mandarin fish (Siniperca chuatsi). AB - Two trypsins of anionic form (trypsin A) and cationic form (trypsin B) from the pyloric caeca of mandarin fish (Siniperca chuatsi) were highly purified by a series of chromatographies, including DEAE-Sephacel, Sephacryl S-200 HR, Q Sepharose or SP-Sepharose. Purified trypsins revealed a single band on native PAGE. The molecular weights of trypsin A and B were 21kDa and 21.5kDa, respectively, as estimated by SDS-PAGE, both under reducing and non-reducing conditions. Zymography analysis showed that both trypsins were active in degrading casein. Trypsin A and B exhibited maximal activity at 35 degrees C and 40 degrees C, respectively, and shared the same optimal pH of 8.5, using Boc-Phe Ser-Arg-MCA as substrate. The two trypsins were stable up to 45 degrees C and in the pH range from 4.5 to 11.0. Trypsin inhibitors are effective on these two enzymes and their susceptibilities were similar. Both trypsins were activated by metal ions such as Ca(2+) and Mg(2+) and inactivated by Fe(2+), Zn(2+), Mn(2+), Cu(2+), Al(3+), Ba(2+) and Co(2+) to different degrees. Apparent Km values of trypsin A and B were 2.18MUM and 1.88MUM, and Kcat values were 81.6S(-1) and 111.3S(-1) for Boc-Phe-Ser-Arg-MCA, respectively. Immunoblotting analysis using anti-common carp trypsin A positively cross-reacted with the two enzymes, suggesting their similarity. The N-terminal amino acid sequence of trypsin B was determined as IVGGYECEAH, which is highly homologous with trypsins from other species of fish. PMID- 26049227 TI - Effect of rootstocks and harvesting time on the nutritional quality of peel and flesh of peach fruits. AB - The influence was evaluated of four rootstocks (Ishtara, Mr. S 2/5, GF 677 and Barrier 1) and of harvesting time (early, middle, late) on the quality characteristics and nutritional value (vitamin C, phenols, carotenoids, total antioxidant capacity) of 'Flavorcrest' peach. The better rootstocks were Mr. S 2/5 (low-vigour) and Barrier 1 (high-vigour). In particular, Flavorcrest fruit on Mr. S 2/5 and on Barrier 1 rootstocks had higher antioxidant capacities and also higher phytochemical content, although fruits on Mr. S 2/5 were less firm. Flesh firmness was best for fruits at mid-harvest (H2, 7 July 2006), whereas phytochemical contents were best at late harvest (H3, 13 July 2006), when, for all rootstocks, the best nutritional characteristics were also recorded. Total antioxidant capacity and phytochemical content were determined for the peel and flesh. The results show that removal of peel from peach results in a significant loss of total antioxidant capacity. PMID- 26049228 TI - Sterolic composition of Chetoui virgin olive oil: Influence of geographical origin. AB - The sterol profile of Tunisian virgin olive oils produced from Chetoui cultivar, the second main variety cultivated in the north of the country, grown under different environmental conditions, was established by gas chromatography using a flame ionisation detector. More than ten compounds were identified and characterised. As expected for virgin olive oil, the main sterols found in all Chetoui olive oils were beta-sitosterol, Delta5-avenasterol, campesterol and stigmasterol. Cholesterol, 24-methylenecholesterol, clerosterol, campestanol, sitostanol, Delta7-stigmastenol, Delta5,24-stigmastadienol, and Delta7 avenasterol were also found in all samples, but in lower amounts. Most of these compounds are significantly affected by the geographical origin. The majority of the Chetoui virgin olive oils analysed respected EC Regulation No. 2568, and in all cases total sterol amounts were higher than the minimum limit set by legislation, ranging from 1017 to 1522mg/kg. Two triterpenic dialcohols (erythrodiol and uvaol), were also detected besides the sterolic components. Their content was below the upper legal limit of 4% in all analysed samples, with a range from 1.2% to 3.2%. These results suggest that, besides the genetic factor, environmental conditions influence the sterolic fraction. PMID- 26049229 TI - Synergistic effect of nisin and garlic shoot juice against Listeria monocytogenes in milk. AB - The aim of this research was to determine the synergistic effect of nisin and garlic shoot juice (GSJ) against Listeria monocytogenes ATCC 19118 found in whole (3.5%), low (1%) and skim (no fat content) milk. Garlic shoot juice (GSJ) at concentrations of 2.5%, 5% and 10% revealed strong and similar patterns of antilisterial effect against L. monocytogenes ATCC 19118 in all categories of milk. Nisin only at concentrations of 62.5, 125, 250 and 500IU/ml displayed a strong antilisterial effect as compared to the control group. Also, the synergistic combinations of GSJ (2.5%, 5%) and nisin (62.5, 125, 250 and 500IU/ml) had a remarkable antilisterial activity in all categories of whole, low and skim milk after 14 days. Results of this study indicated the synergistic effect of GSJ and nisin as a potential antilisterial agent for the food industry. PMID- 26049230 TI - New trends in the seafood market. Sutchi catfish (Pangasius hypophthalmus) fillets from Vietnam: Nutritional quality and safety aspects. AB - Sutchi catfish (Pangasius hypophthalmus) produced in the freshwater basins of Vietnam, available on the Italian market as frozen or thawed fillets, were studied for their nutritional quality and safety aspects. Proximate composition, mineral content, fatty acid profile, unsaponifiable components of the lipid fraction and drip loss during thawing at 5 degrees C were determined on the fillets. Fillets were characterised by high moisture levels (80-85%) and low protein (12.6-15.6%) and lipid (1.1-3.0%) contents. Total lipids were characterised by low cholesterol levels (21-39mg/100g), high percentages of saturated fatty acids (41.1-47.8% of total fatty acid) and low percentages of polyunsaturated fatty acids (12.5-18.8% of total fatty acids), which were mainly represented by linoleic acid (44-59% of total polyunsaturated fatty acids). The mineral composition was characterised by a high sodium content (222-594mg/100g), probably partially due to the sodium tripolyphosphate (E 451) used to retain moisture. As regards safety aspects, the quality of the samples analysed was good, with low residue levels of mercury, organochlorine pesticides and polychlorinated biphenyls. PMID- 26049231 TI - Iron-fortified parboiled rice - A novel solution to high iron density in rice based diets. AB - The present study pioneered an investigation of a novel and cost-effective approach to fortify Fe in rice and to greatly improve Fe nutrition in rice-based diets through parboiling, though it remains at its preliminary phase. Rice grains of seven cultivars were parboiled in deionised water containing different levels of Fe chelate made by mixing different proportions of Fe sulfate (FeSO4) with ethylenediaminetetra-acetic acid disodium salt (Na2EDTA). Adding Fe to the parboiling water resulted in an increased Fe concentration in the most grain, effectively where FeSO4 and Na2EDTA were mixed at 2:1 molar ratio (11.16g Fe per 100g raw paddy grain). This treatment resulted in Fe concentrations in white rice milled for 60s and 120s, which were 20-50 times higher than those in the unfortified milled raw rice grains. The Fe concentrations in milled rice grains were 50-150mg Fe kg(-1) in 60s milled grains with a slight reduction in 120s milled grains. Perls Prussian blue staining of the cross section of Fe-fortified parboiled rice grains suggested inward movement of added Fe into the endosperm through the apoplastic pathway in the dorsal region of the rice grain. The retention rates of fortified Fe varied among the different cultivars, possibly due to different physical-chemical properties of the grains. The percentages of soluble fraction of the total Fe were higher than 50% in all cultivars tested, indicating its high bioavailability potential, though it remains to be evaluated. The present findings provided a preliminary basis for further investigation of this innovative technique, before its adoption by parboiled rice industry, such as optimising the levels of Fe addition and industrial process and Fe bioavailability in Fe-fortified-parboiled rice. PMID- 26049232 TI - Enantioselective degradation of fipronil in Chinese cabbage (Brassica pekinensis). AB - Chiral pesticide enantiomers often show different bioactivity and residual toxicity, but this property is usually ignored when evaluating the environmental risk and public safety. In this study, a convenient and precise chiral method was developed and validated for measuring fipronil enantiomers in Chinese cabbage (Brassica pekinensis) based on a high-performance liquid chromatography (HPLC) using (R,R) Whelk-O 1 column. Then the proposed method was successfully applied to the study of enantioselective degradation of fipronil in Chinese cabbage under field conditions. The results showed that the degradation of the two enantiomers in Chinese cabbage was proved to be enantioselective and followed pseudo first order kinetics (R(2)?0.98). The (R)-enantiomer degraded faster than the (S) enantiomer, resulting in the relative enrichment of (S)-enantiomer in residue. The detected metabolites MB46513 (desthio), MB45950 (sulfide) and MB46136 (sulfone) by GC-MS suggested that degradation was mainly contributed by oxidization, reduction and photodegradation. Due to the more insecticide activity and lower mammalian toxicity of S-form, the higher concentration of S-fipronil may result in higher activity in crop protection and lower risk to environment and human beings compared to the recemate. This result should be considered in future environmental risk and food safety evaluation. PMID- 26049233 TI - Triacylglycerols and their fatty acid composition in edible Mediterranean molluscs and crustacean. AB - The triacylglycerol (TAG) composition of edible Mediterranean molluscs (Eledone moschata, Sepia officinalis, Todarodes sagittatus) and crustacean (Penaeus kerathurus) was studied using a combination of preparative RP-HPLC and GC/MS. In S. officinalis and T. sagittatus mantle TAG, the main fatty acids were C16:0 and C18:0 while in E. moschata they were C18:1omega-9, C16:0, C20:5omega-3 and C22:6omega-3. In P. kerathurus muscle and cephalothorax TAG, the main fatty acids were C16:0, C18:0, C18:1omega-9, C20:4omega-6, C20:5omega-3, C22:6omega-3 and C16:0, C18:1omega-9, C20:4omega-6, C20:5omega-3, C22:6omega-3, respectively. Thirteen TAG species were detected, the distribution of which was found to range according to the partition number from 34 to 48 for molluscs and from 36 to 50 for the crustacean. Over sixty TAG molecular structures were identified in the major TAG species. The most important in quantitative terms were long chain TAGs containing C14:0, C16:0, C18:0 as SFA, C16:1, C18:1 as MUFA and C18:2, C20:4, C20:5, C22:6 as PUFA. PMID- 26049234 TI - Antioxidant properties and sensory profiles of breads containing barley flour. AB - Breads were made by replacing 40% of wheat flour with barley flour. The incorporation of barley increased the antioxidant properties of the breads compared to the control bread. Furthermore, these properties proved to be dependent on the variety of barley as well as the extraction rate of the flour. The amount of free phenolics (TPC-S) decreased during the baking process, while the amount of bound phenolics increased (TPC-IS). At the same time, the measured antioxidant activities (FRAP-S and FRAP-IS) were relatively stable during the baking process. A sensory evaluation showed differences in sensory attributes, depending on the barley variety, and there was a good consistency between the sensory evaluation and the amount of phenolics. The present study showed that utilization of barley in breads has a beneficial health potential. However this will largely depend on the barley variety. PMID- 26049235 TI - The contents of the neuro-excitatory amino acid beta-ODAP (beta-N-oxalyl-l alpha,beta-diaminopropionic acid), and other free and protein amino acids in the seeds of different genotypes of grass pea (Lathyrus sativus L.). AB - The free and protein amino acids of nine different genotypes of grass pea (Lathyrus sativus L.) seeds were analysed by HPLC with pre-column PITC (phenyl isothiocyanate) derivatisation. Among the free amino acids, homoarginine was quantitatively the most important (up to 0.8% seed weight) and stable while the neuro-excitatory amino acid beta-ODAP (beta-N-oxalyl-l-alpha,beta diaminopropionic acid) showed highest variation (0.02-0.54%) in the nine genotypes examined. Among protein amino acids, glutamic acid was quantitatively most significant, followed by aspartic acid, arginine, leucine, lysine and proline. The sulphur amino acid, methionine, showed the lowest concentration in all the L. sativus genotypes, and also in lentil (Lens culinaris) and in soybean (Glycine max) seeds analysed at the same time. PMID- 26049236 TI - Effect of chitosan coating combined with postharvest calcium treatment on strawberry (Fragaria*ananassa) quality during refrigerated storage. AB - Strawberries (Fragaria*ananassa Duch.) were coated with either 1% or 1.5% chitosan (CS) or chitosan combined with calcium gluconate (CaGlu). Following treatment, strawberries were stored at 10 degrees C and 70+/-5% RH for one week. The effectiveness of the treatments in extending fruit shelf-life was evaluated by determining fungal decay, respiration rate, quality attributes and overall visual appearance. No sign of fungal decay was observed during the storage period for fruit coated with 1.5% CS (with or without the addition of CaGlu) or 1% CS+0.5% CaGlu. By contrast, 12.5% of the strawberries coated with 1% CS lacking calcium salt were infected after five days of storage. The chitosan coating reduced respiration activity, thus delaying ripening and the progress of fruit decay due to senescence. Chitosan coatings delayed changes in weight loss, firmness and external colour compared to untreated samples. Strawberries coated with 1.5% chitosan exhibited less weight loss and reduced darkening than did those treated with 1% chitosan, independently of the presence or absence of CaGlu. However, addition of calcium to the 1% chitosan solution increased the firmness of the fruit. Coated samples had greater visual acceptability than had untreated fruits. The addition of calcium gluconate to the chitosan coating formulation increased the nutritional value by incrementing the calcium content of the fruit. PMID- 26049237 TI - Iron-chelating ability and antioxidant properties of phycocyanin isolated from a protean extract of Spirulinaplatensis. AB - The invitro scavenger activities of different reactive oxygen species (superoxide radical, hydroxyl radical, hydrogen peroxide, hypochlorous acid and peroxyl radical), the effects on lipid peroxidation and the iron-chelating ability of a Spirulinaplatensis protean extract and the biliprotein, phycocyanin, isolated from this microalga were studied. S. platensis protean extract inhibited the generation of hydroxyl radical (IC50=537MUg/ml for the system with EDTA and 1500MUg/ml without EDTA), the production of peroxyl radical (IC50=230MUg/ml), and the lipid peroxidation process (IC50=2320MUg/ml for the enzymatic system and 2180MUg/ml for the non-enzymatic system). Besides, phycocyanin inhibited hydroxyl and peroxyl radicals and the lipid peroxidation process. The iron ions decreased the maximum fluorescence emission spectra of S. platensis protean extract and phycocyanin and it was an indicator of the metal-chelating activity. The antioxidant properties of S. platensis and phycocyanin may arise from both radical-scavenging and metal chelation. Our results suggest that S. platensis could be used as a dietary supplement to prevent some diseases where free radicals are involved. PMID- 26049238 TI - Effects of Lycium barbarum extract on production and immunomodulatory activity of the extracellular polysaccharopeptides from submerged fermentation culture of Coriolus versicolor. AB - Polysaccharopeptides (PSPs) from Coriolus versicolor have been used as immunomodulatory and anticancer agents. However, most studies have concentrated on the mycelial PSPs and not those in the fermented broth. On the other hand, Lycium barbarum fruit has been used as a traditional Chinese herbal medicine for two millennia. Its extract contains various nutrients, minerals, and also polysaccharide-protein complexes, which are proven to be bioactive. Herein we report the effects of L. barbarum fruit extract on the mycelial growth and extracellular PSP (ePSP) production of C. versicolor LH1 by using a submerged fermentation process in 20l fermenters. Fermentation production of C. versicolor biomass and its ePSP were augmented in the presence of L. barbarum extract. The ePSP such obtained differs from those obtained with normal culture medium in terms of simple sugar composition and protein content but shows similar overall chemical structures as analyzed by Fourier transformed infrared spectroscopy. Moreover, the ePSP from C. versicolor cultured with supplementary L. barbarum extract exhibits significant immunomodulatory activity as judged by its effects on the production of nitric oxide and several cytokines by murine RAW264.7 macrophages. PMID- 26049239 TI - Genetic variation for grain mineral content in tropical-adapted maize inbred lines. AB - Increasing the concentrations of Fe and Zn in staple food crops through breeding has been proposed as one strategy to minimize the adverse effects of widespread mineral deficiencies in humans. This approach requires the presence of adequate genetic differences in concentrations of grain minerals for improvement. Eight trials involving different sets of tropical maize inbred lines adapted to the lowlands and mid-altitudes were, therefore, evaluated for concentrations of grain Fe, Zn and other minerals in two locations. The combined analyses of variance showed significant variation in concentrations of grain minerals among inbred lines in each trial, which was always greater than the variation caused by locations and line*location interactions. The line*location interaction had no significant effect on concentrations of Fe, Zn, Cu, Mg and P in at least three trials of lowland inbred lines. The line*location interaction also did not significantly affect the concentrations of any minerals, except S, in at least three trials of mid-altitude inbred lines. The best-inbred lines identified from each trial had 32-78% more Fe and 14-180% more Zn than their trial average. The first two principal component axes, which accounted for 55-64% of the total variation in kernel mineral concentrations, stratified the inbred lines in each trial into four groups based on differences in their grain mineral compositions. None of the correlations of Fe and Zn with Mn, Cu, Ca, Mg, K, P and S was significant and negative in the various trials, while the correlations of Fe with Zn were positive and significant (r=0.55 to r=0.68, p<0.0001) in almost all the trials. These results suggest that a genetic potential exists for concurrent improvement of Fe and Zn without lowering the concentrations of other grain minerals in maize. PMID- 26049240 TI - Factors affecting the digestibility of raw and gelatinized potato starches. AB - The enzymatic digestibilities of raw and gelatinized starches in various potato starches, as well as sweet potato, cassava, and yam starches, were estimated, along with other starch properties, such as the phosphorus content, median granule size, and rapid visco analyzer (RVA) pasting properties. Furthermore, correlation coefficients were calculated between the hydrolysis rates (HR) by amylase and other starch quality parameters. A larger granule size was closely associated with a lower HR in raw starch, while the HR in gelatinized starch did not correlate with the median granule size. An increase in phosphorus content resulted in a definitely lower HR in raw starch and tended to decrease the HR in gelatinized starch for the composite of potato and other starches. In contrast, no correlation coefficients of the phosphorus content with the HRs in raw and gelatinized starches were observed within potato starches. Starches with higher peak viscosity and breakdown showed a lower HR in raw starch, while few or no effects of these RVA parameters on the HR in gelatinized starch were observed for the composite of potato and other starches or among potato starches, respectively. PMID- 26049241 TI - Role of fumonisin B1 on the immune system, histopathology, and muscle proteins of white shrimp (Litopenaeus vannamei). AB - White shrimps, Litopenaeus vannamei, were tested in two indoor trials to determine the effect of fumonisin B1 on (i) immune response, (ii) histopathology, and, (iii) muscle proteins. Trial 1: (0, 0.5, 0.75 and 1.0MUg/g of FB1 levels, 18 day duration; shrimp 5-6g) to evaluate the FB1 effect on the immune system and histopathology response. Trial 2: (0.0, 0.5, 0.75 and 1.0MUg/g of FB1 levels, 16 day duration; shrimp 5-6g) to detect FB1 effect on muscle proteins. Prophenoloxidase activity was affected by all FB1 concentrations tested. Both, total haemocyte count and phenoloxidase activity decreased by the 18th day in shrimp exposed to FB1. Marked histological changes in the hepatopancreas of shrimp fed on diet containing FB1, at the all FB1 levels tested, as well as a necrotic tissue were observed. Changes in both, electrophoretic patterns and thermodynamic properties of myosin extracted from shrimp exposed to FB1 were also observed. PMID- 26049242 TI - Chemical characterisation and histamine-forming bacteria in salted mullet roe products. AB - Sixteen salted mullet roe products sold in the retail markets in Taiwan were purchased and tested to determine the occurrence of histamine and histamine forming bacteria. The levels of pH, salt content, water content, total volatile basic nitrogen (TVBN) and aerobic plate count (APC) in all samples ranged from 5.4 to 5.8, 5.1% to 7.2%, 15.4% to 27.3%, 32.0 to 69.6mg/100g and <1.0 to 7.1logCFU/g, respectively. None of these samples contained total coliform and Escherichia coli. The average content of each of the nine biogenic amines in all samples was less than 4mg/100g, and only one mullet roe sample had the histamine content (8.18mg/100g) greater than the 5.0mg/100g allowable limit suggested by the US Food and Drug Administration. Two histamine-producing bacterial strains capable of producing 10.7ppm and 9.6ppm of histamine in trypticase soy broth (TSB) supplemented with 1.0% l-histidine (TSBH) were identified as Staphylococcus carnosus by 16S rDNA sequencing with PCR amplification, and they were isolated from the sample with higher histamine content (8.18mg/100g). PMID- 26049243 TI - Production and functional evaluation of a protein concentrate from giant squid (Dosidicus gigas) by acid dissolution and isoelectric precipitation. AB - A protein concentrate from giant squid (Dosidicus gigas) was produced under acidic conditions and its functional-technological capability evaluated in terms of its gel-forming ability, water holding capacity and colour attributes. Technological functionality of the concentrate was compared with that of squid muscle and a neutral concentrate. Protein-protein aggregates insoluble at high ionic strength (I=0.5M), were detected in the acidic concentrate as result of processing with no preclusion of its gel-forming ability during the sol-to-gel thermal transition. Even though washing under acidic condition promoted autolysis of the myosin heavy chain, the acidic concentrate displayed an outstanding ability to gel giving samples with a gel strength of 455 and 1160gcm at 75% and 90% compression respectively, and an AA folding test grade indicative of high gel strength, elasticity, and cohesiveness. The process proved to be a good alternative for obtaining a functional protein concentrate from giant squid muscle. PMID- 26049244 TI - Effect on both aglycone and sugar moiety towards Phase II metabolism of anthocyanins. AB - The effect of sugar moiety on anthocyanin metabolism was studied using anthocyanidin 3-rutinosides (cyanidin 3-O-rutinoside (Cy3R) and delphinidin 3-O rutinoside (Dp3R)) and 3-O-glucosides (delphinidin 3-O-glucoside (Dp3G)). O methylated Cy3R and Dp3R were detected in rat blood plasma after oral administration of Cy3R and Dp3R (100mg/kg body weight). On the basis of HPLC retention time and UV-visible spectra together with the data of our previous studies on the hydrophobic metabolites of anthocyanidin 3-O-glucosides, it was concluded that both 3'- and 4'-O-methyl Cy3R were metabolites of Cy3R. On the other hand, only 4'-O-methyl Dp3R was detected as hydrophobic metabolite of Dp3R. A group of hydrophilic metabolites was also detected in rat blood plasma after oral administration of anthocyanins (Dp3G, Cy3R and Dp3R) and their structures were determined to be extended glucuronides and their O-methyl analogues by tandem MS analysis. The amounts of extended glucuronides of Dp3G, Cy3R and Dp3R were less than those of cyanidin 3-O-glucoside (Cy3G) reported in our previous study. On the other hand, anthocyanidin-glucuronides (both cyanidin-glucuronide and delphinidin-glucuronide) were not detected after oral administration of Cy3R, Dp3R and Dp3G. These results indicated that both the type of sugar moiety and stability of aglycone largely affected phase II metabolism of anthocyanins, and also indicated that the type of sugar moiety did not affect the O-methylation metabolism but affected glucuronyl conjugation in both liver and small intestine. PMID- 26049245 TI - Comparative essential oil composition of flowers, leavesand stems of basil (Ocimum basilicum L.) used as herb. AB - The chemical composition of flower, leaves and stems from basil (Ocimum basilicum L.) have been examined by GC and GC-MS. The identified components constituting 99.03%, 95.04% and 97.66% of the flower, leaves and stem oils, respectively. The main constituents of the essential oil of flower, leaves and stem oils, respectively, were estragole (58.26%, 52.60% and 15.91%) and limonene (19.41%, 13.64% and 2.40%) and p-cymene (0.38%, 2.32% and 2.40%). Dill apiole (50.07%) was identified as the highest main constituent for stem. Estragole (15.91%), apiole (9.48) and exo-fenchyle acetate (6.14%) followed in order to decreasing them. Minor qualitative and major quantitative variations for some compounds of essential oils were determined with respect to different parts of O. basilicum. It was reported that the chemical composition of different parts oils of basil are very variable. It is known that specific estragole chemotypes are also known. PMID- 26049246 TI - Production of a certified reference material for the acrylamidecontent in toasted bread. AB - The need for a certified matrix reference material (CRM) of acrylamide in a food type matrix was emphasized by the competent authorities as a tool to improve comparability, ensuring accuracy and traceability of analytical results. The institute for reference materials and measurements (IRMM) responded to the international request by producing a certified reference material, ERM-BD273, containing endogenous acrylamide in a toasted bread matrix. This work describes the production of the CRM, according to ISO Guides 34 and 35 [ISO Guide 34 (2000). General requirements for the competence of reference materials producers; ISO Guide 35 (2006). Reference materials - General and statistical principles for certification], which comprises the material processing, homogeneity and stability assessment, material characterisation and the acrylamide mass fraction value assignment in toasted bread. Heterogeneity of the material between the vials processed was determined by an in-house validated gas chromatographic methodology involving acrylamide derivatisation and mass spectrometric detection and found to be below 2%. Potential degradation during storage was also investigated and a shelf-life based on this value was established. A collaborative study for material characterisation involved sixteen laboratories applying different analytical methodologies including gas chromatography or high resolution liquid chromatography and isotopic dilution mass spectrometry. The certified value for acrylamide in ERM-BD273, traceable to the international system of units (SI), is (425+/-29)ngg(-1). PMID- 26049247 TI - Antioxidant and radical-scavenging activities of Slovak honeys - An electron paramagnetic resonance study. AB - The antioxidant properties of 15 honey samples from different floral sources and various Slovak regions were investigated by means of electron paramagnetic resonance spectroscopy. Cation radical of ABTS (2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonate) diammonium salt), DPPH (1,1-diphenyl-2 picrylhydrazyl) and hydroxyl radicals generated by the photochemical decomposition of hydrogen peroxide were used as oxidants. The antioxidant activities found with ABTS(+), expressed as trolox equivalent antioxidant capacity (TEAC), ranged from 0.15 to 1.14mmolkg(-1), and those determined with DPPH, from 0.04 to 0.32mmolkg(-1). TEAC values correlated well with results found by elimination of DPPH, and both values revealed a linear relationship with the concentration of phenolics obtained with the Folin-Ciocalteu phenol test (expressed as gallic acid equivalents, GAE). The colour coordinates (CIE L(*)a(*)b(*)), as well as reflectance spectra determined for original honeys using a white background, demonstrated that the colour difference (DeltaE(*)) and coordinate b(*) interrelate with TEAC values. The radical-scavenging capacities (RSC) of the honey samples determined in the experiments with photochemically decomposed hydrogen peroxide, generating reactive OH radicals in the presence of spin trapping agent, differ from those found with ABTS(+) and DPPH. Here, probably, the reactive OH radicals, having higher redox potential, are scavenged by a variety of compounds not effective with ABTS(+) and DPPH (e.g., saccharides, proteins). PMID- 26049248 TI - HPLC-DAD-MS(n) characterisation of carotenoids from apricots and pumpkins for the evaluation of fruit product authenticity. AB - Carotenoids including carotenoid esters from six apricot (Prunus armeniaca L.) cultivars and from eight cultivars from three pumpkin species (Cucurbita maxima Duch., Cucurbita pepo L., and Cucurbita moschata Duch.) were extracted without saponification, separated on a C-30 reversed-phase column and characterised by high-performance liquid chromatography/atmospheric pressure chemical ionisation mass spectrometry (LC-MS). The predominant free carotenoids were quantified by HPLC with diode array detection. In contrast to previously published data, alpha carotene could not be detected in apricots. Although the pumpkins showed significant differences in their free carotenoid profiles, major unesterified compounds different from those found in apricots could be determined. However, due to the natural heterogeneity, authentication of the apricot products cannot be accomplished exclusively using the profile of free carotenoids. Therefore, the investigations were extended to carotenoid esters. The xanthophyll ester profiles in pumpkins significantly differed from those in apricots in that the latter also contained both saturated and unsaturated fatty acids, whereas in pumpkins exclusively saturated fatty acids were detected. Admixtures of lower cost pumpkins could be detected in quantities of ?5% by increased contents of lutein and zeaxanthin, and by the appearance of antheraxanthin and alpha-carotene, respectively, depending on the added pumpkin cultivar, as well as the presence of characteristic lutein and antheraxanthin esters. However, pronounced differences in the carotenoid profiles of the investigated pumpkins and the partly minor amount of characteristic compounds lead to limitations of the detection of 5% level of admixture of pumpkin to apricot and of the method in general. PMID- 26049249 TI - Solid phase microextraction as a methodology in the detection of irradiation markers in ground beef. AB - The usefulness of solid phase microextraction (SPME) to detect the occurrence of the irradiation markers 2-dodecylcyclobutanone (2-DCB) and 1,3-bis(1,1 dimethylethyl)benzene in irradiated ground beef was evaluated. To that aim, beef samples were irradiated with different irradiation doses and subsequently examined together with non-irradiated beef samples used as control samples. The SPME conditions applied were selected as a result of performing an optimization process including different fibers (PDMS, DVB/CAR/PDMS, polyacrylate and PDMS/DVB), as well as extraction times (10, 25 and 40min) and temperatures (40 and 60 degrees C). For comparison, 2-DCB and 1,3-bis(1,1-dimethylethyl)benzene were additionally identified in some of the samples by steam distillation-solvent extraction (SDE). Although this study is a preliminary work, from the results obtained SPME seemed to be a rapid and valuable technique to determine 2-DCB and 1,3-bis(1,1-dimethylethyl)benzene in ground beef subjected to irradiation, offering advantages over other methods reported in the literature. In addition, SPME allowed to confirm the validity of 2-DCB as an useful marker to distinguish non-irradiated from irradiated ground beef. On the contrary, the occurrence of 1,3-bis(1,1-dimethylethyl)benzene was however established in both types of samples by SPME and SDE. PMID- 26049250 TI - Rapid detection of oilfish and escolar in fish steaks: A tool to prevent keriorrhea episodes. AB - The outbreak of keriorrhea caused by the wax ester-rich oilfish and escolar has become a frequent and worldwide concern. To help prevent such episodes, rapid detection of these fishes in the supply chain of the seafood industry and by food and health inspection agencies is essential. Through a combination of DNA, GC-MS and TLC analyses with reference to authentic samples, fish steaks of oilfish and escolar mislabeled as other species could be accurately identified. The TLC method developed is inexpensive and provides a reliable and importantly rapid identification within 30min. PMID- 26049251 TI - UK Biobank comes of age. PMID- 26049253 TI - 5 year mortality predictors in 498,103 UK Biobank participants: a prospective population-based study. AB - BACKGROUND: To our knowledge, a systematic comparison of predictors of mortality in middle-aged to elderly individuals has not yet been done. We investigated predictors of mortality in UK Biobank participants during a 5 year period. We aimed to investigate the associations between most of the available measurements and 5 year all-cause and cause-specific mortality, and to develop and validate a prediction score for 5 year mortality using only self-reported information. METHODS: Participants were enrolled in the UK Biobank from April, 2007, to July, 2010, from 21 assessment centres across England, Wales, and Scotland with standardised procedures. In this prospective population-based study, we assessed sex-specific associations of 655 measurements of demographics, health, and lifestyle with all-cause mortality and six cause-specific mortality categories in UK Biobank participants using the Cox proportional hazard model. We excluded variables that were missing in more than 80% of the participants and all cardiorespiratory fitness test measurements because summary data were not available. Validation of the prediction score was done in participants enrolled at the Scottish centres. UK life tables and census information were used to calibrate the score to the overall UK population. FINDINGS: About 500,000 participants were included in the UK Biobank. We excluded participants with more than 80% variables missing (n=746). Of 498,103 UK Biobank participants included (54% of whom were women) aged 37-73 years, 8532 (39% of whom were women) died during a median follow-up of 4.9 years (IQR 4.33-5.22). Self-reported health (C index including age 0.74 [95% CI 0.73-0.75]) was the strongest predictor of all cause mortality in men and a previous cancer diagnosis (0.73 [0.72-0.74]) was the strongest predictor of all-cause mortality in women. When excluding individuals with major diseases or disorders (Charlson comorbidity index >0; n=355 043), measures of smoking habits were the strongest predictors of all-cause mortality. The prognostic score including 13 self-reported predictors for men and 11 for women achieved good discrimination (0.80 [0.77-0.83] for men and 0.79 [0.76-0.83] for women) and significantly outperformed the Charlson comorbidity index (p<0.0001 in men and p=0.0007 in women). A dedicated website allows the interactive exploration of all results along with calculation of individual risk through an online questionnaire. INTERPRETATION: Measures that can simply be obtained by questionnaires and without physical examination were the strongest predictors of all-cause mortality in the UK Biobank population. The prediction score we have developed accurately predicts 5 year all-cause mortality and can be used by individuals to improve health awareness, and by health professionals and organisations to identify high-risk individuals and guide public policy. FUNDING: Knut and Alice Wallenberg Foundation and the Swedish Research Council. PMID- 26049252 TI - Middle East respiratory syndrome. AB - Middle East respiratory syndrome (MERS) is a highly lethal respiratory disease caused by a novel single-stranded, positive-sense RNA betacoronavirus (MERS-CoV). Dromedary camels, hosts for MERS-CoV, are implicated in direct or indirect transmission to human beings, although the exact mode of transmission is unknown. The virus was first isolated from a patient who died from a severe respiratory illness in June, 2012, in Jeddah, Saudi Arabia. As of May 31, 2015, 1180 laboratory-confirmed cases (483 deaths; 40% mortality) have been reported to WHO. Both community-acquired and hospital-acquired cases have been reported with little human-to-human transmission reported in the community. Although most cases of MERS have occurred in Saudi Arabia and the United Arab Emirates, cases have been reported in Europe, the USA, and Asia in people who travelled from the Middle East or their contacts. Clinical features of MERS range from asymptomatic or mild disease to acute respiratory distress syndrome and multiorgan failure resulting in death, especially in individuals with underlying comorbidities. No specific drug treatment exists for MERS and infection prevention and control measures are crucial to prevent spread in health-care facilities. MERS-CoV continues to be an endemic, low-level public health threat. However, the virus could mutate to have increased interhuman transmissibility, increasing its pandemic potential. PMID- 26049254 TI - Practical Approach to VTE Management in Hospitalized Patients. AB - Venous thromboembolism (VTE) is a commonly feared life-threatening complication in hospitalized patients. Physicians are frequently consulted to diagnose and manage VTE in obstetrics, neurology, and surgical services. VTE should be treated irrespective of the presentation (incidental or symptomatic), etiology (provoked vs. unprovoked), and location of the venous thrombosis (extremities, abdomen, or cerebral). In patients with high clinical suspicion for VTE, physicians are encouraged to empirically start anticoagulant therapy while awaiting diagnostic testing. Thrombolytic therapy is underused by physicians, which is proven to improve the mortality in hypotensive patients with pulmonary embolism. Retrievable inferior vena cava filters have an important role in the prophylaxis and management of selective groups of VTE patients. Physicians should not hesitate to place retrievable inferior vena cava filters when clinically indicated but also should make every effort to remove them when no longer needed. This article extensively reviews various diagnostic and management options based on several clinical situations. PMID- 26049255 TI - 30-Day morbidity after augmentation enterocystoplasty and appendicovesicostomy: A NSQIP pediatric analysis. AB - INTRODUCTION: Augmentation enterocystoplasty and appendicovesicostomy are complex pediatric urologic procedures. Although there is literature identifying long-term outcomes in these patients, the reporting of short-term postoperative outcomes has been limited by small numbers of cases and lack of prospective data collection. Here we report 30-day outcomes from the first nationally based, prospectively assembled cohort of pediatric patients undergoing these procedures. OBJECTIVE: To determine 30-day complication, readmission and reoperation after augmentation enterocystoplasty and appendicovesicostomy in a large national sample of pediatric patients, and to explore the association between preoperative and intraoperative characteristics and occurrence of any 30-day event. STUDY DESIGN: We queried the 2012 and 2013 American College of Surgeons National Surgical Quality Improvement Program Pediatric database (ACS-NSQIPP) for all patients undergoing augmentation enterocystoplasty and/or appendicovesicostomy. Surgical risk score was classified on a linear scale using a validated pediatric specific comorbidity score. Intraoperative characteristics and postoperative 30 day events were reported from prospectively collected data. A composite measure of complication, readmission and/or reoperation was used as primary outcome for the multivariate logistic regression. RESULTS: There were 461 patients included in the analysis: 245 had appendicovesicostomy, 97 had augmentation enterocystoplasty and 119 had both procedures. There were a total of 110 NSQIP complications seen in 87 patients. The most common complication was urinary tract infection (see Table for 30-day outcomes by patient). The composite measure of any 30-day event was seen in 27.8% of the cohort and this was associated with longer operative time, increased number of procedures done at time of primary surgical procedure and higher surgical risk score. DISCUSSION: The ACS-NSQIPP provides a tool to examine short-term outcomes for these complex urologic procedures that has not been possible before. Although ACS-NSQIP has been used extensively in the adult surgical literature to identify rates of complications, and to determine predictors of readmission and adverse events, its use in pediatric surgery is new. As in the adult literature, the goal is for standardization of practice and transparency in reporting outcomes that may lead to reduction in morbidity and mortality. CONCLUSION: In this cohort, any 30-day event is seen in almost 30% of the patients undergoing these urologic procedures. Operative time, number of concurrent procedures and higher surgical risk score all are associated with higher odds of the composite 30-day event of complication, readmission and/or reoperation. These data can be useful in counseling patients and families about expectations around surgery and in improving outcomes. PMID- 26049256 TI - Activation of endoplasmic reticulum stress is involved in the activity of icariin against human lung adenocarcinoma cells. AB - In this study, we investigated the anticancer activity of icariin (ICA) against human lung adenocarcinoma cells in vitro and in vivo and explored the role of endoplasmic reticulum (ER) stress (ERS) signaling in this process. ICA treatment resulted in a dose- and time-dependent decrease in the viability of human lung adenocarcinoma A549 cells. Additionally, ICA exhibited potent anticancer activity, as evidenced by reductions in A549 cell adhesion, migration and intracellular glutathione (GSH) levels and increases in the apoptotic index, Caspase 3 activity, and reactive oxygen species. Furthermore, ICA treatment increased the expression of ERS-related molecules (p-PERK, ATF6, GRP78, p eIF2alpha, and CHOP), up-regulated the apoptosis-related protein PUMA and down regulated the anti-apoptosis-related protein Bcl2. The down-regulation of ERS signaling using PERK siRNA desensitized lung adenocarcinoma cells to ICA treatment, whereas the up-regulation of ERS signaling using thapsigargin (THA) sensitized lung adenocarcinoma cells to ICA treatment. Additionally, ICA inhibited the growth of human lung adenocarcinoma A549 cell xenografts by increasing the expression of ERS-related molecules (p-PERK and CHOP), up regulating PUMA, and down-regulating Bcl2. These data indicate that ICA is a potential inhibitor of lung adenocarcinoma cell growth by targeting ERS signaling and suggest that the activation of ERS signaling may represent a novel therapeutic intervention for lung adenocarcinoma. PMID- 26049257 TI - Transcranial direct current stimulation: before, during, or after motor training? AB - Noninvasive brain stimulation has recently been used to augment motor training induced plasticity. However, the exact time during which noninvasive brain stimulation can be combined with motor therapy to maximize neuroplasticity and behavioral changes is unknown. We conducted a randomized sham-controlled crossover trial to examine when (before, during, or after training) transcranial direct current stimulation (tDCS) should be applied to best reinforce motor training-induced plasticity in 12 healthy right-handed participants (mean age: 21.8+/-1.6) who underwent active or sham tDCS combined with motor training. Transcranial magnetic stimulation-elicited motor-evoked potentials from the right first dorsal interosseous muscle were recorded before (baseline) and immediately after each session. The training task comprised four practice trials - 3 min each (30 s pause between trials) - of repetitive finger movements (thumb abduction/adduction) with the right hand. Anodal tDCS (1 mA, 13 min, on the motor primary cortex) was applied before, during, and after the training. Compared with baseline motor-evoked potentials and the sham condition, tDCS that was applied before, but not during or after, the motor task enhanced corticospinal excitability. These data suggest that tDCS performed before - not during or after - promotes optimization of motor training-induced plasticity. PMID- 26049258 TI - Detection of Chlamydia pneumoniae in a collection of captive snakes and response to treatment with marbofloxacin. AB - In a collection of 58 snakes comprising predominantly Eurasian vipers in Switzerland, five snakes died unexpectedly during hibernation from 2009 to 2012. In one snake, organisms resembling chlamydiae were detected by immunohistochemistry in multiple histiocytic granulomas. Real-time quantitative PCR and microarray analysis were used to determine the presence of Chlamydia pneumoniae in tissue samples and cloacal/choanal swabs from snakes in the collection; 8/53 (15.1%) of the remaining snakes were positive. Although one infected snake had suppurative periglossitis, infection with C. pneumoniae did not appear to be associated with specific clinical signs in snakes. Of seven snakes treated with 5 mg/kg marbofloxacin IM once daily, five became PCR negative for C. pneumoniae following treatment, whereas one animal remained positive and one snake was lost to follow-up. PMID- 26049259 TI - Oral tylosin administration is associated with an increase of faecal enterococci and lactic acid bacteria in dogs with tylosin-responsive diarrhoea. AB - The term tylosin-responsive diarrhoea (TRD) is used for canine recurrent diarrhoea cases for which no underlying cause can be found after extensive diagnostic investigations, but which show a response to the antibiotic tylosin in a few days. The objective of this prospective, one-arm longitudinal trial was to assess the effects of oral tylosin administration on the faecal levels of potentially probiotic bacteria, such as Enterococcus spp. and lactic acid bacteria (LAB), in dogs with TRD. This trial included 14 client-owned suspected TRD dogs that were on tylosin treatment and had firm faeces. Treatment was then terminated and dogs were followed up for up to 2 months to determine the recurrence of diarrhoea. Once diarrhoea started, dogs received tylosin (orally, 25 mg/kg, once daily for 7 days). At the end of the treatment period, stools were firm again in 11 dogs (TRD dogs); three dogs continued having diarrhoea and were excluded from the study. Faecal samples were collected at all three time-points for culture of LAB and enterococci. In TRD dogs, the colony counts of Enterococcus spp. (P = 0.003), LAB (P = 0.037), tylosin-resistant Enterococcus spp. (P <0.001) and LAB (P <0.001) were significantly higher when the dogs were on tylosin treatment and had normal faecal consistency compared to when they had diarrhoea following discontinuation of tylosin. In conclusion, cessation of diarrhoea in TRD dogs with tylosin treatment could be mediated by selection of a specific lactic acid population, the Enterococcus spp., due to their potential probiotic properties. PMID- 26049260 TI - Frequency and prognosis of acute pancreatitis associated with acute hepatitis E: A systematic review. AB - BACKGROUND: The association of acute pancreatitis (AP) with viral hepatitis is well known, and is usually attributed to HAV, HBV, or HCV. AP related to acute hepatitis E (AHE) has been rarely described, and the typical profile is that of a young male, residing in an endemic area, presenting with mild to moderate pancreatitis, and improving with conservative management. RATIONALE: An increasing number of reports describe AP associated with AHE. Some life threatening complications related to AP may occur, and death has been reported. In addition, it is possible that early diagnosis of these cases may help in reducing the morbidity and mortality. OBJECTIVE: Perform a systematic review to study cases of AP associated with AHE and to assess their prognosis. DATA SOURCES: PubMed, EMBASE, Scopus, and the Cochrane library. STUDY SELECTION: All available studies discussing AP associated with AHE. DATA EXTRACTION AND ASSESSMENT: Two blinded independent observers extracted and assessed the studies for diagnosis of AHE based on serological and/or molecular techniques, diagnosis of fulminant hepatitis based on the American Association for the study of Liver Diseases (AASLD) position paper, diagnosis of AP based on the American College of Gastroenterology (ACG) guidelines, diagnosis of AP associated with AHE based on Makharia's association, and diagnosis of AP severity based on the Revision of the Atlanta Classification (RAC). RESULTS: Thirteen case reports and 4 case series were found with 55 patients meeting the inclusion criteria. All patients originated from Southern Asia or had a recent travel to that area. The mean age at diagnosis was 28 years with a male to female ratio of 18:1. The mean interval between the onset of jaundice and the onset of AP pain was 10 days. AP was mild or moderately severe in 45 patients (82%), and severe in 10 patients (18%). Mortality was reported in 2 patients (3.6%). CONCLUSION: Fifty-five cases of acute pancreatitis associated with AHE are reported in the literature. Acute pancreatitis in this setting is severe in approximately one fifth of patients with an overall mortality rate similar to all other causes of AP. PMID- 26049261 TI - Purinergic signalling in the enteric nervous system (An overview of current perspectives). AB - Purinergic Signalling in the Enteric Nervous System involves the regulated release of ATP (or a structurally-related nucleotide) which activates an extensive suite of membrane-inserted receptors (P2X and P2Y subtypes) on a variety of cell types in the gastrointestinal tract. P2X receptors are gated ion channels permeable to sodium, potassium and calcium. They depolarise cells, act as a pathway for calcium influx to activate calcium-dependent processes and initiate gene transcription, interact at a molecular level as a form of self regulation with lipids within the cell wall (e.g. PIP2) and cross-react with other membrane-inserted receptors to regulate their activity (e.g. nAChRs). P2Y receptors are metabotropic receptors that couple to G-proteins. They may release calcium ions from intracellular stores to activate calcium-dependent processes, but also may activate calcium-independent signalling pathways and influence gene transcription. Originally ATP was a candidate only for NANC neurotransmission, for inhibitory motoneurons supplying the muscularis externa of the gastrointestinal tract and bringing about the fast IJP. Purinergic signalling later included neuron-neuron signalling in the ENS, via the production of either fast or slow EPSPs. Later still, purinergic signalling included the neuro epithelial synapse-for efferent signalling to epithelia cells participating in secretion and absorption, and afferent signalling for chemoreception and mechanoreception at the surface of the mucosa. Many aspects of purinergic signalling have since been addressed in a series of highly-focussed and authoritative reviews. In this overview however, the current focus is on key aspects of purinergic signalling where there remains uncertainty and ambiguity, with the view to stimulating further research in these areas. PMID- 26049262 TI - Open-loop characteristics of the arterial baroreflex after blockade of unmyelinated baroreceptors with resiniferatoxin. AB - Arterial baroreceptors can be divided into two categories dependent on whether their axons are myelinated (A-fiber) or unmyelinated (C-fiber). We investigated the effect of periaxonal resiniferatoxin (RTX), a blocker of C-fiber baroreceptor activity, on the open-loop static characteristics of the arterial baroreflex. The baroreceptor region of the right aortic depressor nerve was isolated, and intra baroreceptor region pressure (BRP) was changed from 60 to 180 mm Hg in 10 anesthetized Sprague-Dawley rats. Open-loop static characteristics of the neural arc from BRP to efferent sympathetic nerve activity (SNA), peripheral arc from SNA to arterial pressure (AP), and total reflex arc from BRP to AP were estimated. Although blocking C-fiber activity with RTX resulted in a lower response range (33.7+/-4.6% and 49.4+/-4.8%, P<0.01) and higher minimum SNA (78.0+/-4.7% and 53.6+/-5.0%, P<0.001) of the steady-state neural arc, the peak SNA response to BRP was greater at a BRP of 160 mm Hg (-37.87+/-5.83% and 26.28+/-4.90%, P=0.01). RTX also resulted in a lower response range (27.8+/-5.0 mm Hg and 40.9+/-5.2 mm Hg, P<0.01) and higher minimum AP (92.4+/-4.7 mm Hg and 79.1+/-4.9 mm Hg, P<0.001) of the total reflex arc. Despite these changes, the maximum slope of the neural arc and the maximum gain of the total reflex arc did not differ significantly after RTX. These data suggest that A-fiber baroreceptors can regulate AP and maintain the maximum gain when systemic AP is around the normal operating range. In contrast, C-fiber baroreceptors are critically important for reductions in SNA and AP when systemic AP is raised above the normal operating range. PMID- 26049263 TI - [Long-term outcomes after hypospadias surgery: Sexual reported outcomes and quality of life in adulthood]. AB - OBJECTIVE: To evaluate outcomes and long-term sexual quality of life after hypospadias surgery. Seventeen-years-old patients operated for a posterior hypospadias in childhood were included in a transversal study. PATIENTS AND METHODS: Fifteen patients, among the forty children treated since 1997, accepted to participate. These young men (mean age at the first surgery was 27.9+/ 20months) were clinically reviewed and responded to questionnaires (EUROQOL 5, IIEF15 and non-validated questionnaire). This study arises about 8.4+/-5years after the last visit in paediatric department. RESULTS: Mean study age was 21.2+/ 4.7years. One third of patients thought that global quality of life was distorted. Although 33% of the patients had erectile dysfunction, 80% were satisfied with their sexual quality of life. The most important complains were relative to the penile appearance. Number of procedures was not predictive of patient's satisfaction about penile function and appearance. Thirty-three percents of the patients would have been satisfied to have psychological and medical support. They would be interested in having contact with patients who suffered from the same congenital abnormality. CONCLUSION: These patients had functional and esthetical disturbances. This visit leads to a specific visit in 20% cases. In this study, medical follow-up does not seem to be counselling and had to be adapted. Adequate follow-up transition between paediatric and adult departments especially during adolescence seems to be necessary. PMID- 26049264 TI - Role of Monitoring Devices in Preventing Heart Failure Admissions. AB - This review aims to discuss and summarize the evidence base for devices that have a role in monitoring patients with heart failure for the purpose of attempting to prevent heart failure-related admissions. Despite contemporary heart failure service provision, many patients continue to need acute admission for decompensation. There is a clinical need for a better strategy for predicting decompensation earlier so that appropriate therapeutic interventions can be commenced sooner in order to prevent the need for acute hospital admission. Between clinical assessment visits, the contemporary approach to management is based primarily on daily home monitoring of weight by patients; while this has proved useful, it falls short. For example, substantial weight gain was seen in only 20% of ADHF admission patients according to data collected in the TEN-HMS home telemonitoring study. Monitoring devices offer the possibility of tracking additional physiological or haemodynamic parameters that may allow for earlier detection and more accurate identification of patients at risk of acute decompensation. PMID- 26049265 TI - What can be learned from our pediatric colleagues? PMID- 26049266 TI - A review of symptom screening tools in pediatric cancer patients. AB - PURPOSE OF REVIEW: Children receiving chemotherapy experience a high burden of symptoms. The purposes of this review were to identify symptom assessment tools used in pediatric cancer patients published in the last year; describe the characteristics of the identified tools; and evaluate their appropriateness for symptom screening and to alter patient management. RECENT FINDINGS: We identified six different symptom screening or assessment tools used across 10 studies in the past year. Four instruments contained 30 or more items. Patient management was not altered on the basis of identified symptoms in any of these studies. SUMMARY: Symptom assessment in pediatric oncology continues to be an active area of study but the available instruments are not yet used to guide symptom management. Future research should focus on implementing active and ongoing symptom screening into clinical practice and determining if active symptom screening improves patient outcomes. Electronic symptom screening tools may improve the feasibility of incorporating symptom screening tools into routine practice. PMID- 26049267 TI - Survivor care for pediatric cancer survivors: a continuously evolving discipline. AB - PURPOSE OF REVIEW: This article summarizes recent findings regarding the prevalence of chronic health conditions, cardiovascular and pulmonary late effects, and second malignancies in childhood cancer survivors (CCSs), and examines facilitators and barriers to survivor care. RECENT FINDINGS: The estimated cumulative prevalence for a serious chronic disease in CCSs is 80% by age 45. The crude prevalence for cardiac conditions is 56.4% and for pulmonary dysfunction is 65.2%. Research in cardio-oncology is focused on better methods of predicting risk for cardiac dysfunction, and better methods of detection and interventions to prevent cardiac late effects. Pulmonary late effects, recognized to be a significant cause of late mortality, were detected by surveillance tests in more than 50% of CCSs but are often subclinical. Rates of subsequent malignant neoplasm continue to increase as the population ages. All of these factors make it clear that life-long surveillance is required and models of care should consider risk for late effects and socioeconomic and patient-specific factors. SUMMARY: It is becoming clear that there is no age after which the occurrence of late effects plateaus and surveillance can be reduced. Survivors should be empowered to advocate for their survivor care and options for follow-up should be tailored to their needs. PMID- 26049268 TI - Screening for psychological late effects in childhood, adolescent and young adult cancer survivors: a systematic review. AB - PURPOSE OF REVIEW: In the past years, increasing evidence showed that many childhood cancer survivors suffer from psychological distress long after treatment ended. However, psychosocial issues are often neglected during follow up care. Including screening for psychological distress before follow-up appointments might help addressing the topic in survivors who need support. Our aim was to systematically review the available evidence on screening for psychological distress in childhood cancer survivors. RECENT FINDINGS: We found eight studies that investigated different screening tools for their utility in detecting psychological distress in childhood cancer survivors. The Brief Symptom Inventory-18 with an adapted cutoff score for childhood cancer survivors, and the newly developed short form of the Beck Depression Index were both shown to be of a potential benefit as brief screening tools in follow-up care. SUMMARY: We identified promising screening tools to be used to detect psychological distress in childhood cancer survivors. However, there is still a lack of studies addressing applicability and effectiveness when screening is routinely implemented into follow-up care. To improve quality of follow-up care, and identify and treat survivors with psychological distress, screening tools should now be implemented and their adequacy further tested in day-to-day clinic life. PMID- 26049269 TI - Social competence in pediatric brain tumor survivors: breadth versus depth. AB - PURPOSE OF REVIEW: The purpose of this article is to review the literature in the area of social competence in pediatric brain tumor survivors published in the last year. RECENT FINDINGS: Research published over the past year examining the social competence of pediatric brain tumor survivors has seen the consistent application of a comprehensive conceptual framework that pertains specifically to children with brain disorders. Subsequent to the application of a comprehensive conceptual framework, more sophisticated research approaches have begun to advance our understanding of deficits among this population. Specifically, operationalization of social competence is evolving. SUMMARY: Continued application of a conceptual framework and investigation into the components that comprise the framework will enhance the depth of our understanding of social competence deficits among this population. Research must continue to use innovative approaches to measuring social competence. Considerable gaps still exist with respect to identifying risk and resilience factors for social competence deficits. PMID- 26049270 TI - Recent developments in supporting adolescent and young adult siblings of cancer patients. AB - PURPOSE OF REVIEW: The psychosocial needs of adolescent and young adult (AYA) siblings of cancer patients are easily overlooked. Accordingly, the evidence base informing short and long-term outcomes for these young people is sparse. This review provides an overview of recent research highlighting the experiences, unmet needs and psychosocial issues of AYA siblings, together with recent interventions. RECENT FINDINGS: The reviewed studies bring focus to the range of informational and supportive care needs that typically remain unmet in AYA siblings. The limited number of interventions designed specifically for this group not only appear to have positive results but also underscore the need for effective risk stratification preintervention and tailoring of interventions to the specific needs of participants. SUMMARY: AYA siblings of cancer patients display a range of psychosocial symptoms that can be ameliorated with age appropriate information and targeted intervention programs. Limited research suggests that the majority of unmet needs for AYA siblings seem to occur during the acute phases of the brother or sister's initial diagnosis, treatment and relapse. Further research is required on siblings' long-term psychosocial assessment and management, bereavement, family systems, the impact of the cancer experience on siblings' personality and identity, and the development and evaluation of tailored psychosocial interventions. Policy research is also required to identify opportunities for expanding established healthcare systems to include sibling support. PMID- 26049271 TI - Synovial sarcoma diagnosis and management in the era of targeted therapies. AB - PURPOSE OF REVIEW: Synovial sarcomas are a distinct soft tissue sarcoma subtype, with a predilection for young adults. Despite its common translocation, there is substantial heterogeneity in patient outcome. This review discusses recent developments in diagnosis, prognostication, and treatments, together with the role of targeted agents and immunotherapy in patients with synovial sarcoma. RECENT FINDINGS: Tumor behavior of synovial sarcomas remains inexplicable and is therefore poorly predictable. Although many variables seem to contribute to and influence patient outcome, no underlying pathophysiology accounting for the variability in behavior has been unraveled. As prognosis remains poor, there is a wistful search for new therapies. In preclinical testing, several receptor tyrosine kinases have been suggested as therapeutic targets with interesting results in vitro or in vivo. However, translating interesting preclinical outcome to clinical results is difficult, to a large extent due to limited patient numbers available to participate in clinical trials. SUMMARY: By defining predictive variables, researchers try to understand the underlying cause of this tumor's biologic behavior and develop new therapeutic targets. Owing to the minimal number of prospective studies usually with small patient numbers, the strength of improving patient outcome will be in collaborative international studies in this rare tumor type. PMID- 26049272 TI - Value added: functional MR imaging in management of bone and soft tissue sarcomas. AB - PURPOSE OF REVIEW: MRI plays a crucial role in the initial diagnosis, treatment planning, and long-term management of bone and soft tissue sarcomas. Technological advances have enabled improvements in both delineation of anatomic detail, and in functional imaging techniques that interrogate tissues at the cellular level. This bears particular relevance in sarcomas as morphological parameters alone do not necessarily correlate with treatment response and prognosis. Here, we describe recent developments in advanced MRI techniques, including chemical-shift MRI, diffusion-weighted imaging (DWI), MR spectroscopy (MRS), and dynamic contrast enhanced (DCE) MRI. RECENT FINDINGS: Chemical-shift MRI allows robust discrimination of marrow infiltrating neoplasms from benign red marrow. DWI reveals tumor cellularity, and aids in distinguishing benign and malignant tumors along with the assessment of treatment response. MRS is technically challenging in the musculoskeletal system, but shows promise as a means to noninvasively assess metabolic aberrations in a variety of sarcomas. DCE is particularly suited to treatment response evaluation, in which traditional size-based assessment criteria may underestimate efficacy in clinical trials. SUMMARY: Functional MRI techniques offer novel imaging biomarkers that effectively complement conventional MRI in the assessment of bone and soft tissue sarcomas at all stages of patient care. PMID- 26049273 TI - Surveillance recommendations for patients with germline TP53 mutations. AB - PURPOSE OF REVIEW: Li-Fraumeni syndrome is associated with germline TP53 mutations and carriers have a high lifetime risk of cancer, the most common being sarcoma, breast cancer, brain tumors, adrenocortical carcinoma and leukemia. Germline TP53 mutation carriers are increasingly being identified as more genomic sequencing is performed in both clinical and research settings. There is a pressing clinical need for effective cancer risk management approaches in this group. RECENT FINDINGS: Current clinical surveillance guidelines mainly focus on breast and bowel cancer risk with little consideration for the other cancers common to the syndrome. Imaging technologies are such that the utilization of whole-body MRI imaging for surveillance is viable. Globally, several research groups have included whole-body MRI along with other diagnostic measures in formulating surveillance protocols for TP53 mutation carriers. Early reports suggest a survival benefit. SUMMARY: Surveillance protocols for TP53 mutation carriers have the potential to improve outcomes in individuals and families. Further research is needed to guide the development of an effective and comprehensive surveillance schedule. PMID- 26049274 TI - The immune system and gastrointestinal stromal tumor: a wealth of opportunities. AB - PURPOSE OF REVIEW: This article reviews the current literature on tumor infiltrating immune cells in gastrointestinal stromal tumor (GIST), and the current status and prospects of effective immunotherapeutic strategies. RECENT FINDINGS: Tumor-infiltrating immune cells populate the microenvironment of GISTs; the most numerous are tumor-associated macrophages (TAMs) and CD3 T cells. TAMs have not been shown to have a relationship with the biological behavior of GISTs; however, the number of CD3 T cells correlates with better outcomes. The prognostic significance of tumor-infiltrating neutrophils, natural killer cells, CD4 T cells, CD8 T cells, and Treg cells remains unknown.Imatinib mesylate achieves a clinical response in 80% of patients with GIST. Its antitumor mechanism is partially immune mediated. The combination of imatinib and interferon-alpha has been shown to be effective against GIST - it eradicates tumor cells including those that are drug resistant. Preclinical trials including cytotoxic T lymphocyte-associated antigen 4 blockade, anti-KIT antibody, and the generation of designer T cells have shown promising therapeutic effect in animal models of GIST. SUMMARY: GIST contains many tumor-infiltrating immune cells and should be susceptible to immunotherapy; early clinical and preclinical trials have shown promising results that should lead to new investigations and effective forms of direct and synergistic therapies. PMID- 26049275 TI - Surgical approach for soft tissue sarcoma: standard of care and future approaches. AB - PURPOSE OF REVIEW: This review highlights the ongoing importance of surgical resection as the primary treatment modality for localized soft tissue sarcomas (STSs) in all locations and for the majority of histologic types. Accomplishing this goal in an oncologic fashion is of paramount importance for all patients eligible for treatment with curative intent and for selected patients with metastatic disease. RECENT FINDINGS: Ongoing advances in combined modality therapy and improved knowledge regarding the natural history and disease biology of individual sarcoma subtypes have allowed for better surgical planning and tailoring of the extent of resection depending on individual clinical, radiographic, and pathologic factors. SUMMARY: Successful therapy for localized STS remains contingent on surgical resection with tumor-free margins. It is hoped that ongoing advances in the molecular and genetic understanding of the pathogenesis and biology of STS will lead to sustained improvements in the care of these patients, and success will come from the ongoing development of targeted therapies and immunotherapies specific to histologic type. PMID- 26049276 TI - Of art and science: is personalized medicine getting personal enough? PMID- 26049277 TI - Cancer survivorship: long-term side-effects of anticancer treatments of gastrointestinal cancer. AB - PURPOSE OF REVIEW: Surveillance of patients with a history of cancer is a frequent practice in oncology. However, it is often aimed at the early diagnosis of relapse and tends to underestimate the evaluation and care of factors impairing quality of life (QoL). Among these, long-term toxicities of anticancer treatments are one of the major threats to a complete physical and psychosocial recovery. We aimed to review the relevant literature on long-term side-effects of treatment in gastrointestinal cancers. RECENT FINDINGS: We focused on esophageal, gastric, pancreatic, liver and colorectal cancers. A significant fraction of patients treated for these cancers suffer with some form of late toxicity from surgery, radiotherapy or chemotherapy. Prompt evaluation and management is of the utmost importance in reducing the impact of these symptoms on QoL. SUMMARY: The knowledge of the reviewed data should encourage a multidisciplinary approach to surveillance and convince clinicians of the comprehensive role of survivorship care. PMID- 26049279 TI - Ten Years of Equine-related Injuries: Severity and Implications for Emergency Physicians. AB - BACKGROUND: The size, speed, and unpredictable nature of horses present a significant risk for injury in all equine-related activities. OBJECTIVE: We sought to examine the mechanism, severity, frequency, body regions affected, surgical requirements, rehabilitation needs, safety equipment utilization, and outcomes of equine-related injured patients. METHODS: Records of inpatients who sustained an equine-related injury from 2002-2011 with International Classification of Diseases, Ninth Revision codes E828 and E906 were retrospectively reviewed for pertinent data. RESULTS: Ninety patients, 70% female, age (mean +/- SD) 37.3 +/- 19.4 years, length of stay 3.7 +/- 4.5 days, Injury Severity Score 12.9 +/- 8.4. Predominant mechanism of injury was fall from horse (46.7%). The chest (23%) was most frequently injured, followed by brain/head (21.5%). Thirty patients (33%) required 57 surgical procedures. Twenty percent of patients required occupational therapy and 33.3% required physical therapy while hospitalized. Only 3% required rehabilitation, with 90% discharged directly home. Safety equipment was not used in 91.9% of patients. One patient sustained a cord injury. Six patients expired, all from extensive head injuries. CONCLUSION: The majority of equine-related injuries occur while pursuing recreational activities and are due to falls. Our patients experienced more severe injuries to the trunk and head and required more surgical intervention for pelvic, facial, and brain injuries than previously reported. Failure to use safety equipment contributes to the risk of severe injury. Education and injury prevention is essential. The need for complex surgical intervention by multiple specialties supports transfer to Level I trauma centers. PMID- 26049280 TI - Age-Disparate Partnerships and Risk of HIV-1 Acquisition Among South African Women Participating in the VOICE Trial. AB - A recent analysis from South Africa reported no association between age-disparate relationships and HIV-1 acquisition. We assessed the association between male partner age and HIV-1 acquisition among South African women participating in the VOICE trial. Of 4077 women enrolled, 3789 had complete data; 26% and 5% reported having a partner >5 and >10 years older at enrollment, respectively. Reporting a partner >5 years older (hazard ratio = 1.00; 95% confidence interval: 0.74 to 1.35) or >10 older (hazard ratio = 0.92; 95% confidence interval: 0.49 to 1.74) was not associated with HIV-1 acquisition. These data corroborate recent reports and may suggest a shift in local epidemiology of heterosexual HIV-1 transmission. PMID- 26049281 TI - Screening for Tuberculosis Among Adults Newly Diagnosed With HIV in Sub-Saharan Africa: A Cost-Effectiveness Analysis. AB - OBJECTIVE: New tools, including light-emitting diode (LED) fluorescence microscopy and the molecular assay Xpert MTB/RIF, offer increased sensitivity for tuberculosis (TB) in persons with HIV but come with higher costs. Using operational data from rural Malawi, we explored the potential cost-effectiveness of on-demand screening for TB in low-income countries of Sub-Saharan Africa. DESIGN AND METHODS: Costs were empirically collected in 4 clinics and in 1 hospital using a microcosting approach, through direct interview and observation from the national TB program perspective. Using decision analysis, newly diagnosed persons with HIV were modeled as being screened by 1 of the 3 strategies: Xpert, LED, or standard of care (ie, at the discretion of the treating physician). RESULTS: Cost-effectiveness of TB screening among persons newly diagnosed with HIV was largely determined by 2 factors: prevalence of active TB among patients newly diagnosed with HIV and volume of testing. In facilities screening at least 50 people with a 6.5% prevalence of TB, or at least 500 people with a 2.5% TB prevalence, Xpert is likely to be cost-effective. At lower prevalence-including that observed in Malawi-LED microscopy may be the preferred strategy, whereas in settings of lower TB prevalence or small numbers of eligible patients, no screening may be reasonable (such that resources can be deployed elsewhere). CONCLUSIONS: TB screening at the point of HIV diagnosis may be cost-effective in low-income countries of Sub-Saharan Africa, but only if a relatively large population with high prevalence of TB can be identified for screening. PMID- 26049282 TI - Evidence-Based Programming of HIV Care and Support: Is the Psychosocial "Optional"? PMID- 26049283 TI - Nutritional Support to HIV Patients Starting ART. PMID- 26049284 TI - Authors' Reply: Race and the Public Health Impact Potential of Pre-Exposure Prophylaxis in the United States. PMID- 26049285 TI - The uses of infrared thermography to evaluate the effects of climatic variables in bull's reproduction. AB - The objective of this study was to evaluate the seasonal effects of the environment on sperm quality in subtropical region determined by temperature and humidity index (THI). We used 20 Brangus bulls (5/8 Angus * 3/8 Nellore) aged approximately 24 months at the beginning of the study. Semen evaluations were performed twice per season during 1 year. Climate THI data were collected from an automatic weather station from the National Institute of Meteorology. Infrared thermography images were used to determine the temperature of the proximal and distal poles of the testis to assess the testicular temperature gradient (TG). The seasonal effects on seminal and climatic variables were analyzed with ANOVA using MIXED procedure of SAS. Sperm motility in spring (60.1%), summer (57.6%), and autumn (64.5%) showed difference compared to winter (73.0%; P < 0.01). TG was negatively correlated with THI at 18 days (spermiogenesis) (-0.76; P < 0.05) and at 12 days (epididymal transit) (-0.85; P < 0.01). Ocular temperature (OcT) had a positive correlation with THI at 18 days (0.78; P < 0.05) and at 12 days (0.84; P < 0.01). Motility showed a negative correlation with THI only at 18 days (-0.79; P < 0.05). During spermiogenesis, the TG had higher negative correlation compared to OcT (-0.97; P < 0.01) and rectal temperature (-0.72; P < 0.05). Spermatozoa with distal midpiece reflex were correlated with THI during transit epididymis (0.72; P < 0.05). Seminal parameters are not affected when THI reaches 93.0 (spermiogenesis) and 88.0 (epididymal transit). We concluded that infrared thermography can be adopted as an indirect method in order to assess the effect of environmental changes in TG and OcT of Brangus bulls. PMID- 26049286 TI - Effects of ventilation behaviour on indoor heat load based on test reference years. AB - Since 2003, most European countries established heat health warning systems to alert the population to heat load. Heat health warning systems are based on predicted meteorological conditions outdoors. But the majority of the European population spends a substantial amount of time indoors, and indoor thermal conditions can differ substantially from outdoor conditions. The German Meteorological Service (Deutscher Wetterdienst, DWD) extended the existing heat health warning system (HHWS) with a thermal building simulation model to consider heat load indoors. In this study, the thermal building simulation model is used to simulate a standardized building representing a modern nursing home, because elderly and sick people are most sensitive to heat stress. Different types of natural ventilation were simulated. Based on current and future test reference years, changes in the future heat load indoors were analyzed. Results show differences between the various ventilation options and the possibility to minimize the thermal heat stress during summer by using an appropriate ventilation method. Nighttime ventilation for indoor thermal comfort is most important. A fully opened window at nighttime and the 2-h ventilation in the morning and evening are more sufficient to avoid heat stress than a tilted window at nighttime and the 1-h ventilation in the morning and the evening. Especially the ventilation in the morning seems to be effective to keep the heat load indoors low. Comparing the results for the current and the future test reference years, an increase of heat stress on all ventilation types can be recognized. PMID- 26049287 TI - Cardiac extracorporeal membrane oxygenation: how to predict the unpredictable. PMID- 26049289 TI - Personalized prediction of live birth: Are we there yet? PMID- 26049291 TI - Journal of Pediatric Orthopaedics. Preface and Introduction. PMID- 26049288 TI - Peritoneal wash contents used to predict mortality in a murine sepsis model. AB - BACKGROUND: Cecal ligation and puncture (CLP) is considered the gold standard for inducing abdominal sepsis in mice. However, the model lacks source control, a component of sepsis management in humans. Using a CLP-excision model, we characterized peritoneal cytokines and cells and hypothesized these analyses would allow us to predict survival. METHODS: Fifty-eight mice were first subjected to CLP. Twenty hours later, the necrotic cecums were debrided, abdominal cavity lavaged, and intraperitoneal antibiotics administered. Peritoneal cytokines and leukocytes collected from the peritoneal lavage were analyzed. These immune parameters were used to generate receiver operator characteristic curves. In separate experiments, the accuracy of the model was verified with a survival cohort. Finally, we collected the peritoneal lavage and analyzed both serum and peritoneal cytokines, bacterial load, and leukocyte functionality. RESULTS: Peritoneal interleukin (IL)-6 levels and neutrophil CD11b intensity were observed to be significantly different in mice that lived versus those who died. In separate experiments, mice predicted to live (P-LIVE) had decreased bacterial loads, systemic IL-10, and neutrophil oxidative burst and increased peritoneal inflammatory monocyte numbers and phagocytosis. CONCLUSIONS: This study couples a clinically relevant sepsis model with methodology to limit pathogen spread. Using surgical waste, stratification of the mice into groups P LIVE and predicted to die was possible with a high degree of accuracy and specificity. In mice P-LIVE, increased inflammatory monocyte recruitment and phagocytosis were associated with decreased systemic IL-10 and bacterial loads. PMID- 26049293 TI - Shifting From Volume to Value: Opportunities and Challenges for the Field of Orthopaedic Surgery. PMID- 26049294 TI - Health System Perspective: Variation, Costs, and Physician Behavior. AB - With the generalized rise in cost of US health care, renewed emphasis has been placed on defining the relationship between costs and outcome. The quality of health care delivery has been uneven, as measured by existing quality and performance measures, significant variation in the delivery of care, lack of standardization of care leading to avoidable error, lack of meaningful outcomes measurement, and apparent disconnect with cost. Orthopaedic surgeons are at the nexus of implementing change, as we are the primary decision makers regarding care of our patients. This summary will review efforts that address quality, cost, outcome, safety, and variation in care. PMID- 26049295 TI - Quality, Safety, and Value: The Current AAOS Initiatives. AB - The AAOS is committed to helping orthopaedists provide safe, effective, and high quality care for their patients. There are a number of very active initiatives focused on patient safety, team performance, and evidence-based quality and value including clinical practice guidelines and appropriate use criteria. This article describes those initiatives. PMID- 26049296 TI - Quality, Safety, Value: From Theory to Practice ABOS Initiatives. PMID- 26049297 TI - Simulation in Pediatric Orthopaedic Surgery. AB - Surgical simulation has become an increasingly important means of improving skills acquisition, optimizing clinical outcomes, and promoting patient safety. While there have been great strides in other industries and other fields of medicine, simulation training is in its relative infancy within pediatric orthopaedics. Nonetheless, simulation has the potential to be an important component of Quality-Safety-Value Initiative of the Pediatric Orthopaedic Society of North America (POSNA). The purpose of this article will be to review some definitions and concepts related to simulation, to discuss how simulation is beneficial both for trainee education as well as value-based health care, and to provide an update on current initiatives within pediatric orthopaedic surgery. PMID- 26049298 TI - The TeamSTEPPS Approach to Safety and Quality. AB - Despite advances in patient safety since the landmark Institute of Medicine Report To Err is Human was published, adverse events and medical errors remain a persistent problem throughout health care. Safety experts have examined the practices in high-risk industries that maintain outstanding safety records for strategies to address the problem. Those efforts led to the development of Team Strategies and Tools to Enhance Performance and Patient Safety (TeamSTEPPS), a patient safety program that incorporates the principles of crew resource management and teamwork successfully used by industry into the health care setting. Evidence supports that the knowledge, skills, and attitudes, that comprise the core of TeamSTEPPS program, can improve safety and outcomes when used by members of the health care team. Successful implementation should assist the transition of health care workers from functioning as individual experts to performing as members of expert teams. PMID- 26049299 TI - Radiation Safety in Pediatric Orthopaedics. AB - Patients, surgeons, and staff are exposed to ionizing radiation in pediatric orthopaedic surgery from diagnostic studies and imaging associated with procedures. Estimating radiation dose to pediatric patients is based on complex algorithms and dose to surgeons and staff is based on dosimeter monitoring. Surgeons can decrease radiation exposure to patients with careful and thoughtful ordering of diagnostic studies and by minimizing exposure intraoperatively. Surgeon and staff radiation exposure can be minimized with educational programs, proper shielding and positioning intraoperatively, and prudent use of intraoperative imaging. Overall, better awareness among pediatric orthopaedic surgeons of our role in radiation exposure can lead to improvements in radiation safety. PMID- 26049300 TI - Practice Improvement Modules: The Pediatric Supracondylar Fracture PIM. PMID- 26049301 TI - POSNA PreCourse Quality, Safety, Value: From Theory to Practice Management Session 4 Deliverables Supracondylar Clinical Pathway. PMID- 26049302 TI - POSNA PreCourse Quality, Safety, Value: From Theory to Practice Management Session 3 AAOS and ABOS Initiatives: "Historical Perspective". PMID- 26049303 TI - POSNA Quality Safety Value Initiative: From Vision to Implementation to Early Results. AB - The POSNA Quality, Safety and Value Initiative (QSVI) formally started with POSNA board approval in early 2011. The initial vision statement was: "To lead in defining our members' value based clinical care. To partner with hospital based and orthopedic organizational efforts to guarantee safe, high quality outcomes for our patients. To communicate our initiatives and results cooperatively with payer, credentialing, and compliance organizations to improve pediatric orthopedic care in North America." PMID- 26049304 TI - Value in Pediatric Orthopaedic Surgery Health Care: the Role of Time-driven Activity-based Cost Accounting (TDABC) and Standardized Clinical Assessment and Management Plans (SCAMPs). AB - The continuing increases in health care expenditures as well as the importance of providing safe, effective, timely, patient-centered care has brought government and commercial payer pressure on hospitals and providers to document the value of the care they deliver. This article introduces work at Boston Children's Hospital on time-driven activity-based accounting to determine cost of care delivery; combined with Systemic Clinical Assessment and Management Plans to reduce variation and improve outcomes. The focus so far has been on distal radius fracture care for children and adolescents. PMID- 26049305 TI - National Surgical Quality Improvement Program-Pediatric (NSQIP) and the Quality of Surgical Care in Pediatric Orthopaedics. AB - In recent years, the safety, quality, and value of surgical care have become increasingly important to surgeons and hospitals. Quality improvement in surgical care requires the ability to collect, measure, and act upon reliable and clinically relevant data. One example of a large-scale quality effort is the American College of Surgeons National Surgical Quality Improvement Program Pediatric (ACS NSQIP-Pediatric), the only nationwide, risk-adjusted, outcomes based program evaluating pediatric surgical care. PMID- 26049306 TI - POSNA Quality, Safety, Value Initiative 3 Years Old and Growing Strong. POSNA Precourse 2014. AB - The purpose of this paper is to summarize the Pediatric Orthopaedic Society of North America (POSNA) quality, safety, and value initiative (QSVI). Specifically, it will outline the history of the program, describe typical quality improvement techniques, and how they differ from traditional research techniques, and, finally, describe some of the many projects completed, currently underway, or in planning for POSNA QSVI. PMID- 26049307 TI - Surgical Site Infection Reduction Program: Challenges and Opportunities. AB - Surgical site infections (SSIs) make up about 23% of hospital-acquired infections and may cost up to 10 billion dollars annually in direct medical expenses. St. Luke's Health System of Boise, Idaho implemented a committee to reduce its incidence of SSIs, focusing on the orthopaedic and neurosurgical departments. After identifying risk factors associated with patient medical comorbidities, operating room practices, and type of procedure, Project Zero recommended changes. The implementation of a preoperative clinic and protocol management of environmental and procedural factors reduced the hospitals rate by 50%. Project Zero continues to research best practices for clean room management and preventative care, striving to reach the overall goal of zero infections. PMID- 26049308 TI - The Wisdom of Crowds. PMID- 26049309 TI - Quality, Safety, Value: From Theory to Practice Management What Should We Measure? AB - Over the past 35 years the health care community and in particular orthopaedic surgery, has undergone a transformation from retrospective case-series-based expert opinion to randomized prospective clinical trials. During this transition, orthopaedic surgeons have become very skilled in the measurement of physician derived outcomes (radiographic angles, complications, recurrences, and mortality); however, these are not patient-centered outcomes and they are of little importance to our patients' satisfaction. Moving forward outcome measurement needs to be restructured to focus more on patient-reported outcomes. This paper outlines why outcome measurement is important, reviews outcome strategies that have been used historically, introduces a new outcome measurement tool and identifies strategies for future implementation and measurement of health care quality and value within pediatric orthopaedics. PMID- 26049310 TI - Value of Pediatric Orthopaedic Surgery. AB - Value has become the buzzword of contemporaneous health care reform. Value is defined as outcomes relative to costs. Orthopaedic surgery has come under increasing scrutiny due to high procedural costs. However, orthopaedic surgery may actually be a great value given the benefits of treatment. The American Academy of Orthopaedic Surgeons (AAOS) Value Project team was tasked to develop a model for assessing the benefits of orthopaedic surgery including indirect costs related to productivity and health-related quality of life. This model was applied to 5 orthopaedic conditions demonstrating robust societal and economic value. In all cost-effectiveness models, younger patients demonstrated greater cost-effectiveness given increased lifespan and productivity. This has tremendous implications within the field of pediatric orthopedic surgery. Pediatric orthopaedics may be the best value in medicine! PMID- 26049311 TI - Acceptability and feasibility of the Leapfrog computerized physician order entry evaluation tool for hospitals outside the United States. AB - BACKGROUND: Computerized physician order entry (CPOE) with clinical decision support is expected to deliver many benefits in terms of patient safety. The Leapfrog tool was developed to allow hospitals to assess their medication-safety related decision support. To explore the approach's generalizability, we examined its acceptability and feasibility through an evaluation using this tool in four Korean hospital systems. METHODS: Four hospitals with locally developed CPOE systems participated, and a cross-sectional study design was used with the approval of the Leapfrog Group and the institutional review board at each hospital site. The hospitals were tertiary and academic institutions with long experience of advanced CPOE. From January 21 to 28, 2014, web-based tests were conducted at each site following the given instructions, and the results were self-reported. We measured each system's response rate, category completion rate, and time to complete the evaluation. Additionally, we compared the evaluation results of the four systems with scores from five US systems, as was reported in another study. RESULTS: The four systems underwent the tests, and the overall category completion rates ranged from 67.9% to 75.5%. The times to finish the tests were tolerable and within the allowed test timeframe. One system did not pass the deception analysis, which checks for false positives, due to a conflict with another type of alert checking for the presence of a medical diagnosis for documentation purposes. The other three systems scored at the completed the evaluation stage, with scores ranging from 21.6% to 36.5%. Of the nine error categories, Drug-Allergy was an area of strength for all systems, whereas the categories of Therapeutic duplication, Drug-Labs, and Drug-Age were areas of weakness for all. In comparison with the US systems, gaps were identified, and further improvement is needed. CONCLUSIONS: The acceptability of the CPOE evaluation tool was moderate, but the feasibility was sufficient to operate the test outside the US, and the results revealed many opportunities for improvement in the Korean systems, as was the case when this application was introduced in the US. PMID- 26049312 TI - Work system factors influencing physicians' screen sharing behaviors in primary care encounters. AB - OBJECTIVE: While the use of electronic health records (EHRs) in primary care has increased dramatically, its potential benefits need to be considered in light of potential negative impacts on physician-patient interactions and the increase in physician cognitive workload. This study aims to understand work system factors contributing to physicians' use of the EHR as a communication tool during primary care encounters. METHODS: We interviewed 14 primary care physicians on their use of EHRs as a communication tool in patient visits. A qualitative content analysis guided by the work system model identified factors influencing physicians' decisions to share or not share the computer screen with their patients. RESULTS: The analysis revealed 26 factors that influenced physicians' decisions to share the screen, most related to the "task" (reviewing lab records), "tools and technology" (using algorithm calculators for risk prediction), or "individual" (patient interest) elements of the work system. The analysis revealed 15 factors that influenced physicians' decisions not to share the screen, most related to the "individual" (patient's acute pain), "organization" (insufficient time), or "task" (documenting embarrassing information) elements of the work system. CONCLUSION: Eleven physicians made individual decisions to share or not to share the screen in a particular visit based on work-system related factors. Three doctors always shared the screen, based on the idea that it is polite and builds trust. However, several physicians also reported that it was time consuming and caused unnecessary distractions. Understanding these factors is essential to effective EHR redesign and training for improving physician-patient communication. PMID- 26049313 TI - Tumor Biology of Vestibular Schwannoma: A Review of Experimental Data on the Determinants of Tumor Genesis and Growth Characteristics. AB - OBJECTIVE: Provide an overview of the literature on vestibular schwannoma biology with special attention to tumor behavior and targeted therapy. BACKGROUND: Vestibular schwannomas are benign tumors originating from the eighth cranial nerve and arise due to inactivation of the NF2 gene and its product merlin. Unraveling the biology of these tumors helps to clarify their growth pattern and is essential in identifying therapeutic targets. METHODS: PubMed search for English-language articles on vestibular schwannoma biology from 1994 to 2014. RESULTS: Activation of merlin and its role in cell signaling seem as key aspects of vestibular schwannoma biology. Merlin is regulated by proteins such as CD44, Rac, and myosin phosphatase-targeting subunit 1. The tumor-suppressive functions of merlin are related to receptor tyrosine kinases, such as the platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Merlin mediates the Hippo pathway and acts within the nucleus by binding E3 ubiquiting ligase CRL4. Angiogenesis is an important mechanism responsible for the progression of these tumors and is affected by processes such as hypoxia and inflammation. Inhibiting angiogenesis by targeting vascular endothelial growth factor receptor seems to be the most successful pharmacologic strategy, but additional therapeutic options are emerging. CONCLUSION: Over the years, the knowledge on vestibular schwannoma biology has significantly increased. Future research should focus on identifying new therapeutic targets by investigating vestibular schwannoma (epi)genetics, merlin function, and tumor behavior. Besides identifying novel targets, testing new combinations of existing treatment strategies can further improve vestibular schwannoma therapy. PMID- 26049314 TI - Benefits of Adaptive Signal Processing in a Commercially Available Cochlear Implant Sound Processor. AB - OBJECTIVE: Cochlear implant recipients often experience difficulty understanding speech in noise. The primary objective of this study was to evaluate the potential improvement in speech recognition in noise provided by an adaptive, commercially available sound processor that performs acoustic scene classification and automatically adjusts input signal processing to maximize performance in noise. RESEARCH DESIGN: Within-subjects, repeated-measures design. SETTING: This multicenter study was conducted across five sites in the U.S.A. and Australia. PATIENTS: Ninety-three adults and children with Nucleus Freedom, CI422, and CI512 cochlear implants. INTERVENTION: Subjects (previous users of the Nucleus 5 sound processor) were fitted with the Nucleus 6 sound processor. Performance was assessed while these subjects used each sound processor in the manufacturer's recommended default program (standard directionality, ASC + ADRO for the Nucleus 5 processor and ASC + ADRO and SNR-NR with SCAN for the Nucleus 6 sound processor). The subjects were also evaluated with the Nucleus 6 with standard directionality, ASC + ADRO and SNR-NR enabled but SCAN disabled. MAIN OUTCOME MEASURES: Speech recognition in noise was assessed with AzBio sentences. RESULTS: Sentence recognition in noise was significantly better with the Nucleus 6 sound processor when used with the default input processing (ASC + ADRO, SNR NR, and SCAN) compared to performance with the Nucleus 5 sound processor and default input processing (standard directionality, ASC + ADRO). Specifically, use of the Nucleus 6 at default settings resulted in a mean improvement in sentence recognition in noise of 27 percentage points relative to performance with the Nucleus 5 sound processor. Use of the Nucleus 6 sound processor using standard directionality, ASC + ADRO and SNR-NR (SCAN disabled) resulted in a mean improvement of 9 percentage points in sentence recognition in noise compared to performance with the Nucleus 5. CONCLUSION: The results of this study suggest that the Nucleus 6 sound processor with acoustic scene classification, automatic, adaptive directionality, and speech enhancement in noise processing provides significantly better speech recognition in noise when compared to performance with the Nucleus 5 processor. PMID- 26049315 TI - [Real alcohol consumption is underestimated]. PMID- 26049317 TI - [Solid nodule of the scalp. Skin metastasis of bronchial carcinoma]. PMID- 26049318 TI - [Mesh-like pigmentation of the thigh. Heat melanosis]. PMID- 26049319 TI - ["PTSD is a significant integration obstacle"]. PMID- 26049320 TI - [My two boys will carry on!]. PMID- 26049322 TI - [Love seeps through every bandage]. PMID- 26049323 TI - [Super emergency physician forgets her electrodes]. PMID- 26049324 TI - [Direct purchase of expensive medicine from the manufacturer may be required]. PMID- 26049325 TI - [Drugs for pregnant patients now without copay]. PMID- 26049326 TI - [LANAR accounting statement uncorrectable]. PMID- 26049327 TI - [Asylum seekers need a permit voucher]. PMID- 26049328 TI - [The Muslim patient: not an unknown entity]. PMID- 26049329 TI - [The arm hurts, the hand becomes weak - what could be the cause?]. PMID- 26049330 TI - [Problems in the anal region]. PMID- 26049331 TI - [From phytotherapy drugs to biologicals]. PMID- 26049332 TI - [What is causing the bone pain?]. PMID- 26049333 TI - [Ticks lurk in the best cared for gardens]. PMID- 26049334 TI - [Pneumococcal vaccination in transition]. PMID- 26049335 TI - [Which tests make sense for whom?]. PMID- 26049336 TI - [Managing the headache]. PMID- 26049337 TI - [Positive expectations increase effectiveness of tablets]. PMID- 26049338 TI - [Migraines in pregnant patients: how safe are triptans?]. PMID- 26049339 TI - [Deficient antibodies?]. PMID- 26049340 TI - [For smoking cessation it is never too late]. PMID- 26049341 TI - [Maggots in the nasal sinus]. PMID- 26049342 TI - [Is the French procedure of renal denervation effective?]. PMID- 26049343 TI - [Neuropathy in too rapid HbA1c decrease]. PMID- 26049344 TI - [Laughter is the best medicine - but it has its risks!]. PMID- 26049345 TI - [Prolonged PPI therapy in reflux esophagitis is sustainable]. PMID- 26049346 TI - [Minor problems of the feet]. PMID- 26049347 TI - [Current concepts in diagnostics and treatment of hallux valgus deformity]. PMID- 26049348 TI - [Hallux rigidus: degenerative osteoarthritis of the first metatarsophalangeal joint]. PMID- 26049349 TI - [Lesser toe deformities: What the general practitioner should know]. PMID- 26049350 TI - [Metatarsalgia: non-specific pain under the ball of the foot]. PMID- 26049351 TI - [Autism and multiple sclerosis following measles vaccination: update on current knowledge]. PMID- 26049352 TI - [Emergency checklist: Spasmodic torticollis]. PMID- 26049353 TI - [Frailty - definition of a common syndrome in the elderly]. PMID- 26049356 TI - [Monitoring of diabetes for general practitioner]. PMID- 26049357 TI - [Red Information Bus tours Germany]. PMID- 26049358 TI - [Optimizing treatment of type 2 diabetic patients]. PMID- 26049359 TI - [Once daily with a powder inhaler]. PMID- 26049360 TI - [Significant decline in the rate of cardiovascular incidents]. PMID- 26049361 TI - [Simplified therapy regimen receives recommendation for approval]. PMID- 26049362 TI - [New ESC guideline takes NOAK into account]. PMID- 26049363 TI - [Rapid and continued treatment]. PMID- 26049364 TI - [Blood pressure before blood glucose treatment]. PMID- 26049365 TI - Echocardiographically derived effective valve opening area in mitral prostheses: a comparative analysis of various calculations using continuity equation and pressure half time method. AB - Detection of dysfunctional mitral valve prostheses (MP) remains complex even though being optimized by considering echocardiographically derived prosthetic effective orifice area (VA). The purpose was to compare VA in MP, calculated by the continuity equation (CE) using peak velocities (CEVpeak), mean velocities (CEVmean), velocity-time integrals (CEVTI) and the pressure half time method using 220 ms as constant first (PHT220) as well as optimized constants. In 267 consecutive patients with normally functioning MP, we investigated VA within the first postoperative month. With increasing prosthetic sizes, mean VA values also increase in all calculations. The statistical curves demonstrate no significant difference in graphical steepness but show different levels. Comparison of mean VA showed the known systematic higher values of PHT220 and significantly decreased results when using CEVTI. This systematic difference between mean VA applying PHT220 versus CEVTI is approximately 1.0 cm(2) for all prosthetic sizes. Calculations via CEVpeak were close to the results of CEVTI. CEVmean produced values, which graphically correspond to the PHT220 curve. Only PHT220 detected the constructional equal prosthetic inner ring width between 29 and 31 mm. To compensate the systematic difference between CEVTI and PHT220, an optimized constant of 140 ms was calculated to be applied in PHT (PHT140). VA is a robust and, therefore, preferable parameter for investigating MP. If needed, both CE and PHT are applicable with a systematical difference between CEVTI and PHT220. An optimized constant of 140 ms (PHT140) should be applied when calculating VA of mitral valve prostheses via PHT. PMID- 26049366 TI - The involvement of c-Myc in the DNA double-strand break repair via regulating radiation-induced phosphorylation of ATM and DNA-PKcs activity. AB - Deregulation of c-Myc often occurs in various human cancers, which not only contributes to the genesis and progression of cancers but also affects the outcomes of cancer radio- or chemotherapy. In this study, we have investigated the function of c-Myc in the repair of DNA double-strand break (DSB) induced by gamma-ray irradiation. A c-Myc-silenced Hela-630 cell line was generated from HeLa cells using RNA interference technology. The DNA DSBs were detected by gamma H2AX foci, neutral comet assay and pulsed-field gel electrophoresis. We found that the capability of DNA DSB repair in Hela-630 cells was significantly reduced, and the repair kinetics of DSB was delayed as compared to the control Hela-NC cells. Silence of c-myc sensitized the cellular sensitivity to ionizing radiation. The phosphorylated c-Myc (Thr58/pSer62) formed the consistent co localisation foci with gamma-H2AX as well as the phosphorylated DNA-PKcs/S2056 in the irradiated cells. Moreover, depression of c-Myc largely attenuated the ionizing radiation-induced phosphorylation of the ataxia telangiectasia mutated (ATM) and decreased the in vitro kinase activity of DNA-PKcs. Taken together, our results demonstrated that c-Myc protein functions in the process of DNA double strand break repair, at least partially, through affecting the ATM phosphorylation and DNA-PKcs kinase activity. The overexpression of c-Myc in tumours can account for the radioresistance of some tumour cell types. PMID- 26049367 TI - Using Web-Based Technology to Promote Physical Activity in Latinas: Results of the Muevete Alabama Pilot Study. AB - Latinas in the US report high levels of physical inactivity and are disproportionally burdened by related health conditions (eg, type 2 diabetes, obesity), highlighting the need for innovative strategies to reduce these disparities. A 1-month single-arm pretest-posttest design was utilized to assess the feasibility and acceptability of a culturally and linguistically adapted Internet-based physical activity intervention for Spanish-speaking Latinas. The intervention was based on the Social Cognitive Theory and the Transtheoretical Model. Changes in physical activity and related psychosocial variables were measured at baseline and the end of the 1-month intervention. The sample included 24 Latina adults (mean age, 35.17+/-11.22 years). Most (83.3%) were born outside the continental US. Intent-to-treat analyses showed a significant increase (P=.001) in self-reported moderate- to vigorous-intensity physical activity from a median of 12.5 min/wk at baseline to 67.5 min/wk at the 1-month assessment. Participants reported significant increases in self-efficacy as well as cognitive and behavioral processes of change. Nearly half of the participants (45.8%) reported advancing at least one stage of change during the course of the 1-month intervention. Findings support the feasibility and acceptability of using interactive Internet-based technology to promote physical activity among Latinas in Alabama. PMID- 26049368 TI - Effects of insistent screening for contralateral patent processus vaginalis in laparoscopic percutaneous extraperitoneal closure to prevent metachronous contralateral onset of pediatric inguinal hernia. AB - PURPOSE: Laparoscopic percutaneous extraperitoneal closure (LPEC) is known to reduce the incidence of metachronous contralateral hernia (MCH) compared to conventional hernia repair. We herein describe the effects of insistent screening for an irregular orifice of the contralateral patent processus vaginalis (CPPV). METHODS: All patients who underwent LPEC between 2003 and 2013 were reviewed. We started insistent screening for a CPPV in July 2010. The surgically treated cases before June 2010 were assigned to the former group, while those treated after July 2010 were in the latter group. The data were retrospectively collected from medical records. The statistical analysis was performed using the Mann-Whitney U test or Chi square test. A value of P < 0.05 was considered to be significant. RESULT: A total of 1113 patients (514 males and 599 females) ranging in age from 3 months old to 15 years old (median 4.6 years old), were reviewed. Of the 626 patients in the former group, a CPPV was detected in 227 patients. Of the 487 patients in the latter group, a CPPV was detected in 271 patients. The incidence of a CPPV significantly increased over time (P < 0.001). We encountered five cases of MCH, all of which belonged to the former group (P = 0.048). CONCLUSIONS: The increased detection of a CPPV by insistent screening seemed to cause a decrease in the incidence of MCH. PMID- 26049371 TI - Diagnostic value of 18F-FDG PET/CT in paediatric neuroblastoma: comparison with 131I-MIBG scintigraphy. AB - PURPOSE: The aim of the study was to evaluate the diagnostic value of fluorine-18 fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) in paediatric patients with neuroblastoma (NB) and compare the results with iodine-131 metaiodobenzylguanidine (131I-MIBG) scintigraphy. METHODS: Data on 40 paediatric patients (age, 5.5 +/- 5.6 years; male, 32; female, eight) with histopathologically proven NB who underwent 18F-FDG PET/CT (staging, 21 patients; restaging/response monitoring, 19 patients) were retrospectively evaluated. I MIBG scintigraphy data were available for 28/40 patients (median interval, 15 days; staging, 20 patients; restaging/response monitoring, eight patients). 131I MIBG scintigraphy and 18F-FDG PET/CT images were evaluated by two nuclear medicine physicians in consensus and in separate sessions. Histopathology (n = 50 lesions) and/or clinical/imaging follow-up (n = 90 lesions) data were taken as the reference standard. RESULTS: Patient-wise sensitivity, specificity, positive predictive value, negative-predictive value and accuracy of 18F-FDG PET/CT were 100, 50, 91.89, 100 and 92.50%, respectively. A total of 140 lesions (primary, 37; lymph node, 31; bone, 50; bone marrow, 15; and others, seven) were detected on PET/CT. In 28 patients undergoing both imaging studies, the sensitivity, specificity, positive-predictive value, negative-predictive value and accuracy of 18F-FDG PET/CT were 100, 60, 92, 100 and 92.80%, respectively, and those of 131I MIBG were 95.65, 60, 91.67, 75 and 89.20%, respectively. In these 28 patients, PET/CT detected 107 lesions (primary, 25; lymph node, 22; bone/bone marrow, 56; and others, four) and 131I-MIBG scintigraphy detected 74 lesions (primary, 24; lymph node, five; and bone/bone marrow, 45). On a patient-based comparison there was no significant difference between 18F-FDG PET/CT and 131I-MIBG (P = 1.000), but 18F-FDG PET/CT was superior to 131I-MIBG on a lesion-based comparison (P < 0.0001). Although no difference was noted for primary lesions (P = 1.000), PET/CT was superior to 131I-MIBG scintigraphy for the detection of lymph nodal (P = 0.001) and bone/bone marrow lesions (P = 0.007). CONCLUSION: 18F-FDG PET/CT shows high accuracy in paediatric patients with NB and demonstrates more lesions as compared with 131I-MIBG scintigraphy. PMID- 26049370 TI - Relation of thyroid hormone abnormalities with subclinical inflammatory activity in patients with type 1 and type 2 diabetes mellitus. AB - Thyroid hormone (TH) abnormalities are common in patients with diabetes mellitus (DM). These thyroid hormone abnormalities have been associated with inflammatory activity in several conditions but this link remains unclear in DM. We assessed the influence of subclinical inflammation in TH metabolism in euthyroid diabetic patients. Cross-sectional study involving 258 subjects divided in 4 groups: 70 patients with T2DM and 55 patients with T1DM and two control groups of 70 and 63 non-diabetic individuals, respectively. Groups were paired by age, sex, and body mass index (BMI). We evaluated the association between clinical and hormonal variables [thyrotropin, reverse T3 (rT3), total and free thyroxine (T4), and triiodothyronine (T3)] with the inflammation markers C-reactive protein (hs-CRP), serum amyloid A (SAA), and interleukin-6 (IL-6). Serum T3 and free T3 were lower in patients with diabetes (all P < 0.001) compared to the control groups. Interleukin-6 showed positive correlations with rT3 in both groups (P < 0.05). IL 6 was independently associated to FT3/rT3 (B = -0.193; 95% CI -0.31; -0.076; P = 0.002) and FT4/rT3 (B = -0.107; 95% CI -0.207; -0.006; P = 0.039) in the T1DM group. In the T2DM group, SAA (B = 0.18; 95% CI 0.089; 0.271; P < 0.001) and hs CRP (B = -0.069; 95% CI -0.132; -0.007; P = 0.03) predicted FT3 levels. SAA (B = 0.16; 95% CI -0.26; -0.061; P = 0.002) and IL6 (B = 0.123; 95% CI 0.005; 0.241; P = 0.041) were related to FT4/FT3. In DM, differences in TH levels compared to non diabetic individuals were related to increased subclinical inflammatory activity and BMI. Altered deiodinase activity was probably involved. These findings were independent of sex, age, BMI, and HbA1c levels. PMID- 26049369 TI - Gene interference strategies as a new tool for the treatment of prostate cancer. AB - Prostate cancer (PCa) is one of the most common cancer in men. It affects older men and the incidence increases with age; the median age at diagnosis is 67 years. The diagnosis of PCa is essentially based on three tools: digital rectal exam, serum concentration of prostate specific antigen, and transrectal ultrasound-guided biopsy. Currently, the therapeutic treatments of this cancer are different and range from the prostatectomy to hormonal therapy, to radiation therapy, to immunotherapy, and to chemotherapy. However, additional efforts are required in order to find new weapons for the treatment of metastatic setting of disease. The purpose of this review is to highlight new therapeutic strategies based on gene interference; in fact, numerous siRNA and miRNA in the therapeutic treatment of PCa are reported below. PMID- 26049372 TI - Additional value of combining low-dose computed tomography to V/Q SPECT on a hybrid SPECT-CT camera for pulmonary embolism diagnosis. AB - OBJECTIVES: The aim of the study was to assess the potential interest of combining a low-dose computed tomography (ldCT) to ventilation/perfusion (V/Q) single-photon emission computed tomography (SPECT) for the diagnosis of pulmonary embolism (PE). We addressed three main questions: Could ldCT be used in substitution to ventilation SPECT? Could ldCT improve the diagnostic performance of V/Q SPECT? Could ldCT provide alternative diagnoses to PE? METHODS: A total of 393 patients previously analysed in a management outcome study that aimed at assessing the safety of V/Q SPECT for PE diagnosis were assessed. All patients underwent an ldCT under the same SPECT-computed tomography camera, which was not used at the time of initial interpretation. Three retrospective analyses were performed: Q SPECT combined with ldCT, V/Q SPECT combined with ldCT and ldCT only. RESULTS: On the basis of initial V/Q SPECT interpretation, 110 (28%) patients were positive and 283 (72%) were negative for PE.With Q SPECT-ldCT, 139 (35%) patients were positive and 254 (65%) were negative, with 55 (19%) discrepancies when compared with V/Q SPECT. Of the 283 patients with negative V/Q SPECT, 42 were positive with V/Q SPECT-ldCT, and among the 110 patients with positive V/Q SPECT 13 were negative with V/Q SPECT-ldCT. On using V/Q SPECT-ldCT, 97 (25%) patients were positive and 296 (75%) were negative, with 13 (3%) discrepancies when compared with V/Q SPECT (all had had a positive V/Q SPECT but a negative V/Q SPECT-ldCT). Finally, 67 (24%) ldCT scans showed a potential alternative diagnosis to PE. CONCLUSION: For PE diagnosis with lung SPECT, the use of ldCT in substitution to ventilation SPECT is associated with a high risk of overdiagnosis. The diagnostic value of ldCT in addition to V/Q SPECT remains unclear. Further studies are needed to determine its potential role in PE diagnosis. PMID- 26049373 TI - Value of 18F-FDG PET negativity and Tg suppressibility as markers of prognosis in patients with elevated Tg and 131I-negative differentiated thyroid carcinoma (TENIS syndrome). AB - AIMS: The aim of the study was to investigate the prognostic value of fluorine-18 fluorodeoxyglucose (18F-FDG) PET negativity and thyroglobulin (Tg) suppressibility in differentiated thyroid carcinoma patients with elevated Tg and a negative radioiodine scan. MATERIALS AND METHODS: The study population was selected from thyroid cancer patients registered at a large tertiary cancer care center for management and consisted of patients with metastatic thyroid cancer with elevated Tg on follow-up, negative 131I whole-body scan and negative 18F-FDG PET/computed tomography (CT) study. Patients with thyroid carcinoma were subjected to a thyroid-stimulating hormone-stimulated assessment on the basis of a 131I whole-body scan, serum Tg level and whole-body 18F-FDG PET/CT scan for evaluation of metastatic disease burden. The same patients were subjected to a follow-up evaluation of serum Tg and whole-body 18F-FDG PET/CT scan under thyroid stimulating hormone suppression while on thyroxine sodium. Comparison was also made between the findings of 18F-FDG PET/CT in patients demonstrating suppressible Tg. RESULTS: A total of 40 (25 male and 15 female) patients were included in the study. All patients had a negative whole-body 18F-FDG PET/CT study but had stimulated Tg more than 5 ng/dl (range: 5.1-> 250 ng/ml), indicating the presence of disease. The patients demonstrated variable Tg suppressibility and were classified on the basis of the extent of Tg suppressibility (%Tg suppressibility > 90% in 21 patients; %Tg suppressibility 65 90% in 12 patients; and %Tg suppressibility < 65% in five patients; and no suppressibility in two patients). 18F-FDG PET was normal in all of these patients both on stimulation and on suppression. All patients were asymptomatic during this period. No definite correlation could be established between the status of metastasis or the histopathology and suppressibility of Tg. The average follow-up data available were for more than 3 years in 26 patients (two patients had no Tg suppressibility in this group), for 1-3 years in 10 patients and for less than 1 year in four patients. At the time of analysis in this study the patients were asymptomatic during the aforementioned follow-up periods (based upon follow-up data available). CONCLUSION: In this study, we observed that 'elevated Tg but normal 18F-FDG PET' exists as a definitive entity in differentiated thyroid carcinoma. On the basis of the studied follow-up, a negative 18F-FDG PET in the setting of elevated Tg level could be regarded as a favorable prognostic indicator to predict symptom-free status during the follow-up period in this group of patients. Suppressibility of Tg (> 65%) is observed in a significant fraction of these patients, which appears to be independent of the status of metastasis or the histopathology. Also patients who show no Tg suppressibility but had a negative 18F-FDG PET/CT scan still had a better prognosis indicated by the disease-free interval in these patients as indicated in our study. Whether there exists any relation between the extent of suppressibility and their long term outcome requires to be further examined in future prospective studies. PMID- 26049374 TI - The role of bone SPECT/CT in the evaluation of painful joint prostheses. AB - OBJECTIVE: In this study, we aimed to evaluate the contribution of single-photon emission computerized tomography/computed tomography (SPECT/CT) to three-phase planar bone scintigraphy/SPECT in the assessment of aseptic and septic prosthesis loosening in patients with painful hip and knee prostheses. METHODS: Fifty patients who had undergone arthroplasties (20 hips and 30 knees) and were suspected to have complications and had undergone revision surgery were included in this study. Technetium-99m methylene diphosphonate three-phase bone scintigraphy and SPECT/CT were performed at the region of prostheses in all patients. Planar bone/SPECT and SPECT/CT images were separately assessed by two nuclear medicine physicians. SPECT/CT findings were compared with the findings of planar images/SPECT. Both planar bone scan/SPECT and SPECT/CT findings were divided into three groups: aseptic loosening, septic loosening, and miscellaneous. In all patients, scintigraphic diagnosis was confirmed by surgical findings. RESULTS: SPECT/CT changed the diagnosis and treatment plan in 8/50 (16%) patients. SPECT/CT was significantly better than planar scan/SPECT imaging for the diagnosis of aseptic and septic loosening in both joints (kappa value: 0.477 for planar scan/SPECT; kappa value: 0.717 for SPECT/CT). Moreover, both planar scan/SPECT and SPECT/CT were statistically successful in knee prostheses than in hip prostheses (kappa value: 0.271 vs. 0.579 for planar/SPECT; kappa value: 0.579 vs. 0.80 for SPECT/CT). For the hip, SPECT/CT was successful on the acetabular component than on the femoral component. For the knee, the results of SPECT/CT were similar for the femoral and tibial components. CONCLUSION: SPECT/CT increases diagnostic accuracy in the evaluation of aseptic and septic loosening in hip and knee prostheses compared with three-phase bone scintigraphy/SPECT. PMID- 26049375 TI - Anticoagulation for percutaneous coronary intervention: a contemporary review. AB - PURPOSE OF REVIEW: Optimal anticoagulation is needed to prevent ischemic complications during percutaneous coronary interventions (PCIs). The efficacy and safety of new anticoagulants to support PCI in different clinical scenarios have been evaluated in large clinical trials. This review summarizes the major issues and current practices for anticoagulation during PCI. RECENT FINDINGS: It is known that thrombotic events during PCI correlate with poor prognosis. However, the prognostic impact of bleeding is similar or even worse compared with ischemic complications. Therefore, the use of more predictable anticoagulants and safe practices in the catheterization laboratory to balance ischemia and bleeding is an important goal. Mindful of this notion, new anticoagulants with a safer profile, such as bivalirudin, have become popular to avoid bleeding. However, this paradigm shift has resulted in increased rates of acute stent thrombosis after primary PCI. SUMMARY: Individual factors associated with increased bleeding risk should be considered in the choice of anticoagulants during PCI. It is now known that the higher bleeding risk observed with heparin-based regimens can be attributed to excessive doses or concomitant use of glycoprotein IIbIIIa inhibitors. In addition to the right anticoagulant choice, operators can avoid bleeding by implementing transradial access and ultrasound-guided and fluoroscopic-guided vascular access. PMID- 26049376 TI - Antithrombotic therapy in the anticoagulated patient undergoing percutaneous coronary intervention with coronary stenting. AB - PURPOSE OF REVIEW: Despite being the subject of extensive research, the optimal antithrombotic therapy for patients on chronic oral anticoagulation (OAC) undergoing percutaneous coronary intervention (PCI) with stent implantation is still unknown. This review presents the latest data regarding this much-debated topic. RECENT FINDINGS: Dual therapy, with clopidogrel (a P2Y12 inhibitor) and OAC, may be an alternative to triple therapy, which usually consists of aspirin and clopidogrel in addition to OAC, in terms of improving clinical outcomes in patients on chronic OAC following PCI with stent implantation. With the arrival of new, safer nonvitamin K antagonists oral anticoagulants (NOACs), the combination of NOAC and clopidogrel may also be an option for replacing triple therapy. In contrast to clopidogrel, combining the more potent P2Y12 inhibitors (prasugrel and ticagrelor) with OAC may only be considered in certain specific circumstances. SUMMARY: Patients on chronic OAC undergoing PCI with stent implantation require triple therapy. However, triple therapy is controversial, because it increases the risk of bleeding. With the introduction of prasugrel, ticagrelor and NOACs, the question arises which P2Y12 inhibitor to choose as part of the triple therapy regime and how NOACs combine with antiplatelet agents when treating patients undergoing PCI. PMID- 26049377 TI - Coronary stent selection and optimal course of dual antiplatelet therapy in patients at high bleeding or thrombotic risk: navigating between limited evidence and clinical concerns. AB - PURPOSE OF REVIEW: Optimal duration of dual antiplatelet therapy (DAPT) after coronary revascularization, in particular after drug-eluting stent (DES) implantation, is a matter of ongoing debate. RECENT FINDINGS: First generation of DES, as compared with bare metal stents (BMS), reduce restenosis rates but increase very late stent thrombosis rates, thus requiring a prolonged course of DAPT. As a consequence, patients with high thrombotic and/or bleeding risk: have been systematically excluded from randomized trials comparing DES versus BMS; remain 'uncertain' DES candidates; should preferentially undergo BMS implantation at the time of percutaneous coronary intervention instead of DES. The Zotarolimus eluting Endeavor Sprint Stent in Uncertain DES Candidates (ZEUS) trial is the first randomized study that demonstrated the superiority of the Zotarolimus eluting Endeavor Sprint versus BMS in uncertain DES candidates who followed a personalized DAPT duration, which was tailored to patients's, not stent's, characteristics. SUMMARY: The results of the ZEUS trial may support a paradigm shift in our current understanding of the most proper use of DES in practice and should trigger further research in patients at high bleeding or thrombotic risk, who have been so far largely deprived of the potential benefit provided by DES. PMID- 26049379 TI - Chronic heart failure: what does the horizon look like? AB - PURPOSE OF REVIEW: This review highlights the most recent developments in the field of heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). RECENT FINDINGS: The largest trial to date in patients with HFrEF demonstrated that LCZ696, a novel combination drug of valsartan and a neprilysin inhibitor, as compared with enalapril, significantly reduced the death rates from any cause and from cardiovascular causes and the rates of hospitalizations for worsening heart failure. Both ivabradine, a novel heart rate lowering therapy, currently approved by the Food and Drug Administration (FDA), and coenzyme Q10, a powerful antioxidant, when used as adjunctive treatment in HFrEF have also been shown to be efficacious in reducing important heart failure-related cardiovascular adverse events. In contrast, clinical trials in HFpEF remain disappointing; however, the recent FDA approval of a novel pulmonary artery pressure monitoring device has the potential to reduce heart failure readmissions in patients with HFpEF or HFrEF. SUMMARY: Novel therapies including LCZ696 and ivabradine have the potential to help curb the burden of heart failure in patients with HFrEF. For now, there continues to remains no clear evidence that novel therapeutic interventions modify the natural history of HFpEF. PMID- 26049378 TI - Ethanol for the treatment of cardiac arrhythmias. AB - INTRODUCTION: Ethanol infusion was an early mode of ablative treatment for cardiac arrhythmias. Its initial descriptions involved coronary intra-arterial delivery, targeting arrhythmogenic substrates in drug-refractory ventricular tachycardia or the atrioventricular node. Largely superseded by radiofrequency ablation (RFA) and other contact-based technologies as a routine ablation strategy, intracoronary arterial ethanol infusion remains as an alternative option in the treatment of ventricular tachycardia when conventional ablation fails. Arrhythmic foci that are deep-seated in the myocardium may not be amenable to catheter ablation from either the endocardium or the epicardium by RFA, but they can be targeted by an ethanol infusion. RECENT FINDINGS: Recently, we have explored ethanol injection through cardiac venous systems, in order to avoid the risks of complications and limitations of coronary arterial instrumentation. Vein of Marshall ethanol infusion is being studied as an adjunctive procedure in ablation of atrial fibrillation, and coronary venous ethanol infusion for ventricular tachycardia. CONCLUSION: Ethanol ablation remains useful as a bail out technique for refractory cases to RFA, or as an adjunctive therapy that may improve the efficacy of catheter ablation procedures. PMID- 26049380 TI - Re-infarction after primary percutaneous coronary intervention. AB - PURPOSE OF REVIEW: Thrombus formation, usually on a ruptured atherosclerotic plaque, is pivotal in the pathogenesis of ST segment elevation myocardial infarction (STEMI). This thrombus formation provides the milieu for re-occlusion of the infarct-related artery, the main location of re-infarction post-STEMI. Although rates of re-infarction are lower after reperfusion by primary percutaneous coronary intervention (PCI) than after fibrinolytic therapy, re infarction remains a major cause of morbidity and mortality. RECENT FINDINGS: The predominant cause of re-infarction after primary PCI is stent thrombosis. Two recent trials [A Prospective, Randomized Trial of Ambulance Initiation of Bivalirudin vs. Heparin +/- Glycoprotein IIb/IIIa Inhibitors in Patients with STEMI Undergoing Primary PCI (EUROMAX) and Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI)] have each reported higher rates of stent thrombosis in the first 24 h after primary PCI in patients assigned to receive bivalirudin, which affects the balance of risks and benefit of bivalirudin post-STEMI. Also, in a subanalysis of the Platelet Inhibition And Patient Outcomes trial, ticagrelor reduces re-infarction compared with clopidogrel in patients with STEMI after primary PCI. Other nonpharmacological or mechanical interventions during primary PCI, with the exception of newer-generation drug-eluting stents in the Swedish Coronary Angiography and Angioplasty Registry, have not affected rates of re-infarction. SUMMARY: Re-infarction remains a major cause of morbidity and mortality. Re infarction rates are altered by pharmacological strategy and stent selection in primary PCI. The design of future trials to detect possible treatment differences in relatively low event rates will provide challenges, and may require more novel strategies such as administrative data collection for patient characteristics and key outcomes. PMID- 26049381 TI - Misconceptions and facts about treating hypertension. PMID- 26049383 TI - Thiazides in advanced chronic kidney disease: time for a randomized controlled trial. AB - PURPOSE OF REVIEW: Chronic kidney disease is common, associated with increased cardiovascular risk, and frequently complicated by hypertension, requiring multiple agents for control. Thiazides are naturally attractive for use in this population; unfortunately, they are classically thought to be ineffective in advanced chronic kidney disease based on both theoretical considerations and the earliest studies of these agents. This report reviews the studies of thiazide use in chronic kidney disease since the 1970s, including five randomized controlled trials, all of which report at least some degree of efficacy. RECENT FINDINGS: Two recent studies add further evidence for the utility and efficacy of thiazides in chronic kidney disease. Of these two, one used gold standard ambulatory blood pressure monitoring in patients with poorly controlled hypertension and advanced chronic kidney disease and found chlorthalidone reduces blood pressure. The second is the largest study to date of thiazides in chronic kidney disease; adding a fixed low-dose chlorthalidone as the first diuretic to the antihypertensive regimen improved blood pressure. SUMMARY: These numerous small but positive studies reinforce the need for a randomized trial to demonstrate safety and efficacy of thiazides in advanced chronic kidney disease. PMID- 26049382 TI - Hydrochlorothiazide is not the most useful nor versatile thiazide diuretic. AB - PURPOSE OF REVIEW: To determine usefulness and versatility of hydrochlorothiazide (HCTZ) relative to other thiazide diuretics in the treatment of hypertension. RECENT FINDINGS: HCTZ was found to be less potent in lowering blood pressure (BP) than other thiazide diuretics, including chlorthalidone (CTD) and bendroflumethiazide. A recent meta-analysis also suggested HCTZ (12.5-25 mg daily) to be less potent than antihypertensive agents from several other classes, including angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and calcium antagonists. The risk of hyponatremia, hypokalemia, and hyperuricemia associated with HCTZ was lower than with CTD, while the risk of gouty arthritis was similar. Despite lower risks of metabolic side-effects, meta analysis of clinical trials showed that, for any given difference in achieved clinic SBP, HCTZ therapy was associated with 18% higher adverse cardiovascular events when compared with CTD. SUMMARY: Increasing evidence suggests inferiority of HCTZ in lowering BP and cardiovascular outcomes in hypertensive patients when compared with other drugs in the same class, particularly CTD and indapamide. Thus, HCTZ is neither more useful nor more versatile than other thiazide diuretics. CTD and indapamide should be preferred over HCTZ in most hypertensive patients when diuretics are required for treatment of hypertension. PMID- 26049384 TI - Dual renin-angiotensin system blockade and outcome benefits in hypertension: a narrative review. AB - PURPOSE OF REVIEW: Inhibition of the renin-angiotensin system (RASi) lowers blood pressure, reduces cardiovascular outcomes and blunts the progressive course of heart failure and of chronic kidney disease. This narrative article summarizes why the hypothesis came up that more complete RASi with two different agents should be more beneficial compared with one agent and how this hypothesis was deflated in randomized clinical trials (RCTs). RECENT FINDINGS: The hypothesis was based on experimental findings and surrogate endpoints in patients, namely lowering of blood pressure and reduction of proteinuria. Three large RCTs in patients with atherosclerotic vascular disease or in diabetic kidney disease randomized almost 40, 000 patients. RASi with one agent was compared with RASi with two agents. All three RCTs ruled out benefits of dual RASi on major cardiovascular outcomes and reported substantial adverse effects of dual RASi. The latter included hyperkalemia, acute kidney injury, symptomatic hypotension and syncope. There was also no substantial advantage of dual over monotherapy on decline in kidney function. In one RCT, there was a hint of nonsustained, early benefit on kidney outcomes with dual therapy. SUMMARY: Outside heart failure, RASi with two agents is not indicated to treat hypertension because of substantial safety concerns and lack of benefit on major cardiovascular and kidney outcomes. PMID- 26049385 TI - The lower the achieved blood pressure goal the better. AB - PURPOSE OF REVIEW: Hypertension is the eminent risk factor for renal and cardiovascular disease (CVD). Its management is a topic of public health priority. As either too high or too low blood pressure (BP) levels can have detrimental effects on health, optimal targets for BP continue to be controversial. The current manuscript will review relevant data published over the last year that add to this topic of controversy. RECENT FINDINGS: Recent studies confirm increased CVD-related risk with increasing SBP levels more than 140 mmHg among patients with hypertension and CVD as well as those over the age of 60 years. A SBP target less than 140 mmHg conveyed lessened risk of CVD related events. There is some evidence suggesting that the ideal BP target lies between 120 and 140 mmHg. SUMMARY: Recent data support a target SBP of less than 140 mmHg among patients with hypertension or CVD, and achievement of this target might benefit those older than 60 years of age as well. Treating to SBPs below 120 mmHg may not result in further benefit. Data from randomized controlled trials specifically addressing the question whether lower BPs are associated with better outcomes are needed to further define ideal BP-target goals. PMID- 26049386 TI - Antihypertensive therapy causes erectile dysfunction. AB - PURPOSE OF REVIEW: Erectile dysfunction is a common sexual disorder affecting 40% of men in the United States. However, the pathophysiologic mechanism involved in the causation of erectile dysfunction is multifactorial and not well delineated. RECENT FINDINGS: Several recent studies disclose that erectile dysfunction is the result of multiple interrelated comorbid conditions that include hypertension, coronary artery disease (CAD), heart failure, and diabetes mellitus among them. In addition to comorbid conditions, certain cardiovascular and antihypertensive drugs are also involved in the development of erectile dysfunction, with the most prominent being the thiazide type diuretics, the aldosterone receptor blockers, and the beta-adrenergic receptor blockers. Also, knowledge by the patient of the drug and its action on erectile dysfunction may increase the incidence of erectile dysfunction (Hawthorn effect). Before treatment is initiated, patients should be screened for the presence of erectile dysfunction, because this condition is associated with hypertension, CAD, heart failure, diabetes mellitus, and their treatment and an appropriate treatment regimen should be selected. If that fails, the addition of phosphodiesterase 5 inhibitors to the treatment regimen is recommended. The only exception is a patient with CAD treated with organic nitrates, in which the coadministration of phosphodiesterase 5 inhibitors is strictly prohibited. SUMMARY: Knowledge of the various comorbid conditions and their treatment associated with the development of erectile dysfunction will help the caring physician to treat his patients appropriately and safely. All these aspects will be discussed in this review. PMID- 26049387 TI - Feto-maternal interactions: a possible clue to explain the 'missed heritability' in arterial hypertension. PMID- 26049388 TI - Fetal programming and epigenetic mechanisms in arterial hypertension. AB - PURPOSE OF REVIEW: To provide an overview of available evidence of the potential role of epigenetics in the pathogenesis of hypertension and vascular dysfunction. RECENT FINDINGS: Arterial hypertension is a highly heritable condition. Surprisingly, however, genetic variants only explain a tiny fraction of the phenotypic variation and the term 'missing heritability' has been coined to describe this phenomenon. Recent evidence suggests that phenotypic alteration that is unrelated to changes in DNA sequence (thereby escaping detection by classic genetic methodology) offers a potential explanation. Here, we present some basic information on epigenetics and review recent work consistent with the hypothesis of epigenetically induced arterial hypertension. SUMMARY: New technologies that enable the rigorous assessment of epigenetic changes and their phenotypic consequences may provide the basis for explaining the missing heritability of arterial hypertension and offer new possibilities for treatment and/or prevention. PMID- 26049389 TI - Birth weight and arterial hypertension. AB - PURPOSE OF REVIEW: To provide an overview of available evidence of the relationship between birth weight and future hypertension development. RECENT FINDINGS: Fetal programming plays a significant role in future hypertension. Both low and high birth weight are able to influence weight gain during childhood, adult weight and blood pressure values during childhood and adulthood. To date, an increasing amount of evidence is available especially for the relationship between low birth weight and hypertension, supported also by pathophysiological studies. SUMMARY: In the era of personalized medicine, the possibility to reduce cardiovascular risk before or soon after birth and intervene on risk factors during childhood is appealing and promising for the future. PMID- 26049390 TI - Arterial hypertension in children. AB - PURPOSE OF REVIEW: Although arterial hypertension is less common in children than in adults, there is growing concern about elevated blood pressure (BP) in children and adolescents not only because of the association of elevated values with the overweight epidemic, but also as cardiovascular functions are determined in childhood and track into adulthood. The purpose of the review is to discuss new aspects of childhood hypertension. RECENT FINDINGS: Guidelines advocate determining BP in children as part of routine health maintenance. This recommendation was recently subject to review by the US Preventive Services Task Force. It was concluded that evidence is insufficient to assess the benefits of this screening. In our opinion, however, assessing BP is part of any thorough physical examination.Sophisticated approaches demonstrate the role of sympathetic nervous system overdrive in the field of sympathetic cardiovascular modulation of childhood arterial hypertension. SUMMARY: Elevated BP in children is increasing in frequency and is now recognized as having relevant short-term and long-term consequences. Although efforts to address the childhood overweight epidemic may eventually reduce the number of young patients with hypertension, improved therapies for childhood hypertension also offer the potential for preventing or ameliorating early cardiovascular disease. PMID- 26049391 TI - Hypertension in pregnancy. AB - PURPOSE OF REVIEW: Hypertension in pregnancy contributes substantially to perinatal mortality and morbidity of both the mother and her child. High blood pressure is mainly responsible for this adverse outcome, in particular when associated with preeclampsia. Although preeclampsia is nowadays a well-known clinical-obstetrical entity, and screening for this complication has been part of routine care during pregnancy for nearly 100 years, its cause is still enigmatic. RECENT FINDINGS: Profound changes of the demographic development of our society, the worldwide rising prevalence of obesity and metabolic disorders, and progress in reproductive medicine will inevitably modify the prevalence of many medical problems in pregnancy. Complications such as gestational diabetes mellitus, chronic hypertension, and preeclampsia will rise and an interdisciplinary approach is necessary to handle these women during pregnancy and also after delivery. Indeed, it is now well established that these women and their offspring born large or small-for-gestational age are at increased risk for severe cardiovascular and metabolic complications later in life. SUMMARY: Knowledge of the pregnancy course is not only important for an obstetrician but also increasingly inevitable for the general practitioner. Recognition, classification, and adequate management of hypertensive pregnancy disorders and associated complications may considerably reduce perinatal death and morbidity. PMID- 26049392 TI - Erectile dysfunction and coronary heart disease. AB - PURPOSE OF REVIEW: This narrative review discusses the associations of erectile dysfunction with coronary heart disease (CHD) morbidity and mortality, all-cause death and CHD risk factors. Treatment strategies for erectile dysfunction are also mentioned. RECENT FINDINGS: Erectile dysfunction shares common pathways and risk factors with vascular diseases. Erectile dysfunction has been reported to independently predict CHD events, thus highlighting its role as a marker of early atherosclerosis. Erectile dysfunction prevalence may be followed by the presentation of CHD symptoms in 2-3 years, and a CHD event may occur in 3-5 years. Furthermore, erectile dysfunction has been associated with stroke, peripheral artery disease, diabetes and chronic kidney disease as well as with several CHD risk factors including hypertension, dyslipidaemia, smoking, obesity, metabolic syndrome, hyperuricaemia, arterial stiffness and obstructive sleep apnea syndrome. On the basis of these data, erectile dysfunction may be regarded as a part of polyvascular disease. SUMMARY: Patients with erectile dysfunction are at an increased risk for CHD morbidity and/or mortality as well as for all cause death. Clinicians should monitor patients with erectile dysfunction by assessing their vascular risk and preventing or adequately treating CHD risk factors. In this context, lifestyle interventions should be recommended in addition to drug treatment to attain better outcomes. PMID- 26049393 TI - Arterial stiffness and coronary artery disease. AB - PURPOSE OF REVIEW: The current traditional risk scores are not sufficient to predict the full incidence of cardiovascular disease. In this brief review, we discuss the pathophysiological mechanisms through which arterial stiffness affects cardiac function and the additive value of markers of arterial stiffness, to detect the presence of coronary artery disease (CAD) and predict adverse outcome in these patients. RECENT FINDINGS: Arterial stiffness causes early arrival of wave reflections in systole instead of diastole and, thus, increases systolic afterload and reduces diastolic coronary perfusion pressure. Abnormal collagen turnover, cytokines, and metalloproteinase activity are common biochemical links between vascular and myocardial stiffness. Pulse wave velocity, augmentation index, and central pressures measured by simple noninvasive methods are related to atheromatic plaque vulnerability, incidence, severity, and extent of CAD. Recent meta-analyses have shown the additive value of markers of arterial stiffness, and particularly of pulse wave velocity, to detect CAD, predict cardiovascular events, and reclassify patients to a higher cardiovascular risk. Studies assessing whether reduction of arterial stiffness is associated with improved prognosis are lacking. SUMMARY: Markers of arterial stiffness are useful tools to identify early atherosclerosis and adverse clinical outcomes in young adults and individuals with a modest risk factor profile. Assessing arterial stiffness may facilitate cardiovascular risk stratification beyond traditional risk scores. PMID- 26049394 TI - The relationship between obstructive sleep apnoea and coronary heart disease. AB - PURPOSE OF REVIEW: Recent studies have provided evidence that severe obstructive sleep apnoea (OSA) may warrant inclusion in the list of coronary heart disease (CHD) equivalents. RECENT FINDINGS: Data within the past 12 months provide insight into complex issues. Specifically, OSA was shown to play an important role in the development of inflammation and atherosclerosis, but its effects on endothelial dysfunction were equivocal. Continuous positive airway pressure (CPAP) treatment was linked with significant improvements in heart function, blood pressure and total cholesterol, but the effect was not always the most significant. SUMMARY: At present, caution is warranted in the interpretation of results. In the future, data from randomized controlled trials with longer duration are expected to shed more light on the relationship between CHD and OSA and on what can be expected from CPAP regarding CHD risk factors. PMID- 26049395 TI - New worldwide lipid guidelines. AB - PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in most countries. Modification of common risk factors such as dyslipidaemia can result in significant reduction of ASCVD incidence in the population and improve clinical outcomes. The purpose of this review is to discuss and compare the latest worldwide lipid guidelines, and to demonstrate the variation in practice in different parts of the world. RECENT FINDINGS: The lipid guidelines have recently been updated in different countries. The National Institute for Health and Care Excellence (NICE) guidelines in the United Kingdom were issued in July 2014, are risk based and are broadly similar to the American College of Cardiology/American Heart Association task force guidelines that were published in November 2013. Both these guidelines are in variance with both the Canadian Guidelines and the European Society of Cardiology/European Atherosclerosis Society guidelines 2011, which are target based and have different risk scoring systems, which results in significant variation in practice and increased healthcare costs in certain countries. SUMMARY: The difference in guidelines in different countries makes it difficult for the clinician to standardize the treatment provided to individuals. The variance in risk scoring systems makes it difficult to compare risk prediction tools across countries and hence the optimum treatment available for a given population. Standardization of guidelines based on randomized controlled trial data and validation and calibration of various risk scoring systems could help improve clinical outcomes in this high-risk group of individuals at risk of ASCVD within individual countries. PMID- 26049396 TI - Renal biomarkers for the prediction of cardiovascular disease. AB - PURPOSE OF REVIEW: Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular disease (CVD). Renal biomarkers might be valuable in predicting CVD. Investigation of these biomarkers may uncover some of the poorly understood mechanisms that link renal and CVD as well as aid in the modification of disease and serve as a useful tool in diagnosing early disease and monitoring therapeutic responses. In this review we discuss the clinical utility of emerging and known renal biomarkers in predicting CVD. RECENT FINDINGS: Prior to adopting a biomarker into routine clinical practice, evidence-based laboratory medicine requires optimal technical and analytical performance, which is a prerequisite to have confidence in the result. Furthermore, an ideal biomarker should have evidence of its utility in predicting clinical, therapeutic and other health outcomes as well as proving its organizational impact and cost-effectiveness. The renal biomarkers that have been associated with CVD include cystatin C as a better marker of glomerular filtration than creatinine, albuminuria, neutrophil gelatinase associated lipocalin, a marker of acute kidney injury, fibroblast growth factor-23 and parathyroid hormone. Only urine albumin has been adopted into routine clinical practice. SUMMARY: Of all the renal biomarkers, only albumin is clearly associated with CVD. The other biomarkers are earlier in clinical development and the evidence base for their clinical utility needs to be expanded substantially before they can be adopted into routine practice. PMID- 26049398 TI - Anticancer Effect and Apoptosis Induction of Gambogic Acid in Human Leukemia Cell Line K562 In Vitro. AB - BACKGROUND: The aim of this study was to investigate the anticancer effect and related mechanisms of gambogic acid (GA), a traditional Chinese medicine, on human leukemia cell line K562, together with the effect on bone marrow mononuclear cells (MNCs). MATERIAL AND METHODS: K562 cells and MNCs were treated with various concentrations and treatment times of GA. Inhibitory rate was detected by use of the Cell Counting Kit-8 (CCK-8) assay. Apoptosis was analyzed by morphological detection, Annexin-V/PI doubling staining, and TUNEL assays. The expression changes of pivotal proteins were evaluated by Western blotting. RESULTS: GA not only suppressed cell proliferation, but also induced apoptosis of K562 cells in a dose-dependent manner. While it did not significantly inhibit cell proliferation of MNCs, it did induce apoptosis in a dose-dependent manner. CCK-8 assay revealed that the proliferation of K562 cells was significantly inhibited when the concentration of GA was more than 0.5 MUM. Morphological detection showed the nuclei became denser and more intense orange in K562 cells after GA treatment compared with the untreated group. The expression levels of BCL-2, nuclear factor-kappaB (NF-kappaB), c-myc, phosphatidylinositol3-kinase (PI3K), and phosphorylation of serine-threonine kinase (p-AKT) were down regulated by GA. CONCLUSIONS: GA significantly suppressed the proliferation of K562 cells, but has less effect on MNCs. The inhibition of K562 cells proliferation and apoptosis induced by GA might be related to the down-regulation of BCL-2, NF-kappaB, c-myc, PI3K, and p-AKT. PMID- 26049399 TI - Delta cell death in the islet of Langerhans and the progression from normal glucose tolerance to type 2 diabetes in non-human primates (baboon, Papio hamadryas). AB - AIMS/HYPOTHESIS: The cellular composition of the islet of Langerhans is essential to ensure its physiological function. Morphophysiological islet abnormalities are present in type 2 diabetes but the relationship between fasting plasma glucose (FPG) and islet cell composition, particularly the role of delta cells, is unknown. We explored these questions in pancreases from baboons (Papio hamadryas) with FPG ranging from normal to type 2 diabetic values. METHODS: We measured the volumes of alpha, beta and delta cells and amyloid in pancreatic islets of 40 baboons (Group 1 [G1]: FPG < 4.44 mmol/l [n = 10]; G2: FPG = 4.44-5.26 mmol/l [n = 9]; G3: FPG = 5.27-6.94 mmol/l [n = 9]; G4: FPG > 6.94 mmol/l [n = 12]) and correlated islet composition with metabolic and hormonal variables. We also performed confocal microscopy including TUNEL, caspase-3, and anti-caspase cleavage product of cytokeratin 18 (M30) immunostaining, electron microscopy, and immuno-electron microscopy with anti-somatostatin antibodies in baboon pancreases. RESULTS: Amyloidosis preceded the decrease in beta cell volume. Alpha cell volume increased ~ 50% in G3 and G4 (p < 0.05), while delta cell volume decreased in these groups by 31% and 39%, respectively (p < 0.05). In G4, glucagon levels were higher, while insulin and HOMA index of beta cell function were lower than in the other groups. Immunostaining of G4 pancreatic sections with TUNEL, caspase-3 and M30 showed apoptosis of beta and delta cells, which was also confirmed by immuno-electron microscopy with anti-somatostatin antibodies. CONCLUSIONS/INTERPRETATION: In diabetic baboons, changes in islet composition correlate with amyloid deposition, with increased alpha cell and decreased beta and delta cell volume and number due to apoptosis. These data argue for an important role of delta cells in type 2 diabetes. PMID- 26049400 TI - A systems view of type 2 diabetes-associated metabolic perturbations in saliva, blood and urine at different timescales of glycaemic control. AB - AIMS/HYPOTHESIS: Metabolomics has opened new avenues for studying metabolic alterations in type 2 diabetes. While many urine and blood metabolites have been associated individually with diabetes, a complete systems view analysis of metabolic dysregulations across multiple biofluids and over varying timescales of glycaemic control is still lacking. METHODS: Here we report a broad metabolomics study in a clinical setting, covering 2,178 metabolite measures in saliva, blood plasma and urine from 188 individuals with diabetes and 181 controls of Arab and Asian descent. Using multivariate linear regression we identified metabolites associated with diabetes and markers of acute, short-term and long-term glycaemic control. RESULTS: Ninety-four metabolite associations with diabetes were identified at a Bonferroni level of significance (p < 2.3 * 10(-5)), 16 of which have never been reported. Sixty-five of these diabetes-associated metabolites were associated with at least one marker of glycaemic control in the diabetes group. Using Gaussian graphical modelling, we constructed a metabolic network that links diabetes-associated metabolites from three biofluids across three different timescales of glycaemic control. CONCLUSIONS/INTERPRETATION: Our study reveals a complex network of biochemical dysregulation involving metabolites from different pathways of diabetes pathology, and provides a reference framework for future diabetes studies with metabolic endpoints. PMID- 26049401 TI - Fructose and uric acid in diabetic nephropathy. AB - Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury. PMID- 26049402 TI - Contribution of brown adipose tissue activity to the control of energy balance by GLP-1 receptor signalling in mice. AB - AIMS/HYPOTHESIS: We assessed the contribution of glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) signalling to thermogenesis induced by high-fat diet (HFD) consumption. Furthermore, we determined whether brown adipose tissue (BAT) activity contributes to weight loss induced by chronic subcutaneous treatment with the GLP-1R agonist, liraglutide, in a model of diet-induced obesity. METHODS: Metabolic phenotyping was performed using indirect calorimetry in wild type (WT) and Glp1r-knockout (KO) mice during chow and HFD feeding at room temperature and at thermoneutrality. In a separate study, we investigated the contribution of BAT thermogenic capacity to the weight lowering effect induced by GLP-1 mimetics by administering liraglutide (10 or 30 nmol kg(-1) day(-1) s.c.) to diet-induced obese (DIO) mice for 6 or 4 weeks, respectively. In both studies, animals were subjected to a noradrenaline (norepinephrine)-stimulated oxygen consumption [Formula: see text] test. RESULTS: At thermoneutrality, HFD-fed Glp1r KO mice had similar energy expenditure (EE) compared with HFD-fed WT controls. However, HFD-fed Glp1r-KO mice exhibited relatively less EE when housed at a cooler standard room temperature, and had relatively lower [Formula: see text] in response to a noradrenaline challenge, which is consistent with impaired BAT thermogenic capacity. In contrast to the loss of function model, chronic peripheral liraglutide treatment did not increase BAT activity as determined by noradrenaline-stimulated [Formula: see text] and BAT gene expression. CONCLUSIONS/INTERPRETATION: These data suggest that although endogenous GLP-1R signalling contributes to increased BAT thermogenesis, this mechanism does not play a significant role in the food intake-independent body weight lowering effect of the GLP-1 mimetic liraglutide in DIO mice. PMID- 26049403 TI - The loss-of-function PCSK9 p.R46L genetic variant does not alter glucose homeostasis. AB - AIMS/HYPOTHESIS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of cholesterol homeostasis. PCSK9 inhibitors are being actively developed to lower LDL-cholesterol levels. However, there are conflicting data regarding the consequences of Pcsk9 deficiency on glucose homeostasis in mouse models. Here, we analysed in humans the association between the PCSK9 p.R46L loss-of-function (LOF) variant and (1) glucose homeostasis variables; (2) type 2 diabetes status; and (3) the risk of 9 year incident type 2 diabetes in a prospective study. METHODS: PCSK9 p.R46L was genotyped in 4630 French participants from the Data from an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study and in 1342 French participants with type 2 diabetes. The association between p.R46L and metabolic traits or type 2 diabetes risk was assessed through linear or logistic regression models adjusted for age, sex and BMI. The association between p.R46L and incident type 2 diabetes was assessed using a Cox regression model adjusted for sex, age and BMI at baseline. RESULTS: Significant associations (p < 10(-6)) were found between p.R46L and lower total cholesterol (-0.394 mmol/l), LDL-cholesterol (-0.393 mmol/l) and apolipoprotein B concentrations (-0.099 g/l). However, no significant association was observed between p.R46L and markers of glucose homeostasis (including fasting glucose, fasting insulin, HbA1c, HOMA-B, HOMA-IR) or type 2 diabetes risk. Furthermore, no significant association between p.R46L variant and risk of incident type 2 diabetes was observed in DESIR. CONCLUSIONS/INTERPRETATION: The PCSK9 p.R46L LOF variant was not associated with impaired glucose homeostasis in humans. These data are reassuring regarding the safety of PCSK9 inhibitors. PMID- 26049404 TI - Mouth rinsing and ingestion of a bitter-tasting solution increases corticomotor excitability in male competitive cyclists. AB - PURPOSE: Recently, we have shown that the combination of mouth rinsing and ingesting a bitter-tasting quinine solution immediately prior to the performance of a maximal 30-s cycling sprint significantly improves mean and peak power output. This ergogenic effect was proposed to be related to the activation of the corticomotor pathway by afferent taste signals originating from bitter taste receptors in the oral cavity. The aim of the present study was to use single pulse transcranial magnetic stimulation to investigate whether mouth rinsing and ingestion of a bitter quinine solution increases corticomotor excitability. METHODS: A series of 10 motor-evoked potentials (MEPs) were recorded from the relaxed first dorsal interosseus muscle in 16 male competitive cyclists immediately before and after they rinsed their mouth for 10 s and then ingested either a 2 mM bitter quinine solution or plain water. RESULTS: Mean MEP amplitude was significantly increased in response to quinine administration by 16% (p < 0.05), with no evidence of a time-dependent effect over the 10 pulses. Mean MEP amplitude also increased by 10% in response to water administration (p < 0.05), though this increase was significantly smaller than the response to quinine (p < 0.05). CONCLUSIONS: We conclude that the activation of bitter taste receptors in the oral cavity and upper gastrointestinal tract has the capacity to increase corticomotor excitability in male competitive cyclists. PMID- 26049405 TI - A new prognostic model for chemotherapy-induced febrile neutropenia. AB - BACKGROUND: The objective of this study was to develop and validate a new prognostic model for febrile neutropenia (FN). METHODS: This study comprised 1001 episodes of FN: 718 for the derivation set and 283 for the validation set. Multivariate logistic regression analysis was performed with unfavorable outcome as the primary endpoint and bacteremia as the secondary endpoint. RESULTS: In the derivation set, risk factors for adverse outcomes comprised age >= 60 years (2 points), procalcitonin >= 0.5 ng/mL (5 points), ECOG performance score >= 2 (2 points), oral mucositis grade >= 3 (3 points), systolic blood pressure <90 mmHg (3 points), and respiratory rate >= 24 breaths/min (3 points). The model stratified patients into three severity classes, with adverse event rates of 6.0 % in class I (score <= 2), 27.3 % in class II (score 3-8), and 67.9 % in class III (score >= 9). Bacteremia was present in 1.1, 11.5, and 29.8 % of patients in class I, II, and III, respectively. The outcomes of the validation set were similar in each risk class. When the derivation and validation sets were integrated, unfavorable outcomes occurred in 5.9 % of the low-risk group classified by the new prognostic model and in 12.2 % classified by the Multinational Association for Supportive Care in Cancer (MASCC) risk index. CONCLUSIONS: With the new prognostic model, we can classify patients with FN into three classes of increasing adverse outcomes and bacteremia. Early discharge would be possible for class I patients, short-term observation could safely manage class II patients, and inpatient admission is warranted for class III patients. PMID- 26049406 TI - Enhanced binding capability of nuclear factor-kappaB with demethylated P2X3 receptor gene contributes to cancer pain in rats. AB - Nuclear factor-kappa B (NF-kappaB) signaling is implicated in both cancer development and inflammation processes. However, the roles and mechanisms of NF kappaB signaling in the development of cancer-induced pain (CIP) remain unknown. This study was designed to investigate the roles of the p65 subunit of NF-kappaB in regulation of the purinergic receptor (P2X3R) plasticity in dorsal root ganglion (DRG) of CIP rats. We showed here that tumor cell injection produced mechanical and thermal hyperalgesia, and an enhanced body weight-bearing difference, which was correlated with an upregulation of p65 and P2X3R expression in lumber DRGs and a potentiation of ATP-evoked responses of tibia-innervating DRG neurons. Inhibition of NF-kappaB signaling using p65 inhibitor pyrrolidine dithiocarbamate, BAY-11-7082, or lentiviral-p65 short-hairpin RNA significantly attenuated CIP and reversed the activities of P2X3R. Interestingly, tumor cell injection led to a significant demethylation of CpG island in p2x3r gene promoter and enhanced ability of p65 to bind the promoter of p2x3r gene. Our findings suggest that upregulation of P2X3R expression was mediated by the enhanced binding capability of p65 with demethylated promoter of p2x3r gene, thus contributing to CIP. NF-kappaBp65 might be a potential target for treating CIP, a neuropathic pain generated by tumor cell-induced injury to nerves that innervate the skin. PMID- 26049408 TI - CACNA1C gene and schizophrenia: a case-control and pharmacogenetic study. AB - AIM: The present study aimed to explore whether 24 single nucleotide polymorphisms (SNPs) within the CACNA1C gene were associated with schizophrenia (SCZ) and antipsychotic response. METHODS: A sample of 176 SCZ inpatients and 326 healthy controls of Korean ethnicity was collected for this purpose. Psychopathological status was evaluated at baseline and at discharge using the Positive and Negative Syndrome Scale (PANSS). RESULTS: In the case-control study, rs1006737 (P=0.05) and rs2239104 (P=0.03) were associated with SCZ. Further, the rs10848635-rs1016388-rs1006737 haplotype was also associated with SCZ (P=0.03, simulate P=0.02). In the pharmacogenetic analyses, we did not find any association among the investigated SNPs and improvement in the PANSS total score. However, rs723672 and rs1034936 were associated with improvement in the PANSS positive subscale (respectively, P=0.02 and 0.05), rs2283271 in the negative subscale (P=0.01), rs10848635 and rs1016388 in the general subscale (respectively, P=0.03 and 0.04), and the rs3819536-rs2238062 haplotype (global statistics, P=0.1; simulate P=0.04). CONCLUSIONS: Our findings further support a role for the CACNA1C gene, particularly for the rs1006737, in SCZ. Further, five SNPs were associated with improvement in PANSS subscales, suggesting a role for this gene in antipsychotic response as well. However, taking into account the limitations of the present study, further research is needed to confirm our findings. PMID- 26049407 TI - Modeling of the redox state dynamics in photosystem II of Chlorella pyrenoidosa Chick cells and leaves of spinach and Arabidopsis thaliana from single flash induced fluorescence quantum yield changes on the 100 ns-10 s time scale. AB - The time courses of the photosystem II (PSII) redox states were analyzed with a model scheme supposing a fraction of 11-25 % semiquinone (with reduced [Formula: see text]) RCs in the dark. Patterns of single flash-induced transient fluorescence yield (SFITFY) measured for leaves (spinach and Arabidopsis (A.) thaliana) and the thermophilic alga Chlorella (C.) pyrenoidosa Chick (Steffen et al. Biochemistry 44:3123-3132, 2005; Belyaeva et al. Photosynth Res 98:105-119, 2008, Plant Physiol Biochem 77:49-59, 2014) were fitted with the PSII model. The simulations show that at high-light conditions the flash generated triplet carotenoid (3)Car(t) population is the main NPQ regulator decaying in the time interval of 6-8 MUs. So the SFITFY increase up to the maximum level [Formula: see text]/F 0 (at ~50 MUs) depends mainly on the flash energy. Transient electron redistributions on the RC redox cofactors were displayed to explain the SFITFY measured by weak light pulses during the PSII relaxation by electron transfer (ET) steps and coupled proton transfer on both the donor and the acceptor side of the PSII. The contribution of non-radiative charge recombination was taken into account. Analytical expressions for the laser flash, the (3)Car(t) decay and the work of the water-oxidizing complex (WOC) were used to improve the modeled P680(+) reduction by YZ in the state S 1 of the WOC. All parameter values were compared between spinach, A. thaliana leaves and C. pyrenoidosa alga cells and at different laser flash energies. ET from [Formula: see text] slower in alga as compared to leaf samples was elucidated by the dynamics of [Formula: see text] fractions to fit SFITFY data. Low membrane energization after the 10 ns single turnover flash was modeled: the ?Psi(t) amplitude (20 mV) is found to be about 5 fold smaller than under the continuous light induction; the time-independent lumen pHL, stroma pHS are fitted close to dark estimates. Depending on the flash energy used at 1.4, 4, 100 % the pHS in stroma is fitted to 7.3, 7.4, and 7.7, respectively. The biggest ?pH difference between stroma and lumen was found to be 1.2, thus pH- dependent NPQ was not considered. PMID- 26049409 TI - A genome-wide association study of late-onset Alzheimer's disease in a Japanese population. AB - OBJECTIVE: Although a number of genome-wide association studies (GWASs) of late onset Alzheimer's disease (LOAD) have been carried out, there have been little GWAS data on East Asian populations. DESIGN: To discover the novel susceptibility loci of LOAD, we carried out a GWAS using 816 LOAD cases and 7992 controls with a replication analysis using an independent panel of 1011 LOAD cases and 7212 controls in a Japanese population. In addition, we carried out a stratified analysis by APOE-epsilon4 status to eliminate the established effect of APOE region. RESULTS: Our data indicated that 18p11.32 (rs1992269, P = 9.77 * 10(-7)), CNTNAP2 (rs802571, P = 1.26 * 10(-6)), and 12q24.23 (rs11613092, P = 6.85 * 10( 6)) were suggestive loci for susceptibility to LOAD. CONCLUSION: We identified three suggestive loci for susceptibility to LOAD in a Japanese population. Among these, rs802571, located at intron 1 of CNTNAP2, was considered to be a plausible candidate locus from a functional perspective. PMID- 26049411 TI - The Contribution of Personality and Refugee Camp Experience to Callous and Unemotional Traits Among Immigrant Adolescents in the United States: Implications for the DSM-5 "Limited Prosocial Emotions" Specifier. AB - Callous and Unemotional (C&U) traits characterize a group of adolescents who engage and persist in especially severe antisocial behaviors. These traits have been included in DSM-5 within a "Limited Prosocial Emotions" (LPE) specifier for Conduct Disorder. To investigate the generalizability of this specifier to non Western cultures, we examined associations among Big Five personality, refugee camp experience, and C&U traits among 81 immigrant adolescents from non-Western cultures. Adolescents with refugee camp history endorsed higher levels of Uncaring than other adolescents. Personality traits explained 6 (Unemotional) to 18 % (Callousness) of the variance in C&U traits. The association between Neuroticism and Callousness held only for adolescents with a refugee camp history. Our results corroborate the importance of considering personality to understand C&U traits and the LPE specifier. Results also raise questions regarding the applicability of C&U traits to non-Western adolescents with varying pre-immigration experiences, and raise the possibility that the LPE specifier is vulnerable to false-positive identifications among such individuals. PMID- 26049410 TI - The Effect of Coumaric Acid on Ischemia-Reperfusion Injury of Sciatic Nerve in Rats. AB - The aim of the study was to determine the effect of coumaric acid on sciatic nerve ischemia/reperfusion (SNI) injury in rats. The rats were randomly divided into four groups: control group (no medication or surgical procedure), SNI group, SNI + coumaric acid (CA) group, and SNI + methylprednisolone (MP) group. Ischemia was achieved by abdominal aorta clamping, and all animals were sacrificed 24 h after ischemia. Harvested sciatic nerve segments were investigated histopathologically and for tissue biochemistry. A significant decrease in MDA, an increase in NRF1 levels, and increase in SOD activity were observed in the groups which received coumaric acid and methylprednisolone when compared to the corresponding untreated group (p < 0.05). Ischemic fiber degeneration significantly reduced in the SNI + CA and SNI + MP groups, especially in the SNI + MP group, compared to the SNI group (p < 0.05). Beta amyloid protein expressions were significantly decreased in the SNI + CA group compared to the SNI group (p < 0.05). Our study revealed that coumaric acid treatment after ischemia/reperfusion in rat sciatic nerves reduced oxidative stress and axonal degeneration. Therefore, coumaric acid may play a role in the treatment of peripheral nerve injuries due to ischemia/reperfusion. PMID- 26049412 TI - Comparative assessment of glucose prediction models for patients with type 1 diabetes mellitus applying sensors for glucose and physical activity monitoring. AB - The present work presents the comparative assessment of four glucose prediction models for patients with type 1 diabetes mellitus (T1DM) using data from sensors monitoring blood glucose concentration. The four models are based on a feedforward neural network (FNN), a self-organizing map (SOM), a neuro-fuzzy network with wavelets as activation functions (WFNN), and a linear regression model (LRM), respectively. For the development and evaluation of the models, data from 10 patients with T1DM for a 6-day observation period have been used. The models' predictive performance is evaluated considering a 30-, 60- and 120-min prediction horizon, using both mathematical and clinical criteria. Furthermore, the addition of input data from sensors monitoring physical activity is considered and its effect on the models' predictive performance is investigated. The continuous glucose-error grid analysis indicates that the models' predictive performance benefits mainly in the hypoglycemic range when additional information related to physical activity is fed into the models. The obtained results demonstrate the superiority of SOM over FNN, WFNN, and LRM with SOM leading to better predictive performance in terms of both mathematical and clinical evaluation criteria. PMID- 26049413 TI - Time-dependent changes in postural control in early Parkinson's disease: what are we missing? AB - Impaired postural control (PC) is an important feature of Parkinson's disease (PD), but optimal testing protocols are yet to be established. Accelerometer based monitors provide objective measures of PC. We characterised time-dependent changes in PC in people with PD and controls during standing, and identified outcomes most sensitive to pathology. Thirty-one controls and 26 PD patients were recruited: PC was measured with an accelerometer on the lower back for 2 minutes (mins). Preliminary analysis (autocorrelation) that showed 2 seconds (s) was the shortest duration sensitive to changes in the signal; time series analysis of a range of PC outcomes was undertaken using consecutive 2-s windows over the test. Piecewise linear regression was used to fit the time series data during the first 30 s and the subsequent 90 s of the trial. PC outcomes changed over the 2 mins, with the greatest change observed during the first 30 s after which PC stabilised. Changes in PC were reduced in PD compared to controls, and Jerk was found to be discriminative of pathology. Previous studies focusing on average performance over the duration of a test may miss time-dependent differences. Evaluation of time-dependent change may provide useful insights into PC in PD and effectiveness of intervention. PMID- 26049414 TI - Abnormal Myocardial Strain Indices in Children Receiving Anthracycline Chemotherapy. AB - Anthracycline chemotherapy (AC) is associated with impaired left ventricular (LV) systolic function. LV ejection fraction (EF %) obtained by two-dimensional echocardiography is the current gold standard for detection and monitoring of LV systolic function. However, dependence on LVEF has been shown to be unreliable due to its inherent limitations. Speckle tracking echocardiography (STE) measures myocardial strain and is a sensitive method to detect LV systolic dysfunction with demonstrated utility in such detection in adult and pediatric cohort studies. Compare myocardial strain indices derived by STE with LVEF to detect ACT induced LV systolic dysfunction. Prospective, cross-sectional measurements of LV myocardial strain indices derived from STE with LVEF. Pediatric cohort of 25 patients (pts): 17 females, eight males with a mean age 9.8 +/- 5.8 years, who received anthracyclines (AC); median cumulative dose >=150 +/- 124.4 mg/m(2), range 60-450 mg/m(2) showing normal LV end-diastolic diameter (mm) and normal LVEF (>=55 %) underwent STE to obtain LV myocardial strain indices: strain and strain rate. The inter- and intraobserver variability for the strain indices was 5 %. Fifteen of 25 pts (60 %) showed abnormal global longitudinal peak systolic strain (GLPSS) and 19/25 pts (76 %) showed abnormal peak circumferential strain (PCS) compared to age-matched controls (p = 0.005). In contrast, no significant differences was observed in either indices with the dose of AC. Likewise, no significant changes in the systolic or diastolic strain rate were noted with the dose of AC (r (2) = 0.0076 for peak E, r (2) = 0.072 for peak A, p = NS). GLPSS and PCS were diminished and, however, correlated poorly with the cumulative dose of AC. These observations indicate an early onset of LV systolic dysfunction by the strain indices in pts who continue to show a normal LVEF implying presence of occult LV systolic dysfunction. These novel strain indices may assist in early detection of LV systolic dysfunction with implications for monitoring and prevention of AC-induced LV systolic dysfunction. PMID- 26049415 TI - "Awake Veno-arterial Extracorporeal Membrane Oxygenation" in Pediatric Cardiogenic Shock: A Single-Center Experience. AB - In pediatric patients with acute refractory cardiogenic shock (CS), extracorporeal membrane oxygenation (ECMO) remains an established procedure to maintain adequate organ perfusion. In this context, ECMO can be used as a bridging procedure to recovery, VAD or transplantation. While being supported by ECMO, most centers tend to keep their patients well sedated and supported by invasive ventilation. This may be associated with an increased risk of therapy related morbidity and mortality. In order to optimize clinical management in pediatric patients with ECMO therapy, we report our strategy of veno-arterial ECMO (VA-ECMO) in extubated awake and conscious patients. We therefore present data of six of our patients with CS, who were treated by ECMO being awake without continuous analgosedation and invasive ventilation. Of these six patients, four were <1 year and two >14 years of age. Median time on ECMO was 17.4 days (range 6.9-94.2 days). Median time extubated, while receiving ECMO support was 9.5 days. Mean time extubated was 78 % of the total time on ECMO. Three patients reached full recovery of cardiac function on "Awake-VA-ECMO," whereas the other three were successfully bridged to destination therapy (VAD, heart transplantation, withdrawal). Four out of our six patients are still alive. Complications related to ECMO therapy (i.e., severe bleeding, site infection or dislocation of cannulas) were not observed. We conclude that "Awake-VA-ECMO" in extubated, spontaneously breathing conscious pediatric patients is feasible and safe for the treatment of acute CS and can be used as a "bridging therapy" to recovery, VAD implantation or transplantation. PMID- 26049418 TI - Preface: Special Topic on Multidimensional Spectroscopy. AB - Multidimensional signals are generated by subjecting molecules to sequences of short optical pulses and recording correlation plots related to the various controlled delay periods. These techniques which span all the way from the THz to the x-ray regimes provide qualitatively new structural and dynamical molecular information not available from conventional one-dimensional techniques. This issue surveys the recent experimental and theoretical progresses in this rapidly developing 20 year old field which illustrates the novel insights provided by multidimensional techniques into electronic and nuclear motions. It should serve as a valuable source for experts in the field and help introduce newcomers to this exciting and challenging branch of nonlinear spectroscopy. PMID- 26049417 TI - Communication: Capturing protein multiscale thermal fluctuations. AB - Existing elastic network models are typically parametrized at a given cutoff distance and often fail to properly predict the thermal fluctuation of many macromolecules that involve multiple characteristic length scales. We introduce a multiscale flexibility-rigidity index (mFRI) method to resolve this problem. The proposed mFRI utilizes two or three correlation kernels parametrized at different length scales to capture protein interactions at corresponding scales. It is about 20% more accurate than the Gaussian network model (GNM) in the B-factor prediction of a set of 364 proteins. Additionally, the present method is able to deliver accurate predictions for some large macromolecules on which GNM fails to produce accurate predictions. Finally, for a protein of N residues, mFRI is of linear scaling (O(N)) in computational complexity, in contrast to the order of O(N(3)) for GNM. PMID- 26049416 TI - APC selectively mediates response to chemotherapeutic agents in breast cancer. AB - BACKGROUND: The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in up to 70% of sporadic breast cancers depending on subtype; however, the effects of APC mutation on tumorigenic properties remain unexplored. Using the ApcMin/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we identified enhanced breast tumorigenesis and alterations in genes critical in therapeutic resistance independent of Wnt/beta-catenin signaling. Apc mutation changed the tumor histopathology from solid to squamous adenocarcinomas, resembling the highly aggressive human metaplastic breast cancer. Mechanistic studies in tumor-derived cell lines demonstrated that focal adhesion kinase (FAK)/Src/JNK signaling regulated the enhanced proliferation downstream of Apc mutation. Despite this mechanistic information, the role of APC in mediating breast cancer chemotherapeutic resistance is currently unknown. METHODS: We have examined the effect of Apc loss in MMTV-PyMT mouse breast cancer cells on gene expression changes of ATP-binding cassette transporters and immunofluorescence to determine proliferative and apoptotic response of cells to cisplatin, doxorubicin and paclitaxel. Furthermore we determined the added effect of Src or JNK inhibition by PP2 and SP600125, respectively, on chemotherapeutic response. We also used the Aldefluor assay to measure the population of tumor initiating cells. Lastly, we measured the apoptotic and proliferative response to APC knockdown in MDA-MB-157 human breast cancer cells after chemotherapeutic treatment. RESULTS: Cells obtained from MMTV-PyMT;ApcMin/+ tumors express increased MDR1 (multidrug resistance protein 1), which is augmented by treatment with paclitaxel or doxorubicin. Furthermore MMTV-PyMT;ApcMin/+ cells are more resistant to cisplatin and doxorubicin-induced apoptosis, and show a larger population of ALDH positive cells. In the human metaplastic breast cancer cell line MDA-MB-157, APC knockdown led to paclitaxel and cisplatin resistance. CONCLUSIONS: APC loss-of-function significantly increases resistance to cisplatin mediated apoptosis in both MDA-MB-157 and the PyMT derived cells. We also demonstrated that cisplatin in combination with PP2 or SP600125 could be clinically beneficial, as inhibition of Src or JNK in an APC-mutant breast cancer patient may alleviate the resistance induced by mutant APC. PMID- 26049419 TI - Focus: Phase-resolved nonlinear terahertz spectroscopy--From charge dynamics in solids to molecular excitations in liquids. AB - Intense terahertz (THz) electric field transients with amplitudes up to several megavolts/centimeter and novel multidimensional techniques are the key ingredients of nonlinear THz spectroscopy, a new area of basic research. Both nonlinear light-matter interactions including the non-perturbative regime and THz driven charge transport give new insight into the character and dynamics of low energy excitations of condensed matter and into quantum kinetic phenomena. This article provides an overview of recent progress in this field, combining an account of technological developments with selected prototype results for liquids and solids. The potential of nonlinear THz methods for future studies of low frequency excitations of condensed-phase molecular systems is discussed as well. PMID- 26049420 TI - Focus: Two-dimensional electron-electron double resonance and molecular motions: The challenge of higher frequencies. AB - The development, applications, and current challenges of the pulsed ESR technique of two-dimensional Electron-Electron Double Resonance (2D ELDOR) are described. This is a three-pulse technique akin to 2D Exchange Nuclear Magnetic Resonance, but involving electron spins, usually in the form of spin-probes or spin-labels. As a result, it required the extension to much higher frequencies, i.e., microwaves, and much faster time scales, with pi/2 pulses in the 2-3 ns range. It has proven very useful for studying molecular dynamics in complex fluids, and spectral results can be explained by fitting theoretical models (also described) that provide a detailed analysis of the molecular dynamics and structure. We discuss concepts that also appear in other forms of 2D spectroscopy but emphasize the unique advantages and difficulties that are intrinsic to ESR. Advantages include the ability to tune the resonance frequency, in order to probe different motional ranges, while challenges include the high ratio of the detection dead time vs. the relaxation times. We review several important 2D ELDOR studies of molecular dynamics. (1) The results from a spin probe dissolved in a liquid crystal are followed throughout the isotropic -> nematic -> liquid-like smectic > solid-like smectic -> crystalline phases as the temperature is reduced and are interpreted in terms of the slowly relaxing local structure model. Here, the labeled molecule is undergoing overall motion in the macroscopically aligned sample, as well as responding to local site fluctuations. (2) Several examples involving model phospholipid membranes are provided, including the dynamic structural characterization of the boundary lipid that coats a transmembrane peptide dimer. Additionally, subtle differences can be elicited for the phospholipid membrane phases: liquid disordered, liquid ordered, and gel, and the subtle effects upon the membrane, of antigen cross-linking of receptors on the surface of plasma membrane, vesicles can be observed. These 2D ELDOR experiments are performed as a function of mixing time, Tm, i.e., the time between the second and third pi/2 pulses, which provides a third dimension. In fact, a fourth dimension may be added by varying the ESR frequency/magnetic field combination. Therefore, (3) it is shown how continuous-wave multifrequency ESR studies enable the decomposition of complex dynamics of, e.g., proteins by virtue of their respective time scales. These studies motivate our current efforts that are directed to extend 2D ELDOR to higher frequencies, 95 GHz in particular (from 9 and 17 GHz), in order to enable multi-frequency 2D ELDOR. This required the development of quasi-optical methods for performing the mm-wave experiments, which are summarized. We demonstrate state-of-the-art 95 GHz 2D ELDOR spectroscopy through its ability to resolve the two signals from a spin probe dissolved in both the lipid phase and the coexisting aqueous phase. As current 95 GHz experiments are restricted by limited spectral coverage of the pi/2 pulse, as well as the very short T2 relaxation times of the electron spins, we discuss how these limitations are being addressed. PMID- 26049421 TI - Multidimensional infrared spectroscopy reveals the vibrational and solvation dynamics of isoniazid. AB - The results of infrared spectroscopic investigations into the band assignments, vibrational relaxation, and solvation dynamics of the common anti-tuberculosis treatment Isoniazid (INH) are reported. INH is known to inhibit InhA, a 2-trans enoyl-acyl carrier protein reductase enzyme responsible for the maintenance of cell walls in Mycobacterium tuberculosis but as new drug-resistant strains of the bacterium appear, next-generation therapeutics will be essential to combat the rise of the disease. Small molecules such as INH offer the potential for use as a biomolecular marker through which ultrafast multidimensional spectroscopies can probe drug binding and so inform design strategies but a complete characterization of the spectroscopy and dynamics of INH in solution is required to inform such activity. Infrared absorption spectroscopy, in combination with density functional theory calculations, is used to assign the vibrational modes of INH in the 1400-1700 cm(-1) region of the infrared spectrum while ultrafast multidimensional spectroscopy measurements determine the vibrational relaxation dynamics and the effects of solvation via spectral diffusion of the carbonyl stretching vibrational mode. These results are discussed in the context of previous linear spectroscopy studies on solid-phase INH and its usefulness as a biomolecular probe. PMID- 26049422 TI - Ultrafast 2DIR spectroscopy of ferric azide precursors for high-valent iron. Vibrational relaxation, spectral diffusion, and dynamic symmetry breaking. AB - Femtosecond mid-infrared pump-probe and two-dimensional mid-infrared spectroscopy have been used to investigate the dynamics of vibrational relaxation and vibrational spectral diffusion of the asymmetric N3-stretching vibration of pseudo-octahedral azidoiron(III) complexes, [L6-nFe(N3)n](+) with n = 1 or 2 and L being an auxiliary ligand of denticity 6-n, in acetonitrile at room temperature. Compared to the free azide anion in acetonitrile solution, the vibrational relaxation dynamics are considerably accelerated. Vibrational energy transfer to the solvent is accelerated by virtue of a resonance with an overtone transition of the solvent. Intramolecular vibrational redistribution is found to be accelerated by virtue of a coupling between the initial azide stretching vibration and the torsional modes involving the axial ligands. Vibrational spectral diffusion within the asymmetric N3-stretching resonance was found to be insensitive to solvent fluctuations because the axial azide ligands are only partially accessible to the solvent. The particular role of intramolecular structural relaxations of the complex for shaping the linear and nonlinear two dimensional infrared spectra is discussed in terms of ultrafast symmetry-breaking torsional fluctuations and on the basis of density functional theory calculations. PMID- 26049423 TI - Impact of environmentally induced fluctuations on quantum mechanically mixed electronic and vibrational pigment states in photosynthetic energy transfer and 2D electronic spectra. AB - Recently, nuclear vibrational contribution signatures in two-dimensional (2D) electronic spectroscopy have attracted considerable interest, in particular as regards interpretation of the oscillatory transients observed in light-harvesting complexes. These transients have dephasing times that persist for much longer than theoretically predicted electronic coherence lifetime. As a plausible explanation for this long-lived spectral beating in 2D electronic spectra, quantum-mechanically mixed electronic and vibrational states (vibronic excitons) were proposed by Christensson et al. [J. Phys. Chem. B 116, 7449 (2012)] and have since been explored. In this work, we address a dimer which produces little beating of electronic origin in the absence of vibronic contributions, and examine the impact of protein-induced fluctuations upon electronic-vibrational quantum mixtures by calculating the electronic energy transfer dynamics and 2D electronic spectra in a numerically accurate manner. It is found that, at cryogenic temperatures, the electronic-vibrational quantum mixtures are rather robust, even under the influence of the fluctuations and despite the small Huang Rhys factors of the Franck-Condon active vibrational modes. This results in long lasting beating behavior of vibrational origin in the 2D electronic spectra. At physiological temperatures, however, the fluctuations eradicate the mixing, and hence, the beating in the 2D spectra disappears. Further, it is demonstrated that such electronic-vibrational quantum mixtures do not necessarily play a significant role in electronic energy transfer dynamics, despite contributing to the enhancement of long-lived quantum beating in 2D electronic spectra, contrary to speculations in recent publications. PMID- 26049424 TI - Couplings between hierarchical conformational dynamics from multi-time correlation functions and two-dimensional lifetime spectra: Application to adenylate kinase. AB - An analytical method based on a three-time correlation function and the corresponding two-dimensional (2D) lifetime spectrum is developed to elucidate the time-dependent couplings between the multi-timescale (i.e., hierarchical) conformational dynamics in heterogeneous systems such as proteins. In analogy with 2D NMR, IR, electronic, and fluorescence spectroscopies, the waiting-time dependence of the off-diagonal peaks in the 2D lifetime spectra can provide a quantitative description of the dynamical correlations between the conformational motions with different lifetimes. The present method is applied to intrinsic conformational changes of substrate-free adenylate kinase (AKE) using long-time coarse-grained molecular dynamics simulations. It is found that the hierarchical conformational dynamics arise from the intra-domain structural transitions among conformational substates of AKE by analyzing the one-time correlation functions and one-dimensional lifetime spectra for the donor-acceptor distances corresponding to single-molecule Forster resonance energy transfer experiments with the use of the principal component analysis. In addition, the complicated waiting-time dependence of the off-diagonal peaks in the 2D lifetime spectra for the donor-acceptor distances is attributed to the fact that the time evolution of the couplings between the conformational dynamics depends upon both the spatial and temporal characters of the system. The present method is expected to shed light on the biological relationship among the structure, dynamics, and function. PMID- 26049425 TI - Femtosecond stimulated Raman spectroscopy by six-wave mixing. AB - Femtosecond Stimulated Raman Spectroscopy (FSRS) is motivated by the knowledge of the molecular geometry changes that accompany sub-picosecond chemical reactions. The detection of vibrational resonances throughout the entire fingerprint region of the spectrum with sub-100-fs delay precision is fairly straightforward to accomplish with the FSRS technique. Despite its utility, FSRS must contend with substantial technical challenges that stem from a large background of residual laser light and lower-order nonlinearities when all laser pulses are electronically resonant with the equilibrium system. In this work, a geometry based on five incident laser beams is used to eliminate much of this undesired background in experiments conducted on metmyoglobin. Compared to a three-beam FSRS geometry with all electronically resonant laser pulses, the five-beam approach described here offers major improvements in the data acquisition rate, sensitivity, and background suppression. The susceptibility of the five-beam geometry to experimental artifacts is investigated using control experiments and model calculations. Of particular concern are undesired cascades of third-order nonlinearities, which are known to challenge FSRS measurements carried out on electronically off-resonant systems. It is generally understood that "forbidden" steps in the desired nonlinear optical processes are the origin of the problems encountered under off-resonant conditions. In contrast, the present experiments are carried out under electronically resonant conditions, where such unfortunate selection rules do not apply. Nonetheless, control experiments based on spectroscopic line shapes, signal phases, and sample concentrations are conducted to rule out significant contributions from cascades of third-order processes. Theoretical calculations are further used to estimate the relative intensities of the direct and cascaded responses. Overall, the control experiments and model calculations presented in this work suggest promise for multidimensional resonance Raman investigations of heme proteins. PMID- 26049426 TI - Ultrafast phosphate hydration dynamics in bulk H2O. AB - Phosphate vibrations serve as local probes of hydrogen bonding and structural fluctuations of hydration shells around ions. Interactions of H2PO4(-) ions and their aqueous environment are studied combining femtosecond 2D infrared spectroscopy, ab-initio calculations, and hybrid quantum-classical molecular dynamics (MD) simulations. Two-dimensional infrared spectra of the symmetric (nuS(PO2(-))) and asymmetric (nuAS(PO2(-))) PO2(-) stretching vibrations display nearly homogeneous lineshapes and pronounced anharmonic couplings between the two modes and with the delta(P-(OH)2) bending modes. The frequency-time correlation function derived from the 2D spectra consists of a predominant 50 fs decay and a weak constant component accounting for a residual inhomogeneous broadening. MD simulations show that the fluctuating electric field of the aqueous environment induces strong fluctuations of the nuS(PO2(-)) and nuAS(PO2(-)) transition frequencies with larger frequency excursions for nuAS(PO2(-)). The calculated frequency-time correlation function is in good agreement with the experiment. The nu(PO2(-)) frequencies are mainly determined by polarization contributions induced by electrostatic phosphate-water interactions. H2PO4(-)/H2O cluster calculations reveal substantial frequency shifts and mode mixing with increasing hydration. Predicted phosphate-water hydrogen bond (HB) lifetimes have values on the order of 10 ps, substantially longer than water-water HB lifetimes. The ultrafast phosphate-water interactions observed here are in marked contrast to hydration dynamics of phospholipids where a quasi-static inhomogeneous broadening of phosphate vibrations suggests minor structural fluctuations of interfacial water. PMID- 26049427 TI - Molecular dynamics study of two-dimensional sum frequency generation spectra at vapor/water interface. AB - Two-dimensional heterodyne-detected vibrational sum frequency generation (2D HD VSFG) spectra at vapor/water interface were studied by molecular dynamics (MD) simulation with a classical flexible and nonpolarizable model. The present model well describes the spectral diffusion of 2D infrared spectrum of bulk water as well as 2D HD-VSFG at the interface. The effect of isotopic dilution on the 2D HD VSFG was elucidated by comparing the normal (H2O) water and HOD water. We further performed decomposition analysis of 2D HD-VSFG into the hydrogen-bonding and the dangling (or free) OH vibrations, and thereby disentangled the different spectral responses and spectral diffusion in the 2D HD-VSFG. The present MD simulation demonstrated the role of anharmonic coupling between these modes on the cross peak in the 2D HD-VSFG spectrum. PMID- 26049428 TI - Dynamics of water, methanol, and ethanol in a room temperature ionic liquid. AB - The dynamics of a series of small molecule probes with increasing alkyl chain length: water, methanol, and ethanol, diluted to low concentration in the room temperature ionic liquid 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, was investigated with 2D infrared vibrational echo (2D IR) spectroscopy and polarization resolved pump-probe (PP) experiments on the deuterated hydroxyl (O-D) stretching mode of each of the solutes. The long timescale spectral diffusion observed by 2D IR, capturing complete loss of vibrational frequency correlation through structural fluctuation of the medium, shows a clear but not dramatic slowing as the probe alkyl chain length is increased: 23 ps for water, 28 ps for methanol, and 34 ps for ethanol. Although in each case, only a single population of hydroxyl oscillators contributes to the infrared line shapes, the isotropic pump-probe decays (normally caused by population relaxation) are markedly nonexponential at short times. The early time features correspond to the timescales of the fast spectral diffusion measured with 2D IR. These fast isotropic pump-probe decays are produced by unequal pumping of the OD absorption band to a nonequilibrium frequency dependent population distribution caused by significant non-Condon effects. Orientational correlation functions for these three systems, obtained from pump-probe anisotropy decays, display several periods of restricted angular motion (wobbling in-a-cone) followed by complete orientational randomization. The cone half angles, which characterize the angular potential, become larger as the experimental frequency moves to the blue. These results indicate weakening of the angular potential with decreasing hydrogen bond strength. The slowest components of the orientational anisotropy decays are frequency-independent and correspond to the complete orientational randomization of the solute molecule. These components slow appreciably with increasing chain length: 25 ps for water, 42 ps for methanol, and 88 ps for ethanol. The shape and volume of the probe, therefore, impact reorientation far more severely than they do spectral diffusion at long times, though these two processes occur on similar timescales at earlier times. PMID- 26049429 TI - Femtosecond transient infrared and stimulated Raman spectroscopy shed light on the relaxation mechanisms of photo-excited peridinin. AB - By means of one- and two-dimensional transient infrared spectroscopy and femtosecond stimulated Raman spectroscopy, we investigated the excited state dynamics of peridinin, a carbonyl carotenoid occurring in natural light harvesting complexes. The presence of singly and doubly excited states, as well as of an intramolecular charge transfer (ICT) state, makes the behavior of carbonyl carotenoids in the excited state very complex. In this work, we investigated by time resolved spectroscopy the relaxation of photo-excited peridinin in solvents of different polarities and as a function of the excitation wavelength. Our experimental results show that a characteristic pattern of one- and two-dimensional infrared bands in the C=C stretching region allows monitoring the relaxation pathway. In polar solvents, moderate distortions of the molecular geometry cause a variation of the single/double carbon bond character, so that the partially ionic ICT state is largely stabilized by the solvent reorganization. After vertical photoexcitation at 400 nm of the S2 state, the off equilibrium population moves to the S1 state with ca. 175 fs time constant; from there, in less than 5 ps, the non-Franck Condon ICT state is reached, and finally, the ground state is recovered in 70 ps. That the relevant excited state dynamics takes place far from the Franck Condon region is demonstrated by its noticeable dependence on the excitation wavelength. PMID- 26049430 TI - The separation of vibrational coherence from ground- and excited-electronic states in P3HT film. AB - Concurrence of the vibrational coherence and ultrafast electron transfer has been observed in polymer/fullerene blends. However, it is difficult to experimentally investigate the role that the excited-state vibrational coherence plays during the electron transfer process since vibrational coherence from the ground- and excited-electronic states is usually temporally and spectrally overlapped. Here, we performed 2-dimensional electronic spectroscopy (2D ES) measurements on poly(3 hexylthiophene) (P3HT) films. By Fourier transforming the whole 2D ES datasets (S(lambda1,T2,lambda3)) along the population time (T2) axis, we develop and propose a protocol capable of separating vibrational coherence from the ground- and excited-electronic states in 3D rephasing and nonrephasing beating maps (S(lambda1,nu2,lambda3)). We found that the vibrational coherence from pure excited electronic states appears at positive frequency (+nu2) in the rephasing beating map and at negative frequency (-nu2) in the nonrephasing beating map. Furthermore, we also found that vibrational coherence from excited electronic state had a long dephasing time of 244 fs. The long-lived excited-state vibrational coherence indicates that coherence may be involved in the electron transfer process. Our findings not only shed light on the mechanism of ultrafast electron transfer in organic photovoltaics but also are beneficial for the study of the coherence effect on photoexcited dynamics in other systems. PMID- 26049431 TI - On the interplay of the potential energy and dipole moment surfaces in controlling the infrared activity of liquid water. AB - Infrared vibrational spectroscopy is a valuable tool for probing molecular structure and dynamics. However, obtaining an unambiguous molecular-level interpretation of the spectral features is made difficult, in part, due to the complex interplay of the dipole moment with the underlying vibrational structure. Here, we disentangle the contributions of the potential energy surface (PES) and dipole moment surface (DMS) to the infrared spectrum of liquid water by examining three classes of models, ranging in complexity from simple point charge models to accurate representations of the many-body interactions. By decoupling the PES from the DMS in the calculation of the infrared spectra, we demonstrate that the PES, by directly modulating the vibrational structure, primarily controls the width and position of the spectroscopic features. Due to the dependence of the molecular dipole moment on the hydration environment, many-body electrostatic effects result in a ~100 cm(-1) redshift in the peak of the OH stretch band. Interestingly, while an accurate description of many-body collective motion is required to generate the correct (vibrational) structure of the liquid, the infrared intensity in the OH stretching region appears to be a measure of the local structure due to the dominance of the one-body and short-ranged two-body contributions to the total dipole moment. PMID- 26049432 TI - Room-temperature ballistic energy transport in molecules with repeating units. AB - In materials, energy can propagate by means of two limiting regimes: diffusive and ballistic. Ballistic energy transport can be fast and efficient and often occurs with a constant speed. Using two-dimensional infrared spectroscopy methods, we discovered ballistic energy transport via individual polyethylene chains with a remarkably high speed of 1440 m/s and the mean free path length of 14.6 A in solution at room temperature. Whereas the transport via the chains occurs ballistically, the mechanism switches to diffusive with the effective transport speed of 130 m/s at the end-groups attached to the chains. A unifying model of the transport in molecules is presented with clear time separation and additivity among the transport along oligomeric fragments, which occurs ballistically, and the transport within the disordered fragments, occurring diffusively. The results open new avenues for making novel elements for molecular electronics, including ultrafast energy transporters, controlled chemical reactors, and sub-wavelength quantum nanoseparators. PMID- 26049433 TI - 2D attenuated total reflectance infrared spectroscopy reveals ultrafast vibrational dynamics of organic monolayers at metal-liquid interfaces. AB - We present two-dimensional infrared (2D IR) spectra of organic monolayers immobilized on thin metallic films at the solid liquid interface. The experiments are acquired under Attenuated Total Reflectance (ATR) conditions which allow a surface-sensitive measurement of spectral diffusion, sample inhomogeneity, and vibrational relaxation of the monolayers. Terminal azide functional groups are used as local probes of the environment and structural dynamics of the samples. Specifically, we investigate the influence of different alkyl chain-lengths on the ultrafast dynamics of the monolayer, revealing a smaller initial inhomogeneity and faster spectral diffusion with increasing chain-length. Furthermore, by varying the environment (i.e., in different solvents or as bare sample), we conclude that the most significant contribution to spectral diffusion stems from intra- and intermolecular dynamics within the monolayer. The obtained results demonstrate that 2D ATR IR spectroscopy is a versatile tool for measuring interfacial dynamics of adsorbed molecules. PMID- 26049434 TI - Coherence and population dynamics of chlorophyll excitations in FCP complex: Two dimensional spectroscopy study. AB - Energy transfer processes and coherent phenomena in the fucoxanthin-chlorophyll protein complex, which is responsible for the light harvesting function in marine algae diatoms, were investigated at 77 K by using two-dimensional electronic spectroscopy. Experiments performed on femtosecond and picosecond timescales led to separation of spectral dynamics, witnessing evolutions of coherence and population states of the system in the spectral region of Qy transitions of chlorophylls a and c. Analysis of the coherence dynamics allowed us to identify chlorophyll (Chl) a and fucoxanthin intramolecular vibrations dominating over the first few picoseconds. Closer inspection of the spectral region of the Qy transition of Chl c revealed previously not identified, mutually non-interacting chlorophyll c states participating in femtosecond or picosecond energy transfer to the Chl a molecules. Consideration of separated coherent and incoherent dynamics allowed us to hypothesize the vibrations-assisted coherent energy transfer between Chl c and Chl a and the overall spatial arrangement of chlorophyll molecules. PMID- 26049435 TI - Solvation of fluoro-acetonitrile in water by 2D-IR spectroscopy: A combined experimental-computational study. AB - The solvent dynamics around fluorinated acetonitrile is characterized by 2 dimensional infrared spectroscopy and atomistic simulations. The lineshape of the linear infrared spectrum is better captured by semiempirical (density functional tight binding) mixed quantum mechanical/molecular mechanics simulations, whereas force field simulations with multipolar interactions yield lineshapes that are significantly too narrow. For the solvent dynamics, a relatively slow time scale of 2 ps is found from the experiments and supported by the mixed quantum mechanical/molecular mechanics simulations. With multipolar force fields fitted to the available thermodynamical data, the time scale is considerably faster--on the 0.5 ps time scale. The simulations provide evidence for a well established CF HOH hydrogen bond (population of 25%) which is found from the radial distribution function g(r) from both, force field and quantum mechanics/molecular mechanics simulations. PMID- 26049436 TI - Ultrafast 2D-IR spectroelectrochemistry of flavin mononucleotide. AB - We demonstrate the coupling of ultrafast two-dimensional infrared (2D-IR) spectroscopy to electrochemistry in solution and apply it to flavin mononucleotide, an important cofactor of redox proteins. For this purpose, we designed a spectroelectrochemical cell optimized for 2D-IR measurements in reflection and measured the time-dependent 2D-IR spectra of the oxidized and reduced forms of flavin mononucleotide. The data show anharmonic coupling and vibrational energy transfer between different vibrational modes in the two redox species. Such information is inaccessible with redox-controlled steady-state FTIR spectroscopy. The wide range of applications offered by 2D-IR spectroscopy, such as sub-picosecond structure determination, IR band assignment via energy transfer, disentangling reaction mixtures through band connectivity in the 2D spectra, and the measurement of solvation dynamics and chemical exchange can now be explored under controlled redox potential. The development of this technique furthermore opens new horizons for studying the dynamics of redox proteins. PMID- 26049437 TI - Vibrational coherence and energy transfer in two-dimensional spectra with the optimized mean-trajectory approximation. AB - The optimized mean-trajectory (OMT) approximation is a semiclassical method for computing vibrational response functions from action-quantized classical trajectories connected by discrete transitions that represent radiation-matter interactions. Here, we extend the OMT to include additional vibrational coherence and energy transfer processes. This generalized approximation is applied to a pair of anharmonic chromophores coupled to a bath. The resulting 2D spectra are shown to reflect coherence transfer between normal modes. PMID- 26049438 TI - Vibrational dynamics of azide-derivatized amino acids studied by nonlinear infrared spectroscopy. AB - Recently, biomolecules which are labeled by azide or thiocyanate groups in solutions and proteins have been studied to examine microscopic environment around a solute by nonlinear infrared (IR) spectroscopy. In this study, we have performed two-dimensional infrared (2D-IR) spectroscopy to investigate the vibrational frequency fluctuations of two different azide-derivatized amino acids, Ala (N3-Ala) and Pro (N3-Pro), and N3(-) in water. From the 2D-IR experiments, it was found that the frequency-frequency time correlation function (FFTCF) of solute can be modeled by a delta function plus an exponential function and constant. FFTCF for each probe molecule has a decay component of about 1 ps, and this result suggests that the stretching mode of the covalently bonded azide group is sensitive to the fluctuations of hydrogen bond network system, as found in previous studies of N3(-) in water. In contrast to FFTCF of N3(-), FFTCF of the azide-derivatized amino acids contains static component. This static component may reflect dynamics of water affected by the solutes or the structural fluctuations of the solute itself. We also performed the IR pump-probe measurements for the probe molecules in water in order to investigate vibrational energy relaxation (VER) and reorientational relaxation. It was revealed that the charge fluctuations in the azide group are significant for the VER of this mode in water, reflecting that the VER rate of N3(-) is faster than those of the azide derivatized amino acids. While the behaviors of the anisotropy decay of N3-Ala and N3(-) are similar to each other, the anisotropy decay of N3-Pro contains much slower decaying component. By considering the structural difference around the vibrational probe between N3-Ala and N3-Pro, it is suggested that the structural freedom of the probe molecules can affect the reorientational processes. PMID- 26049439 TI - Low frequency 2D Raman-THz spectroscopy of ionic solution: A simulation study. AB - The 2D Raman-THz spectrum of the MgCl2 solution was simulated using the molecular dynamics simulation and the stability matrix method and compared with that of the pure water. The 2D Raman-THz signal provides more information on the ion effects on the collective water motion than the conventional 1D signal. The presence of MgCl2 suppresses the cross peak of water between the hydrogen bond bending and the other intermolecular vibrational mode, which clearly illustrates that the water hydrogen bending motion is affected by the confining effect of the ions. Our theoretical work thus demonstrates that the 2D Raman-THz technique can become a valuable nonlinear vibrational probe for the molecular dynamics in the ionic solutions. PMID- 26049440 TI - Lineshape analysis of coherent multidimensional optical spectroscopy using incoherent light. AB - Coherent two-dimensional electronic spectroscopy using incoherent (noisy) light, I((4)) 2D ES, holds intriguing challenges and opportunities. One challenge is to determine how I((4)) 2D ES compares to femtosecond 2D ES. Here, we merge the sophisticated energy-gap Hamiltonian formalism that is often used to model femtosecond 2D ES with the factorized time-correlation formalism that is needed to describe I((4)) 2D ES. The analysis reveals that in certain cases the energy gap Hamiltonian is insufficient to model the spectroscopic technique correctly. The results using a modified energy-gap Hamiltonian show that I((4)) 2D ES can reveal detailed lineshape information, but, contrary to prior reports, does not reveal dynamics during the waiting time. PMID- 26049441 TI - Analysis of 2D THz-Raman spectroscopy using a non-Markovian Brownian oscillator model with nonlinear system-bath interactions. AB - We explore and describe the roles of inter-molecular vibrations employing a Brownian oscillator (BO) model with linear-linear (LL) and square-linear (SL) system-bath interactions, which we use to analyze two-dimensional (2D) THz-Raman spectra obtained by means of molecular dynamics (MD) simulations. In addition to linear infrared absorption (1D IR), we calculated 2D Raman-THz-THz, THz-Raman THz, and THz-THz-Raman signals for liquid formamide, water, and methanol using an equilibrium non-equilibrium hybrid MD simulation. The calculated 1D IR and 2D THz Raman signals are compared with results obtained from the LL+SL BO model applied through use of hierarchal Fokker-Planck equations with non-perturbative and non Markovian noise. We find that all of the qualitative features of the 2D profiles of the signals obtained from the MD simulations are reproduced with the LL+SL BO model, indicating that this model captures the essential features of the inter molecular motion. We analyze the fitted 2D profiles in terms of anharmonicity, nonlinear polarizability, and dephasing time. The origins of the echo peaks of the librational motion and the elongated peaks parallel to the probe direction are elucidated using optical Liouville paths. PMID- 26049442 TI - Biexciton formation and exciton coherent coupling in layered GaSe. AB - Nonlinear two-dimensional Fourier transform (2DFT) and linear absorption spectroscopy are used to study the electronic structure and optical properties of excitons in the layered semiconductor GaSe. At the 1s exciton resonance, two peaks are identified in the absorption spectra, which are assigned to splitting of the exciton ground state into the triplet and singlet states. 2DFT spectra acquired for co-linear polarization of the excitation pulses feature an additional peak originating from coherent energy transfer between the singlet and triplet. At cross-linear polarization of the excitation pulses, the 2DFT spectra expose a new peak likely originating from bound biexcitons. The polarization dependent 2DFT spectra are well reproduced by simulations using the optical Bloch equations for a four level system, where many-body effects are included phenomenologically. Although biexciton effects are thought to be strong in this material, only moderate contributions from bound biexciton creation can be observed. The biexciton binding energy of ~2 meV was estimated from the separation of the peaks in the 2DFT spectra. Temperature dependent absorption and 2DFT measurements, combined with "ab initio" theoretical calculations of the phonon spectra, indicate strong interaction with the A1 (') phonon mode. Excitation density dependent 2DFT measurements reveal excitation induced dephasing and provide a lower limit for the homogeneous linewidth of the excitons in the present GaSe crystal. PMID- 26049443 TI - Linear and third- and fifth-order nonlinear spectroscopies of a charge transfer system coupled to an underdamped vibration. AB - We study hole, electron, and exciton transports in a charge transfer system in the presence of underdamped vibrational motion. We analyze the signature of these processes in the linear and third-, and fifth-order nonlinear electronic spectra. Calculations are performed with a numerically exact hierarchical equations of motion method for an underdamped Brownian oscillator spectral density. We find that combining electron, hole, and exciton transfers can lead to non-trivial spectra with more structure than with excitonic coupling alone. Traces taken during the waiting time of a two-dimensional (2D) spectrum are dominated by vibrational motion and do not reflect the electron, hole, and exciton dynamics directly. We find that the fifth-order nonlinear response is particularly sensitive to the charge transfer process. While third-order 2D spectroscopy detects the correlation between two coherences, fifth-order 2D spectroscopy (2D population spectroscopy) is here designed to detect correlations between the excited states during two different time periods. PMID- 26049444 TI - Distinguishing gramicidin D conformers through two-dimensional infrared spectroscopy of vibrational excitons. AB - Gramicidin D is a short peptide which dimerizes to form helical pores, adopting one of two conformations in the process. These conformations differ primarily in number of residues per turn and the hydrogen-bond registry between rungs of the helix. Using amide I 2D infrared (IR) and FTIR, we have demonstrated that it is possible to distinguish between the different conformers of gramicidin D in solution. We show that the spectra observed for this helical peptide bear no resemblance to the spectra of alpha- or 310-helices and that while the FTIR spectra appear similar to spectra of beta-sheets, 2D IR reveals that the observed resonances arise from vibrational modes unlike those observed in beta-sheets. We also present an idealized model which reproduces the experimental data with high fidelity. This model is able to explain the polarization-dependence of the experimental 2D IR data. Using this model, we show the coupling between the rungs of the helix dominates the spectra, and as a consequence of this, the number of residues per turn can greatly influence the amide I spectra of gramicidin D. PMID- 26049445 TI - Ultrafast vibrational spectroscopy (2D-IR) of CO2 in ionic liquids: Carbon capture from carbon dioxide's point of view. AB - The CO2nu3 asymmetric stretching mode is established as a vibrational chromophore for ultrafast two-dimensional infrared (2D-IR) spectroscopic studies of local structure and dynamics in ionic liquids, which are of interest for carbon capture applications. CO2 is dissolved in a series of 1-butyl-3-methylimidazolium-based ionic liquids ([C4C1im][X], where [X](-) is the anion from the series hexafluorophosphate (PF6 (-)), tetrafluoroborate (BF4 (-)), bis (trifluoromethyl)sulfonylimide (Tf2N(-)), triflate (TfO(-)), trifluoroacetate (TFA(-)), dicyanamide (DCA(-)), and thiocyanate (SCN(-))). In the ionic liquids studied, the nu3 center frequency is sensitive to the local solvation environment and reports on the timescales for local structural relaxation. Density functional theory calculations predict charge transfer from the anion to the CO2 and from CO2 to the cation. The charge transfer drives geometrical distortion of CO2, which in turn changes the nu3 frequency. The observed structural relaxation timescales vary by up to an order of magnitude between ionic liquids. Shoulders in the 2D-IR spectra arise from anharmonic coupling of the nu2 and nu3 normal modes of CO2. Thermal fluctuations in the nu2 population stochastically modulate the nu3 frequency and generate dynamic cross-peaks. These timescales are attributed to the breakup of ion cages that create a well-defined local environment for CO2. The results suggest that the picosecond dynamics of CO2 are gated by local diffusion of anions and cations. PMID- 26049446 TI - High resolution coherent three dimensional spectroscopy of NO2. AB - Expansion from coherent 2D spectroscopy to coherent 3D spectroscopy can provide significant advantages when studying molecules that have heavily perturbed energy levels. This paper illustrates such advantages by demonstrating how high resolution coherent 3D (HRC3D) spectroscopy can be used to study a portion of the visible spectrum of nitrogen dioxide. High resolution coherent 2D spectra usually contain rotational and vibrational patterns that are easy to analyze, but severe congestion and complexity preclude its effective use for many parts of the NO2 spectrum. HRC3D spectroscopy appears to be much more effective; multidimensional rotational and vibrational patterns produced by this new technique are easy to identify even in the presence of strong perturbations. A method for assigning peaks, which is based upon analyzing the resulting multidimensional patterns, has been developed. The higher level of multidimensionality is useful for reducing uncertainty in peak assignments, improving spectral resolution, providing simultaneous information on multiple levels and states, and predicting, verifying, and categorizing peaks. PMID- 26049448 TI - Probing environment fluctuations by two-dimensional electronic spectroscopy of molecular systems at temperatures below 5 K. AB - Two-dimensional (2D) electronic spectroscopy at cryogenic and room temperatures reveals excitation energy relaxation and transport, as well as vibrational dynamics, in molecular systems. These phenomena are related to the spectral densities of nuclear degrees of freedom, which are directly accessible by means of hole burning and fluorescence line narrowing approaches at low temperatures (few K). The 2D spectroscopy, in principle, should reveal more details about the fluctuating environment than the 1D approaches due to peak extension into extra dimension. By studying the spectral line shapes of a dimeric aggregate at low temperature, we demonstrate that 2D spectra have the potential to reveal the fluctuation spectral densities for different electronic states, the interstate correlation of static disorder and, finally, the time scales of spectral diffusion with high resolution. PMID- 26049447 TI - Line shape analysis of two-dimensional infrared spectra. AB - Ultrafast two-dimensional infrared (2D IR) spectroscopy probes femtosecond to picosecond time scale dynamics ranging from solvation to protein motions. The frequency-frequency correlation function (FFCF) is the quantitative measure of the spectral diffusion that reports those dynamics and, within certain approximations, can be extracted directly from 2D IR line shapes. A variety of methods have been developed to extract the FFCF from 2D IR spectra, which, in principle, should give the same FFCF parameters, but the complexity of real experimental systems will affect the results of these analyses differently. Here, we compare five common analysis methods using both simulated and experimental 2D IR spectra to understand the effects of apodization, anharmonicity, phasing errors, and finite signal-to-noise ratios on the results of each of these analyses. Our results show that although all of the methods can, in principle, yield the FFCF under idealized circumstances, under more realistic experimental conditions they behave quite differently, and we find that the centerline slope analysis yields the best compromise between the effects we test and is most robust to the distortions that they cause. PMID- 26049449 TI - Relaxation dynamics and exciton energy transfer in the low-temperature phase of MEH-PPV. AB - Understanding the effects of aggregation on exciton relaxation and energy transfer is relevant to control photoinduced function in organic electronics and photovoltaics. Here, we explore the photoinduced dynamics in the low-temperature aggregated phase of a conjugated polymer by transient absorption and coherent electronic two-dimensional (2D) spectroscopy. Coherent 2D spectroscopy allows observing couplings among photoexcited states and discriminating band shifts from homogeneous broadening, additionally accessing the ultrafast dynamics at various excitation energies simultaneously with high spectral resolution. By combining the results of the two techniques, we differentiate between an initial exciton relaxation, which is not characterized by significant exciton mobility, and energy transport between different chromophores in the aggregate. PMID- 26049450 TI - Multidimensional characterization of stochastic dynamical systems based on multiple perturbations and measurements. AB - Generalized nonlinear response theory is presented for stochastic dynamical systems. Experiments in which multiple measurements of dynamical quantities are used along with multiple perturbations of parameters of dynamical systems are described by generalized response functions (GRFs). These constitute a new type of multidimensional measures of stochastic dynamics either in the time or the frequency domains. Closed expressions for GRFs in stochastic dynamical systems are derived and compared with numerical non-equilibrium simulations. Several types of perturbations are considered: impulsive and periodic perturbations of temperature and impulsive perturbations of coordinates. The present approach can be used to study various types of stochastic processes ranging from single molecule conformational dynamics to chemical kinetics of finite-size reactors such as biocells. PMID- 26049451 TI - 2D heterodyne-detected sum frequency generation study on the ultrafast vibrational dynamics of H2O and HOD water at charged interfaces. AB - Two-dimensional heterodyne-detected vibrational sum-frequency generation (2D HD VSFG) spectroscopy is applied to study the ultrafast vibrational dynamics of water at positively charged aqueous interfaces, and 2D HD-VSFG spectra of cetyltrimethylammonium bromide (CTAB)/water interfaces in the whole hydrogen bonded OH stretch region (3000 cm(-1) <= omegapump <= 3600 cm(-1)) are measured. 2D HD-VSFG spectrum of the CTAB/isotopically diluted water (HOD-D2O) interface exhibits a diagonally elongated bleaching lobe immediately after excitation, which becomes round with a time constant of ~0.3 ps due to spectral diffusion. In contrast, 2D HD-VSFG spectrum of the CTAB/H2O interface at 0.0 ps clearly shows two diagonal peaks and their cross peaks in the bleaching region, corresponding to the double peaks observed at 3230 cm(-1) and 3420 cm(-1) in the steady-state HD-VSFG spectrum. Horizontal slices of the 2D spectrum show that the relative intensity of the two peaks of the bleaching at the CTAB/H2O interface gradually change with the change of the pump frequency. We simulate the pump-frequency dependence of the bleaching feature using a model that takes account of the Fermi resonance and inhomogeneity of the OH stretch vibration, and the simulated spectra reproduce the essential features of the 2D HD-VSFG spectra of the CTAB/H2O interface. The present study demonstrates that heterodyne detection of the time-resolved VSFG is critically important for studying the ultrafast dynamics of water interfaces and for unveiling the underlying mechanism. PMID- 26049452 TI - Energy transfer dynamics in trimers and aggregates of light-harvesting complex II probed by 2D electronic spectroscopy. AB - The pathways and dynamics of excitation energy transfer between the chlorophyll (Chl) domains in solubilized trimeric and aggregated light-harvesting complex II (LHCII) are examined using two-dimensional electronic spectroscopy (2DES). The LHCII trimers and aggregates exhibit the unquenched and quenched excitonic states of Chl a, respectively. 2DES allows direct correlation of excitation and emission energies of coupled states over population time delays, hence enabling mapping of the energy flow between Chls. By the excitation of the entire Chl b Qy band, energy transfer from Chl b to Chl a states is monitored in the LHCII trimers and aggregates. Global analysis of the two-dimensional (2D) spectra reveals that energy transfer from Chl b to Chl a occurs on fast and slow time scales of 240 270 fs and 2.8 ps for both forms of LHCII. 2D decay-associated spectra resulting from the global analysis identify the correlation between Chl states involved in the energy transfer and decay at a given lifetime. The contribution of singlet singlet annihilation on the kinetics of Chl energy transfer and decay is also modelled and discussed. The results show a marked change in the energy transfer kinetics in the time range of a few picoseconds. Owing to slow energy equilibration processes, long-lived intermediate Chl a states are present in solubilized trimers, while in aggregates, the population decay of these excited states is significantly accelerated, suggesting that, overall, the energy transfer within the LHCII complexes is faster in the aggregated state. PMID- 26049453 TI - Ultra-broadband 2D electronic spectroscopy of carotenoid-bacteriochlorophyll interactions in the LH1 complex of a purple bacterium. AB - We investigate the excitation energy transfer (EET) pathways in the photosynthetic light harvesting 1 (LH1) complex of purple bacterium Rhodospirillum rubrum with ultra-broadband two-dimensional electronic spectroscopy (2DES). We employ a 2DES apparatus in the partially collinear geometry, using a passive birefringent interferometer to generate the phase locked pump pulse pair. This scheme easily lends itself to two-color operation, by coupling a sub-10 fs visible pulse with a sub-15-fs near-infrared pulse. This unique pulse combination allows us to simultaneously track with extremely high temporal resolution both the dynamics of the photoexcited carotenoid spirilloxanthin (Spx) in the visible range and the EET between the Spx and the B890 bacterio-chlorophyll (BChl), whose Qx and Qy transitions peak at 585 and 881 nm, respectively, in the near-infrared. Global analysis of the one-color and two color 2DES maps unravels different relaxation mechanisms in the LH1 complex: (i) the initial events of the internal conversion process within the Spx, (ii) the parallel EET from the first bright state S2 of the Spx towards the Qx state of the B890, and (iii) the internal conversion from Qx to Qy within the B890. PMID- 26049454 TI - Vibronic coupling explains the ultrafast carotenoid-to-bacteriochlorophyll energy transfer in natural and artificial light harvesters. AB - The initial energy transfer steps in photosynthesis occur on ultrafast timescales. We analyze the carotenoid to bacteriochlorophyll energy transfer in LH2 Marichromatium purpuratum as well as in an artificial light-harvesting dyad system by using transient grating and two-dimensional electronic spectroscopy with 10 fs time resolution. We find that Forster-type models reproduce the experimentally observed 60 fs transfer times, but overestimate coupling constants, which lead to a disagreement with both linear absorption and electronic 2D-spectra. We show that a vibronic model, which treats carotenoid vibrations on both electronic ground and excited states as part of the system's Hamiltonian, reproduces all measured quantities. Importantly, the vibronic model presented here can explain the fast energy transfer rates with only moderate coupling constants, which are in agreement with structure based calculations. Counterintuitively, the vibrational levels on the carotenoid electronic ground state play the central role in the excited state population transfer to bacteriochlorophyll; resonance between the donor-acceptor energy gap and the vibrational ground state energies is the physical basis of the ultrafast energy transfer rates in these systems. PMID- 26049455 TI - Probing structural features of self-assembled violanthrone-79 using two dimensional infrared spectroscopy. AB - Two-dimensional infrared (2D IR) spectroscopy was used to characterize the structure of a self-assembled polycyclic aromatic hydrocarbon (PAH), violanthrone 79. A local mode basis was constructed using spectroscopic and computational results of anthrone and monomer violanthrone-79. The vibrational modes in the spectral region 1550-1700 cm(-1), carbonyl stretching and in-plane ring breathing, are used as vibrational probes. The local mode basis and an electrostatic coupling model were applied to three nanoaggregate structures: parallel, antiparallel, and a chiral configuration produced by a 28 degrees rotation from parallel. Angular disorder within each nanoaggregate configuration was also explored. This investigation is a first approach to probe self-assembled PAHs with 2D IR spectroscopy. The experimental and calculated 2D IR spectra align best when the violanthrone-79 molecules are in an anti-parallel configuration within the nanoaggregate. PMID- 26049456 TI - Structure and dynamics of a salt-bridge model system in water and DMSO. AB - We study the interaction between the ions methylguanidinium and trifluoroacetate dissolved in D2O and dimethylsulfoxide with linear infrared spectroscopy and femtosecond two-dimensional infrared spectroscopy. These ions constitute model systems for the side chains of arginine and glutamic and aspartic acid that are known to form salt bridges in proteins. We find that the salt-bridge formation of methylguanidinium and trifluoroacetate leads to a significant acceleration of the vibrational relaxation dynamics of the antisymmetric COO stretching vibration of the carboxyl moiety of trifluoroacetate. Salt-bridge formation has little effect on the rate of the spectral fluctuations of the CN stretching vibrations of methylguanidinium. The anisotropy of the cross peaks between the antisymmetric COO stretching vibration of trifluoroacetate and the CN stretching vibrations of methylguanidinium reveals that the salt-bridge is preferentially formed in a bidentate end-on configuration in which the two C=O groups of the carboxylate moiety form strong hydrogen bonds with the two -NH2 groups of methylguanidinium. PMID- 26049457 TI - Application of two-dimensional infrared spectroscopy to benchmark models for the amide I band of proteins. AB - In this paper, we present a novel benchmarking method for validating the modelling of vibrational spectra for the amide I region of proteins. We use the linear absorption spectra and two-dimensional infrared spectra of four experimentally well-studied proteins as a reference and test nine combinations of molecular dynamics force fields, vibrational frequency mappings, and coupling models. We find that two-dimensional infrared spectra provide a much stronger test of the models than linear absorption does. The best modelling approach in the present study still leaves significant room for future improvement. The presented benchmarking scheme, thus, provides a way of validating future protocols for modelling the amide I band in proteins. PMID- 26049459 TI - Probing polariton dynamics in trapped ions with phase-coherent two-dimensional spectroscopy. AB - We devise a phase-coherent three-pulse protocol to probe the polariton dynamics in a trapped-ion quantum simulation. In contrast to conventional nonlinear signals, the presented scheme does not change the number of excitations in the system, allowing for the investigation of the dynamics within an N-excitation manifold. In the particular case of a filling factor one (N excitations in an N ion chain), the proposed interaction induces coherent transitions between a delocalized phonon superfluid and a localized atomic insulator phase. Numerical simulations of a two-ion chain demonstrate that the resulting two-dimensional spectra allow for the unambiguous identification of the distinct phases, and the two-dimensional line shapes efficiently characterize the relevant decoherence mechanism. PMID- 26049458 TI - Hydration and vibrational dynamics of betaine (N,N,N-trimethylglycine). AB - Zwitterions are naturally occurring molecules that have a positive and a negative charge group in its structure and are of great importance in many areas of science. Here, the vibrational and hydration dynamics of the zwitterionic system betaine (N,N,N-trimethylglycine) is reported. The linear infrared spectrum of aqueous betaine exhibits an asymmetric band in the 1550-1700 cm(-1) region of the spectrum. This band is attributed to the carboxylate asymmetric stretch of betaine. The potential of mean force computed from ab initio molecular dynamic simulations confirms that the two observed transitions of the linear spectrum are related to two different betaine conformers present in solution. A model of the experimental data using non-linear response theory agrees very well with a vibrational model comprising of two vibrational transitions. In addition, our modeling shows that spectral parameters such as the slope of the zeroth contour plot and central line slope are both sensitive to the presence of overlapping transitions. The vibrational dynamics of the system reveals an ultrafast decay of the vibrational population relaxation as well as the correlation of frequency frequency correlation function (FFCF). A decay of ~0.5 ps is observed for the FFCF correlation time and is attributed to the frequency fluctuations caused by the motions of water molecules in the solvation shell. The comparison of the experimental observations with simulations of the FFCF from ab initio molecular dynamics and a density functional theory frequency map shows a very good agreement corroborating the correct characterization and assignment of the derived parameters. PMID- 26049460 TI - Extended quantum jump description of vibronic two-dimensional spectroscopy. AB - We calculate two-dimensional (2D) vibronic spectra for a model system involving two electronic molecular states. The influence of a bath is simulated using a quantum-jump approach. We use a method introduced by Makarov and Metiu [J. Chem. Phys. 111, 10126 (1999)] which includes an explicit treatment of dephasing. In this way it is possible to characterize the influence of dissipation and dephasing on the 2D-spectra, using a wave function based method. The latter scales with the number of stochastic runs and the number of system eigenstates included in the expansion of the wave-packets to be propagated with the stochastic method and provides an efficient method for the calculation of the 2D spectra. PMID- 26049461 TI - Correlating solvent dynamics and chemical reaction rates using binary solvent mixtures and two-dimensional infrared spectroscopy. AB - Two-dimensional infrared (2D-IR) spectroscopy was performed on Vaska's complex (VC) and its oxygen adduct (V C-O2) in binary solvent mixtures of chloroform or benzyl alcohol in d6-benzene. The second order rate constants for oxygenation were also measured in these solvent mixtures. The rate constant in chloroform mixtures is linear with mole fraction within the error of the measurements but changes nonlinearly in benzyl alcohol mixtures, displaying a preference for the alcohol over benzene. The rate constants were compared with FTIR spectra of the carbonyl ligand and the frequency-frequency correlation function of this mode determined by 2D-IR. The line shape broadening mechanisms of the linear spectra of the CO bound to VC and V C-O2 are similar to those previously reported for V C I2. There is a particularly strong correlation between rate constants and homogeneous linewidths of the carbonyl vibration on the V C-O2 product state. Concurrently, the FTIR spectra and spectral diffusion observed by 2D-IR corroborate an increase in solvent heterogeneity around the product. We interpret these results in the context of the potential role of solvent dynamics in facilitating chemical reactivity. PMID- 26049462 TI - Quantum process tomography by 2D fluorescence spectroscopy. AB - Reconstruction of the dynamics (quantum process tomography) of the single-exciton manifold in energy transfer systems is proposed here on the basis of two dimensional fluorescence spectroscopy (2D-FS) with phase-modulation. The quantum process-tomography protocol introduced here benefits from, e.g., the sensitivity enhancement ascribed to 2D-FS. Although the isotropically averaged spectroscopic signals depend on the quantum yield parameter Gamma of the doubly excited-exciton manifold, it is shown that the reconstruction of the dynamics is insensitive to this parameter. Applications to foundational and applied problems, as well as further extensions, are discussed. PMID- 26049463 TI - Modeling the high-energy electronic state manifold of adenine: Calibration for nonlinear electronic spectroscopy. AB - Pump-probe electronic spectroscopy using femtosecond laser pulses has evolved into a standard tool for tracking ultrafast excited state dynamics. Its two dimensional (2D) counterpart is becoming an increasingly available and promising technique for resolving many of the limitations of pump-probe caused by spectral congestion. The ability to simulate pump-probe and 2D spectra from ab initio computations would allow one to link mechanistic observables like molecular motions and the making/breaking of chemical bonds to experimental observables like excited state lifetimes and quantum yields. From a theoretical standpoint, the characterization of the electronic transitions in the visible (Vis)/ultraviolet (UV), which are excited via the interaction of a molecular system with the incoming pump/probe pulses, translates into the determination of a computationally challenging number of excited states (going over 100) even for small/medium sized systems. A protocol is therefore required to evaluate the fluctuations of spectral properties like transition energies and dipole moments as a function of the computational parameters and to estimate the effect of these fluctuations on the transient spectral appearance. In the present contribution such a protocol is presented within the framework of complete and restricted active space self-consistent field theory and its second-order perturbation theory extensions. The electronic excited states of adenine have been carefully characterized through a previously presented computational recipe [Nenov et al., Comput. Theor. Chem. 1040-1041, 295-303 (2014)]. A wise reduction of the level of theory has then been performed in order to obtain a computationally less demanding approach that is still able to reproduce the characteristic features of the reference data. Foreseeing the potentiality of 2D electronic spectroscopy to track polynucleotide ground and excited state dynamics, and in particular its expected ability to provide conformational dependent fingerprints in dimeric systems, the performances of the selected reduced level of calculations have been tested in the construction of 2D electronic spectra for the in vacuo adenine monomer and the unstacked adenine homodimer, thereby exciting the Lb/La transitions with the pump pulse pair and probing in the Vis to near ultraviolet spectral window. PMID- 26049464 TI - The structure of salt bridges between Arg(+) and Glu(-) in peptides investigated with 2D-IR spectroscopy: Evidence for two distinct hydrogen-bond geometries. AB - Salt bridges play an important role in protein folding and in supramolecular chemistry, but they are difficult to detect and characterize in solution. Here, we investigate salt bridges between glutamate (Glu(-)) and arginine (Arg(+)) using two-dimensional infrared (2D-IR) spectroscopy. The 2D-IR spectrum of a salt bridged dimer shows cross peaks between the vibrational modes of Glu(-) and Arg(+), which provide a sensitive structural probe of Glu(-)?Arg(+) salt bridges. We use this probe to investigate a beta-turn locked by a salt bridge, an alpha helical peptide whose structure is stabilized by salt bridges, and a coiled coil that is stabilized by intra- and intermolecular salt bridges. We detect a bidentate salt bridge in the beta-turn, a monodentate one in the alpha-helical peptide, and both salt-bridge geometries in the coiled coil. To our knowledge, this is the first time 2D-IR has been used to probe tertiary side chain interactions in peptides, and our results show that 2D-IR spectroscopy is a powerful method for investigating salt bridges in solution. PMID- 26049465 TI - Coherent (photon) vs incoherent (current) detection of multidimensional optical signals from single molecules in open junctions. AB - The nonlinear optical response of a current-carrying single molecule coupled to two metal leads and driven by a sequence of impulsive optical pulses with controllable phases and time delays is calculated. Coherent (stimulated, heterodyne) detection of photons and incoherent detection of the optically induced current are compared. Using a diagrammatic Liouville space superoperator formalism, the signals are recast in terms of molecular correlation functions which are then expanded in the many-body molecular states. Two dimensional signals in benzene-1,4-dithiol molecule show cross peaks involving charged states. The correlation between optical and charge current signal is also observed. PMID- 26049467 TI - Electron-phonon interactions in MoS2 probed with ultrafast two-dimensional visible/far-infrared spectroscopy. AB - An ultrafast two-dimensional visible/far-IR spectroscopy based on the IR/THz air biased coherent detection method and scanning the excitation frequencies is developed. The method allows the responses in the far-IR region caused by various electronic excitations in molecular or material systems to be observed in real time. Using the technique, the relaxation dynamics of the photo-excited carriers and electron/phonon coupling in bulk MoS2 are investigated. It is found that the photo-generation of excited carriers occurs within two hundred fs and the relaxation of the carriers is tens of ps. The electron-phonon coupling between the excitations of electrons and the phonon mode E1u of MoS2 is also directly observed. The electron excitation shifts the frequency of the phonon mode 9 cm( 1) higher, resulting in an absorption peak at 391 cm(-1) and a bleaching peak at 382 cm(-1). The frequency shift diminishes with the relaxation of the carriers. PMID- 26049466 TI - Towards quantification of vibronic coupling in photosynthetic antenna complexes. AB - Photosynthetic antenna complexes harvest sunlight and efficiently transport energy to the reaction center where charge separation powers biochemical energy storage. The discovery of existence of long lived quantum coherence during energy transfer has sparked the discussion on the role of quantum coherence on the energy transfer efficiency. Early works assigned observed coherences to electronic states, and theoretical studies showed that electronic coherences could affect energy transfer efficiency--by either enhancing or suppressing transfer. However, the nature of coherences has been fiercely debated as coherences only report the energy gap between the states that generate coherence signals. Recent works have suggested that either the coherences observed in photosynthetic antenna complexes arise from vibrational wave packets on the ground state or, alternatively, coherences arise from mixed electronic and vibrational states. Understanding origin of coherences is important for designing molecules for efficient light harvesting. Here, we give a direct experimental observation from a mutant of LH2, which does not have B800 chromophores, to distinguish between electronic, vibrational, and vibronic coherence. We also present a minimal theoretical model to characterize the coherences both in the two limiting cases of purely vibrational and purely electronic coherence as well as in the intermediate, vibronic regime. PMID- 26049468 TI - Davydov Ansatz as an efficient tool for the simulation of nonlinear optical response of molecular aggregates. AB - We have developed a variational approach to the description of four-wave-mixing signals of molecular aggregates, in which the third-order response functions are evaluated in terms of the Davydov Ansatze. Our theory treats both singly and doubly excited excitonic states, handling the contributions due to stimulated emission, ground state bleach, and excited state absorption. As an illustration, we simulate a series of optical two-dimensional spectra of model J-aggregates. Our approach may become suitable for the computation of femtosecond optical four wave-mixing signals of molecular aggregates with intermediate-to-strong exciton phonon and exciton-exciton coupling strengths. PMID- 26049469 TI - Dye aggregation identified by vibrational coupling using 2D IR spectroscopy. AB - We report that a model dye, Re(CO)3(bypy)CO2H, aggregates into clusters on TiO2 nanoparticles regardless of our preparation conditions. Using two-dimensional infrared (2D IR) spectroscopy, we have identified characteristic frequencies of monomers, dimers, and trimers. A comparison of 2D IR spectra in solution versus those deposited on TiO2 shows that the propensity to dimerize in solution leads to higher dimer formation on TiO2, but that dimers are formed even if there are only monomers in solution. Aggregates cannot be washed off with standard protocols and are present even at submonolayer coverages. We observe cross peaks between aggregates of different sizes, primarily dimers and trimers, indicating that clusters consist of microdomains in close proximity. 2D IR spectroscopy is used to draw these conclusions from measurements of vibrational couplings, but if molecules are close enough to be vibrationally coupled, then they are also likely to be electronically coupled, which could alter charge transfer. PMID- 26049470 TI - Hydrogen bond dynamics in bulk alcohols. AB - Hydrogen-bonded liquids play a significant role in numerous chemical and biological phenomena. In the past decade, impressive developments in multidimensional vibrational spectroscopy and combined molecular dynamics-quantum mechanical simulation have established many intriguing features of hydrogen bond dynamics in one of the fundamental solvents in nature, water. The next class of a hydrogen-bonded liquid--alcohols--has attracted much less attention. This is surprising given such important differences between water and alcohols as the imbalance between the number of hydrogen bonds, each molecule can accept (two) and donate (one) and the very presence of the hydrophobic group in alcohols. Here, we use polarization-resolved pump-probe and 2D infrared spectroscopy supported by extensive theoretical modeling to investigate hydrogen bond dynamics in methanol, ethanol, and isopropanol employing the OH stretching mode as a reporter. The sub-ps dynamics in alcohols are similar to those in water as they are determined by similar librational and hydrogen-bond stretch motions. However, lower density of hydrogen bond acceptors and donors in alcohols leads to the appearance of slow diffusion-controlled hydrogen bond exchange dynamics, which are essentially absent in water. We anticipate that the findings herein would have a potential impact on fundamental chemistry and biology as many processes in nature involve the interplay of hydrophobic and hydrophilic groups. PMID- 26049471 TI - Pulse-shaping assisted multidimensional coherent electronic spectroscopy. AB - Understanding nuclear and electronic dynamics of molecular systems has advanced considerably by probing their nonlinear responses with a suitable sequence of pulses. Moreover, the ability to control crucial parameters of the excitation pulses, such as duration, sequence, frequency, polarization, slowly varying envelope, or carrier phase, has led to a variety of advanced time-resolved spectroscopic methodologies. Recently, two-dimensional electronic spectroscopy with ultrashort pulses has become a more and more popular tool since it allows to obtain information on energy and coherence transfer phenomena, line broadening mechanisms, or the presence of quantum coherences in molecular complexes. Here, we present a high fidelity two-dimensional electronic spectroscopy setup designed for molecular systems in solution. It incorporates the versatility of pulse shaping methods to achieve full control on the amplitude and phase of the individual exciting and probing pulses. Selective and precise amplitude- and phase-modulation is shown and applied to investigate electronic dynamics in several reference molecular systems. PMID- 26049472 TI - Detection of dark states in two-dimensional electronic photon-echo signals via ground-state coherence. AB - Several recent experiments report on possibility of dark-state detection by means of so called beating maps of two-dimensional photon-echo spectroscopy [Ostroumov et al., Science 340, 52 (2013); Bakulin et al., Ultrafast Phenomena XIX (Springer International Publishing, 2015)]. The main idea of this detection scheme is to use coherence induced upon the laser excitation as a very sensitive probe. In this study, we investigate the performance of ground-state coherence in the detection of dark electronic states. For this purpose, we simulate beating maps of several models where the excited-state coherence can be hardly detected and is assumed not to contribute to the beating maps. The models represent strongly coupled electron-nuclear dynamics involving avoided crossings and conical intersections. In all the models, the initially populated optically accessible excited state decays to a lower-lying dark state within few hundreds femtoseconds. We address the role of Raman modes and of interstate-coupling nature. Our findings suggest that the presence of low-frequency Raman active modes significantly increases the chances for detection of dark states populated via avoided crossings, whereas conical intersections represent a more challenging task. PMID- 26049473 TI - Computationally efficient dielectric calculations of molecular crystals. AB - The microscopic dielectric response is a key quantity for electronic materials such as organic semiconductors. Calculations of this response for molecular crystals are currently either expensive or rely on extreme simplifications such as multipole expansions which lack microscopic detail. We present an alternate approach using a microscopic analogue of the Clausius-Mossotti equation, which constructs the dielectric response of a crystal from an eigenvalue decomposition of the dielectric response of individual molecules. This method can potentially be used to examine the effects of defects, disorder, and surfaces on the dielectric properties of molecular solids. PMID- 26049474 TI - Prediction of core level binding energies in density functional theory: Rigorous definition of initial and final state contributions and implications on the physical meaning of Kohn-Sham energies. AB - A systematic study of the N(1s) core level binding energies (BE's) in a broad series of molecules is presented employing Hartree-Fock (HF) and the B3LYP, PBE0, and LC-BPBE density functional theory (DFT) based methods with a near HF basis set. The results show that all these methods give reasonably accurate BE's with B3LYP being slightly better than HF but with both PBE0 and LCBPBE being poorer than HF. A rigorous and general decomposition of core level binding energy values into initial and final state contributions to the BE's is proposed that can be used within either HF or DFT methods. The results show that Koopmans' theorem does not hold for the Kohn-Sham eigenvalues. Consequently, Kohn-Sham orbital energies of core orbitals do not provide estimates of the initial state contribution to core level BE's; hence, they cannot be used to decompose initial and final state contributions to BE's. However, when the initial state contribution to DFT BE's is properly defined, the decompositions of initial and final state contributions given by DFT, with several different functionals, are very similar to those obtained with HF. Furthermore, it is shown that the differences of Kohn-Sham orbital energies taken with respect to a common reference do follow the trend of the properly calculated initial state contributions. These conclusions are especially important for condensed phase systems where our results validate the use of band structure calculations to determine initial state contributions to BE shifts. PMID- 26049475 TI - Oscillator strengths, first-order properties, and nuclear gradients for local ADC(2). AB - We describe theory and implementation of oscillator strengths, orbital-relaxed first-order properties, and nuclear gradients for the local algebraic diagrammatic construction scheme through second order. The formalism is derived via time-dependent linear response theory based on a second-order unitary coupled cluster model. The implementation presented here is a modification of our previously developed algorithms for Laplace transform based local time-dependent coupled cluster linear response (CC2LR); the local approximations thus are state specific and adaptive. The symmetry of the Jacobian leads to considerable simplifications relative to the local CC2LR method; as a result, a gradient evaluation is about four times less expensive. Test calculations show that in geometry optimizations, usually very similar geometries are obtained as with the local CC2LR method (provided that a second-order method is applicable). As an exemplary application, we performed geometry optimizations on the low-lying singlet states of chlorophyllide a. PMID- 26049476 TI - Analysis and comparison of CVS-ADC approaches up to third order for the calculation of core-excited states. AB - The extended second order algebraic-diagrammatic construction (ADC(2)-x) scheme for the polarization operator in combination with core-valence separation (CVS) approximation is well known to be a powerful quantum chemical method for the calculation of core-excited states and the description of X-ray absorption spectra. For the first time, the implementation and results of the third order approach CVS-ADC(3) are reported. Therefore, the CVS approximation has been applied to the ADC(3) working equations and the resulting terms have been implemented efficiently in the adcman program. By treating the alpha and beta spins separately from each other, the unrestricted variant CVS-UADC(3) for the treatment of open-shell systems has been implemented as well. The performance and accuracy of the CVS-ADC(3) method are demonstrated with respect to a set of small and middle-sized organic molecules. Therefore, the results obtained at the CVS ADC(3) level are compared with CVS-ADC(2)-x values as well as experimental data by calculating complete basis set limits. The influence of basis sets is further investigated by employing a large set of different basis sets. Besides the accuracy of core-excitation energies and oscillator strengths, the importance of cartesian basis functions and the treatment of orbital relaxation effects are analyzed in this work as well as computational timings. It turns out that at the CVS-ADC(3) level, the results are not further improved compared to CVS-ADC(2)-x and experimental data, because the fortuitous error compensation inherent in the CVS-ADC(2)-x approach is broken. While CVS-ADC(3) overestimates the core excitation energies on average by 0.61% +/- 0.31%, CVS-ADC(2)-x provides an averaged underestimation of -0.22% +/- 0.12%. Eventually, the best agreement with experiments can be achieved using the CVS-ADC(2)-x method in combination with a diffuse cartesian basis set at least at the triple-zeta level. PMID- 26049477 TI - Factorized molecular wave functions: Analysis of the nuclear factor. AB - The exact factorization of molecular wave functions leads to nuclear factors which should be nodeless functions. We reconsider the case of vibrational perturbations in a diatomic species, a situation usually treated by combining Born-Oppenheimer products. It was shown [R. Lefebvre, J. Chem. Phys. 142, 074106 (2015)] that it is possible to derive, from the solutions of coupled equations, the form of the factorized function. By increasing artificially the interstate coupling in the usual approach, the adiabatic regime can be reached, whereby the wave function can be reduced to a single product. The nuclear factor of this product is determined by the lowest of the two potentials obtained by diagonalization of the potential matrix. By comparison with the nuclear wave function of the factorized scheme, it is shown that by a simple rectification, an agreement is obtained between the modified nodeless function and that of the adiabatic scheme. PMID- 26049478 TI - Analytical energy gradient for the two-component normalized elimination of the small component method. AB - The analytical gradient for the two-component Normalized Elimination of the Small Component (2c-NESC) method is presented. The 2c-NESC is a Dirac-exact method that employs the exact two-component one-electron Hamiltonian and thus leads to exact Dirac spin-orbit (SO) splittings for one-electron atoms. For many-electron atoms and molecules, the effect of the two-electron SO interaction is modeled by a screened nucleus potential using effective nuclear charges as proposed by Boettger [Phys. Rev. B 62, 7809 (2000)]. The effect of spin-orbit coupling (SOC) on molecular geometries is analyzed utilizing the properties of the frontier orbitals and calculated SO couplings. It is shown that bond lengths can either be lengthened or shortened under the impact of SOC where in the first case the influence of low lying excited states with occupied antibonding orbitals plays a role and in the second case the jj-coupling between occupied antibonding and unoccupied bonding orbitals dominates. In general, the effect of SOC on bond lengths is relatively small (<=5% of the scalar relativistic changes in the bond length). However, large effects are found for van der Waals complexes Hg2 and Cn2, which are due to the admixture of more bonding character to the highest occupied spinors. PMID- 26049479 TI - Quantum treatment of protons with the reduced explicitly correlated Hartree-Fock approach. AB - The nuclear-electronic orbital (NEO) approach treats select nuclei quantum mechanically on the same level as the electrons and includes nonadiabatic effects between the electrons and the quantum nuclei. The practical implementation of this approach is challenging due to the significance of electron-nucleus dynamical correlation. Herein, we present a general extension of the previously developed reduced NEO explicitly correlated Hartree-Fock (RXCHF) approach, in which only select electronic orbitals are explicitly correlated to each quantum nuclear orbital via Gaussian-type geminal functions. Approximations of the electronic exchange between the geminal-coupled electronic orbitals and the other electronic orbitals are also explored. This general approach enables computationally tractable yet accurate calculations on molecular systems with quantum protons. The RXCHF method is applied to the hydrogen cyanide (HCN) and FHF(-) systems, where the proton and all electrons are treated quantum mechanically. For the HCN system, only the two electronic orbitals associated with the CH covalent bond are geminal-coupled to the proton orbital. For the FHF( ) system, only the four electronic orbitals associated with the two FH covalent bonds are geminal-coupled to the proton orbital. For both systems, the RXCHF method produces qualitatively accurate nuclear densities, in contrast to mean field-based NEO approaches. The development and implementation of the RXCHF method provide the framework to perform calculations on systems such as proton coupled electron transfer reactions, where electron-proton nonadiabatic effects are important. PMID- 26049480 TI - Nuclear-electronic orbital reduced explicitly correlated Hartree-Fock approach: Restricted basis sets and open-shell systems. AB - The nuclear electronic orbital (NEO) reduced explicitly correlated Hartree-Fock (RXCHF) approach couples select electronic orbitals to the nuclear orbital via Gaussian-type geminal functions. This approach is extended to enable the use of a restricted basis set for the explicitly correlated electronic orbitals and an open-shell treatment for the other electronic orbitals. The working equations are derived and the implementation is discussed for both extensions. The RXCHF method with a restricted basis set is applied to HCN and FHF(-) and is shown to agree quantitatively with results from RXCHF calculations with a full basis set. The number of many-particle integrals that must be calculated for these two molecules is reduced by over an order of magnitude with essentially no loss in accuracy, and the reduction factor will increase substantially for larger systems. Typically, the computational cost of RXCHF calculations with restricted basis sets will scale in terms of the number of basis functions centered on the quantum nucleus and the covalently bonded neighbor(s). In addition, the RXCHF method with an odd number of electrons that are not explicitly correlated to the nuclear orbital is implemented using a restricted open-shell formalism for these electrons. This method is applied to HCN(+), and the nuclear densities are in qualitative agreement with grid-based calculations. Future work will focus on the significance of nonadiabatic effects in molecular systems and the further enhancement of the NEO-RXCHF approach to accurately describe such effects. PMID- 26049481 TI - Vertical and adiabatic excitations in anthracene from quantum Monte Carlo: Constrained energy minimization for structural and electronic excited-state properties in the JAGP ansatz. AB - We study the ionization energy, electron affinity, and the pi -> pi(*) ((1)La) excitation energy of the anthracene molecule, by means of variational quantum Monte Carlo (QMC) methods based on a Jastrow correlated antisymmetrized geminal power (JAGP) wave function, developed on molecular orbitals (MOs). The MO-based JAGP ansatz allows one to rigorously treat electron transitions, such as the HOMO -> LUMO one, which underlies the (1)La excited state. We present a QMC optimization scheme able to preserve the rank of the antisymmetrized geminal power matrix, thanks to a constrained minimization with projectors built upon symmetry selected MOs. We show that this approach leads to stable energy minimization and geometry relaxation of both ground and excited states, performed consistently within the correlated QMC framework. Geometry optimization of excited states is needed to make a reliable and direct comparison with experimental adiabatic excitation energies. This is particularly important in pi conjugated and polycyclic aromatic hydrocarbons, where there is a strong interplay between low-lying energy excitations and structural modifications, playing a functional role in many photochemical processes. Anthracene is an ideal benchmark to test these effects. Its geometry relaxation energies upon electron excitation are of up to 0.3 eV in the neutral (1)La excited state, while they are of the order of 0.1 eV in electron addition and removal processes. Significant modifications of the ground state bond length alternation are revealed in the QMC excited state geometry optimizations. Our QMC study yields benchmark results for both geometries and energies, with values below chemical accuracy if compared to experiments, once zero point energy effects are taken into account. PMID- 26049482 TI - Computation of virial coefficients from integral equations. AB - A polynomial-time method of computing the virial coefficients from an integral equation framework is presented. The method computes the truncated density expansions of the correlation functions by series transformations, and then extracts the virial coefficients from the density components. As an application, the method was used in a hybrid-closure integral equation with a set of self consistent conditions, which produced reasonably accurate virial coefficients for the hard-sphere fluid and Gaussian model in high dimensions. PMID- 26049483 TI - Assessment of TD-DFT and LF-DFT for study of d - d transitions in first row transition metal hexaaqua complexes. AB - Herein, we present the systematic, comparative computational study of the d - d transitions in a series of first row transition metal hexaaqua complexes, [M(H2O)6](n+) (M(2+/3+) = V (2+/3+), Cr(2+/3+), Mn(2+/3+), Fe(2+/3+), Co(2+/3+), Ni(2+)) by the means of Time-dependent Density Functional Theory (TD-DFT) and Ligand Field Density Functional Theory (LF-DFT). Influence of various exchange correlation (XC) approximations have been studied, and results have been compared to the experimental transition energies, as well as, to the previous high-level ab initio calculations. TD-DFT gives satisfactory results in the cases of d(2), d(4), and low-spin d(6) complexes, but fails in the cases when transitions depend only on the ligand field splitting, and for states with strong character of double excitation. LF-DFT, as a non-empirical approach to the ligand field theory, takes into account in a balanced way both dynamic and non-dynamic correlation effects and hence accurately describes the multiplets of transition metal complexes, even in difficult cases such as sextet-quartet splitting in d(5) complexes. Use of the XC functionals designed for the accurate description of the spin-state splitting, e.g., OPBE, OPBE0, or SSB-D, is found to be crucial for proper prediction of the spin-forbidden excitations by LF-DFT. It is shown that LF-DFT is a valuable alternative to both TD-DFT and ab initio methods. PMID- 26049484 TI - Nodal surfaces and interdimensional degeneracies. AB - The aim of this paper is to shed light on the topology and properties of the nodes (i.e., the zeros of the wave function) in electronic systems. Using the "electrons on a sphere" model, we study the nodes of two-, three-, and four electron systems in various ferromagnetic configurations (sp, p(2), sd, pd, p(3), sp(2), and sp(3)). In some particular cases (sp, p(2), sd, pd, and p(3)), we rigorously prove that the non-interacting wave function has the same nodes as the exact (yet unknown) wave function. The number of atomic and molecular systems for which the exact nodes are known analytically is very limited and we show here that this peculiar feature can be attributed to interdimensional degeneracies. Although we have not been able to prove it rigorously, we conjecture that the nodes of the non-interacting wave function for the sp(3) configuration are exact. PMID- 26049485 TI - A comparison of weighted ensemble and Markov state model methodologies. AB - Computation of reaction rates and elucidation of reaction mechanisms are two of the main goals of molecular dynamics (MD) and related simulation methods. Since it is time consuming to study reaction mechanisms over long time scales using brute force MD simulations, two ensemble methods, Markov State Models (MSMs) and Weighted Ensemble (WE), have been proposed to accelerate the procedure. Both approaches require clustering of microscopic configurations into networks of "macro-states" for different purposes. MSMs model a discretization of the original dynamics on the macro-states. Accuracy of the model significantly relies on the boundaries of macro-states. On the other hand, WE uses macro-states to formulate a resampling procedure that kills and splits MD simulations for achieving better efficiency of sampling. Comparing to MSMs, accuracy of WE rate predictions is less sensitive to the definition of macro-states. Rigorous numerical experiments using alanine dipeptide and penta-alanine support our analyses. It is shown that MSMs introduce significant biases in the computation of reaction rates, which depend on the boundaries of macro-states, and Accelerated Weighted Ensemble (AWE), a formulation of weighted ensemble that uses the notion of colors to compute fluxes, has reliable flux estimation on varying definitions of macro-states. Our results suggest that whereas MSMs provide a good idea of the metastable sets and visualization of overall dynamics, AWE provides reliable rate estimations requiring less efforts on defining macro-states on the high dimensional conformational space. PMID- 26049486 TI - Multiscale model of metal alloy oxidation at grain boundaries. AB - High temperature intergranular oxidation and corrosion of metal alloys is one of the primary causes of materials degradation in nuclear systems. In order to gain insights into grain boundary oxidation processes, a mesoscale metal alloy oxidation model is established by combining quantum Density Functional Theory (DFT) and mesoscopic Poisson-Nernst-Planck/classical DFT with predictions focused on Ni alloyed with either Cr or Al. Analysis of species and fluxes at steady state conditions indicates that the oxidation process involves vacancy-mediated transport of Ni and the minor alloying element to the oxidation front and the formation of stable metal oxides. The simulations further demonstrate that the mechanism of oxidation for Ni-5Cr and Ni-4Al is qualitatively different. Intergranular oxidation of Ni-5Cr involves the selective oxidation of the minor element and not matrix Ni, due to slower diffusion of Ni relative to Cr in the alloy and due to the significantly smaller energy gain upon the formation of nickel oxide compared to that of Cr2O3. This essentially one-component oxidation process results in continuous oxide formation and a monotonic Cr vacancy distribution ahead of the oxidation front, peaking at alloy/oxide interface. In contrast, Ni and Al are both oxidized in Ni-4Al forming a mixed spinel NiAl2O4. Different diffusivities of Ni and Al give rise to a complex elemental distribution in the vicinity of the oxidation front. Slower diffusing Ni accumulates in the oxide and metal within 3 nm of the interface, while Al penetrates deeper into the oxide phase. Ni and Al are both depleted from the region 3-10 nm ahead of the oxidation front creating voids. The oxide microstructure is also different. Cr2O3 has a plate-like structure with 1.2-1.7 nm wide pores running along the grain boundary, while NiAl2O4 has 1.5 nm wide pores in the direction parallel to the grain boundary and 0.6 nm pores in the perpendicular direction providing an additional pathway for oxygen diffusion through the oxide. The proposed theoretical methodology provides a framework for modeling metal alloy oxidation processes from first principles and on the experimentally relevant length scales. PMID- 26049487 TI - Sequential data assimilation for single-molecule FRET photon-counting data. AB - Data assimilation is a statistical method designed to improve the quality of numerical simulations in combination with real observations. Here, we develop a sequential data assimilation method that incorporates one-dimensional time-series data of smFRET (single-molecule Forster resonance energy transfer) photon counting into conformational ensembles of biomolecules derived from "replicated" molecular dynamics (MD) simulations. A particle filter using a large number of "replicated" MD simulations with a likelihood function for smFRET photon-counting data is employed to screen the conformational ensembles that match the experimental data. We examine the performance of the method using emulated smFRET data and coarse-grained (CG) MD simulations of a dye-labeled polyproline-20. The method estimates the dynamics of the end-to-end distance from smFRET data as well as revealing that of latent conformational variables. The particle filter is also able to correct model parameter dependence in CG MD simulations. We discuss the applicability of the method to real experimental data for conformational dynamics of biomolecules. PMID- 26049488 TI - Pair extended coupled cluster doubles. AB - The accurate and efficient description of strongly correlated systems remains an important challenge for computational methods. Doubly occupied configuration interaction (DOCI), in which all electrons are paired and no correlations which break these pairs are permitted, can in many cases provide an accurate account of strong correlations, albeit at combinatorial computational cost. Recently, there has been significant interest in a method we refer to as pair coupled cluster doubles (pCCD), a variant of coupled cluster doubles in which the electrons are paired. This is simply because pCCD provides energies nearly identical to those of DOCI, but at mean-field computational cost (disregarding the cost of the two electron integral transformation). Here, we introduce the more complete pair extended coupled cluster doubles (pECCD) approach which, like pCCD, has mean field cost and reproduces DOCI energetically. We show that unlike pCCD, pECCD also reproduces the DOCI wave function with high accuracy. Moreover, pECCD yields sensible albeit inexact results even for attractive interactions where pCCD breaks down. PMID- 26049489 TI - Rotational spectroscopy and three-wave mixing of 4-carvomenthenol: A technical guide to measuring chirality in the microwave regime. AB - We apply chirality sensitive microwave three-wave mixing to 4-carvomenthenol, a molecule previously uncharacterized with rotational spectroscopy. We measure its rotational spectrum in the 2-8.5 GHz range and observe three molecular conformers. We describe our method in detail, from the initial step of spectral acquisition and assignment to the final step of determining absolute configuration and enantiomeric excess. Combining fitted rotational constants with dipole moment components derived from quantum chemical calculations, we identify candidate three-wave mixing cycles which were further tested using a double resonance method. Initial optimization of the three-wave mixing signal is done by varying the duration of the second excitation pulse. With known transition dipole matrix elements, absolute configuration can be directly determined from a single measurement. PMID- 26049490 TI - Infrared spectrum of the simplest Criegee intermediate CH2OO at resolution 0.25 cm(-1) and new assignments of bands 2nu9 and nu5. AB - The simplest Criegee intermediate CH2OO is important in atmospheric chemistry. It has been detected in the reaction of CH2I + O2 with various spectral methods, including infrared spectroscopy; infrared absorption of CH2OO was recorded at resolution 1.0 cm(-1) in our laboratory. We have improved our system and recorded the infrared spectrum of CH2OO at resolution 0.25 cm(-1) with rotational structures partially resolved. Observed vibrational wavenumbers and relative intensities are improved from those of the previous report and agree well with those predicted with quantum-mechanical calculations using the MULTIMODE method on an accurate potential energy surface. Observed rotational structures also agree with the simulated spectra according to theoretical predictions. In addition to derivation of critical vibrational and rotational parameters of the vibrationally excited states to confirm the assignments, the spectrum with improved resolution provides new assignments for bands 2nu9 at 1234.2 cm(-1) and nu5 at 1213.3 cm(-1); some hot bands and combination bands are also tentatively assigned. PMID- 26049491 TI - Analysis of diffusion trajectories of anisotropic objects. AB - We theoretically analyze diffusion trajectories of an anisotropic object moving on a two dimensional space in the absence of an external field. In determining diffusion parameters associated with the shape anisotropy, we devise a measure based on the gyration tensor and obtain its analytic expression exactly. Its efficiency and statistical convergence are examined in comparison with the fourth cumulant of particle displacement. We find that the estimation of diffusion constants based on the gyration measure is more efficient than the analysis adopting the fourth cumulant. PMID- 26049492 TI - Long-range interactions between polar bialkali ground-state molecules in arbitrary vibrational levels. AB - We have calculated the isotropic C6 coefficients characterizing the long-range van der Waals interaction between two identical heteronuclear alkali-metal diatomic molecules in the same arbitrary vibrational level of their ground electronic state X(1)Sigma(+). We consider the ten species made up of (7)Li, (23)Na, (39)K, (87)Rb, and (133)Cs. Following our previous work [Lepers et al., Phys. Rev. A 88, 032709 (2013)], we use the sum-over-state formula inherent to the second-order perturbation theory, composed of the contributions from the transitions within the ground state levels, from the transition between ground state and excited state levels, and from a crossed term. These calculations involve a combination of experimental and quantum-chemical data for potential energy curves and transition dipole moments. We also investigate the case where the two molecules are in different vibrational levels and we show that the Moelwyn-Hughes approximation is valid provided that it is applied for each of the three contributions to the sum-over-state formula. Our results are particularly relevant in the context of inelastic and reactive collisions between ultracold bialkali molecules in deeply bound or in Feshbach levels. PMID- 26049493 TI - Towards a global model of spin-orbit coupling in the halocarbenes. AB - We report a global analysis of spin-orbit coupling in the mono-halocarbenes, CH(D)X, where X = Cl, Br, and I. These are model systems for examining carbene singlet-triplet energy gaps and spin-orbit coupling. Over the past decade, rich data sets collected using single vibronic level emission spectroscopy and stimulated emission pumping spectroscopy have yielded much information on the ground vibrational level structure and clearly demonstrated the presence of perturbations involving the low-lying triplet state. To model these interactions globally, we compare two approaches. First, we employ a diabatic treatment of the spin-orbit coupling, where the coupling matrix elements are written in terms of a purely electronic spin-orbit matrix element which is independent of nuclear coordinates, and an integral representing the overlap of the singlet and triplet vibrational wavefunctions. In this way, the structures, harmonic frequencies, and normal mode displacements from ab initio calculations were used to calculate the vibrational overlaps of the singlet and triplet state levels, including the full effects of Duschinsky mixing. These calculations have allowed many new assignments to be made, particularly for CHI, and provided spin-orbit coupling parameters and values for the singlet-triplet gaps. In a second approach, we have computed and fit full geometry dependent spin-orbit coupling surfaces and used them to compute matrix elements without the product form approximation. Those matrix elements were used in similar fits varying the anharmonic constants and singlet-triplet gap to reproduce the experimental levels. The derived spin-orbit parameters for carbenes CHX (X = Cl, Br, and I) show an excellent linear correlation with the atomic spin-orbit constant of the corresponding halogen, indicating that the spin-orbit coupling in the carbenes is consistently around 14% of the atomic value. PMID- 26049494 TI - Strong thermal nonequilibrium in hypersonic CO and CH4 probed by CRDS. AB - A new experimental setup coupling a High Enthalpy Source (HES) reaching 2000 K to a cw-cavity ring-down spectrometer has been developed to investigate rotationally cold hot bands of polyatomic molecules in the [1.5, 1.7] MUm region. The rotational and vibrational molecular degrees of freedom are strongly decoupled in the hypersonic expansion produced by the HES and probed by cavity ring-down spectroscopy. Carbon monoxide has been used as a first test molecule to validate the experimental approach. Its expansion in argon led to rotational and vibrational temperatures of 6.7 +/- 0.8 K and 2006 +/- 476 K, respectively. The tetradecad polyad of methane (1.67 MUm) was investigated under similar conditions leading to rotational and vibrational temperatures of 13 +/- 5 K and 750 +/- 100 K, respectively. The rotationally cold structure of the spectra reveals many hot bands involving highly excited vibrational states of methane. PMID- 26049495 TI - IR photodissociation spectroscopy of (OCS)n(+) and (OCS)n(-) cluster ions: Similarity and dissimilarity in the structure of CO2, OCS, and CS2 cluster ions. AB - Infrared photodissociation (IRPD) spectra of (OCS)n(+) and (OCS)n(-) (n = 2-6) cluster ions are measured in the 1000-2300 cm(-1) region; these clusters show strong CO stretching vibrations in this region. For (OCS)2 +) and (OCS)2(-), we utilize the messenger technique by attaching an Ar atom to measure their IR spectra. The IRPD spectrum of (OCS)2 (+)Ar shows two bands at 2095 and 2120 cm( 1). On the basis of quantum chemical calculations, these bands are assigned to a C2 isomer of (OCS)2 (+), in which an intermolecular semi-covalent bond is formed between the sulfur ends of the two OCS components by the charge resonance interaction, and the positive charge is delocalized over the dimer. The (OCS)n(+) (n = 3-6) cluster ions show a few bands assignable to "solvent" OCS molecules in the 2000-2080 cm(-1) region, in addition to the bands due to the (OCS)2(+) ion core at ~2090 and ~2120 cm(-1), suggesting that the dimer ion core is kept in (OCS)3-6(+). For the (OCS)n(-) cluster anions, the IRPD spectra indicate the coexistence of a few isomers with an OCS(-) or (OCS)2(-) anion core over the cluster range of n = 2-6. The (OCS)2(-)Ar anion displays two strong bands at 1674 and 1994 cm(-1). These bands can be assigned to a Cs isomer with an OCS(-) anion core. For the n = 2-4 anions, this OCS(-) anion core form is dominant. In addition to the bands of the OCS(-) core isomer, we found another band at ~1740 cm(-1), which can be assigned to isomers having an (OCS)2(-) ion core; this dimer core has C2 symmetry and (2)A electronic state. The IRPD spectra of the n = 3-6 anions show two IR bands at ~1660 and ~2020 cm(-1). The intensity of the latter component relative to that of the former one becomes stronger and stronger with increasing the size from n = 2 to 4, which corresponds to the increase of "solvent" OCS molecules attached to the OCS(-) ion core, but it suddenly decreases at n = 5 and 6. These IR spectral features of the n = 5 and 6 anions are ascribed to the formation of another (OCS)2(-) ion core having C2v symmetry with (2)B2 electronic state. PMID- 26049496 TI - Understanding the stable boron clusters: A bond model and first-principles calculations based on high-throughput screening. AB - The unique electronic property induced diversified structure of boron (B) cluster has attracted much interest from experimentalists and theorists. B30-40 were reported to be planar fragments of triangular lattice with proper concentrations of vacancies recently. Here, we have performed high-throughput screening for possible B clusters through the first-principles calculations, including various shapes and distributions of vacancies. As a result, we have determined the structures of Bn clusters with n = 30-51 and found a stable planar cluster of B49 with a double-hexagon vacancy. Considering the 8-electron rule and the electron delocalization, a concise model for the distribution of the 2c-2e and 3c-2e bonds has been proposed to explain the stability of B planar clusters, as well as the reported B cages. PMID- 26049497 TI - Backbone NxH compounds at high pressures. AB - Optical and synchrotron x-ray diffraction diamond anvil cell experiments have been combined with first-principles theoretical structure predictions to investigate mixtures of N2 and H2 up to 55 GPa. Our experiments show the formation of structurally complex van der Waals compounds [see also D. K. Spaulding et al., Nat. Commun. 5, 5739 (2014)] above 10 GPa. However, we found that these NxH (0.5 < x < 1.5) compounds transform abruptly to new oligomeric materials through barochemistry above 47 GPa and photochemistry at pressures as low as 10 GPa. These oligomeric compounds can be recovered to ambient pressure at T < 130 K, whereas at room temperature, they can be metastable on pressure release down to 3.5 GPa. Extensive theoretical calculations show that such oligomeric materials become thermodynamically more stable in comparison to mixtures of N2, H2, and NH3 above approximately 40 GPa. Our results suggest new pathways for synthesis of environmentally benign high energy-density materials. These materials could also exist as alternative planetary ices. PMID- 26049498 TI - CH3OH?(H2O)n [n = 1-4] clusters in external electric fields. AB - For hydrogen-bonded neutral molecular clusters, response to an externally applied electric field can critically affect molecular cooperativity. In this light, response of dilute methanol-water admixtures to an external, perturbative electric field is studied at the simplest molecular level in the cluster configurations CH3OH?(H2O)n with "n" chosen to range from 1 to 4, employing the M06-2X hybrid functional in conjunction with the 6-311++G(2d,2p) basis set, well suited for hydrogen bonding. Methanol is seen to favorably bond with the water molecules at its hydroxyl end up to certain characteristic maximum threshold field strengths beyond which the HOMO-LUMO energy-gap abruptly drops to zero culminating into a complete breakdown of the cluster. In the interim regime prior to breakdown, the electric field significantly alters the hydrogen bonding pattern primarily by elongating the cluster, resulting in a marked enhancement in its electric dipole moment leading to alterations in the molecular electrostatic potential. With the application of electric field, certain "exotic" O-H vibration bands appear that at the threshold field fall in the frequency range of 2510 cm( 1)-1880 cm(-1) in the IR spectra, in contrast with their normal (zero-field) counterparts that occur in the range of ~3300-3900 cm(-1). PMID- 26049499 TI - Quantum mechanical calculations of state-to-state cross sections and rate constants for the F + DCl -> Cl + DF reaction. AB - We present accurate state-to-state quantum wave packet calculations of integral cross sections and rate constants for the title reaction. Calculations are carried out on the best available ground 1(2)A' global adiabatic potential energy surface of Deskevich et al. [J. Chem. Phys. 124, 224303 (2006)]. Converged state to-state reaction cross sections have been calculated for collision energies up to 0.5 eV and different initial rotational and vibrational excitations, DCl(v = 0, j = 0 - 1; v = 1, j = 0). Also, initial-state resolved rate constants of the title reaction have been calculated in a temperature range of 100-400 K. It is found that the initial rotational excitation of the DCl molecule does not enhance reactivity, in contract to the reaction with the isotopologue HCl in which initial rotational excitation produces an important enhancement. These differences between the isotopologue reactions are analyzed in detail and attributed to the presence of resonances for HCl(v = 0, j), absent in the case of DCl(v = 0, j). For vibrational excited DCl(v = 1, j), however, the reaction cross section increases noticeably, what is also explained by another resonance. PMID- 26049500 TI - A scheme for a single molecule phase-shift gate in a solid matrix. AB - We propose a feasible scheme to implement a phase-shift gate ((1 0) (0 eigamma)) based on a two-state single molecule in a solid matrix, where gamma is a geometric phase controlled through a fast on-resonant laser field and a slow off resonant radio-frequency field. In our scheme, a non-Hermitian quantum model is employed to characterize the single molecule in a solid matrix including the spontaneous decay effect. By the coupling between the radio-frequency field and the two-state permanent dipole difference resulting from the solid matrix, the spontaneous decay fatal to the preservation of geometric phase can be effectively suppressed for a considerably long waiting time. PMID- 26049501 TI - Velocity map imaging of O-atom products from UV photodissociation of the CH2OO Criegee intermediate. AB - UV excitation of jet-cooled CH2OO X(1)A' to the excited B(1)A' electronic states results in dissociation to two spin-allowed product channels: H2CO X(1)A1 + O (1)D and H2CO a(3)A" + O (3)P. In this study, the higher energy H2CO a(3)A" + O (3)P channel is characterized by velocity map imaging and UV action spectroscopy, in both cases utilizing 2 + 1 resonance enhanced multiphoton ionization detection of O (3)P products, which complements a prior experimental study on the lower energy H2CO X(1)A1 + O (1)D channel [Lehman et al., J. Chem. Phys. 139, 141103 (2013)]. Anisotropic angular distributions indicative of rapid dissociation are obtained at 330 and 350 nm, along with broad and unstructured total kinetic energy distributions that provide insight into the internal excitation of the H2CO a(3)A" co-fragment. A harmonic normal mode analysis points to significant vibrational excitation of the CH2 wag and C-O stretch modes of the H2CO a(3)A" fragment upon dissociation. At each UV wavelength, the termination of the kinetic energy distribution reveals the energetic threshold for the H2CO a(3)A" + O (3)P product channel of ca. 76 kcal mol(-1) (378 nm) and also establishes the dissociation energy from CH2OO X(1)A' to H2CO X(1)A1 + O(1)D products of D0 <= 49.0 +/- 0.3 kcal mol(-1), which is in accord with prior theoretical studies. The threshold for the H2CO a(3)A" + O (3)P channel is also evident as a more rapid falloff on the long wavelength side of the O (3)P action spectrum as compared to the previously reported UV absorption spectrum for jet-cooled CH2OO [Beames et al., J. Am. Chem. Soc. 134, 20045 (2012)]. Modeling suggests that the O (3)P yield increases uniformly from 378 to 300 nm. PMID- 26049502 TI - Kinetic-freezing and unfreezing of local-region fluctuations in a glass structure observed by heat capacity hysteresis. AB - Fluctuations confined to local regions in the structure of a glass are observed as the Johari-Goldstein (JG) relaxation. Properties of these regions and their atomic configuration are currently studied by relaxation techniques, by electron microscopy, and by high-energy X-ray scattering and extended x-ray absorption fine structure methods. One expects that these fluctuations (i) would kinetically freeze on cooling a glass, and the temperature coefficient of its enthalpy, dH/dT, would consequently show a gradual decrease with decrease in T, (ii) would kinetically unfreeze on heating the glass toward the glass-liquid transition temperature, Tg, and dH/dT would gradually increase, and (iii) there would be a thermal hysteresis indicating the time and temperature dependence of the enthalpy. Since no such features have been found, thermodynamic consequences of these fluctuations are debated. After searching for these features in glasses of different types, we found it in one of the most stable metal alloy glasses of composition Pd40Ni10Cu30P20. On cooling from its Tg, dH/dT decreased along a broad sigmoid-shape path as local-region fluctuations kinetically froze. On heating thereafter, dH/dT increased along a similar path as these fluctuations unfroze, and there is hysteresis in the cooling and heating paths, similar to that observed in the Tg-endotherm range. After eliminating other interpretations, we conclude that local-region fluctuations seen as the JG relaxation in the non equilibrium state of a glass contribute to its entropy, and we suggest conditions under which such fluctuations may be observed. PMID- 26049503 TI - On the determination of phase boundaries via thermodynamic integration across coexistence regions. AB - Specialized Monte Carlo methods are nowadays routinely employed, in combination with thermodynamic integration (TI), to locate phase boundaries of classical many particle systems. This is especially useful for the fluid-solid transition, where a critical point does not exist and both phases may notoriously go deeply metastable. Using the Lennard-Jones model for demonstration, we hereby investigate on the alternate possibility of tracing reasonably accurate transition lines directly by integrating the pressure equation of state computed in a canonical-ensemble simulation with local moves. The recourse to this method would become a necessity when the stable crystal structure is not known. We show that, rather counterintuitively, metastability problems can be alleviated by reducing (rather than increasing) the size of the system. In particular, the location of liquid-vapor coexistence can exactly be predicted by just TI. On the contrary, TI badly fails in the solid-liquid region, where a better assessment (to within 10% accuracy) of the coexistence pressure can be made by following the expansion, until melting, of the defective solid which has previously emerged from the decay of the metastable liquid. PMID- 26049504 TI - Local structure of solid Rb at megabar pressures. AB - We have investigated the local and electronic structure of solid rubidium by means of x-ray absorption spectroscopy up to 101.0 GPa, thus doubling the maximum investigated experimental pressure. This study confirms the predicted stability of phase VI and was completed by the combination of two pivotal instrumental solutions. On one side, we made use of nanocrystalline diamond anvils, which, contrary to the more commonly used single crystal diamond anvils, do not generate sharp Bragg peaks (glitches) at specific energies that spoil the weak fine structure oscillations in the x-ray absorption cross section. Second, we exploited the performance of a state-of-the-art x-ray focussing device yielding a beam spot size of 5 * 5 MUm(2), spatially stable over the entire energy scan. An advanced data analysis protocol was implemented to extract the pressure dependence of the structural parameters in phase VI of solid Rb from 51.2 GPa up to the highest pressure. A continuous reduction of the nearest neighbour distances was observed, reaching about 6% over the probed pressure range. We also discuss a phenomenological model based on the Einstein approximation to describe the pressure behaviour of the mean-square relative displacement. Within this simplified scheme, we estimate the Gruneisen parameter for this high pressure Rb phase to be in the 1.3-1.5 interval. PMID- 26049505 TI - Dielectric relaxation of 2-ethyl-1-hexanol around the glass transition by thermally stimulated depolarization currents. AB - We explore new routes for characterizing the Debye-like and alpha relaxation in 2 ethyl-1-hexanol (2E1H) monoalcohol by using low frequency dielectric techniques including thermally stimulated depolarization current (TSDC) techniques and isothermal depolarization current methods. In this way, we have improved the resolution of the overlapped processes making it possible the analysis of the data in terms of a mode composition as expected for a chain-like response. Furthermore the explored ultralow frequencies enabled to study dynamics at relatively low temperatures close to the glass transition (Tg). Results show, on the one hand, that Debye-like and alpha relaxation timescales dramatically approach to each other upon decreasing temperature to Tg. On the other hand, the analysis of partial polarization TSDC data confirms the single exponential character of the Debye-like relaxation in 2E1H and rules out the presence of Rouse type modes in the scenario of a chain-like response. Finally, on crossing the glass transition, the Debye-like relaxation shows non-equilibrium effects which are further emphasized by aging treatment and would presumably emerge as a result of the arrest of the structural relaxation below Tg. PMID- 26049506 TI - Anomaly in dielectric relaxation dispersion of glass-forming alkoxy alcohols. AB - The dielectric relaxations in six primary and secondary alkoxy alcohols with varying molecular size and different separation between -O- and hydroxyl group are studied at temperatures around glass transition. The analyses of the apparent full width at half maximum of the main relaxations of the alkoxy alcohols reveal minima in the temperature dependence of the relaxation dispersions. The stretching exponents for the main relaxations of the alkoxy alcohols are also found not to follow the empirical correlations with other dynamic quantities established for generic liquids. A comparison of the relaxation dispersions in the alkoxy alcohols with those in Debye and non-Debye (generic) liquids is presented. The impacts of the beta-relaxations on the apparent main relaxation widths are reviewed for molecular glass formers. PMID- 26049507 TI - Equations of state of anhydrous AlF3 and AlI3: Modeling of extreme condition halide chemistry. AB - Pressure dependent angle-dispersive x-ray powder diffraction measurements of alpha-phase aluminum trifluoride (alpha-AlF3) and separately, aluminum triiodide (AlI3) were conducted using a diamond-anvil cell. Results at 295 K extend to 50 GPa. The equations of state of AlF3 and AlI3 were determined through refinements of collected x-ray diffraction patterns. The respective bulk moduli and corresponding pressure derivatives are reported for multiple orders of the Birch Murnaghan (B-M), finite-strain (F-f), and higher pressure finite-strain (G-g) EOS analysis models. Aluminum trifluoride exhibits an apparent isostructural phase transition at approximately 12 GPa. Aluminum triiodide also undergoes a second order atomic rearrangement: applied stress transformed a monoclinically distorted face centered cubic (fcc) structure into a standard fcc structural arrangement of iodine atoms. Results from semi-empirical thermochemical computations of energetic materials formulated with fluorine containing reactants were obtained with the aim of predicting the yield of halogenated products. PMID- 26049509 TI - Structure and thermodynamics of core-softened models for alcohols. AB - The phase behavior and the fluid structure of coarse-grain models for alcohols are studied by means of reference interaction site model (RISM) theory and Monte Carlo simulations. Specifically, we model ethanol and 1-propanol as linear rigid chains constituted by three (trimers) and four (tetramers) partially fused spheres, respectively. Thermodynamic properties of these models are examined in the RISM context, by employing closed formulae for the calculation of free energy and pressure. Gas-liquid coexistence curves for trimers and tetramers are reported and compared with already existing data for a dimer model of methanol. Critical temperatures slightly increase with the number of CH2 groups in the chain, while critical pressures and densities decrease. Such a behavior qualitatively reproduces the trend observed in experiments on methanol, ethanol, and 1-propanol and suggests that our coarse-grain models, despite their simplicity, can reproduce the essential features of the phase behavior of such alcohols. The fluid structure of these models is investigated by computing radial distribution function gij(r) and static structure factor Sij(k); the latter shows the presence of a low-k peak at intermediate-high packing fractions and low temperatures, suggesting the presence of aggregates for both trimers and tetramers. PMID- 26049508 TI - The liquid-vapor equilibria of TIP4P/2005 and BLYPSP-4F water models determined through direct simulations of the liquid-vapor interface. AB - In this paper, the surface tension and critical properties for the TIP4P/2005 and BLYPSP-4F models are reported. A clear dependence of surface tension on the van der Waals cutoff radius (rvdw) is shown when van der Waals interactions are modeled with a simple cutoff scheme. A linear extrapolation formula is proposed that can be used to determine the infinite rvdw surface tension through a few simulations with finite rvdw. A procedure for determining liquid and vapor densities is proposed that does not require fitting to a profile function. Although the critical temperature of water is also found to depend on the choice of rvdw, the dependence is weaker. We argue that a rvdw of 1.75 nm is a good compromise for water simulations when long-range van der Waals correction is not applied. Since the majority of computational programs do not support rigorous treatment of long-range dispersion, the establishment of a minimal acceptable rvdw is important for the simulation of a variety of inhomogeneous systems, such as water bubbles, and water in confined environments. The BLYPSP-4F model predicts room temperature surface tension marginally better than TIP4P/2005 but overestimates the critical temperature. This is expected since only liquid configurations were fit during the development of the BLYPSP-4F potential. The potential is expected to underestimate the stability of vapor and thus overestimate the region of stability for the liquid. PMID- 26049510 TI - Formation of methane nano-bubbles during hydrate decomposition and their effect on hydrate growth. AB - Molecular dynamic simulations are performed to study the conditions for methane nano-bubble formation during methane hydrate dissociation in the presence of water and a methane gas reservoir. Hydrate dissociation leads to the quick release of methane into the liquid phase which can cause methane supersaturation. If the diffusion of methane molecules out of the liquid phase is not fast enough, the methane molecules agglomerate and form bubbles. Under the conditions of our simulations, the methane-rich quasi-spherical bubbles grow to become cylindrical with a radius of ~11 A. The nano-bubbles remain stable for about 35 ns until they are gradually and homogeneously dispersed in the liquid phase and finally enter the gas phase reservoirs initially set up in the simulation box. We determined that the minimum mole fraction for the dissolved methane in water to form nano bubbles is 0.044, corresponding to about 30% of hydrate phase composition (0.148). The importance of nano-bubble formation to the mechanism of methane hydrate formation, growth, and dissociation is discussed. PMID- 26049511 TI - Control of optical response of a supported cluster on different dielectric substrates. AB - We develop a computational method for optical response of a supported cluster on a dielectric substrate. The substrate is approximated by a dielectric continuum with a frequency-dependent dielectric function. The computational approach is based on our recently developed first-principles simulation method for photoinduced electron dynamics in real-time and real-space. The approach allows us to treat optical response of an adsorbate explicitly taking account of interactions at an interface between an adsorbate and a substrate. We calculate optical absorption spectra of supported Agn (n = 2, 54) clusters, changing the dielectric function of a substrate. By analyzing electron dynamics in real-time and real-space, we clarify the mechanisms for variations in absorption spectra, such as peak shifts and intensity changes, relating to various experimental results for optical absorption of supported clusters. Attractive and repulsive interactions between an adsorbate and a substrate result in red and blue shifts, respectively, and the intensity decreases by energy dissipation into a substrate. We demonstrate that optical properties can be controlled by varying the dielectric function of a substrate. PMID- 26049512 TI - Squeezing-out dynamics in free-standing smectic films. AB - We have carried out a theoretical study of the dynamics of the removal of one smectic layer from the N-layer free-standing smectic film during the layer thinning process. Squeezing-out is initiated by a thermally activated nucleation process in which a density fluctuation forms a small hole. The dynamics of the bounding area during the layer-thinning transition N -> N - 1, when the nucleation occurs in the center of the circular smectic film and the squeezed-out area increases up to the edge of the circular smectic area, is studied by the use of the conservation laws for mass and linear momentum. The disjoining pressure is the main factor that is responsible for the driving out of one smectic layer from the N-layer smectic film. PMID- 26049513 TI - Mechanism of charge transfer and its impacts on Fermi-level pinning for gas molecules adsorbed on monolayer WS2. AB - Density functional theory calculations were performed to assess changes in the geometric and electronic structures of monolayer WS2 upon adsorption of various gas molecules (H2, O2, H2O, NH3, NO, NO2, and CO). The most stable configuration of the adsorbed molecules, the adsorption energy, and the degree of charge transfer between adsorbate and substrate were determined. All evaluated molecules were physisorbed on monolayer WS2 with a low degree of charge transfer and accept charge from the monolayer, except for NH3, which is a charge donor. Band structure calculations showed that the valence and conduction bands of monolayer WS2 are not significantly altered upon adsorption of H2, H2O, NH3, and CO, whereas the lowest unoccupied molecular orbitals of O2, NO, and NO2 are pinned around the Fermi-level when these molecules are adsorbed on monolayer WS2. The phenomenon of Fermi-level pinning was discussed in light of the traditional and orbital mixing charge transfer theories. The impacts of the charge transfer mechanism on Fermi-level pinning were confirmed for the gas molecules adsorbed on monolayer WS2. The proposed mechanism governing Fermi-level pinning is applicable to the systems of adsorbates on recently developed two-dimensional materials, such as graphene and transition metal dichalcogenides. PMID- 26049514 TI - Optical properties of alkali halide crystals from all-electron hybrid TD-DFT calculations. AB - We present a study of the electronic and optical properties of a series of alkali halide crystals AX, with A = Li, Na, K, Rb and X = F, Cl, Br based on a recent implementation of hybrid-exchange time-dependent density functional theory (TD DFT) (TD-B3LYP) in the all-electron Gaussian basis set code CRYSTAL. We examine, in particular, the impact of basis set size and quality on the prediction of the optical gap and exciton binding energy. The formation of bound excitons by photoexcitation is observed in all the studied systems and this is shown to be correlated to specific features of the Hartree-Fock exchange component of the TD DFT response kernel. All computed optical gaps and exciton binding energies are however markedly below estimated experimental and, where available, 2-particle Green's function (GW-Bethe-Salpeter equation, GW-BSE) values. We attribute this reduced exciton binding to the incorrect asymptotics of the B3LYP exchange correlation ground state functional and of the TD-B3LYP response kernel, which lead to a large underestimation of the Coulomb interaction between the excited electron and hole wavefunctions. Considering LiF as an example, we correlate the asymptotic behaviour of the TD-B3LYP kernel to the fraction of Fock exchange admixed in the ground state functional cHF and show that there exists one value of cHF (~0.32) that reproduces at least semi-quantitatively the optical gap of this material. PMID- 26049515 TI - Theoretical studies of the work functions of Pd-based bimetallic surfaces. AB - Work functions of Pd-based bimetallic surfaces, including mainly M/Pd(111), Pd/M, and Pd/M/Pd(111) (M = 4d transition metals, Cu, Au, and Pt), are studied using density functional theory. We find that the work function of these bimetallic surfaces is significantly different from that of parent metals. Careful analysis based on Bader charges and electron density difference indicates that the variation of the work function in bimetallic surfaces can be mainly attributed to two factors: (1) charge transfer between the two different metals as a result of their different intrinsic electronegativity, and (2) the charge redistribution induced by chemical bonding between the top two layers. The first factor can be related to the contact potential, i.e., the work function difference between two metals in direct contact, and the second factor can be well characterized by the change in the charge spilling out into vacuum. We also find that the variation in the work functions of Pd/M/Pd(111) surfaces correlates very well with the variation of the d-band center of the surface Pd atom. The findings in this work can be used to provide general guidelines to design new bimetallic surfaces with desired electronic properties. PMID- 26049516 TI - Three-dimensional kinetic Monte Carlo simulations of diamond chemical vapor deposition. AB - A three-dimensional kinetic Monte Carlo model has been developed to simulate the chemical vapor deposition of a diamond (100) surface under conditions used to grow single-crystal diamond (SCD), microcrystalline diamond (MCD), nanocrystalline diamond (NCD), and ultrananocrystalline diamond (UNCD) films. The model includes adsorption of CHx (x = 0, 3) species, insertion of CHy (y = 0-2) into surface dimer bonds, etching/desorption of both transient adsorbed species and lattice sidewalls, lattice incorporation, and surface migration but not defect formation or renucleation processes. A value of ~200 kJ mol(-1) for the activation Gibbs energy, DeltaG(?) etch, for etching an adsorbed CHx species reproduces the experimental growth rate accurately. SCD and MCD growths are dominated by migration and step-edge growth, whereas in NCD and UNCD growths, migration is less and species nucleate where they land. Etching of species from the lattice sidewalls has been modelled as a function of geometry and the number of bonded neighbors of each species. Choice of appropriate parameters for the relative decrease in etch rate as a function of number of neighbors allows flat bottomed etch pits and/or sharp-pointed etch pits to be simulated, which resemble those seen when etching diamond in H2 or O2 atmospheres. Simulation of surface defects using unetchable, immobile species reproduces other observed growth phenomena, such as needles and hillocks. The critical nucleus for new layer growth is 2 adjacent surface carbons, irrespective of the growth regime. We conclude that twinning and formation of multiple grains rather than pristine single-crystals may be a result of misoriented growth islands merging, with each island forming a grain, rather than renucleation caused by an adsorbing defect species. PMID- 26049517 TI - Reaction dynamics of initial O2 sticking on Pd(100). AB - We have determined the initial sticking probability of O2 on Pd(100) using the King and Wells method for various kinetic energies, surface temperatures, and incident angles. The data suggest two different mechanisms to sticking and dissociation. Dissociation proceeds mostly through a direct process with indirect dissociation contributing only at low kinetic energies. We suggest a dynamical precursor state to account for the indirect dissociation channel, while steering causes the high absolute reactivity. A comparison of our results to those previously obtained for Pd(111) and Pd(110) highlights how similar results for different surfaces are interpreted to suggest widely varying dynamics. PMID- 26049518 TI - Hydrodynamic segregation in a bidisperse colloidal suspension in microchannel flow: A theoretical study. AB - Colloids in suspension exhibit shear-induced migration towards regions of low viscous shear. In dense bidisperse colloidal suspensions under pressure driven flow large particles can segregate in the center of a microchannel and the suspension partially demixes. To develop a theoretical understanding of these effects, we formulate a phenomenological model for the particle currents based on the work of Phillips et al. [Phys. Fluids 4, 30 (1992)]. We also simulate hard spheres under pressure-driven flow in two and three dimensions using the mesoscale simulation technique of multi-particle collision dynamics. Using a single fit parameter for the intrinsic diffusivity, our theory accurately reproduces the simulated density profiles across the channel. We present a detailed parameter study on how a monodisperse suspension enriches the channel center and quantitatively confirm the experimental observation that a binary colloidal mixture partially segregates into its two species. In particular, we always find a strong accumulation of large particles in the center. Qualitative differences between two and three dimensions reveal that collective diffusion is more relevant in two dimensions. PMID- 26049519 TI - Brownian motion of a particle with arbitrary shape. AB - Brownian motion of a particle with an arbitrary shape is investigated theoretically. Analytical expressions for the time-dependent cross-correlations of the Brownian translational and rotational displacements are derived from the Smoluchowski equation. The role of the particle mobility center is determined and discussed. PMID- 26049520 TI - Multi-scale entropic depletion phenomena in polymer liquids. AB - We apply numerical polymer integral equation theory to study the entropic depletion problem for hard spheres dissolved in flexible chain polymer melts and concentrated solutions over an exceptionally wide range of polymer radius of gyration to particle diameter ratios (Rg/D), particle-monomer diameter ratios (D/d), and chain lengths (N) including the monomer and oligomer regimes. Calculations are performed based on a calibration of the effective melt packing fraction that reproduces the isobaric dimensionless isothermal compressibility of real polymer liquids. Three regimes of the polymer-mediated interparticle potential of mean force (PMF) are identified and analyzed in depth. (i) The magnitude of the contact attraction that dominates thermodynamic stability scales linearly with D/d and exhibits a monotonic and nonperturbative logarithmic increase with N ultimately saturating in the long chain limit. (ii) A close to contact repulsive barrier emerges that grows linearly with D/d and can attain values far in excess of thermal energy for experimentally relevant particle sizes and chain lengths. This raises the possibility of kinetic stabilization of particles in nanocomposites. The barrier grows initially logarithmically with N, attains a maximum when 2Rg ~ D/2, and then decreases towards its asymptotic long chain limit as 2Rg ? D. (iii) A long range (of order Rg) repulsive, exponentially decaying component of the depletion potential emerges when polymer coils are smaller than, or of order, the nanoparticle diameter. Its amplitude is effectively constant for 2Rg <= D. As the polymer becomes larger than the particle, the amplitude of this feature decreases extremely rapidly and becomes negligible. A weak long range and N-dependent component of the monomer-particle pair correlation function is found which is suggested to be the origin of the long range repulsive PMF. Implications of our results for thermodynamics and miscibility are discussed. PMID- 26049521 TI - Molecular recognition by van der Waals interaction between polymers with sequence specific polarizabilities. AB - We analyze van der Waals interactions between two rigid polymers with sequence specific, anisotropic polarizabilities along the polymer backbones, so that the dipole moments fluctuate parallel to the polymer backbones. Assuming that each polymer has a quenched-in polarizability sequence which reflects, for example, the polynucleotide sequence of a double-stranded DNA molecule, we study the van der Waals interaction energy between a pair of such polymers with rod-like structure for the cases where their respective polarizability sequences are (i) distinct and (ii) identical, with both zero and non-zero correlation length of the polarizability correlator along the polymer backbones in the latter case. For identical polymers, we find a novel r(-5) scaling behavior of the van der Waals interaction energy for small inter-polymer separation r, in contradistinction to the r(-4) scaling behavior of distinct polymers, with furthermore a pronounced angular dependence favoring attraction between sufficiently aligned identical polymers. Such behavior can assist the molecular recognition between polymers. PMID- 26049522 TI - Hierarchical self-assembly of nanoparticles in polymer matrix and the nature of the interparticle interaction. AB - Using small angle X-ray scattering (SAXS), we elucidated the spatial organization of palladium (Pd) nanoparticles (NPs) in the polymer matrix of poly(2 vinylpyridine) (P2VP) and the nature of inter-nanoparticle interactions, where the NPs were synthesized in the presence of P2VP by the reduction of palladium acetylacetonate (Pd(acac)2). The experimental SAXS profiles were analysed on the basis of a hierarchical structure model considering the following two types of interparticle potential: (i) hard-core repulsion only (i.e., the hard-sphere interaction) and (ii) hard-core repulsion together with an attractive potential well (i.e., the sticky hard-sphere interaction). The corresponding theoretical scattering functions, which were used for analysing the experimental SAXS profiles, were obtained within the context of the Percus-Yevick closure and the Ornstein-Zernike equation in the fundamental liquid theory. The analyses revealed that existence of the attractive potential well is indispensable to account for the experimental SAXS profiles. Moreover, the morphology of the hybrids was found to be characterized by a hierarchical structure with three levels, where about six primary NPs with the diameter of ca. 1.8 nm (level one) formed local clusters (level two), and these clusters aggregated to build up a large-scale mass-fractal structure (level three) with the fractal dimension of ca. 2.3. The scattering function developed here is of general use for quantitatively characterizing the morphological structures of polymer/NP hybrids and, in particular, for exploring the interaction potential of the NPs on the basis of the fundamental liquid theory. PMID- 26049523 TI - Theory of competitive solvation of polymers by two solvents and entropy-enthalpy compensation in the solvation free energy upon dilution with the second solvent. AB - We develop a statistical mechanical lattice theory for polymer solvation by a pair of relatively low molar mass solvents that compete for binding to the polymer backbone. A theory for the equilibrium mixture of solvated polymer clusters {AiBCj} and free unassociated molecules A, B, and C is formulated in the spirit of Flory-Huggins mean-field approximation. This theoretical framework enables us to derive expressions for the boundaries for phase stability (spinodals) and other basic properties of these polymer solutions: the internal energy U, entropy S, specific heat CV, extent of solvation Phisolv, average degree of solvation , and second osmotic virial coefficient B2 as functions of temperature and the composition of the mixture. Our theory predicts many new phenomena, but the current paper applies the theory to describe the entropy-enthalpy compensation in the free energy of polymer solvation, a phenomenon observed for many years without theoretical explanation and with significant relevance to liquid chromatography and other polymer separation methods. PMID- 26049524 TI - The effect of particle size on the morphology and thermodynamics of diblock copolymer/tethered-particle membranes. AB - A combination of self-consistent field theory and density functional theory was used to examine the effect of particle size on the stable, 3-dimensional equilibrium morphologies formed by diblock copolymers with a tethered nanoparticle attached either between the two blocks or at the end of one of the blocks. Particle size was varied between one and four tenths of the radius of gyration of the diblock polymer chain for neutral particles as well as those either favoring or disfavoring segments of the copolymer blocks. Phase diagrams were constructed and analyzed in terms of thermodynamic diagrams to understand the physics associated with the molecular-level self-assembly processes. Typical morphologies were observed, such as lamellar, spheroidal, cylindrical, gyroidal, and perforated lamellar, with the primary concentration region of the tethered particles being influenced heavily by particle size and tethering location, strength of the particle-segment energetic interactions, chain length, and copolymer radius of gyration. The effect of the simulation box size on the observed morphology and system thermodynamics was also investigated, indicating possible effects of confinement upon the system self-assembly processes. PMID- 26049525 TI - Dissociative electron attachment to the gas-phase nucleobase hypoxanthine. AB - We present high-resolution measurements of the dissociative electron attachment (DEA) to isolated gas-phase hypoxanthine (C5H4N4O, Hyp), a tRNA purine base. The anion mass spectra and individual ion efficiency curves from Hyp were measured as a function of electron energy below 9 eV. The mass spectra at 1 and 6 eV exhibit the highest anion yields, indicating possible common precursor ions that decay into the detectable anionic fragments. The (Hyp - H) anion (C5H3N4O(-)) exhibits a sharp resonant peak at 1 eV, which we tentatively assign to a dipole-bound state of the keto-N1H,N9H tautomer in which dehydrogenation occurs at either the N1 or N9 position based upon our quantum chemical computations (B3LYP/6 311+G(d,p) and U(MP2-aug-cc-pVDZ+)) and prior studies with adenine. This closed shell dehydrogenated anion is the dominant fragment formed upon electron attachment, as with other nucleobases. Seven other anions were also observed including (Hyp - NH)(-), C4H3N4 (-)/C4HN3O(-), C4H2N3 (-), C3NO(-)/HC(HCN)CN(-), OCN(-), CN(-), and O(-). Most of these anions exhibit broad but weak resonances between 4 and 8 eV similar to many analogous anions from adenine. The DEA to Hyp involves significant fragmentation, which is relevant to understanding radiation damage of biomolecules. PMID- 26049526 TI - Crossover of two power laws in the anomalous diffusion of a two lipid membrane. AB - Molecular dynamics simulations of a bi-layer membrane made by the same number of 1-palmitoyl-2-oleoyl-glycero-3-phospho-ethanolamine and palmitoyl-oleoyl phosphatidylserine lipids reveal sub-diffusional motion, which presents a crossover between two different power laws. Fractional Brownian motion is the stochastic mechanism that governs the motion in both regimes. The location of the crossover point is justified with simple geometrical arguments and is due to the activation of the mechanism of circumrotation of lipids about each other. PMID- 26049527 TI - Some thermodynamical aspects of protein hydration water. AB - We study by means of nuclear magnetic resonance the self-diffusion of protein hydration water at different hydration levels across a large temperature range that includes the deeply supercooled regime. Starting with a single hydration shell (h = 0.3), we consider different hydrations up to h = 0.65. Our experimental evidence indicates that two phenomena play a significant role in the dynamics of protein hydration water: (i) the measured fragile-to-strong dynamic crossover temperature is unaffected by the hydration level and (ii) the first hydration shell remains liquid at all hydrations, even at the lowest temperature. PMID- 26049528 TI - Impact of secondary structure and hydration water on the dielectric spectrum of poly-alanine and possible relation to the debate on slaved versus slaving water. AB - Using extensive molecular dynamics simulations of a single eight-residue alanine polypeptide in explicit water, we investigate the influence of alpha-helix formation on the dielectric spectrum. For this, we project long equilibrium trajectories into folded and unfolded states and thereby obtain dielectric spectra representative for disordered as well alpha-helical conformations without the need to change any other system parameter such as pH or temperature. The absorption spectrum in the alpha-helical state exhibits a feature in the sub-GHz range that is significantly stronger than in the unfolded state. As we show by an additional decomposition into peptide and water contributions, this slow dielectric mode, the relaxation time of which matches the independently determined peptide rotational relaxation time, is mostly caused by peptide polarization correlations, but also contains considerable contributions from peptide-water correlations. In contrast, the peptide spectral contribution shows no features in the GHz range where bulk water absorbs, not even in the peptide water correlation part, we conclude that hydration water around Ala8 is more influenced by peptide polarization relaxation effects than the other way around. A further decomposition into water-self and water-collective polarization correlations shows that the dielectric response of hydration water is, in contrast to electrolyte solutions, retarded and that this retardation is mostly due to collective effects, the self relaxation of hydration water molecules is only slightly slowed down compared to bulk water. We find the dynamic peptide water polarization cross correlations to be rather long-ranged and to extend more than one nanometer away from the peptide-water interface into the water hydration shell, in qualitative agreement with previous simulation studies and recent THz absorption experiments. PMID- 26049529 TI - Percolation-like phase transitions in network models of protein dynamics. AB - In broad terms, percolation theory describes the conditions under which clusters of nodes are fully connected in a random network. A percolation phase transition occurs when, as edges are added to a network, its largest connected cluster abruptly jumps from insignificance to complete dominance. In this article, we apply percolation theory to meticulously constructed networks of protein folding dynamics called Markov state models. As rare fluctuations are systematically repressed (or reintroduced), we observe percolation-like phase transitions in protein folding networks: whole sets of conformational states switch from nearly complete isolation to complete connectivity in a rapid fashion. We analyze the general and critical properties of these phase transitions in seven protein systems and discuss how closely dynamics on protein folding landscapes relate to percolation on random lattices. PMID- 26049530 TI - The structure and IR signatures of the arginine-glutamate salt bridge. Insights from the classical MD simulations. AB - Salt bridges and ionic interactions play an important role in protein stability, protein-protein interactions, and protein folding. Here, we provide the classical MD simulations of the structure and IR signatures of the arginine (Arg)-glutamate (Glu) salt bridge. The Arg-Glu model is based on the infinite polyalanine antiparallel two-stranded beta-sheet structure. The 1 MUs NPT simulations show that it preferably exists as a salt bridge (a contact ion pair). Bidentate (the end-on and side-on structures) and monodentate (the backside structure) configurations are localized [Donald et al., Proteins 79, 898-915 (2011)]. These structures are stabilized by the short (+)N-H?O(-) bonds. Their relative stability depends on a force field used in the MD simulations. The side-on structure is the most stable in terms of the OPLS-AA force field. If AMBER ff99SB ILDN is used, the backside structure is the most stable. Compared with experimental data, simulations using the OPLS all-atom (OPLS-AA) force field describe the stability of the salt bridge structures quite realistically. It decreases in the following order: side-on > end-on > backside. The most stable side-on structure lives several nanoseconds. The less stable backside structure exists a few tenth of a nanosecond. Several short-living species (solvent shared, completely separately solvated ionic groups ion pairs, etc.) are also localized. Their lifetime is a few tens of picoseconds or less. Conformational flexibility of amino acids forming the salt bridge is investigated. The spectral signature of the Arg-Glu salt bridge is the IR-intensive band around 2200 cm(-1). It is caused by the asymmetric stretching vibrations of the (+)N-H?O(-) fragment. Result of the present paper suggests that infrared spectroscopy in the 2000-2800 frequency region may be a rapid and quantitative method for the study of salt bridges in peptides and ionic interactions between proteins. This region is usually not considered in spectroscopic studies of peptides and proteins. PMID- 26049531 TI - Erratum: "Spin-unrestricted random-phase approximation with range separation: Benchmark on atomization energies and reaction barrier heights" [J. Chem. Phys. 142, 154123 (2015)]. PMID- 26049532 TI - Electronic health record usability: analysis of the user-centered design processes of eleven electronic health record vendors. AB - The usability of electronic health records (EHRs) continues to be a point of dissatisfaction for providers, despite certification requirements from the Office of the National Coordinator that require EHR vendors to employ a user-centered design (UCD) process. To better understand factors that contribute to poor usability, a research team visited 11 different EHR vendors in order to analyze their UCD processes and discover the specific challenges that vendors faced as they sought to integrate UCD with their EHR development. Our analysis demonstrates a diverse range of vendors' UCD practices that fall into 3 categories: well-developed UCD, basic UCD, and misconceptions of UCD. Specific challenges to practicing UCD include conducting contextually rich studies of clinical workflow, recruiting participants for usability studies, and having support from leadership within the vendor organization. The results of the study provide novel insights for how to improve usability practices of EHR vendors. PMID- 26049533 TI - Comparison of Efficacy of Differing Partner-Assisted Skin Examination Interventions for Melanoma Patients: A Randomized Clinical Trial. AB - IMPORTANCE: Early detection of melanoma may improve survival. The present study continued research establishing that in-person training on skin self-examinations (SSEs) was significantly enhanced when delivered to patients with their partners present instead of to patients alone. OBJECTIVE: To examine 3 alternative SSE training approaches that included partners compared with a treatment-as-usual control condition. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial with 4- and 12-month follow-up visits was conducted at the clinical offices in the ambulatory care area of a hospital. The evaluable population included 494 patients with stage 0 to IIB melanoma and their skin check partners drawn from an electronic medical record melanoma registry and advertisements in large regional newspapers. The study was conducted from June 6, 2011, to April 14, 2014, and analysis was performed between December 4 and December 11, 2014. INTERVENTIONS: Pairs of patients and their partners were randomly assigned to (1) in-person intervention, (2) take-home booklet intervention, and (3) treatment-as-usual controls. An additional subgroup of patients received an electronic interactive tablet personal computer intervention. The MoleScore content was comparable across formats and consisted of demonstrations of the ABCDE (assess border, color, diameter, and evolution of pigmented lesions) rule and skills training. MAIN OUTCOMES AND MEASURES: Outcomes were self-reported SSE of the total body as well as easy-to-see and difficult-to-see regions at baseline, 4 months, and 12 months. RESULTS: No significant differences in SSEs were observed between the 3 intervention conditions on all of the body areas; results for all 3 intervention conditions were significantly higher than for controls at 4- and 12-month follow ups (all P < .05). Mean (SD) body areas examined by control pairs (n = 99) at 4 months (0.98 [1.17]) and 12 months (1.82 [1.43]) were significantly less compared with examination by pairs participating in all interventions at 4 months (workbook [n = 159], 2.68 [1.19]; in-person [n = 165], 2.66 [1.11]; and tablet [n = 71], 2.53 [1.17]) and at 12 months (workbook, 2.53 [1.25]; in-person, 2.59 [1.30]; and tablet, 2.34 [1.37]) (F6,674 = 15.60; P < .001; eta2 = 0.12). CONCLUSIONS AND RELEVANCE: The findings of the research support the sustainability and efficacy at 12 months of partner-assisted SSE interventions for early detection targeting individuals with a history of melanoma. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01432860. PMID- 26049534 TI - HIV disclosure to children in low-and middle-income countries: towards effective interventions. PMID- 26049535 TI - National Institutes of Health investment in studies of HIV disclosure to children. AB - The goals of this manuscript will be to review current and past National Institutes of Health (NIH) funding on maternal and child HIV disclosure research and lay out current research gaps in these areas. Examples of work funded by NIH will highlight how the disclosure needs of families affected by HIV have changed over the past 30 years as well as highlight what we have learned. The review will include the recent NICHD RFA that focused specifically on disclosure of HIV status to children in low and middle-income country settings. A brief description of findings from these NIH-funded grants will be provided. The authors will then describe current research gaps and challenges as they relate to research on HIV disclosure both in the U.S. and internationally. PMID- 26049536 TI - Factors influencing the decision-making of parental HIV disclosure: a socio ecological approach. AB - OBJECTIVES: Using the socio-ecological approach, the current study aims to identify facilitators and barriers to decision-making regarding parental HIV disclosure or nondisclosure at intrapersonal, interpersonal, and sociocultural levels; and examine the unique contribution of factors at different level of influences to the decision of disclosure or nondisclosure. DESIGN: A cross sectional survey was conducted among people living with HIV in Guangxi, China. A sub-sample of 1254 participants, who had children aged 5-16 years, was included in the data analysis in the current study. METHODS: Multivariate models using hierarchical logistic regression were employed to assess the association of parental decision regarding HIV disclosure to children with various factors at intrapersonal, interpersonal, and sociocultural levels controlling background characteristics, and detect the level-specific influence on disclosure decision. RESULTS: Positive coping with HIV infection and a good parent-child relationship facilitated parental HIV disclosure; whereas high level of resilience and fears of parental HIV disclosure impeded their decisions to talk about HIV status to their children. In addition, the current study recognized specific contribution of multiple ecological levels to parental decisions regarding disclosure to children. CONCLUSION: The socio-ecological model is a promising theoretical framework to guide further studies and interventions related to parental HIV disclosure. Directions for further studies using socio-ecological approach were also discussed. PMID- 26049537 TI - SANKOFA: a multisite collaboration on paediatric HIV disclosure in Ghana. AB - With the scale-up of effective antiretroviral therapy in resource-limited settings, many HIV-infected children are now able to survive into adulthood. To achieve this potential, children must navigate normative developmental processes and challenges while living with an unusually complex, stigmatizing, potentially fatal chronic illness and meeting the demands of treatment.Yet many of these children, especially preadolescents, do not know they are HIV-infected. Despite compelling evidence supporting the merits of informing children of their HIV status, there has been little emphasis on equipping the child's caregiver with information and skills to promote disclosure, particularly, when the caregiver faces a variety of sociocultural barriers and is reluctant to do so. In this study, we present the background, process and methods for a first of its kind collaboration that is examining the efficacy of an intervention developed to facilitate the engagement of caregivers in the process of disclosure in a manner suitable to the sociocultural context and developmental age and needs of the child in Ghana. We also report preliminary data that supported the design of the intervention approach and currently available domains of the data system. Finally, we discuss challenges and implications for future research. PMID- 26049538 TI - 'Why did you not tell me?': perspectives of caregivers and children on the social environment surrounding child HIV disclosure in Kenya. AB - OBJECTIVE: We sought to better understand how social factors shape HIV disclosure to children from the perspective of caregivers and HIV-infected children in Kenya. DESIGN: We conducted a qualitative study using focus group discussions (FGDs) to gain perspectives of caregivers and children on the social environment for HIV disclosure to children in western Kenya. FGDs were held with caregivers who had disclosed the HIV status to their child and those who had not, and with HIV-infected children who knew their HIV status. METHODS: FGD transcripts were translated into English, transcribed, and analyzed using constant comparison, progressive coding, and triangulation to arrive at a contextualized understanding of social factors influencing HIV disclosure. RESULTS: Sixty-one caregivers of HIV-infected children participated in eight FGDs, and 23 HIV-infected children participated in three FGDs. Decisions around disclosure were shaped by a complex social environment that included the caregiver-child dyad, family members, neighbors, friends, schools, churches, and media. Whether social actors demonstrated support or espoused negative beliefs influenced caregiver decisions to disclose. Caregivers reported that HIV-related stigma was prominent across these domains, including stereotypes associating HIV with sexual promiscuity, immorality, and death, which were tied to caregiver fears about disclosure. Children also recognized stigma as a barrier to disclosure, but were less specific about the social and cultural stereotypes cited by the caregivers. CONCLUSION: In this setting, caregivers and children described multiple actors who influenced disclosure, mostly due to stigmatizing beliefs about HIV. Better understanding the social factors impacting disclosure may improve the design of support services for children and caregivers. PMID- 26049539 TI - 'HIV is like a tsotsi. ARVs are your guns': associations between HIV-disclosure and adherence to antiretroviral treatment among adolescents in South Africa. AB - OBJECTIVES: WHO guidelines recommend disclosure to HIV-positive children by school age in order to improve antiretroviral therapy (ART) adherence. However, quantitative evidence remains limited for adolescents. This study examines associations between adolescent knowledge of HIV-positive status and ART adherence in South Africa. DESIGN: A cross-sectional study of the largest known community-traced sample of HIV-positive adolescents. Six hundred and eighty-four ART-initiated adolescents aged 10-19 years (52% female, 79% perinatally infected) were interviewed. METHODS: In a low-resource health district, all adolescents who had ever initiated ART in a stratified sample of 39 health facilities were identified and traced to 150 communities [n = 1102, 351 excluded, 27 deceased, 40 (5.5%) refusals]. Quantitative interviews used standardized questionnaires and clinic records. Quantitative analyses used multivariate logistic regressions, and qualitative analyses used grounded theory for 18 months of interviews, focus groups and participant observations with 64 adolescents, caregivers and healthcare workers. RESULTS: About 36% of adolescents reported past-week ART nonadherence, and 70% of adolescents knew their status. Adherence was associated with fewer opportunistic infection symptoms [odds ratio (OR) 0.55; 95% CI 0.40 0.76]. Adolescent knowledge of HIV-positive status was associated with higher adherence, independently of all cofactors (OR 2.18; 95% CI 1.47-3.24). Among perinatally infected adolescents who knew their status (n = 362/540), disclosure prior to age 12 was associated with higher adherence (OR 2.65; 95% CI 1.34-5.22). Qualitative findings suggested that disclosure was undertaken sensitively in clinical and family settings, but that adults lacked awareness about adolescent understandings of HIV status. CONCLUSION: Early and full disclosure is strongly associated with improved adherence amongst ART-initiated adolescents. Disclosure may be an essential tool in improving adolescent adherence and reducing mortality and onwards transmission. PMID- 26049540 TI - Maternal and child psychological outcomes of HIV disclosure to young children in rural South Africa: the Amagugu intervention. AB - OBJECTIVES: Increasingly, HIV-infected parents are surviving to nurture their children. Parental HIV disclosure is beneficial, but disclosure rates to younger children remain low. Previously, we demonstrated that the 'Amagugu' intervention increased disclosure to young children; however, effects on psychological outcomes have not been examined in detail. This study investigates the impact of the intervention on the maternal and child psychological outcomes. METHOD: This pre-post evaluation design enrolled 281 HIV-infected women and their HIV uninfected children (6-10 years) at the Africa Centre for Health and Population Studies, in rural South Africa. The intervention included six home-based counselling sessions delivered by lay-counsellors. Psychological outcomes included maternal psychological functioning (General Health Questionnaire, GHQ12 using 0,1,2,3 scoring); parenting stress (Parenting Stress Index, PSI36); and child emotional and behavioural functioning (Child Behaviour Checklist, CBCL). RESULTS: The proportions of mothers with psychological distress reduced after intervention: GHQ threshold at least 12 (from 41.3 to 24.9%, P < 0.001) and GHQ threshold at least 20 (from 17.8 to 11.7%, P = 0.040). Parenting stress scores also reduced (Pre M = 79.8; Post M = 76.2, P < 0.001): two subscales, parental distress and parent-child relationship, showed significant improvement, while mothers' perception of 'child as difficult' was not significantly improved. Reductions in scores were not moderated by disclosure level (full/partial). There was a significant reduction in child emotional and behavioural problems (CBCL Pre M = 56.1; Post M = 48.9, P < 0.001). CONCLUSION: Amagugu led to improvements in mothers' and children's mental health and parenting stress, irrespective of disclosure level, suggesting general nonspecific positive effects on family relationships. Findings require validation in a randomized control trial. PMID- 26049541 TI - Increasing HIV serostatus disclosure in low and middle-income countries: a systematic review of intervention evaluations. AB - OBJECTIVE: To review the effectiveness of interventions to increase HIV serostatus disclosure in low and middle-income countries. DESIGN: Systematic review of peer-reviewed articles providing prepost or multiarm evaluations of disclosure interventions, defined broadly as any intervention with the goal of increasing rates of voluntary disclosure of HIV serostatus through self disclosure or partner notification. METHODS: Articles were included if they reported postintervention evaluation results and were published between 1 January 1990 and 1 August 2014. Searching was conducted through five electronic databases, secondary searching of four journals, and hand searching reference lists of included articles. Systematic methods were used for screening and data abstraction, which was conducted in duplicate. Study quality (rigor) was assessed with eight items. RESULTS: Fourteen articles evaluating 13 interventions met the inclusion criteria, all from sub-Saharan Africa. Most interventions focused on people living with HIV and used cognitive-behavioral group sessions or peer/community health worker support to encourage disclosure to sexual partners, family members, or friends. One focused on maternal disclosure to HIV-uninfected children, whereas two examined voluntary partner notification interventions. Several studies had limitations due to weak designs, small sample sizes, or high attrition. Findings on disclosure were mixed, with most effect sizes being relatively small, and some more rigorous studies showing no effect. Partner notification interventions had the strongest evidence of impact. CONCLUSION: The existing evidence base for interventions to increase disclosure is limited and shows variable results. Further research is needed to determine whether current approaches to increasing disclosure are effective or whether new approaches should be considered. PMID- 26049542 TI - Growing-up just like everyone else: key components of a successful pediatric HIV disclosure intervention in Namibia. AB - OBJECTIVES: To facilitate replication and adaptation of pediatric HIV disclosure interventions, we identified key components of a child-friendly cartoon book used to guide Namibian caregivers and healthcare workers (HCWs) through a gradual, structured disclosure process. DESIGN: Qualitative interviews were conducted with caregivers and HCWs from four high-volume pediatric HIV clinics in Namibia. METHODS: Semi-structured in-depth interviews with 35 HCWs and 64 caregivers of HIV+ children aged 7-15 were analyzed using constant comparative and modified grounded theory analysis. Major barriers to disclosure were compared to accounts of intervention success, and themes related to key components were identified. RESULTS: The disclosure book overcomes barriers to disclosure by reducing caregiver resistance, increasing HIV and disclosure knowledge, and providing a gradual, structured framework for disclosure. The delayed mention of HIV-specific terminology overcomes caregiver fears associated with HIV stigma, thus encouraging earlier uptake of disclosure initiation. Caregivers value the book's focus on staying healthy, keeping the body strong, and having a future 'like other kids', thus capitalizing on evidence of the positive benefits of resilience and hopefulness rather than the negative consequences of HIV. The book's concepts and images resonate with children who readily adopt the language of 'body soldiers' and 'bad guys' in describing how important it is for them to take their medicine. Discussion cues ease communication between HCWs, caregivers, and pediatric patients. CONCLUSION: Given the urgent need for available pediatric HIV disclosure interventions, easily implementable tools like the Namibian disclosure book should be evaluated for utility in similar settings. PMID- 26049543 TI - Disclosure of their HIV status to perinatally infected youth using the adapted Blasini disclosure model in Haiti and the Dominican Republic: preliminary results. AB - OBJECTIVES: To assess the safety, acceptability, and preliminary efficacy of a culturally-adapted disclosure intervention for perinatally HIV-infected combined antiretroviral therapy patients in Haiti and the Dominican Republic. DESIGN: A quasi-experimental trial was conducted comparing caregiver-youth pairs who completed the intervention [adapted Blasini disclosure model (aBDM)] to pairs who discontinued aBDM participation before disclosure. aBDM consists of five components: structured healthcare worker training; one-on one pre-disclosure intervention/education sessions for youth (describing pediatric chronic diseases including cancer, diabetes and HIV) and for caregivers (strengthening capacity for disclosure); a scheduled supportive disclosure session; and one-on-one postdisclosure support for caregivers and youth. METHODS: Caregivers of nondisclosed combined antiretroviral therapy patients aged 10.0-17.8 years were invited to participate. Data were collected by separate one-on-one face-to-face interviews of caregivers and youth by study staff and medical record review by pediatricians at enrollment and 3 months after disclosure or after intervention discontinuation. RESULTS: To date, 65 Dominican Republic and 27 Haiti caregiver youth pairs have enrolled. At enrollment, only 46.4% of youth had viral suppression and 43.4% of caregivers had clinically significant depressive symptomatology. To date, two serious study-related adverse events have occurred. Seven of the 92 (7.6%, 6 in the Dominican Republic) enrolled pairs discontinued participation before disclosure and 39 had completed postdisclosure participation. Median plasma HIV-RNA concentration was lower in youth who completed aBDM than in youth who discontinued participation before aBDM disclosure (<40 versus 8673 copies/ml; P = 0.027). Completers expressed considerable satisfaction with aBDM. CONCLUSION: Preliminary results suggest safety, acceptability, and possible effectiveness of the aBDM. PMID- 26049544 TI - Nurse-delivered counselling intervention for parental HIV disclosure: results from a pilot randomized controlled trial in China. AB - OBJECTIVE: The objective of this study was to design and conduct a preliminary evaluation of an intervention to assist parents in decision-making about disclosure of their HIV diagnosis to their children. DESIGN: This was a pilot randomized controlled trial (RCT) with blinded assessment. Participants were randomized to intervention or treatment-as-usual (TAU) arms. SETTING: The study occurred at an outpatient HIV primary care centre in Shanghai, China. PARTICIPANTS: Participants were 20 HIV-positive outpatients with at least one child (13-25 years old) who was unaware of the parent's HIV diagnosis. INTERVENTION: The nurse-delivered intervention involved three, hour-long, individual sessions over 4 weeks. Intervention content comprised family assessment, discussion of advantages and disadvantages of disclosure, psycho education about cognitive, social and emotional abilities of children at different developmental stages, and disclosure planning and practicing via role plays. MAIN OUTCOME MEASURE(S): Primary study outcomes for intervention versus TAU arms were self-reported disclosure distress, self-efficacy, and behaviours along a continuum from no disclosure to full disclosure and open communication about HIV. RESULTS: In all cross-sectional (Wald tests) and longitudinal (general estimating equations) analyses, at both postintervention (4 weeks) and follow-up (13 weeks), effects were in the hypothesized directions. Despite the small sample size, most of these between-arm comparisons were statistically significant, with at least one result for each outcome indicating a 'large' effect size. CONCLUSION: Our results suggest that nurses are able to deliver a counselling intervention in a clinic setting with the potential to alleviate parental distress around HIV disclosure to their children. Findings warrant future trials powered for efficacy. PMID- 26049545 TI - Targeting CD133high Colorectal Cancer Cells In Vitro and In Vivo With an Asymmetric Bispecific Antibody. AB - A critical obstacle in advanced colorectal cancer (CRC) treatment is the insufficient improvement on survival of conventional chemotherapy. Cancer stem cells are reported to be one of the crucial explanations. CD133 has been identified as a surface marker of CRC stem cells. Bispecific antibodies (BiAbs) targeting tumor-specific antigens are promising therapeutics for malignant diseases, yet that targeting CD133 produced by genetic engineering has not been published. In the current research, CD133 expression in primary CRC was detected by immunohistochemistry, and an asymmetric BiAb consisting of monomer of chimeric AC133 (mouse anti-human CD133 monoclonal antibody) and single chain of humanized OKT3 was developed to eradicate CD133-expressing tumor cells by arming activated T cells in vitro and in vivo. In immunohistochemical examination, CD133 overexpression (>50% of stained cells) frequency was significantly correlated with lymphatic invasion and clinical stage. The new molecular revealed dual antigen-binding specificity to CD133 and CD3, its distinct structure not only facilitated the purification procedure but also conferred the antibody to ensure a longer and stronger cytotoxic activity. By arming activated T cells, the new antibody displayed impressive cytotoxicity toward CD133(high) but not CD133(low) CRC cells in vitro, produced amounts of cytokines (interferon-gamma and granulocyte-macrophage colony-stimulating factor), and could inhibit tumor growth and retard tumor development in nonobese diabetic-severe combined immunodeficient mice without apparent toxicity. Taken together, the new BiAb possesses prosperities that support that the molecule has the potential of being a promising candidate of new therapeutics for CRC therapy. PMID- 26049546 TI - T Cells Derived From Human Melanoma Draining Lymph Nodes Mediate Melanoma specific Antitumor Responses In Vitro and In Vivo in Human Melanoma Xenograft Model. AB - It has been established in murine models that lymph nodes draining a progressively growing tumor contain antigen-specific T cells capable of mediating protective immune responses upon adoptive transfer. However, naturally occurring human tumor-draining lymph nodes (TDLNs) have yet to be fully investigated. In this study, we analyzed TDLNs from patients with stage III melanoma who were undergoing routine lymph node dissection. Following short-term (14 d) culture activation with anti-CD3/anti-CD28 microbeads and expansion in low concentrations of IL-2, the melanoma-draining lymph node (MDLN) cells were ~ 60% CD4-activated and ~ 40% CD8-activated T cells. The activated MDLN cells demonstrated reactivity in response to overlapping peptides spanning the sequence of 4 different known melanoma antigens MAGEA1, Melan-A/MART-1, NY-ESO-1, and Prame/OIP4, suggesting the presence of melanoma-specific T cells. Coculture of activated MDLN T cells with cancer cells in vitro resulted in preferential apoptosis of human cancer cell lines that were cocultured with T cells with high degree of MHC matching. Adoptive transfer of MDLN T cells with high degree of MHC matching to A375 to mice-bearing human A375 melanoma xenografts resulted in dose-dependent improvement in survival. Although prior human studies have demonstrated the immune responses within melanoma vaccine-draining lymph nodes, this study presents evidence for the first time that naturally occurring human MDLN samples contain melanoma-experienced CD4 and CD8 T cells that can be readily cultured and expanded to mediate protective immune responses both in vitro and in vivo in a human melanoma xenograft model. PMID- 26049547 TI - In Vitro Validation of Survivin as Target Tumor-associated Antigen for Immunotherapy in Uterine Cancer. AB - Survivin is an antiapoptotic protein, not expressed in terminally differentiated adult tissues, yet overexpressed in several tumors. Therefore, it is an interesting target for immunotherapeutic strategies. In addition to specific overexpression in tumors, tumor survival is mediated by survivin and hence, tumor survival can be tackled by targeting survivin. Survivin expression in uterine cancer was validated by quantitative real-time polymerase chain reaction and immunohistochemistry. In addition, we evaluated survivin immunogenicity by analyzing spontaneous B-cell and T-cell responses in patients. Survivin as a protein was expressed in only a minority of normal tissues, whereas it was being expressed in all of the currently analyzed uterine cancers, both endometrial carcinoma (n = 52) and uterine sarcoma (n = 52). Survivin RNA transcripts were overexpressed in more aggressive tumors and survivin protein was overexpressed in recurrent endometrial tumors compared with primary tumors. Spontaneous T-cell responses were seen in 10/39 endometrial cancer patients and 3/16 uterine sarcoma patients. In normal controls, T-cell responses were found only in 1 donor (n = 21). Although increased antibody titers were found in more aggressive and far advanced tumors, no differences in B-cell responses were seen. Overall, when compared with normal controls, a B-cell response was only measured in 1/41 uterine sarcoma patients. In conclusion, we currently validated the presence of survivin in uterine cancer. In addition, spontaneous T-cell responses were found in 23.6% of the total patient population. These data indicate that a survivin specific immune response may be induced spontaneously in patients, further fortifying the eligibility of survivin as an immunotherapeutic target. PMID- 26049548 TI - Large-scale Isolation of Highly Pure "Untouched" Regulatory T Cells in a GMP Environment for Adoptive Cell Therapy. AB - Adoptive cell therapy is an emerging treatment strategy for a number of serious diseases. Regulatory T (Treg) cells represent 1 cell type of particular interest for therapy of inflammatory conditions, as they are responsible for controlling unwanted immune responses. Initial clinical trials of adoptive transfer of Treg cells in patients with graft-versus-host disease were shown to be safe. However, obtaining sufficient numbers of highly pure and functional Treg cells with minimal contamination remains a challenge. We developed a novel approach to isolate "untouched" human Treg cells from healthy donors on the basis of negative selection using the surface markers CD49d and CD127. This procedure, which uses an antibody cocktail and magnetic beads for separation in an automated system (RoboSep), was scaled up and adapted to be compatible with good manufacturing practice conditions. With this setup we performed 9 Treg isolations from large scale leukapheresis samples in a good manufacturing practice facility. These runs yielded sufficient numbers of "untouched" Treg cells for immediate use in clinical applications. The cell preparations consisted of viable highly pure FoxP3-positive Treg cells that were functional in suppressing the proliferation of effector T cells. Contamination with CD4 effector T cells was <10%. All other cell types did not exceed 2% in the final product. Remaining isolation reagents were reduced to levels that are considered safe. Treg cells isolated with this procedure will be used in a phase I clinical trial of adoptive transfer into leukemia patients developing graft-versus-host disease after stem cell transplantation. PMID- 26049550 TI - Day and Night Closed-Loop Control Using the Integrated Medtronic Hybrid Closed Loop System in Type 1 Diabetes at Diabetes Camp. AB - OBJECTIVE: To evaluate the feasibility and efficacy of a fully integrated hybrid closed-loop (HCL) system (Medtronic MiniMed Inc., Northridge, CA), in day and night closed-loop control in subjects with type 1 diabetes, both in an inpatient setting and during 6 days at diabetes camp. RESEARCH DESIGN AND METHODS: The Medtronic MiniMed HCL system consists of a fourth generation (4S) glucose sensor, a sensor transmitter, and an insulin pump using a modified proportional-integral derivative (PID) insulin feedback algorithm with safety constraints. Eight subjects were studied over 48 h in an inpatient setting. This was followed by a study of 21 subjects for 6 days at diabetes camp, randomized to either the closed loop control group using the HCL system or to the group using the Medtronic MiniMed 530G with threshold suspend (control group). RESULTS: The overall mean sensor glucose percent time in range 70-180 mg/dL was similar between the groups (73.1% vs. 69.9%, control vs. HCL, respectively) (P = 0.580). Meter glucose values between 70 and 180 mg/dL were also similar between the groups (73.6% vs. 63.2%, control vs. HCL, respectively) (P = 0.086). The mean absolute relative difference of the 4S sensor was 10.8 +/- 10.2%, when compared with plasma glucose values in the inpatient setting, and 12.6 +/- 11.0% compared with capillary Bayer CONTOUR NEXT LINK glucose meter values during 6 days at camp. CONCLUSIONS: In the first clinical study of this fully integrated system using an investigational PID algorithm, the system did not demonstrate improved glucose control compared with sensor-augmented pump therapy alone. The system demonstrated good connectivity and improved sensor performance. PMID- 26049549 TI - Predictive Low-Glucose Insulin Suspension Reduces Duration of Nocturnal Hypoglycemia in Children Without Increasing Ketosis. AB - OBJECTIVE: Nocturnal hypoglycemia can cause seizures and is a major impediment to tight glycemic control, especially in young children with type 1 diabetes. We conducted an in-home randomized trial to assess the efficacy and safety of a continuous glucose monitor-based overnight predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS: In two age-groups of children with type 1 diabetes (11-14 and 4-10 years of age), a 42-night trial for each child was conducted wherein each night was assigned randomly to either having the PLGS system active (intervention night) or inactive (control night). The primary outcome was percent time <70 mg/dL overnight. RESULTS: Median time at <70 mg/dL was reduced by 54% from 10.1% on control nights to 4.6% on intervention nights (P < 0.001) in 11-14-year-olds (n = 45) and by 50% from 6.2% to 3.1% (P < 0.001) in 4-10-year-olds (n = 36). Mean overnight glucose was lower on control versus intervention nights in both age-groups (144 +/- 18 vs. 152 +/- 19 mg/dL [P < 0.001] and 153 +/- 14 vs. 160 +/- 16 mg/dL [P = 0.004], respectively). Mean morning blood glucose was 159 +/- 29 vs. 176 +/- 28 mg/dL (P < 0.001) in the 11 14-year-olds and 154 +/- 25 vs. 158 +/- 22 mg/dL (P = 0.11) in the 4-10-year olds, respectively. No differences were found between intervention and control in either age-group in morning blood ketosis. CONCLUSIONS: In 4-14-year-olds, use of a nocturnal PLGS system can substantially reduce overnight hypoglycemia without an increase in morning ketosis, although overnight mean glucose is slightly higher. PMID- 26049551 TI - Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes. AB - OBJECTIVE: To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS: We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS: In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS: As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes. PMID- 26049552 TI - Effect of Ranolazine Monotherapy on Glycemic Control in Subjects With Type 2 Diabetes. AB - OBJECTIVE: Ranolazine is an antianginal drug that mediates its effects by inhibition of cardiac late sodium current. Although ranolazine is not approved for the treatment of type 2 diabetes, in post hoc analyses of pivotal angina trials, ranolazine was associated with reductions in percent glycosylated hemoglobin (HbA1c) in subjects with type 2 diabetes. The study prospectively assessed the safety and efficacy of ranolazine in subjects with type 2 diabetes with inadequate glycemic control managed by lifestyle alone. RESEARCH DESIGN AND METHODS: The study was conducted worldwide in 465 subjects, with baseline HbA1c of 7-10% (53-86 mmol/mol) and fasting serum glucose of 130-240 mg/dL, randomized to placebo versus ranolazine. RESULTS: Compared with placebo, there was a greater decline in HbA1c at week 24 from baseline (primary end point) in subjects taking ranolazine (mean difference -0.56% [-6.1 mmol/mol]; P < 0.0001). Moreover, the proportion of subjects achieving an HbA1c <7.0% was greater with ranolazine (25.6% vs. 41.2%; P = 0.0004). Ranolazine was associated with reductions in fasting (mean difference -8 mg/dL; P = 0.0266) and 2-h postprandial glucose (mean difference -19 mg/dL; P = 0.0008 vs. placebo). Subjects taking ranolazine trended toward a greater decrease from baseline in fasting insulin (P = 0.0507), a greater decrease in fasting glucagon (P = 0.0003), and a lower postprandial 3-h glucagon area under the curve (P = 0.0031 vs. placebo). Ranolazine was safe and well tolerated. CONCLUSIONS: Compared with placebo, use of ranolazine monotherapy over 24 weeks, in subjects with type 2 diabetes and inadequate glycemic control on diet and exercise alone, significantly reduced HbA1c and other measures of glycemic control. PMID- 26049553 TI - Negative Middle Ear Pressure and Composite and Component Distortion Product Otoacoustic Emissions. AB - OBJECTIVES: Distortion product otoacoustic emissions (DPOAEs), a by-product of normal outer hair cell function, are used in research and clinical settings to noninvasively test cochlear health. The composite DPOAE recorded in the ear canal is the result of interactions of at least two components: a nonlinear distortion component (the generator component) and a linear reflection component. Negative middle ear pressure (NMEP) results in the tympanic membrane being pulled inward and increases middle ear impedance. This influences both the forward travel of stimuli used to induce distortion products and the reverse travel of the emissions back to the ear canal. NMEP may therefore limit the effectiveness of DPOAEs in clinical settings. DESIGN: Twenty-six normal-hearing subjects were recruited, and eight were able to reliably and consistently induce NMEP using the Toynbee maneuver. Eight interleaved measures of tympanic peak pressure (TPP) were collected for each subject at normal pressure and NMEP. DPOAEs were then collected both when middle ear pressure was normal and during subject-induced NMEP. All measures were interleaved. Two primary tones were swept logarithmically across frequency (1 second per octave) from f1 = 410 to 6560 Hz and f2 = 500 to 8000 Hz (f1/f2 = 1.22), producing 2f1 - f2 DPOAEs from 320 to 5120 Hz. DPOAEs were collected at three equal-level primary level combinations (L65, L70, L75 dB SPL). Before composite and component DPOAE analysis, analysis of the f1 DPOAE primary confirmed that subjects had successfully induced NMEP. DPOAE and component magnitudes were separately analyzed using repeated measures analysis of variances with three factors, primary level (L65, L70, L75 dB SPL), middle ear pressure (normal pressure versus NMEP), and frequency (500 to 4000 Hz). RESULTS: Mean subject-induced NMEP ranged from -65 to -324 daPa. Changes in the magnitude (dB) of the primary tones used to induce the DPOAE provided a reliable indicator of subject-induced NMEP. Composite DPOAE and component levels were significantly affected by NMEP for all the frequencies tested. Changes were most clearly observed for the generator component with one subject demonstrating a mean decrease of 12 dB in magnitude during NMEP. Results were subject-specific, and there was a correlation between the degree of negative TPP induced and the amount of change in DPOAE level. CONCLUSIONS: Mean TPPs collected during NMEP ranged from -65 to -324 daPa and significantly affected composite DPOAE, generator, and reflection component levels. Changes in the magnitude of the swept-primaries as a function of frequency were used to confirm that NMEP had been successfully induced. The patterns of change in the composite DPOAEs were clearer and easier to interpret when the components of the DPOAE were separated with evaluation of the generator component alone. PMID- 26049554 TI - Lung inhomogeneities and time course of ventilator-induced mechanical injuries. AB - BACKGROUND: During mechanical ventilation, stress and strain may be locally multiplied in an inhomogeneous lung. The authors investigated whether, in healthy lungs, during high pressure/volume ventilation, injury begins at the interface of naturally inhomogeneous structures as visceral pleura, bronchi, vessels, and alveoli. The authors wished also to characterize the nature of the lesions (collapse vs. consolidation). METHODS: Twelve piglets were ventilated with strain greater than 2.5 (tidal volume/end-expiratory lung volume) until whole lung edema developed. At least every 3 h, the authors acquired end-expiratory/end inspiratory computed tomography scans to identify the site and the number of new lesions. Lung inhomogeneities and recruitability were quantified. RESULTS: The first new densities developed after 8.4 +/- 6.3 h (mean +/- SD), and their number increased exponentially up to 15 +/- 12 h. Afterward, they merged into full lung edema. A median of 61% (interquartile range, 57 to 76) of the lesions appeared in subpleural regions, 19% (interquartile range, 11 to 23) were peribronchial, and 19% (interquartile range, 6 to 25) were parenchymal (P < 0.0001). All the new densities were fully recruitable. Lung elastance and gas exchange deteriorated significantly after 18 +/- 11 h, whereas lung edema developed after 20 +/- 11 h. CONCLUSIONS: Most of the computed tomography scan new densities developed in nonhomogeneous lung regions. The damage in this model was primarily located in the interstitial space, causing alveolar collapse and consequent high recruitability. PMID- 26049555 TI - Perioperative B-type Natriuretic Peptide/N-terminal pro-B-type Natriuretic Peptide: Next Steps to Clinical Practice. PMID- 26049557 TI - Effect of Proliferator-Activated Receptor-gamma Pro12Ala Polymorphism on Colorectal Cancer Risk: A Meta-Analysis. AB - BACKGROUND: The association between peroxisome proliferators-activated receptor gamma (PPARgamma) Pro12Ala polymorphism and colorectal cancer (CRC) risk is still controversial. A meta-analysis was performed. MATERIAL AND METHODS: We conducted a literature search using PubMed, EMBASE, and Cochran databases. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. Fixed-effects and random-effects models were used. Dominant model, recessive model, and additive model were used in this meta-analysis. RESULTS: Fifteen studies including 13575 cases and 17085 controls were included in our meta-analysis. Result of this meta analysis found that PPARgamma Pro12Ala polymorphism was significantly associated with a reduced risk of CRC (OR=0.90; 95% CI 0.83-0.98; P=0.01). No significant association was found between PPARgamma Pro12Ala polymorphism and CRC risk in Asians (OR=0.80; 95% CI 0.60-1.09; P=0.15). However, PPARgamma Pro12Ala polymorphism was significantly associated with a reduced risk of CRC in Caucasians (OR=0.91; 95% CI 0.83-0.99; P=0.03). When stratified analysis was performed by CRC site, no positive association was found between PPARgamma Pro12Ala polymorphism and rectal cancer (OR=0.95; 95% CI 0.74-1.22; P=0.71). However, a reduced risk of colon cancer was observed (OR=0.85; 95% CI 0.76-0.94; P=0.002). CONCLUSIONS: In summary, this study suggests that PPARgamma Pro12Ala polymorphism was a protective factor of CRC. PMID- 26049584 TI - Influence of the HER2 Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients: a meta-analysis. AB - BACKGROUND: The HER2 655 A>G genetic variant has recently been associated with trastuzumab-induced cardiotoxicity in HER2 breast cancer patients. Considering previous results, the aim of our study was to validate the role of this polymorphism as a predictor of the cardiac toxicity of trastuzumab in breast cancer patients. METHODS: Our study population was composed of 78 HER2 breast cancer patients receiving trastuzumab. The HER2 655 A>G (rs1136201) genetic variant was genotyped using TaqMan allelic discrimination technology. Patients were classified on the basis of the occurrence of cardiotoxic events or the absence of cardiotoxic events during 1 year after the first infusion. RESULTS: The HER2 655 A>G polymorphism was significantly associated with cardiotoxicity: AG versus AA [P=0.012, odds ratio (OR)=5.12, 95% confidence interval (CI) 1.43 18.36], AG+GG versus AA (P=0.01, OR=5.72, 95% CI 1.50-21.76), AG versus AA+GG (P=0.005, OR=7.17, 95% CI 1.82-28.29). A meta-analysis combining these data with the results from previous studies confirmed this association. CONCLUSION: Our results support the role of the HER2 655 A>G polymorphism as a genetic marker of trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients. PMID- 26049556 TI - Early life social stress induced changes in depression and anxiety associated neural pathways which are correlated with impaired maternal care. AB - Exposures to various types of early life stress can be robust predictors of the development of psychiatric disorders, including depression and anxiety. The objective of the current study was to investigate the roles of the translationally relevant targets of central vasopressin, oxytocin, ghrelin, orexin, glucocorticoid, and the brain-derived neurotrophic factor (BDNF) pathway in an early chronic social stress (ECSS) based rodent model of postpartum depression and anxiety. The present study reports novel changes in gene expression and extracellular signal related kinase (ERK) protein levels in the brains of ECSS exposed rat dams that display previously reported depressed maternal care and increased maternal anxiety. Decreases in oxytocin, orexin, and ERK proteins, increases in ghrelin receptor, glucocorticoid and mineralocorticoid receptor mRNA levels, and bidirectional changes in vasopressin underscore related work on the adverse long-term effects of early life stress on neural activity and plasticity, maternal behavior, responses to stress, and depression and anxiety related behavior. The differences in gene and protein expression and robust correlations between expression and maternal care and anxiety support increased focus on these targets in animal and clinical studies of the adverse effects of early life stress, especially those focusing on depression and anxiety in mothers and the transgenerational effects of these disorders on offspring. PMID- 26049585 TI - Genetic polymorphism at Val80 (rs700518) of the CYP19A1 gene is associated with body composition changes in women on aromatase inhibitors for ER (+) breast cancer. AB - OBJECTIVE: Polymorphisms in the CYP19A1 (aromatase) gene influence disease-free survival and bone loss in patients taking aromatase inhibitors (AIs) for estrogen receptor-positive (ER+) breast cancers. Because AI use results in severe estrogen deficiency that may lead to changes in body composition, the aim of this study was to determine the effect of the rs700518 polymorphism in the CYP19A1 gene on the changes in body composition among postmenopausal women who were treated with AIs for ER+ breast cancer. PATIENTS AND METHODS: This was a 1-year prospective study of changes in body composition in postmenopausal women who were initiated on third-generation AIs for ER+ breast cancer. Body composition was measured by dual-energy absorptiometry at 6 and 12 months, serum estradiol by radioimmunoassay, and genotyping by a TaqMan single-nucleotide polymorphism allelic discrimination assay. RESULTS: Eighty-two women could provide at least one follow-up body composition measurement. Women with the GG genotype for the rs700518 (G/A at Val80) developed a significant increase in truncal fat mass index (P=0.03) and a significant decrease in fat-free mass index (P=0.01) at 12 months relative to patients carrying the A allele (GA/AA). There was no significant difference in the changes in estradiol levels among the genotypes. CONCLUSION: Patients with the GG genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for significant loss of fat-free mass and increase in truncal fat with AI therapy. Whether there are associated metabolic abnormalities and whether changes would persist with long-term AI therapy need to be confirmed in a larger study with a longer duration of follow-up. PMID- 26049586 TI - A human leukocyte antigen locus haplotype confers risk for allopurinol-related adverse effects in Caucasian patients with gout. AB - A human leukocyte antigen haplotype comprising six single-nucleotide polymorphisms (SNPs) confers risk for allopurinol hypersensitivity syndrome in Caucasians. The objective of the current study was to test for association of this haplotype with other, less severe adverse effects (AEs) of allopurinol therapy in a large New Zealand gout cohort. A total of 626 Caucasian and 766 Polynesian patients were genotyped for six SNPs (rs2844665, rs9263715, rs3130931, rs3130501, rs3094188, rs9469003) using TaqMan SNP assays. The CACGAC haplotype occurred at a frequency of 0.018 in Caucasians and 0.009 in Polynesians. The CACGAC haplotype occurred at a significantly higher frequency in Caucasian patients who experienced allopurinol-related AEs (13.3 vs. 1.7%, P=8.9e-06, odds ratio=8.9, 95% confidence interval 2.8-27.9), but it was not associated with overall allopurinol toxicity in Polynesians (P>0.05). Our study is the first to demonstrate the potential utility of this six-SNP haplotype as a predictor of milder allopurinol AEs. PMID- 26049588 TI - Kapur-Toriello syndrome: a further case report and expansion of the phenotype. PMID- 26049589 TI - Kabuki syndrome: expanding the phenotype to include microphthalmia and anophthalmia. AB - Kabuki syndrome is a rare genetic malformation syndrome that is characterized by distinct facies, structural defects and intellectual disability. Kabuki syndrome may be caused by mutations in one of two histone methyltransferase genes: KMT2D and KDM6A. We describe a male child of nonconsanguineous Irish parents presenting with multiple malformations, including bilateral extreme microphthalmia; cleft palate; congenital diaphragmatic hernia; duplex kidney; as well as facial features of Kabuki syndrome, including interrupted eyebrows and lower lid ectropion. A de-novo germline mutation in KMT2D was identified. Whole-exome sequencing failed to reveal mutations in any of the known microphthalmia/anopthalmia genes. We also identified four other patients with Kabuki syndrome and microphthalmia. We postulate that Kabuki syndrome may produce this type of ocular phenotype as a result of extensive interaction between KMT2D, WAR complex proteins and PAXIP1. Children presenting with microphthalmia/anophthalmia should be examined closely for other signs of Kabuki syndrome, especially at an age where the facial gestalt might be less readily appreciable. PMID- 26049587 TI - PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. PMID- 26049590 TI - The cauda equina syndrome in pregnant woman with a massive disc herniation. AB - Low back pain during pregnancy is a common cause of medical consultation. Although back pain is very common, the incidence of low back pain secondary to lumbar disk herniation in pregnancy is low (1: 10,000). Cauda equina syndrome from lumbar disk herniation is a serious complication. The delay in diagnosis and treatment can be a cause of chronic disability secondary to neurological sequelae. Numerous cases of disk herniation in pregnancy have been reported, however the association of a cauda equina syndrome as a result of disk herniation is rare. A case is presented of cauda equina syndrome in a pregnant woman at 12 week gestation. PMID- 26049591 TI - Evolutionary dynamics of foot-and-mouth disease virus O/ME-SA/Ind2001 lineage. AB - Foot-and-mouth disease (FMD) virus serotype O Ind2001 lineage within the Middle East-South Asia topotype is the major cause of recent FMD incidences in India. A sub-lineage of Ind2001 caused severe outbreaks in the southern region of the country during 2013 and also reported for the first time from Libya. In this study, we conducted a detailed evolutionary analysis of Ind2001 lineage. Phylogenetic analysis of Ind2001 lineage based on maximum likelihood method revealed two major splits and three sub-lineages. The mean nucleotide substitution rate for this lineage was calculated to be 6.338*10( 3)substitutions/site/year (s/s/y), which is similar to those of PanAsian sub lineages. Evolutionary time scale analysis indicated that the Ind2001 lineage might have originated in 1989. The sub-lineage Ind2001d that caused 2013 outbreaks seems to be relatively more divergent genetically from other Ind2001 sub-lineages. Seven codons in the VP1 region of Ind2001 were found to be under positive selection. Four out of 24 recent Ind2001 strains tested in 2D-MNT had antigenic relationship value of <0.3 with the serotype O vaccine strain indicating intra-epidemic antigenic diversity. Amino acid substitutions found in these minor variants with reference to antigenic diversity have been discussed. The dominance of antigenically homologous strains indicates absence of vaccine immunity in the majority of the affected hosts. Taken together, the evolution of Ind2001 lineage deviates from the strict molecular clock and a typical lineage evolutionary dynamics characterized by periodic emergence and re-emergence of Ind2001 and PanAsia lineage have been observed in respect of serotype O. PMID- 26049594 TI - From the Editor. PMID- 26049592 TI - Characterisation of a mobilisable plasmid conferring florfenicol and chloramphenicol resistance in Actinobacillus pleuropneumoniae. AB - The complete nucleotide sequence of a 7.7kb mobilisable plasmid (pM3446F), isolated from a florfenicol resistant isolate of Actinobacillus pleuropneumoniae, showed extended similarity to plasmids found in other members of the Pasteurellaceae containing the floR gene as well as replication and mobilisation genes. Mobilisation into other Pasteurellaceae species confirmed that this plasmid can be transferred horizontally. PMID- 26049593 TI - Genetic and antigenic characterization of Bungowannah virus, a novel pestivirus. AB - Bungowannah virus, a possible new species within the genus Pestivirus, has been associated with a disease syndrome in pigs characterized by myocarditis with a high incidence of stillbirths. The current analysis of the whole-genome and antigenic properties of this virus confirms its unique identity, and further suggests that this virus is both genetically and antigenically remote from previously recognized pestiviruses. There was no evidence of reactivity with monoclonal antibodies (mAbs) that are generally considered to be pan-reactive with other viruses in the genus, and there was little cross reactivity with polyclonal sera. Subsequently, a set of novel mAbs has been generated which allow detection of Bungowannah virus. The combined data provide convincing evidence that Bungowannah virus is a member of the genus Pestivirus and should be officially recognized as a novel virus species. PMID- 26049595 TI - Guest Editorial The Power of Alignment. PMID- 26049596 TI - The Power of Alignment: Pioneering New Collaborations During Transformational Change. AB - Both health care reform and the Triple Aim call for enhanced patient experience, improved health outcomes, and reduced costs. To achieve these goals, we must collaborate across health care and community organizations, across fields of expertise, and across the continuum of care. As collaboration is one of nursing's core competencies, nurses are ideally positioned to lead the drive toward the Triple Aim. This article outlines 3 key areas of collaboration and describes successful interventions that the Visiting Nurse Service of New York has developed in these areas: as community organizers, partnering with health, grassroots, and government agencies; as transitional integrators, partnering with acute-care facilities to reduce rehospitalizations; and across populations, partnering in new ways to help patients manage chronic and complex health issues in the context of their families and communities. PMID- 26049597 TI - Predictability of a Professional Practice Model to Affect Nurse and Patient Outcomes. AB - Thousands of patients experience needless deaths and injuries as a result of errors while hospitalized for an unrelated problem. The lack of an established professional practice model (PPM) of nursing may be a contributing factor to patient care quality and safety breaches. The PPM of nursing was tested for its ability to affect nurse and patient outcomes. Using a retrospective/prospective research design, secondary data were collected from 2395 staff nurses on 15 inpatient-nursing units covering a 6-year timeframe. Data were analyzed using ANOVA and the Pearson correlation. Nurse and patient outcomes on 2 hospital campuses reached statistical significance. Positive correlations were seen between the initiation of a PPM and subsequent nurses' perception of quality of care, nurse interactions, decision making, autonomy, job enjoyment, and patient satisfaction. This study provides empirical evidence that a uniquely designed PPM in alignment with organizational context can indeed impact nurse and patient outcomes in a community health system. PMID- 26049598 TI - Aligning Provider Team Members With Polyvalent Community Health Workers. AB - In light of the fragmentation of health care services and the need for health promotion and disease prevention, it is time to consider the important role community health workers (CHWs) could play as part of the health care team. Globally, CHWs tend to focus on a single patient condition, resulting in fragmented, uncoordinated health care services. Polyvalent (or multimodal) CHWs can provide a comprehensive, patient-centric range of care coordination services with other members of the health care team, ultimately improving patient outcomes and decreasing the cost of care. The potential benefits of the polyvalent CHW to the health care team are not widely understood in the United States. To fill this knowledge gap, a toolkit for nurse leaders in mainstream health care settings was created. The toolkit outlines the key elements essential to a successful CHW program and offers strategies for navigating the various challenges involved when integrating this new role into existing models of care. PMID- 26049599 TI - The TriCouncil for Nursing: An Interorganizational Collaboration for Advancing the Profession. AB - The TriCouncil for Nursing is a coalition of 4 leading nursing organizations: the American Association of Colleges of Nursing, the American Nurses Association, the American Organization of Nurse Executives, and the National League for Nursing. This informal, yet highly complex, collaboration has endeavored to advance the profession for almost 4 decades despite the inherent challenges in coalition formation and sustainment. Coalition building occurs when organizations seek the potential to advance common issues or protect individual resources or status, and by their very nature have the potential to fail. The history of the TriCouncil for Nursing provides evidence of the challenges associated with the process of developing consensus and the benefits of working to create consensus to achieve common goals. The commitment of the TriCouncil member organizations to sustain this coalition and find consensus across an array of challenging issues and in complex environments has created significant policy advances for the profession, which provides evidence of the benefits associated with this type of collaborative work. This coalition has continued despite the inherent challenges for organizations seeking consensus. The TriCouncil commitment to lead in advocacy for the profession and create significant policy to change health care models the value of this type of effort. PMID- 26049600 TI - Nursing Leader Collaboration to Drive Quality Improvement and Implementation Science. AB - Nursing leadership opportunities to improve quality and align resources in health care exist. An estimated 18% of United States gross domestic product is spent on health care delivery systems that produce poor outcomes. The purpose of this article was to describe how quality improvement and implementation science initiatives enhance outcomes using nursing leadership strategies that play an integral role in aligning key colleagues to drive the collaborative process. A critical appraisal of the literature was conducted, which supports the importance of evidenced-based practice improvement, collaborative change process, and professional role of nursing leadership. Limited evidence exists related to practice strategies for nursing leaders to implement sustainable change at the unit level for successful alignment of resources. Strategies based on Rogers' Diffusion of Innovation Theory are recommended to address the gap in the literature. The strategies aim to increase meaningful knowledge or the "why," create a tipping point, and implement sustainable change starting with the end in mind. Nurse leaders are a central component for driving alignment and implementing change at the unit level. Uses of the described evidenced-based strategies have implications for nursing practice, education, and scholarship. PMID- 26049601 TI - Leading Nursing Into the Future: Development of a Strategic Nursing Platform on a System Level. AB - Leading and orchestrating the mission-essential work of 47 diverse hospitals toward a common vision with a supporting strategy is a challenge for any health care system. Trinity Health embraced this challenge while reorganizing the pivotal role of nursing in designing the future of health care delivery. This article outlines the roadmap utilized to create a common nursing platform to drive strategy aligned to future viability, strength, and growth across a system. PMID- 26049602 TI - Evolution of an Evidence Collaboration: From Initial Goals to Current Initiatives. AB - Best practices based on evidence are needed by every clinician to provide safe, effective, patient-centered care. Determining best practice for a given situation can be difficult. Ideally, the clinician understands how to critically appraise the relevant research, and integrates high-quality research with interdisciplinary clinical expertise and patient and family values and preferences to choose best care for an individual or family. At our organization, we are taking the integration of research, clinical expertise, and patient/family preferences and values to the next level by aligning the evidence work of multiple functional areas and disciplines to improve the safety and effectiveness of clinical practice. The Evidence Collaboration, an interdisciplinary community of practice, has evolved to meet the challenges of helping novices and experts of all disciplines identify, critically appraise, synthesize, and disseminate evidence to inform best practices for patients and families, staff, and institutional processes. By creating a common language for evidence work, resources such as the Let Evidence Guide Every New Decision system, and templates for dissemination, the Evidence Collaboration has moved the organizational culture toward one that encourages the use of evidence in all decisions. Our progress continues as we strive to include patients and families in the decisions about best practices based on evidence. PMID- 26049603 TI - Evaluation of Team-Based Care in an Urban Free Clinic Setting. AB - This article reports the experiences of a school of nursing, academic health center, and community-based organization working via an interprofessional collaborative practice model to meet the mutual goal of serving the health care needs of an indigent, largely minority population in Birmingham, Alabama. The population suffers disproportionately from chronic health problems including diabetes, obesity, cardiovascular disease, asthma, and mental health disorders. The program emphasizes diabetes management because the academic health center recognized the need for transitional and primary care, including mental health services, for the increasing numbers of uninsured patients with diabetes and its comorbidities. Half of the clinicians involved in this project had no prior experience with interprofessional collaborative practice, and there was confusion regarding the roles of team members from the partnering institutions. Activities involving care coordination consistently received low scores on weekly rating scales leading to the creation of positions for a nurse care manager and pharmaceutical patient assistance program coordinator. Conversely, shared decision making and cooperation ratings were consistently high. Evaluation identified the need for reliable, accessible data and data analysis to target clinically effective interventions and care coordination and to assess cost effectiveness. The strengths, challenges, lessons learned, and next steps required for sustainability of this alignment are discussed. PMID- 26049604 TI - Caring for America's Veterans: The Power of Academic-Practice Partnership. AB - Veterans receive care across the entire health system. Therefore, the workforce needs knowledge and awareness of whether patients are Veterans and the impact of their military service on their physical and mental health. Recent reports of limitations in access for Veterans seeking health care have highlighted this need across all health care settings. Academic-practice partnerships are one mechanism to align the need for improved health care services within the Veteran population while advancing nursing practice in the Veterans Health Administration and surrounding communities. The key to strong partnerships and sustained collaboration is shared goals, mutual trust and respect, the development of formal relationships, and support of senior leadership that fosters the joint vision and mission to improve nursing care for Veterans. This article describes the evolving partnership between one Veterans Health Administration Medical Center and a School of Nursing, which aligned strategic goals across both organizations to increase the capacity and capability of services provided to Veterans. PMID- 26049605 TI - The Power of Alignment: Educating Nurses in Quality and Safety. AB - The Quality and Safety Education for Nurses (QSEN) grant was launched over 5 years after the Institute of Medicine's report that shared the stark truth about medical errors. The 4 phases of QSEN have provided a roadmap for nursing prelicensure and graduate students to integrate quality improvement and safety content into educational programs. By fully aligning the resources of academic programs with health care organizations, a more robust and comprehensive approach could be taken to ensure that all nurses receive the benefit of the most up-to date and thorough education about quality and safety. PMID- 26049606 TI - Aligning Nurse Practice Acts: Factors, Forces, Fiction, and Facts. PMID- 26049607 TI - Aligning for Heroes: Partnership for Veteran Care in New Hampshire. AB - A growing number of veterans and service members ("veterans" refers to both veterans and eligible service members) are returning home and may be living with mental health conditions related to their military service. For a variety of reasons, the majority of US veterans receive their health care outside the Veterans Administration or the military health system. Nurse leaders and citizen soldiers were among a number of concerned government officials, health care professionals, service providers, and military leaders in New Hampshire (NH) who joined forces to explore NH veterans' mental health needs and manage provider service capacity. This article describes the formation and efforts of a permanent legislative commission, the NH Commission on PTSD and TBI (COPT), composed of interdisciplinary, multiorganizational, and cross-governmental leaders aligned to address the issues of stigma, military cultural awareness, and integration of care. Commission participants were asked to share their perspectives on the gaps and challenges to veterans' care, opportunities for collaboration, and measurable outcomes. Key challenges included interagency communication and care integration issues, veteran and provider knowledge gaps about needs and system problems. Favorable timing, available funding, and the collaborative environment of the commission were identified as potential opportunities. While still a work in progress, the COPT has begun making an impact. We identify early outcomes and lessons learned. The COPT is a model for leveraging interdisciplinary professional collaboration to improve access to care for veterans. PMID- 26049608 TI - Community Engagement: Leveraging Resources to Improve Health Outcomes. AB - Improving the health of communities requires creating partnerships and leveraging partner resources. Engagement with key stakeholders or partners who engage in collaborative community needs assessments has been linked to improved community health outcomes. Understanding how to engage community stakeholders, identify mutual goals, and establish a shared vision can maximize resources to improve the community's health. We applied our experience to an existing model for community engagement and leveraging of resources to improve the community's health and translate the model to a community case. PMID- 26049609 TI - Oncolytic gene therapy with recombinant vaccinia strain GLV-2b372 efficiently kills hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) commonly presents at a late stage when surgery is no longer a curative option. As such, novel therapies for advanced HCC are needed. Oncolytic viruses are a viable option for cancer therapy owing to their ability to specifically infect, replicate within, and kill cancer cells. In this study, we have investigated the ability of GLV-2b372, a novel light-emitting recombinant vaccinia virus derived from a wild-type Lister strain, to kill HCC. METHODS: Four human HCC cell lines were assayed in vitro for infectivity and cytotoxicity. Viral replication was quantified via standard viral plaque assays. Flank HCC xenografts generated in athymic nude mice were treated with intratumoral GLV-2b372 to assess for tumor growth inhibition and viral biodistribution. RESULTS: Infectivity occurred in a time- and concentration dependent manner with 70% cell death in all cell lines by day 5. All cell lines supported efficient viral replication. At 25 days after infection, flank tumor volumes decreased by 50% whereas controls increased by 400%. Tumor tissue demonstrated substantial GLV-2b372 infection at 24 hours, 48 hours, and 2 weeks. CONCLUSION: We demonstrate that GLV-2b372 efficiently kills human HCC in vitro and in vivo and is a viable treatment option for patients with HCC. PMID- 26049610 TI - Combined flaps based on the superficial temporal vascular system for reconstruction of facial defects. AB - BACKGROUND: Facial defects are multicomponent deficiencies rather than simple soft-tissue defects. Based on different branches of the superficial temporal vascular system, various tissue components can be obtained to reconstruct facial defects individually. METHODS: From January 2004 to December 2013, 31 patients underwent reconstruction of facial defects with composite flaps based on the superficial temporal vascular system. RESULTS: Twenty cases of nasal defects were repaired with skin and cartilage components, six cases of facial defects were treated with double island flaps of the skin and fascia, three patients underwent eyebrow and lower eyelid reconstruction with hairy and hairless flaps simultaneously, and two patients underwent soft-tissue repair with auricular combined flaps and cranial bone grafts. All flaps survived completely. Donor-site morbidity is minimal, closed primarily. Donor areas healed with acceptable cosmetic results. The final outcome was satisfactory. CONCLUSION: Combined flaps based on the superficial temporal vascular system are a useful and versatile option in facial soft-tissue reconstruction. PMID- 26049611 TI - One stage mastopexy augmentation in the ptotic patient. The superiorly based dermal flap for autologous reinforcement of the inferior pole. AB - BACKGROUND: The use of one stage mastopexy augmentation in the ptotic patient remains controversial. Expansion of breast volume and reduction of the skin envelope contradict each other and increase the risks of potential complications. By carefully selecting and consenting patients appropriately I describe the use of the superiorly based dermal flap for autologous reinforcement of the inferior pole to increase safety and reliability in one stage mastopexy augmentation. OBJECTIVES: To determine whether the superiorly based dermal flap could provide a safe and reliable method of one stage mastopexy augmentation. METHODS: 40 one staged mastopexy augmentation procedures were performed on 21 patients. Patients were excluded if they smoked, BMI >30, had significant co-morbidities, had unrealistic expectations, required a nipple lift of >8 cm, wanted >400cc volume in primary cases or >25% increase in volume in secondary mastopexy augmentation. Both round and anatomical implants were used in either the sub glandular or dual plane pocket depending on patient's aesthetic wishes. RESULTS: The average implant size was 290cc and average nipple lift was 5 cm. After an average follow up of 27months there have been no implant based complications, no reoperations and no infections/haematomas/seromas. CONCLUSIONS: Careful selection and consent of patients make the use of the superiorly based dermal flap for autologous reinforcement of the inferior pole a safe reliable technique in one stage mastopexy augmentation. PMID- 26049612 TI - The influence of breast mound reconstruction type on nipple reconstruction projection. PMID- 26049613 TI - Treatment of congenital unilateral hypoplastic breast anomalies using autologous fat grafting: A study of 11 consecutive patients. AB - During the period 2008-2013, 11 women were treated with autologous fat grafting for unilateral congenital breast hypoplasia comprising both tuberous breast and micromastia. No correction of the contralateral breast was done at evaluation. Patients were treated median one time, and they had their inter-breast volume difference reduced from median 175 to 50 ml. Patients showed overall high degree of satisfaction with the treatment, but they were less satisfied when addressing size and shape separately. The median follow-up time was 13 months, and the achieved breast volume sustained throughout the follow-up period. PMID- 26049614 TI - A randomised double-blinded crossover study comparing pain during anaesthetising the eyelids in upper blepharoplasty: First versus second eyelid and lidocaine versus prilocaine. AB - AIM: The aim of this study was to investigate whether infiltration of the upper eyelid skin is less painful with prilocaine than with lidocaine. METHODS: In 40 consecutive patients scheduled for bilateral upper blepharoplasty, one upper eyelid was anaesthetised with lidocaine with epinephrine and the other with prilocaine with felypressin. After injection of each upper eyelid, the patient scored the pain experienced on infiltration using a visual analogue scale (0-10). In addition, the surgeon scored the need for reinjection during the operation; differences in perioperative bleeding; and degree of oedema, erythema and haematoma before discharge on a four-point rating scale (no, minimal, moderate or severe). RESULTS: Pain scores were significantly lower in upper eyelids injected with lidocaine than in those injected with prilocaine (p = 0.036). In addition, scores for oedema, erythema and haematoma were significantly lower in upper eyelids anaesthetised with lidocaine than in those anaesthetised with prilocaine (respectively, p = 0.001, p = 0.004 and p = 0.000). CONCLUSIONS: Compared with prilocaine with felypressin, lidocaine with epinephrine is significantly less painful in anaesthetising the upper eyelids; gives significantly less postoperative oedema, erythema and haematoma; and provides better haemostasis during upper blepharoplasty. LEVEL OF EVIDENCE: This was a level II, randomised double-blinded crossover study. PMID- 26049615 TI - PREVALENCE OF SUBTYPES OF RETICULAR PSEUDODRUSEN IN NEWLY DIAGNOSED EXUDATIVE AGE RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY IN KOREAN PATIENTS. AB - PURPOSE: To evaluate the prevalence and characteristics of subtypes of pseudodrusen in newly diagnosed exudative age-related macular degeneration (AMD) and polypoidal choroidal vasculopathy (PCV). METHODS: This retrospective cross sectional study included 321 eyes of 321 patients who were newly diagnosed with exudative AMD or PCV. Reticular pseudodrusen was classified into dot pseudodrusen and ribbon pseudodrusen; the prevalence of each subtype was estimated and compared between exudative AMD excluding retinal angiomatous proliferation (RAP), PCV, and RAP. Patient age and choroidal thickness were compared between patients with dot pseudodrusen only and those with ribbon pseudodrusen. RESULTS: The prevalence of reticular pseudodrusen was 13.9% (15 of 108 eyes) in exudative AMD excluding RAP, 3.4% (6 of 175 eyes) in PCV, and 68.4% (27 of 38 eyes) in RAP. Among the eyes with pseudodrusen, dot pseudodrusen and ribbon pseudodrusen were noted in 100% and 40.0%, respectively, in exudative AMD excluding RAP, 100% and 16.7%, respectively, in PCV, and 96.2% and 69.2%, respectively, in RAP. Ribbon pseudodrusen was more frequently observed in RAP (P = 0.032). Patients with ribbon pseudodrusen were significantly older (77.3 +/- 6.6 years vs. 72.9 +/- 8.1 years, P = 0.042) than those with dot pseudodrusen only. CONCLUSION: The markedly higher incidence of ribbon pseudodrusen in RAP may suggest possible influence of ribbon pseudodrusen on the development of RAP. PMID- 26049616 TI - INTRAVITREAL ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY FOR CHOROIDAL NEOVASCULARIZATION SECONDARY TO PATHOLOGIC MYOPIA: SIX YEARS OUTCOME. AB - PURPOSE: To report the visual outcome after 6-year follow-up in highly myopic eyes with choroidal neovascularization treated with anti-vascular endothelial growth factor drugs. METHODS: Retrospective, nonrandomized, multicenter, consecutive, and interventional case series. RESULTS: Seventy-eight patients were treated with intravitreal bevacizumab and 19 with ranibizumab. Mean age of the patients was 56.5 years (SD, 13.3). The average number of letters read was 56.7 (SD, 19.0) at baseline; 65.7 (SD, 18.4) at 12 months; 63.6 (SD, 20.6) at 24 months; 62.4 (SD, 21.4) at 36 months; 60.6 (SD, 22.0) at 48 months; 58.9 (SD, 22.9) at 60 months, and 58.4 (SD, 22.7) at 72 months (P < 0.01, between initial vs. 12, 24, and 36 months; P = 0.07, 0.3, and 0.5 between initial vs. 48, 60, and 72 months, respectively; Student's t-test paired data). The mean total number of intravitreal injections was 3.3 (SD, 2.3; range, 1-9). CONCLUSION: Bevacizumab and ranibizumab are effective therapies and show similar clinical effects in myopic eyes with choroidal neovascularization. Visual acuity gain is maintained at a 3-year follow-up. The improvement is no longer statistically significant at Years 4, 5, and 6. PMID- 26049617 TI - SCLERAL BUCKLING VERSUS VITRECTOMY IN THE MANAGEMENT OF MACULA-OFF PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT: A COMPARISON OF VISUAL OUTCOMES. AB - PURPOSE: To compare visual outcomes between pars plana vitrectomy (PPV) with or without scleral buckling (SB) and SB alone in the management of uncomplicated macula-off primary rhegmatogenous retinal detachment. METHODS: Case-control study of 723 patients with uncomplicated macula-off primary rhegmatogenous retinal detachment seen at the Singapore National Eye Centre from 2005 to 2011. The primary outcome measure was the proportion of eyes achieving functional success, defined as logMAR best-corrected visual acuity of <=0.3 logMAR at 6 months postoperatively. Multivariable logistic regression analysis was performed adjusting for the following preoperative covariates: age, gender, race, lens status, number of tears found, presence of proliferative vitreoretinopathy, operative procedure, logMAR best-corrected visual acuity, and duration of symptoms. RESULTS: Three hundred and eight eyes underwent SB alone, and 415 eyes underwent PPV +/- SB. In the SB group, 133 eyes (43.2%) achieved functional success compared with 116 eyes (28.0%) in the PPV +/- SB group. This difference was statistically significant on both univariate (P < 0.001) and multivariable analyses (OR: 1.51, 95% CI: 1.03-2.21, P = 0.03). CONCLUSION: Scleral buckling alone may achieve visual outcomes that are at least comparable with PPV +/- SB in the management of macula-off primary rhegmatogenous retinal detachment. PMID- 26049618 TI - Amaurosis Fugax Captured During Fluorescein Angiography. PMID- 26049619 TI - OCULAR WAVEFRONT ABERRATIONS AND OPTICAL QUALITY IN DIABETIC MACULAR EDEMA. AB - PURPOSE: To evaluate optical quality and internal aberrations in patients with diabetic macular edema. METHODS: In this prospective study, 33 eyes of patients with diabetic macular edema were scanned with a ray-tracing wavefront device. As a control group, wavefront aberrometry was performed in 31 patients. Ocular and internal aberrations and visual quality metrics were evaluated separately to determine whether the source of aberrations was ocular or internal. Main outcome measures included corrected visual acuities, ocular and internal aberrations, Strehl ratio, and modulation transfer function. RESULTS: There was a statistically significant difference between the groups in internal higher order (HO) root mean square (0.34 +/- 0.24 vs. 0.16 +/- 0.05), HO Strehl ratio (0.08 +/ 0.05 vs. 0.18 +/- 0.09), and modulation transfer function (0.29 +/- 0.1 vs. 0.4 +/- 0.1). There was no statistically significant difference in Strehl ratio and HO root mean square between phakic and pseudophakic patients. Height of cystoid spaces was a significant predictor (P < 0.001) of Strehl ratio. Besides inner and outer segment integrity, HO Strehl ratio significantly determined best-corrected visual acuity. CONCLUSION: In eyes with macular edema, internal HO wavefront aberrations were greater than in control eyes. This increase in HO wavefront error seems visually relevant. This study results suggest increased intraretinal edema as the source of HO aberrations. PMID- 26049620 TI - METAMORPHOPSIA AND ITS QUANTIFICATION. AB - PURPOSE: To discuss and analyze the pathophysiologic mechanisms underlying metamorphopsia, the nature of adaptational mechanisms to this symptom, the development and clinical utility of tests of metamorphopsia, and to discuss the cost-effectiveness of screening populations at risk of exudative age-related macular degeneration using such tests. METHODS: A primary literature search of PubMed and Web of Science was conducted for articles covering the mechanisms and/or tests of metamorphopsia. RESULTS: A number of possible mechanisms of metamorphopsia were identified in addition to lateral photoreceptor displacement. These included disorders of image formation, changes in effective axial length, and pathology of the visual pathways and centers. The simplest tests of metamorphopsia rely on highly subjective assessments of regular patterns, as exemplified by Amsler grids. Such tests seem to offer poor sensitivity when used in real-life home-monitoring situations. Newer tests such as so-called preferential hyperacuity perimetry may offer more robust paradigms to assess the perception of distortion but suffer from an inherent disadvantage of being unable to precisely correlate function to structure. The recently published findings of the AREDS2-HOME trial suggest that formalized monitoring of visual function using a preferential hyperacuity perimetry task results in detection of exudative age related macular degeneration when vision is better-preserved. A cost-benefit analysis using the data from the AREDS2-HOME trial suggests that the calculated cost of screening per letter gained/saved is $3,351 per year. CONCLUSION: Metamorphopsia is an important symptom in retinal disease and may occur through a variety of mechanisms. Although the human visual system is exquisitely sensitive to metamorphopsia, commonly used tests of this symptom may be unreliable in real life conditions. Newer tests of metamorphopsia such as preferential hyperacuity perimetry may improve early detection rates of exudative age-related macular degeneration in at-risk populations. PMID- 26049621 TI - AMOUNT OF RESIDUAL SILICONE OIL IN VITREOUS CAVITY IS SIGNIFICANTLY CORRELATED WITH AXIAL LENGTH. AB - PURPOSE: To determine the parameters of the eye that are significantly correlated with the amount of residual silicone oil remaining after most of it is removed by vitrectomy. METHODS: Nineteen eyes of 19 patients who had silicone oil removed were studied. The day after the surgery for silicone oil removal, B-scan ultrasonography was performed, and the residual silicone oil droplets were observed as hyperechoic particles in the ultrasonographic images. The images of the vitreous cavity were binarized, and the ratio of area of hyperechoic particles to the total vitreous area was quantified and named the silicone oil index (SOI). The correlations between SOI and clinical findings were determined. RESULTS: The SOI was significantly and positively correlated with the axial length (AL) and the preoperative intraocular pressure (AL, R = 0.676, P = 0.002; preoperative intraocular pressure, R = 0.771, P < 0.001). Partial correlation analysis showed that the AL remained significantly correlated with the SOI but the preoperative intraocular pressure was not (AL, R = 0.734, P = 0.001; preoperative intraocular pressure, R = 0.417, P = 0.096). None of the other clinical factors was significantly correlated with the SOI. CONCLUSION: Considering the significant correlation between the amount of residual silicone oil and the AL of the eye, myopic eyes should be carefully scrutinized for residual silicone oil. PMID- 26049622 TI - CHOROIDAL THICKNESS AND VOLUME IN A HEALTHY PEDIATRIC POPULATION AND ITS RELATIONSHIP WITH AGE, AXIAL LENGTH, AMETROPIA, AND SEX. AB - PURPOSE: To evaluate choroidal thickness (CT) and volume in healthy pediatric individuals using enhanced depth imaging spectral domain optical coherence tomography (SD-OCT), as well as its association with age, sex, axial length (AL), and refractive error. METHODS: Ninety-three eyes from 93 healthy pediatric individuals were examined. An Early Treatment Diabetic Retinopathy Study grid was applied to analyze CT and volume map in each of its nine sectors. RESULTS: The mean subfoveal CT and volume were 314.22 +/- 55.48 MUm and 0.25 +/- 0.04 mm, respectively. The nasal CT and volume of both the inner and the outer rings were significantly lower than the temporal area of the same ring and lower than the subfoveal choroidal thickness. A significant negative correlation between the subfoveal CT and AL (r = -0.250, P = 0.015) and a significant positive correlation between the subfoveal CT and refractive error (r = 0.238, P = 0.006) were found. The estimation of the variation in the subfoveal CT in relationship to the AL was -13.55 MUm per millimeter. The variation in the subfoveal CT with refractive error was 7.52 MUm per diopter. The estimation of the variation in the total choroidal volume related to the AL and ametropia was, respectively, -0.2354 mm per millimeter and 0.1412 mm per diopter. CONCLUSION: Healthy pediatric subjects exhibit choroidal differences in refractive error and AL. In the study population, CT and volume show an increase with age after adjusting for AL. PMID- 26049623 TI - VARIATION OF 24-HOUR INTRAOCULAR PRESSURE IN SILICONE OIL-FILLED EYES. AB - PURPOSE: To evaluate the variation of 24-hour intraocular pressure (IOP) in silicone oil (SO)-filled eyes. METHODS: Prospective, nonrandomized comparative case series of 42 eyes of 21 patients, each with an SO-filled eye after vitrectomy. The fellow eyes served as controls. Each subject slept the usual 8 hours, and IOPs were measured at 4-hour intervals over 24 hours, twice before sleep (5:30 and 9:30 PM), twice during sleep (1:30 and 5:30 AM), and twice after sleep (9.30 AM and 1:30 PM). Intraocular pressure was measured in the sitting position using a Goldmann applanation tonometer. The SO-filled eyes and fellow eyes were compared with respect to diurnal-to-nocturnal and nocturnal-to-diurnal IOP changes. RESULTS: At all 6 time points, SO-filled eyes had higher mean IOPs than fellow eyes (all P < 0.05). For both groups, mean nocturnal IOP was higher than mean diurnal IOP (both P < 0.001). Changes in diurnal-to-nocturnal IOP and nocturnal-to-diurnal IOP between SO-filled eyes and fellow eyes did not differ significantly (P > 0.05, respectively). The peak IOP occurred in the nocturnal period for all fellow eyes and for 94.7% of SO-filled eyes. CONCLUSION: The IOP of SO-filled eyes varied over a 24-hour period, peaking largely in the nocturnal period, as observed for the IOP of fellow eyes. PMID- 26049624 TI - Re: Polypoidal choroidal vasculopathy in white patients. PMID- 26049625 TI - HANDS-FREE SCLERAL DEPRESSION DEVICES. PMID- 26049626 TI - Accessory tongue: Classification and report of a case. AB - BACKGROUND: Accessory tongue (AT) is a rare congenital anomaly. Due to rarity of AT, various terminologies are applied, including accessory tongue, bifid tongue, double tongue, cleft tongue, and supernumerary tongue. It seems that the anomaly has geographic distribution and most reported cases are from India and Middle East. No comprehensive classification has been introduced yet. So, we present a classification for AT according to review of all papers and documents that we found, and report a 2-month-old male infant with this anomaly. PMID- 26049627 TI - IKAROS: a multifunctional regulator of the polymerase II transcription cycle. AB - Transcription factors are important determinants of lineage specification during hematopoiesis. They favor recruitment of cofactors involved in epigenetic regulation, thereby defining patterns of gene expression in a development- and lineage-specific manner. Additionally, transcription factors can facilitate transcription preinitiation complex (PIC) formation and assembly on chromatin. Interestingly, a few lineage-specific transcription factors, including IKAROS, also regulate transcription elongation. IKAROS is a tumor suppressor frequently inactivated in leukemia and associated with a poor prognosis. It forms a complex with the nucleosome remodeling and deacetylase (NuRD) complex and the positive transcription elongation factor b (P-TEFb), which is required for productive transcription elongation. It has also been reported that IKAROS interacts with factors involved in transcription termination. Here we review these and other recent findings that establish IKAROS as the first transcription factor found to act as a multifunctional regulator of the transcription cycle in hematopoietic cells. PMID- 26049628 TI - Testing for High-Risk APOL1 Alleles in Potential Living Kidney Donors. AB - Accurate risk assessment is critical when evaluating potential living kidney donors. High-risk kidney APOL1 variants have been associated with end-stage renal disease of multiple causes among African Americans, though the predictive power of these variants in population-based studies is small. No studies have looked at the effect of high-risk APOL1 alleles on donor outcomes, though few transplantation centers in the United States offer screening for APOL1 among African American donors. Screening all African Americans for high-risk APOL1 alleles may result in the exclusion of many potential donors (~13% of African Americans). Such an exclusion may have a large effect on the availability of transplants for African Americans, who are already less likely to undergo transplantation. Nephrologists should be prepared to discuss with potential African American donors the relative increase in risk that is likely conferred by carrying 2 high-risk APOL1 alleles and how additional factors such as environmental exposures (eg, viral infections) and/or other genetic susceptibilities may be required for developing kidney disease. In this Perspective, we review the use of APOL1 testing for risk stratification of potential African American kidney donors. PMID- 26049629 TI - You, your children, your grandchildren, and their inflammatory responses are what you eat. PMID- 26049630 TI - Genetic and metabolic determinants of human epigenetic variation. AB - PURPOSE OF REVIEW: Epigenetics has emerged in recent years as one of the most important biological mechanisms linking exposures across the life course to long term health. This article reviews recent developments in our understanding of the metabolic and genetic determinants of epigenetic variation in human populations. RECENT FINDINGS: Epigenetic status is influenced by a range of environmental exposures, including diet and nutrition, social status, the early emotional environment, and infertility and its treatment. The period around conception is particularly sensitive to environmental exposures with evidence for effects on epigenetic imprinting within the offspring. Epigenetic status is also influenced by genotype, and genetic variation in methylene tetrahydrofolate reductase, and the DNA methytransferase and ten-eleven translocation methylcytosine dioxygenase proteins has been linked to the epigenetic status, biological function and disease. SUMMARY: Epigenetics is at the heart of a series of feedback loops linking the environment to the human genome in a way that allows crosstalk between the genome and the environment it exists within. It offers the potential for modification of adverse epigenetic states resulting from events/exposures at earlier life stages. We need to better understand the nutritional programming of epigenetic states, the persistence of these marks in time and their effect on biological function and health in current and future generations. PMID- 26049632 TI - Developmental programming of type 2 diabetes: early nutrition and epigenetic mechanisms. AB - PURPOSE OF REVIEW: The environment experienced during critical windows of development can 'programme' long-term health and risk of metabolic diseases such as type 2 diabetes in the offspring. The purpose of this review is to discuss potential epigenetic mechanisms involved in the developmental programming of type 2 diabetes by early nutrition. RECENT FINDINGS: Maternal and more recently paternal nutrition have been shown to play key roles in metabolic programming of the offspring. Although the exact mechanisms are still not clear, epigenetic processes have emerged as playing a plausible role. Epigenetic dysregulation is associated with several components that contribute to type 2 diabetes risk, including altered feeding behaviour, insulin secretion and insulin action. It may also contribute to transgenerational risk transmission. SUMMARY: Epigenetic processes may represent a central underlying mechanism of developmental programming of type 2 diabetes. During embryonic and foetal development, extensive epigenetic remodelling takes place not only in somatic but also in primordial germ cells. Therefore, concerns have been raised that epigenetic dysregulation induced by a suboptimal early environment could programme altered phenotypes not only in the first generation but also in the subsequent ones. Characterizing these altered epigenetic marks has great implications for identifying individuals at an increased disease risk as well as potentially leading to novel preventive and treatment strategies. PMID- 26049631 TI - You are what you eat: O-linked N-acetylglucosamine in disease, development and epigenetics. AB - PURPOSE OF REVIEW: The O-linked N-acetylglucosamine (O-GlcNAc) modification is both responsive to nutrient availability and capable of altering intracellular cellular signalling. We summarize data defining a role for O-GlcNAcylation in metabolic homeostasis and epigenetic regulation of development in the intrauterine environment. RECENT FINDINGS: O-GlcNAc transferase (OGT) catalyzes nutrient-driven O-GlcNAc addition and is subject to random X-inactivation. OGT plays key roles in growth factor signalling, stem cell biology, epigenetics and possibly imprinting. The O-GlcNAcase, which removes O-GlcNAc, is subject to tight regulation by higher order chromatin structure. O-GlcNAc cycling plays an important role in the intrauterine environment wherein OGT expression is an important biomarker of placental stress. SUMMARY: Regulation of O-GlcNAc cycling by X-inactivation, epigenetic regulation and nutrient-driven processes makes it an ideal candidate for a nutrient-dependent epigenetic regulator of human disease. In addition, O-GlcNAc cycling influences chromatin modifiers critical to the regulation and timing of normal development including the polycomb repression complex and the ten-eleven translocation proteins mediating DNA methyl cytosine demethylation. The pathway also impacts the hypothalamic-pituitary-adrenal axis critical to intrauterine programming influencing disease susceptibility in later life. PMID- 26049633 TI - Epigenetics of obesity: beyond the genome sequence. AB - PURPOSE OF REVIEW: After the study of the gene code as a trigger for obesity, epigenetic code has appeared as a novel tool in the diagnosis, prognosis and treatment of obesity, and its related comorbidities. This review summarizes the status of the epigenetic field associated with obesity, and the current epigenetic-based approaches for obesity treatment. RECENT FINDINGS: Thanks to technical advances, novel and key obesity-associated polymorphisms have been described by genome-wide association studies, but there are limitations with their predictive power. Epigenetics is also studied for disease association, which involves decoding of the genome information, transcriptional status and later phenotypes. Obesity could be induced during adult life by feeding and other environmental factors, and there is a strong association between obesity features and specific epigenetic patterns. These patterns could be established during early life stages, and programme the risk of obesity and its comorbidities during adult life. Furthermore, recent studies have shown that DNA methylation profile could be applied as biomarkers of diet-induced weight loss treatment. SUMMARY: High-throughput technologies, recently implemented for commercial genetic test panels, could soon lead to the creation of epigenetic test panels for obesity. Nonetheless, epigenetics is a modifiable risk factor, and different dietary patterns or environmental insights during distinct stages of life could lead to rewriting of the epigenetic profile. PMID- 26049634 TI - The potential regulatory role of vitamin D in the bioenergetics of inflammation. AB - PURPOSE OF REVIEW: The extraskeletal health benefits of vitamin D still need scientific endorsement. Obesity and related chronic diseases are pathogenically linked by inflammation, which carries a considerable energetic cost. Recent techniques for the determination of the bioenergetic demand of inflammation, offer an avenue to cement the regulatory role of vitamin D in this process. RECENT FINDINGS: Nuclear vitamin D receptors may be translocated into mitochondria of certain cell types, opening up a pathway for direct action on cellular bioenergetics. Classical M1 (inflammatory)/M2(anti-inflammatory) phenotypes can vary with the clinical context. M2 macrophages do not always depend on oxidative metabolism/fatty acid oxidation. Newer methodologies offer real-time bioenergetic measurements that can be used as an index of metabolic health. SUMMARY: Vitamin D may prove to be a therapeutic agent for inflammation of chronic disease and understanding its role in cellular bioenergetics may offer a diagnostic/prognostic indicator of its action. PMID- 26049635 TI - Heat shock proteins and heat therapy for type 2 diabetes: pros and cons. AB - PURPOSE OF REVIEW: Heat therapy, such as sauna and hot tub, has become an increasingly regular therapeutical practice around the world since several studies have shown benefits of heat therapy in metabolic and cardiovascular diseases. The use of heat therapy in people with type 2 diabetes mellitus revealed a striking reduction of 1% unit in the glycated hemoglobin, suggesting this therapy for the treatment of diabetes. Herein, we shall discuss the use of heat therapy and the mechanisms involved, and suggest a provisional guide for the use of heat therapy in obesity and diabetes. RECENT FINDINGS: Human studies indicate that heat therapy reduces fasting glycemia, glycated hemoglobin, body weight, and adiposity. Animal studies have indicated that nitric oxide and the increase in heat shock protein 70 expression is involved in the improvements induced by heat therapy on insulin sensitivity, adiposity, inflammation, and vasomotricity. SUMMARY: Heat therapy is a promising and inexpensive tool for the treatment of obesity and diabetes. We proposed that transient increments in nitric oxide and heat shock protein 70 levels may explain the benefits of heat therapy. We suggest that heat therapy (sauna: 80-100 degrees C; hot tub: at 40 degrees C) for 15 min, three times a week, for 3 months, is a safe method to test its efficiency. PMID- 26049636 TI - Impact of carbohydrates on weight regain. AB - PURPOSE OF REVIEW: Research on obesity treatment has shifted its focus from weight loss to weight-loss maintenance strategies. The conventional approach of a low-fat diet is challenged by insights from glycemic effects of carbohydrates on body weight regulation. RECENT FINDINGS: Metabolic and endocrine adaptations to weight loss that contribute to weight regain involve reduced energy expenditure, increased insulin sensitivity, and enhanced orexigenic signals. This review summarizes the impact of carbohydrates on energetic efficiency, partitioning of weight regain as fat and lean mass, and appetite control. Both the amount and frequency of postprandial glycemia add to body weight regulation after weight loss and strengthen the concept of glycemic index and glycemic load. In addition, dietary fiber and slowly or poorly absorbable functional sugars modify gastrointestinal peptides involved in appetite and metabolic regulation and exert prebiotic effects. SUMMARY: Current evidence suggests that a low-glycemic load diet with a preference for low-glycemic index foods and integration of slowly digestible, poorly absorbable carbohydrates may improve weight-loss maintenance. Future studies should investigate the health benefits of low glycemic functional sweeteners (e.g., isomaltulose and tagatose). PMID- 26049637 TI - The role of polydextrose in body weight control and glucose regulation. AB - PURPOSE OF REVIEW: The purpose of this review was to highlight recent research developments on effects of the dietary fibre polydextrose (PDX) on appetite, satiety and energy intake and glucose metabolism. For this purpose, clinically relevant human studies were reviewed and putative mechanisms and pathways were discussed. RECENT FINDINGS: A number of acute human intervention studies provide strong indications for an energy and glucose metabolism-regulating role of PDX. These effects might be mediated via a reduced gastro-intestinal transit reducing glycaemia and insulinemia after PDX ingestion and the potential of PDX as soluble dietary fibre to alter the intestinal microbial composition, which might lead to changes in signalling in both peripheral and central pathways involved in energy metabolism and glucose homeostasis. SUMMARY: In acute studies, PDX seems to have an inhibiting effect on energy intake and satiety and to reduce glycaemic and insulinemic response through effect on gastro-intestinal transit time and macronutrient absorption as well as through effects of the microbial products such as short-chain fatty acids on energy and substrate metabolism. In particular, well controlled human intervention studies are required to confirm these effects in the long term. Overall, supplement PDX to the daily diet may be a promising approach for the management and treatment of obesity and associated metabolic disorders. PMID- 26049638 TI - Genetics of insulin resistance in polycystic ovary syndrome. AB - PURPOSE OF REVIEW: Polycystic ovary syndrome (PCOS) is a very common endocrine disease in women all over the world. A variety of symptoms such as hirsutism and hyperandrogenism, irregular menstrual cycles and anovulatory infertility together with metabolic dysfunction, insulin resistance, and type 2 diabetes mellitus in lean and obese individuals and the development of consecutive diseases are key problems in this heterogeneous syndrome. RECENT FINDINGS: Disease-modifying and potentially disease-causing candidate genes are described. A number of genetic associations have been investigated, whereby genes related to normal-weight insulin resistance and chronic inflammation are of central interest for PCOS pathomechanisms. New insights in the pharmacogenetics of PCOS might help to individualize therapeutic options. SUMMARY: Enormous progress has been made in the genetics of insulin resistance in PCOS. However, because of the individual heterogeneity of PCOS and the lack of evident functional studies, the syndrome is only partly understood to date. Large studies on selected phenotypes and therapy aspects are ongoing. PMID- 26049639 TI - Glucagon - the new 'insulin' in the pathophysiology of diabetes. AB - PURPOSE OF REVIEW: Autoimmune destruction of the beta cells is considered the key abnormality in type 1 diabetes mellitus and insulin replacement the primary therapeutic strategy. However, a lack of insulin is accompanied by disturbances in glucagon release, which is excessive postprandially, but insufficient during hypoglycaemia. In addition, replacing insulin alone appears insufficient for adequate glucose control. This review focuses on the growing body of evidence that glucagon abnormalities contribute significantly to the pathophysiology of diabetes and on recent efforts to target the glucagon axis as adjunctive therapy to insulin replacement. RECENT FINDINGS: This review discusses recent (since 2013) advances in abnormalities of glucagon regulation and their link to the pathophysiology of diabetes; new mechanisms of glucagon action and regulation; manipulation of glucagon in diabetes treatment; and analytical and systems biology tools to study glucagon regulation. SUMMARY: Recent efforts 'resurrected' glucagon as a key hormone in the pathophysiology of diabetes. New studies target its abnormal regulation and action that is key for improving diabetes treatment. The progress is promising, but major questions remain, including unravelling the mechanism of loss of glucagon counterregulation in type 1 diabetes mellitus and how best to manipulate glucagon to achieve more efficient and safer glycaemic control. PMID- 26049641 TI - Prognostic Value of the Radiologic Appearance of the Navicular Ossification Center in Congenital Talipes Equinovarus. AB - Congenital talipes equinovarus (CTEV), more commonly known as clubfoot, is a deformity of the foot that is not well understood. The tarsal navicular is at the center of the disease process and exhibits abnormal development and delayed ossification. However, its role in the pathologic process is not clear. The aim of the present study was to better understand the role of the tarsal navicular in CTEV by correlating the presence of the navicular ossification center and relapse of clubfoot deformity after surgical treatment. The medical records and radiographs of 34 patients (41 feet) with surgically treated CTEV were reviewed for the presence of the navicular ossification center and the lateral talocalcaneal angles. Of the 41 feet, 17 (41.46%) did not have the tarsal navicular ossification center present before surgery, and 24 (58.54%) did have the ossification center present. The talocalcaneal angles were similar between those with and without the navicular ossification center present. No significant difference was found in the incidence of relapse between the nonossified navicular group (17.6%) and the ossified navicular group (16.7%; p = .63). The presence of the navicular ossification center before surgery does not appear to have prognostic value for the relapse of CTEV after surgical intervention. PMID- 26049643 TI - Community Health Workers: Advocating for a Just Community and Workplace. PMID- 26049645 TI - Community Health Worker Voices. PMID- 26049646 TI - Stories From the Field: My Experience as a Promotora de Salud. PMID- 26049647 TI - Community Health Workers: Bridging the Gap Between the Examination Room and the Shelter. PMID- 26049648 TI - Community Health Worker Profile: The Journey, Job, and Justification. PMID- 26049649 TI - Community Health Volunteer: Experience From Rural Thailand. PMID- 26049650 TI - Siyadingana: We Need Each Other. PMID- 26049651 TI - Practice and Power: Community Health Workers and the Promise of Moving Health Care Upstream. AB - Against the backdrop of historic upheavals in American health care, a resurgent interest in the role of community health workers (CHWs) presents important strategic and technical questions. The ability to successfully navigate these issues and expand the health care role and impact of CHWs will depend on how stakeholders reimagine elements of practice and structures of power in American medicine. Practice redesign and redefined power dynamics can help health care settings successfully integrate CHWs, address social determinants of health for patients and communities, and achieve the Triple Aim of improved outcomes, higher quality of care, and lower costs. PMID- 26049652 TI - Community Health Worker Professional Advocacy: Voices of Action from the 2014 National Community Health Worker Advocacy Survey. AB - This mixed-methods study explores community health worker (CHW) engagement in professional advocacy. Data from the National Community Health Worker Advocacy Survey (n = 1661) assessed the relationship between CHW professional advocacy and CHW demographics, and work characteristics. Qualitative data articulated the quality of professional advocacy efforts. Approximately, 30% of CHW respondents advocated for professional advancement or collaborated with other CHWs to advance the workforce. Advocacy was more prevalent among CHWs affiliated with a professional network. CHW advocacy targeted recognition of the field, appropriate training and compensation, and sustainable funding. CHW professional advocacy is imperative to advancement of the field. PMID- 26049653 TI - Many Ingredients, One Sublime Dish: The Recipe for the Passage of Illinois HB5412 Into Law. AB - This article contextualizes the need for Illinois House Bill 5412 (HB5412), which calls for the establishment of a state board to create recommendations for the community health worker (CHW) field in Illinois, including a scope of practice, core competencies, training and certification standards, and sustainable funding and reimbursement mechanisms. Multisectorial partnerships and their outputs, coupled with frontline CHW interventions, created a synergistic climate conducive to the passing of this historic CHW legislation. This article provides a timeline and recipe for legislative success as described through processes and activities collaboratively undertaken, concentrating on a 5-year period (2009-2014). PMID- 26049654 TI - The Impact of Integrating Community Advocacy Into Community Health Worker Roles on Health-Focused Organizations and Community Health Workers in Southern Arizona. AB - Organizational environments may encourage community health workers (CHWs) to engage community members in improving their communities. We conducted open-ended interviews and focus groups to explore how participation in the Accion intervention, which trained CHWs in community advocacy, affected organizational capacity to support their CHWs. Supervisors described improved organizational recognition and trust of CHWs. Organizational leaders reported organizational benefits and increased appreciation of CHW leadership. Both expressed increased interest in future advocacy trainings. Limiting factors included organizational mission, CHW position descriptions, and funding. Findings indicate that, with training and funding, CHW community advocacy can be integrated into organizations with congruent missions. PMID- 26049655 TI - Strengthening the Effectiveness of State-Level Community Health Worker Initiatives Through Ambulatory Care Partnerships. AB - The transformation of the US health care system and the recognition of the effectiveness of community health workers (CHWs) have accelerated national, state, and local efforts to engage CHWs in the support of vulnerable populations. Much can be learned about how to successfully integrate CHWs into health care teams, how to maximize their impact on chronic disease self-management, and how to strengthen their role as emissaries between clinical services and community resources; we share examples of effective strategies. Ambulatory care staff members are key partners in statewide initiatives to build and sustain the CHW workforce and reduce health disparities. PMID- 26049656 TI - Integrating Community Health Workers Into Primary Care to Support Behavioral Health Service Delivery: A Pilot Study. AB - Community health workers (CHWs) collaborating with health care teams improve health outcomes. The feasibility of employing CHWs to support behavioral health in primary care is unknown. We offered experienced CHWs a 48-hour behavioral health training and placed them at health centers. Supervisors received technical assistance to support integration. We interviewed team members to explore CHW interactions with patients and team members. There was evidence of CHW integration. Major CHW roles included care coordination, outreach, and screening. It may be feasible to integrate behavioral health-focused CHWs into primary care settings. Both CHWs and supervisors need ongoing training and support. PMID- 26049657 TI - Post-operative recurrence in Crohn's disease. Critical analysis of potential risk factors. An update. AB - INTRODUCTION: Crohn's disease is associated with high rates of postoperative recurrence. At 10 years after surgery a high percentage of patients suffer recurrence (as many as 75% and above) and many of these (up to 45%) require re intervention. The aim of the study was to identify, amongst the various "potential predictive factors", those which today should be considered "real risk factors" for postoperative recurrence. METHODS: A review of literature of the last 30 years was carried out. A medical literature search was conducted using Medline, Embase, Ovid Journals, Science Direct, the Cochrane Central Register of Controlled Trials and the Cochrane Database of Systematic Reviews. Potential risk factors related to the patient, disease, type of surgery and pharmacological treatment were analyzed. RESULTS: According to most Authors predictive factors, in addition to smoke, are also represented by an extent of disease superior to 100 cm and by absence of postoperative pharmacological treatment. Moreover, according to "the second European evidence-based Consensus on the diagnosis and the management of Crohn's disease: Special situations", localization of disease in the colon, penetrative behavior of disease, extensive small bowel resection and prior intestinal surgery should also be considered predictive factors. CONCLUSIONS: The high incidence of postoperative recurrence in Crohn's disease mandates a strict follow up (clinical, laboratory and instrumental monitoring). Identifying patients with increased risk would enable physicians to plan a surveillance program and to implement a rational therapeutic prophylaxis. PMID- 26049658 TI - A novel ABCD1 mutation detected by next generation sequencing in presumed hereditary spastic paraplegia: A 30-year diagnostic delay caused by misleading biochemical findings. AB - OBJECTIVES: To present a Greek family in which 5 male and 2 female members developed progressive spastic paraplegia. Plasma very long chain fatty acids (VLCFA) were reportedly normal at first testing in an affected male and for over 30 years the presumed diagnosis was hereditary spastic paraplegia (HSP). Targeted next generation sequencing (NGS) was used as a further diagnostic tool. METHODS: Targeted exome sequencing in the proband, followed by Sanger sequencing confirmation; mutation segregation testing in multiple family members and plasma VLCFA measurement in the proband. RESULTS: NGS of the proband revealed a novel frameshift mutation in ABCD1 (c.1174_1178del, p.Leu392Serfs*7), bringing an end to diagnostic uncertainty by establishing the diagnosis of adrenomyeloneuropathy (AMN), the myelopathic phenotype of X-linked adrenoleukodystrophy (ALD). The mutation segregated in all family members and the diagnosis of AMN/ALD was confirmed by plasma VLCFA measurement. Confounding factors that delayed the diagnosis are presented. CONCLUSIONS: This report highlights the diagnostic utility of NGS in patients with undiagnosed spastic paraplegia, establishing a molecular diagnosis of AMN, allowing proper genetic counseling and management, and overcoming the diagnostic delay that can be rarely caused by false negative VLCFA analysis. PMID- 26049659 TI - Does prediabetes cause small fiber sensory polyneuropathy? Does it matter? AB - BACKGROUND AND OBJECTIVES: The association between prediabetes and distal polyneuropathy (DPN) remains controversial. Here we test whether the prevalence of small fiber sensory distal polyneuropathy is increased in prediabetes. METHODS: Prospectively recruited cohorts of healthy subjects and those with prediabetes from Olmsted County, Minnesota, were assessed for positive neuropathic sensory symptoms, or pain symptoms characteristic of small fiber sensory DPN. Hyperalgesia and hypoalgesia were assessed by "smart" quantitative sensation testing (QST). The prevalence of symptoms and QST abnormalities were compared among the groups. RESULTS: There was no significant increase in the prevalence of positive neuropathic sensory or pain symptoms, nor of hyper- or hypoalgesia in the prediabetes group. There was an increased prevalence of hypoalgesia of the foot only in newly diagnosed diabetes. CONCLUSIONS: Based on positive sensory and pain symptoms and QSTs, we did not find an increase in small fiber sensory DPN in prediabetes. Recognizing that obesity and diabetes mellitus are implicated in macro- and microvessel complications, physicians should encourage healthy living and weight loss in patients with prediabetes. In medical practice, alternate causes should be excluded before concluding that small fiber sensory distal neuropathy is secondary to prediabetes. PMID- 26049660 TI - Is basal haemoglobin level really a prognostic factor for early death of elderly patients undergoing hip fracture surgery? PMID- 26049661 TI - Spinal stab injury with retained knife blades: 51 Consecutive patients managed at a regional referral unit. AB - BACKGROUND: Spinal stab wounds presenting with retained knife blades (RKB) are uncommon, often resulting in spinal cord injury (SCI) with catastrophic neurological consequences. The purpose of this study is to report a single unit's experience in management of this pattern of injury at this regional referral centre. METHODS: Retrospective review of medical records identified 51 consecutive patients with spinal stabs presenting with a RKB at the Neurosurgery Department at Inkosi Albert Luthuli Central Hospital between January 2003 and February 2015. The data was analyzed for patient characteristics, level of the RKB, neurological status using the ASIA impairment scale, associated injuries, radiological investigations, management, hospital length of stay, complications and mortality. RESULTS: The mean age was 28+/-10.9 years (range 14-69), with 45 (88%) males (M: F=7.5:1). The median Injury Severity Score was 16 (range 4-26). RKB were located in the cervical [9,18%], thoracic [38,74%], lumbar [2,4%] and sacral [2,4%] spine. Twelve patients (24%) sustained complete SCI (ASIA A), while 21 (41%) had incomplete (ASIA B, C, D), of which 17 had features of Brown-Sequard syndrome. Eighteen (35%) patients were neurologically intact (ASIA E). There were 8 (16%) associated pneumothoraces and one vertebral artery injury. Length of hospital stay was 10+/-7.1 days (range 1-27). One patient (2%) died during this period. CONCLUSIONS: Stab injuries to the spine presenting with RKB are still prevalent in South Africa. Resources should be allocated to prevention strategies that decrease the incidence of inter-personal violence. All RKBs should be removed in the operating theatre by experienced surgeons to minimise complications. PMID- 26049662 TI - General versus regional anaesthesia for hip fractures. A pilot randomised controlled trial of 322 patients. AB - Uncertainty remains regarding the optimum method of anaesthesia for hip fracture surgery. We randomised 322 patients with a hip fracture to receive either general anaesthesia or regional (spinal) anaesthesia. Surviving patients were followed up to 1 year from injury. There was no notable difference in the outcomes of hospital stay, need for blood transfusion or post-operative complications between groups. 30-day mortality was marginally reduced for spinal anaesthesia 7/164(4.3%) versus 5/158(3.2%) (p=0.57), whilst at 1 year it was less for general anaesthesia 20/163(12.1%) versus 32/158(20.2%) (p=0.05). Within the confines of the limited patient numbers studied we conclude that there are no marked differences in outcome between the two techniques. PMID- 26049663 TI - Ground-glass opacity of the lung in a patient with melanoma: "The radiological seed of doubt". PMID- 26049664 TI - Pancreatic atypical mycobacteriosis evaluated by (18)F-FDG-PET/CT. PMID- 26049665 TI - Lactation and the Substance-Exposed Mother-Infant Dyad. AB - Pregnant and postpartum women with substance use disorders have very unique needs and can present challenges to healthcare providers who are not familiar with how to evaluate and respond properly to their necessities. One such situation frequently arises when women with substance use disorders wish to breast-feed. There are many benefits and challenges to this practice that are specific to this population, and treating practitioners are often unclear on how to address them. The purpose of this article is to identify barriers to lactation in substance exposed dyads and to provide strategies to mitigate these barriers and for promoting lactation in appropriate women with substance use disorders who wish to breast-feed. PMID- 26049666 TI - [Role of metabolic lipases and lipotoxicity in the development of non-alcoholic steatosis and non-alcoholic steatohepatitis]. AB - Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in developed countries, covering a spectrum of pathological conditions ranging from single steatosis to non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. Its pathogenesis has been often interpreted by the "double-hit" hypothesis, where the lipid accumulation in the liver is followed by proinflammatory mediators inducing inflammation, hepatocellular injury and fibrosis. Nowadays, a more complex model suggests that free fatty acids and their metabolites could be the true lipotoxic agents that contribute to the development of NAFLD and hepatic insulin resistance, suggesting a central role for metabolic lipases in that process. PMID- 26049667 TI - LRG1 modulates invasion and migration of glioma cell lines through TGF-beta signaling pathway. AB - Studies have shown that the abnormal expression of leucine-rich alpha2 glycoprotein 1 (LRG1) is associated with multiple malignancies, yet its role in glioma pathology remains to be elucidated. In this study, we investigated the role of LRG1 in regulating proliferation, migration and invasion of glioma cells by establishing glioma cell strains with constitutively silenced or elevated LRG1 expression. LRG1 overexpression and silenced cell lines demonstrated modulation of glioma cellular proliferation, migration and invasion through MTT, cell scratching and Transwell assays. Furthermore, overexpression of LRG1 led to augmented activation of transforming growth factor-beta (TGF-beta) signaling pathway as well as downregulation of E-cadherin and resultant enhanced invasiveness, which was reversed by TGF-beta signaling pathway inhibitor SB431542. In summary, our findings suggest that LRG1 promotes invasion and migration of glioma cells through TGF-beta signaling pathway. PMID- 26049668 TI - Letter to the Editor on "A Prospective, Randomized Comparison of Posterior Stabilized Versus Cruciate-Substituting Total Knee Arthroplasty: A Preliminary Report with Minimum 2-Year Results". PMID- 26049669 TI - A standardized method for quantifying proliferation by Ki-67 and cyclin A immunohistochemistry in breast cancer. AB - Immunohistochemical analysis of proliferation markers such as Ki-67 and cyclin A is widely used in clinical evaluation as a prognostic factor in breast cancer. The proliferation status of tumors is guiding the decision of whether or not a patient should be treated with chemotherapy because low-proliferative tumors are less sensitive by such treatment. However, the lack of optimal cutoff points and selection of tumor areas hamper its use in clinical practice. This study was performed to compare the Ki-67 and cyclin A expression counted in hot-spot vs average counting based on 5 to 14 random tumor areas in 613 breast carcinomas. We correlated the findings with 10-year follow-up in order to standardize the evaluation of proliferation markers in clinical practice. A significant correlation was found between the percentage of positive cells estimated by Ki-67 and cyclin A both by hot-spot and by average counting. Both methods showed that high expression of Ki-67 and cyclin A is associated with more adverse tumor stage. The cutoff value for Ki-67 for distant metastases was set to 22% and to 15%, using hot-spot and average counting, respectively. For cyclin A, the values were set to 14% and 8% using the respective methods. Survival curves revealed that patients with a high hot-spot proliferation index had a significantly greater risk of shorter tumor-free survival. Our findings suggest that the determination of proliferation markers in breast cancer should be standardized to hot-spot counting and that specific cutoff values for proliferation could be useful as prognostic markers in clinical practice. Moreover, we suggest that expression levels of cyclin A could be used as a complementary marker to estimate the proliferation status in tumors, especially those with "borderline" expression levels of Ki-67, in order to more accurately estimate the proliferations status of the tumors. PMID- 26049670 TI - [Are retinal hemorrhages less frequent in very young infants with shaken baby syndrome?]. PMID- 26049671 TI - [Correlation between specific and nonspecific posttraumatic stress disorder symptoms with healthcare consumption among 340 French soldiers]. AB - BACKGROUND: The psychotraumatic disorders are often difficult to diagnose because the specific symptoms of posttraumatic stress disorder (revival, hyperarousal, avoidance) are rarely a direct demand for health care: for reasons determined by the psychopathological structure of trauma, its symptomatology and course, the psychotraumatised subjects seek a care system for nonspecific psychological or somatoform symptoms: depressive episode, cognitive disorders, other anxiety disorders, histrionic and obsessive symptoms, changes in personality, pain disorders and somatization. Somatic pain may also result from a war injury and psychosomatic complications, addictive or consequences of risk behaviours during the evolution of posttraumatic stress disorder. OBJECTIVES: To establish a correlation between the PCLS and the evaluation of the healthcare consumption in a military population. METHODS: We conducted a multicenter epidemiological study analyzing the PCLS and a questionnaire assessing health care consumption. The PCLS has been studied in various forms: quantitative (17 to 85), in qualitative classes (<33, 33 to 43 and >=44), and in five sub-dimensions (flashbacks, avoidance, dissociation, depression and hyperactivity). The sub-dimension revival was then studied item by item. The criteria used care consumption over the last twelve months is the numbers of days of sick leave, days of unavailability (of certain jobs or military activities) and consultations. RESULTS: Our population of 340 subjects cannot be considered representative of the French military population even if only a few characteristics differ. Sixteen of 340 subjects show a positive PCLS is 4.70% of our sample. PCLS average of 23 (+/-9.4) with a median of 19 objectifying much of PCLS have almost zero score. Validating our main hypothesis, we found a statistically significant relationship between elements of the PCLS and variables care consumption: this link exists mainly between the score, classes and sub-dimensions of the PCLS in one hand and number of days of sick leave and unavailability on the other hand. DISCUSSION: Towards a strategy for tracking psychotraumatic disorders, could be developed a score of health care consumption which would include the number of days of sick leave and unavailability, the number and quality of medical consultations, the number and quality of drug and laboratory requirements, the number of hospitalisations. To the identification of posttraumatic stress disorder, the PCLS score as well as the consumer healthcare score are valuable tools but do not replace the subjectivity of the clinical relationship: return to this shared subjectivity with the practitioner remains a diagnostic dimension, but also therapeutic, fundamental. PMID- 26049672 TI - Mediators effecting moderate-to-vigorous physical activity and inactivity for girls from an intervention program delivered in an organised youth sports setting. AB - OBJECTIVES: The objective of this study was to test whether coaches' physical activity levels, contextual variables, and coaches' behavioural variables mediated the effect of an intervention on female basketball players' moderate-to vigorous physical activity (MVPA) and inactivity in an organised youth sport (OYS) setting. DESIGN: Randomised controlled trial METHODS: Data for the current study were derived from a two-armed, parallel-group randomised controlled trial. This study ran over the course of a 5-day OYS basketball program in 2 sports centres in Sydney, Australia. A convenience sample of 76 female players and 8 coaches were recruited. Coaches allocated to the intervention condition attended 2 coach education sessions, where strategies to increase MVPA and decrease inactivity were taught. RESULTS: There was a significant effect between changes in coach MVPA and player MVPA (unstandardised regression coefficient [B] = 0.26, 95% CI = 0.14 to 0.38) which coincided with a significant indirect effect (B = 1.80, 95% CI = 0.85 to 2.85). There was also a significant effect between changes in coach inactivity and player inactivity (B = -0.23, 95% CI = -0.14 to -0.31), which coincided with a significant indirect effect (B = -3.20, 95% CI = -0.14 to 0.31). No significant indirect effects were found for lesson context and coaches' behaviours variables. CONCLUSIONS: Coaches' MVPA and inactivity significantly mediated the effect of the intervention on player MVPA and inactivity, respectively. Consequently, coaches' physical activity levels appear to be important for influencing their players' physical activity levels. PMID- 26049673 TI - Long-acting injectable versus daily oral antipsychotic treatment trials in schizophrenia: pragmatic versus explanatory study designs. AB - Trial design characteristics related to the explanatory : pragmatic spectrum may contribute toward the inconsistent results reported in studies comparing long acting injectable (LAI) versus daily oral antipsychotic (AP) treatments in schizophrenia. A novel approach examined the hypothesis that a more pragmatic design is important to show the advantages of LAI versus oral APs. A literature search identified comparative studies assessing the clinical efficacy/effectiveness of LAI versus oral APs in more than 100 schizophrenia patients, with 6-month or more duration/follow-up, and published between January 1993 and December 2013 (n=11). Each study's design was rated using the six-domain ASPECT-R (A Study Pragmatic : Explanatory Characterization Tool-Rating). Nonparametric Wilcoxon rank-sum tests compared ratings of studies supporting (n=7) and not supporting (n=4) a LAI advantage. ASPECT-R total and domain scores were significantly higher (more pragmatic) in studies finding a LAI versus oral AP treatment advantage than those that did not. The rank order of this significance among domains was as follows: 'participant compliance assessment' (P=0.005), 'medical practice setting/practitioner expertise' (P=0.006), 'intervention flexibility' (P=0.007), 'follow-up intensity/duration' (P=0.009), 'primary trial outcomes' (P=0.012), and 'participant eligibility' (P=0.015). Findings support that more pragmatic, less explanatory design features are important to show advantages for LAI treatment. Explanatory studies may introduce features that obscure advantages related to adherence. PMID- 26049674 TI - Impairment of left ventricular function early in treatment with clozapine: a preliminary study. AB - This preliminary prospective study evaluated cardiac status in 15 treatment resistant schizophrenia patients (aged 18-55 years) without evidence of cardiovascular disease. Patients underwent clinical assessment, blood tests, ECG, and echocardiography before and during clozapine treatment for 4 weeks as doses increased from 25 to 100 mg/day. Serum concentrations of high-sensitivity C reactive protein, troponin-I, brain natriuretic peptide, and clozapine+norclozapine were assayed at week 3; ECG and echocardiography were repeated at week 4. At moderate serum drug concentrations (124 ng/ml), the heart rate increased by 10% and high-sensitivity C-reactive protein levels were slightly elevated, but troponin-I and brain natriuretic peptide levels were not elevated. Echocardiographic indices indicated declining left ventricular (LV) diastolic and systolic function in 60-80% of participants, with an increase in systolic pulmonary artery pressure, A-wave velocity, and LV myocardial performance index by 16-24% in 60-80% of participants and a decrease in the E/A ratio by 29% in 73% of participants - all uncorrelated with drug concentrations. Early treatment with moderate doses of clozapine was associated with subclinical but substantial decreases in LV functioning in surprisingly high proportions of participants. Studies with more participants, higher drug doses, and long-term follow-up are needed to confirm and determine the course of the observed abnormalities and to evaluate their relationship with rare clinical cardiotoxicity associated with clozapine. PMID- 26049675 TI - [The ABLE study: A randomized controlled trial on the efficacy of fresh red cell units to improve the outcome of transfused critically ill adults]. AB - Red blood cell units are stored up to 42 days post-collection. The standard policy of blood banks is to deliver the oldest units in order to limit blood wastage. Many caregivers believe that giving fresh rather than old units can improve the outcome of their transfused patients. The ABLE study aims to check if the transfusion of red blood cell units stored seven days or less (fresh arm) improve the outcome of transfused critically ill adults compared to patients who received units delivered according to the standard delivery policy (control arm). From March 2009 to May 2014, 1211 patients were allocated to the fresh arm, 1219 to the control arm (length of storage: 6.1 +/- 4.9 and 22.0 +/- 8.4 days respectively, P<0.001). The primary outcome measure was 90-day all-cause mortality post-randomisation: there were 448 deaths (37.0%) in the fresh arm and 430 (35.3%) in the control arm (absolute risk difference: 1.7%; 95% confidence interval: -2.1% to 5.5%). In a survival analysis, the risk of death was higher in the fresh arm (hazard ratio: 1.1; 95%CI: 0.9 to 1.2), but the difference was not statistically significant (P=0.38). The same trend against the fresh arm was observed with all but one secondary outcome measures. The conclusion is that the transfusion of red blood cell units stored seven days or less does not improve the outcome of critically ill adults compared to the transfusion of units stored about three weeks (22.0 +/- 8.4 days). PMID- 26049676 TI - Articles Published and Downloaded by Public Health Scientists: Analysis of Data From the CDC Public Health Library, 2011-2013. AB - OBJECTIVE: To describe scientific information usage and publication patterns of the Centers for Disease Control and Prevention (CDC) Public Health Library and Information Center patrons. DESIGN: Administratively collected patron usage data and aggregate data on CDC-authored publications from the CDC Library for 3 consecutive years were analyzed. SETTING: The CDC Public Health Library and Information Center, which serves CDC employees nationally and internationally. PARTICIPANTS: Internal patrons and external users of the CDC Library. MAIN OUTCOME MEASURE(S): Three-year trends in full-text article publication and downloads including most common journals used for each purpose, systematic literature searches requested and completed, and subscriptions to a weekly public health current literature awareness service. RESULTS: From 2011 to 2013, CDC scientists published a total of 7718 articles in the peer-reviewed literature. During the same period, article downloads from the CDC Library increased 25% to more than 1.1 million, completed requests for reviews of the scientific literature increased by 34%, and electronic subscriptions to literature compilation services increased by 23%. CONCLUSIONS: CDC's scientific output and information use via the CDC Library are both increasing. Researchers and field staff are making greater use of literature review services and other customized information content delivery. Virtual public health library access is an increasingly important resource for the scientific practice of public health. PMID- 26049677 TI - Axonal loss in patients with inflammatory demyelinating polyneuropathy as determined by motor unit number estimation and MUNIX. AB - OBJECTIVE: This study quantifies functioning axons and reinnervation by applying two methods multiple point stimulation (MPS) MUNE, and motor unit number index (MUNIX), in patients with acute- and chronic inflammatory demyelinating polyneuropathy (AIDP, CIDP). METHODS: Nineteen patients with inflammatory demyelinating polyneuropathy (eleven AIDP and eight CIDP) were prospectively included. MPS MUNE and MUNIX examinations on the thenar muscle group by stimulating the median nerve were applied on all patients. Motor unit size was calculated as single motor unit potential (sMUP) and motor unit size index (MUSIX). The results were compared with twenty healthy subjects. RESULTS: In AIDP patients mean MPS MUNE (106) and MUNIX (80) were lower than control MPS MUNE (329) and MUNIX (215) (p<0.001). In CIDP patients both MPS MUNE (88) and MUNIX (67) were lower than controls (p<0.001). In CIDP patients sMUP (63) and MUSIX (90) were higher than control sMUP (35) and MUSIX (58) (p<0.05 and p<0.01). When AIDP and CIDP groups were combined the sensitivity for MPS MUNE and MUNIX were 89.5% and 68.4%, respectively. CONCLUSIONS: Decreased MPS MUNE and MUNIX suggest presence of axonal loss or loss of functioning axons in AIDP and CIDP. Increased motor unit size in CIDP patients indicates compensatory reinnervation. Moreover, both MPS MUNE and MUNIX can discriminate between disease versus non-disease. SIGNIFICANCE: Estimation of the number and the average size of motor units may have clinical value for the assessment of axonal loss or loss of functioning axons in patients with AIDP and CIDP. PMID- 26049678 TI - The role of wild canids and felids in spreading parasites to dogs and cats in Europe. Part II: Helminths and arthropods. AB - Over the last few decades, ecological factors, combined with everchanging landscapes mainly linked to human activities (e.g. encroachment and tourism) have contributed to modifications in the transmission of parasitic diseases from domestic to wildlife carnivores and vice versa. In the first of this two-part review article, we have provided an account of diseases caused by protozoan parasites characterised by a two-way transmission route between domestic and wild carnivore species. In this second and final part, we focus our attention on parasitic diseases caused by helminth and arthropod parasites shared between domestic and wild canids and felids in Europe. While a complete understanding of the biology, ecology and epidemiology of these parasites is particularly challenging to achieve, especially given the complexity of the environments in which these diseases perpetuate, advancements in current knowledge of transmission routes is crucial to provide policy-makers with clear indications on strategies to reduce the impact of these diseases on changing ecosystems. PMID- 26049680 TI - Antiphospholipid Antibody Syndrome: Raised Intracranial Pressure Without Cerebral Venous Sinus Thrombosis. AB - Antiphospholipid antibody syndrome (APS) has been reported to cause elevated intracranial pressure, but usually this is due to cerebral venous sinus thrombosis (CVST). We present a 36-year old man with APS with elevated intracranial pressure with neuro-ophthalmic, renal and hematological involvement without identifiable CVST. PMID- 26049681 TI - Improvement in Visual Fields After Treatment of Intracranial Meningioma With Bevacizumab. AB - High-grade (World Health Organization [WHO] Grade II and III) meningiomas constitute a minority of all meningioma cases but are associated with significant morbidity and mortality, due to more aggressive tumor behavior and a tendency to recur despite standard therapy with resection and radiotherapy. They display a higher degree of vascularity than WHO Grade I meningiomas and produce angiogenic and growth factors, including vascular endothelial growth factor (VEGF). Bevacizumab, a humanized monoclonal antibody against VEGF-A, has been used in the treatment of recurrent or progressive meningiomas resistant to standard therapy. We report a patient with a recurrent left frontotemporal meningioma and associated-vision loss who experienced substantial visual field recovery after 3 cycles of bevacizumab. In addition, we provide a review of the literature regarding the efficacy of bevacizumab in the treatment of recurrent meningiomas. PMID- 26049679 TI - Interplay among patient empowerment and clinical and person-centered outcomes in type 2 diabetes. The BENCH-D study. AB - OBJECTIVE: We evaluated empowerment in T2DM and identified its correlates. METHODS: A sample of individuals self-administered the Diabetes Empowerment Scale Short Form (DES-SF) and other 9 validated instruments (person-centered outcomes). Correlates of DES-SF were identified through univariate and multivariate analyses. For person-centered outcomes, ORs express the likelihood of being in upper quartile of DES-SF (Q4) by 5 units of the scale. RESULTS: Overall, 2390 individuals were involved. Individuals in Q4 were younger, more often males, had higher levels of school education, lower HbA1c levels and prevalence of complications as compared to individuals in the other quartiles. The likelihood of being in Q4 was directly associated with higher selfreported self-monitoring of blood glucose (SDSCA6-SMBG) (OR=1.09; 95% CI: 1.03-1.15), higher satisfaction with diabetes treatment (GSDT) (OR=1.15; 95% CI: 1.07-1.25), perceived quality of chronic illness care and patient support (PACIC-SF) (OR=1.23; 95% CI: 1.16-1.31), and better person-centered communication (HCC-SF) (OR=1.10; 95% CI: 1.01-1.19) and inversely associated with diabetes-related distress (PAID-5) (OR=0.95; 95% CI: 0.92-0.98). Adjusted DES-SF mean scores ranged between centers from 69.8 to 93.6 (intra-class correlation=0.10; p<0.0001). CONCLUSIONS: Empowerment was associated with better glycemic control, psychosocial functioning and perceived access to person-centered chronic illness care. Practice of diabetes center plays a specific role. PRACTICE IMPLICATIONS: DES-SF represents a process and outcome indicator in the practice of diabetes centers. PMID- 26049682 TI - Palinopsia and Other Reversible Visual Disturbances Induced by Topiramate. PMID- 26049683 TI - Post-surgical subcutaneous coloid cysts. PMID- 26049684 TI - Total gastroduodenectomy with pancreatic preservation for the treatment of Gardner's syndrome with gastroduodenal polyposis and malignant transformation. PMID- 26049685 TI - Acemannan accelerates cell proliferation and skin wound healing through AKT/mTOR signaling pathway. AB - BACKGROUND: Acemannan is a bioactive polysaccharides promoting tissue repair. However, the roles of acemannan in skin wound healing and the underlying molecular mechanisms are largely unclear. OBJECTIVE: The goal of this study is to investigate the positive role of acemannan in cutaneous wound healing and its mechanism. METHODS: Mouse skin wound model and skin primary fibroblasts were used to demonstrate the positive effect of acemannan on cutaneous wound healing. The expressions of cell proliferation nuclear antigen ki-67, cyclin D1 and activity of AKT/mTOR signaling were analyzed in acemannan-treated fibroblasts and mice. Rapamycin and AKT inhibitor VIII were used to determine the key role of AKT/mTOR signaling in acemannan-promoting cutaneous wound healing. RESULTS: We found that acemannan significantly accelerated skin wound closure and cell proliferation. Acemannan promoted the expression of cyclin D1 in cultured fibroblasts, which was mediated by AKT/mTOR signal pathway leading to enhanced activity of the eukaryotic translation initiation factor-4F (eIF4F) and increased translation of cyclin D1. In contrast, pharmaceutical blockade of AKT/mTOR signaling by mTOR inhibitor rapamycin or AKT inhibitor VIII abolished acemannan-induced cyclin D1 translation and cell proliferation. In vivo studies confirmed that the activation of AKT/mTOR by acemannan played a key role in wound healing, which could be reversed by rapamycin. CONCLUSION: Acemannan promoted skin wound healing partly through activating AKT/mTOR-mediated protein translation mechanism, which may represent an alternative therapy approach for cutaneous wound. PMID- 26049686 TI - Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. AB - BACKGROUND: The use of epidermal growth factor receptor inhibitors to treat metastatic colorectal cancer (mCRC) patients requires prior confirmation of tumour wild type (WT) RAS mutation status (exons 2/3/4 for KRAS or NRAS). This retrospective pooled analysis aims to robustly estimate RAS mutation prevalence and individual variation patterns in mCRC patients. METHOD: Individual patient data from five randomised, controlled panitumumab studies (three phase III, one phase II and one phase Ib/II) were pooled for this analysis. The phase III studies included mCRC patients independent of RAS mutation status; the phase II and Ib/II studies included mCRC patients with confirmed WT KRAS exon 2 status. Four studies conducted RAS testing using Sanger sequencing; one study used a combination of next-generation sequencing and Sanger sequencing. In order to assign overall RAS status, the mutation status of all exons 2/3/4 KRAS or NRAS was required to be known. RESULTS: Data from 3196 mCRC patients from 36 countries were included in the analysis. The overall unadjusted RAS mutation prevalence in mCRC patients was 55.9% (95% confidence interval (CI): [53.9-57.9%]), with the following distribution observed: KRAS exon 2 (prevalence 42.6% [40.7-44.5%]); KRAS exon 3 (3.8% [2.9-4.9%]); KRAS exon 4 (6.2% [5.0-7.6%]); NRAS exon 2 (2.9% [2.1-3.9%]); NRAS exon 3 (4.2% [3.2-5.4%]); NRAS exon 4 (0.3% [0.1-0.7%]). Differences in RAS mutation prevalence estimates were observed by study (p=0.001), gender (p=0.030), and by country (p=0.028). CONCLUSIONS: This analysis provides robust estimates of overall RAS mutation prevalence and individual variation patterns in mCRC patients. PMID- 26049687 TI - Incidence, risk factors and treatment of cervical stenosis after radical trachelectomy: A systematic review. AB - PURPOSE: Cervical stenosis is a major and specific postoperative complication following radical trachelectomy. The current article presents a review of studies describing the incidence, risk factors and treatment methods of cervical stenosis after this fertility sparing procedure. METHODS: We searched PubMed, MEDLINE, Embase (January 1994 through November 2014) using the following terms: uterine cervix neoplasms, cervical cancer, radical trachelectomy, fertility sparing and fertility preservation. We included original articles and case series. Case reports, review articles, articles not in English and articles not mentioning cervical stenosis were all excluded. RESULTS: We identified 1547 patients. The incidence rates of cervical stenosis ranged from 0% to 73.3% with an average rate of 10.5%. Among patients with abdominal, vaginal, laparoscopic and robotic radical trachelectomy, the incidences of cervical stenosis were 11.0%, 8.1%, 9.3% and 0%, respectively. In patients in whom whether cerclage was placed or not, the incidence rates of cervical stenosis were 8.6% and 3.0%, respectively (P=NS). Among those in whom whether anti-stenosis tools were placed or not, the incidences of cervical stenosis were 4.6% and 12.7%, respectively (P<0.001). Cervical stenosis was a potential cause of infertility and increased the use of artificial reproductive technology. Surgical dilatation resolved stenosis in the majority of cases but had to be repeated. CONCLUSIONS: Cervical stenosis is related to the surgical approach, cerclage and anti-stenosis tools utilised. It affects not only the quality of life but also obstetrical outcomes of patients following radical trachelectomy. Greater attention should be given to the prevention and treatment of this complication. PMID- 26049688 TI - Substantial lymph-vascular space invasion (LVSI) is a significant risk factor for recurrence in endometrial cancer--A pooled analysis of PORTEC 1 and 2 trials. AB - BACKGROUND: Lymph-vascular space invasion (LVSI) is an important adverse prognostic factor in endometrial cancer (EC). However, its role in relation to type of recurrence and adjuvant treatment is not well defined, and there is significant interobserver variation. This study aimed to quantify LVSI and correlate this to risk and type of recurrence. METHODS: In the post operative radiation therapy in endometrial carcinoma (PORTEC)-trials stage I EC patients were randomised to receive external beam radiotherapy (EBRT) versus no additional treatment after surgery (PORTEC-1, n=714), or to EBRT versus vaginal brachytherapy (PORTEC-2, n=427). In tumour samples of 926 (81.2%) patients with endometrioid tumours LVSI was quantified using 2-, 3- and 4-tiered scoring systems. Cox proportional hazard models were used for time-to-event analysis. RESULTS: Any degree of LVSI was identified in 129 cases (13.9%). Substantial LVSI (n=44, 4.8%) using the 3-tiered approach had the strongest impact on the risk of distant metastasis (hazard ratio (HR) 4.5 confidence interval (CI) 2.4-8.5). In multivariate analysis (including: age, depth of myometrial invasion, grade, treatment) substantial LVSI remained the strongest independent prognostic factor for pelvic regional recurrence (HR 6.2 CI 2.4-16), distant metastasis (HR 3.6 CI 1.9-6.8) and overall survival (HR 2.0 CI 1.3-3.1). Only EBRT (HR 0.3 CI 0.1-0.8) reduced the risk of pelvic regional recurrence. CONCLUSIONS: Substantial LVSI, in contrast to focal or no LVSI, was the strongest independent prognostic factor for pelvic regional recurrence, distant metastasis and overall survival. Therapeutic decisions should be based on the presence of substantial, not 'any' LVSI. Adjuvant EBRT and/or chemotherapy should be considered for stage I EC with substantial LVSI. PMID- 26049690 TI - Lessons From 30 Years of Teaching About the Microenvironment of Tumors. PMID- 26049689 TI - Human equilibrative nucleoside transporter 1 expression analysed by the clone SP 120 rabbit antibody is not predictive in patients with pancreatic cancer treated with adjuvant gemcitabine - Results from the CONKO-001 trial. AB - BACKGROUND: High expression of human equilibrative nucleoside transporter 1 (hENT1) is considered to predict survival in patients treated with adjuvant gemcitabine for pancreatic cancer. A standard evaluation system for immunohistochemical analysis (antibody, scoring system) has not yet been established. METHODS: CONKO-001, a prospective randomised phase III study investigated the role of adjuvant gemcitabine (gem) as compared to observation (obs). Tumour samples of 156 patients were analysed by immunohistochemistry with the rabbit monoclonal antibody SP120 (Ventana Medical Systems) for expression of hENT1. Kaplan-Meier analyses for median disease-free survival (DFS) and overall survival (OS) were performed in dependence of hENT1 expression measured analogously to Farrell et al. 2009 and Poplin et al. 2013. RESULTS: For the 88 gem and 68 obs patients, median DFS/OS was 12.9/22.7 months and 6.2/19.1 months. High hENT1 expression was not associated with improved median DFS (Farrell: no hENT1 22.2 months, low hENT1 13.7 months, high hENT1 12.1 months, p=0.248; Poplin: low hENT1 13.2 months versus high hENT1 11.5 months, p=0.5) or median OS (Farrell: no hENT1 21.7 months, low hENT1 24.7 months, high hENT1 19.5, p=0.571; Poplin: low hENT1 24.4 months versus high hENT1 19.7 months, p=0.92;) in the gem group or in the obs group (median DFS Farrell: no hENT1 5.1 months, low hENT1 6.2 months, high hENT1 7.5 months, p=0.375; Poplin: low hENT1 6.2 months versus high hENT1 5.9 months, p=0.83; median OS Farrell: no hENT1 20.2months, low hENT1 17.7 months, high HENT1 19.1 months, p=0.738; Poplin: low hENT1 17.7 months versus high hENT1 20.4 months, p=0.65) measured by the Farrell or Poplin Score. CONCLUSIONS: We cannot confirm a predictive role of hENT1 measured by the clone SP120 rabbit antibody in our study population. Reproducible standard procedures are urgently needed prior to the implementation or exclusion of hENT1 as a predictive biomarker in the treatment of pancreatic cancer. TRIAL REGISTRATION: ISRCTN34802808. PMID- 26049692 TI - Trends in Adjuvant and Neoadjuvant Radiotherapy for Cancer Treatment From 1973 to 2011. AB - PURPOSE: Cancer care is becoming increasingly complicated, in particular with the integration of radiation and surgery. Institutions may need to increase coordination between multidisciplinary clinical teams to optimize patient care. This study examines historical trends in adjuvant and neoadjuvant radiation therapy (ANRT) before or after cancer-directed surgery to identify disease sites that may benefit from coordinated care. METHODS: The Surveillance, Epidemiology, and End Results database was queried to identify patients with bladder cancer; breast cancer; cervical cancer; colorectal cancer; kidney cancer; cancer of the lung, bronchus, and pleura; lymphoma; melanoma; cancer of the oral cavity and pharynx; ovarian cancer; pancreatic cancer; prostate cancer; thyroid cancer; and uterine cancer from 1973 to 2011. Number and percentage of patients who received ANRT were calculated from 1973 to 2011. RESULTS: Adjuvant and neoadjuvant radiation therapy usage increased from 14% in 1973 to 19% in 2011. Adjuvant and neoadjuvant radiation therapy use for breast, oral cavity/pharynx, and thyroid cancers increased from 24%, 16%, and 9% in 1973 to 53%, 32%, and 46% in 2011, respectively. Changes in ANRT were seen in gynecologic and genitourinary cancers, with increased use of ANRT in cervical cancer and declines in uterine, ovarian, bladder, prostate, and kidney cancers. There were minimal changes in ANRT usage for patients within other diagnosis groups. DISCUSSION: Overall usage of ANRT is increasing over time, with increased need for coordinated care in breast and head and neck cancers. Adjuvant and neoadjuvant radiation therapy in genitourinary and gynecologic cancers is undergoing significant change. PMID- 26049691 TI - Prevalence of Human Papillomavirus in Oropharyngeal Cancer: A Systematic Review. AB - PURPOSE: The global incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been increasing, and it has been proposed that a rising rate of human papillomavirus (HPV)-associated cancers is driving the observed changes in OPSCC incidence. We carried out this systematic review to further examine the prevalence of HPV in OPSCC over time worldwide. METHODS: A systematic literature search was performed to identify all articles through January 31, 2014, which reported on the prevalence of HPV in OPSCC. Articles that met the inclusion criteria were divided into 4 time frames (pre-1995, 1995-1999, 2000-2004, and 2005 to present) based on the median year of the study's sample collection period. Using a weighted analysis of variance model, we examined the trends of HPV-positivity over time worldwide, in North America, and in Europe. RESULTS: Our literature search identified 699 unique articles. One hundred seventy-five underwent review of the entire study, and 105 met the inclusion criteria. These 105 articles reported on the HPV prevalence in 9541 OPSCC specimens across 23 nations. We demonstrated significant increases in the percentage change of HPV positive OPSCCs from pre-1995 to present: 20.6% worldwide (P for trend: P < 0.001), 21.6% in North America (P = 0.013), and 21.5% in Europe (P = 0.033). CONCLUSIONS: Interestingly, whereas in Europe there was a steady increase in HPV prevalence across all time frames, reaching nearly 50% most recently, in North America HPV prevalence appears to have plateaued over the past decade at about 65%. These findings may have important implications regarding predictions for the future incidence of OPSCC. PMID- 26049693 TI - From the Guest Editor: Illuminating Cancer In Vivo With Molecular Imaging. PMID- 26049694 TI - Imaging Mouse Models of Cancer. AB - Mouse models of cancer have proven to be an indispensable resource in furthering both our basic knowledge of cancer biology and the translation of new cancer treatments and imaging approaches into the clinic. As mouse models have developed and improved in their ability to model many diverse aspects of the human disease, so too has the need for robust imaging approaches to measure key biological parameters noninvasively. The aim of this review is to provide a brief overview of the various imaging approaches available to researchers today for imaging preclinical cancer models, highlighting their relative strengths and weaknesses. The very nature of modeling cancer in the mouse is also changing, and brief mention will be made on how imaging can maximize the utility of these new, accurate, and genetically versatile models. PMID- 26049696 TI - Imaging the Tumor Microenvironment. AB - The tumor microenvironment (TME) is a complex, heterogeneous, and dominant component of solid tumors. Cancer imaging strategies of a subset of characteristics of the TME are under active development, and currently used modalities and novel approaches are summarized in this article. Understanding the dynamic and evolving functions of the TME is critical to accurately inform imaging and clinical care of cancer. Novel insights into distinct roles of the TME in cancer progression urge careful interpretation of imaging data and impel the development of novel modalities. PMID- 26049695 TI - Novel Approaches to Imaging Tumor Metabolism. AB - The field of metabolism research has made a dramatic resurgence in recent years, fueled by a newfound appreciation of the interactions between metabolites and phenotype. Metabolic substrates and their products can be biomarkers of a wide range of pathologies, including cancer, but our understanding of their in vivo interactions and pathways has been hindered by the robustness of noninvasive imaging approaches. The past 3 decades have been flushed with the development of new techniques for the study of metabolism in vivo. These methods include nuclear based, predominantly positron emission tomography and magnetic resonance imaging, many of which have been translated to the clinic. The purpose of this review was to introduce both long-standing imaging strategies as well as novel approaches to the study of perturbed metabolic pathways in the setting of carcinogenesis. This will involve descriptions of nuclear probes labeled with C and F as well C for study using hyperpolarized magnetic resonance imaging. Highlighting both advantages and disadvantages of each approach, the aim of this summary was to provide the reader with a framework for interrogation of metabolic aberrations in their system of interest. PMID- 26049697 TI - Early Cancer Detection at the Epithelial Surface. AB - Malignant neoplastic lesions derived from epithelial tissue, carcinomas, account for 80% to 100% of all human cancers including some of the most deadly diseases such as cervical and non-small cell lung cancer. Many of these carcinomas present at readily accessible epithelial surfaces offering unique detection opportunities. Effective clinical management of carcinomas is enabled by early detection, at a time when full surgical resection is possible and before invasion of adjacent tissue or significant intravasation into blood vessels leading to metastasis. Good prognosis with long-term disease-free survival is more likely after early detection when progression is limited. At present, detection of carcinomas at epithelial surfaces largely relies on routine inspection with the naked eye (e.g., skin and oropharynx) or simple white light tools (e.g., cervix and colon). Emerging optical tools based on differential refraction, absorption, reflection, scattering, or fluorescence of carcinomas relative to normal tissues enable label-free visualization of neoplasia. However, the differences in intrinsic optical properties of normal and malignant tissues can be subtle, and relying on these may lead to high miss rates. Enhanced optical contrast offered by molecularly targeted agents can be used to improve early detection; and given that optical imaging and sensing tools can be readily combined, integrated systems that image over a range of scales, or detect multiple parameters, can be developed to aid in early detection. Diagnosis is, at present, made by histologic examination of tissue biopsies after identification of suspicious lesions. Miniature and handheld microscopic imaging tools have recently been developed, and integration of these tools with wide-field optical surveillance devices offers both rapid detection and confirmatory histologic examination at the point of-care, that can provide guidance for biopsy and/or resection. A wide variety of targeted probe strategies have been described with demonstrated benefit in preclinical models and in a limited number of human studies. Here, we present examples of integrated multimodality optical imaging and sensing tools that use combinations of intrinsic and extrinsic optical contrast for early detection or margin delineation for carcinomas at epithelial surfaces. We will discuss several new technologies that have use in detecting the most common carcinomas that derive from the epithelium of the skin, gastrointestinal and urogenital tracts, and bronchoalveoli. PMID- 26049698 TI - Challenges of Pancreatic Cancer. AB - The development of novel molecular cancer imaging agents has considerably advanced in recent years. Numerous cancer imaging agents have demonstrated remarkable potential for aiding the diagnosis, staging, and treatment planning at the preclinical stage, which in turn has led to a number of agents being approved for human trials. Pancreatic ductal adenocarcinoma is currently the most deadly common carcinoma with an overall 5-year survival rate of about 6%. As detection technologies progress, the need for molecular imaging tools that will allow the diagnosis at an early stage will be crucial to improving patient outcomes. In this review, we will highlight agents that illuminate various cell populations that comprise the tumor: epithelial, endothelial, and stromal tumor cells. PMID- 26049701 TI - Companion Diagnostics and Molecular Imaging. AB - Companion diagnostics (CDx) is a positive attempt in the direction of improving the drug development process, especially in the field of oncology, with the advent of newer targeted therapies. It helps the oncologist in deciding the choice of treatment for the individual patient. The role of CDx assays has attracted the attention of regulators, and especially the US Food and Drug Administration developed regulatory strategies for CDx and the drug-diagnostic codevelopment project. For an increasing number of cancer patients, the treatment selection will depend on the result generated by a CDx assay, and consequently this type of assay has become critical for the care and safety of the patients. In addition to the assay-based approach, molecular imaging with its ability to image at the genetic and receptor level has made foray into the field of drug development and personalized medicine. We shall review these aspects of CDx, with special focus on molecular imaging and the upcoming concept of Theranostics. PMID- 26049700 TI - Image-Guided Tumor Resection. AB - Each year, millions of individuals undergo cancer surgery that is intended to be curative or at least a necessary component of a curative regimen. Particularly for those patients whose cancer harbors cells that are resistant to chemotherapy or radiation, the extent of surgery often defines whether they will be a survivor or casualty of the disease. For many solid tumor types, the difference in survival between patients who undergo gross total resection and those who have residual bulky disease is often profound. With surgery being central to cancer survivorship, it is stunning how few resources have been invested in improving surgical outcomes, particularly in comparison to chemotherapeutic research and discovery. This article reviews recent advances related to developing targeted fluorescent agents to guide surgeons during cancer removal. The goal of these drugs and devices is to clearly distinguish cancer from normal tissue to improve surgical outcome for cancer patients. PMID- 26049699 TI - Optical Imaging, Photodynamic Therapy and Optically Triggered Combination Treatments. AB - Optical imaging is becoming increasingly promising for real-time image-guided resections, and combined with photodynamic therapy (PDT), a photochemistry-based treatment modality, optical approaches can be intrinsically "theranostic." Challenges in PDT include precise light delivery, dosimetry, and photosensitizer tumor localization to establish tumor selectivity, and like all other modalities, incomplete treatment and subsequent activation of molecular escape pathways are often attributable to tumor heterogeneity. Key advances in molecular imaging, target-activatable photosensitizers, and optically active nanoparticles that provide both cytotoxicity and a drug release mechanism have opened exciting avenues to meet these challenges. The focus of the review is optical imaging in the context of PDT, but the general principles presented are applicable to many of the conventional approaches to cancer management. We highlight the role of optical imaging in providing structural, functional, and molecular information regarding photodynamic mechanisms of action, thereby advancing PDT and PDT-based combination therapies of cancer. These advances represent a PDT renaissance with increasing applications of clinical PDT as a frontline cancer therapy working in concert with fluorescence-guided surgery, chemotherapy, and radiation. PMID- 26049702 TI - How Imaging Can Impact Clinical Trial Design: Molecular Imaging as a Biomarker for Targeted Cancer Therapy. AB - The ability to measure biochemical and molecular processes to guide cancer treatment represents a potentially powerful tool for trials of targeted cancer therapy. These assays have traditionally been performed by analysis of tissue samples. However, more recently, functional and molecular imaging has been developed that is capable of in vivo assays of cancer biochemistry and molecular biology and is highly complementary to tissue-based assays. Cancer imaging biomarkers can play a key role in increasing the efficacy and efficiency of therapeutic clinical trials and also provide insight into the biologic mechanisms that bring about a therapeutic response. Future progress will depend on close collaboration between imaging scientists and cancer physicians and on public and commercial sponsors, to take full advantage of what imaging has to offer for clinical trials of targeted cancer therapy. This review will provide examples of how molecular imaging can inform targeted cancer clinical trials and clinical decision making by (1) measuring regional expression of the therapeutic target, (2) assessing early (pharmacodynamic) response to treatment, and (3) predicting therapeutic outcome. The review includes a discussion of basic principles of molecular imaging biomarkers in cancer, with an emphasis on those methods that have been tested in patients. We then review clinical trials designed to evaluate imaging tests as integrated markers embedded in a therapeutic clinical trial with the goal of validating the imaging tests as integral markers that can aid patient selection and direct response-adapted treatment strategies. Examples of recently completed multicenter trials using imaging biomarkers are highlighted. PMID- 26049703 TI - Imaging Genomics in Gliomas. AB - During the last decade, imaging has become the cornerstone for noninvasive diagnosis of different disorders and is currently being used by physicians all over the world. With the emergence of novel advanced imaging techniques that allow microstructural as well as functional tissue characterization along with the extensive work done by The Cancer Genome Atlas focusing on mapping genomic changes in glioblastoma, new correlations have been discovered between alterations at the genomics level and radiological imaging features in cancer patients. This has marked the beginning of a new era in clinical sciences, the era of "imaging genomics," which aims at establishing relationship between radiological imaging features and genomic characteristics of tumors. This article reviews the fundamentals of imaging genomics in glioma, its role in noninvasive genomic detection, and its future potential in personalized treatment planning. PMID- 26049704 TI - Influence of urban/rural and coastal/inland environment on the prevalence, phenotype, and clinical course of inflammatory bowel disease patients from northwest of Spain: a cross-sectional study. AB - BACKGROUND: Data on the influence of rural/urban and coastal/inland environment on inflammatory bowel disease (IBD) are either conflicting or lacking. Our aim was to analyze whether the environment has any influence on the prevalence, phenotype, and course of IBD. MATERIALS AND METHODS: We carried out a multicenter retrospective study in 1194 IBD patients from Galicia, Spain. Urban areas were defined as those with over 25,000 inhabitants. Sex, age, family history, smoking, Montreal classification, extraintestinal manifestations, steroid dependence/refractoriness, and treatment were assessed. We used the Student's t test/Mann-Whitney U tests to compare continuous variables and chi to compare categorical variables. Logistic regression was also used. RESULTS: Living in urban municipalities was a risk factor for Crohn's disease [relative risk (RR) 1.47; 95% confidence interval (CI) 1.25-1.73; P<0.001]; living in coastal municipalities was a protective factor for ulcerative colitis (RR 0.71; 95% CI 0.60-0.85; P<0.001). Crohn's disease patients living on the coast had more frequent ileocolonic disease and needed immunosuppressives more frequently than inland patients (RR for inland 0.65; 95% CI 0.47-0.90; P=0.008). Urban Crohn's disease patients needed immunosuppressives more frequently than rural patients (RR 1.41; 95% CI 1.04-1.92; P=0.027). Urban ulcerative colitis patients had left sided colitis less frequently. Coastal ulcerative colitis patients more frequently had extensive colitis. CONCLUSION: Crohn's disease was found more frequently in urban and coastal areas and ulcerative colitis in inland municipalities. Place of residence may also influence phenotype and clinical course as patients living on the coast have more frequent ileocolonic Crohn's disease phenotype, extensive ulcerative colitis, and greater need for immunosuppressive therapy. PMID- 26049705 TI - A training program for primary care physicians improves the effectiveness of ultrasound surveillance of hepatocellular carcinoma. AB - BACKGROUND AND AIMS: Cirrhosis is the main risk factor of hepatocellular carcinoma (HCC), but only a minority of cirrhotic patients are referred to the hepatologist by primary care physicians (PCP) and receive regular ultrasound surveillance. The aim of this study was to determine whether a training program targeted to PCP could enhance the effectiveness of surveillance in a real-life setting. PATIENTS AND METHODS: A total of 120 PCP in an Italian area with a high incidence of HCC were trained to identify cirrhotic patients, to refer them to the Hepatology Centers of the area, and to start regular ultrasound surveillance. Clinical characteristics, outcome of treatments, and survival of 190 consecutive HCC patients in the same centers after training were compared with 244 HCC referred from the same area before training, and to 232 HCC referred by untrained PCP from other areas. RESULTS: Trained PCP referred significantly more HCC patients detected under surveillance and at an early stage (Barcelona Clinic Liver Cancer-A), suitable for radical treatments. In the intervention area, the 3 and 5-year survival of HCC patients increased after training from 35 to 48% and from 20 to 40%, respectively (P<0.05). In contrast, survival was unchanged in the other areas. At multivariate analysis, independent predictors adversely affecting survival were Child-Pugh B-C, alpha-fetoprotein more than 10 ng/dl, nonviral etiology, intermediate/advanced Barcelona Clinic Liver Cancer stage, and referral by an untrained PCP. CONCLUSION: Specific training of PCP aimed at the identification and referral of cirrhotic patients efficiently improves HCC survival. PMID- 26049706 TI - Magnetic resonance enterography findings as predictors of clinical outcome following antitumor necrosis factor treatment in small bowel Crohn's disease. AB - AIMS: To determine whether specific magnetic resonance enterography (MRE) findings can predict outcome following commencement of antitumor necrosis factor (aTNF) in small bowel Crohn's disease (CD) PATIENTS AND METHODS: This was a single-centre retrospective study of patients with CD who commenced aTNF (infliximab or adalimumab) between 2007 and 2013. Patients who had an MRE within 6 months before commencing aTNF were included. The primary end-point was the need for CD-related surgery. The secondary end-points were time to surgery and time to treatment failure. The relationship between these end-points, clinical variables and specific MRE findings were studied. RESULTS: Four hundred and eighteen patients commenced aTNF for CD during the study period. Seventy-five patients had an MRE within 6 months before commencing aTNF (30 infliximab; 45 adalimumab). The median time from MRE to commencing aTNF was 43 days (IQR 19.5-87 days). Eighteen of 75 (24%) had surgery during a median follow-up of 16.7 months (IQR 9.0-30.1 months). Patients with small bowel stenosis (SBS) on MRE were at a significantly higher risk of requiring surgery: 12/18 (66.7%) versus 6/57 (10.5%) (P<0.001). Time to surgery was significantly shorter in patients with SBS on MRE (P<0.001). In a multivariate analysis, SBS (P<0.0001, hazard ratio 26.45, 95% confidence interval 5.45-128.49) and presence of penetrating complications (P=0.003, hazard ratio 36.53, 95% confidence interval 3.40-393.19) were associated independently with time to surgery. CONCLUSION: SBS and penetrating complications on MRE are associated independently with a need for early surgery and treatment failure in patients commencing aTNF. PMID- 26049707 TI - Noninvasive estimation of disease activity and liver fibrosis in nonalcoholic fatty liver disease using anthropometric and biochemical characteristics, including insulin, insulin resistance, and 13C-methionine breath test. AB - OBJECTIVE: The purpose of this study was to noninvasively estimate disease activity and liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) using anthropometric and biochemical characteristics and the C-methionine breath test (MeBT). METHODS: A total of 164 patients with histologically proven NAFLD and 56 healthy controls were included in the study. Anthropometric and biochemical analyses and the MeBT were performed on all patients and controls. RESULTS: BMI; waist circumference; waist-hip ratio; transaminase, lipid, gamma glutamyl transpeptidase (GGT), glucose, and insulin levels; and insulin resistance were significantly higher in patients with NAFLD than in controls. The GGT level and the MeBT were independent predictors of nonalcoholic steatohepatitis (NASH). Fibrosis was correlated with GGT, bilirubin, cholesterol, and insulin levels, and the MeBT, but the test was the only independent predictor of significant fibrosis. Patients with simple steatosis had similar MeBT values as controls. The MeBT values were significantly lower in NASH and NASH-cirrhosis patients (P<0.001) compared with simple steatosis patients and controls. Patients with advanced fibrosis (F2-3) had significantly lower MeBT values than patients with mild fibrosis (F0-1; P<0.001). The area under the receiving operating characteristic curve for NASH and advanced fibrosis was estimated to be 0.95 in the total cohort. CONCLUSION: This study indicates that anthropometric and biochemical parameters are insufficient for estimating the presence of NASH or the fibrosis stage. However, the MeBT is a suitable noninvasive method for accurately predicting which patients suffer from simple steatosis, NASH, or NASH cirrhosis. PMID- 26049708 TI - Predictability of capsule endoscopy referred to a tertiary care center for double balloon enteroscopy. AB - OBJECTIVES: Patients with obscure gastrointestinal bleeding with 'positive' findings on video capsule endoscopy (VCE) by gastroenterologists practicing in the community are often referred to tertiary care centers for double-balloon enteroscopy (DBE). Our study explores the degree of concordance between these two procedures performed in two different clinical settings. METHODS: Concordance between the procedures was estimated using a kappa-coefficient. RESULTS: A total of 73 patients with obscure gastrointestinal bleeding were referred to our center for DBE after undergoing VCE elsewhere. Ten of these patients (10/73 or 13.7%) had been found to have bleeding in the small bowel on VCE without any concrete diagnosis. DBE revealed the source of bleeding in 17 of the 22 patients (77.3%) with normal VCE. The referral diagnosis was correct in 31 cases (31/73 or 42.5%). The kappa-coefficient for VCE and DBE for the 63 patients was 0.28, suggesting poor agreement between the two procedures. However, most patients with a referral diagnosis of vascular pathology were confirmed to have vascular disease on DBE (19/23 or 82.6%). CONCLUSION: Our study shows that there is a poor concordance between capsule endoscopy performed in the community and confirmatory DBE performed at our tertiary care center. PMID- 26049709 TI - Prospective multicenter validation of the Glasgow Blatchford bleeding score in the management of patients with upper gastrointestinal hemorrhage presenting at an emergency department. AB - BACKGROUND/AIMS: The Glasgow Blatchford Bleeding Score (GBS) has been developed to assess the need for treatment in patients with acute upper gastrointestinal hemorrhage (UGIH) presenting at emergency departments (EDs). We aimed (a) to determine the validity of the GBS and Rockall scoring systems for prediction of need for treatment and (b) to identify the optimal cut-off value of the GBS. METHODS: We carried out a population-based, prospective multicenter study of 520 consecutive patients presenting with acute UGIH at EDs of three hospitals. The accuracy of GBS and Rockall scores in predicting the need for treatment (i.e. endoscopic, surgical, or radiological intervention and blood transfusion) was analyzed using receiver operating characteristic curves. RESULTS: Receiver operating characteristic curve analysis showed that the GBS had a good discriminative ability to determine the need for treatment in patients with acute UGIH (area under the curve: 0.88; 95% confidence interval: 0.85-0.91). The GBS was superior to both the clinical Rockall and the full Rockall score in predicting the need for treatment (area under the curve: 0.86 vs. 0.70 vs. 0.77). At a cut-off value of up to 2, the GBS had the optimal combination of sensitivity (99.4%) and specificity (42.4%). CONCLUSION: The GBS is superior compared with both Rockall scores in predicting the need for treatment in patients with suspected acute UGIH presenting at EDs in the Netherlands. Patients with a GBS of 2 or less form a subgroup of low-risk patients. These low-risk patients are eligible for outpatient management, which might reduce hospital admissions and healthcare costs. PMID- 26049710 TI - Early transjugular intrahepatic portosystemic shunt in cirrhotic patients with acute variceal bleeding: a systematic review and meta-analysis of controlled trials. AB - INTRODUCTION: There is conflicting evidence on the benefit of early transjugular intrahepatic portosystemic shunt (TIPSS) on the survival of patients with acute variceal bleeding (AVB). AIM: To assess the effect of early TIPSS on patient prognosis. MATERIALS AND METHODS: We carried out a meta-analysis of trials evaluating early TIPSS in cirrhotic patients with AVB. RESULTS: Four studies were included. Early TIPSS was associated with fewer deaths [odds ratio (OR)=0.38, 95% confidence interval (CI)=0.17-0.83, P=0.02], with moderate heterogeneity between studies (P=0.15, I=44%). Early TIPSS was not significantly associated with fewer deaths among Child-Pugh B patients (OR=0.35, 95% CI=0.10-1.17, P=0.087) nor among Child-Pugh C patients (OR=0.34, 95% CI=0.10-1.11, P=0.074). There was no heterogeneity between studies in the Child-Pugh B analysis (P=0.6, I=0%), but there was a high heterogeneity in the Child-Pugh C analysis (P=0.06, I=60%). Early TIPSS was associated with lower rates of bleeding within 1 year (OR=0.08, 95% CI=0.04-0.17, P<0.001) both among Child-Pugh B patients, (OR=0.15, 95% CI=0.05-0.47, P=0.001) and among Child-Pugh C patients (OR=0.05, 95% CI=0.02 0.15, P<0.001), with no heterogeneity between studies. Early TIPSS was not associated with higher rates of encephalopathy (OR=0.84, 95% CI=0.50-1.42, P=0.5). CONCLUSION: Cirrhotic patients with AVB treated with early TIPSS had lower death rates and lower rates of clinically significant bleeding within 1 year compared with patients treated without early TIPSS. Additional studies are required to identify the potential risk factors leading to a poor prognosis after early TIPSS in patients with AVB and to determine the impact of the degree of liver failure on the patient's prognosis. PMID- 26049711 TI - Patient and physician preferences for the treatment of chronic hepatitis C virus infections: does the perspective matter? AB - OBJECTIVES: The objectives of this study were to identify and quantify the factors driving patient and physician preferences for treatments of genotype 1 hepatitis C virus infection in the UK. METHODS: A web survey was conducted, including 100 patients (50 treatment-naive and 50 treatment-experienced patients) and 50 physicians (gastroenterologists/ hepatologists and infectious disease specialists). A discrete-choice experiment was conducted to elicit the participants' preferences on the basis of seven attributes with four levels each: efficacy, that is probability of reaching sustained virologic response, treatment duration, treatment convenience (i.e. number of pills and/or injections), gastrointestinal problems, anaemia, dermatological problems and neuropsychological problems. The statistical analysis applied a mixed logit model to estimate preference weights and relative importance scores. RESULTS: Results indicated that the sustained virologic response rate was the most important attribute to participants. Physicians placed an even greater weight on the efficacy of treatments with a relative importance score of 9.33 [95% confidence interval: (6.93-11.91)], as compared with 6.16 [95% confidence interval: (4.34 8.15)] for patients. Neuropsychological problems ranked second for patients and physicians, and were more important to treatment-naive patients than to treatment experienced patients or physicians. Gastrointestinal problems, anaemia and dermatological problems were of minor importance to all participants. These findings may be explained by the improvement in the management of physical adverse reactions over the last few years, thus making treatment easier to tolerate. CONCLUSIONS: This study is the first conjoint analysis assessing and comparing the preferences of patients and physicians in hepatitis C virus. PMID- 26049712 TI - Diagnostic usefulness of FibroMeter VCTE for hepatic fibrosis in patients with nonalcoholic fatty liver disease. AB - BACKGROUND: Liver fibrosis is an important prognostic determinant in patients with nonalcoholic fatty liver disease (NAFLD). The FibroMeter VCTE is a diagnostic tool comprising both biochemical markers and transient elastography (TE) originally developed for the diagnosis of fibrosis in patients with chronic viral hepatitis. In this pilot study, we investigated the diagnostic performance of the FibroMeter VCTE tool for determining fibrosis in patients with biopsy proven NAFLD. Its diagnostic accuracy was also compared with those of the NAFLD fibrosis score (NFSA) and TE alone. PATIENTS AND METHODS: FibroMeter VCTE, NFSA, and TE were determined in 52 patients with NAFLD. The results of liver biopsies were considered the gold standard. Areas under the receiver operating characteristic curve were used to express the diagnostic accuracy of each test. RESULTS: Significant (F>=2) and severe (F>=3) fibrosis were detected in 20 (38%) and 10 (19%) patients, respectively. The sensitivity of FibroMeter VCTE, NFSA, and TE for detecting significant fibrosis was 70, 65, and 75%, respectively, whereas specificity was 88, 81, and 78%. The sensitivity of FibroMeter VCTE, NFSA, and TE for diagnosing severe fibrosis was 90, 90, and 100%, respectively, whereas specificity was 93, 78, and 76%. Receiver operating characteristic analysis showed that FibroMeter VCTE had a significantly larger areas under the receiver operating characteristic curve (0.968) compared with both NFSA (0.833, P<0.001) and TE (0.922, P<0.05) for the detection of severe fibrosis. CONCLUSION: Our preliminary findings indicate that FibroMeter VCTE is superior to both NFSA and TE for the diagnosis of severe fibrosis in patients with NAFLD. PMID- 26049713 TI - Robust and automated three-dimensional segmentation of densely packed cell nuclei in different biological specimens with Lines-of-Sight decomposition. AB - BACKGROUND: Due to the large amount of data produced by advanced microscopy, automated image analysis is crucial in modern biology. Most applications require reliable cell nuclei segmentation. However, in many biological specimens cell nuclei are densely packed and appear to touch one another in the images. Therefore, a major difficulty of three-dimensional cell nuclei segmentation is the decomposition of cell nuclei that apparently touch each other. Current methods are highly adapted to a certain biological specimen or a specific microscope. They do not ensure similarly accurate segmentation performance, i.e. their robustness for different datasets is not guaranteed. Hence, these methods require elaborate adjustments to each dataset. RESULTS: We present an advanced three-dimensional cell nuclei segmentation algorithm that is accurate and robust. Our approach combines local adaptive pre-processing with decomposition based on Lines-of-Sight (LoS) to separate apparently touching cell nuclei into approximately convex parts. We demonstrate the superior performance of our algorithm using data from different specimens recorded with different microscopes. The three-dimensional images were recorded with confocal and light sheet-based fluorescence microscopes. The specimens are an early mouse embryo and two different cellular spheroids. We compared the segmentation accuracy of our algorithm with ground truth data for the test images and results from state-of the-art methods. The analysis shows that our method is accurate throughout all test datasets (mean F-measure: 91%) whereas the other methods each failed for at least one dataset (F-measure<=69%). Furthermore, nuclei volume measurements are improved for LoS decomposition. The state-of-the-art methods required laborious adjustments of parameter values to achieve these results. Our LoS algorithm did not require parameter value adjustments. The accurate performance was achieved with one fixed set of parameter values. CONCLUSION: We developed a novel and fully automated three-dimensional cell nuclei segmentation method incorporating LoS decomposition. LoS are easily accessible features that ensure correct splitting of apparently touching cell nuclei independent of their shape, size or intensity. Our method showed superior performance compared to state-of-the-art methods, performing accurately for a variety of test images. Hence, our LoS approach can be readily applied to quantitative evaluation in drug testing, developmental and cell biology. PMID- 26049714 TI - Providing Quality Therapeutics in Switzerland: Role of the Stakeholders and Recent Incentives for Further Improvements. AB - Quality therapeutics play an important role in Switzerland's health care and economy. Switzerland holds a key position in the world of research and development, as well as in drug production. Recently, new emphasis has been placed on promoting clinical research and maintaining Switzerland's position as a center of excellence in the field. Recent revisions to the law regarding medical trials in human research allow for better allocation of regulatory resources and simplified procedures for drugs already authorized in Switzerland. The country has its own regulatory agency, the Swiss Agency for Therapeutic Products (Swissmedic), which is a public institution of the Swiss government. Swissmedic is responsible for ensuring safety in medicines, particularly regarding authorizations and market surveillance in the sector of medicinal products and medical devices. Although the centralized authorization procedure of the European Union for medicines does not apply to Switzerland, there are mutual recognition mechanisms between the Swiss medicine regulatory authority and the European Medicines Agency. Swissmedic is also in charge of postmarketing safety and oversees the national pharmacovigilance center, which collaborates closely with the World Health Organization center in Uppsala. In addition, university hospital based clinical pharmacologists, who are involved in basic science and clinical research, regulatory affairs, ethics committees, and pharmacovigilance, promote quality therapeutics. This article discusses the role of the various stakeholders and the recent efforts made to provide a better allocation of resources aimed at further improving quality therapeutics in Switzerland. PMID- 26049715 TI - Influenza-attributable deaths in south-eastern France (1999 to 2010): mortality predictions were undependable. AB - BACKGROUND: Following the 2009 influenza pandemic, several studies showed that the mortality pattern associated with the A(H1N1)2009 virus primarily affected children and young adults. In this study, we aimed to estimate the influenza attributable deaths during the periods from 1999 to 2010, in the Provence-Alpes Cote-d'Azur (PACA) region of south-eastern France in order to corroborate the hypothesis that (i) influenza-attributable deaths caused by A(H1N1)2009 strain were much lower than initially expected. METHODS: In order to compare our results with published data, we used the same statistical model of an Austrian team, using a Poisson model adjusted on co-circulating respiratory syncytial virus to explain the weekly mortality. RESULTS: We assessed that 5.7% of the respiratory deaths were attributable to influenza virus during the 2009-2010 pandemic season. This mortality was lower than that observed during the ten preceding epidemic periods (13.8% on average). Age group-based analysis revealed that during the pandemic period, the groups under 65 had a systematically higher excess of respiratory mortality while the age group over 65 had a much lower mortality than during the seasonal epidemic seasons. Similarly, among the less specific outcome (non violent and cardiovascular mortality) the age groups over 45 had higher excess of mortality during the seasonal epidemics than during the pandemic period. CONCLUSIONS: Since most of the influenza mortality is commonly observed in the elderly group (>65 year-old), the moderate elderly mortality during the 2009 pandemic period has impacted the total mortality, and has resulted in a reduced total mortality despite an increased mortality in the young age group. Despite using identical parameters and the same approach as in a previously published study using an Austrian population sample, we observed a lower excess respiratory mortality in the south-eastern France than in Vienna. Thus, the pandemic virus caused less death than the epidemic viruses that circulated during the preceding years. In contrast with catastrophic predictions made in the early phase of the pandemic, human lives were saved during the circulation period of A(H1N1)2009 virus, resulting in a lower overall mortality. PMID- 26049716 TI - Chiari IV malformation: correcting an over one century long historical error. PMID- 26049717 TI - Missed limited dorsal myeloschisis: an unfortunate cause for recurrent tethered cord syndrome. AB - AIM: This study aims to highlight the recurrent tethered cord syndrome in relation to the relatively new pathological entity of limited dorsal myeloschisis (LDM) and to mention the difficulties faced by the paediatric neurosurgeon in developing countries with reference to LDM which was not recognized at initial presentation. MATERIALS AND METHODS: We present three cases of recurrent tethered cord syndrome who were operated early in life (not by paediatric neurosurgeons) as meningoceles and who were then subsequently referred to the senior author as they presented with clinical signs of re-tethering of the cord. RESULTS: The first child of 1 year of age represented with cervicodorsal swelling 10 months after primary surgery for a cervical meningomyelocele done elsewhere on the second day of life. The second was a girl of 3 years of age who was operated at birth and presented with severe brachialgia and neck pain after 2 years. The third was a 19-year-old girl operated at birth presenting with spastic paraparesis and also hand weakness associated with kyphosis. All the three patients improved symptomatically and neurologically after redo surgery. CONCLUSION: The diagnosis of LDMs, especially in developing countries, is frequently missed. This needs to be tackled and addressed so that children with this subset of neural tube defects, who otherwise would normally have a very good outcome, may not be blighted and left scarred for life at an early age. PMID- 26049718 TI - Monitoring the changing pattern of delivery of paediatric epilepsy surgery in England--an audit of a regional service and examination of national trends. PMID- 26049719 TI - Longitudinal Association of Registered Nurse National Nursing Specialty Certification and Patient Falls in Acute Care Hospitals. AB - BACKGROUND: Researchers have studied inpatient falls in relation to aspects of nurse staffing, focusing primarily on staffing levels and proportion of nursing care hours provided by registered nurses (RNs). Less attention has been paid to other nursing characteristics, such as RN national nursing specialty certification. OBJECTIVE: The aim of the study was to examine the relationship over time between changes in RN national nursing specialty certification rates and changes in total patient fall rates at the patient care unit level. METHODS: We used longitudinal data with standardized variable definitions across sites from the National Database of Nursing Quality Indicators. The sample consisted of 7,583 units in 903 hospitals. Relationships over time were examined using multilevel (units nested in hospitals) latent growth curve modeling. RESULTS: The model indices indicated a good fit of the data to the model. At the unit level, there was a small statistically significant inverse relationship (r = -.08, p = .04) between RN national nursing specialty certification rates and total fall rates; increases in specialty certification rates over time tended to be associated with improvements in total fall rates over time. DISCUSSION: Our findings may be supportive of promoting national nursing specialty certification as a means of improving patient safety. Future study recommendations are (a) modeling organizational leadership, culture, and climate as mediating variables between national specialty certification rates and patient outcomes and (b) investigating the association of patient safety and specific national nursing specialty certifications which test plans include patient safety, quality improvement, and diffusion of innovation methods in their certifying examinations. PMID- 26049720 TI - Syndromic and sporadic inflammatory/hyperplastic small-bowel polyps: a comparative study. AB - BACKGROUND: Inflammatory/hyperplastic small-bowel polyps (SBPs) occur either sporadically or in patients with a polyposis syndrome; however, comparison between these two settings of the histological features of SBPs has not been reported and the etiology of sporadic inflammatory/hyperplastic SBPs remains unclear. METHOD: Twenty-eight cases of sporadic inflammatory/hyperplastic SBPs and nine cases of syndromic SBPs were retrieved from the Department of Anatomic Pathology at the Cleveland Clinic. Clinico-demographics and histological features were compared between the two groups. RESULTS: Patients with syndromic inflammatory/hyperplastic SBPs were younger (48 vs. 63 years; P = 0.007) and had higher rates of hemorrhagic telangiectasia (55.6% vs. 0%; P = 0.000), gastric polyps (87.5% vs. 21.4%; P = 0.001), and family history of colon cancer (62.5% vs. 11.1%; P = 0.014). Sporadic cases were more frequently associated with gastro esophageal reflux (35.7% vs. 0%; P = 0.079) and anti-reflux medication use (55.6% vs. 11.1%; P = 0.026). Histologically, the syndromic SBPs were more often of pure intestinal type (45.4% vs. 3.8%; P = 0.005) and had prominent vessels (81.8% vs. 42.3%; P = 0.036). CONCLUSIONS: Patients with syndromic SBPs are younger and have higher rates of hemorrhagic telangiectasia, gastric polyps, and family history of colon cancer. Histologically, syndromic inflammatory/hyperplastic SBPs are more likely to be of pure intestinal type and to have prominent vessels. PMID- 26049722 TI - Evidence of Sex-Linked Familial Transmission of Lateral Preferences for Hand, Foot, Eye, Ear, and Overall Sidedness in a Latent Variable Analysis. AB - This study investigated the familial transmission of handedness, footedness, eyedness, earedness, and of underlying sidedness in a sample of adults (n = 592 families; 1528 individuals in total), using multi-item inventories and probabilistic methods for preference classification. Our results corroborate three classes of lateral preferences and of sidedness each, right, mixed, and left. Consistent with genetic studies, we obtained evidence of parent-of-origin and sex-of-children effects, suggesting important roles of maternal mixed preferences and of paternal left preferences. Further, parental age at conception predicted mixed preferences in the child. We recommend a trichotomous classification of lateral preferences also in future studies, and to intensify research into the genetic bases of footedness, eyedness and earedness. PMID- 26049721 TI - Application of B+M-Mode Ultrasonography in Assessing Deglutitive Tongue Movements in Healthy Adults. AB - BACKGROUND: The purpose of this study was to evaluate tongue movements during swallowing in healthy adults using the B+M-mode ultrasonography, and to determine a common feature in the M-mode traces for quantitative measurement and individual comparison of tongue movements. MATERIAL AND METHODS: Ninety healthy subjects were divided into 3 groups according to age (20-39, 40-59, and 60-80 years). The tongue movements during 3 saliva swallows were examined using real-time B+M-mode ultrasonography. The M-mode traces of tongue movements were recorded and evaluated. RESULTS: Both intra-individual and inter-individual differences were detected in the M-mode traces during the 3 saliva swallows. Characteristic types were seen during the individual swallowing phases of M-mode traces: 2 activity types in phase I, 2 types in phase IIb, and 3 types in phase III. However, no variations were seen during phase IIa, in which all subjects displayed a continuous upsloping trace. The average range of swallow-related tongue radial displacement during phase IIa decreased gradually with age, while the average duration of tongue movement during phase IIa increased gradually with age. These 2 trends were not statistically significant across age groups. However, differences between sexes were found in both the range of tongue radial displacement and the duration of deglutitive lingual actions during phase IIa in all 3 age groups (P<0.05). CONCLUSIONS: B+M-mode ultrasonography may offer a quick and safe alternative for the preliminary evaluation of deglutitive tongue movements. PMID- 26049723 TI - Heritability of Individual Psychotic Experiences Captured by Common Genetic Variants in a Community Sample of Adolescents. AB - Occurrence of psychotic experiences is common amongst adolescents in the general population. Twin studies suggest that a third to a half of variance in adolescent psychotic experiences is explained by genetic influences. Here we test the extent to which common genetic variants account for some of the twin-based heritability. Psychotic experiences were assessed with the Specific Psychotic Experiences Questionnaire in a community sample of 2152 16-year-olds. Self-reported measures of Paranoia, Hallucinations, Cognitive Disorganization, Grandiosity, Anhedonia, and Parent-rated Negative Symptoms were obtained. Estimates of SNP heritability were derived and compared to the twin heritability estimates from the same sample. Three approaches to genome-wide restricted maximum likelihood (GREML) analyses were compared: (1) standard GREML performed on full genome-wide data; (2) GREML stratified by minor allele frequency (MAF); and (3) GREML performed on pruned data. The standard GREML revealed a significant SNP heritability of 20 % for Anhedonia (SE = 0.12; p < 0.046) and an estimate of 19 % for Cognitive Disorganization, which was close to significant (SE = 0.13; p < 0.059). Grandiosity and Paranoia showed modest SNP heritability estimates (17 %; SE = 0.13 and 14 %; SE = 0.13, respectively, both n.s.), and zero estimates were found for Hallucinations and Negative Symptoms. The estimates for Anhedonia, Cognitive Disorganization and Grandiosity accounted for approximately half the previously reported twin heritability. SNP heritability estimates from the MAF-stratified approach were mostly consistent with the standard estimates and offered additional information about the distribution of heritability across the MAF range of the SNPs. In contrast, the estimates derived from the pruned data were for the most part not consistent with the other two approaches. It is likely that the difference seen in the pruned estimates was driven by the loss of tagged causal variants, an issue fundamental to this approach. The current results suggest that common genetic variants play a role in the etiology of some adolescent psychotic experiences, however further research on larger samples is desired and the use of MAF-stratified approach recommended. PMID- 26049726 TI - Extra-Hepatic Bile Duct Resection: an Insight in the Management of Gallbladder Cancer. AB - BACKGROUND: Involvement of extrahepatic bile duct in gallbladder cancer (GBC) is considered a sign of advanced disease; resection of extrahepatic bile duct in GBC has been a contentious issue considering the poor prognosis of the disease. METHODS: This retrospective study was done in two tertiary teaching hospitals of North India. The case records of all the GBC patients who underwent radical cholecystectomy with extra-hepatic bile duct resection were reviewed. Details concerning the clinical presentation, preoperative therapy, operative procedure, indication of bile duct resection, postoperative complications and outcome were retrieved from the case records. Kaplan-Meier analysis was done to estimate median disease-free survival and overall survival. RESULTS: There were 17 GBC patients who underwent radical cholecystectomy with resection of extrahepatic bile duct. Median age of the patients was 51 years (range 35-62); male to female ratio was 5:12. Six patients were diagnosed after histopathological examination of resected gallbladder specimen following cholecystectomy (incidental gallbladder cancer). All the patients had R'0' resection. The indication for extra-hepatic bile duct resection was direct infiltration of hepatoduodenal ligament in nine, positive cystic duct margin in two, densely adherent pericholedochal lymphnodes in one and associated ampullary growth in one patient. Kaplan-Meier analysis predicted median disease-free survival of 20 months and median overall survival of 26 months. CONCLUSION: Extrahepatic bile duct resection to achieve R'0' resection in the management of advanced gallbladder cancer is safe with acceptable postoperative morbidity and has potential to improve survival. PMID- 26049727 TI - Echocardiographic characteristics of patients with acute heart failure requiring tolvaptan: a retrospective study. AB - BACKGROUND: No study has investigated the admission echocardiographic characteristics of acute heart failure (AHF) patients who are resistant to conventional diuretics and require tolvaptan. METHODS: We retrospectively analyzed the echocardiographic characteristics of AHF patients who were resistant to conventional diuretics and took tolvaptan (tolvaptan group: 26 patients), and compared them to those who were sensitive to conventional diuretics (conventional group: 180 patients). RESULTS: The tolvaptan group had a higher left atrial volume index (96.0 +/- 85.0 mL/m2 vs. 45.8 +/- 25.9 mL/m2, p < 0.0001), maximum inferior vena cava diameter (20.7 +/- 6.9 mm vs. 18.1 +/- 4.2 mm, p < 0.01), and higher tricuspid regurgitation grade (1.1 +/- 0.8 vs. 0.8 +/- 0.6, p < 0.05) than the conventional group. However, the left ventricular ejection fraction and end diastolic diameter were similar between the groups. Responders of tolvaptan had no significant echocardiographic differences compared to the non-responders. CONCLUSIONS: The admission echocardiographic characteristics of AHF patients requiring tolvaptan included a larger left atrium, inferior vena cava, and more severe tricuspid regurgitation. Echocardiography may provide useful information for the early and appropriate initiation of tolvaptan. PMID- 26049728 TI - Osteochondromas in fibrodysplasia ossificans progressiva: a widespread trait with a streaking but overlooked appearance when arising at femoral bone end. AB - Metaphyseal bony outgrowths are a well-recognized feature of fibrodysplasia ossificans progressiva (FOP) phenotype, but its genuine frequency, topographic distribution, morphological aspect, and potential implications are not fully established. To better ascertain the frequency and characteristics of osteocartilaginous exostoses in FOP disease, we conducted a cross-sectional radiological study based on all the traceable cases identified in a previous comprehensive national research. Metaphyseal exostoses were present in all the 17 cases of FOP studied. Although most often arising from the distal femoral (where metaphyseal exostoses adopt a peculiar not yet reported appearance) and proximal tibial bones, we have found that they are not restricted to these areas, but rather can be seen scattered at a variety of other skeletal sites. Using nuclear magnetic resonance imaging, we show that these exophytic outgrowths are true osteochondromas. As a whole, these results are in agreement with data coming from the literature review. Our study confirms the presence of metaphyseal osteochondromas as a very frequent trait of FOP phenotype and an outstanding feature of its anomalous skeletal developmental component. In line with recent evidences, this might imply that dysregulation of BMP signaling, in addition to promoting exuberant heterotopic ossification, could induce aberrant chondrogenesis and osteochondroma formation. Unveiling the molecular links between these physiopathological pathways could help to illuminate the mechanisms that govern bone morphogenesis. PMID- 26049729 TI - First Detection of Human Papillomaviruses and Human Polyomaviruses in River Waters in Italy. AB - Waterborne exposure to human viruses is possible through contact with contaminated water environments and can result in infections associated with a wide range of illnesses, including gastrointestinal, respiratory, ear, ocular, and skin infections. Recently, the occurrence in water environments of two groups of human viruses-both known with oncogenic potential, human polyomaviruses (HPyVs) and papillomaviruses (HPVs)-has been reported worldwide. These viruses, responsible for highly prevalent infections worldwide, have recently been proposed as potentially emerging waterborne pathogens. The objective of the present study was to examine the occurrence of HPyVs and HPVs in surface waters, by monitoring two rivers in Northwestern Italy, by nested PCR assays and sequencing. HPyVs (JC, BK, and Merkel cell polyomavirus) were detected in 10/25 (40%) samples. HPVs (HPV8, 17, 21, 25, 32, 80, 99, 105, and putative new HPVs) were identified in 14/25 (56%) river samples. The number of HPV DNA copies in waters was measured by quantitative real-time PCR. To our knowledge, this is the first detection and quantification of HPVs in surface waters. The possibility that HPyVs and HPVs can be transmitted by the waterborne route deserves to be explored in future studies. PMID- 26049731 TI - Crack imaging and quantification in aluminum plates with guided wave wavenumber analysis methods. AB - Guided wavefield analysis methods for detection and quantification of crack damage in an aluminum plate are presented in this paper. New wavenumber components created by abrupt wave changes at the structural discontinuity are identified in the frequency-wavenumber spectra. It is shown that the new wavenumbers can be used to detect and characterize the crack dimensions. Two imaging based approaches, filter reconstructed imaging and spatial wavenumber imaging, are used to demonstrate how the cracks can be evaluated with wavenumber analysis. The filter reconstructed imaging is shown to be a rapid method to map the plate and any existing damage, but with less precision in estimating crack dimensions; while the spatial wavenumber imaging provides an intensity image of spatial wavenumber values with enhanced resolution of crack dimensions. These techniques are applied to simulated wavefield data, and the simulation based studies show that spatial wavenumber imaging method is able to distinguish cracks of different severities. Laboratory experimental validation is performed for a single crack case to confirm the methods' capabilities for imaging cracks in plates. PMID- 26049730 TI - Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study. AB - INTRODUCTION: Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia. METHODS: We performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5-C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0-10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg(-1) Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation. RESULTS: No serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS. CONCLUSIONS: tVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT01944228. Registered 12 September 2013. PMID- 26049732 TI - Plate acoustic wave sensor for detection of small amounts of bacterial cells in micro-litre liquid samples. AB - Ultrasonic acoustic waves propagating in thin piezoelectric plates with free faces are used for bacteria detection in micro-litre liquid samples deposited on one of the plate surface. The limits of the detection at normal conditions are as low as 0.04% for highly diluted rich cultural Luria-Bertani broth (LB-media) in distillate water, 0.07% for bacterial cells in distillate water, and 0.6% for bacterial cells in LB-media. For all analytes the most probable detection mechanism is the change in liquid conductivity. Because of no using any sorbent film the long-term stability of the detection is expected as very high. PMID- 26049733 TI - The renal effects of mineralocorticoid receptor antagonists. AB - Beyond its well known classic effects on renal water and electrolytes metabolism, an increasing amount of experimental and clinical evidence suggests that aldosterone contributes to the pathogenesis and progression of kidney disease. The binding of aldosterone on epithelial and non-epithelial cells of the kidney induces many deleterious effects, such as podocyte apoptosis and injury, mesangial cell proliferation and deformability and tubulointerstitial inflammation, finally resulting in glomerular fibrosis and sclerosis. Moreover, aldosterone acting by fast non-genomic mechanisms, may induce other potential deleterious effects on kidney function and structure. Indeed, many experimental studies have shown that aldosterone participates to the progression of kidney disease through hemodynamic and direct cellular actions and that antagonists of aldosterone may retard the progression of kidney disease, independently of effects on blood pressure. Therefore, blockade of the aldosterone pathway may prove to be a beneficial therapy for kidney disease. In this brief review we summarize the reported data that support an independent role of aldosterone in inducing kidney damage both in human and experimental models, and interventional studies that highlight how strategies aimed to antagonize its action may favorably modify the progressive decline of renal function in patient with kidney disease and in patients with extrarenal disease frequently associated with kidney function impairment. PMID- 26049734 TI - Safety and efficacy of intraurethral alprostadil in patients with erectile dysfunction refractory to treatment using phosphodiesterase-5 inhibitors. AB - INTRODUCTION: Phosphodiesterase-5 inhibitors (PDE5i) are the first choice for treating erectile dysfunction (ED) but are not always effective. The aim of this study was to present our experience in treating patients with ED, refractory to treatment with PDE5i, using intraurethral alprostadil (MUSE). MATERIAL AND METHODS: We conducted a review of 82 patients with ED and no response to PDE5i, from March 2013 to October 2014. Forty-seven patients (57%) had hypertension (AHT), 24 (29%) had diabetes (DM) and 20 (24%) had AHT and DM. Additionally, 19 (23%) had undergone radical prostatic (RP) surgery. The patients were evaluated after the treatment was applied and at 4 weeks using the following validated questionnaires: International Index of Erectile Function (IIEF-5/SHIM), Global Assessment Questionnaire (GAQ), Sexual Encounter Profile (SEP) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS). RESULTS: The mean patient age was 60.5 years (40-80), and the mean follow-up was 11.3 months (1 20). Sixty-eight percent of the treated patients responded to MUSE((r)) (74% in the AHT group, 65% in the AHT+DM group, 62.5% in the DM group and 58% in the RP group). The mean IIEF-5 score was 11.7+/-4.7, which increased to 18.6+/-4.9 after MUSE was administered (P=.027). The mean EDITS score at 4 weeks was 61.6 (6 81.9). The most common adverse effect was urethral burning, which occurred in 24 patients (29%). There were no cases of urinary tract infection, syncope or priapism. CONCLUSIONS: Intraurethral alprostadil is an effective treatment and has a broad safety profile for treating patients with erectile dysfunction refractory to oral treatment with PDE5i. PMID- 26049735 TI - Laparoscopic transplantation of metanephroi: A first step to kidney xenotransplantation. AB - BACKGROUND: Embryonic kidney xenotransplantation could represent a new solution to the scarcity of kidneys for transplantation. OBJECTIVE: To determine the feasibility of allogeneic laparoscopic transplantation of metanephroi (M) in rabbits. MATERIAL AND METHOD: Microscopic dissection was conducted to obtain metanephroi from 14-day-old (24M), 15-day-old (20M) and 16-day-old (26M) embryos. Using single-port abdominal laparoscopy, a spinal needle was inserted percutaneously, through which the metanephroi were deposited (using an epidural catheter) close to a patent blood vessel in the retroperitoneal fat. Seventy metanephroi were transplanted to 18 rabbits. Three weeks later, the animals were examined through open surgery. We compared the embryonic maturity, the morphometric variables of the metanephroi and the development rate of the transplanted metanephroi. RESULTS: The lower time limit for the extraction of metanephroi from the rabbits was day 14. Three weeks after transplantation, only 3/24 14-day-old metanephroi grew at minimal expression (12.5%). In contrast, 10/20 (50%) 15-day-old and 12/26 (46.1%) 16-day-old metanephroi grew. These metanephroi had differentiated sufficiently for the glomeruli, proximal and distal tubules and collecting ducts to develop normally. We detected no relevant immunological changes in the peripheral blood. CONCLUSIONS: We have described for the first time in the literature the allogeneic laparoscopic transplantation of metanephroi from embryos as a feasible and noninvasive technique. The recipients did not require immunosuppression. PMID- 26049736 TI - Dearth of polymorphism associated with a sustained response to selection for flowering time in maize. AB - BACKGROUND: Long term selection experiments bring unique insights on the genetic architecture of quantitative traits and their evolvability. Indeed, they are utilized to (i) monitor changes in allele frequencies and assess the effects of genomic regions involved traits determinism; (ii) evaluate the role of standing variation versus new mutations during adaptation; (iii) investigate the contribution of non allelic interactions. Here we describe genetic and phenotypic evolution of two independent Divergent Selection Experiments (DSEs) for flowering time conducted during 16 years from two early maize inbred lines. RESULTS: Our experimental design uses selfing as the mating system and small population sizes, so that two independent families evolved within each population, Late and Early. Observed patterns are strikingly similar between the two DSEs. We observed a significant response to selection in both directions during the first 7 generations of selection. Within Early families, the response is linear through 16 generations, consistent with the maintenance of genetic variance. Within Late families and despite maintenance of significant genetic variation across 17 generations, the response to selection reached a plateau after 7 generations. This plateau is likely caused by physiological limits. Residual heterozygosity in the initial inbreds can partly explain the observed responses as evidenced by 42 markers derived from both Methyl-Sensitive Amplification- and Amplified Fragment Length- Polymorphisms. Among the 42, a subset of 13 markers most of which are in high linkage disequilibrium, display a strong association with flowering time variation. Their fast fixation throughout DSEs' pedigrees results in strong genetic differentiation between populations and families. CONCLUSIONS: Our results reveal a paradox between the sustainability of the response to selection and the associated dearth of polymorphisms. Among other hypotheses, we discuss the maintenance of heritable variation by few mutations with strong epistatic interactions whose effects are modified by continuous changes of the genetic background through time. PMID- 26049738 TI - The Silence in Hoch et al.'s Commentary about the Rationale for and Objective(s) of Canada's Separate HTA Process for Cancer Drugs: The Importance of Transparency and Accountability when Allocating Taxpayers' Dollars. PMID- 26049737 TI - Predictors for uptake of intermittent preventive treatment of malaria in pregnancy (IPTp) in Tanzania. AB - BACKGROUND: Tanzania adopted Intermittent-preventive treatment of malaria in pregnancy (IPTp) policy in 2000; the guidelines at the time of the study recommended the timing of the first dose of intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) (IPTp-SP) at 20-24 weeks and the timing of the second dose at 28-32 weeks. The aim of this study was to identify factors that are responsible for the uptake of IPTp among pregnant Tanzanian women. Further, this study aims to justify the need for appropriate interventions that would strengthen the Tanzanian IPTp program towards the realization of the Roll Back Malaria (RBM) targets. METHODS: Data were analyzed from the 2011-2012 Tanzania HIV and Malaria Indicators Survey (THMIS) of 1,616 women aged 15-49 years who had a live birth in the 2 years prior to the survey and received antenatal care (ANC) services. RESULTS: Logistic regression analysis results showed that (1) being in the age groups 30-34 and 35-39 versus other age groups and being married or living with partner versus those who reported as never married or divorced/separated were associated with high uptake of IPTp; (2) women pregnant with their first or second child versus those who already have had two or more children had higher odds of completing the recommended number of IPTp dosage; and (3) being a resident from the Eastern Zone versus Lake Zone as well as having the first antenatal visit in the first or second trimester versus third trimester were associated with higher uptake of IPTp. CONCLUSION: Applying these results could contribute to positive social change by helping providers, clinics, and organizations seeking to increase IPTp uptake among ANC attendees and providing health education programs to women, especially those residing in rural areas. This study could also help achieve United Nations Millennium Development Goals (MDG) 6 (combat HIV/AIDS, Malaria and Other Diseases). PMID- 26049739 TI - Retrograde puncture assisted hepatic vein recanalization in treating Budd-Chiari syndrome with segmental obstruction of hepatic vein. AB - PURPOSE: This study aimed at investigating the feasibility and effectiveness of retrograde puncture assisted hepatic vein (HV) recanalization in management of Budd-Chiari syndrome (BCS) patients with segmental obstruction of HV. MATERIALS AND METHODS: From May 2011 to August 2014, 76 BCS patients with obstruction of HV were treated by routine transjugular HV recanalization in our center. Among them, 17 patients with segmental obstruction (obstruction length >1 cm) of HV experienced failure of the routine transjugular HV recanalization and underwent retrograde puncture assisted HV recanalization. Data on technical success, clinical success and follow-up were collected and analyzed retrospectively. RESULTS: Retrograde puncture assisted HV recanalization was technically successful in 14 of 17 (82 %) patients. Of these 14 patients, 12 patients underwent HV balloon dilation, and 2 patients underwent HV stent insertion. No procedure-related complications occurred in any of our patient. Clinical success was achieved in all of the 14 patients who experienced technical success. The mean HV pressure decreased from 43.6 +/- 6.7 cmH2O before treatment to 18.4 +/- 4.8 cmH2O after treatment (P < 0.001). BCS-related symptoms began to improve on the next day following the treatment. During 4-43 months (mean 17.4 +/- 10.8 months) of follow-up, three patients experienced re-obstruction of HV. CONCLUSIONS: Retrograde puncture assisted HV recanalization is a simple, safe, and effective treatment for BCS patients with segmental obstruction of HV. It can serve as an additional treatment option for patients who experience the technical failure of routine transjugular HV recanalization. PMID- 26049740 TI - Streptococcus pneumoniae oropharyngeal colonization in children and adolescents with cystic fibrosis. AB - BACKGROUND: This study was designed to evaluate Streptococcus pneumoniae (S. pneumoniae) carriage rates in patients with cystic fibrosis (CF). METHODS: An oropharyngeal swab was obtained from 212 CF children and adolescents enrolled during routine clinical visits. DNA from swabs was analyzed by real-time polymerase chain reaction. RESULTS: A total of 42 (19.8%) CF patients (mean age+/ standard deviation [SD], 12.0+/-3.3years) were colonized by S. pneumoniae. Carriage was more common in younger patients and tended to decline with age. Administration of systemic and/or inhaled antibiotics in the last 3months significantly correlated with a reduced carrier state [odds ratio (OR) 0.23, 95% confidence interval (CI) 0.07-0.69, and OR 0.26, 95% CI 0.08-0.77, respectively]. Vitamin D serum levels >=30ng/mL were less common in carriers than that in non carriers (OR 0.35; 95% CI 0.08-1.49). In both the vaccinated and unvaccinated subjects, serotypes 19F, 5, 4, and 9V were the most commonly carried serotypes. CONCLUSIONS: S. pneumoniae carrier state of school-age children and adolescents with CF is more prevalent than previously thought, and pneumococcal conjugate vaccination administered in the first year of life does not reduce the risk of re colonization in later childhood and adolescence. PMID- 26049742 TI - Status dissociatus and disturbed dreaming in a patient with Morvan syndrome plus myasthenia gravis. PMID- 26049741 TI - Recognition of and recent issues in hereditary diffuse gastric cancer. AB - In East Asian countries, gastric cancer incidence is high, but detection rates for germline CDH1 mutations that cause hereditary diffuse gastric cancers (HDGCs) are low. Consequently, screens and genetic testing for HDGC are often considered unimportant. Since the first germline truncating CDH1 mutations in Japanese patients were reported, some HDGC cases have been reported, and some of these involve large germline rearrangements and de novo mutation of CDH1. New methods for mutation detection--such as multiplex ligation-dependent probe amplification, array comparative genomic hybridization, and exome sequencing--have become available, as have new experimental models, including novel gene-knockout mice and gastric organoids. Because of these advances, searches for candidate genes (e.g., CTNNA1, MAP3K6) and our understanding of HDGC pathogenesis have improved in recent years; moreover, there have been substantial changes in the field since the current HDGC consensus guidelines were released. This review focuses on recent issues and advances in the study of HDGC. For example, lobular breast cancer cases and de novo occurrences of DGC are unlikely to meet the existing criteria for genetic testing, but current evidence indicates that some such cases may be good candidates for genetic testing. It is important to recognize that HDGC is a syndrome and that lobular breast cancer can be the first manifestation of this syndrome. CDH1 testing, including analyses of large genomic rearrangements, should be recommended even in countries where few HDGC cases have been reported. PMID- 26049743 TI - Full-genome sequence of a novel myovirus, GF-2, infecting Edwardsiella tarda: comparison with other Edwardsiella myoviral genomes. AB - Edwardsiellosis, which is caused by Edwardsiella tarda, a Gram-negative bacterium, is one of the most serious infectious diseases in both marine and freshwater fish farms worldwide. Previously, we reported the complete genome sequences of three E. tarda-lytic bacteriophages (two podoviruses and a myovirus), which were isolated from fish tissues and fish-rearing seawater. Further genomic information regarding E. tarda phages is important for understanding phage-host interactions as well as for applications of the phages for the control of disease. Here, we report the complete genome sequence of a novel E. tarda phage (GF-2) of myovirus morphology (family Myoviridae), isolated from tissue homogenates of a cultured Japanese flounder (Paralichthys olivaceus) that succumbed to edwardsiellosis in Japan. The size of the entire genome was 43,129 bp, with a GC content of 51.3 % and containing 82 open reading frames (ORFs). The GF-2 genome possesses lysogeny-related genes that have not been found in the reported Edwardsiella phage genomes. Comparative genomics of Edwardsiella myophages suggest that the C-terminal domains of the tail fiber proteins have relevance to their host specificity. Thus, GF-2 genome information provides a novel resource for our understanding of the molecular mechanisms involved in their host specificity and for detection of E. tarda in aquaculture environments. PMID- 26049744 TI - Staged resection of bilobar colorectal liver metastases: surgical strategies. AB - BACKGROUND: Radical resection is the treatment of choice for colorectal liver metastases (CLM). Unfortunately, only about 20 % of patients present with initially resectable disease, in most cases due to bilobar disease. In the last two decades, major achievements have been made to extend surgical indications to patients with bilobar CLM, such as two-stage hepatectomy with or without portal vein occlusion and associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). PURPOSE: The purpose of this review article was to summarize current surgical approaches and their safety and efficacy for patients with initially unresectable bilobar CLM. CONCLUSION: In selected patients, two stage hepatectomy and ALPPS are efficient and safe to convert unresectable to resectable CLM. Further studies are required to evaluate long-term outcome of these procedures. PMID- 26049745 TI - Laparoscopic augmentation of the diaphragmatic hiatus with biologic mesh versus suture repair: a systematic review and meta-analysis. AB - PURPOSE: Laparoscopic repair of large hiatal hernias is associated with high recurrence rates. Erosion and mesh migration are rare but devastating complications of synthetic mesh repair, whereas reoperation is accompanied by significant operative morbidity. The aim of this study was to estimate the comparative risk of hernia recurrence following primary suture or biologic mesh repair. METHODS: A systematic literature search of the MEDLINE database was performed and comparative data of relevant studies were combined using the Mantel Haenszel meta-analysis model. The odds ratio (OR) for hernia recurrence with 95 % confidence interval (CI) was calculated. RESULTS: Five relevant studies (two randomized controlled trials and three case-control studies) and one follow-up report of a randomized trial, encompassing 295 patients, were identified. Small intestine submucosa and human acellular cadaveric dermis were used as mesh grafts. Short-term recurrence rates were 16.6 and 3.5 % for suture repair and biologic mesh repair, respectively (OR 3.74, 95 % CI 1.55-8.98, p = 0.003). Long term recurrence based on data provided by one trial only was 51.3 and 42.4 %, respectively (OR 1.43, 95 % CI 0.56-3.63, p = 0.45). Sensitivity analysis of the two randomized trials at short-term follow up demonstrated no significant difference (OR 2.54, 95 % CI 0.92-7.02, p = 0.07). CONCLUSIONS: Biologic mesh repair of large hiatal hernias may confer short-term benefits in terms of hernia recurrence; however, the limited available information does not allow us to make conclusions about the long-term efficacy of biologic mesh in this setting. Individual biologic mesh grafts require further clinical assessment. PMID- 26049747 TI - Role of epigenetic reprogramming in hematopoietic stem cell function. AB - PURPOSE OF REVIEW: Epigenetic regulatory networks determine the fate of dividing hematopoietic stem cells (HSCs). Prior attempts at the ex-vivo expansion of transplantable human HSCs have led to the depletion or at best maintenance of the numbers of HSCs because of the epigenetic events that silence the HSC gene expression pattern. The purpose of this review is to outline the recent efforts to use small molecules to reprogram cultured CD34 cells so as to expand their numbers. RECENT FINDINGS: Chromatin-modifying agents (CMAs) reactivate the gene expression patterns of HSCs that have been silenced as they divide ex vivo. Increasing evidence indicates that CMAs act not only by promoting HSC symmetrical self-renewal divisions, but also by reprogramming progenitor cells, resulting in greater numbers of HSCs. The use of such CMAs for these purposes has not resulted in malignant transformation of the ex-vivo treated cell product. SUMMARY: The silencing of the gene-expression program that determines HSC function after ex vivo culture can be reversed by reprogramming the progeny of dividing HSCs with transient exposure to CMAs. The successful implementation of this approach provides a strategy which might lead to the development of a clinically relevant means of manufacturing increased numbers of HSCs. PMID- 26049746 TI - The importance of hypoxia and extra physiologic oxygen shock/stress for collection and processing of stem and progenitor cells to understand true physiology/pathology of these cells ex vivo. AB - PURPOSE OF REVIEW: Hematopoietic stem (HSCs) and progenitor (HPCs) cells reside in a hypoxic (lowered oxygen tension) environment, in vivo. We review literature on growth of HSCs and HPCs under hypoxic and normoxic (ambient air) conditions with a focus on our recent work demonstrating the detrimental effects of collecting and processing cells in ambient air through a phenomenon termed extra physiologic oxygen shock/stress (EPHOSS), and we describe means to counteract EPHOSS for enhanced collection of HSCs. RECENT FINDINGS: Collection and processing of bone marrow and cord blood cells in ambient air cause rapid differentiation and loss of HSCs, with increases in HPCs. This apparently irreversible EPHOSS phenomenon results from increased mitochondrial reactive oxygen species, mediated by a p53-cyclophilin D-mitochondrial permeability transition pore axis, and involves hypoxia inducing factor-1alpha and micro-RNA 210. EPHOSS can be mitigated by collecting and processing cells in lowered (3%) oxygen, or in ambient air in the presence of, cyclosporine A which effects the mitochondrial permeability transition pore, resulting in increased HSC collections. SUMMARY: Our recent findings may be advantageous for HSC collection for hematopoietic cell transplantation, and likely for enhanced collection of other stem cell types. EPHOSS should be considered when ex-vivo cell analysis is utilized for personalized medicine, as metabolism of cells and their response to targeted drug treatment ex vivo may not mimic what occurs in vivo. PMID- 26049748 TI - Regulation of stress-induced hematopoiesis. AB - PURPOSE OF REVIEW: Hematopoietic stem cells can self-renew and also give rise to the entire repertoire of hematopoietic cells. During acute infectious and inflammatory stresses, the hematopoietic system can quickly adapt to demand by increasing output of innate immune cells many-fold, often at the expense of lymphopoiesis and erythropoiesis. We review recent advances in understanding the regulation of stress-induced hematopoiesis with a specific focus on the direct effects of inflammatory signaling on hematopoietic stem and progenitor cells (HSPCs). RECENT FINDINGS: Recent studies have highlighted several areas of exciting new developments in the field, including the complex interaction and crosstalk within HSPCs and between bone marrow mesenchymal stem cells and endothelial cells needed to achieve regulated myelopoiesis, identification of increased number of inflammatory and infectious molecules with direct effects on HSPCs, the critical role of inflammatory signaling on embryonic specification of hematopoietic stem cells, and the ability of cytokines to instruct lineage choice at the HSPC level. SUMMARY: These exciting new findings will shape our fundamental understanding of how inflammatory signaling regulates hematopoiesis in health and disease, and facilitate the development of potential interventions to treat hematologic diseases associated with altered inflammatory signaling. PMID- 26049749 TI - Fight or flight: regulation of emergency hematopoiesis by pyroptosis and necroptosis. AB - PURPOSE OF REVIEW: A feature of the innate immune response that is conserved across kingdoms is the induction of cell death. In this review, we discuss the direct and indirect effects of increased inflammatory cell death, including pyroptosis - a caspase-1-dependent cell death - and necroptosis - a receptor interacting protein kinase 3/mixed lineage kinase domain-like protein-dependent, caspase-independent cell death - on emergency hematopoiesis. RECENT FINDINGS: Activation of nonapoptotic cell death pathways during infection can trigger release of cytokines and/or damage-associated molecular patterns such as interleukin (IL)-1alpha, IL-1beta, IL-18, IL-33, high-mobility group protein B1, and mitochondrial DNA to promote emergency hematopoiesis. During systemic infection, pyroptosis and necroptosis can directly kill hematopoietic stem and progenitor cells, which results in impaired hematopoiesis, cytopenia, and immunosuppression. Although originally described as discrete entities, there now appear to be more intimate connections between the nonapoptotic and death receptor signaling pathways. SUMMARY: The choice to undergo pyroptotic and necroptotic cell death constitutes a rapid response system serving to eliminate infected cells, including hematopoietic stem and progenitor cells. This system has the potential to be detrimental to emergency hematopoiesis during severe infection. We discuss the potential of pharmacological intervention for the pyroptosis and necroptosis pathways that may be beneficial during periods of infection and emergency hematopoiesis. PMID- 26049750 TI - Role of the mammalian target of rapamycin pathway in lentiviral vector transduction of hematopoietic stem cells. AB - PURPOSE OF REVIEW: A major goal in repopulating hematopoietic stem cell (HSC) gene therapies is achieving high-efficacy gene transfer, while maintaining robust HSC engraftment and differentiation in vivo. Recent studies have documented that rapamycin treatment of HSC during lentiviral vector transduction enhances gene transfer to human and mouse HSCs and maintains engraftment capacity. In this review, we place into context the role of mammalian target of rapamycin (mTOR) pathways in HSC quiescence and function, endocytic regulation, and lentiviral gene delivery. RECENT FINDINGS: Lentiviral vector transduction of human and mouse HSCs is considerably enhanced by rapamycin treatment. Furthermore, rapamycin preserves long-term engraftment of human and mouse HSCs. Investigations of cellular mechanisms that contribute to increased transduction in HSCs uncover a role for mTOR inhibition-dependent activation of endocytosis. SUMMARY: Rapamycin enhances lentiviral vector transduction of HSCs through regulation of endocytic activity via mTOR inhibition. An important attribute of rapamycin treatment during transduction is the preservation of HSC function, allowing reconstitution of long-term hematopoiesis in vivo in murine models. PMID- 26049751 TI - Small molecule regulation of normal and leukemic stem cells. AB - PURPOSE OF REVIEW: Hematopoietic stem and progenitor cell (HSPC) transplantation is frequently used in the treatment of hematological diseases. The outcome of the procedure is strongly influenced by the quantity of injected cells, especially if low cell numbers are infused as frequently encountered with cord blood transplants. Ex-vivo expansion of cord blood HSPCs would increase cell numbers, thus accelerating engraftment and reducing infectious complications and transplant-related mortality. In addition, expansion would maximize accessibility to better HLA-matched units, further improving patients' outcome. Similarly, in vitro maintenance or expansion of leukemic stem cells (LSCs) would enable research into the much awaited targeted therapies that spare normal hematopoietic stem cells (HSCs). Here, we review recent findings on small molecules (excluding biologicals) regulating the activity of normal and leukemic stem cells and provide insights into basic science and clinical implications. RECENT FINDINGS: High-throughput screening of small molecules active on primary hematopoietic cells has led to the identification of two potent series of chemical compounds, best exemplified by StemRegenin1 and UM171, that both expand HSPCs. Current data suggest that the aryl hydrocarbon receptor antagonist StemRegenin1 is most active on primitive normal hematopoietic progenitors and LSCs and that UM171 expands long-term normal HSCs. SUMMARY: Small molecules are clinically useful and powerful tools for expanding HSPCs. They are also of potential value for dissecting the still elusive regulatory networks that govern self-renewal of human HSCs. PMID- 26049752 TI - Progress and obstacles towards generating hematopoietic stem cells from pluripotent stem cells. AB - PURPOSE OF REVIEW: Human pluripotent stem cells (PSCs) have the potential to provide an inexhaustible source of hematopoietic stem cells (HSCs) that could be used in disease modeling and in clinical applications such as transplantation. Although the goal of deriving definitive HSCs from PSCs has not been achieved, recent studies indicate that progress is being made. This review will provide information on the current status of deriving HSCs from PSCs, and will highlight existing challenges and obstacles. RECENT FINDINGS: Recent strides in HSC generation from PSCs has included derivation of developmental intermediates, identification of transcription factors and small molecules that support hematopoietic derivation, and the development of strategies to recapitulate niche like conditions. SUMMARY: Despite considerable progress in defining the molecular events driving derivation of hematopoietic progenitor cells from PSCs, the generation of robust transplantable HSCs from PSCs remains elusive. We propose that this goal can be facilitated by better understanding of the regulatory pathways governing HSC identity, development of HSC supportive conditions, and examining the marrow homing properties of PSC-derived HSCs. PMID- 26049754 TI - The critical and specific transcriptional regulator of the microenvironmental niche for hematopoietic stem and progenitor cells. AB - PURPOSE OF REVIEW: It has been assumed that the special microenvironments known as niches in the marrow play an essential role in maintaining hematopoietic stem and progenitor cells (HSPCs), and the identity of the HSPC niche has been a subject of long-standing debate. Recent studies identified cells, which create microenvironments meeting the criteria for HSPC niches and the critical transcriptional regulators of their development and maintenance. RECENT FINDINGS: Osterix as well as Ebf2 and Bmi1 are critical but not specific transcriptional regulators of HSPC niche development. The transcription factor Foxc1 is expressed preferentially in a population of adipo-osteogenic progenitors, termed CXCL12 abundant reticular (CAR) cells, which create HSPC niches and are largely equivalent to stem cell factor and Lepr-expressing cells, in developing and adult bone marrow. Foxc1 is essential for CAR cell development and maintenance of bone marrow niches for HSPCs upregulating CXCL12 and SCF expression and inhibition of adipogenic processes in CAR cell progenitors. SUMMARY: Foxc1 is the first critical and specific transcriptional regulator that is required for development and maintenance of cells creating HSPC niches, including a specialized population of adipo-osteogenic progenitors in bone marrow. PMID- 26049753 TI - Role of SIRT1 in the growth and regulation of normal hematopoietic and leukemia stem cells. AB - PURPOSE OF REVIEW: Recent studies have enhanced our understanding of the role of the SIRT1 deacetylase in regulation of normal hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), and its importance in regulating autophagy and epigenetic reprogramming in response to metabolic alterations. RECENT FINDINGS: Studies employing conditional deletion mouse models indicate an important role of SIRT1 in maintenance of adult HSCs under conditions of stress. SIRT1 is significantly overexpressed in LSC populations from acute myeloid leukemia (AML) patients with the FLT3-ITD mutation, and maintains their survival, growth and drug resistance, as previously described for chronic myelogenous leukemia (CML). SIRT1 can also enhance leukemia evolution and drug resistance by promoting genetic instability. Recent studies indicate an important role of SIRT1 in regulating autophagy in response to oxidative stress and nutrient requirements, and have elucidated complex mechanisms by which SIRT1 regulates epigenetic reprogramming of stem cells. SUMMARY: SIRT1 inhibition holds promise as a novel approach for ablation of LSCs in chronic phase CML or FLT3-ITD-associated AML. Additional studies to understand the role of SIRT1 in linking metabolic alterations to genomic stability, autophagy and epigenetic reprogramming of stem cells are warranted. PMID- 26049755 TI - Targeting immune checkpoints in lymphoma. AB - PURPOSE OF REVIEW: The purpose of this article is to discuss the tumor microenvironment in lymphoma, and to review potential immune targets that are now becoming relevant because of clinical responses seen with the use of immune checkpoint inhibitors. RECENT FINDINGS: Recent data have shown that cells within the immune microenvironment in lymphoma express programmed death ligand-1 (PD-L1) and many of the intratumoral T cells with an exhausted immune phenotype express programmed cell death-1 (PD-1). This provides a novel opportunity to inhibit the immune checkpoints and initial clinical trials utilizing antibodies that block the interaction between PD-1 and PD-L1 have demonstrated significant clinical responses in various lymphomas, including Hodgkin lymphoma. SUMMARY: The use of immune checkpoint inhibitors, including nivolumab and pembrolizumab, in relapsed and refractory patients with lymphoma is proving highly successful. Patients with Hodgkin lymphoma, in particular, have a very high response rate to PD-1 blockade and responses in these patients appear durable. PMID- 26049756 TI - Genomic alterations underlying immune privilege in malignant lymphomas. AB - PURPOSE OF REVIEW: Malignant lymphomas represent a remarkably heterogeneous group of cancers with respect to their oncogenome, phenotype and clinical presentation. Lymphoma cells benefit from limited immune surveillance and have developed various mechanisms to alter antitumor immune responses. This article summarizes our current knowledge about genomic alterations underlying acquired immune privilege in lymphoid cancers. RECENT FINDINGS: The implementation and broad application of next-generation sequencing techniques have significantly expanded our knowledge about genetic alterations and perturbed cellular pathways underlying lymphomagenesis. Based on key discoveries in the past decade, the purview of subsequent studies expanded beyond the biology of the lymphoma cells to include the pathogenic contribution of immune cells, stromal components and associated crosstalk between malignant and nonmalignant cells in the tumor microenvironment. A number of genetic mechanisms have been described that elucidate how lymphoma cells are selected for evading immune recognition and reprogramming immune responses. These prominently include structural genomic changes of the CIITA and programmed death ligand (CD274/PDCD1LG2) loci, alterations affecting antigen presentation and mutations in JAK-STAT and NFkappaB signaling pathways. SUMMARY: Further investigations will foster our understanding about synergy of immune escape mechanisms, and lay the foundation for the development of predictive biomarkers in the context of conceptually novel therapies targeting microenvironment-related biology, such as immunological checkpoint inhibition. PMID- 26049757 TI - Hairy cell leukemia: update and current therapeutic approach. AB - PURPOSE OF REVIEW: In this review, we discuss the pathogenesis and standard therapeutic approach to hairy cell leukaemia (HCL) as well as newer targeted therapies under investigation showing promising end-points in treating HCL. RECENT FINDINGS: HCL is an indolent B-cell leukaemia. Historically, HCL patients have achieved excellent response to purine nucleoside analogues and single purine analogue treatment with pentostatin or cladribine is currently the standard of care for initial treatment. Most patients achieve complete remission with this form of therapy. However, long-term follow-up has demonstrated that a large number of patients eventually develop relapsed disease. Relapse disease tends to be more difficult to treat and refractory to the same purine analogues. Development of relapsing and refractory disease after initially achieving complete remission with purine analogue treatment has generated a need for alternative therapies. SUMMARY: Identification of the BRAFV600E mutation in nearly 100% of HCL patients has provided rationale for inclusion of BRAF inhibitors into the therapeutic armamentarium to treat HCL. Clinical trials are currently underway measuring efficacy of vemurafenib in achieving clinical response in relapsed/refractory HCL and also toxicity. Other novel therapies with monoclonal and immunotoxin-conjugated antibodies have also shown promising response in recent investigational studies. PMID- 26049758 TI - LymphomiRs: microRNAs with regulatory roles in lymphomas. AB - PURPOSE OF REVIEW: This review provides current knowledge on the role of microRNAs (miRNAs) in lymphoma with an emphasis on mature B-cell lymphoma. RECENT FINDINGS: Although miRNAs were previously used to stratify lymphoma classification, prognosis, or treatment response, recent publications portray this class of small noncoding RNAs as critical players in the lymphomagenesis process. Although functional studies provide ample evidence for their role as lymphoma drivers or suppressors, genetic studies providing the underlying mechanisms for these phenotypes are still lacking. As more whole-genome sequencing of lymphoma cases become available, this gap may be soon filled. SUMMARY: Current findings highlight the potential role of miRNAs molecules as important factors in lymphomagenesis. PMID- 26049763 TI - Pneumothorax related to lung cysts and renal masses. PMID- 26049761 TI - Premalignant cell dynamics in indolent B-cell malignancies. AB - PURPOSE OF REVIEW: Follicular lymphoma and chronic lymphocytic leukemia (CLL) are indolent B-cell malignancies characterized by a long preclinical phase and frequent relapses once treatment is initiated. The present review gathers recent findings on the occurrence, relevance, and dynamics of premalignant cells in the development of follicular lymphoma and CLL. RECENT FINDINGS: The frequency of circulating cells bearing the follicular lymphoma hallmark translocation t(14;18) in healthy persons is correlated to the risk of developing follicular lymphoma later in life. Chronic B-cell receptor stimulation induces cyclic re-entries of BCL2 B cells into germinal centers that propagate clonal evolution and early follicular lymphoma progression. The lymph node microenvironment is a key activation/proliferation niche for malignant cells in CLL, also active in its preclinical antecedent monoclonal B-cell lymphocytosis. SUMMARY: Considering recent studies of premalignant cells in both diseases and of their putative normal cell counterparts, we propose different models of premalignant evolution for the two pathologies. Before overt follicular lymphoma, t(14;18) B cells exploit the dynamics of memory B cells to re-enter multiple times into local or distant germinal centers, gather activation/proliferation signals, and gain additional mutations to progress to malignant lymphoma. In monoclonal B-cell lymphocytosis, CLL-like activated/memory B cells follow cycles of germinal center independent activation/proliferation in lymph node. Finally, we discuss the next level genetic and functional analyses that should result in a better understanding of the origins and mechanisms of frequent relapses in follicular lymphoma and CLL. PMID- 26049759 TI - The role of aberrant proteolysis in lymphomagenesis. AB - PURPOSE OF REVIEW: Deregulated proteolysis is increasingly being implicated in pathogenesis of lymphoma. In this review, we highlight the major cellular processes that are affected by deregulated proteolysis of critical substrates that promote lymphoproliferative disorders. RECENT FINDINGS: Emerging evidence supports the role of aberrant proteolysis by the ubiquitin proteasome system (UPS) in lymphoproliferative disorders. Several UPS mediators are identified to be altered in lymphomagenesis. However, the precise role of their alteration and comprehensive knowledge of their target substrate critical for lymphomagenesis is far from complete. SUMMARY: Many E3 ligase and deubiquitinases that contribute to regulated proteolysis of substrates critical for major cellular processes are altered in various lineages of lymphoma. Understanding of the proteolytic regulatory mechanisms of these major cellular pathways may offer novel biomarkers and targets for lymphoma therapy. PMID- 26049764 TI - Immunomodulating effects of glatiramer acetate and its potential role in pulmonary tuberculosis reactivation. PMID- 26049760 TI - Unexpected functions of nuclear factor-kappaB during germinal center B-cell development: implications for lymphomagenesis. AB - PURPOSE OF REVIEW: B-cell tumors originating from the transformation of germinal center B cells frequently harbor genetic mutations, leading to constitutive activation of the nuclear factor-kappaB (NF-kappaB) signaling pathway. The present review highlights recent insights into the roles of separate NF-kappaB transcription factors in germinal center B-cell development and discusses implications of the results for germinal center lymphomagenesis. RECENT FINDINGS: Understanding how aberrant NF-kappaB activation promotes tumorigenesis requires the understanding of the role of NF-kappaB in the tumor-precursor cells. Despite extensive knowledge on NF-kappaB biology, the function of this complex signaling pathway in the differentiation of germinal center B cells is largely unknown. The present review will discuss recent findings that revealed distinct roles of separate NF-kappaB transcription factors during the germinal center reaction in the context of germinal center lymphomagenesis. Most notably, a single NF-kappaB subunit, c-REL, was found to be required for the maintenance of the germinal center reaction and was associated with the activation of a metabolic program that promotes cell growth. SUMMARY: Identifying the biological roles of the separate NF-kappaB transcription factor subunits in germinal center biology will help to better understand the pathogenic consequences of their constitutive activation in B-cell tumors. This knowledge may be exploited for the development of targeted antitumor therapies aimed at inhibiting selectively those components of aberrant NF-kappaB activity which contribute to pathogenesis. PMID- 26049765 TI - An unusual cause for hemoptysis. PMID- 26049766 TI - Enhanced biomass production, lipid yield and sedimentation efficiency by iron ion. AB - Effects of Fe(3+) on the biomass production, lipid accumulation of Monoraphidium sp. FXY-10 were investigated. Further residual Fe(3+) in the culture medium on the sedimentation efficiency have been also studied. The biomass and lipid productivity of microalgae exhibited an increasing tendency with the concentrations of iron ion augmenting. 150 MUM iron ion added into the culture medium result in highest DCW at 1.42 g L(-1) while the maximum lipid productivity of 10.71 mg L(-1) d(-1) were obtained at 50 MUM. The results showed that appropriate concentrations of iron ion was beneficial for biomass production and lipid accumulation but higher concentration of that will be more in favor of the sedimentation efficiency of Monoraphidium sp. FXY-10. PMID- 26049767 TI - Risks and benefits of UV radiation in older people: More of a friend than a foe? AB - Incident ultraviolet radiation from sunlight varies in intensity and spectrum with season and latitude and has both deleterious and beneficial effects on health in older people. Sunlight is the major preventable risk factor for skin cancer. Non-melanoma skin cancer is the commonest malignancy in a pale skinned older population, but the mortality is extremely low. Intermittent sun exposure is a risk factor for the more dangerous melanoma but chronic sun exposure and outdoor occupation may be protective. Public health advice has tended to concentrate on the dangers of sun exposure despite the absence of any data that increased sun exposure correlates with raised all-cause mortality. Inadequate sun exposure carries its own risks, and the older population are particularly sun deprived as recorded by low serum Vitamin D levels and lack of outdoor activity. Sunlight has health benefits dependently and independently of vitamin D synthesis. Low serum vitamin D levels correlate with increased morbidity and mortality but the direction of association is not always clear. Vitamin D has a causal role in calcium and phosphate metabolism, in skeletal health and probably reduction of colorectal cancer. Evidence is weak for a role in cardiovascular health, but mobilisation of nitric oxide by UVA radiation from nitrate stores in skin, with consequent reduction in BP, may account for the observed reduction in cardiovascular disease and all-cause mortality with increased sun exposure. Advice on healthy sun exposure needs to be reconsidered, with reduction in all cause mortality and morbidity as the primary end point. PMID- 26049768 TI - Headache and ADHD in Pediatric Age: Possible Physiopathological Links. AB - Primary headache and attention-deficit/hyperactivity disorder (ADHD) are common disorders in children and adolescences, frequently associated to severe cognitive, emotional, and behavioral impairments. They both are a disabling condition with consequences on family and child's quality of life. Literature data on their association are contrasting. Dopaminergic system dysfunction, brain iron deficiency, and sleep disturbance should be considered to better understand headache and ADHD overlap. In this review, we analyze the complex association between these two diseases and the potential impact on child neurodevelopment. PMID- 26049769 TI - Supratrochlear and Supraorbital Nerve Stimulation for Chronic Headache: a Review. AB - Chronic daily headache accounts for a significant socioeconomic burden due to decreased productivity, work absenteeism, multiple office and ER visits, and hospital admissions for pain control. Associated comorbidities add to this cost. Current traditional medical therapies may fail to provide adequate relief leading to the search for and use of other therapeutic modalities such as innovative medical devices. It is in this setting of the urgent demand for better pain control and to assimilate chronic headache sufferers back into society that a variety of neuromodulatory approaches have been emerging. This review aims to familiarize the reader with current literature regarding supraorbital and supratrochlear nerve stimulation for chronic headache, point out the advantages of this approach, address unanswered questions about this subject, and highlight future directions. PMID- 26049770 TI - What the Gut Can Teach Us About Migraine. AB - During gestation, cells of the brain and gut develop almost simultaneously into the central nervous system (CNS) and enteric nervous system (ENS), respectively. They remain connected via the vagal nerve lifelong. While it is well known that the brain sends signal to the gut, communication is in fact bidirectional. Just as the brain can modulate gut functioning, the gut, and likely what we ingest, can in fact influence our brain functioning. We will first review both gastrointestinal (GI) function and migraine pathophysiology and then discuss evidence linking the migraine brain to various GI disorders. Lastly, we discuss the effects of gut microbiota on brain functioning and speculate how the gut and particularly diet may affect migraine. PMID- 26049771 TI - Headache and Dizziness: How to Differentiate Vestibular Migraine from Other Conditions. AB - Headache and dizziness are two of the most common symptoms prompting medical evaluation and may be seen in many primary and secondary headache and dizziness syndromes. Many of these disease processes share common characteristics making determination of the diagnosis extremely challenging. As more is understood about the concurrence of these symptoms, new diagnostic considerations have emerged, and the beta version of the latest edition of the International Classification of Headache Disorders describes a new entity termed vestibular migraine that may affect many patients presenting with headache and dizziness. This article examines the epidemiology of headache and dizziness, describes the presenting features of patients with conditions which often express these two symptoms, discusses recommendations for evaluation and testing for these patients, and serves to aid in the differentiation between vestibular migraine and other potential diagnoses. PMID- 26049772 TI - Myofascial Head Pain. AB - Muscle nociception is mainly characterized by local tenderness and referred pain. The neurophysiological basis of muscle pain supports a role of sensitization mechanisms. From a clinical viewpoint, muscle pain is represented by the presence of myofascial trigger points (TrPs). Evidence suggests that TrPs are able to start a peripheral nociceptive mechanism and hence contributing to changes in the central nervous system. Several studies demonstrated that the referred pain elicited by TrPs reproduces the headache pattern in patients with tension-type headache (TTH), migraine, cervicogenic headache and, in some individuals, with cluster headache. In fact, sensitization of nociceptive pain pathways in the central nervous system due to prolonged nociceptive stimuli from TrPs seems to be responsible for the conversion of episodic to chronic TTH. In other headaches, TrPs may be able to stimulate the trigeminal nucleus caudalis and hence triggering a migraine or cluster headache attack. Proper treatment directed towards TrP inactivation has documented positive effects in individuals with these headaches; however, longitudinal studies are needed to further determine the role of TrPs in head pain. PMID- 26049773 TI - Deep Brain Stimulation for Chronic Pain. AB - Deep brain stimulation (DBS) is a commonly performed procedure and has been used for the treatment of chronic pain since the early 1970s. A review of the literature was performed utilizing the PubMed database evaluating the use of DBS in the treatment of various pain syndromes. Literature over the last 30 years was included with a focus on those articles in the last 10 years dealing with pain conditions with the highest success as well as the targets utilized for treatment. DBS carries favorable results for the treatment of chronic pain, especially when other methods have not been successful such as medications, conservative measures, and extracranial procedures. Various chronic pain conditions reported in the literature respond to DBS including failed back surgery syndrome (FBSS), phantom limb pain, and peripheral neuropathic pain with a higher response rate for those with nociceptive pain compared to neuropathic pain. Cephaligias have promising results, with cluster headaches carrying the best success rates. DBS plays a role in the treatment of chronic pain conditions. Although considered investigational in the USA, it carries promising success rates in a recalcitrant patient population. PMID- 26049774 TI - Headache in Drug-Induced Aseptic Meningitis. AB - Drug-associated headache is a quite common phenomenon, e.g. as a side effect of distinct substances such as nitric oxide or as a result of medication overuse of analgesic drugs. A different drug-associated headache entity is headache in drug induced aseptic meningitis (DIAM). This is a rare disorder and only described in few case reports or smaller case series. One of the main clinical features of DIAM despite fever is headache. Based on the literature, no typical or even pathognomonical clinical presentation of this headache entity can be described. Sometimes, migrainous features might be present, and treatment response to triptans was reported in single case reports. Headache in DIAM seems to be emerging from sterile meningeal inflammation, which is suggested to represent the underlying pathology in DIAM. Headache in DIAM usually ceases when treated sufficiently, mainly through termination or withdrawal of the causing agent. Migraine as a predisposing factor of DIAM has been discussed previously but remains unproven. PMID- 26049775 TI - Update on the Epidemiology of Concussion/Mild Traumatic Brain Injury. AB - Mild traumatic injuries to the brain (e.g., concussion) are common and have been recognized since antiquity, although definitions have varied historically. Nonetheless, studying the epidemiology of concussion helps clarify the overall importance, risk factors, and at-risk populations for this injury. The present review will focus on recent findings related to the epidemiology of concussion including definition controversies, incidence, and patterns in the population overall and in the military and athlete populations specifically. Finally, as this is an area of active research, we will discuss how future epidemiologic observations hold promise for gaining greater clarity about concussion and mild traumatic brain injury. PMID- 26049776 TI - Neuroimaging in Secondary Headache Disorders. AB - A secondary headache may develop de novo or in patients with a history of primary headaches, and a thorough history and neurological exam often helps to suspect a secondary etiology. The causes of secondary headaches include tumors, vascular etiologies, structural brain disorders, infection, inflammation, and alterations of cerebrospinal fluid pressure dynamics. Computed tomography (CT) is very sensitive for detecting acute hemorrhage but magnetic resonance imaging (MRI) is preferred over a head CT in subacute and non-emergent cases. Obtaining the correct diagnosis may include incorporation of intravenous contrast agents, special imaging sequences, and functional imaging techniques. PMID- 26049777 TI - Low high-sensitivity troponin I and zero coronary artery calcium score identifies coronary CT angiography candidates in whom further testing could be avoided. AB - RATIONALE AND OBJECTIVES: Pilot study to determine whether among subjects receiving coronary computed tomography angiography (CTA), the combination of high sensitivity troponin I (hsTnI) and coronary artery calcium score (CACS) identifies a low-risk population in whom CTA might be avoided. MATERIALS AND METHODS: A cross-sectional study of 314 symptomatic patients receiving CTA as part of their acute coronary syndrome evaluation was conducted. hsTnI was measured with Abbott Laboratories' hsTnI assay. CACSs were calculated via the Agatston method. Patients were followed for at least 30 days after discharge for the occurrence of major adverse cardiac events (MACEs; all-cause mortality, acute coronary syndrome, and revascularization). RESULTS: Of 314 subjects studied, 213 (67.8%) had no coronary artery stenosis, and 67 (21.3%), 28 (8.9%), and 6 (1.9%) had maximal coronary artery stenosis of 1%-49%, 50%-69%, and 70% or greater, respectively. All MACEs occurred during index hospitalization and include one myocardial infarction and four revascularizations. Sixty-two percent (189/307) of subjects had zero CACS, and 24% (76/314) of subjects had undetected hsTnI. No subjects with undetectable hsTnI or zero CACS had an MACE. A strategy of avoiding further testing in subjects with undetectable initial hsTnI, performing CACS on subjects with detectable initial hsTnI but nonincreased hsTnI (less than 99th percentile), and obtaining CTA in subjects with Agatston greater than 0 will have a negative predictive value of 100.0% (95% confidence interval, 98.2%-100.0%). This strategy will avoid CTA in 63% (198/314) of subjects. CONCLUSIONS: In this pilot study, the addition of CACS to hsTnI improves the identification of low risk subjects in whom CTA might be avoided. PMID- 26049778 TI - Investigation of polycyclic aromatic hydrocarbons (PAHs) and cyclic terpenoid biomarkers in the sediments of fishing harbors in Taiwan. AB - Three fishing harbors were investigated to study the polycyclic aromatic hydrocarbons in the sediments and trace possible anthropogenic sources by identification of cyclic terpenoid biomarkers. Seventeen terpanes, 10 steranes and 10 bicyclic sesquiterpanes in the marine diesel and the three kinds of lubricants that are mainly used by fishing boats were identified and quantified. Eighteen biomarker diagnostic ratios are suggested and the correlation coefficients among the lubricants and sediment samples have the R(2) value greater than 0.73. Analyzed 16 PAHs in the sediment shows non-normal distributions and the Kruskal Wallis Test shows the significant differences (p value smaller than 0.05) with the greatest variability in benzo[g,h,i]perylene which more than 84% of the effective size (E.S.) is accounted. X-ray Photoelectron Spectroscopy (XPS) analysis was applied and the Kruskal Wallis Test shows a significant difference (p value smaller than 0.05) among certain atoms with the effective size greater than 60%. PMID- 26049779 TI - The Local and Systemic Actions of Duloxetine in Allodynia and Hyperalgesia Using a Rat Skin Incision Pain Model. AB - BACKGROUND: Duloxetine is an antidepressant effective for major depressive disorder and also the alleviation of pain for patients with diabetic peripheral neuropathy, chronic musculoskeletal pain, and fibromyalgia. How duloxetine works in pain relief remains unknown. In this study, we address whether duloxetine could act as an analgesic via systemic and local applications. METHODS: Efficacies of bupivacaine and duloxetine applied subcutaneously at the incision site against acute postoperative pain were compared after rat skin incision. Contralateral and intraperitoneal injections were used to assess systemic efficacy of duloxetine. Local anesthetic actions were assayed through functional block of the rat sciatic nerve. Inhibition by duloxetine of neuronal Na channels was characterized in rat GH3 cells. RESULTS: Our studies showed that subcutaneous duloxetine (2 mg) reduced hyperalgesia and allodynia for several days after skin incision, whereas subcutaneous bupivacaine (2 mg) did not. Contralaterally injected duloxetine (10 mg) had minimal effects on postoperative pain. Intraperitoneal duloxetine also reduced both allodynia and hyperalgesia, albeit at higher doses (10-20 mg). Duloxetine (2 mg) inhibited motor and nociceptive functions via sciatic nerve block for approximately 24 hours. It also reduced Na currents with 50% inhibitory concentrations of 30.4 +/- 1.2 MUM and 4.26 +/- 0.19 MUM (n = 8) for resting and fast-inactivated channels, respectively. Furthermore, duloxetine (10 MUM) elicited additional use-dependent block of peak Na currents by approximately 70% when stimulated at 5 Hz. CONCLUSIONS: Our results demonstrate that duloxetine can act as a local anesthetic and an analgesic drug via both local and systemic applications. Because duloxetine inhibits neuronal Na currents with high potency, it may exert its antihyperalgesic effects through inhibition of the spontaneous nerve impulses that result from peripheral injury, encompassing its actions on multiple central nervous system and peripheral targets. PMID- 26049780 TI - Quantification of Fibrinolysis Using Velocity Curves Measured with Thromboelastometry in Children with Congenital Heart Disease. AB - BACKGROUND: In this pilot study, we hypothesized that velocity parameters obtained from changes in clot amplitude (A) and clot elasticity (E) measured with thromboelastometry (ROTEM, Tem International GmbH, Munich, Germany) could improve detection of fibrinolysis in whole blood obtained from children undergoing surgery for congenital heart disease. METHODS: Whole blood samples were obtained after induction of general anesthesia. Seven conditions were studied: native whole blood (baseline) and samples with progressive tissue-type plasminogen activator (t-PA) concentrations (102, 255, 512, 1024, 1535, and 2539 units/mL). We calculated velocity curves based on changes in clot amplitude and elasticity between different time points using ROTEM data. The analysis allowed for the determination of the following parameters: the maximum rate of thrombus formation based on amplitude or elasticity and the maximum rate of thrombus lysis measured based on amplitude (MTL) or maximum rate of thrombus lysis measured based on elasticity (MTLe). We compared these parameters with the lysis in relation to maximal clotting firmness and measured 30 minutes after the clotting time (LI30, in percent). RESULTS: Concentrations of t-PA >= 255 units/mL resulted in a decrease in LI30 (mean difference, 255 units/mL versus baseline, -31.05%, P < 0.0001) and the maximum rate of thrombus formation based on amplitude (mean difference, 255 units/mL versus baseline, -7.5, P = 0.005). Concentrations of t PA >= 512 units/mL resulted in changes in maximum rate of thrombus formation based on elasticity (mean difference, 512 units/mL versus baseline, -10.9, P = 0.010), MTL (mean difference, 255 units/mL versus baseline, -3.2, P = 0.016), and MTLe (mean difference, 255 units/mL versus baseline, -7.8, P = 0.004). For t-PA concentrations >= 512 units/mL, clot formation was abolished. The area under the receiver operating characteristics curves did not differ between LI30, MTL, and MTLe for the detection of minimal fibrinolytic activation (102 units/mL; 0.74, 0.75, and 0.72, respectively, P = 0.708), whereas sensitivity and specificity of the cutoff values 97% for LI30, -0.3 for MTL, and -0.5 for MTLe were 52% and 85%, 83% and 45%, and 83% and 45%, respectively. CONCLUSIONS: Velocity curves based on the amplitudes or clot elasticity could provide objective measurement of clot growth and clot lysis kinetics, allowing detection of even minor fibrinolysis. Further studies are needed to assess the clinical relevance of these parameters. PMID- 26049781 TI - Swallowing Impairment During Propofol Target-Controlled Infusion. AB - BACKGROUND: Sedatives can impair the swallowing process. We assessed the incidence and severity of swallowing impairment in patients sedated with propofol at clinically relevant doses. We also identified factors that were predictive of swallowing impairment. METHODS: In 80 patients scheduled to undergo elective gastrointestinal endoscopy under target-controlled infusion (TCI) propofol sedation, swallowing was evaluated by glottis videoendoscopy, using the Dysphagia Severity Score (DSS) and the Penetration and Aspiration Scale (PAS). The level of sedation was assessed with the Observer's Assessment of Alertness/Sedation (OAAS) scale. Evaluations were obtained within each patient at 3 target effect-site propofol concentrations of 2, 3, and 4 MUg/mL (Marsh model). RESULTS: At 2 MUg/mL TCI, the OAAS score was 2 in 21 (26.25%) patients and 1 in 59 (73.75%). The OAAS score was 1 in all patients at 3 and 4 MUg/mL TCI target. At 3 MUg/mL TCI target, 19 (24.36%) patients had a DSS = 3 and 18 patients (23.08%) had a PAS = 7-8 (severe swallowing impairment). DSS was associated with increasing age (5-year odds ratio [OR] 1.53 [1.22-1.93]; P < 0.001), body mass index (BMI; OR 1.24 [1.08 1.42]; P = 0.002), and TCI target (OR 15.80 [7.76-32.20]; P < 0.001). In an alternative model incorporating OAAS instead of TCI target, DSS was associated with increasing age (5-year OR 1.13 [1.02-1.24]; P = 0.014) and BMI (OR 1.08 [1.02-1.15]; P = 0.006) and decreasing OAAS (OR 0.05 [0.006-0.36]; P = 0.003). PAS was associated with increasing age (5-year OR 1.09 [1.04-1.15]; P < 0.001), BMI (OR 1.23 [1.07-1.41]; P = 0.003), and TCI target (OR 15.23 [7.45-31.16]; P < 0.001). In an alternative model incorporating OAAS instead of TCI target, PAS was associated with increasing age (5-year OR 1.14 [1.04-1.26]; P = 0.007) and BMI (OR 1.09 [1.02-1.15]; P = 0.006) and decreasing OAAS (OR 0.05 [0.006-0.41]; P = 0.005). CONCLUSIONS: Aspiration due to swallowing impairment may occur during deep sedation produced by propofol at commonly used TCI targets. TCI targets are predictors of swallowing impairment; increased age and high BMI are concomitant risk factors. PMID- 26049782 TI - Distinctive Intestinal Lactobacillus Communities in 6-Month-Old Infants From Rural Malawi and Southwestern Finland. AB - OBJECTIVE: Our aim was to compare the composition and diversity of Lactobacillus microbiota in infants living in Malawi and Southwestern Finland. METHODS: The composition and diversity of the Lactobacillus group was analyzed in the feces of healthy 6-month-old infants living in rural Malawi (n = 44) and Southwestern Finland (n = 31), using the quantitative polymerase chain reaction method and PCR denaturing gradient gel electrophoresis fingerprinting. RESULTS: Malawian infants had higher counts of lactobacilli than their Finnish counterparts (7.45 log cells/g vs 6.86 log cells/g, P < 0.001, respectively) and the Lactobacillus community was richer and more diverse in the Malawian infants. Leuconostoc citreum and Weissella confusa were the predominant species in both study groups, but Malawian infants were more often colonized by these species (100% vs 74.2%, P < 0.001; 95.5% vs 41.9%, P < 0.001, respectively). Moreover, Lactobacillus ruminis, Lactobacillus gasseri, Lactobacillus acidophilus, and Lactobacillus mucosae were detected more often in the Malawian infants (59.1% vs 0.0%, P < 0.001; 38.6% vs 9.7%, P = 0.004; 29.5% vs 0.0%, P < 0.001; 22.7% vs 3.2%, P = 0.017, respectively). Lactobacillus casei group species, however, were only detected in the Finnish infants. CONCLUSIONS: Malawian infants have a more abundant Lactobacillus microbiota with a distinct composition compared with Finnish infants. The environment, including diet and hygiene, may be among the factors influencing these differences. PMID- 26049783 TI - Association Analysis of SLC6A20 Polymorphisms With Hirschsprung Disease. AB - PURPOSE: Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder, which is caused by no neuronal ganglion cells in part or all of distal gastrointestinal tract. Recently, our genome-wide association study has identified solute carrier family 6, proline IMINO transporter, member 20 (SLC6A20) as one of the potential risk factors for HSCR development. This study performed a replication study for the association of SLC6A20 polymorphisms with HSCR and an extended analysis to investigate further associations for subgroups and haplotypes. METHODS: For the replication study, a total of 40 single nucleotide polymorphisms (SNPs) of SLC6A20 were genotyped in 187 HSCR subjects composed of 121 short-segment HSCR, 45 long-segment HSCR (L-HSCR), 21 total colonic aganglionosis, and 283 unaffected controls. Imputation was performed using genotype data from our genome-wide association study and this replication study. RESULTS: Imputed meta-analysis revealed that 13 SLC6A20 SNPs (minimum P = 0.0002 at rs6770261) were significantly associated with HSCR even after correction for multiple comparisons using false discovery rate (FDR) (minimum PFDR = .005). In further subgroup analysis, SLC6A20 polymorphisms appeared to have increased associations with L-HSCR. Moreover, haplotype analysis also showed significant associations between 2 haplotypes (BL3_ht2 and BL4_ht2) and HSCR susceptibility (PFDR < .05). CONCLUSIONS: Although further replications and functional evaluations are required, our results suggest that SLC6A20 may have roles in HSCR development and in the extent of aganglionic segment during enteric nervous system development. PMID- 26049784 TI - Eosinophilic Esophagitis: Current Concepts. PMID- 26049785 TI - Comparison of bioactive chemical space networks generated using substructure- and fingerprint-based measures of molecular similarity. AB - Chemical space networks (CSNs) have recently been introduced as a conceptual alternative to coordinate-based representations of chemical space. CSNs were initially designed as threshold networks using the Tanimoto coefficient as a continuous similarity measure. The analysis of CSNs generated from sets of bioactive compounds revealed that many statistical properties were strongly dependent on their edge density. While it was difficult to compare CSNs at pre defined similarity threshold values, CSNs with constant edge density were directly comparable. In the current study, alternative CSN representations were constructed by applying the matched molecular pair (MMP) formalism as a substructure-based similarity criterion. For more than 150 compound activity classes, MMP-based CSNs (MMP-CSNs) were compared to corresponding threshold CSNs (THR-CSNs) at a constant edge density by applying different parameters from network science, measures of community structure distributions, and indicators of structure-activity relationship (SAR) information content. MMP-CSNs were found to be an attractive alternative to THR-CSNs, yielding low edge densities and well resolved topologies. MMP-CSNs and corresponding THR-CSNs often had similar topology and closely corresponding community structures, although there was only limited overlap in similarity relationships. The homophily principle from network science was shown to affect MMP-CSNs and THR-CSNs in different ways, despite the presence of conserved topological features. Moreover, activity cliff distributions in alternative CSN designs markedly differed, which has important implications for SAR analysis. PMID- 26049786 TI - Low bone mineral density among adults with disabilities in Taiwan: A cross sectional descriptive study. AB - BACKGROUND: Low bone mineral density (BMD) is a silent disease that can lead to osteoporosis and is a serious health problem worldwide. People with disabilities are especially at risk for fall-related death. OBJECTIVES: To examine the prevalence of low bone mineral density and associated risk factors among adults with disabilities in Taiwan. METHODS: We conducted a population-based, cross sectional study in 2013; the participants were 572 community adults with disabilities over the age of 20 years. Statistical analyses used to evaluate the association included chi-squared tests, ANOVA, and logistic regression. RESULTS: Over one-third of the participants had an intellectual disability, 26% physical disability, and the remainder had a combination of disabilities. Of the participants, 62.5% had abnormal bone mineral density, and 21.8% met the criteria for osteoporosis. After adjusting for potential confounding variables, the determinant risk factors for low bone mineral density were age (beta = -.14, p = 0.002), gender (beta = -.12, p = 0.004), and level of physical activity (beta = .1, p = 0.024). The majority of participants with low BMD were not aware of abnormal bone density, and only 2.4% had received treatment. CONCLUSIONS: This study identified a high prevalence of low bone mineral density among adults with disabilities; few of the participants possessed awareness of bone health, and very few received early treatment or information on prevention of osteoporosis. The enhancement of osteoporosis interventions and health promotion programs to prevent osteoporosis and related problems are necessary for this population. PMID- 26049787 TI - An exploration of the perceptions of caring held by students entering nursing programmes in the United Kingdom: A longitudinal qualitative study phase 1. AB - In a climate of intense international scrutiny of healthcare and nursing in particular, there is an urgent need to identify, foster and support a caring disposition in student nurses worldwide. Yet relatively little is known about how core nursing values are shaped during education programmes and this warrants further investigation. This longitudinal study commencing in February 2013 examines the impact of an innovative nursing curriculum based on a humanising framework (Todres et al. 2009) and seeks to establish to what extent professional and core values are shaped over the duration of a three year nursing programme. This paper reports on Phase One which explores student nurses' personal values and beliefs around caring and nursing at the start of their programme. Undergraduate pre-registration nursing students from two discrete programmes (Advanced Diploma and BSc (Honours) Nursing with professional registration) were recruited to this study. Utilising individual semi-structured interviews, data collection commenced with February 2013 cohort (n = 12) and was repeated with February 2014 (n = 24) cohort. Findings from Phase One show that neophyte student nurses are enthusiastic about wanting to care and aspire to making a difference to patients and their families. This research promises to offer contributions to the debate around what caring means and in particular how it is understood by student nurses. Findings will benefit educators and students which will ultimately impact positively on those in receipt of healthcare. PMID- 26049788 TI - Eccentric Torque-Producing Capacity is Influenced by Muscle Length in Older Healthy Adults. AB - Considering the importance of muscle strength to functional capacity in the elderly, the study investigated the effects of age on isokinetic performance and torque production as a function of muscle length. Eleven younger (24.2 +/- 2.9 years) and 16 older men (62.7 +/- 2.5 years) were subjected to concentric and eccentric isokinetic knee extension/flexion at 60 and 120 degrees . s(-1) through a functional range of motion. The older group presented lower peak torque (in newton-meters) than the young group for both isokinetic contraction types (age effect, p < 0.001). Peak torque deficits in the older group were near 30 and 29% for concentric and eccentric contraction, respectively. Concentric peak torque was lower at 120 degrees . s(-1) than at 60 degrees . s(-1) for both groups (angular velocity effect, p < 0.001). Eccentric knee extension torque was the only exercise tested that showed an interaction effect between age and muscle length (p < 0.001), which suggested different torque responses to the muscle length between groups. Compared with the young group, the eccentric knee extension torque was 22-56% lower in the older group, with the deficits being lower in the shortened muscle length (22-27%) and higher (33-56%) in the stretched muscle length. In older men, the production of eccentric knee strength seems to be dependent on the muscle length. At more stretched positions, older subjects lose the capacity to generate eccentric knee extension torque. More studies are needed to assess the mechanisms involved in eccentric strength preservation with aging and its relationship with muscle length. PMID- 26049789 TI - Influence of Test Distance on Change of Direction Speed Test Results. AB - This study assessed the relationships between linear running velocity and change of direction (CoD) ability and how assessing CoD ability over distances <=5 m influences test reliability. Participants (n = 15) from amateur rugby league teams performed 3 trials of a 20-m sprint test (light gates at 5, 10, and 20 m) and 6 trials of the 5-0-5 agility test. Twelve participants repeated the 5-0-5 test several weeks later. A three-dimensional motion capture system (250 Hz) was used to track the center of mass at 0.3, 0.5, and 1.0 m either side of the turn and identify specific CoD phase times. Pearson's correlations showed strong significant relationships between the 5-0-5 time and 5-m (r = 0.89, p < 0.001), 10-m (r = 0.91, p < 0.001), and 20-m sprint times (r = 0.93, p < 0.001). However, the strength of these relationships decreased (r < 0.65, p > 0.05) when CoD ability was measured over distances less than 0.5 m. Analysis of coefficient of variation (CV%) data indicated that the 5-0-5 test had high intratest (CV% = 2.8) and intertest reliability (CV% = 1.3), with these data decreasing for distances less than 1 m (CV% = 3.5-6.9). Specific movement phase times were the least reliable measures of CoD ability (CV% = 4.7-53.6). Results suggest a bias between high-speed linear running ability and 5-0-5 time. However, an effective compromise can be found between test reliability and the external validity by assessing CoD ability over 1 m. Findings indicate that the current practice of assessing CoD ability over large distances in questionable. PMID- 26049790 TI - Critical Velocity Is Associated With Combat-Specific Performance Measures in a Special Forces Unit. AB - The purpose of this study was to examine the relationship between critical velocity (CV) and anaerobic distance capacity (ADC) to combat-specific tasks (CST) in a special forces (SFs) unit. Eighteen male soldiers (mean +/- SD; age: 19.9 +/- 0.8 years; height: 177.6 +/- 6.6 cm; body mass: 74.1 +/- 5.8 kg; body mass index [BMI]: 23.52 +/- 1.63) from an SF unit of the Israel Defense Forces volunteered to complete a 3-minute all-out run along with CST (2.5-km run, 50-m casualty carry, and 30-m repeated sprints with "rush" shooting [RPTDS]). Estimates of CV and ADC from the 3-minute all-out run were determined from data downloaded from a global position system device worn by each soldier, with CV calculated as the average velocity of the final 30 seconds of the run and ADC as the velocity-time integral above CV. Critical velocity exhibited significant negative correlations with the 2.5-km run time (r = -0.62, p < 0.01) and RPTDS time (r = -0.71, p < 0.01). In addition, CV was positively correlated with the average velocity during the 2.5-km run (r = 0.64, p < 0.01). Stepwise regression identified CV as the most significant performance measure associated with the 2.5 km run time, whereas BMI and CV measures were significant predictors of RPTDS time (R(2) = 0.67, p <= 0.05). Using the 3-minute all-out run as a testing measurement in combat, personnel may offer a more efficient and simpler way in assessing both aerobic and anaerobic capabilities (CV and ADC) within a relatively large sample. PMID- 26049791 TI - Effect of Physical and Academic Stress on Illness and Injury in Division 1 College Football Players. AB - Stress-injury models of health suggest that athletes experience more physical injuries during times of high stress. The purpose of this study was to evaluate the effect of increased physical and academic stress on injury restrictions for athletes (n = 101) on a division I college football team. Weeks of the season were categorized into 3 levels: high physical stress (HPS) (i.e., preseason), high academic stress (HAS) (i.e., weeks with regularly scheduled examinations such as midterms, finals, and week before Thanksgiving break), and low academic stress (LAS) (i.e., regular season without regularly scheduled academic examinations). During each week, we recorded whether a player had an injury restriction, thereby creating a longitudinal binary outcome. The data were analyzed using a hierarchical logistic regression model to properly account for the dependency induced by the repeated observations over time within each subject. Significance for regression models was accepted at p <= 0.05. We found that the odds of an injury restriction during training camp (HPS) were the greatest compared with weeks of HAS (odds ratio [OR] = 2.05, p = 0.0003) and LAS (OR = 3.65, p < 0.001). However, the odds of an injury restriction during weeks of HAS were nearly twice as high as during weeks of LAS (OR = 1.78, p = 0.0088). Moreover, the difference in injury rates reported in all athletes during weeks of HPS and weeks of HAS disappeared when considering only athletes that regularly played in games (OR = 1.13, p = 0.75) suggesting that HAS may affect athletes that play to an even greater extent than HPS. Coaches should be aware of both types of stressors and consider carefully the types of training methods imposed during times of HAS when injuries are most likely. PMID- 26049792 TI - Novel Resistance Training-Specific Rating of Perceived Exertion Scale Measuring Repetitions in Reserve. AB - The primary aim of this study was to compare rating of perceived exertion (RPE) values measuring repetitions in reserve (RIR) at particular intensities of 1 repetition maximum (RM) in experienced (ES) and novice squatters (NS). Furthermore, this investigation compared average velocity between ES and NS at the same intensities. Twenty-nine individuals (24.0 +/- 3.4 years) performed a 1RM squat followed by a single repetition with loads corresponding to 60, 75, and 90% of 1RM and an 8-repetition set at 70% 1RM. Average velocity was recorded at 60, 75, and 90% 1RM and on the first and last repetitions of the 8-repetition set. Subjects reported an RPE value that corresponded to an RIR value (RPE-10 = 0 RIR, RPE-9 = 1-RIR, and so forth). Subjects were assigned to one of the 2 groups: (a) ES (n = 15, training age: 5.2 +/- 3.5 years) and (b) NS (n = 14, training age: 0.4 +/- 0.6 years). The mean of the average velocities for ES was slower (p <= 0.05) than NS at 100% and 90% 1RM. However, there were no differences (p > 0.05) between groups at 60, 75%, or for the first and eighth repetitions at 70% 1RM. In addition, ES recorded greater RPE at 1RM than NS (p = 0.023). In ES, there was a strong inverse relationship between average velocity and RPE at all percentages (r = -0.88, p < 0.001), and a strong inverse correlation in NS between average velocity and RPE at all intensities (r = -0.77, p = 0.001). Our findings demonstrate an inverse relationship between average velocity and RPE/RIR. Experienced squatter group exhibited slower average velocity and higher RPE at 1RM than NS, signaling greater efficiency at high intensities. The RIR based RPE scale is a practical method to regulate daily training load and provide feedback during a 1RM test. PMID- 26049793 TI - Rate of Force Development, Muscle Architecture, and Performance in Young Competitive Track and Field Throwers. AB - The rate of force development (RFD) is an essential component for performance in explosive activities, although it has been proposed that muscle architectural characteristics might be linked with RFD and power performance. The purpose of the study was to investigate the relationship between RFD, muscle architecture, and performance in young track and field throwers. Twelve young track and field throwers completed 10 weeks of periodized training. Before (T1) and after (T2) training performance was evaluated in competitive track and field throws, commonly used shot put tests, isometric leg press RFD, 1 repetition maximum (1RM) strength as well as vastus lateralis architecture and body composition. Performance in competitive track and field throwing and the shot put test from the power position increased by 6.76 +/- 4.31% (p < 0.001) and 3.58 +/- 4.97% (p = 0.019), respectively. Rate of force development and 1RM strength also increased (p <= 0.05). Vastus lateralis thickness and fascicle length increased by 5.95 +/- 7.13% (p = 0.012) and 13.41 +/- 16.15% (p = 0.016), respectively. Significant correlations were found at T1 and T2, between performance in the shot put tests and both RFD and fascicle length (p <= 0.05). Close correlations were found between RFD, muscle thickness, and fascicle length (p <= 0.05). Significant correlations were found between the % changes in lean body mass and the % increases in RFD. When calculated together, the % increase in muscle thickness and RFD could predict the % increase in shot put throw test from the power position (p = 0.019). These results suggest that leg press RFD may predict performance in shot put tests that are commonly used by track and field throwers. PMID- 26049794 TI - Effects of Rest Interval Length on Acute Battling Rope Exercise Metabolism. AB - The purpose of this study was to quantify and compare the acute metabolic responses to battling rope (BR) exercise using 2 different rest intervals. Twelve men and 10 women (age = 20.8 +/- 1.3 years) performed a control protocol and 2 BR exercise protocols on separate days (48-72 hours) in random order while connected to a metabolic system. The BR protocol consisted of 8 sets of 30-second intervals (15 seconds of single-arm waves and 15 seconds of double-arm waves) using either a 1-minute (1RI) or 2-minute (2RI) rest interval length. A metronome was used to standardize repetition number/frequency for each exercise, that is, 15 waves for each arm for single-arm waves and 15 repetitions of double-arm waves. The mean oxygen consumption (VO2) values for the entire protocol were significantly higher during the 1RI than 2RI protocol, and values in men were 11.1% (1RI) and 13.5% (2RI) higher than women, respectively, and equated to 52.8 +/- 5.5% (men) and 50.0 +/- 11.2% (women) of VO2max during 1RI and 40.5 +/- 4.5% (men) and 37.7 +/- 11.0% (women) of VO2max during 2RI. Energy expenditure values were significantly higher during the 1RI than the 2RI protocol in men (11.93 +/- 1.4 vs. 8.78 +/- 1.4 kcal.min) and women (7.69 +/- 1.3 vs. 5.04 +/- 1.7 kcal.min) with values in men statistically higher than women. Blood lactate, mean protocol minute ventilation, and heart rate were significantly higher during the 1RI protocol than the 2RI protocol, and these data were significantly higher in men compared with women. These data demonstrate that BR exercise poses a significant cardiovascular and metabolic stimulus with the mean effects augmented with the use of a short rest interval. PMID- 26049795 TI - Effects of different wavelengths of light on the biology, behavior, and production of grow-out Pekin ducks. AB - Previous research has shown that red light conditions may improve growth and decrease aggressive behaviors in chickens and turkeys; however, more recent studies suggest that blue-green light may improve production of broilers over red light. To date, no research has been conducted to examine whether different wavelengths of light have an impact on production in the Pekin duck. To determine this, we raised Pekin ducks under aviary conditions that were similar to standard commercial barns. The ducks were kept in 3 different pens: red light (approximately 625 nm), blue light (approximately 425 nm), and white light. Light sources in each pen were standardized to produce a peak energy at 1.6 * 103 MUM photons/m2/s at the level of the ducks' heads. Ducks were given ad libitum access to water and commercial duck diet, and were housed on pine shavings at a density of 0.43 m2/duck. Ducks were evaluated weekly for BW and condition and a subjective measure of the duck's anxiety levels was determined. We found that ducks housed under blue light had significantly (P < 0.01) reduced BW at every age until the end of the study (processing age; 35 d). Unlike ducks housed under red or white light, ducks housed in the blue pen showed a higher level of anxiety; while evaluators were in the pen a majority of them began panting, they were much less inquisitive than other ducks, they took longer to exhibit normal social behavior once evaluation was completed, and they frequently "swarmed" when no people were present. There were no differences in any measurements between the red and white-lighted pens. These data suggest that unlike the chicken, blue lights may be inappropriate for raising Pekin ducks in a commercial setting. PMID- 26049796 TI - The effects of increasing levels of dietary garlic bulb on growth performance, systolic blood pressure, hematology, and ascites syndrome in broiler chickens. AB - The effects of dietary garlic bulb were studied separately on hematological parameters, ascites incidence, and growth performance of an ascites susceptible broiler hybrid under both standard temperature conditions ( STC: ) and cold temperature conditions ( CTC: ). A total of 336 one-day-old male broiler chickens were allocated to 4 experimental groups with 4 replicates of 21 birds each under STC. In addition, the same grouping with another 336 birds was used for CTC. Under CTC, the birds were exposed to cold temperatures for induction of ascites. Experimental groups were defined by the inclusion of 0 (control), 5, 10 or 15 g/kg garlic bulbs in the diets under both STC and CTC. Growth performance, systolic blood pressure (as a measure of systemic arterial blood pressure), physiological and biochemical parameters, as well as ascites indices (right ventricle [ RV: ], total ventricle [ TV: ] weights, and RV/TV: ) were evaluated. Systolic blood pressure was determined using an indirect method with a sphygmomanometer, a pediatric cuff, and a Doppler device. The final body weight decreased quadratically (P = 0.003), with increasing garlic bulb levels in the diets under STC. The feed conversion ratio showed no significant differences among all groups under both STC and CTC. No significant differences were observed in total mortality and ascites-related mortality in all groups under STC, although total mortality (L: P = 0.01; Q: P = 0.001) and ascites-related mortality (L: P = 0.007; Q: P = 0.001) were significantly different among the diets under CTC. Under STC, the systolic blood pressure, packed cell volume, hemoglobin, RV, TV, and RV/TV did not vary significantly among the diets. However, red blood cell count and erythrocyte osmotic fragility decreased linearly (P < 0.005) with increasing garlic bulb levels in the diets under STC. Under CTC, the systolic blood pressure, packed cell volume, red blood cell count, and erythrocyte osmotic fragility decreased (P < 0.05) with increasing garlic levels. It is concluded that the inclusion of 5 g/kg garlic bulb in susceptible broiler chicken diets has a systemic anti-hypertensive effect and could decrease ascites incidence without impairing broiler chicken performance. PMID- 26049797 TI - Bitter, sweet and umami taste receptors and downstream signaling effectors: Expression in embryonic and growing chicken gastrointestinal tract. AB - Taste perception is a crucial biological mechanism affecting food and water choices and consumption in the animal kingdom. Bitter taste perception is mediated by a G-protein-coupled receptor (GPCR) family-the taste 2 receptors (T2R)-and their downstream proteins, whereas sweet and umami tastes are mediated by the GPCR family -taste 1 receptors (T1R) and their downstream proteins. Taste receptors and their downstream proteins have been identified in extra-gustatory tissues in mammals, such as the lungs and gastrointestinal tract (GIT), and their GIT activation has been linked with different metabolic and endocrinic pathways in the GIT. The chicken genome contains three bitter taste receptors termed ggTas2r1, ggTas2r2, and ggTas2r7, and the sweet/umami receptors ggTas1r1 and ggTas1r3, but it lacks the sweet receptor ggTas1r2. The aim of this study was to identify and determine the expression of genes related to taste perception in the chicken GIT, both at the embryonic stage and in growing chickens. The results of this study demonstrate for the first time, using real-time PCR, expression of the chicken taste receptor genes ggTas2r1, ggTas2r2, ggTas2r7, ggTas1r1, and ggTas1r3 and of their downstream protein-encoding genes TRPM5, alpha-gustducin, and PLCbeta2 in both gustatory tissues-the palate and tongue, and extra-gustatory tissues-the proventriculus, duodenum, jejunum, ileum, cecum, and colon of embryonic day 19 (E19) and growing (21 d old) chickens. Expression of these genes suggests the involvement of taste pathways for sensing carbohydrates, amino acids and bitter compounds in the chicken GIT. PMID- 26049798 TI - Taste-active compound levels in Korean native chicken meat: The effects of bird age and the cooking process. AB - The effects of bird age and the cooking process on the levels of several taste active compounds, including inosine 5'-monophosphate (IMP), glutamic acid, cysteine, reducing sugars, as well as oleic, linoleic, arachidonic, and docosahexaenoic acids (DHA), in the breast and leg meats from a certified meat type commercial Korean native chicken (KNC) strain (Woorimatdag) were investigated. KNC cocks were raised under similar standard conditions at a commercial chicken farm, and breast and leg meats from birds of various ages (10, 11, 12, 13, and 14 wk; 10 birds/age group) were obtained. After raw and cooked meat samples were prepared, they were analyzed for the aforementioned taste active compounds. Compared to the leg meat, KNC breast meat had higher levels of IMP, arachidonic acid, and DHA, but lower levels of the other taste-active compounds (P < 0.05). KNC meat lost significant amounts of all the taste-active compounds, excluding oleic and linoleic acids, during the cooking process (P < 0.05). However, bird age only had a minor effect on the levels of these taste active compounds. The results of this study provide useful information regarding the levels of taste-active compounds in KNC meat from birds of different ages, and their fate during the cooking process. This information could be useful for selection and breeding programs, and for popularizing native chicken meat. PMID- 26049799 TI - Effect of Salmonella infection on cecal tonsil regulatory T cell properties in chickens. AB - Two studies were conducted to study regulatory T cell [Treg (CD4+CD25+)] properties during the establishment of a persistent intestinal infection in broiler chickens. Four-day-old broiler chicks were orally gavaged with 5 * 106 CFU/mL Salmonella enteritidis (S. enteritidis) or sterile PBS (control). Samples were collected at 4, 7, 10, and 14 d postinfection. There was a significant (P < 0.05) increase in the number of CD4+CD25+ cells by d 4 postinfection that increased steadily throughout the course of the 14-d infection, whereas the number of CD4+CD25+ cells in the noninfected controls remained steady throughout the study. CD4+CD25+ cells from cecal tonsils of S. enteritidis-infected birds had a higher (P < 0.05) IL-10 mRNA content than CD4+CD25+ cells from the noninfected controls at all time-points studied. The amount of IL-2 mRNA content in the cecal tonsil CD4+CD25- cells from the infected birds did not differ (P > 0.05) when compared to that of noninfected control birds. At a lower effector/responder cell ratio of 0.25:1, CD4+CD25+ cells from cecal tonsils of Salmonella-infected birds suppressed T cell proliferation at d 7 and 14 post-S. enteritidis infection, while CD4+CD25+ cells from noninfected control groups did not suppress T cell proliferation. In the second studu, 1-day-old chickens were orally gavaged with PBS (control) or 1.25 * 108 CFU/bird S. enteritidis. At 7 and 21 d post-Salmonella infection, CD25+ cells collected from cecal tonsils of S. enteritidis-infected birds and restimulated in vitro with Salmonella antigen had higher (P < 0.05) IL-10 mRNA content compared to those in the control group. Spleen CD4+CD25+, CD4+, and CD8+ cell percentage did not differ (P > 0.05) between the Salmonella-infected and control birds. In conclusion, a persistent intestinal S. enteritidis infection increased the Treg percentage, suppressive properties, and IL-10 mRNA amounts in the cecal tonsils of broiler birds. PMID- 26049800 TI - Assessing the sustainability of egg production systems in The Netherlands. AB - Housing systems for laying hens have changed over the years due to increased public concern regarding animal welfare. In terms of sustainability, animal welfare is just one aspect that needs to be considered. Social aspects as well as environmental and economic factors need to be included as well. In this study, we assessed the sustainability of enriched cage, barn, free-range, and organic egg production systems following a predefined protocol. Indicators were selected within the social, environmental, and economic dimensions, after which parameter values and sustainability limits were set for the core indicators in order to quantify sustainability. Uncertainty in the parameter values as well as assigned weights and compensabilities of the indicators influenced the outcome of the sustainability assessment. Using equal weights for the indicators showed that, for the Dutch situation, enriched cage egg production was most sustainable, having the highest score on the environmental dimension, whereas free-range egg production gave the highest score in the social dimension (covering food safety, animal welfare, and human welfare). In the economic dimension both enriched cage egg and organic egg production had the highest sustainability score. When weights were attributed according to stakeholder outputs, individual differences were seen, but the overall scores were comparable to the sustainability scores based on equal weights. The provided method enabled a quantification of sustainability using input from stakeholders to include societal preferences in the overall assessment. Allowing for different weights and compensabilities helps policymakers in communicating with stakeholders involved and provides a weighted decision regarding future housing systems for laying hens. PMID- 26049802 TI - Innate immune response of pullets fed diets supplemented with prebiotics and synbiotics. AB - Prebiotics and synbiotics are considered to be among the most promising replacements for in-feed antibiotic growth promoters (AGP) in poultry feed. The current study was designed to study the effect of Bacitracin methylene disalicylate (BMD) (Control), yeast-derived carbohydrates (YDC), and a blend of YDC and probiotics [Lactobacillus acidophilus, Lactobacillus casei, Streptococcus faecium, Bacillus subtilis, and YDC] (SNB) in the performance and innate immune response of pullets. Feed intake and BW were measured on a weekly basis. At the end of the study (d 21), 10 birds/treatment were sacrificed by cervical dislocation and ileum, cecal tonsil, and spleen samples were collected for gene expression analysis. No significant difference (P > 0.05) in feed intake and G:F was observed among treatments. In the second and third wk age, higher BW gain was observed in SNB treatment compared to control and both control and YDC treatments, respectively. Expression of TLR2b was upregulated in YDC and SNB in the ileum, and in SNB in the spleen (P < 0.05). Expression of TLR4 was downregulated in SNB in the cecal tonsil. Expression of TLR21 was downregulated in YDC in the ileum, while it was upregulated in SNB in the spleen (P < 0.05). In the ileum, YDC resulted in downregulated IL-12p35, CxCLi2, and IL-13, and SNB resulted in upregulated IL-6, interferon (IFN)-gamma, and IL-4 (P < 0.05). In the cecal tonsil, YDC resulted in upregulated IL-12p35, IL-2, IL-13 and IL-10, and SNB resulted in downregulated IL-2 and upregulated IL-13 and IL-10 (P < 0.05). In the spleen, YDC resulted in dowregulated IL-2 and CxCLi2, and SNB resulted in upregulated IL-6, IFN-gamma, IL-4, and IL-10 (P < 0.05). In conclusion, no change in performance was observed. Innate immune response analysis showed SNB with a more potent effect compared to YDC where the former showed a balanced T-helper (Th)-1/Th-2 response locally and a more Th-2-dependent response systemically; SNB might provide a more beneficial immune modulation with maintaining immune homeostasis, which was observed in a strong IL-10 response. PMID- 26049801 TI - The impact of deposition site on vaccination efficiency of a live bacterial poultry vaccine. AB - Vaccines are utilized within the poultry industry to minimize disease-associated losses and spray vaccination is a commonly utilized means for the mass application of poultry vaccines. During this process, vaccine-laden particles are deposited upon target areas (e.g., eyes, nares, and oral cavity) resulting in the direct internalization of the vaccine. However, particles are also deposited on nontarget areas such as the exterior of the subject and its surrounding environment. To better determine the fate of particles deposited upon nontarget areas and the impact of deposition site on the efficiency of vaccine application, a live bacterial poultry vaccine (AviPro((r)) MG F) was applied via spray using a spray cabinet with a slotted partition allowing for head-only, body-only, and whole-bird spray application. At 11 wk age, Hy-Line((r)) W-36 pullets (n = 280) were allocated equally among 7 treatments including: nonvaccinated controls, pullets spray-vaccinated at the manufacturer's recommended dose (1X) in a site specific manner (head-only, body-only, and whole-bird), pullets spray-vaccinated at 5X the recommended level (body-only), pullets vaccinated by manual eye-drop application (1X), and pullets eye-drop vaccinated at a level approximating that achieved during the spray vaccination process (1/700X). At 6 to 7 wk postvaccination, vaccination efficiency was assessed via serological-based assays [serum plate agglutination (SPA) and ELISA] and the detection of vaccine-derived in vivo populations. Results indicate an additive contribution of the vaccine deposited on the body to the overall vaccination efficiency of this live bacterial live poultry vaccine. PMID- 26049803 TI - Assessment of welfare of Brazilian and Belgian broiler flocks using the Welfare Quality protocol. AB - The Welfare Quality consortium has proposed a science-based protocol for assessing broiler chicken welfare on farms. Innovative features make the protocols particularly suited for comparative studies, such as the focus on animal-based welfare measures and an integration procedure for calculating an overall welfare status. These protocols reflect the scientific status up to 2009 but are meant to be updated on the basis of inter alia implementation studies. Because only few such studies have been done, we applied the Welfare Quality protocol to compare the welfare of broiler flocks in Belgium (representing a typical European Union (EU) country which implies stringent animal welfare legislation) versus Brazil (the major broiler meat exporter to the EU and with minimal animal welfare legislation). Two trained observers performed broiler Welfare Quality assessments on a total of 22 farms in Belgium and south Brazil. All of the farms produced for the EU market. Although the overall welfare was categorized as 'acceptable' on all farms, many country differences were observed at the level of the welfare principles, criteria, and measures. Brazilian farms obtained higher scores for 3 of the 4 welfare principles: 'good feeding' (P = 0.007), 'good housing' (P < 0.001), and 'good health' (P = 0.005). Four of the 10 welfare criteria scores were, or tended to be, higher on Brazilian than Belgian farms: 'absence of prolonged thirst' (P < 0.001), 'ease of movement' (P < 0.001), 'absence of injuries' (P = 0.002), and 'positive emotional state' (P = 0.055). The only criteria with a higher score for the Belgian farms than their Brazilian counterparts were 'absence of prolonged hunger' (P = 0.048) and 'good human animal relationship' (P = 0.002). Application of the Welfare Quality protocol has raised several concerns about the validity, reliability, and discriminatory potential of the protocol. The results also call for more research into the effect of animal welfare legislation as broiler welfare on the south Brazilian farms appeared to be superior to that on the Belgian farms. Animal-based welfare assessments on a larger sample of farms are needed to evaluate to what extent these findings may be generalized. PMID- 26049804 TI - Study of protein structural deformations under external mechanical perturbations by a coarse-grained simulation method. AB - The mechanical properties of biomolecules play pivotal roles in regulating cellular functions. For instance, extracellular mechanical stimuli are converted to intracellular biochemical activities by membrane receptors and their downstream adaptor proteins during mechanotransduction. In general, proteins favor the conformation with the lowest free energy. External forces modify the energy landscape of proteins and drive them to unfolded or deformed conformations that are of functional relevance. Therefore, the study of the physical properties of proteins under external forces is of fundamental importance to understand their functions in cellular mechanics. Here, a coarse-grained computational model was developed to simulate the unfolding or deformation of proteins under mechanical perturbation. By applying this method to unfolding of previously studied proteins or protein fragments with external forces, we demonstrated that our results are quantitatively comparable to previous experimental or all-atom computational studies. The model was further extended to the problem of elastic deformation of large protein complexes formed between membrane receptors and their ligands. Our studies of binding between T cell receptor (TCR) and major histocompatibility complex (MHC) illustrated that stretching of MHC ligand initially lowers its binding energy with TCR, supporting the recent experimental report that TCR/MHC complex is formed through the catch-bond mechanism. Finally, the method was, for the first time, applied to pulling of an eight-cadherin cluster that was formed by their trans and cis binding interfaces. Our simulation results show that mechanical properties of adherens junctions are functionally important to cell adhesion. PMID- 26049805 TI - Single-dose intra-articular ropivacaine after arthroscopic knee surgery decreases post-operative pain without increasing side effects: a systematic review and meta analysis. AB - PURPOSE: The purpose of this study was to appraise the efficacy and safety of single-dose intra-articular ropivacaine administered for pain relief after arthroscopic knee surgery. METHODS: PubMed, Embase, and Cochrane Library databases were searched in October 2014 to identify randomized controlled trials of single-dose intra-articular ropivacaine for post-operative pain relief. Post operative pain intensity, the amount of rescue analgesia required, and side effects including local anaesthetic toxicity were assessed. The relative risk (RR), the weighted mean difference (WMD), and their corresponding 95 % confidence intervals (CIs) were calculated. RESULTS: Eight randomized controlled trials were included in the analysis. Statistically significant differences in the visual analogue scale for pain intensity value were observed during the immediate post operative period (WMD -10.35, 95 % CI -17.12 to -3.59, p = 0.003) and the early post-operative period (WMD -11.90, 95 % CI -18.12 to -5.69, p = 0.0002), but not during the late post-operative period (WMD -2.89, 95 % CI -7.46 to 1.68, n.s.). There was no significant difference in the amount of rescue analgesia required (RR 0.76, 95 % CI 0.52-1.11, n.s.). Only two trials reported the incidence of drug-related side effects (including nausea and vomiting): the incidence in the ropivacaine groups was no higher than that in the control groups. Only one trial assessed local anaesthetic toxicity as an outcome, but it was not detected. CONCLUSIONS: Single-dose intra-articular ropivacaine administered at the end of arthroscopic knee surgery provides effective pain relief in the immediate and early post-operative periods without increasing short-term side effects. PMID- 26049806 TI - Referencing the sulcus line of the trochlear groove and removing intraoperative parallax errors improve femoral component rotation in total knee arthroplasty. AB - PURPOSE: Firstly, to assess and compare the accuracy and reproducibility of the sulcus line compared to Whiteside's line. Secondly, to assess the accuracy of intraoperative techniques for using the rotational alignment of the trochlear groove to set femoral rotation. Thirdly, to assess the reproducibility of a trochlear alignment guide which removes parallax errors that occur when projecting the sulcus line onto the surface of the femur. Finally, to measure the result of combining the geometrically accurate sulcus line and the posterior condylar axis. METHODS: Three surgeons measured eight rotational angles on ten cadaveric femora. This included Whiteside's line, the sulcus line and the techniques in which they can be referenced during surgery. RESULTS: Relative to the anatomical epicondylar axis, the sulcus line (mean -2.8 degrees , SD 2.0 degrees , range -5.4 degrees to 0.8 degrees ) had significantly lower variance (F = 5.16, p = 0.036) than Whiteside's line (mean -2.0 degrees , SD 3.7 degrees , range -6.0 degrees to 3.4 degrees ). The trochlear alignment guide produced the best results of the intraoperative techniques by maintaining the accuracy of the sulcus line and projecting it onto the distal cut surface of the femur without change in rotational angle. CONCLUSION: The sulcus line is more accurate and reproducible than Whiteside's line. Removing parallax errors during surgery improves femoral component rotation. The trochlear alignment guide produced accurate results suggesting that it may be beneficial in a clinical setting. Averaging the sulcus line and posterior condylar axis on the cut surface of the femur improved accuracy over the individual landmarks. Femoral component malrotation is a common cause of patient dissatisfaction and revision surgery. By isolating the rotational alignment of the trochlear groove using the sulcus line, and maintaining its accuracy with an intraoperative guide, we can decrease the risk of femoral component malrotation and improve patient outcomes. PMID- 26049807 TI - How is an informal caregiver's psychological distress associated with prolonged caregiving? Evidence from a six-wave panel survey in Japan. AB - PURPOSE: The provision of informal nursing care can adversely affect a caregiver's mental health, but the dynamic association of the variables is still under debate. We examined how an informal caregiver's psychological distress is associated with prolonged caregiving. METHODS: We used data collected from a nationwide six-wave panel survey in Japan, with 25,186 observations of 9192 individuals. We focused on informal caregivers, who provided help and support for ill family members. We used Kessler 6 (K6) scores (range 0-24), where higher scores reflect higher levels of psychological distress. We employed mixed-effects models to examine how caregivers' psychological distress was associated with caregiving commencement and duration. RESULTS: Commencement of caregiving raised the K6 score for female caregivers by 0.55 (equivalent to 0.12 SD, 95 % CI 0.34 0.75) and that for male caregivers by 0.41 (0.09 SD, 95 % CI 0.18-0.63). However, prolonged caregiving had gender-asymmetric, dynamic associations with psychological distress. One additional year of caregiving added 0.22 (0.05 SD, 95 % CI 0.10-0.35) to the K6 score of female caregivers, while it had no significant association for male caregivers. For female caregivers, prolonged caregiving was positively associated with K6 score entirely through its interaction effects with longer hours of care, co-residence with a care recipient, and the non-working status of a caregiver. CONCLUSIONS: Results revealed a gender-asymmetric, dynamic association between informal care provision and caregivers' psychological distress. Additional policy measures targeted at caregivers deeply involved in in house care are needed to reduce their distress. PMID- 26049810 TI - Nurses' perceptions of using an evidence-based care bundle for initial emergency nursing management of patients with severe traumatic brain injury: A qualitative study. AB - Evidence to guide initial emergency nursing care of patients with severe traumatic brain injury (TBI) in Thailand is currently not available in a useable form. A care bundle was used to summarise an evidence-based approach to the initial emergency nursing management of patients with severe TBI and was implemented in one Thai emergency department. The aim of this study was to describe Thai emergency nurses' perceptions of care bundle use. A descriptive qualitative study was used to describe emergency nurses' perceptions of care bundle use during the implementation phase (Phase-One) and then post implementation (Phase-Two). Ten emergency nurses participated in Phase-One, while 12 nurses participated in Phase-Two. In Phase-One, there were five important factors identified in relation to use of the care bundle including quality of care, competing priorities, inadequate equipment, agitated patients, and teamwork. In Phase Two, participants perceived that using the care bundle helped them to improve quality of care, increased nurses' knowledge, skills, and confidence. Care bundles are one strategy to increase integration of research evidence into clinical practice and facilitate healthcare providers to deliver optimal patient care in busy environments with limited resources. PMID- 26049812 TI - New Drugs 2015 Part 2. PMID- 26049811 TI - Induction of apoptosis-like cell death by coelomocyte extracts from Eisenia andrei earthworms. AB - Earthworm's innate immunity is maintained by cellular and humoral components. Our objective was to characterize the cytotoxicity leading to target cell death caused by earthworm coelomocytes. Coelomocyte lysates induced strong cytotoxicity in tumor cell lines. Transmission electron microscopy revealed cell membrane and intracellular damage in cells treated with coelomocyte lysates. Using TUNEL assay, within 5 min of incubation we detected DNA fragmentation. Moreover, we found phosphatidylserine translocation in target cell-membranes. Furthermore, we detected dose-dependent Ca(2+) influx and decrease of mitochondrial membrane potential in coelomocyte lysate-treated cells. Interestingly, caspase 3/8 activation was undetectable in exposed tumor cells. One such cytotoxic molecule, lysenin identified in earthworms binds to sphingomyelin and causes target cell lysis in vertebrates. Pretreatment with our anti-lysenin monoclonal antibody rescued the majority but not all target cells from coelomocyte induced death. These data suggest that, not only lysenin but also other factors participate in the caspase-independent apoptosis induced by coelomocytes. PMID- 26049813 TI - Development and Validation of a Heart Failure-Specific Health Literacy Scale. AB - BACKGROUND: Health literacy (HL) is an important concept for patient education and disease management with heart failure (HF). However, research on HL has predominantly focused on functional HL (ability to read and write). The World Health Organization advocates evaluating comprehensive HL, including the ability to access information (communicative HL) and critically evaluate that information (critical HL). OBJECTIVE: We developed an instrument for measuring functional, communicative, and critical levels of HL in patients with HF. METHODS: We evaluated the reliability and validity of those 3 HL scales in a sample of 191 outpatients with HF (mean [SD] age, 66.9 [13.9] years; 64.9% males). Sociodemographic and clinical characteristics, knowledge of HF, a well as motivation to obtain health information were assessed for each patient through a self-administered questionnaire and review of electronic medical records. RESULTS: We constructed scale items to reflect directly the comprehensive World Health Organization definition of HL. We identified 3 interpretable factors by exploratory factor analysis. Internal consistency was marginally acceptable for total HL (Cronbach alpha = 0.71), functional HL (alpha = 0.73), communicative HL (alpha = 0.68), and critical HL (alpha = 0.69); the interclass correlation coefficients of the functional, communicative, and critical HL subscales were 0.882, 0.898, and 0.882, respectively. Low functional, communicative, and critical HL was characteristic of older patients, those with lower socioeconomic status, patients living alone, those without a high school education, and patients lacking HF knowledge. CONCLUSIONS: Our new HL scale was demonstrated to be a reliable, valid instrument for measuring functional, communicative, and critical HL in patients with HF. Exploring a patient's HL level, including the ability to access, understand, and use health information as well as the ability to read and write, may provide better understanding of patients' potential barriers to self-care. PMID- 26049814 TI - Sewage as a rich source of phage study against Pseudomonas aeruginosa PAO. AB - Pseudomonas aeruginosa is a ubiquitous organism which has emerged as a major public health threat in hospital environments. Overuse of antibiotics has significantly exacerbated the emergence of multi-drug resistant bacteria such as P. aeruginosa. Phages are currently being utilized successfully for aquaculture, agriculture and veterinary applications. The aim of this study was to isolate and characterize of lytic P. aeruginosa phage from sewage of Ilam, Iran. Phage was isolated from sewage that was added to the enrichment along with the host and subsequently filtered. Plaque assay was done by using an overlay method (also called the double agar layer method). Purified plaques were then amplified for characterization. Finally, RAPD-PCR method was conducted for genotyping and Transition electron micrograph (TEM) recruited to determine the morphology and phage family. The phage had high concentration and tremendous effects against a variety of clinical and general laboratory strains (ATCC15693) of P. aeruginosa. Among a set of primers in RAPD panel, only P2 and RAPD5 primers, were useful in differentiating the phages. TEM images revealed that the isolated phages were members of the Siphoviridae family. The phage effectiveness and specificity towards target bacteria and potential to control biofilm formations will be investigate in our further studies. PMID- 26049815 TI - Magnetic Resonance Imaging in Brain Tumors: Update. PMID- 26049816 TI - Response Assessment and Magnetic Resonance Imaging Issues for Clinical Trials Involving High-Grade Gliomas. AB - There exist multiple challenges associated with the current response assessment criteria for high-grade gliomas, including the uncertain role of changes in nonenhancing T2 hyperintensity, and the phenomena of pseudoresponse and pseudoprogression in the setting of antiangiogenic and chemoradiation therapies, respectively. Advanced physiological magnetic resonance imaging (MRI), including diffusion and perfusion (dynamic susceptibility contrast MRI and dynamic contrast enhanced MRI) sensitive techniques for overcoming response assessment challenges, has been proposed, with their own potential advantages and inherent shortcomings. Measurement variability exists for conventional and advanced MRI techniques, necessitating the standardization of image acquisition parameters in order to establish the utility of these imaging methods in multicenter trials for high grade gliomas. This review chapter highlights the important features of MRI in clinical brain tumor trials, focusing on the current state of response assessment in brain tumors, advanced imaging techniques that may provide additional value for determining response, and imaging issues to be considered for multicenter trials. PMID- 26049817 TI - Novel Magnetic Resonance Imaging Techniques in Brain Tumors. AB - Magnetic resonance imaging is a powerful, noninvasive imaging technique with exquisite sensitivity to soft tissue composition. Magnetic resonance imaging is primary tool for brain tumor diagnosis, evaluation of drug response assessment, and clinical monitoring of the patient during the course of their disease. The flexibility of magnetic resonance imaging pulse sequence design allows for a variety of image contrasts to be acquired, including information about magnetic resonance-specific tissue characteristics, molecular dynamics, microstructural organization, vascular composition, and biochemical status. The current review highlights recent advancements and novel approaches in MR characterization of brain tumors. PMID- 26049818 TI - Imaging of the Posttherapeutic Brain. AB - This review covers important topics relating to the imaging evaluation of glioblastoma multiforme after therapy. An overview of the Macdonald and Response Assessment in Neuro-Oncology criteria as well as important questions and limitations regarding their use are provided. Pseudoprogression and pseudoresponse as well as the use of advanced magnetic resonance imaging techniques such as perfusion, diffusion, and spectroscopy in the evaluation of the posttherapeutic brain are also reviewed. PMID- 26049819 TI - Imaging Genomics of Glioblastoma: Biology, Biomarkers, and Breakthroughs. AB - Glioblastoma is regarded as the most aggressive and most common primary malignant brain tumor in adults. Despite advancements in chemotherapy and radiotherapy, prognosis and overall survival of glioblastoma patients remain dismal. Recently, progresses in genetic profiling have increased our understanding of the underlying heterogenous molecular nature of this aggressive tumor. Several prognostic and predictive molecular biomarkers have been identified that have been linked to patient's survival and response to treatment, respectively. Imaging genomics represents a novel entity in clinical sciences that bidirectionally links imaging features with underlying molecular profile and thus can serve as a surrogate for noninvasive genomic correlation, prediction, and identification. PMID- 26049821 TI - Association between thyroid hormones, thyroid antibodies and insulin resistance in euthyroid individuals: A population-based cohort. AB - AIM: The association between insulin resistance and thyroid function in euthyroid subjects has not yet been clarified. This study aimed to investigate the association between thyroid function within the normal reference range and insulin resistance in participants of the Tehran Thyroid Study (TTS). METHODS: This cross-sectional study was conducted within the framework of the TTS. Of 5786 subjects aged >= 20 years, 2758 euthyroid subjects free of thyroid disorders, diabetes, chronic kidney disease and cardiovascular disease, and not taking steroids and lipid-lowering agents, were included. Serum concentrations of free thyroxine (FT4) and TSH were measured. The homoeostasis model assessment index for insulin resistance (HOMA-IR) was used to evaluate IR. RESULTS: On linear regression analysis, a negative association was found between serum FT4 levels and HOMA-IR in the model with age, smoking and physical activity (B = -0.09, P < 0.001) and in the WC-adjusted model with age, smoking and physical activity for men (B = -0.06, P < 0.01). In addition, there was a positive association between serum TSH levels and HOMA-IR in both models [with age, smoking and physical activity (B = 0.07, P = 0.006), and age, smoking, physical activity and adjusted for WC (B = 0.05, P = 0.01)] that was not more significant on logistic regression analysis. In women, neither serum FT4 nor TSH levels were associated with HOMA IR; the prevalence of IR decreased from 27.2 to 19.1 with increasing tertiles of FT4 only in men (P = 0.01). No significant differences were observed in HOMA-IR and its components between thyroid peroxidase antibody (TPOAb)-negative and positive groups. Also, it was found that metabolically healthy but obese (MHO) subjects had higher levels of TSH than individuals who were MONW (metabolically obese but normal weight; P < 0.01). CONCLUSION: Low FT4 was independently associated with IR in healthy euthyroid Iranian men. PMID- 26049822 TI - Age-related cataract and macular degeneration: Oxygen receptor dysfunction diseases. AB - Age-related cataract and age-related macular degeneration (AMD) is the leading cause of vision impairment and blindness in developing and developed countries, respectively. Oxidative stress and oxidation products have been verified to play important roles in these two aging diseases. Recent research has demonstrated that there are significant oxygen gradients in the eye. Therefore, we propose a new hypothesis that these two diseases could be summarized as oxygen receptor dysfunction diseases of which the main points are as follows. Oxygen in the retinal and choroidal vasculature is transferred into the vitreous cavity by a special switching valve or oxygen receptor that might exist in the internal limiting membrane, vascular endothelium or posterior vitreous surface. It is then transported from the posterior segment to the anterior segment by vitreous collagen fibrilla networks, which work similar to a gas pipeline. Posterior vitreous detachment is the starting point of these two diseases by inducing formation of the local hyperoxia region, which results in the occurrence of age related cataract and macular degeneration. Thus, an innovative anti-oxidative therapy should be added to the traditional treatment of age related macular degeneration. Some associated experimental and clinical approaches are suggested in our paper to test this hypothesis. PMID- 26049820 TI - Transcription factor SP4 phosphorylation is altered in the postmortem cerebellum of bipolar disorder and schizophrenia subjects. AB - Transcription factors play important roles in the control of neuronal function in physiological and pathological conditions. We previously reported reduced levels of transcription factor SP4 protein, but not transcript, in the cerebellum in bipolar disorder and associated with more severe negative symptoms in schizophrenia. We have recently reported phosphorylation of Sp4 at S770, which is regulated by membrane depolarization and NMDA receptor activity. The aim of this study was to investigate SP4 S770 phosphorylation in bipolar disorder and its association with negative symptoms in schizophrenia, and to explore the potential relationship between phosphorylation and protein abundance. Here we report a significant increase in SP4 phosphorylation in the cerebellum, but not the prefrontal cortex, of bipolar disorder subjects (n=10) (80% suicide) compared to matched controls (n=10). We found that SP4 phosphorylation inversely correlated with SP4 levels independently of disease status in both areas of the human brain. Moreover, SP4 phosphorylation in the cerebellum positively correlated with negative symptoms in schizophrenia subjects (n=15). Further, we observed that a phospho-mimetic mutation in truncated Sp4 was sufficient to significantly decrease Sp4 steady-state levels, while a non-phosphorylatable mutant showed increased stability in cultured rat cerebellar granule neurons. Our results indicate that SP4 S770 phosphorylation is increased in the cerebellum in bipolar disorder subjects that committed suicide and in severe schizophrenia subjects, and may be part of a degradation signal that controls Sp4 abundance in cerebellar granule neurons. This opens the possibility that modulation of SP4 phosphorylation may contribute to the molecular pathophysiology of psychotic disorders. PMID- 26049823 TI - Hepatocellular carcinoma cells that develop resistance to the telomerase activated prodrug ACV-TP-T may undergo spontaneous apoptosis. PMID- 26049824 TI - Adjuvant role of anti-angiogenic drugs in the management of head and neck arteriovenous malformations. AB - Arteriovenous malformations (AVMs) are high-flow vascular malformations characterised by a complex vessel network directly connecting feeding arteries and draining veins, typically featured by a natural history of progression, while spontaneous regressions are purely anecdotal. AVMs are very aggressive entities that possess a locally infiltrative behaviour like neoplasms. Complete "radical" surgical excision presents the highest chance of cure, but nowadays there is still considerable controversy on how to treat large AVMs that are not amenable of "radical" excision. The aim of this paper is to propose a different approach to treat vast AVMs that cannot be removed radically. The association of an antiangiogenic drug (to be initiated before surgery and to be continued in the post-operative period), could prevent the feared "explosive" growth of the remaining nidus after its partial removal. This could make recontouring and other "aesthetically" focused procedures feasible in these patients, with an obvious leap in their quality of life. The most promising antiangiogenic drug seems to be Thalidomide, but other drugs such as Sirolimus, VEGF pathway inhibitors, Interferon or Matrix Metalloproteinase (MMP) Inhibitors could serve the purpose just as well. Even Propranolol could prove useful in this sense as suggested by some recent researches on retinopathy of prematurity and tumour biology. PMID- 26049826 TI - Pseudoexfoliation in intraocular lens dislocation: Underdiagnosed scourge. PMID- 26049825 TI - Copper-catalyzed ligand-free amidation of aryl iodides and amino acid amides to synthesize C3-(Z)-1H-benzo[e][1,4]diazepin-2(3H)-ones. AB - An effective synthetic method for C3-chiral 1,4-benzodiazepine-2-ones is described in this paper, reporting good yields and high enantioselectivity with a novel approach to an ipso-halo displacement-cyclization benzodiazepine route. PMID- 26049827 TI - George O. Waring III, MD: Ophthalmic Surgeon and Innovator. PMID- 26049828 TI - Intraocular lens exchange technique for an opacified bag-in-the-lens. AB - We describe the intraocular lens (IOL) exchange technique that is specific to the bag-in-the-lens IOL. The subsequent IOL analysis displayed a deep granular opacification consisting predominantly of calcium and phosphates that has been described in hydrophilic IOLs. PMID- 26049829 TI - Effect of position of near addition in an asymmetric refractive multifocal intraocular lens on quality of vision. AB - PURPOSE: To evaluate the impact of the position of an asymmetric multifocal near segment on visual quality. SETTING: Cathedral Eye Clinic, Belfast, United Kingdom. DESIGN: Retrospective comparative case series. METHODS: Data from consecutive patients who had bilateral implantation of the Lentis Mplus LS-312 multifocal intraocular lens were divided into 2 groups. One group received inferonasal near-segment placement and the other, superotemporal near-segment placement. A +3.00 diopter (D) reading addition (add) was used in all eyes. The main outcome measures included uncorrected distance visual acuity (UDVA), uncorrected near visual acuity (UNVA), contrast sensitivity, and quality of vision. Follow-up was 3 months. RESULTS: Patients ranged in age from 43 to 76 years. The inferonasal group comprised 80 eyes (40 patients) and the superotemporal group, 76 eyes (38 patients). The mean 3-month spherical equivalent was -0.11 D +/- 0.49 (SD) in the inferonasal group and -0.18 +/- 0.46 D in the superotemporal group. The mean postoperative UDVA was 0.14 +/- 0.10 logMAR and 0.18 +/- 0.15 logMAR, respectively. The mean monocular UNVA was 0.21 +/- 0.14 logRAD and 0.24 +/- 0.13 logRAD, respectively. No significant differences were observed in the higher-order aberrations, total Strehl ratio (point-spread function), or modulation transfer function between the groups. Dysphotopic symptoms measured with a validated quality-of-vision questionnaire were not significantly different between groups. CONCLUSION: Positioning of the near add did not significantly affect objective or subjective visual function parameters. PMID- 26049830 TI - Posterior capsule opacification and neodymium:YAG laser capsulotomy rates with 2 microincision intraocular lenses: Four-year results. AB - PURPOSE: To compare the development of posterior capsule opacification (PCO) and neodymium:YAG (Nd:YAG) capsulotomy rates between 2 microincision intraocular lenses (IOLs) 4 years after surgery. SETTING: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. DESIGN: Prospective randomized clinical trial. METHODS: Patients randomly received a Y-60H 3-piece hydrophobic IOL (hydrophobic group) in 1 eye and an MI60 1-piece hydrophilic IOL (hydrophilic group) in the contralateral eye during simultaneous bilateral cataract surgery. Eyes were examined 1 week, 20 months, and 4 years postoperatively. Digital retroilluminated images of each eye were evaluated using Automated Quantification of After-Cataract software. The Nd:YAG laser capsulotomy rate was recorded. RESULTS: Sixty patients were enrolled. Objective PCO was significantly higher in the hydrophobic group than in the hydrophilic group before capsulotomy 2 years after cataract surgery (mean score 2.1 +/- 1.8 (SD) versus 1.2 +/- 1.4) (P =.031). At the 4-year follow-up, the hydrophobic group had a statistically significantly higher Nd:YAG rate than the hydrophilic group (77% versus 50%) (P =.012). CONCLUSION: Comparison of 2 microincision IOLs indicated a statistically significant difference in PCO and Nd:YAG capsulotomy rates, with very high Nd:YAG rates 4 years after surgery. PMID- 26049831 TI - Prediction of accommodative optical response in prepresbyopic subjects using ultrasound biomicroscopy. AB - PURPOSE: To determine whether relatively low-resolution ultrasound biomicroscopy (UBM) can be used to predict the accommodative optical response in prepresbyopic eyes as well as in a previous study of young phakic subjects, despite lower accommodative amplitudes. SETTING: College of Optometry, University of Houston, Houston, USA. DESIGN: Observational cross-sectional study. METHODS: Static accommodative optical response was measured with infrared photorefraction and an autorefractor (WR-5100K) in subjects aged 36 to 46 years. A 35 MHz UBM device (Vumax, Sonomed Escalon) was used to image the left eye, while the right eye viewed accommodative stimuli. Custom-developed Matlab image-analysis software was used to perform automated analysis of UBM images to measure the ocular biometry parameters. The accommodative optical response was predicted from biometry parameters using linear regression, 95% confidence intervals (CIs), and 95% prediction intervals. RESULTS: The study evaluated 25 subjects. Per-diopter (D) accommodative changes in anterior chamber depth (ACD), lens thickness, anterior and posterior lens radii of curvature, and anterior segment length were similar to previous values from young subjects. The standard deviations (SDs) of accommodative optical response predicted from linear regressions for UBM-measured biometry parameters were ACD, 0.15 D; lens thickness, 0.25 D; anterior lens radii of curvature, 0.09 D; posterior lens radii of curvature, 0.37 D; and anterior segment length, 0.42 D. CONCLUSIONS: Ultrasound biomicroscopy parameters can, on average, predict accommodative optical responses with SDs of less than 0.55 D using linear regressions and 95% CIs. Ultrasound biomicroscopy can be used to visualize and quantify accommodative biometric changes and predict accommodative optical response in prepresbyopic eyes. PMID- 26049832 TI - Cost analysis of objective resident cataract surgery assessments. AB - PURPOSE: To compare 8 ophthalmology resident surgical training tools to determine which is most cost effective. SETTING: University of Rochester Medical Center, Rochester, New York, USA. DESIGN: Retrospective evaluation of technology. METHODS: A cost-analysis model was created to compile all relevant costs in running each tool in a medium-sized ophthalmology program. Quantitative cost estimates were obtained based on cost of tools, cost of time in evaluations, and supply and maintenance costs. RESULTS: For wet laboratory simulation, Eyesi was the least expensive cataract surgery simulation method; however, it is only capable of evaluating simulated cataract surgery rehearsal and requires supplementation with other evaluative methods for operating room performance and for noncataract wet lab training and evaluation. The most expensive training tool was the Eye Surgical Skills Assessment Test (ESSAT). The 2 most affordable methods for resident evaluation in operating room performance were the Objective Assessment of Skills in Intraocular Surgery (OASIS) and Global Rating Assessment of Skills in Intraocular Surgery (GRASIS). CONCLUSIONS: Cost-based analysis of ophthalmology resident surgical training tools are needed so residency programs can implement tools that are valid, reliable, objective, and cost effective. There is no perfect training system at this time. PMID- 26049833 TI - Standardization of laser in situ keratomileusis surgical technique evaluated by comparison of procedure time between 2 experienced surgeons. AB - PURPOSE: To evaluate the concordance of surgical step pacing between 2 experienced surgeons following a standardized surgical protocol for bilateral laser in situ keratomileusis (LASIK). SETTING: London Vision Clinic, London, United Kingdom. DESIGN: Retrospective comparative case series. METHOD: This was a video review comprising an equal number of consecutive bilateral LASIK patients for 2 surgeons following a standardized surgical protocol using the Visumax femtosecond laser and MEL 80 excimer laser. Timestamps were recorded for flap creation, flap lift, excimer laser ablation, and flap replacement. Total surgery time was defined with the endpoints of speculum insertion and removal. RESULTS: Each surgeon performed bilateral LASIK on 30 patients. The mean total surgery time was 11 minutes 17 seconds +/- 1 minute 46 seconds (SD) for surgeon 1 and 12 minutes 13 seconds +/- 1 minute 37 seconds for surgeon 2. The mean bilateral flap creation time was 3 minutes 5 seconds +/- 24 seconds and 3 minutes 42 seconds +/- 25 seconds, respectively. The mean suction time for an individual eye was 26 seconds +/- 4 seconds for surgeon 1 and 23 seconds +/- 1 second for surgeon 2. The difference in timing was accounted for by differences in the length of surgeon conversation with patients rather than by physical surgical steps. CONCLUSIONS: Bilateral LASIK procedure time was highly concordant within and between surgeons using a standardized surgical protocol. Use of a standardized surgical protocol can optimize the efficiency of corneal suction time as well as total surgical time while providing the expected equivalency in visual outcomes between surgeons. PMID- 26049834 TI - Multiple regression analysis in nomogram development for myopic wavefront laser in situ keratomileusis: Improving astigmatic outcomes. AB - PURPOSE: To describe and evaluate a new multiple regression-derived nomogram for myopic wavefront laser in situ keratomileusis (LASIK). SETTING: Moorfields Eye Hospital, London, United Kingdom. DESIGN: Prospective comparative case series. METHODS: Multiple regression modeling was used to derive a simplified formula for adjusting attempted spherical correction in myopic LASIK. An adaptation of Thibos' power vector method was then applied to derive adjustments to attempted cylindrical correction in eyes with 1.0 diopter (D) or more of preoperative cylinder. These elements were combined in a new nomogram (nomogram II). RESULTS: The 3-month refractive results for myopic wavefront LASIK (spherical equivalent <=11.0 D; cylinder <=4.5 D) were compared between 299 consecutive eyes treated using the earlier nomogram (nomogram I) in 2009 and 2010 and 414 eyes treated using nomogram II in 2011 and 2012. There was no significant difference in treatment accuracy (variance in the postoperative manifest refraction spherical equivalent error) between nomogram I and nomogram II (P = .73, Bartlett test). Fewer patients treated with nomogram II had more than 0.5 D of residual postoperative astigmatism (P = .0001, Fisher exact test). There was no significant coupling between adjustments to the attempted cylinder and the achieved sphere (P = .18, t test). CONCLUSIONS: Discarding marginal influences from a multiple regression-derived nomogram for myopic wavefront LASIK had no clinically significant effect on treatment accuracy. Thibos' power vector method can be used to guide adjustments to the treatment cylinder alongside nomograms designed to optimize postoperative spherical equivalent results in myopic LASIK. mentioned. PMID- 26049835 TI - Comparison of dual rotating Scheimpflug-Placido, swept-source optical coherence tomography, and Placido-scanning-slit systems. AB - PURPOSE: To compare measurements of corneal indices using dual rotating Scheimpflug-Placido, swept-source optical coherence tomography (OCT), and Placido scanning-slit systems. SETTING: Kangbuk Samsung Hospital, Seoul, South Korea. DESIGN: Prospective evaluation of diagnostic tests. METHODS: Corneal topography measurements were performed using dual rotating Scheimpflug-Placido (Galilei G2), swept-source OCT (Casia SS-1000), and Placido-scanning-slit (Orbscan IIz) systems. The intraclass correlation coefficients (ICCs) and Bland-Altman plots were used to evaluate the agreement between measurements. RESULTS: Fifty post refractive surgery eyes and 50 normal eyes were evaluated. The agreement in anterior keratometry and pachymetry between the 3 devices was high in both groups (ICC > 0.9). In both groups, the ICC values for posterior keratometry and eccentricity were high between the dual rotating Scheimpflug-Placido and swept source OCT systems (ICC > 0.9) but not between the Placido-scanning-slit system and the other 2 systems. The Placido-scanning-slit system yielded much steeper values for posterior keratometry in both groups (P < .05). The ICC values for posterior corneal elevation were lower than 0.9 between all 3 devices. The dual rotating Scheimpflug-Placido and swept-source OCT systems showed relatively higher ICC values than the Placido-scanning-slit system in both groups. Maximum posterior elevations were highest with the Placido-scanning-slit system followed by the swept-source OCT system and then the dual rotating Scheimpflug-Placido system. CONCLUSIONS: Anterior keratometry obtained using 3 devices showed high degrees of agreement. Posterior keratometry and eccentricity showed greater agreement between the dual rotating Scheimpflug-Placido and swept-source OCT systems than with the Placido-scanning-slit system. The dual rotating Scheimpflug Placido and swept-source OCT systems were equivalent in detecting the shape of the cornea and could be considered interchangeable. PMID- 26049836 TI - Effect of the equivalent refractive index on intraocular lens power prediction with ray tracing after myopic laser in situ keratomileusis. AB - PURPOSE: To determine the impact of the equivalent refractive index (ERI) on intraocular lens (IOL) power prediction for eyes with previous myopic laser in situ keratomileusis (LASIK) using custom ray tracing. SETTING: AMO B.V., Groningen, the Netherlands, and the Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA. DESIGN: Retrospective data analysis. METHODS: The ERI was calculated individually from the post-LASIK total corneal power. Two methods to account for the posterior corneal surface were tested; that is, calculation from pre-LASIK data or from post-LASIK data only. Four IOL power predictions were generated using a computer-based ray-tracing technique, including individual ERI results from both calculation methods, a mean ERI over the whole population, and the ERI for normal patients. For each patient, IOL power results calculated from the four predictions as well as those obtained with the Haigis-L were compared with the optimum IOL power calculated after cataract surgery. RESULTS: The study evaluated 25 patients. The mean and range of ERI values determined using post-LASIK data were similar to those determined from pre LASIK data. Introducing individual or an average ERI in the ray-tracing IOL power calculation procedure resulted in mean IOL power errors that were not significantly different from zero. The ray-tracing procedure that includes an average ERI gave a greater percentage of eyes with an IOL power prediction error within +/-0.5 diopter than the Haigis-L (84% versus 52%). CONCLUSION: For IOL power determination in post-LASIK patients, custom ray tracing including a modified ERI was an accurate procedure that exceeded the current standards for normal eyes. PMID- 26049837 TI - Influence of intraocular astigmatism on the correction of myopic astigmatism by femtosecond laser small-incision lenticule extraction. AB - PURPOSE: To evaluate the influence of the origin of astigmatism on the correction of myopia or myopic astigmatism by femtosecond laser small-incision lenticule extraction (SMILE). SETTING: Ophthalmology Department, Eye and ENT Hospital, Shanghai, China. DESIGN: Prospective case series. METHODS: Small-incision lenticule extraction was performed to correct myopia or myopic astigmatism. Ocular residual astigmatism (ORA) was determined by vector analysis using manifest refraction and Scheimpflug camera imaging of the anterior cornea. Patients were divided into 2 groups according to ORA (high >1.0 diopter [D]; low <=1.0 D), and procedural efficacy was compared. Patients were examined preoperatively and 1, 3, and 6 months postoperatively. RESULTS: This study comprised 122 right eyes of 122 patients. No significant difference was found in the preoperative manifest astigmatism (target-induced astigmatism [TIA]) between the low ORA group (n = 67) and high ORA group (n = 55). The mean postoperative manifest astigmatism was higher in the high ORA group at all postoperative timepoints (1 month: t = 2.182, P=.031; 3 months: t = 2.30, P=.023; 6 months: t = 2.193, P=.03). The mean index of success (postoperative astigmatism/TIA) was 0.68 in the high ORA group and 0.34 in the low ORA group 1 month postoperatively (t = 2.531, P=.013); 0.73 and 0.39, respectively, at 3 months (t = 2.689, P=.008); and 0.77 and 0.46, respectively, at 6 months (t = 2.105, P=.037). CONCLUSION: Small incision lenticule extraction was effective in correcting astigmatism but may be less effective in correcting ORA. PMID- 26049838 TI - Effect of keratoconus grades on repeatability of keratometry readings: Comparison of 5 devices. AB - PURPOSE: To determine the repeatability of keratometry (K) measurements of a Scheimpflug pachymeter (Pentacam), Placido topographer (Eyesys), scanning-slit corneal topographer (Orbscan), partial coherence interferometry (PCI) device (IOLMaster), and Javal manual keratometer with different grades of keratoconus. SETTING: Noor Eye Hospital, Tehran, Iran. DESIGN: Retrospective case series. METHODS: Keratometry was performed first with Scheimpflug pachymetry followed, in order, by Placido topography, scanning-slit corneal topography, PCI, and manual keratometry. Repeatability was examined in groups with a maximum K of less than 50.0 diopters (D), 50.0 to 55.0 D, and more than 55.0 D. RESULTS: Seventy-eight eyes of 45 keratoconus patients were assessed. In Group 1, repeatability was highest with Scheimpflug pachymetry and lowest with scanning-slit corneal topography (0.36 to 1.24). In Group 2, the intraclass correlation coefficients (ICCs) for maximum K ranged from 0.823 with the scanning-slit corneal topography to 0.974 with Scheimpflug pachymetry. The repeatability index for minimum K (0.53 to 2.11) and maximum K (0.60 to 1.92) in this group was highest with Scheimpflug pachymetry and with for scanning-slit corneal topography. In Group 3, the ICCs for minimum K and maximum K ranged from 0.890 to 0.990, and the repeatability index for minimum K varied between 1.66 with Scheimpflug pachymetry to 2.98 with Placido topography; for maximum K, the index was from 2.15 with PCI to 2.81 with the manual keratometer. CONCLUSIONS: In mild keratoconus, the 5 devices had acceptable repeatability in K readings. In cases with a maximum K reading greater than 55.0 D, all devices had reduced repeatability as a result of measurement errors; thus, measurements might not be so reliable. PMID- 26049839 TI - Amount of aspheric intraocular lens decentration that maintains the intraocular lens' optical advantages. PMID- 26049840 TI - Tale of a twist: Progressive postoperative intraocular lens tilt from a twisted haptic. PMID- 26049841 TI - Cataract Surgical Problem: May consultation #1. PMID- 26049842 TI - May consultation #2. PMID- 26049843 TI - May consultation #3. PMID- 26049844 TI - May consultation #5. PMID- 26049845 TI - May consultation #4. PMID- 26049846 TI - May consultation #7. PMID- 26049847 TI - May consultation #6. PMID- 26049848 TI - May consultation #8. PMID- 26049849 TI - May consultation #9. PMID- 26049850 TI - May consultation #10. PMID- 26049851 TI - Risk of circumferential viscodilation in viscocanalostomy. PMID- 26049852 TI - Reply: To PMID 25450241. PMID- 26049853 TI - Reply: To PMID 25466483. PMID- 26049854 TI - Femtosecond versus (gold) standard phacoemulsification. PMID- 26049855 TI - Reevaluating intracameral cefuroxime as a prophylaxis against endophthalmitis after cataract surgery. PMID- 26049856 TI - Myopic eyes develop cataracts at an earlier age. PMID- 26049857 TI - Reply: To PMID 25661126. PMID- 26049858 TI - Congenital rubella syndrome: Global issue. PMID- 26049859 TI - Reply: To PMID 25641242. PMID- 26049860 TI - Detectable Symptomatology Preceding the Diagnosis of Pancreatic Cancer and Absolute Risk of Pancreatic Cancer Diagnosis. AB - The survival duration for pancreatic cancer is short. Given its low lifetime risk (1.5%), established factors for the disease have insufficient specificity to identify individuals at high risk of nonfamilial cancer, and prediagnostic signs and symptoms are vague and not limited to pancreatic causes. We considered whether statistical models that incorporated both risk factors and prediagnosis symptomatology could improve prediction enough to provide practical risk estimates. We combined US Surveillance Epidemiology and End Results (SEER) incidence data from 2008 to 2010 with regression models from representative case control data from Connecticut (2005-2009) to estimate age- and sex-specific 5 year absolute risks of pancreatic cancer diagnosis. Our risk model included current cigarette smoking (adjusted odds ratio (OR) = 3.3, 95% confidence interval (CI): 2.1, 5.0), current use of proton pump-inhibitor antiheartburn medications (OR = 6.2, 95% CI: 1.7, 23), recent diagnosis of diabetes mellitus (OR = 4.8, 95% CI: 2.2, 11), recent diagnosis of pancreatitis (OR = 19, 95% CI: 3.1, 120), Jewish ancestry (OR = 1.8, 95% CI: 1.1, 3.1), and ABO blood group other than O (OR = 1.3, 95% CI: 1.0, 1.8). In total, 0.87% of controls with combinations of these factors had estimated 5-year absolute risks greater than 5%, and for some, the risks reached more than 10%. Combining risk factors for pancreatic cancer with detectable prediagnostic symptomatology can allow investigators to begin to identify small segments of the population with risks sufficiently high enough to make screening efforts among them potentially useful. PMID- 26049861 TI - Risch et al. Respond to "Clinical Utility of Prediction Models for Rare Outcomes: The Example of Pancreatic Cancer". PMID- 26049862 TI - Invited Commentary: Clinical Utility of Prediction Models for Rare Outcomes--The Example of Pancreatic Cancer. AB - Translating relative risk estimates into absolute risks is important in evaluating the potential clinical and public health relevance of etiologic discoveries. Predicting high absolute risk is challenging, particularly for rare endpoints such as pancreatic cancer. Recent efforts to develop risk prediction models for pancreatic cancer have found moderate risk levels for very small parts of the population. A new approach in which clinical symptoms and medication use are evaluated in addition to information on risk factors is presented by Risch et al. in this issue of the Journal (Am J Epidemiol. 2015;182(1):26-34). The authors estimated absolute risks based on the relative risks obtained from their case control study. Their absolute risk estimates were higher than those from previous approaches but remained restricted to a very small proportion of the general population. In the present commentary, we address issues of absolute risk stratification (particularly for rare diseases), specific analytic methods, and how actionable information will differ based on the disease and possible intervention. We suggest that moving from cancer-specific models to broader models used to predict risk for multiple outcomes can make risk prediction for rare diseases more effective. When considering translational goals, it is important to estimate absolute risk at the early stages of etiologic research. The results can be sobering but allow focusing on the most promising goals. PMID- 26049863 TI - Long-term functional outcomes following non-radiated urethrovaginal fistula repair. AB - OBJECTIVE: To review long-term functional outcomes after urethrovaginal fistula (UVF) repair. MATERIALS AND METHODS: Following IRB approval, women who underwent transvaginal non-irradiated UVF repair with minimum 6-month follow-up were reviewed. Surgical outcomes were assessed by validated questionnaires: UDI-6, IIQ 7, FSFI and visual analogue scale for QoL. Two groups were compared: (1) synthetic sling-related versus (2) non-sling-related UVF. Descriptive statistics were applied with p < 0.05 for significance. RESULTS: From 1996 to 2013, 18 patients underwent UVF repair, with a mean age of 46 years (range 20-66), BMI 29 (range 21-42) and mean follow-up at 52 months (range 9-142). Overall repair success rate was 95%. Prior failed UVF repair was recorded in 11 women (61%). Statistical differences noted for Q4: 1.9 versus 0.8 (p = 0.03) and Q5: 1.3 versus 0 (p = 0.02) and VAS between the two groups, favoring the non-sling group; 1.5 (0.6) versus 5 (4) (p = 0.05). No differences in IIQ-7 were noted between the two groups (p = 0.09). Of the 18 patients, 5 remained sexually active and of those, 2 responded to FSFI (40%) with low scores. Reoperation rate was 33% (6 women) with 3 requiring periurethral-bulking agent for recurrent SUI, 2 transurethral laser for residual urethral sling mesh strands and 1 urethral dilation. CONCLUSION: This large contemporary series of non-radiated UVF indicates a satisfactory outcome in UVF closure repair at a mean 4- to 5-year long-term follow-up, with the synthetic sling-related group performing worse. PMID- 26049864 TI - No matter which way: IS 10 or 11/12 FRENCH access the rising new standard in kidney stone surgery 2015? PMID- 26049865 TI - Psychometric validation of a German language version of a PROM for urethral stricture surgery and preliminary testing of supplementary ED and UI constructs. AB - PURPOSE: To validate a German language version of the patient-reported outcome measurement (PROM) following urethral stricture surgery (USS) in a cohort of men undergoing one-stage buccal mucosa graft urethroplasty (BMGU) for urethral stricture. Furthermore, to explore the responsiveness of erectile function (EF) and urinary incontinence (UI) constructs in the context of this intervention. METHODS: The USS-PROM captures voiding symptoms (ICIQ-MLUTS) and health-related quality of life (HRQoL) (EQ-5D). To evaluate EF and UI, the IIEF-5 and ICIQ-UI SF were included. Between March 2012 and April 2013, all patients undergoing BMGU at our institution were prospectively enrolled in this study. Psychometric assessment included internal consistency, test-retest reliability, criterion validity and responsiveness. RESULTS: Ninety-three men completed the USS-PROM before and 3 months after surgery, with 40 (43 %) also completing the USS-PROM 6 months after surgery to assess reliability. Internal consistency: for the ICIQ MLUTS, Cronbach's alpha was 0.83. The test-retest intraclass correlation coefficient was 0.94. There was a negative correlation between change in ICIQ MLUTS total score and change in Q max (r = -0.40). All values exceeded our predefined thresholds. Significant improvements of voiding symptoms and HRQoL demonstrate responsiveness to change (all p values <0.001). While ICIQ-UI scores did not change (p > 0.05), IIEF-5 scores improved significantly (p = 0.048). CONCLUSIONS: The German language USS-PROM shows similar psychometric properties to the English language version. This instrument can be improved by assessing EF by the use of IIEF-5. Further studies with larger patient cohorts are needed to evaluate the significance of measuring UI in urethroplasty patients. PMID- 26049866 TI - Cranberry fruit powder (FlowensTM) improves lower urinary tract symptoms in men: a double-blind, randomized, placebo-controlled study. AB - BACKGROUND: Lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia increase with age. To date, several medications are available to treat LUTS, including herbal remedies which offer less side effects but lack robust efficacy studies. METHODS: This 6-month, randomized, double-blind, placebo-controlled study aimed at evaluating the dose effect of 250 or 500 mg cranberry powder (FlowensTM) on LUTS and uroflowmetry in men over the age of 45. A total of 124 volunteers with PSA levels <2.5 ng/mL and an international prostate symptoms score (IPSS) score >=8 were recruited and randomized. The primary outcome measure was the IPSS, evaluated at 3 and 6 months. Secondary outcome measures included quality of life, bladder volume (Vol), maximum urinary flow rate (Q max), average urinary flow rate (Q ave), ultrasound-estimated post-void residual urine volume (PVR), serum prostate-specific antigen, selenium, interleukin 6, and C-reactive protein at 6 months. RESULTS: After 6 months, subjects in both FlowensTM groups had a lower IPSS (-3.1 and -4.1 in the 250- and 500-mg groups, p = 0.05 and p < 0.001, respectively) versus the placebo group (-1.5), and a dose-response effect was observed. There were significant differences in Q max, Q ave, PVR, and Vol in the FlowensTM 500-mg group versus baseline (p < 0.05). A dose-dependent effect on Vol was observed, as well as on PVR, for participants with a nonzero PVR. There was no effect on clinical chemistry or hematology markers. CONCLUSIONS: FlowensTM showed a clinically relevant, dose-dependent, and significant reduction in LUTS in men over 45. PMID- 26049868 TI - Current controversies in functional urology. PMID- 26049867 TI - Nrf2 is essential for the anti-inflammatory effect of carbon monoxide in LPS induced inflammation. AB - INTRODUCTION: Carbon monoxide (CO) released from CORM-2 has anti-inflammatory function, but the critical molecule mediating the inflammation inhibition has not been elucidated. Previous studies indicate that CORM-2 can activate Nrf2, a key transcription factor regulating host defense against oxidative stress and inflammation-related disorders. In this study we use Nrf2 knockout mice to determine the role of Nrf2 in mediating the CO anti-inflammatory action. METHODS: We compared CORM-2's inhibiting effect on pro-inflammatory cytokine expressions (TNF-alpha, IL-1beta and IL-6 and iNOS) in primary peritoneal macrophages, mouse liver and brain tissues from Nrf2(+/+) and Nrf2(-/-) mice. We further assayed the inflammatory cell infiltration in both liver and brain tissues of the Nrf2(+/+) and Nrf2(-/-) mice. Finally, we examined CORM's influence on mouse mortality in a mouse sepsis model. RESULTS: Our results showed that CORM-2 dramatically inhibited the expression of pro-inflammatory cytokines in Nrf2(+/+) mice, but not in Nrf2(-/-) mice. Furthermore CORM-2 substantially decreased LPS-induced mouse mortality of Nrf2(+/+) mice, but not of Nrf2(-/-) mice. CONCLUSION: We conclude that Nrf2 is indispensable for CORM-2 inhibition of LPS-induced inflammation. PMID- 26049869 TI - Management of complications of mesh surgery. AB - PURPOSE OF REVIEW: Transvaginal placements of synthetic mid-urethral slings and vaginal meshes have largely superseded traditional tissue repairs in the current era because of presumed efficacy and ease of implant with device 'kits'. The use of synthetic material has generated novel complications including mesh extrusion, pelvic and vaginal pain and mesh contraction. In this review, our aim is to discuss the management, surgical techniques and outcomes associated with mesh removal. RECENT FINDINGS: Recent publications have seen an increase in presentation of these mesh-related complications, and reports from multiple tertiary centers have suggested that not all patients benefit from surgical intervention. SUMMARY: Although the true incidence of mesh complications is unknown, recent publications can serve to guide physicians and inform patients of the surgical outcomes from mesh-related complications. In addition, the literature highlights the growing need for a registry to account for a more accurate reporting of these events and to counsel patients on the risk and benefits before proceeding with mesh surgeries. PMID- 26049870 TI - Evaluation of obstructed voiding in the female: how close are we to a definition? AB - PURPOSE OF REVIEW: The difficulties of defining and evaluating bladder outlet obstruction (BOO) in the female patient have been described for several years. This review aims to examine recent literature to summarize progress in the area. RECENT FINDINGS: Within the last 2 years, functional causes of female BOO have been summarized, new nomograms proposed, several case reports of different causes of BOO have been published and work on surgical outcomes and possible diagnostics reported. SUMMARY: Women complain of voiding dysfunction because of different reasons. For clinical decision-making, and to evaluate different surgical procedures, finding a way of detecting and quantifying infravesical obstruction is immensely helpful. This review aims to clarify questions concerning definitions of BOO in women and provide an update on recent advances. PMID- 26049871 TI - Have mini-slings come of age? AB - PURPOSE OF REVIEW: To highlight the recent data published about mini-slings for management of female stress urinary incontinence, focusing on the past 12 months. RECENT FINDINGS: Mini-slings, implanted by single vaginal incision, have been increasingly used in recent years. SUMMARY: A significant number of new clinical trials have investigated the efficacy of single incision mini-slings (SIMS) in the past years. Meta-analyses have shown growing evidence supporting their use, but a number of limitations go against a wide, immediate, and unconditional diffusion of these techniques. First, the majority of the trials published investigated the TVT-Secur device, which is considered to be inferior to traditional slings and is no more used in clinical practice. All other SIMS have been tested in clinical trials but there is insufficient evidence to routinely recommend their use, mainly because long-term data are lacking. SIMS have to be considered as a heterogeneous group, and results obtained with one device cannot be translated to another. The safety profile of recently introduced SIMS seems good, with potential reduction of postoperative pain and faster recovery. However, further research is necessary to clearly establish their noninferiority regarding efficacy after 1 year compared to traditional transobturator tapes and TVT, and ascertain their benefits in daily clinical practice. PMID- 26049872 TI - What part does mesh play in urogenital prolapse management today? AB - PURPOSE OF REVIEW: The present review examines the pros and cons of the controversial role of mesh in the management of pelvic organ prolapse (POP). With a view to understanding where we are going, we analyzed recent data, highlighting the most important and interesting articles that were published in the past 12 months. RECENT FINDINGS: Four main themes emerged. US Food and Drug Administration warnings stimulated an ongoing debate about the role of controversial trans-vaginal mesh, with some uro-gynaecologists tending to provide evidence that trans-vaginal mesh is safe whereas others advocated less aggressive abdominal procedures because minimally invasive techniques such as laparoscopy and robot-assisted surgery seem to provide similar outcomes. Recent systematic reviews and a meta-analysis of POP surgery compared mesh and native tissues, addressing functional outcomes and complications. Finally, ongoing research into new materials might open up further opportunities in the controversial field of POP surgery with mesh. SUMMARY: The use of mesh for reconstruction of pelvic floor anatomical defects plays a key role in POP management. Given the controversy about the pros and cons of native tissue POP repair versus mesh repair and mesh-related complications, uro-gynaecologists are moving toward alternative surgical approaches and new materials. PMID- 26049873 TI - The management of overactive bladder: percutaneous tibial nerve stimulation, sacral nerve stimulation, or botulinum toxin? AB - PURPOSE OF REVIEW: We have reviewed the evidence published on botulinum toxin A (BoNT/A), percutaneous tibial nerve stimulation (PTNS), and sacral nerve stimulation (SNS) in the management of overactive bladder (OAB). RECENT FINDINGS: BoNT/A is effective irrespectively of the number of previous anticholinergic treatments and of the reason for failure. Doses up to 360U 3-monthly are well tolerated. BoNT/A is well tolerated and effective also in the pediatric population. Bladder instillation of liposome encapsulated BoNT/A is a new approach, deserving further research. When using PTNS, motor response from the electrical stimulus is not required, a sensory response suffices. PTNS has a lasting effect compared to oxybutynin alone. SNS is superior to standard medical treatment but the combination of SNS and anticholinergics is more effective than anticholinergic alone. SUMMARY: The evidence published in the last 18 months has increased the level of evidence on safety and effectiveness of BoNT/A, PTNS, and SNS in the management of OAB. BoNT/A is now recommended as standard third-line treatment for OAB (in the USA) and urgency incontinence (in the USA and in Europe) in selected patients refractory to pharmacological therapy. All available third-line treatment options for OAB/urgency urinary incontinence should be offered before surgery is contemplated. VIDEO ABSTRACT: http://links.lww.com/COU/A7. PMID- 26049874 TI - Pelvic floor spasm as a cause of voiding dysfunction. AB - PURPOSE OF REVIEW: Pelvic floor disorders can present with lower urinary tract symptoms, bowel, sexual dysfunction, and/or pain. Symptoms of pelvic muscle spasm (nonrelaxing pelvic floor or hypertonicity) vary and can be difficult to recognize. This makes diagnosis and management of these disorders challenging. In this article, we review the current evidence on pelvic floor spasm and its association with voiding dysfunction. RECENT FINDINGS: To distinguish between the different causes of voiding dysfunction, a video urodynamics study and/or electromyography is often required. Conservative measures include patient education, behavioral modifications, lifestyle changes, and pelvic floor rehabilitation/physical therapy. Disease-specific pelvic pain and pain from pelvic floor spasm needs to be differentiated and treated specifically. Trigger point massage and injections relieves pain in some patients. Botulinum toxin A, sacral neuromodulation, and acupuncture has been reported in the management of patients with refractory symptoms. SUMMARY: Pelvic floor spasm and associated voiding problems are heterogeneous in their pathogenesis and are therefore often underrecognized and undertreated; it is therefore essential that a therapeutic strategy needs to be personalized to the individual patient's requirements. Therefore, careful evaluation and assessment of individuals using a multidisciplinary team approach including a trained physical therapist/nurse clinician is essential in the management of these patients. PMID- 26049875 TI - Leak point pressures: how useful are they? AB - PURPOSE OF REVIEW: The present article reviews the literature from the last 12 months relevant to our understanding of leak point pressures. RECENT FINDINGS: Literature is reviewed regarding leak point pressures. SUMMARY: There remains a need for larger randomized trials, investigating urodynamic parameters with relation to effective surgical management of urinary stress incontinence. PMID- 26049876 TI - An update on urotrauma. AB - PURPOSE OF REVIEW: The subject of genitourinary trauma was recently reviewed as an American Urologic Association guideline as well as recently updated as a European Association of Urology guideline. These guidelines, while complete and authoritative, deserve review, amplification and clarification. Also, notably absent from the guidelines is a section on the management of renovascular injuries, which will be reviewed here. RECENT FINDINGS: In the 2014, the American Urologic Association and updated European Association of Urology guidelines were published with highlighted features or changes described here. SUMMARY: We report the updated features of the guidelines as well as sections of update from our own experiences in which the guidelines remain vague or are absent. PMID- 26049877 TI - Management of iatrogenic ureteral injury and techniques for ureteral reconstruction. AB - PURPOSE OF REVIEW: Ureteral reconstruction is still a sophisticated approach. Because of an increase in endoscopic procedures for kidney and ureteral stone treatment, radiation therapy and pelvic surgery, ureteral strictures are more frequently observed. Short proximal and distal strictures can be reconstructed by using the renal pelvis or urinary bladder. New techniques are needed for reconstruction of long strictures as well as those located in the middle ureter. RECENT FINDINGS: This article summarizes very recent studies from 2014, investigating new techniques and their functional outcome of procedures for ureteral reconstruction. In an open reconstruction, some new techniques to reconstruct full-length ureter defects using bladder flaps or by intestinal onlay techniques were described. In addition, laparoscopic and robotic reconstruction methods as well as single site procedures demonstrated feasibility. Visualizing the ureter using near-infrared fluorescence techniques for prevention of ureteral injuries is also a new aspect. Future targets focus on the development of artificial transplants by tissue engineering for ureteral reconstruction. SUMMARY: Novel open and minimally invasive techniques for reconstruction of full length and middle ureter strictures demonstrated feasibility in the past year. Although reasonable outcomes were reported, current results are significantly compromised by short-term follow-up. To date, artificial transplants remain experimental. PMID- 26049878 TI - Urethroplasty in radiation-induced strictures. AB - PURPOSE OF REVIEW: In patients presenting with urethral stricture disease, the mainstay of definitive treatment is urethroplasty. Until recently, it was unclear if urethroplasty was a feasible option in patients with urethral stricture secondary to pelvic radiation exposure. We review the feasibility and outcomes for urethroplasty in patients with radiation-induced urethral stricture. RECENT FINDINGS: Urethroplasty in patients exposed to radiation can be technically challenging secondary to stricture location and tissue damage; however, it still has an acceptable success rate with durable outcomes. Most radiation-induced strictures are limited in length, located in the bulbomembranous region, and are amenable to excision and primary anastomosis. There are higher rates of postoperative urinary incontinence in this cohort when compared with outcomes for urethroplasty without radiation exposure; however, erectile function appears to be preserved. SUMMARY: Recent studies highlight that urethroplasty has acceptable success rates in men with radiation-induced urethral stricture. Patients in this cohort need to be counseled on the potential for urinary incontinence following urethroplasty. PMID- 26049879 TI - Contemporary surgical management of female urethral stricture disease. AB - PURPOSE OF REVIEW: Female urethral stricture disease is increasingly recognized as an uncommon but important cause of lower urinary tract symptoms in women, which is amenable to surgical treatment. Several new reconstructive techniques have recently been described. The purpose of this review is to summarize the past literature with a focus on more recent contributions. RECENT FINDINGS: Several new studies have recently been published investigating previously described reconstructive techniques including vaginal flap urethroplasty using the ventral approach, ventral labial graft, dorsal vaginal graft and dorsal buccal mucosal graft urethroplasty. Success rates, variably defined, ranged from 57.1 to 100% in these new contributions. No incidences of stress urinary incontinence were described. There continues to be lack of robust evidence to advocate one technique of urethroplasty for female urethral stricture disease over another, surgeon experience is likely to be an important factor. SUMMARY: Urethroplasty using a flap or graft augmentation is a feasible treatment for female urethral strictures with good reported success rates and a minimal risk of stress of incontinence. Further studies are required to define the optimal technique and approach. PMID- 26049880 TI - The devastated bladder outlet: treatment options. AB - PURPOSE OF REVIEW: The purpose of this study is to review and discuss recently published studies of therapeutic options in cases with the combination of severe sphincteric damage and recurrent stricture of the bladder neck or anastomosis in patients with postradical prostatectomy. RECENT FINDINGS: Recent focus has been on successful management of recurrent bladder neck contracture with urethral dilatation or endoscopic techniques even in patients with prior history of additional radiation therapy. In addition, some authors include injectable agents in their armamentarium for the treatment of recurrent bladder neck stricture. Failure of all attempts to restore the bladder outlet and urethral patency results in a devastated bladder outlet with persistence of urinary incontinence, sometimes worsened when combined with recurrent obstruction. For this small subgroup of patients with severe damage of the lower urinary tract, treatment options are rare. In the current literature, several case series can be found, but no clinical trials exist to provide an evidence-based approach to this severe disorder. Open reconstructive techniques or urinary diversion with reservoirs made from bowel are necessary in these patients. In recent studies, laparoscopic and robot-assisted approaches have also been described. SUMMARY: In case of a 'nonreconstructible' devastated bladder outlet treatment, options are limited. These devastating conditions require a definitive surgical solution. Bladder neck closure, continent vesicostomy in most cases combined with augmentation or urinary diversion with or without cystectomy are last resort techniques for this problem. PMID- 26049882 TI - Quantitative Analysis of the Visor-Like Vertical Motion of the Cricoarytenoid Joint in the Living Subject. AB - OBJECTIVES: The cricoarytenoid joint has a loose capsule and large cavity and may allow the arytenoid distanced from the cricoid cartilage. The objective was to quantify vertical motion of the arytenoid cartilage in the living subject. STUDY DESIGN: This is a prospective study. METHODS: Axial computed tomography images from 35 healthy subjects and seven patients with unilateral vocal fold paralysis were collected at inspiration and phonation. The perpendicular distance from the arytenoid vocal process (VP) or muscular process (MP) to the cricoid plane was measured and analyzed. RESULTS: During phonation, the range of the vertical movement of the VP was significantly wider than that of the MP. The vertical motion varies in sides, sexes, and ages. The vertical gaps of the VP and MP between the paralyzed and contralateral sides were about 0.8 mm and 1.5 mm, respectively. CONCLUSIONS: This study confirms a visor-like downward vertical motion of the arytenoid cartilage during phonation. PMID- 26049883 TI - An ophthalmology update for primary care practitioners from the Canadian Journal of Ophthalmology. PMID- 26049884 TI - Reprint of: Primary care physicians' knowledge of the ophthalmic effects of diabetes. AB - OBJECTIVE: Previous studies suggest that many patients with diabetes do not receive an annual dilated eye examination because of a lack of referrals from primary care physicians (PCPs). This study aims to determine the depth of knowledge of PCPs regarding diabetic eye disease. DESIGN: Cross-sectional assessment. PARTICIPANTS: Ninety-seven PCPs. METHODS: An 8-question, multiple choice assessment was administered over a 3-month period to 208 PCPs in attendance at continuing medical education conferences. RESULTS: Ninety-seven PCPs completed the assessment. Participants had a mean total score of 5.9 of 8 possible (73.8%). Questions regarding screening, clinical findings, and prevention were answered correctly by >= 81% of the respondents. However, questions regarding risk factors and complications were answered correctly by less than 35% of the respondents. No difference in scores was found based on the type of residency training received or the number of years in practice. CONCLUSIONS: Although PCPs may require greater education in the complications and risk factors of diabetic eye disease, study participants demonstrated a good overall depth of knowledge regarding diabetic eye disease. Thus, previous reports of only 35% to 55% of patients with diabetes receiving an annual dilated fundus examination are likely not due to a lack of physician education. PMID- 26049885 TI - Reprint of: Relationship between cataract severity and socioeconomic status. AB - OBJECTIVE: To determine the relationship between cataract severity and socioeconomic status (SES). DESIGN: Retrospective, observational case series. A total of 1350 eyes underwent phacoemulsification cataract extraction by a single surgeon using an Alcon Infiniti system. Cataract severity was measured using phaco time in seconds. SES was measured using area-level aggregate census data: median income, education, proportion of common-law couples, and employment rate. Preoperative best corrected visual acuity was obtained and converted to logarithm of the minimum angle of resolution values. For patients undergoing bilateral surgery, the generalized estimating equation was used to account for the correlation between eyes. Univariate analyses were performed using simple regression, and multivariate analyses were performed to account for variables with significant relationships (p < 0.05) on univariate testing. Sensitivity analyses were performed to assess the effect of including patient age in the controlled analyses. RESULTS: Multivariate analyses demonstrated that cataracts were more severe when the median income was lower (p = 0.001) and the proportion of common-law couples living in a patient's community (p = 0.012) and the unemployment rate (p = 0.002) were higher. These associations persisted even when controlling for patient age. CONCLUSION: Patients of lower SES have more severe cataracts. PMID- 26049886 TI - Reprint of: Survey of patients with age-related macular degeneration: knowledge and adherence to recommendations. AB - OBJECTIVE: To evaluate the patient's understanding of the importance and adherence to the various lifestyle and Age-Related Eye Disease Study (AREDS) supplement recommendations for age-related macular degeneration (AMD). DESIGN: Cross-sectional study. PARTICIPANTS: Patients with AMD treated at the vitreoretinal service clinic. METHODS: Telephone questionnaire survey was administered to assess knowledge and adherence to various recommendations made to patients with AMD about lifestyle and AREDS supplements in this single institution study. RESULTS: Among 92 patients with AMD contacted, dietary modification, exercise and weight reduction, smoking cessation, and AREDS supplementation recommendations were recalled by 47 (51%), 21 (23%), 5 (5%), and 90 (98%) patients, respectively. The necessity of making these interventions was believed by 29 (62%), 16 (76%), 4 (80%), and 67 (74%) patients, respectively. Patient adherence to dietary modification was 81%, to exercise and weight reduction was 76%, to smoking cessation was 0%, and to AREDS supplementation was 88% (71% on correct dose). Financially, 29% of the patients noted a mean increase of $88 per month in expenditure because of making dietary modifications, but most reported such as justified; 61% noted a mean increase of $25 per month in expenditure from consumption of AREDS supplements, and most (96%) believed this was justified. CONCLUSIONS: Patients with AMD recalled recommendations for AREDS supplementation more often than other lifestyle changes but generally felt recommendations were necessary and affordable. Adherence to smoking cessation recommendation was poor (0%), but to other recommendations was good. PMID- 26049887 TI - Reprint of: Aspirin use and early age-related macular degeneration: a meta analysis. AB - OBJECTIVE: The aim of this review was to evaluate the evidence for an association between Aspirin use and early age-related macular degeneration (ARMD). METHODS: A literature search was performed in 5 databases with no restrictions on language or date of publication. Four studies involving 10292 individuals examining the association between aspirin and ARMD met the inclusion criteria. Meta-analysis was carried out by Cochrane Collaboration Review Manager 5.2 software (Cochrane Collaboration, Copenhagen, Denmark). RESULTS: The pooled odd ratios showed that Aspirin use was associated with early ARMD (pooled odds ratio 1.43, 95% CI 1.09 1.88). CONCLUSIONS: There is a small but statistically significant association between Aspirin use and early ARMD, which may warrant further investigation. PMID- 26049889 TI - Reprint of: Barriers to accessing low-vision care: the patient's perspective. AB - OBJECTIVE: To review the literature regarding barriers that hinder access to low vision (LV) care from the perspective of individuals with vision impairment. DESIGN: Literature review. METHODS: PubMed and Scopus were used to identify relevant cross-sectional studies of awareness of, and barriers to, LV rehabilitation. Studies were included if they met the following criteria: (i) year of publication within the past 20 years (between 1992 and 2012), and (ii) participants of the study included individuals with vision impairment. Fourteen studies met the criteria for inclusion and were included in this review. RESULTS: Barriers to accessing low-vision service (LVS), from the perspective of individuals with vision impairment, included the following: misconceptions of LVSs, miscommunication by eye care professionals, lack of awareness, location and transportation, the need to appear independent, negative societal views, influence of family and friends, insufficient visual impairment to warrant services, cost of LVS, and reduced perception of vision loss relative to other losses in life. Other factors that were associated with lower use of LVS included income level, comorbidities, and education level. CONCLUSIONS: The reasons for not accessing LV rehabilitation are complex, and some may be more easily addressed than others. A heightened awareness of LV rehabilitation may be achieved with better communication by eye care professionals and with public education. The stigma associated with the usage of LV aids and admitting a disability still seems to exist, but may be reduced by increasing societal understanding of LV. PMID- 26049890 TI - Reprint of: Health literacy in Canada and the ophthalmology patient. AB - Health literacy represents the cognitive and social skills that determine the motivation and ability of individuals to gain access to, understand, and use information in ways that promote and maintain good health.(1) According to the 2003 International Adult Literacy and Life Skills Survey (IALSS), over 12 million (60%) adult Canadians lack the capacity to obtain, understand, and act on health information and services, as well as make appropriate health decisions on their own.(2,3) Of these 12 million Canadians, the elderly are the most health illiterate age group in Canada. What this suggests for Canadian physicians is that to improve the CanMEDS roles of communicator and health advocate,(4) physicians need to recognize health literacy as a modifiable contributor of poor health outcomes and work to remove literacy-related barriers.(5) This is particularly important for ophthalmologists who manage chronic illnesses in elderly patients.(2,6,7) The objective of this review is 2-fold. The first objective is to describe health literacy in Canada and provide a summary on the current state of health literacy research, both generally in medicine and specifically to Ophthalmology. The second objective is to propose a 3-step approach of evidence based techniques for managing low health literate patients in clinic. PMID- 26049891 TI - The family practitioner's role in ophthalmic care: an update from the CJO. PMID- 26049893 TI - Reprint of: Social phobia and other psychiatric problems in children with strabismus. AB - OBJECTIVE: To investigate the rate of social phobia, anxiety, depression, and other psychiatric problems in children with strabismus. DESIGN: Prospective, cross-sectional, case-control study. PARTICIPANTS: Forty-two children with strabismus and 47 control subjects 8-13 years of age were enrolled in this study. METHODS: After the ophthalmologist's examination, all cases were assessed by a psychiatrist based on the structured interview technique of Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version (Kiddie-SADS-PL). The Screen for Child Anxiety Related Emotional Disorders (SCARED) was administered to each subject to evaluate social phobia. All participants completed the Children's Depression Inventory (CDI). RESULTS: Age as well as sex and income were comparable between the strabismus patients and control groups. Social phobia was diagnosed in 8 (19.04%) of the 42 strabismic children and in 1 (2.12%) of the control subjects. The CDI and SCARED (total score, social phobia, separation anxiety) scores of strabismus patients were significantly higher than the control group (p = 0.001, p = 0.004, p = 0.0001, p = 0.05, respectively). CONCLUSIONS: A relationship between strabismus in children and social phobia, depression, and anxiety on a symptom basis was underlined by our data. PMID- 26049894 TI - Achieving attainable outcomes from good science in an untidy world: case studies in land and air pollution. AB - While scientific understanding of environmental issues develops through careful observation, experiment and modelling, the application of such advances in the day to day world is much less clean and tidy. Merseyside in northwest England has an industrial heritage from the earliest days of the industrial revolution. Indeed, the chemical industry was borne here. Land contamination issues are rife, as are problems with air quality. Through the examination of one case study for each topic, the practicalities of applied science are explored. An integrated, multidisciplinary response to pollution needs more than a scientific risk assessment. The needs of the various groups (from public to government) involved in the situations must be considered, as well as wider, relevant contexts (from history to European legislation), before a truly integrated response can be generated. However, no such situation exists in isolation and the introduction of environmental investigations and the exploration of suitable, integrated responses will alter the situation in unexpected ways, which must be considered carefully and incorporated in a rolling fashion to enable solutions to continue to be applicable and relevant to the problem being faced. This integrated approach has been tested over many years in Merseyside and found to be a robust approach to ever-changing problems that are well described by the management term, "wicked problems". PMID- 26049895 TI - Polychlorobenzenes and polychlorinated biphenyls in ash and soil from several industrial areas in North Vietnam: residue concentrations, profiles and risk assessment. AB - Polychlorinated benzenes (PCBzs) including penta- and hexachlorobenzene can be unintentionally formed from thermal processes in different industrial activities, and very little information is available on the contamination and emission characteristics of these new persistent organic pollutants from industries in Vietnam. In this study, contamination of PCBzs (including penta- and hexachlorobenzene, named PeCBz and HCB, respectively) and PCBs (including CB-28, 52, 101, 153, 138, 180) in fly ash, bottom ash and soil from combustion processes of waste incineration, metallurgy (steel making and zinc production) and cement production from several provinces in the Northern Vietnam, including Hai Duong, Hanoi, Bac Ninh, Hai Phong and Thai Nguyen, was preliminary investigated. The PCBzs concentrations in fly ash, bottom ash and soil ranged from 2.7 to 100 ng g( 1), from 2.7 to 159 ng g(-1) and from 0.28 to 33.9 ng g(-1), respectively. Relatively high residues of PeCBz in fly ash and bottom ash from municipal waste incinerators in some provinces from the Northern Vietnam were encountered. Total PCBs concentrations ranged from 18.0 to 8260 ng g(-1), from 1.0 to 10600 ng g(-1) and from 14.5 to 130 ng g(-1) for the fly ash, bottom ash and soil, respectively. Daily intakes of PeCBz, HCB and PCBs through soil ingestion and dermal exposure estimated for children ranged 0.33-9.93 (mean 3.14), 0.39-21.1 (mean 4.9) and 6.09-1530 ng/kg bw/day (mean 346), respectively; and these intakes were about 4.7 5.4 times higher than those estimated for adult. The intakes of PeCBz and HCB were relatively low, while those for PCBs exceeded WHO TDI for some samples. PMID- 26049897 TI - Activation of Yes-Associated Protein in Low-Grade Meningiomas Is Regulated by Merlin, Cell Density, and Extracellular Matrix Stiffness. AB - The NF2 gene product Merlin is a protein containing ezrin, radixin, and moesin domains; it is a member of the 4.1 protein superfamily associated with the membrane cytoskeleton and also interacts with cell surface molecules. The mammalian Hippo cascade, a downstream signaling cascade of merlin, inactivates the Yes-associated protein (YAP). Yes-associated protein is activated by loss of the NF2 gene and functions as an oncogene in meningioma cells; however, the factors controlling YAP expression, phosphorylation, and subcellular localization in meningiomas have not been fully elucidated. Here, we demonstrate that merlin expression is heterogeneous in 1 NF2 gene-negative and 3 NF2 gene-positive World Health Organization grade I meningiomas. In the NF2 gene-positive meningiomas, regions with low levels of merlin (tumor rims) had greater numbers of cells with nuclear YAP versus regions with high merlin levels (tumor cores). Merlin expression and YAP phosphorylation were also affected by cell density in the IOMM Lee and HKBMM human meningioma cell lines; nuclear localization of YAP was regulated by cell density and extracellular matrix (ECM) stiffness in IOMM-Lee cells. These results suggest that cell density and ECM stiffness may contribute to the heterogeneous loss of merlin and increased nuclear YAP expression in human meningiomas. PMID- 26049896 TI - Successful within-patient dose escalation of olipudase alfa in acid sphingomyelinase deficiency. AB - BACKGROUND: Olipudase alfa, a recombinant human acid sphingomyelinase (rhASM), is an investigational enzyme replacement therapy (ERT) for patients with ASM deficiency [ASMD; Niemann-Pick Disease (NPD) A and B]. This open-label phase 1b study assessed the safety and tolerability of olipudase alfa using within-patient dose escalation to gradually debulk accumulated sphingomyelin and mitigate the rapid production of metabolites, which can be toxic. Secondary objectives were pharmacokinetics, pharmacodynamics, and exploratory efficacy. METHODS: Five adults with nonneuronopathic ASMD (NPD B) received escalating doses (0.1 to 3.0 mg/kg) of olipudase alfa intravenously every 2 weeks for 26 weeks. RESULTS: All patients successfully reached 3.0mg/kg without serious or severe adverse events. One patient repeated a dose (2.0 mg/kg) and another had a temporary dose reduction (1.0 to 0.6 mg/kg). Most adverse events (97%) were mild and all resolved without sequelae. The most common adverse events were headache, arthralgia, nausea and abdominal pain. Two patients experienced single acute phase reactions. No patient developed hypersensitivity or anti-olipudase alfa antibodies. The mean circulating half-life of olipudase alfa ranged from 20.9 to 23.4h across doses without accumulation. Ceramide, a sphingomyelin catabolite, rose transiently in plasma after each dose, but decreased over time. Reductions in sphingomyelin storage, spleen and liver volumes, and serum chitotriosidase activity, as well as improvements in infiltrative lung disease, lipid profiles, platelet counts, and quality of life assessments, were observed. CONCLUSIONS: This study provides proof-of-concept for the safety and efficacy of within patient dose escalation of olipudase alfa in patients with nonneuronopathic ASMD. PMID- 26049898 TI - [Relation between structure and function, of the cerebral artery "carotid" in laboratory rat submitted to atherogenic diet]. AB - OBJECTIVE OF THE STUDY: The aim of our investigation was the study of the pathophysiology of the carotid artery in cases of nutritional stress in male atheroresistant Wistar rats. MATERIALS AND METHODS: Were administered daily by gavage to experimental rats a high fat diet consisting of peanut oil, cholesterol (3%) and sodium cholate (1%). Throughout this experiment, we conducted monitoring of some biochemical parameters and the morpho-histopathology of the carotid cerebral artery. The results obtained are compared to those of control rats in the same experimental conditions. RESULTS: We found that this fat diet resulted in experimental rats disruption of biochemical tests and tissular and cellular alterations in carotid wall. Indeed, the biochemical examination shows a significant increase of the parameters studied. Morphological examination revealed thickening of the carotid wall and histopathological examination of this artery, highlights the installation of a vascular remodeling from thickening of the intima-media to the installation of a probable atherosclerosis accompanied by a possible hyalinization and a net fibrosis. CONCLUSION: At the end of this study, although notes that our fat diet could cause a metabolic disorder that can cause multiple tissue and cell damage observed in cerebral artery "carotid" of atheroresistant rats. PMID- 26049899 TI - [Autonomic angiotensinergic fibres in the human heart with an efferent sympathetic cophenotype]. AB - AIM: The autonomic innervation of the heart consists of sympathetic and parasympathetic nerve fibres, and fibres of the intrinsic ganglionated plexus with noradrenaline and acytylcholine as principal neurotransmitters. The fibres co-release neuropeptides to modulate intracardiac neurotransmission by specific presynaptic and postsynaptic receptors. The coexpression of angiotensin II in sympathetic fibres of the human heart and its role are not known so far. METHODS: Autopsy specimens of human hearts were studied (n=3; ventricles). Using immunocytological methods, cryostat sections were stained by a murine monoclonal antibody (4B3) directed against angiotensin II and co-stained by polyclonal antibodies against tyrosine hydroxylase, a catecholaminergic marker. Visualisation of the antibodies was by confocal light microscopy or laser scanning microscopy. RESULTS: Angiotensin II-positive autonomic fibres with and without a catecholaminergic cophenotype (hydroxylase-positive) were found in all parts of the human ventricles. In the epicardium, the fibres were grouped in larger bundles of up to 100 and more fibres. They followed the preformed anatomic septa and epicardial vessels towards the myocardium and endocardium where the bundles dissolved and the individual fibres spread between myocytes and within the endocardium. Generally, angiotensinergic fibres showed no synaptic enlargements or only a few if they were also catecholaminergic. The exclusively catechalominergic fibres were characterised by multiple beaded synapses. CONCLUSION: The autonomic innervation of the human heart contains angiotensinergic fibres with a sympathetic efferent phenotype and exclusively angiotensinergic fibers representing probably afferents. Angiotensinergic neurotransmission may modulate intracardiac sympathetic and parasympathetic activity and thereby influence cardiac and circulatory function. PMID- 26049900 TI - [Prevalence of target organ damage in patients treated for primary arterial hypertension: Comparison between men and women. ESSENTIELLE study]. AB - OBJECTIVES: To compare the percentages of men and women treated for primary arterial hypertension presenting with at least one target organ damage; to identify factors associated with target organ damage and/or blood pressure control. METHODS: Observational, transverse study carried out between March 2012 and July 2013 on a representative sample of 2666 outpatients (including 1343 men) consulting general practitioners (n=469) or cardiologists (n=250) in routine follow-up. RESULTS: Characteristics "men vs. women" were: mean age (62.6 +/- 11.6 vs. 57.4 +/- 14.7 years; P<0.0001); >= 60 years (61.1% vs. 43.9%; P<0.0001); waist circumference (98.9 +/- 12.2 vs. 89.4 +/- 14.3 cm; P<0.0001); SBP (146.5 +/ 16.1 vs. 145.8 +/- 17.0 mmHg; NS); DBP (85.1 +/- 10.3 vs. 84.2 +/- 10.4; P=0,03). Target organ damage was more frequent in men (37.6% vs. 22.9%; P<0.0001), whether it was subclinical (20.4% vs. 13.6%; P<0.0001) or documented (26.3% vs. 13.5%; P<0.0001); some patients presented with both types of damages. Men developed more often microalbuminuria (6.5% vs. 4.3%; P=0.01) and LVH (16.3% vs. 10.5%; P<0.0001); some patients presented with both types of subclinical injuries. Target organ damage was more common in men without regular physical activity than in those exercising regularly (42.1% vs. 32.5%; P=0.0004). Regular exercises had no effect in women (24.1% vs. 21.3%). For both sexes, other factors associated with target organ damage were: age >= 60 years, myocardial infarction/sudden death in family history, LDL-cholesterol >= 1.60 g/L, HDL cholesterol <= 0.40 g/L. Stroke before 45 years in family history was a predictive factor in women. Hypertension was controlled in one third of patients without difference between sexes. In women, hypertension was less often controlled in case of excessive alcohol consumption compared to normal alcohol intake (17.9% vs. 36.1%; P=0.0007); this factor had no effect in men (28.1% vs. 32.6%). Other factors associated with poor blood pressure control were: BMI (P=0.002), LDL-cholesterol >= 1.60 g/L in women. In men, the factors were: tobacco, presence of LVH, absence of physical activity, HDL-cholesterol <= 0.40 g/L, absence of diet. CONCLUSION: In a hypertensive population, target organ damage is more common among men despite similar blood pressure control rates for both sexes. PMID- 26049901 TI - [Hypertension in scleroderma: A vital emergency]. AB - PURPOSE: In systemic sclerosis, hypertension is feared because it is often heralding severe renal impairment. The objective of our study was to identify the frequency of arterial hypertension and clarify its etiologies in this condition. PATIENTS/METHODS: Our study was prospective. From January 2008 to May 2012, we have included all patients over the age of 16 years which featured a systemic scleroderma meeting the criteria for classification of Leroy and Medsger modified. Blood pressure was systematic and hypertension was defined as a greater than 140/90 mmHg PAS/PAD. RESULTS: We have collected 60 patients. It was 50 women and 10 men with an average age of 41.1 ans +/- 13.03. Arterial hypertension was noted in sixteen patients (26.7%) with an average age of 48.8 years +/- 13.21. It was nine diffuse cutaneous systemic scleroderma of six limited cutaneous scleroderma and one case of scleroderma sine scleroderma. Etiologic research hypertension had concluded to a renal cause in 12 patients. It was five scleroderma renal crisis (SRC), three vascular nephropathies, four chronic kidney failure (CKD) including three terminals and a moderate CKD. An 'essential' so called HTA was observed in four patients. Hypertension was a major sign that reported five cases of SRC. These patients had received treatment anti hypertensive and renal extra cleansing. DISCUSSION: Hypertension is common in systemic scleroderma. Our data approximates of literature when its frequency and severity. CONCLUSION: Hypertension is a major warning sign that under no circumstances should overlook it or novo or secondary aggravation. Its support must be very early under penalty to put at stake the life-threatening in particular during the CRS. PMID- 26049902 TI - The preoperative platelet to lymphocyte ratio is a prognostic marker in patients with stage II colorectal cancer. AB - PURPOSE: The platelet to lymphocyte ratio (PLR) is a potential prognostic marker in a number of different cancers. The aim of this study was to evaluate the prognostic impact of the PLR in patients with stage II colorectal cancer (CRC) who have undergone curative resection but not adjuvant chemotherapy. METHODS: A retrospective review was performed on 234 patients with stage II CRC who underwent curative resection, but not adjuvant chemotherapy, in our institute. The patients were divided into low and high PLR groups, and patient survival as well as several clinicopathological factors were compared between the groups. Disease-free survival (DFS) and cancer-specific survival (CSS) were analyzed by using the Kaplan-Meier method, and multivariate analysis was performed by using the Cox proportional hazard model. RESULTS: The cutoff value of the PLR determined by using a receiver-operating characteristic curve analysis was 25.4. DFS and CSS were significantly better in patients with a low PLR compared to patients with a high PLR (P = 0.002 and P = 0.011, respectively). On multivariate analysis, we identified the PLR as an independent prognostic factor for DFS and CSS, with a hazard ratio of 2.65 (95 % confidence interval [CI], 1.26-5.45; P = 0.011) and 3.61 (95 % CI, 1.08-12.64; P = 0.038, respectively). CONCLUSIONS: The PLR is a good prognostic indicator in patients with stage II CRC who have undergone curative surgery but not adjuvant chemotherapy. PMID- 26049903 TI - [Histological factors predicting loco-regional lymph node metastasis in early invasive colorectal adenocarcinoma pT1]. AB - INTRODUCTION: Endoscopic resection is the common treatment in pT1 colorectal adenocarcinoma whenever possible. The presence of adverse histological factors requires subsequent lymph node evaluation. MATERIALS AND METHODS: We selected 29 colorectal pT1 adenocarcinoma including endoscopic polypectomies and the corresponding surgical specimens. All histologic parameters associated with N+ were evaluated by 2 pathologists, including: tumor differentiation grade, depth of invasion in the submucosa, angiolymphatic invasion (ALI), perineural invasion, chronic inflammation, tumor budding, poorly differentiated cluster, pre-existing adenoma, tumor border, and endoscopic resection margin. Univariate and multivariate logistic regression analysis were performed to assess the individual capacity of each variable to predict N+. RESULTS: In the univariate analysis, rectal tumor localization, ALI and poorly differentiated cluster was significantly associated with N+. Among the significant parameters, ALI had the highest area under the ROC curve (0.875). Multivariate analysis showed no independent variables associated with N+. CONCLUSIONS: We confirm that ALI and the presence of poorly differentiated cluster are frequently associated with N+ in early colorectal cancer. Consequently, these parameters should be routinely evaluated by pathologists. PMID- 26049904 TI - Cutis verticis gyrata and acromegaly. PMID- 26049905 TI - [Cervical spine mass due to beta-2-microglobulin amyloidosis in a long-term hemodialysed patient]. PMID- 26049906 TI - [Chromoblastomycosis: breast solitary lesion]. PMID- 26049907 TI - Physician-assisted deaths in France: results from a nationwide survey. PMID- 26049908 TI - Brown tumors mimicking bone and lung metastases: key role of radionuclide imaging. PMID- 26049909 TI - Giant cell arteritis: a reversible cause of oculomotor nerve palsy. PMID- 26049910 TI - [Destructive polyepiphyseal dysplasia pseudorhumatoid]. PMID- 26049911 TI - [Subconjunctival loiasis: a case report]. PMID- 26049912 TI - [Mucosal healing in ulcerative colitis (UC)]. PMID- 26049913 TI - [Cutaneous metastasis of a sacral chordoma mimicking a proliferating cyst of the scalp]. PMID- 26049914 TI - [Post-staphylococcal acquired digital fibrokeratoma: a new case]. PMID- 26049915 TI - Appendagitis of the lesser omentum - an uncommon cause of acute abdominal pain. PMID- 26049916 TI - [The somatopsychic index, a tool devoted to a practical appraisal of functional impairment among victims of assaults]. PMID- 26049917 TI - Why use long acting bronchodilators in chronic obstructive lung diseases? An extensive review on formoterol and salmeterol. AB - Long-acting beta2-adrenoceptor agonists, formoterol and salmeterol, represent a milestone in the treatments of chronic obstructive lung diseases. Although no specific indications concerning the choice of one molecule rather than another are provided by asthma and COPD guidelines, they present different pharmacological properties resulting in distinct clinical employment possibilities. In particular, salmeterol has a low intrinsic efficacy working as a partial receptor agonist, while formoterol is a full agonist with high intrinsic efficacy. From a clinical perspective, in the presence of low beta2 adrenoceptors availability, like in inflamed airways, a full agonist can maintain its bronchodilatory and non-smooth muscle activities while a partial agonist may be less effective. Furthermore, formoterol presents a faster onset of action than salmeterol. This phenomenon, combined with the molecule safety profile, leads to a prompt amelioration of the symptoms, and allows using this drug in asthma as an "as needed" treatment in patients already on regular treatment. The fast onset of action and the full agonism of formoterol need to be considered in order to select the best pharmacological treatment of asthma and COPD. PMID- 26049918 TI - Hypermagnesemia is a strong independent risk factor for mortality in critically ill patients: results from a cross-sectional study. AB - BACKGROUND: Patients with electrolyte imbalances or disorders have a high risk of mortality. It is unknown if this finding from sodium or potassium disorders extends to alterations of magnesium levels. METHODS AND PATIENTS: In this cross sectional analysis, all emergency room patients between 2010 and 2011 at the Inselspital Bern, Switzerland, were included. A multivariable logistic regression model was performed to assess the association between magnesium levels and in hospital mortality up to 28days. RESULTS: A total of 22,239 subjects were screened for the study. A total of 5339 patients had plasma magnesium concentrations measured at hospital admission and were included into the analysis. A total of 6.3% of the 352 patients with hypomagnesemia and 36.9% of the 151 patients with hypermagnesemia died. In a multivariate Cox regression model hypermagnesemia (HR 11.6, p<0.001) was a strong independent risk factor for mortality. In these patients diuretic therapy revealed to be protective (HR 0.5, p=0.007). Hypomagnesemia was not associated with mortality (p>0.05). Age was an independent risk factor for mortality (both p<0.001). CONCLUSION: The study does demonstrate a possible association between hypermagnesemia measured upon admission in the emergency department, and early in-hospital mortality. PMID- 26049919 TI - Feasibility and repeatability of PET with the hypoxia tracer [(18)F]HX4 in oesophageal and pancreatic cancer. AB - BACKGROUND AND PURPOSE: To investigate the feasibility and to determine the repeatability of recurrent [(18)F]HX4 PET scans in patients with oesophageal (EC) and pancreatic (PC) cancer. MATERIALS AND METHODS: 32 patients were scanned in total; seven patients (4 EC/3 PC) were scanned 2, 3 and 4h post injection (PI) of [(18)F]HX4 and 25 patients (15 EC/10 PC) were scanned twice 3.5h PI, on two separate days (median 4, range 1-9days). Maximum tumour to background ratio (TBRmax) and the tumour hypoxic volume (HV) (TBR>1.0) were calculated. Repeatability was assessed using Bland-Altman analysis. Agreement in localization was calculated as the distance between the centres of mass in the HVs. RESULTS: For EC, the TBRmax in the tumour (mean+/-SD) was 1.87+/-0.46 with a coefficient of repeatability (CoR) of 0.53 (28% of mean). The HV ranged from 3.4 to 98.8ml with a CoR of 5.1ml. For PC, the TBRmax was 1.72+/-0.23 with a CoR of 0.27 (16% of mean). The HV ranged from 4.6 to 104.0ml with a CoR of 7.8ml. The distance between the centres of mass in the HV was 2.2+/-1.3mm for EC and 2.1+/-1.5mm for PC. CONCLUSIONS: PET scanning with [(18)F]HX4 was feasible in both EC and PC patients. Amount and location of elevated [(18)F]HX4 uptake showed good repeatability, suggesting [(18)F]HX4 PET could be a promising tool for radiation therapy planning and treatment response monitoring in EC and PC patients. PMID- 26049921 TI - Changes in fractalkine in patients with ST-elevation myocardial infarction. AB - BACKGROUND: Fractalkine (FKN) was recently shown to play an important role in atherosclerotic plaque rupture and cardiac remodeling and dysfunction. We evaluated the changes in serum FKN (sFKN) in patients with acute ST-elevation myocardial infarction (STEMI) and the influence of a percutaneous coronary intervention (PCI) on the levels of sFKN. METHODS: The study population included 40 patients with acute STEMI [acute myocardial infarction (AMI)+PCI: 20 underwent primary PCI; AMI: 20 without PCI] and 40 patients with symptomatic stable angina pectoris (SAP+PCI: 20 underwent PCI; SAP: 20 without PCI). sFKN were measured at different time points by ELIZA. The gene expression of heart FKN was assessed by real-time reverse transcription-PCR in a model of myocardial infarction mice. RESULTS: We found that the baseline level of sFKN in patients with acute STEMI was significantly higher than that of patients with SAP. Primary PCI in STEMI resulted in a rapid decrease within 24 h and to a similar level after 48 h as in the SAP and SAP+PCI patients, whereas in the AMI group, the sFKN level showed a slight decrease from 6 to 24 h (from 1307.6+/-368.9 to 1092.7+/-258.1 pg/ml, P=0.036) and remained significantly higher at all later time points (P<0.001 for all). The sFKN level at 30 days was correlated positively with the NT-proBNP level (r=0.490, P=0.014). The time course of myocardial FKN gene expression in mice has a pattern similar to sFKN change in AMI patients. CONCLUSION: Our study suggested that STEMI had a higher sFKN level and correlated positively with the NT-proBNP level at 1 month. PCI could lead to a rapid decrease in the sFKN level. PMID- 26049920 TI - Antithymocyte globulin combined with cyclosporine A down-regulates T helper 1 cells by modulating T cell immune response cDNA 7 in aplastic anemia. AB - Antithymocyte globulin (ATG) combined with cyclosporine A (CsA) has been widely used as a standard regimen in the treatment of aplastic anemia (AA), especially in severe aplastic anemia (SAA). Abnormally activated T cells might be the immune pathogenesis of AA. T cell immune response cDNA 7 (TIRC7) has been demonstrated its essential role in T cell activation; however, little is known about the role of TIRC7 in AA. In this study, we documented that TIRC7 levels in CsA group were higher than that in ATG + CsA (AC) group only in the follow-up phase (P < 0.05; P < 0.05); nevertheless, TIRC7 levels in SAA group were elevated than non severe aplastic anemia group not only in the treatment phase (P < 0.05; P < 0.05) but also in the follow-up phase (P < 0.05; P < 0.01). The trend of changes of T helper (Th) 1, Th17 and Th22 levels before and after treatment was similar to the changes of TIRC7 levels in either AC group or CsA group. Thus, TIRC7 might be involved in the pathogenesis of AA and AC might down-regulate Th1 cells by modulating the expression of TIRC7 in AA. PMID- 26049922 TI - Influence of trimetazidine and ranolazine on endothelial function in patients with ischemic heart disease. AB - OBJECTIVE: Endothelial dysfunction is an independent predictor of atherosclerosis progression and cardiovascular events in patients with ischemic heart disease. Ranolazine and trimetazidine are novel drugs that reduce angina symptoms in the above-mentioned patients. The aim of this study was to compare the effects of ranolazine and trimetazidine on flow-mediated (FMD) and nitroglycerine-induced (GTN) dilation of the brachial artery. METHODS: In a prospective, double-blind study, 56 men between 32 and 65 years of age with chronic ischemic heart disease were randomized and subjected to 12 weeks of treatment with either trimetazidine (35 mg twice daily) or ranolazine. Ranolazine was administered at a dose of 375 mg twice daily for 4 weeks and was increased to 500 mg twice daily for the rest of the study. FMD and GTN were measured using high-resolution ultrasound before and after treatment. RESULTS: FMD increased from 3.5+/-7.4 to 13.8+/-9.4% (P<0.013; 294%) in the trimetazidine group and from 2.4+/-4.3 to 9.5+/-7.7% (P<0.037; 296%) in the ranolazine group, with no difference between the groups (P=0.444). GTN increased from 16.1+/-9.2 to 21.2+/-19.3% (P<0.022; 32%) in the trimetazidine group and from 13.8+/-9.6 to 21.7+/-13.7% (P<0.006; 57%) in the ranolazine group, with no difference between the groups (P=0.309). CONCLUSION: Both trimetazidine and ranolazine led to an improvement in FMD and GTN of the brachial artery in patients with ischemic heart disease, with no statistically significant difference between the groups. PMID- 26049923 TI - Myocardial perfusion pattern for stratification of ischemic mitral regurgitation response to percutaneous coronary intervention. AB - OBJECTIVE: Ischemic mitral regurgitation (MR) is common, but its response to percutaneous coronary intervention (PCI) is poorly understood. This study tested the utility of myocardial perfusion imaging (MPI) for the stratification of MR response to PCI. METHODS: MPI and transthoracic echocardiography (echo) were performed among patients undergoing PCI. MPI was used to assess stress/rest myocardial perfusion. MR was assessed via echo (performed before and after PCI). RESULTS: A total of 317 patients with abnormal myocardial perfusion on MPI underwent echo 25+/-39 days before PCI. MR was present in 52%, among whom 24% had advanced (>=moderate) MR. MR was found to be associated with left ventricular (LV) chamber dilation on MPI and echo (both P<0.001). The magnitude of global LV perfusion deficits increased in relation to MR severity (P<0.01). Perfusion differences were greatest for global summed rest scores, which were 1.6-fold higher among patients with advanced MR versus those with mild MR (P=0.004), and 2.4-fold higher versus those without MR (P<0.001). In multivariate analysis, advanced MR was found to be associated with a fixed perfusion defect size on MPI [odds ratio 1.16 per segment (confidence interval 1.002-1.34), P=0.046], independent of LV volume [odds ratio 1.10 per 10 ml (confidence interval 1.04 1.17), P=0.002]. Follow-up via echo (1.0+/-0.6 years) demonstrated MR to decrease (>=1 grade) in 31% of patients and increase in 12% of patients. Patients with increased MR after PCI had more severe inferior perfusion defects on baseline MPI (P=0.028), whereas defects in other distributions and LV volumes were similar (P=NS). CONCLUSION: The extent and distribution of single-photon emission computed tomography-evidenced myocardial perfusion defects impact MR response to revascularization. An increased magnitude of inferior fixed perfusion defects predicts post-PCI progression of MR. PMID- 26049924 TI - Paleoenvironments of the Shungura Formation (Plio-Pleistocene: Ethiopia) based on ecomorphology of the bovid astragalus. AB - The Shungura Formation in southwestern Ethiopia preserves a long and relatively continuous record of eastern African mammalian and hominin evolution. This study reconstructs habitat preferences of the Shungura Formation bovids from ca. 3.4 1.9 Ma (million years ago), based on the ecomorphology of fossil bovid astragali. Habitat predictions are made using a Discriminant Function Analysis informed by functional analysis of the astragalus that controls for body size and phylogenetic signal. The high abundance of astragali in the Shungura record allows for habitat reconstructions on sub-unit timescales, rather than aggregating samples at the level of geological member. During much of the time period examined, the lower Omo Valley was dominated by relatively mesic habitats in close proximity to the ancestral Omo River. Previous research has suggested that environmental change at ~ 2.85 Ma caused significant habitat change at Shungura, but the astragalar data do not support major habitat change at this time. However, there are significant fluctuations in inferred habitats, with more open habitats indicated in sub-units C-08 and C-09 (~ 2.56 Ma), and in unit F-01 (just after 2.36 Ma). The cause of sub-unit fluctuations in habitat signal is difficult to determine, but local factors, including spatial habitat heterogeneity around the river channel and in its floodplain, may play a contributing role. In the light of faunal evidence from elsewhere in the greater Omo-Turkana Basin, hominins in the area likely had access to a variety of heterogeneous habitats. PMID- 26049925 TI - Screening, Characterization and In Vitro Evaluation of Probiotic Properties Among Lactic Acid Bacteria Through Comparative Analysis. AB - The present work aimed to identify probiotic bacteria from healthy human infant faecal and dairy samples. Subsequently, an assay was developed to evaluate the probiotic properties using comparative genetic approach for marker genes involved in adhesion to the intestinal epithelial layer. Several in vitro properties including tolerance to biological barriers (such as acid and bile), antimicrobial spectrum, resistance to simulated digestive fluids and cellular hydrophobicity were assessed. The potential probiotic cultures were rapidly characterized by morphological, physiological and molecular-based methods [such as RFLP, ITS, RAPD and (GTG)5]. Further analysis by 16S rDNA sequencing revealed that the selected isolates belong to Lactobacillus, Pediococcus and Enterococcus species. Two cultures of non-lactic, non-pathogenic Staphylococcus spp. were also isolated. The native isolates were able to survive under acidic, bile and simulated intestinal conditions. In addition, these cultures inhibited the growth of tested bacterial pathogens. Further, no correlation was observed between hydrophobicity and adhesion ability. Sequencing of probiotic marker genes such as bile salt hydrolase (bsh), fibronectin-binding protein (fbp) and mucin-binding protein (mub) for selected isolates revealed nucleotide variation. The probiotic binding domains were detected by several bioinformatic tools. The approach used in the study enabled the identification of potential probiotic domains responsible for adhesion of bacteria to intestinal epithelial layer, which may further assist in screening of novel probiotic bacteria. The rapid detection of binding domains will help in revealing the beneficial properties of the probiotic cultures. Further, studies will be performed to develop a novel probiotic product which will contribute in food and feed industry. PMID- 26049926 TI - Anhedonia in combat veterans with penetrating head injury. AB - Anhedonia is a common symptom following traumatic brain injury. The neural basis of anhedonia is poorly understood, but believed to involve disturbed reward processing, rather than the loss of sense of pleasure. This analysis was undertaken to determine if injury to specific regions of prefrontal cortex (PFC) result in anhedonia. A CT-based lesion analysis was undertaken in 192 participants of the Vietnam Head Injury Study, most with penetrating head injury. Participants were divided into left and right ventrolateral prefrontal, bilateral ventromedial prefrontal, and other injury locations. Anhedonia was measured by self-report in each group using the four-item anhedonia subscale score of the Beck Depression Inventory-II. Individuals with right ventrolateral injury reported greater severity of anhedonia compared to those with injury in the left ventrolateral region. These findings support an association between injury in the right ventrolateral PFC and anhedonia. PMID- 26049927 TI - The association between internet addiction and disordered eating attitudes among Turkish high school students. AB - PURPOSE: The aim of the present study is to investigate the prevalence of disordered eating attitudes (DEAs) and internet addiction (IA) among a non clinical sample of adolescents and to investigate the relationship between IA, DEAs, and selected socio-demographic characteristics. METHODS: A total of 584 adolescents (34.8% n = 203 males and 65.2% n = 381 females) completed three instruments: the Eating Attitude Test-26 (EAT-26), the Internet Addiction Test (IAT), and a socio-demographic questionnaire. RESULTS: It was found that 15.2% (n = 89) of the participants have DEAs, and IA was detected in 10.1% (n = 59) of the participants. There was a statistically significant difference between the IA and non-IA groups in terms of body mass index (chi (2) = 10.31, p < 0.01). We found a significant positive correlation between the IAT and EAT-26 scores (r = 0.34, p < 0.01). The presence of DEAs, male gender, and high BMI were found to be the strongest predictor variables of IA. CONCLUSIONS: IA and DEAs are relatively frequent phenomena among young students in Turkey. Future studies should attempt to determine the predictive factors by identifying the causal relations between IA and DEAs. PMID- 26049928 TI - Lanthanum carbonate hydrate causes artifacts on ultrasound. PMID- 26049929 TI - Clinical applications of intravenous lipid emulsion therapy. AB - Intravenous lipid emulsion (ILE; Intralipid) therapy, a standard treatment in local anesthetic toxicity, has demonstrated therapeutic efficacies for a number of different drug class-mediated toxicities. Some of these varied drug groups include antipsychotics, antidepressants, antiarrhythmics, and calcium channel blockers. To meet the objective of describing the growing number of indications for Intralipid therapy and any diverse effects and/or failures of Intralipid therapy in reversing multiple drug toxicities, we queried several Internet search engines with the key words "intravenous lipid emulsion therapy," "Intralipid," "lipid emulsion," and "local anesthetic systemic toxicity," resulting in the identification of 31 case reports for descriptive analysis. These case reports included 49 separate drug overdose cases involving ten separate drug classes which were successfully reversed with Intralipid. The education of clinicians regarding the beneficial and varied roles of Intralipid therapy in different clinical settings is warranted, particularly in terms of the potential for Intralipid therapy to reverse the toxicities of non-local anesthetic drugs. PMID- 26049930 TI - [Clinical features and in-hospital outcome of ventricular rupture secondary to acute coronary syndrome]. PMID- 26049931 TI - Clinical infectious outcomes associated with biofilm-related bacterial infections: a retrospective chart review. AB - BACKGROUND: Biofilms are associated with persistent infection. Reports characterizing clinical infectious outcomes and patient risk factors for colonization or infection with biofilm forming isolates are scarce. Our institution recently published a study examining the biofilm forming ability of 205 randomly selected clinical isolates. This present study aims to identify potential risk factors associated with these isolates and assess clinical infectious outcomes. METHODS: 221 clinical isolates collected from 2005 to 2012 and previously characterized for biofilm formation were studied. Clinical information from the associated patients, including demographics, comorbidities, antibiotic usage, laboratory values, and clinical infectious outcomes, was determined retrospectively through chart review. Duplicate isolates and non clinical isolates were excluded from analysis. Associations with biofilm forming isolates were determined by univariate analysis and multivariate analysis. RESULTS: 187 isolates in 144 patients were identified for analysis; 113 were biofilm producers and 74 were not biofilm producers. Patients were primarily male (78 %) military members (61 %) with combat trauma (52 %). On multivariate analysis, the presence of methicillin-resistant Staphylococcus aureus (p < 0.01, OR 5.09, 95 % CI 1.12, 23.1) and Pseudomonas aeruginosa (p = 0.02, OR 3.73, 95 % CI 1.46, 9.53) were the only characteristics more likely to be present in the biofilm producing isolate group. Infectious outcomes of patients with non-biofilm forming isolates, including cure, relapse/reinfection, and chronic infection, were similar to infectious outcomes of patients with biofilm-forming isolates. Mortality with initial infection was higher in the biofilm producing isolate group (16 % vs 5 %, p = 0.01) but attributable mortality was low (1 of 14). No characteristics examined in this study were found to be associated with relapse/reinfection or chronic infection on multivariate analysis. CONCLUSIONS: Bacteria species, but not clinical characteristics, were associated with biofilm formation on multivariate analysis. Biofilm forming isolates and non-biofilm forming isolates had similar infectious outcomes in this study. PMID- 26049933 TI - Sensorineural hearing loss--another under-recognized oto-laryngeal complication of Kawasaki disease. PMID- 26049932 TI - Developing an animal model of Dupuytren's disease by orthotopic transplantation of human fibroblasts into athymic rat. AB - BACKGROUND: Dupuytren's disease (DD) is a slow, progressive fibroproliferative disorder affecting the palms of the hands. The disease is characterized by the formation of collagen rich- cords which gradually shorten by the action of myofibroblasts resulting in finger contractures. It is a disease that is confined to humans, and a major limiting factor in investigating this disorder has been the lack of a faithful animal model that can recapitulate its distinct biology. The aim of this study was to develop such a model by determining if Dupuytren's disease (DD)- and control carpal tunnel (CT)-derived fibroblasts could survive in the forepaw of the nude rats and continue to exhibit the distinct characteristics they display in in vitro cultures. METHODS: 1x10(7) fluorescently labeled DD- and CT-derived fibroblasts were transplanted into the left and right forepaws of nude rats respectively. Cells were tracked at regular intervals for a period of two months by quantifying emitted fluorescent signal using an IVIS imaging system. After a period of 62 days rat forepaw connective tissues were harvested for histology and total RNA was isolated. Human-specific probes were used to perform real time RT-PCR assays to examine the expression patterns of gene products associated with fibrosis in DD. Rat forepaw skin was also harvested to serve as an internal control. RESULTS: Both CT- and DD-derived fibroblasts survived for a period of 62 days, but DD-derived cells showed a significantly greater level of persistent fluorescent signal at the end of this time than did CT-derived cells. mRNA expression levels of alpha-smooth muscle actin (alpha-SMA), type I- and type III- collagens were all significantly elevated in the forepaw receiving DD cord derived fibroblasts in comparison to CT-derived fibroblasts. Masson's trichrome stain confirmed increased collagen deposition in the forepaw that was injected with DD cord-derived fibroblasts. CONCLUSIONS: For the first time we describe an animal model for Dupuytren's disease at the orthotopic anatomical location. We further show that gene expression differences between control (CT) and diseased (DD) derived fibroblasts persist when these cells are transplanted to the forepaw of the nude rat. These preliminary findings indicate that, with further refinements, this animal model holds promise as a baseline for investigating novel therapeutic regimens to determine an effective strategy in treating DD. PMID- 26049934 TI - Human Embryonic Stem Cell Research: Ethical Views of Buddhist, Hindu and Catholic Leaders in Malaysia. AB - Embryonic Stem Cell Research (ESCR) raises ethical issues. In the process of research, embryos may be destroyed and, to some, such an act entails the 'killing of human life'. Past studies have sought the views of scientists and the general public on the ethics of ESCR. This study, however, explores multi-faith ethical viewpoints, in particular, those of Buddhists, Hindus and Catholics in Malaysia, on ESCR. Responses were gathered via semi-structured, face-to-face interviews. Three main ethical quandaries emerged from the data: (1) sanctity of life, (2) do no harm, and (3) 'intention' of the research. Concerns regarding the sanctity of life are directed at particular research protocols which interfere with religious notions of human ensoulment and early consciousness. The principle of 'do no harm' which is closely related to ahimsa prohibits all acts of violence. Responses obtained indicate that respondents either discourage research that inflicts harm on living entities or allow ESCR with reservations. 'Intention' of the research seems to be an interesting and viable rationale that would permit ESCR for the Buddhists and Hindus. Research that is intended for the purpose of alleviating human suffering is seen as being ethical. This study also notes that Catholics oppose ESCR on the basis of the inviolability of human life. PMID- 26049935 TI - Spontaneous Membranous Dysmenorrhea in an Adolescent Girl: A Case Report and Literature Review. AB - BACKGROUND: Membranous dysmenorrhea is a rare entity. It involves the sloughing of the endometrium in 1 cylindrical or membranous piece, retaining the shape of the uterine cavity. Herein, we report the first case of spontaneous membranous dysmenorrhea in an adolescent girl. CASE: A 17-year-old girl was admitted to the emergency clinic with severe painful menstrual bleeding and passage of tissue via the vagina. Bloody endometrial tissue resembling the endometrial cavity expulsed from the vagina was seen on inspection. The pathologic diagnosis of the mass was membranous dysmenorrhea. SUMMARY AND CONCLUSION: To our knowledge, this is the first case of the spontaneous occurrence of membranous dysmenorrhea. The relationship between membranous dysmenorrhea and endogenous or exogenous progesterone should be investigated further. A review of the literature on membranous dysmenorrhea is presented. PMID- 26049936 TI - A Case of Obstructed Hemivagina with Ectopic Ureter Leading to Severe Hydrocolpos and Contralateral Renal Outflow Tract Obstruction in a Neonate. AB - BACKGROUND: Renal and Mullerian anomalies are frequently associated. Young age at presentation can present challenges in diagnosis and management. We report a case with an unusual presentation and management of this association in the neonatal period. CASE: A 2-day-old girl had hydronephrosis with a large pelvic fluid collection. Magnetic resonance imaging of the pelvis demonstrated right hydronephrosis and uterine didelphys with an obstructed left hemivagina with hydrocolpos. A tube vaginostomy was used to decompress the vagina. Fluid was consistent with urine from an ectopic ureteral implantation from a dysgenetic left kidney, which was removed. SUMMARY AND CONCLUSION: For obstructed hemivagina in a newborn, expanding fluid collections may be addressed with a drain to avoid mass effect and to aid in the diagnosis. Resection of the vaginal obstruction is performed when the patient is older. A nonfunctional kidney can be removed to eliminate fluid accumulation in the obstructed space. PMID- 26049937 TI - What is the Risk of Metabolic Syndrome in Adolescents with Normal BMI who have Polycystic Ovary Syndrome? AB - OBJECTIVE: The purpose of this study is to evaluate the effect of polycystic ovarian syndrome (PCOS) on the prevalence of metabolic syndrome (MBS) in adolescent girls with normal BMI. MATERIALS AND METHODS: Our study group consisted of 63 pubertal girls with a BMI less than 25 kg/m(2) who were referred to our center with signs of hirsutism or oligomenorrhea. The diagnosis of PCOS was based on the recent ESHRE/ASRM proposal and required that all 3 of the Rotterdam criteria for diagnosing PCOS in adolescents be met. The control group consisted of 159 pubertal girls matched for age and BMI. Glucose, insulin, testosterone, and sex hormone-binding globulin, free testosterone and all lipid parameters measured. For to diagnose the cases with MBS, modified Cook criteria were used and cases who had at least 3 of 5 criteria's were diagnosed as MBS. RESULTS: Girls with PCOS had higher blood pressure parameters (systolic/diastolic) (P < .01), fasting insulin (P = .007), low-density lipoprotein (P = .017), triglyceride (P = .045), total (P < .001) and free testosterone (P = .001) levels compared to control group. There were more cases who had at least 1 Cook criterion in girls with PCOS compared to the control group but the difference was not significant. However, there were more cases who had MBS in girls with PCOS compared to the control group (P = .02). CONCLUSION: MBS prevalence is higher in normal BMI adolescent girls with PCOS compared to age and BMI matched control group. So as clinicians, we must search for the MBS criteria's in girls with PCOS even if they have a normal BMI. PMID- 26049938 TI - Periconceptional Risk Factors for Birth Defects among Younger and Older Teen Mothers. AB - STUDY OBJECTIVES: We sought to determine whether selected periconceptional health behaviors that influence risk for birth defects differ between older and younger adolescents and whether pregnancy intention predicts more positive preconception health behaviors among teens. DESIGN AND PARTICIPANTS: We analyzed interview responses from 954 adolescent control group participants from the National Birth Defects Prevention Study who delivered live infants during 1997-2007. MAIN OUTCOME MEASURES: Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were calculated for factors of interest by age categories (13-15, 16-17, and 18 years, relative to 19 years). To construct a composite periconceptional behavior index, we summed the following healthy behaviors: nonsmoker, nondrinker, folic acid supplementation, and eating 5 or more servings of fruits and vegetables per day. RESULTS: Analyses indicated that women in the youngest group (13-15 years of age) were more likely to be Hispanic (aOR 2.83, 95% CI 1.40-5.70) and less likely to engage in some unhealthy pregnancy-related behaviors compared with 19-year olds, such as smoking (aOR 0.45, 95% CI 0.20-0.99) and being overweight or obese (aOR 0.32, 95% CI 0.16-0.61). However, they were also less likely to have taken periconceptional folic acid (aOR 0.44, 95% CI 0.21-0.90). About one-third of teen mothers indicated that their pregnancies had been intended. Among 18- and 19-year olds, this predicted a higher mean value for the composite periconceptional behavior index (2.30 versus 1.94, P <= .01). CONCLUSIONS: Teen mothers are not a homogeneous group. Each age subgroup presents varied demographic and behavioral factors that put them at varying levels of risk for birth defects. Furthermore, caregivers should not assume that teens do not plan pregnancies or that they need not be informed of the importance of periconceptional health. PMID- 26049939 TI - Adolescent and Young Women's Contraceptive Decision-Making Processes: Choosing "The Best Method for Her". AB - PURPOSE: To evaluate influences on adolescent and young women's contraceptive decision-making processes. METHODS: We conducted 21 individual interviews with women who presented to an adolescent-focused Title X family planning clinic seeking a new contraceptive method. Data were collected using a semi-structured interview guide, audio-taped and transcribed. Three researchers independently coded the transcripts using grounded theory; codes were organized into overarching themes and discrepancies were resolved. RESULTS: After identification of themes, we organized the conceptual framework of the decision-making process using the transtheoretical model of behavior change in which participants move through 4 stages: (1) contemplation, (2) preparation, (3) action, and (4) maintenance. When contemplating contraception, most of our participants were highly motivated to avoid pregnancy. During preparation, participants gathered information related to their contraceptive concerns. Participants cited peers as primary informants and healthcare providers as experts in the field. Participants integrated information received with their personal concerns about contraception initiation; the most common concerns were effectiveness, method duration, convenience, and side effects. When participants acted on choosing a contraceptive method they described how it fit their individual needs. They considered their contraceptive experiences unique and not necessarily applicable to others. During maintenance, they acted as informants for other peers, but most commonly expressed that each individual must choose "the best method for her." CONCLUSIONS: When adolescent and young women select a contraceptive method they balance the benefits and risks of available methods portrayed by peers and provider in the context of their personal concerns. Peer influence appeared to be greatest when participants shared contraceptive concerns and goals. PMID- 26049940 TI - Uterine Cystic Adenomyosis: A Disease of Younger Women. AB - PURPOSE OF REVIEW: We adopted a life-cycle approach to further our understanding of the natural history of the cystic forms of uterine adenomyosis first described by Cullen in 1908. SEARCH STRATEGY: Scopus and PubMed were searched for all terms referring to cystic variant of adenomyosis or adenomyoma. References found in major publications were also included in the review. MAIN FINDINGS: With the introduction of non-invasive imaging techniques, a number of cases of cystic variants of adenomyosis have been reported. Progressive, severe, medication resistant dysmenorrhea is the main clinical feature but delay in diagnosis remains problematic. The life-cycle approach demonstrates that cystic adenomyosis is more relevant to adolescent and young adulthood. Congenital mullerian and wolffian cysts and the uterus-like masses are more frequent in women >30 years of age. The latter is frequently located outside the uterus and may represent a form of endometriosis rather than adenomyosis. Differential diagnosis includes ovarian cysts and congenital uterine anomalies. Menstruation suppression with continuous oral contraceptive pill with ultrasonographic monitoring of cyst regression may prove successful in the young woman, but surgical excision using minimally invasive endoscopy is highly effective. The various terms used in literature to describe these lesions cause considerable confusion. Here we propose a classification into 3 subtypes and standardized reporting criteria to enable comparison. CONCLUSIONS: Endometrial lined myometrial cysts are almost specific to adolescent and young women. We propose a new classification system. PMID- 26049941 TI - Plasma Visfatin Levels in Adolescents with Polycystic Ovary Syndrome: A Prospective Case-Control Study. AB - STUDY OBJECTIVE: We evaluated the plasma visfatin levels in hirsute female adolescents with polycystic ovary syndrome. DESIGN, SETTING, AND PARTICIPANTS: This prospective case-control study included 87 female patients who were seen in our adolescence department. Demographic characteristics and hormonal and biochemical parameters were evaluated between patients with and without polycystic ovary syndrome. Next, we divided the patients with polycystic ovary syndrome into the following subgroups: overweight or obese (body mass index [BMI] >= 25 kg/m(2)) vs normal weight (BMI < 25 kg/m(2)) and hirsute vs nonhirsute. RESULTS: There were statistically significant differences in the BMI, serum androgen levels, homeostasis model assessment-insulin resistance (HOMA-IR) levels, and insulin levels between patients with and without polycystic ovary syndrome (P < .05). The mean visfatin levels showed no statistically significant difference between these 2 groups (P > .05). The serum visfatin levels were similar between the 2 subgroups classified by BMI (P > .05). However, there were statistically significant differences in the total and free testosterone levels, 17-hydroxylase progesterone level, HOMA-IR level, and visfatin level between the 2 subgroups classified by hirsutism (P < .05). The plasma visfatin level was higher in hirsute PCOS than in nonhirsute PCOS patients. CONCLUSION: Significantly higher visfatin levels were found in hirsute than in nonhirsute adolescents with PCOS. According to these results, plasma visfatin levels may be a useful marker in hirsute adolescents with PCOS. PMID- 26049942 TI - Bilateral Florid Juvenile Fibroadenomas of the Breast in an Adolescent: A Rare Indication for Subcutaneous Mastectomy. AB - BACKGROUND: Juvenile fibroadenomas are rare and constitute about 0.5% to 4% of all fibroadenomas. They present as circumscribed, often large breast masses in adolescent females and are usually managed with simple enucleation. CASE: A 15 year-old girl presented with a 6-month history of rapidly growing breasts. On examination, she was found to have large, diffusely nodular breasts with marked asymmetry. Ultrasound and fine needle aspiration cytology results were suggestive of fibroadenomas, and the patient was planned for excision through a submammary incision. SUMMARY AND CONCLUSION: During surgery, both the breasts were found to be studded with nodules of varying sizes with very little normal breast tissue. A bilateral subcutaneous mastectomy was performed for complete removal of the fibroadenomas. Histopathology was reported as multiple juvenile fibroadenomas. Both breasts were later reconstructed with a latissimus dorsi myocutaneous flap with implants. We present this case to highlight a rare indication for bilateral subcutaneous mastectomy for a benign condition of the breast. PMID- 26049943 TI - One year on: vale Joep Lange. PMID- 26049944 TI - Extending access with long-acting antiretroviral therapy: the next advance in HIV 1 therapeutics and prevention. PMID- 26049945 TI - Current state and limitations of daily oral therapy for treatment. AB - PURPOSE OF REVIEW: We aim to review the strengths and weaknesses of current antiretroviral therapy (ART), and describe ongoing research to address limitations to current therapy. RECENT FINDINGS: Current ART is highly effective and well tolerated. As a result of a decrease in medication side-effects and pill burden, and the known health effects of uncontrolled viremia, ART is now recommended at all CD4 cell counts in the USA. Novel medications are being developed to further decrease side-effects and offer alternative options for patients with multiclass resistance. New combination pills will further decrease pill burden. SUMMARY: Current treatment for HIV is characterized by highly potent oral antiretroviral medications, which are well tolerated, resulting in outstanding rates of virologic suppression in patients who are adherent to therapy. Despite the marked improvement in therapeutic options, limitations to therapy still exist including reliance on daily adherence, long-term toxicity of medications, drug-drug interactions, long-term effects of HIV even in the setting of viral suppression, high lifetime cost of treatment, and limited options for some patients with multiclass resistance. Emerging alternative treatment strategies include nucleoside reverse transcriptase inhibitor-sparing or limiting regimens and long-acting injectable combination therapy. PMID- 26049947 TI - Formulation and pharmacology of long-acting rilpivirine. AB - PURPOSE OF REVIEW: Rilpivirine (RPV), a nonnucleoside reverse transcriptase inhibitor, is a potent antiretroviral (ARV) effective for HIV treatment at 25 mg daily oral dose. Its physio-chemical and pharmacological properties enable formulation of RPV as a long-acting injectable nanosuspension. This review summarizes these properties supporting the potential of intermittent parenteral administration of rilpivirine long acting (RPV LA) in both treatment and prevention of HIV-1 infection. RECENT FINDINGS: RPV is unusual among ARVs in that its stability and solubility enable aqueous suspensions with high drug loading, so that injection volumes can be minimized. Such innovative nanosuspensions are well tolerated in animals and humans after intramuscular injection and provide sustained drug concentrations in systemic circulation. The pharmacological findings support further investigations of RPV LA injections every 4 or 8 weeks, both as a single agent for potential preexposure prophylaxis and as two-drug all injectable maintenance therapy with cabotegravir long acting. SUMMARY: By building on expertise with long-acting injectable antipsychotic agents, RPV has been formulated as an agent for infrequent intramuscular dosing, in addition to its conventional oral tablet forms. The advantages of adherence to a regimen of intermittent injections may be significant. PMID- 26049946 TI - The current status of the use of oral medication to prevent HIV transmission. AB - PURPOSE OF REVIEW: This review was designed to evaluate the progress in studies of the use of oral and topical antiretroviral (ARV) medication for primary HIV prevention. RECENT FINDINGS: Nonhuman primate data have suggested that the administration of ARV medication before or after retroviral exposure can protect against the establishment of chronic infection. Over the past two decades, observational studies have demonstrated the safety of ARV agents for postexposure prophylaxis and more recent efficacy studies have demonstrated that tenofovir with or without emtricitabine can protect against HIV when used as preexposure prophylaxis (PrEP). Efficacy studies have been conducted in diverse populations, including men and transgender women who have sex with men, young African heterosexuals, and injection drug users. Three studies in African women evaluating oral and topical tenofovir-based regimens did not demonstrate efficacy, in large part because of suboptimal medication adherence. Further research is underway to determine the optimal ways to provide chemoprophylaxis, the optimal medications, and dosing regimens. SUMMARY: PrEP can be effective in decreasing HIV transmission to at-risk uninfected persons, but further research is needed to determine the optimal modes of delivery. PMID- 26049948 TI - Formulation and pharmacology of long-acting cabotegravir. AB - PURPOSE OF REVIEW: Long-acting cabotegravir may provide a novel therapeutic option for both the treatment and prevention of HIV-1 infection that does not necessitate adherence to a daily regimen. The present review will highlight the unique formulation properties and pharmacologic attributes of long-acting cabotegravir nanosuspension. RECENT FINDINGS: Cabotegravir is a potent integrase strand transfer inhibitor that has been formulated as an oral tablet for daily administration and as a long-acting injectable nanosuspension. Long-acting cabotegravir is readily absorbed following intramuscular and subcutaneous administration and has an elimination half-life of approximately 40 days, allowing for administration on a monthly or less frequent schedule. Repeat-dose pharmacokinetic studies and population pharmacokinetic modeling indicate monthly and bi-monthly dosing achieves clinically relevant plasma concentrations considered effective for HIV maintenance therapy and that quarterly injections are appropriate for investigation as preexposure prophylaxis. Cabotegravir is primarily metabolized by uridine diphosphate glucuronosyltransferase 1A1 and is unlikely to be impacted by the cytochrome P450 metabolic pathway. In vitro and in vivo data suggest cabotegravir has a low propensity to cause, or be subject to, significant drug interactions. SUMMARY: The pharmacologic profile of long-acting cabotegravir supports its continued development for both treatment and prevention of HIV-1 infection. PMID- 26049949 TI - Long-acting antiviral agents for HIV treatment. AB - PURPOSE OF REVIEW: Long-acting antiretroviral (ARV) agents are currently under development for the treatment of chronic HIV infection. This review focuses on data recently produced on injectable ARVs for patients living with HIV/AIDS and on the patients' perspectives on the use of these agents. RECENT FINDINGS: Crystalline nanoparticle formulations of the nonnucleoside reverse transcriptase inhibitor rilpivirine (TMC278) and of the HIV-1 integrase strand transfer inhibitor cabotegravir (GSK1265744) have progressed into phase II clinical trials as injectable maintenance therapy for patients living with HIV/AIDS with an undetectable viral load. SUMMARY: Phase II studies evaluating the coadministration of rilpivirine and cabotegravir intramuscularly to HIV-infected individuals with an undetectable viral load are currently underway. Rilpivirine and cabotegravir are characterized by different mechanisms of action against HIV and a favorable drug interaction profile, providing a rationale for coadministration. The high potency and low daily dosing requirements of oral cabotegravir and rilpivirine facilitate long-acting formulation development. Intramuscular dosing is preceded by an oral lead-in phase to assess safety and tolerability in individual participants. In addition to assessing the safety of injectable therapies in ongoing studies, it will be important to evaluate whether differences in drug adherence between injectable and oral therapies lead to different virologic outcomes, including rates of virologic failure and the emergence of resistance. Long-acting formulations may be associated with challenges, such as the management of adverse effects with persistent drug concentrations and the risk of virologic resistance, as drug concentrations decline following discontinuation. PMID- 26049950 TI - Long-acting rilpivirine for HIV prevention. AB - PURPOSE OF REVIEW: Long-acting injectable antiretroviral (ARV) formulations are being developed for the treatment and prevention of HIV infection. The purpose of this review is to summarize recent preclinical and clinical data on TMC278 (rilpivirine), a nonnucleoside reverse transcriptase inhibitor (NNRTI), that is being developed for both a treatment and prevention indication. RECENT FINDINGS: Long-acting rilpivirine has demonstrated efficacy in preventing HIV acquisition in a humanized mouse model and has been found to be well tolerated and acceptable in several Phase I clinical trials. Pharmacokinetic data from Phase I studies suggest that 1200 mg of long-acting rilpivirine administered every 8 weeks would be associated with plasma and tissue levels of rilpivirine anticipated to be necessary for preventing HIV infection. This regimen is being evaluated in the HPTN-076 Phase II expanded safety study that will enroll women in South Africa, Zimbabwe, and the USA. The HPTN-076 study requires a 4-week run in with oral rilpivirine (25 mg capsules) before receiving 1200 mg of rilpivirine. It is not yet certain whether oral dosing will remain a prerequisite in future trials or post licensure. SUMMARY: Long-acting rilpivirine shows promise as a candidate agent for HIV prevention. Preclinical efficacy has been demonstrated in a murine model. Phase I studies have shown good safety and efficacy, but breakthrough infection and resistance have been documented with lower doses of long-acting rilpivirine. Phase II development for a prevention indication is ongoing. PMID- 26049951 TI - Cabotegravir long-acting for HIV-1 prevention. AB - PURPOSE OF REVIEW: Preexposure prophylaxis (PrEP) with daily Truvada has demonstrated clinical efficacy against HIV-1 acquisition that correlates with high adherence. Long-acting antiretroviral drugs offer an alternative to daily regimens and may improve PrEP adherence. This review summarizes the preclinical nonhuman primate studies for evaluating the efficacy of cabotegravir long-acting as PrEP and the ongoing phase 2a studies assessing safety, tolerability, and acceptability of cabotegravir long-acting. RECENT FINDINGS: Cabotegravir is an HIV-1 integrase strand transfer inhibitor with intrinsic properties that permit its formulation as a long-acting injectable suspension. In clinical evaluation, cabotegravir long-acting has a half-life that permits infrequent dosing, possibly once every 3 months. In validated macaque models, cabotegravir long-acting demonstrated high protection against both rectal and vaginal transmission at clinically achievable drug concentrations. SUMMARY: PrEP, after approval of Truvada, continues to evolve to address adherence limitations of daily dosing. As a long-acting injectable antiretroviral drug, cabotegravir long-acting permits quarterly dosing and demonstrated high efficacy in macaque models supporting dose selection and clinical development. Clinical studies have confirmed dose selection in phase 2a trials with cabotegravir long-acting to ultimately lead to phase 2b/3 PrEP efficacy trials. PMID- 26049952 TI - Recent work on vaginal rings containing antiviral agents for HIV prevention. AB - PURPOSE OF REVIEW: In response to the need for strategies women can use to protect themselves from HIV infection, a new class of product commonly referred to as vaginal 'microbicides' has been under development for the past few decades. Several leading products currently in development contain antiviral agents delivered in a vaginal ring. RECENT FINDINGS: Research published over the past year reports advances in identification and continued formulation of specific antiviral agents that have potential for delivery in vaginal rings, including drug combinations for HIV, other sexually transmitted infections and contraception. Most products are antiretroviral reverse transcriptase inhibitors. Advances in vaginal ring design have also been reported; some of these are designed to release specific antiviral agents, while other designs could be used for multiple drugs. This review focuses both on antiviral agents and vaginal ring designs. SUMMARY: Over the past year, advances continued to be made in the development of vaginal rings to deliver antiviral agents for prevention of HIV. An array of antiviral agents and vaginal ring designs to deliver these products are at various stages in the product pipeline process. Results from the first efficacy trials of an antiretroviral-containing vaginal ring are expected soon and will inform the continued development of this important product class. PMID- 26049954 TI - Regulatory challenges in developing long-acting antiretrovirals for treatment and prevention of HIV infection. AB - PURPOSE OF REVIEW: To outline some of the regulatory challenges inherent to the development of long-acting antiretrovirals (ARVs) for the treatment or prevention of HIV infection. RECENT FINDINGS: Despite advances in drug development that have reduced ARV dosing to once daily, suboptimal drug adherence remains an obstacle to successful HIV treatment. Further, large randomized trials of once daily oral ARVs for preexposure prophylaxis (PrEP) have shown that drug adherence correlates strongly with prophylactic effect and study outcomes. Thus, the prospect of developing long-acting ARVs, which may mitigate drug adherence issues, has attracted considerable attention lately. SUMMARY: Because of their pharmacokinetic properties, the development of long-acting ARVs can present novel regulatory challenges. Chief among them is determining the appropriate dosing regimen, the need for an oral lead-in, and whether existing data with an approved oral agent, if available, can be leveraged for a treatment or prevention indication. For PrEP, because validated biomarkers are lacking, additional nonclinical studies and evaluation of tissue concentrations in multiple compartments may be necessary to identify optimal dosages. Study design and choice of controls for registrational trials of new long-acting PrEP agents might also prove challenging following the availability of an oral PrEP drug. PMID- 26049953 TI - Injectable agents for pre-exposure prophylaxis: lessons learned from contraception to inform HIV prevention. AB - PURPOSE OF REVIEW: Long-acting injectable (LAI) forms of preexposure prophylaxis (PrEP) are in clinical trials, generating much hope for HIV prevention. But this is not the first time that an injectable form of preventive medication has emerged: the contraceptive agent depomedroxyprogesterone acetate (DMPA) has an important precedent. DMPA's long journey, its initial reception, and ongoing implementation challenges can help inform the field of HIV prevention as we plan for approval, acceptance, and scale-up of LAI-PrEP. RECENT FINDINGS: DMPA faced a long regulatory journey in the USA, with a lag of 25 years from initial application (1967) to approval (1992). Acceptance after introduction was rapid, but challenges hampered scale-up. Specific lessons learned include that extensive acceptability work is needed in parallel to product development. Also, low continuation rates, challenges with timing of initiation, and difficulty ensuring access for the most vulnerable populations have limited DMPA's impact. A new subcutaneous formulation presents opportunities for administration outside of clinical settings and for self-administration. SUMMARY: Those involved in LAI PrEP development and those who plan to be involved in its future implementation must consider these lessons and possible solutions from DMPA to ensure a successful future for this new HIV prevention modality. PMID- 26049955 TI - Implementation challenges for long-acting antivirals as treatment. AB - PURPOSE OF REVIEW: Long-acting injectable antiretroviral therapy (ART) formulations hold great promise in helping to close the significant gap between efficacy and effectiveness in HIV treatment by eliminating the requirement for lifelong daily pills. However, significant systems-level and individual challenges to implementation of long-acting ART in HIV treatment are anticipated. RECENT FINDINGS: Studies of long-acting ART formulations are burgeoning, but the drugs are still in early phases of investigation and key knowledge gaps in pharmacokinetics and pharmacodynamics, as well as their effectiveness in settings with the largest burden of HIV disease and in key populations, remain. Extrapolating from the literature on implementation barriers to using long-acting contraception on a global scale, we explore the implementation barriers to rolling-out long-acting ART, including country approval and endorsements; prioritization of patient populations for preferred use, clinic infrastructure requirements, steady supply chains, decentralization of care, provider and patient training programs, and laboratory monitoring; and the need to examine patient preferences and conduct rigorous implementation science research to effectively scale-up this intervention. SUMMARY: Long-acting ART for HIV treatment harbors exciting potential to shift treatment paradigms. Current knowledge gaps in the use of these agents remain, leading to multiple anticipated systems-level and individual-level barriers to implementation. Addressing these gaps and barriers will help fulfill the promise of these agents against the pandemic. PMID- 26049956 TI - Planning ahead for implementation of long-acting HIV prevention: challenges and opportunities. AB - PURPOSE OF REVIEW: Broad-based access, uptake, and dissemination of daily oral HIV preexposure prophylaxis (PrEP) have been slow, despite strong evidence for efficacy. Effective and efficient implementation of long-acting HIV prevention products will require both analysis of the dynamics and determinants of daily oral PrEP implementation and identification of the distinct challenges and opportunities inherent in emerging technologies. RECENT FINDINGS: Evidence suggests the importance of addressing implementation issues at three levels: patient, provider, and system. Patient-level factors include targeted education and messaging, tailored supports to enhance acceptability and uptake, and effective strategies for promoting adherence/persistence and retention in care. Provider-level factors include engaging a broad mix of providers, while ensuring adequate training and support for patient assessment, counseling, and follow-up. Systems-level factors include optimal delivery modalities, resource allocation, and ensuring access to populations most in need of new prevention options. SUMMARY: Formative social/behavioral research must be undertaken proactively to prepare for and address future implementation challenges and reduce the gap between proving efficacy in clinical trials and assuring real-world effectiveness. Conceptualizing new HIV prevention technologies as behavioral interventions at the level of the patient, provider, and system will be paramount to effective and efficient implementation. PMID- 26049958 TI - Focal masses in a non-cirrhotic liver: The additional benefit of CEUS over baseline imaging. AB - Incidentally detected focal liver lesions are commonly encountered in clinical practice presenting a challenge in the daily department work flow. Guidelines for the management of incidental focal liver lesions have been published but comments, illustrations and recommendations regarding practical issues are crucial. The unique features of contrast-enhanced ultrasound in non-invasive assessment of focal liver lesion enhancement throughout the vascular phases in real-time has allowed an impressive improvement in the diagnostic accuracy of ultrasound. We highlight the additional benefit of contrast-enhanced ultrasound over conventional B-mode ultrasound imaging in detection, characterization, differential and final diagnosis of focal liver lesions, as well as for liver metastases screening. The current roles of cross-sectional imaging are explained in detail, with indications and limitations for each procedure. The advantages of CEUS, such as non-ionizing radiation exposure, cost benefits, non-iodinate contrast agents, and repeatability are also described ultimately improving patient management. PMID- 26049959 TI - [Blunted erythropoietic response in the anemia of anorexia nervosa]. AB - BACKGROUND AND OBJECTIVE: The cause of the anemia in anorexia nervosa (AN) has not been fully ascertained. Ferritin, folate and cobalamin values are usually within normal ranges. Anemia does not have a relationship with bone marrow changes and erythropoietin (EPO) levels have not been investigated. The objective of this study was to evaluate the EPO response in a small group of AN patients. PATIENTS AND METHODS: EPO levels were measured in serum samples of 41 female AN patients (11 with anemia, and 30 with normal blood cell count). The adequacy of EPO response was assessed by comparing the increase observed in a group of normal weight patients with anemia. RESULTS: EPO concentrations in anemic AN patients were higher than in non-anemic: 20.63mU/mL (4.04-28.46) vs 8.7mU/mL (3.9-20.93), P=.0088, but the increase in EPO was lower than expected (27.85mU/mL [17.7 118.9]), P=.014. BMI and the difference between actual and expected EPO were inversely correlated. CONCLUSIONS: Inadequate EPO response may partly explain anemia in AN, but further studies are necessary. PMID- 26049960 TI - [Amyotrophic neuralgia associated with bilateral phrenic paralysis treated with non-invasive mechanical ventilation]. AB - Amyotrophic neuralgia is an uncommon neuropathy characterized by severe unilateral shoulder pain. Isolated or concomitant involvement of other peripheral motor nerves depending on the brachial plexus such as phrenic or laryngeal nerves is unusual(1). Its etiology is unknown, yet several explanatory factors have been proposed. Phrenic nerve involvement, either unilateral or bilateral, is exceedingly rare. Diagnosis relies on anamnesis, functional and imaging investigations and electromyogram. We report the case of a 48-year-old woman with a past history of renal transplantation due to proliferative glomerulonephritis with subsequent transplant rejection, who was eventually diagnosed with amyotrophic neuralgia with bilateral phrenic involvement, and who required sustained non-invasive mechanical ventilation. PMID- 26049961 TI - [Clinical significance and prognosis of isolation of Candida spp. in venous catheters]. PMID- 26049962 TI - [Oral ulcers: Differential diagnosis and treatment]. PMID- 26049963 TI - [Widespread pigmentation following long-term minocycline therapy]. PMID- 26049964 TI - Biosimilars in Dermatology: Current Situation (Part II). AB - The first biosimilar version of a biologic agent used to treat psoriasis (infliximab) entered the Spanish market on February 16 of this year, and more biosimilars can be expected to follow in the coming months and years. Logically, this new situation will have economic repercussions and alter prescribing patterns among dermatologists. In this second part of the review, we will look at several somewhat contentious issues, such as the extrapolation of indications, interchangeability, and automatic substitution. We will also review the biosimilars with indications for psoriasis currently in the clinical development pipeline and assess their potential to offer comparable efficacy and safety to the reference product while contributing to the sustainability of the public health care system. PMID- 26049965 TI - Long-term effect on foot and ankle donor site following vascularized fibular graft resection in children. AB - This study was carried out to evaluate the long-term effect on the donor side of the foot and ankle following vascularized fibular graft resection in children. Eight patients underwent resection of the fibula for the purpose of a vascularized fibular graft by a surgical team who practiced leaving at least 6 cm residual distal fibula. The age of these children at the time of surgery was between 3 and 12 years. They were reviewed between 3 and 12 years after surgery. Two patients who underwent resection of the middle shaft of the fibula at 3 and 5 years of age developed abnormal growth of the distal tibia, leading to ankle valgus. They were treated with growth modulation of the distal tibial physis and supramalleolar osteotomy with tibiofibular synostosis. Another patient who underwent the entire proximal fibula resection at the age of 6 years had developed hindfoot valgus because of weakness of the tibialis posterior muscle. He required talonavicular fusion and flexor hallucis to tibialis posterior muscle transfer. Patients operated at the age of older than 8 years neither had ankle nor hindfoot deformity. We concluded that resection of the middle shaft of the fibula for the purpose of a vascularized fibula graft, leaving a 6 cm distal fibular stump in children younger than 6 years old, may give rise to abnormal growth of the distal tibial physis, leading to valgus ankle. The entire proximal fibular resection for the similar purpose in a 6-year-old child may give rise to weakness of tibialis posterior and hindfoot valgus. PMID- 26049966 TI - Hysterical conversion paralysis in an adolescent boy with lumbar spondylolysis. AB - We describe a case of recurrent hysterical paralysis triggered by low back pain because of lumbar spondylolysis. A 16-year-old male soccer player was referred to our institution with five previous episodes of acute paralysis triggered by severe low back pain. We performed direct surgical repair of the terminal-stage bilateral spondylolysis at L4 using a hook-rod system. His chronic low back pain was completely resolved, and no further episodes of hysterical paralysis have occurred after surgery. Spine surgeons should be aware of possible hysterical conversion paralysis when there is discrepancy between radiological and neurological findings. PMID- 26049967 TI - Host susceptibility to non-tuberculous mycobacterial infections. AB - Non-tuberculous mycobacteria cause a broad range of clinical disorders, from cutaneous infections, such as cervical or intrathoracic lymphadenitis in children, to disseminated infections at all ages. Recognition of the underlying immune defect is crucial for rational treatment, preventive care, family screening, and, in some cases, transplantation. So far, at least seven autosomal mutations (in IL12B, IL12RB1, ISG15, IFNGR1, IFNGR2, STAT1, and IRF8) and two X linked mutations (in IKBKG and CYBB), mostly presenting in childhood, have been reported to confer susceptibility to disseminated non-tuberculous mycobacterial infection. GATA2 deficiency and anti-interferon gamma autoantibodies also give rise to disseminated infection, typically in late childhood or adulthood. Furthermore, isolated pulmonary non-tuberculous mycobacterial infection has been increasing in prevalence in people without recognised immune dysfunction. In this Review, we discuss how to detect and differentiate host susceptibility factors underlying localised and systemic non-tuberculous mycobacterial infections. PMID- 26049969 TI - Improved Detection of Sentinel Lymph Nodes in SPECT/CT Images Acquired Using a Low- to Medium-Energy General-Purpose Collimator. PMID- 26049968 TI - Different spontaneous breathing trials in patients with atrial fibrillation. AB - INTRODUCTION: Weaning from mechanical ventilation is one of the most important and challenging problems for most intensive care unit (ICU) patients. Spontaneous breathing trial (SBT) is the most common method used to evaluate patients' ability to breathe by themselves and plays an important role in decision making for weaning. The aim of our study was to investigate the effect of different methods of SBT in respiratory care unit (RCU) patients with atrial fibrillation (AF) on weaning outcome. METHODS: We retrospectively analyzed different methods of SBT in patients with and without AF. We enrolled RCU patients who required mechanical ventilation and had undergone transthoracic echocardiography from January 2011 to January 2012. RESULTS: There was a higher SBT passing rate among AF patients who received pressure support ventilation (PSV) trial than in those who received T-piece trail (92.5% vs. 73.1%, p=0.041). The weaning rates between these two groups were not significantly different (83.8% vs. 94.7%, p=0.403). Total ventilator days were longer in T-piece group than in PSV group (median 40.0, IQR: 18.2-125.1 days vs. 33.0, IQR: 29.6-51.0 days respectively, p=0.580), but this difference was not statistically significant. These results were not found in patients without AF. CONCLUSIONS: The use of PSV trial might be considered first instead of T-piece trial for SBT when AF patients were ready to wean. PMID- 26049970 TI - A Fatal Case of Isolated Methiopropamine (1-(Thiophen-2-yl)-2-Methylaminopropane) Toxicity: A Case Report. AB - Methiopropamine (1-(thiophen-2-yl)-2-methylaminopropane) is a synthetic methamphetamine analogue and is classified as a novel psychoactive substance. The use of novel psychoactive substance has been increasing substantially for recreational purpose in recent years. Methiopropamine was first detected in 2011 in Finland and was later detected in the United Kingdom. It can be purchased on the Internet and is currently poorly regulated. Reported adverse effects of methiopropamine use are mostly anecdotal user reports on Internet forums, and there are limited data on its pharmacodynamics and toxicity in the literature. Death as a direct result from methiopropamine toxicity has not been reported in Australia. We report here the first case of death caused by recreational use of methiopropamine in Australia. This same incident highlights the first ever death from isolated methiopropamine use. Being an analogue of methamphetamine, we hypothesize that the mechanism of death caused by methiopropamine would not be dissimilar to methamphetamine. PMID- 26049971 TI - Sources of Response Bias in Older Ethnic Minorities: A Case of Korean American Elderly. AB - The present study was undertaken to investigate potential sources of response bias in empirical research involving older ethnic minorities and to identify prudent strategies to reduce those biases, using Korean American elderly (KAE) as an example. Data were obtained from three independent studies of KAE (N = 1,297; age >=60) in three states (Florida, New York, and Maryland) from 2000 to 2008. Two common measures, Pearlin's Mastery Scale and the CES-D scale, were selected for a series of psychometric tests based on classical measurement theory. Survey items were analyzed in depth, using psychometric properties generated from both exploratory factor analysis and confirmatory factor analysis as well as correlational analysis. Two types of potential sources of bias were identified as the most significant contributors to increases in error variances for these psychological instruments. Error variances were most prominent when (1) items were not presented in a manner that was culturally or contextually congruent with respect to the target population and/or (2) the response anchors for items were mixed (e.g., positive vs. negative). The systemic patterns and magnitudes of the biases were also cross-validated for the three studies. The results demonstrate sources and impacts of measurement biases in studies of older ethnic minorities. The identified response biases highlight the need for re-evaluation of current measurement practices, which are based on traditional recommendations that response anchors should be mixed or that the original wording of instruments should be rigidly followed. Specifically, systematic guidelines for accommodating cultural and contextual backgrounds into instrument design are warranted. PMID- 26049972 TI - Lateral Mass Fixation in the Subaxial Cervical Spine. AB - The use of lateral mass screws and rods in the subaxial spine has become the standard method of fixation for posterior cervical spine fusions. Multiple techniques have been described for the placement of lateral mass screws, including the Magerl, the Anderson, and the An techniques. While these techniques are all slightly different, the overall goal is to obtain solid bony fixation while avoiding the neurovascular structures. The use of lateral mass screws has been shown to be a safe and effective technique for achieving a posterior cervical fusion. PMID- 26049973 TI - Controlling for Multiple Tests. AB - In a statistical test, the P-value is the likelihood that the observed results are just due to chance, and by convention a P-value of <0.05 is considered significant. However, this means that if a study performs 20 individual statistical analyses, assuming the null hypothesis is true in all of them, we expect one to fall below the P<0.05 threshold and give us a false positive. Advanced statistical tests should be used to prevent this from occurring. PMID- 26049974 TI - MRI factors to predict urinary incontinence after retropubic/laparoscopic radical prostatectomy. AB - PURPOSE: Prostate cancer can be treated by radical prostatectomy (RP) and provoke a troublesome side effect: urinary incontinence (UI). We propose a verification of the usefulness of MRI and an identification of which structures are involved in UI after RP. METHODS: Between September 2002 and December 2011, 550 patients underwent RP. We performed MRI to evaluate extraprostatic disease before surgery. To evaluate patient status, we measured the following structures: length (LP), width (WP), height (HP) and volume (PV) of the prostate, membranous urethral length (MUL), urethral wall thickness (UWT), levator ani muscle (LAM) and obturator internus muscle (OIM) thickness, ratio of levator ani muscle/prostate volume (LAM/PV), volume of the urethra (VU). UI was defined according to ICS definition as the complaint of any involuntary leakage of urine and evaluated 1 year after surgery. Analyses were performed by mean comparisons, univariate and multivariate logistic regression with a 1000-resample bootstrapping. RESULTS: Means of measurements were: LP 4.46 cm, WP 5.15 cm, HP 3.9 cm, PV 49.3 cc; LAM 0.51 cm, OIM 1.46 cm; MUL 1.43 cm, UWT 1.38 cm; and LAM/PV 0.013 cm/cc, VU 2.33 cc. One hundred and twenty-two (22.2 %) patients complained of urine leakage. Univariate obtained differences in PV, OIM, MUL, and UWT. After adjusting by confounders, multivariate analysis showed: MUL: [OR 0.134; CI 95 % (0.022-0.493); P 0.006]; PV: [OR 1.016; CI 95 % (1.004-1.029); P 0.005]; UWT: [OR 6.03; CI 95 % (1.068-44.1); P 0.033]. CONCLUSIONS: MRI is a useful tool to predict UI after RP. The MUL and PV are well-identified structures that are involved in UI. Our study shows that UWT also influences UI. PMID- 26049976 TI - Perirectal recurrence and intraperitoneal dissemination of urothelial carcinoma as plasmacytoid variant: clinical-imaging-histological findings. PMID- 26049975 TI - Evaluation of oxidative stress status and antioxidant capacity in patients with painful bladder syndrome/interstitial cystitis: preliminary results of a randomised study. AB - PURPOSE: This study aimed to investigate oxidative stress in etiopathogenesis by analyzing serum total antioxidant capacity (TAC), total oxidant status (TOS), binding capacity of exogenous cobalt to human albumin (IMA), serum advanced oxidation protein products (AOPP), paraoxonase (PON), arylesterase, IgE, and C reactive protein (CRP) in bladder pain syndrome/interstitial cystitis (BPS/IC). METHODS: The study included 16 female patients diagnosed with BPS/IC and 25 healthy female subjects forming the control group. A bladder biopsy was performed on all patients in the BPS/IC group by carrying out cystoscopy with hydrodistention under general anesthesia. The results of serum TAC, TOS, IMA, AOPP, PON, arylesterase, IgE, and CRP of the subjects in both groups were compared. RESULTS: The mean age of the 16 female patients in the BPS/IC group was 43.6 +/- 14.5 years, and the mean age of the 25 healthy subjects in the control group was 42.0 +/- 10.3 years. According to the criteria of International Society for the Study of Interstitial Cystitis (ESSIC), eight patients were classified as Type 2A, three patients as Type 2B, four patients as Type 2C, and one patient as Type 3C. In the BPS/IC group, while TAC was found significantly lower than in the control group, IMA, IgE, and CRP were found significantly higher (P < 0.05). When binary logistic regression analysis was performed, the created model was determined to have 81.3 % sensitivity and 80 % specifity. CONCLUSIONS: In the etiology of BPS/IC, mechanism of oxidative damage comes into prominence. In the diagnosis of BPS/IC, IgE, CRP, and TAC are not specific markers when used separately; however, a higher specifity and sensitivity could be reached when used jointly in the suspected patients. PMID- 26049977 TI - The indication for hysterectomy as a risk factor for subsequent pelvic organ prolapse repair. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to investigate whether the indication for hysterectomy was itself a risk factor for subsequent pelvic organ prolapse (POP) in Danish women who underwent hysterectomy from 1977 to 2009. METHODS: Data from 154,882 women who underwent hysterectomy for benign conditions during the period 1977 - 2009 were extracted from the Danish National Patient Register. Patients were followed up from hysterectomy to POP surgery, death/emigration, or end of study period. Hazard ratios (HR) for the first POP surgery in each woman were calculated using the Cox proportional hazards model. Survival analysis for each indication for hysterectomy was performed using the Kaplan-Meier product limit method. RESULTS: Fibroids/polyps as the indication was used as the reference when calculating HRs. After adjustment for calendar period, patient age, and hysterectomy route, the HR for POP was 6.57 (95% confidence interval 5.91 - 7.30). The HR for abnormal uterine bleeding (AUB), pain, endometriosis, and "other indications" was significantly higher than the reference. POP surgery was performed predominantly in the posterior compartment for all indications except benign ovarian tumors. CONCLUSIONS: POP as the indication for hysterectomy was associated with the highest cumulative incidence of subsequent POP surgery 32 years after hysterectomy. But the indications AUB, pain, endometriosis, and "other indications" were associated with a higher risk of subsequent POP surgery after hysterectomy than the indication fibroids/polyps. The predominant compartment for POP surgery was the posterior compartment for almost all indications. The indication for hysterectomy and the compartment in which POP surgery was performed subsequent to hysterectomy were associated. PMID- 26049980 TI - World Hepatitis Day: A reminder to screen baby boomers. PMID- 26049978 TI - Thrombus deflector stent for stroke prevention: A simulation study. AB - Atrial fibrillation (AF) is a dysfunction of heart rhythm and represents an increased predisposition to ischemic stroke in AF patients. It has been shown that the AF-induced hemodynamic conditions may contribute to the increased embolic propensity through the carotid arteries. We simulated a stroke-prevention device with a unique strut structure to deflect the trajectory of a blood clot to the carotid artery. We identified the important determinants of functionality in a device design using computational fluid dynamics simulations. Quantitative assessment of deflection efficacy over various clot dimensions was carried out for the device with different strut configurations under AF flow conditions. The simulations demonstrate that the trajectory of a clot destined to the left common carotid artery (LCCA) can be deflected by a strut-structured device at the LCCA inlet with virtually no change in flow resistance. The deflection efficacy of the device is dependent on the clot properties and strut designs of the device. A configuration of 0.75 mm thick and 0.75 mm distant struts with 50% of surface convexity were found to provide maximum deflection efficacy (e.g., 36% greater deflection efficacy than a flat filter) among the strut structures considered. The results suggest that a deflector stent implanted in the aortic branch may be an effective stroke-prevention device. The present simulations motivate pre clinical animal studies as well as further studies on patient-specific design of the device that maximize the deflection efficacy while minimizing device safety issues. PMID- 26049979 TI - The effect of 1:2 Ag(I) thiocyanate complexes in MCF-7 breast cancer cells. AB - There is much interest currently in the design of metal compounds as drugs and various metal compounds are already in clinical use. These include gold(I) compounds such as auranofin and the anti-cancer platinum(II) complex, cisplatin. Bis-chelated gold(I) phosphine complexes have also shown great potential as anticancer agents, however, their efficacy has been limited by their high toxicity. In this study, silver(I) thiocyanate compounds linked to four specific ligands, were synthesized and characterized. These silver-phosphine adducts included [AgSCN{P(4-MeC6H4)3}2]2 (1); [AgSCN{P(4-ClC6H4)3}2]2 (2); [AgSCN{P(4 MeOC6H4)3}2]2 (3); [AgSCN(PPh3)2]2 (4). The compounds were found to be toxic to MCF-7 breast cancer cells while the ligands on their own were not toxic. Our findings further indicate that the silver(I) phosphine compounds induce apoptotic cell death in these breast cancer cells. In addition, the compounds were not toxic to nonmalignant fibroblast cells at the IC50 concentrations. This is an indication that the compounds show selectivity towards the cancer cells. PMID- 26049981 TI - Chemistry, natural sources, dietary intake and pharmacokinetic properties of ferulic acid: A review. AB - Ferulic acid (FA) is an abundant dietary antioxidant which may offer beneficial effects against cancer, cardiovascular disease, diabetes and Alzheimer's disease. The impact of FA on health depends on its intake and pharmacokinetic properties. In this article, the literature pertaining to chemistry, natural sources, dietary intake and pharmacokinetic properties of FA is critically reviewed. High levels of FA are found in both free and bound forms in vegetables, fruits, cereals, and coffee. We have estimated that consumption of these foods may result in approximately 150-250mg/day of FA intake. FA can be absorbed along the entire gastrointestinal tract and metabolized mainly by the liver. The absorption and metabolism of FA seem to be dose dependent at least in experimental settings. Further pharmacokinetic and pharmacodynamic studies are required to characterize the impact of FA on human health. PMID- 26049982 TI - Immobilization and stabilization of pectinase by multipoint attachment onto an activated agar-gel support. AB - Pectinase was immobilized on an activated agar-gel support by multipoint attachment. The maximal activity of immobilized pectinase was obtained at 5 degrees C, pH 3.6, with a 24h reaction time at an enzyme dose of 0.52mg protein/g gel, and the gel was activated with 1.0M glycidol. These conditions increased the thermal stability of the immobilized pectinase 19-fold compared with the free enzyme at 65 degrees C. The optimal temperature for pectinase activity changed from 40 to 50 degrees C after immobilization; however, the optimal pH remained unchanged. The immobilized enzyme also exhibited great operational stability, and an 81% residual activity was observed in the immobilized enzyme after 10 batch reactions. PMID- 26049983 TI - Effects of fermentation on the phytochemical composition and antioxidant properties of soy germ. AB - Soy germ is a remarkable source of bioactive phytochemicals offering an interesting alternative as starting ingredient for fermented food. This work aimed to determine whether lactic acid bacteria fermentation of soy germ induces changes on its phytochemical composition. The antioxidant properties of fermented soy germ samples periodically taken during the fermentation process were evaluated and correlated with the concentration and structural modifications of isoflavones, saponins, phytosterols and tocopherols. Fermented soy germ extracts exhibited a higher inhibition effect against the superoxide anion radical, and lesser but significant ferric-reducing and DPPH radical scavenging effects compared with raw soy germ. By comparison to the traditional whole seed-based products, soy germ exhibits higher levels of isoflavones, saponins, phytosterols and tocopherols. All these phytochemicals contributed to the antioxidant capacity of soy germ and were conserved under lactic acid bacteria fermentation. PMID- 26049984 TI - Differences of volatile constituents between unripe, partially ripe and ripe guayabita del pinar (Psidium salutare H.B.K.) fruit macerates. AB - The effect of the maturation stages on the volatile constituents of the guayabita del pinar (Psidium salutare H.B.K.) fruit macerates was investigated during three different stages (unripe, partially ripe and ripe). Volatile compounds were isolated by continuous liquid-liquid extraction with pentane and analyzed by means of GC-FID and GC-MS. In unripe fruit macerate the fruit volatiles were predominantly the mono- and sesquiterpenes. During maturation, levels of the mono and sesquiterpenes decreased drastically in macerates, whereas levels of some esters (ethyl nicotinate, ethyl malate, ethyl 3-phenylpropanoate, pentyl benzoate, benzyl benzoate and ethyl cinnamates) and cinnamic acid increased significantly. PMID- 26049985 TI - An extra-cellular alkaline metallolipase from Bacillus licheniformisMTCC 6824: Purification and biochemical characterization. AB - An extra-cellular lipase produced by Bacillus licheniformis MTCC 6824 was purified to homogeneity by ammonium sulphate fractionation, ethanol/ether precipitation, dialysis, followed by anion-exchange chromatography on Amberlite IRA 410 (Cl(-) form) and gel exclusion chromatography on Sephadex G 100 using Tris-HCl buffer (pH 8.0). The crude lipase extract had an activity of 41.7LU/ml of culture medium when the bacterium was cultured for 48h at 37 degrees C and pH 8.0 with nutrient broth supplemented with sardine oil as carbon source. The enzyme was purified 208-fold with 8.36% recovery and a specific activity of 520LU/mg after gel exclusion chromatography. The pure enzyme is a monomeric protein and has an apparent molecular mass of 74.8kDa. The lipase had a Vmax and Km of 0.64mM/mg/min and 29mM, respectively, with 4-nitro phenylpalmitate as a substrate, as calculated from the Lineweaver-Burk plot. The lipase exhibited optimum activity at 45 degrees C and pH 8.0, respectively. The enzyme had half lives (T1/2) of 82min at 45 degrees C, and 48min at 55 degrees C. The catalytic activity was enhanced by Ca(2+) (18%) and Mg(2+) (12%) at 30mM. The lipase was inhibited by Co(2+), Cu(2+), Zn(2+), Fe(2) even at low concentration (10mM). EDTA, at 70mM concentration, significantly inhibited the activity of lipase. Phenyl methyl sulfonyl fluoride (PMSF, 70mM) completely inactivated the original lipase. A combination of Ca(2+) and sorbitol induced a synergistic effect on the activity of lipase with a significantly high residual activity (100%), even after 45min, as compared to 91.5% when incubated with Ca(2+) alone. The lipase was found to be hydrolytically resistant toward triacylglycerols with more double bonds. PMID- 26049986 TI - Effects of sources of carbon and nitrogen on production of alpha-glucosidase inhibitor by a newly isolated strain of Bacillus subtilis B2. AB - This study examined production of alpha-glucosidase inhibitors by Bacillus subtilis B2 in Luria-Bertani (LB) fermentation with okara, soy powder, starch or pectin as additional source of carbon and nitrogen. All the fermentation broths of B. subtilis B2 exhibited gradual increase in alpha-glucosidase inhibitory activity during the fermentation process with or without supplemented source of carbon or nitrogen. Addition of okara into the LB medium greatly enhanced the strength (nearly twice as much of that without okara supplement) of alpha glucosidase inhibitory activity of fermentation broth. The alpha-glucosidase inhibitory activity of B. subtilis B2 fermentation broth was positively correlated (p<0.05) with the bacterial populations grown in LB medium containing okara. Glucose and sucrose were not detected in LB medium during the entire fermentation process and were both reduced drastically in media containing okara, soy powder, starch or pectin after 6days of fermentation. The fermented LB medium containing okara by B. subtilis B2 possessed very strong alpha-glucosidase inhibitory activity and contained little glucose and sucrose, suggesting that fermentation of B. subtilis B2 in LB added with okara might be considered as a strategy for preparing functional foods for diabetic patients. PMID- 26049987 TI - Chemical composition and oxidative stability of Tunisian monovarietal virgin olive oils with regard to fruit ripening. AB - The chemical composition of virgin olive oil may be influenced by genotype and different agronomic (i.e. fruit ripeness degree, water supply) and technological factors. This article reports the evaluation of the influence of the olive ripening stage on the quality indices, the major and the minor components and the oxidative stability of the two main monovarietal Tunisian cultivars (cvv. Chetoui and Chemlali) virgin olive oils. Moreover, the olives cv. Chetoui were tested in a rain-fed control and an irrigation regime. The oils sampled at five different ripeness stages were submitted to liquid chromatographic determination (HPLC DAD/MSD) of their quali-quantitative phenolic and tocopherolic profiles. Moreover, the triacylglycerol and fatty acid compositions, and minor components such as squalene, pigments and their relation with the oil oxidative stability were evaluated. The tested oils showed very good correlation between the oxidative stability and the concentrations of total phenols, practically secoiridoids and alpha-tocopherol. PMID- 26049988 TI - Effect of postharvest dehydration on the composition of pinot noir grapes (Vitis vinifera L.) and wine. AB - This study was conducted in order to improve our understanding of how phenolics and aroma compounds change in wine grapes during postharvest dehydration. Pinot noir grapes grown in the Willamette Valley of Oregon were harvested at 22.0 and 24.0 degrees Brix. Grapes harvested at 22.0 degrees Brix were divided into three equal lots with one lot immediately used for wine production, and the remaining two lots placed inside an air tunnel with an air speed of 1.0-1.8ms(-1), 38% relative humidity and a temperature of 22 degrees C. The soluble solids content and weight loss were measured daily and wines were made from grapes when they reached 24.8 and 26.7 degrees Brix. The soluble solids of grapes increased about 1 degrees Brix per day; therefore, on the third and fourth day the berries reached the desired concentration; weight loss was 14 and 16%, respectively. Results from berry phenolic analysis indicated that per berry anthocyanin amount remained unchanged during dehydration. The composition of proanthocyanidins isolated from berries changed during dehydration. Volatile compounds in wines made from dehydrated grapes contained more terpenes and norisoprenoids (beta ionone, beta-damascenone) when compared to wine made from the original fruit. Wines made from increasingly dehydrated grapes tended to resemble the composition and flavour profile of wines made from grapes left on the vine (i.e. with extended ripening). The results of this study suggest that postharvest flavour changes consistent with changes during fruit ripening can occur in grapes when harvested early and allowed to dehydrate under controlled conditions prior to fermentation. PMID- 26049989 TI - Structural and antioxidant properties of gamma irradiated hyaluronic acid. AB - Hyaluronic acid (Hyaluronan, HA) was depolymerised by gamma irradiation and its structural changes and antioxidant activities were investigated. The structural changes of gamma irradiated HA were studied by gel-permeation chromatography (GPC), viscosity, pH, Hunter colour measurement, UV spectrophotometry, and FT-IR spectroscopy. The results demonstrated that gamma irradiation decreased molecular weight size, viscosity and pH of the hyaluronic acid and its colour turned to intense yellow. UV spectra of the irradiated HA showed a change at 265nm, which indicates the formation of double bonds. Differences in the height and shape of certain absorption bonds of FT-IR spectra in the range 1700-1750cm(-1) were also observed, which is associated with the formation of carboxylic acid. From these structural changes of the HA, gamma irradiation may have a role in the formation of pyrancarboxylic acid rings. DPPH radical scavenging ability and the reducing power of gamma irradiated HA were significantly higher than that of non irradiated HA. However, non-irradiated and irradiated HA did not show significant differences in the Rancimat test. PMID- 26049990 TI - Characterisation of the pigment components in red cabbage (Brassica oleracea L. var.) juice and their anti-inflammatory effects on LPS-stimulated murine splenocytes. AB - To determine anti-inflammatory effects of pigments from red cabbage, red cabbage (Brassica oleracea L. var.) juice was prepared, characterized by UV-vis absorption spectra, partially purified by Sephadex LH-20 column, analyzed by HPLC, and administered to lipopolysaccharide (LPS)-stimulated murine splenocyte cultures. The study showed that red cabbage juice (RC) exhibited anti inflammatory effects against LPS-induced inflammation of splenocytes via increasing anti-inflammatory cytokine interleukin (IL)-10 and decreasing pro inflammatory cytokine IL-6 secretions. The maximum absorption peaks of RC and its heated products, but not activated charcoal-adsorbed products, appeared at 280nm with a small shoulder around 310-330nm while there existed a minor peak at 560nm (range from 480 to 630nm), reflecting red cabbage juice included phenolics, flavonoids, and anthocyanins. The lyophilized powder of chromatographic fractions F2, F3, and F4 through Sephadex LH-20 column were rich in phenolics (5.9+/-0.2%, 4.4+/-0.0%, and 3.9+/-0.0%, respectively) and flavonoids (1.8+/-0.3%, 1.8+/-0.3%, and 1.1+/-0.3%, respectively). The results suggest that anti-inflammatory pigment compounds in red cabbage juice were heat stable. Further analysis of chromatograms from HPLC suggests malvidin glycosides including malvidin 3 glucoside (oenin), malvidin 5-glucoside and malvidin 3,5-diglucoside in red cabbage juice could inhibit IL-6 secretion of LPS-stimulated splenocytes. PMID- 26049991 TI - Functional properties of fish protein hydrolysates from Pacific whiting(Merluccius productus) muscle produced by a commercial protease. AB - Pacific whiting (Merluccius productus) muscle was used to produce hydrolysates with 10%, 15% and 20% degree of hydrolysis (DH) using the commercial protease Alcalase((r)) and were characterized at pH 4.0, 7.0 and 10 according their solubility, emulsifying and foaming properties. Protein recovered in soluble fractions increased proportionally with the hydrolytic process, yielded 48.6+/ 1.9, 58.6+/-4.1 and 67.8+/-1.4 of total protein after 10%, 15% and 20% DH, respectively. Freeze-dried hydrolysates presented almost 100% solubility (p>0.05) at the different pHs evaluated. Emulsifying properties (EC, EAI and ESI) were not affected by DH as most samples showed similar (p>0.05) results. Higher EC (p?0.05) than sodium caseinate, used as control, were obtained at pH 4 for most hydrolysates. Hydrolysates showed very low foaming capacity not affected by pH; but foam stability was equal or even better (p>0.05) than bovine serum albumin (BSA), except at pH 4.0. Results suggest that hydrolysates from Pacific whiting muscle can be produced with similar or better functional properties than the food ingredients used as standards. PMID- 26049992 TI - Captan residue reduction in apples as a result of rinsing and peeling. AB - Apples, treated with captan for disease control in a commercial orchard in Quebec, Canada, were collected and sorted into post-harvest preparation types (no preparation; rinse; rinse and peel). Captan residues were greatest (25.5 5100ng/g) in apples with no post-harvest preparation and lowest (0.146-136ng/g) in apples that had been rinsed and peeled prior to extraction and analysis. Residues were significantly lower (p=0.003) in apples that had been rinsed prior to extraction than in apples with no post-harvest preparation. Similarly, apples subjected to rinsing and peeling had significantly lower captan residues than had apples that had been rinsed alone (p<0.0001). Although captan residues in rinsed apples were approximately 50% lower than those in apples that received no post harvest preparation, the reduction associated with peeling of apples was much greater (98%). Estimated mean captan intakes resulting from consumption of raw apples were established and single day intakes, based on apples with no preparation, ranged from 2.58MUg/kg in females >70 years to 9.48MUg/kg for individuals aged three years (at this age no distinction is made between males and females). Mean intakes estimated using rinsed and peeled apples were approximately two orders of magnitude lower than intakes estimated using apples with no post-harvest preparation, demonstrating the effect of post-harvest preparation on captan intakes. Mean captan intake estimates from all post-harvest preparation types were well below the World Health Organization acceptable daily intake of 100MUg/kg/day, based on raw apple consumption. PMID- 26049993 TI - Impact of germination time and type of illumination on carotenoidcontent, protein solubility and in vitro protein digestibility of chickpea(Cicer arietinum L.) sprouts. AB - Sprouts have been reported to be nutritionally superior to their respective seeds with higher levels of nutrients and lower amounts of antinutrients. Significant differences occur in these nutrients and antinutrients with germination under different types of illumination. This paper reports the impact of germination conditions on changes in beta-carotene content, protein solubility and in vitro protein digestibility of chickpea sprouts. The influence of germination time, type of illumination and their interaction on beta-carotene content, protein solubility and in vitro protein digestibility of chickpea sprouts was highly significant (p<0.01). Highest value for beta-carotene were observed for sprouts germinated under yellow light for 72h (131.74mg 100g(-1)) and lowest for blue light group after 120h germination. Sprouts of irradiated group had overall higher content of beta-carotene throughout germination period. Protein solubility was also higher for sprouts of irradiated group and green illumination group after 120h germination. Sprouts of irradiated group had highest value for% in vitro protein digestibility after 96h germination followed by the same group after 120h germination. It is inferred from the study that irradiation of chickpea seed prior to germination improved the beta-carotene content, protein solubility and in vitro protein digestibility of chickpea sprouts. PMID- 26049994 TI - Effect of combined high pressure and thermal treatment on kiwifruit peroxidase. AB - The effects of high pressure and heat treatments on peroxidase (POD) activity in kiwifruit were investigated. Pressure levels ranging from 200 to 600MPa and temperatures varying from 10 to 50 degrees C were applied for up to 30min. Assays were carried out on crude peroxidase in kiwifruit juice and on partially purified peroxidase in a model system. Pressures higher than 400MPa could be combined with mild heat (?50 degrees C) to accelerate enzyme inactivation. Prolongation of the exposure time had no great effect after the first 15min. The slope of POD in kiwifruit juice at 30 degrees C was slightly decreased compared with that in a model system. Furthermore, the optimum pH for POD was 6.0-8.5. The presence of POD isoenzymes and their difference in resistance to pressure were thought to be responsible for the final residual activity observed in this study. PMID- 26049995 TI - Lipid profile of foods fried in thermally polymerized palm oil. AB - Lipids extracted from foods fried in thermally polymerized palm oil were evaluated in papads, French fries and fish fry (Bombay duck) with moisture content ranging between 10% and 75%, in an attempt to investigate the effect of moisture content on lipid quality indices such as free fatty acids, conjugated dienes, p-anisidine value, viscosity, total polar materials and colour values. The quality of lipids in products with high moisture content (50% or more) was found to be inferior to that of the oil left after frying, as evidenced in Bombay duck and French fries from potatoes with initial moisture content of 52-77%. A reverse trend was observed in papads and French fries prepared from dehydrated potatoes with moisture content of 12% or less. The results indicate the moisture content of food plays a definite role in the distribution of the lipid constituents during frying in thermally polymerized oil. PMID- 26049996 TI - Uncertainty estimation and in-house method validation of HPLC analysis of carotenoids for food composition data production. AB - The method for separation and quantitative determination of the main carotenoids in food by high-performance liquid chromatography (HPLC) was in-house validated. Tomato (Lycopersicon esculentum M.) as food matrix was used to demonstrate its linearity, repeatability, intermediate precision, detection and quantification limits, sensitivity and bias. In addition, stability of carotenoids was studied in function of temperature and time. Method accuracy was quantified through measurement uncertainties estimate based on this validation study. Furthermore, a study was conducted to evaluate variability coming from location in an experimental field composed by 12 subfields. The use of two metal free reverse phase columns and an organic mobile phase based on acetonitrile, methanol and dichloromethane enabled the separation of the six target compounds (trans-alpha carotene, trans-beta-carotene, beta-cryptoxanthin, all-lycopene, lutein, zeaxanthin) within a 30min run; detection at 450nm and external calibration allowed the quantification of the analytes. Carotenoids concentration and measurement uncertainty, in mg/100g, in tomato varieties "lido" and "for salad" were, respectively, 1.0+/-0.14 and 0.39+/-0.056 for trans-beta-carotene, 8+/-2.0 and 2.3+/-0.57 for all-lycopene and 0.10+/-0.017 and 0.08+/-0.015 for lutein; trans-alpha-carotene, beta-cryptoxanthin and zeaxanthin were not detected in both varieties (detection limits, in MUg/100g, 0.81, 0.57 and 0.77, respectively). For beta-carotene and lutein, uncertainty associated with the entire process including small-scale within-region variation was statistically different, at a significance level of 5%, from measurement uncertainty (which includes sampling in the laboratory). PMID- 26049997 TI - Post-column on-line photochemical derivatization for the direct isocratic-LC-FLD analysis of resveratrol and piceid isomers in wine. AB - Resveratrol is a stilbene produced by plants, e.g. grapes, in response to stress. Resveratrol is extracted during winemaking, being present in wine as 3-O-beta-d gluocoside (piceid) and as aglycone. Both, resveratrol and piceid exist in two isomeric forms, trans and cis. Resveratrol and piceid are weakly fluorescent in both of their isomeric forms, but highly fluorescent compounds are obtained when the original molecules are UV-irradiated. A chromatographic method with post column on-line photoderivatization, has been developed for the analysis of resveratrol and piceid isomers. The four analytes are firstly separated in a C18 column (150mm*3.9mm i.d., 4MUm) by isocratic elution, at 15 degrees C, with a mobile phase consisting of a mixture acetonitrile:o-phosphoric acid (0.04%), 18:82, v:v, at 0.9mLmin(-1), and secondly they are on-line phototransformed into their fluorescent photoproducts in a 3m PTFE tube coiled around a 4W xenon lamp. The elution conditions have been chemometrically optimized by means of the experimental design and the response surface methodology. Linearity ranges from 0.10 to 1.50 and from 0.10 to 1.00MUgmL(-1) and LOD around 0.001 and 0.01MUgmL( 1) have been calculated for trans- and cis-isomers, respectively. The method has been satisfactorily applied to red and white wine samples by standard addition and external calibration, respectively. PMID- 26049998 TI - A Nafion-coated bismuth film electrode for the determination of heavy metals in vegetable using differential pulse anodic stripping voltammetry: An alternative to mercury-based electrodes. AB - Mercury electrodes have been traditionally employed for achieving high reproducibility and sensitivity of the stripping technique. However, new alternative electrode materials are highly desired because of the toxicity of mercury. Bismuth is an electrode material characterized by its low toxicity and its ability to form alloys with some metals such as cadmium, lead and zinc, allowing their preconcentration at the electrode surface. In this work, we reported the simultaneous determination of Pb(II), Cd(II) and Zn(II) at the low MUg/l concentration levels by differential pulse anodic stripping voltammetry (DPASV) on a Nafion-coated bismuth film electrode (NCBFE) plated in situ, and investigated the application of NCBFE to heavy metals analysis in vegetable samples. The analytical performance of NCBFE was evaluated for simultaneous determination of Pb(II), Cd(II) and Zn(II) in non-deaerated solution, with the limits of determination of 0.30MUg/l for Zn, 0.17MUg/l for Cd and Pb at a preconcentration time of 180s. High reproducibility for NCBFE was indicated from the relative standard deviations of 2.4% for Pb, 2.0% for Cd and 3.4% for Zn at the 15MUg/l level (n=15). The NCBFE was successfully applied to determine Pb and Cd in vegetable samples, and the results were in agreement with those of graphite furnace atomic absorption spectrometry (GFAAS). PMID- 26049999 TI - Raw bovine meat fatty acids profile as an origin discriminator. AB - Consumers are very concerned in "Protected Designation of Origin" (PDO) products, namely meat, since they associate these products to quality and healthy foods. Thus, it is necessary to implement analytical methodologies that could assure consumers about the products they purchase. Since this kind of meat is usually sold with no information concerning cattle sex, age and slaughter season, these characteristics were intentionally not taken into account. In this study, two Portugueses PDO bovine breeds (Mirandesa and Barrosa) and two production sub systems (traditional and organic farming) were studied during a two-year period. Statistical analysis showed that production system and breed had a significant effect on the overall raw meat fatty acids (FA) content. Besides, the FA profiles could be used as an effective tool to differentiate the four groups studied allowing a 100% correct classification. The meat FA content was also correlated with the relative importance of the animal feeding stuff area. PMID- 26050000 TI - The cryogenic grinding as the important homogenization step in analysis of inconsistent food samples. AB - Some homogenisation approaches have been investigated to make easier and overcome troublesome preparation of inconsistent food samples. Contents of Na, Ca, Mg, P, Fe, Mn and Zn in muesli, seed and instant food samples were determined by inductively coupled plasma optical emission spectrometry after their grinding with an agate mortar, a kitchen coffee grinder and a cryogenic mill. The efficiency of a grinding step was evaluated using RSDs and homogeneity factors (H factor). For cryogenically grinded samples, RSDs were detected about 4% and H factors on 10, what is acceptable for the analytical purpose. The results for grinding with an agate mortar as well as a coffee grinder were quite unsatisfactory (RSDs in tens percent). Differences between RSDs and H-factors for the procedures tested were detected to be statistically significant. Different element contents were observed in differently treated samples which is probably a result of an unevenly element distribution in inhomogeneous components forming sample. PMID- 26050001 TI - Fatty acid composition of seed oil of different Sorghum bicolor varieties. AB - In order to find out new sources of premium quality edible oil in the country, seeds of ten varieties of Sorghum bicolor were initially analyzed for their total oil contents. The seed oil was later fractionated into eight fatty acids including two new saturated fatty acids. The oil contents were determined by Soxhlet method and compared with the results obtained by NMR analysis. The total oil contents in the seeds of sorghum ranged from 5.0 to 8.2 % (w/w), indicating non significant difference obtained by two different techniques. The results revealed that oleic acid (31.12-48.99%), Palmitoleic acid (0.43-0.56%), linoleic acids (27.59-50.73%), linolenic acid (1.71-3.89%), stearic acid (1.09-2.59%) and palmitic acid (11.73-20.18%) was present in the seed oil of different sorghum varieties when analyzed by GC-MS. It was observed that in most of the varieties polyunsaturated fatty acids (PUFA) were higher than monounsaturated fatty acids (MUFA). The two atypical SFAs, octanedioic (C8:0) and azelaic acid (C9:0) were found in some varieties. These results suggest that these S. bicolor varieties could be additional sources of edible oil due to presence of clinically important saturated and high concentration of unsaturated fatty acids. A large scale production of the seed oil after refining process can contribute towards alleviation of edible oil shortage in the country with increased use of premium quality oil. PMID- 26050002 TI - Determination of patulin in fruit juices using HPLC-DAD and GC-MSD techniques. AB - A high performance liquid chromatography with a diode-array detector (HPLC-DAD) and a gas chromatography with a mass spectrometer (GC-MSD) are described for the determination of patulin (PAT) in apple juice. The limits of detection (DL) and quantification (QL) for the HPLC-DAD and GC-MSD method were found to be (DL=0.23MUgkg(-1) QL=1.2MUgkg(-1)) and (DL=5.8MUgkg(-1) and QL=13.8MUgkg(-1)), respectively. The recovery factors for HPLC-DAD and GC-MSD were found to be 99.5% (RSD%=0.73) and 41% (RSD%=10.03), respectively. The HPLC-DAD method was used to determine the occurrence of PAT in 90 samples of fruit juices. Results revealed the presence of PAT in 100% of the samples examined. The mean values of PAT in concentrated fruit juices and in the commercial fruit juices collected from the Greek market were found to be 10.54MUg PAT kg(-1) and 5.57MUg PAT kg(-1) juice, respectively. The most contaminated samples were four concentrated juices ranging from 18.10MUg PAT kg(-1) to 36.8MUg PAT kg(-1) juice. The daily exposure to patulin for the consumers of all ages in Greece, is ranging from 0.008MUg PAT kg( 1) bw to 0.1MUg PAT kg(-1) bw if the daily intake of fruit juices is from 0.1 to 0.5kg. With the exception to the most contaminated sample, the daily exposure due to the samples examined, is below the provisional maximum tolerable daily intake for PAT (0.4MUg PAT kg(-1) bw). PMID- 26050003 TI - Rapid, simple and sensitive determination of the apparent formation constants of trans-resveratrol complexes with natural cyclodextrins in aqueous medium using HPLC. AB - The study of the complexation of trans-resveratrol with natural cyclodextrins (CDs) in aqueous medium under different physico-chemical conditions of pH or temperature is essential if this antioxidant compound is to be used successfully in the food industry as ingredient of functional foods, due its poor stability, bioavailability and solubility. In this paper, a rapid, simple and sensitive determination of the apparent formation constant of trans-resveratrol/CD complexes by HPLC in aqueous medium has been investigated for first time. It can be observed that trans-resveratrol forms a 1:1 complex with alpha-, beta- and gamma-CD. The highest value of the apparent formation constant (KF=1922+/-89M( 1)) was found for beta-CD and a strong dependence of KF on pH can be seen in the region where the trans-resveratrol begins the deprotonation of their hydroxyl groups. Moreover, an increase in the system's temperature produced a decrease in the values of KF. Finally, to gain information on the mechanism of the trans resveratrol affinity for CD, the thermodynamic parameters of the complexation were obtained. PMID- 26050004 TI - Analysis of sudan I, sudan II, sudan III, and sudan IV in food by HPLC with electrochemical detection: Comparison of glassy carbon electrode with carbon nanotube-ionic liquid gel modified electrode. AB - A method was developed for analyzing of sudan I, sudan II, sudan III, and sudan IV by high performance liquid chromatography coupled with an electrochemical detector. The electrochemical oxidation of each compound was investigated with a carbon nanotube-ionic liquid gel modified glassy carbon (MWNTs-IL-Gel/GC) electrode using cyclic voltammetry. The results were compared with those of glassy carbon electrodes. At the MWNTs-IL-Gel/GC electrode, highly reproducible, well-defined cyclic voltammograms for sudan oxidation were obtained. In the flow system, MWNTs-IL-Gel/GC exhibited highly reproducible and well-defined amperometric signals without peak tailing. In addition, the determination of sudan dyes by mean of isocratic reverse-phase HPLC, with amperometric detection at MWNTs-IL-Gel/GC and GC electrode, have been investigated. The chromatograms showed excellent separation. The detection limits ranged from 0.001 to 0.005ppm. The method was sensitive, selective and could be applicable for the assay of sudan dyes in soft drink samples. PMID- 26050005 TI - Verification test of sensory analyses of comb and strained honeys produced as pure and feeding intensively with sucrose (Saccharum officinarum L.) syrup. AB - The aims of the study were to discriminate comb and strained honeys produced by the standard beekeeping method (control), shaking method (pure blossom honey), and feeding intensively (100kg/colony) with sucrose (adulterated honey) syrup by using sensory analysis and to develop a method to be used in identification of unknown or suspicion honey samples. In the study, twenty trained panelists assessed honey samples in relation to their properties including taste, odor, color, aroma, viscosity, dissolution in mouth, inflammation in throat, attractiveness, flavor and general impression during four months. There were no differences in odor, viscosity, and dissolution in mouth between comb and strained honey samples which produced by different methods (P > 0.05). Discrimination of strained honey by sensory analysis was more reliable when compared to comb honey. The ratio of correctly classified sample was 78.3% for comb and 86.7% for strained honey. The more honey was pure the more discrimination of honey sample by sensory analysis was reliable. In verification test five unknown honey samples were classified 100% in their real groups by using canonical discriminant function Coefficients of each properties evaluated and the projections of the sample points on the plane of the canonical function-1 and function-2. PMID- 26050006 TI - Application of the standard addition method for the determination of acrylamide in heat-processed starchy foods by gas chromatography with electron capture detector. AB - A gas chromatography electron capture detector (GC-ECD) using the standard addition method was developed for the determination of acrylamide in heat processed foods. The method entails extraction of acrylamide with water, filtration, defatting with n-hexane, derivatization with hydrobromic acid and saturated bromine-water, and liquid-liquid extraction with ethyl acetate. The sample pretreatment required no SPE clean-up and concentration steps prior to injection. The final extract was analyzed by GC-ECD. The chromatographic analysis was performed on polar columns, e.g. Supelcowax-10 capillary column, and good retention and peak response of the analyte were achieved under the optimal conditions. The qualification of the analyte was by identifying the peak with same retention time as standard compound 2,3-DBPA and confirmed by GC-MS. GC-MS analysis confirmed that 2,3-DBPA was converted to 2-BPA nearly completely on the polar capillary column, whether or not treated with triethylamine. A four-point standard addition protocol was used to quantify acrylamide in food samples. The limit of detection (LOD) was estimated to be 0.6MUg/kg on the basis of ECD technique. Validation and quantification results demonstrated that the method should be regarded as a low-cost, convenient, and reliable alternative for conventional investigation of acrylamide. PMID- 26050007 TI - Identification of phenolics in the fruit of emblica (Phyllanthus emblica L.) and their antioxidant activities. AB - An activity-directed fractionation and purification process was used to identify the antioxidative components of emblica fruit. Dried fruit of emblica was extracted with methanol and then partitioned by ethyl ether, ethyl acetate, butanol and water. The ethyl acetate fraction showed the strongest 1,1-diphenyl-2 picrylhydrazyl (DPPH) radical scavenging activity among four fractions. The ethyl acetate fraction was then subjected to separation and purification using Sephadex LH-20 chromatography and reverse-phase high-performance liquid chromatography (HPLC). Six compounds were identified to be geraniin (1), quercetin 3-beta-d glucopyranoside (2), kaempferol 3-beta-d-glucopyranoside (3), isocorilagin (4), quercetin (5), and kaempferol (6), respectively, by spectral methods, (1)H and (13)C nuclear magnetic resonance (NMR) spectroscopy, ultraviolet-visible (UV-Vis) spectrophotometry and mass spectroscopy (MS), and comparison with literatures. Compounds 2-4 and 6 were identified from emblica fruit for the first time. Furthermore, the antioxidant activities of purified compounds were screened for their antioxidative potential using lipid peroxidation and DPPH systems. All the purified compounds showed strong antioxidant and radical scavenging activities. Amongst, geraniin showed the highest antioxidant activity (4.7 and 65.7MUM of IC50 values for DPPH and lipid peroxidation assay, respectively) than other purified compounds. PMID- 26050008 TI - Measurement of anthocyanins and other phytochemicals in purple wheat. AB - The major anthocyanin composition of normal purple wheat and heat stressed purple wheat were measured using HPLC, LC-MS/MS and the pH differential method. The lignan secoisolariciresinol diglucoside (SDG) and melatonin content were also measured. Total anthocyanin profile of normal purple wheat (491.3mg/kg) was significantly (P<0.05) lower than that of the heat stressed purple wheat (522.7mg/kg). Thirteen major anthocyanins were isolated and cyanidin 3-glucoside was the predominant anthocyanin in purple wheat. Using the pH differential method, the total anthocyanin content of normal (500.6mg/kg) and heat stressed (526.0mg/kg) purple wheat were similar to those observed using HPLC. The SDG content of normal and heat stressed purple wheat were 770 and 520MUg/kg, while melatonin content was 4 and 2MUg/kg, respectively. The presence of SDG and melatonin in addition to anthocyanins may contribute to the health benefits associated with consumption of coloured cereal grains. PMID- 26050009 TI - Comparison of microwave-assisted hydrodistillation withthe traditional hydrodistillation method in the extractionof essential oils from Thymus vulgaris L. AB - Microwave-assisted hydrodistillation (MAHD) is an advanced hydrodistillation (HD) technique utilizing a microwave oven in the extraction process. MAHD of essential oils from the aerial parts (tops) of Thymus vulgaris L. (common thyme) was studied and the results were compared with those of the conventional HD in terms of extraction time, extraction yield/efficiency, chemical composition, quality of the essential oils and cost of the operation. MAHD was superior in terms of saving energy and extraction time (75min, compared to 4h in HD). Scanning electron microscopy (SEM) of thyme leaves undergone HD and MAHD provided evidences as to a sudden rupture of essential oil glands with MAHD. Gas chromatography-mass spectrometry analysis of the extracted essential oils indicated that the use of microwave irradiation did not adversely influence the composition of the essential oils. MAHD was found to be a green technology. PMID- 26050010 TI - In Vivo Demonstration of the Lacrimal Pump. PMID- 26050011 TI - Subtypes of psychotic-like experiences are differentially associated with suicidal ideation, plans and attempts in young adults. AB - Psychotic-like experiences (PLEs) have been associated with increased risk of suicidality, but it is unclear whether the level of risk varies with different types of PLE. A cross-sectional online survey was completed by 1610 university students. Respondents completed the Community Assessment of Psychic Experiences 15 (CAPE-P15) assessing PLEs on three subscales: Perceptual Abnormalities (PA), Persecutory Ideation (PI) and Bizarre Experiences (BE). Lifetime suicidal ideation, plans and attempts, cannabis, ecstasy and methamphetamine use and family history of mental disorder were also assessed. Multinomal logistic regression was used to examine unique determinants of lifetime suicidality, defined as any history of (i) suicidal ideation or plans and (ii) any attempt, relative to no lifetime history of suicidality. A lifetime history of PA and PI provided significant unique contributions to the prediction of suicide risk, after control for other significant predictors. BE were not associated with any suicide variable demonstrating the variation in risk of suicidality with different types of PLEs. Perceptual abnormalities and persecutory ideation as measured by the CAPE-P15 are the PLEs associated with a higher risk of lifetime suicidality. PMID- 26050012 TI - Early Postoperative Emergency Department Care of Abdominal Transplant Recipients. AB - BACKGROUND: Research on posttransplant care has predominantly focused on predictors of readmission with little attention to emergency department (ED) visits. The goal of this study was to describe early postoperative ED care of transplant recipients. METHODS: A secondary database analysis of adult patients who underwent abdominal organ transplantation between January 1, 2008, and December 31, 2013, and sought ED care within 1 year after transplantation was conducted. Survival was compared using the Kaplan-Meier method with log-rank test. Cox proportional hazards regression analysis was performed to adjust for pertinent covariates RESULTS: A total of 1900 abdominal organ transplants were performed during the study period. Of these, 37% (N = 711) transplant recipients sought care in the ED (1343 total visits) with 1.89 mean ED visits per recipient. Of recipients seen in the ED, 58% received a kidney transplant and 28% received a liver transplant, with 45% of recipients presenting within the first 60 postoperative days. The most common chief complaints were gastroenterological (17%) and abnormal laboratory values or vital signs (17%). In total, 74% of recipients were readmitted and 50% of admitted patients were discharged in less than 24 hours. Transplant recipients with ED visits had lower 3-year graft (81% vs 87%; P < 0.001) and patient (89% vs 93%; P = 0.002) survival. CONCLUSIONS: Transplant recipients have a high frequency of ED visits in the first posttransplantation year and high rates of subsequent hospital admission. Further investigation is needed to understand what drives recipient presentation to the ED and create care models that achieve the best outcomes. PMID- 26050013 TI - Portal Vein Thrombosis Is a Risk Factor for Poor Early Outcomes After Liver Transplantation: Analysis of Risk Factors and Outcomes for Portal Vein Thrombosis in Waitlisted Patients. AB - BACKGROUND: Portal vein thrombosis (PVT) is common in patients with cirrhosis, but the risk factors associated with PVT and its impact on outcomes following liver transplantation (LT) are not well defined. The objectives of this study were to determine the impact of PVT on post-LT patient and graft survival, waitlist outcomes, and the factors associated with PVT. METHODS: A retrospective review of Organ Procurement and Transplant Network waitlist and LT data between 2002 and 2013 identified 48,570 patients undergoing their first LT, with 3321 (6.8%) reported to have PVT at LT. RESULTS: Portal vein thrombosis was independently associated with increased 90-day mortality (odds ratio, 1.7; 95% confidence interval, 1.45-1.99; P < 0.001) and graft failure (odds ratio, 1.72; 95% confidence interval, 1.51-1.97; P < 0.001). Portal vein thrombosis at listing was not associated with lower transplant rates, or delisting for death, or deterioration. Only 31% of patients with PVT at LT had PVT reported at listing. The predictors of PVT at LT in patients without PVT at listing included: fatty or cryptogenic liver disease, ascites, diabetes mellitus, and obesity. "New" PVT at LT was associated with longer wait-time, higher rate of model of end-stage liver disease increase, and intermediate 90-day survival rates compared to patients with or without PVT at both listing and LT. CONCLUSIONS: Portal vein thrombosis at LT is associated with early (90 days) mortality and graft failure, though a likely but undefined reporting bias for more extensive PVT would overstate estimated risks for all PVT. Further study is needed to better define risks of LT with PVT. PMID- 26050014 TI - Survival With Dialysis Versus Kidney Transplantation in Adult Hemolytic Uremic Syndrome Patients: A Fifteen-Year Study of the Waiting List. AB - BACKGROUND: Survival data are lacking for kidney transplant recipients with rare native end-stage renal disease (ESRD) etiologies. There is currently no large registry study comparing dialysis versus kidney transplantation survival outcomes of waitlisted adults with hemolytic uremic syndrome (HUS). MATERIALS AND METHODS: We retrospectively studied adult-HUS end-stage renal disease patients (n = 559) placed on the US kidney transplant waitlist in 1996 to 2011. We analyzed 5-year transplantation and patient survival probabilities and risk factors using Kaplan Meier and Cox hazards models, respectively. Using similar models, waitlist and transplantation outcomes of patients with diabetes mellitus (DM), hypertension (HTN), and glomerulonephritis (GN) were analyzed, and then compared with HUS patients. RESULTS: Compared with waitlisted adult HUS patients on dialysis, 5 year mortality risks were 73% and 48% lower in recipients of living (hazard ratio [HR], 0.27, 95% confidence interval [95% CI], 0.11-0.65) and standard deceased (HR, 0.52; 95% CI, 0.29-0.94) donor kidney transplants, respectively. Mortality risks over 5 years were 44%, 50%, 54%, and 55% lower in the overall transplant recipient cohorts than in the dialysis-maintained cohorts within the HUS (HR, 0.56; 95% CI, 0.35-0.91), HTN (HR, 0.50; 95% CI, 0.48-0.52), GN (HR, 0.46; 95% CI, 0.44-0.49), and DM (HR, 0.45; 95% CI, 0.44-0.47) groups, respectively. Five year transplantation probability in the waitlisted HUS cohort was 60% versus 42% to 49% (P < 0.001) in the DM and HTN cohorts, and 62% (P = 0.93) in the GN cohort. CONCLUSIONS: Living and standard criteria deceased donor kidney transplants provide significant survival benefit over dialysis in waitlisted adults with HUS. On the waitlist, the 5-year transplantation probability was higher in HUS than in DM and HTN patients. PMID- 26050015 TI - Performance Characteristics of Galactomannan and beta-d-Glucan in High-Risk Liver Transplant Recipients. AB - BACKGROUND: The utility of Aspergillus galactomannan (GM) and beta-D-glucan (BG) in liver transplant recipients remains uncertain. METHODS: As part of a randomized, double-blind trial of antifungal prophylaxis in liver transplant recipients at risk for invasive fungal infections (IFIs), GM and BG were assessed in 199 patients at baseline (enrollment) and weekly thereafter for the duration of study drug. Receiver operating characteristic (ROC) analysis was used to evaluate the accuracy of these for the diagnosis of IFIs. RESULTS: Overall, 46.4% of the patients at baseline had positive GM (index >= 0.5) and 89.6% had BG of 80 pg/mL or greater with BG level of 500 pg/mL or greater in 31.8%. Patients with invasive aspergillosis (IA) (3/3) had positive GM at baseline as did 45.5% of those without IA (P = 0.098); the area under the ROC curve for the diagnosis of IA was 0.77 (fair test, ie, good sensitivity but poor specificity). Using BG cutoff of 80 pg/mL or higher, 100% (12/12) of the patients with IFI had positive baseline BG and as did 88.9% (160/180) of those without IFI (P = 0.618); the area under the ROC curve for predicting IFIs was 0.56 (poor test). In multivariate analyses, GM positivity was associated with study site (P = 0.041), and BG positivity with renal replacement therapy (P = 0.05) and study site (P = 0.01). The GM and BG levels declined over time; positivity at subsequent time points was lower in comparison with baseline (P < 0.001). CONCLUSIONS: The GM and BG tests had significant center variability and limited accuracy for the diagnosis of IFIs in high-risk liver transplant recipients. PMID- 26050017 TI - What Is the Future of Generics in Transplantation? AB - Generic immunosuppressive drugs are available in Europe, Canada, and the United States. Between countries, there are large differences in the market penetration of generic drugs in general, and for immunosuppressive drugs in particular. The registration criteria for generic immunosuppressive drugs are often criticized. However, it is unlikely that the criteria for registration of narrow therapeutic index drugs are going to change, and bioequivalence studies, performed in healthy volunteers, will remain the backbone of the registration process. It would be good if the registration authorities would demand that all generic variants of an innovator drug have the same pill appearance to reduce errors and promote drug adherence.To allow for safe substitution, a number of criteria need to be fulfilled. Generic substitution should not be taken out of the hands of the treating physicians. Generic substitution can only be done safely if initiated by the prescriber, and in well-informed and prepared patients. Payers should refrain from forcing pharmacists to dispense generic drugs in patients on maintenance treatment with innovator drug. Instead, together with transplant societies, they should design guidelines on how to implement generic immunosuppressive drugs into clinical practice. Substitutions must be followed by control visits to check if the patient is taking the medication correctly and if drug exposure remains stable. Inadvertent, uncontrolled substitutions from 1 generic to another, initiated outside the scope of the prescriber, must be avoided as they are unsafe. Repetitive subsequent generic substitutions result in minimal additional cost savings and have an inherent risk of medication errors. PMID- 26050018 TI - Levetiracetam, Calcium Antagonism, and Bipolar Disorder. AB - Hyperactive intracellular calcium ion (Ca) signaling in peripheral cells has been a reliable finding in bipolar disorder. Some established mood stabilizing medications, such as lithium and carbamazepine, have been found to normalize elevated intracellular Ca concentrations ([Ca]i) in platelets and lymphocytes from bipolar disorder patients, and some medications the primary effect of which is to attenuate increased [Ca]i have been reported to have mood stabilizing properties.Hyperactive intracellular Ca signaling has also been implicated in epilepsy, and some anticonvulsants have calcium antagonist properties. This study demonstrated that levetiracetam, an anticonvulsant that has been shown to block N and P/Q-type calcium channels in animal studies does not alter elevated [Ca]i in blood platelets of patients with bipolar disorder. Review of published clinical trials revealed no controlled evidence of efficacy as a mood stabilizer.This study underscores the possibility that pharmacologic actions of a medication in animals and normal subjects may not necessarily predict its pharmacologic or clinical effects in actual patients. Effects of treatments on pathophysiology that is demonstrated in clinical subtypes may be more likely to predict effectiveness in those subtypes than choosing medications based on structural similarities to established treatments. PMID- 26050016 TI - Protection From Varicella Zoster in Solid Organ Transplant Recipients Carrying Killer Cell Immunoglobulin-Like Receptor B Haplotypes. AB - BACKGROUND: Natural killer cell function is regulated by inhibitory and activating killer cell immunoglobulin-like receptors (KIR). Previous studies have documented associations of KIR genotype with the risk of cytomegalovirus (CMV) replication after solid organ transplantation. METHODS: In this study of 649 solid organ transplant recipients, followed prospectively for infectious disease events within the Swiss Transplant Cohort Study, we were interested to see if KIR genotype associated with virus infections other than CMV. RESULT: We found that KIR B haplotypes (which have previously been linked to protection from CMV replication) were associated with protection from varicella zoster virus infection (hazard ratio, 0.43; 95% confidence interval, 0.21-0.91; P = 0.03). No significant associations were detected regarding the risk of herpes simplex, Epstein-Barr virus or BK polyomavirus infections. CONCLUSIONS: In conclusion, these data provide evidence that the relative protection of KIR haplotype B from viral replication after solid organ transplantation may extend beyond CMV to other herpes viruses, such as varicella zoster virus and possibly Epstein-Barr virus. PMID- 26050019 TI - Clinical effect of biapenem on nursing and healthcare-associated pneumonia (NHCAP). AB - The clinical effect of Biapenem (BIPM) on Nursing and Healthcare-associated pneumonia (NHCAP) was evaluated. One hundred and three NHCAP patients (Group B: 52 patients, Group C: 51 patients) to whom BIPM was administered were included in this study. Clinical effect, bacteriological effect, and adverse events were examined. Results revealed efficacy in 45 of 52 patients (efficacy rate: 86.5%) of NHCAP Group B, and 43 of 51 patients (efficacy rate: 84.3%) of NHCAP Group C, 88 of 103 patients (efficacy rate: 85.4%) as a whole. As for bacteriological effect, 10 (76.9%) of 13 Pseudomonas aeruginosa strains, 9 (90.0%) of 10 Klebsiella pneumoniae strains, 7 (87.5%) of 8 methicillin-sensitive Staphlococcus aureus strains, and 7 (100%) of 7 Streptococcus pneumonia strains were eradicated. As a whole, 38 (80.9%) of 47 strains were eradicated. Adverse events included drug fever and drug eruption in one patient each, and abnormal laboratory findings, including mild hepatic dysfunction in 18 patients and mild renal dysfunction in 5 patients. Based on the above, it was concluded that BIPM shows excellent clinical effect on NHCAP with fewer adverse events. PMID- 26050021 TI - Magnetic Resonance Imaging and Computed Tomography of the Brain-50 Years of Innovation, With a Focus on the Future. AB - This review focuses specifically on the developments in brain imaging, as opposed to the spine, and specifically conventional, clinical, cross-sectional imaging, looking primarily at advances in magnetic resonance imaging (MRI) and computed tomography (CT). These fields are viewed from a perspective of landmark publications in the last 50 years and subsequently more in depth using sentinel publications from the last 5 years. It is also written from a personal perspective, with the authors having witnessed the evolution of both fields from their initial clinical introduction to their current state. Both CT and MRI have made tremendous advances during this time, regarding not only sensitivity and spatial resolution, but also in terms of the speed of image acquisition. Advances in CT in recent years have focused in part on reduced radiation dose, an important topic for the years to come. Magnetic resonance imaging has seen the development of a plethora of scan techniques, with marked superiority to CT in terms of tissue contrast due to the many parameters that can be assessed, and their intrinsic sensitivity. Future advances in MRI for clinical practice will likely focus both on new acquisition techniques that offer advances in speed and resolution, for example, simultaneous multislice imaging and data sparsity, and on standardization and further automation of image acquisition and analysis. Functional imaging techniques including specifically perfusion and functional magnetic resonance imaging will be further integrated into the workflow to provide pathophysiologic information that influence differential diagnosis, assist treatment decision and planning, and identify and follow treatment-related changes. PMID- 26050020 TI - Penetration of piperacillin-tazobactam into human prostate tissue and dosing considerations for prostatitis based on site-specific pharmacokinetics and pharmacodynamics. AB - This study aimed to investigate the penetration of PIPC-TAZ into human prostate, and to assess effectiveness of PIPC-TAZ against prostatitis by evaluating site specific PK-PD. Patients with prostatic hypertrophy (n = 47) prophylactically received a 0.5 h infusion of PIPC-TAZ (8:1.2-0.25 g or 4-0.5 g) before transurethral resection of the prostate. PIPC-TAZ concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were analyzed with a three-compartment PK model. The estimated model parameters were, then used to estimate the drug exposure time above the minimum inhibitory concentration for bacteria (T > MIC, the PD indicator for antibacterial effects) in prostate tissue for six PIPC-TAZ regimens (2.25 or 4.5 g; once, twice, three times or four times daily; 0.5 h infusions). Prostate tissue/plasma ratio of PIPC was about 36% both for the maximum drug concentration (Cmax) and the area under the drug concentration-time curve (AUC). Against MIC distributions for isolates of Escherichia coli, Klebsiella species and Proteus species, regimens of 4.5 g twice daily and 2.25 g three times daily achieved a >90% probability of attaining the bacteriostatic target for PIPC (30% T > MIC) in prostate tissue; regimens of 4.5 g three times daily and 2.25 g four times daily achieved a >90% probability of attaining the bactericidal target for PIPC (50% T > MIC) in prostate tissue. However, against Pseudomonas aeruginosa isolates, none of the tested regimens achieved a >90% probability. PIPC-TAZ is appropriate for the treatment of prostatitis from the site-specific PK-PD perspective. PMID- 26050022 TI - Computed Tomography Features of External Auditory Canal Cholesteatoma: A Pictorial Review. AB - Computed tomography (CT) is widely used for evaluation of patients with otologic conditions. External auditory canal cholesteatoma (EACC), although rare, demonstrates characteristic CT appearance. Moreover, the accurate extent of involvement cannot be accurately assessed clinically. This pictorial review aims to illustrate the spectrum of CT features of EACC and highlight the key features that are useful for making an accurate diagnosis of this condition. We have also discussed the radiological and clinical differential diagnoses of external auditory canal lesions that can be mistaken for an EACC. PMID- 26050023 TI - The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma. AB - To explore the correlation between epidermal growth factor receptor (EGFR) mutation status and the risk of brain metastasis (BM) in patients with lung adenocarcinoma, the clinical data of 100 patients with pathologically confirmed lung adenocarcinoma and known EGFR mutation status at exon 18, 19, 20, or 21 were analyzed retrospectively. The incidence of BM was similar between patients with wild-type EGFR and those with EGFR mutations (p = 0.48). However, among patients with EGFR mutations, the incidence of BM was significantly higher in patients with mutation at exon 19 than in patients with mutation at other sites (p = 0.007). Besides, among patients with heterochronous BM, 66.7 % had EGFR mutations. Regarding brain-metastasis-free survival (BMFS), patients with EGFR sensitive mutations (mutation at exon 19/21/and dual mutation) had significantly shorter BMFS compared with patients with wild-type EGFR (p = 0.018). For patients treated only with chemotherapy, BM was an unfavorable prognostic factor. Patients with BM had worse overall survival compared with those without BM (p = 0.035). However, in patients with BM and EGFR sensitive mutations, those treated with tyrosine kinase inhibitors (TKIs) had significantly longer overall survival compared with those treated with chemotherapy only (p = 0.0081). In conclusion, among patients with EGFR mutations, those mutated at exon 19 had the highest incidence of BM. Furthermore, patients with EGFR mutations are more likely to develop heterochronous BM. The BMFS was significantly shorter in patients with EGFR sensitive mutations. TKIs improved the survival of patients with lung adenocarcinoma and BM who harbored EGFR sensitive mutations. PMID- 26050024 TI - Intratumoral immunotherapy for melanoma. AB - Selection of suitable tumor-associated antigens is a major challenge in the development of effective cancer vaccines. Intratumoral (i.t.) immunotherapy empowers the immune system to mount T cell responses against tumor-associated antigens which are most immunogenic. To mediate systemic tumor regression, i.t. immunotherapy must generate systemic T cell responses that can target distant metastases beyond the initially treated tumor mass. Now that promising preclinical results and some initial success in clinical trials have been obtained, we here review i.t. immunotherapy-related preclinical and clinical studies, their mechanisms of action and future prospects. PMID- 26050025 TI - Load to failure of different titanium abutments for an internal hexagon implant. AB - STATEMENT OF PROBLEM: Several aftermarket abutments are available for a commonly used internal hexagonal connection implant. However, their load to failure performance is unknown when compared with the manufacturer's abutment. PURPOSE: The purpose of this in vitro study was to conduct a load to failure comparison of 5 different titanium abutments (manufacturer's and aftermarket) for cement retained restorations used on an implant with an internal hexagon connection. MATERIAL AND METHODS: Five implants (Tapered Screw-Vent, 4.1*11.5 mm; Zimmer Dental) were individually secured in a loading apparatus, and 3 abutment specimens of each of the 5 different titanium abutments (Atlantis, AstraTech TiDesign, Legacy Straight Contoured, Inclusive Custom, and Zimmer PSA) (n=15 total) were loaded at a 30-degree angle until fracture of the implant abutment complex. Data for load to fracture were compared with analysis of variance and a Tukey-Kramer post hoc test (alpha=.05). RESULTS: Significant differences were noted between the fracture loads of some abutment pairs; Atlantis-AstraTech TiDesign, Atlantis-Legacy Straight Contoured, AstraTech TiDesign-Legacy Straight Contoured, Inclusive Custom-AstraTech TiDesign, and Inclusive Custom-Legacy Straight Contoured (P<.05). The highest overall resistance to fracture was achieved by the Legacy Straight Contoured Abutment, which was significantly greater than all other aftermarket abutments (P<.05). Tested abutments fractured at an average of 649.17 N. The Zimmer PSA abutment was the only abutment that showed no fracture of any of the components before implant failure. CONCLUSION: When comparing manufacturer's versus aftermarket brands, the manufacturer's abutment (Zimmer PSA) was the only abutment without fracture of any of the components. Aftermarket brands experienced screw fractures, which could result in further clinical prosthetic complications. The clinical implications of these findings need further investigation. PMID- 26050026 TI - Maxillary and mandibular immediately loaded implant-supported interim complete fixed dental prostheses on immediately placed dental implants with a digital approach: A clinical report. AB - This clinical report describes the treatment of maxillary and mandibular immediate implant placement and immediately loaded implant-supported interim complete fixed dental prostheses with a contemporary digital approach. The virtual diagnostic tooth arrangement eliminated the need for a customized radiographic template, and the diagnostic data collection required for computer guided surgery (digital diagnostic impressions, digital photographs, and a cone beam-computed tomography [CBCT] scan) was completed in a single visit with improved workflow efficiency. Computer-aided design and computer-aided manufacturing (CAD/CAM)-fabricated surgical templates and interim prosthesis templates were made in a dental laboratory to facilitate computer-guided surgery and the immediate loading process. PMID- 26050027 TI - Systematic review of some prosthetic risk factors for periimplantitis. AB - STATEMENT OF PROBLEM: The recent literature underlines a correlation between plaque and the development of periimplantitis but neglects the importance of the prosthetic factors. PURPOSE: The purpose of this systematic review was to appraise the available literature to evaluate the role played by cement excess and misfitting components on the development of periimplantitis. MATERIAL AND METHODS: An electronic search restricted to the English language was performed in PubMed, Embase, and the Cochrane Register up to September 1, 2014, based on a selected search algorithm. Only cohort studies and case-control studies were included without additional restrictions. The presence of periimplantitis and implant failure were considered primary and secondary outcome variables. RESULTS: The search produced 275 potentially relevant titles, of which only 2 were found eligible. They showed a correlation in cemented implant prostheses between cement excess and the presence of periimplant disease, especially in patients with a history of periodontal disease. After cement excess removal by means of debridement, disease symptoms disappeared around most of the implants. CONCLUSIONS: Scientific articles on prosthetic risk factors for periimplantitis are scarce. Although the studies found on cement remnants have a high risk for bias, cement excess seems to be associated with mucositis and possibly with periimplantitis, especially in patients with a history of periodontal disease. PMID- 26050028 TI - Survival rate of lithium disilicate restorations at 4 years: A retrospective study. AB - STATEMENT OF PROBLEM: Ceramic restorations are frequently being placed due to the esthetic demand and the cost of noble metals that has increased considerably. One major disadvantage of ceramic restoration is failure of the material due to fracture by crack propagation. In vitro studies are of little clinical significance and in vivo studies are too short to support clinical success. PURPOSE: The purpose of this retrospective study was to evaluate the failure rate of lithium disilicate restorations (monolithic and layered) at 4 years. MATERIAL AND METHODS: Data were collected over 45 months from 2 commercial laboratories. Restorations were categorized into monolithic restorations and layered restorations. Each category was further classified into complete coverage single crowns, fixed dental prostheses, e.max veneers, and inlay/onlay restorations. Failure rates were compared and analyzed using Chi-square (alpha=.05). RESULTS: A total of 21,340 restorations were evaluated in this study and included 15,802 monolithic restorations and 5538 layered restorations. The failure rate for single crown monolithic restorations was 0.91% and was 1.83% for single crown layered restorations. For fixed dental prostheses, 4.55% of monolithic restorations failed. For e.max veneers, 1.3% of monolithic veneers fractured and 1.53% of layered veneers fractured. Of the inlay/onlay restorations group, 1.01% of monolithic restorations fractured. CONCLUSION: In the short term (45 months), restorations fabricated with the lithium disilicate material (IPS e.max) had relatively low fracture rates. Layered single crowns fractured at approximately 2 times the rate of monolithic crowns. PMID- 26050029 TI - Paying Attention to the Details of Attention. AB - Attention selects behaviorally relevant stimuli for greater neural representation. In this issue of Neuron, Luo and Maunsell (2015) show that attention acts, in part, by boosting the signal-to-noise ratio (SNR) of sensory neurons. PMID- 26050030 TI - Cortical Cliques: A Few Plastic Neurons Get All the Action. AB - Adjustments in neural activity can drive cortical plasticity, but the underlying circuit components remain unclear. In this issue of Neuron, Barnes et al. (2015) show that visual deprivation-induced homeostatic plasticity invokes specific changes among select categories of V1 neurons. PMID- 26050031 TI - Cortical Sensorimotor Reverberations. AB - In this issue of Neuron, Manita et al. (2015) report that reciprocal excitatory interactions between higher-order frontal motor cortex and primary sensorimotor cortex might play a key role in hindlimb sensory perception in mice. PMID- 26050032 TI - The GABAA Receptor as a Therapeutic Target for Neurodevelopmental Disorders. AB - Intellectual disability, autism spectrum disorder, and epilepsy are prime examples of neurodevelopmental disorders that collectively affect a significant percentage of the world population. Recent technological breakthroughs allowed the elucidation of the genetic causes of many of these disorders. As neurodevelopmental disorders are genetically heterogeneous, the development of rational therapy is extremely challenging. Fortunately, many causative genes are interconnected and cluster in specific cellular pathways. Targeting a common node in such a network would allow us to interfere with a series of related neurodevelopmental disorders at once. Here, we argue that the GABAergic system is disturbed in many neurodevelopmental disorders, including fragile X syndrome, Rett syndrome, and Dravet syndrome, and is a key candidate target for therapeutic intervention. Many drugs that modulate the GABAergic system have already been tested in animal models with encouraging outcomes and are readily available for clinical trials. PMID- 26050034 TI - Role of Dopamine Neurons in Reward and Aversion: A Synaptic Plasticity Perspective. AB - The brain is wired to predict future outcomes. Experience-dependent plasticity at excitatory synapses within dopamine neurons of the ventral tegmental area, a key region for a broad range of motivated behaviors, is thought to be a fundamental cellular mechanism that enables adaptation to a dynamic environment. Thus, depending on the circumstances, dopamine neurons are capable of processing both positive and negative reinforcement learning strategies. In this review, we will discuss how changes in synaptic plasticity of dopamine neurons may affect dopamine release, as well as behavioral adaptations to different environmental conditions falling at opposite ends of a saliency spectrum ranging from reward to aversion. PMID- 26050033 TI - Neurotransmitter Switching? No Surprise. AB - Among the many forms of brain plasticity, changes in synaptic strength and changes in synapse number are particularly prominent. However, evidence for neurotransmitter respecification or switching has been accumulating steadily, both in the developing nervous system and in the adult brain, with observations of transmitter addition, loss, or replacement of one transmitter with another. Natural stimuli can drive these changes in transmitter identity, with matching changes in postsynaptic transmitter receptors. Strikingly, they often convert the synapse from excitatory to inhibitory or vice versa, providing a basis for changes in behavior in those cases in which it has been examined. Progress has been made in identifying the factors that induce transmitter switching and in understanding the molecular mechanisms by which it is achieved. There are many intriguing questions to be addressed. PMID- 26050035 TI - Inside-Out Radial Migration Facilitates Lineage-Dependent Neocortical Microcircuit Assembly. AB - Neocortical excitatory neurons migrate radially along the glial fibers of mother radial glial progenitors (RGPs) in a birth-date-dependent inside-out manner. However, the precise functional significance of this well-established orderly neuronal migration remains largely unclear. Here, we show that strong electrical synapses selectively form between RGPs and their newborn progeny and between sister excitatory neurons in ontogenetic radial clones at the embryonic stage. Interestingly, the preferential electrical coupling between sister excitatory neurons, but not that between RGP and newborn progeny, is eliminated in mice lacking REELIN or upon clonal depletion of DISABLED-1, which compromises the inside-out radial neuronal migration pattern in the developing neocortex. Moreover, increased levels of Ephrin-A ligand or receptor that laterally disperse sister excitatory neurons also disrupt preferential electrical coupling between radially aligned sister excitatory neurons. These results suggest that RGP-guided inside-out radial neuronal migration facilitates the initial assembly of lineage dependent precise columnar microcircuits in the neocortex. PMID- 26050036 TI - A Developmental Switch in Place Cell Accuracy Coincides with Grid Cell Maturation. AB - Place cell firing relies on information about self-motion and the external environment, which may be conveyed by grid and border cells, respectively. Here, we investigate the possible contributions of these cell types to place cell firing, taking advantage of a developmental time window during which stable border cell, but not grid cell, inputs are available. We find that before weaning, the place cell representation of space is denser, more stable, and more accurate close to environmental boundaries. Boundary-responsive neurons such as border cells may, therefore, contribute to stable and accurate place fields in pre-weanling rats. By contrast, place cells become equally stable and accurate throughout the environment after weaning and in adulthood. This developmental switch in place cell accuracy coincides with the emergence of the grid cell network in the entorhinal cortex, raising the possibility that grid cells contribute to stable place fields when an organism is far from environmental boundaries. PMID- 26050037 TI - Antagonistic but Not Symmetric Regulation of Primary Motor Cortex by Basal Ganglia Direct and Indirect Pathways. AB - Motor cortex, basal ganglia (BG), and thalamus are arranged in a recurrent loop whose activity guides motor actions. In the dominant model of the function of the BG and their role in Parkinson's disease, direct (dSPNs) and indirect (iSPNs) striatal projection neurons are proposed to oppositely modulate cortical activity via BG outputs to thalamus. Here, we test this model by determining how striatal activity modulates primary motor cortex in awake head-restrained mice. We find that, within 200 ms, dSPN and iSPN activation exert robust and opposite effects on the majority of cortical neurons. However, these effects are heterogeneous, with certain cortical neurons biphasically modulated by iSPN stimulation. Moreover, these striatal effects are diminished when the animal performs a motor action. Thus, the effects of dSPN and iSPN activity on cortex are at times antagonistic, consistent with classic models, whereas in other contexts these effects can be occluded or coactive. PMID- 26050038 TI - Neuronal Modulations in Visual Cortex Are Associated with Only One of Multiple Components of Attention. AB - Neuronal signals related to visual attention are found in widespread brain regions, and these signals are generally assumed to participate in a common mechanism of attention. However, the behavioral effects of attention in detection can be separated into two distinct components: spatially selective shifts in either the criterion or sensitivity of the subject. Here we show that a paradigm used by many single-neuron studies of attention conflates behavioral changes in the subject's criterion and sensitivity. Then, using a task designed to dissociate these two components, we found that multiple aspects of attention related neuronal modulations in area V4 of monkey visual cortex corresponded to behavioral shifts in sensitivity, but not criterion. This result suggests that separate components of attention are associated with signals in different brain regions and that attention is not a unitary process in the brain, but instead consists of distinct neurobiological mechanisms. PMID- 26050040 TI - Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia. AB - We sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and 10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms. PMID- 26050042 TI - Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling. AB - Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD. PMID- 26050041 TI - Distinct Growth Factor Families Are Recruited in Unique Spatiotemporal Domains during Long-Term Memory Formation in Aplysia californica. AB - Several growth factors (GFs) have been implicated in long-term memory (LTM), but no single GF can support all of the plastic changes that occur during memory formation. Because GFs engage highly convergent signaling cascades that often mediate similar functional outcomes, the relative contribution of any particular GF to LTM is difficult to ascertain. To explore this question, we determined the unique contribution of distinct GF families (signaling via TrkB and TGF-betar-II) to LTM formation in Aplysia. We demonstrate that TrkB and TGF-betar-II signaling are differentially recruited during two-trial training in both time (by trial 1 or 2, respectively) and space (in distinct subcellular compartments). These GFs independently regulate MAPK activation and synergistically regulate gene expression. We also show that trial 1 TrkB and trial 2 TGF-betar-II signaling are required for LTM formation. These data support the view that GFs engaged in LTM formation are interactive components of a complex molecular network. PMID- 26050039 TI - Genetic Differences in the Immediate Transcriptome Response to Stress Predict Risk-Related Brain Function and Psychiatric Disorders. AB - Depression risk is exacerbated by genetic factors and stress exposure; however, the biological mechanisms through which these factors interact to confer depression risk are poorly understood. One putative biological mechanism implicates variability in the ability of cortisol, released in response to stress, to trigger a cascade of adaptive genomic and non-genomic processes through glucocorticoid receptor (GR) activation. Here, we demonstrate that common genetic variants in long-range enhancer elements modulate the immediate transcriptional response to GR activation in human blood cells. These functional genetic variants increase risk for depression and co-heritable psychiatric disorders. Moreover, these risk variants are associated with inappropriate amygdala reactivity, a transdiagnostic psychiatric endophenotype and an important stress hormone response trigger. Network modeling and animal experiments suggest that these genetic differences in GR-induced transcriptional activation may mediate the risk for depression and other psychiatric disorders by altering a network of functionally related stress-sensitive genes in blood and brain. PMID- 26050043 TI - Novelty-Induced Phase-Locked Firing to Slow Gamma Oscillations in the Hippocampus: Requirement of Synaptic Plasticity. AB - Temporally precise neuronal firing phase-locked to gamma oscillations is thought to mediate the dynamic interaction of neuronal populations, which is essential for information processing underlying higher-order functions such as learning and memory. However, the cellular mechanisms determining phase locking remain unclear. By devising a virus-mediated approach to perform multi-tetrode recording from genetically manipulated neurons, we demonstrated that synaptic plasticity dependent on the GluR1 subunit of AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionate) receptor mediates two dynamic changes in neuronal firing in the hippocampal CA1 area during novel experiences: the establishment of phase locked firing to slow gamma oscillations and the rapid formation of the spatial firing pattern of place cells. The results suggest a series of events potentially underlying the acquisition of new spatial information: slow gamma oscillations, originating from the CA3 area, induce the two GluR1-dependent changes of CA1 neuronal firing, which in turn determine information flow in the hippocampal entorhinal system. PMID- 26050044 TI - Parvalbumin Interneurons of Hippocampus Tune Population Activity at Theta Frequency. AB - Hippocampal theta rhythm arises from a combination of recently described intrinsic theta oscillators and inputs from multiple brain areas. Interneurons expressing the markers parvalbumin (PV) and somatostatin (SOM) are leading candidates to participate in intrinsic rhythm generation and principal cell (PC) coordination in distal CA1 and subiculum. We tested their involvement by optogenetically activating and silencing PV or SOM interneurons in an intact hippocampus preparation that preserves intrinsic connections and oscillates spontaneously at theta frequencies. Despite evidence suggesting that SOM interneurons are crucial for theta, optogenetic manipulation of these interneurons modestly influenced theta rhythm. However, SOM interneurons were able to strongly modulate temporoammonic inputs. In contrast, activation of PV interneurons powerfully controlled PC network and rhythm generation optimally at 8 Hz, while continuously silencing them disrupted theta. Our results thus demonstrate a pivotal role of PV but not SOM interneurons for PC synchronization and the emergence of intrinsic hippocampal theta. PMID- 26050047 TI - Homing abilities of the tropical primitively eusocial paper wasp Ropalidia marginata. AB - Compared to our extensive knowledge about the navigation and homing abilities of ants and bees, we know rather little about these phenomena in social wasps. Here, we report the homing abilities of the tropical primitively eusocial wasp Ropalidia marginata and the factors that affect their homing success. To determine from how far these wasps can return to their nests, we transported foragers blindfold and released them at gradually increasing distances from their nests in four cardinal directions. Their homing success was determined by checking their presence on their nests on three consecutive nights. All foragers (56 individuals, 115 releases) returned back from an area of 0.73 +/- 0.25 km(2) on the day of release (minimal homing area), whereas 83.8 % of the foragers (217 individuals, 420 releases) returned when we enlarged the area of release to 6.22 +/- 0.66 km(2) around their nests (maximal homing area). Of 66 releases, no wasps returned from beyond the maximal homing area. The minimal homing area might be familiar to the foragers because they probably routinely forage in this area and the maximal homing area represents the maximum distances from which the wasps are capable of returning to their nests, with or without familiarity. PMID- 26050048 TI - Accelerated Second Degree Programs. PMID- 26050045 TI - Subnetwork-Specific Homeostatic Plasticity in Mouse Visual Cortex In Vivo. AB - Homeostatic regulation has been shown to restore cortical activity in vivo following sensory deprivation, but it is unclear whether this recovery is uniform across all cells or specific to a subset of the network. To address this issue, we used chronic calcium imaging in behaving adult mice to examine the activity of individual excitatory and inhibitory neurons in the same region of the layer 2/3 monocular visual cortex following enucleation. We found that only a fraction of excitatory neurons homeostatically recover activity after deprivation and inhibitory neurons show no recovery. Prior to deprivation, excitatory cells that did recover were more likely to have significantly correlated activity with other recovering excitatory neurons, thus forming a subnetwork of recovering neurons. These network level changes are accompanied by a reduction in synaptic inhibition onto all excitatory neurons, suggesting that both synaptic mechanisms and subnetwork activity are important for homeostatic recovery of activity after deprivation. PMID- 26050046 TI - Volumetric intensity-modulated arc therapy vs. 3-dimensional conformal radiotherapy for primary chemoradiotherapy of anal carcinoma: Effects on treatment-related side effects and survival. AB - BACKGROUND: Primary chemoradiotherapy (CRT) is the standard treatment for locally advanced anal carcinoma. This study compared volumetric intensity-modulated arc therapy (VMAT) to 3-dimensional conformal radiotherapy (3DCRT) in terms of treatment-related side effects and survival. PATIENTS AND METHODS: From 1992 2014, 103 consecutive patients with anal carcinoma UICC stage I-III were treated. Concomitant CRT consisted of whole pelvic irradiation, including the iliac and inguinal lymph nodes, with 50.4 Gy (1.8 Gy per fractions) by VMAT (n = 17) or 3DCRT (n = 86) as well as two cycles of 5-fluorouracil and mitomycin C. Acute organ and hematological toxicity were assessed according to the Common Terminology Criteria (CTC) for Adverse Events version 3.0. Side effects >= grade 3 were scored as high-grade toxicity. RESULTS: High-grade acute organ toxicity CTC >= 3 (P < 0.05), especially proctitis (P = 0.03), was significantly reduced in VMAT patients. The 2-year locoregional control (LRC) and disease-free survival (DFS) were both 100 % for VMAT patients compared with 80 and 73 % for 3DCRT patients. CONCLUSION: VMAT was shown to be a feasible technique, achieving significantly lower rates of acute organ toxicity and promising results for LRC and DFS. Future investigations will aim at assessing the advantages of VMAT with respect to late toxicity and survival after a prolonged follow-up time. PMID- 26050049 TI - Nurses' Practices and Lead Selection in Monitoring for Myocardial Ischemia: An Evidence-Based Quality Improvement Project. AB - BACKGROUND: The 5-lead electrocardiogram (ECG) provides key information, including clues that a patient may be experiencing myocardial ischemia, usually demonstrated in the ST segment. Studies have shown that nursing knowledge regarding ischemia monitoring is suboptimal, even though national guidelines for ECG monitoring were published in 2004 by the American Heart Association and endorsed by the American Association of Critical Care Nurses. PURPOSE: The aims of this study were to identify best practice regarding 5-lead ECG myocardial ischemia monitoring, assess current unit-level practice at 1 institution, and to educate nurses on proper monitoring using a nurse-led, evidence-based intervention. METHODS: The authors created an educational PowerPoint designed to educate nurses on proper lead selection to monitor the ST segment for patients admitted with known or suspected myocardial ischemia and developed a 3-part online survey to assess current unit practice and to assess knowledge before and after intervention. RESULTS: A total of 18 registered nurses (RNs) completed the survey. Results indicated that RNs lacked knowledge regarding continuous ECG monitoring for ischemia and had room for improvement in their everyday practice habits. The knowledge preintervention test mean score (out of 9) was 3.11 (SD, 1.68), and the postintervention test mean score was 6.94 (SD, 1.55), which was significant (P = .000). The intervention also significantly improved the monitoring comfort level of RNs, with a preintervention comfort level of 2.53 (SD, 1.07) and a postintervention level of 3.41 (SD, 1.00) (P = .007). The process allowed the authors to reflect on the key steps of implementing evidence based projects in nursing units. CONCLUSIONS: Continuous, 5-lead ECG monitoring is an active process that requires clinical decision making by the nurse and is not a passive activity. Registered nurses in this sample demonstrated a lack of knowledge regarding ECG monitoring for ischemia that was improved with an online educational intervention and reported intentional daily practice pattern changes postintervention testing. A unit-level intervention driven by nurses may be successful at improving fellow RNs' knowledge and evidence-based practice. PMID- 26050050 TI - Your Patient Has Congenital Heart Disease--What Questions Should You Ask to Provide High-Quality Care? AB - Congenital heart disease (CHD) is the most common birth defect. About two-thirds of those individuals living with CHD are now adults. If you do not have in-depth knowledge of CHD, knowing what questions to ask and what resources to use can improve patient outcomes and satisfaction with care. PMID- 26050051 TI - Patients' and Health Care Providers' Perception of Stressors in the Intensive Care Units. AB - PURPOSE: The purposes of this study is first, to investigate intensive care patients' perceptions of stressors; second, to investigate the health care provider's perception of what constitutes a stressor from the patient's perspective; and third, to describe how health care providers manage their patients' stressors. This was a mixed-methods study; the quantitative section replicated Cornock's 1998 study of stress in the intensive care unit (ICU), with difference in sampling to include all health care providers in the ICU, in addition to nurses. The qualitative section added information to the current literature by describing how health care providers manage their patient's stressors. This article reports the quantitative findings of this study, as the qualitative section is presented in a separate article. BACKGROUND AND SIGNIFICANCE: It is important to describe ICU patients' stressful experiences to assess patient's stressors, provide holistic care to eliminate stressors, and provide feedback to health care providers. There is a need to describe the clinical practice related to stress perception and management of stressors in the critical care environment. METHODOLOGY: A mixed-methods comparative descriptive design was used for the quantitative section, and a phenomenological approach guided the qualitative section. Lazarus and Folkman's theory formed the bases for integrating all variables investigated in this study. The sample included 70 ICU patients and 70 ICU health care providers. After consenting to participate in this study, subjects were given a demographic form and a paper-based tool, the Environmental Stressors graphic data form Questionnaire. Questionnaires were filled out by subjects anonymously in the ICU and returned to the researcher in the same setting. FINDINGS: Descriptive statistics were analyzed using SPSS data analysis software. The top 3 most stressful items ranked by the patients included "being in pain," followed by "not being able to sleep" and "financial worries"; on the other hand, health care providers perceived "being in pain" followed by "not being able to communicate" and "not being in control of yourself" as the top 3 stressors perceived by their patients. IMPLICATIONS FOR PRACTICE: The findings of this study are crucial and may inform nursing assessments and care of the ICU patient. In addition, this information may encourage the ICU staff to manipulate and redesign the ICU environment to be less stressful. Also, the findings of this study guided the development of an ICU stressor control policy. PMID- 26050054 TI - Improving Human Immunodeficiency Virus/AIDS Palliative Care in Critical Care. AB - BACKGROUND: Critical care nurses provide palliative care to many patients; often, this includes the patient diagnosed with human immunodeficiency virus (HIV)/AIDS. Ongoing education about both palliative care and this complex diagnosis prepares the nurse to provide compassion and informed care. OBJECTIVES: This study examines the effects of an educational intervention addressing palliative care in the intensive care unit and the needs of the HIV/AIDS patients and families. The study will evaluate the critical care nurses' knowledge and competence in caring for this population following the educational sessions. METHODS: Thirty critical care nurses were recruited from the critical care unit at a hospital in the south. An HIV/AIDS palliative care course provided participants background knowledge, general principles, and opportunities for critical thinking regarding palliative care. A pretest and posttest on palliative care were provided to each subject to assess knowledge and confidence in palliative care in critical care nursing. RESULTS: The convenience sample of 30 nurses attained a mean pretest score of 82.9%. Their scores improved to 93.5% following the palliative care course. The nurses felt they improved in providing palliative care to patients and in taking responsibility for their practice. Ninety-three percent of the participants wanted to incorporate a palliative care course in nursing orientation. DISCUSSION: The course improved nurses' knowledge of palliative care for HIV/AIDS patients and their competency in palliative care. Thus, the palliative care course gave nurses deeper insight and improved their ability to provide competence palliative care. PMID- 26050056 TI - Determining Time of Symptom Onset in Patients With Acute Coronary Syndromes: Agreement Between Medical Record and Interview Data. AB - BACKGROUND: Prehospital delay, the time of symptom onset until the time of hospital arrival, for patients with symptoms of acute coronary syndrome (ACS) is frequently used to determine the course of care. Total ischemic time (time for symptom onset until the time of first coronary artery balloon inflation) is another criterion for quality of care for patients experiencing ST-segment elevation myocardial infarction. However, obtaining the exact time of symptom onset, the starting point of both time intervals, is challenging. Currently 2 methods are used to obtain the time of symptom onset: abstraction of data from the medical record and structured interviews done after the acute event. It is not clear whether these methods are equally accurate. PURPOSE: Using identified search terms, PubMed and the Cumulative Index to Nursing and Allied Health Literature were searched for articles published from 1990 to 2014 to identify studies that examined agreement between the 2 data sources to determine prehospital delay in patients with ACS. CONCLUSIONS: Five studies examined the accuracy and/or agreement of prehospital delay by medical record review and structured patient interviews. In these studies, the percentage of missing/incomplete data in the medical record was higher compared with interviews (14%-40% vs 12%-13%). Three of the 4 studies that compared the 2 data sources reported more than 50% disagreement, with the time of symptom onset starting sooner when obtained by interview compared with the time recorded in their medical record at hospital presentation. CLINICAL IMPLICATIONS: There is a need for a consistent, reliable method to assess the time of symptom onset in patients with ACS. To ensure the accuracy of data collected for the medical record, training of emergency and critical care clinicians should (1) emphasize the importance of assessing symptoms broadly, (2) provide tips on interviewing techniques to help patients pinpoint the time of symptom onset, and (3) instill the value of complete documentation. PMID- 26050057 TI - A Pilot Study: Comparison of Arm Versus Ankle Noninvasive Blood Pressure Measurement at 2 Different Levels of Backrest Elevation. AB - BACKGROUND: Standard practice for obtaining noninvasive blood pressure includes arm blood pressure (BP) cuff placement at the level of the heart; however, some critical care patients cannot have BPs taken in their arm because of various conditions, and ankle BPs are frequently used as substitutes. OBJECTIVE: The aim of this study was to determine if there was a significant variation between upper arm and ankle BP measurements at different backrest elevations with consideration of peripheral edema factors. METHODOLOGY: After institutional review board approval was obtained, a pilot study was implemented to evaluate noninvasive BP measurements of the arm and ankle with backrest elevation at 0 degrees and 30 degrees in a population of medical intensive care unit patients. Participants served as their own controls and were randomly assigned to left- versus right side BP readings. Data were also collected on presence of arm versus ankle edema. RESULTS: A total of 30 participants enrolled in the study and provided 120 BP measurements. Blood pressure readings were analyzed in terms of diastolic and systolic findings as well as backrest elevations and edema presence. Thirteen participants presented with either arm or ankle edema. There was a statistical difference between the systolic arm and ankle BP measurements in the 0 degrees (P = .008) and 30 degrees (P < .001) backrest elevation positions. The correlation between arm and ankle diastolic BP is greater for participants without ankle edema (P = .038, r = 0.54) than for participants with ankle edema (P = .650, r = 0.14), but it is not statistically significant (P = .47). DISCUSSION: Even though ankle BPs are often substituted for arm BPs when the arm is unable to be used, ankle BPs and arm BPs are not interchangeable. Adjustments in backrest elevation and considerations of edema do not normalize the differences. Blood pressures obtained from the ankle are significantly greater than those obtained from the arm. This information needs to be considered when arms are not available and legs are used as surrogates for the upper arm. PMID- 26050058 TI - A Closing Word: The Gift of Summer Reading. PMID- 26050059 TI - A new weighted balance measure helped to select the variables to be included in a propensity score model. AB - OBJECTIVES: The propensity score (PS) is a balancing score. Following PS matching, balance checking usually relies on estimating separately the standardized absolute mean difference for each baseline characteristic. The average standardized absolute mean difference and the Mahalanobis distances have been proposed to summarize the information across the covariates. However, they might be minimized when nondesirable variables such as instrumental variables (IV) are included in the PS model. We propose a new weighted summary balance measure that takes into account, for each covariate, its strength of association with the outcome. STUDY DESIGN AND SETTING: This new measure was evaluated using a simulation study to assess whether minimization of the measure coincided with minimally biased estimates. All measures were then applied to a real data set from an observational cohort study. RESULTS: Contrarily to the other measures, our proposal was minimized when including the confounders, which coincided with minimal bias and mean squared error, but increased when including an IV in the PS model. Similar findings were observed in the real data set. CONCLUSION: A balance measure taking into account the strength of association between the covariates and the outcome may be helpful to identify the most parsimonious PS model. PMID- 26050060 TI - Optimization of dose and image quality of paediatric cardiac catheterization procedure. AB - The purpose of this study is to quantify the quality of the available imaging modes for various iodine-based contrast agent concentration in paediatric cardiology. The figure of merit (FOM) was defined as the squared signal to noise ratio divided by a patient dose related parameter. An in house constructed phantom simulated a series of vessel segments with iodine concentrations from 10% or 30 mg/cc to 16% or 48 mg/cc of iodine in a blood plasma solution, all within the dimensional constraints of a paediatric patient. The phantom also used test inserts of tin (Sn). Measurements of Entrance Surface Air Kerma (ESAK) and exit dose rate were performed along with calculations of the signal-to-noise ratio (SNR) of all the objects. A first result showed that it was favourable to employ low dose fluoroscopy mode and lower frame rate modes in cine acquisition if dynamic information is not critical. Normal fluoroscopy dose mode provided a considerably higher dose level (in comparison to low dose mode) with only a slight improvement in SNR. Higher frame rate cine modes should be used however when the clinical situation dictates so. This work also found that tin should not be intended as iodine replacement material for research purposes due to the mismatching SNR, particularly on small vessel sizes. PMID- 26050061 TI - Determination of optimal planning target volume margins in patients with gynecological cancer. AB - PURPOSE: To define optimal planning target volume (PTV) margins for intensity modulated radiotherapy (IMRT) +/- knee-heel support (KHS) in patients treated with adjuvant radiotherapy. METHODS: Computed tomography (CT) scans +/- KHS of 10 patients were taken before and at 3rd and 5th week of treatment, fused and compared with initial IMRT plans. RESULTS: A PTV margin of 15 mm in anteroposterior (AP) and superoinferior (SI) directions and 5 mm in lateral directions were found to be adequate without any difference between +/- KHS except for the SI shifts in CTV-primary at the 3rd week. Five mm margin for iliac CTV was found to be inadequate in 10-20% of patients in SI directions however when 7 mm margin was given for iliac PTV, it was found to be adequate. For presacral CTV, it was found that the most striking shift of the target volume was in the direction of AP. KHS caused significantly less volume of rectum and bladder in the treated volume. CONCLUSIONS: PTV margin of 15 mm in SI and AP, and 5 mm in lateral directions for CTV-primary were found to be adequate. A minimum of 7 mm PTV margin should be given to iliac CTV. The remarkable shifting in presacral CTV was believed to be due to the unforeseen hip malposition of obese patients. The KHS seems not to provide additional beneficial effect in decreasing the shifts both in CTV-primary and lymphatic, however it may have a beneficial effect of decreasing the OAR volume in PTV margins. PMID- 26050062 TI - Heavy metal accumulation in soils and grains, and health risks associated with use of treated municipal wastewater in subsurface drip irrigation. AB - Constant use of treated wastewater (TWW) for irrigation over prolonged periods may cause buildup of heavy metals up to toxic levels for plants and animals, and entails environmental hazards in different aspects. However, application of TWW on agricultural land might be an effective and sustainable strategy in arid and semi-arid countries where fresh water resources are under great pressure, as long as potential harmful effects on the environment including soil, plants, and fresh water resources, and health risks to humans are minimized. The aim of this study was to assess the effect of deep emitters on limiting potential heavy metal accumulation in soils and grains, and health risk under drip irrigation with treated municipal wastewater. A field experiment was conducted according to a split block design with two treatments (fresh and wastewater) and three sub treatments (0, 15, and 30 cm depth of emitters) in four replicates on a sandy loam Calcic Argigypsids, in Esfahan, Iran. The annual rainfall is about 123 mm, mean annual ETo is 1457 mm, and the elevation is 1590 m above sea level. A two crop rotation of wheat (Triticum spp.) and corn (Zea mays) was established on each plot with wheat growing from February to June and corn from July to September. Soil samples were collected before planting and after harvesting for each crop in each year. Edible grain samples of corn and wheat were collected at harvest. Elemental concentrations (Cu, Zn, Cd, Pb, Cr, Ni) in soil and grains were determined using an atomic absorption spectrophotometer. Results showed that the concentrations of heavy metals in the wastewater-irrigated soils were not significantly different (P > 0.05) compared with the freshwater-irrigated soils. No significant difference (P > 0.05) in heavy metal content in soil between different depths of emitters was found. A pollution load index (PLI) showed that there was no substantial buildup of heavy metals in the wastewater-irrigated soils compared to the freshwater-irrigated soils. Cu, Pb, and Zn concentrations in wheat and corn grains were within the permissible US Environmental Protection Agency (EPA) limits, but concentrations of Cd (in wheat and corn) and Cr (in corn) were above the safe limits of the EPA. In addition, concentrations of Ni in wheat and corn seeds were several folds higher than the EPA standards. A health risk index (HRI) which is usually adopted to assess the health risk to hazard materials in foods showed values higher than 1 for Cd, particularly for wheat grain (HRI >2.5). Results also showed that intake of Cu through consumption of edible wheat grains posed a relatively high potential health risk to children (HRI >1.4), whereas children might also be exposed to health risk from Cd and Cr from corn grains (HRI >1.4). Based on aforementioned results, it can be concluded that the emitter depth in drip irrigation does not play a significant role in the accumulation of heavy metals from TWW in our sandy loam soil. Although their accumulation in the soil was limited and similar to using freshwater, uptake of Cd and Cr by wheat and corn was relatively large and hence resulted in health risk. The results suggest that more attention should be directed towards cultivation of other crops with drip irrigation system for a safe and more productive use of wastewater for irrigation. Alternatively, methods that filter the wastewater before it enters the soil environment might be an option that needs further investigation. PMID- 26050063 TI - 2,4-Dinitrophenylhydrazine functionalized sodium dodecyl sulfate-coated magnetite nanoparticles for effective removal of Cd(II) and Ni(II) ions from water samples. AB - 2,4-Dinitrophenylhydrazine immobilized on sodium dodecyl sulfate (SDS)-coated magnetite and was used for removal of Cd(II) and Ni(II) ions from aqueous solution. The prepared product was characterized by X-ray diffraction (XRD) analysis, Fourier transform infrared spectroscopy (FT-IR), and scanning electron microscopy (SEM). The size of the nanoparticles according to SEM was obtained around 20-35 nm. In batch tests, the effects of pH, contact time, initial metal concentration, and temperature were studied. The kinetic and equilibrium data were modeled with recently developed models. The adsorption kinetics and isotherms were well fitted by the fractal-like pseudo-second-order model and Langmuir-Freundlich model, respectively. Maximum adsorption capacity by this adsorbent is 255.1 mg g(-1) for Cd(II) ion and 319.6 mg g(-1) for Ni(II) ion at pH 7.0 and 25 degrees C. The method was successfully applied to the removal of metal cations in real samples (tap water, river water, and petrochemical wastewater). PMID- 26050064 TI - Mapping availability of sea view for potential building development areas. AB - Scenic attraction can be regarded as one of the most important factors for recreation- and/or tourism-oriented landscape planning and management processes. Sea view is generally one of the most predominant scenery components of coastal landscapes. Therefore, presence and degree of its availability contribute to scenic attraction of residential development sites. This attribute of the environment can be quantified by GIS-based visibility analyses that rely on multiple viewshed calculations, during which observation and/or target locations are taken as variables. The main aim of this paper is to analyze availability of sea view for currently undeveloped (i.e., non-built-up) areas in an urbanized coast in the Mediterranean region of Turkey. Four study sites (sites 1-4) of varying geomorphological and built-up features, located approximately 40 km south of the city of Mersin, were taken into consideration. Multiple viewshed analyses were performed using a high-resolution terrain model and 541, 533, 540, and 532 observation points for the sites, 1, 2, 3, and 4, respectively. Impact of topography and built-up features on sea visibility was discussed in the light of visibility information classified as percentage visibility of the sea surface available from each of the sites. PMID- 26050065 TI - Explosive particle soil surface dispersion model for detonated military munitions. AB - The accumulation of high explosive mass residue from the detonation of military munitions on training ranges is of environmental concern because of its potential to contaminate the soil, surface water, and groundwater. The US Department of Defense wants to quantify, understand, and remediate high explosive mass residue loadings that might be observed on active firing ranges. Previously, efforts using various sampling methods and techniques have resulted in limited success, due in part to the complicated dispersion pattern of the explosive particle residues upon detonation. In our efforts to simulate particle dispersal for high- and low-order explosions on hypothetical firing ranges, we use experimental particle data from detonations of munitions from a 155-mm howitzer, which are common military munitions. The mass loadings resulting from these simulations provide a previously unattained level of detail to quantify the explosive residue source-term for use in soil and water transport models. In addition, the resulting particle placements can be used to test, validate, and optimize particle sampling methods and statistical models as applied to firing ranges. Although the presented results are for a hypothetical 155-mm howitzer firing range, the method can be used for other munition types once the explosive particle characteristics are known. PMID- 26050066 TI - Biosorption of Cd(II) on jatropha fruit coat and seed coat. AB - Jatropha (Jatropha curcas L.) seed coat (JSC) and fruit coat (JFC) were investigated for adsorption of Cd(II) from aqueous solutions. JFC and JSC fine powders were characterized using FTIR and SEM which indicated that both the adsorbents have high surface area, pore space on their surface, and anionic sites for metal ion binding. Batch adsorption study was conducted to study the effect of adsorption time, agitation speed, and initial concentration of Cd(II) ion, pH, and temperature on the adsorption of Cd(II) by adsorbents. The equilibrium isotherm, kinetics, and thermodynamics of the adsorption process were studied. Adsorption equilibrium followed both Langmuir and Freundlich isotherm. The adsorption capacity (Q m ) of Cd(II) on JSC and JFC were 22.83 and 21.97 mg g( 1), respectively. The adsorption of Cd(II) on JSC and JFC is endothermic in nature. The change of free energy (?G) of the biosorption of Cd(II) on JSC ranged from -37.05 to -40.54 kJ mol(-1) and for JFC -34.50 to -37.35 kJ mol(-1). The enthalpy change (?H) and entropy change (?S) was 15.84 kJ mol(-1) and -0.17 kJ mol(-1) K(-1) for JSC and 8.77 kJ mol(-1) and -0.14 kJ mol(-1) K(-1) for JFC. Elovich model provided a better correlation of the experimental data in comparison with pseudo-first-order and pseudo-second-order kinetic models. The study indicated that JFC and JSC have good adsorption capacity for Cd(II). PMID- 26050067 TI - Determination and analysis of the dissipation and residue of cyprodinil and fludioxonil in grape and soil using a modified QuEChERS method. AB - A simple and accurate method coupled with a gas chromatography-nitrogen phosphorus detector was developed to detect cyprodinil and fludioxonil in grape and soil. The accuracy and precision of the method in detecting the two fungicides were evaluated by conducting intra- and inter-day recovery experiments. The limits of detection were 0.017 mg/kg for cyprodinil and 0.030 mg/kg for fludioxonil. The limits of quantitation were 0.05 mg/kg for cyprodinil and 0.10 mg/kg for fludioxonil in grape and soil. The recoveries of the fungicides in grape and soil were investigated at three spiked levels and were found to range from 85.81 to 102.94% for cyprodinil and from 92.00 to 106.86% for fludioxonil, with relative standard deviations below 7%. Field experiments were conducted in two experimental locations in China. The half-lives of cyprodinil were 9.6-20.8 days in grape and 5.8-15.6 day in soil, and the half-lives of fludioxonil were 6.2-7.2 days in grape and 6.0-12.1 days in soil. When the cyprodinil and fludioxonil 62% water-dispersible granule formulation was sprayed at a low dosage three times, terminal residues of cyprodinil and fludioxonil were below 1.0 mg/kg in grape 14 days after harvest. This work may serve as a reference to establish the maximum residue limits for cyprodinil and fludioxonil in grape and promote the proper and safe use of these two fungicides. PMID- 26050068 TI - Higher clonal integration in the facultative epiphytic fern Selliguea griffithiana growing in the forest canopy compared with the forest understorey. AB - BACKGROUND AND AIMS: The advantage of clonal integration (resource sharing between connected ramets of clonal plants) varies and a higher degree of integration is expected in more stressful and/or more heterogeneous habitats. Clonal facultative epiphytes occur in both forest canopies (epiphytic habitats) and forest understories (terrestrial habitats). Because environmental conditions, especially water and nutrients, are more stressful and heterogeneous in the canopy than in the understorey, this study hypothesizes that clonal integration is more important for facultative epiphytes in epiphytic habitats than in terrestrial habitats. METHODS: In a field experiment, an examination was made of the effects of rhizome connection (connected vs. disconnected, i.e. with vs. without clonal integration) on survival and growth of single ramets, both young and old, of the facultative epiphytic rhizomatous fern Selliguea griffithiana (Polypodiaceae) in both epiphytic and terrestrial habitats. In another field experiment, the effects of rhizome connection on performance of ramets were tested in small (10 * 10 cm(2)) and large (20 * 20 cm(2)) plots in both epiphytic and terrestrial habitats. KEY RESULTS: Rhizome disconnection significantly decreased survival and growth of S. griffithiana in both experiments. The effects of rhizome disconnection on survival of single ramets and on ramet number and growth in plots were greater in epiphytic habitats than in terrestrial habitats. CONCLUSIONS: Clonal integration contributes greatly to performance of facultative epiphytic ferns, and the effects were more important in forest canopies than in forest understories. The results therefore support the hypothesis that natural selection favours genotypes with a higher degree of integration in more stressful and heterogeneous environments. PMID- 26050069 TI - MRI evaluation of post-mastectomy irradiated breast implants: prevalence and analysis of complications. AB - AIM: To evaluate the effect of post-mastectomy radiation therapy (RT) on breast implants as detected by magnetic resonance imaging (MRI) searching for short-term complications. MATERIALS AND METHODS: One hundred and forty patients (total of 144 implants) were evaluated by MRI; 80 (group 1) had undergone RT, whereas the remaining 60 patients (group 2) underwent mastectomy with implant reconstruction without RT. Two radiologists evaluated MRI images searching for implant rupture signs, sub-capsular seromas, capsular contracture, soft-tissue oedema, peri implant fluid collections. Implant ruptures were classified as severe complications; seromas and capsular contractures as moderate complications; oedema and fluid collections as mild complications. The prevalence of MRI findings in the two groups was calculated and compared by unpaired t-test. Cohen's kappa statistics was used to assess interobserver agreement. RESULTS: Sixty-nine out of 144 (48%) implants presented pathological findings at MRI with complication rates of 47.5 and 48.4 for groups 1 and 2, respectively. Two (5%) severe complications, 10 (26%) moderate complications, and 26 (69%) mild complications occurred in group 1 and surgical treatment was performed in 10 cases. Two (6%) severe complications, seven (23%) moderate complications, and 22 (71%) mild complications occurred in group 2 and surgical treatment was performed in eight cases. No significant difference between the two groups was found (p>0.1). Almost perfect agreement between the two radiologists was found for MRI image detection (k=0.86). CONCLUSION: RT does not seem to cause a significant effect on breast implants in terms of complication rate in patients undergoing implant-based breast reconstruction. One-stage immediate implant-based breast reconstruction performed at the same time as mastectomy could be proposed. PMID- 26050070 TI - Glenoid notch MRI findings do not predict normal variants of the anterior and superior labrum. AB - AIM: To determine (1) the relationship of a glenoid notch to the presence of a normal labral variant in the anterior-superior glenoid labrum; (2) the inter- and intra-observer reliability of recognising a glenoid notch; and (3) whether magnetic resonance arthrography (MRA) is more reliable than non-contrast magnetic resonance imaging (MRI) in visualising a glenoid notch. MATERIALS AND METHODS: From 1995 through 2010, 104 patients underwent MRI or MRA before diagnostic shoulder arthroscopy by the senior author. Five blinded musculoskeletal radiologists independently read the images twice to evaluate for the presence or absence of a glenoid notch. Fifty-nine (57%) patients had normal anterior superior labral variants. The authors calculated the relationship of the readings to the arthroscopically determined presence or absence of a normal labral variant and the reading's diagnostic performance and rater reliability. RESULTS: On average, 38% (range 9-65%) of the glenoid scans were read as notched. The sensitivity, specificity, positive predictive value, and negative predictive value of the notch relative to the presence of a normal variant were 43.1%, 71.2%, 70.2%, and 48% versus 44.3%, 77.5%, 79.4%, and 56.1% for MRI and MRA, respectively. The overall average intra-observer kappa-values were 0.438 (range 0.203-0.555) and 0.346 (range -0.102 to 0.570) for MRI and MRA, respectively. The average interobserver intra-class correlation coefficient reliability values were 0.730 (range 0.693-0.760) and 0.614 (range 0.566-0.662) for MRI and MRA, respectively. CONCLUSIONS: A notched glenoid on MRI lacks sufficient diagnostic performance and rater reliability for the clinical detection and prediction of normal anterior-superior labral variants. PMID- 26050071 TI - Reply to Morse and Sartor. PMID- 26050072 TI - What Are We Attempting to Improve When We Train Dual-Task Performance? PMID- 26050074 TI - A Randomized Controlled Feasibility Trial of a Specific Cueing Program for Falls Management in Persons With Parkinson Disease and Freezing of Gait. AB - BACKGROUND AND PURPOSE: Freezing of gait (FOG) increases fall risk in persons with Parkinson disease (PD). Cueing improves gait parameters associated with freezing, but it is unclear whether a cueing program can address falling. METHODS: We used a parallel-groups delayed- (n = 12) or immediate-start (n = 9) randomized controlled trial design to evaluate a cueing exercise program for FOG and falls in participants with PD. Each group received preintervention falls monitoring, followed by a 6-month standardized, home-based, cueing exercise and education program. Participant questionnaires rated program value and compliance. Freezing was measured with the New Freezing of Gait Questionnaire (NFOGQ). Falls were recorded by weekly diaries. RESULTS: Self-reported adherence was high; 83% of participants reported exercising after 6 months. Participants reported that the program was beneficial (89%), walking improved (78%), falls were fewer (73%), and self-management of freezing improved (61%). Mean (standard deviation) NFOGQ scores were 14.8 (5.0), for the immediate (n = 10), and 16.0 (7.7) for the delayed group (n = 9), after 6 months (difference -1.0 [95% confidence interval, 7.9 to 6.0; P = 0.78]). With baseline NFOGQ scores as a covariate, the estimate of difference was -0.7 (95% confidence interval, -6.1 to 4.7; P = 0.79). The relative rate of falls for immediate compared with delayed groups was 1.22 (95% confidence interval, 0.45 to 3.26). CONCLUSIONS: The cueing program intervention is acceptable and participants feel they improve; however, this small feasibility study lacks statistical power to detect important changes in falls rates or FOG severity. A larger study is warranted to further investigate the potential to influence FOG and falls.Video Abstract available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A105). PMID- 26050073 TI - Efficacy of Feedback-Controlled Robotics-Assisted Treadmill Exercise to Improve Cardiovascular Fitness Early After Stroke: A Randomized Controlled Pilot Trial. AB - BACKGROUND AND PURPOSE: Cardiovascular fitness is greatly reduced after stroke. Although individuals with mild to moderate impairments benefit from conventional cardiovascular exercise interventions, there is a lack of effective approaches for persons with severely impaired physical function. This randomized controlled pilot trial investigated efficacy and feasibility of feedback-controlled robotics assisted treadmill exercise (FC-RATE) for cardiovascular rehabilitation in persons with severe impairments early after stroke. METHODS: Twenty individuals (age 61 +/- 11 years; 52 +/- 31 days poststroke) with severe motor limitations (Functional Ambulation Classification 0-2) were recruited for FC-RATE or conventional robotics-assisted treadmill exercise (RATE) (4 weeks, 3 * 30-minute sessions/wk). Outcome measures focused on peak cardiopulmonary performance parameters, training intensity, and feasibility, with examiners blinded to allocation. RESULTS: All 14 allocated participants (70% of recruited) completed the intervention (7/group, withdrawals unrelated to intervention), without serious adverse events occurring. Cardiovascular fitness increased significantly in both groups, with peak oxygen uptake increasing from 14.6 to 17.7 mL . kg . min (+17.8%) after 4 weeks (45.8%-55.7% of predicted maximal aerobic capacity; time effect P = 0.01; no group-time interaction). Training intensity (% heart rate reserve) was significantly higher for FC-RATE (40% +/- 3%) than for conventional RATE (14% +/- 2%) (P = 0.001). DISCUSSION AND CONCLUSIONS: Substantive overall increases in the main cardiopulmonary performance parameters were observed, but there were no significant between-group differences when comparing FC-RATE and conventional RATE. Feedback-controlled robotics-assisted treadmill exercise significantly increased exercise intensity, but recommended intensity levels for cardiovascular training were not consistently achieved. Future research should focus on appropriate algorithms within advanced robotic systems to promote optimal cardiovascular stress.Video abstract available for more insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A107). PMID- 26050075 TI - Rasch Analysis of the Wrist and Hand Fugl-Meyer: Dimensionality and Item-Level Characteristics. AB - BACKGROUND AND PURPOSE: Clinical administration of the wrist stability, wrist mobility, and hand items of the upper-extremity Fugl-Meyer (W/H UE FM) may provide a rigorous, easily administered, bedside measure of motor impairment in mildly impaired stroke survivors. The purpose of this study was to evaluate the item structure of the W/H UE FM to better understand its measurement properties using Rasch analysis. METHODS: This was a secondary analysis of W/H UE FM data arising from clinical trials of mildly impaired stroke survivors using latent parallel analysis, ordinal factor analysis, and partial credit model Rasch analyses. RESULTS: Latent parallel analysis and ordinal factor analysis indicated that all W/H UE FM items represent a single unidimensional construct, wrist and hand motor ability. Rasch analysis of data from 150 mildly impaired stroke survivors (94 men; mean age, 57.1 +/- 11.4 years; mean time since stroke, 19.5 months) revealed that the W/H UE FM operated as a reliable, valid, and effective measure of wrist and hand motor ability. These data were compatible with Rasch model assumptions and are consistent with previous W/H UE FM research. Mass flexion and extension movements were the least difficult W/H UE FM items while the radial and hook grasp items were the most difficult. DISCUSSION AND CONCLUSION: The W/H UE FM is well suited to mildly impaired stroke survivors who exhibit the ability to perform mass flexion and mass extension movements. The full-scale UE FM may be preferable for stroke survivors with lower levels of ability.Video abstract available for additional insight from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A108). PMID- 26050076 TI - Effects of Intermittent Versus Continuous Walking on Distance Walked and Fatigue in Persons With Multiple Sclerosis: A Randomized Crossover Trial. AB - BACKGROUND AND PURPOSE: Fatigue is a common, disabling symptom experienced by persons with multiple sclerosis (MS). Evidence shows that intermittent exercise is associated in improved performance and negligible fatigue. The purpose of this study was to examine whether subjects with MS walk greater distances with less fatigue under intermittent (INT) or continuous (CONT) walking condition. METHODS: Twenty-seven subjects with MS (median Extended Disability Severity Scale 3.5, interquartile range 1.6) walked in the CONT (ie, 6 uninterrupted minutes) and INT (ie, three 2-minute walking bouts) conditions in a randomized crossover. Distance was measured for the entire 6-minute walking period and each 2-minute increment. Fatigue was measured as the difference in a visual analog scale of fatigue (DeltaVAS-F) immediately preceding and following each trial. RESULTS: Participants walked greater distances in the INT condition compared to the CONT condition (P = 0.005). There was a significant interaction of walking condition and time (P < 0.001), indicating that the distances walked in the INT condition changed across time. DeltaVAS-F was significantly lower in the INT condition than in the CONT condition (P = 0.036). DISCUSSION AND CONCLUSION: Subjects with MS walked farther, and with less fatigue, when walking intermittently rather than continuously. Persons with MS may be able to tolerate a greater dose of walking training if the walking bouts are intermittent. Further study to determine the benefits of a walking exercise program using intermittent walking is recommended.Video Abstract available for additional insights from the authors (Supplemental Digital Content 1, http://links.lww.com/JNPT/A103). PMID- 26050078 TI - Invasive mole in a perimenopausal woman: a case report and systematic review. AB - OBJECTIVE: Gestational trophoblastic disease (GTD) is a term used for a group of pregnancy-related tumors. We present a case of a perimenopausal woman with invasive mole. A systematic review was performed to identify reports on GTD in older women and to determine adequate treatment options. CASE: A 51-year-old perimenopausal woman was admitted to hospital with abdominal feeling of pressure and nausea. Diagnostic curettage revealed hydatidiform mole. She also presented symptomatic hyperthyroidism with hypertensive blood pressure and uneasiness. After treatment with beta blockers and carbimazole, the patient underwent abdominal hysterectomy and bilateral oophorosalpingectomy. Histopathological examination confirmed an invasive hydatidiform mole (IHM). Serum beta-hCG has decreased from initially 300,000-100 unit/L after 4 weeks. DATA SOURCES: A systematic review was performed to identify all prior cases of GTD in women over 50. We searched in Medline, The Cochrane Library and Embase, to identify any articles published in the English language after 1970 and before Oct 31, 2013 pertaining to GTD in older woman (50 years or older). TABULATION, INTEGRATION, AND RESULTS: Ten records were included in the systematic review, involving 203 cases of trophoblastic disease in older women. Although the diagnosis of GTD in older women is rare, it should be considered especially in patients with suspicious intrauterine findings in transvaginal ultrasound examinations. Different treatments were performed. In a limited number of reports, older women with GTD underwent initial hysterectomy. Benefits are avoidance of chemotherapy induced toxicity and reduced risk of recurrence. Hysterectomy should be performed by an experienced surgeon. CONCLUSION: It is concluded that GTD is very rare in peri- or postmenopausal women. Treatment has to be individualized, and hysterectomy can be considered as an appropriate option. PMID- 26050079 TI - There Is No Such Thing as a "Mid-Pole". PMID- 26050080 TI - Inadvertent ? Accidental. PMID- 26050081 TI - [Noninvasive ventilation for acute respiratory failure in a pulmonary department]. AB - INTRODUCTION: Noninvasive ventilation (NIV) is considered as the first choice treatment for selected patients with acute respiratory failure (ARF), but many hospitals are forced to start NIV on medical wards. METHODS: The aim of this retrospective study was to assess the outcomes of NIV initiated for ARF on a respiratory ward and to find the criteria predictive of failure. All patients were treated in a four-bed ward specifically dedicated to NIV. Failure of NIV was defined as the need for intubation and transfer to ICU, or death. RESULTS: Among 105 admissions with ARF, 49 episodes needed NIV. These episodes were divided into 2 groups: PaCO2<45mmHg (10) and PaCO2>45mmHg (39). The overall failure rate of NIV and overall in-hospital mortality rate were 26.5% and 17% respectively. On multivariate analysis, SAPS II and respiratory acidosis with a pH less than 7.30 were significantly associated with failure of NIV. CONCLUSIONS: NIV is practicable and is effective in the management of mild to moderate ARF on a respiratory ward. However, patients with respiratory acidosis and a pH less than 7.30 are at risk of NIV failure. PMID- 26050082 TI - Health-Related Quality of Life for individuals with hepatitis C: A narrative review. AB - BACKGROUND: The assessment of Health-Related Quality of Life (HRQoL) in hepatitis C (HCV) infected individuals continues to gain importance. However, rarely do reviews of this literature consider quantitative and qualitative accounts of HRQoL collectively, which only allows partial insight into the topic. This narrative review aims to address this gap in the literature. METHODS: Literature searches were conducted using seven databases with two separate search strategies, and results assessed for eligibility using specific inclusion/exclusion criteria; a data extraction sheet was used to identify the dominant themes for each research paradigm which were then distilled to key findings to construct the narrative. RESULTS: Quantitative investigation reveals a low HRQoL in individuals with HCV due to a complex multifactorial cause. During treatment for HCV, a further transient reduction is observed, followed by improvement if a sustained virological response is achieved. Qualitative data provide a recognisable voice to the everyday challenges experienced by individuals with HCV including insights into diagnosis and stigmatisation, contextualising how a reduced HRQoL is experienced day-to-day. Methodological limitations of these findings are then discussed. Much of the quantitative data has little relevance to current substance users as they are excluded from most trials, and appraisal of the qualitative literature reveals a marked difference in the lived experience of HCV infected current substance users and that of other HCV groups. CONCLUSION: Concurrent analysis of quantitative and qualitative paradigms provides a deeper understanding of the true burden of HCV illness on HRQoL. Greater utilisation of qualitative research within international clinical guidelines is likely to be of benefit in identifying relevant HRQoL outcomes for substance users. PMID- 26050083 TI - The Education and Integrated Care Stream. Defining roles and improving outcomes in person-centred care. PMID- 26050084 TI - A Single Injection of Recombinant Adeno-Associated Virus into the Lumbar Cistern Delivers Transgene Expression Throughout the Whole Spinal Cord. AB - The lack of methods to deliver transgene expression in spinal cord has hampered investigation of gene function and therapeutic targets for spinal cord diseases. Here, we report that a single intrathecal injection of recombinant adeno associated virus rhesus-10 (rAAVrh10) into the lumbar cistern led to transgene expression in 60 to 90 % of the cells in the spinal cord. The transgene was expressed in all cell types, including neurons, glia, ependymal cells, and endothelial cells. Additionally, the transgene was expressed in some brain areas up to the frontal cortex and the olfactory bulb. The rAAV was distributed predominantly in the spinal cord, where its genome copy was over ten times that of the peripheral organs. Compared with intravenous injection, another method for rAAV delivery to the broad central nervous system (CNS), the intrathecal injection reduced the dosage of rAAV required to achieve similar or higher levels of transgene expression in the CNS by ~100-fold. Finally, the transduced areas were co-localized with the perivascular spaces of Virchow-Robin, from which the rAAV spreads further into the CNS parenchyma, thus suggesting that rAAV penetrated the CNS parenchyma through this pathway. Taken together, we have defined a fast and efficient method to deliver widespread transgene expression in mature spinal cord in mice. This method can be applied to stably overexpress or silence gene expression in the spinal cord to investigate gene functions in mammalian CNS. Additionally, this method can be applied to validate therapeutic targets for spinal cord diseases. PMID- 26050085 TI - Perihematomal Cellular Injury Is Reduced by Trans-sodium Crocetinate in a Model of Intracerebral Hemorrhage. AB - The carotenoid compound trans-sodium crocetinate (TSC) has been shown to increase oxygenation in various tissues, including the brain. Notably, TSC can enhance oxygenation under conditions of reduced blood flow, thus attenuating the depth of an ischemic challenge. This study examined the impact of TSC on neuronal loss in an animal model of intracerebral hemorrhage (ICH). Utilizing a rat model of collagenase injection, TSC was shown to reduce perihematomal cellular loss after ICH, as assessed by Fluoro-Jade B staining in tissue sections. This is the first evidence demonstrating that TSC is capable of limiting hemorrhagic injury to neurons in the brain. The finding supports the concept that TSC may represent a candidate therapeutic for early intervention regardless of whether a stroke is hemorrhagic or ischemic in nature. PMID- 26050086 TI - Roles of Neuroglobin Binding to Mitochondrial Complex III Subunit Cytochrome c1 in Oxygen-Glucose Deprivation-Induced Neurotoxicity in Primary Neurons. AB - Neuroglobin (Ngb) is a tissue globin specifically expressed in brain neurons. Recent studies by our laboratory and others have demonstrated that Ngb is protective against stroke and related neurological disorders, but the mechanisms remain poorly understood. We previously identified cytochrome c1 (Cyc1) as an Ngb interacting molecule by yeast two-hybrid screening. Cyc1 is a subunit of mitochondria complex III, which is a component of mitochondrial respiratory chain and a major source of reactive oxygen species (ROS) production under both physiological and pathological conditions. In this study, we for the first time defined Ngb-Cyc1 binding, and investigated its roles in oxygen-glucose deprivation (OGD)/reoxygenation-induced neurotoxicity and ROS production in primary neurons. Immunocytochemistry and co-immunoprecipitation validated Ngb Cyc1 binding, which was significantly increased by OGD and Ngb overexpression. We found 4 h OGD with/without 4 h reoxygenation significantly increased complex III activity, but this activity elevation was significantly attenuated in three groups of neurons: Ngb overexpression, specific complex III inhibitor stigmatellin, or stigmatellin plus Ngb overexpression, whereas there was no significant differences between these three groups, suggesting Ngb-Cyc1 binding may function in suppressing OGD-mediated complex III activity elevation. Importantly, these three groups of neurons also showed significant decreases in OGD-induced superoxide anion generation and neurotoxicity. These results suggest that Ngb can bind to mitochondrial complex III subunit Cyc1, leading to suppression of OGD-mediated complex III activity and subsequent ROS production elevation, and eventually reduction of OGD-induced neurotoxicity. This molecular signaling cascade may be at least part of the mechanisms of Ngb neuroprotection against OGD-induced neurotoxicity. PMID- 26050088 TI - Evaluation of duplicate publications: An article retraction by The Journal of Pain. PMID- 26050089 TI - Generation of cell-type-specific gene mutations by expressing the sgRNA of the CRISPR system from the RNA polymerase II promoters. PMID- 26050090 TI - Binding of Shewanella FadR to the fabA fatty acid biosynthetic gene: implications for contraction of the fad regulon. AB - The Escherichia coli fadR protein product, a paradigm/prototypical FadR regulator, positively regulates fabA and fabB, the two critical genes for unsaturated fatty acid (UFA) biosynthesis. However the scenario in the other Gamma-proteobacteria, such as Shewanella with the marine origin, is unusual in that Rodionov and coworkers predicted that only fabA (not fabB) has a binding site for FadR protein. It raised the possibility of fad regulon contraction. Here we report that this is the case. Sequence alignment of the FadR homologs revealed that the N-terminal DNA-binding domain exhibited remarkable similarity, whereas the ligand-accepting motif at C-terminus is relatively-less conserved. The FadR homologue of S. oneidensis (referred to FadR_she) was over-expressed and purified to homogeneity. Integrative evidence obtained by FPLC (fast protein liquid chromatography) and chemical cross-linking analyses elucidated that FadR_she protein can dimerize in solution, whose identity was determined by MALDI-TOF-MS. In vitro data from electrophoretic mobility shift assays suggested that FadR_she is almost functionally-exchangeable/equivalent to E. coli FadR (FadR_ec) in the ability of binding the E. coli fabA (and fabB) promoters. In an agreement with that of E. coli fabA, S. oneidensis fabA promoter bound both FadR_she and FadR_ec, and was disassociated specifically with the FadR regulatory protein upon the addition of long-chain acyl-CoA thioesters. To monitor in vivo effect exerted by FadR on Shewanella fabA expression, the native promoter of S. oneidensis fabA was fused to a LacZ reporter gene to engineer a chromosome fabA-lacZ transcriptional fusion in E. coli. As anticipated, the removal of fadR gene gave about 2-fold decrement of Shewanella fabA expression by beta-gal activity, which is almost identical to the inhibitory level by the addition of oleate. Therefore, we concluded that fabA is contracted to be the only one member of fad regulon in the context of fatty acid synthesis in the marine bacteria Shewanella genus. PMID- 26050091 TI - LSY-2 is essential for maintaining the germ-soma distinction in C. elegans. AB - The mechanisms that specify and maintain the characteristics of germ cells during animal development are poorly understood. In this study, we demonstrated that loss of function of the zinc-finger gene lsy-2 results in various somatic cells adopting germ cells characteristics, including expression of germline-specific P granules, enhanced RNAi activity and transgene silencing. The soma to germ transformation in lsy-2 mutants requires the activities of multiple chromatin remodeling complexes, including the MES-4 complex and the ISW-1 complex. The distinct germline-specific features in somatic cells and the gene expression profile indicate that LSY-2 acts in the Mec complex in this process. Our study demonstrated that lsy-2 functions in the maintenance of the soma-germ distinction. PMID- 26050092 TI - Modeling dry and wet deposition of sulfate, nitrate, and ammonium ions in Jiuzhaigou National Nature Reserve, China using a source-oriented CMAQ model: Part II. Emission sector and source region contributions. AB - A source-oriented Community Multiscale Air Quality (CMAQ) model driven by the meteorological fields generated by the Weather Research and Forecasting (WRF) model was used to study the dry and wet deposition of nitrate (NO3(-)), sulfate (SO4(2-)), and ammonium (NH4(+)) ions in the Jiuzhaigou National Nature Reserve (JNNR), China from June to August 2010 and to identify the contributions of different emission sectors and source regions that were responsible for the deposition fluxes. Contributions from power plants, industry, transportation, domestic, biogenic, windblown dust, open burning, fertilizer, and manure management sources to deposition fluxes in JNNR watershed and four EANET sites are determined. In JNNR, 96%, 82%, and 87% of the SO4(2-), NO3(-) and NH4(+) deposition fluxes are in the form of wet deposition of the corresponding aerosol species. Industry and power plants are the two major sources of SO4(2-) deposition flux, accounting for 86% of the total wet deposition of SO4(2-), and industry has a higher contribution (56%) than that of power plants (30%). Power plants and industry are also the top sources that are responsible for NO3(-) wet deposition, and contributions from power plants (30%) are generally higher than those from industries (21%). The major sources of NH4(+) wet deposition flux in JNNR are fertilizer (48%) and manure management (39%). Source-region apportionment confirms that SO2 and NOx emissions from local and two nearest counties do not have a significant impact on predicted wet deposition fluxes in JNNR, with contributions less than 10%. While local NH3 emissions account for a higher fraction of the NH4(+) deposition, approximately 70% of NH4(+) wet deposition in JNNR originated from other source regions. This study demonstrates that S and N deposition in JNNR is mostly from long-range transport rather than from local emissions, and to protect JNNR, regional emission reduction controls are needed. PMID- 26050093 TI - Novel, Rapid Identification, and Quantification of Adulterants in Extra Virgin Olive Oil Using Near-Infrared Spectroscopy and Chemometrics. AB - A new, rapid Fourier transform near infrared (FT-NIR) spectroscopic procedure is described to screen for the authenticity of extra virgin olive oils (EVOO) and to determine the kind and amount of an adulterant in EVOO. To screen EVOO, a partial least squares (PLS1) calibration model was developed to estimate a newly created FT-NIR index based mainly on the relative intensities of two unique carbonyl overtone absorptions in the FT-NIR spectra of EVOO and other mixtures attributed to volatile (5280 cm(-1)) and non-volatile (5180 cm(-1)) components. Spectra were also used to predict the fatty acid (FA) composition of EVOO or samples spiked with an adulterant using previously developed PLS1 calibration models. Some adulterated mixtures could be identified provided the FA profile was sufficiently different from those of EVOO. To identify the type and determine the quantity of an adulterant, gravimetric mixtures were prepared by spiking EVOO with different concentrations of each adulterant. Based on FT-NIR spectra, four PLS1 calibration models were developed for four specific groups of adulterants, each with a characteristic FA composition. Using these different PLS1 calibration models for prediction, plots of predicted vs. gravimetric concentrations of an adulterant in EVOO yielded linear regression functions with four unique sets of slopes, one for each group of adulterants. Four corresponding slope rules were defined that allowed for the determination of the nature and concentration of an adulterant in EVOO products by applying these four calibration models. The standard addition technique was used for confirmation. PMID- 26050094 TI - Measurement strategy and statistical power in studies assessing gait stability and variability in older adults. AB - BACKGROUND: Gait variability and stability measures might be useful to assess gait quality changes after fall prevention programs. However, reliability of these measures appears limited. AIMS: The objective of the present study was to assess the effects of measurement strategy in terms of numbers of subjects, measurement days and measurements per day on the power to detect relevant changes in gait variability and stability between conditions among healthy elderly. METHODS: Sixteen healthy older participants [65.6 (SD 5.9) years], performed two walking trials on each of 2 days. Required numbers of subjects to obtain sufficient statistical power for comparisons between conditions within subjects (paired, repeated-measures designs) were calculated (with confidence intervals) for several gait measures and for different numbers of trials per day and for different numbers of measurement days. RESULTS: The numbers of subjects required to obtain sufficient statistical power in studies collecting data from one trial on 1 day in each of the two compared conditions ranged from 7 to 13 for large differences but highly correlated data between conditions, up to 78-192 for data with a small effect and low correlation. DISCUSSION: Low correlations between gait parameters in different conditions can be assumed and relatively small effects appear clinically meaningful. This implies that large numbers of subjects are generally needed. CONCLUSION: This study provides the analysis tools and underlying data for power analyses in studies using gait parameters as an outcome of interventions aiming to reduce fall risk. PMID- 26050095 TI - Survival benefit of induction chemotherapy in treatment for locally advanced nasopharyngeal carcinoma--A time-to-event meta-analysis. AB - OBJECTIVES: This paper aims to compare the longtime efficacy of induction chemotherapy followed by concurrent chemoradiotherapy (IC+CCRT) and concurrent chemoradiotherapy (CCRT) alone in locally advanced nasopharyngeal carcinoma (LANPC) by using time-to-event data based on randomized controlled trials (RCTs). MATERIALS AND METHODS: We searched all RCTs comparing the efficacy between IC+CCRT and CCRT of LANPC in major medical databases including Pubmed, web of science, cochrane, China National Knowledge Internet Web (CNKI), Wanfang, and VIP. The Hazard ratios (HR) of time-to-event data on overall survival (OS), progressive free survival (PFS), distant metastasis failure-free survival (D FFS), and loco-regional failure-free survival (L-FFS) from the enrolled studies were calculated for this meta analysis. Our primary endpoints were OS, PFS, D FFS, and L-FFS. RESULTS: Four studies with 798 patients were enrolled for this paper. Compared with in CCRT alone, HRs (95% confidence interval) of OS, PFS, D FFS and L-FFS were 0.52 (0.21-1.29), 0.66 (0.49-0.90), 0.60 (0.39-0.98) and 0.66 (0.16-2.65) respectively in IC+CCRT. CONCLUSIONS: Induction chemotherapy could significantly reduce the hazard of progression and distant metastasis in LANPC on the basis of concurrent chemoradiotherapy, but do less with the hazard of overall death and loco-regional failure. PMID- 26050096 TI - Status of the infection control program in a Nigerian tertiary hospital before and after implementation of an improvement plan. PMID- 26050097 TI - Time-dependent influence on assessment of contaminated environmental surfaces in operating rooms. AB - BACKGROUND: There is no established method to assess the contamination of environmental surfaces because the results change with time. We evaluated current methods for assessment of contamination of environmental surfaces in the operating room (OR). METHODS: Contamination of environmental surfaces in the OR was assessed using an adenosine triphosphate (ATP) test and bacterial culture. We collected 480 ATP test samples from 17 surfaces in 6 ORs to determine the influence of surface features, including frequency of touching and surface orientation on contamination, after completion of daily scheduled operations. Another 54 pairs of ATP and microbial samples were taken from 3 surfaces in each of the same OR except 1 to determine the time course of the results of ATP and microbial tests when ORs were not used. RESULTS: Multivariate analysis demonstrated that the ATP results were strongly influenced by frequency of touching and orientation of environmental surfaces. The microbial counts declined over time, whereas the ATP results remained at a high level. CONCLUSION: The ATP test result could be used as a relatively stable trace of contamination of environmental surfaces; however, it is not a surrogate indicator of the number of viable microbes which declines over time. PMID- 26050098 TI - Impact of a clinical microbiology-intensive care consulting program in a cardiothoracic intensive care unit. AB - A preintervention-postintervention study was carried out over a 4-year period to assess the impact of an antimicrobial stewardship intervention, based on clinical microbiologist ward rounds (clinical microbiology-intensive care partnership [CMICP]), at a cardiothoracic intensive care unit. Comparison of clinical data for 37 patients with diagnosis of bacteremia (18 from preintervention period, 19 from postintervention period) revealed that CMICP implementation resulted in (1) significant increase of appropriate empirical treatments (+34%, P = .029), compliance with guidelines (+28%, P = .019), and number of de-escalations (+42%, P = .032); and (2) decrease (average = 2.5 days) in time to optimization of antimicrobial therapy and levofloxacin (Delta 2009-2012 = -74 defined daily dose [DDD]/1,000 bed days) and teicoplanin (Delta 2009-2012 = -28 DDD/1,000 bed days) use. PMID- 26050099 TI - Prevalence of nasal carriage of methicillin-resistant Staphylococcus aureus in children with diabetes mellitus: Trends between 2005 and 2013. AB - The aim of this prospective study was to establish the methicillin-resistant Staphylococcus aureus (MRSA) colonization rates in pediatric outpatients with type 1 diabetes mellitus, while also evaluating changes in colonization rates over time. There was no significant difference between 2005 and 2013 patients in terms of demographic and clinical findings. MRSA colonization rates were 0.7% (in 101 patients) and 0.9% (in 134 patients) (P = .84). Although increased MRSA colonization has become a significant problem worldwide, it does not seem to be a major issue in our diabetic outpatient population. PMID- 26050100 TI - Highly efficient protocol for callogenesis, somagenesis and regeneration of Indica rice plants. AB - In the present study, we have reported a simple, fast and efficient regeneration protocol using mature embryos as explants, and discovered its effective applicability to a range of Indica rice genotypes. We have considered the response of six varieties in the steps of the regeneration procedure. The results showed that calli were variably developed from the scutellar region of seeds and visible within 6-20 days. The highest and lowest calli induction frequency (70% and 51.66%) and number of induced calli from seeds (14 and 10.33) were observed in MR269 and MRQ74, respectively. The maximum and minimum number (7.66 and 4) and frequency of embryogenic calli (38.33% and 20%) were recorded in MR219 and MRQ74, respectively. However, the highest browning rate was observed in MR84 (87%) and the lowest rate in MRQ50 (46%). The majority of plants regenerated from embryogenic calli were obtained from MRQ50 (54%) and the minimum number of plants from MR84. In this study, the maximum numbers of plantlets were regenerated from the varieties with highest rate of embryogenic calli. Also, various varieties, including MRQ50, MR269, MR276 and MR219, were satisfactorily responding, while MRQ74 and MR84 weakly responded to the procedure. Such a simple, successful and generalized method possesses the potential to become an important tool for crop improvement and functional studies of genes in rice as a model monocot plant. PMID- 26050101 TI - Whole Genome Sequencing in Real-Time Investigation and Management of a Pseudomonas aeruginosa Outbreak on a Neonatal Intensive Care Unit. AB - OBJECTIVE: To use whole genome sequencing to describe the likely origin of an outbreak of Pseudomonas aeruginosa in a neonatal unit. DESIGN: Outbreak investigation. SETTING: The neonatal intensive care unit service of a major obstetric tertiary referral center. PATIENTS: Infants admitted to the neonatal unit who developed P. aeruginosa colonization or infection. METHODS: We undertook whole genome sequencing of P. aeruginosa strains isolated from colonized infants and from the neonatal unit environment. RESULTS: Eighteen infants were colonized with P. aeruginosa. Isolates from 12 infants and 7 environmental samples were sequenced. All but one of the clinical isolates clustered in ST253 and no differences were detected between unmapped reads. The environmental isolates revealed a variety of sequence types, indicating a large diverse bioburden within the unit, which was subsequently confirmed via enterobacterial repetitive intergenic consensus-polymerase chain reaction typing of post-outbreak isolates. One environmental isolate, obtained from a sink in the unit, clustered within ST253 and differed from the outbreak strain by 9 single-nucleotide polymorphisms only. This information allowed us to focus infection control activities on this sink. CONCLUSIONS: Whole genome sequencing can provide detailed information in a clinically relevant time frame to aid management of outbreaks in critical patient management areas. The superior discriminatory power of this method makes it a powerful tool in infection control. PMID- 26050102 TI - Gout: cartoonized and bagatellized and still left untreated. Time to change. PMID- 26050103 TI - Azathioprine during pregnancy in systemic lupus erythematosus patients is not associated with poor fetal outcome. AB - The objective of this study was to evaluate the risk of adverse fetal outcome in systemic lupus erythematosus (SLE) women exposed to azathioprine during pregnancy. We reviewed the medical records of SLE pregnant women followed from January 2005 to April 2013. The patients were evaluated at least once in each trimester and postpartum. Relevant fetal outcomes were extracted, such as rate of liveborns, fetal loss (spontaneous abortion and stillbirth), term delivery, preterm birth, neonatal death, low birth weight, low birth weight at term, and congenital malformations. A detailed history of drug use during pregnancy was obtained. We studied 178 pregnancies (in 172 women), 87 of them were exposed to azathioprine (AZA-group) and the remaining 91 were not exposed (NO AZA-group). Exposure to other drugs was similar in both groups. The rate of live births, spontaneous abortions mean birth weight, weeks of gestation, rate of birth weight <2500 g, and low birth weight at term did not differ between groups. No infant had major congenital abnormalities. Multivariate analysis showed that preeclampsia, premature rupture of membranes (PROM), lupus flare, and anti-DNA positive were associated with an increased risk of poor fetal outcome. Our study suggests that the use of azathioprine is safe and lacks of teratogenity in patients with SLE and pregnancy. Exposure to azathioprine during pregnancy is not associated with poor fetal outcome. PMID- 26050104 TI - Itolizumab in combination with methotrexate modulates active rheumatoid arthritis: safety and efficacy from a phase 2, randomized, open-label, parallel group, dose-ranging study. AB - The objective of this study was to assess the safety and efficacy of itolizumab with methotrexate in active rheumatoid arthritis (RA) patients who had inadequate response to methotrexate. In this open-label, phase 2 study, 70 patients fulfilling American College of Rheumatology (ACR) criteria and negative for latent tuberculosis were randomized to four arms: 0.2, 0.4, or 0.8 mg/kg itolizumab weekly combined with oral methotrexate, and methotrexate alone (2:2:2:1). Patients were treated for 12 weeks, followed by 12 weeks of methotrexate alone during follow-up. Twelve weeks of itolizumab therapy was well tolerated. Forty-four patients reported adverse events (AEs); except for six severe AEs, all others were mild or moderate. Infusion-related reactions mainly occurred after the first infusion, and none were reported after the 11th infusion. No serum anti-itolizumab antibodies were detected. In the full analysis set, all itolizumab doses showed evidence of efficacy. At 12 weeks, 50 % of the patients achieved ACR20, and 58.3 % moderate or good 28-joint count Disease Activity Score (DAS-28) response; at week 24, these responses were seen in 22 and 31 patients. Significant improvements were seen in Short Form-36 Health Survey and Health Assessment Questionnaire Disability Index scores. Overall, itolizumab in combination with methotrexate was well tolerated and efficacious in RA for 12 weeks, with efficacy persisting for the entire 24-week evaluation period. (Clinical Trial Registry of India, http://ctri.nic.in/Clinicaltrials/login.php , CTRI/2008/091/000295). PMID- 26050105 TI - Using segmented regression analysis of interrupted time series data to assess colonoscopy quality outcomes of a web-enhanced implementation toolkit to support evidence-based practices for bowel preparation: a study protocol. AB - BACKGROUND: While there is convincing evidence on interventions to improve bowel preparation for patients, the evidence on how to implement these evidence-based practices (EBPs) in outpatient colonoscopy settings is less certain. The Strategies to Improve Colonoscopy (STIC) study compares the effect of two implementation strategies, physician education alone versus physician education plus an implementation toolkit for staff, on adoption of three EBPs (split-dosing of bowel preparation, low-literacy education, teach-back) to improve pre procedure and intra-procedure quality measures. The implementation toolkit contains a staff education module, website containing tools to support staff in delivering EBPs, tailored patient education materials, and brief consultation with staff to determine how the EBPs can be integrated into the existing workflow. Given adaptations to the implementation plan and intentional flexibility in the delivery of the EBPs, we utilize a pragmatic study to balance external validity with demonstrating effectiveness of the implementation strategies. METHODS/DESIGN: Participants will include all outpatient colonoscopy physicians, staff, and patients from a convenience sample of six endoscopy settings. Aim #1 will explore the relative effect of two strategies to implement patient-level EBPs on adoption and clinical quality outcomes. We will assess the change in level and trends of clinical quality outcomes (i.e., adequacy of bowel preparation, adenoma detection) using segmented regression analysis of interrupted time series data with two groups (intervention and delayed start). Aim #2 will examine the influence of organizational readiness to change on EBP implementation. We use a PRECIS diagram to reflect the extent to which each indicator of the study was pragmatic versus explanatory, revealing a largely pragmatic study. DISCUSSION: Implementation challenges have already motivated several adaptations to the original plan, reflecting the nature of implementation in real-world healthcare settings. The pragmatic study responds to the evolving needs of its healthcare partners and allows for flexibility in intervention delivery, thereby informing clinical decision-making in real-world settings. The current study will provide information about what works (intervention effectiveness), for whom it works (influence of Medicaid versus other insurance), in which contexts it works (setting characteristics that influence implementation), and how it works best (comparison of implementation strategies). PMID- 26050106 TI - Maverick total disc replacement in a real-world patient population: a prospective, multicentre, observational study. AB - PURPOSE: Controlled trials have shown that total disc replacement (TDR) can provide pain and disability relief to patients with degenerative disc disease; however, whether these outcomes can also be achieved for patients treated in normal surgical practice has not been well documented. METHODS: This prospective, international study observed changes in disability and back pain in 134 patients who were implanted with Maverick TDR within the framework of routine clinical practice and followed for 2 years post-surgery. Primary and secondary outcomes were the differences from baseline to 6 months post-surgery in the means of the Oswestry Disability Index and the change in back pain intensity assessed on a 10 cm visual analogue scale, respectively. Mean patient age at surgery was 43 years, but ranged up to 65 years. RESULTS: One hundred twenty-three patients had an implant at one level, 10 patients at two levels, and one patient at three levels. Statistically significant improvements in mean disability (-25.4) and low back pain intensity (-4.0) scores were observed at 6 months postoperatively (P < 0.0001 for both) in the hands of experienced surgeons (>10 TDRs per centre). During the study, 56 patients (42 %) experienced a complication or adverse event. CONCLUSIONS: This is the first international observational study to report outcomes of TDR in real-world clinical settings. We showed statistically significant improvements in disability and pain scores at 6 months following Maverick TDR, which were maintained for 2 years alongside an acceptable rate of perioperative complications. The safety and tolerability shown in this observational study were comparable to those from controlled trials. PMID- 26050107 TI - Compressive myelopathy in severe angular kyphosis: a series of ten patients. AB - OBJECTIVE: Compressive myelopathy in severe angular kyphosis is rare and challenging for surgical treatment. The goal of this retrospective study was to report a series of ten patients with compressive myelopathy in severe angular kyphosis and the results of surgical decompression and correction of kyphosis. METHODS: Between 2010 and 2014, 10 patients were surgically treated for severe angular kyphosis with a progressive onset or a sudden onset of paraplegia in investigator group. In these ten patients (seven males and three females), the etiologic diagnosis included eight cases of congenital kyphosis and two of neurofibromatosis; the distribution of spine level was from C5 to T11; the duration from onset until surgery ranged from 1 to 120 months; follow-up ranged from 12 to 26 months (mean 18.5 months); the kyphosis angle of the patients ranged from 50 degrees to 180 degrees . Magnetic resonance imaging demonstrated the spinal cord thinning and compression at apex in most of patients. All patients underwent decompressive surgery by single-stage posterior vertebral column resection or both anterior corpectomy fusion and posterior fixation. Neurological status was evaluated using the ASIA impairment classification and the motor score. RESULTS: Postoperatively, all patients had different kyphosis correction rate from 24 to 100 %. Nine patients showed neurological improvement; one patient showed no improvement. Among them, one sudden onset ASIA A adolescent paraplegic patient improved to ASIA E within 1 year of follow-up. One ASIA C adolescent paraplegic patients deteriorated neurologically to ASIA A after surgery and improved to ASIA D with 12-month follow-up. CONCLUSIONS: Compressive myelopathy in severe angular congenital kyphosis is usually occurred high incidence rate at apex of upper thoracic spine (T1-T4). The duration from onset of paraplegia until surgery and the severity of paraplegia before surgery are two key factors for neurological prognosis after surgery. PMID- 26050108 TI - Gender differences in patients scheduled for lumbar disc herniation surgery: a National Register Study including 15,631 operations. AB - PURPOSE: Previous studies have shown gender differences in preoperative status and outcome of spine surgery. This study explores whether gender differences in preoperative demographics exist in patients scheduled for lumbar disc herniation (LDH) surgery. METHODS: This study includes the preoperative data of the 15,631 patients operated for LDH between years 2000 and 2010, registered in the national Swedish spine register (SweSpine). We analysed preoperative gender differences in age, smoking habits, walking distance, consumption of analgesics, back and leg pain (Visual Analogue Scale; VAS), quality of life (EuroQol; EQ 5D and Short Form 36 Questionnaire; SF-36) and disability (Oswestry Disability Index; ODI). RESULTS: 44 % of the patients were women (mean age 45 +/- 13) and 56 % men (mean age 44 +/- 13). More women than men were smokers (26 versus 21 %, p < 0.001). Women also reported inferior walking ability (less than 100 metre walking ability 37 vs 30 %; p < 0.001), consumed more analgesics (92 versus 84 %; p < 0.001), reported higher level of pain (mean difference VAS leg 6 (95 % CI 5-7)), had inferior health-related quality of life (mean difference EQ 5D 0.07 (95 % CI 0.05 0.08)) and had higher disability (mean difference ODI 6 (95 % CI 5-6)). CONCLUSIONS: Women scheduled for LDH surgery report inferior clinical status than men scheduled for the same operation. We have in the literature found no evidence based data that support such a difference, and the reason for the discrepancy is unclear. PMID- 26050109 TI - RNA-seq-based transcriptome profiling reveals differential gene expression in the lungs of Sprague-Dawley rats during early-phase acute hypobaric hypoxia. AB - Individuals subjected to hypobaric hypoxia at high altitudes may exhibit differential physiological responses in terms of susceptibility and tolerance to the development of hypoxia-related disorders. We studied early-phase gene expression in the lungs of Sprague-Dawley rats exhibiting such differential physiological responses after exposure to acute hypobaric hypoxia for 1 h at a simulated altitude of 9144 m. RNA-seq transcriptome profiling of lung tissues revealed differential gene expression in tolerant and susceptible groups, subsequently validated by qRT-PCR for ten selected differentially expressed genes. The gene expression pattern indicated hypometabolism and negative regulation of vasoconstriction in all groups except susceptible rats, coupled with altered MAPK, p53 and JAK-STAT signaling. Upregulation of early-phase response genes including Dusp1 (dual specificity phosphatase), Cdkn1a (cyclin dependent kinase inhibitor 1A), Txnip (thioredoxin-interacting protein), Rgs1 (regulator of G-protein signaling 1) and Rgs2 (regulator of G-protein signaling 2) in susceptible rats indicated a progression toward growth arrest and apoptosis. Enhanced expression of cell adhesion molecules, wound healing and repair bioprocesses was observed in tolerant males. Upregulated Kcnj15 (potassium inwardly rectifying channel subfamily j membrane 15) and Vsig4 (V-set and Ig domain containing 4) variants in tolerant females suggested adaptation to hypoxia possibly by fluid reabsorption to avoid edematous conditions and suppression of T cell proliferation to avoid acute lung inflammation. Our study might help in understanding the molecular-physiological mechanisms associated with progressive damage in the lung tissues of susceptible and tissue-protective measures in tolerant rats during acute hypobaric hypoxia. PMID- 26050110 TI - Effect of Ethanol Accumulation on Porcine Interferon-alpha Production by Pichia pastoris and Activities of Key Enzymes in Carbon Metabolism. AB - In production of porcine interferon alpha (pIFN-alpha) by Pichia pastoris, improper glycerol feeding strategy leads to ethanol accumulation in the last stage of growth phase. In the present study, taking two runs with low ethanol accumulation under 2 g/L as control group, effects of long-term (>4 h) and instantaneous high ethanol concentration (>10 g/L) on pIFN-alpha production, and activities of key enzymes in carbon metabolism were discussed. As a result, compared with control group, pIFN-alpha expression level was decreased about 4~12 folds under long-term high ethanol concentration, from the level above 3 g/L to the level under 1 g/L; pIFN-alpha expression level was decreased about 8 folds under instantaneous high ethanol concentration, reaching to the low level of 0.42 g/L. The low production of pIFN-alpha was caused by the severe inhibitory effect of ethanol on these enzymes. PMID- 26050111 TI - Association of Cigarette Smoking and Smoking Cessation with Biochemical Recurrence of Prostate Cancer in Patients Treated with Radical Prostatectomy. AB - BACKGROUND: Cigarette smoking seems to be associated with prostate cancer (PCa) incidence and mortality. OBJECTIVE: To elucidate the association between pretreatment smoking status, cumulative smoking exposure, and time since smoking cessation and the risk of biochemical recurrence (BCR) of PCa in patients treated with radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 6538 patients with pathologically node-negative PCa treated with RP between 2000 and 2011. Clinicopathologic and smoking variables, including smoking status, number of cigarettes per day (CPD), duration in years, and time since smoking cessation were collected. INTERVENTION: RP without neoadjuvant therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Univariable and multivariable Cox regression analyses assessed the association between smoking and risk of PCa BCR. RESULTS AND LIMITATIONS: Of 6538 patients, 2238 (34%), 2086 (32%), and 2214 (34%) were never, former, and current smokers, respectively. Median follow-up for patients not experiencing BCR was 28 mo (interquartile range 14-42). RP Gleason score (p=0.3), extracapsular extension (p=0.2), seminal vesicle invasion (p=0.8), and positive surgical margins (p=0.9) were comparable among the three groups. In multivariable Cox regression analysis, former smokers (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.30-2.04; p<0.001) and current smokers (HR 1.80, 95% CI 1.45-2.24; p<0.001) had a higher risk of PCa BCR compared with non smokers. Smoking cessation for >=10 yr mitigated the risk of BCR in multivariable analyses (HR 0.96, 95% CI 0.68-1.37; p=0.84). In multivariable analysis, no significant association between cumulative smoking exposure and risk of BCR could be detected. Limitations of the study include the retrospective design and potential recall bias regarding smoking history. CONCLUSION: Smoking seems to be associated with a higher risk of PCa BCR after RP. The effects of smoking appear to be mitigated by >=10 yr of cessation. Smokers should be counseled regarding the detrimental effects of smoking on PCa prognosis. PATIENT SUMMARY: We investigated the effect of smoking on the risk of prostate cancer recurrence in patients with treated with surgery. We found that former smokers and current smokers were at higher risk of cancer recurrence compared to patients who never smoked; the detrimental effect of smoking was mitigated after 10 yr or more of smoking cessation. We conclude that smokers should be counseled regarding the detrimental effects on prostate cancer outcomes. PMID- 26050113 TI - Postprostatectomy Radiotherapy: Whether and How Long to Give Concurrent Androgen Deprivation Therapy. PMID- 26050114 TI - Bones and stones, edition 2015. PMID- 26050116 TI - Mineral metabolism in heart disease. AB - PURPOSE OF REVIEW: Strong experimental and clinical evidence points towards a substantial contribution of mineral metabolism disorders to the initiation and progression of cardiovascular disease. Vice versa, recent work suggests that cardiovascular disease may also cause mineral metabolism alterations. RECENT FINDINGS: Experimental studies suggest that hyperphosphatemia, elevated plasma levels of phosphaturic hormones--parathyroid hormone and fibroblast growth factor 23 (FGF-23)--and hypovitaminosis D exert detrimental effects on vascular tissue and on the myocardium. Accordingly, in longitudinal clinical cohort studies, individuals with high plasma levels of phosphate, parathyroid hormone and FGF-23, and with low vitamin D levels, face worst cardiovascular prognosis.Notably, recent evidence suggests that cardiovascular disease may not only follow but also induce mineral metabolism disorders: severe derangements in mineral metabolism were observed in patients with acute heart failure, who face a tremendous increase in plasma FGF-23. Unfortunately, few prospective studies have been completed hitherto that specifically target components of the mineral metabolism for cardiovascular disease prevention or treatment. SUMMARY: A bidirectional interaction exists between mineral metabolism disorders and cardiovascular disease. However, clinical evidence for a cardiovascular benefit of therapeutic interventions into mineral metabolism is outstanding. PMID- 26050115 TI - Pathophysiology of the chronic kidney disease-mineral bone disorder. AB - PURPOSE OF REVIEW: The causes of excess cardiovascular mortality associated with chronic kidney disease (CKD) have been attributed in part to the CKD-mineral bone disorder syndrome (CKD-MBD), wherein, novel cardiovascular risk factors have been identified. The causes of the CKD-MBD are not well known and they will be discussed in this review RECENT FINDINGS: The discovery of WNT (portmanteau of wingless and int) inhibitors, especially Dickkopf 1, produced during renal repair and participating in the pathogenesis of the vascular and skeletal components of the CKD-MBD implied that additional pathogenic factors are critical, leading to the finding that activin A is a second renal repair factor circulating in increased levels during CKD. Activin A derives from peritubular myofibroblasts of diseased kidneys, where it stimulates fibrosis, and decreases tubular klotho expression. The type 2 activin A receptor, ActRIIA, is decreased by CKD in atherosclerotic aortas, specifically in vascular smooth muscle cells (VSMC). Inhibition of activin signaling by a ligand trap inhibited CKD induced VSMC dedifferentiation, osteogenic transition and atherosclerotic calcification. Inhibition of activin signaling in the kidney decreased renal fibrosis and proteinuria. SUMMARY: These studies demonstrate that circulating renal repair factors are causal for the CKD-MBD and CKD associated cardiovascular disease, and identify ActRIIA signaling as a therapeutic target in CKD that links progression of renal disease and vascular disease. PMID- 26050117 TI - Fractures in chronic kidney disease: pursuing the best screening and management. AB - PURPOSE OF REVIEW: Osteoporotic fractures are common and cause increased sickness and death. Men and women with chronic kidney disease (CKD) are at particularly high risk of osteoporotic fractures. Currently, however, there are no guidelines concerning noninvasive methods to assess fracture risk in CKD. Further, approved treatments to prevent fractures in otherwise healthy men and women are only recommended for use with caution in those with CKD. This review focuses on the recent data that support the use of noninvasive methods to assess fracture risk in CKD and highlights new therapies that could be used in fracture prevention in CKD. RECENT FINDINGS: Data from prospective studies demonstrate that low bone mineral density predicts fracture in CKD patients. Post-hoc analyses demonstrate that agents approved for the treatment of postmenopausal osteoporosis (bisphosphonates, denosumab and teriparatide) when given to those with CKD are well tolerated and potentially efficacious with respect to fracture risk reduction. SUMMARY: To date, patients, and nephrologists taking care of them, have largely ignored fracture risk assessment and treatment in CKD. This should change given recent data. Further studies are needed, specifically bone histomorphometric studies, which will increase our understanding of CKD-mineral bone disease (MBD) pathophysiology, and randomized clinical trials of therapy in patients with CKD. PMID- 26050118 TI - The potential use of antisclerostin therapy in chronic kidney disease-mineral and bone disorder. AB - PURPOSE OF REVIEW: Sclerostin is a regulator of the osteoanabolic canonical Wnt signaling pathway, and thus helps to govern rates of bone formation. The Wnt pathway is also recognized as playing an important role in the pathophysiology of the chronic kidney disease-mineral and bone disorder (CKD-MBD). It also may serve as an interface between bone and the vascular system. Pharmacological inhibition of sclerostin has shown promise as an osteoanabolic approach to the treatment of osteoporosis. Inhibition of sclerostin is a potentially useful but unproven strategy in the management of CKD-MBD. RECENT FINDINGS: Clinical trials with humanized monoclonal sclerostin antibodies (Scl-Ab) have shown a rapid initial increase in bone formation and a marked increase in bone mineral density. Although clinical data, to this point, in CKD are not available, animal models of low bone turnover CKD show that Scl-Ab improves trabecular bone volume and mineralization without affecting biochemical indices. SUMMARY: Targeted clinical trials are needed to evaluate the potential effectiveness of Scl-Ab in CKD. Based upon the available data, there is potential not only for this new therapeutic class to improve skeletal health but perhaps also to have substantial cardiovascular benefits in CKD. PMID- 26050119 TI - Novel iron-based phosphate binders in patients with chronic kidney disease. AB - PURPOSE OF REVIEW: Management of hyperphosphatemia remains an integral component in the care of patients with chronic kidney disease on dialysis. In addition to dietary restriction and dialysis, oral phosphate binders remain a key strategy in the control of serum phosphorus levels in this population. We review two new oral phosphate binders that are currently marketed in the United States. RECENT FINDINGS: Sucroferric oxyhydroxide was approved by the U.S. Food and Drug Administration (FDA) in November 2013. A recent international, multicenter study found the drug to be efficacious and noninferior to sevelamer carbonate in magnitude of serum phosphate control. This was achieved with a significantly reduced daily pill burden for sucroferric oxyhydroxide. A second novel agent, ferric citrate was approved by the FDA in September, 2014. The drug was found to have similar phosphate control efficacy to active comparators and was superior to placebo. In addition, the drug delivers a significant amount of iron, resulting in improved erythropoietic parameters. Both drugs had diarrhea as a fairly frequent side-effect. SUMMARY: These new phosphate binders offer alternatives to currently available agents. Both have interesting properties that may make them particularly useful in clinical practice. PMID- 26050121 TI - Endoplasmic reticulum stress in kidney function and disease. AB - PURPOSE OF REVIEW: Recently, a number of papers have reported that endoplasmic reticulum (ER) stress is involved in the onset of various kidney diseases, but the pathological mechanisms responsible have not been clarified. In this review, we summarize recent findings on this issue and try to clarify the pathology of ER stress-induced kidney diseases. RECENT FINDINGS: ER stress is evoked in various kidney diseases, including diabetic nephropathy, renal fibrosis, inflammation or osmolar contrast-induced renal injury, ischemia-reperfusion, genetic mutations of renal proteins, proteinuria and cyclosporine A treatment. In some cases, chemical chaperones, such as 4-phenylbutyrate and taurodeoxycholic acid, relieve the symptoms, indicating that ER stress-induced apoptosis of renal cells is one of the major causes of certain kidney diseases. Actually, the ER stress response provides protection against some kidney diseases, although the PERK-ATF4-CHOP pathway of the ER stress response is proapoptotic in some kidney diseases. The disposal of unfolded proteins by autophagy is also protective for some ER stress induced kidney diseases. SUMMARY: Because ER stress is a major cause of some kidney diseases, the ER stress response and autophagy, which deal with unfolded proteins that accumulate in the ER, are promising therapeutic targets in acute and chronic kidney diseases. PMID- 26050120 TI - Modeling hypercalciuria in the genetic hypercalciuric stone-forming rat. AB - PURPOSE OF REVIEW: In this review, we discuss how the genetic hypercalciuric stone-forming (GHS) rats, which closely model idiopathic hypercalciuria and stone formation in humans, provide insights into the pathophysiology and consequences of clinical hypercalciuria. RECENT FINDINGS: Hypercalciuria in the GHS rats is due to a systemic dysregulation of calcium transport, as manifest by increased intestinal calcium absorption, increased bone resorption and decreased renal tubule calcium reabsorption. Increased levels of vitamin D receptor in intestine, bone and kidney appear to mediate these changes. The excess receptors are biologically active and increase tissue sensitivity to exogenous vitamin D. Bones of GHS rats have decreased bone mineral density (BMD) as compared with Sprague Dawley rats, and exogenous 1,25(OH)2D3 exacerbates the loss of BMD. Thiazide diuretics improve the BMD in GHS rats. SUMMARY: Studying GHS rats allows direct investigation of the effects of alterations in diet and utilization of pharmacologic therapy on hypercalciuria, urine supersaturation, stone formation and bone quality in ways that are not possible in humans. PMID- 26050122 TI - Epigenetics in acute kidney injury. AB - PURPOSE OF REVIEW: Recent advances in epigenetics indicate the involvement of several epigenetic modifications in the pathogenesis of acute kidney injury (AKI). The purpose of this review is to summarize our understanding of recent advances in the epigenetic regulation of AKI and provide mechanistic insight into the role of acetylation, methylation, and microRNA expression in the pathological processes of AKI. RECENT FINDINGS: Enhancement of protein acetylation by pharmacological inhibition of histone deacetylases leads to more severe tubular injury and impairment of renal structural and functional recovery. The changes in promoter DNA methylation occur in the kidney with ischemia/reperfusion. microRNA expression is associated with regulation of both renal injury and regeneration after AKI. SUMMARY: Recent studies on epigenetic regulation indicate that acetylation, methylation, and microRNA expression are critically implicated in the pathogenesis of AKI. Strategies targeting epigenetic processes may hold a therapeutic potential for patients with AKI. PMID- 26050124 TI - Ciliopathies and DNA damage: an emerging nexus. AB - PURPOSE OF REVIEW: In the past decade a wealth of publications have established the central role of cilia and centrosomes in the pathogenesis of cystic kidney diseases, associated or not with extrarenal symptoms. This review outlines recent findings that have unexpectedly linked ciliary and centrosomal proteins to DNA damage and repair and have opened new perspectives for the comprehension of the pathogenesis of these diseases. RECENT FINDINGS: Several ciliopathy proteins that contribute to the pathogenesis of cystic kidney diseases and ciliopathy-related phenotypes have been recently reported to participate in the elaborated pathways that control DNA replication and repair, suggesting that malfunction of these biological processes may be a common denominator of some ciliopathy-related diseases. SUMMARY: In this review, the author briefly describes the established connections existing between cilia, centrosome, and cell cycle and provides basic information about DNA damage and repair. The author then examines more closely the single ciliopathy genes that have been associated with DNA repair pathways and their known biological functions. PMID- 26050123 TI - Flow stimulated endocytosis in the proximal tubule. AB - PURPOSE OF REVIEW: The proximal tubule plays a critical role in the reabsorption of ions, solutes and low molecular weight proteins from the glomerular filtrate. Although the proximal tubule has long been known to acutely modulate ion reabsorption in response to changes in flow rates of the glomerular filtrate, it has only recently been discovered that proximal tubule cells can similarly adjust endocytic capacity in response to flow. This review synthesizes our current understanding of mechanosensitive regulation of endocytic capacity in proximal tubule epithelia and highlights areas of opportunity for future investigations. RECENT FINDINGS: Recent studies have reported that the endocytic capacity of proximal tubule cells is dramatically increased upon exposure to flow and the accompanying fluid shear stress. Modulation of this pathway is dependent on increases in intracellular calcium initiated by bending of the primary cilium, and also requires purinergic receptor activation that is mediated by release of extracellular ATP. This article summarizes what is currently known about the signaling cascade that transduces changes in flow into alterations in endocytosis. We discuss the implications of this newly described regulatory pathway with respect to our understanding of protein retrieval by the kidney under normal conditions, and in diseases that present with low molecular weight proteinuria. SUMMARY: Primary cilia act as mechanotransducers that modulate apical endocytic capacity in proximal tubule cells in response to changes in fluid shear stress. PMID- 26050125 TI - Metabolomics and renal disease. AB - PURPOSE OF REVIEW: This review summarizes recent metabolomics studies of renal disease, outlining some of the limitations of the literature to date. RECENT FINDINGS: The application of metabolomics in nephrology research has expanded from the initial analyses of uremia to include both cross-sectional and longitudinal studies of earlier stages of kidney disease. Although these studies have nominated several potential markers of incident chronic kidney disease (CKD) and CKD progression, a lack of overlap in metabolite coverage has limited the ability to synthesize results across groups. Furthermore, direct examination of renal metabolite handling has underscored the substantial impact kidney function has on these potential markers (and many other circulating metabolites). In experimental studies, metabolomics has been used to identify a signature of decreased mitochondrial function in diabetic nephropathy and a preference for aerobic glucose metabolism in polycystic kidney disease. In each case, these studies have outlined novel therapeutic opportunities. Finally, as a complement to the longstanding interest in renal metabolite clearance, the microbiome has been increasingly recognized as the source of many plasma metabolites, including some with potential functional relevance to CKD and its complications. SUMMARY: The high-throughput, high-resolution phenotyping enabled by metabolomics technologies has begun to provide insight on renal disease in clinical, physiologic, and experimental contexts. PMID- 26050126 TI - Diagnosing kidney disease in the genetic era. AB - PURPOSE OF REVIEW: Recent technological improvements have increased the use of genetic testing in the clinic. This review serves to summarize the many practical benefits of genetic testing, discusses various methodologies that can be used clinically, and exemplifies ways in which genetics is propelling the field forward in nephrology. RECENT FINDINGS: The advent of next-generation sequencing and microarray technologies has heralded an unprecedented number of discoveries in the field of nephrology, providing many opportunities for incorporating genomic diagnostics into clinical care. The use of genetic testing, particularly in pediatrics, can provide accurate diagnoses in puzzling cases, resolve misclassification of disease, and identify subsets of individuals with treatable conditions. SUMMARY: Genetic testing may have broad benefits for patients and their families. Knowing the precise molecular etiology of disease can help clinicians determine the exact therapeutic course, and counsel patients and their families about prognosis. Genetic discoveries can also improve the classification of kidney disease and identify new targets for therapy. PMID- 26050127 TI - Developing therapeutic 'arrows' with the precision of William Tell: the time has come for targeted therapies in kidney disease. AB - PURPOSE OF REVIEW: A core mission for modern medicine is the development of precision therapeutics. Cancer therapies have been at the leading edge of this effort, while nephrology has lagged on the path to precision medicine. Breaking the stalemate, recent work revealed CD80 (B7-1) as a candidate for targeted therapy in the treatment of resistant nephrotic syndrome. This review aims to summarize the current state of our understanding of podocyte CD80 biology, its therapeutic implications and the challenges that lie ahead in essential future validation studies. RECENT FINDINGS: The CD80 targeting agent abatacept (CTLA4 Ig), approved to treat rheumatoid arthritis, was shown to induce remission of nephrotic range proteinuria in four patients with recurrence of disease posttransplant and one patient with primary, treatment resistant nephrotic syndrome. The concept of 'CD80-positive' proteinuric kidney disease due to podocyte CD80 staining in patient kidney biopsies was introduced as a molecular biomarker to define disease and guide treatment. The mechanism of action of CTLA4 Ig in podocytes was shown to centre on beta1 integrin activation in a T-cell independent fashion. Subsequent work revealed a putative role for podocyte CD80 in diabetic kidney disease. SUMMARY: These studies have direct implications for patient care, and intense interest has focused on validating these findings in upcoming clinical trials. PMID- 26050130 TI - A forgotten cause of acute coronary syndrome: Allergic myocardial infarction. PMID- 26050128 TI - Relationship of and cross-talk between physical and biologic properties of the glomerulus. AB - PURPOSE OF REVIEW: Cells and tissues must respond to physical stresses. Cells exist in an elastic environment determined by their matrix, matrix contacts, cell cell contacts, and cytoskeletal structure. We discuss the determinants of the elastic environment of cells and its potential roles in glomerular disease. RECENT FINDINGS: Control of the mechanical environment is sufficient to induce and maintain the differentiated state of cells including myofibroblasts. New experimental techniques permit precise measurement of the elastic characteristics of normal and diseased tissues and cells, and analysis of cell behavior and cytoskeletal structure in response to mechanical and elastic stimuli. Glomeruli become soft early in the course of several disease models, yet late stages are characterized by increased stiffness and fibrosis with loss of organ function. Work in hepatic fibrosis, arterial disease, and oncology demonstrate that increased collagen crosslinking by lysyl oxidase, an early step in the diseases, can result in a sufficient increase in tissue stiffness to alter cell behavior, leading to disease progression. SUMMARY: The elastic environment of cells and tissues provides essential signals in development, differentiation, and disease. Identifying the mechanisms that determine the mechanical environment of glomerular cells will complement other approaches to reduce pathologic fibrosis and loss of tissue function. PMID- 26050131 TI - Surgical emphysema and pneumomediastinum after coronectomy. AB - We report a case of surgical emphysema and pneumomediastinum after coronectomy of the lower right third molar. Surgical emphysema related to dental extractions is well- reported, but not after coronectomy. This case emphasises the importance of avoiding the use of air turbine drills during oral surgery. PMID- 26050132 TI - Optimum use of platelet-rich fibrin: technical note. PMID- 26050133 TI - Weight change following knee and hip joint arthroplasty-a six-month prospective study of adults with osteoarthritis. AB - BACKGROUND: Inconsistent findings of weight change following total knee (TKA) and hip (THA) arthroplasty may largely be attributable to heterogeneous cohorts and varied definitions of weight loss. This study examined weight change following TKA and THA for osteoarthritis (OA). METHODS: 64 participants with hip or knee OA were recruited from orthopaedic joint arthroplasty waiting lists at a single major Australian public hospital between March and October 2011. The Short Form (SF) 12 survey was used to assess baseline physical and mental functioning. 49 participants completed 6 month follow-up (20 from the THA group and 29 from the TKA group). RESULTS: The majority of subjects lost weight (>0 kg) 6 months following THA (70 %) and TKA (58.6 %). When at least a 5 % reduction in total body weight was used to define clinically significant weight loss, the proportion of people with weight loss was 37.9 % for TKA and 25 % for THA. Greater weight loss occurred 6 months following TKA compared with THA (7.2 % versus 3.7 % of body weight; p = 0.04). Worse pre-operative physical functioning (SF-12) was associated with greater weight loss following TKA (beta = 0.22 kg, 95 % CI 0.02 0.42 kg; p = 0.04). CONCLUSION: Most people lost weight (>0 kg) 6 months following TKA and THA and a considerable proportion of people achieved >=5 % loss of body weight. The magnitude of weight loss was greater following TKA than THA, with worse pre-operative function being a predictor of more weight loss. Further attention to weight management is required to assist a greater number of people to achieve a larger magnitude of weight loss following knee and hip joint arthroplasty. PMID- 26050134 TI - Do measures of reactive balance control predict falls in people with stroke returning to the community? AB - OBJECTIVE: To determine if reactive balance control measures predict falls after discharge from stroke rehabilitation. DESIGN: Prospective cohort study. SETTING: Rehabilitation hospital and community. PARTICIPANTS: Independently ambulatory individuals with stroke who were discharged home after inpatient rehabilitation (n=95). MAIN OUTCOME MEASURES: Balance and gait measures were obtained from a clinical assessment at discharge from inpatient stroke rehabilitation. Measures of reactive balance control were obtained: (1) during quiet standing; (2) when walking; and (3) in response to large postural perturbations. Participants reported falls and activity levels up to 6 months post-discharge. Logistic and Poisson regressions were used to identify measures of reactive balance control that were related to falls post-discharge. RESULTS: Decreased paretic limb contribution to standing balance control [rate ratio 0.8, 95% confidence interval (CI) 0.7 to 1.0; P=0.011], reduced between-limb synchronisation of quiet standing balance control (rate ratio 0.9, 95% CI 0.8 to 0.9; P<0.0001), increased step length variability (rate ratio 1.4, 95% CI 1.2 to 1.7; P=0.0011) and inability to step with the blocked limb (rate ratio 1.2, 95% CI 1.0 to 1.3; P=0.013) were significantly associated with increased fall rates when controlling for age, stroke severity, functional balance and daily walking activity. CONCLUSIONS: Impaired reactive balance control in standing and walking predicted increased risk of falls post-discharge from stroke rehabilitation. Specifically, measures that revealed the capacity of both limbs to respond to instability were related to increased risk of falls. These results suggest that post-stroke rehabilitation strategies for falls prevention should train responses to instability, and focus on remediating dyscontrol in the more-affected limb. PMID- 26050135 TI - Validity and reliability of Kinect skeleton for measuring shoulder joint angles: a feasibility study. AB - OBJECTIVE: To test the reliability and validity of shoulder joint angle measurements from the Microsoft KinectTM for virtual rehabilitation. DESIGN: Test retest reliability and concurrent validity, feasibility study. SETTING: Motion analysis laboratory. PARTICIPANTS: A convenience sample of 10 healthy adults. METHODS: Shoulder joint angle was assessed in four static poses, two trials for each pose, using: (1) the Kinect; (2) a three-dimensional motion analysis system; and (3) a clinical goniometer. All poses were captured with the Kinect from the frontal view. The two poses of shoulder flexion were also captured with the Kinect from the sagittal view. MAIN OUTCOME MEASURES: Absolute and relative test retest reliability of the Kinect for the measurement of shoulder angle was determined in each pose with intraclass correlation coefficients (ICCs), standard error of the measure and minimal detectable change. The 95% limits of agreement (LOA) between the Kinect and the standard methods for measuring shoulder angle were computed to determine concurrent validity. RESULTS: While the Kinect provided to be highly reliable (ICC 0.76-0.98) for measuring shoulder angle from the frontal view, the 95% LOA between the Kinect and the two measurement standards were greater than +/-5 degrees in all poses for both views. CONCLUSIONS: Before the Kinect is used to measure movements for virtual rehabilitation applications, it is imperative to understand its limitations in precision and accuracy for the measurement of specific joint motions. PMID- 26050137 TI - Clinical Impact of Cardiac Magnetic Resonance Imaging Versus Echocardiography Guided Patient Selection for Primary Prevention Implantable Cardioverter Defibrillator Therapy. AB - The main eligibility criterion for primary prevention implantable cardioverter defibrillator (ICD) therapy, that is, left ventricular ejection fraction (LVEF), is based on large clinical trials using primarily 2-dimensional echocardiography (2DE). Presently, cardiac magnetic resonance imaging (MRI) is considered the gold standard for LVEF assessment. It has been demonstrated that cardiac MRI assessment results in lower LVEFs compared with 2DE. Consequently, cardiac MRI LVEF assessment may lead to more patients eligible for ICD implantation with potential clinical consequences. The aim of this study was to evaluate the clinical impact of cardiac MRI-LVEF versus 2DE-LVEF assessment for ICD eligibility. A total of 149 patients with cardiac MRI-LVEF <=35% referred for primary prevention ICD implantation who underwent both 2DE and cardiac MRI-LVEF assessment were retrospectively included. 2DE-LVEF was computed by Simpson's biplane method. Cardiac MRI-LVEF was computed after outlining the endocardial contours in short-axis cine images. Appropriate device therapy (ADT) and all cause mortality were evaluated during 2.9 +/- 1.7 years of follow-up. The present study found that cardiac MRI-LVEF was significantly lower compared with 2DE-LVEF (23 +/- 8% vs 30 +/- 8%, respectively, p <0.001), resulting in 29 (19%) more patients eligible for ICD implantation according to the current guidelines (LVEF <=35%). Patients with 2DE-LVEF >35% but cardiac MRI-LVEF <=35% experienced a lower ADT rate compared with patients having 2DE-LVEF <=35% (2.1% vs 10.4% per year, respectively, p = 0.02). Application of cardiac MRI-LVEF cutoff of 30% resulted in 119 eligible patients experiencing 9.9% per year ADT, comparable with 2DE-LVEF cut-off value of 35%. In conclusion, cardiac MRI-LVEF assessment resulted in more patients eligible for ICD implantation compared with 2DE who showed a relatively low event rate during follow-up. The event rate in patients with cardiac MRI-LVEF <=30% was comparable with patients having a 2DE-LVEF <=35%. This study suggests the need for re-evaluation of cardiac MRI-based LVEF cut-off values for ICD eligibility. PMID- 26050136 TI - Current management of pregnancy-related low back pain: a national cross-sectional survey of U.K. physiotherapists. AB - BACKGROUND: Pregnancy-related low back pain (LBP) is very common. Evidence from a systematic review supports the use of exercise and acupuncture, although little is known about the care received by women with pregnancy-related back pain in the U.K. OBJECTIVE: To describe current acupuncture and standard care management of pregnancy-related LBP by U.K. physiotherapists. DESIGN: Cross-sectional survey of physiotherapists with experience of treating women with pregnancy-related LBP from three professional networks of the Chartered Society of Physiotherapy. METHODS: In total, 1093 physiotherapists were mailed a questionnaire. The questionnaire captured respondents' demographic and practice setting information, and experience of managing women with pregnancy-related back pain, and investigated the reported management of pregnancy-related LBP using a patient case vignette of a specific, 'typical' case. RESULTS: The overall response rate was 58% (629/1093). Four hundred and ninety-nine physiotherapists had experience of treating women with pregnancy-related LBP and were included in the analysis. Most respondents worked wholly or partly in the U.K. National Health Service (78%). Most respondents reported that they treat patients with pregnancy-related LBP in three to four one-to-one treatment sessions over 3 to 6 weeks. The results show that a range of management strategies are employed for pregnancy-related LBP, and multimodal management is common. The most common reported treatment was home exercises (94%), and 24% of physiotherapists reported that they would use acupuncture with the patient described in the vignette. CONCLUSIONS: This study provides the first robust data on the management of pregnancy-related LBP by U.K. physiotherapists. Multimodal management is common, although exercise is the most frequently used treatment for pregnancy-related LBP. Acupuncture is used less often for this patient group. PMID- 26050138 TI - Peri-operative practice in knee arthroscopy: a web-based survey of British Association for Surgery of the Knee (BASK) members. PMID- 26050139 TI - Lower limb kinematics of male and female soccer players during a self-selected cutting maneuver: Effects of prolonged activity. AB - BACKGROUND: Despite the recent emphasis on injury prevention, anterior cruciate ligament (ACL) injury rates remain high. This study aimed to ascertain the effects of prolonged activity on lower limb kinematics during a self-selected cutting maneuver. METHODS: Angular kinematics were recorded during an agility test performed until the completion time was greater than the mean plus one SD of baseline trials. Cut type was identified and the hip and knee angles at 33 ms post heel strike were determined. A linear mixed effects model assessed the effects of cut type, gender, and activity status on the hip and knee angles. RESULTS: Males performed sidestep cuts more frequently than females. Females increased the incidence of sidestep cuts after prolonged activity. At the hip, a gender-cut type interaction existed for the transverse (p=0.001) and sagittal (p=0.11) planes. Females showed more internal rotation during sidestep and more external rotation and less flexion during crossover cuts. For the frontal plane, a gender-activity status interaction (p = 0.032) was due to no change within females but greater hip adduction during prolonged activity within males. With prolonged activity, both genders displayed less hip (p=0.29) and knee (p=0.009) flexion and more knee (p=0.001) adduction. Females displayed less hip and knee flexion than men (p=0.001). CONCLUSIONS: Sidestep may be more risky than crossover cuts. Both genders place themselves in at-risk postures with prolonged activity due to less hip and knee flexion. PMID- 26050141 TI - Factors resulting in deferral of diagnostic oral food challenges. PMID- 26050142 TI - Consent to Donate Surgical Biospecimens for Research: Perceptions of People With Colorectal Cancer. AB - BACKGROUND: Biospecimens for cancer research are commonly sought from people who undergo surgery for a new diagnosis of cancer, and the demand for these biospecimens is increasing. OBJECTIVE: The objective of this study was to explore the perceptions of people with colorectal cancer regarding the impact of an opt in model of consent for biospecimen donation. METHODS: The qualitative method of Grounded Theory was used, and data were gathered through digitally recorded semistructured interviews with 18 participants. Data were analyzed using the constant comparative method to the descriptive level. RESULTS: Four major categories were identified describing the response to the consent process used for donating tissue for research purposes. These were as follows: consent is "no big deal" compared with the diagnosis of cancer; helping others; trusting the surgeon; and information related to donation of biospecimens. CONCLUSIONS: Results from this study indicate that the achievement of ideal informed and voluntary consent is difficult when patients are confronted with the trauma of newly diagnosed illness. Innovative approaches are implicated to obtain consent while protecting the autonomy and dignity of patients. IMPLICATIONS FOR PRACTICE: The results from this study can contribute to further development of processes for the donation of biospecimens for research purposes that respect the needs and views of patients. PMID- 26050140 TI - Targeting alpha-synuclein for treatment of Parkinson's disease: mechanistic and therapeutic considerations. AB - Progressive neuronal cell loss in a small subset of brainstem and mesencephalic nuclei and widespread aggregation of the alpha-synuclein protein in the form of Lewy bodies and Lewy neurites are neuropathological hallmarks of Parkinson's disease. Most cases occur sporadically, but mutations in several genes, including SNCA, which encodes alpha-synuclein, are associated with disease development. The discovery and development of therapeutic strategies to block cell death in Parkinson's disease has been limited by a lack of understanding of the mechanisms driving neurodegeneration. However, increasing evidence of multiple pivotal roles of alpha-synuclein in the pathogenesis of Parkinson's disease has led researchers to consider the therapeutic potential of several strategies aimed at reduction of alpha-synuclein toxicity. We critically assess the potential of experimental therapies targeting alpha-synuclein, and discuss steps that need to be taken for target validation and drug development. PMID- 26050143 TI - Effects of Acupuncture on Menopause-Related Symptoms in Breast Cancer Survivors: A Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND: Evidence regarding the effects of acupuncture on hot flashes in breast cancer survivors is conflicting. Little is known about the intermediate term effects of acupuncture on hot flashes and other menopause-related symptoms in breast cancer survivors. OBJECTIVE: The objective of this study was to evaluate the short-term and intermediate-term effects of acupuncture on menopause related symptoms and particularly on hot flashes in breast cancer survivors. METHODS: Electronic databases including EMBASE, PubMed, PsycINFO, Web of Science, CINAHL, Wanfang Data Chinese Database, and China Knowledge Resource Integrated Database from inception until June 15, 2014, were searched. Randomized controlled trials in which acupuncture was compared with sham controls or other interventions according to the reduction of hot flashes or menopause-related symptoms in breast cancer survivors were included. RESULTS: We analyzed 7 studies involving 342 participants. Acupuncture significantly reduced the frequency of hot flashes and severity of menopause-related symptoms (g = -0.23 and -0.36, respectively) immediately after the completion of treatment. In comparison with sham acupuncture, effects of true acupuncture on the frequency and severity of hot flashes were not significantly different. At 1 to 3 months' follow-up, the severity of menopause-related symptoms remained significantly reduced (g = 0.56). CONCLUSION: Acupuncture yielded small-size effects on reducing hot-flash frequency and the severity of menopause-related symptoms. IMPLICATIONS FOR PRACTICE: Acupuncture may be used as a complementary therapy for breast cancer survivors experiencing hot flashes and other menopause-related symptoms; however, whether acupuncture exerts specific treatment effects other than needling or placebo effects needs to be further evaluated. PMID- 26050144 TI - Development of a Needs Scale for Nurses Receiving In-Service Palliative Care Education. AB - BACKGROUND: Nurses play pivotal roles on palliative care teams and are able to spend more time with patients and their families than are other healthcare professionals. As a consequence, assessing the needs for palliative care education in connection with in-service classes for nurses is clearly extremely important and can help in the planning of appropriate palliative care classes to enhance the quality of care. OBJECTIVES: The goals of this study were to investigate the content needs of nurses with regard to a palliative care in service education program and to perform exploratory factor analysis on those needs. METHODS: This study used a cross-sectional questionnaire survey. A total of 614 questionnaires were distributed, and 600 valid questionnaires were returned (97.72%). Data analysis was performed by means of descriptive statistics, reliability analysis, factor analysis, and Pearson correlation. RESULTS: The 6 factors discovered by exploratory factor analysis were handling of pain and symptoms, ethical issues concerning terminal patients, hospice preparation and care, the concept of palliative care, communication and counseling, and cultural and spiritual factors, which together explained 77.22% of the variance. CONCLUSION: The results of this study shed light on the program needs for in-service education about palliative care and the 6 factors most associated with those needs. IMPLICATIONS FOR PRACTICE: In order to realize the whole-person concept of care, future efforts should target the planning of palliative care in-service education programs, strengthening of nurse training, coordination of administrative resources, and interteam cooperation. PMID- 26050145 TI - Systemic immune changes associated with adjuvant interferon-alpha2b-therapy in stage III melanoma patients: failure at the effector phase? AB - Interferon-alpha (IFN-alpha) is the only approved adjuvant treatment for high risk melanoma patients in Europe, but the impact on overall survival is low. Although it is believed that IFN-alpha exerts its effects through immunomodulation, data on its impact on circulating immune cells are scarce. Flow cytometry was performed on peripheral blood mononuclear cells of eight IFN alpha2b-treated stage III melanoma patients and 26 untreated stage III melanoma patients as controls to enumerate myeloid and plasmacytoid dendritic cells (mDC and pDC), monocytic and polymorphonuclear myeloid-derived suppressor cells (mMDSC and pmnMDSC) and cytotoxic and regulatory T-cells (Tregs). The expression of several immunosuppressive markers [indoleamine 2,3-dioxygenase (IDO), programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA4)] was explored. IDO activity in the blood was confirmed by ultra-performance liquid chromatography. Compared with controls, IFN-alpha2b treatment was associated with increased IDO expression by pDCs (P=0.021) and an increased kynurenine/tryptophan ratio in the serum (P=0.004), compatible with IDO enzyme activity. Furthermore, IFN-alpha2b-treated patients had a decreased mDC/DC ratio (P=0.002), decreased CD3+ lymphocytes (P=0.034) and increased circulating Treg (P<0.001) and PD L1+cytotoxic T-cell (P=0.001) frequencies. IDO expression is upregulated in circulating pDCs of high-risk melanoma patients treated with adjuvant IFN alpha2b. This is associated with tryptophan consumption in the patients' serum and higher Treg and PD-L1+cytotoxic T-cell frequencies. We hypothesize that in IFN-alpha2b-treated patients, IDO activity acts as a negative feedback mechanism and might limit the clinical efficacy of IFN-alpha2b therapy. The underlying mechanism should be explored as this could lead to more efficient immunotherapies. PMID- 26050146 TI - A phase 2 study of tremelimumab in patients with advanced uveal melanoma. AB - Similar to cutaneous melanoma, several strategies of immune escape have been documented in uveal melanomas (UMs). We hypothesized that these cancers could respond to cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibition with tremelimumab by potentiating T-cell activation. This was an open-label, multicentre phase 2 study in patients with advanced UM who had not received prior immunotherapy. Patient received tremelimumab at 15 mg/kg administered every 90 days for up to four cycles. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were safety, durable response rate, objective response rate, duration of objective response, duration of complete response, and median overall survival (OS). Eleven patients, all with M1c disease, were enrolled with no responses observed. The median follow-up was 11 months (range 2 36 months). The median PFS was 2.9 months (95% confidence interval 2.8-3.0) and the 6-month PFS rate was 9.1%. The median OS was 12.8 months (95% confidence interval 3.8-19.7). Toxicities were consistent with CTLA-4 blockade and were manageable. Although the median OS of 12.8 months and the manageable toxicity profile of tremelimumab observed in this study seem promising, the modest 6-month PFS and the lack of responses observed resulted in the study being stopped due to futility at the first interim stage. To date, no systemic treatment has demonstrated a survival benefit in patients with advanced UM. The standard treatment for patients with advanced UM should be a clinical trial. PMID- 26050147 TI - Time trends in incidence of cutaneous melanoma by detailed anatomical location and patterns of ultraviolet radiation exposure: a retrospective population-based study. AB - Given the wide public health implications of the melanoma epidemic, ultraviolet radiation (UVR) exposure patterns contributing to cutaneous melanoma development should be clearly identified. To describe time trends of anatomic sites of melanoma using a UVR exposure model based on clothing and sun habits, we reviewed the medical records of all patients diagnosed with primary invasive melanoma or melanoma in situ (MIS) during the years 1977-78, 1983-84, 1989-90, 1995-96, and 2000-01 (n=3058) in one healthcare region of Sweden. Age-standardized incidence rates and relative risks (RRs) of melanoma by calendar period were estimated for intermittent and chronic UVR exposure sites. From 1977-78 to 2000-01, the incidence rates of all melanomas at intermittent UVR exposure sites increased both among men (7.8-16.5/10 person-years) and among women (7.6-14.6/10 person years), with a sex-adjusted and age-adjusted RR of 2.1 [95% confidence interval (CI) 1.8-2.4, Ptrend<0.0001]. This increase was evident for both invasive melanoma and MIS. Melanoma at chronic sites increased among men from 1.7 to 2.3/10 person-years, and among women from 1.4 to 1.8/10 person-years, with a corresponding adjusted RR of 1.4 (95% CI 1.0-1.9, Ptrend=0.01), driven primarily by MIS. For melanomas at intermittent UVR exposure sites, the male sex was positively associated with central (core) areas (chest, back, neck, shoulders, thighs; RR 1.7, 95% CI 1.5-1.9), but negatively associated with peripheral areas (lateral arms, lower legs, dorsum of feet; RR 0.3, 95% CI 0.3-0.4), compared with the female sex. Sex-specific intermittent UVR exposure patterns drove the observed increase in melanoma incidence, whereas chronic UVR exposure contributed less. PMID- 26050148 TI - The Relationship Between the Number of Types of Legal Gambling and the Rates of Gambling Behaviors and Problems Across U.S. States. AB - In this article, we examine the relationship between the total number of types of gambling that are legal in a state and the gambling involvement of state residents. Of particular interest is whether more types of legal gambling are associated with higher rates of problem gambling. Telephone surveys of U.S. adults were conducted in 1999-2000 and 2011-2013. The same questions were used and the data sets were combined for most of the analyses. Gambling exposure was defined as the sum of the number of years that all types were legal. Results tabulated by state showed progressively higher rates of problem gambling, frequent gambling and any past year gambling as the number of legal types of gambling increased. Holding constant the number of legal types, problem gambling rates increased as exposure increased. States with longer exposure to legal lotteries or casinos tended to have higher rates of problem gambling. An analysis was also conducted in which the data sets from 1999 to 2000 and from 2011 to 2013 were compared. Among the states, there was a striking positive relationship between changes in the number of legal types of gambling between the two studies and changes in rates of frequent gambling between the two studies. For states that had fewer types of legal gambling in 2011 than in 1999, the rates of frequent gambling went down. For states that increased their types of legal gambling, rates of frequent gambling typically, but not always, went up. Possible explanations for these results were discussed. PMID- 26050149 TI - Sequential dynamic artificial neural network modeling of a full-scale coking wastewater treatment plant with fluidized bed reactors. AB - This study proposed a sequential modeling approach using an artificial neural network (ANN) to develop four independent models which were able to predict biotreatment effluent variables of a full-scale coking wastewater treatment plant (CWWTP). Suitable structure and transfer function of ANN were optimized by genetic algorithm. The sequential approach, which included two parts, an influent estimator and an effluent predictor, was used to develop dynamic models. The former parts of models estimated the variations of influent COD, volatile phenol, cyanide, and NH4 (+)-N. The later parts of models predicted effluent COD, volatile phenol, cyanide, and NH4 (+)-N using the estimated values and other parameters. The performance of these models was evaluated by statistical parameters (such as coefficient of determination (R (2) ), etc.). Obtained results indicated that the estimator developed dynamic models for influent COD (R (2) = 0.871), volatile phenol (R (2) = 0.904), cyanide (R (2) = 0.846), and NH4 (+)-N (R (2) = 0.777), while the predictor developed feasible models for effluent COD (R (2) = 0.852) and cyanide (R (2) = 0.844), with slightly worse models for effluent volatile phenol (R (2) = 0.752) and NH4 (+)-N (R (2) = 0.764). Thus, the proposed modeling processes can be used as a tool for the prediction of CWWTP performance. PMID- 26050150 TI - Chemical behavior of Cu, Zn, Cd, and Pb in a eutrophic reservoir: speciation and complexation capacity. AB - This research aimed at evaluating cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) speciation in water samples as well as determining water quality parameters (alkalinity, chlorophyll a, chloride, conductivity, dissolved organic carbon, dissolved oxygen, inorganic carbon, nitrate, pH, total suspended solids, and water temperature) in a eutrophic reservoir. This was performed through calculation of free metal ions using the chemical equilibrium software MINEQL+ 4.61, determination of labile, dissolved, and total metal concentrations via differential pulse anodic stripping voltammetry, and determination of complexed metal by the difference between the total concentration of dissolved and labile metal. Additionally, ligand complexation capacities (CC), such as the strength of the association of metals-ligands (logK'ML) and ligand concentrations (C L) were calculated via Ruzic's linearization method. Water samples were taken in winter and summer, and the results showed that for total and dissolved metals, Zn > Cu > Pb > Cd concentration. In general, higher concentrations of Cu and Zn remained complexed with the dissolved fraction, while Pb was mostly complexed with particulate materials. Chemical equilibrium modeling (MINEQL+) showed that Zn(2+) and Cd(2+) dominated the labile species, while Cu and Pb were complexed with carbonates. Zinc was a unique metal for which a direct relation between dissolved species with labile and complexed forms was obtained. The CC for ligands indicated a higher C L for Cu, followed by Pb, Zn, and Cd in decreasing amounts. Nevertheless, the strength of the association of all metals and their respective ligands was similar. Factor analysis with principal component analysis as the extraction procedure confirmed seasonal effects on water quality parameters and metal speciation. Total, dissolved, and complexed Cu and total, dissolved, complexed, and labile Pb species were all higher in winter, whereas in summer, Zn was mostly present in the complexed form. A high degree of deterioration of the reservoir was confirmed by the results of this study. PMID- 26050152 TI - A simple model to predict the biodiesel blend density as simultaneous function of blend percent and temperature. AB - A simple method to estimate the density of biodiesel blend as simultaneous function of temperature and volume percent of biodiesel is proposed. Employing the Kay's mixing rule, we developed a model and investigated theoretically the density of different vegetable oil biodiesel blends as a simultaneous function of temperature and volume percent of biodiesel. Key advantage of the proposed model is that it requires only a single set of density values of components of biodiesel blends at any two different temperatures. We notice that the density of blend linearly decreases with increase in temperature and increases with increase in volume percent of the biodiesel. The lower values of standard estimate of error (SEE = 0.0003-0.0022) and absolute average deviation (AAD = 0.03-0.15 %) obtained using the proposed model indicate the predictive capability. The predicted values found good agreement with the recent available experimental data. PMID- 26050151 TI - Carcinogenic activity of polycyclic aromatic hydrocarbons bounded on particle fraction. AB - Polycyclic aromatic hydrocarbons (PAHs) originate from a variety of natural and industrial processes. In this paper, concentrations of nine PAHs in PM10 particle fraction were measured concurrently at four different sites (rural, urban residential, urban traffic, and residential-industrial) in continental Croatia. Measurements at all of the four sites showed much higher average concentrations for all of the PAHs in the winter period. The highest winter average values were measured at the industrial site and the lowest at the rural and the urban residential site. In the summer, the highest average values were also measured in the industrial area, except for benzo(ghi)perylene and indeno(1,2,3-cd)pyrene, which showed the highest average values in the rural area. Factor analysis has been applied to PAH concentrations to identify their potential sources. Extracted factors have been interpreted on basis of previous studies and weather conditions. The diagnostic ratios calculated in this study indicated mixed sources at all of the sites. The contribution of gasoline and diesel from traffic was significant at all of the sites except for the urban industrial. In the winter, potential PAH sources also arose from wood combustion. The industrial site differed from the other sites with the highest influence of diesel sources and refinery during the summer months. The contribution of BaP in total carcinogenic activity exceeded 50 % in both seasons at all of the measured sites, which suggests that BaP could be suitable as a marker of the carcinogenic potential of a PAH mixture. PMID- 26050153 TI - Regional Heterogeneity in the Configuration of the Intracortical Canals of the Femoral Shaft. AB - Three-dimensional (3D) characterization of cortical porosity, most of which is under 100 um in diameter, is usually confined to measurements made in 3-4 mm diameter cylinders of bone. We used micro-computed tomography (micro-CT) scanning of entire transaxial cross sections of human proximal femoral shafts (30-35 mm diameter) to quantify regional variation in porosity within the same scan. Complete, up to 10-mm-thick, transaxial slices of femoral upper shafts from 8 female cadavers were studied (n = 3 aged 29-37 years, n = 5 aged 72-90 years). Scanning was performed using high-resolution micro-CT (8.65 um/voxel). Micro-CT volumes (10 * 10 * 5 mm) were selected via software in the anterior, medial and lateral regions. Images were segmented with voids appearing as 3D-interconnected canals. The percent void-to-tissue volume (Vo.V/TV) and the corresponding void surface area/TV were 86-309% higher in older than younger subjects in anterior (p = 0.034), medial (p = 0.077), and lateral aspects (p = 0.034). Although not significant, void separation was reciprocally lower by 19-39%, and void diameter was 65% larger in older than younger subjects; void number tended to be 24-25% higher medially and laterally but not anteriorly. For all specimens combined, medially there was higher Vo.V/TV and void surface area/TV than anteriorly (+48%, p = 0.018; +33%, p = 0.018) and laterally (+56%, p = 0.062; +36%, p = 0.043). There is regional heterogeneity in the 3D microarchitecture of the intracortical canals of the femoral shaft. The higher void volume in advanced age appears to be due to larger, rather than more, pores. However, creation of new canals from existing canals may contribute, depending on the location. High-resolution micro computed tomography scanning of entire bone segments enables quantification of the 3D microanatomy of the intracortical void network at multiple locations. PMID- 26050154 TI - Effect of geometry and scale for axial and radial flow membrane chromatography Experimental study of bovin serum albumin adsorption. AB - During the last 10 years, membrane chromatography (MC) has been increasingly reported for biomolecule purification at both small and large scales. Although, several axial and radial flow MC devices are commercialized, the effect of the device dimensions on the adsorption performance has not been fully investigated. In this study, axial and radial flow anion ion-exchange MC devices were used for bovine serum albumin (BSA) adsorption. For both axial and radial flow, three devices at different scales were compared, two having similar diameter and two similar bed height. The pressure drop and the flow distribution using acetone as a non-binding solute were measured, as well as BSA breakthrough curves at different flow rates and BSA loading concentrations. For all devices, it was observed that the flow rate had no effect on the breakthrough curve, which confirms the advantage of MC to be used at high flow rates. In addition, the BSA binding capacity increased with increasing BSA concentration, which suggests that it could be preferable to work with concentrated solutions rather than with very dilute solutions, when using buffer at high phosphate concentration. For both axial and radial flow, the bed height had a negative impact on the binding capacity, as the lowest binding capacities per membrane volume were obtained with the devices having the highest bed height. Radial flow MC has potential at large scale applications, as a short bed thickness can be combined with a large inlet surface area. PMID- 26050155 TI - Internalized HIV and Drug Stigmas: Interacting Forces Threatening Health Status and Health Service Utilization Among People with HIV Who Inject Drugs in St. Petersburg, Russia. AB - Marked overlap between the HIV and injection drug use epidemics in St. Petersburg, Russia, puts many people in need of health services at risk for stigmatization based on both characteristics simultaneously. The current study examined the independent and interactive effects of internalized HIV and drug stigmas on health status and health service utilization among 383 people with HIV who inject drugs in St. Petersburg. Participants self-reported internalized HIV stigma, internalized drug stigma, health status (subjective rating and symptom count), health service utilization (HIV care and drug treatment), sociodemographic characteristics, and health/behavioral history. For both forms of internalized stigma, greater stigma was correlated with poorer health and lower likelihood of service utilization. HIV and drug stigmas interacted to predict symptom count, HIV care, and drug treatment such that individuals internalizing high levels of both stigmas were at elevated risk for experiencing poor health and less likely to access health services. PMID- 26050156 TI - Circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. AB - The anti-estrogen tamoxifen is characterized by a large variability in response, partly due to pharmacokinetic differences. We examined circadian variation in tamoxifen pharmacokinetics in mice and breast cancer patients. Pharmacokinetic analysis was performed in mice, dosed at six different times (24-h period). Tissue samples were used for mRNA expression analysis of drug-metabolizing enzymes. In patients, a cross-over study was performed. During three 24-h periods, after tamoxifen dosing at 8 a.m., 1 p.m., and 8 p.m., for at least 4 weeks, blood samples were collected for pharmacokinetic measurements. Differences in tamoxifen pharmacokinetics between administration times were assessed. The mRNA expression of drug-metabolizing enzymes showed circadian variation in mouse tissues. Tamoxifen exposure seemed to be highest after administration at midnight. In humans, marginal differences were observed in pharmacokinetic parameters between morning and evening administration. Tamoxifen C(max )and area under the curve (AUC)0-8 h were 20 % higher (P < 0.001), and tamoxifen t(max) was shorter (2.1 vs. 8.1 h; P = 0.001), indicating variation in absorption. Systemic exposure (AUC0-24 h) to endoxifen was 15 % higher (P < 0.001) following morning administration. The results suggest that dosing time is of marginal influence on tamoxifen pharmacokinetics. Our study was not designed to detect potential changes in clinical outcome or toxicity, based on a difference in the time of administration. Circadian rhythm may be one of the many determinants of the interpatient and intrapatient pharmacokinetic variability of tamoxifen. PMID- 26050157 TI - Doxorubicin-induced cardiac dysfunction in unselected patients with a history of early-stage breast cancer. AB - Cardiomyopathy is a known complication of anthracycline-based adjuvant chemotherapy and is more commonly reported in population-based studies of breast cancer survivors than in clinical trials. This study prospectively evaluated the prevalence of elevated cardiac biomarkers in unselected patients who had been treated with doxorubicin for early-stage breast cancer and the prevalence of reduced LVEF in patients with an elevated biomarker. All participants underwent an examination, symptom inventory, medical record review, and biomarker analysis for BNP, troponin, and plasma and urine NT-proBNP. Patients who had one or more elevated biomarkers were referred for echocardiogram; systolic dysfunction was defined as LVEF less than 55 %. Multivariable logistic regression was used to determine the associations between age, BMI, cumulative dose of doxorubicin, diabetes, hypertension, and left-sided radiation therapy and the risk of reduced LVEF. Among the 269 patients who underwent lab testing (mean age 56 years, mean time since completion of doxorubicin-based chemotherapy 6 years), 192 (72 %) had one or more elevated biomarker. Among the 166 patients who completed an echocardiogram, 11.5 % had a LVEF < 55 %. After adjusting for covariates known to affect cardiac function, multivariable logistic regression revealed plasma NT proBNP to be the only measured cardiac biomarker associated with systolic dysfunction. There is a relationship between NT-proBNP and the frequency of reduced LVEF in women treated with doxorubicin for curative intent; further study of NT-proBNP as a potential biomarker for subclinical cardiac dysfunction after exposure to anthracyclines is warranted. PMID- 26050158 TI - The clinicopathologic spectrum of anal cancer in KwaZulu-Natal Province, South Africa: Analysis of a provincial database. AB - BACKGROUND: The occurrence of the considered rare anal cancer has not been documented in the South African context. PATIENTS AND METHODS: Analysis of data extracted from a prospectively collected KwaZulu-Natal anal cancer database for the period 2000-2014. Data analysed included demographics, clinical picture, pathology, treatment and outcome. The study outcome measures were clinicopathologic spectrum, treatment and outcome. RESULTS: The study population comprised 244 patients of mean age 50.1 (SD 14.0) years. The age at presentation was lowest for Black African patients compared to Whites and Indians (p<0.001) and lower for HIV positive vs HIV negative patients (p<0.001). Histology was squamous carcinoma in 208 patients (margin 152, canal 56), adenocarcinoma in 34 (all anal canal), neuroendocrine tumour (1) and melanoma (1). Mean age for squamous carcinoma was 48.8 (SD 14.1) years compared to 58.7 years (SD +/-11.1) for adenocarcinoma. Metastatic disease occurred in 22 patients (9%). Patients received definitive (139), palliative (53) and no (52) oncological therapy. Thirty patients (12%) underwent resection, seven of whom had positive margins. Seventy-six patients (31%) have been confirmed dead. The 5-year survival rate was 33.4% (95% CI: 23.4-44.6%). There was a highly significantly worse prognosis for adenocarcinoma compared to squamous cell carcinoma (p=0.038). No significant difference was found in survival prospects based on race and tumour location. CONCLUSION: Squamous carcinoma was more common and presented at a young age. Black African patients and HIV positive patients were younger. Adenocarcinoma was associated with poorer prognosis. Race and tumour location had no influence on survival. PMID- 26050159 TI - Effect of soaking, boiling, and steaming on total phenolic contentand antioxidant activities of cool season food legumes. AB - The effects of soaking, boiling and steaming processes on the total phenolic components and antioxidant activity in commonly consumed cool season food legumes (CSFL's), including green pea, yellow pea, chickpea and lentil were investigated. As compared to original unprocessed legumes, all processing steps caused significant (p<0.05) decreases in total phenolic content (TPC), DPPH free radical scavenging activity (DPPH) in all tested CSFL's. All soaking and atmospheric boiling treatments caused significant (p<0.05) decreases in oxygen radical absorbing capacity (ORAC). However, pressure boiling and pressure steaming caused significant (p<0.05) increases in ORAC values. Steaming treatments resulted in a greater retention of TPC, DPPH, and ORAC values in all tested CSFL's as compared to boiling treatments. To obtain cooked legumes with similar palatability and firmness, pressure boiling shortened processing time as compared to atmospheric boiling, resulted in insignificant differences in TPC, DPPH for green and yellow pea. However, TPC and DPPH in cooked lentils differed significantly between atmospheric and pressure boiling. As compared to atmospheric processes, pressure processes significantly increased ORAC values in both boiled and steamed CSFL's. Greater TPC, DPPH and ORAC values were detected in boiling water than that in soaking and steaming water. Boiling also caused more solid loss than steaming. Steam processing exhibited several advantages in retaining the integrity of the legume appearance and texture of the cooked product, shortening process time, and greater retention of antioxidant components and activities. PMID- 26050160 TI - Proton NMR relaxation study of swelling and gelatinisation process in rice starch water samples. AB - Proton transverse magnetization decay curves of rice flour starch-water samples were measured and analysed for the presence of four components in the relaxation curve. T2 values were interpreted on the basis of the diffusive and chemical exchange model that provided evidence for extra granular bulk water and three more water populations whose relaxation rate is governed by diffusive and chemical exchange with starch components. The analysis of relaxation data provided information on dynamics of water molecules as well as on the size and dispersion of diffusive domains. Furthermore, by measuring solid to liquid ratio, transverse and longitudinal relaxation curves of starch-water mixtures at increasing temperatures - from 20 to 77 degrees C - swelling and gelatinisation processes were monitored. PMID- 26050161 TI - Chemical compositions, functional properties, and microstructure of defatted macadamia flours. AB - The objective of this research was to study the chemical compositions, functional properties, and microstructure of partially defatted flours (PDF, 12-15% fat, dry basis (db)) and totally defatted flours (TDF, 1% db fat) from three macadamia cultivars, PY 741, DS 344, and DS 800, grown in Northern Thailand. The defatted flours were high in protein (30.40-36.45% db) and carbohydrate (49.29-57.09% db). For each macadamia cultivar, while emulsion activities and emulsion stabilities of the TDF tended not to be different from those of the PDF (p>0.05), TDF had significantly greater water absorption capacities (WAC), oil absorption capacities and foaming capacities (FC), but had significantly lower foaming stability (FS) than the PDF (p?0.05). The TDF from PY 741 cultivar possessed the highest WAC and FC but the lowest FS. The variation in the functional properties of the defatted flours could mainly arise from the difference in the quantity and characteristics of the proteins in the flours. Structure determination of macadamia flours showed that the proteins bodies and starch granules were embedded in kernel tissues. The starch granules were oval and approximately 10MUm in diameter. PMID- 26050162 TI - The use of water and ice with bactericide to prevent onboard and onshore spoilage of refrigerated megrim (Lepidorhombus whiffiagonis). AB - This study investigates the effectiveness of ozonated water and flake ice (combined Petfrost system) to increase the quality and stability of fresh megrim on fishing boats. The captured fish were washed, placed in plastic boxes, covered with flake ice and refrigerated at 2 degrees C for up to 2-weeks onboard and, thereafter, for 11 days onshore. The experiments employed sterile, filtered and ozonated water at a concentration of 2ppm for washing the fish and making the flake ice. The results are compared with samples from a traditional treatment consisting of water and flake ice of marine origin. Fish were caught in four different hauls, which took 14, 12, 8 and 3 days in being landed. Subsequently, fish were stored for 1, 5, 7 and 11 days at 3 degrees C. The different treatments were evaluated using sensory, microbiological and chemical techniques. Fish treated with ozone always showed the best quality. Megrim treated with ozone was still suitable for consumption after 14 days on board, and megrim stored for 12, 8 and 3 days on board could be stored for a further five days in the ice state once landed with an acceptable quality. In contrast, control fish were not suitable for consumption if stored for longer than three days on board.The results indicate that treatment with water and ice flakes made from sterile and ozonated water maintains the quality of fresh megrim onboard fishing boats and upon arrival onshore. PMID- 26050163 TI - Conformation and location of amorphous and semi-crystalline regions in C-type starch granules revealed by SEM, NMR and XRD. AB - The conformations and locations of amorphous and semi-crystalline regions in C type starch granules from Chinese yam were evaluated by a combination of morphology and spectroscopy studies during acid hydrolysis. Scanning electron micrographs showed that amorphous or less crystalline areas were essentially located in the centre part of C-type starch granules, whereas the semi crystalline and amorphous growth rings were found mainly in the outer part of the granules. (13)C cross-polarization magic angle spinning NMR ((13)C CP/MAS NMR) showed that amorphous regions were hydrolyzed faster than the crystalline ones. In addition, B-type polymorphs were shown to be hydrolyzed more rapidly than A types. Powder X-ray diffraction (XRD) also revealed that the B-polymorph was hydrolyzed more rapidly than the A-type. XRD showed that the amorphous or less crystalline areas were mainly located in the core of starch granules, while the amorphous growth rings are distributed toward the outside of the granules and alternatively arranged with semi-crystalline growth rings. The amorphous or less crystalline areas predominantly consisted of the B-polymorph whereas the outer semi-crystalline and amorphous growth rings were mostly composed of the A polymorph. PMID- 26050164 TI - Comparative study of phytochemicals and antioxidant potential of wild edible mushroom caps and stipes. AB - A comparative study of the organic acids and phenolics composition and of the total alkaloids content of entire wild edible mushrooms (Russula cyanoxantha, Amanita rubescens, Suillus granulatus and Boletus edulis) and correspondent caps and stipes was performed. All species presented oxalic, citric, malic and fumaric acids, with A. rubescens exhibiting the highest total organic acids content. Organic acids were preferably fixed in the cap. Among phenolics, only p hydroxybenzoic acid was found in A. rubescens and S. granulatus, in very low amounts. B. edulis was the species that presented the highest total alkaloid amounts. Except for this species, alkaloids mainly accumulated in the cap. All of the species exhibited a concentration-dependent scavenging ability against DPPH(.). B. edulis revealed the highest antioxidant capacity. The cap seemed to be the part with highest antioxidant potential. Some relationships between chemical composition and antioxidant capacity were considered. PMID- 26050165 TI - Thermal stability and long-chain fatty acid positional distribution on glycerol of argan oil. AB - The primary aim of this study was to determine the oxidative stability of argan oils by using peroxides and conjugated diene hydroperoxides measurements as analytical indicators. Both food and cosmetic argan oils were investigated. Their oxidative stability was also determined by monitoring the relative changes of their fatty acid profiles by (1)H NMR. In addition, valuable information regarding minor components as well as the acyl positional distribution, were obtained for both grades by high field (1)H and (13)C NMR, respectively. Given that the cosmetic and food grades have a similar profile and content of phenolic antioxidants, vitamers, and squalene, it appears that the ratio of fatty acid aliphatic to bisallylic CH2 groups, much higher in argan oils than in other vegetable oils, is responsible for their higher thermal stability. PMID- 26050166 TI - Bioaccessibility of Ca, Mg, Mn and Cu from whole grain tea-biscuits: Impact of proteins, phytic acid and polyphenols. AB - Levels of some essential minerals (Ca, Mg, Cu and Mn) were determined in ten different types of experimentally prepared hard biscuits. In relation to the wheat flour-based reference sample, other investigated samples were enriched with different ratios of integral raw materials of different origin or various dietary fibers in view of improving their functionality and nutritive quality. The goal of the research was to evaluate enriched biscuits as additional sources of calcium, magnesium, copper and manganese in nutrition and to investigate if the modifications of wheat flour based biscuit composition significantly change the amounts of total and bioaccessible minerals in the final product. Since our results indicated significant changes of mineral bioaccessibility among the samples, obtained results were correlated to the content of proteins, phytic acid and polyphenols for the sake of assessing their impact as limiting factors of mineral bioaccessibility in these types of foods. PMID- 26050167 TI - Isolation and properties of AMP deaminase from jumbo squid (Dosidicus gigas) mantle muscle from the Gulf of California, Mexico. AB - Adenosine monophosphate (AMP) deaminase was purified from jumbo squid mantle muscle by chromatography in cellulose phosphate, Q-Fast and 5'-AMP sepharose. Specific activity of 2.5U/mg protein, 4.5% recovery and 133.68 purification fold were obtained at the end of the experiment. SDS-PAGE showed a single band with 87kDa molecular mass, native PAGE proved a band of 178kDa, whereas gel filtration detected a 180kDa protein, suggesting the homodimeric nature of this enzyme, in which subunits are not linked by covalent forces. Isoelectric focusing of this enzyme showed a pI of 5.76, which agrees with pI values of AMP deaminase from other invertebrate organisms. AMP deaminase presented a kinetic sigmoidal plot with Vmax of 1.16MUM/min/mg, Km of 13mM, Kcat of 3.48MUM.s(-1) and a Kcat/Km of 267 (mol/L)(-1).s(-1). The apparent relative low catalytic activity of jumbo squid muscle AMP deaminase in the absence of positive effectors is similar to that reported for homologous enzymes in other invertebrate organisms. PMID- 26050168 TI - Antioxidant activities of rosemary (Rosmarinus Officinalis L.) extract, blackseed (Nigella sativa L.) essential oil, carnosic acid, rosmarinic acid and sesamol. AB - Antioxidant activities of three pure compounds: carnosic acid, rosmarinic acid and sesamol, as well as two plant extracts: rosemary extract and blackseed essential oil, were examined by applying DPPH and ABTS(+) radical-scavenging assays and the ferric thiocyanate test. All three test methods proved that rosemary extract had a higher antioxidant activity than blackseed essential oil. The order of antioxidant activity of pure compounds showed variations in different tests. This was attributed to structural factors of individual compounds. Phenolic contents of blackseed essential oil and rosemary extract were also determined. Rosemary extract was found to have a higher phenolic content than blackseed essential oil. This fact was utilised in explaining the higher antioxidant activity of rosemary extract. PMID- 26050170 TI - Influence of size distribution of proteins, thiol and disulfide content in whole wheat flour on rheological and chapati texture of Indian wheat varieties. AB - The influence of protein composition, as measured by size-exclusion high performance liquid chromatography (SE-HPLC), on rheological properties and chapati texture was investigated in the whole wheat flours of eight Indian wheat cultivars grown at a single location. Proteins were extracted using two-step procedure: extraction with buffer containing 0.5% SDS (SDS buffer), followed by sonication. The results showed that SDS buffer extracted 72-90% of the total flour protein in different varieties and 7-11% protein was extracted from the remaining residues by sonication. The proteins extracted were fractionated by SE HPLC into large polymeric proteins (>130kDa), small polymeric proteins (80 130kDa) and monomeric proteins (10-80kDa). Total polymeric protein content in the flour protein showed a significant positive correlation with dough hardness (r=0.71, p<0.05) and positive correlation with chapati texture (r=0.58, p<0.05). Of the SDS extractable polymeric proteins, large polymeric protein in flour protein had significant positive correlation to dough hardness (r=0.89, p<0.05) and chapati cutting force, which reflects the chapati texture (r=0.70, p<0.05). Protein disulfide content showed positive correlation to dough hardness (r=0.66, p<0.05) and texture of chapati (r=0.58, p<0.05) while protein thiol content showed significant negative correlation to chapati texture (r=-0.77, p<0.05). Thus, the results indicate that high proportion of SDS extractable large polymeric protein in flour protein increases the toughness of chapati texture while flours having high thiol content decrease the toughness of chapati. PMID- 26050169 TI - Study of major aromatic compounds in port wines from carotenoid degradation. AB - The carotenoids degradation and the formation of volatiles were examined by simulating Port wine aging. A two year old red Port wine was saturated with oxygen, supplemented with lutein and beta-carotene and kept at 60 degrees C during 87h. A similar study was performed in a model wine solution. Results showed that the percentage decrease in lutein levels was, respectively, 79% and 95%, in the wine model solution and in the Port wine, and 55% and 10% for beta carotene, indicating that lutein was more sensitive to degradation than beta carotene. Two other unknown degradation carotenoid compounds were identified by HPLC/DAD (reverse phase lambdamax: 422; 445; 475 and 422; 445; 472) in the lutein supplemented wine. Levels of beta-ionone and beta-cyclocitral increased (2.5 times) in both, wine and wine model solution, supplemented with beta-carotene. Along with these compounds, the same behaviour was observed in beta-damascenone in the supplemented lutein wine and wine model solution. New insights were provided into the understanding of aroma modifications occurring during Port wine aging. The relationship between carotenoid molecules (beta-carotene and lutein) and some volatiles has also been provided. PMID- 26050171 TI - The origin of off-odours in packaged rucola (Eruca sativa). AB - Rucola (Eruca sativa) was decontaminated and then reinoculated with selected microorganisms. The produce was then stored in three different atmospheres and at two temperatures. The accumulation of off-odours in the packaging headspace was analysed. A dozen compounds were detected by olfactometry but only dimethyl sulphide and dimethyl disulphide were considered to have a strong or moderate intensity. Thus, they were identified as the substances causing an unpleasant smell inside the bags. Inoculation with microorganisms resulted in higher production of off-odours. Samples inoculated with Pseudomonadaceae&Xanthamonadaceae were particularly potent in producing the two sulphides. The off-odour problem was much more prominent in samples that were kept in a packaging material that did not allow gas exchange resulting in oxygen levels below 1%. Higher levels of sulphides were detected at 8 degrees C than at 4 degrees C. PMID- 26050172 TI - Composition and properties of flaxseed phenolic oligomers. AB - An extract from flaxseed containing oligomeric structures of the phenolic glucosides secoisolariciresinol diglucoside (SDG), p-coumaric acid glucoside and ferulic acid glucoside was fractionated into three oligomeric fractions (F50, F60 and F70) by reversed phase liquid chromatography and further subfractionated by Sepharose CL-6B. The F50 fraction, which had the highest proportion of hydroxycinnamic acid glucosides, was also fractionated on Sephadex LH-20 according to hydrophobicity and size. The different separations resulted in complex profiles of UV-absorbing molecules. HPLC analyses indicated that reversed phase chromatography separated the oligomers according to composition of the phenolic glucosides, while the subfractionation revealed that other structural features of the oligomers were also important. Using the DPPH radical, SDG and oligomeric fractions showed similar hydrogen-donating abilities comparable to ferulic acid but higher than alpha-tocopherol, which suggests that SDG was the only active antioxidant. PMID- 26050173 TI - Effect of fortification on physico-chemical and microbiological stability of whole wheat flour. AB - Stability of fortified whole wheat flour (WWF) was evaluated using NaFeEDTA, elemental iron, ZnSO4 and ZnO as fortificants. Fortified WWF was stored in tin boxes and polypropylene bags for 60 days under ambient storage condition (ASC) and controlled storage condition (CSC). Fortification significantly (p?0.05) decreased moisture and protein content and increased ash content to 5.44%, 6% and 23%, as compared to control. Fortified WWF, assayed periodically for mould contamination manifested a significant inhibition (~1 log reduction) in flours containing elemental iron. Low storage temperature and relative humidity (RH) indicated lower level of mould count during extended storage time. Tin boxes, as storage material, exhibited a better protection against mould attack, acting as an effective barrier for moisture. Fortificants exerted a slight deteriorative effect on texture characteristics of the chapattis made of these flours but chapattis were still accepted by the judges. Zinc fortificants seemed like having little or no effect on the quality of the flours and chapattis, made of such flours. Shelf life of fortified flour may be extended by using elemental iron as fortificant and storing the product in tin boxes under relatively low temperature and RH. PMID- 26050174 TI - Postharvest shelf life extension of blueberries using a biodegradable package. AB - Small berries are commonly packaged and sold to consumers in vented petroleum based clamshell containers. Biodegradable and compostable packages may be used as an alternative package to reduce waste generation and landfill disposal. In addition, the current clamshell container design does not allow the development of a modified atmosphere that could prolong berry shelf life. Thus, in this study, a non-ventilated biodegradable container was evaluated as a possible alternative to the containers normally used in commercial distribution of small berries. To determine the potential of biodegradable containers for small berries, highbush blueberries were packaged in polylactide (PLA) containers and stored at 10 degrees C for 18 days and at 23 degrees C for 9 days. Commercial vented clamshell containers were used as controls. Physicochemical and microbiological studies were carried out in order to compare the efficacy of both packages. Results showed that the PLA containers prolonged blueberry shelf life at different storage temperatures. PMID- 26050175 TI - Characteristic and antioxidant activity of retorted gelatin hydrolysates from cobia (Rachycentron canadum) skin. AB - Alkali-pretreated cobia (Rachycentron canadum) skin was extracted in a retort (121 degrees C) for 30min to obtain a retorted skin gelatin hydrolysate (RSGH). The molecular mass distributions and antioxidant activities of cobia RSGH and enzyme-treated RSGHs (ET-RSGHs) derived from bromelain, papain, pancreatin, and trypsin digestion were then characterized. The molecular mass distribution of the RSGH ranged mainly between 20,000 and 700Da and those of ET-RSGHs ranged between 6500 and 700Da. The DPPH (alpha,alpha-diphenyl-beta-picrylhydrazyl) radical scavenging effects (%) of 10mg/ml of RSGH and 10mg/ml of the four ET-RSGHs were 55% and 51-61%, respectively. The lipid peroxidation inhibition (%) of RSGH and ET-RSGHs (10mg/ml) were 58% and 60-71% on the fifth day in a linoleic acid model system, respectively. The 3Kd-ET-RSGHs, obtained by using a series of centrifugal ultrafiltration filters (molecular weight cut-offs of 10, 5, and 3kDa done sequentially with decreasing pore size), exhibited dramatically improved antioxidant activity, with most of the molecular mass ranging below 700Da. Compared to 10mg/ml of the RSGH, 10mg/ml of 3Kd-ET-RSGHs exhibited 45-65% more scavenging of DPPH radical and 24-38% more inhibition of lipid peroxidation. The peptides with molecular masses below 700Da in the ET-RSGHs or 3Kd-ET-RSGHs significantly affect the antioxidant properties. These peptides are composed of a small number of amino acids or free amino acids and have the potential to be added as antioxidants in foods. PMID- 26050176 TI - Proteolytic and lipolytic modifications during the manufacture of dry-cured lacon, a Spanish traditional meat product: Effect of some additives. AB - The extractability of sarcoplasmic and myofibrillar proteins, the myofibrillar proteins and their degradation products, classical nitrogen fractions, free amino acids, acidity of the fat, and free fatty acids were determined throughout the manufacturing process of dry-cured lacon, a traditional dry-salted and ripened meat product made in the northwest of Spain from the foreleg of the pig, following a similar technological process to that of dry-cured ham. The effect of the use of additives (glucose, sodium nitrite, sodium nitrate, sodium ascorbate and sodium citrate) on the proteolytic and lipolytic changes was also studied. Throughout the manufacture, approximately 87% of the sarcoplasmic proteins and 91% of the myofibrillar proteins became insoluble. There was a significant (p<0.05) decrease of the myosin heavy chain, actin, and myosin light chains 1, 2 and 3, and also a significant (p<0.05) increase in the components generated as a result of the degradation of these myofibrillar proteins. The content of the different nitrogen fractions and of the free amino acids indicated that protein degradation during the manufacture of dry-cured lacon is only moderate. Data on the acidity of fat and of free fatty acids also indicated that lipolysis in dry cured lacon is lower than in hams. The use of additives did not significantly influence the protein and lipid degradation, which occur throughout the manufacturing process. PMID- 26050177 TI - Purification and identification of a novel heteropolysaccharide RBPS2a with anti complementary activity from defatted rice bran. AB - A novel heteropolysaccharide RBPS2a with anti-complementary activity was obtained from defatted rice bran by hot water extraction, ethanol precipitation, and purified by gel chromatography after anion-exchange chromatography. This fraction exhibited more potent anti-complementary activity than other polysaccharide fractions. RBPS2a was eluted as a single symmetrical narrow peak on high performance gel-permeation chromatography (HPGPC) and the average molecular weight was 90,000Da. We found RBPS2a contained 86.7% polysaccharide and 8.7% protein. The amino acid pattern showed that RBPS2a contained large amount of glutamic acid, arginine, aspartic acid, lysine, and alanine. The molar content of the above five amino acids constituted 59.31% of the total amino acids. Gas chromatography of absolute acid hydrolysate of RBPS2a suggested that it was composed of arabinose, xylose, glucose and galactose with a molar ratio of 4:2:1:4. The Fourier-transform infrared spectra (FT-IR) and (1)H, (13)C NMR spectroscopy analysis revealed that RBPS2a had a backbone consisting of beta-(1 >3)-linked d-galacopyranosyl residues substituted at O-2 with glycosyl residues composed of alpha-d-xylose-(1->4)-alpha-d-arabinose-(1-> and alpha-d-glucose-(1 >4)-alpha-d-arabinose-(1-> linked residues. Furthermore, some of the fractions extracted and purified from defatted rice bran exhibited strong anti complementary activity. Among these fractions, the purified polysaccharide RBPS2a had the highest activity. PMID- 26050178 TI - Organ-specific distribution of phenolic compounds in bilberry (Vaccinium myrtillus) and 'northblue' blueberry (Vaccinium corymbosum x V. angustifolium). AB - Blueberries and bilberries are recognized as some of the best sources of flavonoids, especially anthocyanins. The contents of flavonoids (anthocyanins, proanthocyanidins, flavonols) and hydroxycinnamic acids in the flower, fruit skin and pulp, leaf and rhizome of bilberry and the blueberry cultivar 'Northblue' were analyzed using high-performance liquid chromatography combined with diode array detection. The most striking difference in the fruits was the predominance of hydroxycinnamic acids in blueberry, whereas in bilberry the anthocyanin content was much higher, particularly in the pulp. Differences in flavonoid contents of fruits were already apparent at the flower stage. Bilberry and blueberry leaves both contained high amounts of proanthocyanidins, flavonols and hydroxycinnamic acids. Blueberry rhizomes accumulated high amounts of hydroxycinnamic acids. All plant parts of bilberry and blueberry are potential sources of phenolic compounds for use either as dietary botanicals or by the pharmaceutical industry. PMID- 26050179 TI - Analysis of ginsenosides in Panax ginseng in high pressure microwave-assisted extraction. AB - High pressure microwave assisted extraction (HPMAE) was applied to extract the ginsenosides from Panax ginseng root. The influences of extraction solvent, extraction pressure and extraction time were individually investigated. HPMAE has been compared with other extraction methods, including Soxhlet extraction, ultrasound-assisted extraction and heat reflux extraction. The determination of ginsenosides was performed by HPLC-ESI-MS. The results indicated that the HPMAE not only took a shorter time but also afforded higher extraction yields of ginsenosides, especially ginsenoside Rb1, Rc, Rb2 and Rd. Furthermore, the neutral ginsenosides and malonyl ginsenosides in Panax ginseng root extracts by HPMAE were investigated. The malonyl ginsenoside m-Rb1, m-Rc, m-Rb2 and m-Rd degraded in HPMAE at 400kPa (109-112 degrees C) in 70%(v/v) ethanol-water and at 600kPa (112-115 degrees C) in methanol, and transformed into corresponding neutral ginsenoside Rb1, Rc, Rb2 and Rd. Using water as extraction solution, the neutral ginsenosides degraded under HPMAE at 400kPa (135-140 degrees C), and transformed into less polarity rare ginsenosides. PMID- 26050180 TI - Sediments in coffee extracts: Composition and control by enzymatic hydrolysis. AB - The water-insolubility of some coffee extract components is one of the major limitations in the production of instant coffee. In this work, fractions from coffee extracts and sediments were prepared, and their chemical composition determined. Based on the carbohydrate analysis, galactomannan was found to be the main polysaccharide component of the insoluble fractions and probably responsible for sediment formation. The suitability of twelve commercial enzymes for the hydrolysis of the insoluble fractions was investigated. Pectinase 444L was the most effective enzyme in releasing sugars, mainly mannose and galactose, from these substrates. Biopectinase CCM, Rohapect B1L, Pectinase 444L and Galactomannanase ACH were found to be the most effective enzymes for reducing the sediment of coffee extracts. The highest sediment reduction was obtained using Rohapect B1L and Galactomannanase ACH, at enzyme concentrations of 0.3 and 0.1mg protein/g substrate, respectively. PMID- 26050181 TI - Determination of Cr and Ni in Orujo spirit samples by ETAAS using different chemical modifiers. AB - Several analytical methods are proposed for chromium and nickel determination in Orujo spirit samples using ETAAS. Permanent chemical modifiers such as W, Ir, Ru, W-Ir and W-Ru were comparatively studied in relation to the common chemical modifier employed, Pd(NO3)2-Mg(NO3)2. Taking into account the analytical performance, the method based on the use of Ru as a permanent modifier was selected for further direct Cr determinations in Orujo samples. In the case of Ni, after comparison among the different methods developed, a method with no modifier which allows the direct interpolation in calibration graphs was chosen. Detection limits of 0.13MUgL(-1) and 0.30MUgL(-1) were obtained for Cr and Ni, respectively. For all methods developed, recoveries (ranged 98.6-102%) and precision (RSD<10%) were acceptable. The selected methods were applied for the determination of the Cr and Ni contents in 80 representative Orujo Galician samples. The Cr concentrations ranged from .05) but was significantly correlated with the TUG test (rho = 0.31, P < .05) and gait speed (r = -0.36, P < .05). These relationships remained after adjusting for age and education in multivariate models. Results from post hoc analyses demonstrated that only those with MCI had significant relationships between EF and physical performance measures. TMT-B scores in the MCI group were significantly correlated with gait speed (rho = -0.51, P < .05) and TUG test (rho = 0.58, P < .05). DISCUSSION: A significant relationship exists between performance on clinical assessments of EF and fall risk assessments that integrate a mobility task for those individuals who screen positive for MCI. For those who screened negative, no significant relationship exists. Given the large prevalence of undiagnosed MCI in community-dwelling older adults, this finding could be used as an indication to screen older adults for MCI. CONCLUSIONS: Screening tools that require cognitive resources such as gait speed appear to have significant relationships with performance of EF for those who screen positive for MCI. This information could be used clinically to identify older adults with cognitive limitations, which could put them at higher risk for falling. PMID- 26050195 TI - Alterations of cerebral glutamate in the euthymic state of patients with bipolar disorder. AB - The pathophysiology of bipolar disorder (BD) mostly remains unclear. However, some findings argue for a dysfunction in glutamatergic neurotransmission in BD. Proton magnetic resonance spectroscopy at 3T was used to determine glutamate concentrations in the anterior cingulate cortex (ACC) and the hippocampus (HC) of euthymic outpatients with BP-I disorder and age- and sex-matched healthy controls. In patients with BD, glutamate concentrations were significantly increased in the ACC and decreased in the HC compared with concentrations in controls. Significant group differences were also measured for N-acetyl aspartate and choline; no differences were found for other metabolites examined. An inverse correlation was observed for glutamate concentrations in the ACC and number of episodes. The findings of the study add to the concept of abnormalities in glutamatergic regulation in the ACC and HC in patients with BD. PMID- 26050197 TI - BTG1 expression correlates with pathogenesis, aggressive behaviors and prognosis of gastric cancer: a potential target for gene therapy. AB - Here, we found that BTG1 overexpression inhibited proliferation, migration and invasion, induced G2/M arrest, differentiation, senescence and apoptosis in BGC 823 and MKN28 cells (p < 0.05). BTG1 transfectants showed a higher mRNA expression of Cyclin D1 and Bax, but a lower mRNA expression of cdc2, p21, mTOR and MMP-9 than the control and mock (p < 0.05). After treated with cisplatin, MG132, paclitaxel and SAHA, both BTG1 transfectants showed lower mRNA viability and higher apoptosis than the control in both time- and dose-dependent manners (p < 0.05) with the hypoexpression of chemoresistance-related genes (slug, CD147, GRP78, GRP94, FBXW7 TOP1, TOP2 and GST-pi). BTG1 expression was restored after 5 aza-2'-deoxycytidine treatment in gastric cancer cells. BTG1 expression was statistically lower in gastric cancer than non-neoplastic mucosa and metastatic cancer in lymph node (p < 0.05). BTG1 expression was positively correlated with depth of invasion, lymphatic and venous invasion, lymph node metastasis, TNM staging and worse prognosis (p < 0.05). The diffuse-type carcinoma showed less BTG1 expression than intestinal- and mixed-type ones (p < 0.05). BTG1 overexpression suppressed tumor growth and lung metastasis of gastric cancer cells by inhibiting proliferation, enhancing autophagy and apoptosis in xenograft models. It was suggested that down-regulated BTG1 expression might promote gastric carcinogenesis partially due to its promoter methylation. BTG1 overexpression might reverse the aggressive phenotypes and be employed as a potential target for gene therapy of gastric cancer. PMID- 26050196 TI - Factors involved in CLL pathogenesis and cell survival are disrupted by differentiation of CLL B-cells into antibody-secreting cells. AB - Recent research has shown that chronic lymphocytic leukemia (CLL) B-cells display a strong tendency to differentiate into antibody-secreting cells (ASCs) and thus may be amenable to differentiation therapy. However, the effect of this differentiation on factors associated with CLL pathogenesis has not been reported. In the present study, purified CLL B-cells were stimulated to differentiate into ASCs by phorbol myristate acetate or CpG oligodeoxynucleotide, in combination with CD40 ligand and cytokines in a two-step, seven-day culture system. We investigated (i) changes in the immunophenotypic, molecular, functional, morphological features associated with terminal differentiation into ASCs, (ii) the expression of factors involved in CLL pathogenesis, and (iii) the expression of pro- and anti-apoptotic proteins in the differentiated cells. Our results show that differentiated CLL B-cells are able to display the transcriptional program of ASCs. Differentiation leads to depletion of the malignant program and deregulation of the apoptosis/survival balance. Analysis of apoptosis and the cell cycle showed that differentiation is associated with low cell viability and a low rate of cell cycle entry. Our findings shed new light on the potential for differentiation therapy as a part of treatment strategies for CLL. PMID- 26050198 TI - ZD6474, a new treatment strategy for human osteosarcoma, and its potential synergistic effect with celecoxib. AB - ZD6474, a small molecule VEGFR and EGFR tyrosine kinase inhibitor, has been considered as a promising tumor-targeted drug in various malignancies. EGFR and cyclooxygenase-2 (COX-2) were found overexpressed in osteosarcoma in previous reports, so here we tried to explore the anti-osteosarcoma effect of ZD6474 alone or combination with celecoxib, a COX-2 inhibitor. The data demonstrated that ZD6474 inhibited the growth of osteosarcoma cells, and promoted G1-phase cell cycle arrest and apoptosis by inhibiting the activity of EGFR tyrosine kinase, and consequently suppressing its downstream PI3k/Akt and MAPK/ERK pathway. Additionally, daily administration of ZD6474 produced a dose-dependent inhibition of tumor growth in nude mice. Celecoxib also significantly inhibited the growth of osteosarcoma cells in dose-dependent manner, while combination of ZD6474 and celecoxib displayed a synergistic or additive antitumor effect on osteosarcoma in vitro and in vivo. The possible molecular mechanisms to address the synergism are likely that ZD6474 induces the down-regulation of COX-2 expression through inhibiting ERK phosphorylation, while celecoxib promotes ZD6474-directed inhibition of ERK phosphorylation. In conclusion, ZD6474 exerts direct anti proliferative effects on osteosarcoma cells, and the synergistic antitumor effect of the combination of ZD6474 with celecoxib may indicate a new strategy of the combinative treatment of human osteosarcoma. PMID- 26050199 TI - The indirect NMDAR inhibitor flupirtine induces sustained post-ischemic recovery, neuroprotection and angioneurogenesis. AB - N-methyl-D-aspartate receptor (NMDAR) activation induces excitotoxicity, contributing to post-stroke brain injury. Hitherto, NMDAR deactivation failed in clinical trials due to insufficient pre-clinical study designs and drug toxicity. Flupirtine is an indirect NMDAR antagonist being used as analgesic in patients. Taking into account its tolerability profile, we evaluated effects of flupirtine on post-stroke tissue survival, neurological recovery and brain remodeling.Mice were exposed to stroke and intraperitoneally treated with saline (control) or flupirtine at various doses (1-10 mg/kg) and time-points (0-12 hours). Tissue survival and cell signaling were studied on day 2, whereas neurological recovery and tissue remodeling were analyzed until day 84.Flupirtine induced sustained neuroprotection, when delivered up to 9 hours. The latter yielded enhanced neurological recovery that persisted over three months and which was accompanied by enhanced angioneurogenesis. On the molecular level, inhibition of calpain activation was noted, which was associated with increased signal-transducer-and activator-of-transcription-6 (STAT6) abundance, reduced N-terminal-Jun-kinase and NF-kappaB activation, as well as reduced proteasomal activity. Consequently, blood-brain-barrier integrity was stabilized, oxidative stress was reduced and brain leukocyte infiltration was diminished.In view of its excellent tolerability, considering its sustained effects on neurological recovery, brain tissue survival and remodeling, flupirtine is an attractive candidate for stroke therapy. PMID- 26050200 TI - A model of lung parenchyma stress relaxation using fractional viscoelasticity. AB - Some pulmonary diseases and injuries are believed to correlate with lung viscoelasticity changes. Hence, a better understanding of lung viscoelastic models could provide new perspectives on the progression of lung pathology and trauma. In the presented study, stress relaxation measurements were performed to quantify relaxation behavior of pig lungs. Results have uncovered certain trends, including an initial steep decay followed by a slow asymptotic relaxation, which would be better described by a power law than exponential decay. The fractional standard linear solid (FSLS) and two integer order viscoelastic models - standard linear solid (SLS) and generalized Maxwell (GM) - were used to fit the stress relaxation curves; the FSLS was found to be a better fit. It is suggested that fractional order viscoelastic models, which have nonlocal, multi-scale attributes and exhibit power law behavior, better capture the lung parenchyma viscoelastic behavior. PMID- 26050201 TI - Early detection of abnormal left ventricular relaxation in acute myocardial ischemia with a quadratic model. Med Eng Phys 2014;36(September (9)):1101-5 by Morimont et al. PMID- 26050202 TI - Clinical Analysis of Adverse Drug Reactions between Vincristine and Triazoles in Children with Acute Lymphoblastic Leukemia. AB - BACKGROUND: Vincristine (VCR) is a major chemotherapy drug for treatment of childhood acute lymphoblastic leukemia (ALL). Triazole antifungal drugs (AFD) are the main agents for the prevention/treatment of invasive fungal infection (IFI), a common complication during the treatment of ALL. This study investigated the adverse drug reactions (ADRs) between VCR and AFD. MATERIAL AND METHODS: A retrospective study was performed on 68 children with ALL (39 boys and 29 girls, median age: 5 years) who were treated with VCR chemotherapy (a total of 136 cases, including both induction and reinduction phases) from January 2012 to December 2013 in our hospital. These cases were divided into 4 groups: the control group without AFD prevention/treatment (n=44), the Itra group receiving itraconazole oral solution (n=44), the Fluc group receiving intravenous fluconazole (n=42), and the Vori group receiving voriconazole oral tablets (n=6). The ADRs in each group was recorded and compared. RESULTS: The incidence of ADRs in the Itra and Vori groups were significantly higher compared with the Fluc and the control group (P<0.05). The incidence of ADRs in the Itra group was significantly higher than that in the Vori group, whereas there was no difference in the incidence between the Fluc and control group. CONCLUSIONS: Given the lower incidence of ADRs between VCR and fluconazole compared with voriconazole or itraconazole, it is relatively safer to use fluconazole in ALL patients receiving VCR chemotherapy. The occurrence of ADRs should be closely monitored when triazoles must be administered concomitantly with VCR. PMID- 26050203 TI - Evaluation of Radiographic Instability of the Trapeziometacarpal Joint in Women With Carpal Tunnel Syndrome. AB - PURPOSE: To determine whether median nerve dysfunction measured by electrophysiologic studies in carpal tunnel syndrome (CTS) is associated with thumb trapeziometacarpal (TMC) joint instability. METHODS: We evaluated 71 women with CTS and 31 asymptomatic control women. Patients with generalized laxity or TMC joint osteoarthritis were excluded. We classified the electrophysiologic severity of CTS based on nerve conduction time and amplitude and assessed radiographic instability of the TMC joint based on TMC joint stress radiographs. We compared subluxation ratio between patients with CTS and controls and performed correlation analysis of the relationship between the electrophysiologic grade and subluxation ratio. RESULTS: Thirty-one patients were categorized into the mild CTS subgroup and 41 into the severe CTS subgroup. There was no significant difference in subluxation ratio between the control group and CTS patients or between the control group and CTS subgroup patients. Furthermore, there was no significant correlation between electrophysiologic grade and subluxation ratio. CONCLUSIONS: This study demonstrated that patients with CTS did not have greater radiographic TMC joint instability compared with controls, and suggests that TMC joint stability is not affected by impaired median nerve function. Further studies could investigate how to better evaluate proprioceptive function of TMC joint and whether other nerves have effects on TMC joint motor/proprioceptive function, to elucidate the relationship between neuromuscular control of the TMC joint, its stability, and its progression to osteoarthritis. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic II. PMID- 26050204 TI - Surgical Treatment of Macrodactyly. AB - Macrodactyly, enlargement of one or multiple digits, was described in the literature nearly 200 years ago. This is an exceptionally uncommon diagnosis that has led to a paucity of descriptive literature on the treatment options. Because the literature is scarce, and the frequency with which hand surgeons encounter macrodactyly is even scarcer, treatment can be a formidable task often left exclusively to those trained in congenital hand deformity. This article presents our algorithm and surgical techniques for dealing with children with macrodactyly in such a way that should make a complex problem more easily approachable. PMID- 26050205 TI - Trapeziectomy With a Tendon Tie-in Implant for Osteoarthritis of the Trapeziometacarpal Joint. AB - PURPOSE: To evaluate the early to mid-term clinical and radiological outcomes of trapeziectomy with a tendon tie-in trapezium implant arthroplasty for moderate to severe trapeziometacarpal (TMC) joint osteoarthritis (Eaton stages III to IV). METHODS: We assessed all patients who underwent trapeziectomy and tendon tie-in trapezium implant arthroplasty stabilized with a Weilby flexor carpi radialis tendon sling for osteoarthritis of the TMC joint between 2008 and 2010 at our institution. Twenty-two patients (28 thumbs) who had had an operation at least 12 months earlier were clinically evaluated at an average follow-up of 18 months. Subjective clinical outcomes evaluation included visual analog scale scores and Disabilities of the Arm, Shoulder, and Hand score questionnaires. Objective clinical evaluation included lateral pinch and grip tests and active thumb range of motion. All patients underwent a radiological assessment by 2 independent musculoskeletal radiologists. In cases of unilateral treatment, we compared clinical results obtained from the operated hands with the contralateral hand. RESULTS: The mean preoperative visual analog scale score of the cohort was 7.4. We documented a statistically significant improvement to 1.2 at a mean of 18 months after the operation (range, 12-26 mo). The mean postoperative Disabilities of the Arm, Shoulder, and Hand score was 21. Thumb palmar abduction was 85 degrees ; thumb metacarpophalangeal joint flexion and TMC joint extension were 30 degrees and 10 degrees , respectively. There were 2 cases of prosthesis removal owing to implant dislocation. No late complications were recorded. CONCLUSIONS: Good short-term to mid-term results and stability of TMC arthroplasty implant can be achieved with tie-in trapezium implant stabilized with a Weilby flexor carpi radialis tendon sling. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26050206 TI - Comparison of Flexor Tendon Suture Techniques Including 1 Using 10 Strands. AB - PURPOSE: To compare mechanical properties of a multistrand suture technique for flexor tendon repair with those of conventional suture methods through biomechanical and clinical studies. METHODS: We describe a multistrand suture technique that is readily expandable from 6 to 10 strands of core suture. For biomechanical evaluation, 60 porcine flexor tendons were repaired using 1 of the following 6 suture techniques: Kessler (2-strand), locking cruciate (4-strand), Lim/Tsai's 6-strand, and our modified techniques (6-, 8-, or 10-strand). Structural properties of each tenorrhaphy were determined through tensile testing (ultimate failure load and force at 2-mm gap formation). Clinically we repaired 25 flexor tendons using the described 10-strand technique in zones I and II. Final follow-up results were evaluated according to the criteria of Strickland and Glogovac. RESULTS: In the biomechanical study, tensile properties were strongly affected by repair technique; tendons in the 10-strand group had approximately 106%, 66%, and 39% increased ultimate load to failure (average, 87 N) compared with those in the 4-, 6-, and 8-strand groups, respectively. Tendons in the 10-strand group withstood higher 2-mm gap formation forces (average, 41 N) than those with other suture methods (4-strand, 26 N; 6-strand, 27 N; and 8 strand, 33 N). Clinically, we obtained 21 excellent, 2 good, and 2 fair outcomes after a mean of 16 months (range, 6-53 mo) of follow-up. No patients experienced poor results or rupture. CONCLUSIONS: The 10-strand suture repair technique not only increased ultimate strength and force at the 2-mm gap formation compared with conventional suture methods, it also showed good clinical outcomes. This multistrand suture technique can greatly increase the gap resistance of surgical repair, facilitating early mobilization of the affected digit. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 26050207 TI - A Mechanical Evaluation of Zone II Flexor Tendon Repair Using a Knotless Barbed Suture Versus a Traditional Braided Suture. AB - PURPOSE: To determine repair site bulk, gliding resistance, work of flexion, and 1-mm gap formation force in zone II flexor tendon lacerations repaired with knotless barbed or traditional braided suture. METHODS: Transverse zone II lacerations of the flexor digitorum profundus (FDP) tendon were created in 36 digits from 6 matched human cadaveric pairs. Repair was performed with 2-0 barbed suture (n = 18) or 3-0 polyethylene braided suture (n = 18). Pre- and postrepair cross-sectional area was measured followed by quantification of gliding resistance and work of flexion during cyclic flexion-extension loading at 10 mm/min. Thereafter, the repaired tendons were loaded to failure. The force at 1 mm of gap formation was recorded. RESULTS: Repaired FDP tendon cross-sectional area increased significantly from intact, with no difference noted between suture types. Gliding resistance and work of flexion were significantly higher for both suture repairs; however, we identified no significant differences in either nondestructive biomechanical parameters between repair types. Average 1-mm gap formation force with the knotless barbed suture (52 N) was greater than that of the traditional braided suture (43 N). CONCLUSIONS: We identified no significant advantage in using knotless barbed suture for zone II FDP repair in our primary, nondestructive mechanical outcomes in this in vitro study. CLINICAL RELEVANCE: In vivo studies may be warranted to determine if one suture method has an advantage with respect to the parameters tested at 4, 6, and 12 plus weeks postrepair and the degree of adhesion formation. The combined laboratory and clinical data, in additional to cost considerations, may better define the role of barbed knotless suture for zone II flexor tendon repair. PMID- 26050208 TI - Naringenin Mitigates Iron-Induced Anxiety-Like Behavioral Impairment, Mitochondrial Dysfunctions, Ectonucleotidases and Acetylcholinesterase Alteration Activities in Rat Hippocampus. AB - Studies demonstrated that the iron chelating antioxidant restores brain dysfunction induced by iron toxicity in animals. Earlier, we found that iron overload-induced cerebral cortex apoptosis correlated with oxidative stress could be protected by naringenin (NGEN). In this respect, the present study is focused on the mechanisms associated with the protective efficacy of NGEN, natural flavonoid compound abundant in the peels of citrus fruit, on iron induced impairment of the anxiogenic-like behaviour, purinergic and cholinergic dysfunctions with oxidative stress related disorders on mitochondrial function in the rat hippocampus. Results showed that administration of NGEN (50 mg/kg/day) by gavage significantly ameliorated anxiogenic-like behaviour impairment induced by the exposure to 50 mg of Fe-dextran/kg/day intraperitoneally for 28 days in rats, decreased iron-induced reactive oxygen species formation and restored the iron induced decrease of the acetylcholinesterase expression level, mitochondrial membrane potential and mitochondrial complexes activities in the hippocampus of rats. Moreover, NGEN was able to restore the alteration on the activity and expression of ectonucleotidases such as adenosine triphosphate diphosphohydrolase and 5'-nucleotidase, enzymes which hydrolyze and therefore control extracellular ATP and adenosine concentrations in the synaptic cleft. These results may contribute to a better understanding of the neuroprotective role of NGEN, emphasizing the influence of including this flavonoid in the diet for human health, possibly preventing brain injury associated with iron overload. PMID- 26050209 TI - In vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of pyrazole-based small molecule inhibitors of Mdm2/4-p53 interaction. AB - PURPOSE: The interaction of p53 with its negative regulators Mdm2/4 has been widely studied (Khoury and Domling in Curr Pharm Des 18(30):4668-4678, 2012). In p53(+/+) cells, expression of Mdm2/4 leads to p53 turnover, inhibition of downstream transcription, decreasing cell cycle arrest, or apoptosis. We report in vitro cytotoxicity and in vivo efficacy, pharmacokinetics, and metabolism of YH264, YH263, and WW751, three proposed small molecule inhibitors of the Mdm2/4 p53 interaction. METHODS: MTT cytotoxicity assays were performed, and alterations in proteins were examined using western blots. Mice were dosed 150 mg/kg YH264 or YH263 IV or PO QDx5. Mice were IV dosed 88, 57, or 39 mg/kg WW751 for 3, 5, or 5 days. YH264, YH263, and WW751 and metabolites were quantitated by LC-MS/MS. RESULTS: IC50 values for YH264, YH263, and WW751 against p53 wild-type HCT 116 cells after 72 h of incubation were 18.3 +/- 2.3, 8.9 +/- 0.6, and 3.1 +/- 0.2 MUM, respectively. Only YH264 appeared to affect p53 expression in vitro. None of the compounds affected the growth of HCT 116 xenografts in C.B-17 SCID mice. YH264 plasma half-life was 147 min; YH263 plasma half-life was 263 min; and WW751 plasma half-life was less than 120 min. CONCLUSIONS: Despite dosing the mice at the maximum soluble doses, we could not achieve tumor concentrations equivalent to the intracellular concentrations required to inhibit cell growth in vitro. YH263 and WW751 do not appear to affect p53/Mdm2, and none of the three were active in a subcutaneous HCT 116 p53(+/+) xenograft model. PMID- 26050210 TI - Phase I trial of 5-FU, docetaxel, and nedaplatin (UDON) combination therapy for recurrent or metastatic esophageal cancer. AB - PURPOSE: The aims of this dose-escalating phase I study were to determine the maximum tolerable dose (MTD) and recommended dose (RD) of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for future phase II studies, and to evaluate the safety and efficacy of this regimen in patients with untreated recurrent or metastatic esophageal cancer. METHODS: Patients were administered 5-FU on days 1-5, docetaxel on days 1 and 15, and nedaplatin on day 1 at 4-week intervals. The dose levels of 5-FU/docetaxel/nedaplatin were escalated as follows (mg/m(2)): level 1, 800/30/80; level 2, 800/30/90; and level 3, 800/35/90. Toxicity was evaluated using Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Overall, nine patients were enrolled in this study. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 and were diagnosed with squamous cell carcinoma. No dose-limiting toxicity was observed at any level, and planned dose escalation was completed without reaching the MTD. No grade 4 or higher toxicity was observed in this study. The observed grade 3 hematological toxicities included neutropenia in five patients (55.6 %) and leukopenia in three patients (33.3 %). None of the patients developed febrile neutropenia, and no grade 3 or 4 non-hematological toxicities were observed. The overall response rate was 77.8 %, including two complete responses, and the disease control rate was 100 %. CONCLUSION: The RD of UDON was identified as level 3. The good tolerability and high antitumor efficacy of this regimen warrant further evaluation in this setting. PMID- 26050211 TI - A prospective investigation of neurodevelopmental risk factors for adult antisocial behavior combining official arrest records and self-reports. AB - Neurodevelopmental deficits are postulated to play an important role in the etiology of persistent antisocial behavior (ASB). Yet it remains uncertain as to which particular deficits are most closely associated with ASB. We seek to advance this understanding using prospectively collected data from a birth cohort in which multiple indices of neurodevelopmental functioning and ASB were assessed. Participants (n = 2776) were members of the Providence, Rhode Island cohort of the Collaborative Perinatal Project. Information on demographic and neurodevelopmental variables was collected from pregnancy through age 7. When all offspring had reached 33 years of age an adult criminal record check was conducted. A subset of subjects also self-reported on their engagement in serious ASB. Bivariate logistic regression was used to examine the relationship between each neurodevelopmental factor and adult ASB and test whether associations varied depending on how ASB was ascertained. After controlling for background and contextual characteristics, maternal smoking during pregnancy, lower childhood verbal and performance IQ, and age 7 aggressive/impulsive behavior all significantly increased the odds of adult ASB. Associations were not modified by sex and did not depend on how ASB was assessed. However, while both males and Black participants were more likely to engage in ASB than their respective female and White counterparts, relationships were significantly stronger for official records than for self-reports. Results point to a particular subset of early neurodevelopmental risks for antisocial outcomes in adulthood. Findings also suggest that prior contradictory results are not due to the use of official records versus self-reported outcomes. PMID- 26050213 TI - Ultrasound Detection of Retained Hair Tracts in Hidradenitis Suppurativa. PMID- 26050212 TI - Chaperone roles for TMAO and HSP70 during hyposmotic stress in the spiny dogfish shark (Squalus acanthias). AB - Salinity decreases are experienced by many marine elasmobranchs. To understand how these fishes cope with hyposmotic stress on a cellular level, we used the spiny dogfish shark (Squalus acanthias) as a model to test whether a reciprocal relationship exists between the cell's two primary protein protection mechanisms, the chemical (e.g., trimethylamine oxide, TMAO) and molecular (e.g., heat shock protein 70, HSP70) chaperone systems. This relationship is interesting given that many elasmobranchs are expected to gain water and lose osmolytes, chemical chaperones, and ions as they osmoconform to new, lowered salinity. Dogfish were cannulated for repeated blood sampling and exposed to 70% seawater (SW) for 48 h. These hyposmotic conditions had no effect on red blood cell (RBC) and white muscle TMAO concentrations, and did not result in HSP70 induction or signs of protein damage (i.e., increased ubiquitin), suggesting that TMAO levels were sufficiently protective in these tissues. However, in the gill, we observed a significant decrease in TMAO concentration and a significant induction of HSP70 as well as signs of protein damage. In the face of this cellular stress response, gill Na(+)/K(+)-ATPase (NKA) activity significantly increased during hyposmotic conditions, as expected. We suggest that this functional preservation in the gill is partly the result of HSP70 induction with lowered salinity. We conclude a reciprocal relationship between TMAO and HSP70 in the gills of dogfish as a result of in vivo hyposmotic stress. When osmotically induced protein damage surpasses the protective capacity of remaining TMAO, HSP70 is induced to preserve tissue and organismal function. PMID- 26050214 TI - Association Between Mohs Surgery Wait Times and Surgical Defect Size in Patients With Squamous Cell or Basal Cell Carcinoma of the Skin. AB - BACKGROUND: Consequences of delays in treatment of nonmelanoma skin cancers (NMSCA) are largely unstudied. OBJECTIVE: To determine the relationship between Mohs micrographic surgery (MMS) delay time and final MMS defect size. METHODS: A retrospective chart review was performed to identify patients who underwent MMS for biopsy-proven basal cell carcinoma (BCC) or squamous cell carcinoma (SCC) between 2004 and 2006. Time delay between date of biopsy and date of surgery and lesion diameter increase between biopsy and surgical defect were calculated. RESULTS: Two hundred eighty-three lesions qualified for inclusion in the study. No significant difference in mean change of major diameter between primary and recurrent tumors (1.0 vs 1.1 cm, p = .67), between BCCs and SCCs (both were 1.0 cm, p = .99), and between tumor size at presentation <1.0 versus >=1.0 cm (1.1 vs 0.8 cm, p = .11) were found. However, the mean number of MMS layers taken was significantly different between BCCs and SCCs (1.9 vs 1.5, respectively; p = .0022). Linear regression analysis of major diameter change versus time delay to MMS showed no significant increasing trend over time. CONCLUSION: No evidence was found that time delays of up to 1 year from biopsy to MMS impact the growth of NMSCA. PMID- 26050215 TI - Long-term Follow-up of Positive Surgical Margins in Basal Cell Carcinoma of the Face. AB - BACKGROUND: Basal cell carcinoma (BCC) in central facial locations and tumors with positive margins are at a higher risk of recurrence. The most effective treatment is total excision, which includes an adequate pathological margin. OBJECTIVE: To evaluate the outcome of the patients who underwent surgery for BCCs of the head and neck and of those who had positive surgical margins where Mohs surgery is not available. METHODS: This study was conducted at Ege University Medical School between 2004 and 2014. One hundred thirty patients with 154 BCC who underwent surgical excision were included. In the histopathologic report, the existence of positive margin, BCC subtype, localization of the tumor, and distance of margins to the tumor were evaluated. RESULTS: Twenty-three lesions (14.9%) of 22 patients revealed positive surgical margins. Six patients (26.1%) had recurrences on the surgical site. The BCC subtypes of recurrent patients were reported to be multifocal superficial in 2 (33.3%), infiltrative (16.7%) in 1, and micronodular (50%) in 3. CONCLUSION: Patients with superficial multifocal or micronodular tumors should undergo reoperation because of high recurrence rates. PMID- 26050216 TI - Intraoperative real-time reflectance confocal microscopy for guiding surgical margins of lentigo maligna melanoma. PMID- 26050217 TI - Partial Necrosis of the Hallux in a Patient Treated With Laser for Onychomycosis: Is This Procedure Really Worthwhile? PMID- 26050218 TI - Cutaneous Metastasis of Cecal Carcinoma With Epidermotropism. PMID- 26050219 TI - Broad-scale genetic patterns of New Zealand abalone, Haliotis iris, across a distribution spanning 13 degrees latitude and major oceanic water masses. AB - The New Zealand black-foot abalone, Haliotis iris, or paua, is endemic to the rocky reefs surrounding New Zealand, whose main land mass spans 13 degrees of latitude and separates the Tasman Sea from the Pacific Ocean. In this study, we examined the population genetic structure of this important commercial, cultural and recreational species by genotyping nine microsatellite loci in 485 paua from 27 locations distributed across mainland New Zealand and the Chatham Islands. We found low, but significant, levels of genetic differentiation. Key genetic breaks were identified among the Chatham Islands and mainland samples; patterns that are strongly corroborated by prior work employing mtDNA sequences. AMOVAs indicated that samples from the south of the North Island were more similar to the South Island samples than to other North Island samples, however multivariate analysis and Bayesian clustering could not identify a significant pattern. Differentiation between the Chatham Islands and the mainland is most likely due to isolation by distance, while differentiation of North Island samples corresponds with major components of New Zealand's oceanography, Cook Strait and the East Cape. Despite intense fishing pressure, we detected no signature of genetic bottlenecks in any region suggesting that population sizes have remained relatively stable over recent time or that the census size of this species is much larger than its effective population size. PMID- 26050220 TI - Dissociating hyper and hypoself biases to a core self-representation. AB - Biases to favour self-related information over information related to other people have been demonstrated across a range of both high- and low-level tasks, but it is unclear whether these tasks 'tap' the same types of self representation. Here we assess results from two patients with damage primarily to (i) left ventro-medial prefrontal (vmPFC) cortex and the insula (patient SC), and (ii) temporo-parietal (TP) cortex (patient RR). We report evidence from both low level perceptual matching tasks and episodic memory showing that SC has a hypoself bias across the tasks. RR in contrast had a hyperself bias confined to perceptual matching. Both patients also showed hypobias effects for reward. We argue that the different brain lesions compromise (i) the use of a core self representation which modulates both perceptual and memorial levels of processing (the vmPFC), and (ii) attentional responses to social cues (the TP cortex), and, furthermore, these effects can dissociate from those of reward and general effects of brain lesion and/or impaired executive control. We suggest that the vmPFC is critical for access to a core self-representation while TP damage can reduce top-down control of attention to salient stimuli and exaggerates the effects of strong (self-related) attentional signals. PMID- 26050221 TI - Female sex, central lymph node metastasis and dissection are causes of globus symptom after thyroidectomy. AB - Globus symptoms are not uncommon after an uncomplicated thyroidectomy. However, their associated factors and etiology have not been investigated. We investigated the etiology and factors related to globus symptoms after thyroidectomy. The medical records of 289 patients who underwent thyroidectomy and completed a voice analysis, psychiatric screening, and voice-related questionnaires before and 1 month after the surgery were reviewed. Patients were excluded if they had globus symptoms before surgery or scored high on the psychiatric questionnaire. The selected patients were divided into two groups according to development of globus symptoms after surgery. Clinicopathological parameters and results of the voice analysis and voice-related questionnaires were compared between the two groups. A total of 157 patients were enrolled, and more than half (80/155, 51 %) showed development of globus symptoms 1 month after thyroidectomy. Female patients [hazard ratio (HR), 2.605; P = 0.010], patients who had central lymph node metastasis (HR, 3.533; P = 0.001), and patients who underwent central neck dissection (HR, 3.652; P = 0.014) had a higher probability of developing globus symptoms. Patients who developed globus symptoms scored higher on the voice related questionnaire, and had a greater decrease in speaking fundamental frequency (P < 0.001). Globus symptoms developed after 1 month in more than half of patients who underwent thyroidectomy. Female sex and central lymph node metastasis and dissection increased the possibility of developing the symptoms. PMID- 26050222 TI - Comparison of clinical tests of olfactory function. AB - To assess olfactory function, various measures are used in clinical routine. In this study, the Sniff Magnitude Test (SMT), a test considering the sniff response to an odor, was applied to patients with olfactory dysfunction (n = 49) and to a control group without subjective olfaction disorder (n = 21). For comparison, the validated "Sniffin' Sticks" test battery, a psychophysical olfactory test consisting of tests for phenyl ethyl alcohol odor threshold, odor discrimination, and odor identification was performed. Analyses indicated that the SMT showed significant differences between patients and controls (p = 0.003). Furthermore, results from the SMT and the "Sniffin' Sticks" correlated significantly (p < 0.001). In conclusion, the SMT appears to be a useful addition to the battery of available clinical tests to assess olfactory function. PMID- 26050223 TI - Recurrent constrictive pericarditis: A diagnostic and therapeutic challenge. AB - Recurrent right-sided heart failure after pericardiectomy may be caused by incomplete pericardiectomy, recurrent constriction, diastolic dysfunction or myocardial involvement. Identifying recurrent constrictive pericarditis (CP) in patients who have recurring symptoms after pericardiectomy is challenging, since the characteristic Doppler echocardiographic features may not be present if a portion of the ventricles are free of constricting pericardium, and there are no diagnostic or treatment guidelines for management of recurrent CP. The authors report the case of a 59-year-old man with a history of pericardiectomy for tuberculous CP in 1984, admitted to our hospital with signs and symptoms of right heart failure. After a complete diagnostic workup, recurrent CP was diagnosed. Given the scarcity of cases reported on this disease, three possible therapeutic approaches are discussed: a second pericardiectomy, heart transplantation and medical therapy. PMID- 26050224 TI - A rare cause of subendocardial ischemia. PMID- 26050225 TI - Use of implantable cardioverter-defibrillators in athletes: A systematic review. AB - International guidelines exclude athletes with implantable cardioverter defibrillators (ICDs) from participating in sports, except those of low intensity (category IA, such as golf, billiards or bowling). However, these guidelines are based on expert consensus, and thus the safety and risks of participating in sports in this population are still largely unknown in the medical community. We performed a systematic review of the literature in PubMed using the following search string: "((sudden cardiac death) AND (sport OR physical exercise)) AND defibrillator". After the application of pre-defined inclusion and exclusion criteria, 36 results were selected, which are explored in this paper. Preliminary results on ICD use in this population appear to demonstrate the safety and efficacy of the device in this context. Further studies, with longer follow-up and with larger samples, may provide stronger evidence to support these findings. In the meantime, disqualifying almost all ICD patients from participating in sports, without taking into consideration their individual needs and characteristics, may be prejudicial to a considerable number of patients by preventing them from exercising their profession or engaging in recreational sport, for which their risk of sudden cardiac death may be low. PMID- 26050226 TI - Gabarapl1 mediates androgen-regulated autophagy in prostate cancer. AB - Autophagy plays an important role in prostate cancer development. It promotes tumor cell survival and was found to be associated with androgen pathway. In the present study, we found that GABA(A) receptor-associated protein like 1 (Gabarapl1), a ubiquitin-like modifier, participates in the regulation of autophagy. Gabarapl1 is transcriptionally regulated by androgen receptor (AR) and has a repressive role in autophagy. Androgen deprivation downregulates Gabarapl1 in an AR dependent manner, resulting in the increase of autophagy flux. Elevated Gabarapl1 also represses the proliferation of prostate cancer cells. In summary, our study provides evidence to show that Gabarapl1 is a mediator involved in androgen-regulated autophagy process. PMID- 26050227 TI - Aberrant expression of long noncoding RNAs in colorectal cancer with liver metastasis. AB - Long noncoding RNA (lncRNA) plays a crucial role in the regulation of various cellular processes and human diseases. However, little is known about the role of lncRNAs in colorectal liver metastasis (CLM). In the present study, we aimed to determine whether lncRNAs are differentially expressed in CLM tissue and to further assess their clinical value. lncRNA arrays were employed to screen for differentially expressed lncRNAs in colorectal cancer (CRC) tissues with synchronous, metachronous, or nonliver metastasis. Based on bioinformatics data, a quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assay was performed to identify target lncRNAs in an expanded set of CRC samples with various subtypes of liver metastasis. The relationships between the target lncRNAs and the clinical characteristics and patient prognosis were further analyzed. After determining the expression profile of lncRNAs (n = 1332) in CLM tissue, 40 differentially expressed lncRNAs that were potentially related to CLM were selected for further examination in an expanded set of clinical samples, and three novel target lncRNAs, termed lncRNA-CLMAT1-3, were verified. High lncRNA CLMAT3 expression strongly correlated with liver metastasis (P = 0.03) and lymph node metastasis (P = 0.009). Moreover, patients displaying high lncRNA-CLMAT3 expression exhibited a shorter median overall survival duration than those displaying low lncRNA-CLMAT3 expression (30.7 vs. 35.2 months, P = 0.007). Multivariate analysis demonstrated that the lncRNA-CLMAT3 expression level is an independent prognostic factor (hazard ratio 2.05, P = 0.02) after adjusting for other known prognostic factors. lncRNA-CLMAT3 over-expression was significantly associated with CLM and was an independent predictor of poor survival for patients with CRC. PMID- 26050228 TI - Macrophages of M1 phenotype have properties that influence lung cancer cell progression. AB - Stromal macrophages of different phenotypes can contribute to the expression of proteins that affects metastasis such as urokinase-type plasminogen activator (uPA), its receptor uPAR, and plasminogen activator inhibitor-1 (PAI-1), but knowledge of how essential their contribution is in comparison to the cancer cells in small cell lung cancer (SCLC) and lung squamous cell carcinoma (SCC) is lacking. The expression of uPA, uPAR, and PAI-1 and of the matrix metalloproteinases (MMP)-2 and MMP-9 were studied in human macrophages of M1 and M2 phenotype and compared to a lung SCC (NCI-H520) and a SCLC (NCI-H69) cell line. Effects of treatment with conditioned media (CM) from M1 and M2 macrophages on the expression of these genes in H520 and H69 cells as well as effects on the cell growth were investigated. In addition, data on the stromal macrophages immunoreactivity of uPAR, MMP-2, and MMP-9 in a few SCC and SCLC biopsies was included. uPAR, MMP-2, and MMP-9 were confirmed in stromal cells including macrophages in the SCC and SCLC biopsies. In vitro, both macrophage phenotypes expressed considerably higher mRNA levels of uPA, uPAR, PAI-1, and MMP-9 compared to the cancer cell lines, and regarding uPAR, the highest level was found in the M1 macrophage phenotype. Furthermore, M1 CM treatment not only induced an upregulation of PAI-1 in both H520 and H69 cells but also inhibited cell growth in both cell lines, giving M1 macrophages both tumor-promoting and tumor-killing potential. PMID- 26050229 TI - Sam68 promotes cellular proliferation and predicts poor prognosis in esophageal squamous cell carcinoma. AB - Sam68 (Src-associated in mitosis of 68 kD) is a KH domain RNA-binding protein. The expression of Sam68 was correlated with kinds of tumors. Yet, the expression mechanisms and physiological significance of Sam68 in ESCC remains unclear. In this study, we clarified a potential role of Sam68 in the treatment of ESCC. Western blot and immunohistochemistry (IHC) analysis revealed that the protein level of Sam68 was higher in ESCC tumor tissues and cell lines. In addition, IHC stain revealed that Sam68 was positively correlated with clinical pathologic variables such as tumor grade and tumor invasion. In addition, Sam68 could be an independent prognostic indicator for patients' overall survival. In vitro studies such as starvation and refeeding assay along with Sam68-shRNA transfection assay demonstrated that Sam68 expression promoted proliferation of ESCC cells. And Sam68 downregulation caused decreased rate of cell growth and colony formation. Reasons are associated with growth arrest of cell cycle at G1/S phase. Moreover, our results clarified that Sam68 could promote ESCC cell proliferation via the activation of Akt/GSK-3beta pathway. This research indicated that Sam68 might accelerate the cell cycle progression and be considered as a new therapy target in ESCC. PMID- 26050230 TI - RAS Mutations Beyond KRAS Exon 2: A Review and Discussion of Clinical Trial Data. AB - Opinion statement: The addition of targeted therapy to a 5-FU chemotherapy backbone is now a standard of care in metastatic colorectal cancer. Epidermal growth factor receptor (EGFR) inhibitors have been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in the first line for patients with tumors that do not harbor KRAS exon 2 mutations. Eligibility criteria for most clinical trials involving EGFR inhibitors in recent years have used the absence of KRAS exon 2 mutation as the sole criteria for entry, as this specific mutation has been consistently shown to be predictive of a poor response to EGFR inhibitors. However, expanded analyses of first-line metastatic trials reveal that other RAS mutations, such as other KRAS mutations in exons 3 and 4, along with NRAS mutations, are predictive of poor responses to EGFR inhibitors as well. Testing for a full panel of these RAS mutations should be done prior to initiating treatment with an EGFR inhibitor. Further clinical trials are required to determine the predictive impact of each of these individual mutations. To date, they have been analyzed in the aggregate. The addition of targeted therapy, bevacizumab or an EGFR inhibitor, to a chemotherapy backbone should be considered for all appropriate patients. The relevant clinical trials that evaluated patients without any RAS mutation and compared an EGFR inhibitor to chemotherapy alone show a distinct advantage in overall survival and progression-free survival to the groups that received EGFR inhibition. The largest trial that compared bevacizumab with an EGFR inhibitor in the first line, CALGB/SWOG 80405, did not show a statistically significant difference between the two groups, making the use of bevacizumab, cetuximab, or panitumumab reasonable in the first line. PMID- 26050231 TI - Sporadic PEO caused by a novel POLG variation and a Twinkle mutation: digenic inheritance? AB - Progressive external ophthalmoplegia (PEO) with multiple deletions of mitochondrial DNA (mtDNA) is associated with several mutations in nuclear genes. They include POLG, POLG2, ANT1, C10orf2/Twinkle, and OPA1. However, digenic inheritance in mitochondrial disorders has been documented in a few cases over the years. Here we describe an 80-year-old man with sporadic PEO associated with mtDNA deletions. Sequencing of the POLG revealed a novel heterozygous mutation (c.2831A>G; p.Glu944Gly), predicted in silico as damaging, in the patient who also carried a heterozygous mutation in C10orf2/Twinkle (c.1142T>C; p.Leu381Pro). This case provides a second report of a PEO with different mutations in the POLG and C10orf2/Twinkle genes, supporting the hypothesis that the PEO phenotype can be determined by the co-existence of two abnormalities in separate genes, both involved in the maintenance and stability of mtDNA. Finally, this study expands the spectrum of POLG mutations and highlights the need to sequence the whole set of nuclear genes associated with PEO and multiple mtDNA deletions. PMID- 26050232 TI - Change in cognitive performance is associated with functional recovery during post-acute stroke rehabilitation: a multi-centric study from intermediate care geriatric rehabilitation units of Catalonia. AB - Recovery after a stroke is determined by a broad range of neurological, functional and psychosocial factors. Evidence regarding these factors is not well established, in particular influence of cognition changes during rehabilitation. We aimed to investigate whether selective characteristics, including cognitive performance and its change over time, modulate functional recovery with home discharge in stroke survivors admitted to post-acute rehabilitation units. We undertook a multicenter cohort study, including all patients discharged from acute wards to any geriatric rehabilitation unit in Catalonia-Spain during 2008. Patients were assessed for demographics, clinical and functional variables using Conjunt Minim Basic de Dades dels Recursos Sociosanitaris (CMBD-RSS), which adapts the Minimum Data Set tool used in America's nursing homes. Baseline-to discharge change in cognition was calculated on repeated assessments using the Cognitive Performance Scale (CPS, range 0-6, best-worst cognition). The multivariable effect of these factors was analyzed in relation to the outcome. 879 post-stroke patients were included (mean age 77.48 +/- 10.18 years, 52.6% women). A worse initial CPS [OR (95% CI) = 0.851 (0.774-0.935)] and prevalent fecal incontinence [OR (95% CI) = 0.560 (0.454-0.691)] reduced the likelihood of returning home with functional improvement; whereas improvement of CPS, baseline to discharge, [OR (95% CI) = 1.348 (1.144-1.588)], more rehabilitation days within the first 2 weeks [OR (95% CI) = 1.011 (1.006-1.015)] and a longer hospital stay [OR (95% CI) = 1.011 (1.006-1.015)] were associated with the outcome. In our sample, different clinical characteristics, including cognitive function and its improvement over time, are associated with functional improvement in stroke patients undergoing rehabilitation. Our results might provide information to further studies aimed at exploring the influence of cognition changes during rehabilitation. PMID- 26050233 TI - Severe aquaporin-4 IgG-positive neuromyelitis optica spectrum disorder with short myelitis lesion and favourable outcome. PMID- 26050234 TI - A survey to assess the educational-level interference on self-evaluation of acute pain. AB - OBJECTIVE: The present study aimed to evaluate whether patient education level interferes in the percentage of pain relief or increase using visual analogue scale (VAS) and subjective pain perception. PATIENTS AND METHODS: Ninety-five patients presenting acute shoulder pain due to enthesitis were evaluated. They were asked to quantify the pain using VAS before steroid articular infiltration. One week later, patients reevaluated the pain using VAS and orally stated the percentage of perceived pain increase or relief. The information gathered was then compared among three patient educational levels (elementary, high school, and university). RESULTS: Percentages of improvement stated orally and utilizing VAS presented no statistically significant differences among the three educational status levels (p = 0.804). CONCLUSION: Patient educational status caused no impact in the results of acute pain self-assessment with VAS and oral evaluation. PMID- 26050235 TI - Porous tantalum in spinal surgery: an overview. AB - Porous tantalum is an open-cell metal structure that approximates the appearance of human cancellous bone. It has a low modulus of elasticity, close to that of subchondral and cancellous bones, leading to better load transfer and minimizing the stress-shielding phenomenon. Its coefficient of friction is one of the highest among biomaterials, allowing for sufficient primary stabilization of implants, possibly even without screw fixation. Different fusion rates have been achieved in anterior cervical fusion, which lead to contradictory views among spine surgeons. However, in the lumbar spine, trabecular metal has been demonstrated to be effective in obtaining fusion and improving patient outcomes after anterior as well as posterior lumbar interbody fusion. PMID- 26050236 TI - Effects of Arsenic Trioxide Exposure on Heat Shock Protein Response in the Immune Organs of Chickens. AB - Arsenic trioxide (As2O3), a kind of pentavalent arsenic, has recently been linked to disrupted immune function. Heat shock proteins (Hsps), a group of highly conserved proteins, are rapidly synthesised when living organisms are exposed to various stress conditions. The objective of this study is to determine the effects of As2O3 on the expression level of Hsps (Hsp90, Hsp70, Hsp60, Hsp40 and Hsp27) in the immune organs (spleen, thymus and bursa of Fabricius (BF)) of chickens. A total of 72 1-day-old male Hy-line chickens were randomly divided into four groups, including the low-As group (L group), middle-As group (M group), high-As group (H group) and control group (C group). Immune organs were collected, and levels of Hsp messenger RNA (mRNA) and protein were examined on days 30, 60 and 90. The results showed that the levels of Hsp mRNA (Hsp90, Hsp70, Hsp60, Hsp40 and Hsp27) and protein (Hsp70 and Hsp60) expression were significantly increased (p < 0.05 or p < 0.01) in the As2O3 treatment groups compared with the corresponding control groups. Taken together, these results suggest that As2O3 influences the level of Hsps in immune organs. PMID- 26050237 TI - Silicon Reverses Lipid Peroxidation but not Acetylcholinesterase Activity Induced by Long-Term Exposure to Low Aluminum Levels in Rat Brain Regions. AB - Aluminum (Al) is the most widely distributed metal in the environment and is extensively used in daily life leading to easy exposure to human beings. Besides not having a recognized physiological role, Al may produce adverse effects through the interaction with the cholinergic system contributing to oxidative stress. The present study evaluated, in similar conditions of parenteral nutrition, whether the reaction of silicon (SiO2) with Al(3+) to form hydroxyaluminosilicates (HAS) reduces its bioavailability and toxicity through intraperitoneal administrations of 0.5 mg Al/kg/day and/or 2 mg Si/kg/day in Wistar rats. Al and Si concentrations were determined in rat brain tissue and serum. Acetylcholinesterase (AChE) activity and lipid peroxidation (LPO) were analyzed in the cerebellum, cortex, hippocampus, striatum, hypothalamus, and blood. An increase in the Al concentration was verified in the Al + Si group in the brain. All the groups demonstrated enhanced Si compared to the control animals. Al(3+) increased LPO measured by thiobarbituric acid reactive substances (TBARS) in cerebellum and hippocampus, whereas SiO2 reduced it when compared with the control group. An increase of AChE activity was observed in the Al-treated group in the cerebellum whereas a decrease of this enzyme activity was observed in the cortex and hippocampus in the Al and Al + Si groups. Al and Si concentrations increased in rat serum; however, no effect was observed in blood TBARS levels and AChE activity. SiO2 showed a protective effect in the hippocampus and cerebellum against cellular damage caused by Al(3+)-induced lipid peroxidation. Thus, SiO2 may be considered an important protector in LPO induced by Al(3+). PMID- 26050238 TI - The Yale Pharyngeal Residue Severity Rating Scale: An Anatomically Defined and Image-Based Tool. AB - The Yale Pharyngeal Residue Severity Rating Scale was developed, standardized, and validated to provide reliable, anatomically defined, and image-based assessment of post-swallow pharyngeal residue severity as observed during fiberoptic endoscopic evaluation of swallowing (FEES). It is a five-point ordinal rating scale based on residue location (vallecula and pyriform sinus) and amount (none, trace, mild, moderate, and severe). Two expert judges reviewed a total of 261 FEES evaluations and selected a no residue exemplar and three exemplars each of trace, mild, moderate, and severe vallecula and pyriform sinus residue. Hard copy color images of the no residue, 12 vallecula, and 12 pyriform sinus exemplars were randomized by residue location for hierarchical categorization by 20 raters with a mean of 8.3 years of experience (range 2-27 years) performing and interpreting FEES. Severity ratings for all images were performed by the same 20 raters, 2 weeks apart, and with the order of image presentations randomized. Intra-rater test-retest reliability, inter-rater reliability, and construct validity were determined by pooled multi-category multi-rater kappa statistics. Residue ratings were excellent for intra-rater reliability for vallecula (kappa = 0.957 +/- 0.014) and pyriform sinus (kappa = 0.854 +/- 0.021); very good to excellent for inter-rater reliability for vallecula (kappa = 0.868 +/- 0.011) and pyriform sinus (kappa = 0.751 +/- 0.011); and excellent for validity for vallecula (kappa = 0.951 +/- 0.014) and pyriform sinus (kappa = 0.908 +/- 0.017). Clinical uses include accurate classification of vallecula and pyriform sinus residue severity patterns as none, trace, mild, moderate, or severe for diagnostic purposes, determination of functional therapeutic change, and precise dissemination of shared information. Scientific uses include tracking outcome measures, demonstrating efficacy of interventions to reduce pharyngeal residue, investigating morbidity and mortality in relation to pharyngeal residue severity, and improving training and accuracy of FEES interpretation by students and clinicians. The Yale Pharyngeal Residue Severity Rating Scale is a reliable, validated, anatomically defined, and image-based tool to determine residue location and severity based on FEES. PMID- 26050239 TI - Health-Seeking Behaviors of Filipino Migrants in Australia: The Influence of Persisting Acculturative Stress and Depression. AB - This study examined the relationships among the constructs of acculturative stress, depression, English language use, health literacy, and social support and the influence of these factors on health-seeking behaviors of Filipino Australians. Using a self-administered questionnaire, 552 respondents were recruited from November 2010 to June 2011. Structural equation modelling was used to examine relationships. A direct and negative relationship between health seeking behaviors and depression, and an indirect relationship with acculturative stress, was observed mediated through depression. Social support had an important moderating influence on these effects. Although there was an inverse relationship between age and English language usage and depression, age was positively related to health-seeking behavior. Despite their long duration of stay, Filipino Australian migrants continue to experience acculturative stress and depression leading to lower health-seeking behaviors. This study highlights the importance of screening for acculturative stress and depression in migrants and fostering social support. PMID- 26050240 TI - The first artificial Mn4Ca-cluster mimicking the oxygen-evolving center in photosystem II. PMID- 26050241 TI - Severe opioid withdrawal syndrome after a single dose of nalmefene. PMID- 26050242 TI - Predictors of Change in BMI From the Age of 4 to 8. AB - OBJECTIVES: To examine appetite traits, level of physical activity, and television (TV) time as predictors of change in Body Mass Index Standard Deviation Score (BMI SDS) from age 6 to 8 and to explore the effect of BMI SDS (from age 4) on appetite traits. METHODS: In all, 995 Norwegian children participated at age 4; 760 and 687 of these children took part in the assessment at ages 6 and 8, respectively. Appetite traits were assessed using the Children's Eating Behavior Questionnaire, activity was measured using accelerometers, and TV time was based on parental reports. RESULTS: High food responsiveness predicted a steeper increase in BMI SDS. A reversed effect was also observed: High BMI SDS predicted increased food responsiveness and decreased satiety responsiveness. Physical activity and TV time were unrelated to BMI SDS. CONCLUSION: Children whose eating is especially triggered by the sight and smell of food show prospective increased weight gain. Excess weight and weight gain also predict increased food-approaching behavior. PMID- 26050243 TI - Risk Factors for Disordered Eating in Overweight Adolescents and Young Adults. AB - OBJECTIVE: To investigate risk factors for disordered eating among overweight youth, a subset of the population particularly at risk for such behaviors. METHODS: A population-based sample of overweight youth (n = 553) self-reported their disordered eating (binge eating, extreme weight control behaviors), depression-related symptoms, body dissatisfaction, and weight-related teasing at 5-year intervals spanning early/middle adolescence (Time 1; T1), middle adolescence/early young adulthood (Time 2; T2), and early/middle young adulthood (Time 3; T3). RESULTS: Using logistic regression, we found that T2 depression related symptoms (p = .02) and body dissatisfaction (p = .01), and increases in body dissatisfaction from T1 to T2 (p = .03), predicted disordered eating incidence at T3. CONCLUSIONS: Depression-related symptoms and body dissatisfaction appear to be important risk factors for disordered eating among overweight youth. Eating disorder prevention programs should address these factors along with behaviors maintaining or exacerbating excess weight status. PMID- 26050244 TI - Topical Review: Translating Translational Research in Behavioral Science. AB - OBJECTIVE: To present a model of translational research for behavioral science that communicates the role of behavioral research at each phase of translation. METHODS: A task force identified gaps in knowledge regarding behavioral translational research processes and made recommendations regarding advancement of knowledge. RESULTS: A comprehensive model of translational behavioral research was developed. This model represents T1, T2, and T3 research activities, as well as Phase 1, 2, 3, and 4 clinical trials. Clinical illustrations of translational processes are also offered as support for the model. CONCLUSIONS: Behavioral science has struggled with defining a translational research model that effectively articulates each stage of translation and complements biomedical research. Our model defines key activities at each phase of translation from basic discovery to dissemination/implementation. This should be a starting point for communicating the role of behavioral science in translational research and a catalyst for better integration of biomedical and behavioral research. PMID- 26050245 TI - Adolescent Peer Victimization and Physical Health Problems. AB - OBJECTIVE: Peer victimization (PV) is a key interpersonal stressor that can be traumatizing for youth. This study evaluated the relationships between overt, relational, reputational, and cyber PV and adolescents' somatic complaints and sleep problems. Symptoms of depression and social anxiety were examined as potential mediators. METHOD: Adolescents (N = 1,162; M age = 15.80 years; 57% female; 80% Hispanic) were assessed at three time points, 6 weeks apart, using standardized measures of PV, depression, social anxiety, sleep problems, and somatic complaints. Structural equation modeling evaluated key study aims. RESULTS: Relational, reputational, and cyber PV, but not overt PV, were directly or indirectly associated with subsequent somatic complaints and/or sleep problems. Depression and social anxiety mediated relationships between relational PV and health outcomes, whereas reputational PV was indirectly associated with somatic complaints via depression only. DISCUSSION: The stress of PV may contribute to adolescents' sleep problems and somatic complaints and has implications for pediatric psychologists. PMID- 26050246 TI - Bounagaea algeriensis gen. nov., sp. nov., an extremely halophilic actinobacterium isolated from a Saharan soil of Algeria. AB - A novel halophilic actinobacterium strain, designated H8(T), was isolated from a Saharan soil sample collected in El-Golea, South Algeria. Strain H8(T) was identified as representing a new genus using a polyphasic taxonomic approach. Phylogenetic analysis revealed that strain H8(T) shared the highest degree of 16S rRNA gene sequence similarity with 'Mzabimyces algeriensis' DSM 46680(T) (93.0 %), Saccharopolyspora ghardaiensis DSM 45606(T) (91.2 %), Halopolyspora alba DSM 45976(T) (90.8 %) and Actinopolyspora mortivallis DSM 44261(T) (90.0 %). The strain was found to grow optimally at 28-35 degrees C, at pH 6.0-7.0, and in the presence of 15-25 % (w/v) NaCl. The substrate mycelium was observed to be well developed and fragmented in liquid medium and on solid medium. The aerial mycelium was observed to be moderately abundant and to form long chains with non motile, smooth-surfaced and ovoid or spherical spores at maturity. The cell wall of strain H8(T) was found to contain meso-diaminopimelic acid. The whole-cell hydrolysates were found to mainly contain arabinose and galactose. The diagnostic phospholipid detected was phosphatidylcholine, and MK-9(H4), MK-9(H2) and MK 10(H2) were found to be the predominant menaquinones. The major cellular fatty acids were determined to be anteiso-C17:0 and iso-C15:0. The genomic DNA G+C content of strain H8(T) was determined to be 71.3 mol%. The genotypic and phenotypic data showed that the strain represents a novel genus and species, for which the name Bounagaea algeriensis gen. nov., sp. nov. is proposed, with the type strain H8(T) (=DSM 45966(T) = CECT 8470(T)). PMID- 26050247 TI - Can the Anesthesiologist Use the Radial Artery for Monitoring After Transradial Artery Catheterization? AB - The use of transradial coronary angiography and intervention is growing because of its advantages over the femoral approach. However, the small size of the radial artery can contribute to complications. We present a case of an in situ access complication of transradial coronary artery catheterization. It is important for the anesthesiologist to know about the short-term and long-term consequences of this intervention, which could lead to narrowing of the artery even beyond the site of puncture. Understanding these changes could help anesthesiologists make better decisions about using the radial artery for monitoring after transradial coronary artery catheterization procedures. PMID- 26050248 TI - Presumed Group B Streptococcal Meningitis After Epidural Blood Patch. AB - Bacterial meningitis after epidural catheter placement is rare. We describe a case in which a parturient received labor epidural analgesia for vaginal delivery complicated by dural puncture. The patient developed postdural puncture headache and underwent 2 separate epidural blood patch procedures. She subsequently developed a headache with fever and focal neurologic deficits. She was treated with broad spectrum antibiotics for presumed meningitis, and she made a full recovery. Blood cultures subsequently grew group B streptococcus. PMID- 26050249 TI - Cesarean Delivery in a Parturient with Left Ventricular Noncompaction Complicated by Acute Pulmonary Hypertension After Methylergonovine Administration for Postpartum Hemorrhage. AB - Left ventricular noncompaction is a rare congenital cardiomyopathy that is an arrest in the normal process of cardiac compaction, resulting in the development of multiple prominent trabeculations in the left ventricle. We report a case of a parturient with left ventricular noncompaction causing decompensated heart failure who underwent cesarean delivery that was complicated by an acute pulmonary hypertensive crisis. PMID- 26050250 TI - Lack of Effect of Platelet Transfusions and Desmopressin on Intracranial Bleeding in a Patient Receiving Ticagrelor. AB - We describe a case of a 67-year-old man who required emergency surgery for acute intracranial bleeding after having received a loading dose of aspirin and ticagrelor for an acute ST-elevation myocardial infarction. Before and during the craniocervical decompression, the assessment of platelet function was performed using the Multiplate(r) analyzer. Biological evaluation of platelet function was consistent with the clinical impression, suggesting that platelet transfusion and desmopressin administration in the presence of ticagrelor had very little, if any, hemostatic effect. PMID- 26050251 TI - A retrospective study of cutaneous drug reactions in an outpatient population. AB - BACKGROUND: Adverse cutaneous drug reactions (ACDR) are unexpected cutaneous changes occurring at drug dosages that are normally used for disease prophylaxis, diagnosis or treatment. OBJECTIVE: The aim of the study was to determine the clinical types of ACDR, the causative agents, the latency time between drug intake and onset of ACDR and the recovery time in an outpatient population. METHOD: Ninety-five patients diagnosed with ACDR at the Department of Dermatology of the University of Genoa between 2003 and 2012 were retrospectively studied. RESULTS: Antimicrobials, especially cephalosporins, were the most responsible for ACDR, followed by non-steroidal anti-inflammatory drugs and antihypertensives. The most common clinical manifestations were exanthema (42.1%), erythema multiforme (10.53%) and vasculitis (9.53%). Patients with peripheral eosinophilia showed a more severe clinical manifestation, they were treated with systemic therapies and their recovery time was longer. CONCLUSION: It is important to have an appropriate clinical approach according to the ACDR severity degree. We think that eosinophilia may characterise severe cutaneous eruptions and that it should always be investigated when ACDR is suspected in order to manage the patient with the appropriate treatment. PMID- 26050252 TI - Colonization of Hospital Water Networks by Gemmata massiliana, a New Planctomycetes Bacterium. AB - Planctomycetes have been isolated from various hydric environments. These fastidious bacteria are overlooked by routine 16S rRNA gene-based PCR detection in hospital laboratories, and their presence has not been documented in the health-care environment. Using a specific culture protocol, we recently isolated a new, non-filterable Planctomycetes species, Gemmata massiliana, from one hospital water network. The goal of the study was to monitor the presence of G. massiliana in two hospital water networks. We developed a G. massiliana-specific real-time PCR system and monitored the presence of the Planctomycetes for 12 months in two hospital water networks, in filtered water collected at the intensive care unit and in non-filtered water collected from dental chairs, tanks, and usage points. Four of 180 (2.2%) filtered water samples tested positive versus 23 of 204 (11.3%) non-filtered points (p < 0.05), including 18 of 128 (14.1%) dental chairs, 3 of 51 (5.9%) usage points, and two of 25 (8%) tank specimens. There was no significant difference in the prevalence of G. massiliana between the two hospitals (p > 0.05). However, this organism was detected significantly more frequently during April and September than the 10 other months. Because G. massiliana is deeply entrenched in the hospitalized patient's environment, evaluating this organism as a new opportunistic, health-care associated pathogen is warranted. PMID- 26050253 TI - Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. AB - BACKGROUND: The number of Mendelian randomization analyses including large numbers of genetic variants is rapidly increasing. This is due to the proliferation of genome-wide association studies, and the desire to obtain more precise estimates of causal effects. However, some genetic variants may not be valid instrumental variables, in particular due to them having more than one proximal phenotypic correlate (pleiotropy). METHODS: We view Mendelian randomization with multiple instruments as a meta-analysis, and show that bias caused by pleiotropy can be regarded as analogous to small study bias. Causal estimates using each instrument can be displayed visually by a funnel plot to assess potential asymmetry. Egger regression, a tool to detect small study bias in meta-analysis, can be adapted to test for bias from pleiotropy, and the slope coefficient from Egger regression provides an estimate of the causal effect. Under the assumption that the association of each genetic variant with the exposure is independent of the pleiotropic effect of the variant (not via the exposure), Egger's test gives a valid test of the null causal hypothesis and a consistent causal effect estimate even when all the genetic variants are invalid instrumental variables. RESULTS: We illustrate the use of this approach by re analysing two published Mendelian randomization studies of the causal effect of height on lung function, and the causal effect of blood pressure on coronary artery disease risk. The conservative nature of this approach is illustrated with these examples. CONCLUSIONS: An adaption of Egger regression (which we call MR Egger) can detect some violations of the standard instrumental variable assumptions, and provide an effect estimate which is not subject to these violations. The approach provides a sensitivity analysis for the robustness of the findings from a Mendelian randomization investigation. PMID- 26050254 TI - Data Resource Profile: Clinical Practice Research Datalink (CPRD). AB - The Clinical Practice Research Datalink (CPRD) is an ongoing primary care database of anonymised medical records from general practitioners, with coverage of over 11.3 million patients from 674 practices in the UK. With 4.4 million active (alive, currently registered) patients meeting quality criteria, approximately 6.9% of the UK population are included and patients are broadly representative of the UK general population in terms of age, sex and ethnicity. General practitioners are the gatekeepers of primary care and specialist referrals in the UK. The CPRD primary care database is therefore a rich source of health data for research, including data on demographics, symptoms, tests, diagnoses, therapies, health-related behaviours and referrals to secondary care. For over half of patients, linkage with datasets from secondary care, disease specific cohorts and mortality records enhance the range of data available for research. The CPRD is very widely used internationally for epidemiological research and has been used to produce over 1000 research studies, published in peer-reviewed journals across a broad range of health outcomes. However, researchers must be aware of the complexity of routinely collected electronic health records, including ways to manage variable completeness, misclassification and development of disease definitions for research. PMID- 26050255 TI - Sex hormone-binding globulin associations with circulating lipids and metabolites and the risk for type 2 diabetes: observational and causal effect estimates. AB - BACKGROUND: The causal role of circulating sex hormone-binding globulin (SHBG) for type 2 diabetes is controversial. Information on the relations between SHBG and new biomarkers of cardiometabolic risk is scarce. METHODS: We applied quantitative nuclear magnetic resonance metabolomics in three Finnish population based cohorts to comprehensively profile circulating lipids and metabolites and study their associations with SHBG. Mendelian randomization was used to examine potential causality of SHBG on the metabolic measures and insulin resistance. Prospective associations and causal effect estimates of SHBG on type 2 diabetes were assessed via meta-analysis including summary statistics from the DIAGRAM consortium. RESULTS: In cross-sectional analysis in 6475 young adults (mean age 31, 57% men), higher SHBG was linked with a more favourable cardiometabolic risk profile, including associations with lipoprotein subclasses, fatty acid composition, amino acids, ketone bodies and inflammation-linked glycoproteins. Prospective analysis of 1377 young adults with 6-year follow-up indicated that SHBG is also associated with future insulin resistance. Mendelian randomization suggested only minor, if any, causal effects of SHBG on lipid and metabolite measures and insulin resistance(n = 10,895).Causal effect estimates on type 2 diabetes for 41,439 cases and 103,870 controls indicated a causative protective role of SHBG (OR = 0.83 per 1-SD, 95% CI: 0.76, 0.91); however, effects were considerably weaker than observed in meta-analysis of prospective studies [hazard ratio (HR) = 0.47 per 1-SD, 95% CI: 0.41, 0.53]. CONCLUSION: Circulating SHBG is strongly associated with systemic metabolism and predictive for insulin resistance and diabetes. The weaker causal estimates suggest that the observational associations are partly confounded rather than conferred directly via circulating SHBG. PMID- 26050256 TI - Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium. AB - BACKGROUND: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). METHODS: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49,066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17,672/31,394 with/without periodontitis); 68,761 participants with BMI and genotype data; and 57,871 participants (18,881/38,990 with/without periodontitis) with data on BMI and periodontitis. RESULTS: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. CONCLUSIONS: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals. PMID- 26050260 TI - Desmoplastic melanoma, neurotropism, and neurotrophin receptors--what we know and what we do not. AB - Desmoplastic melanoma (DM) is a relatively rare cytomorphologic variant of melanoma with a marked propensity for perineural invasion (PNI). Historically, DMs that display PNI have been grouped under the umbrella term of neurotropic melanoma (NM). However, definitions for NM and desmoplastic NM are not consistent in the literature, presenting a barrier to a comprehensive understanding of these lesions. In this review, we parse the literature on DM, NM, and desmoplastic NM, to clarify definitions and ascertain the incidence of PNI, with a view toward understanding its prognostic relevance. Neurotrophins, which represent a family of signaling peptides important to the development and maintenance of the peripheral nervous system, have been implicated in the pathogenesis of PNI in select lineage-unrelated malignancies. Given this, we also detail evidence linking neurotrophins and their receptors (TrkA, RET, p75NGFR, and NCAM) to the pathogenesis of PNI in melanoma. PMID- 26050257 TI - Anthropometry and head and neck cancer:a pooled analysis of cohort data. AB - BACKGROUND: Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies. METHODS: We pooled data from 1,941,300 participants, including 3760 cases, in 20 cohort studies and used multivariable adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status. RESULTS: Greater waist circumference (per 5 cm: HR = 1.04, 95% CI 1.03-1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05-1.09, P value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m(2): HR = 1.15, 95% CI 1.06-1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m(2): HR = 0.99, 95% CI 0.93-1.06, P value for trend = 0.79) or current smokers (per 5 kg/m(2): HR = 0.76, 95% CI 0.71 0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5 cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers. CONCLUSIONS: Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers. PMID- 26050261 TI - Malignant sweat gland tumors: an update. AB - Sweat gland carcinomas represent an important and somewhat contentious group of tumors in diagnostic skin pathology. Although their overall incidence is rare, they show a wide range of histologic features, and reliable classification is often challenging. Awareness and recognition of these tumors is, however, important as they may be associated with significant morbidity and even disease related mortality, especially if left untreated. According to their behavior, sweat gland carcinomas are traditionally separated into tumors with low-grade and high-grade malignant behavior. This article is aimed at increasing awareness and providing an overview of malignant sweat gland tumors with emphasis on recently reported and novel findings and diagnostically challenging and potentially underrecognized entities. It further aims to illustrate the wide morphologic range of these tumors and provides a discussion of the relevant immunohistochemistry, disease-specific behavior, and differential diagnosis. PMID- 26050259 TI - Carbohydrate-binding activities of coagulation factors fibrinogen and fibrin. AB - The coagulation factors fibrinogen and fibrin play important roles in the final stage of the blood coagulation cascade. It has not been revealed whether fibrinogen has lectin activity or not. Here we demonstrate that fibrinogen and fibrin have carbohydrate-specific binding activities that inhibit fibrin clot formation. A solid-phase binding study using sugar-biotinyl polymer probes revealed that fibrinogen has the highest affinity to mannose (Man) in both the presence and absence of 5 mM Ca(2+). Fibrin, which is proteolytically produced from fibrinogen by thrombin, binds to the same sugar residues as fibrinogen in the presence of 5 mM Ca(2+), while it markedly binds to N-acetylneuraminic acid in the absence of Ca(2+). Thrombin-induced fibrin polymerization was monitored by turbidity at 350 nm. In the presence of Ca(2+), Man and sugars having N-acetyl groups were found to inhibit the increase in turbidity, but only Man inhibited it in the absence of Ca(2+). Scanning electron microscopy observation of fibrin clots formed in the presence of various sugars showed that fibrin fibers formed in the presence of Man and N-acetyl group sugars were thinner and more branched. In contrast, thrombin has neither carbohydrate-binding activity nor is affected by sugars. These results suggest that carbohydrates and glycoconjugates may regulate fibrin clot formation in vivo. PMID- 26050258 TI - Paramagnetic NMR probes for characterization of the dynamic conformations and interactions of oligosaccharides. AB - Paramagnetism-assisted nuclear magnetic resonance (NMR) techniques have recently been applied to a wide variety of biomolecular systems, using sophisticated immobilization methods to attach paramagnetic probes, such as spin labels and lanthanide-chelating groups, at specific sites of the target biomolecules. This is also true in the field of carbohydrate NMR spectroscopy. NMR analysis of oligosaccharides is often precluded by peak overlap resulting from the lack of variability of local chemical structures, by the insufficiency of conformational restraints from nuclear Overhauser effect (NOE) data due to low proton density, and moreover, by the inherently flexible nature of carbohydrate chains. Paramagnetic probes attached to the reducing ends of oligosaccharides cause paramagnetic relaxation enhancements (PREs) and/or pseudocontact shifts (PCSs) resolve the peak overlap problem. These spectral perturbations can be sources of long-range atomic distance information, which complements the local conformational information derived from J couplings and NOEs. Furthermore, paramagnetic NMR approaches, in conjunction with computational methods, have opened up possibilities for the description of dynamic conformational ensembles of oligosaccharides in solution. Several applications of paramagnetic NMR techniques are presented to demonstrate their utility for characterizing the conformational dynamics of oligosaccharides and for probing the carbohydrate recognition modes of proteins. These techniques can be applied to the characterization of transient, non-stoichiometric interactions and will contribute to the visualization of dynamic biomolecular processes involving sugar chains. PMID- 26050262 TI - Composite hemangioendothelioma: clinical and histologic features of an enigmatic entity. AB - Composite hemangioendotheliomas are rare vascular neoplasms of intermediate biological potential, characterized by a complex admixture of benign, low-grade malignant, and malignant vascular components. They can affect both adults and children, and occur predominantly as long-standing lesions in the dermis and subcutis of the extremities, but have also been increasingly reported at other sites, including the oral cavity and in viscera such as kidney and spleen. These usually behave in a low-grade manner, with a relatively high rate of local recurrence and rarely lymph node and distant metastases, but no tumor-related deaths have been reported. Microscopically these are heterogenous neoplasms with merging of different vascular patterns, which immunohistochemically variably express vascular endothelial markers. Because of the wide morphologic spectrum, they can be difficult to recognize, but accurate diagnosis is crucial for correct treatment and prognostication. We review the literature, discussing clinical and histopathologic features, and the differential diagnosis of these rare tumors. PMID- 26050263 TI - Differential diagnostic considerations of desmoid-type fibromatosis. AB - Fibrous and myofibroblastic tumors of soft tissue often present the surgical pathologist with a difficult differential diagnosis because of the number of diagnostic possibilities and morphologic similarities among cytologically bland spindle-cell tumors. Prototypical in this regard is desmoid-type fibromatosis. In a review of 320 surgical specimens diagnosed as desmoid tumor, 94 (29%) were discovered to be misclassified as such. The most common lesions in this series were Gardner fibroma, scar tissue, superficial fibromatosis, nodular fasciitis, myofibroma, and collagenous fibroma. Four sarcomas were also misinterpreted as desmoid-type fibromatosis (3 low-grade fibromyxoid sarcomas and 1 unclassified spindle-cell sarcoma). We take this opportunity to compare and contrast desmoid tumor and several of the soft tissue tumors that should be considered in the differential diagnosis thereof. PMID- 26050264 TI - Pathology to enhance precision medicine in oncology: lessons from landscape ecology. AB - A major goal of modern medicine is increasing patient specificity so that the right treatment is administered to the right patient at the right time with the right dose. While current cancer studies have largely focused on identification of genetic or epigenetic properties of tumor cells, emerging evidence has clearly demonstrated substantial genetic heterogeneity between tumors in the same patient and within subclones of a single tumor. Thus, molecular analysis from populations of cells (either a whole tumor or small biopsy of that tumor) is, at best, an incomplete representation of the underlying biology. These observations indicate a significant need to define intratumoral evolutionary dynamics that yield the observed spatial variations in cellular properties. It is generally accepted that genetic heterogeneity among cancer cells is a manifestation of intratumoral evolution, and this is typically viewed as a consequence of random mutations generated by genomic instability within the cancer cells. We suggest that this represents an incomplete view of Darwinian dynamics, which typically are governed by phenotypic variations in response to spatial and temporal heterogeneity in environmental selection forces. We propose that pathologic feature analysis can provide precise information regarding regional variations in environmental selection forces and phenotypic adaptations. These observations can be integrated using quantitative, spatially explicit methods developed in landscape ecology to interrogate heterogenous biological processes in tumors within individual patients. The ability to investigate tumor heterogeneity has been shown to inform physicians regarding critical aspects of cancer progression including invasion, metastasis, drug resistance, and disease relapse. PMID- 26050265 TI - Selected cases from the Arkadi M. Rywlin international pathology slide series: granular cell nevus of congenital type: a melanocytic proliferation exhibiting distinct morphologic, immunohistochemical, and ultrastructural features. AB - A case of combined melanocytic nevus characterized by extensive granular cytoplasmic changes is described. Clinically, the lesion presented as an irregular, slightly asymmetric, and raised pigmented lesion of back with indistinct borders. Microscopically, a congenital pattern of distribution of melanocytes could be recognized growing along follicular and adnexal units. Melanocytes were arranged in sheets of epithelioid cells with abundant granular cytoplasm. A minor component featuring conventional dermal melanocytes was also present. Mitotic figures were not recognized. Immunohistochemistry was positive for Melan A and S100 protein in both conventional melanocytes and granular cells. In addition, the granular cells were also strongly positive for HMB45 and NKI-C3. The proliferative marker Ki67/MIB1 was nonreactive. Ultrastructural examination showed large cells with round to oval nuclei and numerous scattered cytoplasmic granules showing features consistent with lysosomes or autophagosomes. No premelanosomes, glycogen, lipid, or other distinctive organelles could be identified. Clinical follow-up at 2 years was uneventful. This unusual lesion may represent a peculiar dermal melanocytic proliferation in which the abundant granular cytoplasm is most likely due to degeneration of melanosomes induced by autophagocytic activity. The striking cytoplasmic granularity observed in this lesion may lead to confusion with other conditions, thus warranting adding granular cell nevus to the phenotypic spectrum of benign melanocytic proliferations. PMID- 26050266 TI - The quest for diagnosis of minor salivary gland neoplasms from biopsy. PMID- 26050267 TI - Pitfalls in the biopsy diagnosis of intraoral minor salivary gland neoplasms: diagnostic considerations and recommended approach. PMID- 26050269 TI - Review of the 2014-2015 influenza season in the northern hemisphere. PMID- 26050270 TI - Clinical advisory warning: increased incidence of severe sore throats with glide scope single-use disposable covers. PMID- 26050268 TI - Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with Type 1 diabetes. AB - BACKGROUND: Rapid glomerular filtration rate (GFR) decline (>3 mL/min/1.73 m(2)) is an increasingly recognized high-risk diabetic nephropathy (DN) phenotype in Type 1 diabetes. Rapid GFR decline is a recognized predictor of impaired GFR (<60 mL/min/1.73 m(2)). However, the association between rapid GFR decline and renal hyperfiltration is not well described in Type 1 diabetes. We hypothesized that renal hyperfiltration (estimated glomerular filtration rate, eGFR >= 120 mL/min/1.73 m(2)) would predict rapid GFR decline over 6 years and that rapid GFR decline would predict impaired GFR at 6 years in adults with Type 1 diabetes. METHODS: GFR was calculated by chronic kidney disease epidemiology (CKD-EPI) creatinine in 646 adults with Type 1 diabetes in the coronary artery calcification in Type 1 diabetes study. Logistic multivariable models were employed to investigate the relationships between renal hyperfiltration and rapid GFR decline, and rapid GFR decline and incident impaired GFR over 6 years. RESULTS: Renal hyperfiltration predicted greater odds of rapid GFR decline over 6 years [odds ratio (OR): 5.00, 95% confidence interval (CI): 3.03-8.25, P < 0.0001] adjusting for hemoglobin A1c (HbA1c), systolic blood pressure (SBP), low density lipoprotein cholesterol (LDL-C), sex, duration, log of albumin/creatinine ratio and estimated insulin sensitivity. Furthermore, rapid GFR decline predicted greater odds of incident impaired eGFR (OR: 15.99, 95% CI 2.34-114.37, P = 0.006) in a similarly adjusted model. Sensitivity analyses with GFR calculated by CKD EPI combined creatinine and cystatin C, and renal hyperfiltration defined as >=135 mL/min/1.73 m(2) yielded similar results. CONCLUSIONS: In adults with Type 1 diabetes, rapid GFR decline over 6 years was associated with baseline renal hyperfiltration and incident GFR impairment. These observations may suggest an intermediate and predictive role of rapid GFR decline in the progression of DN. PMID- 26050271 TI - Anesthesia and safety considerations for office-based cosmetic surgery practice. PMID- 26050272 TI - Anesthesia and safety considerations for office-based cosmetic surgery practice. PMID- 26050273 TI - The role of the AANA Education Committee in developing education standards. AB - The purpose of this column is to describe the involvement over time of the AANA Education Committee in the development of education standards for nurse anesthetists. Collaboration between the Education Committee, Council on Accreditation of Nurse Anesthesia Educational Programs, and nurse anesthesia community of interest in developing quality doctoral standards is discussed. PMID- 26050274 TI - Isobaric spinal anesthesia: a suitable approach for a morbidly obese patient. AB - Morbid obesity is a relatively common and vastly increasing condition that can have a profound impact on morbidity and mortality during the administration and maintenance of general and regional anesthesia. Physiological derangements, difficult airway management, and biological augmentation in pharmacokinetics are some of the clinical challenges involved with this particular patient population. This case report discusses the advantages of regional versus general anesthesia in the morbidly obese patient population, in conjunction with an analysis of the various types of spinal anesthetics. This will be followed by a focused discussion related to the management of a morbidly obese patient undergoing a nonelective orthopedic procedure. PMID- 26050275 TI - Awake video laryngoscope intubation: case report of a patient with a nasopharyngeal mass. AB - Difficult airway management remains central to anesthesia practice. Video laryngoscopes have been an adjunct to airway management since the early 2000s. They have been shown to improve visualization of the glottic opening and have become a useful aid in managing difficult airways. To date, the preferred method for difficult airway management remains awake fiberoptic intubation. The purpose of this article is to summarize the use of a video laryngoscope for an awake intubation and to suggest alternative uses of these devices in other awake intubation scenarios. The case report presented offers a description of successful awake intubation using a video laryngoscope in a patient with a large pedunculated mass arising from the nasopharynx and extending down into the oropharynx. PMID- 26050276 TI - Anesthetic implications of postpolio syndrome: new concerns for an old disease. AB - Poliomyelitis was pandemic in the United States and much of the world in the first half of the 20th century. The uses of polio vaccines have essentially eradicated the disease in the United States today. But poliovirus infection survivors who had experienced a paralytic attack can see a return of some symptoms, which is a syndrome called postpolio syndrome (PPS). The anesthetist must preoperatively assess reported amounts of patient physical activity and patient age, which can indicate the amount of muscle degeneration that may have already occurred. Patients with PPS demonstrate altered respiratory function, cold intolerance, a risk for aspiration, and experience chronic pain in muscles and joints. Patients with PPS display an increased sensitivity to some anesthetic agents such as long-acting narcotics and potent inhaled anesthetic gases with a high blood-gas partition coefficient, along with report of increased fatigue, weakness, and somnolence after anesthesia. Anesthesia care must center on the preservation of muscle function postoperatively. The anesthetist should consider the use of short-acting anesthetic agents, increased doses of analgesics, the use of warming devices, and careful attention to patient positioning. Prolonged postoperative care and hospital admission after surgery are possible. PMID- 26050277 TI - Ease of intubation with the Parker Flex-Tip or a standard Mallinckrodt endotracheal tube using a video laryngoscope (GlideScope). AB - Two endotracheal tubes (ETTs) are available for use in operative suites for intubation: the Parker Flex-Tip (PFT, Parker Medical) and the standard Mallinckrodt (Covidien). To the authors' knowledge, no study has compared these 2 ETTs with each other when the anesthesia provider uses the GlideScope video laryngoscope (Verathon) for intubation. The purpose of the study was to determine if there are differences related to ease of intubation reported by anesthesia providers who use the PFT tube compared with the standard tube while using the GlideScope. The study was a randomized block intervention design. The sample consisted of 58 observed intubations in an operating room setting. Data analysis was completed with a 2-factor analysis of covariance using 2 covariates. The PFT tube in suboptimal conditions demonstrated a significantly greater ease of intubation, as measured by decreased time for ETT insertion and greater ease of ETT insertion score. The number of redirections at the glottis to intubate the trachea once the glottis was visualized was not statistically different. Based on the findings from this study, anesthesia providers may want to consider the use of the PFT tube when using the GlideScope to promote ease of intubation. PMID- 26050278 TI - A Cesarean hysterectomy for invading placenta percreta: anesthetic safety considerations--a case report. AB - A 41-year-old woman presented to the surgical suite with an undiagnosed placenta percreta invading the bladder. The patient lost 16,000 mL of blood before the hemorrhage was surgically controlled, and a successful cesarean delivery, as well as a total abdominal hysterectomy, were performed. Ultimately, the patient was discharged 1 week later with a healthy baby. Unlike placenta accreta where the placenta strictly adheres to the musculature of the uterus, placenta percreta is a rare condition in which the placenta invades the full thickness of the myometrium and possibly other intra-abdominal organ structures. A review of the current literature yields recommendations for anesthetic management of this challenging and potentially life-threatening obstetric scenario. This case underlines the importance of a well-coordinated multidisciplinary approach to a complex condition. PMID- 26050279 TI - Emergency cesarean delivery in primigravida with portal hypertension, esophageal varices, and preeclampsia. AB - The incidence of cirrhosis and advanced portal hypertension during pregnancy is very low, and the literature is scarce with regard to the anesthetic management of a parturient with this coexisting disease. We report the successful perioperative management of a parturi- ent with a history of cirrhosis and portal hypertension with esophageal varices and mild preeclampsia who presented at 38 weeks' gestation in active labor with a breech presentation requiring emergency cesarean delivery. She required endoscopic esophageal varices banding during the second trimester of pregnancy. After correction of her coagulopathy, she was administered subarachnoid block and cesarean delivery, which was conducted uneventfully. Anesthetic management of these patients depends on understanding and avoiding variceal hemorrhage, encephalopathy, renal failure, and careful fluid and electrolyte management. PMID- 26050280 TI - Dexmedetomidine infusion as an adjunct anesthetic for tetralogy of fallot repair during a pediatric cardiac mission trip in Jamaica: a case report. AB - Dexmedetomidine was used as an adjunct anesthetic for an infant with tetralogy of Fallot (TOF). who underwent complete surgical repair during a mission trip in Jamaica. Anesthetic maintenance was achieved with the concomitant use of dexmedetomidine and remifentanil infusions, as well as inhalational sevoflurane. The dexmedetomidine infusion ranged from 0.3 to 0.5 ug/kg/h and the remifentanil infusion ranged from 0.5 to 2 ug/kg/min, with end-tidal sevoflurane ranging from 0.8% to 6%. The continuous infusion of dexmedetomidine in a complex pediatric cardiac surgical patient provides sedation, decreases the need for narcotics and volatile agents, while also providing improved hemodynamic stability. This report includes a review of the anatomy and pathophysiology of tetralogy of Fallot, medical and surgical treatments, anesthetic management, as well as global health issues involved in caring for complex cardiac patients in this underserved population. The expertise and dedication of medical mission professionals ensures that children in developing Caribbean countries receive life-saving heart surgery that would otherwise not be available. Collaboration between pediatric cardiac surgery programs in the United States and developing programs in the Caribbean is vital to the future of a self-sustaining cardiac program that will provide the knowledge and resources to care for these complex cardiac patients. PMID- 26050281 TI - Is that snoring something to worry about? Anesthetic implications for obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a chronic disease that is underdiagnosed. It is characterized by repetitive pauses in breathing during sleep that can last for several seconds and can subsequently cause hypoxia-related complications. This apnea can lead to significant medical problems, daytime somnolence, cognitive impairment, decreased work productivity, and an increased risk of motor vehicle crashes. Patients having diagnostic procedures or surgeries in which sedation or anesthesia will be received should be evaluated for OSA to prevent or reduce postoperative complications. The Berlin Questionnaire and the STOP-BANG Questionnaire are useful tools that can be used preoperatively to identify patients at risk for surgical complications. If patients who have OSA or who are at risk for having OSA are identified before surgery, anesthesia providers can take action to prevent perioperative complications. Guidelines published by the American Society of Anesthesiologists provide helpful anesthetic considerations for patients with OSA undergoing surgery in an effort to decrease morbidity and mortality. While research into the effects of surgery and anesthesia in patients affected by OSA is ongoing, compliance with these recommendations, along with vigilance, will help ensure that many patients with OSA can be managed safely during their surgical experiences. PMID- 26050282 TI - Enlightened or barbaric? Re-evaluating shell shock treatment. AB - The vastly contrasting treatment approaches for shell shock devised by Dr William Rivers at the Craiglockhart War Hospital in Edinburgh and Dr LewisYealland at the Queen Square Neurological Hospital in London are indicative of the disparate response of WWI medical professionals to the unprecedented number of afflicted soldiers. Their respective legacies have been subject to equally contrasting evaluations in modern times: Rivers is heralded as a 'founding father' in psychotherapy; his methods celebrated for their compassion and humanity, while Yealland's techniques have found closer comparison with torture and sadistic experimentation. This paper argues that judgments of these two physicians are guilty of oversight, and consequently, in Yealland's case particularly, warrant a more nuanced assessment. Besides the miles of destroyed countryside, maimed bodies, and interminable bloodshed, the horrors of trench warfare gave rise to a new kind of malady. It chose no sides, but in all cases, having suffered no discernible physical injury, soldiers succumbed to a variety of debilitating and yet mysterious behaviours: shrieking fits, paralysis, blindness or muteness, to name but a few. This neurosis decimated the soldier's ability to function, let alone fight, and the victims began to congest military hospitals, puzzling doctors more accustomed to dealing with conventional battle field casualties. Charles Myers, a British psychologist, ascribed the symptoms to extreme mental stress, utilising a term already familiar to men in the trenches: 'shell shock'. PMID- 26050283 TI - Professor Frantisek Por, MD--an outstanding internist in the former Czechoslovakia. AB - Professor Frantisek Por, MD, (1899-1980) graduated at the German Medical Faculty of Charles University (GMF-CHU) in Prague in 1926. In January 26, 1945 he was captured, together with his wife, by the Gestapo and they were deported to the concentration camp to Sered' and later to Terezin (Czechoslovakia) from where they were liberated by the Soviet Army on May 8, 1945. He was a founder and the head of the Internal Clinic of the new Medical Faculty in Kosice, from October 1, 1948 until 1971. Professor Por, MD created a school of internal medicine specialists in Eastern Slovakia and many of his co-workers achieved considerable success in internal medicine in Slovakia. He was the founder of Eastern Slovakian Medical Meetings in Novy Smokovec, in the High Tatras, in 1961, the 50th Meeting was held in 2011. Since 1994 the Medical Society in Kosice has organized an annual Meeting in his memory. PMID- 26050284 TI - A victory over the plague in Moscow 1770-1772. AB - The Great Plague in Moscow 1770-1772 was suppressed in four months due to the strict and effective administrative measures and outstanding efforts of the doctors in Moscow. For many decades of the previous century the role of the Russian nobility in this victory was "forgotten". In this paper, based on the original documents published just after the Plague in 1775, a real historical picture of that Great Victory has been reconstructed. Many errors and inaccuracies in our historical-medical literature have been corrected and the forgotten role of the Russian nobility in suppressing this serious epidemic has been resurrected. This includes the role of the Senate, the Empress Catherine the Great and Count Gregory Orlov who had been sent by her to Moscow with unlimited power "to put everything in due order", as well as contribution of the Russian scientists in the worldwide struggle against plague. PMID- 26050285 TI - Fighting disease and epidemics: Ricardo Jorge and the internationalization of Portuguese science. AB - Ricardo Jorge was one of the principal doctors responsible for the sanitary transition in Portugal. He created and enforced the most important policies for disease control, both endemic and epidemic, which scourged the western world between the mid nineteenth century and beginning of the twentieth. His professional training and academic and scientific performances reveal Ricardo Jorge's value in Portuguese science and his efforts for its internationalization. His capacities were confirmed by the emergency of the sanitary situations with which he was confronted and by the authorities' confidence in him, by putting him in charge of the bubonic plague elimination process. PMID- 26050286 TI - The County Council of the Order of Physicians in Ille et Vilaine (France) during the Second World War. AB - Initially, the examination of the archives from the Ille et Vilaine Council of the College of Physicians was based solely on the findings of Dr. George from Rennes who had helped Jews during the Occupation. Gradually I perceived that the quality of available documents permitted writing this article to show a contrasting view of this dark period in our history. This work aimed to analyze the role of the County Council (CC) of Ille et Vilaine through minutes of their meetings and to compare, year by year, directives and circulars from the Supreme Council of the Order of Physicians (SCO) sent to CC at this period. We will observe see that between the institution, acting by strictly following the orders from the "French State", and the county councils, for some at least, there was a gap that men of good will knew not to cross. PMID- 26050287 TI - Surgical pain management at the Medical School of Salerno (11th-13th centuries). AB - Before the advent of general anesthesia, only poorly effective remedies were known to relieve pain. Although classical medical authorities describe a number of elaborate surgical techniques, no references about some forms of anesthesia are reported. Only the authors of pharmaceutical or botanical texts mention the use of substances, especially mandrake, to induce sleep in the patient. The first and most detailed evidences of general anesthesia described in medical texts of the western world can be found at the Medical School of Salerno. However, the use of substances aimed to relieve pain or to induce sleep during surgery is mentioned only by the authors of pharmaceutical or botanical texts and not by surgeons. Furthermore, the efficacy of these preparations to produce a profound and lasting sleep is doubtful. The general impression is that surgeons knew how to relieve pain, but considered it a necessary appendix of surgery and therefore an incisive effort to eliminate it was not pursued. PMID- 26050288 TI - The Dracula romance in the context of 19th century medicine. PMID- 26050289 TI - The confrontation between the 'pro-cesareans and the 'anti-cesareans' in eighteenth century France. AB - Cesarean section is a one of the earliest and the most fascinating surgical procedures. Descriptions of first authentic successful cases of cesarean delivery of a living woman appeared in the 16th century. Still, mainly due to poor outcome, the performance of cesarean section remained controversial for the next three centuries. In the 18th century France, a hasty debate had commenced between the 'pro-cesareans' (represented by Jean-Louis Baudelocque) and the 'anti cesareans' (represented by Jean Francois Sacombe) that involved medical as well as judicial issues. It seems that the 'pro-cesareans' had overcome the 'anti cesareans' in this debate at that time. PMID- 26050290 TI - WVSMA--working for you. PMID- 26050291 TI - West Virginia Perinatal Partnership. PMID- 26050292 TI - Treatment of holocord spinal epidural abscess via alternating side unilateral approach for bilateral laminectomy. AB - To date, this is the first reported case of the surgical management of a holocord epidural abscess done through level-skipping laminectomies. It is also the first reported case of these laminectomies being performed via an alternating side unilateral approach for this condition. A 51-year-old patient presenting with progressive lower extremity weakness secondary to a spinal epidural abscess extending from C4 to S1. A minimally disruptive method of relieving the spinal cord compression via evacuation of the abscess was employed successfully. This report demonstrates the efficacy of level skipping laminectomies via a unilateral approach for holocord epidural abscesses (extending 20 vertebral levels). Performing the laminectomies via a unilateral approach as well as alternating the side of the approach minimized iatrogenic instability risk. Both strategies were designed to minimize incision size, tissue disruption, and the amount of muscular weakness/imbalance postoperatively. PMID- 26050293 TI - Benign mesothelial mesenteric cyst: case report and literature review. AB - A rare case of a benign mesothelial cyst arising from the mesentery of the descending colon is presented. A 73 year old female presented with an asymptomatic mesenteric cyst on CT scan. Colonoscopy revealed extrinsic compression of the descending colon. Surgical resection of the cyst necessitated partial colon resection due to the adherent nature of the cyst to the colon and its mesentery. The details of the case are presented as well as a brief review of the relevant literature. PMID- 26050294 TI - Transvaginal cervical length and tobacco use in Appalachian women: association with increased risk for spontaneous preterm birth. AB - Currently ACOG recommends that a mid-term screening strategy may be considered to identify short cervix in low risk populations in an effort to prevent preterm birth. Vaginal progesterone is recommended for women with a cervical length <=20 mm. Cerclage is recommended for women with prior spontaneous preterm birth who are already receiving progesterone supplementition and CL is <25 mm. This study examined risk factors for spontaneous preterm birth (SPB) <35 weeks among a general obstetrical population prior to these ACOG recommendations. However, cervical cerclage was a possible intervention. Study population included 1,074 patients from 1 Jan 2007-30 Jun 2008 receiving mid-trimester transvaginal ultrasounds during prenatal care at a tertiary medical center clinic. Receiver operator characteristic (ROC) curve cutoff optimal value was <=34 mm, (n=224), corresponding to 8.9% SPB with shortened cervices compared to 1.4% in patients with normal cervices (>34 mm; n=850; p<0.001 (Area Under the Curve (AUC) 76.6, p<0.001). Cervical lengths <30 mm had 12 times the risk of SPB (p<0.001) while 30 34 mm had 5 times (p=0.005). Tobacco use (>=10 cigarettes per day), p=0.030, and low BMI, p=0.034, had additive effect. Shortened cervical length during routine screening independently predicted SPB while heavy smoking with shortened cervix during pregnancy doubled risk compared to shortened cervix alone. PMID- 26050295 TI - Intraoperative neuronavigation for transoral surgical approach: use of frameless stereotaxy with 3D rotational C-arm for image acquisition. AB - The transoral route is a standard surgical approach to the anterior craniovertebral junction, where neuronavigation is difficult secondary to the mobility of the cervical spine in relation to the cranium. We describe the use of neuronavigation combined with intraoperative 3D C-arm to direct our approach and resection of two lesions of the craniovertebral junction. Neuronavigation was employed in planning of incision, bony resection, and assessment of lesion resection. Both patients underwent transoral approach without complication using this method. Frameless stereotaxy with BrainLab VectorVision and 3D C-arm is an effective method of neuronavigated approach to the anterior craniocervical junction, which may contribute to the safety of this approach. PMID- 26050296 TI - Pulmonary nocardiosis in an adolescent patient with Crohn's disease treated with infliximab: a serious complication of TNF-alpha blockers. AB - Nocardiosis is a serious complication of tumor necrosis factor (TNF) alpha blockers. With the increasing use of biologics for inflammatory bowel disease, it is to be anticipated that opportunistic infections such as nocardia will be more frequently encountered in children. We present the case of a 16 year old male with Crohn's disease who developed pulmonary nocardiosis during the course of his treatment with infliximab. This case illustrates the diagnostic and therapeutic challenges faced in patients with inflammatory bowel disease infected with opportunistic organisms. Pediatric health care providers need to be aware so that early diagnosis and treatment can be provided thereby preventing disseminated disease and having favorable outcomes. Although TNF blocker therapy must be discontinued in the presence of such infections, biologic therapy may be reintroduced after successful treatment with trimethoprim-sulfamethoxazole to control underlying symptoms of inflammatory bowel disease. PMID- 26050297 TI - Stefan Maxwell, MD speaks before the Oversight and Investigations Subcommittee. PMID- 26050298 TI - Frivolous lawsuit alert. PMID- 26050299 TI - Stroke--a time critical condition. "If there's uncertainty, consider it an emergency". PMID- 26050300 TI - [Infectious diseases and Koch's postulates: turning the page]. PMID- 26050301 TI - [Non-HIV infectious disease outpatient consultations: a 5-year study in a Swiss University Hospital]. AB - Few studies have examined the workload or clinical spectrum of non-HIV infectious diseases outpatient consultations (IDOC). This retrospective study aims to describe IDOC referrals over the past 5 years. In total, 483 patients were referred (with an increase of 63% between 2009 and 2013). Most referrals were received from primary care clinicians (45%). Median patient age was 47 years, 57% of patients were men and 17% were immunosuppressed. Of the diagnoses retained, 74% were infectious, 20% were non-infectious and 6% were of unknown aetiology. Two community outbreaks were identified (tattoo-related mycobacterial infection and Q fever). In conclusion, the infectious diseases outpatient clinic, which has expanded progressively in the past 5 years, provides a specialised service for primary health clinicians and for public health. PMID- 26050302 TI - [Diagnosis of bacterial gastroenteritis]. AB - The etiologic agents of acute gastroenteritis are diverse. The diagnosis of bacterial pathogens is particularly challenging given the large amount of vastly diverse indigenous gastrointestinal organisms present in stool. Multiple methods must be used by the clinical microbiology laboratories to diagnose the cause of acute gastroenteritis, including bacterial cultures, ELISA, and microscopy. Due to the limitations of conventional methods, there is still room for improvement in the detection of pathogens by using the molecular methods. This paper discusses these different diagnostic approaches and limitations. PMID- 26050303 TI - [Community-acquired bacterial septic arthritis in adults: diagnosis and treatment]. AB - The diagnosis of acute native joint bacterial infection can be difficult, because of its non- specific clinical and biological manifestation. Its management is often an emergency. Following a joint puncture, early joint lavage is performed, either by surgical drainage or by repeated arthrocentesis; and accompanied by systemic antibiotics, of which the ideal duration and route of administration remains unknown. The postoperative care is characterized by joint mobilization to avoid joint stiffening. PMID- 26050304 TI - [Strongyloidiasis: who is at risk of severe infection and how to prevent it?]. AB - Strongyloides stercoralis hyperinfection syndrome, which carries a high mortality (60%), occurs usually after immunosuppressive therapy. Cellular immunosuppression allows the parasite to reactivate and stimulate its cycle of auto-infection. It is therefore important to prevent this syndrome by screening at risk patients at risk for chronic strongyloidiasis before starting immunosuppressive treatment and especially before treatment with corticosteroids, even that of short duration. Ivermectine is the treatment of choice. PMID- 26050305 TI - [Leptospirosis in a family after whitewater rafting in Thailand]. AB - Leptospirosis is a zoonosis found worldwide, with an incidence that is approximately 10 times higher in the tropics than in temperate regions. The main reservoir of leptospirosis is the rat and human infection usually results from exposure to infected animal urine or tissues. Only 10% of cases are symptomatic. We present here two confirmed and two probable cases of leptospirosis in a family returning from whitewater rafting in Thailand, illustrating the wide variety of the clinical manifestations of this infection. Two of the patients were hospitalized and presented a probable Jarisch-Herxheimer reaction after initiation of beta-lactam therapy. The two others patients were treated empirically with doxycycline. We discuss here some relevant aspects of the epidemiology, clinical manifestations, therapy and the challenge of an early diagnosis of leptospirosis. PMID- 26050306 TI - [Ebola: the unexpected emerging disease]. AB - In one year, Ebola virus disease has already been responsible of around 10000 deaths. 24 patients have been medically evacuated in different University Hospitals in Europe or in the United States. One medical doctor, infected during a humanitarian mission in the field has been treated in Geneva at the end of 2014. This review aims to summarize the epidemiology of the current outbreak, to describe the main virological and clinical characteristics of Ebola virus disease, and to address the most important experimental treatments available. Although the number of cases has fallen the last two months, the outbreak is not over. A safe and proctective vaccine is still needed in the race to fight this emerging viral disease. PMID- 26050307 TI - [About training in maternal and fetal medicine]. PMID- 26050308 TI - [Franco-German medical resonance of the Germanwings crash]. PMID- 26050309 TI - [The beat of his heart has stopped]. PMID- 26050310 TI - [Hepatitis C: in 2015, who should be screened first?]. PMID- 26050311 TI - [Financing of continuing education]. PMID- 26050312 TI - [Effective prevention of pneumococcal infections in adults aged 65 and over]. PMID- 26050313 TI - [Mysimba, an American appetite suppressant and the logic of the single European market]. PMID- 26050314 TI - [The Zurich pharmacists will soon vaccinate]. PMID- 26050315 TI - [The CHUV launches a pilot project of the sobering unit]. PMID- 26050316 TI - [The taste of the provisional]. PMID- 26050317 TI - [Frailty, poverty and end of life, an accumulation of sorrow]. PMID- 26050318 TI - [The patient-tracer, a new method for quality of health care improvement]. PMID- 26050319 TI - [A new study on night-shift work]. PMID- 26050320 TI - [Improving detection of adolescent depression]. PMID- 26050321 TI - [Prematurity in France, results from Epipage 2 study]. PMID- 26050322 TI - [Clues to aging well]. PMID- 26050323 TI - [#talkingcancer]. PMID- 26050324 TI - [Health campaign for cervical cancer screening]. PMID- 26050325 TI - [Stillbirths rate in slight decrease in France]. PMID- 26050326 TI - [Preliminary report on suicide from National Observatoire]. PMID- 26050327 TI - [Respiratory allergies in children and school]. PMID- 26050328 TI - [A workshop to gather political stakeholders over childhood]. PMID- 26050329 TI - [693,000 residents in housing for elderly in 2011]. PMID- 26050330 TI - ["When hypertension makes you lose your head"]. PMID- 26050331 TI - [Fight against childhood poverty]. PMID- 26050332 TI - [Aged human rights declaration, recall]. PMID- 26050333 TI - [Between Love and Hate, children's jealousy]. PMID- 26050334 TI - [Chocolate does not lift moods anymore]. PMID- 26050335 TI - [Hearing, communication and old age]. PMID- 26050336 TI - [Swimming to improve postural balance in seniors]. PMID- 26050337 TI - [Delegation of care of aged dependents]. PMID- 26050338 TI - [A "program for each child", UNICEF's wish]. PMID- 26050339 TI - [Bronchiolitis, status of the 2014-2015 epidemic]. PMID- 26050340 TI - [Key numbers on education and young children enrollment in France]. PMID- 26050341 TI - [Hospitalization without consent and information disclosure duty]. PMID- 26050342 TI - [To improve hyperactive children' sleep]. PMID- 26050343 TI - Principles of reconstruction with tissue expanders as immediate reconstruction after mastectomy for breast cancer. AB - The aim of reconstruction with expanders is to restore breast shape and volume as close as possible to the contralateral breast and to reconstruct the inframammary fold with adequate ptosis. PMID- 26050344 TI - Fertility drugs and breast cancer risk. AB - PURPOSE OF INVESTIGATION: Female infertility is a widespread problem in Western countries. During past years, an association between ovarian stimulation in unfertile women and breast cancer risk has been hypothesized. OBJECTIVE: Purpose of the present investigation was to comment the most updated studies about an eventual relationship between fertility drugs and breast cancer risk. MATERIALS AND METHODS: The authors performed a review of the current literature regarding the possible association between the use of fertility drugs and the enhanced risk of breast cancer. They searched digital databases including Pubmed, EMBASE, and the Cochrane Library. The literature search was performed using various combinations of keywords. They carefully analyzed only the full versions of all relevant studies. RESULTS: Using various combination of keywords, the authors examined 930 papers. They considered only papers written in English. With these criteria they selected the studies that had been discussed in detail on the text. CONCLUSION: None of the works commented provides an indisputable evidence about a link between ovarian stimulation and breast cancer risk. On the contrary, most of them actually suggest a lack of interaction between them or even a protective role of ovarian stimulation. PMID- 26050345 TI - Cyclin E is overexpressed by clear cell carcinomas of the endometrium and is a prognostic indicator of survival. AB - OBJECTIVE: Upregulation of cyclin E and cyclin D1-6 accelerates the transition from G1 to S phase. The objective of this study was to determine if cyclin D1 and E are prognostic indicators in endometrial cancer. MATERIALS AND METHODS: Surgically-treated patients with endometrial carcinoma had their tumors stained for nuclear expression of cyclin D1 and E. Quantification of staining and measurement of growth phase fraction were performed using image analysis. FIGO stage, grade, and histology were also analyzed. RESULTS: Cyclin D1 and E expression was unrelated to DNA index (p = 0.93). While cyclin D1 expression did not correlate with S+G2M phase fraction (p = 0.69), increased cyclin E expression was directly correlated with increased S+G2M phase fraction (p = 0.002). Cyclin E expression was highest in clear cell carcinomas (p = 0.042) while cyclin D1 expression was highest in adenosquamous carcinomas (p = 0.028). Patients dying from cancer had significantly higher expression of cyclin D1 (p = 0.042) and E (p = 0.02) as compared to patients surviving their disease. Multivariate logistic regression revealed FIGO stage, grade, and lack of cyclin E overexpression to be independent prognostic indicators of survival. CONCLUSION: Cyclin E expression is related to increased growth fraction, clear cell histology, and decreased survival in patients with endometrial cancer. PMID- 26050346 TI - Sensitization of suberoylanilide hydroxamic acid (SAHA) on chemoradiation for human cervical cancer cells and its mechanism. AB - PURPOSE: To explore the sensitization of suberoylanilide hydroxamic acid (SAHA) on chemoradiation for cervical cancer cells and its mechanism. MATERIALS AND METHODS: After human cervical cancer SiHa cells were treated with SAHA and cisplatin (DDP) of different concentrations, inhibition and apoptosis rates, and cell cycle were detected. SiHa cells underwent radiation of various doses after treated with 20% IC50 of SAHA for 24 hours. The survival fraction of SiHa cells was calculated by colony-forming assay, and related parameters were calculated. mRNA and protein expressions of P21, Bax and Ku70 were detected. RESULTS: The inhibition rate was higher in SD (SAHA combined with DDP) group than in D (DDP alone) group (p < 0.05). The number of cells in G0/G1 phase was higher, and the number of cells in G2/M+S phase and PI (proliferation index) were lower in S (SAHA), D, and SD groups than in control group, and in SD group than in S and D groups (p < 0.05). The apoptosis rate and the expressions of mRNA and protein of Bax and P21 were higher in SD group than in S or D group (p < 0.05). The cell survival fraction was lower in SAHA combined with radiotherapy group than in radiotherapy alone group (p < 0.05). Do, N, and Dq values were 2.329, 2.761, and 1.721, respectively, in radiotherapy alone group and 1.213, 4.770, and 0.823, respectively, in SAHA combined with radiotherapy group. SER was 1.92. Bax mRNA and protein expressions were higher but Ku70 mRNA and protein expressions were lower in SAHA combined with radiotherapy group than in radiotherapy alone group (p < 0.05). CONCLUSION: SAHA promotes SiHa apoptosis in chemotherapy through up regulation of mRNA and protein of p21 and Bax which leads to cell cycle arrest in G0/G1 phase. Low dose of SAHA promotes SiHa apoptosis and inhibits cell repair in radiotherapy through Bax up-regulation and Ku70 down-regulation. PMID- 26050347 TI - Expression of estrogen receptors in melanoma and sentinel lymph nodes; a "female" clinical entity or a possible treatment modality? AB - PURPOSE: The natural history of human malignant melanoma suggests that steroid hormones may affect the biological behavior of this tumor. The purpose of the current study was to investigate the specific immunostaining patterns of estrogen receptors in malignant melanomas and their sentinel lymph nodes (SLNs), as well as to examine any possible association with patients' prognosis and overall survival. MATERIALS AND METHODS: A retrospective analysis of prospectively collected data was conducted during a 12-year period (2001-2012). Sixty patients with mean age of 54.4 +/- 14.5 years diagnosed with melanomas of varying depth (Clark) and thickness (Breslow) after excision biopsy of pre-existing melanocytic lesions, were included in the study. All patients underwent wide excision of the primary tumor and SLN identification. Determination of estrogen receptor alpha (ERa) and beta (ERb) status by immunohistochemistry on tumor and nodal paraffin blocks was performed in all feasible cases. RESULTS: ERb but not ERa was the predominant estrogen receptor found in all primary tumors and SLNs examined. The most intense ERb immunostaining was seen in negative SLNs associated with thinner, less invading melanomas. ERb expression in the primary tumor seems to correlate with the cellular microenvironment, possibly altering the process of SLN invasion. CONCLUSIONS: ERb expression is down-regulated in aggressive melanomas with sentinel nodal metastatic disease, suggesting its possible usefulness as a surrogate marker for metastatic potential and prognosis in malignant melanoma. PMID- 26050348 TI - Isolated axillary nodal swelling and cancer of unknown primary. AB - INTRODUCTION: The literature reports rare cases of isolated axillary lymph node metastasis from cancer of unknown primary (CUP). The authors reviewed the prevalence and outcome of patients with isolated axillary nodal swelling suspicious for malignancy affected or not by isolated axillary node metastasis from CUP. MATERIALS AND METHODS: The authors collected data about 65 patients presented with isolated axillary lymph node swelling who underwent axillary lymph node excisional biopsy for malignancy suspicion, between January 2005 and December 2011, in the absence of any specific diagnosis. RESULTS: Histological examination revealed a metastatic infiltration by an occult solid cancer in 16 cases (24%), ten of which were occult breast cancers. Histological patterns and molecular markers allowed in all cases of occult cancer a probable identification of the primary tumor site, while a definitive diagnosis was possible only in the 56.25% of cases (9/16). The prognosis of these patients was very poor with a five year overall survival of 28%, and thus very similar to patients affected by Stage IV overt breast cancer. CONCLUSIONS: Among occult malignancies presenting with sole axillary lymph node metastasis, breast cancer remains the more probable primary cancer, but many other sites should be taken into consideration by negative breast imaging. Positron-emission tomography computed tomography (PET CT) resulted helpful in the primary site detection, but has nonetheless a margin of failure. Occult breast cancers behave very similar to Stage IV overt breast cancers, and should be treated accordingly. PMID- 26050349 TI - S100P is a useful marker for differentiation of ovarian mucinous tumors. AB - The S100P protein stimulates cell proliferation and survival, thereby contributing to tumor progression. The purpose of this study was to evaluate S100P expression in the three subtypes of mucinous cystic tumors, cystadenomas, borderline tumors, and adenocarcinomas. The authors examined nuclear S100P expression in 60 mucinous ovarian tumor specimens, including 24 specimens of mucinous cystadenoma, 15 of borderline tumors, and 21 of adenocarcinomas. Immunohistochemistry revealed S100P expression followed one of three patterns: (1) Expressed in most nuclei of mucinous epithelial cells, (2) sporadic (spotted or patchy) expression, or (3) absent or rarely expressed in the nuclei of mucinous epithelial cells. Most adenomas showed the first expression pattern, and borderline tumors often showed a patchy expression pattern. Adenocarcinomas generally demonstrated absence of S100P expression. These data suggest that S100P is a useful histological marker to differentiate between benign, borderline, and malignant mucinous tumors of the ovary. PMID- 26050350 TI - Pelvic exenteration--our initial experience in 15 cases. AB - OBJECTIVE: To analyse the initial experience of pelvic exenteration for gynaecological malignancies in a tertiary referral center. MATERIALS AND METHODS: Between 2011 and 2013, 15 patients underwent a pelvic exenteration for gynaecological malignancies. RESULTS: Out of the 15 exenterations, six were total, four anterior, and five posterior. The indication was cervical (nine patients), advanced vaginal (one patient), and ovarian cancer (in five patients). A Bricker non-continent ileal urinary conduit was performed in all ten anterior and total exenterations. In-hospital complications occurred in six patients (40%) of whom two perioperative deaths (13%). Among the 15 patients, at this moment, eight are alive and six died because of the disease, and one was lost to follow up. CONCLUSION: Pelvic exenterantion for recurrent or advanced pelvic malignancies can be associated with long-term survival and even cure without high perioperative mortality in properly selected patients. However, postoperative complications are common and can be lethal. PMID- 26050351 TI - Correlations of leukemia inhibitory factor and macrophage migration inhibitory factor with endometrial carcinoma. AB - OBJECTIVE: To investigate the correlations of leukemia inhibitory factor (LIF) and macrophage migration inhibitory factor (MIF) with endometrial carcinoma. MATERIALS AND METHODS: The study included 113 endometrial specimens from the Fourth Affiliated Hospital of Harbin Medical University, collected from May 2006 to October 2008, classified into normal endometrium, simple hyperplasia, complex hyperplasia, atypical hyperplasia, and endometrial carcinoma. The LIF and MIF expression of all 113 specimens was detected with immunohistochemistrical (IHC) method. RESULTS: The MIF expression in hyperplastic endometrium and endometrial carcinoma increased significantly as compared with that in normal endometrium (p < 0.05 and p < 0.001, respectively), and its expression in endometrial carcinoma was also remarkably higher than that in hyperplastic endometrium (p < 0.001). The expressions of LIF in atypical hyperplasia and endometrial carcinoma were also significantly higher than that in the normal endometrium (p < 0.05), but it is not obviously higher in simple hyperplasia and complex hyperplasia than in the normal endometrium (p > 0.05). Furthermore, the expression of LIF showed no statistical difference between hyperplastic endometrium and endometrial carcinoma. CONCLUSION: It could be speculated that MIF may be correlated with the occurrence of endometrial carcinoma. However, whether LIF also has a correlation with the occurrence of endometrial carcinoma still cannot be presumed. PMID- 26050352 TI - Clinical significance of ASCUS and ASC-H cytological abnormalities: a six-year experience at a single center. AB - BACKGROUND: To evaluate colposcopic biopsy results of patients with cervical cytological findings of atypical squamous cells of undetermined significance (ASC US) and atypical squamous cells with high-grade lesions that cannot be excluded (ASC-H). MATERIALS AND METHODS: A retrospective evaluation of data from 358 patients, who had cervical cytological findings of ASC-US (n = 335) and ASC-H (n = 23), and had colposcopic assessments between 2005 and 2011. RESULTS: Cervical biopsy results of patients diagnosed with ASC-US cytology (n = 335) revealed cervical squamous cell carcinoma 0.9 % (n = 3) at biopsy, cervical intraepithelial neoplasia 3 (CIN 3) in 3.8 % (n = 13), cervical intraepithelial neoplasia 2 (CIN 2) in 1.1 % (n = 4), cervical intraepithelial neoplasia 1 (CIN 1) in 35.2% (n = 118), and benign lesions in 59 % (n = 197). Cervical biopsy results of patients diagnosed with ASC-H cytology (n = 23) revealed CIN 3 at biopsy in 39.3% (n = 9), CIN 2 in 21.7% (n = 5), CIN 1 in 26% (n = 6), carcinoma in situ in 8.7% (n = 2), and squamous cell cancer in one patient (4.3%). CONCLUSION: The cytological diagnosis of ASC-US may lead to the diagnosis of cervical intraepithelial lesion of higher grades as well as cervical cancer and should be evaluated by colposcopic cervical biopsy. PMID- 26050353 TI - Disease-free ovarian cancer patients report severe pain and fatigue over time: prospective quality of life assessment in a consecutive series. AB - objective: Among ovarian cancer patients, cancer treatment is aggressive and yet survival is often so limited; hence, this study sought to measure quality of life with the ultimate goal of identifying ways of improving it over the duration of these patients' lives. MATERIALS AND METHODS: The medical records of all ovarian cancer patients who received some/all of their initial chemotherapy at the Mayo Clinic in Rochester, Minnesota from late 2010 through 2012 were reviewed. Patient reported quality of life was derived from the following ten-point linear analogue scale questions which had been administered to all patients: 1) How would you describe your degree of pain, on average? 2) How would you describe your level of fatigue, on average? 3) How would you describe your overall quality of life? Quality of life data were censored upon cancer recurrence. RESULTS: Among 59 eligible patients, the median cumulative interval during which quality of life was serially assessed was 1.15 years (range: three months, 3.2 years). Area under the curve for pain, fatigue, and global quality of life showed no statistically significant differences between patients treated with dose-dense chemotherapy with carboplatin/paclitaxel (n = 10) versus three-week chemotherapy with carboplatin/paclitaxel (n = 36) versus other (n = 13). Although pain, fatigue, and global quality of life improved over time, 35 of 59 (59%) patients reported grade 4 or worse pain during follow up, and 47 of 59 (80%) reported grade 4 or worse fatigue (higher scores denote worse pain or fatigue). After completion of cancer treatment, 30 (51%) described grade 4 or worse pain or fatigue. The most common pain site was the abdomen/pelvis, followed by the back, followed by the hands, feet, fingers, and toes. CONCLUSION: In ovarian cancer patients who remain cancer-free, severe pain and fatigue occur years after cancer treatment. Further research should focus on how best to address these symptoms. PMID- 26050354 TI - Primary fallopian tube carcinoma--a retrospective analysis of 66 cases. AB - BACKGROUND: Primary fallopian tube carcinoma (PFTC) is a rare malignant gynecologic oncology. There was no consensus on the outcome related clinicopathological characteristics. Present study aims to determine the prognosis associate factors in PFTC. MATERIALS AND METHODS: In this retrospective study, the authors identified 50 PFTC patients in Jiangsu Institute of Cancer Research and 16 cases in the Affiliated People's Hospital of Inner Mongolia Medical College between 1988 and 2013. Disease surveillance was conducted based on the follow-up protocol of MD Anderson Cancer Center. Cox proportional hazards model and log-rank test were used to assess the associations between potential clinicpathologic characteristics and the survival durations. RESULTS: The median progression free survival (PFS) and overall survival (OS) of PFTC were 36.9 and 62.7 months, respectively. FIGO Stage (p < 0.01, 0.01), grade (p = 0.02, 0.03), tumor residual after initial debulking surgery (p = 0.05, 0.01), nadir CA-125 (p = 0.01, 0.01) were independently related with PFS and OS. The PFS and OS of patients with Stage II PFTC were similar as those with Stage III-IV (30.7 vs 28.3 and 61.9 vs 49.2 months, respectively) but poorer than those of Stage I cases (N/A). The PFS of patients with paclitaxel-based chemotherapy was longer than those with other regime (51.3 vs 33.1 months), but not OS (62.7 vs 42.6 months). The outcome of patients underwent optimal initial cytoreduction surgery was better than those of suboptimal ones (PFS 56.4 vs 21.2 months and OS 65.3 vs 47.9 months, respectively). CONCLUSIOn: PFTC patients with FIGO Stage II disease should be regarded as advanced disease. Paclitaxel based chemotherapy was associated with longer PFS but not OS in PFTC. PMID- 26050355 TI - Chemotherapy-induced thrombocytopenia and clinical bleeding in patients with gynecologic malignancy. AB - OBJECTIVES: Chemotherapy-induced thrombocytopenia seems to be a relevant problem and the risk or clinical bleeding in patients wim gynecologic malignancy is reported to be higher than other malignancy. In this study, the authors investigated chemotherapy-induced thrombocytopenia recently performed in all patients with gynecologic malignancy. MATERIALS AND METHODS: Between January 2009 and December 2011, the authors examined reported chemotherapy-induced thrombocytopenia using the Common Terminology Criteria for Adverse Events (CTCAE) v.4.0. They analyzed the incidence and clinical features of chemotherapy-induced thrombocytopenia in patients with gynecologic malignancy. RESULTS: During this period they administered over 1,614 infusions (29 regimens) to 291 patients. Chemotherapy-induced thrombocytopenia occurred in 43 (14.8%) patients over 56 (3.5%) chemotherapy cycles. Bleeding occurred in 13 (4.5%) patients over 14 (0.9%) cycles. Platelet transfusions were administered for eight (2.7%) patients over eight (0.5%) cycles. Median platelet count at platelet transfusions was 17,000 /MUl. Chemotherapy-induced thrombocytopenia was associated with more than five previous chemotherapy cycles, previous radiotherapy, disseminated disease, distant metastatic disease, poor performance status, and taxane-including regimens. Clinical bleeding was associated with previous radiotherapy, distant metastatic disease, poor performance status, and taxane-including regimens. CONCLUSIONS: Estimating bleeding risk factor such as previous radiotherapy, distant metastatic disease, poor performance status, and taxane-including regimens seem to be important for safe management of chemotherapy-induced thrombocytopenia. PMID- 26050356 TI - Metabolomics analysis of cervical cancer, cervical intraepithelial neoplasia and chronic cervicitis by 1H NMR spectroscopy. AB - Metabolomics profiles of serum samples from women with chronic cervicitis, cervical intraepithelial neoplasia (CIN), and cervical cancer were characterized by proton nuclear magnetic resonance (1H NMR). These spectral profiles were subjected to partial least-squares discriminant analysis (PLS-DA), and good discriminations between cancerand non-cancer groups (chronic cervicitis and CIN) were achieved by multivariate modeling of serum profiles. The main metabolites contributing to these discriminations, as highlighted by multivariate analysis and confirmed by spectral integration, were formate, tyrosine, beta-glucose, inositol, glycine, carnitine, glutamine, acetate, alanine, valine, isoleucine, and very-low-density lipoprotein (VLDL). Metabolomics analysis for chronic cervicitis, CIN, and cervical cancer is significant, which give a systemic metabolic response of these female diseases. The systemic metabolic response may be used to identify the potential biomarkers for the diseases. PMID- 26050357 TI - Expression of PKCalpha, PKCepsilon, and P-gp in epithelial ovarian carcinoma and the clinical significance. AB - AIM: To inspect the expression of two protein kinase PKC isozyme hypotype PKCalpha and PKCepsilon in the epithelial ovarian carcinoma tissue, and investigate their relation with multi-drug resistance with P-glycoprotein (P-gp) medium. MATERIALS AND METHODS: Adopted immunohistochemistry SP method to determine expression of PKCalpha, PKCepsilon, and P-gp in 64 cases of epithelial ovarian carcinoma, 18 cases of epithelial borderline ovarian carcinoma, 15 cases of epithelial ovarian benign tumor, and 15 cases of normal ovarian tissue. RESULTS: The expression of PKCalpha, PKCepsilon, and P-gp in the epithelial ovarian carcinoma is obviously higher than expression in the normal, benign. and borderline epithelial ovarian carcinoma; the expression of PKCalpha, PKCepsilon, and P-gp in the recurrent carcinoma tissue is obviously higher than that in the person with initial treatment; the expression of above-mentioned three indicators in epithelial ovarian carcinoma is unrelated with the pathological type, pathological grade, and clinical stage during initial treatment of the carcinoma; there is a close relation among PKCalpha, PKCepsilon, and P-gp in epithelial ovarian carcinoma (p < 0.01). It is indicated through research that PKCalpha, PKCepsilon, and P-gp is related with the survival time and poor prognosis of the patient of epithelial ovarian carcinoma, i.e., the positive expression rate of PKCalpha, PKCepsilon, and P-gp of the person with recurrent carcinoma is higher than that of the person without recurrent car- cinoma (p < 0.05). However, the survival rate of the patients with positive expression of three indicators is remarkably lower than those with negative expression (p < 0.05). CONCLUSION: There is a consistency between expression of PKCalpha, PKCepsilon, and P-gp in the epithelial ovarian carcinoma, which indicates that the expression of both plays an important role in generation of drug resistance in chemotherapy of ovarian carcinoma with P-gp medium. Joint detection of three indicators has an active guiding role in judgment of the therapeutic effect of clinical chemotherapy and prognosis estimation of the patient. PMID- 26050358 TI - A diagnostic dilemma for solid ovarian masses: the clinical and radiological aspects with differential diagnosis of 23 cases. AB - OBJECTIVE: This study aimed to analyze the clinical characteristics and diagnostic features of ovarian fibromatous masses. MATERIALS AND METHODS: The authors reviewed the records of 23 women who underwent laparotomic surgeries and whose final histopathological diagnoses were ovarian fibroma, cellular fibroma, or fibrothecoma from January 2005 to January 2013. The clinical, ultrasonographic, magnetic resonance imaging, tumor marker, therapeutic, and histologic data were analyzed. RESULTS: The mean age of the patients was 50.9 years. Sixteen patients were menopausal. The preoperative ultrasonography examination incorrectly diagnosed seven lesions as uterine fibromas, and the magnetic resonance imaging examination incorrectly labeled three lesions as pedunculated subserous uterine fibromas. The cancer antigen-125 levels of 17 cases were measured, with four being abnormal. Twenty-three patients underwent a laparotomy. Twenty patients underwent a total hysterectomy with bilateral salpingo-oophorectomy, and three underwent a tumorectomy. The histological diagnosis was fibrothecoma in 21 cases, fibroma in one case, and cellular fibroma in one case. Histopathologic examination of the endometrium of seven of the 20 patients who underwent hysterectomy revealed simple endometrial hyperplasia without atypia. CONCLUSION: Ovarian fibromas and fibrothecomas are often misdiagnosed as uterine fibromas and occasionally mistaken for malignant tumors of the ovary preoperatively. As these tumors originate from ovarian stroma, they may be hormone-active tumors. Therefore, they may lead to premalignant changes in the endometrium. The preoperative evaluation of the endometrium is recommended. PMID- 26050359 TI - Evaluation of the human papillomavirus mRNA test for the detection of cervical lesions in Japan. AB - AIMS: For the screening of cervical abnormalities, human papillomavirus (HPV) DNA testing is widely used along with Papanicolaou (Pap) testing. Although the sensitivity of the HPV DNA testing is good, its specificity is relatively low. In the present study, the authors evaluated the use of the Gen-Probe APTIMA HPV Assay for the detection of HPV mRNA and compared it with HPV DNA testing. MATERIALS AND METHODS: Liquid cervical Pap specimens collected from 410 women were assessed using the APTIMA test, the Qiagen Hybrid Capture 2 HPV DNA (HC2) Test, and the AMPLICOR HPV Test. RESULTS: The sensitivity and specificity for the detection of high-risk HPV were 85.6% and 99.2% for the APTIMA test, 94.1% and 98.4% for the HC2 test, and 90.2% and 95.7% for the AMPLICOR test, respectively. As the severity of the cervical lesion progressed, the positive rate of the three tests indicated a similar increase. The clinical sensitivity and specificity for the detection of squamous intraepithelial lesion (SIL) were 91.2% and 84.2% for the APTIMA test, 94.5% and 80.4% for the HC2 test, and 87.9% and 78.2% for the AMPLICOR test, respectively. CONCLUSION: The APTIMA is sensitive and specific for the detection of high-risk HPV. In the specimens with SIL, the APTIMA test is more specific than the HC2 and the AMPLICOR tests. This indicates that the APTIMA test may improve patient management and reduce the cost of screening. PMID- 26050360 TI - Protective and sensitive effects of melatonin combined with adriamycin on ER+ (estrogen receptor) breast cancer. AB - OBJECTIVE: This study aims to investigate the protective and sensitive effects of melatonin (MLT) in the treatment of breast cancer. MATERIALS AND METHODS: ER+ breast cancer rat model was established and then rats were randomly divided into five different groups as follows: control group, Diss group, adriamycin (ADM) group, MLT group, and MLT combined with adriamycin (M+A) group. Tumor weights and one month survival rate were compared among these groups. In addition, changes of tumor tissues and expression of E-cadherin were observed under optical microscopy or electro-microscopy. RESULTS: Tumor weights were significantly lighter in M+A group than those in ADM group (p < 0.05). Under optical and electro-microscopy, tumor cell apoptosis was obviously increased in MLT group, and tumor cell injury was more severe in M+A group than that in ADM group; additionally, expression of E-cadherin was higher in MLT group and M+A group than that in other groups. Moreover, MLT group had the highest one month survival rate (100%), there was the poorest life quality in ADM group, but the best life quality in MLT. CONCLUSION: MLT could enhance the sensitivity of tumor to ADM in vivo and improve patient's life quality. PMID- 26050361 TI - A large ovarian leiomyoma discovered incidentally in a 76-year-old woman: case report. AB - BACKGROUND: Ovarian leiomyoma is very rare type of ovarian tumor. This benign tumor is seen in the pediatric age group to premenopausal women. CASE: A 76-year old woman had a huge leiomyoma (19 x 11 x 10 cm) of the right ovary. The preoperative diagnosis was difficult to distinguish from a broad ligament leiomyoma or ovarian cancer. CONCLUSIONS: Although theses tumors are benign, its extreme rarity led us to report an additional and rather unusual case of ovarian leiomyoma, and to focus some attention on this type of tumor. PMID- 26050362 TI - Coexistence of mature cystic teratoma and adenocarcinoma in situ within atypical proliferative mucinous tumour of ovary--a case report of 35-year-old woman. AB - Combined ovarian tumors are found in common pathologic practice due to amazing potential of ovarian tissue to copy almost every tissue of human body and imitate many neoplasms of various other organs in a very flexible way. A multicystic tumor is presented in this case report of 35-year-old woman. It consisted of a cyst with sebum and hair and cavities with papillomatous projections and mucus. The ovarian tumor was diagnosed a mature cystic teratoma presenting mainly as dermoid cyst and mucinous adenocarcinoma in situ, arising within atypical proliferative mucinous tumor. This report demonstrates how histoformative properties are reflected in ovarian tumorigenesis. Such a stunning histoformativity makes ovaries the possible site of primary origin for malignant tumors that mimic extra ovarian differentiation. In the authors' point of view, the diagnosis of primary ovarian mucinous tumor within cystic teratoma is firm, whenever simultaneous extraovarian involvement by mucinous neoplasm is excluded. PMID- 26050363 TI - Angioleiomyoma of the uterus: report of a distinctive benign leiomyoma variant. AB - Angioleiomyoma is a relatively rare type of leiomyoma of the uterus that originates from smooth muscle cells and contains thick-walled vessels. Angioleiomyoma is usually found in the skin of the lower extremities. Uterine angioleiomyoma has similar morphological features to that of the skin. The authors present a case of a 50-year-old woman who was admitted to the present hospital with the complaint of lower abdominal pain. On clinical examination, she was found to have a palpable lower central abdominal mass. Pelvic ultrasound revealed uterine enlargement, multiple small leiomyomas, and a large mass in the myometrium. The patient underwent total hysterectomy and bilateral salpingo oophorectomy. On histological examination, the mass was diagnosed as angioleiomyoma. Hemangioma, angiofibroma or angiomyofibroblastoma were also included in the differential diagnosis. The treatment of choice for angioleiomyoma is surgical excision, and either angiomyomectomy or simple hysterectomy are proven to be equally effective; the decision depends on the patient's symptoms and her desire to preserve fertility. PMID- 26050364 TI - Adenocarcinoma of the cervix associated with a neuroendocrine small cell carcinoma of the cervix in the spectrum of Muir-Torre syndrome. AB - Muir-Torre syndrome (MTS) is an autosomal genodermatosis that is diagnosed by the presence of at least one sebaceous gland tumor and at least one visceral malignancy. The most frequent visceral malignancies reported in literature are low-grade colon-rectal and genitourinary cancers, with prolonged survival. The authors report the case of a 52-year-old female, with a positive familial history for MTS, who developed a cutaneous sebaceous carcinoma, a synchronous colon rectal adenocarcinoma, and a metachronous endocervical adenocarcinoma associated with a neuroendocrine small cell carcinoma of the cervix (SCNC), with lymph node metastasis. The rare occurrence in literature of the cervical SCNC and the rarest occurrence of a neuroendocrine carcinoma in the context of a MTS deviate from the usual and low-grade types of cancers normally described with MTS. It should be always appropriate to assess any symptoms that might reveal an underlying malignancy, although not within the spectrum of neoplasms most associated with this rare syndrome. PMID- 26050365 TI - Three synchronous primary pelvic cancers--a case report. AB - The occurrence of synchronous primary gynaecologic malignancies is a relatively common event. However, the occurrence of three different pelvic cancers is very rare. In this report, the authors describe the clinical, surgical, and pathological findings of a patient with synchronous primary malignancies of the fallopian tube, endometrium, and sigmoid colon. To the authors' knowledge, it is the first case described in the literature with such an association of primary synchronous cancers. PMID- 26050366 TI - Metastases of renal clear cell carcinoma to ovary--case report and review of the literature. AB - In the literature the renal-ovarian axis has been demonstrated. Although, kidney and ovary are in a very distant anatomic position, they are supposed to have a lot of in common. This unusual connection begins from embryology, vascularization, and metastasizing tumors to each other. In the present systemic review the authors showed 24 case reports published in the literature, describing the metastases of primary renal cancer to ovary and only four cases reporting primary ovarian cancer metastases to kidney. Finding primary origin of the tumor is crucial in diagnostic process and subsequent therapy. The present case is a 25th case of renal cell carcinoma (RCC) metastasizing to ovary. The authors report the case of 51-year old woman with a four-year history of metastatic renal clear cell carcinoma (MRCC) presented in the present hospital with contralateral metastasis in right ovary. PMID- 26050367 TI - Spindle-cell epithelioma of the vagina diagnosed during pregnancy--a case report. AB - Spindle-cell epithelioma or "mixed tumor" of the vagina is an unusual and intriguing vaginal tumor consisting of both epithelial and mesenchymal components. A case of spindle-cell epithelioma of the vagina diagnosed at delivery of a 31-year-old primiparous woman is described. The excision of the mass was performed immediately after the delivery, which was uneventful. The patient was regularly followed up and no evidence of local recurrence or dissemination was found 40 months after surgery. The presentation and the diagnosis of this kind of tumor in pregnancy, and its effect on the pregnancy and delivery are still largely unknown. Since it is unlikely that any institution will have a large number of patients with this rare disease, case reports add further information to this entity. As the number of cases studied is small, close follow-up is recommended although there has been no report in the literature of metastasis so far. PMID- 26050368 TI - Rectal carcinoma in pregnancy--a case report. AB - The authors present a case of a pregnant woman suffering from colorectal cancer in order to contribute to the knowledge regarding this situation and to optimise its management. Rectal cancer in pregnancy is a rare disease, challenging clinicians as there are no generally accepted guidelines regarding diagnosis or treatment. Early diagnosis remains to be the key. When the disease is particularly aggressive, the prognosis remains poor despite pregnancy cessation and radical therapy. PMID- 26050369 TI - Spontaneous intrauterine pregnancy following abdominal radical trachelectomy--a case report. AB - The authors describe a case report of spontaneous pregnancy after an abdominal radical trachelectomy because of cervical cancer Stage IB2. PMID- 26050370 TI - Uterine extra gastrointestinal stromal tumor presenting as intramural leiomyoma. AB - Extra gastrointestinal stromal tumors (EGIST) are reported in different sites and organs. This tumors are rare in gynecologic apparatus. Here the authors report an uterine unique tumor represented as intramural leiomyoma. Because of different treatment options, clinicians should be aware of this rare tumor which may be located in uterus and confused with a smooth muscle tumor. PMID- 26050371 TI - Biomedical HIV prevention research and development in Africa. PMID- 26050372 TI - Some ethical issues in HIV/AIDS care. PMID- 26050374 TI - Medicalization of HIV and the African response. AB - Since the discovery of HIV, the advent of anti-retrovirals in the late 80s heralded an era of medicalization of HIV and fostered major advancements in the management of the disease. Africa, despite its high HIV burden, lagged behind in the adoption of these advancements due to major resource and logistical constraints. Innovative responses such as family-centered models of care, community systems strengthening, integration of HIV care with existing health services, and economic and mobile phone- based approaches have been critical in the successful roll-out of evidence-based HIV/AIDS treatment even in the most resource- limited settings. PMID- 26050373 TI - HIV prevention and research considerations for women in sub-Saharan Africa: moving toward biobehavioral prevention strategies. AB - This paper addresses current and emerging HIV prevention strategies for women in Sub-Saharan Africa, in light of recent trial results and ongoing research. What are the major opportunities and challenges for widespread implementation of new and emerging HIV prevention strategies? The paper discusses the major individual, social and structural factors that underpin women's disproportionate risk for HIV infection, with attention to gender, adolescents as a vulnerable population, and the need to engage men. Also, the influence of these factors on the ultimate success of both behavioral and biomedical HIV prevention technologies for women in sub-Saharan Africa is discussed. Finally, the paper examined how the new and emerging biobehavioral prevention strategies served as tools to empower women to adopt healthy HIV preventive and reproductive health behaviors. PMID- 26050375 TI - The Abuja +12 declaration: implications for HIV response in Africa. AB - Heads of State and Governments of the Organization of African Unity now the African Union (AU) met in April 2001 at a Special Summit held in Abuja to address the challenges of HIV/AIDS, Tuberculosis, Malaria and other related infectious diseases in Africa. In May 2006, at the Special Summit under the theme: "Universal Access to HIV/AIDS, Tuberculosis and Malaria Services by 2010", the African Union Heads of States and Governments adopted the "Abuja Call for Accelerated Action towards Universal Access to HIV/AIDS, Tuberculosis and Malaria Services in Africa" and related commitments thus reaffirming earlier commitments. In July 2013, African leaders once again gathered in Abuja for the Abuja +12 summit, which focused on the theme 'Ownership, Accountability and Sustainability of HIV/AIDS, Tuberculosis and Malaria in Africa: Past, Present and the Future'. At the meeting, African leaders noted the tremendous progress that has been made in addressing HIV and AIDS, and made further commitments to effectively tackle the HIV epidemic on the continent. This article presents a critical look at each of these commitments and makes recommendations that would assist African countries in developing policies to end the HIV/AIDS epidemic in the region. PMID- 26050376 TI - From addiction to infection: managing drug abuse in the context of HIV/AIDS in Africa. AB - People who use drugs are at higher risk of HIV: directly through the sharing of injecting equipment, indirectly through associated risk behavior, and physiologically through the substances' impact on the immune system. Drug users, especially people who inject drugs (PWID) are a bridge to the general population. The treatment of drug addiction and provision of harm reduction interventions have impact on HIV transmission and incidence. Addiction treatment reduces the frequency of drug-related risky behaviors and enhances access and adherence to HIV treatment, resulting in fewer new infections. However, the drug policies of many African countries are punitive and hostile to harm reduction programs. These fuel criminalization of drug use and discrimination against the drug user thereby preventing individuals with drug addiction from accessing treatment programs. There is need to formulate policies aimed at protecting the rights of people with drug addiction and address the ethical aspects of treatment. PMID- 26050377 TI - Standards and guidelines for HIV prevention research: considerations for local context in the interpretation of global ethical standards. AB - While international standards are important for conducting clinical research, they may require interpretation in particular contexts. Standard of care in HIV prevention research is now complicated, given that there are now two new biomedical prevention interventions - 'treatment-as-prevention', and pre-exposure prophylaxis--in addition to barrier protection, counselling, male circumcision and treatment of sexually transmissible infections. Proper standards of care must be considered with regard to both normative guidance and the circumstances of the particular stakeholders--the community, trial population, researchers and sponsors. In addition, the special circumstances of the lives of participants need to be acknowledged in designing trial protocols and study procedures. When researchers are faced with the dilemma of interpretation of international ethics guidelines and the realities of the daily lives of persons and their practices, the decisions of the local ethics committee become crucial. The challenge then becomes how familiar ethics committee members in these local settings are with these guidelines, and how their interpretation and use in the local context ensures the respect for persons and communities. It also includes justice and the fair selection of study participants without compromising data quality, and ensuring that the risks for study participants and their community do not outweigh the potential benefits. PMID- 26050378 TI - Development of guidelines for the conduct of HIV research monitoring by ethics committees in Nigeria. AB - Nigerian research ethics committees are charged with the responsibility to monitor ongoing research to ensure compliance with ethical standards. Recent evidence from qualitative studies on research conduct however, indicate that many research studies fail to implement their protocols as written, and that this is not reported due to a failure of comprehensive monitoring. As Nigeria is in many respects a highly suitable country in which to conduct HIV biomedical prevention research, we argue there is a need to reprioritise the strengthening of the monitoring capacity of ethics committees so that such vital and ethically complex research can be conducted with confidence. We identify the need for (i) improved resourcing and training of ethics committee members, and (ii) comprehensive planning of research monitoring as part of the ethics committee protocol review process. We also highlight the significance of community collaboration and the establishment of a central pool of national monitors, as essential components for reinvigorating monitoring capacity. PMID- 26050379 TI - The promise and peril of pre-exposure prophylaxis (PrEP): using social science to inform prep interventions among female sex workers. AB - Advances in biomedical interventions to prevent HIV offer great promise in reducing the number of new infections across sub- Saharan Africa, particularly among vulnerable populations such as female sex workers. Several recent trials testing pre-exposure prophylaxis (PrEP) have demonstrated efficacy, although others have been stopped early for futility. Given the importance and complexities of social and behavioural factors that influence biomedical approaches to prevention, we discuss several key areas of consideration moving forward, including trial participation, adherence strategies, social relationships, and the structural factors that shape PrEP interest, use, and potential effectiveness among female sex workers in sub-Saharan Africa. Our review highlights the importance of involving social scientists in clinical and community-based research on PrEP. We advocate for a shift away from a singular "re-medicalization" of the HIV epidemic to that of a "reintegration" of interdisciplinary approaches to prevention that could benefit female sex workers and other key populations at risk of acquiring HIV. PMID- 26050380 TI - Money, power and HIV: economic influences and HIV among men who have sex with men in sub-Saharan Africa. AB - Despite consistent evidence, effective interventions and political declarations to reduce HIV infections among men who have sex with men (MSM), coverage of MSM programmes in sub-Saharan Africa (SSA) remains low. Punitive legal frameworks and hostile social circumstances and inadequate health systems further contribute to the high HIV burden among MSM in SSA. The authors use the Modified Social Ecological Model to discuss economic influences in relation to HIV and MSM in SSA. Nigerian, South African and Ugandan case studies are used to highlight economic factors and considerations related to HIV among MSM. The authors argue that criminalisation of consensual sexual practices among adults increases the frequency of human rights violations contributing to the incidence of HIV infections. Furthermore, marginalisation and disempowerment of MSM limits their livelihood opportunities, increases the prevalence of sex work and drug use and limits financial access to HIV services. Sexual and social networks are complex and ignoring the needs of MSM results in increased risks for HIV acquisition and transmission to all sexual partners with cumulative economic and health implications. The authors recommend a public health and human rights approach that employs effective interventions at multiple levels to reduce the HIV burden among MSM and the general population in SSA. PMID- 26050381 TI - Addressing the socio-development needs of adolescents living with HIV/AIDS in Nigeria: a call for action. AB - The widespread use of antiretroviral therapy and remarkable success in the treatment of paediatric HIV infection has changed the face of the Human Immunodeficiency Virus (HIV) epidemic in children from a fatal disease to that of a chronic illness. Many children living with HIV are surviving into adolescence. This sub-population of people living with HIV is emerging as a public health challenge and burden in terms of healthcare management and service utilization than previously anticipated. This article provides an overview of the socio developmental challenges facing adolescents living with HIV especially in a resource-limited setting like Nigeria. These include concerns about their healthy sexuality, safer sex and transition to adulthood, disclosure of their status and potential stigma, challenges faced with daily living, access and adherence to treatment, access to care and support, and clinic transition. Other issues include reality of death and implications for fertility intentions, mental health concerns and neurocognitive development. Coping strategies and needed support for adolescents living with HIV are also discussed, and the implications for policy formulation and programme design and implementation in Nigeria are highlighted. PMID- 26050382 TI - Tackling the sexual and reproductive health and rights of adolescents living with HIV/AIDS: a priority need in Nigeria. AB - Very little is known about the sexual and reproductive health (SRH) needs of adolescents living with HIV (ALHIV) in general and the needs of those in Nigeria specifically. A review was conducted to identify the SRH of ALHIV, assess if these are different from the SRH of adolescents who are free from HIV infection, and from those of adults living with HIV. Few research have been conducted on how ALHIV deal with sexual and reproductive health challenges faced in their everyday lives - as adolescents and as persons living with HIV living in sub-Saharan Africa - to help make any meaningful inferences on these differing needs. The review suggests that the SRH needs and practices of ALHIV may differ from that of other adolescents and that of adults living with HIV. ALHIV would require support to cope with sex and sexual needs, through full integration of individualized SRH services into the HIV services received. Service providers need to appreciate the individualistic nature of health problems of ALHIV and address their health care from this holistic perspective. A 'one-size-fits-all' approach for designing SRH programmes for ALHIV would not be appropriate. We conclude that research evidence should inform the design and implementation of ALHIV friendly SRH programmes services in both urban and rural settings in Nigeria. PMID- 26050383 TI - Changes in sexual risk behavior among adolescents: is the HIV prevention programme in Nigeria yielding results? AB - This study conducted an analysis of the 2007 and 2012 National HIV and AIDS Reproductive Health Survey data with the aim of identifying the changes in high risk sexual behaviour among adolescents aged 15-19 years. It focused on changes in the history of use of condom with boyfriends/girlfriends, engagement in transactional sex, sex with multiple partners and age of sexual debut. Bivariate analysis was conducted to ascertain differences in the number of adolescents who engaged in these high sexual risk behaviours over the five-year study period. Data was also analysed for association between risk behaviour and possible predisposing factors. Over the five year period, HIV prevalence in the population increased significantly (p = 0.02) especially in female (p = 0.008). The number of female adolescents who became sexually active decreased significantly (p = 0.02), and use of condom at last sexual act with non-marital sexual partners significantly increased (p = 0.01). There was an insignificant increase in the proportion of males and females who engaged in transactional sex and who had multiple sex partners over the study period. More females who engaged in transactional sex were HIV positive (p = 0.01), and more males who were sexually active in the last 12 months were HIV positive (p = 0.01). There may be a need to redress the current HIV prevention intervention strategies. Attention needs to be paid to the national programme for the prevention of mother to child transmission of HIV programme as well as HIV prevention needs of female adolescents. PMID- 26050385 TI - The use of antiretroviral therapy for the prevention of new HIV infection in populations at high risk for HIV sero-conversion in Nigeria. AB - The last few years have witnessed a renewed commitment to HIV prevention. The evidence to support the use of antiretroviral therapy (ART) for prevention of new HIV infection in the form of Pre-exposure prophylaxis (PrEP) among men who have sex with men, transgender, people who inject drugs, heterosexual men and women and HIV-1 serodiscordant couples, or treatment as prevention (TasP) for serodiscordant couples have also grown. The need to explore the possible use of ART for HIV prevention in Nigeria has become imperative in view of its high HIV burden and the current slow pace of effort to achieve the universal target of reducing its HIV incidence by 50%. While PrEP and TasP are welcome addendum to the existing HIV prevention armamentarium, it is still important to conduct a demonstration project to identify strategies that can facilitate access to PrEP and TasP taking cognizance of the peculiar local challenges with respect to ART and HIV prevention commodity access. The country has therefore drawn a roadmap for itself on how to introduce ART for use for HIV prevention as either PrEP or TasP. This paper discusses the three year national roadmap that would enable the country generated the needed scientific evidence as well as extensive community support for use of ART for HIV prevention in Nigeria. This process includes the conduct of modeling and formative studies, and the implementation of a 24 months demonstration project. The outcome of the demonstration project would inform plans for the scale up of pre-exposure prophylaxis (PrEP) access for population(s) at high risk for HIV infection in Nigeria. PMID- 26050386 TI - Ethics of ancillary care in clinical trials in low income countries: a Nigerian case study. AB - The ethical conduct of HIV prevention researchers is subject to scrutiny. Many clinical trials take place in low and middle income countries where HIV incidence is high, but the benefits of research are often first enjoyed in high income countries. The provision of ancillary care--medical care provided to clinical trial participants during a trial, which is not related to the research question- is one way in which trial participants can receive direct benefits from their participation in research. We argue that such care is a legitimate benefit of research participation. This care does not constitute 'undue inducement' if the research study itself involves minimal risk and is subject to ethical and regulatory oversight. We also argue that research teams working with populations who have sub-optimal healthcare access have a duty to provide ancillary care within agreed limits. These limits should be negotiated to ensure that the research remains feasible and economically viable. PMID- 26050384 TI - Beyond informed consent: ethical considerations in the design and implementation of sexual and reproductive health research among adolescents. AB - Interest in addressing the ethical issues related to adolescents' engagement in research, especially sexual and reproductive health and rights (SRHR) research is increasing in view of the need to design and implement research that address peculiar SRHR needs of adolescents. These needs include issues of sexually transmitted infections, HIV, AIDS, adverse pregnancy outcomes, community, family and relationship violence and mental health. Unfortunately, adolescents' voluntary participation in research has been limited due to their perceived potential to be coerced into participation, and concerns that they may not fully comprehend the issues related to research risks. As such, many of the regulations for engaging research participants have been defined by age rather than due consideration of psychological development. This paper examines the various potential ethical issues that may impact on decision making when adolescents are engaged in research. These include the need to minimise therapeutic misconception, considerations for recruitment and retention, types and amounts for reimbursement, and engagement of communities of adolescents on advisory boards of studies that involve their population. The potential challenges associated with recruitment of adolescents in early child marriages were also highlighted. PMID- 26050387 TI - [National council of nurses is still in limbo]. PMID- 26050389 TI - [No more silent in front of rampant homophobia]. PMID- 26050388 TI - [WHO reinforces fight against Ebola virus]. PMID- 26050390 TI - [Research for more efficiency in public health care costs]. PMID- 26050391 TI - [Morphine sulfate usage among drug abusers]. PMID- 26050392 TI - [Second look at mental disorders and their management]. PMID- 26050393 TI - [Surveillance and prevention of patient blood exposure accidents]. PMID- 26050394 TI - [The law is acting for real gender equality]. PMID- 26050395 TI - [Insuring patient safety during oral chemotherapy]. PMID- 26050396 TI - [HIV, reinforcing prevention using pre-exposure prophylaxis]. PMID- 26050397 TI - [Simulation, an emerging learning tool]. AB - Simulation in healthcare is part of an innovative pedagogical approach. Confronted with concrete work situations, "learners" are faced with dummies in typical working conditions. They are thereby able to practise technical procedures without any risk. Multi-professional and multi-disciplinary groups are favoured and emphasis is placed on the understanding of the job and discussion around nursing practices. PMID- 26050398 TI - [From the theory to the practice of simulation in healthcare]. AB - Simulation in healthcare is directly inspired by high-risk industries such as the aeronautical industry. The recent rapid growth in its use in healthcare is explained by the need to improve the quality and safety of care. It must go hand in hand with the development of a real safety culture. PMID- 26050399 TI - [The construction of simulation in healthcare]. AB - As is the case in the fields of industry and transport, the healthcare sector, which is a high-risk environment, increasingly uses simulation to train caregivers and future caregivers. The aim of this teaching method is to reduce the risk of real errors and improve the care provided to patients. PMID- 26050400 TI - [A Serious Game for the prevention of risks in the home]. AB - A Serious Game is a tool based on new technologies. It encompasses the notion of entertainment and learning. It has several purposes and is aimed at professionals as well as the general public. It can be used for educational purposes and integrated into training programmes. PMID- 26050401 TI - [Simulation and video debriefing: feedback]. AB - Understanding the interactions between different players, learning technical procedures in nursing situations and developing skills are some of the benefits of using simulation. This pedagogical approach has been used for several years at the Quimper nurse training institute. PMID- 26050402 TI - [Developing new nursing roles in gerontology]. AB - Brigitte Feuillebois began her twenty-year long nursing career in hospitals. She then went on to work with prisoners before moving into gerontology. Interested in the transfer of knowledge and experience, she now devotes her time to training nurse coordinators in the gerontological field. PMID- 26050403 TI - [Practice analysis, time for oneself]. AB - The emotional strain which comes with caregiving affects the feeling of wellbeing at work. The patient's psychological space resonates with that of the caregivers, often without them realising. By offering a form of support which enables caregivers to regulate difficult psychological tensions and maintain their desire for the work, the practice analysis group helps to preserve quality of life at work. PMID- 26050404 TI - [Nursing diagnoses and educational diagnosis, differences and complementarity]. AB - The coordination between nursing diagnoses and the educational diagnosis still remains a difficult task. The educational approach arises from clinical reasoning derived from the caregiving approach. In collaboration with the team, the nurse analyses the data collected, makes nursing diagnoses and then shares with the patient care objectives and educational objectives. PMID- 26050405 TI - [Supporting patients at the end of life at home based on the hospital at home model]. AB - Hospital at home structures aim to assure the transition between hospital and home, including by supporting a life project through to its last moments. Good coordination between the different players and constant consideration of the patient and their family are necessary in order to ensure that the quality of care at home is equivalent to what provided in hospital. PMID- 26050406 TI - [A prevalence study to monitor the consumption of antibiotics]. AB - Following the second Antibiotics Plan, in association with the hospital hygiene operational team, the hospital pharmacy department of the Desgenettes military teaching hospital led a study into the prevalence of the prescribing of antibiotics in December 2011. The study highlighted the trends in prescriptions and assessed the effectiveness of corrective or preventive actions implemented following the first prevalence study of 2006, in particular the multidisciplinary antibiotherapy coordination meetings. PMID- 26050407 TI - [Homage to the Righteous Among the Nations French nurses]. AB - Thirty five nurses and one male nurse received the Righteous Among the Nations title awarded by the Yad Vashem remembrance authority in Jerusalem for having rescued or assisted Jews during the Holocaust. This article looks back on their heroic actions. PMID- 26050408 TI - [The nurse and burns management]. PMID- 26050409 TI - [The nurse facing a suicide risk]. PMID- 26050410 TI - At the Nursing Exhibition. PMID- 26050411 TI - [Patient education method on preventing elderly persons falls ]. PMID- 26050412 TI - [Assisted circulation with counter-pulse]. PMID- 26050413 TI - Broader relationship, larger story. PMID- 26050414 TI - The West Virginia WISEWOMAN Program. AB - This article describes moving The Well-Integrated Screening and Evaluation for WOMen Across the Nation (WISEWOMAN) Program from research to practice in a population of low-income, uninsured, or underinsured women in West Virginia (WV) between the ages of 40 and 64 years. Cardiovascular disease risk factors were evident using screening and health history data from women in all stages of change as well as in different phases of the program. An indicator of program success was women's increased activities to improve their cardiovascular health. Women using an interactive Web program, coupled with appropriately delivered health information, can and do make behavior changes. As the WV WISEWOMAN Program moved from research to practice, clinician training and changes to policies and procedures were needed. Clinicians became skilled at motivational interviewing and targeting information to connect women to community resources for ongoing support. The program continues to help clinicians alert women to cardiovascular risks and guide them to take responsibility for their health. Partnerships between women and their providers are the key to successful implementation of healthier lifestyles. PMID- 26050415 TI - An academic-practice partnership in a medically underserved community. AB - The University of Washington School of Nursing faculty partnered with leaders of a local community with the shared intention of improving health services for needy populations and preparing nursing students to collaborate with communities in caring for such populations. The resulting clinic has operated for more than a decade and has continually grown, now serving about 1,000 patients per month. More than 300 students have completed clinical or research activities at the clinic. Challenges have included provision of culturally informed, evidence-based care; integration of mental and primary health care services; chronic disease management; leveraging community partnerships in support of needy populations; and fiscal sustainability. A new project uses team-based approaches to implement interprofessional, relationship-centered care for families of newborns. PMID- 26050416 TI - Paving the way for health promotion nurses: an international perspective. AB - This article calls for an evolution of the nursing role to incorporate time and resources into promoting health through coaching and empowering clients to make healthy life choices. Health promotion practice needs to be incorporated into nursing role descriptions, and nurses must be given the scope to carry out this practice without being distracted by other activities deemed more urgent or important. Integrating this practice may be difficult in a system that itself does not support health promotion or consider it a priority. The health promotion nurse role is one solution to our current health problems and an investment in the wellness of our population. Just as the arena of curative care belongs to the medical profession, the realm of preventive care and health promotion belongs to nurses. This article considers the role of nurses as health promotion practitioners and supports the implementation of a system that focuses on proactive choices and holistic care. PMID- 26050417 TI - Concept analysis of culture applied to nursing. AB - Culture is an important concept, especially when applied to nursing. A concept analysis of culture is essential to understanding the meaning of the word. This article applies Rodgers' (2000) concept analysis template and provides a definition of the word culture as it applies to nursing practice. This article supplies examples of the concept of culture to aid the reader in understanding its application to nursing and includes a case study demonstrating components of culture that must be respected and included when providing health care. PMID- 26050418 TI - Sustaining self-management in diabetes mellitus. AB - Successful management of diabetes depends on the individual's ability to manage and control symptoms. Self-management of diabetes is believed to play a significant role in achieving positive outcomes for patients. Adherence to self management behaviors supports high-quality care, which reduces and delays disease complications, resulting in improved quality of life. Because self-management is so important to diabetes management and involves a lifelong commitment for all patients, health care providers should actively promote ways to maintain and sustain behavior change that support adherence to self-management. A social ecological model of behavior change (McLeroy, Bibeau, Steckler, & Glanz, 1988) helps practitioners provide evidence-based care and optimizes patients' clinical outcomes. This model supports self-management behaviors through multiple interacting interventions that can help sustain behavior change. Diabetes is a complex chronic disease; successful management must use multiple-level interventions. PMID- 26050419 TI - Reflections on self in relation to other: core community values of a moral/ethical foundation. AB - One of the first steps toward reaffirming the core community values of nursing as we see, feel, hear, and acknowledge them is the awareness of a moral/ethical foundation that preserves, promotes, and protects human dignity. This foundation serves as a starting point and evolutionary path for education, research, and practice (Watson, 2008). Nursing-specific malignancies of compassion fatigue, burnout, moral distress, and nurse-to-nurse bullying can metastasize throughout nursing communities in which caring environments are not nourished as priorities and starting points for being, doing, knowing, and belonging. An understanding that we all participate in holographic membership results in an ethical display of moral empathy, so that the complexities of nursing can be articulated and validated in safe environments. In addition, preparing for our deaths in a way that celebrates and honors life may potentially lead to peaceful relationships with self, other, and the community as a whole. The nature of such a community implies that nurses are invested in ensuring the integrity of the human experience, will serve as advocates of ethical/moral engagement, and are the embodiment of the sacred, if we so choose to honor it. PMID- 26050420 TI - Conquering chlamydia. AB - Chlamydia trachomatis, a gram-negative bacterium that often causes no symptoms, is creating a hidden epidemic. The asymptomatic nature of chlamydia promotes its spread; chlamydia is the most commonly reported notifiable disease in the United States. Nurse practitioners, as community members, create the optimal foundation for a healthy community. An interventional community approach to capture and treat asymptomatic chlamydia through the use of open and honest communication in a university health setting was used. A group of 550 sexually active males and females ages 18-24 years who accessed a university health service were provided with chlamydia education and an opportunity for routine chlamydia screening. Overall, 13.1% of the total population offered chlamydia screening were tested for chlamydia; of these, 5.6% tested positive. Routine chlamydia screening and education provides an opportunity to normalize sexual health in a population at high risk for chlamydia infection and offers the most robust chance of capturing and treating asymptomatic chlamydia. PMID- 26050421 TI - Ethical implications of mandatory reporting of intimate partner violence. AB - Nurses are expected to provide a safe haven for clients. When clients seek the services of nurses, they are vulnerable, and they expect privacy and confidentiality. Reporting acknowledged or suspected intimate partner violence (IPV) to authorities can impact nurse-client trust relationships. This article discusses the legal ramifications of reporting of IPV and their implications in a health care setting. PMID- 26050422 TI - Addressing health concerns of pregnant African American women using the lens of complexity theory. AB - Pregnant African American women are at higher risk for multiple complex health issues, including depression, than their European American counterparts (Canady, Bullen, Holzman, Broman, & Tian, 2008; Martin et al, 2011; Mathews & MacDorman, 2007; Orr, Blazer, & James, 2006; Segre, Losch, & O'Hara, 2006). Various strategies must be used to address depression through preventive care and promotion of access to appropriate mental health services. Nurses and other health care providers need to examine the relationships between the multifactorial problems to improve the health and well-being of pregnant African American women and their unborn children. This article presents a case study demonstrating the use of complexity science theory to understand and prevent poor health outcomes for pregnant African American women with depression and their unborn children. PMID- 26050423 TI - The Army's first School of Nursing and its influence on nursing education. AB - The history of the Army School of Nursing, from its origins during the Civil War to its second iteration in the war in Vietnam, includes events and decisions that had far-reaching effects on nursing education in the United States. For the first time, apprenticeship and on-the-job training were replaced by personal instruction from dedicated clinical educators, freeing staff nurses to care for their patients. PMID- 26050424 TI - [The injured of the summer of 1914 and their stories]. AB - The situation of the French Military Health Service was particularly precarious at the beginning of the Great War. Contemporary novelists wished to expose the lies of propaganda and described without any complacency the disorganisation, the improvisation and the mistakes of the first weeks of the conflict. In this context they show the initiatives taken by civilians, especially the ladies from the aristocracy, to help the wounded. From the battlefield to the hospitals they describe the stations of the cross of the soldiers, those hoping for "la bonne blessure" and those who end up being amputated when alternatives could have been possible. PMID- 26050425 TI - [Two French pioneers of plastic surgery: Francois Dubois and Raymond Passot]. AB - After World War, especially during the interwar years, new plastic surgical techniques were highly developed by I two French surgeons: Dr Raymond Passot, a pupil of Pr Hippolyte Morestin, Head of surgery department in Val-de-Grace military hospital, Father of the Gueules cassees and Dr Francois Dubois, a pupil of Pr Sebileau, head of ear nose throat disorders department at Lariboisiere Hospital in Paris. By the way of papers, publications and interviews to media, they described new French cosmetic techniques (rhitidectomy, sutures, liposuccion) and extensively developed this outpatient surgery. They used to renove famous actresse's and actors' face and nose and those of hundreds of patients. They participate to French societies of plastic surgery meetings and publications. Their enthusiastic dare largely participated to the current success of cosmetic surgery in France. PMID- 26050426 TI - [Jacques Monod: some unpublished pages of his life]. AB - The friendship and affinity of thought between Albert Camus and Jacques Monod were little highlighted in France. A book published in the U.S. in 2013 over the period of the Second World War in France shows their importance. It seemed useful to collect the elements of correspondence and writings reflecting their common concerns,frequent meetings and friendship. PMID- 26050427 TI - [Louis Vincelet, medical historian, chronicler of the work of de Maupassant, a Normand passionate about the sea and a dreamer of becoming a white clown]. AB - Son, grandson, great grandson, grandnephew of a medical doctor on both sides, Louis Vincelet dreamt of becoming a white clown, and ultimately his medical uniform in the merchant navy was not so different, during his long career with the Transatlantic General Company up to the age of 55. The sea has been his great source of inspiration, even when he had settled in Paris, taking care of the "forts des halles" and of artists in the main Parisian circuses. PMID- 26050428 TI - [The diseases of Bossuet]. AB - Jacques Benigne Bossuet--nicknamed 'the Bright Eagle from Meaux' by Voltaire- died at 77, in his Parisian place of residence, on April 12th 1704. Which disease so took this robust prelate of Burgundian origin, bishop since he was 53 and whose active life had been filled with important duties and honours. If bibliography about his life is copious we owe before any trusting the testimony of his private secretary, priest Francois Le Dieu, whose diary describes everyday life in detail. Thus we know his fevers, skin rashes in 1699, and his bronchial and digestive problems and we can follow the evolution of his vesical lithiasis complicated with purulent, necrosing cystisis which led to the lethal evolution in spite of the efforts of renowned praticians. PMID- 26050429 TI - [Jan Swammerdam, physician and naturalist of the 17th century]. AB - Jan Swammerdam (1637-1680) was a physician and a naturalist who clarified some details of human anatomy and who made many microscopic observations on insects and their metamorphosis. His life was marked by spirituality and a malaria which caused his death and prevented him from publishing his works which were edited after a long delay. PMID- 26050430 TI - [The physicist Felix Savart (1791-1841). Physician/Surgeon, pioneer in the study of acoustics]. AB - Felix Savart (1791-1841) was both a physician and a physicist, and also a pioneer of acoustics and psycho-acoustics. In 1819 Savart scientifically devised and contructed a trapezoidal violin with the advice of Paris string-instrument maker J-B Vuillaume. This violin drew the attention of J-B Biot who suggested young Savart to work with him on such acoustic researches. From this collaboration proceeded the so-called "law of Biot-Savart" about magnetic power which was in fact formulated by Pierre Simon de Laplace (1749-1827). Savart worked on numerous and diversified acoustic researches. Lord John Rayleigh described them as "beautiful experiments", and he became a foreign correspondant member of the Royal Society in 1839. PMID- 26050431 TI - [Strength training at the beginning of the 19th century]. AB - At the beginning of the 19th century, the therapies of strength had part task to revive vital energy and thus to restore the body forces. Under the method assigned with this objective, there were the baths, body exercises and a continuation of preservation recommended by hygiene. On a general level, the doctor had in hearth to harder the body and to make it robust and healthy. He is to the sick of the head could benefit from this care. Electrification made demonstration of its curative action and its interest to treat the languid state. Considered under this angle, strength could not be then the prerogative of the only muscles. PMID- 26050432 TI - [Embalming: ritual and symbol of power in the West]. AB - Western embalming follows two main goals: a practical function of post-mortem body conservation at least the long time necessary for the organization of a funeral ceremony. But also a theological function with the transformation of the dead body into a good smelling corpse that will be received in Paradise during the "apotheosis". Several forensic anthropological and osteo-archaeological recent studies have enlightened the complexity of such practices. We present here the main results of such studies carried out by our research team. PMID- 26050433 TI - [The patent of Dr. Thibert: models of organs and his secret modeling at the beginning of the 19th century. Analysis of the stomach model (a8n degrees 8) at the Conservatory of Montpellier]. AB - In the early 19th century, Dr. Thibert discovered a process to overcome the difficulties of casting soft and moist organs. However, the analysis of a stomach made by Thibert reveals a modeling, changing the strict mechanical objectivity of the cast. This modeling inside the cast named "reparation" structures the illusionism of this cast. The scientific and artistic aspect of this study is to establish the typology of a secret modeling. This last one is the inheritance of the tricks of the mediocritas: between material and matter, so valuable for the goldsmiths of the 16th century. PMID- 26050434 TI - [Hygiene, hygienism and public health policy in late 19th century France]. AB - In France the desire to expand public health developed mainly because of the hygienist movement which prevailed in the 19th century. This paper aims to show how medical doctors committed themselves deeply at the Chambre des deputes and Senat with the objective of creating the legislation to control sanitary standards which was written between 1870 and 1914. PMID- 26050435 TI - Infectious disease outbreak. A patient's GI illness prompts detective work and a call to public health. PMID- 26050436 TI - A revolution in stroke care. The results of recent stroke trials will have a profound impact on the EMS community. PMID- 26050437 TI - Researchers developing tools to help EMS providers 'COPE' with pediatric deaths. PMID- 26050438 TI - Public access bleeding kits can help save lives. PMID- 26050440 TI - New ambulance design aims to improve safety. PMID- 26050439 TI - Why you should accredit your MIH-CP program. As programs mature, accreditation is a logical next step. PMID- 26050441 TI - The little picture. Too much attention to detail can have big consequences. PMID- 26050442 TI - Treating patients out of a 2007 Toyota Camry. PMID- 26050443 TI - Incidence of flap procedures in the management of burn patients. AB - Increased survival of burn patients presents opportunities for reconstructive strategies to improve outcomes in management of acute and secondary burn injuries. To assess one such strategy, namely flap reconstruction, we reviewed cases performed during the first 4.5 years of the JMS Burn and Reconstruction Center. We found that flap procedures accounted for 0.8% of acute cases (23 of 2723 procedures) and 33% of secondary cases (260 of 790 procedures). This initial finding shows that in this practice flap procedures are applied to a small number of acute problems while flap procedures comprise 33% of secondary procedures. Reconstructive flap surgery plays a measurable role in burn treatment at this center. Further study of outcomes and timing could lead to better understanding of optimal strategies for flap reconstruction in burns. PMID- 26050444 TI - Bedside gallbladder ultrasound for the primary care physician. AB - Modern ultrasound machines are relatively inexpensive to own and simple to operate. Basic ultrasound exams can be easily learned and mastered. As with any clinical exam skill, practice makes perfect. Providers interested in learning ultrasound should seek hands-on guidance from an expert in the field. There are several quality hands-on ultrasound courses (http:// emergencyultrasound.com/) as well as free online videos (http:// emergency ultrasound teaching.com/index.html). The emergency ultrasound team at UMMC will be offering a hands-on ultrasound training course in the spring of 2015. Please contact Dr Brian Tollefson for specific dates and times of the course (btollefson@umc.edu). PMID- 26050445 TI - About colorectal cancer (CRC) in Mississippi. PMID- 26050446 TI - Measles is scary. . PMID- 26050447 TI - [Solidarity is what is needed]. PMID- 26050448 TI - [Different, isolated, but with solidarity]. PMID- 26050449 TI - ["The involved patients need recognition"]. PMID- 26050450 TI - ["Discriminated against, ignored and psychologized"]. PMID- 26050451 TI - [Care in nursing - an obsolete model?]. PMID- 26050452 TI - [Reconsidering respite care for family caregivers]. PMID- 26050453 TI - [Bold action is required]. PMID- 26050454 TI - [Correct wound nursing care is central]. PMID- 26050455 TI - [Heart failure education shows effect]. PMID- 26050456 TI - [Nursing care profile for reliable management]. PMID- 26050457 TI - ["Thinking family"]. PMID- 26050458 TI - [Carlo Janka as "savior in adversity"]. PMID- 26050460 TI - [Classification of security service]. PMID- 26050459 TI - [Contrary destinies]. PMID- 26050461 TI - [My first internship: a revelation]. PMID- 26050462 TI - [Malnutrition is everyone's responsibility]. PMID- 26050463 TI - [Update on advanced practice nursing]. PMID- 26050464 TI - [An insidious water pollution]. PMID- 26050465 TI - [Fragile as a butterfly]. PMID- 26050466 TI - [P4-ATP-ase Atp8b1/FIC1: structural properties and (patho)physiological functions]. AB - P4-ATP-ases comprise an interesting family among P-type ATP-ases, since they are thought to play a major role in the transfer of phospholipids such as phosphatydylserine from the outer leaflet to the inner leaflet. Isoforms of P4 ATP-ases are partially interchangeable but peculiarities of tissue-specific expression of their genes, intracellular localization of proteins, as well as regulatory pathways lead to the fact that, on the organismal level, serious pathologies may develop in the presence of structural abnormalities in certain isoforms. Among P4-ATP-ases a special place is occupied by ATP8B1, for which several mutations are known that lead to serious hereditary diseases: two forms of congenital cholestasis (PFIC1 or Byler disease and benign recurrent intrahepatic cholestasis) with extraliver symptoms such as sensorineural hearing loss. The physiological function of the Atp8b1/FIC1 protein is known in general outline: it is responsible for transport of certain phospholipids (phosphatydylserine, cardiolipin) for the outer monolayer of the plasma membrane to the inner one. It is well known that perturbation of membrane asymmetry, caused by the lack of Atp8B1 activity, leads to death of hairy cells of the inner ear, dysfunction of bile acid transport in liver-cells that causes cirrhosis. It is also probable that insufficient activity of Atp8b1/FIC1 increases susceptibility to bacterial pneumonia.Regulatory pathways of Atp8b1/FIC1 activity in vivo remain to be insufficiently studied and this opens novel perspectives for research in this field that may allow better understanding of molecular processes behind the development of certain pathologies and to reveal novel therapeutical targets. PMID- 26050467 TI - [Cys-containing peptides cause migration of monocytes]. AB - Automated Fmoc solid-phase technique was used to synthesize Cys-containing linear peptide fragments of monocyte chemoattractant protein-1 and chemokine domain of fractalkine along with their analogues with Cys residue being either modified or replaced with Ser. Chimeric symmetric and asymmetric disulfides were also prepared from the former linear precursors. A SAR study on a set of the newly synthesized peptides revealed that capacity to stimulate migration of monocytes and to influence cell motility in vitro, in general, critically depends on the presence of Cys free thiol group in the molecule. Notably, all analogs lacking this feature, including chimeric disulfides, demonstrated lack of effect on monocyte migration. PMID- 26050468 TI - [Tyramine and tryptamine as ligands for medical and biotechnological affinity sorbents]. AB - A novel technique for preparation affinity sorbent based on tyramine and tryptamine was proposed. It was shown that tryptamine-Sepharose and tyramine Sepharose effectively bind IgG, IgA, lipoprotein (a) (Lp(a)) and low density lipoproteins (LDL) from blood plasma. The sorption capacity is 4-9 mg of IgG, 2-4 mg IgA, 3-5:mg of Lp(a) and 5-7 mg of LDL per mL of gel. It was found that new sorbents can bind Lp(a) and IgG as themselves or in a complex of Lp(a) with IgG. The existence of this complex may indicate the presence of anti-Lp(a) autoantibodies in the blood of some patients. The advantages of new sorbents are easiness of its synthesis and stability during use and storage. In practice they can be applied for medical and biotechnological purposes where it is necessary to bind Lp(a), LDL, IgG, IgA. PMID- 26050469 TI - [The study of protease primary specificity by statistical analysis of MALDI mass spectra of proteolysis products]. AB - Experimental verification for studying of proteolytic enzymes' primary specificity by statistical analysis of MALDI (matrix-assisted laser desorption/ionization) mass spectra of products obtained by protein substrates proteolysis was done by the use of proteinases with known substrate specificity (trypsin and glutamylendopeptidase). Proposed technique not requires direct determination of proteolysis products amino acid sequences, reliably establishes proteinases with anarrow substrate specificity and shows a relative tolerance for the presence in MALDI mass-spectra peaks of contaminants. It was shown that the pseudo-positive results exception requires the use of protein substrates series with the following averaging received statistical data. PMID- 26050470 TI - [Identification of 2',3'-cGMP as an intermediate of RNA catalytic cleavage by binase and evaluation of its biological action]. AB - Binase--Bacillus pumilus RNase--endonuclease cleaves the phosphodiester bond between the 3'-guanylic residue and the 5'-OH residue of adjacent nucleotides with the formation of corresponding intermediate 2',3'-cGMP. Subsequent hydrolysis of 2',3'-cGMP into 3'-phosphate is highly specific and occurs slowly So the question arises about the existing time of that positional isomer during RNA catalytic cleavage by binase and about 2',3'-cGMP role in antitumor activity of the enzyme: In present work by means of enzyme-linked immunosorbent assay we established that during catalytic cleavage of RNA by binase 2',3'-cGMP is preserved in reaction mixture for an hour, at the same time phosphodiesterases activation doesn't lead to the total elimination of 2',3'-cGMP. The highest amount of 2',3'-cGMP was observed under the pH 8.5, it reaches nanomolar concentration at initial RNA concentration of 100-1000 MUg/mL. Exogenous 2',3' cGMP, like its positional isomer 3',5'-cGMP, doesn't trigger an apoptosis of human lung adenocarcinoma A549 cells, which are sensitive to binase apoptogenic action. Taking into account data about binase internalization and activation of mitochondrial pores opening by 2',3'-cyclic guanosine phosphates we may consider that 2',3'-cGMP can contribute to the apoptosis initiated by binase only when 2',3'-cGMP is generated intracellularly. PMID- 26050471 TI - [The synthesis of psi-(2-aryl-1,3-dioxolan-2-yl) alkyl derivatives of purines and their activity towards HIV reverse transcriptase]. AB - Novel non-competitive inhibitors of HIV RT were synthesized by alkylation of 6 substituted purines with different 2-(chloroalkyl)-2-aryl-1,3-dioxolanes and related compounds. The structure-activity relationship within the synthesized compounds was studied. PMID- 26050472 TI - [A prototype of oligonucleotide microarray for detection of pathogens relating to arena- and Filoviridae families]. AB - A prototype of oligonucleotide microarray for detection of Lassa, Junin, Machupo, Guanarito viruses (Arenaviridae family), Ebola and Marburg viruses (Filoviridae family) was presented. An original approach founded on virus proteins (nucleocapsid protein for Junin, Guanarito, Machupo viruses and RNA-dependent RNA polymerase for Lassa, Ebola and Marburg viruses) amino acid sequences analysis with subsequent transform of revealed unique peptides into due sets of oligonucleotides was used to design probes for hybridization and primers. PMID- 26050473 TI - [Comparative evaluation of antimicrobial activity of oligochitosans against Klebsiella pneumoniae]. AB - Antibacterial activity of chitosan with different molecular weight at different pH values against gram-negative Klebsiella pneumoniae was studied. It was found that the dependence of inhibition activity of chitosan on its molecular weight was inversed when the medium pH was increased above 7.0. In acidic media higher molecular weight chitosan had the higher antibacterial activity was occured while and in weak alkaline media oligomeric forms of chitosan displayed the inhibition effect only. Our results showed that the antibacterial activity of chitosan against Klebsiella pneumoniae was closely connected with its polycationic nature, and was dependent on the degree of protonation of chitosan amino groups, which at the same time depended on the degree of polymerization and solution pH values. PMID- 26050474 TI - [The optimization of the nitric oxide quantitative analysis for its determination in the cultural medium of mammalian cell culture]. AB - The protocol for the quantitative analysis of nitric oxide as nitrite-ion suitable for determination of its production by a mammalian cell culture was developed. The optimal results were obtained using microvolume-adjusted Griess method after the preliminary reduction of NO3- to NO2- with non-activated cadmium. The protocol was verified on a rat glioma C6 cell culture. The developed method may be used for the nitric oxide determination in 96-well and 48-well microplates; the detection limit is 2.1 +/- 0.1 MUM for NO2- and 2.9 +/- 0.1 MUM for NO3-. PMID- 26050475 TI - [Synthesis of new analogues of combretastatin A-4 and the study of their anti inflammatory activity]. AB - New approach to synthesis of analogs of natural Combretastatin A-4 based on interaction of alpha-acetylenic ketones with secondary amines (diethyl amine, pyrrolidine, piperidine, morpholine) is offered. Unknown analogs of Combretastatin A-4 with beta-aminovinylcarbonyl bridges are received earlier. Anti-inflammatory activity of the received connections is studied. PMID- 26050476 TI - [Synthesis and membrane protective properties of sulfanylimines based on neomenthane and isobornane thiols]. AB - Synthesis of sulfanylimines based on neomenthane and isobornane thiol was carried out with yields up to 85%. On the model of H2O2- and AAPH-induced hemolysis of blood erythrocytes it was found that the sulfenimines have membrane protective and antioxidant activities and inhibit the accumulation of secondary products of lipid peroxidation and oxidation of hemoglobin. PMID- 26050477 TI - [Synthesis and Anti-Inflammatory activity of the propargylamino derivatives of naphthoquinonlevopimaric acid]. AB - Modification of naphthoquinonlevopimaric acid was carried out by introducing of propargylamino residues. Anti-inflammatory activity Mannich bases were studied. PMID- 26050478 TI - Anti-inflammatory activities of some newly synthesized pyridinyl- and indazolyl benzamide derivatives. AB - A series of substituted (pyridin-4-yl)phenyl-2-methoxybenzamide and their derivatives were prepared and screened for their anti-inflammatory activities. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. Some of the newly synthesized compounds exhibited better pharmacological and biological responses than the reference controls with low concentrations. The structures of newly synthesized compounds were confirmed by chemical, elemental and spectroscopic evidences. PMID- 26050479 TI - A convenient synthesis and biological activity of novel thieno[2,3-c]pyrazole compounds as antimicrobial and anti-inflammatory agents. AB - A new method for synthesizing 4-amino-3-methyl-1-phenyl-1H-5-substituted thieno[2,3-c]pyrazole was reported. The substituted groups at position 5 include carbonitrile, carboxamide, N-phenyl carboxamide, and benzoyl groups. The newly synthesized compounds and their derivatives were characterized by elemental analysis and spectroscopy (IR, 1H NMR, and mass spectra). Furthermore, some of these synthesized compounds were screened against various pathogenic bacterial and fungal strains. The results demonstrate that most of the synthesized compounds possess a significant antibacterial activity against gram-positive and gram-negative bacteria. In addition, most of these compounds showed a remarkable anti-fungal activity. On the other hand, some of the synthesized compounds possess high anti-inflammatory activity, which was demonstrated using the carrageenan-induced rat paw edema assay. PMID- 26050480 TI - [The synthesis of P1-[11-(anthracen-9-ylmethoxy)undecyl]-P2(2-Acetamido-2-deoxy alpha-D-glucopyranosyl) diphosphate and the study of its acceptor properties in the enzymic reaction catalyzed by D-rhamnosyltransferase from Pseudomonas aeruginosa]. AB - P1-[11-(Anthracen-9-ylmethoxy)undecyl]-P2-(2-acetamido-2-deoxy-alpha-D glucopyranosyl) diphosphate, a fluorescent derivative of undecyl diphosphate 2 acetamido-2-deoxyglucose, was chemically synthesized. The ability of the compound to serve as acceptor substrate of D-rhamnose residue in the enzymatic reaction catalyzed by D-rhamnosyltransferase from Pseudomonas aeruginosa PAO1 was demonstrated. PMID- 26050481 TI - [On-microchip PCR for detection of influenza A viruses subtypes, circulating in the human population]. AB - A oligonucleotide microchip was developed for revealing Influenza A viruses subtypes, circulating in human population: pandemic H1N1 swine influenza viruses, seasonal H1N1, H2N2, H3N2, H5N1, H9N2, H7N9. Typing of influenza virus was performed by on-microchip PCR. We used immobilized primers-probes selected for the neuraminidase gene that allows determining both subtype of neuraminidase and subtype of hemagglutinin. PMID- 26050482 TI - [Relationship between respiratory function and myocardial structure and function in patients with type 2 diabetes mellitus and ischemic heart disease]. AB - PURPOSE: To analyze main parameters of respiratory dysfunction in patients with type 2 diabetes mellitus (DM) with and without concomitant ischemic heart disease (IHD). MATERIAL AND METHODS: We examined 104 patients with DM without (n = 64, 61.5%) and with (n = 40, 38.5%) concomitant IHD. Examination included taking medical history, registration of parameters of myocardial and respiratory function and lung diffusion capacity. RESUTS: Respiratory dysfunction in patients with DM was related to disease duration and glycose level. Presence of IHD and chronic heart failure of high functional class was associated with more pronounced reduction of forced expiratory volume in 1 sec and lung diffusion capacity. CONCLUSION: Revealed association between respiratory parameters and characteristics of the state of myocardium evidence for possible contribution of the latter in development of respiratory dysfunction in patients with DM. PMID- 26050483 TI - [Anxiety and polymorphism Val66Met of BDNF gene--predictors of depression severity in ischemic heart disease]. AB - In a framework of search for early predictors of depression in patients with ischemic heart disease (IHD) we studied effect of molecular-genetic factors (polymorphism of brain-derived neirotrophic factor--BDNF), personality traits (anxiety, neuroticism), IHD severity, and psychosocial stressors on manifestations of depression in men with verified diagnosis of IHD. Severity of depression was assessed by Hamilton Depression Rating Scale 21-item (HAMD 21), anxiety and neuroticism were evaluated by the Spielberger State-Trait Anxiety Inventory and "Big Five" questionnaire, respectively. It wa shown that personal anxiety and ValVal genotype of BDNF gene appeared to be predictors of moderate and severe depression. PMID- 26050484 TI - [Content of circulating endothelial progenitor cells in patients with chronic ischemic heart failure with preserved left ventricular ejection fraction]. AB - PURPOSE: To assess content of various subpopulations of endothelial progenitor cells (EPC) with CD45-CD34+, CD14+CD309+ and CD14+CD309+Tie2+ phenotypes in patients with chronic heart failure (CHF) of ischemic origin with preserved left ventricular ejection fraction. MATERIAL AND METHODS: We included into the study 126 patients (54 men) aged 48-62 years with angiographically confirmed ischemic heart disease (IHD) and 25 healthy volunteers. Eighty two (65%) patients had NYHA class I-II CHF. Phenotyping of populations of mononuclear cells was performed by flow cytometry with the use of fluorochrome-labeled monoclonal antibodies. Circulating EPC were determined as CD45-CD34+. For identification of subpopulations of EPC coexpressing CD14 antigen we determined CD309(VEGFR2) and Tie2 antigens. RESULTS: In the group of patients with IHD level of circulating proatherogenic mononuclear cells of CD14+CD309+ and CD14+CD309+Tie2+ phenotype depended more on the presence of CHF and number of risk factors of cardiovascular complications (CVC) but not on severity and extent of coronary atherosclerosis. Most important independent predictors of lowering of circulating EPC with CD14+CD309+Tie2+ phenotype were CHF (odds ratio [OR] 1.45, 95% confidence interval [CI] 1.12 to 1.88, p = 0.004), type 2 diabetes (OR 1.21, 95% Cl 1.10 to 1.40; p = 0.008), NT-proBNP > 154 rg/ml (OR 1.13, 95% Cl 1.04 to 1.18, p = 0.003), hyperlipidemia (OR 1.12, 95% CI 1.05 to 1.23, p = 0.005), and presence of +/- 3 traditional cardiovascular risk factors (OR 1.31, 95% CL 1.12 to 1.49, p = 0.008). CONCLUSION: Negative impact of factors of risk of CVC relative to manifestation of ischemic CHF might by mediated by deficit of nonhemopoetic circulating EPC, mobilization of which from peripheral tissues if reduced at early stages of formation of myocardial dysfunction. PMID- 26050485 TI - [Assessment of the therapeutic efficacy and safety of the original bisoprolol and its generic biprol in patients with stable angina]. PMID- 26050486 TI - [Renal dysfunction in patients with ischemic heart disease]. AB - We studied effects of various forms of coronary heart disease on the progression of renal dysfunction. Three groups of patients were examined: 1--patients with exertional angina (n = 29), 2--patients with old myocardial infarction (postinfarction cardiosclerosis) and exertional angina (n = 22), 3--patients with atrial fibrillation and exertional angina (n = 21). Most pronounced anatomic and functional abnormalities of cardiac action and respective statistically more significant renal dysfunction were revealed in group 3. PMID- 26050487 TI - [Cognitive impairment in postmenopausal women with arterial hypertension]. AB - The aim of the study was to assess relationship between organ damage and changes of cognitive function in postmenopausal women with arterial hypertension during 3 years of follow-up. A total of 55 women (aged 69 +/- 9,5 years) with stable course of hypertension were included. During period of observation and treatment cognitive function deteriorated in 40 and improved in 60% of women. Cox regression analysis showed that worsening of cognitive function was associated with low level of education (OR 3.85, p = 0.021), lack of work (OR 5.71, p = 0.035), left ventricular (LV) end-diastolic diameter (OR 6.89, p = 0.019), LV end systolic diameter (OR 3.21, p = 0.047), left atrium (OR 15.20, p = 0.020), microalbuminuria (OR 11.14, p = 0.041) and duration of chair-rising test (OR 7.0, p = 0.025). Our findings indicate that progressive organ damage, low level of education and lack of work are associated with deterioration of cognitive function and functional mobility in women with hypertension. Our results reinforce the need for early detection of cognitive impairment as a marker of subclinical brain damage to prevent dementia. PMID- 26050488 TI - [Cardiotropic action of oxacom in experimental heart failure]. AB - Prolonged hypotensive effect of oxacom (dinitrosyl iron complexes with ligand glutathione) has been well documented in animals and healthy volunteers, but effect on the heart is not defined. In this work, the blood pressure (BP), and the pressure in the left ventricle (LV) were recorded in rats. Intravenous bolus injection of oxacom (10 mg/kg) caused an immediate average BP decrease by 20-30 mm Hg followed by a slow recovery. The LV systolic and diastolic pressures did not change, but the maximal speed of pressure development, and contractility index at peak action of oxacom increased by 26-33%, while isovolumic relaxation constant fell by 30%. These changes gradually normalized within 10-15 minutes. Effect of oxacom on hearts with isoproterenol-induced diffuse ischemic myocardial lesions and diastolic heart failure was similar to that observed in the control group except the isovolumic relaxation constant rose 1.5-fold while elevated LV diastolic pressure fell. Results suggest that oxacom exerts the positive cardiotropic action especially at heart failure. PMID- 26050489 TI - [Microvolt T-wave alternans in adolescent elite athletes]. AB - Microvolt T-wave alternans (MTA) is one of markers of electrical myocardial instability. STUDY AIM: To elucidate normal range of MTA parameters during bicycle exercise test (ET) in adolescent elite athletes. MATERIAL AND METHODS: We examined 500 athletes aged 9-18 (mean 16.1 +/- 2.2) years members of national teams of 27 kinds of sport. There were 333 females with mean age 16.0 +/- 1.01 years and 167 males with mean age 16.3 +/- 1.4. All athletes underwent ECG registration in clino- and ortho- positions and bicycle ET with automatic analysis of MTAT-wave alternans. RESULTS: Mean MTA value was 26 +/- 13 (9-51) mV. MTA above 65 mV was registered in 10 persons (2.1%) 5 of whom had signs of overtraining. Sensitivity (Se) of MTA for detection of overtraining state was 21%, specificity (Sp)--99%, positive and negative predictive value--50 and 96%, respectively. CONCLUSION: Normal MTA range during ET is 9-51 mV. MTA values during ET do not depend on age and sex but are determined by duration of participation in sports and myocardial mass. MTA value is related to length of QT interval. Increase of maximal MTA values above 65 mV is insensitive (Se 21%) but highly specific (Sp 99%) sign of overtraining in adolescent elite athletes. PMID- 26050490 TI - [Connected high cardiovascular mortality in Russia with incorrect coding of causes of death?]. AB - In this article we present data indicative of overestimation of mortality from cardiovascular diseases related to inadequate filling of certificates of causes of death and misuse of ICD-10 codes. Significant errors in coding causes of death result in significant differences in mortality with other countries what precludes correct comparison of mortality from cardiovascular diseases, the development of programs aimed at reducing mortality in the target groups. PMID- 26050491 TI - [The use of novel technologies for assessment of myocardial function in clinical practice]. AB - Key factors defining the prognosis of patients with heart failure (HF) are cardiac remodeling and myocardial contractility. New methods of visualization of myocardial motion gave impulse to research in the area of heart physiology and pathology. However in clinical practice these methods are still rarely used. Evaluation of systolic and diastolic functions based on tissue Doppler (TD), 2D and 3D speckle tracking data provides information on the pressure of left ventricular (LV) filling and enables carrying out differential diagnosis between constrictive pericarditis and myocardial diseases with diastolic dysfunction, dyspnea caused by cardiac and extracardiac causes. It also helps to understand physiology of systolic and diastolic dysfunction, impairment of LV pump function. It also enables monitoring response to HF treatment. Myocardial function analysis gives an opportunity to carry out early diagnostics, to detect subclinical LV dysfunction, to detect dyssynchrony and to predict response to resynchronising therapy. In this article we sum up indicators of systolic and diastolic dysfunction in various types of pathology and present assessment of mechanical dyssynchrony with the aid of TD, 2D and 3D speckle tracking. It is stressed that these methods allow carrying out quantitative analysis of myocardial motion. Practically all analyzed parameters are nonspecific and similar to parameters of remodeling change unidirectionally irrespective of pathology. The aim of this article is to summarize available data and knowledge on the determination of myocardial function. This is important for clinical practice and understanding of future development of the above methods. PMID- 26050492 TI - [Twelve or thirty months of dual antiplatelet Therapy after drug-eluting stents. Results of the DAPT trial]. PMID- 26050493 TI - [To the centennial of Norman Holter (1914-1983)]. AB - The article is devoted to the centennial of the founder of ambulatory ECG monitoring Norman Jeffrey Holter (1914-1983). It contains brief history of the scientist's family, and depiction of his own educational way from magister of chemistry and physics to specialist in nuclear research. His activity during World War II, research related to impact of nuclear tests on environment after the war is also described. The fact is stressed that N. Holter was organizer and first president of Society of Nuclear Medicine. But most prominent contribution of N. Holter was elaboration of the method of long-term ECG monitoring of freely active patients--the method which was later named Holter Monitoring (HM). The article also contains data of first clinical trials of HM systems and stresses contribution of Holter team-mates and colleagues (B. Del Mar, G. Kennedy, S. Stern and others) in their conduct. It shows technical and ideological evolution of HM systems from large apparatuses weighting 40 kg to modern portable devices capable of collecting, storing and processing huge amounts of information, transmitting it over internet to any distance. Nontriviality and serendipity of N. Holter's approach to obtaining novel unpredictable knowledge allowed him to realize his numerous talents and abilities. PMID- 26050494 TI - [Scientific conference "a new era in the treatment of acute decompensated heart failure: focus on innovation"]. PMID- 26050495 TI - [The role of intracardiac echocardiography in clinical practice]. AB - The article contains review of possibilities of the method of intracardiac echocardiography (ICE) in clinical electrophysiology, delineation of indications to its use, and perspectives of development of this technology. Characteristics of technical variants of the method and special features of their application are also given. Technique of performance of interventions under ICE control is described in detail. Foreign experience of ICE use is summarized, and own experience is presented. PMID- 26050496 TI - [The role of markers of organ damage in patients with chronic heart failure]. AB - This review is devoted to the studies of the role of modern markers of myocardial and renal damage (high sensitivity troponin T [hsTnT] and urinary neutrophil gelatinase-associated lipocain [NGA/lipocalin-2] in patients with chronic heart failure (CHF). It contains description of nature, mechanism of synthesis, and release of hsTnT and NGAL, problems of variability of determination of these biomarkers, consideration of causes of elevation of their activity in CHF. Both hsTnT and NGAL have high diagnostic and prognostic significance. Determination of these biomarkers in combination with natriuretic peptides gives complimentary information for more accurate stratification of risk of development of possible complications. Measurement of activity of hsTnT and NGAL (lipocalin-2) will make it easier for a physician to solve the problem of optimization of therapy and management of a concrete patient. PMID- 26050497 TI - [Novel algorithms in treatment of dyslipidemia: comparative analysis of new American and European recommendations]. AB - This analytical review is devoted to analysis of discrepancies between new American and European recommendations/Significance of level of cardiovascular risk, taget levels of lipids, intensity of therapy, application of therapy with statins and/or expedience of the use of other lipid lowering drugs. Main differences between two recommendations and their similarities are summarized in a table. Schematic representation of suggested consensus on treatment of dyslipidemia with consideration of both recommendations is given in a separate part. PMID- 26050498 TI - [Transcatheter treatment of degenerative critical aortic valve stenosis in a patient with severe heart failure and chronic lymphocytic leukemia]. AB - Surgical aortic valve replacement is the standard therapy for severe aortic valve stenosis, however one third of patients are rejected because of high surgical risk. Under medical treatment alone these patients have a very poor prognosis with a high mortality rate. We present a case of 70-year-old male patient with degenerative symptomatic critical aortic stenosis and chronic lymphocytic leukemia. Due to recurrence of leukemia, the patient was denied conventional open heart surgery. Within few months of palliative chemotherapy decompensated aortic stenosis with severe congestive heart failure developed. Such therapeutic alternative as transcatheter aortic valve implantation (TAVI) emerged as a lifesaving procedure for the patient that allowed performing full-dose chemotherapy later. We provide a comprehensive review of current indications and contraindications for TAVI. PMID- 26050499 TI - [Chiari network and pulmonary embolism]. AB - We present the case of a patient with acute pulmonary embolism, Chiari network thrombus, and deep vein thrombosis in lower extremities. Chiari networks are present in the right atrium in a minority of population and are usually of no clinical significance. On the other hand it may be associated with such pathological changes as patent foramen ovale, intraatrial thrombus, or atrial arrhythmias. In our case thrombus was trapped by a Chiari's network. PMID- 26050500 TI - [Hypertrophic cardiomyopathy in a patient with dextrocardia]. PMID- 26050501 TI - [Corticosteroids treatments and osteonecrosis of the femoral head]. PMID- 26050502 TI - Japanese soybean paste miso lessens sympathovagal imbalance and attenuates brain sodium sensitivity in mice with pressure overload. AB - Miso is a traditional Japanese food that is made from fermented soybeans, and it can attenuate salt-induced hypertension in salt-sensitive hypertensive rats. We also recently demonstrated that regular miso intake inhibits salt-sensitive sympathoexcitation in mice with pressure overload (CPO). In this context, sympathoexcitation contributes to the pathogenesis of hypertension, including salt-sensitive hypertension. Therefore, we hypothesized that miso might be able to improve sympathovagal imbalance, thereby attenuating salt-induced hypertension. We first treated mice with an intraperitoneal (IP) injection of miso supernatant that was suspended in a 0.28 M sodium solution. Five hours after the miso injection, the mice's systolic blood pressure and heart rate had decreased, with a lower ratio of low frequency (LF) to high frequency (HF) power of heart rate variability. However, an IP injection of high-sodium saline solution (0.28 M sodium) alone had no effects on these parameters. To evaluate the effects of miso on sodium sensitivity in CPO-mice, we also performed aortic banding. At 4 weeks after the surgery, the mice received an IP injection of miso supernatant or high-sodium saline. The ratio of LF/HF increased after the high sodium saline injection, although not after the miso injection, which indicated that miso inhibited the enhanced sodium sensitivity for sympathetic activity in CPO-mice. We also pre-treated CPO-mice with an intracerebroventricular infusion of miso supernatant to evaluate its effect on increased cerebrospinal fluid (CSF) sodium-induced hypertension. Diluted miso supernatant (in a 0.14 M sodium solution) attenuated the increased CSF sodium-induced hypertension, although pre treatment with normal-sodium (0.14 M) saline failed to change the hypertension. These results suggest that miso acts on the brain to sway the sympathovagal balance towards a parasympathetic nerve dominant state, and to attenuate the brain sodium sensitivity for sympathoexcitation in CPO-mice. PMID- 26050503 TI - [Legislation for training system for nurses engaging in specific medical practice]. PMID- 26050504 TI - [Activities of the Scientific Committee of the Japan Surgical Society]. PMID- 26050505 TI - [Recent trend in surgical treatment for inflammatory bowel diseases]. PMID- 26050506 TI - [Current trends in the management of Crohn's disease]. AB - The medical therapy of Crohn's disease has improved markedly in recent years. In large part, this was due to the introduction of novel biologics. Biological therapy provides superior efficacy; however, these drugs should be given to selected patients who do not respond to first-line medications because of validated safety concerns like infections and malignancy as well as high cost. It remains unclear whether the preoperative use of biologic agents increases the risk of complications after surgery for Crohn's disease. Further research is necessary to evaluate the impact of biologic therapy on postoperative complications. Recent clinical trials have shown that biologic therapy with infliximab and adalimumab is useful for the prevention of postoperative recurrence of Crohn's disease. Further studies are warranted to determine suitable candidates for postoperative biologic therapy and the best time to start treatment. In the surgical management of Crohn's disease, there has been an increasing trend toward limited resection and the use of strictureplasty to preserve small bowel length. Currently, less invasive laparoscopic surgery is used to treat Crohn's disease, which is safe and feasible. PMID- 26050507 TI - [Surgical treatment for perianal Crohn's disease]. AB - Perianal lesions are a frequent complication of Crohn's disease (CD) and include fistula, abscess, anal ulcer, skin tag, anal stricture, and carcinoma. Perianal fistula is the most commonly observed condition and exhibits multiple incidence and intractable characteristics. The starting point for the management of perianal fistula is an accurate diagnosis, which requires careful exploration during an EUA. The condition is treated with medications such as antibiotics, immunosuppressants, or anti-tumor necrosis factor agents. However, it is difficult to maintain long-term remission. Surgical therapy is selected according to the type of fistula and can include conventional fistulotomy, seton drainage, diverting stoma, and anorectal amputation. After fistulotomy, recurrence is frequent and there is an increased risk of incontinence. Seton drainage is the preferred treatment to improve symptoms and preserve anal function. Stoma is useful to relieve symptoms but difficult to indicate for young patients. The optimum treatment for perianal fistula associated with CD remains controversial. Currently, the goal of therapy for these patients has shifted from complete fistula closure to reducing drainage from the fistula to improve their quality of life. Ongoing careful management is important to control anal symptoms and maintain long-term anal function in the treatment of patients with CD, while monitoring them to detect possible progression to anorectal carcinoma. PMID- 26050508 TI - [Surgical management of intestinal Crohn's disease]. AB - Various intestinal conditions such as stricture, fistula, abscess, perforation, and hemorrhage are complications of Crohn's disease. Surgical intervention remains important, even in the era of biologic therapy. Limited surgical resection is essential to avoid short bowel syndrome after massive resection or multiple operations. Strictureplasty is effective for short, isolated stricture of the small intestine and provides good results equivalent to those of intestinal resection. Fecal diversion in the case of very complicated lesions not suitable for immediate resection can offer patients general and local improvement. Although bypass surgery is currently not performed because of the possibility of deterioration or carcinogenesis of the bypassed segment, bypass surgery is useful for avoiding stoma. Laparoscopic surgery is indicated for patients with nonperforating, localized ileocecal lesions, and for those presenting initially. The cumulative postoperative reoperation rate is about 50% to 60% at 10 years. The risk factors for early recurrence are smoking, perforating type, previous reoperation, and small intestinal disease. During postoperative follow-up and maintenance treatment, the importance of an algorithm comprising regular check-ups with ileocolonoscopy and the use of thioprines and biologics has been proposed. PMID- 26050509 TI - [Recent advances in medical and surgical treatment of ulcerative colitis]. AB - Recent advances in both medical and surgical treatment of ulcerative colitis have been remarkable. Changes in medical treatment are mainly good results of therapy with the anti-TNF-alpha antibody, tacrolimus, and those in surgical treatment are an expansion of the surgical indications to include patients with intractable disease, such as treatment refractoriness and chronic corticosteroid dependence, by a better postoperative clinical course after pouch surgery, improred selection of surgical procedures and the timing of surgery in elderly patients. To offer the optimal treatment for patients with ulcerative colitis, new medical therapies should be analyzed from the standpoint of the efficacy and limitations of effect. Long postoperative clinical course of surgical patients including colitic cancer, prevention of postoperative complications should be also analyzed. PMID- 26050510 TI - [Advances in research on ulcerative colitis]. AB - The cause of ulcerative colitis remains unknown, and there is no established medical cure for this disease. Recent progress in genome-wide association studies and research to identify the susceptibility gene have gradually determined the pathophysiology of ulcerative colitis. Focused target therapy resulted in the development of new therapeutic agents that regulate inflammation and gut immunity, which have been applied in the clinical setting. Epigenetic approaches such as microRNA and DNA methylation show promise for the discovery of novel biomarkers for diagnosis or prognosis and predictive response to medical therapy. Now we are attempting to detect specific epigenetic biomarkers of ulcerative colitis-associated cancer. Total proctocolectomy and J-pouch anal anastomosis remain important options in the treatment of ulcerative colitis. These studies may help us to establish highly reliable surgical indications and indicate prognostic risk factors for postoperative complications, making an important contribution to all colorectal surgeons. PMID- 26050511 TI - [Surgery for ulcerative colitis]. AB - Surgical therapy for ulcerative colitis (UC) is affected by medical therapy for the condition. However, that therapy has changed greatly over the past 10 years. Furthermore, there has been a sharp increase in the number of patients with cancer/dysplasia with indications for surgery. The increase in the choices available for effective medical treatment has led to changes in therapeutic medicine. When such treatments are ineffective, emergency surgery is performed, and thus emergency surgery cases are also showing an increasing trend. Patients with indications for surgery are becoming significantly older, and it is not unusual to perform surgery on those more than 70 years of age. Unfortunately, the prognosis is poor in elderly patients who undergo emergency surgery, and thus the timing of surgery is especially important. The primary surgical procedure used for UC is restorative proctocolectomy with an ileal pouch-anal anastomosis or anal-canal anastomosis. Consensus has been reached that anal anastomosis is performed for patients with cancer, while anal-canal anastomosis is performed in older patients. Pouchitis is a frequently reported postoperative complication, although the number of cases of postoperative aggravation of gastroduodenal and small intestinal lesions has been reported to be increasing. Notably, hemorrhaging can be fatal, as hemostasis is sometimes difficult to achieve. PMID- 26050512 TI - [Current status of anorectal transplantation and issues for clinical application for stoma patients]. PMID- 26050513 TI - [What we can learn from a case of medical malpractice--case of wrongful death due to negligent administration of anesthesia: anesthesiologists is found guilty of negligent administration of general and loccal anesthesia that caused a cardiac arrest during surgery and resulted in death]. PMID- 26050514 TI - [Nipple-sparing mastectomy for breast cancer]. PMID- 26050515 TI - [The team approach and trial for nursing new system about specific medical practices--our strategy based on hospital management issue]. PMID- 26050516 TI - ["Let's become the surgeon" the present status of the medical course beside teaching in Department of surgery, Daisan Hospital the Jikei University School of medicine: based on the experience OF clinical Clark ship for 5 years]. AB - In Department of Surgery, Daisan Hospital, The Jikei University School of Medicine, Clinical Clark ship (C.C.) is positively taken in the bedside teaching of the medical course fifth and sixth grader from April, 2010. We think that the C.C. is a good opportunity to tell the charm of the surgeon to the students. We introduce a bedside teaching going in our Department, based on the experience of the C.C. for 5 years. In the bedside teaching of our department, there are many tasks not to advance before when students do not have discussion with preceptors, about participation in surgery, presentation of the preoperative conference, visiting of outpatient care and night practice. Moreover, students decide the theme about submitting report and research presentation. For our department which built a bedside teaching with on the job training as a concept from 2010, "students in the C.C." is welcome and beneficial for the doctors, the students itself and the patients. When C.C. will be introduced into all Department of our university in earnest from 2016, we have to examine the merits and demerits in future so that C.C. functions going well. PMID- 26050518 TI - [Participation in the 100th ACS Annual Meeting and a tour of facilities in United States]. PMID- 26050517 TI - Physician assistant (PA) training in the United States--with a surgical emphasis. PMID- 26050519 TI - Selectfluor-Mediated Simultaneous Cleavage of C-O and C-C Bonds in alpha,beta Epoxy Ketones Under Transition-Metal-Free Conditions: A Route to 1,2-Diketones. AB - Selectfluor-mediated simultaneous cleavage of C-O and C-C bonds in alpha,beta epoxy ketones has been successfully achieved under transition-metal-free conditions. The reaction gives 1,2-diketone compounds in moderate to good yields involving a ring-opening/benzoyl rearrangement/C-C bond cleavage sequence under oxidative conditions. PMID- 26050520 TI - Epidemiological, clinical, and immunological characteristics of neuromyelitis optica: A review. AB - The aim of this study was to review the epidemiological and clinical characteristics of neuromyelitis optica (NMO) and the immunopathological mechanisms involved in the neuronal damage. NMO is an inflammatory demyelinating autoimmune disease of the central nervous system that most commonly affects the optic nerves and spinal cord. NMO is thought to be more prevalent among non Caucasians and where multiple sclerosis (MS) prevalence is low. NMO follows a relapsing course in more than 80-90% of cases, which is more commonly in women. It is a complex disease with an interaction between host genetic and environmental factors and the main immunological feature is the presence of anti aquaporin 4 (AQP4) antibodies in a subset of patients. NMO is frequently associated with multiple other autoantibodies and there is a strong association between NMO with other systemic autoimmune diseases. AQP4-IgG can cause antibody dependent cellular cytotoxicity (ADCC) when effector cells are present and complement-dependent cytotoxicity (CDC) when complement is present. Acute therapies, including corticosteroids and plasma exchange, are designed to minimize injury and accelerate recovery. Several aspects of NMO pathogenesis remain unclear. More advances in the understanding of NMO disease mechanisms are needed in order to identify more specific biomarkers to NMO diagnosis. PMID- 26050521 TI - Ataxia-telangiectasia - A historical review and a proposal for a new designation: ATM syndrome. AB - The authors review ataxia telangiectasia, emphasizing historical aspects, genetic discoveries, and the clinical presentations of the classical and atypical forms. In fact, ataxia telangiectasia represents a multisystem entity with pleomorphic neurological and systemic manifestations. ATM syndrome is proposed as a more adequate designation for this entity. PMID- 26050522 TI - Rapidly progressive dementia with false-positive PCR Tropheryma whipplei in CSF. A case of Hashimoto's encephalopathy. PMID- 26050523 TI - Interordinal gene capture, the phylogenetic position of Steller's sea cow based on molecular and morphological data, and the macroevolutionary history of Sirenia. AB - The recently extinct (ca. 1768) Steller's sea cow (Hydrodamalis gigas) was a large, edentulous North Pacific sirenian. The phylogenetic affinities of this taxon to other members of this clade, living and extinct, are uncertain based on previous morphological and molecular studies. We employed hybridization capture methods and second generation sequencing technology to obtain >30kb of exon sequences from 26 nuclear genes for both H. gigas and Dugong dugon. We also obtained complete coding sequences for the tooth-related enamelin (ENAM) gene. Hybridization probes designed using dugong and manatee sequences were both highly effective in retrieving sequences from H. gigas (mean=98.8% coverage), as were more divergent probes for regions of ENAM (99.0% coverage) that were designed exclusively from a proboscidean (African elephant) and a hyracoid (Cape hyrax). New sequences were combined with available sequences for representatives of all other afrotherian orders. We also expanded a previously published morphological matrix for living and fossil Sirenia by adding both new taxa and nine new postcranial characters. Maximum likelihood and parsimony analyses of the molecular data provide robust support for an association of H. gigas and D. dugon to the exclusion of living trichechids (manatees). Parsimony analyses of the morphological data also support the inclusion of H. gigas in Dugongidae with D. dugon and fossil dugongids. Timetree analyses based on calibration density approaches with hard- and soft-bounded constraints suggest that H. gigas and D. dugon diverged in the Oligocene and that crown sirenians last shared a common ancestor in the Eocene. The coding sequence for the ENAM gene in H. gigas does not contain frameshift mutations or stop codons, but there is a transversion mutation (AG to CG) in the acceptor splice site of intron 2. This disruption in the edentulous Steller's sea cow is consistent with previous studies that have documented inactivating mutations in tooth-specific loci of a variety of edentulous and enamelless vertebrates including birds, turtles, aardvarks, pangolins, xenarthrans, and baleen whales. Further, branch-site dN/dS analyses provide evidence for positive selection in ENAM on the stem dugongid branch where extensive tooth reduction occurred, followed by neutral evolution on the Hydrodamalis branch. Finally, we present a synthetic evolutionary tree for living and fossil sirenians showing several key innovations in the history of this clade including character state changes that parallel those that occurred in the evolutionary history of cetaceans. PMID- 26050524 TI - Adults with mild hearing impairment: Are we meeting the challenge? AB - OBJECTIVE: Acquired hearing impairment is recognized by the World Health Organization as the third leading cause of disability, with a mild impairment being the most prevalent. The aim of this study was to review research literature concerned with adults with acquired mild hearing impairment; the definitions and prevalence, the resulting activity limitations and participation restrictions, and hearing-aid interventions. DESIGN: This study involved a systematized review of research literature identified through searches in citation databases and through reference checking. STUDY SAMPLE: A total of 151 papers were identified and of these, 33 papers were included in this review. RESULTS: Prevalence rates are significantly influenced by the definition used for mild hearing impairment, and range from 1 in 3 to 1 in 5 adults. The weak correlations between audiological assessments and self-reported difficulties suggest that further assessment of individuals with mild hearing impairment is warranted. The most common intervention is the provision of hearing aids with varying rates of use, benefit, and satisfaction. CONCLUSIONS: The development of appropriate audiological assessment in the clinic, and further evaluation of the real-world listening needs and performance of people with mild hearing impairment is required to provide a more effective pathway for this clinical population. PMID- 26050527 TI - Macyranones: Structure, Biosynthesis, and Binding Mode of an Unprecedented Epoxyketone that Targets the 20S Proteasome. AB - In our screening efforts to identify unique scaffolds from myxobacteria for the drug discovery process, we used LC-SPE-NMR-MS techniques to isolate six linear peptides, termed macyranone A-F, from Cystobacter fuscus MCy9118. The macyranones are characterized by a rare 2-methylmalonamide moiety and an alpha-amino ketone fragment including an alpha',beta'-epoxyketone in macyranone A. Gene disruption experiments confirmed the biosynthetic gene cluster of the macyranones as PKS/NRPS hybrid. Detailed in silico and phylogenetic analysis unraveled that the biosynthesis involves two conspicuous amide bond formations accomplished by an amidotransferase and a unique condensation domain. The gene cluster provides further insights into the formation of the powerful epoxyketone residue involving an acyl-CoA dehydrogenase and an unconventional free-standing thioesterase. Macyranone A was found to inhibit the chymotrypsin-like activity of the yeast 20S proteasome with an IC50 of 5.9 nM and the human constitutive proteasome and immunoproteasome with IC50 values of 21 and 15 nM, respectively. The beta5 subunit of the 20S proteasome was characterized as target by X-ray crystallography revealing an irreversible binding mode similar to the natural product epoxomicin. The presence of the methylmalonamide residue facilitates the stabilization of macyranone A with the active beta5 subunit of the proteasome. Macyranone A exhibits a potent inhibitory effect against the parasites Trypanosoma brucei rhodesiense and Leishmania donovani with IC50 values of 1.55 and 0.22 MUM, respectively. PMID- 26050528 TI - Developments in extracorporeal therapy for the poisoned patient. AB - The modern use of extracorporeal therapies to treat poisoning and drug overdoses dates back to the early 20th century and has evolved along with their use as treatment for acute kidney injury or as maintenance therapy in advanced kidney disease. As our understanding of drug pharmacokinetics and membrane materials has increased, the technologies of extracorporeal therapy and their applications have become more sophisticated. Despite that, there is little robust evidence to guide clinicians on the optimal use of extracorporeal therapy in treating poisoning beyond case reports and series. New efforts are underway to remedy that: the Extracorporeal Treatments in Poisoning Workgroup (EXTRIP) is an international effort on the part of nephrologists, pharmacists and toxicologists to review the available data and formulate evidence-based guidelines on how to use extracorporeal techniques to treat poisoning and improve patient outcomes. Meanwhile, new techniques and membranes are under development. This review will summarize those key scientific and technologic developments, the efforts to optimize their use and new directions in research. PMID- 26050529 TI - Biomedical applications of polymers derived by reversible addition - fragmentation chain-transfer (RAFT). AB - RAFT- mediated polymerization, providing control over polymer length and architecture as well as facilitating post polymerization modification of end groups, has been applied to virtually every facet of biomedical materials research. RAFT polymers have seen particularly extensive use in drug delivery research. Facile generation of functional and telechelic polymers permits straightforward conjugation to many therapeutic compounds while synthesis of amphiphilic block copolymers via RAFT allows for the generation of self-assembled structures capable of carrying therapeutic payloads. With the large and growing body of literature employing RAFT polymers as drug delivery aids and vehicles, concern over the potential toxicity of RAFT derived polymers has been raised. While literature exploring this complication is relatively limited, the emerging consensus may be summed up in three parts: toxicity of polymers generated with dithiobenzoate RAFT agents is observed at high concentrations but not with polymers generated with trithiocarbonate RAFT agents; even for polymers generated with dithiobenzoate RAFT agents, most reported applications call for concentrations well below the toxicity threshold; and RAFT end-groups may be easily removed via any of a variety of techniques that leave the polymer with no intrinsic toxicity attributable to the mechanism of polymerization. The low toxicity of RAFT-derived polymers and the ability to remove end groups via straightforward and scalable processes make RAFT technology a valuable tool for practically any application in which a polymer of defined molecular weight and architecture is desired. PMID- 26050530 TI - Treatment of stress urinary incontinence with a generic transobturator tape. AB - OBJECTIVE: To evaluate the efficacy and safety of using a generic tape tailored from type 1 monofilamentous, macroporous polypropylene mesh during transobturator tape (TOT) surgery. METHODS: A prospective study was performed in a tertiary center in Cairo, Egypt, between July 2004 and December 2013. Women with stress urinary incontinence scheduled for TOT surgery using the outside-in technique were recruited. Monarc tape was used in all patients until November 2005, after which it was used for patients who could afford it only; generic tape was used in the other patients. The primary outcome measures were the objective and subjective cure rates. RESULTS: Overall, 431 women were included in analyses. After 5 years of follow-up, objective cure was achieved in 143 (94.1%) of 152 women who received Monarc tape and 249 (89.2%) of 279 who received the generic tape (P=0.135). Subjective cure was achieved in 121 (79.6%) women who received the Monarc tape and 236 (84.6%) women who received the generic tape (P=0.229). There were no significant between-group differences in postoperative urgency, de novo urgency, urge incontinence, voiding dysfunction, urinary retention, vaginal erosion, or the frequency of TOT-related reoperation or repeat anti-incontinence procedures. CONCLUSION: The TOT outside-in procedure can be easily, safely, and effectively performed in low-resource settings using a generic polypropylene tape. PMID- 26050531 TI - Some thoughts on disrespect and abuse in childbirth in response to FIGO's Mother Baby Friendly Birthing Facilities Initiative. PMID- 26050532 TI - Predictive validity of the Braden Scale for pressure ulcer risk in hospitalized patients. AB - PURPOSE: Although the Braden Scale has been used as a basic tool to assess pressure ulcer risk, the validity of its effectiveness and accuracy was insufficient. Therefore, this study developed the groundwork for the predictive validity of the Braden Scale through a meta-analysis of prospective diagnosis assessment research. METHODS: Articles published between 1966 and 2013 from periodicals indexed in the Ovid Medline, Embase, CINAHL, KoreaMed, NDSL and other databases were selected, using the keyword 'pressure ulcer'. QUADAS-II was applied to assess the internal validity of the diagnostic studies. Selected studies were analyzed using meta-analysis with MetaDiSc 1.4. RESULTS: Twenty-one diagnostic studies with high methodological quality, involving 6070 patients, were included. The meta-analysis revealed that the pooled sensitivity was 0.72 (95% CI 0.68, 0.75); pooled specificity was 0.81 (95% CI 0.80, 0.82), and the sROC AUC was 0.84 (SE = 0.02). A detail analysis confirmed that age and reference standards were the factors that affected the diagnostic accuracy of the Braden Scale. CONCLUSION: The results suggest that the Braden Scale has a moderate predictive validity. This research also revealed the possibility that the predictive validity of the Braden Scale could be enhanced if it was applied differently according to the attributes of the study subjects. PMID- 26050533 TI - Evaluation of image quality and dose reduction of 80 kVp neck computed tomography in patients with suspected peritonsillar abscess. AB - AIM: To evaluate neck computed tomography (CT) with a reduced tube voltage of 80 kVp in patients with suspected peritonsillar abscess (PTA) regarding objective and subjective image quality, and the potential for dose reduction. MATERIALS AND METHODS: Forty-seven patients with clinically suspected PTA were retrospectively analysed. Patients were examined using dual-source CT in dual-energy mode. The objective and subjective image quality of 80 kVp images were compared with linearly blended 120 kVp images (M_0.3; 30% of 80 kV, 70% of 140 kV spectrum). Attenuation of abscess rim enhancement, central necrosis, and several other anatomical landmarks were measured. The signal-to-noise ratio (SNR), contrast-to noise ratio (CNR), and rim-to-abscess CNR (raCNR) were calculated. Radiation dose was assessed as size-specific dose estimates (SSDE). Subjective image quality was assessed according to the European guidelines on quality criteria for CT. Interobserver agreement was calculated using the intraclass correlation coefficient (ICC). RESULTS: Attenuation of inflamed soft tissue (141.7 +/- 16.3 versus 93.7 +/- 9.3 HU, p < 0.001), CNR (9.6 +/- 4.8 versus 5.6 +/- 3.8, p = 0.001), raCNR (14.3 +/- 5.9 versus 12.4 +/- 4.4, p = 0.02), and subjective image sharpness (3.6 +/- 0.6 versus 2.8 +/- 0.7, p < 0.001) were significantly increased in the 80 kVp compared to 120 kVp, whereas subjective and objective image noise were significantly increased with 80 kVp acquisition (p < 0.001). Overall interobserver agreement was almost perfect (ICC, 0.87). Calculated SSDE of 80 kVp acquisition was decreased by 49.7% compared to 120 kVp (10.58 +/- 0.76 versus 21.04 +/- 1.43 mGy, p < 0.001). CONCLUSION: Low-tube-voltage 80 kVp neck CT provides increased enhancement of soft-tissue inflammation, CNR, raCNR, and improved abscess delineation in patients with PTA compared to standard 120 kVp acquisition while resulting in a significant reduction of radiation exposure. PMID- 26050534 TI - Diffusion-weighted signal patterns of intracranial haemorrhage. AB - The signal pattern of intracranial haemorrhage on diffusion-weighted imaging (DWI) as it evolves over time is rarely discussed due to the sensitivity of T2* weighted sequences and the specificity of classic signal patterns on T1 and T2 weighted sequences. The DWI signal is strongly affected by the magnetic susceptibility of paramagnetic blood products and, therefore, is markedly hypointense in the same phases that demonstrate hypointensity on T2*-weighted sequences; however, hyperacute haemorrhage (oxyhaemoglobin-predominant clot) and late subacute haemorrhage (extracellular methaemoglobin) do not demonstrate T2* hypointensity. Moreover, T2*-weighted sequences are less sensitive to the presence of extra-axial haemorrhage than to intraparenchymal haemorrhage. At these stages of evolution, haemorrhage demonstrates high DWI signal in association with low ADC values, which may be more pronounced than even its corresponding fluid-attenuated inversion recovery (FLAIR) signal. DWI is useful for identifying hyperacute subarachnoid haemorrhage and as a problem-solving tool in challenging cases. PMID- 26050536 TI - Varicella Zoster Virus in Ischemic Optic Neuropathy. PMID- 26050535 TI - Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses and children. AB - AIM: To compare the diagnostic accuracy of non-invasive cerebral post-mortem magnetic resonance imaging (PMMRI) specifically for cerebral and neurological abnormalities in a series of fetuses and children, compared to conventional autopsy. MATERIALS AND METHODS: Institutional ethics approval and parental consent was obtained. Pre-autopsy cerebral PMMRI was performed in a sequential prospective cohort (n = 400) of fetuses (n = 277; 185 <= 24 weeks and 92 > 24 weeks gestation) and children <16 years (n = 123) of age. PMMRI and conventional autopsy findings were reported blinded and independently of each other. RESULTS: Cerebral PMMRI had sensitivities and specificities (95% confidence interval) of 88.4% (75.5 to 94.9), and 95.2% (92.1 to 97.1), respectively, for cerebral malformations; 100% (83.9 to 100), and 99.1% (97.2 to 99.7) for major intracranial bleeds; and 87.5% (80.1 to 92.4) and 74.1% (68 to 79.4) for overall brain pathology. Formal neuropathological examination was non-diagnostic due to maceration/autolysis in 43/277 (16%) fetuses; of these, cerebral PMMRI imaging provided clinically important information in 23 (53%). The sensitivity of PMMRI for detecting significant ante-mortem ischaemic injury was only 68% (48.4 to 82.8) overall. CONCLUSIONS: PMMRI is an accurate investigational technique for identifying significant neuropathology in fetuses and children, and may provide important information even in cases where autolysis prevents formal neuropathological examination; however, PMMRI is less sensitive at detecting hypoxic-ischaemic brain injury, and may not detect rarer disorders not encountered in this study. PMID- 26050537 TI - Repeat Descemet Membrane Endothelial Keratoplasty: Secondary Grafts with Early Intervention Are Comparable with Fellow-Eye Primary Grafts. AB - PURPOSE: To evaluate the outcomes of secondary Descemet membrane endothelial keratoplasty (DMEK) after failed primary DMEK. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Fifty-five DMEK recipients 42 to 89 years of age. METHODS: An initial consecutive series of 1655 DMEK surgeries was reviewed to identify cases of secondary DMEK after failed primary DMEK (n = 55). A paired fellow-eye analysis was performed with a subgroup of 29 patients who underwent secondary DMEK in 1 eye and successful primary DMEK in the fellow eye. MAIN OUTCOME MEASURES: Corrected distance visual acuity (CDVA), central corneal thickness, and 1-year endothelial cell loss. RESULTS: The median follow-up after DMEK regraft was 18 months (range, 3-61 months). All 55 regrafts cleared, 8 (15%) had air reinjected to promote attachment, 1 eye (2%) with trabeculectomy and progressive synechiae demonstrated late endothelial failure, and no rejection episodes occurred (0%). In the paired analysis, the median duration of endothelial decompensation before the regraft was 21 days (range, 2-133 days). At 1, 3, 6, or 12 months, CDVA did not differ between the primary and secondary grafts in fellow eyes (mean difference, <=2 Snellen letters; P > 0.05 at all examinations). At 1 year, the visual acuity was >=20/20 in 61%, >=20/25 in 81%, and >=20/40 in 100% of the secondary grafts in the paired analysis, excluding 1 eye with retinal problems. Vision differed by <=1 line between fellow eyes in all but the 1 patient with the longest time to regraft (133 days), who demonstrated central haze and irregular astigmatism from anterior stromal scarring during that period. At 1 year, CDVA associated with the scarring was 20/40 versus 20/20 for the fellow-eye primary graft. The central corneal thickness was comparable between fellow-eye primary and secondary grafts at 3, 6, and 12 months (mean difference at 1 year, 2 MUm; P = 0.57). The 1-year endothelial cell loss was comparable in primary and secondary grafts (27% vs. 31%, respectively; P = 0.58). CONCLUSIONS: In patients who received prompt intervention to minimize the duration of central corneal decompensation, the visual outcomes with secondary DMEK matched the fellow-eye visual outcomes with primary DMEK. PMID- 26050538 TI - Ocular Surface Squamous Neoplasia in 200 Patients: A Case-Control Study of Immunosuppression Resulting from Human Immunodeficiency Virus versus Immunocompetency. AB - PURPOSE: To describe and compare the clinical presentation, treatment outcomes, and histopathologic features of ocular surface squamous neoplasia (OSSN) based on human immunodeficiency virus (HIV) status. DESIGN: Case-control study. PARTICIPANTS: A total of 200 patients with OSSN, of whom 83 (41%) had positive results for HIV and were classified as cases and 117 (59%) had negative results for HIV and were classified as controls. METHODS: Enzyme-linked immunosorbent assay for HIV, conjuntival excision biopsy, extended enucleation, orbital exenteration. MAIN OUTCOME MEASURES: Clinical features, treatment outcomes, and histopathologic characteristics. RESULTS: The mean age at presentation of OSSN in both cases and controls was 40 years (median, 40 years; range, 13-65 years) and in controls was 40 years (median, 38 years; range, 15-80 years). On comparison of cases versus controls with OSSN, HIV-positive individuals had larger (12 vs. 8 mm; P < 0.001) and thicker (3.2 vs. 2.3 mm; P = 0.041) tumors, with a higher incidence of corneal (60% vs. 40%; P = 0.007), scleral (19% vs. 9%; P = 0.044), and orbital (13% vs. 3%; P = 0.019) invasion and a higher need for extended enucleation or exenteration (27% vs. 11%; P < 0.001). The bilateral presentation (11% vs. 4%; P = 0.13), need for lamellar sclerectomy (13% vs. 8%; P = 0.29), and tumor recurrence after primary treatment (30% vs. 20%; P = 0.12) was higher in HIV-positive cases compared with HIV-negative controls. However, these features were not statistically significant. Based on American Joint Committee on Cancer classification, T1 tumor was more common in controls (13% in cases vs. 35% in controls; P = 0.0009), and T4 tumor was more common in cases (13% in cases vs. 4% in controls; P = 0.019). None of the patients demonstrated systemic metastases or died of disease during a mean follow-up period of 10 months (median, 4 months; range, <1-75 months) in cases and 9 months (median, 4 months; range, <1-99 months) in controls. CONCLUSIONS: Ocular surface squamous neoplasia in HIV positive individuals is aggressive with larger and thicker tumors and with higher incidence of corneal, scleral, and orbital invasion. These patients are associated with poor ocular prognosis with higher need for extended enucleation, exenteration, or both. PMID- 26050539 TI - Incidence and Characteristics of Cataract Surgery in France from 2009 to 2012: A National Population Study. AB - PURPOSE: To report age- and sex-specific incidence rates of cataract surgery in France and evaluate the trends of cataract surgery from 2009 to 2012. DESIGN: Cohort study. SUBJECTS: Data for all patients who underwent primary cataract surgery in France between January 2009 and December 2012 were collected from the national database. METHODS: Annual incidence rates were calculated and adjusted to the corresponding-year national population data from the French National Institute of Statistics. Kaplan-Meier analysis was used to assess the time between surgeries for both eyes. MAIN OUTCOME MEASURES: Age- and sex-specific incidence of cataract surgery. RESULTS: Over the 4 years, 2 717 203 eyes in 1 817 865 patients (59.1% were women; mean age, 73.5+/-0.015 years) underwent cataract surgery. Between 2009 and 2012, the total number of operated eyes per year increased, from 634 070 to 723 172 (+14.0%), and the number of patients with 1 or both eyes undergoing cataract surgery decreased, from 475 301 to 449 318 (-5.5%). The incidence of cataract surgery increased from 9.86 to 11.08/1000 person-years and that of operated patients (1 or both eyes) decreased from 7.39 to 6.89/1000 person-years. The incidence of cataract surgery ranged from 1.06/1000 person years for patients aged 40 to 49 years to 65.94/1000 person-years for those aged 80 to 89 years. Between 2009 and 2012, the probability of second-eye surgery 12 months after the first-eye surgery increased from 40.6% to 51.2% (P < 0.0001). The median interval for surgery between eyes was 29 (interquartile range, 14-86) days. The rate of posterior capsular tear was 0.20%, with a higher proportion from extracapsular extraction than phacoemulsification (7.9% vs. 0.15%; P < 0.0001). The proportion of patients who underwent cataract surgery with a history of high myopia, eye trauma, or retinal detachment was 0.49%, 0.21%, and 0.80%, respectively. CONCLUSIONS: This study documented the incidence and trends in cataract surgery in the overall population in France. Between 2009 and 2012, the number of people undergoing cataract surgery slightly decreased, but the total number of operated eyes increased because the proportion of surgeries on the second eye increased. PMID- 26050540 TI - The Relationship between Medicare Payment and Service Volume for Retina Procedures from 2005 through 2009. AB - PURPOSE: To calculate the relationship between Medicare payment and service volume for the 3 highest-volume retina procedures: intravitreal injection (Current Procedural Terminology [CPT] code 67028), laser treatment for retinal edema (CPT code 67210), and laser treatment for proliferative retinopathy (CPT code 67228). DESIGN: Retrospective, longitudinal database study. PARTICIPANTS: One hundred percent dataset of all retina procedures performed on Medicare Part B beneficiaries within the United States from 2005 through 2009. METHODS: Fixed effects regression model using Medicare Part B carrier data for all 50 states and the District of Columbia, controlling for time-invariant carrier-specific characteristics, national trends in service volume, Medicare beneficiary population, number of ophthalmologists, and income per capita. MAIN OUTCOME MEASURES: Medicare payment-service volume elasticities, defined as the percent change in service volume per 1% change in Medicare payment, for intravitreal injection, laser treatment for retinal edema, and laser treatment for proliferative retinopathy. RESULTS: For all 3 retina procedures, the regression coefficients representing the Medicare payment-service volume elasticity were nonsignificant: intravitreal injection elasticity, -0.75 (95% confidence interval [CI], -1.62 to 0.13; P = 0.09); laser treatment for retinal edema elasticity, 0.14 (95% CI, -0.38 to 0.65; P = 0.59); and laser treatment for proliferative retinopathy elasticity, 0.05 (95% CI, -0.26 to 0.35; P = 0.77). CONCLUSIONS: This study found no evidence suggesting that there is an association between Medicare payment and service volume for the 3 highest-volume retina procedures from 2005 through 2009. PMID- 26050541 TI - Influence of Glycosylated Hemoglobin on the Efficacy of Ranibizumab for Diabetic Macular Edema: A Post Hoc Analysis of the RIDE/RISE Trials. AB - PURPOSE: To investigate the influence of glycosylated hemoglobin (HbA1c) on treatment outcomes in patients with diabetic macular edema (DME) receiving intravitreal ranibizumab. DESIGN: Post hoc analysis of 2 identical phase III clinical trials assessing the efficacy and safety of intravitreal ranibizumab in DME over 36 months (RIDE: NCT00473382/RISE: NCT00473330). PARTICIPANTS: A total of 483 adults with vision loss from DME treated with ranibizumab were included in this analysis from RIDE/RISE. Participants received monthly intravitreal ranibizumab (0.3 or 0.5 mg). MAIN OUTCOME MEASURES: Differences in visual and anatomic outcomes, and diabetic retinopathy (DR) severity score, between subgroups of patients with baseline HbA1c <=7% versus HbA1c >7% at 36 months. RESULTS: There were 195 patients in RIDE/RISE who were treated with ranibizumab with a baseline HbA1c <=7% and 288 patients with a baseline HbA1c >7% included in this analysis. The mean improvement in visual acuity (VA) at 36 months was +13 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in patients with baseline HbA1c <=7% compared with +11 ETDRS letters in the patients with a baseline HbA1c >7% (P = 0.17). After adjustment for baseline central foveal thickness (CFT) and duration of diabetes, the mean CFT reduction was -268 MUm in patients with a baseline HbA1c <=7% and -269 MUm in patients with a baseline HbA1c >7% (P = 0.98; 95% confidence interval, -22.93 to 23.54). The proportion of patients with a >=2-step improvement in DR severity score was 38% in patients with baseline HbA1c <=7% compared with 41% in the patients with a baseline HbA1c >7% (P = 0.53). There was no correlation of baseline HbA1c with any visual or anatomic parameter. CONCLUSIONS: The improvement in VA, anatomic reduction of macular edema, and improvement in DR severity score with ranibizumab treatment seem to be independent of baseline HbA1c. PMID- 26050542 TI - In Vivo Confocal Microscopy 1 Year after Autologous Cultured Limbal Stem Cell Grafts. AB - PURPOSE: To correlate clinical, impression cytologic, and in vivo confocal microscopy findings on the corneal surface after cultured limbal stem cell transplantation. DESIGN: Prospective, interventional, noncomparative, masked case series. PARTICIPANTS: Thirteen patients with limbal stem cell deficiency after unilateral (9 eyes) or bilateral (2 eyes) chemical burn, liquid nitrogen injury (1 eye), or herpes simplex virus infection (1 eye). METHODS: Limbal cells were harvested from healthy or less affected eyes, cultured on 3T3 cells and fibrin glue, and transplanted to the patient's injured eye. Patients underwent clinical examination and impression cytologic examination of the central cornea before and 1 year after intervention. In vivo confocal microscopy scans were obtained in all corneal quadrants after 1 year. The interexamination agreement was established by calculation of the Cohen's kappa coefficient. MAIN OUTCOME MEASURES: Results of surgery were assessed considering clinical signs (successful: restoration of transparent, avascular, and stable corneal epithelium without neovascularization in central corneal surface; partially successful: recurrence of superficial neovascularization; failed: recurrent epithelial defects, pannus, and inflammation), phenotype of cells covering the corneal surface (conjunctivalized corneal surface: cytokeratin 12 [cK12]-negative and mucin 1 [MUC1]-positive cells; mixed epithelium: cK12-positive and MUC1-positive cells; corneal epithelium: cK12-positive and MUC1-negative cells), and cell morphologic features (corneal epithelium: multilayered polygonal and flat cells with hyperreflective nuclei; conjunctival epithelium: stratified cuboidal or polygonal cells, hyperreflective cytoplasm, and barely defined borders; epithelial transition: transition of epithelial cells from the cornea to the conjunctiva over the corneal surface). RESULTS: We found a moderate to substantial degree of concordance between confocal microscopy and clinical evaluation (kappa = 0.768) and between confocal microscopy and impression cytologic analysis (kappa = 0.629). Confocal microscopy showed that 46.2% of patients exhibited corneal epithelium in the central and peripheral cornea, 30.8% showed an irregular mixed corneal and conjunctival epithelium, and 23.0% showed conjunctival epithelium. Palisades of Vogt were absent in all (100.0%) patients, and the cornea conjunctiva epithelial transition localized approximately 1 mm internally on the cornea. CONCLUSIONS: Confocal microscopy provides objective measures of the corneal epithelium and may significantly improve the evaluation of outcomes after cultured limbal stem cell graft. PMID- 26050544 TI - Extracting order from elegant chaos: implications of the marine diversity spectrum. AB - How do we begin to extract order from the elegant chaos of natural ecosystems? In a landmark new paper published in this issue, Reuman et al. (2014) go back to first principles, combining a range of established body size- and species-centred ecological theories with empirically well-supported relationships to construct a model that enables them to predict key features using only remarkably simple biological and environmental measurements. They test this model using widely available data on the communities living in all of the world's coastal seas. Here, I discuss the key features of their model, and especially how the general patterns they document can lead to further, empirically driven tests of theory across multiple ecosystems. PMID- 26050543 TI - Corneal High-Order Aberrations and Backscatter in Fuchs' Endothelial Corneal Dystrophy. AB - PURPOSE: Suboptimal visual acuity after endothelial keratoplasty has been attributed to increased anterior corneal high-order aberrations (HOAs). In this study, we determined anterior and posterior corneal HOAs over a range of severity of Fuchs' endothelial corneal dystrophy (FECD). DESIGN: Cross-sectional study. PARTICIPANTS: A total of 108 eyes (62 subjects) with a range of severity of FECD and 71 normal eyes (38 subjects). METHODS: All corneas were examined by using slit-lamp biomicroscopy to determine the severity of FECD versus normality. Fuchs' endothelial corneal dystrophy corneas were categorized as mild, moderate, or advanced according to the area and confluence of guttae and the presence of clinically visible edema. Normal corneas were devoid of any guttae. Wavefront errors from the anterior and posterior corneal surfaces were derived from Scheimpflug images and expressed as Zernike polynomials through the sixth order over a 6-mm diameter optical zone. Backscatter from the anterior 120 MUm and posterior 60 MUm of the cornea also was measured from Scheimpflug images and was standardized to a fixed scatter source. Variables were compared between FECD and control eyes by using generalized estimating equation models to adjust for age and correlation between fellow eyes. MAIN OUTCOME MEASURES: High-order aberrations, expressed as root mean square of wavefront errors, and backscatter of the anterior and posterior cornea. RESULTS: Total anterior corneal HOAs were increased in moderate (0.61+/-0.27 MUm, mean +/- standard deviation; P = 0.01) and advanced (0.66+/-0.28 MUm; P = 0.01) FECD compared with controls (0.47+/-0.16 MUm). Total posterior corneal HOAs were increased in mild (0.22+/-0.09 MUm; P = 0.017), moderate (0.22+/-0.08 MUm; P < 0.001), and advanced (0.23+/-0.09 MUm; P < 0.001) FECD compared with controls (0.16+/-0.03 MUm). Anterior and posterior corneal backscatter were higher for all severities of FECD compared with controls (P <= 0.02, anterior; P <= 0.001, posterior). CONCLUSIONS: Anterior and posterior corneal HOAs and backscatter are higher than normal even in early stages of FECD. The early onset of HOAs in FECD might contribute to the persistence of HOAs and incomplete visual rehabilitation after endothelial keratoplasty. PMID- 26050545 TI - Spatial analyses for nonoverlapping objects with size variations and their application to coral communities. AB - Spatial distributions of individuals are conventionally analysed by representing objects as dimensionless points, in which spatial statistics are based on centre to-centre distances. However, if organisms expand without overlapping and show size variations, such as is the case for encrusting corals, interobject spacing is crucial for spatial associations where interactions occur. We introduced new pairwise statistics using minimum distances between objects and demonstrated their utility when examining encrusting coral community data. We also calculated the conventional point process statistics and the grid-based statistics to clarify the advantages and limitations of each spatial statistical method. For simplicity, coral colonies were approximated by disks in these demonstrations. Focusing on short-distance effects, the use of minimum distances revealed that almost all coral genera were aggregated at a scale of 1-25 cm. However, when fragmented colonies (ramets) were treated as a genet, a genet-level analysis indicated weak or no aggregation, suggesting that most corals were randomly distributed and that fragmentation was the primary cause of colony aggregations. In contrast, point process statistics showed larger aggregation scales, presumably because centre-to-centre distances included both intercolony spacing and colony sizes (radius). The grid-based statistics were able to quantify the patch (aggregation) scale of colonies, but the scale was strongly affected by the colony size. Our approach quantitatively showed repulsive effects between an aggressive genus and a competitively weak genus, while the grid-based statistics (covariance function) also showed repulsion although the spatial scale indicated from the statistics was not directly interpretable in terms of ecological meaning. The use of minimum distances together with previously proposed spatial statistics helped us to extend our understanding of the spatial patterns of nonoverlapping objects that vary in size and the associated specific scales. PMID- 26050546 TI - Large pleomorphic hyalinizing angiectatic tumor of the forearm: A multidisciplinary perspective. PMID- 26050547 TI - Tim-3 pathway affects NK cell impairment in patients with active tuberculosis. AB - Active tuberculosis (TB) patients show impaired NK cell function, and the underlying mechanism remains largely unknown. In this study, we confirmed the decrease in activation, cytokine secretion, and degranulation potential of NK cells in active TB patients. We further investigated whether coinhibitory receptor Tim-3 was involved with impairment of NK cells. Our results revealed that the expression of Tim-3 on NK cells was increased in active TB patients. Tim 3 expression was inversely correlated with IL-12-stimualted IFN-gamma production. Moreover, blocking the Tim-3 pathway restored IFN-gamma secretion and degranulation of NK cells. Blocking this pathway also increased NK cell cytotoxicity against K562 target cells, and improved the ability of NK cells to control Mtb growth in monocyte-derived macrophages. The Tim-3 expression on NK cells was also observed to be significantly decreased in TB patients post treatment. In this study, we have identified that Tim-3 is involved with NK cell impairment in TB patients. PMID- 26050548 TI - Six Protocols, Neuroscience, and Near Death: An Emerging Paradigm Incorporating Nonlocal Consciousness. PMID- 26050549 TI - Traction stress analysis and modeling reveal that amoeboid migration in confined spaces is accompanied by expansive forces and requires the structural integrity of the membrane-cortex interactions. AB - Leukocytes and tumor cells migrate via rapid shape changes in an amoeboid-like manner, distinct from mesenchymal cells such as fibroblasts. However, the mechanisms of how rapid shape changes are caused and how they lead to migration in the amoeboid mode are still unclear. In this study, we confined differentiated human promyelocytic leukemia cells between opposing surfaces of two pieces of polyacrylamide gels and characterized the mechanics of fibronectin-dependent mesenchymal versus fibronectin-independent amoeboid migration. On fibronectin coated gels, the cells form lamellipodia and migrate mesenchymally. Whereas in the absence of cell-substrate adhesions through fibronectin, the same cells migrate by producing blebs and "chimneying" between the gel sheets. To identify the orientation and to quantify the magnitude of the traction forces, we found by traction force microscopy that expanding blebs push into the gels and generate anchoring stresses whose magnitude increases with decreasing gap size while the resulting migration speed is highest at an intermediate gap size. To understand why there exists such an optimal gap size for migration, we developed a computational model and showed that the chimneying speed depends on both the magnitude of intracellular pressure as well as the distribution of blebs around the cell periphery. The model also predicts that the optimal gap size increases with weakening cell membrane to actin cortex adhesion strength. We verified this prediction experimentally, by weakening the membrane-cortex adhesion strength using the ezrin inhibitor, baicalein. Thus, the chimneying mode of amoeboid migration requires a balance between intracellular pressure and membrane-cortex adhesion strength. PMID- 26050550 TI - Spread of MERS to South Korea and China. PMID- 26050551 TI - Emerging therapy for endometriosis. AB - INTRODUCTION: Endometriosis is a chronic disease manifested by pain and infertility due to ectopic implantation of endometrial glands and stroma causing inflammation. Treatment of endometriosis utilizes a significant amount of health care resources and requires chronic therapy. Management involves a combination of surgical and medical interventions and requires long-term treatment to avoid repeated surgeries. AREAS COVERED: Whereas medical therapies exist for management of endometriosis-related pain, each class has its limitations including side effects, cost, and known duration of relief of symptoms. Development of effective, well-tolerated medical therapies that are appropriate for long-term use is crucial to provide adequate treatment for this chronic disease. This review discusses the various medical therapies available, their limitations, and emerging therapies being developed to address many of these concerns. EXPERT OPINION: The authors recommend chronic suppressive therapy for management of endometriosis symptoms, particularly in the postoperative setting. Empiric treatment is appropriate for those patients without evidence of severe disease. Currently available option may not be effective for nor tolerated by all patients. Newer compounds, including gonadotropin-releasing antagonists and aromatase inhibitors combined with hormonal contraceptives, offer possible alternatives to currently available therapies. PMID- 26050552 TI - Self-reactions in the HCl(+) (DCl(+)) + HCl system: a state-selective investigation of the role of rotation. AB - The self-reaction of state-selected HCl(+) (DCl(+)) ions with HCl has been investigated in a guided ion beam setup. The absolute cross sections for proton transfer and deuteron transfer decrease with increasing center of mass collision energy, Ec.m.. The cross section for charge transfer (DCl(+) + HCl) exhibits a maximum at Ec.m. = 0.5 eV. The cross section for PT and DT decrease significantly with increasing rotational angular momentum in the molecular ion, for the PT the cross section increases again for the highest angular momentum investigated. The rotational dependence of the cross section is rationalized by a simple model in which both the collision energy and part of the rotational energy are available for the reaction. The contribution of the rotation to the total energy available itself depends on the collision energy. PMID- 26050553 TI - Band Gap Tuning of CH3NH3Pb(Br(1-x)Clx)3 Hybrid Perovskite for Blue Electroluminescence. AB - We report on the structural, morphological and optical properties of AB(Br(1 x)Cl(x))3 (where, A = CH3NH3(+), B = Pb(2+) and x = 0 to 1) perovskite semiconductor and their successful demonstration in green and blue emissive perovskite light emitting diodes at room temperature. The bandgap of perovskite thin film is tuned from 2.42 to 3.16 eV. The onset of optical absorption is dominated by excitonic effects. The coulomb field of the exciton influences the absorption at the band edge. Hence, it is necessary to explicitly account for the enhancement of the absorption through the Sommerfield factor. This enables us to correctly extract the exciton binding energy and the electronic bandgap. We also show that the lattice constant varies linearly with the fractional chlorine content satisfying Vegards law. PMID- 26050554 TI - Use of Seeds as Fungus Garden Substrate Changes the Organization of Labor Among Leaf-Cutting Ant Workers. AB - Seeds of different plant species constitute an alternative but also significant substrate that leaf-cutting ants use to cultivate their fungus garden. However, how they are processed inside the nest and if their use implies differential allocation of worker size classes are still poorly known. Using laboratory colonies of Acromyrmex subterraneus (Forel) as a model, the behaviors related to the processing of three different seeds (sesame, guava, and grape) as fungus substrate were listed. At the same time, we measured how each worker size class contributed to the execution of these behaviors by registering their respective frequency. It was found that medium-sized (1.2 > head width < 1.6 mm) and minimum sized (head width <1.1 mm) workers assumed the role of incorporation for sesame and grape seeds, respectively. Major-sized workers (head width >1.7 mm) were concentrated on licking and holding guava seeds. Tegument removal was the only task observed that differs between treatment of seeds and treatment of leaves before their incorporation, as described in the literature. It was verified that different species of seeds imply a differential allocation of worker size classes and the inclusion or exclusion of some tasks from the behavioral repertoire. Regardless of the substrate type, leaf-cutting ant workers follow a coordinated and specialized procedure to cultivate the fungus garden but always maintain a high degree of cooperation. PMID- 26050555 TI - Sumatran orangutans and the World War II. PMID- 26050556 TI - Herbs to curb cyclic nucleotide phosphodiesterase and their potential role in Alzheimer's disease. AB - Cyclic nucleotides viz., cAMP/cGMP has been well known to play important role in cellular function and deficiency in their levels has been implicated in the pathogenesis of various neurodegenerative disorders including Alzheimer's disease (AD). Phosphodiesterases (PDE) are the enzymes involved in the metabolism of cyclic nucleotides and the inhibition of phosphodiesterases is considered to be viable strategy to restore the level of cyclic nucleotides and their functions in the brain. Various synthetic PDE inhibitors had been used clinically for various disorders and also suggested to be useful candidates for treating neurological disorders. However, side effects of these synthetic PDE inhibitors have limited their use in clinical practice. Natural plant extracts or their bio-active compounds are considered to be safe and are widely acceptable. During the last decade, many plant extracts or their bio-active compounds were tested pre clinically for PDE inhibitory activity and are reported to be equally potent in inhibiting PDE's, as that of synthetic compounds. The present review is aimed to discuss the potential plant extract/compounds with PDE inhibitory activity and critically discuss their potential role in Alzheimer's disease. PMID- 26050557 TI - Functional polymorphism rs710218 in the gene coding GLUT1 protein is associated with in-stent restenosis. AB - AIM: To analyze the association between in-stent restenosis (ISR) and polymorphisms in genes coding IGF-1, IGFBP3, ITGB3 and GLUT1, which play an important role in the smooth muscle cell proliferation and extracellular matrix synthesis - the main components of neointima. MATERIALS & METHODS: We analyzed 265 patients who underwent bare metal stent implantation. RESULTS: The differences in the occurrence of ISR between genotypes of the analyzed polymorphisms in the IGF-1, IGFBP3 and ITGB3 were not statistically significant. The T/T genotype of the rs710218 polymorphism in the GLUT1 (SLC2A1) gene was more common in the ISR group compared with non-ISR patients (81.1 vs 64.8%; p = 0.02). In a multivariable model the A/A and A/T genotype remained correlated with lower occurrence of ISR (odds ratio: 0.45; 95% CI: 0.21-0.97; p = 0.03). CONCLUSION: The rs710218 polymorphism in the gene coding GLUT1 protein is a novel risk factor for ISR. PMID- 26050558 TI - Low-Dose Ketamine Infusion for Managing Acute Pain. PMID- 26050559 TI - Predictors of postpericardiotomy syndrome. PMID- 26050560 TI - Complete blood count at the ED: preanalytic variables for hemoglobin and leukocytes. AB - OBJECTIVE: The objective of this study is to determine the ways in which preanalytic factors related to physiologic status can affect the complete blood cell count (CBC) in patients referring to an emergency department (ED). METHODS: Over a 1-year period, the results of hemoglobin (Hb) level and white blood cell (WBC) counts of the first CBC tests undertaken in consecutive patients (n = 11487) referring to the ED were compared with those obtained in the same patients at a second test undertaken within 24 hours of admission. A prospective evaluation of the same differences was made in another group (group 2) of 1025 consecutive ED patients, several clinical characteristics being taken into consideration. RESULTS: Mean Hb concentrations were higher in the first (range, 8.0-15.9 g/dL) than in the second test results (median overestimation, 0.4-0.8 g/dL; P < .0001). At multivariate analysis of results in group 2 patients, fluid administration (>0.5 L) and the presence of edema played a significant role in the initial overestimation of Hb level (P = .001 and P = .045, respectively). The comparison between leukocyte counts (WBC) showed that values from the first were higher than those in the second test (median overestimation ranging from 0.42 to 3.63 * 10(9)/L cells, in the range counts from 4.0 to 30.0 * 10(9)/L). None of the clinical factors studied appeared to have affected this overestimation. CONCLUSIONS: On interpreting CBC results in patients admitted to the ED, physicians must consider the effect of physiologic variables on Hb level (mainly hydration status) and WBC count (mental and physical stress). PMID- 26050561 TI - Embryonic sex steroid hormones accumulate in the eggshell of loggerhead sea turtle (Caretta caretta). AB - Steroids hormones such as estradiol-17beta (E2) and testosterone (T) are involved in gonadal differentiation of oviparous animals with temperature-dependent sex determination (TSD), and are greatly distributed. This hypothesizes that these embryonic steroid hormones probably accumulate in the eggshell throughout blood or/and chorioallantoic fluid in sea turtle species with TSD, producing females at higher temperature. To demonstrate this hypothesis, concentrations of E2 and T in the blood plasma from the hatchling loggerhead sea turtle (Caretta caretta) and in their eggshells were measured by radioimmunoassay. In the present study we propose that both concentrations of E2 and T in the blood plasma are correlated with amounts of these sex steroids in the eggshell. Moreover, contents of E2 in the eggshell showed a significant positive correlation with mean incubation temperatures during a thermosensitive period in the experimental nests, whereas T contents in the eggshell did not. Taken together, these findings indicated that embryonic E2 and T that accumulated in the eggshell can be extracted and measured. Furthermore, the present study suggested that contents of E2 in the eggshell may differ between male and female, and monitoring of these steroids is a useful method to identify the sex of loggerhead sea turtle hatchling. PMID- 26050562 TI - Comparative analysis reveals the underlying mechanism of vertebrate seasonal reproduction. AB - Animals utilize photoperiodic changes as a calendar to regulate seasonal reproduction. Birds have highly sophisticated photoperiodic mechanisms and functional genomics analysis in quail uncovered the signal transduction pathway regulating avian seasonal reproduction. Birds detect light with deep brain photoreceptors. Long day (LD) stimulus induces secretion of thyroid-stimulating hormone (TSH) from the pars tuberalis (PT) of the pituitary gland. PT-derived TSH locally activates thyroid hormone (TH) in the hypothalamus, which induces gonadotropin-releasing hormone (GnRH) and hence gonadotropin secretion. However, during winter, low temperatures increase serum TH for adaptive thermogenesis, which accelerates germ cell apoptosis by activating the genes involved in metamorphosis. Therefore, TH has a dual role in the regulation of seasonal reproduction. Studies using TSH receptor knockout mice confirmed the involvement of PT-derived TSH in mammalian seasonal reproduction. In addition, studies in mice revealed that the tissue-specific glycosylation of TSH diversifies its function in the circulation to avoid crosstalk. In contrast to birds and mammals, one of the molecular machineries necessary for the seasonal reproduction of fish are localized in the saccus vasculosus from the photoreceptor to the neuroendocrine output. Thus, comparative analysis is a powerful tool to uncover the universality and diversity of fundamental properties in various organisms. PMID- 26050563 TI - Inflammatory potential of diet and risk of colorectal cancer: a case-control study from Italy. AB - Diet and inflammation have been suggested to be important risk factors for colorectal cancer (CRC). In the present study, we examined the association between the dietary inflammatory index (DII) and the risk of CRC in a multi centre case-control study conducted between 1992 and 1996 in Italy. The study included 1225 incident colon cancer cases, 728 incident rectal cancer cases and 4154 controls hospitalised for acute non-neoplastic diseases. The DII was computed based on dietary intake assessed using a validated seventy-eight-item FFQ that included assessment of alcohol intake. Logistic regression models were used to estimate the OR adjusted for age, sex, study centre, education, BMI, alcohol drinking, physical activity and family history of CRC. Energy intake was adjusted using the residual method. Subjects with higher DII scores (i.e. with a more pro-inflammatory diet) had a higher risk of CRC, with the DII being used both as a continuous variable (OR(continuous) 1.13, 95 % CI 1.09, 1.18) and as a categorical variable (OR(quintile 5 v. 1) 1.55, 95 % CI 1.29, 1.85; P for trend < 0.0001). Similar results were observed when the analyses were carried out separately for colon and rectal cancer cases. These results indicate that a pro inflammatory diet is associated with an increased risk of CRC. PMID- 26050564 TI - Relationship between increased left atrial volume and microvascular complications in patients with type 2 diabetes. AB - AIMS: We assessed whether left atrial volume index (LAVI) was associated with the presence of microvascular complications in patients with type 2 diabetes, and whether this association was independent of hemodynamic and non-hemodynamic factors. METHODS: We studied 157 consecutive outpatients with type 2 diabetes with no previous history of ischemic heart disease, chronic heart failure and valvular diseases. A transthoracic echocardiography and myocardial perfusion scintigraphy were performed in all participants. Presence of microvascular complications was also recorded. RESULTS: Overall, 51 patients had decreased estimated glomerular filtration rate and/or abnormal albuminuria, 24 had diabetic retinopathy, 22 had lower-extremity sensory neuropathy, and 67 (42.7%) patients had one or more of these microvascular complications (i.e., combined endpoint). After stratifying patients by LAVI, those with LAVI >=32 ml/m(2) had a greater prevalence of microvascular complication, lower left ventricular (LV) ejection fraction, higher LV mass index and higher E/e' ratio than those with LAVI <32 ml/m(2). Logistic regression analyses revealed that microvascular complications (singly or in combination) were associated with increased LAVI, independently of age, sex, diabetes duration, hemoglobin A1c, hypertension, LV-ejection fraction, LV mass index and the E/e' ratio. CONCLUSIONS: These results indicate that microvascular diabetic complications are associated with increased LAVI in well controlled type 2 diabetic patients with preserved systolic function and free from ischemic heart disease, independently of multiple potential confounders. PMID- 26050565 TI - A novel nonsense mutation of the HNF1alpha in maturity-onset diabetes of the young type 3 in Asian population. AB - We reported a novel nonsense mutation, R54X of the hepatic nuclear factor 1alpha (HNF1alpha) gene in a Chinese family. The mutation was identified in a 47 years old woman and her 19 years old daughter within a five-family members tested. Both the two patients were sensitive to insulin and glibenclamide treatments. PMID- 26050566 TI - Pestiviruses: old enemies and new challenges. AB - The genesis for this special issue on pestiviruses was a joint meeting on pestiviruses organized by the US BVDV Symposia Committee and the European Society for Veterinary Virology that was held October 14 and 15, 2014 in Kansas City, MO. The theme of the meeting was "Pestiviruses: Old enemies and new challenges". The impetus for this joint effort was the recognition that regional approaches to disease control are at odds with the worldwide traffic in animal products and biologics. Further, the control of newly recognized pestiviruses, such as HoBi like viruses, is more effective when approached as a global challenge rather than any one nation's problem. The joint meeting featured talks by researchers from North America, South America, Australia and Europe. The papers in this issue arose from keynote talks presented at the joint meeting and are organized around the following themes; pestiviruses and the immune system, genetic variability, the emergence of new pestiviruses and pestivirus control programs. PMID- 26050567 TI - Immune response to bovine viral diarrhea virus--looking at newly defined targets. AB - Bovine viral diarrhea virus (BVDV) has long been associated with a wide variety of clinical syndromes and immune dysregulation, many which result in secondary bacterial infections. Current understanding of immune cell interactions that result in activation and tolerance are explored in light of BVDV infection including: depletion of lymphocytes, effects on neutrophils, natural killer cells, and the role of receptors and cytokines. In addition, we review some new information on the effect of BVDV on immune development in the fetal liver, the role of resident macrophages, and greater implications for persistent infection. PMID- 26050568 TI - Innate and adaptive immune responses to in utero infection with bovine viral diarrhea virus. AB - Infection of pregnant cows with noncytopathic (ncp) bovine viral diarrhea virus (BVDV) induces rapid innate and adaptive immune responses, resulting in clearance of the virus in less than 3 weeks. Seven to 14 days after inoculation of the cow, ncpBVDV crosses the placenta and induces a fetal viremia. Establishment of persistent infection with ncpBVDV in the fetus has been attributed to the inability to mount an immune response before 90-150 days of gestational age. The result is 'immune tolerance', persistent viral replication and shedding of ncpBVDV. In contrast, we describe the chronic upregulation of fetal Type I interferon (IFN) pathway genes and the induction of IFN-gamma pathways in fetuses of cows infected on day 75 of gestation. Persistently infected (PI) fetal IFN gamma concentrations also increased at day 97 at the peak of fetal viremia and IFN-gamma mRNA was significantly elevated in fetal thymus, liver and spleen 14-22 days post maternal inoculation. PI fetuses respond to ncpBVDV infection through induction of Type I IFN and IFN-gamma activated genes leading to a reduction in ncpBVDV titer. We hypothesize that fetal infection with BVDV persists because of impaired induction of IFN-gamma in the face of activated Type I IFN responses. Clarification of the mechanisms involved in the IFN-associated pathways during BVDV fetal infection may lead to better detection methods, antiviral compounds and selection of genetically resistant breeding animals. PMID- 26050569 TI - BVDV vaccination in North America: risks versus benefits. AB - The control and prevention of bovine viral diarrhea virus (BVDV) infections has provided substantial challenges. Viral genetic variation, persistent infections, and viral tropism for immune cells have complicated disease control strategies. Vaccination has, however, provided an effective tool to prevent acute systemic infections and increase reproductive efficiency through fetal protection. There has been substantial controversy about the safety and efficacy of BVDV vaccines, especially when comparing killed versus modified-live viral (MLV) vaccines. Furthermore, numerous vaccination protocols have been proposed to protect the fetus and ensure maternal antibody transfer to the calf. These issues have been further complicated by reports of immune suppression during natural infections and following vaccination. While killed BVDV vaccines provide the greatest safety, their limited immunogenicity makes multiple vaccinations necessary. In contrast, MLV BVDV vaccines induce a broader range of immune responses with a longer duration of immunity, but require strategic vaccination to minimize potential risks. Vaccination strategies for breeding females and young calves, in the face of maternal antibody, are discussed. With intranasal vaccination of young calves it is possible to avoid maternal antibody interference and induce immune memory that persists for 6-8 months. Thus, with an integrated vaccination protocol for both breeding cows and calves it is possible to maximize disease protection while minimizing vaccine risks. PMID- 26050570 TI - Genetic variability and distribution of Classical swine fever virus. AB - Classical swine fever is a highly contagious disease that affects domestic and wild pigs worldwide. The causative agent of the disease is Classical swine fever virus (CSFV), which belongs to the genus Pestivirus within the family Flaviviridae. On the genome level, CSFV can be divided into three genotypes with three to four sub-genotypes. Those genotypes can be assigned to distinct geographical regions. Knowledge about CSFV diversity and distribution is important for the understanding of disease dynamics and evolution, and can thus help to design optimized control strategies. For this reason, the geographical pattern of CSFV diversity and distribution are outlined in the presented review. Moreover, current knowledge with regard to genetic virulence markers or determinants and the role of the quasispecies composition is discussed. PMID- 26050571 TI - Impact of species and subgenotypes of bovine viral diarrhea virus on control by vaccination. AB - Bovine viral diarrhea viruses (BVDV) are diverse genetically and antigenically. This diversity impacts both diagnostic testing and vaccination. In North America, there are two BVDV species, 1 and 2 with 3 subgenotypes, BVDV1a, BVDV1b and BVDV2a. Initially, US vaccines contained BVDV1a cytopathic strains. With the reporting of BVDV2 severe disease in Canada and the USA there was focus on protection by BVDV1a vaccines on BVDV2 disease. There was also emphasis of controlling persistently infected (PI) cattle resulted in studies for fetal protection afforded by BVDV1a vaccines. Initially, studies indicated that some BVDV1a vaccines gave less than 100% protection against BVDV2 challenge for fetal infection. Eventually vaccines in North America added BVDV2a to modified live virus (MLV) and killed BVDV1a vaccines. Ideally, vaccines should stimulate complete immunity providing 100% protection against disease, viremias, shedding, and 100% fetal protection in vaccinates when challenged with a range of diverse antigenic viruses (subgenotypes). There should be a long duration of immunity stimulated by vaccines, especially for fetal protection. MLV vaccines should be safe when given according to the label and free of other pathogens. While vaccines have now included BVDV1a and BVDV2a, with the discovery of the predominate subgenotype of BVDV in the USA to be BVDV1b, approximately 75% or greater in prevalence, protection in acute challenge and fetal protection studies became more apparent for BVDV1b. Thus many published studies examined protection by BVDV1a and BVDV2a vaccines against BVDV1b in acute challenge and fetal protection studies. There are no current BVDV1b vaccines in the USA. There are now more regulations on BVDV reproductive effects by the USDA Center for Veterinary Biologics (CVB) regarding label claims for protection against abortion, PI calves, and fetal infections, including expectations for studies regarding those claims. Also, the USDA CVB has a memorandum providing the guidance for exemption of the warning label statement against the use of the MLV BVDV in pregnant cows and calves nursing pregnant cows. In reviews of published studies in the USA, the results of acute challenge and fetal protection studies are described, including subgenotypes in vaccines and challenge strains and the results in vaccinates and the vaccinates' fetuses/newborns. In general, vaccines provide protection against heterologous strains, ranging from 100% to partial but statistically significant protection. In recent studies, the duration of immunity afforded by vaccines was investigated and reported. Issues of contamination remain, especially since fetal bovine serums may be contaminated with noncytopathic BVDV. In addition, the potential for immunosuppression by MLV vaccines exists, and new vaccines will be assessed in the future to prove those MLV components are not immunosuppressive by experimental studies. As new subgenotypes are found, the efficacy of the current vaccines should be evaluated for these new strains. PMID- 26050572 TI - Emerging pestiviruses infecting domestic and wildlife hosts. AB - Until the early 1990 s there were just three recognized species in the pestivirus genus, bovine viral diarrhea virus (BVDV), border disease virus (BDV) and classical swine fever virus (CSFV). Subsequently BVDV were divided into two different species, BVDV1 and BVDV2 and four additional putative pestivirus species have been identified, based on phylogenetic analysis. The four putative pestivirus specices, listed in chronological order of published reports, are Giraffe (isolated from one of several giraffes in the Nanyuki District of Kenya suffering from mucosal disease-like symptoms), HoBi (first isolated from fetal bovine serum originating in Brazil and later from samples originating in Southeast Asia), Pronghorn (isolated from an emaciated blind pronghorn antelope in the USA), and Bungowannah (isolated following an outbreak in pigs, resulting in still birth and neonatal death, in Australia). In addition to the emergence of putative new species of pestivirus, changes in host and virulence of recognized or 'classic' pestiviruses have led to reevaluation of disease control programs and management of domestic and wildlife populations. PMID- 26050573 TI - Bungowannah virus--a probable new species of pestivirus--what have we found in the last 10 years? AB - Bungowannah virus was discovered following an outbreak of stillbirths and sudden death in young pigs. Affected animals consistently showed a myocardopathy with signs of cardiac failure. After virus isolation and PCR investigations were unsuccessful, direct fetal inoculation was undertaken. Nucleic acid purified from serum from infected fetuses was subjected to sequence-independent single-primer amplification and nucleic acid sequencing. Sequences consistent with a pestivirus were obtained. The entire genome was identified but was genetically remote from the recognized pestivirus species. This virus was not recognized by pan pestivirus reactive monoclonal antibodies but was subsequently detected in cell cultures by immunoperoxidase staining using convalescent sow serum. Experimental infections of sows at different stages of gestation reproduced the myocarditis syndrome. Pre-weaning losses of 70 and 29% were observed following infection at days 35 and 90, respectively. Piglets infected at day 35 were shown to be persistently infected, while chronic infections were observed after fetal infection at day 55. Chronically infected piglets showed growth retardation and were viremic for up to 7 months. Myocarditis was associated with infection in late gestation (day 90). Non-pregnant sheep and cattle have been experimentally infected but with no evidence of disease. Infection of pregnant cattle in early gestation resulted in both maternal and fetal infection, but all infected fetuses mounted an antibody response to the virus. Analysis of the nucleic acid sequence confirmed that Bungowannah has a number of changes not observed in other pestiviruses. Genes encoding some of the structural proteins remain fully functional when inserted into a bovine viral diarrhea virus (BVDV) backbone. Cell culture-based studies have shown that Bungowannah virus will grow in cells extending from humans to bats as well as farm animals. PMID- 26050574 TI - HoBi-like viruses--the typical 'atypical bovine pestivirus'. AB - HoBi-like viruses, also referred to as bovine viral diarrhea virus 3 (BVDV-3) and atypical pestivirus, have been proposed as a new putative bovine pestivirus species. These viruses were first identified in the last decade and are currently distributed in at least three continents. Published findings suggest that these viruses may be endemic at least in parts of South America and Asia. The clinical presentations in cattle, described in field outbreaks and controlled studies, are similar to those associated with BVDV and range from subclinical to mild clinical signs, sporadically associated with reproductive losses, respiratory illness and hemorrhagic syndrome. The complete host range of HoBi-like virus is unknown, but data suggest higher adaptation of HoBi-like viruses to ruminants than swine. Acute infections, characterized by mild clinical signs, such as low-grade pyrexia and leukopenia, have been observed in both cattle and sheep. Virus has been isolated from nasal swabs indicating that virus was being shed. While seroconversion has been observed in pigs, no clinical presentation or viral shedding was evident following inoculation. While some commercial BVDV diagnostic tests may detect HoBi-like viruses, these tests do not differentiate between BVDV and HoBi-like viruses. The differentiation of BVDV and HoBi-like viruses is critical to the design of surveillance programs for these viruses. PMID- 26050575 TI - The two sides of border disease in Pyrenean chamois (Rupicapra pyrenaica): silent persistence and population collapse. AB - In 2001, border disease virus (BDV) was identified as the cause of a previously unreported disease in Pyrenean chamois (Rupicapra pyrenaica) in Spain. Since then, the disease has caused a dramatic decrease, and in some cases collapse, of chamois populations and has expanded to nearly the entire distribution area in the Pyrenees. Chamois BDV was characterized as BDV-4 genotype and experimental studies confirmed that it was the primary agent of the disease. The infection has become endemic in the Central and Eastern Pyrenees. However, while most Pyrenean chamois populations have been severely affected by the disease, others have not, despite the circulation of BDV in apparently healthy individuals, suggesting the existence of different viral strategies for persisting in the host population. Changes in the interplay of pathogen, host and environmental factors may lead to the formation of different disease patterns. A key factor influencing disease emergence may be pathogen invasiveness through viral mutation. Host factors, such as behavior, immunity at the population level and genetic variability, may also have driven different epidemiological scenarios. Climatic and other ecological factors may have favored secondary infections, such as pneumonia, that under particular circumstances have been major contributing factors in the high mortality observed in some areas. PMID- 26050576 TI - Perspective on BVDV control programs. AB - Programs for control and eradication of bovine viral diarrhea virus (BVDV) are often considered prudent when the expense of a control program within a specified time frame effectively prevents loss due to disease and the expense of control does not exceed the costs associated with infection. In some geographic areas, concerns about animal welfare or desires to reduce antibiotic usage may motivate BVDV control even when control programs are associated with a lack of financial return on investment. In other geographic areas, concerns about financial return on investment may be the key motivating factor in considering implementation of BVDV control programs. Past experiences indicate that systematic, well coordinated control programs have a clear potential for success, while voluntary control programs in cultures of distributed decision-making often result in notable initial progress that ultimately ends in dissolution of efforts. Segmentation of the cattle industry into cow-calf producers, stocker/backgrounders, and feedlot operators amplifies the distribution of decision-making regarding control programs and may result in control measures for one industry segment that are associated with significant costs and limited rewards. Though the host range of BVDV extends well beyond cattle, multiple eradication programs that focus only on testing and removal of persistently infected (PI) cattle have proven to be effective in various countries. While some individuals consider education of producers to be sufficient to stimulate eradication of BVDV, research surrounding the adoption of innovative health care procedures suggests that the process of adopting BVDV control programs has a social element. Collegial interactions and discussions may be crucial in facilitating the systematic implementation necessary to optimize the long-term success of control programs. Compulsory control programs may be considered efficient and effective in some regions; however, in a nation where individual identification of cattle remains voluntary, the likelihood of effective compulsion to control BVDV within a farm or ranch appears to be very unlikely. While currently available diagnostic tests are sufficient to support BVDV eradication via systematic, well-coordinated programs, the development of a diagnostic procedure to safely and consistently detect the gestation of a PI fetus after 5 months of gestation would be a valuable research breakthrough. This desired testing modality would allow diagnosis of PI calves, while the dam continues to provide biocontainment of the infected fetus. This development could speed the progress of control programs in achieving the goal of BVDV control and eventual eradication. PMID- 26050577 TI - Pestivirus control programs: how far have we come and where are we going? AB - Classical swine fever (CSF) is endemic in large parts of the world and it is a major threat to the pig industry in general. Vaccination and stamping out have been the most successful tools for the control and elimination of the disease. The systematic use of modified live vaccines (MLV), which are very efficacious and safe, has often preceded the elimination of CSF from regions or countries. Oral vaccination using MLV is a powerful tool for the elimination of CSF from wild boar populations. Bovine virus diarrhea (BVD) is endemic in bovine populations worldwide and programs for its control are only slowly gaining ground. With two genotypes BVD virus (BVDV) is genetically more diverse than CSF virus (CSFV). BVDV crosses the placenta of pregnant cattle resulting in the birth of persistently infected (PI) calves. PI animals shed enormous amounts of virus for the rest of their lives and they are the reservoir for the spread of BVDV in cattle populations. They are the main reason for the failure of conventional control strategies based on vaccination only. In Europe two different approaches for the successful control of BVD are being used: Elimination of PI animals without or with the optional use of vaccines, respectively. PMID- 26050578 TI - Sirolimus and everolimus in kidney transplantation. AB - The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown their efficacy in kidney transplantation, but their wider introduction has been limited by relative high discontinuation rates. Their main advantage compared with calcineurin inhibitors (CNIs) is their relative lack of nephrotoxicity. They differ mainly in pharmacokinetic characteristics and have variable inter- and intra-individual pharmacokinetics. They are metabolized by cytochrome (CYP)-3A4/5 and CYP2C8 enzymes and are substrates for P-glycoprotein (P-gp). Their most important adverse effects are thrombocytopenia, leukopenia, hypercholesterolemia, stomatitis, diarrhea, and, although rare, interstitial pneumonitis. The narrow therapeutic window makes therapeutic drug monitoring (TDM) essential to prevent toxicity or rejection. As we discuss here, the main future challenge is to further optimize mTOR inhibitor (mTORi)-based immunosuppressive therapy. PMID- 26050579 TI - Breaking free from chemical spreadsheets. AB - Drug discovery scientists often consider compounds and data in terms of groups, such as chemical series, and relationships, representing similarity or structural transformations, to aid compound optimisation. This is often supported by chemoinformatics algorithms, for example clustering and matched molecular pair analysis. However, chemistry software packages commonly present these data as spreadsheets or form views that make it hard to find relevant patterns or compare related compounds conveniently. Here, we review common data visualisation and analysis methods used to extract information from chemistry data. We introduce a new framework that enables scientists to work flexibly with drug discovery data to reflect their thought processes and interact with the output of algorithms to identify key structure-activity relationships and guide further optimisation intuitively. PMID- 26050580 TI - Applying genetics in inflammatory disease drug discovery. AB - Recent groundbreaking work in genetics has identified thousands of small-effect genetic variants throughout the genome that are associated with almost all major diseases. These genome-wide association studies (GWAS) are often proposed as a source of future medical breakthroughs. However, with several notable exceptions, the journey from a small-effect genetic variant to a functional drug has proven arduous, and few examples of actual contributions to drug discovery exist. Here, we discuss novel approaches of overcoming this hurdle by using instead public genetics resources as a pragmatic guide alongside existing drug discovery methods. Our aim is to evaluate human genetic confidence as a rationale for drug target selection. PMID- 26050581 TI - Insulinoma: a multicenter, retrospective analysis of three decades of experience (1983-2014). AB - OBJECTIVE: To analyze the clinical features, diagnostic procedures, treatment, and clinical outcome of insulinomas diagnosed and treated in the period 1983-2014 in four Spanish hospitals. METHODS: All patients with either biochemical and morphological criteria of insulinoma and/or histological demonstration of insulin secreting tumor were included. RESULTS: Twenty-nine patients [23 women (79.3%); mean age 48.7+/-17.4 years (range, 16-74)] were recruited. Twenty-six patients (89.7%) had sporadic tumors, and the rest (3 women, 10.3%) developed in the context of multiple endocrine neoplasia type 1. There were 3 (10.3%) multiple insulinomas, one associated with multiple endocrine neoplasia type 1, and two (6.9%) malignant insulinomas, both sporadic. Most patients (n=18, 62.1%) had fasting hypoglycemia, about a third (31%) both postprandial and fasting hypoglycemia, and 6.9% postprandial hypoglycemia only. Time to glucose nadir (37.3+/-6.5mg/dL) in the fasting test was 9.0+/-4.4h, with maximal insulin levels of 25.0+/-20.3MUU/mL. Abdominal CT detected insulinoma in 75% of patients. Twenty seven (93.1%) patients underwent surgery [enucleation, 18 (66.7%) and subtotal pancreatectomy, 9 (33.3%); tumor size, 1,7+/-0,7cm]. Surgery achieved cure in the majority (n=24, 88.9%) of patients. CONCLUSION: In our setting, insulinoma is usually a benign, small, and solitary tumor, mainly affecting women aged 45-50 years, and usually localized with abdominal CT. The most commonly used surgical technique is enucleation, which achieves a high cure rate. PMID- 26050582 TI - Minimally invasive parathyroidectomy in patients with previous thyroid surgery. PMID- 26050583 TI - Cognitive impairment and severe hypocalcemia in a patient with hypoparathyroidism and systemic sclerosis. Report of a case. PMID- 26050584 TI - Introduction: recent advances in the biology and treatment of low- grade gliomas. PMID- 26050586 TI - Advances in Magnetic Resonance Imaging and Positron Emission Tomography Imaging for Grading and Molecular Characterization of Glioma. AB - In recent years, the management of glioma has evolved significantly, reflecting our better understanding of the underlying mechanisms of tumor development, tumor progression, and treatment response. Glioma grade, along with a number of underlying molecular and genetic biomarkers, has been recognized as an important prognostic and predictive factor that can help guide the management of patients. This article highlights advances in magnetic resonance imaging (MRI), including diffusion-weighted imaging, diffusion tensor imaging, magnetic resonance spectroscopy, dynamic contrast-enhanced imaging, and perfusion MRI, as well as position emission tomography using various tracers including methyl-(11)C-l methionine and O-(2-(18)F-fluoroethyl)-l-tyrosine. Use of multiparametric imaging data has improved the diagnostic strength of imaging, introduced the potential to noninvasively interrogate underlying molecular features of low-grade glioma and to guide local therapies such as surgery and radiotherapy. PMID- 26050585 TI - Molecular Markers in Low-Grade Glioma-Toward Tumor Reclassification. AB - Low-grade diffuse gliomas are a heterogeneous group of primary glial brain tumors with highly variable survival. Currently, patients with low-grade diffuse gliomas are stratified into risk subgroups by subjective histopathologic criteria with significant interobserver variability. Several key molecular signatures have emerged as diagnostic, prognostic, and predictor biomarkers for tumor classification and patient risk stratification. In this review, we discuss the effect of the most critical molecular alterations described in diffuse (IDH1/2, 1p/19q codeletion, ATRX, TERT, CIC, and FUBP1) and circumscribed (BRAF-KIAA1549, BRAF(V600E), and C11orf95-RELA fusion) gliomas. These molecular features reflect tumor heterogeneity and have specific associations with patient outcome that determine appropriate patient management. This has led to an important, fundamental shift toward developing a molecular classification of World Health Organization grade II-III diffuse glioma. PMID- 26050587 TI - Advances in Magnetic Resonance and Positron Emission Tomography Imaging: Assessing Response in the Treatment of Low-Grade Glioma. AB - Following combined-modality therapy for the treatment of low-grade gliomas, the assessment of treatment response and the evaluation of disease progression are uniformly challenging. In this article, we review existing response criteria, and discuss the limitations of conventional magnetic resonance imaging to distinguish between progression and treatment effect. We review the data on advanced imaging techniques including positron emission tomography and functional magnetic resonance imaging, which may enhance the interpretation of posttreatment changes, and enable the earlier assessment of the efficacy and toxicity of therapy in these patients with prolonged survival. PMID- 26050589 TI - Recent Technical Advances and Indications for Radiation Therapy in Low-Grade Glioma. AB - The use of radiotherapy in low-grade glioma has been a topic of controversy over the past 2 decades. Although earlier studies showed no overall survival benefit and no dose response, recent studies demonstrate a possible synergism between radiotherapy and chemotherapy. However, many questions remained unanswered regarding the proper management including the potential roles of biological imaging in treatment planning, the role of reirradiation after recurrence, the role of intensity-modulated radiation therapy and proton beam radiotherapy, and the proper choice of chemotherapy agents. Further clinical trials are necessary to help integrate these new therapies and technologies into clinical practice. PMID- 26050588 TI - Advances in the Surgical Management of Low-Grade Glioma. AB - Over the past 2 decades, extent of resection has emerged as a significant prognostic factor in patients with low-grade gliomas (LGGs). Greater extent of resection has been shown to improve overall survival, progression-free survival, and time to malignant transformation. The operative goal in most LGG cases is to maximize extent of resection, while avoiding postoperative neurologic deficits. Several advanced surgical techniques have been developed in an attempt to better achieve maximal safe resection. Intraoperative magnetic resonance imaging, fluorescence-guided surgery, intraoperative functional pathway mapping, and neuronavigation are some of the most commonly used techniques with multiple studies to support their efficacy in glioma surgery. By using these techniques either alone or in combination, patients harboring LGGs have a better prognosis with less surgical morbidity following tumor resection. PMID- 26050590 TI - Radiation Therapy Oncology Group 9802: Controversy or Consensus in the Treatment of Newly Diagnosed Low-Grade Glioma? AB - Treatment of newly diagnosed or suspected low-grade glioma (LGG) is one of the most controversial areas in neuro-oncology. The heterogeneity of these tumors, concern regarding morbidity of treatment, and absence of proven overall survival benefit from any known treatment have resulted in a lack of consensus regarding the timing and extent of surgery, timing of radiotherapy (RT), and role of chemotherapy. The long-term results of Radiation Therapy Oncology Group (RTOG) 9802, a phase III randomized trial comparing RT alone with RT and 6 cycles of adjuvant procarbazine, CCNU, vincristine (PCV), demonstrated an unprecedented 5.5 year improvement in median overall survival with the addition of PCV chemotherapy in high-risk patients with LGG. These results are practice changing and define a new standard of care for these patients. However, in the intervening decade since the trial was completed, novel molecular markers as well as newer chemotherapy agents such as temozolomide have been developed, which make these results difficult to incorporate into clinical practice. This review summarizes the evidence for and against the role of upfront RT and PCV in newly diagnosed patients with LGG. PMID- 26050592 TI - Neurocognitive Function Following Therapy for Low-Grade Gliomas. AB - Low-grade gliomas (LGGs) are a heterogenous group of primary brain neoplasms that most commonly occur in children and young adults, characterized by a slow, indolent course and overall favorable prognosis. Standard therapies used to treat LGGs have included surgical resection, radiotherapy, chemotherapy, or a combination thereof. Given the anticipated long survival and typical young age of patients with LGG, the long-term sequelae of therapy require special attention, especially as they affect neurocognitive function and quality of life. We review the complex interplay of baseline and treatment-related factors that perturb neurocognition as well as the effect of each treatment modality on altering neurocognitive outcomes in this patient population. PMID- 26050591 TI - Indications for Treatment: Is Observation or Chemotherapy Alone a Reasonable Approach in the Management of Low-Grade Gliomas? AB - The treatment of newly diagnosed low-grade gliomas remains controversial. Recently published results from the long-term follow-up of Radiation Therapy Oncology Group (RTOG) trial 9802 demonstrated medically meaningful and statistically significant survival prolongation by adding chemotherapy with procarbazine, lomustine (CCNU), and vincristine after radiotherapy (RT) vs RT alone for "high"-risk patients (median 13.3 vs 7.8 years, hazard ratio = 0.59, P = 0.03). However, in the 17 years since that trial was launched, there have been advances in the understanding of low-grade gliomas biology and patient heterogeneity, an increased recognition of late neurocognitive injury from early RT, and the emergence of temozolomide as an alternative chemotherapy to procarbazine, lomustine (CCNU), and vincristine. These and other changes in the treatment landscape make the applicability of results from RTOG 9802 to all patients less clear. Moreover, in some patients, especially those at the lowest risk for early disease progression, deferred RT in favor of active surveillance or chemotherapy alone may remain a reasonable treatment approach. PMID- 26050593 TI - Clinical Management of Seizures in Patients With Low-Grade Glioma. AB - Seizures, transient disruptions of normal brain electrical activity, are common for patients with low-grade glioma (LGG) and significantly affect quality of life. Up to 75% of patients with a LGG will have seizures in the course of their disease (compared with 1%-2% of the general population). Depending on the type of abnormal electrical activity, the functional implications of seizure can impact any domain, including mental status, sensation or strength. In most cases, either the seizure or the medications used to treat the seizure may contribute to cognitive and psychosocial difficulties of various degrees of severity. Hence, effective management of seizures is a major priority for patients with LGG. Evidence-based guidelines suggest that levetiracetam is the best first-line agent for treatment of seizures in this population due to both its efficacy and tolerability. An important consideration in the field of neuro-oncology is that levetiracetam has very few drug interactions. Unfortunately, approximately one third of patients with LGG have refractory epilepsy where additional agents such as valproic acid, or lacosamide, lamotrigine and nonpharmacologic therapies such as diet-based interventions, epilepsy surgery, and devices are considered. PMID- 26050594 TI - A versatile mathematical work-flow to explore how Cancer Stem Cell fate influences tumor progression. AB - BACKGROUND: Nowadays multidisciplinary approaches combining mathematical models with experimental assays are becoming relevant for the study of biological systems. Indeed, in cancer research multidisciplinary approaches are successfully used to understand the crucial aspects implicated in tumor growth. In particular, the Cancer Stem Cell (CSC) biology represents an area particularly suited to be studied through multidisciplinary approaches, and modeling has significantly contributed to pinpoint the crucial aspects implicated in this theory. More generally, to acquire new insights on a biological system it is necessary to have an accurate description of the phenomenon, such that making accurate predictions on its future behaviors becomes more likely. In this context, the identification of the parameters influencing model dynamics can be advantageous to increase model accuracy and to provide hints in designing wet experiments. Different techniques, ranging from statistical methods to analytical studies, have been developed. Their applications depend on case-specific aspects, such as the availability and quality of experimental data, and the dimension of the parameter space. RESULTS: The study of a new model on the CSC-based tumor progression has been the motivation to design a new work-flow that helps to characterize possible system dynamics and to identify those parameters influencing such behaviors. In detail, we extended our recent model on CSC-dynamics creating a new system capable of describing tumor growth during the different stages of cancer progression. Indeed, tumor cells appear to progress through lineage stages like those of normal tissues, being their division auto-regulated by internal feedback mechanisms. These new features have introduced some non-linearities in the model, making it more difficult to be studied by solely analytical techniques. Our new work-flow, based on statistical methods, was used to identify the parameters which influence the tumor growth. The effectiveness of the presented work-flow was firstly verified on two well known models and then applied to investigate our extended CSC model. CONCLUSIONS: We propose a new work-flow to study in a practical and informative way complex systems, allowing an easy identification, interpretation, and visualization of the key model parameters. Our methodology is useful to investigate possible model behaviors and to establish factors driving model dynamics. Analyzing our new CSC model guided by the proposed work-flow, we found that the deregulation of CSC asymmetric proliferation contributes to cancer initiation, in accordance with several experimental evidences. Specifically, model results indicated that the probability of CSC symmetric proliferation is responsible of a switching-like behavior which discriminates between tumorigenesis and unsustainable tumor growth. PMID- 26050595 TI - A Surgical Case of Bronchial Artery Aneurysm Directory Connecting with Pulmonary Artery. AB - We present a surgical case of bronchial artery aneurysm (BAA) connecting pulmonary artery accompanied with racemose hemangioma. This is a third surgical case report of BAA directly connecting pulmonary artery in the English literature. A 63-year-old female was found a BAA, 2 cm in diameter, connecting right A4 pulmonary artery. The patient underwent two attempts for embolization. However, due to extensive collaterals, there was persistent flow in the aneurysm. Standard lateral thoracotomy was performed. A BAA was located between A4 and A5 PA. A small branch of A4 PA was separated, and the small vessel connecting to the BAA could be ligated. A5 PA was separated similarly, however BAA was ruptured not to identify the other small vessel connecting to the BAA. After a clamp of the BAA, middle lobe lobectomy was performed. We removed the aneurysm with dilated bronchial artery connecting to the aneurysm. The postoperative course was uneventful. PMID- 26050597 TI - Cross-cultural adaptation of the Schizophrenia Caregiver Questionnaire (SCQ) and the Caregiver Global Impression (CaGI) Scales in 11 languages. AB - BACKGROUND: The Schizophrenia Caregiver Questionnaire (SCQ) was developed to provide a comprehensive view of caregivers' subjective experiences of the impacts of caring for someone with schizophrenia. The Caregiver Global Impression (CaGI) scales were designed to assess their perception of the severity of the schizophrenia symptoms, of change in schizophrenia symptoms and in the experience of caring since the beginning of the study. The objectives of the study were to translate the SCQ and CaGI scales in 11 languages [French (Canada, France), English (Canada, UK, Australia), German (Germany), Italian (Italy), Spanish (Spain), Dutch (the Netherlands), Finnish (Finland), and Swedish (Sweden)], to present evidence that the translations capture the concepts of the original questionnaires and are well understood by caregivers of patients with schizophrenia in each target country. METHODS: The different language versions were developed using a standard or adjusted linguistic validation process fully complying with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) recommended procedures. RESULTS: Interviews were conducted with 55 caregivers of patients with schizophrenia from 10 countries representing the 11 different languages. Participants ranged in age from 28 to 84 years and had 5 to 16 years of education. Women represented 69.1 % (38/55) of the sample. Fourteen out of the 32 items of the SCQ generated difficulties which were mostly of semantic origin (13 items). The translation of the CaGI scales did not raise any major difficulty. Only five out of the 55 caregivers had difficulty understanding the meaning of the translations of "degree" in the expressions "degree of change in experience of caring" and "degree of change in symptoms". CONCLUSIONS: Translations of the SCQ and CaGI scales into 11 languages adequately captured the concepts in the original English versions of the questionnaires, thereby demonstrating the conceptual, semantic, and cultural equivalence of each translation. PMID- 26050598 TI - A nano-scale triangular ring cluster of indium-selenide: the structure and templating effect. AB - Different from the dominating supertetrahedral structure of InSe clusters, co assembled nano-scale In33Se60 triangular ring clusters and wheel-shaped In18Se30 clusters have been found. The unusual second-sphere coordination templating effect of the Mn(dach) complexes and the central Mn(2+) ion is responsible for the formation of the triangular ring. The optical and electronic properties are discussed. PMID- 26050599 TI - Consensus Paper: Probing Homeostatic Plasticity of Human Cortex With Non-invasive Transcranial Brain Stimulation. AB - Homeostatic plasticity is thought to stabilize neural activity around a set point within a physiologically reasonable dynamic range. Over the last ten years, a wide range of non-invasive transcranial brain stimulation (NTBS) techniques have been used to probe homeostatic control of cortical plasticity in the intact human brain. Here, we review different NTBS approaches to study homeostatic plasticity on a systems level and relate the findings to both, physiological evidence from in vitro studies and to a theoretical framework of homeostatic function. We highlight differences between homeostatic and other non-homeostatic forms of plasticity and we examine the contribution of sleep in restoring synaptic homeostasis. Finally, we discuss the growing number of studies showing that abnormal homeostatic plasticity may be associated to a range of neuropsychiatric diseases. PMID- 26050600 TI - New Quantitative Analyses Following Price & Hamilton's Critique do not Change Original Findings of Horvath et al. PMID- 26050601 TI - Report of Transient Paresthesia Following Transcranial Stimulation. PMID- 26050602 TI - Feasibility study of high intensity focused ultrasound (HIFU) for the treatment of hydatid cysts of the liver. AB - This study evaluates the feasibility of using high intensity focused ultrasound (HIFU) for the treatment of hydatid cysts of the liver. HIFU ablation was carried out in 62 patients with echinococcosis of the liver. The mean age of patients was 40.76+/-14.84 (range: 17-72 years). The effectiveness of the treatment was monitored in real-time by changes in the gray-scale, and by morphological studies, computed tomography, magnetic resonance imaging, and ultrasound. Criteria for evaluating the effectiveness of treatment in real time were outlines. Cytomorphological picture of destructive changes of parasitic elements was presented as well. Loss of embryonic elements of the parasite was observed at the subcellular level after HIFU-ablation and underlines the effectiveness of HIFU. PMID- 26050603 TI - Minimal invasive treatments for liver malignancies. AB - Minimal invasive therapies have proved useful in the management of primary and secondary hepatic malignancies. The most relevant aspects of all these therapies are their minimal toxicity profiles and highly effective tumor responses without affecting the normal hepatic parenchyma. These unique characteristics coupled with their minimally invasive nature provide an attractive therapeutic option for patients who previously may have had few alternatives. Combination of these therapies might extend indications to bring curative treatment to a wider selected population. The results of various ongoing combination trials of intraarterial therapies with targeted therapies are awaited to further improve survival in this patient group. This review focuses on the application of ablative and intra-arterial therapies in the management of hepatocellular carcinoma and hepatic colorectal metastasis. PMID- 26050604 TI - High-intensity focused ultrasound (HIFU) for adenomyosis: Two-year follow-up results. AB - OBJECTIVE: To evaluate the long-term improvement of clinical symptoms of adenomyosis after treatment with ultrasound-guided high intensity focused ultrasound (USgHIFU). METHODS: From January 2010 to December 2011, 350 patients with adenomyosis were treated with USgHIFU. Among the 350 patients, 224 of them completed the two years follow-up. The patients were followed up at 3 months, 1 year, and 2 years after HIFU treatment. Adverse effects and complications were recorded. RESULTS: All patients completed HIFU ablation without severe postoperative complications. 203 of the 224 patients who showed varying degrees of dysmenorrhea before treatment had the symptom scores decreased significantly after treatment (P<0.001). The relief rate was 84.7%, 84.7%, and 82.3%, respectively at 3 months, 1 year, and 2 years after treatment. The menstrual volume in 109 patients with menorrhagia was significantly improved after treatment (P<0.001) with a relief rate of 79.8%, 80.7%, and 78.9%, respectively at 3 months, 1 year, and 2 years after HIFU treatment. CONCLUSION: With its ability to sustain long-term clinical improvements, HIFU is a safe and effective treatment for adenomyosis. PMID- 26050605 TI - A perspective on the developmental toxicity of inhaled nanoparticles. AB - This paper aimed to clarify whether maternal inhalation of engineered nanoparticles (NP) may constitute a hazard to pregnancy and fetal development, primarily based on experimental animal studies of NP and air pollution particles. Overall, it is plausible that NP may translocate from the respiratory tract to the placenta and fetus, but also that adverse effects may occur secondarily to maternal inflammatory responses. The limited database describes several organ systems in the offspring to be potentially sensitive to maternal inhalation of particles, but large uncertainties exist about the implications for embryo-fetal development and health later in life. Clearly, the potential for hazard remains to be characterized. Considering the increased production and application of nanomaterials and related consumer products a testing strategy for NP should be established. Due to large gaps in data, significant amounts of groundwork are warranted for a testing strategy to be established on a sound scientific basis. PMID- 26050606 TI - Phospholipid hydroperoxide glutathione peroxidase is involved in the maintenance of male fertility under cryptorchidism in mice. AB - Severe oxidative stress by cryptorchidism leads to infertility. To assess the functional significance of phospholipid hydroperoxidase glutathione peroxidase (PHGPx) under cryptorchidism, PHGPx expression was spatiotemporally analyzed in testes and epididymis excised at 1, 4, 7, 14, 21, and 28 days after experimental bilateral cryptorchidism in adult mice. In testes, while apoptosis-related caspase 3 and Bcl-xL mRNAs were significantly changed after 14 days, 3 beta hydroxysteroid dehydrogenase mRNA was greatly reduced immediately after cryptorchidism. Under cryptorchidism, PHGPx was significantly decreased in both organs after 21 days, while its mRNA was greatly reduced in testes after 14 days and in epididymis after 4 days. However, PHGPx was upregulated in degenerative spermatids, multinucleated giant cells, and Leydig cells in testes and desquamous spermatids in epididymis until 21 days, but was weakly detected in the spermatids at 28 days. These findings suggest that PHGPx is necessary for maintenance of male fertility under cryptorchidism in testes. PMID- 26050607 TI - Accumulation of organotins in seafood leads to reproductive tract abnormalities in female rats. AB - Organotins (OTs) are environmental contaminants used as biocides in antifouling paints that have been shown to be endocrine disrupters. However, studies evaluating the effects of OTs accumulated in seafood (LNI) on reproductive health are particularly sparse. This study demonstrates that LNI leads to impairment in the reproductive tract of female rats, as the estrous cycle development, as well as for ovary and uterus morphology. Rats were treated with LNI, and their reproductive morphophysiology was assessed. Morphophysiological abnormalities, such as irregular estrous cycles, abnormal ovarian follicular development and ovarian collagen deposition, were observed in LNI rats. An increase in luminal epithelia and ERalpha expression was observed in the LNI uteri. Together, these data provide in vivo evidence that LNI are toxic for reproductive morphophysiology, which may be associated with risks to reproductive function. PMID- 26050608 TI - Trajectory Modulated Arc Therapy: A Fully Dynamic Delivery With Synchronized Couch and Gantry Motion Significantly Improves Dosimetric Indices Correlated With Poor Cosmesis in Accelerated Partial Breast Irradiation. AB - PURPOSE: To develop planning and delivery capabilities for linear accelerator based nonisocentric trajectory modulated arc therapy (TMAT) and to evaluate the benefit of TMAT for accelerated partial breast irradiation (APBI) with the patient in prone position. METHODS AND MATERIALS: An optimization algorithm for volumetrically modulated arc therapy (VMAT) was generalized to allow for user defined nonisocentric TMAT trajectories combining couch rotations and translations. After optimization, XML scripts were automatically generated to program and subsequently deliver the TMAT plans. For 10 breast patients in the prone position, TMAT and 6-field noncoplanar intensity modulated radiation therapy (IMRT) plans were generated under equivalent objectives and constraints. These plans were compared with regard to whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose. RESULTS: For TMAT APBI, nonisocentric collision-free horizontal arcs with large angular span (251.5 +/- 7.9 degrees ) were optimized and delivered with delivery time of ~4.5 minutes. Percentage changes of whole breast tissue volume receiving more than 100%, 80%, 50%, and 20% of the prescription dose for TMAT relative to IMRT were 10.81% +/- 6.91%, -27.81% +/- 7.39%, -14.82% +/- 9.67%, and 39.40% +/- 10.53% (P<=.01). CONCLUSIONS: This is a first demonstration of end-to-end planning and delivery implementation of a fully dynamic APBI TMAT. Compared with IMRT, TMAT resulted in marked reduction of the breast tissue volume irradiated at high doses. PMID- 26050609 TI - Competing Risk Analysis of Neurologic versus Nonneurologic Death in Patients Undergoing Radiosurgical Salvage After Whole-Brain Radiation Therapy Failure: Who Actually Dies of Their Brain Metastases? AB - PURPOSE: To estimate the hazard for neurologic (central nervous system, CNS) and nonneurologic (non-CNS) death associated with patient, treatment, and systemic disease status in patients receiving stereotactic radiosurgery after whole-brain radiation therapy (WBRT) failure, using a competing risk model. PATIENTS AND METHODS: Of 757 patients, 293 experienced recurrence or new metastasis following WBRT. Univariate Cox proportional hazards regression identified covariates for consideration in the multivariate model. Competing risks multivariable regression was performed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for both CNS and non-CNS death after adjusting for patient, disease, and treatment factors. The resultant model was converted into an online calculator for ease of clinical use. RESULTS: The cumulative incidence of CNS and non-CNS death at 6 and 12 months was 20.6% and 21.6%, and 34.4% and 35%, respectively. Patients with melanoma histology (relative to breast) (aHR 2.7, 95% CI 1.5-5.0), brainstem location (aHR 2.1, 95% CI 1.3-3.5), and number of metastases (aHR 1.09, 95% CI 1.04-1.2) had increased aHR for CNS death. Progressive systemic disease (aHR 0.55, 95% CI 0.4-0.8) and increasing lowest margin dose (aHR 0.97, 95% CI 0.9-0.99) were protective against CNS death. Patients with lung histology (aHR 1.3, 95% CI 1.1-1.9) and progressive systemic disease (aHR 2.14, 95% CI 1.5-3.0) had increased aHR for non-CNS death. CONCLUSION: Our nomogram provides individual estimates of neurologic death after salvage stereotactic radiosurgery for patients who have failed prior WBRT, based on histology, neuroanatomical location, age, lowest margin dose, and number of metastases after adjusting for their competing risk of death from other causes. PMID- 26050610 TI - Macroscopic and microscopic evaluation of Eurasian lynx (Lynx lynx) female tubular reproductive organs in relation to ovarian structures. AB - Although monitoring wild animals in the field is essential for estimations of population size and development, there are pitfalls associated with field monitoring. In addition, some detailed data about reproductive physiology can be difficult to obtain in wild live animals. Studying reproductive organs from the Eurasian lynx killed at hunting or found dead could be used as a valuable addition to other field data. We evaluated reproductive organs from 39 Eurasian lynx females (Lynx lynx) killed in Sweden during the hunting seasons in 2009, 2010, and 2011. According to notes on ovarian structures, the animals were categorized as being in one of four different reproductive stages: juvenile (n = 10), follicular stage (n = 8), luteal stage (n = 11), and anestrus (n = 10). Corpora lutea were classified as fresh CL from the present season or as luteal bodies from previous cycles. Microscopic evaluations were blindly coded while the outer measurements of the vagina and uterus were taken at the time of organ retrieval. The width of the endometrium, myometrium, outer width of the uterine horns, and the diameter of the vagina differed significantly with the reproductive stage (P < 0.001) and were largest in the follicular and luteal phases. The number of endometrial glands evaluated blindly coded on a subjective scale was significantly associated with the reproductive stage (P < 0.0001) and was significantly higher in the luteal phase than that in any other reproductive stages (P < 0.05). Cornification of the vaginal epithelium was only observed in females in the follicular stage or in females with signs of a recent ovulation. In conclusion, both macroscopic and histologic measurements are useful for a correct classification of the reproductive stage when evaluating reproductive organs in the Eurasian lynx killed during the hunting season. Routine evaluation of reproductive organs has a potential to be a useful additional tool to field studies of live lynx to monitor their reproduction. PMID- 26050611 TI - Seasonally different reproductive investment in a medium-sized rodent (Cavia aperea). AB - Pronounced seasonal variations in day length, temperature, and resource availability characterize the temperate regions and strongly influence the animals living in these environments. To survive and reproduce successfully, animals must allocate resources among competing physiological systems, and they usually adjust their time of breeding to the most adequate season. Here, we examined whether reproductive investment in the wild guinea pig (Cavia aperea) differs across seasons. We kept animals in combined indoor-outdoor enclosures under natural light and temperature year-round. We measured littering probability, litter size, and birth weight, as well as maternal weight loss during lactation. In addition, we measured ovulation rate as a parameter to adjust reproductive investment prenatally. Our data reveal strong seasonal variations in reproductive traits despite the fact that the animals reproduced year-round. The results show a reduced reproductive investment in winter, indicated by a lower litter size and birth weight of pups, whereas investment was highest in warm seasons (summer and autumn) with higher litter size and birth weight. Maternal weight loss in lactation was highest in cold seasons even if the litter size was lower. Furthermore, we found the regulation on the proximate level of the reproductive investment, the ovulation rate, to differ significantly between the seasons. PMID- 26050612 TI - Effect of extracellular adenosine 5'-triphosphate on cryopreserved epididymal cat sperm intracellular ATP concentration, sperm quality, and in vitro fertilizing ability. AB - Intracellular adenosine 5'-triphosphate (ATP) is essential for supporting sperm function in the fertilization process. During cryopreservation, damage of sperm mitochondrial membrane usually leads to compromised production of intracellular ATP. Recently, extracellular ATP (ATPe) was introduced as a potent activator of sperm motility and fertilizing ability. This study aimed to evaluate (1) levels of intracellular ATP in frozen-thawed epididymal cat sperm after incubation with ATPe and (2) effects of ATPe on epididymal cat sperm parameters after freezing and thawing. Eighteen male cats were included. For each replicate, epididymal sperm from two cats were pooled to one sample (N = 9). Each pooled sample was cryopreserved with the Tris-egg yolk extender into three straws. After thawing, the first and second straws were incubated with 0-, 1.0-, or 2.5-mM ATPe for 10 minutes and evaluated for sperm quality at 10 minutes, 1, 3, and 6 hours after thawing and fertilizing ability. The third straw was evaluated for intracellular ATP concentration in control and with 2.5-mM ATPe treatment. Higher concentration of intracellular sperm ATP was observed in the samples treated with 2.5-mM ATPe compared to the controls (0.339 +/- 0.06 MUg/2 * 10(6) sperm vs. 0.002 +/- 0.003 MUg/2 * 10(6) sperm, P <= 0.05). In addition, incubation with 2.5-mM ATPe for 10 minutes promoted sperm motility (56.7 +/- 5.0 vs. 53.3 +/- 4.4%, P <= 0.05) and progressive motility (3.1 +/- 0.2 vs. 2.8 +/- 0.4, P <= 0.05), mitochondrial membrane potential (36.4 +/- 5.5 vs. 28.7 +/- 4.8%, P <= 0.05), and blastocyst rate (36.1 +/- 7.0 and 28.8 +/- 7.4%, P <= 0.05) compared with the controls. In contrast, ATPe remarkably interfered acrosome integrity after 6 hours of postthawed incubation. In sum, the present finding that optimal incubation time of postthaw epididymal cat sperm under proper ATPe condition might constitute a rationale for the studies on other endangered wild felids regarding sperm quality and embryo development. PMID- 26050613 TI - Effects of ground semen collection on weight bearing on hindquarters, libido, and semen parameters in stallions. AB - Collection of semen on the ground from the standing stallion represents an alternative method to dummy mount semen collection and is of increasing popularity for sport stallions, males suffering from health problems, or in studs without a dummy or suitable mare at disposal. Our aim was to collect and compare spermatological and physiological data associated with traditional and ground semen collection. Twelve of 23 Franches-Montagnes stallions were selected to carry out semen collection on a dummy and while standing in a crossed experimental protocol. Semen quantity and quality parameters, weight bearing on hindquarters, and behavioral and libido data were recorded. Ground versus dummy mount semen collection was accompanied by lower seminal volume (15.9 +/- 14.6 vs. 22.0 +/- 13.3 mL; P < 0.01) and lower total sperm count (4.913 +/- 2.721 * 10(9) vs. 6.544 +/- 2.856 * 10(9) sperm; P < 0.001). No significant differences were found concerning sperm motility and viability. Time to ejaculation was longer, and the number of attempts to ejaculation was higher (P = 0.053) in the standing position compared with the mount on the dummy. A higher (P < 0.01) amount of tail flagging was manifested by the stallions during ejaculation on the dummy compared to when standing. There was no difference in weight bearing on hindquarters when comparing dummy collection (51.2 +/- 2.5%) and standing collection (48.9 +/- 5.5%). Ground semen collection can be considered as a viable option for stallions that cannot mount a dummy or a mare. However, it requires training and may be not easily accepted by all stallions. Owners should be advised that ground semen collection is associated with significantly lower sperm numbers than with dummy mount semen collection. PMID- 26050615 TI - A nucleus-coupled electron transfer mechanism for TiO2-catalyzed water splitting. AB - Based on first-principles calculations, we reveal that in the photocatalytic oxygen evolution reaction (OER) at the TiO2/water interface, the formation of an O-O bond always involves the anti-bonding sigma2p* state elevated from the valence band into the conduction band of TiO2 regardless of a detailed reaction pathway. The role of photoholes is to deplete this anti-bonding state once it emerges into the band gap. The reaction barrier is thus determined by the onset where photoholes enter the reaction. This process represents a new reaction mechanism, termed nucleus-coupled electron transfer (NCET), where electron transfer is enabled by the movement of nuclei that promotes the reactive orbital to become the frontier orbital. The NCET mechanism for the OER is shown to exhibit an overall kinetic barrier surmountable at room temperature. PMID- 26050616 TI - Stereoselective formation of coordination polymers with 1,4-diaminonaphthalene on various Cu substrates. AB - Polymerization of 1,4-diaminonaphthalene on various Cu substrates resulting in stereoselectively well-defined metal-organic coordination polymers is reported. By using different crystallographic planes (111), (110) and (100) of a Cu substrate the structure of the resulting coordination polymer was controlled. PMID- 26050614 TI - An international perspective on using opioid substitution treatment to improve hepatitis C prevention and care for people who inject drugs: Structural barriers and public health potential. AB - People who inject drugs (PWID) are central to the hepatitis C virus (HCV) epidemic. Opioid substitution treatment (OST) of opioid dependence has the potential to play a significant role in the public health response to HCV by serving as an HCV prevention intervention, by treating non-injection opioid dependent people who might otherwise transition to non-sterile drug injection, and by serving as a platform to engage HCV infected PWID in the HCV care continuum and link them to HCV treatment. This paper examines programmatic, structural and policy considerations for using OST as a platform to improve the HCV prevention and care continuum in 3 countries-the United States, Estonia and Viet Nam. In each country a range of interconnected factors affects the use OST as a component of HCV control. These factors include (1) that OST is not yet provided on the scale needed to adequately address illicit opioid dependence, (2) inconsistent use of OST as a platform for HCV services, (3) high costs of HCV treatment and health insurance policies that affect access to both OST and HCV treatment, and (4) the stigmatization of drug use. We see the following as important for controlling HCV transmission among PWID: (1) maintaining current HIV prevention efforts, (2) expanding efforts to reduce the stigmatization of drug use, (3) expanding use of OST as part of a coordinated public health approach to opioid dependence, HIV prevention, and HCV control efforts, (4) reductions in HCV treatment costs and expanded health system coverage to allow population level HCV treatment as prevention and OST as needed. The global expansion of OST and use of OST as a platform for HCV services should be feasible next steps in the public health response to the HCV epidemic, and is likely to be critical to efforts to eliminate or eradicate HCV. PMID- 26050617 TI - Response to Esteve-Gassent et al.: flaB sequences obtained from Texas PCR products are identical to the positive control strain Borrelia burgdorferi B31. AB - Feria-Arroyo et al. had reported previously that, based on PCR analysis, 45% of Ixodes scapularis ticks collected in Texas and Mexico were infected with the Lyme disease spirochete Borrelia burgdorferi (Parasit. Vectors 2014, 7:199). However, our analyses of their initial data (Parasit. Vectors 2014, 7:467) and a recent response by Esteve-Gassent et al. (Parasit. Vectors 2015, 8:129) provide evidence that the positive PCR results obtained from both ribosomal RNA intergenic sequences and the flagellin gene flaB are highly likely due to contamination by the B. burgdorferi B31 positive control strain. PMID- 26050618 TI - Activating ERBB4 mutations in non-small cell lung cancer. AB - Recent efforts to comprehensively characterize the mutational landscape of non small cell lung cancer have identified frequent mutations in the receptor tyrosine kinase ERBB4. However, the significance of mutated ERBB4 in non-small cell lung cancer remains elusive. Here, we have functionally characterized nine ERBB4 mutations previously identified in lung adenocarcinoma. Four out of the nine mutations, Y285C, D595V, D931Y and K935I, were found to be activating, increasing both basal and ligand-induced ErbB4 phosphorylation. According to structural analysis, the four activating mutations were located at critical positions at the dimerization interfaces of the ErbB4 extracellular (Y285C and D595V) and kinase (D931Y and K935I) domains. Consistently, the mutations enhanced ErbB4 dimerization and increased the trans activation in ErbB4 homodimers and ErbB4-ErbB2 heterodimers. The expression of the activating ERBB4 mutants promoted survival of NIH 3T3 cells in the absence of serum. Interestingly, serum starvation of NIH 3T3 cells expressing the ERBB4 mutants only moderately increased the phosphorylation of canonical ErbB signaling pathway effectors Erk1/2 and Akt as compared with wild-type ERBB4. In contrast, the mutations clearly enhanced the proteolytic release of signaling-competent ErbB4 intracellular domain. These results suggest the presence of activating driver mutations of ERBB4 in non-small cell lung cancer. PMID- 26050619 TI - The biology of circulating tumor cells. AB - Metastasis is a biologically complex process consisting of numerous stochastic events which may tremendously differ across various cancer types. Circulating tumor cells (CTCs) are cells that are shed from primary tumors and metastatic deposits into the blood stream. CTCs bear a tremendous potential to improve our understanding of steps involved in the metastatic cascade, starting from intravasation of tumor cells into the circulation until the formation of clinically detectable metastasis. These efforts were propelled by novel high resolution approaches to dissect the genomes and transcriptomes of CTCs. Furthermore, capturing of viable CTCs has paved the way for innovative culturing technologies to study fundamental characteristics of CTCs such as invasiveness, their kinetics and responses to selection barriers, such as given therapies. Hence the study of CTCs is not only instrumental as a basic research tool, but also allows the serial monitoring of tumor genotypes and may therefore provide predictive and prognostic biomarkers for clinicians. Here, we review how CTCs have contributed to significant insights into the metastatic process and how they may be utilized in clinical practice. PMID- 26050620 TI - Shp2 promotes metastasis of prostate cancer by attenuating the PAR3/PAR6/aPKC polarity protein complex and enhancing epithelial-to-mesenchymal transition. AB - Epithelial-to-mesenchymal transition (EMT), marked by the dissolution of cell cell junctions, loss of cell polarity and increased cell motility, is one of the essential steps for prostate cancer metastasis. However, the underlying mechanism has not been fully explored. We report in this study that Shp2 is upregulated in prostate cancers and is associated with a poor disease outcome, namely tumor metastasis and shortened patient survival. Overexpression of wild-type Shp2 or an oncogenic Shp2 mutant leads to increased prostate cancer cell proliferation, colony and sphere formation, and in vivo tumor formation. Opposite effects are seen in Shp2-knockdown cells. Moreover, Shp2 promotes in vitro migration and in vivo metastasis of prostatic tumor cells. Mechanistically, Shp2 interacts with PAR3 (partitioning-defective 3) via its Src homology-2 domain. Ectopic expression of Shp2 attenuates the phosphorylation of PAR3 and the formation of the PAR3/PAR6/atypical protein kinase C polarity protein complex, resulting in disrupted cell polarity, dysregulated cell-cell junctions and increased EMT. These findings provide a novel mechanism by which oncogenic signal-transduction molecules regulate cell polarity and induction of EMT. PMID- 26050621 TI - Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity. AB - Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand cytokine known for its cytotoxic activity against malignantly transformed cells. TRAIL induces cell death through binding to death receptors DR4 and DR5. The inhibitory decoy receptors (DcR1 and DcR2) co-expressed with death receptor 4 (DR4)/DR5 on the same cell can block the transmission of the apoptotic signal. Here, we show that DcRs also regulate TRAIL sensitivity at a supracellular level and thus represent a mechanism by which the microenvironment can diminish tumour TRAIL sensitivity. Mathematical modelling and layered or spheroid stroma extracellular matrix-tumour cultures were used to model the tumour microenvironment. By engineering TRAIL to escape binding by DcRs, we found that DcRs do not only act in a cell-autonomous or cis-regulatory manner, but also exert trans-cellular regulation originating from stromal cells and affect tumour cells, highlighting the potent inhibitory effect of DcRs in the tumour tissue and the necessity of selective targeting of the two death-inducing TRAIL receptors to maximise efficacy. PMID- 26050623 TI - In situ nanoparticle sizing with zeptomole sensitivity. AB - We present the basis for an entirely new approach to in situ nanoparticle sizing. Nanoparticles containing just 12 zeptomoles (1 zeptomole = 10(-21) moles) of silver, are detected via in situ particle coulometry. These stochastic charge measurements correspond to the transfer of only 7000-8000 electrons, yielding direct information relating to the individual nanoparticle volumes. The resulting particle size distribution (average equivalent radius 5 nm) obtained via nanoparticle coulometry is in excellent correspondence with that attained from TEM analysis. Moreover, the measurable particle size limit by this electrochemical method is shown to be significantly below that of more common optical nanoparticle tracking techniques, and as such can be viewed as a potential disruptive nano-technology. PMID- 26050624 TI - A closer look at epsilon-caprolactone polymerization catalyzed by alkyl aluminum complexes: the effect of induction period on overall catalytic activity. AB - Previous studies on the ring-opening polymerization of epsilon-caprolactone using structurally related aluminum complexes as pre-catalysts showed inconsistent trends in the total conversion time. We propose that an induction period for Al complexes for conversion to real catalytic species, Al alkoxide, should be considered because the total conversion time consists of both an induction period and polymer propagation time. Herein, the polymerization rate of a series of Al complexes bearing ketimine ligands was investigated. The catalytic results indicated complexes with more steric hindrance with an electron-withdrawing group on the ligands, or the fact that less chelating ligands demonstrated greater propagation activity. The opposite trend for these structural effects was observed on the measurement of induction periods. These features on ligands of aluminum complexes are responsible for facilitating the conversion process to Al alkoxides. The overall catalytic performance should consider both the induction period and the propagation time. PMID- 26050625 TI - Intra-individual and inter-individual variability in daily sitting time and MVPA. AB - OBJECTIVES: Little is known about how much variability exists in free-living sitting time within individuals. The purpose of this study was to examine intra individual variability of objectively determined daily sitting time and to determine if this variability was related to weekly averages of sitting duration or recommended moderate-vigorous physical activity (MVPA). Also, this study determined the reliability of free-living sitting and MVPA time as it useful for guiding researchers in determining how many days of monitoring are needed. DESIGN: An activPAL monitor was worn for 7 consecutive days by 68 women (52+/-8 years). METHODS: Intra-individual range of daily sitting time was calculated. Generalizability theory analysis determined the reliability of daily sitting and recommended MVPA. RESULTS: Mean sitting time was 9.0+/-1.8h/day and the within individual weekly mean range was 4.5+/-1.7h/day. Similarly, there was a 4.5h/day difference in sitting time between the mean of the lowest sitting (6.7+/-0.8) and highest sitting (11.3+/-1.1h/day) quartiles. The intra-individual range in daily sitting did not differ among quartiles of sitting time (i.e., 4.9+/-1.9, 4.1+/ 1.9, 5.1+/-1.5, 3.9+/-1.1h/day for the 1st-4th quartiles) nor among quartiles of MVPA (i.e., 4.2+/-1.8, 4.7+/-2.0, 4.6+/-1.5, 4.4+/-1.3h/day for the 1st-4th quartiles). A reliability coefficient of 0.80 was achieved with 4 days of objectively measured sitting time and 7 days for MVPA. CONCLUSIONS: The findings suggest exposure to relatively high levels of sedentary time may occur in people regardless of weekly averages in sitting and regular exercise due to the high day to-day variation in daily sitting time (4.5h/d range within a week). PMID- 26050627 TI - Development of optical biosensor technologies for cardiac troponin recognition. AB - Acute myocardial infarction (AMI) is the leading cause of death among cardiovascular diseases. Among the numerous attempts to develop coronary marker concepts into clinical strategies, cardiac troponin is known as a specific marker for coronary events. The cardiac troponin concentration level in blood has been shown to rise rapidly for 4-10 days after onset of AMI, making it an attractive approach for a long diagnosis window for detection. The extremely low clinical sensing range of cardiac troponin levels consequently makes the methods of detection highly sensitive. In this review, by taking into consideration optical methods applied for cardiac troponin detection, we discuss the most commonly used methods of optical immunosensing and provide an overview of the various diagnostic cardiac troponin immunosensors that have been employed for determination of cardiac troponin over the last several years. PMID- 26050626 TI - Does playing a sports active video game improve young children's ball skill competence? AB - OBJECTIVES: Actual and perceived object control (commonly ball) skill proficiency is associated with higher physical activity in children and adolescents. Active video games (AVGs) encourage whole body movement to control/play the electronic gaming system and therefore provide an opportunity for screen time to become more active. The purpose of this study was to determine whether playing sports AVGs has a positive influence on young children's actual and perceived object control skills. DESIGN: Two group pre/post experimental design study. METHODS: Thirty-six children aged 6-10 years old from one school were randomly allocated to a control or intervention condition. The Test of Gross Motor Development-3 assessed object control skill. The Pictorial Scale of Perceived Competence for Young Children assessed perceived object control skill. The intervention consisted of 6*50min lunchtime AVG sessions on the Xbox Kinect. Two to three sport games were chosen for participants to play each session. General linear models with either perceived object control or actual object control skill as the outcome variables were conducted. Each base model adjusted for intervention status and pre-score of the respective outcome variable. Additional models adjusted for potential confounding variables (sex of child and game at home). RESULTS: No significant differences between the control and intervention groups were observed for both outcomes. CONCLUSIONS: This study found that playing the Xbox Kinect does not significantly influence children's perceived or actual object control skills, suggesting that the utility of the Xbox Kinect for developing perceived and actual object control skill competence is questionable. PMID- 26050628 TI - An improvement on mass spectrometry-based epigenetic analysis of large histone derived peptides by using the Ionization Variable Unit interface. AB - Highly protonated histone-derived peptides impede a sufficient mass spectrometry (MS)-based epigenetic analysis because their relatively low m/z, due to a high degree of proton addition to peptides, would make it difficult to analyze the resulting complex MS/MS spectra. To reduce the degree of protonations, we have developed a new interface, the Ionization Variable Unit (IVU), in which peptides are ionized under a vaporized organic solvent. It is demonstrated that the doubly charged histone tail H2B peptide, PEPAKSAPAPKKGSKKAVTKAQKK (m/z 1238.243, +2), which was not detectable before, can be detected by using the IVU interface and sequenced. PMID- 26050622 TI - Context-dependent actions of Polycomb repressors in cancer. AB - Polycomb Group (PcG) proteins form Polycomb Repressive Complexes (PRCs) that function as epigenetic repressors of gene expression. The large variety of PcG proteins, in addition to the high number of paralogs, allows for the formation of diverse PRCs with different properties, providing fine-tuned control over cell specification. Initially identified as being oncogenes, a small number of PcG genes are involved in tumor development in part through the repression of the CDKN2A locus. Therefore, enhanced PcG-mediated repression has long been assumed to be cancer promoting. However, recent data have revealed that for some cancers, PcG proteins act as tumor suppressors, indicating that this traditional view is oversimplified. In this review, we present an overview of the roles of PcG genes in oncogenesis and how the nature of their role is context dependent. PMID- 26050629 TI - Highly specific fluorescence detection of T4 polynucleotide kinase activity via photo-induced electron transfer. AB - Sensitive and reliable study of the activity of polynucleotide kinase (PNK) and its potential inhibitors is of great importance for biochemical interaction related to DNA phosphorylation as well as development of kinase-targeted drug discovery. To achieve facile and reliable detection of PNK activity, we report here a novel fluorescence method for PNK assay based on a combination of exonuclease cleavage reaction and photo-induced electron transfer (PIET) by using T4 PNK as a model target. The fluorescence of 3'-carboxyfluorescein-labeled DNA probe (FDNA) is effectively quenched by deoxyguanosines at the 5' end of its complementary DNA (cDNA) due to an effective PIET between deoxyguanosines and fluorophore. Whereas FDNA/cDNA hybrid is phosphorylated by PNK and then immediately cleaved by lambda exonuclease (lambda exo), fluorescence is greatly restored due to the break of PIET. This homogeneous PNK activity assay does not require a complex design by taking advantage of the quenching ability of deoxyguanosines, making the proposed strategy facile and cost-effective. The activity of PNK can be sensitively detected in the range of 0.005 to 10 U mL(-1) with a detection limit of 2.1*10(-3) U mL(-1). Research on inhibition efficiency of different inhibitors demonstrated that it can be explored to evaluate inhibition capacity of inhibitors. The application for detection of PNK activity in complex matrix achieved satisfactory results. Therefore, this PIET strategy opens a promising avenue for studying T4 PNK activity as well as evaluating PNK inhibitors, which is of great importance for discovering kinase-targeted drugs. PMID- 26050630 TI - Pseudogene-free amplification of HPRT1 in quantitative reverse transcriptase polymerase chain reaction. AB - Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) provides a powerful tool for precise gene expression analysis. The accuracy of the results highly depends on careful selection of a reference gene for data normalization. HPRT1 (hypoxanthine phosphoribosyl transferase 1) is a frequently used housekeeping gene for normalizing relative expression values. However, the existence of processed pseudogenes for HPRT1 might interfere with reliable results obtained in qRT-PCR due to amplification of unintended products. Here, we designed a primer pair for pseudogene-free amplification of HPRT1 in qRT-PCR. We demonstrate that this primer pair specifically amplified HPRT1 messenger RNA (mRNA) sequence while avoiding coamplification of the pseudogenes. PMID- 26050631 TI - Ribonuclease-neutralized pancreatic microsomal membranes from livestock for in vitro co-translational protein translocation. AB - Here, we demonstrate that pancreatic microsomal membranes from pigs, sheep, or cattle destined for human consumption can be used as a valuable and ethically correct alternative to dog microsomes for cell-free protein translocation. By adding adequate ribonuclease (RNase) inhibitors to the membrane fraction, successful in vitro co-translational translocation of wild-type and chimeric pre prolactin into the lumen of rough microsomes was obtained. In addition, the human type I integral membrane proteins CD4 and VCAM-1 were efficiently glycosylated in RNase-treated microsomes. Thus, RNase-neutralized pancreatic membrane fractions from pig, cow, or sheep are a cheap, easily accessible, and fulfilling alternative to canine microsomes. PMID- 26050633 TI - The effect of temperature on thermoelectric properties of n-type Bi2Te3 nanowire/graphene layer-by-layer hybrid composites. AB - The thermoelectric properties of Bi2Te3 nanowire/graphene composites prepared at different sintering temperatures have been investigated. The as-synthesized ultrathin Bi2Te3 nanowires are uniformly distributed between the graphene layers, leading to the formation of Bi2Te3 nanowire/graphene layer-by-layer hybrid structures. The electrical conductivity of the as-sintered composites increases dramatically with the sintering temperature, as the relative density and grain size increase and the interface density decreases. This in turn lowers the Seebeck coefficient due to the reduction of the potential barrier for carriers and their scattering at the interface. The fabricated n-type Bi2Te3 nanowire/graphene composites exhibit an enhanced figure of merit of 0.25 at an optimal sintering temperature of 623 K. PMID- 26050632 TI - 10-Hydroxy-2-decenoic acid inhibiting the proliferation of fibroblast-like synoviocytes by PI3K-AKT pathway. AB - To reveal the mechanism of 10H2DA inhibiting the proliferation of fibroblast-like synoviocytes (FLSs) of RA patients. Cell proliferation, HDAC activity and histone acetylation level of FLS cells treated with 10H2DA were detected by MTT assay, Colorimetric HDAC Activity Assay and Western-blot. Different genes in FLS cells from RA patients were primary cultured and treated with 10H2DA. They were then screened by Human Transcriptome 1.0 ST microarrays and verified by real-time PCR. The results showed dose-dependent and time-dependent decreases in cell viability and HDAC activity in FLSs treated with 10H2DA, and time-dependent induction in the acetylation of H3 and H4 at the same time. 697 different genes were identified by HTA 1.0. The expressions of 7 target genes of the PI3K-AKT pathway were decreased and 4 target genes of cytokine-cytokine receptor interaction were increased verified by real-time PCR. These results imply that 10H2DA is a potential HDACI which inhibits the proliferation of FLS cells by PI3K-AKT pathway. PMID- 26050634 TI - The role of active vaccination in cancer immunotherapy: lessons from clinical trials. AB - In the past few years, a number of different immunotherapeutic strategies have shown impressive results in cancer patients. These successful approaches include blockade of immunosuppressive molecules like PD-1 and CTLA-4, adoptive transfer of patient derived and genetically modified T-cells, and vaccines that stimulate tumor antigen specific T-cells. However, several large vaccine trials recently failed to reach designated primary endpoints. In light of the success of other immunotherapeutic approaches, these negative results raise the questions of why vaccines have not generated a better response, and what the role of active vaccination will be moving forward in cancer immunotherapy. PMID- 26050635 TI - Spatially and temporally controlled immune cell interactions using microscale tools. AB - Many critical immunological responses are mediated by cell-cell interactions. Despite their capabilities, traditional techniques that rely on snapshot analysis or ensemble measurements can only provide a fragmentary picture of the complexity of these interactions. Emerging classes of new and versatile microscale tools hold great potential for enabling detailed investigation of these interactions with precise control in space and time, multiplexed measurement capability and high-throughput single-cell analysis. These features allow new ways of examining immune cell interactions that are not possible with traditional methods, improve the extent of information extracted from experiments, and reveal new findings. Here, we review recent developments in microscale tools that are paving the way for comprehensive analyses of cell-cell interactions in the immune system. PMID- 26050636 TI - Prevention of bacterial adhesion and biofilm formation on a vitamin E-blended, cross-linked polyethylene surface with a poly(2-methacryloyloxyethyl phosphorylcholine) layer. AB - In the construction of artificial hip joint replacements, the surface and substrate of a cross-linked polyethylene (CLPE) liner are designed to achieve high wear resistance and prevent infection by bacteria. In this study, we fabricated a highly hydrophilic and antibiofouling poly(2-methacryloyloxyethyl phosphorylcholine [MPC]) (PMPC)-graft layer on the vitamin E-blended CLPE (HD CLPE(VE)) surface. The 100-nm-thick, smooth, and electrically neutral PMPC layer was successfully fabricated on the HD-CLPE(VE) surface using photoinduced graft polymerization. The PMPC-grafted HD-CLPE(VE) was found to prevent bacterial adherence and biofilm formation on the surface because of the formation of a highly hydrophilic polyzwitterionic layer on the surface of HD-CLPE(VE), which can serve as an extremely efficient antibiofouling layer. The number of bacterial adhered on the PMPC-grafted HD-CLPE(VE) surface was reduced by 100-fold or more by PMPC grafting, regardless of the biofilm-production characteristics of the strains. In contrast, vitamin E blending did not affect bacterial adhesion. Moreover, the number of planktonic bacteria did not differ significantly, regardless of PMPC grafting and vitamin E blending. In conclusion, the PMPC grafted HD-CLPE(VE) provided bacteriostatic effects associated with smooth, highly hydrophilic surfaces with a neutral electrostatic charge owing to the zwitterionic structure of the MPC unit. Thus, this modification may prove useful for the production of artificial hip joint replacement materials. STATEMENT OF SIGNIFICANCE: Our preliminary in vitro findings suggest that improved bacteriostatic performance of the HD-CLPE(VE) surface in orthopedic implants is possible via PMPC grafting. The results also indicate that surface modifications affect the anti-infection properties of the orthopedic implants and demonstrate that the application of a PMPC-grafted HD-CLPE(VE) surface may be a promising approach to extend the longevity and clinical outcomes of total hip arthroplasty. Further research is needed to evaluate the resistance to infection of PMPC grafted HD-CLPE(VE) in terms of the varieties of biofilm formation tests including fluid flow conditions and animal experiments, which may offer useful clues to the possible performance of these materials in vivo. PMID- 26050637 TI - Gray and white matter alterations in hereditary spastic paraplegia type SPG4 and clinical correlations. AB - Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous disorders with the hallmark of progressive spastic gait disturbance. We used advanced neuroimaging to identify brain regions involved in SPG4, the most common HSP genotype. Additionally, we analyzed correlations between imaging and clinical findings. We performed 3T MRI scans including isotropic high-resolution 3D T1, T2-FLAIR, and DTI sequences in 15 adult patients with genetically confirmed SPG4 and 15 age- and sex-matched healthy controls. Brain volume loss of gray and white matter was evaluated through voxel-based morphometry (VBM) for supra- and infratentorial regions separately. DTI maps of axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD), fractional anisotropy (FA), and measured anisotropy (MA1) were analyzed through tract-based special statistics (TBSS). VBM and TBSS revealed a widespread affection of gray and white matter in SPG4 including the corpus callosum, medio dorsal thalamus, parieto-occipital regions, upper brainstem, cerebellum, and corticospinal tract. Significant correlations with correlation coefficients r > 0.6 between clinical data and DTI findings could be demonstrated for disease duration and disease severity as assessed by the spastic paraplegia rating scale for the pontine crossing tract (AD) and the corpus callosum (RD and FA). Imaging also provided evidence that SPG4 underlies a primarily axonal rather than demyelinating damage in accordance with post-mortem data. DTI is an attractive tool to assess subclinical affection in SPG4. The correlation of imaging findings with disease duration and severity suggests AD, RD, and FA as potential progression markers in interventional studies. PMID- 26050639 TI - Frederic Andrews Gibbs (1903-1992). PMID- 26050638 TI - Ambiguous value of anti-ganglioside IgM autoantibodies in Guillain-Barre syndrome and its variants. AB - Anti-ganglioside autoantibodies of the IgG type are detected in a half of patients with Guillain-Barre syndrome (GBS), and their detection strongly supports the diagnosis of GBS. In contrast, anti-ganglioside IgM antibodies are also often detected in GBS patients, but it remains unclear whether IgM antibodies indicate a diagnosis of GBS. We identified four GBS patients (3.3%) who tested positive for IgM antibodies but negative for IgG antibodies among 122 patients with GBS and its variants. These four patients were all adolescents or young adults (age 13-22 years), experienced preceding gastrointestinal symptoms, and had serological and/or bacterial evidence of recent Campylobacter jejuni enteritis. Serum IgG reacted strongly with the lipo-oligosaccharide (LOS) of the C. jejuni isolates from these patients' stool specimens. Thin-layer chromatography with immunostaining showed that their serum IgG reacted with resorcinol-positive portion of LOS, suggesting that these patients had IgG autoantibodies against sialic acid-containing epitopes, probably unrecognized ganglioside-like structures on the bacterial LOS. We also examined anti ganglioside autoantibodies in 22 patients with C. jejuni enteritis without subsequent neurological disorders and detected IgM antibodies in seven (32%) patients. Our data indicate that anti-ganglioside IgM antibodies can be detected in C. jejuni enteritis without complication of GBS, and that the detection of anti-ganglioside IgM antibodies does not always support a diagnosis of GBS. IgG autoantibodies against unrecognized gangliosides might play a role in the development of disease in patients with GBS in whom only anti-ganglioside IgM antibodies are detected by routine clinical testing. PMID- 26050640 TI - Neuroprotective effect of epigallocatechin-3-gallate in a mouse model of chronic glaucoma. AB - Epigallocatechin-3-gallate (EGCG) is a powerful antioxidant with suggested neuroprotective action. This study investigated the protective effects of EGCG against retinal ganglion cells (RGCs) degeneration in an animal model of glaucoma. C57BL/6J mice (n=54) were divided randomly into four groups: normal control group (group A, n=12); EGCG control group with EGCG in drinking water (group B, n=12); microbeads control group with anterior chamber microbeads injection to induce elevation in intraocular pressure (IOP) plus normal drinking water (group C, n=18); and EGCG study group receiving an anterior chamber microbeads injection plus EGCG in drinking water (group D, n=12). Animals were treated orally with either vehicle or EGCG (50mg/kg*d). IOP was measured and animals were sacrificed at days 15 and 27. Neurons were retrograde-labeled by fluorogold and immnunolabeled by class III beta-tubulin to quantify RGCs in the retinal ganglion cell layer on flat mounts histologically and compared. All mice that received microbeads injections (groups C and D) developed IOP elevation higher than un-injected control mice. At days 15 and 27, progressive loss of RGCs was observed after microbeads injection in group C (P<0.01). In contrast, the fluorogold-labeled RGC density and class III beta-tubulin-positive RGC density were significantly higher in group D as compared to group C (P<0.01) but significantly lower than group B (P<0.01). These parameters did not differ significantly between groups A and B (P>0.05). The findings suggest the consumption of EGCG plays a neuroprotective role on RGCs in a mouse model of elevated IOP. PMID- 26050641 TI - An unprecedented base-promoted domino reaction of methyleneindolinones and N tosyloxycarbamates for the construction of bispirooxindoles and spiroaziridine oxindoles. AB - An efficient and unprecedented domino reaction of methyleneindolinones and N tosyloxycarbamates has been developed to afford structurally complex and diverse bispirooxindoles in excellent yields (up to 98%) and spiroaziridine oxindoles in moderate to good yields (55-91%). Moreover, this protocol could also provide the unsymmetrical bispirooxindoles and various fused spirocyclic pyrrolidines in excellent yields. PMID- 26050642 TI - Effect of epidermal growth factor (EGF) on the phosphorylation of mitogen activated protein kinase (MAPK) in the bovine oviduct in vitro: Alteration by heat stress. AB - Epidermal growth factor (EGF) has been shown to be involved in control of the oviductal microenvironment. To elucidate the potential mechanisms responsible for the detrimental effect of heat stress and to identify the relation with the endocrine status, the effects of EGF on the level of phosphorylated mitogen activated-protein kinase (MAPK) and proliferation of bovine oviductal epithelial cells (OECs) exposed to different cyclic ovarian steroidal environments (luteal phase (LP), follicular phase (FP) and postovulatory phase (PO)) and temperatures (mild heat stress (40 C) and severe heat stress (43 C)) were investigated. Western blot was performed to evaluate phosphorylated MAPK, while proliferation was analyzed by MTT assay. Stimulation of OECs with EGF alone or with EGF in the PO and FP environments significantly increased the amount of phosphorylated MAPK, with MAPK 44 phosphorylation being highest during exposure to PO conditions. These effects were not observed in the LP. Heat treatment completely blocked effects of EGF on phosphorylated MAPK. Additionally, severe heat stress led to a significantly lower basal level of phosphorylated MAPK. PD98059 (MAPK inhibitor) completely abolished EGF-stimulated MAPK phosphorylation and OECs proliferation. Overall the results indicate that EGF has the potential to increase the amount of phosphorylated MAPK in OECs and therefore could be involved in regulation of the bovine oviductal microenvironment. However, these regulatory mechanisms may be compromised in the presence of heat stress (high ambient temperature), leading to low fertility rates and impaired embryo survival. PMID- 26050644 TI - Rational design of host materials for phosphorescent organic light-emitting diodes by modifying the 1-position of carbazole. AB - A novel carbazole moiety with bromine at the 1-position of carbazole was synthesized and four carbazole compounds derived from the 1-position modified carbazole were developed as the host materials for phosphorescent organic light emitting diodes. The 1-position modified carbazole was coupled with another carbazole to prepare bicarbazole intermediates, which were substituted with 4,6 diphenyltriazine to yield four bicarbazole derivatives modified with the electron deficient diphenyltriazine unit. The triplet host materials showed high quantum efficiency above 20% and low driving voltage below 5.0 V at 1000 cd m(-2) in green phosphorescent organic light-emitting diodes. PMID- 26050643 TI - Was the media campaign that supported Australia's new pictorial cigarette warning labels and plain packaging policy associated with more attention to and talking about warning labels? AB - BACKGROUND: Population-level interventions can possibly enhance each other's effects when they are implemented simultaneously. When the plain packaging policy was implemented in Australia, pictorial health warning labels (HWLs) on cigarette packages were also updated and a national mass media campaign was aired. This study examined whether smokers who recalled the media campaign reported more attention to and talking about HWLs. METHODS: Longitudinal survey data was obtained among Australian adult smokers, aged 18 years and older, from an online consumer panel. One survey wave was conducted before (September 2012) and two waves were conducted after (January 2013 and May 2013) the interventions. The sample was replenished to maintain a sample size of 1000 participants at each wave. Generalized Estimating Equations analyses were performed. RESULTS: Compared to wave 1, attention to HWLs increased at wave 2 (b=0.32, SE=0.06, p<0.001), but not at wave 3 (b=0.10, SE=0.08, p=0.198). Talking about HWLs increased over time (IRR=1.82, 95% CI=1.58-2.09 and IRR=1.25, 95% CI=1.05-1.47, at wave 2 and wave 3 respectively). Campaign recall was significantly associated with more attention to HWLs (b=0.29, SE=0.05, p<0.001) and with more talking about HWLs (IRR=1.17, 95% CI=1.06-1.29) with similar effects across waves 2 and 3. CONCLUSIONS: Recall of the campaign was associated with more attention to and talking about HWLs. When adjusting for campaign recall, there was still an increasing trend in attention and talking. This suggests that the media campaign and the new packaging and labeling policies had independent and positive effects on attention to and talking about HWLs. PMID- 26050645 TI - A polymerizable supramolecular approach for the fabrication of patterned magnetic nanoparticles. AB - A simple and highly effective method for the fabrication of patterned magnetic nanoparticles was developed. The procedure utilizes a UV irradiation-wet etching calcination sequence starting with a magnetic nanoparticle embedded polymerizable diacetylene film. PMID- 26050646 TI - A Sweet Spot for Molecular Diagnostics: Coupling Isothermal Amplification and Strand Exchange Circuits to Glucometers. AB - Strand exchange nucleic acid circuitry can be used to transduce isothermal nucleic acid amplification products into signals that can be readable on an off the-shelf glucometer. Loop-mediated isothermal amplification (LAMP) is limited by the accumulation of non-specific products, but nucleic acid circuitry can be used to probe and distinguish specific amplicons. By combining this high temperature isothermal amplification method with a thermostable invertase, we can directly transduce Middle-East respiratory syndrome coronavirus and Zaire Ebolavirus templates into glucose signals, with a sensitivity as low as 20-100 copies/MUl, equating to atto-molar (or low zepto-mole). Virus from cell lysates and synthetic templates could be readily amplified and detected even in sputum or saliva. An OR gate that coordinately triggered on viral amplicons further guaranteed fail-safe virus detection. The method describes has potential for accelerating point-of care applications, in that biological samples could be applied to a transducer that would then directly interface with an off-the-shelf, approved medical device. PMID- 26050647 TI - Quercetin Enhances Chemosensitivity to Gemcitabine in Lung Cancer Cells by Inhibiting Heat Shock Protein 70 Expression. AB - Quercetin is a bioflavonoid known for antioxidation and antiproliferation activities. We demonstrated that quercetin inhibited cancer cell growth and sensitized cancer cells to gemcitabine treatment by promoting apoptosis via inhibiting heat shock protein 70 expression. Our results suggest that quercetin might have potential to increase sensitivity to chemotherapy and that heat shock protein 70 could be a new target for lung cancer treatment. BACKGROUND: Quercetin is a bioflavonoid with antiproliferative and proapoptotic activity in various cancer cells. However, little is known about the mechanism by which quercetin inhibits cancer growth or its potential role as a chemosensitizer in lung cancer cells. We investigated whether quercetin-induced inhibition of heat shock protein 70 (HSP70) is involved in its anticancer activity and whether it could modulate the responsiveness of lung cancer cells to chemotherapy. MATERIALS AND METHODS: Various concentrations of quercetin and gemcitabine, either alone or in combination, were applied to lung cancer cells (A549 and H460 cells). We evaluated cell viability with the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide salt assay, apoptotic activity by determining caspase 3 and caspase-9 activities, and HSP70 expression using Western blot analysis after treatment. RESULTS: Quercetin reduced cell viability and suppressed HSP70 expression in both cell lines dose-dependently. Adding a fixed quercetin dose enhanced gemcitabine-induced cell death, which was related to increased caspase-3 and caspase-9 activities. Combination treatment with quercetin and gemcitabine downregulated HSP70 expression more prominently than treatment with quercetin or gemcitabine alone. CONCLUSION: Quercetin-induced HSP70 inhibition was involved in growth inhibition and sensitization to chemotreatment in lung cancer cells. Quercetin might have potential as a chemosensitizer in lung cancer treatment. PMID- 26050648 TI - The leukemia-associated RUNX1/ETO oncoprotein confers a mutator phenotype. PMID- 26050649 TI - BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. AB - Although high brain and acute leukemia, cytoplasmic (BAALC) expression is a well characterized poor prognostic factor in acute myeloid leukemia (AML), neither the exact mechanisms by which BAALC drives leukemogenesis and drug resistance nor therapeutic approaches against BAALC-high AML have been properly elucidated. In this study, we found that BAALC induced cell-cycle progression of leukemia cells by sustaining extracellular signal-regulated kinase (ERK) activity through an interaction with a scaffold protein MEK kinase-1 (MEKK1), which inhibits the interaction between ERK and MAP kinase phosphatase 3 (MKP3/DUSP6). BAALC conferred chemoresistance in AML cells by upregulating ATP-binding cassette proteins in an ERK-dependent manner, which can be therapeutically targeted by MEK inhibitor. We also demonstrated that BAALC blocks ERK-mediated monocytic differentiation of AML cells by trapping Kruppel-like factor 4 (KLF4) in the cytoplasm and inhibiting its function in the nucleus. Consequently, MEK inhibition therapy synergizes with KLF4 induction and is highly effective against BAALC-high AML cells both in vitro and in vivo. Our data provide a molecular basis for the role of BAALC in regulating proliferation and differentiation of AML cells and highlight the unique dual function of BAALC as an attractive therapeutic target against BAALC-high AML. PMID- 26050650 TI - IKZF1 deletion is an independent prognostic marker in childhood B-cell precursor acute lymphoblastic leukemia, and distinguishes patients benefiting from pulses during maintenance therapy: results of the EORTC Children's Leukemia Group study 58951. AB - The added value of IKZF1 gene deletion (IKZF1(del)) as a stratifying criterion in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is still debated. We performed a comprehensive analysis of the impact of IKZF1(del) in a large cohort of children (n=1223) with BCR-ABL1-negative BCP-ALL treated in the EORTC-CLG trial 58951. Patients with IKZF1(del) had a lower 8-year event-free survival (EFS, 67.7% versus 86.5%; hazard ratio (HR)=2.41; 95% confidence interval (CI)=1.75-3.32; P<0.001). Importantly, despite association with high-risk features such as high minimal residual disease, IKZF1(del) remained significantly predictive in multivariate analyses. Analysis by genetic subtype showed that IKZF1(del) increased risk only in the high hyperdiploid ALLs (HR=2.57; 95% CI=1.19-5.55; P=0.013) and in 'B-other' ALLs, that is, lacking classifying genetic lesions (HR=2.22; 95% CI=1.45-3.39; P<0.001), the latter having then a dramatically low 8-year EFS (56.4; 95% CI=44.6-66.7). Among IKZF1(del)-positive patients randomized for vincristine-steroid pulses during maintenance, those receiving pulses had a significantly higher 8-year EFS (93.3; 95% CI=61.3-99.0 versus 42.1; 95% CI=20.4-62.5). Thus, IKZF1(del) retains independent prognostic significance in the context of current risk-adapted protocols, and is associated with a dismal outcome in 'B-other' ALL. Addition of vincristine-steroid pulses during maintenance may specifically benefit to IKZF1(del) patients in preventing relapses. PMID- 26050651 TI - Characterization of the 4,6-alpha-glucanotransferase GTFB enzyme of Lactobacillus reuteri 121 isolated from inclusion bodies. AB - BACKGROUND: The GTFB enzyme of the probiotic bacterium Lactobacillus reuteri 121 is a 4,6-alpha-glucanotransferase of glycoside hydrolase family 70 (GH70; http://www.cazy.org ). Contrary to the glucansucrases in GH70, GTFB is unable to use sucrose as substrate, but instead converts malto-oligosaccharides and starch into isomalto-/malto- polymers that may find application as prebiotics and dietary fibers. The GTFB enzyme expresses well in Escherichia coli BL21 Star (DE3), but mostly accumulates in inclusion bodies (IBs) which generally contain wrongly folded protein and inactive enzyme. METHODS: Denaturation followed by refolding, as well as ncIB preparation were used for isolation of active GTFB protein from inclusion bodies. Soluble, refolded and ncIB GTFB were compared using activity assays, secondary structure analysis by FT-IR, and product analyses by NMR, HPAEC and SEC. RESULTS: Expression of GTFB in E. coli yielded > 100 mg/l relatively pure and active but mostly insoluble GTFB protein in IBs, regardless of the expression conditions used. Following denaturing, refolding of GTFB protein was most efficient in double distilled H2O. Also, GTFB ncIBs were active, with approx. 10 % of hydrolysis activity compared to the soluble protein. When expressed as units of activity obtained per liter E. coli culture, the total amount of ncIB GTFB expressed possessed around 180 % hydrolysis activity and 100 % transferase activity compared to the amount of soluble GTFB enzyme obtained from one liter culture. The product profiles obtained for the three GTFB enzyme preparations were similar when analyzed by HPAEC and NMR. SEC investigation also showed that these 3 enzyme preparations yielded products with similar size distributions. FT-IR analysis revealed extended beta-sheet formation in ncIB GTFB providing an explanation at the molecular level for reduced GTFB activity in ncIBs. The thermostability of ncIB GTFB was relatively high compared to the soluble and refolded GTFB. CONCLUSION: In view of their relatively high yield, activity and high thermostability, both refolded and ncIB GTFB derived from IBs in E. coli may find industrial application in the synthesis of modified starches. PMID- 26050652 TI - Molecular Mechanisms of Several Novel Dipeptides with Angiotensin-I-converting Enzyme Inhibitory Activity from In-silico Screening of Silkworm Pupae Protein. AB - An in silico screening method for novel dipeptides from a dipeptide training set was performed. A 3D pharmacophore model with three H-bond acceptor projections (Acc2), and one H-bond donor projection (Don2) was obtained. To validate the pharmacophore model, a test set containing 10 reported dipeptides was screened and all were found to be bioactive. Eleven novel dipeptides (IF, GD, DA, TE, TA, ES, SS, ST, SD, QD, QE) from the silkworm pupae protein peptide database were predicted to have ACE inhibitory bioactivity. The interaction mechanisms of the dipeptides with the ACE active pocket were elucidated by molecule docking, and besides involving interaction bonds, the interaction force equipoise of the peptides was also an important factor in their bioactivity. PMID- 26050653 TI - Pharmacology and Clinical Effect of Platonin, a Cyanine Photosensitizing Dye: Potential Molecular Targets. AB - Platonin, a photosensitizing dye, is known to possess antioxidant and anti inflammatory activity. Platonin has been used to treat trauma, ulcers and some acute inflammations and it also reported to improve blood circulation and reduce mortality in endotoxin-induced rat models. Our previous studies established that platonin suppresses the lipopolysaccharides (LPS)-induced inflammatory cytokines, including interleukin-1beta (IL-1beta-+), IL-6, tumor necrosis factor-alpha (TNF alpha), and inducible nitric oxide synthase (iNOS). Nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) transcription factors are reported to be essential in mediating the endotoxin-induced production of inflammatory molecules. In vivo studies from our groups revealed that platonin has potential effects on inhibiting pyrogen release, tissue damage and ischemia during heatstroke, ischemia reperfusion injury in lungs and also improve the survival of skin allografts in rats. Clinically, this compound has been proven to cure juvenile rheumatoid arthritis (JRA) and polyarteritis nodosa (PN). In this review, we summarize the pharmacological and clinical effects of platonin via describing the potential molecular mechanism of regulation of inflammatory molecules of mitogen activated protein kinases (MAPKs), including extracellular regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 MAPK and also NF-kB activation. Moreover, this paper discusses the signaling pathways expedited by NF-kB, AP-1, MAPKs and NO/NOS, these all have been reflected in inflammatory processes, and could be the encouraging molecular targets for the design of pharmaceutical drugs targeting antiinflammatory therapy. PMID- 26050654 TI - The potential application of PET/MRI to clinical Nuclear Medicine. PMID- 26050655 TI - PET/MRI and PET/CT in Lung Lesions and Thoracic Malignancies. AB - More than one decade ago, introduction of integrated PET/CT scanners changed oncologic imaging and oncologic patient management profoundly. With these systems, the metabolic information acquired by PET can be anatomically localized even to small structures such as small primary tumors, lymph nodes, and soft tissue masses owing to the high-resolution multidetector CT scanners. This has made PET/CT a most reliable method for tumor detection, characterization, staging, and response monitoring. The importance of an integrated functional and morphologic approach to better understand the biology of oncologic disease and to improve therapy planning is underlined by the increasing number of PET/CT systems worldwide, leading to an increasing number of scientific publications in the field. The paradigmatic indication of integrated PET/CT is staging of patients with lung cancer, as PET/CT allows for precise pretherapeutic staging and also posttreatment restaging according to the TNM criteria. The growing numbers of targeted therapy strategies in the fields of surgery, chemotherapy, and radiation therapy, which are adapted to dedicated tumor stages, require the exact classifications of each patient's tumor stage. In this context, whole-body examinations using integrated (18)F-FDG-PET/CT have been shown to reduce the side effects of futile invasive procedures and reduce additional costly staging procedures. In this review article, the diagnostic and therapeutic effects of PET/CT examinations are highlighted and compared with some competitive techniques such as scintigraphy, MRI, and, where possible, integrated PET/MRI. PMID- 26050656 TI - PET/MRI in the Upper Abdomen. AB - PET/CT and contrast-enhanced CT have been considered the standard imaging modalities in the diagnosis of upper abdominal malignancies. PET/CT can be challenging in soft tissue delineation, especially in the upper abdomen. The recent development of PET/MRI for clinical use has shown promising results, with MRI providing superior soft tissue contrast and PET providing biochemical and metabolic information. Combined PET/MRI may allow simultaneous benefit in the assessment of patients in a single session, improving patient journey, lesion detectability, diagnostic performance, and prognostic information. PET/MRI also provides the ability for tissue characterization and reduces radiation exposure. The most powerful driver is PET, and the newer PET radiopharmaceuticals with the addition of dynamic contrast-enhanced MRI, diffusion-weighted imaging, and MR spectroscopy may increase the sensitivity and specificity of disease recognition and have clinical effect. In this article, we review the advantages and limitations of PET/MRI in upper abdominal malignancies. PMID- 26050657 TI - PET/MRI Evaluation of Gynecologic Malignancies and Prostate Cancer. AB - PET combined with cross-sectional anatomical imaging is an essential part of workup for most malignancies, in which CT or MRI provides anatomical context to the functional information from PET. Hybrid imaging with PET/CT has been extensively researched and implemented clinically in the evaluation and management of patients with gynecologic malignancies. Lately, integrated PET/MR scanners have become available. This new technology is fast gaining a role in clinical applications in the fields of oncology, neurology, and cardiology. MRI provides excellent soft tissue contrast especially in the pelvis and has been proven very useful for imaging prostate and female genital pathologies. The ability of PET to provide accurate functional imaging data with high sensitivity combined with the strength of MRI to provide accurate depiction of anatomy with high contrast and spatial resolution renders combined PET/MRI a desirable method for evaluation of gynecologic malignancies and other pelvic cancers such as prostate cancer. The goal of this article is to provide an overview of the published literature using PET/MRI in gynecologic and prostate cancers. PMID- 26050658 TI - PET/MR in Breast Cancer. AB - Breast cancer is an international public health concern in which an optimal treatment plan requires a precise staging. Both MRI and PET imaging techniques have made significant progress in the last decades with constant improvements that made both modalities clinically relevant in several stages of breast cancer management and follow-up. On one hand, specific breast MRI permits high diagnostic accuracy for local tumor staging, and whole-body MRI can also be of great use in distant staging, eventually accompanied by organ-specific MRI sequences. Moreover, many different MRI sequences can be performed, including functional MRI, letting us foresee important improvements in breast cancer characterization in the future. On the contrary, (18)F-FDG-PET has a high diagnostic performance for the detection of distant metastases, and several other tracers currently under development may profoundly affect breast cancer management in the future with better determination of different types of breast cancers allowing personalized treatments. As a consequence PET/MR is a promising emerging technology, and it is foreseeable that in cases where both PET and MRI data are needed, a hybrid acquisition is justified when available. However, at this stage of deployment of such hybrid scanners in a clinical setting, more data are needed to demonstrate their added value beyond just patient comfort of having to undergo a single examination instead of two, and the higher confidence of diagnostic interpretation of these co-registered images. Optimized imaging protocols are still being developed and are prone to provide more efficient hybrid protocols with a potential improvement in diagnostic accuracy. More convincing studies with larger number of patients as well as cost-effectiveness studies are needed. This article provides insights into the current state-of-the art of PET/MR in patients with breast cancer and gives an outlook on future developments of both imaging techniques and potential applications in the future. PMID- 26050659 TI - PET/CT, MR, and PET/MR in Lymphoma and Melanoma. AB - With the introduction of hybrid imaging technologies such as PET/CT and recently PET/MRI, staging and therapy-response monitoring have evolved. PET/CT has been shown to be of value for routine staging of FDG-avid lymphomas before as well as at the end of treatment. For interim staging, trials are ongoing to evaluate the use of PET/CT. In melanoma, PET/CT can be recommended for stages III and IV diseases for initial staging and before surgery. Studies investigating the use of PET/CT for early therapy response are promising. The role of PET/MR in lymphoma and melanoma imaging has to be defined because no larger studies exist so far. There may be an application of PET/MR in research especially for tumor characterization and therapy response. Furthermore, the potential role of non-FDG tracers is elucidated regarding the assessment of treatment response in targeted drug regimens. PMID- 26050660 TI - Workflow in Simultaneous PET/MRI. AB - The advent of simultaneous PET/MRI brought a large amount of possibilities in research and clinical applications into hybrid imaging. Unlike in PET/CT protocols, the MR component provides an almost unlimited number of pulse sequences and possibilities of different protocols in PET/MRI. Nevertheless, there is an imperative to reduce excessive imaging protocols to realistic clinical practice imaging acquisition. The design of a concise and indication adapted protocol that provides an efficient workflow in a clinical reality is necessary to transform PET/MRI to a cost-effective imaging modality in addition to PET/CT. The aim of the current article is to point out the main considerations regarding workflow, imaging protocols, and image analysis in simultaneous PET/MRI system in oncology and share our thoughts and experience in acquisition optimization compared with the current literature. PMID- 26050662 TI - Visible Light Photoinitiated Metal-Free Living Cationic Polymerization of 4 Methoxystyrene. AB - Metal-free, visible light-initiated, living cationic polymerization of 4 methoxystyrene using 2,4,6-tri(p-tolyl)pyrylium tetrafluoroborate and methanol is demonstrated. Molecular weight and dispersity are controlled by the concentration of methanol. Initial mechanistic analysis suggests that methanol likely serves to regulate propagation of the cation chain end via reversible chain transfer in a manner analogous to reversible addition-fragmentation chain transfer polymerization. PMID- 26050661 TI - Single-molecule modeling of mRNA degradation by miRNA: Lessons from data. AB - Recent experimental results on the effect of miRNA on the decay of its target mRNA have been analyzed against a previously hypothesized single molecule degradation pathway. According to that hypothesis, the silencing complex (miRISC) first interacts with its target mRNA and then recruits the protein complexes associated with NOT1 and PAN3 to trigger deadenylation (and subsequent degradation) of the target mRNA. Our analysis of the experimental decay patterns allowed us to refine the structure of the degradation pathways at the single molecule level. Surprisingly, we found that if the previously hypothesized network was correct, only about 7% of the target mRNA would be regulated by the miRNA mechanism, which is inconsistent with the available knowledge. Based on systematic data analysis, we propose the alternative hypothesis that NOT1 interacts with miRISC before binding to the target mRNA. Moreover, we show that when miRISC binds alone to the target mRNA, the mRNA is degraded more slowly, probably through a deadenylation-independent pathway. The new biochemical pathway proposed here both fits the data and paves the way for new experimental work to identify new interactions. PMID- 26050663 TI - [Life-threatening airway obstruction accompanied by vocal cord paralysis due to indwelling nasogastric tube in malnourished elderly patients: a report of four cases]. AB - We report 4 cases of elderly patients with abrupt onset of serious airway obstruction that is presumed to be due to indwelling nasogastric tube. 2 cases are patients of cerebral infarction and 2 cases are patients of Parkinson disease. The average number of days until NGTS is 17.8 days. In all cases, fiber optic examination revealed complete loss of adduction in both vocal cords. Infection in the posterior cricoid region caused by ulcerative lesions at the upper end of the esophagus has been implicated as a pathophysiological mechanism of this syndrome, but it was not possible to confirm in the 4 cases. Because it is difficult to exactly diagnose with NGTS in clinical practice, there is a need to consider the inducing factor and response. Body mass index is very low in each of the 4 cases, ranging from 14.2 to 18.0, implying a severely malnourished or immunocompromised state, and may represent a high risk factor for this syndrome. Whenever this life-threatening syndrome is suspected, direct vocal cord examination and removal of the tube are recommended. In addition, the clinicians should not hesitate about doing intubation or tracheotomy in emergency. PMID- 26050664 TI - [Complex partial status epilepticus with recurrent episodes of complex visual hallucinations: study by using 123I-IMP-SPECT, brain MRI and EEG]. AB - We report a 72-year-old woman with complex partial status epilepticus who showed recurrent episodes of complex visual hallucinations (CVH). Brain diffusion weighted magnetic resonance images revealed gyriform cortical hyperintensity in the right parietal, occipital and temporal lobes, and brain magnetic resonance angiograhy revealed a hyperintensity in the right dilated middle cerebral artery during ictal period. Ictal N-isopropyl-p-(iodine-123)-iodoamphetamine single photon emission computed tomography (123I-IMP-SPECT) with three-dimensional stereotactic surface projection (3D-SSP) 14 days after the onset of the first CVH revealed hyperperfusion in the right latero-inferior occipito-temporal region with relation to motion. CVH spontaneously subsided 17 days after the onset of the first CVH. CVH recurred one year after the first CVH. Ictal 123I-IMP-SPECT with 3D-SSP revealed marked hyperperfusion in the right lateral parietal region probably with relation to face and figure hallucinations. Ictal scalp EEGs revealed rhythmic polyspikes at 12 Hz with high amplitude (100-200 MUV) in bilateral posterior occipital and temporal region with the right side dominance for 20 seconds and more in several occasions. Interictal 123I-IMP-SPECT with 3D SSP 28 days after recurrence of CVH revealed marked hypoperfusion in the right lateral parietal region, and recovery of hypoperfusion in the right latero inferior occipito-temporal region. These findings suggest that ictal CVH might be induced by the spread of epileptic discharges from the right parieto-occipito temporal region with the old brain contusion (epileptogenic region) to the right latero-inferior occipito-temporal region and the right lateral parietal region (symptomatogenic regions). PMID- 26050665 TI - [A case of limb-girdle muscular dystrophy 2M diagnosed by the occurence of dilated cardiomyopathy]. AB - We report a 24-year-old Japanese man initially suspected to have Becker's muscular dystrophy at the age of 6 years, because of a high level of creatine kinase in serum, though he discontinued visiting the hospital. At the age of 23, he was admitted to the hospital for severe dilated cardiomyopathy, and subsequently diagnosed with limb-girdle muscular dystrophy2M (LGMD2M) based on muscle biopsy and gene analysis. It was recently reported that some patients with fukutinopathy develop LGMD. Most of the cases reported in Japan showed mild skeletal muscle involvement despite serious cardiomyopathy, which may sometimes the initial symptom of the disease. Since muscular dystrophy patients can develop severe cardiac failure, irrespective of the severity of skeletal muscle involvement, regular examinations of cardiopulmonary function are necessary. PMID- 26050666 TI - Direct Growth of Freestanding ZnO Tetrapod Networks for Multifunctional Applications in Photocatalysis, UV Photodetection, and Gas Sensing. AB - Growth of freestanding nano- and microstructures with complex morphologies is a highly desired aspect for real applications of nanoscale materials in various technologies. Zinc oxide tetrapods (ZnO-T), which exhibit three-dimensional (3D) shapes, are of major importance from a technological applications point of view, and thus efficient techniques for growth of different varieties of tetrapod-based networks are demanded. Here, we demonstrate the versatile and single-step synthesis of ZnO-T with different arm morphologies by a simple flame transport synthesis (FTS) approach, forming a network. Morphological evolutions and structural intactness of these tetrapods have been investigated in detail by scanning electron microscopy, X-ray diffraction, and micro-Raman measurements. For a deeper understanding of the crystallinity, detailed high-resolution transmission electron microscopic studies on a typical ZnO tetrapod structure are presented. The involved growth mechanism for ZnO tetrapods with various arm morphologies is discussed with respect to variations in experimental conditions. These ZnO-T have been utilized for photocatalytic degradation and nanosensing applications. The photocatalytic activities of these ZnO-T with different arm morphologies forming networks have been investigated through the photocatalytic decolorization of a methylene blue (MB) solution under UV light illumination at ambient temperature. The results show that these ZnO-T exhibit strong photocatalytic activities against MB and its complete degradation can be achieved in very short time. In another application, a prototype of nanoelectronic sensing device has been built from these ZnO-T interconnected networks and accordingly utilized for UV detection and H2 gas sensing. The fabricated device structures showed excellent sensing behaviors for promising practical applications. The involved sensing mechanisms with respect to UV photons and H2 gas are discussed in detail. We consider that such multifunctional nanodevices based on ZnO tetrapod interconnected networks will be of interest for various advanced applications. PMID- 26050667 TI - Human Brown Adipose Tissue: What We Have Learned So Far. AB - Brown adipose tissue (BAT) is a unique tissue that is able to convert chemical energy directly into heat when activated by the sympathetic nervous system. While initially believed to be of relevance only in human newborns and infants, research during recent years provided unequivocal evidence of active BAT in human adults. Moreover, it has become clear that BAT plays an important role in insulin sensitivity in rodents and humans. This has opened the possibility for exciting new therapies for obesity and diabetes. This review summarizes the current state of research with a special focus on recent advances regarding BAT and insulin resistance in human adults. Additionally, we provide an outlook on possible future therapeutic uses of BAT in the treatment of obesity and diabetes. PMID- 26050668 TI - Exercise Effects on White Adipose Tissue: Beiging and Metabolic Adaptations. AB - Regular physical activity and exercise training have long been known to cause adaptations to white adipose tissue (WAT), including decreases in cell size and lipid content and increases in mitochondrial proteins. In this article, we discuss recent studies that have investigated the effects of exercise training on mitochondrial function, the "beiging" of WAT, regulation of adipokines, metabolic effects of trained adipose tissue on systemic metabolism, and depot-specific responses to exercise training. The major WAT depots in the body are found in the visceral cavity (vWAT) and subcutaneously (scWAT). In rodent models, exercise training increases mitochondrial biogenesis and activity in both these adipose tissue depots. Exercise training also increases expression of the brown adipocyte marker uncoupling protein 1 (UCP1) in both adipose tissue depots, although these effects are much more pronounced in scWAT. Consistent with the increase in UCP1, exercise training increases the presence of brown-like adipocytes in scWAT, also known as browning or beiging. Training results in changes in the gene expression of thousands of scWAT genes and an altered adipokine profile in both scWAT and vWAT. Transplantation of trained scWAT in sedentary recipient mice results in striking improvements in skeletal muscle glucose uptake and whole-body metabolic homeostasis. Human and rodent exercise studies have indicated that exercise training can alter circulating adipokine concentration as well as adipokine expression in adipose tissue. Thus, the profound changes to WAT in response to exercise training may be part of the mechanism by which exercise improves whole body metabolic health. PMID- 26050669 TI - Transcriptional Regulatory Circuits Controlling Brown Fat Development and Activation. AB - Brown and beige adipose tissue is specialized for heat production and can be activated to reduce obesity and metabolic dysfunction in animals. Recent studies also have indicated that human brown fat activity levels correlate with leanness. This has revitalized interest in brown fat biology and has driven the discovery of many new regulators of brown fat development and function. This review summarizes recent advances in our understanding of the transcriptional mechanisms that control brown and beige fat cell development. PMID- 26050670 TI - Brown and Beige Fat: Molecular Parts of a Thermogenic Machine. AB - The epidemic of obesity and type 2 diabetes has increased interest in pathways that affect energy balance in mammalian systems. Brown fat, in all of its dimensions, can increase energy expenditure through the dissipation of chemical energy in the form of heat, using mitochondrial uncoupling and perhaps other pathways. We discuss here some of the thermodynamic and cellular aspects of recent progress in brown fat research. This includes studies of developmental lineages of UCP1(+) adipocytes, including the discovery of beige fat cells, a new thermogenic cell type. We also discuss the physiology and transcriptional control of brown and beige cells in rodents and the state of current knowledge about human brown fat. PMID- 26050672 TI - Levels of infection and seasonal occurrence of Gyrodactylus alviga (Monogenea: Gyrodactylidae) on the whiting Merlangius merlangus off the Turkish and Russian coasts of the Black Sea. AB - Gyrodactylus alviga is a generalist species reported in many Black Sea fish species, but whiting is known to be its main host. It is the only monogenean parasite that has been reported so far on the skin, fins and gills of whiting Merlangius merlangus in the Black Sea. A total of 690 fish from Turkey and 423 fish from Russia were examined to detect parasites. Infection indices of prevalence, mean intensity and mean abundance values were calculated for length classes and sex of fish, as well as for the seasons. There is a gradual increase in infection indices in relation with increasing host length classes and there are higher infection indices on female fish. Furthermore, despite lower prevalence indices in spring and winter, higher parasite intensity values were determined in these seasons. It is concluded that larger fish provided more space and food for G. alviga, and female fish were more parasitized as they were more active in searching for food, which enables the parasite to switch between hosts. In addition, winter and spring were more appropriate for reproduction of G. alviga. PMID- 26050673 TI - Therapeutic affect reduction, emotion regulation, and emotional memory reconsolidation: A neuroscientific quandary. AB - Lane et al. emphasize the role of emotional arousal as a precipitating factor for successful psychotherapy. However, as therapy ensues, the arousal diminishes. How can the unfolding therapeutic process generate long-term memories for reconsolidated emotional material without the benefit of arousal? Studies investigating memory for emotionally regulated material provide some clues regarding the neural pathways that may underlie therapy-based memory reconsolidation. PMID- 26050671 TI - Expression and functional characterisation of System L amino acid transporters in the human term placenta. AB - BACKGROUND: System L transporters LAT1 (SLC7A5) and LAT2 (SLC7A8) mediate the uptake of large, neutral amino acids in the human placenta. Many System L substrates are essential amino acids, thus representing crucial nutrients for the growing fetus. Both LAT isoforms are expressed in the human placenta, but the relative contribution of LAT1 and LAT2 to placental System L transport and their subcellular localisation are not well established. Moreover, the influence of maternal body mass index (BMI) on placental System L amino acid transport is poorly understood. Therefore the aims of this study were to determine: i) the relative contribution of the LAT isoforms to System L transport activity in primary human trophoblast (PHT) cells isolated from term placenta; ii) the subcellular localisation of LAT transporters in human placenta; and iii) placental expression and activity of System L transporters in response to maternal overweight/obesity. METHODS: System L mediated leucine uptake was measured in PHT cells after treatment with si-RNA targeting LAT1 and/or LAT2. The localisation of LAT isoforms was studied in isolated microvillous plasma membranes (MVM) and basal membranes (BM) by Western blot analysis. Results were confirmed by immunohistochemistry in sections of human term placenta. Expression and activity System L transporters was measured in isolated MVM from women with varying pre-pregnancy BMI. RESULTS: Both LAT1 and LAT2 isoforms contribute to System L transport activity in primary trophoblast cells from human term placenta. LAT1 and LAT2 transporters are highly expressed in the MVM of the syncytiotrophoblast layer at term. LAT2 is also localised in the basal membrane and in endothelial cells lining the fetal capillaries. Measurements in isolated MVM vesicles indicate that System L transporter expression and activity is not influenced by maternal BMI. CONCLUSIONS: LAT1 and LAT2 are present and functional in the syncytiotrophoblast MVM, whereas LAT2 is also expressed in the BM and in the fetal capillary endothelium. In contrast to placental System A and beta amino acid transporters, MVM System L activity is unaffected by maternal overweight/obesity. PMID- 26050674 TI - Memory reconsolidation, repeating, and working through: Science and culture in psychotherapeutic research and practice. AB - Hypothesizing that an effective common feature in divergent forms of psychotherapy is a process of memory reconsolidation integrating new emotional experiences, Lane et al. usefully shift the focus away from established and/or specialized techniques to deeper questions about the underlying principles of psychotherapeutic change. More research attention to cultural factors influencing the definition and treatment of psychopathology is also needed. PMID- 26050675 TI - Memory reconsolidation and psychotherapeutic process. AB - Lane et al. propose a heuristic model in which distinct, and seemingly irreconcilable, therapies can coexist. Authors postulate that memory reconsolidation is a key common neurobiological process mediating the therapeutic effects. This conceptualization raises a set of important questions regarding neuroscience and translational aspects of fear memory reconsolidation. We discuss the implications of the target article's memory reconsolidation model in the development of more effective interventions, and in the identification of less effective, or potentially harmful approaches, as well as concepts of contextualization, optimal arousal, and combined therapy. PMID- 26050676 TI - Reconsolidation or re-association? AB - The target article argues memory reconsolidation demonstrates how therapeutic change occurs, grounding psychotherapy in brain science. However, consolidation has become an ambiguous term, a disadvantage applying also to its derivative - reconsolidation. The concept of re-association (involving active association between memories during rapid eye movement [REM] dreams followed by indexation and network junction instantiation during non-rapid eye movement [NREM] periods) brings greater specificity and explanatory power to the possible brain correlates of therapeutic change. PMID- 26050677 TI - The relevance of maintaining and worsening processes in psychopathology. AB - The states called "psychopathology" are very diverse, but Lane et al.'s single process explanation does little to account for this diversity. Moreover, some other crucial phenomena of psychopathology do not fit this theory: the role of negative evaluations of conscious emotions, and the role of emotions without physiological correlates. And it does not consider the processes maintaining disorders. PMID- 26050678 TI - Social-psychological evidence for the effective updating of implicit attitudes. AB - Recent findings in social psychology show how implicit affective responses can be changed, leading to strong, fast, and durable updating. This work demonstrates that new information viewed as diagnostic or which prompts reinterpretations of previous learning produces fast revision, suggesting two factors that might be leveraged in clinical settings. Reconsolidation provides a plausible route for making such reasoning possible. PMID- 26050679 TI - Top-down versus bottom-up perspectives on clinically significant memory reconsolidation. AB - Lane et al. are right: Troublesome memories can be therapeutically recontextualized. Reconsolidation of negative/traumatic memories within the context of positive/prosocial affects can facilitate diverse psychotherapies. Although neural mechanisms remain poorly understood, we discuss how nonlinear dynamics of various positive affects, heavily controlled by primal subcortical networks, may be critical for optimal benefits. PMID- 26050680 TI - Trade-offs between the accuracy and integrity of autobiographical narrative in memory reconsolidation. AB - Lane et al. propose an integrative model for the reconsolidation of traces in their timely and impressive article. This commentary draws attention to trade offs between accuracy and self-narrative integrity in the model. The trade-offs concern the sense of agency in memory and its role in both implicit and explicit memory reconsolidation, rather than balances concerning degrees of emotional arousal. PMID- 26050681 TI - Emotion regulation as a main mechanism of change in psychotherapy. AB - A model that suggests reconsolidation of traumatic memories as a mechanism of change in therapy is important, but problematic to generalize to disorders other than post-traumatic and acute-stress disorder. We suggest that a more plausible mechanism of change in psychotherapy is acquisition of adaptive emotion regulation strategies. PMID- 26050682 TI - How do we remember traumatic events? Exploring the role of neuromodulation. AB - The seemingly puzzling datum that behavior decreases after punishing stimulation while individuals are still able to remember traumatic episodes is discussed in relation to dopaminergic and noradrenergic neuromodulation. The described mechanisms may contribute to an understanding of how occurrences of learning reconsolidation yield different outcomes across intra- and extra-therapeutic settings. PMID- 26050683 TI - Psychopathology arises from intertemporal bargaining as well as from emotional trauma. AB - The role of emotional trauma in psychopathology is limited. One additional mechanism is predictable from hyperbolic discounting: When a person uses willpower to control urges each success or failure takes on extra significance through recursive self-prediction, potentially motivating several constricting defense mechanisms. The need for eliciting emotion in psychotherapy is as the authors say it is, but their hypothesis about reconsolidation of memories adds no explanatory power. PMID- 26050684 TI - Memory reconsolidation keeps track of emotional changes, but what will explain the actual "processing"? AB - We question memory reconsolidation and emotional arousal as sufficient determinants of therapeutic change. Generating new feelings and meanings must be contrasted with activating and stabilizing the evolving memories that reflect those novel experiences. Some therapeutic changes are not attributable to a memory model alone. "Emotional processing" is also needed and is often an undeclared form of complex executive problem solving. PMID- 26050685 TI - Let's be skeptical about reconsolidation and emotional arousal in therapy. AB - Lane et al. imply hypotheses that are questionable: that emotional arousal is a cause of positive change and reconsolidation research can be applied to therapy to alter memory. Given the history of problematic attempts to incorporate memory distortion or high emotional arousal into therapeutic techniques, both of which heralded premature optimism and hubris, I urge open-minded skepticism. PMID- 26050686 TI - Multiple traces or Fuzzy Traces? Converging evidence for applications of modern cognitive theory to psychotherapy. AB - Neurobiologically informed integration of research on memory, emotion, and behavior change in psychotherapy is needed, which Lane at al. advance. Memory reconsolidation that incorporates new emotional experience plays an important role in therapeutic change, converging with evidence for Fuzzy Trace Theory. Applications of Fuzzy Trace Theory to Cognitive Behavioral Therapy (CBT) for youth at risk for psychosis, and to other aspects of behavior change, are discussed. PMID- 26050687 TI - How does psychotherapy work? A case study in multilevel explanation. AB - Multilevel explanations abound in psychiatry. However, formulating useful such explanations is difficult or (some argue) impossible. I point to several ways in which Lane et al. successfully use multilevel explanations to advance understanding of psychotherapeutic effectiveness. I argue that the usefulness of an explanation depends largely on one's purpose, and conclude that this point has been inadequately recognised in psychiatry. PMID- 26050688 TI - Reconsolidation: Turning consciousness into memory. AB - The purpose of learning is not to maintain records but to generate predictions. Successful predictions remain implicit; only prediction errors ("surprises") attract consciousness. This is what Freud had in mind when he declared that "consciousness arises instead of a memory-trace." The aim of reconsolidation, and of psychotherapy, is to improve predictions about how to meet our needs in the world. PMID- 26050689 TI - Disruption of reconsolidation processes is a balancing act - can it really account for change in psychotherapy? AB - Lane et al. argue that any psychotherapeutic intervention at its core acts on reactivated memories via the process of reconsolidation which leads to modified memory traces. From our perspective, this model (1) only explains a small subsegment of psychotherapeutic mechanisms and (2) ignores the difficulties of generating reliable experimental conditions that allow interference with reconsolidation processes and - if successful - their transient nature. PMID- 26050690 TI - Deconstructing the process of change in cognitive behavioral therapy: An alternative approach focusing on the episodic retrieval mode. AB - Lane et al. view the process of memory reconsolidation as a main ingredient of psychotherapeutic change. They ascertain that in cognitive behavioral therapy (CBT) high priority is given to the "semantic structure." We argue that memory related mechanisms of change in CBT are more nuanced than the target article presents. Furthermore, we propose to partially shift the focus from the process of reconsolidation to the retrieval operations. PMID- 26050691 TI - Focus on emotion as a catalyst of memory updating during reconsolidation. AB - We share the idea of Lane et al. that successful psychotherapy exerts its effects through memory reconsolidation. To support it, we add further evidence that a behavioral interference may trigger memory update during reconsolidation. Furthermore, we propose that - in addition to replacing maladaptive emotions - new emotions experienced in the therapeutic process catalyze reconsolidation of the updated memory structure. PMID- 26050692 TI - Mental model construction, not just memory, is a central component of cognitive change in psychotherapy. AB - We challenge the idea that a cognitive perspective on therapeutic change concerns only memory processes. We argue that inclusion of impairments in more generative cognitive processes is necessary for complete understanding of cases such as depression. In such cases what is identified in the target article as an "integrative memory structure" is crucially supported by processes of mental model construction. PMID- 26050693 TI - Memory reconsolidation and self-reorganization. AB - Lane et al. propose that memory reconsolidation through new emotional experiences is an integrative pathway to change in psychotherapy. My commentary suggests that memory reconsolidation is an element within self-reorganization. Given the focal nature of the self to every aspect of psychotherapy, it is a more useful construct on which to build integrative models than memory reconsolidation. PMID- 26050694 TI - The importance of the rites of passage in assigning semantic structures to autobiographical memory. AB - As cultural anthropologists, we noticed an unexpected and interesting convergence of the therapeutic practices suggested in the target article and the rites of passage occurring across multiple societies, as individuals make the transition from one significant age or status to another. PMID- 26050695 TI - Reconsolidation versus retrieval competition: Rival hypotheses to explain memory change in psychotherapy. AB - I suggest it is premature to assume memory reconsolidation provides a unifying model of psychotherapeutic change given our current state of knowledge, and that other basic memory mechanisms, also supported by neuroscience, have a stronger claim at present. In particular, I propose that retrieval competition provides a more plausible alternative to memory reconsolidation. PMID- 26050696 TI - Clinical applications of counterfactual thinking during memory reactivation. AB - The Integrative Memory Model offers a strong foundation upon which to build successful strategies for clinical intervention. The next challenge is to figure out which cognitive strategies are more likely to bring about successful and beneficial modifications of reactivated memories during therapy. In this commentary we suggest that exercising emotional regulation during episodic counterfactual thinking is likely to be a successful therapeutic strategy to bring about beneficial memory modifications. PMID- 26050697 TI - Changing maladaptive memories through reconsolidation: A role for sleep in psychotherapy? AB - Like Lane et al., we believe that change in psychotherapy comes about by updating dysfunctional memories with new adaptive experiences. We suggest that sleep is essential to (re-)consolidate such corrective experiences. Sleep is well-known to strengthen and integrate new memories into pre-existing networks. Targeted sleep interventions might be promising tools to boost this process and thereby increase therapy effectiveness. PMID- 26050698 TI - Minding the findings: Let's not miss the message of memory reconsolidation research for psychotherapy. AB - That memory reconsolidation is the process underlying decisive, lasting therapeutic change has long been our proposal, and the recognition of its critical role by Lane et al. is a welcome development. However, in our view their account has significant errors due to neglect of research findings and neglect of previous work on the clinical application of those findings. PMID- 26050699 TI - A clinician's perspective on memory reconsolidation as the primary basis for psychotherapeutic change in posttraumatic stress disorder (PTSD). AB - Lane et al.'s proposal that psychotherapeutic change comes about through memory reconsolidation is compelling; however, the model would be strengthened by the inclusion of predictions regarding additional factors that might influence treatment response, predictions for improving outcomes for non-responsive patients, and a discussion of how the proposed model might explain individual differences in vulnerability for mental health problems. PMID- 26050700 TI - The nature of the semantic/episodic memory distinction: A missing piece of the "working through" process. AB - The relations between the semantic and episodic-autobiographical memory systems are more complex than described in the target article. We argue that understanding the noetic/autonoetic distinction provides critical insights into the foundation of the delineation between the two memory systems. Clarity with respect to the criteria for classification of these two systems, and the evolving conceptualization of episodic memory, can further neuroscientifically informed therapeutic approaches. PMID- 26050701 TI - Advances in Gene/Cell Therapy in Epidermolysis Bullosa. AB - In the past few years, substantial preclinical and experimental advances have been made in the treatment of the severe monogenic skin blistering disease epidermolysis bullosa (EB). Promising approaches have been developed in the fields of protein and cell therapies, including allogeneic stem cell transplantation; in addition, the application of gene therapy approaches has become reality. The first ex vivo gene therapy for a junctional EB (JEB) patient was performed in Italy more than 8 years ago and was shown to be effective. We have now continued this approach for an Austrian JEB patient. Further, clinical trials for a gene therapy treatment of recessive dystrophic EB are currently under way in the United States and in Europe. In this review, we aim to point out that sustainable correction of autologous keratinocytes by stable genomic integration of a therapeutic gene represents a realistic option for patients with EB. PMID- 26050703 TI - High-dose colistin for microbiologically documented serious respiratory infections associated with carbapenem-resistant Acinetobacter baummannii in critically ill cancer patients: a retrospective cohort study. AB - BACKGROUND: Recent studies suggested that high doses of colistin are necessary in the treatment of serious infections. However, few studies have evaluated such treatment. The objective of this study was to evaluate the effectiveness and nephrotoxicity of high-dose colistin in critically ill patients with respiratory infections associated with carbapenem-resistant Acinetobacter baumannii (CRAB). METHODS: This was a retrospective cohort study of critically ill cancer patients who received high-dose intravenous colistin for treatment of CRAB-related respiratory infections. Patients received colistimethate sodium 9 million IU/day or an equivalent dose, adjusted for renal function. Treatment effectiveness was evaluated by determining the microbiological clearance, recurrent and new CRAB related infections, and mortality in the intensive care unit (ICU). Nephrotoxicity was defined according to the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria. RESULTS: A total of 89 patients met the inclusion criteria. Microbiological clearance was observed in 51 (66.2%) subjects who had at least 2 follow-up cultures (n = 77). In patients who achieved microbiological clearance, recurrent and new CRAB-related infections occurred in 3 (5.9%) and 9 (17.6%) subjects, respectively. Fifty-seven patients (64%) died in the ICU. Thirty-five (39.3%) subjects developed nephrotoxicity according to the RIFLE criteria, which was classified as risk in 4 (11.4%) subjects, injury in 8 (22.8%) subjects, and failure in 21 (60%) subjects. CONCLUSIONS: In critically ill cancer patients, high-dose colistin was associated with microbiological clearance in about two-thirds of the subjects with CRAB-related respiratory infections but mortality was high. A significant portion of patients developed nephrotoxicity while receiving colistin therapy. PMID- 26050704 TI - Sex in the marketplace--what has love got to do with it? PMID- 26050705 TI - Intermanual transfer in an artist with Parkinson's disease. AB - A professional right-handed painter with Parkinson's disease (PD) broke his right arm and continued to paint with his left hand, showing an intact intermanual transfer of skills. This neurocognitive process is related to the supplementary motor area, a brain region that has also been shown to be involved in PD. This observation raises questions about the exact neural underpinnings of intermanual transfer and the possible impact of neurodegenerative disease and medication. PMID- 26050706 TI - A double-blinded, placebo-controlled, multicenter clinical trial of N acetylcysteine for preventing amphotericin B-induced nephrotoxicity. AB - OBJECTIVE: To evaluate the effectiveness of oral N-acetylcysteine (NAC) co treatment in preventing amphotericin B (AmB)-induced nephrotoxicity (AIN), including creatinine clearance and biomarkers of renal function (cystatin C [Cys C] and kidney injury molecule-1 [KIM-1]). METHODS: Either placebo or 600 mg oral NAC was given twice daily during the treatment course of AmB. Renal function test, serum as well as urinary level of Cys C and urinary KIM-1 were determined. RESULTS: Among the study population (n = 54), 23 (42.59%) patients developed AmB nephrotoxicity during their treatment course. NAC co-treatment was significantly associated with mitigating AmB nephrotoxicity (OR = 0.286, 95% CI: 0.082 - 0.993; p = 0.049). No statistically significant difference regarding accuracy of measured biomarkers including serum creatinine, serum and urine Cys C and urine KIM-1 at days 0 and 7 of treatment in predicting and detecting AmB nephrotoxicity was identified. The changes in mean serum and urine Cys C and urine KIM during AmB treatment within and between treatment groups were not statistically significant. CONCLUSIONS: Co-treatment with 600 mg oral NAC twice a day during AmB treatment, after adjusting for multiple variables, was associated with prevention of AIN. However, significantly higher adverse reactions developed in the patients who were treated with NAC. PMID- 26050707 TI - Anatomic and Functional Connectivity Relationship in Autistic Children During Three Different Experimental Conditions. AB - A group of 21 autistic children were studied for determining the relationship between the anatomic (AC) versus functional (FC) connectivity, considering short range and long-range brain networks. AC was assessed by the DW-MRI technique and FC by EEG coherence calculation, in three experimental conditions: basal, watching a popular cartoon with audio (V-A), and with muted audio track (VwA). For short-range connections, basal records, statistical significant correlations were found for all EEG bands in the left hemisphere, but no significant correlations were found for fast EEG frequencies in the right hemisphere. For the V-A condition, significant correlations were mainly diminished for the left hemisphere; for the right hemisphere, no significant correlations were found for the fast EEG frequency bands. For the VwA condition, significant correlations for the rapid EEG frequencies mainly disappeared for the right hemisphere. For long range connections, basal records showed similar correlations for both hemispheres. For the right hemisphere, significant correlations incremented to all EEG bands for the V-A condition, but these significant correlations disappeared for the fast EEG frequencies in the VwA condition. It appears that in a resting-state condition, AC is better associated with functional connectivity for short-range connections in the left hemisphere. The V-A experimental condition enriches the AC and FC association for long-range connections in the right hemisphere. This might be related to an effective connectivity improvement due to full video stimulation (visual and auditory). An impaired audiovisual interaction in the right hemisphere might explain why significant correlations disappeared for the fast EEG frequencies in the VwA experimental condition. PMID- 26050708 TI - The hierarchical organization of natural protein interaction networks confers self-organization properties on pseudocells. AB - BACKGROUND: Cell organization is governed and maintained via specific interactions among its constituent macromolecules. Comparison of the experimentally determined protein interaction networks in different model organisms has revealed little conservation of the specific edges linking ortholog proteins. Nevertheless, some topological characteristics of the graphs representing the networks--namely non-random degree distribution and high clustering coefficient--are shared by networks of distantly related organisms. Here we investigate the role of the topological features of the protein interaction network in promoting cell organization. METHODS: We have used a stochastic model, dubbed ProtNet representing a computer stylized cell to answer questions about the dynamic consequences of the topological properties of the static graphs representing protein interaction networks. RESULTS: By using a novel metrics of cell organization, we show that natural networks, differently from random networks, can promote cell self-organization. Furthermore the ensemble of protein complexes that forms in pseudocells, which self-organize according to the interaction rules of natural networks, are more robust to perturbations. CONCLUSIONS: The analysis of the dynamic properties of networks with a variety of topological characteristics lead us to conclude that self organization is a consequence of the high clustering coefficient, whereas the scale free degree distribution has little influence on this property. PMID- 26050710 TI - Radical Reactions of N-Heterocyclic Carbene Boranes with Organic Nitriles: Cyanation of NHC-Boranes and Reductive Decyanation of Malononitriles. AB - The observation that NHC-boryl radicals abstract cyano groups from various organic nitriles has been parlayed into two complementary transformations. In the main group chemistry aspect, reactions of various NHC-boranes with simple organic dinitriles selectively provide stable NHC-boryl mono- or dinitriles, depending on the nitrile source. In the organic synthesis aspect, reaction of malononitriles and related derivatives with readily available 1,3-dimethylimidazol-2-ylidene borane provides reductively decyanated products in good yields. PMID- 26050709 TI - Density Functional Theory Insights into the Role of the Methionine-Tyrosine Tryptophan Adduct Radical in the KatG Catalase Reaction: O2 Release from the Oxyheme Intermediate. AB - Density functional theory was employed for a comprehensive study that provided electronic and structural insights into the KatG catalase reaction that involves oxyheme. The catalytic role of a unique amino acid cofactor Met-Tyr-Trp (MYW) in its radical form found in KatG was thereby elucidated. It was established that the MYW-radical is flexible such that a "hinge-like opening" rotation of the Trp 107 ring with respect to the Tyr-229 ring along their covalent C-C bond is an inherent feature of its catalytic properties. Also, an H-bond between the Tyr-229 and the mobile side chain of Arg-418 further enables the catalytic events. The opening process breaks an H-bond between the N-H of Trp-107 and the inner oxygen of the Fe-O2 (oxyheme) complex present in the closed conformation of the MYW radical. This motion lowers the spin-crossing energy barrier between the ground state and the catalytically active high-spin states and enables electron transfer from the oxyheme group to the MYW-radical. The release of molecular oxygen is thereby catalyzed and leaves ferric-heme poised for another catalytic cycle. The energy barrier for the oxyheme state to complete the catalytic event, when assisted by the radical opening process, is thereby reduced and estimated to be 5.6 kcal/mol. PMID- 26050712 TI - Rupture of Calcified Nodule 105 Months After Sirolimus-Eluting Stent Implantation Observed on Coronary Angioscopy and Optical Frequency Domain Imaging In Vivo. PMID- 26050711 TI - Prognostic Impact of Anemia in Patients With Chronic Heart Failure- With Special Reference to Clinical Background: Report From the CHART-2 Study. AB - BACKGROUND: We aimed to elucidate the prognostic impact of anemia with special reference to the clinical background of patients with chronic heart failure (CHF). METHODS AND RESULTS: We examined 4,646 consecutive patients with Stage C/D CHF registered in the Chronic Heart Failure Analysis and Registry in the Tohoku District-2 (CHART-2) Study (n=10,219). Among them, 1,627 (35%) had anemia and were characterized by higher age (74 vs. 66 years), lower estimated glomerular filtration rate (52.8 vs. 66.1 ml/min/1.73 m(2)) and higher B-type natriuretic peptide levels (154.5 vs. 81.8 pg/ml) (all P<0.001) but comparable left ventricular ejection fraction (LVEF; 57.5 vs. 56.7%). Anemic patients were more frequently treated with diuretics (55.1 vs. 42.3%) but less often treated with beta-blockers (45.4 vs. 51.1%) (both P<0.001). During a median follow-up of 3.8 years, 371 and 272 patients died with and without anemia, respectively (22.8 vs. 9.0%, adjusted hazard ratio 1.40; 95% confidence interval 1.15-1.71, P=0.001). Subgroup analysis revealed that the prognostic impact of anemia was comparable in terms of age, sex, renal function and double product, but differed by LVEF level and CHF etiology (both, P for interaction <0.001). In particular, a difference in the prognostic impact of LVEF level was noted in patients with ischemic heart disease. CONCLUSIONS: These results indicate that the prognostic impact of anemia is evident in CHF patients with preserved EF and it differs by CHF etiology. PMID- 26050713 TI - Halogenated flame retardants in the Great Lakes environment. AB - Flame retardants are widely used industrial chemicals that are added to polymers, such as polyurethane foam, to prevent them from rapidly burning if exposed to a small flame or a smoldering cigarette. Flame retardants, especially brominated flame retardants, are added to many polymeric products at percent levels and are present in most upholstered furniture and mattresses. Most of these chemicals are so-called "additive" flame retardants and are not chemically bound to the polymer; thus, they migrate from the polymeric materials into the environment and into people. As a result, some of these chemicals have become widespread pollutants, which is a concern given their possible adverse health effects. Perhaps because of their environmental ubiquity, the most heavily used group of brominated flame retardants, the polybrominated diphenyl ethers (PBDEs), was withdrawn from production and use during the 2004-2013 period. This led to an increasing demand for other flame retardants, including other brominated aromatics and organophosphate esters. Although little is known about the use or production volumes of these newer flame retardants, it is evident that some of these chemicals are also becoming pervasive in the environment and in humans. In this Account, we describe our research on the occurrence of halogenated and organophosphate flame retardants in the environment, with a specific focus on the Great Lakes region. This Account starts with a short introduction to the first generation of brominated flame retardants, the polybrominated biphenyls, and then presents our measurements of their replacement, the PBDEs. We summarize our data on PBDE levels in babies, bald eagles, and in air. Once these compounds came off the market, we began to measure several of the newer flame retardants in air collected on the shores of the Great Lakes once every 12 days. These new measurements focus on a tetrabrominated benzoate, a tetrabrominated phthalate, a hexabrominated diphenoxyethane, several brominated benzenes, and a highly chlorinated norbornene compound called Dechlorane Plus. Most recently, we have begun measuring the atmospheric concentrations of several organophosphate esters, which are an increasing part of the flame retardant market. The interesting feature of this story is how one compound or set of compounds has followed another out of and into the marketplace even though none of them have been officially regulated. This replacement of one commercial product by another with similar functions shows that the chemical industry does respond to scientific environmental measurements and to the resulting bad publicity. This is a good thing. The problem is that often the replacement chemicals also become environmentally ubiquitous. PMID- 26050714 TI - Identification and validation of mixed anxiety-depression. AB - BACKGROUND: Mixed anxiety-depression (MAD) has been under scrutiny to determine its potential place in psychiatric nosology. The current study sought to investigate its prevalence, clinical characteristics, course and potential validators. METHOD: Restricted latent-class analyses were fit to 12-month self reports of depression and anxiety symptom criteria in a large population-based sample of twins. Classes were examined across an array of relevant indicators (demographics, co-morbidity, adverse life events, clinical significance and twin concordance). Longitudinal analyses investigated the stability of, and transitions between, these classes for two time periods approximately 1.5 years apart. RESULTS: In all analyses, a class exhibiting levels of MAD symptomatology distinctly above the unaffected subjects yet having low prevalence of either major depression (MD) or generalized anxiety disorder (GAD) was identified. A restricted four-class model, constraining two classes to have no prior disorder history to distinguish residual or recurrent symptoms from new onsets in the last year, provided an interpretable classification: two groups with no prior history that were unaffected or had MAD and two with prior history having relatively low or high symptom levels. Prevalence of MAD was substantial (9-11%), and subjects with MAD differed quantitatively but not qualitatively from those with lifetime MD or GAD across the clinical validators examined. CONCLUSIONS: Our findings suggest that MAD is a commonly occurring, identifiable syndromal subtype that warrants further study and consideration for inclusion in future nosologic systems. PMID- 26050715 TI - Disability Grant: a precarious lifeline for HIV/AIDS patients in South Africa. AB - BACKGROUND: In South Africa, HIV/AIDS remains a major public health problem. In a context of chronic unemployment and deepening poverty, social assistance through a Disability Grant (DG) is extended to adults with HIV/AIDS who are unable to work because of a mental or physical disability. Using a mixed methods approach, we consider 1) inequalities in access to the DG for patients on ART and 2) implications of DG access for on-going access to healthcare. METHODS: Data were collected in exit interviews with 1200 ART patients in two rural and two urban health sub-districts in four different South African provinces. Additionally, 17 and 18 in-depth interviews were completed with patients on ART treatment and ART providers, respectively, in three of the four sites included in the quantitative phase. RESULTS: Grant recipients were comparatively worse off than non-recipients in terms of employment (9.1 % vs. 29.9 %) and wealth (58.3 % in the poorest half vs. 45.8 %). After controlling for socioeconomic and demographic factors, site, treatment duration, adherence and concomitant TB treatment, the regression analyses showed that the employed were significantly less likely to receive the DG than the unemployed (p < 0.001). Also, patients who were longer on treatment and receiving concomitant treatment (i.e., ART and tuberculosis care) were more likely to receive the DG (significant at the 5 % level). The qualitative analyses indicated that the DG alleviated the burden of healthcare related costs for ART patients. Both patients and healthcare providers spoke of the complexity of the grants process and eligibility criteria as a barrier to accessing the grant. This impacted adversely on patient-provider relationships. CONCLUSIONS: These findings highlight the appropriateness of the DG for people living with HIV/AIDS. However, improved collaboration between the Departments of Social Development and Health is essential for preparing healthcare providers who are at the interface between social security and potential recipients. PMID- 26050716 TI - Blowback: new formal perspectives on agriculturally driven pathogen evolution and spread. AB - By their diversity in time, space, and mode, traditional and conservation agricultures can create barriers limiting pathogen evolution and spread analogous to a sterilizing temperature. Large-scale monocropping and confined animal feeding-lot operations remove such barriers, resulting, above agroecologically specific thresholds, in the development and wide propagation of novel disease strains. We apply a newly developed class of necessary-conditions statistical models of evolutionary process, first using the theory on an evolutionarily stable viral pathogen vulnerable to vaccine treatment: post-World War II poliomyelitis emerged in the UK and USA from sudden widespread adoption of automobile ownership and usage. We then examine an evolutionarily variable pathogen, swine influenza in North America. The model suggests epidemiological blowback from globalizing intensive husbandry and the raising and shipping of monoculture livestock across increasing expanses, is likely to be far more consequential, driving viral selection for greater virulence and lowered response to biomedical intervention. PMID- 26050717 TI - Recent increase in prevalence of antibodies to Dobrava-Belgrade virus (DOBV) in yellow-necked mice in Northern Italy. AB - Dobrava-Belgrade virus (DOBV) is the most pathogenic hantavirus in Europe with a case-fatality rate of up to 12%. To detect changes in risk for humans, the prevalence of antibodies to DOBV has been monitored in a population of Apodemus flavicollis in the province of Trento (northern Italy) since 2000, and a sudden increase was observed in 2010. In the 13-year period of this study, 2077 animals were live-trapped and mean hantavirus seroprevalence was 2.7% (s.e. = 0.3%), ranging from 0% (in 2000, 2002 and 2003) to 12.5% (in 2012). Climatic (temperature and precipitation) and host (rodent population density, rodent weight and sex, and larval tick burden) variables were analysed using Generalized Linear Models and multi-model inference to select the best model. Climatic changes (mean annual precipitation and maximum temperature) and individual body mass had a positive effect on hantavirus seroprevalence. Other possible drivers affecting the observed pattern need to be studied further. PMID- 26050719 TI - [The 56(th) Annual Meeting of the Japanese Society of Gastroenterology]. PMID- 26050720 TI - [Helicobacter pylori infection and endoscopic gastritis -Kyoto classification of gastritis]. PMID- 26050721 TI - [Diagnosis for Helicobacter pylori infection]. PMID- 26050722 TI - [Eradication therapy and resistance to antibiotics]. PMID- 26050723 TI - [Gastric mucosal improvement and gastric cancer following H. pylori eradication]. PMID- 26050724 TI - [A case of eosinophilic esophagitis caused by a cedar ball]. AB - A 65-year-old woman presented to our hospital with chief complaints of a strange sensation in her pharynx, dysphagia, and odynophagia. Upper gastrointestinal endoscopy showed multiple aphthae in the esophagus and she was diagnosed with eosinophilic esophagitis based on the results of biopsy. Swallowing therapy with fluticasone was scheduled; however, she subsequently developed urticaria. She was treated with systemic steroid therapy at another hospital, which improved her symptoms and endoscopic images. A detailed history revealed that she had experienced significant facial edema after making a cedar ball. It was considered that the eosinophilic esophagitis was possibly caused by cedar pollen. PMID- 26050725 TI - [A case of AL amyloidosis due to multiple myeloma presenting with a huge gastric submucosal hematoma during anticoagulant therapy]. AB - A 43-year-old woman who had received anticoagulant therapy for atrial fibrillation for 2 years was admitted to our hospital with hematemesis. Endoscopy revealed a huge submucosal hematoma in the antrum of the stomach. Repeat endoscopy on day 6 showed that the submucosal hematoma had developed into a giant ulcer. Gastric mucosal biopsy and general examination confirmed a diagnosis of AL amyloidosis due to multiple myeloma. Although patients with cardiac involvement of AL amyloidosis often require anticoagulant therapy, gastrointestinal bleeding may occur. Therefore, the potential benefits of anticoagulation must be carefully weighed against the risk of hemorrhage. PMID- 26050726 TI - [Three cases of pedunculated gastric hamartomatous inverted polyps resected endoscopically]. AB - We report three cases of pedunculated gastric hamartomatous inverted polyps (HIPs) that were successfully treated by endoscopic polypectomy. The first case involved an 87-year-old woman with mild anemia. Esophagogastroduodenoscopy (EGD) revealed a pedunculated, reddish polyp located at the greater curvature of the upper stomach. The second case involved a 34-year-old woman in whom a pedunculated polyp was found at the gastric fundus during routine EGD. The third patient was a 59-year-old woman with epigastric discomfort. EGD revealed a pedunculated polyp in the gastric fundus. Polypectomy was successfully performed in all three cases. Histological examination revealed that the tumors comprised submucosal proliferation of cystically dilated gastric glands and hyperplastic glands;thus, we diagnosed gastric HIPs, which are rare and typically difficult to diagnose. Gastric HIPs should be considered in the differential diagnosis of elevated gastric lesions. PMID- 26050727 TI - [A case of Kaposi's sarcoma of the rectum presenting with hematochezia and rectal pain]. AB - A man in his 20s was referred to our hospital with hematochezia and rectal pain. Total colonoscopy revealed a reddish, protruding, ulcerated lesion occupying approximately half of the luminal circumference of the rectum. Examination of biopsy specimens showed proliferating spindle cells infiltrating the lamina propria, a finding consistent with Kaposi's sarcoma. The patient was also found to be anti-human immunodeficiency virus (HIV) antibody positive;therefore, we diagnosed acquired immunodeficiency syndrome (AIDS). The lesions of Kaposi's sarcoma were also seen in the skin, lung, and lymph nodes, but there were no lesions elsewhere in the gastrointestinal tract other than the rectum. We started anti-HIV therapy and chemotherapy against these lesions, and the lesions subsequently reduced in size. We present a rare case of a man with Kaposi's sarcoma presenting with a rectal lesion. PMID- 26050728 TI - [A case of transcatheter arterial embolization for reduction of a hemorrhagic rectal gastrointestinal stromal tumor]. AB - A 91-year-old woman was referred to our hospital with a primary complaint of hematochezia. A rectal submucosal tumor and an acute hemorrhagic rectal ulcer were noted on colonoscopy. After hemostasis was achieved with APC, the patient was diagnosed with a GIST by EUS-FNA. We performed TAE of the middle and inferior rectal artery to secure hemostasis, because these arteries were also observed to be bleeding during hospitalization. A CT scan and colonoscopy revealed that the rectal GIST had reduced and that the acute rectal ulcer had been successfully treated. We report a case in which TAE was used to achieve tumor reduction of a hemorrhagic rectal GIST. PMID- 26050729 TI - [A case of drug-induced liver injury caused by Keishi-karyukotsu-boreito and Shin i-seihaito]. AB - A 43-year-old woman was admitted to our hospital due to liver dysfunction. She had a history of liver injury induced by the herbal medicine Keishi-karyukotsu boreito, which occurred at the age of 35 years. On the present occasion, she had taken the herbal medicine Shin-i-seihaito to treat her sinusitis for one month. We diagnosed liver injury caused by Shin-i-seihaito, and her liver dysfunction normalized after discontinuation of Shin-i-seihaito. This is the first reported case of drug-induced liver injury caused by the herbal medicines Keishi karyukotsu-boreito and Shin-i-seihaito. PMID- 26050730 TI - [Hypoxemia due to pulmonary tumor microembolisms from a hepatocellular carcinoma: a case report]. AB - We report a case of pulmonary tumor embolism due to hepatocellular carcinoma (HCC). A woman in her 60s was treated with sorafenib 800 mg daily for HCC with lymph node metastasis. Approximately 50 days after taking sorafenib, she experienced dyspnea and was admitted to the hospital on account of hypoxia. Although her oxygen saturation levels deteriorated, we could find no obvious cause for the hypoxia; despite artificial respiration and oxygenation, she died of respiratory failure on the fourth day of admission. Tissue samples revealed that the HCC cells had infiltrated her lung arterioles; therefore, we concluded that multiple tumor microembolisms from the HCC to the lungs had caused death via respiratory failure. Cases of hypoxia caused by multiple invisible embolisms from HCCs are rarely reported. We believe that infiltration into the lymphatic system may have been related to the development of pulmonary tumor microembolisms. PMID- 26050731 TI - [A case of serous cystic neoplasm with atypical imaging results suggestive of a prismatic internal structure]. AB - The patient was a 67-year-old man with a 39-mm unilocular pancreatic tumor detected by computed tomography (CT). Further examinations with contrast-enhanced CT, magnetic resonance imaging, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography revealed an internal heterogeneous structure attributed to bleeding or necrosis. Consequently, we expected either a pancreatic neuroendocrine tumor or a solid pseudopapillary neoplasm and performed pancreaticoduodenectomy. Pathological examination showed that the tumor had a denatured structure with evidence of internal bleeding and cubic epithelial cysts of various sizes. The final diagnosis was a macrocystic-type serous cystic neoplasm. PMID- 26050732 TI - Editorial: Nanotechnology for Drug Delivery: Part I. PMID- 26050733 TI - IGF-1 Levels, Complex Formation, and IGF Bioactivity in Growth Hormone-Treated Children With Prader-Willi Syndrome. AB - CONTEXT: Children with Prader-Willi syndrome (PWS) attain high-serum immunoreactive IGF-1 levels during a standard-dose GH treatment, which leads to concern, but lowering the dose deteriorates their body composition. OBJECTIVE: The objective of the study was to evaluate serum IGF-1, IGF binding protein (IGFBP)-3, and acid-labile subunit (ALS) levels, complex formation, and IGF bioactivity in GH-treated PWS children. DESIGN: This was a cross-sectional study. SETTING: The setting of the study was a Dutch PWS cohort. PARTICIPANTS: Forty GH treated PWS children compared with 41 age- and sex-matched healthy controls participated in the study. INTERVENTIONS: Interventions included GH treatment (1.0 mg/m(2) . d = ~0.035 mg/kg . d). MAIN OUTCOME MEASURES: Serum IGF-1, IGFBP 3, and ALS levels, complex formation, and IGF bioactivity by IGF-1 receptor kinase activation assay were measured. RESULTS: Serum IGF-1, IGFBP-3, and ALS levels and IGF-1 to IGFBP-3 ratio were significantly higher in GH-treated PWS children than in healthy controls. The 150-kDa ternary complex formation was, however, also significantly higher than in controls, indicating that most of serum IGF-1 is sequestered in the ternary 150-kDa complex with ALS and IGFBP-3. Young GH-treated PWS children [median (interquartile range) aged 5.2 (4.3-7.2) y] exhibited higher serum IGF bioactivity than controls, but no difference was observed in IGF bioactivity between older GH-treated PWS children, aged 14.9 (13.8-16.2) years, and controls. The proportion of IGF bioactivity of total serum IGF-1 was, however, lower in GH-treated PWS children than in controls. Serum immunoreactive IGF-1 levels did not correlate with IGF bioactivity in GH-treated children with PWS, in contrast to a strong positive correlation in healthy controls. CONCLUSIONS: In GH-treated PWS children, most serum IGF-1 is sequestered in the 150-kDa complex. Higher IGF bioactivity was found only in young GH-treated PWS children and not in the older ones. IGF bioactivity during GH showed a wide variation, and there was a disrupted correlation with immunoreactive IGF-1 levels, which makes immunoreactive IGF-1 levels an inappropriate indicator for GH dosing in PWS children. PMID- 26050735 TI - Nature and uses of fluorescent dyes for drug transporter studies. AB - INTRODUCTION: Drug transporters are now recognized as major players involved in pharmacokinetics and toxicology. Methods for assessing their activity are important to consider, particularly owing to regulatory requirements with respect to inhibition of drug transporter activity and prediction of drug-drug interactions. In this context, the use of fluorescent-dye-based transport assays is likely to deserve attention. AREAS COVERED: This review provides an overview of the nature of fluorescent dye substrates for ATP-binding cassette and solute carrier drug transporters. Their use for investigating drug transporter activity in cultured cells and clinical hematological samples, drug transporter inhibition, drug transporter imaging and drug transport at the organ level are summarized. EXPERT OPINION: A wide range of fluorescent dyes is now available for use in various aspects of drug transporter studies. The use of these dyes for transporter analyses may, however, be hampered by classic pitfalls of fluorescence technology, such as quenching. Transporter-independent processes such as passive diffusion of dyes through plasma membrane or dye sequestration into subcellular compartments must also be considered, as well as the redundant handling by various distinct transporters of some fluorescent probes. Finally, standardization of dye-based transport assays remains an important on-going issue. PMID- 26050734 TI - Bile acid effects are mediated by ATP release and purinergic signalling in exocrine pancreatic cells. AB - BACKGROUND: In many cells, bile acids (BAs) have a multitude of effects, some of which may be mediated by specific receptors such the TGR5 or FXR receptors. In pancreas systemic BAs, as well as intra-ductal BAs from bile reflux, can affect pancreatic secretion. Extracellular ATP and purinergic signalling are other important regulators of similar secretory mechanisms in pancreas. The aim of our study was to elucidate whether there is interplay between ATP and BA signalling. RESULTS: Here we show that CDCA (chenodeoxycholic acid) caused fast and concentration-dependent ATP release from acini (AR42J) and duct cells (Capan-1). Taurine and glycine conjugated forms of CDCA had smaller effects on ATP release in Capan-1 cells. In duct monolayers, CDCA stimulated ATP release mainly from the luminal membrane; the releasing mechanisms involved both vesicular and non vesicular secretion pathways. Duct cells were not depleted of intracellular ATP with CDCA, but acinar cells lost some ATP, as detected by several methods including ATP sensor AT1.03(YEMK). In duct cells, CDCA caused reversible increase in the intracellular Ca(2+) concentration [Ca(2 +)]i, which could be significantly inhibited by antagonists of purinergic receptors. The TGR5 receptor, expressed on the luminal side of pancreatic ducts, was not involved in ATP release and Ca(2+) signals, but could stimulate Na(+)/Ca(2+) exchange in some conditions. CONCLUSIONS: CDCA evokes significant ATP release that can stimulate purinergic receptors, which in turn increase [Ca(2+)]i. The TGR5 receptor is not involved in these processes but can play a protective role at high intracellular Ca(2+) conditions. We propose that purinergic signalling could be taken into consideration in other cells/organs, and thereby potentially explain some of the multifaceted effects of BAs. PMID- 26050736 TI - Ciprofloxacin adsorption on graphene and granular activated carbon: kinetics, isotherms, and effects of solution chemistry. AB - Ciprofloxacin (CIP) is a commonly used antibiotic and widely detected in wastewaters and farmlands nowadays. This study evaluated the efficacy of next generation adsorbent (graphene) and conventional adsorbent (granular activated carbon, GAC) for CIP removal. Batch experiments and characterization tests were conducted to investigate the adsorption kinetics, equilibrium isotherms, thermodynamic properties, and the influences of solution chemistry (pH, ionic strength, natural organic matter (NOM), and water sources). Compared to GAC, graphene showed significantly faster adsorption and reached equilibrium within 3 min, confirming the rapid access of CIP into the macroporous network of high surface area of graphene as revealed by the Brunner-Emmet-Teller measurements analysis. The kinetics was better described by a pseudo-second-order model, suggesting the importance of the initial CIP concentration related to surface site availability of graphene. The adsorption isotherm on graphene followed Langmuir model with a maximum adsorption capacity of 323 mg/g, which was higher than other reported carbonaceous adsorbents. The CIP adsorption was thermodynamically favourable on graphene and primarily occurred through pi - pi interaction, according to the FTIR spectroscopy. While the adsorption capacity of graphene decreased with increasing solution pH due to the speciation change of CIP, the adverse effects of ionic strength (0.01-0.5 mol L(-1)), presence of NOM (5 mg L-1), and different water sources (river water or drinking water) were less significant on graphene than GAC. These results indicated that graphene can serve as an alternative adsorbent for CIP removal in commonly encountered field conditions, if proper separation and recovery is available in place. PMID- 26050737 TI - Echocardiographic Surrogate Marker for Diabetic Cardiomyopathy. PMID- 26050738 TI - Analysis of Distinct Roles of CaMKK Isoforms Using STO-609-Resistant Mutants in Living Cells. AB - To assess the isoform specificity of the Ca(2+)/calmodulin-dependent protein kinase kinase (CaMKK)-mediated signaling pathway using a CaMKK inhibitor (STO 609) in living cells, we have established A549 cell lines expressing STO-609 resistant mutants of CaMKK isoforms. Following serial mutagenesis studies, we have succeeded in obtaining an STO-609-resistant CaMKKalpha mutant (Ala292Thr/Leu233Phe) and a CaMKKbeta mutant (Ala328Thr/Val269Phe), which showed sensitivity to STO-609 that was 2-3 orders of magnitude lower without an appreciable effect on kinase activity or CaM requirement. These results are consistent with the results obtained for CaMKK activities in the extracts of A549 cells stably expressing the mutants of CaMKK isoforms. Ionomycin-induced 5'-AMP activated protein kinase (AMPK) phosphorylation at Thr172 in A549 cells expressing either the wild-type or the STO-609-resistant mutant of CaMKKalpha was completely suppressed by STO-609 treatment but resistant to the inhibitor in the presence of the CaMKKbeta mutant (Ala328Thr/Val269Phe). This result strongly suggested that CaMKKbeta is responsible for ionomycin-induced AMPK activation, which supported previous reports. In contrast, ionomycin-induced CaMKIV phosphorylation at Thr196 was resistant to STO-609 treatment in A549 cells expressing STO-609-resistant mutants of both CaMKK isoforms, indicating that both CaMKK isoforms are capable of phosphorylating and activating CaMKIV in living cells. Considering these results together, STO-609-resistant CaMKK mutants developed in this study may be useful for distinguishing CaMKK isoform-mediated signaling pathways in combination with the use of an inhibitor compound. PMID- 26050739 TI - A longitudinal twin study of borderline and antisocial personality disorder traits in early to middle adulthood. AB - BACKGROUND: Antisocial personality disorder (ASPD) and borderline personality disorder (BPD) share genetic and environmental risk factors. Little is known about the temporal stability of these etiological factors in adulthood. METHOD: DSM-IV criteria for ASPD and BPD were assessed using structured interviews in 2282 Norwegian twins in early adulthood and again approximately 10 years later. Longitudinal biometric models were used to analyze the number of endorsed criteria. RESULTS: The mean criterion count for ASPD and BPD decreased 40% and 28%, respectively, from early to middle adulthood. Rank-order stability was 0.58 for ASPD and 0.45 for BPD. The best-fitting longitudinal twin model included only genetic and individual-specific environmental factors. Genetic effects, both those shared by ASPD and BPD, and those specific to each disorder remained completely stable. The unique environmental effects, however, changed substantially, with a correlation across time of 0.19 for the shared effects, and 0.39 and 0.15, respectively, for those specific to ASPD and BPD. Genetic effects accounted for 71% and 72% of the stability over time for ASPD and BPD, respectively. The genetic and environmental correlations between ASPD and BPD were 0.73, and 0.43, respectively, at both time points. CONCLUSION: ASPD and BPD traits were moderately stable from early to middle adulthood, mostly due to genetic risk factors which did not change over the 10-year assessment period. Environmental risk factors were mostly transient, and appear to be the main source of phenotypic change. Genetic liability factors were, to a large extent, shared by ASPD and BPD. PMID- 26050740 TI - Prognostic factors for progression of clinical osteoarthritis of the knee: a systematic review of observational studies. AB - INTRODUCTION: We performed a systematic review of prognostic factors for the progression of symptomatic knee osteoarthritis (OA), defined as increase in pain, decline in physical function or total joint replacement. METHOD: We searched for available observational studies up to January 2015 in Medline and Embase according to a specified search strategy. Studies that fulfilled our initial inclusion criteria were assessed for methodological quality. Data were extracted and the results were pooled, or if necessary summarized according to a best evidence synthesis. RESULTS: Of 1,392 articles identified, 30 met the inclusion criteria and 38 determinants were investigated. Pooling was not possible due to large heterogeneity between studies. The best evidence synthesis showed strong evidence that age, ethnicity, body mass index, co-morbidity count, magnetic resonance imaging (MRI)-detected infrapatellar synovitis, joint effusion and baseline OA severity (both radiographic and clinical) are associated with clinical knee OA progression. There was moderate evidence showing that education level, vitality, pain-coping subscale resting, MRI-detected medial femorotibial cartilage loss and general bone marrow lesions are associated with clinical knee OA progression. However, evidence for the majority of determinants was limited (including knee range of motion or markers) or conflicting (including age, gender and joint line tenderness). CONCLUSION: Strong evidence was found for multiple prognostic factors for progression of clinical knee OA. A large variety in definitions of clinical knee OA (progression) remains, which makes it impossible to summarize the evidence through meta-analyses. More research on prognostic factors for knee OA is needed using symptom progression as an outcome measure. Remarkably, only few studies have been performed using pain progression as an outcome measure. The pathophysiology of radiographic factors and their relation with symptoms should be further explored. PMID- 26050741 TI - Intratympanic injection in delayed endolymphatic hydrops. AB - CONCLUSIONS: The present study showed that intratympanic dexamethasone injection (ITD) is a promising approach for the treatment of contralateral and ipsilateral delayed endolymphatic hydrops (DEH). Moreover, intratympanic gentamicin injection (ITG), as a chemical labyrinthectomy, is a simple alternative for controlling vertigo in patients with ipsilateral DEH. OBJECTIVE: This study examined the effect of ITD or ITG on DEH. METHODS: Fourteen patients with DEH completed the clinical and audio-vestibular evaluation. Among them, 10 cases (ipsilateral type: nine cases, contralateral type: one case) were treated with intratympanic injection. Four patients with ipsilateral DEH underwent ITG, five patients with ipsilateral type and one patient with contralateral type received ITD. All 10 cases were followed up for 8-48 months. RESULTS: Complete and substantial vertigo control was achieved in four of nine ipsilateral DEH patients treated with ITG. In the other five ipsilateral cases who received ITD, two accomplished complete vertigo control and two had substantial control. In one case, the vertigo was not effectively controlled. One case of contralateral DEH underwent ITD and this case had complete vertigo control. The vertigo intensity, vertigo frequency, vertigo duration and the functional level scale after intratympanic injection was decreased significantly. PMID- 26050744 TI - Corrigendum. PMID- 26050743 TI - The evolutionary significance of latent reproductive rate in a long-lived vertebrate. AB - Chambert, Rotella & Garrott () used long-term data to assess the evolutionary significance of individual latent reproductive rate in female Weddell seals. Latent reproductive rates capture the differences among individuals in terms of their propensity to breed; they are conceptual and mathematical constructs. Neither recruitment probability nor age of first breeding of daughters was related to the mother's latent reproductive rate, but there was evidence of a weak positive relationship between the latent reproductive rates of mothers and daughters, suggesting some degree of heritability in this trait. Females with a high latent reproductive rate were expected to produce 2.0 times as many recruited females and 2.1 times as many grandchildren as females with a low reproductive rate. There was substantial stochastic variation in the number of offspring and grandchildren produced, but the inter-individual variability in female latent reproductive rate may have important fitness consequences. PMID- 26050742 TI - DT-Web: a web-based application for drug-target interaction and drug combination prediction through domain-tuned network-based inference. AB - BACKGROUND: The identification of drug-target interactions (DTI) is a costly and time-consuming step in drug discovery and design. Computational methods capable of predicting reliable DTI play an important role in the field. Algorithms may aim to design new therapies based on a single approved drug or a combination of them. Recently, recommendation methods relying on network-based inference in connection with knowledge coming from the specific domain have been proposed. DESCRIPTION: Here we propose a web-based interface to the DT-Hybrid algorithm, which applies a recommendation technique based on bipartite network projection implementing resources transfer within the network. This technique combined with domain-specific knowledge expressing drugs and targets similarity is used to compute recommendations for each drug. Our web interface allows the users: (i) to browse all the predictions inferred by the algorithm; (ii) to upload their custom data on which they wish to obtain a prediction through a DT-Hybrid based pipeline; (iii) to help in the early stages of drug combinations, repositioning, substitution, or resistance studies by finding drugs that can act simultaneously on multiple targets in a multi-pathway environment. Our system is periodically synchronized with DrugBank and updated accordingly. The website is free, open to all users, and available at http://alpha.dmi.unict.it/dtweb/. CONCLUSIONS: Our web interface allows users to search and visualize information on drugs and targets eventually providing their own data to compute a list of predictions. The user can visualize information about the characteristics of each drug, a list of predicted and validated targets, associated enzymes and transporters. A table containing key information and GO classification allows the users to perform their own analysis on our data. A special interface for data submission allows the execution of a pipeline, based on DT-Hybrid, predicting new targets with the corresponding p-values expressing the reliability of each group of predictions. Finally, It is also possible to specify a list of genes tracking down all the drugs that may have an indirect influence on them based on a multi-drug, multi target, multi-pathway analysis, which aims to discover drugs for future follow-up studies. PMID- 26050746 TI - Catalytic C-H bond functionalisation of purine and pyrimidine nucleosides: a synthetic and mechanistic perspective. AB - C-H bond functionalisation of heteroarenes, especially nucleosides, has received a lot of attention in the past few years. This review describes the state-of the art in this area with a global aspiration for possibly functionalising purine and pyrimidine moieties in more complex biomolecular systems, such as DNA/RNA in the near future.' PMID- 26050747 TI - Structural organization of surfactant aggregates in vacuo: a molecular dynamics and well-tempered metadynamics study. AB - Experimental investigations using mass spectrometry have established that surfactant molecules are able to form aggregates in the gas phase. However, there is no general consensus on the organization of these aggregates and how it depends on the aggregation number and surfactant molecular structure. In the present paper we investigate the structural organization of some surfactants in vacuo by molecular dynamics and well-tempered metadynamics simulations to widely explore the space of their possible conformations in vacuo. To study how the specific molecular features of such compounds affect their organization, we have considered as paradigmatic surfactants, the anionic single-chain sodium dodecyl sulfate (SDS), the anionic double-chain sodium bis(2-ethylhexyl) sulfosuccinate (AOT) and the zwitterionic single-chain dodecyl phosphatidyl choline (DPC) within a wide aggregation number range (from 5 to 100). We observe that for low aggregation numbers the aggregates show in vacuo the typical structure of reverse micelles, while for large aggregation numbers a variety of globular aggregates occur that are characterized by the coexistence of interlaced domains formed by the polar or ionic heads and by the alkyl chains of the surfactants. Well tempered metadynamics simulations allows us to confirm that the structural organizations obtained after 50 ns of molecular dynamics simulations are practically the equilibrium ones. Similarities and differences of surfactant aggregates in vacuo and in apolar media are also discussed. PMID- 26050748 TI - One-pot synthesis of oxamidato-bridged hexarhenium trigonal prisms adorned with ester functionality. AB - Oxamidato-bridged Re(I)-based hexanuclear trigonal prisms with ester functionality have been synthesised via a multicomponent self-assembly process under solvothermal conditions. The self-assembly of Re2(CO)10, oxamide ligands (H2L1 = N,N'-dibutyloxamide, H2L2 = N,N'-dioctyloxamide, H2L3 = N,N' didodecyloxamide and H2L4 = N,N'-dibenzyloxamide) and phenyl-1,3,5 tris(isonicotinate) (ptin) resulted in the formation of metallaprisms with the general formula [{(CO)3Re(MU-eta(4)-L)Re(CO)3}3(MU3-ptin)2] (1-4). The metallaprisms 1-4 have been characterised using spectroscopic techniques, and the molecular structure of 4 has been elucidated by single-crystal X-ray diffraction methods. Investigations on the guest binding ability of 2 with a few aromatic alcohols and L-tryptophan using UV-vis and fluorescence spectroscopic titration experiments revealed strong host-guest interactions. The luminescence enhancement studies of 2 and 3 have been carried out using organic-aqueous solvent mixtures. PMID- 26050749 TI - Human serum biomarker detection based on a cascade signal amplification strategy by a DNA molecule machine. AB - A convenient method is presented that employs a DNA machine for protein biomarker detection. The detection limit is 400 times lower compared to the method without a DNA machine. This study provides a promising method that could realize most protein biomarker detections without the corresponding aptamers, using a DNA machine for signal amplification. PMID- 26050750 TI - Comparative study of dermal components and plasma TGF-beta1 levels in Slc39a13/Zip13-KO mice. AB - Ehlers-Danlos syndrome (EDS) is a group of disorders caused by abnormalities that are identified in the extracellular matrix. Transforming growth factor-beta1 (TGF beta1) plays a crucial role in formation of the extracellular matrix. It has been reported that the loss of function of zinc transporter ZRT/IRT-like protein 13 (ZIP13) causes the spondylocheiro dysplastic form of EDS (SCD-EDS: OMIM 612350), in which dysregulation of the TGF-beta1 signaling pathway is observed, although the relationship between the dermis abnormalities and peripheral TGF-beta1 level has been unclear. We investigated the characteristics of the dermis of the Zip13 knockout (KO) mouse, an animal model for SCD-EDS. Both the ratio of dermatan sulfate (DS) in glycosaminoglycan (GAG) components and the amount of collagen were decreased, and there were very few collagen fibrils with diameters of more than 150 nm in Zip13-KO mice dermis. We also found that the TGF-beta1 level was significantly higher in Zip13-KO mice serum. These results suggest that collagen synthesis and collagen fibril fusion might be impaired in Zip13-KO mice and that the possible decrease of decorin level by reduction of the DS ratio probably caused an increase of free TGF-beta1 in Zip13-KO mice. In conclusion, skin fragility due to defective ZIP13 protein may be attributable to impaired extracellular matrix synthesis accompanied by abnormal peripheral TGF-beta homeostasis. PMID- 26050751 TI - Measurement of feline lipase activity using a dry-chemistry assay with a triolein substrate and comparison with pancreas-specific lipase (Spec fPL(TM)). AB - Pancreatic lipase immunoreactivity (Spec fPL) is currently considered to be the most accurate blood test for the diagnosis of feline pancreatitis. In this study, we measured lipase activity in cats using a newer catalytic lipase assay of dry chemistry system (FDC-v-LIP) to determine the reference range and compared the results with those for Spec fPL. Based on the results of healthy cats, the reference range of FDC-v-LIP was determined to be less than 30 U/l. FDC-v-lip did not show a strong correlation with Spec fPL in cats with various diseases, which resulted in the low sensitivity and positive predictive value. However, the relatively high (>90%) specificity and negative predictive value indicated that FDC-v-LIP could be a useful patient-side screening test for the exclusion of feline pancreatitis. PMID- 26050752 TI - The first report of the ante-mortem diagnosis of Ollulanus tricuspis infection in two dogs. AB - Ollulanus tricuspis is a small nematode parasite of the stomach, and its infection has been reported worldwide in cats but only one report in dogs as post mortem diagnosis. Two dogs, kept in the Tokyo area, were presented for chronic vomiting. Chronic gastritis was diagnosed histologically, and many nematodes were detected in endoscopically-biopsied gastric samples and in the mucus of vomitus in both dogs. The parasites were small (<1 mm), and their morphological characteristics were consistent with those previously reported for O. tricuspis. The symptoms in one dog completely disappeared after anthelmintic therapy. To our knowledge, this is the first report describing ante-mortem diagnosis of spontaneous gastric O. tricuspis infection in dogs in which infectivity and pathogenicity of the nematode are suggested. PMID- 26050754 TI - Highly-efficient cocatalyst-free H2-evolution over silica-supported CdS nanoparticle photocatalysts under visible light. AB - A silica-supported CdS nanoparticle photocatalyst exhibits excellent visible light driven H2 evolution activity without the use of a cocatalyst. The apparent quantum yield can reach 42% under 420 nm light illumination. PMID- 26050753 TI - Endostatin inhibits bradykinin-induced cardiac contraction. AB - Endogenous fragments of extracellular matrix are known to possess various biological effects. Levels of endostatin, a fragment of collagen type XVIII, increase in certain cardiac diseases, such as cardiac hypertrophy and myocardial infarction. However, the influence of endostatin on cardiac contraction has not been clarified. In the present study, we investigated the effects of endostatin on bradykinin-induced atrial contraction. Isometric contractile force of mouse isolated left atria induced by electrical current pulse was measured. Voltage dependent calcium current of guinea pig ventricular myocytes was measured by a whole-cell patch-clamp technique. Endostatin (100-1,000 ng/ml) alone treatment had no influence on left atrial contraction. On the other hand, pretreatment with endostatin (300 ng/ml) significantly inhibited bradykinin (1 uM)-induced contraction and voltage-dependent calcium current. These data suggest that endostatin may decrease bradykinin-induced cardiac contraction perhaps through the inhibition of voltage-dependent calcium channel. PMID- 26050756 TI - A review of electrolyte materials and compositions for electrochemical supercapacitors. AB - Electrolytes have been identified as some of the most influential components in the performance of electrochemical supercapacitors (ESs), which include: electrical double-layer capacitors, pseudocapacitors and hybrid supercapacitors. This paper reviews recent progress in the research and development of ES electrolytes. The electrolytes are classified into several categories, including: aqueous, organic, ionic liquids, solid-state or quasi-solid-state, as well as redox-active electrolytes. Effects of electrolyte properties on ES performance are discussed in detail. The principles and methods of designing and optimizing electrolytes for ES performance and application are highlighted through a comprehensive analysis of the literature. Interaction among the electrolytes, electro-active materials and inactive components (current collectors, binders, and separators) is discussed. The challenges in producing high-performing electrolytes are analyzed. Several possible research directions to overcome these challenges are proposed for future efforts, with the main aim of improving ESs' energy density without sacrificing existing advantages (e.g., a high power density and a long cycle-life) (507 references). PMID- 26050757 TI - Thermal and light induced spin crossover behavior of a dinuclear Fe(II) compound. AB - A dinuclear Fe(II) compound has been prepared through the reaction of 2,5 dichloride-4-phenylimino-1,2,4-triazole (L) with Fe(BF4)2.6H2O, with the formula [Fe2(L)5(SCN)4](H2O) (1). X-ray, magnetic, and (57)Fe Mossbauer characterizations showed that compound exhibited a spin crossover (SCO) behavior with T1/2 = 150 K. The study shows that introducing chloride groups on the ligand exerts a positive effect on increasing T1/2 and making SCO more complete. A LIESST effect was also observed for through a light irradiation experiment. PMID- 26050758 TI - Interaction of 4-imidazolemethanol with a copper electrode revealed by isotope edited SERS and theoretical modeling. AB - Adsorption of 4-imidazolemethanol (ImMeOH) on a copper electrode has been investigated by in situ isotope-edited (H/D and (63)Cu/(65)Cu) surface enhanced Raman spectroscopy (SERS) in aqueous solutions at physiological pH (7.0) in a potential window from -0.500 to -1.100 V. Theoretical modeling by DFT calculations at the B3LYP/6-311++G(d,p) level for light atoms and LANL2DZ with ECP for copper atoms have been employed for the interpretation of experimental data. The copper surface was modeled by a cluster of 6 atoms. It was found that the imidazole ring adopts Tautomer-I form in the adsorbed state and coordinates with the Cu surface through the N3 atom. Linear potential-dependence of nu(C4=C5) mode with the slope of (15 +/- 1) cm(-1) V(-1) was experimentally observed. The imidazole ring mode near 1492 cm(-1) primarily due to nu(C2-N3) + beta(C2H) vibration has also showed a considerable decrease in frequency at more negative electrode potentials with the slope of (9 +/- 2) cm(-1) V(-1). Both modes can be used as sensitive probes for analysis of interaction of the imidazole ring with the metal surface. In agreement with experimental data theoretical modeling has predicted higher stability of surface bound Tautomer-I compared with Tautomer-II. The formation of a covalent bond between the metal and adsorbate was experimentally evidenced by metal isotopic ((63)Cu/(65)Cu) frequency shift of nu(Cu-N) mode at 222 cm(-1), combined with theoretical modeling of the surface complex. PMID- 26050759 TI - On-chip gradient generation in 256 microfluidic cell cultures: simulation and experimental validation. AB - A microfluidic diffusion diluter was used to create a stable concentration gradient for dose response studies. The microfluidic diffusion diluter used in this study consisted of 128 culture chambers on each side of the main fluidic channel. A calibration method was used to find unknown concentrations with 12% error. Flow rate dependent studies showed that changing the flow rates generated different gradient patterns. Mathematical simulations using COMSOL Multi-physics were performed to validate the experimental data. The experimental data obtained for the flow rate studies agreed with the simulation results. Cells could be loaded into culture chambers using vacuum actuation and cultured for long times under low shear stress. Decreasing the size of the culture chambers resulted in faster gradient formation (20 min). Mass transport into the side channels of the microfluidic diffusion diluter used in this study is an important factor in creating the gradient using diffusional mixing as a function of the distance. To demonstrate the device's utility, an H2O2 gradient was generated while culturing Ramos cells. Cell viability was assayed in the 256 culture chambers, each at a discrete H2O2 concentration. As expected, the cell viability for the high concentration side channels increased (by injecting H2O2) whereas the cell viability in the low concentration side channels decreased along the chip due to diffusional mixing as a function of distance. COMSOL simulations were used to identify the effective concentration of H2O2 for cell viability in each side chamber at 45 min. The gradient effects were confirmed using traditional H2O2 culture experiments. Viability of cells in the microfluidic device under gradient conditions showed a linear relationship with the viability of the traditional culture experiment. Development of the microfluidic device used in this study could be used to study hundreds of concentrations of a compound in a single experiment. PMID- 26050760 TI - Vibrational spectroscopy of Methyl benzoate. AB - Methyl benzoate is studied as a model compound for the development of new IR pulse schemes with possible applicability to biomolecules. Anharmonic vibrational modes of Methyl benzoate are calculated on different level (MP2, SCS, CCSD(T) with varying basis sets) ab initio PESs using the vibrational self-consistent field (VSCF) method and its correlation corrected extensions. Dual level schemes, combining different quantum chemical methods for diagonal and coupling potentials, are systematically studied and applied successfully to reduce the computational cost. Isotopic substitution of beta-hydrogen by deuterium is studied to obtain a better understanding of the molecular vibrational coupling topology. PMID- 26050761 TI - N-type pyrazine and triazole-based luminogens with aggregation-enhanced emission characteristics. AB - N-type pyrazine-based 1,4- and 1,5-disubstituted 1,2,3-triazole derivatives, showing unique aggregation-enhanced emission characteristics, were facilely prepared via Cu- and Ru-catalysed azide-alkyne cycloadditions, respectively. Thanks to their electron-deficient properties, they could readily form red emissive charge transfer complexes with electron-donating triphenylamine in the aggregate and solid states. PMID- 26050762 TI - Teaching emotional intelligence. PMID- 26050763 TI - Study of treatments for cardiac arrest named trial of the year. PMID- 26050764 TI - Managers are recruiting too few senior practitioners. PMID- 26050765 TI - Trusts must redouble their efforts to meet rising demand. PMID- 26050766 TI - RCN Scotland calls for less emphasis on meeting targets. PMID- 26050768 TI - Long waiting times violate human rights, claims inquiry. PMID- 26050769 TI - Redesign can help people with mental health problems. PMID- 26050770 TI - Overlong waiting times are 'inhuman and degrading'. PMID- 26050771 TI - Board's eye view--Screening for falls. PMID- 26050779 TI - Management of pain in pre-hospital settings. AB - Assessment and management of pain in pre-hospital care settings are important aspects of paramedic and clinical team roles. As emergency department waiting times and delays in paramedic-to-nurse handover increase, it becomes more and more vital that patients receive adequate pre-hospital pain relief. However, administration of analgesia can be inadequate and can result in patients experiencing oligoanalgesia, or under-treated pain. This article examines these issues along with the aetiology of trauma and the related socioeconomic background of traumatic injury. It reviews validated pain-assessment tools, outlines physiological responses to traumatic pain and discusses some of the misconceptions about the provision of effective analgesia in pre-hospital settings. PMID- 26050780 TI - Dynamic nurse leadership in high-pressure situations. AB - Traditionally, healthcare professionals have been expected to acquire technical skills while minimal attention has been paid to the non-technical skills (NTS) they require to work in complex health environments, such as resuscitation rooms. This article explains the importance of NTS in improving patient outcomes and why a model of dynamic nurse leadership is useful in resuscitative care. PMID- 26050781 TI - Do emergency nurses have enough emotional intelligence? AB - A significant body of research suggests there is a correlation between measured emotional intelligence (EI) abilities and performance in nursing. The four critical elements of EI, namely the abilities to identify emotions correctly in self and others, using emotions to support reasoning, understanding emotions and managing emotions, apply to emergency care settings and are important for safe patient care, teamwork, retention and burnout prevention. This article describes 'emotional labour' and the importance of EI abilities for emergency nurses, and suggests that such abilities should be considered core competencies for the profession. PMID- 26050782 TI - Diagnosing meniscal tears in the emergency department. AB - Acute meniscal knee injuries can lead to instability of the joint if they are left untreated, but clinical examinations of patients' acutely injured knees can be challenging because of the pain and swelling involved. Although magnetic resonance imaging and arthroscopy are the gold standard investigations for the diagnosis of meniscal tears they cannot always be carried out in acute or emergency department settings. It is therefore essential that emergency care practitioners have good clinical examination skills to ensure safe and effective patient management, diagnosis, and outcomes, as well as the skills and knowledge required to carry out meniscal tear tests. This article reviews the literature on the most common examination techniques associated with acute injuries, especially meniscal injuries, to knees: joint line tenderness assessment, McMurray's test and the Apley's grind test. It analyses the sensitivity and specificity for each test to help practitioners understand the clinical significance of positive and negative findings. PMID- 26050783 TI - From maverick to guru. PMID- 26050784 TI - Biocontrol Activity of Bacillus subtilis Isolated from Agaricus bisporus Mushroom Compost Against Pathogenic Fungi. AB - Bacillus subtilis strain B154, isolated from Agaricus bisporus mushroom compost infected by red bread mold, exhibited antagonistic activities against Neurospora sitophila. Antifungal activity against phytopathogenic fungi was also observed. The maximum antifungal activity was reached during the stationary phase. This antifungal activity was stable over a wide pH and temperature range and was not affected by proteases. Assay of antifungal activity in vitro indicated that a purified antifungal substance could strongly inhibit mycelia growth and spore germination of N. sitophila. In addition, treatment with strain B154 in A. bisporus mushroom compost infected with N. sitophila significantly increased the yield of bisporus mushrooms. Ultraviolet scan spectroscopy, tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis, matrix-associated laser desorption ionization time-of-flight mass spectrometry, and electrospray ionization tandem mass spectrometry analyses revealed a molecular weight consistent with 1498.7633 Da. The antifungal compound might belong to a new type of lipopeptide fengycin. PMID- 26050785 TI - H-Bonding and charging mediated aggregation and emission for fluorescence turn-on detection of hydrazine hydrate. AB - In situ morphological transition and turn-on fluorescence of self-assembled NDI derivatives driven by hydrazine hydrate are realized through H-bonding and charging of aromatic building blocks, demonstrating a stimuli-responsive supramolecular system useful for visual detection of hydrazine hydrate. PMID- 26050786 TI - External Fixation combined with Limited Internal Fixation versus Open Reduction Internal Fixation for Treating Ruedi-Allgower Type III Pilon Fractures. AB - BACKGROUND: The optimal treatment of type III pilon fractures remains controversial. Hence, we performed this study to investigate whether open reduction and internal fixation (ORIF) is superior to external fixations combined with limited internal fixations (EFLIF). MATERIAL AND METHODS: From January 2012 to October 2013, a total of 78 patients were included. Twenty-six patients underwent EFLIF and 52 patients underwent ORIF. All subjects were followed up at 1, 3, 6, and 12 months postoperatively. All outcomes and complications were recorded. RESULTS: No statistical differences were observed in Mazur score or ROM between the 2 groups. There were significant differences between the 2 groups in hospital stay (P<0.001), reduction results (P=0.019), screw loosening (P=0.025), and traumatic arthritis (P=0.037). CONCLUSIONS: Similar functional outcomes were achieved in EFLIF and ORIF groups. Due to several limitations of this study, a well-designed randomized controlled trial involving more patients and long-term follow-up is needed to find an optimal treatment protocol. PMID- 26050787 TI - Polarized Neutron Reflectometry of Nickel Corrosion Inhibitors. AB - Polarized neutron reflectometry has been used to investigate the detailed adsorption behavior and corrosion inhibition mechanism of two surfactants on a nickel surface under acidic conditions. Both the corrosion of the nickel surface and the structure of the adsorbed surfactant layer could be monitored in situ by the use of different solvent contrasts. Layer thicknesses and roughnesses were evaluated over a range of pH values, showing distinctly the superior corrosion inhibition of one negatively charged surfactant (sodium dodecyl sulfate) compared to a positively charged example (dodecyl trimethylammonium bromide) due to its stronger binding interaction with the surface. It was found that adequate corrosion inhibition occurs at significantly less than full surface coverage. PMID- 26050788 TI - Neural responses to monetary incentives among self-injuring adolescent girls. AB - Rates of self-inflicted injury among adolescents have risen in recent years, yet much remains to be learned about the pathophysiology of such conduct. Self injuring adolescents report high levels of both impulsivity and depression behaviorally. Aberrant neural responding to incentives, particularly in striatal and prefrontal regions, is observed among both impulsive and depressed adolescents, and may mark common vulnerability to symptoms of anhedonia, irritability, and low positive affectivity. To date, however, no studies have examined associations between central nervous system reward responding and self injury. In the current study, self-injuring (n = 19) and control (n = 19) adolescent females, ages 13-19 years, participated in a monetary incentive delay task in which rewards were obtained on some trials and losses were incurred on others. Consistent with previous findings from impulsive and depressed samples, self-injuring adolescents exhibited less activation in both striatal and orbitofrontal cortex regions during anticipation of reward than did controls. Self-injuring adolescents also exhibited reduced bilateral amygdala activation during reward anticipation. Although few studies to date have examined amygdala activity during reward tasks, such findings are common among adults with mood disorders and borderline personality disorder. Implications for neural models of impulsivity, depression, heterotypic comorbidity, and development of both self injury and borderline personality traits are discussed. PMID- 26050789 TI - Preface: BITS2014, the annual meeting of the Italian Society of Bioinformatics. AB - This Preface introduces the content of the BioMed Central journal Supplements related to BITS2014 meeting, held in Rome, Italy, from the 26th to the 28th of February, 2014. PMID- 26050790 TI - Effects of an 18-week exercise programme started early during breast cancer treatment: a randomised controlled trial. AB - BACKGROUND: Exercise started shortly after breast cancer diagnosis might prevent or diminish fatigue complaints. The Physical Activity during Cancer Treatment (PACT) study was designed to primarily examine the effects of an 18-week exercise intervention, offered in the daily clinical practice setting and starting within 6 weeks after diagnosis, on preventing an increase in fatigue. METHODS: This multi-centre controlled trial randomly assigned 204 breast cancer patients to usual care (n = 102) or supervised aerobic and resistance exercise (n = 102). By design, all patients received chemotherapy between baseline and 18 weeks. Fatigue (i.e., primary outcome at 18 weeks), quality of life, anxiety, depression, and physical fitness were measured at 18 and 36 weeks. RESULTS: Intention-to-treat mixed linear model analyses showed that physical fatigue increased significantly less during cancer treatment in the intervention group compared to control (mean between-group differences at 18 weeks: -1.3; 95 % CI -2.5 to -0.1; effect size 0.30). Results for general fatigue were comparable but did not reach statistical significance (-1.0, 95%CI -2.1; 0.1; effect size -0.23). At 18 weeks, submaximal cardiorespiratory fitness and several muscle strength tests (leg extension and flexion) were significantly higher in the intervention group compared to control, whereas peak oxygen uptake did not differ between groups. At 36 weeks these differences were no longer statistically significant. Quality of life outcomes favoured the exercise group but were not significantly different between groups. CONCLUSIONS: A supervised 18-week exercise programme offered early in routine care during adjuvant breast cancer treatment showed positive effects on physical fatigue, submaximal cardiorespiratory fitness, and muscle strength. Exercise early during treatment of breast cancer can be recommended. At 36 weeks, these effects were no longer statistically significant. This might have been caused by the control participants' high physical activity levels during follow-up. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43801571, Dutch Trial Register NTR2138. Trial registered on December 9th, 2009. PMID- 26050792 TI - Systematic Review and Quality Appraisal of International Guidelines on Perinatal Care of Extremely Premature Infants. AB - OBJECTIVES: Clinicians often refer to published or local guidelines when counselling expectant parents on perinatal care decisions at the limits of viability. The objectives of this study are to systematically review the literature and assess the quality of published international guidelines regarding perinatal care of 22-25 week gestational age infants. STUDY DESIGN: MEDLINE, Pre MEDLINE and TRIP databases were systematically searched for guidelines on perinatal management of extremely premature infants. Included guidelines were: created by an institution that regularly cared for extremely premature infants; offered comprehensive care plans; and, published after 1999 in English. The final selected guidelines were appraised using the validated AGREE-II (Appraisal of Guidelines for Research & Evaluation) tool which consists of six quality domains (Scope and Purpose, Stakeholder Involvement, Rigour of Development, Clarity of Presentation, Applicability, and Editorial Independence). Overall guideline quality was rated and each appraiser was asked whether they recommended the guideline for use. RESULTS: Electronic and grey searches yielded 263 publications. Screening left 37 guidelines, 16 of which met inclusion criteria. Appraisal revealed deficits within all quality domains, predominantly 'Applicability', 'Editorial Independence' and 'Rigour of Development'. A wide range of mean domain scores within each guideline was observed. Overall quality scores ranged from 11%-61%; no guideline was assessed as suitable for use without modifications. CONCLUSION: Based on the AGREE-II criteria, we identified deficits in the quality of all of the published international guidelines, highlighting the need for rigorously and transparently developed guidelines to inform practice related to perinatal care of 22-25 week gestational age infants. PMID- 26050793 TI - Ni3S2@CoS core-shell nano-triangular pyramid arrays on Ni foam for high performance supercapacitors. AB - In this study, we demonstrate a facile method to fabricate novel Ni3S2 nano triangular pyramid (NTP) arrays on Ni foam through a hydrothermal process and build unique Ni3S2@CoS core-shell NTP arrays by electro-deposition. The obtained Ni3S2@CoS material displays twice the specific capacitance of the pure Ni3S2 material in both a three-electrode system (4.89 F cm(-2) at 4 mA cm(-2)) and asymmetric supercapacitor device (0.69 F cm(-2) at 1.43 mA cm(-2)). In addition, the asymmetric supercapacitor demonstrates the outstanding energy density of 28.24 W h kg(-1) at a power density of 134.46 W kg(-1), with a stable cycle life (98.83% retained after 2000 cycles). The unique structure of the Ni3S2@CoS core shell NTP arrays, which provides an ultra-thin CoS shell to enlarge efficient areas, introduces good conductivity, and short transportation lengths for both ions and electrons, contributes most to its excellent performance. Moreover, the bare Ni3S2 NTP arrays can be used as a new template to build other potential electrode materials. PMID- 26050791 TI - Validation and utilization of an internally controlled multiplex Real-time RT-PCR assay for simultaneous detection of enteroviruses and enterovirus A71 associated with hand foot and mouth disease. AB - BACKGROUND: Hand foot and mouth disease (HFMD) is a disease of public health importance across the Asia-Pacific region. The disease is caused by enteroviruses (EVs), in particular enterovirus A71 (EV-A71). In EV-A71-associated HFMD, the infection is sometimes associated with severe manifestations including neurological involvement and fatal outcome. The availability of a robust diagnostic assay to distinguish EV-A71 from other EVs is important for patient management and outbreak response. METHODS: We developed and validated an internally controlled one-step single-tube real-time RT-PCR in terms of sensitivity, linearity, precision, and specificity for simultaneous detection of EVs and EV-A71. Subsequently, the assay was then applied on throat and rectal swabs sampled from 434 HFMD patients. RESULTS: The assay was evaluated using both plasmid DNA and viral RNA and has shown to be reproducible with a maximum assay variation of 4.41 % and sensitive with a limit of detection less than 10 copies of target template per reaction, while cross-reactivity with other EV serotypes was not observed. When compared against a published VP1 nested RT-PCR using 112 diagnostic throat and rectal swabs from 112 children with a clinical diagnosis of HFMD during 2014, the multiplex assay had a higher sensitivity and 100 % concordance with sequencing results which showed EVs in 77/112 (68.8 %) and EV A71 in 7/112 (6.3 %). When applied to clinical diagnostics for 322 children, the assay detected EVs in throat swabs of 257/322 (79.8 %) of which EV-A71 was detected in 36/322 (11.2 %) children. The detection rate increased to 93.5 % (301/322) and 13.4 % (43/322) for EVs and EV-A71, respectively, when rectal swabs from 65 throat-negative children were further analyzed. CONCLUSION: We have successfully developed and validated a sensitive internally controlled multiplex assay for rapid detection of EVs and EV-A71, which is useful for clinical management and outbreak control of HFMD. PMID- 26050795 TI - Stacking Structures of Few-Layer Graphene Revealed by Phase-Sensitive Infrared Nanoscopy. AB - The stacking orders in few-layer graphene (FLG) strongly influences the electronic properties of the material. To explore the stacking-specific properties of FLG in detail, one needs powerful microscopy techniques that visualize stacking domains with sufficient spatial resolution. We demonstrate that infrared (IR) scattering scanning near-field optical microscopy (sSNOM) directly maps out the stacking domains of FLG with a nanometric resolution, based on the stacking-specific IR conductivities of FLG. The intensity and phase contrasts of sSNOM are compared with the sSNOM contrast model, which is based on the dipolar tip-sample coupling and the theoretical conductivity spectra of FLG, allowing a clear assignment of each FLG domain as Bernal, rhombohedral, or intermediate stacks for tri-, tetra-, and pentalayer graphene. The method offers 10-100 times better spatial resolution than the far-field Raman and infrared spectroscopic methods, yet it allows far more experimental flexibility than the scanning tunneling microscopy and electron microscopy. PMID- 26050794 TI - A knowledge base for Vitis vinifera functional analysis. AB - BACKGROUND: Vitis vinifera (Grapevine) is the most important fruit species in the modern world. Wine and table grapes sales contribute significantly to the economy of major wine producing countries. The most relevant goals in wine production concern quality and safety. In order to significantly improve the achievement of these objectives and to gain biological knowledge about cultivars, a genomic approach is the most reliable strategy. The recent grapevine genome sequencing offers the opportunity to study the potential roles of genes and microRNAs in fruit maturation and other physiological and pathological processes. Although several systems allowing the analysis of plant genomes have been reported, none of them has been designed specifically for the functional analysis of grapevine genomes of cultivars under environmental stress in connection with microRNA data. DESCRIPTION: Here we introduce a novel knowledge base, called BIOWINE, designed for the functional analysis of Vitis vinifera genomes of cultivars present in Sicily. The system allows the analysis of RNA-seq experiments of two different cultivars, namely Nero d'Avola and Nerello Mascalese. Samples were taken under different climatic conditions of phenological phases, diseases, and geographic locations. The BIOWINE web interface is equipped with data analysis modules for grapevine genomes. In particular users may analyze the current genome assembly together with the RNA-seq data through a customized version of GBrowse. The web interface allows users to perform gene set enrichment by exploiting third-party databases. CONCLUSIONS: BIOWINE is a knowledge base implementing a set of bioinformatics tools for the analysis of grapevine genomes. The system aims to increase our understanding of the grapevine varieties and species of Sicilian products focusing on adaptability to different climatic conditions, phenological phases, diseases, and geographic locations. PMID- 26050796 TI - Development of a pharmacogenetic-based warfarin dosing algorithm and its performance in Brazilian patients: highlighting the importance of population specific calibration. AB - BACKGROUND: The main aims of the present study were to develop a pharmacogenetic based warfarin dosing algorithm and to validate it in a highly admixed population. MATERIALS & METHODS: We included two patient cohorts treated with warfarin (first cohort, n = 832; and second cohort, n = 133). RESULTS: Our algorithm achieved a determination coefficient of 40% including the variables age, gender, weight, height, self-declared race, amiodarone use, enzyme inducers use, VKORC1 genotypes and predicted phenotypes according to CYP2C9 polymorphisms. CONCLUSION: Data suggest that our developed algorithm is more accurate than the IWPC algorithm when the application is focused on patients from the Brazilian population. Population-specific derivation and/or calibration of warfarin dosing algorithms may lead to improved performance compared with general use dosing algorithms currently available. Original submitted 26 November 2014; Revision submitted 9 April 2015. PMID- 26050797 TI - Transformation of azulenes to bicyclic [4]dendralene and heptafulvene derivatives via photochemical cycloaddition of dialkylsilylene. AB - Regioselective cycloaddition of dialkylsilylene upon irradiation at 440 nm converts azulene and guaiazulene to bicyclic [4]dendralene and heptafulvene derivatives, respectively. Significant sigma-pi interactions in the resulting new silacycles were suggested using UV-vis spectra and theoretical calculations. PMID- 26050799 TI - Essential and current methods for a practical approach to comparative neuropathology. AB - The understanding of mechanisms that provoke neurological diseases in humans and in animals has progressed rapidly in recent years, mainly due to the advent of new research instruments and our increasing liability to assemble large, complex data sets acquired across several approaches into an integrated representation of neural function at the molecular, cellular, and systemic levels. Nevertheless, morphology always represents the essential approaches that are crucial for any kind of interpretation of the lesions or to explain new molecular pathways in the diseases. This mini-review has been designed to illustrate the newest and also well-established principal methods for the nervous tissue collection and processing as well as to describe the histochemical and immunohistochemical staining tools that are currently most suitable for a neuropathological assessment of the central nervous system. We also present the results of our neuropathological studies covering material from 170 cases belonging to 10 different species of mammals. Specific topics briefly addressed in this paper provide a technical and practical guide not only for researchers that daily focus their effort on neuropathology studies, but also to pathologists who occasionally have to approach to nervous tissue evaluation to answer questions about neuropathology issues. PMID- 26050800 TI - Anatomy and clinical significance of the maxillary nerve: a literature review. AB - BACKGROUND: The aim of this paper was to summarise the anatomical knowledge on the subject of the maxillary nerve and its branches, and to show the clinical usefulness of such information in producing anaesthesia in the region of the maxilla. MATERIALS AND METHODS: A literature search was performed in Pubmed, Scopus, Web of Science and Google Scholar databases, including studies published up to June 2014, with no lower data limit. RESULTS: The maxillary nerve (V2) is the middle sized branch of the trigeminal nerve - the largest of the cranial nerves. The V2 is a purely sensory nerve supplying the maxillary teeth and gingiva, the adjoining part of the cheek, hard and soft palate mucosa, pharynx, nose, dura mater, skin of temple, face, lower eyelid and conjunctiva, upper lip, labial glands, oral mucosa, mucosa of the maxillary sinus, as well as the mobile part of the nasal septum. The branches of the maxillary nerve can be divided into four groups depending on the place of origin i.e. in the cranium, in the sphenopalatine fossa, in the infraorbital canal, and on the face. CONCLUSIONS: This review summarises the data on the anatomy and variations of the maxillary nerve and its branches. A thorough understanding of the anatomy will allow for careful planning and execution of anaesthesiological and surgical procedures involving the maxillary nerve and its branches. PMID- 26050798 TI - Maternal Encouragement to Approach Novelty: A Curvilinear Relation to Change in Anxiety for Inhibited Toddlers. AB - Various parenting behaviors (e.g., protection, intrusiveness, sensitivity) have been shown to impact young children's anxiety development, particularly for temperamentally inhibited children. These behaviors have sometimes predicted both increases and decreases in anxiety in inhibited children, suggesting that linear relations may not adequately model their influence. In the current study, we proposed the dimension of encouragement to approach novelty to characterize parenting behavior ranging from very little encouragement (i.e., protective behavior) to very strong encouragement (i.e., intrusiveness), with gentle encouragement residing in the middle. In a sample of 110 toddlers (48 female, 62 male) and their mothers, the linear and curvilinear effects of this parenting dimension were investigated in relation to change in child separation anxiety and shyness from age 2 to age 3. Inhibited temperament was also investigated as a moderator. Encouragement to approach novelty displayed the hypothesized curvilinear relation to change in separation anxiety, but not shyness, at extreme levels of inhibited temperament. Toddlers increased in separation anxiety when mothers' encouragement resided at either extreme end of the continuum, with lower child anxiety occurring when mothers displayed behavior closer to the middle of the continuum. Implications for the study of parenting outcomes for inhibited toddlers are discussed. PMID- 26050801 TI - The biology behind the human intervertebral disc and its endplates. AB - The intervertebral discs (IVDs) are roughly cylindrical, fibrocartilaginous, articulating structures connecting the vertebral bodies, and allowing movement in the otherwise rigid anterior portion of the vertebral column. They also transfer loads and dissipate energy. Macroscopically the intervertebral disc can be divided into an outer annulus fibrosus surrounding a centrally located nucleus pulposus. The endplates surround the IVD from both the cranial and caudal ends, and separate them from the vertebral bodies and prevent the highly hydrated nucleus pulposus from bulging into the adjacent vertebrae. The IVD develop from the mesodermal notochord and receive nutrients mostly through the cartilaginous endplates. Physiologically they are innervated only in the outer annulus fibrosus by sensory and sympathetic perivascular nerve fibres, branches from the sinuvertebral nerve, the ventral rami of spinal nerves or from the grey rami communicantes. The IVD undergo changes with ageing and degeneration, the latter having two types i.e. "endplate-driven" involving endplate defects and inward collapse of the annulus fibrosus and "annulus-driven" involving a radial fissure and/or an IVD prolapse. This review summarises and updates the current state of knowledge on the embryology, structure, and biomechanics of the IVD and its endplates. To further translate this into a more clinical context this review also demonstrates the impact of ageing and degeneration on the above properties of both the IVD and its endplates. PMID- 26050802 TI - Collagen types I and II distribution: a relevant indicator for the functional properties of articular cartilage in immobilised and remobilised rabbit knee joints. AB - The objective of the present work was to study changes in collagen type I and type II distribution in the articular cartilage of immobilised and remobilised rabbit knee joints. Twenty-four adult male rabbits were divided into three groups. One of the groups was a control group with free movement. The right knee joints of animals of the other two groups were immobilised for 4 weeks, followed by a period of 10 weeks of remobilisation for animals of group 3. Collagen type I and type II in the articular cartilage of tibial medial condyle of the right knee joint were estimated immunohistochemically in all groups. A degenerative process was evident after 4 weeks of immobilisation of rabbit knee joint leading to a partial shift in the density of collagen composition from type II to type I. After a period of 10 weeks of remobilisation, regenerative processes, evidenced by a restoration of collagen type II to normal, proceeded on top of degenerative processes, evidenced by the significantly higher content of collagen type I compared with normal. The present study pointed to the importance of assessment of collagen distribution as a relevant indicator for the functional properties of articular cartilage in immobilised and remobilised joints. PMID- 26050803 TI - Immunohistochemical evidence of the co-localisation of cocaine and amphetamine regulatory peptide with neuronal isoform of nitric oxide synthase, vasoactive intestinal peptide and galanin within the circular muscle layer of the human caecum. AB - The enteric nervous system consists of about one hundred million of neurons. In big mammals (including humans) intestinal enteric neuronal cells are grouped into three types of intramural ganglia located within myenteric, as well as outer and inner submucosal plexuses, which are connected by numerous nerve fibres. Both nerve fibres and cell bodies located in the gastrointestinal tract utilise a broad spectrum of active substances. One of them is cocaine- and amphetamine regulated transcript peptide (CART). The goal of the current study was to determinate the distribution and degree of co-localisation of CART with substances taking part in intestinal motor activity by double labelling immunofluorescence technique. During the study CART-, neuronal isoform of nitric oxide synthase (nNOS)-, vasoactive intestinal peptide (VIP)- and/or galanin (GAL) - like immunoreactive (LI) nerve fibres in the circular muscle layer of the human caecum were observed in all patients studied. The degree of co-localisation of particular substances with CART depended on their type. The majority of CART-LI fibres contained simultaneously nNOS, slightly lower degree of co-localisation was observed in the case of the VIP, while simultaneously CART- and GAL-positive nerve fibres were observed less often. PMID- 26050804 TI - Morphometric studies of the mandibular and maxillofacial regions of the Kuri cattle and the implications in regional anaesthesia. AB - This work investigated and analysed some morphometrical measurements of mandibles and maxillofacial regions of ten adult Kuri cattle (above 5 years) skulls that were apparently free from musculoskeletal deformity. A total of 19 (13 mandibular and 6 maxillofacial) parameters were taken. The mean mandibular length and height were found to be 41.3 +/- 2.35 cm and 22.6 +/- 1.40 cm, while the mean mental foramen height and width were 0.8 +/- 0.08 cm and 1.5 +/- 0.25 cm, respectively. The mean distances from lateral alveolar root to mental foramen and from the latter to the most caudal border of the mandible were 4.8 +/- 0.61 cm and 34.2 +/ 1.93 cm, respectively. The mean mandibular foramen width was 1.1 +/- 0.14 cm, while the distance from this foramen to the caudal border of mandible at that level was 4.0 +/- 0.32 cm. The mean distances from facial tuberoses to the infraorbital foramen and from the latter to the alveolar root ventral to it were 5.3 +/- 0.63 cm and 3.7 +/- 0.47 cm, whereas the mean infraorbital foramen height and width stood at 1.2 +/- 0.18 cm and 1.0 +/- 0.22 cm, respectively. The infraorbital foramens in 60% of the specimen were located above the first upper premolar, while 20% were above second premolar, and another 20% at the junction above first and second upper premolars. These findings provide important landmarks needed for clinical manoeuvres on the head of the Kuri cattle for regional anaesthesia in procedures like trephination, dehorning, tooth extraction and oral and dental surgeries. PMID- 26050805 TI - Morphometrics of foramen magnum in African four-toed hedgehog (Atelerix albiventris). AB - The purpose of this study was to examine the morphometry of the foramen magnum of African four-toed hedgehog (Atelerix albiventris) in Maiduguri. Fourteen hedgehog skulls (7 male and 7 female each) were used for this study. The overall mean value of foramen magnum height and width were 0.51 +/- 0.05 cm and 0.64 +/- 0.04 cm while occipital condylar and interparacondylar widths were 1.00 +/- 0.12 cm and 1.62 +/- 0.07 cm, respectively. There was no significant difference between the two sexes. The foramen magnum index was 83.4 +/- 5.51 cm in males and was significantly higher than 76.3 +/- 6.37 cm observed in females. The presences of dorsal notches (occipital dysplasia) were observed, that were of three distinct types. It is envisaged, that the study will provide a valuable database on the anatomy of foramen magnum of hedgehogs in Nigeria for morphological, neurological, zooarchaeological, and comparative anatomical studies. PMID- 26050806 TI - Anatomic variation of alveolar antral artery. AB - The alveolar antral artery (AAA) was unanimously encountered in a few available studies with an intraosseous course to anastomose with the infraorbital artery. We report here two cases in which dissection revealed an extraosseous placement of this artery, between the lateral wall of the maxillary sinus and the Schneiderian membrane. The frequency of occurrence of the intraosseous anastomosis should be so modified from 100% to < 100%. This arterial course over the Schneiderian membrane is important during surgical procedures: if it is identified preoperatively it can be avoided, or ligaturated, if not, it may be accidentally severed and uncomfortable haemorrhage may disturb the surgical procedure. In the first case reported here hybrid morphology of the AAA was also found, demonstrating that arterial anatomy should be considered with caution, on a case-by-case basis. PMID- 26050807 TI - Histological, histochemical and fine structure studies of the lacrimal gland and superficial gland of the third eyelid and their significance on the proper function of the eyeball in alpaca (Vicugna pacos). AB - The lacrimal gland (LG) and superficial gland of the third eyelid (SGTE) belong to accessory organs of the eye. The aim of the present studies was to evaluate the histological, histochemical and fine structure of the LG and SGTE obtained from 3 adult females and 2 adult males of alpaca (Vicugna pacos). The LG was situated in the dorsolateral angle of the orbit between the dorsal rectus and the lateral rectus muscles. The SGTE was located between the medial rectus muscle, the ventral rectus muscle and was partially covered by the ventral oblique muscle of the eyeball. There were no effect of gender on the morphometry of examined LG and SGTE. The third eyelid resembles an anchor in shape. During histological and ultrastructural analyses using light and transmission electron microscopy, it was established that the LG and SGTE are tubulo-acinar glands with mucoserous characters. The LG contains either lymphocytes or plasma cells, while SGTE had rare plasma cells and numerous lymphocytes in connective tissue. The cartilage of the third eyelid was composed of hyaline tissue. Numerous aggregations of lymphocytes as lymph nodules in bulbar surface of the third eyelid were observed. The LG and SGTE secretory cells exhibited a similar ultrastructure appearance in electron microscopic examination, with secretory cells tightly filled with intracytoplasmatic secretory granules and numerous clusters of mucus of different sizes which were observed in the peripheral cells compartment. PMID- 26050808 TI - Morphological variation of carotid artery bifurcation level in digital angiography. AB - Knowing of the level of carotid artery bifurcation (CB) is important for vascular surgery in the neck, radical neck dissections, carotid sinus baroreceptor stimulation, catheterisations, and aneurysms. The aim of this study was to determine the CB level in relation with the cervical vertebral levels, compare them on the right and the left sides, and investigate the relation of CB level with the length of neck. In this study, 100 conventional carotid angiographies were performed. The CB level was determined in relation with 10 different levels which were the levels of the cervical vertebrae and intervertebral disks, and the relation of CB level with the length of neck was investigated. The right and left CB levels of the patients were also determined, and compared. The highest level of CB was at the level of C2 vertebra, and the lowest level of CB was at the level of C6-C7 intervertebral disk in both male and female. When all patients were taken into consideration, CB level was most frequently seen at the level of C4-C5 (29%) on the right side, and at the level of C4 (26%) on the left side. The CB levels were not symmetrical in 10 female and 23 male. Knowing of the anatomical variations of CB level is important in surgical procedures. The anatomical differences must be taken into consideration since the neighbouring structures of CB change in case of variations. We believe that the results of this study will shed light to planning of all interventional methods concerning common carotid artery and its branches as well as surgery in the neck, and will help to minimise the complications. PMID- 26050809 TI - The Turin Shroud face: the evidence of maxillo-facial trauma. AB - The Turin Shroud (TS) is a linen cloth commonly associated with Jesus Christ, his crucifixion and burial. Several medical specialists have debated the injuries of the TS Man, nevertheless there are no detailed and quantitative data about the anatomy of the TS face. The purpose of this study was to analyse the cephalometric measurements of the face image of the TS. The TS face image was acquired by a picture and processed using a cephalometric software, Oris Ceph(r) (Up to date 2012). The image of the soft tissues was processed in order to obtain skeletal points and a cephalometric analysis of the soft and skeletal tissues was performed. Image processing of the TS face shows that the Man represented in it has undergone a maxillo-facial trauma, especially a left displacement of the mandible, probably due to temporo-mandibular joint lesions. This condition has not been described before, despite several studies on the subject. PMID- 26050810 TI - Septal aperture aetiology: still more questions than answers. AB - Many theories have been suggested in order to explain the aetiology of septal aperture. The influence of genes, the size and shape of ulna processes, joint laxity, bone robusticity, osteoarthritis, and osteoporosis has been discussed; however, the problem has not yet been solved. The aim of the study was to examine the correlations between musculoskeletal stress markers, humeral robusticity and septal aperture. Additionally, the frequency of septal aperture according to sex, age, and skeletal side had been analysed. The skeletal material had come from a medieval cemetery in Cedynia, Poland. Skeletons of 201 adults (102 males, 99 females) had been examined and septal aperture had been scored. Six muscle attachment sites of upper limb bones had been analysed. Humeral robusticity had been calculated by use of the humeral robusticity index. The frequency of septal aperture among the population from Cedynia is 7.5%. There are no differences in septal aperture prevalence between males and females, the skeletal sides or age groups. In the analysed material, males with less developed muscle markers of right upper bones proved a higher predictable rate in having septal aperture (R = -0.34). On the left bones and among females, the converse correlation had also been found, but it is not statistically significant. The correlation between septal aperture and humeral robusticity is converse, yet small and insignificant. These results can confirm the theory of joint laxity and suggest that stronger bones (heavier muscles, more robust bones) increase joint tightness, and therefore protect the humeral lamina from septal aperture formation. But this theory needs a further detailed analysis. PMID- 26050811 TI - Left ventricular false tendons: echocardiographic characteristics in the Polish population. AB - BACKGROUND: False tendon (FT) is described in a wide range (40% to 62%) of the examined hearts depending on age and additional heart abnormalities. On echocardiography, the range is even wider (1.6-78%), depending on study design and inclusion criteria. Ultrasonographic characteristics of left ventricular FTs in the Polish population are not well known. MATERIALS AND METHODS: Echocardiographic examinations of 1,679 consecutive patients were evaluated. All cases were classified according to American Society of Echocardiography Committee of Nomenclature and Standards Document on Identification of the Segments of the Heart Muscle. RESULTS: In our study, fibrous structures in the lumen of the left ventricle were detected in 100 (6%) subjects of the study group. The age of the subjects ranged from 16 to 87 years (mean age 47.9), 50 were males and 50 were females. In 94% of the subjects, FT was a single structure. No patient had clinically evident arrhythmia. CONCLUSIONS: In the Polish population, FT can be identified in all age groups, and the prevalence is similar to that reported in the literature. PMID- 26050812 TI - Intermediate veins in swine (Sus scrofa domestica) kidney: authors' own anatomical classification. AB - BACKGROUND: The use of domestic swine as an experimental animal is increasing steadily. Swine organs are the best animal model for urological experiments. The aim of the study was to evaluate the course and size of intermediate veins in a swine kidney. The research results were compared with the results obtained from studies on venous vascularisation of human kidneys. The knowledge of the above mentioned vessels is important both in human and veterinary medicine and will enable researchers to compare and notice differences between human and swine organs. MATERIALS AND METHODS: The study was conducted on 94 kidneys, 47 right ones and 47 left ones, taken from adult domestic swines (Sus scrofa domestica). The kidneys were prepared and corrosion casts were made. RESULTS: The average lumen diameter of secondary intermediate veins was 7.96 mm. The average diameter of the primary intermediate veins directly inserted in the renal vein (type A) and primary intermediate veins inserted in the secondary intermediate veins (type B) amounted to 6.7 mm and 4.75 mm, respectively. The average length of primary intermediate veins of type A was 21.91 mm. Secondary intermediate veins were shorter - on average 19.83 mm. Primary intermediate veins of type B were on average 12.91 mm long. CONCLUSIONS: Intermediate veins are formed in the area of vascular anastomoses on the level of renal papillae. The following veins can be distinguished: primary intermediate veins of type A and type B, as well as secondary intermediate veins. Secondary intermediate veins and primary intermediate veins of type A run only on the ventral side of the renal pelvis. Only the primary intermediate veins of type B can run on the dorsal side. From the anatomy point of view, intermediate veins of swine kidneys are very similar to equivalent vessels in human kidneys as regards their run and anastomoses. PMID- 26050813 TI - The abducens nerve: its topography and anatomical variations in intracranial course with clinical commentary. AB - BACKGROUND: The sixth cranial nerve (CN VI) - or the abducens nerve - in humans supplies only the lateral rectus muscle. Due to its topographic conditions, including angulations and fixation points along its course from the brainstem to the lateral rectus muscle, the CN VI is vulnerable to injury. Every case of CN VI palsy requires precise diagnostics, which is facilitated by an understanding of the anatomy. The present article's aims include a detailed study of the intracranial course of the CN VI, determination of occurrence of its particular anatomical variations, as well as presentation of some essential anatomical conditions which may conduce to CN VI palsy. Special emphasis was put on the correlation between craniometric measurements and a particular variation of the CN VI, which complements the data that can be found in literature. MATERIALS AND METHODS: Twenty randomly selected specimens of cadaveric heads fixed in a 10% formalin solution were studied. The study used 40 specimens of the CN VI in order to examine its course variations within the section between the pontomedullary sulcus and the superior orbital fissure. RESULTS: Detailed analysis of the CN VI topography and anatomy in its intracranial course revealed 3 anatomical variations of the nerve in the studied specimens. Variation I, found in 70% of cases, covers those cases in which the CN VI was found to be a single trunk. Those cases in which there was a branching of the CN VI exclusively inside the cavernous sinus were classified as variation II, occurring in 20% of cases. Cases of duplication of the CN VI were classified as variation III, found in 10% of the specimens. In 75% of cases of CN VI duplication one of the nerve trunks ran upwards from the petrosphenoidal ligament, outside Dorello's canal. CONCLUSIONS: The CN VI throughout its intracranial course usually runs as a single trunk, however, common variations include also branching of the nerve in the cavernous sinus or duplication. Topographic relations of the CN VI with adjacent structures account for the risk of injuries which may be caused to the nerve as a result of a disease or surgical procedures. PMID- 26050814 TI - Sexual dimorphism of human vallate papillae: an in vivo study of normative morphology. AB - The perimeters of vallate papillae (VP) house approximately half of the taste buds on the human tongue. However, little information exists regarding perimeter measurements of VP. Likewise, great diversity exists among reports of the number of VP and diameter of VP, in general. The research presents an analysis of the perimeters, counts, and diameters of VP in vivo. Endoscopic examination was performed on 79 individuals (40 females, 39 males) between 18 and 26 years of age. A total of 583 VP were counted, 565 of which were able to be measured. Data revealed a statistically significant difference between male and female VP count (t(75.6) = 4.5; p = 0.00003). Females had, on average, 2.22 more VP than males. Males were found to have larger mean VP diameter per person and mean VP perimeter per person than females (t(58.9) = -2.4; p = 0.021 and t(59.3) = -2.4; p = 0.019, respectively). The report demonstrates that VP are sexually dimorphic at the gross anatomical level. PMID- 26050815 TI - Early development of the facial nerve in human embryos at stages 13-15. AB - Study was made on 16 human embryos at developmental stages 13-15 (fifth week). The facial nerve was traced on serial sections made in three planes (sagittal, frontal and horizontal) and stained with routine histological methods and impregnated with silver. In embryos at stage 13 the facial ganglion forms a complex structure with the vestibulocochlear ganglion. It is of fusiform shape in contact with epipharyngeal placode and is located anteriorly and ventrally to the vestibulocochlear ganglion. In embryos at stage 14 the facial ganglion separates from the vestibular and cochlear ganglia and the chorda tympani as the first branch appears. During stage 15 the main trunk of the facial nerve elongates and the greater petrosal nerve originates at the level of the facial ganglion and above the origin of the chorda tympani. PMID- 26050816 TI - Comparison of formaldehyde and methanol fixatives used in the detection of ion channel proteins in isolated rat ventricular myocytes by immunofluorescence labelling and confocal microscopy. AB - In this study, a fixation protocol using a 10% neutral buffered formalin (FA) solution and another protocol using a methanol (MeOH) solution were compared for detection of ion channels, Kv1.5, Kv4.2, Cav1.2, Kir6.2, Nav1.5 and Nav1.1 in rat myocytes by immunolabelling. Kv1.5 and Kv4.2 at intercalated discs and Cav1.2 at transverse tubules were not detected by FA but were detected by MeOH. Kir6.2 at transverse tubules and Nav1.5 at sarcolemma were detected by FA but not by MeOH. It is suggested that both FA and MeOH fixation protocols should be used for the detection of cardiac ion channels by immunolabelling. PMID- 26050817 TI - Hypertrophy of palmaris longus muscle, a rare anatomic aberration. AB - The palmaris longus muscle (PLM) is considered to be a phylogenetically degenerate muscle. For many authors, this may be the cause of its great variability. The loss of function in the PLM makes it an important muscle in plastic and reconstructive surgery. During a study of PLM agenesis rate in the Hungarian population, a 22-year-old female showed an unusual pattern of muscles in her left forearm, which was found to be a hypertrophied PLM. The hypertrophied muscle was causing symptoms of median and ulnar nerve compression. PMID- 26050818 TI - Bilateral large vestibular aqueduct syndrome in an 11-year-old boy. Radiological and clinical findings. AB - Clinical observations supplemented with imaging examination show that the large vestibular aqueduct syndrome (LVAS) is a rare developmental anomaly of the inner ear, which leads to hearing loss. The authors present a case history, results of imaging examination (high resolution CT, MRI), results of hearing acuity examinations (tonal audiometry, otoacoustic emissions, brainstem auditory evoked potentials) and results of balance examinations (videonystagmography) in an 11 year-old boy suffering from deep mixed progressive hearing loss of the right ear due to head trauma. The aim of this paper is to specify the most typical clinical, radiological and anatomopathological manifestations of this pathology of the inner ear. The authors describe the diagnostic and identification difficulties associated with the mixed hearing loss observed in this case. The article also discusses the child's activity limitations, which should be taken into account once diagnosis of this rare labyrinthine pathology is established. PMID- 26050819 TI - Relationship between mean platelet volume and retinopathy of prematurity. PMID- 26050820 TI - Anion coordination selective [Mn3] and [Mn4] assemblies: synthesis, structural diversity, magnetic properties and catechol oxidase activity. AB - Syntheses, crystal structures, magnetic properties and catechol oxidation behavior are presented for [Mn3] and [Mn4] aggregates, [MnMn(II)(O2CMe)4(dmp)2(H2O)2].2H2O (1.2H2O), [MnMn(II)(O2CCH2Cl)4(dmp)2(H2O)2].H2O.MeOH (2.H2O.MeOH), [Mn(MU3-O)(dmp)4(MU DMSO)(N3)(DMSO)(H2O)]ClO4.DMSO (3.ClO4.DMSO), and [Mn(MU3-O)(dmp)4(MU DMSO)(ClO4)(DMSO)(H2O)]ClO4.DMSO (4.ClO4.DMSO), developed with single type ligand H2dmp, 2-[(2-hydroxy-1,1-dimethyl-ethylimino)-methyl]-phenol. The successful isolation of 1-4 resulted from a systematic exploration of the effect of Mn(II) salts, added carboxylates, Mn/H2dmp ratio, presence of azide, and other reaction conditions. The cores of 1 and 2 are similar and consist of a linear Mn(III)Mn(II)Mn(III) unit in a carboxylate and H2dmp environment, revealing a central Mn(II) ion in a different environment and terminal Mn(III) ions available for the introduction of structural and magnetic anisotropy to the system. The cores of 3 and 4 are also similar and consist of a distorted incomplete adamantane type Mn4 coordination assembly in a carboxylate-free environment built on a triangular [Mn(MU3-O)] unit. The magnetic behavior of complexes 1-3 is dominated by antiferromagnetic exchange coupling that results in ground state spin values of S = 3/2 for 1 and 2 and S = 0 for 3. In solution, all four complexes 1-4 show catechol oxidation activity towards 3,5-DTBC. The catalytic activity for the oxidation of 3,5-DTBC in air followed the order 4 < 3 < 1 < 2. PMID- 26050821 TI - Bringing animal personality research into the food web arena. AB - While the concept of consistent behavioural differences among individuals of the same population has gained a lot of scientific attention over the last decade, its implementation into a community context with a focus on species-level interactions is still in its infancy. In their study on the effects of animal personalities on predator-prey functional responses of mussel-eating crabs, Toscano & Griffen (2014) introduce a promising avenue for future research synthesizing concepts and ideas from animal behaviour and food web ecology. More precisely, by showing that the interplay of animal personalities and predator and prey body sizes significantly alters the outcome of predator-prey interactions, this study provides important evidence that the concept of animal personalities needs greater consideration if we want to refine and improve current models of predator-prey interactions and the impact of individual-level variation on quantitative food-web dynamics. PMID- 26050822 TI - Effect of the functionalisation route on a Zr-MOF with an Ir-NHC complex for catalysis. AB - A new iridium N-heterocyclic carbene (NHC) metallolinker has been synthesised and introduced into a metal-organic framework (MOF), for the first time, via two different routes: direct synthesis and postsynthetic exchange (PSE). The two materials were compared in terms of the Ir loading and distribution using X-ray energy dispersive spectroscopy (EDS), the local Ir structure using X-ray absorption spectroscopy (XAS) and the catalytic activity. The materials showed good activity and recyclability as catalysts for the isomerisation of an allylic alcohol. PMID- 26050823 TI - Computed tomography-guided radiofrequency ablation is a safe and effective treatment of osteoid osteoma located outside the spine. AB - INTRODUCTION: The aim of this study was to evaluate the long-term clinical outcome after computed tomography (CT)-guided radiofrequency ablation (RFA) in patients diagnosed with osteoid osteoma (OO) located in the upper and lower extremities. METHODS: The study population included 52 patients with a typical clinical history and radiologically confirmed OO who received CT-guided RFA treatment from 1998 to February 2014 at Aarhus University Hospital, Denmark. The clinical outcome was evaluated based on patient-reported outcome measures and medical record review. RESULTS: The response rate was 52/60 (87%). Pain relief after the first RFA treatment was found in 46/52 (88%) of the patients and after re-RFA in 51/52 (98%) of the patients. One patient underwent open resection after RFA. No major complications occurred, and four patients reported minor complications in terms of small skin burn, minor skin infection and hypoaesthesia at the entry point. In all, 50 of 52 (96%) patients reported to be "very satisfied" with the RFA treatment. CONCLUSION: CT-guided RFA is a safe and effective treatment with high patient satisfaction and it provides robust pain relief and improves the patients' quality of life. RFA should be the treatment of choice for most OO. FUNDING: not relevant. TRIAL REGISTRATION: The Danish Data Protection Agency approved the project with record number 2007-58-0010. PMID- 26050824 TI - The Danish preventive child health examination should expand on mental health and the well-being of the family. AB - INTRODUCTION: In Denmark, around one in six children has significant somatic, psychological or social health problems, often in combination. The preventive child health examinations have a high participation rate; and they produce significant findings, predominantly concerning the child's physical health. The aim of this study was to explore how the child's physical, cognitive and psychosocial health are examined and assessed at the health examinations of children aged 0-5 years in general practice. METHODS: Our study employed observations of the consultations as well as individual interviews. A total of nine doctors from seven clinics participated. We included 21 cases in our study, each consisting of a consultation and subsequent interviews with the child's parents and with the doctor. RESULTS: The examination of the child's physical health and development is an important feature of the health examination. Motor, cognitive, social skills and mental health are assessed globally through observation and communication with the child, and, to a lesser degree, through conversation with the parents. The child health examination rarely has a family perspective, unless the doctor is already aware of problems in the family. CONCLUSION: The preventive child health examination is an important platform for examination and dialogue concerning a child's health. The physical aspect works well, but there is a need for development of the assessment of the child's mental health and the well-being of the family. FUNDING: Postdoctoral Fellowships in General Practice/Family Medicine - Denmark. TRIAL REGISTRATION: not relevant. PMID- 26050825 TI - High success rate after arterial renal embolisation. AB - INTRODUCTION: The objective of this study was to present patients who underwent either elective or acute renal embolisation in a single centre where embolisation was available at all hours. METHODS: The records of all patients who underwent transcatheter arterial embolisation (TAE) at Odense University Hospital from October 2010 to July 2013 were extracted retrospectively and examined to determine the indication for treatment, procedural details and complications. Patients were divided into four groups: renal cancer, trauma, angiomyolipoma (AML) and others. When there was indication for embolisation, a renal angiography was performed and followed by embolisation, if possible. The procedure was performed in local analgesia via the common femoral artery and as a super selective procedure to save as many viable nephrons as possible. The most commonly used embolisation materials were coils. RESULTS: In total, 35 patients were included; their mean age was 64 years (range: 17-95 years): eight females and 27 males. A total of 15 patients underwent embolisation due to renal cancer; nine elective and six acute procedures. Seven traumas were embolised. Five AML patients underwent embolisation of which three were treated acutely. Finally, eight patients were treated because of spontaneous bleeding, arteriovenous malformation or aneurisms; three elective, five acute. The post-embolisation syndrome occurred in 22 patients (63%) and six patients (17%) were re-embolised. One patient had persistent infection (3%). Post-embolisation nephrectomy was performed in four patients (11%). CONCLUSION: The most common reason for TAE was renal cancer. TAE is a safe modality with few complications both when performed acutely and electively. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050826 TI - Experience from multidisciplinary follow-up on critically ill patients treated in an intensive care unit. AB - INTRODUCTION: International literature describes that former intensive care unit (ICU) patients suffer considerable physical and neuropsychological complications. Systematic data on Danish ICU survivors are scarce as standardised follow-up after intensive care has yet to be described. This article describes and evaluates the knowledge gained from outpatient follow-up at a tertiary intensive care unit at Rigshospitalet, Copenhagen, during a three-year period. METHODS: A total of 101 adult former ICU patients attended the outpatient clinic over a three-year period. Patients included were medical and surgical patients with a length of stay exceeding four days. Patients attended the clinic after discharge from hospital and for a minimum of two months from their discharge from the ICU. The patients were assessed for physical, neuropsychological and psychological problems and, if necessary, further treatment or rehabilitation was initiated. RESULTS: Reduced physical ability was seen in 82%. A total of 89% suffered a substantial weight loss. 83.2% had signs indicating acute brain dysfunction during the ICU stay, and approximately half of the patients still had cognitive problems. A total of 66 interventions were initiated. CONCLUSION: Our data confirmed that a large proportion of ICU survivors suffer considerable long-term physical and neuropsychological sequelae. Intensive care follow-up may contribute to address these specific problems and to initiate the needed interventions. Research is needed to determine whether specialised rehabilitation is required. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050827 TI - Routine examination for tuberculosis is still indicated during bronchoscopy for pulmonary infiltrates. AB - INTRODUCTION: Tuberculosis (TB) can present in numerous ways and can be radiological indistinguishable from cancer. In several guidelines for bronchoscopy (FOB) in low-incidence areas, a Mycobacterium tuberculosis test is only recommended when TB is clinically suspected. Due to the expenses associated with M. tuberculosis cultures, we did an analysis of tests obtained by FOB and other invasive procedures (endoscopic ultrasound (EUS)-guided needle biopsy via the oesophagus or trachea and percutaneous needle lung biopsy (PNLB)). METHODS: All patients tested positive for M. tuberculosis by culture and with samples obtained by FOB, EUS or PNLB in the 2008-2012 period were identified retrospectively in two centres in a low-incidence area (Copenhagen, Denmark). Patient records and radiological reports were reviewed. RESULTS: A total of 57 (1.2%) patients out of the 4,680 tested were M. tuberculosis culture positive. Of the 57 patients, 40.3% (n = 23) presented with isolated upper lobe infiltrates and 29.8% (17) with cavitating infiltrates. Isolated chest lymphadenopathy was seen in 8.8% (n = 5). In 33.3% (n = 19) of the patients, radiography was not typical of TB (not upper lobe, no cavity, not isolated lympadenopathy, not miliary). Of the 57 patients, 48 were diagnosed by FOB, six by EUS and three by PNLB. M. tuberculosis samples were taken in an estimated 34% of all procedures. CONCLUSION: M. tuberculosis culturing should always be considered when performing FOB in patients with lung infiltrates of unknown origin, even in a low-incidence country as Denmark. EUS and PNLB should also be considered when sampling material. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050828 TI - Dysphagia training after head and neck cancer fails to follow legislation and national recommendations. AB - INTRODUCTION: Dysphagia is a known sequela after head and neck cancer (HNC) and causes malnutrition, aspiration pneumonia and a reduced quality of life. Due to improved survival rates, the number of patients with sequelae is increasing. Evidence on the ideal HNC-specific rehabilitation of dysphagia is lacking, but several studies indicate that early initiation is crucial. The aim of this study was to map the existing dysphagia rehabilitation programmes for HNC patients in Denmark. METHODS: Occupational therapists (OTs), oncologists and surgeons from five hospitals participated in a nationwide questionnaire-based survey, along with OTs from 39 municipal health centres. RESULTS: HNC patients rarely receive preventive occupational therapy before treatment, and hospital-based OTs mainly attend to HNC patients undergoing surgery. Far from all oncology and surgical departments complete the required rehabilitation plans upon discharge which leaves many patients untreated. There are vast differences between the municipalities' rehabilitation programmes and between the expertise employed in municipalities and hospitals. CONCLUSION: Existing HNC rehabilitation does not meet official Danish guidelines. Only a fraction of HNC patients are offered rehabilitation and often long after completing treatment. Municipal rehabilitation services vary considerably in terms of type, duration, intensity and expertise. Dysphagia-related rehabilitation requires an improved monitoration, possibly with an increase in the uptake of centralised dysphagia rehabilitation. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050829 TI - Lack of nationwide Danish guidelines on mammography before non-oncological breast surgery. AB - INTRODUCTION: Non-oncological breast surgery like breast reduction and mastopexy are often performed in younger patients, i.e. in women who have not yet had mammography. Breast cancer is, however, a very frequent disease that is increasingly prevalent in women below 50 years of age. Occult breast cancer may not be recognised before breast surgery, which may result in several disadvantages for the women. Therefore, detecting a breast cancer before a woman undergoes non-oncological breast surgery is of paramount importance. METHODS: All public plastic surgery and breast surgery departments and all private clinics or hospitals providing plastic surgery were asked two questions: 1) When do you recommend a mammography prior to non-oncological breast surgery? 2) How old must a mammogram be before it needs to be repeated? RESULTS: Answers were received from all plastic surgery and breast surgery departments, and all but three of the private clinics and hospitals. Overall, information was obtained from 95.5% of the respondents (n = 63). CONCLUSION: Currently, there are no Danish guidelines on mammography before non-oncological breast surgery. A national guideline could recommend a preoperative mammogram from the age of 40 years stipulating that the mammogram should have been made within the past 12 months; however, the final recommendation should be prepared by a multidisciplinary working group counting experts from plastic surgery, breast surgery, pathology and radiology. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050830 TI - Diagnostic and therapeutic challenges in superficial CNS siderosis. AB - INTRODUCTION: Superficial CNS siderosis was previously almost unknown but is now diagnosed with increasing frequency owing to magnetic resonance imaging. Patients may present with sensory deafness, gait ataxia, various sensorimotor signs and, eventually, cognitive decline. They typically have a history of traumatic brain or spinal cord injury or previous neurosurgery, or may harbour congenital malformations. However, knowledge about treatment outcomes remains scarce. METHODS: We present a series of nine consecutive patients from a large tertiary neuroscience centre in order to highlight the challenges related to the diagnosis and treatment of superficial siderosis. RESULTS: A potential bleeding aetiology was identified in all patients, but removal of the offending bleeding source was achieved only in three (33%). Symptom progression was halted in just one patient (11%), which suggests that neurodegeneration due to haemosiderin-associated iron toxicity becomes irreversible with time. CONCLUSION: Surgical therapy in superficial CNS siderosis is rarely achieved. We suggest that prospective, large scale multicentre studies are needed to search for non-surgical therapies that reverse (or prevent) ongoing neurotoxicity due to accumulating iron toxicity. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050831 TI - Manual protection of the perineum reduces the risk of obstetric anal sphincter ruptures. AB - INTRODUCTION: During vaginal delivery, the risk of obstetric anal sphincter injuries (OASIS) is well-known. Despite sufficient repair, 30-50% of women will experience anal incontinence. Recent studies from Norway have shown a reduction in the incidence of OASIS when the perineum is supported manually. In Denmark, the frequency of OASIS is the highest in Scandinavia and it is increasing. The aim of this study was to reduce the incidence of OASIS through an interventional programme. METHODS: We conducted a study inspired by the Norwegian intervention. Our focus was on four points: 1) good communication between the delivering woman and the birth assistant, 2) visualisation of the perineum in the last stages of delivery, 3) support of the perineum during the final minutes of pushing and 4) episiotomy only on indication. A total of 768 primiparous and 1,175 multiparous women were enrolled in this quality improvement cohort study. Data were analysed for association with the occurrence of OASIS. RESULTS: The proportions of parturients with anal sphincter ruptures decreased significantly during the first year of the study from 4.4% to 1.7% (p < 0.001). The decrease was more pronounced for primiparous women: from 7.2% to 2.9% (p = 0.006). A similar decrease was observed for instrumental deliveries although this was not significant for primiparous women, probably due to the size of the study population. Episiotomies increased significantly from 4.4% to 7.1% for all deliveries. CONCLUSION: After the first year of intervention, our results demonstrate that manual protection of the perineum reduces the overall risk of OASIS significantly. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050832 TI - Cryptosporidium infections in Denmark, 2010-2014. AB - INTRODUCTION: The incidence of cryptosporidiosis in Denmark is unknown. Here, we present the number of cases detected in the 2010-2014 period along with data on species and subtypes. METHODS: Complete national data retrieved from the Danish Microbiology Database and Statens Serum Institut (SSI) comprised test results on cryptosporidia detected by microscopy or polymerase chain reaction (PCR) between 1 January 2010 and 30 April 2014. Samples that tested positive at the SSI were submitted to species and subtype analysis by conventional PCR and sequencing of ribosomal and gp60 genes, respectively. RESULTS: A total of 689 Cryptosporidium positive stool samples were submitted by 387 patients. Limiting case episodes to two months (60 days), a total of 388 case episodes representing 387 patients were identified. Cryptosporidiosis was most common among infants and toddlers. Moreover, a peak in incidence was observed among younger adults aged 23-24 years. In 43 Cryptosporidium-positive faecal samples, identification was performed to species and subtype level. Cryptosporidium parvum was found in 34 samples, C. hominis in eight, and C. meleagridis in one sample; C. parvum subtypes IIaA15G2R1 (n = 10) and IIaA16G3R1 (n = 5) were predominating. CONCLUSION: Cryptosporidia are a significant cause of diarrhoea in Denmark. Outbreaks may not be detected due to continued use of diagnostic tests of limited sensitivity and due to lack of surveillance. With molecular methods now being introduced in many Danish laboratories, we propose establishing national surveillance of cryptosporidiosis. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 26050833 TI - Predictive value of the official cancer alarm symptoms in general practice--a systematic review. AB - INTRODUCTION: The objective of this study was to investigate the evidence for positive predictive value (PPV) of alarm symptoms and combinations of symptoms for colorectal cancer, breast cancer, prostate cancer and lung cancer in general practice. METHODS: This study is based on a literature search performed in PubMed, Embase, the Cochrane database and at ClinicalTrials.gov in accordance with the PRISMA guidelines. The main outcome measure used was PPV. RESULTS: A total of 16 eligible studies were identified. The intervals in the brackets refer to the variation of the results in the studies. Colorectal cancer: The PPV of "rectal bleeding" was high for patients > 60 years (6.6-21.2%), but much lower in younger age groups. For "change in bowel habits" and "significant general symptoms", the PPV was 3.5-8.5%. Breast cancer: "Palpable suspected tumour" was well supported (8.1-24%). No studies on the predictive value of "pitting of the skin", "papil-areola eczema/ulceration" and "suspect axillary lymph nodes" were found. Prostate cancer: One study showed a high PPV for positive rectal examination (12%). The value for "lower urinary tract symptoms" was low (1.0 3.0%). PPV for "perianal pain" and "haemospermia" were not found. Lung cancer: For "haemoptysis" the PPV increased from 8.4 in patients aged 55 years to 20.4 at the age of > 85 years. PPV for "cough", "pain in the thorax", "dyspnoea" and "general symptoms" were low (0.4-1.1%). Using a new algorithm that estimates the PPV of combinations of symptoms and risk factors, a higher PPV may be achieved. CONCLUSION: A few of the alarm symptoms show a high PPV, whereas the PPV for some symptoms currently remains unknown. To improve the GPs' diagnostic judgment, a new algorithm for calculating the PPV for combinations of symptoms and risk factors seems promising. PMID- 26050834 TI - MicroRNAs as novel biomarkers in diffuse large B-cell lymphoma--a systematic review. AB - INTRODUCTION: MicroRNAs (miRNAs) are short non-coding RNAs that have the ability to regulate gene expression at the post-transcriptional level. MiRNAs are deregulated in many cancer types, and several miRNAs have been suggested as novel diagnostic and prognostic biomarkers in diffuse large B-cell lymphoma (DLBCL). The objective of this study was to systematically collect and evaluate current knowledge of miRNAs functioning as diagnostic and prognostic biomarkers within DLBCL. METHODS: This review was conducted according to the Preferred Reporting for Systematic Reviews and Meta-analyses guidelines. A systematic search of literature in PubMed and Embase was made and supplemented by screening of reference lists. Only original peer-reviewed studies written in English were included and screened based on miRNA expression, molecular subtypes of DLBCL and patient outcome. RESULTS: Out of 277 candidate records, a total of 20 studies qualified for inclusion in this review. In all, 11 studies reported a total of 48 miRNAs with expression patterns associated with specific molecular DLBCL subtypes, and 14 studies reported a total of 30 miRNAs associated with patient outcome. However, only few miRNAs showed significant results in more than one study. CONCLUSION: MiRNAs qualify as potential diagnostic and prognostic biomarkers in DLBCL. However, more clinical validation including prospective and cross-centre studies are required before specific miRNAs can be integrated into the daily practice as biomarkers in DLBCL, which would contribute to an era of more personalised medicine. PMID- 26050835 TI - Treatment of non-IBD anal fistula. AB - The course of the fistula tract in relation to the anal sphincter is identified by clinical examination under general anaesthesia using a fistula probe and injection of fluid into the external fistula opening. In the event of a complex fistula or in the case of fistula recurrence, this should be supplemented with an endoluminal ultrasound scan and/or an MRI scan. St. Mark's fistula chart should be used for the description. Simple fistulas are amenable to fistulotomy, whereas treatment of complex fistulas requires special expertise and management of all available treatment modalities to tailor the right operation to the individual patient. The given levels of evidence and grades of recommendations are according to the Oxford Centre for Evidence-based Medicine (www.cemb.net). PMID- 26050836 TI - Danish clinical guidelines for examination and treatment of overweight and obese children and adolescents in a pediatric setting. AB - Overweight children are at an increased risk of becoming obese adults, which may lead to shorter life expectancies in the current generation of children as compared to their parents. Furthermore, being an overweight child has a negative psycho-social impact. We consider obesity in children and adolescents a chronic illness, which is in line with the American Medical Society. We summarize the evidence for the efficacy of a combination of diet, physical activity and behavior-focused interventions in a family-based setting. The present guidelines propose a multidisciplinary service implemented as a "chronic care model" based on "best clinical practice" inspired by an American expert committee and the daily practice of The Children's Obesity Clinic at Copenhagen University Hospital Holbaek. Children and adolescents should be referred for examination and treatment in a pediatric setting when BMI corresponds to an isoBMI of minimum 30 or BMI corresponds to an isoBMI of 25 and complex obesity is suspected. Obtaining a thorough medical history is pivotal. We propose a structured interview to ensure collection of all relevant information. We recommend physical examination focused on BMI, waist circumference, growth, pubertal stage, blood pressure, neurology and skin and provide comprehensive paraclinical investigations for obesity and obesity related conditions. Treatment of obesity in children and adolescents is fully dependent on the combined effort of the entire family. This cannot be overemphasized! The main principle of the treatment is developing an individual detailed plan for every patient to reduce caloric intake whilst increasing physical activity, leaving no ambiguity with the recommendations. PMID- 26050837 TI - Iodine status in pregnant and breastfeeding women: a Danish regional investigation. PMID- 26050838 TI - Sealing of gastrointestinal anastomoses with fibrin glue coated collagen patch. AB - BACKGROUND: Colorectal cancer (CRC) is the most common cancer of the gastrointestinal tract. In Denmark is CRC the 3. most frequent form of cancer and the 3. leading cause of cancer-related death. Anastomoses: Surgical resection is the only curative treatment of CRC and in Denmark about 85% of patients with CRC are therefore operated. An anastomosis will be established in most cases. Colorectal anastomoses are established in the treatment of benign diseases too, i.e. as part of the surgical treatment of inflammatory bowel disease and in acute surgery. Furthermore anastomoses are conducted in other parts of the gastrointestinal tract i.e. esophagus, stomach, small bowel and bile system. Anastomotic leakage (AL): AL is the most serious complication of gastrointestinal surgery with a 30-day mortality of 13-27%. The reported AL rate ranges from 1 to 39%. In addition to immediate clinical consequences AL is an independent predictor of reduced general and cancer-specific survival. Leakage can manifest as generalized peritonitis, requiring acute resurgery or as a more localized accumulation/abscess or as a subclinical leakage. Sealing of anastomoses: Numerous studies on anastomotic sealing have been conducted with the aim of reducing the number of AL's. The results of these are conflicting and predominantly disappointing. The drug Tacho-Sil (TS) consists of a collagen patch, which on the one side is coated with fibrin glue (FG), which gives it an adhesive property. TS is registered for use in surgical hemostasis. Animal models: Spontaneous AL in animals is infrequent. It is therefore necessary to use a model of AL. No such model exists and must be developed. OBJECTIVE: To clarify if the sealing of anastomoses with TS is feasible and safe in an experimental design. To develop a standardized model of AL in pigs. To clarify if sealing of colon-anastomoses with TS can reduce the number of clinical ALs in an experimental design. To clarify whether there is evidence that FG influences healing of gastrointestinal anastomosis. STUDIES: Safety study, that examines whether it is safe to seal anastomoses with a TS. Experimental study on pigs. Two anastomoses on each pig, one sealed with TS. After 1-6 weeks of observation the anastomosis were examined for AL, stenoses, strength and compared microscopic. RESULTS: No difference between sealed and unsealed anastomosis. This study is completed and published. Model study, to develop model of AL on pigs. A total of 22 pigs had an anastomosis of colon. All anastomoses were left with a standardized defect on 5-21 mm. The pigs were observed in order to assess how big the defect should be before the pigs developed visible leakage and/or fecal peritonitis. RESULTS: Model developed. 21 mm defect significant. This study is completed and published. Efficacy study, testing if TachoSil can seal an AL and thus prevent that this becomes clinically significant. A total of 20 pigs had a colon-anastomoses with a standardized defect of 21 mm. The pigs were randomized to sealing with TS or no sealing. Re-laparotomy after 7 days examining for visible leakage and/or fecal peritonitis. RESULTS: TachoSil(r) able to seal the defect (p=0.0055). This study is completed and published. Systematic review, with the purpose to study whether there is evidence that FG influence the healing of gastrointestinal anastomosis. RESULTS: Conflicting. FG does not seem to have an effect. This study completed and published. CONCLUSIONS: Sealing of GI anastomosis with TachoSil is safe and feasible. A defect of at least 21mm must be left in colon anastomosis to induce clinical peritonitis. Sealing of defect colon anastomosis in pigs with TachoSil can prevent clinical leakage and peritonitis. FG has no positive effect on microscopically healing of GI-anastomosis. PMID- 26050839 TI - A cohort of anti-TNF treated Danish patients with inflammatory bowel disease, used for identifying genetic markers associated with treatment response. PMID- 26050840 TI - Distribution of IS629 and stx genotypes among enterohemorrhagic Escherichia coli O157 isolates in Yamaguchi Prefecture, Japan, 2004-2013. AB - Patterns of insertion sequence (IS)629, norV genotype, and Shiga toxin (Stx) genotype distribution were investigated amongst 203 enterohemorrhagic Escherichia coli O157 isolates collected in Yamaguchi Prefecture, Japan, between 2004 and 2013. A total of 114 IS629 patterns were identified; these were divided into eight IS groups (A-H). Ninety isolates carried an intact norV gene, whereas 113 isolates carried a norV with a 204-bp deletion. Other than one isolate from IS group G, all isolates with an intact norV belonged to groups A-F, whereas isolates with a mutant norV belonged to IS groups G and H. Seven stx genotypes were identified, and of those, stx1a/stx2a was predominant (n=105), followed by stx2c (n=32) and stx2a (n=27). The stx1a/stx2a genotype was associated with the mutant norV isolates, whereas isolates with an intact norV had the stx2c genotype. Therefore, certain combinations of IS type and stx genotype appear to be more frequent among O157 clades which may be useful for detection of predominant subtypes in the interest of public health. PMID- 26050841 TI - Induction of non-specific suppression in chicks by specific combination of maternal antibody and related antigen. AB - Specific immune suppression in newly hatched chicks induced by specific maternal antibodies has been reported. Laying hens were immunized with dinitrophenyl keyhole limpet hemocyanin (DNP-KLH). Purified maternal anti-DNP and non-specific immunoglobulin (Ig) Y antibodies were transferred by yolk sac inoculation to newly hatched chicks, and then, they were immunized with an optimum immunogenic dose of DNP-KLH at 1 and 4 weeks of age. Concentrations of anti-DNP antibodies in serum samples of these chicks were measured by using Enzyme-linked immunosorbent assay (ELISA). Proportions of T-cell subsets in peripheral blood of these chicks were also measured by flow cytometric analysis at 5 weeks of age (one week after the second immunization). Suppression of anti-DNP antibody response and down regulation of CD3(+)CD4(+) cells were observed in the chicks received high dose of maternal anti-DNP antibodies and immunized with DNP-KLH. On the other hand, normal anti-DNP antibody response and normal proportion of CD3(+)CD4(+) cells were observed in the chicks received high dose of non-specific IgY antibodies and immunized with DNP-KLH. Furthermore, when chicks received high dose of maternal anti-DNP antibodies and immunized with DNP-KLH at 1 and 4 weeks of age and then with rabbit serum albumin (RSA) at 5 and 8 weeks of age, their primary anti-RSA response was also significantly suppressed. We indicate here that specific maternal antibodies can affect both B and T cell responses and induce non specific suppression against different antigens. However, this non-specific suppression does not continue for a long time. PMID- 26050842 TI - Oral ingestion of collagen peptide causes change in width of the perimysium of the chicken iliotibialis lateralis muscle. AB - Skeletal muscle is mainly composed of myofibers and intramuscular connective tissue. Bundles composed of many myofibers, with each myofiber sheathed in connective tissue called the endomysium, are packed in the perimysium, which occupies the vast bulk of the intramuscular connective tissue. The perimysium is a major determination factor for muscle texture. Some studies have reported that collagen peptide (Col-Pep) ingestion improves the connective tissue architecture, such as the tendon and dermis. The present study evaluated the effects of Col-Pep ingestion on the chicken iliotibialis lateralis (ITL) muscle. Chicks were allocated to three groups: the 0.15% or 0.3% Col-Pep groups and a control group. Col-Pep was administered by mixing in with commercial food. On day 49, the ITL muscles were analyzed by morphological observation and the textural property test. The width of the perimysium in the 0.3% Col-Pep group was significantly larger than other two groups. Although scanning electron microscopic observations did not reveal any differences in the architecture of the endomysium, elastic improvement of the ITL muscle was observed as suggested by an increase of the width of perimysium and improved rheological properties. Our results indicate that ingestion of Col-Pep improves the textural property of ITL muscle of chickens by changing structure of the perimysium. PMID- 26050844 TI - Silicon nanowire arrays coupled with cobalt phosphide spheres as low-cost photocathodes for efficient solar hydrogen evolution. AB - We demonstrate the first example of silicon nanowire array photocathodes coupled with hollow spheres of the emerging earth-abundant cobalt phosphide catalysts. Compared to bare silicon nanowire arrays, the hybrid electrodes exhibit significantly improved photoelectrochemical performance toward the solar-driven H2 evolution reaction. PMID- 26050843 TI - Hypoxia inducible factor 1alpha expression and effects of its inhibitors in canine lymphoma. AB - Hypoxic conditions in various cancers are believed to relate with their malignancy, and hypoxia inducible factor-1alpha (HIF-1alpha) has been shown to be a major regulator of the response to low oxygen. In this study, we examined HIF 1alpha expression in canine lymphoma using cell lines and clinical samples and found that these cells expressed HIF-1alpha. Moreover, the HIF-1alpha inhibitors, echinomycin, YC-1 and 2-methoxyestradiol, suppressed the proliferation of canine lymphoma cell lines. In a xenograft model using NOD/scid mice, echinomycin treatment resulted in a dose-dependent regression of the tumor. Our results suggest that HIF-1alpha contributes to the proliferation and/or survival of canine lymphoma cells. Therefore, HIF-1alpha inhibitors may be potential agents to treat canine lymphoma. PMID- 26050846 TI - Introducing a pyrazole/imidazole based hybrid cyclophane: a hydrogen bond sensor and binucleating ligand precursor. AB - A novel cyclophane consisting of methylene-bridged imidazolium- and pyrazole moieties (calix[4]imidazolium[2]pyrazole) and two of its applications are presented. First, supramolecular recognition of an acetonitrile molecule by hydrogen bonding in the solid state is examined. Second, the capability to act as a ligand precursor is shown by the synthesis and characterisation of the respective dinuclear NHC-nickel(II) complex. PMID- 26050847 TI - Protective Effects of Processed Ginseng and Its Active Ginsenosides on Cisplatin Induced Nephrotoxicity: In Vitro and in Vivo Studies. AB - Although cisplatin can dramatically improve the survival rate in cancer patients, its use is limited by its nephrotoxicity. Previous investigations showed that Panax ginseng contains components that exhibit protective activity against cisplatin-induced nephropathy. The aim of the present study is to investigate the effect of microwave-assisted processing on the protective effect of ginseng and identify ginsenosides that are active against cisplatin-induced kidney damage to evaluate the potential of using ginseng in the management of nephrotoxicity. The LLC-PK1 cell damage by cisplatin was significantly decreased by treatment with microwave-processed ginseng (MG) and ginsenosides Rg3, Rg5, and Rk1. Reduced expression of p53 and c-Jun N-terminal kinase proteins by cisplatin in LLC-PK1 cells was markedly ameliorated after Rg3 and Rg5/Rk1 treatment. Additionally, elevated expression of cleaved caspase-3 was significantly reduced by ginsenosides Rg5, Rk1, and with even greater potency, Rg3. Moreover, MG and its fraction containing active ginsenosides showed protective effects against cisplatin-induced nephropathy in mice. We found that ginsenosides Rg3, Rg5, and Rk1 generated during the heat treatment of ginseng ameliorate renal damage by regulating inflammation and apoptosis. Results of current experiments provide evidence of the renoprotective effects and therapeutic potential of MG and its active ginsenosides, both in vitro and in vivo. PMID- 26050848 TI - Repair of anomalous aortic origin of coronary arteries with combined unroofing and unflooring technique. PMID- 26050849 TI - Pathogenic structural heart changes in early tricuspid regurgitation. AB - OBJECTIVE: Severe, late functional tricuspid regurgitation is characterized by annulus dilation, right ventricular enlargement, and papillary muscle displacement with leaflet tethering. However, the early stages of mild tricuspid regurgitation and its progression are poorly understood. This study examined structural heart changes in mild, early tricuspid regurgitation. METHODS: Sequential patients undergoing cardiac computed tomography and transthoracic echocardiography with tricuspid regurgitation were identified and evaluated. The tricuspid annulus area and chamber volumes were measured by computed tomography angiography and categorized by tricuspid regurgitation severity. RESULTS: Patients (n = 622) were divided into 3 groups by tricuspid regurgitation severity: no/trace (n = 386), mild (n = 178), and moderate/severe tricuspid regurgitation (n = 58). Annulus area was highly dependent on and proportional to regurgitation severity and correlated with both right/left atrial enlargement. Annulus area most strongly correlated with right and left atrial volume, and the annulus shape changed from elliptical to circular in moderate/severe tricuspid regurgitation. Mild tricuspid regurgitation was associated with less right/left atrial enlargement than significant tricuspid regurgitation, normal right ventricular size, and annular dilation. Significant tricuspid regurgitation was associated with annular dilation, circularization, and right ventricular enlargement. Mild and significant tricuspid regurgitation were differentiated by annulus area and indexed right ventricular volume. CONCLUSIONS: Tricuspid annular dilation and right/left atrial enlargement comprise early events in mild functional tricuspid regurgitation. Atrial enlargement occurs before right ventricular dilation, which occurs late, when tricuspid regurgitation is severe. Atrial volume and tricuspid annular dilation are early and sensitive indicators of tricuspid regurgitation significance. PMID- 26050850 TI - Nodal metastases in non-small cell lung cancer: Hop, skip, or jump? PMID- 26050851 TI - Acute type A aortic dissection: To crossclamp or not to crossclamp? That is the question. PMID- 26050852 TI - Hearing outcomes after suppurative chronic otitis media surgery. AB - OBJECTIVES: This study aims to compare the hearing outcomes after canal wall up mastoidectomy (CWUM) and canal wall down mastoidectomy (CWDM). PATIENTS AND METHODS: Ninety-two patients (74 males, 18 females; mean age 30.1 years; range 9 to 67 years) who were diagnosed with chronic suppurative otitis media (CSOM) between January 2009 and May 2011 were enrolled in this retrospective study. Based on hospital data, patients were separated into two groups as having mucosal or squamous disease. Patients were also categorized into two groups based on the type of mastoidectomy: CWUM (n=51) and CWDM (n=41). Hearing results between the groups were evaluated using the air-bone gap (ABG) recorded by audiogram before surgery and at three months after ossiculoplasty. Relationship between obtained hearing results and performed ossiculoplasty techniques were also discussed. RESULTS: We were able to perform ossiculoplasty in 42.3% (n=39) of patients diagnosed with CSOM. Presurgical ABG in CWUM and CWDM groups were 35.38+/-10.82 dB and 37.92+/-5.80 dB, respectively. Postsurgical ABG value was <=20 dB in 27% of CWUM patients and 7.7% of CWDM patients. Mean hearing gain of patients with active squamous disease was 3.8 dB in CWUM group and 11.9 dB in CWDM group (p<0.5). CONCLUSION: The pathology affecting the middle ear had influence on the hearing results of the two groups. Canal wall down mastoidectomy may be a beneficial procedure to improve hearing in patients with CSOM. PMID- 26050854 TI - Retrospective analysis of surgical treatment of choanal polyps. AB - OBJECTIVES: This study aims to discuss the efficacy of the surgical method performed in patients with choanal polyp in the light of the literature. PATIENTS AND METHODS: The study included 76 patients (42 males, 34 females; mean age 25.36 years; range 7 to 73 years) diagnosed with choanal polyp in the sinonasal region between January 2005 and December 2013 in the otorhinolaryngology clinic of Kocaeli University. Age, sex, and presenting complaints of the patients, as well as the characteristics of the polyps (localization, direction) were retrospectively investigated. RESULTS: The majority (98.68%) of the patients with choanal polyp presented with nasal obstruction, followed by snoring, sleeping with the mouth open (25.0%), and nasal discharge (21.05%). According to their localizations, the origin of the polyps was the maxillary sinus in 65 patients, sphenoid sinus in six patients, middle turbinate in two patients, septum in two patients, and ethmoid sinus in one patient. CONCLUSION: Endoscopic approach is a safe and effective procedure for choanal polyp treatment. There was no significant difference between the success rates of the endoscopic approach and combined approaches. PMID- 26050853 TI - The effectiveness of Tualang honey in reducing post-tonsillectomy pain. AB - OBJECTIVES: This study aims to evaluate the effectiveness of Tualang honey in reducing post-tonsillectomy pain. PATIENTS AND METHODS: The study included 63 patients (31 males, 32 females; mean age 10+/-4.16 years; range 3 to 18 years) who were planned to undergo tonsillectomy. Patients were randomized into two groups. Treatment group received topical Tualang honey intraoperatively followed by oral consumption of Tualang honey three times daily for seven days with intravenous sultamicillin three times daily for first and second day followed by oral sultamicillin twice daily for five days. Control group received intravenous sultamicillin for two days followed by oral sultamicillin twice daily for five days. Patients' pain was assessed according to visual analog scale, frequency of waking up at night due to pain, and additional use of analgesic from postoperative first to seventh day. Results from each group were statistically compared. RESULTS: Early postoperative pain was relieved slightly faster in Tualang honey + antibiotic group; however, the difference between groups was not statistically significant. On postoperative seventh day, all of patients (100%) in Tualang honey + antibiotic group experienced no pain compared to the antibiotic only group. Frequencies of waking up at night and use of analgesic were lower in the Tualang honey + antibiotic group compared to antibiotic only group. CONCLUSION: Early postoperative pain was relieved slightly faster in Tualang honey + antibiotic group, which may be attributed to the soothing effect of honey. PMID- 26050855 TI - Necessity of mastoidectomy in patients with chronic otitis media having sclerotic mastoid bone: a retrospective clinical study. AB - OBJECTIVES: This study aims to investigate the efficiency of mastoidectomy during tympanoplasty procedures in patients having sclerotic mastoid bone with dry or dried up tympanic cavity. PATIENTS AND METHODS: The study included 146 patients (66 males, 80 females; mean age 28.6 years; range 16 to 52 years) having sclerotic mastoid bone who underwent tympanoplasty between March 2010 and March 2013. Patients were divided into two groups: group A (34 males, 58 females; mean age 25.8 years; range 17 to 47 years) underwent only tympanoplasty, while tympanoplasty + mastoidectomy were performed on group B (32 males, 22 females; mean age 29.8 years; range 16 to 52 years). All outcomes were evaluated including the actual state of the tympanic membrane graft and level of hearing. RESULTS: While postoperative perforation and retraction rates were not significantly different between the two groups, results of group A were superior to group B in terms of operation duration and hearing results. CONCLUSION: Mastoidectomy is not an efficient procedure in chronic otitis media patients having sclerotic mastoid bone with dry or dried up tympanic cavity. PMID- 26050856 TI - Study of hearing aid effectiveness and patient satisfaction. AB - OBJECTIVES: This study aims to investigate hearing aid using rate, patient satisfaction rate and achievements in social communication of patients by assessing the hearing thresholds before and after device use in patients who were determined as suitable for hearing aid use. PATIENTS AND METHODS: Hundred eighty patients who were admitted to Otolaryngology Clinic of Sakarya University Medical Faculty and approved of hearing aid usage between January 2013 and May 2013 were included in the study. Patients (21 males, 26 females; mean age 61.91+/-12.82; range 24 to 85 years) were performed free field audiometry with and without the device by the same audiometrist and Turkish version of the International Outcome Inventory for Hearing Aids by the same otolaryngologist. RESULTS: Of patients, 14.28% did not obtain the hearing aid even though they received a hearing aid approval report. Assessment of the answers of inventory questions revealed that 87% of patients used hearing aid more than four hours a day, 72% benefited significantly from hearing aid, and 64% had no complaint or had few complaints compared to the before-hearing aid period. CONCLUSION: Using hearing aid affects daily activities of patients slightly or moderately and increases their communication skills. PMID- 26050857 TI - [Turkey's place in Europe in respect of pediatric otorhinolaryngology publications in scope of Science Citation Index]. AB - OBJECTIVES: This study aims to evaluate quantitatively the pediatric otorhinolaryngology (ORL) publications belonging to the ORL journals of the Science Citation Index (SCI) made by Turkey and other European countries between five year periods during 1995 and 2012. MATERIALS AND METHODS: After SCI journals of 1995, 2000, 2005, 2010 and 2012 under the ORL heading were determined, the publications of all European countries in these journals were detected electronically using PubMed search engine. Then, the number of pediatric ORL publications and the journals which included them were determined and counted manually for each country. RESULTS: The number of total publications and pediatric ORL publications made by European countries in the mentioned years were 539/98, 737/123, 747/158, 757/175, and 746/171 respectively. Turkey was the country with the highest number of pediatric ORL publications in all years except 1995. It was detected that more than half of the total pediatric ORL publications were included in International Journal of Pediatric Otorhinolaryngology. CONCLUSION: It is pleasing that Turkey is ahead of many developed European countries in respect of the number of pediatric ORL publications. Further studies on type, evidence-based medicine or citation analysis of these publications will also enable qualitative evaluation. PMID- 26050858 TI - Concurrent medullary and papillary carcinoma of thyroid. AB - Simultaneous occurrence of papillary thyroid carcinoma (PTC) and medullary thyroid carcinoma (MTC) in the same thyroid gland is a rare condition. These tumors derive from different cells; PTC originates from follicular cells whereas MTC originates from parafollicular cells. Because of this, the treatment of these tumors also differs. This article describes two rare cases of the simultaneous occurrence of MTC and PTC in the thyroid gland. PMID- 26050859 TI - Sinonasal inflammatory myofibroblastic pseudotumor (plasma cell granuloma). AB - Inflammatory myofibroblastic pseudotumor (plasma cell granuloma) is a soft tissue lesion consisting of myofibroblasts, mature lymphocytes, histiocytes, plasma cells, eosinophils, and extracellular collagen. Various sites in the body may harbor these lesions. Lungs, omentum, intestines, mesentery, and urinary system are the most susceptible areas. It is usually seen in children and young adults. The lesion is rarely detected in the head and neck region. The orbit and the upper respiratory system are the most common localizations in the head and neck region. Sinonasal tract is a rare site of involvement. The differential diagnosis includes squamous cell carcinoma (spindle cell variant), inflammatory fibrosarcoma, leiomyosarcoma, schwannoma, and nonspecific inflammation. Our patient who had a sinonasal mass showed a benign tumor consisting of spindle tumor cells and inflammatory cells histopathologically. This case was presented due to its rare existence to this site. PMID- 26050860 TI - Oncocytoma of the parotid gland complicated by hypercalcemia: a case report. AB - Salivary gland tumors are rare head and neck tumors. The majority of these tumors are benign and include pleomorphic adenoma, monomorphic adenoma, oncocytoma, and papillary cystadenoma lymphomatosum. Oncocytoma is a rare benign salivary gland tumor. In this article, we report a 69-year-old female case of oncocytoma of the right parotid gland in whom fine needle aspiration cytology result was reported as a Warthin's tumor. PMID- 26050861 TI - [Congenital vomer agenesis]. AB - Congenital vomer agenesis is a very rare condition. Usually, it is discovered incidentally. Nasal and otologic diseases accompany the cases. In this article, we report two cases of isolated congenital vomer agenesis who were admitted to our clinic with complaint of nasal obstruction. On endoscopic examination, deviated septum and inferior turbinate hypertrophy were observed in both patients. One patient was performed septoplasty, inferior turbinate radiofrequency, and functional endoscopic sinus surgery. Other patient was advised follow-up since the patient did not consent to operation. PMID- 26050862 TI - [Foreign body in the submandibular gland: a tooth extraction complication]. AB - The head and neck region includes many vital anatomic structures. So, diseases of this region may have a more morbid and mortal course compared to other anatomic regions. In this article, we report a patient showing various symptoms due to a suture needle which was left in the surgical region during the extraction of the left inferior molar tooth three years ago. PMID- 26050863 TI - Giant cell granuloma of the temporomandibular joint: a report of the two cases. PMID- 26050864 TI - Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis. AB - Osteoarthritis (OA), a leading cause of disability, affects 27 million people in the United States and its prevalence is rising along with the rise in obesity. So far, biomechanical or behavioral interventions as well as attempts to develop disease-modifying OA drugs have been unsuccessful. This may be partly due to antiquated imaging outcome measures such as radiography, which are still endorsed by regulatory agencies such as the United States Food and Drug Administration (FDA) for use in clinical trials. Morphological magnetic resonance imaging (MRI) allows unparalleled multi-feature assessment of the OA joint. Furthermore, advanced MRI techniques also enable evaluation of the biochemical or ultrastructural composition of articular cartilage relevant to OA research. These compositional MRI techniques have the potential to supplement clinical MRI sequences in identifying cartilage degeneration at an earlier stage than is possible today using morphologic sequences only. The purpose of this narrative review is to describe compositional MRI techniques for cartilage evaluation, which include T2 mapping, T2* Mapping, T1 rho, dGEMRIC, gagCEST, sodium imaging and diffusion weighted imaging (DWI). We also reviewed relevant clinical studies that have utilized these techniques for the study of OA. The different techniques are complementary. Some focus on isotropy or the collagen network (e.g., T2 mapping) and others are more specific in regard to tissue composition, e.g., gagCEST or dGEMRIC that convey information on the GAG concentration. The application and feasibility of these techniques is also discussed, as they will play an important role in implementation in larger clinical trials and eventually clinical practice. PMID- 26050865 TI - Three-dimensional MRI-based statistical shape model and application to a cohort of knees with acute ACL injury. AB - OBJECTIVE: The aim of this study is to develop a novel 3D magnetic resonance imaging (MRI)-based Statistical Shape Modeling (SSM) and apply it in knee MRIs in order to extract and compare relevant shapes of the tibia and femur in patients with and without acute Anterior cruciate ligament (ACL) injuries. METHODS: Bilateral MR images were acquired and analyzed for 50 patients with acute ACL injuries and for 19 control subjects. A shape model was extracted for the tibia and femur using an SSM algorithm based on a set of matched landmarks that are computed in a fully automatic manner. RESULTS: Shape differences were detected between the knees in the ACL-injury group and control group, suggesting a common shape feature that may predispose these knees to injury. Some of the detected shape features that discriminate between injured and control knees are related to intercondylar width and posterior tibia slope, features that have been suggested in previous studies as ACL morphological risk factors. However, shape modeling has the great potential to quantify these characteristics with a comprehensive description of the surfaces describing complex 3D deformation that cannot be represented with simple geometric indexes. CONCLUSIONS: 3D MRI-based bone shape quantification has the ability to identify specific anatomic risk factors for ACL injury. A better understanding of the role in bony shape on ligamentous injuries could help in the identification of subjects with an increased risk for an ACL tear and to develop targeted prevention strategies, including education and training. PMID- 26050866 TI - Reply Letter to the Editor: Knee joint replacement and individual susceptibility for progression of knee osteoarthritis and tibial cartilage volume loss: not only genes run in the family. PMID- 26050867 TI - The micromechanics of the superficial zone of articular cartilage. AB - OBJECTIVE: To investigate the relationships between the unique mechanical and structural properties of the superficial zone of articular cartilage on the microscopic scale. DESIGN: Fresh unstained equine metacarpophalangeal cartilage samples were mounted on tensile and compressive loading rigs on the stage of a multiphoton microscope. Sequential image stacks were acquired under incremental loads together with simultaneous measurements of the applied stress and strain. Second harmonic generation was used to visualise the collagen fibre network, while two photon fluorescence was used to visualise elastin fibres and cells. The changes visualised by each modality were tracked between successive loads. RESULTS: The deformation of the cartilage matrix was heterogeneous on the microscopic length scale. This was evident from local strain maps, which showed shearing between different regions of collagen under tensile strain, corrugations in the articular surface at higher tensile strains and a non-uniform distribution of compressive strain in the axial direction. Chondrocytes elongated and rotated under tensile strain and were compressed in the axial direction under compressive load. The magnitude of deformation varied between cells, indicating differences in either load transmission through the matrix or the mechanical properties of individual cells. Under tensile loading the reorganisation of the elastin network differed from a homogeneous elastic response, indicating that it forms a functional structure. CONCLUSIONS: This study highlights the complexity of superficial zone mechanics and demonstrates that the response of the collagen matrix, elastin fibres and chondrocytes are all heterogeneous on the microscopic scale. PMID- 26050868 TI - Projecting the direct cost burden of osteoarthritis in Canada using a microsimulation model. AB - OBJECTIVES: To estimate the future direct cost of OA in Canada using a population based health microsimulation model of osteoarthritis (POHEM-OA). METHODS: We used administrative health data from the province of British Columbia (BC), Canada, a survey of a random sample of BC residents diagnosed with OA (Ministry of Health of BC data), Canadian Institute of Health Information (CIHI) cost data and literature estimates to populate a microsimulation model. Cost components associated with pharmacological and non-pharmacological treatments, total joint replacement (TJR) surgery, as well as use of hospital resources and management of complications arising from the treatment of osteoarthritis (OA) were included. Future costs were then simulated using the POHEM-OA model to construct profiles for each adult Canadian. RESULTS: From 2010 to 2031, as the prevalence of OA is projected to increase from 13.8% to 18.6%, the total direct cost of OA is projected to increase from $2.9 billion to $7.6 billion, an almost 2.6-fold increase (in 2010 $CAD). From the highest to the lowest, the cost components that will constitute the total direct cost of OA in 2031 are hospitalization cost ($2.9 billion), outpatient services ($1.2 billion), alternative care and out-of pocket cost categories ($1.2 billion), drugs ($1 billion), rehabilitation ($0.7 billion) and side-effect of drugs ($0.6 billion). CONCLUSIONS: Projecting the future trends in the cost of OA enables policy makers to anticipate the significant shifts in its distribution of burden in the future. PMID- 26050869 TI - Knee joint replacement and individual susceptibility for progression of knee osteoarthritis and tibial cartilage volume loss: not only genes run in the family. PMID- 26050870 TI - Meta-analysis of the efficacy of the fentanyl iontophoretic transdermal system versus intravenous patient-controlled analgesia in postoperative pain management. AB - OBJECTIVE: This meta-analysis was conducted to analyze and compare the efficacy outcomes associated with the fentanyl iontophoretic transdermal system (ITS) and morphine intravenous (IV) patient-controlled analgesia (PCA) in the management of postoperative pain. RESEARCH DESIGN AND METHODS: This meta-analysis assessed the efficacy of the fentanyl ITS versus morphine IV PCA using data from four randomized, active-controlled trials (n = 1271 fentanyl ITS and 1298 morphine IV PCA patients). Main outcome measures were patient global assessment (PGA) of the method of pain control at 24 h. RESULTS: Fentanyl ITS and morphine IV PCA did not significantly differ regarding 'good' and 'excellent' ratings on the PGA of the method of pain control at 24 h (odds ratio = 0.95, p = 0.66), however, fentanyl ITS was superior in terms of 'excellent' PGA ratings at that time point (odds ratio = 1.53, p < 0.0001). No significant differences were found in weighted mean pain intensity scores at 24, 48 and 72 h. CONCLUSIONS: In this meta-analysis, fentanyl ITS was as efficacious as morphine IV PCA and may offer additional benefits as demonstrated by its 'excellent' PGA ratings. PMID- 26050871 TI - Improving mediated electron transport in anodic bioelectrocatalysis. AB - A novel design of a microbial fuel cell is realized by constructing bio cocatalyst beads immobilized with riboflavin-secreting Escherichia coli and decoupling them from an anodic biocatalyst. A microbial fuel cell loaded with these bio-cocatalyst beads shows significantly enhanced performance without occupying an active electrode surface area. PMID- 26050872 TI - Persons with unilateral transfemoral amputation have altered lumbosacral kinetics during sitting and standing movements. AB - Increases in spinal loading have been related to altered movements of the lower back during gait among persons with lower limb amputation, movements which are self-perceived by these individuals as contributing factors in the development of low back pain. However, the relationships between altered trunk kinematics and associated changes in lumbosacral kinetics during sit-to-stand and stand-to-sit movements in this population have not yet been assessed. Three-dimensional lumbosacral kinetics (joint moments and powers) were compared between 9 persons with unilateral transfemoral amputation (wearing both a powered and passive knee device), and 9 uninjured controls, performing five consecutive sit-to-stand and stand-to-sit movements. During sit-to-stand movements, lumbosacral joint moments and powers were significantly larger among persons with transfemoral amputation relative to uninjured controls. During stand-to-sit movements, lumbosacral joint moments and powers were also significantly larger among persons with transfemoral amputation relative to uninjured controls, with the exception of sagittal joint powers. Minimal differences in kinetic measures were noted between the powered and passive knee devices among persons with transfemoral amputation across all conditions. Altered lumbosacral kinetics during sitting and standing movements, important activities of daily living, may play a biomechanical role in the onset and/or recurrence of low back pain or injury among persons with lower-limb amputation. PMID- 26050873 TI - The Shank-to-Vertical-Angle as a parameter to evaluate tuning of Ankle-Foot Orthoses. AB - The effectiveness of an Ankle-Foot Orthosis footwear combination (AFO-FC) may be partly dependent on the alignment of the ground reaction force with respect to lower limb joint rotation centers, reflected by joint angles and moments. Adjusting (i.e. tuning) the AFO-FC's properties could affect this alignment, which may be guided by monitoring the Shank-to-Vertical-Angle. This study aimed to investigate whether the Shank-to-Vertical-Angle during walking responds to variations in heel height and footplate stiffness, and if this would reflect changes in joint angles and net moments in healthy adults. Ten subjects walked on an instrumented treadmill and performed six trials while walking with bilateral rigid Ankle-Foot Orthoses. The AFO-FC heel height was increased, aiming to impose a Shank-to-Vertical-Angle of 5 degrees , 11 degrees and 20 degrees , and combined with a flexible or stiff footplate. For each trial, the Shank-to Vertical-Angle, joint flexion-extension angles and net joint moments of the right leg at midstance were averaged over 25 gait cycles. The Shank-to-Vertical-Angle significantly increased with increasing heel height (p<0.001), resulting in an increase in knee flexion angle and internal knee extensor moment (p<0.001). The stiff footplate reduced the effect of heel height on the internal knee extensor moment (p=0.030), while the internal ankle plantar flexion moment increased (p=0.035). Effects of heel height and footplate stiffness on the hip joint were limited. Our results support the potential to use the Shank-to-Vertical-Angle as a parameter to evaluate AFO-FC tuning, as it is responsive to changes in heel height and reflects concomitant changes in the lower limb angles and moments. PMID- 26050874 TI - Comparison of two methods of determining patellofemoral joint stress during dynamic activities. AB - BACKGROUND: Joint specific models rely on muscle force estimates to quantify tissue specific stresses. Traditionally, muscle forces have been estimated using inverse dynamics alone. Inverse dynamics coupled with static optimization techniques allow for an alternative method in estimating muscle forces. Differences between these two techniques have not been compared for determining the quadriceps force for estimating patellofemoral joint stress. METHODS: Eleven female participants completed five squats and ten running trials. Motion capture and force platform data were processed using both solely inverse dynamics and inverse dynamics with static optimization to estimate the quadriceps force in a patellofemoral joint model. FINDINGS: Patellofemoral joint stress calculations were consistently higher when using the combination of inverse dynamics and static optimization as compared to the inverse dynamics alone (p<0.05) yielding estimates that were 30-106% greater. INTERPRETATION: When implementing joint models to estimate tissue specific stresses, the choice of technique used to estimate muscle forces plays an important role in determining the magnitude of estimated stresses in patellofemoral joint models. PMID- 26050875 TI - The effect of face exploration on postural control in healthy children. AB - The objective was to explore how face exploration affects postural control in healthy children. The novelty here is that eye movements and posture were simultaneously recorded. Three groups of children participated in the study: 12 children of 7.8+/-0.5 years old, 13 children of 10.4+/-0.5 years old and 12 children of 15.7+/-0.9 years old. Eye movements were recorded by video oculography and postural stability was recorded by a platform. Children were invited to explore five emotional faces (neutral, happy, sad fear and angry). Analysis of eye movements was done on saccadic latency, percentage of exploration time spent and number of saccades for each specific region of interest (ROI): eyes, nose and mouth. Analysis of posture was made on surface area, sway length and mean velocity of the center of pressures (CoP). Results showed that visual strategies, exploration and postural control develop during childhood and adolescence. Indeed, after nine years-old, children started to look the eyes ROI firstly, then the nose ROI and finally the mouth ROI. The number of saccades decreased with the age of children. The percentage of exploration time spent in eyes ROI was longer than the others ROIs and greater for unpleasant faces (sad, fear and angry) with respect to pleasant emotional face (happy). We found that in front of sad and happy faces the surface area of the CoP was significantly larger compared to other faces (neutral and angry). These results suggest that visual strategies and postural control change during children's development and can be influenced by the emotional face. PMID- 26050876 TI - Comparison of Speed of Sound Measures Assessed by Multisite Quantitative Ultrasound to Bone Mineral Density Measures Assessed by Dual-Energy X-Ray Absorptiometry in a Large Canadian Cohort: the Canadian Multicentre Osteoporosis Study (CaMos). AB - Dual-energy X-ray absorptiometry (DXA) is an important tool for the estimate of fracture risk through the measurement of bone mineral density (BMD). Similarly, multisite quantitate ultrasound can prospectively predict future fracture through the measurement of speed of sound (SOS). This investigation compared BMD (at the femoral neck, total hip, and lumbar spine) and SOS measures (at the distal radius, tibia, and phalanx sites) in a large sample of randomly-selected and community-based individuals from the Canadian Multicentre Osteoporosis Study. Furthermore, mass, height, and age were also compared with both measures. There were 4123 patients included with an age range of 30-96.8 yr. Pearson product moment correlations between BMD and SOS measures were low (0.21-0.29; all p<0.001), irrespective of site. Mass was moderately correlated with BMD measures (0.40-0.58; p<0.001), but lowly correlated with SOS measures (0.03-0.13; p<0.05). BMD and SOS were negatively correlated to age (-0.17 to -0.44; p<0.001). When regression analyses were performed to predict SOS measures at the 3 sites, the models predicted 20%-23% of the variance, leaving 77%-80% unaccounted for. The SOS measures in this study were found to be largely independent from BMD measures. In areas with no or limited access to DXA, the multisite quantitative ultrasound may act as a valuable tool to assess fracture risk. In locales with liberal access to DXA, the addition of SOS to BMD and other clinical risk factors may improve the identification of those patients at high risk for future fracture. PMID- 26050877 TI - Relationship Between BMD and Prevalent Vertebral Fractures in Indian Women Older Than 50 Yr. AB - The purpose of the study was to study the relationship of morphometric vertebral fractures with bone mineral density (BMD) in Indian women older than 50 yr. Four hundred fifteen healthy Indian women older than 50 yr (mean age: 62.8 yr) underwent lateral X-rays of the lumbar and thoracic spine. Genant's semiquantitative method was used to diagnose and classify morphometric vertebral fractures. BMD was measured by DXA at lumbar spine and total hip. Recruited subjects underwent anthropometric, biochemical, and hormonal evaluation. Vertebral fractures were present in 17.1% (95% confidence interval: 13.5, 20.8) subjects. Prevalence of osteoporosis based on BMD was 35.7%. By adding those with prevalent fractures, the number of women requiring therapy for osteoporosis would increase to 46.5%. The BMD measured at femur neck, total hip, and lumbar spine (L1eL4) was not found to be lower in women with vertebral fractures as compared with those without fractures. BMD was not found to be lower in women with vertebral fractures as compared with those without fractures. Significant number of additional subjects with BMD in the normal or osteopenic range become eligible for osteoporosis treatment when presence of vertebral fracture is used as an independent indication for such treatment. PMID- 26050878 TI - Protein-ligand docking using fitness learning-based artificial bee colony with proximity stimuli. AB - Protein-ligand docking is an optimization problem, which aims to identify the binding pose of a ligand with the lowest energy in the active site of a target protein. In this study, we employed a novel optimization algorithm called fitness learning-based artificial bee colony with proximity stimuli (FlABCps) for docking. Simulation results revealed that FlABCps improved the success rate of docking, compared to four state-of-the-art algorithms. The present results also showed superior docking performance of FlABCps, in particular for dealing with highly flexible ligands and proteins with a wide and shallow binding pocket. PMID- 26050879 TI - Spectroscopic studies on peptides and proteins with cysteine-containing heme regulatory motifs (HRM). AB - The role of heme as a cofactor in enzymatic reactions has been studied for a long time and in great detail. Recently it was discovered that heme can also serve as a signalling molecule in cells but so far only few examples of this regulation have been studied. In order to discover new potentially heme-regulated proteins, we screened protein sequence databases for bacterial proteins that contain sequence features like a Cysteine-Proline (CP) motif, which is known for its heme binding propensity. Based on this search we synthesized a series of these potential heme regulatory motifs (HRMs). We used cw EPR spectroscopy to investigate whether these sequences do indeed bind to heme and if the spin state of heme is changed upon interaction with the peptides. The corresponding proteins of two potential HRMs, FeoB and GlpF, were expressed and purified and their interaction with heme was studied by cw EPR and UV-Visible (UV-Vis) spectroscopy. PMID- 26050880 TI - Metalated nucleotide chemisorption on hydroxyapatite. AB - The experiments here reported evidence on the importance of the residual charge of a nucleotide derivative, for the adsorption on nHAP (hydroxyapatite nanocrystals), in water solution. We found that the simple presence of phosphates on the nucleotide derivative does not guarantee adsorption on nHAP. On the other hand, we demonstrated that a cationic or neutral charge on a nucleotide derivative produces a strongly reduced chemical adsorption (chemisorption) whereas, in the presence of a net negative charge, relevant adsorption on nHAP is observed. The number of phosphates can only modulate the adsorption efficiency of a molecule provided that this latter bears an overall negative charge. The neutral zwitterionic nucleotide Pt(II) complexes, bearing negatively charged phosphates, are unable to give stable chemisorption. Previous considerations are important to model the binding ability of phosphate bearing nucleotide derivatives or molecules on hydroxyapatite. The findings reported in the present paper could be relevant in bone tissue targeting or nHAP mediated drug delivery. PMID- 26050881 TI - Carboxymethyl chitosan represses tumor angiogenesis in vitro and in vivo. AB - Carboxymethyl chitosan (CMCS), with potent water solubility, biocompatibility, and non-toxicity, has emerged as a promising candidate for biomedical applications. In this study, the anti-tumor angiogenesis effects of CMCS were evaluated in vitro and in vivo. Our results showed that CMCS could inhibit the 2 dimensional and 3-dimensional migration of human umbilical vein endothelial cells (HUVECs) in vitro. CMCS significantly inhibited the growth of mouse hepatocarcinoma 22 tissues and could promote tumor cell necrosis as suggested by pathological observations. The CD34 expression in H22 tumor tissue, the levels of vascular endothelial growth factor and tissue inhibitor of metalloproteinase 1 in serum was regulated by CMCS treatment. CMCS could significantly improve thymus index, spleen index, tumor necrosis factor alpha and interferon gamma level. In a conclusion, CMCS possessed potent anti-tumor effects by inhibiting tumor angiogenesis, stimulating immune functions. Our date provide more foundation for application of CMCS in biomedicine or biomaterials for targeted anticancer drugs delivery. PMID- 26050882 TI - Characterization and evaluation of synthetic riluzole with beta-cyclodextrin and 2,6-di-O-methyl-beta-cyclodextrin inclusion complexes. AB - beta-Cyclodextrin (beta-CD) and 2,6-di-O-methyl-beta-cyclodextrin (DM-beta-CD) inclusion complexes with riluzole (RLZ) were prepared to improve water solubility and broaden potential pharmaceutical applications. CDs/RLZ inclusion complexes were confirmed via phase solubility studies, FT-IR spectroscopy, PXRD, DSC, (1)H NMR, and SEM. Phase solubility studies indicated that beta-CD and DM-beta-CD can form 1:1 inclusion complexes with RLZ, and the stability constants were 663.17 and 1609.07M(-1), respectively. Water solubility and dissolution rate of RLZ were significantly improved in complex forms, implying that the inclusion complexes may develop pharmaceutical applications. Preliminary in vitro cytotoxicity assay also showed that RLZ hepatotoxicity was not increased in the inclusion complexes. PMID- 26050883 TI - Collagen cryogel cross-linked by naturally derived dialdehyde carboxymethyl cellulose. AB - We present the use of a natural derivative, dialdehyde carboxymethyl cellulose (DCMC) as the cross-linker for the preparation of spongy collagen cryogels by freezing-thawing method. The DCMC has been characterized by laser light scattering (LLS), showing the molecular weight of 2.38 * 10(5)g/mol. FT-IR studies demonstrate that the cross-linking reaction and the cryogenic treatment do not destroy the triple helix of collagen. SEM images indicate that the cryogel has a heterophase structure with interconnecting macropores. DSC measurements reveal that the incorporation of a very small amount of DCMC can significantly improve the thermal stability of collagen. Moreover, the cryogels exhibit fast swelling rate, and their equilibrium swelling ratio is related to DCMC content and pH-dependent. The in vitro blood-compatibility tests prove that the introduction of DCMC does not cause the reducing performance in hemolysis and blood clotting compared with pure collagen. Hence, the low-cost and non-toxic nature of DCMC confers the cryogel great potential in tissue engineering and other biomedical applications. PMID- 26050884 TI - Polymeric nanoparticles based on chitooligosaccharide as drug carriers for co delivery of all-trans-retinoic acid and paclitaxel. AB - An amphiphilic all-trans-retinoic acid (ATRA)-chitooligosaccharide (RCOS) conjugate was synthesized to form self-assembled polymeric nanoparticles to facilitate the co-delivery of ATRA and paclitaxel (PTX). The blank RCOS nanoparticles possessed low hemolytic activity and cytotoxicity, and could efficiently load PTX with a drug loading of 22.2% and a high encapsulation efficiency of 71.3%. PTX-loaded RCOS nanoparticles displayed a higher cytotoxicity to HepG2 cells compared to PTX plus ATRA solution when corrected by the accumulated drug release. Cellular uptake profiles of RCOS nanoparticles were evaluated via confocal laser scanning microscope and flow cytometry with FITC as a fluorescent mark. The RCOS nanoparticles could be rapidly and continuously taken up by HepG2 cells via endocytosis and transported into the nucleus, and the uptake rates increased with particle concentration. These results revealed the promising potential of RCOS nanoparticles as drug carriers for co-delivery of ATRA and PTX or other hydrophobic therapeutic agents. PMID- 26050885 TI - Improved welan gum production by Alcaligenes sp. ATCC31555 from pretreated cane molasses. AB - Welan gum production by Alcaligenes sp. ATCC31555 from cane molasses was studied in batch fermentation to reduce production costs and enhance gum production. The pretreatment of cane molasses, agitation speed and the addition of supplements were investigated to optimize the process. Sulfuric acid hydrolysis was found to be the optimal pretreatment, resulting in a maximum gum concentration of 33.5 g/L, which is 50.0% higher than those obtained from the molasses' mother liquor. Agitation at 600 rpm at 30 degrees C and addition of 10% n-dodecane following fermentation for 36 h increased the maximum gum production up to 41.0 +/- 1.41 g/L, which is 49.1% higher than the greatest welan gum concentration in the literature so far. The welan gum product showed an acceptable molecular weight, similar rheological properties and better thermal stability to that obtained from glucose. These results indicate that cane molasses may be a suitable and inexpensive substrate for cost-effective industrial-scale welan gum production. PMID- 26050886 TI - Joint action of ultrasonic and Fe3+ to improve selectivity of acid hydrolysis for microcrystalline cellulose. AB - In this study, the combination of Fe(3+)/HCl and ultrasonic treatment was applied to selectively hydrolyze cellulose for the preparation of microcrystalline cellulose (MCC). It was found that the crystallinity and specific surface area of hydrocellulose samples were higher (78.92% and 2.23581 m(2)g(-1), respectively), compared with the method that only used Fe(3+)/HCl catalyst without ultrasonic treatment. Meanwhile, the hydrolysate can be extracted and reused for cellulose hydrolysis for three runs, which was effective in saving the dosage of chemicals and reducing the pollution of the environment without affecting the properties of hydrocellulose. Moreover, the increased concentration of total reducing sugar (TRS) after three runs may be used as a valuable source in biofuels production. The technology of cellulose hydrolysis, by retaining the crystalline region for MCC products while promoting hydrolysis of amorphous region for further utilization is of great novelty, which may prove valuable in converting biomass into chemicals and biofuels, environmentally and economically. PMID- 26050887 TI - Anti-tumor activity and the mechanism of SIP-S: A sulfated polysaccharide with anti-metastatic effect. AB - Our previous studies demonstrated that SIP-S had anti-metastatic activity and inhibited the growth of metastatic foci. Here we report the anti-tumor and immunoregulatory potential of SIP-S. SIP-S could significantly inhibit tumor growth in S180-bearing mice, and the inhibition rates was 43.7% at 30 mg/kg d. Besides, SIP-S could improve the thymus and spleen indices of S180-bearing mice and the mice treated with CTX. The combination of SIP-S (15 mg/kg d) with CTX (12.5 mg/kg d) showed higher anti-tumor potency than CTX (25 mg/kg d) alone. These results indicated that SIP-S had immunoenhancing and anticancer activity, and the immunoenhancing activity might be one mechanism for its anti-tumor activity. Flow cytometry results showed that SIP-S could induce tumor cells apoptosis. Western blot analysis indicated that SIP-S could upregulate the expression of pro-apoptotic proteins, caspase-3, -8, -9 and Bax, and downregulate the expression of anti-apoptotic protein PARP-1 in tumor cells in a dose dependent manner. In summary, SIP-S has anti-tumor activity, which may be associated with its immunostimulating and pro-apoptotic activity. PMID- 26050888 TI - Characterization and antitumor activities of a water-soluble polysaccharide from Ampelopsis megalophylla. AB - A water-soluble polysaccharide named as AMP was isolated and purified from the leaves of Ampelopsis megalophylla by DEAE-52 Cellulose and Sephadex G-100 column chromatography. AMP had an average molecular weight of about 8.4 * 10(4)Da and was composed of galactose (Gal), mannose (Man), glucose (Glc), arabinose (Ara), and rhamnose (Rha) in a molar ratio of 2.7:1.6:1.1:0.6:0.3. After 10 days of AMP (50, 100, and 200mg/kg) treatment once daily in tumor-bearing mice, AMP oral administration could inhibit the growth of transplantable Sarcoma 180 (S180) tumor in mice and increase the spleen index and body weight. Furthermore, AMP also promote splenocytes' proliferation induced by concanavalin A (ConA) and lipopolysaccharide (LPS), strengthen peritoneal macrophages to devour neutral red and increase the production of interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in serum. These results suggest that AMP had clear antitumor activity, which might be related to its regulation of immune function in mice. PMID- 26050889 TI - Understanding starch gelatinization: The phase diagram approach. AB - By constructing a detailed phase diagram for the potato starch-water system based on data from optical microscopy, synchrotron X-ray scattering and differential scanning calorimetry, we show that gelatinization can be interpreted in analogy with a eutectic transition. The phase rule explains why the temperature of the gelatinization transition (G) is independent on water content. Furthermore, the melting (M1) endotherm observed in DSC represents a liquidus line; the temperature for this event increases with increasing starch concentration. Both the lamellar spacing and the inter-helix distance were observed to decrease with increasing starch content for starch concentrations between approximately 65 wt% and 75 wt%, while the inter-helix distance continued decreasing upon further dehydration. Understanding starch gelatinization has been a longstanding challenge. The novel approach presented here shows interpretation of this phenomenon from a phase equilibria perspective. PMID- 26050890 TI - Complexes of dextran sulfate and anthocyanins from Vaccinium myrtillus: Formation and stability. AB - To improve the stability and antioxidant activity of anthocyanins (ATC), complexes of dextran sulfate (DESU) and ATC extracted from Vaccinium myrtillus were formed during electrostatic interaction between sulfo groups of DESU and cationic moieties of ATC. At the optimal weight ratio DESU/ATC=0.4 g/g, the amount of ATC introduced into a complex depended on the total concentration of the reagents. About 1.7 g of ATC per g of DESU could be incorporated into a complex. The formation of DESU/ATC complexes was confirmed by HPLC and FT-IR spectroscopy. According to HPLC analysis, the amount of individual ATC incorporated into a complex varied from 73.7% in the case of malvidin-3-O glucoside to 90.8% in the case of delphinidin-3-arabinoside. PMID- 26050891 TI - Optimization and kinetic analysis on the sulfuric acid - Catalyzed depolymerization of wheat straw. AB - The objectives of this work were to optimize the experimental condition and to study the kinetic behavior of wheat straw depolymerization with sulfuric acid (2 wt%, 3 wt%, and 4 wt%) at different temperatures (120 degrees C, 130 degrees C, and 140 degrees C). The two-fraction kinetic model was obtained for the prediction of the generations of product and by-product during depolymerization. The kinetic parameters of the two-fraction model were analyzed using an Arrhenius type equation. Applying the kinetic two-fraction model, the optimum condition for wheat straw depolymerization was 3 wt% H2SO4 at 130 degrees C for 75 min, which yielded a high concentration of fermentable sugars (xylose 8.934 g/L, glucose 1.363 g/L, and arabinose 1.203 g/L) and low concentrations of microbial inhibitors (furfural 0.526 g/L and acetic acid 1.192 g/L). These results suggest that the model obtained in this study can satisfactorily describe the formation of degradation products and the depolymerization mechanism of wheat straw. PMID- 26050892 TI - Preparation of hydroxypropyl agars and their properties. AB - A series of hydroxypropyl agars (HPAs) with different hydroxypropyl molar substitution (MS) were prepared and their physicochemical properties were characterized. After hydroxypropylation, the dissolving temperature, the gelling temperature, the gel melting temperature, the gel strength, and the thermal stability of agar all decreased except that its hygroscopicity increased. The gel skeleton structures of raw agar and HPAs were all of the porous network structures, but the pores of gel skeleton structure of HPAs became smaller and denser. PMID- 26050893 TI - The biosynthesis, structure and gelatinization properties of starches from wild and cultivated African rice species (Oryza barthii and Oryza glaberrima). AB - The molecular structure and gelatinization properties of starches from domesticated African rice (Oryza glaberrima) and its wild progenitor (Oryza barthii) are determined and comparison made with Asian domesticated rice (Oryza sativa), the commonest commercial rice. This suggests possible enzymatic processes contributing to the unique traits of the African varieties. These have similar starch structures, including smaller amylose molecules, but larger amounts of amylose chains across the whole amylose chain-length distribution, and higher amylose contents, than O. sativa. They also show a higher proportion of two- and three-lamellae spanning amylopectin branch chains (degree of polymerization 34-100) than O. sativa, which contributes to their higher gelatinization temperatures. Fitting amylopectin chain-length distribution with a biosynthesis-based mathematical model suggests that the reason for this difference might be because O. glaberrima and O. barthii have more active SSIIIa and/or less active SBEIIb enzymes. PMID- 26050894 TI - Microwave assisted extraction of sulfated polysaccharides (fucoidan) from Ascophyllum nodosum and its antioxidant activity. AB - Sulfated polysaccharides (fucoidan) from brown seaweed Ascophyllum nodosum were extracted by microwave assisted extraction (MAE) technology. Different conditions of temperature (90-150 degrees C), extraction time (5-30 min) were evaluated and optimal fucoidan yield was 16.08%, obtained from 120 degrees C for 15 min's extraction. Compositional analysis, GPC, HPAEC and IR analysis were employed for characterization of extracted sulfated polysaccharides. Fucose was the main monosaccharide of fucoidan extracted at 90 degrees C while glucuronic acid was the main monosaccharide of fucoidan extracted at 150 degrees C. Both the molecular weight and sulfate content of extracted fucoidan increased with decreasing extraction temperature. All fucoidans exhibited antioxidant activities as measured by DPPH scavenging and reducing power, among which fucoidan extracted at 90 degrees C was highest. This study shows that MAE is an efficient technology to extract sulfated polysaccharides from seaweed and Ascophyllum nodosum could potentially be a resource for natural antioxidants. PMID- 26050895 TI - Combined effects of independent variables on yield and protein content of pectin extracted from sugar beet pulp by citric acid. AB - The extraction of pectin from sugar beet pulp by citric acid was carried out under different conditions using Box-Behnken design for four independent variables (pH, temperature, time and liquid to solid ratio). The yield of sugar beet pulp pectin ranged from 6.3% to 23.0%, and the content of protein from 1.5% to 4.5%. All independent variables significantly affected the yield, and all variables except liquid to solid ratio significantly affected the protein content. The yield increased as decreasing pH of extracting solution, extending time and advancing temperature, and an opposite relationship of effects between variables and content of protein was obtained. The chemical composition of collected samples was determined. Moreover, from the results of emulsifying properties study, the extracted pectin from sugar beet pulp could prepare steady oil-in-water emulsions. Therefore, it was inferred that the extraction conditions could influence yield and protein content, resulting in different emulsifying property. PMID- 26050896 TI - Removal of Cu2+ from aqueous solutions by the novel modified bagasse pulp cellulose: Kinetics, isotherm and mechanism. AB - This study designed and synthesized a novel cellulose-based heavy metal adsorption material. One kind of bagasse pulp cellulose was pretreated under microwave 200 W for 3 min before the epoxidation, amination and ultrasonic enhancement sulfonation reaction. Heavy metal adsorption groups N and S were grafted onto the bagasse pulp cellulose. Furthermore, the effects of solution pH, adsorption temperature, adsorbent dosage, Cu(2+) concentration, and adsorbent recycling on adsorption capacity were investigated. Under the optimum condition, the adsorption amount of Cu(2+) was 35.2mg/g adsorbent. Compared with other cellulose-based adsorbents, this kind of adsorbent could be easily prepared and effectively recycled. Except for the normal fitting of adsorption process with the Langmuir isotherm adsorption model, Freundlich isotherm adsorption model and secondary adsorption kinetics model, the solid-liquid phase adsorption mechanism was also introduced to explain the Cu(2+) adsorption process. Three consecutive stages were deeply discussed and verified, where the surface diffusion and particle internal diffusion process were the primary along with a quick adsorption of the adsorbate onto the in-hole surface of the cellulose-based adsorbent. PMID- 26050897 TI - Antimicrobial nanostructured starch based films for packaging. AB - Montmorillonite modified with a quaternary ammonium salt C30B/starch nanocomposite (C30B/ST-NC), silver nanoparticles/starch nanocomposite (Ag-NPs/ST NC) and both silver nanoparticles/C30B/starch nanocomposites (Ag-NPs/C30B/ST-NC) films were produced. The nanoclay (C30B) was dispersed in a starch solution using an ultrasonic probe. Different concentrations of Ag-NPs (0.3, 0.5, 0.8 and 1.0mM) were synthesized directly in starch and in clay/starch solutions via chemical reduction method. Dispersion of C30B silicate layers and Ag-NPs in ST films characterized by X-ray and scanning electron microscopy showed that the presence of Ag-NPs enhanced clay dispersion. Color and opacity measurements, barrier properties (water vapor and oxygen permeabilities), dynamic mechanical analysis and contact angle were evaluated and related with the incorporation of C30B and Ag-NPs. Films presented antimicrobial activity against Staphylococcus aureus, Escherichia coli and Candida albicans without significant differences between Ag NPs concentrations. The migration of components from the nanostructured starch films, assessed by food contact tests, was minor and under the legal limits. These results indicated that the starch films incorporated with C30B and Ag-NPs have potential to be used as packaging nanostructured material. PMID- 26050898 TI - Chitosan hydrogels enriched with polyphenols: Antibacterial activity, cell adhesion and growth and mineralization. AB - Injectable hydrogels for bone regeneration consisting of chitosan, sodium beta glycerophosphate (Na-beta-GP) and alkaline phosphatase (ALP) were enriched with the polyphenols phloroglucinol (PG) and gallic acid (GA) and characterized physicochemically and biologically with respect to properties relevant for applications in bone regeneration, namely gelation kinetics, mineralizability, antioxidant properties, antibacterial activity, cytocompatibility and ability to support adhesion and growth of human osteoblast-like MG63 cells. Enrichment with PG and GA had no negative effect on gelation kinetics and mineralizability. PG and GA both enhanced antioxidant activity of unmineralized hydrogels. Mineralization reduced antioxidant activity of hydrogels containing GA. Hydrogels containing GA, PG and without polyphenols reduced colony forming ability of Escherichia coli after 1h, 3h and 6h incubation and slowed E. coli growth in liquid culture for 150min. Hydrogels containing GA were cytotoxic and supported cell growth more poorly than polyphenol-free hydrogels. PG had no negative effect on cell adhesion and growth. PMID- 26050899 TI - Isolation and structural characterization of chondroitin sulfate from bony fishes. AB - Chondroitin sulfate (CS) was purified from the bones of common fishes, monkfish, cod, spiny dogfish, salmon and tuna, and characterized in an effort to find alternative sources and new peculiar structures of this complex biomacromolecule utilized in the pharmaceutical and nutraceutical industry. Quantitative analyses yielded a CS content ranging from 0.011% for cod up to 0.34% for monkfish. The disaccharide pattern showed the presence of nonsulfated disaccharide, monosulfated species DeltaDi6s and DeltaDi4s, and disulfated disaccharides in different percentages. The disulfated species DeltaDi2,6dis was present in all CS extracts in a range of 1.3-10.5%. The presence of these disulfated disaccharides may be a useful marker for the marine origin of CS. The newly identified sources would certainly enable the production of CS with unique disaccharide composition and properties. PMID- 26050900 TI - Biosynthesis of bacterial cellulose in the presence of different nanoparticles to create novel hybrid materials. AB - The unique micro-nano porous three-dimensional network of bacterial cellulose (BC) can facilitate the incorporation of nanoparticles (NPs) into the BC matrix to create advanced BC-based functional nanomaterials for diverse applications. In this study, novel nanomaterials comprised of bacterial cellulose (BC) synthesized in the presence of different NPs (cellulose nanofibrils (CNF), exfoliated graphite nanoplatelets (xGnP), and nanoclay (NC)) were prepared using an in situ approach. NPs at 0.5 wt.% loading were added into the BC culture medium and their effect on the resulting nanocomposite structure was studied by field emission scanning electron microscopy (FE-SEM), X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). All BC-based nanomaterials produced, exhibited good dispersion of the NPs within the BC matrix and the NPs were found embedded among the voids and microfibrils. The thermal stability and residual mass of BC-xGnP and BC-NC nanomaterials was significantly increased compared with the neat BC. CNF incorporation into the BC matrix did not change the thermal stability and residual mass of the BC matrix. This study also provides novel insights into the properties of the hybrid materials, and shows the approach used to make these materials which results in increased performance for chosen applications. PMID- 26050901 TI - Bio-nanocomposite films reinforced with cellulose nanocrystals: Rheology of film forming solutions, transparency, water vapor barrier and tensile properties of films. AB - This study was aimed to develop bio-nanocomposite films of carboxymethyl cellulose (CMC)/starch (ST) polysaccharide matrix reinforced with cellulose nanocrystals (CNC) using the solution casting method. The CNC were extracted at the nanometric scale from sugarcane bagasse via sulfuric acid hydrolysis and used as reinforcing phase to produce CMC/ST-CNC bio-nanocomposite films at different CNC loading levels (0.5-5.0 wt%). Steady shear viscosity and dynamic viscoelastic measurements of film-forming solution (FFS) of neat CMC, CMC/ST blend and CMC/ST CNC bio-nanocomposites were evaluated. Viscosity measurements revealed that a transition from Newtonian behavior to shear thinning occurred when CNC were added. The dynamic tests confirmed that all FFS have a viscoelastic behavior with an entanglement network structure, induced by the hydrogen bonding. In regard to the cast film quality, the rheological data showed that all FFS were suitable for casting of films at ambient temperature. The effect of CNC addition on the optical transparency, water vapor permeability (WVP) and tensile properties of bio-nanocomposite films was studied. It was found that bio-nanocomposite films remain transparent due to CNC dispersion at the nanoscale. The WVP was significantly reduced and the elastic modulus and tensile strength were increased gradually with the addition of CNC. Herein, the steps to form new eco-friendly bio-nanocomposite films were described by taking advantage of the combination of CMC, ST and CNC. The as-produced films exhibited good optical transparency, reduced WVP and enhanced tensile properties, which are the main properties required for packaging applications. PMID- 26050902 TI - The change in excited-state proton transfer kinetics of 1-naphthol i micelles upon the binding of polymers: The influence of hyaluronan hydration. AB - The fast deprotonation of 1-naphthol was studied in aqueous solution and in polymer-cetyltrimethylammonium bromide (CTAB) mixtures using picosecond fluorescence spectroscopy to study the influence of hyaluronan hydration in polymer-surfactant interactions. The aqueous micelle solution showed the expected change of proton transfer rate around the reported critical micelle concentration (~1 mM). The proton transfer rate dependence on CTAB concentration in the hyaluronan-CTAB and polystyrenesulfonate-CTAB systems differed significantly from that in the aqueous micelle solution. The dynamic study of excited state proton transfer (ESPT) revealed the significant influence of hyaluronan hydration in CTAB micelles. When hyaluronan-CTAB aggregates were formed at the CTAB concentration of 0.5mM, a tenfold decrease in the rate of deprotonation was observed when compared to polystyrenesulfonate-CTAB aggregates due to hyaluronan hydration. In 2mM CTAB-hyaluronan aggregates, the rate of deprotonation was found to be almost two times faster than in the 2mM CTAB or polystyrenesulfonate-CTAB system. Furthermore, the study of excited-state proton transfer of 1-naphthol confirmed that hyaluronan hydration layer penetrates into the micelle and changes the emission characteristics of 1-naphthol. PMID- 26050903 TI - Liposomes incorporating cyclodextrin-drug inclusion complexes: Current state of knowledge. AB - Cyclodextrins (CDs) are cyclic oligosaccharides, consisting of glucopyranose units, which are able to form host-guest inclusion complexes with lipophilic molecules. The ability of CD to increase drug solubility may be used to increase drug entrapment in the aqueous compartment of liposomes and liposomes can protect CD/drug inclusion complexes until drug release. Liposomes are phospholipid vesicles composed of lipid bilayers enclosing one or more aqueous compartments. They have been widely used as safe and effective carriers for both hydrophilic and lipophilic drugs. However, lipophilic drugs incorporated in the membrane bilayers can be rapidly released, which limits the effectiveness of this drug delivery system. The coupling of both delivery systems by encapsulating CD/drug inclusion complex into liposomes is proposed to circumvent the drawbacks of each separate system. Here, we review the literature regarding the encapsulation of CD/drug inclusion complex into conventional, deformable and double loaded liposomes. The review highlights the characteristics of these systems and presents the advantages and disadvantages of each one. PMID- 26050904 TI - Effect of dynamic high pressure on technological properties of cashew tree gum (Anacardium occidentale L.). AB - Dynamic high pressure (DHP) appears to be an alternative approach to physical modification of polysaccharides aimed improving their technological properties. Therefore, its effect on the functional properties of polysaccharides (i.e., oil absorption capacity, emulsifier, and rheology) needs to be investigated. Cashew tree gum (CG) is a biological macromolecule that has been proposed to be used as an emulsifier in beverage emulsions. To the best of our knowledge, none of the articles in the literature investigates the effect of DHP on the CG properties. This work presents a study on the evaluation of the effects of DHP on functional characteristics of CG, including rheological properties, molecular weight, glycosyl-linkage analysis, solubility, swelling and oil absorption capacity (OAC). The results suggest that DHP is able to modify the technological properties of cashew tree gum (increasing solubility and decreasing apparent viscosity). PMID- 26050905 TI - Enzymatic production of specifically distributed hyaluronan oligosaccharides. AB - High-molecular-mass hyaluronan (HA) was controllably depolymerized in pure aqueous solution with recombinant leech hyaluronidase (HAase). The HAase concentration per unit HA and hydrolysis time played important roles in molecular mass distribution. By modulating the concentrations of HAase and controlling the hydrolysis time, any molar-mass-defined HA oligomers could be efficiently and specifically produced on a large scale (40 g/L), such as HA oligosaccharides with weight-average molar mass of 4000, 10,000, and 30,000Da and end hydrolysates containing only HA6 and HA4. High performance liquid chromatography-size exclusion chromatography, polyacrylamide gel electrophoresis, capillary zone electrophoresis, and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry confirmed low polydispersity of the produced molar-mass-defined HA oligosaccharides. Therefore, large-scale production of defined HA oligosaccharides with narrow molecular mass distribution will significantly promote progress in related research and its potential applications. PMID- 26050906 TI - Fractionation of bamboo hemicelluloses by graded saturated ammonium sulphate. AB - The hemicelluloses were isolated with 10% KOH at 25 degrees C from dewaxed and delignified bamboo powder. The alkali-soluble hemicelluloses from Sinocalamus affinis were fractionated by ammonium sulphate precipitation method. The bamboo alkali-soluble hemicelluloses yielded seven hemicellulosic fractions obtained at 0, 5, 15, 25, 40, 55, and 70% saturation with ammonium sulphate. It was found that the more branched hemicelluloses were precipitated at higher ammonium sulphate concentrations (55 and 70%), the more linear hemicelluloses were precipitated at lower ammonium sulphate concentrations (0, 5, 15, 25, and 40%). The molecular weights of hemicellulosic fractions become lower from 35,270 (H0) to 18,680 (H70)gmol(-1) with the increasing concentrations of saturated ammonium sulphate from 0 to 70%. Based on the FT-IR, (1)H, (13)C and 2D HSQC NMR studies, the alkali-soluble hemicelluloses were 4-O-methyl-glucuronoarabinoxylans composed of the (1->4)-linked beta-d-xylopyranosyl backbone with branches at O-3 of alpha L-arabinofuranosyl or at O-2 of 4-O-methyl-alpha-d-glucuronic acid. PMID- 26050907 TI - Reinforcement and nucleation of acetylated cellulose nanocrystals in foamed polyester composites. AB - The biodegradable foamed nanocomposites were developed from the reinforcement of surface acetylated cellulose nanocrystals (ACNC) as bionanofillers and the poly(butylene succinate) (PBS) as polymeric matrix. The surface modification of high-efficiency acetylation on the cellulose nanocrystals converted the hydrophilic hydroxyl groups to hydrophobic acetyl groups, which improved the compatibility between rigid nanoparticles and polyester matrix through the similar ester groups of two components. With the introduction of 5 wt% ACNC, the specific flexural strength (sigma/rhof) and the specific flexural modulus (E/rhof) of the foamed composites significantly increased by 75.7% and 57.2% in comparison with those of the neat PBS foamed material. Meanwhile, with the change of the ACNC concentrations, the cell size and cell density of the foamed composites can be regulated and achieved the high cell density of 1.95 * 10(5)cells/cm(3) bearing the small average cell size of 178.84 MUm (5 wt% ACNC). The microstructure observation of the foamed composites indicated the moderate loading levels of rigid ACNC can serve as the reinforcing phase for the stress transfer and promote the crystallinity advancement of the foamed composites. PMID- 26050908 TI - Transient and quasi-permanent networks in xyloglucan solutions. AB - Viscoelastic properties of aqueous solutions of xyloglucan extracted from Hymenaea courbaril seeds (Jatoba gum) were investigated by rheology over a wide range of concentrations and temperatures. The polymer was characterized in dilute solutions by light scattering measurements and size exclusion chromatography. Xyloglucan formed, in semi-dilute solutions (C 0.3 wt%), a transient network with cross-links characterized by a broad distribution of lifetimes, independent of the temperature and concentration. Progressively, at higher temperatures (>60 degrees C), a second much weaker quasi-permanent network was formed and attributed to the exchange of intra- to inter-chain bonds. The stiffness of the second network increased with decreasing temperature, but it could be easily broken by applying a relatively weak shear stress and is readily reversible on re heating, and partially reversible on resting at 20 degrees C. PMID- 26050909 TI - Iodine derivatives of chemically modified gum Arabic microspheres. AB - Acetylated gum Arabic (AGA) derivatives with different degrees of substitution (DS 0.97-2.74) were synthesized using acetyl chloride and a base under varying reaction conditions. The AGA derivatives were obtained in the form of microspheres and thereafter stable iodine products were prepared by doping the microspheres with an iodinating agent, iodine monochloride (ICl). The reaction between electrophilic iodine and polar carbonyl groups was studied by FT-IR, (1)H NMR, and UV-VIS spectroscopies. The products were also characterized by DSC, TGA and SEM studies. The incorporated iodine was released in aqueous medium as iodide ions (I(-)). A reaction scheme has been proposed for the iodination and de iodination of the gum derivatives. This work suggests that the iodine derivatives of modified gum Arabic could be used as a source of iodide ions which is the nutritional form of iodine. PMID- 26050910 TI - [Fever, parotid swelling, otorrhea and retroauricular fistula in a child]. PMID- 26050911 TI - Delayed Newcastle disease virus replication using RNA interference to target the nucleoprotein. AB - Each year millions of chickens die from Newcastle disease virus (NDV) worldwide leading to severe economic and food losses. Current vaccination campaigns have limitations especially in developing countries, due to elevated costs, need of trained personnel for effective vaccine administration, and functional cold chain network to maintain vaccine viability. These problems have led to heightened interest in producing new antiviral strategies, such as RNA interference (RNAi). RNAi methodology is capable of substantially decreasing viral replication at a cellular level, both in vitro and in vivo. In this study, we utilize microRNA (miRNA)-expressing constructs (a type of RNA interference) in an attempt to target and knockdown five NDV structural RNAs for nucleoprotein (NP), phosphoprotein (P), matrix (M), fusion (F), and large (L) protein genes. Immortalized chicken embryo fibroblast cells (DF-1) that transiently expressed miRNA targeting NP mRNA, showed increased resistance to NDV-induced cytopathic effects, as determined by cell count, relative to the same cells expressing miRNA against alternative NDV proteins. Upon infection with NDV, DF-1 cells constitutively expressing the NP miRNA construct had improved cell survival up to 48 h post infection (h.p.i) and decreased viral yield up to 24 h.p.i. These results suggest that overexpression of the NP miRNA in cells and perhaps live animal may provide resistance to NDV. PMID- 26050912 TI - Comparison of the pathogenicity of the USDA challenge virus strain to a field strain of infectious laryngotracheitis virus. AB - Infectious laryngotracheitis virus (ILTV) causes respiratory disease in chickens. This alphaherpesvirus infects laryngeal tracheal epithelial cells and causes outbreaks culminating in decreases in egg production, respiratory distress in chickens and mortality. There are several different vaccines to combat symptoms of the virus, including chicken embryo origin, tissue culture origin and recombinant vaccines. All vaccines licensed for use in the U.S. are tested for efficacy and potency according to U.S. federal regulation using a vaccine challenge assay involving the use of an ILT challenge virus. This challenge virus is provided to biologics companies by the Center for Veterinary Biologics (CVB), United States Department of Agriculture (USDA). The current USDA challenge virus originated from a vaccine strain and has been subjected to multiple passages in eggs, and may not represent what is currently circulating in the field. The objective of this study was to evaluate and compare the pathogenicity of USDA's challenge virus strain to the pathogenicity of a recent ILT field isolate. Using the challenge virus and various dilutions of the field isolate, clinical signs, mortality and pathology were evaluated in chickens. Results indicate that the field isolate at a 1:20 dilution is comparable in pathogenicity to the USDA challenge virus at a 1:4 dilution, and that the ILTV field isolate is a viable candidate that could be used as a challenge virus when evaluating vaccine efficacy. PMID- 26050913 TI - Translating school health research to policy. School outcomes related to the health environment and changes in mathematics achievement. AB - This paper describes an exploration of the relationship between mathematic achievement and the school health environment relative to policy-driven changes in the school setting, specifically with regard to physical education/physical activity. Using school-level data, the authors seek to understand the relationship between mathematics achievement and the school health environment and physical education minutes. This work provides a description of the aspects of the school health environment, an exploration of the interrelationships between school health and student achievement, and an assessment of the effects of the school health policy and practice on student performance and health status. Based on these findings, we identify additional research necessary to describe the relationship between obesity and learning in children. PMID- 26050914 TI - Stakeholder reactions toward iodine biofortified foods. An application of protection motivation theory. AB - OBJECTIVE/PURPOSE: To use Protection Motivation Theory (PMT) to evaluate stakeholders' intention to adopt iodine biofortified foods as an alternative means to improve children's iodine status and overall school performance. METHODS: A survey was administered with 360 parents of primary school children and 40 school heads. Protection motivation is measured through matching the cognitive processes they use to evaluate iodine deficiency (threat appraisal), as well as iodine biofortified foods to reduce the threat (coping appraisal). Data were analyzed through Robust (Cluster) regression analysis. RESULTS: Gender had a significant effect on coping appraisal for school heads, while age, education, occupation, income, household size and knowledge were significant predictors of threat, coping appraisal and/or protection motivation intention among parents. Nevertheless, in the overall protection motivation model, only two coping factors, namely self-efficacy (parents) and response cost (school heads), influenced the intention to adopt iodine biofortified foods. CONCLUSION: School feeding programs incorporating iodine biofortification should strive to increase not only consumer knowledge about iodine but also its association to apparent deficiency disorders, boost self-efficacy and ensure that the costs incurred are not perceived as barriers of adoption. The insignificant threat appraisal effects lend support for targeting future communication on biofortification upon the strategies itself, rather than on the targeted micronutrient deficiency. PMT, and coping factors in particular, seem to be valuable in assessing intentions to adopt healthy foods. Nevertheless, research is needed to improve the impacts of threat appraisal factors. PMID- 26050915 TI - Parent emotional distress and feeding styles in low-income families. The role of parent depression and parenting stress. AB - PURPOSE: Depression and other stressors have been associated with general parenting and child outcomes in low-income families. Given that parents shape child eating behaviors through their feeding interactions with their child, it is important to investigate factors that may influence parental feeding of young children. The aim of this study was to examine how depressive symptoms and parenting stress might influence the nature of parent feeding styles in low income families. METHODS: Questionnaires were completed by 290 African-American and Hispanic parents residing in a large urban city in the southwestern United States. Twenty-six percent of the parents reported depressive symptoms above the clinical cutoff. Multivariate logistic regression was used to examine how depressive symptoms and parenting stress might influence the nature of parent feeding styles. RESULTS: After adjusting for potential confounding variables (e.g., ethnicity, education, age), parents with an uninvolved feeding style reported less positive affect and more parenting stress than parents showing the other three feeding styles - authoritative, authoritarian, and indulgent. CONCLUSIONS: Because feeding styles tend to be associated with child obesity in low income samples, the results of this study provide important information regarding the parent-child eating dynamic that may promote less optimal child eating behaviors and the development of childhood obesity. This information could be useful for prevention studies aimed at changing parent behaviors that negatively impact the socialization of child eating behaviors. PMID- 26050916 TI - Identifying relationships between the professional culture of pharmacy, pharmacists' personality traits, and the provision of advanced pharmacy services. AB - BACKGROUND: Legislative changes are affording pharmacists the opportunity to provide more advanced pharmacy services. However, many pharmacists have not yet been able to provide these services sustainably. Research from implementation science suggests that before sustained change in pharmacy can be achieved an improved understanding of pharmacy context, through the professional culture of pharmacy and pharmacists' personality traits, is required. OBJECTIVE: The primary objective of this study was to investigate possible relationships between cultural factors, and personality traits, and the uptake of advanced practice opportunities by pharmacists in British Columbia, Canada. METHODS AND MATERIALS: The study design was a cross-sectional survey of registered, and practicing, pharmacists from one Canadian province. The survey gauged respondents' characteristics, practice setting, and the provision of advanced pharmacy services, and contained the Organizational Culture Profile (OCP), a measure of professional culture, as well as the Big Five Inventory (BFI), a measure of personality traits. RESULTS: A total of 945 completed survey instruments were returned. The majority of respondents were female (61%), the average age of respondents was 42 years (SD: 12), and the average number of years in practice was 19 (SD: 12). A significant positive relationship was identified for respondents perceiving greater value in the OCP factors competitiveness and innovation and providing a higher number of all advanced services. A positive relationship was observed for respondents scoring higher on the BFI traits extraversion and the immunizations provided, and agreeableness and openness and medication reviews completed. CONCLUSION: This is the first work to identify statistically significant relationships between the OCP and BFI, and the provision of advanced pharmacy services. As such, this work serves as a starting place from which to develop more detailed insight into how the professional culture of pharmacy and pharmacists personality traits may influence the adoption of advanced pharmacy services. PMID- 26050917 TI - An olfactory receptor from Apolygus lucorum (Meyer-Dur) mainly tuned to volatiles from flowering host plants. AB - Apolygus lucorum (Meyer-Dur) (Hemiptera: Miridae) is one of the most serious agricultural pests, feeding on a wide range of cultivated plants, including cotton, cereals and vegetables in the north of China. This insect can frequently switch between habitats and host plants over seasons and prefer plants in bloom. A. lucorum relies heavily on olfaction to locate its host plants finely discriminating different plant volatiles in the environment. Despite its economical importance, research on the olfactory system of this species has been so far very limited. In this study, we have identified and characterized an olfactory receptor which is sensitively tuned to (Z)-3-Hexenyl acetate and several flowering compounds. Besides being present in the bouquet of some flowers, these compounds are produced by plants that have suffered attacks and are supposed to act as chemical messengers between plants. This OR may play an important role in the selection of host plants. PMID- 26050918 TI - High sucrose consumption promotes obesity whereas its low consumption induces oxidative stress in Drosophila melanogaster. AB - The effects of sucrose in varied concentrations (0.25-20%) with constant amount of yeasts in larval diet on development and metabolic parameters of adult fruit fly Drosophila melanogaster were studied. Larvae consumed more food at low sucrose diet, overeating with yeast. On high sucrose diet, larvae ingested more carbohydrates, despite consuming less food and obtaining less protein derived from yeast. High sucrose diet slowed down pupation and increased pupa mortality, enhanced levels of lipids and glycogen, increased dry body mass, decreased water content, i.e. resulted in obese phenotype. Furthermore, it suppressed reactive oxygen species-induced oxidation of lipids and proteins as well as the activity of superoxide dismutase. The activity of catalase was gender-related. In males, at all sucrose concentrations used catalase activity was higher than at its concentration of 0.25%, whereas in females sucrose concentration virtually did not influence the activity. High sucrose diet increased content of protein thiols and the activity of glucose-6-phosphate dehydrogenase. The increase in sucrose concentration also enhanced uric acid level in females, but caused opposite effects in males. Development on high sucrose diets was accompanied by elevated steady-state insulin-like peptide 3 mRNA level. Finally, carbohydrate starvation at yeast overfeeding on low sucrose diets resulted in oxidative stress reflected by higher levels of oxidized lipids and proteins accompanied by increased superoxide dismutase activity. Potential mechanisms involved in regulation of redox processes by carbohydrates are discussed. PMID- 26050919 TI - Identification and expression of a new member of the pyrokinin/pban gene family in the sand fly Phlebotomus papatasi. AB - The major family of neuropeptides (NPs) derived from the pk (pyrokinin)/pban (pheromone biosynthesis activating neuropeptide) gene are defined by a common FXPRL-NH2 or similar sequence at the C-termini. This family of peptides has been found in all insect groups investigated to date and is implicated in regulating various physiological functions, including pheromone biosynthesis and diapause, but other functions are still largely unknown in specific life stages. Here we identify two isoforms of pk/pban cDNA encoding the PBAN domain from the sand fly Phlebotomus papatasi. The two pk/pban isoforms have the same sequence except for a 63 nucleotide difference between the long and short forms, and contain no alternative mRNA splicing site. Two NP homologues, DASGDNGSDSQRTRPPFAPRLamide and SLPFSPRLamide are expected, however, sequence corresponding to the diapause hormone was not found in the P. papatasi pk/pban gene. The PBAN-like amino acid sequence homologue SNKYMTPRL is conserved in the gene, but there is no cleavage site for processing a functional peptide. Characterizing the expression of the isoforms in developmental stages and adults indicates that the short form is differentially transcribed depending on the life stage. The P. papatasi pk/pban gene is the only known pk/pban gene with two transcriptional isoforms and from examination of endoproteolytic cleavage sites is expected to produce fewer peptides than most of the pk/pban genes elucidated to date; only Drosophila melanogaster is simpler with a single NP detected by mass spectroscopy. A phylogenetic analysis showed P. papatasi pk/pban grouped more closely with other nematoceran flies rather than higher flies. PMID- 26050920 TI - The antitumor effect of metformin with and without carboplatin on primary endometrioid endometrial carcinoma in vivo. AB - OBJECTIVES: New treatment options for advanced and recurrent endometrial carcinoma (EC) are necessary. Epidemiological studies showed that diabetic patients using metformin have reduced risks of endometrial cancer (EC) incidence. Moreover, pre- and clinical studies demonstrated an antitumor effect by metformin, with and without additional treatments, for different solid malignancies. However, cancer cell-autonomous effects of metformin on EC have not been fully characterized yet. The aim of this study was to investigate the effect of metformin, with or without carboplatin, on patient-derived primary endometrioid EC cells xenografted in nude mice, to assess its ability to reduce or impair growth in already established tumors. METHODS: Two xenograft models were established by subcutaneous inoculation of primary endometrioid EC cell suspensions. Tumors were allowed to grow and then mice were treated with metformin (250 mg/kg, daily, p.o.), carboplatin (50 mg/kg, 1*/week, i.p.), or the combination of both compounds at the same concentration as single treatment, for three weeks. Effects of metformin treatment on the tumor mass were determined by tumor growth follow-up. Metformin influences on AMPK/mTOR cell signaling were evaluated by investigating AKT, AMPK and S6 phosphorylation levels. RESULTS: In vivo, metformin did not affect the growth of EC tumors established from patient derived primary cultures and the phosphorylation of AKT, AMPK and S6. In addition, no enhanced antitumor effect was determined by combining metformin and carboplatin treatments. CONCLUSIONS: Metformin, at clinically relevant concentrations, did not show effects on the growth of already established tumors. Adding metformin to carboplatin did not have synergistic effects. PMID- 26050921 TI - Neoadjuvant chemotherapy followed by large cone resection as fertility-sparing therapy in stage IB cervical cancer. AB - BACKGROUND: Standard treatment of cervical cancer FIGO stage IB1 is a radical hysterectomy with pelvic lymphadenectomy. As the number of patients with a preserved fertility wish has increased, the need for fertility sparing surgery emerges. In this study we discuss 11 patients with cervical carcinoma stage IB treated with neoadjuvant chemotherapy followed by large cone resection. METHODS: In this retrospective study we included 10 patients with FIGO stage IB1 and 1 patient with IB2 cervical cancer, who first received a pelvic lymphadenectomy followed by neoadjuvant chemotherapy and conization. Paclitaxel-ifosfamide carboplatin or a combination of paclitaxel-carboplatin was used as neoadjuvant chemotherapy. RESULTS: Complete response after chemotherapy was observed in 64%, partial response in 27% and 9% had progressive disease. All patients with response underwent a conization, with no residual disease on pathology in 80%. Patients with residual disease were treated by radical hysterectomy. In 9 patients fertility sparing surgery could be performed and 6 (67%) got pregnant. Five patients had 7 children and two patients had four missed abortions. Two premature deliveries at 32 and 33weeks were described, both in the same patient. Recurrence was observed in one patient that was treated with simple hysterectomy followed by radiochemotherapy. Median follow up time is 58months with all patients alive and no evidence of disease until now. CONCLUSIONS: Neoadjuvant chemotherapy followed by conization seems to be a promising new fertility sparing treatment modality in patients with cervical carcinoma stage IB1, but further studies with larger populations should confirm these data. PMID- 26050922 TI - In vivo tumor growth of high-grade serous ovarian cancer cell lines. AB - OBJECTIVE: Genomic studies of ovarian cancer (OC) cell lines frequently used in research revealed that these cells do not fully represent high-grade serous ovarian cancer (HGSOC), the most common OC histologic type. However, OC lines that appear to genomically resemble HGSOC have not been extensively used and their growth characteristics in murine xenografts are essentially unknown. METHODS: To better understand growth patterns and characteristics of HGSOC cell lines in vivo, CAOV3, COV362, KURAMOCHI, NIH-OVCAR3, OVCAR4, OVCAR5, OVCAR8, OVSAHO, OVKATE, SNU119 and UWB1.289 cells were assessed for tumor formation in nude mice. Cells were injected intraperitoneally (i.p.) or subcutaneously (s.c.) in female athymic nude mice and allowed to grow (maximum of 90 days) and tumor formation was analyzed. All tumors were sectioned and assessed using H&E staining and immunohistochemistry for p53, PAX8 and WT1 expression. RESULTS: Six lines (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, and OVSAHO) formed i.p xenografts with HGSOC histology. OVKATE and COV362 formed s.c. tumors only. Rapid tumor formation was observed for OVCAR3, OVCAR5 and OVCAR8, but only OVCAR8 reliably formed ascites. Tumors derived from OVCAR3, OVCAR4, and OVKATE displayed papillary features. Of the 11 lines examined, three (Kuramochi, SNU119 and UWB1.289) were non-tumorigenic. CONCLUSIONS: Our findings help further define which HGSOC cell models reliably generate tumors and/or ascites, critical information for preclinical drug development, validating in vitro findings, imaging and prevention studies by the OC research community. PMID- 26050923 TI - Long-term mortality among women with epithelial ovarian cancer. AB - OBJECTIVES: Patients with solid tumors are at greatest risk for dying from their cancers in the five years following diagnosis. For most malignancies, deaths from other chronic diseases begin to exceed those from cancer at some point. As little is known about the causes of death among long-term survivors of ovarian cancer, we examined causes of death by years from diagnosis. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify women diagnosed with ovarian cancer between 1988 and 2012. We compared causes of death by stage, age, and interval time after diagnosis. RESULTS: A total of 67,385 women were identified. For stage I neoplasms, 13.6% (CI, 13.0-14.2%) died from ovarian cancer, 4.2% (CI, 3.8-4.5%) from cardiovascular disease, 3.6% (CI, 3.3 3.9%) from other causes and 2.6% (CI, 2.4-2.9%) from other tumors; ovarian cancer was the leading cause of death until 7 years after diagnosis after which time deaths are more frequently due to other causes. For those with stage III-IV tumors, 67.8% (CI, 67.3-68.2%) died from ovarian cancer, 2.8% (CI, 2.6-2.9%) from other causes, 2.3% (CI, 2.2-2.4%) from cardiovascular disease and 1.9% (CI, 1.7 2.0%) from other cancers; ovarian cancer was the most frequent cause of death in years 1-15 after which time deaths were more commonly due to other causes. CONCLUSIONS: The probability of dying from ovarian cancer decreases with time. Ovarian cancer remains the most common cause of death for 15 years after diagnosis in women with stage III-IV tumors. PMID- 26050924 TI - Panic symptoms and elevated suicidal ideation and behaviors among trauma exposed individuals: Moderating effects of post-traumatic stress disorder. AB - Panic attacks (PAs) are highly prevalent among trauma exposed individuals and have been associated with a number of adverse outcomes. Despite high suicide rates among trauma exposed individuals, research to date has not examined the potential relation between panic symptoms and suicidal ideation and behaviors among this high risk population. The current study tested the association of panic with suicidal ideation and behaviors among a large sample of trauma exposed smokers. Community participants (N=421) who reported a lifetime history of trauma exposure were assessed concurrently for current panic, suicidal ideation and behaviors, and psychiatric diagnoses. Those who met criteria for a current panic disorder diagnosis were removed from analyses to allow for the assessment of non PD related panic in line with the recent addition of the PA specifier applicable to all DSM-5 disorders. Findings indicated that panic symptoms were significantly associated with suicidal ideation and behaviors beyond the effects of depression and number of trauma types experienced. Further, post-traumatic stress disorder (PTSD) diagnostic status significantly moderated this relationship, indicating that the relationship between panic and suicidal ideation and behaviors is potentiated among individuals with a current PTSD diagnosis. This investigation suggests that panic symptoms may be a valuable clinical target for the assessment and treatment of suicidal ideation and behaviors among trauma exposed individuals. PMID- 26050925 TI - Fatal human eosinophilic meningo-encephalitis caused by CNS co-infection with Halicephalobus gingivalis and West Nile virus. AB - The saprophytic nematode Halicephalobus is a rare cause of fatal human meningo encephalitis, and West Nile virus is neurotropic flavivirus implicated in a variety of clinical neurologic syndromes. Here we report a case of rapidly progressive CNS encephalopathy and death. Serologic, immuno-histochemical, histopathologic and nucleic acid studies demonstrate the presence of active Halicephalobus and West Nile virus in the CNS tissue. This is the first reported case of co-infection with these neurotropic pathogens. PMID- 26050926 TI - Determination of phytochemicals, antioxidant activity and total phenolic content in Andrographis paniculata using chromatographic methods. AB - Antioxidant activity, total phenolics content and selected phytochemicals (alkaloids and andrographolides) were determined in Andrographis paniculata and in dietary supplements containing this plant. Antioxidant activity was measured by FRAP, CUPRAC and DPPH procedures and ranged from 503.36 to 6164.09MUmol TE/100g d.m. depending on methods, part of plant and kind of dietary supplement. The total phenolics (175.13-1723.79mg GAE/100g) and andrographolides content (19.44-85.13mg/g) in the studied samples were correlated with antioxidant activities determined by CUPRAC, FRAP and DPPH (r>0.95, p<0.05 level). Purine alkaloids: caffeine, theobromine, theophylline and indole alkaloids: harmine, harmane, harmol, yohimbine, brucine and strychnine were detected in the studied samples by different chromatographic techniques (HPLC-DAD, LC-MS/MS, GC-MS). The total alkaloids content in APs-roots and APs-leaves varies from 50.71+/-0.36mg/g d.m. to 78.71+/-0.48mg/g d.m., respectively, whereas for dietary supplements (Pn and DK) TAC was found between 19.52+/-0.15mg/g and 22.18+/-0.15mg/g d.m.. The highest concentration of andrographolides was found in A. paniculata leaves, whereas the lowest in dietary supplement Pn. Moreover principal component analysis, cluster analysis and one-way ANOVA follow by Duncan's tests were also performed. PMID- 26050927 TI - Frequency and efficacy of additional investigations following incomplete colonoscopies: A population-based analysis. AB - BACKGROUND: Limited data are available on the follow-up of patients with incomplete colonoscopy following positive faecal occult blood testing. Our study aimed to determine the proportion of and reasons for incomplete colonoscopies, the proportion of patients who completed colonic evaluations, the methods used and the subsequent findings. METHODS: A total of 9483 colonoscopies performed after positive testing in a colorectal cancer screening programme setting were included. The study was prospective for index colonoscopy findings and partly retrospective for follow-up. RESULTS: Overall 297 colonoscopies were incomplete (3.2%). A secondary colonic evaluation was deemed necessary in 245 patients, of which 126 underwent an additional examination (51.4%). Radiology was the primary method used for complete colonic evaluation, whereas a repeat colonoscopy was performed in only 6.4%; the examination was normal in 119 patients (94.4%). A mucosal high-grade neoplasia was removed in 1, and multiple (>=3) adenomas were removed in 2 patients. CONCLUSIONS: The present screening programme with biennial faecal occult blood testing revealed a high colonoscopy completion rate, a low rate of secondary colonic evaluation, infrequent use of colonoscopy for completion, and a low detection rate of significant neoplasia. PMID- 26050928 TI - Transcriptome-wide Analysis Reveals Hallmarks of Human Intestine Development and Maturation In Vitro and In Vivo. AB - Human intestinal organoids (HIOs) are a tissue culture model in which small intestine-like tissue is generated from pluripotent stem cells. By carrying out unsupervised hierarchical clustering of RNA-sequencing data, we demonstrate that HIOs most closely resemble human fetal intestine. We observed that genes involved in digestive tract development are enriched in both fetal intestine and HIOs compared to adult tissue, whereas genes related to digestive function and Paneth cell host defense are expressed at higher levels in adult intestine. Our study also revealed that the intestinal stem cell marker OLFM4 is expressed at very low levels in fetal intestine and in HIOs, but is robust in adult crypts. We validated our findings using in vivo transplantation to show that HIOs become more adult-like after transplantation. Our study emphasizes important maturation events that occur in the intestine during human development and demonstrates that HIOs can be used to model fetal-to-adult maturation. PMID- 26050929 TI - The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice. AB - Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS) strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC) frequency. Among 108 strains, we observed ~120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx). Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx-/- mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system. PMID- 26050931 TI - Direct force measurements between silica particles in aqueous solutions of ionic liquids containing 1-butyl-3-methylimidazolium (BMIM). AB - Direct force measurements between silica particles were carried out using the colloidal probe technique, which is based on an atomic force microscope (AFM). The forces were investigated in aqueous solutions of ionic liquids (ILs) containing 1-butyl-3-methylimidazolium (BMIM) cations and chloride, dicyanamide, and thiocyanate as anions up to concentrations of about 1 M. The results were compared with the simple electrolyte KCl. ILs behave similar to the simple electrolyte at low concentrations, as the ILs dissociate fully into ions, and they lead to repulsive double layer forces. At higher concentrations, attractive van der Waals forces set in, but they are enhanced in the presence of ILs by additional attractive force, whose strength depends on the type of IL. This additional attraction probably originates from the interaction of adsorbed IL layers. PMID- 26050930 TI - Integrative Analysis of the Acquisition of Pluripotency in PGCs Reveals the Mutually Exclusive Roles of Blimp-1 and AKT Signaling. AB - Primordial germ cells (PGCs) are lineage-restricted unipotent cells that can dedifferentiate into pluripotent embryonic germ cells (EGCs). Here we performed whole-transcriptome analysis during the conversion of PGCs into EGCs, a process by which cells acquire pluripotency. To examine the molecular mechanism underlying this conversion, we focused on Blimp-1 and Akt, which are involved in PGC specification and dedifferentiation, respectively. Blimp-1 overexpression in embryonic stem cells suppressed the expression of downstream targets of the pluripotency network. Conversely, Blimp-1 deletion in PGCs accelerated their dedifferentiation into pluripotent EGCs, illustrating that Blimp-1 is a pluripotency gatekeeper protein in PGCs. AKT signaling showed a synergistic effect with basic fibroblast growth factor plus 2i+A83 treatment on EGC formation. AKT played a major role in suppressing genes regulated by MBD3. From these results, we defined the distinct functions of Blimp-1 and Akt and provided mechanistic insights into the acquisition of pluripotency in PGCs. PMID- 26050932 TI - Prevalence of E. coli O157:H7 in water sources: an overview on associated diseases, outbreaks and detection methods. AB - Escherichia coli O157:H7 is a zoonotic pathogen with its ability to cause human illness ranging from diarrheal disease to fatal hemolytic uremic syndrome. E. coli O157:H7 had been associated with waterborne outbreaks resulting in high morbidity and mortality worldwide. Therefore, it is important to investigate the prevalence of E. coli O157:H7 in water sources especially used for drinking and to develop the diagnostic methods for its early detection. The review describes traditional cultural methods, immunological techniques, and polymerase chain reaction (PCR)-based methods for detection of this bacterium in water sources. The current PCR-based techniques such as real-time PCR are more specific and sensitive and require less detection time (<3 hours). These methods can be applied for regular water monitoring and proper management of water sources to prevent waterborne diseases due to E. coli O157:H7. PMID- 26050934 TI - Coupling scales for modelling heavy metal vaporization from municipal solid waste incineration in a fluid bed by CFD. AB - Municipal Solid Waste Incineration (MSWI) in fluidized bed is a very interesting technology mainly due to high combustion efficiency, great flexibility for treating several types of waste fuels and reduction in pollutants emitted with the flue gas. However, there is a great concern with respect to the fate of heavy metals (HM) contained in MSW and their environmental impact. In this study, a coupled two-scale CFD model was developed for MSWI in a bubbling fluidized bed. It presents an original scheme that combines a single particle model and a global fluidized bed model in order to represent the HM vaporization during MSW combustion. Two of the most representative HM (Cd and Pb) with bed temperatures ranging between 923 and 1073K have been considered. This new approach uses ANSYS FLUENT 14.0 as the modelling platform for the simulations along with a complete set of self-developed user-defined functions (UDFs). The simulation results are compared to the experimental data obtained previously by the research group in a lab-scale fluid bed incinerator. The comparison indicates that the proposed CFD model predicts well the evolution of the HM release for the bed temperatures analyzed. It shows that both bed temperature and bed dynamics have influence on the HM vaporization rate. It can be concluded that CFD is a rigorous tool that provides valuable information about HM vaporization and that the original two scale simulation scheme adopted allows to better represent the actual particle behavior in a fluid bed incinerator. PMID- 26050933 TI - Impaired Bottom-Up Effective Connectivity Between Amygdala and Subgenual Anterior Cingulate Cortex in Unmedicated Adolescents with Major Depression: Results from a Dynamic Causal Modeling Analysis. AB - Major depressive disorder (MDD) is a significant contributor to lifetime disability and frequently emerges in adolescence, yet little is known about the neural mechanisms of MDD in adolescents. Dynamic causal modeling (DCM) analysis is an innovative tool that can shed light on neural network abnormalities. A DCM analysis was conducted to test several frontolimbic effective connectivity models in 27 adolescents with MDD and 21 healthy adolescents. The best neural model for each person was identified using Bayesian model selection. The findings revealed that the two adolescent groups fit similar optimal neural models. The best across groups model was then used to infer upon both within-group and between-group tests of intrinsic and modulation parameters of the network connections. First, for model validation, within-group tests revealed robust evidence for bottom-up connectivity, but less evidence for strong top-down connectivity in both groups. Second, we tested for differences between groups on the validated parameters of the best model. This revealed that adolescents with MDD had significantly weaker bottom-up connectivity in one pathway, from amygdala to sgACC (p=0.008), than healthy controls. This study provides the first examination of effective connectivity using DCM within neural circuitry implicated in emotion processing in adolescents with MDD. These findings aid in advancing understanding the neurobiology of early-onset MDD during adolescence and have implications for future research investigating how effective connectivity changes across contexts, with development, over the course of the disease, and after intervention. PMID- 26050936 TI - WITHDRAWN: Removal and separation of bromine epoxy resin for recovering valuable materials from waste printed circuit board using organic solvent. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26050935 TI - Characterization of crumb rubber from end-of-life tyres for paving applications. AB - Crumb rubber (CR) derived from grinding of end-of-life tyres (ELTs) may be successfully used as a bitumen modifier or as a supplementary component in the production of bituminous mixtures employed for the construction and maintenance of road pavements. However, CRs deriving from different sources and production processes yield effects on performance of corresponding paving mixtures under traffic loading and on gaseous emissions produced during laying on site which may change considerably depending upon their physical and chemical properties. In order to quantitatively assess the possible variability of CR characteristics, 16 samples were taken from 9 Italian and 2 foreign ELT processing plants. Investigation activities included field surveys, during which plants were examined in detail, and laboratory tests, which focused on physical and chemical characterization of CR. Based on the analysis of available technical information and experimental data, it was possible to find relationships between the peculiar characteristics of treatment cycles and corresponding CR properties. PMID- 26050937 TI - Vitreous hemorrhage secondary to iridociliary cyst. AB - CASE REPORT: An 18-year-old man, presented a lower vitreous hemorrhage of unknown cause. Multiple tests are performed, including Ophthalmic Ultrasound and Fluorescein Angioghaphy (FA), they did not find justification of bleeding. Finally, we decide to do a Biomocroscopia Ultrasonic (UBM) showing an iridociliary cyst. DISCUSSION: The iridociliary cysts are single or multiple, primary or secondary. The primaries are usually benign so, they do not require treatment. When the cyst has a considerable size, it may produce a focal plateau iris with or without angle-closure. Our case reveals an unusual complication that should take notice of when you have an unknown vitreous hemorrhage. PMID- 26050938 TI - N-Heterocyclic carbene-phosphino-picolines as precursors of anionic 'pincer' ligands with dearomatised pyridine backbones; transmetallation from potassium to chromium. AB - Deprotonation of the alpha-picolinyl-CH2 in the hybrid ligands R2P-NCNHC (-N = substituted 2-picoline, R = Cy, t-Bu; CNHC = N-heterocyclic carbene) (L(R)) with KN(SiMe3)2 in ether gave [KL(Cy)-H(ether)]2 featuring a dearomatised picoline backbone. Assisted by 18-crown-6, K+ dissociation afforded the Z- and E-isomers of [L(R)-H](-). Transmetallation of L(R)-H from KL(R)-H led to [CrCl(L(t-Bu)-H)]. PMID- 26050939 TI - Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline. AB - We evaluated a multiple consanguineous Turkish family with two children, a boy and a girl, affected by severe encephalopathy, hypotonia, microcephaly and retinal dystrophy by a combination of linkage analysis and Whole Exome Sequencing (WES). We analyzed the sequence data by two different bioinformatics pipelines which did not differ in overall processing strategy but involved differences in software used, minor allele frequency (MAF) thresholds and reference data sets, the usage of in-house control exomes and filter settings to prioritize called variants. Assuming autosomal recessive mode of inheritance, only homozygous variants present in both children were considered. The resulting variant lists differed partially (nine variants identified by both pipelines, ten variants by only one pipeline). Major reasons for this discrepancy were different filters for MAF and different variant prioritizations. Combining the variant lists with the results of linkage analysis and further prioritization by expression data and prediction tools, an intronic homozygous splice variant (c.1090-2A>G; IVS9-2A>G; p.?) in PGAP1 (Post-GPI Attachment To Proteins 1) was identified and validated by cDNA analysis. PGAP1 ensures the first step of maturation of GPI (glycosylphosphatidylinositol)-anchor proteins. Recently, a homozygous loss-of function mutation in PGAP1 has been reported in one family with two children affected by a similar phenotype. The present report not only illustrates the possible influence of specific filtering settings on the results of WES but also confirms PGAP1 as a cause of severe encephalopathy. PMID- 26050940 TI - What next-generation sequencing (NGS) technology has enabled us to learn about primary autosomal recessive microcephaly (MCPH). AB - The impact that next-generation sequencing technology (NGS) is having on many aspects of molecular and cell biology, is becoming increasingly apparent. One of the most noticeable outcomes of the new technology in human genetics, has been the accelerated rate of identification of disease-causing genes. Especially for rare, heterogeneous disorders, such as autosomal recessive primary microcephaly (MCPH), the handful of genes previously known to harbour disease-causing mutations, has grown at an unprecedented rate within a few years. Knowledge of new genes mutated in MCPH over the last four years has contributed to our understanding of the disorder at both the clinical and cellular levels. The functions of proteins such as WDR62, CASC5, PHC1, CDK6, CENP-E, CENP-F, CEP63, ZNF335, PLK4 and TUBGPC, have been added to the complex network of critical cellular processes known to be involved in brain growth and size. In addition to the importance of mitotic spindle assembly and structure, centrosome and centriole function and DNA repair and damage response, new mechanisms involving kinetochore-associated proteins and chromatin remodelling complexes have been elucidated. Two of the major contributions to our clinical knowledge are the realisation that primary microcephaly caused by mutations in genes at the MCPH loci is seldom an isolated clinical feature and is often accompanied either by additional cortical malformations or primordial dwarfism. Gene-phenotype correlations are being revisited, with a new dimension of locus heterogeneity and phenotypic variability being revealed. PMID- 26050941 TI - The dnaJ gene as a molecular discriminator to differentiate among species and strain within the Lactobacillus casei group. AB - Identifying Lactobacillus casei and its closely related taxa at the species and strain level using only phenotypic and genotypic (16S rDNA sequence homology analysis) techniques often yields inaccurate results. In this study, the dnaJ chaperone gene was investigated as a molecular target for inter- and intraspecies discrimination within the Lb. casei group as well as for the development of specific primers for species identification. The results showed that most of the examined strains could be clearly distinguished from closely related species based on the sequenced fragments. At the interspecies level, the dnaJ sequence similarities were 81.7%-85.5%. However, at the intraspecies level, the dnaJ sequence similarities were 96.2-100% and could be assigned to different haplotypes in Lactobacillus paracasei and Lactobacillus rhamnosus, respectively. Compared to the 16S rRNA gene, the dnaJ sequence showed greater variation at both the species and strain level. Thus, the dnaJ gene can be proposed as an alternative marker for the Lb. casei group that provides higher discriminatory power than the 16S rRNA gene. In addition, species-specific primers were developed and subsequently employed in two-plex minisequencing analysis and shown to be specific for Lb. paracasei and Lb. rhamnosus. Our data indicate that phylogenetic relationships in the Lb. casei group can be resolved using comparative sequence analysis of the dnaJ gene and that the Lb. paracasei and Lb. rhamnosus species can be simultaneously identified using a novel species-specific minisequencing assay. PMID- 26050942 TI - The Basic Principles of FDG-PET/CT Imaging. AB - Positron emission tomography (PET) imaging with 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) forms the basis of molecular imaging. FDG-PET imaging is a multidisciplinary undertaking that requires close interdisciplinary collaboration in a broad team comprising physicians, technologists, secretaries, radio chemists, hospital physicists, molecular biologists, engineers, and cyclotron technicians. The aim of this review is to provide a brief overview of important basic issues and considerations pivotal to successful patient examinations, including basic physics, instrumentation, radiochemistry, molecular and cell biology, patient preparation, normal distribution of tracer, and potential interpretive pitfalls. PMID- 26050943 TI - Fluorodeoxyglucose PET in Neurology and Psychiatry. AB - PET imaging with the most widely available PET tracer, 2-deoxy-2-[(18)F]fluoro-d glucose (FDG), is a powerful tool in the differential diagnosis of numerous neurologic and psychiatric disorders, particularly in early disease stages. It also plays an important role in the longitudinal evaluation of treatment effects and the depiction of disease courses. A selection of established and eligible application areas of FDG PET in neurology and psychiatry, such as different types of dementia, epilepsy, schizophrenia, and bipolar disorder, are reviewed in this article. A general methodology for clinical FDG PET examinations and typical diagnostic criteria and pitfalls are addressed. PMID- 26050944 TI - [18F]Fluorodeoxyglucose PET in Thoracic Malignancies. AB - [(18)F]Fluorodeoxyglucose (FDG) PET is a robust quantitative molecular imaging technique that complements available structural imaging techniques for the detection and characterization of malignancy. This article provides an overview of the utility and applications of FDG-PET for the evaluation of patients with thoracic malignancy. PMID- 26050945 TI - [18F]Fluorodeoxyglucose PET/Computed Tomography in Gastrointestinal Malignancies. AB - This article discusses the current state-of-the-art application of 2-deoxy-2 [(18)F]fluoro-d-glucose (FDG)-PET and FDG-PET/computed tomography (CT) in the management of patients with gastrointestinal malignancies. Gastrointestinal malignancies include many different cell types, several common malignancies of which may be imaged by FDG-PET/CT. This review focuses on gastric carcinoma, pancreatic carcinoma, hepatocellular carcinoma, cholangiocarcinoma, colorectal carcinoma, and stroma cell tumors. The role of FDG-PET/CT in staging these malignancies is discussed, in addition to (re)staging, detection of recurrent disease, patient selection/prognostication, and response assessment, using the currently available literature. PMID- 26050946 TI - Fluorine-18-fluorodeoxyglucose Positron Emission Tomography in Diffuse Large B cell Lymphoma. AB - Diffuse large B-cell lymphoma (DLBCL) is an aggressive and potentially curable type of lymphoma. Fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) is part of clinical routine for DLBCL in most hospitals and also recommended for staging and end-of-therapy evaluation. FDG-PET/computed tomography (CT) is able to identify nodal and extranodal sites with greater accuracy than CT alone. Little evidence supports the use of surveillance FDG-PET imaging in the follow-up setting because of high rates of false-positive scans and because most studies are retrospective. This article discusses FDG-PET assessment methods and the clinical application of FDG-PET for management of DLBCL. PMID- 26050947 TI - FDG in Urologic Malignancies. AB - Kidney, bladder, and prostate cancer account for more than one-eighth of new cancer cases worldwide. Imaging in kidney cancer is dominated by computed tomography (CT). Positron emission tomography (PET) imaging of bladder cancer is hampered by the urinary excretion of the most common PET tracer, 18F-fluoro-deoxy glucose (FDG). PET imaging has been applied more often in prostate cancer. FDG PET/CT is claimed to have a high frequency of false-negative results in urologic cancers; however, this finding may instead reflect correctly the state of disease being due to slow-growing cancers with a good prognosis and without a need of therapy. PMID- 26050948 TI - [18F]Fluorodeoxyglucose PET for Interventional Oncology in Liver Malignancy. AB - [(18)F]Fluorodeoxyglucose (FDG) PET is a functional imaging tool that provides metabolic information, which has the potential to detect a lesion before it becomes anatomically apparent. This ability constitutes a strong argument for using FDG-PET/computed tomography (CT) in the management of oncology patients. Many studies have investigated the accuracy of FDG-PET or FDG-PET/CT for these purposes, but with small sample sizes based on retrospective cohorts. This article provides an overview of the role of FDG-PET or FDG-PET/CT in patients with liver malignancies treated by means of surgical resection, ablative therapy, chemoembolization, radioembolization, and brachytherapy, all being liver-directed oncologic interventions. PMID- 26050949 TI - FDG-PET/CT in Infectious and Inflammatory Diseases. AB - Nuclear medicine techniques have been an integral part of infection and inflammation imaging for decades; in recent years, fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) has taken over many indications. This review provides a comprehensive overview of the current and potential applications for FDG-PET/CT in infectious and inflammatory diseases (ie, systemic infections, bone infections, vascular infection and inflammation, thoracic and abdominal inflammation) and potential novel applications in both infection and inflammation. PMID- 26050950 TI - FDG-PET/CT: Quo vadis? PMID- 26050951 TI - An observational study on outcome of hemispherotomy in children with refractory epilepsy. AB - INTRODUCTION: The current study aimed to evaluate the clinical characteristics and outcome of hemispherotomy in children with refractory hemispherical epilepsy. METHODS: Retrospective analysis of data in twenty one children aged <=12 years who underwent hemispherotomy and had at least two years post surgery follow-up was performed. Sixteen children underwent Delalande's vertical para-sagittal hemispherotomy (VPH), while lateral peri-insular functional hemispherotomy was performed in the rest. RESULTS & DISCUSSION: The average age of onset for epilepsy in the study population was 2.9 +/- 2.4 years; the average duration of epilepsy was 4.0 +/- 2.9 years. The mean age at surgery of the study population was 6.8 +/- 2.8 years. Six (28.5%) children were girls. Gliosis due to presumed childhood infarct was most common etiology, observed in 13 (62.0%) of the children, followed by Rasmussen's encephalitis in six (28.5%). There was no significant difference between the surgery groups for the reported acute post operative seizures (APOS) (20.0% vs. 25.0%; p = 1.000). At last follow up 90.5% patients were seizure free; there was no difference between the groups for seizure freedom (60.0% vs. 87.5%; p = 0.228). When analyzed for outcome between the etiologies, seizure freedom was similar for gliosis due to infarct (76.9%), Rassmussens encephalitis (83.3%) and malformations of cortical development (MCD) (100.0%). Moreover, improved quality of life in epilepsy (QOLIE) scores was observed in 80.0% of the lateral peri-insular functional hemispherotomy group and 87.5% children in VPH group at the last follow-up. CONCLUSION: Gliosis due to presumed childhood infarct was the leading cause of medically refractory epilepsy caused by hemispheric lesions in the current study. Encouragingly, hemispherotomy offers seizure freedom (in 90.5% patients) and improvement in QOLIE scores at two years follow up. PMID- 26050952 TI - FibroScan predicts ascites after liver resection for hepatitis B virus-related hepatocellular carcinoma: A prospective cohort study. AB - OBJECTIVE: To assess the correlation of preoperative FibroScan value and postoperative ascites in patients undergoing liver resection for hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). METHODS: A prospective study group of consecutive HBV-related HCC patients considered eligible for liver resection was conducted from 2012 to 2014 (N = 77). Liver stiffness measured by FibroScan was administrated to all patients. Patient's pre- and intra-operative variables were prospectively collected. RESULTS: FibroScan was successfully performed in 75 patients. Postoperative ascites was observed in 13 patients. Univariate analyses suggested tumor size, high preoperative hepatitis B viral load, intraoperative blood loss, major hepatectomy and FibroScan value were potential risk factors for postoperative ascites. However, in multivariate analysis, only FibroScan value (OR = 1.506, 95%CI = 1.21-1.87) showed prognostic power. The best cut-off value of FibroScan value to predict postoperative ascites was 15.6 kpa with a sensitivity of 76.9% and a specificity of 98.4%. The corresponding area under the receiver operating curve was 0.902. CONCLUSIONS: FibroScan value was a reliable surrogate marker for predicting postoperative ascites should be routinely performed in patients with HBV-related HCC undergoing liver resection. PMID- 26050953 TI - Medical grade honey in the management of chronic venous leg ulcers. AB - A best evidence topic in vascular surgery was written according to a structured protocol. The question addressed was: In patients with chronic venous leg ulcers (CVLU), does the use of medical grade honey as compared to standard wound therapy improve clinical outcomes? A total of 299 papers were identified using the search protocol described, of which five represented the best evidence available to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Two randomised controlled trials arrived at contradictory conclusions: one showing better outcomes for CVLU healing with use of honey over standard wound therapy and the other showing equivalent outcomes but more adverse effects. A third randomised controlled trial showed a non significant reduction in bacterial colonisation of CVLU with honey compared to standard therapy. Two further studies--a prospective cohort study and a case series--supported the use of honey, but these were of lower grade evidence and had numerous methodological faults. Therefore, the clinical bottom line is that there is no conclusive evidence that honey improves outcome in patients with CVLU, and until more robust trials are conducted, its benefit should be considered unproven. PMID- 26050954 TI - Proposed Recommendations for Myocardial Revascularisation. AB - This discussion paper presents proposed recommendations for myocardial revascularisation in the Australasian clinical setting based on underlying evidence-based principles and an understanding of local factors which may limit the provision of ideal practice. Recommendations are proposed for myocardial revascularisation in common clinical scenarios and also for special categories, such as patients with diabetes, chronic renal impairment, advanced age, chronic total occlusions and Indigenous patients. PMID- 26050955 TI - Quantification of wall shear stress using a finite-element method in multidimensional phase-contrast MR data of the thoracic aorta. AB - We present a computational method for calculating the distribution of wall shear stress (WSS) in the aorta based on a velocity field obtained from two-dimensional (2D) phase-contrast magnetic resonance imaging (PC-MRI) data and a finite-element method. The WSS vector was obtained from a global least-squares stress-projection method. The method was benchmarked against the Womersley model, and the robustness was assessed by changing resolution, noise, and positioning of the vessel wall. To showcase the applicability of the method, we report the axial, circumferential and magnitude of the WSS using in-vivo data from five volunteers. Our results showed that WSS values obtained with our method were in good agreement with those obtained from the Womersley model. The results for the WSS contour means showed a systematic but decreasing bias when the pixel size was reduced. The proposed method proved to be robust to changes in noise level, and an incorrect position of the vessel wall showed large errors when the pixel size was decreased. In volunteers, the results obtained were in good agreement with those found in the literature. In summary, we have proposed a novel image-based computational method for the estimation of WSS on vessel sections with arbitrary cross-section geometry that is robust in the presence of noise and boundary misplacements. PMID- 26050956 TI - The effect of scaling physiological cross-sectional area on musculoskeletal model predictions. AB - Personalisation of model parameters is likely to improve biomechanical model predictions and could allow models to be used for subject- or patient-specific applications. This study evaluates the effect of personalising physiological cross-sectional areas (PCSA) in a large-scale musculoskeletal model of the upper extremity. Muscle volumes obtained from MRI were used to scale PCSAs of five subjects, for whom the maximum forces they could exert in six different directions on a handle held by the hand were also recorded. The effect of PCSA scaling was evaluated by calculating the lowest maximum muscle stress (sigmamax, a constant for human skeletal muscle) required by the model to reproduce these forces. When the original cadaver-based PCSA-values were used, strongly different between-subject sigmamax-values were found (sigmamax=106.1+/-39.9 N cm(-2)). A relatively simple, uniform scaling routine reduced this variation substantially (sigmamax=69.4+/-9.4 N cm(-2)) and led to similar results to when a more detailed, muscle-specific scaling routine was used (sigmamax=71.2+/-10.8 N cm( 2)). Using subject-specific PCSA values to simulate an shoulder abduction task changed muscle force predictions for the subscapularis and the pectoralis major on average by 33% and 21%, respectively, but was <10% for all other muscles. The glenohumeral (GH) joint contact force changed less than 1.5% as a result of scaling. We conclude that individualisation of the model's strength can most easily be done by scaling PCSA with a single factor that can be derived from muscle volume data or, alternatively, from maximum force measurements. However, since PCSA scaling only marginally changed muscle and joint contact force predictions for submaximal tasks, the need for PCSA scaling remains debatable. PMID- 26050957 TI - Efavirenz treatment causes arterial stiffening in apolipoprotein E-null mice. AB - The development of highly active antiretroviral therapy (HAART) has transformed HIV-1 infection from a terminal diagnosis to a chronic, yet manageable disease. However, people living with HIV-1 exhibit a host of non-AIDS-related co morbidities including cardiovascular disease (CVD). Several HAART drugs have been implicated in the development of CVD; however, the role of efavirenz (EFV), a highly prescribed HAART drug, in early-onset CVD is poorly understood. We treated apolipoprotein E-null (ApoE(-/-)) mice with EFV (75 mg/kg/day) or vehicle, via oral gavage, for 35 days and quantified commonly measured preclinical markers of CVD (intima-media thickening, arterial stiffening) and plaque area. Suprarenal abdominal aortas were subjected to cylindrical biaxial biomechanical testing and standard histology. Aortas from EFV-treated mice demonstrated decreased compliance (i.e., increased arterial stiffness) and decreased axial force and a trend toward decreased in vivo axial stretch, but EFV treatment had no effect on intima-media thickness of the aortic wall or plaque coverage in thoracic aortas and aortic arches. Taken together, these data suggest that EFV leads to arterial stiffening but, for the dose and duration tested, did not lead to elevated plaque progression in ApoE(-/-) mice. PMID- 26050958 TI - Embryonic stem cells growing in 3-dimensions shift from reliance on the substrate to each other for mechanical support. AB - Embryonic stem cells (ESCs) grow into three-dimensional (3D) spheroid structures en-route to tissue growth. In vitro spheroids can be controllably induced on a two-dimensional (2D) substrate with high viability. Here we use a method for inducing pluripotent embryoid body (EB) formation on flat polyacrylamide gels while simultaneously evaluating the dynamic changes in the mechano-biology of the growing 3D spheroids. During colony growth in 3D, pluripotency is conserved while the spheroid-substrate interactions change significantly. We correlate colony size, cell-applied traction-forces, and expressions of cell-surface molecules indicating cell-cell and cell-substrate interactions, while verifying pluripotency. We show that as the colony size increases with time, the stresses applied by the spheroid to the gel decrease in the 3D growing EBs; control cells growing in 2D-monolayers maintain unvarying forces. Concurrently, focal-adhesion mediated cell-substrate interactions give way to E-cadherin cell-cell connections, while pluripotency. The mechano-biological changes occurring in the growing embryoid body are required for stabilization of the growing pluripotent 3D-structure, and can affect its potential uses including differentiation. This could enable development of more effective expansion, differentiation, and separation approaches for clinical purposes. PMID- 26050959 TI - Assessing groundwater pollution hazard changes under different socio-economic and environmental scenarios in an agricultural watershed. AB - This paper proposes a modeling approach for assessing changes in groundwater pollution hazard under two different socio-economic and environmental scenarios: The first one considers an exponential growth of agriculture land-use (Relegated Sustainability), while the other deals with regional economic growth, taking into account, the restrictions put on natural resources use (Sustainability Reforms). The recent (2011) and forecasted (2030) groundwater pollution hazard is evaluated based on hydrogeological parameters and, the impact of land-use changes in the groundwater system, coupling together a land-use change model (Dyna-CLUE) with a groundwater flow model (MODFLOW), as inputs to a decision system support (EMDS). The Dulce Stream Watershed (Pampa Plain, Argentina) was chosen to test the usefulness and utility of this proposed method. It includes a high level of agricultural activities, significant local extraction of groundwater resources for drinking water and irrigation and extensive available data regarding aquifer features. The Relegated Sustainability Scenario showed a negative change in the aquifer system, increasing (+20%; high-very high classes) the contribution to groundwater pollution hazard throughout the watershed. On the other hand, the Sustainability Reforms Scenario displayed more balanced land-use changes with a trend towards sustainability, therefore proposing a more acceptable change in the aquifer system for 2030 with a possible 2% increase (high-very high classes) in groundwater pollution hazard. Results in the recent scenario (2011) showed that 54% of Dulce Stream Watershed still shows a moderate to a very low contribution to groundwater pollution hazard (mainly in the lower area). Therefore, from the point of view of natural resource management, this is a positive aspect, offering possibilities for intervention in order to prevent deterioration and protect this aquifer system. However, since it is quite possible that this aquifer status (i.e. groundwater quality) changes in the near future, the implementation of planning measures and natural resource management is recommended. PMID- 26050960 TI - Storm loads of culturable and molecular fecal indicators in an inland urban stream. AB - Elevated concentrations of fecal indicator bacteria in receiving waters during wet-weather flows are a considerable public health concern that is likely to be exacerbated by future climate change and urbanization. Knowledge of factors driving the fate and transport of fecal indicator bacteria in stormwater is limited, and even less is known about molecular fecal indicators, which may eventually supplant traditional culturable indicators. In this study, concentrations and loading rates of both culturable and molecular fecal indicators were quantified throughout six storm events in an instrumented inland urban stream. While both concentrations and loading rates of each fecal indicator increased rapidly during the rising limb of the storm hydrographs, it is the loading rates rather than instantaneous concentrations that provide a better estimate of transport through the stream during the entire storm. Concentrations of general fecal indicators (both culturable and molecular) correlated most highly with each other during storm events but not with the human-associated HF183 Bacteroides marker. Event loads of general fecal indicators most strongly correlated with total runoff volume, maximum discharge, and maximum turbidity, while event loads of HF183 most strongly correlated with the time to peak flow in a hydrograph. These observations suggest that collection of multiple samples during a storm event is critical for accurate predictions of fecal indicator loading rates and total loads during wet-weather flows, which are required for effective watershed management. In addition, existing predictive models based on general fecal indicators may not be sufficient to predict source-specific genetic markers of fecal contamination. PMID- 26050961 TI - Snail1-driven plasticity of epithelial and mesenchymal cells sustains cancer malignancy. AB - The transcription factor Snail1 induces epithelial-to-mesenchymal transition (EMT) in tumor epithelial cells, a process associated with the emergence of stemness, invasion and cancer malignancy. Here, we review recent reports indicating that Snail1 also regulates mesenchymal plasticity and paracrine signaling and propose that Snail1 orchestrates the generation of cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs). Our view supports the current models for tumorigenesis that consider stemness and tumor microenvironment as retroactive actors for metastasis formation, revealing Snail1 as a regulator of these metastatic forces. This view offers new perspectives for understanding and targeting metastasis. PMID- 26050962 TI - The Hippo signal transduction pathway in soft tissue sarcomas. AB - Sarcomas are rare cancers (~1% of all solid tumours) usually of mesenchymal origin. Here, we review evidence implicating the Hippo pathway in soft tissue sarcomas. Several transgenic mouse models of Hippo pathway members (Nf2, Mob1, LATS1 and YAP1 mutants) develop various types of sarcoma. Despite that, Hippo member genes are rarely point mutated in human sarcomas. Instead, WWTR1-CAMTA1 and YAP1-TFE3 fusion genes are found in almost all cases of epithelioid haemangioendothelioma. Also copy number gains of YAP1 and other Hippo members occur at low frequencies but the most likely cause of perturbed Hippo signalling in sarcoma is the cross-talk with commonly mutated cancer genes such as KRAS, PIK3CA, CTNNB1 or FBXW7. Current Hippo pathway-targeting drugs include compounds that target the interaction between YAP and TEAD G protein-coupled receptors (GPCR) and the mevalonate pathway (e.g. statins). Given that many Hippo pathway modulating drugs are already used in patients, this could lead to early clinical trials testing their efficacy in different types of sarcoma. PMID- 26050964 TI - Electronic resistance switching in the Al/TiO(x)/Al structure for forming-free and area-scalable memory. AB - Electronic bipolar resistance switching (eBRS) in an Al/TiOx/Al structure, where the TiOx layer was reactively sputter-deposited, was examined in conjunction with a structural analysis using transmission electron microscopy. A thin (3-5 nm) insulating Al(Ti)Ox layer was formed at the bottom Al electrode interface, which provided the necessary asymmetric potential barrier for the eBRS to emerge, whereas the top Al electrode interface appeared to have provided the fluent carrier (electron) injection. The set and reset switching were related to the trapping and detrapping of the carriers at the trap centers, the characteristic energy of which was ~0.86 eV, across the entire electrode area. The general features of this material system as the feasible RS memory were insufficient: endurance cycle, <~8000, and retention time at 85 degrees C, 10(6) s. However, the detailed analysis of the switching behavior based on the space-charge limited current conduction mechanism, and its variation with the switching cycles, provided useful information on the general features of the eBRS, which could also be applicable to other binary (or even ternary) metal-oxide RS systems based on the electronic switching mechanism. PMID- 26050963 TI - Gut bacteria and cancer. AB - Microbiota on the mucosal surfaces of the gastrointestinal (GI) tract greatly outnumbers the cells in the human body. Effects of antibiotics indicate that GI tract bacteria may be determining the fate of distal cancers. Recent data implicate dysregulated host responses to enteric bacteria leading to cancers in extra-intestinal sites. Together these findings point to novel anti-cancer strategies aimed at promoting GI tract homeostasis. PMID- 26050965 TI - Sequential phosphorylation analysis using dye-tethered peptides and microfluidic isoelectric focusing electrophoresis. AB - We report a simple method for analyzing sequential phosphorylation by protein kinases using fluorescent peptide substrates and microfluidic isoelectric focusing (MUIEF) electrophoresis. When a dye-labeled peptide substrate was sequentially phosphorylated by two consecutive protein kinases (mitogen-activated protein kinase (MAPK) and glycogen synthase kinase 3 (GSK3)), its differently phosphorylated forms were easily separated and visualized by fluorescent focusing zones in the MUIEF channel based on a change in the isoelectric point (pI) by phosphorylation. As a result, ratiometric and quantitative analysis of the fluorescent focusing regions shifted by phosphorylation enabled the analysis of phosphorylation efficiency and the relevant inhibition of protein kinases (MAPK and GSK3) with high simplicity and selectivity. Furthermore, the GSK3 activity in the cell lysates was elucidated by MUIEF electrophoresis in combination with immunoprecipitation. Our results suggest that this method has great potential for analyzing the sequential phosphorylation of multiple protein kinases that are implicated in cellular signaling pathways. PMID- 26050966 TI - A letter to the editor on the ACTIVNES study. PMID- 26050969 TI - Exceptionally Slow Movement of Gold Nanoparticles at a Solid/Liquid Interface Investigated by Scanning Transmission Electron Microscopy. AB - Gold nanoparticles were observed to move at a liquid/solid interface 3 orders of magnitude slower than expected for the movement in a bulk liquid by Brownian motion. The nanoscale movement was studied with scanning transmission electron microscopy (STEM) using a liquid enclosure consisting of microchips with silicon nitride windows. The experiments involved a variation of the electron dose, the coating of the nanoparticles, the surface charge of the enclosing membrane, the viscosity, and the liquid thickness. The observed slow movement was not a result of hydrodynamic hindrance near a wall but instead explained by the presence of a layer of ordered liquid exhibiting a viscosity 5 orders of magnitude larger than a bulk liquid. The increased viscosity presumably led to a dramatic slowdown of the movement. The layer was formed as a result of the surface charge of the silicon nitride windows. The exceptionally slow motion is a crucial aspect of electron microscopy of specimens in liquid, enabling a direct observation of the movement and agglomeration of nanoscale objects in liquid. PMID- 26050967 TI - V0162 a new long-acting bronchodilator for treatment of chronic obstructive lung diseases: preclinical and clinical results. AB - BACKGROUND: Long acting bronchodilators are the standard of care in the management of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the efficacy and safety of V0162, a novel anticholinergic agent with bronchodilator properties, in preclinical models and in patients with COPD. METHODS: Guinea pigs were used to evaluate the impact of V0162 on the acetylcholine or histamine-induced bronchoconstriction. V0162 was also investigated in an allergic asthma model on ovalbumin-sensitized guinea pig. For clinical investigations, healthy volunteers were included in a dose-escalation, randomized, placebo-controlled phase I study to determine the maximal tolerated dose, followed by a randomized, placebo-controlled, cross-over phase II study in patients with COPD. V0162 was given via inhalation route. The objectives of the phase I/II study were to assess the safety and efficacy of V0162, in terms of bronchodilation and reduction in hyperinflation. RESULTS: Preclinical results showed that V0162 was able to prevent bronchoconstriction induced either by acetylcholine or histamine. V0162 reversed the bronchoconstriction and airway inflammation caused by ovalbumin challenge in sensitized guinea pigs. In the healthy volunteers study, 88 subjects were enrolled: 66 received V0162 and 22 received placebo. No particular safety concerns were raised. The maximal tolerated dose was not reached and the dose escalation was stopped at 2400 MUg. A total of 20 patients with COPD were then enrolled. All patients received a single dose of V0162 1600 MUg and of placebo in two alternating periods. In COPD patients, V0162 demonstrated a significant increase in FEV1 compared with placebo (148 +/- 137 ml vs. 36 +/- 151 ml, p = 0.003). This bronchodilatory effect was corroborated by a reduction in hyperinflation. There was a trend toward dyspnea relief (change in visual analog scale at 22 h, -15.1 +/- 26.0 mm vs.- 5.3 +/- 28.8 mm with placebo, p = 0.054). No serious adverse events (AEs) were reported. Most common AEs were productive and non-productive cough, dyspnea and pruritus. CONCLUSIONS: V0162 improved pulmonary function and tended to improve dyspnea in patients with COPD over more than 24 h. The slight plasmatic exposure observed might support the good safety profile. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01348555. PMID- 26050968 TI - A rat model of radiation injury in the mandibular area. AB - BACKGROUND: Radiation technology focuses on delivering the radiation as precisely as possible to the tumor, nonetheless both acute and long-term damage to surrounding normal tissue may develop. Injuries to the surrounding normal tissue after radiotherapy of head and neck cancer are difficult to manage. An animal model is needed to elucidate good treatment modalities. The aim of this study was to establish a rat model where a certain radiation dose gives reproducible tissue reactions in the mandibular area corresponding to injuries obtained in humans. METHOD: The left mandible of male Sprague Dawley rats was irradiated by external radiotherapy (single fraction 15 Gy, total dose 75 Gy) every second week five times. Endpoint was six weeks after last radiation treatment, and the test group was compared to non-irradiated controls. Morphological alterations of the soft tissues, bone and tooth formation, as well as alterations of salivation, vascularity and collagen content were assessed. An unpaired, non-parametric Mann Whitney test was used to compare the statistical differences between the groups. RESULTS: Analysis of the soft tissues and mandible within the radiation field revealed severe unilateral alopecia and dermatitis of the skin, extensive inflammation of the submandibular gland with loss of serous secretory cells, hyperkeratinization and dense connective fiber bundles of the gingival tissue, and disturbed tooth development with necrosis of the pulp. Production of saliva and the vascularity of the soft tissues were significantly reduced. Furthermore, the collagen fibril diameter was larger and the collagen network denser compared to non-irradiated control rats. CONCLUSION: We have established an animal model of radiation injury demonstrating physiological and histological changes corresponding to human radiation injuries, which can be used for future therapeutic evaluations. PMID- 26050970 TI - Best choice of perforator vessel in autologous breast reconstruction: Virtual reality navigation vs radiologist analysis. A prospective study. AB - BACKGROUND: Computed tomographic angiography (CTA) is being considered as the current "gold standard" for the preoperative planning of DIEP flaps. The aim of the study was to demonstrate the concordance between the preoperative choice of the best perforator vessel by the radiologist using CTA and the surgeon using the VirSSPA software. METHODS: A prospective and comparative study was conducted in patients needing immediate or secondary breast reconstruction. The radiologist (CTA) and the surgeon (VirSSPA software) analyzed the number of perforators, their course, their location, and then determined the best perforator of the DIEP flap. RESULTS: Best perforator concordance was 33% between the radiologist and the surgeon. The perforator used for reconstruction was chosen by the radiologist in 16 cases (53%) and in 10 cases (33%) by the surgeon. In only nine cases was the same perforator chosen by both of them. Distances of the best perforator from the umbilicus measured by VirSSPA showed an error margin varying from 1-47 mm from the real distances measured by CTA. The Pearson product-moment correlation coefficient was found to be 0.0235 (p = 0.94), reflecting a non-linear relationship. CONCLUSIONS: CTA with a well-trained radiologists continues to be, for us, the gold standard for the preoperative choice of the best perforator. PMID- 26050971 TI - Alternative splicing detection workflow needs a careful combination of sample prep and bioinformatics analysis. AB - BACKGROUND: RNA-Seq provides remarkable power in the area of biomarkers discovery and disease characterization. Two crucial steps that affect RNA-Seq experiment results are Library Sample Preparation (LSP) and Bioinformatics Analysis (BA). This work describes an evaluation of the combined effect of LSP methods and BA tools in the detection of splice variants. RESULTS: Different LSPs (TruSeq unstranded/stranded, ScriptSeq, NuGEN) allowed the detection of a large common set of splice variants. However, each LSP also detected a small set of unique transcripts that are characterized by a low coverage and/or FPKM. This effect was particularly evident using the low input RNA NuGEN v2 protocol. A benchmark dataset, in which synthetic reads as well as reads generated from standard (Illumina TruSeq 100) and low input (NuGEN) LSPs were spiked-in was used to evaluate the effect of LSP on the statistical detection of alternative splicing events (AltDE). Statistical detection of AltDE was done using as prototypes for splice variant-quantification Cuffdiff2 and RSEM-EBSeq. As prototype for exon level analysis DEXSeq was used. Exon-level analysis performed slightly better than splice variant-quantification approaches, although at most only 50% of the spiked-in transcripts was detected. The performances of both splice variant quantification and exon-level analysis improved when raising the number of input reads. CONCLUSION: Data, derived from NuGEN v2, were not the ideal input for AltDE, especially when the exon-level approach was used. We observed that both splice variant-quantification and exon-level analysis performances were strongly dependent on the number of input reads. Moreover, the ribosomal RNA depletion protocol was less sensitive in detecting splicing variants, possibly due to the significant percentage of the reads mapping to non-coding transcripts. PMID- 26050972 TI - Mitochondrial DNA: Radically free of free-radical driven mutations. AB - Mitochondrial DNA has long been posited as a likely target of oxidative damage induced mutation during the ageing process. Research over the past decades has uncovered the accumulation of mitochondrial DNA mutations in association with a mosaic pattern of cells displaying mitochondrial dysfunction in ageing individuals. Unfortunately, the underlying mechanisms are far less straightforward than originally anticipated. Recent research on mitochondria reveals that these genomes are far less helpless than originally envisioned. Additionally, new technologies have allowed us to analyze the mutational signatures of many more somatic mitochondrial DNA mutations, revealing surprising patterns that are inconsistent with a DNA-oxidative damage based hypothesis. In this review, we will discuss these recent observations and new insights into the eccentricities of mitochondrial genetics, and their impact on our understanding of mitochondrial mutations and their role in the ageing process. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging. PMID- 26050974 TI - The role of mitochondrial dysfunction in age-related diseases. AB - The aging process is accompanied by the onset of disease and a general decline in wellness. Insights into the aging process have revealed a number of cellular hallmarks of aging, among these epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, and stem cell exhaustion. Mitochondrial dysfunction increasingly appears to be a common factor connecting several of these hallmarks, driving the aging process and afflicting tissues throughout the body. Recent research has uncovered a much more complex involvement of mitochondria in the cell than has previously been appreciated and revealed novel ways in which mitochondrial defects feed into disease pathology. In this review we evaluate ways in which problems in mitochondria contribute to disease beyond the well-known mechanisms of oxidative stress and bioenergetic deficits, and we predict the direction that mitochondrial disease research will take in years to come. PMID- 26050973 TI - Mitochondrial dysfunction in aging: Much progress but many unresolved questions. AB - The free radical theory of aging is almost 60 years old. As mitochondria are the principle source of intracellular reactive oxygen species (ROS), this hypothesis suggested a central role for the mitochondrion in normal mammalian aging. In recent years, however, much work has questioned the importance of mitochondrial ROS in driving aging. Conversely new evidence points to other facets of mitochondrial dysfunction which may nevertheless suggest the mitochondrion retains a critical role at the center of a complex web of processes leading to cellular and organismal aging. PMID- 26050975 TI - The dynamic relationship between cash transfers and child health: can the child support grant in South Africa make a difference to child nutrition? AB - OBJECTIVE: Cash transfer programmes targeting children are considered an effective strategy for addressing child poverty and for improving child health outcomes in developing countries. In South Africa, the Child Support Grant (CSG) is the largest cash transfer programme targeting children from poor households. The present paper investigates the association of the duration of CSG receipt with child growth at 2 years in three diverse areas of South Africa. DESIGN: The study analysed data on CSG receipt and anthropometric measurements from children. Predictors of stunting were assessed using a backward regression model. SETTING: Paarl (peri-urban), Rietvlei (rural) and Umlazi (urban township), South Africa, 2008. SUBJECTS: Children (n 746), median age 22 months. RESULTS: High rates of stunting were observed in Umlazi (28 %), Rietvlei (20 %) and Paarl (17 %). Duration of CSG receipt had no effect on stunting. HIV exposure (adjusted OR=2.30; 95 % CI 1.31, 4.03) and low birth weight (adjusted=OR 2.01, 95 % CI 1.02, 3.96) were associated with stunting, and maternal education had a protective effect on stunting. CONCLUSIONS: Our findings suggest that, despite the presence of the CSG, high rates of stunting among poor children continue unabated in South Africa. We argue that the effect of the CSG on nutritional status may have been eroded by food price inflation and limited progress in the provision of other important interventions and social services. PMID- 26050976 TI - Anaphylaxis. PMID- 26050977 TI - Epidemiology of asthma in Poland in urban and rural areas, based on provided health care services. AB - INTRODUCTION: Asthma is a serious health and social problem, also in Poland. The epidemiological data indicate that the problem of asthma concerns approximately 4 million people in Poland, whereas almost approximately 70% of them have no diagnosis and are not aware of their illness, and on the other hand in 39% of persons who declared the diagnosis of asthma in a survey the diagnosis was negatively verified (overdiagnosis of asthma). So far, no detailed comparative studies for asthma incidence rate in urban and rural areas were conducted in Poland. The aim of the study was to analyze patients with asthma in Poland in the years 2008-2012, with regard to province and type of commune (rural/urban). MATERIAL AND METHODS: The study used data from National Health Fund (NFZ) - reported by health care providers regarding the patients diagnosed with asthma. Using structured query language (SQL) a set of patients was selected and created, for whom at the same time ICD-10 code: J45.X-bronchial asthma was reported. In order to estimate the number of patients with asthma we used the PESEL social security number as a unique identifier of the patient. Code of the patient's commune of residence in conjunction with the Central Statistical Office data formed the basis for the division of municipalities into urban and rural areas. The analysis of asthma incidence trends in Poland was performed on the basis of health services provided to patients. The analysis was performed by using the Statistica 10 software using a negative binomial regression model. RESULTS: In 2009 a significant increase in the number of patients with asthma was observed compared with the previous year, whereas after 2009 the number of patients diagnosed with asthma remained relatively constant. A significant increase of predominance of women among asthma patients in recent years can be noticed: from 107% in 2008 to almost 115% in 2012 (F:M ratio). Regardless of the analyzed year and the diagnosis the incidence rate remained constant: approximately 55-57% for urban areas and about 43-45% in rural areas. CONCLUSIONS: The average prevalence rate for rural areas is significantly lower than for urban areas. The use of adjusted incidence rate leads to the conclusion that the number of sufferers in urban areas is higher (about 10%) of the number of sufferers in the rural areas. The results of the analysis are consistent with information from previous studies in Poland and in the world. PMID- 26050978 TI - Anaphylaxis as a cause of hospitalization--a single academic centre experience. AB - INTRODUCTION: In recent years, more and more often the increase in incidence of allergies is observed. According to the WHO, they are getting the fourth position amongst the most frequent diseases after cancers, cardiovascular diseases and AIDS. Anaphylaxis is a severe, life-threatening, systemic or generalised immediate hypersensitivity reaction. The analysis of the causes and the clinical picture of anaphylaxis in patients treated at single academic hospital centre was the purpose of the study. MATERIAL AND METHODS: The study was based on retrospective analysis of case records of the patients hospitalised at the Chair and Department of Allergology, Clinical Immunology and Internal Diseases, the Jan Biziel University Hospital in Bydgoszcz in the years 2005-2010. 132 patients, in whom anaphylactic reaction appeared, were analysed. The examined population included 70 men and 62 women at 16-95 years of age. RESULTS: The conducted examinations allowed to obtain information about the causes and the course of anaphylactic reactions. The problem of hypersensitivity to substances of various origin (biological or synthetic) can concern everyone irrespective of sex and age. Nevertheless, the phenomenon of anaphylaxis more often occurred in the examined men than women. Most cases of anaphylactic reactions were reported in the 26-50 age range. Based on the presented results, no regularity was observed in anaphylaxis clinical picture and its causative factor. CONCLUSIONS: It is difficult to forecast the course of the reaction based on the causative factor, for anaphylactic reaction is characterised by a great individual changeability and intensity of the first symptoms. PMID- 26050979 TI - Causes of deaths in COPD patients in primary care setting--a 6-year follow-up. AB - INTRODUCTION: COPD is one of the most frequent respiratory diseases responsible for patients' disability and mortality. In 2005 a single primary care practice, COPD was diagnosed in 183 out of 1,960 eligible subjects >= 40 years (9.3%). The aim of this study was to assess mortality rate and causes of deaths in this group after 6 years. MATERIAL AND METHODS: In 2011 we invited all 183 patients with COPD recognised in 2005. We performed spirometry, physical examination, questionnaire of respiratory symptoms, smoking habits, concomitant diseases and treatment. Information about deaths was taken from primary care register, furthermore, family members were asked to deliver medical documentation or death certificate. RESULTS: In 2011 we studied only 74 subjects (40.4%), 43 subjects died (23.5%) and 66 subjects were lost from the follow-up (36.1%). Cardiovascular diseases were the most frequent causes of deaths - 21 subjects (48.8%) (heart attack - 8 patients and stroke - 8 patients). Respiratory failure in the course of COPD exacerbation was the cause of 10 deaths (23.3%). Neoplastic diseases lead to 9 deaths (20.9%) (lung cancer 7 patients). Renal insufficiency was responsible for one death (2.325%), and the causes of 2 deaths remained unknown (4.65%). Subjects who died (predominantly males) were older, had higher MRC score and lower FEV1. CONCLUSIONS: Study performed six years after COPD diagnosis revealed that 23.5% of subjects died. The main causes of deaths were the following: cardiovascular diseases (mainly heart attack and stroke), COPD exacerbations and lung cancer (more than 75%). Death risk in COPD patients was associated with age, male sex, dyspnoea and severity of the disease. PMID- 26050980 TI - High-mobility group box 1 protein levels in serum of subjects after exposure to fire smoke--short communication. AB - INTRODUCTION: Fire smoke inhalation a recognized etiologic factor of airway injuries. The objective of this study was evaluation of serum high-mobility group box 1 (HMGB1) protein concentration in subjects exposed to fire smoke (SEFS). MATERIAL AND METHODS: The study group consisted of 40 consecutive patients admitted to the Toxicology Unit, Lodz, Poland after exposure to fire smoke. Serum HMGB1 concentrations were measured upon admission to hospital and rechecked on the 2nd and on the day of discharge. Patients also underwent routine toxicological diagnostic procedures applied in case of those exposures, such as carboxyhaemoglobin (COHb) levels and urinary thiocyanate concentrations. The same diagnostic tests were performed in 10 healthy volunteers not exposed to smoke of the control group. RESULTS: The average serum SEFS concentration of HMGB1 protein was not significantly higher on admission in comparison with the respective values recorded on the 2nd day and on the day of discharge. The mean serum level of HMGB1 protein of exposed group was higher than that one in the control group, however the difference was not statistically significant. The highest concentration of HMGB1 protein was noted in serum of 28 subjects exposed to fire smoke reporting at least one symptom and the difference was statistically significant in a comparison with the control group. CONCLUSION: As indicated, an acute exposure to smoke may lead to transient increase of HMGB1 in serum in exposed subjects. Further studies are necessary in order to confirm the importance of this protein in pathogenesis of acute airway injury due to exposure to fire smoke. PMID- 26050981 TI - Bronchioloalveolar cell carcinoma presenting as a "non-resolving consolidation" for two years. AB - Bronchioloalveolar carcinoma (BAC), a rare form of lung malignancy, is usually seen in non-smokers and women. Three distinct histological forms have been identified viz, mucinous, non-mucinous and mixed or indeterminate. The mucinous variety of BAC may present as a consolidation which is very difficult to differentiate from an infective pneumonia. We present a case of a middle aged female who was evaluated for a "non-resolving consolidation" for a period of two years. She had undergone an inconclusive bronchoscopy and had received several courses of antibiotics including anti-tuberculous therapy without relief. The size of the lesion had remained largely unchanged during this period and there was no significant clinical deterioration in the patient. Transbronchial biopsy done on presentation revealed BAC of the mucinous variety. BAC presenting as a large consolidation without significant change for a period of two years has rarely been documented in the literature. PMID- 26050982 TI - Synchronous two distinct neuroendocrine lung cancer lesions. AB - The synchronous primary lung tumors is a rare condition and presented patient is the first reported case of simultaneous two distinct neuroendocrine lung cancer lesions in the same lobe. We present the case of a 55-year-old woman with synchronous two distinct neuroendocrine lung cancer lesions in the right upper lobe. Initially she showed no signs or symptoms related to lung lesions and was admitted to Thoracic Surgery Ward for the investigation of two oval, solitary pulmonary nodules (11 and 19 mm in diameter) detected on a chest X-ray performed three months earlier. The radiological imaging showed a variability of growth of both lesions (smaller tumor has enlarged while the larger one remained unchanged). After the CT-guided lung biopsy, patient underwent right upper lobectomy. Histological examination revealed a small cell carcinoma in one of the tumors and a large cell neuroendocrine carcinoma in the other one. The patient was discharged in good condition and lung inflation in chest X-ray and qualified for adjuvant chemotherapy with a combination of cisplatin and etoposide and the prophylactic cranial irradiation. Very important issues, having impact on outcome of patients with multiple lung tumours is differentiation whether the lesions are metastases or synchronous primary lung tumors and the optimal management of these patients. PMID- 26050983 TI - Acute laryngeal dyspnea as first presentation of granulomatosis with polyangiitis. AB - Granulomatosis with polyangiitis (GPA) is a multi-organ disease which mostly affects lungs, kidney, and head and neck region. We report a rare case of acute laryngeal dyspnea and rapidly progressive pulmonary changes as first manifestations of disease. A 53 year-old woman presented with symptoms of two week dyspnea, which aggravated rapidly in the preceding hours. Laryngological examination revealed subglottic infiltrations and vocal fold oedema which required urgent tracheotomy. During few days she developed gingival ulcerations and pulmonary infiltration with negative serum c-ANCA titers. The histopathological examination of subglottic and gingival biopsies and the clinical picture established the diagnosis of GPA. She was treated with prednisone and cyclophosphamide with recovery; however, during over 3 years of follow-up, pulmonary symptoms relapsed and subglottic stenosis persisted. The difficulties in diagnosis and treatment in this unusual presentation of GPA are outlined with conclusion that in patients with subglottic infiltration, which develops rapidly, even when this is a sole presentation of the disease, and when c-ANCA are negative, GPA should always be considered. PMID- 26050984 TI - The role of questionnaires in the assessment of asthma control. AB - The achievement and the maintenance of asthma control is currently considered the main goal of asthma treatment. Recent guidelines recommend regular assessment of asthma control and indicate questionnaires as important tools that can facilitate its evaluation. Questionnaires relate to GINA or NAEPP guidelines. Questionnaires constitute complex numerical or categorical scales and consist of several to over a dozen questions relating to the patient's symptoms of asthma, limitations in daily activities and usage of rescue medications within a period of time. Each questionnaire is characterized by the features that affect its reliability and usefulness. In the following paper we discuss most of the questionnaires which assess asthma control. We focus on the items they include and present the results of studies that prove the effectiveness of individual questionnaires in assessment of asthma control. Attention was drawn to the patient groups to which the questionnaires are addressed. We list the features of the questionnaire which should be considered before choosing a test, so that it satisfies both the doctor's and the patient's needs. The role of questionnaires as the easy-to-use tools is growing steadily. Unfortunately, not all are available in Polish language. Conducting appropriate validation studies may allow to use many of them in Polish conditions. PMID- 26050985 TI - Tiotropium and its efficacy in the treatment of COPD. AB - Exacerbations of chronic obstructive pulmonary disease (COPD) have a negative effect on the clinical course and outcome of the disease thus causing considerable social and economic burden. As the natural course of the disease may vary, the treatment should take into account an individual approach to a patient. The appropriate treatment makes it possible to control the symptoms, improves effort tolerance and decreases the risk of exacerbations and death. Tiotropium is a muscarinic receptor antagonist, which is taken once daily, in maintenance therapy, in every stage of the disease progress. The efficacy of tiotropium in regards to exacerbations of chronic obstructive pulmonary disease has been evaluated in many clinical trials against placebo and several different active comparators. This review presents the results of those studies with the main goal to evaluate the efficacy of treatment with tiotropium in terms of prevention and course of exacerbations. PMID- 26050986 TI - Bird fancier's lung--comment on: Kumar R., Singh M. "Bird fancier's lung: clinical-radiological presentation in 15 cases". PMID- 26050987 TI - Basophil activation tests (BAT): wheat and chaff. PMID- 26050988 TI - Basophil activation test--brief comment and response. PMID- 26050989 TI - Sequence-engineered mRNA Without Chemical Nucleoside Modifications Enables an Effective Protein Therapy in Large Animals. AB - Being a transient carrier of genetic information, mRNA could be a versatile, flexible, and safe means for protein therapies. While recent findings highlight the enormous therapeutic potential of mRNA, evidence that mRNA-based protein therapies are feasible beyond small animals such as mice is still lacking. Previous studies imply that mRNA therapeutics require chemical nucleoside modifications to obtain sufficient protein expression and avoid activation of the innate immune system. Here we show that chemically unmodified mRNA can achieve those goals as well by applying sequence-engineered molecules. Using erythropoietin (EPO) driven production of red blood cells as the biological model, engineered Epo mRNA elicited meaningful physiological responses from mice to nonhuman primates. Even in pigs of about 20 kg in weight, a single adequate dose of engineered mRNA encapsulated in lipid nanoparticles (LNPs) induced high systemic Epo levels and strong physiological effects. Our results demonstrate that sequence-engineered mRNA has the potential to revolutionize human protein therapies. PMID- 26050990 TI - HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells. AB - The human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) response is critical in controlling HIV infection. Since the immune response does not eliminate HIV, it would be beneficial to develop ways to enhance the HIV specific CTL response to allow long-term viral suppression or clearance. Here, we report the use of a protective chimeric antigen receptor (CAR) in a hematopoietic stem/progenitor cell (HSPC)-based approach to engineer HIV immunity. We determined that CAR-modified HSPCs differentiate into functional T cells as well as natural killer (NK) cells in vivo in humanized mice and these cells are resistant to HIV infection and suppress HIV replication. These results strongly suggest that stem cell-based gene therapy with a CAR may be feasible and effective in treating chronic HIV infection and other morbidities. PMID- 26050991 TI - Galectin-1 Protein Therapy Prevents Pathology and Improves Muscle Function in the mdx Mouse Model of Duchenne Muscular Dystrophy. AB - Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by mutations in the dystrophin gene, leading to the loss of a critical component of the sarcolemmal dystrophin glycoprotein complex. Galectin-1 is a small 14 kDa protein normally found in skeletal muscle and has been shown to be a modifier of immune response, muscle repair, and apoptosis. Galectin-1 levels are elevated in the muscle of mouse and dog models of DMD. Together, these findings led us to hypothesize that Galectin-1 may serve as a modifier of disease progression in DMD. To test this hypothesis, recombinant mouse Galectin-1 was produced and used to treat myogenic cells and the mdx mouse model of DMD. Here we show that intramuscular and intraperitoneal injections of Galectin-1 into mdx mice prevented pathology and improved muscle function in skeletal muscle. These improvements were a result of enhanced sarcolemmal stability mediated by elevated utrophin and alpha7beta1 integrin protein levels. Together our results demonstrate for the first time that Galectin-1 may serve as an exciting new protein therapeutic for the treatment of DMD. PMID- 26050993 TI - Remarkable conformational flexibility of aqueous 18-crown-6 and its strontium(II) complex-ab initio molecular dynamics simulations. AB - Ab initio QMCF-MD simulations of aqueous 18-crown-6 (18C6) and strontium(II)-18 crown-6 (18C6-Sr) were performed to gather insight into their hydration properties. Strongly different characteristics were found for the two solutes in terms of structure and dynamics such as H-bonding. They, however, have in common that their backbone shows high flexibility in aqueous medium, adopting structures significantly differing from idealized gas phase geometries. In particular, planar oxyethylene units stable in the picosecond range occurred in 18C6, while the strontium complex readily exhibits a bent structure. Detailed analysis of this high flexibility was done via two dimensional root mean square deviation plots as well as the evolution of dihedral angles and angles within the simulation trajectory. The vibrational spectra obtained from the QMCF-MD simulations are in excellent agreement with experimental data and show a pronounced blueshift upon complexation of the strontium(II) ion in 18C6. PMID- 26050992 TI - MiR-26a Rescues Bone Regeneration Deficiency of Mesenchymal Stem Cells Derived From Osteoporotic Mice. AB - Osteoporosis, caused by a relative increase of bone resorption over bone formation, is characterized by decreased bone mass and bone strength, resulting in an increased incidence of bone fractures, which often leads to further disability and early mortality in the elderly due to impaired bone healing ability. The majority of therapeutics currently used in clinics for the treatment of osteoporosis are antiresorptive agents that exert their clinical effect by decreasing the rate of bone resorption. However, strategies solely aimed at antiresorption have limited therapeutic efficacy in restoring bone remodeling balance and enhancing osteoporotic fracture healing. Here, we report that miR-26a plays a critical role in modulating bone formation during osteoporosis. We found that miR-26a treatment could effectively improve the osteogenic differentiation capability of mesenchymal stem cells isolated from littermate-derived ovariectomized osteoporotic mice both in vitro and in vivo. MiR-26a exerts its effect by directly targeting Tob1, the negative regulator of BMP/Smad signaling pathway by binding to the 3'-untranslated region and thus repressing Tob1 protein expression. Our findings indicate that miR-26a may be a promising therapeutic candidate to enhance bone formation in treatment of osteoporosis and to promote bone regeneration in osteoporotic fracture healing. PMID- 26050994 TI - An efficient transformation of primary halides into nitriles through palladium catalyzed hydrogen transfer reaction. AB - Two-step one-pot transformation of primary halides into corresponding nitriles is successfully achieved. Nucleophilic substitution of primary halides with sodium azide and subsequent palladium-catalyzed hydrogen transfer proceeds smoothly in the presence of sterically bulky ligand dicyclohexyl(2',4',6' triisopropylbiphenyl-2-yl)phosphine (XPhos) in acetone to produce nitriles in satisfactory to good yields. PMID- 26050995 TI - Modelling the effects of cell-to-cell variability on the output of interconnected gene networks in bacterial populations. AB - BACKGROUND: The interconnection of quantitatively characterized biological devices may lead to composite systems with apparently unpredictable behaviour. Context-dependent variability of biological parts has been investigated in several studies, measuring its entity and identifying the factors contributing to variability. Such studies rely on the experimental analysis of model systems, by quantifying reporter genes via population or single-cell approaches. However, cell-to-cell variability is not commonly included in predictability analyses, thus relying on predictive models trained and tested on central tendency values. This work aims to study in silico the effects of cell-to-cell variability on the population-averaged output of interconnected biological circuits. METHODS: The steady-state deterministic transfer function of individual devices was described by Hill equations and lognormal synthetic noise was applied to their output. Two- and three-module networks were studied, where individual devices implemented inducible/repressible functions. The single-cell output of such networks was simulated as a function of noise entity; their population-averaged output was computed and used to investigate the expected variability in transfer function identification. The study was extended by testing different noise models, module logic, intrinsic/extrinsic noise proportions and network configurations. RESULTS: First, the transfer function of an individual module was identified from simulated data of a two-module network. The estimated parameter variability among different noise entities was limited (14%), while a larger difference was observed (up to 62%) when estimated and true parameters were compared. Thus, low variability parameter estimates can be obtained for different noise entities, although deviating from the true parameters, whose measurement requires noise knowledge. Second, the black-box input-output function of a two/three-module network was predicted from the knowledge of the transfer function of individual modules, identified in the presence of noise. Estimates variability was low (16%); however, differences up to 68% were observed by simulating a typical experimental study where the predictions obtained above were compared to network outputs generated in the presence of noise. Network predictions can, thus, deviate from real outputs when modules are characterized and re-used in different noise contexts. CONCLUSIONS: The adopted approach can support predictability studies in synthetic biology by distinguishing between actual unpredictability and contribution of noise and by guiding researchers in the design of suitable experimental measurement for gene networks. PMID- 26050996 TI - Preconception counseling: do patients learn about genetics from their obstetrician gynecologists? AB - PURPOSE: The purpose of this observational survey study is to assess genetic knowledge in reproductive-aged women and to determine the role played by their obstetricians in their education. METHODS: A 31-item survey was distributed via an internet survey service to women between the ages of 18 and 45. The survey included subject demographics, a query regarding the source of subjects' knowledge of genetics, and 6 question genetics quiz with 3 fundamental questions and 3 advanced questions. Subjects were divided into parous and nulliparous groups, and responses were compared using student's t-test for continuous variables and chi square for proportions. RESULTS: Participants included 207 parous and 221 nulliparous women. There were no differences in demographic characteristics including age and education. Parous women scored significantly higher than nulliparous women on the fundamental genetics quiz (71 vs 61 %, p = 0.03). This difference remained but was no longer significant when the 3 advanced questions were included (48 vs 42 %). Only 39 % of parous and 8 % of nulliparous subjects listed their physician as one of their main sources of genetic information. 78 % of all subjects stated that they would prefer to receive genetic information from their physicians over other sources. CONCLUSIONS: Recently parous women scored higher on a genetics assessment quiz than did their nulliparous counterparts, but the majority did not cite their obstetrician gynecologists as a main source of information. As genetic counseling and testing are becoming increasingly important aspects of obstetrical care, obstetricians should play a more substantial role in educating their patients. PMID- 26050997 TI - Vitamin D level is not a predictor of hypocalcemia after total thyroidectomy. AB - PURPOSE: As the incidence of thyroid cancer has increased, hypocalcemia, a common complication of thyroid surgery, has become a serious problem. However, no definite predictor of postoperative hypocalcemia is known. In this study, our purpose was to investigate the potential role of vitamin D as a predictor of postoperative hypocalcemia. METHODS: A prospective observational study was performed on patients who underwent total thyroidectomy for thyroid cancer performed by a single experienced surgeon between October 2013 and September 2014. MEASUREMENTS: Their serum 25-OH vitamin D levels were measured preoperatively. On the day after surgery, serum calcium and intact parathyroid hormone levels were measured, and symptoms of hypocalcemia were recorded. RESULTS: Of the 134 patients, laboratory and symptomatic hypocalcemia developed in 52 patients (39 %) and 25 patients (19 %), on the day after surgery. The preoperative vitamin D level was 16.5 +/- 9.2 ng/mL, and this value did not differ according to laboratory or symptomatic hypocalcemia (p = 0.94). The incidence of laboratory or symptomatic hypocalcemia did not differ according to vitamin D deficiency. Only incidental parathyroidectomy was associated with symptomatic hypocalcemia (p = 0.03). CONCLUSIONS: Vitamin D level is not a predictor of hypocalcemia after total thyroidectomy for thyroid cancer. Thus, routine preoperative screening for vitamin D is not recommended. PMID- 26050998 TI - Isotetronic acids from an oxidative cyclization. AB - Oxidation of alpha,beta-unsaturated methyl ketones with selenium dioxide leads to a cascade of reactions culminating in the formation of isotetronic acids. PMID- 26050999 TI - The RAB5-GEF Function of RIN1 Regulates Multiple Steps During Listeria monocytogenes Infection. PMID- 26051000 TI - Cranial morphological homogeneity in two subspecies of water deer in China and Korea. AB - The water deer (Hydropotes inermis) has conventionally been classified into two subspecies according to geographic distribution and pelage color pattern: H. i. inermis from China and H. i. argyropus from Korea. However, the results of a recent molecular study have called this into question. To further reappraise this classification, we examined morphological variation in craniodental measurements of these 2 subspecies. Results of univariate and multivariate analyses demonstrated that these 2 subspecies are not well-differentiated, suggesting that individuals of the 2 populations share common morphological traits. Despite the distribution of the subspecies at different latitudes, no clear morphocline was detected, suggesting that Bergmann's rule does not apply in this case. Discriminant analysis indicated that the characteristics of individuals are shared by both populations, suggesting that not all individuals can be assigned to their original population. Results of principal component analysis showed that the two populations shared more than 75% of individuals, congruent with the "75% rule" of subspecies classification. In both the neighbor-joining and unweighted pair group methods with arithmetic mean cluster analyses, specimens of H. i. argyropus and H. i. inermis were highly mixed within the cladograms. These results suggest that the overall morphological variation in the 2 subspecies overlaps considerably and that there is no coherent craniofacial difference between the 2 groups. The present findings combined with prior observations from molecular biogeography point out that the taxonomic division of water deer into 2 subspecies should be revisited. PMID- 26051001 TI - Fibronectin modified expression of Sonic hedgehog in ATRA-mediated neuronal differentiation. AB - In this study, the effect of fibronectin on the neurite outgrowth from embryoid bodies (EBs) in neurodifferentiated embryonal carcinoma P19 cells was examined. The neurite outgrowth on fibronectin was maintained for a longer time in comparison with those on collagen or laminin. Quantitative RT-PCR revealed that mRNA level corresponding to sonic hedgehog (Shh) in neurodifferentiated P19 cells was upregulated on fibronectin, whereas collagen or laminin did not affect. Further knockdown of integrin alphav subunit in P19 cells demonstrated that expression of Shh was mediated through interaction between fibronectin and integrin. Additionally, exogenous Shh agonist accelerated neurite outgrowth from embryonic stem cell-derived EBs without large change of neuronal phenotype expression. Taken together, fibronectin could maintain neurite outgrowth via increased Shh expression. PMID- 26051002 TI - New thiocyanate-free ruthenium(II) sensitizers with different pyrid-2-yl tetrazolate ligands for dye-sensitized solar cells. AB - The synthesis of two new thiocyanate free Ru(II) complexes with different pyrid-2 yl tetrazolate ligands is reported, along with their electrochemical, spectroscopic and theoretical characterization. The corresponding dye-sensitized solar cell devices were prepared, leading to 3.4% conversion efficiency, promising data, considering the simplicity of the ligands and the high chemical stability of the complexes. PMID- 26051004 TI - Ir-Catalyzed enantioselective group transfer reactions. AB - Recently, several novel iridium complexes have been shown to catalyse group transfer reactions in a highly selective fashion. Rhodium complexes, and in particular dirhodium tetracarboxylate salts, have proven to be a remarkably useful class of catalysts for these reactions through several decades of development. Recent results suggest that iridium may offer opportunities to address challenges in this chemistry and provide complementary reactivity patterns. This tutorial review outlines the recent developments in Ir-catalyzed enantioselective group transfer chemistry with highlights on examples which display this unique reactivity. PMID- 26051005 TI - Two nanosized 3d-4f clusters featuring four Ln6 octahedra encapsulating a Zn4 tetrahedron. AB - Two high-nuclearity 3d-4f clusters Ln24Zn4 (Ln = Gd and Sm) featuring four Ln6 octahedra encapsulating a Zn4 tetrahedron were obtained through the self-assembly of Zn(OAc)2 and Ln(ClO4)3. Quantum Monte Carlo (QMC) simulations show the antiferromagnetic coupling between Gd(3+) ions. Studies of the magnetocaloric effect (MCE) show that the Gd24Zn4 cluster exhibits the entropy change (-DeltaSm) of 31.4 J kg(-1) K(-1). PMID- 26051006 TI - Investigations of freezing and cold storage for the analysis of peatland dissolved organic carbon (DOC) and absorbance properties. AB - Although measured rates of biological degradation of DOC are typically low under dark conditions, it is assumed that water samples must be analysed soon after collection to provide an accurate measure of DOC concentration and UV-visible absorbance. To examine the impact of storage on DOC quality and quantity, we took water samples from an ombrotrophic peatland, and stored them in the dark at 4 degrees C for 138-1082 days. A median of 29% of DOC was lost during storage, but losses of absorbance at 254 nm were less. DOC loss followed a first-order exponential decay function, and was dependent on storage time. DOC half-life was calculated as 1253 days. Specific absorbance at 254 nm suggested that samples containing more aromatic DOC were more resistant to degradation, although time functioned as the primary control. Samples from two fens showed that loss of absorbance was greater at 400 nm rather than 254 nm, after 192 days storage, suggesting that non-aromatic DOC is preferentially degraded. These results suggest that samples can be stored for several months before losses of DOC become detectable, and that it is possible to back-calculate initial DOC concentrations in long-term stored samples based on known decay rates. Freeze/thaw experiments using samples from a range of peatlands suggested that DOC concentration was mostly unaffected by the process, but DOC increased 37% in one sample. Freezing had unpredictable and sometimes strong effects on absorbance, SUVA and E ratios, therefore freezing is not recommended as a method of preservation for these analyses. PMID- 26051007 TI - Proteomic Analysis of G2/M Arrest Triggered by Natural Borneol/Curcumin in HepG2 Cells, the Importance of the Reactive Oxygen Species-p53 Pathway. AB - Curcumin (Cur), an active ingredient from the rhizome of the plant Curcuma longa, has wide anticancer activities. However, due to its poor solubility and hence poor absorption, Cur has limited clinical applications. It is therefore important to develop an effective method to improve its absorption. Natural borneol (NB), a terpene and bicyclic organic compound, has been extensively used as a food additive, and our previous studies show that it can improve the uptake of Cur in cancer cells. However, the anticancer mechanism of NB/Cur remains unclear. In this study, the effects of NB/Cur on HepG2 cells were investigated by proteomic analysis. The results showed that 32 differentially expressed proteins identified by matrix assisted laser desorption ionization time-of-flight mass spectrometry were significantly changed after NB/Cur treated HepG2 cells for 24 h. Moreover, 17 proteins increased and 12 proteins decreased significantly. Biological progress categorization demonstrated that the identified proteins were mainly associated with cell cycle and apoptosis (28.1%). Subcellular location categorization exhibited that the identified proteins were mainly located in nucleus (28.1%) and mitochondrion (21.9%). Among of all proteins, we selected three differential proteins (hnRNPC1/C2, NPM, and PSMA5), which were associated with the p53 pathway. Down-regulation of hnRNPC1/C2 and NPM contributed to the enhancement of phosphorylated p53. Activated p53 and down-regulation of PSMA5 resulted in an increase in p21 protein. Further studies showed that NB/Cur induced reactive oxygen species (ROS) generation, indicating that ROS might be upstream of the G2/M arrest signaling pathway. In summary, the results exhibited the whole proteomic response of HepG2 cells to NB/Cur, which might lead to a better understanding of its underlying anticancer mechanisms. PMID- 26051008 TI - Reducing the risk of heart disease among Indian Australians: knowledge, attitudes, and beliefs regarding food practices - a focus group study. AB - BACKGROUND: Australia has a growing number of Asian Indian immigrants. Unfortunately, this population has an increased risk for coronary heart disease (CHD). Dietary adherence is an important strategy in reducing risk for CHD. This study aimed to gain greater understanding of the knowledge, attitudes and beliefs relating to food practices in Asian Indian Australians. METHODS: Two focus groups with six participants in each were recruited using a convenience sampling technique. Verbatim transcriptions were made and thematic content analysis undertaken. RESULTS: Four main themes that emerged from the data included: migration as a pervasive factor for diet and health; importance of food in maintaining the social fabric; knowledge and understanding of health and diet; and elements of effective interventions. DISCUSSION: Diet is a complex constructed factor in how people express themselves individually, in families and communities. There are many interconnected factors influencing diet choice that goes beyond culture and religion to include migration and acculturation. CONCLUSIONS: Food and associated behaviors are an important aspect of the social fabric. Entrenched and inherent knowledge, attitudes, beliefs and traditions frame individuals' point of reference around food and recommendations for an optimal diet. PMID- 26051009 TI - Comparative effectiveness of Mitraclip plus medical therapy versus medical therapy alone in high-risk surgical patients: a comprehensive review. AB - In recent years, Mitraclip has become available as a treatment option for mitral regurgitation in high-risk surgical patients. Focusing on the incremental effectiveness of Mitraclip versus the current standard of care, this article provides a comparative review of the evidence on Mitraclip and standard medical therapy (MT) in high-risk mitral regurgitation patients. Evidence was retrieved from seven major databases. Results suggest that Mitraclip presents a high safety profile and a good middle-term effectiveness performance. Evidence on long-term effectiveness is limited both for Mitraclip and MT. Few studies allow a comparison with MT and comparative results on different endpoints are mixed. Therefore, the available evidence does not conclusively inform whether or under which circumstances Mitraclip should be preferred over MT in the treatment of high-risk patients. Head-to-head real-world studies would be needed, as they would provide great and timely insights to support policy decisions when medical devices are at stake. PMID- 26051010 TI - Lithium ion diffusion measurements on a garnet-type solid conductor Li6.6La3Zr1.6Ta0.4O12 by using a pulsed-gradient spin-echo NMR method. AB - The garnet-type solid conductor Li7-xLa3Zr2-xTaxO12 is known to have high ionic conductivity. We synthesized a series of compositions of this conductor and found that cubic Li6.6La3Zr1.6Ta0.4O12 (LLZO-Ta) has a high ionic conductivity of 3.7*10(-4)Scm(-1) at room temperature. The (7)Li NMR spectrum of LLZO-Ta was composed of narrow and broad components, and the linewidth of the narrow component varied from 0.69kHz (300K) to 0.32kHz (400K). We carried out lithium ion diffusion measurements using pulsed-field spin-echo (PGSE) NMR spectroscopy and found that echo signals were observed at T>=313K with reasonable sensitivity. The lithium diffusion behavior was measured by varying the observation time and pulsed-field gradient (PFG) strength between 313 and 384K. We found that lithium diffusion depended significantly on the observation time and strength of the PFG, which is quite different from lithium ion diffusion in liquids. It was shown that lithium ion migration in the solid conductor was distributed widely in both time and space. PMID- 26051011 TI - Online electrochemical systems for continuous neurochemical measurements with low potential mediator-based electrochemical biosensors as selective detectors. AB - This study demonstrates a new strategy to develop online electrochemical systems (OECSs) for continuously monitoring neurochemicals by efficiently integrating in vivo microdialysis with an oxidase-based electrochemical biosensor with low potential electron mediators to shuttle the electron transfer of the oxidases. By using thionine and xanthine oxidase (XOD) as examples of low-potential mediators and oxidases, respectively, we demonstrate that the use of low-potential mediators to shuttle the electron transfer of oxidases would offer a new approach to the development of oxidase-based biosensors with theoretical and technical simplicity. To construct the XOD-based biosensor, thionine was adsorbed onto carbon nanotubes and used to shuttle the electron transfer of XOD. The XOD-based biosensor was positioned into an electrochemical cell that was directly coupled with in vivo microdialysis to form an online electrochemical system (OECS) for continuous and selective measurements of the substrate of XOD (with hypoxanthine as an example). The OECS based on the low-potential mediators is highly selective against the species endogenously existing in the brain system, which is attributed to the low operation potential benefited from the low redox potentials of the mediators. Moreover, the OECS demonstrated here is stable and reproducible and could thus be envisaged to find some interesting applications in physiological and pathological investigations. This study essentially offers a new strategy to develop online electrochemical systems, which is of great importance in understanding the molecular basis of physiological and pathological events. PMID- 26051013 TI - Extending the chemistry of carbones: P-N bond cleavage via an S(N)2'-like mechanism. AB - The reactivity of nucleophilic carbodiphosphorane (C(PPh3)2, 1) and carbodicarbene (C(C(NMe)2C6H4)2, 2) towards various dichlorophosphines has been explored. In most cases the expected carbone-for-chloride ligand exchange was observed. However, the use of MeN(PCl2)2 resulted in a unique P-N bond cleavage that, according to computational studies, occurred via an SN2'-like mechanism. PMID- 26051012 TI - Heart Failure in Non-Caucasians, Women, and Older Adults: A White Paper on Special Populations From the Heart Failure Society of America Guideline Committee. AB - The presentation, natural history, clinical outcomes, and response to therapy in patients with heart failure differ in some ways across populations. Women, older adults, and non-Caucasian racial or ethnic groups compose a substantial proportion of the overall heart failure population, but they have typically been underrepresented in clinical trials. As a result, uncertainty exists about the efficacy of some guideline-directed medical therapies and devices in specific populations, which may result in the under- or overtreatment of these patients. Even when guideline-based treatments are prescribed, socioeconomic, physical, or psychologic factors may affect non-Caucasian and older adult patient groups to a different extent and affect the application, effectiveness, and tolerability of these therapies. Individualized therapy based on tailored biology (genetics, proteomics, metabolomics), socioeconomic and cultural considerations, and individual goals and preferences may be the optimal approach for managing diverse patients. This comprehensive approach to personalized medicine is evolving, but in the interim, the scientific community should continue efforts focused on intensifying research in special populations, prescribing guideline-directed medical therapy unless contraindicated, and implementing evidence-based strategies including patient and family education and multidisciplinary team care in the management of patients. PMID- 26051014 TI - How do divergent ecological strategies emerge among marine bacterioplankton lineages? AB - Heterotrophic bacteria in pelagic marine environments are frequently categorized into two canonical ecological groups: patch-associated and free-living. This framework provides a conceptual basis for understanding bacterial utilization of oceanic organic matter. Some patch-associated bacteria are ecologically linked with eukaryotic phytoplankton, and this observation fits with predicted coincidence of their genome expansion with marine phytoplankton diversification. By contrast, free-living bacteria in today's oceans typically live singly with streamlined metabolic and regulatory functions that allow them to grow in nutrient-poor seawater. Recent analyses of marine Alphaproteobacteria suggest that some free-living bacterioplankton lineages evolved from patch-associated ancestors up to several hundred million years ago. While evolutionary analyses agree with the hypothesis that natural selection has maintained these distinct ecological strategies and genomic traits in present-day populations, they do not rule out a major role for genetic drift in driving ancient ecological switches. These two evolutionary forces may have acted on ocean bacteria at different geological time scales and under different geochemical constraints, with possible implications for future adaptations to a changing ocean. New evolutionary models and genomic data are leading to a more comprehensive understanding of marine bacterioplankton evolutionary history. PMID- 26051015 TI - Predicting delirium: a review of risk-stratification models. AB - BACKGROUND: Delirium is a common condition in hospitalized patients and is associated with multiple adverse outcomes. There is increasing evidence to support interventions that prevent delirium, so the identification of patients at high risk is of significant clinical value. Numerous risk factors have been identified, including both premorbid patient characteristics and acute precipitants. Despite this, predicting the occurrence of delirium remains a clinical challenge. OBJECTIVE: This article reviews studies of validated risk stratification models for delirium. We discuss possible barriers to use of these models and future directions for research. METHODS: A comprehensive review of the literature was completed using PubMed and Embase. The resulting citations were filtered in a structured process. Inclusion criteria were original research, adult medical inpatient population and presence of a validation group in the study design. RESULTS: Ten cohort studies met inclusion criteria. The quality of the studies was moderate to good. All studies proposed models using clinical data to predict the risk of patients' developing delirium. CONCLUSION: The most common risk factors identified were preexisting cognitive impairment, medical comorbidity, elevated Blood Urea Nitrogen, and impairment in activities of daily living. While multiple validated predictive models exist, there is substantial heterogeneity between models, and only one replication study has been performed. In addition, difficulties in implementation may be a barrier to broader use of these models. There is limited support for an accurate and reliable tool to predict inpatient delirium. Further research is needed in this clinically important area. PMID- 26051016 TI - [Access to public health research data: efficiency and reproducibility versus confidentiality]. PMID- 26051017 TI - [Frequent users of hospital emergency departments]. PMID- 26051018 TI - [Secondary school menu in Madrid (Spain): knowledge and adherence to the Spanish National Health System recommendations]. AB - OBJECTIVE: To establish the degree of knowledge and adherence to the Spanish National Health System recommendations on nutrition in schools in the Autonomous Community of Madrid. METHODS: Cross-sectional study of a random sample of 182 secondary schools from Madrid, during 2013-2014 school year. Information on the characteristics of the schools and the knowledge of the recommendations was collected by internet and telephone interviews, as well as a copy of the school menu. The average number of rations per week offered for each food item and the percentage of schools within the recommended range were calculated. The overall adherence was obtained as the mean of food items (0-12) within the range. RESULTS: 65.5% of the schools were unaware of the national recommendations. The supply of rice, pasta, fish, eggs, salad and fruit was lower than recommended, whereas for meat, accompaniment and other desserts was higher. The percentage of schools within the range for each food item varied between 13% and 95%. The mean of overall adherence was 6.3, with no differences depending on whether the menu was prepared or not at schools or there was or not a person in charge of nutrition standards. CONCLUSIONS: The degree of adherence to the recommendations was variable, being advised to increase the supply of cereals, eggs, fish, salad and fruit. Programs for dissemination and implementation of the recommendations, leaded by trained professionals, are required to improve the nutritional value of school menu. PMID- 26051019 TI - A method for measuring disease-specific iduronic acid from the non-reducing end of glycosaminoglycan in mucopolysaccharidosis type II mice. AB - Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder arising from deficiency of iduronate-2-sulfatase (IDS), which results in progressive accumulation of glycosaminoglycans (GAGs) in multiple tissues. Accumulated GAGs are generally measured as the amount of total GAGs. However, we recently demonstrated that GAG accumulation in the brain of MPS II model mice cannot be reliably detected by conventional dye-binding assay measuring total GAGs. Here we developed a novel quantitative method for measurement of disease specific GAGs based on the analysis of 2-sulfoiduronic acid levels derived from the non-reducing terminal end of the polysaccharides by using recombinant human IDS (rhIDS) and recombinant human iduronidase (rhIDUA). This method was evaluated on GAGs obtained from the liver and brain of MPS II mice. The GAGs were purified from tissue homogenates and then digested with rhIDS and rhIDUA to generate a desulfated iduronic acid from their non-reducing terminal end. HPLC analysis revealed that the generated iduronic acid levels were markedly increased in the liver and cerebrum of the MPS II mice, whereas the uronic acid was not detected in wild-type mice. These results indicate that this assay clearly detects the disease-specific GAGs in tissues from MPS II mice. PMID- 26051020 TI - Combining gas phase electron capture and IRMPD action spectroscopy to probe the electronic structure of a metastable reduced organometallic complex containing a non-innocent ligand. AB - Combining electron capture dissociation mass spectrometry and infrared multiple photon dissociation action spectroscopy allows the formation, selection and characterisation of reduced metal complexes containing non-innocent ligands. Zinc complexes containing diazafluorenone ligands have been studied and the localisation of the single electron on the metal atom in the mono-ligated complex has been demonstrated. PMID- 26051022 TI - Gender Differences in Service Utilization among OEF/OIF Veterans with Posttraumatic Stress Disorder after a Brief Cognitive-Behavioral Intervention to Increase Treatment Engagement: A Mixed Methods Study. AB - PURPOSE: Women veterans who served in Iraq and Afghanistan (Operation Enduring Freedom and Operation Iraqi Freedom [OEF/OIF]) have a moderately higher risk of developing posttraumatic stress disorder (PTSD) than male veterans. However, gender disparities in treatment engagement may prevent women veterans from initiating the care they need. Understanding gender differences in predictors of and barriers to treatment is essential to improving engagement and mental health outcomes. The purpose of this study was to examine gender differences in treatment utilization after a brief, cognitive-behavioral therapy (CBT) intervention among male and female OEF/OIF veterans. METHODS: Participants were assigned randomly to either the intervention or control conditions. Intervention participants received the telephone-based CBT intervention. Participants were 35 female and 238 male OEF/OIF veterans who screened positive for PTSD and had never initiated PTSD treatment. Participants were asked about treatment utilization, beliefs about PTSD treatment, and symptoms at months 1, 3, and 6 months subsequent to the baseline telephone assessment. The PTSD Checklist-Military Version was used to assess PTSD and the Patient's Health Questionnaire was used to assess symptoms of depression. FINDINGS: Female veterans who received an intervention were significantly more likely to have attended treatment over the 6 month follow-up period than male veterans who received an intervention (chi(2) = 7.91; df = 3; odds ratio, 3.93; p = .04). CONCLUSIONS: The CBT intervention may be a critical mechanism to engage female veterans in treatment. Further research is needed to understand how to engage male veterans with PTSD in treatment. PMID- 26051023 TI - The Signature of the Five-Stranded vRRM Fold Defined by Functional, Structural and Computational Analysis of the hnRNP L Protein. AB - The RNA recognition motif (RRM) is the far most abundant RNA binding domain. In addition to the typical beta1alpha1beta2beta3alpha2beta4 fold, various sub structural elements have been described and reportedly contribute to the high functional versatility of RRMs. The heterogeneous nuclear ribonucleoprotein L (hnRNP L) is a highly abundant protein of 64 kDa comprising four RRM domains. Involved in many aspects of RNA metabolism, hnRNP L specifically binds to RNAs containing CA repeats or CA-rich clusters. However, a comprehensive structural description of hnRNP L including its sub-structural elements is missing. Here, we present the structural characterization of the RRM domains of hnRNP L and demonstrate their function in repressing exon 4 of SLC2A2. By comparison of the sub-structural elements between the two highly similar paralog families of hnRNP L and PTB, we defined signatures underlying interacting C-terminal coils (ICCs), the RRM34 domain interaction and RRMs with a C-terminal fifth beta-strand, a variation we denoted vRRMs. Furthermore, computational analysis revealed new putative ICC-containing RRM families and allowed us to propose an evolutionary scenario explaining the origins of the ICC and fifth beta-strand sub-structural extensions. Our studies provide insights of domain requirements in alternative splicing mediated by hnRNP L and molecular descriptions for the sub-structural elements. In addition, the analysis presented may help to classify other abundant RRM extensions and to predict structure-function relationships. PMID- 26051021 TI - Long-Term Worries after Colposcopy: Which Women Are at Increased Risk? AB - BACKGROUND: A colposcopy examination is the main management option for women with an abnormal cervical screening test result. Although some women experience adverse psychological effects after colposcopy, those at greatest risk are unknown. We investigated predictors of worries about cervical cancer, sex, future fertility and general health during 12 to 30 months after colposcopy. METHODS: We invited 1,515 women, aged 20 to 59 years with low-grade cervical cytology who attended colposcopy to complete questionnaires at recruitment (~8 weeks after cytology result) and after 12, 18, 24, and 30 months of follow up. Outcomes were worries about having cervical cancer, having sex, future fertility, and general health at any time during follow-up. Factors significantly associated with each outcome were identified using multiple logistic regression. RESULTS: At one or more time points during follow-up, 40% of women reported worries about having cervical cancer, 26% about having sex, 24% about future fertility, and 60% about general health. For all outcomes except sex, worries reported at recruitment were associated with significantly increased risk of worries during follow-up. Significant anxiety at recruitment was associated with all worries during follow up. Women diagnosed with CIN2+ had significantly higher risks of worries about cervical cancer and future fertility. Management received was associated significantly with worries about cervical cancer and having sex. Younger women significantly more often reported worries about future fertility, whereas women who had children had reduced risk of future fertility worries but increased risk of cervical cancer worries. CONCLUSION: Clinical, sociodemographic, lifestyle, and psychological factors predicted risk of reporting worries after colposcopy. PMID- 26051024 TI - Understanding peptide biology: The discovery and characterization of the novel hormone, neuronostatin. AB - The Human Genome Project provided the opportunity to use bioinformatic approaches to discover novel, endogenous hormones. Using this approach we have identified two novel peptide hormones and review here our strategy for the identification and characterization of the hormone, neuronostatin. We describe in this mini review our strategy for determining neuronostatin's actions in brain, heart and pancreas. More importantly, we detail our deductive reasoning strategy for the identification of a neuronostatin receptor and our progress in establishing the physiological relevance of the peptide. PMID- 26051025 TI - Chronic mild stress and imipramine treatment elicit opposite changes in behavior and in gene expression in the mouse prefrontal cortex. AB - Many studies suggest that the prefrontal cortex (PFC) is a target limbic region for stress response because a dysfunction here is linked to anhedonia, a decrease in reactivity to rewards, and to anxiety. It is suggested that stress-induced persistent molecular changes in this brain region could bring some light on the mechanisms perpetuating depressive episodes. In order to address this issue, here we have studied the long-term PFC gene expression pattern and behavioral effects induced by a chronic mild stress (CMS) model and antidepressant treatment in mice. CMS was applied to mice for six weeks and imipramine (10mg/kg, i.p.) or saline treatment was administered for five weeks starting from the third week of CMS. Mice were sacrificed one month after CMS and following two weeks after the discontinuation of drug treatment and the PFC was dissected and prepared for gene (mRNA) and protein expression studies. Using the same experimental design, a separate group of mice was tested for anhedonia, recognition memory, social interaction and anxiety. CMS induced a long-term altered gene expression profile in the PFC that was partially reverted by imipramine. Specifically, the circadian rhythm signaling pathway and functions such as gene expression, cell proliferation, survival and apoptosis as well as neurological and psychiatric disorders were affected. Of these, some changes of the circadian rhythm pathway (Hdac5, Per1, and Per2) were validated by RT-PCR and western-blot. Moreover, CMS induced long-lasting anhedonia that was reverted by imipramine treatment. Impaired memory, decreased social interaction and anxiety behavior were also induced by chronic stress. We have identified in the PFC molecular targets oppositely regulated by CMS and imipramine that could be relevant for chronic depression and antidepressant action. Among these, a possible candidate for further investigation could be the circadian rhythm pathway. PMID- 26051026 TI - Rapamycin suppresses PTZ-induced seizures at different developmental stages of zebrafish. AB - The mTORC1 complex integrates different inputs from intracellular and extracellular signals to control various cellular processes. Therefore, any disruption in the mTORC1 pathway could promote different neurological disorders. mTORC1 overactivation has been verified in different genetic and acquired epilepsy animal models. Therefore, inhibitors of this complex could have both antiepileptogenic and antiseizure effects. In our study, we investigated the effects of rapamycin pretreatment on pentylenetetrazole (PTZ)-induced seizures in zebrafish. Our results have shown that the latency to reach the tonic-clonic stage (stage III) of progressive behavioral alterations shown during PTZ-induced seizures was prolonged in larval (7days post fertilization, 7dpf), juvenile (45days post fertilization, 45dpf) and adult (6-8months) zebrafish after pretreatment with rapamycin. Furthermore, rapamycin pretreatment did not alter the locomotor activity in zebrafish. Therefore, the results obtained in our study indicate that rapamycin pretreatment is an important mechanism to control the progress of seizures in zebrafish throughout different developmental stages (larval, juvenile, and adult). Taken as a whole, our data support that rapamycin has immediate antiseizure effects and could be a potential alternative therapy for seizure control in epilepsy. PMID- 26051028 TI - Ultrasonic temperature distribution reconstruction for circular area based on Markov radial basis approximation and singular value decomposition. AB - Temperature distribution reconstruction is of critical importance for circular area, and an ultrasonic technique is investigated to meet this demand in this paper. Considering the particularity of circular area, algorithm based on Markov radial basis approximation and singular value decomposition is proposed, while ultrasonic transducers layout and division of measured area are properly designed. The reconstruction performance is validated via numerical experiments using different temperature distribution models, and is compared with algorithm based on least square method. To study the anti-interference, various noises are adding to the theoretical value of time-of-flight. Experiment results indicate that the proposed algorithm can reconstruct temperature distribution with higher accuracy and stronger anti-interference, while without the problem of algorithm based on least square method that its reconstructions will lose much temperature information near the edge of measured area. PMID- 26051027 TI - Latent Class Analysis of DSM-5 Alcohol Use Disorder Criteria Among Heavy-Drinking College Students. AB - The DSM-5 has created significant changes in the definition of alcohol use disorders (AUDs). Limited work has considered the impact of these changes in specific populations, such as heavy-drinking college students. Latent class analysis (LCA) is a person-centered approach that divides a population into mutually exclusive and exhaustive latent classes, based on observable indicator variables. The present research was designed to examine whether there were distinct classes of heavy-drinking college students who met DSM-5 criteria for an AUD and whether gender, perceived social norms, use of protective behavioral strategies (PBS), drinking refusal self-efficacy (DRSE), self-perceptions of drinking identity, psychological distress, and membership in a fraternity/sorority would be associated with class membership. Three-hundred and ninety-four college students who met DSM-5 criteria for an AUD were recruited from three different universities. Two distinct classes emerged: Less Severe (86%), the majority of whom endorsed both drinking more than intended and tolerance, as well as met criteria for a mild AUD; and More Severe (14%), the majority of whom endorsed at least half of the DSM-5 AUD criteria and met criteria for a severe AUD. Relative to the Less Severe class, membership in the More Severe class was negatively associated with DRSE and positively associated with self-identification as a drinker. There is a distinct class of heavy drinking college students with a more severe AUD and for whom intervention content needs to be more focused and tailored. Clinical implications are discussed. PMID- 26051029 TI - Microspherical hydrogel particles based on silica nanoparticle-webbed polymer networks. AB - Spherical hybrid hydrogel microparticles were facilely fabricated by particulation of an aqueous mixture of hydrophilic copolymer with alkoxysilyl side chains and silica nanoparticles in water/silicone oil suspensions. Inside the aqueous phase, the copolymers were webbed with silica nanoparticles to form polymer network through the silane coupling reactions between reactive side chains of copolymer with the silanol groups on silica nanoparticles. An amino functionalized silane coupling reagent was used to terminate remaining reactive sites at the surface of the hydrogel particles to avoid aggregation. The size of the spherical hydrogel particles was well controlled by the viscosity of the silicone oil, whereas their properties were controlled by composition. The mechanical strength of the microspherical hybrid hydrogel was increased significantly with increasing the concentration of silica nanoparticles. PMID- 26051030 TI - A 'build-bottle-around-ship' method to encapsulate ammonium molybdophosphate in zeolite Y. An efficient adsorbent for cesium. AB - The faujasite-Y confined ammonium molybdophosphate (AMP-Y) were successfully synthesized for the first time using ammonium molybdophosphate and natural clay from Qaidam Basin as starting materials. The final products were characterized by XRF, XRD, FTIR, (27)Al and (31)P MAS NMR, and N2 adsorption/desorption, which indicated that Qaidam natural clay is a promising low-cost precursor for the production of zeolite Y support. Various loadings of ammonium molybdophosphate could be well encapsulated in the supercage of Y zeolite using a 'build-bottle around-ship' method. The resultant composite materials were effective for the adsorption of cesium ion from solution. PMID- 26051031 TI - General electrokinetic model for concentrated suspensions in aqueous electrolyte solutions: Electrophoretic mobility and electrical conductivity in static electric fields. AB - In recent years different electrokinetic cell models for concentrated colloidal suspensions in aqueous electrolyte solutions have been developed. They share some of its premises with the standard electrokinetic model for dilute colloidal suspensions, in particular, neglecting both the specific role of the so-called added counterions (i.e., those released by the particles to the solution as they get charged), and the realistic chemistry of the aqueous solution on such electrokinetic phenomena as electrophoresis and electrical conductivity. These assumptions, while having been accepted for dilute conditions (volume fractions of solids well below 1%, say), are now questioned when dealing with concentrated suspensions. In this work, we present a general electrokinetic cell model for such kind of systems, including the mentioned effects, and we also carry out a comparative study with the standard treatment (the standard solution only contains the ions that one purposely adds, without ionic contributions from particle charging or water chemistry). We also consider an intermediate model that neglects the realistic aqueous chemistry of the solution but accounts for the correct contribution of the added counterions. The results show the limits of applicability of the classical assumptions and allow one to better understand the relative role of the added counterions and ions stemming from the electrolyte in a realistic aqueous solution, on electrokinetic properties. For example, at low salt concentrations the realistic effects of the aqueous solution are the dominant ones, while as salt concentration is increased, it is this that progressively takes the control of the electrokinetic response for low to moderate volume fractions. As expected, if the solids concentration is high enough the added counterions will play the dominant role (more important the higher the particle surface charge), no matter the salt concentration if it is not too high. We hope this work can help in setting up the real limits of applicability of the standard cell model for concentrated suspensions by a quantitative analysis of the different effects that have been classically disregarded, showing that in many cases they can be determinant to get rigorous predictions. PMID- 26051032 TI - Edema and Cirrhosis Caused by Wilson's Disease. PMID- 26051033 TI - Ketogenic Diet as a Therapeutic Option in Super-refractory Status Epilepticus. PMID- 26051034 TI - Insights into C4 metabolism from comparative deep sequencing. AB - C4 photosynthesis suppresses the oxygenation activity of Ribulose Bisphosphate Carboxylase Oxygenase and so limits photorespiration. Although highly complex, it is estimated to have evolved in 66 plant lineages, with the vast majority lacking sequenced genomes. Transcriptomics has recently initiated assessments of the degree to which transcript abundance differs between C3 and C4 leaves, identified novel components of C4 metabolism, and also led to mathematical models explaining the repeated evolution of this complex phenotype. Evidence is accumulating that this complex and convergent phenotype is partly underpinned by parallel evolution of structural genes, but also regulatory elements in both cis and trans. Furthermore, it appears that initial events associated with acquisition of C4 traits likely represent evolutionary exaptations related to non-photosynthetic processes. PMID- 26051035 TI - Leaf oil bodies are subcellular factories producing antifungal oxylipins. AB - Oil bodies act as lipid storage compartments in plant cells. In seeds they supply energy for germination and early seedling growth. Oil bodies are also present in the leaves of many vascular plants, but their function in leaves has been poorly understood. Recent studies with oil bodies from senescent Arabidopsis thaliana leaves identified two enzymes, peroxygenase (CLO3) and alpha-dioxygenase (alpha DOX), which together catalyze a coupling reaction to produce an antifungal compound (2-hydroxy-octadecanoic acid) from alpha-linolenic acid. Leaf oil bodies also have other enzymes including lipoxygenases, phospholipases, and triacylglycerol lipases. Hence, leaf oil bodies might function as intracellular factories to efficiently produce stable compounds via unstable intermediates by concentrating the enzymes and hydrophobic substrates. PMID- 26051036 TI - Engineering of plant cell walls for enhanced biofuel production. AB - The biomass of plants consists predominately of cell walls, a sophisticated composite material composed of various polymer networks including numerous polysaccharides and the polyphenol lignin. In order to utilize this renewable, highly abundant resource for the production of commodity chemicals such as biofuels, major hurdles have to be surpassed to reach economical viability. Recently, major advances in the basic understanding of the synthesis of the various wall polymers and its regulation has enabled strategies to alter the qualitative composition of wall materials. Such emerging strategies include a reduction/alteration of the lignin network to enhance polysaccharide accessibility, reduction of polymer derived processing inhibitors, and increases in polysaccharides with a high hexose/pentose ratio. PMID- 26051038 TI - Dynamic of Posidonia oceanica seagrass meadows in the northwestern Mediterranean: Could climate change be to blame? AB - The distribution and the vitality of the P. oceanica meadow were monitored in the western Mediterranean at 15 sites along the coasts of Corsica (1000 km of coastline) using two monitoring systems, the Posidonia Monitoring Network and SeagrassNet, between 2004 and 2013. While the vitality of the meadow is satisfactory overall, due to the low impact of human pressure along these coasts, patterns of change over time show a slight degradation of the main descriptors of the meadow. The meadow's vitality index had declined on average by 8.6%, the BiPo index by 9.8%, and there was a regression of the lower limit at six sites. While this pattern of change may reflect local alterations in the environment (increase or decline in human pressure), the regressive dynamic of the meadow observed at the lower limit at several reference sites (e.g., Marine Protected Areas, sites distant from sources of human impact) is more worrying. Two hypotheses might explain the regression observed: (i) the rise in mean sea level during the study period, which may have resulted in a significant regression in sectors where the slope is relatively slight, and (ii) the North Atlantic Oscillation (NAO), which declined from 2002 to reach very low values in 2010. PMID- 26051039 TI - The value of male height in the marriage market. AB - Analyzing the Indonesian Family Life Survey 2007, this paper estimates the value of relative height (relative to the spouse's height) in the marriage market of a developing country. The results indicate that the value of a 1cm reduction in the husband's height relative to his wife's height is about 3% of his earnings. 3% of the mean of yearly earnings amounts to Rp. 492,000 or US$54 in 2007. That value is reduced to 1% when earnings-generating attributes are controlled for. This difference of 2% points can be considered the value that women attach to their husbands' earnings-generating attributes; meanwhile, the remaining 1% suggests that there are still other attributes that women look for in male height. PMID- 26051037 TI - The gut microbiota and Type 1 Diabetes. AB - Type 1 Diabetes (T1D) is a multifactorial, immune-mediated disease, which is characterized by the progressive destruction of autologous insulin-producing beta cells in the pancreas. The risk of developing T1D is determined by genetic, epigenetic and environmental factors. In the past few decades there has been a continuous rise in the incidence of T1D, which cannot be explained by genetic factors alone. Changes in our lifestyle that include diet, hygiene, and antibiotic usage have already been suggested to be causal factors for this rising T1D incidence. Only recently have microbiota, which are affected by all these factors, been recognized as key environmental factors affecting T1D development. In this review we will summarize current knowledge on the impact of gut microbiota on T1D development and give an outlook on the potential to design new microbiota-based therapies in the prevention and treatment of T1D. PMID- 26051040 TI - Nanostructure of the Ionic Liquid-Graphite Stern Layer. AB - Ionic liquids (ILs) are attractive solvents for devices such as lithium ion batteries and capacitors, but their uptake is limited, partially because their Stern layer nanostructure is poorly understood compared to molecular solvents. Here, in situ amplitude-modulated atomic force microscopy has been used to reveal the Stern layer nanostructure of the 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide (EMIm TFSI)-HOPG (highly ordered pyrolytic graphite) interface with molecular resolution. The effect of applied surface potential and added 0.1 wt/wt % Li TFSI or EMIm Cl on ion arrangements is probed between +/-1 V. For pure EMIm TFSI at open-circuit potential, well-defined rows are present on the surface formed by an anion-cation-cation-anion (A-C-C-A) unit cell adsorbed with like ions adjacent. As the surface potential is changed, the relative concentrations of cations and anions in the Stern layer respond, and markedly different lateral ion arrangements ensue. The changes in Stern layer structure at positive and negative potentials are not symmetrical due to the different surface affinities and packing constraints of cations and anions. For potentials outside +/-0.4 V, images are featureless because the compositional variation within the layer is too small for the AFM tip to detect. This suggests that the Stern layer is highly enriched in either cations or anions (depending on the potential) oriented upright to the surface plane. When Li(+) or Cl(-) is present, some Stern layer ionic liquid cations or anions (respectively) are displaced, producing starkly different structures. The Stern layer structures elucidated here significantly enhance our understanding of the ionic liquid electrical double layer. PMID- 26051041 TI - Novel SNPs in the Ankyrin 1 gene and their association with beef quality traits. AB - Single nucleotide polymorphisms (SNPs) in the promoter region of bovine Ankyrin 1 (ANK1) have been associated with tenderness and intramuscular fat level in beef. The objectives of this study were to characterise novel DNA variants in the coding region of bovine ANK1 and test for association with beef quality traits. A 3kb region of ANK1 cDNA was amplified and sequenced in 32 Charolais cattle using five sets of overlapping primers. Eighteen SNPs were identified and a predicted exon was confirmed. An in silico translation indicated that SNP4 and SNP16 were non-conservative. Three SNPs were genotyped in 158 crossbred cattle (n=158) with associated meat quality data. SNP6 was associated with texture scores while SNP17 was associated with juiciness. Haplotype (cHAP) 1 was associated with lightness, redness, ultimate pH, as well as sarcomere length. Alleles of the ANK1 gene could be potential targets for gene-assisted selection to improve a range of meat quality traits in beef. PMID- 26051042 TI - Evolution of extreme stomach pH in bilateria inferred from gastric alkalization mechanisms in basal deuterostomes. AB - The stomachs of most vertebrates operate at an acidic pH of 2 generated by the gastric H(+)/K(+)-ATPase located in parietal cells. The acidic pH in stomachs of vertebrates is believed to aid digestion and to protect against environmental pathogens. Little attention has been placed on whether acidic gastric pH regulation is a vertebrate character or a deuterostome ancestral trait. Here, we report alkaline conditions up to pH 10.5 in the larval digestive systems of ambulacraria (echinoderm + hemichordate), the closest relative of the chordate. Microelectrode measurements in combination with specific inhibitors for acid-base transporters and ion pumps demonstrated that the gastric alkalization machinery in sea urchin larvae is mainly based on direct H(+) secretion from the stomach lumen and involves a conserved set of ion pumps and transporters. Hemichordate larvae additionally utilized HCO3(-) transport pathways to generate even more alkaline digestive conditions. Molecular analyses in combination with acidification experiments supported these findings and identified genes coding for ion pumps energizing gastric alkalization. Given that insect larval guts were also reported to be alkaline, our discovery raises the hypothesis that the bilaterian ancestor utilized alkaline digestive system while the vertebrate lineage has evolved a strategy to strongly acidify their stomachs. PMID- 26051043 TI - Graphene allotropes under extreme uniaxial strain: an ab initio theoretical study. AB - Using density functional theory calculations, we study the response of three representative graphene allotropes (two pentaheptites and octagraphene) as well as graphene, to uniaxial strain up to their fracture limit. Those allotropes can be seen as distorted graphene structures formed upon periodically arranged Stone Walles transformations. We calculate their mechanical properties (Young's modulus, Poisson's ratio, speed of sound, ultimate tensile strength and the corresponding strain), and we describe the pathways of their fracture. Finally, we study strain as a factor for the conversion of graphene into those allotropes upon Stone-Walles transformations. For specific sets of Stone-Walles transformations leading to an allotrope, we determine the strain directions and the corresponding minimum strain value, for which the allotrope is more favorable energetically than graphene. We find that the minimum strain values which favor those conversions are of the order of 9-13%. Moreover, we find that the energy barriers for the Stone-Walles transformations decrease dramatically under strain, however, they remain prohibitive for structural transitions. Thus, strain alone cannot provide a synthetic route to these allotropes, but could be a part of composite procedures for this purpose. PMID- 26051044 TI - New forms of insulin and insulin therapies for the treatment of type 2 diabetes. AB - Insulin is a common treatment option for many patients with type 2 diabetes, and is generally used late in the natural history of the disease. Its injectable delivery mode, propensity for weight gain and hypoglycaemia, and the paucity of trials assessing the risk-to-safety ratio of early insulin use are major shortcomings associated with its use in patients with type 2 diabetes. Development of new insulins-such as insulin analogues, including long-acting and short-acting insulins-now provide alternative treatment options to human insulin. These novel insulin formulations and innovative insulin delivery methods, such as oral or inhaled insulin, have been developed with the aim to reduce insulin associated hypoglycaemia, lower intraindividual pharmacokinetic and pharmacodynamic variability, and improve imitation of physiological insulin release. Availability of newer glucose-lowering drugs (such as glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and sodium glucose co-transporter-2 inhibitors) also offers the opportunity for combination treatment; the results of the first trials in this area of research suggest that such treatment might lead to use of reduced insulin doses, less weight gain, and fewer hypoglycaemic episodes than insulin treatment alone. These and future developments will hopefully offer better opportunities for individualisation of insulin treatment for patients with type 2 diabetes. PMID- 26051045 TI - Preface. Welcome to the topic of Congenital Lung Lesions in this issue. PMID- 26051046 TI - Lung development. AB - The development of the human lung starts at 4 weeks of gestation with the appearance of the tracheal outgrowth from the foregut and continues into early childhood. Survival at birth is dependent on adequate development and maturation of the lung in utero. Abnormal bronchopulmonary development results in congenital lung malformations, and inadequate development is thought to contribute to bronchopulmonary dysplasia. Complex processes and factors influencing lung development are beginning to be elucidated, and further knowledge will hopefully lead to improved interventions to enhance outcomes in vulnerable or affected infants. PMID- 26051047 TI - Congenital lung lesions: Prenatal diagnosis and intervention. AB - Congenital lung lesions are common sonographic findings in pregnancy, usually detected at the routine 20 weeks scan. The most common is cystic adenomatous malformation of the lung (CCAM). This usually causes few prenatal problems; however, fetal hydrops occurs in about 5%. Prenatal intervention for these is possible in many to allow survival to birth. Bronchoplumonary sequestration (BPS), with an aberrant "feeder" vessel arising from the aorta may co-exist but is detectable as a separate entity by visualization of this vessel. Symptomatic or curative prenatal intervention is again possible in the few severe cases where hydrops or pleural effusions develop. Pleural effusions may be due to a primary leak usually of chylous fluid: prenatal thoracoamniotic shunting may prevent pulmonary hyoplasia or cure the consequent fetal hydrops. More often, however, effusions are a consequence of an underlying abnormality, including many structural or chromosomal abnormalities that may also cause co-existing fetal hydrops. Congenital high airway obstruction (CHAOS) is commonly fatal but cases potentially amenable to prenatal intervention or to immediate perinatal management may be identified using ultrasound or MRI. PMID- 26051048 TI - Congenital lung lesions: Postnatal management and outcome. AB - Antenatal diagnosis of lung lesion has become more accurate resulting in dilemma and controversies of its antenatal and postnatal management. Majority of antenatally diagnosed congenital lung lesions are asymptomatic in the neonatal age group. Large lung lesions cause respiratory compromise and inevitably require urgent investigations and surgery. The congenital lung lesion presenting with hydrops requires careful postnatal management of lung hypoplasia and persistent pulmonary hypertension. Preoperative stabilization with gentle ventilation with permissive hypercapnia and delayed surgery similar to congenital diaphragmatic hernia management has been shown to result in good outcome. The diagnostic investigations and surgical management of the asymptomatic lung lesions remain controversial. Postnatal management and outcome of congenital cystic lung lesions are discussed. PMID- 26051049 TI - Imaging of congenital lung malformations. AB - Congenital lung malformations are a heterogeneous group of anomalies that involve the lungs and tracheobronchial tree (congenital airway pulmonary malformation, bronchial atresia, bronchogenic cyst, congenital lobar overinflation, pulmonary cyst, hamartoma, pulmonary isomerism and azygous lobe), vascular abnormalities (arteriovenous malformations, anomalous pulmonary venous return, pulmonary artery sling, interrupted pulmonary artery, pulmonary varix, pulmonary vein stenosis and pulmonary lymphangiectasia), or frequently both entities (pulmonary sequestration, pulmonary maldevelopment and scimitar syndrome). Advances in diagnostic imaging (including sonography, multi-detector computer tomography, magnetic resonance imaging and angiography) have increased their detection during both antenatal and postnatal periods, and radiological characterisation, which in turn influence patient counselling and management stratification. An educational illustration of the clinical application in characterisation of these malformations is presented. PMID- 26051050 TI - The pathology of congenital lung lesions. AB - The spectrum of complications associated with congenital lung malformation is wide. They can range from fetal hydrops in utero to postnatal problems of ventilation, obstruction and infection; presentation may occur from the neonatal period to adulthood. Many lesions will remain asymptomatic while at the other end of the complication spectrum, there is a small risk of neoplasia associated with some forms of cystic lung. A better understanding of the pathology has shown that bronchial atresia/obstruction is the likely hidden pathology underlying many congenital lung lesions leading to downstream cystic maldevelopment. Earlier diagnosis has led to increasing difficulties in ascribing malformations to conventional categories that were originally described in postnatal lungs. It is probably more important to be aware of the potential combination of vascular and airway connections and complications than to try and prescribe a classification of pulmonary lesions associated with rigid definitions. PMID- 26051051 TI - The argument for a non-operative approach to asymptomatic lung lesions. AB - The controversy surrounding the management of congenital lung malformations (CLMs) centre on how best to manage the increasing population of asymptomatic antenatally detected infants. Should elective surgery be offered? Or is a "watch and-wait" policy safe? This will be addressed in this review by examining the reported complications of surgery, the risk of symptom development if lesions are left in situ and whether this may alter surgical outcomes, and importantly whether there is any long-term risk of malignancy that can be negated by surgical resection in infancy. PMID- 26051052 TI - The argument for operative approach to asymptomatic lung lesions. AB - Antenatal detection of congenital pulmonary airway malformations (CPAM) has improved immeasurably from its initial application in the 1980s and probably encompasses >80% of all such lesions. Accurate diagnosis still remains less reliable and definitive diagnosis requires detailed anatomical imaging (typically with CT scan) in the post-natal period. About 10% of all lesions will present with symptoms during the neonatal period and the choice of surgical intervention is then easy. For those that remain asymptomatic then there is still a degree of controversy about elective surgical resection. This article presents the case for elective surgery within the first year of life and aims to quantify the risks of non-intervention such as abscess, empyema, recurrent pneumonia, air-leak, and pneumothorax and various types of malignancy in such cases. The current surgical approach now includes both open muscle-sparing thoracotomy and thoracoscopic resection. PMID- 26051053 TI - Adult lung tumours of childhood origin. AB - The remit of this article is principally to explore the risk of malignancy developing in a congenital cystic adenomatoid malformation (CCAM) in adulthood. PMID- 26051054 TI - Commentary: Fold (intertriginous) dermatoses: When skin touches skin. PMID- 26051055 TI - Acrodermatitis enteropathica and other nutritional diseases of the folds (intertriginous areas). AB - The appropriate intake and metabolism of vitamins and minerals are critical to maintaining homeostasis. Imbalance in essential nutrients, either through dietary excess or deficiency or disorders in metabolism, can result in a spectrum of dermatologic and systemic manifestations. Certain nutrient deficiencies produce a characteristic pattern of cutaneous eruption. Recognition of these patterns is important, as they can alert the physician to an underlying nutritional disease. We review nutritional diseases involving zinc, biotin, essential fatty acids, vitamin B6 (pyridoxine), and riboflavin that present specifically with intertriginous eruptions. PMID- 26051056 TI - Bacterial infections of the folds (intertriginous areas). AB - The axillary, inguinal, post-auricular, and inframammary areas are considered skin folds, where one skin layer touches another. Skin fold areas have a high moisture level and elevated temperature, both of which increase the possibility of microorganism overgrowth. A massive amount of bacteria live on the surface of the skin. Some are purely commensal; thus, only their overgrowth can cause infections, most of which are minor. In some cases, colonization of pathogenic bacteria causes more serious infections. This contribution reviews the bacterial infections of the skin fold areas. PMID- 26051057 TI - Viral infections of the folds (intertriginous areas). AB - Viruses are considered intracellular obligates with a nucleic acid, either RNA or DNA. They have the ability to encode proteins involved in viral replication and production of the protective coat within the host cells but require host cell ribosomes and mitochondria for translation. The members of the families Herpesviridae, Poxviridae, Papovaviridae, and Picornaviridae are the most commonly known agents for the cutaneous viral diseases, but other virus families, such as Adenoviridae, Togaviridae, Parvoviridae, Paramyxoviridae, Flaviviridae, and Hepadnaviridae, can also infect the skin. Though the cutaneous manifestations of viral infections are closely related to the type and the transmission route of the virus, viral skin diseases may occur in almost any part of the body. In addition to friction caused by skin-to-skin touch, skin folds are warm and moist areas of the skin that have limited air circulation. These features provide a fertile breeding ground for many kinds of microorganisms, including bacteria and fungi. In contrast to specific bacterial and fungal agents that have an affinity for the skin folds, except for viral diseases of the anogenital area, which have well-known presentations, viral skin infections that have a special affinity to the skin folds are not known. Many viral exanthems may affect the skin folds during the course of the infection, but here we focus only on the ones that usually affect the fold areas and also on the less well-known conditions or recently described associations. PMID- 26051058 TI - Fungal infections of the folds (intertriginous areas). AB - Superficial fungal infections are widespread, regardless of age and gender, in populations all around the world and may affect the skin and skin appendages. Although there are thousands of fungal infections from various genera and families in nature, those that are pathogenic for humans and nesting in skin folds are limited in number. The prevalence and distribution of these fungi vary according to the patients and certain environmental factors. Because the areas including the lids, external auditory canal, behind the ears, navel, inguinal region, and axillae, also called flexures, are underventilated and moist areas exposed to friction, they are especially sensitive to fungal infections. Fungi can both directly invade the skin, leading to infections, and indirectly stimulate immune mechanisms due to tissue interaction and their antigenic character and contribute to the development or exacerbation of secondary bacterial infections, seborrheic dermatitis, atopic dermatitis, and psoriasis. Superficial fungal infections can be classified and studied as dermatophyte infections, candidal infections, Malassezia infections, and other superficial infections independently from the involved skin fold areas. PMID- 26051059 TI - Darier disease: A fold (intertriginous) dermatosis. AB - Darier disease, also known as Darier-White disease, is characterized by yellow to brown, oily keratotic papules and plaques in the seborrheic areas of the face and chest. This disorder may show different clinical manifestations, such as palmoplantar pits and nail abnormalities. The trigger factors are mechanical trauma, heat, humidity, ultraviolet B, and pyogenic infections. The disease usually becomes apparent in the second decade of life. The ATP2 A2 (SERCA2) gene mutation was detected in all patients. Histopathologic changes include epidermal adhesion loss, acantholysis, abnormal keratinization, eosinophilic dyskeratotic cells in the spinous layer known as corps ronds, and the presence of grains in the stratum corneum. Although the treatment for Darier disease is unsatisfactory, some relief has been achieved with the use of corticosteroids and retinoids. PMID- 26051060 TI - Hailey-Hailey disease: A fold (intertriginous) dermatosis. AB - Hailey-Hailey disease, also called benign familial pemphigus, is a late-onset blistering disorder that affects the flexures. There are typically painful erosions and cracks in affected areas. Lesions generally begin between 20 and 40 years of age. In two third of all cases, positive family history is detected. In pathogenesis, there is a defect in keratinocyte adhesion due to ATP2 C1 gene mutation. The result of the desmosomal decomposition is acantholysis. Menstruation, pregnancy, skin infections, physical trauma, excessive sweating and exposure to ultraviolet radiation are important triggering factors. Histopathologic changes are suprabasal acantholysis and formation of intraepidermal bullae. In the epidermis, a partial acantholysis that looks like broken bricks is observed. PMID- 26051061 TI - Psoriasis inversa: A separate identity or a variant of psoriasis vulgaris? AB - Psoriasis is a chronic skin disorder affecting approximately 2% of the European and American population. The most common form of psoriasis is the chronic plaque type. Inverse psoriasis, also named flexural or intertriginous psoriasis, is not considered a separate disease entity but rather a special site of involvement of plaque psoriasis, characterized by its localization to inverse/intertriginous/flexural body sites. We review current evidence and establish whether inverse psoriasis is a separate disease entity based on characteristics in terms of epidemiology, pathogenesis, clinical and histologic presentation, microbiology, and treatment. PMID- 26051062 TI - Baboon syndrome and toxic erythema of chemotherapy: Fold (intertriginous) dermatoses. AB - Three decades ago, researchers described an eruption with a very characteristic distribution pattern that was confined to the buttocks and the intertriginous and flexor areas. They gave this reaction pattern one of the most unforgettable names in dermatology, baboon syndrome (BS), due to the characteristic, bright-red, well demarcated eruption predominantly on the buttocks and genital area, reminiscent of the red bottom of a baboon. The authors described three cases provoked by ampicillin, nickel, and mercury. They were convinced that BS represented a special form of hematogenous or systemic contact-type dermatitis, but several important papers that appeared during the past decade disagreed and suggested that BS should be distinguished from hematogenous or systemic contact-type dermatitis. A new acronym, SDRIFE (symmetrical drug-related intertriginous and flexoral exanthema), was proposed along with five diagnostic criteria: (1) exposure to a systemically administered drug at the time of first or repeated doses (contact allergens excluded), (2) sharply demarcated erythema of the gluteal/perianal area and/or V-shaped erythema of the inguinal/perigenital area, (3) involvement of at least one other intertriginous/flexural fold, (4) symmetry of affected areas, and (5) absence of systemic symptoms and signs. Although there are merits to the arguments in favor of SDRIFE, many of us still prefer to use the wittier name baboon syndrome, and even more authors use both terms. We confess that we find it difficult to relinquish the term BS, which has served us so well for years; however, recognition, familiarity, and knowledge of the characteristics of this form of drug eruption must supersede sentimental attachment to a certain nomenclature and so, however reluctantly, we must embrace change. Another intertriginous drug eruption is the one induced by chemotherapy. Toxic erythema of chemotherapy (TEC) is a useful clinical term that recently has been introduced to describe this group of chemotherapy-induced eruptions. This group of overlapping toxic reactions is characterized by areas of painful erythema often accompanied by edema usually involving the hands and feet, intertriginous zones (eg, axilla, groin), and, less often, the elbows, knees, and ears. Toxic erythema of chemotherapy is briefly discussed. PMID- 26051063 TI - Acanthosis nigricans: A fold (intertriginous) dermatosis. AB - Acanthosis nigricans (AN) is a mucocutaneous disorder that is characterized by focal or diffuse hyperkeratotic, surfaces, which are symmetrically distributed hyperpigmented lesions of the skin. It rarely affects mucosal surfaces like oral cavities. Although it is commonly seen in adolescents, AN is also increasingly seen in children who are obese. Recent studies have found that AN can be a cutaneous indicator of insulin resistance and malignancy. Acanthosis nigricans has been associated with type 2 diabetes mellitus, obesity, endocrinopathies, drugs, and malignancies. PMID- 26051064 TI - Pemphigus vegetans of the folds (intertriginous areas). AB - Pemphigus vegetans (P Veg), the rarest form of pemphigus, is thought to be a variant of pemphigus vulgaris (PV). Classically, two subtypes of P Veg are recognized: (1) Neumann P Veg, which usually begins as PV with vesicles and bullae that rupture to form hypertrophic granulating erosions, then evolving into vegetating exuding masses; (2) Hallopeau P Veg, initially characterized by pustular lesions that, after rupturing, merge and gradually evolve into vegetating erosions with a centrifugal expansion. The disease typically affects the big folds (axillary, inframammary, inguinocrural, intergluteal), where semiocclusion, maceration, and mixed infections continuously incite exudation and granulation tissue formation (wet P Veg). In nonintertriginous locations, the vegetating buttons can dry out to change into warty, fissured, painful, seborrheic keratosis-like lesions (dry P Veg). Histologic examination indicates hyperplastic epidermis with intramalpighian leukocyte microabscesses and indistinct traits of suprabasal acantholysis. Immunofluorescence findings are similar to those of PV. Diagnosis is straightforward when PV lesions coexist. Difficulties can arise in cases with nonflexural location. Cytology (Tzanck test), histology, immunofluorescence, and ELISA search for anti-desmoglein antibodies are the diagnostic laboratory tools. Systemic treatment is similar to that for PV, high-dose steroids being the first choice therapy. Immunosuppressive agents and etretinate may allow a steroid-sparing effect. Topical treatment is aimed at countering the granulation tissue formation by means of several strategies (sublesional steroid injection, application of medicated gauzes in the involved flexures, chemical cautery or surgical excision of vegetating lesions). PMID- 26051065 TI - Diaper (napkin) dermatitis: A fold (intertriginous) dermatosis. AB - Diaper (napkin) dermatitis is an acutely presenting inflammatory irritant contact dermatitis of the diaper region. It is one of the most common dermatologic diseases in infants and children. In the past, the disease was thought to be caused by ammonia; however, a number of factors, such as friction, wetness, inappropriate skin care, microorganisms, antibiotics, and nutritional defects, are important. Diaper dermatitis commonly affects the lower parts of the abdomen, thighs, and diaper area. Involvement of skin fold regions is typical with diaper dermatitis. At the early stages of the disease, only dryness is observed in the affected area. At later stages, erythematous maceration and edema can be seen. Secondary candidal and bacterial infections can complicate the dermatitis. In the differential diagnosis of the disease, allergic contact dermatitis, intertrigo, psoriasis, atopic and seborrheic dermatitis, and the other diseases should be considered. Causes of the disease should be determined and eliminated primarily. Families need to be informed about the importance of a clean, dry diaper area and the frequency of diaper changes. The use of superabsorbent disposable diapers has decreased the incidence of the disease. Soap and alcohol-containing products should be avoided in cleaning the area. In some cases, corticosteroids and antifungal agents can be administered. If necessary, antibacterial agents and calcineurin inhibitors can also be beneficial. PMID- 26051066 TI - Hyperhidrosis, bromhidrosis, and chromhidrosis: Fold (intertriginous) dermatoses. AB - Human sweat glands disorders are common and can have a significant impact on the quality of life and on professional, social, and emotional burdens. It is of paramount importance to diagnose and treat them properly to ensure optimal patient care. Hyperhidrosis is characterized by increased sweat secretion, which can be idiopathic or secondary to other systemic conditions. Numerous therapeutic options have been introduced with variable success. Novel methods with microwave based and ultrasound devices have been developed and are currently tested in comparison to the conventional approaches. All treatment options for hyperhidrosis require frequent monitoring by a dermatologist for evaluation of the therapeutic progress. Bromhidrosis and chromhidrosis are rare disorders but are still equally disabling as hyperhidrosis. Bromhidrosis occurs secondary to excessive secretion from either apocrine or eccrine glands that become malodorous on bacterial breakdown. The condition is further aggravated by poor hygiene or underlying disorders promoting bacterial overgrowth, including diabetes, intertrigo, erythrasma, and obesity. Chromhidrosis is a rare dermatologic disorder characterized by secretion of colored sweat with a predilection for the axillary area and the face. Treatment is challenging in that the condition usually recurs after discontinuation of therapy and persists until the age related regression of the sweat glands. PMID- 26051067 TI - The checklist: BEST medical center employment requirements 2015. AB - Dr. Ida Lystic, a newly minted gastroenterologist, has accepted a job at the Byron Edwards & Samuel Thompson (BEST) Medical Center. On her first day, after six months of preliminary paper work, she completes multiple checklists mandated by the center: dress code, employee health, and class checklists. Her open-toe pumps have been replaced by disposable paper booties and her polished fingernails have been covered with blue latex-free gloves. Nicotine screening (the use of which is prohibited not only while at work at the BEST Medical Center, but also while at home) was performed, and she had a mask fitting for tuberculosis. Her next two weeks were to be occupied with over 70 hours of required classes; however, after receiving a mandatory flu shot, she became sick and missed the first week of classes, and so her start date for seeing patients is delayed by two months. Although she was hired because she received the outstanding fellow award at the place where she trained (the OTHER--Owen T. Henry and Eugene Rutherford--Medical Center), her competence needs to be documented by a junior faculty member who is assigned to do this for all incoming physicians, including the world-renowned, new center director. The human resources manager smirks as she indicates that no one meets their relative value unit (RVU) work targets at BEST, and so Dr. Lystic must prepay for all the paperwork/tests. While Dr. Ida Lystic and "the BEST Medical Center" are creations of the authors' imagination, most of the items on her checklists are real. PMID- 26051068 TI - Eros or Ethnos: Pioneering statistical survey on prostitution at the beginning of the 20th century. AB - The earliest serious investigation into prostitution in Croatia was a survey conducted in 1907 by the physician Fran Gundrum. His study was an attempt at a comprehensive exploration of prostitution, which tried to reconstruct demographic, anthropologic, and sociologic features of prostitutes. I present an analysis of his study and argue that Gundrum consistently found himself vacillating between blaming society and charging the nature of women to explain the existence of prostitution. This ambivalence was a result of embracing both the power of Enlightenment, which believed that human morality could be improved by the process of learning, and the notion of hereditary degeneration, which regarded human improvement by reeducation as futile. Heavily influenced by his Catholic upbringing and political conservatism, Gundrum married the "scientific" notion of innate prostitution with a pervasive view of women as flirtatious and materialistic. His survey reveals the typical personality of the period, a scientific enthusiast advocating the medical control of the population and the use of statistics in realizing that goal. It was, essentially, an attempt to construct and verify widespread attitudes toward public health as a method of monitoring venereal diseases and social control in general. PMID- 26051069 TI - Using injectable hydrogel markers to assess resimulation for boost target volume definition in a patient undergoing whole-breast radiotherapy. AB - Several publications have recommended that patients undergoing whole-breast radiotherapy be resimulated for boost planning. The rationale for this is that the seroma may be smaller when compared with the initial simulation. However, the decision remains whether to use the earlier or later images to define an appropriate boost target volume. A patient undergoing whole-breast radiotherapy had new, injectable, temporary hydrogel fiducial markers placed 1 to 3cm from the seroma at the time of initial simulation. The patient was resimulated 4.5 weeks later for conformal photon boost planning. Computed tomography (CT) scans acquired at the beginning and the end of whole-breast radiotherapy showed that shrinkage of the lumpectomy cavity was not matched by a corresponding reduction in the surrounding tissue volume, as demarcated by hydrogel markers. This observation called into question the usual interpretation of cavity shrinkage for boost target definition. For this patient, it was decided to define the boost target volume on the initial planning CT instead of the new CT. PMID- 26051070 TI - Aqueous light driven hydrogen production by a Ru-ferredoxin-Co biohybrid. AB - Herein we report the creation of a novel solar fuel biohybrid for light-driven H2 production utilizing the native electron transfer protein ferredoxin (Fd) as a scaffold for binding of a ruthenium photosensitizer (PS) and a molecular cobaloxime catalyst (Co). EPR and transient optical experiments provide direct evidence of a long-lived (>1.5 ms) Ru(III)-Fd-Co(I) charge separated state formed via an electron relay through the Fd [2Fe-2S] cluster, initiating the catalytic cycle for 2H(+) + 2e(-) -> H2. PMID- 26051071 TI - Metabolic regulation in model ascomycetes--adjusting similar genomes to different lifestyles. AB - The related yeasts Saccharomyces cerevisiae and Candida albicans have similar genomes but very different lifestyles. These fungi have modified transcriptional and post-translational regulatory processes to adapt their similar genomes to the distinct biological requirements of the two yeasts. We review recent findings comparing the differences between these species, highlighting how they have achieved specialized metabolic capacities tailored to their lifestyles despite sharing similar genomes. Studying this transcriptional and post-transcriptional rewiring may improve our ability to interpret phenotype from genotype. PMID- 26051072 TI - Addressing changed sexual functioning in cancer patients: A cross-sectional survey among Dutch oncology nurses. AB - PURPOSE: In most types of cancer, the disease and its treatment can result in altered sexual function (SF). Oncology nurses are strategically placed to address SF since they have frequent patient interaction. Our aim was to establish their knowledge about and attitudes to SF in oncology care and identify their perceived barriers to addressing the subject. METHODS: A 37-item questionnaire was administered during the 2012 Dutch Oncology Nursing Congress and mailed to 241 Dutch oncology nursing departments. RESULTS: The majority of 477 nurses (87.6%) agreed that discussing SF is their responsibility. Discussing SF routinely is performed by 33.4% of these nurses, consultations mainly consisted of mentioning treatment side-effects affecting SF (71.3%). There were significant differences depending on experience, knowledge, age, academic degree and department policy. Nurses <=44 years old (p < 0.001), with <10 years oncology experience (p = 0.001), insufficient knowledge (p < 0.001), no academic degree (p < 0.001), and in whose department policy was lacking or inadequate (p < 0.001), were less comfortable discussing SF. Barriers included lack of training, presence of a third party and no angle or motive for initiating discussion. CONCLUSIONS: Findings suggest oncology nurses consider counselling on sexual issues to be an important responsibility, in line with discussing other side-effects caused by the disease or its treatment. Nevertheless, cancer patients may not routinely be receiving a sexual health evaluation by oncology nurses. Results emphasize the potential benefit of providing knowledge, including practical training and a complete department protocol. PMID- 26051073 TI - Physical activity following a breast cancer diagnosis: Implications for self rated health and cancer-related symptoms. AB - PURPOSE: Studies have consistently shown an association between physical activity and increased health and well-being after a cancer diagnosis. Nevertheless, large proportions of breast cancer survivors do not meet recommended levels of physical activity. The aim of this study was to describe physical activity levels during the first two years after being diagnosed with breast cancer, and to explore the predictive ability of physical inactivity on longer-term self-rated health, physical symptoms, and psychological distress. METHOD: Study participants were women recently having had a first breast cancer surgery at one of the three main hospitals in Stockholm between 2007 and 2009. A total of 726 women were included and responded to six questionnaire assessments during the 24 months following diagnosis. RESULTS: Less than one third of the participants were sufficiently physically active at baseline. Physical activity decreased after surgery, increased at 8 month follow-up, and subsequently decreased slightly during the subsequent follow-up period. Physical inactivity was related to reduced health, increased symptoms such as pain, depression, and anxiety. CONCLUSION: This study provides additional support for the beneficial consequences of being physically active after a breast cancer diagnosis and highlights a potential target for intervention. This study provides additional support showing that being physically active even at a very low level seems to result in health benefits. Physical activity should be encouraged among patients treated for breast cancer. PMID- 26051074 TI - The feasibility of a brain tumour website. AB - PURPOSE: Patients with a high-grade glioma (HGG) and their caregivers have imminent and changing informational and supportive care needs. The purpose of this study was to investigate the feasibility and safety of a Danish brain tumour website (BTW) in patients with HGG and their caregivers. We hypothesized that the BTW would be feasible, safe, helpful and convenient for individuals to obtain support and information. METHODS: This is an exploratory, prospective six-month feasibility study. Two separate samples were collected: 1) a nationwide sample consisting of BTW visitors over a six-month period and 2) a sample of patients with HGG (n = 9) and their caregivers (n = 8) interviewed three months after being introduced to the BTW. RESULTS: The BTW was accessed from 131 different Danish towns and cities, and from ten different countries. The website had 637 unique users. The interviews identified one overarching theme 'challenges and barriers'. Being newly diagnosed, patients described a chaotic and overwhelming life situation and had difficulties in identifying with their new and changed role. When using the BTW, some patients and caregivers experienced technological challenges, while the former also experienced cognitive difficulties. Caregivers greatly appreciated that the BTW was available and that easily accessible specialists could answer their questions. CONCLUSION: The BTW attracted nationwide interest and activity, but the burden of being newly diagnosed with HGG combined with a low level of internet skills and cognitive deficits were barriers to participation. TRIAL REGISTRATION NUMBER: ISRCTN22038059. PMID- 26051075 TI - Breast cancer knowledge, attitudes and screening behaviors among Indian Australian women. AB - PURPOSE OF RESEARCH: The aims of the study were to report breast cancer screening practices among Indian-Australian women and to examine the relationship between demographic characteristics, cultural beliefs and women's breast cancer screening (BCS) behaviors. METHOD: A descriptive and cross-sectional method was used. Two hundred and forty two Indian-Australian women were recruited from several Indian organizations. English versions of the Breast Cancer Screening Beliefs Questionnaire (BCSBQ) were administered. The main research variables are BCS practices, demographic characteristics and total scores on each of the BCSBQ subscales. RESULT: The majority of participants (72.7%-81.4%) had heard of breast awareness, clinical breast examination (CBE) and mammograms. Only 28.9% performed a BSE monthly and although 60% had practiced CBE, only 27.3% of women within the targeted age group had annual CBE. Only 23.6% of women within the targeted age group reported they had a mammogram biennial. Marital status and length of stay in Australia were positively associated with women's screening behaviors. In terms of BCSBQ score, women who had the three screening practices regularly as recommended obtained significantly higher scores on the "attitude towards general health check-ups" and "barriers to mammographic screening" subscales. There was a significant difference in the mean score of the "knowledge and perceptions about breast cancer" between women who did and who did not engage in breast awareness. CONCLUSIONS: Our study reveals that attitudes toward health check-ups and perceived barriers to mammographic screening were influential in determining compliance with breast cancer screening practices among Indian-Australian women. PMID- 26051076 TI - Examining patterns of multivariate, longitudinal symptom experiences among older adults with type 2 diabetes and cancer via cluster analysis. AB - PURPOSE: Diabetes and cancer are chronic conditions that produce symptoms, some unique to each condition and others common to both. Previous studies have reported on subgroups of patients who experience distinct combinations of symptoms in cross-sectional samples and the univariate longitudinal trajectories of individual symptoms. The literature currently lacks examples of research that take a multivariate longitudinal perspective to understanding patients' symptom experiences. The purpose of this study was to identify subgroups of patients who share distinct multivariate longitudinal profiles with respect to how symptom severity changes over time for a set of five symptoms (pain, fatigue, change in appetite, nausea, and numbness and tingling). METHODS: This exploratory study included 43 participants with pre-existing diabetes from eight community-based cancer centers who were receiving chemotherapy for a solid tumor. Using baseline and 8-week data, a model-based cluster analysis with Bayesian regularization was used to identify subgroups. RESULTS: Two groups were identified. Group 1 experienced mild symptoms that changed very little at 8 weeks; group 2 experienced mild to moderate symptom severity, with small increases in fatigue, nausea, and numbness and tingling. Effect size confidence intervals suggest that level of depression, length of time with diabetes, and severity of diabetes at baseline may differ between groups. CONCLUSIONS: More research in this area is needed to further test this model, address limitations associated with analyzing a small sample, and explore factors that may be associated with changes in the overall symptom experience for patients with diabetes and cancer. PMID- 26051077 TI - Mercury (II) removal by resistant bacterial isolates and mercuric (II) reductase activity in a new strain of Pseudomonas sp. B50A. AB - This study aimed to isolate mercury resistant bacteria, determine the minimum inhibitory concentration for Hg, estimate mercury removal by selected isolates, explore the mer genes, and detect and characterize the activity of the enzyme mercuric (II) reductase produced by a new strain of Pseudomonas sp. B50A. The Hg removal capacity of the isolates was determined by incubating the isolates in Luria Bertani broth and the remaining mercury quantified by atomic absorption spectrophotometry. A PCR reaction was carried out to detect the merA gene and the mercury (II) reductase activity was determined in a spectrophotometer at 340 nm. Eight Gram-negative bacterial isolates were resistant to high mercury concentrations and capable of removing mercury, and of these, five were positive for the gene merA. The isolate Pseudomonas sp. B50A removed 86% of the mercury present in the culture medium and was chosen for further analysis of its enzyme activity. Mercuric (II) reductase activity was detected in the crude extract of this strain. This enzyme showed optimal activity at pH 8 and at temperatures between 37 degrees C and 45 degrees C. The ions NH4(+), Ba(2+), Sn(2+), Ni(2+) and Cd(2+) neither inhibited nor stimulated the enzyme activity but it decreased in the presence of the ions Ca(2+), Cu(+) and K(+). The isolate and the enzyme detected were effective in reducing Hg(II) to Hg(0), showing the potential to develop bioremediation technologies and processes to clean-up the environment and waste contaminated with mercury. PMID- 26051079 TI - Acute tuberculous abscess of the larynx. An unusual presentation. PMID- 26051078 TI - Interferon Gamma-treated Dental Pulp Stem Cells Promote Human Mesenchymal Stem Cell Migration In Vitro. AB - INTRODUCTION: Chronic inflammation disrupts dental pulp regeneration by disintegrating the recruitment process of progenitors for repair. Bone marrow derived mesenchymal stem cells (BM-MSCs) share the common features with dental pulp stem cells (DPSCs). The aim of the study was to investigate the migration of BM-MSCs toward DPSCs in response to inflammatory chemoattractants. Additionally, our studies also delineated the signaling mechanisms from BM-MSCs in mediating the proliferation and differentiation of DPSCs in vitro. METHODS: Human DPSCs and BM-MSCs between passages 2 and 4 were used and were grown in odontogenic differentiation medium. Mineralization was determined by alizarin red staining analysis. Migration was assessed using crystal violet staining in cells grown in Boyden chamber Transwell inserts (Corning Inc Foundation, Tewksbury, MA). The mineralization potential of DPSCs was evaluated using alkaline phosphatase activity assay. Real-time polymerase chain reaction analysis was performed to assess the gene expression profile of chemokine (C-X-C motif) ligand (Cxcl) 3, 5, 6, 10, 11, 12, 14, and 16; stromal cell-derived factor (SDF) alpha; vascular endothelial growth factor; and fibroblast growth factor. RESULTS: Interferon gamma (FN-gamma) treatment significantly abrogated the differentiation potential of DPSCs as shown by using alizarin red and alkaline phosphatase activity analysis. An increase in the migration of BM-MSCs was documented when cocultured with IFN-gamma-treated DPSCs. RNA expression studies showed an increase in the levels of Cxcl6 and Cxcl12 in BM-MSCs when cocultured with IFN-gamma-treated DPSCs. Additionally, an up-regulation of proangiogenic factors vascular endothelial growth factor and fibroblast growth factor were observed in DPSCs exposed to IFN-gamma. CONCLUSIONS: Our findings indicate that inflamed IFN-gamma treated DPSCs release factors (presumably Cxcl6 and 12) that contribute to the homing of MSCs. This model might provide a potential research tool for studying MSC-DPSC cross talk and for future studies involving the recruitment and sustainability of progenitor stem cells sustaining the inflammatory cascade to treat pulp inflammation. PMID- 26051080 TI - Split thickness skin grafts in four cases of medial meatal fibrosis of the external auditory canal. AB - Medial meatal fibrosis is a rare condition in which the medial portion of the external auditory canal is obliterated with fibrous tissue. We selected 4 cases of patients with medial meatal fibrosis with a history of recurrent otorrhea who underwent surgery during the years of 2012 and 2013, presenting the surgical results here. Physical examination showed an obliterated external auditory canal and conductive hypoacusis. All cases were solved using a split thickness skin graft from the thigh. The surgical principles that appear to correlate with a favorable outcome are the removal of all fibrous tissue and unhealthy skin, a wide canaloplasty and the use of a split thickness skin graft. PMID- 26051081 TI - Pesticide residues in chicken eggs - A sample preparation methodology for analysis by gas and liquid chromatography/tandem mass spectrometry. AB - A sample preparation method was developed for the analysis of chicken eggs to determine 97 GC and 81 LC amenable residues, including organophosphates, organochlorines, pyrethroids, triazoles, carboxyl-containing compounds, and the indicator PCBs. Hereby, considerations were given to the recoveries of the analytes, the method's suitability for routine analysis, and the assessment of the clean-up effect, for which a simple thin layer chromatography was implemented to visualize the most important lipid classes. The procedure consisted of (I) the extraction by matrix solid phase dispersion, and the clean-up by means of (II) small-scale gel permeation chromatography (GPC) and (III) two different solid phase extractions (SPE) for GC and LC amenable analytes, as well as (IV) the quantification using GC-MS/MS and LC-MS/MS. Cyclohexane/ethyl acetate was chosen as extraction solvent due to its suitability for extracting strong non-polar but also more polar analytes. The classical GPC was scaled down to ensure a 50% lower solvent consumption. The comprehensive investigation of conventional and modern zirconium-oxide-coated SPE materials resulted in the selection of octadecyl modified silica (C18) combined with primary secondary amine using acetonitrile as elution solvent for GC amenable analytes and pure C18 in combination with acidified methanol for LC amenable pesticides. Compared to the currently established EN 1528 method the sample preparation proposed offered a higher sample throughput and a lower solvent consumption. Furthermore, for the first time the clean-up effectiveness of the sample preparation steps was documented as shown by means of thin-layer chromatography. The validation of chicken eggs proved the fulfillment of the quality control criteria for 164 of the 178 analytes tested, mostly at the lowest validated level of 5MUg/kg for pesticides and 0.5MUg/kg for the single indicator PCBs. However, the analysis of strongly polar analytes was still problematic, which could be attributed to the extraction and the GPC step. Nevertheless, the successful investigation of EU proficiency test materials (EUPT AO 07-09) confirmed the comparability of the results with the currently established sample preparation procedures and demonstrated the potential of the applicability of the presented method to other matrices as exemplified for lean poultry meat and fatty liquid cream. PMID- 26051082 TI - Heterogeneous glycoform separation by process chromatography: I: Monomer purification and characterization. AB - Fc fusion proteins with high and low sialylation were purified and separated by preparative ion-exchange and hydrophobic interaction chromatography. Heterogeneity in sialylation and glycosylation led to variation in surface charge and hydrophobicity, and resulted in multiple distinct glycoform populations in response to various purification conditions. Monomer with high sialic acid content has higher surface charge and adsorbs stronger to ion-exchange resin, while the less sialylated monomer interacts more favorably with hydrophobic resin. Extensive biophysical characterization was carried out for purified monomers at different level of sialylation. In general, different monomeric glycoforms have different surface charge and hydrophobicity, different thermal stability, and different aggregation propensity. The surface charge corresponds well with sialic acid content, as evidenced by electrophoresis, N-link domain analysis, and zeta potential results. The sialylation also contributes to minor modification of protein size, molecular mass and tertiary structure. Notably, fluorescence emission spectra and thermal transition became less distinguishable when the monomers containing low and high sialic acid were prepared in high ionic strength solution. Such finding reiterates the fact that the electrostatic forces, which are largely dependent on sialic acid content of protein, plays a dominant role in many intra- and inter-molecular interactions. Overall, the characterization data agreed well with separation behaviors and provided valuable insight to control of glycoform profile in purification process. PMID- 26051083 TI - Integrated system for temperature-controlled fast protein liquid chromatography. II. Optimized adsorbents and 'single column continuous operation'. AB - Continued advance of a new temperature-controlled chromatography system, comprising a column filled with thermoresponsive stationary phase and a travelling cooling zone reactor (TCZR), is described. Nine copolymer grafted thermoresponsive cation exchangers (thermoCEX) with different balances of thermoresponsive (N-isopropylacrylamide), hydrophobic (N-tert-butylacrylamide) and negatively charged (acrylic acid) units were fashioned from three cross linked agarose media differing in particle size and pore dimensions. Marked differences in grafted copolymer composition on finished supports were sourced to base matrix hydrophobicity. In batch binding tests with lactoferrin, maximum binding capacity (qmax) increased strongly as a function of charge introduced, but became increasingly independent of temperature, as the ability of the tethered copolymer networks to switch between extended and collapsed states was lost. ThermoCEX formed from Sepharose CL-6B (A2), Superose 6 Prep Grade (B2) and Superose 12 Prep Grade (C1) under identical conditions displayed the best combination of thermoresponsiveness (qmax,50 degrees C/qmax,10 degrees C ratios of 3.3, 2.2 and 2.8 for supports 'A2', 'B2' and 'C1' respectively) and lactoferrin binding capacity (qmax,50 degrees C~56, 29 and 45mg/g for supports 'A2', 'B2' and 'C1' respectively), and were selected for TCZR chromatography. With the cooling zone in its parked position, thermoCEX filled columns were saturated with lactoferrin at a binding temperature of 35 degrees C, washed with equilibration buffer, before initiating the first of 8 or 12 consecutive movements of the cooling zone along the column at 0.1mm/s. A reduction in particle diameter (A2->B2) enhanced lactoferrin desorption, while one in pore diameter (B2->C1) had the opposite effect. In subsequent TCZR experiments conducted with thermoCEX 'B2' columns continuously fed with lactoferrin or 'lactoferrin+bovine serum albumin' whilst simultaneously moving the cooling zone, lactoferrin was intermittently concentrated at regular intervals within the exiting flow as sharp uniformly sized peaks. Halving the lactoferrin feed concentration to 0.5mg/mL, slowed acquisition of steady state, but increased the average peak concentration factor from 7.9 to 9.2. Finally, continuous TCZR mediated separation of lactoferrin from bovine serum albumin was successfully demonstrated. While the latter's presence did not affect the time to reach steady state, the average lactoferrin mass per peak and concentration factor both fell (respectively from 30.7 to 21.4mg and 7.9 to 6.3), and lactoferrin loss in the flowthrough between elution peaks increased (from 2.6 to 12.2mg). Fouling of the thermoCEX matrix by lipids conveyed into the feed by serum albumin is tentatively proposed as responsible for the observed drops in lactoferrin binding and recovery. PMID- 26051084 TI - Cyclotriveratrylene as a new-type stationary phase for gas chromatographic separations of halogenated compounds and isomers. AB - Cyclotriveratrylene (CTV) is reported here for the first time as stationary phase for capillary gas chromatographic (GC) separations. CTV stationary phase showed weak polarity comparable to the conventional 5% phenyl polysiloxane stationary phase but exhibited different retention behaviours and higher resolution for some of the indicated analytes. Most importantly, CTV stationary phase exhibited preferential selectivity for halogenated compounds, positional and geometrical isomers. Effect of column temperature on retention and thermal stability of CTV column were also investigated. Moreover, CTV capillary column showed good repeatability in terms of run-to-run, day-to-day and column-to-column. The unique physicochemical features and efficient separation ability for analytes of close properties show the potential of CTV as a new-type stationary phase in GC as well as separation science. PMID- 26051085 TI - Determination of suspected fragrance allergens extended list by two-dimensional gas chromatography-mass spectrometry in ready-to-inject samples. AB - A new strategy was developed to elucidate and quantify 56 (69 analytes including isomers) suspected chemically defined fragrance allergens in perfumes that were recently targeted by the Scientific Committee on Consumer Safety (SCCS). Samples were analyzed with a two-dimensional gas chromatography-quadrupole mass spectrometry system (GC-GC-MS). Method performance was evaluated by the accuracy profile approach to determine uncertainties around the regulation limit of 10mg/kg. This strategy was finally applied to 62 commercialized perfumes, analyzed in the routine workflow. Depending on the matrix, an acceptable result was obtained for 88-100% of the target analytes, which means that results were accurately defined under or above 10mg/kg. This method saves considerable time for complete analysis and could be adopted for routine analysis due to its ruggedness and cost effectiveness. PMID- 26051086 TI - Rapid method for determination of carbonyl groups in lignin compounds by headspace gas chromatography. AB - The paper reports on a novel method for rapid determination of carbonyl in lignins by headspace gas chromatography (HS-GC). The method involves the quantitative carbonyl reduction for aldehydes in 2min at room temperature or for acetones in 30min at 80 degrees C by sodium borohydride solution in a closed headspace sample vial. After the reaction, the solution was acidified by injecting sulfuric acid solution and the hydrogen released to the headspace was determined by GC using thermal-conductivity detector. The results showed that with the addition of SiO2 powder, the reduction reaction of carbonyl groups can be greatly facilitated. The method has a good measurement precision (RSD<7.74%) and accuracy (relative error <10% compared with a reference method) in the carbonyl quantification. It is suitable to be used for rapid determination of carbonyl content in lignin and related materials. PMID- 26051087 TI - Pallidifloside D from Smilax riparia enhanced allopurinol effects in hyperuricemia mice. AB - Pallidifloside D, a saponin glycoside constituent from the total saponins of Smilax riparia, had been proved to be effective in hyperuricemic control. Allopurinol is a commonly used medication to treat hyperuricemia and its complications. In this study, we evaluated whether Pallidifloside D could enhance allopurinol's effects by decreasing the serum uric acid level in a hyperuricemic mouse model induced by potassium oxonate. We found that, compared with allopurinol alone, the combination of allopurinol and Pallidifloside D significantly decreased the serum uric acid level and increased the urine uric acid level (both P<0.05), leading to the normalized serum and urine uric acid concentrations. Data on serum, urine creatinine and BUN supported these observations. Our results showed that the synergistic effects of allopurinol combined with Pallidifloside D were linked to the inhibition of both serum and hepatic xanthine oxidase (XOD), the down-regulation of renal mURAT1 and mGLUT9, and the up-regulation of mOAT1. Our data may have a potential value in clinical practice in the treatment of gout and other hyperuricemic conditions. PMID- 26051088 TI - Multiple alternative substrate kinetics. AB - The specificity of enzymes for their respective substrates has been a focal point of enzyme kinetics since the initial characterization of metabolic chemistry. Various processes to quantify an enzyme's specificity using kinetics have been utilized over the decades. Fersht's definition of the ratio kcat/Km for two different substrates as the "specificity constant" (ref [7]), based on the premise that the important specificity existed when the substrates were competing in the same reaction, has become a consensus standard for enzymes obeying Michaelis-Menten kinetics. The expansion of the theory for the determination of the relative specificity constants for a very large number of competing substrates, e.g. those present in a combinatorial library, in a single reaction mixture has been developed in this contribution. The ratio of kcat/Km for isotopologs has also become a standard in mechanistic enzymology where kinetic isotope effects have been measured by the development of internal competition experiments with extreme precision. This contribution extends the theory of kinetic isotope effects to internal competition between three isotopologs present at non-tracer concentrations in the same reaction mix. This article is part of a special issue titled: Enzyme Transition States from Theory and Experiment. PMID- 26051089 TI - Biomarkers in Paediatric Cystic Fibrosis Lung Disease. AB - Biomarkers in cystic fibrosis are used i. for the measurement of cystic fibrosis transmembrane regulator function in order to diagnose cystic fibrosis, and ii. to assess aspects of lung disease severity (e.g. inflammation, infection). Effective biomarkers can aid disease monitoring and contribute to the development of new therapies. The tests of cystic fibrosis transmembrane regulator function each have unique strengths and weaknesses, and biomarkers of inflammation, infection and tissue destruction have the potential to enhance the management of cystic fibrosis through the early detection of disease processes. The development of biomarkers of cystic fibrosis lung disease, in particular airway inflammation and infection, is influenced by the challenges of obtaining relevant samples from infants and children for whom early detection and treatment of disease might have the greatest long term benefits. PMID- 26051090 TI - Stem cell niche engineering through droplet microfluidics. AB - Stem cells reside in complex niches in which their behaviour is tightly regulated by various biochemical and biophysical signals. In order to unveil some of the crucial stem cell-niche interactions and expedite the implementation of stem cells in clinical and pharmaceutical applications, in vitro methodologies are being developed to reconstruct key features of stem cell niches. Recently, droplet-based microfluidics has emerged as a promising strategy to build stem cell niche models in a miniaturized and highly precise fashion. This review highlights current advances in using droplet microfluidics in stem cell biology. We also discuss recent efforts in which microgel technology has been interfaced with high-throughput analyses to engender screening paradigms with an unparalleled potential for basic and applied biological studies. PMID- 26051091 TI - Uterine volume and endometrial thickness in healthy girls evaluated by ultrasound (3-dimensional) and magnetic resonance imaging. AB - OBJECTIVE: To report normative data on uterine volume and endometrial thickness in girls, according to pubertal stages; to evaluate factors that affect uterine volume; and to compare transabdominal ultrasound (TAUS) and magnetic resonance imaging (MRI). DESIGN: Cross-sectional study of a nested cohort of girls participating in The Copenhagen Mother-Child Cohort. SETTING: General community. PATIENT(S): One hundred twenty-one healthy girls, aged 9.8-14.7 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical examination, including pubertal breast stage (Tanner classification: B1-B5). Uterine volume: ellipsoid TAUS (n = 112) and 3-dimensional TAUS (n = 111); ellipsoid MRI (n = 61). Endometrial thickness: TAUS (n = 110) and MRI (n = 60). RESULT(S): Uterine volume and endometrial thickness were positively correlated with pubertal stages; e.g., ellipsoid TAUS: r = 0.753, and endometrium TAUS: 0.648. In multiple regression analyses, uterine volume was associated with the number of large follicles (TAUS >5 mm) (Beta 0.270); estradiol (E2) (Beta 0.504); and height (Beta 0.341). Volumes from ellipsoid vs. 3-dimensional TAUS were strongly correlated (r = 0.931), as were TAUS and MRI: ellipsoid volume (r = 0.891) and endometrial thickness (r = 0.540). Uterine volume was larger in TAUS compared with MRI; mean difference across the measured range: 7.7 (5.2-10.2) cm(3). Agreement was best for small uteri. CONCLUSION(S): Uterine volume and endometrial thickness increased as puberty progressed. Circulating E2 from large follicles was the main contributor to uterine and endometrial growth. The TAUS and MRI assessments of uterus and endometrium were strongly correlated. PMID- 26051092 TI - Spermatozoa micro ribonucleic acid-34c level is correlated with intracytoplasmic sperm injection outcomes. AB - OBJECTIVE: To assess the effects of micro ribonucleic acid (miR)-34b/c expression levels in human spermatozoa on intracytoplasmic sperm injection (ICSI) outcomes. DESIGN: Retrospective observational study. SETTING: In vitro fertilization center. PATIENT(S): A total of 162 patients with idiopathic male infertility who had undergone first ICSI cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The levels of miR-34b/c in spermatozoa were measured using real-time polymerase chain reaction. Fertilization, early cleavage, day-3 good-quality embryo, pregnancy, implantation, and live birth rate were assessed. A receiver operating characteristic curve was employed to analyze the cutoff values. RESULT(S): No correlation was found between the spermatozoa miR-34b/c levels and the 2 pronuclei early cleavage rate. A correlation was seen between an increased level of miR-34c and a higher percentage of good-quality embryos on day 3. Although miR 34b and miR-34c levels were higher in the pregnancy group, compared with the nonpregnancy group, receiver operating characteristic curve analysis showed that miR-34c levels in spermatozoa were more strongly correlated with ICSI treatment outcomes, compared with miR-34b (area under the curve = 0.75). Patients in the miR-34c-positive group were more likely to exhibit higher rates of good-quality embryos, implantation, pregnancy, and live birth. A multivariable logistic regression analysis showed that miR-34c in spermatozoa (odds ratio: 5.699, with 95% confidence interval [CI]: 2.687-12.088) and woman's age (odds ratio: 0.843, with 95% CI: 0.736-0.966) were the 2 parameters that were significantly correlated with pregnancy. CONCLUSION(S): Our results demonstrate that miR-34c levels in spermatozoa are correlated with ICSI outcomes, suggesting that paternal miR-34c may play a role in the early phases of embryonic development. Levels of MiR-34c in human spermatozoa may be used as an indicator for ICSI outcomes. PMID- 26051093 TI - Mild ovarian stimulation with clomiphene citrate launch is a realistic option for in vitro fertilization. AB - OBJECTIVE: To validate the use of clomiphene citrate in IVF when mild stimulation approaches are chosen to reduce patient discomfort, risk, and cost. DESIGN: Prospective cohort study. SETTING: Private IVF clinic. PATIENT(S): A total of 163 patients undergoing IVF and with a good prognosis (defined as <=38 years old with normal ovarian reserve and normovulatory cycles, body mass index <29 kg/m(2), no previous assisted reproductive technology cycles, no severe endometriosis, no history of recurrent miscarriage, no endocrine/autoimmune diseases, and no surgical semen extraction). INTERVENTION(S): Mild stimulation using a fixed protocol of clomiphene citrate (100 mg/d from cycle days 3 to 7) in combination with low doses of gonadotropins (150 IU of recombinant FSH on cycle days 5, 7, and 9) and GnRH antagonist. MAIN OUTCOME MEASURE(S): The cumulative delivery rate per patient after three fresh and/or frozen embryo transfers and time to pregnancy. RESULT(S): No dropouts were observed. The cumulative delivery rate was 70%, and the mean time to pregnancy was 2.4 months. CONCLUSION(S): Mild stimulation using clomiphene citrate in combination with low doses of gonadotropins can be considered a realistic option for good-prognosis patients undergoing IVF. PMID- 26051094 TI - Involvement of estrogen-related receptor-gamma and mitochondrial content in intrauterine growth restriction and preeclampsia. AB - OBJECTIVE: To measure mitochondrial content and the expression of estrogen related receptor-gamma (ERRgamma, a major inducer of mitochondrial biogenesis) in placentas from women with intrauterine growth restriction (IUGR) associated or not with pre-eclampsia (PE), relative to control placentas. DESIGN: Case-control study. SETTING: Teaching hospital and university research laboratory. PATIENT(S): Thirty-nine placentas from women with IUGR, 8 IUGR+PE, and 30 controls. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mitochondrial DNA and protein content, gene and protein expression. RESULT(S): We observed significantly lower placental mitochondrial DNA and protein contents (associated with down-regulation of ERRgamma expression) in IUGR and IUGR+PE placentas, relative to control placentas. Our results also revealed that the placental mitochondrial DNA content was directly correlated with fetal weight. Moreover, we observed significantly lower peroxisome proliferator-activated receptor-gamma coactivator-1alpha and sirtuin 1 messenger RNA expression levels in IUGR+PE placentas, relative to control placentas. CONCLUSION(S): The low mitochondrial DNA and protein contents observed in IUGR placentas are probably due to down-regulation of ERRgamma expression. This finding suggests that ERRgamma has a major role in the control of placental development. PMID- 26051095 TI - Randomized, triple-blind, placebo-controlled clinical trial examining the effects of alpha-lipoic acid supplement on the spermatogram and seminal oxidative stress in infertile men. AB - OBJECTIVE: To evaluate effects of supplementation with alpha-lipoic acid (ALA) on the spermatogram and seminal oxidative stress biomarkers. DESIGN: Randomized, triple-blind, placebo-controlled clinical trial. SETTING: Infertility clinic. PATIENT(S): Infertile men. INTERVENTION(S): ALA (600 mg) or placebo for 12 weeks. MAIN OUTCOME MEASURE(S): Semen analysis, anthropometric, dietary, and physical activity assessments, total antioxidant capacity, and malondialdehyde. RESULT(S): At the end of study, the total sperm count, sperm concentration, and motility in the intervention group were significantly higher than in the control group. In the ALA group, the total sperm count, sperm concentration, and motility levels were also significantly increased at the end of study compared with baseline values. However, there were no significant differences in ejaculate volume, normal morphology percentage, and live sperm between groups. ALA supplementation also resulted in a significant improvement in seminal levels of total antioxidant capacity (TAC) and malondialdehyde compared with the placebo. CONCLUSION(S): According to the results, medical therapy of asthenoteratospermia with ALA supplement could improve quality of semen parameters. However, further investigation is suggested in this regard. CLINICAL TRIAL REGISTRATION NUMBER: IRCT2013111010181N3. PMID- 26051096 TI - Embryo transfer practices and perinatal outcomes by insurance mandate status. AB - OBJECTIVE: To use linked assisted reproductive technology (ART) surveillance and birth certificate data to compare ET practices and perinatal outcomes for a state with a comprehensive mandate requiring coverage of IVF services versus states without a mandate. DESIGN: Retrospective cohort study. SETTING: Not applicable. PATIENT(S): Live-birth deliveries ascertained from linked 2007-2009 National ART Surveillance System and birth certificate data for a state with an insurance mandate (Massachusetts) and two states without a mandate (Florida and Michigan). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Number of embryos transferred, multiple births, low birth weight, preterm delivery. RESULT(S): Of the 230,038 deliveries in the mandate state and 1,026,804 deliveries in the nonmandate states, 6,651 (2.9%) and 8,417 (0.8%), respectively, were conceived by ART. Transfer of three or more embryos was more common in nonmandate states, although the effect was attenuated for women 35 years or older (33.6% vs. 39.7%; adjusted relative risk [RR], 1.46; 95% confidence interval [CI], 1.17-1.81) versus women younger than 35 (7.0% vs. 26.9%; adjusted RR, 4.18; 95% CI, 2.74-6.36). Lack of an insurance mandate was positively associated with triplet/higher order deliveries (1.0% vs. 2.3%; adjusted RR, 2.44; 95% CI, 1.81-3.28), preterm delivery (22.6% vs. 30.7%; adjusted RR, 1.31; 95% CI, 1.20-1.42), and low birth weight (22.3% vs. 29.5%; adjusted RR, 1.28; 95% CI, 1.17-1.40). CONCLUSION(S): Compared with nonmandate states, the mandate state had higher overall rates of ART use. Among ART births, lack of an infertility insurance mandate was associated with increased risk for adverse perinatal outcomes. PMID- 26051098 TI - Validity of adiponectin-to-leptin and adiponectin-to-resistin ratios as predictors of polycystic ovary syndrome. AB - OBJECTIVE: To evaluate the association of changes in adipokine ratios with polycystic ovary syndrome (PCOS) and related features as altered levels of the adipokines adiponectin, leptin, and resistin were linked with the pathogenesis of PCOS. DESIGN: Case-control retrospective study. SETTING: Outpatient obstetrics/gynecology and adult endocrinology clinics. PATIENT(S): Unrelated women with PCOS (n = 211) and age-matched control women (n = 215). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Utility of adiponectin/leptin and adiponectin/resistin ratios as potential biomarkers of PCOS and associated features. RESULT(S): Significant differences in adiponectin but not leptin or resistin serum levels were seen between women with PCOS and control women. Ratios of adiponectin/leptin and adiponectin/resistin, but not leptin/resistin ratios, were statistically significantly different between PCOS cases and control women. Receiver operated characteristics area under the curve demonstrated sensitivity and specificity for adiponectin/leptin and adiponectin/resistin but not leptin/resistin ratios or individual adipokines as predictors of PCOS. Adiponectin/leptin and adiponectin/resistin ratios negatively correlated with body mass index, homeostatic model assessment, insulin resistance, and free insulin, testosterone, and sex hormone-binding globulin. In addition, adiponectin/resistin ratio negatively correlated with menarche. CONCLUSION(S): Ratios of adiponectin/leptin and adiponectin/resistin constitute novel predictor factors to explain PCOS and associated features and thus may present target for novel therapeutics in PCOS. PMID- 26051097 TI - Noninvasive detection of trophoblast protein signatures linked to early pregnancy loss using trophoblast retrieval and isolation from the cervix (TRIC). AB - OBJECTIVE: To examine the expression pattern of biomarker proteins in extravillous trophoblast (EVT) cells obtained noninvasively by trophoblast retrieval and isolation from the cervix (TRIC) in patients with early pregnancy loss compared with control patients with uncomplicated term delivery. DESIGN: Case-control study. SETTING: Academic medical center. PATIENT(S): Women with either early pregnancy loss (EPL, n = 10) or an uncomplicated term delivery (N = 10). INTERVENTION(S): Endocervical specimens obtained from ongoing pregnancies at gestational ages of 5-10 weeks to generate an archive of EVT cells isolated by TRIC, with medical records examined to select specimens matched for gestational age at the time of endocervical sampling. MAIN OUTCOME MEASURE(S): Known serum biomarkers for adverse pregnancy outcome that are expressed by EVT cells were evaluated by semiquantitative immunocytochemistry, using antibodies against endoglin (ENG), FMS-like tyrosine kinase-1 (FLT-1), alpha-fetoprotein (AFP), pregnancy-associated plasma protein-A (PAPP-A), galectin-13 (LGALS13), galectin 14 (LGALS14), and placental growth factor (PGF). RESULT(S): The EVT purity was over 95% in all specimens, based on chorionic gonadotropin expression; however, the number of EVT cells obtained was significantly lower in women with EPL than the control group. There was a statistically significant elevation of AFP, ENG, and FLT-1, and statistically significant reduction of PAPP-A, LGALS14, and PGF in the EPL group compared with controls. CONCLUSION(S): In this pilot study, EVT cells isolated by TRIC early in gestation exhibited altered protein expression patterns before an EPL compared with uncomplicated term pregnancies. PMID- 26051099 TI - Ultrasound techniques in the diagnosis of deep pelvic endometriosis: algorithm based on a systematic review and meta-analysis. AB - OBJECTIVE: To collate all available evidence with respect to ultrasound techniques in the management of deep pelvic endometriosis (DPE) and compare the sensitivity and specificity of each to determine the most suitable site-specific method. We aim to provide clinicians with information to improve the diagnosis and management of patients with DPE. DESIGN: Systematic review of the literature and meta-analysis. SETTING: Not applicable. PATIENT(S): None. INTERVENTIONS(S): Review of MEDLINE, EMBASE, ScienceDirect, Cochrane Library. MAIN OUTCOME MEASURE(S): For each study we calculated the sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and positive/negative likelihood ratio regarding DPE sites. We then compared the specificity and sensitivity of each technique. Forest plots with the corresponding 95% confidence interval using fixed/random effects for each approach (both separately and summarized according to the weight of any single study) were used. RESULT(S): A key word search strategy identified 441 manuscripts, 35 of which were eligible for the review (32 for meta-analysis). Standard transvaginal sonography (TVS) showed specificity greater than 85% for all DPE sites, despite sensitivity ranging between 50% (bladder, vaginal wall, and rectovaginal septum) and 84% (rectosigmoid). Modified techniques such as bladder site tenderness-guided TVS showed a value of 97.4% for both sensitivity and specificity. Rectal endoscopy sonography and rectal water contrast TVS were both superior to TVS in detecting rectosigmoid endometriosis with sensitivities and specificities over 92%. Promising data were reported by using rectal water contrast TVS for rectovaginal septum disease (sensitivity, 97.1%; specificity, 99.3%). CONCLUSION(S): The summary of data regarding diagnostic specificity and sensitivity of TVS in women undergoing surgery for deep endometriosis may allow us to conclude that TVS should remain the first-line method in the evaluation of patients with suspicion of DPE. When TVS is insufficient, second-line "modified-techniques" should be considered. Choosing the most effective technique is a challenge and should be based on patient history and clinical signs/symptoms. PMID- 26051100 TI - European view of subspecialty training on behalf of the European Society of Human Reproduction and Embryology (ESHRE). AB - Specialist training in reproductive medicine within Europe continues to evolve. Recent revisions, updates, and initiatives have helped to refine the core educational needs for the specialist trainee. PMID- 26051101 TI - Android fat distribution affects some hemostatic parameters in women with polycystic ovary syndrome compared with healthy control subjects matched for age and body mass index. AB - OBJECTIVE: To correlate hemostatic parameters with clinical markers of fat distribution and laboratory variables in women with polycystic ovary syndrome (PCOS) compared with healthy control subjects. DESIGN: Cross-sectional study. SETTING: Tertiary teaching hospital. PATIENT(S): Forty-five women with PCOS and 45 control women matched for age and body mass index (BMI). INTERVENTION(S): Clinical evaluation and venipuncture. MAIN OUTCOME MEASURE(S): Age, BMI, waist circumference (WC), hip circumference (HC), waist-hip ratio (WHR), Ferriman Gallwey index, fasting glucose, fasting insulin, total testosterone, free testosterone (FT), thrombin-activatable fibrinolysis inhibitor (TAFI), D-dimer, plasminogen activator inhibitor (PAI) 1, and the parameters of thrombin generation test (TGT), including the lag time (Tlag), time to peak thrombin generation (Tmax), peak concentration (Cmax), and the area under the thrombin generation curve (TAUC). RESULT(S): In the PCOS group, BMI and WC correlated positively with TAFI, D-dimer, PAI-1, Cmax, and TAUC; HC with D-dimer and PAI-1; WHR with TAFI, D-dimer, and PAI-1; glucose with TAFI; insulin and homeostasis model assessment of insulin resistance with PAI-1; and FT with Cmax and TAUC. Age correlated positively with D-dimer and PAI-1, and negatively with Tlag and Tmax. In the control group, there were no correlations between clinical markers of fat distribution and hemostatic parameters, but age and fasting glucose correlated positively with PAI-1, and FT with Tmax and TAUC. CONCLUSION(S): In PCOS, android body fat distribution may directly affect hemostatic parameters, particularly in young and overweight women. Further studies are needed to establish a correlation between these results and an increase in thromboembolic risk. PMID- 26051102 TI - Mitochondrial DNA content as a viability score in human euploid embryos: less is better. AB - OBJECTIVE: To investigate the clinical relevance of mitochondrial DNA (mtDNA) content as a viability score in human euploid embryos. DESIGN: Retrospective analysis of mtDNA content of transferred euploid embryos. SETTING: Reproductive genetics laboratory. PATIENT(S): Single-embryo transfer in 270 patients who underwent preimplantation genetic screening (205 day-3 blastomere biopsies, and 65 day-5 trophectoderm biopsies), and 10 patients with double-embryo transfer (male-female). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Normalized mtDNA content versus nuclear DNA (nDNA) from transferred euploid embryos. RESULT(S): A high mtDNA copy number in euploid embryos is indicative of lower embryo viability and implantation. Using the normalized mtDNA content, we created the mitochondrial score or Mitoscore (Ms). Day-3 embryos with <34 (MsA) had an implantation rate (IR) of 59% (n = 51); those with 34-52 (MsB) had an IR of 44% (n = 52); those with 52-97 (MsC) had an IR of 42% (n = 50); and those with >97 (MsD) had an IR of 25% (n = 52). Embryos with Ms >160 (n = 22) never implanted. Day-5 embryos with <18.19 (MsA) had an IR of 81%; those with 18.19-24.15 (MsB) had an IR of 50% (n = 16); those with 24.15-50.58 (MsC) had an IR of 62% (n = 16); and those with levels >50.58 (MsD) had an IR of 18% (n = 17). Embryos with levels >60 (n = 7) never implanted. CONCLUSION(S): An increased amount of mtDNA in euploid embryos is related to poor implantation potential and may be indicative of reduced metabolic fuel during oocyte maturation. We are implementing Ms in our preimplantation genetic screening platform to prospectively analyze its clinical relevance. PMID- 26051103 TI - Dienogest enhances autophagy induction in endometriotic cells by impairing activation of AKT, ERK1/2, and mTOR. AB - OBJECTIVE: To elucidate the therapeutic mechanisms of progestin and the effects of progesterone and progestin (dienogest) on autophagy induction and regulation in endometriotic cells, specifically the effects of progesterone and dienogest on the phosphoinositide-3/protein kinase B (PI3K-AKT) and mitogen-activated protein kinase kinases 1 and 2 (MEK1/2)/extracellular-signal-regulated kinase 1/2 (ERK1/2) pathways, which activate mammalian target of rapamycin (mTOR), a major negative regulator of autophagy. DESIGN: In vitro study using human endometriotic cyst stromal cells (ECSCs). SETTING: University medical center. PATIENT(S): Fifteen patients with ovarian endometrioma. INTERVENTION(S): ECSCs treated with progesterone or dienogest. MAIN OUTCOME MEASURE(S): Autophagy as measured by the expression of the microtubule-associated protein light chain 3-II (LC3-II) and autophagosome formation, and levels of AKT, ERK1/2, and mTOR activity to quantify the phosphorylation of AKT, ERK1/2, and S6K (the downstream target of mTOR). RESULT(S): Progesterone treatment had not statistically significant effect on LC3 II expression, autophagosome formation, or phosphorylation of AKT, ERK1/2, or S6K in estrogen-treated ECSCs. However, dienogest treatment up-regulated LC3-II expression and stimulated autophagosome formation. These effects were accompanied by decreased activation of AKT, ERK1/2, and S6K. Furthermore, incubation of ECSCs with AKT and ERK1/2 inhibitors, which mimicked dienogest-mediated inhibition of AKT and ERK1/2 activity, suppressed S6K activity, followed by an increase in LC3 II expression. In addition, cotreatment with dienogest and 3-methyladenine (autophagy inhibitor) decreased the levels of apoptosis of ECSCs compared with the single treatment with dienogest. CONCLUSION(S): Our results suggest that dienogest treatment of endometriotic cells suppresses AKT and ERK1/2 activity, thereby in turn inhibiting mTOR, inducing autophagy, and promoting apoptosis. PMID- 26051104 TI - Operando spectroscopic analysis of an amorphous cobalt sulfide hydrogen evolution electrocatalyst. AB - The generation of chemical fuel in the form of molecular H2 via the electrolysis of water is regarded to be a promising approach to convert incident solar power into an energy storage medium. Highly efficient and cost-effective catalysts are required to make such an approach practical on a large scale. Recently, a number of amorphous hydrogen evolution reaction (HER) catalysts have emerged that show promise in terms of scalability and reactivity, yet remain poorly understood. In this work, we utilize Raman spectroscopy and X-ray absorption spectroscopy (XAS) as a tool to elucidate the structure and function of an amorphous cobalt sulfide (CoSx) catalyst. Ex situ measurements reveal that the as-deposited CoSx catalyst is composed of small clusters in which the cobalt is surrounded by both sulfur and oxygen. Operando experiments, performed while the CoSx is catalyzing the HER, yield a molecular model in which cobalt is in an octahedral CoS2-like state where the cobalt center is predominantly surrounded by a first shell of sulfur atoms, which, in turn, are preferentially exposed to electrolyte relative to bulk CoS2. We surmise that these CoS2-like clusters form under cathodic polarization and expose a high density of catalytically active sulfur sites for the HER. PMID- 26051105 TI - Forming End-to-End Oligomers of Gold Nanorods Using Porphyrins and Phthalocyanines. AB - The illumination of aggregated metal nanospecies can create strong local electric fields to brighten Raman scattering. This study describes a procedure to self assemble gold nanorods (NRs) through the use of porphyrin and phthalocyanine agents to create reproducibly stable and robust NR aggregates in the form of end to-end oligomers. Narrow inter-rod gaps result, creating electric field "hot spots" between the NRs. The organic linker molecules themselves are potential Raman-based optical labels, and the result is significant numbers of Raman-active species located in the hot spots. NR polymerization was quenched by phospholipid encapsulation, which allows for control of the polydispersity of the aggregate solution, to optimize the surface-enhanced Raman scattering (SERS) enhancement and permitted the aqueous solubility of the aggregates. The increased presence of Raman-active species in the hot spots and the optimizing of solution polydispersity resulted in the observation of scattering enhancements by encapsulated porphyrins/phthalocyanines of up to 3500-fold over molecular chromophores lacking the NR oligomer host. PMID- 26051106 TI - Differential diagnosis of pleural mesothelioma using Logic Learning Machine. AB - BACKGROUND: Tumour markers are standard tools for the differential diagnosis of cancer. However, the occurrence of nonspecific symptoms and different malignancies involving the same cancer site may lead to a high proportion of misclassifications. Classification accuracy can be improved by combining information from different markers using standard data mining techniques, like Decision Tree (DT), Artificial Neural Network (ANN), and k-Nearest Neighbour (KNN) classifier. Unfortunately, each method suffers from some unavoidable limitations. DT, in general, tends to show a low classification performance, whereas ANN and KNN produce a "black-box" classification that does not provide biological information useful for clinical purposes. METHODS: Logic Learning Machine (LLM) is an innovative method of supervised data analysis capable of building classifiers described by a set of intelligible rules including simple conditions in their antecedent part. It is essentially an efficient implementation of the Switching Neural Network model and reaches excellent classification accuracy while keeping low the computational demand. LLM was applied to data from a consecutive cohort of 169 patients admitted for diagnosis to two pulmonary departments in Northern Italy from 2009 to 2011. Patients included 52 malignant pleural mesotheliomas (MPM), 62 pleural metastases (MTX) from other tumours and 55 benign diseases (BD) associated with pleurisies. Concentration of three tumour markers (CEA, CYFRA 21-1 and SMRP) was measured in the pleural fluid of each patient and a cytological examination was also carried out. The performance of LLM and that of three competing methods (DT, KNN and ANN) was assessed by leave-one-out cross-validation. RESULTS: LLM outperformed all other considered methods. Global accuracy was 77.5% for LLM, 72.8% for DT, 54.4% for KNN, and 63.9% for ANN, respectively. In more details, LLM correctly classified 79% of MPM, 66% of MTX and 89% of BD. The corresponding figures for DT were: MPM = 83%, MTX = 55% and BD = 84%; for KNN: MPM = 58%, MTX = 45%, BD = 62%; for ANN: MPM = 71%, MTX = 47%, BD = 76%. Finally, LLM provided classification rules in a very good agreement with a priori knowledge about the biological role of the considered tumour markers. CONCLUSIONS: LLM is a new flexible tool potentially useful for the differential diagnosis of pleural mesothelioma. PMID- 26051107 TI - Influence of acidic pH on keratinocyte function and re-epithelialisation of human in vitro wounds. AB - BACKGROUND: Chronic wounds are one of the greatest challenges for the healthcare system. Today, a plethora of dressings are used in the treatment of these wounds, each with specific influence on the wound environment. Due to differences in the permeability of the dressings the use will result in differences in the pH balance in the wound bed. However, little is known about how changes in the pH in the wound environment affect the different phases of the healing process. AIM: The aim of the present study was to investigate the effects of acidic pH on the regeneration phase by studying keratinocyte function in vitro and re epithelialisation in an in vitro model of human skin. RESULTS: In vitro assays showed reduced viability and migration rates in human keratinocytes when pH was lowered. Real time PCR revealed differential expression of genes related to wound healing and environmental impairment. Tissue culture showed no re epithelialisation of wounds subjected to pH 5.0 and moderate re-epithelialisation at pH 6.0, compared to controls at pH 7.4. CONCLUSION: The results indicate that lowering pH down to pH 5.0 in wounds is counterproductive in aspect of keratinocyte function which is crucial for successful wound healing. PMID- 26051108 TI - Novel chemical scaffolds of the tumor marker AKR1B10 inhibitors discovered by 3D QSAR pharmacophore modeling. AB - AIM: Recent evidence suggests that aldo-keto reductase family 1 B10 (AKR1B10) may be a potential diagnostic or prognostic marker of human tumors, and that AKR1B10 inhibitors offer a promising choice for treatment of many types of human cancers. The aim of this study was to identify novel chemical scaffolds of AKR1B10 inhibitors using in silico approaches. METHODS: The 3D QSAR pharmacophore models were generated using HypoGen. A validated pharmacophore model was selected for virtual screening of 4 chemical databases. The best mapped compounds were assessed for their drug-like properties. The binding orientations of the resulting compounds were predicted by molecular docking. Density functional theory calculations were carried out using B3LYP. The stability of the protein ligand complexes and the final binding modes of the hit compounds were analyzed using 10 ns molecular dynamics (MD) simulations. RESULTS: The best pharmacophore model (Hypo 1) showed the highest correlation coefficient (0.979), lowest total cost (102.89) and least RMSD value (0.59). Hypo 1 consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one ring aromatic and one hydrophobic feature. This model was validated by Fischer's randomization and 40 test set compounds. Virtual screening of chemical databases and the docking studies resulted in 30 representative compounds. Frontier orbital analysis confirmed that only 3 compounds had sufficiently low energy band gaps. MD simulations revealed the binding modes of the 3 hit compounds: all of them showed a large number of hydrogen bonds and hydrophobic interactions with the active site and specificity pocket residues of AKR1B10. CONCLUSION: Three compounds with new structural scaffolds have been identified, which have stronger binding affinities for AKR1B10 than known inhibitors. PMID- 26051109 TI - Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel MU opioid receptor ligands. AB - AIM: Tramadol is an atypical opioid analgesic with low potential for tolerance and addiction. However, its opioid activity is much lower than classic opiates such as morphine. To develop novel analgesic and further explore the structure activity relationship (SAR) of tramadol skeleton. METHODS: Based on a three dimensional (3D) structure superimposition and molecular docking study, we found that M1 (the active metabolite of tramadol) and morphine have common pharmacophore features and similar binding modes at the MU opioid receptor in which the substituents on the nitrogen atom of both compounds faced a common hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. In this study, N phenethylnormorphine was docked to the MU opioid receptor. It was found that the N-substituted group of N-phenethylnormorphine extended into a hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. This hydrophobic interaction may contribute to the improvement of its opioid activities as compared with morphine. The binding modes of M1, morphine and N-phenethylnormorphine overlapped, indicating that the substituent on the nitrogen atoms of the three compounds may adopt common orientations. A series of N-phenylalkyl derivatives from the tramadol scaffold were designed, synthesized and assayed in order to generate a new type of analgesics. RESULTS: As a result, compound 5b was identified to be an active candidate from these compounds. Furthermore, the binding modes of 5b and morphine derivatives in the MU opioid receptor were comparatively studied. CONCLUSION: Unlike morphine-derived structures in which bulky N-substitution is associated with improved opioid-like activities, there seems to be a different story for tramadol, suggesting the potential difference of SAR between these compounds. A new type of interaction mechanism in tramadol analogue (5b) was discovered, which will help advance potent tramadol-based analgesic design. PMID- 26051110 TI - The efficacy and safety of weekly 35-mg risedronate dosing regimen for Chinese postmenopausal women with osteoporosis or osteopenia: 1-year data. AB - AIM: Oral risedronate is effective in the treatment of postmenopausal osteoporosis when administered daily, weekly, or monthly. In this 1-year, randomized, double-blind, multicenter study we compared the weekly 35-mg and daily 5-mg risedronate dosing regimens in the treatment of Chinese postmenopausal women with osteoporosis or osteopenia. METHODS: Postmenopausal women with primary osteoporosis or osteopenia were randomly assigned to the weekly group or daily group (n=145 for each) that received oral risedronate 35 mg once a week or 5 mg daily, respectively, for 1 year. The subjects' bone mineral densities (BMDs), bone turnover markers (P1NP and beta-CTX), new vertebral fractures, and adverse events were assessed at baseline and during the treatments. RESULTS: All subjects in the weekly group and 144 subjects in the daily group completed the study. The primary efficacy endpoint after 1 year, ie the mean percent changes in the lumbar spine BMD (95% CI) were 4.87% (3.92% to 5.81%) for the weekly group and 4.35% (3.31% to 5.39%) for the daily group. The incidences of clinical adverse events were 48.3% in the weekly group and 54.2% in the daily group. CONCLUSION: The weekly 35-mg and daily 5-mg risedronate dosing regimens during 1 year of follow up show similar efficacy in improving BMDs and biochemical markers of bone turnover in Chinese postmenopausal women with osteoporosis or osteopenia. Moreover, the two dosing regimens exhibit similar safety and tolerability. PMID- 26051111 TI - Intestinal absorption characteristics of imperialine: in vitro and in situ assessments. AB - AIM: Imperialine is an effective compound in the traditional Chinese medicine chuanbeimu (Bulbus Fritillariae Cirrhosae) that has been used as antitussive/expectorant in a clinical setting. In this study we investigated the absorption characteristics of imperialine in intestinal segments based on an evaluation of its physicochemical properties. METHODS: Caco-2 cells were used to examine uptake and transport of imperialine in vitro, and a rat in situ intestinal perfusion model was used to characterize the absorption of imperialine. The amount of imperialine in the samples was quantified using LC MS/MS. RESULTS: The aqueous solubility and oil/water partition coefficient of imperialine were determined. This compound demonstrated a relatively weak alkalinity with a pKa of 8.467+/-0.028. In Caco-2 cells, the uptake of imperialine was increased with increasing pH in medium, but not affected by temperature. The apparent absorptive and secretive coefficient was (8.39+/ 0.12)*10(-6) cm/s and (7.78+/-0.09)*10(-6) cm/s, respectively. Furthermore, neither the P-glycoprotein inhibitor verapamil nor Niemann-Pick C1-Like 1 transporter inhibitor ezetimibe affected the absorption and secretion of imperialine in vitro. The in situ intestinal perfusion study showed that the absorption parameters of imperialine varied in 4 intestinal segments (duodenum, jejunum, ileum and colon) with the highest ones in the colon, where a greater number of non-ionized form of imperialine was present. CONCLUSION: The intestinal absorptive characteristics of imperialine are closely related to its physicochemical properties. The passive membrane diffusion dominates the intestinal absorption of imperialine. PMID- 26051113 TI - Vitamin D deficiency and its associated risk factors in children and adolescents in southern Iran. AB - OBJECTIVES: To evaluate prevalence of vitamin D deficiency and its associated factors in southern Iranian children. DESIGN: Cross-sectional study. Anthropometric and pubertal characteristics were assessed by a trained physician. Physical activity and sun exposure were evaluated using standard questionnaires. Body composition measurements were performed using dual-energy X-ray absorptiometry. Serum Ca, P alkaline phosphatase and 25-hydroxyvitamin D (25(OH)D) were assessed in all children. Statistical analysis was done using the statistical software package IBM SPSS Statistics 18.0. SUBJECTS: Iranian children (n 477) aged 9-18 years. SETTING: Fars Province, Iran, 2011. RESULTS: Of the children, 81.3 % were 25(OH)D deficient. There was no significant difference in 25(OH)D concentration between boys and girls (P=0.3). 25(OH)D concentration was associated with BMI (r=-0.1, P=0.02), pubertal status (r=-0.08, P=0.04) and sun exposure (r=0.10, P=0.04). Fat mass index was associated with 25(OH)D concentration (r=-0.13, P=0.03), but not lean mass index (P=0.86). In multiple regression analysis with adjustment for confounding factors, age and puberty were found to be independently associated with 25(OH)D concentration (P=0.008 and P=0.006); there was a significant correlation between exercise and 25(OH)D concentration after adjustment for either BMI (P=0.01) or fat mass index (P=0.02). CONCLUSIONS: 25(OH)D deficiency is highly prevalent among children in the south of Iran. It is related to insufficient sun exposure, low physical activity, advancing age and pubertal stage. Measures should be taken to improve the health of southern Iranian children in this critical age group by preventing 25(OH)D deficiency. PMID- 26051112 TI - Inhibition of Nav1.7 channels by methyl eugenol as a mechanism underlying its antinociceptive and anesthetic actions. AB - AIM: Methyl eugenol is a major active component extracted from the Chinese herb Asari Radix et Rhizoma, which has been used to treat toothache and other pain. Previous in vivo studies have shown that methyl eugenol has anesthetic and antinociceptive effects. The aim of this study was to determine the possible mechanism underlying its effect on nervous system disorders. METHODS: The direct interaction of methyl eugenol with Na(+) channels was explored and characterized using electrophysiological recordings from Nav1.7-transfected CHO cells. RESULTS: In whole-cell patch clamp mode, methyl eugenol tonically inhibited peripheral nerve Nav1.7 currents in a concentration- and voltage-dependent manner, with an IC50 of 295 MUmol/L at a -100 mV holding potential. Functionally, methyl eugenol preferentially bound to Nav1.7 channels in the inactivated and/or open state, with weaker binding to channels in the resting state. Thus, in the presence of methyl eugenol, Nav1.7 channels exhibited reduced availability for activation in a steady-state inactivation protocol, strong use-dependent inhibition, enhanced binding kinetics, and slow recovery from inactivation compared to untreated channels. An estimation of the affinity of methyl eugenol for the resting and inactivated states of the channel also demonstrated that methyl eugenol preferentially binds to inactivated channels, with a 6.4 times greater affinity compared to channels in the resting state. The failure of inactivated channels to completely recover to control levels at higher concentrations of methyl eugenol implies that the drug may drive more drug-bound, fast-inactivated channels into drug-bound, slow-inactivated channels. CONCLUSION: Methyl eugenol is a potential candidate as an effective local anesthetic and analgesic. The antinociceptive and anesthetic effects of methyl eugenol result from the inhibitory action of methyl eugenol on peripheral Na(+) channels. PMID- 26051114 TI - Synthetic sugar cassettes for the efficient production of flavonol glycosides in Escherichia coli. AB - BACKGROUND: A multi-monocistronic synthetic vector was used to assemble multiple genes of a nucleotide diphosphate (NDP)-sugar biosynthetic pathway to construct robust genetic circuits for the production of valuable flavonoid glycosides in Escherichia coli. Characterized functional genes involved in the biosynthesis of uridine diphosphate (UDP)-glucose and thymidine diphosphate (TDP)-rhamnose from various microbial sources along with glucose facilitator diffusion protein (glf) and glucokinase (glk) from Zymomonas mobilis were assembled and overexpressed in a single synthetic multi-monocistronic operon. RESULTS: The newly generated NDP sugars biosynthesis circuits along with regiospecific glycosyltransferases from plants were introduced in E. coli BL21 (DE3) to probe the bioconversion of fisetin, a medicinally important polyphenol produced by various plants. As a result, approximately 1.178 g of fisetin 3-O-glucoside and 1.026 g of fisetin 3-O rhamnoside were produced in UDP-glucose and TDP-rhamnose biosynthesis systems respectively, after 48 h of incubation in 3 L fermentor while supplementing 0.9 g of fisetin. These yields of fisetin glycosides represent ~99% of bioconversion of exogenously supplemented fisetin. The systems were also found to be highly effective in bio-transforming other flavonols (quercetin, kaempferol, myricetin) into their respective glycosides, achieving over 95% substrate conversion. CONCLUSION: The construction of a synthetic expression vector for bacterial cell factory followed by subsequent re-direction of metabolic flux towards desirable products have always been revolutionized the biotechnological processes and technologies. This multi-monocistronic synthetic vector in a microbial platform is customizable to defined task and would certainly be useful for applications in producing and modifying such therapeutically valued plant secondary metabolites. PMID- 26051115 TI - Difficulties in using Oswestry Disability Index in Indian patients and validity and reliability of translator-assisted Oswestry Disability Index. AB - BACKGROUND AND AIM OF THE STUDY: In Indian patients, in view of language plurality and illiteracy, self-reporting of English version of Oswestry Disability Index (ODI) is not practical. Our study aim was to find out to what extent self-reporting of ODI was possible and in cases where self-reporting was not possible, to see validity and reliability of a translator-assisted ODI score. MATERIALS AND METHODS: Fifty patients with low backache and who could not use the English version were assessed with ODI with the use of two translators at a gap of 3 h in a test and retest manner. Patients were also asked to report the most important disabling activity in their day-to-day life. RESULTS: A total of 58 questionnaires were filled during the study period out of which eight patients (14%) self-reported English version; while 50 patients needed a translator. The Cronbach's alpha between two translators for the ODI scores of 50 patients was 0.866, but aggregate of difference between two scores for each ODI component shows high difference between two translators for question nos. 3, 9, and 10. Cronbach's alpha was best when item no. 3 was deleted (0.875, translator 1; 0.777, translator 2). Thirty-seven people did not answer the question related to sexual activity. Agreement between two values was assessed using Kendall's tau and was found good (0.585, Spearman's coefficient 0.741). Kendall's tau values correlating total ODI score and individual components show that all the items move together, but correlation was poor for question no. 3 (P value 0.16 for translator 2). CONCLUSIONS: Translator-assisted ODI is a good outcome assessment tool in backache assessment in places where validated local language versions are not available, but in Indian patients, inclusion of question nos. 3 and 8 related to weight lifting and sexual function needs to be reviewed. PMID- 26051116 TI - Erratum to: Mass spectrometric analysis of protein tyrosine nitration in aging and neurodegenerative diesases. PMID- 26051117 TI - Nanoscale crosslinking in thermoset polymers: a molecular dynamics study. AB - In this paper, the nanoscale crosslinking process of thermoset polymer is studied using all-atom molecular dynamics. Based on the crosslinking simulations, the elastic properties of typical E51/593 thermoset polymer are predicted and verified by tensile experiments within a 10% error. The proposed method reveals a reliable understanding of the nanoscale crosslinking reactions occurring in thermoset polymers. Changes in system energy and overall density distribution, as well as the quantification of bond formation, yield a better insight into thermoset crosslinking that would be difficult to obtain through experimentation. The results give us confidence in realizing the virtual design of thermosets leading to tunable properties. PMID- 26051118 TI - Functional native disulfide bridging enables delivery of a potent, stable and targeted antibody-drug conjugate (ADC). AB - Herein we report the use of next generation maleimides (NGMs) for the construction of a potent antibody-drug conjugate (ADC) via functional disulfide bridging. The linker has excellent stability in blood serum and the ADC, armed with monomethyl auristatin E (MMAE), shows excellent potency and cancer cell selectivity in vitro. PMID- 26051119 TI - Signal-sequence induced conformational changes in the signal recognition particle. AB - Co-translational protein targeting is an essential, evolutionarily conserved pathway for delivering nascent proteins to the proper cellular membrane. In this pathway, the signal recognition particle (SRP) first recognizes the N-terminal signal sequence of nascent proteins and subsequently interacts with the SRP receptor. For this, signal sequence binding in the SRP54 M domain must be effectively communicated to the SRP54 NG domain that interacts with the receptor. Here we present the 2.9 A crystal structure of unbound- and signal sequence bound SRP forms, both present in the asymmetric unit. The structures provide evidence for a coupled binding and folding mechanism in which signal sequence binding induces the concerted folding of the GM linker helix, the finger loop, and the C terminal alpha helix alphaM6. This mechanism allows for a high degree of structural adaptability of the binding site and suggests how signal sequence binding in the M domain is coupled to repositioning of the NG domain. PMID- 26051120 TI - A renewal model for the emergence of anomalous solute crowding in liposomes. AB - A fundamental evolutionary step in the onset of living cells is thought to be the spontaneous formation of lipid vesicles (liposomes) in the pre-biotic mixture. Even though it is well known that hydrophobic forces drive spontaneous liposome formation in aqueous solutions, how the components of the earliest biochemical pathways were trapped and concentrated in the forming vesicles is an issue that still needs to be clarified. In recent years, some authors carried out a set of experiments where a unexpectedly high amount of solutes were found in a small number of liposomes, spontaneously formed in aqueous solution. A great number of empty liposomes were found in the same experiments and the global observed behavior was that of a distribution of solute particles into liposomes in agreement with a inverse power-law function rather than with the expected Poisson distribution. The chemical and physical mechanisms leading to the observed "anomalous solute crowding" are still unclear, but the non-Poisson power-law behavior is associated with some cooperative behavior with strong non-linear interactions in the biochemical processes occurring in the solution. For tackling this issue we propose a model grounding on the Cox's theory of renewal point processes, which many authors consider to play a central role in the description of complex cooperative systems. Starting from two very basic hypotheses and the renewal assumption, we derive a model reproducing the behavior outlined above. In particular, we show that the assumption of a "cooperative" interaction between the solute molecules and the forming liposomes is sufficient for the emergence of the observed power-law behavior. Even though our approach does not provide experimental evidences of the chemical and physical bases of the solute crowding, it suggests promising directions for experimental research and it also provide a first theoretical prediction that could possibly be tested in future experimental investigations. PMID- 26051122 TI - Enantioselective formation of tertiary and quaternary allylic C-N bonds via allylation of tetrazoles. AB - Rhodium-catalyzed regio- and enantioselective coupling of tetrazoles with allenes are reported. Asymmetric construction of tertiary and quaternary allylic C-N bonds were achieved using a Rh(I)/JoSPOphos catalyst. This method permits the atom-economic synthesis of various valuable N(2)-allylic tetrazoles. PMID- 26051121 TI - Energy patterns in twist-opening models of DNA with solvent interactions. AB - Energy localization, via modulation instability, is addressed in a modified twist opening model of DNA with solvent interactions. The Fourier expansion method is used to reduce the complex roto-torsional equations of the system to a set of discrete coupled nonlinear Schrodinger equations, which are used to perform the analytical investigation of modulation instability. We find that the instability criterion is highly influenced by the solvent parameters. Direct numerical simulations, performed on the generic model, further confirm our analytical predictions, as solvent interactions bring about highly localized energy patterns. These patterns are also shown to be robust under thermal fluctuations. PMID- 26051123 TI - A constant area monolayer method to assess optimal lipid packing for lipolysis tested with several secreted phospholipase A2. AB - We present an analysis of lipid monolayer hydrolysis at a constant area to assess the optimal lateral surface pressure value (Piopt) and thus, the surface packing density of the lipid, at which the activity of a given lipolytic enzyme is maximal. This isochoric method consists of a measurement of the decrease down to zero of the Piopt of phospholipid substrate monolayer due to continuous hydrolysis using only one reaction compartment. We performed the comparison of both approaches using several commercially available and literature-evaluated sPLA2s. Also, we characterized for the first time the profile of hydrolysis of DLPC monolayers catalyzed by a sPLA2 from Streptomyces violaceoruber and isoenzymes purified from Bothrops diporus venom. One of these viper venom enzymes is a new isoenzyme, partially sequenced by a mass spectrometry approach. We also included the basic myotoxin sPLA2-III from Bothrops asper. Results obtained with the isochoric method and the standard isobaric one produced quite similar values of Piopt, validating the proposal. In addition, we propose a new classification parameter, a lipolytic ratio of hydrolysis at two lateral pressures, 20 mN.m(-1) and 10 mN.m(-1), termed here as LR20/10 index. This index differentiates quite well "high surface pressure" from "low surface pressure" sPLA2s and, by extension; it can be used as a functional criterion for the quality of a certain enzyme. Also, this index could be added to the grouping systematic criteria for the superfamily proposed for phospholipase A2. PMID- 26051124 TI - Site of fluorescent label modifies interaction of melittin with live cells and model membranes. AB - The mechanism of membrane disruption by melittin (MLT) of giant unilamellar vesicles (GUVs) and live cells was studied using fluorescence microscopy and two fluorescent synthetic analogues of MLT. The N-terminus of one of these was acylated with thiopropionic acid to enable labeling with maleimido-AlexaFluor 430 to study the interaction of MLT with live cells. It was compared with a second analogue labeled at P14C. The results indicated that the fluorescent peptides adhered to the membrane bilayer of phosphatidylcholine GUVs and inserted into the plasma membrane of HeLa cells. Fluorescence and light microscopy revealed changes in cell morphology after exposure to MLT peptides and showed bleb formation in the plasma membrane of HeLa cells. However, the membrane disruptive effect was dependent upon the location of the fluorescent label on the peptide and was greater when MLT was labeled at the N-terminus. Proline at position 14 appeared to be important for antimicrobial activity, hemolysis and cytotoxicity, but not essential for cell membrane disruption. PMID- 26051125 TI - Membrane proteins occupy a central role in cellular physiology. Introduction. PMID- 26051126 TI - Defensive remodeling: How bacterial surface properties and biofilm formation promote resistance to antimicrobial peptides. AB - Multidrug resistance bacteria are a major concern worldwide. These pathogens cannot be treated with conventional antibiotics and thus alternative therapeutic agents are needed. Antimicrobial peptides (AMPs) are considered to be good candidates for this purpose. Most AMPs are short and positively charged amphipathic peptides, which are found in all known forms of life. AMPs are known to kill bacteria by binding to the negatively charged bacterial surface, and in most cases cause membrane disruption. Resistance toward AMPs can be developed, by modification of bacterial surface molecules, secretion of protective material and up-regulation or elimination of specific proteins. Because of the general mechanisms of attachment and action of AMPs, bacterial resistance to AMPs often involves biophysical and biochemical changes such as surface rigidity, cell wall thickness, surface charge, as well as membrane and cell wall modification. Here we focus on the biophysical, surface and surrounding changes that bacteria undergo in acquiring resistance to AMPs. In addition we discuss the question of whether bacterial resistance to administered AMPs might compromise our innate immunity to endogenous AMPs. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID- 26051127 TI - The Cryo-EM structure of the CorA channel from Methanocaldococcus jannaschii in low magnesium conditions. AB - CorA channels are responsible for the uptake of essential magnesium ions by bacteria. X-ray crystal structures have been resolved for two full-length CorA channels, each in a non-conducting state with magnesium ions bound to the protein: These structures reveal a homo-pentameric quaternary structure with approximate 5-fold rotational symmetry about a central pore axis. We report the structure of the detergent solubilized Methanocaldococcus jannaschii CorA channel determined by Cryo-Electron Microscopy and Single Particle Averaging, supported by Small Angle X-ray Scattering and X-ray crystallography. This structure also shows a pentameric channel but with a highly asymmetric domain structure. The asymmetry of the domains includes differential separations between the trans membrane segments, which reflects mechanical coupling of the cytoplasmic domain to the trans-membrane domain. This structure therefore reveals an important aspect of the gating mechanism of CorA channels by providing an indication of how the absence of magnesium ions leads to major structural changes. PMID- 26051128 TI - Molecular characterisation of three regions of the nuclear ribosomal DNA unit and the mitochondrial cox1 gene of Sarcocystis fusiformis from water buffaloes (Bubalus bubalis) in Egypt. AB - A total of 33 macroscopically visible (3-11 * 1-5 mm) sarcocysts of Sarcocystis fusiformis were excised from the oesophagus of 12 freshly slaughtered water buffalos in Giza, Egypt. Genomic DNA was extracted from the sarcocysts, and all isolates were characterised at the mitochondrial cytochrome c oxidase subunit I (cox1) gene through PCR amplification and direct sequencing, whereas a few selected isolates were characterised at the 18S and 28S ribosomal (r) RNA genes and the internal transcribed spacer 1 (ITS1) region of the nuclear rDNA unit following cloning. Among the 33 cox1 sequences (1,038-bp long), there was a total of 13 haplotypes, differing from each other by one to seven substitutions and sharing an identity of 99.3-99.9 %. In comparison, the sequence identity was 98.8 99.0 % among eight complete 18S rRNA gene sequences (1,873-1,879-bp long), 98.1 100 % among 28 complete ITS1 sequences (853-864-bp long) and 97.4-99.6 % among five partial 28S rRNA gene sequences (1,607-1,622 bp). At the three nuclear loci, the intraspecific (and intra-isolate) sequence variation was due to both substitutions and indels, which necessitated cloning of the PCR products before sequencing. Some additional clones of the 18S and 28S rRNA genes were highly divergent from the more typical clones, but the true nature of these aberrant clones could not be determined. Sequence comparisons and phylogenetic analyses based on either 18S rRNA gene or cox1 nucleotide sequences, placed S. fusiformis closest to Sarcocystis cafferi from the African buffalo, but only the analyses based on cox1 data separated the two taxa clearly from each other and showed that they were separate species (monophyletic clusters and 93 % sequence identity at cox1 versus interleaved sequences and 98.7-99.1 % sequence identity at the 18S rRNA gene). Two cats experimentally infected with sarcocysts of S. fusiformis started shedding small numbers of sporocysts 8-10 days post-infection (dpi) and were euthanized 15 dpi. Sporocysts isolated from the intestinal mucosa of both cats were identified molecularly as belonging to S. fusiformis through PCR amplification and sequencing of the partial cox1. The two sporocyst-derived cox1 sequences were identical with the most common sarcocyst-derived cox1 haplotype. PMID- 26051130 TI - Self-assembled BiVO4/Bi2WO6 microspheres: synthesis, photoinduced charge transfer properties and photocatalytic activities. AB - Three-dimensional (3D) BiVO4/Bi2WO6 composite microspheres with enhanced visible light (lambda > 420 nm) photodegradation activity of methylene blue (MB) were synthesized by a simple, one-pot, template-free solvothermal method. A mixture of ethylene glycol (EG) and H2O (volume ratio of EG-H2O was 1 : 1) was used as the solvent. To investigate the relationship between structure and photocatalytic performance, the as-synthesized samples were characterized by XRD, FESEM, HRTEM, UV-vis DRS, SPS and TPV. Structural characterizations indicated that the composite nanostructure mainly consisted of two single-crystal phases, which were BiVO4 and Bi2WO6. In addition, a possible growth mechanism of this microsphere composite and the separation process of photoinduced charge carriers in the heterojunction are discussed. PMID- 26051129 TI - Time-dependent changes in inhibitory action of lipopolysaccharide on intestinal motility in rat. AB - Endotoxin causes gastrointestinal motility disorder. Aim of this study is to clarify inhibitory mechanisms of lipopolysaccharide (LPS) on smooth muscle contraction in rat ileum. Ileal tissues were isolated from control rat or from LPS-induced peritonitis model rat. Treatment with LPS inhibited carbachol (CCh) mediated contraction in a time-dependent manner. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes were also upregulated, but iNOS expression was preceded by a rising of COX-2. All subtypes of prostaglandin E2 (PGE2) receptors (EP1-EP4) were expressed in ileum, and PGE2 and selective EP2 or EP4 agonist inhibited CCh-mediated contraction. Selective iNOS inhibitor did not reverse LPS-induced inhibition of contraction by CCh at 1 and 2 hr, but reduced the inhibitory action at 4 hr after the LPS treatment. COX-2 inhibitor reversed the inhibitory action by LPS in all exposure time. Finally, in ileal tissues isolated from peritonitis model rat, iNOS expression was upregulated only at 4 hr after LPS administration, resulting in enhanced inhibitory action of LPS against CCh-induced contraction. In conclusion, LPS induces COX-2 to produce PGE2, which initially activates EP2 and/or EP4 on smooth muscle cells to inhibit the contractility in early phase of LPS exposure. Moreover, in late phase of LPS treatment, iNOS is expressed to produce NO, which in turn inhibited the contraction by CCh. The inhibitory cascade is similar in the ileum isolated from peritonitis model rat, indicating time-dependent changes of inhibitory action by LPS on intestinal motility in peritonitis. PMID- 26051131 TI - [Inequalities in cervical screening practices]. AB - Theoretically, the cytology-based cervical screening is capable of early detection of precancerous epithelial lesions of cervix uteri and its cancer, and of early referral to treatment. In this way, screening can inmprove the quality of life of the patients and reduce mortality from the target disease. Unfortunately, this often remains unexploited, because there might be inequalities on both "supply" and "demand" side of screening. In addition to the geopolitical situation of a country, inequalities might result from differences in the health care systems, and heavy access to the screening services. On the other hand, the socioeconomic status, the health-conciousness of the target population, and their knowledge and information of the benefits and potential harms of screening examination might have a bearing on the acceptance or refusal of the offered screening. Efforts need to be made to increase the uptake of cervical screening programmes. PMID- 26051132 TI - [Automated measurement of biomarkers for the diagnosis of acute myocardial infarction]. AB - INTRODUCTION: Cardiac biomarkers have a prominent role in the diagnosis of acute myocardial infarction. AIM: The aim of the authors was to study the diagnostic effectiveness of automated measurement of cardiac biomarkers. METHOD: Myeloperoxidase, high-sensitivity C-reactive protein, myoglobin, heart-type fatty acid binding protein, creatine kinase, creatine kinase MB, high-sensitivity troponin I and T were measured. RESULTS: The high-sensitivity troponin I was the most effective (area under curve: 0.86; 95% confidence interval: 0.77-0.95; p<0.001) for the diagnosis of acute myocardial infarction. Considering a critical value of 0.35 ng/mL, its sensitivity and specificity were 81%, and 74%, respectively. Combined evaluation of the high-sensitivity troponin T and I, chest pain, and the electrocardiogram gave the best results for separation of acute myocardial infarction from other diseases (correct classification in 62.5% and 98.9% of patients, respectively). CONCLUSIONS: Until a more sensitive and specific cardiac biomarker becomes available, the best method for the diagnosis of acute myocardial infarction is to evaluate electrocardiogram and biomarker concentration and to repeat them after 3-6 hours. PMID- 26051133 TI - [Relationships between right atrial and left ventricular size and function in health subjects. Results from the three-dimensional speckle-tracking echocardiographic MAGYAR-Healthy Study]. AB - INTRODUCTION: The heart cycle includes systole and diastole when the heart chambers are characterized by a complex motion. AIM: The present study was designed to test whether relationships exist between three-dimensional speckle tracking echocardiography-derived right atrial and routine two-dimensional echocardiography-derived left ventricular volumetric and functional parameters is healthy subjects. METHOD: The present study comprised 20 healthy volunteers. Complete two-dimensional echocardiography and three-dimensional speckle-tracking echocardiography were perfomed in all cases. RESULTS: Left ventricular ejection fraction showed correlations with systolic and diastolic right atrial volumes and area strain characterzing atrial contraction in diastole. Right atrial volumes respective of cardiac cycle correlated only with left ventricular end-systolic diameter and volume, while similar relationships could not be confirmed with end diastolic parameters. CONCLUSIONS: Relationships could be demonstrated between three-dimensional speckle-tracking echocardiography-derived right atrial and two dimensional echocardiography-derived left ventricular volumetric and functional parameters in healthy subjects. PMID- 26051134 TI - [The tip of the iceberg: multiple cutaneous sebaceous tumor in colon cancer. Muir Torre syndrome--case report]. AB - Muir-Torre syndrome is a rare genodermatosis with autosomal dominant inheritance. The syndrome is considered to be a subtype of the hereditary nonpolyposis colorectal cancer (or Lynch-syndrome). In two-third of the cases, it develops as the consequence of germline mutations in mismatch-repair genes--most commonly MutS Homolog-2 and MutL Homolog-1. Its diagnosis can be established if at least one sebaceous tumor (sebaceoma, sebaceous adenoma, epithelioma, carcinoma or basal-cell carcinoma with sebaceous differentiation) and/or keratoacanthoma and at least one internal neoplasm are present. Here the authors present the history of a 52-year-old man with multiple sebaceous carcinomas on his back. Immunohistochemical analysis showed the lack of MutL Homolog-1 protein expression in the tumor cells. Detailed clinical workup in order to identify internal malignancy found malignant coecum tumor. Histopathological evaluation of the sample from the right hemicolectomy revealed mid-grade adenocarcinoma with MutL Homolog-1 and postmeiotic segregation increased-2 deficiency. The detection of the cutaneous sebaceous carcinoma and the application of the modern diagnostic methods resulted in identification of the associated colorectal cancer in an early stage; hence, definitive treatment was available for the patient. PMID- 26051135 TI - [Significance of journal articles within the scientific literature of various disciplines: trends over the past two decades]. AB - Trends of preferred publication channels in selected categories of Sciences, Social Sciences and Arts & Humanities were studied by determining the percentage share of references in reviews to serials (journals) in all references. It was found that in the period 1995-2014, the fraction of articles published in journals was increasing in all selected areas of science and scholarship. The most dynamical increase was found in Social Sciences. PMID- 26051136 TI - [Lights and shadows in Sherwin B. Nuland's portrait of Semmelweis]. PMID- 26051138 TI - Photoelectrochemical CO2 reduction using a Ru(II)-Re(I) multinuclear metal complex on a p-type semiconducting NiO electrode. AB - A photocathode for CO2 reduction was successfully developed using a hybrid electrode comprising a Ru(II)-Re(I) supramolecular photocatalyst and a NiO electrode. Selective photoexcitation of the Ru photosensitizer unit of the photocatalyst at -1.2 V vs. Ag/AgNO3 selectively afforded CO with high faradaic efficiency. PMID- 26051139 TI - From the Editor in Chief. PMID- 26051141 TI - Whooping cough, twenty years from acellular vaccines introduction. AB - Clinical pertussis resulting from infection with B. pertussis is a significant medical and public health problem, despite the huge success of vaccination that has greatly reduced its incidence. The whole cell vaccine had an undeniable success over the last 50 years, but its acceptance was strongly inhibited by fear, only partially justified, of severe side effects, but also, in the Western world, by the difficulty to enter in combination with other vaccines: today multi vaccine formulations are essential to maintain a high vaccination coverage. The advent of acellular vaccines was greeted with enthusiasm by the public health world: in the Nineties, several controlled vaccine trials were carried out: they demonstrated a high safety and good efficacy of new vaccines. In fact, in the Western world, the acellular vaccines completely replaced the whole cells ones. In the last years, ample evidence on the variety of protection of these vaccines linked to the presence of different antigens of Bordetella pertussis was collected. It also became clear that the protection provided, on average around 80%, leaves every year a significant cohort of vaccinated susceptible even in countries with a vaccination coverage of 95%, such as Italy. Finally, it was shown that, as for the pertussis disease, protection decreases over time, to leave a proportion of adolescents and adults unprotected. Waiting for improved pertussis vaccines, the disease control today requires a different strategy that includes a booster at 5 years for infants, but also boosters for teenagers and young adults, re-vaccination of health care personnel, and possibly of pregnant women and of those who are in contact with infants (cocooning). Finally, the quest for better vaccines inevitably tends towards pertussis acellular vaccines with at least three components, which have demonstrated superior effectiveness and have been largely in use in Italy for fifteen years. PMID- 26051140 TI - Adapted Physical Activity for the Promotion of Health and the Prevention of Multifactorial Chronic Diseases: the Erice Charter. AB - The Erice Charter was unanimously approved at the conclusion of the 47th Residential Course "Adapted Physical Activity in Sport, Wellness and Fitness: New Challenges for Prevention and Health Promotion", held on 20-24 April 2015 in Erice, Italy, at the "Ettore Majorana" Foundation and Centre for Scientific Culture, and promoted by the International School of Epidemiology and Preventive Medicine "G. D'Alessandro" and the Study Group on Movement Sciences for Health of the Italian Society of Hygiene, Preventive Medicine and Public Health. After an intense discussion the participants identified the main points associated with the relevance of physical activity for Public Health, claiming the pivotal role of the Department of Prevention in coordinating and managing preventive actions. The participants underlined the importance of the physicians specialized in Hygiene, Preventive Medicine and Public Health. The contribution of other operators such as physicians specialized in Sport Medicine was stressed. Further, the holders of the new degree in Human Movement and Sport Sciences were considered fundamental contributors for the performance of physical activity and their presence was seen as a promising opportunity for the Departments of Prevention. Primary prevention based on recreational physical activities should become easily accessible for the population, avoiding obstacles such as certification steps or complex bureaucracy. The Sport Doctor is recognized as the principal referent for preliminary physical evaluation and clinical monitoring in secondary and tertiary prevention actions based on adapted physical activities. Developing research in the field is essential as well as implementing higher education on physical activity management in Schools of Public Health. PMID- 26051142 TI - Effects of a school based intervention to promote healthy habits in children 8-11 years old, living in the lowland area of Bologna Local Health Unit. AB - BACKGROUND: A school based health promotion intervention was performed with the aim of increasing physical activity and improving the dietary habits of primary school pupils, using integrated educational strategies involving schools, families, public bodies, sports associations and public health operators. METHODS: The intervention concerned 11 classes during 3 school years from 2009-10 (231 third-year school children) to 2011-12 (234 fifth-year school children). Information was collected both before and after the intervention about the dietary habits and the physical activities practised by the children, using the questionnaires of the project !OKkio alla Salute! which were administered to both children and parents. At the same time anthropometric measurements were taken (height, weight, BMI) and motor skills were assessed using standardized tests: Sit & Reach, medicine-ball forward throw, standing long jump, 20 m running speed, and forward roll. At the end of the intervention 12 different expected outcomes were assessed (5 about dietary habits, 5 about motor habits, 1 about anthropometric characteristics, 1 about motor skills). RESULTS: At baseline, 35.8% of the children show excess weight (23.4% overweight; 12.4% obese); this percentage falls to 29.3% (25.3% overweight; 4% obese) after the intervention (p <0.05). The dietary habits improve from the pre- to the post-intervention: there is a rise in the percentage of children who receive an adequate mid-morning snack (p <0.0001), a fall in the percentage of children who consume snacks and drinks after the dinner (p <0.01), and an increase in the percentage of those who take five or more portions of fruits and vegetables daily. The motor habits do not improve in the same way, since there is the increasing tendency with age to skip from a regular daily practice of physical exercise to favour of the occasional practice of a sport. The motor performances, compared after normalization for modifications due to the process of growth, improve between the third and fifth years of primary school, but with no significant differences. To achieve this objective more focused measures are necessary in the administration of moderate to intense physical exercise. CONCLUSIONS: The results point to a positive assessment of the intervention, thus highlighting the importance of planning integrated and multisectorial actions in school-based programmes to promote correct dietary and motor habits and for the control of body weight, also involving non scholastic areas. PMID- 26051143 TI - Towards a smoke-free hospital: how the smoking status of health professionals influences their knowledge, attitude and clinical activity. Results from a hospital in central Italy. AB - OBJECTIVES: In Italy, the prevalence of smoking among health professionals is higher than in the general population and this might hamper their role in the promotion of health. This study aimed to investigate how the smoking status of healthcare professionals might influence knowledge, attitudes and clinical practice in a hospital in central Italy in order to enforce effective tobacco control measures. METHODS: Physicians and professionals of the hospital were asked to complete an anonymous questionnaire which yielded epidemiological and environmental information on knowledge, attitude, clinical practice and quality of the hospital environments, in relation to smoking. RESULTS: Overall, among the employees of the hospital, the smoking prevalence was 47%, (42% among physicians and 43% among nurses); 30% admitted smoking in the hospital and three quarters of the smokers would like to quit. Some knowledge, opinions and attitudes differ statistically among the smoking categories. For example, only 35% of the smokers admitted that smoking is more dangerous to health than atmospheric and car pollution compared with 60% of the ex or never smokers (p=0.04). Fewer smokers realize that their behavior is seen as a role model by patients. A greater percentage of smokers state that patients (34%) and visitors (43%) often smoke in hospital and these percentages are significantly higher than those reported by ex or never smokers (p<=0.05). All smokers claim that they never smoke in patient rooms, infirmaries and clinics, whereas over 20% of ex or never smokers report that smoking sometimes occurs in these places (p=0.015). The mean concentration of PM 2.5 in the 25 rooms was 2.4 MUg/m3 with a range from 1 to 7 MUg/m3. CONCLUSIONS: This study implies that the prevalence of smoking among health professionals may be very high, and might be twice the rate observed in the general population. Generally, smokers report less knowledge compared with ex and never-smokers and it seems that they systematically underestimate the dangers related to smoking both in their knowledge and in their behavior, and try to socially "normalize" smoking. All this and the evidence of cigarette butts in hospital rooms and clinics, notwithstanding the good quality of the air thanks to the modern ventilation system, imply that there is still a long way to go towards a smoke-free hospital. PMID- 26051144 TI - Trend of Legionella colonization in hospital water supply. AB - BACKGROUND: In many nosocomial Legionella outbreaks water distribution systems are the most frequent source of infection. OBJECTIVES: Considering the hospital waterline old age, an investigation on colonization by Legionella spp was carried out in order to evaluate the pipeline system weaknesses and to implement environmental preventive measures. METHODS: From 2004 to 2010, overall 97 samples from the water line were collected. The samples were analyzed according to the italian Legionella spp standard methods; water temperature, pH and residual free chlorine were determined at the time of collection. X2 test, exact-test and t test were used to compare proportions and means. RESULTS: Overall 28 samples (23.7%) were positive for Legionella spp, and five of them (17.9%) exceeded the threshold level >104 cfu/L. The number of positive samples varied along the years, showing a significant increasing trend (X2 for trend = 11.5; p<0.01), but most occurred in 2008 (53,6%), when the hospital underwent major building reconstruction. Samples positive for Legionella spp by comparison to negative ones showed a lower free chlorine concentration (0.08 mg/L vs 0.15 mg/L) and a higher water temperature (46.1 degrees vs 42.7 degrees ). Actually the percentage of positive samples decreased significantly with the increasing in free chlorine in the water (X2 for trend = 8.53; p<0.01). The samples collected at the connection between public water line with the hospital supply network were always free from Legionella. All hospital buildings were colonized by Legionella spp, although 80% of samples >104 cfu/L occurred in the C-building. No cases of nosocomial legionellosis were reported during the study period. CONCLUSIONS: Hospital water system showed a diffuse colonization by Legionella spp, although the degree of contamination reached the threshold level (>104 cfu/L) only in a small percentage of samples, showing a substantial effectiveness of the control measures applied. PMID- 26051145 TI - Assessment of tetanus immunity status by tetanus quick stick and anamnesis: a prospective double blind study. AB - BACKGROUND: In patients with wounds admitted to Emergency Departments (ED) acquiring tetanus vaccination history by interview is very unreliable. Protected patients may receive unnecessary prophylaxis and unprotected nothing. Aim of the study was to evaluate tetanus immunity status comparing the traditional anamnestic method with the Tetanus Quick Stick (TQS), a rapid immunochromatographic test. METHODS: A double-blind prospective study was carried out in the ED of the 1,000 bed teaching hospital Umberto I in Rome. Adult patients (>=18) with wounds attending at the ED were randomly included. Tetanus immunity status was evaluated by healthcare workers (HCWs) comparing the TQS test with the anamnesis. TQS test was performed by a trained HCW and afterwards the anamnesis about tetanus immunity status was collected by another HCW unaware of the TQS result. Also cost analysis was carried out. RESULTS: Overall 400 patients (242 males and 158 females) were included, mean age was 46.7 +/- 20.2 years (median 44 range 18 - 109), 304 (76.0%) were italians and 96 foreigners (24.0%). Overall, 209 (52.2%) resulted TQS +, and protective immunity level was associated to lower mean age (40.1 +/- 16.8 vs 53.8 +/- 21,1; p<0,01). Using the anamnestic method 336 (84.0%) patients resulted "unprotected", 52 (13.0%) "partially unprotected" and 12 (3.0%) "completely protected". TQS test results showed that 154 (45.8%) out of 336 "unprotected" and 45 (86.5%) out of 52 "partially unprotected" actually had a protective antibody level. Finally two (16.7%) out of 12 "completely protected" group presented a non protective antibody level. Following only the anamnestic method 201 (50.0%) patients would have received some inappropriate treatment. Adopting TQS test in all patients would also be cost-effective saving ? 1.95/patient. As tetanus immunity is inversely related to age, for <51 years old patients unnecessary treatment would have been avoided in 57.1% of patients, with a mean reduction per patient of ? 7.50/patient with the TQS vs. ? 12.69/patient without. CONCLUSIONS: The study showed that tetanus protective immunity prevalence among adult patients attending our ED is about 50% and is mainly influenced by class age. TQS use allowed to reduce drastically inappropriate tetanus vaccine and immunoglobulins booster treatment. Also TQS use reduced costs. PMID- 26051146 TI - Environmental quality of the operating theaters in Campania Region: long lasting monitoring results. AB - BACKGROUND: The health risk level in the operating theaters is directly correlated to the safety level offered by the healthcare facilities. This is the reason why the national Authorities released several regulations in order to monitor better environmental conditions of the operating theaters, to prevent occupational injuries and disease and to optimize working conditions. For the monitoring of environmental quality of the operating theaters following parameters are considered: quantity of supplied gases, anesthetics concentration, operating theatres volume measurement, air change rate, air conditioning system and air filtration. The objective is to minimize the risks in the operating theaters and to provide the optimal environmental working conditions. This paper reports the environmental conditions of operating rooms performed for several years in the public hospitals of the Campania Region. METHODS: Investigation of environmental conditions of 162 operating theaters in Campania Region from January 2012 till July 2014 was conducted. Monitoring and analysis of physical and chemical parameters was done. The analysis of the results has been made considering specific standards suggested by national and international regulations. RESULTS: The study showed that 75% of the operating theaters presented normal values for microclimatic monitoring, while the 25% of the operating theaters had at least one parameter outside the limits. The monitoring of the anesthetics gases showed that in 9% of measurements of nitrous oxides and 4% of measurements of halogenated was not within the normal values. PMID- 26051147 TI - Hand hygiene in preventing nosocomial infections:a nursing research. AB - OBJECTIVES: To verify whether there is some correlation between the nursing workload and the occurrence of healthcare-associated infections. MATERIAL AND METHODS: An anonymous questionnaire made up of 20 items has been drafted for this specific purpose and delivered to a sample of 70 participants, including 33 nurses and 37 nursing students of a well-known University Hospital in Rome. The study is supported by extensive documental research, and a specific literature review. RESULTS: Hand hygiene is a mandatory daily practice, simple but critical, but not always clear enough for both nurses and students. The investigation demonstrated inconsistencies between nurses' and students' behaviour and what is recommended by the new WHO international guidelines. The documented correlation between the workload and the occurrence of healthcare-associated infections may be explained by the negative effect of nursing workload on correct hand-washing procedures. Out of the total sample, 58.6% answered affirmatively to both the presence of healthcare-associated infections within their unit and an excessive daily workload. Indeed, the remaining 41.4% of the sample do not report an excessive workload and states that "there are no healthcare-associated infections within their operational reality, at least not in the time period covered by the present investigation". Although limited to a small sample, this study may reveal that the correct practice of hand washing, prompted and considered fundamental by WHO, is still much underrated. CONCLUSIONS: Hand hygiene should be better understood and practiced in all healthcare facilities, through a series of interventions such as: specific training courses, the presence of a gel sanitizer next to each patient's bed or in each patient's room, as well as the adoption of the new international guidelines in all units. The analysis of other correlations found the presence of a protective factor (RR<1) regarding the replacement of gloves for each patient and the use of disinfectant gel, both related to the excessive workload and the presence of infections. In fact, we found no statistically significant values to support such considerations (p>0.05). The same considerations could be also inferred as far as the presence of gel dispensers and disposable wipes near hospital beds are concerned, for the distribution of information leaflets about proper hand hygiene and the frequency of updating courses declared by both nurses and nursing students. The quality of health care starts from the simplest things, such proper hand hygiene. PMID- 26051148 TI - Latent Growth Modeling of nursing care dependency of acute neurological inpatients. AB - Longitudinal three-time point study, addressing how neurological adult patient care dependency varies from the admission time to the 3rd day of acute hospitalization. Nursing care dependency was measured with the Care Dependency Scale (CDS) and a Latent Growth Modeling approach was used to analyse the CDS trend in 124 neurosurgical and stroke inpatients. Care dependence followed a decreasing linear trend. Results can help nurse-managers planning an appropriate amount of nursing care for acute neurological patients during their initial stage of hospitalization. Further studies are needed aimed at investigating the determinants of nursing care dependence during the entire in-hospital stay. PMID- 26051149 TI - The Official Control beyond the Official Control. How To Plan And Schedule Controls Starting From Risk Assessment Along The Agro-Food Supply Chain. AB - Every year the Italian Ministry of Health, on the basis of regional data, draws up the "Report on Official Controls" to be submitted to the Parliament. The report contains abundant data, diagrams and charts and illustrates the number and type of official controls (OC) performed by the pertinent Bodies (Ministry of Health, Regional and Local Health Authorities) over the previous year on Food Business Operators (FBO), in accordance with the EC Regulation 882/2004. The trend - which has consolidated over the years - relates to the multiplicity of OC and shows a decrease of such controls compared to an increase in "non conformities". OC frequency is established by the Regional Authorities on the basis of the categorisation of both a "generic risk" for companies calculated taking into account the probability of occurrence of a "non-conformity", and a "specific" risk, assessed on the basis of the results of the OC actually performed on a given "Operatore del Settore Alimentare" (Food Sector Operator, in Italian: OSA). Thus, categorisation (i.e. the probability of occurrence of non conformities) is the main driver of the OC scheduling and planning process. We have been asking ourselves whether the current OC planning/scheduling method is still suitable for ensuring food safety in the face of internalisation of the food supply chain. As a matter of fact, food safety is now becoming increasingly variable due to the globalization of consumption where "farm to fork", rather than "border to fork", food safety must be ensured. On the basis of these considerations, a different OC planning /scheduling method is being proposed based on the assessment of risks and the estimation of the occurrence of the same along the agro-food chain. PMID- 26051150 TI - Living in a Semi-basement in the Era of Floods. Italian Laws Cause Inequalities in Health Protection. PMID- 26051151 TI - 3D Printing in Drug Delivery Formulation: You Can Dream it, Design it and Print it. How About Patent it? PMID- 26051152 TI - Antimicrobial Efficacy of Extemporaneously Prepared Herbal Mouthwashes. AB - Natural products like plants and its components have been in use for treatment and cure of diseases all around the globe from ancient times much before the discovery of the current modern drugs. These substances from the nature are well known to contain components which have therapeutic properties and can also behave as precursors for the synthesis of potential drugs. The beneficial results from herbal drugs are well reported where their popularity in usage has increased across the globe. Subsequently developing countries are now recognizing the many positive advantages from their use which has engaged the expansion of R & D from herbal research. The flow on effect from this expansion has increased the awareness to develop new herbal products and the processes, throughout the entire world. Mouth washes and mouth rinses which have plant oils, plant components or extracts have generated particular attention. High prevalence of gingival inflammation and periodontal diseases, suggests majority of the patients practice inadequate plaque control. Of the currently available mouthwashes in the market, Chlorhexidine gluconate (CHX) has been investigated on a larger scale with much detail. CHX is associated with side effects like staining of teeth when used daily as well as the bitter taste of the mouthwash which leads to patient incompliance. The present research encompasses the antibacterial activity of extemporaneously prepared herbal mouthwash using natural herbs and therefore allows for the potential commercialization with in the herbal and pharmaceutical industries. Also, the present research article reviewed details of various existing patents of herbal mouthwashes which shows the trend of existing market and significance of emerging mouthwashes in both pharmaceutical and herbal industries. The antimicrobial activity of prepared mouthwashes was found to be effective against various strains of bacteria. It also suggests that the prepared herbal mouthwashes may provide an alternative to those containing chemical entities, with enhanced antimicrobial properties and better patient compliance. PMID- 26051153 TI - Novel Soluble Dietary Fiber-Tannin Self-Assembled Film: A Promising Protein Protective Material. AB - In this experiment, a natural promising protein protective film was fabricated through soluble dietary fiber (SDF)-tannin nanocluster self-assembly. FT-IR, XRD, and DSC tests were employed to investigate the interaction between the SDF and tannins before and after cross-linking induced by calcium ion. On the other hand, referring to the SEM and TEM results, the self-assembly process of the protein protective film could be indicated as follows: first, calcium ion, with its cross ability, served as the "nucleus"; SDF and tannins were combined to prepare the nanoscale SDF-tannin clusters; then, the clusters were homogeneously deposited on the surface of protein to form a protective film by self-assembling hydrogen bond between tannin component of clusters as "adhesive" and protein in aqueous solutions under very mild conditions. Film thickness could also be controlled by tannin of different concentrations ranging from 114 to 1384 MUm. Antibacterial test and in vitro cytotoxicity test proved that the film had a broad spectrum of antimicrobial properties and excellent cell biocompatibility, respectively, which might open up new applications in the food preservation and biomedical fields. PMID- 26051154 TI - Marine litter in the upper Sao Vicente submarine canyon (SW Portugal): Abundance, distribution, composition and fauna interactions. AB - Marine litter has become a worldwide environmental problem, tainting all ocean habitats. The abundance, distribution and composition of litter and its interactions with fauna were evaluated in the upper S. Vicente canyon using video images from 3 remote operated vehicle exploratory dives. Litter was present in all dives and the abundance was as high as 3.31 items100m(-1). Mean abundance of litter over rock bottom was higher than on soft substrate. Mean litter abundance was slightly higher than reported for other canyons on the Portuguese margin, but lower in comparison to more urbanized coastal areas of the world. Lost fishing gear was the prevalent type of litter, indicating that the majority of litter originates from maritime sources, mainly fishing activity. Physical contact with sessile fauna and entanglement of specimens were the major impacts of lost fishing gear. Based on the importance of this region for the local fishermen, litter abundance is expected to increase. PMID- 26051155 TI - l-Arginine supplementation enhances antioxidant activity and erythrocyte integrity in sickle cell anaemia subjects. AB - The effect of oral, low-dose l-arginine supplementation (1g/day for 6 weeks) on antioxidant activity, haematological parameters and osmotic fragility of red blood cells was investigated in sickle cell disease sufferers. Twenty eight sickle cell anaemia subjects were recruited for the study. Five millilitres of blood was withdrawn from an ante-cubital vein for the estimation of plasma arginine concentration ([R]), total antioxidant enzymes (TAE) activity, malondialdehyde concentration ([MDA]), RBC count, [Hb], PCV, MCHC, MCV, MCH, percent irreversibly sickled cells (%ISC)) and osmotic fragility of red blood cells in the subjects. l-arginine supplementation increased [R] (p<0.001), TAE activity (p<0.05) and MCV (<0.05) but reduced plasma [MDA], MCHC, MCH and %ISC (p<0.001, respectively). Delta[R] correlated positively with DeltaTAE (r=0.8) and negatively with Delta[MDA] (r=-0.7) and Delta%ISC (r=-0.5). Also DeltaTAE activity correlated negatively with Delta[MDA] (r=-0.7) and Delta%ISC (r=-0.6). Supplementation shifted the osmotic fragiligram to the right and reduced the concentrations of NaCl at which initial and complete lyses of erythrocytes occurred. Study showed that low-dose, oral l-arginine increased antioxidant activity, red blood cell resistance to osmotic lysis but reduced red cell density in SCD. PMID- 26051156 TI - Immunotherapy for non-small cell lung cancer: are we on the cusp of a new era? AB - In this editorial, we highlight the exciting advances in immunotherapy for the treatment of non-small cell lung cancer, with nivolumab being the first immunotherapeutic agent to be approved by the US FDA for the treatment of squamous lung cancer and several other promising immune checkpoint inhibitors currently being evaluated in clinical trials. The next step is to understand the mechanisms of resistance and develop rational combinations in an attempt to further improve the responses and survival in lung cancer. PMID- 26051157 TI - WormGUIDES: an interactive single cell developmental atlas and tool for collaborative multidimensional data exploration. AB - BACKGROUND: Imaging and image analysis advances are yielding increasingly complete and complicated records of cellular events in tissues and whole embryos. The ability to follow hundreds to thousands of cells at the individual level demands a spatio-temporal data infrastructure: tools to assemble and collate knowledge about development spatially in a manner analogous to geographic information systems (GIS). Just as GIS indexes items or events based on their spatio-temporal or 4D location on the Earth these tools would organize knowledge based on location within the tissues or embryos. Developmental processes are highly context-specific, but the complexity of the 4D environment in which they unfold is a barrier to assembling an understanding of any particular process from diverse sources of information. In the same way that GIS aids the understanding and use of geo-located large data sets, software can, with a proper frame of reference, allow large biological data sets to be understood spatially. Intuitive tools are needed to navigate the spatial structure of complex tissue, collate large data sets and existing knowledge with this spatial structure and help users derive hypotheses about developmental mechanisms. RESULTS: Toward this goal we have developed WormGUIDES, a mobile application that presents a 4D developmental atlas for Caenorhabditis elegans. The WormGUIDES mobile app enables users to navigate a 3D model depicting the nuclear positions of all cells in the developing embryo. The identity of each cell can be queried with a tap, and community databases searched for available information about that cell. Information about ancestry, fate and gene expression can be used to label cells and craft customized visualizations that highlight cells as potential players in an event of interest. Scenes are easily saved, shared and published to other WormGUIDES users. The mobile app is available for Android and iOS platforms. CONCLUSION: WormGUIDES provides an important tool for examining developmental processes and developing mechanistic hypotheses about their control. Critically, it provides the typical end user with an intuitive interface for developing and sharing custom visualizations of developmental processes. Equally important, because users can select cells based on their position and search for information about them, the app also serves as a spatially organized index into the large body of knowledge available to the C. elegans community online. Moreover, the app can be used to create and publish the result of exploration: interactive content that brings other researchers and students directly to the spatio-temporal point of insight. Ultimately the app will incorporate a detailed time lapse record of cell shape, beginning with neurons. This will add the key ability to navigate and understand the developmental events that result in the coordinated and precise emergence of anatomy, particularly the wiring of the nervous system. PMID- 26051158 TI - Need and utility of a polyethylene glycol marker to ensure against urine falsification among heroin users. AB - BACKGROUND: Deceptive methods of falsifying urine samples are of concern for anyone who relies on accurate urine toxicology results. A novel method to combat these efforts utilizes polyethylene glycol (PEG) markers administered orally prior to providing a urine sample. By using various PEG combinations to create a tracer capsule of unique composition, each urine sample can be matched to that individual. The goal of this study was to determine the effectiveness of using the PEG marker system among active heroin users screening for research studies. METHODS: Upon each screening visit, participants (N=55) were randomized to provide an unobserved urine sample, or the PEG tracer procedure was used. LCMS analysis was used to distinguish the PEG combinations, and allowed us to provide a unique qualitative analysis of patterns of drug use (N=168, total urine specimens). RESULTS: The unique composition of the tracer capsules was accurately detected in 83.5% of the urine specimens. Analyses of inconsistencies implicated a number of possible attempts at fraudulence (11.4%) and investigator/lab error (5.1%). Among this sample, the concurrent use of multiple classes of psychoactive drugs was more common than not, though concomitant drug use was often underreported. CONCLUSION: Urine drug testing should be the minimum standard for obtaining information about drug use as self-report was unreliable even in a situation where there were no perceived adverse consequences for full disclosure. In cases where there are significant pressures for individuals to falsify these data, more protective collection methods such as the PEG marker system should be considered. PMID- 26051159 TI - The role of sexual expectancies of substance use as a mediator between adult attachment and drug use among gay and bisexual men. AB - BACKGROUND: Research exploring substance use in gay and bisexual men has increasingly paid attention to interpersonal dynamics and relational concerns associated with the use of substances. The current study explored the role of adult attachment style on drug use as well as the potential mediating role of sexual expectancies of substance use among gay and bisexual men. METHODS: Online survey data were gathered from 122 gay and bisexual men across the U.S., with a mean age of 33 years. All participants were HIV-negative and identified their relationship status as single. Survey measures included attachment style, sexual expectancies of substance use, and recent drug use. RESULTS: While neither anxious or avoidant attachment were directly associated with the odds of recent drug use, they were positively associated with sexual expectancies of substance use (beta=0.27, p<0.01, and beta=0.21, p<0.05) which, in turn, were positively associated with the odds of drug use (expB=1.09, p<0.01). Bootstrapping tests of indirect effects revealed a significant indirect relationship between anxious attachment and drug use through sexual expectancies of substance use (beta=0.11, p<0.05), but not for avoidant attachment. CONCLUSIONS: This study highlights the importance of interpersonal expectancies as motivators for drug use among gay and bisexual men. Sexual expectancies of substance use were associated with drug use and anxious adult attachment was associated indirectly with drug use through these sexual expectancies. PMID- 26051160 TI - Association between monoamine oxidase gene polymorphisms and smoking behavior: A meta-analysis. AB - BACKGROUND: A number of studies have researched the association between monoamine oxidase gene (MAO) polymorphisms and smoking behavior, but the conclusion is quite inconsistent. A meta-analysis was conducted to assess the association of MAO-A C1460T, MAO-A VNTR and MAO-B G644A polymorphisms with smoking behavior. METHODS: A comprehensive search was performed to identify all eligible studies. Meta-analysis was applied to calculate the pooled effect values and their 95% confidence intervals. Meta-regression and the 'leave one out' sensitivity analysis were used to explore potential sources of heterogeneity. The risk of bias was assessed by the Egger regression asymmetry test. RESULTS: 11 articles conformed to the inclusion criteria. The meta-analysis showed T allele in MAO-A C1460T reduced the risk of heavy smoking (OR=0.66, 95% CI: 0.52-0.84; I(2)=0.0%), especially in Caucasians; the active group in MAO-A VNTR increased the likelihood of failed smoking cessation in males (OR=1.49, 95% CI: 1.01-2.22; I(2)=0.0%); A allele in MAO-B G644A reduced the risk of heavy smoking in males (OR=0.20, 95% CI: 0.04-0.98). CONCLUSION: Our findings indicate that the low activity of monoamine oxidase gene polymorphisms has a protective effect on smoking cessation and heaviness. Some associations and applications should be further confirmed. PMID- 26051161 TI - Spousal resemblance for smoking: Underlying mechanisms and effects of cohort and age. AB - BACKGROUND: In this study we ask why spouses resemble each other in smoking behaviour and assess if such resemblance depends on period of data collection or age. Spousal similarity may reflect different, not mutually exclusive, processes. These include phenotypic assortment (choice of spouse is based on phenotype) or social homogamy at the time spouses first meet, and marital interaction during the relationship. METHODS: Ever and current smoking were assessed between 1991 and 2013 in surveys of the Netherlands Twin Register for 14,230 twins and 1,949 of their spouses (mean age 31.4 [SD=14.0]), and 11,536 parents of twins (53.4 [SD=8.6]). Phenotypic assortment and social homogamy were examined cross sectionally by calculating the probability of agreement between twins and their spouses, twins and their co-twin's spouse and spouses of both twins as a function of zygosity. Marital interaction was tested by investigating the association between relationship duration and spousal resemblance. RESULTS: Between 1991 and 2013 smoking declined in all age groups for both genders. Spousal resemblance for ever and current smoking was higher when data were more recent. For ever smoking, a higher age of men was associated with lower spousal resemblance. Phenotypic assortment was supported for both smoking measures, but social homogamy could not be excluded. No effect of marital interaction was found. CONCLUSIONS: Differences in smoking prevalence across time and age influence spousal similarity. Individuals more often choose a spouse with similar smoking behaviour (phenotypic assortment) causing higher genotypic similarity between them. Given the heritability of smoking this increases genetic risk of smoking in offspring. PMID- 26051162 TI - Is cannabis use associated with less opioid use among people who inject drugs? AB - BACKGROUND: Clinical, experimental, and ethnographic research suggests that cannabis may be used to help manage pain. Ethnographic research has revealed that some people are using cannabis to temper their illicit opioid use. We seek to learn if there is an association between cannabis use and the frequency of nonmedical opioid use among people who inject drugs (PWID). METHODS: PWID were recruited using targeted sampling methods in Los Angeles and San Francisco, California, 2011-2013. We limited analysis to people who used opioids in past 30 days (N=653). OUTCOME VARIABLE: number of times used any opioids non-medically in past 30 days. Explanatory variable: any cannabis use past 30 days. STATISTICS: multivariable linear regression with a log-transformed outcome variable. RESULTS: About half reported cannabis use in the past 30 days. The mean and median number of times using opioids in past 30 days were significantly lower for people who used cannabis than those who did not use cannabis (mean: 58.3 vs. 76.4 times; median: 30 vs 60 times, respectively; p<0.003). In multivariable analysis, people who used cannabis used opioids less often than those who did not use cannabis (Beta: -0.346; 95% confidence interval: -0.575, -0.116; p<0.003). CONCLUSIONS: There is a statistical association between recent cannabis use and lower frequency of nonmedical opioid use among PWID. This may suggest that PWID use cannabis to reduce their pain and/or nonmedical use of opioids. However, more research, including prospective longitudinal studies, is needed to determine the validity of these findings. PMID- 26051164 TI - FT-IR imaging for quantitative determination of liver fat content in non alcoholic fatty liver. AB - In this work we apply FT-IR imaging of large areas of liver tissue cross-section samples (~5 cm * 5 cm) for quantitative assessment of steatosis in murine model of Non-Alcoholic Fatty Liver (NAFLD). We quantified the area of liver tissue occupied by lipid droplets (LDs) by FT-IR imaging and Oil Red O (ORO) staining for comparison. Two alternative FT-IR based approaches are presented. The first, straightforward method, was based on average spectra from tissues and provided values of the fat content by using a PLS regression model and the reference method. The second one - the chemometric-based method - enabled us to determine the values of the fat content, independently of the reference method by means of k-means cluster (KMC) analysis. In summary, FT-IR images of large size liver sections may prove to be useful for quantifying liver steatosis without the need of tissue staining. PMID- 26051163 TI - The effect of motivational lung age feedback on short-term quit rates in smokers seeking intensive group treatment: A randomized controlled pilot study. AB - BACKGROUND: A brief "Lung Age" feedback intervention has shown promise for personalizing the health impact of smoking and promoting cessation in unselected smokers. Now that many healthcare organizations provide face-to-face cessation services, it is reasonable to ask whether such motivational feedback of lung function tests might improve treatment compliance and cessation rates in smokers wanting to quit. This study assessed effects of baseline motivational spirometry based "Lung Age" feedback on treatment compliance and tobacco abstinence at 28 day follow-up. METHODS: This randomized controlled pilot study took place in Penn State University-affiliated outpatient medical practices. Participants were 225 adult smokers (>=5 cigarettes/day) willing to attend tobacco dependence treatment. At assessment lung function (FEV-1) and exhaled carbon-monoxide (CO) were assessed. The Intervention group (n=120) were randomly allocated to receive motivational "Lung Age" feedback estimated by FEV-1 and on exhaled CO; Control group (n=105) received minimal feedback. Participants were offered 6 weekly group smoking cessation sessions and nicotine patches and followed-up 28 days after target quit date. The primary outcome measure was self-reported 7-day tobacco abstinence, confirmed by CO<10ppm at 28-day follow-up. RESULTS: Quit rates were similar at follow-up (Intervention 50.8%; Control 52.4%; p=0.65) after controlling for abstinence predictors. Group attendance and patch use were similar. Among those attending follow-up (n=164, 73%), a greater proportion of the Intervention group had improved lung function (67% vs. 46%; p=0.0083). CONCLUSIONS: Baseline Lung Age feedback did not improve quit rates or compliance at 28-day follow-up in smokers seeking intensive treatment. PMID- 26051165 TI - Risk factors for pre-term birth in a Canadian cohort of HIV-positive women: role of ritonavir boosting? AB - BACKGROUND: The risk of pre-term birth (PTB) associated with the use of protease inhibitors (PIs) during pregnancy remains a subject of debate. Recent data suggest that ritonavir boosting of PIs may play a specific role in the initiation of PTB, through an effect on the maternal-fetal adrenal axis. The primary objective of this study is to compare the risk of PTB among women treated with boosted PI versus non-boosted PIs during pregnancy. METHODS: Between 1988 and 2011, 705 HIV-positive women were enrolled into the Centre Maternel et Infantile sur le SIDA mother-infant cohort at Centre Hospitalier Universitaire Sainte Justine in Montreal, Canada. Inclusion criteria for the study were: 1) attendance at a minimum of two antenatal obstetric visits and 2) singleton live birth, at 24 weeks gestational or older. The association between PTB (defined as delivery at <37 weeks gestational age), antiretroviral drug exposure and maternal risk factors was assessed retrospectively using logistic regression. RESULTS: A total of 525 mother-infant pairs were included in the analysis. Among them, PI-based combination anti-retroviral therapy was used in 37.4%, boosted PI based in 24.4%, non-nucleoside reverse transcriptase inhibitor (NNRTI) or nucleoside reverse transcriptase inhibitor based in 28.1%, and no treatment was given in 10.0% of cases. Overall, 13.5% of women experienced PTB. Among women treated with antiretroviral therapy, the risk of PTB was significantly higher among women who received boosted versus non-boosted PI (OR 2.01, 95% CI 1.02-3.97). This remained significant after adjusting for maternal age, delivery CD4 count, hepatitis C co infection, history of previous PTB, and parity (aOR 2.17, 95% CI 1.05-4.51). There was no increased risk of PTB with the use of unboosted PIs as compared to NNRTI- or NRTI-based regimens. CONCLUSION: While previous studies on the association between PTB and PI use have generally considered all PIs the same, our results would indicate a possible role of ritonavir boosting as a risk factor for PTB. Further work is needed to understand the pathophysiologic mechanisms involved, and to identify the safest ARV regimens to be used in pregnancy. PMID- 26051166 TI - Aldosterone biosynthesis in the human adrenal cortex and associated disorders. AB - Aldosterone is one of the mineralocorticoids synthesized and secreted by the adrenal glands, and it plays pivotal roles in regulating extracellular fluid volume and blood pressure. Autonomous excessive aldosterone secretion resulting from adrenocortical diseases is known as primary aldosteronism, and it constitutes one of the most frequent causes of secondary hypertension. Therefore, it is important to understand the molecular mechanisms of aldosterone synthesis in both normal and pathological adrenal tissues. Various factors have been suggested to be involved in regulation of aldosterone biosynthesis, and several adrenocortical cell lines have been developed for use as in vitro models of adrenal aldosterone-producing cells, for analysis of the underlying molecular mechanisms. In this review, we summarize the available reports on the regulation of aldosterone biosynthesis in the normal adrenal cortex, in associated disorders, and in in vitro models. PMID- 26051167 TI - Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. AB - Various cellular perturbations implicated in the pathophysiology of human diseases, including cardiovascular and neurodegenerative diseases, diabetes mellitus, obesity, and liver diseases, can alter endoplasmic reticulum (ER) function and lead to the abnormal accumulation of misfolded proteins. This situation configures the so-called ER stress, a form of intracellular stress that occurs whenever the protein-folding capacity of the ER is overwhelmed. Reduction in blood flow as a result of atherosclerotic coronary artery disease causes tissue hypoxia, a condition that induces protein misfolding and ER stress. In addition, ER stress has an important role in cardiac hypertrophy mainly in the transition to heart failure (HF). ER transmembrane sensors detect the accumulation of unfolded proteins and activate transcriptional and translational pathways that deal with unfolded and misfolded proteins, known as the unfolded protein response (UPR). Once the UPR fails to control the level of unfolded and misfolded proteins in the ER, ER-initiated apoptotic signaling is induced. Furthermore, there is considerable evidence that implicates the presence of oxidative stress and subsequent related cellular damage as an initial cause of injury to the myocardium after ischemia/reperfusion (I/R) and in cardiac hypertrophy secondary to pressure overload. Oxidative stress is counterbalanced by complex antioxidant defense systems regulated by a series of multiple pathways, including the UPR, to ensure that the response to oxidants is adequate. Nuclear factor-E2-related factor (Nrf2) is an emerging regulator of cellular resistance to oxidants; Nrf2 is strictly interrelated with the UPR sensor called pancreatic endoplasmic reticulum kinase. A series of studies has shown that interventions against ER stress and Nrf2 activation reduce myocardial infarct size and cardiac hypertrophy in the transition to HF in animals exposed to I/R injury and pressure overload, respectively. Finally, recent data showed that Nrf2/antioxidant-response element pathway activation may be of importance also in ischemic preconditioning, a phenomenon in which the heart is subjected to one or more episodes of nonlethal myocardial I/R before the sustained coronary artery occlusion. PMID- 26051168 TI - Role of cystathionine beta-synthase in human breast Cancer. AB - Cystathionine beta-synthase (CBS) is an enzyme in the transulfuration pathway that can catalyze the condensation of homocysteine (Hcy) and cysteine (Cys) to hydrogen sulfide (H2S) and cystathionine (CTH). CBS-derived H2S is important in angiogenesis and drug resistance in colon and ovarian cancers, respectively. However, the mechanisms by which cancer cell-derived H2S is utilized by cancer cells as a protective agent against host-derived activated macrophages are not yet investigated. This study investigated the mechanistic role of CBS-derived H2S in the protection of human breast cancer (HBC) cells against activated macrophages. HBC patient-derived tissue arrays and immunoblot analysis of HBC cells exhibited significantly increased levels of CBS when compared with their normal counterparts. This was associated with increased levels of H2S and CTH. Silencing of CBS in HBC cells caused a significant decrease in the levels of H2S and CTH but did not affect the growth of these cells per se, in in vitro cultures. However CBS-silenced cells exhibited significantly reduced growth in the presence of activated macrophages and in xenograft models. This was associated with an increase in the steady state levels of reactive aldehyde derived protein adducts. Exogenous addition of H2S countered the effects of CBS silencing in the presence of macrophages. Conversely overexpression of CBS in human breast epithelial (HBE) cells (which do not naturally express CBS) protected them from activated macrophages, which were otherwise susceptible to the latter. PMID- 26051169 TI - Pomegranate ellagitannins stimulate growth of gut bacteria in vitro: Implications for prebiotic and metabolic effects. AB - The present study investigated the effect of pomegranate extract (POMx) and pomegranate juice (POM juice) on the growth of major groups of intestinal bacteria: Enterobacteriaceae, Bacteroides fragilis group, clostridia, bifidobacteria, and lactobacilli, and the utilization of pomegranate polyphenols by Bifidobacterium and Lactobacillus. The total phenolic content of the pomegranate extract and juice was determined using the Folin-Ciocalteau colorimetric method and reported as gallic acid equivalent (GAE). The polyphenol composition was determined by HPLC. Stool specimens were incubated with 400, 100, and 25 MUg/ml GAE POMx and POM juice and subjected to selective culture. Bifidobacterium and Lactobacillus strains were incubated with 400 MUg/ml GAE POMx and POM juice and metabolites were analyzed. POMx and POM juice increased the mean counts of Bifidobacterium and Lactobacillus and significantly inhibited the growth of B. fragilis group, clostridia, and Enterobacteriaceae in a dose response manner. Bifidobacterium and Lactobacillus utilized ellagic acid and glycosyl ellagic acid but little or no punicalin was utilized. Neither POMx nor POM juice was converted to urolithins by the test bacteria or the in vitro stool cultures. The effect of pomegranate on the gut bacteria considered to be beneficial (Bifidobacterium and Lactobacillus) suggests that pomegranate may potentially work as a prebiotic. The concept that polyphenols such as those in pomegranate impact gut microbiota populations may establish a new role for polyphenols in human health. PMID- 26051170 TI - Endovascular treatment of wide-neck anterior communicating artery aneurysms using the LVIS Junior stent. AB - We performed this retrospective study to assess the clinical safety and efficacy of the low-profile visualized intraluminal support junior (LVIS Jr.; MicroVention, Aliso Viejo, CA, USA) stent placement in anterior communicating artery (ACA) aneurysms. ACA aneurysms are some of the most common intracranial aneurysms. Stent placement is particularly difficult due to the complexity of the vascular anatomy and the small vessels of the ACA complex. From November 2013 and June 2014, LVIS Jr. stent-assisted coiling was performed in 11 patients with 12 wide-neck ACA aneurysms. Patient demographics, morphologic features of the aneurysm, clinical results and follow-up results are presented. Successful deployment of the LVIS Jr. stent in the targeted artery was achieved in all patients. Complete occlusion was achieved in seven patients, neck remnant in three, and partial occlusion in two. The angiographic follow-up of nine patients (mean 4.4 months) showed that all aneurysms remained stable or improved. There was no in-stent stenosis, recurrence or retreatment. The modified Rankin scale score at discharge was 0 in eight patients and 1 in three patients. The LVIS Jr. stent provided excellent trackability and deliverability and is safe and effective for the treatment of wide-necked ACA aneurysms. Further follow-up is needed to assess the long-term efficacy of LVIS Jr. stent placement in ACA. PMID- 26051171 TI - The efficacy of levetiracetam for patients with supratentorial brain tumors. AB - We conducted a meta-analysis to comprehensively evaluate the current data on the overall efficacy of levetiracetam (LEV), a new generation antiepileptic drug, in patients with brain tumors. The efficacy of LEV in patients diagnosed with brain tumors has been evaluated in several studies, however, with inconsistent results. Bibliographic searches of the EMBASE, MEDLINE, ClinicalTrials.gov and Cochrane Central Register of the Controlled Trials databases were performed to identify articles and conference abstracts that investigated the efficacy of LEV in the treatment of brain tumor patients. Fourteen studies were included in this meta analysis. Among the 14 included studies, two were randomized controlled trials. The subgroup analysis demonstrated that the complete response rate of LEV was 94% during the postoperative period and 84% during the long-term follow-up period. Our results suggest that LEV is a relatively effective drug for the treatment of brain tumor patients and its efficacy is slightly lower during the long-term follow-up period than during the postoperative period. Further randomized controlled trials are warranted. PMID- 26051172 TI - Neutrophil-to-lymphocyte ratio as an independent predictor of left main and/or three-vessel disease in patients with non-ST-segment elevation myocardial infarction. AB - BACKGROUND/PURPOSE: Patients with acute coronary syndrome due to left main and/or three-vessel disease (LM/3VD) are at the highest risk of short- and long-term adverse cardiovascular events. Neutrophil-to-lymphocyte ratio (NLR) has been shown to predict the severity of coronary artery disease in various clinical settings, but its independent predictive value for LM/3VD has not been investigated in patients with non-ST-segment elevation myocardial infarction (NSTEMI). We aimed to evaluate the independent predictive value of NLR for LM/3VD in NSTEMI patients. METHODS/MATERIALS: We performed a retrospective analysis of consecutive NSTEMI patients who underwent coronary angiography. NLR was calculated as the ratio of neutrophil to lymphocyte based on the laboratory data on admission. The primary outcome was the presence of LM/3VD. RESULTS: In all, 396 patients were included in the final analysis. Median NLR in the entire study population was 3.43 (interquartile range, 2.12-5.51). By receiver operating characteristics curve analysis, the optimal cutoff value of NLR in predicting LM/3VD was 2.80 (area under the curve 0.60, sensitivity 73%, specificity 43%). Of the 396 patients, 244 patients (62%) had NLR >=2.8. Patients with NLR >=2.8 were older and had a higher prevalence of LM/3VD (30 % vs. 18%, p=0.005). According to multivariate logistic regression analysis, NLR >=2.8 was an independent predictor of LM/3VD after adjusting for other clinical variables including ST depression and ST elevation in lead aVR (odds ratio 1.83, 95% confidence interval 1.07-3.21, p=0.03). CONCLUSION: Our study demonstrates that NLR >=2.8 is an independent predictor of LM/3VD in patients with NSTEMI. PMID- 26051173 TI - Reversal of pulmonary hypertension after percutaneous closure of congenital renal arteriovenous fistula in a 74-year old woman. AB - We report the case of a large right renal arteriovenous fistula (AVF) in a 74 year old woman who presented with heart failure. Transthoracic echocardiography revealed normal left ventricular size and systolic function (ejection fraction 60 65%), moderately dilated right ventricle with severely depressed systolic function, and severe pulmonary hypertension. Right heart catheterization confirmed the elevated pulmonary pressures and showed a high cardiac output. Physical examination was remarkable for a right flank bruit. An abdominal ultrasound revealed an AVF originating from the distal right renal artery and dilated suprarenal inferior vena cava and hepatic veins. These findings were confirmed with an abdominal MRI. Percutaneous endovascular closure of the right renal AVF was successfully performed, with immediate reduction of pulmonary pressures and normalization of cardiac output. The patient's symptoms improved, and a post intervention echocardiogram revealed normalization of right ventricular size. PMID- 26051174 TI - A rapidly growing coronary pseudoaneurysm. AB - Little is known regarding the evolution of coronary aneurysms. We report on a rapidly growing coronary pseudoaneurysm with the aim to underline the reasons for rapid coronary aneurysm enlargement and the different therapeutics options available to face this rare clinical condition. PMID- 26051175 TI - "I will guide you" The indirect link between overparenting and young adults' adjustment. AB - This study addresses knowledge gaps regarding family dynamics, and identifies young adults at-risk for psychopathological symptoms. In particular, we examined overparenting and its associations with young adults' adjustment (distress and interpersonal sensitivity). Both direct and indirect relations were assessed, the latter through young adults' relational characteristics (attachment, psychological control perception, and boundaries diffusion perception). Also, the contribution of gender of parents and young adults was addressed. Questionnaires were collected from 89 Jewish-Israeli intact families. Mothers reported significantly more use of overparenting than fathers. More overparenting of fathers had a direct relation with less adjustment in young adults. This direct relation was partially mediated by higher levels of young adults' attachment anxiety (for the dependent variables distress and interpersonal sensitivity) and young adults' perceptions of parental psychological control (for the dependent variable distress). More overparenting of mothers was related to less interpersonal sensitivity for male young adults and for young adults who reported less parental psychological control. This study showed that parenting qualities and their interplay with young adults' relational characteristics continue to play an important role in the lives of young adult offspring. Therefore, clinicians dealing with young adults at risk for, or suffering from, psychopathology, should be attentive to overparenting and its possible implications. PMID- 26051176 TI - Nice or effective? Social problem solving strategies in patients with major depressive disorder. AB - Our study addressed distinct aspects of social problem solving in 28 hospitalized patients with Major Depressive Disorder (MDD) and 28 matched healthy controls. Three scenario-based tests assessed the ability to infer the mental states of story characters in difficult interpersonal situations, the capacity to freely generate good strategies for dealing with such situations and the ability to identify the best solutions among less optimal alternatives. Also, standard tests assessing attention, memory, executive function and trait empathy were administered. Compared to controls, MDD patients showed impaired interpretation of other peoples' sarcastic remarks but not of the mental states underlying other peoples' actions. Furthermore, MDD patients generated fewer strategies that were socially sensitive and practically effective at the same time or at least only socially sensitive. Overall, while the free generation of adequate strategies for difficult social situations was impaired, recognition of optimal solutions among alternatives was spared in MDD patients. Higher generation scores were associated with higher trait empathy and cognitive flexibility scores. We suggest that this specific pattern of impairments ought to be considered in the development of therapies addressing impaired social skills in MDD. PMID- 26051177 TI - Obg and Membrane Depolarization Are Part of a Microbial Bet-Hedging Strategy that Leads to Antibiotic Tolerance. AB - Within bacterial populations, a small fraction of persister cells is transiently capable of surviving exposure to lethal doses of antibiotics. As a bet-hedging strategy, persistence levels are determined both by stochastic induction and by environmental stimuli called responsive diversification. Little is known about the mechanisms that link the low frequency of persisters to environmental signals. Our results support a central role for the conserved GTPase Obg in determining persistence in Escherichia coli in response to nutrient starvation. Obg-mediated persistence requires the stringent response alarmone (p)ppGpp and proceeds through transcriptional control of the hokB-sokB type I toxin-antitoxin module. In individual cells, increased Obg levels induce HokB expression, which in turn results in a collapse of the membrane potential, leading to dormancy. Obg also controls persistence in Pseudomonas aeruginosa and thus constitutes a conserved regulator of antibiotic tolerance. Combined, our findings signify an important step toward unraveling shared genetic mechanisms underlying persistence. PMID- 26051178 TI - Histone Variant H2A.Z.2 Mediates Proliferation and Drug Sensitivity of Malignant Melanoma. AB - Histone variants are emerging as key regulatory molecules in cancer. We report a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. H2A.Z.2 is highly expressed in metastatic melanoma, correlates with decreased patient survival, and is required for cellular proliferation. Our integrated genomic analyses reveal that H2A.Z.2 controls the transcriptional output of E2F target genes in melanoma cells. These genes are highly expressed and display a distinct signature of H2A.Z occupancy. We identify BRD2 as an H2A.Z-interacting protein, levels of which are also elevated in melanoma. We further demonstrate that H2A.Z.2-regulated genes are bound by BRD2 and E2F1 in an H2A.Z.2-dependent manner. Importantly, H2A.Z.2 deficiency sensitizes melanoma cells to chemotherapy and targeted therapies. Collectively, our findings implicate H2A.Z.2 as a mediator of cell proliferation and drug sensitivity in malignant melanoma, holding translational potential for novel therapeutic strategies. PMID- 26051179 TI - Skp2-Mediated RagA Ubiquitination Elicits a Negative Feedback to Prevent Amino Acid-Dependent mTORC1 Hyperactivation by Recruiting GATOR1. AB - The regulation of RagA(GTP) is important for amino-acid-induced mTORC1 activation. Although GATOR1 complex has been identified as a negative regulator for mTORC1 by hydrolyzing RagA(GTP), how GATOR1 is recruited to RagA to attenuate mTORC1 signaling remains unclear. Moreover, how mTORC1 signaling is terminated upon amino acid stimulation is also unknown. We show that the recruitment of GATOR1 to RagA is induced by amino acids in an mTORC1-dependent manner. Skp2 E3 ligase drives K63-linked ubiquitination of RagA, which facilitates GATOR1 recruitment and RagA(GTP) hydrolysis, thereby providing a negative feedback loop to attenuate mTORC1 lysosomal recruitment and prevent mTORC1 hyperactivation. We further demonstrate that Skp2 promotes autophagy but inhibits cell size and cilia growth through RagA ubiquitination and mTORC1 inhibition. We thereby propose a negative feedback whereby Skp2-mediated RagA ubiquitination recruits GATOR1 to restrict mTORC1 signaling upon sustained amino acid stimulation, which serves a critical mechanism to maintain proper cellular functions. PMID- 26051180 TI - HLTF's Ancient HIRAN Domain Binds 3' DNA Ends to Drive Replication Fork Reversal. AB - Stalled replication forks are a critical problem for the cell because they can lead to complex genome rearrangements that underlie cell death and disease. Processes such as DNA damage tolerance and replication fork reversal protect stalled forks from these events. A central mediator of these DNA damage responses in humans is the Rad5-related DNA translocase, HLTF. Here, we present biochemical and structural evidence that the HIRAN domain, an ancient and conserved domain found in HLTF and other DNA processing proteins, is a modified oligonucleotide/oligosaccharide (OB) fold that binds to 3' ssDNA ends. We demonstrate that the HIRAN domain promotes HLTF-dependent fork reversal in vitro through its interaction with 3' ssDNA ends found at forks. Finally, we show that HLTF restrains replication fork progression in cells in a HIRAN-dependent manner. These findings establish a mechanism of HLTF-mediated fork reversal and provide insight into the requirement for distinct fork remodeling activities in the cell. PMID- 26051181 TI - Quantitative Proteomic Atlas of Ubiquitination and Acetylation in the DNA Damage Response. AB - Execution of the DNA damage response (DDR) relies upon a dynamic array of protein modifications. Using quantitative proteomics, we have globally profiled ubiquitination, acetylation, and phosphorylation in response to UV and ionizing radiation. To improve acetylation site profiling, we developed the strategy FACET IP. Our datasets of 33,500 ubiquitination and 16,740 acetylation sites provide valuable insight into DDR remodeling of the proteome. We find that K6- and K33 linked polyubiquitination undergo bulk increases in response to DNA damage, raising the possibility that these linkages are largely dedicated to DDR function. We also show that Cullin-RING ligases mediate 10% of DNA damage-induced ubiquitination events and that EXO1 is an SCF-Cyclin F substrate in the response to UV radiation. Our extensive datasets uncover additional regulated sites on known DDR players such as PCNA and identify previously unknown DDR targets such as CENPs, underscoring the broad impact of the DDR on cellular physiology. PMID- 26051183 TI - Cyclodextrin-based switchable DNA condenser. AB - Switchable DNA condensers based on beta-cyclodextrin derivates bearing cationic imidazolium moieties and hydrolysable ester linkages were synthesized, showing base-responsive or enzyme-responsive switchable DNA condensation ability under physiological conditions. PMID- 26051182 TI - The Unfolded Protein Response Triggers Site-Specific Regulatory Ubiquitylation of 40S Ribosomal Proteins. AB - Insults to ER homeostasis activate the unfolded protein response (UPR), which elevates protein folding and degradation capacity and attenuates protein synthesis. While a role for ubiquitin in regulating the degradation of misfolded ER-resident proteins is well described, ubiquitin-dependent regulation of translational reprogramming during the UPR remains uncharacterized. Using global quantitative ubiquitin proteomics, we identify evolutionarily conserved, site specific regulatory ubiquitylation of 40S ribosomal proteins. We demonstrate that these events occur on assembled cytoplasmic ribosomes and are stimulated by both UPR activation and translation inhibition. We further show that ER stress stimulated regulatory 40S ribosomal ubiquitylation occurs on a timescale similar to eIF2alpha phosphorylation, is dependent upon PERK signaling, and is required for optimal cell survival during chronic UPR activation. In total, these results reveal regulatory 40S ribosomal ubiquitylation as an important facet of eukaryotic translational control. PMID- 26051184 TI - Optimization of Melatonin Dissolution from Extended Release Matrices Using Artificial Neural Networking. AB - BACKGROUND: Efficacy of melatonin in treating sleep disorders has been demonstrated in numerous studies. Being with short half-life, melatonin needs to be formulated in extended-release tablets to prevent the fast drop of its plasma concentration. However, an attempt to mimic melatonin natural plasma levels during night time is challenging. METHODS: In this work, Artificial Neural Networks (ANNs) were used to optimize melatonin release from hydrophilic polymer matrices. Twenty-seven different tablet formulations with different amounts of hydroxypropyl methylcellulose, xanthan gum and Carbopol(r)974P NF were prepared and subjected to drug release studies. Using dissolution test data as inputs for ANN designed by Visual Basic programming language, the ideal number of neurons in the hidden layer was determined trial and error methodology to guarantee the best performance of constructed ANN. RESULTS: Results showed that the ANN with nine neurons in the hidden layer had the best results. ANN was examined to check its predictability and then used to determine the best formula that can mimic the release of melatonin from a marketed brand using similarity fit factor. CONCLUSION: This work shows the possibility of using ANN to optimize the composition of prolonged-release melatonin tablets having dissolution profile desired. PMID- 26051185 TI - Preparation Procedure and Pharmacokinetic Study of Water-in-Oil Nanoemulsion of Panax Notoginseng Saponins for Improving the Oral Bioavailability. AB - BACKGROUND: Due to the effects of gastric acid, glycosidase and intestinal flora in the gastrointestinal environment, panax notoginseng saponins (PNS) can easily be resolved and metabolized when it is administered orally, limiting its oral bioavailability. METHODS: The formula of PNS nanoemulsion (PNS-N) was optimized using a pseudoternary phase diagram, and the PNS-N was prepared by high pressure homogenization. The type, particle size, polydispersity index (PDI), refractive index, pH and content of PNS-N were characterized. In vitro characteristics were investigated by drug release and physical stability. The pharmacokinetic properties of PNS-N were studied with rat intestine and SD rats. The optimized nanoemulsion formulation was Labrafil M 1944CS (58%), SP/EtOH (Km=1) (25%), solution of PNS (400mg/ml) (17%). RESULTS: The results showed that the average particle size was (28.17+/-0.39) nm with PDI of 0.116+/-0.032, refractive index of 1.4491+/-0.0009 and pH of 4.58+/-0.03. In addition, the contents of R1, Rg1 and Rb1 were (4.64+/-0.21) mg/mL, (19.16+/-0.27) mg/mL and (11.77+/-0.08) mg/mL, respectively. The optimized PNS-N formulation exhibited a sustained drug release with good stability. PNS-N is still clear and transparent, without layering and precipitation after six months. In the study of absorption kinetics of PNS-N in rat intestine, the Papp of three main components of PNS-N increased 5 times than PNS solution (PNS-SOL) in rat intestine. And pharmacokinetic study in SD rats suggested a 2.58-fold increase of oral bioavailability compared with PNS-SOL. CONCLUSION: The PNS-N has increased the absolute availability of PNS obviously and nanoemulsion is a potential formulation to improve oral bioavailability for PNS. PMID- 26051186 TI - Local order and long range correlations in imidazolium halide ionic liquids: a combined molecular dynamics and XAS study. AB - A thorough characterization of the structural properties of alkylimidazolium halide ionic liquids (ILs), namely 1-alkyl-3-methylimidazolium bromide ([Cnmim]Br with n = 5, 6, 8, 10) and iodide ([C6mim]I), has been carried out by combining molecular dynamics simulations and EXAFS spectroscopy. The existence of a local order in [Cnmim]Br ILs has been evidenced, with anions and imidazolium head groups forming a local three-dimensional bonding pattern that is common to all the [Cnmim]Br IL family, regardless of the length of the alkyl chain attached to the cation. On the other hand, upon alkyl chain elongation significant differences have been highlighted in the long-range structure of these ILs. Theoretical X-ray structure factors have been calculated from MD simulations and a low q peak has been found for all [Cnmim]Br ILs, indicating the existence of long-range structural correlations. The low q peak moves to smaller q values corresponding to longer distances, increases in intensity and sharpens with increasing alkyl chain length on the cation. Similarities and differences between the ion three-dimensional arrangements in [C6mim]Br and [C6mim]I were highlighted and the structural arrangement of Br(-) and I(-) was found to be different in the proximity of the most acidic hydrogen atom of the imidazolium ring: the I(-) ion is preferentially located above and below the ring plane, while the Br(-) ion has a high probability also to be coplanar with the imidazolium ring. A quantitative analysis of the Br and I K-edge EXAFS spectra of alkylimidazolium halide ILs has been carried out based on the microscopic description of the systems derived from MD simulations. A very good agreement between theoretical and experimental EXAFS signals has been obtained, allowing us to assess the reliability of the MD structural results for all the alkylimidazolium halide ILs investigated in this work. PMID- 26051187 TI - [Abnormal bone scintigraphy]. PMID- 26051188 TI - [Fever, weight loss, and lumbar pain in a 44-year-old woman]. PMID- 26051189 TI - [Survey of the prescriptions of proton pump inhibitors in patients admitted in an internal medicine ward: how is the compliance to the French guidelines?]. AB - PURPOSE: In June 2009, the national French authority for Health reported many off label uses of proton pump inhibitors (PPI). Our objective was to analyse the justification and modalities of PPI prescriptions in patients before their admission in a department of internal medicine. METHODS: Data were prospectively collected during 5months. At admission, all prescriptions of PPI by general practitioners (GP) were recorded. The accordance of the prescriptions with the marketing authorization indications and the French guidelines in terms of duration of treatment or dosage was analyzed. These informations were obtained from computerized medical records and, if necessary, by contacting GPs. RESULTS: We collected 173 prescriptions. Fifty-six (32%) were in accordance with marketing authorization indications and, among them, 15 prescriptions (9% of all) respected the French guidelines about dosage and duration of treatment. One hundred and six prescriptions (61%) were not adequate and among them an off-label use was notified in 91 (53% of all); among them 33% for simple dyspeptic disorders, 23% for the prevention of NSAID-induced lesions in patients without risk factors, and finally 17% for the prevention of stress ulcer. Fifty-two prescriptions (30%) were unclassified due to incomplete data. CONCLUSION: Our study showed that a vast majority of the prescriptions for PPIs are not in accordance with French guidelines. Preventive actions against abusive prescriptions, withdrawal strategies or replacement of already prescribed PPIs should be implemented to reduce the risk of side effects and the economic impact of long term use of PPIs. PMID- 26051190 TI - [Chronic cutaneous lesions in a 73-year-old patient]. PMID- 26051191 TI - Altruism and anonymity: A behavioral analysis. AB - The effect of anonymity on altruism was examined in a social discounting task with hypothetical rewards. Social discounting - the rate at which increases in social distance decrease value to the participant - was compared across three groups. Participants in the Anonymous group were told that recipients would not know who they were. Participants in the Observed group were asked to imagine that each of their choices was being observed by the recipient. Participants in the Standard group were given no special instructions with respect to anonymity or identity. Social discounting was measured at each of 7 social distances ranging from first closest friend or relative to the 100th closest. Social discount rates for all three groups were well described by hyperbolic functions. Participants in the Observed group were willing to forgo more money for the benefit of others (were more altruistic) than were those in the other two groups. Although participants in the Anonymous group, with no prospect of reciprocation, were willing to forgo less money for the sake of others than were those in the Observed group, they did express willingness to forgo significant amounts. This is some evidence that individual altruistic acts cannot be explained wholly by the possibility of reciprocation. PMID- 26051192 TI - Behavioral evidence illuminating the visual abilities of the terrestrial Caribbean hermit crab Coenobita clypeatus. AB - Hermit crabs hide into shells when confronted with potential dangers, including images presented on a monitor. We do not know, however, what hermit crabs can see and how they perceive different objects. We examined the hiding response of the Caribbean hermit crab (Coenobita clypeatus) to various stimuli presented on a monitor in seven experiments to explore whether crabs could discriminate different properties of a threatening digital image, including color, brightness, contrast, shape and orientation. We found crabs responded differently to expanding circles presented in wavelengths of light corresponding to what humans see as red, blue, and green. "Blue" stimuli elicited the strongest hiding response (Experiments 1, 2, & 7). "Blue" was also more effective than a gray stimulus of similar brightness (Experiment 3). Hermit crabs were sensitive to the amount of contrast between a stimulus and its background rather than absolute brightness of the stimulus (Experiment 4). Moreover, we did not find evidence that crabs could discriminate orientation (Experiment 6), and mixed evidence that they could discriminate stimulus shape (Experiments 5 & 7). These results suggest that the Caribbean hermit crab is sensitive to color features, but not spatial features, of a threatening object presented on a computer screen. This is the first study to use the hiding response of the hermit crab to examine its visual ability, and demonstrates that the hiding response provides a useful behavioral approach with which to study learning and discrimination in the hermit crab. PMID- 26051194 TI - Lack of phonotactic preferences of female frogs and its consequences for signal evolution. AB - Sexual selection is one of the main evolutionary forces that drive signal evolution. In previous studies, we have found out that males of Pleurodema thaul, a frog with an extensive latitudinal distribution in Chile, emits advertisement calls that show remarkable variation among populations. In addition, this variation is related to intense inter-male acoustic competition (intra-sexual selection) occurring within each population. However, the extent to which female preferences contribute to the signal divergence observed is unclear. To study the responsiveness of females in each population, we stimulated females with synthetic calls designed with the acoustic structure of their own population and subsequently responsive females were subjected to a two-choice experiment, where they were stimulated with synthetic calls of their own population versus a call of a foreign population. Females do not show phonotactic preferences for calls of their own or foreign populations as measured with both linear and circular variables. The lack of phonotactic preferences suggests an absence of participation of inter-sexual selection processes in the divergence of the acoustic signals of P. thaul, highlighting the importance of intra-sexual selection for the evolution of these signals. These results concur with studies in other vertebrates emphasizing the relevance of interactions among males for the evolution of acoustic communication systems. PMID- 26051193 TI - Spatial discrimination reversal and incremental repeated acquisition in adolescent and adult BALB/c mice. AB - Adolescence is characterized by neural and behavior development that includes increases in novel experiences and impulsive choice. Experimental rodent models can characterize behavior phenotypes that typify adolescence. The present experiment was designed to characterize differences between adolescent (post natal day (PND) 34-60) and adult (PND 70-96) BALB/c mice using a response initiated spatial discrimination reversal (SDR) and incremental repeated acquisition of response chains (IRA) procedures. During SDR, adolescents omitted more trials and were slower to initiate trials than adults, but the age groups did not differ on accuracy and perseveration measures. During IRA, adolescents displayed poorer overall performance (measured by progress quotient), lower accuracy at individual chain links, and completed fewer long response chains (>3 links) than adults. In both procedures (SDR and IRA), the poorer performance of adolescents appeared to be related to the use of a response device that was spatially removed from reinforcer delivery. These results indicate that SDR and IRA performance can be established during the brief rodent adolescent period but that these two age groups' performances differ. We hypothesize that adolescent behavior is more sensitive than adult behavior to the spatiotemporal distance between response device and location of reinforcer delivery. PMID- 26051195 TI - The evolution of paternal care can lead to population growth in artificial societies. AB - Evolutionary models of paternal care predict that when female reproductive effort is higher than male reproductive effort, selection might favour the emergence of unconditional male cooperation towards females, even when the latter group does not reciprocate. However, previous models have assumed constant population sizes, so the ecology of interacting individuals and its effects on population dynamics have been neglected. This paper reports an agent-based model that incorporates ecological dynamics into evolutionary game dynamics by allowing populations to vary. As previous models demonstrate, paternal care only evolves when female reproductive effort is higher than that of males, and the optimal strategy for females is to exploit male unconditional cooperation. The model also shows that evolution of this behaviour drives some simulations towards regimes of population growth. Thanks to the evolution of paternal care, females' inter-birth intervals are shortened and causing them to reproduce faster. Thus, it is suggested that the evolution of paternal care in species with differential reproductive effort between sexes could be associated to population growth. Nevertheless, the modelled evolutionary dynamics are stochastic, so differences in reproductive effort are necessary but not sufficient conditions for the evolution of paternal care. PMID- 26051196 TI - Effectiveness of contact investigations for tuberculosis control in Arkansas. AB - Comprehensive assessment of the effectiveness of contact investigations for tuberculosis (TB) control is still lacking. In this study, we use a computational model, calibrated against notification data from Arkansas during the period 2001 2011, that reproduces independent data on key features of TB transmission and epidemiology. The model estimates that the Arkansas contact investigations program has avoided 18.6% (12.1-25.9%) of TB cases and 23.7% (16.4-30.6%) of TB deaths that would have occurred during 2001-2014 if passive diagnosis alone were implemented. If contacts of sputum smear-negative cases had not been included in the program, the percentage reduction would have been remarkably lower. In addition, we predict that achieving national targets for performance indicators of contact investigation programs has strong potential to further reduce TB transmission and burden. However, contact investigations are expected to have limited effectiveness on avoiding reactivation cases of latent infections over the next 60 years. PMID- 26051197 TI - Physician communication about adolescent vaccination: How is human papillomavirus vaccine different? AB - BACKGROUND: Low human papillomavirus (HPV) vaccination coverage stands in stark contrast to our success in delivering other adolescent vaccines. To identify opportunities for improving physicians' recommendations for HPV vaccination, we sought to understand how the communication context surrounding adolescent vaccination varies by vaccine type. METHODS: A national sample of 776 U.S. physicians (53% pediatricians, 47% family medicine physicians) completed our online survey in 2014. We assessed physicians' perceptions and communication practices related to recommending adolescent vaccines for 11- and 12-year-old patients. RESULTS: About three-quarters of physicians (73%) reported recommending HPV vaccine as highly important for patients, ages 11-12. More physicians recommended tetanus, diphtheria, and acellular pertussis (Tdap) (95%) and meningococcal vaccines (87%, both p<0.001) as highly important for this age group. Only 13% of physicians perceived HPV vaccine as being highly important to parents, which was far fewer than perceived parental support for Tdap (74%) and meningococcal vaccines (62%, both p<0.001). Physicians reported that discussing HPV vaccine took almost twice as long as discussing Tdap. Among physicians with a preferred order for discussing adolescent vaccines, most (70%) discussed HPV vaccine last. CONCLUSIONS: Our findings suggest that primary care physicians perceived HPV vaccine discussions to be burdensome, requiring more time and engendering less parental support than other adolescent vaccines. Perhaps for this reason, physicians in our national study recommended HPV vaccine less strongly than other adolescent vaccines, and often chose to discuss it last. Communication strategies are needed to support physicians in recommending HPV vaccine with greater confidence and efficiency. PMID- 26051198 TI - Neighborhood environmental attributes and adults' sedentary behaviors: Review and research agenda. AB - OBJECTIVE: Physical activity recommendations are beginning to address sedentary behaviors - time spent sitting. Environmental and policy initiatives for physical activity might assist in addressing sedentary behaviors, but sedentary-specific innovations may be required. This review synthesizes current evidence on associations of neighborhood environmental attributes with adults' sedentary behaviors. METHODS: A search was conducted using three electronic databases (PubMed, Web of Science, and Transport Research Information Services). Relevant articles were assessed for their eligibility for inclusion (English-language articles with a quantitative examination of associations of neighborhood environmental attributes with adults' sedentary behaviors). RESULTS: Within 17 studies meeting inclusion criteria, associations of environmental attributes with sedentary behaviors were examined in 89 instances. Significant associations were found in 28% (n=25) of them; however, non-significant associations were found in 56% (n=50) of these instances. The most consistent association was for lower levels of sedentary behavior among residents of urban compared to regional areas. CONCLUSIONS: There is a modest but mixed initial evidence in associations of neighborhood environmental attributes with adults' sedentary behaviors. A research agenda required for this emerging field should include the development of more relevant conceptual models, measuring domain-specific sedentary behavior objectively, examining environments in close vicinity of and a larger area around home, and the use of prospective designs. PMID- 26051199 TI - Co-occurring obesity and smoking among U.S. women of reproductive age: Associations with educational attainment and health biomarkers and outcomes. AB - INTRODUCTION: Obesity and smoking are independently associated with socioeconomic disadvantage and adverse health effects in women of reproductive age and their children, but little is known about co-occurring obesity and smoking. The purpose of this study was to investigate relationships between co-occurring obesity and smoking, socioeconomic status, and health biomarkers and outcomes in a nationally representative sample. METHODS: Data from non-pregnant women of reproductive age were obtained from the U.S. National Health and Nutrition Examination Surveys reported between 2007 and 2010. Linear and logistic regressions were used to examine associations between obesity and smoking alone and in combination with educational attainment and a range of health biomarkers and outcomes. RESULTS: Prevalence of co-occurring obesity and smoking was 8.1% (~4.1 million U.S. women of reproductive age) and increased as an inverse function of educational attainment, with the least educated women being 11.6 times more likely to be obese smokers than the most educated. Compared to women with neither condition, obese smokers had significantly poorer cardiovascular and glycemic biomarker profiles, and higher rates of menstrual irregularity, hysterectomy, oophorectomy, physical limitations, and depression. Obese smokers also had significantly worse high-density lipoprotein (HDL) cholesterol levels, physical mobility, and depression scores than those with obesity or smoking alone. CONCLUSIONS: Co occurring obesity and smoking is highly associated with low educational attainment, a marker of socioeconomic disadvantage, and a broad range of adverse health biomarkers and outcomes. Interventions specifically targeting co-occurring obesity and smoking are likely necessary in efforts to reduce health disparities among disadvantaged women and their children. PMID- 26051200 TI - Diminished Alternative Reinforcement as a Mechanism Underlying Socioeconomic Disparities in Adolescent Substance Use. AB - OBJECTIVE: This study examined socioeconomic disparities in adolescent substance use utilizing a behavioral economic theoretical framework. We tested the hypothesis that teens of lower (vs. higher) socioeconomic status (SES) are vulnerable to substance use because they engage in fewer pleasurable substance free activities that provide reinforcement and may deter substance use. METHOD: In a cross-sectional correlational design, 9th grade students (N=2839; mean age=14.1years) in Los Angeles, California, USA completed surveys in Fall 2013 measuring SES (i.e., parental education), alternative reinforcement (engagement in pleasurable substance-free activities, e.g., hobbies), substance use susceptibility, initiation, and frequency, and other factors. RESULTS: For multi substance composite outcomes, lower parental education was associated with greater likelihood of substance use initiation in the overall sample, frequency of use among lifetime substance users, and susceptibility to substance use in never users. Substance-specific analyses revealed that lower parental education was associated with higher likelihood of initiating cigarettes, alcohol, and marijuana use as well as greater susceptibility to use cigarettes in never smokers. Each inverse association between parental education and substance related outcomes was statistically mediated by diminished alternative reinforcement; lower parental education was associated with lower engagement in alternative reinforcers, which, in turn, was associated with greater substance use susceptibility, initiation, and frequency. CONCLUSION: These results point to a behavioral economic interpretation for socioeconomic disparities in adolescent substance use. Replication and extension of these findings would suggest that prevention programs that increase access to and engagement in healthy and fun activities may reduce youth socioeconomic health disparities related to substance use. PMID- 26051201 TI - Long-term effect of a low-intensity smoking intervention embedded in an adherence program for patients with hypercholesterolemia: Randomized controlled trial. AB - OBJECTIVE: We evaluated the long-term effect of a smoking intervention embedded in an adherence program in patients with an increased risk for cardiovascular disease. METHOD: Secondary analysis of a randomized controlled trial: In 2002 2004, 8108 patients with hypercholesterolemia were enrolled from general practices in Germany. Patients received a 12-month adherence program and statin medication (intervention) or statin medication only (control). The program aimed to improve adherence to medication and lifestyle by educational material, mailings, and phone calls. Smoking was self-reported at baseline and every 6months during the 3-year follow-up. RESULTS: In total, 7640 patients were analyzed. At baseline, smoking prevalence was 21.7% in the intervention and 21.5% in the control group. Prevalence decreased in both groups to 16.6% vs. 19.5%, 15.3% vs. 16.8%, and 14.2% vs. 15.6% at the 12-, 24-, and 36-month follow-up. The intervention had a beneficial effect on smoking differing over time (group*time: P=0.005). The effect was largest after 6 and 12months [odds ratios (95% confidence intervals): 0.67 (0.54-0.82) and 0.63 (0.51-0.78)]. The effect decreased until the 18-month follow-up [0.72 (0.58-0.90)] and was not significant after 24months. CONCLUSION: A low-intensity smoking intervention embedded in an adherence program can contribute to smoking cessation although the intervention effect diminished over time. TRIAL REGISTRATION: ClinicalTrials.gov (www.clinicaltrials.gov): NCT00379249. PMID- 26051202 TI - Coverage of a national cardiovascular risk assessment and management programme (NHS Health Check): Retrospective database study. AB - OBJECTIVE: To determine coverage of NHS Health Check, a national cardiovascular risk assessment programme in England, in the first four years after implementation, and to examine prevalence of high cardiovascular disease (CVD) risk and uptake of statins in high risk patients. METHOD: Study sample was 95,571 patients in England aged 40-74years continuously registered with 509 practices in the Clinical Practice Research Datalink between April 2009 and March 2013. Multilevel logistic regression models were used to assess predictors of Health Check attendance; elevated CVD risk factors and statin prescribing among attendees. RESULTS: Programme coverage was 21.4% over four years, with large variations between practices (0%-72.7%) and regions (9.4%-30.7%). Coverage was higher in older patients (adjusted odds ratio 2.88, 95% confidence interval 2.49 3.31 for patients 70-74years) and in patients with a family history of premature coronary heart disease (2.37, 2.22-2.53), but lower in Black Africans (0.75, 0.61 0.92) and Chinese (0.68, 0.47-0.96) compared with White British. Coverage was similar in patients living in deprived and affluent areas. Prevalence of high CVD risk (QRISK2>=20%) among attendees was 4.6%. One third (33.6%) of attendees at high risk were prescribed a statin after Health Checks. CONCLUSIONS: Coverage of the programme and statin prescribing in high risk individuals was low. Coverage was similar in deprived and affluent groups but lower in some ethnic minority groups, possibly widening inequalities. These findings raise a question about whether recommendations by WHO to develop CVD risk assessment programmes internationally will deliver anticipated health benefits. PMID- 26051203 TI - Smoking-attributable medical expenditures by age, sex, and smoking status estimated using a relative risk approach. AB - OBJECTIVE: To accurately assess the benefits of tobacco control interventions and to better inform decision makers, knowledge of medical expenditures by age, gender, and smoking status is essential. METHOD: We propose an approach to distribute smoking-attributable expenditures by age, gender, and cigarette smoking status to reflect the known risks of smoking. We distribute hospitalization days for smoking-attributable diseases according to relative risks of smoking-attributable mortality, and use the method to determine national estimates of smoking-attributable expenditures by age, sex, and cigarette smoking status. Sensitivity analyses explored assumptions of the method. RESULTS: Both current and former smokers ages 75 and over have about 12 times the smoking attributable expenditures of their current and former smoker counterparts 35 54years of age. Within each age group, the expenditures of formers smokers are about 70% lower than current smokers. In sensitivity analysis, these results were not robust to large changes to the relative risks of smoking-attributable mortality which were used in the calculations. CONCLUSION: Sex- and age-group specific smoking expenditures reflect observed disease risk differences between current and former cigarette smokers and indicate that about 70% of current smokers' excess medical care costs is preventable by quitting. PMID- 26051204 TI - Evaluation of physical activity reporting in community Diabetes Prevention Program lifestyle intervention efforts: A systematic review. AB - INTRODUCTION: The Diabetes Prevention Program (DPP) lifestyle intervention has been translated to community settings using the DPP goals of 7% weight loss and 150min of moderate physical activity (PA) per week. Given that PA is a primary lifestyle goal and has been linked to improvements in metabolic health in the DPP, it is important to understand the role that PA plays in translation effort success. The purpose of this review is to thoroughly evaluate the reporting of PA methodology and results in DPP-based translations in order to guide future prevention efforts. METHODS: PubMed and Ovid databases were searched to identify peer-reviewed original research articles on DPP-based translations for adults at risk for developing diabetes or cardiovascular disease, limited to English language publications from January 2002-March 2015. RESULTS: 72 original research articles describing 57 translation studies met eligibility criteria. All 57 study interventions included a PA goal, 47 studies (82%) collected participant PA information, and 34 (60%) provided PA results. CONCLUSIONS: Despite PA being a primary intervention goal, PA methodology and results are under-reported in published DPP translation studies. This absence and inconsistency in reporting PA needs addressed in order to fully understand translation efforts' impact on participant health. PMID- 26051206 TI - Burden of stroke in women. AB - Stroke is the fifth cause of death in the United States and the first cause of disability. While reductions in stroke mortality have occurred, stroke remains a significant burden in women. In addition to traditional cardiovascular risk factors, there are specific risk factors in women that need to be addressed to further reduce deaths in women from stroke. Atrial fibrillation is common in women and needs proper evaluation for anticoagulation for risk reduction. Stroke in women remains a serious cause of preventable deaths, disability, and cost. Implementation of the new guidelines for stroke prevention in women is critical for reducing the burden of stroke in women. PMID- 26051205 TI - The mediation of coronary calcification in the association between risk scores and cardiac troponin T elevation in healthy adults: Is atherosclerosis a good prognostic precursor of coronary disease? AB - BACKGROUND: Conventional cardiac risk scores may not be completely accurate in predicting acute events because they only include factors associated with atherosclerosis, considered as the fundamental precursor of cardiovascular disease. In UK in 2006-2008 (Whitehall II study) we tested the ability of several risk scores to identify individuals with cardiac cell damage and assessed to what extent their estimates were mediated by the presence of atherosclerosis. METHODS: 430 disease-free, low-risk participants were tested for high-sensitivity cardiac troponin-T (HS-CTnT) and for coronary calcification using electron-beam, dual source, computed tomography (CAC). We analysed the data cross-sectionally using ROC curves and mediation tests. RESULTS: When the risk scores were ranked according to the magnitude of ROC areas for HS-CTnT prediction, a score based only on age and gender came first (ROC area=0.79), followed by Q-Risk2 (0.76), Framingham (0.70), Joint-British-Societies (0.69) and Assign (0.68). However, when the scores were ranked according to the extent of mediation by CAC (proportion of association mediated), their order was essentially reversed (age&gender=6.8%, Q-Risk2=9.7%, Framingham=16.9%, JBS=17.8%, Assign=17.7%). Therefore, the more accurate a score is in predicting detectable HS-CTnT, the less it is mediated by CAC; i.e. the more able a score is in capturing atherosclerosis the less it is able to predict cardiac damage. The P for trend was 0.009. CONCLUSIONS: The dynamics through which cardiac cell damage is caused cannot be explained by 'classic' heart disease risk factors alone. Further research is needed to identify precursors of heart disease other than atherosclerosis. PMID- 26051207 TI - Stress-induced cardiac arrhythmias: The heart-brain interaction. PMID- 26051208 TI - Lessons learned from the Multicenter Automatic Defibrillator Implantation Trial Cardiac Resynchronization Therapy (MADIT-CRT). AB - Cardiac resynchronization therapy (CRT) has evolved as a Class I treatment indication with Level of Evidence A, in patients with mild heart failure, depressed left ventricular ejection fraction, and wide QRS. In this review article, we will discuss the major findings of sub-studies published from the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). PMID- 26051209 TI - Effects of prenatal immune activation on amphetamine-induced addictive behaviors: Contributions from animal models. AB - BACKGROUND: Prenatal environmental adversities may affect brain development and are associated with increased risk for schizophrenia, an illness with 50% comorbidity with addiction. Maternal immune activation by poly-inosinic-citidilic acid (Poly(I:C)) exposure can promote behavioral alterations consistent with schizophrenia symptoms in rodents. OBJECTIVES: Considering the vulnerability to addiction in patients with schizophrenia, we evaluated the interactions between prenatal Poly(I:C) administration and addiction in two animal models (behavioral sensitization and conditioned place preference - CPP) in mice repeatedly treated with amphetamine (AMP). Additionally, stereotyped behavior and cross sensitization with cocaine (COC) were also investigated. METHODS: Swiss male mice offspring were submitted to prenatal administration of 5mg/kg Poly(I:C) in the 9(th) day of pregnancy. At the age of 90days, mice were treated with 2.5mg/kg AMP for 9days to evaluate behavioral sensitization or stereotyped behavior. Cross sensitization with 10mg/kg COC was evaluated 24h after the last treatment day. For AMP-induced CPP evaluation, mice were treated during 8 consecutive days. RESULTS: Prenatal Poly(I:C) administration potentiated both AMP-induced behavioral sensitization and CPP. Furthermore, Poly(I:C) increased cross sensitization with COC. CONCLUSIONS: Prenatal administration of Poly(I:C) is able to potentiate vulnerability to addiction in two animal models, without however modulating stereotyped behavior. PMID- 26051210 TI - Identification of tick species and disseminate pathogen using hemolymph by MALDI TOF MS. AB - BACKGROUND: Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) is increasingly emerging tool for identification of arthropods including tick vectors using whole or body part of specimens. The challenges of the present study were to assess MALDI-TOF MS profiling for the both identification of tick species and Rickettsia spp. in infected ticks using hemolymph as protein mixture. METHODS: Firstly, hemolymph protein mixture from legs of 5 tick species, Rhipicephalus sanguineus, Rhipicephalus bursa, Dermacentor marginatus, Hyalomma marginatum rufipes and Amblyomma variegatum infected by Rickettsia africae were submitted to MALDI-TOF MS to assess tick species identification ability. Secondly, hemolymph MS spectra from Rh. sanguineus infected or not by Rickettsia c. conorii were compared to detect protein profiles changes. Finally, leg hemolymph MS spectra from new specimens of the 5 tick species were tested blindly including ticks infected by R. c. conorii. Discriminating mass peaks distinguishing the R. c. conorii infected and non infected Rh sanguineus were determined. RESULTS: Consistent and reproducible MS profiles were obtained into each tick species. Comparison of MS spectra revealed distinct hemolymph protein profiles according to tick species. MS spectra changes were observed between hemolymphs from R. c. conorii-infected and non-infected Rh. sanguineus specimens, revealing 17 discriminating mass peaks. Clustering analysis based on MS protein profiles highlighted that hemolymph samples were grouped according to tick species. All tick hemolymph samples blindly tested against our home-made arthropod MS reference database were correctly identified at the species distinguishing also R. c. conorii-infected from Rickettsia-free Rh. sanguineus specimens. CONCLUSION: The present study demonstrated the use of hemolymph MS profiles for dual identification of tick species and associated pathogens. This concomitant identification could be helpful for tick entomological diagnosis, notably for specimens removed directly on patients. PMID- 26051212 TI - 'Human subjects research' as stigmatized activity: Implications for oversight reform. PMID- 26051211 TI - An alphavirus temperature-sensitive capsid mutant reveals stages of nucleocapsid assembly. AB - Alphaviruses have a nucleocapsid core composed of the RNA genome surrounded by an icosahedral lattice of capsid protein. An insertion after position 186 in the capsid protein produced a strongly temperature-sensitive growth phenotype. Even when the structural proteins were synthesized at the permissive temperature (28 degrees C), subsequent incubation of the cells at the non-permissive temperature (37 degrees C) dramatically decreased mutant capsid protein stability and particle assembly. Electron microscopy confirmed the presence of cytoplasmic nucleocapsids in mutant-infected cells cultured at the permissive temperature, but these nucleocapsids were not stable to sucrose gradient separation. In contrast, nucleocapsids isolated from mutant virus particles had similar stability to that of wildtype virus. Our data support a model in which cytoplasmic nucleocapsids go through a maturation step during packaging into virus particles. The insertion site lies in the interface between capsid proteins in the assembled nucleocapsid, suggesting the region where such a stabilizing transition occurs. PMID- 26051213 TI - Horizontal gene transfer in parasitic plants. AB - Horizontal gene transfer (HGT) between species has been a major focus of plant evolutionary research during the past decade. Parasitic plants, which establish a direct connection with their hosts, have provided excellent examples of how these transfers are facilitated via the intimacy of this symbiosis. In particular, phylogenetic studies from diverse clades indicate that parasitic plants represent a rich system for studying this phenomenon. Here, HGT has been shown to be astonishingly high in the mitochondrial genome, and appreciable in the nuclear genome. Although explicit tests remain to be performed, some transgenes have been hypothesized to be functional in their recipient species, thus providing a new perspective on the evolution of novelty in parasitic plants. PMID- 26051214 TI - Macromolecule exchange in Cuscuta-host plant interactions. AB - Cuscuta species (dodders) are parasitic plants that are able to grow on many different host plants and can be destructive to crops. The connections between Cuscuta and its hosts allow movement of not only water and small nutrients, but also macromolecules including mRNA, proteins and viruses. Recent studies show that RNAs move bidirectionally between hosts and parasites and involve a large number of different genes. Although the function of mobile mRNAs has not been demonstrated in this system, small RNAs are also transmitted and a silencing construct expressed in hosts is able to affect expression of the target gene in the parasite. High throughput sequencing of host-parasite associations has the potential to greatly accelerate understanding of this remarkable interaction. PMID- 26051215 TI - What the transcriptome does not tell - proteomics and metabolomics are closer to the plants' patho-phenotype. AB - The proteome and metabolome of the plant provide a wealth of additional information on plant-microbe interactions since they not only represent additional levels of regulation, but often they harbor the end products of regulatory processes. Proteomics has contributed to our understanding of plant microbe research by increasing the spatial resolution of the analysis within the infected tissue, because components of the basal immunity were uncovered in the apoplast. Metabolomics has developed into a powerful approach to discover the role of small molecules during plant-microbe interactions in non-model plants since it does not depend on the availability of genome or transcriptome data. Moreover, novel molecules involved in systemic acquired resistance and the precursors for the formation of molecules that provide physical barriers to prevent spreading of pathogens were identified. PMID- 26051216 TI - Dual and Opposite Effects of hRAD51 Chemical Modulation on HIV-1 Integration. AB - The cellular DNA repair hRAD51 protein has been shown to restrict HIV-1 integration both in vitro and in vivo. To investigate its regulatory functions, we performed a pharmacological analysis of the retroviral integration modulation by hRAD51. We found that, in vitro, chemical activation of hRAD51 stimulates its integration inhibitory properties, whereas inhibition of hRAD51 decreases the integration restriction, indicating that the modulation of HIV-1 integration depends on the hRAD51 recombinase activity. Cellular analyses demonstrated that cells exhibiting high hRAD51 levels prior to de novo infection are more resistant to integration. On the other hand, when hRAD51 was activated during integration, cells were more permissive. Altogether, these data establish the functional link between hRAD51 activity and HIV-1 integration. Our results highlight the multiple and opposite effects of the recombinase during integration and provide new insights into the cellular regulation of HIV-1 replication. PMID- 26051217 TI - Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4. AB - BRD4, a bromodomain and extraterminal domain (BET) family member, is an attractive target in multiple pathological settings, particularly cancer. While BRD4 inhibitors have shown some promise in MYC-driven malignancies such as Burkitt's lymphoma (BL), we show that BRD4 inhibitors lead to robust BRD4 protein accumulation, which may account for their limited suppression of MYC expression, modest antiproliferative activity, and lack of apoptotic induction. To address these limitations we designed ARV-825, a hetero-bifunctional PROTAC (Proteolysis Targeting Chimera) that recruits BRD4 to the E3 ubiquitin ligase cereblon, leading to fast, efficient, and prolonged degradation of BRD4 in all BL cell lines tested. Consequently, ARV-825 more effectively suppresses c-MYC levels and downstream signaling than small-molecule BRD4 inhibitors, resulting in more effective cell proliferation inhibition and apoptosis induction in BL. Our findings provide strong evidence that cereblon-based PROTACs provide a better and more efficient strategy in targeting BRD4 than traditional small-molecule inhibitors. PMID- 26051218 TI - Distinct Substrate Specificity and Catalytic Activity of the Pseudoglycosyltransferase VldE. AB - The pseudoglycosyltransferase (PsGT) VldE is a glycosyltransferase-like protein that is similar to trehalose 6-phosphate synthase (OtsA). However, in contrast to OtsA, which catalyzes condensation between UDP-glucose and glucose 6-phosphate, VldE couples two pseudosugars to give a product with an alpha,alpha-N pseudoglycosidic linkage. Despite their unique catalytic activity and important role in the biosynthesis of natural products, little is known about the molecular basis governing their substrate specificity and catalysis. Here, we report comparative biochemical and kinetic studies using recombinant OtsA, VldE, and their chimeric proteins with a variety of sugar and pseudosugar substrates. We found that the chimeric enzymes can produce hybrid pseudo-(amino)disaccharides, and an amino group in the acceptor is necessary to facilitate a coupling reaction with a pseudosugar donor. Furthermore, we found that the N-terminal domains of the enzymes not only play a major role in selecting the acceptors, but also control the type of nucleotidyl diphosphate moiety of the donors. PMID- 26051219 TI - A Systematic Review of Prospective Studies Reporting Adverse Events of Commonly Used Opioids for Cancer-Related Pain: A Call for the Use of Standardized Outcome Measures. AB - Data on the tolerability of opioids in patients with cancer-related pain are limited. Here, we report a systematic review that includes all published prospective studies reporting adverse events (AEs) of morphine, oxycodone, fentanyl, methadone, or hydromorphone for cancer-related pain in patients naive for these opioids. We included 25 studies describing 31 treatment cohorts, made an overview of study characteristics, and reported rates of AEs per type of opioid. The frequency of the most commonly reported AEs varied widely: nausea from 3 to 85%, vomiting from 4 to 50%, constipation from 5 to 97%, drowsiness from 3 to 88%, and dry mouth from 1 to 94%. There was a large heterogeneity among included studies, especially regarding the assessment and reporting of AEs. We describe how differences in assessment and reporting influence outcome rates. Although AEs are an important issue in daily clinical practice, realistic incidence rates of AEs per type of opioid are unknown because of the immense heterogeneity among studies. PERSPECTIVE: Although opioid-related adverse events are an important issue when treating cancer-related pain, realistic rates of adverse events per type of opioid are unknown because of immense heterogeneity among studies and lack of systematic assessment and reporting. There is an urgent need for studies with standardized outcome measures and reporting. PMID- 26051220 TI - Fifteen Years of Explaining Pain: The Past, Present, and Future. AB - The pain field has been advocating for some time for the importance of teaching people how to live well with pain. Perhaps some, and maybe even for many, we might again consider the possibility that we can help people live well without pain. Explaining Pain (EP) refers to a range of educational interventions that aim to change one's understanding of the biological processes that are thought to underpin pain as a mechanism to reduce pain itself. It draws on educational psychology, in particular conceptual change strategies, to help patients understand current thought in pain biology. The core objective of the EP approach to treatment is to shift one's conceptualization of pain from that of a marker of tissue damage or disease to that of a marker of the perceived need to protect body tissue. Here, we describe the historical context and beginnings of EP, suggesting that it is a pragmatic application of the biopsychosocial model of pain, but differentiating it from cognitive behavioral therapy and educational components of early multidisciplinary pain management programs. We attempt to address common misconceptions of EP that have emerged over the last 15 years, highlighting that EP is not behavioral or cognitive advice, nor does it deny the potential contribution of peripheral nociceptive signals to pain. We contend that EP is grounded in strong theoretical frameworks, that its targeted effects are biologically plausible, and that available behavioral evidence is supportive. We update available meta-analyses with results of a systematic review of recent contributions to the field and propose future directions by which we might enhance the effects of EP as part of multimodal pain rehabilitation. Perspective: EP is a range of educational interventions. EP is grounded in conceptual change and instructional design theory. It increases knowledge of pain-related biology, decreases catastrophizing, and imparts short-term reductions in pain and disability. It presents the biological information that justifies a biopsychosocial approach to rehabilitation. PMID- 26051221 TI - Control of an H1N1 outbreak in a correctional facility in central Taiwan. AB - BACKGROUND: Controlling the outbreak of H1N1 in correctional facilities is difficult due to the inevitable close and prolonged contact between inmates. The current study reports an H1N1 outbreak in a correction facility and investigates the effectiveness of oseltamivir to control the spread of H1N1. METHODS: All 2690 inmates at the prison received medical service from a single hospital. A list of patients with a diagnosis of influenza was compiled based on medical diagnoses with respiratory symptoms during the outbreak period. The outbreak was then investigated using both chart review and questionnaires. RESULTS: In the 4-week outbreak period, 24.6% (663/2690) of inmates experienced influenza-associated symptoms, 50.5% (335/663) fulfilled the criteria for influenza-like illness (ILI) with fever, and the overall attack rate of ILI was 12.8%. Twelve inmates were admitted for complicated influenza, and three of them experienced respiratory failure. Oseltamivir was provided at the end of the 2nd week, and the effectiveness of oseltamivir in the 1004 inmates from seven major sections in the prison was analyzed. The ILI incidence rate reduced from 12.6 +/- 4.1% between the 1st and 2nd weeks to 4.8 +/- 2.4% between the 3rd and 4th weeks (p = 0.018) after the oseltamivir intervention. In the 878 uninfected inmates 47.0% (413/878) of inmates received prophylactic oseltamivir at the end of the 2nd week, the incidence of ILI was lower than those without prophylaxis (6.2% versus 2.4%; p = 0.013). CONCLUSION: H1N1 influenza spread rapidly in the correctional facility. The use of oseltamivir may be a practical intervention to control an H1N1 outbreak an enclosed environment such as this. PMID- 26051222 TI - Seroprevalence of Bartonella henselae in patients awaiting heart transplant in Southern Italy. AB - BACKGROUND: Bartonella henselae is the etiologic agent of cat-scratch disease. B. henselae infections are responsible for a widening spectrum of human diseases, although often symptomless, ranging from self-limited to life-threatening and show different courses and organ involvement due to the balance between host and pathogen. The role of the host immune response to B. henselae is critical in preventing progression to systemic disease. Indeed in immunocompromised patients, such as solid organ transplant patients, B. henselae results in severe disseminated disease and pathologic vasoproliferation. The purpose of this study was to determine the seroprevalence of B. henselae in patients awaiting heart transplant compared to healthy individuals enrolled in the Regional Reference Laboratory of Transplant Immunology of Second University of Naples. METHODS: Serum samples of 38 patients awaiting heart transplant in comparison to 50 healthy donors were examined using immunfluorescence assay. RESULTS: We found a B. henselae significant antibody positivity rate of 21% in patients awaiting heart transplant (p = 0.002). There was a positive rate of 8% (p > 0.05) for immunoglobulin (Ig)M and a significant value of 13% (p = 0.02) for IgG, whereas controls were negative both for IgM and IgG antibodies against B. henselae. The differences in comorbidity between cases and controls were statistically different (1.41 +/- 0.96 vs 0.42 +/- 0.32; p = 0.001). CONCLUSIONS: Although this study was conducted in a small number of patients, we suggest that the identification of these bacteria should be included as a routine screening analysis in pretransplant patients. PMID- 26051223 TI - Line and Point Defects in MoSe2 Bilayer Studied by Scanning Tunneling Microscopy and Spectroscopy. AB - Bilayer (BL) MoSe2 films grown by molecular-beam epitaxy (MBE) are studied by scanning tunneling microscopy and spectroscopy (STM/S). Similar to monolayer (ML) films, networks of inversion domain boundary (DB) defects are observed both in the top and bottom layers of BL MoSe2, and often they are seen spatially correlated such that one is on top of the other. There are also isolated ones in the bottom layer without companion in the top-layer and are detected by STM/S through quantum tunneling of the defect states through the barrier of the MoSe2 ML. Comparing the DB states in BL MoSe2 with that of ML film reveals some common features as well as differences. Quantum confinement of the defect states is indicated. Point defects in BL MoSe2 are also observed by STM/S, where ionization of the donor defect by the tip-induced electric field is evidenced. These results are of great fundamental interests as well as practical relevance of devices made of MoSe2 ultrathin layers. PMID- 26051224 TI - A novel capsule-based self-recovery system with a chloride ion trigger. AB - Steel is prone to corrosion induced by chloride ions, which is a serious threat to reinforced concrete structures, especially in marine environments. In this work, we report a novel capsule-based self-recovery system that utilizes chloride ions as a trigger. These capsules, which are functionalized via a smart response to chloride ions, are fabricated using a silver alginate hydrogel that disintegrates upon contact with chloride ions, and thereby releases the activated core materials. The experimental results show that the smart capsules respond to a very low concentration of chloride ions (0.1 wt%). Therefore, we believe that this novel capsule-based self-recovery system will exhibit a promising prospect for self-healing or corrosion inhibition applications. PMID- 26051225 TI - Fabrication method, structure, mechanical, and biological properties of decellularized extracellular matrix for replacement of wide bone tissue defects. AB - The present paper was focused on the development of a new method of decellularized extracellular matrix (DECM) fabrication via a chemical treatment of a native bone tissue. Particular attention was paid to the influence of chemical treatment on the mechanical properties of native bones, sterility, and biological performance in vivo using the syngeneic heterotopic and orthotopic implantation models. The obtained data indicated that after a chemical decellularization treatment in 4% aqueous sodium chlorite, no noticeable signs of the erosion of compact cortical bone surface or destruction of trabeculae of spongy bone in spinal channel were observed. The histological studies showed that the chemical treatment resulted in the decellularization of both bone and cartilage tissues. The DECM samples demonstrated no signs of chemical and biological degradation in vivo. Thorough structural characterization revealed that after decellularization, the mineral frame retained its integrity with the organic phase; however clotting and destruction of organic molecules and fibers were observed. FTIR studies revealed several structural changes associated with the destruction of organic molecules, although all organic components typical of intact bone were preserved. The decellularization-induced structural changes in the collagen constituent resulted changed the deformation under compression mechanism: from the major fracture by crack propagation throughout the sample to the predominantly brittle fracture. Although the mechanical properties of radius bones subjected to decellularization were observed to degrade, the mechanical properties of ulna bones in compression and humerus bones in bending remained unchanged. The compressive strength of both the intact and decellularized ulna bones was 125-130 MPa and the flexural strength of humerus bones was 156 and 145 MPa for the intact and decellularized samples, respectively. These results open new avenues for the use of DECM samples as the replacement of wide bone tissue defects. PMID- 26051226 TI - A first-principles study of sodium adsorption and diffusion on phosphorene. AB - The structural, electronic, electrochemical as well as diffusion properties of Na doped phosphorene have been investigated based on first-principles calculations. The strong binding energy between Na and phosphorene indicates that Na could be stabilized on the surface of phosphorene without clustering. By comparing the adsorption of Na atoms on one side and on both sides of phosphorene, it has been found that Na-Na exhibits strong repulsion at the Na-Na distance of less than 4.35 A. The Na intercalation capacity is estimated to be 324 mA h g(-1) and the calculated discharge curve indicates quite a low Na(+)/Na voltage of phosphorene. Moreover, the diffusion energy barrier of Na atoms on the phosphorene surface at both low and high Na concentrations is as low as 40-63 meV, which implies the high mobility of Na during the charge/discharge process. PMID- 26051227 TI - PIN proteins and the evolution of plant development. AB - Many aspects of development in the model plant Arabidopsis thaliana involve regulated distribution of the hormone auxin by the PIN-FORMED (PIN) family of auxin efflux carriers. The role of PIN-mediated auxin transport in other plants is not well understood, but studies in a wider range of species have begun to illuminate developmental mechanisms across land plants. In this review, I discuss recent progress in understanding the evolution of PIN-mediated auxin transport, and its role in development across the green plant lineage. I also discuss the idea that changes in auxin biology led to morphological novelty in plant development: currently available evidence suggests major innovations in auxin transport are rare and not associated with the evolution of new developmental mechanisms. PMID- 26051228 TI - Editorial overview: Genome architecture and expression. PMID- 26051229 TI - Editorial overview: Developmental mechanisms, patterning and organogenesis. PMID- 26051231 TI - Pd nanoparticles supported on hierarchically porous carbons derived from assembled nanoparticles of a zeolitic imidazolate framework (ZIF-8) for methanol electrooxidation. AB - Hierarchically porous carbons with both micro- and mesopores synthesized by direct carbonization of assembled nanoparticles of ZIF-8 have been used as supports for Pd electrocatalysts for methanol electrooxidation for the first time. The Pd/ZC-1000 catalyst exerts extremely high catalytic activity and electrochemical stability for methanol electrooxidation. PMID- 26051230 TI - Association of obesity with glucose, blood pressure, and lipid goals attainment in patients with concomitant diabetes and hypertension. AB - OBJECTIVE: To investigate the associations between obesity and any significant improvements in glycemic control, blood pressure, and lipid targets in Chinese patients with concomitant type 2 diabetes mellitus (T2DM) and hypertension. METHODS AND RESULTS: A total of 3041 dyslipidemia patients with an average age of 65.7 +/- 10.53 years and comorbid conditions of T2DM and hypertension from the DYSlipidemia International Study (DYSIS) - China were included in the present subgroup analysis. Patients' demographic data, medication use, blood glucose, and lipid parameters were analyzed retrospectively. Body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WtHR) differed significantly among participants according to the attainment of treatment targets. Among female patients, significant differences in the rate of target attainment were observed among different WC, WtHR, and BMI quartile groups, whereas no significant differences in goal attainment were found according to WC and WtHR quartiles in male patients. Among the female patients, the results of logistic regression supported a significant association of anthropometric indices and the achievement of targets. CONCLUSION: A considerable proportion of dyslipidemia patients failed to achieve guideline-recommended targets in China, and this apparent treatment gap was more pronounced among women with central adiposity and patients with an elevated BMI. Based on the limitations of this cross-sectional study, further investigation of the mechanism at the molecular level is necessary. PMID- 26051232 TI - Influence of restoration thickness and dental bonding surface on the fracture resistance of full-coverage occlusal veneers made from lithium disilicate ceramic. AB - OBJECTIVES: The purpose of this in-vitro study was to evaluate the influence of ceramic thickness and type of dental bonding surface on the fracture resistance of non-retentive full-coverage adhesively retained occlusal veneers made from lithium disilicate ceramic. METHODS: Seventy-two extracted molars were divided into three test groups (N=24) depending on the location of the occlusal veneer preparation: solely within enamel, within enamel and dentin or within enamel and an occlusal composite resin filling. For each test group, occlusal all-ceramic restorations were fabricated from lithium disilicate ceramic blocks (IPS e.max CAD) in three subgroups with different thicknesses ranging from 0.3 to 0.7mm in the fissures and from 0.6 to 1.0mm at the cusps. The veneers were etched (5% HF), silanated and adhesively luted using a self etching primer and a composite luting resin (Multilink Primer A/B and Multilink Automix). After water storage at 37 degrees C for 3 days and thermal cycling for 7500 cycles at 5-55 degrees C, specimens were subjected to dynamic loading in a chewing simulator with 600,000 loading cycles at 10kg combined with thermal cycling. Unfractured specimens were loaded until fracture using a universal testing machine. Statistical analysis was performed using Kruskal-Wallis and Wilcoxon tests with Bonferroni-Holm correction for multiple testing. RESULTS: Only specimens in the group with the thickest dimension (0.7mm in fissure, 1.0mm at cusp) survived cyclic loading without any damage. Survival rates in the remaining subgroups ranged from 50 to 100% for surviving with some damage and from 12.5 to 75% for surviving without any damage. Medians of final fracture resistance ranged from 610 to 3390N. In groups with smaller ceramic thickness, luting to dentin or composite provided statistically significant (p<=0.05) higher fracture resistance than luting to enamel only. The thickness of the occlual ceramic veneers had a statistically significant (p<=0.05) influence on fracture resistance. SIGNIFICANCE: The results suggest to use a thickness of 0.7-1mm for non-retentive full-coverage adhesively retained occlusal lithium disilicate ceramic restorations. PMID- 26051233 TI - EGFR mutations and EGFR tyrosine kinase inhibitors. PMID- 26051234 TI - New scale assesses benefits of cancer medicines. PMID- 26051235 TI - Global cancer cases on the rise. PMID- 26051237 TI - GP behaviour and cancer survival? PMID- 26051236 TI - Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX Lung 2, LUX-Lung 3, and LUX-Lung 6. AB - BACKGROUND: Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non small-cell lung cancer that have tumours harbouring uncommon EGFR mutations. METHODS: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393. FINDINGS: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71.1%, 95% CI 54.1-84.6) patients in group 1 had objective responses, as did two (14.3%, 1.8-42.8) in group 2 and two (8.7%, 1.1-28.0) in group 3. Median progression-free survival was 10.7 months (95% CI 5.6-14.7) in group 1, 2.9 months (1.2-8.3) in group 2; and 2.7 months (1.8-4.2) in group 3. Median overall survival was 19.4 months (95% CI 16.4-26.9) in group 1, 14.9 months (8.1-24.9) in group 2, and 9.2 months (4.1-14.2) in group 3. For the most frequent uncommon mutations, 14 (77.8%, 95% CI 52.4-93.6) patients with Gly719Xaa had an objective response, as did nine (56.3%, 29.9-80.2) with Leu861Gln, and eight (100.0%, 63.1-100.0) with Ser768Ile. INTERPRETATION: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations. FUNDING: Boehringer Ingelheim. PMID- 26051238 TI - Toxic epidermal necrolysis induced by vemurafenib. PMID- 26051239 TI - Comparative proteomic analysis of the silkworm middle silk gland reveals the importance of ribosome biogenesis in silk protein production. AB - The silkworm middle silk gland (MSG) is the sericin synthesis and secretion unique sub-organ. The molecular mechanisms of regulating MSG protein synthesis are largely unknown. Here, we performed shotgun proteomic analysis on the three MSG subsections: the anterior (MSG-A), middle (MSG-M), and posterior (MSG-P) regions. The results showed that more strongly expressed proteins in the MSG-A were involved in multiple processes, such as silk gland development and silk protein protection. The proteins that were highly expressed in the MSG-M were enriched in the ribosome pathway. MSG-P proteins with stronger expression were mainly involved in the oxidative phosphorylation and citrate cycle pathways. These results suggest that the MSG-M is the most active region in the sericin synthesis. Furthermore, comparing the proteome of the MSG with the posterior silk gland (PSG) revealed that the specific and highly expressed proteins in the MSG were primarily involved in the ribosome and aminoacyl-tRNA biosynthesis pathways. These results indicate that silk protein synthesis is much more active as a result of the enhancement of translation-related pathways in the MSG. These results also suggest that enhancing ribosome biogenesis is important to the efficient synthesis of silk proteins. PMID- 26051240 TI - Predictive Biomarker Profiling of > 6000 Breast Cancer Patients Shows Heterogeneity in TNBC, With Treatment Implications. AB - BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive disease without established targeted treatment options for patients with metastatic disease. This study was undertaken to evaluate potentially actionable biomarkers in a large cohort of TNBC and compare them with non-TNBCs. MATERIALS AND METHODS: We evaluated 6341 (2111 TNBC and 4230 non-TNBC) breast cancer samples at a central laboratory for biomarkers of potential drug response across multiple platforms, including gene sequencing, protein expression, and gene copy number. RESULTS: TNBC expresses androgen receptor (AR) in a significantly (P < .05) lower percentage of cases (17%) than hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive breast carcinomas (59% and 79%, respectively), and gene comutations were differentially associated with AR positive versus AR-negative cases. Higher AR expression levels in TNBC predicted for lower Ki-67 levels. Seventy percent of TNBC harbored a phosphatidylinositol 4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), v-akt murine thymoma viral oncogene homolog 1 (AKT1), or phosophatase and tensin homolog (PTEN) aberration. TNBC patients had a significantly lower PIK3CA mutation rate (13%) than all other subtypes (P < .05) and a higher tumor protein p53 (TP53) mutation rate (64%) than the estrogen receptor (ER)-positive cases (approximately 30%; P < .05). Topoisomerase 2 (TOP2A) amplification was observed in 1.3% of TNBC and in 1.6% of HER2-negative, HR-positive cancers; in contrast, HER2-positive, HR negative or HR-positive cancers exhibited TOP2A amplification in 19% and 40% of cases, respectively (P <.05). CONCLUSION: Multi-platform molecular profiling identifies subgroups of TNBC with different biomarker profiles, suggesting numerous potentially targetable alterations in TNBC. TNBC is further characterized by different gene mutations and proliferative activity relative to AR expression, highlighting a need for comprehensive pathologic examination with potential to develop different, individualized treatment options. PMID- 26051241 TI - Sleeping Beauty transposon insertional mutagenesis based mouse models for cancer gene discovery. AB - Large-scale genomic efforts to study human cancer, such as the cancer gene atlas (TCGA), have identified numerous cancer drivers in a wide variety of tumor types. However, there are limitations to this approach, the mutations and expression or copy number changes that are identified are not always clearly functionally relevant, and only annotated genes and genetic elements are thoroughly queried. The use of complimentary, nonbiased, functional approaches to identify drivers of cancer development and progression is ideal to maximize the rate at which cancer discoveries are achieved. One such approach that has been successful is the use of the Sleeping Beauty (SB) transposon-based mutagenesis system in mice. This system uses a conditionally expressed transposase and mutagenic transposon allele to target mutagenesis to somatic cells of a given tissue in mice to cause random mutations leading to tumor development. Analysis of tumors for transposon common insertion sites (CIS) identifies candidate cancer genes specific to that tumor type. While similar screens have been performed in mice with the PiggyBac (PB) transposon and viral approaches, we limit extensive discussion to SB. Here we discuss the basic structure of these screens, screens that have been performed, methods used to identify CIS. PMID- 26051242 TI - A method making fewer assumptions gave the most reliable estimates of exposure outcome associations in stratified case-cohort studies. AB - OBJECTIVE: A case-cohort study is an efficient epidemiological study design for estimating exposure-outcome associations. When sampling of the subcohort is stratified, several methods of analysis are possible, but it is unclear how they compare. Our objective was to compare five analysis methods using Cox regression for this type of data, ranging from a crude model that ignores the stratification to a flexible one that allows nonproportional hazards and varying covariate effects across the strata. STUDY DESIGN AND SETTING: We applied the five methods to estimate the association between physical activity and incident type 2 diabetes using data from a stratified case-cohort study and also used artificial data sets to exemplify circumstances in which they can give different results. RESULTS: In the diabetes study, all methods except the method that ignores the stratification gave similar results for the hazard ratio associated with physical activity. In the artificial data sets, the more flexible methods were shown to be necessary when certain assumptions of the simpler models failed. The most flexible method gave reliable results for all the artificial data sets. CONCLUSION: The most flexible method is computationally straightforward, and appropriate whether or not key assumptions made by the simpler models are valid. PMID- 26051243 TI - Reducing publication bias in biomedical research: reviewing and registering protocol with a suitable journal. PMID- 26051246 TI - Base-free Knoevenagel condensation catalyzed by copper metal surfaces. AB - For the first time Knoevenagel condensation has been catalyzed by elemental copper with unexpected activity and excellent isolated yields. Inexpensive, widely available copper powder was used to catalyze the condensation of cyanoacetate and benzaldehyde under mild conditions. To ensure general applicability, a wide variety of different substrates was successfully reacted. PMID- 26051245 TI - Relapsing tricuspid valve endocarditis by multidrug-resistant Pseudomonas aeruginosa in 11 years: tricuspid valve replacement with an aortic valve homograft. AB - Eleven years ago, a 27-year-old non-drug abuser woman was admitted to the hospital due to a burn injury. During the treatment, she was diagnosed with tricuspid valve infective endocarditis caused by multi-drug resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa). She underwent tricuspid valve replacement (TVR) using a bioprosthetic valve, followed by 6 weeks of meropenem antibiotic therapy. Ten years later, she was again diagnosed with prosthetic valve infective endocarditis caused by MDR P. aeruginosa. She underwent redo-TVR with a bioprosthetic valve and was treated with colistin and ciprofloxacin. Ten months later, she was again diagnosed with prosthetic valve infective endocarditis with MDR P. aeruginosa as a pathogen. She underwent a second redo-TVR with a tissue valve and was treated with colistin. Two months later, her fever recurred and she was again diagnosed with prosthetic valve infective endocarditis caused by MDR P. aeruginosa. She eventually underwent a third redo-TVR using an aortic valve homograft and was discharged from the hospital after additional 6 weeks' of antibiotic therapy. All the strains of P. aeruginosa isolated from each event of infective endocarditis were analyzed by repetitive deoxyribonucleic acid sequence based polymerase chain reaction (rep-PCR) deoxyribonucleic acid (DNA) strain typing to determine the correlation of isolates. All of the pathogens in 11 years were similar enough to be classified as the same strain, and this is the first case report of TVR using an aortic valve homograft to treat relapsing endocarditis. PMID- 26051244 TI - A systematic review of barriers to optimal outpatient specialist services for individuals with prevalent chronic diseases: what are the unique and common barriers experienced by patients in high income countries? AB - Health utilization and need assessment data suggest there is considerable variation in access to outpatient specialist care. However, it is unclear if the types of barriers experienced are specific to chronic disease groups or experienced universally. This systematic review provides a detailed summary of common and unique barriers experienced by chronic disease groups when accessing and receiving care, and a synthesized list of possible health service initiatives to improve equitable delivery of optimal care in high-income countries. Quantitative articles describing barriers to specialist outpatient services were retrieved from CINAHL, MEDLINE, Embase, and PyscINFO. To be eligible for review, studies: were published from 2002 to May 2014; included samples with cancer, diabetes mellitus, osteoporosis, arthritis, ischaemic heart disease, stroke, asthma, chronic pulmonary disorder (COPD) or depression; and, were conducted in high-income countries. Using a previously validated model of access (Penchansky and Thomas' model of fit), barriers were grouped according to five overarching domains and defined in more detail using 33 medical subject headings. Results from reviewed articles, including the scope and frequency of reported barriers, are conceptualized using thematic analysis and framed as possible health service initiatives. A total of 3181 unique records were screened for eligibility, of which 74 studies were included in final analysis. The largest proportion of studies reported acceptability barriers (75.7 %), of which demographic disparities (44.6 %) were reported across all diseases. Other frequently reported barriers included inadequate need assessment (25.7 %), information provision (32.4 %), or health communication (20 %). Unique barriers were identified for oncology, mental health, and COPD samples. Based on the scope, frequency and measurement of reported barriers, eight key themes with associated implications for health services are presented. Examples include: common accommodation and accessibility barriers caused on service organization or physical structure, such as parking and appointment scheduling; common barriers created by poor coordination of care within the healthcare team; and unique barriers resulting from inadequate need assessment and referral practices. Consideration of barriers, across and within chronic diseases, suggests a number of specific initiatives are likely to improve the delivery of patient-centered care and increase equity in access to high-quality health services. PMID- 26051247 TI - Missing memories of death: Dissociative amnesia in the bereaved the day after a cancer death. AB - OBJECTIVE: The death of a loved one is one of the most stressful events of life, and such stress affects the physical and psychological well-being of the bereaved. Dissociative amnesia is characterized by an inability to recall important autobiographical information. Dissociative amnesia in the bereaved who have lost a loved one to cancer has not been previously reported. We discuss herein the case of a patient who developed dissociative amnesia the day after the death of here beloved husband. METHOD: A 38-year-old woman was referred for psychiatric consultation because of restlessness and abnormal behavior. Her 44 year-old husband had died of pancreatic cancer the day before the consultation. On the day of the death, she looked upset and began to hyperventilate. The next day, she behaved as if the deceased were still alive, which embarrassed her family. At her initial psychiatric consultation, she talked and behaved as if her husband was still alive and in the hospital. RESULTS: Her psychiatric features fulfilled the DSM-V criteria for dissociative amnesia. The death of her husband had been very traumatic for her and was considered to have been one of the causes of this dissociation. SIGNIFICANCE OF RESULTS: This report adds to the list of psychiatric symptoms in the bereaved who have lost a loved one to cancer. In an oncology setting, we should consider the impact of death, the concomitant defense mechanisms, and the background of the families. PMID- 26051249 TI - Modelling non-Markovian dynamics in biochemical reactions. AB - BACKGROUND: Biochemical reactions are often modelled as discrete-state continuous time stochastic processes evolving as memoryless Markov processes. However, in some cases, biochemical systems exhibit non-Markovian dynamics. We propose here a methodology for building stochastic simulation algorithms which model more precisely non-Markovian processes in some specific situations. Our methodology is based on Constraint Programming and is implemented by using Gecode, a state-of the-art framework for constraint solving. RESULTS: Our technique allows us to randomly sample waiting times from probability density functions that not necessarily are distributed according to a negative exponential function. In this context, we discuss an important case-study in which the probability density function is inferred from single-molecule experiments that describe the distribution of the time intervals between two consecutive enzymatically catalysed reactions. Noticeably, this feature allows some types of enzyme reactions to be modelled as non-Markovian processes. CONCLUSIONS: We show that our methodology makes it possible to obtain accurate models of enzymatic reactions that, in specific cases, fit experimental data better than the corresponding Markovian models. PMID- 26051250 TI - A novel autoregulatory loop between the Gcn2-Atf4 pathway and l-Proline metabolism controls stem cell identity. PMID- 26051251 TI - Experimental and theoretical studies of highly emissive dinuclear Cu(I) halide complexes with delayed fluorescence. AB - A series of luminescent homo-dinuclear Cu(I) halide complexes, [PPh2PAr2Cu(MU X)2CuPPh2PAr2] (X = I (1), Br (2), Cl (3)) (PPh2PAr2 = (1-bis(2 methylphenyl)phosphino-2-diphenylphosphino)benzene) were synthesized from the reaction of the corresponding cuprous halide and the chelating bisphosphine ligand PPh2PAr2 in CH3CN. The complexes were structurally characterized by X-ray single crystal analysis. Their photophysical properties were studied in detail. The Cu(I) atoms in these complexes are four-coordinated and adopt a tetrahedral coordination geometry. In each complex, the copper centers are bridged by two halide anions and each Cu(I) is chelated further terminally by a PPh2PAr2 ligand. The[Cu(MU-X)2Cu] cores have similar butterfly-type configurations. The distances between the Cu(I) atoms in each complex are over 2.94 A. In the solid state, these complexes are highly emissive and exhibit bluish-green photoluminescence (emission peaks, lambdamax = 488 nm (1), 482 nm (2), 490 nm (3)) with short lifetimes (4.9-5.9 MUs) and high quantum yields (phi = 0.42-0.95) at room temperature. In this series of complexes, the ligand-field strengths of the ions (I(-) < Br(-) < Cl(-)) do not have obvious effect on the emission maxima. The studies on varied temperature emission spectra and decay behaviours of these complexes indicate that the mechanism of their emissions involves two thermal equilibrium excited states. At room temperature, the complexes display thermally activated delayed fluorescences with short decay lifetimes. With a decrease of the temperature, a significant increase of emission decay times by almost 2 orders of magnitude is observed. At temperatures below T ~ 100 K, the decay times of the studied complexes are over one hundred microseconds long, which indicates that the emission originates mainly from the triplet state (T1 state). To interpret the varied temperature photophysics of these complexes, an equilibrated 2 excited states model S0 <- T1 <-> S1 -> S0 was used. The results of the experimental and DFT calculations suggest that the emission in the solid state originates from the (1,3)(MLCT + XLCT + ILCT) excited states, in which emissive excited states, (1)S and (3)T, are in equilibrium with an energy difference of about 0.055 eV. The process of the reverse intersystem crossing was estimated to be in the order of 2 ns. PMID- 26051248 TI - A fluorogenic aryl fluorosulfate for intraorganellar transthyretin imaging in living cells and in Caenorhabditis elegans. AB - Fluorogenic probes, due to their often greater spatial and temporal sensitivity in comparison to permanently fluorescent small molecules, represent powerful tools to study protein localization and function in the context of living systems. Herein, we report fluorogenic probe 4, a 1,3,4-oxadiazole designed to bind selectively to transthyretin (TTR). Probe 4 comprises a fluorosulfate group not previously used in an environment-sensitive fluorophore. The fluorosulfate functional group does not react covalently with TTR on the time scale required for cellular imaging, but does red shift the emission maximum of probe 4 in comparison to its nonfluorosulfated analogue. We demonstrate that probe 4 is dark in aqueous buffers, whereas the TTR.4 complex exhibits a fluorescence emission maximum at 481 nm. The addition of probe 4 to living HEK293T cells allows efficient binding to and imaging of exogenous TTR within intracellular organelles, including the mitochondria and the endoplasmic reticulum. Furthermore, live Caenorhabditis elegans expressing human TTR transgenically and treated with probe 4 display TTR.4 fluorescence in macrophage-like coelomocytes. An analogue of fluorosulfate probe 4 does react selectively with TTR without labeling the remainder of the cellular proteome. Studies on this analogue suggest that certain aryl fluorosulfates, due to their cell and organelle permeability and activatable reactivity, could be considered for the development of protein selective covalent probes. PMID- 26051252 TI - Light-weight reference-based compression of FASTQ data. AB - BACKGROUND: The exponential growth of next generation sequencing (NGS) data has posed big challenges to data storage, management and archive. Data compression is one of the effective solutions, where reference-based compression strategies can typically achieve superior compression ratios compared to the ones not relying on any reference. RESULTS: This paper presents a lossless light-weight reference based compression algorithm namely LW-FQZip to compress FASTQ data. The three components of any given input, i.e., metadata, short reads and quality score strings, are first parsed into three data streams in which the redundancy information are identified and eliminated independently. Particularly, well designed incremental and run-length-limited encoding schemes are utilized to compress the metadata and quality score streams, respectively. To handle the short reads, LW-FQZip uses a novel light-weight mapping model to fast map them against external reference sequence(s) and produce concise alignment results for storage. The three processed data streams are then packed together with some general purpose compression algorithms like LZMA. LW-FQZip was evaluated on eight real-world NGS data sets and achieved compression ratios in the range of 0.111 0.201. This is comparable or superior to other state-of-the-art lossless NGS data compression algorithms. CONCLUSIONS: LW-FQZip is a program that enables efficient lossless FASTQ data compression. It contributes to the state of art applications for NGS data storage and transmission. LW-FQZip is freely available online at: http://csse.szu.edu.cn/staff/zhuzx/LWFQZip. PMID- 26051253 TI - First detection of Pasteurella multocida type B:2 in Hungary associated with systemic pasteurellosis in backyard pigs. AB - This is the first report of Pasteurella multocida type B in Hungarian pigs. This disease was observed in backyard-raised pigs in three households within a small area. Neither the source of the infection nor the epidemiological connection between any of the premises could be determined. The most consistent lesion was dark red discolouration of the skin of the ventral neck and brisket, with accompanying oedema and haemorrhages. The morbidity was low and lethality relatively high, with three dead (50%) and two euthanised (33%) out of six affected animals. A total of three isolates of P. multocida (P55, P56 and P57) were cultured from these cases and examined in detail. These were identified as P. multocida ssp. multocida biovar 3. All were toxA negative and belonged to serotype B:2. Multilocus sequence typing was used to assign these to a new sequence type (ST61) that is closely related to other haemorrhagic septicaemia causing strains of P. multocida regardless of the host. M13 polymerase chain reaction and virulence-associated gene typing also show that type B strains form a highly homogeneous, distinct phylogenic group within P. multocida. PMID- 26051254 TI - Different sample types in pigs challenged with Haemophilus parasuis following two treatment schemes with tulathromycin. AB - This study aimed to test the efficacy of samplings for the detection of Haemophilus parasuis after metaphylactic treatment and subsequent challenge using an established model for Glasser's disease. In this model, 36 piglets were equally assigned to a negative control, a positive control, and two trial groups receiving tulathromycin 7 or 4 days prior to challenge. The piglets of three groups were challenged intratracheally with H. parasuis serovar 5. As a result, four pigs in each challenged group died or had to be euthanised within 10 days post challenge. The remaining 15 pigs of these challenged groups survived until termination of the experiment (days 14-15). All pigs were necropsied and collective swabs of serosal surfaces were tested by bacterial culture and PCR. Samples of tarsal synovial fluid and joint capsule, cerebrospinal fluid (CSF) and brain swabs were tested by PCR. A total of 22 out of the 27 challenged animals had macroscopically detectable polyserositis and all of them tested positive in the collective swab samples. Haemophilus parasuis was more frequently detected in pigs that died within the first 10 days compared to those surviving until days 14 15 (P < 0.001), and those that succumbed within 10 days showed higher positivity rates in the brain and CSF. All pigs which were positive in the CSF had detectable meningitis. At days 14-15, joint samples from 5 of the remaining 15 pigs tested positive for H. parasuis. Four of these five animals did not show any macroscopic or histological lesions in the joints. In conclusion, collective swabs were the best sample material in acute cases, whereas samples from the joints gave the best results in chronic cases. In this challenge model it was not possible to prove the metaphylactic effect of tulathromycin administered 4 and 7 days prior to infection with H. parasuis. PMID- 26051255 TI - Flow cytometry follow-up analysis of peripheral blood leukocyte subpopulations in calves experimentally infected with field isolates of Mycoplasma bovis. AB - Changes in peripheral blood leukocyte subpopulations were investigated in calves challenged intratracheally with three different Mycoplasma bovis isolates in Groups E1, E2, and E3. The controls received a placebo. Blood samples were collected before challenge and then at days 1 to 7, 14, 21 and 28. White blood cells (WBC), polymorphonuclear leukocytes (PMNLs), lymphocytes (LYMs), monocytes, eosinophils and basophils (mid-size cells, MID), as well as CD2(+), CD4(+), CD8(+), WC4(+) lymphocyte subsets with CD4:CD8 ratio were also analysed. A transient increase of WBC and PMNLs in all challenged calves was observed on day 1. Increased LYM counts were observed in E1 throughout the study, whereas in E2 the LYM counts were higher only between days 14 and 28, and consistently lower in E3. The MID count had broadly comparable values for all groups. Stimulation of the CD2(+) response was observed in E2 and E3 in contrast with E1 which had a lower CD2(+) throughout. The CD4(+) response was dominant in E1 and E2, whereas in E3 a parallel CD4(+) and CD8(+) stimulation was observed. The B-cell response (WC4(+)) and an increased CD4:CD8 ratio was most apparent in E1. The main host responses to M. bovis infections are a stimulation of CD4(+) cells and an enhancement of the WC4(+) response. PMID- 26051256 TI - Effect of feeding different oils on plasma corticosterone in broiler chickens. AB - A study was conducted to examine the effects of different oils on the plasma corticosterone concentrations of broiler chickens fed ad libitum or deprived of feed for 24 hours. A total of 36 Ross broilers were randomly assigned to one of three dietary treatments at 10 days of age and fed a grower diet supplemented with 60 g/kg soybean oil (rich in linoleic acid, C18:2n-6), linseed oil (rich in a-linolenic acid, C18:3n-3) or fish oil (rich in C14:0, C16:0, C16:1n-7, C20:1n 9; eicosapentaenoic acid and docosahexaenoic acid, EPA, C20:5n-3 and DHA, C22:6n 3), respectively, for 18 days. Dietary supplementation of fish oil resulted in lower (P < 0.05) baseline plasma corticosterone levels of chickens fed ad libitum for 18 days compared to soybean and linseed oil supplementations. Feed deprivation for 24 h induced a significant (P < 0.05) increase in corticosterone concentration in every treatment group compared to the ad libitum-fed birds. The hormone levels of feed-deprived birds did not differ significantly among groups fed diets supplemented with different oils. PMID- 26051257 TI - Intestinal helminth parasites of the grey wolf (Canis lupus L.) in Serbia. AB - The grey wolf (Canis lupus L.) is the most widespread large carnivore in Europe with large populations in the Eastern part of Europe and the Balkan Peninsula. In this study, a total of 102 wolves were examined for intestinal helminth parasites. The carcasses were collected within the Serbian part of the wolf's range during the period 2009-2014. Nine helminth species were found: one nematode, Toxocara canis (3.9%), one trematode, Alaria alata (1.0%), and seven cestodes, Taenia pisiformis (1.0%), T. hydatigena (9.8%), T. polyacantha (2.9%), T. taeniaeformis (2.0%), T. (syn. Multiceps) multiceps (3.9%), T. serialis (1.0%) and Mesocestoides litteratus (1.0%). Taenia (syn. Hydatigera) taeniaeformis has been registered for the first time in a wolf from Europe. An overall moderate prevalence (16.7%) of infected wolves was recorded. There was no statistically significant difference in prevalence between sexes. Of the years studied, the highest prevalence was found in 2014 (57.1%). The maximum number of helminth species per host specimen was four. PMID- 26051258 TI - Clinical babesiosis and molecular identification of Babesia canis and Babesia gibsoni infections in dogs from Serbia. AB - Canine babesiosis is a frequent and clinically significant tick-borne disease. Sixty symptomatic dogs with clinical findings compatible with babesiosis were included in this study conducted in Serbia. After clinical examination, blood samples were taken for microscopic examination, complete blood count (CBC), Canine SNAP 4Dx Test, DNA analyses and sequencing. The main clinical signs included apathy, anorexia, fever, brown/red discoloration of urine, pale mucous membranes, icterus, splenomegaly, and vomiting. The main clinicopathological findings in Babesia infections were a slight to severe thrombocytopenia and a mild to very severe normocytic normochromic anaemia. Microscopic evaluation revealed 58 positive samples with the presence of large and small intraerythrocytic piroplasms in 57 and 1 sample(s), respectively. No co infections were found using SNAP test. Two Babesia species, B. canis (58/60) and B. gibsoni (2/60), were differentiated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Species identification was further confirmed by sequencing PCR products of B. gibsoni samples and six randomly selected B. canis samples. All dogs were treated with imidocarb dipropionate (6.6 mg/kg of body weight), given intramuscularly twice at an interval of 14 days. This report presents the first molecular evidence of the occurrence of B. gibsoni and B. canis, confirmed by DNA sequencing, in sick dogs from Serbia. PMID- 26051259 TI - Heat shock protein 70 and nitric oxide concentrations in non-tumorous and neoplastic canine mammary tissues: preliminary results - Short communication. AB - The concentrations of heat shock protein 70 (Hsp70) and nitric oxide ions (NO), measured as nitrite, were determined in canine mammary tumours and nontumorous mammary gland tissues. The concentrations of Hsp70 and NO were significantly higher in both benign and malignant tumours than in non-tumorous mammary tissues. Hsp70 concentration decreased with the increase in the grade of histological malignancy. A strong positive correlation was found between the concentrations of Hsp70 and NO in the benign tumours as well as in grade I and grade II malignant tumours. The results indicate that the process of neoplastic transformation in the canine mammary gland is related to a significant increase in Hsp70 and NO concentration in tumour tissues, and an interdependence between Hsp70 and nitrite ion production can be observed. PMID- 26051260 TI - Vascular lesions and pneumonia in a pig fetus infected by porcine circovirus type 2. AB - Porcine circovirus type 2 (PCV2) associated reproductive disease was diagnosed in a herd containing only gilts. A single case of abortion occurred and no other disorder was evident in the herd. PCV2 antigen and/or DNA were detected in two aborted fetuses. One of the fetuses, revealing both PCV2 DNA and antigen, presented multinucleated giant cells, severe vascular lesions (intramural oedema, fibrinoid necrosis, mild lympho-histiocytic vasculitis, fibrin thrombi) and mild non-suppurative inflammation in the lungs. Other abortifacient infections were not found. This is the only report of PCV2-induced abortion in Hungary since 1999, when PCV2-associated disease was first discovered in the country. PMID- 26051261 TI - Effects of long-term vaccination against Coxiella burnetii on the fertility of high-producing dairy cows. AB - The impact of long-term vaccination against Coxiella burnetii on the fertility of cows was studied. Double vaccinations three weeks apart at the start of the third trimester of gestation in each of two consecutive pregnancies were applied. The final study population consisted of 410 cows after the first vaccination round. Based on the odds ratios, the likelihood of early fetal loss (pregnancy loss following a positive pregnancy diagnosis before Day 90 of gestation) was higher in control cows (OR = 1.42) than in vaccinated cows. The final study population consisted of 336 cows after the second round of vaccination. According to the odds ratios, vaccinated C. burnetii seronegative cows were less likely to be subfertile (> 3 AI) (OR = 0.4) compared to non-vaccinated seronegative animals, and the likelihood of early fetal loss was lower in vaccinated C. burnetii seropositive animals (OR = 0.3) compared to non-vaccinated seronegative cows. Seropositivity to C. burnetii was positively related to twin pregnancy after the two rounds of vaccination (OR = 2.1 and 3.5, respectively). These results indicate that two consecutive vaccination rounds against C. burnetii in advanced gestation reduce subfertility and early fetal loss in dairy cows. PMID- 26051262 TI - Use of retinoids during oocyte maturation diminishes apoptosis in caprine embryos. AB - Exposure of caprine oocytes and embryos to retinoids enhances embryonic development, but the mechanisms governing this phenomenon have not been characterised. The aim of the present study was to evaluate if the incidence of apoptosis is affected by the addition of retinyl acetate (RAc) and 9-cis-retinoic acid (RA) during in vitro maturation (IVM) of caprine oocytes. Embryonic development was recorded on days 3 and 8 post-fertilisation, and apoptosis was measured by caspase activity and DNA fragmentation (TUNEL assay). Control zygotes had lower capacity to cleave and reach the blastocyst stage (24.45 +/- 2.32 and 5.32 +/- 0.81, respectively) than those of RAc- (29.96 +/- 1.62 and 7.94 +/- 0.93, respectively) and RA-treated groups (30.12 +/- 1.51 and 7.36 +/- 1.02, respectively). Oocytes and blastocysts positive for TUNEL assay were more frequent, respectively, in the controls (8.20 +/- 0.78, 8.70 +/- 1.05) than in RAc (5.60 +/- 0.52, 4.80 +/- 0.51) and RA (6.40 +/- 0.69, 5.40 +/- 0.69). Caspase activity did not differ between control oocytes (7.20 +/- 0.91), RAc (6.60 +/- 0.68) and RA (7.30 +/- 0.67), but it was reduced in RAc- (5.05 +/- 0.62) and RA treated blastocysts (5.75 +/- 0.22) compared to controls (8.35 +/- 0.71). These results indicate that the addition of retinoids during IVM increases the developmental potential of goat embryos with a concomitant reduction in apoptosis rates. PMID- 26051263 TI - Urokinase-type plasminogen activator does not affect in vitro bovine embryo development and quality. AB - The effects of modification of the in vitro embryo culture media (IVC) with the addition of urokinase-type plasminogen activator (u-PA) on the yield and/or quality of bovine embryos were examined in two experiments. In Experiment 1, denuded embryos were cultured in semi-defined synthetic oviductal fluid (SOF) for seven days, while in Experiment 2 embryos were co-cultured with cumulus cell monolayer in a serum-containing SOF medium. Plasminogen activator activity (PAA) and plasminogen activator inhibition (PAI) were determined in all spent IVC media. At the activity used (5 IU/ml), u-PA had no effect either on in vitro embryo production rates or on embryo quality as revealed by gene expression analysis of 10 important mRNA transcripts related to apoptosis, oxidation, implantation and metabolism. PAA and PAI analysis indicated the need for wellbalanced plasminogen activators and inhibitors as a culture environment for embryo development. However, more research is needed to unveil the mechanism by which u-PA is involved in in vitro embryo production systems. PMID- 26051264 TI - Seroprevalence of bovine viral diarrhoea virus in Hungary - situation before launching an eradication campaign. AB - Bovine viral diarrhoea (BVD) is a viral disease appearing in various forms and causing high economic losses in the cattle stocks of Hungary. The aim of the present study was to determine the prevalence of bovine viral diarrhoea virus (BVDV) in Hungary through a monitoring survey carried out on samples collected in cattle-keeping units throughout the country. Since no such survey had been carried out in Hungary during the last thirty years, our study may serve as a basis for later monitoring investigations aimed at following the progress of an expected eradication campaign of BVD. The tests were carried out using an ELISA method, on a total of 1200 blood samples submitted from 54 cattle herds. The herds had not been vaccinated against BVDV before the sampling. Out of the 1200 samples, 521 proved to be positive (43.4%), 40 gave doubtful result (3.3%) and 639 were negative (53.3%). In some stocks the samples were collected from cows having completed several lactation periods, and therefore the seronegativity indicates the BVDV-free status of the given stock. Moreover, among the positive herds we found a few where the seropositivity rate was rather low (< 5%). According to the results of the survey, a rather high portion (about one third) of the cattle-keeping units of Hungary can be regarded as BVDV free, which ratio is much higher than had been expected on the basis of surveys carried out on a lower number of samples and in smaller regions of the country. Hence, the chances of an eradication campaign launched in the near future, or carried out parallel to the IBR eradication programme, are better than previously expected. PMID- 26051265 TI - Fast randomized approximate string matching with succinct hash data structures. AB - BACKGROUND: The high throughput of modern NGS sequencers coupled with the huge sizes of genomes currently analysed, poses always higher algorithmic challenges to align short reads quickly and accurately against a reference sequence. A crucial, additional, requirement is that the data structures used should be light. The available modern solutions usually are a compromise between the mentioned constraints: in particular, indexes based on the Burrows-Wheeler transform offer reduced memory requirements at the price of lower sensitivity, while hash-based text indexes guarantee high sensitivity at the price of significant memory consumption. METHODS: In this work we describe a technique that permits to attain the advantages granted by both classes of indexes. This is achieved using Hamming-aware hash functions--hash functions designed to search the entire Hamming sphere in reduced time--which are also homomorphisms on de Bruijn graphs. We show that, using this particular class of hash functions, the corresponding hash index can be represented in linear space introducing only a logarithmic slowdown (in the query length) for the lookup operation. We point out that our data structure reaches its goals without compressing its input: another positive feature, as in biological applications data is often very close to be un compressible. RESULTS: The new data structure introduced in this work is called dB-hash and we show how its implementation--BW-ERNE--maintains the high sensitivity and speed of its (hash-based) predecessor ERNE, while drastically reducing space consumption. Extensive comparison experiments conducted with several popular alignment tools on both simulated and real NGS data, show, finally, that BW-ERNE is able to attain both the positive features of succinct data structures (that is, small space) and hash indexes (that is, sensitivity). CONCLUSIONS: In applications where space and speed are both a concern, standard methods often sacrifice accuracy to obtain competitive throughputs and memory footprints. In this work we show that, combining hashing and succinct indexing techniques, we can attain good performances and accuracy with a memory footprint comparable to that of the most popular compressed indexes. PMID- 26051266 TI - Interplay of donor-acceptor interactions in stabilizing boron nitride compounds: insights from theory. AB - The stability of a variety of linear and cyclic (BN)n (n = 1-3) adducts with N heterocyclic carbene (ImMe2; ImMe2 = [(HCNMe)2C:]), N-heterocyclic olefin (ImMe2CH2) and Wittig (Me3PCH2) donors has been examined using M05-2X/cc-pVTZ computations. The strength and nature of the bonds have been investigated using natural bond orbital (NBO) and atoms-in-molecules (AIM) analyses. Complementary energy decomposition analysis (EDA-NOCV) has been carried out based on BP86/TZ2P computations. In agreement with NBO and AIM analyses, the orbital interaction energy obtained from EDA contributes at least 50% to the total attractive interactions for the carbon-boron bonds indicating their largely covalent nature. The feasibility of isolating monomeric (BN)n units using a donor/acceptor protocol was also investigated in a series of adducts of the general form: LB.(BN)n.BH3 and LB.(BN)n.W(CO)5 (n = 1-3; LB = Lewis bases). Moreover, EDA-NOCV analysis of ImMe2.BN.W(CO)5 and ImMe2.B3N3.W(CO)5 shows that the carbene-boron bonds are stronger in the presence of W(CO)5 as a Lewis acid mainly because of a dramatic decrease in the amount of Pauli repulsion rather than an increase in the electrostatic/orbital attraction terms. PMID- 26051267 TI - An in situ assembly of a DNA-streptavidin dendrimer nanostructure: a new amplified quartz crystal microbalance platform for nucleic acid sensing. AB - We developed a target-triggered in situ layer-by-layer assembled DNA-streptavidin dendrimer nanostructure as an efficient mass amplifier to create a facile quartz crystal microbalance platform for highly sensitive and selective nucleic acid sensing. PMID- 26051268 TI - Risk of Herpes Zoster and Disseminated Varicella Zoster in Patients Taking Immunosuppressant Drugs at the Time of Zoster Vaccination. AB - OBJECTIVE: To determine the risks associated with zoster vaccine when administered to patients taking immunosuppressant medications. PATIENTS AND METHODS: Patients enrolled in 1 of 7 managed care organizations affiliated with the Vaccine Safety Datalink between January 1, 2006, and December 31, 2009, were eligible. The exposure of interest was zoster vaccination in patients with current or remote immunosuppressant drug use. The primary outcomes were disseminated varicella zoster virus (VZV) and herpes zoster in the 42 days after vaccination. Automated data were collected on immunosuppressant drugs and baseline medical conditions. A logistic regression model using inverse probability treatment weights was used to estimate the odds of developing VZV or herpes zoster. RESULTS: A total of 14,554 individuals had an immunosuppressant medication dispensed around the time of vaccination, including 4826 with current use and 9728 with remote use. Most patients were taking low-dose corticosteroids. No cases of disseminated VZV were found in the current or remote users. The risk of herpes zoster was elevated in the 42 days after vaccination in current vs remote users (adjusted odds ratio, 2.99; 95% CI, 1.58-5.70). CONCLUSION: We found that patients taking immunosuppressant medications at the time of vaccination had a modest increased risk of herpes zoster in the 42 days after vaccination. The development of herpes zoster within 42 days after vaccination suggests that this is more likely due to reactivation of latent zoster virus than dissemination of the vaccine-derived varicella virus. These findings support the current zoster vaccination guidelines. PMID- 26051269 TI - Reprogenetics, Genetic Tools and Reproductive Risk: Attitudes and Understanding Among Ethnic Groups in Israel. AB - The present study investigated a possible relationship between the attitudes toward genetic technologies and the understanding of genetics, reproduction, and reproductive risk among Israeli Arabs and Israeli Jews. The study included 203 respondents, who answered a structured self-report questionnaire. They were recruited using a snowball method, which increased the participation of Israeli Arabs in the sample, although the sample was not representative of the Israeli population as a whole (there were more Arabs and fewer men). The respondents in this study expressed a positive attitude toward genetic technologies, but were less in favor of using genetic tools for non-medical purposes. Respondents of both groups were not knowledgeable of genetics; however, they scored higher on the items related to reproductive risk, which suggests that some awareness about genetic risk exists in both sectors of the Israeli population. Nevertheless, Israeli Arabs were less positive than Israeli Jews regarding the application of genetic tools. Moreover, although an understanding of genetics correlated positively with the attitude among Arabs, it did not affect the attitude of Jews, who remained very positive, regardless of their level of understanding. This result suggests that other social and cultural factors, besides understanding, might be at work among these two major ethnic sectors. Further studies that integrate educational, social, and cultural aspects among ethnic sectors of the population are required to improve health services and genetic counselling in Israel and in other countries. PMID- 26051270 TI - [Eosinophilic gastroenteritis and colitis in pediatric patients: Increasingly frequent diseases]. AB - Eosinophilic gastrointestinal disorders are a heterogeneous group of disorders characterized by no specific digestive symptoms associated with dense eosinophilic inflammation of the gastrointestinal tract in the absence of known causes for such tissue eosinophilia. Among these diseases, eosinophilic gastroenteritis (EGE) and colitis (EC) are less common than esophagitis, but their incidence and prevalence have been increasing over the past decade due in part to increased disease recognition. The exact pathophysiology is not clear: EGE and EC are immune-mediated diseases implicating adaptive T-helper cell type 2 immunity. According to the site of eosinophilic infiltration, there is a wide spectrum of digestive symptoms ranging from food refusal, nausea, vomiting, abdominal pain, weight loss, gastrointestinal bleeding (anemia), protein loosing enteropathy, ascites, bowel obstruction or perforation for EGE and diarrhea +/- bleeding for CE. Endoscopic lesions are not specific: friability, erythematous mucosa with superficial erosions, or ulceration is often observed. Histologically, markedly increased numbers of mucosal eosinophils are seen in biopsy specimens. However, no standards for the diagnosis of EGE or CE exist and few findings support the diagnosis: intraepithelial eosinophils, eosinophil crypt abscesses, and eosinophils in muscularis mucosa and/or submucosa. Other organs are not involved. The other causes of tissue eosinophilia (infections, inflammatory bowel diseases) should be excluded. Food allergy appears to play a central role in driving inflammation in EGE and CE, as evidenced by symptomatic improvement with initiation of food exclusion or elemental diets. Dietary treatment should be the first therapeutic option in children. If the elimination diet fails, corticosteroids are currently the best characterized treatment but appropriate duration is unknown and relapses are frequent. In severe forms, immunomodulators or biologic agents (anti-IL5, anti-IgE, or anti-TNFa) can potentially play a role in the treatment of EGE and CE. PMID- 26051271 TI - Respiratory Electrodialysis. A Novel, Highly Efficient Extracorporeal CO2 Removal Technique. AB - RATIONALE: We developed an innovative, minimally invasive, highly efficient extracorporeal CO2 removal (ECCO2R) technique called respiratory electrodialysis (R-ED). OBJECTIVES: To evaluate the efficacy of R-ED in controlling ventilation compared with conventional ECCO2R technology. METHODS: Five mechanically ventilated swine were connected to a custom-made circuit optimized for R-ED, consisting of a hemofilter, a membrane lung, and an electrodialysis cell. Electrodialysis regionally modulates blood electrolyte concentration to convert bicarbonate to CO2 before entering the membrane lung, enhancing membrane lung CO2 extraction. All animals underwent three repeated experimental sequences, consisting of four steps: baseline (1 h), conventional ECCO2R (2 h), R-ED (2 h), and final NO-ECCO2R (1 h). Blood and gas flow were 250 ml/min and 10 L/min, respectively. Tidal volume was set at 8 ml/kg, and respiratory rate was adjusted to maintain arterial Pco2 at 50 mm Hg. MEASUREMENTS AND MAIN RESULTS: During R ED, chloride and H(+) concentration increased in blood entering the membrane lung, almost doubling CO2 extraction compared with ECCO2R (112 +/- 6 vs. 64 +/- 5 ml/min, P < 0.001). Compared with baseline, R-ED and ECCO2R reduced minute ventilation by 50% and 27%, respectively. Systemic arterial gas analyses remained stable during the experimental phases. No major complication occurred, but there was an increase in creatinine level. CONCLUSIONS: In this first in vivo application, we proved electrodialysis feasible and effective in increasing membrane lung CO2 extraction. R-ED was more effective than conventional ECCO2R technology in controlling ventilation. Further studies are warranted to assess the safety profile of R-ED, especially regarding kidney function. PMID- 26051273 TI - Nickel inhibits mitochondrial fatty acid oxidation. AB - Nickel exposure is associated with changes in cellular energy metabolism which may contribute to its carcinogenic properties. Here, we demonstrate that nickel strongly represses mitochondrial fatty acid oxidation-the pathway by which fatty acids are catabolized for energy-in both primary human lung fibroblasts and mouse embryonic fibroblasts. At the concentrations used, nickel suppresses fatty acid oxidation without globally suppressing mitochondrial function as evidenced by increased glucose oxidation to CO2. Pre-treatment with l-carnitine, previously shown to prevent nickel-induced mitochondrial dysfunction in neuroblastoma cells, did not prevent the inhibition of fatty acid oxidation. The effect of nickel on fatty acid oxidation occurred only with prolonged exposure (>5 h), suggesting that direct inhibition of the active sites of metabolic enzymes is not the mechanism of action. Nickel is a known hypoxia-mimetic that activates hypoxia inducible factor-1alpha (HIF1alpha). Nickel-induced inhibition of fatty acid oxidation was blunted in HIF1alpha knockout fibroblasts, implicating HIF1alpha as one contributor to the mechanism. Additionally, nickel down-regulated the protein levels of the key fatty acid oxidation enzyme very long-chain acyl-CoA dehydrogenase (VLCAD) in a dose-dependent fashion. In conclusion, inhibition of fatty acid oxidation by nickel, concurrent with increased glucose metabolism, represents a form of metabolic reprogramming that may contribute to nickel induced carcinogenesis. PMID- 26051274 TI - Succinate causes alpha-SMA production through GPR91 activation in hepatic stellate cells. AB - Succinate acts as an extracellular signaling molecule as well as an intermediate in the citric acid cycle. It binds to and activates its specific G protein coupled receptor 91 (GPR91). GPR91 is present in hepatic stellate cells (HSCs), but its role in hepatic fibrogenesis remains unclear. Cultured HSCs treated with succinate showed increased protein expression of GPR91 and alpha-smooth muscle actin (alpha-SMA), markers of fibrogenic response. Succinate also increased mRNA expression of alpha-SMA, transforming growth factor beta (TGF-beta), and collagen type I. Transfection of siRNA against GPR91 abrogated succinate-induced increases in alpha-SMA expression. Malonate, an inhibitor of succinate dehydrogenase (SDH), increased succinate levels in cultured HSCs and increased GPR91 and alpha-SMA expression. Feeding mice a methionine- and choline-deficient (MCD) diet is a widely used technique to create an animal model of nonalcoholic steatohepatitis (NASH). HSCs cultured in MCD media showed significantly decreased SDH activity and increased succinate concentration and GPR91 and alpha-SMA expression. Similarly, palmitate treatment significantly decreased SDH activity and increased GPR91 and alpha-SMA expression. Finally, C57BL6/J mice fed the MCD diet had elevated succinate levels in their plasma. The MCD diet also decreased SDH activity, increased succinate concentration, and increased GPR91 and alpha-SMA expression in isolated HSCs. Collectively, our results show that succinate plays an important role in HSC activation through GPR91 induction, and suggest that succinate and GPR91 may represent new therapeutic targets for modulating hepatic fibrosis. PMID- 26051272 TI - Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk. AB - RATIONALE: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far. OBJECTIVES: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci. METHODS: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single nucleotide polymorphisms. MEASUREMENTS AND MAIN RESULTS: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3. CONCLUSIONS: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics. PMID- 26051276 TI - Bax and Bif-1 proteins interact on Bilayer Lipid Membrane and form pore. AB - Bax and Bax interacting factor-1(Bif-1) are cytosolic proteins, which translocate towards mitochondria during mitochondria-mediated apoptosis. Bif-1 has been identified to co-immunoprecipitate with Bax in apoptotic cells. We have studied the interaction of Bax and Bif-1 on Bilayer Lipid Membrane (BLM) through electrophysiological experiments. It has been observed that Bax-Bif-1 equimolar mixture can form a pore. The pore conductance is in the range of 4.96-5.41 nS. It also displays a sub-state with a conductance of 2.6 nS. No pore activity is observed on BLM when monomeric Bax and Bif-1 proteins are tested independently. The above-mentioned pore forming activity could be relevant in mitochondria mediated apoptosis. PMID- 26051275 TI - IL-1beta irreversibly inhibits tenogenic differentiation and alters metabolism in injured tendon-derived progenitor cells in vitro. AB - Tendon injuries are common, and the damaged tendon often turns into scar tissue and never completely regains the original biomechanical properties. Previous studies have reported that the mRNA levels of inflammatory cytokines such as IL 1beta are remarkably up-regulated in injured tendons. To examine how IL-1beta impacts tendon repair process, we isolated the injured tendon-derived progenitor cells (inTPCs) from mouse injured Achilles tendons and studied the effects of IL 1beta on the inTPCs in vitro. IL-1beta treatment strongly reduced expression of tendon cell markers such as scleraxis and tenomodulin, and also down-regulated gene expression of collagen 1, collagen 3, biglycan and fibromodulin in inTPCs. Interestingly, IL-1beta stimulated lactate production with increases in hexokinase II and lactate dehydrogenase expression and a decrease in pyruvate dehydrogenase. Inhibition of lactate production restored IL-1beta-induced down regulation of collagen1 and scleraxis expression. Furthermore, IL-1beta significantly inhibited adipogenic, chondrogenic and osteogenic differentiation of inTPCs. Interestingly, inhibition of tenogenic and adipogenic differentiation was not recovered after removal of IL-1beta while chondrogenic and osteogenic differentiation abilities were not affected. These findings indicate that IL 1beta strongly and irreversibly impairs tenogenic potential and alters glucose metabolism in tendon progenitors appearing in injured tendons. Inhibition of IL 1beta may be beneficial for maintaining function of tendon progenitor cells during the tendon repair process. PMID- 26051277 TI - Dietary obacunone supplementation stimulates muscle hypertrophy, and suppresses hyperglycemia and obesity through the TGR5 and PPARgamma pathway. AB - Obacunone is a limonoid that is predominantly found in Citrus. Although various biological activities of limonoids have been reported, little is known about the beneficial effects of obacunone on metabolic disorders. In the present study, we examined the effects of dietary obacunone supplementation on obese KKAy mice, to clarify the function of obacunone in metabolic regulation. Mice were pair-fed a normal diet either alone or supplemented with 0.1% w/w obacunone for 28 days. Compared with the control, obacunone-fed mice had lower glycosylated hemoglobin, blood glucose, and white adipose tissue weight, although there was no significant difference in body weight. Obacunone treatment also significantly increased the weight of the gastrocnemius and quadriceps muscles. Reporter gene assays revealed that obacunone stimulated the transcriptional activity of the bile acids-specific G protein-coupled receptor, TGR5, in a dose-dependent manner. In addition, obacunone inhibited adipocyte differentiation in 3T3-L1 cells and antagonized ligand-stimulated peroxisome proliferator-activated receptor gamma (PPARgamma) transcriptional activity. These results suggest that obacunone stimulates muscle hypertrophy and prevents obesity and hyperglycemia, and that these beneficial effects are likely to be mediated through the activation of TGR5 and inhibition of PPARgamma transcriptional activity. PMID- 26051279 TI - WITHDRAWN: Lentiviral Mediated Overexpression of Sema3A in Oral Cancer Cells Decreases Tumor Growth by Inhibiting Angiogenesis. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 26051278 TI - The novel mitochondrial iron chelator 5-((methylamino)methyl)-8-hydroxyquinoline protects against mitochondrial-induced oxidative damage and neuronal death. AB - Abundant evidence indicates that iron accumulation, oxidative damage and mitochondrial dysfunction are common features of Huntington's disease, Parkinson's disease, Friedreich's ataxia and a group of disorders known as Neurodegeneration with Brain Iron Accumulation. In this study, we evaluated the effectiveness of two novel 8-OH-quinoline-based iron chelators, Q1 and Q4, to decrease mitochondrial iron accumulation and oxidative damage in cellular and animal models of PD. We found that at sub-micromolar concentrations, Q1 selectively decreased the mitochondrial iron pool and was extremely effective in protecting against rotenone-induced oxidative damage and death. Q4, in turn, preferentially chelated the cytoplasmic iron pool and presented a decreased capacity to protect against rotenone-induced oxidative damage and death. Oral administration of Q1 to mice protected substantia nigra pars compacta neurons against oxidative damage and MPTP-induced death. Taken together, our results support the concept that oral administration of Q1 is a promising therapeutic strategy for the treatment of NBIA. PMID- 26051280 TI - The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis. AB - Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC50 of 0.06-0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway. PMID- 26051281 TI - The crux and crust of ebolavirus: Analysis of genome sequences and glycoprotein gene. AB - The recent 2013-15 epidemic of Ebola virus disease (EVD) has initiated extensive sequencing and analysis of ebolavirus genomes. All ebolavirus genomes available until December 2014 have been collated and analyzed in this study to obtain phylogenetic relationship and uncover the variations amongst them. The terminal 'leader' and 'trailer' nucleotide sequences of the genomes were omitted and analysis of the intermediate region accommodating the sole seven genes (hepta-CDS region) of the virus showed relative stability of the genome, including the ones isolated from the current epidemic. The genome information was scrutinized to detect the variation in the surface glycoprotein gene and annotate its three protein products, resulting from its atypical transcription. This study will make an easy understanding of the genomes for those who desire to exploit the genome sequences for different investigations in EVD. PMID- 26051283 TI - Correction: Introduction of a mediator for enhancing photocatalytic performance via post-synthetic metal exchange in metal-organic frameworks (MOFs). AB - Correction for 'Introduction of a mediator for enhancing photocatalytic performance via post-synthetic metal exchange in metal-organic frameworks (MOFs)' by Dengrong Sun et al., Chem. Commun., 2015, 51, 2056-2059. PMID- 26051282 TI - Study of the anti-inflammatory effects of low-dose radiation: The contribution of biphasic regulation of the antioxidative system in endothelial cells. AB - BACKGROUND: We examined (a) the expression of the antioxidative factor glutathione peroxidase (GPx) and the transcription factor nuclear factor E2 related factor 2 (Nrf2) following low-dose X-irradiation in endothelial cells (ECs) and (b) the impact of reactive oxygen species (ROS) and Nrf2 on functional properties of ECs to gain further knowledge about the anti-inflammatory mode of action of low doses of ionizing radiation. MATERIAL AND METHODS: EA.hy926 ECs and primary human dermal microvascular ECs (HMVEC) were stimulated by tumor necrosis factor-alpha (TNF-alpha, 20 ng/ml) 4 h before irradiation with single doses ranging from 0.3 to 3 Gy. The expression and activity of GPx and Nrf2 were analyzed by flow cytometry, colorimetric assays, and real-time PCR. The impact of ROS and Nrf2 on peripheral blood mononuclear cell (PBMC) adhesion was assayed in the presence of the ROS scavenger N-acetyl-L-cysteine (NAC) and Nrf2 activator AI 1. RESULTS: Following a low-dose exposure, we observed in EA.hy926 EC and HMVECs a discontinuous expression and enzymatic activity of GPx concomitant with a lowered expression and DNA binding activity of Nrf2 that was most pronounced at a dose of 0.5 Gy. Scavenging of ROS by NAC and activation of Nrf2 by AI-1 significantly diminished a lowered adhesion of PBMC to EC at a dose of 0.5 Gy. CONCLUSION: Low-dose irradiation resulted in a nonlinear expression and activity of major compounds of the antioxidative system that might contribute to anti inflammatory effects in stimulated ECs. PMID- 26051284 TI - Gynecomastia: A systematic review. AB - BACKGROUND: Gynecomastia is a common medical problem presenting in nearly a third of the male population. Treatment for gynecomastia can be either pharmacological or surgical. Patients with gynecomastia often experience affected quality-of life. The aim of this systematic review was to analyze the quality of evidence of the current literature in relation to different treatment modalities and Quality of-Life in patients with gynecomastia. METHODS: A systematic search of the literature was performed in PubMed, Medline, Scopus, The Cochrane Library, and SveMed+ in accordance with the PRISMA statement. All searches were undertaken between September-November 2014. The PICOS (patients, intervention, comparator, outcomes, and study design) approach was used to specify inclusion criteria. Methodological quality was graded according to MINORS. Quality of evidence was rated according to GRADE. Data from the included studies were extracted based on study characteristics, participants specifics, type of intervention/treatment, and type of outcome measures into data extraction forms. RESULTS: A total of 134 abstracts were identified in the literature search. Seventeen studies met inclusion criteria, 14 concerning treatment and three concerning Quality-of-Life. All studies were non-randomised with a high risk of bias and very low quality of evidence according to GRADE. CONCLUSIONS: Several different surgical methods have been described with good results, minimal scars, and various levels of complications. Traditional surgical excision of glandular tissue combined with liposuction provides most consistent results and a low rate of complications. Pubertal gynecomastia may safely be managed by pharmacological anti-oestrogen treatment. PMID- 26051285 TI - Metabolic fingerprints in testicular biopsies from type 1 diabetic patients. AB - Diabetes mellitus (DM) is a metabolic disease that has grown to pandemic proportions. Recent reports have highlighted the effect of DM on male reproductive function. Here, we hypothesize that testicular metabolism is altered in type 1 diabetic (T1D) men seeking fertility treatment. We propose to determine some metabolic fingerprints in testicular biopsies of diabetic patients. For that, testicular tissue from five normal and five type 1 diabetic men was analyzed by high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy. mRNA and protein expression of glucose transporters and glycolysis-related enzymes were also evaluated. Our results show that testes from diabetic men presented decreased levels of lactate, alanine, citrate and creatine. The mRNA levels of glucose transporter 1 (GLUT1) and phosphofructokinase 1 (PFK1) were decreased in testes from diabetic men but only GLUT3 presented decreased mRNA and protein levels. Lactate dehydrogenase (LDH) and glutamate pyruvate transaminase (GPT) protein levels were also found to be decreased in testes from diabetic men. Overall, our results show that T1D alters glycolysis-related transporters and enzymes, compromising lactate content in the testes. Moreover, testicular creatine content was severely depressed in T1D men. Since lactate and creatine are essential for germ cells development and support, the data discussed here open new insights into the molecular mechanism by which DM promotes subfertility/infertility in human males. PMID- 26051286 TI - Auditory system: development, genetics, function, aging, and diseases. PMID- 26051287 TI - Relationship between morningness-eveningness typology and cumulative fatigue or depression among Japanese male workers. AB - This study clarified relationships between morningness-eveningness typology and cumulative fatigue or depressive state in Japanese male workers. 959 male chemical factory workers answered a questionnaire that included the MEQ, SDS, CFSI, age, marital status, sleep indexes, life habits, and labor load. Logistic regression analysis was performed with SDS and CFSI as objective variables. We obtained valid responses from 884 subjects, who were classified according to MEQ into definitely morning type (4.1%), moderately morning type (38.6%), intermediate type (55.1%), moderately evening type (2.3%), and definitely evening type (0%). The results of logistic regression analysis show that the odds ratio of a subscale among CFSI, chronic fatigue in the moderately evening type (3.33, p=0.046) was elevated compared with that in the intermediate type (2.07, p=0.004). However, the odds ratio of SDS (1.67, p=0.028) and two subscales among CFSI, decreased vitality (1.67, p=0.021), and depressive feelings (2.02, p=0.001), for which significant relationships were found only in the intermediate type, were higher in the moderately evening type than in the intermediate type. These results suggest that relationships between cumulative fatigue or depressive state and circadian typology exist among workers independent of working hours, sleep indexes, or life habits. PMID- 26051288 TI - A systematic review of diagnostic performance of quantitative tests to assess musculoskeletal disorders in hand-arm vibration syndrome. AB - The purpose was to systematically review the published reports for the clinical utility of quantitative objective tests commonly used for diagnosing musculoskeletal disorders in hand-arm vibration syndrome (HAVS). Two reviewers independently conducted a computerized literature search in PubMed and Scopus using predefined criteria, and relevant papers were identified. The articles were screened in several stages and considered for final inclusion. Quality of the selected papers was evaluated by a modified QUADAS tool. Relevant data were extracted as necessary. For this review, only 4 relevant studies could be identified for detailed examination. Grip strength, pinch strength, and Purdue pegboard tests were commonly used with their reported sensitivity and specificity ranging between 1.7 to 65.7% and 65.2 to 100%, 1.7 to 40% and 94 to 100%, and 44.8 to 85% and 78 to 95%, respectively. A considerable difference across the studies was observed with respect to patient and control populations, diagnostic performance and cut-off values of different tests. Overall, currently available English-language limited literature do not provide enough evidence in favour of the application of grip strength and pinch strength tests for diagnosing musculoskeletal injuries in HAVS; Purdue pegboard test seems to have some diagnostic value in evaluating impaired dexterity in HAVS. PMID- 26051289 TI - Assessment of psychosocial risk factors for the development of non-specific chronic disabling low back pain in Japanese workers-findings from the Japan Epidemiological Research of Occupation-related Back Pain (JOB) study. AB - To investigate the associations between psychosocial factors and the development of chronic disabling low back pain (LBP) in Japanese workers. A 1 yr prospective cohort of the Japan Epidemiological Research of Occupation-related Back Pain (JOB) study was used. The participants were office workers, nurses, sales/marketing personnel, and manufacturing engineers. Self-administered questionnaires were distributed twice: at baseline and 1 yr after baseline. The outcome of interest was the development of chronic disabling LBP during the 1 yr follow-up period. Incidence was calculated for the participants who experienced disabling LBP during the month prior to baseline. Logistic regression was used to assess risk factors for chronic disabling LBP. Of 5,310 participants responding at baseline (response rate: 86.5%), 3,811 completed the questionnaire at follow up. Among 171 eligible participants who experienced disabling back pain during the month prior to baseline, 29 (17.0%) developed chronic disabling LBP during the follow-up period. Multivariate logistic regression analysis implied reward to work (not feeling rewarded, OR: 3.62, 95%CI: 1.17-11.19), anxiety (anxious, OR: 2.89, 95%CI: 0.97-8.57), and daily-life satisfaction (not satisfied, ORs: 4.14, 95%CI: 1.18-14.58) were significant. Psychosocial factors are key to the development of chronic disabling LBP in Japanese workers. Psychosocial interventions may reduce the impact of LBP in the workplace. PMID- 26051290 TI - Association of active and passive smoking with occupational injury in manual workers: a cross-sectional study of the 2011 Korean working conditions survey. AB - This study was conducted to investigate the relationship of active and passive smoking with occupational injury among manual workers. Data from the 2011 Korean Working Conditions Survey were analyzed for 12,507 manual workers aged >=15 yr. Overall, 60.4% of men and 5.8% of women were current smokers. The prevalence of injury was higher among never smokers who were exposed to secondhand smoke (SHS) (7.7% in men and 8.1% in women) than current smokers (4.2% in men and 4.1% in women). After controlling for potential confounders, in men, compared to those who never smoked and were not exposed to SHS, people who never smoked and were exposed to SHS (adjusted odds ratio (aOR)=3.7, 2.2-6.4) and current smokers (aOR=2.5, 1.6-3.8) were more likely to experience injury. Among women, the aORs of occupational injury were 8.4 (4.2-16.7) for never smoking women with occasional exposure to SHS and 3.5 (95% CI: 1.4-8.7) for current smokers, in comparison to never smoking women who were never exposed to SHS at work (reference group). The present study suggests that exposure to SHS is a possible risk factor of occupational injury for never smoking men and women. PMID- 26051291 TI - Chirality- and sequence-selective successive self-sorting via specific homo- and complementary-duplex formations. AB - Self-recognition and self-discrimination within complex mixtures are of fundamental importance in biological systems, which entirely rely on the preprogrammed monomer sequences and homochirality of biological macromolecules. Here we report artificial chirality- and sequence-selective successive self sorting of chiral dimeric strands bearing carboxylic acid or amidine groups joined by chiral amide linkers with different sequences through homo- and complementary-duplex formations. A mixture of carboxylic acid dimers linked by racemic-1,2-cyclohexane bis-amides with different amide sequences (NHCO or CONH) self-associate to form homoduplexes in a completely sequence-selective way, the structures of which are different from each other depending on the linker amide sequences. The further addition of an enantiopure amide-linked amidine dimer to a mixture of the racemic carboxylic acid dimers resulted in the formation of a single optically pure complementary duplex with a 100% diastereoselectivity and complete sequence specificity stabilized by the amidinium-carboxylate salt bridges, leading to the perfect chirality- and sequence-selective duplex formation. PMID- 26051292 TI - Best Practice & Research Clinical Endocrinology & Metabolism. Hormone replacement strategies in paediatric and adolescent endocrine disorders. Preface. PMID- 26051293 TI - Closed loop insulin delivery in diabetes. AB - The primary goal of type 1 diabetes treatment is attaining near-normal glucose values. This currently remains out of reach for most people with type 1 diabetes despite intensified insulin treatment in the form of insulin analogues, educational interventions, continuous glucose monitoring, and sensor augmented insulin pump. The main remaining problem is risk of hypoglycaemia, which cannot be sufficiently reduced in all patient groups. Additionally, patients' burn-out often develops with years of tedious day-to-day diabetes management, rendering available diabetes-related technology less efficient. Over the past 40 years, several attempts have been made towards computer-programmed insulin delivery in the form of closed loop, with faster developments especially in the past decade. Automated insulin delivery has reduced human error in glycaemic control and considerably lessened the burden of routine self-management. In this chapter, data from randomized controlled trials with closed-loop insulin delivery that included type 1 diabetes population are summarized, and an evidence-based vision for possible routine utilization of closed loop is provided. PMID- 26051294 TI - Childhood obesity: Current and novel approaches. AB - The prevalence of childhood obesity has increased over the last fifty years by approximately 5% per decade, and approximately a quarter of all children are now either overweight or obese. These children have a significantly increased risk of many future health problems including adult obesity, type 2 diabetes and heart disease. Despite this relentless increase, common-sense approaches aimed at prevention and treatment have failed to solve the problem. Current approaches at prevention have faced major challenges with some progress in implementing smaller scale programs and social marketing, but little action on broad public policy approaches which often appears unpalatable to society or individual governments. Meanwhile, treatment approaches have mainly focused on lifestyle change, and novel approaches are urgently needed. Prevention needs to shift to improving maternal health prior to conception, with more research focussed on the impact of early years in programming offspring to future overweight/obesity. Likewise, treatment paradigms need to move from simply thinking that obesity can be solved by readdressing diet and activity levels. Novel approaches are needed which take into consideration the complex physiology which regulates early childhood growth and the development of obesity in susceptible individuals. PMID- 26051295 TI - Hormone replacement therapy in children: The use of growth hormone and IGF-I. AB - Recombinant human GH (rhGH) has been available since 1985. This article gives an overview, what has been achieved over the past 30 years in respect to optimization of rhGH treatment for the individual child with GH deficiency and what are the safety issues concerned with this treatment. In the last twenty years significant scientific progress has been made in the diagnosis of GH deficiency, the genetic disorders that are associated with pituitary GH deficiency and the genetics that influence growth in general. On the other hand rhGH is not only used in states of GH deficiency but also various conditions without a proven GH deficiency by classical standards. Clinical studies that investigated both the genetics of growth and the individual responses to rhGH therapy in these patient populations were able to refine our concept about the physiology of normal growth. In most patients under rhGH treatment there is a considerable short-term effect, however the overall gain in growth obtained by a long-term treatment until final height still remains a matter of debate in some of the conditions treated. Also first studies on the long-term safety risks of rhGH treatment have raised the question whether this treatment is similarly safe for all the patient groups eligible for such a treatment. Therefore even in the face of a longstanding safety record of this drug replacement therapy the discussion about the right cost and risk to benefit ratio is continuing. Consequently there is still a need for carefully conducted long-term studies that use modern anthropometric, genetic, and laboratory techniques in order to provide the necessary information for clinicians to select the patients that will benefit best from this valuable treatment without any long term risk. PMID- 26051296 TI - Novel approaches to short stature therapy. AB - Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C natriuretic peptide analog offers hope for children with achondroplasia. PMID- 26051297 TI - Pubertal induction in hypogonadism: Current approaches including use of gonadotrophins. AB - Primary disorders of the gonad or those secondary to abnormalities of the hypothalamic pituitary axis result in hypogonadism. The range of health problems of childhood and adolescence that affect this axis has increased, as most children now survive chronic illness, but many have persisting deficits in gonadal function as a result of their underlying condition or its treatment. An integrated approach to hormone replacement is needed to optimize adult hormonal and bone health, and to offer opportunities for fertility induction and preservation that were not considered possible in the past. Timing of presentation ranges from birth, with disorders of sexual development, through adolescent pubertal failure, to adult fertility problems. This review addresses diagnosis and management of hypogonadism and focuses on new management strategies to address current concerns with fertility preservation. These include Turner syndrome, and fertility presevation prior to childhood cancer treatment. New strategies for male hormone replacement therapy that may impinge upon future fertility are emphasized. PMID- 26051298 TI - Complications of vitamin D deficiency from the foetus to the infant: One cause, one prevention, but who's responsibility? AB - Calcium and phosphorus represent building material for bones. The supplier of these bone minerals is the hormone calcitriol, which originates from vitamin D, itself made by sunshine in human skin. Requirement for bone minerals is highest during phases of rapid growth, and no one grows faster than the foetus and the infant, making them particularly vulnerable. Deprivation of calcium, whether through low calcium intake or low vitamin D, leads to serious health consequences throughout life, such as hypocalcaemic seizures, dilated cardiomyopathy, skeletal myopathy, congenital and infantile rickets, and osteomalacia. These 5 conditions are often summarised as 'symptomatic vitamin D deficiency', are fully reversible but also fully preventable. However, the increasing prevalence of rickets and osteomalacia, and the deaths from hypocalcaemic cardiomyopathy, demand action from global health care providers. Clarification of medical and parental responsibilities is a prerequisite to deliver successful prevention programmes. The foetus and infant have the human right to be protected against harm, and vitamin D supplementation has the same public health priority as vaccinations. PMID- 26051299 TI - Treatment of congenital thyroid dysfunction: Achievements and challenges. AB - The active thyroid hormone tri-iodothyronine (T3) is essential for a normal development of children. Especially within the first years of life, thyroid hormone is pivotal in enabling maturation of complex brain function and somatic growth. The most compelling example for a life without thyroid hormone are those historical cases of children who came to birth without a thyroid gland - as shown in autopsy-studies- and who suffered from untreated hypothyroidism, at that time initially called "sporadic congenital hypothyroidism" (CH). In the last decades huge achievements resulted in a normal development of these children based on newborn screening programs that enable an early onset of a high dose LT4 treatment. Further progress will be necessary to further tailor an individualized thyroid hormone substitution approach and to identify those more complex patients with congenital hypothyroidism and associated defects, who will not benefit from an even optimized LT4 therapy. Besides the primary production of thyroid hormone a variety of further mechanisms are necessary to mediate the function of T3 on normal development that are located downstream of thyroid hormone production. Abnormalities of these mechanisms include the MCT8-transport defect, deiodinase insufficiency and thyroid hormone receptor alpha-and beta defects. These thyroid hormone resistant diseases can not be treated with classical LT4 substitution alone. The development of new treatment options for those rare cases of thyroid hormone resistance is one of the most challenging tasks in the field of congenital thyroid diseases today. PMID- 26051300 TI - Management of diabetes insipidus and adipsia in the child. AB - Central diabetes insipidus (CDI) is a complex and heterogeneous clinical syndrome affecting the hypothalamic-neurohypophyseal network and water balance. A recent national surveillance in Denmark showed a prevalence rate of twenty-three CDI patients per 100,000 inhabitants in five years. The differential diagnosis between several presenting conditions with polyuria and polydipsia is puzzling, and the etiological diagnosis of CDI remains a challenge before the identification of an underlying cause. For clinical practice, a timely diagnosis for initiating specific treatment in order to avoid central nervous system damage, additional pituitary defects and the risk of dissemination of germ cell tumor is advisable. Proper etiological diagnosis can be achieved via a series of steps that start with careful clinical observation of several signs and endocrine symptoms and then progress to more sophisticated imaging tools. This review summarizes the best practice and approach for the diagnosis and treatment of patients with CDI. PMID- 26051301 TI - Hormone replacement in disorders of sex development: Current thinking. AB - Congenital disruptions of sex hormone production lead to wide-ranging developmental and physiological effects in individuals who have atypical chromosomal, gonadal or anatomic sex. Aberrant developmental sex hormone exposure causes disorders of genital anatomy, attainment of secondary sexual characteristics and has long-term effects on metabolism, fertility and psychological functioning. Principles in the management of disorders of sex development (DSD) aim to improve physiological health and long-term outcome, as well as development of male or female sexual anatomy. Concerns raised by DSD patient advocacy groups about beneficence and autonomy with respect to prescribed hormone treatments and avoidance of unnecessary genital and gonadal surgery have demanded greater informed consent and attention to long-term outcome. Hormone treatment is influenced by underlying clinical diagnosis and by factors such as sex of rearing and gender identity of the affected individual. We describe diagnostic criteria for different DSDs, clinical considerations in management protocols, together with current concepts and detailed practical hormone treatments for male and female individuals with DSD. Gender identity issues requiring multidisciplinary consensus, ethical consideration and informed consent or assent from the young person are also addressed. PMID- 26051302 TI - Current and novel approaches to children and young people with congenital adrenal hyperplasia and adrenal insufficiency. AB - Congenital adrenal hyperplasia (CAH) represents a group of autosomal recessive conditions leading to glucocorticoid deficiency. CAH is the most common cause of adrenal insufficiency (AI) in the paediatric population. The majority of the other forms of primary and secondary adrenal insufficiency are rare conditions. It is critical to establish the underlying aetiology of each specific condition as a wide range of additional health problems specific to the underlying disorder can be found. Following the introduction of life-saving glucocorticoid replacement sixty years ago, steroid hormone replacement regimes have been refined leading to significant reductions in glucocorticoid doses over the last two decades. These adjustments are made with the aim both of improving the current management of children and young persons and of reducing future health problems in adult life. However despite optimisation of existing glucocorticoid replacement regimens fail to mimic the physiologic circadian rhythm of glucocorticoid secretion, current efforts therefore focus on optimising replacement strategies. In addition, in recent years novel experimental therapies have been developed which target adrenal sex steroid synthesis in patients with CAH aiming to reduce co-morbidities associated with sex steroid excess. These developments will hopefully improve the health status and long-term outcomes in patients with congenital adrenal hyperplasia and adrenal insufficiency. PMID- 26051303 TI - Fetal endocrine therapy for congenital adrenal hyperplasia should not be done. AB - Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus remains a controversial experimental treatment. Review of data from animal experimentation and human trials indicates that dexamethasone cannot be considered safe for the fetus. In animals, prenatal dexamethasone decreases birth weight, affects renal, pancreatic beta cell and brain development, increases anxiety and predisposes to adult hypertension and hyperglycemia. In human studies, prenatal dexamethasone is associated with orofacial clefts, decreased birth weight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of adrenal hyperplasia with dexamethasone is not appropriate for routine clinical practice and should only be done in Institutional Review Board approved, prospective clinical research settings with written informed consent. The data indicate that this treatment is inconsistent with the classic medical ethical maxim to 'first do no harm'. PMID- 26051304 TI - Adolescents with gender dysphoria. AB - Young people with gender dysphoria are increasingly seen by pediatric endocrinologists. Mental health child specialists assess the adolescent and give advice about psychological or medical treatment. Provided they fulfill eligibility and readiness criteria, adolescents may receive pubertal suspension, consisting of using gonadotrophin-releasing hormone analogs, later followed by cross-sex hormones (sex steroids of the experienced gender). If they fulfill additional criteria, they may have various types of gender affirming surgery. Current issues involve safety aspects. Although generally considered safe in the short-term, the long-term effects regarding bone health and cardiovascular risks are still unknown. Therefore, vigilance is warranted during and long after completion of the last gender affirming surgeries. The timing of the various treatment steps is also under debate: instead of fixed age limits, the cognitive and emotional maturation, along with the physical development, are now often considered as more relevant. PMID- 26051305 TI - Transition to adult endocrine services: What is achievable? The diabetes perspective. AB - Transition is defined as the 'purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centred to adult-oriented health care systems' by Blum RW, (2002). The primary goal of transition is to ensure an uninterrupted process in healthcare delivery between the paediatric and adult settings; however, losses to follow up and decreased engagement with specialist services are common during this time. The current transition literature specifically pertaining to type 1 diabetes mellitus (T1DM) is often limited by incomplete data, the absence of control data and lack of follow up data spanning both the paediatric and adult years. This paper serves to review the current transition literature base, highlighting areas which warrant further study. PMID- 26051306 TI - Transition of adolescents and young adults with endocrine diseases to adult health care. AB - The transition of adolescents with chronic endocrine diseases to adult care remains a major challenge for all those participating in the process. In paediatric endocrinology, a variety of diseases pose different challenges in the transitional process. The outcome of this transitional process is often judged by what happens after transfer. The young patient needs to be educated early on about continuing treatment into adulthood, resulting in full autonomy over their health care in early adulthood. Therefore, to optimize transition, paediatric and adult endocrinologists must work together to achieve continuity and to meet the needs of young patients. PMID- 26051307 TI - miRNAs in pregnancy-related complications. AB - MicroRNAs (miRNAs) constitute a highly conserved class of small non-coding RNAs, involved in post-transcriptional regulation processes by modifying the expression of specific mRNAs. During placental development, cell differentiation, adhesion, migration, apoptosis and angiogenesis are regulated by specific miRNAs and aberrant expression has been associated with the pathogenesis of pregnancy related complications. Recent studies focusing on placental and maternal peripheral blood miRNA profiling showed different expression between normal and complicated pregnancies, providing valuable information about the pathophysiological role of miRNAs and identifying potential biomarkers for monitoring pregnancy complications. This review summarizes the current knowledge in the field and presents the possible use of miRNAs as biomarkers for early detection and monitoring of these complications. PMID- 26051308 TI - Does it hurt to ask? A meta-analysis of participant reactions to trauma research. AB - Institutional Review Boards (IRBs) are sometimes hesitant to approve trauma related research due to concerns that asking participants about traumatic experiences will induce extreme distress. Despite the growing empirical literature examining participants' reactions to trauma-related research, no quantitative reviews have been conducted. The present multilevel meta-analysis was undertaken to quantify: (1) how participants react to trauma-related research overall; (2) to what extent reactions to trauma-related research differ by participant characteristics, including personal history of trauma, PTSD symptoms, and gender; and (3) to what extent (a) type of traumatic experience and (b) mode of administration moderate these effects. Studies examining adult participants' reactions to trauma assessments in the context of research were included. Results from 73,959 participants across 70 samples suggest that although trauma-related research can lead to some immediate psychological distress, this distress is not extreme. This distress is greater for individuals with a trauma history or PTSD, particularly in studies involving interviews. However, individuals generally find research participation to be a positive experience and do not regret participation, regardless of trauma history or PTSD. There were no gender differences in reactions. Present findings, which suggest that trauma-related research can continue without harming participants, may help inform IRB decisions on trauma research. PMID- 26051311 TI - Effect of feeding 25-hydroxyvitamin D3 with a negative cation-anion difference diet on calcium and vitamin D status of periparturient cows and their calves. AB - Holstein cows (>1 gestation) were fed 1 of 3 diets during the last 13 d of gestation (ranged from 22 to 7 d). The control diet (16 cows) was formulated to provide 18,000 IU/d of vitamin D3 and had a dietary cation-anion difference (DCAD) of 165mEq/kg (DCAD=Na + K - Cl - S). The second diet (DCAD + D) provided the same amount of vitamin D3 but had a DCAD of -139mEq/kg (17 cows). The third diet (DCAD + 25D) had no supplemental vitamin D3 but provided 6mg/d of 25-(OH) vitamin D3 [25-(OH)D3] with a DCAD of -138mEq/kg (20 cows). Diets were fed until parturition and then all cows were fed a common lactation diet that contained vitamin D3. Negative DCAD diets reduced urine pH, with the greatest decrease occurring with the DCAD + D treatment. Urinary Ca excretion was greatest for cows fed DCAD + 25D followed by cows fed DCAD + D. Urinary pH was negatively correlated with urinary excretion of Ca for cows fed DCAD + D. No such correlation was observed with the DCAD + 25D treatment because substantial excretion of urinary Ca occurred at moderate urinary pH values for that treatment. Cows fed DCAD + 25D had greater serum concentrations of 25-(OH)D3 than other treatments from 5 d after supplementation started through 7 d in milk. Concentrations of 1,25-(OH)2D3 in serum were greatest in DCAD + 25D cows starting at 2 d before calving and continued through 7 d in milk. Serum Ca concentrations 5 d before calving were greatest for cows fed DCAD + 25D, but at other time points before and after parturition treatment did not affect serum Ca. Incidence of clinical hypocalcemia was not statistically different between treatments, but cows fed DCAD + 25 had the highest incidence rate (12.5, 0, and 20% for control, DCAD + D, and DCAD + 25D). Calves born from cows fed DCAD + 25D had greater concentrations of 25-(OH)D3 in serum at birth than calves from other treatments (before colostrum consumption), but concentrations were similar by 3 d of age. Concentrations of 25-(OH)D3 in colostrum and transition milk were increased by feeding DCAD + 25D, but by 28 d in milk treatment effects no longer existed. Overall, feeding 25-OH vitamin D with a negative DCAD diet increased vitamin D status of the cow and her newborn calf but had minimal effects on calcium status and did not have positive effects on the incidence of hypocalcemia. PMID- 26051309 TI - Using passive cavitation images to classify high-intensity focused ultrasound lesions. AB - Passive cavitation imaging provides spatially resolved monitoring of cavitation emissions. However, the diffraction limit of a linear imaging array results in relatively poor range resolution. Poor range resolution has limited prior analyses of the spatial specificity and sensitivity of passive cavitation imaging in predicting thermal lesion formation. In this study, this limitation is overcome by orienting a linear array orthogonal to the high-intensity focused ultrasound propagation direction and performing passive imaging. Fourteen lesions were formed in ex vivo bovine liver samples as a result of 1.1-MHz continuous wave ultrasound exposure. The lesions were classified as focal, "tadpole" or pre focal based on their shape and location. Passive cavitation images were beamformed from emissions at the fundamental, harmonic, ultraharmonic and inharmonic frequencies with an established algorithm. Using the area under a receiver operating characteristic curve (AUROC), fundamental, harmonic and ultraharmonic emissions were found to be significant predictors of lesion formation for all lesion types. For both harmonic and ultraharmonic emissions, pre-focal lesions were classified most successfully (AUROC values of 0.87 and 0.88, respectively), followed by tadpole lesions (AUROC values of 0.77 and 0.64, respectively) and focal lesions (AUROC values of 0.65 and 0.60, respectively). PMID- 26051312 TI - Mechanisms of Clostridium tyrobutyricum removal through natural creaming of milk: A microscopy study. AB - Clostridium tyrobutyricum is the main spoilage agent of late blowing defect (LBD) in Grana Padano and Parmigiano-Reggiano cheeses; LBD is characterized by openings and holes and is sometimes accompanied by cracks and an undesirable flavor. Even a very few spores remaining in the cheese curd may cause LBD; thus, it is essential to eradicate them during milk natural creaming. By this process, most of the bacteria, somatic cells, and spores rise to the top of the milk, together with the fat globules, and are removed with the cream. Previous studies suggested that milk immunoglobulins mediate the interactions between fat globules and bacteria that occur upon creaming but no direct evidence for this has been found. Moreover, other physical chemical interactions could be involved; for example, physical entrapment of spores among globule clusters. To maximize the efficiency of the natural creaming step in removing Cl. tyrobutyricum, it is essential to understand the nature of spore-globule interactions. With this aim, raw milk was contaminated with spores of Cl. tyrobutyricum before going to creaming overnight at 8 degrees C, after which spore and bacteria removal was >90%. The obtained cream was analyzed by light interference contrast and fluorescence microscopy and by transmission electron microscopy (TEM). Results showed that most of the vegetative cells and spores, which were stained with malachite green before addition to milk, adhered tightly to the surface of single fat globules, the membranes of which appeared heterogeneous when stained with the fluorescent dye DilC18(3)-DS. Using the same dye, we observed transient and persistent interactions among globules, with formation of clusters of different sizes and partial coalescence of adhering membranes. Transmission electron microscopy examination of replicates of freeze-fractured cream allowed us to observe tight adhesion of spores to fat globules. Ultrathin sections revealed that this adhesion is mediated by an amorphous, slightly electron-opaque material, sometimes granular in appearance. Bacteria also adhered to different fat globules, linking them together, which suggests that adhesion was strong enough to maintain a stable contact. Although we cannot exclude physical entrapment of bacteria among fat globule clusters, we show for the first time that most of the bacteria are adhered to fat globules by an electron-opaque material whose nature has yet to be determined. Immunoglobulins are certainly the best candidates for adhesion but other compounds may be involved. PMID- 26051313 TI - The effect of age at separation from the dam and presence of social companions on play behavior and weight gain in dairy calves. AB - Play behavior positively affects welfare of farm animals, yet impoverished social environment during early ontogeny may limit the opportunity or motivation to play. This study investigated the independent and the combined effects of the presence of the dam during the colostrum feeding period and subsequent group housing on play behavior and growth in dairy calves. Forty female calves were allocated to 1 of 4 treatments according to a 2*2 factorial design. The treatments were with or without mother during the 4d after birth and companion housing (single pens or grouped housing in pens of 4 calves between 1 and 8wk of age). After 8wk of age all calves were housed in groups of 4 calves. Play behavior of the calves was observed at 2, 5, and 12wk of age in the following situations: 6 h of spontaneous behavior in the home pen, a 15-min open-field test, and a 15-min social test with an unfamiliar calf. Additionally, play behavior after grouping or relocation at 8wk of age was recorded during two 2-h sessions. There were no significant effects of the mother by companion interaction either on the amount of play behavior in any of the tests or on the body weights of the calves. Presence of the mother after birth did not increase later playfulness, with the exception of higher spontaneous play at 12wk of age. When calves were housed in groups of 4, they played more in the home pen on wk 2 and 5 than individually housed calves of the same age. In contrast, individually housed calves were more playful during open-field tests and social tests on wk 2 and 5. At 8wk, single calves that were placed in a new pen with 3 unfamiliar calves played more than twice as much as grouped calves that were just moved to a new pen with familiar companions. These results show that single-housed calves are deprived of natural levels of play, as demonstrated by both their lower spontaneous play behavior and the higher rebound effect when they are exposed to larger spaces or larger spaces plus companions. Calves that stayed with their mothers for 4d postpartum grew much better until the end of the second week. After that, grouped calves grew better until wk 10 and they tended to be heavier for at least 2wk after relocation or mixing at wk 8. The study shows that brief maternal rearing and group housing independently improve different aspects of performance and welfare of dairy calves. PMID- 26051314 TI - The effect of high and low levels of supplementation on milk production, nitrogen utilization efficiency, and milk protein fractions in late-lactation dairy cows. AB - To fill the feed deficit in the autumn/late lactation period in a seasonal grazing system, supplementation is required. This study aimed to investigate the use of baled grass silage or concentrate as supplementation to grazing dairy cows in late lactation. Eighty-four grass-based spring-calving dairy cows, averaging 212d in milk, were allocated to 1 of 6 treatments [high grass allowance (HG), low grass allowance (LG), grass with a low concentrate allocation (GCL), grass with a low grass silage allocation (GSL), grass with a high concentrate allocation (GCH), and grass with a high grass silage allocation (GSH)] to measure the effects of using baled grass silage or concentrate as supplements to grazed grass. Effects on intake, milk yield, milk composition and N fractions, and N utilization efficiency were measured. Treatments HG and LG received 17 and 14kg of dry matter (DM) grass/cow per d, respectively. Treatments GCL and GSL were offered 14kg of DM grass/cow per d and 3kg of DM of supplementation/cow per d. Treatments GCH and GSH were offered 11kg of DM grass/cow per d and 6kg of DM of supplementation/cow per d. Milk yield was greatest in the GCH treatment and milk solids yield was greatest in both concentrate-supplemented treatments. The HG and LG treatments excreted a greater quantity of N as a proportion of N intake than the supplemented treatments. The HG treatment also excreted the greatest total quantity of N. This indicates an improvement in N utilization efficiency when supplementation is offered compared with grazing only. Offering 6kg of DM of either grass silage or concentrate as supplementation decreased milk true protein concentration compared with offering a grass-only diet. This suggests that increasing the proportion of supplementation relative to grass may negatively affect milk processability, which is associated with milk true protein concentration. PMID- 26051315 TI - Milk skimming, heating, acidification, lysozyme, and rennet affect the pattern, repeatability, and predictability of milk coagulation properties and of curd firming model parameters: A case study of Grana Padano. AB - Milk coagulation properties are used to evaluate the cheesemaking aptitude of milk samples. No international standard procedure exists, although laboratories often mimic the production of a full-fat fresh cheese for milk coagulation properties. Questions have arisen about the predictability of such a procedure for different types of cheese production. The aim of this study was to establish a procedure mimicking the production conditions of a long-ripened hard cheese, taking Protected Designation of Origin Grana Padano as a case study. With respect to the traditional conditions (standard procedure; SP), the Grana Padano procedure (GP) modifications were the use of standardized milk, coagulation lower temperature, previous milk acidification, lysozyme addition, and rennet type. Each modification was tested in turn versus the SP and also all together in the GP. Another 3 tests were carried out: SP on naturally creamed milk, SP with double the quantity of rennet, and a simplified GP on a full-fat milk sample. The 10 procedures were tested on 2 subsamples with 2 replicates each and were repeated using individual milk samples from 15 dual-purpose Simmental cows in 4 sessions for a total of 600 tests. Two Formagraph instruments (Foss Electric A/S, Hillerod, Denmark) measuring curd firmness every 15 s were used, prolonging test duration to 60min to obtain 5 traditional single-point milk coagulation properties and 3 parameters of the curd firming model using all 240 points recorded for each replicate. The 8 traits of each replicate were analyzed according to a mixed model with fixed effects of 4 sessions, 10 treatments, 2 instruments, and 16microvats, and random effects of 15 animals and 300 subsamples. Compared with the SP, the coagulation and curd firming was slowed by low temperature and was accelerated by acidification and by adding a double amount of rennet; natural creaming, fat standardization, and rennet with 5% pepsin affected only some traits, whereas lysozyme addition affected none. Combination of all modifications tended to compensate for each of their effects, resulting in similar average patterns between GP and SP. Modifications to repeatability were found for all traits with the exception of 2. The ability of the SP to predict GP, tested through correlations between procedures, was not very high. Whereas SP is used for both research and in the dairy industry, better results for Grana Padano cheesemaking can only be achieved by adopting specific, more complex, and labor-intensive procedures at the research level or, possibly, by specific calibrations through Fourier-transform infrared spectroscopy at the industry level. PMID- 26051316 TI - Habituation of dairy heifers to milking routine-Effects on human avoidance distance, behavior, and cardiac activity during milking. AB - The onset of lactation marks a significant turning point in a heifer's life, and prior experience with the milking routine could have positive effects on animal welfare and productivity. The objectives of this multifarm (n=5) study were to investigate (1) whether prelactation training sessions affected behavior during milking, cardiac activity, human avoidance distance, and milk yield, and (2) whether these responses would be modified by the heifer's initial level of fear of humans. Trained heifers (TH, n=30) experienced the routine in the milking parlor on at least 10 d prepartum, whereas untrained heifers (UH, n=29) entered the parlor for the first time after calving. Behavior and cardiac activity were recorded on d 1 and 7 after calving, and an avoidance test was carried out on the day of integration into the dairy herd as well as on d 1, 7, and 28 postpartum. Each animal's initial level of fear of humans was classified as high or low based on the first human avoidance distance measured toward an unknown person. Results showed that TH showed less stepping and kicking during the udder preparation phase in the parlor and UH had higher probabilities to put their ears flat on the head, clamp their tail between the hind legs, and have their eyes wide open throughout the different phases in the milking parlor. Heart rate decreased from d 1 to 7, increased from before to during and to after milking and was slightly elevated in TH compared with UH. Milk yield did not differ between TH and UH. Human avoidance distance was not influenced by training, but distance decreased in heifers with a high initial level of fear of humans across repetitions of the test, whereas heifers with a low initial level of fear of humans had generally short avoidance distances. However, initial level of fear of humans neither determined behavior and heart rate during milking nor milk yield of TH and UH. The results indicate that the training regimen applied in the present study habituated heifers, to some extent, to the milking routine. PMID- 26051317 TI - Genome-wide association study for semen production traits in Holstein-Friesian bulls. AB - Identifying genomic regions, particularly individual genes associated with semen quality traits, may be very important for improving sire fertility via selective breeding. The aim of the study was to estimate (co)variance components and effects of single nucleotide polymorphisms (SNP) from the Illumina BovineSNP50 BeadChip (Illumina, San Diego, CA) on semen production traits and to find candidate genes for these traits. The analyzed data set originates from the Polish Holstein-Friesian dairy cattle population and consists of 1,212 bulls kept at 4 artificial insemination stations. For each bull, 5 semen production traits were collected: sperm concentration, semen volume, number of spermatozoa, motility, and motility score. A multitrait mixed model was used to estimate genetic parameters. The parameters obtained were used to estimate SNP effects for each trait separately by the mixed model, which is used in the Polish direct genomic value project. Additionally, genes located in the vicinity of significant SNP were selected as candidate genes. For motility, 20 genome-wide significant SNP, located on 12 autosomes, were identified. For sperm concentration, we found 7 significant SNP: 3 on chromosome X, and 1 on chromosomes 1, 6, 23, and 24. For semen volume and motility score, 3 and 1 significant SNP were detected, respectively. All these SNP were located on chromosome X. For the number of spermatozoa, 12 significant SNP were observed. Six SNP were located on chromosome X, 3 on chromosome 8, and 1 on chromosomes 2, 7, and 16. This study clearly indicated a key role of the X chromosome in the determination of semen quality and emphasized that including such traits into genetic evaluation should be strongly considered. PMID- 26051318 TI - Short communication: Species group-specific predictors at the cow and quarter level for intramammary infection with coagulase-negative staphylococci in dairy cattle throughout lactation. AB - Coagulase-negative staphylococci (CNS) are frequently isolated from quarters with subclinical mastitis, teat apices, and the cows' environment. Virulence, ecology, epidemiological behavior, and effect on udder health vary between different CNS species. Staphylococcus chromogenes, Staph. simulans, and Staph. xylosus are frequently present in milk and have a more substantial effect on quarter milk somatic cell count than other species. Therefore, these species are considered the "more relevant" CNS. As species-specific factors associated with CNS intramammary infection (IMI) have not yet been identified and susceptibility for IMI differs between cows and quarters, this study aimed to identify predictors for CNS IMI at the cow and quarter level (some of them changing over time) with a specific focus on the aforementioned more relevant CNS. Precise data were available from a longitudinal study (3,052 observations from 344 quarters from 86 dairy cows belonging to 3 commercial dairy herds). All CNS were molecularly identified to the species level, and multivariable, multilevel logistic regression models taking into account the longitudinal nature of the data, were fit to study the likelihood of infection. Staphylococcus chromogenes, Staph. xylosus, and Staph. cohnii were the most frequently isolated species from CNS IMI in older cows, whereas Staph. chromogenes, Staph. xylosus, and Staph. simulans were the main species found in IMI in heifers. Quarters from heifers (as opposed to multiparous cows), from heifers and multiparous cows in third or fourth month in lactation (as opposed to early lactation, <60 d in milk), and with an increasing quarter milk SCC were more likely to be infected with the more relevant CNS species. Quarter milk SCC was identified as the sole statistically significant predictor for IMI with other CNS species, although the size of the effect was lower [odds ratio of 1.6 (1.4-1.9) vs. 2.1 (1.8-2.5)] than the effect for IMI with the more relevant CNS. As a strong herd effect was present, studying herd-level predictors is warranted. PMID- 26051319 TI - Evaluation of X-ray fluorescence spectroscopy as a method for the rapid and direct determination of sodium in cheese. AB - Cheese manufacturers indirectly determine Na in cheese by analysis of Cl using the Volhard method, assuming that all Cl came from NaCl. This method overestimates the actual Na content in cheeses when Na replacers (e.g., KCl) are used. A direct and rapid method for Na detection is needed. X-ray fluorescence spectroscopy (XRF), a mineral analysis technique used in the mining industry, was investigated as an alternative method of Na detection in cheese. An XRF method for the detection of Na in cheese was developed and compared with inductively coupled plasma optical emission spectroscopy (ICP-OES; the reference method for Na in cheese) and Cl analyzer. Sodium quantification was performed by multi-point calibration with cheese standards spiked with NaCl ranging from 0 to 4% Na (wt/wt). The Na concentration of each of the cheese standards (discs: 30mm*7mm) was quantified by the 3 methods. A single laboratory method validation was performed; linearity, precision, limit of detection, and limit of quantification were determined. An additional calibration graph was created using cheese standards made from natural or process cheeses manufactured with different ratios of Na:K. Both Na and K calibration curves were linear for the cheese standards. Sodium was quantified in a variety of commercial cheese samples. The Na data obtained by XRF were in agreement with those from ICP-OES and Cl analyzer for most commercial natural cheeses. The XRF method did not accurately determine Na concentration for several process cheese samples, compared with ICP-OES, likely due to the use of unknown types of Na-based emulsifying salts (ES). When a calibration curve was created for process cheese with the specific types of ES used for this cheese, Na content was successfully predicted in the samples. For natural cheeses, the limit of detection and limit of quantification for Na that can be determined with an acceptable level of repeatability, precision, and trueness was 82 and 246mg/100g of cheese, respectively. Calibration graphs should be created with standards that reflect the concentration range, ratio, and salt type present in the cheeses. This XRF method can be successfully used for the rapid and direct measurement of Na content in a wide variety of natural cheeses. Commercial process cheese manufacturers use proprietary blends of ES. We did find that the XRF technique worked for process cheese when the calibration graphs were created with the specific types of ES actually used. PMID- 26051320 TI - Pyrosequencing reveals shifts in the bacterial epimural community relative to dietary concentrate amount in goats. AB - Ecological balance in the rumen is highly sensitive to concentrate-rich diets. Yet the effects of these feeding practices on the caprine bacterial epimural microbiome (CBEM), a microbial community with putative important physiological functions in the rumen, are largely unexplored. This study aimed to investigate the effect of dietary concentrate amount on ruminal CBEM. Seventeen growing goats were fed diets with 0 [n=5; 6.2MJ of metabolizable energy (ME)/d], 30 (n=6; 7.3MJ of /d), or 60% (n=6; 10.2MJ of ME/d) concentrate for 6 wk. Two hours after their last feeding, goats were euthanized and tissue samples of the ventral rumen wall were collected, washed in phosphate-buffered saline to detach loosely attached bacteria, and stored at -20 degrees C for further processing. Genomic DNA was isolated from thawed rumen mucosa samples and used for Roche/454 Life Science (Branford, CT) 16S rRNA gene amplicon pyrosequencing yielding 122,458 reads. Pyrosequencing data were clustered into 1,879 operational taxonomic units (OTU; 0.03 distance level). Pyrosequencing revealed Proteobacteria, Bacteroidetes, Firmicutes, and Spirochaetes as the most abundant phyla (97.7%). Compared with the 30% group, both the 60 and 0% concentrate groups harbored significantly more Firmicutes and SR1, respectively. On an OTU level, a Bergeriella-related OTU was most abundant in the CBEM, followed by 2 Campylobacter OTU, which responded differently to diets: 1 OTU was significantly increased whereas the other significantly decreased with highest concentrate amount in the diet. At the genus level, the 0% concentrate group harbored increased Kingella-like sequences compared with the other feeding groups. Furthermore, the 0% concentrate group tended to have more Bergeriella than the 30 and 60% concentrate groups. The genus Bergeriella was significantly decreased in the 60% feeding group compared with the other diets. In conclusion, this is the first report of CBEM using deep sequencing methods on the genus and OTU level, and our study revealed major shifts in the CBEM in response to concentrate-rich diets with potential health relevance in goats. PMID- 26051321 TI - Reviewing biomolecular crystallography proposals: time for a paradigm change. PMID- 26051322 TI - Histidine-rich glycoprotein blocks collagen-binding integrins and adhesion of endothelial cells through low-affinity interaction with alpha2 integrin. AB - The plasma protein histidine-rich glycoprotein (HRG) affects the morphology and function of both endothelial cells (ECs) and monocytes/macrophages in cancer. Here, we examined the mechanism of action of HRG's effect on ECs. HRG suppressed adhesion, spreading and migration of ECs specifically on collagen I (COL I) whereas ECs seeded on other extracellular matrix proteins were insensitive to HRG. HRG did not bind specifically to COL I or to the alpha-integrin binding site on collagen, GFOGER. Furthermore, HRG's inhibition of EC adhesion was not dependent upon heparan sulfate (HS) moieties as heparitinase-treated ECs remained sensitive to HRG. C2C12 cells expressing alpha2 integrin, the major collagen binding alpha-integrin subunit in ECs, showed increased binding of HRG compared with wild type C2C12 cells lacking the alpha2 subunit. Recombinant alpha2 I domain protein bound HRG and to a higher extent when in active conformation. However, the alpha2 I-domain bound weakly to HRG compared with COL I and the purified alpha2beta1 ectodomain complex failed to retain HRG. We conclude that HRG binds to alpha2 integrin through low-affinity interactions in a HS independent manner, thereby blocking EC-adhesion to COL I. PMID- 26051323 TI - Modeling vapor uptake induced mobility shifts in peptide ions observed with transversal modulation ion mobility spectrometry-mass spectrometry. AB - Low field ion mobility spectrometry-mass spectrometry (IMS-MS) techniques exhibit low orthogonality, as inverse mobility often scales with mass to charge ratio. This inadequacy can be mitigated by adding vapor dopants, which may cluster with analyte ions and shift their mobilities by amounts independent of both mass and mobility of the ion. It is therefore important to understand the interactions of vapor dopants with ions, to better quantify the extent of dopant facilitated mobility shifts. Here, we develop predictive models of vapor dopant facilitated mobility shifts, and compare model calculations to measurements of mobility shifts for peptide ions exposed to variable gas phase concentrations of isopropanol. Mobility measurements were made at atmospheric pressure and room temperature using a recently developed transversal modulation ion mobility spectrometer (TMIMS). Results are compared to three separate models, wherein mobility shifts due to vapor dopants are attributed to changes in gas composition and (I) no vapor dopant uptake is assumed, (II) site-specific dopant uptake by the ion is assumed (approximated via a Langmuir adsorption model), and (III) site unspecific dopant uptake by the ion is assumed (approximated via a classical nucleation model). We find that mobility shifts in peptide ions are in excellent agreement with model II, site-specific binding predictions. Conversely, mobility shifts of tetraalkylammonium ions from previous measurements were compared with these models and best agreement was found with model III predictions, i.e. site unspecific dopant uptake. PMID- 26051324 TI - A time space translation hypothesis for vertebrate axial patterning. AB - How vertebrates generate their anterior-posterior axis is a >90-year-old unsolved probem. This mechanism clearly works very differently in vertebrates than in Drosophila. Here, we present evidence from the Amphibian Xenopus that a time space translation mechanism underlies initial axial patterning in the trunk part of the axis. We show that a timer in the gastrula's non organiser mesoderm (NOM) undergoes sequential timed interactions with the Spemann organiser (SO) during gastrulation to generate the spatial axial pattern. Evidence is also presented that this mechanism works via Hox collinearity and that it requires Hox functionality. The NOM timer is putatively Hox temporal collinearity. This generates a spatially collinear axial Hox pattern in the emerging dorsal central nervous system and dorsal paraxial mesoderm. The interactions with the organiser are mediated by a BMP-anti BMP dependent mechanism. Hox functionality is implicated because knocking out the Hox1 paralogue group not only disrupts expression of Hox1 genes but also of the whole spatially collinear axial Hox sequence in the early embryo's A-P axis. This mechanism and its nature are discussed. The evidence supporting this hypothesis is presented and critically assessed. Strengths and weaknesses, questions, uncertainties and holes in the evidence are identified. Future directions are indicated. PMID- 26051325 TI - Titanate nanosheets as highly efficient non-light-driven catalysts for degradation of organic dyes. AB - A novel non-light-driven catalysis by the delaminated two dimensional titanate nanosheets (TNSs) has been explored for degradation of organic dyes with hydrogen peroxide (H2O2). This catalyst can efficiently remove dyes at high concentration and over a wide pH range, as well as with a long cycle number and superior universality. PMID- 26051326 TI - Does the setup of Monte Carlo simulations influence the calculated properties and effect of gold nanoparticles in radiation therapy? AB - PURPOSE: To investigate whether the dose-scoring process of Monte Carlo (MC) simulations of Gold nanoparticles (GNPs) in radiation therapy affects the results. METHODS: The GATE MC toolkit was used to simulate the irradiation of a water phantom containing a single solid or hollow GNP with 250 kVp and 6 MV photons. The dose was scored in 20 nm * 20 nm * 50 MUm, 100 nm * 100 nm * 50 MUm and 200 nm * 200 nm * 50 MUm volumes using dose-scoring voxels of size 1 nm * 1 nm * 50 MUm, 10 nm * 10 nm * 50 MUm, 50 nm * 50 nm * 50 MUm and 100 nm * 100 nm * 50 MUm Epsilonxcess dose depth-dose (EDDD) curves and lateral beam profiles were used to compare the dose-scoring voxels. RESULTS: In a given volume, neither the EDDD curves nor the lateral beam profiles are affected by the size of the dose scoring voxels, subject to noise and uncertainty. Certain features of the EDDD curves are clearly seen in larger volumes, but hidden within the uncertainty and noise levels in smaller volumes. For the lateral beam profiles, it is the larger volumes that result in misleading results and the smaller ones that give the expected results. However, the limited statistics result in asymmetries and skewness in the profiles. CONCLUSION: For a given volume, the dose curves are not affected by the size of the dose-scoring voxels. However, the voxel size may hide or reveal the finer structure of the dose curves and/or may result in misleading curves. PMID- 26051327 TI - The seroprevalence and salivary shedding of herpesviruses in Behcet's syndrome and recurrent aphthous stomatitis. AB - BACKGROUND: Behcet's syndrome (BS) is one of the multisystemic diseases that presents with oral ulceration and several other systemic manifestations including genital ulceration, folliculitis, erythema nodosum-like lesions, uveitis, and arthropathy. Ocular manifestation, central nervous system involvement, and gastrointestinal manifestation account for most of the complications of this disease, whereas orogenital ulceration and dermatological involvement affects the quality of life. The cause of the disease is not fully elucidated; however, herpesviruses have long been thought to play a pivotal role in the disease pathogenesis. OBJECTIVE: To investigate the seroprevalence and salivary shedding of herpesviruses in BS. METHOD: The levels of specific immunoglobulin G in six different herpesviruses in serum samples collected from 54 BS, 28 healthy controls (HC), and 7 recurrent aphthous stomatitis (RAS) patients were investigated. Salivary viral load was also quantified for these viruses in matched saliva samples using quantitative real-time polymerase chain reaction. RESULTS: The BS had lower cytomegalovirus (CMV) IgG level in comparison to HC (p=0.0226) and RAS (p=0.0450). There was statistically significant higher salivary shedding of Epstein-Barr virus (EBV) in BS in comparison to HC (p=0.0052), but not RAS (p=0.3318). CONCLUSIONS: A high EBV shedding was observed in both BS and RAS and a lower level of CMV IgG was observed in BS only. The reason for the observed lower level of CMV IgG in BS is not clear. However, one explanation might be a defect in the cross-talk between innate and adaptive immune responses which was suggested by a previously described defect in the toll like receptor 1 and 2 heterodimer formation and function, this being the initial receptor sensing of CMV. PMID- 26051328 TI - The role of cytoreductive surgery and HIPEC in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the most common cause of death from gynecological cancer in the Western world. The current standard treatment of these patients consists of cytoreduction and systemic chemotherapy. One of the most distinct features of EOC is the tendency to disseminate into the peritoneal cavity and remain confined to the peritoneum and intra-abdominal viscera. This makes it an ideal target for loco-regional therapy. Improved long-term results can be achieved in highly selected patients using cytoreductive surgery (CRS), in combination with intra-operative hyperthermic intra-peritoneal chemotherapy (HIPEC). Optimal cytoreduction of advanced ovarian cancer is currently the most relevant prognostic factor. However, even when a complete resection is possible, the appearance of recurrences during follow-up is very common, due to the presence of microscopic residual disease, not visible to the surgeon. HIPEC has become a useful therapeutic strategy to obtain a higher degree of debulking by trying to eliminate the residual microscopic component responsible for recurrences. A summary of the current clinical evidence suggests that the most interesting settings first to explore in randomized trials are secondary CRS after upfront incomplete CRS for stage III ovarian cancer and salvage CRS for recurrent ovarian cancer, two time-points representing failure to initial standard therapy. There is much less indirect evidence for a potential benefit of HIPEC for less advanced stages (I - II) and for earlier time-points in the treatment of ovarian cancer (upfront, interval and consolidation). CRS and HIPEC offer a significant survival benefit in patients with recurrent EOC. This observation applies to both platinum-sensitive and platinum-resistant disease. PMID- 26051329 TI - Management of peritoneal metastases - Basic concepts. AB - Despite the fact that cytoreductive surgery (CRS) and hyperthermic perioperative chemotherapy (HIPEC) is conceptually simplistic, optimal implementation of this combined treatment remains complex. Multiple patient-related variables, methodologic variables, and pharmacologic variables need to be considered in devising an optimal treatment strategy. Working through these variables considering the pathophysiology of peritoneal metastases and their possible treatments is more likely to provide guidance in terms of successful management than multiple randomized controlled trials. The principles of management include: 1) A surgical technology involving peritonectomy procedures and visceral resections that will result in a complete cytoreduction. 2) Treatment of patients at a maximal low peritoneal cancer index (PCI) will maximize the benefits especially in those patients who have high grade peritoneal metastases from gastric cancer, colorectal cancer, or ovarian malignancy. 3) Tumor cell entrapment should be avoided by preventing major surgical procedures prior to the definitive treatment with CRS and HIPEC. 4) Mechanical removal of cancer cells and small nodules by mechanical irrigation prior to HIPEC is necessary. 5) A response must be generated using cancer chemotherapy to eradicate small volume residual disease that will remain even after a complete cytoreduction by visual inspection. 6) The benefits of multiple cycles of normothermic intraperitoneal and intravenous chemotherapy (NIPEC) used long-term to help preserve the surgical complete response needs to be integrated into the overall plan of management. Currently, with peritoneal metastases from high grade disease perioperative chemotherapy usually fails to maintain the surgical complete response. Major modifications of the perioperative chemotherapy using HIPEC, early postoperative intraperitoneal chemotherapy (EPIC) and NIPEC long-term will go far towards optimizing the treatment of peritoneal metastases no matter what the primary gastrointestinal or gynecologic malignancy is being treated. PMID- 26051330 TI - Problems in pelvic cytoreduction - Hostile pelvis. AB - Surgeons learn over time when it is appropriate to recommend an operation. This is particularly true in the management of pelvic carcinomatous disease, which often gives rise to symptoms that are debilitating and difficult to manage by non surgical means. Radical pelvic cytoreduction, complete resection of all visible tumor, remains the established operation for the treatment of carefully selected patients with biologically favorable tumors. Complexities in pelvic surgery and pelvic cytoreduction cover the strategic evaluation, specific approaches, and management techniques. The essential principle to removal of a very advanced pelvic disease lies in the retroperitoneal surgery. The retroperitoneal approach allows for dissection of the pan-pelvic tumoral mass and deposits using the peritoneum as a pseudo-capsule while identifying vital retroperitoneal structures such as the iliac vessels and ureter. Despite the fact that there are several considerations in favor of cytoreductive surgery, overall morbidity due to its application depends not only on the extent of the surgical procedure but also on the patient's medical fitness, the experience and expertise of the operating surgeon, as well as the quality of the supportive care, particularly anesthesia and critical care. The major source of trouble is the hostile pelvis itself. The reasons are fairly clear: most patients have had incomplete 'in-line' resective attempts, irradiation, and inflammation due to prior overhealing. Many of the complications of the procedure can be ameliorated or eliminated by careful attention to patient preparation, intraoperative meticulous technique, and post cytoreductive intensive care. Achieving success and safety with these cytoreductive techniques requires extensive knowledge of pelvic anatomy, the use of special techniques of exposure and methods of dissection, a clear understanding of the objectives of the operation, and a flexibility of mind. PMID- 26051331 TI - Optimal drugs for HIPEC in different tumors. AB - Although there is adequate evidence to support treatment of primary and secondary peritoneal surface malignancies with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), the latter procedure is still far from standardized and optimization of its aspects may be warranted. Significant variations remain in HIPEC procedures and include also the drug choice. In this manuscript the characteristics of the optimal HIPEC drug will be discussed. Subsequently, the drug choice for HIPEC treatment of different peritoneal surface malignancies will be briefly analyzed. Prospective randomized trials are warranted to determine which drug is the most effective for HIPEC in each type of peritoneal surface malignancy. In the future, it would be of major significance when the choice of the most optimal drug in HIPEC may be tailored to the patient's individual tumor by adequate drug sensitivity testing of the tumor cells. PMID- 26051332 TI - Management of pseudomyxoma peritonei. AB - Pseudomyxoma peritonei (PMP) is an uncommon clinical condition that typically originates from a perforated epithelial neoplasm of the appendix. The clinical presentation is variable, often with non-specific symptoms and is associated with abdominal distension in advanced cases. Whilst traditionally considered benign, it is apparent that PMP represents a spectrum of disease and, at best, should be considered a "border-line" malignancy. The condition is characterised by the development of mucinous ascites. Tumour cells and mucin accumulate at characteristic sites within the peritoneal cavity according to the redistribution phenomenon, usually sparing the mobile small bowel. In advanced cases, high volume disease and mucinous ascites lead to compression of the gastrointestinal tract, bowel obstruction, and ultimately, starvation. Controversy still exists over the pathological classification of PMP and its prognostic value. Computed tomography remains the optimal preoperative staging investigation. Elevation of serum tumour markers correlates with a worse prognosis. Optimal treatment involves cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). With complete cytoreduction and HIPEC an 80% 5 year survival can be achieved in patients with low grade disease. Maximal tumour debulking can produce good palliation and long term survival in a small number of patients. Initial high morbidity and mortality is seen to decrease with increasing experience and this is likely to represent improvement in patient selection and postoperative management as well as surgical expertise. PMID- 26051333 TI - HIPEC in controversial digestive tumors. AB - Local-regional and peritoneal metastases still develop despite improvements in surgical techniques. Intraperitoneal chemotherapy has been proved to be effective in reducing the rate of local-regional and peritoneal metastases in many malignancies. There is adequate evidence that intraperitoneal perioperative chemotherapy after aggressive resection of locally advanced tumors of the digestive system may be helpful in decreasing the rate of local-regional and peritoneal metastases. Prospective trials and meta-analyses have shown that patients with locally advanced gastric or colorectal carcinomas are offered significant survival benefit and develop reduced number of local-regional metastases with surgery combined with perioperative intraperitoneal chemotherapy. In pancreatic cancer the preliminary results have shown that these patients do not develop local-regional recurrences with R0 resection in combination with hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC). Further studies are required to document these findings. PMID- 26051334 TI - Digestive fistulas after cytoreductive surgery & HIPEC in peritoneal carcinomatosis. AB - PURPOSE: The development of digestice fistulas is a complication of gastrointestinal operations during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). In this article we present the incidence, management and outcome of enterocutaneous digestive fistulas after CRS and HIPEC. METHODS: Over the past 10 years (2005-2014), 184 patients with peritoneal carcinomatosis underwent CRS and HIPEC. HIPEC was administered in the operating room immediately after CRS, but in 48 (26%) patients this happened before the formation of intestinal anastomosis or repair of seromuscular tears, using the open (coliseum) technique; in the remaining 137 (74%) patients the anastomoses were performed before HIPEC. All patients were operated on by the same surgical team. RESULTS: Of the 185 patients 16 (8.6%) developed an enterocutaneous digestive fistula. Spontaneous fistula closure was observed in 14 (87.5%) patients. The median duration of spontaneous closure was 18 days (range 9-56). Reoperation was needed in 2 (12.5%) patients. There were 2 (12.5%) deaths. CONCLUSION: CRS and HIPEC is a well-known treatment modality for peritoneal carcinomatosis. The incidence of digestive fistulas is increased a little compared to that of conventional digestive surgery. PMID- 26051335 TI - Mapping the location of peritoneal metastases using the peritoneal cancer index and the correlation with overall survival: a retrospective study. AB - PURPOSE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment for patients with peritoneal carcinomatosis (PC). Our objective was to identify new prognostic factors within the Peritoneal Cancer Index (PCI) score in PC patients. METHODS: 140 patients (60 ovarian, 45 colon, 14 gastric, 10 pseudomyxoma peritonei, 5 mesothelioma, 6 sarcoma) with PC treated with CRS+HIPEC from 2007 to December 2013 were retrospectively included. Tumor extent and location were assessed by the PCI and residual disease was recorded using the Completeness of Cytoreduction (CC) score. All clinical data were computed in univariate and multivariate analysis using survival as primary endpoint. RESULTS: The PCI remains the most important factor concerning the long-term survival. Involved areas 4, 5 and 8 are more favorable in survival vs areas 9, 10 and 11, which predict a significantly worse outcome (p<0.002). Prognosis varies not only depending on how many peritoneal areas are involved but also on the location of the primary tumor. CONCLUSION: We demonstrated that the involvement of different areas in the PCI system has a significant impact on the final prognosis and survival. PMID- 26051336 TI - Management of colorectal cancer patients at high risk of peritoneal metastases. AB - PURPOSE: Colorectal cancer (CRC) has potential to spread within the peritoneal cavity, and this transcoelomic dissemination is termed "peritoneal metastases" (PM). Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a radical strategy to treat selected CRC patients with PM. Studies suggest that identification of CRC patients at high risk of PM may lead to earlier treatment strategies and improve survival in this subset of patients. The aim of this article was to summarise the current evidence regarding CRC patients at high risk of PM. METHODS: A retrospective review of articles on CRC patients with high risk of PM published up to December 2014 in PubMed, Medline, Embase, and Ovid search engines was conducted. The following combination of search terms were used: "intraperitoneal chemotherapy", "HIPEC", "colorectal cancer", "peritoneal carcinomatosis", "peritoneal metastases", "high risk", "peritoneal recurrence". RESULTS: Although opinions differ, CRC patients identified as "high risk" of PM included: limited, synchronous PM completely resected with the primary tumor, ovarian metastases (synchronous or metachronous) and spontaneous or iatrogenic perforation of the bowel by the primary tumor. Aggressive early treatment strategies currently used are: CRS and HIPEC for high-risk primary tumors and second-look CRS and HIPEC often following systematic chemotherapy for the primary resection. Positive results have been shown with both approaches in a number of studies. With CRS/HIPEC for the primary tumor, the overall survival in the two groups (25 patients treated with CRS/HIPEC vs 50 treated with conventional surgery) was significantly improved (p<0.03), as was disease-free survival (p<0.04). For second look surgery, in 29 patients treated with CRS and HIPEC, this resulted in 14% morbidity and 0% mortality and a 2-year disease-free survival rate in excess of 50%. CONCLUSIONS: We are progressively moving to an era of individualised treatment strategies. The management of CRC patients with high risk of PM is ever evolving, with early detection and early treatment strategies showing promising results. The optimal timing of early surgery remains unclear and requires further evaluation. Should current and future randomized trials demonstrate long-term survival benefit, we may potentially see a change in treatment paradigm from current conventional surgery to a more aggressive, early radical approach as the standard of care. PMID- 26051337 TI - Cytoreductive surgery and HIPEC for peritoneal carcinomatosis. A review on morbidity and mortality. AB - PURPOSE: To review morbidity and mortality of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis. METHODS: A literature search was conducted to identify studies from centers that perform CRS and HIPEC, and to collect and analyse data about morbidity and mortality. RESULTS: Twenty-five articles, published from 2006 to 2014 were reviewed. The studies included 24-1069 patients that had been treated with CRS and HIPEC for peritoneal carcinomatosis. The overall rate of severe perioperative morbidity ranged from 0 to 62% and the mortality rate varied from 0 to 10%. Major morbidity was correlated with age, peritoneal carcinomatosis index (PCI), comorbidities, number of digestive anastomoses and institution where the treatment was performed. CONCLUSION: Although the resultant morbidity is not negligible, with good patient selection this modality appears to be overall safe and effective in experienced hands. The results indicated that this treatment should be practised by institutions with expertise in the management of peritoneal carcinomatosis. PMID- 26051338 TI - Critical analysis of spectral solvent shifts calculated by the contemporary PCM approaches of a representative series of charge-transfer complexes between tetracyanoethylene and methylated benzenes. AB - Applications of contemporary polarisable continuum model (PCM) quantum chemical approaches to account for the solvent shifts of UV-Vis absorption charge transfer (CT) transitions in electron donor-acceptor (EDA) complexes (as well as to account for their stability and other properties in solvents) have been rather rare until now. In this study, we systematically applied different - mainly state specific - PCM approaches to examine excited state properties, namely, solvatochromic excitation energy shifts in a series of EDA complexes of a tetracyanoethylene (TCNE) acceptor with methyl substituted benzenes with different degrees of methylation N (NMB). For these complexes, representative and reliable experimental data exist both for the gas phase and in solution (dichloromethane). We have found that the linear response (LR) solvent shifts are too small compared to the experimental values, while self-consistent SS approaches give values that are too large. The best agreement with experimental values was obtained by corrected LR (cLR). The transition energies were calculated by means of TD-DFT methodology with PBE0, CAM-B3LYP and M06-2X functionals as well as the wave function CC2 method for the gas phase, and the PCM solvent shifts were added to account for the solvent effects. The best results for transition energies in solvents were obtained using the CC2 method complemented by CAM-B3LYP/cLR for the gas phase transition energy red solvent shift, while all three TD-DFT approaches used gave insufficient values (ca. 50%) of the slope of the dependence of the transition energies on N compared to experimental values. PMID- 26051339 TI - Moles, misjudgement and moral character: A last response to John Paley. PMID- 26051340 TI - Development and characterization of a novel GHR antibody antagonist, GF185. AB - Here, we describe the development of a panel of monoclonal antibodies targeting the growth hormone receptor (GHR). Of these monoclonal antibodies (Mabs), GF185 was selected for further characterization due to its activities. Competitive receptor-binding assays and Western blotting analyses were used to demonstrate that GF185's epitopes are localized within subdomain 1 of the growth hormone receptor extracellular domain (GHR-ECD). Subsequently, we evaluated GF185's antagonistic activities in vivo and in vitro and showed that GF185 was able to neutralize growth hormone (GH) signalling and inhibit GH-induced Ba/F3-GHR proliferation. Our findings suggest that GF185 may serve as an attractive tool for GHR-related research and has a potential future application for the treatment of GH-dependent disease. PMID- 26051341 TI - Polyelectrolyte complex containing silver nanoparticles with antitumor property on Caco-2 colon cancer cells. AB - Polyelectrolyte complex (beads) based on N,N,N-trimethyl chitosan/alginate was successful obtained and silver nanoparticles (AgNPs) were loaded within beads. In vitro cytotoxicity assays using beads/silver nanoparticles (beads/AgNPs) provided results, indicating that this material significantly inhibited the growth of colon cancer cells (Caco-2). In vitro release studies showed that the beads stabilized AgNPs and repressed Ag(0) oxidation under gastric conditions (pH 2.0). On the other hand, at physiological condition (pH 7.4) the beads/AgNPs released 3.3 MUg of Ag(+) per each beads milligram. These studies showed that the concentration of Ag(+) released (3.3 MUg) was cytotoxic for the Caco-2 cells and was not cytotoxic on healthy VERO cells. This result opens new perspectives for the manufacture of biomaterials based on beads/AgNPs with anti-tumor properties. PMID- 26051342 TI - Purification, partial characterization and antioxidant activity of polysaccharides from Glycyrrhiza uralensis. AB - Glycyrrhiza uralensis, an important Chinese medicine, has a long history of use in China. In this study, three water-soluble polysaccharides fractions (GUPs-1, GUPs-2 and GUPs-3) were isolated and purified from the root of G. uralensis by DEAE-52 and Sephadex G-100 column chromatography. Physicochemical properties and antioxidant activities of the three purified polysaccharides were investigated. The molecular weights of GUPs-1, GUPs-2 and GUPs-3 were 10,160, 11,680 and 13,360 Da, and the ratios of glucose were 23.4%, 14% and 1.13%, respectively. The antioxidant activities of the three purified polysaccharides followed the order: GUPs-1>GUPs-2>GUPs-3. GUPs with lower molecular weight and higher ratio of glucose, basically exhibited higher antioxidant activities at the same concentration. This indicated that the molecular weight and the ratio of monosaccharide composition of the GUPs could affect the antioxidant activities. PMID- 26051343 TI - Preparation and characterization of vanillin-crosslinked chitosan therapeutic bioactive microcarriers. AB - Chitosan microspheres with diameter of 14.3-48.5 MUm were prepared by emulsion method and using natural vanillin as cross-linking agent. The surface morphology and microstructure of the microspheres were characterized by scanning electron microscopy, X-ray diffraction and Fourier-transform infrared spectroscopy, etc. The hollow microspheres showed a well-defined spherical shape with median diameter of 30.3 MUm and possessed a uniform surface with micro-wrinkles, which is in favor of the drug release. Interpenetrating network cross-linking mechanism might result from the Schiff base reaction and the acetalization of hydroxyl and carbonyl between chitosan and vanillin. Berberine, as a model drug, was loaded in the microspheres and released in a sustainable manner. The drug loading ratio could change from 9.16% to 29.70% corresponding to the entrapment efficiency of 91.61% to 74.25%. In vitro cell culture study using MG63 cells and in vivo implantation clearly showed that the microspheres could provide favorable cell attachment and biocompatibility. The results confirm that the drug-loaded vanillin-crosslinked chitosan microspheres could be a worthy candidate either as carriers of drugs and cells, or as therapeutic matrix for bone repair and regeneration. PMID- 26051344 TI - Heterotaxia with Polysplenia. PMID- 26051345 TI - Substrates of acute coronary syndromes: new insights into plaque rupture and erosion. PMID- 26051346 TI - Leaders in Cardiovascular Medicine. Eugene Braunwald MD: an icon of the 20th century still going strong. AB - Considered one of the pre-eminent cardiologists of our time, Dr Eugene Braunwald, MD, has extended knowledge of congestive heart failure, coronary artery disease, and valvular heart disease. Having published hundreds of papers and medical articles, with his textbook Braunwald's Heart Disease cited worldwide, Dr Braunwald has received numerous honours and awards. Born in Austria in 1929, his family emigrated to the USA during World War II and after his studies he began a long, successful and hugely-influential career as a cardiologist. Now well into his 80s, he still practices medicine and continues to contribute to the field of cardiology. PMID- 26051347 TI - Gastroretentive Ranitidine Hydrochloride Tablets with Combined Floating and Bioadhesive Properties: Factorial Design Analysis, In Vitro Evaluation and In Vivo Abdominal X-Ray Imaging. AB - Ranitidine HCl is an H2-antagonist that suffers from low oral bioavailability of 50%. The site-specific absorption from the upper part of the small intestine and the colonic metabolism of the drug could partially contribute to its reduced bioavailability. To surmount these drawbacks, this work aimed at the formulation of Ranitidine HCl gastroretentive floating-biaodhesive tablets. A 3(2) factorial design was applied to assess the effects of matrix former (HPMC K100M): drug ratio, and the release retardant (Carbopol 971) amount on the characteristics of the tablets prepared using direct compression technique. The prepared tablets were thoroughly evaluated for physical properties, floating, swelling, bioadhesive and in vitro release behaviors. Statistical analysis of the results revealed significant effects for both formulation variables on the swelling index, maximum detachment force and cumulative percent drug released after 6 hours. In addition, the matrix- former: drug ratio showed a statistically significant effect on the floating lag time. Kinetic analysis of the release data indicated Higuchi diffusion kinetics and anomalous transport mechanism for all formulations. Scanning electron micrographs of the selected tablet formulation; F8, revealed intact surface without any perforations or channels in the dry state, while polymer expansion (relaxation) with some perforated areas were observed on the surface of the tablets after 12 hours dissolution in 0.1 N HCl. Furthermore, in vivo abdominal x-ray imaging showed good floating behavior of the selected formulation; F8, for up to 6 hours with appropriate bioadhesive property. In conclusion, the selected ranitidine HCl floating-bioadhesive tablets could be regarded as a promising gastroretentive drug delivery system that could deliver the drug at a controlled rate. PMID- 26051349 TI - Atorvastatin induced hepatic oxidative stress and apoptotic damage via MAPKs, mitochondria, calpain and caspase12 dependent pathways. AB - Atorvastatin (ATO), a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, is used widely for the treatment of hypercholesterolemia and hypertriglyceridemia. Application of this drug has now been made somehow limited because of ATO associated several acute and chronic side effects. The present study has been carried out to investigate the dose-dependent hepatic tissue toxicity in ATO induced oxidative impairment and cell death in mice. Administration of ATO enhanced ALT, ALP level, increased reactive oxygen species (ROS) production and altered the pro oxidant-antioxidant status of liver by reducing intracellular GSH level, anti-oxidant enzymes activities and increasing intracellular lipid peroxidation. Our experimental evidence suggests that ATO markedly decreased mitochondrial membrane potential, disturbed the Bcl-2 family protein balance, enhanced cytochrome c release in the cytosol, increased the levels of Apaf1, caspase-9, -3, cleaved PARP protein and ultimately led to apoptotic cell death. Besides, ATO distinctly increased the phosphorylation of p38, JNK, and ERK MAPKs, enhanced Caspase12 and calpain level. Histological studies also support the dose dependent toxic effect of ATO in these organs pathophysiology. These results reveal that ATO induces hepatic tissue toxicity via MAPKs, mitochondria and ER dependent signaling pathway, in which calcium ions and ROS act as the pivotal mediators of the apoptotic signaling. PMID- 26051350 TI - Aflatoxin B1 and aflatoxin M1 induced cytotoxicity and DNA damage in differentiated and undifferentiated Caco-2 cells. AB - Aflatoxin B1 (AFB1) and aflatoxin M1 (AFM1) are natural mycotoxins that frequently present in food and feed and pose risks to human health. There are few data in the literature regarding the impairment of them in the intestine. Therefore, the present study investigated their cytotoxic effect on Caco-2 cells, especially the differentiated ones that resemble mature small intestinal enterocytes. Both undifferentiated (UC) and differentiated (DC) cells were treated with AFB1 and AFM1 at various concentrations for up to 72 h. Cell viability, lactate dehydrogenase (LDH) release, reactive oxygen species (ROS) production and DNA damage were determined. Data showed that AFB1 and AFM1 significantly inhibited UC and DC cell growth, increased LDH and caused genetic damage in a time- and dose-dependent manner (p < 0.05). In comparison, AFB1 was found to be more toxic than AFM1 on both UC and DC. All these cytotoxic outcomes might be associated with intracellular ROS generation, leading to membrane damage and DNA strand break. Additionally, DC was found to be more sensitive to aflatoxins, which might be due to the alteration of enzymes during cell differentiation. The present study provided the first in vitro evidence of DNA damage of DC induced by AFB1 and AFM1. PMID- 26051348 TI - The safety of green tea extract supplementation in postmenopausal women at risk for breast cancer: results of the Minnesota Green Tea Trial. AB - Green tea is thought to provide health benefits, though adverse reactions to green tea extract (GTE) have been reported. We conducted a randomized, double blind, placebo-controlled study of GTE on breast cancer biomarkers, including mammographic density, in which 1075 postmenopausal women were randomly assigned to consume GTE containing 843 mg (-)-epigallocatechin-3-gallate (EGCG) or placebo daily for one year. There were no significant differences in % of women with adverse events (AEs, 75.6% and 72.8% of the GTE group and placebo group, respectively) or serious AEs (2.2 % and 1.5% of GTE and placebo groups, respectively). Women on GTE reported significantly higher incidence of nausea (P < 0.001) and dermatologic AEs (P = 0.05) and significantly lower diarrhea incidence (P = 0.02). More women in the GTE group experienced an alanine aminotransferase (ALT) elevation compared with placebo group (n = 36, (6.7%) vs. n = 4, (0.7%); P < 0.001). There were no statistically significant differences between groups in frequencies of other AEs. Overall, AEs were mainly mild and transient, indicating that daily consumption of GTE containing 843 mg EGCG is generally well tolerated by a group of predominantly Caucasian postmenopausal women. However, 6.7% of GTE consumers experienced ALT elevations, with 1.3% experiencing ALT-related serious AEs. PMID- 26051351 TI - The immunomodulatory effects of titanium dioxide and silver nanoparticles. AB - Due to their characteristic physical, chemical and optical properties, titanium dioxide and silver nanoparticles are attractive tools for use in a wide range of applications. The use of nanoparticles for biological applications is, however, dependent upon their biocompatibility with living cells. Because of the importance of inflammation as a modulator of human health, the safe and efficacious in vivo use of titanium dioxide and silver nanoparticles is inherently linked to a favorable interaction with immune system cells. However, both titanium dioxide and silver nanoparticles have demonstrated potential to exert immunomodulatory and immunotoxic effects. Titanium dioxide and silver nanoparticles are readily internalized by immune system cells, may accumulate in peripheral lymphoid organs, and can influence multiple manifestations of immune cell activity. Although the factors influencing the biocompatibility of titanium dioxide and silver nanoparticles with immune system cells have not been fully elucidated, nanoparticle core composition, size, concentration and the duration of cell exposure seem to be important. Because titanium dioxide and silver nanoparticles are widely utilized in pharmaceutical, commercial and industrial products, it is vital that their effects on human health and immune system function be more thoroughly evaluated. PMID- 26051352 TI - Lineage-related and particle size-dependent cytotoxicity of chitosan nanoparticles on mouse bone marrow-derived hematopoietic stem and progenitor cells. AB - Chitosan nanoparticles (CSNPs) have potential applications in stem cell research. In this study, ex vivo cytotoxicity of CSNPs on mouse bone marrow-derived (MBMCs) hematopoietic stem and progenitor cells (HSPCs) was determined. MBMCs were exposed to CSNPs of different particle sizes at various concentrations for up to 72 h. Cytotoxicity effect of CSNPs on MBMCs was determined using MTT, Live/Dead Viability/Cytotoxicity assays and flow cytometry analysis of surface antigens on HSCs (Sca-1(+)), myeloid-committed progenitors (CD11b(+), Gr-1(+)), and lymphoid committed progenitors (CD45(+), CD3e(+)). At 24 h incubation, MBMCs' viability was not affected by CSNPs. At 48 and 72 h, significant reduction was detected at higher CSNPs concentrations. Small CSNPs (200 nm) significantly reduced MBMCs' viability while medium-sized particle (~400 nm) selectively promoted MBMCs growth. Surface antigen assessment demonstrated lineage-dependent effect. Significant decrease in Sca-1(+) cells percentage was observed for medium-sized particle at the lowest CSNPs concentration. Meanwhile, reduction of CD11b(+) and Gr-1(+) cells percentage was detected at high and intermediate concentrations of medium-sized and large CSNPs. Percentage of CD45(+) and CD3e(+) cells along with ROS levels were not significantly affected by CSNPs. In conclusion, medium-sized and large CSNPs were relatively non-toxic at lower concentrations. However, further investigations are necessary for therapeutic applications. PMID- 26051353 TI - Arthroscopy-Assisted Surgery for Acute Ankle Fractures: A Systematic Review. AB - PURPOSE: To summarize the clinical findings of adult patients undergoing arthroscopy-assisted open reduction-internal fixation for acute ankle fractures. METHODS: A systematic electronic search of the PubMed databases was performed for all published literature on December 8, 2014. All English-language clinical studies on acute ankle fractures treated with arthroscopy-assisted open reduction internal fixation were eligible for inclusion. Basic information related to the surgical procedure was collected. RESULTS: The search criteria initially identified 187 articles, and 10 studies were included in this systematic review. There were 2 prospective, randomized studies; 2 prognostic studies; and 6 case series studies. There were a total of 861 patients included in this systematic review. Danis-Weber type B fractures (335 of 483 patients) and supination external rotation fractures (187 of 366 patients) were the most common types of all the ankle fractures. Concomitant injuries were common: 63.3% of patients had chondral lesions, 60.9% had deltoid ligament injuries, and 77.9% had tibiofibular syndesmosis injuries. Lavage and debridement of the ankle joint were performed by almost all the surgeons. Chondral lesions were treated with shaving, excision, or microfracture. The mean American Orthopaedic Foot & Ankle Society hindfoot score was 91.7. Only mild complications were reported. CONCLUSIONS: Acute ankle fractures are commonly concomitant with multiple soft-tissue injuries in which arthroscopy may serve as a method for accurate diagnosis and appropriate treatment. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, II, III, and IV studies. PMID- 26051354 TI - Internal Snapping Hip Syndrome: Incidence of Multiple-Tendon Existence and Outcome After Endoscopic Transcapsular Release. AB - PURPOSE: To report the frequency of presentation of bifid or multiple iliopsoas tendons in patients who underwent endoscopic release for internal snapping hip syndrome (ISHS) and to compare both groups. METHODS: A consecutive series of patients with ISHS were treated with endoscopic transcapsular release of the iliopsoas tendon at the central compartment and prospectively followed up. The inclusion criteria were patients with a diagnosis of ISHS with failure of conservative treatment. During the procedure, the presence of a bifid tendon was intentionally looked for. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were evaluated preoperatively and at last follow-up. Four patients presented with a bifid tendon and one patient had 3 tendons. At a minimum of 12 months' follow-up, the presence of snapping recurrence was evaluated and the WOMAC scores were compared between both groups. RESULTS: Among 279 hip arthroscopies, 28 patients underwent central transcapsular iliopsoas tendon release. The mean age was 29.25 years (range, 16 to 65 years; 6 left and 22 right hips). Group 1 included 5 patients with multiple tendons; the remaining patients formed group 2 (n = 23). None of the patients presented with ISHS recurrence. The mean WOMAC score in group 1 was 39 points (95% confidence interval [CI], 26.2 to 55.4 points) preoperatively and 73.6 points (95% CI, 68.4 to 79.6 points) at last follow-up. In group 2 the mean WOMAC score was 47.21 points (95% CI, 44.4 to 58.2 points) preoperatively and 77.91 points (95% CI, 67.8 to 83.4 points) at last follow-up. We identified a bifid tendon retrospectively on magnetic resonance arthrograms in 3 of the 5 cases that were found to have multiple tendons during surgery. None of these were recognized before the procedures. CONCLUSIONS: In this series the surgeon intentionally looked for multiple tendons, which were found in 17.85% of the cases. Clinical results in patients with single- and multiple-tendon snapping seem to be similarly adequate. However, the possibility of a type II error should be considered given the small number of patients. LEVEL OF EVIDENCE: Level IV. PMID- 26051355 TI - Stress Distribution in Superior Labral Complex and Rotator Cuff During In Vivo Shoulder Motion: A Finite Element Analysis. AB - PURPOSE: To quantitatively and qualitatively evaluate the impingement behavior between structures within the glenohumeral joint under simulated abduction external rotation (ABER) motion using finite element analysis. METHODS: Computed tomography (CT) scanning of 1 shoulder in a volunteer was performed at 0 degrees and 120 degrees of shoulder abduction with external rotation (ABER position), followed by magnetic resonance imaging at 0 degrees of abduction. The CT and magnetic resonance images were then imported into a customized software program to undergo 3-dimensional reconstruction followed by finite element modeling of the bone and soft tissue including the upper part of the rotator cuff and glenohumeral labral complex. Glenohumeral motion from 0 degrees to the ABER position was simulated by CT images in 2 different humeral positions. On the basis of simulated humeral motion with respect to the scapula, we measured the stress value on the biceps-labral complex and upper part of the rotator cuff as a consequence of their structural deformation. In addition, we intended to design 2 types of labra--a normal stable labrum and an unstable posterosuperior labrum--to evaluate the geometric alteration and resulting stress change on the posterosuperior labrum against a compressive force from the humeral head and rotator cuff. RESULTS: In the ABER position, the posterosuperior labrum was deformed by the humeral head and interposed posterior part of the rotator cuff. When viewed from the rotator cuff, the posterior part of the rotator cuff came into contact with the posterosuperior labrum as external rotation increased. The measured peak contact stress values were 19.7 MPa and 23.5 MPa for the posterosuperior labrum and the upper rotator cuff, respectively. The stress values for both structures decreased to 5.8 MPa and 18.1 MPa, respectively, in the simulated SLAP model. The root of the long head of the biceps became compressed halfway through the range of motion by the humeral head, especially from the part involving horizontal extension and external rotation, resulting in a high stress of 22.4 MPa. CONCLUSIONS: In this simulated SLAP model, the posterosuperior labrum was medially displaced by the humeral head and upper rotator cuff in the ABER position, causing a functional loss of the spacer effect. CLINICAL RELEVANCE: In SLAP lesions, the posterosuperior labrum loses its ability to function as a spacer in certain positions (especially ABER) and may decrease the important spacer effect between the humerus and the rotator cuff; this may lead to posterosuperior subluxation of the humeral head or rotator cuff abnormalities and tears during repetitive ABER tasks. PMID- 26051356 TI - Enhanced digestion of waste activated sludge using microbial electrolysis cells at ambient temperature. AB - This study examined the effects of the microbial electrolysis cell (MEC) reactions on anaerobic digestion of waste activated sludge from municipal wastewater treatment under ambient temperature conditions (22-23 degrees C). Two lab-scale digesters, a control anaerobic digester and an electrically-assisted digester (EAD - equipped with a MEC bioanode and cathode) were operated under three solids retention times (SRT = 7, 10 and 14 days) at 22.5 +/- 0.5 degrees C. A numerical model was also built by including the MEC electrode reactions in Anaerobic Digestion Model No.1. In experiments, the EAD showed reduced concentration of acetic acid, propionic acid, n-butyric acid and iso-butyric acid. This improved performance of the EAD is thought to be achieved by direct oxidation of the short-chain fatty acids at the bioanode as well as indirect contribution of low acetic acid concentration to enhancing beta-oxidation. The VSS and COD removal was consistently higher in the EAD by 5-10% compared to the control digester for all SRT conditions at 22.5 +/- 0.5 degrees C. When compared to mathematical model results, this additional COD removal in the EAD was equivalent to that which would be achieved with conventional digesters at mesophilic temperatures. The magnitude of electric current in the EAD was governed by the organic loading rate while conductivity and acetic acid concentration showed negligible effects on current generation. Very high methane content (~95%) in the biogas from both the EAD and control digester implies that the waste activated sludge contained large amounts of lipids and other complex polymeric substances compared to primary sludge. PMID- 26051357 TI - High APOBEC3B expression is a predictor of recurrence in patients with low-risk clear cell renal cell carcinoma. AB - PURPOSE: APOBEC3B is a member of the cytosine deaminase family, which converts cytosine to uracil during RNA editing and retrovirus or retrotransposon restriction. Recent evidence has revealed that APOBEC3B-catalyzed genomic DNA deamination could provide genetic fuel for cancer development, metastasis, and even treatment resistance. The aim of this study was to assess the association between APOBEC3B expression and the risk of recurrence after surgery in patients with renal cell carcinoma (RCC). METHODS: We retrospectively enrolled 299 consecutive patients with RCC who underwent nephrectomy at a single center in 2008. Clinicopathologic variables and recurrence-free survival (RFS) were recorded. APOBEC3B expression levels were determined by immunohistochemistry in tumor tissues. Kaplan-Meier method was applied to compare survival curves. Cox regression models were fitted to analyze the effect of prognostic factors on RFS. The Harrell concordance index was calculated to assess predictive accuracy. RESULTS: High APOBEC3B expression was associated with an increased risk of recurrence in patients with clear cell RCC (ccRCC) (P<0.001) rather than in patients with non-ccRCC (P = 0.247). After backward elimination, APOBEC3B expression was identified as an independent prognostic factor for RFS in patients with clear cell histology (P = 0.016). The predictive accuracy of the Leibovich prognostic score was improved when APOBEC3B expression was incorporated. Notably, the improvement in prediction mainly took place in patients with low-risk disease defined by the Leibovich score. CONCLUSIONS: High APOBEC3B expression is an independent predictor of recurrence in patients with ccRCC, and the prognostic value is most prominent in those with low-risk disease. PMID- 26051359 TI - Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases. AB - Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings. PMID- 26051360 TI - Zygotic genome activation and imprinting: parent-of-origin gene regulation in plant embryogenesis. AB - Parent-of-origin dependent gene expression refers to differential activity of alleles inherited from the egg and sperm. In plants, zygotic genome activation (ZGA) and gene imprinting are two examples of this phenomenon, both of which occur during seed development. As its name implies, ZGA is a genome-wide process that occurs in embryos during the first few days after fertilization. Evidence exists that maternal alleles initially predominate during ZGA, although most genes also show some paternal activity. By contrast, imprinting can be defined as a bias in gene expression that lasts beyond the first few days of seed development. Hundreds of imprinted genes have been discovered in the endosperm, and a few have been described in the embryo. This review discusses recent advances in our understanding of the phenomena and mechanisms of ZGA and imprinting in seeds, with an emphasis on embryo development. Important unanswered questions and areas for future research are highlighted. PMID- 26051358 TI - Glycogen synthase kinase-3: a potential preventive target for prostate cancer management. AB - OBJECTIVES: Prostate cancers are the frequently diagnosed cancers in men, and patients with metastatic disease only have 28% chance for 5-year survival. Patients with low-risk tumors are subjected to active surveillance, whereas high risk cases are actively treated. Unfortunately, there is no cure for patients with late-stage disease. Glycogen synthase kinase-3 (GSK-3, alpha and beta) is a protein serine/threonine kinase and has diverse cellular functions and numerous substrates. We sought to summarize all the studies done with GSK-3 in prostate cancers and to provide a prospective direction for future work. METHODS AND MATERIALS: A comprehensive search of the literature on the electronic databases PubMed was conducted for the subject terms of GSK-3 and prostate cancer. Gene mutation and expression information was extracted from Oncomine and COSMIC databases. Case reports were not included. RESULTS: Accumulating evidence indicates that GSK-3alpha is mainly expressed in low-risk prostate cancers and is related to hormone-dependent androgen receptor (AR)-mediated gene expression, whereas GSK-3beta is mainly expressed in high-risk prostate cancers and is related to hormone-independent AR-mediated gene expression. GSK-3 has been demonstrated as a positive regulator in AR transactivation and prostate cancer growth independent of the Wnt/beta-catenin pathway. Different types of GSK 3inhibitors including lithium show promising results in suppressing tumor growth in different animal models of prostate cancer. Importantly, clinical use of lithium is associated with reduced cancer incidence in psychiatric patients. CONCLUSIONS: Taken together, GSK-3 inhibition might be implicated in prostate cancer management as a preventive treatment. PMID- 26051361 TI - Mechanistic Influence of Nanometer Length-Scale Surface Chemistry on DNA Hybridization. AB - Hybridization of surface-immobilized oligonucleotides to their complementary counterparts is central to the rational design of novel nanodevices and DNA sensors. In this study, we have adopted a unified approach of combining sensing experiments with molecular dynamics simulations to characterize the hybridization of a 23 nucleotide long single-strand probe DNA tethered to a gold surface. Experiments indicate significant conformational changes of DNA in close vicinity (~1 nm) of the gold surface upon hybridization and also conformational heterogeneity within hybridized DNA, consistent with simulation results. Simulations show that the conformational heterogeneity on a gold surface arises due to stabilization of surface-adsorbed partial and full duplexes, resulting in impeded hybridization in comparison to what observed on a repulsive surface. Furthermore, these simulations indicate that hybridization could be improved by tuning the nonspecific adsorption on a nanopatterned surface with an optimal patterning length. Simulations were performed on the probe tethered to gold nanodots of varying (2-8 nm) diameter. An improved hybridization of the present probe sequence was only observed for the 6 nm gold dots patterned on a repulsive surface. Results reveal that the 2D nanoconfinement provided by the 6 nm gold dot is optimal for reducing conformational heterogeneity for the specific sequence used in this study. Thus, improved DNA hybridization can be achieved on a gold nanodot patterned repulsive surface, where the optimal dot diameter will depend on the probe length and sequence. In summary, this study provides mechanistic insights onto hybridization on gold and offers a unique method toward improved hybridization on a nanopatterned surface with an optimized patterning length. PMID- 26051362 TI - [Recurrent abdominal crises can have genetic origin]. PMID- 26051363 TI - Hydroxylation of a metal-supported hexagonal boron nitride monolayer by oxygen induced water dissociation. AB - Hydroxylated hexagonal boron nitride (h-BN) nanosheets exhibit potential application in nanocomposites and functional surface coating. Our first principles calculations reveal possible hydroxylation of a h-BN monolayer on a Ni substrate by surface O adatom induced spontaneous dissociation of water molecules. Here one H atom is split from a water molecule by bonding with the O adatom on the B atom and the resulting O-H radical then bonds with an adjacent B atom, which leads to two hydroxyl groups formed on h-BN/Ni. Hydroxylation slightly influences the electronic properties of a Ni-supported h-BN layer. Similar water dissociation and hydroxylation can occur on the surface of O functionalized h-BN/Cu depending on the O adsorption configuration. Metal substrates play an important catalytic role in enhancing the chemical reactivity of O adatoms on h-BN with water molecules through transferring additional charges to them. PMID- 26051364 TI - Evaluation of the RapidHITTM 200 System: A comparative study of its performance with Maxwell((r)) DNA IQTM/Identifiler((r)) Plus/ABI 3500xL workflow. AB - RapidHIT(TM) System is a rapid DNA instrument that is capable of processing forensic samples from extraction through to capillary electrophoresis and profile generation within two hours. Evaluation of the RapidHIT(TM) 200 System was conducted to examine several key performance indicators of the instrument, including reproducibility, contamination, sensitivity, versatility and the possibility of sample re-extraction. Results indicated that the RapidHIT(TM) 200 System was capable of generating high quality DNA profiles which were comparable to those from the standard protocol comprising of Maxwell((r)) 16 DNA IQ(TM) System, Identifiler((r)) Plus and ABI 3500xL. No contamination was detected during the studies. Results also showed that the instrument was able to generate DNA profiles from samples containing lower amounts of DNA (0.5 MUl of blood) albeit with more allele and locus dropouts when compared to the standard protocol. The ability to process blood swabs, blood-stained FTA punches, semen swabs, buccal swabs, product of conception (POC), bone marrow, fingernail clippings and cigarette butts at a good success rate indicated the robustness and versatility of the RapidHIT(TM) 200 System. Furthermore, additional alleles could be recovered via re-analysis of the failed samples using the standard protocol. In summary, our results showed that the RapidHIT(TM) 200 System was able to process casework samples for the purpose of providing rapid intelligence through DNA database searches and reference matching. Confirmative DNA results can be obtained through either concurrent processing of duplicate samples via standard protocol or re-extraction of samples retrieved from the RapidHIT(TM) sample cartridge. PMID- 26051366 TI - Ana Langer: global leader in women's health. PMID- 26051367 TI - Do we need more psoriasis therapies? PMID- 26051368 TI - Valuing the health and contribution of women is central to global development. PMID- 26051365 TI - Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial. AB - BACKGROUND: New therapeutic options are needed for patients with psoriasis. Tofacitinib, an oral Janus kinase inhibitor, is being investigated as a treatment for moderate-to-severe chronic plaque psoriasis. In this study, we aimed to compare two tofacitinib doses with high-dose etanercept or placebo in this patient population. METHODS: In this phase 3, randomised, multicentre, double dummy, placebo-controlled, 12-week, non-inferiority trial, adult patients with chronic stable plaque psoriasis (for >=12 months) who were candidates for systemic or phototherapy and had a Psoriasis Area and Severity Index (PASI) score of 12 or higher and a Physician's Global Assessment (PGA) of moderate or severe, and had failed to respond to, had a contraindication to, or were intolerant to at least one conventional systemic therapy, were enrolled from 122 investigational dermatology centres worldwide. Eligible patients were randomly assigned in a 3:3:3:1 ratio to receive tofacitinib 5 mg or 10 mg twice daily at about 12 h intervals, etanercept 50 mg subcutaneously twice weekly at about 3-4 day intervals, or placebo. Randomisation was done by a computer-generated randomisation schedule, and all patients and study personnel were masked to treatment assignment. The co-primary endpoints were the proportion of patients at week 12 with at least a 75% reduction in the PASI score from baseline (PASI75 response) and the proportion of patients achieving a PGA score of "clear" or "almost clear" (PGA response), analysed in the full analysis set (all patients who were randomised and received at least one dose of study drug). This study is registered with ClinicalTrials.gov, number NCT01241591. FINDINGS: Between Nov 29, 2010, and Sept 13, 2012, we enrolled 1106 eligible adult patients with chronic plaque psoriasis and randomly assigned them to the four treatment groups (330 to tofacitinib 5 mg twice daily, 332 to tofacitinib 10 mg twice daily, 336 to etanercept 50 mg twice weekly, and 108 to placebo). Of these patients, 1101 actually received their assigned study medication (329 in the tofactinib 5 mg group, 330 in the tofacitinib 10 mg group, 335 in the etanercept group, and 107 in the placebo group). At week 12, PASI75 responses were recorded in 130 (39.5%) of 329 patients in the tofacitinib 5 mg group, 210 (63.6%) of 330 in the tofacitinib 10 mg group, 197 (58.8%) of 335 in the etanercept group, and six (5.6%) of 107 in the placebo group. A PGA response was achieved by 155 (47.1%) of 329 patients in the tofacitinib 5 mg group, 225 (68.2%) of 330 in the tofacitinib 10 mg group, 222 (66.3%) of 335 in the etanercept group, and 16 (15.0%) of 107 in the placebo group. The rate of adverse events was similar across the four groups, with serious adverse events occurring in seven (2%) of 329 patients in the tofacitinib 5 mg group, five (2%) of 330 in the tofacitinib 10 mg group, seven (2%) of 335 in the etanercept group, and two (2%) of 107 in the placebo group. Three (1%) of 329 patients in the tofacitinib 5 mg group, ten (3%) of 330 in the tofacitinib 10 mg group, 11 (3%) of 335 in the etanercept group, and four (4%) of 107 patients in the placebo group discontinued their assigned treatment because of adverse events. INTERPRETATION: In patients with moderate-to-severe plaque psoriasis, the 10 mg twice daily dose of tofacitinib was non-inferior to etanercept 50 mg twice weekly and was superior to placebo, but the 5 mg twice daily dose did not show non-inferiority to etanercept 50 mg twice weekly. The adverse event rates over 12 weeks were similar for tofacitinib and etanercept. This study indicates that in the future tofacitinib could provide a convenient and well-tolerated therapeutic option for patients with moderate-to-severe plaque psoriasis. FUNDING: Pfizer Inc. PMID- 26051369 TI - Making women count. PMID- 26051370 TI - Women and Health: the key for sustainable development. PMID- 26051371 TI - Promoting women's health for sustainable development. PMID- 26051372 TI - Determinants of out-of-pocket health expenditure on children: an analysis of the 2004 Pelotas Birth Cohort. AB - BACKGROUND: The present study aimed to examine the impact of socioeconomic, demographic, and health status-related factors on out-of-pocket expenditure on health care for children. METHODS: Data were obtained from a birth cohort study conducted in the city of Pelotas, state of Rio Grande do Sul (RS), southern Brazil, in 2004. The final sample is a result of adjusts made in order to keep in the analysis only those that attended to 3 follow-ups (at 12, 24 and 48 months of age). Estimates were carried out using the Panel Data Tobit Model with random effects. RESULTS: The study showed that expenditure on medicines was 20 % less likely in those considered healthy children by their mothers and, if there was any expenditure with healthy children, the expected expenditure was reduced by 58 %. A 1 % increase in household income increased the expected expenditure on medicines by 16 %, and by 23 % in children with private health insurance coverage. CONCLUSIONS: All types of health care expenditures examined were higher for children covered by private health insurance. Although total health care expenditure was higher for children of better-off families, it represented a lower share of these families' income evidencing income inequality in health care expenditures. PMID- 26051373 TI - Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life. AB - Kallmann syndrome (KS) patients carrying FGFR1 mutations can transmit the disorder to their offspring as can asymptomatic female carriers of mutations in KAL1. We describe for the first time two cases in which KS was suspected during fetal life because of the family context and malformation detection by fetal ultrasound: syndactyly or unilateral renal agenesis in subjects with respectively FGFR1 and KAL1 mutations. In relevant family history, ultrasound monitoring can detect KS associated signs before birth and thus enable neonatal diagnosis and early management. These observations also underline the importance of genetic counselling for patients who may transmit KS to their offspring. PMID- 26051375 TI - Erythropoietin in Traumatic Brain Injury: An Answer Will Come Soon. PMID- 26051374 TI - Parallel subfunctionalisation of PsbO protein isoforms in angiosperms revealed by phylogenetic analysis and mapping of sequence variability onto protein structure. AB - BACKGROUND: PsbO, the manganese-stabilising protein, is an indispensable extrinsic subunit of photosystem II. It plays a crucial role in the stabilisation of the water-splitting Mn4CaO5 cluster, which catalyses the oxidation of water to molecular oxygen by using light energy. PsbO was also demonstrated to have a weak GTPase activity that could be involved in regulation of D1 protein turnover. Our analysis of psbO sequences showed that many angiosperm species express two psbO paralogs, but the pairs of isoforms in one species were not orthologous to pairs of isoforms in distant species. RESULTS: Phylogenetic analysis of 91 psbO sequences from 49 land plant species revealed that psbO duplication occurred many times independently, generally at the roots of modern angiosperm families. In spite of this, the level of isoform divergence was similar in different species. Moreover, mapping of the differences on the protein tertiary structure showed that the isoforms in individual species differ from each other on similar positions, mostly on the luminally exposed end of the beta-barrel structure. Comparison of these differences with the location of differences between PsbOs from diverse angiosperm families indicated various selection pressures in PsbO evolution and potential interaction surfaces on the PsbO structure. CONCLUSIONS: The analyses suggest that similar subfunctionalisation of PsbO isoforms occurred parallelly in various lineages. We speculate that the presence of two PsbO isoforms helps the plants to finely adjust the photosynthetic apparatus in response to variable conditions. This might be mediated by diverse GTPase activity, since the isoform differences predominate near the predicted GTP binding site. PMID- 26051376 TI - Molecular Modeling, Synthesis and Pharmacological Evaluation of 1,3,4- Thiadiazoles as Anti-inflammatory and Analgesic Agents. AB - A series of novel substituted 2-amino-5-(1-(4-isobutylphenyl)ethyl)-1,3,4 thiadiazoles were designed, synthesized and evaluated as anti-inflammatory and analgesic agents. Compounds were characterized by elemental and spectroscopic analysis. Compounds possessing significant activities were screened for ulcerogenic activity. Compound-5 (2-(4-isobutylphenyl)-N-(5-(1-(4- isobutylphenyl)ethyl)-1,3,4-thiadiazol-2-yl)-propanamide) produces significant in vitro antiinflammatory activity (72.5%) as compared to ibuprofen (47.7%), while compound-3f (2-(Ncyclohexyl- N-methylamino)-N-(5-(1-(4-isobutylphenyl)-ethyl) 1,3,4-thiadiazol-2-yl)-acetamide) showed 64.1% activity. Results indicate that compound-4 (N-(5-(1-(4-isobutyl-phenyl)-ethyl)-1,3,4-thiadiazol-2-yl)-acetamide) exhibited highest analgesic activity (69.8%), where as compound-5 possessed 65.5% activity. Structure based drug design was also investigated to reveal the mechanism of action and specificity of our compounds against COX-2 enzyme. Anti inflammatory activity and ulcerogenic potential were in agreement with the molecular modeling studies carried out on cycloxygenase enzyme. PMID- 26051377 TI - Patients With Suspected Coronary Artery Disease Referred for Examinations in the Era of Coronary Computed Tomography Angiography. AB - Invasive coronary angiography (ICA) is the gold standard in the diagnosis of coronary artery disease (CAD), however, associated with rare but severe complications. Patients with a high pretest risk should be referred directly for ICA, whereas a noninvasive strategy is recommended in the remaining patients. In the setting of a university hospital, we investigated the pattern of diagnostic tests used in daily clinical practice. During a 1-year period, consecutive patients with new symptoms suggestive of CAD and referred for exercise stress test, coronary computed tomography angiography (CCTA), single-photon emission computed tomography (SPECT), or ICA qualified for inclusion. The patients were followed for 1 year, and additional downstream diagnostic tests and need of coronary revascularization were registered. A total of 1,069 patients were included. A noninvasive test was the first examination in 797 patients (75%; exercise stress test in 37, CCTA in 450, and SPECT in 310), whereas 272 (25%) were referred directly to ICA. The ICA group had a significant higher pretest probability for CAD, and the percentage of patients with evidence of significant CAD was 31% (84 of 272 patients), whereas 18% (144 of 797 patients) in the noninvasive group (p <0.0001). In the comparison between CCTA and SPECT, there were no significant differences in downstream testing (16% [72 of 444 patients] vs 17% [53 of 310], p = 0.55), and revascularization rate (20% [14 of 69 patients with positive findings] vs 9% [6 of 67], p = 0.09). In conclusion, a noninvasive diagnostic test was chosen as the first test in 3 of 4 patients. Of the patients referred directly for noninvasive examination, 1/5 had significant CAD, whereas 1/3 of those for invasive examination. PMID- 26051378 TI - The Benefit from Anti-Inflammatory Properties of Colchicine in Cardiovascular Diseases. PMID- 26051379 TI - Meta-Analysis of Randomized Controlled Trials Comparing Risk of Major Adverse Cardiac Events and Bleeding in Patients With Prasugrel Versus Clopidogrel. AB - The use of prasugrel in patients with coronary artery disease (CAD) has been associated with decreased major adverse cardiac events (MACEs) compared with clopidogrel but with an increased risk of bleeding. However, it remains unclear if the risks of bleeding outweigh those of MACEs in patients on prasugrel treatment. We systematically reviewed randomized controlled trials comparing prasugrel with clopidogrel in patients with CAD. We performed a literature search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trial databases from inception to November 25, 2014, and reviewed the reference lists of retrieved articles. A comparative estimate was made for the combined rates of MACEs and bleeding from the same trials in the framework of this meta-analysis and expressed as odds ratios (ORs) and 95% confidence intervals (CIs) in both random- and fixed-effects models. Nine studies involving 25,214 patients were included in our meta-analysis. In both the random- and fixed-effects models, the risks of MACEs outweighed those of major bleeding (OR 7.48, 95% CI 3.75 to 14.94, p <0.0001, random effects) and of minor bleeding (OR 3.77, 95% CI 1.73 to 8.22, p = 0.009, random effects). Results were corroborated in a standard-dose clopidogrel subgroup analysis (OR 7.46, 95% CI 3.54 to 15.68, p <0.0001, and OR 6.44, 95% CI 2.80 to 14.80, p <0.0001, random effects, respectively). In conclusion, despite the increased risk of bleeding associated with prasugrel treatment compared with clopidogrel, the risk of MACEs far outweighed the risk of bleeding. PMID- 26051380 TI - In operando study of the high voltage spinel cathode material LiNi(0.5)Mn(1.5)O4 using two dimensional full-field spectroscopic imaging of Ni and Mn. AB - LiNi0.5Mn1.5O4 spinel cathode was studied during the first discharge cycle using combined full field Transmission X-ray Microscopy (TXM) and X-ray Absorption Near Edge Structure Spectroscopy (XANES) techniques to follow the chemical phase transformation as well as the microstructural evolution of cathode materials upon operation within an electrochemical cell. The spatial distribution and electrochemical process of the spinel material with spherical granules of 30 MUm and 3 MUm crystallite size was investigated. The spectroscopic imaging of the cathode within field of view of 40 * 32 MUm(2) and spatial resolution of 40 nm has revealed an increase of the LiNi0.5Mn1.5O4 granule size during lithiation providing an insight into the effect of the particle size and morphology on the electrochemical process. The chemical elemental distribution and the content of the different oxidation states of the two absorbing elements (Ni and Mn) have been determined in operando from the XANES imaging. A gradual increase in the content of the oxidation state Mn(3+) from 8% up to 64% has been recorded during the discharge from 5 V to 2.7 V. The study of the local oxidation reduction behavior of Mn(3+) reveals a reversibility aspect in the local electrochemical reaction of Mn(4+) toward Mn(3+) in areas located in the center of the aggregate as well as in areas closed to the electrolyte. During the discharge process, a mixture of Mn(3+) and Mn(4+) has been detected while only single electron valence states have been found in the case of Ni. Probing the chemical changes during the discharge using two-dimensional XANES reveals spatial differences in the electrochemical activities of the two absorbing elements Ni and Mn. PMID- 26051381 TI - The emperor's new dystrophin: finding sense in the noise. AB - Targeted dystrophin exon removal is a promising therapy for Duchenne muscular dystrophy (DMD); however, dystrophin expression in some reports is not supported by the associated data. As in the account of 'The Emperor's New Clothes', the validity of such claims must be questioned, with critical re-evaluation of available data. Is it appropriate to report clinical benefit and induction of dystrophin as dose dependent when the baseline is unclear? The inability to induce meaningful levels of dystrophin does not mean that dystrophin expression as an end point is irrelevant, nor that induced exon skipping as a strategy is flawed, but demands that drug safety and efficacy, and study parameters be addressed, rather than questioning the strategy or the validity of dystrophin as a biomarker. PMID- 26051382 TI - Local and afferent synaptic pathways in the striatal microcircuitry. AB - The striatum is the largest structure of the basal ganglia, receiving synaptic input from multiple regions including the neocortex, thalamus, external globus pallidus, and midbrain. Earlier schemes of striatal connectivity presented a relatively simple architecture which included primarily excitatory input from the neocortex, dopaminergic input from the midbrain, and intrastriatal connectivity between projection neurons and a small number of interneuron types. In recent years this picture has changed, largely due to the introduction of new experimental methods to reveal cell types and their connectivity. The striatal microcircuit is now considered to consist of several newly defined neuron types which are intricately and selectively interconnected. New afferent pathways have been discovered, as well as novel properties of previously known afferents such as the midbrain dopaminergic inputs. In this review we aim to provide a summary of these recent discoveries. PMID- 26051383 TI - Can we observe epigenetic effects on human brain function? AB - Imaging genetics has identified many contributions of DNA sequence variation to individual differences in brain function, behavior, and risk for psychopathology. Recent studies have extended this work beyond the genome by mapping epigenetic differences, specifically gene methylation in peripherally assessed DNA, onto variability in behaviorally and clinically relevant brain function. These data have generated understandable enthusiasm for the potential of such research to illuminate biological mechanisms of risk. We use our research on the effects of genetic and epigenetic variation in the human serotonin transporter on brain function to generate a guardedly optimistic opinion that the available data encourage continued research in this direction, and suggest strategies to promote faster progress. PMID- 26051385 TI - Pregabalin to treat ciguatera fish poisoning. PMID- 26051384 TI - 'Activity-silent' working memory in prefrontal cortex: a dynamic coding framework. AB - Working memory (WM) provides the functional backbone to high-level cognition. Maintenance in WM is often assumed to depend on the stationary persistence of neural activity patterns that represent memory content. However, accumulating evidence suggests that persistent delay activity does not always accompany WM maintenance but instead seems to wax and wane as a function of the current task relevance of memoranda. Furthermore, new methods for measuring and analysing population-level patterns show that activity states are highly dynamic. At first glance, these dynamics seem at odds with the very nature of WM. How can we keep a stable thought in mind while brain activity is constantly changing? This review considers how neural dynamics might be functionally important for WM maintenance. PMID- 26051386 TI - Vitamin D Deficiency May Be Associated with a More Rapid Decline in CD4 Cell Count to <350 Cells/uL in Untreated HIV-Infected Adults. AB - OBJECTIVES: Low vitamin D status is associated with both increased disease progression and mortality in people with HIV receiving antiretroviral therapy (ART). However, data are lacking on effects of vitamin status on disease progression and CD4 cell count in people with HIV not receiving ART. We therefore evaluated effects of vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] <50 nmol/L) on the decline in CD4 cell count in people with HIV not receiving ART. METHODS: A retrospective cohort study including people with HIV not receiving ART and with an HIV viral load of >400 copies/mL. A proportional hazards model was fitted to evaluate the effect of vitamin D status on the time to decline in CD4 cell count (<350 cells/uL), adjusted for nadir CD4 cell count, time since HIV diagnosis, previous ART use and HIVviral load. RESULTS: 224 participants fulfilled the inclusion criteria and were followed for a median of 11 months (range or IQR). At baseline, 42% had vitamin D deficiency and the median (interquartile range) CD4 cell count was 502 (355, 662) cells/uL. HIV infected individuals with vitamin D deficiency had an increased risk of CD4 decline to <350 cells/uL [Hazard ratio (HR) 2.15 (95% CI 1.05, 4.38, p=0.04)]. CONCLUSION: Vitamin D deficiency was independently associated with an increased time to decline in CD4 cell count to <350 cells/uL, but not with a change in CD4 overall in people with HIV not receiving ART. PMID- 26051387 TI - Restriction Factors in HIV-1 Disease Progression. AB - About 35 million people worldwide were living with HIV-1 at the end of 2013 and over 25 million have already died of AIDS. AIDS patients show high variability in the speed of disease progression in the absence of treatment. While certain immunological traits have been shown to correlate with accelerated or slowed progression in some subjects, including slow progressors, factors controlling HIV 1 replication and disease kinetics remain largely enigmatic. The importance of T lymphocytes and of protective HLA-alleles is undeniable, but not sufficient to explain every attenuated phenotype. A thorough understanding of HIV-1 infection control in these patient subsets may help the development of novel strategies for treatment and prevention. Restriction factors are type I interferon-induced specialized cellular proteins that block viruses at different steps of their life cycle. TRIM5alpha, Mx2/MxB, TRIM22/Staf50, SAMHD1, p21/CDKN1, tetherin/BST2/CD137, APOBEC3G and APOBEC3F have all been proposed to inhibit HIV 1, often with gene variant- or cellular context-specificity. Recent evidence highlights their possible implication in AIDS disease progression. In this review, we depict their restrictive activity against HIV-1 and recapitulate the latest data on their potential role in vivo, in both normal and slow progressors. PMID- 26051388 TI - High-Throughput Determination of Mercury in Tobacco and Mainstream Smoke from Little Cigars. AB - A method was developed that utilizes a platinum trap for mercury from mainstream tobacco smoke, which represents an improvement over traditional approaches that require impingers and long sample preparation procedures. In this approach, the trapped mercury is directly released for analysis by heating the trap in a direct mercury analyzer. The method was applied to the analysis of mercury in the mainstream smoke of little cigars. The mercury levels in little cigar smoke obtained under Health Canada Intense smoking machine conditions ranged from 7.1 * 10(-3) to 1.2 * 10(-2) mg/m(3). These air mercury levels exceed the chronic inhalation minimal risk level corrected for intermittent exposure to metallic mercury (e.g., 1 or 2 h per day, 5 days per week) determined by the Agency for Toxic Substances and Disease Registry. Multivariate statistical analysis was used to assess associations between mercury levels and little cigar physical design properties. Filter ventilation was identified as the principal physical parameter influencing mercury concentrations in mainstream little cigar smoke generated under ISO machine smoking conditions. With filter ventilation blocked under Health Canada Intense smoking conditions, mercury concentrations in tobacco and puff number (smoke volume) were the primary physical parameters that influenced mainstream smoke mercury concentrations. PMID- 26051389 TI - Nitrogen-doped, thiol-functionalized carbon dots for ultrasensitive Hg(II) detection. AB - Nitrogen-doped, PEGylated carbon dots (C-dots) have been synthesized for the detection of mercury ions (Hg(2+)). The detection limit was found to be 6.8 nM. However, upon functionalization with dithiothreitol (DTT), it reached to as low as 18 pM. The C-dots-Hg(2+) system was also able to efficiently detect biothiols. PMID- 26051391 TI - Factors Associated With Efficacy of Nurse-led Bowel Training of Patients With Chronic Constipation. AB - BACKGROUND & AIMS: It is not clear whether nurse-led bowel training (NBT), an individually tailored biofeedback strategy designed to improve the physiological process of defecation by operant conditioning and trial and error learning, is effective for patients with chronic constipation. We assessed the ability of NBT to reduce symptoms and increase quality of life in patients with constipation at a large tertiary medical center. METHODS: We performed a retrospective analysis of data from 347 patients (median age, 50 years) who underwent a median 3 sessions of NBT for chronic constipation from January 2011 through December 2013 at St Marks Hospital in the United Kingdom. The NBT comprised a combination of sensory retraining, pelvic floor conditioning, and advice on diet and toileting behavior. Data on patient demographics (age, sex, type of constipation) were collected alongside their assessments of constipation, which were based on Patient Assessment of Constipation Quality of Life (PAC-QoL) and patient satisfaction scores. We performed binary logistic regression analysis. Each variable was tested first at the univariate level; those with significance (P < .10) were included in a multivariate model. RESULTS: At the end of NBT, 62.5% of the patients (217/347) reported reduced symptoms, and 40.2% of the patients (41/102) reported a reduction of at least 1 point on the PAC-QoL score. The mean PAC-QoL scores before and after NBT were 2.42 and 1.41, respectively (P = .001). Multivariate analysis demonstrated that increasing age (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.02-2.87; P = .042), greater number of sessions (OR, 4.14; 95% CI, 2.09-8.20; P < .001), and non-irrigation (OR, 4.39; 95% CI, 1.89-10.19; P = .001) were independent predictors of patient satisfaction. CONCLUSIONS: Data collected immediately after patients with chronic constipation received NBT indicate that it is an effective treatment for most patients. Older patients with dyssynergic defecation benefit most from at least 4 sessions. PMID- 26051390 TI - Primary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management. AB - Primary sclerosing cholangitis (PSC) is a premalignant biliary tract disease that confers a significant risk for the development of cholangiocarcinoma (CCA). The chronic biliary tract inflammation of PSC promotes pro-oncogenic processes such as cellular proliferation, induction of DNA damage, alterations of the extracellular matrix, and cholestasis. The diagnosis of malignancy in PSC can be challenging because inflammation-related changes in PSC may produce dominant biliary tract strictures mimicking CCA. Biomarkers such as detection of methylated genes in biliary specimens represent noninvasive techniques that may discriminate malignant biliary ductal changes from PSC strictures. However, conventional cytology and advanced cytologic techniques such as fluorescence in situ hybridization for polysomy remain the practice standard for diagnosing CCA in PSC. Curative treatment options of malignancy arising in PSC are limited. For a subset of patients selected by using stringent criteria, liver transplantation after neoadjuvant chemoradiation is a potential curative therapy. However, most patients have advanced malignancy at the time of diagnosis. Advances directed at identifying high-risk patients, early cancer detection, and development of chemopreventive strategies will be essential to better manage the cancer risk in this premalignant disease. A better understanding of dysplasia definition and especially its natural history is also needed in this disease. Herein, we review recent developments in our understanding of the risk factors, pathogenic mechanisms of PSC associated with CCA, as well as advances in early detection and therapies. PMID- 26051392 TI - Level of Fecal Calprotectin Correlates With Endoscopic and Histologic Inflammation and Identifies Patients With Mucosal Healing in Ulcerative Colitis. AB - BACKGROUND & AIMS: In patients with ulcerative colitis (UC), mucosal healing is an important goal of treatment. However, mucosal healing is difficult to determine on the basis of clinical evaluation alone, and endoscopy is uncomfortable and can cause complications. Fecal calprotectin (FC) is a marker of inflammation, and its levels have been associated with disease activity. We investigated the association between level of FC and mucosal healing and clinical disease activity in patients with UC. METHODS: We performed an observational cross-sectional study of 120 patients with active or inactive UC who underwent sigmoidoscopy at Copenhagen University Hospital Hvidovre from September 2012 through 2014. Endoscopic inflammation was evaluated by using the Mayo Endoscopic Score (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and histologic inflammatory activity by a slightly modified Harpaz Index, which measures acute inflammation. The Partial Mayo Score was used to measure the clinical disease activity. RESULTS: A cutoff level of FC of 192 mg/kg identified patients with endoscopic evidence of mucosal healing, which was based on the MES and UCEIS, with positive predictive values of 0.71 and 0.65, respectively; negative predictive values were 0.90 and 0.93, respectively. A cutoff level of 171 mg/kg identified patients with histologic evidence of mucosal healing, with positive predictive value of 0.75 and negative predictive value of 0.90. Levels of FC increased significantly with increases in endoscopic and histologic disease activity. There was high concordance between MES and UCEIS as well as between MES or UCEIS and histologic inflammatory activity. The histologic activity index had an interobserver variation of 4.35%. CONCLUSIONS: Level of FC identifies patients with UC who have endoscopic and histologic features of mucosal healing and correlates with endoscopic and histologic inflammatory activity. The UCEIS seems to be as accurate as the MES in identifying patients with mucosal healing and as easy to use. The histologic activity index had a high concordance with recognized endoscopic score systems. PMID- 26051393 TI - Caution About Overinterpretation of Number of Reflux Episodes in Reflux Monitoring for Refractory Gastroesophageal Reflux Disease. PMID- 26051394 TI - [Evolution of cardiovascular risk factors in patients undergoing percutaneous coronary intervention]. AB - AIM: Controlling cardiovascular risk factors (CVRF) is important for the outcome of interventional practices (percutaneous coronary intervention [PCI]) in ischemic heart disease. The aim is to determine the evolution of the CVRF 6 months after the intervention and their relationship with new events. METHOD: A descriptive study was conducted on a case series. The variables recorded were: age, sex and chronic kidney disease (CKD), as well as total (TC) and HDL cholesterol, systolic (SBP) and diastolic blood pressure (DBP), smoking habit, and body mass index (BMI), before PCI and after 6 months. The occurrence of death or new PCI during the follow-up was considered an independent variable in a logistic regression analysis. A P<.05 was assumed significant. RESULTS: A total of 222 cases (75.2% males) were included, with a mean age of 70.2 (SD 11.9) years, of whom 57.7% were hypertensive patients, 55.9% had hyperlipidemia, 50.4% were smokers or ex-smokers, and 28.2% were diabetics. After 6 months, 5% died, and 15.3% needed a new PCI, while 33% of the sample had all the CVRF considered. Decreases were observed in SBP (-3.3 mmHg), DBP (-2.6 mmHg), and TC (-35.2mg/dl). The emergence of new event was associated with age (OR: 1.06; P=.003) and CKD (OR: 3.7; P=.04). CONCLUSIONS: There is a high prevalence of CVRF. After 6 months, there was a decrease in blood pressure and TC, although incomplete control of CVRF was found. One fifth of the patients had an event in that period, showing association with age and CKD. PMID- 26051395 TI - [Suicide in nurses. The risk is real]. PMID- 26051396 TI - [Ultrasound-guided peripheral catheterization]. AB - BACKGROUND: Peripheral catheterization is a technique that can be difficult in some patients. Some studies have recently described the use of ultrasound to guide the venous catheterization. OBJECTIVE: To describe the success rate, time required, complications of ultrasound-guided peripheral venous catheterization. and patients and professionals satisfaction METHODS: The search was performed in databases (Medline-PubMed, Cochrane Library, CINAHL and Cuiden Plus) for studies published about ultrasound-guided peripheral venous catheterization performed on patients that provided results on the success of the technique, complications, time used, patient satisfaction and the type of professional who performed the technique. RESULTS: A total of 21 studies were included. Most of them get a higher success rate 80% in the catheterization ecoguide and time it is not higher than the traditional technique. The Technical complications analyzed were arterial puncture rates and lower nerve 10%. In all studies measuring and comparing patient satisfaction in the art ecoguide is greater. Various professional groups perform the technique. CONCLUSIONS: The use of ultrasound for peripheral pipes has a high success rate, complications are rare and the time used is similar to that of the traditional technique. The technique of inserting catheters through ultrasound may be learned by any professional group performing venipuncture. Finally, it gets underscores the high patient satisfaction with the use of this technique. PMID- 26051397 TI - [Study of knowledge in cardiopulmonary resuscitation and automated external defibrillation in sports instructors of public sport centers in Asturias (Spain)]. AB - OBJECTIVE: A study was conducted to determine the level of knowledge about cardiopulmonary resuscitation and automated external defibrillation (AED) in sport instructors working in public sport centers in Asturias. METHODS: A cross sectional study was conducted on sports instructors in May 2014, by completing a self-administered questionnaire on cardiopulmonary resuscitation and use of AED, with 25 items and four possible answers, only one valid, divided into five categories (emergency medical system in Asturias, initial assessment, circulation,airway and use of AED). Age, gender, work experience as sports instructor, previous training courses, education and training and employment contract were studied as epidemiological variables. RESULTS: A total 26 questionnaires (52%) were collected in public sports centers, and 84% of total responses were correct. It should be emphasized that among the wrong answers, 42.30% did not know what was the first action in a cardiac arrest, and 36.62% did not know how to perform a complete cardiopulmonary resuscitation if the person affected had a perioral injury, with 46.15% not knowing how to respond to a cardiac arrest due to drowning. CONCLUSIONS: It is recommended to include the management of cardiac arrest in their workplace in the training plans and the continuing education of sports instructors, at least every two years, according to national laws and laws from Asturias, including also training on the use and management of AED. PMID- 26051398 TI - Improvement of spatial learning by facilitating large-conductance calcium activated potassium channel with transcranial magnetic stimulation in Alzheimer's disease model mice. AB - Transcranial magnetic stimulation (TMS) is fragmentarily reported to be beneficial to Alzheimer's patients. Its underlying mechanism was investigated. TMS was applied at 1, 10 or 15 Hz daily for 4 weeks to young Alzheimer's disease model mice (3xTg), in which intracellular soluble amyloid-beta is notably accumulated. Hippocampal long-term potentiation (LTP) was tested after behavior. TMS ameliorated spatial learning deficits and enhanced LTP in the same frequency dependent manner. Activity of the large conductance calcium-activated potassium (Big-K; BK) channels was suppressed in 3xTg mice and recovered by TMS frequency dependently. These suppression and recovery were accompanied by increase and decrease in cortical excitability, respectively. TMS frequency-dependently enhanced the expression of the activity-dependently expressed scaffold protein Homer1a, which turned out to enhance BK channel activity. Isopimaric acid, an activator of the BK channel, magnified LTP. Amyloid-beta lowering was detected after TMS in 3xTg mice. In 3xTg mice with Homer1a knocked out, amyloid-beta lowering was not detected, though the TMS effects on BK channel and LTP remained. We concluded that TMS facilitates BK channels both Homer1a-dependently and independently, thereby enhancing hippocampal LTP and decreasing cortical excitability. Reduced excitability contributed to amyloid-beta lowering. A cascade of these correlated processes, triggered by TMS, was likely to improve learning in 3xTg mice. PMID- 26051399 TI - Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence. AB - An effort has been mounted to understand the mechanisms of alcohol dependence in a way that may allow for greater efficacy in treatment. It has long been suggested that drugs of abuse seize fundamental reward pathways and disrupt homeostasis to produce compulsive drug seeking behaviors. Ghrelin, an endogenous hormone that affects hunger state and release of growth hormone, has been shown to increase alcohol intake following administration, while antagonists decrease intake. Using rodent models of dependence, the current study examined the effects of two ghrelin receptor antagonists, [DLys3]-GHRP-6 (DLys) and JMV2959, on dependence-induced alcohol self-administration. In two experiments adult male C57BL/6J mice and Wistar rats were made dependent via intermittent ethanol vapor exposure. In another experiment, adult male C57BL/6J mice were made dependent using the intragastric alcohol consumption (IGAC) procedure. Ghrelin receptor antagonists were given prior to voluntary ethanol drinking. Ghrelin antagonists reduced ethanol intake, preference, and operant self-administration of ethanol and sucrose across these models, but did not decrease food consumption in mice. In experiments 1 and 2, voluntary drinking was reduced by ghrelin receptor antagonists, however this reduction did not persist across days. Despite the transient effects of ghrelin antagonists, the drugs had renewed effectiveness following a break in administration as seen in experiment 1. The results show the ghrelin system as a potential target for studies of alcohol abuse. Further research is needed to determine the central mechanisms of these drugs and their influence on addiction in order to design effective pharmacotherapies. PMID- 26051401 TI - Maternal lipopolysaccharide treatment differentially affects 5-HT(2A) and mGlu2/3 receptor function in the adult male and female rat offspring. AB - Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. However, it is still not fully understood which biochemical mechanisms are responsible for the emergence of neuropsychiatric symptoms following prenatal immune activation. The serotonin (5 hydroxytryptamine, 5-HT) and glutamate system have prominently been associated with the schizophrenia pathophysiology but also with the mechanism of antipsychotic drug actions. Here, we investigated the behavioral and cellular response to 5-HT2A and metabotropic glutamate (mGlu)2/3 receptor stimulation in male and female offspring born to lipopolysaccharide (LPS)-treated mothers. Additionally, we assessed protein expression levels of prefrontal 5-HT2A and mGlu2 receptors. Prenatally LPS-exposed male and female offspring showed locomotor hyperactivity and increased head-twitch behavior in response to the 5 HT2A receptor agonist DOI. In LPS-exposed male offspring, the mGlu2/3 receptor agonist LY379268 failed to reduce DOI-induced prepulse inhibition deficits. In LPS-males, the behavioral changes were further accompanied by enhanced DOI induced c-Fos protein expression and an up-regulation of prefrontal 5-HT2A receptors. No changes in either 5-HT2A or mGlu2 receptor protein levels were found in female offspring. Our data support the hypothesis of an involvement of maternal infection during pregnancy contributing, at least partially, to the pathology of schizophrenia. Identifying biochemical alterations that parallel the behavioral deficits may help to improve therapeutic strategies in the treatment of this mental illness. Since most studies in rodents almost exclusively include male subjects, our data further contribute to elucidating possible gender differences in the effects of prenatal infection on 5-HT2A and mGlu2/3 receptor function. PMID- 26051400 TI - Different sites of alcohol action in the NMDA receptor GluN2A and GluN2B subunits. AB - The NMDA receptor is a major target of alcohol action in the CNS, and recent behavioral and cellular studies have pointed to the importance of the GluN2B subunit in alcohol action. We and others have previously characterized four amino acid positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN2A subunit that influence both ion channel gating and alcohol sensitivity. In this study, we found that substitution mutations at two of the four corresponding positions in the GluN2B subunit, F637 and G826, influence ethanol sensitivity and ion channel gating. Because position 826 contains a glycine residue in the native protein, we focused our attention on GluN2B(F637). Substitution mutations at GluN2B(F637) significantly altered ethanol IC50 values, glutamate EC50 values for peak (Ip) and steady-state (Iss) current, and steady state to peak current ratios (Iss:Ip). Changes in apparent glutamate affinity were not due to agonist trapping in desensitized states, as glutamate Iss EC50 values were not correlated with Iss:Ip values. Ethanol sensitivity was correlated with values of both Ip and Iss glutamate EC50, but not with Iss:Ip. Values of ethanol IC50, glutamate EC50, and Iss:Ip for mutants at GluN2B(F637) were highly correlated with the corresponding values for mutants at GluN2A(F636), consistent with similar functional roles of this position in both subunits. These results demonstrate that GluN2B(Phe637) regulates ethanol action and ion channel function of NMDA receptors. However, despite highly conserved M domain sequences, ethanol's actions on GluN2A and GluN2B subunits differ. PMID- 26051402 TI - Simvastatin prevents beta-amyloid(25-35)-impaired neurogenesis in hippocampal dentate gyrus through alpha7nAChR-dependent cascading PI3K-Akt and increasing BDNF via reduction of farnesyl pyrophosphate. AB - Simvastatin (SV) is reported to improve cognition and slow progression of Alzheimer's disease (AD), however underlying mechanism still remains unclear. In hippocampal dentate gyrus (DG), beta-amyloid (Abeta) selectively impairs survival and neurite growth of newborn neurons in the 2(nd) week after birth. The aim of this study was to examine the effects of SV on the impairment of neurogenesis and the spatial cognitive deficits in Abeta25-35 (3 nmol)-injected (i.c.v.) mice (Abeta25-35-mice). Herein, we reported that the SV-treatment (20 mg/kg) on days 2 14 after BrdU-injection could dose-dependently protect the survival and neurite growth of newborn neurons, which was blocked by the alpha7nAChR antagonist MLA or the farnesol (FOH) that can convert to farnesyl pyrophosphate (FPP), but not the alpha4beta2nAChR antagonist DHbetaE. The SV-treatment in Abeta25-35-mice rescued the decline of Akt phosphorylation and increased the ERK1/2 phosphorylation in hippocampus, which was sensitive to MLA and FOH. The PI3K inhibitor LY294002 could abolish the SV-protected neurogenesis in Abeta25-35-mice, but the MEK inhibitor U0126 had no effects. The SV-treatment could correct the decline of hippocampal BDNF concentration in Abeta25-35-mice, which was blocked by MLA and FOH. Using Morris water maze and Y-maze tasks, we further observed that the SV treatment in Abeta25-35-mice could improve their spatial cognitive deficits, which was sensitive to the application of FOH. The results indicate that the SV treatment in Abeta25-35-mice via reduction of FPP can protect neurogenesis through alpha7nAChR-cascading PI3K-Akt and increasing BDNF, which may improve spatial cognitive function. PMID- 26051403 TI - Allosteric mechanisms within the adenosine A2A-dopamine D2 receptor heterotetramer. AB - The structure constituted by a G protein coupled receptor (GPCR) homodimer and a G protein provides a main functional unit and oligomeric entities can be viewed as multiples of dimers. For GPCR heteromers, experimental evidence supports a tetrameric structure, comprised of two different homodimers, each able to signal with its preferred G protein. GPCR homomers and heteromers can act as the conduit of allosteric interactions between orthosteric ligands. The well-known agonist/agonist allosteric interaction in the adenosine A2A receptor (A2AR) dopamine D2 receptor (D2R) heteromer, by which A2AR agonists decrease the affinity of D2R agonists, gave the first rationale for the use of A2AR antagonists in Parkinson's disease. We review new pharmacological findings that can be explained in the frame of a tetrameric structure of the A2AR-D2R heteromer: first, ligand-independent allosteric modulations by the D2R that result in changes of the binding properties of A2AR ligands; second, differential modulation of the intrinsic efficacy of D2R ligands for G protein-dependent and independent signaling; third, the canonical antagonistic Gs-Gi interaction within the frame of the heteromer; and fourth, the ability of A2AR antagonists, including caffeine, to also exert the same allosteric modulations of D2R ligands than A2AR agonists, while A2AR agonists and antagonists counteract each other's effects. These findings can have important clinical implications when evaluating the use of A2AR antagonists. They also call for the need of monitoring caffeine intake when evaluating the effect of D2R ligands, when used as therapeutic agents in neuropsychiatric disorders or as probes in imaging studies. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26051404 TI - Rapid correction of severe hyponatremia after hysteroscopic surgery - a case report. AB - BACKGROUND: One of the most feared complications during hysteroscopic surgery is haemodilution by absorption of distension media. One facet of haemodilution, i.e. hyponatremia, can lead to respiratory distress, pulmonary oedema, as well as cardiovascular collapse. CASE PRESENTATION: Here we report the swift recovery of a 45 year, female, Caucasian patient with acute hyponatremia (74 mEq/L) and pulmonary oedema by the employment of rapid correctional strategies. CONCLUSION: The absorption of irrigation fluids, as presented in this case, is an inevitable side effect of hysteroscopic surgery. Utmost caution should, therefore, be mandatory to reduce and actively monitor fluid intake. If these measures fail, as in the case presented here, it is essential to rapidly eliminate any free water and to normalize the sodium levels. Anecdotal reports of pontine myelinolysis are not in line with literature concerning acute hyponatremia and should, therefore, not obstruct determined action against it. PMID- 26051405 TI - Excited State Relaxation of Neutral and Basic 8-Oxoguanine. AB - 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo) is one of the most common forms of DNA oxidative damage. Recent studies have shown that 8-oxo-dGuo can repair cyclobutane pyrimidine dimers in double-stranded DNA when photoexcited, making its excited state dynamics of particular interest. The excited state lifetimes of 8-oxo-dGuo and its anion have been previously probed using transient absorption spectroscopy; however, more information is required to understand the decay mechanisms. In this work, excited state potential energy surfaces for the neutral and deprotonated forms of the free base, 8-oxoguanine (8-oxo-G), are explored theoretically using multireference methods while the nucleoside is experimentally studied using steady-state fluorescence spectroscopy. It is determined that the neutral species exhibits ultrafast radiationless decay via easy access to conical intersections. The relatively long lifetime for the anion can be explained by the existence of sizable barriers between the Franck-Condon region and two S1/S0 minimum energy conical intersections. A Strickler-Berg analysis of the experimentally measured fluorescence quantum yields and lifetimes is consistent with emission from pipi* excited states in line with theoretical predictions. PMID- 26051407 TI - Contractile function of smooth muscle retained after overnight storage. AB - The functional responses of different overnight-stored in vitro tissues are not clearly described in any animal model. The influence of overnight storage in an animal model may vary between tissue types. We employed Sprague-Dawley rat as our animal model and investigated the functional changes of rat aorta, trachea, bronchus and bladder that were used (i) immediately after surgical removal (denoted as fresh) and (ii) after storage in aerated (95% O2, 5% CO2) Krebs Ringer bicarbonate solution at 4 degrees C for 24 h (denoted as stored). The aorta ring was pre-contracted with phenylephrine, and the functional response of the tissue was investigated using isoprenaline, forskolin and carbachol. Carbachol was also used to increase the tone in trachea, bronchus rings and bladder strips. A clear reduced function of endothelium, with a minor if any effect in the smooth muscle function in rat aorta was observed after overnight storage. The contractile response of overnight-stored rat airway (trachea and bronchus) and bladder smooth muscles remained unchanged. Among all tested tissues, only bronchus showed a reduced response rate (only 40% responded) after storage. In vitro rat tissues that are stored in Krebs solution at 4 degrees C for 24 h can still be used to investigate smooth muscle responses, however, not endothelium-mediated responses for aorta. The influence of overnight storage on different tissues from an animal model (Sprague-Dawley rat in our study) also provides an insight in maximising the use of sacrificed animals. PMID- 26051406 TI - Computational Study of Rh-Catalyzed Carboacylation of Olefins: Ligand-Promoted Rhodacycle Isomerization Enables Regioselective C-C Bond Functionalization of Benzocyclobutenones. AB - The mechanism, reactivity, regio- and enantioselectivity of the Rh-catalyzed carboacylation of benzocyclobutenones are investigated using density functional theory (DFT) calculations. The calculations indicate that the selective activation of the relatively unreactive C1-C2 bond in benzocyclobutenone is achieved via initial C1-C8 bond oxidative addition, followed by rhodacycle isomerization via decarbonylation and CO insertion. Analysis of different ligand steric parameters, ligand steric contour maps, and the computed activation barriers revealed the origin of the positive correlation between ligand bite angle and reactivity. The increase of reactivity with bulkier ligands is attributed to the release of ligand-substrate repulsions in the P-Rh-P plane during the rate-determining CO insertion step. The enantioselectivity in reactions with the (R)-SEGPHOS ligand is controlled by the steric repulsion between the C8 methylene group in the substrate and the equatorial phenyl group on the chiral ligand in the olefin migratory insertion step. PMID- 26051408 TI - Minimally invasive surgery for femoral neck fractures using bone cement infusible hollow-perforated screw in high-risk patients with advanced cancer. AB - OBJECTIVE: Pathologic or osteoporotic femoral neck fractures usually treated with joint replacement surgery rather than joint-preserving surgery because multiple screw fixation has a high risk for fixation failure and nonunion as well as the need for a postoperative protection period. However, joint-preserving surgery might be preferable in high-risk patients with short life expectancy due to advanced disease. Recently introduced hollow-perforated screws are devices for achieving percutaneous fixation by simultaneous injection to the weak bone area through its multiple side holes. We report our experience of surgical treatment of femoral neck fractures by controlled bone cement injection into the femoral head and neck through a modified hollow-perforated screw in patients with advanced cancer. METHODS: We modified the hollow perforated screw with variable placing of screw-side holes as fracture patterns. Polymethylmethacrylate (PMMA) bone cement was injected through the screw holes to control its injection into the selective areas of the femoral head and neck while avoiding the fracture sites. One or two of these were fixed percutaneously in 12 patients who have Garden stage I or II femoral neck fractures in the advanced state of advanced cancer. Seven patients had pathologic fracture by metastatic cancer, but 5 had osteoporotic fractures. RESULTS: Eleven patients died a mean of 4.1 months after surgery and 1 patient lived with ability to walk for 48 months. Sixteen modified hollow perforated-screws and 16 standard cannulated screws were used for fixation. The mean volume of cement injection was 13.8 ml. The complication developed in 4 patients: cement leakage to the hip joint in 2 patients, subtrochanteric fracture in 1 patient (5 months after surgery) and fixation failure in 1 patients (2 months after surgery). Nine patients could walk with or without a walking aid, and all others also could return to the prefracture ambulation state with effective pain relief on the third postoperative day. CONCLUSION: This current surgical method could be useful in patients with short life expectancy because of quick pain relief, early return to ambulation, simple operative procedures and short hospital stay. The modified hollow perforated screw which has a diversity of side hole locations for the regulation of bone cement injection into the planned area seems useful for selective femoral neck fractures. PMID- 26051409 TI - adLIMS: a customized open source software that allows bridging clinical and basic molecular research studies. AB - BACKGROUND: Many biological laboratories that deal with genomic samples are facing the problem of sample tracking, both for pure laboratory management and for efficiency. Our laboratory exploits PCR techniques and Next Generation Sequencing (NGS) methods to perform high-throughput integration site monitoring in different clinical trials and scientific projects. Because of the huge amount of samples that we process every year, which result in hundreds of millions of sequencing reads, we need to standardize data management and tracking systems, building up a scalable and flexible structure with web-based interfaces, which are usually called Laboratory Information Management System (LIMS). METHODS: We started collecting end-users' requirements, composed of desired functionalities of the system and Graphical User Interfaces (GUI), and then we evaluated available tools that could address our requirements, spanning from pure LIMS to Content Management Systems (CMS) up to enterprise information systems. Our analysis identified ADempiere ERP, an open source Enterprise Resource Planning written in Java J2EE, as the best software that also natively implements some highly desirable technological advances, such as the high usability and modularity that grants high use-case flexibility and software scalability for custom solutions. RESULTS: We extended and customized ADempiere ERP to fulfil LIMS requirements and we developed adLIMS. It has been validated by our end-users verifying functionalities and GUIs through test cases for PCRs samples and pre sequencing data and it is currently in use in our laboratories. adLIMS implements authorization and authentication policies, allowing multiple users management and roles definition that enables specific permissions, operations and data views to each user. For example, adLIMS allows creating sample sheets from stored data using available exporting operations. This simplicity and process standardization may avoid manual errors and information backtracking, features that are not granted using track recording on files or spreadsheets. CONCLUSIONS: adLIMS aims to combine sample tracking and data reporting features with higher accessibility and usability of GUIs, thus allowing time to be saved on doing repetitive laboratory tasks, and reducing errors with respect to manual data collection methods. Moreover, adLIMS implements automated data entry, exploiting sample data multiplexing and parallel/transactional processing. adLIMS is natively extensible to cope with laboratory automation through platform-dependent API interfaces, and could be extended to genomic facilities due to the ERP functionalities. PMID- 26051411 TI - Kynurenine Aminotransferases and the Prospects of Inhibitors for the Treatment of Schizophrenia. AB - Schizophrenia is a complex neuropsychiatric disorder with limited treatment options and highly debilitating symptoms, leading to poor personal, social, and occupational outcomes for an afflicted individual. Our current understanding of schizophrenia suggests that dopaminergic and glutamatergic systems have a significant role in the pathogenesis of the disease. Kynurenic acid, an endogenous glutamate antagonist, is found in elevated concentrations in the prefrontal cortex and cerebrospinal fluid of patients with schizophrenia, and this affects neurotransmitter release in a similar manner to previously observed psychotomimetic agents, such as phencyclidine, underlining the molecular basis to its link in schizophrenia pathophysiology. Kynurenic acid is a breakdown product of tryptophan degradation, through a transamination process mediated by kynurenine aminotransferase (KAT) enzymes. There are four KAT homologues reported, all of which are pyridoxal 5'- phosphate-dependent enzymes. All four KAT isoforms have been analysed structurally and biochemically, however the most extensive research is on KAT-I and KAT-II. These two enzymes have been targeted in structure-based drug design as a means of normalising raised kynurenic acid levels. The most potent KAT-I inhibitors and KAT-II inhibitors include phenylhydrazone hexanoic acid derivatives and a pyrazole series of compounds, respectively. KAT inhibitors have been shown to be effective in reducing kynurenic acid production, with accompanying changes in neurotransmitter release and pro-cognitive effects seen in animal studies. This review will discuss the characteristics pertaining to the different KAT isoforms, and will highlight the development of significant KAT inhibitors. KAT inhibitors have great potential for therapeutic application and represent a novel way in treating schizophrenia. PMID- 26051410 TI - Synthesizing qualitative and quantitative evidence on non-financial access barriers: implications for assessment at the district level. AB - INTRODUCTION: A key element of the global drive to universal health coverage is ensuring access to needed health services for everyone, and to pursue this goal in an equitable way. This requires concerted efforts to reduce disparities in access through understanding and acting on barriers facing communities with the lowest utilisation levels. Financial barriers dominate the empirical literature on health service access. Unless the full range of access barriers are investigated, efforts to promote equitable access to health care are unlikely to succeed. This paper therefore focuses on exploring the nature and extent of non financial access barriers. METHODS: We draw upon two structured literature reviews on barriers to access and utilization of maternal, newborn and child health services in Ghana, Bangladesh, Vietnam and Rwanda. One review analyses access barriers identified in published literature using qualitative research methods; the other in published literature using quantitative analysis of household survey data. We then synthesised the key qualitative and quantitative findings through a conjoint iterative analysis. RESULTS: Five dominant themes on non-financial access barriers were identified: ethnicity; religion; physical accessibility; decision-making, gender and autonomy; and knowledge, information and education. The analysis highlighted that non-financial factors pose considerable barriers to access, many of which relate to the acceptability dimension of access and are challenging to address. Another key finding is that quantitative research methods, while yielding important findings, are inadequate for understanding non-financial access barriers in sufficient detail to develop effective responses. Qualitative research is critical in filling this gap. The analysis also indicates that the nature of non-financial access barriers vary considerably, not only between countries but also between different communities within individual countries. CONCLUSIONS: To adequately understand access barriers as a basis for developing effective strategies to address them, mixed methods approaches are required. From an equity perspective, communities with the lowest utilisation levels should be prioritised and the access barriers specific to that community identified. It is, therefore, critical to develop approaches that can be used at the district level to diagnose and act upon access barriers if we are to pursue an equitable path to universal health coverage. PMID- 26051412 TI - Editorial: New Antimicrobial Therapeutics. PMID- 26051413 TI - Vascular Inflammation and Atherosclerosis: The Role of Estrogen Receptors. AB - Estrogen receptors mediate numerous favorable effects on cells and molecules implicated in vascular inflammation and atherogenic process. However, harmful effects have also been suggested. Actually, premenopausal women have a significantly lower risk for cardiovascular disease compared to postmenopausal women or age matched males while the incidence of cardiovascular disease is greater in postmenopausal than premenopausal women of the same age. The balance between the expression of ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful. The activation of the newly discovered estrogen receptor GPR30 appears to be of great potential as therapeutic target in coronary heart disease, though the signaling mechanisms mediated GPR30 function still have not fully elucidated. The aim of this review is to summarize the current state of knowledge on the role of each estrogen receptor subtype in mediating the direct estrogen actions on different cellular components that participate in the atherosclerotic inflammatory process. We hope this knowledge will shed some light on the cause of the paradoxical characterization of estrogens as both beneficial and harmful, and advance the research in the development of specific ER-agonists/ antagonists with improved benefit/risk ratio. PMID- 26051414 TI - FCRL3 gene polymorphisms confer risk for sudden sensorineural hearing loss in a Chinese Han Population. AB - Fc receptor-like 3 (FCRL3) has recently been associated with susceptibility to several immune-related diseases. In this study, we evaluated the potential association of FCRL3 polymorphisms with sudden sensorineural hearing loss (SSNHL) in a Chinese Han population. Five single-nucleotide polymorphisms (SNPs) in FCRL3 rs945635, rs3761959, rs7522061, rs10489678, and rs7528684-were genotyped in 630 patients with SSNHL and 600 healthy controls by using a PCR-restriction fragment length polymorphism assay. The allele, genotype, and haplotype frequencies in the patients and the controls were compared using a chi(2) test. Moreover, we performed haplotype analysis by using the online software platform SHEsis. The results revealed a significant association between three SNPs-rs7528684, rs3761959, and rs7522061-and SSNHL in the studied Chinese Han population. Furthermore, the AGT and GAC haplotypes were associated with a significantly higher prevalence of SSNHL than were the GAT, GGC and GGT haplotypes. However, no significant differences were detected in either the genotype or allele frequencies of the other two SNPs, rs945635 and rs10489678, between the SSNHL and control groups. Overall, this study has identified an association between FCRL3 polymorphisms and increased risk of SSNHL in a Chinese Han population. PMID- 26051415 TI - Identification of three IFN-gamma inducible lysosomal thiol reductase (GILT)-like genes in mud crab Scylla paramamosain with distinct gene organizations and patterns of expression. AB - Vertebrate gamma-interferon inducible lysosomal thiol reductase (GILT) is an IFN gamma-inducible protein and is involved in MHCII-restricted antigen processing and cross-presentation of MHCI-restricted antigens in adaptive immunity. Outside of the endocytic MHC pathway, GILT regulates the cellular redox state, inhibits T cell activation, neutralizes extracellular pathogens and is also a host factor of some bacterial pathogens. In this report, we isolated and characterized three divergent GILT-like genes, GILT1, GILT2 and GILT3, which share only 30.9-40.4% identities in a crustacean mud crab Scylla paramamosain. Whilst the crab GILT1 and GILT3 possess four and five exons, respectively, the GILT2 is intronless, suggesting that GILT2 may arise from a recent retroposition event. The invertebrate GILT-like genes have diverse gene organizations and may be evolved in a species/lineage-specific manner as suggested by phylogenetic tree analysis. The amino acid sequences equivalent to human mature GILT are well conserved, including the GILT signature and nine of the ten cysteine residues that potentially form 5 disulfide bonds in human GILT, across the animal kingdom. However, most invertebrate GILT-like molecules lack the human-type N-terminal propeptide, as well as the human-type C-terminal with a conserved cysteine residue, suggesting differences in post translational processing and mode of action. All the three GILT-like genes are highly expressed in the hepatopancreas and up-regulated by pathogenic bacterial infection suggesting a role in immune defense against bacterial diseases. This study may provide the basis for further investigation of the expanding functions of GILT-like molecules in immunity and other physiological processes in mud crabs and other animals. PMID- 26051416 TI - Reference genes for real-time qPCR in leukocytes from asthmatic patients before and after anti-asthma treatment. AB - The aim of this study was to develop a set of reference genes whose expression is stable and suitable for normalization of target gene expression measured in asthma patients during anti-asthmatic treatment. Real-time qPCR was used to determine expression of 7 candidate reference genes (18S rRNA, ACTB, B2M, GAPDH, POLR2A, RPL13A and RPL32) and 7 target genes in leukocytes from asthma patients before and after treatment with inhaled corticosteroids and leukotriene receptor antagonist. Variance of Cq values was analyzed and stability ranking was determined with geNorm. We further investigated how the different normalization strategies affected the consistency of conclusions if the specific investigated target gene is down-regulated or up-regulated after anti-asthmatic therapy. The top-ranking reference genes determined by geNorm, when samples before and after therapy were analyzed (ACTB, B2M and GAPDH) were different from those (POLR2A and B2M) when only samples before treatment were analyzed. Using only a single reference gene for normalization of 7 target gene expression compared to our strategy, there would be as low as 19% of consistency in conclusions. We suggest the use of the geometric mean of ACTB, B2M and GAPDH for normalization of qPCR data of target genes in pharmacogenomics studies in asthma patients before and after anti-asthmatic therapy, however if gene expression is measured only before anti-asthmatic treatment, we recommend the use of the geometric mean of POLR2A and B2M. PMID- 26051417 TI - Association of adiponectin gene polymorphism rs266729 with type two diabetes mellitus in Iraqi population. A pilot study. AB - BACKGROUND: Diabetes incidence is increasing worldwide. Many studies demonstrated that polymorphisms within the adiponectin gene could be associated with type 2 diabetes mellitus (T2DM). METHODS: A case-control study was conducted to find the association between SNP rs266729 and T2DM in Iraqi population. The study included 135 patients referring to diabetic clinic in Najaf city randomly selected based on World Health Organization (WHO) guidelines and 135 healthy controls. DNA was extracted from blood and genotyped by PCR-RFLP by using (HhaI) enzyme. Multinomial logistic regression was applied to compare the proportions of genotypes and alleles. The odds ratio for risk of developing T2DM was calculated with and without adjustment for age, sex, and BMI. RESULTS: The frequency of the G allele of rs266729 (C/G) polymorphism was significantly higher (p=0.00) in diabetic subjects (28%) compared to that in normal subjects (14%). The homozygous genotype (GG) significantly (OR=3.67, CI 95%(1.25-10.76), P=0.01) increased the risk of T2DM by three folds with respect to those of the wild type (CC) after adjustment for age, sex and BMI, furthermore the heterozygous CG genotype significantly (OR=2.45, CI 95%(1.41-4.26), P=0.001) raised the risk of T2DM by two folds. Homozygous and heterozygous genotypes of rs266729 polymorphism exhibited significant association with raised fasting insulin values (p=0.01), and decreased HDL levels (p=0.00). CONCLUSION: Adiponectin gene polymorphism rs266729 is involved in the pathogenesis of T2DM. In addition this SNP may play a role in the development of cardiovascular diseases and metabolic syndrome by affecting HDL and insulin levels. PMID- 26051419 TI - Circulating brain derived neurotrophic factor levels and its relation with exercise in chronic patients with schizophrenia. PMID- 26051418 TI - Asymptomatic individuals with high HDL-C levels overexpress ABCA1 and ABCG1 and present miR-33a dysregulation in peripheral blood mononuclear cells. AB - Considering the growing knowledge and perspectives on microRNAs (miRNAs) that control high-density lipoprotein cholesterol (HDL-C) levels and metabolism, this study aimed at evaluating whether hsa-miR-33a and hsa-miR-128a are differentially expressed in peripheral blood mononuclear cells from asymptomatic individuals with low and high HDL-C, as well as at investigating the potential relationships with ATP binding cassete transporter A1 (ABCA1) expression, cholesterol efflux capacity and other parameters related with reverse cholesterol transport. In addition, the associations with cardiovascular risk were investigated by carotid intima media thickness (cIMT). Asymptomatic volunteers of both genders (n=51) were classified according to HDL-C (mg/dL) in hypoalphalipoproteinemics (hypo, HDL-C <=3 9), hyperalphalipoproteinemics (hyper, HDL-C >= 68) and controls (CTL, HDL-C >= 40<68). cIMT, lipids, lipoproteins, HDL size and volume, C reactive protein and insulin were determined, as well as the activities of several proteins and enzymes related to HDL metabolism. In a subgroup of 19 volunteers the cellular cholesterol efflux and HDL composition were determined. Total RNA was extracted from peripheral blood mononuclear cells for relative quantification experiments. Hypo volunteers presented significantly higher levels of triglycerides, VLDL-C and insulin; in addition, HDL size and volume decreased when compared with CTL and hyper. Regarding gene expression analysis, the hyper group presented a decrease of 72% in hsa-miR-33a and higher mRNA expression of ABCA1 and ABCG1 when compared with CTL. No significant differences in hsa-miR 128a expression, cholesterol efflux, cIMT or plaques were found. Further studies are necessary to elucidate the mechanisms underlying the complex miRNA network, regulating cellular cholesterol homeostasis in humans and its clinical repercussions. PMID- 26051420 TI - Motor Learning Consolidates Arc-Expressing Neuronal Ensembles in Secondary Motor Cortex. AB - Motor behaviors recruit task-specific neuronal ensembles in motor cortices, which are consolidated over subsequent learning. However, little is known about the molecules that can identify the participating neurons and predict the outcomes of the consolidation process. Using a mouse rotarod-learning task, we showed that lesion or inactivation of the secondary motor (M2) cortex disrupts learning of skilled movements. We tracked the endogenous promoter activity of the neuronal activity-regulated gene Arc in individual M2 neurons during rotarod learning by in vivo two-photon imaging of a knockin reporter. We found that task training initially recruits Arc-promoter-activated neurons and then consolidates them into a specific ensemble exhibiting persistent reactivation of Arc-promoter. The intensity of a neuron's initial Arc-promoter activation predicts its reactivation probability and neurons with weak initial Arc-promoter activation are dismissed from the ensemble during subsequent training. Our findings demonstrate a task specific Arc-dependent cellular consolidation process in M2 cortex during motor learning. PMID- 26051421 TI - Learning Enhances Sensory and Multiple Non-sensory Representations in Primary Visual Cortex. AB - We determined how learning modifies neural representations in primary visual cortex (V1) during acquisition of a visually guided behavioral task. We imaged the activity of the same layer 2/3 neuronal populations as mice learned to discriminate two visual patterns while running through a virtual corridor, where one pattern was rewarded. Improvements in behavioral performance were closely associated with increasingly distinguishable population-level representations of task-relevant stimuli, as a result of stabilization of existing and recruitment of new neurons selective for these stimuli. These effects correlated with the appearance of multiple task-dependent signals during learning: those that increased neuronal selectivity across the population when expert animals engaged in the task, and those reflecting anticipation or behavioral choices specifically in neuronal subsets preferring the rewarded stimulus. Therefore, learning engages diverse mechanisms that modify sensory and non-sensory representations in V1 to adjust its processing to task requirements and the behavioral relevance of visual stimuli. PMID- 26051422 TI - Cortical Feedback Decorrelates Olfactory Bulb Output in Awake Mice. AB - The olfactory bulb receives rich glutamatergic projections from the piriform cortex. However, the dynamics and importance of these feedback signals remain unknown. Here, we use multiphoton calcium imaging to monitor cortical feedback in the olfactory bulb of awake mice and further probe its impact on the bulb output. Responses of feedback boutons were sparse, odor specific, and often outlasted stimuli by several seconds. Odor presentation either enhanced or suppressed the activity of boutons. However, any given bouton responded with stereotypic polarity across multiple odors, preferring either enhancement or suppression. Feedback representations were locally diverse and differed in dynamics across bulb layers. Inactivation of piriform cortex increased odor responsiveness and pairwise similarity of mitral cells but had little impact on tufted cells. We propose that cortical feedback differentially impacts these two output channels of the bulb by specifically decorrelating mitral cell responses to enable odor separation. PMID- 26051426 TI - Light induced E-Z isomerization in a multi-responsive organogel: elucidation from (1)H NMR spectroscopy. AB - A multiresponsive organogel of (E)-N'-(anthracene-10-ylmethylene)-3,4,5 tris(dodecyloxy)benzohydrazide (I) showed a decrease of fluorescence intensity, decrease in mechanical strength and a change in gel morphology on irradiation with a wavelength of 365 nm. This is attributed to the E-Z isomerization across the C=N bond of I as evidenced from (1)H NMR spectroscopy. PMID- 26051423 TI - Representations of Taste Modality in the Drosophila Brain. AB - Gustatory receptors and peripheral taste cells have been identified in flies and mammals, revealing that sensory cells are tuned to taste modality across species. How taste modalities are processed in higher brain centers to guide feeding decisions is unresolved. Here, we developed a large-scale calcium-imaging approach coupled with cell labeling to examine how different taste modalities are processed in the fly brain. These studies reveal that sweet, bitter, and water sensory cells activate different cell populations throughout the subesophageal zone, with most cells responding to a single taste modality. Pathways for sweet and bitter tastes are segregated from sensory input to motor output, and this segregation is maintained in higher brain areas, including regions implicated in learning and neuromodulation. Our work reveals independent processing of appetitive and aversive tastes, suggesting that flies and mammals use a similar coding strategy to ensure innate responses to salient compounds. PMID- 26051427 TI - Modeling the evolving oscillatory dynamics of the rat locus coeruleus through early infancy. AB - The mammalian locus coeruleus (LC) is a brainstem structure that displays extensive interconnections with numerous brain regions, and in particular plays a prominent role in the regulation of sleep and arousal. Postnatal LC development is known to drastically alter sleep-wake switching behavior through early infancy, and, in rats, exerts its most significant influence from about postnatal day 8 to postnatal day 21 (P8-P21). Physiologically, several dramatic changes are seen in LC functionality through this time period. Prior to P8, LC neurons are extensively coupled via electrical gap junctions and chemical synapses, and the entire LC network exhibits synchronized ~0.3 Hz subthreshold oscillations and spiking. From P8 to P21, the network oscillation frequency rises up to ~3 Hz (at P21) while the amplitude of the network oscillation decreases. Beyond P21, synchronized network oscillations vanish and gap junction coupling is sparse or nonexistent. In this work, we develop a large-scale, biophysically realistic model of the rat LC and we use this model to examine the changing physiology of the LC through the pivotal P8-P21 developmental period. We find that progressive gap junction pruning is sufficient to account for all of the physiological changes observed from P8 to P21. PMID- 26051428 TI - Effects of Pringle maneuver and partial hepatectomy on the pharmacokinetics and blood-brain barrier permeability of sodium fluorescein in rats. AB - Liver diseases are known to affect the function of remote organs. The aim of the present study was to investigate the effects of Pringle maneuver, which results in hepatic ischemia-reperfusion (IR) injury, and partial hepatectomy (Hx) on the pharmacokinetics and brain distribution of sodium fluorescein (FL), which is a widely used marker of blood-brain barrier (BBB) permeability. Rats were subjected to Pringle maneuver (total hepatic ischemia) for 20 min with (HxIR) or without (IR) 70% hepatectomy. Sham-operated animals underwent laparotomy only. After 15 min or 8h of reperfusion, a single 25-mg/kg dose of FL was injected intravenously and serial (0-30 min) blood and bile and terminal brain samples were collected. Total and free (ultrafiltration) plasma, total brain homogenate, and bile concentrations of FL and/or its glucuronidated metabolite (FL-Glu) were determined by HPLC. Both IR and HxIR caused significant reductions in the biliary excretions of FL and FL-Glu, resulting in significant increases in the plasma AUC of the marker. Additionally, the free fraction of FL in plasma was significantly increased by HxIR. Although the brain concentrations of FL were increased by almost twofold in both IR and HxIR animals, the brain concentrations corrected by the free FL AUC (and not the total AUC) were similar in both groups at either time points. It is concluded that Pringle maneuver and/or partial hepatectomy substantially alters the hepatobiliary disposition, plasma AUC, plasma free fraction, and brain accumulation of FL without altering the BBB permeability to the marker. PMID- 26051429 TI - Secoiridoids delivered as olive leaf extract induce acute improvements in human vascular function and reduction of an inflammatory cytokine: a randomised, double blind, placebo-controlled, cross-over trial. AB - The leaves of the olive plant (Olea europaea) are rich in polyphenols, of which oleuropein and hydroxytyrosol (HT) are most characteristic. Such polyphenols have been demonstrated to favourably modify a variety of cardiovascular risk factors. The aim of the present intervention was to investigate the influence of olive leaf extract (OLE) on vascular function and inflammation in a postprandial setting and to link physiological outcomes with absorbed phenolics. A randomised, double-blind, placebo-controlled, cross-over, acute intervention trial was conducted with eighteen healthy volunteers (nine male, nine female), who consumed either OLE (51 mg oleuropein; 10 mg HT), or a matched control (separated by a 4 week wash out) on a single occasion. Vascular function was measured by digital volume pulse (DVP), while blood collected at baseline, 1, 3 and 6 h was cultured for 24 h in the presence of lipopolysaccharide in order to investigate effects on cytokine production. Urine was analysed for phenolic metabolites by HPLC. DVP stiffness index and ex vivo IL-8 production were significantly reduced (P< 0.05) after consumption of OLE compared to the control. These effects were accompanied by the excretion of several phenolic metabolites, namely HT and oleuropein derivatives, which peaked in urine after 8-24 h. The present study provides the first evidence that OLE positively modulates vascular function and IL-8 production in vivo, adding to growing evidence that olive phenolics could be beneficial for health. PMID- 26051430 TI - Blood Eosinophils: A Biomarker of Response to Extrafine Beclomethasone/Formoterol in Chronic Obstructive Pulmonary Disease. PMID- 26051431 TI - Categorical versus continuous circulating tumor cell enumeration as early surrogate marker for therapy response and prognosis during docetaxel therapy in metastatic prostate cancer patients. AB - BACKGROUND: Circulating tumor cell (CTCs) counts might serve as early surrogate marker for treatment efficacy in metastatic castration-resistant prostate cancer (mCRPC) patients. We prospectively assessed categorical and continuous CTC-counts for their utility in early prediction of radiographic response, progression-free (PFS) and overall survival (OS) in mCRPC patients treated with docetaxel. METHODS: CTC-counts were assessed in 122 serial samples, as continuous or categorical (<5 vs. >=5 CTCs) variables, at baseline (q0) and after 1 (q1), 4 (q4) and 10 (q10) cycles of docetaxel (3-weekly, 75 mg/m2) in 33 mCRPC patients. Treatment response (TR) was defined as non-progressive (non-PD) and progressive disease (PD), by morphologic RECIST or clinical criteria at q4 and q10. Binary logistic and Cox proportional hazards regression analyses were used as statistical methods. RESULTS: Categorical CTC-count status predicted PD at q4 already after one cycle (q1) and after 4 cycles (q4) of chemotherapy with an odds ratio (OR) of 14.9 (p=0.02) and 18.0 (p=0.01). Continuous CTC-values predicted PD only at q4 (OR 1.04, p=0.048). Regarding PFS, categorical CTC-counts at q1 were independent prognostic markers with a hazard ratio (HR) of 3.85 (95% CI 1.1-13.8, p=0.04) whereas early continuous CTC-values at q1 failed significance (HR 1.02, 95% CI 0.99-1.05, p=0.14). For OS early categorical and continuous CTC-counts were independent prognostic markers at q1 with a HR of 3.0 (95% CI 1.6-15.7, p=0.007) and 1.02 (95% CI 1.0-1.040, p=0.04). CONCLUSIONS: Categorical CTC-count status is an early independent predictor for TR, PFS and OS only 3 weeks following treatment initiation with docetaxel whereas continuous CTC-counts were an inconsistent surrogate marker in mCRPC patients. For clinical practice, categorical CTC-counts may provide complementary information towards individualized treatment strategies with early prediction of treatment efficacy and optimized sequential treatment. PMID- 26051433 TI - [Tumor mass in the right upper limb]. PMID- 26051432 TI - Risk of thromboembolism with thrombopoietin receptor agonists in adult patients with thrombocytopenia: Systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVE: Romiplostim and eltrombopag are thrombopoietin receptor (TPOr) agonists that promote megakaryocyte differentiation, proliferation and platelet production. In 2012, a systematic review and meta-analysis reported a non-statistically significant increased risk of thromboembolic events for these drugs, but analyses were limited by lack of statistical power. Our objective was to update the 2012 meta-analysis examining whether TPOr agonists affect thromboembolism occurrence in adult thrombocytopenic patients. MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). Updated searches were conduced on PubMed, Cochrane Central, and publicly available registries (up to December 2014). RCTs using romiplostim or eltrombopag in at least one group were included. Relative risks (RR), absolute risk ratios (ARR) and number needed to harm (NNH) were estimated. Heterogeneity was analyzed using Cochran's Q test and I(2) statistic. RESULTS: Fifteen studies with 3026 adult thrombocytopenic patients were included. Estimated frequency of thromboembolism was 3.69% (95% CI: 2.95-4.61%) for TPOr agonists and 1.46% (95% CI: 0.89-2.40%) for controls. TPOr agonists were associated with a RR of thromboembolism of 1.81 (95% CI: 1.04-3.14) and an ARR of 2.10% (95% CI: 0.03-3.90%) meaning a NNH of 48. Overall, we did not find evidence of statistical heterogeneity (p=0.43; I(2)=1.60%). CONCLUSIONS: Our updated meta analysis suggested that TPOr agonists are associated with a higher risk of thromboemboembolic events compared with controls, and supports the current recommendations included in the European product information on this respect. PMID- 26051434 TI - [Current treatment for gestational diabetes]. PMID- 26051435 TI - [Smoking impact on mortality in Spain in 2012]. AB - BACKGROUND AND OBJECTIVE: Smoking is an important public health problem, and is one of the main avoidable causes of morbidity and early mortality. The aim was to estimate the mortality attributable to smoking and its impact on premature mortality in Spain in the year 2012. PATIENTS AND METHODS: Descriptive, cross sectional study, carried out on the Spanish population aged >= 18 years in 2012. The prevalence of smoking by age and sex was obtained from the National Health Survey 2011-2012, and the number of deaths by age, sex and cause was obtained from the vital statistics of the National Institute of Statistics. The proportion of deaths attributable to smoking was calculated according to sex and age group, from the etiological fraction of the population. Likewise, loss of potential years of life lost (PYLL) and the mean potential years of life lost (MPYLL) were also calculated. RESULTS: In 2012, smoking caused 60,456 deaths which accounted for 15.23% of all deaths. Trachea-bronchial-lung cancer in men and other cardiopathies in women mostly contributed to this mortality. The PYLL were 184,426, and the MPYLL were 3.25 years in men and 2.42 years in women. CONCLUSIONS: In 2012, every day, 125 men and 40 women die from smoking-related conditions. The smoking prevalence has diminished in comparison with previous years and the number and percentage of deaths attributable to the smoking have increased in the last 20 years. PMID- 26051436 TI - [Patient information through informed consent form]. PMID- 26051437 TI - [Cystatin C as a mortality predictor in a hypertensive population in Extremadura, Spain]. AB - BACKGROUND AND OBJECTIVES: Cystatin C has proven to be a useful parameter to evaluate renal and cardiovascular risk. Nevertheless, there are scanty reports on the utility of this test in the Spanish population. We performed a survey in a group of patients followed up in Primary Care settings. MATERIAL AND METHODS: Prospective follow up of Primary Care attended patients recruited in 2008 and the first half of 2009. The sample included 142 subjects (mean age 64.2+/-14.6 years, 59.2% men). In all cases, cystatin C was determined and glomerular filtration rate (GFR) was estimated through the Hoek formula. Serum creatinine was also quantified as it was GFR estimated using CKD-EPI equation. The primary objective was a combination of death and major cardiovascular events incidence. RESULTS: There were 29 events registered (4 of them were deaths) and 9 non cardiovascular deaths. The odds ratio for the primary objective was 5.74 for the last quartile of cystatin C distribution (>1mg/l) (P=.002), while it was 6.44 for cystatin C derived GFR (P=.008) and 5.59 for CKD-EPI estimated GFR (P=.002, Mantel-Haenszel test). CONCLUSIONS: Cystatin C showed a good association with general mortality and the incidence of cardiovascular events in the Spanish population. Nevertheless, it was not better than the observed relationship with GFR, estimated from creatinine. PMID- 26051438 TI - The Radiotherapy Clinical Trial Research Landscape in the UK Between 2004 and 2013: A Cross-sectional Analysis. PMID- 26051439 TI - MRI evaluation of the knee with non-ferromagnetic external fixators: cadaveric knee model. AB - INTRODUCTION: The advent of MRI-compatible external fixation devices has made the use of MRI possible in patients who have been treated with external fixation. However, although there have been multiple studies determining the safety of MRI scans with external fixator devices, there are no studies determining the artifact effect these devices can have on the MRI image. The purpose of our study was to evaluate the effect of two popular brands (Stryker and Synthes) of MRI compatible external fixators on the diagnostic capacity of a knee MRI. We hypothesize that (1) MRI images would have higher noise due to the presence of an external fixator and (2) images of high diagnostic capacity will be obtainable in the presence of each external fixator spanning the knee. METHODS: Using seven cadaveric knees, a study was performed to analyze MRI images taken in the presence each external fixator. Scans taken with no external fixator present served as controls. Signal-to-noise ratios (SNRs) were measured at five anatomic structures. These structures were compared as a quantitative measure of image quality. A qualitative analysis was also performed using a five-point grading scale to assess the influence of metal artifact on the quality of the images. Each scan was graded by three blinded musculoskeletal radiologists focusing on six key anatomic structures. RESULTS: A reduction in SNR was identified on the external fixator group compare to the control groups at the patella tendon, MM and PCL. Qualitative scoring by three expert radiologists showed no difference in ability to identify the six key anatomic landmarks between the Stryker, Synthes and control images. CONCLUSION: Although the presence of external fixation devices does increase the noise artifact in MRI scans, patients treated with these external fixators can undergo MRI of local structures with high likelihood of obtaining diagnostic quality images. PMID- 26051440 TI - Symmetries of quantum transport with Rashba spin-orbit: graphene spintronics. AB - The lack of some spatial symmetries in planar devices with Rashba spin-orbit interactions opens up the possibility of producing spin polarized electrical currents in the absence of external magnetic fields or magnetic impurities. We study how the direction of the spin polarization of the current is related to spatial symmetries of the device. As an example of these relations we study numerically the spin-resolved current in graphene nanoribbons. Different configurations are explored and analyzed to demonstrate that graphene nanoflakes may be used as excellent spintronic devices in an all-electrical setup. PMID- 26051441 TI - Genital Human Papillomavirus Infection Progression to External Genital Lesions: The HIM Study. AB - BACKGROUND: Human papillomavirus (HPV) causes two types of external genital lesions (EGLs) in men: genital warts (condyloma) and penile intraepithelial neoplasia (PeIN). OBJECTIVE: The purpose of this study was to describe genital HPV progression to a histopathologically confirmed HPV-related EGL. DESIGN, SETTING, AND PARTICIPANTS: A prospective analysis nested within the HPV Infection in Men (HIM) study was conducted among 3033 men. At each visit, visually distinct EGLs were biopsied; the biopsy specimens were subjected to pathologic evaluation and categorized by pathologic diagnoses. Genital swabs and biopsies were used to identify HPV types using the Linear Array genotyping method for swabs and INNO LiPA for biopsy specimens. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: EGL incidence was determined among 1788 HPV-positive men, and cumulative incidence rates at 6, 12, and 24 mo were estimated. The proportion of HPV infections that progressed to EGL was also calculated, along with median time to EGL development. RESULTS AND LIMITATIONS: Among 1788 HPV-positive men, 92 developed an incident EGL during follow-up (9 PeIN and 86 condyloma). During the first 12 mo of follow up, 16% of men with a genital HPV 6 infection developed an HPV 6-positive condyloma, and 22% of genital HPV 11 infections progressed to an HPV 11-positive condyloma. During the first 12 mo of follow-up, 0.5% of men with a genital HPV 16 infection developed an HPV 16-positive PeIN. Although we expected PeIN to be a rare event, the sample size for PeIN (n=10) limited the types of analyses that could be performed. CONCLUSIONS: Most EGLs develop following infection with HPV 6, 11, or 16, all of which could be prevented with the 4-valent HPV vaccine. PATIENT SUMMARY: In this study, we looked at genital human papillomavirus (HPV) infections that can cause lesions in men. The HPV that we detected within the lesions could be prevented by a vaccine. PMID- 26051442 TI - Diagnostic implications of associated defects in patients with typical orofacial clefts. AB - OBJECTIVES: To describe prevalence of associated defects and clinical-genetic characteristics of patients with typical orofacial clefts seen at a reference genetic service. METHODS: Descriptive study conducted between September of 2009 and July of 2014. Two experienced dysmorphologists personally collected and coded clinical data using a validated, standard multicenter protocol. Syndromic cases were defined by the presence of four or more minor defects, one or more major defects, or recognition of a specific syndrome. Fisher's exact and Kruskal-Wallis tests were used for statistics. RESULTS: Among 141 subjects, associated defects were found in 133 (93%), and 84 (59.5%) were assigned as syndromic. Cleft palate was statistically associated with a greater number of minor defects (p<0.0012) and syndromic assignment (p<0.001). Syndromic group was associated with low birth weight (p<0.04) and less access to surgical treatment (p<0.002). There was no statistical difference between syndromic and non-syndromic groups regarding gender (p<0.55), maternal age of 35 years and above (p<0.50), alcohol (p<0.50) and tobacco consumption (p<0.11), consanguinity (p<0.59), recurrence (p<0.08), average number of pregnancies (p<0.32), and offspring (p<0.35). CONCLUSIONS: There is a lack of information on syndromic clefts. The classification system for phenotype assignment adopted in this study has facilitated recognition of high prevalence of associated defects and syndromic cases. This system may be a useful strategy to gather homogeneous samples, to elect appropriate technologies for etiologic and genotype-phenotype approaches, and to assist with multiprofessional care and genetic counseling. PMID- 26051443 TI - Antibody treatment against pulmonary exposure to abrin confers significantly higher levels of protection than treatment against ricin intoxication. AB - Abrin, a potent plant-derived toxin bearing strong resemblance to ricin, irreversibly inactivates ribosomes by site-specific depurination, thereby precipitating cessation of protein synthesis in cells. Due to its high availability and ease of preparation, abrin is considered a biological threat, especially in context of bioterror warfare. To date, there is no established therapeutic countermeasure against abrin intoxication. In the present study, we examined the progress of pulmonary abrin intoxication in mice, evaluated the protective effect of antibody-based post-exposure therapy, and compared these findings to those observed for ricin intoxication and therapy. Salient features of abrin intoxication were found to be similar to those of ricin and include massive recruitment of neutrophils to the lungs, high levels of pro-inflammatory markers in the bronchoalveolar lavage fluid and damage of the alveolar-capillary barrier. In contrast, the protective effect of anti-abrin antibody treatment was found to differ significantly from that of anti-ricin treatment. While anti-ricin treatment efficiency was quite limited even at 24h post-exposure (34% protection), administration of polyclonal anti-abrin antibodies even as late as 72h post-exposure, conferred exceedingly high-level protection (>70%). While both anti-toxin antibody treatments caused neutrophil and macrophage levels in the lungs to revert to normal, only anti-abrin treatment brought about a significant decline in the pulmonary levels of the pro-inflammatory cytokine IL-6. The differential ability of the anti-toxin treatments to dampen inflammation caused by the two similar toxins, abrin and ricin, could explain the radically different levels of protection achieved following antibody treatment. PMID- 26051444 TI - Successful Desensitization Protocol for Hypersensitivity Reaction Caused by Irinotecan in a Patient With Metastatic Colorectal Cancer. PMID- 26051446 TI - Racial disparities in the use of SBRT for treating early-stage lung cancer. AB - OBJECTIVES: Prior studies have shown that the surgical resection rate for black patients with early-stage lung cancer is significantly lower than that of white patients, which may partially explain the worse outcomes observed in this group. Over the past decade, however, there has been increasing utilization of stereotactic body radiotherapy (SBRT) as an alternative to surgical resection for inoperable patients. We undertook a population-based study to evaluate potential racial disparities in the use of SBRT. MATERIALS AND METHODS: Using the National Cancer Database, black and white patients with Stage I NSCLC between 2003 and 2011 were identified. Patients were categorized based on primary treatment modality. Univariable and multivariable analyses were performed to identify demographic predictors of SBRT utilization in the non-operative population. RESULTS: A total of 113,312 patients met the inclusion criteria. When compared to white patients, black patients were less likely to receive surgical intervention (66% vs. 58%, P<0.001) or SBRT (6.1% vs. 5.5%, P<0.001), and more likely to receive standard fractionated external beam radiation (EBRT) or no treatment. When confined to the non-operative cohort, multivariable logistic regression confirmed black race to be negatively associated with SBRT use compared to less aggressive therapy. CONCLUSION: In this national dataset, we confirmed prior observations that black patients are less likely to receive surgery than white patients, and also found that black patients are less likely to receive SBRT. This suggests that even with emerging utilization of SBRT for inoperable candidates, black patients continue to receive less aggressive therapy. PMID- 26051445 TI - Rehabilitation in patients with radically treated respiratory cancer: A randomised controlled trial comparing two training modalities. AB - INTRODUCTION: The evidence on the effectiveness of rehabilitation in lung cancer patients is limited. Whole body vibration (WBV) has been proposed as an alternative to conventional resistance training (CRT). METHODS: We investigated the effect of radical treatment (RT) and of two rehabilitation programmes in lung cancer patients. The primary endpoint was a change in 6-min walking distance (6MWD) after rehabilitation. Patients were randomised after RT to either CRT, WBVT or standard follow-up (CON). Patients were evaluated before, after RT and after 12 weeks of intervention. RESULTS: Of 121 included patients, 70 were randomised to either CON (24), CRT (24) or WBVT (22). After RT, 6MWD decreased with a mean of 38m (95% CI 22-54) and increased with a mean of 95m (95% CI 58 132) in CRT (p<0.0001), 37m (95% CI -1-76) in WBVT (p=0.06) and 1m (95% CI -34 36) in CON (p=0.95), respectively. Surgical treatment, magnitude of decrease in 6MWD by RT and allocation to either CRT or WBVT were prognostic for reaching the minimally clinically important difference of 54m increase in 6MWD after intervention. CONCLUSIONS: RT of lung cancer significantly impairs patients' exercise capacity. CRT significantly improves and restores functional exercise capacity, whereas WBVT does not fully substitute for CRT. PMID- 26051447 TI - Effect of wheat dried distillers grains and enzyme supplementation on growth rates, feed conversion ratio and beef fatty acid profile in feedlot steers. AB - The objectives of this study were to determine: (1) the effect of wheat dried distillers grain with solubles (DDGS) inclusion, and (2) dietary feed enzyme (FE; Econase XT) supplementation in a finishing diet containing wheat DDGS on fatty acid profile of the pars costalis diaphragmatis muscle of beef cattle. A total of 160 crossbred yearling steers with initial BW of 495 +/- 38 kg were blocked by BW and randomized into 16 pens (10 head/pen). The pens were randomly assigned to one of the four treatments: (1) control (CON; 10% barley silage and 90% barley grain based concentrate, dry matter (DM) basis); (2) diet containing 30% wheat DDGS in place of barley grain without FE (WDG); (3) WDG diet supplemented with low FE (WDGL; 1 ml FE/kg DM); and (4) WDG diet supplemented with high FE (2 ml FE/kg DM). The pars costalis diaphragmatis muscle samples were collected from cattle at slaughter at the end of the finishing period (120 days) with a targeted live weight of 650 kg. No differences in organic matter intake, final BW and average daily gain were observed among treatments. However, steers fed WDG had greater (P<0.01) feed conversion ratio than those fed CON, and increasing FE application in wheat DDGS-based diets tended (P<0.10) to linearly decrease feed conversion ratio. In assessing the effects of including WDG diets without FE, concentration of total polyunsaturated fatty acids (PUFA) in muscle tended to be greater (P<0.10) for steers fed WDG than steers fed CON. In addition, inclusion of wheat DDGS into the diet increased (P<0.05) concentration of CLA and vaccenic acid (VA) in muscle and also resulted in a higher (P<0.05) ratio of n-6/n-3 PUFA compared with that from steers fed CON diet. Increasing FE application in wheat DDGS-based diets did not modify the concentrations of individual or total fatty acids. These results suggest that inclusion of wheat DDGS in finishing diets may improve fatty acid profile of beef muscle which could benefit human health. PMID- 26051448 TI - Assembly of bioactive multilayered nanocoatings on pancreatic islet cells: incorporation of alpha1-antitrypsin into the coatings. AB - A spontaneous multilayer deposition approach for presenting therapeutic proteins onto pancreatic islet surfaces, using a heparin polyaldehyde and glycol chitosan alternating layering scheme, has been developed to enable the nanoscale engineering of a microenvironment for transplanted cells. The nanocoating incorporating alpha1-antitrypsin, an anti-inflammatory protein, exhibited effective anti-coagulant activities in vitro. PMID- 26051449 TI - [Liver abscess caused by migration of an ingested foreign body]. PMID- 26051450 TI - Scleromyxedema (papular mucinosis) with dermato-neuro syndrome: a rare, potentially fatal complication. PMID- 26051451 TI - [A fatal overwhelming post-splenectomy infection for a patient without prophylaxis]. PMID- 26051452 TI - X-ray structurally characterized sensors for ratiometric detection of Zn(2+) and Al(3+) in human breast cancer cells (MCF7): development of a binary logic gate as a molecular switch. AB - A very simple molecule derived from salicylaldehyde and N-phenyl ethylenediamine (L1) functions as dual-mode ratiometric fluorescence "turn on" sensors for Zn(2+) and Al(3+) at two different wavelengths. The sensing is based on the combined effect of inhibition of excited-state intra-molecular proton transfer (ESIPT), CH=N isomerization and chelation-enhanced fluorescence (CHEF). Moreover, the [L1 Zn(2+)] system functions as a better Al(3+) sensor where Al(3+) ratiometrically displaces Zn(2+) from the [L1-Zn(2+)] complex. Emission wavelength dependent differentiation of Zn(2+) and Al(3+) using L1 allows us to develop a binary logic gate that functions as a molecular switch. L1 efficiently detects Zn(2+) and Al(3+) in human breast cancer cells (MCF7) while the [L1-Zn(2+)] complex specifically detects Al(3+) in the said cells. PMID- 26051453 TI - Robust quantum metrological schemes based on protection of quantum Fisher information. AB - Fragile quantum features such as entanglement are employed to improve the precision of parameter estimation and as a consequence the quantum gain becomes vulnerable to noise. As an established tool to subdue noise, quantum error correction is unfortunately overprotective because the quantum enhancement can still be achieved even if the states are irrecoverably affected, provided that the quantum Fisher information, which sets the ultimate limit to the precision of metrological schemes, is preserved and attained. Here we develop a theory of robust metrological schemes that preserve the quantum Fisher information instead of the quantum states themselves against noise. After deriving a minimal set of testable conditions on this kind of robustness, we construct a family of 2t+1 qubits metrological schemes being immune to t-qubit errors after the signal sensing. In comparison, at least five qubits are required for correcting arbitrary 1-qubit errors in standard quantum error correction. PMID- 26051454 TI - Neuronal basis of reproductive dysfunctions associated with diet and alcohol: From the womb to adulthood. AB - The theory that individuals are born as tabula rasa and that their knowledge comes from experience and perception is no longer true. Studies suggest that experience is gained as early as in the mother's womb. Moreover, environmental stressors like alcohol or inadequate diet can affect physiological systems such as the hypothalmic-pituitary-gonadal (HPG) axis. The effects of these stressors can manifest as alterations in sexual development and adult reproductive functions. In this review, we consider and compare evidence from animal models and human studies demonstrating the role of environmental stressors (alcohol and under- or overnutrition) on the HPG axis. We review the role of alcohol and inadequate diet in prenatal reproductive system programming and consider specific candidate neurons in the adult hypothalamus through which reproductive function is being regulated. Finally, we review evidence from animal studies on the role that alcohol and diet play in fertility and reproductive disorders. We conclude that in order to better understand reproductive failure in animals and humans we need to consider in utero development and pay more attention to early life experience when searching for the origins of reproductive diseases. PMID- 26051455 TI - Serum biomarkers may help predict successful misoprostol management of early pregnancy failure. AB - In order to simplify management of early pregnancy loss, our goal was to elucidate predictors of successful medical management of miscarriage with a single dose of misoprostol. In this secondary analysis of data from a multicenter randomized controlled trial, candidate biomarkers were compared between 49 women with missed abortion who succeeded in passing their pregnancy with a single dose of misoprostol and 46 women who did not pass their pregnancy with a misoprostol single dose. We computed the precision of trophoblastic protein and hormone concentrations to discriminate between women who succeed or fail single dose misoprostol management. We also included demographic factors in our analyses. We found overlap in the concentrations of the individual markers between women who succeeded and failed single-dose misoprostol. However, hCG levels >= 4000 mIU/mL and ADAM-12 levels >= 2500 pg/mL were independently associated with complete uterine expulsion after one dose of misoprostol in our population. A multivariable logistic model for success included non-Hispanic ethnicity and parity <2 in addition to hCG >= 4000 mIU/mL and ADAM-12 >= 2500 pg/mL and had an area under the receiver operating characteristic (ROC) of 0.81 (95% confidence interval: 72-90%). Categorizing women with a predicted probability of >= 0.65 resulted in a sensitivity of 75.0%, specificity 77.1% and positive predictive value of 81.8%. While preliminary, our data suggest that serum biomarkers, especially when combined with demographic characteristics, may be helpful in guiding patient decision-making regarding the management of early pregnancy failure (EPF). Further study is warranted. PMID- 26051456 TI - Astaxanthin present in the maturation medium reduces negative effects of heat shock on the developmental competence of porcine oocytes. AB - Astaxanthin, one of the most common carotenoids, elicits antioxidant effects on cellular viability and embryonic development. This study was conducted to investigate the effects of astaxanthin on maturation, fertilization and development of porcine oocytes matured in vitro under heat stress conditions, and then fertilized and cultured under standard conditions. Porcine oocytes were cultured in maturation medium supplemented with different concentrations of astaxanthin (0, 0.25, 0.5 or 1 ppm) for 46 h at either 38.5 or 41 degrees C. In comparison to oocytes cultured at 38.5 degrees C, the exposure of porcine oocytes to 41.0 degrees C during in vitro maturation (IVM) significantly inhibited maturation and development of fertilized oocytes to the blastocyst stage. Supplementation of maturation medium with astaxanthin (0.5 ppm) significantly improved oocyte maturation, fertilization and development to the blastocysts stage in both oocyte groups. However, the total cell number and apoptosis index of blastocysts did not differ among groups. Moreover, astaxanthin (0.5 ppm) significantly increased the rate of oocytes that reached metaphase II and decreased proportion of apoptotic oocytes exposed to H2O2 (1.0mM) during IVM. In summary, we demonstrated that supplementation of maturation medium with astaxanthin (0.5 ppm) exerted antioxidative effects and improved the ability of maturation, fertilization, and development of porcine oocytes exposed to heat stress. PMID- 26051457 TI - The effect of sperm DNA fragmentation on the dynamics of the embryonic development in intracytoplasmatic sperm injection. AB - The genetic integrity of sperm DNA can contribute to the infertility problems experienced by couples. Sperm DNA fragmentation (SDF) is the most common DNA abnormality in male gametes, and yet its effect on embryo kinetics has not been widely studied. Embryo morphokinetic parameters during the first days of embryo culture after intracytoplasmatic sperm injection (ICSI) are weakly predictive of both embryo development and pregnancy outcome. This study investigated the effect of SDF on embryo morphokinetic parameters following ICSI. The DNA fragmentation index (DFI) in spermatozoa from all males in the study (n = 165) was determined before ICSI and the morphokinetic parameters of the embryos (n = 165) were monitored via time-lapse recording. We found that a low DFI index in spermatozoa corresponded with embryos that reached the blastocyst stage at a faster rate after ICSI. Overall, lower SDF levels were also found in the group of patients that achieved pregnancy. Thus, higher SDF levels can slow down embryo morphokinetic parameters, and may be predictive of pregnancy outcomes after ICSI. PMID- 26051458 TI - Tauroursodeoxycholic acid improves the implantation and live-birth rates of mouse embryos. AB - We previously demonstrated that tauroursodeoxycholic acid (TUDCA) improved the developmental competence of mouse embryos by attenuating endoplasmic reticulum (ER) stress-induced apoptosis during preimplantation development. Here, we present a follow-up study examining whether TUDCA enhances the implantation and live-birth rate of mouse embryos. Mouse 2-cell embryos were collected by oviduct flushing and cultured in the presence or absence of 50 MUM TUDCA. After culture (52 h), blastocysts were transferred to 2.5-day pseudopregnant foster mothers. It was found that the rates of pregnancy and implantation as well as the number of live pups per surrogate mouse were significantly higher in the TUDCA-treated group compared to the control group, but there was no significant difference in the mean weights of the pups or placentae. Thus, we report for the first time that TUDCA supplementation of the embryo culture medium increased the implantation and livebirth rates of transferred mouse embryos. PMID- 26051459 TI - Gonadogenesis and slow proliferation of germ cells in juveniles of cultured yellowfin tuna, Thunnus albacares. AB - To develop techniques for seedling production of yellowfin tuna, the behavior of primordial germ cells (PGCs) and gonadogenesis were examined at 1-30 days post hatching (dph) using morphometric analysis, histological examination, and in situ hybridization. Immediately after hatching, PGCs were located on the dorsal side of the posterior end of the rectum under the peritoneum of the larvae, and at 3 dph they came into contact with stromal cells. PGCs and stromal cells gradually moved forward from the anus prior to 5 dph. At 7-10 dph, germ cells were surrounded by stromal cells and the gonadal primordia were formed. In individuals collected at 12 dph, PGCs were detected by in situ hybridization using a vasa mRNA probe that is a germ-cell-specific detection marker. The proliferation of germ cells in the gonadal primordia began at 7-10 dph. We observed double the number of germ cells at 30 dph (22 +/- 3.2 cells), compared to that at 1 dph (11 +/- 2.1 cells). Therefore, based on our data and previous reports, the initial germ cell proliferation of yellowfin tuna is relatively slower than that of other fish species. PMID- 26051460 TI - Rapid and simultaneous screening of 47,XXY and AZF microdeletions by quadruplex real-time polymerase chain reaction. AB - We developed a quadruplex real-time PCR assay that allows rapid and simultaneous detection of 47,XXY and azoospermia factor (AZF) microdeletions on Y chromosome. The quadruplex assay consisted of four hydrolysis probes and primer sets. Three probes and the corresponding primers were used to qualitatively detect AZFa, AZFb, and AZFc deletions. For the detection of 47,XXY, the hydrolysis probe mediated melting analysis was conducted to analyze the relative amounts of X and Y chromosomes. The quadruplex assay for detecting 47,XXY was characterized by very high analytical specificity (100%) in a wide template DNA range (2-100 ng). The detection limit of the assay was 2 ng of genomic DNA, and the optimal template DNA amount for the detection of 47,XXY was 25 ng. The quadruplex assay for detecting 47,XXY and AZF microdeletions has also demonstrated very high diagnostic sensitivity and specificity (100%). The assay was found to be rapid, sensitive, reliable, and inexpensive. This method is suggested to be applied as a first-step tool in genetic screening of patients with non-obstructive azoospermia and severe oligospermia. PMID- 26051461 TI - Time-lapse videography of human embryos: Using pronuclear fading rather than insemination in IVF and ICSI cycles removes inconsistencies in time to reach early cleavage milestones. AB - Time-lapse videography showed that human early cleavage embryos were quicker following intracytoplasmic sperm injection to reach developmental milestones compared to in vitro fertilization when using insemination as the timing start point (t0), due to differences in the time taken for embryos to reach pronuclear fading (PNF). These differences disappeared when PNF was used as t0. Using a biological rather than procedural t0 will allow a unified assessment strategy to be applied to all cycles irrespective of the insemination method. PMID- 26051462 TI - Effects of N-acetyl-L-cysteine and catalase on the viability and motility of chicken sperm during liquid storage. AB - The purpose of the current study was to investigate the effects of N-acetyl-L cysteine (NAC) and catalase (CAT) on chicken sperm parameters during liquid storage for up to 48 h at 5 degrees C. Supplementation of EK extender with NAC (15 mM) increased sperm motility after 24h. After 48 h, an increase in sperm viability with NAC (5, 15 mM) and CAT (100, 300 U/mL) was observed, but only treatment with 15 mM NAC improved sperm progressive motility. PMID- 26051463 TI - Editorial overview: Virus structure and expression. PMID- 26051464 TI - 2014 update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological therapies in rheumatoid arthritis. AB - OBJECTIVE: To establish recommendations for the management of patients with rheumatoid arthritis (RA) to serve as a reference for all health professionals involved in the care of these patients, and focusing on the role of available synthetic and biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: Consensual recommendations were agreed on by a panel of 14 experts selected by the Spanish Society of Rheumatology (SER). The available scientific evidence was collected by updating three systematic reviews (SR) used for the EULAR 2013 recommendations. A new SR was added to answer an additional question. The literature review of the scientific evidence was made by the SER reviewer's group. The level of evidence and the degree of recommendation was classified according to the Oxford Centre for Evidence-Based Medicine system. A Delphi panel was used to evaluate the level of agreement between panellists (strength of recommendation). RESULTS: Thirteen recommendations for the management of adult RA were emitted. The therapeutic objective should be to treat patients in the early phases of the disease with the aim of achieving clinical remission, with methotrexate playing a central role in the therapeutic strategy of RA as the reference synthetic DMARD. Indications for biologic DMARDs were updated and the concept of the optimization of biologicals was introduced. CONCLUSIONS: We present the fifth update of the SER recommendations for the management of RA with synthetic and biologic DMARDs. PMID- 26051465 TI - Construction of an Aptamer-SiRNA Chimera-Modified Tissue-Engineered Blood Vessel for Cell-Type-Specific Capture and Delivery. AB - The application of tissue-engineered blood vessels (TEBVs) is the main developmental direction of vascular replacement therapy. Due to few and/or dysfunctional endothelial progenitor cells (EPCs), it is difficult to successfully construct EPC capture TEBVs in diabetes. RNA has a potential application in cell protection and diabetes treatment, but poor specificity and low efficiency of RNA transfection in vivo limit the application of RNA. On the basis of an acellular vascular matrix, we propose an aptamer-siRNA chimera modified TEBV that can maintain a satisfactory patency in diabetes. This TEBV consists of two parts, CD133-adenosine kinase (ADK) chimeras and a TEBV scaffold. Our results showed that CD133-ADK chimeras could selectively capture the CD133 positive cells in vivo, and then captured cells can internalize the bound chimeras to achieve RNA self-transfection. Subsequently, CD133-ADK chimeras were cut into ADK siRNA by a dicer, resulting in depletion of ADK. An ADK-deficient cell may act as a bioreactor that sustainably releases adenosine. To reduce nonspecific RNA transfection, we increased the proportion of HAuCl4 during the material preparation, through which the transfection capacity of polyethylenimine (PEI)/polyethylene glycol (PEG)-capped gold nanoparticles (PEI/PEG-AuNPs) was significantly decreased and the ability of TEBV to resist tensile and liquid shear stress was greatly enhanced. PEG and 2'-O-methyl modification was used to enhance the in vivo stability of RNA chimeras. At day 30 postgrafting, the patency rate of CD133-ADK chimera-modified TEBVs reached 90% in diabetic rats and good endothelialization was observed. PMID- 26051466 TI - Central Nervous System Activities of Indole Derivatives: An Overview. AB - Indole and its derivatives are continuously drawing interest of researchers in the field of medicinal chemistry for development of newer significant moieties due to their wide range of biological activities. In recent years, indole nucleus has been used to a greater extent for the development of agents acting on central nervous system (CNS) disorders like epilepsy. Binedaline, Amedalin, Pindolol, Siramesine and Oxypertine are the marketed drugs used in CNS disorders having indole moiety. So, keeping this point in mind, the review is specially focused on pharmacological activities of indole derivatives acting on central nervous system like anticonvulsant, antidepressant and sedative-hypnotic activities. The present study covers updated information on the most potent indole derivatives during the past years and also its recent developments. These results may help the researchers to develop novel ideas for future molecular modifications of indole derivatives with potent pharmacological activities and least side effects may be derived. PMID- 26051467 TI - Bone morphogenetic protein signaling in bone homeostasis. AB - Bone morphogenetic proteins (BMPs) are cytokines belonging to the transforming growth factor-beta (TGF-beta) superfamily. They play multiple functions during development and tissue homeostasis, including regulation of the bone homeostasis. The BMP signaling pathway consists in a well-orchestrated manner of ligands, membrane receptors, co-receptors and intracellular mediators, that regulate the expression of genes controlling the normal functioning of the bone tissues. Interestingly, BMP signaling perturbation is associated to a variety of low and high bone mass diseases, including osteoporosis, bone fracture disorders and heterotopic ossification. Consistent with these findings, in vitro and in vivo studies have shown that BMPs have potent effects on the activity of cells regulating bone function, suggesting that manipulation of the BMP signaling pathway may be employed as a therapeutic approach to treat bone diseases. Here we review the recent advances on BMP signaling and bone homeostasis, and how this knowledge may be used towards improved diagnosis and development of novel treatment modalities. This article is part of a Special Issue entitled "Muscle Bone Interactions". PMID- 26051468 TI - Glucocorticoids, bone and energy metabolism. AB - Prolonged exposure to excessive levels of endogenous or exogenous glucocorticoids is associated with serious clinical features including altered body composition and the development of insulin resistance, impaired glucose tolerance and diabetes. It had been assumed that these adverse effects were mediated by direct effects of glucocorticoids on tissues such as adipose or liver. Recent studies have however indicated that these effects are, at least in part, mediated through the actions of glucocorticoids on bone and specifically the osteoblast. In mice, targeted abrogation of glucocorticoid signalling in osteoblasts significantly attenuated the changes in body composition and systemic fuel metabolism seen during glucocorticoid treatment. Heterotopic expression of osteocalcin in the liver of normal mice was also able to protect against the metabolic changes induced by glucocorticoids indicating that osteocalcin was the likely factor connecting bone osteoblasts to systemic fuel metabolism. Studies are now needed in humans to determine the extent to which glucocorticoid induced changes in body composition and systemic fuel metabolism are mediated through bone. This article is part of a Special Issue entitled Bone and diabetes. PMID- 26051469 TI - Age dependent regulation of bone-mass and renal function by the MEPE ASARM-motif. AB - CONTEXT: Mice with null mutations in matrix extracellular phosphoglycoprotein (MEPE) have increased bone mass, increased trabecular density and abnormal cancellous bone (MN-mice). These defects worsen with age and MEPE overexpression induces opposite effects. Also, genome wide association studies show that MEPE plays a major role in bone mass. We hypothesized that the conserved C-terminal MEPE ASARM-motif is chiefly responsible for regulating bone mass and trabecular structure. DESIGN: To test our theory we overexpressed C-terminal ASARM-peptide in MN-mice using the Col1alpha1 promoter (MNAt-mice). We then compared the bone and renal phenotypes of the MNAt-mouse with the MN-mouse and the X-linked hypophosphatemic rickets mouse (HYP). The HYP mouse overexpresses ASARM-peptides and is defective for the PHEX gene. RESULTS: The MN-mouse developed increased bone mass, bone strength and trabecular abnormalities that worsened markedly with age. Defects in bone formation were chiefly responsible with suppressed sclerostin and increased active beta-catenin. Increased uric acid levels also suggested that abnormalities in purine-metabolism and a reduced fractional excretion of uric acid signaled additional renal transport changes. The MN mouse developed a worsening hyperphosphatemia and reduced FGF23 with age. An increase in the fractional excretion of phosphate (FEP) despite the hyperphosphatemia confirms an imbalance in kidney-intestinal phosphate regulation. Also, the MN mice showed an increased creatinine clearance suggesting hyperfiltration. A reversal of the MN bone-renal phenotype changes occurred with the MNAt mice including the apparent hyperfiltration. The MNAt mice also developed localized hypomineralization, hypophosphatemia and increased FGF23. CONCLUSIONS: The C terminal ASARM-motif plays a major role in regulating bone-mass and cancellous structure as mice age. In healthy mice, the processing and release of free ASARM peptide are chiefly responsible for preserving normal bone and renal function. Free ASARM-peptide also affects renal mineral phosphate handling by influencing FGF23 expression. These findings have implications for understanding age dependent osteoporosis, unraveling drug-targets and developing treatments. PMID- 26051470 TI - Ewing's sarcoma of bone tumor cells produces MCSF that stimulates monocyte proliferation in a novel mouse model of Ewing's sarcoma of bone. AB - Ewing's sarcoma of bone is a primary childhood malignancy of bone that is treated with X-radiation therapy in combination with surgical excision and chemotherapy. To better study Ewing's sarcoma of bone we developed a novel model of primary Ewing's sarcoma of bone and then treated animals with X-radiation therapy. We identified that uncontrolled tumor resulted in lytic bone destruction while X radiation therapy decreased lytic bone destruction and increased limb-length asymmetry, a common, crippling complication of X-radiation therapy. Osteoclasts were indentified adjacent to the tumor, however, we were unable to detect RANK ligand in the Ewing's tumor cells in vitro, which lead us to investigate alternate mechanisms for osteoclast formation. Ewing's sarcoma tumor cells and archival Ewing's sarcoma of bone tumor biopsy samples were shown to express MCSF, which could promote osteoclast formation. Increased monocyte numbers were detected in peripheral blood and spleen in animals with untreated Ewing's sarcoma tumor while monocyte number in animals treated with x-radiation had normal numbers of monocytes. Our data suggest that our Ewing's sarcoma of bone model will be useful in the study Ewing's sarcoma tumor progression in parallel with the effects of chemotherapy and X-radiation therapy. PMID- 26051471 TI - Clinical and molecular heterogeneity in a large series of patients with hypophosphatemic rickets. AB - CONTEXT: Hypophosphatemic rickets (HR) is a rare disease that includes a group of hereditary and sporadic conditions characterized by renal phosphate loss associated with normal to low vitamin D serum concentration. The most common form is the X-linked hypophosphatemic rickets, with an incidence of 1:20,000. Several mutations have recently been identified in the PHEX, FGF23, DMP1 and ENPP1 genes in patients with HR. Moreover, in vitro and in vivo studies suggested an involvement of MEPE for defective mineralization in HR. OBJECTIVE: The present case series describes the clinical features and the analysis of genes implicated in HR in a cohort of 26 Italian HR patients. SETTING AND DESIGN: All patients were analyzed for the PHEX and FGF23 genes by direct sequencing. When no mutations were detected, Multiplex Ligation-dependent Probe Amplification (MLPA) analysis was performed. The negative patients were screened for the DMP1, MEPE and ENPP1 genes by direct sequencing. RESULTS: Twenty-two patients (84%) harbored mutations in the PHEX gene. In particular, we detected 19 different mutations, 15 of which were novel. One patient presented a novel splice variation in the ENPP1 gene while no alterations were identified in the FGF23, DMP1 and MEPE genes. The genetic study of the families showed that 11 patients (55%) had de novo mutations. Clinical presentation and disease severity did not show an evident correlation between the mutation types. CONCLUSIONS: This report represents the first large familial study performed on Italian patients. It confirms that mutations in PHEX are the most frequent cause of HR. Furthermore, the variety of clinical manifestations identified in our HR patients underlines the extreme clinical and genetic heterogeneity of this disease. PMID- 26051472 TI - Primary melanoma of the hand: An algorithmic approach to surgical management. AB - PURPOSE: Melanoma, the skin cancer with the lowest incidence, causes the majority of all skin cancer-related deaths. Early detection has led to the discovery of melanoma at less advanced stages, thus shifting the reconstructive paradigm from sole survivorship to the improvement of function and cosmesis while still maintaining an overall adequate outcome. Reconstructive approaches rely on two main factors: location of the lesion and size of the lesion. Due to the complexity of the hand, reconstructive options are quite heterogeneous. The purpose of this study is to explore the clinical data and reconstructive strategies of hand and digital cutaneous melanoma and subungual melanoma, review the current reconstructive options presented in the medical literature, and offer a reconstructive algorithm to surgically approach primary melanoma of the hand. METHODS: A retrospective chart review was conducted for all patients undergoing oncologic resection of primary melanoma of the hand at New York University Langone Medical Center (NYULMC) between April 2003 and October 2011. Variables collected included age, race, gender, type of melanoma, Breslow depth, stage, oncologic resection, reconstructive surgery, and outcomes. RESULTS: A total of 35 patients with primary melanoma of the hand comprised the study cohort. The mean age of presentation was 56 years with a total of 24 women and 11 men. The average Breslow depth of the cohort was 1.58 mm. There were 13 cases of melanoma in situ (MIS). All MIS cases were treated with wide local excision, yet the subungual group needed more extensive reconstruction including paronychial advancement flaps and full-thickness skin grafts (FTSG). Twenty-two cases presented as malignant melanoma. The majority of the patients with cutaneous melanoma underwent wide local excision with primary closure or FTSG. In the subungual group, all patients underwent amputation at the most distal interphalangeal joint or wide local excision. The reconstruction consisted of local advancement flaps, FTSG, or primary closure. CONCLUSION: Reconstructive options for primary melanoma of the hand are quite varied without strong guidelines as to which technique is superior. Location, size, and type of lesion (cutaneous or subungual) help shape which reconstructive strategies are optimal. With more conservative oncologic approaches and advanced reconstructive techniques, patients are able to maintain function with a satisfactory degree of cosmesis. PMID- 26051473 TI - A novel azopyridine-based Ru(II) complex with GSH-responsive DNA photobinding ability. AB - A novel azopyridine-based Ru(II) complex [Ru(bpy)2(L1)2](2+) (bpy = 2,2' bipyridine, L1 = 4,4'-azopyridine) was designed and synthesized as a potential glutathione (GSH)-responsive photoactivated chemotherapy (PACT) agent, the DNA covalent binding capability of which can only be activated after GSH reduction and visible light irradiation. PMID- 26051474 TI - The non-canonical Wnt pathway negatively regulates dendritic cell differentiation by inhibiting the expansion of Flt3(+) lymphocyte-primed multipotent precursors. AB - The differentiation of dendritic cells (DC) is affected by the aging process. However, the molecular mechanisms responsible for the alteration of DC development in aged mice have not been clarified. Recently, Wnt5a was reported to be an important aging-related molecule in hematopoietic systems. Here, we hypothesized that the increased expression of Wnt5a in aged hematopoietic precursors led to deficient DC differentiation in aged mice. The percentages and cell numbers of plasmacytoid DC (pDC) and CD172a(-)CD8alpha(+)conventional DC (cDC) were decreased in aged mice compared to young mice. Further analysis indicated that the hematopoietic precursors that gave rise to DC, including Flt3(+) lymphoid-primed multipotent precursors (LMPP), common lymphoid progenitors (CLP) and common DC precursors (CDP), were all decreased in the bone marrow of aged mice. Overexpression of Wnt5a in hematopoietic precursors strongly affected the differentiation of cDC and pDC in vivo. Treatment of hematopoietic stem cells (HSC) with Wnt5a led to a significant decrease in the differentiation of the LMPP, CLP and CDP populations that was similar to the decrease observed in the bone marrow (BM) HSC of aged mice. Molecular studies demonstrated that Wnt5a negatively regulated the expression of an array of genes important for DC differentiation, including Flt3, Gfi-1, Ikaros, Bcl11a, and IL-7R, by activating the Wnt5a-Cdc42 pathway. Finally, we rejuvenated DC differentiation from aged precursors by blocking the non-canonical Wnt pathway. Our study identified the key roles of the non-canonical Wnt pathway in DC differentiation and DC aging. PMID- 26051476 TI - A porphyrin photosensitized metal-organic framework for cancer cell apoptosis and caspase responsive theranostics. AB - A photosensitized and caspase-responsive multifunctional nanoprobe was designed by assembling a porphyrin, a folate targeting-motif and a dye-labelled peptide in a metal-organic framework (MOF) cage, which significantly increases the singlet oxygen quantum yield of porphyrin by 6.2 times, and achieves high efficient cancer therapy and in situ therapeutic monitoring with caspase-3 activation. The integration of theranostic functions in a single nanocarrier holds great promise in precision cancer diagnosis and treatment. PMID- 26051475 TI - Type 1 regulatory T cells: a new mechanism of peripheral immune tolerance. AB - The lack of immune response to an antigen, a process known as immune tolerance, is essential for the preservation of immune homeostasis. To date, two mechanisms that drive immune tolerance have been described extensively: central tolerance and peripheral tolerance. Under the new nomenclature, thymus-derived regulatory T (tT(reg)) cells are the major mediators of central immune tolerance, whereas peripherally derived regulatory T (pT(reg)) cells function to regulate peripheral immune tolerance. A third type of T(reg) cells, termed iT(reg), represents only the in vitro-induced T(reg) cells(1). Depending on whether the cells stably express Foxp3, pT(reg), and iT(reg) cells may be divided into two subsets: the classical CD4(+)Foxp3(+) T(reg) cells and the CD4(+)Foxp3(-) type 1 regulatory T (Tr1) cells(2). This review focuses on the discovery, associated biomarkers, regulatory functions, methods of induction, association with disease, and clinical trials of Tr1 cells. PMID- 26051477 TI - The innate capacity of proteins to protect against reactive radical species. AB - Maintaining redox homeostasis, or the balance of oxidant and antioxidant forces, is essential for proper cellular functioning in biology. Although the antioxidant nature of many small molecules such as vitamin c and glutathione have been thoroughly investigated, contributions to redox homeostasis from larger biomolecules have received less attention. Evidence has shown that some proteins are antioxidant (in a non-catalytic sense), but large scale examination of this property for a diverse set of proteins has proven difficult. Herein, radical directed dissociation mass spectrometry (RDD-MS) is used to examine the antioxidant capacity of a series of proteins with diverse biological roles, persistence intervals, and localizations. Digestion of these proteins reveals that all contain antioxidant peptide regions. Examination of the amino acid content of the antioxidant peptides does not reveal significant differences relative to normal peptides, suggesting that sequence may be more important than residue content. Sequence homology analysis across organisms reveals that antioxidant regions are frequently conserved, although many of these regions are also known to have other functions which may have influenced evolutionary pressure. Regardless of the origin, it is clear that many proteins may play secondary roles as sacrificial antioxidants within the cellular milieu. PMID- 26051478 TI - Bovine anaplasmosis in Turkey: First laboratory confirmed clinical cases caused by Anaplasma phagocytophilum. AB - Anaplasma species are obligate intracellular rickettsial pathogens that affect the health of humans and other animals. Clinical cases of anaplasmosis caused by Anaplasma phagocytophilum were evaluated, and the frequency of bovine Anaplasma species was determined in cattle. Blood samples and thin blood smears were collected from 10 cattle exhibiting clinical signs of tick-borne fever. In addition, blood samples were collected from 123 apparently healthy cattle from the same area. DNA was screened by reverse line blot assay for the presence of the hypervariable V1 region of the 16S rRNA gene of Anaplasma/Ehrlichia species. Intracytoplasmic inclusion bodies of A. phagocytophilum were observed in neutrophils of 6 sick animals. Parasitemia ranged from 0.2 to 1.6% in individual slides. Reverse line blot showed 45.1% (60/133) of the sampled cattle to be positive for one or more of five Anaplasma species. The frequency of single infections was 20.3% (27/133), while mixed infections were found in 24.8% (33/133) of samples with six different combinations of species and a maximum of four pathogens detected. A. phagocytophilum was the most prevalent (41/133, 30.8%) followed by Anaplasma marginale (25/133, 18.8%), Anaplasma centrale (24/133, 18%), Ehrlichia sp. strain Omatjenne (18/133, 13.5%) and Anaplasma bovis (1/133, 0.7%). This is the first report of A. bovis in a cow from Turkey. This is also the first report of clinical cases caused by A. phagocytophilum in cattle from the country. Therefore, A. phagocytophilum should be taken into account as differential diagnosis in cases of high fever and anorexia in pastured animals. PMID- 26051479 TI - Activity of 10 antimicrobial agents against intracellular Rhodococcus equi. AB - Studies with facultative intracellular bacterial pathogens have shown that evaluation of the bactericidal activity of antimicrobial agents against intracellular bacteria is more closely associated with in vivo efficacy than traditional in vitro susceptibility testing. The objective of this study was to determine the relative activity of 10 antimicrobial agents against intracellular Rhodococcus equi. Equine monocyte-derived macrophages were infected with virulent R. equi and exposed to erythromycin, clarithromycin, azithromycin, rifampin, ceftiofur, gentamicin, enrofloxacin, vancomycin, imipenem, or doxycycline at concentrations achievable in plasma at clinically recommended dosages in foals. The number of intracellular R. equi was determined 48h after infection by counting colony forming units (CFUs). The number of R. equi CFUs in untreated control wells were significantly higher than those of monolayers treated with antimicrobial agents. Numbers of R. equi were significantly lower in monolayers treated with enrofloxacin followed by those treated with gentamicin, and vancomycin, when compared to monolayers treated with other antimicrobial agents. Numbers of R. equi in monolayers treated with doxycycline were significantly higher than those of monolayers treated with other antimicrobial agents. Differences in R. equi CFUs between monolayers treated with other antimicrobial agents were not statistically significant. Enrofloxacin, gentamicin, and vancomycin are the most active drugs in equine monocyte-derived macrophages infected with R. equi. Additional studies will be needed to determine if these findings correlate with in vivo efficacy. PMID- 26051481 TI - Re-evaluation of bone pain in patients with type 1 Gaucher disease suggests that bone crises occur in small bones as well as long bones. AB - Bone crises in type 1 Gaucher disease are reported in long bones and occasionally in weight bearing bones and other bones, but rarely in small bones of the hands and feet. We retrospectively examined the incidence of bone pain in patients followed at the Rabin Medical Center, Israel, before and following the initiation of enzyme replacement therapy (ERT) and evaluated them for bone crises. Of 100 type I Gaucher disease patients, 30 (30%) experienced one or more bone crises. Small bone crises represented 31.5% of all bone crises and were always preceded by crises in other bones. While the incidence of long bone crises reduced after the initiation of ERT, small bone crises increased. Almost 60% of patients with bone crises were of the N370S/84GG genotype suggesting a greater susceptibility of N370S/84GG patients to severe bone complications. These patients also underwent the greatest number of splenectomies (70.6% of splenectomised patients). Splenectomised patients showed a trend towards increased long and small bone crises after surgery. Active investigation of acute pain in the hands and feet in patients in our cohort has revealed a high incidence of small bone crises. Physicians should consider imaging studies to investigate unexplained pain in these areas. PMID- 26051482 TI - Influence of mechanical unloading on histological changes of the patellar tendon insertion in rabbits. AB - BACKGROUND: The purpose of this study was to clarify the influence of mechanical unloading on histological changes of the patellar tendon (PT) insertion in rabbits. MATERIALS AND METHODS: The PT was completely released from stress by drawing the patella toward the tibial tubercle with a stainless steel wire installed between the patella and tibial tubercle (mechanical unloading group, n=28). The animals of the sham group underwent the same surgical procedure; however, the wire was not tightened (n=28). The average thickness of the Safranin O-stained glycosaminoglycan (GAG) area, chondrocyte apoptosis rate and chondrocyte proliferation rate of the cartilage layer at the insertion were measured at one, two, four, and six weeks. RESULTS: The chondrocyte apoptosis rate in the mechanical unloading group was significantly higher than that in the sham group at one and four weeks (p<0.05). The chondrocyte proliferation rate in the mechanical unloading group was significantly lower than that in the sham group at four and six weeks (p<0.05). The average thickness of the GAG-stained area in the mechanical unloading group was significantly lower than that in the sham group at six weeks (p<0.05). CONCLUSION: Mechanical unloading significantly affected the increase in the chondrocyte apoptosis rate, decrease in the chondrocyte proliferation rate, and decrease in the GAG layer thickness at the PT insertion for up to six weeks in rabbits. CLINICAL RELEVANCE: We suggest that more than 6 weeks of mechanical unloading should be avoided to prevent degeneration at the PT insertion. PMID- 26051483 TI - Post-operative bracing after ACL reconstruction has no effect on knee joint effusion. A prospective, randomized study. AB - BACKGROUND: It is unclear what factors contribute to knee joint effusion after anterior cruciate ligament (ACL) injury and reconstruction. Knee homeostasis after injury and surgery is crucial for rehabilitation and knee well-being. We examined if effusion was affected by post-operative bracing, and if patients with effusion fit into a common profile. METHODS: Patients were randomized to wearing or not wearing a post-operative brace for three weeks after ACL reconstruction with semitendinosus-gracilis tendons. Knee joint effusion was detected by computed tomography in 60 patients (22 women), before and three and 12 months after surgery. Joint effusion, clinical and subjective tests were analyzed. RESULTS: This is the first prospective, randomized study on post-operative bracing for patients with a semitendinosus-gracilis graft showed that bracing had no effect on three-months presence of joint effusion. Excessive joint effusion was present in 68% of the patients three months after surgery and was associated to prior meniscus injury (p=0.05) and higher prior Tegner activity level (p=0.006). We found a positive association between longer time from injury to surgery and joint effusion three months post-operatively (rho=0.29, p<0.05). Twelve months post-operatively, joint effusion had diminished to baseline levels. Subjective scores and activity levels were lower for women. Three-months joint effusion predicted lower final outcome scores in women. CONCLUSION: Prior meniscus injury and pre-injury Tegner activity levels are predictive significant variables for excessive knee joint effusion after ACL reconstruction. Post operative bracing had no effect. A larger clinical cohort is needed to confirm findings of this logistic regression. PMID- 26051484 TI - Evaluating patient education material regarding unicompartmental knee arthroplasty. AB - BACKGROUND: Variability in quality and accuracy of information has been well documented in other orthopedic procedures. Given the growing role of the Internet in patient education, it is important to assess the quality of material provided. The purpose of this study was to evaluate online patient education materials regarding unicompartmental knee arthroplasty (UKA). METHOD: The first 50 websites generated from a search of the term, partial knee replacement, using three search engines, Google, Yahoo!, and Bing, were analyzed for quality, content, and authorship. Categorical data between the three search engines were compared using the Freeman-Halton extension for the Fisher's exact test. Fisher's exact test was used to compare categorical data between the search terms partial knee replacement and unicompartmental knee arthroplasty. RESULTS: Most websites mentioned benefits of UKA (69%) but only a minority (39%) mentioned risks. A more technical search term, unicompartmental knee arthroplasty, yielded fewer websites authored by manufacturers/industry and miscellaneous sources (p=0.018 and p=0.039, respectively), more mentions of risks (p=0.0014), and more references to peer-reviewed literature (p=0.0026). CONCLUSIONS: Overall, online information related to UKA is of questionable quality and may be geared more towards attracting patients than providing high-quality information. PMID- 26051485 TI - Giant right groin lipoma mimicking inguinal hernia. AB - INTRODUCTION: Groin lipoma is a rare condition. Such localization may lead to erroneous interpretation of inguinal hernia diagnosis. In case of incorrect diagnosis, there is clinically high risk for development of intraoperative complications. METHODS: The medical history of 70-year old female patient P., who has been hospitalized at Surgical Department No.1 of Danylo Halytsky Lviv National Medical University (Surgical Department of Lviv Regional Clinical Hospital), was processed retrospectively. RESULT: Medical case history totals approximately 20 years. Examination in the right groin revealed a tumor falling to the right labia lip: soft, elastic, moderately painful, passive and active reduction into the abdominal cavity was impossible, and the "cough impulse" symptom was negative. CT correctly diagnosed giant right groin lipoma, which was intraoperatively confirmed. CONCLUSION: Lipoma in the groin may be treated as inguinal hernia. Thus, for the accurate verification of correct diagnosis, it is necessary to perform a follow-up examination involving computer tomography (CT) and nuclear magnetic resonance imaging (NMRI). PMID- 26051486 TI - Comparisons of Objective Sleep Quality Between Elderly Individuals With and Without Cataract Surgery: A Cross-Sectional Study of the HEIJO-KYO Cohort. AB - BACKGROUND: Cataract surgery (CS) drastically increases the capacity for light reception to the retina. Several previous studies have suggested the beneficial effect of CS on subjectively measured sleep quality; however, the association between CS and objectively measured sleep quality remains uncertain. METHODS: To evaluate the association between CS and objectively measured sleep quality in home settings, we conducted a cross-sectional study in 1037 elderly individuals (mean age, 71.9 years). We evaluated actigraphically measured sleep quality, urinary 6-sulfatoxymelatonin excretion, and ambulatory light levels, in addition to CS status. RESULTS: The CS group (n = 174) showed significantly higher sleep efficiency and shorter wake after sleep onset than the no CS group (n = 863), even after adjustment for age, gender, body mass index, current smoking status, alcohol consumption, hypertension, diabetes, sleep medication, bedtime, rising time, daytime physical activity, daytime and nighttime light exposure, and urinary 6-sulfatoxymelatonin excretion (sleep efficiency: 85.8% in the CS group vs 84.4% in the no CS group, P = 0.042; wake after sleep onset: 45.7 min vs 50.6 min, respectively, P = 0.033). In contrast, urinary 6-sulfatoxymelatonin excretion, sleep onset latency, total sleep time, and sleep-mid time did not differ significantly between the CS and no CS groups. CONCLUSIONS: Among a community-dwelling elderly population, CS is significantly associated with objectively measured sleep quality, but urinary levels of melatonin metabolite do not differ between individuals with and without CS. These associations are independent of daily light exposure profiles. PMID- 26051487 TI - The classical versus the Cabrera presentation system for resting electrocardiography: Impact on recognition and understanding of clinically important electrocardiographic changes. AB - The classical system for presentation of the 12-lead electrocardiogram (ECG) reflects the electrical activity of the heart as viewed in the transverse plane by 6 leads with a single anatomically ordered sequence, V1-V6; but in the frontal plane by 6 leads with dual sequences, I, II, and III, and aVR, aVL, and aVF. However, there is also a single anatomically ordered sequence of leads, called the Cabrera display that presents the six frontal plane leads in their anatomically ordered sequence of: aVL, I, -aVR, II, aVF, and III. Although it has been recognized that the Cabrera system has clinical diagnostic advantages compared to the classical display, it is currently only used in Sweden. The primary explanation of why the Cabrera system has not been adopted internationally has been that analog ECG recorders had technical limitations. Currently, however, the classical system is most often seen as a historical remnant that prevails because of conservatism within the cardiology community. PMID- 26051488 TI - The nature of NO-bonding in N-oxide group. AB - The nature of the NO-bond in the N-oxide group was investigated by means of combined theoretical calculations (including QTAIM and NBO approaches) and statistical analyses of the contents of crystal structure databases. The N-O bond in the N-oxide group should be classified as the NO donating bond with an important contribution of ON back-donation (of the pi-electron type, when available). The visualization of the Laplacian of electron density in the region of an oxygen valence sphere suggests the presence of two lone pairs for the imine N-oxide group (characterized by effective ON back-donation). A detailed bonding analysis performed by means of natural resonance theory indicates that the N->O bond is of an order of magnitude clearly greater than 1. In addition, the stability of the N->O bond in various N-oxides was estimated. The analyses of the hydrogen- and halogen-bonded complexes of the N-oxides reveal strong Lewis basicity of the N-oxide group. The formation of H- and X-bonding leads to N->O bond elongation due to its structural, topological and spectroscopic characteristics. Moreover, in pyridine-N-oxide, the electron-withdrawing -NO2 group additionally stabilizes the N->O bond, whereas the opposite effect can be observed for the electron-donating-NH2 substituent. This is due to a substituent effect on the pi-type ON back-donation. As a result, the oxygen atom in pyridine N-oxide may change its availability during intermolecular interaction formation, as revealed in the interaction energy, which changes by about half of the estimated total interaction energy. PMID- 26051489 TI - The Aspergillus fumigatus septins play pleiotropic roles in septation, conidiation, and cell wall stress, but are dispensable for virulence. AB - Septins are a conserved family of GTPases that regulate important cellular processes such as cell wall integrity, and septation in fungi. The requirement of septins for virulence has been demonstrated in the human pathogenic yeasts Candida albicans and Cryptococcus neoformans, as well as the plant pathogen Magnaporthe oryzae. Aspergillus spp. contains five genes encoding for septins (aspA-E). While the importance of septins AspA, AspB, AspC, and AspE for growth and conidiation has been elucidated in the filamentous fungal model Aspergillus nidulans, nothing is known on the role of septins in growth and virulence in the human pathogen Aspergillus fumigatus. Here we deleted all five A. fumigatus septins, and generated certain double and triple septin deletion strains. Phenotypic analyses revealed that while all the septins are dispensable in normal growth conditions, AspA, AspB, AspC and AspE are required for regular septation. Furthermore, deletion of only the core septin genes significantly reduced conidiation. Concomitant with the absence of an electron-dense outer conidial wall, the DeltaaspB strain was also sensitive to anti-cell wall agents. Infection with the DeltaaspB strain in a Galleria mellonella model of invasive aspergillosis showed hypervirulence, but no virulence difference was noted when compared to the wild-type strain in a murine model of invasive aspergillosis. Although the deletion of aspB resulted in increased release of TNF-alpha from the macrophages, no significant inflammation differences in lung histology was noted between the DeltaaspB strain and the wild-type strain. Taken together, these results point to the importance of septins in A. fumigatus growth, but not virulence in a murine model. PMID- 26051490 TI - An Aspergillus flavus secondary metabolic gene cluster containing a hybrid PKS NRPS is necessary for synthesis of the 2-pyridones, leporins. AB - The genome of the filamentous fungus, Aspergillus flavus, has been shown to harbor as many as 56 putative secondary metabolic gene clusters including the one responsible for production of the toxic and carcinogenic, polyketide synthase (PKS)-derived aflatoxins. Except for the production of aflatoxins, cyclopiazonic acid and several other metabolites the capability for metabolite production of most of these putative clusters is unknown. We investigated the regulation of expression of the PKS-non-ribosomal peptide synthetase (NRPS) containing cluster 23 and determined that it produces homologs of the known 2-pyridone leporin A. Inactivation and overexpression of a cluster 23 gene encoding a putative Zn(2) Cys(6) transcription factor (AFLA_066900, lepE) resulted in downregulation of nine and up-regulation of 8, respectively, of the fifteen SMURF-predicted cluster 23 genes thus allowing delineation of the cluster. Overexpression of lepE (OE::lepE) resulted in transformants displaying orange-red pigmented hyphae. Mass spectral analysis of A. flavus OE::lepE extracts identified the known 2-pyridone metabolite, leporin B, as well as the previously unreported dehydroxy-precursor, leporin C. We provide strong evidence that leporin B forms a unique trimeric complex with iron, not found previously for other 2-pyridones. This iron complex demonstrated antiinsectan and antifeedant properties similar to those previously found for leporin A. The OE::lepE strain showed reduced levels of conidia and sclerotia suggesting that unscheduled leporin production affects fungal developmental programs. PMID- 26051491 TI - Development of an Agrobacterium-mediated transformation system for the cold adapted fungi Pseudogymnoascus destructans and P. pannorum. AB - The mechanisms of cold adaptation by fungi remain unknown. This topic is of high interest due to the emergence of white-nose syndrome (WNS), a skin infection of hibernating bats caused by Pseudogymnoascus destructans (Pd). Recent studies indicated that apart from Pd, there is an abundance of other Pseudogymnoascus species in the hibernacula soil. We developed an Agrobacterium tumefaciens mediated transformation (ATMT) system for Pd and a related fungus Pseudogymnoascus pannorum (Pp) to advance experimental studies. URE1 gene encoding the enzyme urease was used as an easy to screen marker to facilitate molecular genetic analyses. A Uracil-Specific Excision Reagent (USER) Friendly pRF-HU2 vector containing Pd or Pp ure1::hygromycin (HYG) disruption cassette was introduced into A. tumefaciens AGL-1 cells by electroporation and the resulting strains were co-cultivated with conidia of Pd or Pp for various durations and temperatures to optimize the ATMT system. Overall, 680 Pd (0.006%) and 1800 Pp (0.018%) transformants were obtained from plating of 10(7) conidia; their recoveries were strongly correlated with the length of the incubation period (96h for Pd; 72h for Pp) and with temperature (15-18 degrees C for Pd; 25 degrees C for Pp). The homologous recombination in transformants was 3.1% for Pd and 16.7% for Pp. The availability of a standardized ATMT system would allow future molecular genetic analyses of Pd and related cold-adapted fungi. PMID- 26051492 TI - A ToxA-like protein from Cochliobolus heterostrophus induces light-dependent leaf necrosis and acts as a virulence factor with host selectivity on maize. AB - ToxA, the first discovered fungal proteinaceous host-selective toxin (HST), was originally identified in 1989 from the tan spot fungus Pyrenophora tritici repentis (Ptr). About 25years later, a homolog was identified in the leaf/glume blotch fungus Stagonospora nodorum (Parastagonospora nodorum), also a pathogen of wheat. Here we report the identification and function of a ToxA-like protein from the maize pathogen Cochliobolus heterostrophus (Ch) that possesses necrosis inducing activity specifically against maize. ChToxA is encoded by a 535-bp open reading frame featuring a ToxA-specific intron with unusual splicing sites (5' ATAAGT...TAC-3') at conserved positions relative to PtrToxA. The protein shows 64% similarity to PtrToxA and is predicted to adopt a similar three-dimensional structure, although lacking the arginyl-glycyl-aspartic acid (RGD) motif reported to be required for internalization into sensitive wheat mesophyll cells. Reverse transcriptase PCR revealed that the ChTOXA gene expression is up-regulated in planta, relative to axenic culture. Plant assays indicated that the recombinant ChToxA protein induces light-dependent leaf necrosis in a host-selective manner on maize inbred lines. Gene deletion experiments confirmed that ChtoxA mutants are reduced in virulence on specific ChToxA-sensitive maize lines, relative to virulence caused by wild-type strains. Database searches identified potential ChToxA homologues in other plant-pathogenic ascomycetes. Sequence and phylogenetic analyses revealed that the corresponding ToxA-like proteins include one member recently shown to be associated with formation of penetration hypha. These results provide the first evidence that C. heterostrophus is capable of producing proteinaceous HSTs as virulence factors in addition to well-known secondary metabolite-type toxins produced biosynthetically by polyketide synthase megaenzymes. Further studies on ChToxA may provide new insights into effector evolution in host-pathogen interactions. PMID- 26051493 TI - Reply: Green tea EGCG plus fish oil omega-3 dietary supplements rescue mitochondrial dysfunctions and are safe in a Down's syndrome child. PMID- 26051494 TI - Chronic consumption of an inositol-enriched carob extract improves postprandial glycaemia and insulin sensitivity in healthy subjects: A randomized controlled trial. AB - BACKGROUND & AIMS: Inositols are thought to be mediators of the insulin signalling pathway. We assessed the effects of inositols on glycaemic control in fasting and postprandial states and evaluated lipoprotein profile and LDL particle size in healthy population. METHODS: A 12-week double-blind clinical trial was performed with forty healthy subjects administered either an inositol enriched beverage (IEB) -containing 2.23 g of inositols in 250 ml- or a sucrose sweetened beverage (SB) twice a day. Anthropometric measurements, fasting glucose levels, insulin and HOMA-IR index, lipoprotein profile and postprandial glucose concentrations (measured using the continuous glucose monitoring system (CGMS)) were recorded throughout the intervention period. RESULTS: Following the 12-week trial subjects receiving the IEB exhibited a significant decrease in insulin, HOMA-IR and Apo B and an increase in LDL particle size, whereas the SB group showed increases in BMI and fasting glucose concentration. Analysis of postprandial glucose levels at breakfast, lunch and dinner revealed a mean reduction of glucose of ~14% and a significant reduction in the area under the curve at 24 h after consumption of the IEB. CONCLUSIONS: Our results show that chronic IEB supplementation induces a significant improvement in carbohydrated metabolism parameters in healthy subjects. PMID- 26051495 TI - Combined intervention of protein supplementation and resistance training in medical patients. PMID- 26051496 TI - Chemical absorption and CO2 biofixation via the cultivation of Spirulina in semicontinuous mode with nutrient recycle. AB - The chemical absorption of carbon dioxide (CO2) is a technique used for the mitigation of the greenhouse effect. However, this process consumes high amounts of energy to regenerate the absorbent and to separate the CO2. CO2 removal by microalgae can be obtained via the photosynthesis process. The objective of this study was to investigate the cultivation and the macromolecules production by Spirulina sp. LEB 18 with the addition of monoethanolamine (MEA) and CO2. In the cultivation with MEA, were obtained higher results of specific growth rate, biomass productivity, CO2 biofixation, CO2 use efficiency, and lower generation time. Besides this, the carbohydrate concentration obtained at the end of this assay was approximately 96.0% higher than the control assay. Therefore, Spirulina can be produced using medium recycle and the addition of MEA, thereby promoting the reduction of CO2 emissions and showing potential for areas that require higher concentrations of carbohydrates, such as in bioethanol production. PMID- 26051497 TI - Effects of hydrolysis and carbonization reactions on hydrochar production. AB - Hydrothermal carbonization (HTC) is a thermal conversion process which converts wet biomass into hydrochar. In this study, a low-energy HTC process named "Two stage HTC" comprising of hydrolysis and carbonization stages using faecal sludge as feedstock was developed and optimized. The experimental results indicated the optimum conditions of the two-stage HTC to be; hydrolysis temperature of 170 degrees C, hydrolysis reaction time of 155 min, carbonization temperature of 215 degrees C, and carbonization reaction time of 100 min. The hydrolysis reaction time and carbonization temperature had a statistically significant effect on energy content of the produced hydrochar. Energy input of the two-stage HTC was about 25% less than conventional HTC. Energy efficiency of the two-stage HTC for treating faecal sludge was higher than that of conventional HTC and other thermal conversion processes such as pyrolysis and gasification. The two-stage HTC could be considered as a potential technology for treating FS and producing hydrochar. PMID- 26051498 TI - The novel intubating laryngeal tube (iLTS-D) is comparable to the intubating laryngeal mask (Fastrach) - a prospective randomised manikin study. AB - BACKGROUND: Supraglottic devices are helpful for inexperienced providers who perform ventilation in emergency situations. Most supraglottic devices do not allow secondary tracheal intubation through the device. The novel intubating laryngeal tube (iLTS-D) and the intubating laryngeal mask (Fastrach) are devices that offer supraglottic ventilation and secondary tracheal intubation. METHODS: We evaluated the novel iLTS-D and compared it to the established Fastrach using a manikin-based study. Participants used both devices in a randomised order. The participants conducted four consecutive trials on a manikin. One trial was composed of the following procedures. First, participants ventilated the manikin using either iLTS-D or Fastrach. 'Time to ventilation', success rates and number of attempts were recorded for the supraglottic device. Second, participants intubated the manikin through the previously inserted supraglottic device. 'Time to tracheal ventilation', success rate and tube localisation were recorded. The primary endpoint was the results of the final fourth trial, which mirrored the standardised training of trials 1, 2 and 3. RESULTS: A total of 64 participants were enrolled. All of the participants successfully inserted both devices on their first attempt in trial 4. Fastrach was applied 1 s faster in trial 4 than the iLTS-D (median 'time to ventilation' Fastrach: 13.5 s., iLTS-D: 14.5 s., p = 0.04). All participants successfully intubated through both devices in trial 4. There was no difference in 'time to tracheal ventilation' by tracheal intubation between either device (median 'time to tracheal ventilation': Fastrach: 14.0 s., iLTS-D: 14.0 s., p = 0.16). CONCLUSION: The iLTS-D performed similarly to the ILMA in insertion and intubation times in a manikin setting. PMID- 26051499 TI - Late toxicity after radical treatment for locally advanced head and neck cancer. AB - BACKGROUND: Multimodal treatment for locally advanced head and neck carcinomas (LAHNC) has been reported to improve survival. However, it is less clear to what extent this survival gain is given at the expense of an impact on the quality of life of our patients. Our aim is to analyze the ongoing late toxic effects among long survivors, to determine how much these impairments affect their QoL, and if there is any factor that clearly impacts on this toxicity. METHODS: 152 Patients diagnosed with LAHNC were treated radically in our clinical practice, either with concomitant chemoradiotherapy or bioradiotherapy, with or without induction chemotherapy. We prospectively assessed these patients' treatment-related late toxicities according to the Radiation Therapy Oncology Group scoring system, and patients answered a QoL question to subjectively evaluate the degree of impact caused by these sequelae in their daily life. Multivariate logistic regressions were performed to detect factors that could influence in toxicity. RESULTS: 21.9% Patients experienced grade 3-4 toxicity. Concomitant chemoradiation with cisplatin was found to be a risk factor of moderate and severe late toxicity compared to concomitant cetuximab in the adjusted analysis by RT fractionation. OR for moderate toxicity 0.292 (CI: 0.125-0.680, p=0.004); OR for severe toxicity: 0.299 (CI: 0.0909-0.999, p=0.05). Induction chemotherapy was found to be a protective factor for moderate late toxicity compared to concomitant treatment alone. CONCLUSION: Patients treated with concomitant chemoradiation with cisplatin have significantly more late toxicity compared to bioradiotherapy, whereas induction chemotherapy prevents from developing moderate late toxicity. PMID- 26051500 TI - Nanodiamonds and silicon quantum dots: ultrastable and biocompatible luminescent nanoprobes for long-term bioimaging. AB - Fluorescence bioimaging is a powerful, versatile, method for investigating, both in vivo and in vitro, the complex structures and functions of living organisms in real time and space, also using super-resolution techniques. Being poorly invasive, fluorescence bioimaging is suitable for long-term observation of biological processes. Long-term detection is partially prevented by photobleaching of organic fluorescent probes. Semiconductor quantum dots, in contrast, are ultrastable, fluorescent contrast agents detectable even at the single nanoparticle level. Emission color of quantum dots is size dependent and nanoprobes emitting in the near infrared (NIR) region are ideal for low back ground in vivo imaging. Biocompatibility of nanoparticles, containing toxic elements, is debated. Recent safety concerns enforced the search for alternative ultrastable luminescent nanoprobes. Most recent results demonstrated that optimized silicon quantum dots (Si QDs) and fluorescent nanodiamonds (FNDs) show almost no photobleaching in a physiological environment. Moreover in vitro and in vivo toxicity studies demonstrated their unique biocompatibility. Si QDs and FNDs are hence ideal diagnostic tools and promising non-toxic vectors for the delivery of therapeutic cargos. Most relevant examples of applications of Si QDs and FNDs to long-term bioimaging are discussed in this review comparing the toxicity and the stability of different nanoprobes. PMID- 26051501 TI - Reprint of: Semantic impairment disrupts perception, memory, and naming of secondary but not primary colours. AB - To investigate how basic aspects of perception are shaped by acquired knowledge about the world, we assessed colour perception and cognition in patients with semantic dementia (SD), a disorder that progressively erodes conceptual knowledge. We observed a previously undocumented pattern of impairment to colour perception and cognition characterized by: (i) a normal ability to discriminate between only subtly different colours but an impaired ability to group different colours into categories, (ii) normal perception and memory for the colours red, green, and blue but impaired perception and memory for colours lying between these regions of a fully-saturated and luminant spectrum, and (iii) normal naming of polar colours in the opponent-process colour system (red, green, blue, yellow, white, and black) but impaired naming of other basic colours (brown, gray, pink, and orange). The results suggest that fundamental aspects of perception can be shaped by acquired knowledge about the world, but only within limits. PMID- 26051502 TI - [The efficacy of physical activity as an aid to smoking cessation]. AB - One over two smokers who smokes all his lifetime will die from a disease related to tobacco use. Tobacco smoking is the primary cause of avoidable death in the world. Medications have an important role in smoking cessation, but physical activity, as well as improving health generally may also represent an important non-pharmacological therapy to help people to stop smoking. The aim of this review was to evaluate the use of physical activity as an aid for smoking cessation and maintaining abstinence. We included 17 randomized controlled trials where the main objective was stopping smoking, and which included at least a six month follow-up of participants. At the end of this review, only 4 trials revealed a benefit of physical activity on smoking cessation; two of them did not show any persistent benefit after the end of the exercise program. On the basis of this, physical activity cannot itself be considered as a way to help stopping smoking. The heterogeneity among studies summarized in this review was an important methodological bias. However, there is strong evidence that physical activity reduces withdrawal symptoms, craving, negative affect and weight gain during smoking cessation. Advice to practice physical activity should therefore be incorporated into smoking cessation programs. PMID- 26051503 TI - [Management of chemotherapy-induced anemia in lung cancer]. AB - INTRODUCTION: The prevalence of chemotherapy-induced anemia in lung cancer is estimated at about 80%. STATE OF ART: There are currently no specific recommendations for the management of chemotherapy-induced anemia in lung cancer. In this paper, we propose a synthesis of currently existing data in the literature on the management of chemotherapy-induced anemia in general, supplemented with specific data about the efficacy and safety of erythropoietic therapy in lung cancer. PERSPECTIVES: Better management of chemotherapy-induced anemia improves patient's quality of life and reduces red blood cell transfusion requirement. In the meantime, in respect to currently missing data, thoracic oncologists should develop specific recommendations for the management of chemotherapy-induced anemia in lung cancer, with specific studies in this domain. CONCLUSIONS: Since the prevalence of chemotherapy-induced anemia in patients with lung cancer is high and has a significant impact on these patients quality of life, a specific prospective management should be implemented as early as possible. PMID- 26051504 TI - High performance of Mn-Co-Ni-O spinel nanofilms sputtered from acetate precursors. AB - Mn-Co-Ni-O (MCN) spinel oxide material, a very important transition metal oxide (TMO) with the best application prospects in information and energy fields, was discovered over five decades ago, but its applications have been impeded by the quality of its films due to the magnitude of deposition challenge. Here we report that high quality of MCN nanofilms can be achieved by sputtering deposition via acetate precursors whose decomposition temperatures are matched to the initial synthesis temperature of the MCN thin films. Excellent performance of MCN nanofilms is demonstrated, combining for the first time preferred orientation, high temperature coefficient of resistance, and moderate resistivity. The film devices show an intrinsic recombination with a much faster rate of the order of a microsecond for the laser-pumped carriers, which is ~3 orders of magnitude larger compared with that of the ceramic material. The electronic structure of the thin films confirms that it is indeed of n-type nature, exhibiting appropriate electronic states consistent with the levels of metal electrodes and semiconductors. The results offer a vital avenue for depositing high performance TMO thin films for advanced oxide devices, and will have great significance for exploiting new applications in modern oxide electronics and optoelectronics. PMID- 26051505 TI - Disease burden of chronic hepatitis C in Brazil. AB - BACKGROUND: Hepatitis C virus infection is a major cause of cirrhosis; hepatocellular carcinoma; and liver transplantation. The aim of this study was to estimate hepatitis C virus disease progression and the burden of disease from a nationwide perspective. METHODS: Using a model developed to forecast hepatitis C virus disease progression and the number of cases at each stage of liver disease; hepatitis C virus-infected population and associated disease progression in Brazil were quantified. The impact of two different strategies was compared: higher sustained virological response and treatment eligibility rates (1) or higher diagnosis and treatment rates associated with increased sustained virological response rates (2). RESULTS: The number of infected individuals is estimated to decline by 35% by 2030 (1,255,000 individuals); while the number of cases of compensated (n=325,900) and decompensated (n=45,000) cirrhosis; hepatocellular carcinoma (n=19,100); and liver-related deaths (n=16,700) is supposed to peak between 2028 and 2032. In strategy 2; treated cases increased over tenfold in 2020 (118,800 treated) as compared to 2013 (11,740 treated); with sustained virological response increased to 90% and treatment eligibility to 95%. Under this strategy; the number of infected individuals decreased by 90% between 2013 and 2030. Compared to the base case; liver-related deaths decreased by 70% by 2030; while hepatitis C virus-related liver cancer and decompensated cirrhosis decreased by 75 and 80%; respectively. CONCLUSIONS: While the incidence and prevalence of hepatitis C virus in Brazil are decreasing; cases of advanced liver disease continue to rise. Besides higher sustained virological response rates; new strategies focused on increasing the proportion of diagnosed patients and eligibility to treatment should be adopted in order to reduce the burden of hepatitis C virus infection in Brazil. PMID- 26051506 TI - Panobinostat: a novel pan-deacetylase inhibitor for the treatment of relapsed or relapsed and refractory multiple myeloma. AB - Outcomes for patients with multiple myeloma (MM) have improved significantly over the past decade. Despite these advances, MM remains incurable and an unmet medical need remains for patients who are relapsed and/or refractory. Panobinostat is a potent, oral pan-deacetylase inhibitor that elicits anti myeloma activity through epigenetic modulation of gene expression and disruption of protein metabolism. Preclinical data demonstrated that panobinostat has synergistic effects on myeloma cells when combined with bortezomib and dexamethasone. In a Phase III clinical trial evaluating bortezomib and dexamethasone in combination with panobinostat or placebo in patients with relapsed or relapsed and refractory MM (PANORAMA 1), panobinostat led to a significant increase in median progression-free survival. Panobinostat is currently under regulatory review with a recent accelerated approval granted for the treatment of relapsed disease, in which both bortezomib and immunomodulatory drugs have failed. Here, we summarize the preclinical, pharmacokinetic and clinical data for panobinostat in MM. PMID- 26051507 TI - Placenta mediates the association between maternal second-hand smoke exposure during pregnancy and small for gestational age. AB - INTRODUCTION: The causal relationship between maternal second-hand smoke (SHS) exposure during pregnancy and small for gestational-age (SGA) has been affirmed, but the mechanism is still unclear. Previous studies have found that the placenta remarkably affects fetal intrauterine growth and that SHS exposure during pregnancy impairs placental growth and decreases placental weight. Therefore, the placenta may mediate the association between maternal SHS exposure during pregnancy and SGA. This study explores whether and to what extent the association between maternal SHS exposure during pregnancy and SGA is mediated by the placenta. METHODS: We investigated 562 pregnant women delivering SGA newborns (cases) and 1581 delivering appropriate-for-gestational-age newborns (controls) in this case-control study. Information on maternal SHS exposure during pregnancy, socio-demographic characteristics and obstetric conditions, including placental weight, were collected at the Maternity and Child Health Care Hospitals of Shenzhen and Foshan in Guangdong, China. Linear and hierarchical logistic regression models were fitted to examine the mediation effects of placental weight on the association between maternal SHS exposure during pregnancy and SGA. RESULTS: After controlling for ethnicity, maternal age, educational level, family income, pre-pregnancy body mass index (BMI), parity, gestational age and newborn gender, maternal SHS exposure during pregnancy was associated with a higher SGA risk (adjusted odds ratio (OR) = 1.26; 95% confidence interval (CI) = 1.03-1.55) and lower placental weight (standard deviation (SD) = -0.15, SE = 0.04). Regression models illustrated that placental weight partially mediated (49.6%; 95% CI = 35.9-63.3%) the association between SHS exposure during pregnancy and SGA. DISCUSSION: Our findings suggest that the placenta plays an intermediary role in how maternal prenatal SHS exposure affects fetal growth. PMID- 26051508 TI - Effects of Personalized Feedback Interventions on Drug-Related Reoffending: a Pilot Study. AB - Addiction is serious problem that requires effective treatment. Previous studies support personalized feedback interventions (PFIs) as an effective treatment for drinking; however, the potential beneficial effects of this treatment on illegal drug use have not been explored. The present study examined the effects of PFIs in a sample of repetitive drug-related offenders. Participants were 50 repetitive drug-related offenders incarcerated in a Japanese prison. They were randomly assigned to the PFIs (n = 20) or control (n = 30) group. The PFIs group received six letters for 3 months, whereas the control group did not undergo any interventions. We defined relapse and recidivism as drug-related reoffending and reentering prison after release, respectively. In the 3.6-year follow-up analysis (range, 0.1-5.8 years), participants' criminal records were examined, and results indicated a decreased risk of relapse and recidivism for the PFIs group relative to the control group, even when controlling for age, educational level, number of prison terms, and sentence length. Thus, our findings suggest that PFIs reduce the likelihood of relapse and recidivism in drug-related offenders. PMID- 26051509 TI - Whole genome sequences of a free-living Pseudomonas sp. strain ML96 isolated from a freshwater Maar Lake. AB - A free living freshwater Pseudomonas strain ML96 was isolated from the Huguangyan Maar Lake in southern China. Genome sequencing of strain ML96 revealed a 4.7 Mb long draft genome consisting of 47 contigs with a G+C content of 64.8%. Its 16S and 23S rRNA gene sequences were 99.8% and 99.3% identical to those of its closest relative, Pseudomonas alcaligenes NBRC 14159, respectively. ML96's genome shared 73% orthologous CDS (3256/4457) with the genome of NBRC 14159. Comparative genomics analysis provide further insight into the diversity and evolution of aquatic Pseudomonas species, which may help enhance our understanding of this both environmentally and medically important group of bacteria. PMID- 26051510 TI - Adherence to cancer prevention recommendations and antioxidant and inflammatory status in premenopausal women. AB - For cancer prevention, the World Cancer Research Fund and American Institute for Cancer Research (WCRF/AICR) emphasise recommendations to improve individual behaviour, including avoidance of tobacco products, maintaining a lean body mass, participating in physical activity, consuming a plant-based diet, and minimising the consumption of energy-dense foods, such as sodas, red and processed meats and alcohol. In the present study of 275 healthy premenopausal women, we explored the association of adherence scores with levels of three biomarkers of antioxidant and inflammation status: serum C-reactive protein (CRP), serum gamma-tocopherol and urinary F2-isoprostane. The statistical analysis applied linear regression across categories of adherence to WCRF/AICR recommendations. Overall, seventy-two women were classified as low ( <= 4), 150 as moderate (5-6), and fifty-three as high adherers ( >= 7). The unadjusted means for CRP were 2.7, 2.0 and 1.7 mg/l for low, moderate and high adherers (P trend= 0.03); this association was strengthened after adjustment for confounders (P trend= 0.006). The respective values for serum gamma-tocopherol were 1.97, 1.63 and 1.45 MUg/ml (P trend= 0.02 before and P trend= 0.03 after adjustment). Only for urinary F2-isoprostane, the lower values in high adherers (16.0, 14.5, and 13.3 ng/ml) did not reach statistical significance (P trend= 0.18). In an analysis by BMI, overweight and obese women had higher biomarker levels than normal weight women; the trend was significant for CRP (P trend< 0.001) and gamma-tocopherol (P trend= 0.003) but not for F2-isoprostane (P trend= 0.14). These findings suggest that both adherence to the WCRF/AICR guidelines and normal BMI status are associated with lower levels of biomarkers that indicate oxidative stress and inflammation. PMID- 26051511 TI - Adults with mild to moderate depression exhibit more alcohol related problems compared to the general adult population: a cross sectional study. AB - BACKGROUND: Alcohol use has been shown to interfere with treatment for depression, but consumption habits are not routinely screened in primary care. To date, few studies have compared the alcohol consumption habits of patients with depression to the general population. The purpose of this study was to compare alcohol habits in adults diagnosed with depression in primary care to the general adult population in Sweden. METHODS: Nine hundred fourty six patients diagnosed with mild to moderate depression, without a primary substance use disorder, in primary care settings located across Sweden completed the Alcohol Use Disorders Identification Test (AUDIT). Consumptions habits and alcohol related problems in the depressed sample were compared to those in the general adult population (n = 663). Analyses were stratified by gender and age. RESULTS: Ratings of alcohol problems and measures of hazardous drinking and binge drinking were significantly higher among patients seeking treatment for depression in primary care compared to the general population. Male patients scored higher on the AUDIT total and AUDIT-C (consumption) subscale than men in the general population. Compared to younger adults (aged 17-27) older depressed adults (aged 28-50 and 51-71) exhibited higher rates of consumption and problems related to alcohol. CONCLUSIONS: Compared to the general adult population, consumption and problems related to alcohol use were substantially higher among patients with mild to moderate depression in primary care. Routine screening of alcohol use in primary care is recommended for patients presenting with depression. PMID- 26051512 TI - The swine CD81 enhances E2-based DNA vaccination against classical swine fever. AB - Classical swine fever (CSF) is a highly contagious and economically important viral disease that affects the pig industry worldwide. The glycoprotein E2 of CSFV can induce neutralizing antibodies and protective immunity, and is widely used for novel vaccine development. The objective of this study was to explore whether a tetraspanin molecule CD81 could improve the immune responses of an E2 based DNA vaccine. Plasmids pVAX-CD81, pVAX-E2 and pVAX-CD81-E2 were constructed and the expression of target proteins was confirmed in BHK-21 cells by indirect immunofluorescence assay. BALB/c mice were divided into 5 groups and immunized with different plasmids (pVAX-E2, pVAX-CD81-E2, pVAX-E2+pVAX-CD81, pVAX-CD81 and PBS) three times with two weeks interval. The results showed that the introduction of CD81 promoted higher humoral and cellular immune responses than E2 expression alone (P<0.05). In addition, immunization with pVAX-CD81-E2 induced stronger immune responses than pVAX-E2+pVAX-CD81. Furthermore, four groups of pigs were immunized with pVAX-E2, pVAX-CD81-E2, pVAX-CD81 and PBS, respectively. Humoral and cellular immune responses detection showed similar results with those in mice. Compared to pVAX-E2, pVAX-CD81-E2 induced higher titers of neutralizing antibodies after viral challenge and conferred stronger protection. These results confirmed the capacity of swine CD81 enhancing the humoral and cellular responses with an adjuvant effect on CSFV DNA vaccine. This is the first report demonstrating the adjuvant effect of CD81 to enhance the DNA vaccination for swine pathogen. PMID- 26051513 TI - Vaccination of pigs reduces Torque teno sus virus viremia during natural infection. AB - Anelloviruses are a group of single-stranded circular DNA viruses infecting several vertebrate species. Four species have been found to infect swine, namely Torque teno sus virus (TTSuV) 1a and 1b (TTSuV1a, TTSuV1b; genus Iotatorquevirus), TTSuVk2a and TTSuVk2b (genus Kappatorquevirus). TTSuV infection in pigs is distributed worldwide, and is characterized by a persistent viremia. However, the real impact, if any, on the pig health is still under debate. In the present study, the impact of pig immunization on TTSuVk2a loads was evaluated. For this, three-week old conventional pigs were primed with DNA vaccines encoding the ORF2 gene and the ORF1-A, ORF1-B, and ORF1-C splicing variants and boosted with purified ORF1-A and ORF2 Escherichia coli proteins, while another group served as unvaccinated control animals, and the viral load dynamics during natural infection was observed. Immunization led to delayed onset of TTSuVk2a infection and at the end of the study when the animals were 15 weeks of age, a number of animals in the immunized group had cleared the TTSuVk2a viremia, which was not the case in the control group. This study demonstrated for the first time that TTSuV viremia can be controlled by a combined DNA and protein immunization, especially apparent two weeks after the first DNA immunization before seroconversion was observed. Further studies are needed to understand the mechanisms behind this and its impact for pig producers. PMID- 26051514 TI - Global age distribution of pediatric norovirus cases. AB - Norovirus is increasingly recognized as a major cause of acute gastroenteritis among children <5 years of age. We searched for publications that reported detailed age distributions of pediatric norovirus cases, and assessed associations between age distribution and socio-demographic factors to identify the most critical age periods to prevent norovirus cases among young children. Approximately 70% of pediatric norovirus cases occurred between 6 and 23 months of age. A younger age distribution was found in lower income countries and inpatient settings. These findings suggest that a norovirus immunization schedule completed by 6 months could have the potential to prevent about 85% of pediatric cases, while a vaccine delivered at 12 months of age would only have the potential to prevent about 50% of pediatric cases. With a younger age distribution in lower income settings, early prevention would be even more critical. PMID- 26051515 TI - Modelling the immunological response to a tetravalent dengue vaccine from multiple phase-2 trials in Latin America and South East Asia. AB - BACKGROUND: The most advanced dengue vaccine candidate is a live-attenuated recombinant vaccine containing the four dengue viruses on the yellow fever vaccine backbone (CYD-TDV) developed by Sanofi Pasteur. Several analyses have been published on the safety and immunogenicity of the CYD-TDV vaccine from single trials but none modelled the heterogeneity observed in the antibody responses elicited by the vaccine. METHODS: We analyse the immunogenicity data collected in five phase-2 trials of the CYD-TDV vaccine. We provide a descriptive analysis of the aggregated datasets and fit the observed post-vaccination PRNT50 titres against the four dengue (DENV) serotypes using multivariate regression models. RESULTS: We find that the responses to CYD-TDV are principally predicted by the baseline immunological status against DENV, but the trial is also a significant predictor. We find that the CYD-TDV vaccine generates similar titres against all serotypes following the third dose, though DENV4 is immunodominant after the first dose. CONCLUSIONS: This study contributes to a better understanding of the immunological responses elicited by CYD-TDV. The recent availability of phase-3 data is a unique opportunity to further investigate the immunogenicity and efficacy of the CYD-TDV vaccine, especially in subjects with different levels of pre-existing immunity against DENV. Modelling multiple immunological outcomes with a single multivariate model offers advantages over traditional approaches, capturing correlations between response variables, and the statistical method adopted in this study can be applied to a variety of infections with interacting strains. PMID- 26051516 TI - A commercial PCV2a-based vaccine is effective in protection from experimental challenge of PCV2 mutant with two amino acids elongation in capsid protein. AB - Current commercial PCV2 vaccines are almost based on PCV2a and have been shown to be effective in reducing PCV2a and PCV2b viremia and PCV2-associated lesions and diseases. The recent emergence of novel mutant PCV2 (mPCV2) strains and linkage of mPCV2 with cases of porcine circovirus associated disease (PCVAD) in pig herds have raised concerns over emergence of vaccine-escape mutants and reduced efficacy of PCV2a-based vaccines. The aim of this study was to determine the ability of a commercial PCV2a-based vaccine developed by our laboratory to protect conventional pigs against experimental challenge with mPCV2 at 9 weeks of age. Twenty 4-week-old pigs free of PCV2 infection were randomly divided into four treatment groups with 5 pigs each. Two groups were unvaccinated as positive and negative controls. Another two groups were vaccinated with the commercial PCV2a-based vaccine (PCV2-LG strain, China) at 4 weeks of age and identical booster immunization was conducted 3 weeks post primary immunization. At 9 weeks of age, all pigs except the negative control were challenged with a mutant PCV2b/YJ (mPCV2b/YJ) with two amino acids elongation in capsid protein. The experiment was terminated 28 days after challenge. Under the conditions of this study, vaccinated pigs were protected against PCV2 viremia and lesions whereas unvaccinated pigs were not. Moreover, mPCV2b/YJ infection was demonstrated in positive control and almost all had macroscopic or microscopic lesions consistent with PCVAD while negative control did not develop PCVAD. This study indicates that mPCV2b/YJ infection alone can trigger PCVAD development and that the commercial vaccine (PCV2-LG) is still effective in protecting conventional pigs against the emerging mPCV2b/YJ strain in China. PMID- 26051517 TI - A novel linear neutralizing epitope of hepatitis E virus. AB - Hepatitis E virus (HEV) is a serious public health problem that causes acute hepatitis in humans and is primarily transmitted through fecal and oral routes. The major anti-HEV antibody responses are against conformational epitopes located in a.a. 459-606 of HEV pORF2. All reported neutralization epitopes are present on the dimer domain constructed by this peptide. While looking for a neutralizing monoclonal antibody (MAb)-recognized linear epitope, we found a novel neutralizing linear epitope (L2) located in a.a. 423-437 of pORF2. Moreover, epitope L2 is proved non-immunodominant in the HEV-infection process. Using the hepatitis B virus core protein (HBc) as a carrier to display this novel linear epitope, we show herein that this epitope could induce a neutralizing antibody response against HEV in mice and could protect rhesus monkeys from HEV infection. Collectively, our results showed a novel non-immunodominant linear neutralizing epitope of hepatitis E virus, which provided additional insight of HEV vaccine. PMID- 26051519 TI - Modulation effects of sweroside isolated from the Lonicera japonica on melanin synthesis. AB - In the course of screening for the melanogenesis inhibitors, sweroside was isolated from Lonicera japonica. Its chemical structure was determined on the basis of spectroscopic analysis, including mass spectroscopy and nuclear magnetic resonance analysis. Sweroside inhibited potent melanogenesis in melan-a cells at 300MUM without cytotoxicity. Also, sweroside decreased tyrosinase, tyrosinase related protein-1 (TRP-1) and TRP-2 protein production in melan a cells. To identify the signaling pathway of sweroside, the ability of sweroside to influence Akt and extracellular signal-regulated protein kinase (ERK) activation was investigated. Sweroside induced Akt and ERK in a dose-dependent manner. In addition, the specific inhibition of the Akt and ERK signaling pathways were studied by specific inhibitor LY294002 and U0126, respectively and it was causing the increased melanin synthesis. Furthermore, sweroside presented inhibition of the body pigmentation and tyrosinase activity in zebrafish in vivo model. These results suggest that sweroside isolated from L. japonica may be an effective skin whitening agent through the regulates the expression of MAP kinase and melanogenic enzymes. PMID- 26051518 TI - Bioreactor-engineered cancer tissue-like structures mimic phenotypes, gene expression profiles and drug resistance patterns observed "in vivo". AB - Anticancer compound screening on 2D cell cultures poorly predicts "in vivo" performance, while conventional 3D culture systems are usually characterized by limited cell proliferation, failing to produce tissue-like-structures (TLS) suitable for drug testing. We addressed engineering of TLS by culturing cancer cells in porous scaffolds under perfusion flow. Colorectal cancer (CRC) HT-29 cells were cultured in 2D, on collagen sponges in static conditions or in perfused bioreactors, or injected subcutaneously in immunodeficient mice. Perfused 3D (p3D) cultures resulted in significantly higher (p < 0.0001) cell proliferation than static 3D (s3D) cultures and yielded more homogeneous TLS, with morphology and phenotypes similar to xenografts. Transcriptome analysis revealed a high correlation between xenografts and p3D cultures, particularly for gene clusters regulating apoptotic processes and response to hypoxia. Treatment with 5-Fluorouracil (5-FU), a frequently used but often clinically ineffective chemotherapy drug, induced apoptosis, down-regulation of anti-apoptotic genes (BCL-2, TRAF1, and c-FLIP) and decreased cell numbers in 2D, but only "nucleolar stress" in p3D and xenografts. Conversely, BCL-2 inhibitor ABT-199 induced cytotoxic effects in p3D but not in 2D cultures. Our findings advocate the importance of perfusion flow in 3D cultures of tumor cells to efficiently mimic functional features observed "in vivo" and to test anticancer compounds. PMID- 26051520 TI - Anti-inflammatory effect of thalidomide dithiocarbamate and dithioate analogs. AB - Thalidomide has anti-inflammatory, immunomodulatory, and anti-angiogenic properties. It has been used to treat a variety of cancers and autoimmune diseases. This study aimed to characterize anti-inflammatory activities of novel thalidomide analogs by exploring their effects on splenocytes proliferation and macrophage functions and their antioxidant activity. MTT assay was used to assess the cytotoxic effect of thalidomide analogs against splenocytes. Tumor necrosis factor (TNF-alpha) and nuclear factor kappa B (NF-kappaB-P65) were determined by enzyme-linked immunosorbent assay (ELISA). Nitric oxide (NO) was estimated by colorimetric assay. Antioxidant activity was examined by ORAC assay. Our results demonstrated that thalidomide dithioate analog 2 and thalidomide dithiocarbamate analog 4 produced a slight increase in splenocyte proliferation compared with thalidomide. Thalidomide dithiocarbamate analog 1 is a potent inhibitor of TNF alpha production, whereas thalidomide dithiocarbamate analog 5 is a potent inhibitor of both TNF-alpha and NO. Analog 2 has a pronounced inhibitory effect on NF-kappaB-P65 production level. All thalidomide analogs showed prooxidant activity against hydroxyl (OH) radical. Analog 1 and thalidomide dithioate analog 3 have prooxidant activity against peroxyl (ROO) radical in relation to thalidomide. On the other hand, analog 4 has a potent scavenging capacity against peroxyl (ROO) radical compared with thalidomide. Taken together, the results of this study suggest that thalidomide analogs might have valuable anti-inflammatory activities with more pronounced effect than thalidomide itself. PMID- 26051521 TI - Structure based 3D-QSAR studies of Interleukin-2 inhibitors: Comparing the quality and predictivity of 3D-QSAR models obtained from different alignment methods and charge calculations. AB - Interleukin-2 is an essential cytokine in an innate immune response, and is a promising drug target for several immunological disorders. In the present study, structure-based 3D-QSAR modeling was carried out via Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Index Analysis (CoMSIA) methods. Six different partial charge calculation methods were used in combination with two different alignment methods to scrutinize their effects on the predictive power of 3D-QSAR models. The best CoMFA and CoMSIA models were obtained with the AM1 charges when used with co-conformer based substructure alignment (CCBSA) method. The obtained models posses excellent correlation coefficient value and also exhibited good predictive power (for CoMFA: q(2)=0.619; r(2)=0.890; r(2)Pred=0.765 and for CoMSIA: q(2)=0.607; r(2)=0.884; r(2)Pred=0.655). The developed models were further validated by using a set of another sixteen compounds as external test set 2 and both models showed strong predictive power with r(2)Pred=>0.8. The contour maps obtained from these models better interpret the structure activity relationship; hence the developed models would help to design and optimize more potent IL-2 inhibitors. The results might have implications for rational design of specific anti-inflammatory compounds with improved affinity and selectivity. PMID- 26051522 TI - Nitrite attenuated hypochlorous acid-mediated heme degradation in hemoglobin. AB - Hypochlorous acid (HOCl) is elevated in many inflammatory diseases and causes the accumulation of free iron. Through the Fenton reaction, free iron has the ability to generate free radicals and subsequently is toxic. Recent studies have demonstrated that HOCl participates in heme destruction of hemoglobin (Hb) and free iron release. In this study, it was showed that nitrite (NO2(-)) could prevent HOCl-mediated Hb heme destruction and free iron release. Also, NO2(-) prevented HOCl-mediated loss of Hb peroxidase activity. After the NO2(-)/HOCl treatment, Tyr 42 in alpha-chain was found to be nitrated in Hb, attenuating the electron transferring abilities of phenolic compounds. The protective effects of NO2(-) on HOCl-induced heme destruction were attributed to its reduction of ferryl Hb and/or direct scavenging of HOCl. Therefore, NO2(-) could show protective effects in some inflammatory diseases by preventing HOCl-mediated heme destruction of hemoproteins and free iron release. PMID- 26051523 TI - Hydrogen production from continuous flow, microbial reverse-electrodialysis electrolysis cells treating fermentation wastewater. AB - A microbial reverse-electrodialysis electrolysis cell (MREC) was used to produce hydrogen gas from fermentation wastewater without the need for additional electrical energy. Increasing the number of cell pairs in the reverse electrodialysis stack from 5 to 10 doubled the maximum current produced from 60 A/m(3) to 120 A/m(3) using acetate. However, more rapid COD removal required a decrease in the anolyte hydraulic retention time (HRT) from 24 to 12 h to stabilize anode potentials. Hydrogen production using a fermentation wastewater (10 cell pairs, HRT=8 h) reached 0.9+/-0.1 L H2/Lreactor/d (1.1+/-0.1 L H2/g COD), with 58+/-5% COD removal and a coulombic efficiency of 74+/-5%. These results demonstrated that consistent rates of hydrogen gas production could be achieved using an MREC if effluent anolyte COD concentrations are sufficient to produce stable anode potentials. PMID- 26051524 TI - Microbial surface displayed enzymes based biofuel cell utilizing degradation products of lignocellulosic biomass for direct electrical energy. AB - In this work, a bacterial surface displaying enzyme based two-compartment biofuel cell for the direct electrical energy conversion from degradation products of lignocellulosic biomass is reported. Considering that the main degradation products of the lignocellulose are glucose and xylose, xylose dehydrogenase (XDH) displayed bacteria (XDH-bacteria) and glucose dehydrogenase (GDH) displayed bacteria (GDH-bacteria) were used as anode catalysts in anode chamber with methylene blue as electron transfer mediator. While the cathode chamber was constructed with laccase/multi-walled-carbon nanotube/glassy-carbon-electrode. XDH-bacteria exhibited 1.75 times higher catalytic efficiency than GDH-bacteria. This assembled enzymatic fuel cell exhibited a high open-circuit potential of 0.80 V, acceptable stability and energy conversion efficiency. Moreover, the maximum power density of the cell could reach 53 MUW cm(-2) when fueled with degradation products of corn stalk. Thus, this finding holds great potential to directly convert degradation products of biomass into electrical energy. PMID- 26051525 TI - Analysis of organic gas phase compounds formed by hydrothermal liquefaction of Dried Distillers Grains with Solubles. AB - This work provides a comprehensive characterization of the gas phase from hydrothermal liquefaction of Dried Distillers Grains with Solubles (DDGS) collected during a 24-h continuous experiment. The gas consisted mainly of CO2, CO, H2, CH4 and C2H6 accounting for 96 v/v% while further analysis by gas chromatography coupled to mass spectrometry (GC-MS) showed additionally 62 compounds of which 54 were tentatively identified. These products included methanethiol, dimethyl sulfide, various olefins and several aromatic compounds. The composition provided clear indication of the steady state of the system. Apart from CO2, olefins were the most abundant compound class and could provide a source of revenue. PMID- 26051526 TI - Drawing and writing: An ALE meta-analysis of sensorimotor activations. AB - Drawing and writing are the two major means of creating what are referred to as "images", namely visual patterns on flat surfaces. They share many sensorimotor processes related to visual guidance of hand movement, resulting in the formation of visual shapes associated with pictures and words. However, while the human capacity to draw is tens of thousands of years old, the capacity for writing is only a few thousand years old, and widespread literacy is quite recent. In order to compare the neural activations for drawing and writing, we conducted two activation likelihood estimation (ALE) meta-analyses for these two bodies of neuroimaging literature. The results showed strong overlap in the activation profiles, especially in motor areas (motor cortex, frontal eye fields, supplementary motor area, cerebellum, putamen) and several parts of the posterior parietal cortex. A distinction was found in the left posterior parietal cortex, with drawing showing a preference for a ventral region and writing a dorsal region. These results demonstrate that drawing and writing employ the same basic sensorimotor networks but that some differences exist in parietal areas involved in spatial processing. PMID- 26051527 TI - The time course for visual extinction after a 'virtual' lesion of right posterior parietal cortex. AB - Our understanding of the attentional networks in the human brain largely relies on neuropsychological studies in patients with lesions to the posterior parietal cortex (PPC), particularly in the right hemisphere, that may cause severe disruptions of attentional functions. However, lesion studies only capture a point in time when the dysfunctions caused by the damage have triggered a chain of adaptive responses in the brain. To disentangle deficits and ensuing cortical plasticity, here we examined the time course for one's ability to detect objects in the visual periphery after an inhibitory continuous theta-burst stimulation (cTBS) protocol to the left or right PPC. Our results showed that cTBS of right PPC caused participants to be less sensitive to objects appearing on the left side as well as to objects appearing on both sides at the same time, consistent with an overall shift of attention to the right side of space. In addition, we found that participants missed more objects during bilateral presentations similar to patients with visual extinction. Critically, extinction evolved over time; that is, visual extinction for ipsilateral objects improved after 10 min whereas contralateral extinction peaked around 15-25 min after cTBS. Our findings suggest that lesions to the PPC impair competition between the two visual hemifields, resulting in contralateral extinction as a secondary response, arguably due to ensuing disruptions in interhemispheric balance. PMID- 26051528 TI - Advanced life simulation: High-fidelity simulation without the high technology. AB - Simulation-based resuscitation education has emerged as a key to improving patient safety and numerous healthcare organisations have invested in high fidelity simulation training centres. However, the high purchasing cost, limited portability, technical expertise and organisational skills required to coordinate these high-fidelity simulation centres are factors that limit their use as a wide spread teaching and learning method. Creative innovation is required. The aim of this study was to pilot an inexpensive, portable, novel high fidelity humanistic simulation modality, for educating nurses and doctors in recognising and responding to the deteriorating patient. Analysis of five focus group discussions revealed the main theme of engagement in the simulation experience with three main subthemes of realism of the character, believability of the experience and being more connected. In conclusion, this innovative simulation modality offers a viable alternative for resuscitation training. PMID- 26051529 TI - Control of ventricular excitability by neurons of the dorsal motor nucleus of the vagus nerve. AB - BACKGROUND: The central nervous origins of functional parasympathetic innervation of cardiac ventricles remain controversial. OBJECTIVE: This study aimed to identify a population of vagal preganglionic neurons that contribute to the control of ventricular excitability. An animal model of synuclein pathology relevant to Parkinson's disease was used to determine whether age-related loss of the activity of the identified group of neurons is associated with changes in ventricular electrophysiology. METHODS: In vivo cardiac electrophysiology was performed in anesthetized rats in conditions of selective inhibition of the dorsal vagal motor nucleus (DVMN) neurons by pharmacogenetic approach and in mice with global genetic deletion of all family members of the synuclein protein. RESULTS: In rats anesthetized with urethane (in conditions of systemic beta adrenoceptor blockade), muscarinic and neuronal nitric oxide synthase blockade confirmed the existence of a tonic parasympathetic control of cardiac excitability mediated by the actions of acetylcholine and nitric oxide. Acute DVMN silencing led to shortening of the ventricular effective refractory period (vERP), a lowering of the threshold for triggered ventricular tachycardia, and prolongation of the corrected QT (QTc) interval. Lower resting activity of the DVMN neurons in aging synuclein-deficient mice was found to be associated with vERP shortening and QTc interval prolongation. CONCLUSION: Activity of the DVMN vagal preganglionic neurons is responsible for tonic parasympathetic control of ventricular excitability, likely to be mediated by nitric oxide. These findings provide the first insight into the central nervous substrate that underlies functional parasympathetic innervation of the ventricles and highlight its vulnerability in neurodegenerative diseases. PMID- 26051530 TI - Stepwise ablation approach versus pulmonary vein isolation in patients with paroxysmal atrial fibrillation: Randomized controlled trial. AB - BACKGROUND: Pulmonary vein isolation (PVI) is a central procedure for the treatment of paroxysmal atrial fibrillation (PAF). However, in patients with PAF and structural atrial disease, PVI may fail and cause progressive atrial remodeling, often leading to persistent/permanent atrial fibrillation. OBJECTIVE: We performed a prospective, single-blind, 2-center randomized controlled trial to compare the efficacy of PVI alone with that of PVI plus stepwise ablation in achieving sinus rhythm and nonatrial arrhythmia inducibility in patients with PAF refractory to antiarrhythmic therapy. METHODS: Patients were randomized to perform a first catheter ablation procedure either through PVI alone or through PVI plus substrate modification in stepwise ablation. Data were recorded at 3, 6, and 12 months after both ablation procedures. Patients who experienced atrial fibrillation/atrial tachycardia (AF/AT) recurrence were encouraged to undergo repeat ablation using the technique of the first ablation procedure. RESULTS: A total of 150 patients were enrolled (mean age 62.8 +/- 8.7 years; 92 (61.3%) men; 104 (69.3%) hypertensive; AF mean duration 10.7 months), with 75 patients in each group. After 12 months of the first procedure, patients who were converted to sinus rhythm using stepwise ablation showed a significantly lower rate of AF/AT recurrence (26.7%) than did those who were treated using PVI alone (46.7%; P < .001). Similar results were observed in the 52 patients who underwent a second catheter ablation procedure. After adjusting for several potential confounders, the hazard ratio of 12-month AF/AT recurrence after the first ablation procedure was 0.53 (95% confidence interval 0.30-0.91) for those treated using stepwise ablation. CONCLUSION: In addition to PVI, stepwise ablation achieving sinus rhythm and nonatrial arrhythmia inducibility has relevantly improved the clinical outcome of the PAF control strategy. PMID- 26051531 TI - Association of pretreatment with angiotensin-converting enzyme inhibitors with improvement in ablation outcome in atrial fibrillation patients with low left ventricular ejection fraction. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) reduce the incidence of atrial fibrillation (AF). OBJECTIVE: The purpose of this study was to assess the impact of upstream ACEI therapy on postablation AF recurrence and hospitalization in patients with low left ventricular ejection fraction (LVEF). METHODS: Three hundred forty-five consecutive patients undergoing first AF ablation with low LVEF (<=45%) were classified into group 1 (ACEI+, n = 187 [54%], of whom 44 patients [23.5%] had paroxysmal AF [PAF]) or group 2 (ACEI-, n = 158 [46%]; 31 of these 158 patients [19.6%] had PAF). Additionally, 703 consecutive patients with LVEF >45% undergoing first AF ablation were included for a secondary analysis to evaluate the effect of ACEI treatment in normal ejection fraction. In group 1, ACEI therapy started >=3 months before ablation and continued through follow-up. RESULTS: Baseline characteristics were similar except for hypertension, which was significantly more prevalent in ACEI+ (71% vs 51%, P < .001). At 24 +/- 7 months of follow-up, 109 nonparoxysmal AF patients in group 1 (76%) and 81 (64%) in group 2 (P = .015) were recurrence free. In multivariate analysis, ACEI therapy was an independent predictor of recurrence (hazard ratio for ACEI-, 1.7, 95% confidence interval 1.1-2.7; P = .026]. However, among PAF patients, ACEI use was not associated with ablation success (80% vs 77% in ACEI+ and ACEI-, respectively; P = .82). In the normal-EF population, the success rates between ACEI+ and ACEI- cohorts were similar (71% vs 74%, P = .31). After the index procedure, 17 patients (9.1%) in the ACEI+ group and 28 (17.7%) in the ACEI- cohort (P= .02) required rehospitalization, for a 49% relative risk reduction (relative risk 0.51, 95% confidence interval 0.29 0.90). CONCLUSION: Preablation use of an ACEI is associated with improvement in ablation outcome in patients with nonparoxysmal AF with low LVEF. PMID- 26051532 TI - What can mechanics teach electricians about arrhythmias in heart failure? PMID- 26051533 TI - Effects of different electrolytes on the electrochemical and dynamic behavior of electric double layer capacitors based on a porous silicon carbide electrode. AB - Controlling the structure and morphology of porous electrode materials is an effective strategy for realizing a high surface area and efficient paths for ion diffusion. Moreover, excellent electrical conductivity can significantly decrease the internal resistance of an electrode by the formation of a conductive network and facilitate the application of electrostatic charges, which favors the accumulation of an electrical double layer. In light of these facts, we demonstrate the fabrication of beta-polytype porous silicon carbide spheres (PSiCS) with a hierarchical pore structure in which micro- and mesopores are interconnected with a mesoporous network. Further, to investigate the effects of the electrolyte on the electrochemical and dynamic behavior, two-electrode symmetrical supercapacitors based on the PSiCS electrode with an aqueous electrolyte (1 M potassium chloride, KCl) or an organic electrolyte (1 M tetraethylammonium tetrafluoroborate in acetonitrile, TEABF4/AN) were assembled. The symmetrical supercapacitor based on the PSiCS electrode with the aqueous electrolyte exhibited a high charge-storage capacity with a specific capacitance of 82.9 F g(-1) at a scan rate of 5 mV s(-1), which is much higher than that obtained using the organic electrolyte (60.3 F g(-1) at a scan rate of 5 mV s( 1)). However, the energy density of the organic electrolyte system was 102.59 W h kg(-1) at a scan rate of 5 mV s(-1), which is greatly superior to that of the aqueous electrolyte system (energy density: 29.47 W h kg(-1)) owing to the wide cell operating voltage range. PMID- 26051534 TI - Impaired E Prostanoid2 Expression and Resistance to Prostaglandin E2 in Nasal Polyp Fibroblasts from Subjects with Aspirin-Exacerbated Respiratory Disease. AB - Recurrent, rapidly growing nasal polyps are hallmarks of aspirin-exacerbated respiratory disease (AERD), although the mechanisms of polyp growth have not been identified. Fibroblasts are intimately involved in tissue remodeling, and the growth of fibroblasts is suppressed by prostaglandin E2 (PGE2), which elicits antiproliferative effects mediated through the E prostanoid (EP)2 receptor. We now report that cultured fibroblasts from the nasal polyps of subjects with AERD resist this antiproliferative effect. Fibroblasts from polyps of subjects with AERD resisted the antiproliferative actions of PGE2 and a selective EP2 agonist (P < 0.0001 at 1 MUM) compared with nasal fibroblasts from aspirin-tolerant control subjects undergoing polypectomy or from healthy control subjects undergoing concha bullosa resections. Cell surface expression of the EP2 receptor protein was lower in fibroblasts from subjects with AERD than in fibroblasts from healthy control subjects and aspirin-tolerant subjects (P < 0.01 for both). Treatment of the fibroblasts with trichostatin A, a histone deacetylase inhibitor, significantly increased EP2 receptor mRNA in fibroblasts from AERD and aspirin-tolerant subjects but had no effect on cyclooxygenase-2, EP4, and microsomal PGE synthase 1 (mPGES-1) mRNA levels. Histone acetylation (H3K27ac) at the EP2 promoter correlated strongly with baseline EP2 mRNA (r = 0.80; P < 0.01). These studies suggest that the EP2 promotor is under epigenetic control, and one explanation for PGE2 resistance in AERD is an epigenetically mediated reduction of EP2 receptor expression, which could contribute to the refractory nasal polyposis typically observed in this syndrome. PMID- 26051536 TI - [Failure mode and effects analysis on computerized drug prescriptions]. AB - OBJECTIVE: To identify and analyze errors in drug prescriptions of patients treated in a "high resolution" hospital by applying a Failure mode and effects analysis (FMEA).Material and methods A multidisciplinary group of medical specialties and nursing analyzed medical records where drug prescriptions were held in free text format. An FMEA was developed in which the risk priority index (RPI) was obtained from a cross-sectional observational study using an audit of the medical records, carried out in 2 phases: 1) Pre-intervention testing, and (2) evaluation of improvement actions after the first analysis. An audit sample size of 679 medical records from a total of 2,096 patients was calculated using stratified sampling and random selection of clinical events. RESULTS: Prescription errors decreased by 22.2% in the second phase. FMEA showed a greater RPI in "unspecified route of administration" and "dosage unspecified", with no significant decreases observed in the second phase, although it did detect, "incorrect dosing time", "contraindication due to drug allergy", "wrong patient" or "duplicate prescription", which resulted in the improvement of prescriptions. CONCLUSIONS: Drug prescription errors have been identified and analyzed by FMEA methodology, improving the clinical safety of these prescriptions. This tool allows updates of electronic prescribing to be monitored. To avoid such errors would require the mandatory completion of all sections of a prescription. PMID- 26051538 TI - GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson's disease. AB - Lewy pathology affects the gastrointestinal tract in Parkinson's disease (PD) and recent reports suggest a link between the disorder and gut inflammation. In this study, we investigated enteric neuroprotection and macrophage immunomodulation by 17beta-estradiol (E2) and the G protein-coupled estrogen receptor 1 (GPER1) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model. We found that both E2 and the GPER1 agonist G1 are protective against the loss of dopamine myenteric neurons and inhibited enteric macrophage infiltration in MPTP-treated mice. Coadministration of GPER1 antagonist G15, while completely blocking the neuroprotective and anti-inflammatory effects of G1 also partially prevented those of E2. Interestingly, we found that E2 and G1 treatments could directly alter MPTP-mediated immune responses independently from neurodegenerative processes. Analyses of monocyte/macrophage NF-kappaB and iNOS activation and FACs immunophenotype indicated that 1-methyl-4-phenylpyridinium (MPP(+)) treatment induces a strong immune response in monocytes, comparable to that of canonical challenge by lipopolysaccharide. In these cells, G1 and E2 treatment are equally potent in promoting a shift toward an anti-inflammatory "M2" immunophenotype reducing MPP(+)-induced NF-kappaB and iNOS activation. Moreover, G15 also antagonized the immunomodulatory effects of G1 in MPP(+)-treated macrophages. Together these data provide the first evidence for the role of GPER1 in enteric immunomodulation and neuroprotection. Considering increasing recognition for myenteric pathology as an early biomarker for PD, these findings provide a valuable contribution for better understanding and targeting of future therapeutic strategies. PMID- 26051537 TI - Activated immune response in an inherited leukodystrophy disease caused by the loss of oligodendrocyte gap junctions. AB - Oligodendrocyte:oligodendrocyte (O:O) gap junction (GJ) coupling is a widespread and essential feature of the CNS, and is mediated by connexin47 (Cx47) and Cx32. Loss of function mutations affecting Cx47 results in a severe leukodystrophy, Pelizeus-Merzbacher-like disease (also known as Hypomyelinating Leukodystrophy 2), which can be reproduced in mice lacking both Cx47 and Cx32. Here we report the gene expression profile of the cerebellum--an affected brain region--in mice lacking both Cx47 and Cx32. Of the 43,174 mRNA probes examined, we find decreased expression of 23 probes (corresponding to 23 genes) and increased expression of 545 probes (corresponding to 348 genes). Many of the genes with reduced expression map to oligodendrocytes, and two of them (Fa2h and Ugt8a) are involved in the synthesis of myelin lipids. Many of the genes with increased expression map to lymphocytes and microglia, and involved in leukotrienes/prostaglandins synthesis and chemokines/cytokines interactions and signaling pathways. In accord, immunostaining showed T- and B-cells in the cerebella of mutant mice as well as activated microglia and astrocytes. Thus, in addition to the loss of GJ coupling, there is a prominent immune response in mice lacking both Cx47 and Cx32. PMID- 26051539 TI - Mechanical Allostery: Evidence for a Force Requirement in the Proteolytic Activation of Notch. AB - Ligands stimulate Notch receptors by inducing regulated intramembrane proteolysis (RIP) to produce a transcriptional effector. Notch activation requires unmasking of a metalloprotease cleavage site remote from the site of ligand binding, raising the question of how proteolytic sensitivity is achieved. Here, we show that application of physiologically relevant forces to the Notch1 regulatory switch results in sensitivity to metalloprotease cleavage, and bound ligands induce Notch signal transduction in cells only in the presence of applied mechanical force. Synthetic receptor-ligand systems that remove the native ligand receptor interaction also activate Notch by inducing proteolysis of the regulatory switch. Together, these studies show that mechanical force exerted by signal-sending cells is required for ligand-induced Notch activation and establish that force-induced proteolysis can act as a mechanism of cellular mechanotransduction. PMID- 26051540 TI - Cdk1 Activates Pre-mitotic Nuclear Envelope Dynein Recruitment and Apical Nuclear Migration in Neural Stem Cells. AB - Dynein recruitment to the nuclear envelope is required for pre-mitotic nucleus centrosome interactions in nonneuronal cells and for apical nuclear migration in neural stem cells. In each case, dynein is recruited to the nuclear envelope (NE) specifically during G2 via two nuclear pore-mediated mechanisms involving RanBP2 BicD2 and Nup133-CENP-F. The mechanisms responsible for cell-cycle control of this behavior are unknown. We now find that Cdk1 serves as a direct master controller for NE dynein recruitment in neural stem cells and HeLa cells. Cdk1 phosphorylates conserved sites within RanBP2 and activates BicD2 binding and early dynein recruitment. Late recruitment is triggered by a Cdk1-induced export of CENP-F from the nucleus. Forced NE targeting of BicD2 overrides Cdk1 inhibition, fully rescuing dynein recruitment and nuclear migration in neural stem cells. These results reveal how NE dynein recruitment is cell-cycle regulated and identify the trigger mechanism for apical nuclear migration in the brain. PMID- 26051541 TI - MIM-Induced Membrane Bending Promotes Dendritic Spine Initiation. AB - Proper morphogenesis of neuronal dendritic spines is essential for the formation of functional synaptic networks. However, it is not known how spines are initiated. Here, we identify the inverse-BAR (I-BAR) protein MIM/MTSS1 as a nucleator of dendritic spines. MIM accumulated to future spine initiation sites in a PIP2-dependent manner and deformed the plasma membrane outward into a proto protrusion via its I-BAR domain. Unexpectedly, the initial protrusion formation did not involve actin polymerization. However, PIP2-dependent activation of Arp2/3-mediated actin assembly was required for protrusion elongation. Overexpression of MIM increased the density of dendritic protrusions and suppressed spine maturation. In contrast, MIM deficiency led to decreased density of dendritic protrusions and larger spine heads. Moreover, MIM-deficient mice displayed altered glutamatergic synaptic transmission and compatible behavioral defects. Collectively, our data identify an important morphogenetic pathway, which initiates spine protrusions by coupling phosphoinositide signaling, direct membrane bending, and actin assembly to ensure proper synaptogenesis. PMID- 26051542 TI - Nup153 Recruits the Nup107-160 Complex to the Inner Nuclear Membrane for Interphasic Nuclear Pore Complex Assembly. AB - In metazoa, nuclear pore complexes (NPCs) are assembled from constituent nucleoporins by two distinct mechanisms: in the re-forming nuclear envelope at the end of mitosis and into the intact nuclear envelope during interphase. Here, we show that the nucleoporin Nup153 is required for NPC assembly during interphase but not during mitotic exit. It functions in interphasic NPC formation by binding directly to the inner nuclear membrane via an N-terminal amphipathic helix. This binding facilitates the recruitment of the Nup107-160 complex, a crucial structural component of the NPC, to assembly sites. Our work further suggests that the nuclear transport receptor transportin and the small GTPase Ran regulate the interaction of Nup153 with the membrane and, in this way, direct pore complex assembly to the nuclear envelope during interphase. PMID- 26051543 TI - In-vitro and in-vivo evaluation of taste-masked cetirizine hydrochloride formulated in oral lyophilisates. AB - The use of solid oral dosage forms is typically favored with regard to stability and ease of administration. The aim of this study was to investigate whether cyclodextrins (CD) or ion exchange resins (IER) could be used to taste-mask cetirizine HCl when formulated in a freeze-dried oral formulation. The oral lyophilisates were produced using the Zydis((r)) technology that offer the opportunity to produce the dosage form directly in the aluminum laminate blister packs. This study confirmed that a pre-formed resinate of cetirizine HCl and various cyclodextrins can be successfully incorporated into the Zydis((r)) oral lyophilisate. A chemically stable product with acceptable release profile was obtained in the case of cyclodextrin. This study has also demonstrated that the Insent((r)) taste sensing system is a useful technique for predicting the taste masking potential of Zydis((r)) formulations. The electronic taste sensing system (e-tongue) data can be used to provide guidance on the selection of taste-masked formulations. Principal component analysis (PCA) of sensor data by plotting the PCA scores revealed the effects of used taste-masking techniques on the e-tongue sensors, indicating the successful taste improvement. The PCA plot of the taste sensor data revealed larger distances between the non-taste-masked sample and the CD- and IER-loaded samples, and the shift toward the drug-free formulations and excipient signals indicates a modification of the product taste. The human taste trial confirms the acceptability of the selected promising formulations. The taste evaluation results showed that an effectively taste-masked formulation has been achieved using beta-cyclodextrin and cherry/sucralose flavor system with over 80% of volunteers finding the tablet to be acceptable. PMID- 26051544 TI - Cell line-dependent cytotoxicity of poly(isobutylcyanoacrylate) nanoparticles coated with chitosan and thiolated chitosan: Insights from cultured human epithelial HeLa, Caco2/TC7 and HT-29/MTX cells. AB - Nanoparticles composed of poly(isobutylcyanoacrylate) core coated with a mixture of chitosan and thiolated chitosan have already shown promising results in terms of mucoadhesion and permeation enhancement properties of pharmaceutical active drugs delivered via mucosal routes. In the present work, the cytotoxicity of these nanoparticles was first investigated using direct contact assay on undifferentiated human cervix epithelial HeLa cells. The results showed strong toxicity in HeLa cells for the two investigated concentrations 25 and 50 MUg/mL. The cytotoxic effect was mainly attributed to the poly(isobutylcyanoacrylate) core since no significant differences in nanoparticle cytotoxicity were reported when nanoparticle shell composition was modified by adding chitosan or thiolated chitosan. In contrast, lower nanoparticle toxicity was reported using human fully differentiated enterocyte-like Caco-2/TC7, and fully-differentiated mucus secreting HT-29/MTX cells forming monolayer in culture mimicking an intestinal epithelial barrier. This study demonstrated that the toxicity of poly(isobutylcyanoacrylate) nanoparticles is highly cell line-dependent. PMID- 26051545 TI - Prevalence of Phosphorus-Based Additives in the Australian Food Supply: A Challenge for Dietary Education? AB - OBJECTIVE: Phosphorus-based food additives may pose a significant risk in chronic kidney disease given the link between hyperphosphatemia and cardiovascular disease. The objective of the study was to determine the prevalence of phosphorus based food additives in best-selling processed grocery products and to establish how they were reported on food labels. DESIGN: A data set of 3000 best-selling grocery items in Australia across 15 food and beverage categories was obtained for the 12 months ending December 2013 produced by the Nielsen Company's Homescan database. The nutrition labels of the products were reviewed in store for phosphorus additives. The type of additive, total number of additives, and method of reporting (written out in words or as an E number) were recorded. MAIN OUTCOME MEASURES: Presence of phosphorus-based food additives, number of phosphorus-based food additives per product, and the reporting method of additives on product ingredient lists. RESULTS: Phosphorus-based additives were identified in 44% of food and beverages reviewed. Additives were particularly common in the categories of small goods (96%), bakery goods (93%), frozen meals (75%), prepared foods (70%), and biscuits (65%). A total of 19 different phosphorus additives were identified across the reviewed products. From the items containing phosphorus additives, there was a median (minimum-maximum) of 2 (1-7) additives per product. Additives by E number (81%) was the most common method of reporting. CONCLUSION: Phosphorus-based food additives are common in the Australian food supply. This suggests that prioritizing phosphorus additive education may be an important strategy in the dietary management of hyperphosphatemia. Further research to establish a database of food items containing phosphorus-based additives is warranted. PMID- 26051546 TI - A randomized controlled trial of the different impression methods for the complete denture fabrication: Patient reported outcomes. AB - OBJECTIVES: To compare the effect of conventional complete dentures (CD) fabricated using two different impression methods on patient-reported outcomes in a randomized controlled trial (RCT). METHODS: A cross-over RCT was performed with edentulous patients, required maxillomandibular CDs. Mandibular CDs were fabricated using two different methods. The conventional method used a custom tray border moulded with impression compound and a silicone. The simplified used a stock tray and an alginate. Participants were randomly divided into two groups. The C-S group had the conventional method used first, followed by the simplified. The S-C group was in the reverse order. Adjustment was performed four times. A wash out period was set for 1 month. The primary outcome was general patient satisfaction, measured using visual analogue scales, and the secondary outcome was oral health-related quality of life, measured using the Japanese version of the Oral Health Impact Profile for edentulous (OHIP-EDENT-J) questionnaire scores. RESULTS: Twenty-four participants completed the trial. With regard to general patient satisfaction, the conventional method was significantly more acceptable than the simplified. No significant differences were observed between the two methods in the OHIP-EDENT-J scores. CONCLUSIONS: This study showed CDs fabricated with a conventional method were significantly more highly rated for general patient satisfaction than a simplified. CLINICAL SIGNIFICANCE: CDs, fabricated with the conventional method that included a preliminary impression made using alginate in a stock tray and subsequently a final impression made using silicone in a border moulded custom tray resulted in higher general patient satisfaction. TRIAL REGISTRATION: UMIN000009875. PMID- 26051547 TI - Still trying to solve the catatonic dilemma--A comment on the Letter to the Editor by Loeb et al. (Psychopharmacology, 2015). PMID- 26051548 TI - Copper(II)/amine synergistically catalyzed enantioselective alkylation of cyclic N-acyl hemiaminals with aldehydes. AB - The first catalytic asymmetric alkylation of N-acyl quinoliniums with aldehydes has been described. A copper/amine synergistic catalytic system has been developed, allowing the addition of functionalized aldehydes to a wide range of electronically varied N-acyl quinoliniums in good yields with excellent enantiocontrol. The synergistic catalytic system was also effective for N-acyl dihydroisoquinoliniums and beta-caboliniums, demonstrating the general applicability of the protocol in the enantioselective alkylation of diverse cyclic N-acyl hemiaminals. PMID- 26051549 TI - Effect of Methylation on the Properties of the H-Bridges in DNA. A Systematic Theoretical Study on the Couples of Base Pairs. AB - The effects of the addition of one (hemimethylation) or two (methylation) methyl groups on the 10 different couples of base pairs of DNA (three dimers of A-T, three of C-G, and four mixed A-T and C-G complexes) has been studied. Changes in the main static properties (energy, structure, atomic charges) and dynamics (movement of hydrogen atoms from one base to the other) have been considered and analyzed. The results of this study support the idea that the quantitative effects of the methylation of these complexes depend on the specific system under consideration and on the H-bridge studied. In any case, some general behavior can be highlighted. In particular, the relationship between the transfer of hydrogen atoms between the bases (with the possible generation of mutation points) and the methylation can be schematized in the two most important methylated bases: adenine and cytosine. A different behavior has been found in these two cases, and we suggest that this could be related to the different amounts of these methylated systems in prokaryotes and eukaryotes. In particular, this different behavior could explain why adenine methylation is present mainly in the bacteria and cytosine methylation is present in more complex organisms. PMID- 26051550 TI - Proton conduction in Mo(VI)-based metallo-supramolecular polymers. AB - High proton conduction (8.5 * 10(-2) mS cm(-1)) was observed in a Mo(vi)-based metallo-supramolecular polymer with carboxylic acids at 95%RH. The integration of OH groups into the polymer was analysed using FTIR spectroscopy and found to be crucial for the proton transport in the polymer. PMID- 26051551 TI - Manipulating Overflow Separation Directions by Wettability Boundary Positions. AB - Facile strategies to realize controllable overflow separation are urgently needed for advances in liquid-directional transportation systems and liquid delivery devices. Here, we present a wettability boundary based destabilization mechanism for direct separation of liquid flow from the solid edge at the (super)hydrophilic-superhydrophobic dividing line. Macroscale fluid dynamics is precisely controlled by modifying micro- and nanoscale surface structures and chemical compositions. Coupling surface wettability boundaries with flow inertia, flow separation angles are finely adjusted. These findings not only provide physicochemical insight into the understanding of the mechanisms on the dynamics of fluid at solid edges, but also promote the development of nanoscience in hydrodynamic applications. PMID- 26051552 TI - Ruthenium bipyridyl tethered porous organosilica: a versatile, durable and reusable heterogeneous photocatalyst. AB - A versatile heterogeneous photocatalysis protocol was developed by using ruthenium bipyridyl tethered porous organosilica (Ru-POS). The versatility of the Ru-POS catalyst in organo-photocatalysis was explored by (i) oxidative aromatization of Hantzsch ester, (ii) reductive dehalogenation of alkyl halides, and (iii) functional group interconversion (FGI) of alcohols to alkyl halides. PMID- 26051553 TI - Assessing nest-building behavior of mice using a 3D depth camera. AB - We developed a novel method to evaluate the nest-building behavior of mice using an inexpensive depth camera. The depth camera clearly captured nest-building behavior. Using three-dimensional information from the depth camera, we obtained objective features for assessing nest-building behavior, including "volume," "radius," and "mean height". The "volume" represents the change in volume of the nesting material, a pressed cotton square that a mouse shreds and untangles in order to build its nest. During the nest-building process, the total volume of cotton fragments is increased. The "radius" refers to the radius of the circle enclosing the fragments of cotton. It describes the extent of nesting material dispersion. The "radius" averaged approximately 60mm when a nest was built. The "mean height" represents the change in the mean height of objects. If the nest walls were high, the "mean height" was also high. These features provided us with useful information for assessment of nest-building behavior, similar to conventional methods for the assessment of nest building. However, using the novel method, we found that JF1 mice built nests with higher walls than B6 mice, and B6 mice built nests faster than JF1 mice. Thus, our novel method can evaluate the differences in nest-building behavior that cannot be detected or quantified by conventional methods. In future studies, we will evaluate nest-building behaviors of genetically modified, as well as several inbred, strains of mice, with several nesting materials. PMID- 26051554 TI - An experimental evaluation of a new designed apparatus (NDA) for the rapid measurement of impaired motor function in rats. AB - BACKGROUND: Assessment of the ability of rat to balance by rotarod apparatus (ROTA) is frequently used as a measure of impaired motor system function. Most of these methods have some disadvantages, such as failing to sense motor coordination rather than endurance and as the sensitivity of the method is low, more animals are needed to obtain statistically significant results. NEW METHOD: We have designed and tested a new designed apparatus (NDA) to measure motor system function in rats. Our system consists of a glass box containing 4 beams which placed with 1cm distance between them, two electrical motors for rotating the beams, and a camera to record the movements of the rats. The RPM of the beams is adjustable digitally between 0 and 50 rounds per minute. RESULTS: We evaluated experimentally the capability of the NDA for the rapid measurement of impaired motor function in rats. Also we demonstrated that the sensitivity of the NDA increases by faster rotation speeds and may be more sensitive than ROTA for evaluating of impaired motor system function. COMPARISON WITH EXISTING METHODS: Compared to a previous version of this task, our NDA provides a more efficient method to test rodents for studies of motor system function after impaired motor nervous system. CONCLUSIONS: In summary, our NDA will allow high efficient monitoring of rat motor system function and may be more sensitive than ROTA for evaluating of impaired motor system function in rats. PMID- 26051555 TI - AngleJ: A new tool for the automated measurement of neurite growth orientation in tissue sections. AB - BACKGROUND: Regeneration of axons is one means to restore function after central nervous system and peripheral nervous system injury. Besides increasing the number of regenerating axons, guidance of axons over long distances into and across a lesion site are important determinants for efficient functional restoration. Quantification of axon growth directions is therefore an important measure for the efficacy of neuroregenerative approaches. While several methods exist to manually or automatically trace neurites in images of neuronal cultures to determine their length, tools to automatically measure the effect of neurite guidance in tissue sections do not exist. NEW METHOD: Because manual measurements of the orientation of regenerating axons are labor-intensive, time-consuming and unreliable, a plugin called AngleJ for the open source software ImageJ was developed that automatically determines axonal orientation in images of immunohistochemically labeled sections of the spinal cord. RESULTS: Given user defined filters and thresholds, the plugin accurately detects neurites in sections of the intact spinal cord white matter and a spinal cord hemisection lesion model and measures the distribution pattern of axonal angles. COMPARISON WITH EXISTING METHODS: Values of automatically measured angles strongly correlate with angles obtained by manual measurements in ImageJ (Pearson correlation 0.88 0.97 for white matter and 0.76-0.94 for axons sprouting into a lesion site). CONCLUSIONS: AngleJ can be used as a fast alternative to manual angle measurement in conjunction with ImageJ and its source code is freely available to the community. PMID- 26051556 TI - A study to enhance medical students' professional decision-making, using teaching interventions on common medications. AB - AIM: To create sustained improvements in medical students' critical thinking skills through short teaching interventions in pharmacology. METHOD: The ability to make professional decisions was assessed by providing year-4 medical students at a UK medical school with a novel medical scenario (antenatal pertussis vaccination). Forty-seven students in the 2012 cohort acted as a pretest group, answering a questionnaire on this novel scenario. To improve professional decision-making skills, 48 students from the 2013 cohort were introduced to three commonly used medications, through tutor-led 40-min teaching interventions, among six small groups using a structured presentation of evidence-based medicine and ethical considerations. Student members then volunteered to peer-teach on a further three medications. After a gap of 8 weeks, this cohort (post-test group) was assessed for professional decision-making skills using the pretest questionnaire, and differences in the 2-year groups analysed. RESULTS: Students enjoyed presenting on medications to their peers but had difficulty interpreting studies and discussing ethical dimensions; this was improved by contextualising information via patient scenarios. After 8 weeks, most students did not show enhanced clinical curiosity, a desire to understand evidence, or ethical questioning when presented with a novel medical scenario compared to the previous year group who had not had the intervention. Students expressed a high degree of trust in guidelines and expert tutors and felt that responsibility for their own actions lay with these bodies. CONCLUSION: Short teaching interventions in pharmacology did not lead to sustained improvements in their critical thinking skills in enhancing professional practice. It appears that students require earlier and more frequent exposure to these skills in their medical training. PMID- 26051557 TI - Kissing loop interaction in adenine riboswitch: insights from umbrella sampling simulations. AB - INTRODUCTION: Riboswitches are cis-acting regulatory RNA elements prevalently located in the leader sequences of bacterial mRNA. An adenine sensing riboswitch cis-regulates adeninosine deaminase gene (add) in Vibrio vulnificus. The structural mechanism regulating its conformational changes upon ligand binding mostly remains to be elucidated. In this open framework it has been suggested that the ligand stabilizes the interaction of the distal "kissing loop" complex. Using accurate full-atom molecular dynamics with explicit solvent in combination with enhanced sampling techniques and advanced analysis methods it could be possible to provide a more detailed perspective on the formation of these tertiary contacts. METHODS: In this work, we used umbrella sampling simulations to study the thermodynamics of the kissing loop complex in the presence and in the absence of the cognate ligand. We enforced the breaking/formation of the loop loop interaction restraining the distance between the two loops. We also assessed the convergence of the results by using two alternative initialization protocols. A structural analysis was performed using a novel approach to analyze base contacts. RESULTS: Contacts between the two loops were progressively lost when larger inter-loop distances were enforced. Inter-loop Watson-Crick contacts survived at larger separation when compared with non-canonical pairing and stacking interactions. Intra-loop stacking contacts remained formed upon loop undocking. Our simulations qualitatively indicated that the ligand could stabilize the kissing loop complex. We also compared with previously published simulation studies. DISCUSSION AND CONCLUSIONS: Kissing complex stabilization given by the ligand was compatible with available experimental data. However, the dependence of its value on the initialization protocol of the umbrella sampling simulations posed some questions on the quantitative interpretation of the results and called for better converged enhanced sampling simulations. PMID- 26051558 TI - Mortality, material deprivation and urbanization: exploring the social patterns of a metropolitan area. AB - INTRODUCTION: Socioeconomic inequalities affecting health are of major importance in Europe. The literature enhances the role of social determinants of health, such as socioeconomic characteristics and urbanization, to achieve health equity. Yet, there is still much to know, mainly concerning the association between cause specific mortality and several social determinants, especially in metropolitan areas. This study aims to describe the geographical pattern of cause-specific mortality in the Lisbon Metropolitan Area (LMA), at small area level (parishes), and analyses the statistical association between mortality risk and health determinants (material deprivation and urbanization level). Fourteen causes have been selected, representing almost 60% of total mortality between 1995 and 2008, particularly those associated with urbanization and material deprivation. METHODS: A cross-sectional ecological study was carried out. Using a hierarchical Bayesian spatial model, we estimated sex-specific smoothed Standardized Mortality Ratios (sSMR) and measured the relative risks (RR), and 95% credible intervals, for cause-specific mortality relative to 1. urbanization level, 2. material deprivation and 3. material deprivation adjusted by urbanization. RESULTS: The statistical association between mortality and material deprivation and between mortality and urbanization changes by cause of death and sex. Dementia and MN larynx, trachea, bronchus and lung are the causes of death showing higher relative risk associated with urbanization. Infectious and parasitic diseases, Chronic liver disease and Diabetes are the causes of death presenting higher relative risk associated with material deprivation. Ischemic heart disease was the only cause with a statistical association with both determinants, and MN female breast was the only without any statistical association. Urbanization level reduces the impact of material deprivation for most of the causes of death. Men face a higher impact of material deprivation and urbanization level, than women, in most cause-specific mortality, even when considering the adjusted model. CONCLUSIONS: Our findings explore the specific pattern of fourteen causes of death in LMA and reveals small areas with an excess risk of mortality associated with material deprivation, thereby identifying problematic areas that could potentially benefit from public policies effecting social inequalities. PMID- 26051559 TI - Occlusal and facial features in Amazon indigenous: An insight into the role of genetics and environment in the etiology dental malocclusion. AB - BACKGROUND: Indigenous people of the Xingu river present a similar tooth wear pattern, practise exclusive breast-feeding, no pacifier use, and have a large intertribal genetic distance. OBJECTIVE: To revisit the etiology of dental malocclusion features considering these population characteristics. DESIGN: Occlusion and facial features of five semi-isolated Amazon indigenous populations (n=351) were evaluated and compared to previously published data from urban Amazon people. RESULTS: Malocclusion prevalence ranged from 33.8% to 66.7%. Overall this prevalence is lower when compared to urban people mainly regarding posterior crossbite. A high intertribal diversity was found. The Arara-Laranjal village had a population with a normal face profile (98%) and a high rate of normal occlusion (66.2%), while another group from the same ethnicity presented a high prevalence of malocclusion, the highest occurrence of Class III malocclusion (32.6%) and long face (34.8%). In Pat-Kro village the population had the highest prevalence of Class II malocclusion (43.9%), convex profile (38.6%), increased overjet (36.8%) and deep bite (15.8%). Another village's population, from the same ethnicity, had a high frequency of anterior open bite (22.6%) and anterior crossbite (12.9%). The highest occurrence of bi-protrusion was found in the group with the lowest prevalence of dental crowding, and vice versa. CONCLUSIONS: Supported by previous genetic studies and given their similar environmental conditions, the high intertribal diversity of occlusal and facial features suggests that genetic factors contribute substantially to the morphology of occlusal and facial features in the indigenous groups studied. The low prevalence of posterior crossbite in the remote indigenous populations compared with urban populations may relate to prolonged breastfeeding and an absence of pacifiers in the indigenous groups. PMID- 26051560 TI - Longitudinal analysis of residual feed intake and BW in mink using random regression with heterogeneous residual variance. AB - The aim of this study was to determine the genetic background of longitudinal residual feed intake (RFI) and BW gain in farmed mink using random regression methods considering heterogeneous residual variances. The individual BW was measured every 3 weeks from 63 to 210 days of age for 2139 male+female pairs of juvenile mink during the growing-furring period. Cumulative feed intake was calculated six times with 3-week intervals based on daily feed consumption between weighing's from 105 to 210 days of age. Genetic parameters for RFI and BW gain in males and females were obtained using univariate random regression with Legendre polynomials containing an animal genetic effect and permanent environmental effect of litter along with heterogeneous residual variances. Heritability estimates for RFI increased with age from 0.18 (0.03, posterior standard deviation (PSD)) at 105 days of age to 0.49 (0.03, PSD) and 0.46 (0.03, PSD) at 210 days of age in male and female mink, respectively. The heritability estimates for BW gain increased with age and had moderate to high range for males (0.33 (0.02, PSD) to 0.84 (0.02, PSD)) and females (0.35 (0.03, PSD) to 0.85 (0.02, PSD)). RFI estimates during the growing period (105 to 126 days of age) showed high positive genetic correlations with the pelting RFI (210 days of age) in male (0.86 to 0.97) and female (0.92 to 0.98). However, phenotypic correlations were lower from 0.47 to 0.76 in males and 0.61 to 0.75 in females. Furthermore, BW records in the growing period (63 to 126 days of age) had moderate (male: 0.39, female: 0.53) to high (male: 0.87, female: 0.94) genetic correlations with pelting BW (210 days of age). The result of current study showed that RFI and BW in mink are highly heritable, especially at the late furring period, suggesting potential for large genetic gains for these traits. The genetic correlations suggested that substantial genetic gain can be obtained by only considering the RFI estimate and BW at pelting, however, lower genetic correlations than unity indicate that extra genetic gain can be obtained by including estimates of these traits during the growing period. This study suggests random regression methods are suitable for analysing feed efficiency and BW gain; and genetic selection for RFI in mink is promising. PMID- 26051561 TI - Climbing the social ladder: the molecular evolution of sociality. AB - Genomic tools are allowing us to dissect the roles of genes and genetic architecture in social evolution, and eusocial insects are excellent models. Numerous hypotheses for molecular evolution of eusociality have been proposed, ranging from regulatory shifts in 'old' genes to rapid evolution of 'new' genes. A broad model to explain this major transition in evolution has been lacking. We provide a synthetic framework centered on the idea that different evolutionary processes dominate during different transitional stages, beginning with changes in gene regulation and culminating in novel genes later on. By considering multiple mechanisms as we 'climb the social ladder', we can test whether the transitions from solitary to simple sociality to complex sociality represent incremental changes or genetic revolutions. PMID- 26051562 TI - Evolving away from the linear model of research: a response to Courchamp et al. PMID- 26051563 TI - Back to the fundamentals: a reply to Barot et al. PMID- 26051564 TI - Influence of adjunctive classical homeopathy on global health status and subjective wellbeing in cancer patients - A pragmatic randomized controlled trial. AB - OBJECTIVES: The use of complementary and alternative medicine has increased over the past decade. The aim of this study was to evaluate whether homeopathy influenced global health status and subjective wellbeing when used as an adjunct to conventional cancer therapy. DESIGN: In this pragmatic randomized controlled trial, 410 patients, who were treated by standard anti-neoplastic therapy, were randomized to receive or not receive classical homeopathic adjunctive therapy in addition to standard therapy. The study took place at the Medical University Vienna, Department of Medicine I, Clinical Division of Oncology. MAIN OUTCOME MEASURES: The main outcome measures were global health status and subjective wellbeing as assessed by the patients. At each of three visits (one baseline, two follow-up visits), patients filled in two different questionnaires. RESULTS: 373 patients yielded at least one of three measurements. The improvement of global health status between visits 1 and 3 was significantly stronger in the homeopathy group by 7.7 (95% CI 2.3-13.0, p=0.005) when compared with the control group. A significant group difference was also observed with respect to subjective wellbeing by 14.7 (95% CI 8.5-21.0, p<0.001) in favor of the homeopathic as compared with the control group. Control patients showed a significant improvement only in subjective wellbeing between their first and third visits. CONCLUSION: Results suggest that the global health status and subjective wellbeing of cancer patients improve significantly when adjunct classical homeopathic treatment is administered in addition to conventional therapy. PMID- 26051565 TI - Curcumin attenuates severity of premenstrual syndrome symptoms: A randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: Most women experience premenstrual syndrome (PMS) at their reproductive age. PMS is a combination of psychological, physical and behavioral changes that interfere with familial communication and social activities. OBJECTIVES: Different methods have been suggested for treating PMS and one of them is herbal medicine. This study was done to evaluate the effects of curcumin on severity of PMS symptoms. METHODS: This research was a clinical trial, double blinded study. After having identified persons suffering from PMS, participants were randomly allocated to placebo (n=35) and curcumin (n=35) groups. Then each participant received two capsules daily for seven days before menstruation and for three days after menstruation for three successive cycles and they recorded severity of the symptoms by daily record questionnaire. RESULTS: The baseline level of PMS symptoms of before intervention did not differ between groups. While after three consecutive cycles treatment with curcumin, total severity of PMS score had reduced from 102.06+/-39.64 to 42.47+/-16.37 (mean change: 59.59; 95% confidence interval [CI]: 46.19-72.99) and in Placebo, total severity of PMS score changed from 106.06+/-44.12 to 91.60+/-43.56 (mean change: 14.45; 95% CI: 2.69 to 26.22). Furthermore, difference between mean changes was significant (mean difference: 45.14; 95% CI: 6.10-14.98). CONCLUSIONS: Our results for the first time showed a potential advantageous effect of curcumin in attenuating severity of PMS symptoms, which were probably mediated by modulation of neurotransmitters and anti-inflammatory effects of curcumin. PMID- 26051566 TI - The effect of topical application of lavender essential oil on the intensity of pain caused by the insertion of dialysis needles in hemodialysis patients: A randomized clinical trial. AB - BACKGROUND: Patients undergoing hemodialysis experience constant fear and anxiety due to the pain of the insertion of dialysis needles, which might lead to certain physiological and psychological complications for them in the long term. It is therefore essential to control their pain through a simple, safe method. OBJECTIVE: The present study was conducted to determine the effect of the topical application of lavender essential oil on the intensity of pain during the insertion of dialysis needles in hemodialysis patients. DESIGN: This open crossover study was conducted on 34 hemodialysis patients with arteriovenous fistula (AVF) admitted to the dialysis unit of one of the hospitals of Semnan University of Medical Sciences in 2013. The intensity of pain was measured in all the patients in three different states during the insertion of arterial needles for hemodialysis: (1) The topical application of 100% lavender essential oil, (2) no intervention, (3) placebo (with water). MAIN OUTCOME MEASURES: Pain intensity was measured in this study through the numeric rating scale (NRS) of pain. RESULTS: The findings showed that the mean+/-SD of pain intensity was 2.91+/-1.69 with the topical application of lavender, 4.59+/-2.02 in the no intervention state and 4.18+/-1.66 with the placebo state. Statistical tests showed a significant difference between the patients' intensity of pain in the three different states (p=0.001). CONCLUSION: Based on the findings of the study, the topical application of lavender decreases moderate intensities of pain during the insertion of dialysis needles. Accordingly, lavender oil may be an option to reduce pain by insertion of hemodialysis needles. PMID- 26051567 TI - Effect of inhalation aromatherapy with lavender essential oil on stress and vital signs in patients undergoing coronary artery bypass surgery: A single-blinded randomized clinical trial. AB - OBJECTIVES: At present, aromatherapy is used widely in medical research. This study aimed to investigate the effects of inhalation aromatherapy using lavender essential oil to reduce mental stress and improve the vital signs of patients after coronary artery bypass surgery (CABG). DESIGN: A single-blinded randomized controlled trial was conducted with 60 patients who had undergone CABG in a 2-day intervention that targeted stress reduction. PARTICIPANTS: Sixty subjects following coronary artery bypass surgery in two aromatherapy and control groups. SETTING: The study was conducted in Ekbatan Therapeutic and Educational Center, Hamadan, Iran, in 2013. INTERVENTIONS: On the second and third days after surgery, the aromatherapy group patients received two drops of 2% lavender essential oil for 20min and the control group received two drops of distilled water as a placebo. MAIN OUTCOME MEASURES: The primary outcome was mental stress, which was measured before and after the intervention using the DASS-21 questionnaire. The secondary outcomes were vital signs, including the heart rate, respiratory rate, and systolic and diastolic blood pressure, which were measured before and after the intervention. RESULTS: The individual characteristics of the aromatherapy and control groups were the same. There were no significant difference in the mean mental stress scores and vital signs of the aromatherapy and control groups on the second or third days after surgery. CONCLUSION: Inhalation aromatherapy with lavender essential oil had no significant effects on mental stress and vital signs in patients following CABG, except the systolic blood pressure. PMID- 26051568 TI - Acupressure improves the postoperative comfort of gastric cancer patients: A randomised controlled trial. AB - OBJECTIVE: This pilot study evaluated whether acupressure affected the postoperative comfort of gastric cancer patients following a subtotal gastrectomy. METHODS: A randomised controlled trial was conducted. Sixty patients were recruited from 141-bed general surgery ward at a 3000-bed medical centre in Northern Taiwan. Participants were randomly assigned to either a control group receiving regular postoperative care or to the experimental group receiving additional acupressure at acupoints of Neiquan (P6) and Zusanli (ST36) for 3 consecutive days. RESULTS: The similarities between two groups were in postoperative pain and the onset of postoperative nausea and vomiting (PONV) at the baseline. Following acupressure, significant differences were found in postoperative pain (P=.03) and time of first flatus (P=.04); but not PONV (P=.49), nor the time of first defecation (P=.34). CONCLUSIONS: Acupressure is a simple, noninvasive, safe, and economical procedure for improving the comfort of patients who undergo surgery for gastric cancer. Acupressure at the P6 and ST36 acupoints can improve postoperative comfort by alleviating pain and decreasing the time until first flatus. However, additional research is necessary to elucidate how acupressure can improve postoperative outcomes. PMID- 26051569 TI - The effect of an acupressure backrest on pain and disability in office workers with chronic low back pain: A randomized, controlled study and patients' preferences. AB - OBJECTIVE: This study investigated the effects of an acupoint-stimulating lumbar backrest on pain and disability in office workers who suffering from low back pain (LBP) as well as the preference influence on pain and disability. METHODS: Sixty-four participants were randomly assigned to two groups: one with no intervention (n=32) and another with 1 month of backrest use (n=32). An additional group (n=37) who wished to try 1 month of acupressure backrest were recruited to indicate the preference effect. Pain and disability were two key outcomes. RESULTS: Significant differences between control and randomized acupressure backrest groups were found at 2 week period for disability and at 4 weeks for pain after the backrest use. Also, significant differences were found in both groups for 3 month period with an increase of the treatment effect on pain and disability. Both control and randomized acupressure backrest groups showed greater improvement in pain and disability scores which were more than the minimal clinically important change (30% improvement for both outcomes). No significant difference was found for pain and disability between the randomized and preferred backrest groups. CONCLUSION: These findings suggested 1-month of acupressure backrest use could improve LBP conditions. Preference was not a powerful moderator to the significant treatment effect. PMID- 26051570 TI - Prevention of irinotecan induced diarrhea by probiotics: A randomized double blind, placebo controlled pilot study. AB - PURPOSE: Diarrhea is one of the dose limiting toxicity of irinotecan. SN-38 is main irinotecan metabolite responsible for diarrhea development, which is excreted in glucuronidated form into the intestine. This study aimed to determine the effectiveness of the probiotics in the prevention of irinotecan induced diarrhea due to reduction of intestinal beta-d-glucuronidase activity. METHODS: Between January 2011 and December 2013, 46 patients with colorectal cancer starting a new line of irinotecan based therapy were included. Patients were randomized 1:1 to probiotics (PRO) or placebo (PLA). Probiotic formula Colon DophilusTM, was administered at a dose of 10*10(9)CFU of bacteria tid, orally for 12 weeks of chemotherapy. The study was prematurely terminated due to slow accrual, when 46 of 220 planned patients were accrued. RESULTS: Twenty-three patients were randomized to PRO and 23 patients to PLA. Administration of probiotics compared to placebo led to a reduction in the incidence of severe diarrhea of grade 3 or 4 (0% for PRO vs. 17.4% for PLA, p=0.11), as well as reduction of the overall incidence of diarrhea (39.1% for PRO vs. 60.9% for PLA, p=0.24) and incidence of enterocolitis (0% for PRO vs. 8.7% for PLA). Patients on PRO used less antidiarrheal drugs compared to PLA. There was no infection caused by probiotic strains recorded. CONCLUSIONS: Administration of probiotics in patients with colorectal cancer treated with irinotecan-based chemotherapy is safe and could lead to a reduction in the incidence and severity of gastrointestinal toxicity. PMID- 26051571 TI - Use of traditional Chinese medicine (Ren Shen Yang Rong Tang) against microinflammation in hemodialysis patients: An open-label trial. AB - BACKGROUND: Complementary and alternative medicine such as traditional Chinese medicine (TCM) is now frequently used combined with Western medicine for treatment in chronic kidney disease (CKD). OBJECTIVE: We designed an open-label trial to investigate the safety and potential therapeutic effects of Ren Shen Yang Rong Tang (R-S-Y-R-T) in hemodialysis (HD) patients. METHODS: The experimental group was treated with additional R-S-Y-R-T combined with routine western medicine, while the control group was treated only with routine western medicine. The duration of study was 6 months. Primary outcomes were to evaluate the changes in serum hematocrit and albumin levels. Secondary outcomes including blood inflammatory markers (c-reactive protein [CRP], interleukin-6 [IL-6], and tumor necrosis factor-alpha [TNF-alpha]) were checked. Finally we also followed up the change of quality of life (QOL) in our subjects. RESULTS: Sixty nine respondents were enrolled in this trial. Finally a total of 59 patients (27 R-S-Y R-T group, 32 control group) completed the 6-month follow-up. Primary outcomes showed no significant statistical change of hematocrit in either 2 group (P>0.05). But the R-S-Y-R-T group had a statistical increase in serum albumin (P<0.05). Secondary outcomes were that both TNF-alpha (P=0.003) and IL-6 (P=0.001) showed evident decrease in the R-S-Y-R-T group. CRP was identified without statistical difference in both groups (P=0.226). The R-S-Y-R-T group also had a significant improvement in QOL (P<0.05). CONCLUSIONS: Our study suggests that R-S-Y-R-T could decrease chronic inflammation and increase the life quality in HD patients. Further larger clinical trial of long-term treatment with R-S-Y-R T is necessary for evaluating treatment use. PMID- 26051572 TI - Wrist acupressure for post-operative nausea and vomiting (WrAP): A pilot study. AB - Post-operative nausea and vomiting are undesirable complications following anaesthesia and surgery. It is thought that acupressure might prevent nausea and vomiting through an alteration in endorphins and serotonin levels. In this two group, parallel, superiority, randomised control pilot trial we aimed to test pre defined feasibility outcomes and provide preliminary evidence for the efficacy of PC 6 acupoint stimulation vs. placebo for reducing post-operative nausea and vomiting in cardiac surgery patients. Eighty patients were randomly assigned to either an intervention PC 6 acupoint stimulation via beaded intervention wristbands group (n=38) or placebo sham wristband group (n=42). The main outcome was assessment of pre-defined feasibility criteria with secondary outcomes for nausea, vomiting, rescue anti-emetic therapy, quality of recovery and adverse events. Findings suggest that a large placebo-controlled randomised controlled trial to test the efficacy of PC 6 stimulation on PONV in the post-cardiac surgery population is feasible and justified given the preliminary clinically significant reduction in vomiting in the intervention group in this pilot. The intervention was tolerated well by participants and if wrist acupressure of PC 6 acupoint is proven effective in a large trial it is a simple non-invasive intervention that could easily be incorporated into practice. PMID- 26051573 TI - Conventional cancer treatment alone or with regional hyperthermia for pain relief in lung cancer: A case-control study. AB - OBJECTIVE: To investigate the effect of combining conventional treatment with regional hyperthermia on cancer pain in lung cancer patients. DESIGN: Case control study. SETTING: One Korean university hospital and three complementary cancer clinics. MAIN OUTCOMES AND MEASURES: Main outcome was effective analgesic score (EAS, PI[1+(M/10)], 1: anti-inflammatory drug consumption at a regular dosage, M: weekly dose (mg) of oral morphine equivalent and PI: pain intensity) at four time points (baseline (days -30 to 0), time 1 (days 1-60), time 2 (days 61-120), and time 3 (days 121-180)). Propensity score matching between the hyperthermia and control groups was performed using a 1:5 ratio. A linear mixed effects model was employed to measure EAS changes over time in the two groups. RESULTS: At baseline, there were 83 subjects in the control group and 32 subjects in the hyperthermia group. At time 3, there were 49 subjects in the control group and 16 subjects in the hyperthermia group. Analyses showed rate of change of EAS, treatment*time was significant (p=0.038). This significant difference was mainly observed for time 1 (mean difference: 101.76 points, 95% confidence interval: 10.20-193.32 points, p=0.030). CONCLUSIONS: Our results indicate an increase in cancer pain in lung cancer patients administered regional hyperthermia, particularly during the early stage of hyperthermia treatment. PMID- 26051574 TI - Hypertonic dextrose injection (prolotherapy) for knee osteoarthritis: Long term outcomes. AB - OBJECTIVE: Knee osteoarthritis (OA) is a common, debilitating chronic disease. Prolotherapy is an injection therapy for chronic musculoskeletal pain. Recent 52 week randomized controlled and open label studies have reported improvement of knee OA-specific outcomes compared to baseline status, and blinded saline control injections and at-home exercise therapy (p<0.05). However, long term effects of prolotherapy for knee OA are unknown. We therefore assessed long-term effects of prolotherapy on knee pain, function and stiffness among adults with knee OA. DESIGN: Post clinical-trial, open-label follow-up study. SETTING: Outpatient; adults with mild-to-severe knee OA completing a 52-week prolotherapy study were enrolled. INTERVENTION AND OUTCOME MEASURES: Participants received 3-5 monthly interventions and were assessed using the validated Western Ontario McMaster University Osteoarthritis Index, (WOMAC, 0-100 points), at baseline, 12, 26, 52 weeks, and 2.5 years. RESULTS: 65 participants (58+/-7.4 years old, 38 female) received 4.6+/-0.69 injection sessions in the initial 17-week treatment period. They reported progressive improvement in WOMAC scores at all time points in excess of minimal clinical important improvement benchmarks during the initial 52 week study period, from 13.8+/-17.4 points (23.6%) at 12 weeks, to 20.9+/-2.8 points, (p<0.05; 35.8% improvement) at 2.5+/-0.6 years (range 1.6-3.5 years) in the current follow-up analysis. Among assessed covariates, none were predictive of improvement in the WOMAC score. CONCLUSIONS: Prolotherapy resulted in safe, significant, progressive improvement of knee pain, function and stiffness scores among most participants through a mean follow-up of 2.5 years and may be an appropriate therapy for patients with knee OA refractory to other conservative care. PMID- 26051575 TI - Effects of inhaled ginger aromatherapy on chemotherapy-induced nausea and vomiting and health-related quality of life in women with breast cancer. AB - OBJECTIVE: To assess the efficacy of inhaled ginger aromatherapy on nausea, vomiting and health-related quality of life (HRQoL) in chemotherapy breast cancer patients. DESIGN: Single-blind, controlled, randomized cross-over study. Patients received 5-day aromatherapy treatment using either ginger essential oil or fragrance-matched artificial placebo (ginger fragrance oil) which was instilled in a necklace in an order dictated by the treatment group sequence. SETTING: Two oncology clinics in the East Coast of Peninsular Malaysia. MAIN OUTCOME MEASURES: VAS nausea score, frequency of vomiting and HRQoL profile (EORTC QLQ-C30 scores). RESULTS: Sixty female patients completed the study (age=47.3+/-9.26 years; Malay=98.3%; on highly emetogenic chemotherapy=86.7%). The VAS nausea score was significantly lower after ginger essential oil inhalation compared to placebo during acute phase (P=0.040) but not sustained for overall treatment effect (treatment effect: F=1.82, P=0.183; time effect: F=43.98, P<0.001; treatment*time effect: F=2.04; P=0.102). Similarly, there was no significant effect of aromatherapy on vomiting [F(1, 58)=0.29, P=0.594]. However, a statistically significant change from baseline for global health status (P<0.001) was detected after ginger essential oil inhalation. A clinically relevant 10 points improvement on role functioning (P=0.002) and appetite loss (P<0.001) were also documented while patients were on ginger essential oil. CONCLUSION: At present time, the evidence derived from this study is not sufficiently convincing that inhaled ginger aromatherapy is an effective complementary therapy for CINV. The findings for HRQoL were however encouraging with significant improvement in several domains. PMID- 26051576 TI - Stress Management and Relaxation Techniques use among underserved inpatients in an inner city hospital. AB - OBJECTIVE: Little is known about the use of Stress Management and Relaxation Techniques (SMART) in racially diverse inpatients. We hope to identify socioeconomic status (SES) factors, health behavior factors, and clinical factors associated with the use of SMART. DESIGN AND MAIN OUTCOME MEASURES: We conducted a secondary analysis of baseline data from 623 hospitalized patients enrolled in the Re-Engineered Discharge (RED) clinical trial. We assessed socio-demographic characteristics and use of SMART. We used bivariate and multivariate logistic regression to test the association of SMART with socio-demographic characteristics, health behaviors, and clinical factors. RESULTS: A total of 26.6% of participants reported using SMART and 23.6% used mind body techniques. Thirty six percent of work disabled patients, 39% of illicit drug users, and 38% of participants with depressive symptoms used SMART. Patients who both reported illicit drug use and screened positive for depression had significantly increased odds of using SMART [OR=4.94, 95% CI (1.59, 15.13)]. Compared to non-Hispanic whites, non-Hispanic blacks [0.55 (0.34-0.87)] and Hispanic/other race individuals [0.40 (0.20-0.76)] were less likely to use SMART. CONCLUSIONS: We found greater utilization of SMART among all racial groups compared to previous national studies. In the inner city inpatient setting, patients with depression, illicit drug use, and work disability reported higher rates of using SMART. PMID- 26051577 TI - Effects of a pain education program in Complementary and Alternative Medicine treatment utilization at a VA medical center. AB - BACKGROUND: Past studies have shown that U.S. Veterans are consumers of CAM. However, more than 75% of Veteran non-users report they would utilize these treatment options if made available. Thus, Veterans may not be fully aware of the CAM options currently available to them in the current U.S. VA health care system. OBJECTIVES: The current study tested the hypothesis that Veterans would report an increase in CAM utilization after completing a formal pain education program in a VA medical center. DESIGN: The study used a quasi-experimental, one group, pre/post-test design. SETTING: Midwestern, U.S. VA Medical Center. PARTICIPANTS: The responses from 103 Veterans who elected to participate in the program and the assessment measures were included in the outcome analyses. INTERVENTION: "Pain Education School" is a 12-week, educational program that is open to all Veterans and their families. It is a comprehensive program that introduces patients to 23 different disciplines at the VA Medical Center that deal with chronic, non-cancer pain. MAIN OUTCOME MEASURES: An adaptation of the Complementary and Alternative Medicine Questionnaire((c)), SECTION A: Use of Alternative Health Care Providers. RESULTS: There was a significant difference found in overall utilization of CAM after completing the pain education program. The most utilized CAM modality was the chiropractor; the least utilized were hypnosis and aromatherapy. CONCLUSIONS: Not all health care systems or providers may have access to an education-focused, professionally driven program as an amenity. However, lessons can be learned from this study in terms of what pain providers may be able to accomplish in their practice. PMID- 26051578 TI - Characteristics of acupuncture users among internal medicine patients in Germany. AB - OBJECTIVES: To identify socio-demographic and health-related factors associated with (a) acupuncture use and (b) the rated helpfulness of acupuncture among internal medicine patients. METHODS: Data from a larger cross-sectional trial were reanalyzed. Patients who had used acupuncture for managing their primary medical complaint were compared to patients who had not. Predictors for (a) acupuncture use and (b) rated helpfulness were determined using logistic regression analyses. RESULTS: Of 2486 included patients, 51.49% reported acupuncture use and 39.22% reported no prior use. The use of acupuncture was associated with higher age, i.e. those aged 50-64 were more likely to have used acupuncture, while those younger than 30 were less likely. Patients with spinal pain, fibromyalgia, or headache were more likely to be acupuncture users; while IBS patients were less likely. Patients with good to excellent health status, high external-social health locus of control and current smokers were less likely to have used acupuncture. Among those who had used acupuncture, 42.34% perceived the treatment as helpful, while 35.94% did not. Rated helpfulness was associated with female gender, full-time employment, high health satisfaction, and high internal health locus of control. Those with a diagnosis of osteoarthritis or inflammatory bowel disease were more likely to find acupuncture helpful; those with headache or other types of chronic pain were less likely to find acupuncture helpful. CONCLUSION: Acupuncture was used by more than half of internal medicine patients. Prevalence and rated helpfulness of acupuncture use was associated with the patients' medical condition, sociodemography, and health locus of control. PMID- 26051579 TI - Developing clinical practice guidelines for Chinese herbal treatment of polycystic ovary syndrome: A mixed-methods modified Delphi study. AB - OBJECTIVES: Preliminary evidence suggests Chinese herbal medicine (CHM) could be a viable treatment option for polycystic ovary syndrome (PCOS). Prior to conducting a clinical trial it is important to consider the characteristics of good clinical practice. This study aims to use professional consensus to establish good clinical practice guidelines for the CHM treatment of PCOS. DESIGN AND SETTING: CHM practitioners participated in a mixed-methods modified Delphi study involving three rounds of structured group communication. Round 1 involved qualitative interviews with practitioners to generate statements regarding good clinical practice. In round 2, these statements were distributed online to the same practitioners to rate their agreement using a 7-point Likert scale, where group consensus was defined as a median rating of >=5. Statements reaching consensus were accepted for consideration onto the guideline whilst those not reaching consensus were re-distributed for consideration in round 3. Statements presented in the guidelines were graded from A (strong consensus) to D (no consensus) determined by median score and interquartile range. RESULTS: 11 CHM practitioners in the UK were recruited. After three Delphi rounds, 91 statement items in total had been considered, of which 89 (97.8%) reached consensus and 2 (2.2%) did not. The concluding set of guidelines consists of 85 items representing key features of CHM prescribing for PCOS. CONCLUSIONS: These guidelines can be viewed as an initial framework that captures fundamental principles of good clinical practice for CHM. PMID- 26051580 TI - Does spatial location matter? Traditional therapy utilisation among the general population in a Ghanaian rural and urban setting. AB - Despite the recognition for rising consumption rate of traditional medicine (TRM) in health and spatio-medical literature in the global scale, the impact of location in traditional therapy use has been explored least in Ghana. This paper analysed the role of spatial variation in TRM use in Kumasi Metropolis and Sekyere South District of Ashanti Region, Ghana. A retrospective cross-sectional and place-based survey was conducted in a representative sample (N=324) selected through systematic random sampling technique. Structured interviewer-administered questionnaires were espoused as the main research instruments. Data were analysed with Pearson's Chi-square and Fisher's exact tests from the Predictive Analytics Software (PASW) version 17.0. The study found that over 86% reported TRM use. Whilst majority (59.1%) of the respondents had used TRM two or more times within the last 12 months, biologically-based therapies and energy healing were common forms of TRM accessed. Although, the use of TRM did not vary (p>0.05), knowledge about TRM, modalities of TRM and the sources of TRM differed significantly across geographically demarcated rural and urban splits (p<0.005). The study advances our understanding of the spatial dimensions as regards TRM utilisation. PMID- 26051581 TI - Teachers of the Alexander Technique in the UK and the people who take their lessons: A national cross-sectional survey. AB - OBJECTIVES: Given the rising profile of the Alexander Technique in the UK, there is a need for a comprehensive description of its teachers and of those who currently take lessons. In a national survey of Alexander teachers, we set out to address this information gap. DESIGN: A cross-sectional survey of 871 UK members of three main Alexander Technique teachers' professional associations was conducted. A questionnaire requested information about their professional background, teaching practice and methods, and about the people who attend lessons and their reasons for seeking help. RESULTS: With an overall response rate of 61%, 534 teachers responded; 74% were female with median age of 58 years, 60% had a higher education qualification, and 95% were self-employed, many with additional non-Alexander paid employment. The majority (87%) offered lessons on their own premises or in a privately rented room, and 19% provided home visits; both individual and group lessons were provided. People who took lessons were predominantly female (66%) with a median age of 48 years, and 91% paid for their lessons privately. Nearly two-thirds (62%) began lessons for reasons related to musculoskeletal conditions, including back symptoms, posture, neck pain, and shoulder pain. Other reasons were general (18%, including well-being), performance-related (10%, including voice-, music-, and sport-related), psychological (5%) and neurological (3%). We estimate that Alexander teachers in the UK provide approximately 400,000 lessons per year. CONCLUSIONS: This study provides an overview of Alexander Technique teaching in the UK today and data that may be useful when planning future research. PMID- 26051582 TI - Differences in referral and use of complementary and alternative medicine between pediatric providers and patients. AB - OBJECTIVES: The goal of this study was to compare pediatric complementary and alternative medicine (CAM) use and pediatric health care provider CAM referral as well as identify predictors of use and referral. DESIGN: Surveys were administered to 283 parents/caregivers of pediatric patients and 200 pediatric health care providers (HCP). SETTING: This study took place at the Children's Hospital of Orange County (CHOC Children's) in Orange, CA. MAIN OUTCOME MEASURES: Caregivers and HCP were provided a list of 32 CAM interventions and asked to indicate which treatments their child had ever used or which they would consider using for their child and which treatments they had ever referred or which they would consider referring, respectively. The main outcome variables were the number and type of CAM therapies endorsed by participants. RESULTS: Providers referred the majority of CAM therapies significantly more often than patients used each therapy and more often than caregivers would consider each therapy for their child. In addition, children from families with higher incomes, whose parents were older and had more education, who were White, and whose primary language spoken at home was English were more likely to use CAM therapies, all p's<0.05. HCP CAM referral was not significantly predicted by number of years a health care provider practiced or health care profession, all p's<0.05. CONCLUSIONS: HCP referred CAM therapies more often than parents reported use for their children. Findings may imply that parents/caregivers are underutilizing CAM therapies for their children. Potential barriers to CAM use in pediatric patients needs to be explored. PMID- 26051583 TI - Zusanli (ST36) acupoint injection for preventing postoperative ileus: A systematic review and meta-analysis of randomized clinical trials. AB - OBJECTIVE: To evaluate the preventive effect of Zusanli (ST36) acupoint injections with various agents, for postoperative ileus (POI). METHODS: We searched electronic databases for randomized controlled trials from inception to 1st February 2015 evaluating ST36 acupoint injection for preventing POI. Revman 5.2.0 was used for data analysis with effect estimates presented as mean difference (MD) with 95% confidence interval (CI). Statistical heterogeneity was tested using I(2) (defined as significant if I(2)>75%). We used a random effects model (REM) for pooling data with significant heterogeneity. RESULTS: Thirty trials involving 2967 participants were included. All trials were assessed as high risk of bias (poor methodological quality). For time to first flatus, meta analysis favored ST36 acupoint injection of neostigmine (MD -20.70h, 95% CI 25.53 to -15.87, 15 trials, I(2)=98%, REM), vitamin B1 (MD -11.22h, 95% CI -17.01 to -5.43, 5 trials, I(2)=98%, REM), and metoclopramide (MD -15.65h, 95% CI -24.77 to -6.53, 3 trials, I(2)=94%, REM) compared to usual care alone. Meta-analysis of vitamin B1 favored ST36 acupoint injection compared to intra-muscular injection (MD -17.21h, 95% CI -21.05 to -13.36, 4 trials, I(2)=89%, REM). Similarly, for time to bowel sounds recovery and first defecation, ST36 acupoint injection also showed positive effects. CONCLUSIONS: ST36 acupoint injections with various agents may have a preventive effect for POI. Safety is inconclusive as few of included trials reported adverse events. Due to the poor methodological quality and likely publication bias further robust clinical trials are required to arrive at a definitive conclusion. PMID- 26051584 TI - Shenqi pill, a traditional Chinese herbal formula, for the treatment of hypertension: A systematic review. AB - BACKGROUND: Shenqi pill, a traditional Chinese herbal formula, is widely prescribed for hypertensive patients with kidney yang deficiency syndrome in China. This study aims to examine the efficacy and safety of Shenqi pill for the treatment of hypertension. METHODS: A systematic search of the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, the Chinese National Knowledge Infrastructure, the Chinese Scientific Journal Database, the Chinese Biomedical Literature Database, and the Wanfang Database was conducted from their inception up to October 7, 2014. All randomized controlled trials (RCTs) testing Shenqi pill alone or combined with western medicine against placebo, no intervention or western medicine in hypertensive patients were included. RESULTS: A total of 4 RCTs comparing Shenqi pill plus western medicine with western medicine were included. Shenqi pill as complementary therapy exhibited a relatively small with no significant reduction on blood pressure, and showed remarkable improvement on sexual function, lipid profile and some biochemical indicators of hypertensive renal damage compared to western medicine used alone. The safety of Shenqi pill is still unknown. CONCLUSIONS: This systematic review firstly provided no definite evidence for the efficacy and safety of Shenqi pill for hypertension based on the insufficient data. More rigorously designed RCTs focusing on sexual dysfunction and hypertensive renal damage are warranted to give high level of evidence. PMID- 26051585 TI - Efficacy of Chinese herbal medicine on health-related quality of life (SF-36) in hypertensive patients: A systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: This study aims to evaluate published randomized controlled trials (RCTs) of Chinese Herbal Medicine (CHM) improving health-related quality of life (HRQL) in hypertensive patients that employ the Short-Form 36-Item Health questionnaire (SF-36) as an outcome measure. METHODS: Five electronic databases were searched up to October 2013 to identify RCTs of CHM for hypertension. The primary outcome was SF-36. Trial selection, data extraction, methodological quality assessment, and data analyses were conducted according to the Cochrane handbook. RESULTS: Eleven RCTs with total of 1043 participants were identified. The majority of the included trials were assessed to be of poor methodological quality and high clinical heterogeneity. Meta-analysis shows a significant improvement both in physical component summary (PCS) measure and mental component summary (MCS) measure of SF-36, with physical functioning (WMD=8.54[5.34, 11.74], p<0.001), role physical (WMD=13.32[7.03, 19.61], p<0.001), bodily pain (WMD=10.53[6.46, 14.60], p<0.001), general health (WMD=-5.56[2.09, 9.02], p<0.001), vitality (WMD=6.84[4.33, 9.53], p<0.001), social functioning (WMD=7.50[2.63, 12.36], p<0.001), role emotional (WMD=12.06[4.45, 19.68], p<0.001) and mental health (WMD=-5.68[2.90, 8.47], p<0.001). CHM can also decrease systolic blood pressure (WMD=-4.45 [-6.71, -2.19], p<0.001) and relieve symptoms related to hypertension. CONCLUSIONS: CHM appears to have beneficial effects on improvement of HRQL in hypertensive patients. However, the findings should be interpreted with caution due to the poor methodological quality and high clinical heterogeneity of the included trials. Further clinical trials should be carried out to provide more reliable evidence. PMID- 26051586 TI - Why West Africa rejected donation of Chinese medicine for treating Ebola recommended by Chinese government? PMID- 26051587 TI - An Atypical Presentation of Vaginal Agenesis. AB - BACKGROUND: Vaginal agenesis is rare and generally presents with primary amenorrhea and cyclic abdominal pain. We describe a case in which the diagnosis was delayed due to lack of initial pelvic examination and atypical findings on imaging. CASE: A 13-year-old girl with a known renal anomaly presented to the emergency department with primary amenorrhea and cyclic abdominal pain. She declined a pelvic examination and had normal laboratory testing and pelvic magnetic resonance imaging results. At 16 months later, she presented again and was diagnosed with vaginal agenesis and a large endometrioma. SUMMARY AND CONCLUSION: This case illustrates the importance of the physical examination in the evaluation of primary amenorrhea. Further, it demonstrates that hematometra may not be present on imaging. Here, an endometrioma was the only abnormality noted on magnetic resonance imaging after 18 months of retrograde menstruation. PMID- 26051588 TI - 2015, day-surgery year in France? PMID- 26051589 TI - Developing vaccines to prevent malaria in pregnant women. AB - INTRODUCTION: Placental malaria (PM) is a major public health problem that constitutes a significant health concern for the mother, and especially for the developing fetus and offspring. Current means of prevention have limitations, including a restricted window of intervention that excludes the first trimester of pregnancy, and the fact that very few drugs can be used for this purpose. The identification of the VAR2CSA antigen, specific to PM parasites, offers an excellent opportunity to develop a vaccine against this disease. Proof of concept of a first-generation vaccine is nearing completion, and two clinical trials are underway. AREAS COVERED: This review focuses on PM, which is mainly caused by Plasmodium falciparum. The review highlights recent advances and the key milestones that led to the identification of the optimal vaccine target within the large VAR2CSA protein. The paper also points out how future improvements can strengthen this process to achieve an effective vaccine in the field. EXPERT OPINION: The approach taken to develop a P. falciparum erythrocyte membrane protein 1-based vaccine to protect pregnant women is very promising in view of the current difficulties of achieving a sterilizing vaccine against malaria parasite. This approach could help us to control the deleterious effect of malaria infections that characterize severe clinical forms. PMID- 26051590 TI - Toxicity of oral cadmium intake: Impact on gut immunity. AB - Gastrointestinal tract is one of the main targets of cadmium (Cd), an important food and drinking water contaminant. In the present study, the effect of subchronic (30 days) oral (in water) intake of 5ppm and 50ppm of cadmium on immune responses in the gut was examined in rats. Cadmium consumption resulted in reduction of bacteria corresponding to Lactobacillus strain, tissue damage and intestinal inflammation [increases in high mobility group box 1 (HMGB1 molecules), superoxide dismutase (SOD) and catalase (CAT) activity and proinflammatory cytokine (TNF, IL-1beta, IFN-gamma, IL-17) content]. Draining (mesenteric) lymph node (MLN) stress response was observed [elevation of MLN glutathione (GSH) and metallothionein (MT) mRNA levels] and stimulation of both adaptive [cellularity, proliferation, proinflammatory (IFN-gamma and IL-17) MLN cell cytokine responses] as well as innate immune activity (increases in numbers of NK and CD68(+) cells, oxidative activities, IL-1beta). In contrast to proinflammatory milieu in MLN, decreased or unchanged antiinflammatory IL-10 response was observed. Stimulation of immune activities of MLN cells have, most probably, resulted from sensing of cadmium-induced tissue injury, but also from bacterial antigens that breached compromised intestinal barrier. These effects of cadmium should be taken into account when assessing dietary cadmium as health risk factor. PMID- 26051591 TI - Co-occurrence of thoracolumbar intramedullary lipoma and intracranial lipoma during Gardner's syndrome: a rare occurrence. PMID- 26051592 TI - The long insular perforating arteries are essential cerebral perforating vessels too. PMID- 26051593 TI - Efficient T-cell priming and activation requires signaling through prostaglandin E2 (EP) receptors. AB - Understanding the regulation of T-cell responses during inflammation and auto immunity is fundamental for designing efficient therapeutic strategies against immune diseases. In this regard, prostaglandin E2 (PGE2) is mostly considered a myeloid-derived immunosuppressive molecule. We describe for the first time that T cells secrete PGE2 during T-cell receptor stimulation. In addition, we show that autocrine PGE2 signaling through EP receptors is essential for optimal CD4(+) T cell activation in vitro and in vivo, and for T helper 1 (Th1) and regulatory T cell differentiation. PGE2 was found to provide additive co-stimulatory signaling through AKT activation. Intravital multiphoton microscopy showed that triggering EP receptors in T cells is also essential for the stability of T cell-dendritic cell (DC) interactions and Th-cell accumulation in draining lymph nodes (LNs) during inflammation. We further demonstrated that blocking EP receptors in T cells during the initial phase of collagen-induced arthritis in mice resulted in a reduction of clinical arthritis. This could be attributable to defective T-cell activation, accompanied by a decline in activated and interferon-gamma-producing CD4(+) Th1 cells in draining LNs. In conclusion, we prove that T lymphocytes secret picomolar concentrations of PGE2, which in turn provide additive co stimulatory signaling, enabling T cells to attain a favorable activation threshold. PGE2 signaling in T cells is also required for maintaining long and stable interactions with DCs within LNs. Blockade of EP receptors in vivo impairs T-cell activation and development of T cell-mediated inflammatory responses. This may have implications in various pathophysiological settings. PMID- 26051594 TI - Emergence of spin-orbit fields in magnetotransport of quasi-two-dimensional iron on gallium arsenide. AB - The desire for higher information capacities drives the components of electronic devices to ever smaller dimensions so that device properties are determined increasingly more by interfaces than by the bulk structure of the constituent materials. Spintronic devices, especially, benefit from the presence of interfaces--the reduced structural symmetry creates emergent spin-orbit fields that offer novel possibilities to control device functionalities. But where does the bulk end, and the interface begin? Here we trace the interface-to-bulk transition, and follow the emergence of the interfacial spin-orbit fields, in the conducting states of a few monolayers of iron on top of gallium arsenide. We observe the transition from the interface- to bulk-induced lateral crystalline magnetoanisotropy, each having a characteristic symmetry pattern, as the epitaxially grown iron channel increases from four to eight monolayers. Setting the upper limit on the width of the interface-imprinted conducting channel is an important step towards an active control of interfacial spin-orbit fields. PMID- 26051595 TI - Operational resilience of reservoirs to climate change, agricultural demand, and tourism: A case study from Sardinia. AB - Many (semi-) arid locations globally, and particularly islands, rely heavily on reservoirs for water supply. Some reservoirs are particularly vulnerable to climate and development changes (e.g. population change, tourist growth, hydropower demands). Irregularities and uncertainties in the fluvial regime associated with climate change and the continuous increase in water demand by different sectors will add new challenges to the management and to the resilience of these reservoirs. The resilience of vulnerable reservoirs must be studied in detail to prepare for and mitigate potential impacts of these changes. In this paper, a reservoir balance model is developed and presented for the Pedra e' Othoni reservoir in Sardinia, Italy, to assess resilience to climate and development changes. The model was first calibrated and validated, then forced with extensive ensemble climate data for representative concentration pathways (RCPs) 4.5 and 8.5, agricultural data, and with four socio-economic development scenarios. Future projections show a reduction in annual reservoir inflow and an increase in demand, mainly in the agricultural sector. Under no scenario is reservoir resilience significantly affected, the reservoir always achieves refill. However, this occurs at the partial expenses of hydropower production with implications for the production of renewable energy. There is also the possibility of conflict between the agricultural sector and hydropower sector for diminishing water supply. Pedra e' Othoni reservoir shows good resilience to future change mostly because of the disproportionately large basin feeding it. However this is not the case of other Sardinian reservoirs and hence a detailed resilience assessment of all reservoirs is needed, where development plans should carefully account for the trade-offs and potential conflicts among sectors. For Sardinia, the option of physical connection between reservoirs is available, as are alternative water supply measures. Those reservoirs at risk to future change should be identified, and mitigating measures investigated. PMID- 26051596 TI - EPHECT I: European household survey on domestic use of consumer products and development of worst-case scenarios for daily use. AB - Consumer products are frequently and regularly used in the domestic environment. Realistic estimates for product use are required for exposure modelling and health risk assessment. This paper provides significant data that can be used as input for such modelling studies. A European survey was conducted, within the framework of the DG Sanco-funded EPHECT project, on the household use of 15 consumer products. These products are all-purpose cleaners, kitchen cleaners, floor cleaners, glass and window cleaners, bathroom cleaners, furniture and floor polish products, combustible air fresheners, spray air fresheners, electric air fresheners, passive air fresheners, coating products for leather and textiles, hair styling products, spray deodorants and perfumes. The analysis of the results from the household survey (1st phase) focused on identifying consumer behaviour patterns (selection criteria, frequency of use, quantities, period of use and ventilation conditions during product use). This can provide valuable input to modelling studies, as this information is not reported in the open literature. The above results were further analysed (2nd phase), to provide the basis for the development of 'most representative worst-case scenarios' regarding the use of the 15 products by home-based population groups (housekeepers and retired people), in four geographical regions in Europe. These scenarios will be used for the exposure and health risk assessment within the EPHECT project. To the best of our knowledge, it is the first time that daily worst-case scenarios are presented in the scientific published literature concerning the use of a wide range of 15 consumer products across Europe. PMID- 26051597 TI - Graphene Quantum Dots Supported by Graphene Nanoribbons with Ultrahigh Electrocatalytic Performance for Oxygen Reduction. AB - A new class of oxygen reduction reaction (ORR) catalysts based on graphene quantum dots (GQDs) supported by graphene nanoribbons (GNRs) has been developed through a one-step simultaneous reduction reaction, leading to ultrahigh performance for O reduction with an excellent electrocatalytic activity (higher limiting current density and lower overpotential than those of platinum) and high selectivity and stability in alkaline media comparable to the best C-based ORR catalysts reported so far. Electron microscopy revealed numerous surface/edge defects on the GQD/GNR surfaces and at their interface to act as the active sites. This, coupled with efficient charge transfer between the intimately contacted GQDs and GNRs, rationalized the observed ultrahigh electrocatalytic performance for the resultant GQD-GNR hybrids. Thus, this study opens a new direction for developing low-cost, highly efficient, C-based ORR electrocatalysts. PMID- 26051598 TI - Tuning magnetism by biaxial strain in native ZnO. AB - Magnetic ZnO, one of the most important diluted magnetic semiconductors (DMS), has attracted great scientific interest because of its possible technological applications in optomagnetic devices. Magnetism in this material is usually delicately tuned by the doping level, dislocations, and local structures. The rational control of magnetism in ZnO is a highly attractive approach for practical applications. Here, the tuning effect of biaxial strain on the d(0) magnetism of native imperfect ZnO is demonstrated through first-principles calculations. Our calculation results show that strain conditions have little effect on the defect formation energy of Zn and O vacancies in ZnO, but they do affect the magnetism significantly. For a cation vacancy, increasing the compressive strain will obviously decrease its magnetic moment, while tensile strain cannot change the moment, which remains constant at 2 MUB. For a singly charged anion vacancy, however, the dependence of the magnetic moment on strain is opposite to that of the Zn vacancy. Furthermore, the ferromagnetic state is always present, irrespective of the strain type, for ZnO with two zinc vacancies, 2VZns. A large tensile strain is favorable for improving the Curie temperature and realizing room temperature ferromagnetism for ZnO-based native semiconductors. For ZnO with two singly charged oxygen vacancies, 2Vs, no ferromagnetic ordering can be observed. Our work points the way to the rational design of materials beyond ZnO with novel non-intrinsic functionality by simply tuning the strain in a thin film form. PMID- 26051600 TI - Improved selectivity for Pb(II) by sulfur, selenium and tellurium analogues of 1,8-anthraquinone-18-crown-5: synthesis, spectroscopy, X-ray crystallography and computational studies. AB - We report here a series of heteroatom-substituted macrocycles containing an anthraquinone moiety as a fluorescent signaling unit and a cyclic polyheteroether chain as the receptor. Sulfur, selenium, and tellurium derivatives of 1,8 anthraquinone-18-crown-5 (1) were synthesized by reacting sodium sulfide (Na2S), sodium selenide (Na2Se) and sodium telluride (Na2Te) with 1,8-bis(2 bromoethylethyleneoxy)anthracene-9,10-dione in a 1 : 1 ratio. The optical properties of the new compounds are examined and the sulfur and selenium analogues produce an intense green emission enhancement upon association with Pb(II) in acetonitrile. Selectivity for Pb(II) is markedly improved as compared to the oxygen analogue 1 which was also competitive for Ca(II) ion. UV-Visible and luminescence titrations reveal that 2 and 3 form 1 : 1 complexes with Pb(II), confirmed by single-crystal X-ray studies where Pb(II) is complexed within the macrocycle through coordinate covalent bonds to neighboring carbonyl, ether and heteroether donor atoms. Cyclic voltammetry of 2-8 showed classical, irreversible oxidation potentials for sulfur, selenium and tellurium heteroethers in addition to two one-electron reductions for the anthraquinone carbonyl groups. DFT calculations were also conducted on 1, 2, 3, 6, 6 + Pb(II) and 6 + Mg(II) to determine the trend in energies of the HOMO and the LUMO levels along the series. PMID- 26051601 TI - 6-Phenoxy-2-phenylbenzoxazoles, novel inhibitors of receptor for advanced glycation end products (RAGE). AB - Receptor for advanced glycation end products (RAGE) is known to be involved in the transportation of amyloid beta (Abeta) peptides and causes the accumulation of Abeta in the brain. Moreover, recent studies suggest that the interactions between RAGE and Abeta peptides may be the culprit behind Alzheimer's disease (AD). Inhibitors of the RAGE-Abeta interactions would not only prevent the accumulation of toxic Abeta in the brain, and but also block the progress of AD, therefore, have the potential to provide a 'disease-modifying therapy'. In this study, we have developed a series of 6-phenoxy-2-phenylbenzoxazole analogs as novel inhibitors of RAGE. Among these derivatives, we found several effective inhibitors that block the RAGE-Abeta interactions without causing significant cellular toxicity. Further testing showed that compound 48 suppressed Abeta induced toxicity in mouse hippocampal neuronal cells and reduced Abeta levels in the brains of a transgenic mouse model of AD after oral administration. PMID- 26051602 TI - Design, synthesis and biological evaluation of a novel series of peripheral selective noradrenaline reuptake inhibitor. AB - Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4 oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl) 1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites. PMID- 26051603 TI - Dehydroepiandrosterone prevents linoleic acid-induced endothelial cell senescence by increasing autophagy. AB - BACKGROUND: Autophagy has emerged as a potentially important factor in the pathogenesis of atherosclerosis. Dehydroepiandrosterone (DHEA) is an adrenal steroid of great recent interest due to its anti-aging and anti-atherogenic effects; however, little is known about its role in autophagy and endothelial senescence. OBJECTIVE: The aim of this study was to investigate whether DHEA prevents linoleic acid (LA)-induced endothelial senescence by enhancing autophagy. MATERIALS/METHODS: After pre-treatement with or without DHEA prior to LA treatment in human aortic endothelial cells (HAECs), the level of senescence was compared by senescence-associated acidic beta-galactosidase (SA-beta-Gal) staining and hyperphosphorylated pRB (ppRB) protein level. Autophagy was detected by LC3 conversion and measuring the level of p62/SQSTM1 (sequestosome 1), a protein degraded by autophagy. The fusion of autophagosome and lysosome was confirmed by fluorescence microscopy. RESULTS: Pre-treatment with DHEA inhibited LA-induced endothelial senescence. DHEA increased the conversion of LC3-I to LC3 II and decreased the level of p62 in a time- and dose-dependent manner. Although both DHEA and LA treatment increased the conversion of LC3-I to LC3-II, treatment of LA increased p62 and decreased fusion of autophagosome and lysosome, which reflected decreased autophagic flux. However, pre-treatment with DHEA restored autophagic flux inhibited by LA. When we evaluated signaling pathways, we found that JNK activation involved in LC3 conversion induced by DHEA. CONCLUSION: DHEA prevents LA-induced endothelial senescence by restoring autophagy and autophagic flux through JNK activation. PMID- 26051604 TI - IQGAPs as Key Regulators of Actin-cytoskeleton Dynamics. AB - The actin-cytoskeleton plays a critical role in various biological processes, including cell migration, development, tissue remodeling, and memory formation. Both extracellular and intracellular signals regulate reorganization of the actin cytoskeleton to modulate tissue architecture and cellular morphology in a spatiotemporal manner. Since the discovery that activation of Rho family GTPases induces actin-cytoskeleton reorganization, the mode of action of Rho family GTPases has been extensively studied and individual effectors have been characterized. The actin-binding protein IQGAP1 was identified as an effector of Rac and Cdc42 and is the founding member of the IQGAP family with two additional isoforms. The IQGAP family shows conserved domain organization, and each member displays a specific expression pattern in mammalian tissues. IQGAPs regulate the actin-cytoskeleton alone and with their binding partners, thereby controlling diverse cellular processes, such as cell migration and adhesion. Here, we introduce IQGAPs as an actin-cytoskeleton regulator. PMID- 26051605 TI - Structure-based discovery of an immunomodulatory inhibitor of TLR1-TLR2 heterodimerization from a natural product-like database. AB - We report herein the identification of an immunomodulatory natural product-like compound as a direct inhibitor of TLR1-TLR2 heterodimerization. Compound suppressed TNF-alpha and IL-6 secretion in Pam3CSK4-induced macrophages. Moreover, compound inhibited the phagocytic activity of macrophages, presumably through modulation of TLR1-TLR2 signaling and inactivation of NF-kappaB. Molecular docking revealed that compound bound to the interface region of TLR1 TLR2 by forming two hydrogen bonds with residues lining the binding site. To our knowledge, compound has been only the second inhibitor overall of TLR1-TLR2 heterodimerization reported to date. PMID- 26051606 TI - Imaging evaluation of osteoporotic vertebral fracture. PMID- 26051608 TI - Corrigendum. PMID- 26051607 TI - Changes in attitudes towards mental disorders and psychiatric treatment 1976-2014 in a Swedish population. AB - BACKGROUND: Mental illness has always been subject to stigma and discrimination. There are a number of studies on public attitudes towards people with mental illness. Long-term studies, however, examining changes over time are scarce. AIMS: The aim of this study was to examine potential changes concerning attitudes between 1976 and 2014 in Vilhelmina, a community in northern Sweden. METHODS: A postal questionnaire was sent out to a random sample of 500 adults aged 18-70 years. The same questionnaire has previously been used in 1976 and 2003. RESULTS: The attitudes towards people with mental illness have not generally become more positive over the years. In 2014 almost a quarter of the population still think that "people with mental illness commit violentX acts more than others". Even more people in 2014 than in 1976 agree to the statement that "mental illness harms the reputation more than a physical disease" (77.2% versus 52.8%). People with low educational level have more negative views than people with higher education. Younger respondents, < 20 years, had a more positive view than the older age groups. Almost 70% of the respondents would advise someone with psychological problems to seek a psychiatrist but only 23% of the respondents would follow their own advice. Psychotherapy has been and is still highly appreciated. As regards medication the perception is more critical, but there has been a significant change, however, to a more positive attitude towards medication since 1976. CONCLUSION: Attitudes towards mental illness and mentally ill people have not changed substantially over time. PMID- 26051609 TI - The role of RFamide-related peptide 3 (RFRP3) in regulation of the neuroendocrine reproductive and growth axes of the boar. AB - RFamide-related peptide 3 (RFRP3) has been implicated in regulating reproduction and growth. This regulation appears to be dependent upon sex, species, physiological status, and developmental stage. The objective of the present study was to evaluate the effects of RFRP3 on circulating concentrations of luteinizing hormone (LH) and growth hormone (GH) in mature boars. The hypothesis was RFRP3 would reduce circulating concentrations of LH and increase concentrations of GH. Meishan boars (716.6+/-2.8 days of age; 125.0+/-12.4kg BW) were randomly assigned to treatment: saline (n=4) or RFRP3 (8.5mg; n=5). Plasma was collected at 15-min intervals during 3 periods: pre-treatment, treatment, and post-treatment. During the treatment period, saline or RFRP3 were administered at 15-min intervals. Treatment was administered as a loading dose of 5mg RFRP3, followed by seven repeated injections of 0.5mg RFRP3. Pulsatile secretion of LH and GH were not affected by saline treatment. Mean concentrations of LH in RFRP3-treated boars were greater (P<0.01) in the pre-treatment period than in the treatment and post treatment periods; however, the individual response to RFRP3 challenge was varied. RFRP3 suppressed (P<0.05) mean concentrations of GH during the treatment period. It is concluded that RFRP3 can act to suppress LH secretion in some boars, but the minimal and varied response between animals does not strongly support the idea that RFRP3 is a potent hypohysiotropic hormone in the pig. Results indicate that RFRP3 may function in regulating the growth axis of swine. PMID- 26051610 TI - Differential changes in luteinizing hormone secretion after administration of the investigational metastin/kisspeptin analog TAK-683 in goats. AB - This study aimed to evaluate the hormonal and ovarian responses to the administration of a metastin/kisspeptin analog (TAK-683) under the endocrine environments of luteal and follicular phases in goats. Five estrous cycling goats received a prostaglandin F2alpha injection followed by 10 days of progesterone treatment by CIDR. The TAK-683 (35nmol) was intravenously administered (Hour 0) on 3 days after CIDR insertion (luteal phase condition; LC) and at 12h after CIDR removal (follicular phase condition; FC). Blood samples were collected at 10min ( 2 to 6h), 2h (6-24h) or 6h intervals (24-48h). In the LC, small increases in the basal concentrations of LH were observed after TAK-683 administration from 0 to 6h, which were associated with an increase in estradiol concentration, followed by a surge-like release of LH with a peak at 12.5+/-1.0h (n=4) after TAK-683 administration. In the FC, a surge-like release of LH occurred immediately after TAK-683 administration with a peak at 6.0+/-3.5h (n=5), which was earlier than that in the LC (P<0.01). The peak concentration of estradiol did not differ between the two conditions, whereas the time interval from TAK-683 treatment to estradiol peak in the LC was longer than that in the FC (12.0+/-0.0 compared with 6.0+/-4.2h, P<0.05). These findings suggest that the timing of surge-like release of LH after TAK-683 administration is associated with blood estradiol concentration at the time of treatment. PMID- 26051611 TI - Natriuretic peptides stimulate oocyte meiotic resumption in bovine. AB - The aim of the present study was to evaluate the expression of mRNA encoding natriuretic peptides (NPs) and their receptors in the cumulus-oocyte complex in cattle, a monovular mammalian species, and also to investigate the role of NPs in oocyte meiotic resumption in vitro. mRNA was observed for the NP precursor type-A (NPPA), type-C (NPPC), NP receptor-1 (NPR-1), receptor-2 (NPR-2) and receptor-3 (NPR-3) in bovine cumulus cells, and NPR-2 mRNA was observed in oocytes. These results are different from those obtained in mouse and pig models. The effects of NPPA, NP precursor type-B (NPPB) and NPPC on the resumption of arrested meiosis maintained by forskolin were studied at three different doses (10, 100 and 1000nM) with a 12h culture system. The germinal vesicle breakdown rates were greater (P<=0.05) in oocytes that were cultured in the presence of one or a combination of NPs (from 44% to 73%) than the negative control (from 24% to 27%). Additionally, it was demonstrated that the concentration of cyclic guanosine 3',5'-monophosphate (cGMP) is increased by NPPA and NPPC in oocytes and cumulus cells after 3h of in vitro maturation. However, in both groups, the concentration of cyclic adenosine 3',5'-monophosphate (cAMP) in the oocyte did not increase between 3 and 6h of culture, even when forskolin was used. In summary, we observed the presence of mRNA for NPs and their receptors in the bovine cumulus oocyte complex and demonstrated that, in vitro, NPPA, NPPB and NPPC stimulate oocyte meiotic resumption in a monovular species. PMID- 26051612 TI - Transcript levels of the soluble sperm factor protein phospholipase C zeta 1 (PLCzeta1) increase through induced spermatogenesis in European eel. AB - Activation at fertilization of the vertebrate egg is triggered by Ca(2+) waves. Recent studies suggest the phospholipase C zeta (PLCzeta), a sperm-specific protein, triggers egg activation by an IP3-mediated Ca(2+) release and allow Ca(2+) waves at fertilization. In the present study we cloned, characterized, and phylogenetically positioned the European eel PLCzeta (PLCzeta1). It is 1521 bp long, with 10 exons encoding an open reading frame of 506 amino acids. The amino acid sequence contains an EF-hand domain, X and Y catalytic domains, and a carboxy-terminal C2 domain, all typical of other PLCzeta orthologous. The tissue distribution was studied, and the gene expression was determined in testis during induced sexual maturation at three different thermal regimes. Also, brain and pituitary expression was studied through sex maturation at constant temperature. plczeta1 was expressed in brain of male and female, in testis but not in ovaries. By first time in vertebrates, it is reported plczeta1 expression in the pituitary gland. Testis plczeta1 expression increased through spermatogenesis under all the thermal regimes, but being significantly elevated at lower temperatures. It was very low when testis contained only spermatogonia or spermatocytes, while maximum expression was found during spermiogenesis. These results support the hypothesis for an eel sperm-specific PLCzeta1 inducing egg activation, similarly to mammals and some teleosts, but different from some other teleost species, which express this protein in ovaries, but not in testes. PMID- 26051613 TI - Two cholecystokinin receptor subtypes are identified in goldfish, being the CCKAR involved in the regulation of intestinal motility. AB - Cholecystokinin (CCK) plays a key role in the digestive physiology of vertebrates. However, very little is known about the role of CCK on intestinal functions in fish. The present study identifies two CCK receptor subtypes in a stomachless teleost, the goldfish (Carassius auratus), and investigates by using an in vitro system their involvement mediating the effects of the sulfated octapeptide of CCK (CCK-8S) on the motility of isolated proximal intestine. Partial-length mRNAs encoding two CCK receptor isoforms (CCKAR and CCKBR.I) were sequenced and the structural analysis showed that both receptors belong to the G protein coupled receptor superfamily. Both goldfish CCK receptor sequences were more closely related to zebrafish sequences, sharing the lowest similarities with cavefish and tilapia. The highest expression of goldfish CCKAR was observed along the whole intestine whereas the CCKBR gen was predominantly expressed in the hypothalamus, vagal lobe and posterior intestine. Application of CCK-8S to the organ bath evoked a concentration-dependent contractile response in intestine strips. The contractions were not blocked by either tetrodotoxin or atropine, suggesting that CCK-8S acts on the gut smooth muscle directly. Preincubations of intestine strips with devazepide and L365,260 (CCKAR and CCKBR receptor selective antagonists) showed that the CCK-8S-induced contraction could be partially mediated by the CCKAR receptor subtype, which is also the most abundant CCK receptor found in gastrointestinal tissues. In conclusion, two CCK receptors with a differential distribution pattern has been identified in goldfish, and the CCKAR subtype is mainly involved in the regulation of intestinal motility by the CCK-8S. PMID- 26051614 TI - Energetic costs of protein synthesis do not differ between red- and white-blooded Antarctic notothenioid fishes. AB - Antarctic icefishes (Family Channichthyidae) within the suborder Notothenioidei lack the oxygen-binding protein hemoglobin (Hb), and six of the 16 species of icefishes lack myoglobin (Mb) in heart ventricle. As iron-centered proteins, Hb and Mb can promote the formation of reactive oxygen species (ROS) that damage biological macromolecules. Consistent with this, our previous studies have shown that icefishes have lower levels of oxidized proteins and lipids in oxidative muscle compared to red-blooded notothenioids. Because oxidized proteins are usually degraded by the 20S proteasome and must be resynthesized, we hypothesized that rates of protein synthesis would be lower in icefishes compared to red blooded notothenioids, thereby reducing the energetic costs of protein synthesis and conferring a benefit to the loss of Hb and Mb. Rates of protein synthesis were quantified in hearts, and the fraction of oxygen consumption devoted to protein synthesis was measured in isolated hepatocytes and cardiomyocytes of notothenioids differing in the expression of Hb and cardiac Mb. Neither rates of protein synthesis nor the energetic costs of protein synthesis differed among species, suggesting that red-blooded species do not degrade and replace oxidatively modified proteins at a higher rate compared to icefishes but rather, persist with higher levels of oxidized proteins. PMID- 26051615 TI - Two-dimensional Raman correlation spectroscopy reveals molecular structural changes during temperature-induced self-healing in polymers based on the Diels Alder reaction. AB - The thermally healable polymer P(LMA-co-FMA-co-MIMA) has been studied by temperature-dependent FT-Raman spectroscopy, two-dimensional Raman correlation analysis and density functional theory (DFT) calculations. To the best of our knowledge this study reports for the first time on the investigation of a self healing polymer by means of two-dimensional correlation techniques. The synchronous correlation spectrum reveals that the spectrally overlapping C[double bond, length as m-dash]C stretching vibrations at 1501, 1575, 1585 and 1600 cm( 1) are perfect marker bands to monitor the healing process which is based on a Diels-Alder reaction of furan and maleimide. The comparison between experimental and calculated Raman spectra as well as their correlation spectra showed a good agreement between experiment and theory. The data presented within this study nicely demonstrate that Raman correlation analysis combined with a band assignment based on DFT calculations presents a powerful tool to study the healing process of self-healing polymers. PMID- 26051616 TI - Pilot evaluation of an optimized context-specific drug-drug interaction alerting system: A controlled pre-post study. AB - OBJECTIVES: Clinical decision support (CDS) systems are frequently used to reduce unwanted drug-drug interactions (DDIs) but often result in alert fatigue. The main objective of this study was to investigate whether a newly developed context specific DDI alerting system would improve alert acceptance. METHODS: A controlled pre-post intervention study was conducted in 4 departments in a university hospital. After a 7-month pre-intervention period, the new system was activated in the intervention departments, while the old system remained activated in the control departments. Post-intervention data was collected for a 7-month period. RESULTS: A significant increase of the overall acceptance rate was observed between the pre- and post-intervention period (2.2% versus 52.4%; p<0.001) for the intervention departments and between the intervention and control departments (2.5% versus 52.4%; p<0.001) in the post-intervention period. There were no significant differences in acceptance rates between the pre- and post-intervention period in the control departments and also not between the control and intervention departments in the pre-intervention period. CONCLUSIONS: The improvement was probably related to several optimization strategies including the customization of the severity classification, the creation of individual screening intervals, the inclusion of context factors for risk assessment, the new alert design and the creation of a follow-up system. The marked increase in alert acceptance looks promising and should be further evaluated after hospital wide implementation. System aspects that require further optimization were identified and will be developed. Further research is warranted to develop context-aware algorithms for complex class-class interactions. PMID- 26051617 TI - Neonatal blood stream infections in tertiary referral hospitals in Kurdistan, Iran. AB - BACKGROUND: Bloodstream infection (BSI) is one of the most common causes of nosocomial infection in neonatal intensive care units (NICU). The aim of the present study was to determine bacterial agents and their susceptibility patterns to antibiotics and to investigate the risk factors associated with BSI. METHODS: This was a nested case-control study carried out from September 2009 to June 2010 in the NICU wards in Sanandaj hospitals western Iran. Cases were patients with BSI and controls were other patients who had negative blood culture. Bacteriologic diagnosis and antibiotic susceptibility pattern was performed based on the Edward & Ewings and the National Committee of Clinical Laboratory (NCCL) Standards. RESULTS: Of 472 patients who hospitalized in NICU, 6.4% had BSI (n = 30) including 17girls (56.7%) and 13 boys (43.3%). Enterobacter SPP was the predominant isolated bacteria from blood culture (36.7%). The maximum antibiotic resistance and sensitivity were observed by Tetracycline and Ciprofloxacin respectively. Risk factors associated with BSI were age <= 7 days (p = 0.001), previous antibiotic consumption (p = 0.013), and low birth weight (LBW), (p = 0.001). CONCLUSIONS: Gram negative bacteria and Entrobacter in particular are the most common pathogens. Improving prenatal health care, standards of infection control and choosing accurate antibiotics are recommended to avoid BSI in neonatal intensive care units. PMID- 26051618 TI - Oral Anticoagulants, Health Technology Assessment, and Health Policy. PMID- 26051619 TI - Reply to Letter From Santoro et al.-Long Live beta-Blockers in Takotsubo Outflow Obstruction! Rather With a Short Half-Life? PMID- 26051620 TI - Reply to Xu-Oral Anticoagulants, Health Technology Assessment, and Health Policy. PMID- 26051621 TI - Persistent J-ST Changes: Suspect Ongoing Pericardial Irritation! PMID- 26051622 TI - Preserved Estimated Ejection Fraction in a Patient With Takotsubo Cardiomyopathy Due to Good News. PMID- 26051623 TI - Spontaneous Coronary Artery Dissection Associated With Ascending Aortic Dystrophy: A Tear for Fear. AB - A 36-year-old man with a recent history of surgery for an aortic valve ascending aortic aneurysm was admitted for non-ST-elevation myocardial infarction. Cardiac magnetic resonance imaging showed a limited necrotic lesion in the anterior wall. Coronary angiography showed no significant stenosis, but a mild distal dynamic tortuosity was seen on the left anterior descending artery. Optical coherence tomography analysis confirmed the absence of any significant atherosclerotic infiltration but revealed the presence of a localized short arterial dissection within the kinked zone. The patient was managed with a conservative medical approach. The subsequent evolution was uneventful. PMID- 26051624 TI - Nitric oxide metabolites, nitrative stress, and paraoxonase activity in hepatopulmonary syndrome. AB - AIM: To investigate possible abnormalities of vasoactive compounds, nitrative stress, and antioxidant activity of paraoxonase (PONa) in human hepatopulmonary syndrome (HPS), we determined endothelin-1 (ET), nitric oxide (NOx) metabolites, PONa alongside crude plasma nitrotyrosine (NT) as surrogate marker of nitrative stress. MATERIAL AND METHODS: Liver cirrhosis (LC) patients with HPS (n = 12) were matched by age, sex, and Child-Pugh score to LC patients without HPS (n = 15) and to healthy controls (CTR) (n = 15); plasma NO2(-) (nitrite) (vascular metabolite), NO3(-) (nitrate) (inflammatory metabolite), and PONa were determined by a colorimetric assay, ET, and NT by immunoassays. RESULTS: HPS patients showed higher level of ET (p = 0.0002), NO2(-) (p = 0.002), NO3(-) (p = 0.0001), NT (p < 0.0001), and lower PONa (p = 0.0004) than CTR; post-hoc analysis revealed greater ET (p < 0.05) and NO3(-) (p < 0.005) in LC patients with HPS than in LC patients without HPS. NT correlated to Child-Pugh score within HPS (p = 0.04) and LC (p = 0.02). CONCLUSION: Our HPS patients are characterized by elevated plasma levels of ET and NOx metabolites and lower PONa. Reduced PONa alongside elevated NO3(-) and NT suggests that defective antioxidation may favor nitrative stress and both may be implicated in the pathogenesis of HPS. PMID- 26051625 TI - P300 event-related potential in abstinent methamphetamine-dependent patients. AB - BACKGROUND: Substance use and abuse are characterized by biases in the attentional processing of substance-related stimuli. There are no event related potential (ERP)-based studies of attentional bias for substance-related cues among methamphetamine (MA) dependent patients. The study aimed to measure changes in P300 event-related potentials elicited by MA-related words in MA-dependent individuals at baseline and after 3 and 6 months of abstinence, examining the relationship of ERP changes to craving. METHOD: 26 MA-dependent patients (14 male) newly enrolled in two compulsory treatment centers in China and 29 healthy controls (15 male) were included in this study. At baseline (2-3 weeks in treatment) and after 3 and 6 months of abstinence from MA use, we obtained ERP data during a Stroop color-matching task using MA-related and neutral words. Self reported craving was measured by a Visual Analog Scale (VAS). FINDINGS: Increased P300 amplitudes elicited by MA-related words were observed over left-anterior electrode sites. Abnormal P300 amplitudes declined to the normal levels of healthy controls at the end of 3 months of abstinence, and the decrease was maintained up to the end of 6 months of abstinence. The behavioral data did not show similar changes. The positive relationship between the changes of VAS scores for MA craving and the changes of P300 amplitudes over left anterior electrode sites elicited by MA-related words within the first 3 months was significant. CONCLUSION: These findings highlight the potential use of ERP as an objective index to track changes in subjective MA craving among abstinent MA-dependent patients. PMID- 26051626 TI - Dietary proanthocyanidins modulate BMAL1 acetylation, Nampt expression and NAD levels in rat liver. AB - Metabolism follows circadian rhythms, which are driven by peripheral clocks. Clock genes in the liver are entrained by daytime meals and food components. Proanthocyanidins (PAs), the most abundant flavonoids in the human diet, modulate lipid and glucose metabolism. The aim of this study was to determine whether PAs could adjust the clock system in the liver. Male Wistar rats were orally gavaged with 250 mg grape seed proanthocyanidin extract (GSPE)/kg body weight at zeitgeber time (ZT) 0 (light turned on), at ZT12 (light turned off), or before a 6 hour jet-lag and sacrificed at different times. The 24 hour rhythm of clock core and clock-controlled gene expression indicated that nicotinamide phosphoribosyltransferase (Nampt) was the most sensitive gene to GSPE. However, Nampt was repressed or overexpressed after GSPE administration at ZT0 or ZT12, respectively. NAD levels, which are controlled by Nampt and also exhibit circadian rhythm, decreased or increased according to Nampt expression. Moreover, the ratio of acetylated Bmal1, that directly drives Nampt expression, only increased when GSPE was administered at ZT12. Therefore, GSPE modulated the clock system in the liver, suggesting that PAs can regulate lipid and glucose metabolism by adjusting the circadian rhythm in the liver. PMID- 26051627 TI - Dipeptidylpeptidase 4 (DPP4, CD26) activity in the blood serum of term and preterm neonates with cerebral ischemia. AB - BACKGROUND: To investigate the mechanisms of inflammation in neonates after cerebral ischemia (CI), we evaluated the DPP4 activity in their blood sera and compared these values with clinical indicators. METHODS: The activity of DPP4 was determined in blood serum by a fluorescent method. We studied the correlation between the blood serum DPP4 activity and clinical, neurological and biochemical parameters in neonates with CI. RESULTS: No correlation between the DPP4 activity in umbilical blood and the venous blood of mothers was discovered. Increased blood serum DPP4 activity in full-term and pre-term newborns with CI is demonstrated. The interrelation between serum DPP4 activity and the functional disturbances of CNS (such as depression or excitement) was found in mature but not in premature newborns. Enzyme activity was still elevated at 2-3weeks after birth. CONCLUSION: It is possible that in neonates this enzymatic system operates independently from mothers. It is assumed that increased DPP4 activity in newborns with CI is apparently connected with immune system activation in response to hypoxic stress. The obtained data support the participation of DPP4 in adaptive reactions of newborns and its regulating influence during hypoxemic damage of the CNS due to inflammation and neurodegeneration. PMID- 26051628 TI - Targeting inflammation in the prevention of cardiovascular disease in patients with inflammatory arthritis. AB - Patients with inflammatory arthritis have increased risk of cardiovascular diseases (CVDs) compared with the general population. Subclinical carotid atherosclerosis and increased arterial stiffness are also common in these patients, which may serve as surrogate end points for cardiovascular (CV) events in clinical trials. Although exact mechanisms are still unclear, persistent systemic inflammation in patients with inflammatory arthritis may contribute to the development of CVD. Dysregulated innate immunity pathways in these patients may also play a role in accelerating atherosclerosis. During the last decade, effective suppression of inflammation by biological disease-modifying antirheumatic drugs has improved the disease outcome dramatically in patients with inflammatory arthritis. Growing evidence suggests that antitumor necrosis factor (TNF) therapy may prevent CVD in patients with rheumatoid arthritis. Nonetheless, data on non-TNF biologics are limited. Whether anti-TNF therapy may prevent CVD in patients with spondyloarthritis also remained unclear. In this review, we summarized the effect of both anti-TNF and non-TNF biologics on the CV system, including traditional CVD risk factors, endothelial function, arterial stiffness, subclinical atherosclerosis, and clinical CVD in patients with inflammatory arthritis. PMID- 26051629 TI - Metadherin is required for the proliferation, migration, and invasion of esophageal squamous cell carcinoma and its meta-analysis. AB - Metadherin (MTDH) was found to be highly expressed in various squamous cell carcinomas (SCCs); however, meta-analysis evaluating the association of MTDH in SCC has not been performed. The purpose of this study was to explore the biological functions of MTDH in esophageal squamous cell carcinoma (ESCC) and to meta-analyze the association between MTDH and SCC. Immunohistochemistry was performed to examine MTDH expression using an ESCC tissue array consisting of 86 ESCC and 78 paired normal adjacent tissues (NATs). MTDH was significantly overexpressed in ESCC tissues compared with NATs and was significantly associated with lymph node metastasis, differentiation, and prognosis. Knockdown of MTDH using an MTDH-short hairpin RNA plasmid caused cell cycle arrest at the G0/G1 phase and induced apoptosis of EC9706 cells. Knockdown of MTDH suppressed the proliferation, invasion, and migration of ESCC cells. Furthermore, meta-analysis revealed that overexpression of MTDH was significantly associated with the lymph node metastasis, advanced clinical stage, and T classification of tissues in SCC, suggesting that MTDH might be used as a potential therapeutic target in the lymph node metastasis of ESCC. PMID- 26051631 TI - Characterization of an abnormal photoluminescence behavior upon crystal-phase transition of perovskite CH3NH3PbI3. AB - Solution-processed hybrid perovskite of CH3NH3PbI3 (MAPbI3) exhibits an abnormal luminescence behavior at around the tetragonal-orthorhombic phase transition temperature. The combination of time resolved photoluminescence (PL), variable excitation power PL, and variable-temperature X-ray diffraction (XRD) allows us to clearly interpret the abnormal luminescence features in the phase transition region of MAPbI3. Both PL and XRD results unambiguously prove the coexistence of the tetragonal and orthorhombic phases of MAPbI3 in the temperature range of 150 to 130 K. The two luminescence features observed in the orthorhombic phase at T < 130 K originate from free excitons and donor-acceptor-pair (DAP) transitions, respectively. The comprehensive understanding of optical properties upon phase transition in MAPbI3 will benefit the development of new optoelectronic devices. PMID- 26051632 TI - Downregulation of myeloma-induced ICOS-L and regulatory T cell generation by lenalidomide and dexamethasone therapy. AB - Multiple myeloma (MM) produces significant cellular and humoral immune defects. We have previously reported that MM induces CD4(+)CD25(+)FoxP3(+) cells (TRegs), via tumour expression of the immune checkpoint regulator, ICOS-L. We sought to define what impact the immunomodulatory drug lenalidomide, alone or with dexamethasone, has on TReg cell generation. Lenalidomide pre-treatment of MM cell lines reduced TReg generation and the concomitant TReg:TEff (CD4(+)CD25(+)FoxP3( ): effector T cells) ratio, as a consequence of reduced ICOSL transcription. Dexamethasone did not affect surface ICOS-L expression but did induce TReg cell apoptosis without impacting on TEff cell survival. Combined lenalidomide and dexamethasone significantly reduced both TReg induction and the TReg:TEff cell ratio. In vivo, serial analysis of the TReg:TEff ratio in MM patients on lenalidomide-dexamethasone therapy revealed a progressive reduction towards age matched control values, though not complete correction. Our data demonstrate for the first time immune synergism to explain the observed immune-modulation associated with lenalidomide-dexamethasone therapy. PMID- 26051630 TI - Connexin and pannexin signaling in gastrointestinal and liver disease. AB - Gap junctions, which mediate intercellular communication, are key players in digestive homeostasis. They are also frequently involved in gastrointestinal and liver pathology. This equally holds true for connexin (Cx) hemichannels, the structural precursors of gap junctions, and pannexin (Panx) channels, Cx-like proteins assembled in a hemichannel configuration. Both Cx hemichannels and Panx channels facilitate extracellular communication and drive a number of deteriorative processes, such as cell death and inflammation. Cxs, Panxs, and their channels underlie a wide spectrum of gastrointestinal and liver diseases, including gastritis and peptic ulcer disease, inflammatory intestinal conditions, acute liver failure, cholestasis, hepatitis and steatosis, liver fibrosis and cirrhosis, infectious gastrointestinal pathologies, and gastrointestinal and liver cancer. This could open promising perspectives for the characterization of new targets and biomarkers for therapeutic and diagnostic clinical purposes in the area of gastroenterology and hepatology. PMID- 26051634 TI - Determinants of serum 25-hydroxyvitamin D in Hong Kong. AB - Vitamin D plays an important role in skeletal health throughout life. Some studies have hypothesised that vitamin D may reduce the risk of other diseases. Our study aimed to estimate age-specific and sex-specific serum 25-hydroxyvitamin D (25(OH)D) status and to identify the determinants of serum 25(OH)D status in Hong Kong, a subtropical city in southern China. In 2009-2010, households in Hong Kong were followed up to identify acute respiratory illnesses, and sera from 2694 subjects were collected in three to four different study phases to permit measurement of 25(OH)D levels at different times of the year. A questionnaire survey on diet and lifestyle was conducted among children, with simultaneous serum collection in April and May 2010. The mean of serum 25(OH)D levels in age groups ranged from 39 to 63 nmol/l throughout the year with the mean values in all age groups in spring below 50 nmol/l. Children aged 6-17 years, and girls and women had significantly lower serum 25(OH)D levels than adults, and boys and men, respectively (all P< 0.001). We estimated that serum 25(OH)D levels in Hong Kong followed a lagged pattern relative to climatic season by 5 weeks with lowest observed levels in early spring (March). For children aged 6-17 years, reporting a suntan, having at least 1 servings of fish/week and having at least 1 serving of eggs/week were independently associated with higher serum 25(OH)D levels. Adequate sunlight exposure and increased intake of dietary vitamin D could improve vitamin D status, especially for children and females in the winter and spring. PMID- 26051633 TI - The inverted CD4:CD8 ratio is associated with gender-related changes in oxidative stress during aging. AB - Aging has been associated with increased generation of free radicals as well as immunosenescence. Previous studies have identified older individuals with inverted T CD4:CD8 cell ratio and increased immunity to cytomegalovirus (CMV). Here, we investigated markers of oxidative stress and antioxidant defences in older individuals with inverted CD4:CD8 T-cell ratio. Sixty-one subjects were identified with inverted CD4:CD8 ratio. Older individuals with a CD4:CD8 ratio <1 had increased levels of plasma advanced oxidation protein products (AOPP) and ferric reducing ability of plasma (FRAP), but reduced levels of thiobarbituric acid reactive substances (TBARS) as compared to subjects with normal CD4:CD8 ratio. The CMV IgG serology was negatively correlated with CD4:CD8 ratio. These markers were more evident among elderly men than women. Our data suggest a close relationship between chronic CMV infection and oxidative profile in older individuals in the midst of its influence on the peripheral T-cell subsets. PMID- 26051635 TI - Free triiodothyronine, not thyroid stimulating hormone, should be focused on for risk stratification in acute decompensated heart failure. PMID- 26051636 TI - Gender and creativity: an overview of psychological and neuroscientific literature. AB - The topic of gender differences in creativity is one that generates substantial scientific and public interest, but also courts considerable controversy. Owing to the heterogeneous nature of the findings associated with this line of research, the general picture often appears puzzling or obscure. This article presents a selective overview of psychological and neuroscientific literature that has a relevant bearing on the theme of gender and creativity. Topics that are explored include the definition and methods of assessing creativity, a summary of behavioral investigations on gender in relation to creativity, postulations that have been put forward to understand gender differences in creative achievement, gender-based differences in the structure and function of the brain, gender-related differences in behavioral performance on tasks of normative cognition, and neuroscientific studies of gender and creativity. The article ends with a detailed discussion of the idea that differences between men and women in creative cognition are best explained with reference to the gender dependent adopted strategies or cognitive style when faced with generative tasks. PMID- 26051637 TI - Potential Pathways Involved in the Rapid Antidepressant Effects of Nitrous Oxide. PMID- 26051638 TI - Cytokines as Suicide Risk Biomarkers. PMID- 26051639 TI - Risk and Resilience: Animal Models Shed Light on the Pivotal Role of Inflammation in Individual Differences in Stress-Induced Depression. PMID- 26051640 TI - Preparation and evaluation of kaempferol-phospholipid complex for pharmacokinetics and bioavailability in SD rats. AB - As one of the dietary flavonoids, kaempferol (KP) has been well known to show strong anti-oxidative effect along with other biological properties. However, the oral bioavailability of KP is relatively low due to its poor solubility. In this study, we intended to increase the solubility and bioavailability of KP by preparing kaempferol-phospholipid complex (KP-PC). The KP-PC's physicochemical properties were characterized in terms of infrared spectroscopy (IR), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), water/n-Octanol solubility and in vitro dissolution. KP-PC exhibited higher solubility and dissolution rate than KP, indicating a significant improvement in hydrophilicity. A UPLC-ESI-MS/MS method was developed and validated for the determination of KP in Sprague-Dawley (SD) rat plasma, so as to investigate the oral bioavailability of KP-PC versus KP. Results showed that Cmax and AUC(0-48 h) of KP from the complex (Cmax: 3.94 +/- 0.83 MUg/mL, AUC(0-48 h): 57.81 +/- 9.43 mg/Lh) were higher than that of KP (Cmax: 1.43 +/- 0.21 MUg/mL, AUC(0-48 h): 13.65 +/- 3.12 mg/Lh). This research indicated that phospholipid complex (PC) might be one of the suitable approachs to improve the oral bioavailability of KP and other poor-solubility flavonoids. PMID- 26051641 TI - Non-extended cryoablation could be a new strategy in lung cancer management: An experiment on green fluorescent protein-labeled Lewis lung cancer-bearing mice. AB - Modern cryoablation has been performed in solid tumor management for more than two decades. Following the surgical spirits, it seems natural to pursue radical procedures in clinical practice, which results in unnecessary adverse effects. The attempt to use non-extended procedure made some marked achievements in practice but was criticized severely, because it was supposed to induce residual tumors, which would trigger the rapid development of cancer. Oncologists favored this procedure, however, claiming that non-extended cryoablation let lung cancer patients have higher quality of lives and longer survivals, in light of clinical observations. Therefore, this study was conducted trying to solve this controversy. In this study, fifty female C57BL/6J mice were grafted green fluorescent protein (GFP)-labeled Lewis lung cancer and randomized into two groups. The bidirectional diameters and fluorescence intensity of tumors, and the body weight of mice were recorded. Two weeks after the intervention, tumor volumes increased 20.95% in the cryoablation group, significantly different from that in the control group; the fluorescence intensity decreased 49.85% in the cryoablation group but increased 125.07% in the control group. Lung metastases could be observed in only 20% of mice in the cryosurgery group, contrasted to 64% in the control group. The non-extended lung cancer cryoablation does induce marginal tumor residuals, but will not trigger rapid tumor development. Inversely, the residual tumor cells are severely struck and the metastases are suppressed after the intervention. It could be a new strategy in lung cancer management, even for patients not in early stage. PMID- 26051642 TI - Low-frequency vibrational properties of crystalline and glassy indomethacin probed by terahertz time-domain spectroscopy and low-frequency Raman scattering. AB - In order to clarify the intermolecular vibrations, the low-frequency modes of the glassy and crystalline states of model pharmaceutical indomethacin have been studied using broadband terahertz time-domain spectroscopy and low-frequency Raman scattering. In the crystalline gamma-form, the center of symmetry was suggested by the observation of the exclusion principle of the infrared (IR) and Raman selection rules in the frequency range between 0.2 and 6.5 THz. In addition, a boson peak of the glassy state was observed in both IR and Raman spectra and their frequency showed apparent discrepancy. The intermediate correlation length of the glassy structure was estimated to be about 2.5 nm. The existence of hydrogen bonded cyclic dimers in a glassy state was suggested by the observation of the infrared active intermolecular vibrational mode of the hydrogen bonded cyclic dimers as a broad peak at 3.0 THz in the IR spectrum. PMID- 26051643 TI - CdTe quantum dots as a novel biosensor for Serratia marcescens and Lipopolysaccharide. AB - The main objective of this work is to synthesize CdTe quantum dots (QDs) conjugated with Concanavalin A (Con A) as a novel biosensor to be selective and specific for the detection of Lipopolysaccharide (LPS). In addition, the conjugated CdTe QDs-Con A was used as fluorescence labels to capture Serratia marcescens bacteria through the recognition between CdTe QDs-Con A and LPS of S. marcescens. The appearance of the lattice plans in the high resolution transmission electron photograph indicated a high crystalline with an average size of 4-5 nm for the CdTe QDs. The results showed that the relative fluorescence intensity of CdTe QDs-Con A decreased linearly with LPS concentration in the range from 10 to 90 fg/mL and with correlation coefficient (R(2)) equal to 0.9713. LPS surrounding the S. marcescens bacteria was bound to the CdTe QDs-Con A and leads to quenching of PL intensity. It was found that a good linear relationship between the relative PL intensity and the logarithmic of cell population of S. marcescens in range from 1*10 to 1*10(6) CFU/mL at pH 7 with R(2) of 0.952 was established. PMID- 26051644 TI - Experimental and theoretical spectroscopic study and structural determination of nickel(II) tridentate Schiff base complexes. AB - Some new complexes of [NiL(PR3)] (where L=(E)-1-[(2-amino-5-nitrophenyl)iminio methyl]naphthalene-2-olate (L(1)), (E)-1-[(2-hydroxiphenyl)iminio methyl]naphthalene-2-olate (L(2)), R=Bu and Ph) containing tridentate ONN and ONO Schiff bases were synthesized and characterized by IR, UV-Vis, (1)H-NMR spectroscopy and elemental analysis. The geometry of [NiL(1)(PBu3)] and [NiL(2)(PBu3)] complexes were determined by X-ray crystallography. It was indicated that the complexes have a square planar structure and four coordinates in the solid state. Theoretical calculations were also performed to optimize the structures of the ligands and complexes in the gas phase and ethanol solvent, separately to confirm the structures proposed by X-ray crystallography. In addition, UV-Visible and IR spectra of the complexes were calculated and compared with the corresponding experimental spectra to complete the experimental structural identification. PMID- 26051645 TI - Synthesis of Ag-ZnO with multiple rods (multipods) morphology and its application in the simultaneous photo-catalytic degradation of methyl orange and methylene blue. AB - In this study, the photo-decolorization of a mixture of methylene blue (MB) and methyl orange (MO) was investigated using Ag-ZnO multipods. The photo-catalyst used, ZnO multipods, was successfully synthesized. The surface of ZnO microstructure was modified by deposition of different amounts of Ag nanoparticles (Ag NPs) using the photo-reduction method. The as-prepared samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), UV-Vis and atomic absorption spectroscopy. The photo-catalytic efficiency of Ag-ZnO is mainly controlled by the amount of Ag NPs deposited on the ZnO surface. The results obtained suggest that Ag-ZnO containing 6.5% Ag NPs, has the highest photo-catalytic performance in the simultaneous photo-degradation of dyes at a shorter time. PMID- 26051646 TI - Fourier transform infrared spectroscopy provides an evidence of papain denaturation and aggregation during cold storage. AB - Papain is a cysteine protease with wide substrate specificity and many applications. Despite its widespread applications, cold stability of papain has never been studied. Here, we used differential spectroscopy to monitor thermal denaturation process. Papain was the most stabile from 45 degrees C to 60 degrees C with DeltaG degrees 321 of 13.9+/-0.3 kJ/mol and Tm value of 84+/-1 degrees C. After cold storage, papain lost parts of its native secondary structures elements which gave an increase of 40% of intermolecular beta-sheet content (band maximum detected at frequency of 1621 cm(-1) in Fourier transform infrared (FT-IR) spectrum) indicating the presence of secondary structures necessary for aggregation. The presence of protein aggregates after cold storage was also proven by analytical size exclusion chromatography. After six freeze thaw cycles around 75% of starting enzyme activity of papain was lost due to cold denaturation and aggregation of unfolded protein. Autoproteolysis of papain did not cause significant loss of the protein activity. Upon the cold storage, papain underwent structural rearrangements and aggregation that correspond to other cold denatured proteins, rather than autoproteolysis which could have the commercial importance for the growing polypeptide based industry. PMID- 26051647 TI - Structural and spectroscopic characterization of 4-(3-methyl-3-phenylcyclobutyl) 2-(2-propylidenehydrazinyl)thiazole: A combined experimental and DFT analysis. AB - We investigated the structural and spectroscopic properties of the title compound by means of experimental and DFT quantum chemical methods. The crystal structure of compound was brought to light by single crystal X-ray diffraction method, and were characterized spectroscopically using FT-IR and NMR spectra. FT-IR spectrum in solid state was observed in the region 4000-400 cm(-1). The (1)H and (13)C NMR spectra were recorded in CDCl3 solution. The molecular geometry were those obtained from the X-ray structure determination was optimized using density functional theory (DFT/B3LYP) method with the 6-31G(d, p) and 6-31+G(d, p) basis sets in ground state. From the optimized geometry of the molecule, geometric parameters (bond lengths, bond angles, torsion angles), vibrational assignments and chemical shifts of the title compound have been calculated theoretically and compared with the experimental data. Although theoretical calculations were carried out in gas phase, no significant differences in these values. PMID- 26051648 TI - Sequence selective tagging of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) using PNAs. AB - 8-Oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) is a commonly formed DNA lesion that is useful as a biomarker for oxidative stress. Methods for detecting 8 oxodGuo at specific positions within DNA could be useful for correlating DNA damage with mutational hotspots and repair enzyme accessibility. We describe a method for covalently linking ('tagging') peptide nucleic acids (PNAs) containing terminal nucleophiles under oxidative conditions to 8-oxodGuo at specific sites within DNA. Several nucleophiles were examined and the epsilon-amine of lysine was selected for further studies. As little as 10 fmol of 8-oxodGuo were detected by gel shift using (32)P-labeled target DNA and no tagging of dG at the same site or 8-oxodGuo at a distal site was detected when potassium ferricyanide was used as oxidant in substrates as long as 221 bp. PMID- 26051649 TI - Mixed up minor groove binders: Convincing A.T specific compounds to recognize a G.C base pair. AB - DNA minor-groove-binding compounds have limited biological applications, in part due to problems with sequence specificity that cause off-target effects. A model to enhance specificity has been developed with the goal of preparing compounds that bind to two AT sites separated by G.C base pairs. Compounds of interest were probed using thermal melting, circular dichroism, mass spectrometry, biosensor SPR, and molecular modeling methods. A new minor groove binder that can strongly and specifically recognize a single G.C base pair with flanking AT sequences has been prepared. This multi-site DNA recognition mode offers novel design principles to recognize entirely new DNA motifs. PMID- 26051650 TI - Factors influencing the implementation of a school-based parental support programme to promote health-related behaviours--interviews with teachers and parents. AB - BACKGROUND: The 'Healthy School Start' programme was developed to promote healthy dietary habits and physical activity, targeting parents of 6-year-old children in pre-school class. Knowledge of barriers and facilitators of implementation is crucial before introducing this kind of programme on a larger scale. The aim of this study was to explore the views of teachers and parents regarding factors influencing the implementation of a school-based parental support programme to promote physical activity and healthy diet. METHODS: An inductive qualitative method was used to explore the experiences and views of teachers and parents involved in the programme. A group discussion was held with three teachers, and semi-structured interviews were conducted with 14 parents. Data were analysed using qualitative content analysis. RESULTS: Clear communication on roles and responsibilities was identified as an overarching theme, emphasising the importance of clear information and well-functioning cooperation between project management, schools and parents when implementing the programme in a school setting. Five categories at a manifest level described aspects influencing the implementation: 1) 'The programme' underlining the importance of flexibility and feed-back; 2) 'the school' referring to management and work routines; 3) 'family conditions', implying various life situations; 4) 'group dynamics' dealing with attitudes among children and parents; and 5) 'the surrounding community' including accessibility and attitudes within society. CONCLUSIONS: When implementing a parental support programme in a school setting it is important to facilitate communication and clearly define the division of responsibilities between project management, schools and parents. This emphasises the need for managerial support, and a professional prevention support system. PMID- 26051651 TI - Nanoparticles in medicine: Current challenges facing inorganic nanoparticle toxicity assessments and standardizations. AB - Although nanoparticles research is ongoing since more than 30years, the development of methods and standard protocols required for their safety and efficacy testing for human use is still in development. The review covers questions on toxicity, safety, risk and legal issues over the lifecycle of inorganic nanoparticles for medical applications. The following topics were covered: (i) In vitro tests may give only a very first indication of possible toxicity as in the actual methods interactions at systemic level are mainly neglected; (ii) the science-driven and the regulation-driven approaches do not really fit for decisive strategies whether or not a nanoparticle should be further developed and may receive a kind of "safety label". (iii) Cost and time of development are the limiting factors for the drug pipeline. Knowing which property of a nanoparticle makes it toxic it may be feasible to re-engineer the particle for higher safety (safety by design). FROM THE CLINICAL EDITOR: Testing the safety and efficacy of nanoparticles for human use is still in need of standardization. In this concise review, the author described and discussed the current unresolved issues over the application of inorganic nanoparticles for medical applications. PMID- 26051652 TI - Optimizing the design of protein nanoparticles as carriers for vaccine applications. AB - Successful vaccine development remains a huge challenge for infectious diseases such as malaria, HIV and influenza. As a novel way to present antigenic epitopes to the immune system, we have developed icosahedral self-assembling protein nanoparticles (SAPNs) to serve as a prototypical vaccine platform for infectious diseases. Here we examine some biophysical factors that affect the self-assembly of these nanoparticles, which have as basic building blocks coiled-coil oligomerization domains joined by a short linker region. Relying on in silico computer modeling predictions, we selected five different linker regions from the RCSB protein database that connect oligomerization domains, and then further studied the self-assembly and stability of in vitro produced nanoparticles through biophysical characterization of formed particles. One design in particular, T2i88, revealed excellent self-assembly and homogeneity thus paving the way toward a more optimized nanoparticle for vaccine applications. FROM THE CLINICAL EDITOR: Despite the widespread use of vaccines worldwide, successful development of vaccines against some diseases remains a challenge still. In this article, the authors investigated the physic-chemical and biological properties of icosahedral self-assembling protein nanoparticles (SAPNs), which mimic viral particles, in order to utilize this technology as potential platform for future design of vaccines. PMID- 26051654 TI - Anomalous doping effect in black phosphorene using first-principles calculations. AB - Using first-principles density functional theory calculations, we investigate the geometries, electronic structures, and thermodynamic stabilities of substitutionally doped phosphorene sheets with group III, IV, V, and VI elements. We find that the electronic properties of phosphorene are drastically modified by the number of valence electrons in dopant atoms. The dopants with an even number of valence electrons enable the doped phosphorenes to have a metallic feature, while the dopants with an odd number of valence electrons retain a semiconducting feature. This even-odd oscillating behavior is attributed to the peculiar bonding characteristics of phosphorene and the strong hybridization of sp orbitals between dopants and phosphorene. Furthermore, the calculated formation energies of various substitutional dopants in phosphorene show that such doped systems can be thermodynamically stable. These results propose an intriguing route to tune the transport properties of electronic and photoelectronic devices based on phosphorene. PMID- 26051653 TI - Kinetics of Mycobacterium tuberculosis-specific IFN-gamma responses and sputum bacillary clearance in HIV-infected adults during treatment of pulmonary tuberculosis. AB - In HIV-uninfected adults with pulmonary tuberculosis (TB), anti-TB treatment is associated with changes in Mycobacterium tuberculosis (Mtb)-specific immune responses, which correlate with sputum bacillary load. It is unclear if this occurs in HIV-infected TB patients. We investigated changes in Mtb-specific immune responses and sputum bacillary clearance during anti-TB treatment in HIV infected and HIV-uninfected adults with pulmonary TB. Sputum bacillary load was assessed by smear microscopy and culture. Mtb-specific IFN-gamma secreting peripheral blood mononuclear cells were enumerated using an ELISPOT assay following stimulation with PPD, ESAT-6 and CFP-10. The baseline frequency of Mtb specific IFN-gamma secreting cells was lower in HIV-infected than HIV-uninfected patients (median PPD 32 vs. 104 Spot Forming Units (SFU), p = 0.05; CFP-10 19 vs. 74 SFU, p = 0.01). ESAT-6-specific IFN-gamma secreting cells and sputum bacillary load declined progressively during treatment in both HIV-infected and HIV uninfected patients. HIV infection did not influence the 2-month sputum culture conversion rate (Odds Ratio 0.89, p = 0.95). These findings suggest that changes in ESAT-6-specific immune responses during anti-TB treatment correspond with changes in sputum bacillary load irrespective of host HIV infection status. The utility of Mtb-specific IFN-gamma responses as a proxy measure of treatment response in HIV-infected TB patients warrants further evaluation in other settings. PMID- 26051655 TI - Characterisation of interfacial segregation to Cu-enriched precipitates in two thermally aged reactor pressure vessel steel welds. AB - To understand the contribution of long term thermal ageing to Reactor Pressure Vessel (RPV) embrittlement two high Cu steel welds with different Ni contents were thermally aged for times up to 100,000 h at 330 degrees C and 365 degrees C. Microstructural characterisation using Atom Probe Tomography was performed. Thermal ageing produced a high number density of nano-scale Cu-enriched precipitates. The precipitate-matrix interfaces were enriched in Ni, Mn and Si. The characterisation of these interfaces using a double cluster search approach is the subject of this work. The interface region around thermally-induced precipitates was found to be wider in steels with higher bulk Ni contents and where precipitates had larger core radii. The effect of ageing temperature on interface width was small when comparing precipitates of equal core radius. The narrower interface width in the lower Ni steels is reflected in the composition of the interface, which has a lower Ni content than in the higher Ni material. The reduction in interfacial energy due to the segregation of Ni, Mn and Si has been calculated and shows enhanced reductions in interfacial energy with increasing precipitate size, but no obvious effect of temperature. PMID- 26051656 TI - Effect of substrate interface on the magnetism of supported iron nanoparticles. AB - In situ X-ray photo-emission electron microscopy is used to investigate the magnetic properties of iron nanoparticles deposited on different single crystalline substrates, including Si(001), Cu(001), W(110), and NiO(001). We find that, in our room temperature experiments, Fe nanoparticles deposited on Si(001) and Cu(001) show both superparamagnetic and magnetically stable (blocked) ferromagnetic states, while Fe nanoparticles deposited on W(110) and NiO(001) show only superparamagnetic behaviour. The dependence of the magnetic behaviour of the Fe nanoparticles on the contact surface is ascribed to the different interfacial bonding energies, higher for W and NiO, and to a possible relaxation of point defects within the core of the nanoparticles on these substrates, that have been suggested to stabilise the ferromagnetic state at room temperature when deposited on more inert surfaces such as Si and Cu. PMID- 26051657 TI - Correction of the deterministic part of space-charge interaction in momentum microscopy of charged particles. AB - Ultrahigh spectral brightness femtosecond XUV and X-ray sources like free electron lasers (FEL) and table-top high harmonics sources (HHG) offer fascinating experimental possibilities for analysis of transient states and ultrafast electron dynamics. For electron spectroscopy experiments using illumination from such sources, the ultrashort high-charge electron bunches experience strong space-charge interactions. The Coulomb interactions between emitted electrons results in large energy shifts and severe broadening of photoemission signals. We propose a method for a substantial reduction of the effect by exploiting the deterministic nature of space-charge interaction. The interaction of a given electron with the average charge density of all surrounding electrons leads to a rotation of the electron distribution in 6D phase space. Momentum microscopy gives direct access to the three momentum coordinates, opening a path for a correction of an essential part of space-charge interaction. In a first experiment with a time-of-flight momentum microscope using synchrotron radiation at BESSY, the rotation in phase space became directly visible. In a separate experiment conducted at FLASH (DESY), the energy shift and broadening of the photoemission signals were quantified. Finally, simulations of a realistic photoemission experiment including space-charge interaction reveals that a gain of an order of magnitude in resolution is possible using the correction technique presented here. PMID- 26051658 TI - Tuning the deposition of molecular graphene nanoribbons by surface functionalization. AB - We show that individual, isolated graphene nanoribbons, created with a molecular synthetic approach, can be assembled on functionalised wafer surfaces treated with silanes. The use of surface groups with different hydrophobicities allows tuning the density of the ribbons and assessing the products of the polymerisation process. PMID- 26051659 TI - Prostate cancer radiotherapy: potential applications of metal nanoparticles for imaging and therapy. AB - Prostate cancer (CaP) is the most commonly diagnosed cancer in males. There have been dramatic technical advances in radiotherapy delivery, enabling higher doses of radiotherapy to primary cancer, involved lymph nodes and oligometastases with acceptable normal tissue toxicity. Despite this, many patients relapse following primary radical therapy, and novel treatment approaches are required. Metal nanoparticles are agents that promise to improve diagnostic imaging and image guided radiotherapy and to selectively enhance radiotherapy effectiveness in CaP. We summarize current radiotherapy treatment approaches for CaP and consider pre clinical and clinical evidence for metal nanoparticles in this condition. PMID- 26051660 TI - [Ablative treatments in localized renal cancer: literature review for 2014]. AB - OBJECTIVE AND METHOD: To focus on indications and results of ablative treatments (cyoablation, radiofrequency) for small renal masses, a bibliographic research was conducted in MedLine database using terms of "ablative treatment", "cryotherapy", "radiofrequency", "kidney cancer", "renal cell carcinoma". Sixty four articles were selected. RESULTS: Carcinologic outcomes seem to be better with cryoablation than with radiofrequency. Available results have to be balanced according to surgical approach, teams' experience and duration of follow-up. Tumour's size and central localization are the main factors of failure. The size of 3cm is the most generally validated. Hospital stay and complications seem to be better with ablative therapies than with surgical approach, especially with percutaneous approach. The renal function preservation appears to be better with ablative therapies. It could be an interesting alternative to partial nephrectomy for small masses, in particular for fragile patients or in particular indications (multifocal tumors, in case of solitary kidney or transplanted kidney). The indications in elderly people must be proposed with care after the comorbidities have been evaluated. CONCLUSION: Indications of ablative treatment for small renal masses improve, but the gold standard treatment remains partial nephrectomy and indications must be individually discussed. Other ablative treatments are under-development, needing further studies. PMID- 26051661 TI - A novel inhaled Syk inhibitor blocks mast cell degranulation and early asthmatic response. AB - Spleen tyrosine kinase (Syk) is essential for signal transduction of immunoreceptors. Inhibition of Syk abrogates mast cell degranulation and B cell responses. We hypothesized that Syk inhibition in the lung by inhaled route could block airway mast cells degranulation and the early asthmatic response without the need of systemic exposure. We discovered LAS189386, a novel Syk inhibitor with suitable properties for inhaled administration. The aim of this study was to characterize the in vitro and in vivo profile of LAS189386. The compound was profiled in Syk enzymatic assay, against a panel of selected kinases and in Syk dependent cellular assays in mast cells and B cells. Pharmacokinetics and in vivo efficacy was assessed by intratracheal route. Airway resistance and mast cell degranulation after OVA challenge was evaluated in an ovalbumin-sensitized Brown Norway rat model. LAS189386 potently inhibits Syk enzymatic activity (IC50 7.2 nM), Syk phosphorylation (IC50 41 nM), LAD2 cells degranulation (IC50 56 nM), and B cell activation (IC50 22 nM). LAS189386 inhibits early asthmatic response and airway mast cell degranulation without affecting systemic mast cells. The present results support the hypothesis that topical inhibition of Syk in the lung, without systemic exposure, is sufficient to inhibit EAR in rats. Syk inhibition by inhaled route constitutes a promising therapeutic option for asthma. PMID- 26051662 TI - Epidemiologic Trends in Hospitalized Ischemic Stroke from 2002 to 2010: Results from a Large Italian Population-Based Study. AB - BACKGROUND: To describe the incidence of ischemic stroke, short-term mortality, recurrences, and prescription patterns. METHODS: Data from administrative health databases of the Lombardy Region from 2002 to 2010 (about 4 million people) were analyzed for stroke incidence and recurrence, mortality, and drug prescriptions after an ischemic stroke. RESULTS: A total of 43,352 patients with a first hospital admission for ischemic stroke were identified. During 8 years, stroke incidence decreased from 3.2 of 1000 to 2.4 of 1000 (P < .001) in people aged 65 74 years, from 7.1 of 1000 to 5.3 of 1000 (P < .001) at ages 75-84 years and from 11.9 of 1000 to 9.4 of 1000 (P < .001) at age 85 years or older. Stroke recurrences dropped by 30% (from 10.0% to 7.0%, P < .001) and 30-day mortality rate also decreased. Prescription trends showed linear increase in antiplatelets and lipid-lowering drugs, respectively, from 60.2% to 65.0% (P < .001) and from 19.1% to 34.6% (P < .001), whereas antihypertensive prescriptions did not change appreciably. Anticoagulant prescription increased in patients with atrial fibrillation, from 64.8% to 72.1% in the 65-74 years age group, (P = .004) and from 40.2% to 53.7% in the 75-84 years age group (P < .001); less than 20% of the 85 years or older age group were treated with anticoagulants (P < .0001). CONCLUSIONS: Stroke incidence, recurrence, and 30-day mortality decreased from 2002 to 2010 concomitant with an increase in prescriptions of secondary stroke prevention drugs. PMID- 26051663 TI - In What Daily Activities Do Patients Achieve Independence after Stroke? AB - BACKGROUND: The aim of the study is to determine the probability of achieving independence and the related prognostic factors with regard to single activities of daily living after 3 months of rehabilitation following stroke. METHODS: This longitudinal observational study, conducted in a neurorehabilitation unit of a research and health care institute, involved 435 subjects who were affected by stroke (age, 68 +/- 14 years, 230 men). Barthel index (BI) scores were recorded at admission and dismissal 3 months later. RESULTS: The highest improvement after rehabilitation was observed for bowel and bladder function and transfer and mobility, whereas the lowest improvement was seen in bathing, grooming, dressing, and stair climbing. CONCLUSIONS: Severity of stroke, presence of unilateral neglect, age, gender, and onset-to-admission interval (OAI) were significant prognostic factors for 6 of 10 activities, as assessed by BI subscores. Feeding was influenced only by neglect and OAI, whereas OAI did not affect bowel or bladder function recovery. PRACTICE: Patients and their relatives could be informed about the specific activities in which patients will be expected to be independent after rehabilitation and the specific needs that they might have on returning home. IMPLICATION: Our results might help optimize the management of the rehabilitative process. PMID- 26051664 TI - Early Dynamics of P-selectin and Interleukin 6 Predicts Outcomes in Ischemic Stroke. AB - BACKGROUND: Thromboinflammatory molecules connect the prothrombotic state, endothelial dysfunction, and systemic/local inflammation in the acute phase of ischemic stroke. METHODS: We prospectively investigated (1) serial changes in the levels of thromboinflammatory biomarkers in 76 patients with acute ischemic stroke (6, 24, and 72 hours after onset); (2) compared with 44 patients with asymptomatic severe (>=70%) carotid stenosis and 66 patients with Parkinson disease; and (3) we applied multiple regression methods, relating biological biomarkers combined with demographic data and comorbidities to poststroke infection, death, and functional outcome, and assessed the ability of the models to predict each outcome. RESULTS: Interleukin 6 (IL-6) levels and change of IL-6 concentrations by 72 hours correlated with the size of tissue damage indicated by S100B titers. Levels of IL-6 and P-selectin at 72 hours were higher in patients with large-artery versus lacunar stroke. High concentration of IL-6, monocyte chemotactic protein 1, and S100B at 6 hours were associated with poststroke infections; high concentration of IL-6, S100B, and high-sensitivity C-reactive protein (hsCRP) correlated with death. Change of P-selectin from 6 to 72 hours by 1 unit increased the incidence of poststroke infections with an odds ratio of 22.7; each 100 units of IL-6 at baseline increased the odds of death by 90/00, and at 72 hours, the odds of poststroke infections by 40/00. Each unit of baseline hsCRP elevated the odds of death by 7%. CONCLUSIONS: In regression models, in which biological, demographic, and comorbid factors were combined, those biological biomarkers predicted poor outcome with high accuracy, which were characterized by an increasing concentration by 72 hours. Two particular biomarkers emerged to predict outcomes besides hsCRP: early dynamic changes in the systemic levels of P-selectin and IL-6. PMID- 26051665 TI - Comparison of Stroke Codes in the Emergency Room and Inpatient Setting. AB - BACKGROUND: Outcomes of acute stroke management are time dependent. Intravenous tissue plasminogen activator (t-PA) is indicated within 3-4.5 hours of symptom onset and endovascular intervention within 6 hours. Time to treatment may depend on the patient's location. This study seeks to determine whether there is a difference in the timing of key aspects of stroke codes between the emergency room and the inpatient setting. METHODS: Stroke codes ending in t-PA administration or endovascular intervention between 2010 and 2013 were included. Emergency room stroke codes were compared with those in the inpatient setting. Data were obtained from the Yarmon Stroke Center log. The variables were time to neurological evaluation, time to computed tomography (CT) scan, time to t-PA administration, time from CT scan to t-PA, and time to endovascular intervention. The variables were compared using the t test. RESULTS: One hundred twenty-two stroke codes were included (106 from emergency room and 16 from inpatient setting). There was no difference in the time to neurological evaluation (P = .19). The time to CT scan and to t-PA administration was significantly increased in the inpatient group (P <= .001 and P = .01, respectively). There was no difference in the time from CT scan to t-PA (P = .09) and in the time to endovascular intervention (P = .21). CONCLUSIONS: Our results show that in the inpatient setting, there was a significant delay in the time to CT scan and to t PA administration and that the source of the delay is the time to CT scan. PMID- 26051666 TI - Stroke-Associated Pneumonia in Thrombolyzed Patients: Incidence and Outcome. AB - BACKGROUND: Stroke-associated pneumonia often negatively influences the prognosis of stroke patients. The aims of this study were to determine the frequency of pneumonia and to investigate the correlation between pneumonia and prognosis in stroke patients receiving intravenous thrombolysis with recombinant tissue plasminogen activator (IV thrombolysis). METHODS: Between 2008 and 2013, 538 consecutive stroke patients (mean age, 72 +/- 13 years; 50.4% women) receiving IV thrombolysis at the Department of Neurology, University of Lubeck, were investigated. RESULTS: Pneumonia occurred among 122 patients (23%; 95% confidence interval [CI], 19.1-26.2). Pneumonia patients were older (76 versus 71 years; P < .001), more severely affected at admission (National Institutes of Health Stroke Scale [NIHSS] score, 13 versus 9; P < .001), and more likely to have atrial fibrillation (54% versus 42%; P = .02) than patients without pneumonia. They had also a longer hospitalization (15 versus 10 days; P < .001). Using logistic regression analysis, the occurrence of pneumonia was associated with male sex (odds ratio [OR], 1.9; 95% CI, 1.2-3.1; P = .006), neurologic deficit severity (NIHSS score >=10; OR, 4.4; 95% CI, 2.5-7.4; P < .0019), previous stroke (OR, 1.5; 95% CI, 1.0-2.2; P = .06), and occurrence of symptomatic intracerebral hemorrhage (OR, 1.6; 95% CI, 1.0-3.2; P = .048). Mortality rates (in-hospital mortality [18.9% versus 7.0; P < .0019]; 3-month mortality [34.3% versus 10.6%; P < .001], and 12-month mortality [53.6% versus 19.6%; P < .001]) were higher in pneumonia patients than those without. A favorable outcome (modified Rankin Scale score <=2) was more likely in patients without pneumonia than those with pneumonia (42% versus 7%; P < .001). CONCLUSION: Pneumonia was correlated with increased age, male sex, neurologic deficit severity, and a less favorable prognosis. PMID- 26051667 TI - Association of Insurance Status with Stroke-Related Mortality and Long-term Survival after Stroke. AB - BACKGROUND: Lack of insurance is a barrier to optimal stroke risk factor control but data on its long-term impact on stroke outcomes are sparse. We assessed the association between health insurance and long-term mortality after stroke. METHODS: Using data from the National Health and Nutrition Examination Surveys 1999-2004 with follow-up mortality assessment through 2006, we examined the independent effect of health insurance on (1) stroke mortality among all adult participants (n = 15,049) and (2) vascular and all-cause mortality rates among participants with self-reported stroke (n = 563). RESULTS: Among individuals without a previous stroke, uninsured individuals aged less than 65 years were more likely to die of stroke than those with insurance (adjusted hazard ratio [HR], 3.13; 95% confidence interval [CI], .96-10.23); however, among those aged 65 years or older, those with private insurance, private plus Medicare, or Medicare plus Medicaid had similar risk of stroke mortality when compared to those with Medicare alone. Stroke survivors aged 65 years or older with private insurance were less likely to die from vascular causes (adjusted HR, .38; 95% CI, .23-.63) compared to those with Medicare alone. For stroke survivors aged less than 65 years, uninsured individuals had similar all-cause mortality rates compared to their counterparts with insurance. CONCLUSIONS: Insurance status influences risk of dying from a stroke in the general population, as well as long term mortality rates among stroke survivors in the United States, but these relationships vary by age. PMID- 26051668 TI - Auditory Spatial Deficits in the Early Stage of Ischemic Cerebral Stroke. AB - BACKGROUND: Clinical research, together with computed tomography/magnetic resonance imaging findings, proves that ischemic stroke (IS) that damages auditory pathways can cause hearing loss and impairment of higher auditory processes such as sound localization. The goal of the study was to find possible correlations between the IS risk factors, ischemic lesion volume and localization, neurologic status, and the sound localization capability in acute IS patients. METHODS: We consecutively enrolled 61 IS patients into the study. The control group consisted of 60 healthy volunteers. All neuro-otological evaluations were performed up to 30 days from the incidence of stroke. All the subjects underwent the horizontal minimum audible angle test (HMAAT) and standard tonal and speech audiometric assessments. RESULTS: HMMAT results were significantly worse in the IS patients and were present in 82.0% of the patients. There were more patients with unilateral disturbances than with bilateral ones (54.1% versus 27.9%). It was the characteristics of the ischemic lesions that correlated strongly with the sound localization deterioration, that is, their bilateral (the 90 degrees azimuth, P = .018; the 180 degrees , P = .002), multiple (the 45 degrees , P = .020; the 180 degrees , P = .007; the 225 degrees , P = .047), and lacunar character (the 90 degrees , P = .015; the 225 degrees , P = .042). Differences in the types of HMAAT results were significant for lesions in the frontal and the temporal lobe (P = .018 and P = .040). In addition, worse sound localization ability was more common in patients with poor speech discrimination and the bilateral sensorineural hearing loss. We have not found statistically significant correlations for other analyzed factors such as the cortical/subcortical character of the lesions, the patients' neurologic status, and cerebrovascular risk factors. CONCLUSIONS: Sound localization impairment is common in IS patients and it is the multiple, bilateral, and lacunar character of the ischemic lesions that seems to be strongly positively correlated with the disturbance of the sound localization ability. PMID- 26051669 TI - Secreted xylanase XynA mediates utilization of xylan as sole carbon source in Candida utilis. AB - The fodder yeast Candida utilis is able to use xylose mono- and oligomers as sources of carbon but not the abundant polymer xylan. C. utilis transformants producing the Penicillium simplicissimum xylanase XynA were constructed using expression vectors encoding fusions of the Saccharomyces cerevisiae Mfalpha1 pre pro secretion leader to XynA. The Mfalpha1-XynA fusion was efficiently processed in transformants and XynA was secreted almost quantitatively into the culture medium. Secreted XynA was enzymatically active and allowed transformants to grow on xylan as the sole carbon source. Addition of a second expression unit for the heterologous green fluorescent protein (GFP) generated C. utilis transformants, which showed intracellular GFP fluorescence during growth on xylan. The results suggest that xylanase-producing C. utilis is suited as a cost-effective host organism for heterologous protein production and for other biotechnical applications. PMID- 26051670 TI - Isolation of phenazine 1,6-di-carboxylic acid from Pseudomonas aeruginosa strain HRW.1-S3 and its role in biofilm-mediated crude oil degradation and cytotoxicity against bacterial and cancer cells. AB - Pseudomonas sp. has long been known for production of a wide range of secondary metabolites during late exponential and stationary phases of growth. Phenazine derivatives constitute a large group of secondary metabolites produced by microorganisms including Pseudomonas sp. Phenazine 1,6-di-carboxylic acid (PDC) is one of such metabolites and has been debated for its origin from Pseudomonas sp. The present study describes purification and characterization of PDC isolated from culture of a natural isolate of Pseudomonas sp. HRW.1-S3 while grown in presence of crude oil as sole carbon source. The isolated PDC was tested for its effect on biofilm formation by another environmental isolate of Pseudomonas sp. DSW.1-S4 which lacks the ability to produce any phenazine compound. PDC showed profound effect on both planktonic as well as biofilm mode of growth of DSW.1-S4 at concentrations between 5 and 20 MUM. Interestingly, PDC showed substantial cytotoxicity against three cancer cell lines and against both Gram-positive and Gram-negative bacteria. Thus, the present study not only opens an avenue to understand interspecific cooperation between Pseudomonas species which may lead its applicability in bioremediation, but also it signifies the scope of future investigation on PDC for its therapeutic applications. PMID- 26051672 TI - Antibacterial evaluation of flavonoid compounds against E. coli by microcalorimetry and chemometrics. AB - Fighting against multidrug-resistant bacteria requires reliable methods to evaluate the effect of antibacterial agents. As a universal, non-destructive, and highly sensitive tool, microcalorimetry has been used in many biological investigations to provide continuous real-time monitoring of the metabolic activity. This method, based on heat-flow output, was used to evaluate the influence of two flavonoid compounds (liquiritigenin and liquiritin) on Escherichia coli. Some crucial information, such as the thermogenic power-time curve and thermokinetic parameters of E. coli growth affected by the two compounds, was obtained and further studied by chemometric techniques including similarity analysis, multivariate analysis of variance, and principal component analysis. By comparing the values of two main parameters, k 2 (growth rate constant of the second exponential phase) and Q 1 (heat output of the first exponential growth phase) of E. coli based on the box and whisker plot, liquiritigenin and liquiritin could be differentiated according to their antibacterial effects; liquiritin with IC50 (half-inhibitory concentration) of 198.6 MUg mL(-1) expressed a stronger antibacterial effect than liquiritigenin with IC50 of 337.8 MUg mL(-1). The glucoside group in liquiritin containing four additional free hydroxyls in the diphenylpropane skeleton was crucial for inducing the antibacterial effect. Liquiritin might be a promising candidate against E. coli. This study provides a valuable method for searching for novel antibacterial agents using microcalorimetry with chemometrics. PMID- 26051671 TI - PEP3 overexpression shortens lag phase but does not alter growth rate in Saccharomyces cerevisiae exposed to acetic acid stress. AB - In fungi, two recognized mechanisms contribute to pH homeostasis: the plasma membrane proton-pumping ATPase that exports excess protons and the vacuolar proton-pumping ATPase (V-ATPase) that mediates vacuolar proton uptake. Here, we report that overexpression of PEP3 which encodes a component of the HOPS and CORVET complexes involved in vacuolar biogenesis, shortened lag phase in Saccharomyces cerevisiae exposed to acetic acid stress. By confocal microscopy, PEP3-overexpressing cells stained with the vacuolar membrane-specific dye, FM4-64 had more fragmented vacuoles than the wild-type control. The stained overexpression mutant was also found to exhibit about 3.6-fold more FM4-64 fluorescence than the wild-type control as determined by flow cytometry. While the vacuolar pH of the wild-type strain grown in the presence of 80 mM acetic acid was significantly higher than in the absence of added acid, no significant difference was observed in vacuolar pH of the overexpression strain grown either in the presence or absence of 80 mM acetic acid. Based on an indirect growth assay, the PEP3-overexpression strain exhibited higher V-ATPase activity. We hypothesize that PEP3 overexpression provides protection from acid stress by increasing vacuolar surface area and V-ATPase activity and, hence, proton sequestering capacity. PMID- 26051673 TI - Methylotrophs in natural habitats: current insights through metagenomics. AB - The focus of this review is on the recent data from the omics approaches, measuring the presence of methylotrophs in natural environments. Both Bacteria and Archaea are considered. The data are discussed in the context of the current knowledge on the biochemistry of methylotrophy and the physiology of cultivated methylotrophs. One major issue discussed is the recent metagenomic data pointing toward the activity of "aerobic" methanotrophs, such as Methylobacter, in microoxic or hypoxic conditions. A related issue of the metabolic distinction between aerobic and "anaerobic" methylotrophy is addressed in the light of the genomic and metagenomic data for respective organisms. The role of communities, as opposed to single-organism activities in environmental cycling of single carbon compounds, such as methane, is also discussed. In addition, the emerging issue of the role of non-traditional methylotrophs in global metabolism of single carbon compounds and the role of methylotrophy pathways in non-methylotrophs is briefly mentioned. PMID- 26051674 TI - Excessive precipitation of CaCO3 as aragonite in a continuous aerobic granular sludge reactor. AB - A hybrid airlift reactor was adopted to retain aerobic granules in the reactor successfully for continuous operation. It was found that aerobic granules maintained excellent physical structure stability in the continuous-flow reactor with reactor performance as good as batch operation. However, flocs appeared after batch operation was switched to continuous operation, and chemical oxygen demand (COD) in the wastewater was thus removed by co-existed granules and flocs in the reactor. Furthermore, excessive precipitation of CaCO3 as needled shaped aragonite in the continuous aerobic granular sludge reactor was observed, which led to the further enhancement of settling ability of granules with sludge volume index (SVI) reduction from 32 to 2 ml g(-1) but specific oxygen utilization rate (SOUR) decrease from 61 to 23 mg O2 g(-1) MLVSS h(-1). Thus, apart from the physical structure stability, bioactivity stability of granules should be also considered as an important parameter to evaluate the continuous operation of aerobic granular sludge. Furthermore, the decrease in granule polysaccharide content implied that protein was more important for aragonite precipitation. The excessive aragonite precipitation in the continuous-flow reactor could be due to the competition between flocs and granules. In addition, the degradation of polysaccharide in aerobic granules under a continuous-flow mode may also contribute to excessive aragonite precipitation. PMID- 26051675 TI - Deep catalytic oxidative desulfurization (ODS) of dibenzothiophene (DBT) with oxalate-based deep eutectic solvents (DESs). AB - An oxalate-based DES with a tetrabutyl ammonium chloride and oxalate acid molar ratio of 1/2 (TBO1 : 2) exhibited high activity in oxidative desulfurization (ODS) of dibenzothiophene (DBT) under mild reaction conditions. It is potentially a promising and highly environmentally friendly approach for desulfurization of fuels. PMID- 26051676 TI - Experimental Null Method to Guide the Development of Technical Procedures and to Control False-Positive Discovery in Quantitative Proteomics. AB - Comprehensive and accurate evaluation of data quality and false-positive biomarker discovery is critical to direct the method development/optimization for quantitative proteomics, which nonetheless remains challenging largely due to the high complexity and unique features of proteomic data. Here we describe an experimental null (EN) method to address this need. Because the method experimentally measures the null distribution (either technical or biological replicates) using the same proteomic samples, the same procedures and the same batch as the case-vs-contol experiment, it correctly reflects the collective effects of technical variability (e.g., variation/bias in sample preparation, LC MS analysis, and data processing) and project-specific features (e.g., characteristics of the proteome and biological variation) on the performances of quantitative analysis. To show a proof of concept, we employed the EN method to assess the quantitative accuracy and precision and the ability to quantify subtle ratio changes between groups using different experimental and data-processing approaches and in various cellular and tissue proteomes. It was found that choices of quantitative features, sample size, experimental design, data processing strategies, and quality of chromatographic separation can profoundly affect quantitative precision and accuracy of label-free quantification. The EN method was also demonstrated as a practical tool to determine the optimal experimental parameters and rational ratio cutoff for reliable protein quantification in specific proteomic experiments, for example, to identify the necessary number of technical/biological replicates per group that affords sufficient power for discovery. Furthermore, we assessed the ability of EN method to estimate levels of false-positives in the discovery of altered proteins, using two concocted sample sets mimicking proteomic profiling using technical and biological replicates, respectively, where the true-positives/negatives are known and span a wide concentration range. It was observed that the EN method correctly reflects the null distribution in a proteomic system and accurately measures false altered proteins discovery rate (FADR). In summary, the EN method provides a straightforward, practical, and accurate alternative to statistics-based approaches for the development and evaluation of proteomic experiments and can be universally adapted to various types of quantitative techniques. PMID- 26051677 TI - Aza-BODIPY dyes with enhanced hydrophilicity. AB - Attempts to make a diamino disulfonic acid derivative of an aza-BODIPY showed it was difficult to add BF2 to a disulfonated azadipyrromethene, and sulfonation of an aza-BODIPY resulted in loss of the BF2 fragment. We conclude the electron deficient character of aza-BODIPY dyes destabilizes them relative to BODIPY dyes. Consequently, sulfonation of the aza-BODIPY core is not a viable strategy to increase water solubility. This assertion was indirectly supported via stability studies of a BODIPY and an aza-BODIPY in aqueous media. To afford the desired compound type, an aza-BODIPY with two amino and two sulfonic acid groups was prepared via modification of the aryl substituents with cysteic acid. PMID- 26051678 TI - RNA editing of non-coding RNA and its role in gene regulation. AB - It has for a long time been known that repetitive elements, particularly Alu sequences in human, are edited by the adenosine deaminases acting on RNA, ADAR, family. The functional interpretation of these events has been even more difficult than that of editing events in coding sequences, but today there is an emerging understanding of their downstream effects. A surprisingly large fraction of the human transcriptome contains inverted Alu repeats, often forming long double stranded structures in RNA transcripts, typically occurring in introns and UTRs of protein coding genes. Alu repeats are also common in other primates, and similar inverted repeats can frequently be found in non-primates, although the latter are less prone to duplex formation. In human, as many as 700,000 Alu elements have been identified as substrates for RNA editing, of which many are edited at several sites. In fact, recent advancements in transcriptome sequencing techniques and bioinformatics have revealed that the human editome comprises at least a hundred million adenosine to inosine (A-to-I) editing sites in Alu sequences. Although substantial additional efforts are required in order to map the editome, already present knowledge provides an excellent starting point for studying cis-regulation of editing. In this review, we will focus on editing of long stem loop structures in the human transcriptome and how it can effect gene expression. PMID- 26051679 TI - Highly Stretchable 2D Fabrics for Wearable Triboelectric Nanogenerator under Harsh Environments. AB - Highly stretchable 2D fabrics are prepared by weaving fibers for a fabric structured triboelectric nanogenerator (FTENG). The fibers mainly consist of Al wires and polydimethylsiloxane (PDMS) tubes with a high-aspect-ratio nanotextured surface with vertically aligned nanowires. The fabrics were produced by interlacing the fibers, which was bonded to a waterproof fabric for all-weather use for fabric-structured triboelectric nanogenerator (FTENG). It showed a stable high-output voltage and current of 40 V and 210 MUA, corresponding to an instantaneous power output of 4 mW. The FTENG also exhibits high robustness behavior even after 25% stretching, enough for use in smart clothing applications and other wearable electronics. For wearable applications, the nanogenerator was successfully demonstrated in applications of footstep-driven large-scale power mats during walking and power clothing attached to the elbow. PMID- 26051680 TI - An electron-conducting pyrene-fused phenazinothiadiazole. AB - A pyrene-fused phenazinothiadiazole that shows electron mobilities (MUe = 0.016 cm(2) V(-1) s(-1)) two orders of magnitude higher than those reported for pyrene fused pyrazaacenes is described. PMID- 26051681 TI - Mesenchymal stem cells and infectious diseases: Smarter than drugs. AB - After bone marrow stromal cells (BMSCs also known as mesenchymal stem cells of bone marrow origin) were used successfully to treat graft versus host disease in a single human subject [1], many investigators studied the immune-suppressive properties of BMSCs and later adipose tissue derived MSCs (AMSC). The field has expanded significantly and there are many ongoing clinical trials that are trying to exploit the amazing abilities of MSCs from many tissues to regulate the immune system. In addition to "supervising" cells of the innate immune system, MSCs have also been shown to have anti-microbial properties. They appear to make molecules with direct effects on bacteria. Many questions about MSCs remain, however. We still need to determine how to isolate subpopulations of cells with specific immunomodulatory or antibacterial actions from the heterogeneous pool of cultured BMSCs. We need to find ways to prime cells to improve their immune regulatory activities, and while we have some ideas about mechanisms that underlie MSC/immune cell interactions, there is still much to discover before we can take full advantage of the regulatory abilities of MSCs to treat human diseases. PMID- 26051682 TI - Granzyme A as a potential biomarker of Mycobacterium tuberculosis infection and disease. AB - Cytotoxic molecules such as granulysin, perforin and granzymes produced by cytolytic T cells directly contribute to immune defense against tuberculosis (TB). In search for novel TB biomarkers, we have evaluated the levels of granzyme A in plasma obtained from QuantiFERON-TB Gold In tube (QFT-IT) assays from patients with active TB disease and subjects with latent TB infection (LTBI). Granzyme A serum levels in TB patients were significantly lower than values found in LTBI subjects even after subtraction of the unstimulated levels from the antigen-stimulated responses. The receiver operator characteristics (ROC) curve analysis comparing TB patients and LTBI groups, showed that at a cut-off value of granzyme A of <3.425pg/ml, the sensitivity and the specificity of the assay were 29.41% and 94.74%, respectively. Our results suggest that granzyme A could be considered another biomarker of TB, that can be used, other than IFN-gamma, to discriminate between patients with active TB and LTBI subjects in a well characterized cohort of confirmed Mycobacterium tuberculosis-infected individuals. PMID- 26051683 TI - Investigation of CTLA-4-318C/T gene polymorphism in cases with type 1 diabetes of Azerbaijan, Northwest Iran. AB - This study analyzed the association of CTLA-4-318C/T gene polymorphism with susceptibility, clinical course and laboratory findings of Type 1 diabetes (T1D). One hundred and fifty-three T1D patients and 189 healthy controls entered this study. CTLA-4-318C/T genotyping was performed by tetra-primer amplification refractory mutation system-polymerase chain reaction (T-ARMS-PCR) analysis. The allelic and genotypic frequencies of -318C/T gene polymorphism were similar in patients and controls. However, younger age, earlier age at onset, higher HbA1c levels, higher frequency of Glutamic acid decarboxylase antibodies (GADA) and Insulinoma Associated-2 Autoantibodies (IA-2A) were observed in T1D patient carriers of CT genotype. The current study demonstrates that although CTLA-4 318C/T polymorphism was not linked with a higher genetic risk for T1D, the presence of a CT genotype was associated with a younger age of onset, poor control of HbA1c level and positive anti-GAD or IA-2 serum autoantibodies in Iranian Azeri population. PMID- 26051684 TI - Cinnarizine: Comprehensive Profile. AB - Cinnarizine is a piperazine derivative with antihistaminic, antiserotonergic, antidopaminergic, and calcium channel-blocking activities. A comprehensive profile was performed on cinnarizine including its description and the different methods of analysis. The 1H NMR and 13C one- and two-dimensional NMR methods were used. In addition, infrared and mass spectral analyses were performed which all confirmed the structure of cinnarizine. PMID- 26051685 TI - Glutathione. AB - Glutathione is an endogenous peptide with antioxidant and other metabolic functions. The nomenclature, formulae, elemental composition, and appearance and uses of the drug are included. The methods used for the synthesis and biosynthesis of glutathione are described. This profile contains the physical characteristics of the drug including: solubility, X-ray powder diffraction pattern, crystal structure, melting point, and differential scanning calorimetry. The spectral methods that were used for both the identification and analysis of glutathione include ultraviolet spectrum, vibrational spectrum, 1H and 13C nuclear magnetic resonance spectra, and mass spectrum. The profile also includes the compendial methods of analysis and the other methods of analysis that are reported in the literature. These other methods of e-analysis are: potentiometric, voltammetric, amperometric, spectrophotometric, specrtofluorometric, chemiluminescence, chromatographic and immunoassay methods. The stability of and several reviews on drug are also provided. More than 170 references are listed at the end this comprehensive profile on glutathione. PMID- 26051686 TI - Losartan: Comprehensive Profile. AB - Losartan (CozaarTM) is an angiotensin II receptor antagonist with antihypertensive activity. It is used in the management of hypertension and heart failure. Nomenclature, formulae, elemental analysis, and appearance of the drug are included in this review. The uses, applications, and the variety of synthetic pathways of this drug are outlined. Physical characteristics including: ionization constant, solubility, X-ray powder diffraction pattern, thermal methods of analysis, UV spectrum, IR spectrum, mass spectrum with fragmentation patterns, and NMR (1H and 13C) spectra of losartan together with the corresponding figures and/or tables are all produced. This profile also includes the monograph of British Pharmacopoeia, together with several reported analytical methods including: spectrophotometric, electrochemical, chromatographic, and capillary electrophoretic methods. The stability, the pharmacokinetic behavior and the pharmacology of the drug are also provided. PMID- 26051687 TI - Prasugrel Hydrochloride. AB - A comprehensive profile of prasugrel HCl is reported herein with 158 references. A full description including nomenclature, formulae, elemental analysis, and appearance is included. Methods of preparation for prasugrel HCl, its intermediates, and derivatives are fully discussed. In addition, the physical properties, analytical methods, stability, uses and applications, and pharmacology of prasugrel HCl are also discussed. PMID- 26051688 TI - Salmeterol Xinafoate. AB - Salmeterol xinafoate is a potent and a long-acting beta2-adrenoceptor agonist. It is prescribed for the treatment of severe persistent asthma and chronic obstructive pulmonary disease. Different methods were used to prepare (R)-(-) salmeterol such as: mixing a sample of 4-benzyloxy-3-hydroxymethyl-omega bromoacetophenone with sodium lauryl sulfate and the mixture was added to the microbial culture of Rhodotorula rubra, treatment of p-hydroxyacetophenone with Eschenmoser's salt and carbonate exchange resin followed by a sequence of supported reagents and scavenging agents or via Rh-catalyzed asymmetric transfer hydrogenation. The enantioselective synthesis of (S)-salmeterol was achieved via asymmetric reduction of the azidoketone 4 by Pichia angusta yeast. Physical characteristics of salmeterol xinafoate were confirmed via: X-ray powder diffraction pattern, thermal analysis and UV, vibrational, nuclear magnetic resonance, and mass spectroscopical data. Initial improvement in asthma control may occur within 30 min following oral inhalation of salmeterol in fixed combination with fluticasone propionate. Clinically important improvements are maintained for up to 12 h in most patients. It is extensively metabolized in the liver by hydroxylation, thus increased plasma concentrations may occur in patients with hepatic impairment. PMID- 26051689 TI - Telmisartan. AB - Telmisartan is an angiotensin-II receptor antagonist (ARB) used in the treatment of hypertension. Generally, angiotensin-II receptor blockers such as telmisartan bind to the angiotensin-II type 1 receptors with high affinity, causing inhibition of the action of angiotensin II on vascular smooth muscle, ultimately leading to a reduction in arterial blood pressure. The present study gives a comprehensive profile of telmisartan, including detailed nomenclature, formulae, elemental analysis, and appearance of the drug are mentioned. The uses and applications and the several methods described for its preparation of the drug are outlined. The profile contains the physicochemical properties including: pKa value, solubility, X-ray powder diffraction, melting point, and methods of analysis (including compendial, electrochemical, spectroscopic, and chromatographic methods of analysis). Developed validated stability-indicating (HPLC and biodiffusion assay methods under accelerated acidic, alkaline, and oxidative conditions, in addition to effect of different types of light, temperature, and pH. Detailed Pharmacology also presented (Pharmacological actions, Therapeutic uses and Dosing, Interactions, and adverse effects and precautions). More than 80 references were given as a proof of the above mentioned studies. PMID- 26051690 TI - Valsartan. AB - Valsartan is an antihypertensive drug which selectively inhibits angiotensin receptor type II. Generally, valsartan is available as film-coated tablets. This review summarizes thermal analysis, spectroscopy characteristics (UV, IR, MS, and NMR), polymorphism forms, impurities, and related compounds of valsartan. The methods of analysis of valsartan in pharmaceutical dosage forms and in biological fluids using spectrophotometer, CE, TLC, and HPLC methods are discussed in details. Both official and nonofficial methods are described. It is recommended to use LC-MS method for analyzing valsartan in complex matrices such as biological fluids and herbal preparations; in this case, MRM is preferred than SIM method. PMID- 26051691 TI - Preface to Volume 40. PMID- 26051692 TI - Teachers' Health. AB - BACKGROUND: Almost 800,000 teachers were working in Germany in the 2012-13 school year. A determination of the most common medical problems in this large occupational group serves as the basis for measures that help maintain teachers' health and their ability to work in their profession. METHODS: We present our own research findings, a selective review of the literature, and data derived from the German statutory health insurance scheme concerning medical disability, long term illness, and inability to work among teachers. RESULTS: Compared to the general population, teachers have a more healthful lifestyle and a lower frequency of cardiovascular risk factors (except hypertension). Like non teachers, they commonly suffer from musculoskeletal and cardiovascular diseases. Mental and psychosomatic diseases are more common in teachers than in non teachers, as are nonspecific complaints such as exhaustion, fatigue, headache, and tension. It is commonly said that 3-5% of teachers suffer from "burnout," but reliable data on this topic are lacking, among other reasons because the term has no standard definition. The percentage of teachers on sick leave is generally lower than the overall percentage among statutory insurees; it is higher in the former East Germany than in the former West Germany. The number of teachers taking early retirement because of illness has steadily declined from over 60% in 2001 and currently stands at 19%, with an average age of 58 years, among tenured teachers taking early retirement. The main reasons for early retirement are mental and psychosomatic illnesses, which together account for 32-50% of cases. CONCLUSION: Although German law mandates the medical care of persons in the teaching professions by occupational physicians, this requirement is implemented to varying extents in the different German federal states. Teachers need qualified, interdisciplinary occupational health care with the involvement of their treating physicians. PMID- 26051694 TI - Nanostructure formation-induced fluorescence turn-on for selectively detecting protein thiols in solutions, bacteria and live cells. AB - We report the design and synthesis of a light-up probe of DBT-2(EEGK-maleimide), which can serve as a unique probe for selectively detecting protein thiols in various environments, including aqueous solutions, bacteria and live cells. PMID- 26051693 TI - The Surgical Correction of Congenital Deformities: The Treatment of Diaphragmatic Hernia, Esophageal Atresia and Small Bowel Atresia. AB - BACKGROUND: More than half of all congenital deformities can be detected in utero. The initial surgical correction is of paramount importance for the achievement of good long-term results with low surgical morbidity and mortality. METHODS: Selective literature review and expert opinion. RESULTS: Congenital deformities are rare, and no controlled trials have been performed to determine their optimal treatment. In this article, we present the prenatal assessment, treatment, and long-term results of selected types of congenital deformity. Congenital diaphragmatic hernia (CDH) affects one in 3500 live-born infants, while esophageal atresia affects one in 3000 and small-bowel atresia one in 5000 to 10,000. If a congenital deformity is detected and its prognosis can be reliably inferred from a prenatal assessment, the child should be delivered at a specialized center (level 1 perinatal center). The associated survival rates are 60-80% after treatment for CDH and well over 90% after treatment for esophageal or small-bowel atresia. Despite improvements in surgical correction over the years, complications and comorbidities still affect 20-40% of the treated children. These are not limited to surgical complications in the narrow sense, such as recurrence, postoperative adhesions and obstruction, stenoses, strictures, and recurrent fistulae, but also include pulmonary problems (chronic lung disease, obstructive and restrictive pulmonary dysfunction), gastrointestinal problems (dysphagia, gastro-esophageal reflux, impaired intestinal motility), and failure to thrive. Moreover, the affected children can develop emotional and behavioral disturbances. Minimally invasive surgery in experienced hands yields results as good as those of conventional surgery, as long as proper selection criteria are observed. CONCLUSION: Congenital deformities should be treated in recognized centers with highly experienced interdisciplinary teams. As no randomized trials of surgery for congenital deformities are available, longitudinal studies and registries will be very important in the future. PMID- 26051695 TI - ComiRNet: a web-based system for the analysis of miRNA-gene regulatory networks. AB - BACKGROUND: The understanding of mechanisms and functions of microRNAs (miRNAs) is fundamental for the study of many biological processes and for the elucidation of the pathogenesis of many human diseases. Technological advances represented by high-throughput technologies, such as microarray and next-generation sequencing, have significantly aided miRNA research in the last decade. Nevertheless, the identification of true miRNA targets and the complete elucidation of the rules governing their functional targeting remain nebulous. Computational tools have been proven to be fundamental for guiding experimental validations for the discovery of new miRNAs, for the identification of their targets and for the elucidation of their regulatory mechanisms. DESCRIPTION: ComiRNet (Co-clustered miRNA Regulatory Networks) is a web-based database specifically designed to provide biologists and clinicians with user-friendly and effective tools for the study of miRNA-gene target interaction data and for the discovery of miRNA functions and mechanisms. Data in ComiRNet are produced by a combined computational approach based on: 1) a semi-supervised ensemble-based classifier, which learns to combine miRNA-gene target interactions (MTIs) from several prediction algorithms, and 2) the biclustering algorithm HOCCLUS2, which exploits the large set of produced predictions, with the associated probabilities, to identify overlapping and hierarchically organized biclusters that represent miRNA gene regulatory networks (MGRNs). CONCLUSIONS: ComiRNet represents a valuable resource for elucidating the miRNAs' role in complex biological processes by exploiting data on their putative function in the context of MGRNs. ComiRnet currently stores about 5 million predicted MTIs between 934 human miRNAs and 30,875 mRNAs, as well as 15 bicluster hierarchies, each of which represents MGRNs at different levels of granularity. The database can be freely accessed at: http://comirnet.di.uniba.it. PMID- 26051696 TI - Through the looking glass: Basics and principles of reflectance confocal microscopy. AB - Reflectance confocal microscopy (RCM) offers high-resolution, noninvasive skin imaging and can help avoid obtaining unnecessary biopsy specimens. It can also increase efficiency in the surgical setting by helping to delineate tumor margins. Diagnostic criteria and several RCM algorithms have been published for the differentiation of benign and malignant neoplasms. We provide an overview of the basic principles of RCM, characteristic RCM features of normal skin and cutaneous neoplasms, and the limitations and future directions of RCM. PMID- 26051697 TI - Comparing cutaneous research funded by the US National Institutes of Health (NIH) with the US skin disease burden. AB - BACKGROUND: Disease burden should be an important component for guiding research funding. OBJECTIVE: We sought to examine the relationship between dermatologic research funded from 2012 to 2013 by the National Institutes of Health (NIH) and US skin disease burden as measured by disability-adjusted life years in the Global Burden of Disease 2010 study. METHODS: A cross-sectional analysis was independently performed by 2 researchers who matched projects from the 2012 to 2013 NIH Research Portfolio Online Reporting Tools with 15 skin conditions and their respective disability-adjusted life years from Global Burden of Disease 2010. RESULTS: The NIH funded 1108 projects spanning the 15 skin conditions. Melanoma received almost half of the total skin condition budget (49.5%). Melanoma, nonmelanoma skin cancer, and leprosy were funded above what would be suggested by their disease burden, whereas dermatitis, acne vulgaris, pruritus, urticaria, decubitus ulcer, fungal skin diseases, alopecia areata, cellulitis, and scabies appeared underfunded. Bacterial skin diseases, viral skin diseases, and psoriasis were well matched with disease burden. LIMITATIONS: Disease burden is one of many factors that may be used to guide priority-setting decisions. CONCLUSION: Skin disease burden measured by disability-adjusted life year metrics partially correlates with NIH funding prioritization. Comparing US disease burden with NIH funding suggests possible underfunded and overfunded skin diseases. PMID- 26051698 TI - Early microbial contact, the breast milk microbiome and child health. AB - The significance of contact with microbes in early life for subsequent health has been the subject of intense research during the last 2 decades. Disturbances in the establishment of the indigenous intestinal microbiome caused by cesarean section delivery or antibiotic exposure in early life have been linked to the risk of immune-mediated and inflammatory conditions such as atopic disorders, inflammatory bowel disease and obesity later in life. Distinct microbial populations have recently been discovered at maternal sites including the amniotic cavity and breast milk, as well as meconium, which have previously been thought to be sterile. Our understanding of the impact of fetal microbial contact on health outcomes is still rudimentary. Breast milk is known to modulate immune and metabolic programming. The breast milk microbiome is hypothesized to guide infant gut colonization and is affected by maternal health status and mode of delivery. Immunomodulatory factors in breast milk interact with the maternal and infant gut microbiome and may mediate some of the health benefits associated with breastfeeding. The intimate connection between the mother and the fetus or the infant is a potential target for microbial therapeutic interventions aiming to support healthy microbial contact and protect against disease. PMID- 26051699 TI - Bony skull development in the Argus monitor (Squamata, Varanidae, Varanus panoptes) with comments on developmental timing and adult anatomy. AB - Varanids represent one of the most charismatic squamate clades and include the largest living lizards; however, little is known about their embryonic development and what it might reveal about the origin of their derived anatomy. In the present study, we describe external organogenesis and skull formation of Varanus panoptes in great detail. We compared timing of ossification with the patterns seen in other squamates, using three major hypotheses of squamate interrelationship as phylogenetic templates, and were able to detect heterochronic patterns in ossification that are associated with adult anatomy in each phylogeny. However, we refrain from preferring one topology given the current lack of congruence between molecular and morphological data sets. The rule of thumb that early appearance of developmental characters is correlated to larger prominence in adults is critically discussed and we conclude that such simple correlations are the exception rather than the rule. The entanglement of developmental processes detected herein highlights the non-independent formation of adult characters that are usually treated as independent in phylogenetic studies, which may bias the output of such studies. Our comprehensive descriptions of embryonic development may serve as a resource for future studies integrating the complex processes of embryogenesis into broad-scale phylogenetic analyses that are likely to show that change in embryonic timing is one of the major sources of morphological diversification. PMID- 26051700 TI - Necitumumab for non-small cell lung cancer. AB - INTRODUCTION: Targeting the EGFR pathway is a rational approach to treat patients with advanced NSCLC. Necitumumab, a second-generation recombinant fully human immunoglobulin G1 monoclonal antibody directed against EGFR, has recently been assessed in combination with first-line cisplatin-based chemotherapy. AREAS COVERED: This article reviews literature on necitumumab development, from preclinical data to results of Phase III clinical trials, either published or presented in international scientific conferences. Ongoing clinical trials were searched with the clinical-trials.gov website. EXPERT OPINION: During the last decade, advances in treatment of metastatic NSCLC have been exclusively achieved in patients with non-squamous histology. In this context, any treatment improvement, even modest, was eagerly awaited for patients with squamous NSCLC. In this patient's population, the SQUIRE Phase III study demonstrated a relatively small, but statistically significant survival benefit in patients treated with necitumumab in combination with standard chemotherapy (cisplatin and gemcitabin) compared with those treated with chemotherapy alone. However, the identification of predictive biomarker for treatment outcome is still needed to select the patients who will experience a large benefit from the targeted treatment. PMID- 26051701 TI - President's page--The definition of cardiac CT = resilience. PMID- 26051703 TI - Association of TNF-alpha gene promoter region polymorphisms in bovine leukemia virus (BLV)-infected cattle with different proviral loads. AB - Tumor necrosis factor alpha (TNF-alpha) is a pleiotropic cytokine involved in the immune response against viral and other infections. Its expression levels are affected by a polymorphism in the promoter region of the gene. Bovine leukemia virus is a retrovirus that infects cattle and develops two different infection profiles in the host. One profile is characterized by a high number of proviral copies integrated into the host genome and a strong immune response against the virus, while the most relevant property of the other profile is that the number of copies integrated into the host genome is almost undetectable and the immune response is very weak. We selected a population of cattle sufficiently large for statistical analysis and classified them according to whether they had a high or low proviral load (HPL or LPL). Polymorphisms in the promoter region were identified by PCR-RFLP. The results indicated that, in the HPL group, the three possible genotypes were normally distributed and that, in the LPL group, there was a significant association between the proviral load and a low frequency of the G/G genotype at position -824. PMID- 26051702 TI - The associations between environmental quality and preterm birth in the United States, 2000-2005: a cross-sectional analysis. AB - BACKGROUND: Many environmental factors have been independently associated with preterm birth (PTB). However, exposure is not isolated to a single environmental factor, but rather to many positive and negative factors that co-occur. The environmental quality index (EQI), a measure of cumulative environmental exposure across all US counties from 2000-2005, was used to investigate associations between ambient environment and PTB. METHODS: With 2000-2005 birth data from the National Center for Health Statistics for the United States (n = 24,483,348), we estimated the association between increasing quintiles of the EQI and county level and individual-level PTB; we also considered environmental domain-specific (air, water, land, sociodemographic and built environment) and urban-rural stratifications. RESULTS: Effect estimates for the relationship between environmental quality and PTB varied by domain and by urban-rural strata but were consistent across county- and individual-level analyses. The county-level prevalence difference (PD (95% confidence interval) for the non-stratified EQI comparing the highest quintile (poorest environmental quality) to the lowest quintile (best environmental quality) was -0.0166 (-0.0198, -0.0134). The air and sociodemographic domains had the strongest associations with PTB; PDs were 0.0196 (0.0162, 0.0229) and -0.0262 (-0.0300, -0.0224) for the air and sociodemographic domain indices, respectively. Within the most urban strata, the PD for the sociodemographic domain index was 0.0256 (0.0205, 0.0307). Odds ratios (OR) for the individual-level analysis were congruent with PDs. CONCLUSION: We observed both strong positive and negative associations between measures of broad environmental quality and preterm birth. Associations differed by rural-urban stratum and by the five environmental domains. Our study demonstrates the use of a large scale composite environment exposure metric with preterm birth, an important indicator of population health and shows potential for future research. PMID- 26051704 TI - Direct characterization of photoinduced lattice dynamics in BaFe2As2. AB - Ultrafast light pulses can modify electronic properties of quantum materials by perturbing the underlying, intertwined degrees of freedom. In particular, iron based superconductors exhibit a strong coupling among electronic nematic fluctuations, spins and the lattice, serving as a playground for ultrafast manipulation. Here we use time-resolved X-ray scattering to measure the lattice dynamics of photoexcited BaFe2As2. On optical excitation, no signature of an ultrafast change of the crystal symmetry is observed, but the lattice oscillates rapidly in time due to the coherent excitation of an A1g mode that modulates the Fe-As-Fe bond angle. We directly quantify the coherent lattice dynamics and show that even a small photoinduced lattice distortion can induce notable changes in the electronic and magnetic properties. Our analysis implies that transient structural modification can be an effective tool for manipulating the electronic properties of multi-orbital systems, where electronic instabilities are sensitive to the orbital character of bands. PMID- 26051705 TI - Maternal obesity: significance on the preterm neonate. AB - BACKGROUND: What is known of neonatal outcomes associated with maternal obesity is limited. The impact on the preterm neonate, delivery room (DR) course and need for neonatal intensive care unit (NICU) admission has not been well established. METHODS: A review was done of our 17 county perinatal regions from the New York State Perinatal Data System database over the 3-year period of 1 January 2010-31 December 2012 for mother/baby dyad information for all live births 34-36 6/7 weeks' gestation. The National Institutes of Health body mass index (BMI) classification was used for maternal BMI with the category definitions of underweight, normal, overweight, obese Level I, obese Level II, and obese Level III. RESULTS: Information was obtained on 2155 women. In this group, 29% had obese BMIs. The incidence of pre-pregnancy diabetes mellitus (DM), DM during gestation and cesarean delivery (CD) in obese mothers was significantly different from normal weight mothers, P<0.001. More infants of Level III mothers required DR resuscitation when compared with infants of normal BMI mothers, 36 vs 16%, P <0.001. The need for assisted ventilation beyond 6 h of age and need for NICU admission was more likely in infants of Level III mothers, P<0.001. Women in all of the obese subgroups had preterm infants with increased birth weights (BWs) compared with preterm infants of normal weight mothers, P<0.001. DISCUSSION: Late preterm infants born to obese mothers are more likely to be delivered by cesarean section and have larger BWs. We found that infants born to obese Level III mothers are much more likely to require assisted ventilation in the DR and NICU admission. PMID- 26051708 TI - A differentially selective molecular probe for detection of trivalent ions (Al(3+), Cr(3+) and Fe(3+)) upon single excitation in mixed aqueous medium. AB - A chemosensor was developed which could selectively detect and differentiate trivalent metal ions (Al(3+), Cr(3+) and Fe(3+)) upon single excitation at two different wavelengths in aqueous medium. This probe selectively detects trivalent ions in the presence of different metal ions in aqueous medium. It shows an excellent performance in the "dipstick" method. PMID- 26051706 TI - Does gait speed contribute to sarcopenia case-finding in a postacute rehabilitation setting? AB - OBJECTIVE: The European Working Group of Sarcopenia in Older People (EWGSOP) has developed an algorithm based on gait speed measurement to begin sarcopenia case finding in clinical practice, in which a cut-off point of <0.8m/s identifies risk for sarcopenia in community-dwelling older people. The objective of this study was to assess the application of the EWGSOP algorithm in hospitalised elderly patients with impaired functional capacity. METHODS: One hundred in-patients (aged 84.1 SD 8.5, 62% women) were prospectively studied in a postacute care geriatric unit focused on rehabilitation. Sarcopenia was assessed by corporal composition (electrical bioimpedance), handgrip strength, and physical performance (gait speed). Other measurements were Charlson index, length of stay, and functional gain at discharge and 3-month follow-up. All patients were screened by the EWGSOP algorithm and sarcopenia was confirmed according to diagnostic criteria. RESULTS: Gait speed was <0.8m/s in all cases and 58 patients had low muscle mass, which, according to the EWGSOP-algorithm, would indicate a diagnosis of sarcopenia. No differences were observed in functional capacity between these patients and those with normal muscle mass. When decreased handgrip strength was considered, 47 of these patients met the EWGSOP criteria for severe sarcopenia. In this group, differences in functional capacity were observed at discharge (Barthel 45.2 vs. 56.3, p=0.042) and 3-month follow-up (48.3 vs. 59.8, p=0.047). CONCLUSION: The application of the EWGSOP algorithm in hospitalised, postacute, elderly patients with low gait speed suggested that muscle strength should be considered before confirming or discarding a sarcopenia diagnosis. PMID- 26051709 TI - Insight into the Oriented Growth of Surface-Attached Metal-Organic Frameworks: Surface Functionality, Deposition Temperature, and First Layer Order. AB - The layer-by-layer growth of a surface-attached metal-organic framework (SURMOF), [Cu2(F4bdc)2(dabco)] (F4bdc = tetrafluorobenzene-1,4-dicarboxylate and dabco = 1,4-diazabicyclo-[2.2.2]octane), on carboxylate- and pyridine-terminated surfaces has been investigated by various surface characterization techniques. Particular attention was paid to the dependency of the crystal orientation and morphology on surface functionality, deposition temperature, and first layer order. For the fully oriented deposition of SURMOFs, not only a suitable surface chemistry but also the appropriate temperature has to be chosen. In the case of carboxylate terminated surfaces, the expected [100] oriented [Cu2(F4bdc)2(dabco)] SURMOF can be achieved at low temperatures (5 degrees C). In contrast, the predicted [001] oriented SURMOF on pyridine-terminated surface was obtained only at high deposition temperatures (60 degrees C). Interestingly, we found that rearrangement processes in the very first layer determine the final orientation (distribution) of the growing crystals. These effects could be explained by a surprisingly hampered substitution at the apical position of the Cu2-paddle wheel units, which requires significant thermal activation, as supported by quantum chemical calculations. PMID- 26051712 TI - Distinctive Properties of the Nuclear Localization Signals of Inner Nuclear Membrane Proteins Heh1 and Heh2. AB - Targeting of ER-synthesized membrane proteins to the inner nuclear membrane (INM) has long been explained by the diffusion-retention model. However, several INM proteins contain non-classical nuclear localization signal (NLS) sequences, which, in a few instances, have been shown to promote importin alpha/beta- and Ran-dependent translocation to the INM. Here, using structural and biochemical methods, we show that yeast INM proteins Heh2 and Src1/Heh1 contain bipartite import sequences that associate intimately with the minor NLS-binding pocket of yeast importin alpha and unlike classical NLSs efficiently displace the IBB domain in the absence of importin beta. In vivo, the intimate interactions at the minor NLS-binding pocket make the h2NLS highly efficient at recruiting importin alpha at the ER and drive INM localization of endogenous Heh2. Thus, h1/h2NLSs delineate a novel class of super-potent, IBB-like membrane protein NLSs, distinct from classical NLSs found in soluble cargos and of general interest in biology. PMID- 26051713 TI - Insights into Autoregulation of Notch3 from Structural and Functional Studies of Its Negative Regulatory Region. AB - Notch receptors are transmembrane proteins that undergo activating proteolysis in response to ligand stimulation. A negative regulatory region (NRR) maintains receptor quiescence by preventing protease cleavage prior to ligand binding. We report here the X-ray structure of the NRR of autoinhibited human Notch3, and compare it with the Notch1 and Notch2 NRRs. The overall architecture of the autoinhibited conformation, in which three LIN12-Notch repeat (LNR) modules wrap around a heterodimerization domain, is preserved in Notch3, but the autoinhibited conformation of the Notch3 NRR is less stable. The Notch3 NRR uses a highly conserved surface on the third LNR module to form a dimer in the crystal. Similar homotypic interfaces exist in Notch1 and Notch2. Together, these studies reveal distinguishing structural features associated with increased basal activity of Notch3, demonstrate increased ligand-independent signaling for disease-associated mutations that map to the Notch3 NRR, and identify a conserved dimerization interface present in multiple Notch receptors. PMID- 26051714 TI - Structural Characterization of the Chaetomium thermophilum TREX-2 Complex and its Interaction with the mRNA Nuclear Export Factor Mex67:Mtr2. AB - The TREX-2 complex integrates mRNA nuclear export into the gene expression pathway and is based on a Sac3 scaffold to which Thp1, Sem1, Sus1, and Cdc31 bind. TREX-2 also binds the mRNA nuclear export factor, Mex67:Mtr2, through the Sac3 N-terminal region (Sac3N). Here, we characterize Chaetomium thermophilum TREX-2, show that the in vitro reconstituted complex has an annular structure, and define the structural basis for interactions between Sac3, Sus1, Cdc31, and Mex67:Mtr2. Crystal structures show that the binding of C. thermophilum Sac3N to the Mex67 NTF2-like domain (Mex67(NTF2L)) is mediated primarily through phenylalanine residues present in a series of repeating sequence motifs that resemble those seen in many nucleoporins, and Mlp1 also binds Mex67:Mtr2 using a similar motif. Deletion of Sac3N generated growth and mRNA export defects in Saccharomyces cerevisiae, and we propose TREX-2 and Mlp1 function to facilitate export by concentrating mature messenger ribonucleoparticles at the nuclear pore entrance. PMID- 26051715 TI - GTP-Dependent K-Ras Dimerization. AB - Ras proteins recruit and activate effectors, including Raf, that transmit receptor-initiated signals. Monomeric Ras can bind Raf; however, activation of Raf requires its dimerization. It has been suspected that dimeric Ras may promote dimerization and activation of Raf. Here, we show that the GTP-bound catalytic domain of K-Ras4B, a highly oncogenic splice variant of the K-Ras isoform, forms stable homodimers. We observe two major dimer interfaces. The first, highly populated beta-sheet dimer interface is at the Switch I and effector binding regions, overlapping the binding surfaces of Raf, PI3K, RalGDS, and additional effectors. This interface has to be inhibitory to such effectors. The second, helical interface also overlaps the binding sites of some effectors. This interface may promote activation of Raf. Our data reveal how Ras self-association can regulate effector binding and activity, and suggest that disruption of the helical dimer interface by drugs may abate Raf signaling in cancer. PMID- 26051717 TI - Recent advances in the development of synthetic chemical probes for glycosidase enzymes. AB - The emergence of synthetic glycoconjugates as chemical probes for the detection of glycosidase enzymes has resulted in the development of a range of useful chemical tools with applications in glycobiology, biotechnology, medical and industrial research. Critical to the function of these probes is the preparation of substrates containing a glycosidic linkage that when activated by a specific enzyme or group of enzymes, irreversibly releases a reporter molecule that can be detected. Starting from the earliest examples of colourimetric probes, increasingly sensitive and sophisticated substrates have been reported. In this review we present an overview of the recent advances in this field, covering an array of strategies including chromogenic and fluorogenic substrates, lanthanide complexes, gels and nanoparticles. The applications of these substrates for the detection of various glycosidases and the scope and limitations for each approach are discussed. PMID- 26051716 TI - Saccharomyces cerevisiae Ski7 Is a GTP-Binding Protein Adopting the Characteristic Conformation of Active Translational GTPases. AB - Ski7 is a cofactor of the cytoplasmic exosome in budding yeast, functioning in both mRNA turnover and non-stop decay (NSD), a surveillance pathway that degrades faulty mRNAs lacking a stop codon. The C-terminal region of Ski7 (Ski7C) shares overall sequence similarity with the translational GTPase (trGTPase) Hbs1, but whether Ski7 has retained the properties of a trGTPase is unclear. Here, we report the high-resolution structures of Ski7C bound to either intact guanosine triphosphate (GTP) or guanosine diphosphate-Pi. The individual domains of Ski7C adopt the conformation characteristic of active trGTPases. Furthermore, the nucleotide-binding site of Ski7C shares similar features compared with active trGTPases, notably the presence of a characteristic monovalent cation. However, a suboptimal polar residue at the putative catalytic site and an unusual polar residue that interacts with the gamma-phosphate of GTP distinguish Ski7 from other trGTPases, suggesting it might function rather as a GTP-binding protein than as a GTP-hydrolyzing enzyme. PMID- 26051718 TI - Clinical effects of immunotherapy of DC-CIK combined with chemotherapy in treating patients with metastatic breast cancer. AB - This study aimed to analyze the clinical effects of dendritic cell (DC) and cytokine-induced killer (CIK) immunotherapy combined with chemotherapy on patients with metastatic breast cancer. Twenty patients were included into this study who were diagnosed as metastatic breast cancer (MBC). DC and CIK were augmented by in vitro culture and then rein fused into body through vein.The pain relief rate (RR), toxic and side effects of chemotherapy, immunity functions and living quality of patients were observed. DC and CIK cells were induced by the autologous peripheral blood mononuclear cells (PBMC). Meanwhile, flow cytometry was used to measure T cell subsets and natural killer T (NKT) cells in patients in the two groups before and after the biological treatment. After DC and CIK were rein fused into the patients body, no severe side-effect was found. It was also found that cellular immunotherapy combined with chemotherapy the immunotherapy of cells improved the immunity, the living quality of patients and the disease control rate (DCR). In conclusion, cellular immunotherapy produces small side effects; it combined with chemotherapyis able to improve the DCR and living quality of patients and prolong their lives. PMID- 26051719 TI - Analysis on the Alpinia katsumadai components of Zingiberaceae plants and their functions on myeloma resistance. AB - Generally speaking, zingiberaceae plants with sweet fragrance are commonly seen as perennial herbs that contains numerous well-known crude drugs and fragrant plants like Amomum villosum, Amomumtsao-ko, Ginger, Alpinia katsumadai and Radix curcumae, which are widely used in daily life. This paper analyzed chemical components of Alpinia katsumadai of zingiberaceae and applied several laminar analysis to further develop its active ingredients, aiming to make sure its function on tumor assistance. Actually, cardamomin contained in Alpinia katsumadai has been recorded to act notably in myeloma resistance, which was verified by cholecystokinin-octopeptide (CCK-8) in this paper. Cardamom in is proved to have multiple anti-myeloma effects, including myeloma cell activity and proliferation control, cell cycle retardant and apoptosis induction, which indicates its value in the field of medical pharmacy. PMID- 26051720 TI - Investigation of VIM, IMP, NDM-1, KPC AND OXA-48 enzymes in Enterobacteriaceae strains. AB - Gram-negative bacteria especially Enterobacteriaceae species have become an increasing etiologic agent of nosocomial infections. The development of resistance to carbapenems have become an increasing problem in the treatment of nosocomial infections. Especially carbapenamases are common for Enterobacteriaceae strains. This study was performed to detect the types of carbapenemases in Enterobacteriaceae strains isolated from various clinical samples. Enterobacteriaceae species were isolated from urine, blood, tracheal aspirates, wound, and other respiratory samples. Susceptibility of isolates to imipenem, meropenem and ertapenem was tested. Carbapenemase genes were studied using HyplexSuperBug ID kit. VIM (1-13), IMP (1-22), NDM-1, KPC(1-10) and OXA-48 genes were investigated. Ninety-five isolates of Enterobacteriaceae spp. were included in the study. Sixty isolates were resistant to imipenem, meropenem and ertapenem and 20 isolates were found resistant to imipenem or ertapenem while 15 were susceptible to all carbapenems. Among the isolates with carbapenem resistance, 57 were positive for one carbapenemase gene and susceptible isolates did not have carbapenemase gene. OXA-48 was found in 49 of the isolates (86%), NDM-1 in 6 (10.5%) isolates, VIM in 2 isolates. IMP and KPC gene loci were not identified. Carbapenemase genes play a crucial role in the development and spread of resistant strains. PMID- 26051721 TI - Clinical curative effect of percutaneous vertebroplasty combined with 125I-seed implantation in treating spinal metastatic tumor. AB - This paper selected and studied 15 in-hospital patients to analyze and discuss the clinical curative effect of percutaneous vertebroplasty (PVP) combined with (125)I-seed implantation in treating spinal metastatic tumor. The evaluation of clinical curative effects was based on the observation of several factors, namely recovery conditions of vertebral body's leading edge and middle section before and after surgery, improvements of kyphosis Cobb angle, visual analog scale (VAS), and Barthel Index (BI). The paper found significant difference between preoperative VAS and postoperative VAS, and the same situation occurred to BI. However, compared to the loss rate of vertebral body's leading edge and middle section and the improvement of Cobb angle before operative, postoperative loss rate and Cobb angle did not show statistical difference. Thus the conclusion is that PVP combined with (125)I-seed implantation is a minimally invasive surgery for effectively treating spinal metastatic tumor, which does well in rapidly releasing pains, improving patients' daily life activities and life qualities. PMID- 26051722 TI - Analgesic and anti-inflammatory effects of hydroalcoholic extract isolated from Semen vaccariae. AB - Semen vaccariae, the seeds of Vaccaria segetalis (Neck.) Garcke, is usually used as an important medication for female mammary gland diseases; it has also been used to promote lactation for centuries in China. The purpose of this work was to evaluate the analgesic and anti-inflammatory effects of hydroalcoholic extract from semen vaccariae (HESV) with oral doses of 50, 100 and 200mg/kg*bw in mice and rats. We observed that the HESV could effectively inhibit acetic acid-induced abdominal contraction and could elevate the latency time to thermal stimuli in the hot-plate test in mice. In the xylene-induced ear-swelling test in mice, HESV could suppress the ear swelling. Additionally, HESV could significantly decrease the peritoneal capillary permeability and leukocyte infiltration in mice induced by the intraperitoneal injection of acetic acid. HESV also significantly reduced paw thickness 2-4 hours after the injection of carrageenan in the carrageenan induced rat paw edema test. This study was the first to demonstrate that the oral administration of HESV might play an important role in the process of analgesia and anti-inflammation, supporting its use for female mammary gland diseases in traditional medicine. PMID- 26051723 TI - Assessment of postoperative adhesion formation in a rat cecum model using different techniques. AB - Adhesion-related complications after abdominal surgery bring out momentous morbidity and costs. Outcomes from animal experiments investigating prevention of adhesions are limited due to lack of consistency in existing animal models. Different intraperitoneal adhesion models were compared the inter observer variability was evaluated to seek for best model. Forty male SD rats weighting 250-300g were included and assigned randomly to four groups with diverse techniques, (A) postoperative adhesion cecum rat model abraded with sterile rasp; (B) postoperative adhesion cecum rat model abraded with sterile dry gauze; (C) postoperative adhesion cecum rat model abraded with sterile blade; (D) postoperative adhesion cecum rat model abraded with vascular clamp. Macroscopic adhesion scores were evaluated by Bigatti scoring system, and the incidence of adhesion were surveyed on the 7th day after the surgery. The results showed that four techniques currently used Bigatti adhesion scoring system are subjective, the sterile rasp is the most consistent and reproducible tool to establish an intraperitoneal adhesion model which is helpful for related studies and the development of new substances for adhesion prevention in the future. PMID- 26051724 TI - The expression of ATF3, MMP-2 and maspin in tissue chip of glioma. AB - This paper tested and analyzed the expression of ATF3 (activating transcription factor), MMP-2 (matrix metalloprotease) and maspin in tissue chip of glioma and its correlation with glioma advancement. Based on immunohistochemical staining, this paper selected 100 patients with glioma and 13 healthy persons to test the relative expression of ATF3, MMP-2 and maspin. The result witnessed 72.0% of ATF3 expression in glioma and 15.4% in healthy brain tissues with P<0.05; glioma had 76.0% of MMP-2 expression while healthy brain tissues only had 7.7% (P<0.05); but maspin expression with 53.0% in glioma was much lower than that with 100% in healthy tissues with P<0.05. If the pathological stage of glioma rose up, the expression of ATF3 and MMP-2 accordingly increased while maspin expression decreased. The correlation between ATF3 expression and MMP-2 expression was positive with r=0.553 and p<0.01; negative correlation between ATF3 expression and maspin expression was found with r=-0.457 and p<0.01; and the expression of MMP-2 and maspin were negatively related with r=-0.551 and p<0.01. According to the above results, it could be concluded that the expression of ATF3, MMP-2 and maspin did relate with each other. Besides, the high expression of ATF3 and MMP-2 as well as the low expression of maspin had great influence on glioma, playing a key role in glioma's occurrence, advancement, invasion and metastasis. PMID- 26051725 TI - Relationship of chemical composition and cytotoxicity of water-soluble polysaccharides from Lentinus edodes fruiting bodies. AB - Six water-soluble polysaccharides (S-WPLE-I-a, S-WPLE-I-b, S-WPLE-II-a, S-WPLE-II b, S-WPLE-III-a and S-WPLE-III-b) were obtained from Lentinus edodes and purified by gel-permeation chromatography (GPC). The fractions were analyzed for monosaccharide composition, molecular weight, and then tested for cytotoxicity activity. The results from high performance liquid chromatography (HPLC) revealed that the water-soluble fractions were heteroglucan containing mainly glucose (Glc), galactose (Gal) and mannose (Man) at various ratios. All the polysaccharide fractions exhibited antitumor activities against Sarcoma 180 (S 180) solid tumor cells and human colorectal cancer cell lines (HT-29 and HCT-116) in vitro at the dose of 5mg/ml. The antitumor activities of the polysaccharides were related to their monosaccharide content and molecular weight. The effects of Gal, Man and bound protein on the improvement of antitumor activities of polysaccharides might not be negligible. The results also revealed that there was selectively higher antitumor activity of the polysaccharides against suspended cells (S-180) than adherent ones (HT-29 and HCT-116). PMID- 26051726 TI - The influence of joint application of arsenic trioxide and daunorubicin on primary acute promyelocytic leukaemia cells and apoptosis and blood coagulation of cell strain. AB - This test cultivated three groups of acute promyelocytic leukemia (APL) and NB4 cells in liquid in vitro, processed them with arsenic trioxide (ATO), daunorubicin (DNR), ATO+DNR respectively, and then set up blank control group. Apoptosis of cells in each group was observed using flow cytometry, procoagulant activity of APL and NB4 cells in each group was detected with recalcification time, and expressions of tissue factor (TF), thrombomodulin and annexin II of NB4 cells in each group were measured using ELISA method. The results showed that the apoptosis rate increased 4-8 times compared with blank control group after processing APL and NB4 cells with ATO and DNR; procoagulant activity decreased obviously; and expression of TF and annexin II of NB4 cells reduced significantly (P<0.05). We concluded that combination of ATO and DNR could promote APL and NB4 cell apoptosis effectively without aggravating blood coagulation disorders, which might improve coagulation function of APL by inhibiting coagulation and hyperfibrinolysis through reducing expression of TF and annexin II. This drug combination may be a safe and effective method in the treatment of APL of primary high white blood cells type. PMID- 26051727 TI - In vitro evaluation of cytotoxic and antimicrobial potentials of the Saudi traditional plant Alhagi graecorum boiss. AB - Various species of Alhagi are known for a wide diversity of ethnopharmacological uses. This study explored the in vitro antimicrobial and cytotoxic potentials of the crude ethanolic extract and isolated fractions from the traditional Saudi plant Alhagi graecorum. The antimicrobial activity was evaluated against 19 pathogenic microbial strains using the broth micro dilution assay. On the other hand, the cytotoxicity was assessed using the crystal violet staining method on MCF-7, HepG-2, HCT-116, A-549, and HEp-2human cell lines. Results showed that the highest antimicrobial activity was shown by the ethyl acetate extract, followed by the dichloromethane and total alcohol extracts. The aqueous extract had no effect on any of the tested microorganisms at 20mg/ml. In addition, the ethyl acetate extract displayed remarkable cytotoxic activity on all five human cell lines with IC50 values ranging from 2.7 to 8.23 MUg/mL, followed by the dichloromethane extract with IC(50) values between 9.4 and 19.7MUg/mL using doxorubicin as a reference drug. PMID- 26051728 TI - Probiotics in the treatment of peptic ulcer infected by helicobacter pylory and its safety. AB - This paper aimed to study the curative effect of probiotics in the treatment of peptic ulcer (PU) infected with Helicobacter Pylory (H. Pylory). A total of 132 cases of patients with PU infected by H. Pylory who were received and treated by department of gastroenterology from Binjiang Hospital, Guangxi from May 2013 to 2014 were recruited in the study. They were divided into observation group and control group based on random number table, 66 cases in each group. Patients in observation group were given probiotics combined with triple therapy while patients in control group were treated by traditional triple therapy. After one month treatment, all the patients were examined by (14)C urea breath test for checking the treatment condition of H. Pylory and reviewed by gastroscope for checking union of ulcer. In addition, clinical effect and improvement of digestive tract symptom were compared between two groups. It was found that, the content of (14)C urea detected by breath test was 95.15 dpm/mmol +/- 8.34 dpm/mmol in observation group after treatment; eradication rate of H. Pylory was 87.9%; symptom remission rate was 97%; adverse reaction rate was 4.5%; total effective rate of clinical treatment was 97%; while in control group, the content of (14)C urea was 100.3 dpm/mmol +/- 10.34 dpm/mmol, eradication rate was 63.6%, symptom remission rate was 93.9%, adverse reaction rate was 18.2%, and total effective rate was 83.3%. These results demonstrated that, the symptom remission rate of the observation group and the control group was not obvious, but the content of (14)C urine, eradication rate of H. Pylory, incidence of adverse reaction and total effective rate were of significant significance in two groups (P<0.05). In conclusion, probiotics combined with triple therapy for treating PU infected by H. Pylory can greatly improve the eradication rate of H. Pylory and increase recovery rate of patients, with less adverse reaction. Therefore, the method is worth for promotion. PMID- 26051729 TI - Isolation and characterization of a new oxygenated homoditerpenoid from leaves of Centaurothamnus maximus with antimicrobial potential. AB - A new bioactive oxygenated homoditerpenic compound along with one known compound from the antimicrobial active ethanol extract of leaves of an endemic plant Centaurothamnus maximus was isolated. The n -hexane, dichloromethane, ethyl acetate and ethanol fractions of C. maximus leaves were evaluated for their antimicrobial potential by using standard agar well diffusion method against various microorganisms viz. B. subtilis, S. aureus, E. coli, P. aeruginosa, C. albicans and M. smegmatis. The results revealed that only ethanol extract was active against all microbes except the fungus C. albicans. A new compound 2alpha, 3alpha-dihydroxy-8alpha-methoxy-15-hydroxy-methylene- pimar-5,9 (11)-diene (CM-1) was isolated along with a known compound alpha-D-xylose (CM-2) from ethanol extract by reverse phase (RP-18) column chromatography and 1D and 2D NMR (DEPT, COSY, HMBC and HSQC) aided by EIMS mass and IR spectra were used to establish the structure. CM-1 was found to be active against B. subtilis, S. aureus and M. smegmatis (P>0.005) at MIC 20 MUg/ml. Findings of this study may provide a lead for synthesis of more potent antimicrobial agents to serve the humanity against multidrug-resistant bacterial infections. PMID- 26051730 TI - Influence of high intensity focused ultrasound (HIFU) treatment to the pancreatic function in pancreatic cancer patients. AB - Present study was designed to investigate the pancreatic endocrine and exocrine function damage after High Intensity Focused Ultrasound (HIFU) therapy in patients with advanced pancreatic cancer. It was a retrospective analysis of blood glucose and amylase changes in 59 advanced pancreatic cancer patients treated with HIFU from 2010 February to 2014 January. The mean glucose and amylase before HIFU treatment were 6.02mmol/L and 59.17 U/L respectively. After HIFU treatment, it was shown that the mean glucose and amylase levels were 5.66mmol/L and 57.86/L respectively. There was no statistical significance between them. No acute pancreatitis was observed. The endocrine and exocrine function of pancreatic cancer patients was not damaged by HIFU treatment. HIFU treatment for the pancreatic cancer patients seems to be safe. PMID- 26051731 TI - Association study between 5-HT2A and NET gene polymorphisms and recurrent major depression disorder in Chinese Han population. AB - A functional NET T-182C polymorphism (rs2242446) in the promoter region, a synonymous polymorphisms G1287A in the exon 9(rs5569) and a functional serotonin 2A (5-HT2A) receptor (rs6311) genes in the promoter region were associated with MDD in different populations. However, few studies have focused on the relationship between these three polymorphisms and recurrent MDD patients in Chinese Han population. Three hundred MDD patients (112 males, 188 females) and three hundre unrelated healthy controls were enrolled in the study. POST-PCR ligase detection reaction genotype assay method was used for the genotypic analyses. There existed significant differences both in the frequencies of alleles and genotypes between patients and controls for the 5-HT2A receptor gene polymorphism (chi2=9.267, p=0.01 for genotype; chi2=7.615,p=0.006 for allele). No difference in genotype and allele distribution of G1287A, T182C were found in MDD patients and controls. Our results suggest that the rs6311 polymorphism seems to be the susceptibility factor in etiology of recurrent MDD. In conclusion, 5-HT2A receptor gene variants may be involved in the etiology of MDD, although the results must be verified in larger samples and different ethnicities. PMID- 26051732 TI - Abnormal expressions of inflammatory-related mediators and inhibition of fat metabolism in mice infected with influenza a virus. AB - The pathophysiological role of influenza infection is poorly understood. In this study, one non-neurovirulent virus (IAV/Aichi/2/68/H3N2) strain was used to infect intra-nasally mice at different age to investigate the mechanism of cerebral edema formation and lower activities of mitochondria enzymes after influenza A virus (IAV) infection. Mice suffered 46.4% mortality in newborn compared with 96.0% in weanling, 100% in adult on day 7, respectively. IAV-RNA was easily detected in the brain of newborn mice. Significant production of endothelin-1 and inducible nitric oxide syntheses were increased on the 3rd and 5th day after IAV infection, associated with increasing blood-brain barrier permeability, brain edema formation and the higher mortality of animals. Production of tumor necrosis factor-alpha was related to inhibition of mitochondrial enzyme activities, suggesting that over expression of inflammatory cytokines and lower enzyme activities in mitochondria after IAV infection. PMID- 26051733 TI - Optimization of enzyme complexes for efficient hydrolysis of corn stover to produce glucose. AB - Hydrolysis of cellulose to glucose is the critical step for transferring the lignocellulose to the industrial chemicals. For improving the conversion rate of cellulose of corn stover to glucose, the cocktail of celllulase with other auxiliary enzymes and chemicals was studied in this work. Single factor tests and Response Surface Methodology (RSM) were applied to optimize the enzyme mixture, targeting maximum glucose release from corn stover. The increasing rate of glucan to-glucose conversion got the higher levels while the cellulase was added 1.7MUl tween-80/g cellulose, 300MUg beta-glucosidase/g cellulose, 400MUg pectinase/g cellulose and 0.75mg/ml sodium thiosulphate separately in single factor tests. To improve the glucan conversion, the beta-glucosidase, pectinase and sodium thiosulphate were selected for next step optimization with RSM. It is showed that the maximum increasing yield was 45.8% at 377MUg/g cellulose Novozyme 188, 171MUg/g cellulose pectinase and 1mg/ml sodium thiosulphate. PMID- 26051734 TI - The establish of the HPLC method to examine the plasma concentration of lamotrigine and oxcarbazepine. AB - To establish the HPLC method to examine plasma concentration of lamotrigine and oxcarbazepine. This study set chlorzoxazone as the internal standard, chromatographic column was Column C18 (200*4.6mm, 5um) of DIKMA company, the mobile phase was methanol, water and trifluoroacetic acid, with rate of 40: 60: 0.0005, at a flow rate of 1 mllmin(-1), the detected wavelength was 240 nm. The plasma concentrations of lamotrigine was 0.5-50ug*mL(-1), the standard curve was excellent for Y=0.5511C-0.5669, r=0.9940, average recovery was 91.40%; The plasma concentrations of oxcarbazepine was 0.5-50ugmL-1, the standard curve was good for Y=0.4026C-0.5895, r=0.9925, and the average recovery was 89.59%; The three plasma concentrations of lamotrigine were respectively 25MUg*mL(-1), 10 MUg*mL(-1) and 2MUg*mL(-1) and its five parallel sample for injection RSD were respectively 4.01%, 6.15% and 4.64%; The three plasma concentration of oxcarbazepine were 25MUg*mL(-1)-1(-1), 10MUg*mL(-1)-1(-1) and 2MUg*mL(-1)-1(-1), and its five parallel sample for injection RSD were respectively 3.05%, 4.27% and 9.01%. This method was easy to operate, high recovery and high precision, and was applicable to the clinical detection for plasma concentration of lamotrigine and oxcarbazepine. PMID- 26051735 TI - Evaluation of anti-hyperglycemic effect of Actinidia kolomikta (Maxim. etRur.) Maxim. root extract. AB - This study aimed to evaluate the anti-hyperglycemic effect of ethanol extract from Actinidia kolomikta (Maxim. etRur.) Maxim. root (AKE).An in vitro evaluation was performed by using rat intestinal alpha-glucosidase (maltase and sucrase), the key enzymes linked with type 2 diabetes. And an in vivo evaluation was also performed by loading maltose, sucrose, glucose to normal rats. As a result, AKE showed concentration-dependent inhibition effects on rat intestinal maltase and rat intestinal sucrase with IC(50) values of 1.83 and 1.03mg/mL, respectively. In normal rats, after loaded with maltose, sucrose and glucose, administration of AKE significantly reduced postprandial hyperglycemia, which is similar to acarbose used as an anti-diabetic drug. High contents of total phenolics (80.49 +/- 0.05mg GAE/g extract) and total flavonoids (430.69 +/- 0.91mg RE/g extract) were detected in AKE. In conclusion, AKE possessed anti-hyperglycemic effects and the possible mechanisms were associated with its inhibition on alpha-glucosidase and the improvement on insulin release and/or insulin sensitivity as well. The anti-hyperglycemic activity possessed by AKE maybe attributable to its high contents of phenolic and flavonoid compounds. PMID- 26051736 TI - Phenylthiocarbamide taste perception as a possible genetic association marker for nutritional habits and obesity tendency of people. AB - Ability to taste Phenylthiocarbamide (PTC) a bitter molecule, is usually used to know the heritable characteristic in both genetic and physiological studies. So far, no research has yet attested whether PTC blindness relation with obesity and some nutrition behaviors of human. This study is the first attempt on a large scale to examine PTC sensitivity in healthy and overweight people in Turkish population to define in the perception of bitter senses which is associated with nutrition habits, body mass index, age, gender, and to be in stable weight. PTC taste perception was measured by tasting PTC solution filtered in a paper. The results showed that tasters were significantly more frequent (81,8%) than nontasters (18,2%) in all population. A higher proportion of nontasters were observed in the quite fat individual group (BMI >40kg/m(2)). Alterations explained these differences in basic taste sensitivity, age, gender, BMI, individuals' family obesity situations, vegetarian nourishment. Increased frequency of nontasters allele is evident with obesity condition. This could be due to lack of preference for nutrition among nontasters. So the phenotypic variation in PTC sensitivity is genetic in origin; it may represent an association with obesity, dietary habits, regular weight, gender, and age. PMID- 26051737 TI - Distribution and drug resistance profile of methicillin-resistant Staphylococcus aureus after orthopaedic surgery. AB - This paper is aimed to comprehend clinical distribution and drug-resistance situation of methicillin-resistant Staphylococcus aureus. This study applied automatic microbe instrument Microscan W/A 96 for strain identification and drug susceptibility screening on the isolated strains. It was found that 312 MRSA strains were isolated in three years, which account for 58.1% of Staphylococcus aureus. MRSA were mainly focused in wound secretion, purulent sputum and prostatic fluid and a few of them were isolated from blood specimens; Endemic area distribution was mainly located in intensive care unit, neurosurgery, respiratory department, dermatology, orthopaedic burns and orthopaedics. MRSA strains showed high drug resistance of 82.37%~100% to most of the antibiotics including vancomycin, cotrimoxazole and rifampicin. Strain was 100% resistance towards ampicillin, amoxicillin/acid, cefalotin, cefazolin, tienam, benzylpenicillin, penicillin and tetracycline and 90% strains resisted clindamycin, cefotaxime, clarithromycin and gentamicin. PMID- 26051738 TI - Clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor. AB - Aiming at exploring clinical curative effect of oxaliplatin combined with flurouracil in the treatment of gastrointestinal tumor, this study divided 60 patients with gastrointestinal tumor into control and observation groups, each containing 30 patients. The observation group was treated with oxaliplatin combined with flurouracil, while the control was treated with FOLFOX4, i.e., intravenously dropping 85mg/m(2)Oxaliplatin (L-OHP), 200mg/m(2) calcium folinate (CF) and intravenously injecting 400mg/m(2) 5-fluorouracil (5-Fu), and 600mg/m(2) 5-Fu; then continuously performing intravenous drop infusion for 22h, every two weeks for a cycle. Hypodermic injection of granulocyte colony-stimulating factor (G-CSF) was conducted immediately when leukocytes occurred the III, IV degree of inhibition. The observation results of curative effect and negative reaction indicated higher effective rate with 83.33% in the observation and 50.00% in the control. Besides, in the observation, negative reactions possessed 10.00% that was much lower than 33.33% in the control. Thereby, the conclusion reached that the treatment of gastrointestinal tumor with oxaliplatin combined with flurouracil was worth promoting. PMID- 26051739 TI - Report: Analysis on pathogen distribution and drug-resistance of incision infection caused by vascular operation. AB - To investigate pathogen distribution and drug resistance of incision infection caused by vascular operation to reduce postoperative incision infection, this paper retrospectively reviewed and analyzed 635 in-hospital patients taking vascular operation during Jan. 2008 and Dec. 2012. Analyzed data were statistically processed by SPSS 13.0 software, which resulted in 16 infected cases with 2.52% infection rate. A total of 27 pathogens wasisolated from specimens submitted for inspection, including 17 strains of Gram positive bacteria (62.96%) and 10 Gram negative bacteria (37.04%). Besides high sensitivity to imipenem, all bacteria were able to resist antibacterial drugs. Incision infection is proved in this research to be reduced effectively by some means, like complication correction before operation and reasonable application of antibacterial drugs after operation. While during an operation, it is necessary to operate strictly in a bacterium-free environment and wash incisions thoroughly. PMID- 26051740 TI - Report: Distribution and clinical characteristics of pathogenic bacteria causing catheter-related bloodstream infections. AB - This paper on analysis pathogenic bacterial distribution of central veins Catheter-related Blood-Stream infection (CRBS) and clinical features of different infection. Ninety-one patients with CRBSI were selected, to analyze and research for etiological distribution, clinical characteristics, inflammatory markers and prognosis.Among the 91 cases, 31 cases were infected by Candida, accounting for 34.1%; 31 cases were infected by Gram-negative bacilli, accounting for 34.1%; 29 cases were infected by Gram-positive cocci, accounting for 31.8%. The CRBSI clinical features of Candida and Gram-negative bacilli high fever and chills, and Gram-positive coccal' moderate fever, chills. The pathogens CRBSI inflammatory markers in these 3 groups all were increased, but, the CRBSI inflammatory reaction of Candida and Gram-negative bacilli were more severe, the CRBSI fatality rate by Candida was high (P<0.05). Candida, Gram-negative bacilli and Gram-positive cocci were all the CRBSI common pathogenic bacterium. It shall pay attention to etiology research, at the same time, it shall take empiric therapy to decrease CRBSI fatality rate based on clinical features. PMID- 26051741 TI - Report: Osteocyte enhancement function of bisphosphonates in prosthetic replacement. AB - Aseptic loosening after prosthetic replacement is the primary cause of shortened service life and lowered stability of prosthesis, and increased revision rate after joint replacement. Factors of causing the loosening of joint prosthesis include mechanical factors and biological factors. The mechanical effect of bisphosphonates (BP) is quite obvious, which can enhance osteocyte function, accelerate the generation of new bone and lower bone resorption activity of osteoclast and macrophage. In animal experiment and adjuvant therapy of patients after joint replacement, BP also shows up the functions of reducing osteolysis induced by wear debris, preventing stress shielding and interface fretting and enhancing bone density. This paper elaborated the mechanism of BP adjusting bone metabolism, and analyzed the action principle and the vital function of it in prosthetic replacement. It has proved that BP can effectively reduce the early peri-prosthesis bone absorption after total hip replacement and improve bone mass peri-prosthesis. It is currently the significant choice of preventing bone lose of peri-prosthesis after operation. PMID- 26051743 TI - Erratum. PMID- 26051742 TI - Review: Pharmacological ins and outs of medicinal plants against Helicobacter pylori: A review. AB - Since Helicobacter pylori was discovered in 1980, it has been considered as a major cause in the pathogenesis of gastric ulcer, mucosa-associated lymphoid tissue (MALT) lymphomas, and gastric cancer. Eventually antibiotics were designed to eradicate this bacterium, which not only prevent peptic ulcer recurrence but also decrease the chances of developing gastric cancer. Propitious consequences of these antibiotic regimens and better hygienic conditions, particularly in developed countries, resulted in significant decline in the prevalence of H. pylori infection. However, persistent high H. pylori infection in developing countries, decreased patience compliance and emerging antibiotic resistance forced researchers to quest for novel candidates. Herbal medicines have always served as a leading source in drug discovery. Since time immemorial, herbs have been used to treat various disorders covering from minor illnesses as pain to life threatening conditions like cancer. Ample amount of studies from different parts of the world have shown promising activities of medicinal herbs not only against H. pylori but also associated disorders while employing in vitro, in vivo and clinical studies. In this review, these multiple pharmacological effects of medicinal plants and their chemical constituents will be discussed in relation to H. pylori not only to scientifically evaluate the beneficial effects of these medicinal plants but to also critically analyze their plausible role as chemo preventive agents against H. pylori-associated disorders. PMID- 26051744 TI - Hyperthermic intraperitoneal chemotherapy + early postoperative intraperitoneal chemotherapy versus hyperthermic intraperitoneal chemotherapy alone: assessment of survival outcomes for colorectal and high-grade appendiceal peritoneal carcinomatosis. AB - BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have improved survival for colorectal and high-grade appendiceal carcinomatosis. We compared the overall and recurrence-free survival (OS and RFS) of patients treated with HIPEC with mitomycin c and early postoperative intraperitoneal chemotherapy (EPIC) with fluorouracil versus HIPEC alone using oxaliplatin and simultaneous IV infusion of fluorouracil. METHODS: Ninety-three patients with colorectal or high-grade appendiceal carcinomatosis were treated with CRS and HIPEC + EPIC or HIPEC alone. OS and RFS were analyzed using Kaplan-Meier curves and log-rank testing. RESULTS: Survival did not differ between HIPEC regimens. The 3-year OS and RFS rates were 50% and 21% for HIPEC + EPIC and 46% and 6% for HIPEC alone (P = .72 and P = .89, respectively). HIPEC + EPIC patients experienced more grade III/IV complications (43.2% vs 19.6%, P = .01). CONCLUSIONS: There was no difference in OS and RFS between colorectal and high-grade appendiceal adenocarcinoma patients treated with CRS and HIPEC + EPIC versus HIPEC alone. However, HIPEC + EPIC patients suffered greater morbidity, making HIPEC alone the preferable regimen. PMID- 26051745 TI - Delayed repair of obstructing ventral hernias is associated with higher mortality and morbidity. AB - BACKGROUND: Patients presenting with ventral hernia-related obstruction are commonly managed with emergent ventral hernia repair (VHR). Selected patients with resolution of obstruction may be managed in a delayed manner. This study sought to assess the effect of delay on VHR outcomes. METHODS: The American College of Surgeons' National Surgical Quality Improvement Program database from 2005 to 2011 was queried using diagnosis codes for ventral hernia with obstruction. Those who underwent repair over 24 hours after admission were classified as delayed repair. Preoperative comorbid conditions, American Society of Anesthesiology (ASA) scores, and 30-day outcomes were evaluated. RESULTS: We identified 16,881 patients with a mean age of 58 +/- 15 years and body mass index of 36 +/- 10. Delayed repair occurred in 27.7% of the patients. After controlling for comorbidities and ASA score, delayed VHR was independently associated with mortality (odds ratio [OR] 1.9, 95% confidence interval [CI] 1.41 to 2.48, P < .001), morbidity (OR 1.4, 95% CI 1.24 to 1.50, P < .001), surgical site infection (OR 1.2, 95% CI 1.03 to 1.35, P = .016), and concurrent bowel resection (OR 1.2, 95% CI 1.03 to 1.34, P = .016). CONCLUSIONS: VHR for obstructed patients is frequently performed over 24 hours after admission. After adjusting for comorbid conditions and ASA score, delayed VHR is independently associated with worse outcomes. Prompt repair after appropriate resuscitation should be the management of choice. PMID- 26051746 TI - Diagnosing acute appendicitis with blood markers: is there any problem? PMID- 26051747 TI - Does the derived neutrophil/lymphocyte ratio predict clinical outcome in soft tissue sarcoma patients? PMID- 26051748 TI - Design of an ectoine-responsive AraC mutant and its application in metabolic engineering of ectoine biosynthesis. AB - Advanced high-throughput screening methods for small molecules may have important applications in the metabolic engineering of the biosynthetic pathways of these molecules. Ectoine is an excellent osmoprotectant that has been widely used in cosmetics. In this study, the Escherichia coli regulatory protein AraC was engineered to recognize ectoine as its non-natural effector and to activate transcription upon ectoine binding. As an endogenous reporter of ectoine, the mutated AraC protein was successfully incorporated into high-throughput screening of ectoine hyper-producing strains. The ectoine biosynthetic cluster from Halomonas elongata was cloned into E. coli. By engineering the rate-limiting enzyme L-2,4-diaminobutyric acid (DABA) aminotransferase (EctB), ectoine production and the specific activity of the EctB mutant were increased. Thus, these results demonstrated the effectiveness of engineering regulatory proteins into sensitive and rapid screening tools for small molecules and highlighted the importance and efficacy of directed evolution strategies applied to the engineering of genetic components for yield improvement in the biosynthesis of small molecules. PMID- 26051749 TI - Challenging lanthanide relaxation theory: erbium and thulium complexes that show NMR relaxation rates faster than dysprosium and terbium analogues. AB - Measurements of the proton NMR paramagnetic relaxation rates for several series of isostructural lanthanide(III) complexes have been performed in aqueous solution over the field range 1.0 to 16.5 Tesla. The field dependence has been modeled using Bloch-Redfield-Wangsness theory, allowing values for the electronic relaxation time, Tle and the magnetic susceptibility, MUeff, to be estimated. Anomalous relaxation rate profiles were obtained, notably for erbium and thulium complexes of low symmetry 8-coordinate aza-phosphinate complexes. Such behaviour challenges accepted theory and can be interpreted in terms of changes in Tle values that are a function of the transient ligand field induced by solvent collision and vary considerably between Ln(3+) ions, along with magnetic susceptibilities that deviate significantly from free-ion values. PMID- 26051751 TI - The effect of optokinetic and galvanic vestibular stimulations in reducing post stroke postural asymmetry. AB - OBJECTIVE: To investigate the postural effect of 2 types of sensory stimulation in patients with a left hemispheric lesion (LHL) or right hemispheric lesion (RHL) compared with controls. METHODS: 35 patients (18 LHL, 17 RHL) and 27 controls (mean age 54.1 years), with a mean delay post-stroke of 3.0 months were enrolled. Subjects stood on a force platform and were stimulated on the left and right side by optokinetic (Okn) and galvanic vestibular (Gv) stimulation. Lateral displacement following stimulation toward the right and left directions was calculated as the mean position of the centre of pressure (CP) during the stimulation period minus the mean position at rest. RESULTS: Postural asymmetry was reduced in LHL and RHL patients. CP displacement was higher in cases of left sided stimulation in the RHL group compared with control subjects and LHL patients (respectively 2.8 and 2.4 times higher, group effect, p<0.001, group * direction of stimulation interaction, p=0.007). The magnitude of displacement under Okn significantly correlated with Gv in all cases (rho=0.635, p<0.001). CONCLUSIONS: Both GV and Okn stimulations can modulate hemiparetic's CP and their postural effects are correlated. SIGNIFICANCE: Results support a high level cortical postural effect of sensory stimulation on supramodal spatial network. PMID- 26051750 TI - Resting-state EEG, impulsiveness, and personality in daily and nondaily smokers. AB - OBJECTIVES: Resting EEG is sensitive to transient, acute effects of nicotine administration and abstinence, but the chronic effects of smoking on EEG are poorly characterized. This study measures the resting EEG profile of chronic smokers in a non-deprived, non-peak state to test whether differences in smoking behavior and personality traits affect pharmaco-EEG response. METHODS: Resting EEG, impulsiveness, and personality measures were collected from daily smokers (n=22), nondaily smokers (n=31), and non-smokers (n=30). RESULTS: Daily smokers had reduced resting delta and alpha EEG power and higher impulsiveness (Barratt Impulsiveness Scale) compared to nondaily smokers and non-smokers. Both daily and nondaily smokers discounted delayed rewards more steeply, reported lower conscientiousness (NEO-FFI), and reported greater disinhibition and experience seeking (Sensation Seeking Scale) than non-smokers. Nondaily smokers reported greater sensory hedonia than nonsmokers. CONCLUSIONS: Altered resting EEG power in daily smokers demonstrates differences in neural signaling that correlated with greater smoking behavior and dependence. Although nondaily smokers share some characteristics with daily smokers that may predict smoking initiation and maintenance, they differ on measures of impulsiveness and resting EEG power. SIGNIFICANCE: Resting EEG in non-deprived chronic smokers provides a standard for comparison to peak and trough nicotine states and may serve as a biomarker for nicotine dependence, relapse risk, and recovery. PMID- 26051752 TI - Imaging epileptogenic brain using high density EEG source imaging and MRI. PMID- 26051753 TI - Effects of training and motivation on auditory P300 brain-computer interface performance. AB - OBJECTIVES: Brain-computer interface (BCI) technology aims at helping end-users with severe motor paralysis to communicate with their environment without using the natural output pathways of the brain. For end-users in complete paralysis, loss of gaze control may necessitate non-visual BCI systems. The present study investigated the effect of training on performance with an auditory P300 multi class speller paradigm. For half of the participants, spatial cues were added to the auditory stimuli to see whether performance can be further optimized. The influence of motivation, mood and workload on performance and P300 component was also examined. METHODS: In five sessions, 16 healthy participants were instructed to spell several words by attending to animal sounds representing the rows and columns of a 5 * 5 letter matrix. RESULTS: 81% of the participants achieved an average online accuracy of ? 70%. From the first to the fifth session information transfer rates increased from 3.72 bits/min to 5.63 bits/min. Motivation significantly influenced P300 amplitude and online ITR. No significant facilitative effect of spatial cues on performance was observed. CONCLUSIONS: Training improves performance in an auditory BCI paradigm. Motivation influences performance and P300 amplitude. SIGNIFICANCE: The described auditory BCI system may help end-users to communicate independently of gaze control with their environment. PMID- 26051754 TI - Assessing cost and effectiveness of radiation decontamination in Fukushima Prefecture, Japan. AB - Despite the enormous cost of radiation decontamination in Fukushima Prefecture, it is not clear what levels of reduction in external radiation exposure are possible in the Special Decontamination Area, the Intensive Contamination Survey Areas and the whole of Fukushima. The objective of this study was to evaluate the cost and effectiveness of radiation decontamination in Fukushima Prefecture in its entirety. Using a geographic information system, we calculated the costs of removal, storage containers, transport, and temporary and interim storage facilities as well as the reduction in air dose rate for a cumulative external exposure for 9000 1 km * 1 km mesh units incorporating 51 municipalities. The decontamination cost for the basic scenario, for which forested areas within 20 m of habitation areas were decontaminated, was JPY2.53-5.12 trillion; the resulting reduction in annual external dose was about 2500 person-Sv. The transport, storage, and administrative costs of decontamination waste and removed soil reached JPY1.55-2.12 trillion under this scenario. Although implementing decontamination of all forested areas provides some major reductions in the external radiation dose for the average inhabitant, decontamination costs could potentially exceed JPY16 trillion. These results indicate that technologies for reducing the volume of decontamination waste and removed soil should be considered to reduce storage costs and that further discussions about forest decontamination policies are needed. PMID- 26051755 TI - New monomeric and dimeric uridinyl derivatives as inhibitors of chitin synthase. AB - This study described the synthesis and in vitro evaluation of eight new derivatives of uridine as antifungal agents and inhibitors of chitin synthase. Dimeric uridinyl derivatives synthesized by us did not exhibit significant activity. One of the studied monomeric derivative, 5'-(N-succinyl)-5'-amino-5' deoxyuridine methyl ester (compound 7) showed activities against several fungal strains (MIC range 0.06-1.00 mg/mL) and inhibited chitin synthase from Saccharomyces cerevisiae (IC50=0.8mM). Moreover compound 7 exhibited synergistic interaction with caspofungin against Candida albicans (FIC index=0.28). PMID- 26051756 TI - Preventing coronary occlusion with a retrievable aortic valve. PMID- 26051757 TI - Mortality and cardiovascular morbidity within 30 days of discharge following acute coronary syndrome in a contemporary European cohort of patients: How can early risk prediction be improved? The six-month GRACE risk score. AB - OBJECTIVES: Given the increasing focus on early mortality and readmission rates among patients with acute coronary syndrome (ACS), this study was designed to evaluate the accuracy of the GRACE risk score for identifying patients at high risk of 30-day post-discharge mortality and cardiovascular readmission. METHODS: This was a retrospective study carried out in a single center with 4229 ACS patients discharged between 2004 and 2010. The study endpoint was the combination of 30-day post-discharge mortality and readmission due to reinfarction, heart failure or stroke. RESULTS: One hundred and fourteen patients had 30-day events: 0.7% mortality, 1% reinfarction, 1.3% heart failure, and 0.2% stroke. After multivariate analysis, the six-month GRACE risk score was associated with an increased risk of 30-day events (HR 1.03, 95% CI 1.02-1.04; p<0.001), demonstrating good discrimination (C-statistic: 0.79 +/- 0.02) and optimal fit (Hosmer-Lemeshow p=0.83). The sensitivity and specificity were adequate (78.1% and 63.3%, respectively), and negative predictive value was excellent (99.1%). In separate analyses for each event of interest (all-cause mortality, reinfarction, heart failure and stroke), assessment of the six-month GRACE risk score also demonstrated good discrimination and fit, as well as adequate predictive values. CONCLUSIONS: The six-month GRACE risk score is a useful tool to predict 30-day post-discharge death and early cardiovascular readmission. Clinicians may find it simple to use with the online and mobile app score calculator and applicable to clinical daily practice. PMID- 26051758 TI - An extremely rare malformation of an atrial septal defect closure device and use of a new corrective technique. AB - Tulip malformation is a newly defined complication of transcatheter atrial septal defect closure. This complication, in which the left atrial disc becomes concave, makes it impossible to fully retract the device into the delivery sheath. The case presented is the first report describing a simple new technique which overcomes this novel complication. PMID- 26051759 TI - Murmur from a bullet: Old lesion, new treatment. AB - Aortic disease can be highly variable in terms of lesion morphology, clinical presentation and etiology. We present the case of a young man who suffered a gunshot injury at the age of 12, resulting in paraplegia. Later a murmur was detected and at age 25 a pseudoaneurysm was diagnosed, with fistulization to the left pulmonary artery. Given his good functional status, he was initially managed by a conservative strategy, with regular follow-up. At age 35 left ventricular dilatation was observed with tachycardia and systolic dysfunction, and he was referred for transcatheter aortic valve replacement. Currently, at age 41, he is well in cardiovascular terms, with a good procedural result and professionally active. PMID- 26051760 TI - Inheriting the Heritage, and Preparing for the Future. PMID- 26051761 TI - Scaphoid Fracture--Overview and Conservative Treatment. AB - Scaphoid fracture is the most common fracture in carpal bones. Although the reported union rate of conservatively-treated fractures is more than 90%, there is a controversy over the most appropriate treatment. In recent years, many reports have compared the clinical outcomes of conservatively-treated scaphoid fractures with the results of operatively treated ones using randomized controlled trials and meta-analyses. However, there is no consensus regarding the optimal treatment. In this paper, based on literature review, we provide an overview of the management of the acute scaphoid fractures particularly focusing on the issues related to conservative treatment. PMID- 26051762 TI - Operative Treatment of Acute Scaphoid Fractures. AB - Optimal treatment of acute scaphoid fractures is a necessary goal for many reasons. One is that the scaphoid is the most commonly fractured carpal bone. Another is that a missed diagnosis of an acute scaphoid fracture leads to the more challenging situation of a delayed union, non-union and risk for premature radiocarpal arthrosis. Because the scaphoid has an inherent risk for nonunion due to its the tenuous blood supply, timely diagnosis and appropriate treatment are considered critical to achieving acceptable results and to avoiding the consequences of failed union. PMID- 26051763 TI - Arthroscopic Management of Scaphoid Nonunions. AB - The difficulty in healing scaphoid nonunions is challenged further by the dynamic, unstable nature of the fracture-fragment interface. Recently, several investigators have introduced a minimally invasive technique for scaphoid nonunion repair, which has the advantages of minimal morbidity and accurate articular reduction, resulting in less postoperative stiffness and increased functional outcomes. However, failure to recognize the critical steps during minimally invasive surgery can result in incorrect treatment or limit any chances for successful bone repair. We reviewed the selected literature pertinent to arthroscopic techniques in the treatment of scaphoid nonunions. Furthermore, we presented a new arthroscopic approach that can be used in place of traditional formal open exposures in challenging cases of nonunion. PMID- 26051764 TI - Bone Grafts for Scaphoid Nonunion: An Overview. AB - The scaphoid is the most common fractured bone in the wrist. Despite adequate non surgical treatment, around 10% to 15% of these fractures will not heal. Untreated scaphoid non-union can cause a scaphoid non-union advance collapse (SNAC), this is a progressive deformity and can cause degenerative changes in the wrist. Surgery is focused on achieving consolidation, pain reduction and a good position of the scaphoid while preventing osteoarthritis in the long-term. Surgery consists of reduction and fixation of the scaphoid with a non-vascularized or vascularized bone graft. An overview of the most used vascularized and non vascularized bone grafts and their indications are presented. PMID- 26051765 TI - Radiographic Assessment of the Robert and Lateral Views in Trapeziometacarpal Osteoarthrosis. AB - BACKGROUND: To evaluate the effectiveness of the Robert view in assessing trapeziometacarpal arthrosis and to compare the accuracy of the Robert and lateral views in staging trapeziometacarpal (TM) joint arthrosis. METHODS: Patient demographics were obtained. Four participating raters reviewed 62 randomly selected thumb x-rays of patients presenting with thumb TM joint pain. Lateral and Robert-hyperpronation views were assessed using an analysis of 13 criteria. RESULTS: X-rays of 62 thumbs for 58 patients were evaluated. The average patients' age was 64 (47-87) and 51 (80%) were females. The majority of X rays evaluated fell into stage 3. Stage 2 was the second most common level of arthritis encountered and the least was stage 1. More osteophytes were encountered in the trapezium than metacarpal on both the Robert and lateral views. The Robert view was superior in detecting osteophytes on the trapezium than the lateral view. Osteophyte size varied from 1.7 to 2 mm. The lateral view displayed 61 cases with dorsal metacarpal subluxation (98%). The Robert view displayed 48 cases (77%) with radial metacarpal subluxation and 9 cases (15%) with ulnar metacarpal subluxation. Thumb metacarpal adduction deformity was encountered on the lateral view in 20 cases (32%) whereas on the Robert view it was encountered in 14 cases (23%). Subchondral sclerosis was encountered on the Robert view in 56 thumbs (90%) while it was seen on the lateral view in 52 thumbs (84%). Pantrapezial arthritis involving the STT joint was encountered equally in 16 cases (26%) on the Robert view and the lateral views. The study found a moderate level of interrater reliability on both the lateral and Robert views. With the exception of osteophytes encountered on the trapezium versus the metacarpal, there were no other statistically significant findings. CONCLUSIONS: This study confirms that each of the Robert and lateral views offer unique information and combining both views enhances the ability to assess radiographic disease severity, and should be the recommended set of X-rays for assessing TM osteoarthrosis. PMID- 26051766 TI - Ulna Nerve Decompression at the Elbow in Patients with Normal Nerve Conduction Tests. AB - BACKGROUND: Ulna nerve compression at the elbow is the second most common neuropathy of the upper limb. It has been suggested that nerve conduction tests are required to correctly make the diagnosis. The aim of this study was to assess whether patients with normal nerve conduction testing benefitted from surgical release of the ulna nerve. METHODS: 56 patients with symptoms of ulna nerve compression at the elbow were evaluated prospectively. All patients underwent electrophysiology testing followed by ulna nerve decompression irrespective of the results of the electrophysiology testing. Functional scores using the QuickDASH and PEM score were collected up to 12 months post-surgery. RESULTS: No difference was found between the group with normal and the group with abnormal electrophysiology studies. CONCLUSIONS: We conclude that patients who clinically have ulna nerve compression still benefit from ulna nerve decompression despite normal nerve conduction tests. PMID- 26051767 TI - The Adipofascial Radial Artery Perforator Flap: A Versatile Reconstructive Option in Upper Limb Surgery. AB - BACKGROUND: Flaps have been used in upper limb surgery for varied indications including coverage of soft tissue defects, interposition and to provide a pliable bed for gliding structures among others. METHODS: We report our use of the radial artery perforator based adipofascial flap in nine patients, five with rigid radioulnar synostosis, three with recalcitrant carpal tunnel syndrome and one with a soft tissue defect. RESULTS: All our patients with radioulnar synostosis regained good functional rotations of the forearm with no recurrence at follow up. The patients with recalcitrant carpal tunnel also had resolution of symptoms with no recurrence. The flap healed well in all the patients. CONCLUSIONS: We propose this flap as a viable, versatile reconstructive option for the hand and upper limb. PMID- 26051768 TI - The Effect of Screw Design on Union Rates in Scaphoid Nonunions. AB - BACKGROUND: The purpose of this study is to compare the outcome of the conical fully threaded headless screw to that of a smooth shaft headless screw in a series of scaphoid nonunions requiring screw fixation to determine if screw design had an influence on union rates. METHODS: We retrospectively reviewed 104 cases of surgically treated scaphoid nonunions. After eliminating cases with our exclusion criteria, the study cohort had 40 cases for analysis. A comparison and analysis of union rates was undertaken between the fully threaded Acutrak 2 mini screw and the smooth shaft Herbert screw. RESULTS: Overall union rate for screw fixation was 88%. The fully threaded conical screw fixation had a significantly lower union rate of 50% compared to 97% for the smooth shaft screws. CONCLUSIONS: Our data revealed that the fully threaded conical screws were associated with significantly lower union rate compared to the smooth shaft Herbert type screws. PMID- 26051769 TI - Scaphoid Excision and Four-Corner Fusion for Neglected Perilunate Dislocations: Preliminary Results. AB - BACKGROUND: Perilunate dislocations are severe uncommon carpal injuries. They are sometimes missed with a reported incidence of up to 25%. Neglect for a period of time allows for soft tissue contractures, as well as bony changes that make reduction extremely difficult. For neglected cases, procedures such as staged open reduction, proximal row carpectomy, and wrist arthrodesis have been offered. The objective of this study was to examine whether scaphoid excision and four corner fusion could be used to treat neglected perilunate dislocations. METHODS: Ten patients with neglected perilunate dislocations were managed by scaphoid excision and four-corner fusion. The dominant hand was involved in eight cases. Graft material for the fusion was obtained from the excised scaphoid. RESULTS: Six patients had complete relief of pain both at rest and during stressful activities. Two patients had no pain at rest and mild pain on stressful activities. The remaining two patients had mild pain at rest and moderate pain on stressful activities. The arc of extension/flexion of the wrist and grip strength both improved as compared to their preoperative levels. The average postoperative Quick DASH score was 12.5. CONCLUSIONS: Scaphoid excision with four corner fusion could be used to treat neglected perilunate dislocations with good pain relief and good hand function. PMID- 26051770 TI - Functional Outcomes Following Pilon Fractures of the Middle Phalanx Managed with the Ligamentotaxor External Fixator. AB - BACKGROUND: The surgical aims in managing displaced intra-articular fractures of the base of the middle phalanx include early joint reduction, maintaining congruence and early mobilization. Achieving this can be a challenge. However dynamic external fixators offer a solution. The study aim was to evaluate the use and outcomes of the Ligamentotaxor external fixator in patients with such injuries. METHODS: A total of 12 patients were managed with this device and outcomes were assessed. All patients reached clinical and radiological union. RESULTS: An average range of movement to the proximal interphalangeal joint of 63 degrees was noted along with an average end of care-cycle quick-DASH score of 9.1. Two patients developed pin-site infections. CONCLUSIONS: The outcomes seen support the use of the Ligamentotaxor in the management of middle phalanx intra articular fractures. It is simple to apply, potentially avoids the secondary complications of open reduction and gives reproducible results. However judicious patient selection is advised. PMID- 26051771 TI - Critical Angles of Deformity in Dupuytren's Contracture of the Little and Ring Fingers. AB - BACKGROUND: We aimed to determine the degree of contracture in the ring and little fingers at which hand function became importantly impaired. METHODS: Five activities of daily living were incorporated into a newly developed and validated Dupuytren's assessment tool (DAT). Sixty healthy participants were assessed with the DAT wearing a range of 12 dorsal blocking splints. Half wore them on their right little finger, the other half on their ring finger. These induced flexion deformities mimicking DC of the MCPJ, PIPJ and a combination of the two. The angles of flexion deformity at which important hand disability occurred were calculated using receiver operating characteristic curves. RESULTS: Clinically important hand disability occurred for the little finger MCPJ, PIPJ and combined MCPJ and PIPJ angulation at 52.5, 67.5, and 75 degrees respectively. For the ring finger joint, the angulations were 52.5, 67.5 and 75 degrees respectively. CONCLUSIONS: This information will provide information for clinicians and patients as to when clinically important disability tends to occur in DC. PMID- 26051772 TI - Simultaneous Regional Fasciectomy, Skin Grafting, and Distraction Arthrolysis of the Proximal Interphalangeal Joint for Dupuytren's Contracture of the Little Finger. AB - We present a 58-year-old right-handed man, who consulted us with an 11-year history of Dupuytren's disease. To correct contracture of the little finger, we performed regional fasciectomy, skin grafting, and distraction arthrolysis of the proximal interphalangeal (PIP) joint using an external fixator. Preoperative or postoperative skeletal traction has been advocated to treat potential or residual stiffness of the PIP joint in Dupuytren's contracture, but its intraoperative use has not been reported before. Our method has the advantage of treating each problem caused by Dupuytren's disease. A good range of painless PIP joint motion is achieved by our intraoperative distraction technique without interfering with the skin graft and without reducing extensor tone, while the healing period is shortened by performing all procedures simultaneously. PMID- 26051773 TI - Interfascicular Neurolysis for Incomplete Spontaneous Posterior Interosseous Nerve Palsy with a Surgical Delay of 17 Years: Is It Still Effective? AB - A 55-year-old woman with incomplete spontaneous posterior interosseous nerve (PIN) palsy underwent interfascicular neurolysis and tendon transfer, 17 years after its onset. After one year, her nerve function partially recovered electrophysiologically. This case suggests that incomplete spontaneous PIN palsy may recover by interfascicular neurolysis, even with a long preoperative delay. PMID- 26051774 TI - Irreducible Palmar Dislocation of the Distal Interphalangeal Joint Due to Closed Degloving of the Distal Phalanx of the Little Finger. AB - Since irreducible dislocation of the distal interphalangeal joint (DIP joint) is dorsal dislocation, irreducible palmar dislocation of the DIP Joint is very rare. This case was associated with a closed degloving injury of the distal phalanx of the little finger and required operative treatment. PMID- 26051775 TI - Limb Preservation in Recurrent Giant Cell Tumour of Distal End of Radius with Fibular Graft Fracture: Role of Ulnocarpal Arthrodesis. AB - Giant cell tumors of distal radius are locally aggressive tumors with a high rate of recurrence. Though surgery remains the mainstay of treatment, reconstruction remains a challenge in cases of recurrence. Recurrences of GCT in autogenous fibular grafts have been rarely reported and pathological fractures through such grafts are even rarer. Ulnocarpal arthrodesis has never been described as a limb preservation procedure in such a recurrent lesion in distal radius with pathological fracture through a well incorporated fibular graft. A case of pathological fracture in a well incorporated autogenous non-vascularized fibular bone graft in recurrent GCT of distal radius and its successful management with ulnocarpal arthrodesis is reported. In such a scenario where other reconstructive options like allograft or prosthetic reconstructions are not likely to succeed, ulnocarpal arthrodesis may be considered as a salvage procedure. PMID- 26051776 TI - A Huge Angioleiomyoma of the Finger. AB - Vascular leiomyoma is a rare soft tissue lesion in the upper limbs. We reported a case of vascular leiomyoma in a 77-year-old female. It presented with a large painless slow growing lesion in the finger, which had grown to size up to 4 * 3 cm. X-ray and MRI were performed pre-operatively. Surgical excision was performed and the histological findings confirm the diagnosis. PMID- 26051777 TI - Trans-Scaphoid Perilunate Dislocation: Union of an Extruded Scaphoid Proximal Pole Fragment. AB - We present an unusual case of a closed perilunate dorsal-dislocation of the carpus, with an associated scaphoid fracture. In this extreme case, the proximal scaphoid pole was extruded volarly and proximally. After closed manipulation, the proximal pole of the scaphoid was further dislocated dorsally, a phenomenon not previously described in the literature. At open reduction this fragment was noted to have no soft tissue attachment but after reduction, distal radius bone graft and compression screw fixation the scaphoid went on to unite with a good functional result. This case highlights a rare but serious injury to the wrist with an unusual dislocation pattern not previously described. It demonstrates that early surgical intervention to fix such fractures with an avascular fragment can still achieve fracture union, despite the severity. PMID- 26051778 TI - Intratendinous Ganglion of the Extensor Tendon of the Hand. AB - Ganglion is a common benign lesion that usually arises adjacent to the joints or tendons of the hand. However, an intratendinous ganglion is a rare condition. We report two cases of intratendinous ganglion of the extensor tendon of the hand which were treated with excision. PMID- 26051779 TI - Avulsion Injuries of the Flexor Digitorum Profundus Tendon: An Unclassified Pattern of Injury. AB - Closed avulsion of the flexor digitorum profundus (FDP) tendon is classified based on the impact of injury on the management plan. In this report, we present a case with unclassified pattern of FDP tendon avulsion. The injury involves an intra-articular fracture of the volar part of distal phalanx of the little finger resulting into two bony fragments, one attached to the retracted avulsed tendon and another separated and incarcerated at A4 pulley, and an intact dorsal cortex of the phalanx. Based on that, we recommend the development of a new classification scheme for this condition. PMID- 26051780 TI - Extensive Periosteal Chondroma in the Middle Phalanx with Pathological Fracture Reconstructed with Strut Bone Grafting. AB - We report of a pathological fracture of the middle phalanx of the little finger due to periosteal chondroma. The periosteal chondroma occupied an extensive area of the middle phalanx extending to the proximal interphalangeal joint, and the fracture involved the distal interphalangeal articular surface. The fracture was internally fixed using a strut bone grafting after resection of the chondroma. One year and four months after the operation, remodeling of the phalanx had completed without recurrence and functional loss. PMID- 26051781 TI - Various Diagnostic and Treatment Pitfalls of Combined Fracture Dislocations of Trapezoid and Multiple Carpometacarpal Joints. AB - We report a rare case of combined fracture dislocations of the trapezoid and multiple carpometacarpal joints that became chronic due to inappropriate treatments. Although an acceptable clinical result was obtained with limited intercarpal fusion, correct diagnosis and initial treatments including anatomical reduction and fixation for obtaining a good clinical result, are important for complex trapezoid injury. PMID- 26051782 TI - Osteonecrosis of Interphalangeal Joint of Thumb Two Months after Rattlesnake Bite. AB - This case report details the osteonecrosis of the interphalangeal (IP) joint of the thumb two months after a rattlesnake bite. It describes the clinical presentation, imaging studies, histological review, pathology review, and review of literature. Our patient was a fifty-one year-old male who obtained a poisonous snakebite to the thumb. While in the hospital for acute treatment, a blood blister was debrided. He was seen two weeks after discharge for further debridement of epidermolysis. Patient presented one month later with a hand x-ray demonstrating bony erosions, and a bone scan showing active changes in the IP joint of his right thumb. He was taken to the OR for further debridement and definitive diagnosis. Pathology results confirmed osteonecrosis with negative bone cultures. The clinical presentation, diagnosis, and operative management of osteonecrosis offer a unique challenge, especially in a patient presenting with osteonecrosis from a poisonous snakebite. PMID- 26051783 TI - Biological determinants of bladder cancer gene expression subtypes. AB - Molecular stratification of tumors by gene expression profiling has been applied to a large number of human malignancies and holds great promise for personalized treatment. Comprehensive classification schemes for urothelial carcinoma have been proposed by three separate groups but have not previously been evaluated simultaneously in independent data. Here we map the interrelations between the proposed molecular subtypes onto the intrinsic structure of a rich independent dataset and show that subtype stratification within each scheme can be explained in terms of a set of common underlying biological processes. We highlight novel biological and genomic drivers of urothelial carcinoma molecular subtypes and show that tumors carrying genomic aberrations characteristic of distinct molecular pathways converge on a common top level phenotype corresponding to the two major molecular subtypes of non-muscle invasive disease. PMID- 26051784 TI - New biaryl-chalcone derivatives of pregnenolone via Suzuki-Miyaura cross-coupling reaction. Synthesis, CYP17 hydroxylase inhibition activity, QSAR, and molecular docking study. AB - A new class of steroids is being synthesized for its ability to prevent intratumoral androgen production by inhibiting the activity of CYP17 hydroxylase enzyme. The scheme involved the synthesis of chalcone derivative of pregnenolone 5 which was further modified to the corresponding biaryl-chalcone pregnenolone analogs 16-25 using Suzuki-Miyaura cross-coupling reaction. The synthesized compounds were tested for activity using human CYP17alpha hydroxylase expressed in Escherichia coli. Compounds 21 was the most active inhibitor in this series, with IC50 values of 0.61MUM and selectivity profile of 88.7% inhibition of hydroxylase enzyme. Molecular docking study of 21 was performed and showed the hydrogen bonds and hydrophobic interaction with the amino acid residues of the active site of CYP17. PMID- 26051785 TI - Fighting the battle on the home front: Prevention and intervention of child maltreatment for the military family: The U.S. Air Force Family Advocacy Program seeks to provide safe and nurturing homes for children. PMID- 26051786 TI - Higher colistin dose during continuous renal replacement therapy: look before leaping! PMID- 26051787 TI - Design and fabrication of mesoporous heterogeneous basic catalysts. AB - Mesoporous solid bases are extremely desirable in green catalytic processes, due to their advantages of accelerated mass transport, negligible corrosion, and easy separation. Great progress has been made in mesoporous solid bases in the last decade. In addition to their wide applications in the catalytic synthesis of organics and fine chemicals, mesoporous solid bases have also been used in the field of energy and environmental catalysis. Development of mesoporous solid bases is therefore of significant importance from both academic and practical points of view. In this review, we provide an overview of the recent advances in mesoporous solid bases, which is basically grouped by the support type and each category is illustrated with typical examples. Cooperative catalysts derived from the incorporation of additional functionalities (i.e. acid and metal) into mesoporous solid bases are also included. The fundamental principles of how to design and fabricate basic materials with mesostructure are highlighted. The mechanism of the formation of basic sites in different mesoporous systems is discussed as well. PMID- 26051788 TI - Psychotic-like experiences and associated socio-demographic factors among adolescents in China. AB - OBJECTIVE: Adolescents with persistent psychotic-like experiences (PLEs) may be at high risk for later development of psychoses. Exploring early age risk factors for PLEs may provide useful information for prevention of mental disorders and improvement of mental health. METHOD: A total of 5427 adolescents (aged between 10 and 16) participated in a cross-sectional survey, with social and demographic information collected. The Positive Subscale of Community Assessment of Psychic Experiences (CAPE) was used to measure PLEs, and the CAPE Depressive and Negative Subscales were used to examine depressive and negative experiences. The Trauma History Questionnaire (child version) was used to assess experiences of previous traumatic events. RESULTS: In our study, 95.7% of the adolescents reported more than one episode of PLEs, while 17.2% reported "nearly always" having PLEs. High positive correlations were shown both between frequency scores among experiences of three dimensions (PLEs, depressive and negative experiences), and between frequency and distress scores. Factors associated with a higher risk for more frequent and distressing PLEs include: urban setting, family history of psychiatric illnesses, and higher impact from previous traumatic events at present. CONCLUSIONS: Episodes of PLEs are common in Chinese adolescents, however only a small proportion have persistent PLEs, with worsening distress as the frequency increased. PLEs shared similar environmental and genetic risk factors not only with the clinical phenotypes, which is consistent with the continuity model of PLEs, but also with depressive and negative experiences, which may imply etiologic relation between different dimensions of psychosis at the subclinical level. PMID- 26051789 TI - Protective Role of Selenium Compounds on the Proliferation, Apoptosis, and Angiogenesis of a Canine Breast Cancer Cell Line. AB - We herein examined the effects of different doses, forms, and compatibilities of selenium on a canine mammary gland tumor cell line, CTM1211, and explored the related mechanisms. Three selenium compounds, sodium selenite (SSE), methylseleninic acid (MSA), and methylselenocysteine (MSC), were selected for these experiments, and cyclophosphamide (CTX) served as a positive control. In the cell viability assay, the cell viability of each group at 48/72 h decreased significantly compared with the control group (p < 0.05), and the cell viability of the CTX + MSA group was lower than that of CTX and MSA groups (p < 0.05). Moreover, the inhibitory effect of selenium on cell proliferation was time dependent but not concentration-dependent. In the cell apoptosis assay, the apoptosis values of each group increased significantly compared with the control group, and the apoptosis values of the CTX + MSA group increased the most significantly (p < 0.01). The protein and mRNA expression levels of vascular endothelial growth factor-alpha (VEGF-alpha), angiopoietin-2 (Ang-2), and hypoxia inducible factor-1 alpha (HIF-1 alpha) were downregulated in each group, while that of phosphatase and tensin homolog (PTEN) were upregulated (p < 0.05). In conclusion, these three selenium compounds, especially MSA, could significantly inhibit the viability and growth of the CTM1211 cell line, which is partly due to the induction of apoptosis and regulation of tumor angiogenesis. PMID- 26051790 TI - Relative prolactin-to-progesterone concentrations around farrowing influence colostrum yield in primiparous sows. AB - In swine, colostrum production is induced by the drop of progesterone (P4) concentrations which leads to the prepartum peak of prolactin (PRL). PRL regulates mammary cell turnover and stimulates lacteal nutrient synthesis. P4 inhibits PRL secretion and downregulates the PRL receptor in the mammary gland. The aim of the present study was to determine if the relative prepartum concentrations of P4 and PRL (PRL/P4 ratio) influence sow colostrum production. The performance of 29 Landrace * Large White primiparous sows was analyzed. Colostrum yield was estimated during 24 h starting at the onset of parturition (T0) using litter weight gains. Colostrum was collected at T0 and 24 h later (T24). Repeated jugular blood samples were collected during the peripartum period, that is, from -72 to +24 h related to farrowing and were assayed for P4 and PRL. Sows were retrospectively categorized in 2 groups according to their PRL/P4 ratio 24 h before farrowing being either <2 (low PRL/P4, n = 16) or >3 (high PRL/P4, n = 13). During the peripartum period, the circulating concentrations of P4 were lower (P < 0.05) and those of PRL tended to be greater (P < 0.10) in high PRL/P4 compared with low PRL/P4 sows. Colostrum yield was greater in high PRL/P4 compared with low PRL/P4 sows (4.11 vs 3.48 kg [root mean square error = 0.69], P < 0.05). Colostrum composition (dry matter, energy, protein, lipid, and lactose contents) and IgG and IgA concentrations did not differ between the 2 groups of sows (P > 0.10). The Na/K ratio in colostrum 24 h after the onset of farrowing was lower in high PRL/P4 compared with low PRL/P4 sows (P < 0.05). Piglet mortality between birth and T24 averaged 10.0% in low PRL/P4 litters and 7.0% in high PRL/P4 litters (P = 0.29). In conclusion, a greater PRL/P4 ratio 24 h prepartum, characterized by lower P4 concentrations and a trend for greater PRL concentrations peripartum, led to increased colostrum yield in primiparous sows. PMID- 26051791 TI - Role of the serotonergic axis in the reproductive failure associated with aging broiler breeder roosters. AB - Reproductive failure associated with aging is a well-known phenomenon. However, the mechanism by which this failure occurs in broiler breeder roosters is still unclear. A previous study conducted in our laboratory, comparing young and aging broiler breeder roosters, demonstrated an elevation in hypothalamic vasoactive intestinal peptide (VIP) and pituitary prolactin (PRL) gene expression accompanied by a deterioration of gonadal axis function. This resulted in a decrease in semen-quality variables as roosters aged. The objective of this study was to examine the involvement of the serotonergic axis in the age-associated reproductive failure in broiler breeder roosters. Cobb roosters aged 64 wk were divided into 3 groups (n = 20 each): parachlorophenylalanine (PCPA) administration, active immunization against chicken VIP, and controls. At 69 wk of age, each group was divided into 2 equal subgroups: 1 received ovine PRL and the other served as controls. Weekly semen volume, concentration and motility, and plasma testosterone, estradiol, and PRL concentrations were examined. At the end of the experiment, roosters were euthanized, testes were weighed, and hypothalamus and pituitary were removed to assay the expression of genes encoding hypothalamic GnRH-I, pituitary FSH, pituitary LH, hypothalamic VIP, and pituitary PRL. Both PCPA administration and active immunization against chicken VIP significantly increased testis weight, semen volume, sperm concentration, ejaculation grade, plasma testosterone level, and GnRH-I, FSH and LH gene expression compared with controls (P <= 0.05). In addition, a decrease in plasma estradiol and PRL concentrations and VIP and PRL gene expression was observed in PCPA- and VIP-immunized birds compared with controls (P <= 0.05). Administration of PRL in all groups decreased gonadal axis function and semen-quality variables (P <= 0.05). Collectively, these results suggest that the increasing expression levels of the serotonergic axis in aging broiler breeder roosters inhibit proper gonadal function and reproductive performance. This article establishes for the first time the inhibitory role of serotonin on reproduction in aging roosters. PMID- 26051792 TI - IL-33 and Thymic Stromal Lymphopoietin in mast cell functions. AB - Thymic Stromal Lymphopoietin (TSLP) and Interleukin 33 (IL-33) are two cytokines released by cells that are in proximity to our environment, e.g., keratinocytes of the skin and epithelial cells of the airways. Pathogens, allergens, chemicals and other agents induce the release of TSLP and IL-33, which are recognized by mast cells. TSLP and IL-33 affect several mast cell functions, including growth, survival and mediator release. These molecules do not directly induce exocytosis, but cause release of de novo synthesized lipid mediators and cytokines. TSLP and IL-33 are also implicated in inflammatory diseases where mast cells are known to be an important part of the pathogenesis, e.g., asthma and atopic dermatitis. In this chapter we describe and discuss the implications of TSLP and IL-33 on mast cell functions in health and disease. PMID- 26051793 TI - Demystifying reflective practice: Using the DATA model to enhance evaluators' professional activities. AB - Reflective practice (RP), one of six essential competency domains in evaluation identified by Stevahn, King, Ghere, and Minnema (2005), refers to thinking critically about one's evaluation practice, alone or with other people, and using critical insights to improve one's practice. Currently, evaluators have minimal guidance in navigating this essential professional competency, professed to be a necessary part of their practice. This article focuses on how RP can serve as a tool for evaluators through the use of the "DATA" integrated RP framework, developed by Peters (1991, 2009). DATA is an acronym with each letter standing for a different step in the process of reflective practice. The "D" step of the acronym focuses on (D)escribing what is or has been happening in practice. The "A" step refers to (A)nalyzing the current state of practice-why is this happening the way it is? The "T" concentrates on a practice-oriented form of (T)heorizing, which comes from analysis and serves as a basis for the resulting (A)ct. The last "A" focuses on the specifics of an action plan to change one's evaluation practice in light of the practical theory developed through theorizing. This paper describes the DATA model and introduces the application of the framework in a practice context. PMID- 26051794 TI - Evaluation of photosynthetic electrons derivation by exogenous redox mediators. AB - Oxygenic photosynthesis is the complex process that occurs in plants or algae by which the energy from the sun is converted into an electrochemical potential that drives the assimilation of carbon dioxide and the synthesis of carbohydrates. Quinones belong to a family of species commonly found in key processes of the Living, like photosynthesis or respiration, in which they act as electron transporters. This makes this class of molecules a popular candidate for biofuel cell and bioenergy applications insofar as they can be used as cargo to ship electrons to an electrode immersed in the cellular suspension. Nevertheless, such electron carriers are mostly selected empirically. This is why we report on a method involving fluorescence measurements to estimate the ability of seven different quinones to accept photosynthetic electrons downstream of photosystem II, the first protein complex in the light-dependent reactions of oxygenic photosynthesis. To this aim we use a mutant of Chlamydomonas reinhardtii, a unicellular green alga, impaired in electron downstream of photosystem II and assess the ability of quinones to restore electron flow by fluorescence. In this work, we defined and extracted a "derivation parameter" D that indicates the derivation efficiency of the exogenous quinones investigated. D then allows electing 2,6-dichlorobenzoquinone, 2,5-dichlorobenzoquinone and p phenylbenzoquinone as good candidates. More particularly, our investigations suggested that other key parameters like the partition of quinones between different cellular compartments and their propensity to saturate these various compartments should also be taken into account in the process of selecting exogenous quinones for the purpose of deriving photoelectrons from intact algae. PMID- 26051795 TI - The changing role of axillary treatment in breast cancer: Who will remain at risk for developing arm morbidity in the future? AB - Primary aim is to give an overview of changes in axillary staging and treatment of breast cancer patients. Secondly, we aim to identify patients with a high arm/shoulder morbidity risk, and describe a strategy to improve early detection and treatment. Recent and initiated studies on axillary staging and treatment were evaluated and clustered for clinically node negative and clinically node positive breast cancer patients, together with studies on pathology, detection and (surgical) prevention and treatment of lymphedema. For clinically node negative patients, the indication for axillary lymph node dissection in sentinel node positive patients is fading. On the contrary, clinically node positive patients are routinely subjected to an axillary lymph node dissection, in combination with other therapies associated with an increased lymphedema risk, such as mastectomy, adjuvant radiation- and (taxane-based) chemotherapy. Techniques for prevention, early detection and (surgical) treatment of lymphedema are being developed. Axillary staging and treatment in breast cancer patients with a clinically node negative status will become less invasive, thereby reducing the incidence of morbidity. Nevertheless, in patients with a clinically node positive status, aggressive treatment will still be required for oncologic control. For these patients, a surveillance program should be implemented in order to apply (curative) surgical treatment for lymphedema. PMID- 26051796 TI - Challenges associated with recruiting multigenerational, multicultural families into a randomised controlled trial: Balancing feasibility with validity. AB - Recruitment of participants into research studies has become an increasingly difficult task with justifiable criticisms of representativeness of samples. The difficulties of recruitment are exacerbated when the study is longitudinal, requires multiple members from one family and incorporates people from non dominant ethnic backgrounds. This paper describes a complex trial's recruitment process. Family groups were required for a longitudinal randomised controlled trial investigating links between health and dietary behaviours with an aim to improve primary prevention health messages and initiatives. To be representative of the multi-ethnic composition of the South Australian population, families from three of South Australia's largest ethnic backgrounds were invited to participate. Of these, only families with participating members spanning three generations were enrolled, so that links between health and lifestyle behaviours with possible generational ties could be investigated. Immense difficulties were faced during recruitment and significant modifications to the initial recruitment plan were necessary to enable the enrolment of 96 families. Challenges faced included lack of response to recruitment materials displaying complex eligibility criteria and different response outcomes from different communities. Solutions implemented included simplifying materials and tailoring recruitment activities to specific communities' needs. This trial's recruitment journey will be used as a case study to highlight the practicalities of recruiting for complex trials. Recommendations will be provided for future researchers seeking to recruit multigenerational, multi-ethnic families into the same study, along with issues to consider regarding the implications of the recruitment journey on the integrity of a complex trial and the potential threats to internal validity. PMID- 26051797 TI - Evaluation of lymphocytes inactivation by extracorporeal photopheresis using tetrazolium salt based-assay. AB - Extracorporeal photopheresis (ECP) is accepted as a second-line therapy for the treatment of acute and chronic steroid-refractory graft versus host disease (GvHD), cutaneous T-cell lymphoma and solid organ transplantation. ECP should be validated: we compared in parallel apoptosis and proliferation analysis of patient lymphocytes treated with 8-MOP ECP using respectively Annexin V/7 aminoactinomycin D (7-AAD) and CFSE with a tetrazolium salt (WST-1) method. Using WST-1 assay we found a significant decrement (p < 0.01) of metabolic activity at 4 days between ECP-treated and untreated cells. This finding was confirmed by the significant decrease of cell proliferation and increase of cell death observed by CFSE and 7AAD-Annexin V, respectively. Accordingly, once validated against a reference method, WST-1 could represent a rapid and easy assay for routinely quality control of ECP. PMID- 26051798 TI - Heat conduction in double-walled carbon nanotubes with intertube additional carbon atoms. AB - Heat conduction of double-walled carbon nanotubes (DWCNTs) with intertube additional carbon atoms was investigated for the first time using a molecular dynamics method. By analyzing the phonon vibrational density of states (VDOS), we revealed that the intertube additional atoms weak the heat conduction along the tube axis. Moreover, the phonon participation ratio (PR) demonstrates that the heat transfer in DWCNTs is dominated by low frequency modes. The added atoms cause the mode weight factor (MWF) of the outer tube to decrease and that of the inner tube to increase, which implies a lower thermal conductivity. The effects of temperature, tube length, and the number and distribution of added atoms were studied. Furthermore, an orthogonal array testing strategy was designed to identify the most important structural factor. It is indicated that the tendencies of thermal conductivity of DWCNTs with added atoms change with temperature and length are similar to bare ones. In addition, thermal conductivity decreases with the increasing number of added atoms, more evidently for atom addition concentrated at some cross-sections rather than uniform addition along the tube length. Simultaneously, the number of added atoms at each cross-section has a considerably more remarkable impact, compared to the tube length and the density of chosen cross-sections to add atoms. PMID- 26051799 TI - Microbiology and antibiotic resistance in severe burns patients: A 5 year review in an adult burns unit. AB - BACKGROUND: Infections are a major problem in burns patients. Knowledge of the incidence and antimicrobial sensitivities of the microorganisms commonly encountered within each institution's burns unit is important as it informs and directs empiric antibiotic therapy. METHODS: This was a retrospective review of patients admitted from 1 January 2008 to 31 December 2012 to an adult burns intensive care unit. Specimens chosen for analysis were wound swabs, blood cultures, venous catheter tips, tracheal aspirates, sputum, urine and wound tissue. Records were accessed from the admission register and laboratory information system to obtain the relevant data. RESULTS: During the study period, 352 patients were admitted to the adult burns intensive care unit, of which, 341 patients were included. The mortality rate was 44.6%. Flame burns were the commonest. Mortality rate amongst patients with bacteremia was 46.9%. Acinetobacter baumannii, Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus (MRSA) were found to be the most common organisms cultured in most specimens. CONCLUSION: The main three organisms identified in specimen cultures in our adult burns intensive care unit were A. baumannii, P. aeruginosa and MRSA. This study has helped establish a better empiric approach to the management of our septic burns patients. PMID- 26051800 TI - Fibulin-2 is a key mediator of the pro-neurogenic effect of TGF-beta1 on adult neural stem cells. AB - Transforming growth factor beta 1 (TGF-beta1), an anti-inflammatory cytokine, has been shown to have pro-neurogenic effects on adult Neural Stem Cells (aNSC) from the dentate gyrus and in vivo models. Here, we expanded the observation of the pro-neurogenic effect of TGF-beta1 on aNSC from the subventricular zone (SVZ) of adult rats and performed a functional genomic analysis to identify candidate genes to mediate its effect. 10 candidate genes were identified by microarray analysis and further validated by qRT-PCR. Of these, Fibulin-2 was increased 477 fold and its inhibition by siRNA blocks TGF-beta1 pro-neurogenic effect. Curiously, Fibulin-2 was not expressed by aNSC but by a GFAP-positive population in the culture, suggesting an indirect mechanism of action. TGF-beta1 also induced Fibulin-2 in the SVZ in vivo. Interestingly, 5 out of the 10 candidate genes identified are known to interact with integrins, paving the way for exploring their functional role in adult neurogenesis. In conclusion, we have identified 10 genes with putative pro-neurogenic effects, 5 of them related to integrins and provided proof that Fibulin-2 is a major mediator of the pro neurogenic effects of TGF-beta1. These data should contribute to further exploring the molecular mechanism of adult neurogenesis of the genes identified and the involvement of the integrin pathway on adult neurogenesis. PMID- 26051801 TI - Decrease in catalytic capacity of gamma-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease can be a result of an age-induced disparity between increase in cellular metabolism of Abeta peptides and decrease in maximal activity of a membrane-embedded protease gamma-secretase. RESULTS: We compared activity of WT gamma-secretase with the activity of 6 FAD mutants in its presenilin-1 component and 5 FAD mutants in Abeta-part of its APP substrate (Familial Alzheimer's disease). All 11 FAD mutations show linear correlation between the decrease in maximal activity and the clinically observed age-of-onset and age-of-death. Biphasic-inhibitors showed that a higher ratio between physiological Abeta-production and the maximal activity of gamma-secretase can be observed in cells that can facilitate pathogenic changes in Abeta-products. For example, Abeta production in cells with WT gamma-secretase is at 11% of its maximal activity, with delta-exon-9 mutant at 26%, while with M139V mutant is at 28% of the maximal activity. In the same conditions, G384A mutant is fully saturated and at its maximal activity. Similarly, Abeta production in cells with gamma-secretase complex carrying Aph1AL component is 12% of its maximal activity, while in cells with Aph1B complex is 26% of its maximal activity. Similar to the cell-based studies, clinical studies of biphasic dose-response in plasma samples of 54 healthy individuals showed variable ratios between physiological Abeta production and the maximal activity of gamma-secretase. CONCLUSIONS: The increase in the ratio between physiological Abeta production and maximal activity of gamma secretase can be an early sign of pathogenic processes in enzyme-based, cell based, and clinical studies of sporadic and Familiar Alzheimer's disease. PMID- 26051802 TI - Is supplemental external beam radiation therapy necessary for patients with higher risk prostate cancer treated with 103Pd? Results of two prospective randomized trials. AB - PURPOSE: To determine the necessity and/or dose of supplemental external beam radiotherapy (EBRT) in conjunction with palladium-103 ((103)Pd) brachytherapy for high-risk prostate cancer patients. METHODS AND MATERIALS: Trial 44/20 randomized patients to 44 Gy plus 90 Gy (103)Pd vs. 20 Gy with 115 Gy (103)Pd, and the subsequent trial randomized patients to the 20 Gy arm vs. 125 Gy (103)Pd without EBRT (20/0 trial). Eligibility criteria included clinically organ-confined disease with Gleason scores 7-9 and/or a pretreatment prostate-specific antigen (PSA) 10-20 ng/mL. The brachytherapy prescription dose was prescribed to the prostate gland with generous periprostatic margins. Biochemical failure (BF) was defined as a PSA >0.40 ng/mL after nadir. Median Day 0 minimum dose covering 90% of the prostate volume (D90) was >121.0% of the prescription dose. Multiple parameters were evaluated for effect on outcomes. RESULTS: In 44/20 trial, 13 year BF, prostate cancer-specific mortality (PCSM), and overall mortality (OM) were 8.2%, 4.0%, and 42.8% vs. 8.0%, 1.0%. and 40.3% for the 44 and 20 Gy arms. In 20/0 trial, 8-year BF, PCSM, and OM were 2.1%, 0%, and 14.4% vs. 3.6%, 0%, and 16.1% in the 20 vs. 0 Gy arms. When stratified by either pretreatment PSA or by Gleason score, supplemental EBRT dose did not impact BF, PCSM, or OM. In multivariate analysis, BF was most closely related to percent positive biopsies and prostate volume. In both trials, patients with biochemically controlled disease had a median PSA of <0.02 ng/mL. CONCLUSIONS: With high-quality brachytherapy dose distributions, supplemental EBRT did not influence BF or PCSM for patients with intermediate-risk disease. The number of patients with Gleason score 8-9 was too small to determine the role of supplemental EBRT in that cohort. PMID- 26051803 TI - Assessing changes to the brachytherapy target for cervical cancer using a single MRI and serial ultrasound. AB - PURPOSE: To assess changes to the brachytherapy target over the course of treatment and the impact of these changes on planning and resources. METHODS AND MATERIALS: Patients undergoing curative treatment with radiotherapy between January 2007 and March 2012 were included in the study. Intrauterine applicators were positioned in the uterine canal while patients were under anesthesia. Images were obtained by MRI and ultrasound at Fraction 1 and ultrasound alone at Fractions 2, 3, and 4. Cervix and uterine dimensions were measured on MRI and ultrasound and compared using Bland-Altman plots and repeated measures one-way analysis of variance. RESULTS: Of 192 patients who underwent three fractions of brachytherapy, 141 of them received four fractions. Mean differences and standard error of differences between MRI at Fraction 1 and ultrasound at Fraction 4 for anterior cervix measurements were 2.9 (0.31), 3.5 (0.25), and 4.2 (0.27) mm and for posterior cervix 0.8 (0.3), 0.3 (0.3), and 0.9 (0.3) mm. All differences were within clinically acceptable limits. The mean differences in the cervix over the course of brachytherapy were less than 1 mm at all measurement points on the posterior surface. Replanning occurred in 11 of 192 (5.7%) patients, although changes to the cervix dimensions were not outside clinical limits. CONCLUSIONS: There were small changes to the cervix and uterus over the course of brachytherapy that were not clinically significant. Use of intraoperative ultrasound as a verification aid accurately assesses the target at each insertion, reduces uncertainties in treatment delivery, and improves efficiency of the procedure benefiting both the patient and staff. PMID- 26051804 TI - Prescribing to tumor apex in episcleral plaque iodine-125 brachytherapy for medium-sized choroidal melanoma: A single-institutional retrospective review. AB - PURPOSE: To report an institutional experience with episcleral plaque brachytherapy for medium-sized uveal melanoma. Variations in prescription dose point and dose rate were compared with Collaborative Ocular Melanoma Study (COMS) Group. METHODS AND MATERIALS: A retrospective review was performed for 116 patients treated with iodine-125 plaque brachytherapy. About 85 Gy was prescribed to either the tumor apex (108 patients) or at 5 mm (8 patients) with dose rate ranging from 50.6 to 98.2 cGy/h. Patients were followed up for local tumor control, eye preservation, and vision retention. Dose and dose rate to tumor and sensitive structures were calculated. Multivariate and univariate analyses were performed to investigate correlation between clinical outcomes and dose/dose rate variables. RESULTS: Patients in this study were slightly older with worse visual acuity at baseline, but tumor size and position and ratio of ciliary body involvement were comparable to COMS population. Outcomes data were comparable to COMS: 95.3% local tumor control at 5 years and 77.7% vision preservation at 3 years. Only 4 patients needed enucleation because of tumor growth. Significant correlation was found between enucleation and tumor height and maximal scleral dose/dose rate as well as vision retention and tumor height and macula dose/dose rate. CONCLUSIONS: For tumors with <5 mm height, prescribing to tumor apex enabled to decrease dose to all sensitive structures without any loss of local control. Although dose rate was lowered to 50.6 cGy/h from the American Brachytherapy Society guidelines (60-105 cGy/h) because of limited availability of operating room (i.e., weekly), there was no difference in either local tumor control or complications. PMID- 26051805 TI - Irreducible superolateral dislocation of the glenohumeral joint. AB - The overwhelming majority of glenohumeral dislocations are anterior dislocations that either spontaneously reduce or are reduced at the point of care without significant complications. Posterior dislocations are uncommon, and superior and inferior dislocations are even rarer. We present a case of "superolateral" shoulder dislocation in which the entire rotator cuff was torn either off its insertion or at the musculotendinous junction in combination with a large longitudinal split tear of the deltoid muscle. This allowed the humeral head to dislocate both superiorly and laterally into a subcutaneous position through the tear of the anterolateral deltoid muscle with an associated de-gloving soft tissue lesion. Buttonholing of the humeral head through the deltoid and interposition of the dislocated long head of the biceps tendon and macerated rotator cuff prevented closed reduction of the glenohumeral joint. The resultant radiographic appearance and treatment of this dislocation is unique. To our knowledge, this is the first reported case of this dislocation in the literature. PMID- 26051806 TI - Normal spinous process metaphyseal-equivalent lucency simulating infant abuse fractures. AB - We report a normal radiographic finding that may be mistaken for child abuse trauma in the posterior thoracolumbar spinous processes of young infants after the first week of life. A lucency paralleling the posterior margin of the ossified spinous process is equivalent to the metaphyseal lucent bands seen normally after about a week of the child's age at the ends of long tubular bones. A similar lucency is seen just under the growth plate of vertebral bodies at that early age, giving the bone-in-bone appearance. Our index case was imaged at 3 weeks and then at 5 weeks of age, with no evidence of periosteal reaction or endosteal callus on that follow-up study, confirming the lack of fractures. PMID- 26051808 TI - A comparison of video review and feedback device measurement of chest compressions quality during pediatric cardiopulmonary resuscitation. AB - AIM: To describe chest compression (CC) rate, depth, and leaning during pediatric cardiopulmonary resuscitation (CPR) as measured by two simultaneous methods, and to assess the accuracy and reliability of video review in measuring CC quality. METHODS: Resuscitations in a pediatric emergency department are videorecorded for quality improvement. Patients aged 8-18 years receiving CPR under videorecording were eligible for inclusion. CPR was recorded by a pressure/accelerometer feedback device and tabulated in 30-s epochs of uninterrupted CC. Investigators reviewed videorecorded CPR and measured rate, depth, and release by observation. Raters categorized epochs as 'meeting criteria' if 80% of CCs in an epoch were done with appropriate depth (>45 mm) and/or release (<2.5 kg leaning). Comparison between device measurement and video was made by Spearman's rho for rate and by kappa statistic for depth and release. Interrater reliability for depth and release was measured by kappa statistic. RESULTS: Five patients underwent videorecorded CPR using the feedback device. 97 30-s epochs of CCs were analyzed. CCs met criteria for rate in 74/97 (76%) of epochs; depth in 38/97 (39%); release in 82/97 (84%). Agreement between video and feedback device for rate was good (rho = 0.77); agreement was poor for depth and release (kappa 0.04-0.41). Interrater reliability for depth and release measured by video was poor (kappa 0.04-0.49). CONCLUSION: Video review measured CC rate accurately; depth and release were not reliably or accurately assessed by video. Future research should focus on the optimal combination of methods for measuring CPR quality. PMID- 26051807 TI - A cationic gadolinium contrast agent for magnetic resonance imaging of cartilage. AB - A new cationic gadolinium contrast agent is reported for delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC). The agent partitions into the glycosaminoglycan rich matrix of articular cartilage, based on Donnan equilibrium theory, and its use enables imaging of the human cadaveric metacarpal phalangeal joint. PMID- 26051809 TI - Mechanical ventilation and resuscitation under water: Exploring one of the last undiscovered environments--A pilot study. AB - INTRODUCTION: Airway management, mechanical ventilation and resuscitation can be performed almost everywhere--even in space--but not under water. The present study assessed the technical feasibility of resuscitation under water in a manikin model. METHODS: Tracheal intubation was assessed in a hyperbaric chamber filled with water at 20 m of depth using the Pentax AWS S100 video laryngoscope, the FastrachTM intubating laryngeal mask and the Clarus optical stylet with guidance by a laryngeal mask airway (LMA) and without guidance. A closed suction system was used to remove water from the airways. A test lung was ventilated to a maximum depth of 50 m with a modified Oxylator((r)) EMX resuscitator with its expiratory port connected either to a demand valve or a diving regulator. Automated chest compressions were performed to a maximum depth of 50 m using the air-driven LUCASTM 1. RESULTS: The mean cumulative time span for airway management until the activation of the ventilator was 36 s for the FastrachTM, 57 s for the Pentax AWS S100, 53s for the LMA-guided stylet and 43 s for the stylet without LMA guidance. Complete suctioning of the water from the airways was not possible with the suction system used. The Oxylator((r)) connected to the demand valve ventilated at 50 m depth with a mean ventilation rate of 6.5 min(-1) vs. 14.7 min(-1) and minute volume of 4.5 l min(-1) vs. 7.6 l min(-1) compared to the surface. The rate of chest compression at 50 m was 228 min(-1) vs. 106 min(-1) compared to surface. The depth of compressions decreased with increasing depth. CONCLUSION: Airway management under water appears to be feasible in this manikin model. The suction system requires further modification. Mechanical ventilation at depth is possible but modifications of the Oxylator((r)) are required to stabilize ventilation rate and administered minute volumes. The LUCASTM 1 cannot be recommended at major depth. PMID- 26051810 TI - Clinical course and long-term outcome following venoarterial extracorporeal life support-facilitated interhospital transfer of patients with circulatory failure. AB - BACKGROUND: Interhospital transfer of patients experiencing circulatory failure and shock has a significant risk of cardiovascular deterioration and death. Extracorporeal life support (ECLS) is a rescue tool for hemodynamic stabilization that makes patient transportation much safer. METHODS: Demographic data, clinical course, and outcome data were reviewed for patients who underwent placement of a venoarterial ECLS in a remote hospital and were transported to our tertiary care facility. RESULTS: 68 patients were transported to our center with ECLS. The majority of these patients (79%) underwent cardiopulmonary resuscitation during or immediately prior to ECLS initiation. The mean patient age was 52 years, and 53 patients were male. The most common underlying diagnosis was acute coronary syndrome (60%). Overall, 23 patients underwent consecutive cardiosurgical procedures, including coronary artery bypass grafting in 12, and left ventricular assist device and biventricular assist device implantation in 11. The median duration of ECLS was 5 days. None of the patients died during transportation. Twelve of the surgically treated patients survived, as well as 21 patients with non-surgical treatment, which resulted in an overall survival of 33 patients (48.5%). CONCLUSION: ECLS-facilitated patient transfer enables safe interhospital transfer of critically ill patients. In this study, a relevant percentage of patients were in need of a cardiosurgical intervention. The long-term survival rate of these patients supports the further use of this time-, cost- and personnel-demanding strategy. PMID- 26051811 TI - Chest compression rate feedback based on transthoracic impedance. AB - BACKGROUND: Quality of cardiopulmonary resuscitation (CPR) is an important determinant of survival from cardiac arrest. The use of feedback devices is encouraged by current resuscitation guidelines as it helps rescuers to improve quality of CPR performance. AIM: To determine the feasibility of a generic algorithm for feedback related to chest compression (CC) rate using the transthoracic impedance (TTI) signal recorded through the defibrillation pads. METHODS: We analysed 180 episodes collected equally from three different emergency services, each one using a unique defibrillator model. The new algorithm computed the CC-rate every 2s by analysing the TTI signal in the frequency domain. The obtained CC-rate values were compared with the gold standard, computed using the compression force or the ECG and TTI signals when the force was not recorded. The accuracy of the CC-rate, the proportion of alarms of inadequate CC-rate, chest compression fraction (CCF) and the mean CC-rate per episode were calculated. RESULTS: Intervals with CCs were detected with a mean sensitivity and a mean positive predictive value per episode of 96.3% and 97.0%, respectively. Estimated CC-rate had an error below 10% in 95.8% of the time. Mean percentage of accurate alarms per episode was 98.2%. No statistical differences were found between the gold standard and the estimated values for any of the computed metrics. CONCLUSION: We developed an accurate algorithm to calculate and provide feedback on CC-rate using the TTI signal. This could be integrated into automated external defibrillators and help improve the quality of CPR in basic life-support settings. PMID- 26051812 TI - Can binary early warning scores perform as well as standard early warning scores for discriminating a patient's risk of cardiac arrest, death or unanticipated intensive care unit admission? AB - INTRODUCTION: Although the weightings to be summed in an early warning score (EWS) calculation are small, calculation and other errors occur frequently, potentially impacting on hospital efficiency and patient care. Use of a simpler EWS has the potential to reduce errors. METHODS: We truncated 36 published 'standard' EWSs so that, for each component, only two scores were possible: 0 when the standard EWS scored 0 and 1 when the standard EWS scored greater than 0. Using 1564,153 vital signs observation sets from 68,576 patient care episodes, we compared the discrimination (measured using the area under the receiver operator characteristic curve--AUROC) of each standard EWS and its truncated 'binary' equivalent. RESULTS: The binary EWSs had lower AUROCs than the standard EWSs in most cases, although for some the difference was not significant. One system, the binary form of the National Early Warning System (NEWS), had significantly better discrimination than all standard EWSs, except for NEWS. Overall, Binary NEWS at a trigger value of 3 would detect as many adverse outcomes as are detected by NEWS using a trigger of 5, but would require a 15% higher triggering rate. CONCLUSIONS: The performance of Binary NEWS is only exceeded by that of standard NEWS. It may be that Binary NEWS, as a simplified system, can be used with fewer errors. However, its introduction could lead to significant increases in workload for ward and rapid response team staff. The balance between fewer errors and a potentially greater workload needs further investigation. PMID- 26051813 TI - Evaluation of remote ischaemic post-conditioning in a pig model of cardiac arrest: A pilot study. AB - BACKGROUND: Remote ischaemic post-conditioning (RIPoC) in which transient episodes of ischaemia (e.g. by inflation and deflation of a blood pressure cuff) are applied after a prolonged ischaemia/reperfusion injury, may have the potential to improve patient outcome and survival following cardiac arrest. In this study we employed a pig model of cardiac arrest and successful cardiopulmonary resuscitation to evaluate the effects of RIPoC on haemodynamics, cardiac tissue damage and neurologic deficit. MATERIALS AND METHODS: A total of 22 pigs were subjected to ventricular fibrillation, cardiopulmonary resuscitation and randomly assigned to Control or RIPoC treatment consisting of 4 cycles of 5 min femoral artery occlusion followed by 5 min of reperfusion starting 10min after return of spontaneous circulation (ROSC). Post-resuscitation was evaluated by haemodynamics using left ventricular conductance catheters, quantification of cardiac troponin T (cTnT), lactate dehydrogenase (LDH) and creatine kinase (CK). Neurological testing was performed 24h after return of spontaneous circulation (ROSC). RESULTS: RIPoC resulted in a statistically significant reduction of serum cTnT levels 4h after ROSC (P <= 0.01). LDH and CK concentrations were significantly lower in RIPoC treated pigs 24h after ROSC (P <= 0.001), suggesting tissue and/or cardioprotective effects of RIPoC. End-systolic pressure volume relationship was significantly increased in RIPoC treated animals 4h after ROSC (P <= 0.05). Neurological testing revealed a trend towards an improved outcome in RIPoC treated animals. CONCLUSIONS: We propose that RIPoC applied immediately after ROSC reduces serum concentrations of markers for cell damage and improves end-systolic pressure volume relationship 4h after ROSC. PMID- 26051814 TI - Reply to Letter: Different methods are mixed up in the meta-analysis. PMID- 26051815 TI - First tetrazole-bridged d-f heterometallic MOFs with a large magnetic entropy change. AB - A novel 3D tetrazole-bridged 3d-4f heterometallic MOF {(H3O)3[Gd3Mn2(Trz)4].12H2O}n (1) with a hexanuclear [Gd6] cluster was obtained via in situ [2+3] cycloaddition reaction and structurally characterized, possessing good solvent and thermal stabilities, as well as a large magnetic entropy change -DeltaS(m) = 40.3 J kg(-1) K(-1) for DeltaH = 7 T at 2.0 K. To our knowledge, it is the first example of tetrazole-bridged 3d-4f heterometallic MOFs. PMID- 26051816 TI - Frontal alpha asymmetry as a pathway to behavioural withdrawal in depression: Research findings and issues. AB - Depression has been described as a process of behavioural withdrawal from overwhelming aversive stressors, and which manifests itself in the diagnostic symptomatology for Major Depressive Disorder (MDD). The underlying neurobiological pathways to that behavioural withdrawal are suggested to include greater activation in the right vs the left frontal lobes, described as frontal EEG asymmetry. However, despite a previous meta-analysis that provided overall support for this EEG asymmetry hypothesis, inconsistencies and several methodological confounds exist. The current review examines the literature on this issue, identifies inconsistencies in findings and discusses several key research issues that require addressing for this field to move towards a defensible theoretical model of depression and EEG asymmetry. In particular, the position of EEG asymmetry in the brain, measurement of severity and symptoms profiles of depression, and the effects of gender are considered as potential avenues to more accurately define the specific nature of the depression-EEG asymmetry association. PMID- 26051817 TI - Opioid-dependent regulation of high and low fear responses in two inbred mouse strains. AB - The molecular mechanisms underlying the susceptibility or resilience to trauma related disorders remain incompletely understood. Opioids modulate emotional learning, but the roles of specific receptors are unclear. Here, we aimed to analyze the contribution of the opioid system to fear responses in two inbred mouse strains exhibiting distinct behavioral phenotypes. SWR/J and C57BL/6J mice were subjected to five consecutive electric footshocks (1mA each), and the contextual freezing time was measured. Stress-induced alterations in gene expression were analyzed in the amygdala and the hippocampus. In both strains, the fear response was modulated using pharmacological tools. SWR/J mice did not develop conditioned fear but exhibited increased transcriptional expression of Pdyn and Penk in the amygdala region. Blocking opioid receptors prior to the footshocks using naltrexone (2 mg/kg) or naltrindole (5 mg/kg) increased the freezing responses in these animals. The C57BL/6J strain displayed high conditioned fear, although no alteration in the mRNA abundance of genes encoding opioid precursors was observed. Double-injection of morphine (20 mg/kg) following stress and upon context re-exposure prevented the enhancement of freezing. Moreover, selective delta and kappa agonists caused a reduction in conditioned fear responses. To summarize, the increased expression of the Pdyn and Penk genes corresponded to reduced intensity of fear responses. Blockade of the endogenous opioid system restored freezing behavior in stress-resistant animals. The pharmacological stimulation of the kappa and delta opioid receptors in stress susceptible individuals may alleviate fear. Thus, subtype-selective opioid receptor agonists may protect against the development of trauma-related disorders. PMID- 26051818 TI - Venlafaxine reverses decreased proliferation in the subventricular zone in a rat model of early life stress. AB - It is believed that glucocorticoids control the proliferation of neural progenitor cells, and this process is highly involved in mood disorders and cognitive processes. Using the maternal separation model of chronic neonatal stress, it has been found that stress induced depressive-like behavior, cognitive deficits and a decrease in proliferation in the subventricular zone (SVZ). Venlafaxine reversed all deleterious effects of chronic stress by modulating HPA activity. These outcomes suggest modulation of stress-mediated glucocorticoid secretion as a target for the treatment of mood disorders and neurodegenerative processes. PMID- 26051819 TI - Defect-enhanced void filling and novel filled phases of open-structure skutterudites. AB - We report the design of novel filled CoSb3 skutterudite phases based on a combination of filling and Sb-substituted Ga/In defects. Ga/In doped skutterudite phases with Li-, Nd-, and Sm-fillings can be formed via this strategy, which can have relatively wider ranges of carrier concentration than other conventional filled skutterudite phases. PMID- 26051820 TI - Parallel temporal dynamics in hierarchical cognitive control. AB - Cognitive control allows us to follow abstract rules in order to choose appropriate responses given our desired outcomes. Cognitive control is often conceptualized as a hierarchical decision process, wherein decisions made at higher, more abstract levels of control asymmetrically influence lower-level decisions. These influences could evolve sequentially across multiple levels of a hierarchical decision, consistent with much prior evidence for central bottlenecks and seriality in decision-making processes. However, here, we show that multiple levels of hierarchical cognitive control are processed primarily in parallel. Human participants selected responses to stimuli using a complex, multiply contingent (third order) rule structure. A response deadline procedure allowed assessment of the accuracy and timing of decisions made at each level of the hierarchy. In contrast to a serial decision process, error rates across levels of the decision mostly declined simultaneously and at identical rates, with only a slight tendency to complete the highest level decision first. Simulations with a biologically plausible neural network model demonstrate how such parallel processing could emerge from a previously developed hierarchically nested frontostriatal architecture. Our results support a parallel processing model of cognitive control, in which uncertainty on multiple levels of a decision is reduced simultaneously. PMID- 26051821 TI - Automatising the analysis of stochastic biochemical time-series. AB - BACKGROUND: Mathematical and computational modelling of biochemical systems has seen a lot of effort devoted to the definition and implementation of high performance mechanistic simulation frameworks. Within these frameworks it is possible to analyse complex models under a variety of configurations, eventually selecting the best setting of, e.g., parameters for a target system. MOTIVATION: This operational pipeline relies on the ability to interpret the predictions of a model, often represented as simulation time-series. Thus, an efficient data analysis pipeline is crucial to automatise time-series analyses, bearing in mind that errors in this phase might mislead the modeller's conclusions. RESULTS: For this reason we have developed an intuitive framework-independent Python tool to automate analyses common to a variety of modelling approaches. These include assessment of useful non-trivial statistics for simulation ensembles, e.g., estimation of master equations. Intuitive and domain-independent batch scripts will allow the researcher to automatically prepare reports, thus speeding up the usual model-definition, testing and refinement pipeline. PMID- 26051823 TI - Oxygenation and Ventilation. AB - Perioperative complications commonly include oxygenation and ventilation abnormalities. The best outcome is associated with prevention. Ventilation impairment may be due to either neurologic compromise such as cervical intervertebral disk disease or severe parenchymal disease, while oxygenation failure may result from either the underlying disease or severe complications such as aspiration pneumonia, volume overload, pulmonary thromboembolism, or acute respiratory distress syndrome. This article reviews the approach to the patient with perioperative complications and provides recommendations on the management approach. PMID- 26051822 TI - Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/beta catenin pathway during brain angiogenesis. AB - Despite the critical role of endothelial Wnt/beta-catenin signaling during central nervous system (CNS) vascularization, how endothelial cells sense and respond to specific Wnt ligands and what aspects of the multistep process of intra-cerebral blood vessel morphogenesis are controlled by these angiogenic signals remain poorly understood. We addressed these questions at single-cell resolution in zebrafish embryos. We identify the GPI-anchored MMP inhibitor Reck and the adhesion GPCR Gpr124 as integral components of a Wnt7a/Wnt7b-specific signaling complex required for brain angiogenesis and dorsal root ganglia neurogenesis. We further show that this atypical Wnt/beta-catenin signaling pathway selectively controls endothelial tip cell function and hence, that mosaic restoration of single wild-type tip cells in Wnt/beta-catenin-deficient perineural vessels is sufficient to initiate the formation of CNS vessels. Our results identify molecular determinants of ligand specificity of Wnt/beta-catenin signaling and provide evidence for organ-specific control of vascular invasion through tight modulation of tip cell function. PMID- 26051824 TI - The chewing gum controversy--time for a consensus? PMID- 26051825 TI - A posterior approach to cervical nerve root block and pulsed radiofrequency treatment for cervical radicular pain: a retrospective study. AB - BACKGROUND: Catastrophic complications have been reported for selective cervical nerve root block (SCNRB) or pulsed radiofrequency (PRF) via an anterolateral transforaminal approach. A posterior approach to these procedures under computed tomography guidance has been reported. Here, we report the clinical outcomes of 42 patients with chronic cervical radicular pain (CCRP) treated with a combination of SCNRB and PRF through a posterior approach under fluoroscopy guidance. METHODS: We retrospectively reviewed the clinical outcomes of 42 consecutive patients with CCRP who received a combination of SCNRB and PRF through a posterior approach under fluoroscopy guidance. The thresholds of electrical stimulation and imaging of the nerve roots after contrast injection were used to evaluate the accuracy of needle placement. The numeric rating scale was used to measure the pain and numbness levels as primary clinical outcomes, which were evaluate in scheduled follow-up visits of up to 3 months. RESULTS: A total of 53 procedures were performed on 42 patients at the levels of C5-C8. All patients reported concordant paresthesia in response to electrical stimulation. The average sensory and motor thresholds of stimulation were 0.28 +/- 0.14 and 0.36 +/- 0.14 V, respectively. Injection of nonionic contrast resulted in excellent spread along the target nerve root in large majority of the procedures. The numeric rating scale scores for both pain and numbness improved significantly at 1 day, 1 week, and 1 and 3 months after the treatment. No serious adverse effects were observed in any of the patients. CONCLUSIONS: The posterior approach to combined SCNRB and PRF under fluoroscopy guidance appears to be safe and efficacious in the management of CCRP. PMID- 26051826 TI - Evaluation of coat uniformity and taste-masking efficiency of irregular-shaped drug particles coated in a modified tangential spray fluidized bed processor. AB - OBJECTIVE: To explore the feasibility of coating irregular-shaped drug particles in a modified tangential spray fluidized bed processor (FS processor) and evaluate the coated particles for their coat uniformity and taste-masking efficiency. METHODS: Paracetamol particles were coated to 20%, w/w weight gain using a taste-masking polymer insoluble in neutral and basic pH but soluble in acidic pH. In-process samples (5, 10 and 15%, w/w coat) and the resultant coated particles (20%, w/w coat) were collected to monitor the changes in their physicochemical attributes. RESULTS: After coating to 20%, w/w coat weight gain, the usable yield was 81% with minimal agglomeration (< 5%). Some aerodynamic modifications to particle shape and surface morphology were observed for the in process samples with 5 and 10% coat compared with the uncoated particles. A 15%, w/w coat was optimal for inhibiting drug release in salivary pH with subsequent fast dissolution in simulated gastric pH. CONCLUSION: The FS processor shows promise for direct coating of irregular-shaped drug particles with wide size distribution. The coated particles with 15% coat were sufficiently taste masked and could be useful for further application in orally disintegrating tablet platforms. PMID- 26051827 TI - Ultrastructural localization of NADPH diaphorase and nitric oxide synthase in the neuropils of the snail CNS. AB - Comparative studies on the nervous system revealed that nitric oxide (NO) retains its function through the evolution. In vertebrates NO can act in different ways: it is released solely or as a co-transmitter, released from presynaptic or postsynaptic site, spreads as a volumetric signal or targets synaptic proteins. In invertebrates, however, the possible sites of NO release have not yet been identified. Therefore, in the present study, the subcellular distribution of the NO synthase (NOS) was examined in the central nervous system (CNS) of two gastropod species, the terrestrial snail, Helix pomatia and the pond snail, Lymnaea stagnalis, which are model species in comparative neurobiology. For the visualization of NOS NADPH-diaphorase histochemistry and an immunohistochemical procedure using a universal anti-NOS antibody were applied. At light microscopic level both techniques labeled identical structures in sensory tracts ramifying in the neuropils of central ganglia and cell bodies of the Lymnaea and Helix CNS. At ultrastructural level NADPH-d reactive/NOS-immunoreactive materials were localized on the nuclear envelope and membrane segments of the rough and smooth endoplasmic reticulum, as well as the cell membrane and axolemma of positive perikarya. NADPH-d reactive and NOS-immunoreactive varicosities connected to neighboring neurons with both unspecialized and specialized synaptic contacts. In the varicosities, the majority of the NADPH-d reactive/NOS-immunoreactive membrane segments were detected in round and pleomorph agranular vesicles of small size (50-200 nm). However, only a small portion (16%) of the vesicles displayed the NADPH-d reactivity/NOS-immunoreactivity. No evidence for the postsynaptic location of NOS was found. Our results suggest that the localization of NADPH-diaphorase and NOS is identical in the snail nervous system. In contrast to vertebrates, however, NO seems to act exclusively in an anterograde way possibly released from membrane segments of the presynaptic transmitter vesicle surface. Based on the subcellular distribution of NOS, NO could be both a volume and a synaptic mediator, in addition NO may function as a co-transmitter. PMID- 26051828 TI - Diagnostic/therapeutic management of pancreatic neuroendocrine tumours associated with MEN 1 syndrome. PMID- 26051829 TI - Outcomes of liver transplant with donors over 70 years of age. AB - Organ shortage has forced transplant teams to progressively expand the acceptance of marginal donors. METHODS: We performed a comparative analysis of the post transplant evolution depending on donor age (group I: less than 70 years old (n=474) vs. group II: 70 or more years old [n=105]) over a 10 year period (2002 2011). RESULTS: Donors over 70 years old were similar to donors less than 70 years old in terms of ICU stay, gender, weight, laboratory results, and use of vasoactive drugs. However, the younger donor group presented with cardiac arrest more often (GI: 14 vs. GII: 3%, P=.005). There were no differences in initial poor function (GI: 6% vs. GII: 7,7%; P=.71), ICU stay (GI: 2.7+/-2 vs. GII: 3.3+/ 3.8, P=.46), hospital stay (GI: 13.5+/-10 vs. GII: 15.5+/-11, P=.1), or hospital mortality (GI: 5.3 vs. GII: 5.8%, P=.66) between receptors of more or less than 70 year old grafts. After a median follow up of 32 months, no differences were found in the incidence of biliary tract complications (GI: 17 vs. GII: 20%, P=.4) or vascular complications (GI: 11 vs. GII: 9%, P=.69). The actuarial 5 year survival was similar for both study groups (GI: 70 vs. GII: 76%, P=.54). CONCLUSIONS: In our experience, the use of grafts from donors older than 70 years, when other risk factors are avoided (cold ischemia, steatosis, sodium levels), does not worsen the results of liver transplantation on the short or long term. PMID- 26051830 TI - Xanthii fructus extract inhibits TNF-alpha/IFN-gamma-induced Th2-chemokines production via blockade of NF-kappaB, STAT1 and p38-MAPK activation in human epidermal keratinocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xanthii fructus (XF) is an herb widely used in medicine for the treatment of a variety of inflammatory pathologies. Chemokines are important mediators of cell migration, and thymus and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22) are well known typical inflammatory chemokines involved in atopic dermatitis (AD). However, the anti-inflammatory mechanisms of XF have not been elucidated in tumor necrosis factor (TNF)-alpha/interferon (IFN)-gamma-stimulated HaCaT cells. The purpose of this study was to investigate the effect of XF on TNF-alpha/IFN-gamma induced production of TARC/CCL17 and MDC/CCL22 in HaCaT cells. MATERIALS AND METHODS: HaCaT cells were stimulated by TNF-alpha/IFN-gamma in the presence of XF. TRAC/CCL17 and MDC/CCL22 productions were monitored by ELISA on the cell culture supernatant and by RT-PCR on total RNA extract. We use immunoblotting to analyze the effect of XF on activation of the NF-kappaB, STAT1 and MAPK pathways. RESULTS: Ethanol extract of XF (EXF) inhibited mRNA expression and production of TARC/CCL17 and MDC/CCL22 induced by TNF-alpha/IFN-gamma in a dose-dependent manner. It also significantly inhibited TNF-alpha/IFN-gamma-induced activation of NF-kappaB, STAT1 and p38-MAPK. Furthermore, we observed that p38-MAPK contributes to the inhibition of TNF-alpha/IFN-gamma-induced TARC/CCL17 and MDC/CCL22 production by blocking NF-kappaB and STAT1 activation in HaCaT cells. CONCLUSIONS: These results demonstrate that developing therapeutic applications XF for the prevention of inflammatory skin diseases are feasible. PMID- 26051831 TI - Antidiabetic effects of flavonoids from Sophora flavescens EtOAc extract in type 2 diabetic KK-ay mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bitter and cold Chinese medicines have been long used for the treatment for diabetes mellitus (DM) for thousands of years in China. The roots of Sophora flavescens Ait., one of bitter and cold Chinese medicines commonly used to remove lung heat have been used to counteract DM and exerted good clinical effects for diabetic patients in some folk hospitals in Fujian province, PR China. However, the corresponding active principles and antidiabetic mechanism of this Traditional Chinese Medicine remain unclear. Therefore, in this study, we aim at chemical profiling of the active principles, validating the potential antidiabetic effects of the active EtOAc extract (SF EtOAc) in vitro and in vivo, and elucidating its probable antidiabetic mechanism as well as evaluating its acute oral toxicity. MATERIALS AND METHODS: An off-line semi-preparative LC-NMR and LC-UV-ESI MS protocol was developed to determine the chemical principles of the active EtOAc extract rapidly and unambiguously. The effect of SF-EtOAc on the glucose transporter type 4 (GLUT4) translocation in L6 myotubes was examined. T2DM KK-Ay mice were induced by high-fat diet. SF-EtOAc was orally administration at the dose of 30, 60 and 120 mg/kg/d, for 21 days. Metformin was used as positive control. Body weight, plasma glucose, oral glucose tolerance test, serum insulin and blood-lipid indexes were measured. Phosphorylation of the AMP-activated protein kinase (AMPK) expression in liver was measured. RESULTS: We found that SF-EtOAc significantly improved oral glucose tolerance, increased serum high density lipoprotein cholesterol (HDL-C) and reduced body weight, blood glucose levels and other related blood-lipid indexes. Mechanistically, SF-EtOAc elevated phosphorylation of AMP-activated protein kinase (AMPK) and stimulated membrane translocation of GLUT4. Moreover, it was unveiled that oral median lethal dose (LD50) of SF-EtOAc was more than 7500 mg/kg, suggesting that SF-EtOAc was practically non-toxic for mice. CONCLUSIONS: SF-EtOAc improves glucose tolerance, reduces hyperglycemia and resumes insulin levels, at least in part, by activating GLUT4 translocation which may be modulated by AMPK pathway. According to the results of the present study, SF EtOAc possesses a potent antidiabetic activity and could be used as a safe remedy for the treatment of diabetes. PMID- 26051832 TI - Bioactivity-guided isolation of anti-hepatitis B virus active sesquiterpenoids from the traditional Chinese medicine: Rhizomes of Cyperus rotundus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The rhizome of Cyperus rotundus (C. rotundus) is a well-known traditional Chinese medicine to cure hepatitis in many formulae, but the active components responsible for hepatitis have not been elucidated. According to our bioassay on HepG2.2.15 cell line in vitro, the ethanol extract of C. rotundus demonstrated potent anti-HBV activity. This current study was designed to isolate and identify the anti-HBV active constituents from the rhizomes of C. rotundus. MATERIAL AND METHODS: Bioactivity and LC-MS guided fractionation on the extract of C. rotundus using various chromatographic techniques including open-column, Sephadex LH-20 and semi-preparative high performance liquid chromatography led to the isolation and identification of thirty-seven sesquiterpenoids. Structural elucidation of the isolates was carried out by extensive spectroscopic analyses (UV, IR, HRMS, 1D- and 2D -NMR). The anti HBV activity and cytotoxicity were evaluated on the HBV-transfected HepG2.2.15 cell line in vitro. The cytotoxicity effects of the isolates were assessed by a MTT assay. The secretions of HBsAg and HBeAg in the culture medium were detected by ELISA method, and the load of HBV DNA was quantified by real-time fluorescent PCR technique. RESULTS: Five new patchoulane-type sesquiterpenoids, namely cyperene-3, 8-dione (1), 14-hydroxy cyperotundone (2), 14-acetoxy cyperotundone (3), 3beta-hydroxycyperenoic acid (4) and sugetriol-3, 9-diacetate (5), along with 32 known sesquiterpenoids were isolated from the active fractions of C. rotundus. Compounds 2 and 3 were the first cyperotundone-type sesquiterpenoids with a hydroxyl group at C-14 position. Nine eudesmane-type sesquiterpenoids (15 21 and 23-24) significantly inhibited the HBV DNA replication with IC50 values of 42.7+/-5.9, 22.5+/-1.9, 13.2+/-1.2, 10.1+/-0.7, 14.1+/-1.1, 15.3+/-2.7, 13.8+/ 0.9, 19.7+/-2.1 and 11.9+/-0.6 MUM, respectively, of which, compounds 17, 21, 23 and 24 possessed high SI values of 250.4, 125.5,>259.6 and 127.5, respectively. Two patchoulane-type sesquiterpenoids (4 and 7) effectively suppressed the secretion of HBsAg in a dose-dependent manner with IC50 values of 46.6+/-14.3 (SI=31.0) and 77.2+/-13.0 (SI=1.7) MUM, respectively. Compounds 2, 8, 12, 15, 17 and 25 possessed moderate activities against HBeAg secretion with IC50 values of 162.5+/-18.9 (SI=13.3), 399.2+/-90.0 (SI=10.6), 274.7+/-70.8 (SI=5.2), 313.9+/ 87.5 (SI=7.2), 334.0+/-70.4 (SI=9.9) and 285.3+/-20.9 (SI=15.5) MUM, respectively. CONCLUSIONS: This is the first study to reveal the anti-HBV constituents of C. rotundus, demonstrating that the eudesmane-type sesquiterpenoids might contribute to the anti-HBV activity of the rhizomes of C. rotundus. PMID- 26051833 TI - Prescription patterns of Chinese herbal products for patients with uterine fibroid in Taiwan: A nationwide population-based study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Uterine fibroid (myoma) is one of the most common diseases in women. Although there are several studies on the efficacy of Chinese herbs, there is a lack of large-scale survey on the use of traditional Chinese medicine (TCM) for the treatment of uterine fibroid. This study aimed to investigate the utilization of Chinese herbal products for patients with uterine fibroid, prescribed by licensed TCM doctors in Taiwan. MATERIALS AND METHODS: A random sample comprised of one million individuals with newly diagnosed uterine fibroid between 2002 and 2010 from the Taiwanese National Health Insurance Research Database was analyzed. Demographic characteristics, TCM usage, the frequency as well as average daily dose of Chinese herbal formulas and the single herbs prescribed for patients with uterine fibroid, were analyzed. RESULTS: Overall, 35,786 newly diagnosed subjects with uterine fibroid were included. Majority of these patients (87.1%; n=31,161) had visited TCM clinics. Among them, 61.8% of their visits used Chinese herbal remedies. Patients less than 45 years of age tended to use TCM more frequently than elder patients. Gui-Zhi-Fu-Ling-Wan (Cinnamon Twig and Poria Pill) was the most frequently prescribed Chinese herbal formula, while San-Leng (Rhizoma Sparganii) was the most commonly prescribed single herb. CONCLUSIONS: Our study identified the characteristics and prescription patterns of TCM for patients with uterine fibroid in Taiwan. Further basic mechanistic studies and clinical trials are needed to confirm the therapeutic effects and mechanisms. PMID- 26051834 TI - Evaluation of vascular endothelial growth factor-A and Endostatin levels in induced sputum and relationship to bronchial hyperreactivity in patients with persistent allergic rhinitis monosensitized to house dust. AB - BACKGROUND: Studies about the pathogenesis of bronchial hyperreactivity (BHR) in patients with persistent allergic rhinitis (PAR) and its relationship with lower airway remodeling are extremely limited. OBJECTIVE: This study evaluated bronchial vascular remodeling via the measurement of angiogenic factor, vascular endothelial growth factor-A (VEGF-A), and anti-angiogenic factor, Endostatin, and evaluated their relationship with BHR in patients with PAR. METHODS: The study group consisted of 30 patients with PAR monosensitized to house dust mites and 14 non-allergic healthy controls. All subjects underwent induced sputum and methacholine (M) bronchial provocation tests. VEGF-A and Endostatin levels were measured by ELISA in induced sputum supernatants. RESULTS: The percentages of eosinophils in induced sputum were significantly increased in patients with PAR compared with healthy controls. There were no significant differences between patients with PAR and healthy controls in terms of levels of VEGF (37.9pg/ml, min max: 5-373pg/ml vs. 24.9, min-max: 8-67pg/ml, p=0.8 respectively), Endostatin (532.5pg/ml, min-max: 150-2125pg/ml vs. 644, min-max: 223-1123pg/ml, p=0.2 respectively) and VEGF/Endostatin ratio (0.057 vs. 0.045, p=0.8 respectively). In addition, there were no significant differences between patients who are BHR positive (n=8), or negative to M (n=22) in terms of levels of VEGF, Endostatin and VEGF/Endostatin ratio and no correlations among value of PD20 to M and levels of VEGF, Endostatin and VEGF/Endostatin ratio. CONCLUSION: We conclude that VEGF A and Endostatin did not differ between patients with PAR and healthy controls regardless of BHR to M. PMID- 26051835 TI - Salivary mucin MUC7 oligosaccharides in patients with recurrent aphthous stomatitis. AB - OBJECTIVES: The aetiology of recurrent aphthous stomatitis remains unknown. In this study, we investigate the composition of oligosaccharides from mucin MUC7 in recurrent aphthous stomatitis as these heavily O-glycosylated mucins confer many of saliva's protective properties such as defence against mucosal pathogens. MATERIALS AND METHODS: Unstimulated whole saliva samples were collected from six individuals, three with recurrent aphthous stomatitis and three corresponding sibling, without this condition. Oligosaccharides from salivary MUC7 were isolated and analysed by liquid chromatography-tandem mass spectrometry. RESULTS: The types of oligosaccharides identified in the patients and control subjects were similar; however, statistical evaluation indicated semi-quantitative differences between specific oligosaccharide classes. These changes focused on a reduction in terminal glycan residues including fucosylation, sialylation and sulfation on galactose. CONCLUSIONS: This study was able to show differential MUC7 glycosylation in the patients suggesting functional changes to salivary mucins in this condition. The terminal glycans altered in disease have been shown to be important for a range of immunological and bacterial binding roles. Further investigation of these epitopes in a larger study may provide critical insights into the pathology of recurrent aphthous stomatitis. CLINICAL RELEVANCE: MUC7 glycosylation is altered in recurrent aphthous stomatitis. This may change the protective properties of this mucin against mucosal pathogens, which may effect this condition. PMID- 26051836 TI - In vitro comparison of implant- versus gingiva-supported removable dentures in anterior and posterior applications. AB - OBJECTIVES: Removable dentures with different denture teeth may provide different performance and resistance in implant and gingival situations, or anterior and posterior applications. MATERIALS AND METHODS: Two situations of removable dentures were investigated: gingiva (flexible) and implant (rigid) bearing. For simulating the gingiva/jaw situation, the dentures were supported with flexible lining material. For the implant situation, implants (d = 4.1 mm) were screwed into polymethylenmethacrylate (PMMA) resin. Two commercial (Vita-Physiodens MRP, SR Vivodent/Orthotyp DCL) and two experimental materials (EXP1, EXP2) were investigated in anterior (A) and posterior (P) tooth locations. Chewing simulation was performed, and failures were analyzed (microscopy, SEM). Fracture strength of surviving dentures was determined. RESULTS: Only EXP1 revealed failures during chewing simulation. Failures varied between anterior and posterior locations, and between implant (P:4x; A:7x) or gingiva (P:1x; A:2x) situations. Kaplan-Meier log-rank test revealed significant differences for implant situations (p < 0.002), but not for gingiva bearing (p > 0.093). Fracture testing in the implant situation provided significantly highest values for EXP2 (1476.4 +/- 532.2 N) in posterior location, and for DCL (1575.4 +/- 264.4 N) and EXP2 (1797.0 +/- 604.2 N) in anterior location. For gingival bearing, significantly highest values were found for DCL/P (2148.3 +/- 836.3 N), and significantly lowest results for EXP1/A (308.2 +/- 115.6 N). For EXP1 + EXP2 + Vita/P and for EXP1/A no significant differences were found between implant- or gingiva-supported situations. CONCLUSIONS: Anterior and posterior teeth showed different material-dependent in vitro performance, further influenced by implant/gingiva bearing. While an implant in anterior application increased fracture strength of two materials, it decreased fracture values of 3/4 of the materials in posterior application. CLINICAL RELEVANCE: Survival of denture teeth may be influenced by material, oral position, and bearing situation. PMID- 26051837 TI - The German 19-item version of the Child Oral Health Impact Profile: translation and psychometric properties. AB - OBJECTIVES: This study seeks to develop and validate the 19-item German version of the Child Oral Health Impact Profile (COHIP-G19), an instrument to assess the oral health-related quality of life (OHRQoL) in children and adolescents. MATERIALS AND METHODS: The 19 items of the original English-language COHIP were translated into German using an established forward-backward approach. For the assessment of the psychometric properties of the COHIP-G19, children and adolescents aged 7-17 years came from two samples: 112 patients were consecutively recruited at a university-based orthodontic clinic and 313 came from a convenience sample of students in public schools. RESULTS: Internal consistency of the COHIP-G19 was satisfactory in both populations (Cronbach's alpha, 0.78/0.80; average inter-item correlation, 0.16/0.17). The COHIP-G19 summary scores were correlated in the expected direction with a global oral health rating (r = 0.46/0.40) and two measures for perceived general health (EQ 5D-Y: r = 0.26/0.29; KIDSCREEN-27: r = 0.40/0.33). While COHIP-G19 summary scores did not significantly differ with respect to the presence of caries or gingivitis (p > 0.05), malocclusion and insufficient oral hygiene behavior were related to more impaired OHRQoL, represented in significantly lower COHIP-G19 summary scores in students in public schools (p < 0.05), but not in orthodontic patients. CONCLUSIONS: While this study revealed some potential to improve reliability and validity in scores of the German version of the COHIP-19, overall, the study proved the instrument has sufficient psychometric properties and is well comparable to the original English-language version. CLINICAL RELEVANCE: The COHIP-G19 is a valid and reliable instrument to assess OHRQoL in German children and adolescents in clinical and community settings. PMID- 26051838 TI - Effective heritable gene knockdown in zebrafish using synthetic microRNAs. AB - Although zebrafish is used to model human diseases through mutational and morpholino-based knockdown approaches, there are currently no robust transgenic knockdown tools. Here we investigate the knockdown efficiency of three synthetic miRNA-expressing backbones and show that these constructs can downregulate a sensor transgene with different degrees of potency. Using this approach, we reproduce spinal muscular atrophy (SMA) in zebrafish by targeting the smn1 gene. We also generate different transgenic lines, with severity and age of onset correlated to the level of smn1 inhibition, recapitulating for the first time the different forms of SMA in zebrafish. These lines are proof-of-concept that miRNA based approaches can be used to generate potent heritable gene knockdown in zebrafish. PMID- 26051839 TI - The Impact of Tumor Diameter and Tumor Necrosis on Oncologic Outcomes in Patients With Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy. AB - OBJECTIVE: To evaluate the influence of tumor diameter and tumor necrosis on oncologic outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy (RC). MATERIALS AND METHODS: We treated 517 consecutive patients with urothelial carcinoma of the bladder treated with RC without neoadjuvant chemotherapy at our institution between 1996 and 2011. All RC specimens were meticulously re-reviewed for the largest residual tumor diameter and for the presence and extent of tumor necrosis. Cox regression models evaluated the association with disease recurrence and cancer-specific survival. RESULTS: At RC, 155 patients (30.0%) had a residual tumor diameter >=3 cm and tumor necrosis was present in 156 patients (30.2%). Tumor diameter and necrosis were significantly correlated (P <.001). Both a tumor diameter >=3 cm and the presence of tumor necrosis were associated with an older age, advanced tumor stage, higher tumor grade, lymph node metastasis, positive surgical margin status, lymphovascular invasion, and administration of adjuvant chemotherapy (P values <=.009). A tumor diameter >=3 cm and the presence of tumor necrosis were associated with disease recurrence and cancer-specific mortality in Kaplan-Meier analyses, respectively (pairwise P values <.001). In addition, a tumor diameter >=3 cm was an independent predictor of cancer-specific mortality in multivariate analysis that adjusted for standard clinicopathologic features. CONCLUSION: Tumor diameter and necrosis are closely correlated and associated with aggressive tumor features and inferior oncologic outcomes. A residual tumor diameter >=3 cm is an independent predictor of cancer-specific mortality. This additional information should be considered to be reported in every pathology report for consideration in patient counseling and treatment decision making. In addition, these results underscore the importance of a thorough transurethral resection of the bladder tumor before RC. PMID- 26051840 TI - Management of Bladder Diverticula in Menkes Syndrome: A Case Report and Review of the Literature. AB - Menkes syndrome is a genetic disorder of copper metabolism, often with urologic complications, including bladder diverticula and vesicoureteral reflux. A 1-year old boy with Menkes syndrome presented with recurrent urinary tract infections and incomplete bladder emptying secondary to 2 large bladder diverticula. He underwent robot-assisted excision of both diverticula with subsequent improved emptying and resolution of urinary tract infections. There is no consensus on management of bladder diverticula in Menkes syndrome. Because the life span of these patients is significantly shortened, one must select an intervention based on their clinical condition, potential morbidities, and informed expectations of the family. PMID- 26051841 TI - Delayed Presentation of Ureteropelvic Junction Obstruction and Loss of Renal Function After Initially Mild (SFU Grade 1-2) Hydronephrosis. AB - We report 4 pediatric cases of ureteropelvic junction obstruction involving delayed progression of initially mild postnatal hydronephrosis. All 4 children became symptomatic; however, 3 already had a substantial decrement of ipsilateral kidney function by the time of diagnosis. Two of these 3 patients had previous renal scintigraphy demonstrating normal differential function. We caution that counseling regarding hydronephrosis should emphasize the importance of prompt re evaluation for any symptoms potentially referable to delayed presentation of ureteropelvic junction obstruction, irrespective of initial hydronephrosis grade. Future studies are needed to determine the optimal follow-up regimen for conservative management of hydronephrosis. PMID- 26051842 TI - Alterations in microRNAs miR-21 and let-7a correlate with aberrant STAT3 signaling and downstream effects during cervical carcinogenesis. AB - BACKGROUND: Present study provides clinical evidence of existence of a functional loop involving miR-21 and let-7a as potential regulators of aberrant STAT3 signaling recently reported by our group in an experimental setup (Shishodia et al. BMC Cancer 2014, 14:996). The study is now extended to a set of cervical tissues that represent natural history of human papillomavirus (HPV)-induced tumorigenic transformation. MATERIALS AND METHODS: Cervical tissues from histopathologically-confirmed pre-cancer (23) and cancer lesions (56) along with the normal control tissues (23) were examined for their HPV infection status, expression level of miR-21 & let-7a and STAT3 & pSTAT3 (Y705) by PCR-based genotyping, quantitative real-time PCR and immunoblotting. RESULTS: Analysis of cancer tissues revealed an elevated miR-21 and reduced let-7a expression that correspond to the level of STAT3 signaling. While miR-21 showed direct association, let-7a expression was inversely related to STAT3 expression and its activation. In contrast, a similar reciprocal expression kinetics was absent in LSIL and HSIL tissues which overexpressed let-7a. miR-21 was found differentially overexpressed in HPV16-positive lesions with a higher oncoprotein E6 level. Overexpression of miR-21 was accompanied by elevated level of other STAT3 regulated gene products MMP-2 and MMP-9. Enhanced miR-21 was found associated with decreased level of STAT3 negative regulator PTEN and negative regulator of MMPs, TIMP-3. CONCLUSION: Overall, our study suggests that the microRNAs, miR-21 and let-7a function as clinically relevant integral components of STAT3 signaling and are responsible for maintaining activated state of STAT3 in HPV-infected cells during cervical carcinogenesis. PMID- 26051844 TI - A first-principles study on the magnetic properties of nonmetal atom doped phosphorene monolayers. AB - In order to induce magnetism in two-dimensional semiconductors for their applications in spintronic devices and novel chemical and electronic properties of semiconducting phosphorene, the geometrical structure, electronic and magnetic properties of doped phosphorene monolayers with a series of nonmetal atoms, including H, F, Cl, Br, I, B, C, Si, N, As, O, S and Se, were systematically investigated using first-principles calculations. The results show that although the substitutional doping of H, F, Cl, Br, I, B, N, O, S or Se results in large structural deformation at the doping sites of phosphorene monolayers, all neutral nonmetal atom doped systems are stable. The calculated formation energies reveal that the substitutional doping of numerous nonmetal atoms in phosphorene monolayer are possible under appropriate experimental conditions, and the charged dopants C(-), Si(-), S(+) and Se(+) are stable. Moreover, the substitutional doping of H, F, Cl, Br, I, B, N, As, C(-), Si(-), S(+) or Se(+) cannot induce magnetism in phosphorene monolayer due to the saturation or pairing of valence electrons of dopant and its neighboring P atoms, whereas ground states of neutral C, Si, O, S or Se doped systems are magnetic due to the appearance of an unpaired valence electron of C and Si or the formation of a nonbonding 3p electron of a neighboring P atom around O, S and Se. Furthermore, the magnetic coupling between the moments induced by two Si, O, S or Se are long-range anti-ferromagnetic and the coupling can be attributed to the hybridization interaction involving polarized electrons, whereas the coupling between the moments induced by two C is weak. PMID- 26051843 TI - Testing Eurasian wild boar piglets for serum antibodies against Mycobacterium bovis. AB - Animal tuberculosis (TB) caused by infection with Mycobacterium bovis and closely related members of the M. tuberculosis complex (MTC), is often reported in the Eurasian wild boar (Sus scrofa). Tests detecting antibodies against MTC antigens are valuable tools for TB monitoring and control in suids. However, only limited knowledge exists on serology test performance in 2-6 month-old piglets. In this age-class, recent infections might cause lower antibody levels and lower test sensitivity. We examined 126 wild boar piglets from a TB-endemic site using 6 antibody detection tests in order to assess test performance. Bacterial culture (n=53) yielded a M. bovis infection prevalence of 33.9%, while serum antibody prevalence estimated by different tests ranged from 19% to 38%, reaching sensitivities between 15.4% and 46.2% for plate ELISAs and between 61.5% and 69.2% for rapid immunochromatographic tests based on dual path platform (DPP) technology. The Cohen kappa coefficient of agreement between DPP WTB (Wildlife TB) assay and culture results was moderate (0.45) and all other serological tests used had poor to fair agreements. This survey revealed the ability of several tests for detecting serum antibodies against the MTC antigens in 2-6 month-old naturally infected wild boar piglets. The best performance was demonstrated for DPP tests. The results confirmed our initial hypothesis of a lower sensitivity of serology for detecting M. bovis-infected piglets, as compared to older wild boar. Certain tests, notably the rapid animal-side tests, can contribute to TB control strategies by enabling the setup of test and cull schemes or improving pre movement testing. However, sub-optimal test performance in piglets as compared to that in older wild boar should be taken into account. PMID- 26051845 TI - Stepwise synthesis and characterization of germa[4], [5], [8], and [10]pericyclynes. AB - The stepwise syntheses of germa[N]pericyclynes, including [5]pericyclynes, and their characterization are described. The yields of germa[4] and [8]pericyclynes were improved significantly compared to those obtained in previous studies. The routes reported herein afforded the novel germa[5] and [10]pericyclynes, which were characterized by X-ray crystallography, UV-Vis spectroscopy, and fluorescence emission spectroscopy. A unique fluorescence emission was observed for the large germa[10]pericyclyne ring. PMID- 26051846 TI - Evaluation of the effectiveness of three physiotherapeutic treatments for subacromial impingement syndrome: a randomised clinical trial. AB - OBJECTIVE: To determine whether dexketoprofen administered by phonophoresis or iontophoresis is more effective for the treatment of subacromial impingement syndrome (SIS) than conventional ultrasound therapy. DESIGN: Randomised clinical trial. SETTING: University hospital. PARTICIPANTS: Ninety-nine participants with SIS without a complete tear of the rotator cuff were assigned at random to three intervention groups. INTERVENTION GROUPS: Participants received ultrasound (n=32), phonophoresis with dexketoprofen (50mg/session) (n=33) or iontophoresis with dexketoprofen (50mg/session) (n=34). All participants completed 20 treatment sessions plus exercise therapy and cryotherapy. OUTCOME MEASURES: A visual analogue scale (VAS), the Constant-Murley Scale (CMS) and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire were administered pre-treatment (baseline), post-treatment and 1 month post-treatment. RESULTS: At baseline, there were no differences between the groups. Post-treatment, VAS score improved by -1.2 points and CMS score improved by 8.9 points in the ultrasound group compared with the iontophoresis group [95% confidence interval (CI) -0.2 to -2.2 and 95% CI 17.0 to 0.7, respectively]. CMS score improved by 7.1 points in the phonophoresis group compared with the iontophoresis group (95% CI 14.8 to -0.7). At 1 month post-treatment, no significant differences were detected between the groups. VAS, CMS and DASH scores of all groups improved post-treatment and at 1 month post-treatment. CONCLUSION: Ultrasound, iontophoresis with dexketoprofen and phonophoresis with dexketoprofen can improve pain, shoulder function, and physical functioning and symptoms in the upper limb in patients with SIS without a complete tear of the rotator cuff. CLINICAL TRIALS. GOV REGISTRATION NUMBER: NCT01748188. PMID- 26051847 TI - What is the role of the physiotherapist in paediatric intensive care units? A systematic review of the evidence for respiratory and rehabilitation interventions for mechanically ventilated patients. AB - BACKGROUND: Physiotherapy in intensive care units (ICU) has traditionally focussed on the respiratory management of mechanically ventilated patients. Gradually, focus has shifted to include rehabilitation in adult ICUs, though evidence of a similar shift in the paediatric ICU (PICU) is limited. OBJECTIVES: Review the evidence to determine the role of physiotherapists in the management of mechanically ventilated patients in PICU. DATA SOURCES: A search was conducted of: PEDro, CINAHL, Medline, PubMed and the Cochrane Library. ELIGIBILITY CRITERIA: Studies involving PICU patients who received physiotherapy while invasively ventilated were included in this review. Those involving neonatal or adult ICU patients, or patients on non-invasive or long-term ventilation, were not included in the study. STUDY APPRAISAL: All articles were critically appraised by two reviewers and results were analysed descriptively. RESULTS: Six studies on chest physiotherapy (CPT) met the selection criteria. Results support the use of the expiratory flow increase technique and CPT, especially manual hyperinflation and vibrations, for secretion clearance. Evidence does not support the routine use of either CPT or suction alone. No studies investigating rehabilitation in PICU met selection criteria. LIMITATIONS: A lack of high level evidence was available to inform this review. CONCLUSION: Evidence indicates that CPT is still the focus of physiotherapy intervention in PICU for mechanically ventilated patients, and supports its use for secretion clearance in this setting. PROSPERO register for systematic reviews (registration no. CRD42014009582). PMID- 26051848 TI - The formation of the foramen magnum and its role in developing ventriculomegaly and Chiari I malformation in children with craniosynostosis syndromes. AB - OBJECT: Craniosynostosis syndromes are characterized by prematurely fused skull sutures, however, less is known about skull base synchondroses. This study evaluates how foramen magnum (FM) size, and closure of its intra-occipital synchondroses (IOS) differ between patients with different craniosynostosis syndromes and control subjects; and whether this correlates to ventriculomegaly and/or Chiari malformation type I (CMI), intracranial disturbances often described in these patients. METHODS: Surface area and anterior-posterior (A-P) diameter were measured in 175 3D-CT scans of 113 craniosynostosis patients, and in 53 controls (0-10 years old). Scans were aligned in a 3D multiplane-platform. The frontal and occipital horn ratio was used as an indicator of ventricular volume, and the occurrence of CMI was recorded. Synchondroses were studied in scans with a slice thickness <=1.25 mm. A generalized linear mixed model and a repeated measures ordinal logistic regression model were used to study differences. RESULTS: At birth, patients with craniosynostosis syndromes have a smaller FM than controls (p < 0.05). This is not related to the presence of CMI (p = 0.36). In Crouzon-Pfeiffer patients the anterior and posterior IOS fused prematurely (p < 0.01), and in Apert patients only the posterior IOS fused prematurely (p = 0.028). CONCLUSION: The FM is smaller in patients with craniosynostosis syndromes than in controls, and is already smaller at birth. In addition to the timing of IOS closure, other factors may influence FM size. PMID- 26051849 TI - Mandibular condylar-ramal reconstruction using vascularised costochondral graft based on the serratus anterior composite flap. AB - BACKGROUND: Nonvascularised autogenous costochondral rib grafts are the gold standard for replacement of the mandibular ramus and condyle. However, condylar defects present a difficult condition to treat when soft tissue defects are involved. Thus, we used vascularised costochondral grafts (VCGs) with a cartilaginous cap based on the serratus anterior muscle flap to reconstruct these composite defects. The purpose of this study was to evaluate the advantages and effectiveness of VCGs based on long-term observation. METHODS: We evaluated 15 patients who underwent mandibular condyle and ramus reconstruction using VCG after a mean follow-up of 75.9 months (range 46-156 months). Our 15 case of mandibular reconstruction with a serratus anterior/rib composite free flap due to congenital or acquired defects involved a total of 18 condyles (bilateral reconstruction in 3 cases and unilateral reconstruction in 12 cases). RESULTS: Our success rate with the use of the serratus anterior/rib composite free flap was 100%, and there were no cases of resorption or malunion of the graft. The mean maximum mouth opening (MMO) at the last follow-up was 31.29 +/- 7.56 mm (range 15-45 mm). Although two patients exhibited excessive growth of the graft, deficient growth of the graft was also found in our paediatric patients. Four patients who developed ankylosed TMJ during the follow-up period received additional gap arthroplasty. CONCLUSION: VCG based on a serratus anterior flap was an excellent treatment modality for patients with uni-or bilateral composite defects of the ramus and condyle, in which soft tissue and hard tissue, including both bone and cartilage, were necessary. PMID- 26051850 TI - Effect of concurrent mental nerve reconstruction at the same time as mandibular reconstruction using a fibula osteoseptocutaneous flap. AB - The damage of inferior alveolar nerve causes some functional problem including numbness of lower lip and drooling. During segmental mandibulectomy, inferior alveolar nerve commonly resected, therefore, it is ideal to reconstruct the nerve to get better functional result. Sensory recovery was assessed after mandibular reconstruction using free fibula osteoseptocutaneous flap in thirteen cases. In six cases, the mental nerve reconstruction was performed simultaneously, and in seven cases, the mental nerve reconstruction was not performed. In the case that the mental nerve was reconstructed simultaneously, unilateral mental nerve reconstruction was performed in five cases, and bilateral mental nerve reconstruction was performed in one cases. More than one year after the reconstruction, sensory recovery was assessed and compared between the group that the mental nerve was reconstructed and the group that was not reconstructed. Our results showed almost a normal sensory recovery of the lips on the reconstructed side more than one year after the reconstruction in reconstructed group. In contrast, sensory recovery was poor in non-reconstructed group and non reconstructed side. These results showed that mental nerve reconstruction at the same time as mandibular reconstruction affects the postoperative mandibular function. The sural nerve can be harvested from the same donor site of the free fibula osteoseptocutaneous flap and such mental nerve reconstruction with nerve grafting can be completed within an hour. Most cases of mandibular reconstruction using a free fibula osteoseptocutaneous flap transfer can therefore be candidates for mental nerve reconstruction at the time of mandibular reconstruction. PMID- 26051851 TI - Modifications of the deep circumflex iliac artery free flap for reconstruction of the maxilla. AB - BACKGROUND: The deep circumflex iliac artery (DCIA) free flap remains underused in maxillectomy reconstruction. A number of surgical techniques have been described however, maxillary defects vary greatly and modifying techniques to account for such variation can be challenging. PURPOSE: This article presents the first standardized approach to DCIA free flap modification for maxillary reconstruction where graded modifications are made to a standard procedure based on defect grade. A review of 11 cases that underwent maxillectomy reconstruction with this technique is presented. METHODS: Defect complexity is stratified according to the Brown Classification System and graded modifications of increasing complexity are made to a standard harvest and flap inset technique. Modifications include increasing the depth of the harvested iliac crest bone to correspond to the height of the anterior maxillary wall defect, addition of a titanium mesh plate to reconstruct the orbital floor and harvest of the internal oblique muscle to fill the orbital cavity. Short and long-term outcomes and complications of 11 cases that underwent maxillectomy reconstruction according to this technique were documented. RESULTS: Defects ranged from Brown Class I-IV, b c. All but two patients had malignant diagnoses with squamous cell carcinoma (n = 5) being the most prevalent. Short-term flap related complications were neck cellulitis (n = 1) and donor site haematoma (n = 2) whilst long-term flap related complications were mild trismus (n = 1) and donor site pain (n = 1). There were no reported problems with speech, swallowing or vision. CONCLUSIONS: This stepwise approach to DCIA free flap modification for maxillectomy defect reconstruction may be used as a guide for future maxillary reconstruction. PMID- 26051852 TI - Position-specific performance indicators that discriminate between successful and unsuccessful teams in elite women's indoor field hockey: implications for coaching. AB - The aim of this investigation was to establish median performance profiles for the six playing positions in elite women's indoor hockey and then identify whether these position-specific profiles could discriminate between qualifying (top four), mid-table and relegated teams in the 2011-2012 England Hockey premier league. Successful passing in relegated teams was significantly lower (P < 0.008) than in mid-table and qualifying teams in four of the five outfield positions. Furthermore, the right backs of qualifying teams demonstrated significantly fewer (P < 0.008) unsuccessful passes (x = 15.5 +/- CLs 15.0 and 10.0, respectively) and interceptions (x = 4.0 +/- CLs 4.0 and 3.0, respectively) than relegated teams (x = 19.5 +/- CLs 21.0 and 17.0; x = 7.5 +/- CLs 8.0 and 6.0, respectively). Finally, the right forwards of relegated teams demonstrated significantly fewer (P < 0.008) successful interceptions (x = 4.0 +/- CLs 5.0 and 4.0, respectively) than qualifying teams (x = 5.0 +/- CLs 6.0 and 3.0, respectively) and significantly more (P < 0.008) unsuccessful interceptions (x = 5.5 +/- CLs 6.0 and 4.0, respectively) than mid-table teams (x = 3.0 +/- CLs 3.0 and 2.0, respectively). Based on these findings, coaches should adapt tactical strategies and personnel deployment accordingly to enhance the likelihood of preparing a qualifying team. Research should build from these data to examine dribbling, pressing and patterns of play when outletting. PMID- 26051853 TI - Highly nanoporous silicas with pore apertures near the boundary between micro- and mesopores through an orthogonal self-assembly approach. AB - Nanoporous silicas having some periodicity, high surface area (up to 1230 m(2) g( 1)), and pore diameters near the boundary between micro- and mesopores are synthesized using aromatic compounds bearing anionic end-groups as novel structure-directing agents (SDAs) that can facilitate multiple interactions between SDAs, co-SDAs and silica frameworks orthogonally. PMID- 26051854 TI - [Place of clinical pharmacist in the management of drugs in patients with hypertension]. AB - PURPOSE: To synthesize pharmacists' interventions made in the department of internal medicine and hypertension of university hospital of Toulouse and assess the impact on medication orders. METHODS: This is a single-center, prospective study using pharmacists' interventions recorded between September 2013 and March 2014 on the Act-IP((c)) website of the French Society of Clinical Pharmacy. The clinical pharmacist is present everyday in the unit to establish the medication reconciliation of new patients (the process of comparing a patient's medication orders to all of the medications that the patient has been taking), and analysis of medication orders. When a risk of iatrogenic drug is identified, a therapeutic change is proposed to the prescriber. RESULTS: A total of 2491 medication orders were analyzed for 7 months, leading to 39 pharmacists' interventions (1.6 pharmacists' interventions per 100 medication orders). The most commonly identified drug-related problems were improper administration (33%, n=13), not prescribed drug (21%, n=8), non-conformity to guidelines (18%, n=7), supratherapeutic dose (15%, n=6), and 13% (n=5) targeted prescribed treatment not administered, underdosing, incorrect administration or drug interaction. The most relevant molecules were atorvastatin (10%), bromazepam (8%) and levothyroxine (8%) and only 2 interventions targeted antihypertensive drugs. The rate of physicians' acceptance was 92%. CONCLUSION: Pharmacists' interventions mainly concern the co-prescriptions of antihypertensive drugs and very few antihypertensive drugs. The clinical pharmacist contributes to preventing iatrogenic in patients with hypertension with a very good acceptance by the clinician. PMID- 26051855 TI - [Not isolated ventricular compaction in an infant]. AB - Not isolated ventricular compaction cardiomyopathy is a rare deasese described both in children than in adults. It due to the interruption of the embryogenic compaction process of the normal myocardium. We report a pediatric observation of noncompaction of the left ventricle. CASE REPORT: This is a 4-month girl who was admitted to an array of heart failure with systolic murmur to FM. Chest radiography showed cardiomegaly. The ECG showed repolarization disorder. The echocardiography objectified dilated left cavities with thickened wall and anechoic areas (sinusoidal), a mitral regurgitation GII and minimal tricuspid regurgitation. CONCLUSION: NCVI is a rare cause of heart failure in infants. The management is based on guidelines for various clinical symptomatology. Its discovery in children should lead to screening of first-degree relative. PMID- 26051856 TI - Effect of postural changes on aldosterone to plasma renin ratio in patients with suspected secondary hypertension. AB - AIMS: To study the influence of postural changes on aldosterone to renin ratio (ARR) in patients with suspected secondary hypertension and to evaluate the sensitivity and specificity of the recommended seated ARR compared to supine and upright ARR for primary aldosteronism screening. METHODS: Fifty-three hypertensive patients were prospectively hospitalized for secondary hypertension exploration (age: 51 +/- 12, 66% males). After withdrawal of drugs interfering with renin angiotensin system, plasma aldosterone and direct renin concentration were measured in the morning, at bed after an overnight supine position, then out of bed after 1 hour of upright position and finally 2 hours later after 15 minutes of seating. Minimal renin value was set at 5 MUUI/mL. RESULTS: Referring to ARR cut-off of 23 pg/MUUI, the sensitivity of seated ARR was 57.1% and specificity was 92.3%. The negative and positive predictive values were 95.1% and 45.2% respectively. Compared to these results, a cut-off of 19 improved sensitivity to 85.7% with a specificity of 89.7%. Negative and positive predictive values were 98.3% and 41.1% respectively. Seated ARR mean value was lower than supine and upright ARR mean values, due to an overall increase in renin at seating compared to the supine position by factor 1.9 while aldosterone just slightly increased by factor 1.2. Seated ARR correlated to supine and upright ARR: correlation coefficients (r) 0.90 and 0.93 respectively (P<0.001). CONCLUSIONS: Current recommended measurement of ARR in the seating position is fairly correlated to supine and upright ARR. A suggested cut-off value of 19 instead of 23 pg/MUUI increased the discriminating power of this test. PMID- 26051857 TI - Integrating comparative functional response experiments into global change research. AB - There is a growing appreciation for the importance of non-consumptive effects in predator-prey interaction research, which can often outweigh the importance of direct feeding. Barrios-O'Neill et al. (2014) report a novel method to characterize such effects by comparing the functional response of native and introduced intermediate consumers in the presence and absence of a higher predator. The invader exhibited stronger direct feeding and was also more resistant to intimidation by the higher predator. This experimental framework may be incorporated into mainstream global change research, for example, to quantify the importance of non-consumptive effects for the success or failure of biological invasions. PMID- 26051858 TI - The leukotriene B4 receptor (BLT) antagonist BIIL284 decreases atherosclerosis in ApoE-/- mice. AB - Leukotriene B4 (LTB4) induces proinflammatory signaling through BLT receptors expressed in atherosclerotic lesions. Either genetic or pharmacological targeting of the high affinity LTB4 receptor, BLT1, reduces atherosclerosis in different mouse models. The low affinity BLT2 receptor for LTB4 may transduce additional pro-atherogenic signaling, but combined BLT1 and BLT2 receptor antagonism has not previously been explored in atherosclerosis. The aim of the present study was to unravel the effects of the BLT receptor antagonist BIIL284 in apolipoprotein E deficient mice in terms of atherosclerotic lesion size and composition, as well as on arterial matrixmetalloproteinase (MMP) activity and plasma cytokines. Oral administration of BIIL284 (0.3-3mg/kg) dose-dependently decreased atherosclerotic lesion size after 12 weeks. In addition, significantly smaller aortic lesions were observed in mice treated with BIIL284 (3mg/kg) for 24 weeks. The reduced atherosclerosis was associated with less lesion smooth muscle cells, less arterial MMP activities and lower plasma levels of TNF-alpha and IL-6. Taken together, these results suggest a therapeutic value of BLT receptor antagonism in atherosclerosis. PMID- 26051859 TI - Burkholderiales participating in pentachlorophenol biodegradation in iron reducing paddy soil as identified by stable isotope probing. AB - As the most prevalent preservative worldwide for many years, pentachlorophenol (PCP) has attracted much interest in the study of biodegradation in soil and aquatic ecosystems. However, the key microorganisms involved in anaerobic degradation are less well understood. Hence, we used DNA-based stable isotope probing (SIP) to identify the PCP-degrading microorganisms in iron-rich paddy soil under anaerobic conditions. (12)C- and (13)C-labeled PCP were almost completely degraded in 30 days under iron-reducing conditions. The results of terminal restriction fragment length polymorphism (T-RFLP) of 16S rRNA genes showed that 197 and 217 bp (HaeIII digests) restriction fragments (T-RFs) were enriched in heavy DNA fractions of (13)C-labeled samples, and the information from 16S rRNA gene clone libraries suggested that the microorganisms corresponding to these T-RF fragments, which increased in relative abundance during incubation, belonged to the order of Burkholderiales, in which 197 and 217 bp were classified as unclassified Burkholderiales and the genus Achromobacter, respectively. The results of the present study indicated that Burkholderiales affiliated microorganisms were responsible for PCP degradation in anaerobic paddy soil and shed new light on in situ bioremediation in anaerobic PCP contaminated soil. PMID- 26051860 TI - [Prevention of venous thromboembolic events by fondaparinux 2.5mg in patients hospitalized for an acute medical illness. ArchiMed Study]. AB - OBJECTIVE: To evaluate the average duration of in-hospital treatment with fondaparinux 2.5mg prescribed for venous thromboprophylaxis in acutely ill medical patients and to describe the treatment population. METHODS: Prospective, observational, national, multicentre, epidemiological study, performed in France at the request of the Transparency Commission of the French National Health Authority (Haute Autorite de Sante). This is part of a larger study program that also included a study with similar design in the general practice setting. The hospital practice part of the study was conducted by hospital pharmacists who were asked to include the first 15 adult subjects hospitalized in a non-surgical ward for whom fondaparinux 2.5mg was initiated for prophylaxis. RESULTS: Fifty three pharmacists (49.5%) included a total of 718 patients. The average age was 71 +/- 16 years (47%<75 years old); 54% were women. For 41% of patients, duration of fondaparinux 2.5mg administration ranged from 6 to 14 days. Eighty-five percent of patients had at least one acute illness related to the prescription of fondaparinux 2.5mg for thromboprophylaxis. Ten percent of the population had at least one risk factor listed on the Case Report Form. Characteristics of patients from the hospital practice study differ from those included in the general practice part of the ArchiMed Study program. CONCLUSION: The hospital practice part of the ArchiMed Study, which is similar to "audits of practices", shows that the real-life conditions of prescription of fondaparinux 2.5mg in patients hospitalized are generally in line with guidelines with respect to indication for thromboprophylaxis in acute medical illness. PMID- 26051862 TI - Adatom bond-induced geometric and electronic properties of passivated armchair graphene nanoribbons. AB - The geometric and electronic properties of passivated armchair graphene nanoribbons, enriched by strong chemical bonding between edge-carbons and various adatoms, are investigated by first-principle calculations. Adatom arrangements, bond lengths, charge distributions, and energy dispersions are dramatically changed by edge passivation. Elements with an atomic number of less than 20 are classified into three types depending on the optimal geometric structures: planar and non-planar structures, the latter of which are associated with specific arrangements and stacked configurations of adatoms. Especially, the nitrogen passivated nanoribbon is the most stable one with a heptagon-pentagon structure at the edges. The low-lying band structures are drastically varied, exhibiting non-monotonous energy dispersions and adatom-dominated bands. A relationship between energy gaps and ribbon widths no longer exists, and some adatoms further induce a semiconductor-metal transition. All the main characteristics are directly reflected in the density of states, revealing dip structures, plateaus, symmetric peaks, and square-root divergent asymmetric peaks. PMID- 26051861 TI - [The PROMET study: Prophylaxis for venous thromboembolic disease in at-risk patients hospitalized in Algeria]. AB - PROMET is an observational study aimed to assess the management of patients at venous thromboembolism risk in the Algerian hospitals and to evaluate the proportion of at-risk patients treated with an adequate prophylaxis. Following the ENDORSE study achieved five years before with a similar protocol, PROMET included 435hospitalized patients (229 in medical units and 206 in surgical units). Compared to the ENDORSE results, the PROMET data reflect progress in the management of venous thromboembolism: 73.3% of at-risk patients received prophylaxis (57.6% of medical patients and 90.8% of surgical patients). In 93.1% of cases, this prophylaxis was provided by a low molecular weight heparin, mainly at the dose of one injection per day. In medical population, the prescription was triggered by long-term immobilization (P=0.01; OR=5.8 95%CI [1.5-23.0]), associated risk factors (P=0.025; OR=4.13 [1.2-14.2]) and the cause of hospitalization (P=0.056). In surgical departments, the therapeutic decision depended on the nature of the surgical intervention and was influenced by the presence of a contraindication for prophylaxis (P<0.001; OR=0.02 [0.00-0.14]) or a high hemorrhagic risk (P<0.001; OR=0.02). The assessment and management of thromboembolic risk were in accordance with ACCP recommendations for surgical patients. However efforts are needed for medical patients for whom the risk is underestimated and insufficiently supported. Unlike surgery where procedures are well established, there are real difficulties in medicine to define the at-risk patients who will benefit from thromboprophylaxis. The process of preventive treatment (particularly the optimal duration) needs to be clarified. PMID- 26051863 TI - Historical trends of organochlorine pesticides in a sediment core from the Gulf of Batabano, Cuba. AB - Sediments can be natural archives to reconstruct the history of pollutant inputs into coastal areas. This is important to improve management strategies and evaluate the success of pollution control measurements. In this work, the vertical distribution of organochlorine pesticides (DDTs, Lindane, HCB, Heptachlor, Aldrin and Mirex) was determined in a sediment core collected from the Gulf of Batabano, Cuba, which was dated by using the (210)Pb dating method and validated with the (239,240)Pu fallout peak. Results showed significant changes in sediment accumulation during the last 40 years: recent mass accumulation rates (0.321 g cm(-2) yr(-1)) double those estimated before 1970 (0.15 g cm(-2) yr(-1)). This change matches closely land use change in the region (intense deforestation and regulation of the Colon River in the late 1970s). Among pesticides, only DDTs isomers, Lindane and HCB were detected, and ranged from 0.029 to 0.374 ng g(-1) dw for DDTs, from<0.006 to 0.05 ng g(-1) dw for Lindane and from<0.04 to 0.134 ng g(-1) dw for HCB. Heptachlor, Aldrin and Mirex were below the detection limits (~0.003 ng g(-1)), indicating that these compounds had a limited application in the Coloma watershed. Pesticide contamination was evident since the 1970s. DDTs and HCB records showed that management strategies, namely the banning the use of organochlorine contaminants, led to a concentration decline. However, Lindane, which was restricted in 1990, can still be found in the watershed. According to NOAA guidelines, pesticides concentrations encountered in these sediments are low and probably not having an adverse effect on sediment dwelling organisms. PMID- 26051864 TI - Daytime napping and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis of prospective cohort studies. AB - OBJECTIVES: The association between daytime napping and mortality remains controversial. We conducted a meta-analysis to examine the associations between daytime napping and the risks of death from all causes, cardiovascular disease (CVD), and cancer. METHODS: PubMed and Embase databases were searched through 19 September 2014. Prospective cohort studies that provided risk estimates of daytime napping and mortality were eligible for our meta-analysis. Two investigators independently performed study screening and data extraction. A random-effects model was used to estimate the combined effect size. Subgroup analyses were conducted to identify potential effect modifiers. RESULTS: Twelve studies, involving 130,068 subjects, 49,791 nappers, and 19,059 deaths, were included. Our meta-analysis showed that daytime napping was associated with an increased risk of death from all causes [n = 9 studies; hazard ratio (HR), 1.22; 95% confidence interval (CI), 1.14-1.31; I(2) = 42.5%]. No significant associations between daytime napping and the risks of death from CVD (n = 6 studies; HR, 1.20; 95% CI, 0.96-1.50; I(2) = 75.0%) and cancer (n = 4 studies; HR, 1.07; 95% CI, 0.99-1.15; I(2) = 8.9%) were found. There were no significant differences in risks of all-cause and CVD mortality between subgroups stratified by the prevalence of napping, follow-up duration, outcome assessment, age, and sex. CONCLUSIONS: Daytime napping is a predictor of increased all-cause mortality but not of CVD and cancer mortality. However, our findings should be treated with caution because of limited numbers of included studies and potential biases. PMID- 26051865 TI - Comparison of Cup Alignment, Jump Distance, and Complications in Consecutive Series of Anterior Approach and Posterior Approach Total Hip Arthroplasty. AB - The purpose of this study was to compare cup position, jump distance, and rate of dislocations in 100 total hip arthroplasty (THA) cases performed with the direct anterior approach (DAA) and 100 cases performed with the posterior approach (PA). Abduction and anteversion angles were measured using Martell Hip Analysis software. The average cup anteversion in the DAA group (17.6 degrees ) was significantly different than the PA average (22.6 degrees ), P<.001. The average cup abduction angle was similar between groups (DAA 44.2 degrees vs. PA 44.3 degrees , P=.87), but the variance was significantly reduced with the direct anterior approach, P=.02. The use of intraoperative fluoroscopy with the DAA allowed for more accurate cup placement and eliminated severely vertical cups (>55 degrees ) seen with the PA. PMID- 26051866 TI - Evaluation of the anterior mandibular donor site one year after secondary reconstruction of an alveolar cleft: 3-dimensional analysis using cone-beam computed tomography. AB - The aim of this study was to analyse changes in the volume of the chin after harvest of a bone graft for secondary reconstruction of an alveolar cleft. Cone beam computed tomographic (CT) scans of 27 patients taken preoperatively, and immediately and one year postoperatively, were analysed, and 3-dimensional hard tissue reconstructions made. The hard-tissue segmentation of the scan taken one year postoperatively was subtracted from the segmentation of the preoperative scan to calculate the alteration in the volume of bone at the donor site (chin). A centrally-orientated persistent concavity at the buccal side of the chin was found (mean (range) 160 (0-500) mm(3)). At the lingual side of the chin, a central concavity remained (mean (range) volume 20 (0-80) mm(3)). Remarkably, at the periphery of this concavity there was overgrowth of new bone (mean (range) volume 350 (0-1600) mm(3)). Re-attachment of the muscles of the tongue resulted in a significantly larger central lingual defect one year postoperatively (p=0.01). We also measured minor alterations in volume of the chin at one year. Whether these alterations influence facial appearance and long term bony quality is to be the subject of further research. PMID- 26051867 TI - Reconstruction of the orbital floor with polydioxanone: a long-term clinical survey of up to 12 years. AB - Fractures of the orbital floor are common in injured patients, who often require operation to prevent complications and, among other materials, polydioxanone is widely used. The aim of this study was to evaluate the long-term outcomes of fractures of the orbital floor that had been reconstructed with polydioxanone foil. A total of 101 patients (73 men and 28 women) who had reconstruction of the orbital floor for defects of 2cm(2) or smaller with polydioxanone implants, over a mean (SD) time period of 8 (2) years were evaluated. Sensitivity of the infraorbital nerve, ocular motility, and diplopia were evaluated and correlated with perioperative values. Persistent hyperaesthesia was found in 15 patients, whereas in another 15 the hyperaesthesia recovered completely over time. Three patients had double vision during follow-up. Twenty patients with preoperative diplopia had no persistent double vision postoperatively, and 15 patients with disturbed ocular motility recovered completely. Two patients had persistently disturbed motility, and one patient had enophthalmos. There was a significant association between hyperaesthesia preoperatively and postoperatively (p= 0.005). In most patients reconstruction of the orbital floor with polydioxanone was successful. Long-term complications such as diplopia, compromised bulbar motility, and hyperaesthesia of the cheek were seen in a few cases, but might not have been solely related to the use of polydioxanone. PMID- 26051868 TI - Heat generation and drill wear during dental implant site preparation: systematic review. AB - To identify factors that minimise damage during the drilling of sites for dental implants, we reviewed published papers on the amount of heat that is generated. We systematically searched English language studies published between January 2000 and February 2014 on MEDLINE/PubMed and found 41 articles, of which 27 related to an increase in temperature during preparation of the site. We found only basic research with a low level of evidence. Most of the studies were in vitro, and osteotomies were usually made in non-vital bone from cows or pigs. To measure heat in real time, thermocouples were used in 18 studies and infrared thermographs in 7. Three studies reported the use of immunohistochemical analysis to investigate immediate viability of cells. The highest temperature measured was 64.4 degrees C and the lowest 28.4 degrees C. Drill wear was reported after preparation of 50 sites, and there was a significant increase in temperature and a small change in the physiological balance of the proteins in the bone cells. Differences in the study designs meant that meta-analysis was not appropriate. For future work, we recommend the use of standard variables: an axial load of 2kg, drilling speed of 1500rpm, irrigation, standard artificial bone blocks, and the use of infrared thermography. PMID- 26051869 TI - The nasal lift technique for augmentation of the maxillary ridge: technical note. AB - Placement of dental implants in a severely resorbed anterior maxillary alveolar ridge is limited by the fact that implants may penetrate the nasal cavity. However, when the maxilla shows unusual anatomical changes, reconstruction with implants can be a challenge. Options to increase the bone in this region to permit placement of implants include: maxillary onlay bone graft, Le Fort I interpositional bone graft, and augmentation of the nasal floor, which is a procedure where only the piriform rim and the anterior nasal spine are exposed through an intraoral approach. In our case we modified this to what we call the nasal lift technique, which is a combination of turbinectomy followed by lifting of the anteroposterior nasal floor through a lateral window using autogenous bone or bone substitutes to augment the space. PMID- 26051870 TI - Does True Neurocognitive Dysfunction Contribute to Minnesota Multiphasic Personality Inventory-2nd Edition-Restructured Form Cognitive Validity Scale Scores? AB - Previous research has demonstrated RBS and FBS-r to identify non-credible reporters of cognitive symptoms, but the extent that these scales might be influenced by true neurocognitive dysfunction has not been previously studied. The present study examined the relationship between these cognitive validity scales and neurocognitive performance across seven domains of cognitive functioning, both before and after controlling for PVT status in 120 individuals referred for neuropsychological evaluations. Variance in RBS, but not FBS-r, was significantly accounted for by neurocognitive test performance across most cognitive domains. After controlling for PVT status, however, relationships between neurocognitive test performance and validity scales were no longer significant for RBS, and remained non-significant for FBS-r. Additionally, PVT failure accounted for a significant proportion of the variance in both RBS and FBS-r. Results support both the convergent and discriminant validity of RBS and FBS-r. As neither scale was impacted by true neurocognitive dysfunction, these findings provide further support for the use of RBS and FBS-r in neuropsychological evaluations. PMID- 26051871 TI - Large increase in fracture resistance of stishovite with crack extension less than one micrometer. AB - The development of strong, tough, and damage-tolerant ceramics requires nano/microstructure design to utilize toughening mechanisms operating at different length scales. The toughening mechanisms so far known are effective in micro-scale, then, they require the crack extension of more than a few micrometers to increase the fracture resistance. Here, we developed a micro mechanical test method using micro-cantilever beam specimens to determine the very early part of resistance-curve of nanocrystalline SiO2 stishovite, which exhibited fracture-induced amorphization. We revealed that this novel toughening mechanism was effective even at length scale of nanometer due to narrow transformation zone width of a few tens of nanometers and large dilatational strain (from 60 to 95%) associated with the transition of crystal to amorphous state. This testing method will be a powerful tool to search for toughening mechanisms that may operate at nanoscale for attaining both reliability and strength of structural materials. PMID- 26051872 TI - Taxifolin protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. AB - Cardiac hypertrophy is a key pathophysiological component to biomechanical stress, which has been considered to be an independent and predictive risk factor for adverse cardiovascular events. Taxifolin (TAX) is a typical plant flavonoid, which has long been used clinically for treatment of cardiovascular and cerebrovascular diseases. However, very little is known about whether TAX can influence the development of cardiac hypertrophy. In vitro studies, we found that TAX concentration-dependently inhibited angiotensin II (Ang II) induced hypertrophy and protein synthesis in cardiac myocytes. Then we established a mouse model by transverse aortic constriction (TAC) to further confirm our findings. It was demonstrated that TAX prevented pressure overload induced cardiac hypertrophy in mice, as assessed by ventricular mass/body weight, echocardiographic parameters, myocyte cross-sectional area, and the expression of ANP, BNP and beta-MHC. The excess production of reactive oxygen species (ROS) played critical role in the development of cardiac hypertrophy. TAX arrested oxidative stress and decreased the expression of 4-HNE induced by pressure overload. Moreover, TAX negatively modulated TAC-induced phosphorylation of ERK1/2 and JNK1/2. Further studies showed that TAX significantly attenuated left ventricular fibrosis and collagen synthesis through abrogating the phosphorylation of Smad2 and Smad2/3 nuclear translocation. These results demonstrated that TAX could inhibit cardiac hypertrophy and attenuate ventricular fibrosis after pressure overload. These beneficial effects were at least through the inhibition of the excess production of ROS, ERK1/2, JNK1/2 and Smad signaling pathways. Therefore, TAX might be a potential candidate for the treatment of cardiac hypertrophy and fibrosis. PMID- 26051873 TI - Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R. AB - PRX-105 is a plant-derived recombinant version of the human 'read-through' acetylcholinesterase splice variant (AChE-R). Its active site structure is similar to that of the synaptic variant, and it displays the same affinity towards organophosphorus (OP) compounds. As such, PRX-105 may serve as a bio scavenger for OP pesticides and chemical warfare agents. To assess its potential use in prophylaxis and treatment of OP poisoning we conducted several preliminary tests, reported in this paper. Intravenous (IV) PRX-105 was administered to mice either before or after exposure to an OP toxin. All mice who received an IV dose of 50nmol/kg PRX-105, 2min before being exposed to 1.33*LD50 and 1.5*LD50 of toxin and 10min after exposure to 1.5*LD50 survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t1/2) in mice was 994 (+/-173) min. Additionally, a first in-human study, to assess the safety, tolerability and pharmacokinetics of the compound, was conducted in healthy volunteers. The t1/2 in humans was substantially longer than in mice (average 26.7h). Despite the small number of animals and human subjects who were assessed, the fact that PRX-105 exerts a protective and therapeutic effect following exposure to lethal doses of OP, its favorable safety profile and its relatively long half-life, renders it a promising candidate for treatment and prophylaxis against OP poisoning and warrants further investigation. PMID- 26051874 TI - Pharmacokinetics of Empagliflozin and Pioglitazone After Coadministration in Healthy Volunteers. AB - PURPOSE: The aim was to investigate the effects of coadministration of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin with the thiazolidinedione pioglitazone. METHODS: In study 1, 20 healthy volunteers received 50 mg of empagliflozin alone for 5 days, followed by 50 mg of empagliflozin coadministered with 45 mg of pioglitazone for 7 days and 45 mg of pioglitazone alone for 7 days in 1 of 2 treatment sequences. In study 2, 20 volunteers received 45 mg of pioglitazone alone for 7 days and 10, 25, and 50 mg of empagliflozin for 9 days coadministered with 45 mg of pioglitazone for the first 7 days in 1 of 4 treatment sequences. FINDINGS: Pioglitazone exposure (Cmax and AUC) increased when coadministered with empagliflozin versus monotherapy in study 1. The geometric mean ratio (GMR) for pioglitazone Cmax at steady state (Cmax,ss) and for AUC during the dosing interval at steady state (AUCtau,ss) when coadministered with empagliflozin versus administration alone was 187.89% (95% CI, 166.35%-212.23%) and 157.97% (95% CI, 148.02%-168.58%), respectively. Because an increase in pioglitazone exposure was not expected, based on in vitro data, a second study was conducted with the empagliflozin doses tested in Phase III trials. In study 2, pioglitazone exposure decreased marginally when coadministered with empagliflozin. The GMR for pioglitazone Cmax,ss when coadministered with empagliflozin versus administration alone was 87.74% (95% CI, 73.88%-104.21%) with empagliflozin 10 mg, 90.23% (95% CI, 66.84%-121.82%) with empagliflozin 25 mg, and 89.85% (95% CI, 71.03%-113.66%) with empagliflozin 50 mg. The GMR for pioglitazone AUCtau,ss when coadministered with empagliflozin versus administration alone was 90.01% (95% CI, 77.91%-103.99%) with empagliflozin 10 mg, 88.98% (95% CI, 72.69%-108.92%) with empagliflozin 25 mg, and 91.10% (95% CI, 77.40%-107.22%) with empagliflozin 50 mg. The effects of empagliflozin on pioglitazone exposure are not considered to be clinically relevant. Empagliflozin exposure was unaffected by coadministration with pioglitazone. Empagliflozin and pioglitazone were well tolerated when administered alone or in combination. In study 1, adverse events were reported in 1 of 19 participants on empagliflozin 50 mg alone, 4 of 20 on pioglitazone alone, and 5 of 18 on combination treatment. In study 2, adverse events were reported in 8 of 20 participants on pioglitazone alone, 10 of 18 when coadministered with empagliflozin 10 mg, 5 of 17 when coadministered with empagliflozin 25 mg, and 6 of 16 when coadministered with empagliflozin 50 mg. IMPLICATIONS: These results indicate that pioglitazone and empagliflozin can be coadministered without dose adjustments. EudraCT identifiers: 2008-006087-11 (study 1) and 2009-018089-36 (study 2). PMID- 26051875 TI - Phosphorus promotion and poisoning in zeolite-based materials: synthesis, characterisation and catalysis. AB - Phosphorus and microporous aluminosilicates, better known as zeolites, have a unique but poorly understood relationship. For example, phosphatation of the industrially important zeolite H-ZSM-5 is a well-known, relatively inexpensive and seemingly straightforward post-synthetic modification applied by the chemical industry not only to alter its hydrothermal stability and acidity, but also to increase its selectivity towards light olefins in hydrocarbon catalysis. On the other hand, phosphorus poisoning of zeolite-based catalysts, which are used for removing nitrogen oxides from exhaust fuels, poses a problem for their use in diesel engine catalysts. Despite the wide impact of phosphorus-zeolite chemistry, the exact physicochemical processes that take place require a more profound understanding. This review article provides the reader with a comprehensive and state-of-the-art overview of the academic literature, from the first reports in the late 1970s until the most recent studies. In the first part an in-depth analysis is undertaken, which will reveal universal physicochemical and structural effects of phosphorus-zeolite chemistry on the framework structure, accessibility, and strength of acid sites. The second part discusses the hydrothermal stability of zeolites and clarifies the promotional role that phosphorus plays. The third part of the review paper links the structural and physicochemical effects of phosphorus on zeolite materials with their catalytic performance in a variety of catalytic processes, including alkylation of aromatics, catalytic cracking, methanol-to-hydrocarbon processing, dehydration of bioalcohol, and ammonia selective catalytic reduction (SCR) of NOx. Based on these insights, we discuss potential applications and important directions for further research. PMID- 26051876 TI - Treatment with low-dose cytokines reduces oxidative-mediated injury in perilesional keratinocytes from vitiligo skin. AB - BACKGROUND: Vitiligo is a systemic dermatological disorder characterized by the loss of skin pigmentation due to melanocyte injury or aberrant functioning. Recent data underline its multifactorial etiology with significant involvement of autoimmune and redox alterations. The major role in vitiligo cellular immunity is displayed by augmented Th1 and Th17 and suppressed TREGs and Th2 lymphocyte populations. Our previous studies indicate a marked redox imbalance in perilesional ("PL", i.e. obtained from visibly unaffected skin surrounding the depigmented area in vitiligo patients) keratinocytes where the massive infiltration of inflammatory cells takes place. No defined therapy exists for vitiligo. Although a number of approaches have been used for the induction of TREGs and Th2 cells, they may be associated with significant off-target effects. OBJECTIVE: In order to identify a targeted approach for vitiligo treatment we, first, aimed to investigate the possible source of ROS overproduction in PL keratinocytes. Second, we tested the effect of low-dose selected cytokines, on intra- and extracellular ROS production, cell viability and cell cycle of PL keratinocytes. METHODS: The in vitro study was conducted on primary PL keratinocytes obtained from the skin of vitiligo patients in our previous studies. The activity of NADPH oxidase was measured on intact PL and control keratinocytes, treated or not with cytokines, by luminometric assay. The following cytokines were selected for PL keratinocytes treatment: IL-10 and IL-4 (produced by TREGs and Th2, respectively), basic fibroblasts growth factor (bFGF) and neuropeptide beta-endorphin (modulating the cellular resistance to oxidative stress and the immune response, respectively). All cytokines were used at concentration of 10fg/ml and were prepared by sequential-kinetic-activation (SKA). Intracellular ROS production and cell cycle were analyzed by flow cytometry using H2DCFDA and propidium iodide dyes, respectively. Cell viability was measured by fluorometric resazurin reduction method. RESULTS: Our results suggest that NADPH oxidase represents one of the main sources of ROS overproduction by PL keratinocytes. Further, SKA low-dose IL-10, beta-endorphin and, particularly, IL-4 and bFGF display a positive effect on redox dyshomeostasis and viability and, in our experimental conditions, don't affect the cell cycle of PL keratinocytes. CONCLUSION: Our preliminary data suggest that low-dose IL-10, IL-4, beta-endorphin and bFGF can be proposed as a new therapeutic tool for vitiligo treatment. PMID- 26051877 TI - Plexin-B1 and semaphorin 4D cooperate to promote cutaneous squamous cell carcinoma cell proliferation, migration and invasion. AB - BACKGROUND OBJECTIVES: Semaphorin 4D (Sema4D) and its receptor, Plexin-B1, are involved in the pathogenesis of squamous cell carcinoma (SCC) by mediating angiogenesis or perineural invasion through the interaction between Sema4D expression on SCC cells and Plexin-B1 expression on endothelial cells or nerves. Plexin-B1 was also recently found to be expressed on SCC cells. Plexin-B1 expression on several types of tumor cells could mediate various, and occasionally opposing, effects, including tumor cell survival, proliferation, angiogenesis, invasion, and metastasis. However, whether Sema4D exerts paracrine or autocrine effects on SCC via Plexin-B1 remains unclear. OBJECTIVES: The aim of this study is to explore the effects of Sema4D/Plexin-B1 interaction on SCC via Plexin-B1 expressed on the tumor cells. METHODS: In the present study, we detected the expression of Plexin-B1 and Sema4D in cutaneous SCC (cSCC) tissues and in the cSCC cell line A431 and analyzed the effects of the Sema4D/Plexin-B1 interaction on cSCC cell proliferation, migration, and invasion, as well as on the signaling pathway downstream of Plexin-B1. RESULTS: We observed significantly increased Plexin-B1 and Sema4D expression in keratinocytes in cSCC lesions and in A431 cells compared with that in normal skin tissue and in non-malignant keratinocytes. Plexin-B1 silencing reduced the growth, proliferation, migration, and invasion of A431 cells and inhibited the phosphorylation of Akt and extracellular signal-regulated protein kinase (Erk). Soluble recombinant Sema4D promoted the growth, proliferation, migration, and invasion of A431 cells; Akt and Erk phosphorylation is also involved in these processes with a Plexin-B1 dependent manner. CONCLUSION: Plexin-B1 induces cSCC cell proliferation, migration, and invasion by interacting with Sema4D. Plexin-B1 might serve as a useful biomarker and/or as a novel therapeutic target for cSCC. PMID- 26051878 TI - Mammalian target of rapamycin and tuberous sclerosis complex. AB - Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is a member of the phosphoinositide 3-kinase (PI3K) related kinase (PIKK) family. mTOR forms two distinct complexes, mTORC1 and mTORC2. mTORC1 has emerged as a central regulator of cellular metabolism, cell proliferation, cellular differentiation, autophagy and immune response regulation. In contrast to mTORC1, mTORC2, which is not well understood, participates in cell survival and the regulation of actin and cytokeratin organization. In addition, mTORC1 has been implicated in many diseases, including cancer, metabolic diseases, neurological disease, genetic diseases and longevity/aging. One of the diseases resulting from dysfunction of mTORC1 is tuberous sclerosis complex (TSC), which reflects all the symptoms that arise in response to mTORC1 dysfunction. TSC is a multiple hamartomas syndrome with epilepsy, autism, mental retardation and hypopigmented macules that are caused by the constitutive activation of mTORC1 resulting from genetic mutation of TSC1 or TSC2. Inhibitors of mTORC1, such as rapamycin, effectively suppress the symptoms of TSC. This article summarizes the current knowledge on mTOR and the efficacy of mTORC1 inhibitors in the treatment of TSC. PMID- 26051879 TI - Portal Plate with Hyaline Cartilage in Biliary Atresia. PMID- 26051880 TI - Myofibrillogenesis regulator-1 attenuates hypoxia/reoxygenation-induced injury by repairing microfilaments in neonatal rat cardiomyocytes. AB - Hypoxia/reoxygenation (H/R) injury is characterized by microfilament reorganization in cardiomyocytes. Previous studies have shown that myofibrillogenesis regulator-1 (MR-1) is expressed in the myocardium and promotes actin organization in cardiomyocytes. The purpose of this study was to investigate the role of MR-1 in attenuating hypoxia/reoxygenation injury in cardiomyocytes through promoting restoration of the microfilament. To address this aim, an H/R model of cultured neonatal cardiomyocytes was used to assess filamentous actin (F-actin) and alpha-actinin organization through immunofluorescence microscopy analysis. RT-PCR was used to detect mRNA levels of MR-1 and myosin regulatory light chain-2 (MLC-2). Western blot analysis was used to detect protein levels of MR-1 and filamentous actin/globular actin (F-/G actin) as well as MLC-2 and myosin light chain kinase (MLCK) phosphorylation and protein expression. We also explored the effects of overexpressing or knocking down MR-1 on H/R injury and the MLCK/MLC-2/F-actin pathway. We found that H/R induced cardiomyocyte injury and disruption of F-actin and alpha-actinin with a decrease in the F-/G-actin ratio compared with controls. Compared with the H/R group, MR-1 overexpression attenuated H/R-induced injury and disruption of F actin and alpha-actinin in cardiomyocytes with an increase in the F-/G-actin ratio. MR-1 overexpression also up-regulated H/R-induced MLCK and MLC-2 phosphorylation. However, MR-1 knockdown aggravated H/R injury by further disrupting F-actin and alpha-actinin, as well as decreasing the F-/G-actin ratio. MR-1 knockdown also down-regulated MLCK and MLC-2 phosphorylation induced by H/R injury. These findings suggest that MR-1 attenuates H/R-induced cardiomyocyte injury by promoting microfilament reorganization through the activation of the MLCK/MLC-2 pathway. PMID- 26051881 TI - Percutaneous versus open pedicle screw fixation for treatment of thoracolumbar fractures: Systematic review and meta-analysis of comparative studies. AB - BACKGROUND: The main aims of managing thoracolumbar fractures involve stabilization of traumatized regions, to promote vertebral healing or segmental fusion. Recently, percutaneous pedicle screw fixation has evolved as an alternative approach for the treatment of thoracolumbar fractures, aiming to minimize soft tissue injury and perioperative morbidity. A systematic review and meta-analysis was conducted to compare outcomes of percutaneous versus open pedicle screw fixation for thoracolumbar fractures. METHODS: Relevant articles were identified from six electronic databases from their inception to December 2014. RESULTS: From 12 relevant studies identified, 279 patients undergoing percutaneous fixation were compared with 340 open fixation procedures. Operative duration was significantly shorter in the percutaneous group by 19 min (P = 0.0002). The percutaneous approach was also associated with shorter hospital stay by 5.7 days (P = 0.0007). Whilst there was no difference in screw malpositioning (RR, 0.77; 95% CI, 0.33, 1.83; P = 0.56), the percutaneous approach had lower rates of infections (RR, 0.36; 95% CI, 0.13, 1.00; P = 0.05), and superior visual analogue scale clinical outcomes (P = 0.001). No difference was found between the groups in terms of postoperative Cobb angle (P = 0.22), postoperative body angle (P = 0.66), and postoperative anterior body height (P = 0.19). CONCLUSIONS: The percutaneous approach was associated with shorter operative duration and hospital stay, reduced intraoperative blood loss and reduced infection rates. Given the lack of robust clinical evidence, these findings warrant verification in large prospective registries and randomized trials. PMID- 26051882 TI - Parent-child interaction during feeding or joint eating in parents of different weights. AB - The current study investigates parent-child interaction during feeding or during joint eating, and aimed to explore differences in feeding interactions between mothers and fathers, as well as between overweight, obese and not overweight parents. 148 mothers and 148 fathers with children aged between 7 and 47months were observed during feeding of or joint eating with their child in the laboratory. The videotaped mother-child and father-child dyads were coded using the Chatoor Feeding Scale. This scale consists of 5 subscales: Dyadic Reciprocity, Dyadic Conflict, Talk and Distraction during Feeding, Struggle for Control, and Non-Contingency. Compared to mothers, fathers showed higher readings on the Talk and Distraction scale; in all other subscales no differences were found. The comparison between overweight, obese and not overweight mother-child dyads revealed no significant differences. Differences in father-child dyads between overweight, obese and not overweight fathers were identified in the subscale Struggle for Control: overweight fathers were marked by a higher amount of Struggle for Control than obese and not overweight fathers. Taken together, differences found in the present observational study are small to moderate, and thus the current results support extant literature demonstrating that there are no differences in feeding behaviour between mothers and fathers or between obese and non-obese parents. PMID- 26051883 TI - Spinal immobilisaton in pre-hospital and emergency care: A systematic review of the literature. AB - BACKGROUND: Spinal immobilisation has been a mainstay of trauma care for decades and is based on the premise that immobilisation will prevent further neurological compromise in patients with a spinal column injury. The aim of this systematic review was to examine the evidence related to spinal immobilisation in pre hospital and emergency care settings. METHODS: In February 2015, we performed a systematic literature review of English language publications from 1966 to January 2015 indexed in MEDLINE and Cochrane library using the following search terms: 'spinal injuries' OR 'spinal cord injuries' AND 'emergency treatment' OR 'emergency care' OR 'first aid' AND immobilisation. EMBASE was searched for keywords 'spinal injury OR 'spinal cord injury' OR 'spine fracture AND 'emergency care' OR 'prehospital care'. RESULTS: There were 47 studies meeting inclusion criteria for further review. Ten studies were case series (level of evidence IV) and there were 37 studies from which data were extrapolated from healthy volunteers, cadavers or multiple trauma patients. There were 15 studies that were supportive, 13 studies that were neutral, and 19 studies opposing spinal immobilisation. CONCLUSION: There are no published high-level studies that assess the efficacy of spinal immobilisation in pre-hospital and emergency care settings. Almost all of the current evidence is related to spinal immobilisation is extrapolated data, mostly from healthy volunteers. PMID- 26051884 TI - Assessment of the IFN-beta response to four feline caliciviruses: Infection in CRFK cells. AB - Feline calicivirus (FCV) is a highly contagious pathogen with a widespread distribution. Although the cat genome has been sequenced, little is known about innate immunity in cats, which limits the understanding of FCV pathogenesis. To investigate the IFN-beta response during FCV infection in CRFK cells, we first cloned and identified the feline IFN-beta promoter sequence and the positive regulatory domain (PRD) motifs, which shared a high similarity with human and porcine IFN-beta promoters. Next, we found that infections with FCV strains F9, Bolin and HRB-SS at the 100 or 1000 TCID50 doses could not activate the IFN-beta promoter at 12 and 24h post-infection. Only strain 2280 infection at a 1000 TCID50 dose could induce the IFN-beta promoter mainly through IRF3 and partially through NF-kappaB, at 24h post-infection. However, the IFN response occurred much later and was smaller in magnitude compared with that following Sendai virus (SeV) infection. Further, we found that induction of the IFN-beta promoter by FCV 2280 infection depended on dsRNA and not on viral proteins. Finally, we examined whether the IFN-beta response had an antiviral effect against FCV replication. The over-expression of IFN-beta before exposure to the virus reduced viral yields by a range of 2.2-3.2 log10TCID50, but its over-expression at 12h post-infection did not inhibit FCV replication. Our results indicate that some FCV strains cannot induce IFN-beta expression in vitro, which may be a potential factor for FCV survival in cats. Whether this is important in evading the host interferon response in vivo must be investigated. PMID- 26051885 TI - Population structure and genetic diversity of the parasite Trichomonas vaginalis in Bristol, UK. AB - The protozoan parasite Trichomonas vaginalis is the causative agent of trichomoniasis, an extremely common, but non-life-threatening, sexually transmitted disease throughout the world. Recent population genetics studies of T. vaginalis have detected high genetic diversity and revealed a two-type population structure, associated with phenotypic differences in sensitivity to metronidazole, the drug commonly used for treatment, and presence of T. vaginalis virus. There is currently a lack of data on UK isolates; most isolates examined to date are from the US. Here we used a recently described system for multilocus sequence typing (MLST) of T. vaginalis to study diversity of clinical isolates from Bristol, UK. We used MLST to characterise 23 clinical isolates of T. vaginalis collected from female patients during 2013. Seven housekeeping genes were PCR-amplified for each isolate and sequenced. The concatenated sequences were then compared with data from other MLST-characterised isolates available from http://tvaginalis.mlst.net/ to analyse the population structure and construct phylogenetic trees. Among the 23 isolates from the Bristol population of T. vaginalis, we found 23 polymorphic nucleotide sites, 25 different alleles and 19 sequence types (genotypes). Most isolates had a unique genotype, in agreement with the high levels of heterogeneity observed elsewhere in the world. A two-type population structure was evident from population genetic analysis and phylogenetic reconstruction split the isolates into two major clades. Tests for recombination in the Bristol population of T. vaginalis gave conflicting results, suggesting overall a clonal pattern of reproduction. We conclude that the Bristol population of T. vaginalis parasites conforms to the two-type population structure found in most other regions of the world. We found the MLST scheme to be an efficient genotyping method. The online MLST database provides a useful repository and resource that will prove invaluable in future studies linking the genetics of T. vaginalis with the clinical manifestation of trichomoniasis. PMID- 26051886 TI - Evaluation of the zoonotic potential of a novel reassortant H1N2 swine influenza virus with gene constellation derived from multiple viral sources. AB - In 2011-2012, contemporary North American-like H3N2 swine influenza viruses (SIVs) possessing the 2009 pandemic H1N1 matrix gene (H3N2pM-like virus) were detected in domestic pigs of South Korea where H1N2 SIV strains are endemic. More recently, we isolated novel reassortant H1N2 SIVs bearing the Eurasian avian-like swine H1-like hemagglutinin and Korean swine H1N2-like neuraminidase in the internal gene backbone of the H3N2pM-like virus. In the present study, we clearly provide evidence on the genetic origins of the novel H1N2 SIVs virus through genetic and phylogenetic analyses. In vitro studies demonstrated that, in comparison with a pre-existing 2012 Korean H1N2 SIV [A/swine/Korea/CY03-11/2012 (CY03-11/2012)], the 2013 novel reassortant H1N2 isolate [A/swine/Korea/CY0423/2013 (CY0423-12/2013)] replicated more efficiently in differentiated primary human bronchial epithelial cells. The CY0423-12/2013 virus induced higher viral titers than the CY03-11/2012 virus in the lungs and nasal turbinates of infected mice and nasal wash samples of ferrets. Moreover, the 2013 H1N2 reassortant, but not the intact 2012 H1N2 virus, was transmissible to naive contact ferrets via respiratory-droplets. Noting that the viral precursors have the ability to infect humans, our findings highlight the potential threat of a novel reassortant H1N2 SIV to public health and underscore the need to further strengthen influenza surveillance strategies worldwide, including swine populations. PMID- 26051887 TI - Assessing the epidemiological effect of wolbachia for dengue control. AB - Dengue viruses cause more human morbidity and mortality than any other arthropod borne virus. Dengue prevention relies mainly on vector control; however, the failure of traditional methods has promoted the development of novel entomological approaches. Although use of the intracellular bacterium wolbachia to control mosquito populations was proposed 50 years ago, only in the past decade has its use as a potential agent of dengue control gained substantial interest. Here, we review evidence that supports a practical approach for dengue reduction through field release of wolbachia-infected mosquitoes and discuss the additional studies that have to be done before the strategy can be validated and implemented. A crucial next step is to assess the efficacy of wolbachia in reducing dengue virus transmission. We argue that a cluster randomised trial is at this time premature because choice of wolbachia strain for release and deployment strategies are still being optimised. We therefore present a pragmatic approach to acquiring preliminary evidence of efficacy through various complementary methods including a prospective cohort study, a geographical cluster investigation, virus phylogenetic analysis, virus surveillance in mosquitoes, and vector competence assays. This multipronged approach could provide valuable intermediate evidence of efficacy to justify a future cluster randomised trial. PMID- 26051888 TI - Replication fork progression during re-replication requires the DNA damage checkpoint and double-strand break repair. AB - Replication origins are under tight regulation to ensure activation occurs only once per cell cycle [1, 2]. Origin re-firing in a single S phase leads to the generation of DNA double-strand breaks (DSBs) and activation of the DNA damage checkpoint [2-7]. If the checkpoint is blocked, cells enter mitosis with partially re-replicated DNA that generates chromosome breaks and fusions [5]. These types of chromosomal aberrations are common in numerous human cancers, suggesting that re-replication events contribute to cancer progression. It was proposed that fork instability and DSBs formed during re-replication are the result of head-to-tail collisions and collapse of adjacent replication forks [3]. However, previously studied systems lack the resolution to determine whether the observed DSBs are generated at sites of fork collisions. Here, we utilize the Drosophila ovarian follicle cells, which exhibit re-replication under precise developmental control [8-10], to model the consequences of re-replication at actively elongating forks. Re-replication occurs from specific replication origins at six genomic loci, termed Drosophila amplicons in follicle cells (DAFCs) [10-12]. Precise developmental timing of DAFC origin firing permits identification of forks at defined points after origin initiation [13, 14]. Here, we show that DAFC re-replication causes fork instability and generates DSBs at sites of potential fork collisions. Immunofluorescence and ChIP-seq demonstrate the DSB marker gammaH2Av is enriched at elongating forks. Fork progression is reduced in the absence of DNA damage checkpoint components and nonhomologous end joining (NHEJ), but not homologous recombination. NHEJ appears to continually repair forks during re-replication to maintain elongation. PMID- 26051889 TI - Positively Frequency-Dependent Interference Competition Maintains Diversity and Pervades a Natural Population of Cooperative Microbes. AB - Positively frequency-dependent selection is predicted from theory to promote diversity in patchily structured populations and communities, but empirical support for this prediction has been lacking. Here, we investigate frequency dependent selection among isolates from a local natural population of the highly social bacterium Myxococcus xanthus. Upon starvation, closely related cells of M. xanthus cooperate to construct multicellular fruiting bodies, yet recently diverged genotypes co-residing in a local soil population often antagonize one another during fruiting-body development in mixed groups. In the experiments reported here, both fitness per se and strong forms of interference competition exhibit pervasive and strong positive frequency dependence (PFD) among many isolates from a centimeter-scale soil population of M. xanthus. All strains that compete poorly at intermediate frequency are shown to be competitively dominant at high frequency in most genotype pairings during both growth and development, and strongly so. Interference competition is often lethal and appears to be contact dependent rather than mediated by diffusible compounds. Finally, we experimentally demonstrate that positively frequency-dependent selection maintains diversity when genotype frequencies vary patchily in structured populations. These results suggest that PFD contributes to the high levels of local diversity found among M. xanthus social groups in natural soil populations by reinforcing social barriers to cross-territory invasion and thereby also promotes high within-group relatedness. More broadly, our results suggest that potential roles of PFD in maintaining patchily distributed diversity should be investigated more extensively in other species. PMID- 26051890 TI - Genomic signatures of cooperation and conflict in the social amoeba. AB - Cooperative systems are susceptible to invasion by selfish individuals that profit from receiving the social benefits but fail to contribute. These so-called "cheaters" can have a fitness advantage in the laboratory, but it is unclear whether cheating provides an important selective advantage in nature. We used a population genomic approach to examine the history of genes involved in cheating behaviors in the social amoeba Dictyostelium discoideum, testing whether these genes experience rapid evolutionary change as a result of conflict over spore stalk fate. Candidate genes and surrounding regions showed elevated polymorphism, unusual patterns of linkage disequilibrium, and lower levels of population differentiation, but they did not show greater between-species divergence. The signatures were most consistent with frequency-dependent selection acting to maintain multiple alleles, suggesting that conflict may lead to stalemate rather than an escalating arms race. Our results reveal the evolutionary dynamics of cooperation and cheating and underscore how sequence-based approaches can be used to elucidate the history of conflicts that are difficult to observe directly. PMID- 26051891 TI - Cell growth of wall-free L-form bacteria is limited by oxidative damage. AB - The peptidoglycan (PG) cell wall is a defining feature of the bacterial lineage and an important target for antibiotics, such as beta-lactams and glycopeptides. Nevertheless, many bacteria are capable of switching into a cell-wall-deficient state, called the "L-form" [1-3]. These variants have been classically identified as antibiotic-resistant forms in association with a wide range of infectious diseases [4]. L-forms become completely independent of the normally essential FtsZ cell division machinery [3, 5]. Instead, L-form proliferation is driven by a simple biophysical process based on an increased ratio of surface area to cell volume synthesis [6, 7]. We recently showed that only two genetic changes are needed for the L-form transition in Bacillus subtilis [7]. Class 1 mutations work to generate excess membrane synthesis [7]. Until now, the function of the class 2 mutations was unclear. We now show that these mutations work by counteracting an increase in the cellular levels of reactive oxygen species (ROS) originating from the electron transport pathway, which occurs in wall-deficient cells. Consistent with this, addition of a ROS scavenger or anaerobic culture conditions also worked to promote L-form growth without the class 2 mutations in both Gram positive B. subtilis and Gram-negative Escherichia coli. Our results suggest that physiological compensation for the metabolic imbalance that occurs when cell wall synthesis is blocked is crucial for L-form proliferation in a wide range of bacteria and also provide new insights into the mode of action of antibiotics that target the bacterial cell wall. PMID- 26051892 TI - A new horned dinosaur reveals convergent evolution in cranial ornamentation in Ceratopsidae. AB - Ceratopsid (horned) dinosaurs are an iconic group of large-bodied, quadrupedal, herbivorous dinosaurs that evolved in the Late Cretaceous and were largely restricted to western North America [1-5]. Ceratopsids are easily recognized by their cranial ornamentation in the form of nasal and postorbital horns and frill (capped by epiossifications); these structures show high morphological disparity and also represent the largest cranial display structures known to have evolved [2, 4]. Despite their restricted occurrence in time and space, this group has one of the best fossil records within Dinosauria, showing a rapid diversification in horn and frill morphology [1]. Here a new genus and species of chasmosaurine ceratopsid is described based on a nearly complete and three-dimensionally preserved cranium recovered from the uppermost St. Mary River Formation (Maastrichtian) of southwestern Alberta. Regaliceratops peterhewsi gen. et sp. nov. exhibits many unique characters of the frill and is characterized by a large nasal horncore, small postorbital horncores, and massive parietal epiossifications. Cranial morphology, particularly the epiossifications, suggests close affinity with the late Campanian/early Maastrichian taxon Anchiceratops, as well as with the late Maastrichtian taxon Triceratops. A median epiparietal necessitates a reassessment of epiossification homology and results in a more resolved phylogeny. Most surprisingly, Regaliceratops exhibits a suite of cranial ornamentations that are superficially similar to Campanian centrosaurines, indicating both exploration of novel display morphospace in Chasmosaurinae, especially Maastrichtian forms, and convergent evolution in horn morphology with the recently extinct Centrosaurinae. This marks the first time that evolutionary convergence in horn-like display structures has been demonstrated between dinosaur clades, similar to those seen in fossil and extant mammals [6]. PMID- 26051893 TI - Assembly of IFT trains at the ciliary base depends on IFT74. AB - Intraflagellar transport (IFT) moves IFT trains carrying cargoes from the cell body into the flagellum and from the flagellum back to the cell body. IFT trains are composed of complexes IFT-A and IFT-B and cargo adaptors such as the BBSome. The IFT-B core proteins IFT74 and IFT81 interact directly through central and C terminal coiled-coil domains, and recently it was shown that the N termini of these proteins form a tubulin-binding module important for ciliogenesis. To investigate the function of IFT74 and its domains in vivo, we have utilized Chlamydomonas reinhardtii ift74 mutants. In a null mutant, lack of IFT74 destabilized IFT-B, leading to flagella assembly failure. In this null background, expression of IFT74 lacking 130 amino acids (aa) of the charged N terminus stabilized IFT-B and promoted slow assembly of nearly full-length flagella. A further truncation (lacking aa 1-196, including part of coiled-coil 1) also stabilized IFT-B, but failure in IFT-A/IFT-B interaction within the pool at the base of the flagellum prevented entry of IFT-A into the flagellum and led to severely decreased IFT injection frequency and flagellar-assembly defects. Decreased IFT-A in these short flagella resulted in aggregates of stalled IFT-B in the flagella. We conclude that IFT74 is required to stabilize IFT-B; aa 197 641 are sufficient for this function in vivo. The N terminus of IFT74 may be involved in, but is not required for, tubulin entry into flagella. It is required for association of IFT-A and IFT-B at the base of the flagellum and flagellar import of IFT-A. PMID- 26051894 TI - Esco1 Acetylates Cohesin via a Mechanism Different from That of Esco2. AB - Sister chromatid cohesion is mediated by cohesin and is essential for accurate chromosome segregation. The cohesin subunits SMC1, SMC3, and Rad21 form a tripartite ring within which sister chromatids are thought to be entrapped. This event requires the acetylation of SMC3 and the association of sororin with cohesin by the acetyltransferases Esco1 and Esco2 in humans, but the functional mechanisms of these acetyltransferases remain elusive. Here, we showed that Esco1 requires Pds5, a cohesin regulatory subunit bound to Rad21, to form cohesion via SMC3 acetylation and the stabilization of the chromatin association of sororin, whereas Esco2 function was not affected by Pds5 depletion. Consistent with the functional link between Esco1 and Pds5, Pds5 interacted exclusively with Esco1, and this interaction was dependent on a unique and conserved Esco1 domain. Crucially, this interaction was essential for SMC3 acetylation and sister chromatid cohesion. Esco1 localized to cohesin localization sites on chromosomes throughout interphase in a manner that required the Esco1-Pds5 interaction, and it could acetylate SMC3 before and after DNA replication. These results indicate that Esco1 acetylates SMC3 via a mechanism different from that of Esco2. We propose that, by interacting with a unique domain of Esco1, Pds5 recruits Esco1 to chromatin-bound cohesin complexes to form cohesion. Furthermore, Esco1 acetylates SMC3 independently of DNA replication. PMID- 26051895 TI - Prosocial Choice in Rats Depends on Food-Seeking Behavior Displayed by Recipients. AB - Animals often are prosocial, displaying behaviors that result in a benefit to one another [1-15] even in the absence of self-benefit [16-21] (but see [22-25]). Several factors have been proposed to modulate these behaviors, namely familiarity [6, 13, 18, 20] or display of seeking behavior [16, 21]. Rats have been recently shown to be prosocial under distress [17, 18] (but see [26-29]); however, what drives prosociality in these animals remains unclear. To address this issue, we developed a two-choice task in which prosocial behavior did not yield a benefit or a cost to the focal rat. We used a double T-maze in which only the focal rat controlled access to the food-baited arms of its own and the recipient rat's maze. In this task, the focal rat could choose between one side of the maze, which yielded food only to itself (selfish choice), and the opposite side, which yielded food to itself and the recipient rat (prosocial choice). Rats showed a high proportion of prosocial choices. By manipulating reward delivery to the recipient and its ability to display a preference for the baited arm, we found that the display of food-seeking behavior leading to reward was necessary to drive prosocial choices. In addition, we found that there was more social investigation between rats in selfish trials than in prosocial trials, which may have influenced the focals' choices. This study shows that rats provide access to food to others in the absence of added direct self-benefit, bringing new insights into the factors that drive prosociality. PMID- 26051896 TI - Dynamic microtubules drive circuit rewiring in the absence of neurite remodeling. AB - A striking neuronal connectivity change in C. elegans involves the coordinated elimination of existing synapses and formation of synapses at new locations, without altering neuronal morphology. Here, we investigate the tripartite interaction between dynamic microtubules (MTs), kinesin-1, and vesicular cargo during this synapse remodeling. We find that a reduction in the dynamic MT population in motor neuron axons, resulting from genetic interaction between loss of function in the conserved MAPKKK dlk-1 and an alpha-tubulin mutation, specifically blocks synapse remodeling. Using live imaging and pharmacological modulation of the MT cytoskeleton, we show that dynamic MTs are increased at the onset of remodeling and are critical for new synapse formation. DLK-1 acts during synapse remodeling, and its function involves MT catastrophe factors including kinesin-13/KLP-7 and spastin/SPAS-1. Through a forward genetic screen, we identify gain-of-function mutations in kinesin-1 that can compensate for reduced dynamic MTs to promote synaptic vesicle transport during remodeling. Our data provide in vivo evidence supporting the requirement of dynamic MTs for kinesin-1 dependent axonal transport and shed light on the role of the MT cytoskeleton in facilitating neural circuit plasticity. PMID- 26051898 TI - Periaortitis induced by metformin. PMID- 26051897 TI - C-H functionalization of cyclic amines: redox-annulations with alpha,beta unsaturated carbonyl compounds. AB - Cyclic amines such as pyrrolidine and 1,2,3,4-tetrahydroisoquinoline undergo redox-annulations with alpha,beta-unsaturated aldehydes and ketones. Carboxylic acid promoted generation of a conjugated azomethine ylide is followed by 6pi electrocylization, and, in some cases, tautomerization. The resulting ring-fused pyrrolines are readily oxidized to the corresponding pyrroles or reduced to pyrrolidines. PMID- 26051899 TI - Stability and ionic mobility in argyrodite-related lithium-ion solid electrolytes. AB - In the search for fast lithium-ion conducting solids for the development of safe rechargeable all-solid-state batteries with high energy density, thiophosphates and related compounds have been demonstrated to be particularly promising both because of their record ionic conductivities and their typically low charge transfer resistances. In this work we explore a wide range of known and predicted thiophosphates with a particular focus on the cubic argyrodite phase with a robust three-dimensional network of ion migration pathways. Structural and hydrolysis stability are calculated employing density functional method in combination with a generally applicable method of predicting the relevant critical reaction. The activation energy for ion migration in these argyrodites is then calculated using the empirical bond valence pathway method developed in our group, while bandgaps of selected argyrodites are calculated as a basis for assessing the electrochemical window. Findings for the lithium compounds are also compared to those of previously known copper argyrodites and hypothetical sodium argyrodites. Therefrom, guidelines for experimental work are derived to yield phases with the optimum balance between chemical stability and ionic conductivity in the search for practical lithium and sodium solid electrolyte materials. PMID- 26051900 TI - Ruthenium-catalyzed ortho alkenylation of aromatic nitriles with activated alkenes via C-H bond activation. AB - The ruthenium-catalyzed ortho alkenylation of substituted aromatic and heteroaromatic nitriles with activated alkenes providing ortho alkenylated aromatic and heteroaromatic nitriles in a highly regio- and stereoselective manner is described. PMID- 26051901 TI - Selective inhibition of the hypoxia-inducible factor prolyl hydroxylase PHD3 by Zn(II). AB - We report herein that Zn(II) selectively inhibits the hypoxia-inducible factor prolyl hydroxylase PHD3 over PHD2, and does not compete with Fe(II). Independent of the oligomer formation induced by Zn(II), inhibition of the activity of PHD3 by Zn(II) involves Cys42 and Cys52 residues distantly located from the active site. PMID- 26051902 TI - Plasma microRNA-586 is a new biomarker for acute graft-versus-host disease. AB - Acute graft-versus-host disease (aGVHD) is one of the major causes of morbidity and mortality in patients receiving allogeneic hematopoietic cell transplantation (allo-HSCT). MicroRNAs (miRs) were found to have the potential to be the new biomarkers of aGVHD. In this study, we collected samples from 98 patients who underwent allo-HSCT; 63 patients developed aGVHD, and 35 patients did not. Plasma samples were collected at three time points (before aGVHD, at the onset of aGVHD, and after aGVHD) from 52 patients, and the miR-586 expression level was detected by quantitative real-time PCR. We found that the plasma miR-586 level was decreased at the onset of grade I-II aGVHD (P = 0.074). In contrast, when infections were detected, plasma miR-586 level was increased. Moreover, we detected the miR-586 expression level in patients who had infections but did not have aGVHD, and we found that miR-586 was upregulated (P = 0.005). We also compared the plasma miR-586 level at day 7 after transplantation between aGVHD patients and control patients. In the aGVHD group, there was a considerably higher miR-586 expression in comparison with the non-aGVHD group (P < 0.05). A more significant difference between the two groups was found when the patients with infections were excluded (P = 0.004). Furthermore, receive operating characteristic (ROC) analysis indicated that a higher expression level of miR-586 at day 7 could predict impending aGVHD. The optimal cutoff value of miR-586 to predict aGVHD was 2200 copies/MUL with a sensitivity of 87.5 % and specificity of 55.0 %, and the area under the curve (AUC) was 0.739 (95 % CI 0.598-0.880, P = 0.004). Our study suggests that miR-586 might participate in the occurrence of aGVHD and could be a putative target for novel aGVHD therapy. The plasma level of miR-586 at day 7 after allo-HSCT would be a potential biomarker for predicting the occurrence of aGVHD. PMID- 26051903 TI - Atypical presentations of thrombotic thrombocytopenic purpura in middle-aged women with recurrent cerebral macrovascular thrombosis: a case report. PMID- 26051904 TI - A novel MYH9 mutation in a patient with MYH9 disorders and platelet size-specific effect of romiplostim on macrothrombocytopenia. PMID- 26051905 TI - Time-lapse imaging of morphological changes in a single neuron during the early stages of apoptosis using scanning ion conductance microscopy. AB - Apoptosis plays an important role in many physiologic and pathologic conditions. The biochemical and morphological characteristics of apoptosis including cellular volume decrease, cell membrane blebbing, and phosphatidylserine translocation from the inner to the outer leaflet of the cell membrane are considered important events for phagocyte detection. Despite its importance, the relationship between the biological and morphological changes in a living cell has remained controversial. Scanning ion conductance microscopy is a suitable technique for investigating a series of these changes, because it allows us to observe the morphology of living cells without any mechanical interactions between the probe and the sample surface with a high resolution. Here, we investigated the biochemical and morphological changes in single neurons during the early stages of apoptosis, including apoptotic volume decrease, membrane blebbing and phosphatidylserine translocation, by using scanning ion conductance microscopy. Time-course imaging of apoptotic neurons showed there was a reduction in apoptotic volume after exposure to staurosporine and subsequent membrane bleb formation, which has a similar onset time to phosphatidylserine translocation. Our results show that a reduction in cellular volume is one of the earliest morphological changes in apoptosis, and membrane blebbing and phosphatidylserine translocation occur as subsequent biological and morphological changes. This is the first report to describe this series of morphological and biochemical changes ranging from an apoptotic volume decrease to membrane blebbing and PS translocation by scanning ion conductance microscopy (SICM). This new and direct imaging technique will provide new insight into the relationship between biochemical events inside a cell and cellular morphological changes. PMID- 26051907 TI - Moving your laboratories to the field--Advantages and limitations of the use of field portable instruments in environmental sample analysis. AB - The recent rapid progress in technology of field portable instruments has increased their applications in environmental sample analysis. These instruments offer a possibility of cost-effective, non-destructive, real-time, direct, on site measurements of a wide range of both inorganic and organic analytes in gaseous, liquid and solid samples. Some of them do not require the use of reagents and do not produce any analytical waste. All these features contribute to the greenness of field portable techniques. Several stationary analytical instruments have their portable versions. The most popular ones include: gas chromatographs with different detectors (mass spectrometer (MS), flame ionization detector, photoionization detector), ultraviolet-visible and near-infrared spectrophotometers, X-ray fluorescence spectrometers, ion mobility spectrometers, electronic noses and electronic tongues. The use of portable instruments in environmental sample analysis gives a possibility of on-site screening and a subsequent selection of samples for routine laboratory analyses. They are also very useful in situations that require an emergency response and for process monitoring applications. However, quantification of results is still problematic in many cases. The other disadvantages include: higher detection limits and lower sensitivity than these obtained in laboratory conditions, a strong influence of environmental factors on the instrument performance and a high possibility of sample contamination in the field. This paper reviews recent applications of field portable instruments in environmental sample analysis and discusses their analytical capabilities. PMID- 26051906 TI - Structure of EspB, a secreted substrate of the ESX-1 secretion system of Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis secretes multiple virulence factors during infection via the general Sec and Tat pathways, and via specialized ESX secretion systems, also referred to as type VII secretion systems. The ESX-1 secretion system is an important virulence determinant because deletion of ESX-1 leads to attenuation of M. tuberculosis. ESX-1 secreted protein B (EspB) contains putative PE (Pro-Glu) and PPE (Pro-Pro-Glu) domains, and a C-terminal domain, which is processed by MycP1 protease during secretion. We determined the crystal structure of PE-PPE domains of EspB, which represents an all-helical, elongated molecule closely resembling the structure of the PE25-PPE41 heterodimer despite limited sequence similarity. Also, we determined the structure of full-length EspB, which does not have interpretable electron density for the C-terminal domain confirming that it is largely disordered. Comparative analysis of EspB in cell lysate and culture filtrates of M. tuberculosis revealed that mature secreted EspB forms oligomers. Electron microscopy analysis showed that the N-terminal fragment of EspB forms donut-shaped particles. These data provide a rationale for the future investigation of EspB's role in M. tuberculosis pathogenesis. PMID- 26051908 TI - Longitudinal studies: An essential component for complex psychiatric disorders. AB - Most psychiatric syndromes are chronic and lifetime in course. Kraepelin's seminal work pointed out a century ago that longitudinal/lifetime assessments were powerful aids in differentiating dementia praecox from manic-depressive disorder. Despite this, clinical research investigations in psychiatry have historically emphasized short-term and cross-sectional approaches. This review of an array of longitudinal studies supports that they are arguably an essential component of psychiatric investigations, but that they must be coupled with other approaches. The use of standardized, validated, repeated assessments in a disease over the course of time must be incorporated with pathophysiology investigations to identify underlying mechanisms, biomarker studies, comparative effectiveness clinical trials to identify the best treatments for different causes, and translational strategies to provide the right treatments to the right patients at the right time. Strategies for incorporating longitudinal assessments into newer diagnostic proposals, such as the Research Domain Criteria (RDoC), are discussed. PMID- 26051909 TI - E-selectin and P-selectin expression in endothelium of leprosy skin lesions. AB - Leprosy is an infectious-contagious disease whose clinical evolution depends on the immune response pattern of the host. Adhesion molecules and leukocyte migration from blood to tissue are of the utmost importance for the recognition and elimination of infectious pathogens. Selectins are transmembrane glycoproteins that share a similar structural organization and can be divided into three types according to their site of expression. The biopsies were cut into 5MUm thick sections and submitted to immunohistochemistry using antibodies against E-selectin and P-selectin. The number of E-selectin-positive cells was significantly higher in the tuberculoid form than in the lepromatous form. The immunostaining pattern of P-selectin differed from that of E-selectin. Analysis showed a larger number of endothelial cells expressing CD62P in the lepromatous form compared to the tuberculoid form. The presence of these adhesins in the endothelium contributing to or impairing the recruitment of immune cells to inflamed tissue and consequently influences the pattern of immune response and the clinical presentation of the disease. PMID- 26051910 TI - Reservoir host competence and the role of domestic and commensal hosts in the transmission of Trypanosoma cruzi. AB - We review the epidemiological role of domestic and commensal hosts of Trypanosoma cruzi using a quantitative approach, and compiled >400 reports on their natural infection. We link the theory underlying simple mathematical models of vector borne parasite transmission to the types of evidence used for reservoir host identification: mean duration of infectious life; host infection and infectiousness; and host-vector contact. The infectiousness of dogs or cats most frequently exceeded that of humans. The host-feeding patterns of major vectors showed wide variability among and within triatomine species related to their opportunistic behavior and variable ecological, biological and social contexts. The evidence shows that dogs, cats, commensal rodents and domesticated guinea pigs are able to maintain T. cruzi in the absence of any other host species. They play key roles as amplifying hosts and sources of T. cruzi in many (peri)domestic transmission cycles covering a broad diversity of ecoregions, ecotopes and triatomine species: no other domestic animal plays that role. Dogs comply with the desirable attributes of natural sentinels and sometimes were a point of entry of sylvatic parasite strains. The controversies on the role of cats and other hosts illustrate the issues that hamper assessing the relative importance of reservoir hosts on the basis of fragmentary evidence. We provide various study cases of how eco-epidemiological and genetic-marker evidence helped to unravel transmission cycles and identify the implicated hosts. Keeping dogs, cats and rodents out of human sleeping quarters and reducing their exposure to triatomine bugs are predicted to strongly reduce transmission risks. PMID- 26051911 TI - Local hyperthermia combined with radiotherapy and-/or chemotherapy: recent advances and promises for the future. AB - Hyperthermia, one of the oldest forms of cancer treatment involves selective heating of tumor tissues to temperatures ranging between 39 and 45 degrees C. Recent developments based on the thermoradiobiological rationale of hyperthermia indicate it to be a potent radio- and chemosensitizer. This has been further corroborated through positive clinical outcomes in various tumor sites using thermoradiotherapy or thermoradiochemotherapy approaches. Moreover, being devoid of any additional significant toxicity, hyperthermia has been safely used with low or moderate doses of reirradiation for retreatment of previously treated and recurrent tumors, resulting in significant tumor regression. Recent in vitro and in vivo studies also indicate a unique immunomodulating prospect of hyperthermia, especially when combined with radiotherapy. In addition, the technological advances over the last decade both in hardware and software have led to potent and even safer loco-regional hyperthermia treatment delivery, thermal treatment planning, thermal dose monitoring through noninvasive thermometry and online adaptive temperature modulation. The review summarizes the outcomes from various clinical studies (both randomized and nonrandomized) where hyperthermia is used as a thermal sensitizer of radiotherapy and-/or chemotherapy in various solid tumors and presents an overview of the progresses in loco-regional hyperthermia. These recent developments, supported by positive clinical outcomes should merit hyperthermia to be incorporated in the therapeutic armamentarium as a safe and an effective addendum to the existing oncological treatment modalities. PMID- 26051912 TI - Ultrasensitive and feasibly achieved protein detection based on the integration of three signal amplification reactions via sharing a DNA sequence. AB - This communication reports a novel strategy for the detection of proteins based on the integration of three signal amplification reactions via sharing a specially designed DNA sequence. This strategy has been demonstrated by the assay of human TNF-alpha in the serum of ovarian cancer patients, showing potential clinical applications. PMID- 26051917 TI - Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases. AB - Inflammatory diseases of the aorta include routine atherosclerosis, aortitis, periaortitis, and atherosclerosis with excessive inflammatory responses, such as inflammatory atherosclerotic aneurysms. The nomenclature and histologic features of these disorders are reviewed and discussed. In addition, diagnostic criteria are provided to distinguish between these disorders in surgical pathology specimens. An initial classification scheme is provided for aortitis and periaortitis based on the pattern of the inflammatory infiltrate: granulomatous/giant cell pattern, lymphoplasmacytic pattern, mixed inflammatory pattern, and the suppurative pattern. These inflammatory patterns are discussed in relation to specific systemic diseases including giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegener's), rheumatoid arthritis, sarcoidosis, ankylosing spondylitis, Cogan syndrome, Behcet's disease, relapsing polychondritis, syphilitic aortitis, and bacterial and fungal infections. PMID- 26051918 TI - Index sorting resolves heterogeneous murine hematopoietic stem cell populations. AB - Recent advances in the cellular and molecular biology of single stem cells have uncovered significant heterogeneity in the functional properties of stem cell populations. This has prompted the development of approaches to study single cells in isolation, often performed using multiparameter flow cytometry. However, many stem cell populations are too rare to test all possible cell surface marker combinations, and virtually nothing is known about functional differences associated with varying intensities of such markers. Here we describe the use of index sorting for further resolution of the flow cytometric isolation of single murine hematopoietic stem cells (HSCs). Specifically, we associate single-cell functional assay outcomes with distinct cell surface marker expression intensities. High levels of both CD150 and EPCR associate with delayed kinetics of cell division and low levels of differentiation. Moreover, cells that do not form single HSC-derived clones appear in the 7AAD(dim) fraction, suggesting that even low levels of 7AAD staining are indicative of less healthy cell populations. These data indicate that when used in combination with single-cell functional assays, index sorting is a powerful tool for refining cell isolation strategies. This approach can be broadly applied to other single-cell systems, both to improve isolation and to acquire additional cell surface marker information. PMID- 26051919 TI - Insights into cell ontogeny, age, and acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a heterogenous disease of hematopoietic stem cells (HSCs) and progenitor cells (HSPCs). The pathogenesis of AML involves cytogenetic abnormalities, genetic mutations, and epigenetic anomalies. Although it is widely accepted that the cellular biology, gene expression, and epigenetic landscape of normal HSCs change with age, little is known about the interplay between the age at which the cell becomes leukemic and the resultant leukemia. Despite its rarity, childhood AML is a leading cause of childhood cancer mortality. Treatment is in general extrapolated from adult AML on the assumption that adult AML and pediatric AML are similar biological entities. However, distinct biological processes and epigenetic modifications in pediatric and adult AML may mean that response to novel therapies in children may differ from that in adults with AML. A better understanding of the key pathways involved in transformation and how these differ between childhood and adult AML is an important step in identifying effective treatment. This review highlights both the commonalities and differences between pediatric and adult AML disease biology with respect to age. PMID- 26051920 TI - Development of epilepsy after neonatal seizures. PMID- 26051921 TI - From the Editor. PMID- 26051922 TI - Personalizing precision medicine. PMID- 26051923 TI - Comparison of Morisky Medication Adherence Scale with therapeutic drug monitoring in apparent treatment-resistant hypertension. AB - The Morisky Medication Adherence Scale (MMAS-8) is a questionnaire developed for screening of non-adherence in patients with several chronic conditions, including uncomplicated hypertension. However, its accuracy in predicting non-adherence in patients with apparent treatment-resistant hypertension (a-TRH) is not known. Accordingly, we performed a retrospective study in 47 patients with a-TRH who had completed the eight-item MMAS during the initial clinic visit. Non-adherence was defined as presence of undetected serum levels of at least one prescribed antihypertensive drug by therapeutic drug monitoring. We found that 26% of patients were considered to have low adherence score (<6), while the actual prevalence of non-adherence was 51% by therapeutic drug monitoring. Sensitivity of the MMAS-8 was 26% (95% confidence interval, 10.3%-48.4%) with specificity of 75% (95% confidence interval, 53.3%-90.2%). By multivariate analysis, the MMAS-8 score was not an independent predictor of non-adherence, while certain clinical parameters such as heart rate were found to be independent predictors of non adherence. Our study suggested limited accuracy of the MMAS-8 in detecting medication non-adherence in a-TRH. PMID- 26051924 TI - The impact of kidney transplantation on 24-hour ambulatory blood pressure in end stage renal disease patients. AB - In this study, we prospectively investigated the impact of kidney transplantation (KT) on the status of hypertension, including circadian rhythm in end-stage renal disease (ESRD) patients. We performed 24-hour ambulatory blood pressure (BP) monitoring and office BP measurement in 48 patients before and 1 year after KT. According to the nocturnal reduction in systolic BP (DeltaSBP), the patients were divided into dippers, non-dippers, and reverse dippers. After KT, the mean BP value in office BP and 24-hour ambulatory BP monitoring did not change, but the proportion of patients taking anti-hypertensive drugs and the pill number significantly decreased. In contrast, the mean DeltaSBP significantly decreased, and the proportion of non-dippers and reverse dippers did not decrease. Decrease in DeltaSBP after KT was associated with inferior allograft function during follow-up. Our study suggests that KT improved the overall BP level, but it did not affect abnormal circadian rhythm in ESRD patients. PMID- 26051925 TI - Effects of carotid body tumor resection on the blood pressure of essential hypertensive patients. AB - Removal of carotid body (CB) improves animal models of hypertension (HTN) and heart failure, via withdrawal of chemoreflex-induced sympathetic activation. Effect of CB tumor (CBT) resection on blood pressure (BP) in subjects with HTN is unknown. A retrospective analysis of 20 subjects with HTN (BP>=140/90 mmHg or anti-hypertensives use) out of 134 with CBT resection. Short-term (30 days from surgery) and long-term (slope of regressions on time over the entire follow-up) changes in BP and heart rate were adjusted for covariates (interval between readings, total follow-up, number of readings and changes in therapy). Age and duration of HTN were 56+/-4 and 9+/-5 years. Adjusted short-term decreases in systolic (SBP: -9.9+/-3.1, p<0.001) and pulse pressures (PP: -7.9+/-2.7, p<0.002) were significant and correlated with their respective long-term changes (SBP: r=0.47, p=0.047; PP: r=0.54, p=0.019). There was a strong relationship between adjusted short-term changes in SBP and PP (r=0.64, p<0.004). Six (50% of responders or 33% of the total) had short-term falls of SBP >=10 mmHg and of PP >= 5 mmHg. First study to show that unilateral CBT resection is associated with sustained reduction of BP in hypertensive patients. Targeted CB chemoreflex removal could play a role in the therapy of human HTN. PMID- 26051926 TI - Regional and physician specialty-associated variations in the medical management of atherosclerotic renal-artery stenosis. AB - For people enrolled in Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL), we sought to examine whether variation exists in the baseline medical therapy of different geographic regions and if any variations in prescribing patterns were associated with physician specialty. Patients were grouped by location within the United States (US) and outside the US (OUS), which includes Canada, South America, Europe, South Africa, New Zealand, and Australia. When comparing US to OUS, participants in the US took fewer anti-hypertensive medications (1.9 +/- 1.5 vs. 2.4 +/- 1.4; P < .001) and were less likely to be treated with an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker (46% vs. 62%; P < .001), calcium channel antagonist (37% vs. 58%; P < .001), and statin (64% vs. 75%; P < .05). In CORAL, the identification of variations in baseline medical therapy suggests that substantial opportunities exist to improve the medical management of patients with atherosclerotic renal artery stenosis. PMID- 26051927 TI - Effectiveness of contact precautions against multidrug-resistant organism transmission in acute care: a systematic review of the literature. AB - Contact precautions are widely recommended to prevent multidrug-resistant organism (MDRO) transmission. However, conflicting data exist regarding their effectiveness. Prior systematic reviews examined contact precautions as part of a larger bundled approach, limiting ability to understand their effectiveness. The aim of this review was to characterize the effectiveness of contact precautions alone against transmission of any MDRO among adult acute care patients. Directed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, comprehensive searches of four electronic scientific literature databases were conducted for studies published in English from January 2004 to June 2014. Studies were included if interventional, original research, evaluating contact isolation precautions against MDRO transmission among inpatients. Searches returned 284 studies, six of which were included in the review. These studies measured four different MDROs with one study showing a reduction in transmission. Whereas studies were of high quality regarding outcome operationalization and statistical analyses, overall quality was moderate to low due to poor intervention description, population characterization and potential biases. Where compliance was measured (N = 4), it presented a threat to validity because it included select parts of the intervention, ranged from 21% to 87%, and was significantly different across study phases (N = 2). The poor quality of evidence on this topic continues to limit interpretation of these data. Hence, this conflicting body of literature does not constitute evidence for or against contact precautions. We recommend that researchers consider power calculation, compliance monitoring, non-equivalent concurrent controls when designing future studies on this topic. PMID- 26051928 TI - Thalassemia and risk of dementia: a nationwide population-based retrospective cohort study. AB - BACKGROUND: This study is a nationwide population-based retrospective cohort study to investigate the risk for developing dementia in thalassemia population. METHODS: In a longitudinal cohort of 1 million insured people, we identified 871 thalassemia patients who were newly diagnosed between 2000 and 2004 and selected a comparison cohort of 3484 subjects without thalassemia. We analyzed the risks for thalassemia and dementia using Cox proportional hazard regression models to assess the dementia risk in thalassemia patients after adjusting for age, gender, insured amount, urbanization and comorbidities. RESULTS: The overall risks for developing dementia were 1.88-fold (95% CI=1.10-3.21) in patients with thalassemia compared with the comparison cohort after adjusting for age, sex, insured amount, urbanization and comorbidities. The combined effects measured for patients afflicted with thalassemia and the comorbidities of diabetes, hypertension, CAD, head injury, depression, CKD, or substance-related disorder exhibited a significant association with hyperlipidemia risk compared with that measured for patients without thalassemia and without any counterpart comorbidities. In subgroup analysis, the HRs of dementia increased, from 1.69 (95% CI=0.93-3.07) for those who had not undergone transfusion to 2.72 (95% CI=1.09-6.78) for those experienced transfusion compared with the no thalassemia cohort (p for trend<0.01). CONCLUSION: Our long-term cohort study result showed that thalassemia should be considered a crucial risk factor for developing dementia. PMID- 26051929 TI - [Features associated with retinal thickness extension in diabetic macular oedema]. AB - BACKGROUND: Clinically significant macular edema has features that are associated with a major risk of visual loss, with thickening that involves the centre of the macula, field 7 or visual deficiency, although it is unknown if these features are related to retinal thickness extension. MATERIAL AND METHODS: An observational, analytical, prospective, cross-sectional and open study was conducted. The sample was divided into initial visual acuity >=0.5, central field thickness, center point thickness, field 7 and macular volume more than the reported 2 standard deviation mean value in eyes without retinopathy. The extension was determined by the number of the central field area equivalent thickening and these features were compared with by Student's t test for independent samples. RESULTS: A total of 199 eyes were included. In eyes with visual acuity of >=0.5, the mean extension was 2.88+/-1.68 and 3.2+/-1.63 in area equivalent in eyes with visual acuity <0.5 (p=0.12). The mean extension in eyes with less than 2 standard deviation of central field thickness, center point thickness, field 7 and macular volume was significantly lower than in eyes with more than 2 standard deviations (1.9+/-0.93 vs. 4.07+/-1.49, 2.44+/-1.47 vs. 3.94+/-1.52, 1.79+/-1.07 vs. 3.61+/-1.57 and 1.6+/-0.9 vs. 3.9+/-1.4, respectively, p<0.001). CONCLUSIONS: The extension of retinal thickness is related with the anatomical features reported with a greater risk of visual loss, but is not related to initial visual deficiency. PMID- 26051930 TI - Age-related intraneuronal accumulation of alphaII-spectrin breakdown product SBDP120 in the human cerebrum is enhanced in Alzheimer's disease. AB - Spectrins are a part of cytoskeletal platform that lines the intracellular side of plasma membrane, which can be proteolyzed by calcium-sensitive enzymes including calpains and caspases. Caspase-3 mediated alphaII-spectrin proteolysis results in the release of a 120kDa spectrin breakdown product (SBDP120), known to occur in conditions with cell death. In rodents, intraneuronal SBDP120 accumulation in the forebrain develops with age, which is enhanced in transgenic models of Alzheimer's disease (AD). The present study was set to explore age related SBDP120 formation and its relevance to AD-type hallmark lesions in the human brains. SBDP120 immunoreactivity (IR) was detected in neuronal somata and dendrites in the cortex and hippocampal formation in postmortem brains from aged (n=10, mean age=84.2) and AD (n=10, mean age=84.8) subjects, but not mid-aged controls (n=10, mean age=58.2). The overall density of SBDP120 IR quantified in the temporal neocortex was increased in the aged and AD groups, more robust in the latter, relative to mid-aged control, while no regional, laminar or cellular association was found between SBDP120 accumulation and Abeta deposition or phosphorylated-tau aggregation. In cultured rat retinal ganglion cells (RGC-5), SBDP120 elevation occurred with caspase-3 activation following oxygen as well as serum deprivation, suggestive of SBDP120 formation in stressful conditions with and without apparent neuronal death. These results confirm an age-related intraneuronal SBDP120 accumulation in the human cerebrum that is enhanced in AD. This neuronal change appears to occur independent of amyloid deposition, tau pathology and overt neuronal death. PMID- 26051931 TI - Interleukin-6 as a first-rated serum inflammatory marker to predict mortality and hospitalization in the oldest old: A regression and CART approach in the BELFRAIL study. AB - BACKGROUND: Certain inflammatory biomarkers increase with age, provide information about general burden of illness and could cause or reflect any collateral damage to healthy cells and organs. However, comparative studies to predict adverse outcomes are missing. Therefore, our study validated and identified the principal prognostic marker to predict important adverse outcomes in the oldest old from an extensive battery of serum inflammatory markers. METHODS: A large battery of potential 'inflammaging' markers (IL-1alpha, IL1 beta, IL-4, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma, EGF, VEGF, MCP-1, usCRP, prealbumin) was assessed in a representative sample of 415 heterogenic individuals 80years of age or older in the BELFRAIL study. Kaplan-Meier, Cox proportional hazards and CART analyses determined the overall prognostic value of these markers for predicting all-cause, cardiovascular and non-cardiovascular mortality as well as hospitalization. RESULTS: Serum IL-6 and usCRP levels were strongly associated with time of survival, independent of cause of death. Serum IL-6 levels had the most robust dose-response relationship with mortality. To a lesser extent, IL-10 and IL-1beta were associated with all-cause mortality but were restricted to non-cardiovascular or cardiovascular mortality, respectively. Having a low IL-6 at baseline (<1.77pg/ml) could predict 90% of those who were not at risk for all-cause mortality after 3years, even after adjusting for confounders. Similarly, we observed an 83.6% chance of identifying those cases with 0 or 1 hospitalization using low IL-6 serum levels. CONCLUSION: The results suggest that a single measurement of low IL-6 serum levels is the first choice to guide clinical practice in the oldest old and could summarize the short-term risk of death and hospitalization. PMID- 26051932 TI - Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms. AB - Fragile X mental retardation protein (FMRP) and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2) is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development. PMID- 26051933 TI - Production of Extrachromosomal MicroDNAs Is Linked to Mismatch Repair Pathways and Transcriptional Activity. AB - MicroDNAs are <400-base extrachromosomal circles found in mammalian cells. Tens of thousands of microDNAs have been found in all tissue types, including sperm. MicroDNAs arise preferentially from areas with high gene density, GC content, and exon density from promoters with activating chromatin modifications and in sperm from the 5'-UTR of full-length LINE-1 elements, but are depleted from lamin associated heterochromatin. Analysis of microDNAs from a set of human cancer cell lines revealed lineage-specific patterns of microDNA origins. A survey of microDNAs from chicken cells defective in various DNA repair proteins reveals that homologous recombination and non-homologous end joining repair pathways are not required for microDNA production. Deletion of the MSH3 DNA mismatch repair protein results in a significant decrease in microDNA abundance, specifically from non-CpG genomic regions. Thus, microDNAs arise as part of normal cellular physiology-either from DNA breaks associated with RNA metabolism or from replication slippage followed by mismatch repair. PMID- 26051934 TI - Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers. AB - A highly glycosylated, trimeric envelope glycoprotein (Env) mediates HIV-1 cell entry. The high density and heterogeneity of the glycans shield Env from recognition by the immune system, but paradoxically, many potent broadly neutralizing antibodies (bNAbs) recognize epitopes involving this glycan shield. To better understand Env glycosylation and its role in bNAb recognition, we characterized a soluble, cleaved recombinant trimer (BG505 SOSIP.664) that is a close structural and antigenic mimic of native Env. Large, unprocessed oligomannose-type structures (Man8-9GlcNAc2) are notably prevalent on the gp120 components of the trimer, irrespective of the mammalian cell expression system or the bNAb used for affinity purification. In contrast, gp41 subunits carry more highly processed glycans. The glycans on uncleaved, non-native oligomeric gp140 proteins are also highly processed. A homogeneous, oligomannose-dominated glycan profile is therefore a hallmark of a native Env conformation and a potential Achilles' heel that can be exploited for bNAb recognition and vaccine design. PMID- 26051935 TI - Quaternary Structure Defines a Large Class of Amyloid-beta Oligomers Neutralized by Sequestration. AB - The accumulation of amyloid-beta (Abeta) as amyloid fibrils and toxic oligomers is an important step in the development of Alzheimer's disease (AD). However, there are numerous potentially toxic oligomers and little is known about their neurological effects when generated in the living brain. Here we show that Abeta oligomers can be assigned to one of at least two classes (type 1 and type 2) based on their temporal, spatial, and structural relationships to amyloid fibrils. The type 2 oligomers are related to amyloid fibrils and represent the majority of oligomers generated in vivo, but they remain confined to the vicinity of amyloid plaques and do not impair cognition at levels relevant to AD. Type 1 oligomers are unrelated to amyloid fibrils and may have greater potential to cause global neural dysfunction in AD because they are dispersed. These results refine our understanding of the pathogenicity of Abeta oligomers in vivo. PMID- 26051936 TI - Developmental Alterations in Heart Biomechanics and Skeletal Muscle Function in Desmin Mutants Suggest an Early Pathological Root for Desminopathies. AB - Desminopathies belong to a family of muscle disorders called myofibrillar myopathies that are caused by Desmin mutations and lead to protein aggregates in muscle fibers. To date, the initial pathological steps of desminopathies and the impact of desmin aggregates in the genesis of the disease are unclear. Using live, high-resolution microscopy, we show that Desmin loss of function and Desmin aggregates promote skeletal muscle defects and alter heart biomechanics. In addition, we show that the calcium dynamics associated with heart contraction are impaired and are associated with sarcoplasmic reticulum dilatation as well as abnormal subcellular distribution of Ryanodine receptors. Our results demonstrate that desminopathies are associated with perturbed excitation-contraction coupling machinery and that aggregates are more detrimental than Desmin loss of function. Additionally, we show that pharmacological inhibition of aggregate formation and Desmin knockdown revert these phenotypes. Our data suggest alternative therapeutic approaches and further our understanding of the molecular determinants modulating Desmin aggregate formation. PMID- 26051938 TI - Aurora Kinase B Regulates Telomerase Activity via a Centromeric RNA in Stem Cells. AB - Non-coding RNAs can modulate histone modifications that, at the same time, affect transcript expression levels. Here, we dissect such a network in mouse embryonic stem cells (ESCs). It regulates the activity of the reverse transcriptase telomerase, which synthesizes telomeric repeats at the chromosome ends. We find that histone H3 serine 10 phosphorylation set by Aurora kinase B (AURKB) in ESCs during the S phase of the cell cycle at centromeric and (sub)telomeric loci promotes the expression of non-coding minor satellite RNA (cenRNA). Inhibition of AURKB induces silencing of cenRNA transcription and establishment of a repressive chromatin state with histone H3 lysine 9 trimethylation and heterochromatin protein 1 accumulation. This process results in a continuous shortening of telomeres. We further show that AURKB interacts with both telomerase and cenRNA and activates telomerase in trans. Thus, in mouse ESCs, telomere maintenance is regulated via expression of cenRNA in a cell-cycle-dependent manner. PMID- 26051937 TI - Acute Lung Injury Results from Innate Sensing of Viruses by an ER Stress Pathway. AB - Incursions of new pathogenic viruses into humans from animal reservoirs are occurring with alarming frequency. The molecular underpinnings of immune recognition, host responses, and pathogenesis in this setting are poorly understood. We studied pandemic influenza viruses to determine the mechanism by which increasing glycosylation during evolution of surface proteins facilitates diminished pathogenicity in adapted viruses. ER stress during infection with poorly glycosylated pandemic strains activated the unfolded protein response, leading to inflammation, acute lung injury, and mortality. Seasonal strains or viruses engineered to mimic adapted viruses displaying excess glycans on the hemagglutinin did not cause ER stress, allowing preservation of the lungs and survival. We propose that ER stress resulting from recognition of non-adapted viruses is utilized to discriminate "non-self" at the level of protein processing and to activate immune responses, with unintended consequences on pathogenesis. Understanding this mechanism should improve strategies for treating acute lung injury from zoonotic viral infections. PMID- 26051939 TI - Glucose-Regulated Phosphorylation of the PUF Protein Puf3 Regulates the Translational Fate of Its Bound mRNAs and Association with RNA Granules. AB - PUF proteins are post-transcriptional regulators that bind to the 3' UTRs of mRNA transcripts. Herein, we show how a yeast PUF protein, Puf3p, responds to glucose availability to switch the fate of its bound transcripts that encode proteins required for mitochondrial biogenesis. Upon glucose depletion, Puf3p becomes heavily phosphorylated within its N-terminal region of low complexity, associates with polysomes, and promotes translation of its target mRNAs. Such nutrient responsive phosphorylation toggles the activity of Puf3p to promote either degradation or translation of these mRNAs according to the needs of the cell. Moreover, activation of translation of pre-existing mRNAs might enable rapid adjustment to environmental changes without the need for de novo transcription. Strikingly, a Puf3p phosphomutant no longer promotes translation but becomes trapped in intracellular foci in an mRNA-dependent manner. Our findings suggest that the inability to properly resolve Puf3p-containing RNA-protein granules via a phosphorylation-based mechanism might be toxic to a cell. PMID- 26051940 TI - ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis. AB - ASXL2 is an ETP family protein that interacts with PPARgamma. We find that ASXL2 /- mice are insulin resistant, lipodystrophic, and fail to respond to a high-fat diet. Consistent with genetic variation at the ASXL2 locus and human bone mineral density, ASXL2-/- mice are also severely osteopetrotic because of failed osteoclast differentiation attended by normal bone formation. ASXL2 regulates the osteoclast via two distinct signaling pathways. It induces osteoclast formation in a PPARgamma/c-Fos-dependent manner and is required for RANK ligand- and thiazolidinedione-induced bone resorption independent of PGC-1beta. ASXL2 also promotes osteoclast mitochondrial biogenesis in a process mediated by PGC-1beta but independent of c-Fos. Thus, ASXL2 is a master regulator of skeletal, lipid, and glucose homeostasis. PMID- 26051941 TI - Single-Cell Network Analysis Identifies DDIT3 as a Nodal Lineage Regulator in Hematopoiesis. AB - We explore cell heterogeneity during spontaneous and transcription-factor-driven commitment for network inference in hematopoiesis. Since individual genes display discrete OFF states or a distribution of ON levels, we compute and combine pairwise gene associations from binary and continuous components of gene expression in single cells. Ddit3 emerges as a regulatory node with positive linkage to erythroid regulators and negative association with myeloid determinants. Ddit3 loss impairs erythroid colony output from multipotent cells, while forcing Ddit3 in granulo-monocytic progenitors (GMPs) enhances self-renewal and impedes differentiation. Network analysis of Ddit3-transduced GMPs reveals uncoupling of myeloid networks and strengthening of erythroid linkages. RNA sequencing suggests that Ddit3 acts through development or stabilization of a precursor upstream of GMPs with inherent Meg-E potential. The enrichment of Gata2 target genes in Ddit3-dependent transcriptional responses suggests that Ddit3 functions in an erythroid transcriptional network nucleated by Gata2. PMID- 26051942 TI - NRP1 Regulates CDC42 Activation to Promote Filopodia Formation in Endothelial Tip Cells. AB - Sprouting blood vessels are led by filopodia-studded endothelial tip cells that respond to angiogenic signals. Mosaic lineage tracing previously revealed that NRP1 is essential for tip cell function, although its mechanistic role in tip cells remains poorly defined. Here, we show that NRP1 is dispensable for genetic tip cell identity. Instead, we find that NRP1 is essential to form the filopodial bursts that distinguish tip cells morphologically from neighboring stalk cells, because it enables the extracellular matrix (ECM)-induced activation of CDC42, a key regulator of filopodia formation. Accordingly, NRP1 knockdown and pharmacological CDC42 inhibition similarly impaired filopodia formation in vitro and in developing zebrafish in vivo. During mouse retinal angiogenesis, CDC42 inhibition impaired tip cell and vascular network formation, causing defects that resembled those due to loss of ECM-induced, but not VEGF-induced, NRP1 signaling. We conclude that NRP1 enables ECM-induced filopodia formation for tip cell function during sprouting angiogenesis. PMID- 26051943 TI - Somatic Cell Fusions Reveal Extensive Heterogeneity in Basal-like Breast Cancer. AB - Basal-like and luminal breast tumors have distinct clinical behavior and molecular profiles, yet the underlying mechanisms are poorly defined. To interrogate processes that determine these distinct phenotypes and their inheritance pattern, we generated somatic cell fusions and performed integrated genetic and epigenetic (DNA methylation and chromatin) profiling. We found that the basal-like trait is generally dominant and is largely defined by epigenetic repression of luminal transcription factors. Definition of super-enhancers highlighted a core program common in luminal cells but a high degree of heterogeneity in basal-like breast cancers that correlates with clinical outcome. We also found that protein extracts of basal-like cells are sufficient to induce a luminal-to-basal phenotypic switch, implying a trigger of basal-like autoregulatory circuits. We determined that KDM6A might be required for luminal basal fusions, and we identified EN1, TBX18, and TCF4 as candidate transcriptional regulators of the luminal-to-basal switch. Our findings highlight the remarkable epigenetic plasticity of breast cancer cells. PMID- 26051944 TI - Deletion of Inpp5a causes ataxia and cerebellar degeneration in mice. AB - The progressive and permanent loss of cerebellar Purkinje cells (PC) is a hallmark of many inherited ataxias. Mutations in several genes involved in the regulation of Ca(2+) release from intracellular stores by the second messenger IP3 have been associated with PC dysfunction or death. While much is known about the defects in production and response to IP3, less is known about the defects in breakdown of the IP3 second messenger. A mutation in Inpp4a of the pathway is associated with a severe, early-onset PC degeneration in the mouse model weeble. The step preceding the removal of the 4-phosphate is the removal of the 5 phosphate by Inpp5a. Gene expression analysis was performed on an Inpp5a (Gt(OST50073)Lex) mouse generated by gene trap insertion using quantitative real time PCR (qRT-PCR), immunohistochemistry, and Western blot. Phenotypic analyses were performed using rotarod, beta-galactosidase staining, and phosphatase activity assay. Statistical significance was calculated. The deletion of Inpp5a causes an early-onset yet slowly progressive PC degeneration and ataxia. Homozygous mutants (90%) exhibit perinatal lethality; surviving homozygotes show locomotor instability at P16. A consistent pattern of PC loss in the cerebellum is initially detectable by weaning and widespread by P60. Phosphatase activity toward phosphoinositol substrates is reduced in the mutant relative to littermates. The ataxic phenotype and characteristics neurodegeneration of the Inpp5a (Gt(OST50073)Lex) mouse indicate a crucial role for Inpp5a in PC survival. The identification of the molecular basis of the selective PC survival will be important in defining a neuroprotective gene applicable to establishing a disease mechanism. PMID- 26051945 TI - Site-specific processing of Ras and Rap1 Switch I by a MARTX toxin effector domain. AB - Ras (Rat sarcoma) protein is a central regulator of cell growth and proliferation. Mutations in the RAS gene are known to occur in human cancers and have been shown to contribute to carcinogenesis. In this study, we show that the multifunctional-autoprocessing repeats-in-toxin (MARTX) toxin-effector domain DUF5(Vv) from Vibrio vulnificus to be a site-specific endopeptidase that cleaves within the Switch 1 region of Ras and Rap1. DUF5(Vv) processing of Ras, which occurs both biochemically and in mammalian cell culture, inactivates ERK1/2, thereby inhibiting cell proliferation. The ability to cleave Ras and Rap1 is shared by DUF5(Vv) homologues found in other bacteria. In addition, DUF5(Vv )can cleave all Ras isoforms and KRas with mutations commonly implicated in malignancies. Therefore, we speculate that this new family of Ras/Rap1-specific endopeptidases (RRSPs) has potential to inactivate both wild-type and mutant Ras proteins expressed in malignancies. PMID- 26051946 TI - Safety evaluation of olaparib for treating ovarian cancer. AB - INTRODUCTION: Olaparib (Lynparza(r)) is an oral, small molecule, poly (ADP ribose) polymerase inhibitor that has become the first 'personalized' therapy available for patients with BRCA mutation-positive ovarian cancer (OC). A capsule formulation of the drug has recently received approval for use in this population for platinum-sensitive recurrent disease for maintenance therapy following platinum-based chemotherapy in Europe and as third- or fourth-line platinum sensitive therapy in the USA. AREAS COVERED: This article reviews the development of olaparib in OC with a focus on safety evaluation. Data are based on published literature and reports available from the olaparib development program database. EXPERT OPINION: Oral olaparib 400 mg twice daily has acceptable tolerability when administered as maintenance monochemotherapy in women with relapsed OC. The common toxicities - nausea/vomiting, fatigue and anemia - are mild or moderate in severity and appear consistent across subgroups (BRCA carriers/wild-type). Though the risk is low, long-term monitoring of patients is warranted to determine the potential risk for hematological complications such as anemia, myelodysplastic syndrome or acute myeloid leukemia. PMID- 26051948 TI - Role of platelets in allergic airway inflammation. AB - Increasing evidence suggests an important role for platelets and their products (e.g., platelet factor 4, beta-thromboglobulin, RANTES, thromboxane, or serotonin) in the pathogenesis of allergic diseases. A variety of changes in platelet function have been observed in patients with asthma, such as alterations in platelet secretion, expression of surface molecules, aggregation, and adhesion. Moreover, platelets have been found to actively contribute to most of the characteristic features of asthma, including bronchial hyperresponsiveness, bronchoconstriction, airway inflammation, and airway remodeling. This review brings together the current available data from both experimental and clinical studies that have investigated the role of platelets in allergic airway inflammation and asthma. It is anticipated that a better understanding of the role of platelets in the pathogenesis of asthma might lead to novel promising therapeutic approaches in the treatment of allergic airway diseases. PMID- 26051947 TI - Platelets in patients with aspirin-exacerbated respiratory disease. AB - Aspirin-exacerbated respiratory disease (AERD) is a chronic inflammatory disease characterized clinically by the triad of asthma, nasal polyposis, and pathognomonic respiratory reactions after ingestion of aspirin. It is a distinct syndrome associated with eosinophilic infiltration of respiratory tissues and excessive production of cysteinyl leukotrienes. Despite the consistent clinical phenotype of the respiratory disease, the underlying pathogenesis of the disease remains unclear. In addition to their role in hemostasis, platelets have the capacity to influence the activation state and function of other immune cells during inflammation and to facilitate granulocyte recruitment into the tissues. Platelets also possess a repertoire of potent preformed mediators of inflammation that are released on activation and are a rich source of newly synthesized lipid mediators that alter vascular permeability and smooth muscle tone. Accordingly, platelet activity has been linked to diverse inflammatory diseases, including asthma. Both human and animal studies strongly suggest that platelet activity is uniquely associated with the pathophysiology of AERD. This article summarizes the evidence supporting an effector role for platelets in asthmatic patients in general and in patients with AERD in particular and considers the potential therapeutic implications. PMID- 26051949 TI - Platelets in the immune response: Revisiting platelet-activating factor in anaphylaxis. AB - Anaphylaxis is an acute, severe, life-threatening multisystem allergic reaction resulting from the sudden systemic release of biochemical mediators and chemotactic substances. Release of both preformed granule-associated mediators and newly generated lipid-derived mediators contributes to the amplification and prolongation of anaphylaxis. Platelet-activating factor (PAF) is a potent phospholipid-derived mediator the central role of which has been well established in experimental models of both immune-mediated and non-immune mediated anaphylaxis. It is produced and secreted by several types of cells, including mast cells, monocytes, tissue macrophages, platelets, eosinophils, endothelial cells, and neutrophils. PAF is implicated in platelet aggregation and activation through release of vasoactive amines in the inflammatory response, resulting in increased vascular permeability, circulatory collapse, decreased cardiac output, and various other biological effects. PAF is rapidly hydrolyzed and degraded to an inactive metabolite, lysoPAF, by the enzyme PAF acetylhydrolase, the activity of which has shown to correlate inversely with PAF levels and predispose to severe anaphylaxis. In addition to its role in anaphylaxis, PAF has also been implicated as a mediator in both allergic and nonallergic inflammatory diseases, including allergic rhinitis, sepsis, atherosclerotic disease, and malignancy, in which PAF signaling has an established role. The therapeutic role of PAF antagonism has been investigated for several diseases, with variable results thus far. Further investigation of its role in pathology and therapeutic modulation is highly anticipated because of the pressing need for more selective and targeted therapy for the management of severe anaphylaxis. PMID- 26051951 TI - Asthma exacerbations: Looking back to the future. PMID- 26051953 TI - Preventing atopic eczema from birth using emollients. PMID- 26051954 TI - Reply: To PMID 25282563. PMID- 26051952 TI - Pediatric Eosinophilic Esophagitis Symptom Scores (PEESS v2.0) identify histologic and molecular correlates of the key clinical features of disease. AB - BACKGROUND: The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS v2.0) measures patient-relevant outcomes. However, whether patient-identified domains (dysphagia, gastroesophageal reflux disease [GERD], nausea/vomiting, and pain) align with clinical symptomology and histopathologic and molecular features of eosinophilic esophagitis (EoE) is unclear. OBJECTIVE: The purpose of this study was to determine whether clinical features of EoE, measured through PEESS v2.0, associate with histopathologic and molecular features of EoE. This represents a novel approach for analysis of allergic diseases, given the availability of allergic tissue biopsy specimens. METHODS: We systematically recruited treated and untreated pediatric patients with EoE (aged 2-18 years) and examined parent proxy-reported symptoms using the PEESS v2.0. Clinical symptomology was collected by questionnaire. Esophageal biopsy samples were quantified for levels of eosinophils, eosinophil peroxidase (EPX) immunohistochemical staining, and mast cells. Molecular features were assessed by using the EoE Diagnostic Panel (94 EoE related gene transcripts). Associations between domain scores and clinical symptoms and biological features were analyzed with Wilcoxon rank sum and Spearman correlation. RESULTS: The PEESS v2.0 domains correlated to specific parent-reported symptoms: dysphagia (P = .0012), GERD (P = .0001), and nausea/vomiting (P < .0001). Pain correlated with multiple symptoms (P < .0005). Dysphagia correlated most strongly with overall histopathology, particularly in the proximal esophagus (P <= .0049). Markers of esophageal activity (EPX) were significantly associated with dysphagia (strongest r = 0.37, P = .02). Eosinophil levels were more associated with pain (r = 0.27, P = .06) than dysphagia (r = 0.24, P = .13). The dysphagia domain correlated most with esophageal gene transcript levels, predominantly with mast cell-specific genes. CONCLUSION: We have (1) established a validated, parent proxy-reported measure for pediatric EoE, the PEESS v2.0; (2) verified that the parent proxy effectively captures symptoms; (3) determined that the dysphagia domain most closely aligns with symptoms and tissue-based molecular biomarkers; (4) established that symptoms correlate with EPX staining; and (5) observed association between mast cells and dysphagia. PMID- 26051955 TI - The risk of sensitization to furry animals in patients already sensitized to cat/dog: An in vitro evaluation using molecular-based allergy diagnostics. PMID- 26051956 TI - Reply: To PMID 25282018. PMID- 26051957 TI - The predominance of Lactobacillus sanfranciscensis in French organic sourdoughs and its impact on related bread characteristics. AB - Fourteen bakeries located in different regions of France were selected. These bakers use natural sourdough and organic ingredients. Consequently, different organic sourdoughs used for the manufacture of French bread were studied by the enumeration of lactic acid bacteria (LAB) and 16S rRNA sequencing of the isolates. In addition, after DNA extraction the bacterial diversity was assessed by pyrosequencing of the 16S rDNA V1-V3 region. Although LAB counts showed significant variations (7.6-9.5log10CFU/g) depending on the sourdough studied, their identification through a polyphasic approach revealed a large predominance of Lactobacillus sanfranciscensis in all samples. In ten sourdoughs, both culture and independent methods identified L. sanfranciscensis as the dominant LAB species identified. In the remaining sourdoughs, culture methods identified 30 80% of the LAB as L. sanfranciscensis whereas more than 95% of the reads obtained by pyrosequencing belonged to L. sanfranciscensis. Other sub-dominant species, such as Lactobacillus curvatus, Lactobacillus hammesii, Lactobacillus paralimentarius, Lactobacillus plantarum, Lactobacillus pentosus, and Lactobacillus sakei, were also identified. Quantification of L. sanfranciscensis by real-time PCR confirmed the predominance of this species ranging from 8.24 to 10.38log10CFU/g. Regarding the acidification characteristics, sourdough and related bread physico-chemical characteristics varied, questioning the involvement of sub-dominant species or L. sanfranciscensis intra-species diversity and/or the role of the baker's practices. PMID- 26051958 TI - A genomic and transcriptomic approach to investigate the blue pigment phenotype in Pseudomonas fluorescens. AB - Pseudomonas fluorescens is a well-known food spoiler, able to cause serious economic losses in the food industry due to its ability to produce many extracellular, and often thermostable, compounds. The most outstanding spoilage events involving P. fluorescens were blue discoloration of several food stuffs, mainly dairy products. The bacteria involved in such high-profile cases have been identified as belonging to a clearly distinct phylogenetic cluster of the P. fluorescens group. Although the blue pigment has recently been investigated in several studies, the biosynthetic pathway leading to the pigment formation, as well as its chemical nature, remain challenging and unsolved points. In the present paper, genomic and transcriptomic data of 4 P. fluorescens strains (2 blue-pigmenting strains and 2 non-pigmenting strains) were analyzed to evaluate the presence and the expression of blue strain-specific genes. In particular, the pangenome analysis showed the presence in the blue-pigmenting strains of two copies of genes involved in the tryptophan biosynthesis pathway (including trpABCDF). The global expression profiling of blue-pigmenting strains versus non pigmenting strains showed a general up-regulation of genes involved in iron uptake and a down-regulation of genes involved in primary metabolism. Chromogenic reaction of the blue-pigmenting bacterial cells with Kovac's reagent indicated an indole-derivative as the precursor of the blue pigment. Finally, solubility tests and MALDI-TOF mass spectrometry analysis of the isolated pigment suggested that its molecular structure is very probably a hydrophobic indigo analog. PMID- 26051959 TI - Identification of food and beverage spoilage yeasts from DNA sequence analyses. AB - Detection, identification and classification of yeasts have undergone major changes in the last decade and a half following application of gene sequence analyses and genome comparisons. Development of a database (barcode) of easily determined DNA sequences from domains 1 and 2 (D1/D2) of the nuclear large subunit rRNA gene and from ITS now permits many laboratories to identify species quickly and accurately, thus replacing the laborious and often inaccurate phenotypic tests previously used. Phylogenetic analysis of gene sequences has resulted in a major revision of yeast systematics resulting in redefinition of nearly all genera. This new understanding of species relationships has prompted a change of rules for naming and classifying yeasts and other fungi, and these new rules are presented in the recently implemented International Code of Nomenclature for algae, fungi, and plants (Melbourne Code). The use of molecular methods for species identification and the impact of Code changes on classification will be discussed, especially in the context of food and beverage spoilage yeasts. PMID- 26051960 TI - Rhenium(I)-based bridgeless double metallocalix[4]arenes. AB - Bridgeless double metallocalix[4]arenes possessing two orthogonally arranged dinuclear cavitands were obtained from a Re2(CO)10, rigid bis-chelating OO donor (H2-L), and a flexible bis-ditopic NN donor (L') by a one-pot approach. PMID- 26051961 TI - Self-reported health-related quality of life in kindergarten children: psychometric properties of the Kiddy-KINDL. AB - OBJECTIVES: To assess the psychometric properties of the German self-reported version of the Kiddy-KINDL that measures Health Related Quality of Life (HRQoL) in 3 to 5 year old kindergarten children. STUDY DESIGN: The population of the study comprised baseline data of a longitudinal study whose main aim is to investigate self-reported health outcomes in young children (N = 317). METHODS: Missing values, the distribution of data, internal consistency (Cronbach's alpha and Guttman's lambda), and reliability (split half and two weeks test-retest) were analysed. To assess discriminant validity, mean differences were tested splitting the sample regarding socio-emotional competences (VBV 3-6), age and gender. Structural validity was investigated with Confirmatory Factor Analysis (CFA). RESULTS: Mean HRQoL was 69.79 (SD 16.84). Overall missing values were 8.1%, overall Cronbach's alpha was 0.75 and overall Guttman's lambda was 0.77; for the whole scale Spearman-Brown test for split half reliability resulted in 0.80 and ICC for test-retest in 0.83. Discriminant validity investigation differentiated groups with high and low socio-emotional competence and those children who were 4.5 years or older, compared to the younger ones. Differences between boys and girls were also found. CFA suggested two main dimensions: physical and socio-emotional. CONCLUSION: This preliminary validation of the Kiddy-KINDL in very young children shows satisfactory psychometric properties. However, results of the Cronbach's alpha, Guttman's lambda and the CFA depicted problems, mainly in the psychological dimension. Due to these we recommend to use the Kiddy-KINDL as an instrument with only two dimensions. Further studies in general population samples are needed. PMID- 26051962 TI - Voltammetric behavior of 1- and 4-[S2V(V)W17O62]5- in acidified acetonitrile. AB - Data derived from a voltammetric and spectroscopic study of the V(V/IV) couple associated with the initial reduction of the Wells-Dawson-type mono vanadium substituted polyoxometalates, 1- and 4-[S2V(V)W17O62](5-) in CH3CN as a function of CF3SO3H acid concentration have been obtained. (51)V NMR (V(V) component) and EPR (V(IV) component) spectra were measured in CH3CN in the presence and absence of an acid. These data showed a small fraction of the 1-isomer in the 4 [S2V(V)W17O62](5-) sample and that protonation could occur at both redox levels for both isomers. On the basis of the mechanism postulated from the voltammetric and spectroscopic data, simulations of cyclic voltammograms were undertaken for the reduction of the isomerically pure 1-[S2V(V)W17O62](5-) isomer over a wide acid concentration range, and the results were compared with experimental data. Cyclic voltammograms of the V(V/IV) couple derived from the reduction of 1- and 4 [X2V(V)W17O62](7-) (X = P, As) were also obtained in CH3CN and the results were compared with those for 1- and 4-[S2V(V)W17O62](5-). Reversible potentials for the V(V/IV) couple are dependent on the anion charge of the polyoxometalate. Analysis of cyclic voltammograms obtained for 1- and 4-[S2V(V)W17O62](5-) in acetonitrile, acetone, dimethyl sulfoxide, dimethyl formamide and nitromethane showed that these V(V/IV) reversible potentials are also dependent on the acceptor numbers and the polarity index (E(T)(N)) values of the organic solvents. PMID- 26051963 TI - Inactivation of the Deg protease family in the cyanobacterium Synechocystis sp. PCC 6803 has impact on the outer cell layers. AB - The serine type Deg/HtrA proteases are distributed in a wide range of organisms from Escherichia coli to humans. The cyanobacterium Synechocystis sp. PCC 6803 possesses three Deg protease orthologues: HtrA, HhoA and HhoB. Previously we compared Synechocystis 6803 wild type cells exposed to mild or severe stress conditions with a mutant lacking all three Deg proteases and demonstrated that stress had strong impact on the proteomes and metabolomes. To identify the biochemical processes, which this protease family is involved in, here we compared Synechocystis sp. PCC 6803 wild type cells with a mutant lacking all three Deg proteases grown under normal growth conditions (30 degrees C and 40 MUmol photons m(-2) s(-1)). Deletion of the Deg proteases lead to the down regulation of proteins related to the biosynthesis of outer cell layers (e.g. the GDP mannose 4,6-dehydratase) and affected protein secretion. During the late growth phase of the culture Deg proteases were found to be secreted to the extracellular medium of the Synechocystis sp. PCC 6803 wild type strain. While cyanobacterial Deg proteases seem to act mainly in the periplasmic space, deletion of the three proteases influences the proteome and metabolome of the whole cell. Impairments in the outer cell layers of the triple mutant might explain the higher sensitivity toward light and oxidative stress, which was observed earlier by Barker and coworkers. PMID- 26051964 TI - An online tuned novel nonlinear PI controller for stiction compensation in pneumatic control valves. AB - A novel Nonlinear PI Controller (NPIC) has been proposed for effective control of flow process employing a sticky pneumatic control valve. The proposed control scheme has been inherited from a classical PI control structure with a difference that the integral gain has been varied in accordance with the instantaneous error and the rate of change of error. The tuning of controller has been carried out online using Differential Evolution algorithm. To evaluate the effectiveness of the proposed controller, a comparative study with the conventional PI controller has also been carried out for the setpoint tracking, disturbance rejection and robustness to parameter uncertainties on account of operating point change on a laboratory scale nonlinear flow process. Based on these intensive experimental evidences, it has been concluded that the NPIC performed far better than the conventional PI controller for all the case studies and suppressed effectively any stiction induced oscillations. PMID- 26051965 TI - Ultra-fast formation control of high-order discrete-time multi-agent systems based on multi-step predictive mechanism. AB - This paper deals with the ultra-fast formation control problem of high-order discrete-time multi-agent systems. Using the local neighbor-error knowledge, a novel ultra-fast protocol with multi-step predictive information and self feedback term is proposed. The asymptotic convergence factor is improved by a power of q+1 compared to the routine protocol. To some extent, the ultra-fast algorithm overcomes the influence of communication topology to the convergence speed. Furthermore, some sufficient conditions are given herein. The ones decouple the design of the synchronizing gains from the detailed graph properties, and explicitly reveal how the agent dynamic and the communication graph jointly affect the ultra-fast formationability. Finally, some simulations are worked out to illustrate the effectiveness of our theoretical results. PMID- 26051966 TI - Patient-centered care for chronic pain in the emergency department: A qualitative study. AB - Pain is a common problem for which patients seek care in the emergency department, accounting for up to 42% of all ED visits. The purpose of this study was to explore qualitatively the reasons for use of the emergency department (ED) by those frequenting the ED for treatment of chronic pain. The settings for the study were two sites of a large U.S. Midwestern healthcare system. The sample comprised patients who used the ED four or more times in the 3-month time of data collection. From a total of 85 frequent users identified through retrospective chart reviews, a computer generated random sample of patients was selected to explore their reasons for use of ED for treatment of chronic pain. Content analysis was used to identify themes from the interviews. Four themes emerged from the qualitative data analysis: time of day, pain intensity, barriers to and reasons for using the emergency department for care, and lack of individualized plan of care. Reasons patients use the ED for chronic pain are numerous and complex. Leaders of healthcare organizations must address patient-centered care, with specific alternatives to the emergency department such as individualized care plans, and care transition interventions. PMID- 26051967 TI - A novel mechanochemical method for reconstructing the moisture-degraded HKUST-1. AB - A novel mechanochemical method was proposed to reconstruct quickly moisture degraded HKUST-1. The degraded HKUST-1 can be restored within minutes. The reconstructed samples were characterized, and confirmed to have 95% surface area and 92% benzene capacity of the fresh HKUST-1. It is a simple and effective strategy for degraded MOF reconstruction. PMID- 26051968 TI - Microwave freeze-thaw technique of injectable drugs. A review from 1980 to 2014. AB - OBJECTIVE: Microwave freeze-thaw treatment (MFTT) of injectable drugs can support the development of centralized intravenous admixtures services (CIVAS). The aim of the review is to collect information and results about this method. METHODS: A systematic review of the scientific literature about injectable drug stability studies was performed. The data are presented in a table and describe name of the drug, producer, final concentration, temperature and time of freezing storage, type of microwave oven, thawing power, method of dosage and results after treatment or final long-term storage at 5+/-3 degrees C. RESULTS: From 1980 to 2014, 59 drugs were studied by MFTT and the results were presented in 49 publications. Forty papers were presented by 8 teams (2 to 18 by team). The temperatures of freezing storage vary from -70 degrees C to -10 degrees C, the time storage from 4 hours to 12 months, the thaw from low to full power. Dosages are mainly made by high performance liquid chromatography. Most of the 59 drugs are stable during and after treatment. Only 3 teams have tested the long-term stability after MFTT, the first for ganciclovir after 7 days, the second for ceftizoxime after 30 days and the third for 19 drugs after 11 to 70 days. CONCLUSIONS: This review can help CIVAS to take in charge the productions of ready-to-use injectable drugs. PMID- 26051969 TI - Distribution and Within-Family Specificity of Quantitative Autistic Traits in Patients with Neurofibromatosis Type I. AB - OBJECTIVE: To examine the distribution of quantitative autistic traits (QATs) in an independent neurofibromatosis type I (NF1) sample, the relationships between QAT, sex, and attention deficit hyperactivity disorder (ADHD) symptomatology, and to explore evidence for QAT mutational specificity within families. STUDY DESIGN: Age-appropriate versions of the Social Responsiveness Scale, second edition and the Conners Adult ADHD Rating Scales were completed for 103 patients with NF1 from the Washington University Neurofibromatosis Center. RESULTS: Patients with NF1 exhibited a pathologically shifted unimodal distribution for QAT. Forty-four percent of the subjects exhibited a QAT burden at or above 1 SD from the population mean; 13% scored at or above the extreme first percentile of the general population distribution. Elevations in ADHD symptomatology exhibited a distinct bimodal distribution; however, mean ADHD index scores were equivalent in patients who had been diagnosed in the community with ADHD compared with those who had not. We observed striking within-family associations for QAT, reflected by an Social Responsiveness Scale, second edition intraclass correlation of 0.77 in pairings of first degree relatives with NF1. CONCLUSIONS: Impairments in reciprocal social behavior and attention affect a large proportion of patients with NF1 throughout life and are often clinically unrecognized. Further exploration of genotype-phenotype correlation is strongly warranted for the purpose of gaining insights into mechanisms by which specific mutational variations in the NF1 gene may influence autistic trait severity. PMID- 26051970 TI - Missed Pediatric Monteggia Fracture: A 63-Year Follow-Up. PMID- 26051971 TI - Age of Menarche and Oligomenorrhea in Adolescence: Cardiometabolic Ramifications in Adulthood. PMID- 26051972 TI - Vasopressin in arterial hypotension in extremely low birth weight infants. PMID- 26051973 TI - Are Infants with Bronchopulmonary Dysplasia Prone to Gastroesophageal Reflux? A Prospective Observational Study with Esophageal pH-Impedance Monitoring. AB - OBJECTIVE: To perform an observational cohort study with esophageal pH multichannel intraluminal impedance (pH-MII) monitoring in symptomatic preterm infants with and without bronchopulmonary dysplasia (BPD). STUDY DESIGN: We prospectively studied 46 infants born <=32 weeks gestational age: 12 infants with BPD and 34 infants without BPD. Each patient had symptoms consistent with gastroesophageal reflux and had 24-hour pH-MII, which were compared between BPD and non-BPD by univariate analysis and quantile regression analysis. RESULTS: Demographic and clinical characteristics were similar between infants with and without BPD, except for fluid administration (145 vs 163 mL/kg/d, P = .003), length of stay (92 vs 69 days, P = .019), and time to achieve complete oral feeding (76 vs 51 days, P = .013). The analysis of 1104 hours of pH-MII tracings demonstrated that infants with BPD compared with infants without BPD had increased numbers of pH-only events (median number 21 vs 9) and a higher symptom sensitivity index for pH-only events (9% vs 4.9%); the number and characteristics of acid, weakly acid, nonacid and gas gastroesophageal reflux events, acid exposure, esophageal clearance, and recorded symptoms did not significantly differ between the 2 groups. CONCLUSIONS: The increased number of (and sensitivity for) pH-only events among infants with BPD may be explained by several factors, including lower milk intake, impaired esophageal motility, and a peculiar autonomic nervous system response pattern. PMID- 26051974 TI - "Melioidosis in Antioquia, Colombia: an emerging or endemic disease? A cases series". AB - BACKGROUND: Melioidosis is endemic in Malaysia, the southwest of Thailand, and northern Australia. The incidence in Thailand is 4.4/1000000 inhabitants, where it causes 19% of community-acquired pneumonia (CAP) and 20% of bacteremic pneumonia, and the mortality is 50%. Sporadic cases have been described in Central and South America. The objective of this study was to describe the clinical and epidemiological features and ecological characteristics of melioidosis in Antioquia, Colombia. METHODS: This is a case series description. RESULTS: Seven cases were identified. Burkholderia pseudomallei was isolated from peripheral blood, pleural fluid, and urine and was identified by the automated system VITEK 2 (bioMerieux) and API 20NE biochemical kit. Five of the cases had a bacteremic form with shock and pulmonary compromise and two of these patients died. The non-bacteremic melioidosis cases had genitourinary, abdominal, and osteoarticular compromise. All patients had comorbidities and lived in rural hot and humid areas in the west central region of Colombia (Antioquia). Diabetes mellitus, renal insufficiency, and other chronic diseases are important risk factors for the development of severe forms. CONCLUSIONS: The cases presented here are similar to those occurring in endemic areas regarding comorbidity, risk factors, clinical presentation, and environmental conditions. It is necessary to establish whether melioidosis is an endemic and under-diagnosed disease or an emerging disease in Colombia. PMID- 26051975 TI - Persistence of a major endemic clone of oxacillin-resistant Staphylococcus lugdunensis sequence type 6 at a tertiary medical centre in northern Taiwan. AB - OBJECTIVES: The aim of this study was to investigate the molecular epidemiology and clinical characteristics of a major clone of oxacillin-resistant Staphylococcus lugdunensis in a tertiary hospital. METHODS: All S. lugdunensis isolated from sterile sites between June 2003 and May 2013 were collected for analysis. Pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) were performed to study their genetic relationships. RESULTS: A total of 118 S. lugdunensis isolates were analysed by PFGE. Three major PFGE pulsotypes were found: A, H, and L. Most of the pulsotype A isolates were oxacillin resistant, and SCCmec type V and type VT. Isolates from another major clonal group that consisted primarily of pulsotype L were oxacillin-resistant and SCCmec type II. These 14 SCCmec type II S. lugdunensis isolates demonstrated high PFGE similarity and were obtained in the study hospital over a period of 40 months. Three of these 14 patients had clinically significant bacteraemia, and all three cases were in the intensive care unit. Further MLST analysis of the isolates identified an endemic S. lugdunensis strain of sequence type 6, clonal complex 1. CONCLUSIONS: This study identified a major endemic clone of S. lugdunensis that is oxacillin-resistant, SCCmec type II, ST6, and capable of long-term persistence in the hospital. Continuous infection control surveillance and monitoring of S. lugdunensis should be considered in endemic areas. PMID- 26051976 TI - Community- and healthcare-associated infections in critically ill patients: a multicenter cohort study. AB - OBJECTIVE: To compare the spectrum of infection, comorbidities, outcomes, and mortality of patients admitted to the intensive care unit (ICU) due to community acquired or healthcare-associated severe sepsis. METHODS: This prospective cohort study was conducted in three university medical centers in Lebanon from February 2005 to December 2006. Patients with severe sepsis were included and followed up until hospital discharge or death. RESULTS: One hundred and twenty patients were included of whom 60% had community-acquired infections (CAI) and 40% had healthcare-associated infections (HAI). The most common infection in both groups was pneumonia. Hematologic malignancies were the only comorbidity more prevalent in HAI than in CAI (p=0.047). Fungal infections and extended-spectrum beta lactamase (ESBL) organisms were more frequent in HAI than in CAI (p=0.04 and 0.029, respectively). APACHE and SOFA scores were high and did not differ between the two groups, nor did the proportion of septic shock, while mortality was significantly higher in the HAI patients than in the CAI patients (p=0.004). On multivariate analysis for mortality, independent risk factors were the source of infection acquisition (p=0.004), APACHE II score (p=0.006), multidrug-resistant Pseudomonas infections (p=0.043), and fungal infections (p=0.006). CONCLUSIONS: Severe sepsis and septic shock had a high mortality rate, especially in the HAI group. Patients with risk factors for increased mortality should be monitored and aggressive treatment should be administered. PMID- 26051977 TI - Leiomyomas in the gastric cardia: CT findings and differentiation from gastrointestinal stromal tumors. AB - OBJECTIVE: To describe CT findings of leiomyomas and gastrointestinal stromal tumors (GISTs) in the gastric cardia and to identify their differentiating features. MATERIALS AND METHODS: CT images of pathologically proven leiomyomas (n=26) and GISTs (n=19) in the gastric cardia were retrospectively reviewed for esophagogastric junction (EGJ) involvement, contour, surface, growth pattern, enhancement pattern and degree of the tumor, and the presences of intralesional low attenuation, calcification and surface dimples or ulcers. The long (LD) and short diameters (SD), LD/SD ratio, and attenuation value of each lesion were measured. RESULTS: EGJ involvement, homogeneous enhancement, intermediate or low enhancement, absences of intralesional low attenuation and surface dimples or ulcers, LD/SD ratio >1.2, and attenuation value <=71.2HU were significant findings for differentiating leiomyomas from GISTs (P<0.05 for each finding). An LD/SD ratio of >1.2 and attenuation value of <=71.2HU yielded sensitivities of 84.6% and 61.5%, and specificities of 52.6% and 84.2%, respectively, on the receiver operating characteristic curve analysis. When at least five of these seven criteria were used in combination, the sensitivity and specificity for diagnosing leiomyomas were 100% (26 of 26) and 89.5% (17 of 19), respectively. When any six of these criteria were used, a specificity of 100% was achieved. CONCLUSIONS: CT features including EGJ involvement, enhancement pattern and degree, presences of intralesional low attenuation and surface dimples or ulcers, LD/SD ratio, and attenuation value could help differentiating leiomyomas from GISTs in the gastric cardia, particularly in the manner of combination. PMID- 26051978 TI - Short-chain chlorinated paraffins in cooking oil and related products from China. AB - Short-chain chlorinated paraffins (SCCPs) are emerging persistent organic pollutants. It has been found that dietary intakes of SCCPs in China have recently increased and are now higher than in Japan and Korea. The contribution of cooking oil to dietary exposure to SCCPs in China was evaluated by analyzing SCCPs in cooking oil, raw seeds used to produce cooking oil, and fried confectionery products collected in China in 2010 and 2012. Detectable amounts of SCCP homologs were found in 48 out of the 49 cooking oil samples analyzed, and the SCCP concentrations varied widely, from <9 to 7500 ng g(-1). Estimated dietary intakes of total SCCPs in cooking oil ranged from <0.78 to 38 MUg d(-1). The estimated dietary intake of SCCPs was relatively high (mean 14.8 MUg d(-1)) for residents of Beijing. Fried confectionery was found to contain SCCP concentrations of 11-1000 ng g(-1). Cooking oil might therefore be one of the sources of SCCPs to Chinese diets. SCCPs were also detected in raw seeds used to produce cooking oil, but the concentrations varied widely. The SCCP homolog patterns in the raw seed and cooking oil samples were different, implying that the seeds used to produce the oil (and therefore the soil on which the seeds were produced) were unlikely to be the sources of SCCPs in cooking oil. Further investigations are needed to determine the routes through which cooking oil becomes contaminated with SCCPs during the production and processing of the oil. PMID- 26051979 TI - Atmospheric degradation of lindane and 1,3-dichloroacetone in the gas phase. Studies at the EUPHORE simulation chamber. AB - The gas-phase degradation of lindane (gamma-isomer of hexachlorocyclohexane) towards OH radical was investigated under atmospheric conditions at the large outdoor European simulation chamber (EUPHORE) in Valencia, Spain. The rate coefficient for the reaction of hydroxyl radicals with lindane was measured using a conventional relative rate technique leading to a value of kOH(lindane)=(6.4+/ 1.6)*10(-13) cm(3) molecule(-1) s(-1) at 300+/-5 K and atmospheric pressure. The results suggest that the tropospheric lifetime of lindane with respect to OH radicals is approximately 20 days. The product distribution studies on the OH initiated oxidation of lindane provided evidence that the major initial carbon containing oxidation product is pentachlorocyclohexanone. 1,3-Dichloroacetone was employed as a model compound for pentachlorocyclohexanone, and an investigation of its photolysis and reaction with OH radicals under atmospheric conditions was carried out. The data indicate that the atmospheric degradation of pentachlorocyclohexanone would be relatively rapid, and would not form persistent organic compounds. Theoretical study was also employed to calculate possible degradation pathways. Mechanism for reaction of lindane with OH radicals is proposed, and C-Cl bond cleavage is discussed. OH abstraction is considered to be a reasonable way for Cl to escape during degradation. The atmospheric implications of the use of lindane as an insecticide are discussed. PMID- 26051980 TI - Role of renal replacement therapy in patients with type 1 hepatorenal syndrome receiving combination treatment of vasoconstrictor plus albumin. AB - PURPOSE: Utilization of renal replacement therapy (RRT) in cirrhotic patients has been controversial and is typically dependent on the status of transplantation. A better understanding of the central role for arterial vasodilatation in the pathogenesis of hepatorenal syndrome (HRS) has led to routine use of vasoconstrictors in combination with albumin as a medical therapy for HRS with prolonged patient survival. The role of RRT in HRS patients receiving such treatment, however, has not yet been examined. METHODS: A total of 80 patients with type 1 HRS who received a combination therapy of vasoconstrictors and albumin were enrolled into a retrospective cohort study. The effects of RRT status on clinical outcome were analyzed. RESULTS: Both short-term (30 days) and long-term (180 days) survival was similar between RRT and non-RRT groups of patients, but the length of hospital stay was significantly longer among patients in the RRT group, which remain unchanged despite adjustment of status for liver transplantation. CONCLUSIONS: Based on our observation, routine use of RRT may not be beneficial in patients with type 1 HRS receiving combination treatment of vasoconstrictor plus albumin. Further prospective studies are needed to validate these findings and refine the specific indications for RRT in this patient population. PMID- 26051981 TI - The direct costs of intensive care management and risk factors for financial burden of patients with severe sepsis and septic shock. AB - PURPOSE: The costs of severe sepsis care from middle-income countries are lacking. This study investigated direct intensive care unit (ICU) costs and factors that could affect the financial outcomes. METHODS: A prospective cohort study was conducted in the medical ICU of a tertiary referral university teaching hospital in Thailand. RESULTS: A total of 897 patients were enrolled in the study, with 683 (76.1%) having septic shock. Community-, nosocomial, and ICU acquired infections were documented in 574, 282, and 41 patients, respectively. The median ICU costs per patient were $2716.5 ($1296.1-$5367.6) and $599.9 ($414.3-$948.6) per day. The ICU costs accounted for 64.7% of the hospital costs. In 2008 to 2011, the ICU costs significantly decreased by 40% from $3542.5 to $2124.9, whereas, the daily ICU costs decreased only 3.3% from $609.7 to $589.7. By multivariate logistic regression analysis, age, nosocomial or ICU infection, admission from the emergency department, number of organ failures, ICU length of stay, and fluid balance the first 72 hours were independently associated with ICU costs. CONCLUSION: The ICU costs of severe sepsis management significantly declined in our study. However, the ICU costs were a financial burden accounting for two thirds of the hospital costs. It is essential for intensivists to contribute a high standard of care within a restricted budget. PMID- 26051982 TI - [Successful treatment of aortic dissection in pregnant patient: Bentall procedure and hemiarch]. PMID- 26051983 TI - Predictors of childbirth fear among pregnant Chinese women: A cross-sectional questionnaire survey. AB - OBJECTIVE: to examine childbirth fear and identify its predictors among pregnant Chinese women. DESIGN AND SETTING: a cross-sectional descriptive questionnaire survey was conducted in a regional teaching hospital in Guangzhou, China, between October and November 2013. PARTICIPANTS: 353 pregnant Chinese women who were at least 18 years old, with a singleton fetus, in the third trimester of pregnancy, not at high risk for complications of pregnancy, and not having had a previous caesarean section. MEASUREMENTS: a social-demographic data sheet; the Chinese version of the Childbirth Attitude Questionnaire and the Spielberger's State Trait Anxiety Inventory; and the short form of 32-item Chinese Childbirth Self Efficacy Inventory. FINDINGS: the pregnant Chinese women reported moderate levels of childbirth fear. The pregnant Chinese women who were younger, with lower educational level, not satisfied with their husbands' support, and with previous experience of miscarriage reported higher level of childbirth fear. Pregnant women's childbirth self-efficacy, state anxiety and trait anxiety were correlated with childbirth fear. The best-fit regression analysis revealed four variables that explained 28% of variance in childbirth fear: trait anxiety, state anxiety, age and previous experience of miscarriage. CONCLUSION: this study highlighted the connection between childbirth fear, state and trait anxiety, childbirth self efficacy, age, education and previous miscarriage among pregnant Chinese women. IMPLICATIONS FOR PRACTICE: the CAQ was an appropriate method to measure childbirth fear in pregnant Chinese women. The health-care professionals should be sensitive toward issues that could affect levels of childbirth fear in pregnant Chinese women, including age, education and previous miscarriage. PMID- 26051984 TI - Moisture-responsive films of cellulose stearoyl esters showing reversible shape transitions. AB - Moisture-responsive materials are gaining greater interest for their potentially wide applications and the readily access to moisture. In this study, we show the fabrication of moisture-responsive, self-standing films using sustainable cellulose as starting material. Cellulose was modified by stearoyl moieties at first, leading to cellulose stearoyl esters (CSEs) with diverse degrees of substitution (DSs). The films of CSE with a low DS of 0.3 (CSE0.3) exhibited moisture-responsive properties, while CSEs with higher DSs of 1.3 or 3 (CSE1.3 and CSE3) not. The CSE0.3 films could reversibly fold and unfold as rhythmical bending motions within a local moisture gradient due to the ab- and desorption of water molecules at the film surface. By spray-coating CSE3 nanoparticles (NPs) onto CSE0.3 films, moisture-responsive films with non-wetting surface were obtained, which can perform quick reversible bending movements and continuous shape transition on water. Furthermore, bilayer films containing one layer of CSE0.3 at one side and one layer of CSE3 at the other side exhibited combined responsiveness to moisture and temperature. By varying the thickness of CSE0.3 films, the minimal bending extent can be adjusted due to altered mechanical resistances, which allows a bending movement preferentially beginning with the thinner side. PMID- 26051985 TI - Bacteria do not incorporate beta-N-methylamino-L-alanine into their proteins. AB - beta-N-methylamino-l-alanine (BMAA), is commonly found in both a free and proteinassociated form in various organisms exposed to the toxin. The long latency of development of neurodegeneration attributed to BMAA, is hypothesized to be the result of excitotoxicity following slow release of the toxin from protein reservoirs. It was recently suggested that these BMAA-protein associations may reflect misincorporation of BMAA in place of serine, as occurs, for example, when canavanine misincorporates in place of arginine. We therefore compared BMAA and canavanine toxicty in various bacterial species, and misincorporation of these amino acids into proteins in a bacterial protein expression system. None of the bacterial species showed any physiological stress responses to BMAA in contrast to the growth reduction observed when cultures were incubated in media containing canavanine. LC-MS analysis confirmed uptake of BMAA from growth media. However, after immobilized metal affinity chromatography and SDS-PAGE purification of proteins produced in an E scherichia coli expression system, no BMAA was detected by either LC-MS or LC-MS/MS analysis using two derivatization methods, or by orbitrap MS of trypsin digests of the protein. We therefore conclude that BMAA is not misincorporated into proteins in bacteria and that the observed BMAA-protein association in bacteria is superficial. PMID- 26051986 TI - Moral justification of anatomical dissection and conquest in the Spanish Chronicles of the Indies. AB - Three cases of dissections of dead bodies are included in the Spanish Chronicles of the Indies. By reporting on these advanced medico-scientific practices, the chroniclers appear to be confirming the superiority of the conquistadors over the natives and justifying the conquest. However, they problematize this supposed superiority by framing the events in complex scenarios that resound of some of the controversies surrounding dissection in the period. This contradictory treatment of dissection can be interpreted as a manifestation of the conquistadors' anxiety around being physically identical to the natives except for a fragile, skin-deep veneer of civilized behaviour. PMID- 26051987 TI - Structural design of graphene for use in electrochemical energy storage devices. AB - There are many practical challenges in the use of graphene materials as active components in electrochemical energy storage devices. Graphene has a much lower capacitance than the theoretical capacitance of 550 F g(-1) for supercapacitors and 744 mA h g(-1) for lithium ion batteries. The macroporous nature of graphene limits its volumetric energy density and the low packing density of graphene based electrodes prevents its use in commercial applications. Increases in the capacity, energy density and power density of electroactive graphene materials are strongly dependent on their microstructural properties, such as the number of defects, stacking, the use of composite materials, conductivity, the specific surface area and the packing density. The structural design of graphene electrode materials is achieved via six main strategies: the design of non-stacking and three-dimensional graphene; the synthesis of highly packed graphene; the production of graphene with a high specific surface area and high conductivity; the control of defects; functionalization with O, N, B or P heteroatoms; and the formation of graphene composites. These methodologies of structural design are needed for fast electrical charge storage/transfer and the transport of electrolyte ions (Li(+), H(+), K(+), Na(+)) in graphene electrodes. We critically review state-of-the-art progress in the optimization of the electrochemical performance of graphene-based electrode materials. The structure of graphene needs to be designed to develop novel electrochemical energy storage devices that approach the theoretical charge limit of graphene and to deliver electrical energy rapidly and efficiently. PMID- 26051988 TI - Daptomycin combinations as alternative therapies in experimental foreign-body infection caused by meticillin-susceptible Staphylococcus aureus. AB - Whilst levofloxacin (LVX) in combination with rifampicin (RIF) is considered the optimal treatment for prosthetic joint infection (PJI) caused by meticillin susceptible Staphylococcus aureus (MSSA), no therapeutic alternatives have been accurately evaluated. Based on the high effectiveness of the combination of daptomycin (DAP) plus RIF against meticillin-resistant S. aureus (MRSA) in this setting, in this study the efficacy of DAP+RIF and DAP+LVX combinations was tested as alternative therapies for foreign-body infections (FBIs) caused by MSSA. A tissue-cage infection model was performed using an MSSA strain. Male Wistar rats were treated for 7 days with LVX, DAP, RIF or the combinations LVX+RIF, DAP+RIF and DAP+LVX. Antibiotic efficacy was evaluated by bacterial counts from tissue cage fluid (TCF) and the cure rate was determined from adhered bacteria. Resistance was screened. Monotherapies were less effective than combinations (P<0.05), and resistance to DAP and RIF emerged. DAP+RIF (decrease in bacterial counts in TCF, -4.9logCFU/mL; cure rate, 92%) was the most effective therapy (P<0.05). There were no differences between LVX+RIF (-3.4logCFU/mL; 11%) and DAP+LVX (-3.3logCFU/mL; 47%). No resistant strains appeared with combined therapies. In conclusion, the combinations DAP+RIF and DAP+LVX showed good efficacy and prevented resistance. DAP+RIF provided higher efficacy than LVX+RIF. These DAP combinations were efficacious alternatives therapies for MSSA FBI. Further studies should confirm whether DAP+RIF may be useful as a first-line therapy in the setting of PJI caused by MSSA. PMID- 26051989 TI - Phosphatidylethanol Levels Are Elevated and Correlate Strongly with AUDIT Scores in Young Adult Binge Drinkers. AB - AIMS: To compare levels of phosphatidylethanol (PEth) to self-reported alcohol intake among young adult binge drinkers (18-30 years). METHODS: Abstainers (n = 23), moderate (n = 22), and binge drinkers (n = 58) completed an alcohol consumption questionnaire and the AUDIT. PEth was measured in whole blood and dried blood spots via high-performance liquid chromatography with tandem mass spectrometry. Also measured was mean corpuscular volume (MCV) and gamma glutamyl transpeptidase (GGT). RESULTS: Most subjects were female (65%) and Caucasian (73%). Among binge drinkers, past-month average number of binge episodes was 7.2 +/- 4; average duration of binge drinking behavior was 4.3 +/- 3 years. AUDIT scores and PEth levels (ng/ml) in whole blood or dried blood spots were significantly (P < 0.001) greater in binge drinkers (13 +/- 4, 186 +/- 170, and 65 +/- 53, respectively) compared to moderate drinkers (6 +/- 3, 24 +/- 29, and 11 +/- 13, respectively) and abstainers (0.6 +/- 0.89, 0, and 0, respectively). No differences were found in MCV and GGT among groups. There were significant correlations between whole blood and dried blood spot PEth levels and AUDIT scores (Spearman's r = 0.745 and 0.738, P < 0.0001, respectively), and whole blood and dried blood spot PEth levels were significantly correlated (0.899, P < 0.0001). CONCLUSIONS: PEth levels measured in whole blood and dried blood spots were significantly greater in binge drinkers compared to abstainers and moderate drinkers, and these levels were positively correlated with AUDIT scores. PMID- 26051990 TI - Novel benzimidazole salts for lithium ion battery electrolytes: effects of substituents. AB - In this paper, we report on our effort to design a novel lithium salt derived from bis(trifluoroborane)benzimidazolide by using density functional theory (DFT) calculations. The effects of different substituents are investigated with respect to ion pair dissociation energies and intrinsic anion oxidation potential of the molecules. Based on our calculations, we have found that ion pair dissociation energies and intrinsic anion oxidation potentials of the anions are mainly affected by the position and the type of substituents introduced into the parent structure. Compared to -CH3, substitution at the C2 position of the parent bis(trifluoroborane)benzimidazole (BTB(-)) by -CF3 results in an increase in anion oxidation stability. However, we observed a negligible change in the intrinsic anion oxidation potential as the length of the fluoroalkyl group increased to -C2F5. The most promising anions are generated by considering double substitution at C2 and C5 positions. Among the possible anions, bis(trifluoroborane)-5-nitro-2-(trifluoromethyl) benzimidazolide (BTNTB(-)), with the calculated intrinsic anion oxidation potential of 5.50 V vs. Li(+)/Li, can be considered as a potential candidate for high voltage Li-ion batteries. PMID- 26051992 TI - Removal of element mercury by medicine residue derived biochars in presence of various gas compositions. AB - Pyrolyzed biochars from an industrial medicinal residue waste were modified by microwave activation and NH4Cl impregnation. Mercury adsorption of different modified biochars was investigated in a quartz fixed-bed reactor. The results indicated that both physisorption and chemisorption of Hg(0) occurred on the surface of M6WN5 which was modified both microwave and 5wt.% NH4Cl loading, and exothermic chemisorption process was a dominant route for Hg(0) removal. Microwave activation improved pore properties and NH4Cl impregnation introduced good active sites for biochars. The presence of NO and O2 increased Hg(0) adsorption whereas H2O inhibited Hg(0) adsorption greatly. A converse effect of SO2 was observed on Hg(0) removal, namely, low concentration of SO2 promoted Hg(0) removal obviously whereas high concentration of SO2 suppressed Hg(0) removal. The Hg(0) removal by M6WN5 was mainly due to the reaction of the C-Cl with Hg(0) to form HgCl2, and the active state of C-Cl(*) groups might be an intermediate group in this process. Thermodynamic analysis showed that mercury adsorption by the biochars was exothermic process and apparent adsorption energy was 43.3 kJ/mol in the range of chemisorption. In spite of low specific surface area, M6WN5 proved to be a promising Hg(0) sorbent in flue gas when compared with other sorbents. PMID- 26051991 TI - Animal models of glucocorticoid-induced glaucoma. AB - Glucocorticoid (GC) therapy is widely used to treat a variety of inflammatory diseases and conditions. While unmatched in their anti-inflammatory and immunosuppressive activities, GC therapy is often associated with the significant ocular side effect of GC-induced ocular hypertension (OHT) and iatrogenic open angle glaucoma. Investigators have generated GC-induced OHT and glaucoma in at least 8 different species besides man. These models mimic many features of this condition in man and provide morphologic and molecular insights into the pathogenesis of GC-OHT. In addition, there are many clinical, morphological, and molecular similarities between GC-induced glaucoma and primary open-angle glaucoma (POAG), making animals models of GC-induced OHT and glaucoma attractive models in which to study specific aspects of POAG. PMID- 26051993 TI - Can the algicidal material Ca-aminoclay be harmful when applied to a natural ecosystem? An assessment using microcosms. AB - We assessed the ability of an artificial clay (Ca-aminoclay) to suppress harmful algal bloom species (HABs) such as Cochlodinium polykrikoides and Chattonella marina and investigated the ecological responses in the closed and open microcosm systems. The Ca-aminoclay induced rapidly and selectively cell lysis in the HABs. However, applying Ca-aminoclay could cause adverse impacts in terms of biological and environmental changes. The bacterioplankton abundance increased and then, the abundances of heterotrophic nanoflagellates and ciliates increased rapidly. Extremely poor environmental conditions such as increase in nutrients and development of anoxic conditions were sustained continuously in a closed system, while the environmental conditions in open systems deteriorated before recovering to the initial conditions. We evaluated the potential for the occurrence of a bloom of another phytoplankton after HABs had been controlled using the Ca aminoclay. The Ca-aminoclay controlled blooms of Chattonella marina in mixed cell cultures containing a Tetraselmis chui. However, T. chui increased over time and then bloomed. Therefore, caution should be taken when considering the direct application of Ca-aminoclay in natural environments even though it offers the rapid removal of HABs. PMID- 26051994 TI - Anaplastic lymphoma kinase inhibitors. AB - The anaplastic lymphoma kinase (ALK) gene is a member of the insulin receptor superfamily and it has been associated with more than twenty distinct chimera, including established drivers of several human cancers. Multiple clinical trials have proven that the pharmacological inhibition of ALK signaling leads to remarkable clinical improvement and improves the quality of life of ALK+ cancer patients. Crizotinib was the first ALKi to achieve approval from the Food and Drug Administration, although additional compounds are now moving into diversified clinical trials. PMID- 26051995 TI - CSF-1/CSF-1R targeting agents in clinical development for cancer therapy. AB - Macrophage infiltration has been identified as an independent poor prognostic factor for several cancer entities. In mouse tumor models macrophages orchestrate various tumor-promoting processes. This observation sparked an interest to therapeutically target these plastic innate immune cells. To date, blockade of colony stimulating factor-1 or its receptor represents the only truly selective approach to manipulate macrophages in cancer patients. Here, we discuss the currently available information on efficacy and safety of various CSF-1/CSF-1R inhibitors in cancer patients and highlight potential combination partners emerging from preclinical studies while considering the differences between mouse and human macrophage biology. PMID- 26051996 TI - Developmental trajectories of mother reported regulatory problems from toddlerhood to preschool age. AB - Developmental trajectories of mother-reported regulatory problems of typically developing children from age one and a half to four years old and possible predictors of various trajectories are analyzed in this study. Participants were 281 children born as full-term babies and their mothers. The attention and behavior regulation (ABR) problems and emotion regulation (ER) problems scales derived from maternal ratings on CBCL/11/2-5 were used. Also, data on the neonate's functioning, problem behaviors in infancy, maternal postpartum depressiveness, SES, maternal self-efficacy, and parenting practices were gathered prospectively at different time points and were analyzed as factors of regulatory problems. The latent class analysis for ABR problems over time suggested a 4-class solution: 35% of children were classified as having stable low, 27.6% - stable medium, 22.6% - decreasing and 14.1% - stable high levels of problems. Analysis of ER problems suggested a 3-class solution: 65% showed stable low, 25.1% - decreasing and 9.2% - increasing level of problems. Results showed the significance of maternal self-efficacy in predicting mother-rated emotional and behavioral regulation problems. Young maternal age and non-marital status resulted as risk factors for ABR problems, and lower maternal education differentiated the increasing from decreasing ER problems trajectories. Maternal depressiveness was found to be an additional risk factor for stable high ABR problems as opposed to decreasing trajectory, and lower scores of supportive responses predicted increasing vs. decreasing ER problems. Apgar scores were added only for high vs. medium ABR problems, and behavior problems in infancy for increasing vs. low ER problems trajectory in the study sample. Female gender was a stable predictor for a trajectory of low ABR problems. Early risk factors related with high ABR problems or increasing ER problems trajectories that may be important targets for intervention practices as well as further research are discussed. PMID- 26051998 TI - Regulation of epithelial sodium channel expression by oestradiol and progestogen in alveolar epithelial cells. AB - Oestrogen (E) and progestogen (P) exert regulatory effects on the epithelial Na(+) channel (ENaC) in the kidneys and the colon. However, the effects of E and P on the ENaC and on alveolar fluid clearance (AFC) remain unclear, and the mechanisms of action of these hormones are unknown. In this study, we showed that E and/or P administration increased AFC by more than 25% and increased the expression of the alpha and gamma subunits of ENaC by approximately 35% in rats subjected to oleic acid-induced acute lung injury (ALI). A similar effect was observed in the dexamethasone-treated group. Furthermore, E and/or P treatment inhibited 11beta-hydroxysteroid dehydrogenase (HSD) type 2 (11beta-HSD2) activity, increased corticosterone expression and decreased the serum adrenocorticotrophic hormone (ACTH) levels. These effects were similar to those observed following treatment with carbenoxolone (CBX), a nonspecific HSD inhibitor. Further investigation showed that CBX further significantly increased AFC and alpha-ENaC expression after treatment with a low dose of E and/or P. In vitro, E or P alone inhibited 11beta-HSD2 activity in a dose-dependent manner and increased alpha-ENaC expression by at least 50%, and E combined with P increased alpha-ENaC expression by more than 80%. Thus, E and P may augment the expression of alpha-ENaC, enhance AFC, attenuate pulmonary oedema by inhibiting 11beta-HSD2 activity, and increase the active glucocorticoid levels in vivo and in vitro. PMID- 26051997 TI - An integrated genomic analysis of papillary renal cell carcinoma type 1 uncovers the role of focal adhesion and extracellular matrix pathways. AB - Papillary renal cell carcinoma (pRCC) is the second most common RCC subtype and can be further classified as type 1 (pRCC1) or 2 (pRCC2). There is currently minimal understanding of pRCC1 pathogenesis, and treatment decisions are mostly empirical. The aim of this study was to identify biological pathways that are involved in pRCC1 pathogenesis using an integrated genomic approach. By microarray analysis, we identified a number of significantly dysregulated genes and microRNAs (miRNAs) that were unique to pRCC1. Integrated bioinformatics analyses showed enrichment of the focal adhesion and extracellular matrix (ECM) pathways. We experimentally validated that many members of these pathways are dysregulated in pRCC1. We identified and experimentally validated the downregulation of miR-199a-3p in pRCC1. Using cell line models, we showed that miR-199a-3p plays an important role in pRCC1 pathogenesis. Gain of function experiments showed that miR-199a-3p overexpression significantly decreased cell proliferation (p = 0.013). We also provide evidence that miR-199a-3p regulates the expression of genes linked to the focal adhesion and ECM pathways, such as caveolin 2 (CAV2), integrin beta 8 (ITGB8), MET proto-oncogene and mammalian target of rapamycin (MTOR). Using a luciferase reporter assay, we further provide evidence that miR-199a-3p overexpression decreases the expression of MET and MTOR. Using an integrated gene/miRNA approach, we provide evidence linking miRNAs to the focal adhesion and ECM pathways in pRCC1 pathogenesis. This novel information can contribute to the development of effective targeted therapies for pRCC1, for which there is none currently available in the clinic. PMID- 26051999 TI - Can urinary nerve growth factor and bladder wall thickness correlation in children have a potential role to predict the outcome of non-monosymptomatic nocturnal enuresis? AB - INTRODUCTION: Measurement of bladder wall thickness (BWTh) by ultrasound has been introduced as a new and promising technique to assess bladder dysfunction, and increased levels of nerve growth factor have also been reported in the bladder tissue and urine of patients with sensory urgency and detrusor overactivity (DO). OBJECTIVE: In this study we aimed to generate a clinically useful tool with urinary nerve growth factor levels and ultrasonographic BWTh to find possible pathogenetic clues and prognostic indicators as guides for the choice of therapy of non-monosymptomatic nocturnal enuresis. METHODS: A total of 110 children, aged 6-16 years old, were involved in this prospective study. Group 1 consisted of children with non-monosymptomatic nocturnal enuresis (n = 40), Group 2 of children with monosymptomatic nocturnal enuresis (n = 40) and Group 3 of children with healthy normal controls (n = 30). Children were evaluated with detailed history and physical examination, including neurologic examination; they were asked to complete a self-reported questionnaire and a 3-day bladder diary with the aid of their parents. The number of wet nights, the number of voids per night, the presence of daytime voiding symptoms (urgency, urge incontinence, incontinence, holding maneuvers, frequency), fluid intake, and any history of urinary tract infections (UTIs) were recorded. Monosymptomatic nocturnal enuresis and non-monosymptomatic nocturnal enuresis diagnosis was made using the International Children's Continence Society definition. Urinary nerve growth factor levels were measured by enzyme-linked immunosorbent assay and BWTh was measured transabdominally by a uroradiologist who specialized in pediatric ultrasonography. Urinary nerve growth factor levels were normalized by urinary creatinine levels and compared in all subgroups. RESULTS: The mean age of the study group was 9.6 (range 6-16) years. The mean BWTh was significantly increased in Group 1 compared with Group 2 (4.33 +/- 1.12 mm, 2.33 +/- 1.03 mm; p < 0.001) and healthy controls (4.33 +/- 1.12 mm, 1.86 +/- 0.57 mm; p < 0.001, respectively). Urinary levels of nerve growth factor corrected to urine creatinine (NGF/Cr) significantly increased in Group 1 with to Group 2 (2.75 +/- 1.15 vs. 0.58 +/- 0.15; p < 0.001) and controls (2.75 +/- 1.15 vs.0.28 +/- 0.10; p < 0.001, respectively). In receiver operating characteristic analysis, BWTh was found to have sensitivity of 95% and specificity of 85.7% (3.00 area under the curve [AUC] 0.937; 95%) and NGF/Cr had sensitivity of 97.5% and specificity of 98.6% (0.885; AUC, 999; 95%) in predicting lower urinary tract symptoms (LUTS) for non-monosymptomatic nocturnal enuresis (NMNE) (Figure). DISCUSSION: In our study we have investigated that BWTh together with urinary NGF levels normalized to the concentration of urinary creatinine (NGF/Cr) may predict daytime voiding problems in children with primary nocturnal enuresis (PNE). The main basis of this study is previous findings which demonstrated that ultrasonography (US) based measurement of BWTh is a useful diagnostic parameter for LUTS in children, and that increased levels of NGF in bladder tissue and urine such as sensory urgency, DO, and overactive bladder (OAB) was indicated by clinical and experimental studies. The present study demonstrated that urinary NGF/Cr levels and BWTh measurements were significantly increased in patients with NMNE with daytime urinary symptoms (urgency, urge-incontinence, incontinence, frequency) showing symptoms of an OAB than controls and MNE. CONCLUSION: BWTh measurements and NGF/Cr values, as non-invasive tools, may guide therapy and improve outcomes in the treatment of children with NMNE. Further studies including a larger number of patients would be of great interest. PMID- 26052000 TI - Robot-assisted laparoscopic pyeloplasty: Multi-institutional experience in infants. AB - INTRODUCTION: Robot-assisted laparoscopic pyeloplasty (RALP) has been gaining acceptance among pediatric urologists. Over 300 have been described in the literature, but few studies have evaluated the role of RALP in infants alone. OBJECTIVE: We sought to examine the operative experience and outcomes of RALP in a cohort of infants treated at multiple institutions across the United States. Our primary aim was to describe the safety and efficacy of RALP within this cohort. We recognize the challenges of performing minimally invasive surgery in small patients. In our paper, we address some technical considerations for the infant population. STUDY DESIGN: This multi-centered observational study collected data on subjects one year of age or less who underwent RALP between April 2006 and July 2012 at five institutions. The primary outcome was resolution of hydronephrosis, and secondary outcomes included surgical time and complications. RESULTS: A total of 60 patients (62 procedures) underwent RALP by six surgeons during the study period. All surgeons had > 5 years of experience beyond fellowship training. Mean surgical age was 7.3 months (SD +/- 1.7 mo), 56 patients (95%) were diagnosed prenatally, and 59 patients (95%) had follow up imaging. Of these patients, 91% showed resolution or improvement of hydronephrosis. Two patients had recurrent obstruction and required additional surgery. Mean surgical time was 3 hours 52 minutes (SD +/- 43 minutes). Seven (11%) patients reported intra-operative or immediate post-operative complications. DISCUSSION: This series found a 91% success rate for reduction or resolution of hydronephrosis, and an 11% complication rate. This is equivalent to modern series comparing open pyeloplasty to pure laparoscopic and robotic assisted laparoscopic pyeloplasty, which report success rates ranging from 70 96%, and complication rates ranging from 0-24% for open pyeloplasty. We lacked a standardized technique amongst institutions. This was not surprising since there are not established technical benchmarks for this surgery. However, we specified multiple technical considerations for this unique patient population. CONCLUSION: The advantages of using robot-assistance to perform pyeloplasty in infants remain to be defined. This study cannot make that assessment due to small sample size. Nonetheless, this cohort is the largest robotic pyeloplasty series in infants to date. Seeing an excellent success rate and a low complication rate in this infant cohort is encouraging. PMID- 26052001 TI - Incontinence in children with autism spectrum disorder. AB - INTRODUCTION: Autism spectrum disorder (ASD) and incontinence (nocturnal enuresis (NE), daytime urinary incontinence (DUI), fecal incontinence (FI)) are relevant disorders in childhood. In general, children with special needs such as intellectual disability (ID) or ASD are more often affected by incontinence than typically developing children. OBJECTIVE: In the few studies conducted on children with ASD, gastrointestinal (GI) symptoms have received more attention than NE, DUI and lower urinary tract symptoms (LUTS). The aim of the present study was to assess the prevalence of incontinence, LUTS and psychological symptoms/disorders in children with ASD compared to controls. STUDY DESIGN: Forty children with ASD (12 children with infantile or childhood autism, 15 with atypical autism and 13 with Asperger's syndrome) (mean age 11.3 years) and 43 age matched control children (mean age 10.7 years) were assessed. A questionnaire referring to incontinence and the International Consultation on Incontinence Questionnaire-Pediatric LUTS (ICIQ-CLUTS) were administered. Child psychopathology was assessed with the Child Behavior Checklist (CBCL/4-18). Child psychiatric ICD-10 diagnoses were based on a structured psychiatric interview (Kinder-DIPS). RESULTS: Children with ASD showed increased rates of NE (30.0% vs 0%) and DUI (25.0% vs 4.7%) compared to controls. Among children with ASD, daytime bladder control (>=5 years of age: 20.5% vs 0%) and bowel control (>=4 years of age: 42.5% vs 7.5%) were delayed compared to controls. Children with ASD had a higher LUTS score. Additionally, children with ASD were more often affected by psychological symptoms and disorders. Rates of clinically relevant externalizing symptoms (32.5% vs 0%), internalizing symptoms (67.5% vs 9.3%) and total problem score (70.0% vs 2.1%) were higher in children with ASD than the controls (see table). Children with ASD had more ICD-10 diagnoses than the controls (47.5% vs 4.7%). DISCUSSION: The present study showed that children with ASD are more at risk of DUI and NE than healthy controls. In addition, children with ASD had more LUTS, especially urgency and postponement, and they needed a longer time to become dry and continent. Additionally, according to the parental CBCL questionnaire, children with ASD showed higher rates of clinically relevant psychological symptoms (externalizing and internalizing symptoms), and according to the psychiatric interview, they had higher rates of comorbid psychological disorders. CONCLUSION: Autism spectrum disorder is an incapacitating disorder with significant impairment in social functioning. In most cases, psychological symptoms and disorders co-occur. Additionally, children with ASD are at a greater risk of being affected by different forms of incontinence and LUTS. Therefore, screening for incontinence and, if indicated, treatment of these disorders is recommended. PMID- 26052002 TI - Putting the past behind us: Social stress-induced urinary retention can be overcome. AB - INTRODUCTION: To study the pathophysiology of dysfunctional voiding, we have previously developed a model of stress-induced voiding dysfunction. We have shown that cyclosporine A (CsA), an inhibitor of the Ca(2+)-calmodulin complex, can prevent social stress-induced urinary retention. However, treatment with cyclosporine has not had an effect on the increase in the stress peptide corticotrophin-releasing factor (CRF) in Barrington's nucleus, which is involved in the micturition pathway. OBJECTIVE: We now investigate whether cyclosporine administered after stress can reverse the abnormal voiding phenotype, and whether it has effects on the bladder wall itself, or on the stress response within Barrington's nucleus. MATERIALS AND METHODS: Six-week old Swiss-Webster mice were exposed to aggressor males for 1 h a day, followed by 23 h of barrier separation. In a long-term trial, 1 month of stress was followed by single-cage housing for 6 months. In a separate CsA reversal trial, mice either received CsA in drinking water or had plain drinking water during 1 month of single-cage housing during recovery. Bladder contractile function was examined on a Guth myograph. Nuclear translocation of myocyte enhancing factor (MEF)-2 and NFAT (nuclear factor of activated T cells) in the bladder was assessed using electrophoretic mobility shift assays (EMSAs). The expression of CRF was determined in Barrington's nucleus using in situ hybridization. RESULTS: Voiding dysfunction persisted for up to 6 months after stress exposure while mice recovered in single-cage housing. In the CsA reversal trial, voiding patterns improved when they received CsA in water during single-cage housing following stress, whereas those that underwent single-cage housing alone had persistent abnormal voiding (Fig. A). There was no difference between CRF levels in Barrington's nucleus between reversal groups (p = 0.42) (Fig. B), possibly indicating a direct effect on the bladder rather than a persistent stress effect. There were no differences in the contractility of bladder wall muscle. CsA decreased the nuclear translocation of MEF-2 and NFAT induced by stress (Fig. C,D). CONCLUSION: CsA reverses stress-induced urinary retention, but does not change the stress-induced CRF increase in Barrington's nucleus. Furthermore, bladder smooth muscle contractility is unchanged by CsA; however, there are changes in the levels of the downstream transcription factors MEF-2 and NFAT. We suspect that additional CsA responsive neural changes play a pivotal role in the abnormal voiding phenotype following social stress. PMID- 26052003 TI - Practice patterns and outcomes of pediatric partial nephrectomy in the United States: Comparison between pediatric urology and general pediatric surgery. AB - BACKGROUND: In the United States, both pediatric urologists (PUROs) and general pediatric surgeons (GPSs) perform nephrectomies in children, with PUROs performing more nephrectomies overall, most commonly for benign causes. GPSs perform more nephrectomies for malignant causes. We questioned whether the same trends persisted for partial nephrectomy. OBJECTIVE: We hypothesized that PUROs performed more partial nephrectomies for all causes, including malignancy. Our primary aim was to characterize the number of partial nephrectomies performed by PUROs and GPSs. We also compared short-term outcomes between subspecialties. STUDY DESIGN: We analyzed the Pediatric Health Information System (PHIS), a database encompassing data from 44 children's hospitals. Patients were <=18 years old and had a partial nephrectomy (ICD-9 procedure code 554) carried out by PUROs or GPSs between 1 January, 2004 and June 30, 2013. Queried data points included surgeon subspecialty, age, gender, 3MTM All Patient Refined Diagnosis Related Groups (3MTM APR DRG) code, severity level, mortality risk, length of stay (LOS), and medical/surgical complication flags. Data points were compared in patients on whom PUROs and GPSs had operated. Statistical analysis included the Student t test, chi-square test, analysis of covariance, and logistic regression. RESULTS: Results are presented in the table. While PUROs performed the majority of partial nephrectomies, GPSs operated more commonly for malignancy. For surgeries performed for non-malignant indications, PURO patients had a shorter LOS and lower complication rate after controlling for statistically identified covariates. There was no difference in LOS or complication rate for patients with malignancy. DISCUSSION: A Pediatric Health Information System study of pediatric nephrectomy demonstrated PUROs performed more nephrectomies overall, but GPSs performed more surgeries for malignancy. The difference was less dramatic for partial nephrectomies (63% GPS, 37% PURO) than for radical nephrectomies (90% GPS, 10% PURO). PUROs performed more partial nephrectomies for benign indications (94% PURO, 6% GPS) at an even greater rate than nephrectomies (88% PURO, 12% GPS). As a national database study, there are a number of inherent limitations: applicability of results to non-participating hospitals, possibility of inaccurate data entry/coding, and lack of data points that would be relevant to the study. CONCLUSIONS: While most partial nephrectomies in the United States are performed by PUROs, GPSs perform the majority of surgeries for malignancy. There is no difference in LOS or complication rate undergoing nephron-sparing surgery for malignant disease; however, PUROs had a shorter LOS and lower complication rate when operating for benign diseases. PMID- 26052004 TI - Pediatric calyceal diverticulum treatment: An experience with endoscopic and laparoscopic approaches. AB - INTRODUCTION: The symptomatic calyceal diverticulum is a rare event in the pediatric population. In adults, surgical options include ureteroscopy, percutaneous ablation, and laparoscopic decortication but there is a lack of experience in the literature with these techniques. OBJECTIVE: We present our experience with both the ureteroscopic and laparoscopic approach to treating the pediatric calyceal diverticulum. STUDY DESIGN: We performed a retrospective case series looking at patients who underwent treatment for calyceal diverticulum at our institution from January 2009 to May 2014. We reviewed patient demographics, indications for intervention, radiographic appearance, type of intervention, and perioperative outcomes. Ureteroscopic approach included dilation of infundibulum and ablation of diverticular cavity. Laparoscopic approach included ablation of the diverticulum with argon diathermy with or without surgical closure of the ostium. RESULTS: There were 13 patients who underwent 15 procedures for symptomatic calyceal diverticulum (Table). Median age was 11 years. Indications for intervention were: pain and increasing size of diverticulum (8/15, 55%), hematuria (3/15, 20%), UTI (3/15, 20%), and calculi (1/15, 5%). 11/15 (73%) procedures were managed endoscopically and 4/15 (27%) were managed with laparoscopic decortication. Ureteral stent was left in all patients for a mean duration of 51 days (15-120 days). Follow up imaging at median of 2.1 years (0.5 4 years) revealed an initial success rate of 85% (11/13 patients). Two patients failed initial intervention (persistent pain/increasing size) necessitating successful secondary minimally invasive procedures. There were 2 (13%) complications: a perinephric hematoma post endoscopic ablation which resolved spontaneously and a deep venous thrombosis in a patient with a coagulation disorder in the laparoscopic group. DISCUSSION: Limitations of our study include its retrospective design, lack of standardization of the treatment approach amongst the four treating surgeons, and the small number of patients requiring intervention for this relatively rare diagnosis. Our study is the largest to date in the pediatric population and is the first to report outcomes with ureteroscopic management of the calyceal diverticulum. CONCLUSIONS: We found that the pediatric calyceal diverticulum can be successfully treated in a minimally invasive manner. The endoscopic approach should be the first line option for patients with small, endophytic diverticula, particularly those located in the upper and mid pole. The laparoscopic approach is more invasive but should be considered for large diverticula that are exophytic with thin overlying parenchyma. PMID- 26052005 TI - Single-molecule insights into mRNA dynamics in neurons. AB - Targeting of mRNAs to neuronal dendrites and axons plays an integral role in intracellular signaling, development, and synaptic plasticity. Single-molecule imaging of mRNAs in neurons and brain tissue has led to enhanced understanding of mRNA dynamics. Here we discuss aspects of mRNA regulation as revealed by single molecule detection, which has led to quantitative analyses of mRNA diversity, localization, transport, and translation. These exciting new discoveries propel our understanding of the life of an mRNA in a neuron and how its activity is regulated at the single-molecule level. PMID- 26052007 TI - Cardiac biomarkers in blood, and pericardial and cerebrospinal fluids of forensic autopsy cases: A reassessment with special regard to postmortem interval. AB - Previous studies suggested possible application of postmortem biochemistry of myocardial biomarkers to the investigation of sudden cardiac death; however, differences from clinical findings should be considered in autopsy materials. The present study involved a comprehensive investigation of cardiac troponin T and I (cTnT and cTnI), and creatine kinase MB (CK-MB) in cardiac and peripheral external iliac venous blood, pericardial fluid (PCF) and cerebrospinal fluid (CSF) for reassessment, with special regard to the estimated postmortem interval in relation to the cause of death, reviewing a large number of forensic autopsy cases (n=1923). These cardiac biomarkers showed cause-of-death- and postmortem time-dependent differences: blood and PCF levels of each marker were higher in hyperthermia (heatstroke), bathwater drowning and chronic congestive heart disease in cases of postmortem interval (PMI) <12h. After 12h postmortem, these markers were also higher in fatal drug abuse, spontaneous cerebral/subarachnoid bleeding, electrocution and pulmonary embolism. In addition, most other causes of death, including ischemic heart disease, showed substantial elevations, while these markers remained low in acute hemorrhagic death from sharp instrument injury, hypothermia (cold exposure) and sea-/freshwater drowning during PMI of <48h. CSF cTnI and CK-MB showed similar findings. There was no difference between myocardial infarction and other causes of death to be discriminated, including asphyxiation, drowning and fire fatality. These findings are similar to clinical observations in critical ill patients, suggesting that elevated cardiac biomarkers cannot be a specific finding for death from acute ischemic heart disease, but indicate the severity of myocardial injury in postmortem investigation. PMID- 26052006 TI - Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease. AB - The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S) trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4 analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-alpha and CD11c(+) M1-macrophages (MPhis), while restoring CD206(+) M2-MPhis and increasing Annexin-A1. LXs did not affect renal or hepatic MPhis, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies. PMID- 26052008 TI - A controllable bacterial lysis system to enhance biological safety of live attenuated Vibrio anguillarum vaccine. AB - Bacterial strains used as backbone for the generation of vaccine prototypes should exhibit an adequate and stable safety profile. Given the fact that live attenuated vaccines often contain some potential risks in virulence recovery and spread infections, new approaches are greatly needed to improve their biological safety. Here, a critically iron-regulated promoter PviuA was screened from Vibrio anguillarum, which was demonstrated to respond to iron-limitation signal both in vitro and in vivo. By using PviuA as a regulatory switch to control the expression of phage P22 lysis cassette 13-19-15, a novel in vivo inducible bacterial lysis system was established in V. anguillarum. This system was proved to be activated by iron-limitation signals and then effectively lyse V. anguillarum both in vitro and in vivo. Further, this controllable bacterial lysis system, after being transformed into a live attenuated V. anguillarum vaccine strain MVAV6203, was confirmed to significantly improve biological safety of the live attenuated vaccine without impairing its immune protection efficacy. PMID- 26052009 TI - Characterization of the duodenase-1 gene and its associations with resistance to Streptococuus agalactiae in hybrid tilapia (Oreochromis spp.). AB - Tilapia is a group of cultured teleost fishes whose production is threatened by some diseases. Identification of DNA markers associated with disease resistance in candidate genes may facilitate to accelerate the selection of disease resistance. The gene encoding a duodenase, which can trigger immune response, has not been studied in fish. We characterized the cDNA of duodenase-1 gene of hybrid tilapia. Its ORF is 759 bp, encoding a serine protease of 252 amino acids. This gene consisted of five exons and four introns. Its expression was detected in all 10 tissues examined, and it was highly expressed in the intestine and kidney. After a challenge with the bacterial pathogen, Streptococcus agalactiae, its expression was up-regulated significantly in the intestine, liver and spleen. We identified seven SNPs in the gene and found that four of them were significantly associated with the resistance to S. agalactiae (P < 0.05). The CGTCC haplotype, CAGTC/CGGTC and CGTCC/CGTCC diplotype were significantly associated with the resistance to S. agalactiae (P = 0.00, 0.04 and < 0.0001, respectively). In addition, one SNP was associated significantly with growth traits (P < 0.05). These findings suggest that the duodenase-1 gene plays an important role in the resistance to S. agalactiae in tilapia. The SNP markers in the duodenase-1 gene associated with resistance to the bacterial pathogen, may facilitate the selection of tilapia resistant to the bacterial disease. PMID- 26052010 TI - Rearing effect of biofloc on antioxidant and antimicrobial transcriptional response in Litopenaeus stylirostris shrimp facing an experimental sub-lethal hydrogen peroxide stress. AB - This study compares the antioxidant and antimicrobial transcriptional expression of blue shrimps reared according to two different systems, BioFloc Technology (BFT) and Clear sea Water (CW) and their differential responses when facing an experimental sublethal hydrogen peroxide stress. After 30 days of rearing, juvenile shrimps were exposed to H2O2 stress at a concentration of 30 ppm during 6 h. The oxidative stress caused by H2O2 was examined in the digestive glands of the shrimp, in which antioxidant enzyme (AOE) and antimicrobial peptide (AMP) gene expression were analysed by quantitative real-time PCR. Results showed that rearing conditions did not affect the expression of genes encoding AOEs or AMPs. However, H2O2 stress induced a differential response in expression between shrimps from the two rearing treatments (BFT and CW). Comparative analysis of the expression profiles indicates that catalase transcripts were significantly upregulated by H2O2 stress for BFT shrimps while no change was observed for CW shrimps. In contrast, H2O2 caused down-regulation of superoxide dismutase and glutathione transferase transcripts and of the three AMP transcripts studied (penaeidin 2 and 3, and crustin) for CW shrimps, while no effect was observed on BFT shrimp transcript levels. These results suggested that BFT shrimps maintained antioxidant and AMP responses after stress and therefore can effectively protect their cells against oxidative stress, while CW shrimp immune competence seems to decrease after stress. PMID- 26052011 TI - Temperature-dependent regulation of gene expression in poly (I:C)-treated Japanese flounder, Paralichthys olivaceus. AB - Gene expression profiling of poly (I:C)-treated Japanese flounder, Paralichthys olivaceus, under different temperatures was investigated using microarray analysis. The response was analyzed in spleen tissue at 3 and 24 h post injection (hpi) at 15 degrees C and 25 degrees C. A large number of genes in fish treated with poly (I:C) at 25 degrees C were expressed at 3 hpi, whereas the expression profiles at 24 hpi appeared to be similar to those of the controls. Cluster analysis of the different expression profiles showed three distinct groups of up regulated genes in fish reared at 15 degrees C. These were early (3 hpi), early to-late (3 and 24 hpi), and late (24 hpi) up-regulated genes. These genes included type I IFN-related genes and inflammatory genes. Among the up-regulated genes, most of the type I IFN-related genes played early-to-late- and late responding genes at 15 degrees C but early-responding genes at 25 degrees C. Thus, several up-regulated genes in these groups from the microarray result were further verified by qPCR. These results indicate that the type I IFN gene expressions of P. olivaceus treated with poly (I:C) can be regulated in a temperature-dependent manner. PMID- 26052012 TI - Effects of dietary Bacillus cereus G19, B. cereus BC-01, and Paracoccus marcusii DB11 supplementation on the growth, immune response, and expression of immune related genes in coelomocytes and intestine of the sea cucumber (Apostichopus japonicus Selenka). AB - Probiotics have positive effects on the nutrient digestibility and absorption, immune responses, and growth of aquatic animals, including the sea cucumber (Apostichopus japonicus Selenka). A 60-day feeding trial was conducted to evaluate the effects of Bacillus cereus G19, B. cereus BC-01 and Paracoccus marcusii DB11 supplementation on the growth, immune response, and expression level of four immune-related genes (Aj-p105, Aj-p50, Aj-rel, and Aj-lys) in coelomocytes and the intestine of juvenile sea cucumbers. One group was fed the basal diet (control group), while three other groups were fed the basal diet supplemented with B. cereus G19 (G19 group), B. cereus BC-01 (BC group), or P. marcusii DB11 (PM group). The growth rate of sea cucumbers fed diets with probiotics supplementation was significantly higher than that of the control group (P < 0.05). Sea cucumbers in the G19 and PM groups had a significantly greater phagocytic activity of coelomocytes compared to the control group (P < 0.05), while those in the G19 and BC groups had a greater respiratory burst activity (P < 0.05). The alkaline phosphatase (AKP) activity of coelomocytes in sea cucumbers fed diets with probiotics supplementation was significantly higher than the control group (P < 0.05). Comparatively, superoxide dismutase (SOD) activity of coelomocytes for sea cucumber in the PM group was significantly greater (P < 0.05). As for the immune-related genes, B. cereus G19 supplementation significantly increased the expression level of the Aj-rel gene in coelomocytes (P < 0.05), while B. cereus BC-01 supplementation significantly increased that of the Aj-p50 gene as compared to the control group (P < 0.05). In the intestine, the relative expression level of Aj-p105, Aj-p50, and Aj-lys genes in the PM group was significantly higher than that in the control group (P < 0.05). These results suggested that B. cereus G19 and B. cereus BC-01 supplementation could improve the growth performance and the immune response in coelomocytes, while P. marcusii DB11 supplementation could have a positive effect on the growth performance and immune response in coelomocytes and the intestine of sea cucumbers. PMID- 26052013 TI - Effects of somatotrophic axis (GH/GHR) double transgenesis on structural and molecular aspects of the zebrafish immune system. AB - The development of growth hormone (GH) transgenic fish has been shown to be a promising method to improve growth rates. However, the role of GH is not restricted only to processes involved in growth. Several others physiological processes, including immune function, are impaired due to GH imbalances. Given the importance of generating GH transgenic organisms for aquaculture purposes, it is necessary to develop strategies to reduce or compensate for the collateral effects of GH. We hypothesized that the generation of double transgenic fish that overexpress GH and growth hormone receptor (GHR) in the skeletal muscle could be a possible alternative to compensate for the deleterious effects of GH on the immune system. Specifically, we hypothesized that increased GHR amounts in the skeletal muscle would be able to reduce the level of circulating GH, attenuating the GH signaling on the immune cells while still increasing the growth rate. To test this hypothesis, we evaluated the size of the immune organs, T cell content in the thymus and head kidney, and expression of immune-related genes in double transgenic fish. Contrary to our expectations, we found that the overexpression of GHR does not decrease the deleterious effect of GH excess on the size of the thymus and head kidney, and in the content of CD3(+) and CD4(+) cells in the thymus and head kidney. Unexpectedly, the control GHR transgenic group showed similar impairments in immune system parameters. These results indicate that GHR overexpression does not reverse the impairments caused by GH and, in addition, could reinforce the damage to the immune functions in GH transgenic zebrafish. PMID- 26052014 TI - Cellular and molecular markers in monitoring the fate of lymphoid cell culture from Penaeus monodon Fabricius (1798). AB - Lymphoid cell culture from penaeid shrimps has gained much acceptance as an in vitro platform to facilitate research on the development of prophylaxis, and therapeutic strategies against viruses and for cell line development. However, lymphoid cells can be used as platform for in vitro research, only if they are in metabolically and mitotically active state in vitro with unaltered cell surface receptors. Through this study, we addressed the response of lymphoid cells to a new microenvironment at cellular and molecular levels; including the study of mitotic events, DNA synthesis, expression profile of cell cycle genes, cytoskeleton organization, metabolic activity and viral susceptibility. The S phase entry and synthesis of new DNA was recorded by immunoflourescent technique. Cdc2, CycA, CycB, EF-1alpha and BUB3 genes involved in cell cycle were studied in both the cells and tissue, of which EF-1alpha showed an elevated expression in cells in vitro (~ 19.7%). Cytoskeleton network of the cell was examined by studying the organization of actin filaments. As the markers for metabolic status, mitochondrial dehydrogenase, protein synthesis and glucose assimilation by the cells were also assessed. Viral susceptibility of the cell was determined using WSSV to confirm the preservation of cellular receptors. This study envisages to strengthen the shrimp cell line research and to bring forth lymphoid cell culture system as a 'model' in vitro system for shrimp and crustaceans altogether. PMID- 26052015 TI - Thioredoxin of golden pompano involved in the immune response to Photobacterium damselae. AB - Thioredoxin (TRX) is one of the key systems responsible for keeping the intracellular environment in a highly reduced state. In this study, a full-length TRX cDNA sequence (ToTRX) from golden pompano Trachinotus ovatus was identified after pyrosequencing of golden pompano cDNA library. ToTRX cDNA is comprised of 786 bp, and contained a 324 bp open reading frame (ORF) encoding a 107 amino acid polypeptide, a 5' untranslated region (UTR) of 116 bp, and a long 3'- UTR of 346 bp. Multiple sequence alignment revealed that ToTRX contained the highly conserved redox active disulphide/dithiol site (CGPC) of the thioredoxin active family, and phylogenetic tree showed that ToTRX had a closer evolution relationship with TRX from Oplegnathus fasciatus and Anoplopoma fimbria. ToTRX mRNA is ubiquitously expressed in all detected tissues with the higher expression levels in the stomach, gill and fin tissues. The expression of ToTRX mRNA was significantly up-regulated in liver, kidney, intestine and spleen of golden pompano injected with Photobacterium damselae. The recombinant ToTRX protein (rToTRX) was expressed in Escherichia coli BL21 (DE3), and then purified and refolded. The insulin disulfides assay was performed to investigate the enzymatic oxidoreductase activity of rToTRX, and the results demonstrated that rToTRX exhibited a high reducing activity in presence of DTT, while no activity was observed in the regroup without DTT and blank control group. Over all, the study provided the useful information to help further understand the functional mechanism of TRX in marine fish immunity. PMID- 26052016 TI - Grouper voltage-dependent anion selective channel protein 2 is required for nervous necrosis virus infection. AB - Nervous necrosis virus (NNV) is a non-enveloped virus with 2 segmented positive sense single-stranded RNAs. NNV-induced mass mortality has occurred worldwide in many species of cultured marine fish and resulted in substantial economic losses. In our previous study, we cloned the gene of voltage-dependent anion selective channel protein 2 (GVDAC2), and the NNV RNA2 expression level decreased in GVDAC2 knockdown GF-1 cells 24 h after infection. Here, we investigated the role of GVDAC2 in the NNV infection in GF-1 cells. NNV infection did not considerably affect GVDAC2 gene expression. After performing immunostaining, we detected GVDAC2 at the mitochondria and GVDAC2 was colocalized with NNV-RNA-dependent RNA polymerase. However, these 2 proteins did not interact with each other in immunoprecipitation assay. The cellular ATP level in GVDAC2-downregulated cells was lower than that in control cells, and NNV-induced apoptosis was delayed in GVDAC2-siRNA-transfected cells. Therefore, we suggest that GVDAC2 is required for NNV infection for maintaining the cellular ATP level and has positive impact on virus-induced apoptosis. PMID- 26052017 TI - Critical roles of sea cucumber C-type lectin in non-self recognition and bacterial clearance. AB - C-type lectin is one important pattern recognition receptor (PRR) that plays crucial roles in multiple immune responses. A C-type lectin from sea cucumber Apostichopus japonicus (AjCTL-1) was characterized in the present study. The amino acid sequence of AjCTL-1 shared high similarities with other C-type lectins from invertebrates and vertebrates. The C-type lectin domain (CTLD) of AjCTL-1 contained a Ca(2+)-binding site 2 and four conserved cysteine residues. AjCTL-1 mRNA expression patterns in tissues and after bacterial challenge were then analysed. Quantitative PCR revealed that AjCTL-1 mRNA was widely expressed in the tested tissues of healthy sea cucumber. The highest expression level occurred in gonad followed by body wall, coelomocytes, tentacle, intestinum and longitudinal muscle, and the lowest expression level was in respiratory tree. AjCTL-1 mRNA expression in coelomocytes was significantly induced by gram-negative Listonella anguillarum and gram-positive Micrococcus luteus, with different up-regulation patterns post-challenge. Recombinant AjCTL-1 exhibited the ability to bind peptidoglycan directly, agglutinate M. luteus, Staphylococcus aureus and Escherichia coli, in a Ca(2+)-dependant manner, and enhance the phagocytosis of coelomocytes against E. coli in vitro. The results indicated that AjCTL-1 could act as a PRR in Apostichopus japonicus and had critical roles in non-self recognition and bacterial clearance against invading microbes. PMID- 26052018 TI - CsCCL17, a CC chemokine of Cynoglossus semilaevis, induces leukocyte trafficking and promotes immune defense against viral infection. AB - CC chemokines are the largest subfamily of chemokines, which are important components of the innate immune system. To date, sequences of several CC chemokines have been identified in half-smooth tongue sole (Cynoglossus semilaevis); however, the activities and functions of these putative chemokines remain unknown. Herein, we characterized a CC chemokine, CsCCL17, from tongue sole, and examined its activity. CsCCL17 contains a 303 bp open reading frame, which encodes a polypeptide of 100 amino acids with a molecular mass of 12 kDa CsCCL17 is phylogenetically related to the CCL17/22 group of CC chemokines and possesses the typical arrangement of four cysteines and an SCCR motif found in known CC chemokines. Under normal physiological conditions, CsCCL17 expression was detected in spleen, liver, heart, gill, head kidney, muscle, brain, and intestine. When the fish were infected by bacterial and viral pathogens, CsCCL17 expression was significantly up-regulated in a time-dependent manner. Chemotactic analysis showed that recombinant CsCCL17 (rCsCCL17) induced migration of peripheral blood leukocytes. A mutagenesis study showed that when the two cysteine residues in the SCCR motif were replaced by serine, no apparent chemotactic activity was observed in the mutant protein rCsCCL17M. rCsCCL17 enhanced the resistance of tongue sole against viral infection, but rCsCCL17M lacked this antiviral effect. Taken together, these findings indicate that CsCCL17 is a functional CC chemokine with the ability to recruit leukocytes and enhance host immune defense in a manner that requires the conserved SCCR motif. PMID- 26052019 TI - Functional characterization of viral tumor necrosis factor receptors encoded by cyprinid herpesvirus 3 (CyHV3) genome. AB - Cyprinid herpesvirus 3 (CyHV3) is a large double-stranded DNA virus of Alloherpesviridae family in the order Herpesvirales. It causes significant morbidity and mortality in common carp and its ornamental koi variety, and threatens the aquaculture industries worldwide. Mimicry of cytokines and cytokine receptors is a particular strategy for large DNA viruses in modulating the host immune response. Here, we report the identification and characterization of two novel viral homologues of tumor necrosis factor receptor (TNFR) encoded by CyHV3 ORF4 and -ORF12, respectively. CyHV3-ORF4 was identified as a homologue of HVEM and CyHV3-ORF12 as a homologue of TNFRSF1. Overexpression of ORF4 and ORF12 in zebrafish embryos results in embryonic lethality, morphological defects and increased apoptosis. Although we failed to identify any interaction between the two vTNFRs and their potential ligands in zebrafish TNF superfamily by yeast two hybrid system, the expression of some genes in TNF superfamily or TNFR superfamily were mis-regulated in ORF4 or ORF12-overexpressing embryos, especially the death receptor zHDR and its cognate ligand DL1b. Further studies showed that the apoptosis induced by the both CyHV3 vTNFRs is mainly activated through the intrinsic apoptotic pathway and requires the crosstalk between the intrinsic and extrinsic apoptotic pathway. Additionally, using RT-qPCR and Western blot assays, the expression patterns of the both vTNFRs were also analyzed during CyHV3 productive infection. Collectively, this is the first functional study of two unique vTNFRs encoded by a herpesvirus infecting non mammalian vertebrates, which may provide novel insights into viral immune regulation mechanism and the pathogenesis of CyHV3 infection. PMID- 26052020 TI - Generation of G gene-deleted viral hemorrhagic septicemia virus (VHSV) and evaluation of its vaccine potential in olive flounder (Paralichthys olivaceus). AB - Generation of recombinant viruses lacking an essential gene for the production of infective viral particles would be a way to produce safety-enhanced live viral vaccines. The rhabdoviral envelope-spiked glycoprotein (G) plays critical roles in the attachment of viruses on the cell surface receptor and in the transfer of endocytosed viruses to the cytoplasm by fusion to the endosomal membrane. In the present study, we produced a G gene-lacking recombinant viral hemorrhagic septicemia virus (rVHSV-DeltaG) that has no ability to form plaques in the cells without a trans-supply of the G protein, which suggests that rVHSV-DeltaG is a single cycle virus and progenies of rVHSV-DeltaG are not infectious. One of the major advantages of attenuated vaccines is the maintenance of replication ability in the host, which enforces the adaptive immune responses. However, in spite of lacking an ability to produce infective viral particles, immunization with the present rVHSV-DeltaG induced significantly higher serum neutralization titers and survival rates against virulent VHSV challenge in olive flounder (Paralichthys olivaceus) fingerlings, indicating that the present rVHSV-DeltaG has a high potential as a prophylactic vaccine. PMID- 26052021 TI - Disruption of lig4 improves gene targeting efficiency in the oleaginous fungus Mortierella alpina 1S-4. AB - The oil-producing zygomycete Mortierella alpina 1S-4 is known to accumulate beneficial polyunsaturated fatty acids. We identified the lig4 gene that encodes for a DNA ligase 4 homolog, which functions to repair double strand breaks by non homologous end joining. We disrupted the lig4 gene to improve the gene targeting efficiency in M. alpina. The M. alpina 1S-4 Deltalig4 strains showed no defect in vegetative growth, formation of spores, and fatty acid production, but exhibited high sensitivity to methyl methansulfonate, an agent that causes DNA double strand breaks. Importantly, gene replacement of ura5 marker by CBXB marker occurred in 67% of Deltalig4 strains and the gene targeting efficiency was 21 fold greater than that observed in disruption of the lig4 gene in the M. alpina 1S-4 host strain. Further metabolic engineering of the Deltalig4 strains is expected to result in strains that produce higher levels of rare and beneficial polyunsaturated fatty acids and contribute to basic research on the zygomycete. PMID- 26052022 TI - Comparative study of the effect of chloro-, dichloro-, bromo-, and dibromoacetic acid on necrotic, apoptotic and morphological changes in human peripheral blood mononuclear cells (in vitro study). AB - In this study, the effect of monochloroacetic acid (MCAA), dichloroacetic acid (DCAA), monobromoacetic acid (MBAA) and dibromoacetic acid (DBAA) on human peripheral blood mononuclear cells (PBMCs) was assessed. HAAs studied induced at millimolar concentrations necrotic alterations in PBMCs with the strongest effect noted for MBAA and DBAA. Chloro- and bromoacetic acids also provoked changes in PBMCs morphology because they caused a strong decrease in cell size (particularly DCAA and DBAA) and increase in cell granulation (mainly MBAA and DBAA). All HAAs studied, and DCAA and DBAA in particular (at lower concentrations than those, which caused necrosis) induced apoptotic changes, which was confirmed by analysis of alterations in cell membrane permeability and caspase 8, 9 and 3 activation. Moreover, HAAs examined (mainly dihalogenated acids) strongly increased transmembrane mitochondrial potential and enhanced ROS (mainly hydroxyl radical) formation, which was possibly associated with apoptotic changes provoked by those substances. The results showed that DBAA exhibited the strongest effects on PBMCs. PMID- 26052023 TI - Potential advantages of health system consolidation and integration. PMID- 26052024 TI - Aortic Regurgitation Is Common in Ankylosing Spondylitis: Time for Routine Echocardiography Evaluation? AB - OBJECTIVES: The aim of this study was to assess the prevalence of aortic regurgitation and any relation to disease activity and specific human leukocyte antigen (HLA)-B27 subtypes in patients with ankylosing spondylitis. METHODS: Transthoracic echocardiography was performed in 187 patients (105 men), mean age (SD) 50 (13) years, and mean disease duration 24 (13) years, and was related to demographic, clinical, radiographic, electrocardiographic, and laboratory data. RESULTS: Aortic regurgitation was found in 34 patients (18%; 95% confidence interval [CI], 12%-24%): mild in 24, moderate in 9, and severe in one. The prevalence was significantly higher than expected from population data. Conduction system abnormalities were documented in 25 patients (13%; 95% CI, 8% 18%), and significantly more likely in the presence of aortic regurgitation (P = .005), which was related to increasing age and longstanding disease, and increased from ~20% in the 50s to 55% in the 70s. It was also independently associated with disease duration, with higher modified Stoke Ankylosing Spondylitis Spine Score, and with a history of anterior uveitis. HLA-B27 was present in similar proportions in the presence vs absence of aortic regurgitation. For comparison, clinically significant coronary artery disease was present in 9 patients (5%; 95% CI, 2%-8%). CONCLUSION: Patients with ankylosing spondylitis frequently have cardiac abnormalities, but they more often consist of disease-related aortic regurgitation or conduction system abnormalities than manifestations of atherosclerotic heart disease. Because aortic regurgitation or conduction abnormalities might cause insidious symptoms not easily interpreted as of cardiac origin, we suggest that both electrocardiography and echocardiography evaluation should be part of the routine management of patients with ankylosing spondylitis. PMID- 26052025 TI - Update in outpatient general internal medicine: practice-changing evidence published in 2014. AB - The practice of outpatient general internal medicine requires a diverse and evolving knowledge base. General internists must identify practice-changing shifts in the literature and reflect on their impact. Accordingly, we conducted a review of practice-changing articles published in outpatient general internal medicine in 2014. To identify high-quality, clinically relevant publications, we reviewed all titles and abstracts published in the following primary data sources in 2014: New England Journal of Medicine, Journal of the American Medical Association (JAMA), Annals of Internal Medicine, JAMA Internal Medicine, and the Cochrane Database of Systematic Reviews. All 2014 primary data summaries from Journal Watch-General Internal Medicine and ACP JournalWise also were reviewed. The authors used a modified Delphi method to reach consensus on inclusion of 8 articles using the following criteria: clinical relevance to outpatient internal medicine, potential for practice change, and strength of evidence. Clusters of important articles around one clinical question were considered as a single candidate series. The article merits were debated until consensus was reached on the final 8, spanning a variety of topics commonly encountered in outpatient general internal medicine. PMID- 26052026 TI - An Iatrogenic Metastasis. PMID- 26052027 TI - Chagas Heart Disease: An Update. AB - Chagas disease, also known as American trypanosomiasis, results from infection by the protozoan Trypanosoma cruzi, and is a major cause of cardiac disease worldwide. Until recently, Chagas disease was confined to those areas of South and Central America where Trypanosoma cruzi is endemic. With the migration of infected individuals, however, the disease has spread, and it is estimated that 6 7 million people worldwide are infected. In the US alone, more than 7 million people from Trypanosoma cruzi-endemic countries became legal US residents by the turn of the century, resulting in a surge of Chagas disease in this country. According to preliminary estimates, the US now ranks seventh in the Western Hemisphere in number of individuals infected with Trypanosoma cruzi, and the disease has become a major public health concern due to limited awareness in the medical community. PMID- 26052028 TI - Summer syncope syndrome redux. AB - BACKGROUND: While antihypertensive therapy is known to reduce the risk for heart failure, myocardial infarction, and stroke, it can often cause orthostatic hypotension and syncope, especially in the setting of polypharmacy and possibly, a hot and dry climate. The objective of the present study was to investigate whether the results of our prior study involving continued use of antihypertensive drugs at the same dosage in the summer as in the winter months for patients living in the Sonoran desert resulted in an increase in syncopal episodes during the hot summer months. METHODS: All hypertensive patients who were treated with medications and admitted with International Classification of Diseases, 9th Revision code diagnosis of syncope were included. This is a 3-year retrospective chart review study. They were defined as "cases" if they presented during the summer months (May to September) and "controls" if they presented during the winter months (November to March). The primary outcome measure was the presence of clinical dehydration. The statistical significance was determined using the 2-sided Fisher's exact test. RESULTS: A total of 834 patients with an International Classification of Diseases, 9th Revision code diagnosis of syncope were screened: 477 in the summer months and 357 in the winter months. In patients taking antihypertensive medications, there was a significantly higher number of cases of syncope secondary to dehydration during the summer months (40.5%) compared with the winter months (29%) (P = .04). No difference was observed in the type of antihypertensive medication used and syncope rate. The number of antihypertensives used did not increase the cases of syncope in either summer or winter. CONCLUSIONS: An increased number of syncope events was observed in the summer months among people who reside in a dry desert climate and who are taking antihypertensive medications. The data confirm our earlier observations that demonstrated a greater number of cases of syncope among people who reside in a dry desert climate who were taking antihypertensive medications during summer months. We recommend judicious reduction of antihypertensive therapy in patients residing in a hot and dry climate, particularly during the summer months. PMID- 26052029 TI - The long QT teaser: loperamide abuse. PMID- 26052030 TI - Keep Your Hands Off My Insulin Pump! The Dilemma of the Hospitalized Insulin Pump Patient. PMID- 26052031 TI - Modulation of c-Jun N-terminal kinase signaling and specific glucocorticoid receptor phosphorylation in the treatment of major depression. AB - Glucocorticoid resistance is a common finding in major depressive disorder. Increased glucocorticoid receptor (GR) phosphorylation at serine 226 is associated with increased glucocorticoid resistance. Previously we have demonstrated that depressed patients exhibit higher levels of GR phosphorylated at serine 226 compared to healthy controls. The enzyme that is involved in this specific GR phosphorylation is c-Jun N-terminal kinase (JNK). We propose that modulation of glucocorticoid phosphorylation at serine 226, by targeting JNK signaling pathway, could be a potential strategy for antidepressant treatment. We base this assumption on the results of previous research that examined GR phosphorylation and JNK signaling in animal models and human studies. We also discuss the potential challenges in targeting JNK signaling pathway in depression. PMID- 26052032 TI - How the cation-cation pi-pi stacking occurs: A theoretical investigation into ionic clusters of imidazolium. AB - The cation-cation pi-pi stacking is uncommon but it is essential for the understanding of some supramolecular structures. We explore theoretically the nature of non-covalent interaction occurring in the stacked structure within modeled clusters of 1,3-dimethylimidazolium and halide. The evidences of the energy decomposition analysis (EDA) and reduced density gradient (RDG) approach are different from those of common pi-pi interaction. Isosurfaces with RDG also illustrate the strength of the titled pi-pi interaction and their region. Additionally, we find that the occurrence of this interaction is attributed to a few C-H...X interactions, as depicted using atom in molecule (AIM) method. This work presents a clear picture of the typical cation-cation pi-pi interaction and can serve to advance the understanding of this uncommon interaction. PMID- 26052033 TI - Roles of miR-196a on gene regulation of neuroendocrine tumor cells. AB - This study aims at investigating miR-196a roles using in vitro models. miR-196a was detected in small intestinal neuroendocrine tumors (SI-NETs) and lung NETs. miR-196a target prediction analysis suggested HOXA9, HOXB7, LRP4 and RSPO2 genes for further investigation. The level of these four genes is detectable in SI-NET tissue specimens at different disease stages and serum samples of untreated and somatostatin analogs treated patients with liver metastases. A miR-196a inhibitor was used to silence its effects in NET cells. We show that the four target genes were significantly upregulated at transcriptional level in silenced NET cells. HOXA9, HOXB7, LRP4 and RSPO2 encoded proteins are also upregulated at translational level in miR-196a silenced NET cells. miR-196a downstream genes BMP4, ETS1, CTNNB1, FZD5, LRP5 and LRP6 were significantly upregulated at transcriptional level in miR-196a silenced CNDT2.5 and NCI-H727 cells. In addition, miR-196a clearly does not play a role in NET cell growth control. PMID- 26052035 TI - Exposure to gun violence and asthma among children in Puerto Rico. AB - BACKGROUND AND OBJECTIVES: Although community violence may influence asthma morbidity by increasing stress, no study has assessed exposure to gun violence and childhood asthma. We examined whether exposure to gun violence is associated with asthma in children, particularly in those reporting fear of leaving their home. METHODS: Case-control study of 466 children aged 9-14 years with (n = 234) and without (n = 232) asthma in San Juan, Puerto Rico. Lifetime exposure to gun violence was defined as hearing a gunshot more than once. We also assessed whether the child was afraid to leave his/her home because of violence. Asthma was defined as physician-diagnosed asthma and wheeze in the prior year. We used logistic regression for the statistical analysis. All multivariate models were adjusted for age, gender, household income, parental asthma, environmental tobacco smoke, prematurity and residential distance from a major road. RESULTS: Cases were more likely to have heard a gunshot more than once than control subjects (n = 156 or 67.2% vs. n = 122 or 52.1%, P < 0.01). In a multivariate analysis, hearing a gunshot more than once was associated with asthma (odds ratio [OR] = 1.8, 95% confidence interval [CI] = 1.1-1.7, P = 0.01). Compared with children who had heard a gunshot not more than once and were not afraid to leave their home because of violence, those who had heard a gunshot more than once and were afraid to leave their home due to violence had 3.2 times greater odds of asthma (95% CI for OR = 2.2-4.4, P < 0.01). CONCLUSIONS: Exposure to gun violence is associated with asthma in Puerto Rican children, particularly in those afraid to leave their home. Stress from such violence may contribute to the high burden of asthma in Puerto Ricans. PMID- 26052036 TI - Prognosis of new-onset asthma diagnosed at adult age. AB - BACKGROUND: Asthma is a common chronic disease, which can affect patients at any age. Recently, cluster analyses have suggested that patients with asthma can be divided into different phenotypes and that the age at the onset of the disease is a critical defining factor. The prognosis of allergic childhood-onset asthma is relatively well known, whereas the prognosis of adult-onset asthma remains unclear. METHODS: We undertook a systematic review to identify studies that evaluated the long-term prognosis of new-onset asthma diagnosed at adult age. Criteria used (set 1) were: 1. adult-onset asthma, 2. physician diagnosed asthma (including objective lung-functions) < 1 year before the first visit, 3. follow up time of at least 5 years, 4. objective lung function measurements used at follow-up and 5. not a comparative trial. Another set of studies (set 2) with less strict criteria were gathered. RESULTS: The main result of this systematic review is that the amount of evidence on the prognosis of new-onset asthma diagnosed at adult age is very limited. Only one study (n = 250) fulfilled the criteria (set 1) and it suggests that the five-year prognosis of new-onset asthma diagnosed at adult age may not be favorable, the proportion of patients being in remission was less than 5%. Furthermore, six additional follow-up studies (n = 964) were identified including mainly patients with adult-onset asthma (set 2). These studies had variable endpoints and the results could not be combined. CONCLUSION: Further follow-up studies that recruit patients with new-onset adult asthma are needed to understand the prognostic factors in adult-onset asthma. PMID- 26052037 TI - COPD prevalence in a north-eastern Italian general population. AB - BACKGROUND: COPD prevalence estimates vary mostly depending on different study methodologies. We evaluated the prevalence and clinical features of COPD, as defined by GOLD and ERS/ATS recommendations in a representative sample of Northern Italy general population. METHODS: A randomized cross-sectional study was performed. The study participants completed a questionnaire covering: key indicators for considering a diagnosis of COPD, self-reported physician diagnoses of respiratory disease, pharmacological treatment for respiratory disease, indirect costs, occupational and environmental exposures. They also underwent spirometry and physician assessment. RESULTS: We evaluated 1236 subjects. Daily respiratory symptoms were experienced by 26.7%. Of this group, only 30.7% had previously performed a spirometry. The overall COPD prevalence was: 11.7% according to GOLD criterion; 9.1% according to LLN criterion; 6.8% according to self-reported physician diagnosis. Of note, 48,8% of subjects with a reported diagnosis of COPD had never undergone a spirometry before the study. CONCLUSIONS: Our study provides an estimation of COPD prevalence in a representative sample of Northern Italy general population relying on both clinical symptoms and spirometry outcomes, and describes the different prevalence rates depending on the adopted diagnostic criterion. Spirometry underuse may account for under diagnosis and misdiagnosis of COPD. It may result in a major impact on quality of life as well as in economic burden. PMID- 26052034 TI - The molecular, cellular and clinical consequences of targeting the estrogen receptor following estrogen deprivation therapy. AB - During the past 20 years our understanding of the control of breast tumor development, growth and survival has changed dramatically. The once long forgotten application of high dose synthetic estrogen therapy as the first chemical therapy to treat any cancer has been resurrected, refined and reinvented as the new biology of estrogen-induced apoptosis. High dose estrogen therapy was cast aside once tamoxifen, from its origins as a failed "morning after pill", was reinvented as the first targeted therapy to treat any cancer. The current understanding of the mechanism of estrogen-induced apoptosis is described as a consequence of acquired resistance to long term antihormone therapy in estrogen receptor (ER) positive breast cancer. The ER signal transduction pathway remains a target for therapy in breast cancer despite "antiestrogen" resistance, but becomes a regulator of resistance. Multiple mechanisms of resistance come into play: Selective ER modulator (SERM) stimulated growth, growth factor/ER crosstalk, estrogen-induced apoptosis and mutations of ER. But it is with the science of estrogen-induced apoptosis that the next innovation in women's health will be developed. Recent evidence suggests that the glucocorticoid properties of medroxyprogesterone acetate blunt estrogen-induced apoptosis in estrogen deprived breast cancer cell populations. As a result breast cancer develops during long term hormone replacement therapy (HRT). A new synthetic progestin with estrogen like properties, such as the 19 nortestosterone derivatives used in oral contraceptives, will continue to protect the uterus from unopposed estrogen stimulation but at the same time, reinforce apoptosis in vulnerable populations of nascent breast cancer cells. PMID- 26052040 TI - Leukocytes apoptosis and adipocytokines in children with beta thalassemia major. AB - beta-Thalassemia is a significant public health problem in Egypt. Infectious complications represent the second most common cause of mortality and the major cause of morbidity in beta-thalassemia major (BTM). The increased susceptibility of these patients to infectious diseases has been attributed to the abnormalities of the immune system, which is evident by systemic inflammation and immune deficiency. In a case control study, 35 patients with BTM were compared with 30 sex- and age-matched children who served as controls. Serum ferritin, high sensitive CRP (hsCRP), leptin and adiponectin levels were determined in all subjects. Apoptosis of neutrophils and lymphocytes was measured by the Annexin V fluoroisothiocyanate binding assay. Serum leptin was significantly lower in patients when compared to controls. In contrast, adiponectin and hsCRP levels were significantly higher in the patients than the controls. Positive correlation was found between adiponectin and hsCRP. BTM patients had significantly higher total leukocytes, neutrophils and lymphocytes compared with controls. BTM children exhibited a significantly increased apoptosis in T-lymphocytes; however, there was no significant difference in the percentage of apoptosis of B lymphocytes and neutrophils between the patients and the controls. There was a significant negative correlation between serum leptin and the percentage of apoptotic T-lymphocytes. Our BTM patients had a high percentage of apoptotic T lymphocyte in comparison with controls. In addition, they had disturbed serum levels of adipocytokines and inflammatory markers. These derangements could have a role in the immunological disturbance observed in thalassemic patients. PMID- 26052039 TI - Increased Serotonin Transporter Expression Reduces Fear and Recruitment of Parvalbumin Interneurons of the Amygdala. AB - Genetic association studies suggest that variations in the 5-hydroxytryptamine (5 HT; serotonin) transporter (5-HTT) gene are associated with susceptibility to psychiatric disorders such as anxiety or posttraumatic stress disorder. Individuals carrying high 5-HTT-expressing gene variants display low amygdala reactivity to fearful stimuli. Mice overexpressing the 5-HTT (5-HTTOE), an animal model of this human variation, show impaired fear, together with reduced fear evoked theta oscillations in the basolateral amygdala (BLA). However, it is unclear how variation in 5-HTT gene expression impacts on the microcircuitry of the BLA to change behavior. We addressed this issue by investigating the activity of parvalbumin (PV)-expressing interneurons (PVINs), the biggest IN population in the basal amygdala (BA). We found that increased 5-HTT expression impairs the recruitment of PVINs (measured by their c-Fos immunoreactivity) during fear. Ex vivo patch-clamp recordings demonstrated that the depolarizing effect of 5-HT on PVINs was mediated by 5-HT2A receptor. In 5-HTTOE mice, 5-HT-evoked depolarization of PVINs and synaptic inhibition of principal cells, which provide the major output of the BA, were impaired. This deficit was because of reduced 5 HT2A function and not because of increased 5-HT uptake. Collectively, these findings provide novel cellular mechanisms that are likely to contribute to differences in emotional behaviors linked with genetic variations of the 5-HTT. PMID- 26052038 TI - A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects. AB - The CB1 receptor represents a promising target for the treatment of several disorders including pain-related disease states. However, therapeutic applications of Delta(9)-tetrahydrocannabinol and other CB1 orthosteric receptor agonists remain limited because of psychoactive side effects. Positive allosteric modulators (PAMs) offer an alternative approach to enhance CB1 receptor function for therapeutic gain with the promise of reduced side effects. Here we describe the development of the novel synthetic CB1 PAM, 6-methyl-3-(2-nitro-1-(thiophen-2 yl)ethyl)-2-phenyl-1H-indole (ZCZ011), which augments the in vitro and in vivo pharmacological actions of the CB1 orthosteric agonists CP55,940 and N arachidonoylethanolamine (AEA). ZCZ011 potentiated binding of [(3)H]CP55,940 to the CB1 receptor as well as enhancing AEA-stimulated [(35)S]GTPgammaS binding in mouse brain membranes and beta-arrestin recruitment and ERK phosphorylation in hCB1 cells. In the whole animal, ZCZ011 is brain penetrant, increased the potency of these orthosteric agonists in mouse behavioral assays indicative of cannabimimetic activity, including antinociception, hypothermia, catalepsy, locomotor activity, and in the drug discrimination paradigm. Administration of ZCZ011 alone was devoid of activity in these assays and did not produce a conditioned place preference or aversion, but elicited CB1 receptor-mediated antinociceptive effects in the chronic constriction nerve injury model of neuropathic pain and carrageenan model of inflammatory pain. These data suggest that ZCZ011 acts as a CB1 PAM and provide the first proof of principle that CB1 PAMs offer a promising strategy to treat neuropathic and inflammatory pain with minimal or no cannabimimetic side effects. PMID- 26052041 TI - Dietary Supplementation in Children with Autism Spectrum Disorders: Common, Insufficient, and Excessive. AB - BACKGROUND: Little is known about the effect on dietary adequacy of supplements given to children with autism spectrum disorder (ASD). OBJECTIVE: This cross sectional study examines dietary supplement use and micronutrient intake in children with ASD. DESIGN: Three-day diet/supplement records and use of a gluten/casein-free diet (GFCF) were documented. Estimates of usual intake of micronutrients from food and supplements were compared with the Dietary Reference Intakes. PARTICIPANTS: Children aged 2 to 11 years (N=288) with ASD from five Autism Treatment Network sites from 2009-2011. MAIN OUTCOME MEASURES: Percentage of children meeting or exceeding upper limits of micronutrient intake with or without supplements and relative to GFCF diet status. STATISTICAL ANALYSIS: Micronutrient intake from food and supplements was compared by Spearman rank correlation. Usual intake was estimated by the National Cancer Institute method adjusted for age, sex, supplement use, and GFCF diet. Adequacy of intake was compared between supplement use status and between food and total intake in supplement users relative to Dietary Reference Intakes limits. RESULTS: Dietary supplements, especially multivitamin/minerals, were used by 56% of children with ASD. The most common micronutrient deficits were not corrected (vitamin D, calcium, potassium, pantothenic acid, and choline) by supplements. Almost one third of children remained deficient for vitamin D and up to 54% for calcium. Children receiving GFCF diets had similar micronutrient intake but were more likely to use supplements (78% vs 56%; P=0.01). Supplementation led to excess vitamin A, folate, and zinc intake across the sample, vitamin C, and copper among children aged 2 to 3 years, and manganese and copper for children aged 4 to 8 years. CONCLUSIONS: Few children with ASD need most of the micronutrients they are commonly given as supplements, which often leads to excess intake. Even when supplements are used, careful attention should be given to adequacy of vitamin D and calcium intake. PMID- 26052042 TI - Association between Cardiometabolic Profile and Dietary Characteristics among Adults with Type 1 Diabetes Mellitus. AB - BACKGROUND: The Mediterranean-style dietary pattern has been associated with several cardiometabolic benefits, yet no study has assessed the potential benefits of this diet in adults with type 1 diabetes mellitus (T1DM). OBJECTIVE: The objective of the present study was to examine the association between cardiometabolic profile and alignment of the diet with 1) Canadian nutrient recommendations for T1DM in terms of fat, protein, carbohydrate, saturated fat, dietary fiber, and sodium and 2) a Mediterranean-style dietary pattern among adults with T1DM. DESIGN/PARTICIPANTS/SETTING: This is a cross-sectional analysis including 118 adults with T1DM recruited between 2011 and 2013 in Montreal, Canada. STATISTICAL ANALYSES: Body mass index (calculated as kg/m(2)), waist circumference, truncal fat percentage (dual-energy x-ray absorptiometry), blood pressure, and lipid profile values were measured. Insulin sensitivity was estimated (estimated glucose disposal rate). A 3-day food record was completed and physical activity was measured with a motion sensor. Differences for the cardiometabolic profile between groups with a diet meeting the Canadian nutrient recommendations for T1DM (percentage of energy from fat, protein, carbohydrate, saturated fat, as well as grams of dietary fiber and milligrams of sodium) or not were examined with general linear models. A Mediterranean diet score was calculated (range=0 to 44) and Pearson correlations between this score and cardiometabolic variables were computed. Significance was set at P<=0.05. RESULTS: Participants' mean +/- standard deviation age was 44.3+/-12.3 years, glycated hemoglobin was 8.0%+/-1.1%, and Mediterranean diet score was 20.2+/-5.0. Having a diet that meets at least three nutritional recommendations was associated with a lower truncal fat percentage (28.0% vs 32.2%; P=0.01) only. In contrast, the Mediterranean diet score was inversely correlated with body mass index (r=-0.30, P=0.002), waist circumference (r=-0.31, P=0.002), truncal fat percentage (r=-0.38, P<0.001), systolic (r=-0.20, P=0.03) and diastolic blood pressure (r=-0.23, P=0.01), and was directly correlated with estimated glucose disposal rate (r=0.22, P=0.03), after adjustments for energy intake, sex, and age. The association with estimated glucose disposal rate was no longer significant (P=0.055) after adjustment for physical activity level. CONCLUSIONS: These results suggest that a higher Mediterranean diet score in the context of T1DM is associated with a favorable cardiometabolic profile. Further research is needed to confirm these findings. PMID- 26052043 TI - Assessment of spermicidal activity of the antimicrobial peptide sarcotoxin Pd: A potent contraceptive agent. AB - OBJECTIVES: In searching for new spermicidal microbicides for use in the prevention of unplanned pregnancy and sexually transmitted infections (STIs) we investigated the spermicidal and cytotoxicity activities of the antimicrobial peptide sarcotoxin Pd. METHODS: Washed sperm from 10 healthy, normal volunteers was treated with different concentrations of sarcotoxin Pd. Sperm motility and morphology were assessed at 0, 0.3, 5, 10 and 15 min. The cytotoxicity of sarcotoxin Pd in normal human cervical HeLa cells was measured. Percentage cell survival was expressed as the number of live cells in the test group. RESULTS: The cytotoxic effect of sarcotoxin Pd was concentration-dependent. Significant cytotoxicity was observed at concentrations above 24 MUg/ml. Sarcotoxin Pd immobilised 100% of spermatozoa at a dose of 90 and 80 MUg/ml after 0.3 and 5 min, respectively, and immobilised 50% of spermatozoa after 15 min at lower doses. Sarcotoxin Pd inhibited sperm motility in a dose-dependent manner. The peptide immobilised sperm within 20 s at its maximal effective concentration of 90 MUg/ml. CONCLUSIONS: Sarcotoxin Pd appears to be a good candidate for a contraceptive agent in the prevention of unplanned pregnancy and STIs. PMID- 26052044 TI - Effect of nasal packs in septoplasty. PMID- 26052045 TI - Combined approach sialendoscopy for management of submandibular gland sialolithiasis. AB - PURPOSE: Sialolithiasis is the primary cause of obstructive sialadenitis, affecting the submandibular gland in 80-90% of cases. Sialendoscopy has dramatically changed the diagnosis and management of salivary gland diseases. However, in cases in which endoluminal removal via sialendoscopy is not successful, a combined approach using a limited intraoral incision under guidance of sialendoscopy can facilitate stone removal. We reviewed our institution's experience with combined approach sialendoscopy and evaluated its role in managing sialolithiasis of the submandibular gland. MATERIALS AND METHODS: Retrospective study of the treatment of sialolithiasis in the submandibular gland via combined approach sialendoscopy from January 2010 through March 2014. Demographics, clinical data, intraoperative findings and post-operative course were reviewed. RESULTS: Most sialoliths (56.5%) were over 10 mm in size and were in the hilus of the gland (56%). The success rate of the combined approach was 87%. No significant complications were documented. Symptoms resolved in 75.7% of patients; however, this did not correlate with placement of an intraductal stent (p=0.7) or steroid irrigation (p=0.1). An overall gland preservation rate of 94.9% was achieved. CONCLUSIONS: Combined approach sialendoscopy offers a minimally invasive technique for treating refractory sialolithiasis not amenable to removal via sialendoscopy alone. The procedure is well-tolerated, performed under local anesthesia with low morbidity and a high success rate. PMID- 26052046 TI - Activity-Induced DNA Breaks Govern the Expression of Neuronal Early-Response Genes. AB - Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience-driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next-generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIbeta (Topo IIbeta), and knockdown of Topo IIbeta attenuates both DSB formation and early-response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons. PMID- 26052048 TI - Limited advances in therapy of glioblastoma trigger re-consideration of research policy. AB - Glioblastoma (GB - WHO grade IV) is the most frequent and lethal primary brain tumour with median overall survival of 7-15 months after diagnosis. As in other cancer research areas, an overwhelming amount of pre-clinical research acquisitions in the GB field have not been translated to patients' benefit, potentially due to inappropriate treatment schedules and/or trial designs in the clinical setting. The recent failure of promising anti-VEGF bevacizumab to improve GB patients' overall survival recapitulates this sense of frustration. The following measures are proposed. PMID- 26052047 TI - Optimization of Codon Translation Rates via tRNA Modifications Maintains Proteome Integrity. AB - Proteins begin to fold as they emerge from translating ribosomes. The kinetics of ribosome transit along a given mRNA can influence nascent chain folding, but the extent to which individual codon translation rates impact proteome integrity remains unknown. Here, we show that slower decoding of discrete codons elicits widespread protein aggregation in vivo. Using ribosome profiling, we find that loss of anticodon wobble uridine (U34) modifications in a subset of tRNAs leads to ribosome pausing at their cognate codons in S. cerevisiae and C. elegans. Cells lacking U34 modifications exhibit gene expression hallmarks of proteotoxic stress, accumulate aggregates of endogenous proteins, and are severely compromised in clearing stress-induced protein aggregates. Overexpression of hypomodified tRNAs alleviates ribosome pausing, concomitantly restoring protein homeostasis. Our findings demonstrate that modified U34 is an evolutionarily conserved accelerator of decoding and reveal an unanticipated role for tRNA modifications in maintaining proteome integrity. PMID- 26052049 TI - Papillary renal cell carcinoma: A review of the current therapeutic landscape. AB - Renal cell carcinoma (RCC) is the most common cancer of the kidney and accounts for 2-3% of all adult malignancies. Clear cell carcinoma represents the most common histologic subtype, while papillary Renal Cell Carcinoma (pRCC) accounts for 10-20% of all renal cell cancers. While the inactivation of VHL gene can be found in the majority of clear cell carcinomas, different molecular mechanisms are involved into pRCC biology. Mutations in the MET oncogene are an essential step into the pathogenesis of hereditary pRCC forms, but they can be found only in a small rate of sporadic cases. Several agents, including anti-VEGF drugs and mTOR inhibitors, are possible options in the treatment of advanced and metastatic pRCC, following the demonstration of efficacy obtained in clinical trials including all RCC histologic subtypes. However, data specifically obtained in the subgroup of patients affected by pRCC are limited and not conclusive. Several ongoing trials are evaluating the efficacy of targeted therapy in papillary form. However, more rationale approaches based on molecular studies would help improving the outcome of these patients. Among others, MET inhibitors and targeted immunotherapy are promising new strategies for hereditary and sporadic disease. This review summarizes current knowledge on pRCC tumorigenesis and discusses recent and ongoing clinical trials with new therapeutic agents. PMID- 26052050 TI - The third line of treatment for metastatic prostate cancer patients: Option or strategy? AB - New agents for metastatic castration-resistant prostate cancer (CRPC) developed in the past 3 years include cabaziataxel (Cbz), abiraterone acetate (AA) and enzalutamide (E). In this review, the results of clinical studies in which one of these drugs is included as the third line of treatment are discussed. Our review suggests that AA and E have limited activity, while Cbz seems to retain its efficacy. Prospective studies that further examine sequential treatments are warranted. PMID- 26052051 TI - Fifth metatarsal fractures - Is routine follow-up necessary? AB - BACKGROUND: Fifth metatarsal fractures are common, and the outcome with conservative treatment is generally very satisfactory. Operative treatment is only used for selected injuries, particularly stress fractures. Traditionally these patients are routinely reviewed at a fracture clinic, mainly due to the perceived risk of non-union with a Jones' fracture. In 2011 we introduced a standardised protocol to promote weight bearing as pain allowed with an elasticated support or a removable boot. Patients were discharged with structured advice and a help-line number to access care if required, but no further face-to face review was arranged. More complex cases were reviewed at a "virtual clinic." Our hypothesis was that the introduction of this standardised protocol would be safe, patient-centred and significantly reduce unnecessary outpatient clinic review. PATIENTS AND METHODS: We audited fracture clinic attendance and outcomes 1 year before and 1 year after the protocol was introduced in 2011. All radiographs taken at the Emergency Department (ED) presentation were reviewed and classified independently for validation. RESULTS: From 2009 to 2010, 279 patients who presented to the ED with fifth metatarsal fractures were referred to a fracture clinic. Of these 279 patients, 267 (96%) attended the fracture clinic, resulting in an overall total of 491 outpatient attendances. Three (1%) were treated operatively for delayed/non-union. From 2011 to 2012, 339 patients presented to the ED with fifth metatarsal fractures - only 67 (20%) were referred to a fracture clinic. 62 (18%) attended clinic appointments with 102 appointments in total. Five (1%) required operative intervention. CONCLUSION: Our study showed no added clinical value for routine outpatient follow-up of fifth metatarsal fractures. Patients can be safely discharged and allowed to bear weight at the time of initial ED presentation if they are provided with appropriate information and ready access to experienced fracture clinic staff. PMID- 26052052 TI - Percutaneous iliosacral screw fixation after osteoporotic posterior ring fractures of the pelvis reduces pain significantly in elderly patients. AB - INTRODUCTION: Osteoporotic posterior ring fractures of the pelvis are common injuries in the elderly, but the treatment of these fractures still remains controversial. Percutaneous iliosacral screw fixation is one surgical option if conservative treatment cannot provide sufficient pain reduction. The aim of this study is to provide short-term results of elderly patients with percutaneous screw fixation. METHODS: 30 patients with posterior ring fractures were treated between 12/2009 and 01/2014 with percutaneous iliosacral screw fixation. Patients' mean age was 78.4 years. Concerning short-term outcome, we focused on initial pain level and postoperative pain reduction together with intra- and postoperative complications. RESULTS: The average hospital stay was 23.7 days, with surgical treatment performed after an average of 9.2 days. 90% of our patients were female. All 30 patients had a lower level of pain at discharge compared with admission or immediately prior to surgery. The difference in pain level at admission compared with the pain level upon discharge showed a mean reduction from 6.8 to 1.8 with a statistically significant change (P<=0.001). 24 of 30 patients had no registered complications, one screw malpositioning with postoperative nerve irritation occurred. DISCUSSION: Conventional percutaneous iliosacral screw fixation is a successful operative treatment for elderly patients with persistent lower back pain after unstable posterior ring fractures of the pelvis. Intra- and postoperative complications are rare, so this treatment can be regarded as a safe procedure. LEVEL OF EVIDENCE: IV (retrospective study). PMID- 26052053 TI - Protective effects of minocycline on experimental spinal cord injury in rats. AB - BACKGROUND: The effects of minocycline on neuronal injury after spinal cord injury (SCI) are limited and controversial. Therefore we aimed to investigate the protective effects of minocycline on tissue and on serum concentrations of malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity, glutathione peroxidase (GSH-Px) activity, tissue total antioxidant and oxidant status (TAS and TOS, respectively), and AST and LDH levels in rats with SCI. METHODS: This study was performed on 7-8 weeks 38 male Wistar albino rats. The animals were randomly divided into five groups: group 1, Sham (n=8); group 2, SCI (spinal cord injury)/control (n=8); group 3, SCI+minocycline3 (n=7); group 4, SCI+minocycline30 (n=8) and group 5 SCI+minocycline90 (n=7). Blood and tissue samples were analysed for MDA, SOD, GSH-Px, TAS, TOS, AST and LDH levels. RESULTS: The MDA levels were significantly higher in SCI group compared to sham group (p<0.001), and MDA levels were also significantly higher in SCI group compared to SCI+M3, SCI+M30, SCI+M90 (p<0.05). SOD levels were significantly higher in SCI+M30 when compared to SCI and SCI+M3 groups (p<0.05). GSH-Px levels decreased significantly in SCI and SCI+M3 groups compared to sham (p<0.05). SCI+M3 group showed significantly decreased levels of TAS and TOS compared to SCI group (p<0.05). TAS and TOS levels significantly increased in SCI+M90 group compared to SCI+M3 and SCI+M30 groups (p<0.05). CONCLUSIONS: The present study demonstrates the dose-dependent antioxidant activity of minocycline against spinal cord injury in rats. Minocycline administration increased antioxidant enzyme levels and improved total antioxidant status. PMID- 26052054 TI - Nail-medullary canal ratio affects mechanical axis deviation during femoral lengthening with an intramedullary distractor. AB - INTRODUCTION: Callus distraction of the femur using an intramedullary distractor has several advantages over the use of external fixators. However, difficulty in controlling the mechanical axis during lengthening may cause deformities and knee osteoarthritis. Purpose of the study is to answer the following questions: (1) is lengthening with an intramedullary device associated with a medial or lateral shift of the mechanical axis? (2) Which factors are associated with varisation/valgisation of the mechanical axis during lengthening? MATERIALS AND METHODS: We analysed pre-treatment and post-treatment radiographs from 20 patients who underwent unilateral femoral-lengthening procedures using intramedullary distractors. Patients with acute correction of pre-existing deformities or combined ipsilateral femoral and tibial lengthening were excluded. Mechanical axis deviations, osteotomy level, and nail-medullary canal ratio were recorded. RESULTS: Compared to the preoperative axis, the mechanical axis shifted medially in 7 patients (varisation group) and laterally in 13 patients (valgisation group). The groups did not significantly differ regarding preoperative leg length discrepancy (LLD), mechanical axis alignment, LLD-cause and implants used. The nail-medullary canal ratio significantly differed between groups (p<0.001), being <85% in the varisation group and >85% in the valgisation group. The distance between the lesser trochanter and the osteotomy site was significantly longer in the valgisation group (58.9+/-16.3mm, middle third of the femur) compared to the varisation group (40.6+/-11.4mm, proximal third of the femur; p=0.02). CONCLUSION: The nail-medullary canal ratio should be considered during preoperative planning. To avoid a varisation effect-for example, in cases with pre-existing varus alignment-it would be advisable to perform an osteotomy at the middle third of the femur with implantation of a nail that fully covers the medullary canal at the osteotomy site. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 26052055 TI - Cervical spondylodiscitis with epidural abscess after knife stab wounds to the neck: A case report. AB - INTRODUCTION: Cervical spondylodiscitis is usually caused by pyogenic infections, associated with retropharyngeal abscesses, or due to the swallowing of foreign bodies. No cases of cervical spondylodiscitis caused by a penetrating neck injury have been published in the literature. We describe a case of cervical spondylodiscitis after multiple knife stab wounds to the lateral soft tissue of the neck. MATERIALS AND METHODS: Case report and review of the literature. RESULTS: A 54-year-old patient was brought to our clinic with destructive spondylodiscitis C3/4 with paravertebral and epidural abscesses. He had been involved in a fight and had suffered multiple stab wounds to his neck with a knife 1 month prior. The initial CT scan had revealed one deeper wound canal behind the sternocleidomastoid muscle on the left side without any injury to the vessels. The wound was cleaned and an antibiotic therapy with cefuroxime was given for 1 week. After an uneventful and complete healing of the wound the patient developed severe neck pain. Inflammatory laboratory parameters were elevated, and a MRI of the neck revealed a distinct spondylodiscitis C3/4 with paravertebral and epidural abscess formations. Surgery was performed and included debridement, abscess drainage, decompression of the spinal canal, fusion of the C3/4 segment using an autologous iliac crest bone graft and a plate osteosynthesis. A course of calculated antibiotic therapy was administered for 8 weeks. Normal laboratory parameters and no radiological signs of an ongoing inflammatory process were observed during follow-up examinations. The C3/4 segment was consolidated. CONCLUSION: Stab wound injuries to the neck not only bear the risk of injuries to the nerves, vessels and organs of the neck but also increase the risk of developing secondary spondylodiscitis. Specifically, cervical spondylodiscitis can result in distinct neurological symptoms, and surgical intervention should be performed in a timely manner. PMID- 26052056 TI - Treatment of chronic (>1 year) fracture nonunion: heal rate in a cohort of 767 patients treated with low-intensity pulsed ultrasound (LIPUS). AB - BACKGROUND: Established fracture nonunions rarely heal without secondary intervention. Revision surgery is the most common intervention, though non surgical options for nonunion would be useful if they could overcome nonunion risk factors. Our hypothesis is that low-intensity pulsed ultrasound (LIPUS) can enhance heal rate (HR) in fractures that remain nonunion after one year, relative to the expected HR in the absence of treatment, which is expected to be negligible. METHODS: We collated outcomes from a prospective patient registry required by the U.S. Food & Drug Administration. Patient data were collected over a 4-year period beginning in 1994 and were individually reviewed and validated by a registered nurse. Patients were only included if they had four data points available: date when fracture occurred; date when LIPUS treatment began; date when LIPUS treatment ended; and a dichotomous outcome of healed vs. failed, assessed by clinical and radiological criteria. Data were used to calculate two derived variables: days to treatment (DTT) with LIPUS, and days on treatment (DOT) with LIPUS. Every validated chronic nonunion patient (DTT>365 days) with complete data is reported. RESULTS: Heal rate for chronic nonunion patients (N=767) treated with LIPUS was 86.2%. Heal rate was 82.7% among 98 patients with chronic nonunion >=5 years duration, and 12 patients healed after chronic nonunion >10 years (HR=63.2%). There was more patient loss to follow-up, non compliance, and withdrawal, comparing chronic nonunion patients to all other patients (p<0.0001). Patient age was the only factor associated with failure to heal among chronic nonunions (p<0.004). Chronic nonunion patients averaged 3.1 surgical procedures prior to LIPUS, but some LIPUS-treated patients were able to heal without revision surgery. Among 91 patients who received LIPUS >=90 days after their last surgery, HR averaged 85.7%, and the time from last surgery to index use of LIPUS averaged 449.6 days. CONCLUSIONS: Low-intensity pulsed ultrasound enhanced HR among fractures that had been nonunion for at least 1 year, and even healed fractures that had been nonunion >10 years. LIPUS resulted in successful healing in the majority of nonunions without further surgical intervention. PMID- 26052057 TI - Intertrochanteric femur fractures in the elderly treated with either proximal femur nailing or hemiarthroplasty: A prospective randomised clinical study. AB - INTRODUCTION: The purpose of this prospective randomised study is to compare in the elderly the functional results of intertrochanteric femur fractures treated either with closed reduction and internal fixation with proximal femoral nailing or cemented hemiarthroplasty. MATERIALS AND METHODS: The study included patients above the age of 75 who were diagnosed with intertrochanteric femur fracture and admitted to the Department of Orthopaedics and Traumatology, Ege University Hospital between October 2006 and December 2012. After informed consent was obtained from the patients, they were randomised via sealed opaque envelops into two groups. Patients in Group 1 were internally fixated utilizing proximal femoral nail, whilst the patients in Group 2 were treated with a cemented hemiarthroplasty. Complications were recorded and functional results were evaluated using the Harris Hip score. The mean time of follow up was 31.72 months (min. 18-max. 47, std. dev. +/-10.68). RESULTS: A total of 54 patients were included in the study. 21 of them (38.9%) received a proximal femoral nail whilst 33 (61.1%) were treated with hemiarthroplasty. Average age of the patients was 82.24 (min. 75-max. 97). Average age in Group 1 was 79.57 (min. 75-max. 91), whilst it was 83.94 in Group 2 (min. 75-max. 97). Harris Hip score analysis revealed that the difference between the patients treated with hemiarthroplasty and proximal femoral nailing was statistically significant in favour of the hemiarthroplasty group within the first 3 months. However, this difference diminished at the 6th month time point, and even reversed as of the 12th month postoperatively. DISCUSSION AND CONCLUSIONS: Although cases with hemiarthroplasty achieved a better level of activity in the beginning, cases with proximal femoral nailing reached a comparable level of activity within a short period of time, faster than those treated with hemiarthroplasty, displaying a better level of activity in the end. PMID- 26052058 TI - Hybrid PET/MRI as a tool to detect brown adipose tissue: Proof of principle. AB - OBJECTIVE: The purpose of this study was to assess the performance of (18)F-FDG hybrid PET/MRI to detect and localise the presence of metabolically active brown adipose tissue (BAT). METHODS: We retrospectively analyzed 197 consecutive (18)F flurodeoxyglucose ((18)F-FDG) positron-emission tomographic (PET) and magnetic resonance imaging (MRI) images performed with a hybrid whole-body PET-MRI tomography in 192 patients. These patients were originally investigated mainly for oncological staging, in the absence of a cooling protocol. The presence of BAT was defined as a soft tissue structure that was larger than 4mm in diameter, had the characteristics of fat tissue on MRI and had a maximal standardised uptake value (SUV) of (18)F-FDG of at least 2.0. No specific MRI sequences for BAT detection were acquired. RESULTS: PET/MRI identified the presence of metabolically active BAT in 5 out of 192 patients (2.6%). BAT positive subjects were all female, significantly younger and with significantly lower body weight than BAT negative subjects. CONCLUSIONS: Whole body hybrid PET/MRI allowed for the identification of BAT, with a low prevalence, comparable to previous retrospective PET/CT studies realised in the absence of a cooling protocol. The main advantages of the PET/MRI hybrid technique, as compared with PET/CT, includes a lower radiation burden, and the possibility to combine a multiparameter fat characterization by dedicated MRI sequences. Hybrid PET/MRI might represent the ideal tool for BAT evaluation. PMID- 26052059 TI - The Society of Thoracic Surgeons Adult Cardiac Surgery Database Version 2.73: More Is Better. AB - BACKGROUND: With the introduction of version 2.73, several new patient risk factors are now captured in The Society of Thoracic Surgeons' (STS) Adult Cardiac Surgery Database. We sought to evaluate the potential association of these risk factors with mortality. METHODS: We reviewed all patients with an STS predicted risk of mortality in our statewide quality collaborative database from July 2011 to September 2013 (N = 19,743). Univariate analyses were used to determine significant associations between mortality and the new risk factors in version 2.73. We then performed multivariable analysis, incorporating the STS predicted risk of mortality into our regression. RESULTS: In the univariate model, patients with illicit drug use, syncope, unresponsive neurologic state, cancer within the last 5 years, current smoking history, other tobacco use, or sleep apnea had no significant difference in mortality (p > 0.05). Patients with liver disease, elevated Model for End-Stage Liver Disease score, mediastinal radiation, prolonged 5-meter walk test, home oxygen use, inhaled medications or bronchodilator therapy, decreased forced expiratory volume, and history of recent pneumonia had significant increases in operative mortality (p < 0.05). In multivariable analysis incorporating the STS predicted risk models, liver disease, elevated Model for End-Stage Liver Disease score, prolonged 5-meter walk test, home oxygen use, bronchodilator therapy, and abnormal pulmonary function tests were independently predictive of mortality. CONCLUSIONS: Several of the new STS data variables were significantly associated with operative mortality after cardiac surgery. The addition of these patient factors improves our understanding of evolving patient demographics and comorbid conditions and their impact on perioperative risk. This will improve both shared decision making and assessments of provider performance. PMID- 26052060 TI - Age- and sex-specific associations between adverse life events and functional bodily symptoms in the general population. AB - OBJECTIVE: To test age- and sex-specific associations between adverse life events and functional bodily symptoms (FBS) in the general population. METHODS: In a population-based cohort, 964 participants (mean age 55 years SD 11, 48% male) completed two measurements waves of the present study. Lifetime exposure to 12 adverse life events was assessed through a modified version of the List of Threatening Experiences. Stress-sensitive personality was assessed with the 12 item neuroticism scale of the Eysenck Personality Questionnaire-Revised. Socio economic status was retrieved from questionnaires. Participants completed the somatization section of the Composite International Diagnostic Interview to survey the presence of 42 FBS in the previous year. RESULTS: Regression analyses, adjusted for age, revealed that lifetime scores of adverse life events were significantly associated with FBS in the previous year, an association that was nearly identical for females (beta=0.18, t=4.07, p<0.01) and males (beta=0.19, t=4.24, p<0.01). This association remained statistically significant when stress sensitive personality and socio-economic status were added to the model. Associations between adverse life events during childhood and FBS were statistically significant in females (beta=0.13, t=2.90, p=0.04) but not in males (beta=0.06, t=1.24, p=0.22), whereas there was a stronger association with adverse life events during adulthood in males (beta=0.20, t=4.37, p<0.01) compared to females (beta=0.15, t=3.38, p=0.01). Life events in the previous year were not associated with FBS in the previous year. CONCLUSION: Adverse life events during lifetime were associated with FBS in the previous year. This association was dependent on age and sex but largely independent of having a stress-sensitive personality or low socio-economic status. Future studies could adopt a life course perspective to study the role of adverse life events in FBS. PMID- 26052061 TI - Identification of detoxification pathways in plants that are regulated in response to treatment with organic compounds isolated from oil sands process affected water. AB - Bitumen mining in the Athabasca oil sands region of northern Alberta results in the accumulation of large volumes of oil sands process-affected water (OSPW). The acid-extractable organic (AEO) fraction of OSPW contains a variety of compounds, including naphthenic acids, aromatics, and sulfur- and nitrogen-containing compounds that are toxic to aquatic and terrestrial organisms. We have studied the effect of AEO treatment on the transcriptome of root and shoot tissues in seedlings of the model plant, Arabidopsis thaliana. Several genes encoding enzymes involved in the xenobiotic detoxification pathway were upregulated, including cytochrome P450s (CYPs), UDP-dependent glycosyltransferases (UGTs), glutathione-S-transferases (GSTs), and membrane transporters. In addition, gene products involved in oxidative stress, beta-oxidation, and glucosinolate degradation were also upregulated, indicating other potential mechanisms of the adaptive response to AEO exposure. These results provide insight into the pathways that plants use to detoxify the organic acid component of OSPW. Moreover, this study advances our understanding of genes that could be exploited to potentially develop phytoremediation and biosensing strategies for AEO contaminants resulting from oil sands mining. PMID- 26052062 TI - Is Xpert MRSA/SA SSTI real-time PCR a reliable tool for fast detection of methicillin-resistant coagulase-negative staphylococci in periprosthetic joint infections? AB - Periprosthetic joint infections (PJIs) are frequently caused by methicillin resistant coagulase-negative staphylococci (CoNS). Cultures remain the gold standard but often require a few days. Thus, a rapid test could be interesting to guide antibiotic strategy earlier. The purpose of this study was to evaluate the performances of RT-PCR Xpert(r) MRSA/SA technique for the detection of methicillin-resistant CoNS (MRCoNS) from deep samples in patients with PJIs. RT PCR was tested on 72 samples. Sensitivity, specificity, positive predictive value, and negative predictive value of RT-PCR method were 0.36, 0.98, 0.90, and 0.74, respectively. Although RT-PCR may allow early microbial diagnosis of PJI due to Staphylococcus aureus (MSSA and MRSA), the low sensitivity and the high cost of this method to detect MRCoNS could limit its use in this field. PMID- 26052063 TI - High bacterial titers in urine are predictive of abnormal postvoid residual urine in patients with urinary tract infection. AB - Urine bacterial titers (BTs) are influenced by bacterial and host factors. The impact of an abnormal postvoid residual (PVR) on BT in urine was investigated. A total of 103 inpatients with a urine growing Enterobacteriacae (>= 10(2) CFU/mL) and a PVR measure were analyzed, mostly female (62%), elderly (mean age: 72 years), with urinary tract infection (25% of asymptomatic bacteriuria) due to Escherichia coli (85%). Fifty-two subjects (56%) had BT >= 10(6) CFU/mL; 48 (53%) had a PVR <= 100 mL, while 26 (25%) had a PVR >250 mL. PVR increased with BT, and a significant (P<0.0001) threshold was reached for 10(6) CFU/mL: 100mL mean PVR for patients with BT <= 10(5) CFU/mL versus 248 mL for patients with BT >10(5) CFU/mL. High PVR and BT were associated with complicated infections, concomitant bacteremia, and delayed apyrexia. Screening for patients with BT >= 10(6) CFU/mL is an easy way to identify patients at high risk for acute retention and voiding disorders. PMID- 26052065 TI - Attolitre-sized lipid bilayer chamber array for rapid detection of single transporters. AB - We present an attolitre-sized arrayed lipid bilayer chamber system (aL-ALBiC) for rapid and massively parallel single-molecule assay of membrane transporter activity. Because of the small reaction volume (200 aL), the aL-ALBiC performed fast detection of single transporter activity, thereby enhancing the sensitivity, throughput, and accuracy of the analysis. Thus, aL-ALBiC broadens the opportunities for single-molecule analysis of various membrane transporters and can be used in pharmaceutical applications such as drug screening. PMID- 26052064 TI - Characterization of chemokine and chemokine receptor expression during Pneumocystis infection in healthy and immunodeficient mice. AB - We examined gene expression levels of multiple chemokines and chemokine receptors during Pneumocystis murina infection in wild-type and immunosuppressed mice, using microarrays and qPCR. In wild-type mice, expression of chemokines that are ligands for Ccr2, Cxcr3, Cxcr6, and Cxcr2 increased at days 32-41 post-infection, with a return to baseline by day 75-150. Concomitant increases were seen in Ccr2, Cxcr3, and Cxcr6, but not in Cxcr2 expression. Induction of these same factors also occurred in CD40-ligand and CD40 knockout mice but only at a much later time point, during uncontrolled Pneumocystis pneumonia (PCP). Expression of CD4 Th1 markers was increased in wild-type mice during clearance of infection. Ccr2 and Cx3cr1 knockout mice cleared Pneumocystis infection with kinetics similar to wild type mice, and all animals developed anti-Pneumocystis antibodies. Upregulation of Ccr2, Cxcr3, and Cxcr6 and their ligands supports an important role for T helper cells and mononuclear phagocytes in the clearance of Pneumocystis infection. However, based on the current and prior studies, no single chemokine receptor appears to be critical to the clearance of Pneumocystis. PMID- 26052066 TI - Mature cystic teratoma of the pancreas: Role of endoscopic ultrasound. AB - Cystic teratomas are a rare type of germ cell neoplasms derived from one or more germ layers. They can be classified as mature and immature teratomas based on the maturity of neuroectodermal elements within the tumor. Mature teratomas are benign, well-differentiated lesions, which may be solid or cystic. Mature cystic teratomas (MCTs) are also called dermoid cysts - a term likely coming from early surgical literature when the resected cysts resembled skin. Immature teratomas are malignant, undifferentiated tumors and generally solid. The most common location for MCTs is sacrococcygeus followed by ovaries and testes. MCTs in the pancreas are extremely rare with only few published case reports. Diagnosis of teratomas is challenging since there are no definitive preoperative diagnostic tests or pathognomonic findings. Even though EUS is commonly used for diagnosis of pancreatic cysts, the imaging features and cyst fluid characteristics of MCTs on EUS FNA have not been described. We describe a challenging case of a 65-year old patient who had a 9 cm * 7 cm MCT in the body of the pancreas and discuss the role of EUS in diagnosis and management of these rare lesions. Complete surgical removal seems to be the current standard of care. PMID- 26052067 TI - Serum N-glycan profiles in patients with intraductal papillary mucinous neoplasms of the pancreas. AB - BACKGROUND/OBJECTIVES: Diagnosing the invasiveness of intraductal papillary mucinous neoplasms (IPMNs) is difficult, especially by blood test. Alterations in serum glycan profiles have been reported for several cancers, but changes in serum glycan profiles have not been investigated in patients with IPMNs. The objectives of this study were to determine the serum N-glycan profile and to investigate its clinical utility in patients with IPMNs. METHODS: We measured serum N-glycan profiles in 79 patients with IPMNs, including 13 invasive IPMNs, by performing comprehensive glycome analysis and assessed the relationship between N-glycan changes and clinical parameters. RESULTS: Seventy glycans were identified and their expression profiles were significantly different depending on the cyst size, the presence of an enhancing solid component, and the histological grade of the IPMN. Nine glycans were highly expressed in patients with invasive IPMNs. The glycan m/z 3195, which is a fucosylated tri-antennary glycan, had the highest diagnostic value for distinguishing invasive IPMNs from non-invasive IPMNs (area under the receiver operating characteristic curve = 0.803). Multivariate analyses revealed high levels of m/z 3195 [odds ratio (OR), 20.5; 95% confidence interval (CI) 2.60-486.4] and the presence of enhancing solid components (OR, 35.8; 95% CI, 5.39-409.6) were significant risk factors for invasive IPMNs. CONCLUSIONS: We performed a comprehensive evaluation of the changes in serum N-glycan profiles in patients with IPMNs for the first time. We determined that increased expression of fucosylated complex-type glycans, especially m/z 3195, is a potential marker for invasive IPMNs. PMID- 26052068 TI - Stance limb ground reaction forces in high functioning stroke and healthy subjects during gait initiation. AB - BACKGROUND: Following stroke, little is known about ground reaction forces during gait initiation. OBJECTIVE: To compare stroke patients' with healthy subjects' anterior, medial, and lateral ground reaction forces generated during gait initiation. METHODS: Patients with left paresis, right paresis, and age-similar healthy subjects were recruited. During gait initiation the average peak anterior, medial, and lateral ground reaction forces acting on each lower limb were calculated when it was the stance limb. FINDINGS: Anterior ground reaction forces acting on the right and left stance limbs of healthy subjects were greater than anterior forces acting on the nonparetic and paretic limbs of stroke patients. Medial ground reaction forces for the nonparetic and paretic limbs of stroke patients and for the right and left stance limbs of healthy subjects were equivalent. While lateral ground reaction forces acting on the nonparetic and paretic limbs were equivalent for left paretic patients, for right paretic patients lateral forces acting on the nonparetic limb were greater compared to the paretic limb and also greater compared to the left limb of healthy subjects. INTERPRETATION: An effect of side-of-lesion was revealed in average peak lateral ground reaction force data. Larger lateral ground reaction forces acting on the left nonparetic stance limb of right paretic patients compared to the right nonparetic stance limb of left paretic patients during gait initiation may be an indication of differing adaptations that depend on the side-of-lesion. PMID- 26052069 TI - Frontal plane kinematics in walking with moderate hip osteoarthritis: Stability and fall risk. AB - BACKGROUND: Hip abductor weakness and unilateral pain in patients with moderate hip osteoarthritis may induce changes in frontal plane kinematics during walking that could affect stability and fall risk. METHODS: In 12 fall-prone patients with moderate hip osteoarthritis, 12 healthy peers, and 12 young controls, we assessed the number of falls in the preceding year, hip abductor strength, fear of falling, Harris Hip Score, and pain. Subjects walked on a treadmill with increasing speeds, and kinematics were measured opto-electronically. Parameters reflecting gait stability and regressions of frontal plane center of mass movements on foot placement were calculated. We analyzed the effects of, and interactions with group, and regression of all variables on number of falls. FINDINGS: Patients walked with quicker and wider steps, stood shorter on their affected leg, and had larger peak speeds of frontal plane movements of the center of mass, especially toward their unaffected side. Patients' static margins of stability were larger, but the unaffected dynamic margin of stability was similar between groups. Frontal plane position and acceleration of the center of mass predicted subsequent step width. The peak speed of frontal plane movements toward unaffected had 55% common variance with number of falls, and adding the Harris Hip Score into bivariate regression led to 83% "explained" variance. INTERPRETATION: Quickening and widening steps probably increase stability. Shorter affected side stance time to avoid pain, and/or weakened affected side hip abductors, may lead to faster frontal plane trunk movements toward the unaffected side, which could contribute to fall risk. PMID- 26052070 TI - Identification of peptidic inhibitors of the alternative complement pathway based on Staphylococcus aureus SCIN proteins. AB - The complement system plays a central role in a number of human inflammatory diseases, and there is a significant need for development of complement-directed therapies. The discovery of an arsenal of anti-complement proteins secreted by the pathogen Staphylococcus aureus brought with it the potential for harnessing the powerful inhibitory properties of these molecules. One such family of inhibitors, the SCINs, interact with a functional "hot-spot" on the surface of C3b. SCINs not only stabilize an inactive form of the alternative pathway (AP) C3 convertase (C3bBb), but also overlap the C3b binding site of complement factors B and H. Here we determined that a conserved Arg residue in SCINs is critical for function of full-length SCIN proteins. Despite this, we also found SCIN-specific differences in the contributions of other residues found at the C3b contact site, which suggested that a more diverse repertoire of residues might be able to recognize this region of C3b. To investigate this possibility, we conducted a phage display screen aimed at identifying SCIN-competitive 12-mer peptides. In total, seven unique sequences were identified and all exhibited direct C3b binding. A subset of these specifically inhibited the AP in assays of complement function. The mechanism of AP inhibition by these peptides was probed through surface plasmon resonance approaches, which revealed that six of the seven peptides disrupted C3bBb formation by interfering with factor B/C3b binding. To our knowledge this study has identified the first small molecules that retain inhibitory properties of larger staphylococcal immune evasion proteins. PMID- 26052071 TI - Functions of dendritic-cell-bound IgE in allergy. AB - Immunoglobulin E (IgE) functions as an Fc-receptor-bound antigen sensor for mast cells and basophils, the classical effector cells of allergy. A cell-bound IgE pool is formed when monomeric IgE binds to FcERI, the high affinity IgE Fc receptor on these cells, and minor amounts of antigen are sufficient to trigger the pro-allergic innate IgE effector axis. Additionally, FcERI is constitutively expressed on human dendritic cells (DCs), and thus the latter cell type also receives signals via cell-bound IgE. Notably, steady-state expression of FcERI on DCs is absent in SPF-housed mice. How DCs integrate IgE/FcERI-derived signals into their sentinel functions as gatekeepers of immunity was therefore only recently studied with transgenic mice that phenocopy human FcERI expression. In this review, we summarize advances in our understanding of the functions of DC bound IgE which demonstrate that IgE-mediated activation of DCs in allergic Th2 type inflammation appears to be immune regulatory rather than pro-inflammatory. PMID- 26052072 TI - Prognosis of invasive breast cancer after adjuvant therapy evaluated with VEGF microvessel density and microvascular imaging. AB - The aim of this study was to investigate the role of ultrasonographic microvascular imaging in the evaluation of prognosis of patients with invasive breast cancer treated by adjuvant therapies. A total of 121 patients with invasive breast cancer underwent ultrasonographic contrast-enhanced imaging, vascular endothelial growth factor (VEGF) staining, and microvessel density (MVD) counts. The parameters of microvascular imaging and the expression of VEGF and MVD in primary breast cancer were calculated. The correlation between these factors and the overall and progression-free survival rate were analyzed using the Kaplan-Meier method. Among 121 cases, the positive VEGF cases were 75 and negative ones were 46. The cut point of 52.3 was calculated by the regressive curve for MVD counts. The data showed the mean intensity (MI) was positively associated with both the MVD counts (r = .51, p < .001) and VEGF expression (r = .35, p < .001). For the prognosis of patients, high VEGF expression and MVD counts were associated with reduced progressive and survival times (PFS, p = .032 and p = .034; OS, p = .041 and p = .038, respectively). The correlation between parameters of microvascular imaging, VEGF expressive status, and the MVD counts were established. The cut point of mean intensity (MI = 40) was used to investigate as an independent predictor for PFS (p = .021) and OS (p = .025), respectively, due to a strong correlation between MVD counts and VEGF expression in patients with invasive breast cancer. The microvascular imaging could be a visual and helpful tool to predict the prognosis of patients with invasive breast cancer treated by adjuvant therapies. PMID- 26052073 TI - Gender differences in psychotropic use across Europe: Results from a large cross sectional, population-based study. AB - BACKGROUND: In many epidemiological studies, women have been observed to consume psychotropic medication more often than men. However, the consistency of this relationship across Europe, with differences in mental health care (MHC) resources and reimbursement policies, is unknown. METHODS: Questions on 12-month psychotropic use (antidepressants, benzodiazepines, antipsychotics, mood stabilizers) were asked to 34,204 respondents from 10 European countries of the EU-World Mental Health surveys. Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria were used to determine 12-month prevalence of mood/anxiety disorders using the Composite International Diagnostic Interview (v3.0). RESULTS: For all participating countries, women were significantly more likely than men to use psychotropic medication within the previous 12 months (overall-OR=2.04, 95% CI: 1.81-2.31). This relationship remained significant after adjusting for common sociodemographic factors (age, income level, employment status, education, marital status) and country-level indicators (MHC provision, private household out-of-pocket expenditure, and Gender Gap Index). In multivariable gender-stratified risk-factor analysis, both women and men were more likely to have taken psychotropic medication with increasing age, decreasing income level, and mental health care use within the past 12 months, with no significant differences between genders. When only including participants with a mental disorder, gender differences overall were still significant with any 12 month mood disorder but not with any 12-month anxiety disorder, remaining so after adjusting for sociodemographic characteristics and country-level indicators. CONCLUSIONS: Women use psychotropic medication consistently more often than men, yet reasons for their use are similar between genders. These differences also appear to be contingent on the specific mental disorder. PMID- 26052074 TI - T Cells Engineered to Express a T-Cell Receptor Specific for Glypican-3 to Recognize and Kill Hepatoma Cells In Vitro and in Mice. AB - BACKGROUND & AIMS: Cancer therapies are being developed based on our ability to direct T cells against tumor antigens. Glypican-3 (GPC3) is expressed by 75% of all hepatocellular carcinomas (HCC), but not in healthy liver tissue or other organs. We aimed to generate T cells with GPC3-specific receptors that recognize HCC and used them to eliminate GPC3-expressing xenograft tumors grown from human HCC cells in mice. METHODS: We used mass spectrometry to obtain a comprehensive peptidome from GPC3-expressing hepatoma cells after immune-affinity purification of human leukocyte antigen (HLA)-A2 and bioinformatics to identify immunodominant peptides. To circumvent GPC3 tolerance resulting from fetal expression, dendritic cells from HLA-A2-negative donors were cotransfected with GPC3 and HLA-A2 RNA to stimulate and expand antigen-specific T cells. RESULTS: Peptide GPC3367 was identified as a predominant peptide on HLA-A2. We used A2-GPC3367 multimers to detect, select for, and clone GPC3-specific T cells. These clones bound the A2 GPC3367 multimer and secreted interferon-gamma when cultured with GPC3367, but not with control peptide-loaded cells. By genomic sequencing of these T-cell clones, we identified a gene encoding a dominant T-cell receptor. The gene was cloned and the sequence was codon optimized and expressed from a retroviral vector. Primary CD8(+) T cells that expressed the transgenic T-cell receptor specifically bound GPC3367 on HLA-A2. These T cells killed GPC3-expressing hepatoma cells in culture and slowed growth of HCC xenograft tumors in mice. CONCLUSIONS: We identified a GPC3367-specific T-cell receptor. Expression of this receptor by T cells allows them to recognize and kill GPC3-positive hepatoma cells. This finding could be used to advance development of adoptive T-cell therapy for HCC. PMID- 26052076 TI - CUDA ClustalW: An efficient parallel algorithm for progressive multiple sequence alignment on Multi-GPUs. AB - For biological applications, sequence alignment is an important strategy to analyze DNA and protein sequences. Multiple sequence alignment is an essential methodology to study biological data, such as homology modeling, phylogenetic reconstruction and etc. However, multiple sequence alignment is a NP-hard problem. In the past decades, progressive approach has been proposed to successfully align multiple sequences by adopting iterative pairwise alignments. Due to rapid growth of the next generation sequencing technologies, a large number of sequences can be produced in a short period of time. When the problem instance is large, progressive alignment will be time consuming. Parallel computing is a suitable solution for such applications, and GPU is one of the important architectures for contemporary parallel computing researches. Therefore, we proposed a GPU version of ClustalW v2.0.11, called CUDA ClustalW v1.0, in this work. From the experiment results, it can be seen that the CUDA ClustalW v1.0 can achieve more than 33* speedups for overall execution time by comparing to ClustalW v2.0.11. PMID- 26052075 TI - Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair. AB - Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk. PMID- 26052077 TI - The 5th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures. AB - This paper describes the 5th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in London on April 9-11 2015. It reviews the progress made in this field since 2007, when the first London-Innsbruck Colloquium was held, and the program of the 2015 meeting. This article is part of a Special Issue entitled "Status Epilepticus". PMID- 26052078 TI - Review of the use of botanicals for epilepsy in complementary medical systems- Traditional Chinese Medicine. AB - In traditional Chinese medicine, botanical remedies have been used for centuries to treat seizures. This review aimed to summarize the botanicals that have been used in traditional Chinese medicine to treat epilepsy. We searched Chinese online databases to determine the botanicals used for epilepsy in traditional Chinese medicine and identified articles using a preset search syntax and inclusion criteria of each botanical in the PubMed database to explore their potential mechanisms. Twenty-three botanicals were identified to treat epilepsy in traditional Chinese medicine. The pharmacological mechanisms of each botanical related to antiepileptic activity, which were mainly examined in animal models, were reviewed. We discuss the use and current trends of botanical treatments in China and highlight the limitations of botanical epilepsy treatments. A substantial number of these types of botanicals would be good candidates for the development of novel AEDs. More rigorous clinical trials of botanicals in traditional Chinese medicine for epilepsy treatment are encouraged in the future. This article is part of a Special Issue entitled "Botanicals for Epilepsy". PMID- 26052080 TI - Pulmonary embolism and gastrointestinal leak following bariatric surgery: when do major complications occur? AB - BACKGROUND: Complications following bariatric surgery are uncommon but potentially life threatening. OBJECTIVES: The aim of this study was to assess the timing of gastrointestinal leaks (GIL) and pulmonary embolism (PE) in patients undergoing bariatric surgery. SETTING: Retrospective analysis of the nationwide American College of Surgeons National Surgical Quality Improvement Program database from 2006 to 2011. METHODS: Data on patient demographic characteristics, baseline co-morbidities, procedural events, and postoperative occurrences were analyzed. Thirty-day morbidity was assessed. Median (interquartile range) and frequencies are reported. RESULTS: We identified 71,694 bariatric surgery patients; median age was 45 years (range 36-54 yr), and median body mass index was 44.8 kg/m(2) (range 40.8-50.3 kg/m(2)). Laparoscopic Roux-en-Y gastric bypass was performed in 39,480 patients, laparoscopic adjustable band in 21,104, laparoscopic sleeve gastrectomy in 3225, open Roux-en-Y gastric bypass in 4243, duodenal switch in 1064, revisional surgery in 1182, and other procedures in 1396 patients. Of these patients, 95.2% had no complications. GIL was found in 441 (.6%), deep vein thrombosis in 184 (.3%), and PE in 134 (.2%). These complications occurred 10 (5-15), 13 (7-20), and 11 (4-19) days after surgery, respectively. GIL and PE developed after discharge in 275 (62.4%) and 96 (71.6%), respectively. Only 35 (26.1%) of the patients who developed PE had deep vein thrombosis. There were no differences in patient characteristics between the groups of early PE versus postdischarge PE. Patients diagnosed with in-hospital GIL were more obese with more severe systemic disease compared with patients with postdischarge diagnosis. CONCLUSIONS: The majority of GILs and PEs after bariatric surgery occur after discharge. This finding goes against the routine use of contrast studies to rule out GIL. The risk of PE remains after discharge from bariatric surgery. PMID- 26052079 TI - Clinical features of and risk factors for major depression with history of postpartum episodes in Han Chinese women: A retrospective study. AB - BACKGROUND: We sought to investigate the clinical features of and risk factors for recurrent major depression (MD) with history of postpartum episodes (PPD) in Han Chinese women and the differences between first-onset postpartum MD (MD that has its first lifetime depressive episode in the postpartum period) and first onset non-postpartum MD (MD with history of PPD and has its first lifetime depressive episode in a period other than postpartum). METHODS: Data were derived from the China, Oxford and Virginia Commonwealth University Experimental Research on Genetic Epidemiology (CONVERGE) study (N=6017 cases) and analyzed in two steps. We first examined the clinical features of and risk factors for MD patients with (N=981) or without (N=4410) a history of PPD. We then compared the differences between first-onset postpartum MD (N=583) and first-onset non postpartum MD (N=398) in those with a history of PPD. Linear, logistic and multinomial logistic models were employed to measure the associations. RESULTS: A history of PPD was associated with more guilt feelings, greater psychiatric comorbidity, higher neuroticism, earlier onset and more chronicity (OR 0.2-2.8). Severe premenstrual symptoms (PMS) and more childbirths increased the risk of PPD, as did a family history of MD, childhood sexual abuse, stressful life events and lack of social support (OR 1.1-1.3). In the MD with history of PPD subsample, first-onset postpartum MD was associated with fewer recurrent major depressive episodes, less psychiatric comorbidity, lower neuroticism, less severe PMS and fewer disagreements with their husbands (OR 0.5-0.8), but more childbirths (OR 1.2). LIMITATIONS: Data were obtained retrospectively through interview and recall bias may have affected the results. CONCLUSIONS: MD with history of PPD in Han Chinese women is typically chronic and severe, with particular risk factors including severe PMS and more childbirths. First-onset postpartum MD and first onset non-postpartum MD can be partly differentiated by their clinical features and risk factors, but are not clearly distinctive. PMID- 26052081 TI - Clinical impact of Mediterranean-enriched-protein diet on liver size, visceral fat, fat mass, and fat-free mass in patients undergoing sleeve gastrectomy. AB - BACKGROUND: Weight loss before laparoscopic sleeve gastrectomy (LSG) is desirable because it can reduce visceral fat and liver size thereby facilitating the surgical procedure. Preoperative very-low-energy diets have been demonstrated to decrease weight, visceral fat, and liver size. However, no studies have been conducted using the Mediterranean-protein-enriched diet (MPED) or on the amount of preoperative weight loss attributed to the loss of fat-free mass (FFM). OBJECTIVES: To evaluate the effect of the MPED on weight, visceral fat, liver size, fat mass (FM), and FFM in obese patients undergoing LSG. SETTING: University Hospital, Italy. MATERIALS AND METHODS: Obese male patients (n = 37) with a mean body mass index (BMI) of 45.2 kg/m(2) scheduled for LSG underwent an 8-week preoperative MPED. Their weight, visceral fat, body composition, liver size, and biochemical and metabolic patterns were measured before and after the diet. Patient compliance was assessed by the presence of ketonuria and weight loss. Qualitative methods (5-point Likert questionnaire) were used to measure diet acceptability and side effects. RESULTS: We observed highly significant decreases in weight, liver size, visceral fat, and FM; however, there was no significant reduction in FFM. All tested patients showed a high frequency of acceptability and compliance in following the diet, and no secondary effects were observed. CONCLUSION: Based on our findings, we were able to support the hypothesis that MPED might be associated with significant reductions in weight loss, FM, and liver size without a significant loss of FFM. PMID- 26052082 TI - Discovering frequency sensitive thalamic nuclei from EEG microstate informed resting state fMRI. AB - Microstates (MS), the fingerprints of the momentarily and time-varying states of the brain derived from electroencephalography (EEG), are associated with the resting state networks (RSNs). However, using MS fluctuations along different EEG frequency bands to model the functional MRI (fMRI) signal has not been investigated so far, or elucidated the role of the thalamus as a fundamental gateway and a putative key structure in cortical functional networks. Therefore, in the current study, we used MS predictors in standard frequency bands to predict blood oxygenation level dependent (BOLD) signal fluctuations. We discovered that multivariate modeling of BOLD-fMRI using six EEG-MS classes in eight frequency bands strongly correlated with thalamic areas and large-scale cortical networks. Thalamic nuclei exhibited distinct patterns of correlations for individual MS that were associated with specific EEG frequency bands. Anterior and ventral thalamic nuclei were sensitive to the beta frequency band, medial nuclei were sensitive to both alpha and beta frequency bands, and posterior nuclei such as the pulvinar were sensitive to delta and theta frequency bands. These results demonstrate that EEG-MS informed fMRI can elucidate thalamic activity not directly observable by EEG, which may be highly relevant to understand the rapid formation of thalamocortical networks. PMID- 26052084 TI - Coxsackievirus B3 2A protease promotes encephalomyocarditis virus replication. AB - To determine whether 2A protease of the enterovirus genus with type I internal ribosome entry site (IRES) effect on the viral replication of type II IRES, coxsackievirus B3(CVB3)-encoded protease 2A and encephalomyocarditis virus (EMCV) IRES (Type II)-dependent or cap-dependent report gene were transiently co expressed in eukaryotic cells. We found that CVB3 2A protease not only inhibited translation of cap-dependent reporter genes through the cleavage of eIF4GI, but also conferred high EMCV IRES-dependent translation ability and promoted EMCV replication. Moreover, deletions of short motif (aa13-18 RVVNRH, aa65-70 KNKHYP, or aa88-93 PRRYQSH) resembling the nuclear localization signals (NLS) or COOH terminal acidic amino acid motif (aa133-147 DIRDLLWLEDDAMEQ) of CVB3 2A protease decreased both its EMCV IRES-dependent translation efficiency and destroy its cleavage on eukaryotic initiation factor 4G (eIF4G) I. Our results may provide better understanding into more effective interventions and treatments for co infection of viral diseases. PMID- 26052085 TI - Prion-like diseases: Looking for their niche in the realm of infectious diseases. PMID- 26052083 TI - Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS. AB - The responsiveness to non-invasive neuromodulation protocols shows high inter individual variability, the reasons of which remain poorly understood. We here tested whether the response to intermittent theta-burst stimulation (iTBS) - an effective repetitive transcranial magnetic stimulation (rTMS) protocol for increasing cortical excitability - depends on network properties of the cortical motor system. We furthermore investigated whether the responsiveness to iTBS is dose-dependent. To this end, we used a sham-stimulation controlled, single blinded within-subject design testing for the relationship between iTBS aftereffects and (i) motor-evoked potentials (MEPs) as well as (ii) resting-state functional connectivity (rsFC) in 16 healthy subjects. In each session, three blocks of iTBS were applied, separated by 15min. We found that non-responders (subjects not showing an MEP increase of >=10% after one iTBS block) featured stronger rsFC between the stimulated primary motor cortex (M1) and premotor areas before stimulation compared to responders. However, only the group of responders showed increases in rsFC and MEPs, while most non-responders remained close to baseline levels after all three blocks of iTBS. Importantly, there was still a large amount of variability in both groups. Our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) depends upon the pre interventional network connectivity of the stimulated region. Of note, increasing iTBS dose did not turn non-responders into responders. The finding that higher levels of pre-interventional connectivity precluded a response to iTBS could reflect a ceiling effect underlying non-responsiveness to iTBS at the systems level. PMID- 26052086 TI - Chorioretinal folds in eyes with myopic staphyloma. AB - PURPOSE: To determine the frequency and clinical characteristics of chorioretinal folds emanating from the edge of a staphyloma in highly myopic patients. DESIGN: Observational case series. METHODS: Eight hundred and eighty-three eyes of 463 patients with an axial length >=26.5 mm in at least 1 eye were studied. The fellow eyes of patients with unilateral high myopia were also included. Wide field fundus images and fundus autofluorescence images were used to detect chorioretinal folds emanating from the staphyloma edge. In 100 patients, the eye shape was analyzed by 3-dimensional magnetic resonance imaging (3D MRI). RESULTS: A posterior staphyloma was found in 459 of the 883 eyes (52.0%). Choroidal folds radiating from the staphyloma edge were found in 6 of the 459 eyes (1.3%) with a posterior staphyloma in wide-field autofluorescent images. The axial length varied greatly from 24.3 mm to 32.5 mm. Regardless of the axial length, all of the 6 eyes had a wide, macular type of staphyloma. Chorioretinal folds emanated from the upper or upper-temporal staphyloma edge. 3D MRI images showed the presence of a notch along the upper or temporal edge of the outpouching, and the eye curvature became flatter toward the steep edge of the outpouching. CONCLUSIONS: Chorioretinal folds can emanate from the staphyloma edge in highly myopic patients even though the edge was away from the macula. Some directional force toward the steeper edge of the staphyloma might be related to the development of chorioretinal folds. PMID- 26052087 TI - Predictive value of screening tests for visually significant eye disease. AB - PURPOSE: To determine the predictive value of ophthalmic screening tests with visually significant eye disease in a cohort of American Indian/Alaskan Natives from the Pacific Northwest. DESIGN: Validity assessment of a possible screening protocol. METHODS: Ophthalmic technicians performed a screening examination including medical and ocular history, best-corrected visual acuity, limbal anterior chamber depth assessment, frequency-doubling technology perimetry (FDT, C-20-5), confocal scanning laser ophthalmoscopy, nonmydriatic digital photography, and tonometry on 429 participants. An ophthalmologist performed a comprehensive eye examination on subjects with 1 or more abnormal screening tests and a random selection of those with normal screening tests. We used univariate and multivariate logistic regression to determine the association between abnormal screening test results and visually significant eye disease. We also determined the predictive value of screening tests with ocular disease. RESULTS: Univariate analysis identified history of eye disease or diabetes mellitus (P < .001), visual acuity <20/40 (P < .001), abnormal/poor-quality confocal scanning laser ophthalmoscopy (P < .001), abnormal FDT (P < .001), and abnormal/poor quality nonmydriatic imaging (P < .001) as associated with visually significant eye disease. A multivariate analysis found visually significant eye disease to be associated (P < .001; receiver operating characteristic curve area = 0.827, negative predictive value = 84%) with 4 screening tests: visual acuity <20/40, abnormal/poor-quality nonmydriatic imaging, abnormal FDT, and abnormal/poor quality confocal scanning laser ophthalmoscopy. CONCLUSIONS: Ophthalmic technicians performing a subset of screening tests may provide an accurate and efficient means of screening for eye disease in an American Indian/Alaskan Native population. Confirmation of these results in other populations, particularly those with a different profile of disease prevalence, is needed. PMID- 26052088 TI - Macular ganglion cell complex and retinal nerve fiber layer comparison in different stages of age-related macular degeneration. AB - PURPOSE: To employ optical coherence tomography (OCT) to analyze the morphologic changes in the inner retina in different categories of age-related macular degeneration (AMD). DESIGN: Observational cross-sectional study. METHODS: Single center study. Inclusion criteria were age over 50, diagnosis of Age-Related Eye Disease Study (AREDS) category 2 and 3, naive neovascular AMD, and atrophic AMD. Healthy patients of similar age acted as a control group. Primary outcome measures were the changes in ganglion cell complex (GCC) and retinal nerve fiber layer (RNFL). Secondary outcomes included modifications of rim area and cup-to disc ratio. RESULTS: One hundred and thirty eyes of 130 patients were recruited: 26 eyes for AREDS category 2, 26 for AREDS category 3, 26 for neovascular AMD, 26 with atrophic AMD, and 26 controls. Mean peripapillary RNFL thickness was significantly lower in neovascular AMD, compared to controls (P = .004); peripapillary RNFL did not significantly vary among AREDS category 2 and 3 and atrophic AMD groups, compared to controls. Mean GCC thickness was higher in the control group, becoming progressively thinner up to neovascular and atrophic AMD groups (P < .0001). Rim area was significantly thinner in the neovascular AMD group compared with controls (P = .047); cup-to-disc ratio was higher in the neovascular AMD group compared with the control group (P = .047). CONCLUSIONS: This study demonstrates that eyes with neovascular AMD display reduced RNFL and GCC thickness. RNFL is partially spared in atrophic advanced AMD. The identification of alteration in RNFL and GCC thickness may reveal useful for future therapeutic implications. PMID- 26052089 TI - Relationship between daytime variability of blood pressure or ocular perfusion pressure and glaucomatous visual field progression. AB - PURPOSE: To study daytime or nighttime variability of mean arterial pressure and ocular perfusion pressure in untreated normal-tension glaucoma (NTG) patients and determine whether increased short-term mean arterial pressure and/or ocular perfusion pressure variability are associated with greater risk of visual field (VF) progression. DESIGN: Longitudinal, retrospective, observational study. METHODS: This study enrolled 237 eyes of 237 untreated NTG patients who underwent 24-hour intraocular pressure and ambulatory blood pressure monitoring in the habitual position, and had >=5 reliable VF tests during follow-up. Kaplan-Meier analyses were performed to compare outcomes with reference to the level of short term mean arterial pressure and ocular perfusion pressure standard deviation for VF deterioration. Hazard ratios for the association between clinical factors, including short-term mean arterial pressure and ocular perfusion pressure standard deviation, and VF progression were obtained using Cox proportional hazards models. RESULTS: Over-dipper NTG patients showed significantly larger daytime and nighttime mean arterial pressure and ocular perfusion pressure standard deviation than non-dippers or dippers. Both increased daytime and nighttime mean arterial pressure or ocular perfusion pressure standard deviation were associated with greater VF progression probabilities. Increased daytime mean arterial pressure or ocular perfusion pressure standard deviation was a significant predictor of subsequent VF progression (P = .023 and P < .001, respectively). CONCLUSIONS: Over-dipper NTG eyes showed significantly higher daytime or nighttime mean arterial pressure and ocular perfusion pressure variabilities than non-dipper and dipper NTG eyes. Increased daytime mean arterial pressure and ocular perfusion pressure standard deviation at baseline were significant predictors of future VF progression in NTG. PMID- 26052090 TI - Determination and characterization of two degradant impurities in bendamustine hydrochloride drug product. AB - Bendamustine hydrochloride is an alkylating antitumor agent with a good efficacy in the treatment of chronic lymphocytic leukemia (CLL) and B-cell non-Hodgkin's lymphoma (B-NHL). Under the stressed conditions, two degradant impurities in bendamustine hydrochloride drug product were detected by high-performance liquid chromatography. These two degradant impurities were isolated from preparative liquid chromatography, and were further characterized using Q-TOF/MS and nuclear magnetic resonance (NMR). Based on the MS and NMR spectral data, they were characterized as 4-[5-(2-chloro-ethylamino)-1-methyl-1H-benzoimidazol-2-yl] butyric acid hydrochloride (impurity-A) and 4-{5-[[2-(4-{5-[bis-(2-chloroethyl) amino]-1-methyl-1H-benzoimidazol-2-yl}-butyryloxy)-ethyl]-(2-chloroethyl)amino]-1 methyl-3a, 7a-dihydro-1H-benzoimidazol-2-yl} butyric acid hydrochloride (impurity B). Isolation, structural elucidation of these two impurities by spectral data (Q TOF/MS, (1)H NMR, (13)C NMR, D2O exchange NMR and two-dimensional NMR) and the probable formation mechanism of the impurities were discussed. PMID- 26052091 TI - betaI-tubulin mutations in the laulimalide/peloruside binding site mediate drug sensitivity by altering drug-tubulin interactions and microtubule stability. AB - Peloruside A (PLA) and laulimalide (LAU) are potent microtubule-stabilizing natural products that are effective against a broad spectrum of cancer cells. The interactions of PLA and LAU with tubulin have attracted a great deal of attention, mainly because they bind to beta-tubulin at a site that is different from the classical taxoid site. Multiple betaI-tubulin amino acid residues have been predicted by computer modelling studies and more recently by protein crystallography to participate in the binding of PLA and LAU to tubulin. The relevance of these residues in determining cellular sensitivity to the compounds, however, remains largely uncertain. To determine the role of four binding site residues, Q291, D295, V333, and N337 on PLA and LAU activity, we introduced single mutations to these sites by site-directed mutagenesis and transfected each mutant tubulin separately into HEK and/or HeLa cells. We found that a Q291M betaI tubulin mutation increased sensitivity of the cells to PLA, but not to LAU, paclitaxel (PTX), or vinblastine (VBL). In contrast, V333W and N337L mutations led to less stable microtubules, with the V333W causing resistance to PLA and PTX, but not LAU, and the N337L causing resistance to PLA, LAU, and PTX. Moreover, cells expressing either W333 or L337 were hypersensitive to the microtubule-destabilizing agent, VBL. The D295I mutation conferred resistance to both PLA and LAU without affecting microtubule stability or sensitivity to PTX or ixabepilone (IXB). This study identifies the first mammalian betaI-tubulin mutation that specifically increases sensitivity to PLA, and reports mutations at PLA and LAU binding site residues that can either reduce microtubule stability or impair drug-tubulin binding, conferring resistance to these microtubule stabilizing agents. This information provides insights on beta-tubulin residues important for maintaining microtubule structural integrity and for sensitivity to microtubule-targeting agents, and suggests novel directions for rational structure-based design of new and more potent agents for cancer treatment that target the LAU/PLA site. PMID- 26052092 TI - Circular RNA: A new star of noncoding RNAs. AB - Circular RNAs (circRNAs) are a novel type of RNA that, unlike linear RNAs, form a covalently closed continuous loop and are highly represented in the eukaryotic transcriptome. Recent studies have discovered thousands of endogenous circRNAs in mammalian cells. CircRNAs are largely generated from exonic or intronic sequences, and reverse complementary sequences or RNA-binding proteins (RBPs) are necessary for circRNA biogenesis. The majority of circRNAs are conserved across species, are stable and resistant to RNase R, and often exhibit tissue/developmental-stage-specific expression. Recent research has revealed that circRNAs can function as microRNA (miRNA) sponges, regulators of splicing and transcription, and modifiers of parental gene expression. Emerging evidence indicates that circRNAs might play important roles in atherosclerotic vascular disease risk, neurological disorders, prion diseases and cancer; exhibit aberrant expression in colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC); and serve as diagnostic or predictive biomarkers of some diseases. Similar to miRNAs and long noncoding RNAs (lncRNAs), circRNAs are becoming a new research hotspot in the field of RNA and could be widely involved in the processes of life. Herein, we review the formation and properties of circRNAs, their functions, and their potential significance in disease. PMID- 26052093 TI - Synergistic antitumor effects of radiation and proteasome inhibitor treatment in pancreatic cancer through the induction of autophagy and the downregulation of TRAF6. AB - Ninety percent of human pancreatic cancer is characterized by activating K-RAS mutations. TRAF6 is an oncogene that plays a vital role in K-RAS-mediated oncogenesis. We investigated the synergistic effect of combining ionizing radiation (IR) and proteasome inhibitor (MG132). Furthermore, following combined treatment with IR and MG132, we analyzed the expression of TRAF6 and the mechanism of human pancreatic cancer cell death in vitro and in an orthotopic pancreatic cancer mouse model. The combined treatment groups displayed synergistic cell killing effects and induced endoplasmic reticulum stress in human pancreatic cancer cells. The combined treatment groups were characterized by enhanced cytotoxicity, which resulted from increased autophagy induction through the inhibition of TRAF6. Significantly reduced cytotoxicity was observed following MG132 and IR treatment of MIA PaCa-2 cells pre-treated with 3-MA (an autophagy inhibitor). Down-regulation of TRAF6 led to a significant increase in apoptosis and autophagy. In an orthotopic xenograft model of SCID mice, combination MG132 and IR therapy resulted in a significant increase in the tumor growth delay time and a decreased tumor tissue expression of TRAF6. IR combined with a proteasome inhibitor or TRAF6 inhibition could represent a new therapeutic strategy for human pancreatic cancer. PMID- 26052094 TI - Construction of multi-gene classifier for prediction of response to and prognosis after neoadjuvant chemotherapy for estrogen receptor positive breast cancers. AB - The aims of this study were to develop a multi-gene expression-based prediction model for pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) and to evaluate its prognosis prediction for estrogen receptor (ER) positive breast cancers. The training set included the NAC-treated patients (n = 104) with ER+ breast tumors in our hospital and the validation set included the NAC-treated patients (n = 259) with ER+/HER2- breast tumors in the public database (GSE25066). Gene expression in the tumor biopsy specimens obtained before NAC was analyzed with DNA microarray, and the prediction model (MPCP155) for pCR was constructed for the training set by using the genes (155 probes) involved in the metabolic pathways which the pathway analysis identified as being significantly associated with pathological response. With MPCP155, the tumors in the validation set could be classified into low chemo-sensitive (low-CS) (pCR rate = 2.6%) and high-CS (pCR rate = 15.3%; P = 0.0006) groups. Furthermore, the low-CS group showed a significantly better prognosis than the high-CS group (P = 2.0E-6). Moreover, prognosis prediction by MPCP155 was independent of the residual cancer burden score. MPCP155 may be helpful for decision making regarding the indication for neoadjuvant chemotherapy. In addition, MPCP155 was found to be useful for prognosis prediction for NAC-treated patients with ER+/HER2- tumors. PMID- 26052095 TI - MT1-MMP silencing by an shRNA-armed glioma-targeted conditionally replicative adenovirus (CRAd) improves its anti-glioma efficacy in vitro and in vivo. AB - MMP14 (MT1-MMP) is a cell membrane-associated proteinase of the extracellular matrix, whose biological roles vary from angiogenesis to cell proliferation and survival. We recently found a direct correlation between MMP14 expression levels in brain tumors of glioma patients and the disease progression. By using gene silencing as an experimental approach we found that MMP14 knockdown decreases production of pro-angiogenic factors such as VEGF and IL8 and thereby suppresses angiogenesis in glioma tumors. Although the clinical relevance of MMP14 down regulation and its possible implications for glioma therapy in humans remain unclear, we observed a significant improvement in animal survival upon down regulation of MMP14 in murine intracranial glioma xenografts infected with MMP14 shRNA-expressing CRAd. We further found that down-regulation of MMP14 in gliomas by combinational treatment with CRAd-S-5/3 and Marimastat, a chemical inhibitor of metalloproteinases, augments suppression of pro-angiogenic factors, caused by the replication-competent adenovirus. We also demonstrated that delivery of MMP14 targeting shRNA by a fiber-modified adenoviral vector to the glioma cells effectively suppresses their proliferation in vitro and in vivo. Thus our data indicate that inhibition of MMP14 expression in tumors in combination with glioma virotherapy could be effectively utilized to suppress angiogenesis and neovascularization of glioma tumors by decreasing production of pro-angiogenic factors. PMID- 26052096 TI - Mucosal immunology: Message in a bottle. PMID- 26052097 TI - Viral infection: Cytokine cooperation. PMID- 26052098 TI - Aicardi-Goutieres syndrome and the type I interferonopathies. AB - Dissection of the genetic basis of Aicardi-Goutieres syndrome has highlighted a fundamental link between nucleic acid metabolism, innate immune sensors and type I interferon induction. This had led to the concept of the human interferonopathies as a broader set of Mendelian disorders in which a constitutive upregulation of type I interferon activity directly relates to disease pathology. Here, we discuss the molecular and cellular basis of the interferonopathies, their categorization, future treatment strategies and the insights they provide into normal physiology. PMID- 26052099 TI - Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications. AB - Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, whilst activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p=0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p=0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning. PMID- 26052100 TI - Reducing catheter-associated urinary tract infections in a neuro-spine intensive care unit. AB - A collaborative effort reduced catheter-associated urinary tract infections in the neuro-spine intensive care unit where the majority of infections occurred at our institution. Our stepwise approach included retrospective data review, daily rounding with clinicians, developing and implementing an action plan, conducting practice audits, and sharing of real-time data outcomes. The catheter-associated urinary tract infection rate was reduced from 8.18 to 0.93 per 1,000 catheter days and standardized infection ratio decreased from 2.16 to 0.37. PMID- 26052101 TI - Response to the Letter to the Editor regarding Comparison of hand hygiene monitoring using the My 5 Moments for Hand Hygiene method versus the Wash In-Wash Out method. PMID- 26052102 TI - Investigating the failure of repeated standard cleaning and disinfection of a Pseudomonas aeruginosa-infected pancreatic and biliary endoscope. AB - Digestive endoscopy is an important technique for the diagnosis and treatment of digestive system disease. To assure medical safety, a digestive endoscope must be cleaned and disinfected before its use in an operation on the next patient. The most common treatment procedure on a digestive endoscope is high-level disinfection. The potential risk associated with digestive endoscopes is always the focus of endoscopic management in clinical practice. In this study, a polluted pancreatic and biliary endoscope after surgery was cleaned and disinfected multiple times with the standard procedure but still tested positive for Pseudomonas aeruginosa culture, which is very rare and has not been reported in China or abroad. PMID- 26052103 TI - Seasonal variation of respiratory pathogen colonization in asymptomatic health care professionals: A single-center, cross-sectional, 2-season observational study. AB - BACKGROUND: The purpose of this study was to determine the seasonal variance of potentially pathogenic bacterial and viral organisms in nasopharyngeal specimens obtained from asymptomatic health care professionals (HCPs) during the 2014 winter and summer months. METHODS: Nasopharyngeal specimens from 100 HCPs were collected from Huntsville Hospital (Huntsville, AL) during the winter and from 100 HCPs during the summer. All subjects were tested for 22 viruses and 19 bacteria using Target Enriched Multiplex Polymerase Chain Reaction. Both seasonal cohorts were composed of students, nurses, physicians, and residents. RESULTS: Of the 100 HCPs tested during the winter, 34 subjects were colonized with at least 1 bacterium, and 11 tested positive for at least 1 virus. Methicillin-resistant Staphylococcus aureus (MRSA), Moraxella catarrhalis, and coronavirus were the most frequently detected potentially infectious agents. Of the 100 HCPs tested during the summer, 37 tested positive for at least 1 bacterium, and 4 tested positive for a viral agent. The most prevalent bacteria were MRSA and Klebsiella pneumonia. CONCLUSION: Nasopharyngeal carriage among asymptomatic HCPs was common, but the frequency and presence of potential pathogens varied with each season. Understanding the colonization and infection potential of upper respiratory organisms is important, particularly for viruses. Although asymptomatic HCPs certainly harbor a number of different potentially infectious agents, future studies are needed to determine whether colonized pathogens are transmitted or initiate infection in at-risk patient populations. PMID- 26052104 TI - Candida guilliermondii fungemia in hospitalized patients epidemiologically linked to a patient care attendant. AB - We investigated an outbreak of Candida guilliermondii fungemia with a fatality rate of 54% that occurred during a 19-month period among patients hospitalized in a tertiary care hospital. The hiring of an external care attendant during hospitalization was epidemiologically linked to case patients (100% vs 3% of the controls, P < .001). Subsequent investigation of the outbreak and disclosure of the findings were associated with an end to the epidemic. PMID- 26052105 TI - Impact of previous abdominal surgery on the outcome of laparoscopic resection for colorectal cancer: a case-control study in 756 patients. AB - BACKGROUND: A history of previous abdominal surgery (PAS) may increase the complexity of laparoscopic colorectal surgery. The aim of this study was to investigate the impact of PAS on the outcomes of laparoscopic colorectal resection for colorectal cancer. METHODS: A total of 378 colorectal cancer patients (group A) with a history of PAS were 1:1 matched to 378 controls (group B) without PAS from our prospective laparoscopic colorectal surgery database. The two groups were matched for age, gender, body mass index, American Society of Anesthesiology score, tumor location, type of surgical procedure, and tumor stage. RESULTS: Patients in the two groups were well balanced with respect to baseline demographic and clinical characteristics. Group A was associated with significantly longer median operating time (220 versus 200 min; P = 0.002). Conversion rate in group A (63/378, 16.67%) was almost twice as high as that in group B (36/378, 9.55%; P = 0.004). Conversions caused by adhesion were more common in patients with a history of PAS (55.56% [35/63] versus 27.78% [10/36], P = 0.008). Postoperative recovery time, length of postoperative hospital stay, perioperative mortality and morbidity rate, lymph nodes harvested, circumferential resection margin positive rate, 3-y disease-free survival, and overall survival rate were not significantly different between the two groups. CONCLUSIONS: Laparoscopic colorectal surgery for colorectal cancer patients with PAS is time consuming, but the incidence of a successfully completed laparoscopic colorectal resection remains high, and the short- and long-term outcomes are not affected by PAS. PMID- 26052106 TI - Ultra-sensitive protein detection via Single Molecule Arrays towards early stage cancer monitoring. AB - The early diagnosis of cancers and continued monitoring of tumor growth would be greatly facilitated by the development of a blood-based, non-invasive, screening technique for early cancer detection. Current technologies for cancer screening and detection typically rely on imaging techniques or blood tests that are not accurate or sensitive enough to definitively diagnose cancer at its earliest stages or predict biologic outcomes. By utilizing Single Molecule Arrays (SiMoA), an ultra-sensitive enzyme-linked immunosorbent assay (ELISA) technique, we were able to measure increasing levels of prostate specific antigen (PSA) within murine serum over time, which we attribute to tumor development. The measured concentrations of PSA were well below the detectable limits of both a leading clinical diagnostic PSA ELISA assay as well as a commercial ultra-sensitive PSA assay. Our work benchmarks the role of SiMoA as a vital tool in monitoring previously non-detectable protein biomarkers in serum for early cancer detection and offers significant potential as a non-invasive platform for the monitoring of early stage cancer. PMID- 26052107 TI - Nano-porous calcium phosphate balls. AB - By dropping a NaH2PO4.H2O precursor solution to a CaCl2 solution at 90 degrees C under continuous stirring in presence of two biopolymers, i.e. gelatin (G) and chitosan (C), supramolecular calcium phosphate (CP) card house structures are formed. Light microscopic investigations in combination with scanning electron microscopy show that the GC-based flower-like structure is constructed from very thin CP platelets. Titration experiments indicate that H-bonding between both biopolymers is responsible for the synergistic effect in presence of both polymers. Gelatin-chitosan-water complexes play an important role with regard to supramolecular ordering. FTIR spectra in combination with powder X-ray diffraction show that after burning off all organic components (heating up >600 degrees C) dicalcium and tricalcium phosphate crystallites are formed. From high resolution transmission electron microscopy (HR-TEM) it is obvious to conclude, that individual crystal platelets are dicalcium phosphates, which build up ball like supramolecular structures. The results reveal that the GC guided crystal growth leads to nano-porous supramolecular structures, potentially attractive candidates for bone repair. PMID- 26052108 TI - Quantification of aldehyde terminated heparin by SEC-MALLS-UV for the surface functionalization of polycaprolactone biomaterials. AB - A straight forward strategy of heparin surface grafting employs a terminal reactive-aldehyde group introduced through nitrous acid depolymerization. An advanced method that allows simultaneously monitoring of both heparin molar mass and monomer/aldehyde ratio by size exclusion chromatography, multi-angle laser light scattering and UV-absorbance (SEC-MALLS-UV) has been developed to improve upon heparin surface grafting. Advancements over older methods allow quantitative characterization by direct (aldehyde absorbance) and indirect (Schiff-based absorbance) evaluation of terminal functional aldehydes. The indirect quantitation of functional aldehydes through labeling with aniline (and the formation of a Schiff-base) allows independent quantitation of both polymer mass and terminal functional groups with the applicable UV mass extinction coefficients determined. The protocol was subsequently used to synthesize an optimized heparin-aldehyde that had minimal polydispersity (PDI<2) and high reaction yields (yield >60% by mass). The 8 kDa weight averaged molar mass heparin-aldehyde was then grafted on polycaprolactone (PCL), a common implant material. This optimized heparin-aldehyde retained its antithrombin activity, assessed in freshly drawn blood or surface immobilized on PCL films. Anticoagulant activity was equal to or better than the 24 kDa unmodified heparin it was fragmented from. PMID- 26052109 TI - Qualitative and quantitative detection of T7 bacteriophages using paper based sandwich ELISA. AB - Viruses cause many infectious diseases and consequently epidemic health threats. Paper based diagnostics and filters can offer attractive options for detecting and deactivating pathogens. However, due to their infectious characteristics, virus detection using paper diagnostics is more challenging compared to the detection of bacteria, enzymes, DNA or antigens. The major objective of this study was to prepare reliable, degradable and low cost paper diagnostics to detect viruses, without using sophisticated optical or microfluidic analytical instruments. T7 bacteriophage was used as a model virus. A paper based sandwich ELISA technique was developed to detect and quantify the T7 phages in solution. The paper based sandwich ELISA detected T7 phage concentrations as low as 100 pfu/mL to as high as 10(9) pfu/mL. The compatibility of paper based sandwich ELISA with the conventional titre count was tested using T7 phage solutions of unknown concentrations. The paper based sandwich ELISA technique is faster and economical compared to the traditional detection techniques. Therefore, with proper calibration and right reagents, and by following the biosafety regulations, the paper based technique can be said to be compatible and economical to the sophisticated laboratory diagnostic techniques applied to detect pathogenic viruses and other microorganisms. PMID- 26052110 TI - New perspectives in Medical Humanities. PMID- 26052111 TI - Critical medical humanities: embracing entanglement, taking risks. AB - What can the medical humanities achieve? This paper does not seek to define what is meant by the medical humanities, nor to adjudicate the exact disciplinary or interdisciplinary knowledges it should offer, but rather to consider what it might be capable of doing. Exploring the many valences of the word 'critical', we argue here for a critical medical humanities characterised by: (i) a widening of the sites and scales of 'the medical' beyond the primal scene of the clinical encounter; (ii) greater attention not simply to the context and experience of health and illness, but to their constitution at multiple levels; (iii) closer engagement with critical theory, queer and disability studies, activist politics and other allied fields; (iv) recognition that the arts, humanities and social sciences are best viewed not as in service or in opposition to the clinical and life sciences, but as productively entangled with a 'biomedical culture'; and, following on from this, (v) robust commitment to new forms of interdisciplinary and cross-sector collaboration. We go on to introduce the five other articles published in this special issue of the journal, reflecting on the ways in which collaboration and critique are articulated in their analyses of immunology, critical neuroscience, toxicity, global clinical labour, and psychological coercion and workfare. As these articles demonstrate, embracing the complex role of critical collaborator--one based on notions of entanglement, rather than servility or antagonism--will, we suggest, develop the imaginative and creative heterodox qualities and practices which have long been recognised as core strengths of the medical humanities. PMID- 26052112 TI - Homo immunologicus: on the limits of critique. AB - Through a discussion of a range of research drawn from the humanities and social sciences, and with a particular emphasis on work that tackles questions about the discourse of the life sciences, this paper considers some of the difficulties with research that aims to offer a critical analysis of immunology and its relationship to culture. It considers in particular arguments made on behalf of a biopolitical reading of the life sciences and, by examining the uncertain shift between discursive analysis and philosophical claim, it seeks to address some of the underlying assumptions made about the relations between different kinds of knowledge practice in the interplay between life science, philosophy and culture. Drawing on the work of Belgian philosopher of science Isabelle Stengers to consider the ways in which critical and philosophical appraisals of immunology adopt a characteristically modern stance in the way that they address the life sciences, it further seeks to characterise some of the limits that such forms of critique display. PMID- 26052113 TI - From critique to practice: a response to Andrew Goffey. PMID- 26052114 TI - Critical neuroscience meets medical humanities. AB - This programmatic theory paper sketches a conceptual framework that might inspire work in critical Medical Humanities. For this purpose, Kaushik Sunder Rajan's account of biocapital is revisited and discussed in relation to the perspective of a critical neuroscience. Critical neuroscience is an encompassing positioning towards the recent public prominence of the brain and brain-related practices, tools and discourses. The proposed analytical scheme has five focal nodes: capital, life, technoscience, (neoliberal) politics and subjectivity. A special emphasis will be placed on contemporary framings of subjectivity, as it is here where deep-reaching entanglements of personhood with scientific practice and discourse, medical and informational technologies, and economic formations are most evident. Notably, the emerging subject position of the 'prospective health consumer' will be discussed as it figures prominently in the terrain between neuroscience and other medico-scientific disciplines. PMID- 26052115 TI - Moving beyond discourse? A response to Jan Slaby. PMID- 26052116 TI - Unpacking intoxication, racialising disability. AB - This article examines concepts whose strictly medical applications have only partly informed their widespread use and suggests that demonstrably shared logics motivate our thinking across domains in the interest of a politically just engagement. It considers exchanges between the culturally complex concepts of 'toxicity' and 'intoxication', assessing the racialised conditions of their animation in several geopolitically--and quite radically--distinct scenarios. First, the article sets the framework through considering the racial implications of impairment and disability language of 'non-toxic' finance capital in the contemporary US financial crisis. Shifting material foci from 'illiquid financial bodies' to opiates while insisting that neither is 'more' metaphorically toxic than the other, the article turns to address the role of opium and temporality in the interanimations of race and disability in two sites of 19th-century British empire: Langdon Down's clinic for idiocy, and China's retort on opium to Queen Victoria. The article concludes with a provocation that suggests yet another crossing of borders, that between researcher and researched: 'intoxicated method' is a hypothetical mode of approach that refuses idealised research positions by 'critically disabling' the idealised cognitive and conceptual lens of analysis. PMID- 26052117 TI - Intoxicated method, thinking in difference: a response to Mel Chen. PMID- 26052118 TI - Narratives of neoliberalism: 'clinical labour' in context. AB - Cross-border reproductive care has been thrust under the international spotlight by a series of recent scandals. These have prompted calls to develop more robust means of assessing the exploitative potential of such practices and the need for overarching and normative forms of national and international regulation. Allied theorisations of the emergence of forms of clinical labour have cast the outsourcing of reproductive services such as gamete donation and gestational surrogacy as artefacts of a wider neoliberalisation of service provision. These accounts share with many other narratives of neoliberalism a number of key assertions that relate to the presumed organisation of labour relations within this paradigm. This article critically engages with four assumptions implicit in these accounts: that clinical labourers constitute a largely homogeneous underclass of workers; that reproductive labour has been contractualised in ways that disembed it from wider social and communal relations; that contractualisation can provide protection for clinical labour lessening the need for formal regulatory oversight; and that the transnationalisation of reproductive service labour is largely unidirectional and characterised by a dynamic of provision in which 'the rest' services 'the West'. Drawing on the first findings of a large-scale ethnographic research project into assisted reproduction in India I provide evidence to refute these assertions. In so doing the article demonstrates that while the outsourcing and contractualisation of reproductive labour may be embedded in a wider neoliberal paradigm these practices cannot be understood nor their impacts be fully assessed in isolation from their social and cultural contexts. PMID- 26052119 TI - Considering pregnancy in commercial surrogacy: a response to Bronwyn Parry. PMID- 26052120 TI - Positive affect as coercive strategy: conditionality, activation and the role of psychology in UK government workfare programmes. AB - Eligibility for social security benefits in many advanced economies is dependent on unemployed and underemployed people carrying out an expanding range of job search, training and work preparation activities, as well as mandatory unpaid labour (workfare). Increasingly, these activities include interventions intended to modify attitudes, beliefs and personality, notably through the imposition of positive affect. Labour on the self in order to achieve characteristics said to increase employability is now widely promoted. This work and the discourse on it are central to the experience of many claimants and contribute to the view that unemployment is evidence of both personal failure and psychological deficit. The use of psychology in the delivery of workfare functions to erase the experience and effects of social and economic inequalities, to construct a psychological ideal that links unemployment to psychological deficit, and so to authorise the extension of state-and state-contracted-surveillance to psychological characteristics. This paper describes the coercive and punitive nature of many psycho-policy interventions and considers the implications of psycho-policy for the disadvantaged and excluded populations who are its primary targets. We draw on personal testimonies of people experiencing workfare, policy analysis and social media records of campaigns opposed to workfare in order to explore the extent of psycho-compulsion in workfare. This is an area that has received little attention in the academic literature but that raises issues of ethics and professional accountability and challenges the field of medical humanities to reflect more critically on its relationship to psychology. PMID- 26052121 TI - Workfare and the medical humanities: a response to Lynne Friedli and Robert Stearn. PMID- 26052135 TI - New nitrogenous compounds from a Red Sea sponge from the Gulf of Aqaba. AB - Chemical investigation of an unknown marine sponge, which was collected in the Gulf of Aqaba (Jordan), afforded a new brominated alkaloid 3-amino-1-(2-amino-4 bromophenyl)propan-1-one (1), as well as 7-bromoquinolin-4(1H)-one (2) which had previously only been reported as a synthetic compound. In addition, caulerpin (6), previously only known to be produced by algae, was likewise isolated. Furthermore, three known alkaloids including (Z)-5-(4-hydroxybenzylidene) hydantoin, (Z)-6-bromo-3'-deimino-2',4'-bis(demethyl)-3'-oxoaplysinopsin, and 6 bromoindole-3-carbaldehyde (3-5), were also obtained. All compounds were unambiguously elucidated based on extensive 1D and 2D NMR spectroscopy, LCMS, as well as by comparison with the literature and tested for their cytotoxic activity toward the mouse lymphoma cell line L5178Y. PMID- 26052136 TI - Computational and experimental analysis of TMS-induced electric field vectors critical to neuronal activation. AB - OBJECTIVE: Transcranial magnetic stimulation (TMS) represents a powerful technique to noninvasively modulate cortical neurophysiology in the brain. However, the relationship between the magnetic fields created by TMS coils and neuronal activation in the cortex is still not well-understood, making predictable cortical activation by TMS difficult to achieve. Our goal in this study was to investigate the relationship between induced electric fields and cortical activation measured by blood flow response. Particularly, we sought to discover the E-field characteristics that lead to cortical activation. APPROACH: Subject-specific finite element models (FEMs) of the head and brain were constructed for each of six subjects using magnetic resonance image scans. Positron emission tomography (PET) measured each subject's cortical response to image-guided robotically-positioned TMS to the primary motor cortex. FEM models that employed the given coil position, orientation, and stimulus intensity in experimental applications of TMS were used to calculate the electric field (E field) vectors within a region of interest for each subject. TMS-induced E-fields were analyzed to better understand what vector components led to regional cerebral blood flow (CBF) responses recorded by PET. MAIN RESULTS: This study found that decomposing the E-field into orthogonal vector components based on the cortical surface geometry (and hence, cortical neuron directions) led to significant differences between the regions of cortex that were active and nonactive. Specifically, active regions had significantly higher E-field components in the normal inward direction (i.e., parallel to pyramidal neurons in the dendrite-to-axon orientation) and in the tangential direction (i.e., parallel to interneurons) at high gradient. In contrast, nonactive regions had higher E field vectors in the outward normal direction suggesting inhibitory responses. SIGNIFICANCE: These results provide critical new understanding of the factors by which TMS induces cortical activation necessary for predictive and repeatable use of this noninvasive stimulation modality. PMID- 26052137 TI - Antibacterial, anti-inflammatory and neuroprotective layer-by-layer coatings for neural implants. AB - OBJECTIVE: Infection, inflammation, and neuronal loss are common issues that seriously affect the functionality and longevity of chronically implanted neural prostheses. Minocycline hydrochloride (MH) is a broad-spectrum antibiotic and effective anti-inflammatory drug that also exhibits potent neuroprotective activities. In this study, we investigated the development of biocompatible thin film coatings capable of sustained release of MH for improving the long term performance of implanted neural electrodes. APPROACH: We developed a novel magnesium binding-mediated drug delivery mechanism for controlled and sustained release of MH from an ultrathin hydrophilic layer-by-layer (LbL) coating and characterized the parameters that control MH loading and release. The anti biofilm, anti-inflammatory and neuroprotective potencies of the LbL coating and released MH were also examined. MAIN RESULTS: Sustained release of physiologically relevant amount of MH for 46 days was achieved from the Mg(2+) based LbL coating at a thickness of 1.25 MUm. In addition, MH release from the LbL coating is pH-sensitive. The coating and released MH demonstrated strong anti biofilm, anti-inflammatory, and neuroprotective potencies. SIGNIFICANCE: This study reports, for the first time, the development of a bioactive coating that can target infection, inflammation, and neuroprotection simultaneously, which may facilitate the translation of neural interfaces to clinical applications. PMID- 26052138 TI - Impact of one-hour postchallenge glucose on the relationship between insulin sensitivity and secretion. AB - The impact of postchallenge glucose on the relationship between insulin sensitivity (SI) and secretion (beta) is unknown. We analyzed data from 2,264 health examinees (male/female 1,524/740, median age 54 yrs) with normal glucose tolerance (NGT, n = 1,623), non-diabetic hyperglycemia (NDH, n = 555), or diabetes (DM, n = 86) using OGTT-derived indices of SI (insulin sensitivity index [ISI]-Matsuda, 1/HOMA-IR, and 1/fasting IRI) and beta (deltaIRI0-30/deltaPG0-30, and Stumvoll 1st [Stumvoll-1] and 2nd [Stumvoll-2] phases). The combination of 1/HOMA-IR and Stumvoll-1 recapitulated the hyperbolic SI-beta relationship with the slope of the fitted line -1.000 in NGT subjects, and therefore it was utilized in the following analysis of the SI-beta correlation. In multiple regression analysis of the relationship between SI and beta, an independent correlation was found for 1 h-plasma glucose (PG; PG60) but not for 2 h-PG. When the NGT subjects were grouped by PG60 quartile (Q), the fitted line was flat in Q1 but progressively steeper from Q2 to Q4, with a slope (95%CI) of -0.663 ( 0.726~-0.605), -0.680 (-0.745~-0.622), -0.847 (-0.922~-0.779), and -1.259 ( 1.370~-1.158) (P for trend < 0.05). The fitted line steepened further in the NDH and DM groups, with a slope of -1.545 and -1.915, respectively (P < 0.01 for the difference). The intercept of the fitted line for SI-beta correlation was also progressively lower across the PG60 Q for NGT, NDH, and DM. In conclusion, using the 1/HOMA-IR-Stumvoll-1 pair for an analysis of the SI-beta relationship, elevated PG60 was associated with steepening and downward shifting of the fitted line for the SI-beta correlation. The finding suggests impaired beta cell function. PMID- 26052139 TI - Clinicopathological features of Riedel's thyroiditis associated with IgG4-related disease in Japan. AB - Riedel's thyroiditis (RT) is a rare chronic fibrosing disorder characterized by a hard, infiltrative lesion in the thyroid gland, which is often associated with multifocal fibrosclerosis. Immunoglobulin G4-related disease (IgG4-RD) is typified by infiltration of IgG4-positive plasma cells into multiple organs, resulting in tissue fibrosis and organ dysfunction. In order to evaluate the clinicopathological features of RT and its relationship with IgG4-RD, we performed a Japanese literature search using the keywords "Riedel" and "Riedel's thyroiditis." We used the electronic databases Medline and Igaku Chuo Zasshi, the latter of which is the largest medical literature database in Japan. The diagnosis of RT was based on the presence of a fibroinflammatory process with extension into surrounding tissues. Only 10 patients in Japan fulfilled RT diagnostic criteria during the 25-year period between 1988 and 2012. Two patients with confirmed IgG4/IgG immunohistochemical findings demonstrated 43 and 13 IgG4 positive plasma cells per high-power field, respectively, and the IgG4 positive/IgG-positive plasma cell ratios of 20% and less than 5%. Of the 10 patients with RT, two received glucocorticoids, one of whom experienced marked shrinkage of the thyroid lesion. One patient had extra-thyroid involvement in the form of retroperitoneal fibrosis. Although the clinicopathological features of RT suggest that IgG4-RD may be the underlying condition in some cases, further investigation is needed to clarify the etiology of RT in relation to IgG4-RD. PMID- 26052140 TI - The Effect of LDL-Apheresis and Rheohaemapheresis Treatment on Vitamin E. AB - Lipid apheresis (extracorporeal lipoprotein elimination) is administered to patients with familial hypercholesterolemia who fail to respond to standard therapy. The nature of the treatment process raises the suspicion that it decreases not only cholesterol but also antioxidants. A group of 12 patients (average age 47+/-17 y, 4 homozygous and 8 heterozygous individuals) with familial hypercholesterolemia treated by LDL-apheresis or rheohaemapheresis for 3 12 y was included in the study. In addition to cholesterol and triacylglycerol levels, vitamin E and vitamin A and also other markers of antioxidant activity were investigated. Nevertheless, the most important determined parameter was the vitamin E/cholesterol ratio in serum and lipoproteins. The results indicate that both extracorporeal elimination methods are effective and suitable ways to treat severe familial hypercholesterolemia, as the LDL fraction of cholesterol decreased by approximately 77% and 66% following LDL-apheresis and rheohaemapheresis, respectively. In addition, the serum vitamin E decreased by 54% and 57% and the decrease of the serum vitamin A was approximately 20%. However, the main marker of antioxidant capacity, vitamin E/cholesterol ratio, in the serum, VLDL and LDL significantly increased. The increase of vitamin E levels in the erythrocyte membranes of 2% following LDL-apheresis and a significant increase of 4% following rheohaemapheresis were confirmed. The presented results indicate that LDL-apheresis and rheohaemapheresis can be considered to be safe procedures according to the antioxidant capacity of the serum, VLDL and LDL lipoprotein fractions and the erythrocyte membrane. PMID- 26052141 TI - Effect of Dietary Vitamin E Supplementation on Liver Oxidative Damage in Rats with Water-Immersion Restraint Stress. AB - We examined how dietary supplementation of vitamin E protects against liver oxidative damage in rats with water-immersion restraint stress (WIRS). Before WIRS exposure, rats received a normal diet (ND) or vitamin E-supplemented diet (VESD) (500 IU alpha-tocopherol/kg diet) at a mean dose of 15 g/animal/d for 4 wk. The two diet groups had serum transaminases and lactate dehydrogenase activities and adrenocorticotropic hormone, corticosterone, and glucose levels to a similar extent. VESD-fed rats had higher liver alpha-tocopherol concentrations and lower liver ascorbic acid, total coenzyme Q9 (CoQ9), reduced CoQ9, reduced CoQ10, and lipid peroxide (LPO) concentrations than ND-fed rats. When the two diet groups were exposed to 6 h of WIRS, the serum liver cell damage index enzyme activities increased more greatly in ND-fed rats than in VESD-fed rats but the serum stress marker levels increased to a similar extent. The WIRS exposure caused no change in liver LPO concentration with the further increase in liver alpha-tocopherol concentration in VESD-fed rats but increased liver LPO concentration without changing liver alpha-tocopherol concentration in ND-fed rats. Upon the WIRS exposure, liver reduced glutathione concentration decreased with the further decrease in liver ascorbic acid concentration in VESD-fed rats and those concentrations decreased in ND-fed rats. The WIRS exposure recovered the decreased liver total CoQ9 and reduced CoQ9 concentrations in VESD-fed rats but decreased liver total CoQ9, reduced CoQ9, and reduced CoQ10 concentrations in ND-fed rats. These results indicate that dietary vitamin E supplementation protects against liver oxidative damage without affecting the stress response in rats with WIRS. PMID- 26052142 TI - A Simple Evaluation Method for the Quality of Dietary Protein in Rats Using an Indicator Amino Acid Oxidation Technique. AB - We demonstrated that the indicator amino acid oxidation (IAAO) method could be employed for the evaluation of quality of dietary protein by comparing the protein intakes required to meet metabolic demand in rats fed different proteins. The objective of this study was to validate a simple evaluation method for determining the quality of dietary protein using the IAAO technique. Male Sprague Dawley rats (5-6 wk old) were fed meals composed of graded protein, using either casein, wheat gluten (WG), soy protein isolate (SPI), or egg white protein (EW), every 3 h from 09:00 to 18:00. Administration of L-[1-(13)C]phenylalanine was performed hourly from 15:00 to 18:00. The (13)CO2 level in breath CO2 was measured at 18:30. The protein intake values required to meet the metabolic demand based on the breath (13)CO2 data for the dietary casein, WG, SPI, and EW intake were 18.0, 22.2, 17.5, and 10.1 g/kg BW/d, respectively. The breath (13)CO2 concentrations corresponding to the protein intake of 7.5 g/kg BW/d for casein, WG, SPI, and EW were 9.8, 10.9, 10.3, and 8.9 (0/00)/100 g BW, respectively. A significant correlation was demonstrated between the protein intake required to meet the metabolic demands and the (13)CO2 concentration in the breath for a protein intake of 7.5 g/kg BW/d (r=0.967; p<0.05). These results demonstrated that the protein intake required to meet metabolic demand could be estimated and that the quality of the dietary protein could be evaluated using the (13)CO2 concentration in the breath with a protein intake of 7.5 g/kg BW/d. PMID- 26052143 TI - Preventive Effect of Lactobacillus fermentum Zhao on Activated Carbon-Induced Constipation in Mice. AB - The aim of this study was to investigate the effects of Lactobacillus fermentum Zhao (LF-Zhao) on activated carbon-induced constipation in ICR mice. ICR mice were administered lactic acid bacteria by gavage for 9 d. Body weight, diet intake, drinking amount, stool status, gastrointestinal transit distance and stool time, in addition to motilin (MTL), gastrin (Gas), endothelin (ET), somatostatin (SS), acetylcholinesterase (AChE), substance P (SP) and vasoactive intestinal peptide (VIP) levels in serum were monitored to evaluate the preventive effects of LF-Zhao on constipation. Bisacodyl, a laxative drug, was used as a positive control. Times to the first black stool for normal (untreated), control (no lactic acid bacteria treatment but activated carbon treated), bisacodyl-treated and L. delbrueckii subsp. bulgaricus (LB), LF-Zhao (L) (low concentration of 1*10(8) CFU/mL)- and LF-Zhao (H) (high concentration of 1*10(9) CFU/mL)-treated mice induced by activated carbon were 90, 218, 117, 180, 169 and 156 min, respectively. Following the consumption of LB, LF-Zhao (L) and LF-Zhao (H) or the oral administration of bisacodyl, the gastrointestinal transit distances were reduced by 55.2%, 61.3%, 70.6% and 94.6%, respectively. The serum levels of MTL, Gas, ET, AChE, SP and VIP were significantly increased and the serum levels of SS were reduced in the mice treated with LF-Zhao compared with those in the control mice (p<0.05). These results demonstrated that lactic acid bacteria demonstrate preventive effects on mouse constipation and that LF-Zhao alleviated constipation symptoms better than LB. PMID- 26052144 TI - Influence of Dietary Sodium and Potassium Intake on the Heart Rate Corrected-QT Interval in Elderly Subjects. AB - It is well known that imbalances in the dietary electrolytes are associated with a significantly higher incidence of cardiovascular disease (CVD). On the other hand, a prolonged heart rate corrected-QT (QTc) interval is associated with an increased risk of cardiac autonomic nervous system dysfunction, the incidence of CVD and sudden cardiac death. This study was designed to clarify the association between the nutritional status and the QTc interval in elderly subjects. The subjects included 119 elderly subjects (46 males and 73 females, age; 72.9+/-4.8 y) without a history of CVD, who were taking cardioactive drugs. Resting 12-lead electrocardiography was performed, while the QTc interval was calculated according to Bazett's formula. The nutritional status was assessed using a brief self-administered diet history questionnaire. The subjects were divided into three categories, which were defined as equally trisected distributions of the body mass index (BMI). The QTc interval was significantly longer in both the low and high BMI groups than in the moderate BMI group in both genders (p<0.05, respectively). A stepwise multiple regression analysis showed the QTc interval to be independently associated with the potassium intake in the low BMI group and the sodium intake in the high BMI group in both genders (p<0.05, respectively). These results suggest that the body mass, especially lean body mass and overweight, were associated with a prolonged QTc interval and dietary electrolytes in elderly subjects. Based on our results, we consider that it is necessary to perform dietary counseling, especially focusing on sodium and potassium intake, depending on the body mass. PMID- 26052145 TI - Vitamin A Deficiency Impairs Induction of Oral Tolerance in Mice. AB - Oral tolerance is a phenomenon of induction of systemic unresponsiveness to antigens ingested by the oral route and loss of immune response. Studies have shown the importance of vitamin A in oral tolerance in vitro but not in an in vivo experimental model. Therefore, we carried out experiments to determine how vitamin A deficiency affects tolerance induction and the ability of mesenteric lymph node (MLN) CD11c(+) cells to induce regulatory T cells (Tregs). Immunological tolerance was induced by oral ovalbumin (OVA) administration in vitamin A-sufficient mice. OVA-specific antibody and cytokine production were significantly reduced. On the other hand, in vitamin A-deficient mice, both OVA specific antibody and cytokine production were not suppressed by oral OVA administration. Regarding induction of Tregs, the conversion rate of Foxp3(+) cells from naive CD4(+) cell by CD11c(+) cells was decreased in vitamin A deficient mice. Our study indicates that vitamin A deficiency causes the breakdown of oral tolerance in vivo. PMID- 26052146 TI - Selective Regulation of FGF19 and FGF21 Expression by Cellular and Nutritional Stress. AB - Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor alpha (PPARalpha) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress. ATF4 is also activated by oxidative stress and amino acid deprivation. In this study, we investigated FGF19 and FGF21 expression in response to oxidative stress and amino acid deprivation. We found that FGF19 mRNA is induced by oxidative stress inducers in Caco-2 cells, which are derived from the human intestinal epithelium, and rat intestinal epithelial IEC6 cells. In contrast, ileal FGF15 expression, the rodent ortholog of human FGF19, is not increased by oxidative stress. No notable changes in expression of FGF15/19 took place under amino acid deprivation either in vitro or in vivo. In contrast, FGF21 expression is induced by oxidative stress and amino acid deprivation both in vitro and in vivo. These results indicate distinctive patterns of regulation of FGF19 expression by ER stress, and FGF21 expression by ER stress, oxidative stress, and amino acid deprivation through ATF4 activation. PMID- 26052147 TI - Effects of Acute Beta-Alanine Supplementation on Anaerobic Performance in Trained Female Cyclists. AB - Longitudinal beta-alanine (BA) supplementation can improve exercise performance in males through increases in carnosine; however, females experience greater relative increases in carnosine compared to males. This potentially allows females to benefit from acute BA doses; however, effects of an acute BA dose on performance in females remain unknown. The purpose of this investigation was to evaluate how an acute dose of 1.6 g BA affects anaerobic performance in female cyclists. Twelve females (age=26.6+/-1.3 y) volunteered to participate in this randomized, double-blind study. All participants completed two supplement trials: 1) Placebo=34 g dextrose and 2) BA=1.6 g BA + 34 g dextrose. Thirty-minutes after supplementation, participants performed three repeated Wingate cycling tests with 2 min of active rest after each. Fatigue index, mean power, and peak power were measured during each Wingate. Lactate, heart rate, and rating of perceived exertion (RPE) were measured at rest, immediately after each Wingate, and after each active rest period. RPE significantly decreased (p<0.001) immediately following Wingates 1 and 2 and after each 2-min rest period for the BA trials; however, no differences were observed immediately after Wingate 3 (p>0.05). No significant supplementation effect was observed for any performance or physiological variable (p>0.05 for all variables). Findings suggest that an acute dose of BA (1.6 g) decreases RPE during anaerobic power activities in trained female cyclists. PMID- 26052148 TI - Stachys sieboldii (Labiatae, Chorogi) Protects against Learning and Memory Dysfunction Associated with Ischemic Brain Injury. AB - Stachys sieboldii (Labiatae; Chinese artichoke, a tuber), "chorogi" in Japanese, has been extensively used in folk medicine, and has a number of pharmacological properties, including antioxidative activity. However, few studies have examined the neuroprotective effects of S. sieboldii tuber extract (chorogi extract), and it remains unknown whether the extract can alleviate learning and memory dysfunction associated with vascular dementia or Alzheimer's disease. Therefore, in this study, we investigated the neuroprotective effects of chorogi extract, and examined its protection against learning and memory dysfunction using Ginkgo biloba leaf extract (ginkgo extract) as a positive control. Mice were subjected to bilateral carotid artery occlusion (BCAO) for 30 min. Oral administration of chorogi extract or ginkgo extract significantly reduced post-ischemic glucose intolerance on day 1 and neuronal damage including memory impairment on day 3 after BCAO, compared with the vehicle-treated group. Neither herbal medicine affected locomotor activity. Furthermore, neither significantly alleviated scopolamine-induced learning and memory impairment. In primary neurons, neuronal survival rate was significantly reduced by hydrogen peroxide treatment. This hydrogen peroxide-induced neurotoxicity was significantly suppressed by chorogi extract and ginkgo extract. Taken together, our findings suggest that chorogi extract as well as ginkgo extract can protect against learning and memory dysfunction associated with ischemic brain injury through an antioxidative mechanism. PMID- 26052149 TI - Acute and Subacute Toxicity Studies on Rutin-Rich Tartary Buckwheat Dough in Experimental Animals. AB - In order to investigate the toxicity of rutin-rich dough from the Tartary buckwheat variety 'Manten-Kirari,' acute and subacute toxicity studies (10,000 and 5,000 mg/kg flour, respectively) were performed using rats. In the acute toxicity study, no toxic symptoms were observed and no rats died during the test. Body weight in the 'Manten-Kirari'-treated group was not significantly different when compared with that of the control group. On pathologico-anatomic observation, no unusual symptoms were observed in the 'Manten-Kirari'-treated group when compared with the control group. In the subacute toxicity study, no toxic symptoms were observed and no rats died during the test. Body weight and food intake in the 'Manten-Kirari'-treated and common buckwheat groups were not significantly different when compared with the control group. However, some investigated properties, such as urine protein and serum albumin, were significantly different in the 'Manten-Kirari' and common buckwheat groups when compared with the control group. However, these changes were not caused by toxicity, but by transient changes. On pathologico-anatomic observation, some abnormalities were observed in the liver, kidneys, heart, lung, bronchi and pituitary gland in some rats. However, the incidental rates in the 'Manten Kirari' and common buckwheat groups did not differ when compared to controls. Therefore, these abnormalities may be caused by natural generation. Based on these results, we concluded that dough at a dose of 5,000 mg flour/kg is at a non effect level. PMID- 26052150 TI - The Improvement of Sleep by Oral Intake of GABA and Apocynum venetum Leaf Extract. AB - The effects of two food materials, gamma-aminobutyric acid (GABA) produced by natural fermentation and Apocynum venetum leaf extract (AVLE), on the improvement of sleep were investigated in humans. The electroencephalogram (EEG) test revealed that oral administration of GABA (100 mg) and AVLE (50 mg) had beneficial effects on sleep. GABA shortened sleep latency by 5.3 min and AVLE increased non-rapid eye movement (REM) sleep time by 7.6%. Simultaneous intake of GABA and AVLE shortened sleep latency by 4.3 min and increased non-REM sleep time by 5.1%. The result of questionnaires showed that GABA and AVLE enabled subjects to realize the effects on sleep. These results mean that GABA can help people to fall asleep quickly, AVLE induces deep sleep, and they function complementarily with simultaneous intake. Since both GABA and AVLE are materials of foods and have been ingested for a long time, they can be regarded as safe and appropriate for daily intake in order to improve the quality of sleep. PMID- 26052151 TI - Flavones Inhibit LPS-Induced Atrogin-1/MAFbx Expression in Mouse C2C12 Skeletal Myotubes. AB - Muscle atrophy is a complex process that occurs as a consequence of various stress events. Muscle atrophy-associated genes (atrogenes) such as atrogin 1/MAFbx and MuRF-1 are induced early in the atrophy process, and the increase in their expression precedes the loss of muscle weight. Although antioxidative nutrients suppress atrogene expression in skeletal muscle cells, the inhibitory effects of flavonoids on inflammation-induced atrogin-1/MAFbx expression have not been clarified. Here, we investigated the inhibitory effects of flavonoids on lipopolysaccharide (LPS)-induced atrogin-1/MAFbx expression. We examined whether nine flavonoids belonging to six flavonoid categories inhibited atrogin-1/MAFbx expression in mouse C2C12 myotubes. Two major flavones, apigenin and luteolin, displayed potent inhibitory effects on atrogin-1/MAFbx expression. The pretreatment with apigenin and luteolin significantly prevented the decrease in C2C12 myotube diameter caused by LPS stimulation. Importantly, the pretreatment of LPS-stimulated myoblasts with these flavones significantly inhibited LPS induced JNK phosphorylation in C2C12 myotubes, resulting in the significant suppression of atrogin-1/MAFbx promoter activity. These results suggest that apigenin and luteolin, prevent LPS-mediated atrogin-1/MAFbx expression through the inhibition of the JNK signaling pathway in C2C12 myotubes. Thus, these flavones, apigenin and luteolin, may be promising agents to prevent LPS-induced muscle atrophy. PMID- 26052152 TI - Effects of Dietary Calcium Supplementation on Bone Metabolism, Kidney Mineral Concentrations, and Kidney Function in Rats Fed a High-Phosphorus Diet. AB - We investigated the effects of dietary calcium (Ca) supplementation on bone metabolism, kidney mineral concentrations, and kidney function in rats fed a high phosphorus (P) diet. Wistar strain rats were randomly divided into 4 dietary groups and fed their respective diets for 21 d: a diet containing 0.3% P and 0.5% Ca (C), a diet containing 1.5% P and 0.5% Ca (HP), a diet containing 0.3% P and 1.0% Ca (HCa), or a diet containing 1.5% P and 1.0% Ca (HPCa). Compared to the C group, the high-P diet increased serum parathyroid hormone concentration, markers of bone turnover, receptor activator of NF-kappaB ligand mRNA expression of the femur, kidney Ca and P concentrations, urinary N-acetyl-beta-D-glucosaminidase activity, and urinary beta2-microglobulin excretion, and decreased bone mineral content and bone mineral density of the femur and tibia. Dietary Ca supplementation improved the parameters of bone metabolism and kidney function in rats fed the high-P diet, while there were no significant differences in kidney Ca or P concentrations between the HP and HPCa groups. These results suggest that dietary Ca supplementation prevented the bone loss and decline in kidney function induced by a high-P diet, whereas dietary Ca supplementation did not affect kidney mineral concentrations in rats fed the high-P diet. PMID- 26052153 TI - Anti-Androgenic Activity of Icarisid II from Epimedium Herb in Prostate Cancer LNCaP Cells. AB - Anti-androgens are regarded as potential therapeutic agents for the treatment of prostate cancer. We determined that an epimedium herb (EH) extract exhibited anti androgenic activity in a luciferase assay using androgen receptor-positive prostate cancer LNCaP cells. Nine EH-derived flavonoids were examined. The results identified icarisid II as a very potent anti-androgenic EH-derived flavonoid. A quantitative RT-PCR analysis confirmed that the flavonol suppressed the expression of the androgen-responsive KLK3 gene. PMID- 26052154 TI - Junction-mediating and regulatory protein (JMY) is essential for early porcine embryonic development. AB - Junction-mediating and regulatory protein (JMY) is a regulator of both transcription and actin filament assembly. JMY is a critical nucleation-promoting factor (NPF); however, its role in the development of mammalian embryos is poorly understood. In the current study, we investigated the functional roles of the NPF JMY in porcine embryos. Porcine embryos expressed JMY mRNA and protein, and JMY protein moved from the cytoplasm to the nucleus at later embryonic developmental stages. Knockdown of JMY by RNA interference markedly decreased the rate of blastocyst development, validating its role in the development of porcine embryos. Furthermore, injection of JMY dsRNA also impaired actin and Arp2 expression, and co-injection of actin and Arp2 mRNA partially rescued blastocyst development. Taken together, our results show that the NPF JMY is involved in the development of porcine embryos by regulating the NPF-Arp2-actin pathway. PMID- 26052155 TI - Development of a programmable piggyback syringe pump and four-times-a-day injection regimen for superovulation in non-lactating Holstein cows. AB - The objectives of the present study were to develop a programmable piggyback syringe pump for bovine superovulation and to evaluate the effects of a four times-a-day injection regimen using the pump. Non-lactating Holstein cows were treated with a total of 30 armour units of porcine FSH by injection four times a day with the pump (study, n = 9) or injection twice a day manually (control, n = 9) for four consecutive days from D10 of the estrous cycle. The pump-driven program successfully induced superovulation in all cows tested. The numbers of small (3- < 5 mm in diameter) and large (>= 10 mm in diameter) follicles were greater in the study group on D11-13 and D14, respectively. There were fewer unovulated follicles detected on D21 (7 days after estrus) in the study group than in the control group (1.2 +/- 0.4 and 3.2 +/- 0.6, respectively). PMID- 26052156 TI - Health outcomes for children born to teen mothers in Cape Town, South Africa. AB - This paper analyzes whether children born to teen mothers in Cape Town, South Africa are disadvantaged in terms of their health outcomes because their mother is a teen. Exploiting the longitudinal nature of the Cape Area Panel Study, we assess whether observable differences between teen mothers and slightly older mothers can explain why first-born children of teen mothers appear disadvantaged. Our balanced regressions indicate that observed characteristics cannot explain the full extent of disadvantage of being born to a teen mother, with children born to teen mothers continuing to have significantly worse child health outcomes, especially among coloured children. In particular, children born to teens are more likely to be underweight at birth and to be stunted with the disadvantage for coloured children four times the size for African children. PMID- 26052157 TI - Drive-field Frequency Dependent MPI Performance of Single-Core Magnetite Nanoparticle Tracers. AB - The drive-field frequency of Magnetic Particle Imaging (MPI) systems plays an important role for system design, safety requirements and tracer selection. Because the commonly utilized MPI drive-field frequency of 25 kHz might be increased in future system generations to avoid peripheral nerve stimulation, a performance evaluation of tracers at higher frequencies is desirable. We have studied single-core magnetite nanoparticles that were optimized for MPI applications, utilizing Magnetic Particle Spectrometers (MPS) with drive-field frequencies in the range from 1 kHz up to 100 kHz. The particles have core diameters of 25 nm and a hydrodynamic size of 77 nm. Measurements in the frequency range above 5 kHz were carried out with a newly designed MPS system. In addition, to exclude possible particle interaction, samples of different concentrations were characterized and compared. PMID- 26052158 TI - Structural and Biophysical Characterization of a Cyclic Bioadhesive With Cell Attachment Ability. AB - Structural and cellular attachment analysis identified overall bent helical regions of adhesive peptides identified within mussel adhesive protein (MAP) capable of also attaching cells. DOPA (L-DOPA, 3,4-dihydroxyphenylalanine) is frequently identified and credited for the attachment ability of several marine proteins [Olivieri, MP, et al. (2002), Biofouling18, 149-159]. Newly designed cyclic peptides (DOPA-G-G-C-G-K-A-K-G-C [cyc-DOPA] & Y-G-G-C-G-K-A-K-G-C [cyc-Y]) derived from structurally conserved regions of several MAP peptides were examined to assist in the understanding of both surface and cellular attachment. Solution state proton nuclear magnetic resonance (NMR) spectroscopy coupled with molecular modeling and dynamics revealed minimal differences in the structures of the proposed cellular attachment domain within these two peptides. Multiple attenuated internal reflection infrared (MAIR-IR) spectroscopy, ellipsometry and advancing contact angle analyses showed that formation of thin films by these peptides was L-DOPA and pH dependent. When compared to control surfaces, undifferentiated leukocyte cells (MOLT-4) significantly attached and spread onto films created from the cyc-DOPA. The culmination of these structural, biophysical and cellular attachment techniques reveal a conformation of cyc-DOPA that is capable of both adsorbing to surfaces and then attaching cells that spread. This work supports the sequence, K-A-K, as the cellular attachment domain, especially when held in a reliable structural conformation.,. PMID- 26052159 TI - Can music with prosocial lyrics heal the working world? A field intervention in a call center. AB - Music with lyrics about helping is shown to reduce aggression in the laboratory. This paper tests whether the prosocial lyric effect generalizes to reducing customer aggression in the workplace. A field experiment involved changing the hold music played to customers of a call center. The results of a 3 week study suggested that music significantly affected customers, but not in the way suggested by previous laboratory experiments; compared with days when instrumental background music was played, caller anger and employee exhaustion were lower on days when callers were played popular music with neutral, but not prosocial, lyrics. The findings suggest that music influences customer aggression, but that the prosocial lyric effect may not generalize from the laboratory to the call center. PMID- 26052160 TI - Undergraduate Laboratory Module for Implementing ELISA on the High Performance Microfluidic Platform. AB - Implementing enzyme-linked immunosorbent assays (ELISA) in microchannels offers several advantages over its traditional microtiter plate-based format, including a reduced sample volume requirement, shorter incubation period, and greater sensitivity. Moreover, microfluidic ELISA platforms are inexpensive to fabricate and allow integration of analytical procedures, such as sample preconcentration, that further enhance the performance of the immunoassay. In view of the scientific potential of microfluidic ELISAs, inclusion of this technique into an undergraduate curriculum is valuable in preparing the next generation of scientists and engineers. Here, an experimental module is presented for this immunoassay method that can be completed in an undergraduate laboratory setting within two 3-h periods (including all incubation and data analyses procedures) using only a microliter of sample and reagents per assay. In addition to acquainting students with the microfluidic technology, the reported module provides training in quantitating ELISAs using the kinetic format of the assay. Furthermore, it offers a useful educational tool for introducing undergraduates to basic image analysis techniques, as well as signal-to-noise ratio and limit of detection calculations that are valuable in characterizing any analytical method. PMID- 26052161 TI - Racial Diversity in the Medical Profession: The Impact of Affirmative Action Bans on Underrepresented Student of Color Matriculation in Medical Schools. AB - This study examines the impact of affirmative action bans in six states (California, Washington, Florida, Texas, Michigan, and Nebraska) on the matriculation rates of historically underrepresented students of color in public medical schools in these states. Findings show that affirmative action bans have led to about a 17% decline (from 18.5% to 15.3%) in the first-time matriculation of medical school students who are underrepresented students of color. This decline is similar to drops in the enrollment of students of color that have taken place across other educational sectors, including the nation's most selective public undergraduate institutions, law schools, and various graduate fields of study, after bans on affirmative action were enacted in some of these states. The findings suggest that statewide laws banning the consideration of race in postsecondary admissions pose serious obstacles for the medical profession to address the health-care crisis facing the nation. PMID- 26052162 TI - How Much In-Kind Support Do Low-Income Nonresident Fathers Provide? A Mixed Method Analysis. AB - Past child support research has largely focused on cash payments made through the courts (formal support) or given directly to the mother (informal support), almost to the exclusion of a third type: non-cash goods (in-kind support). Drawing on repeated, semistructured interviews with nearly 400 low-income noncustodial fathers, the authors found that in-kind support constitutes about one quarter of total support. Children in receipt of some in-kind support receive, on average, $60 per month worth of goods. Multilevel regression analyses demonstrated that children who are younger and have more hours of visitation, as well as those whose father has a high school education and no current substance abuse problem, receive in-kind support of greater value. Yet children whose fathers lack stable employment, or are Black, receive a greater proportion of their total support in kind. A subsequent qualitative analysis revealed that fathers' logic for providing in-kind support is primarily relational, and not financial. PMID- 26052163 TI - Coparenting and Nonresident Fathers' Monetary Contributions to Their Children. AB - The percentage of children in the United States living apart from their biological father has increased, while public assistance for single mothers has diminished. This has resulted in a need to better understand and promote nonresident fathers' economic support of their children. In the present study the author used data from the Fragile Families and Child Wellbeing Study (N = 1,752) to examine how coparenting-the degree to which parents are mutually supportive and cooperative in raising their child-is related to nonresident fathers' monetary contributions. Results from pooled regression and fixed effects models indicate that coparenting is positively associated with fathers' likelihood of paying formal and informal child support and the amount of these payments. Findings from cross-lagged structural equation models suggest that the association between coparenting and fathers' payments is reciprocal but that coparenting has a stronger effect on fathers' payments than fathers' payments do on coparenting. PMID- 26052164 TI - Does grassroots democracy reduce income inequality in China? AB - Using village and household survey data collected from 48 villages of eight Chinese provinces for the period 1986-2002, this paper studies how the introduction of village elections affects income distribution at the village level. We estimate both a static fixed-effect panel model and a dynamic panel model for the within-village Gini coefficient and take care of the endogeneity of the introduction of elections. The dynamic panel model shows that having elections reduces the Gini coefficient by 0.04, or 14.3% of the sample average. We also find that elections tend to increase the income shares of poorer portions of the population. Further econometric analysis based on dynamic panel models shows that elections increase per-capita public expenditures by 271 Yuan, but do not increase the level or progressiveness of net or total income transfer in a village. Therefore, elections' positive role in reducing income inequality is not played through more income redistribution, but through more pro-poor public investment. PMID- 26052165 TI - The garden as a laboratory: the role of domestic gardens as places of scientific exploration in the long 18th century. AB - Eighteenth-century gardens have traditionally been viewed as spaces designed for leisure, and as representations of political status, power and taste. In contrast, this paper will explore the concept that gardens in this period could be seen as dynamic spaces where scientific experiment and medical practice could occur. Two examples have been explored in the pilot study which has led to this paper - the designed landscapes associated with John Hunter's Earl's Court residence, in London, and the garden at Edward Jenner's house in Berkeley, Gloucestershire. Garden history methodologies have been implemented in order to consider the extent to which these domestic gardens can be viewed as experimental spaces. PMID- 26052166 TI - Cohort Abortion Measures for the United States. PMID- 26052167 TI - Stress-Related Changes in Attentional Bias to Social Threat in Young Adults: Psychobiological Associations with the Early Family Environment. AB - This study investigated the association of chronic childhood stress exposure with acute stress-related attentional alterations that have been previously linked to vulnerability to mental and physical illness in early adulthood. Participants were randomized in a crossover design to complete both a mild laboratory social stress task and a computerized task assessing attentional bias to socially threatening words. Salivary cortisol was measured throughout the study. Exposure to acute laboratory stress altered attentional processing, and this relationship was moderated by chronic childhood stress exposure. Also, a positive association between cortisol reactivity and attentional bias was observed, with cortisol reactivity negatively related to childhood chronic stress exposure. While previous work has supported a role for early chronic stress exposure in influencing acute stress reactivity, this work provides initial insight into how both prior chronic childhood stress and current acute stress together relate to the attentional gateway and may be associated with stress adaptation and psychological vulnerability into adulthood. PMID- 26052168 TI - Confirming the Multidimensionality of Psychologically Controlling Parenting among Chinese-American Mothers: Love Withdrawal, Guilt Induction, and Shaming. AB - Despite the theoretical conceptualization of parental psychological control as a multidimensional construct, the majority of previous studies have examined psychological control as a unidimensional scale. Moreover, the conceptualization of shaming and its associations with love withdrawal and guilt induction are unclear. The current study aimed to fill these gaps by evaluating the latent factor structure underlying 18 items from Olsen et al. (2002) that were conceptually relevant to love withdrawal, guilt induction, and shaming practices in a sample of 169 mothers of Chinese-American preschoolers. A multidimensional three-factor model and bi-factor model were specified based on our formulated operational definitions for the three dimensions of psychological control. Both models were found to be superior to the unidimensional model. In addition, results from the bi-factor model and an additional second-order factor model indicated that psychological control is essentially empirically isomorphic with guilt induction. Although love withdrawal and shaming factors were also fairly strong indicators of psychological control, each exhibited important additional unique variability and mutual distinctiveness. Implications for the conceptualization of love withdrawal, guilt induction, and shaming as well as directions for future studies are discussed. PMID- 26052169 TI - Direct formulation to Cholesky decomposition of a general nonsingular correlation matrix. AB - We present two novel and explicit parametrizations of Cholesky factor of a nonsingular correlation matrix. One that uses semi-partial correlation coefficients, and a second that utilizes differences between the successive ratios of two determinants. To each, we offer a useful application. PMID- 26052170 TI - A memory-retrieval view of discourse representation: The recollection and familiarity of text ideas. AB - According to most theories of text comprehension, readers construct and store in memory at least two inter-related representations: a text base containing the explicit ideas in a text and a discourse model that contains the overall meaning or "gist" of a text. The authors propose a refinement of this view in which text representations are distinguished by both encoding and retrieval processes. Some encoding processes "unitize" concepts in a text and some "relate" units to one another. Units are retrieved based on familiarity processes in recognition, whereas related units are retrieved based on recollective processes. This distinction was tested in two experiments. In Experiment 1, readers comprehended sentence pairs in which some could be related by means of a causal inference, whereas others were only temporally related. Overall recognition was high in both conditions, but recollection, much more than familiarity, was sensitive to the causal manipulation. In Experiment 2, sentences began with a definite article as a linguistic cue to connect noun phrases or began with an indefinite article. The discourse manipulation had its primary influence on recollection. The authors suggest that the discourse model may be a collection of text ideas that are available to consciousness at retrieval. The gist-level representation of a text may not be a pre-stored structure; rather, it may be generated, in part, as a summary description of recollected text ideas. PMID- 26052171 TI - Generalized adaptive intelligent binning of multiway data. AB - NMR metabolic fingerprinting methods almost exclusively rely upon the use of one dimensional (1D) 1H NMR data to gain insights into chemical differences between two or more experimental classes. While 1D 1H NMR spectroscopy is a powerful, highly informative technique that can rapidly and nondestructively report details of complex metabolite mixtures, it suffers from significant signal overlap that hinders interpretation and quantification of individual analytes. Two-dimensional (2D) NMR methods that report heteronuclear connectivities can reduce spectral overlap, but their use in metabolic fingerprinting studies is limited. We describe a generalization of Adaptive Intelligent binning that enables its use on multidimensional datasets, allowing the direct use of nD NMR spectroscopic data in bilinear factorizations such as principal component analysis (PCA) and partial least squares (PLS). PMID- 26052172 TI - Adapting an evidence based parenting program for child welfare involved teens and their caregivers. AB - The scarcity of caregivers and the unique vulnerability of teens involved with the child welfare system necessitate effective strategies for ensuring that caregivers are prepared and supported in the important role they play with children and youth within the child welfare system. They are in a position, through the establishment of a strong, positive, supportive connection with the youth, to potentially minimize the impacts of recent trauma and interrupt a negative trajectory by preventing the youth's initiation of high-risk behavior. In this paper we describe the process used to systematically adapt Staying Connected with Your TeenTM, an evidence-based, prevention-focused parenting program found in other studies to reduce the initiation of teens' risky behaviors, for use with foster teens and their relative or foster caregivers. This work has been guided by the ADAPT-ITT framework developed by Wingood and DiClemente (2008) for adapting evidence-based interventions. Qualitative work conducted in Phase 1 of this study identified the need for the development of a trusted connection between foster youth and their caregivers, as well as tools for helping them access community resources, social services, and educational supports. This paper describes the process used to develop new and adapted program activities in response to the needs identified in Phase 1. We conducted a theater test with dyads of foster youth and their caregivers to get feedback on the new activities. Findings from the theater test are provided and next steps in the research are discussed which include examining program usability, fidelity, feasibility, and testing this new prevention program that has been tailored for child welfare involved youth and their caregivers. This intervention program has the potential to fill an important gap in the availability of preventive programming for caregivers of teens in foster care. PMID- 26052173 TI - In search of connection: The foster youth and caregiver relationship. AB - Placement instability is an ongoing challenge for the 125,000 foster youth aged 14 - 18 that are living in foster care, with youth living in approximately 3 placements before aging out of the system. Despite the importance caring adult relationships can play in promoting positive youth development and resiliency, there has been limited inquiry into the characteristics of the foster youth and caregiver relationship. The goal of this paper is to provide a descriptive account of the foster youth and caregiver relationship, and explore what qualities and experiences foster youth desire from their caregivers. Qualitative data were gathered from 9 focus groups. Data were analyzed using thematic content analysis approaches. Foster youth, caregivers, and child welfare staff described relationships lacking in formative bonds and connection, where youth didn't "fit in", and chaotic homes marked by reactivity and judgment. Characteristics of supportive foster homes include a sense of belonging, structure, guidance, and consistency. This research underscores the important role positive relationships can play in foster youth's feelings of well-being and points to the need for foster parent training to include tangible strategies to develop stronger bonds. PMID- 26052174 TI - Why children differ in motivation to learn: Insights from over 13,000 twins from 6 countries. AB - Little is known about why people differ in their levels of academic motivation. This study explored the etiology of individual differences in enjoyment and self perceived ability for several school subjects in nearly 13,000 twins aged 9-16 from 6 countries. The results showed a striking consistency across ages, school subjects, and cultures. Contrary to common belief, enjoyment of learning and children's perceptions of their competence were no less heritable than cognitive ability. Genetic factors explained approximately 40% of the variance and all of the observed twins' similarity in academic motivation. Shared environmental factors, such as home or classroom, did not contribute to the twin's similarity in academic motivation. Environmental influences stemmed entirely from individual specific experiences. PMID- 26052175 TI - Predictors of Quality of Life in Cancer Survivors: White and Asian American Women. AB - The purpose of this study is to compare the pathways through which multiple contextual factors influence the quality of life in Asian American and White women living with cancer. This is a secondary analysis of the data from 95 Asian American women and 113 White women. The data were analyzed using hierarchical multiple regression analyses and structural equation modeling. Multiple factors explained higher percent of total variances of the quality of life scores in Whites compared with that in Asian Americans. PMID- 26052176 TI - Task-driven imaging in cone-beam computed tomography. AB - PURPOSE: Conventional workflow in interventional imaging often ignores a wealth of prior information of the patient anatomy and the imaging task. This work introduces a task-driven imaging framework that utilizes such information to prospectively design acquisition and reconstruction techniques for cone-beam CT (CBCT) in a manner that maximizes task-based performance in subsequent imaging procedures. METHODS: The framework is employed in jointly optimizing tube current modulation, orbital tilt, and reconstruction parameters in filtered backprojection reconstruction for interventional imaging. Theoretical predictors of noise and resolution relates acquisition and reconstruction parameters to task based detectability. Given a patient-specific prior image and specification of the imaging task, an optimization algorithm prospectively identifies the combination of imaging parameters that maximizes task-based detectability. Initial investigations were performed for a variety of imaging tasks in an elliptical phantom and an anthropomorphic head phantom. RESULTS: Optimization of tube current modulation and view-dependent reconstruction kernel was shown to have greatest benefits for a directional task (e.g., identification of device or tissue orientation). The task-driven approach yielded techniques in which the dose and sharp kernels were concentrated in views contributing the most to the signal power associated with the imaging task. For example, detectability of a line pair detection task was improved by at least three fold compared to conventional approaches. For radially symmetric tasks, the task-driven strategy yielded results similar to a minimum variance strategy in the absence of kernel modulation. Optimization of the orbital tilt successfully avoided highly attenuating structures that can confound the imaging task by introducing noise correlations masquerading at spatial frequencies of interest. CONCLUSIONS: This work demonstrated the potential of a task-driven imaging framework to improve image quality and reduce dose beyond that achievable with conventional imaging approaches. PMID- 26052178 TI - Evaluating the effectiveness of Washington state repeated job search services on the employment rate of prime-age female welfare recipients. AB - This paper uses an unbalanced panel dataset to evaluate how repeated job search services (JSS) and personal characteristics affect the employment rate of the prime-age female welfare recipients in the State of Washington. We propose a transition probability model to take into account issues of sample attrition, sample refreshment and duration dependence. We also generalize Honore and Kyriazidou's [Honore, B.E., Kyriazidou, E., 2000. Panel data discrete choice models with lagged dependent variables. Econometrica 68 (4), 839-874] conditional maximum likelihood estimator to allow for the presence of individual-specific effects. A limited information test is suggested to test for selection issues in non-experimental data. The specification tests indicate that the (conditional on the set of the confounding variables considered) assumptions of no selection due to unobservables and/or no unobserved individual-specific effects are not violated. Our findings indicate that the first job search service does have positive and significant impacts on the employment rate. However, providing repeated JSS to the same client has no significant impact. Further, we find that there are significant experience-enhancing effects. These findings suggest that providing one job search services training to individuals may have a lasting impact on raising their employment rates. PMID- 26052177 TI - Nuclear resonance vibrational spectroscopy (NRVS) of rubredoxin and MoFe protein crystals. AB - We have applied 57Fe nuclear resonance vibrational spectroscopy (NRVS) for the first time to study the dynamics of Fe centers in Fe-S protein crystals, including oxidized wild type rubredoxin crystals from Pyrococcus furiosus, and the MoFe protein of nitrogenase from Azotobacter vinelandii. Thanks to the NRVS selection rule, selectively probed vibrational modes have been observed in both oriented rubredoxin and MoFe protein crystals. The NRVS work was complemented by extended X-ray absorption fine structure spectroscopy (EXAFS) measurements on oxidized wild type rubredoxin crystals from Pyrococcus furiosus. The EXAFS spectra revealed the Fe-S bond length difference in oxidized Pf Rd protein, which is qualitatively consistent with the X-ray crystal structure. PMID- 26052179 TI - Bank Size and Small- and Medium-sized Enterprise (SME) Lending: Evidence from China. AB - Using panel data collected in 2005, we evaluate how bank size, discretion over credit, incentive schemes, competition, and the institutional environment affect lending to small- and medium-sized enterprises in China. We deal with the endogeneity problem using instrumental variables, and a reduced-form approach is also applied to allow for weak instruments in estimation. We find that total bank asset is an insignificant factor for banks' decision on small- and medium enterprise (SME) lending, but more local lending authority, more competition, carefully designed incentive schemes, and stronger law enforcement encourage commercial banks to lend to SMEs. PMID- 26052180 TI - Psychometric Evaluation of the Substance Use Risk Profile Scale (SURPS) in an Inpatient Sample of Substance Users Using Cue-Reactivity Methodology. AB - The current project sought to examine the psychometric properties of a personality based measure (Substance Use Risk Profile Scale; SURPS: introversion hopelessness, anxiety sensitivity, impulsivity, and sensation seeking) designed to differentially predict substance use preferences and patterns by matching primary personality-based motives for use to the specific effects of various psychoactive substances. Specifically, we sought to validate the SURPS in a clinical sample of substance users using cue reactivity methodology to assess current inclinations to consume a wide range of psychoactive substances. Using confirmatory factor analysis and correlational analyses, the SURPS demonstrated good psychometric properties and construct validity. Further, impulsivity and sensation-seeking were associated with use of multiple substances but could be differentiated by motives for use and susceptibility to the reinforcing effects of stimulants (i.e., impulsivity) and alcohol (i.e. sensation-seeking). In contrast, introversion-hopelessness and anxiety sensitivity demonstrated a pattern of use more focused on reducing negative affect, but were not differentiated based on specific patterns of use. Taken together, results suggests that among those receiving inpatient treatment for substance use disorders, the SURPS is a valid instrument for measuring four distinct personality dimensions that may be sensitive to motivational susceptibilities to specific patterns of alcohol and drug use. PMID- 26052182 TI - Sequential Monte Carlo for Maximum Weight Subgraphs with Application to Solving Image Jigsaw Puzzles. AB - We consider a problem of finding maximum weight subgraphs (MWS) that satisfy hard constraints in a weighted graph. The constraints specify the graph nodes that must belong to the solution as well as mutual exclusions of graph nodes, i.e., pairs of nodes that cannot belong to the same solution. Our main contribution is a novel inference approach for solving this problem in a sequential monte carlo (SMC) sampling framework. Usually in an SMC framework there is a natural ordering of the states of the samples. The order typically depends on observations about the states or on the annealing setup used. In many applications (e.g., image jigsaw puzzle problems), all observations (e.g., puzzle pieces) are given at once and it is hard to define a natural ordering. Therefore, we relax the assumption of having ordered observations about states and propose a novel SMC algorithm for obtaining maximum a posteriori estimate of a high-dimensional posterior distribution. This is achieved by exploring different orders of states and selecting the most informative permutations in each step of the sampling. Our experimental results demonstrate that the proposed inference framework significantly outperforms loopy belief propagation in solving the image jigsaw puzzle problem. In particular, our inference quadruples the accuracy of the puzzle assembly compared to that of loopy belief propagation. PMID- 26052181 TI - Contributions of Dynamic Systems Theory to Cognitive Development. AB - This paper examines the contributions of dynamic systems theory to the field of cognitive development, focusing on modeling using dynamic neural fields. A brief overview highlights the contributions of dynamic systems theory and the central concepts of dynamic field theory (DFT). We then probe empirical predictions and findings generated by DFT around two examples-the DFT of infant perseverative reaching that explains the Piagetian A-not-B error, and the DFT of spatial memory that explain changes in spatial cognition in early development. A systematic review of the literature around these examples reveals that computational modeling is having an impact on empirical research in cognitive development; however, this impact does not extend to neural and clinical research. Moreover, there is a tendency for researchers to interpret models narrowly, anchoring them to specific tasks. We conclude on an optimistic note, encouraging both theoreticians and experimentalists to work toward a more theory-driven future. PMID- 26052183 TI - Location-tuned relaxivity in Gd-doped mesoporous silica nanoparticles. AB - In tuning the sub-particle localisation of Gd(III) binding macrocycles within a mesoporous scaffold, nanoparticle contrast agents of unprecedented relaxivity and low Gd(III) loadings can be realised. PMID- 26052184 TI - Parent Management Training-Oregon Model (PMTOTM) in Mexico City: Integrating Cultural Adaptation Activities in an Implementation Model. AB - This article describes the process of cultural adaptation at the start of the implementation of the Parent Management Training intervention-Oregon model (PMTO) in Mexico City. The implementation process was guided by the model, and the cultural adaptation of PMTO was theoretically guided by the cultural adaptation process (CAP) model. During the process of the adaptation, we uncovered the potential for the CAP to be embedded in the implementation process, taking into account broader training and economic challenges and opportunities. We discuss how cultural adaptation and implementation processes are inextricably linked and iterative and how maintaining a collaborative relationship with the treatment developer has guided our work and has helped expand our research efforts, and how building human capital to implement PMTO in Mexico supported the implementation efforts of PMTO in other places in the United States. PMID- 26052185 TI - Surface- and Tip-Enhanced Raman Spectroscopy as Operando Probes for Monitoring and Understanding Heterogeneous Catalysis. AB - ABSTRACT: Surface-enhanced Raman spectroscopy (SERS) and tip-enhanced Raman spectroscopy (TERS) were until recently limited in their applicability to the majority of heterogeneous catalytic reactions. Recent developments begin to resolve the conflicting experimental requirements for SERS and TERS on the one hand, and heterogeneous catalysis on the other hand. This article discusses the development and use of SERS and TERS to study heterogeneous catalytic reactions, and the exciting possibilities that may now be within reach thanks to the latest technical developments. This will be illustrated with showcase examples from photo- and electrocatalysis. GRAPHICAL ABSTRACT: PMID- 26052186 TI - Biomineralization of a self-assembled-, soft-matrix precursor: Enamel. AB - Enamel is the bioceramic covering of teeth, a composite tissue composed of hierarchical organized hydroxyapatite crystallites fabricated by cells under physiologic pH and temperature. Enamel material properties resist wear and fracture to serve a lifetime of chewing. Understanding the cellular and molecular mechanisms for enamel formation may allow a biology-inspired approach to material fabrication based on self-assembling proteins that control form and function. Genetic understanding of human diseases expose insight from Nature's errors by exposing critical fabrication events that can be validated experimentally and duplicated in mice using genetic engineering to phenocopy the human disease so that it can be explored in detail. This approach led to assessment of amelogenin protein self-assembly which, when altered, disrupts fabrication of the soft enamel protein matrix. A misassembled protein matrix precursor results in loss of cell to matrix contacts essential to fabrication and mineralization. PMID- 26052187 TI - Synthesis and evaluation of a novel co-initiator for dentin adhesives: polymerization kinetics and leachables study. AB - A new tertiary amine co-initiator (TUMA) containing three methacrylate-urethane groups was synthesized for application in dentin adhesives. The photopolymerization kinetics and leaching of unreacted components from methacrylate-based dental polymers formulated with this new co-initiator were determined. The newly synthesize co-initiator showed good chemical stability and decreased amine release from the initiator system. This study provides important information for the future development of biocompatible dentin adhesives/composites. PMID- 26052188 TI - What a Dentist Should Know About Oral and Pharyngeal Cancer in Florida. PMID- 26052189 TI - Daily Associations Between Drinking and Sex Among College Students: A Longitudinal Measurement Burst Design. AB - Daily links between alcohol use and sexual behaviors were examined in a longitudinal study of college students. Hierarchical linear models predicted sexual behaviors by characteristics of persons (N=731; Level 3), semesters (N=4,345, Level 2), and days (N=56,372, Level 1). On a given day, consuming more drinks and binge drinking were associated with greater odds of kissing, touching, oral sex, and penetrative sex. Consistent with alcohol myopia and expectancy theories, associations between binge drinking and sexual behaviors were stronger for students not in romantic relationships, for students with stronger alcohol sex expectancies, and for oral and penetrative sex. Findings suggest that within day links between alcohol use and sexual behaviors are evident across college, with variations based on individual and relationship factors. PMID- 26052190 TI - Objective Quality and Intelligibility Prediction for Users of Assistive Listening Devices. AB - This article presents an overview of twelve existing objective speech quality and intelligibility prediction tools. Two classes of algorithms are presented, namely intrusive and non-intrusive, with the former requiring the use of a reference signal, while the latter does not. Investigated metrics include both those developed for normal hearing listeners, as well as those tailored particularly for hearing impaired (HI) listeners who are users of assistive listening devices (i.e., hearing aids, HAs, and cochlear implants, CIs). Representative examples of those optimized for HI listeners include the speech-to-reverberation modulation energy ratio, tailored to hearing aids (SRMR-HA) and to cochlear implants (SRMR CI); the modulation spectrum area (ModA); the hearing aid speech quality (HASQI) and perception indices (HASPI); and the PErception MOdel - hearing impairment quality (PEMO-Q-HI). The objective metrics are tested on three subjectively-rated speech datasets covering reverberation-alone, noise-alone, and reverberation-plus noise degradation conditions, as well as degradations resultant from nonlinear frequency compression and different speech enhancement strategies. The advantages and limitations of each measure are highlighted and recommendations are given for suggested uses of the different tools under specific environmental and processing conditions. PMID- 26052191 TI - Super-secondary structure peptidomimetics: design and synthesis of an alpha-alpha hairpin analogue. AB - The alpha-alpha helix motif presents key recognition domains in protein-protein and protein-oligonucleotide binding, and is one of the most common super secondary structures. Herein we describe the design, synthesis and structural characterization of an alpha-alpha hairpin analogue based on a tetra-coordinated Pd(II) bis-(iminoisoquinoline) complex as a template for the display of two alpha helix mimics. This approach is exemplified by the attachment of two biphenyl peptidomimetics to reproduce the side-chains of the i and i+4 residues of two helices. PMID- 26052192 TI - Development of Ultrasound-switchable Fluorescence Imaging Contrast Agents based on Thermosensitive Polymers and Nanoparticles. AB - In this work we first introduced a recently developed high-resolution, deep tissue imaging technique, ultrasound-switchable fluorescence (USF). The imaging principles based on two types of USF contrast agents were reviewed. To improve USF imaging techniques further, excellent USF contrast agents were developed based on high-performance thermoresponsive polymers and environment-sensitive fluorophores. Herein, such contrast agents were synthesized and characterized with five key parameters: (1) peak excitation and emission wavelengths (lambdaex and lambdaem), (2) the fluorescence intensity ratio between on and off states (IOn/IOff), (3) the fluorescence lifetime ratio between on and off states (tauOn/tauOff), (4) the temperature threshold to switch on fluorophores (Tth), and (5) the temperature transition bandwidth (TBW). We mainly investigated fluorescence intensity and lifetime changes of four environment-sensitive dyes [7 (2-Aminoethylamino)-N,N-dimethyl-4-benzofurazansulfonamide (DBD-ED), St633, Sq660, and St700] as a function of temperature, while the dye was attached to poly(N-isopropylacrylamide) linear polymers or encapsulated in nanoparticles. Six fluorescence resonance energy transfer systems were invented in which both the donor (DBD-ED or ST425) and the acceptor (Sq660) were adopted. Our results indicate that three Forster resonance energy transfer systems, where both IOn/IOff and tauOn/tauOff are larger than 2.5, are promising for application in future surface tissue bioimaging by USF technique. PMID- 26052193 TI - Palliative management of malignant upper urinary tract obstruction. AB - Malignancies of the genitourinary tract are diagnosed with increased frequency compared to the past. Currently prostate and bladder cancer account for the majority of urological malignancies. While for prostate cancer recent developments in the management of local and metastatic disease are likely to lead the majority of patients to either cure from the disease or to longer survival time, for bladder cancer advanced disease will unfortunately lead to death within months. However, the common clinical scenario in both prostate and bladder cancer includes, in high incidence, upper urinary tract obstruction in the advanced stages of these malignancies. This coupled with the fact that average life expectancy in the western world is increasing, will result in a significant patient population with either advanced, non-curable disease or with problems related to the received therapeutic surgical or medical interventions. There is no doubt that in both circumstances the room and role of palliation therapy is increasing. The care of patients with advanced urologic malignancies requires a multi-disciplinary effort from physicians of many specialties under the guiding role of the treating urologist. This review focuses on currently available palliative therapeutic options for upper urinary tract obstruction in the setting of patients with advanced malignancies of the urinary tract, as recently significant advancements have been witnessed in this field. PMID- 26052194 TI - Caesarean deliveries in the Mother-Child (Rhea) cohort in Crete, Greece: almost as frequent as vaginal births and even more common in first-time mothers. AB - BACKGROUND: Caesarean deliveries are on the increase in Greece and around the world. The objective of the present study was to assess the frequency of planned and emergency caesarean deliveries and their socio-demographic predictors in women with singleton pregnancies followed-up from early pregnancy to delivery. METHODS: The mother-child cohort in Crete examines a population sample of pregnant women recruited during one year beginning in February 2007. A cohort of 1096 women, with singleton pregnancies, was included in the present analyses. Multivariable Poisson regression models with robust error variance were used. RESULTS: Overall, 48% of the women had a caesarean delivery, with a higher percentage observed in women having their first child (52%). Maternal age was a predictor for caesarean deliveries; type of hospital was associated with the risk for an emergency caesarean, whereas women with lower education were at an increased risk of having a planned caesarean delivery among primiparae. Prior caesarean delivery was by far the strongest predictor (RR=7.68, 95% CI 5.71, 10.33) for a subsequent one among multiparae. CONCLUSIONS: Caesarean deliveries are almost as frequent as vaginal births in the study population and even more frequent in first-time mothers. The study findings support that risk factors are indeed mode of delivery and parity status specific. As such, it is becoming clearer which groups of women, especially first-time mothers, need to be targeted in future research and interventions so as to understand better and achieve an appropriate caesarean delivery risk. PMID- 26052195 TI - Delay in starting insulin after failure of other treatments in patients with type 2 diabetes mellitus. AB - BACKGROUND AND AIM: In type 2 diabetes mellitus (T2DM), therapies to maintain blood glucose control usually fail after several years. The aim of this study was to estimate the time to insulin initiation, the glycemic burden that patients are exposed prior to conversion to insulin and their HbA1c level at that time and a year later. MATERIAL AND METHODS: Five hundred nine patients were included in this retrospective study. We identified patients with T2DM who started insulin therapy from 01/01/2002 to 30/06/2011, from the Scottish Care Information Diabetes Collaboration (SCI-DC) database of Western General Hospital, Edinburgh, Scotland. We estimated the duration of diabetes prior to conversion to insulin therapy, the months they spent with glycated hemoglobin (HbA1c) above 7%, 8% or 9% until starting insulin, HbA1c and body weight (BW) at the time of conversion, at 6 and at 12 months before and after conversion. RESULTS: Patients started insulin therapy after a median period of 6.2 (1-30) years after diagnosis of T2DM. Median HbA1c was 10% (range 7.2-17.9) at the time of conversion, 8.8% (5. 8 16.9) at six months before and 8.3% (5.2-15) at 12 months before conversion, and 8.4% (4.7-14.3) at 6 months and 8.2% (5-14.7) at 12 months after conversion. Body weight (BW) was 86.6 kg (39.6-179.8) at the time of conversion and 91 kg (42.7 196) at 12 months after conversion. Patients spent a median period of 49 (0-325) months with HbA1c >7%, 25 (0-163) months with HbA1c >8% and 10 (0-135) months with HbA1c >9%. Insulin treatment resulted in a decrease in HbA1c at 12 months of 1.8% (p<0.05) but in an increase in BW by 2.9 kg (p<0.05). CONCLUSION: Healthcare professionals delay the initiation of insulin in patients with type 2 diabetes until their HbA1c exceeds 10%. As a result, patients are exposed to a significant glycemic burden. Change in treatment improves their glycemic control for the next 12 months. Hippokratia 2014; 18 (4): 306-309. PMID- 26052196 TI - Manual ability and manual dexterity in children with cerebral palsy. AB - INTRODUCTION: Manual ability and performance of dexterity tasks require both gross and fine hand motions and coordination. The aim of this study was to determine the level of manual dexterity (capacity) and investigate its relationship with manual ability (performance) in children with cerebral palsy. METHOD: This study was designed as a cross-sectional study of 30 children with cerebral palsy (aged 8-15 years). In order to assess gross manual dexterity the Box and Block Test was used. Manual ability was assessed according to Manual Ability Classification System (MACS). RESULTS: A relationship between the level of manual ability impairment and performance on manual dexterity tasks was expressed. Participants at MACS level IV demonstrated slowest times and transferred the smallest number of blocks (p<0.01). This study also found that correlation between Gross Motor Function Classification Scale (GMFCS) and MACS is statistically significant (p<0.001). All hand skills were more impaired in the non-dominant hand compared to the dominant hand but there were no statistically significant difference (p=0.06). CONCLUSION: The results suggest that gross manual dexterity is a good predictor of manual abilities in children with cerebral palsy. These results provide better understanding of the relationship between manual dexterity and activity limitations and lend credibility to the use of these classification systems and assessments in order to optimize treatment planning and evaluate interventions and progress. Hippokratia 2014; 18 (4): 310 314. PMID- 26052197 TI - Dose equivalence between continuous erythropoietin receptor activator (CERA), Darbepoetin and Epoetin in patients with advanced chronic kidney disease. AB - BACKGROUND: Anemia is a prevalent situation in patients with chronic kidney disease (CKD) and can be well managed with erythropoiesis-stimulating agents (ESAs). Continuous erythropoietin receptor activator (CERA) has a long half-life that allows to be administered once monthly. The lowest recommended dose for patients with non dialysis CKD is 120 MUg per month. The objectives were to assess the efficacy of subcutaneous monthly dosing of CERA in CKD stages 4 and 5 not on dialysis, and to determine the equivalent dose to epoetin beta and darbepoetin alpha. METHODS: This is a cohort study. A 30-patient group that ESAs was changed to CERA (MUg/month) was used as treatment group. We used the following clinically-based equivalent dosing: epoetin beta (IU/week) and darbepoetin alpha (MUg/week): 3000/15= 50; 4000/20=75; 6000/30=100; 8000/40=150. Another group of 30 patients with similar characteristics was used as control group and received the same epoetin beta and darbepoetin alpha doses. RESULTS: The mean CERA initial dose and at 6 months was 81.9 +/- 35.2 and 82.0 +/- 37.82 MUg/month (p=0.37). The mean erythropoietin resistance index (ERI) and hemoglobin at baseline and at 6 months in the CERA group and in the control group were not statistically significant. CONCLUSION: Monthly dosing treatment with CERA is safe and effective. A dose of 75-100 MUg/month is enough to maintain stable levels of hemoglobin. Hippokratia 2014; 18 (4): 315-318. PMID- 26052198 TI - Warfarin dose requirement in Turkish patients: the influences of patient characteristics and polymorphisms in CYP2C9, VKORC1 and factor VII. AB - BACKGROUND: To determine the contribution of cytochrome P4502C9 (CYP2C9), vitamin K epoxide reductase (VKORC1) and factor VII genotypes, age, body mass index (BMI), international normalized ratio (INR) and other individual patient characteristics on warfarin dose requirements in an adult Turkish population. METHODS: Blood samples were collected from 101 Turkish patients. Genetic analyses for CYP2C9*2 and *3, VKORC1 -1639 G>A and factor VII -401 G>T polymorphisms were performed. Age, INR, BMI values and other individual patient characteristics were also recorded. RESULTS: The mean daily warfarin dosage was significantly higher in patients with the CYP2C9*1/*1 genotype than in the CYP2C9*2/*2 and CYP2C9*1/*3 groups (p <= 0.05). With respect to the VKORC1 -1639 G>A polymorphism, the mean warfarin daily dose requirement was higher in the wild type group compared to the heterozygous group (p<=0.001). The mean daily dose requirement for patients with the GG form of factor VII was significantly higher than that of patients with the TT genotype (p <= 0.05). Age, gender, BMI, INR had no statistically significant correlation with warfarin dose (p >= 0.05). CONCLUSIONS: Polymorphisms in CYP2C9, VKORC1 and factor VII did partially affect daily warfarin dose requirements, while age, gender, BMI and INR do not. However, further case-control studies with a larger study size and different genetic loci are needed to confirm our study. PMID- 26052199 TI - microRNA-183 down-regulates the expression of BKCabeta1 protein that is related to the severity of chronic obstructive pulmonary disease. AB - OBJECTIVES: The aim of this study was to investigate the relationship between the expression of microRNA (miRNA)-183 and Ca(2+)-activated K(+) channels beta1 subunit (BKCabeta1) in the lung tissues of patients with chronic obstructive pulmonary disease (COPD). METHODS: Quantitative real-time polymerase chain reaction and Western blotting were used for detecting the expression of miRNA-183 and BKCabeta1 in the lung tissues from 45 COPD patients and 30 lung cancer patients without COPD. Possible miRNAs that target BKCabeta1 were forecasted by bioinformatics. The expression of these miRNAs in the peripheral blood of COPD patients was also examined. After transfecting vascular smooth muscle cells with pGCMV/EGFP/miR-183 plasmid, the expression of miRNA-183 and BKCabeta1 were detected by quantitative real-time polymerase chain reaction and Western blotting. RESULTS: The expression of BKCabeta1 in the lung tissues of COPD patients was significantly lower than control. Western blotting data showed that the expression of BKCabeta1 protein in COPD group was significantly lower than control. After transfecting the vascular smooth muscle cells with pGCMV/EGFP/miR 183 plasmid, we found that the level of BKCabeta1 mRNA was not significantly reduced by the increase of miRNA-183 level, but the expression of BKCabeta1 protein was down-regulated. CONCLUSIONS: The present study indicated that miRNA 183 might play a role in the expression of BKCabeta1, and the expression of miRNA 183 and BKCabeta1 were possibly related with the pathogenetic pathways of COPD. Hippokratia 2014; 18 (4): 328-332. PMID- 26052200 TI - Risk stratification in submassive pulmonary embolism via alveolar-arterial oxygen gradient. AB - AIM: This study investigated the utility of the alveolar-arterial (AaDO2) gradient in predicting the short-term prognosis of submassive pulmonary embolism (PE). MATERIAL AND METHODS: This study retrospectively enrolled 124 patients with acute submassive PE. During the first 24 h of admission, all patients had initial artery blood gas collected under room air. Cardiac troponin T (cTn-T) was measured and on spiral computed tomography pulmonary angiography (CTPA) and echocardiography both right ventricle diameter and left ventricle diameter was calculated (RV/LV ratio). Patients who did not have objectively confirmed submassive PE and who had curative anticoagulant treatment for more than 24 hours and had a life expectancy less than 3 months were excluded from the study. RESULTS: The best cut-off value for AaDO2 was 42.38 mmHg and using this, fourteen of 15 patients who died had AaO2 >= 42.38 and 71 of 109 patients who survived had a AaO2 lower than 42.38 with a sensitivity, specificity and negative predictive value (NPV) for overall deaths were 93.3%, 65.1% and 98.6% respectively. In addition, AaDO2 < 42.38 showed significant survival benefit for overall mortality rates. In this study, having high cTn-T and PaO2/ PaCO2 < 1.83 and pulmonary artery pressure > 47.5 were also an indicator of poor prognosis for patients with submasssive PE. CONCLUSION: The AaDO2 measurement is a highly useful and simple measurement for predicting short-term prognosis in patients with submassive PE. It may be used in risk stratification of patients with submassive PE. Aggressive thrombolytic treatment strategies may be considered for patients who have AaO2 < 42.38. Hippokratia 2014; 18 (4): 333-339. PMID- 26052201 TI - Effectiveness of azelastine nasal spray in the treatment of adenoidal hyper trophy in children. AB - AIM: To evaluate the effects of topical azelastine treatment on symptoms related to adenoid hypertrophy and the size of adenoid tissue in children. MATERIAL AND METHODS: In total, 60 children who were found to have adenoid hypertrophy were included. A questionnaire on nasal symptoms, nasal endoscopy and skin prick tests was administered to all patients. All patients had complaints of chronic nasal obstruction symptoms and nasal endoscopy showed > 75% choanal obstruction, attributable to adenoid pads. The adenoid/nasopharyngeal areas were calculated. All of the patients underwent azelastine nasal spray therapy (1 spray per nostril, twice daily; 0.28 mg/dose) for 30 days. After 1 month, all children were reassessed. The efficacy of therapy, symptoms, adenoid / nasopharynx ratio, and obstruction ratio, obtained by endoscopy, were compared. RESULTS: Azelastine treatment was well tolerated by all patients. After the first treatment period, the severity of symptoms, endoscopic grade, and adenoid size decreased in all of the 60 patients. There were significant improvements in total subjective symptoms (nasal obstruction, rhinorrhea, cough, snoring, and obstructive sleep apnea) post treatment. CONCLUSIONS: Azelastine nasal spray may be useful in decreasing adenoid pad size and the severity of symptoms related to adenoidal hypertrophy. Hippokratia 2014; 18 (4): 340-345. PMID- 26052202 TI - Effects of folinic acid and fluorouracil chemotherapy on right ventricle func tions as assessed with tricuspid annular plane systolic excursion. AB - AIM: This study aimed to investigate the effects of folinic acid and fluorouracil (bolus FUFA regimen) chemotherapy on right ventricle (RV) functions. MATERIALS AND METHODS: Thirty-four gastrointestinal (GI) cancer patients treated with antineoplastic drugs were included the study. All participants received FUFA chemotherapy protocol for colorectal, gastric and pancreatic cancer (i.e. fluorouracil 400-425 mg/m(2) intravenous day 1-5 + folinic acid 20-25 mg/m2 intravenous day 1-5 every 28 days x6 cycles) with or without radiation therapy according to the cancer and patient status. All participants have undergone complete physical and laboratory examination and complete echocardiographic evaluation including detailed right ventricle functional evaluations before the onset of chemotherapy and 6 months after the start of treatment. RESULTS: Mean RV thickness was 0.49 cm before chemotherapy and 0.62 cm at the end of the treatment (p=0.29). Mean tricuspid annular plane systolic excursion (TAPSE) values were 2.08 +/- 0.3 and 2.00 +/- 0.39 cm, respectively (p=0.25). RV total ejection isovolumic (Tei) index related to the chemotherapy did not change significantly (0.24 and 0.29, respectively, p=0.07). Also we did not find significant chance in the RV end diastolic diameter, RV end systolic diameter, vena cava diameter on inspiration and expiration. CONCLUSION: Bolus FUFA regimen chemotherapy does not diminish the RV functions as assessed by TAPSE and RV Tei index in GI cancer patients. PMID- 26052203 TI - The effect of intraoperative lavage with short chain fatty acids (SCFAs) on rectal anastomosis of rats receiving corticosteroids. AB - BACKGROUND: Anastomotic failure is one of the most frequent complications in rectal surgery. The present study aims to elucidate the effect of intraoperative lavage with short chain fatty acids (SCFAs) on rectal anastomosis of rats receiving corticosteroids. METHODS: Fifty male Wistar rats were divided into five groups. Group A (control group, without lavage and medication), group B (lavage with saline solution and no medication), group C (lavage with SCFAs and no medication), group D (lavage with saline solution and injection of 30mg/kg methylprednisolone 7 days pre-operatively and 4 days post-operatively), group E (lavage with a SCFAs and methylprednisolone). On the 4(th) postoperative day the animals were sacrificed and bursting pressure of the anastomosis, CRP, IL-6 and TNF-a were measured. RESULTS: Kruskal-Wallis variance analysis showed statistically significant differences between the groups (p<0.001). The bursting pressure of the anastomosis was lower in groups B and D, while it was higher in group C. TNF-a values displayed differences between group D and groups A, C, E. CONCLUSIONS: Intraoperative lavage with SCFAs increases anastomotic strength by increasing the bursting pressure of anastomosis in rats receiving corticosteroid, while lavage with saline solution decreases it. Rectal irrigation with short chain fatty acids may improve anastomotic healing, especially in patients receiving corticosteroids. PMID- 26052204 TI - Resection of endobronchial hamartoma causing recurrent hemoptysis by electrocautery and cryotherapy. AB - BACKGROUND: Pulmonary hamartomas are rare benign tumors of the lung with an incidence of 0.025%-0.32%. Endobronchial benign lesions can cause bronchial obstruction and recurrent respiratory infections or obstructive pneumonia and recurrent hemopthysis. CASE REPORT: A 66-year-old male with recurrent hemoptysis and pneumonias for a year, was referred to our department for an endoscopic resection of an endobronchial hamartoma. Initially he refused any intervention but, as he suffered additional episodes of hemoptysis and chest infections during a year on follow up, he finally underwent interventional bronchoscopy and the lesion was cauterized using snare electrocautery probe and removed with cryoextraction. The patient has been followed for two years in our outpatient clinic, with no further problems. CONCLUSION: Endoscopic treatment with flexible bronchoscope, electrocautery and cryotherapy provides an excellent outcome. Surgical therapy, should be reserved for the hamartomas that cannot be approached through endoscopy. Hippokratia 2014; 18 (4): 355-356. PMID- 26052205 TI - Struma ovarii. A case report. AB - BACKGROUND: Struma ovarii is the presence of thyroid tissue as a major cellular component in an ovarian teratoma. CASE REPORT: A 46-year-old old woman, with a palpable mass at the anatomical position of the right adnexa known for the preceding 3 years underwent a total abdominal hysterectomy and bilateral salpingo oophorectomy. Histology reported struma ovarii. CONCLUSION: Struma ovarii is a rare tumor of the ovaries and its clinical appearance may vary: it may be asymptomatic, mimic malignant ovarian tumor, or present with symptoms of hyperthyroidism and, in rare cases, it can even be a malignant tumor. PMID- 26052206 TI - Myocardial crypts as a preclinical sign of hypertrophic cardiomyopathy. AB - BACKGROUND: The identification by cardiac magnetic resonance of myocardial crypts in the left ventricle (LV) of individuals carrying hypertrophic cardiomyopathy causative mutations, but without overt hypertrophy, has been proposed as an early sign of the disease. Myocardial crypts are usually identified in the offsprings of patients with a complete penetrance of the disease. CASE DESCRIPTION: We present a case of familial hypertrophic cardiomyopathy displaying an unusual pattern of disease distribution; the 14-year-old child was affected, demonstrating a typical LV asymmetrical hypertrophy, his grandfather, and the 2 brothers of his mother were also affected, but the 41-year-old mother was unaffected (no hypertrophy) displaying 3 myocardial crypts in inferior LV wall, suggesting a preclinical involvement. CONCLUSION: The findings underscore the diverse clinical spectrum of the disease, even in a single family and also the need to revise the diagnostic criteria of hypertrophic cardiomyopathy.Hippokratia 2014; 18 (4): 359-361. PMID- 26052207 TI - Neuroendocrine carcinoma in adenoma of the sigmoid. AB - BACKGROUND: Neuroendocrine cell tumor in adenoma of the sigmoid is a rare neoplasm coexistence and it is considered as a mixed glandular-neuroendocrine neoplasm. DESCRIPTION OF CASE: An 84-year-old woman underwent surgical removal of a tumor located in the sigmoid, diagnosed as adenocarcinoma on a previous biopsy. On gross examination, apart from the ulcerated tumor, a polyp measuring 2 cm was observed, which histologically corresponded to a villotubular adenoma. In two sites of the adenoma, solid nests of smaller cells were observed, having small amount of cytoplasm, round nuclei with finely stippled chromatin. Mitoses were abundant. These cells were located in the lamina propria and muscularis mucosa, without disturbing the polyp architecture, and showed immunophenotypic characteristics of neuroendocrine carcinoma (NEC). The histologic findings set the diagnosis of mixed adenoma and NEC. The patient remains free of recurrence or metastasis by NEC, after two years of follow up. CONCLUSION: The recognition of NEC in an adenoma will help to avoid potential diagnostic pitfalls. Mixed adenoma and NEC is rare, with uncertain biological behavior. This case reinforces the view that NECs without infiltration of submucosa may have a better prognosis. PMID- 26052208 TI - Ovarian carcinosarcoma in a renal transplant recipient. A unique case of a rare tumor. AB - INTRODUCTION: De novo malignancies have become one of the leading causes of late mortality after renal transplantation, with their incidence being 2-15 fold higher than in general population. We present herein a unique case of ovarian carcinosarcoma in a renal transplant recipient. CASE REPORT: A 69-year-old female renal transplant recipient presented with progressive distension and vague abdominal pain. Clinical examination revealed a large abdominal mass. Magnetic resonance imaging scan verified the presence of the mass. An exploratory laparotomy was performed, identifying a giant tumor measuring 33 x 22 x 10 cm. Optimal debulking surgery was performed, the postoperative course was uneventful and she was discharged on the 8(th) postoperative day. The final diagnosis was ovarian carcinosarcoma. The patient received adjuvant chemotherapy and at 6-month follow-up, she was disease-free. CONCLUSION: Ovarian Carcinosarcoma is a rare and aggressive neoplasia, comprising 1-2 % of all ovarian tumors. Radical surgical approach, as well as appropriate chemotherapy are the cornerstone of treatment. In the presented case, where immunosuppression is involved, further evaluation should be made as far as immunosuppression dose reduction or switch is concerned. PMID- 26052209 TI - Radiologic and pathologic features of a primary chloroma of the testis: a case report and brief review of the literature. AB - AIM: To describe a case of primary granulocytic sarcoma. CASE DESCRIPTION: A 43 year-old man presented with a painless testicular swelling. There was no previous history of malignancy or hematologic disease. Ultrasound and magnetic resonance imaging examination showed an intratesticular mass extending to the surrounding scrotal tissues including the epididymis. Inguinal radical orchiectomy was followed by a macroscopic and microscopic evaluation of the tumor. Immunohistochemistry demonstrated the strong positivity of the neoplastic cells for leucocyte common antigen (LCA), myeloperoxidase, CD-34 and CD-117. All imaging and laboratory tests for metastatic or hematologic disease, including a bone marrow biopsy, were negative, leading to the diagnosis of a primary granulocytic sarcoma of the testis. CONCLUSION: Although chloromas usually manifest in patients with a hematologic malignancy, isolated cases may occur. The low specificity of imaging and, occasionally, microscopic examination is challenging for the right diagnosis. The role of immunohistochemistry in conjunction with the clinical, imaging and laboratory findings is crucial to reach the correct diagnosis. PMID- 26052210 TI - Monoclonal antibody Rituximab for severe immune thrombocytopenia after pegylated interferon for hepatitis C infection. AB - BACKGROUND: Severe immune thrombocytopenia displays a rare side effect of pegylated interferon therapy for Hepatitis C infection. Our aim is to report a case of severe and late onset immune thrombocytopenia due to pegylated interferon treatment that was effectively managed with the anti-CD20 monoclonal antibody Rituximab. DESCRIPTION OF THE CASE: A 27-year-old male, Hepatitis C infected patient, presented with sudden, severe immune thrombocytopenia at the end of a standard 24-week antiviral treatment, as a side effect of pegylated interferon. Platelet count rapidly normalized with Rituximab infusions. CONCLUSION: Rituximab could be a valuable treatment option in pegylated interferon related immune thrombocytopenia, when patients are resistant to conventional treatment or when physicians are reluctant to administer corticosteroids. PMID- 26052211 TI - Nephrotic syndrome and Hodgkin lymphoma in children. Report of two cases. AB - BACKGROUND: The association of nephrotic syndrome (NS) and Hodgkin's lymphoma (HL), although rare, is well recognised. In the majority of cases of HL, minimal change NS is detected. DESCRIPTION OF CASES: This report presents the occurrence of NS in two children with HL. In the first case, NS preceded the diagnosis of lymphoma by 3 months, while in the other child, the two disorders occurred simultaneously. In both cases, clinical manifestations and laboratory parameters (proteinuria) of NS resolved after effective treatment for active HL. CONCLUSION: Prolonged proteinuria may be a paraneoplastic syndrome and HL should be considered in the diagnosis as it is crucial for the management of both entities. PMID- 26052212 TI - Aggressive malignant peripheral nerve sheath tumor of the lower limb in a patient with neurofibromatosis-1 and multiple spinal cord neurofibromas. PMID- 26052213 TI - Be careful before prescribing warfarin and octreotide together: a new drug-drug interaction report. PMID- 26052214 TI - Pedestal sign in cementless total hip replacement. PMID- 26052215 TI - Mucous retention cysts of the paranasal sinuses. PMID- 26052216 TI - A case of cryptococcal meningitis successfully treated with a combination of liposomal amphotericin-B and fluconazole. PMID- 26052217 TI - When is the appropriate timing of surgical repair for congenital diaphragmatic hernia? PMID- 26052218 TI - Severe renal osteodystrophy in early infancy. PMID- 26052219 TI - Is there any room for General Practice in Greece? A proposal to scientific and academic stakeholders. PMID- 26052220 TI - Proliferative Dynamics and the Role of FGF2 During Myogenesis of Rat Satellite Cells on Isolated Fibers. AB - Myogenic precursors in adult skeletal muscle (satellite cells) are mitotically quiescent but can proliferate in response to a variety of stresses including muscle injury. To gain further understanding of adult myoblasts, we are analyzing myogenesis of satellite cells on fibers isolated from adult rat muscle. In this culture model, satellite cells are maintained in their in situ position underneath the fiber basement membrane. Employing two different approaches to monitor proliferation of satellite cells on isolated fibers (autoradiography following 3H-thymidine incorporation and immunofluorescence of cells positive for proliferating cell nuclear antigen (PCNA)), we show in the present study that satellite cells initiate cell proliferation at 12 to 24 hours following fiber culture establishment and that cell proliferation is reduced to minimal levels by 60 to 72 hours in culture. Maximal number of proliferating cells is seen at 36 to 48 hours in culture. These PCNA+ satellite cells transit into the differentiated, myogenin+ state following about 24 hours in the proliferative state. Continuous exposure of the fiber culture to FGF2 (basic FGF; added at the time of culture establishment) leads to a 2 fold increase in the number of PCNA+ cells by 48 hours in culture but the overall schedule of proliferation and transition into the myogenin+ state is not affected. Delaying the addition of FGF2 until 15 to 18 hours following the initiation of the fiber culture does not reduce its effect. However, the addition of FGF2 at 24 hours or later results in a progressive reduction in the number of proliferating satellite cells. Exposure of fiber cultures to transforming growth factor beta (TGFbeta1) leads to a reduction in the number of proliferating cells in both the absence or presence of FGF2. We propose that FGF2 enhances the number of proliferating cells by facilitating the recruitment of additional satellite cells from the quiescent state. However, satellite cells on isolated fibers conform to a highly coordinated program and rapidly transit from proliferation to differentiation regardless of the presence of FGF. The identification of agents that can prolong the proliferative state of satellite cells when the cells undergo myogenesis in their native position by the intact myofiber might be useful in improving myoblast transplantation into skeletal muscle for cell-mediated gene therapy. PMID- 26052222 TI - Inferring Stable Acquisition Durations for Applications of Perfusion Imaging in Oncology. AB - Tissue perfusion plays a critical role in oncology. Growth and migration of cancerous cells requires proliferation of networks of new blood vessels through the process of tumor angiogenesis. Many imaging technologies developed recently attempt to measure characteristics pertaining to the passage of fluid through blood vessels, thereby providing a noninvasive means for cancer detection, as well as treatment prognostication, prediction, and monitoring. However, because these techniques require a sequence of successive imaging scans under administration of intravenous imaging tracers, the quality of the resulting perfusion data depends on the acquisition protocol. In this paper, we explain how to infer stability for stochastic curve estimation. The topic is motivated by two recent attempts to determine stable acquisition durations for acquiring perfusion characteristics using dynamic computed tomography, wherein inference used inappropriate statistical methods. Notably, when appropriate statistical techniques are used, the resulting conclusions deviate substantially from those previously reported in the literature. PMID- 26052221 TI - Identifying CDKN3 Gene Expression as a Prognostic Biomarker in Lung Adenocarcinoma via Meta-analysis. AB - Lung cancer is among the major causes of cancer deaths, and the survival rate of lung cancer patients is extremely low. Recent studies have demonstrated that the gene CDKN3 is related to neoplasia, but in the literature severe controversy exists over whether it is involved in cancer progression or, conversely, tumor inhibition. In this study, we investigated the expression of CDKN3 and its association with prognosis in lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) using datasets in Lung Cancer Explorer (LCE; http://qbrc.swmed.edu/lce/). We found that CDKN3 was up-regulated in ADC and SCC compared to normal tissues. We also found that CDKN3 was expressed at a higher level in SCC than in ADC, which was further validated through meta-analysis (coefficient = 2.09, 95% CI = 1.50-2.67, P < 0.0001). In addition, based on meta analysis for the prognostic value of CDKN3, we found that higher CDKN3 expression was associated with poorer survival outcomes in ADC (HR = 1.65, 95% CI = 1.39 1.96, P < 0.0001), but not in SCC (HR = 1.10, 95% CI = 0.84-1.44, P = 0.494). Our findings indicate that CDKN3 may be a prognostic marker in ADC, though the detailed mechanism is yet to be revealed. PMID- 26052223 TI - Penalized Ordinal Regression Methods for Predicting Stage of Cancer in High Dimensional Covariate Spaces. AB - The pathological description of the stage of a tumor is an important clinical designation and is considered, like many other forms of biomedical data, an ordinal outcome. Currently, statistical methods for predicting an ordinal outcome using clinical, demographic, and high-dimensional correlated features are lacking. In this paper, we propose a method that fits an ordinal response model to predict an ordinal outcome for high-dimensional covariate spaces. Our method penalizes some covariates (high-throughput genomic features) without penalizing others (such as demographic and/or clinical covariates). We demonstrate the application of our method to predict the stage of breast cancer. In our model, breast cancer subtype is a nonpenalized predictor, and CpG site methylation values from the Illumina Human Methylation 450K assay are penalized predictors. The method has been made available in the ordinalgmifs package in the R programming environment. PMID- 26052224 TI - Immunomodulatory Effects of Probiotic Supplementation in Schizophrenia Patients: A Randomized, Placebo-Controlled Trial. AB - Although peripheral immune system abnormalities have been linked to schizophrenia pathophysiology, standard antipsychotic drugs show limited immunological effects. Thus, more effective treatment approaches are required. Probiotics are microorganisms that modulate the immune response of the host and, therefore, may be beneficial to schizophrenia patients. The aim of this study was to examine the possible immunomodulatory effects of probiotic supplementation in chronic schizophrenia patients. The concentrations of 47 immune-related serum proteins were measured using multiplexed immunoassays in samples collected from patients before and after 14 weeks of adjuvant treatment with probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12; n = 31) or placebo (n = 27). Probiotic add-on treatment significantly reduced levels of von Willebrand factor (vWF) and increased levels of monocyte chemotactic protein-1 (MCP-1), brain-derived neurotrophic factor (BDNF), RANTES, and macrophage inflammatory protein-1 beta (MIP-1) beta with borderline significance (P <= 0.08). In silico pathway analysis revealed that probiotic-induced alterations are related to regulation of immune and intestinal epithelial cells through the IL-17 family of cytokines. We hypothesize that supplementation of probiotics to schizophrenia patients may improve control of gastrointestinal leakage. PMID- 26052225 TI - Differentiation of Cardiomyocytes from Human Pluripotent Stem Cells Using Monolayer Culture. AB - Human pluripotent stem cells (PSCs) are a promising cell source for cardiac tissue engineering and cell-based therapies for heart repair because they can be expanded in vitro and differentiated into most cardiovascular cell types, including cardiomyocytes. During embryonic heart development, this differentiation occurs under the influence of internal and external stimuli that guide cells to go down the cardiac lineage. In order to differentiate PSCs in vitro, these or similar stimuli need to be provided in a controlled manner. However, because it is not possible to completely recapitulate the embryonic environment, the factors essential for cardiac differentiation of PSCs in vitro need to be experimentally determined and validated. Since PSCs were first developed, significant progress has been made in optimizing techniques for their differentiation toward cardiomyocytes. In this review, we will summarize recent advances in these techniques, with particular focus on monolayer-based methods that have improved the efficiency and scalability of cardiomyocyte differentiation. PMID- 26052227 TI - Serum Neopterin Levels Among Hepatitis C-Positive Living-Donor Renal Transplant Recipients. AB - BACKGROUND: The role of neopterin as a marker of cell-mediated immunity for immunological monitoring after transplantation is of great potential interest. Neopterin levels among hepatitis C virus (HCV)-positive recipients of living donor renal transplantation (LDRT) have not been previously described. METHODS: Twenty-two HCV-positive (group I) and 10 HCV-negative (group II) recipients of LDRT were serially monitored for serum neopterin levels by enzyme-linked immunosorbent assay (ELISA). Group I patients were monitored thrice, ie, before transplantation, day 10, and 6 months post transplantation, while group II patients were monitored twice (day 10 and 6 months post transplantation). Peripheral blood T-lymphocyte subsets (CD3, CD4, CD8, CD4(+)CD25(+), CD16+56) and Th1/Th2 cytokines were monitored concomitantly by flow cytometry. RESULTS: Ten days post transplantation, there was a significant increase in neopterin and neopterin/creatnine levels among group I patients. There was a positive correlation between activated T-lymphocyte (CD4(+)CD25(+)) and neopterin early post transplantation (day 10). Th2 cytokines IL-10 and IL-5 showed a positive correlation with neopterin levels on day 10 and 6 months post transplantation, respectively. Neopterin levels did not show association with either HCV viral load or allograft rejection among our study cohort. CONCLUSION: Increased monocyte/macrophage activation with elevated serum neopterin was detected among group I patients on day 10 post transplantation, but it could not predict rejection. It appears that IL-10 either from a regulatory or nonregulatory source helps in the maintenance of stable graft early post transplantation. Further, it would be of interest to assess the role of neopterin in chronic allograft nephropathy and long-term graft outcome. PMID- 26052228 TI - Brain Metastases from Breast Cancer and Response to Treatment with Eribulin: A Case Series. AB - Brain metastases are common in patients with advanced breast cancer (BC), causing considerable morbidity and mortality. Eribulin is a microtubule dynamics inhibitor approved for treating certain patients with metastatic BC, previously treated with an anthracycline and a taxane. In the 301 phase 3 study in 1102 women with advanced BC, eribulin and capecitabine treatments did not differ for co-primary endpoints (overall survival [OS]: 15.9 vs 14.5 months, P = 0.056; progression-free survival [PFS]: 4.1 vs 4.2 months, P = 0.30). Here, we report outcomes for six patients (eribulin, n = 3; capecitabine, n = 3) who had received treatment for brain metastases from BC (BCBM) at baseline. All eribulin-treated patients experienced brain lesion shrinkage at some point during treatment, compared with one capecitabine-treated patient. Fewer patients in study 301 developed new BCBM with eribulin (13/544, 2.4%) compared with capecitabine (25/546, 4.6%). Eribulin does not cross the healthy blood-brain barrier (BBB), but could have the potential to do so after cranial radiation therapy. Capecitabine may cross the BBB and has demonstrated activity in BCBM. Data from these patients and previous cases suggest that further investigation of eribulin for BCBM may be warranted. PMID- 26052229 TI - Effects of Radiation Therapy on Breast Epithelial Cells in BRCA1/2 Mutation Carriers. AB - Women carrying BRCA1 and BRCA2 mutations have significantly elevated risk of developing breast and ovarian cancers. BRCA1-associated breast cancer likely originates from progenitors of the luminal epithelial lineage. Recent studies indicate that radiation therapy (RT) for BRCA1 cancer patients is associated with lower incidence of developing subsequent ipsilateral breast cancer. In the current study, we analyzed tumor-free breast tissue procured via prophylactic bilateral mastectomy from three BRCA1 and one BRCA2 mutation carriers, who had been previously treated with RT for unilateral breast cancers. Freshly isolated breast cells from the irradiated and nonirradiated breast tissue of the same individuals were subjected to flow cytometry, using established cell-surface markers. Two out of the three BRCA1 carriers and one BRCA2 carrier exhibited significantly diminished luminal cell population in the irradiated breast versus the nonirradiated side. There was also RT-associated reduction in the colony forming ability of the breast epithelial cells. Our finding suggests that prior RT could result in the depletion of the luminal epithelial compartment and thus reduced incidence of BRCA1/2-associated breast cancer. PMID- 26052226 TI - Biomaterial Approaches for Stem Cell-Based Myocardial Tissue Engineering. AB - Adult and pluripotent stem cells represent a ready supply of cellular raw materials that can be used to generate the functionally mature cells needed to replace damaged or diseased heart tissue. However, the use of stem cells for cardiac regenerative therapies is limited by the low efficiency by which stem cells are differentiated in vitro to cardiac lineages as well as the inability to effectively deliver stem cells and their derivatives to regions of damaged myocardium. In this review, we discuss the various biomaterial-based approaches that are being implemented to direct stem cell fate both in vitro and in vivo. First, we discuss the stem cell types available for cardiac repair and the engineering of naturally and synthetically derived biomaterials to direct their in vitro differentiation to the cell types that comprise heart tissue. Next, we describe biomaterial-based approaches that are being implemented to enhance the in vivo integration and differentiation of stem cells delivered to areas of cardiac damage. Finally, we present emerging trends of using stem cell-based biomaterial approaches to deliver pro-survival factors and fully vascularized tissue to the damaged and diseased cardiac tissue. PMID- 26052230 TI - Efficacy and Safety of Rituximab for Refractory and Relapsing Thrombotic Thrombocytopenic Purpura: A Cohort of 10 Cases. AB - OBJECTIVE: Idiopathic thrombotic thrombocytopenic purpura (TTP) is a life threatening disorder mediated by autoantibodies directed against ADAMTS13. This provides a rationale for the use of rituximab in this disorder. We report our experience and the outcome of 10 cases of TTP (9 refractory and 1 relapsing) successfully treated with rituximab in combination with plasma exchange (PE) and other immunosuppressive treatments. METHODS: The diagnosis of TTP was based on clinical criteria and supported by severe deficiency of ADAMTS13 activity and presence of inhibitors in seven cases. Rituximab was started after a median of 18.6 sessions of PE (range: 5-35) at the dose of 375 mg/m(2)/week for 4-8 weeks. RESULTS: Complete remission was achieved in all patients after a median time of 14.4 days of the first dose (range: 6-30). After a median follow-up of 30 months (range: 8-78), eight patients were still in remission and two developed multiple relapses, treated again with the same therapy, and achieved complete responses; they are alive, and in complete remission after a follow-up of 12 and 16 months. CONCLUSION: Rituximab appears to be a safe and effective therapy for refractory and relapsing TTP. However, longer follow-up is recommended to assess relapse and detect possible long-term side effects of this therapy. PMID- 26052231 TI - Exploring Guidelines for Classification of Major Heart Failure Subtypes by Using Machine Learning. AB - BACKGROUND: Heart failure (HF) manifests as at least two subtypes. The current paradigm distinguishes the two by using both the metric ejection fraction (EF) and a constraint for end-diastolic volume. About half of all HF patients exhibit preserved EF. In contrast, the classical type of HF shows a reduced EF. Common practice sets the cut-off point often at or near EF = 50%, thus defining a linear divider. However, a rationale for this safe choice is lacking, while the assumption regarding applicability of strict linearity has not been justified. Additionally, some studies opt for eliminating patients from consideration for HF if 40 < EF < 50% (gray zone). Thus, there is a need for documented classification guidelines, solving gray zone ambiguity and formulating crisp delineation of transitions between phenotypes. METHODS: Machine learning (ML) models are applied to classify HF subtypes within the ventricular volume domain, rather than by the single use of EF. Various ML models, both unsupervised and supervised, are employed to establish a foundation for classification. Data regarding 48 HF patients are employed as training set for subsequent classification of Monte Carlo-generated surrogate HF patients (n = 403). Next, we map consequences when EF cut-off differs from 50% (as proposed for women) and analyze HF candidates not covered by current rules. RESULTS: The training set yields best results for the Support Vector Machine method (test error 4.06%), covers the gray zone, and other clinically relevant HF candidates. End-systolic volume (ESV) emerges as a logical discriminator rather than EF as in the prevailing paradigm. CONCLUSIONS: Selected ML models offer promise for classifying HF patients (including the gray zone), when driven by ventricular volume data. ML analysis indicates that ESV has a role in the development of guidelines to parse HF subtypes. The documented curvilinear relationship between EF and ESV suggests that the assumption concerning a linear EF divider may not be of general utility over the complete clinically relevant range. PMID- 26052232 TI - The Volume Regulation Graph versus the Ejection Fraction as Metrics of Left Ventricular Performance in Heart Failure with and without a Preserved Ejection Fraction: A Mathematical Model Study. AB - In left ventricular heart failure, often a distinction is made between patients with a reduced and a preserved ejection fraction (EF). As EF is a composite metric of both the end-diastolic volume (EDV) and the end-systolic ventricular volume (ESV), the lucidity of the EF is sometimes questioned. As an alternative, the ESV-EDV graph is advocated. This study identifies the dependence of the EF and the EDV-ESV graph on the major determinants of ventricular performance. Numerical simulations were made using a model of the systemic circulation, consisting of an atrium-ventricle valves combination; a simple constant pressure as venous filling system; and a three-element Windkessel extended with a venous system. ESV-EDV graphs and EFs were calculated using this model while varying one by one the filling pressure, diastolic and systolic ventricular elastances, and diastolic pressure in the aorta. In conclusion, the ESV-EDV graph separates between diastolic and systolic dysfunction while the EF encompasses these two pathologies. Therefore, the ESV-EDV graph can provide an advantage over EF in heart failure studies. PMID- 26052233 TI - Reversible Cardiomyopathies. AB - Cardiomyopathies (CMs) have many etiological factors that can result in severe structural and functional dysregulation. Fortunately, there are several potentially reversible CMs that are known to improve when the root etiological factor is addressed. In this article, we discuss several of these reversible CMs, including tachycardia-induced, peripartum, inflammatory, hyperthyroidism, Takotsubo, and chronic illness-induced CMs. Our discussion also includes a review on their respective pathophysiology, as well as possible management solutions. PMID- 26052234 TI - Complications of Continuous-Flow Mechanical Circulatory Support Devices. AB - Left ventricular assist devices (LVADs), more importantly the continuous-flow subclass, have revolutionized the medical field by improving New York Heart Association (NYHA) functional class status, quality of life, and survival rates in patients with advanced systolic heart failure. From the first pulsatile device to modern day continuous-flow devices, LVADs have continued to improve, but they are still associated with several complications. These complications include infection, bleeding, thrombosis, hemolysis, aortic valvular dysfunction, right heart failure, and ventricular arrhythmias. In this article, we aim to review these complications to understand the most appropriate approach for their prevention and to discuss the available therapeutic modalities. PMID- 26052235 TI - Percutaneous Mechanical Support in Cardiogenic Shock: A Review. AB - Cardiogenic shock (CS) is a life-threatening condition associated with significant morbidity and mortality. Pharmacological therapy is often the first line of treatment but mechanical support can provide substantial hemodynamic improvement in refractory CS. Percutaneous mechanical support devices are placed in a minimally invasive manner and provide life-saving assistance to the failing myocardium. We review the percutaneous devices currently available, the evidence behind their use, and the new advances in percutaneous technology being evaluated for the treatment of CS. PMID- 26052236 TI - Review of the millipede genus Eutrichodesmus Silvestri, 1910, in China, with descriptions of new cavernicolous species (Diplopoda, Polydesmida, Haplodesmidae). AB - The Eutrichodesmus fauna of mainland China, by far the largest genus in the Indo Australian family Haplodesmidae, is reviewed and shown to encompass 23 species (of a total of 45), all keyed. The following nine new species, all presumed troglobites, are described: Eutrichodesmustriangularis sp. n., from Sichuan, Eutrichodesmuslipsae sp. n., from Guangxi, Eutrichodesmustenuis sp. n., Eutrichodesmustrontelji sp. n., Eutrichodesmuslatellai sp. n., Eutrichodesmusobliteratus sp. n. and Eutrichodesmustroglobius sp. n., all from Guizhou, Eutrichodesmussketi sp. n., from Hunan, and Eutrichodesmusapicalis sp. n., from Hubei. PMID- 26052237 TI - Corophiine amphipods of the genera Chelicorophium and Paracorophium from the lower Gulf of Thailand (Crustacea, Amphipoda, Corophiidae, Corophiinae). AB - Two species of corophiine amphipods from Songkhla Lake, in the lower Gulf of Thailand, are described and illustrated. Chelicorophiummadrasensis (Nayar, 1950), found in the mangrove forest, has not previously been observed in Thai waters. Paracorophiumangsupanichae sp. n. is characterized by its chelate male gnathopod 2, obtuse palm with subrectangular distomedial elevation, and urosomites 1-3 free. This is the first record of the genus Chelicorophium and Paracorophium in Thai waters. All specimens are deposited in the Princess Maha Chakri Sirindhorn Natural History Museum, Prince of Songkla University, Thailand and the Museum fur Naturkunde, Berlin. PMID- 26052238 TI - New synonyms of two Arabian ants of the genus Monomorium Mayr, 1855 (Hymenoptera, Formicidae). AB - Synonymy of two Arabian Monomorium Mayr, 1855 species is proposed: Monomoriumexiguum Forel, 1894 = Monomoriumdesertorum Collingwood & Agosti, 1996, syn. n.; Monomoriumsubopacum Smith, 1858 = Monomoriummintiribe Collingwood & Agosti, 1996, syn. n. A lectotype for Monomoriumvenustum Smith, 1858 is designated. Information on nesting habits of Monomoriumexiguum and Monomoriumvenustum in the Kingdom of Saudi Arabia are provided for the first time. Recently collected records for Monomoriumexiguum, Monomoriumsubopacum, and Monomoriumvenustum from the Kingdom of Saudi Arabia and United Arab Emirates are listed. PMID- 26052239 TI - Redescription of Crematogastercypria Santschi, 1930, new status, with description of two new related species from Greece and Turkey (Hymenoptera, Formicidae). AB - Crematogaster (Crematogaster) jehovaevar.cypria Santschi, 1930 is raised to species rank. Two new, related species are described from the north-eastern part of the Mediterranean Basin: Crematogaster (Crematogaster) erectepilosasp. n. (Dodecanese, Greece) and Crematogaster (Crematogaster) gullukdagensissp. n. (Antalya Prov., Turkey). These three species are well distinguished from other species of the subgenus Crematogaster of the north-eastern part of the Mediterranean Basin in their first gastral tergite bearing numerous erect setae. Colour photographs of all taxa are provided, a key to the species of Crematogastercypria group and species groups of the Crematogaster s. str. from the north-eastern Mediterranean region are given and a list of Crematogaster s. str. described from this region is provided (see Appendix). PMID- 26052240 TI - Redescription of Chrysoctonus and description of Chrysoctonoides (Hymenoptera, Mymaridae), a new genus from the Australian Region. AB - Chrysoctonoideslongisetosa Huber & Triapitsyn (Hymenoptera: Mymaridae), gen. n. and sp. n., is described from Australia. It is compared with the related genus Chrysoctonus, known from Africa and the New World. Myrmecomymar Yoshimoto, syn. n., is synonymized under Chrysoctonus Mathot and its type species is transferred to Chrysoctonus as Chrysoctonusmasneri (Yoshimoto), comb. n. PMID- 26052241 TI - New species of Triplocania Roesler (Psocodea, 'Psocoptera', Ptiloneuridae), from Brazil and Ecuador. AB - Four species of Triplocania, three with M3 simple, based on male specimens and one with forewing M3 forked, based on male and female specimens, are here described and illustrated, namely: Triplocaniabravoi sp. n. (Napo: Ecuador), Triplocaniaerwini sp. n. (Napo: Ecuador), Triplocaniatrifida sp. n. (Mato Grosso and Rondonia: Brazil) and Triplocanialamasoides sp. n. (Rondonia: Brazil). They differ from all the other species in the genus, in which the males are known, by the hypandrium and phallosome structures. The female is first described for the M3 forked group. The identification key for males of the M3 forked group is updated. PMID- 26052242 TI - Review of the West Indian genus Monotalla Bechyne (Coleoptera, Chrysomelidae, Galerucinae, Alticini) with description of five new species. AB - The West Indian genus Monotalla Bechyne is reviewed, redescribed and illustrated. Five new species are added: Monotalladominica sp. n. (Dominica); Monotallalecticofolia sp. n. (St. Lucia); Monotallamaierae sp. n. (St. Lucia); Monotallaobrienorum sp. n. (Grenada); and Monotallaviridis sp. n. (St. Lucia). A key to Monotalla species is provided. PMID- 26052243 TI - Availability of eleven species names of Eupelmus (Hymenoptera, Eupelmidae) proposed in Al khatib et al. (2014). AB - This paper is an addendum for the availability of the names of 11 new species proposed in Al khatib et al. (2014). PMID- 26052244 TI - A new species and additional records of Rugilus Leach from Qinling, China (Coleoptera, Staphylinidae, Paederinae). AB - A new species of Rugilus Leach, Rugilus (Rugilus) huanghaoisp. n. from Qinling, Shaanxi Province, China, is described and illustrated. Additional records of seven species from Qinling are reported. PMID- 26052245 TI - Computing a ranking network with confidence bounds from a graph-based Beta random field. AB - We address two largely overlooked, fundamental issues in computing a ranking hierarchy within a society: which information in the network is relevant, and what effect chance has on the hierarchy. To properly account for uncertainty from limited data, we construct a random field in a matrix form having entry-wise posterior Beta distributions based on a graph of pairwise conflict outcomes. To evaluate relevant network information using information transitivity, another random matrix of synthesized transitive dominance odds is computed collectively along observed dominance paths. These two matrices are coupled together to fuse both direct and indirect dominance information. An ensemble of realizations of this fused random matrix facilitates an ensemble of optimal ranking networks by means of simulated annealing. Conditional statistical inferences regarding network features are derived, manifesting the effect of uncertainty. Our computational approach is suitable for large graphs of pairwise conflict outcomes, and can accommodate tremendous data heterogeneity-a typical feature in such studies. We also demonstrate the infeasibility of the classical maximum likelihood approach, and expose the mechanistic flaws that stem from completely ignoring relevant information residing in the graph. We analyse two real datasets of decisive conflict outcomes, the first involving college football teams, and the second involving an adult rhesus macaque society in captivity. PMID- 26052246 TI - COVARIATE DECOMPOSITION METHODS FOR LONGITUDINAL MISSING-AT-RANDOM DATA AND PREDICTORS ASSOCIATED WITH SUBJECT-SPECIFIC EFFECTS. AB - Investigators often gather longitudinal data to assess changes in responses over time within subjects and to relate these changes to within-subject changes in predictors. Missing data are common in such studies and predictors can be correlated with subject-specific effects. Maximum likelihood methods for generalized linear mixed models provide consistent estimates when the data are 'missing at random' (MAR) but can produce inconsistent estimates in settings where the random effects are correlated with one of the predictors. On the other hand, conditional maximum likelihood methods (and closely related maximum likelihood methods that partition covariates into between- and within-cluster components) provide consistent estimation when random effects are correlated with predictors but can produce inconsistent covariate effect estimates when data are MAR. Using theory, simulation studies, and fits to example data this paper shows that decomposition methods using complete covariate information produce consistent estimates. In some practical cases these methods, that ostensibly require complete covariate information, actually only involve the observed covariates. These results offer an easy-to-use approach to simultaneously protect against bias from both cluster-level confounding and MAR missingness in assessments of change. PMID- 26052247 TI - Development of maizeSNP3072, a high-throughput compatible SNP array, for DNA fingerprinting identification of Chinese maize varieties. AB - Single nucleotide polymorphisms (SNPs) are abundant and evenly distributed throughout the maize (Zea mays L.) genome. SNPs have several advantages over simple sequence repeats, such as ease of data comparison and integration, high throughput processing of loci, and identification of associated phenotypes. SNPs are thus ideal for DNA fingerprinting, genetic diversity analysis, and marker assisted breeding. Here, we developed a high-throughput and compatible SNP array, maizeSNP3072, containing 3072 SNPs developed from the maizeSNP50 array. To improve genotyping efficiency, a high-quality cluster file, maizeSNP3072_GT.egt, was constructed. All 3072 SNP loci were localized within different genes, where they were distributed in exons (43 %), promoters (21 %), 3' untranslated regions (UTRs; 22 %), 5' UTRs (9 %), and introns (5 %). The average genotyping failure rate using these SNPs was only 6 %, or 3 % using the cluster file to call genotypes. The genotype consistency of repeat sample analysis on Illumina GoldenGate versus Infinium platforms exceeded 96.4 %. The minor allele frequency (MAF) of the SNPs averaged 0.37 based on data from 309 inbred lines. The 3072 SNPs were highly effective for distinguishing among 276 examined hybrids. Comparative analysis using Chinese varieties revealed that the 3072SNP array showed a better marker success rate and higher average MAF values, evaluation scores, and variety-distinguishing efficiency than the maizeSNP50K array. The maizeSNP3072 array thus can be successfully used in DNA fingerprinting identification of Chinese maize varieties and shows potential as a useful tool for germplasm resource evaluation and molecular marker-assisted breeding. PMID- 26052248 TI - Attitudes on marriage and new relationships: Cross-national evidence on the deinstitutionalization of marriage. AB - BACKGROUND: Consistent with the deinstitutionalization-of-marriage thesis, studies report a decline in support for marital conventions and increased approval of other relationship types. Generalizations are limited by the lack of cross-national research for a broad domain of attitudes on marriage and alternative arrangements, and by the lack of consensus on what counts as evidence. OBJECTIVE: Acknowledging the conceptual distinction between expectations for behavior inside and outside marriage, we address the deinstitutionalization debate by testing whether support for marital conventions has declined for a range of attitudes across countries. METHODS: Based on eleven International Social Survey Program items replicated between the late 1980s and the 2000s, OLS regressions evaluate attitude changes in up to 21 countries. RESULTS: Consistent with the deinstitutionalization argument, disapproval declined for marital alternatives (cohabitation, unmarried parents, premarital and same-sex sex). For attitudes on the behavior of married people and the nature of marriage the results are mixed: despite a shift away from gender specialization, disapproval of extramarital sex increased over time. On most items, most countries changed as predicted by the deinstitutionalization thesis. CONCLUSIONS: Attitude changes on 'new relationships' and marital alternatives are compatible with the deinstitutionalization of marriage. Beliefs arguably more central to the marital institution do not conform as neatly to this thesis. Because results are sensitive to the indicators used, the deinstitutionalization of marriage argument merits greater empirical and conceptual attention. PMID- 26052249 TI - Shotgun lipidomic analysis of chemically sulfated sterols compromises analytical sensitivity: Recommendation for large-scale global lipidome analysis. PMID- 26052250 TI - Impact of add-on laboratory testing at an academic medical center: a five year retrospective study. AB - BACKGROUND: Clinical laboratories frequently receive orders to perform additional tests on existing specimens ('add-ons'). Previous studies have examined add-on ordering patterns over short periods of time. The objective of this study was to analyze add-on ordering patterns over an extended time period. We also analyzed the impact of a robotic specimen archival/retrieval system on add-on testing procedure and manual effort. METHODS: In this retrospective study at an academic medical center, electronic health records from were searched to obtain all add-on orders that were placed in the time period of May 2, 2009 to December 31, 2014. RESULTS: During the time period of retrospective study, 880,359 add-on tests were ordered on 96,244 different patients. Add-on testing comprised 3.3 % of total test volumes. There were 443,411 unique ordering instances, leading to an average of 1.99 add-on tests per instance. Some patients had multiple episodes of add-on test orders at different points in time, leading to an average of 9.15 add-on tests per patient. The majority of add-on orders were for chemistry tests (78.8 % of total add-ons) with the next most frequent being hematology and coagulation tests (11.2 % of total add-ons). Inpatient orders accounted for 66.8 % of total add-on orders, while the emergency department and outpatient clinics had 14.8 % and 18.4 % of total add-on orders, respectively. The majority of add-ons were placed within 8 hours (87.3 %) and nearly all by 24 hours (96.8 %). Nearly 100 % of add-on orders within the emergency department were placed within 8 hours. The introduction of a robotic specimen archival/retrieval unit saved an average of 2.75 minutes of laboratory staff manual time per unique add-on order. This translates to 24.1 hours/day less manual effort in dealing with add-on orders. CONCLUSION: Our study reflects the previous literature in showing that add-on orders significantly impact the workload of the clinical laboratory. The majority of add-on orders are clinical chemistry tests, and most add-on orders occur within 24 hours of original specimen collection. Robotic specimen archival/retrieval units can reduce manual effort in the clinical laboratory associated with add-on orders. PMID- 26052251 TI - Expression of long non-coding RNA DLX6-AS1 in lung adenocarcinoma. AB - BACKGROUND: Lung adenocarcinoma (LAC), the primary histological type of non-small cell lung cancer (NSCLC), has displayed an increasing incidence and mortality worldwide. However, therapeutic approaches were limited. Dysregulation of some lncRNAs has been shown in various types of cancers including LAC. The aim of the present study was to vertify lncRNA DLX6-AS1 expression in LAC. METHODS: Microarray assay revealed expression profile of lncRNAs in LAC. qRT-PCR ( quantitative reverse transcription PCR) was performed to identify lncRNA DLX6-AS1 expression level in 72 paired LAC and adjacent normal lung tissues. qRT-PCR and Western blotting were used to verify that down-regulation lncRNA DLX6-AS1 decreased DLX6 (distal-less homeobox 6) mRNA and protein expression. RESULTS: Microarray analysis identified up-regulation of 272 lncRNAs and down-regulation of 635 lncRNAs in LAC tissues. The expression level of lncRNA DLX6-AS1 in LAC tissues was significantly higher compared to paired adjacent normal lung tissues (P< 0.05). In addition, its expression level was closed correlated with both histological differentiation (P = 0.004) and TNM stage (P = 0.033). qRT-PCR and Western blotting analysis showed that DLX6 mRNA and protein levels were lower in si-LncRNA group than in the NC (negative control) and Blank groups. CONCLUSIONS: Microarray analysis identified that lncRNA DLX6-AS1 was up-regulated in LAC tissues. High DLX6-AS1 expression levels were significantly associated with both histological differentiation and TNM stage. Down-regulation of lncRNA DLX6-AS1 expression decreased the DLX6 mRNA and protein levels. PMID- 26052252 TI - Knockdown of WAVE3 impairs HGF induced migration and invasion of prostate cancer cells. AB - BACKGROUND: The WASP (Wiskott-Aldrich syndrome protein) and WAVE (WASP Verpolin homologous) family of proteins are structurally related and responsible for regulation of actin polymerization through their interaction with actin related proteins 2&3 (ARP 2/3). WAVE-3 has exhibited an association with disease progression and poorer prognosis of certain malignancies. In the current study, we determined the role of WAVE-3 in hepatocyte growth factor induced cellular changes including cell matrix interaction, invasion and cellular motility, and pathways that may be responsible for the changes in prostate cancer cells. METHODS: We used hammer head ribozymes to knock down the expression of WAVE-3 in PC-3 prostate cancer cell line. In vitro cellular functional assays including growth, invasion, adhesion, motility and invasion, were performed to assess the effects of WAVE-3 knock down. Further experimentation was performed to investigate the role of different pathway through expression and phosphorylation status of various intermediate proteins. RESULTS: WAVE-3 knockdown reduced invasive potential and motility of prostate cancer cells. Following addition of HGF, control cells showed significantly increased invasion and motility (p value <0.5) and marked increase in cellular growth. However, WAVE-3 knockdown cell line failed to show any increase in these trends (p value <0.5) except increased growth compared with control cells. Further experiments revealed that HGF-induced activation of Paxillin was weakened by the knockdown of WAVE-3. Our study also indicated that reduced invasiveness following WAVE-3 knockdown, may be related to reduce activity of MMP-2. CONCLUSIONS: Our studies suggest a vital role of WAVE-3 in HGF induced invasion and migration in which Paxillin and MMP-2 are involved. Further study will shed light on its potential as therapeutic target to suppress local invasion and metastasis of prostate cancer cells. PMID- 26052253 TI - Suramin inhibits cell proliferation in ovarian and cervical cancer by downregulating heparanase expression. AB - BACKGROUND: Aberrant expression of heparanase (Hpa) is associated with apoor prognosis in ovarian and cervical cancer patients. Inhibitors of Hpa can prevent the growth and metastasis of malignant tumor cells, and suramin may be such a compound that has strong anti-proliferative effects on several kinds of cancer cells. We have therefore tested whether the growth inhibiting effect of suramin on ovarian and cervical cancer cells is due to downregulation of Hpa expression. RESULTS: Suramin at 300-600 MUg/ml significantly inhibited HO-8910 PM and HeLa cell growth at 24 h, in both a time-dependent and dose-dependent manner, with an IC50 of 320 MUg/ml and 475 MUg/ml, respectively. Suramin at 300 MUg/ml significantly decreased the expression of Hpa mRNA (P < 0.005) and protein (P < 0.005) in both HO-8910 PM and HeLa cells at 48 h. CONCLUSIONS: The inhibitory effect of suramin on Hpa enzyme may be due to downregulating of its expression in cancer cells. These findings confirm the importance of Hpa in tumor growth and the potential clinical application of Hpa inhibitors in the treatment of ovarian and cervical cancer. PMID- 26052254 TI - What do infants see in faces? ERP evidence of different roles of eyes and mouth for face perception in 9-month-old infants. AB - The study examined whether face-specific perceptual brain mechanisms in 9-month old infants are differentially sensitive to changes in individual facial features (eyes vs. mouth) and whether sensitivity to such changes is related to infants' social and communicative skills. Infants viewed photographs of a smiling unfamiliar female face. On 30% of the trials, either the eyes or the mouth of that face were replaced by corresponding parts from a different female. Visual event-related potentials (ERPs) were recorded to examine face-sensitive brain responses. Results revealed that increased competence in expressive communication and interpersonal relationships was associated with a more mature response to faces, as reflected in a larger occipito-temporal N290 with shorter latency. Both eye and mouth changes were detected, though infants derived different information from these features. Eye changes had a greater impact on the face perception mechanisms and were not correlated with social or communication development, whereas mouth changes had a minimal impact on face processing but were associated with levels of language and communication understanding. PMID- 26052255 TI - The Effect of Biofeedback as a Psychological Intervention in Multiple Sclerosis: A Randomized Controlled Study. AB - BACKGROUND: Relaxation, mindfulness, social support, and education (RMSSE) have been shown to improve emotional symptoms, coping, and fatigue in multiple sclerosis (MS). Biofeedback was trialed as a psychological intervention, designed to improve self-control, in two groups of patients with MS. Both groups received RMSSE, and one group additionally received biofeedback. METHODS: Forty people with relapsing-remitting MS were recruited from three sites in Sydney, Australia. The mean disability score (Expanded Disability Status Scale; EDSS) was 2.41 +/- 1.46 (95% confidence interval [CI], 1.46-3.36); the mean age in years was 45.9 +/ 12.42 (95% CI, 41.92-49.87). Participants were randomly assigned to two active treatment groups (n = 20 per group). All participants received one 1-hour session per week for 3 weeks of RMSSE, while biofeedback equipment measured breathing rate and muscle tension. Members of one group used biofeedback screens to regulate physiological response. RESULTS: Whole-group pre- and post-treatment scores demonstrated a reduction of 38% for anxiety and 39% for depression scores (P = .007 and P = .009, respectively). A post-treatment comparison failed to demonstrate any significant difference between the two active treatment groups in anxiety and depression scores. The biofeedback group showed significant pre- to post-treatment improvement or trends toward improvement in anxiety, fatigue, and stress (P = .05, .02, and .03, respectively). Comparison of pre-post treatment results between groups showed improvements for the biofeedback group in breathing rate and muscle tension (P = .06 and .09). CONCLUSIONS: For relapsing-remitting MS patients receiving biofeedback in addition to RMSSE, there was a demonstrable reduction in anxiety, fatigue, and stress. There was also a trend toward significant reduction of breathing rate and muscle tension in favor of biofeedback. PMID- 26052256 TI - Perspectives on Physical Activity Among People with Multiple Sclerosis Who Are Wheelchair Users: Informing the Design of Future Interventions. AB - BACKGROUND: People with advanced multiple sclerosis (MS) are less physically active than those with milder forms of the disease, and wheelchair use has a negative association with physical activity participation. Thus, wheelchair users with MS are doubly disadvantaged for accruing the benefits of physical activity and exercise. Appropriate physical activity and exercise interventions are needed for this population. METHODS: We undertook a qualitative study to explore the meanings, motivations, and outcomes of physical activity in wheelchair users with MS. We sought to understand daily opportunities to accumulate physical activity and exercise, and to identify perceived barriers, facilitators, and benefits that might inform the design of future interventions. RESULTS: We interviewed 15 wheelchair users (mean age, 52 +/- 8.8 years; n = 12 women). Data were transcribed and analyzed to identify and explore common themes. Our first theme was the reduced opportunity to participate in physical activity due to participants' dependence on mobility devices, environmental adaptations, and tangible support. Our second theme was the importance of incorporating physical activity and exercise into the everyday environment, highlighting the need for adaptive exercise and accessible environments. This indicated the need to incorporate behavior change modulators into physical activity and exercise interventions for those with advanced MS. Health-care professionals played an important role in promoting increased physical activity and exercise participation in those with advanced MS. CONCLUSIONS: Our findings may inform future interventions to increase initiation and maintenance of physical activity and exercise among people with advanced MS. PMID- 26052257 TI - Barriers and Facilitators Related to Rehabilitation Stays in Multiple Sclerosis: A Qualitative Study. AB - BACKGROUND: Studies have shown the positive effects of multidisciplinary rehabilitation on disability and health-related quality of life in multiple sclerosis (MS). However, many patients do not seek such treatment, even if it is available free of charge. The aim of this study was to identify facilitators and barriers related to use of such treatment options. METHODS: Five focus group interviews with 27 MS patients were conducted. Three groups included patients who had been admitted to a multidisciplinary MS rehabilitation institution, and two groups included outpatients of a university hospital who had not applied for specialized rehabilitation. Interviews were audiotaped and transcribed, and were analyzed qualitatively by means of a modified form of systematic text condensation. RESULTS: Important factors influencing the use of an MS rehabilitation service were 1) the availability and suitability of initial information about the disease and the service, 2) assumptions and expectations about such a service, and 3) practical barriers in the patient's life. The prospect of having a retreat from work and family was described as a motivational factor. Lack of reorientation after diagnosis, fears and perceptions of being labeled as an MS patient, or having information overload and being confronted with disabled individuals were identified as barriers. CONCLUSIONS: Communication skills, including information-giving skills, of neurologists in relation to newly diagnosed MS patients need improvement. Rehabilitation programs for MS patients should include stays of different durations and purposes to fit patients' needs. Health-care authorities should take measures to secure equal access to information about rehabilitation options across institutions and practicing physicians. PMID- 26052258 TI - Managing Neuropsychological Impairment in Multiple Sclerosis: Pilot Study on a Standardized Metacognitive Intervention. AB - BACKGROUND: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system of potential autoimmune origin that is frequently associated with psychological disorders and cognitive deficits, as well as with fatigue, stress, and psychosocial burden. These factors often cause decreased quality of life, social withdrawal, and unemployment. We describe the development of a cognitive-behavioral group intervention based on the concept of metacognition and evaluation of the feasibility and acceptance of the program as a rehabilitation tool. METHODS: Metacognitive Training in MS (MaTiMS) consists of six modules, each 90 minutes in duration. We tested acceptance and design of the program in six focus groups (entire sample, n = 27). Framework analysis of transcripts was used to identify key topics and categories. Program modules were revised in accordance with appropriate recommendations of focus group members. We subsequently evaluated MaTiMS in two groups (n = 5, n = 6) in a rehabilitation center. Neuropsychological functioning as well as coping self-efficacy, depression, stress, perceived cognitive deficit, fatigue, and quality of life were assessed. Acceptance of MaTiMS from the patient perspective was also studied. RESULTS: The modules were highly accepted by patients. Pre-post assessments showed significant improvements in the Coping Self Efficacy Scale (P = .007), the Wurzburger Fatigue Inventory for MS Score (P = .028), and the Hamburg Quality of Life Questionnaire in Multiple Sclerosis Mood subscale (P = .046). CONCLUSIONS: These preliminary results suggest that MaTiMS represents a feasible psychological group training program that may foster improvements in self-efficacy, fatigue, and mood. The next step will be an evaluation of the program in a randomized controlled trial. PMID- 26052259 TI - Evaluation of Dalfampridine Extended Release 5 and 10 mg in Multiple Sclerosis: A Randomized Controlled Trial. AB - BACKGROUND: Dalfampridine extended-release (ER) tablets, 10 mg twice daily, have been shown to improve walking in people with multiple sclerosis. We evaluated the safety and efficacy of dalfampridine-ER 5 mg compared with 10 mg. METHODS: Patients were randomized to double-blind treatment with twice-daily dalfampridine ER tablets, 5 mg (n = 144) or 10 mg (n = 143), or placebo (n = 143) for 4 weeks. Primary efficacy endpoint was change from baseline walking speed by the Timed 25 Foot Walk 3 to 4 hours after the last dose. At 40% of sites, 2-week change from baseline walking distance was measured by the 6-Minute Walk test. RESULTS: At 4 weeks, walking speed changes from baseline were 0.363, 0.423, and 0.478 ft/s (placebo, dalfampridine-ER 5 mg, and dalfampridine-ER 10 mg, respectively [P = NS]). Post hoc analysis of average changes between pretreatment and on-treatment showed that relative to placebo, only dalfampridine-ER 10 mg demonstrated a significant increase in walking speed (mean +/- SE): 0.443 +/- 0.042 ft/s versus 0.303 +/- 0.038 ft/s (P = .014). Improvement in 6-Minute Walk distance was significantly greater with dalfampridine-ER 10 mg (128.6 ft, P = .014) but not with 5 mg (76.8 ft, P = .308) relative to placebo (41.7 ft). Adverse events were consistent with previous studies. No seizures were reported. CONCLUSIONS: Dalfampridine-ER 5 and 10 mg twice daily did not demonstrate efficacy on the planned endpoint. Post hoc analyses demonstrated significant increases in walking speed relative to placebo with dalfampridine-ER 10 mg. No new safety signals were observed. PMID- 26052261 TI - Editorial. PMID- 26052260 TI - Association of Postural Sway with Disability Status and Cerebellar Dysfunction in People with Multiple Sclerosis: A Preliminary Study. AB - BACKGROUND: The aims of this study were 1) to examine postural sway in the eyes open (EO) and eyes closed (EC) conditions in people with multiple sclerosis (MS) with moderate levels of disability compared with controls and 2) to examine relationships between postural sway and total Expanded Disability Status Scale (EDSS) scores, functional system subscores, and clinical measures of strength and spasticity in the MS group. METHODS: Thirty-four people with moderate MS and ten matched controls completed measures of postural sway with EO and EC, knee extension and ankle dorsiflexion isometric strength, EDSS total score and subscores, and spasticity levels. RESULTS: Participants with MS swayed significantly more with EO and EC and had reduced knee extension and ankle dorsiflexion strength compared with controls (P < .001). In the MS group, increased sway was associated with higher total EDSS scores and cerebellar function subscores, whereas increased sway ratio (EC/EO) was associated with reduced sensory function subscores. Postural sway was not significantly associated with strength or spasticity. CONCLUSIONS: Participants with MS swayed more and were significantly weaker than controls. Cerebellar dysfunction was identified as the EDSS domain most strongly associated with increased sway, and sensory loss was associated with a relatively greater dependence on vision for balance control. These findings suggest that exercise interventions targeting sensory integration and cerebellar ataxia may be beneficial for enhancing balance control in people with MS. PMID- 26052262 TI - Marketing, Technology, and Medicine: Recommendations on How to Incorporate Psychological Principles into New Technologies to Promote Healthy Behaviors. AB - Although technologies have provided new forms of entertainment and improved our work efficiency, they have also reduced our need to engage in healthy physical activities. We believe that the psychological principles that make sedentary entertainment technologies (such as television and video games) engaging can be incorporated into new technologies to make new technologies both engaging and promote healthy behaviors. This short report aims to 1) describe how technology has traditionally reduced motivation to engage in health behaviors, 2) discuss key elements that may make sedentary technology (in this case, television) engaging, and 3) provide examples of how these same elements can be incorporated into new technologies to increase engagement and promote health behaviors. PMID- 26052264 TI - Information Age: Do Urban African American Youth Find Sexual Health Information Online? PMID- 26052263 TI - Physics-Based Potentials for Coarse-Grained Modeling of Protein-DNA Interactions. AB - Physics-based potentials have been developed for the interactions between proteins and DNA for simulations with the UNRES + NARES-2P force field. The mean field interactions between a protein and a DNA molecule can be divided into eight categories: (1) nonpolar side chain-DNA base, (2) polar uncharged side chain-DNA base, (3) charged side chain-DNA base, (4) peptide group-phosphate group, (5) peptide group-DNA base, (6) nonpolar side chain-phosphate group, (7) polar uncharged side chain-phosphate group, and (8) charged side chain-phosphate group. Umbrella-sampling molecular dynamics simulations in explicit TIP3P water using the AMBER force field were carried out to determine the potentials of mean force (PMF) for all 105 pairs of interacting components. Approximate analytical expressions for the mean-field interaction energy of each pair of the different kinds of interacting molecules were then fitted to the PMFs to obtain the parameters of the analytical expressions. These analytical expressions can reproduce satisfactorily the PMF curves corresponding to different orientations of the interacting molecules. The results suggest that the physics-based mean field potentials of amino acid-nucleotide interactions presented here can be used in coarse-grained simulation of protein-DNA interactions. PMID- 26052265 TI - Time dependency of craving and response inhibition during nicotine abstinence. AB - BACKGROUND: Nicotine withdrawal produces increased craving for cigarettes and deficits in response inhibition, and these withdrawal symptoms are predictive of relapse. Although it is well-established that these symptoms emerge early during abstinence, there is mixed evidence regarding whether they occur simultaneously. Given the importance of the early withdrawal period, this study examined craving and response inhibition at 24h and 72h abstinence. METHODS: Twenty-one non treatment seeking adult smokers were evaluated at baseline, 24h, and 72h abstinence for craving (Questionnaire on Smoking Urges - Brief) and response inhibition (Stop Signal Task, Stroop Task, Continuous Performance Task). Generalized linear regression models were used for primary outcomes, and Pearson correlations for examining the association between craving and response inhibition. RESULTS: Factor 2 craving (anticipated relief of negative affect) increased from baseline to 24h abstinent (p=0.004), which subsided by 72h (p=0.08). Deficits in response inhibition measured by the Stop Signal Task were observed at 72h (p=0.046), but not 24h (p=0.318). No correlation was found between response inhibition and craving at any time point (p-values>0.19), except between the Stroop Task and factor 1 craving at baseline (p=0.025). CONCLUSIONS: Factor 2 craving peaked at 24h, whereas deficits in response inhibition did not emerge until 72h, indicating that need to target craving and cognitive function during early abstinence may not occur simultaneously. Further characterizing the time course of withdrawal symptoms may guide development of targeted treatments for smoking cessation. PMID- 26052266 TI - Genotype-phenotype correlation in neuronal migration disorders and cortical dysplasias. AB - Neuronal migration disorders are human (or animal) diseases that result from a disruption in the normal movement of neurons from their original birth site to their final destination during early development. As a consequence, the neurons remain somewhere along their migratory route, their location depending on the pathological mechanism and its severity. The neurons form characteristic abnormalities, which are morphologically classified into several types, such as lissencephaly, heterotopia, and cobblestone dysplasia. Polymicrogyria is classified as a group of malformations that appear secondary to post-migration development; however, recent findings of the underlying molecular mechanisms reveal overlapping processes in the neuronal migration and post-migration development stages. Mutations of many genes are involved in neuronal migration disorders, such as LIS1 and DCX in classical lissencephaly spectrum, TUBA1A in microlissencephaly with agenesis of the corpus callosum, and RELN and VLDLR in lissencephaly with cerebellar hypoplasia. ARX is of particular interest from basic and clinical perspectives because it is critically involved in tangential migration of GABAergic interneurons in the forebrain and its mutations cause a variety of phenotypes ranging from hydranencephaly or lissencephaly to early onset epileptic encephalopathies, including Ohtahara syndrome and infantile spasms or intellectual disability with no brain malformations. The recent advances in gene and genome analysis technologies will enable the genetic basis of neuronal migration disorders to be unraveled, which, in turn, will facilitate genotype-phenotype correlations to be determined. PMID- 26052267 TI - The Maze of APP Processing in Alzheimer's Disease: Where Did We Go Wrong in Reasoning? AB - Why has Alzheimer's disease (AD) remained a conundrum today? The main reason is the stagnation in understanding the origins of plaques and tangles. While they are widely thought to be the products of the "aberrant" pathways, we believe that plaques and tangles result from natural aging. From this new perspective, we have proposed that age-related inefficiency of alpha-secretase is the underpinning for Abeta overproduction. This view contrasts sharply with the current doctrine that Abeta overproduction is the product of the "overactivated" beta- and gamma secretases. Following this doctrine, it has been claimed that the two secretases are "positively identified" and that their inhibitors have "successfully reduced Abeta levels." But, why have these studies not led to the understanding of AD or successful clinical trials? And if so, where did they go off course in reasoning? These questions may touch the basics of biological science and must be answered. In this paper, I dissected several prevailing assumptions and some influential reports with an attempt to trace the origins of the conundrum. This work led me to an original model for Abeta overproduction and also to a serious question: given the universal knowledge that boosting alpha-secretase reduces Abeta, a straightforward highway for intervention, then why is there such an obsession on "inhibiting beta- and gamma-secretases," a much more costly and twisting road even if possible? This issue requires the attention of policymakers and all researchers. I therefore call for a game change in AD study. PMID- 26052268 TI - Early transcriptional response to aminoglycoside antibiotic suggests alternate pathways leading to apoptosis in sensory hair cells in the mouse inner ear. AB - Aminoglycoside antibiotics are "the drug of choice" for treating many bacterial infections, but their administration results in hearing loss in up to one fourth of the patients who receive them. Several biochemical pathways have been implicated in aminoglycoside antibiotic ototoxicity; however, little is known about how hair cells respond to aminoglycoside antibiotics at the transcriptome level. Here we have investigated the genome-wide response to the aminoglycoside antibiotic gentamicin. Using organotypic cultures of the perinatal organ of Corti, we performed RNA sequencing using cDNA libraries obtained from FACS purified hair cells. Within 3 h of gentamicin treatment, the messenger RNA level of more than three thousand genes in hair cells changed significantly. Bioinformatic analysis of these changes highlighted several known signal transduction pathways, including the JNK pathway and the NF-kappaB pathway, in addition to genes involved in the stress response, apoptosis, cell cycle control, and DNA damage repair. In contrast, only 698 genes, mainly involved in cell cycle and metabolite biosynthetic processes, were significantly affected in the non hair cell population. The gene expression profiles of hair cells in response to gentamicin share a considerable similarity with those previously observed in gentamicin-induced nephrotoxicity. Our findings suggest that previously observed early responses to gentamicin in hair cells in specific signaling pathways are reflected in changes in gene expression. Additionally, the observed changes in gene expression of cell cycle regulatory genes indicate a disruption of the postmitotic state, which may suggest an alternate pathway regulating gentamicin induced apoptotic hair cell death. This work provides a more comprehensive view of aminoglycoside antibiotic ototoxicity, and thus contributes to identifying potential pathways or therapeutic targets to alleviate this important side effect of aminoglycoside antibiotics. PMID- 26052270 TI - Functional dissection of synaptic circuits: in vivo patch-clamp recording in neuroscience. AB - Neuronal activity is dominated by synaptic inputs from excitatory or inhibitory neural circuits. With the development of in vivo patch-clamp recording, especially in vivo voltage-clamp recording, researchers can not only directly measure neuronal activity, such as spiking responses or membrane potential dynamics, but also quantify synaptic inputs from excitatory and inhibitory circuits in living animals. This approach enables researchers to directly unravel different synaptic components and to understand their underlying roles in particular brain functions. Combining in vivo patch-clamp recording with other techniques, such as two-photon imaging or optogenetics, can provide even clearer functional dissection of the synaptic contributions of different neurons or nuclei. Here, we summarized current applications and recent research progress using the in vivo patch-clamp recording method and focused on its role in the functional dissection of different synaptic inputs. The key factors of a successful in vivo patch-clamp experiment and possible solutions based on references and our experiences were also discussed. PMID- 26052269 TI - Advances in imaging ultrastructure yield new insights into presynaptic biology. AB - Synapses are the fundamental functional units of neural circuits, and their dysregulation has been implicated in diverse neurological disorders. At presynaptic terminals, neurotransmitter-filled synaptic vesicles are released in response to calcium influx through voltage-gated calcium channels activated by the arrival of an action potential. Decades of electrophysiological, biochemical, and genetic studies have contributed to a growing understanding of presynaptic biology. Imaging studies are yielding new insights into how synapses are organized to carry out their critical functions. The development of techniques for rapid immobilization and preservation of neuronal tissues for electron microscopy (EM) has led to a new renaissance in ultrastructural imaging that is rapidly advancing our understanding of synapse structure and function. PMID- 26052272 TI - New neurons from old beliefs in the adult piriform cortex? A Commentary on: "Occurrence of new neurons in the piriform cortex". PMID- 26052271 TI - FIB/SEM technology and high-throughput 3D reconstruction of dendritic spines and synapses in GFP-labeled adult-generated neurons. AB - The fine analysis of synaptic contacts is usually performed using transmission electron microscopy (TEM) and its combination with neuronal labeling techniques. However, the complex 3D architecture of neuronal samples calls for their reconstruction from serial sections. Here we show that focused ion beam/scanning electron microscopy (FIB/SEM) allows efficient, complete, and automatic 3D reconstruction of identified dendrites, including their spines and synapses, from GFP/DAB-labeled neurons, with a resolution comparable to that of TEM. We applied this technology to analyze the synaptogenesis of labeled adult-generated granule cells (GCs) in mice. 3D reconstruction of dendritic spines in GCs aged 3-4 and 8 9 weeks revealed two different stages of dendritic spine development and unexpected features of synapse formation, including vacant and branched dendritic spines and presynaptic terminals establishing synapses with up to 10 dendritic spines. Given the reliability, efficiency, and high resolution of FIB/SEM technology and the wide use of DAB in conventional EM, we consider FIB/SEM fundamental for the detailed characterization of identified synaptic contacts in neurons in a high-throughput manner. PMID- 26052273 TI - Percept of the duration of a vibrotactile stimulus is altered by changing its amplitude. AB - There have been numerous studies conducted on time perception. However, very few of these have involved tactile stimuli to assess a subject's capacity for duration discrimination. Previous optical imaging studies in non-human primates demonstrated that increasing the duration of a vibrotactile stimulus resulted in a consistently longer and more well defined evoked SI cortical response. Additionally, and perhaps more interestingly, increasing the amplitude of a vibrotactile stimulus not only evoked a larger magnitude optical intrinsic signal (OIS), but the return to baseline of the evoked response was much longer in duration for larger amplitude stimuli. This led the authors to hypothesize that the magnitude of a vibrotactile stimulus could influence the perception of its duration. In order to test this hypothesis, subjects were asked to compare two sets of vibrotactile stimuli. When vibrotactile stimuli differed only in duration, subjects typically had a difference limen (DL) of approximately 13%, and this followed Weber's Law for standards between 500 and 1500 ms, as increasing the value of the standard yielded a proportional increase in DL. However, the percept of duration was impacted by variations in amplitude of the vibrotactile stimuli. Specifically, increasing the amplitude of the standard stimulus had the effect of increasing the DL, while increasing the amplitude of the test stimulus had the effect of decreasing the DL. A pilot study, conducted on individuals who were concussed, found that increasing the amplitude of the standard did not have an impact on the DL of this group of individuals. Since this effect did not parallel what was predicted from the optical imaging findings in somatosensory cortex of non-human primates, the authors suggest that this particular measure or observation could be sensitive to neuroinflammation and that neuron-glial interactions, impacted by concussion, could have the effect of ignoring, or not integrating, the increased amplitude. PMID- 26052274 TI - Morphine administration during low ovarian hormone stage results in transient over expression of fear memories in females. AB - Acute exposure to morphine after a traumatic event reduces trauma related symptoms in humans and conditioned fear expression in male rats. We aimed to determine whether acute administration of morphine alters consolidation of fear learning and extinction. Male and female rats in proestrus and metaestrus (high and low ovarian hormones respectively) underwent fear conditioning and received saline or morphine (2.5 mg/kg s.c.). The next day they underwent extinction. Results showed increased freezing during extinction only in the morphine metaestrus group while morphine did not affect males or proestrus females. Recall of extinction was similar on all groups. On a second experiment, a subset of rats conditioned during metaestrus was administered morphine prior to extinction producing no effects. We then measured mu opioid receptor (MOR) expression in the amygdala and periaqueductal gray (PAG) at the end of extinction (day 2). In males and proestrus females, morphine caused an increase in MOR in the amygdala but no in the PAG. In metaestrus females, morphine did not change MOR expression in either structure. These data suggests that ovarian hormones may interact with MORs in the amygdala to transiently alter memory consolidation. Morphine given after trauma to females with low ovarian hormones might increase the recall of fear responses, making recovery harder. PMID- 26052275 TI - Cognitive function and brain structure after recurrent mild traumatic brain injuries in young-to-middle-aged adults. AB - Recurrent mild traumatic brain injuries (mTBIs) are regarded as an independent risk factor for developing dementia in later life. We here aimed to evaluate associations between recurrent mTBIs, cognition, and gray matter volume and microstructure as revealed by structural magnetic resonance imaging (MRI) in the chronic phase after mTBIs in young adulthood. We enrolled 20 young-to-middle-aged subjects, who reported two or more sports-related mTBIs, with the last mTBI > 6 months prior to study enrolment (mTBI group), and 21 age-, sex- and education matched controls with no history of mTBI (control group). All participants received comprehensive neuropsychological testing, and high resolution T1 weighted and diffusion tensor MRI in order to assess cortical thickness (CT) and microstructure, hippocampal volume, and ventricle size. Compared to the control group, subjects of the mTBI group presented with lower CT within the right temporal lobe and left insula using an a priori region of interest approach. Higher number of mTBIs was associated with lower CT in bilateral insula, right middle temporal gyrus and right entorhinal area. Our results suggest persistent detrimental effects of recurrent mTBIs on CT already in young-to-middle-aged adults. If additional structural deterioration occurs during aging, subtle neuropsychological decline may progress to clinically overt dementia earlier than in age-matched controls, a hypothesis to be assessed in future prospective trials. PMID- 26052277 TI - Extreme Metal Music and Anger Processing. AB - The claim that listening to extreme music causes anger, and expressions of anger such as aggression and delinquency have yet to be substantiated using controlled experimental methods. In this study, 39 extreme music listeners aged 18-34 years were subjected to an anger induction, followed by random assignment to 10 min of listening to extreme music from their own playlist, or 10 min silence (control). Measures of emotion included heart rate and subjective ratings on the Positive and Negative Affect Scale (PANAS). Results showed that ratings of PANAS hostility, irritability, and stress increased during the anger induction, and decreased after the music or silence. Heart rate increased during the anger induction and was sustained (not increased) in the music condition, and decreased in the silence condition. PANAS active and inspired ratings increased during music listening, an effect that was not seen in controls. The findings indicate that extreme music did not make angry participants angrier; rather, it appeared to match their physiological arousal and result in an increase in positive emotions. Listening to extreme music may represent a healthy way of processing anger for these listeners. PMID- 26052276 TI - Toward a radically embodied neuroscience of attachment and relationships. AB - Attachment theory (Bowlby, 1969/1982) posits the existence of internal working models as a foundational feature of human bonds. Radical embodied approaches instead suggest that cognition requires no computation or representation, favoring a cognition situated in a body in an environmental context with affordances for action (Chemero, 2009; Barrett, 2011; Wilson and Golonka, 2013; Casasanto and Lupyan, 2015). We explore whether embodied approaches to social soothing, interpersonal warmth, separation distress, and support seeking could replace representational constructs such as internal working models with a view of relationship cognition anchored in the resources afforded to the individual by their brain, body, and environment in interaction. We review the neurobiological bases for social attachments and relationships and attempt to delineate how these systems overlap or don't with more basic physiological systems in ways that support or contradict a radical embodied explanation. We suggest that many effects might be the result of the fact that relationship cognition depends on and emerges out of the action of neural systems that regulate several clearly physically grounded systems. For example, the neuropeptide oxytocin appears to be central to attachment and pair-bond behavior (Carter and Keverne, 2002) and is implicated in social thermoregulation more broadly, being necessary for maintaining a warm body temperature (for a review, see IJzerman et al., 2015b). Finally, we discuss the most challenging issues around taking a radically embodied perspective on social relationships. We find the most crucial challenge in individual differences in support seeking and responses to social contact, which have long been thought to be a function of representational structures in the mind (e.g., Baldwin, 1995). Together we entertain the thought to explain such individual differences without mediating representations or computations, but in the end propose a hybrid model of radical embodiment and internal representations. PMID- 26052278 TI - The eyes test is influenced more by artistic inclination and less by sex. AB - The "Reading the Mind in the Eyes" test was developed by Baron-Cohen and his co workers. This test provides them the unique opportunity to evaluate social cognition assessing the ability to recognize the mental state of others using only the expressions around the eyes. In healthy populations, however, it has produced conflicting results, particularly regarding sex differences and number of items to use. In this study we performed two studies: The first one investigated the presence of gender effects and the sensitivity of test stimuli; the second one considered other individual factors (i.e., artistic attitude, social empathy and personality traits) that could influence the ability to understand emotions from gaze. Our results demonstrated a sex effect, which can be more or less attenuated by the nature of the stimuli. This could be as aforementioned the result of the following, empathy or artistic attitude in being proficient in understanding the mental states of others. PMID- 26052279 TI - Modeling place field activity with hierarchical slow feature analysis. AB - What are the computational laws of hippocampal activity? In this paper we argue for the slowness principle as a fundamental processing paradigm behind hippocampal place cell firing. We present six different studies from the experimental literature, performed with real-life rats, that we replicated in computer simulations. Each of the chosen studies allows rodents to develop stable place fields and then examines a distinct property of the established spatial encoding: adaptation to cue relocation and removal; directional dependent firing in the linear track and open field; and morphing and scaling the environment itself. Simulations are based on a hierarchical Slow Feature Analysis (SFA) network topped by a principal component analysis (ICA) output layer. The slowness principle is shown to account for the main findings of the presented experimental studies. The SFA network generates its responses using raw visual input only, which adds to its biological plausibility but requires experiments performed in light conditions. Future iterations of the model will thus have to incorporate additional information, such as path integration and grid cell activity, in order to be able to also replicate studies that take place during darkness. PMID- 26052280 TI - Segmental Bayesian estimation of gap-junctional and inhibitory conductance of inferior olive neurons from spike trains with complicated dynamics. AB - The inverse problem for estimating model parameters from brain spike data is an ill-posed problem because of a huge mismatch in the system complexity between the model and the brain as well as its non-stationary dynamics, and needs a stochastic approach that finds the most likely solution among many possible solutions. In the present study, we developed a segmental Bayesian method to estimate the two parameters of interest, the gap-junctional (gc ) and inhibitory conductance (gi ) from inferior olive spike data. Feature vectors were estimated for the spike data in a segment-wise fashion to compensate for the non-stationary firing dynamics. Hierarchical Bayesian estimation was conducted to estimate the gc and gi for every spike segment using a forward model constructed in the principal component analysis (PCA) space of the feature vectors, and to merge the segmental estimates into single estimates for every neuron. The segmental Bayesian estimation gave smaller fitting errors than the conventional Bayesian inference, which finds the estimates once across the entire spike data, or the minimum error method, which directly finds the closest match in the PCA space. The segmental Bayesian inference has the potential to overcome the problem of non stationary dynamics and resolve the ill-posedness of the inverse problem because of the mismatch between the model and the brain under the constraints based, and it is a useful tool to evaluate parameters of interest for neuroscience from experimental spike train data. PMID- 26052281 TI - Multisensory integration using dynamical Bayesian networks. PMID- 26052282 TI - Text mining for neuroanatomy using WhiteText with an updated corpus and a new web application. AB - We describe the WhiteText project, and its progress towards automatically extracting statements of neuroanatomical connectivity from text. We review progress to date on the three main steps of the project: recognition of brain region mentions, standardization of brain region mentions to neuroanatomical nomenclature, and connectivity statement extraction. We further describe a new version of our manually curated corpus that adds 2,111 connectivity statements from 1,828 additional abstracts. Cross-validation classification within the new corpus replicates results on our original corpus, recalling 67% of connectivity statements at 51% precision. The resulting merged corpus provides 5,208 connectivity statements that can be used to seed species-specific connectivity matrices and to better train automated techniques. Finally, we present a new web application that allows fast interactive browsing of the over 70,000 sentences indexed by the system, as a tool for accessing the data and assisting in further curation. Software and data are freely available at http://www.chibi.ubc.ca/WhiteText/. PMID- 26052283 TI - Anterior cingulate cortex mediates the relationship between O3PUFAs and executive functions in APOE e4 carriers. AB - INTRODUCTION: Although diet has a substantial influence on the aging brain, the relationship between biomarkers of diet and aspects of brain health remains unclear. This study examines the neural mechanisms that mediate the relationship between omega-3 polyunsaturated fatty acids (O3PUFAs) and executive functions in at-risk (APOE e4 carriers), cognitively intact older adults. We hypothesized that higher levels of O3PUFAs are associated with better performance in a particular component of the executive functions, namely cognitive flexibility, and that this relationship is mediated by gray matter volume of a specific region thought to be important for cognitive flexibility, the anterior cingulate cortex. METHODS: We examined 40 cognitively intact adults between the ages of 65 and 75 with the APOE e4 polymorphism to investigate the relationship between biomarkers of O3PUFAs, tests of cognitive flexibility (measured by the Delis-Kaplan Executive Function System Trail Making Test), and gray matter volume within regions of the prefrontal cortex (PFC). RESULTS: A mediation analysis revealed that gray matter volume within the left rostral anterior cingulate cortex partially mediates the relationship between O3PUFA biomarkers and cognitive flexibility. CONCLUSION: These results suggest that the anterior cingulate cortex acts as a mediator of the relationship between O3PUFAs and cognitive flexibility in cognitively intact adults thought to be at risk for cognitive decline. Through their link to executive functions and neuronal measures of PFC volume, O3PUFAs show potential as a nutritional therapy to prevent dysfunction in the aging brain. PMID- 26052285 TI - AD genetic risk factors and tau spreading. PMID- 26052284 TI - On the central role of brain connectivity in neurodegenerative disease progression. AB - Increased brain connectivity, in all its variants, is often considered an evolutionary advantage by mediating complex sensorimotor function and higher cognitive faculties. Interaction among components at all spatial scales, including genes, proteins, neurons, local neuronal circuits and macroscopic brain regions, are indispensable for such vital functions. However, a growing body of evidence suggests that, from the microscopic to the macroscopic levels, such connections might also be a conduit for in intra-brain disease spreading. For instance, cell-to-cell misfolded proteins (MP) transmission and neuronal toxicity are prominent connectivity-mediated factors in aging and neurodegeneration. This article offers an overview of connectivity dysfunctions associated with neurodegeneration, with a specific focus on how these may be central to both normal aging and the neuropathologic degenerative progression. PMID- 26052286 TI - Curcuminoids and omega-3 fatty acids with anti-oxidants potentiate cytotoxicity of natural killer cells against pancreatic ductal adenocarcinoma cells and inhibit interferon gamma production. AB - Pancreatic cancer has a poor prognosis attributed in part to immune suppression and deactivation of natural killer (NK) cells. Curcuminoids have a potential for improving the therapy of pancreatic cancer given promising results in cancer models and a clinical trial, but their oral absorption is limited. Our objective in this study is to show curcuminoid anti-oncogenic effects alone and together with human NK cells. We tested curcuminoids in an emulsion of omega-3 fatty acids and anti-oxidants ("Smartfish") regarding their direct cytocidal effect and enhancement of the cytocidal activity of NK cells in pancreatic ductal adenocarcinoma (PDAC) cells (Mia Paca 2 and L3.6). Curcuminoids (at >=10 MUM) with omega-3 fatty acids and anti-oxidants or with the lipidic mediator resolvin D1 (RvD1) (26 nM) induced high caspase-3 activity in PDAC cells. Importantly, curcuminoids with omega-3 fatty acids and anti-oxidants or with RvD1 significantly potentiated NK cell cytocidal function and protected them against degradation. In a co-culture of cancer cells with NK cells, interferon-gamma (IFN gamma) production by NK cells was not altered by omega-3 fatty acids with anti oxidants or by RvD1 but was inhibited by curcuminoids. The inhibition was not eliminated by omega-3 fatty acids or RvD1 but was relieved by removing curcuminoids after adding NK cells. In conclusion, curcuminoids with omega-3 fatty acids and anti-oxidants or with RvD1 have increased cytotoxic activity on PDAC cells alone and with NK cells. The effects of curcuminoids with omega-3 fatty acids and anti-oxidants on pancreatic cancer will be investigated in a mouse model with humanized immune system. PMID- 26052287 TI - The blood pressure sensitivity to changes in sodium intake is similar in Asians, Blacks and Whites. An analysis of 92 randomized controlled trials. AB - The purpose of the meta-analysis of randomized trials was to analyze the significance of ethnicity on the effect of sodium reduction (SR) on blood pressure (BP) by estimating the effect of SR on BP in Asians, Blacks and Whites under conditions, which were adjusted with respect to baseline BP, baseline sodium intake and quantity of SR. Relevant studies were retrieved from a pool of 167 RCTs published in the period 1973-2010 and identified in a previous Cochrane review. 9 Asian, 9 Black, and 74 White populations standardized with respect to the range of baseline blood pressure, the range of baseline sodium, duration of SR (at least 7 days) and baseline sodium intake (at maximum 250 mmol) intake were included. In the cross-sectional analysis, there was no difference in change in SBP to SR between the ethnic groups, but there was a small difference in SR induced change in DBP between Blacks and Whites (p = 0.04). The comparison of changes in SBP and DBP to SR in ethnic groups compared in identical studies showed no statistically significant differences between the groups. PMID- 26052288 TI - Spontaneous preferences and core tastes: embodied musical personality and dynamics of interaction in a pedagogical method of improvisation. PMID- 26052289 TI - Failing to get the gist of what's being said: background noise impairs higher order cognitive processing. AB - A dynamic interplay is known to exist between auditory processing and human cognition. For example, prior investigations of speech-in-noise have revealed there is more to learning than just listening: Even if all words within a spoken list are correctly heard in noise, later memory for those words is typically impoverished. These investigations supported a view that there is a "gap" between the intelligibility of speech and memory for that speech. Here, the notion was that this gap between speech intelligibility and memorability is a function of the extent to which the spoken message seizes limited immediate memory resources (e.g., Kjellberg et al., 2008). Accordingly, the more difficult the processing of the spoken message, the less resources are available for elaboration, storage, and recall of that spoken material. However, it was not previously known how increasing that difficulty affected the memory processing of semantically rich spoken material. This investigation showed that noise impairs higher levels of cognitive analysis. A variant of the Deese-Roediger-McDermott procedure that encourages semantic elaborative processes was deployed. On each trial, participants listened to a 36-item list comprising 12 words blocked by each of 3 different themes. Each of those 12 words (e.g., bed, tired, snore...) was associated with a "critical" lure theme word that was not presented (e.g., sleep). Word lists were either presented without noise or at a signal-to-noise ratio of 5 decibels upon an A-weighting. Noise reduced false recall of the critical words, and decreased the semantic clustering of recall. Theoretical and practical implications are discussed. PMID- 26052290 TI - On the evolutionary origins of differences in sexual preferences. AB - A novel explanation of the evolutionary process leading to the appearance of differences in sexual preferences is proposed. The explanation is fully general: it is not specific to any particular type of sexual preferences, nor to any species or population. It shows how different sexual preferences can appear in any large group-living population in which sexual selection is sufficiently strong in each sex. The main idea is that the lack of interest toward a member of the opposite sex may be interpreted as a signal of popularity, and thus of reproductive success. It is then boosted by the Fisher runaway process far beyond the point where it becomes costly, resulting in a generalized trait-lack of interest toward the opposite sex. If the interest diverts toward other targets then different sexual preferences emerge. This hypothesis is placed into the context of other works on different sexual preferences in animals; supporting evidence from the literature is reviewed and additional research needed to confirm or refute the hypothesis in any given species is outlined. PMID- 26052291 TI - The hand grasps the center, while the eyes saccade to the top of novel objects. AB - In the present study, we investigated whether indenting the sides of novel objects (e.g., product packaging) would influence where people grasp, and hence focus their gaze, under the assumption that gaze precedes grasping. In Experiment 1, the participants grasped a selection of custom-made objects designed to resemble typical packaging forms with an indentation in the upper, middle, or lower part. In Experiment 2, eye movements were recorded while the participants viewed differently-sized (small, medium, and large) objects with the same three indentation positions tested in Experiment 1, together with a control object lacking any indentation. The results revealed that irrespective of the location of the indentation, the participants tended to grasp the mid-region of the object, with their index finger always positioned slightly above its midpoint. Importantly, the first visual fixation tended to fall in the cap region of the novel object. The participants also fixated for longer in this region. Furthermore, participants saccaded more often, as well saccading more rapidly when directing their gaze to the upper region of the objects that they were required to inspect visually. Taken together, these results therefore suggest that different spatial locations on target objects are of interest to our eyes and hands. PMID- 26052292 TI - Symptoms of cybersex addiction can be linked to both approaching and avoiding pornographic stimuli: results from an analog sample of regular cybersex users. AB - There is no consensus regarding the phenomenology, classification, and diagnostic criteria of cybersex addiction. Some approaches point toward similarities to substance dependencies for which approach/avoidance tendencies are crucial mechanisms. Several researchers have argued that within an addiction-related decision situation, individuals might either show tendencies to approach or avoid addiction-related stimuli. In the current study 123 heterosexual males completed an Approach-Avoidance-Task (AAT; Rinck and Becker, 2007) modified with pornographic pictures. During the AAT participants either had to push pornographic stimuli away or pull them toward themselves with a joystick. Sensitivity toward sexual excitation, problematic sexual behavior, and tendencies toward cybersex addiction were assessed with questionnaires. Results showed that individuals with tendencies toward cybersex addiction tended to either approach or avoid pornographic stimuli. Additionally, moderated regression analyses revealed that individuals with high sexual excitation and problematic sexual behavior who showed high approach/avoidance tendencies, reported higher symptoms of cybersex addiction. Analogous to substance dependencies, results suggest that both approach and avoidance tendencies might play a role in cybersex addiction. Moreover, an interaction with sensitivity toward sexual excitation and problematic sexual behavior could have an accumulating effect on the severity of subjective complaints in everyday life due to cybersex use. The findings provide further empirical evidence for similarities between cybersex addiction and substance dependencies. Such similarities could be retraced to a comparable neural processing of cybersex- and drug-related cues. PMID- 26052293 TI - Initial retrieval shields against retrieval-induced forgetting. AB - Testing, as a form of retrieval, can enhance learning but it can also induce forgetting of related memories, a phenomenon known as retrieval-induced forgetting (RIF). In four experiments we explored whether selective retrieval and selective restudy of target memories induce forgetting of related memories with or without initial retrieval of the entire learning set. In Experiment 1, subjects studied category-exemplar associations, some of which were then either restudied or retrieved. RIF occurred on a delayed final test only when memories were retrieved and not when they were restudied. In Experiment 2, following the study phase of category-exemplar associations, subjects attempted to recall all category-exemplar associations, then they selectively retrieved or restudied some of the exemplars. We found that, despite the huge impact on practiced items, selective retrieval/restudy caused no decrease in final recall of related items. In Experiment 3, we replicated the main result of Experiment 2 by manipulating initial retrieval as a within-subject variable. In Experiment 4 we replicated the main results of the previous experiments with non-practiced (Nrp) baseline items. These findings suggest that initial retrieval of the learning set shields against the forgetting effect of later selective retrieval. Together, our results support the context shift theory of RIF. PMID- 26052294 TI - The architecture of embodied cue integration: insight from the "motivation as cognition" perspective. PMID- 26052295 TI - How to go beyond the body: an introduction. PMID- 26052296 TI - Trust matters: a cross-cultural comparison of Northern Ghana and Oaxaca groups. AB - A cross-cultural analysis of trust and cooperation networks in Northern Ghana (NGHA) and Oaxaca (OAX) was carried out by means of ego networks and interviews. These regions were chosen because both are inhabited by several ethnic groups, thus providing a good opportunity to test the cultural group selection hypothesis. Against the predictions of this approach, we found that in both regions cooperation is grounded in personal trust groups, and that social cohesion depends on these emotional bonds. Moreover, in agreement with Fiske's notion of "evolved proclivities," we also found two distinct kinds of trust networks, one for each region, which vary in terms of the degree of ethnic interrelation. This pattern suggests that social cohesion increases when environmental resources are scarce. PMID- 26052297 TI - Impact of stimulus uncanniness on speeded response. AB - In the uncanny valley phenomenon, the causes of the feeling of uncanniness as well as the impact of the uncanniness on behavioral performances still remain open. The present study investigated the behavioral effects of stimulus uncanniness, particularly with respect to speeded response. Pictures of fish were used as visual stimuli. Participants engaged in direction discrimination, spatial cueing, and dot-probe tasks. The results showed that pictures rated as strongly uncanny delayed speeded response in the discrimination of the direction of the fish. In the cueing experiment, where a fish served as a task-irrelevant and unpredictable cue for a peripheral target, we again observed that the detection of a target was slowed when the cue was an uncanny fish. Conversely, the dot probe task suggested that uncanny fish, unlike threatening stimulus, did not capture visual spatial attention. These results suggested that stimulus uncanniness resulted in the delayed response, and importantly this modulation was not mediated by the feelings of threat. PMID- 26052299 TI - Assessing and correcting for regression toward the mean in deviance-induced social conformity. AB - Our understanding of the mechanisms underlying social conformity has recently advanced due to the employment of neuroscience methodology and novel experimental approaches. Most prominently, several studies have demonstrated the role of neural reinforcement-learning processes in conformal adjustments using a specifically designed and frequently replicated paradigm. Only very recently, the validity of the critical behavioral effect in this very paradigm was seriously questioned, as it invites the unwanted contribution of regression toward the mean. Using a straightforward control-group design, we corroborate this recent finding and demonstrate the involvement of statistical distortions. Additionally, however, we provide conclusive evidence that the paradigm nevertheless captures behavioral effects that can only be attributed to social influence. Finally, we present a mathematical approach that allows to isolate and quantify the paradigm's true conformity effect both at the group level and for each individual participant. These data as well as relevant theoretical considerations suggest that the groundbreaking findings regarding the brain mechanisms of social conformity that were obtained with this recently criticized paradigm were indeed valid. Moreover, we support earlier suggestions that distorted behavioral effects can be rectified by means of appropriate correction procedures. PMID- 26052298 TI - Reorganization of brain networks in aging: a review of functional connectivity studies. AB - Healthy aging (HA) is associated with certain declines in cognitive functions, even in individuals that are free of any process of degenerative illness. Functional magnetic resonance imaging (fMRI) has been widely used in order to link this age-related cognitive decline with patterns of altered brain function. A consistent finding in the fMRI literature is that healthy old adults present higher activity levels in some brain regions during the performance of cognitive tasks. This finding is usually interpreted as a compensatory mechanism. More recent approaches have focused on the study of functional connectivity, mainly derived from resting state fMRI, and have concluded that the higher levels of activity coexist with disrupted connectivity. In this review, we aim to provide a state-of-the-art description of the usefulness and the interpretations of functional brain connectivity in the context of HA. We first give a background that includes some basic aspects and methodological issues regarding functional connectivity. We summarize the main findings and the cognitive models that have been derived from task-activity studies, and we then review the findings provided by resting-state functional connectivity in HA. Finally, we suggest some future directions in this field of research. A common finding of the studies included is that older subjects present reduced functional connectivity compared to young adults. This reduced connectivity affects the main brain networks and explains age-related cognitive alterations. Remarkably, the default mode network appears as a highly compromised system in HA. Overall, the scenario given by both activity and connectivity studies also suggests that the trajectory of changes during task may differ from those observed during resting-state. We propose that the use of complex modeling approaches studying effective connectivity may help to understand context-dependent functional reorganizations in the aging process. PMID- 26052300 TI - The role of the positive emotional attractor in vision and shared vision: toward effective leadership, relationships, and engagement. AB - Personal and shared vision have a long history in management and organizational practices yet only recently have we begun to build a systematic body of empirical knowledge about the role of personal and shared vision in organizations. As the introductory paper for this special topic in Frontiers in Psychology, we present a theoretical argument as to the existence and critical role of two states in which a person, dyad, team, or organization may find themselves when engaging in the creation of a personal or shared vision: the positive emotional attractor (PEA) and the negative emotional attractor (NEA). These two primary states are strange attractors, each characterized by three dimensions: (1) positive versus negative emotional arousal; (2) endocrine arousal of the parasympathetic nervous system versus sympathetic nervous system; and (3) neurological activation of the default mode network versus the task positive network. We argue that arousing the PEA is critical when creating or affirming a personal vision (i.e., sense of one's purpose and ideal self). We begin our paper by reviewing the underpinnings of our PEA-NEA theory, briefly review each of the papers in this special issue, and conclude by discussing the practical implications of the theory. PMID- 26052301 TI - Blending transcranial direct current stimulations and physical exercise to maximize cognitive improvement. PMID- 26052302 TI - Basic understanding of posterior probability. PMID- 26052303 TI - Virtual reality, real emotions: a novel analogue for the assessment of risk factors of post-traumatic stress disorder. AB - Most people are exposed to a violent or life-threatening situation during their lives, but only a minority develops post-traumatic stress disorder (PTSD). Experimental studies are necessary to assess risk factors, such as imagery ability, for the development of PTSD. Up to now the trauma film paradigm (TFP) has functioned as an analogue for PTSD. This paradigm is known to induce involuntary intrusions, a core symptom of PTSD. Though useful, the film paradigm has a drawback, the participant remains an "outsider" and does not immerse in the film scenes. The aim of the present study was to develop a fitting virtual reality (VR) analogue for PTSD and to assess risk factors for the development of PTSD-symptoms, such as intrusions. To this end a novel VR paradigm was compared to the traditional TFP. Both the VR and TFP elicited a negative mood and induction-related intrusions. More immersion was observed in the VR paradigm compared to the TFP. The results of the risk factors were mixed; more imagery ability coincided with a higher intrusion frequency, but also with less distressing intrusions. The results, implications and suggestions for future research are discussed. PMID- 26052304 TI - Enhanced cognitive and perceptual processing: a computational basis for the musician advantage in speech learning. AB - Long-term music training can positively impact speech processing. A recent framework developed to explain such cross-domain plasticity posits that music training-related advantages in speech processing are due to shared cognitive and perceptual processes between music and speech. Although perceptual and cognitive processing advantages due to music training have been independently demonstrated, to date no study has examined perceptual and cognitive processing within the context of a single task. The present study examines the impact of long-term music training on speech learning from a rigorous, computational perspective derived from signal detection theory. Our computational models provide independent estimates of cognitive and perceptual processing in native English speaking musicians (n = 15, mean age = 25 years) and non-musicians (n = 15, mean age = 23 years) learning to categorize non-native lexical pitch patterns (Mandarin tones). Musicians outperformed non-musicians in this task. Model-based analyses suggested that musicians shifted from simple unidimensional decision strategies to more optimal multidimensional (MD) decision strategies sooner than non-musicians. In addition, musicians used optimal decisional strategies more often than non-musicians. However, musicians and non-musicians who used MD strategies showed no difference in performance. We estimated parameters that quantify the magnitude of perceptual variability along two dimensions that are critical for tone categorization: pitch height and pitch direction. Both musicians and non-musicians showed a decrease in perceptual variability along the pitch height dimension, but only musicians showed a significant reduction in perceptual variability along the pitch direction dimension. Notably, these advantages persisted during a generalization phase, when no feedback was provided. These results provide an insight into the mechanisms underlying the musician advantage observed in non-native speech learning. PMID- 26052305 TI - Polarity correspondence effect between loudness and lateralized response set. AB - Performance is better when a high pitch tone is associated with an up or right response and a low pitch tone with a down or left response compared to the opposite pairs, which is called the spatial-musical association of response codes effect. The current study examined whether polarity codes are formed in terms of the variation in loudness. In Experiments 1 and 2, in which participants performed a loudness-judgment task and a timbre-judgment task respectively, the correspondence effect was obtained between loudness and response side regardless of whether loudness was relevant to the task or not. In Experiments 3 and 4, in which the identical loudness- and timbre-judgment tasks were conducted while the auditory stimulus was presented only to the left or right ear, the correspondence effect was modulated by the ear to which the stimulus was presented, even though the effect was marginally significant in Experiment 4. The results suggest that loudness produced polarity codes that influenced response selection (Experiments 1 and 2), and additional spatial codes provided by stimulus position modulated the effect, generating the stimulus eccentricity effect (Experiments 3 and 4), which is consistent with the polarity correspondence principle. PMID- 26052306 TI - Inhibitory control may not explain the link between approximation and math abilities in kindergarteners from middle class families. AB - Past research suggests that individual differences in the acuity of the approximate number system (ANS) are associated with children's math abilities. However, some recent work has argued that these associations can be explained through shared reliance on inhibitory control. Here, we test this claim in two separate experiments. In Experiment 1, forty-two 5- and 6-year-old children completed a non-symbolic number comparison task to assess ANS acuity as well as standardized experimenter-administered assessments for inhibitory control and math ability. Children's accuracy in the number comparison task and scores on the math assessment were significantly correlated, even when controlling for performance on the inhibitory control task. To rule out that our findings were due to the nature of the inhibitory control task, in Experiment 2, we administered a different, computerized inhibitory control task, and similar tasks to assess ANS acuity and math ability as in Experiment 1 to children aged 3-6 years (N = 169). Similar to the result of Experiment 1, we found that associations between accuracy in the number comparison task and math ability persisted when controlling for performance on the inhibitory control task. Together these results suggest that ANS acuity is uniquely associated with early math abilities, independent of the effect of inhibitory control at least in children from middle- to high-SES families. PMID- 26052307 TI - Editorial: Behavioral and physiological bases of attentional biases: paradigms, participants, and stimuli. PMID- 26052308 TI - Voluntary initiation of movement: multifunctional integration of subjective agency. AB - This paper investigates subjective agency (SA) as a special type of efficacious action consciousness. Our central claims are, firstly, that SA is a conscious act of voluntarily initiating bodily motion. Secondly, we argue that SA is a case of multifunctional integration of behavioral functions being analogous to multisensory integration of sensory modalities. This is based on new perspectives on the initiation of action opened up by recent advancements in robot assisted neuro-rehabilitation which depends on the active participation of the patient and yields experimental evidence that there is SA in terms of a conscious act of voluntarily initiating bodily motion (phenomenal performance). Conventionally, action consciousness has been considered as a sense of agency (SoA). According to this view, the conscious subject merely echoes motor performance and does not cause bodily motion. Depending on sensory input, SoA is implemented by means of unifunctional integration (binding) and inevitably results in non-efficacious action consciousness. In contrast, SA comes as a phenomenal performance which causes motion and builds on multifunctional integration. Therefore, the common conception of the brain should be shifted toward multifunctional integration in order to allow for efficacious action consciousness. For this purpose, we suggest the heterarchic principle of asymmetric reciprocity and neural operators underlying SA. The general idea is that multifunctional integration allows conscious acts to be simultaneously implemented with motor behavior so that the resulting behavior (SA) comes as efficacious action consciousness. Regarding the neural implementation, multifunctional integration rather relies on operators than on modular functions. A robotic case study and possible experimental setups with testable hypotheses building on SA are presented. PMID- 26052309 TI - Implicit theories and ability emotional intelligence. AB - Previous research has shown that people differ in their implicit theories about the essential characteristics of intelligence and emotions. Some people believe these characteristics to be predetermined and immutable (entity theorists), whereas others believe that these characteristics can be changed through learning and behavior training (incremental theorists). The present study provides evidence that in healthy adults (N = 688), implicit beliefs about emotions and emotional intelligence (EI) may influence performance on the ability-based Mayer Salovey-Caruso Emotional Intelligence Test (MSCEIT). Adults in our sample with incremental theories about emotions and EI scored higher on the MSCEIT than entity theorists, with implicit theories about EI showing a stronger relationship to scores than theories about emotions. Although our participants perceived both emotion and EI as malleable, they viewed emotions as more malleable than EI. Women and young adults in general were more likely to be incremental theorists than men and older adults. Furthermore, we found that emotion and EI theories mediated the relationship of gender and age with ability EI. Our findings suggest that people's implicit theories about EI may influence their emotional abilities, which may have important consequences for personal and professional EI training. PMID- 26052310 TI - Identification of Putative Natriuretic Hormones Isolated from Human Urine. AB - This brief review describes some representative methodological approaches to the isolation of putative endogenous inhibitors of epithelial sodium transport - i.e., as ouabain-like factors (OLF) that inhibit the sodium transport enzyme Na-K ATPase or inhibit the epithelial sodium channel (ENaC). Gel chromatography and reverse-phase (RP)-high performance liquid chromatography (HPLC) of lyophilized and reconstituted 24 h-urine from salt-loaded healthy humans led to two active fractions, a hydrophilic OLF-1 and a lipophilic OLF-2, whose mass (Ms) spectroscopic data indicate a Mr of 391 (1, 2). Further identification was attempted by Ms-, infrared (IR)-, ultraviolet (UV)-, and (1)H-NMR-spectroscopy. OLF-1 and OLF-2 may be closely related if not identical to (di)ascorbic acid or its salts such as vanadium (V)-V(v)-diascorbate with Mr 403 (3) and V(IV) diascorbate. OLF-1 and V(v)-diascorbate are about 10-fold stronger inhibitors of Na-K-ATPase than OLF-2 and V(IV)-diascorbate, respectively. In conscious rats, i.v. infusion of OLF-1 and OLF-2 resulted in a strong natriuresis. In a similar study, Cain et al. (4) isolated a sodium transport inhibitor from the urine of uremic patients by gel chromatography and RP-HPLC. In uremic rats, a natriuretic response to the injection of the active material was found. Xanthurenic acid 8-O beta-d-glucoside (Mr 368) and xanthurenic acid 8-O-sulfate (Mr 284) were identified as endogenous inhibitors of sodium transport acting, e.g., by ENaC blockade. No definite relation to blood pressure, body fluid volume, or sodium balance has been reported for any of these above factors, and further studies to identify the natriuretic and/or ouabain-like compound(s) or hormone(s) will be needed. PMID- 26052311 TI - Hypothesis: Coupling between Resorption and Formation in Cancellous bone Remodeling is a Mechanically Controlled Event. AB - Coupling is the process that links bone resorption to formation in a temporally and spatially coordinated manner within the remodeling cycle. In order to maintain skeletal integrity, it is of crucial importance that the amount of bone resorbed matches the amount of newly formed bone in each remodeling site. Although a number of different explanatory models have been developed, the mechanisms that couple bone resorption and formation in bone remodeling are still a matter of controversy. Here, I propose a model in which coupling is achieved by biomechanical strain sensed by osteocytes within the newly built bone package. In this model, the resorption cavity created by osteoclasts results in mechanical weakening of the structural element, and, thus, in increased strain under constant loading conditions. Subsequent bone formation is initiated by strain sensitive osteocytes in the underlying bone matrix. After osteoblastic bone formation has started, the newly built osteocyte-osteoblast network detects strain. Once the mechanical strain within the newly built bone structural unit falls below a certain threshold, bone formation stops. In this biomechanical strain-driven model, osteoblasts do not need to "know" how much bone was previously resorbed in a given site. In addition, this model does not require the transfer of any information from bone-resorbing osteoclasts to bone-forming osteoblasts, because biomechanical strain "guides" osteoblasts through their job of re-filling the resorption cavity. PMID- 26052312 TI - Sfp-type PPTase inactivation promotes bacterial biofilm formation and ability to enhance wheat drought tolerance. AB - Paenibacillus polymyxa is a common soil bacterium with broad range of practical applications. An important group of secondary metabolites in P. polymyxa are non ribosomal peptide and polyketide derived metabolites (NRPs/PKs). Modular non ribosomal peptide synthetases catalyze main steps in the biosynthesis of the complex secondary metabolites. Here we report on the inactivation of an A26 Sfp type 4'-phosphopantetheinyl transferase (Sfp-type PPTase). The inactivation of the gene resulted in loss of NRPs/PKs production. In contrast to the former Bacillus spp. model the mutant strain compared to wild type showed greatly enhanced biofilm formation ability. A26Deltasfp biofilm promotion is directly mediated by NRPs/PKs, as exogenous addition of the wild type metabolite extracts restores its biofilm formation level. Wheat inoculation with bacteria that had lost their Sfp-type PPTase gene resulted in two times higher plant survival and about three times increased biomass under severe drought stress compared to wild type. Challenges with P. polymyxa genetic manipulation are discussed. PMID- 26052313 TI - Corrigendum: The pathogenesis, detection, and prevention of Vibrio parahaemolyticus. AB - [This corrects the article on p. 144 in vol. 6, PMID: 25798132.]. PMID- 26052314 TI - Production of plasmid-encoding NDM-1 in clinical Raoultella ornithinolytica and Leclercia adecarboxylata from China. AB - Raoultella ornithinolytica YNKP001 and Leclercia adecarboxylata P10164, which harbor conjugative plasmids pYNKP001-NDM and pP10164-NDM, respectively, were isolated from two different Chinese patients, and their complete nucleotide sequences were determined. Production of NDM-1 enzyme by these plasmids accounts for the carbapenem resistance of these two strains. This is the first report of bla NDM in L. adecarboxylata and third report of this gene in R. ornithinolytica. pYNKP001-NDM is very similar to the IncN2 NDM-1-encoding plasmids pTR3, pNDM ECS01, and p271A, whereas pP10164-NDM is similar to the IncFIIY bla NDM-1 carrying plasmid pKOX_NDM1. The bla NDM-1 genes of pYNKP001-NDM and pP10164-NDM are embedded in Tn125-like elements, which represent two distinct truncated versions of the NDM-1-encoding Tn125 prototype observed in pNDM-BJ01. Flanking of these two Tn125-like elements by miniature inverted repeat element (MITE) or its remnant indicates that MITE facilitates transposition and mobilization of bla NDM 1 gene contexts. PMID- 26052315 TI - Assessment of the stoichiometry and efficiency of CO2 fixation coupled to reduced sulfur oxidation. AB - Chemolithoautotrophic sulfur oxidizing bacteria (SOB) couple the oxidation of reduced sulfur compounds to the production of biomass. Their role in the cycling of carbon, sulfur, oxygen, and nitrogen is, however, difficult to quantify due to the complexity of sulfur oxidation pathways. We describe a generic theoretical framework for linking the stoichiometry and energy conservation efficiency of autotrophic sulfur oxidation while accounting for the partitioning of the reduced sulfur pool between the energy generating and energy conserving steps as well as between the main possible products (sulfate vs. zero-valent sulfur). Using this framework, we show that the energy conservation efficiency varies widely among SOB with no apparent relationship to their phylogeny. Aerobic SOB equipped with reverse dissimilatory sulfite reductase tend to have higher efficiency than those relying on the complete Sox pathway, whereas for anaerobic SOB the presence of membrane-bound, as opposed to periplasmic, nitrate reductase systems appears to be linked to higher efficiency. We employ the framework to also show how limited rate measurements can be used to estimate the primary productivity of SOB without the knowledge of the sulfate-to-zero-valent-sulfur production ratio. Finally, we discuss how the framework can help researchers gain new insights into the activity of SOB and their niches. PMID- 26052316 TI - Pivotal roles of phyllosphere microorganisms at the interface between plant functioning and atmospheric trace gas dynamics. AB - The phyllosphere, which lato sensu consists of the aerial parts of plants, and therefore primarily, of the set of photosynthetic leaves, is one of the most prevalent microbial habitats on earth. Phyllosphere microbiota are related to original and specific processes at the interface between plants, microorganisms and the atmosphere. Recent -omics studies have opened fascinating opportunities for characterizing the spatio-temporal structure of phyllosphere microbial communities in relation with structural, functional, and ecological properties of host plants, and with physico-chemical properties of the environment, such as climate dynamics and trace gas composition of the surrounding atmosphere. This review will analyze recent advances, especially those resulting from environmental genomics, and how this novel knowledge has revealed the extent of the ecosystemic impact of the phyllosphere at the interface between plants and atmosphere. Highlights * The phyllosphere is one of the most prevalent microbial habitats on earth. * Phyllosphere microbiota colonize extreme, stressful, and changing environments. * Plants, phyllosphere microbiota and the atmosphere present a dynamic continuum. * Phyllosphere microbiota interact with the dynamics of volatile organic compounds and atmospheric trace gasses. PMID- 26052317 TI - Identification of a transporter Slr0982 involved in ethanol tolerance in cyanobacterium Synechocystis sp. PCC 6803. AB - Cyanobacteria have been engineered to produce ethanol through recent synthetic biology efforts. However, one major challenge to the cyanobacterial systems for high-efficiency ethanol production is their low tolerance to the ethanol toxicity. With a major goal to identify novel transporters involved in ethanol tolerance, we constructed gene knockout mutants for 58 transporter-encoding genes of Synechocystis sp. PCC 6803 and screened their tolerance change under ethanol stress. The efforts allowed discovery of a mutant of slr0982 gene encoding an ATP binding cassette transporter which grew poorly in BG11 medium supplemented with 1.5% (v/v) ethanol when compared with the wild type, and the growth loss could be recovered by complementing slr0982 in the Deltaslr0982 mutant, suggesting that slr0982 is involved in ethanol tolerance in Synechocystis. To decipher the tolerance mechanism involved, a comparative metabolomic and network-based analysis of the wild type and the ethanol-sensitive Deltaslr0982 mutant was performed. The analysis allowed the identification of four metabolic modules related to slr0982 deletion in the Deltaslr0982 mutant, among which metabolites like sucrose and L-pyroglutamic acid which might be involved in ethanol tolerance, were found important for slr0982 deletion in the Deltaslr0982 mutant. This study reports on the first transporter related to ethanol tolerance in Synechocystis, which could be a useful target for further tolerance engineering. In addition, metabolomic and network analysis provides important findings for better understanding of the tolerance mechanism to ethanol stress in Synechocystis. PMID- 26052318 TI - Antagonistic interactions are sufficient to explain self-assemblage of bacterial communities in a homogeneous environment: a computational modeling approach. AB - Most of the studies in Ecology have been devoted to analyzing the effects the environment has on individuals, populations, and communities, thus neglecting the effects of biotic interactions on the system dynamics. In the present work we study the structure of bacterial communities in the oligotrophic shallow water system of Churince, Cuatro Cienegas, Mexico. Since the physicochemical conditions of this water system are homogeneous and quite stable in time, it is an excellent candidate to study how biotic factors influence the structure of bacterial communities. In a previous study, the binary antagonistic interactions of 78 bacterial strains, isolated from Churince, were experimentally determined. We employ these data to develop a computer algorithm to simulate growth experiments in a cellular grid representing the pond. Remarkably, in our model, the dynamics of all the simulated bacterial populations is determined solely by antagonistic interactions. Our results indicate that all bacterial strains (even those that are antagonized by many other bacteria) survive in the long term, and that the underlying mechanism is the formation of bacterial community patches. Patches corresponding to less antagonistic and highly susceptible strains are consistently isolated from the highly-antagonistic bacterial colonies by patches of neutral strains. These results concur with the observed features of the bacterial community structure previously reported. Finally, we study how our findings depend on factors like initial population size, differential population growth rates, homogeneous population death rates, and enhanced bacterial diffusion. PMID- 26052319 TI - Genome wide transcriptional profiling of Herbaspirillum seropedicae SmR1 grown in the presence of naringenin. AB - Herbaspirillum seropedicae is a diazotrophic bacterium which associates endophytically with economically important gramineae. Flavonoids such as naringenin have been shown to have an effect on the interaction between H. seropedicae and its host plants. We used a high-throughput sequencing based method (RNA-Seq) to access the influence of naringenin on the whole transcriptome profile of H. seropedicae. Three hundred and four genes were downregulated and seventy seven were upregulated by naringenin. Data analysis revealed that genes related to bacterial flagella biosynthesis, chemotaxis and biosynthesis of peptidoglycan were repressed by naringenin. Moreover, genes involved in aromatic metabolism and multidrug transport efllux were actived. PMID- 26052320 TI - The dynamic nature and territory of transcriptional machinery in the bacterial chromosome. AB - Our knowledge of the regulation of genes involved in bacterial growth and stress responses is extensive; however, we have only recently begun to understand how environmental cues influence the dynamic, three-dimensional distribution of RNA polymerase (RNAP) in Escherichia coli on the level of single cell, using wide field fluorescence microscopy and state-of-the-art imaging techniques. Live-cell imaging using either an agarose-embedding procedure or a microfluidic system further underscores the dynamic nature of the distribution of RNAP in response to changes in the environment and highlights the challenges in the study. A general agreement between live-cell and fixed-cell images has validated the formaldehyde fixing procedure, which is a technical breakthrough in the study of the cell biology of RNAP. In this review we use a systems biology perspective to summarize the advances in the cell biology of RNAP in E. coli, including the discoveries of the bacterial nucleolus, the spatial compartmentalization of the transcription machinery at the periphery of the nucleoid, and the segregation of the chromosome territories for the two major cellular functions of transcription and replication in fast-growing cells. Our understanding of the coupling of transcription and bacterial chromosome (or nucleoid) structure is also summarized. Using E. coli as a simple model system, co-imaging of RNAP with DNA and other factors during growth and stress responses will continue to be a useful tool for studying bacterial growth and adaptation in changing environment. PMID- 26052321 TI - Bacteria in the injection water differently impacts the bacterial communities of production wells in high-temperature petroleum reservoirs. AB - Water flooding is widely used for oil recovery. However, how the introduction of bacteria via water flooding affects the subsurface ecosystem remains unknown. In the present study, the distinct bacterial communities of an injection well and six adjacent production wells were revealed using denaturing gradient gel electrophoresis (DGGE) and pyrosequencing. All sequences of the variable region 3 of the 16S rRNA gene retrieved from pyrosequencing were divided into 543 operational taxonomic units (OTUs) based on 97% similarity. Approximately 13.5% of the total sequences could not be assigned to any recognized phylum. The Unifrac distance analysis showed significant differences in the bacterial community structures between the production well and injection water samples. However, highly similar bacterial structures were shown for samples obtained from the same oil-bearing strata. More than 69% of the OTUs detected in the injection water sample were absent or detected in low abundance in the production wells. However, the abundance of two OTUs reached as high as 17.5 and 26.9% in two samples of production water, although the OTUs greatly varied among all samples. Combined with the differentiated water flow rate measured through ion tracing, we speculated that the transportation of injected bacteria was impacted through the varied permeability from the injection well to each of the production wells. Whether the injected bacteria predominate the production well bacterial community might depend both on the permeability of the strata and the reservoir conditions. PMID- 26052322 TI - Methane production potentials, pathways, and communities of methanogens in vertical sediment profiles of river Sitka. AB - Biological methanogenesis is linked to permanent water logged systems, e.g., rice field soils or lake sediments. In these systems the methanogenic community as well as the pathway of methane formation are well-described. By contrast, the methanogenic potential of river sediments is so far not well-investigated. Therefore, we analyzed (a) the methanogenic potential (incubation experiments), (b) the pathway of methane production (stable carbon isotopes and inhibitor studies), and (c) the methanogenic community composition (terminal restriction length polymorphism of mcrA) in depth profiles of sediment cores of River Sitka, Czech Republic. We found two depth-related distinct maxima for the methanogenic potentials (a) The pathway of methane production was dominated by hydrogenotrophic methanogenesis (b) The methanogenic community composition was similar in all depth layers (c) The main TRFs were representative for Methanosarcina, Methanosaeta, Methanobacterium, and Methanomicrobium species. The isotopic signals of acetate indicated a relative high contribution of chemolithotrophic acetogenesis to the acetate pool. PMID- 26052323 TI - Synergistic function of four novel thermostable glycoside hydrolases from a long term enriched thermophilic methanogenic digester. AB - In biofuel production from lignocellulose, low thermostability and product inhibition strongly restrict the enzyme activities and production process. Application of multiple thermostable glycoside hydrolases, forming an enzyme "cocktail", can result in a synergistic action and therefore improve production efficiency and reduce operational costs. Therefore, increasing enzyme thermostabilities and compatibility are important for the biofuel industry. In this study, we reported the screening, cloning and biochemical characterization of four novel thermostable lignocellulose hydrolases from a metagenomic library of a long-term dry thermophilic methanogenic digester community, which were highly compatible with optimal conditions and specific activities. The optimal temperatures of the four enzymes, beta-xylosidase, xylanase, beta-glucosidase, and cellulase ranged from 60 to 75 degrees C, and over 80% residual activities were observed after 2 h incubation at 50 degrees C. Mixtures of these hydrolases retained high residual synergistic activities after incubation with cellulose, xylan, and steam-exploded corncob at 50 degrees C for 72 h. In addition, about 55% dry weight of steam-exploded corncob was hydrolyzed to glucose and xylose by the synergistic action of the four enzymes at 50 degrees C for 48 h. This work suggested that since different enzymes from a same ecosystem could be more compatible, screening enzymes from a long-term enriching community could be a favorable strategy. PMID- 26052324 TI - A critical role for hemolysin in Vibrio fluvialis-induced IL-1beta secretion mediated by the NLRP3 inflammasome in macrophages. AB - Vibrio fluvialis causes human diarrhea, but the pathogenesis is not well-studied. We hypothesized that V. fluvialis-secreted hemolysin (VFH) may induce IL-1beta secretion through the activation of the NLRP3 inflammasome and contribute to the pathogenicity of V. fluvialis. To examine this possibility, we constructed VFH mutant and complement strains and demonstrated that V. fluvialis-induced IL-1beta production and cytotoxicity in human monocytic THP-1 cells and mouse macrophages is attributed to VFH. To evaluate the role of VFH in vivo, we infected adult C57BL/6 mice intraperitoneally and suckling C57/B6 mice orally with various strains. The mice treated with 10(8) CFU wild-type V. fluvialis or cell-free supernatant containing VFH induced significantly higher IL-1beta production in peritoneal lavage fluid or in colon compared with those infected with the mutant strain, while no effect on TNF and IL-6 production was observed at day 5 or 24 h post-infection. VFH contributed to pathological changes and IL-1beta release independent of colonization of V. fluvialis in the colon. VFH has no effect on the synthesis of pro-IL-1beta, but rather it triggers the processing of pro-IL 1beta into IL-1beta. Furthermore, using deficient mouse strains, we verified that V. fluvialis-induced IL-1beta is mediated through activation of Caspase-1 and the NLRP3 inflammasome ex vivo. Confocal microscopy suggests that VFH contributes to cathepsin B release. Furthermore, V. fluvialis-induced IL-1beta secretion requires potassium (K(+)) efflux and reactive oxygen species production. Our results provide new evidence for the role of VFH in the activation of the NLRP3 inflammasome and pathogenesis in response to V. fluvialis infection. Summary Sentence: Vibrio fluvialis-secreted hemolysin induces IL-1beta secretion through the activation of the NLRP3 inflammasome and contributes to the pathogenicity of V. fluvialis. PMID- 26052326 TI - Human seroprevalence indicating hantavirus infections in tropical rainforests of Cote d'Ivoire and Democratic Republic of Congo. AB - Hantaviruses are members of the Bunyaviridae family carried by small mammals and causing human hemorrhagic fevers worldwide. In Western Africa, where a variety of hemorrhagic fever viruses occurs, indigenous hantaviruses have been molecularly found in animal reservoirs such as rodents, shrews, and bats since 2006. To investigate the human contact to hantaviruses carried by these hosts and to assess the public health relevance of hantaviruses for humans living in the tropical rainforest regions of Western and Central Africa, we performed a cross sectional seroprevalence study in the region of Tai National Park in Cote d'Ivoire and the Bandundu region near the Salonga National Park in the Democratic Republic (DR) of Congo. Serum samples were initially screened with enzyme-linked immunosorbent assays using nucleoproteins of several hantaviruses as diagnostic antigens. Positive results were confirmed by Western blotting and immunofluorescence testing. Seroprevalence rates of 3.9% (27/687) and 2.4% (7/295), respectively, were found in the investigated regions in Cote d'Ivoire and the DR Congo. In Cote d'Ivoire, this value was significantly higher than the seroprevalence rates previously reported from the neighboring country Guinea as well as from South Africa. Our study indicates an exposure of humans to hantaviruses in West and Central African tropical rainforest areas. In order to pinpoint the possible existence and frequency of clinical disease caused by hantaviruses in this region of the world, systematic investigations of patients with fever and renal or respiratory symptoms are required. PMID- 26052327 TI - Survey and rapid detection of Klebsiella pneumoniae in clinical samples targeting the rcsA gene in Beijing, China. AB - Klebsiella pneumoniae is a wide-spread nosocomial pathogen. A rapid and sensitive molecular method for the detection of K. pneumoniae in clinical samples is needed to guide therapeutic treatment. In this study, we first described a loop-mediated isothermal amplification (LAMP) method for the rapid detection of capsular polysaccharide synthesis regulating gene rcsA from K. pneumoniaein clinical samples by using two methods including real-time turbidity monitoring and fluorescence detection to assess the reaction. Then dissemination of K. pneumoniae strains was investigated from ICU patients in three top hospitals in Beijing, China. The results showed that the detection limit of the LAMP method was 0.115 pg/MUl DNA within 60 min under isothermal conditions (61 degrees C), a 100-fold increase in sensitivity compared with conventional PCR. All 30 non- K. pneumoniae strains tested were negative for LAMP detection, indicating the high specificity of the LAMP reaction. To evaluate the application of the LAMP assay to clinical diagnosis, of 110 clinical sputum samples collected from ICU patients with clinically suspected multi-resistant infections in China, a total of 32 K. pneumoniae isolates were identified for LAMP-based surveillance of rcsA. All isolates belonged to nine different K. pneumoniae multilocus sequence typing (MLST) groups. Strikingly, of the 32 K. pneumoniae strains, 18 contained the Klebsiella pneumoniae Carbapenemase (KPC)-encoding gene bla KPC-2 and had high resistance to beta-lactam antibiotics. Moreover, K. pneumoniae WJ-64 was discovered to contain bla KPC-2 and bla NDM-1genes simultaneously in the isolate. Our data showed the high prevalence of bla KPC-2 among K. pneumoniae and co occurrence of many resistant genes in the clinical strains signal a rapid and continuing evolution of K. pneumoniae. In conclusion, we have developed a rapid and sensitive visual K. pneumoniae detection LAMP assay, which could be a useful tool for clinical screening, on-site diagnosis and primary quarantine purposes. PMID- 26052325 TI - Broad-spectrum antiviral agents. AB - Development of highly effective, broad-spectrum antiviral agents is the major objective shared by the fields of virology and pharmaceutics. Antiviral drug development has focused on targeting viral entry and replication, as well as modulating cellular defense system. High throughput screening of molecules, genetic engineering of peptides, and functional screening of agents have identified promising candidates for development of optimal broad-spectrum antiviral agents to intervene in viral infection and control viral epidemics. This review discusses current knowledge, prospective applications, opportunities, and challenges in the development of broad-spectrum antiviral agents. PMID- 26052328 TI - Tweeters, Woofers and Horns: The Complex Orchestration of Calcium Currents in T Lymphocytes. AB - Elevation of intracellular calcium ion (Ca(2+)) levels is a vital event that regulates T lymphocyte homeostasis, activation, proliferation, differentiation, and apoptosis. The mechanisms that regulate intracellular Ca(2+) signaling in lymphocytes involve tightly controlled concinnity of multiple ion channels, membrane receptors, and signaling molecules. T cell receptor (TCR) engagement results in depletion of endoplasmic reticulum (ER) Ca(2+) stores and subsequent sustained influx of extracellular Ca(2+) through Ca(2+) release-activated Ca(2+) (CRAC) channels in the plasma membrane. This process termed store-operated Ca(2+) entry (SOCE) involves the ER Ca(2+) sensing molecule, STIM1, and a pore-forming plasma membrane protein, ORAI1. However, several other important Ca(2+) channels that are instrumental in T cell function also exist. In this review, we discuss the role of additional Ca(2+) channel families expressed on the plasma membrane of T cells that likely contribute to Ca(2+) influx following TCR engagement, which include the TRP channels, the NMDA receptors, the P2X receptors, and the IP3 receptors, with a focus on the voltage-dependent Ca(2+) (CaV) channels. PMID- 26052329 TI - Adoptive T Cell Therapy Targeting CD1 and MR1. AB - Adoptive T cell immunotherapy has demonstrated clinically relevant efficacy in treating malignant and infectious diseases. However, much of these therapies have been focused on enhancing, or generating de novo, effector functions of conventional T cells recognizing HLA molecules. Given the heterogeneity of HLA alleles, mismatched patients are ineligible for current HLA-restricted adoptive T cell therapies. CD1 and MR1 are class I-like monomorphic molecules and their restricted T cells possess unique T cell receptor specificity against entirely different classes of antigens. CD1 and MR1 molecules present lipid and vitamin B metabolite antigens, respectively, and offer a new front of targets for T cell therapies. This review will cover the recent progress in the basic research of CD1, MR1, and their restricted T cells that possess translational potential. PMID- 26052331 TI - Sequence and expression analysis of the AMT gene family in poplar. AB - Ammonium transporters (AMTs) are plasma membrane proteins that exclusively transport ammonium/ammonia. These proteins are encoded by an ancient gene family with many members. The molecular characteristics and evolutionary history of AMTs in woody plants are still poorly understood. We comprehensively evaluated the AMT gene family in the latest release of the Populus trichocarpa genome (version 3.0; Phytozome 9.0), and identified 16 AMT genes. These genes formed four clusters; AMT1 (7 genes), AMT2 (2 genes), AMT3 (2 genes), and AMT4 (5 genes). Evolutionary analyses suggested that the Populus AMT gene family has expanded via whole-genome duplication events. Among the 16 AMT genes, 15 genes are located on 11 chromosomes of Populus. Expression analyses showed that 14 AMT genes were vegetative organs expressed; AMT1;1/1;3/1;6/3;2 and AMT1;1/1;2/2;2/3;1 had high transcript accumulation level in the leaves and roots, respectively and strongly changes under the nitrogen-dependent experiments. The results imply the functional roles of AMT genes in ammonium absorption in poplar. PMID- 26052330 TI - Novel Genome-Editing Tools to Model and Correct Primary Immunodeficiencies. AB - Severe combined immunodeficiency (SCID) and other severe non-SCID primary immunodeficiencies (non-SCID PID) can be treated by allogeneic hematopoietic stem cell (HSC) transplantation, but when histocompatibility leukocyte antigen-matched donors are lacking, this can be a high-risk procedure. Correcting the patient's own HSCs with gene therapy offers an attractive alternative. Gene therapies currently being used in clinical settings insert a functional copy of the entire gene by means of a viral vector. With this treatment, severe complications may result due to integration within oncogenes. A promising alternative is the use of endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 to introduce a double stranded break in the DNA and thus induce homology-directed repair. With these genome-editing tools a correct copy can be inserted in a precisely targeted "safe harbor." They can also be used to correct pathogenic mutations in situ and to develop cellular or animal models needed to study the pathogenic effects of specific genetic defects found in immunodeficient patients. This review discusses the advantages and disadvantages of these endonucleases in gene correction and modeling with an emphasis on CRISPR/Cas9, which offers the most promise due to its efficacy and versatility. PMID- 26052332 TI - Extensive sequence variation in rice blast resistance gene Pi54 makes it broad spectrum in nature. AB - Rice blast resistant gene, Pi54 cloned from rice line, Tetep, is effective against diverse isolates of Magnaporthe oryzae. In this study, we prospected the allelic variants of the dominant blast resistance gene from a set of 92 rice lines to determine the nucleotide diversity, pattern of its molecular evolution, phylogenetic relationships and evolutionary dynamics, and to develop allele specific markers. High quality sequences were generated for homologs of Pi54 gene. Using comparative sequence analysis, InDels of variable sizes in all the alleles were observed. Profiling of the selected sites of SNP (Single Nucleotide Polymorphism) and amino acids (N sites >= 10) exhibited constant frequency distribution of mutational and substitutional sites between the resistance and susceptible rice lines, respectively. A total of 50 new haplotypes based on the nucleotide polymorphism was also identified. A unique haplotype (H_3) was found to be linked to all the resistant alleles isolated from indica rice lines. Unique leucine zipper and tyrosine sulfation sites were identified in the predicted Pi54 proteins. Selection signals were observed in entire coding sequence of resistance alleles, as compared to LRR domains for susceptible alleles. This is a maiden report of extensive variability of Pi54 alleles in different landraces and cultivated varieties, possibly, attributing broad-spectrum resistance to Magnaporthe oryzae. The sequence variation in two consensus region: 163 and 144 bp were used for the development of allele specific DNA markers. Validated markers can be used for the selection and identification of better allele(s) and their introgression in commercial rice cultivars employing marker assisted selection. PMID- 26052333 TI - Photochemical and antioxidative responses of the glume and flag leaf to seasonal senescence in wheat. AB - The non-leaf photosynthetic organs have recently attracted much attention for the breeding and screening of varieties of cereal crops to achieve a high grain yield. However, the glume photosynthetic characteristics and responses to high temperature at the late stages of grain filling are not well known in winter wheat (Triticum aestivum L.). In the present study, an experiment was conducted to investigate the anatomy, chloroplast temporal changes, chlorophyll fluorescence, xanthophyll cycle and antioxidative defense system in glumes of field-grown wheat during grain filling compared with flag leaves. Observations using a light microscope revealed that the glumes developed a solid structural base for performing photosynthesis. Compared with the flag leaves, the glumes preserved a more integral ultrastructure, as observed under transmission electron microscopy, and had higher values of Fv/Fm and PhiPSII at the maturity stage. Further analysis of the chlorophyll fluorescence demonstrated that the glumes experienced high non-photochemical quenching (NPQ) at the late stages. Determination of the pool size of the xanthophyll cycle suggested that the (A+Z)/(V+A+Z) ratio was consistently higher in glumes than in flag leaves and that the V+A+Z content was considerably higher in glumes at the maturity stage. In addition, the glumes exhibited a higher antioxidant enzyme activity and a lower accumulation of reactive oxygen species. These results suggest that the glumes are photosynthetically active and senesce later than the flag leaves; the advantages may have been achieved by coordinated contributions of the structural features, higher NPQ levels, greater de-epoxidation of the xanthophyll cycle components and antioxidative defense metabolism. PMID- 26052334 TI - Physiological response to drought stress in Camptotheca acuminata seedlings from two provenances. AB - Drought stress is a key environmental factor limiting the growth and productivity of plants. The purpose of this study was to investigate the physiological responses of Camptotheca acuminata (C. acuminata) to different drought stresses and compare the drought tolerance between the provenances Kunming (KM) and Nanchang (NC), which are naturally distributed in different rainfall zones with annual rainfalls of 1000-1100 mm and 1600-1700 mm, respectively. We determined relative water content (RWC), chlorophyll content [Chl(a+b)], net photosynthesis (Pn), gas exchange parameters, relative leakage conductivity (REC), malondialdehyde (MDA) content and superoxide dismutase (SOD) and peroxidase (POD) activities of C. acuminata seedlings under both moderate (50% of maximum field capacity) and severe drought stress (30% of maximum field capacity). As the degree of water stress increased, RWC, Chl(a+b) content, Pn, stomatal conductance (Gs), transpiration rate (Tr) and intercellular CO2 concentration (Ci) values decreased, but water use efficiency (WUE), REC, MDA content and SOD and POD activities increased in provenances KM and NC. Under moderate and severe drought stress, provenance KM had higher RWC, Chl(a+b), Pn, WUE, SOD, and POD and lower Gs, Tr, Ci, and REC in leaves than provenance NC. The results indicated that provenance KM may maintain stronger drought tolerance via improvements in water retention capacity, antioxidant enzyme activity, and membrane integrity. PMID- 26052335 TI - Trees as huge flowers and flowers as oversized floral guides: the role of floral color change and retention of old flowers in Tibouchina pulchra. AB - Floral color changes and retention of old flowers are frequently combined phenomena restricted to the floral guide or single flowers in few-flowered inflorescences. They are thought to increase the attractiveness over long distances and to direct nearby pollinators toward the rewarding flowers. In Tibouchina pulchra, a massively flowering tree, the whole flower changes its color during anthesis. On the first day, the flowers are white and on the next 3 days, they change to pink. This creates a new large-scale color pattern in which the white pre-changed flowers contrast against the pink post-changed ones over the entire tree. We describe the spectral characteristics of floral colors of T. pulchra and test bumblebees' response to this color pattern when viewed at different angles (simulating long and short distances). The results indicated the role of different color components in bumblebee attraction and the possible scenario in which this flower color pattern has evolved. We tested bumblebees' preference for simulated trees with 75% pink and 25% white flowers resembling the color patterns of T. pulchra, and trees with green leaves and pink flowers (control) in long-distance approach. We also compared an artificial setting with three pink flowers and one white flower (T. pulchra model) against four pink flowers with white floral guides (control) in short-distance approach. Bumblebees spontaneously preferred the simulated T. pulchra patterns in both approaches despite similar reward. Moreover, in short distances, pollinator visits to peripheral, non-rewarding flowers occurred only half as frequently in the simulated T. pulchra when compared to the control. Thefore, this exceptional floral color change and the retention of old flowers in T. pulchra favors the attraction of pollinators over long distances in a deception process while it honestly directs them toward the rewarding flowers at short distances possibly exploring their innate color preferences. PMID- 26052336 TI - BrAD-seq: Breath Adapter Directional sequencing: a streamlined, ultra-simple and fast library preparation protocol for strand specific mRNA library construction. AB - Next Generation Sequencing (NGS) is driving rapid advancement in biological understanding and RNA-sequencing (RNA-seq) has become an indispensable tool for biology and medicine. There is a growing need for access to these technologies although preparation of NGS libraries remains a bottleneck to wider adoption. Here we report a novel method for the production of strand specific RNA-seq libraries utilizing the terminal breathing of double-stranded cDNA to capture and incorporate a sequencing adapter. Breath Adapter Directional sequencing (BrAD seq) reduces sample handling and requires far fewer enzymatic steps than most available methods to produce high quality strand-specific RNA-seq libraries. The method we present is optimized for 3-prime Digital Gene Expression (DGE) libraries and can easily extend to full transcript coverage shotgun (SHO) type strand-specific libraries and is modularized to accommodate a diversity of RNA and DNA input materials. BrAD-seq offers a highly streamlined and inexpensive option for RNA-seq libraries. PMID- 26052337 TI - Cloning and functional validation of early inducible Magnaporthe oryzae responsive CYP76M7 promoter from rice. AB - Cloning and functional characterization of plant pathogen inducible promoters is of great significance for their use in the effective management of plant diseases. The rice gene CYP76M7 was up regulated at 24, 48, and 72 hours post inoculation (hpi) with two isolates of Magnaporthe oryzae Mo-ei-11 and Mo-ni-25. In this study, the promoter of CYP76M7 gene was cloned from rice cultivar HR-12, characterized and functionally validated. The Transcription Start Site of CYP76M7 was mapped at 45 bases upstream of the initiation codon. To functionally validate the promoter, 5' deletion analysis of the promoter sequences was performed and the deletion fragments fused with the beta-glucuronidase (GUS) reporter gene were used for generating stable transgenic Arabidopsis plants as well as for transient expression in rice. The spatial and temporal expression pattern of GUS in transgenic Arabidopsis plants and also in transiently expressed rice leaves revealed that the promoter of CYP76M7 gene was induced by M. oryzae. The induction of CYP76M7 promoter was observed at 24 hpi with M. oryzae. We report that, sequences spanning -222 bp to -520 bp, with the cluster of three W-boxes, two ASF1 motifs and a single GT-1 element may contribute to the M. oryzae inducible nature of CYP76M7 promoter. The promoter characterized in this study would be an ideal candidate for the overexpression of defense genes in rice for developing durable blast resistance rice lines. PMID- 26052339 TI - Detection of social group instability among captive rhesus macaques using joint network modeling. AB - Social stability in group-living animals is an emergent property which arises from the interaction amongst multiple behavioral networks. However, pinpointing when a social group is at risk of collapse is difficult. We used a joint network modeling approach to examine the interdependencies between two behavioral networks, aggression and status signaling, from four stable and three unstable groups of rhesus macaques in order to identify characteristic patterns of network interdependence in stable groups that are readily distinguishable from unstable groups. Our results showed that the most prominent source of aggression-status network interdependence in stable social groups came from more frequent dyads than expected with opposite direction status-aggression (i.e. A threatens B and B signals acceptance of subordinate status). In contrast, unstable groups showed a decrease in opposite direction aggression-status dyads (but remained higher than expected) as well as more frequent than expected dyads with bidirectional aggression. These results demonstrate that not only was the stable joint relationship between aggression and status networks readily distinguishable from unstable time points, social instability manifested in at least two different ways. In sum, our joint modeling approach may prove useful in quantifying and monitoring the complex social dynamics of any wild or captive social system, as all social systems are composed of multiple interconnected networks. PMID- 26052338 TI - Genetic variants in microRNA genes: impact on microRNA expression, function, and disease. AB - MicroRNAs (miRNAs) are important regulators of gene expression and like any other gene, their coding sequences are subject to genetic variation. Variants in miRNA genes can have profound effects on miRNA functionality at all levels, including miRNA transcription, maturation, and target specificity, and as such they can also contribute to disease. The impact of variants in miRNA genes is the focus of the present review. To put these effects into context, we first discuss the requirements of miRNA transcripts for maturation. In the last part an overview of available databases and tools and experimental approaches to investigate miRNA variants related to human disease is presented. PMID- 26052341 TI - A bioinformatics approach to distinguish plant parasite and host transcriptomes in interface tissue by classifying RNA-Seq reads. AB - BACKGROUND: The genus Cuscuta is a group of parasitic plants that are distributed world-wide. The process of parasitization starts with a Cuscuta plant coiling around the host stem. The parasite's haustorial organs then establish a vascular connection allowing for access to the phloem content. The host and the parasite form new cellular connections, suggesting coordination of developmental and biochemical processes. Simultaneous monitoring of gene expression in the parasite's and host's tissues may shed light on the complex events occurring between the parasitic and host cells and may help to overcome experimental limitations (i.e. how to separate host tissue from Cuscuta tissue at the haustorial connection). A novel approach is to use bioinformatic analysis to classify sequencing reads as either belonging to the host or to the parasite and to characterize the expression patterns. Owing to the lack of a comprehensive genomic dataset from Cuscuta spp., such a classification has not been performed previously. RESULTS: We first classified RNA-Seq reads from an interface region between the non-model parasitic plant Cuscuta japonica and the non-model host plant Impatiens balsamina. Without established reference sequences, we classified reads as originating from either of the plants by stepwise similarity search against de novo assembled transcript sets of C. japonica and I. balsamina, unigene sets of the same genus, and cDNA sequences of the same family. We then assembled de novo transcriptomes from the classified read sets. We assessed the quality of the classification by mapping reads to contigs of both plants, achieving a misclassification rate low enough (0.22-0.39%) to be used reliably for differential gene expression analysis. Finally, we applied our read classification method to RNA-Seq data from the interface between the non-model parasitic plant C. japonica and the model host plant Glycine max. Analysis of gene expression profiles at 5 parasitizing stages revealed differentially expressed genes from both C. japonica and G. max, and uncovered the coordination of cellular processes between the two plants. CONCLUSIONS: We demonstrated that reliable identification of differentially expressed transcripts in undissected interface region of the parasite-host association is feasible and informative with respect to differential-expression patterns. PMID- 26052340 TI - E2F8 promotes hepatic steatosis through FABP3 expression in diet-induced obesity in zebrafish. AB - BACKGROUND: Diet-induced hepatic steatosis is highly associated with nonalcoholic fatty liver disease, which is related to the development of metabolic syndrome. While advanced stage nonalcoholic hepatic steatosis and steatohepatitis (NASH) result ultimately in fibrosis and cirrhosis, the molecular basis for lipid droplet formation is poorly understood. Common pathways underlie the pathology of mammalian obesity and the zebrafish diet-induced obesity model (DIO-zebrafish) used in this study. METHODS: Our analysis involved a combination of transcriptome (DNA microarray) and proteome (two-dimensional electrophoresis) methods using liver tissue from DIO-zebrafish to find candidate genes involved in hepatic steatosis. We conducted intraperitoneal injection (i.p.) of morpholino antisense oligonucleotides (MOs) for each gene into DIO-zebrafish. We also conducted in vitro overexpression in human cells. Additionally, we examined gene expression during feeding experiments involving anti-obesity compounds, creatine and anserine. RESULTS: We found that fatty acid binding protein 3 (fabp3) and E2F transcription factors were upregulated in hepatic steatosis. E2f8 MO i.p. suppressed fabp3 expression in liver, and ameliorated hepatic steatosis. In human cells (HepG2), E2F8 overexpression promoted FABP3 expression. Additionally, co administration of creatine and anserine suppressed obesity associated phenotypes including hepatic steatosis as indicated by e2f8 and fabp3 down regulation. CONCLUSION: We discovered that the e2f8-fabp3 axis is important in the promotion of hepatic steatosis in DIO-zebrafish. The combination of transcriptome and proteome analyses using the disease model zebrafish allow identification of novel pathways involved in human diseases. PMID- 26052342 TI - PrimerView: high-throughput primer design and visualization. AB - BACKGROUND: High-throughput primer design is routinely performed in a wide number of molecular applications including genotyping specimens using traditional PCR techniques as well as assembly PCR, nested PCR, and primer walking experiments. Batch primer design is also required in validation experiments from RNA-seq transcriptome sequencing projects, as well as in generating probes for microarray experiments. The growing popularity of next generation sequencing and microarray technology has created a greater need for more primer design tools to validate large numbers of candidate genes and markers. RESULTS: To meet these demands I here present a tool called PrimerView that designs forward and reverse primers from multi-sequence datasets, and generates graphical outputs that map the position and distribution of primers to the target sequence. This module operates from the command-line and can collect user-defined input for the design phase of each primer. CONCLUSIONS: PrimerView is a straightforward to use module that implements a primer design algorithm to return forward and reverse primers from any number of FASTA formatted sequences to generate text based output of the features for each primer, and also graphical outputs that map the designed primers to the target sequence. PrimerView is freely available without restrictions. PMID- 26052343 TI - School-based screening for psychiatric disorders in Moroccan-Dutch youth. AB - BACKGROUND: While ethnic diversity is increasing in many Western countries, access to youth mental health care is generally lower among ethnic minority youth compared to majority youth. It is unlikely that this is explained by a lower prevalence of psychiatric disorders in minority children. Effective screening methods to detect psychiatric disorders in ethnic minority youth are important to offer timely interventions. METHODS: School-based screening was carried out at primary and secondary schools in the Netherlands with the Strengths and Difficulties Questionnaire (SDQ) self report and teacher report. Additionally, internalizing and psychotic symptoms were assessed with the depressive, somatic and anxiety symptoms scales of the Social and Health Assessment (SAHA) and items derived from the Kiddie-Schedule for Affective Disorders and Schizophrenia (K SADS). Of 361 Moroccan-Dutch youths (ages 9 to 16 years) with complete screening data, 152 children were diagnostically assessed for psychiatric disorders using the K-SADS. The ability to screen for any psychiatric disorder, and specific externalizing or internalizing disorders was estimated for the SDQ, as well as for the SAHA and K-SADS scales. RESULTS: Twenty cases with a psychiatric disorder were identified (13.2 %), thirteen of which with externalizing (8.6 %) and seven with internalizing (4.6 %) diagnoses. The SDQ predicted psychiatric disorders in Moroccan-Dutch youth with a good degree of accuracy, especially when the self report and teacher report were combined (AUC = 0.86, 95 % CI = 0.77-0.94). The SAHA scales improved identification of internalizing disorders. Psychotic experiences significantly predicted psychiatric disorders, but did not have additional discriminatory power as compared to screening instruments measuring non-psychotic psychiatric symptoms. CONCLUSIONS: School-based screening for psychiatric disorders is effective in Moroccan-Dutch youth. We suggest routine screening with the SDQ self report and teacher report at schools, supplemented by the SAHA measuring internalizing symptoms, and offering accessible non stigmatizing interventions at school to children scoring high on screening questionnaires. Further research should estimate (subgroup-specific) norms and optimal cut-offs points in larger groups for use in school-based screening methods. PMID- 26052344 TI - Tolerance and adaptive evolution of triacylglycerol-producing Rhodococcus opacus to lignocellulose-derived inhibitors. AB - BACKGROUND: Lignocellulosic biomass has been investigated as a renewable non-food source for production of biofuels. A significant technical challenge to using lignocellulose is the presence of microbial growth inhibitors generated during pretreatment processes. Triacylglycerols (TAGs) are potential precursors for lipid-based biofuel production. Rhodococcus opacus MITXM-61 is an oleaginous bacterium capable of producing large amounts of TAGs on high concentrations of glucose and xylose present in lignocellulosic hydrolysates. However, this strain is sensitive to ligonocellulose-derived inhibitors. To understand the toxic effects of the inhibitors in lignocellulosic hydrolysates, strain MITXM-61 was examined for tolerance toward the potential inhibitors and was subjected to adaptive evolution for the resistance to the inhibitors. RESULTS: We investigated growth-inhibitory effects by potential lignocellulose-derived inhibitors of phenols (lignin, vanillin, 4-hydroxybenzaldehyde (4-HB), syringaldehyde), furans (furfural and 5-hydroxymethyl-2-furaldehyde), and organic acids (levulinic acid, formic acid, and acetic acid) on the growth and TAG production of strain MITXM 61. Phenols and furans exhibited potent inhibitory effects at a concentration of 1 g L(-1), while organic acids had insignificant impacts at concentrations of up to 2 g L(-1). In an attempt to improve the inhibitor tolerance of strain MITXM 61, we evaluated the adaptation of this strain to the potential inhibitors. Adapted mutants were generated on defined agar media containing lignin, 4-HB, and syringaldehyde. Strain MITXM-61(SHL33) with improved multiple resistance of lignin, 4-HB, and syringaldehyde was constructed through adaptive evolution-based strategies. The evolved strain exhibited a two- to threefold increase in resistance to lignin, 4-HB, and syringaldehyde at 50% growth-inhibitory concentrations, compared to the parental strain. When grown in genuine lignocellulosic hydrolysates of corn stover, wheat straw, and hardwood containing growth inhibitors, strain MITXM-61(SHL33) exhibited a markedly shortened lag phase in comparison with that of strain MITXM-61. CONCLUSION: This study provides important clues to overcome the negative effects of inhibitors in lignocellulosic hydrolysates on TAG production of R. opacus cells. The findings can contribute to significant progress in detoxified pretreatment of hydrolysates and development of more efficient strains for industrial TAG fermentations of R. opacus using lignocellulosic biomass. PMID- 26052345 TI - Enzyme activity highlights the importance of the oxidative pentose phosphate pathway in lipid accumulation and growth of Phaeodactylum tricornutum under CO2 concentration. AB - BACKGROUND: Rising CO2 concentration was reported to increase phytoplankton growth rate as well as lipid productivity. This has raised questions regarding the NADPH supply for high lipid synthesis as well as rapid growth of algal cells. RESULTS: In this study, growth, lipid content, photosynthetic performance, the activity, and expression of key enzymes in Calvin cycle and oxidative pentose phosphate pathway (OPPP) were analyzed in the marine diatom Phaeodactylum tricornutum under three different CO2 concentrations (low CO2 (0.015 %), mid CO2 (atmospheric, 0.035 %) and high CO2 (0.15 %)). Both the growth rate and lipid content of P. tricornutum increased significantly under the high CO2 concentration. Enzyme activity and mRNA expression of three Calvin cycle-related enzymes (Rubisco, 3-phosphoglyceric phosphokinase (PGK), phosphoribulokinase (PRK)) were also increased under high CO2 cultivation, which suggested the enhancement of Calvin cycle activity. This may account for the observed rapid growth rate. In addition, high activity and mRNA expression of G6PDH and 6PGDH, which produce NADPH through OPPP, were observed in high CO2 cultured cells. These results indicate OPPP was enhanced and might play an important role in lipid synthesis under high CO2 concentration. CONCLUSIONS: The oxidative pentose phosphate pathway may participate in the lipid accumulation in rapid-growth P. tricornutum cells in high CO2 concentration. PMID- 26052346 TI - Genomic instability of human embryonic stem cell lines using different passaging culture methods. AB - BACKGROUND: Human embryonic stem cells exhibit genomic instability that can be related to culture duration or to the passaging methods used for cell dissociation. In order to study the impact of cell dissociation techniques on human embryonic stem cells genomic instability, we cultured H1 and H9 human embryonic stem cells lines using mechanical/manual or enzymatic/collagenase-IV dissociation methods. Genomic instability was evaluated at early (p60) passages by using oligonucleotide based array-comparative genomic hybridization 105 K with a mean resolution of 50 Kb. RESULTS: DNA variations were mainly located on subtelomeric and pericentromeric regions with sizes <100 Kb. In this study, 9 recurrent genomic variations were acquired during culture including the well known duplication 20q11.21. When comparing cell dissociation methods, we found no significant differences between DNA variations number and size, DNA gain or DNA loss frequencies, homozygous loss frequencies and no significant difference on the content of genes involved in development, cell cycle tumorigenesis and syndrome disease. In addition, we have never found any malignant tissue in 4 different teratoma representative of the two independent stem cell lines. CONCLUSIONS: These results show that the occurrence of genomic instability in human embryonic stem cells is similar using mechanical or collagenase IV-based enzymatic cell culture dissociation methods. All the observed genomic variations have no impact on the development of malignancy. PMID- 26052347 TI - Clinical and molecular characterization of a patient with interstitial 6q21q22.1 deletion. AB - BACKGROUND: Interstitial 6q deletions, involving the 6q15q25 chromosomal region, are rare events characterized by variable phenotypes and no clear karyotype/phenotype correlation has been determined yet. RESULTS: We present a child with a 6q21q22.1 deletion, characterized by array-CGH, associated with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, skeletal, muscle, and brain anomalies. DISCUSSION: In our patient, the 6q21q22.1 deleted region contains ten genes (TRAF3IP2, FYN, WISP3, TUBE1, LAMA4, MARCKS, HDAC2, HS3ST5, FRK, COL10A1) and two desert gene regions. We discuss here if these genes had some role in determining the phenotype of our patient in order to establish a possible karyotype/phenotype correlation. PMID- 26052348 TI - Why is Tanimoto index an appropriate choice for fingerprint-based similarity calculations? AB - BACKGROUND: Cheminformaticians are equipped with a very rich toolbox when carrying out molecular similarity calculations. A large number of molecular representations exist, and there are several methods (similarity and distance metrics) to quantify the similarity of molecular representations. In this work, eight well-known similarity/distance metrics are compared on a large dataset of molecular fingerprints with sum of ranking differences (SRD) and ANOVA analysis. The effects of molecular size, selection methods and data pretreatment methods on the outcome of the comparison are also assessed. RESULTS: A supplier database (https://mcule.com/) was used as the source of compounds for the similarity calculations in this study. A large number of datasets, each consisting of one hundred compounds, were compiled, molecular fingerprints were generated and similarity values between a randomly chosen reference compound and the rest were calculated for each dataset. Similarity metrics were compared based on their ranking of the compounds within one experiment (one dataset) using sum of ranking differences (SRD), while the results of the entire set of experiments were summarized on box and whisker plots. Finally, the effects of various factors (data pretreatment, molecule size, selection method) were evaluated with analysis of variance (ANOVA). CONCLUSIONS: This study complements previous efforts to examine and rank various metrics for molecular similarity calculations. Here, however, an entirely general approach was taken to neglect any a priori knowledge on the compounds involved, as well as any bias introduced by examining only one or a few specific scenarios. The Tanimoto index, Dice index, Cosine coefficient and Soergel distance were identified to be the best (and in some sense equivalent) metrics for similarity calculations, i.e. these metrics could produce the rankings closest to the composite (average) ranking of the eight metrics. The similarity metrics derived from Euclidean and Manhattan distances are not recommended on their own, although their variability and diversity from other similarity metrics might be advantageous in certain cases (e.g. for data fusion). Conclusions are also drawn regarding the effects of molecule size, selection method and data pretreatment on the ranking behavior of the studied metrics. Graphical AbstractA visual summary of the comparison of similarity metrics with sum of ranking differences (SRD). PMID- 26052350 TI - Analysis and Prediction of User Editing Patterns in Ontology Development Projects. AB - The development of real-world ontologies is a complex undertaking, commonly involving a group of domain experts with different expertise that work together in a collaborative setting. These ontologies are usually large scale and have complex structures. To assist in the authoring process, ontology tools are key at making the editing process as streamlined as possible. Being able to predict confidently what the users are likely to do next as they edit an ontology will enable us to focus and structure the user interface accordingly and to facilitate more efficient interaction and information discovery. In this paper, we use data mining, specifically the association rule mining, to investigate whether we are able to predict the next editing operation that a user will make based on the change history. We simulated and evaluated continuous prediction across time using sliding window model. We used the association rule mining to generate patterns from the ontology change logs in the training window and tested these patterns on logs in the adjacent testing window. We also evaluated the impact of different training and testing window sizes on the prediction accuracies. At last, we evaluated our prediction accuracies across different user groups and different ontologies. Our results indicate that we can indeed predict the next editing operation a user is likely to make. We will use the discovered editing patterns to develop a recommendation module for our editing tools, and to design user interface components that better fit with the user editing behaviors. PMID- 26052349 TI - Cumulative impact of health deficits, social vulnerabilities, and protective factors on cognitive dynamics in late life: a multistate modeling approach. AB - INTRODUCTION: Many factors influence late-life cognitive changes, and evaluating their joint impact is challenging. Typical approaches focus on average decline and a small number of factors. We used multistate transition models and index variables to look at changes in cognition in relation to frailty (accumulation of health deficits), social vulnerability, and protective factors in the Honolulu Asia Aging Study (HAAS). METHODS: The HAAS is a prospective cohort study of 3,845 men of Japanese descent, aged 71 to 93 years at baseline. Cognitive function was measured using the Cognitive Abilities Screening Instrument (CASI). Baseline index variables were constructed of health deficits (frailty), social vulnerabilities, and protective factors. The chances of improvement/stability/decline in cognitive function and death were simultaneously estimated using multistate transition modeling for 3- and 6-year transitions from baseline. RESULTS: On average, CASI scores declined by 5.3 points (standard deviation (SD) = 10.0) over 3 years and 9.5 points (SD = 13.9) over 6 years. After adjusting for education and age, baseline frailty was associated with an increased risk of cognitive decline at 3 years (beta = 0.18, 95% confidence interval (CI), 0.08 to 0.29) and 6 years (beta = 0.40, 95% CI, 0.27 to 0.54). The social vulnerability index was associated with 3-year changes (beta = 0.16, 95% CI, 0.09 to 0.23) and 6-year changes (beta = 0.14, 95% CI, 0.05 to 0.24) in CASI scores. The protective index was associated with reductions in cognitive decline over the two intervals (3-year: beta = -0.16, 95% CI, -0.24 to -0.09; 6-year: beta = -0.21, 95% CI, -0.31 to -0.11,). CONCLUSIONS: Research on cognition in late life needs to consider overall health, the accumulation of protective factors, and the dynamics of cognitive change. Index variables and multistate transition models can enhance understanding of the multifactorial nature of late life changes in cognition. PMID- 26052351 TI - Robotic anterior resection in a patient with situs inversus: is it merely a mirror image of everything? AB - Situs inversus (SI) is a rare condition involving transposition of internal organs. In performing minimally invasive surgeries for these patients, exact mirror image of the usual technique may not be easily achieved, especially for right-handed surgeons. We describe a case of robotic anterior resection in a patient with rectal cancer and SI, illustrating the technique and how robotic system facilitates the procedure. A 59-year-old gentleman presented with altered bowel habit. Colonoscopy showed an obstructing tumour at 10 cm from the anal verge. Computed tomography did not show distant metastasis, but revealed the diagnosis of SI. Intraoperative laparoscopy revealed peritoneal metastasis. Total robotic, single docking, anterior resection was performed to palliate his obstructive symptoms. The operation lasted for 3 h and 24 min. Blood loss was 100 ml. There were no intraoperative or postoperative complications. The patient was discharged on day four. The final pathology was T3N2M1. PMID- 26052352 TI - The Action-Sentence Compatibility Effect in ASL: the role of semantics vs. perception. AB - Embodied theories of cognition propose that humans use sensorimotor systems in processing language. The Action-Sentence Compatibility Effect (ACE) refers to the finding that motor responses are facilitated after comprehending sentences that imply movement in the same direction. In sign languages there is a potential conflict between sensorimotor systems and linguistic semantics: movement away from the signer is perceived as motion toward the comprehender. We examined whether perceptual processing of sign movement or verb semantics modulate the ACE. Deaf ASL signers performed a semantic judgment task while viewing signed sentences expressing toward or away motion. We found a significant congruency effect relative to the verb's semantics rather than to the perceived motion. This result indicates that (a) the motor system is involved in the comprehension of a visual-manual language, and (b) motor simulations for sign language are modulated by verb semantics rather than by the perceived visual motion of the hands. PMID- 26052353 TI - Joint Analysis of Survival Time and Longitudinal Categorical Outcomes. AB - In biomedical or public health research, it is common for both survival time and longitudinal categorical outcomes to be collected for a subject, along with the subject's characteristics or risk factors. Investigators are often interested in finding important variables for predicting both survival time and longitudinal outcomes which could be correlated within the same subject. Existing approaches for such joint analyses deal with continuous longitudinal outcomes. New statistical methods need to be developed for categorical longitudinal outcomes. We propose to simultaneously model the survival time with a stratified Cox proportional hazards model and the longitudinal categorical outcomes with a generalized linear mixed model. Random effects are introduced to account for the dependence between survival time and longitudinal outcomes due to unobserved factors. The Expectation-Maximization (EM) algorithm is used to derive the point estimates for the model parameters, and the observed information matrix is adopted to estimate their asymptotic variances. Asymptotic properties for our proposed maximum likelihood estimators are established using the theory of empirical processes. The method is demonstrated to perform well in finite samples via simulation studies. We illustrate our approach with data from the Carolina Head and Neck Cancer Study (CHANCE) and compare the results based on our simultaneous analysis and the separately conducted analyses using the generalized linear mixed model and the Cox proportional hazards model. Our proposed method identifies more predictors than by separate analyses. PMID- 26052354 TI - Inter- and transgenerational epigenetic inheritance: evidence in asthma and COPD? AB - Evidence is now emerging that early life environment can have lifelong effects on metabolic, cardiovascular, and pulmonary function in offspring, a concept also known as fetal or developmental programming. In mammals, developmental programming is thought to occur mainly via epigenetic mechanisms, which include DNA methylation, histone modifications, and expression of non-coding RNAs. The effects of developmental programming can be induced by the intrauterine environment, leading to intergenerational epigenetic effects from one generation to the next. Transgenerational epigenetic inheritance may be considered when developmental programming is transmitted across generations that were not exposed to the initial environment which triggered the change. So far, inter- and transgenerational programming has been mainly described for cardiovascular and metabolic disease risk. In this review, we discuss available evidence that epigenetic inheritance also occurs in respiratory diseases, using asthma and chronic obstructive pulmonary disease (COPD) as examples. While multiple epidemiological as well as animal studies demonstrate effects of 'toxic' intrauterine exposure on various asthma-related phenotypes in the offspring, only few studies link epigenetic marks to the observed phenotypes. As epigenetic marks may distinguish individuals most at risk of later disease at early age, it will enable early intervention strategies to reduce such risks. To achieve this goal further, well designed experimental and human studies are needed. PMID- 26052357 TI - Special Mitral Valve Issue. PMID- 26052355 TI - The GALNT9, BNC1 and CCDC8 genes are frequently epigenetically dysregulated in breast tumours that metastasise to the brain. AB - BACKGROUND: Tumour metastasis to the brain is a common and deadly development in certain cancers; 18-30 % of breast tumours metastasise to the brain. The contribution that gene silencing through epigenetic mechanisms plays in these metastatic tumours is not well understood. RESULTS: We have carried out a bioinformatic screen of genome-wide breast tumour methylation data available at The Cancer Genome Atlas (TCGA) and a broad literature review to identify candidate genes that may contribute to breast to brain metastasis (BBM). This analysis identified 82 candidates. We investigated the methylation status of these genes using Combined Bisulfite and Restriction Analysis (CoBRA) and identified 21 genes frequently methylated in BBM. We have identified three genes, GALNT9, CCDC8 and BNC1, that were frequently methylated (55, 73 and 71 %, respectively) and silenced in BBM and infrequently methylated in primary breast tumours. CCDC8 was commonly methylated in brain metastases and their associated primary tumours whereas GALNT9 and BNC1 were methylated and silenced only in brain metastases, but not in the associated primary breast tumours from individual patients. This suggests differing roles for these genes in the evolution of metastatic tumours; CCDC8 methylation occurs at an early stage of metastatic evolution whereas methylation of GANLT9 and BNC1 occurs at a later stage of tumour evolution. Knockdown of these genes by RNAi resulted in a significant increase in the migratory and invasive potential of breast cancer cell lines. CONCLUSIONS: These findings indicate that GALNT9 (an initiator of O glycosylation), CCDC8 (a regulator of microtubule dynamics) and BNC1 (a transcription factor with a broad range of targets) may play a role in the progression of primary breast tumours to brain metastases. These genes may be useful as prognostic markers and their products may provide novel therapeutic targets. PMID- 26052356 TI - MicroRNA expression profiling predicts clinical outcome of carboplatin/paclitaxel based therapy in metastatic melanoma treated on the ECOG-ACRIN trial E2603. AB - BACKGROUND: Carboplatin/paclitaxel (CP), with or without sorafenib, result in objective response rates of 18-20 % in unselected chemotherapy-naive patients. Molecular predictors of survival and response to CP-based chemotherapy in metastatic melanoma (MM) are critical to improving the therapeutic index. Intergroup trial E2603 randomized MM patients to CP with or without sorafenib. Expression data were collected from pre-treatment formalin-fixed paraffin embedded (FFPE) tumor tissues from 115 of 823 patients enrolled on E2603. The selected patients were balanced across treatment arms, BRAF status, and clinical outcome. We generated data using Nanostring array (microRNA (miRNA) expression) and DNA-mediated annealing, selection, extension and ligation (DASL)/Illumina microarrays (HT12 v4) (mRNA expression) with protocols optimized for FFPE samples. Integrative computational analysis was performed using a novel Tree guided Recursive Cluster Selection (T-ReCS) [1] algorithm to select the most informative features/genes, followed by TargetScan miRNA target prediction (Human v6.2) and mirConnX [2] for network inference. RESULTS: T-ReCS identified PLXNB1 as negatively associated with progression-free survival (PFS) and miR-659-3p as the primary miRNA associated positively with PFS. miR-659-3p was differentially expressed based on PFS but not based on treatment arm, BRAF or NRAS status. Dichotomized by median PFS (less vs greater than 4 months), miR-659-3p expression was significantly different. High miR-659-3p expression distinguished patients with responsive disease (complete or partial response) from patients with stable disease. miR-659-3p predicted gene targets include NFIX, which is a transcription factor known to interact with c-Jun and AP-1 in the context of developmental processes and disease. CONCLUSIONS: This novel integrative analysis implicates miR-659-3p as a candidate predictive biomarker for MM patients treated with platinum-based chemotherapy and may serve to improve patient selection. PMID- 26052358 TI - Spatial information enhanced by non-spatial information in hippocampal granule cells. AB - The hippocampus organizes sequential memory composed of non-spatial information (such as objects and odors) and spatial information (places). The dentate gyrus (DG) in the hippocampus receives two types of information from the lateral and medial entorhinal cortices. Non-spatial and spatial information is delivered respectively to distal and medial dendrites (MDs) of granule cells (GCs) within the molecular layer in the DG. To investigate the role of the association of those two inputs, we measured the response characteristics of distal and MDs of a GC in a rat hippocampal slice and developed a multi-compartment GC model with dynamic synapses; this model reproduces the response characteristics of the dendrites. Upon applying random inputs or input sequences generated by a Markov process to the computational model, it was found that a high-frequency random pulse input to distal dendrites (DDs) and, separately, regular burst inputs to MDs were effective for inducing GC activation. Furthermore, when the random and theta burst inputs were simultaneously applied to the respective dendrites, the pattern discrimination for theta burst input to MDs that caused slight GC activation was enhanced in the presence of random input to DDs. These results suggest that the temporal pattern discrimination of spatial information is originally involved in a synaptic characteristic in GCs and is enhanced by non spatial information input to DDs. Consequently, the co-activation of two separate inputs may play a crucial role in the information processing on dendrites of GCs by usefully combing each temporal sequence. PMID- 26052359 TI - Multi-dimensional modulations of alpha and gamma cortical dynamics following mindfulness-based cognitive therapy in Major Depressive Disorder. AB - To illuminate candidate neural working mechanisms of Mindfulness-Based Cognitive Therapy (MBCT) in the treatment of recurrent depressive disorder, parallel to the potential interplays between modulations in electro-cortical dynamics and depressive symptom severity and self-compassionate experience. Linear and nonlinear alpha and gamma EEG oscillatory dynamics were examined concomitant to an affective Go/NoGo paradigm, pre-to-post MBCT or natural wait-list, in 51 recurrent depressive patients. Specific EEG variables investigated were; (1) induced event-related (de-) synchronisation (ERD/ERS), (2) evoked power, and (3) inter-/intra-hemispheric coherence. Secondary clinical measures included depressive severity and experiences of self-compassion. MBCT significantly downregulated alpha and gamma power, reflecting increased cortical excitability. Enhanced alpha-desynchronisation/ERD was observed for negative material opposed to attenuated alpha-ERD towards positively valenced stimuli, suggesting activation of neural networks usually hypoactive in depression, related to positive emotion regulation. MBCT-related increase in left-intra-hemispheric alpha-coherence of the fronto-parietal circuit aligned with these synchronisation dynamics. Ameliorated depressive severity and increased self-compassionate experience pre-to-post MBCT correlated with alpha-ERD change. The multi dimensional neural mechanisms of MBCT pertain to task-specific linear and non linear neural synchronisation and connectivity network dynamics. We propose MBCT related modulations in differing cortical oscillatory bands have discrete excitatory (enacting positive emotionality) and inhibitory (disengaging from negative material) effects, where mediation in the alpha and gamma bands relates to the former. PMID- 26052360 TI - UKF-based closed loop iterative learning control of epileptiform wave in a neural mass model. AB - A novel closed loop control framework is proposed to inhibit epileptiform wave in a neural mass model by external electric field, where the unscented Kalman filter method is used to reconstruct dynamics and estimate unmeasurable parameters of the model. Specifically speaking, the iterative learning control algorithm is introduced into the framework to optimize the control signal. In the proposed method, the control effect can be significantly improved based on the observation of the past attempts. Accordingly, the proposed method can effectively suppress the epileptiform wave as well as showing robustness to noises and uncertainties. Lastly, the simulation is carried out to illustrate the feasibility of the proposed method. Besides, this work shows potential value to design model-based feedback controllers for epilepsy treatment. PMID- 26052361 TI - Monitoring depth of anesthesia using combination of EEG measure and hemodynamic variables. AB - Monitoring depth of anesthesia (DOA) via vital signs is a major ongoing challenge for anesthetists. A number of electroencephalogram (EEG)-based monitors such as the Bispectral (BIS) index have been proposed. However, anesthesia is related to central and autonomic nervous system functions whereas the EEG signal originates only from the central nervous system. This paper proposes an automated DOA detection system which consists of three steps. Initially, we introduce multiscale modified permutation entropy index which is robust in the characterization of the burst suppression pattern and combine multiscale information. This index quantifies the amount of complexity in EEG data and is computationally efficient, conceptually simple and artifact resistant. Then, autonomic nervous system activity is quantified with heart rate and mean arterial pressure which are easily acquired using routine monitoring machine. Finally, the extracted features are used as input to a linear discriminate analyzer (LDA). The method is validated with data obtained from 25 patients during the cardiac surgery requiring cardiopulmonary bypass. The experimental results indicate that an overall accuracy of 89.4 % can be obtained using combination of EEG measure and hemodynamic variables, together with LDA to classify the vital sign into awake, light, surgical and deep anesthetised states. The results demonstrate that the proposed method can estimate DOA more effectively than the commercial BIS index with a stronger artifact-resistance. PMID- 26052362 TI - Long range temporal correlations in EEG oscillations of subclinically depressed individuals: their association with brooding and suppression. AB - Long-range temporal correlations (LRTC) in brain oscillations have been found to be associated with depression severity in clinically depressed patients. Less is known, however, about the relationships between LRTC and proneness to engage in depression-related cognitive emotion regulation (ER) strategies which characterize both clinically and subclinically depressed (SBD) people. In this study we applied detrended fluctuation analysis to the amplitude envelope of broad band, theta band, and alpha band spontaneous EEG oscillations of a group of SBD individuals and a group of non-depressed individuals (both groups from a sample of healthy adults, N = 120), to whom brooding and thought suppression questionnaires were administered. Between-groups differences were not found for any band scaling exponents at any brain location, but linear correlations pointed out several associations between exponents at frontal, central, parietal, temporal, and occipital sites and maladaptive ER strategies. These results suggest that alterations in brain dynamics are related with the proneness that depressive individuals show to engage in brooding and thought suppression in order to cognitively regulate their emotions. PMID- 26052363 TI - Reduced multiple empirical kernel learning machine. AB - Multiple kernel learning (MKL) is demonstrated to be flexible and effective in depicting heterogeneous data sources since MKL can introduce multiple kernels rather than a single fixed kernel into applications. However, MKL would get a high time and space complexity in contrast to single kernel learning, which is not expected in real-world applications. Meanwhile, it is known that the kernel mapping ways of MKL generally have two forms including implicit kernel mapping and empirical kernel mapping (EKM), where the latter is less attracted. In this paper, we focus on the MKL with the EKM, and propose a reduced multiple empirical kernel learning machine named RMEKLM for short. To the best of our knowledge, it is the first to reduce both time and space complexity of the MKL with EKM. Different from the existing MKL, the proposed RMEKLM adopts the Gauss Elimination technique to extract a set of feature vectors, which is validated that doing so does not lose much information of the original feature space. Then RMEKLM adopts the extracted feature vectors to span a reduced orthonormal subspace of the feature space, which is visualized in terms of the geometry structure. It can be demonstrated that the spanned subspace is isomorphic to the original feature space, which means that the dot product of two vectors in the original feature space is equal to that of the two corresponding vectors in the generated orthonormal subspace. More importantly, the proposed RMEKLM brings a simpler computation and meanwhile needs a less storage space, especially in the processing of testing. Finally, the experimental results show that RMEKLM owns a much efficient and effective performance in terms of both complexity and classification. The contributions of this paper can be given as follows: (1) by mapping the input space into an orthonormal subspace, the geometry of the generated subspace is visualized; (2) this paper first reduces both the time and space complexity of the EKM-based MKL; (3) this paper adopts the Gauss Elimination, one of the on-the-shelf techniques, to generate a basis of the original feature space, which is stable and efficient. PMID- 26052364 TI - Effects on hypothalamus when CPG is fed back to basal ganglia based on KIV model. AB - The KIV model approximates the operation of the basic vertebrate forebrain together with the basal ganglia and motor systems. In KIV model, the hypothalamus and the basal ganglia which are two important parts in the midline forebrain are closely associated with the locomotion. The CPG model with time delay is established in this paper and the stability of this CPG model is discussed. The CPG output is treated as the proprioception and fed back to the basal ganglia. We focus on the effects on the hypothalamus and the basal ganglia when the time delay parameter a d , the CPG amplitude parameter e and the CPG frequency parameter T r are changed. Through analysis, we find that there exists optimum value of the parameters a d or T r which can make the synchronization of the hypothalamus optimum when the CPG is added into the basal ganglia. The results could have important implications for biological processes which are about interaction between the neural network and the CPG. PMID- 26052365 TI - Local and global synchronization transitions induced by time delays in small world neuronal networks with chemical synapses. AB - Effects of time delay on the local and global synchronization in small-world neuronal networks with chemical synapses are investigated in this paper. Numerical results show that, for both excitatory and inhibitory coupling types, the information transmission delay can always induce synchronization transitions of spiking neurons in small-world networks. In particular, regions of in-phase and out-of-phase synchronization of connected neurons emerge intermittently as the synaptic delay increases. For excitatory coupling, all transitions to spiking synchronization occur approximately at integer multiples of the firing period of individual neurons; while for inhibitory coupling, these transitions appear at the odd multiples of the half of the firing period of neurons. More importantly, the local synchronization transition is more profound than the global synchronization transition, depending on the type of coupling synapse. For excitatory synapses, the local in-phase synchronization observed for some values of the delay also occur at a global scale; while for inhibitory ones, this synchronization, observed at the local scale, disappears at a global scale. Furthermore, the small-world structure can also affect the phase synchronization of neuronal networks. It is demonstrated that increasing the rewiring probability can always improve the global synchronization of neuronal activity, but has little effect on the local synchronization of neighboring neurons. PMID- 26052366 TI - Lessons Learned from Animal Models of Inherited Bleeding Disorders. AB - Advances in treatment of hemophilia and von Willebrand disease (VWD) depend heavily on the availability of well-characterized animal models. These animals faithfully recapitulate the severe bleeding phenotype that occurs in humans with these inherited bleeding disorders. Research in these animal models represents important early and intermediate steps of translational research aimed at addressing current limitations in treatment such as the development of inhibitory antibodies to coagulation factors VIII and IX (FVIII, FIX) or von Willebrand factor (VWF), the life-long need for frequent venous access, the expense of therapy, and the ongoing need for improved ex vivo coagulation assays and in vivo methods for assessing hemostasis. The primary strengths of research that utilizes these highly relevant animal models include the development of better and safer treatments for hemophilia and VWD. Careful consideration of the strengths and limitations of the specific models is essential for optimizing chances for successful translation of advances to clinical medicine that benefits humans and animals. PMID- 26052367 TI - Mass reconstruction methods for PM2.5: a review. AB - Major components of suspended particulate matter (PM) are inorganic ions, organic matter (OM), elemental carbon (EC), geological minerals, salt, non-mineral elements, and water. Since oxygen (O) and hydrogen (H) are not directly measured in chemical speciation networks, more than ten weighting equations have been applied to account for their presence, thereby approximating gravimetric mass. Assumptions for these weights are not the same under all circumstances. OM is estimated from an organic carbon (OC) multiplier (f) that ranges from 1.4 to 1.8 in most studies, but f can be larger for highly polar compounds from biomass burning and secondary organic aerosols. The mineral content of fugitive dust is estimated from elemental markers, while the water-soluble content is accounted for as inorganic ions or salt. Part of the discrepancy between measured and reconstructed PM mass is due to the measurement process, including: (1) organic vapors adsorbed on quartz-fiber filters; (2) evaporation of volatile ammonium nitrate and OM between the weighed Teflon-membrane filter and the nylon-membrane and/or quartz-fiber filters on which ions and carbon are measured; and (3) liquid water retained on soluble constituents during filter weighing. The widely used IMPROVE equations were developed to characterize particle light extinction in U.S. national parks, and variants of this approach have been tested in a large variety of environments. Important factors for improving agreement between measured and reconstructed PM mass are the f multiplier for converting OC to OM and accounting for OC sampling artifacts. PMID- 26052368 TI - Phytoremediation of particulate matter from indoor air by Chlorophytum comosum L. plants. AB - Higher plants, including spider plants, are able to take up and degrade/detoxify various pollutants in the air. Although nearly 120 plant species have been tested for indoor air phytoremediation, to the best of the authors' knowledge, data on particulate matter (PM) phytoremediation from indoor air are not yet available in literature. This work determined the ability of spider plants to take up PM, one of the most harmful pollutants to man, in the indoor air of five rooms housing different activities (a dental clinic, a perfume-bottling room, a suburban house, an apartment and an office). It was found that spider plants accumulate PM of both categories (water washable and trapped in waxes) and in all three size fractions determined and that the amount differed depending on the type of activity taking place in the particular rooms ranging from 13.62 to 19.79 MUg/cm2. The amount of wax deposited on the leaves of plants grown in these rooms also differed (34.46-72.97 MUg/cm2). The results of this study also demonstrated that the amount of PM accumulated on aluminium plates was always significantly lower than that accumulated on the plants' leaves, showing that more than simply gravity forces are involved in PM accumulation on leaf blades. PMID- 26052369 TI - Association of weather and air pollution interactions on daily mortality in 12 Canadian cities. AB - It has been well established that both meteorological attributes and air pollution concentrations affect human health outcomes. We examined all cause nonaccident mortality relationships for 28 years (1981-2008) in relation to air pollution and synoptic weather type (encompassing air mass) data in 12 Canadian cities. This study first determines the likelihood of summertime extreme air pollution events within weather types using spatial synoptic classification. Second, it examines the modifying effect of weather types on the relative risk of mortality (RR) due to daily concentrations of air pollution (nitrogen dioxide, ozone, sulfur dioxide, and particulate matter <2.5 MUm). We assess both single- and two-pollutant interactions to determine dependent and independent pollutant effects using the relatively new time series technique of distributed lag nonlinear modeling (DLNM). Results display dry tropical (DT) and moist tropical plus (MT+) weathers to result in a fourfold and twofold increased likelihood, respectively, of an extreme pollution event (top 5 % of pollution concentrations throughout the 28 years) occurring. We also demonstrate statistically significant effects of single-pollutant exposure on mortality (p < 0.05) to be dependent on summer weather type, where stronger results occur in dry moderate (fair weather) and DT or MT+ weather types. The overall average single-effect RR increases due to pollutant exposure within DT and MT+ weather types are 14.9 and 11.9 %, respectively. Adjusted exposures (two-way pollutant effect estimates) generally results in decreased RR estimates, indicating that the pollutants are not independent. Adjusting for ozone significantly lowers 67 % of the single pollutant RR estimates and reduces model variability, which demonstrates that ozone significantly controls a portion of the mortality signal from the model. Our findings demonstrate the mortality risks of air pollution exposure to differ by weather type, with increased accuracy obtained when accounting for interactive effects through adjustment for dependent pollutants using a DLNM. PMID- 26052370 TI - Ten modifiers of BRCA1 penetrance validated in a Norwegian series. AB - BACKGROUND: Common genetic variants have been shown to modify BRCA1 penetrance. The aim of this study was to validate these reports in a special cohort of Norwegian BRCA1 mutation carriers that were selected for their extreme age of onset of disease. METHODS: The ten variants rs13387042, rs3803662, rs8170, rs9397435, rs700518, rs10046, rs3834129, rs1045485, rs2363956 and rs16942 were selected to be tested on samples from our biobank. We selected female BRCA1 mutation carriers having had a diagnosis of breast or ovarian cancer below 40 years of age (young cancer group, N = 40), and mutation carriers having had neither breast nor ovarian cancer above 60 years of age (i.e., old no cancer group, N = 38). Relative risks and odd ratios of belonging to the young cancer versus old no cancer groups were calculated as a function of having or not having the SNPs in question. RESULTS: Five of the ten variants were found to be significantly associated with early onset cancer. Some of the variation between our results and those previously reported may be ascribed to stochastic effects in our limited number of patient studies, and/or genetic drift in linkage disequilibrium in the genetically isolated Norwegian population. This is in accordance with the understanding that the SNPs are markers in linkage disequilibrium with their respective disease-causing genetic variants, and that this may vary between different populations. CONCLUSIONS: The results confirmed associations previously reported, with the notion that the degree of association may differ between other populations, which must be considered when discussing the clinical use of the associations described. PMID- 26052372 TI - A Test of Learned Industriousness in the Physical Activity Domain. AB - BACKGROUND: The Theory of Learned Industriousness states that durable individual differences in industriousness are due in part to differences in the extent to which individuals were rewarded for high effort at an earlier time. Individuals rewarded for high effort during training are thought to generalize greater persistence to subsequent tasks than those rewarded for low effort. This study tested whether rewarded physical and/or mental effort at different intensities generalized to greater persistence at a subsequent mental task. METHODS: 80 inactive 18-25 year-olds were randomized into four groups: Low Mental Effort, High Mental Effort, Low Physical Effort, and High Physical Effort. Each completed group-specific effort training and a mental persistence task at baseline and posttest. RESULTS: Factorial analysis of covariance revealed a significant domain x effort interaction on persistence (F[1,75]=4.93, p=.029). High Mental Effort and Low Mental Effort groups demonstrated similar gains in persistence (d=-0.08, p>.05) and points earned (d=0.11, p>.05) following effort training. High Physical Effort and Low Physical Effort diverged on persistence (d=-0.49, p=.004) but not points earned (d =-0.12, p>.05). CONCLUSIONS: Findings suggest either that training and test stimuli were too dissimilar to cue effects of associative learning in physical effort groups, or that effects were present but overpowered by the affective and neurocognitive consequences of an acute bout of intense aerobic physical activity. Findings do not support the Theory of Learned Industriousness nor generalization of effort across physical and mental domains. PMID- 26052373 TI - A Simple Class of Bayesian Nonparametric Autoregression Models. AB - We introduce a model for a time series of continuous outcomes, that can be expressed as fully nonparametric regression or density regression on lagged terms. The model is based on a dependent Dirichlet process prior on a family of random probability measures indexed by the lagged covariates. The approach is also extended to sequences of binary responses. We discuss implementation and applications of the models to a sequence of waiting times between eruptions of the Old Faithful Geyser, and to a dataset consisting of sequences of recurrence indicators for tumors in the bladder of several patients. PMID- 26052371 TI - Recent Advances in the Genetics of Vocal Learning. AB - Language is a complex communicative behavior unique to humans, and its genetic basis is poorly understood. Genes associated with human speech and language disorders provide some insights, originating with the FOXP2 transcription factor, a mutation in which is the source of an inherited form of developmental verbal dyspraxia. Subsequently, targets of FOXP2 regulation have been associated with speech and language disorders, along with other genes. Here, we review these recent findings that implicate genetic factors in human speech. Due to the exclusivity of language to humans, no single animal model is sufficient to study the complete behavioral effects of these genes. Fortunately, some animals possess subcomponents of language. One such subcomponent is vocal learning, which though rare in the animal kingdom, is shared with songbirds. We therefore discuss how songbird studies have contributed to the current understanding of genetic factors that impact human speech, and support the continued use of this animal model for such studies in the future. PMID- 26052374 TI - A simulation study evaluating bio-creep risk in serial non-inferiority clinical trials for preservation of effect. AB - In non-inferiority trials, acceptable efficacy of an experimental treatment is established by ruling out some defined level of reduced effect relative to an effective active control standard. Serial use of non-inferiority trials may lead to newly approved therapies that provide meaningfully reduced levels of benefit; this phenomenon is called bio-creep. Simulations were designed to facilitate understanding of bio-creep risk when approval of an experimental treatment with efficacy less than some proportion of the effect of the active control treatment would constitute harm, such as when new antibiotics that are meaningfully less effective than the most effective current antibiotic would be used for treatment of Community-Acquired Bacterial Pneumonia. In this setting, risk of approval of insufficiently effective therapies may be great, even when the standard treatment effect satisfies constancy across trials. Modifiable factors contributing to this manifestation of bio-creep included the active control selection method, the non inferiority margin, and bias in the active control effect estimate. Therefore, when non-inferiority testing is performed, the best available treatment should be used as the standard, and margins should be based on the estimated effect of this control, accounting for the variability and for likely sources of bias in this estimate, and addressing the importance of preservation of some portion of the standard's effect. PMID- 26052375 TI - Pathophysiological mechanisms involved in non-alcoholic steatohepatitis and novel potential therapeutic targets. AB - Non-alcoholic fatty liver disease (NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as non-alcoholic fatty liver (NAFL) or simple steatosis, and non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms, such as, insulin resistance (IR), lipotoxicity, inflammation, oxidative stress, and recently the gut-liver axis interaction has been described. Incretin-based therapies could play a role in the treatment of NAFLD. Glucagon like peptide-1 (GLP-1) is an intestinal mucosa-derived hormone which is secreted into the bloodstream in response to nutrient ingestion; it favors glucose stimulated insulin secretion, inhibition of postprandial glucagon secretion and delayed gastric emptying. It also promotes weight loss and is involved in lipid metabolism. Once secreted, GLP-1 is quickly degraded by dipeptidyl peptidase-4 (DPP-4). Therefore, DPP-4 inhibitors are able to extend the activity of GLP-1. Currently, GLP-1 agonists and DPP-4 inhibitors represent attractive options for the treatment of NAFLD and NASH. The modulation of lipid and glucose metabolism through nuclear receptors, such as the farsenoid X receptor, also constitutes an attractive therapeutic target. Obeticholic acid is a potent activator of the farnesoid X nuclear receptor and reduces liver fat content and fibrosis in animal models. Ursodeoxycholic acid (UDCA) is a hydrophilic bile acid with immunomodulatory, anti-inflammatory, antiapoptotic, antioxidant and anti-fibrotic properties. UDCA can improve IR and modulate lipid metabolism through its interaction with nuclear receptors such as, TGR5, farnesoid X receptor-alpha, or the small heterodimeric partner. Finally, pharmacologic modulation of the gut microbiota could have a role in the therapy of NAFLD and NASH. Probiotics prevent bacterial translocation and epithelial invasion, inhibit mucosal adherence by bacteria, and stimulate host immunity. In animal models, probiotics prevent obesity, decrease transaminase levels, and improve IR and liver histology in NASH. PMID- 26052376 TI - Hemodynamic monitoring during liver transplantation: A state of the art review. AB - Orthotopic liver transplantation can be marked by significant hemodynamic instability requiring the use of a variety of hemodynamic monitors to aide in intraoperative management. Invasive blood pressure monitoring is essential, but the accuracy of peripheral readings in comparison to central measurements has been questioned. When discrepancies exist, central mean arterial pressure, usually measured at the femoral artery, is considered more indicative of adequate perfusion than those measured peripherally. The traditional pulmonary artery catheter is less frequently used due to its invasive nature and known limitations in measuring preload but still plays an important role in measuring cardiac output (CO) when required and in the management of portopulmonary hypertension. Pulse wave analysis is a newer technology that uses computer algorithms to calculate CO, stroke volume variation (SVV) and pulse pressure variation (PPV). Although SVV and PPV have been found to be accurate predicators of fluid responsiveness, CO measurements are not reliable during liver transplantation. Transesophageal echocardiography is finding an increasing role in the real-time monitoring of preload status, cardiac contractility and the diagnosis of a variety of pathologies. It is limited by the expertise required, limited transgastric views during key portions of the operation, the potential for esophageal varix rupture and difficulty in obtaining quantitative measures of CO in the absence of tricuspid regurgitation. PMID- 26052377 TI - Targeted proteomics for biomarker discovery and validation of hepatocellular carcinoma in hepatitis C infected patients. AB - Hepatocellular carcinoma (HCC)-related mortality is high because early detection modalities are hampered by inaccuracy, expense and inherent procedural risks. Thus there is an urgent need for minimally invasive, highly specific and sensitive biomarkers that enable early disease detection when therapeutic intervention remains practical. Successful therapeutic intervention is predicated on the ability to detect the cancer early. Similar unmet medical needs abound in most fields of medicine and require novel methodological approaches. Proteomic profiling of body fluids presents a sensitive diagnostic tool for early cancer detection. Here we describe such a strategy of comparative proteomics to identify potential serum-based biomarkers to distinguish high-risk chronic hepatitis C virus infected patients from HCC patients. In order to compensate for the extraordinary dynamic range in serum proteins, enrichment methods that compress the dynamic range without surrendering proteome complexity can help minimize the problems associated with many depletion methods. The enriched serum can be resolved using 2D-difference in-gel electrophoresis and the spots showing statistically significant changes selected for identification by liquid chromatography-tandem mass spectrometry. Subsequent quantitative verification and validation of these candidate biomarkers represent an obligatory and rate limiting process that is greatly enabled by selected reaction monitoring (SRM). SRM is a tandem mass spectrometry method suitable for identification and quantitation of target peptides within complex mixtures independent on peptide specific antibodies. Ultimately, multiplexed SRM and dynamic multiple reaction monitoring can be utilized for the simultaneous analysis of a biomarker panel derived from support vector machine learning approaches, which allows monitoring a specific disease state such as early HCC. Overall, this approach yields high probability biomarkers for clinical validation in large patient cohorts and represents a strategy extensible to many diseases. PMID- 26052379 TI - Liver steatosis in hepatitis C patients. AB - There is controversy regarding some aspects of hepatitis C virus (HCV) infection associated liver steatosis, and their relationship with body fat stores. It has classically been found that HCV, especially genotype 3, exerts direct metabolic effects which lead to liver steatosis. This supports the existence of a so called viral steatosis and a metabolic steatosis, which would affect HCV patients who are also obese or diabetics. In fact, several genotypes exert metabolic effects which overlap with some of those observed in the metabolic syndrome. In this review we will analyse the pathogenic pathways involved in the development of steatosis in HCV patients. Several cytokines and adipokines also become activated and are involved in "pure" steatosic effects, in addition to inflammation. They are probably responsible for the evolution of simple steatosis to steatohepatitis, making it difficult to explain why such alterations only affect a proportion of steatosic patients. PMID- 26052380 TI - Liver transplantation as a management of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has a poor prognosis if untreated. It is ranked the third among the causes of cancer-related death. There are multiple etiologic factors that can lead to HCC. Screening for early HCC is challenging due to the lack of well specific biomarkers. However, early diagnosis through successful screening is very important to provide cure rate. Liver transplantation (LT) did not gain wide acceptance until the mid-1980s, after the effective immunosuppression with cyclosporine became available. Orthotopic LT is the best therapeutic option for early, unresectable HCC. It is limited by both, graft shortage and the need for appropriate patient selection. It provides both, the removal of tumor and the remaining cirrhotic liver. In Milan, a prospective cohort study defined restrictive selection criteria known as Milan criteria (MC) that led to superior survival for transplant patients in comparison with any other previous experience with transplantation or other options for HCC. When transplantation occurs within the established MC, the outcomes are similar to those for nonmalignant liver disease after transplantation. The shortage of organs from deceased donors has led to the problems of long waiting times and dropouts. This has led to the adoption of extended criteria by many centers. Several measures have been taken to solve these problems including prioritization of patients with HCC, use of pretransplant adjuvant treatment, and living donor LT. PMID- 26052378 TI - Oxidative stress: New insights on the association of non-alcoholic fatty liver disease and atherosclerosis. AB - Non-alcoholic fatty liver disease (NAFLD) represents the most common and emerging chronic liver disease worldwide. It includes a wide spectrum of liver diseases ranging from simple fatty liver to non-alcoholic steatohepatitis (NASH), which may progress to fibrosis and more severe liver complications such as cirrhosis, hepatocellular carcinoma and liver mortality. NAFLD is strongly associated with obesity, insulin resistance, hypertension, and dyslipidaemia, and is now regarded as the liver manifestation of the metabolic syndrome. The increased mortality of patients with NAFLD is primarily a result of cardiovascular disease and, to a lesser extent, to liver related diseases. Increased oxidative stress has been reported in both patients with NAFLD and patient with cardiovascular risk factors. Thus, oxidative stress represents a shared pathophysiological disorder between the two conditions. Several therapeutic strategies targeting oxidative stress reduction in patients with NAFLD have been proposed, with conflicting results. In particular, vitamin E supplementation has been suggested for the treatment of non-diabetic, non-cirrhotic adults with active NASH, although this recommendation is based only on the results of a single randomized controlled trial. Other antioxidant treatments suggested are resveratrol, silybin, L carnitine and pentoxiphylline. No trial so far, has evaluated the cardiovascular effects of antioxidant treatment in patients with NAFLD. New, large-scale studies including as end-point also the assessment of the atherosclerosis markers are needed. PMID- 26052381 TI - Review on immunosuppression in liver transplantation. AB - The optimal level of immunosuppression in solid organ transplantation, in particular for the liver, is a delicate balance between the benefit of preventing rejection and the adverse side effects of immunosuppression. There is uncertainty about when this level is achieved in any individual recipient. Immunosuppression regimens vary between individual centers and changes with time as new agents and data are available. Presently concerns about the adverse side effects of calcineurin inhibitor, the main class of immunosuppressive agents used in liver transplantation (LT), has led to consideration of the use of antibody induction therapies for patients at higher risk of developing adverse side effects. The longevity of the transplanted organ is potentially improved by better management of rejection episodes and special consideration for tailoring of immunosuppression to the individual with viral hepatitis C, hepatocellular carcinoma or pregnancy. This review provides an overview of the current strategies for post LT immunosuppression and discusses modifications to consider for special patient populations. PMID- 26052382 TI - Non-alcoholic fatty liver disease - the heart of the matter. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease in the Western world. There is a close association with the metabolic syndrome and NAFLD is considered to be the hepatic manifestation of the metabolic syndrome. The components of the metabolic syndrome include hypertension, obesity and insulin resistance which are well established cardiovascular risk factors. The mortality rate of NAFLD patients from myocardial infarction is higher than that in the general United States population and there is also an increased risk of non-fatal cardiovascular events. This article reviews the cardiovascular complications associated with NAFLD. In order to provide comprehensive care of NAFLD patients, physicians need to be aware of, and search for, the cardiac morbidity associated with NAFLD. PMID- 26052383 TI - Hepatitis C virus: Virology, diagnosis and treatment. AB - More than twenty years of study has provided a better understanding of hepatitis C virus (HCV) life cycle, including the general properties of viral RNA and proteins. This effort facilitates the development of sensitive diagnostic tools and effective antiviral treatments. At present, serologic screening test is recommended to perform on individuals in the high risk groups and nucleic acid tests are recommended to confirm the active HCV infections. Quantization and genotyping of HCV RNAs are important to determine the optimal duration of anti viral therapy and predict the likelihood of response. In the early 2000s, pegylated interferon plus ribavirin became the standard anti-HCV treatment. However, this therapy is not ideal. To 2014, boceprevir, telaprevir, simeprevir, sofosbuvir and Harvoni are approved by Food and Drug Administration for the treat of HCV infections. It is likely that the new all-oral, interferon-free, pan genotyping anti-HCV therapy will be available within the next few years. Majority of HCV infections will be cured by these anti-viral treatments. However, not all patients are expected to be cured due to viral resistance and the high cost of antiviral treatments. Thus, an efficient prophylactic vaccine will be the next challenge in the fight against HCV infection. PMID- 26052385 TI - Current concepts in the immunohistochemical evaluation of liver tumors. AB - Immunohistochemistry often plays an important role in the evaluation of liver tumors. Recent advances have established a classification system for hepatocellular adenomas (HCAs) based on morphology, molecular alterations, and immunohistochemistry. Specifically, loss of liver fatty acid binding protein is seen in HNF1alpha-inactivated HCA, staining with serum amyloid A is seen in inflammatory HCA, and diffuse staining with glutamine synthetase (GS) is seen in beta-catenin activated HCA. A panel of immunohistochemical stains including glypican-3 (GPC-3), heat shock protein 70, and GS are useful in distinguishing HCC from non-malignant dysplastic nodules. Immunohistochemistry is also useful to determine whether a liver tumor is of primary hepatocellular or metastatic origin. Recently described markers useful for this purpose include arginase-1, GPC-3, and bile salt export pump. These newer markers may offer superior utility when compared to traditional markers of hepatocellular differentiation such as alpha-fetoprotein, hepatocyte paraffin-1, polyclonal carcinoembryonic antigen, and CD10. This paper will review recent advances in the immunohistochemical evaluation of liver tumors. PMID- 26052384 TI - Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. AB - The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC. PMID- 26052387 TI - Management of chronic hepatitis B before and after liver transplantation. AB - Liver transplantation remains the only curative option for eligible patients with complications of chronic hepatitis B (CHB) infection, including severe acute hepatitis flares, decompensated cirrhosis, and hepatocellular carcinoma. In general, all patients with CHB awaiting liver transplantation should be treated with oral nucleos(t)ide analogs (NAs) with high barriers to resistance to prevent potential flares of hepatitis and reduce disease progression. After liver transplantation, lifelong antiviral therapy is also required to prevent graft hepatitis, which may lead to subsequent graft loss. Although combination therapy using NA and hepatitis B immune globulin (HBIG) has been the regimen most widely adopted for over a decade, recent studies have demonstrated that newer NAs with low rates of resistance are effective in preventing graft hepatitis even without the use of HBIG, achieving excellent long term outcome. For patients without pre existing resistant mutations, monotherapy with a single NA has been shown to be effective. For those with resistant strains, a combination of nucleoside analog and nucleotide analog should be used. To date, clinical trials using therapeutic vaccination have shown suboptimal response, as CHB patients likely have an immune deficit against HBV epitopes. Future strategies include targeting different sites of the hepatitis B replication cycle and restoring the host immunity response to facilitate complete viral eradication. PMID- 26052388 TI - Alpha-1 antitrypsin deficiency and the risk of hepatocellular carcinoma in end stage liver disease. AB - AIM: To evaluate the association between alpha-1 antitrypsin deficiency (A1ATD) and hepatocellular carcinoma (HCC) in patients with end-stage liver disease (ESLD). METHODS: Patients with cirrhosis and ESLD referred to the Cleveland Clinic Foundation for liver transplantation between 2003 and 2014 were included in the study (N = 675). ESLD was defined as having histological features of cirrhosis and/or radiological evidence of cirrhosis in the context of portal hypertension (ascites, variceal bleeding, thrombocytopenia, or hepatic encephalopathy). A1ATD was diagnosed using phenotype characterization (MZ or ZZ), liver biopsy detection of PAS-positive diastase-resistant (PAS+) globules, or both. Patients with other causes of liver diseases such as hepatitis C virus (HCV), alcoholic liver disease and non-alcoholic steatohepatitis (NASH) or NASH were also included in the study. HCC was diagnosed by using imaging modalities, biopsy findings, or explanted liver inspection. Follow-up time was defined as the number of years from the diagnosis of cirrhosis to the diagnosis of hepatocellular carcinoma, or from the diagnosis of cirrhosis to the last follow up visit. The rate of HCC was assessed using time-to-interval analysis for interval censored data. RESULTS: This study included 675 patients. 7% of subjects had A1ATD (n = 47). Out of all subjects who did not have A1ATD, 46% had HCV, 17% had alcoholic liver disease, 19% had NASH and 18% had another primary diagnosis. Of the 47 subjects with A1ATD, 15 had a primary diagnosis of A1ATD (PI*ZZ phenotype and PAS+ globules), 8 had a PI*MZ phenotype alone, 14 had PAS+ alone, and 10 had both the PI*MZ phenotype and PAS+. Median follow-up time was 3.4 (25(th), 75(th) percentiles: 1, 5.2) years. The overall rate of hepatocellular carcinoma in all subjects was 29% (n = 199). In the A1ATD group, the incidence rate of HCC was 8.5% compared to 31% in the group of patients with other causes of cirrhosis (P = 0.001). Patients with ESLD due to A1ATD had the lowest yearly cumulative rate of hepatocellular carcinoma at 0.88% per year compared to 2.7% for those with HCV cirrhosis, 1.5% in patients with NASH and 0.9% in alcohol induced liver disease (P < 0.001). CONCLUSION: Within this group of patients with ESLD, there was no significant association between A1ATD and increased risk of HCC. PMID- 26052386 TI - Current systemic treatment of hepatocellular carcinoma: A review of the literature. AB - Hepatocellular carcinoma (HCC) is the fifth most common form of human cancer worldwide and the third most common cause of cancer-related deaths. The strategies of various treatments for HCC depend on the stage of tumor, the status of patient's performance and the reserved hepatic function. The Barcelona Clinic Liver Cancer (BCLC) staging system is currently used most for patients with HCC. For example, for patients with BCLC stage 0 (very early stage) and stage A (early stage) HCC, the curable treatment modalities, including resection, transplantation and radiofrequency ablation, are taken into consideration. If the patients are in BCLC stage B (intermediate stage) and stage C (advanced stage) HCC, they may need the palliative transarterial chemoembolization and even the target medication of sorafenib. In addition, symptomatic treatment is always recommended for patients with BCLC stage D (end stage) HCC. In this review, we will attempt to summarize the historical perspective and the current developments of systemic therapies in BCLC stage B and C in HCC. PMID- 26052389 TI - Genetic ancestry analysis in non-alcoholic fatty liver disease patients from Brazil and Portugal. AB - AIM: To study the association between genetic ancestry, non-alcoholic fatty liver disease (NAFLD) metabolic characteristics in two cohorts of patients, from Brazil and Portugal. METHODS: We included 131 subjects from Brazil [(n = 45 with simple steatosis (S. Steatosis) and n = 86 with nonalcoholic steatohepatitis (NASH)] and 90 patients from Portugal (n = 66, S. Steatosis; n = 24, NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis: simple steatosis or non alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers (AT3-I/D, LPL, Sb19.3, APO, FY-Null, PV92, and CKMM) with the greatest ethnic-geographical differential frequencies (>= 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP online and the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant (P < 0.05). RESULTS: In the Brazilian sample, NASH was significantly more frequent among the elderly patients with diabetes (NASH 56 +/- 1.1 years old vs S. Steatosis 51 +/- 1.5 years old, P = 3.7 x 10(-9)), dyslipidemia (NASH 63% vs S. Steatosis 37%, P = 0.009), higher fasting glucose levels (NASH 124 +/- 5.2 vs S. Steatosis 106 +/- 5.3, P = 0.001) and Homeostatic Model of Assessment index > 2.5 [NASH 5.3 (70.8%) vs S. Steatosis 4.6 (29.2%) P = 0.04]. In the Portuguese study population, dyslipidemia was present in all patients with NASH (P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group (P = 0.003, respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort (Brazilian cohort: P = 0.75; Portuguese cohort: P = 0.97). Nonetheless, the genetic ancestry contribution of the Brazilian and Portuguese population were different, and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH and S. Steatosis groups. CONCLUSION: There was no difference between the genetic ancestry contribution among Brazilian and Portuguese individuals with NASH and S. Steatosis from each cohort. PMID- 26052390 TI - Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease. AB - Lately, the world has faced tremendous progress in the understanding of non alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs. PMID- 26052391 TI - Hepatocellular carcinoma: From diagnosis to treatment. AB - Hepatocellular carcinoma (HCC) is the sixth most prevalent malignancy worldwide and is a rising cause of cancer related mortality. Risk factors for HCC are well documented and effective surveillance and early diagnosis allow for curative therapies. The majority of HCC appears to be caused by cirrhosis from chronic hepatitis B and hepatitis C virus. Preventive strategies include vaccination programs and anti-viral treatments. Surveillance with ultrasonography detects early stage disease and improves survival rates. Many treatment options exist for individuals with HCC and are determined by stage of presentation. Liver transplantation is offered to patients who are within the Milan criteria and are not candidates for hepatic resection. In patients with advanced stage disease, sorafenib shows some survival benefit. PMID- 26052392 TI - Current and future antiviral drug therapies of hepatitis B chronic infection. AB - Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon (IFN)-alpha and monotherapy with five nucleos(t)ide analogues (NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish long-term control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection. PMID- 26052393 TI - Advanced hepatocellular carcinoma and sorafenib: Diagnosis, indications, clinical and radiological follow-up. AB - Advanced stage hepatocellular carcinoma (HCC) is a category of disease defined by radiological, clinical and hepatic function parameters, comprehending a wide range of patients with different general conditions. The main therapeutic option is represented by sorafenib treatment, a multi-kinase inhibitor with anti proliferative and anti-angiogenic effect. Trans-arterial Radio Embolization also represents a promising new approach to intermediate/advanced HCC. Post-marketing clinical studies showed that only a portion of patients actually benefits from sorafenib treatment, and an even smaller percentage of patients treated shows partial/complete response on follow-up examinations, up against relevant costs and an incidence of drug related adverse effects. Although the treatment with sorafenib has shown a significant increase in mean overall survival in different studies, only a part of patients actually shows real benefits, while the incidence of drug related significant adverse effects and the economic costs are relatively high. Moreover, only a small percentage of patients also shows a response in terms of lesion dimensions reduction. Being able to properly differentiate patients who are responding to the therapy from non-responders as early as possible is then still difficult and could be a pivotal challenge for the future; in fact it could spare several patients a therapy often difficult to bear, directing them to other second line treatments (many of which are at the moment still under investigation). For this reason, some supplemental criteria to be added to the standard modified Response Evaluation Criteria in Solid Tumors evaluation are being searched for. In particular, finding some parameters (cellular density, perfusion grade and enhancement rate) able to predict the sensitivity of the lesions to anti-angiogenic agents could help in stratifying patients in terms of treatment responsiveness before the beginning of the therapy itself, or in the first weeks of sorafenib treatment. This would bring a strongly desirable help in clinical managements of these patients. PMID- 26052394 TI - Percutaneous microwave ablation vs radiofrequency ablation in the treatment of hepatocellular carcinoma. AB - Hepatocellular cancer ranks fifth among cancers and is related to chronic viral hepatitis, alcohol abuse, steatohepatitis and liver autoimmunity. Surgical resection and orthotopic liver transplantation have curative potential, but fewer than 20% of patients are suitable candidates. Interventional treatments are offered to the vast majority of patients. Radiofrequency (RFA) and microwave ablation (MWA) are among the therapeutic modalities, with similar indications which include the presence of up to three lesions, smaller than 3 cm in size, and the absence of extrahepatic disease. The therapeutic effect of both methods relies on thermal injury, but MWA uses an electromagnetic field as opposed to electrical current used in RFA. Unlike MWA, the effect of RFA is partially limited by the heat-sink effect and increased impedance of the ablated tissue. Compared with RFA, MWA attains a more predictable ablation zone, permits simultaneous treatment of multiple lesions, and achieves larger coagulation volumes in a shorter procedural time. Major complications of both methods are comparable and infrequent (approximately 2%-3%), and they include haemorrhage, infection/abscess, visceral organ injury, liver failure, and pneumothorax. RFA may incur the additional complication of skin burns. Nevertheless, there is no compelling evidence for differences in clinical outcomes, including local recurrence rates and survival. PMID- 26052395 TI - Risk for hepatocellular carcinoma in the course of chronic hepatitis B virus infection and the protective effect of therapy with nucleos(t)ide analogues. AB - Hepatocellular carcinoma (HCC) is a major health problem worldwide, representing one of the leading causes of death. Chronic hepatitis B virus (HBV) infection (CHB) is the most important etiologic factor of this tumor, accounting for the development of more than 50% of the cases in the world. Primary prevention of HCC is possible by hepatitis B vaccination conferring protection from HBV infection. However, according to the World Health Organization Hepatitis B Fact sheet N degrees 204 (update of July 2014) globally there exists a large pool of > 240 million people chronically infected with HBV who are at risk for development of HCC. These individuals represent a target population for secondary prevention both of cirrhosis and of HCC. Since ongoing HBV replication in CHB is linked with the progression of the underlying liver disease to cirrhosis as well as with the development of HCC, effective antiviral treatment in CHB has also been evaluated in terms of secondary prevention of HCC. Currently, most patients with active CHB are subjected to long term treatment with the first line nucleos(t)ide analogues entecavir and tenofovir. These compounds are of high antiviral potency and have a high barrier to HBV resistance compared to lamivudine, adefovir dipivoxil and even telbivudine. Many studies have shown that patients under antiviral treatment, especially those in virological remission, develop less frequently HCC compared to the untreated ones. However, the risk for development of HCC cannot be eliminated. Therefore, surveillance for the development of HCC of patients with chronic hepatitis B must be lifelong or until a time in the future when new treatments will be able to completely eradicate HBV from the liver particularly in the early stages of CHB infection. In this context, the aim of this review is to outline the magnitude of the risk for development of HCC among patients with CHB, in the various phases of the infection and in relation to virus, host and environmental factors as evaluated in the world literature. Moreover, the benefits of antiviral treatment of CHB with nucleos/tide analogs, which have changed the natural history of the disease and have reduced but not eliminated the risk of HCC are also reviewed. PMID- 26052396 TI - Autoantibodies in chronic hepatitis C: A clinical perspective. AB - Non-organ-specific autoantibodies and thyroid autoantibodies have been frequently found in chronic carriers of hepatitis C virus (HCV). With respect to endomysial antibodies and tissue transglutaminase, it is controversial whether the prevalence of gluten-related seromarkers is higher in patients with HCV. In such cases, in addition to acknowledging any currently existing autoimmune disease, recognizing the risk of the patient developing an autoimmune disease during interferon (IFN)-based treatment must be a principle concern. From a clinical point-of-view, the presence of autoantibodies arouses suspicion that an autoimmune disease may be present or may be precipitated by IFN-based HCV treatment. In this paper, we review the prevalence of autoantibodies in individuals with hepatitis C, the clinical significance of these autoantibodies, and the approach recommended for such situations. PMID- 26052397 TI - Clinical relevance of hepatitis B virus variants. AB - The hepatitis B virus (HBV) is a global public health problem with more than 240 million people chronically infected worldwide, who are at risk for end-stage liver disease and hepatocellular carcinoma. There are an estimated 600000 deaths annually from complications of HBV-related liver disease. Antiviral therapy with nucleos/tide analogs (NA) targeting the HBV polymerase (P) can inhibit disease progression by long-term suppression of HBV replication. However, treatment may fail with first generation NA therapy due to the emergence of drug-resistant mutants, as well as incomplete medication adherence. The HBV replicates via an error-prone reverse transcriptase leading to quasispecies. Due to overlapping open reading frames mutations within the HBV P can cause concomitant changes in the HBV surface gene (S) and vice versa. HBV quasispecies diversity is associated with response to antiviral therapy, disease severity and long-term clinical outcomes. Specific mutants have been associated with antiviral drug resistance, immune escape, liver fibrosis development and tumorgenesis. An understanding of HBV variants and their clinical relevance may be important for monitoring chronic hepatitis B disease progression and treatment response. In this review, we will discuss HBV molecular virology, mechanism of variant development, and their potential clinical impact. PMID- 26052398 TI - Role of antiviral therapy in the natural history of hepatitis B virus-related chronic liver disease. AB - Hepatitis B virus (HBV) infection is a dynamic state of interactions among HBV, hepatocytes, and the host immune system. Natural history studies of chronic hepatitis B (CHB) infection have shown an association between active viral replication and adverse clinical outcomes such as cirrhosis and hepatocellular carcinoma. The goal of therapy for CHB is to improve quality of life and survival by preventing progression of the disease to cirrhosis, decompensation, end-stage liver disease, hepatocellular carcinoma (HCC) and death. This goal can be achieved if HBV replication is suppressed in a sustained manner. The accompanying reduction in histological activity of CHB lessens the risk of cirrhosis and of HCC, particularly in non-cirrhotic patients. However, CHB infection cannot be completely eradicated, due to the persistence of covalently closed circular DNA in the nucleus of infected hepatocytes, which may explain HBV reactivation. Moreover, the integration of the HBV genome into the host genome may favour oncogenesis, development of HCC and may also contribute to HBV reactivation. PMID- 26052399 TI - Prevention of hepatocellular carcinoma by correction of metabolic abnormalities: Role of statins and metformin. AB - Hepatocellular carcinoma is the third leading cause of cancer-related deaths in the world. It is associated with an important mortality rate and the incidence is increasing. Patients showing metabolic syndrome seem to have higher incidence and mortality rates from hepatocellular carcinoma than healthy subjects, especially those with type 2 diabetes mellitus and obesity. Thus, metformin and statins, both to treat features of metabolic syndrome, have been proposed to decrease the risk of hepatocellular carcinoma. Otherwise, liver cancer is the result of a complex process which impairs several signaling cascades, such as RAS/RAF/mitogen activated protein kinase kinase (MEK)/extracellular-signal-regulated kinase (ERK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) and Wnt/beta-catenin signaling. Metformin (through 5' adenosine monophosphate-activated protein kinase pathway activation) and statins (through 3-hydroxy-3-methylglutaryl coenzyme A inhibition) show anti-tumoral properties modifying several steps of RAS/RAF/MEK/ERK, PI3K/AKT/mTOR and Wnt/beta catenin signaling cascades. On the other hand, metformin and statins have been found to reduce the risk of hepatocellular carcinoma up to 50% and 60%, respectively. Furthermore, both drugs have shown a dose-dependent protective effect. However, information about chemopreventive role of metformin and statins is mainly obtained of observational studies, which could not take into account some bias. In conclusion, given the rising of incidence of hepatocellular carcinoma and the important morbidity and mortality rates associated with this cancer, looking for chemopreventive strategies is an essential task. Randomized controlled trials are needed to determine the definite role of metformin and statins on the prevention of hepatocellular carcinoma. PMID- 26052400 TI - Adrenal insufficiency in patients with decompensated cirrhosis. AB - Adrenal reserve depletion and overstimulation of the hypothalamus-pituitary adrenal (HPA) axis are causes for adrenal insufficiency (AI) in critically ill individuals. Cirrhosis is a predisposing condition for AI in cirrhotics as well. Both stable cirrhotics and liver transplant patients (early and later after transplantation) have been reported to present AI. The mechanisms leading to reduced cortisol production in cirrhotics are the combination of low cholesterol levels (the primary source of cortisol), the increased cytokines production that overstimulate and exhaust HPA axis and the destruction of adrenal glands due to coagulopathy. AI has been recorded in 10%-82% cirrhotics depending on the test used to evaluate adrenal function and in 9%-83% stable cirrhotics. The similarity of those proportions support the assumption that AI is an endogenous characteristic of liver disease. However, the lack of a gold standard method for AI assessment and the limitation of precise thresholds in cirrhotics make difficult the recording of the real prevalence of AI. This review aims to summarize the present data over AI in stable, critically ill cirrhotics and liver transplant recipients. Moreover, it provides information about the current knowledge in the used diagnostic tools and the possible effectiveness of corticosteroids administration in critically ill cirrhotics with AI. PMID- 26052401 TI - Natural interferon-beta treatment for patients with chronic hepatitis C in Japan. AB - Chronic hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma (HCC). Several studies have demonstrated that the eradication of HCV reduces the occurrence of HCC. In Japan, as many people live to an advanced age, HCV-infected patients are also getting older, and the age at HCC diagnosis has also increased. Although older HCV-infected patients have a risk of developing HCC, the treatment response to peginterferon-alpha plus ribavirin therapy is relatively poor in these patients because of drop-out or discontinuation of this treatment due to adverse events. It is established that the mechanism of action between interferon-alpha and interferon-beta is slightly different. Short-term natural interferon-beta monotherapy is effective for patients with acute hepatitis C and patients infected with HCV genotype 2 and low viral loads. Natural interferon-beta plus ribavirin for 48 wk or for 24 wk are also effective for some patients with HCV genotype 1 or HCV genotype 2. Natural interferon-beta plus ribavirin has been used for certain "difficult-to-treat" HCV infected patients. In the era of direct-acting anti-virals, natural interferon beta plus ribavirin may be one of the therapeutic options for special groups of HCV-infected patients. In the near future, signal transduction pathways of interferon-beta will inform further directions. PMID- 26052402 TI - Antiviral therapies for chronic hepatitis C virus infection with cirrhosis. AB - Patients who are infected with hepatitis C virus (HCV) and also have advanced fibrosis or cirrhosis have been recognized as "difficult-to-treat" patients during an era when peginterferon and ribavirin combination therapy is the standard of care. Recent guidelines have clearly stated that treatment should be prioritized in this population to prevent complications such as decompensation and hepatocellular carcinoma. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents (DAAs). Boceprevir and telaprevir are first-generation DAAs that inhibit the HCV NS3/4A protease. Boceprevir or telaprevir, in combination with peginterferon and ribavirin, improved the sustained virological response rates compared with peginterferon and ribavirin alone and were tolerated in patients with HCV genotype 1 infection without cirrhosis or compensated cirrhosis. However, the efficacy is lower especially in prior non-responders with or without cirrhosis. Furthermore, a high incidence of adverse events was observed in patients with advanced liver disease, including cirrhosis, in real-life settings. Current guidelines in the United States and in some European countries no longer recommend these regimens for the treatment of HCV. Next-generation DAAs include second-generation HCV NS3/4A protease inhibitors, HCV NS5A inhibitors and HCV NS5B inhibitors, which have a high efficacy and a lower toxicity. These drugs are used in interferon-free or in interferon-based regimens with or without ribavirin in combination with different classes of DAAs. Interferon-based regimens, such as simeprevir in combination with peginterferon and ribavirin, are well tolerated and are highly effective especially in treatment-naive patients and in patients who received treatment but who relapsed. The efficacy is less pronounced in null responders and in patients with cirrhosis. Interferon-free regimens in combination with ribavirin and/or two or more DAAs could be used for treatment naive, treatment-experienced and even for interferon-ineligible or interferon intolerant patients. Some clinical trials have demonstrated promising results, and have shown that the efficacy and safety were not different between patients with and without cirrhosis. There are also promising regimens for genotypes other than genotype 1. Interferon is contraindicated in patients with decompensated cirrhosis, and further studies are needed to establish the optimal treatment regimen for this population. In the future, interferon-free and ribavirin-free regimens with high efficacy and improved safety are expected for HCV-infected patients with advanced liver diseases. PMID- 26052403 TI - Management of recurrent hepatocellular carcinoma after liver transplant. AB - Hepatocellular carcinoma (HCC) is the leading cause of deaths in patients with hepatitis B or C, and its incidence has increased considerably over the past decade and is still on the rise. Liver transplantation (LT) provides the best chance of cure for patients with HCC and liver cirrhosis. With the implementation of the MELD exception system for patients with HCC waitlisted for LT, the number of recipients of LT is increasing, so is the number of patients who have recurrence of HCC after LT. Treatments for intrahepatic recurrence after transplantation and after other kinds of surgery are more or less the same, but long-term cure of posttransplant recurrence is rarely seen as it is a "systemic" disease. Nonetheless, surgical resection has been shown to be effective in prolonging patient survival despite the technical difficulty in resecting graft livers. Besides surgical resection, different kinds of treatment are also in use, including transarterial chemoembolization, radiofrequency ablation, high intensity focused ultrasound ablation, and stereotactic body radiation therapy. Targeted therapy and modulation of immunosuppressants are also adopted to treat the deadly disease. PMID- 26052404 TI - Normal liver stiffness: A study in living donors with normal liver histology. AB - AIM: To define the normal range of liver stiffness (LS) values using transient elastography in living-related liver transplantation candidate donors with normal liver histology. METHODS: LS was measured using Fibroscan in 50 (16 women, 34 men) healthy potential donors (mean age 28.4 +/- 5.9 years) who were being evaluated for liver donation for their relatives at the National Liver Institute, Menoufeya University, Egypt. All potential donors had normal liver tests and were negative for hepatitis B or C virus infection. Abdominal ultrasounds showed normal findings. None of the subjects had diabetes, hypertension, renal impairment, heart disease, or body mass index > 30 kg/m(2). All subjects had normal liver histology upon liver biopsy. They all donated the right lobe of their liver with successful outcomes. RESULTS: The mean LS was 4.3 +/- 1.2 kPa (range: 1.8-7.1 kPa). The 5(th) and 95(th) percentiles of normal LS were 2.6 kPa and 6.8 kPa, respectively, with a median of 4 kPa; the interquartile range was 0.6 +/- 0.4. LS measurements were not significantly different between men and women (4.4 +/- 1.1 kPa vs 3.9 +/- 1.3 kPa) and did not correlate with age. However, stiffness values were significantly lower in subjects with a body mass index < 26 kg/m(2) compared to those with an index >= 26 kg/m(2) (4.0 +/- 1.1 kPa vs 4.6 +/- 1.2 kPa; P <0.05). There were no differences in hospital stay or postoperative bilirubin, albumin,alanine and aspartate transaminases, or creatinine levels (at discharge) between donors with livers stiffness <= 4 kPa and those with stiffness > 4 kPa. CONCLUSION: Healthy donors with normal liver histology have a median LS of 4 kPa. Stiffness values are elevated relative to increase in body mass index. PMID- 26052405 TI - Low-dose fractionated radiation with induction chemotherapy for locally advanced head and neck cancer: 5 year results of a prospective phase II trial. AB - OBJECTIVE: This study aims to report the long-term outcomes of a novel treatment approach utilizing induction low-dose fractionated radiation therapy (LDFRT) and chemotherapy for locally advanced squamous cell carcinoma of head and neck (SCCHN). METHODS: We prospectively enrolled 40 patients with locally advanced SCCHN (77 % stage IV) on a phase II clinical trial and treated with induction paclitaxel (225 mg/m2), carboplatin (AUC 6), and LDFRT (80 cGy BID on days 1 and 2) every 21 days for two cycles. RESULTS: Forty patients enrolled; 39 were evaluable. The acute toxicity and response data have been previously reported; overall response rate (RR) was 82 %. After induction, definitive therapy was concurrent chemoradiation (CRT) in 51 %, XRT alone in 39 %, surgery in 5 %, and surgery and XRT in 5 %. The long-term outcomes are now reported with a median follow-up of 83 months. Locoregional control (LRC) is 80 % and distant control (DC) is 77 %. Five-year overall survival (OS), disease-specific survival, and progression-free survival (PFS) are 62 %, 66 %, and 58 %, respectively. CONCLUSION: Induction chemotherapy with LDFRT has a high initial RR, comparable toxicity to two-drug induction regimens, but adds a third novel and effective agent, LDFRT. Five-year follow-up shows favorable outcomes compared to historical controls and excellent compliance with definitive therapy. This novel treatment approach is now planned for phase 3 trial evaluation. PMID- 26052406 TI - RAMHeR: Reuse And Mining Health2.0 Resources. PMID- 26052407 TI - Negative Chronotropic and Antidysrhythmic Effects of Hydroalcoholic Extract of Lemon Balm (Melissa Officinalis L.) on CaCl2-Induced Arrhythmias in Rats. AB - BACKGROUND: In many cases, myocardial infarction leads to arrhythmia. Since antioxidant agents have an important protective role in heart disease, these compounds in medicinal plants are used in traditional medicine. Lemon balm extract, compared to other plants of the lamiaceae family, has been proven to have significant amounts of antioxidant compounds. The aim of this study was to assess the effect of the hydroalcoholic extract of lemon balm (Melissa officinalis L.) on CaCl2-induced arrhythmias in rats. METHODS: This research is an experimental study; male adult Sprague Dawley rats that weighed 200-250 g were divided randomly into three groups, i.e., 1) control (normal saline, 1 ml/kg/day), 2) extract (100 mg/kg), and 3) extract (200 mg/kg). The normal saline and the extracts were gavaged for 14 consecutive days. After anesthesia, lead II electrocardiograms were recorded for calculating the rats' heart rates (HRs). Arrhythmia was induced by intravenous injection of CaCl2 solution (140 mg/kg), and the percentages of incidence of ventricular tachycardia (VT), ventricular fibrillation (VF), and ventricular premature beats (VPB) were recorded. The results were analyzed by using Fisher's exact test and one-way ANOVA. P-values less than 0.05 were considered as significant level. RESULTS: Heart rates and percentages of incidence of VPB, VT, and VF were reduced significantly in extract groups (with the highest activity at 200 mg/kg) in comparison with the control group. CONCLUSION: Melissa officinalis was considered to be an antiarrhythmic agent because it reduced the percentage of incidence of VPB, VT, and VF in the groups that received it. The results indicated that Melissa officinalis had a protective effect on the heart. PMID- 26052408 TI - Production, quality control, and bio-distribution studies of (159)Gd-EDTMP as a palliative agent for bone pain. AB - INTRODUCTION: Particle-emitting, bone-seeking radiopharmaceuticals have attracted the attention of the nuclear medicine community over the last three decades for the treatment of the pain of osteoblastic metastases. The objectives of this research were to produce quality-controlled (159)Gd-EDTMP in order to provide a new therapeutic radiopharmaceutical for use in clinical applications. METHODS: The investigation was an experimental study in which (159)Gd (T1/2=18.479 h, Ebeta (max)=970.60 keV, Egamma=363.55 (11.4%) keV] was produced by thermal neutron bombardment of natural Gd2O3 at the Tehran Research Reactor (TRR) for a period of 7 d at a flux of 3-4*10(13) neutrons/cm(2).s. It was then quality controlled and used to radio-label the in-house prepared ethylene diamine tetra acetic acid (EDTM). RESULTS: Complexation parameters were optimized to achieve maximum yields (>99%). The radiochemical purity of (159)Gd-EDTMP was checked by radio thin layer chromatography RTLC. It was found to retain its stability at room temperature (>95%). Bio-distribution studies of the complexes conducted in wild rats showed significant bone uptake with rapid clearance from blood. CONCLUSION: The properties of the (159)Gd-EDTMP that was produced suggest then use of a new, efficient, palliative therapeutic agent for metastatic bone pain instead of some other current radiopharmaceuticals. PMID- 26052409 TI - Association between Hepatitis G and Unknown Chronic Hepatitis. AB - BACKGROUND: Hepatitis G virus (HGV) is a hepatotrope virus with unknown importance. The genome of the virus has been detected in patients with acute or chronic non-A-E hepatitis, cirrhosis, and hepatocellular carcinoma. The aim of this study was to determine the association between hepatitis G and unknown chronic hepatitis. METHODS: This case-control study was performed in Ebne-Sina military hospital in Hamadan, Iran. The cases were 35 military staff with unknown chronic hepatitis. The control group consisted of 59 healthy subjects who had normal levels of serum alanine aminoteransferase (ALT). The data were analyzed by SPSS, version18, using Fisher's exact test, the Student's t-test, and multivariate logistic regression analysis. RESULTS: Only one patient in the case group (2.9%) tested positive for HGV antibodies, and no one was infected in the control group. There was no association between HGV infection and unknown chronic hepatitis in our study (P=0.37). A significant association was found between the male gender and unknown chronic hepatitis (OR=14.9, P=0.01). CONCLUSION: No association between HGV infection and unknown chronic hepatitis was found in our study, so it was not necessary to evaluate these patients for HGV infection. PMID- 26052410 TI - Healthcare-Seeking Behaviors of Mothers regarding their Children in a Tribal Community of Gujarat, India. AB - BACKGROUND: The mortality and morbidity from the diseases which contribute to the deaths among children can be reduced if early intervention is made in terms of appropriate care and treatment. Thus, utmost care should be taken to prevent diseases, recognize the danger signals, and treat them urgently. Thus, healthcare seeking behavior is of prime importance and is pivotal in the well-being of the individual as well as the community. The aims of this research were to determine the possible factors that affect the healthcare-seeking behavior of mothers for their children in a tribal community of Narmada district and to determine the reasons for not seeking curative care for children who are perceived to be sick. METHODS: A cross-sectional, community-based study of 405 mothers of the Dediyapada Block in Narmada District Gujarat, India, was undertaken, using a two stage, cluster-sampling technique. The study was conducted from June through August 2011 using the questionnaire method. The chi squared test was used to determine the association between various factors and the healthcare-seeking behaviors of mothers. RESULTS: The mothers were in the age range of 17 to 44 years, with the mean (+SD) being 26.2+3.2 years. Ninety-one percent of the children, irrespective of gender, had completed their primary immunization. Regarding curative healthcare-seeking behavior, 16.5% of the males and 42% of the females received no treatment. Joint family structure (P<0.05, df=1, chi(2)=41.39), mass media exposure (P<0.05, df=1, chi(2)=16.42), literacy status (P<0.05, df=1, chi(2)=60.76), socioeconomic status of the mothers (P<0.05, df=1, chi(2)=56.08), and gender differences among children (P<0.05, df=1, chi(2)=21.18) were found to be associated significantly with the healthcare-seeking behavior of the mothers. CONCLUSION: Increased maternal education, generation of intensified awareness through the mass media approach, implementing gender-sensitive interventions, and counseling may have positive implications in the future, leading to better health outcomes and favorable health indicators. PMID- 26052411 TI - High prevalence of type 2 diabetes and pre-diabetes in adult Zoroastrians in Yazd, Iran: a cross-sectional study. AB - BACKGROUND: The prevalence of type 2 diabetes mellitus (T2DM) varies among ethnic groups. We aimed to estimate the prevalence of diagnosed and undiagnosed diabetes mellitus, impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) for the first time in an ethnic population, specifically Zoroastrian citizens in Yazd, Iran whose ages were 30 or older. METHODS: In a cross-sectional study, participants aged>=30 years were selected using systematic random sampling. An inventory, including socio-demographic data, was completed. Weight, height, body mass index (BMI), and blood pressure (BP) were measured using standard methods. Also, blood levels of glucose, triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), urea, creatinine (Cr), and uric acid were measured. The latest criteria established by the American Diabetes Association (ADA) were used to diagnose DM. RESULTS: The mean age of the participants (n=403) was 56.9+/-12.8 years. The total prevalence of diabetes, including previously diagnosed and undiagnosed diabetes, IFG, and IGT was 26.1%, 18.6%, 7.5%, 34.7% and 25.8%, respectively. Participants with diabetes had higher fasting blood sugar (FBS) (P<0.001), oral glucose tolerance test (OGTT) (P<0.001), urea (P=0.019), BMI (P=0.001), systolic blood pressures (P<0.001), TG (P=0.007) and lower HDL (P=0.034) than patients with IFG, IGT, and normoglycemic subjects. CONCLUSIONS: The current study showed a high prevalence of T2DM in the Zoroastrian population of Yazd, Iran. One-third of the total cases with diabetes were undiagnosed. PMID- 26052412 TI - A study of the relationship between gender/age and apparent diffusion coefficient values in spleen of healthy adults using diffusion-weighted magnetic resonance imaging. AB - BACKGROUND: Diffusion-weighted magnetic resonance imaging (DWI) systems are very effective in detecting strokes, and they also have shown significant promise in the detection of fibrosis and cirrhosis of the liver. However, such systems have the disadvantages of poor reproducibility and noise, which can diminish the accuracy of the apparent diffusion coefficients (ADCs) provided by the DWI process. The main aim of this study was to determine the relationship between the age and gender of healthy adults in terms of the ADC values of the spleen measured by DWI. METHODS: Sixty-nine subjects selected for this study from people who were referred to the Tabesh Medical Imaging Center in Tabriz, Iran, in 2013. Each subject underwent echo-planar DWI for her or his ADC values of the spleen with b-values of 50, 400, and 800 s/mm2, and the resulting ADC values were evaluated. RESULTS: No significant differences were observed in ADC values of the spleen among the female and male participants or those from various ages (P>0.05). CONCLUSIONS: Based on the findings of this study, it was concluded that the effect of age and gender on the spleen's ADC values can be omitted from the spleen-diagnosis procedure. In other words, the spleen's ADC values are not related to the age or the gender of healthy adults. PMID- 26052413 TI - Relationship between periodontal status and C-reactive protein and interleuckin-6 levels among atherosclerotic patients in Bandar Abbas, Iran in 2014. AB - BACKGROUND: Recent studies have reported an association between periodontitis and cardiovascular diseases. Atherosclerosis is also a risk factor for cardiovascular diseases. IL-6 and CRP are important inflammatory markers that are important because they have been shown to be higher when a patient has periodontitis, and they are related to atherosclerosis. The aim of this study was to assess the relationship between periodontitis and CRP and IL-6 in atherosclerotic patients. METHODS: The study population in this case control study was atherosclerotic patients in Bandar Abbas, Iran in 2014. The participants included 30 individuals with periodontal diseases and 30 individuals without periodontal diseases, and they were allocated into two groups according to probe depth (PD) and clinical attachment loss (CAL). Inflammatory markers, including CRP and IL-6 were measured in the two groups. The data were analyzed using IBM SPSS 21 statistical software. Descriptive statistics, chi-squared, independent samples t-test, and Mann-Whitney tests were used to analyze the data. RESULTS: Individuals with abnormal CRP had significantly higher PD and CAL than individuals with normal CRP (P<0.001). Although PD was not significantly different in individuals with normal and abnormal IL-6 (P=0.124), CAL was significantly higher in individuals with abnormal IL-6 than in the other individuals (P=0.005). CONCLUSION: The results of this study showed that CRP and IL-6 are associated with periodontal diseases in atherosclerotic patients. Treatment of periodontal diseases is recommended in atherosclerotic patients. PMID- 26052414 TI - Skeletal muscle triad junction ultrastructure by Focused-Ion-Beam milling of muscle and Cryo-Electron Tomography. AB - Cryo-electron tomography (cryo-ET) has emerged as perhaps the only practical technique for revealing nanometer-level three-dimensional structural details of subcellular macromolecular complexes in their native context, inside the cell. As currently practiced, the specimen should be 0.1- 0.2 microns in thickness to achieve optimal resolution. Thus, application of cryo-ET to intact frozen (vitreous) tissues, such as skeletal muscle, requires that they be sectioned. Cryo-ultramicrotomy is notoriously difficult and artifact-prone when applied to frozen cells and tissue, but a new technique, focused ion beam milling (cryo FIB), shows great promise for "thinning" frozen biological specimens. Here we describe our initial results in applying cryo-FIB and cryo-ET to triad junctions of skeletal muscle. PMID- 26052416 TI - Neural development in the tardigrade Hypsibius dujardini based on anti-acetylated alpha-tubulin immunolabeling. AB - BACKGROUND: The tardigrades (water bears) are a cosmopolitan group of microscopic ecdysozoans found in a variety of aquatic and temporarily wet environments. They are members of the Panarthropoda (Tardigrada + Onychophora + Arthropoda), although their exact position within this group remains contested. Studies of embryonic development in tardigrades have been scarce and have yielded contradictory data. Therefore, we investigated the development of the nervous system in embryos of the tardigrade Hypsibius dujardini using immunohistochemical techniques in conjunction with confocal laser scanning microscopy in an effort to gain insight into the evolution of the nervous system in panarthropods. RESULTS: An antiserum against acetylated alpha-tubulin was used to visualize the axonal processes and general neuroanatomy in whole-mount embryos of the eutardigrade H. dujardini. Our data reveal that the tardigrade nervous system develops in an anterior-to-posterior gradient, beginning with the neural structures of the head. The brain develops as a dorsal, bilaterally symmetric structure and contains a single developing central neuropil. The stomodeal nervous system develops separately and includes at least four separate, ring-like commissures. A circumbuccal nerve ring arises late in development and innervates the circumoral sensory field. The segmental trunk ganglia likewise arise from anterior to posterior and establish links with each other via individual pioneering axons. Each hemiganglion is associated with a number of peripheral nerves, including a pair of leg nerves and a branched, dorsolateral nerve. CONCLUSIONS: The revealed pattern of brain development supports a single-segmented brain in tardigrades and challenges previous assignments of homology between tardigrade brain lobes and arthropod brain segments. Likewise, the tardigrade circumbuccal nerve ring cannot be homologized with the arthropod 'circumoral' nerve ring, suggesting that this structure is unique to tardigrades. Finally, we propose that the segmental ganglia of tardigrades and arthropods are homologous and, based on these data, favor a hypothesis that supports tardigrades as the sister group of arthropods. PMID- 26052417 TI - The making of an octopus arm. AB - BACKGROUND: Most of our current findings on appendage formation and patterning stem from studies on chordate and ecdysozoan model organisms. However, in order to fully understand the evolution of animal appendages, it is essential to include information on appendage development from lophotrochozoan representatives. Here, we examined the basic dynamics of the Octopus vulgaris arm's formation and differentiation - as a highly evolved member of the lophotrochozoan super phylum - with a special focus on the formation of the arm's musculature. RESULTS: The octopus arm forms during distinct phases, including an early outgrowth from an epithelial thickening, an elongation, and a late differentiation into mature tissue types. During early arm outgrowth, uniform proliferation leads to the formation of a rounded bulge, which subsequently elongates along its proximal-distal axis by means of actin-mediated epithelial cell changes. Further differentiation of all tissue layers is initiated but end differentiation is postponed to post-hatching stages. Interestingly, muscle differentiation shows temporal differences in the formation of distinct muscle layers. Particularly, first myocytes appear in the area of the future transverse prior to the longitudinal muscle layer, even though the latter represents the more dominant muscle type at hatching stage. Sucker rudiments appear as small epithelial outgrowths with a mesodermal and ectodermal component on the oral part of the arm. During late differentiation stages, cell proliferation becomes localized to a distal arm region termed the growth zone of the arm. CONCLUSIONS: O. vulgaris arm formation shows both, similarities to known model species as well as species-specific patterns of arm formation. Similarities include early uniform cell proliferation and actin-mediated cell dynamics, which lead to an elongation along the proximal-distal axis. Furthermore, the switch to an adult-like progressive distal growth mode during late differentiation stages is reminiscent of the vertebrate progress zone. However, tissue differentiation shows a species specific delay, which is correlated to a paralarval pelagic phase after hatching and concomitant emerging behavioral modifications. By understanding the general dynamics of octopus arm formation, we established a basis for further studies on appendage patterning, growth, and differentiation in a representative of the lophotrochozoan super phylum. PMID- 26052418 TI - Development of somites and their derivatives in amphioxus, and implications for the evolution of vertebrate somites. AB - BACKGROUND: Vertebrate somites are subdivided into lineage compartments, each with distinct cell fates and evolutionary histories. Insights into somite evolution can come from studying amphioxus, the best extant approximation of the chordate ancestor. Amphioxus somites have myotome and non-myotome compartments, but development and fates of the latter are incompletely described. Further, while epithelial to mesenchymal transition (EMT) is important for most vertebrate somitic lineages, amphioxus somites generally have been thought to remain entirely epithelial. Here, we examined amphioxus somites and derivatives, as well as extracellular matrix of the axial support system, in a series of developmental stages by transmission electron microscopy (TEM) and in situ hybridization for collagen expression. RESULTS: The amphioxus somite differentiates medially into myotome, laterally into the external cell layer (a sub-dermal mesothelium), ventrally into a bud that forms mesothelia of the perivisceral coelom, and ventro medially into the sclerotome. The sclerotome forms initially as a monolayered cell sheet that migrates between the myotome and the notochord and neural tube; subsequently, this cell sheet becomes double layered and encloses the sclerocoel. Other late developments include formation of the fin box mesothelia from lateral somites and the advent of isolated fibroblasts, likely somite derived, along the myosepta. Throughout development, all cells originating from the non-myotome regions of somites strongly express a fibrillar collagen gene, ColA, and thus likely contribute to extracellular matrix of the dermal and axial connective tissue system. CONCLUSIONS: We provide a revised model for the development of amphioxus sclerotome and fin boxes and confirm previous reports of development of the myotome and lateral somite. In addition, while somite derivatives remain almost entirely epithelial, limited de-epithelialization likely converts some somitic cells into fibroblasts of the myosepta and dermis. Ultrastructure and collagen expression suggest that all non-myotome somite derivatives contribute to extracellular matrix of the dermal and axial support systems. Although amphioxus sclerotome lacks vertebrate-like EMT, it resembles that of vertebrates in position, movement to surround midline structures and into myosepta, and contribution to extracellular matrix of the axial support system. Thus, many aspects of the sclerotome developmental program evolved prior to the origin of the vertebrate mineralized skeleton. PMID- 26052415 TI - Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism. AB - Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event. PMID- 26052419 TI - Plasmon-induced artificial photosynthesis. AB - We have successfully developed a plasmon-induced artificial photosynthesis system that uses a gold nanoparticle-loaded oxide semiconductor electrode to produce useful chemical energy as hydrogen and ammonia. The most important feature of this system is that both sides of a strontium titanate single-crystal substrate are used without an electrochemical apparatus. Plasmon-induced water splitting occurred even with a minimum chemical bias of 0.23 V owing to the plasmonic effects based on the efficient oxidation of water and the use of platinum as a co catalyst for reduction. Photocurrent measurements were performed to determine the electron transfer between the gold nanoparticles and the oxide semiconductor. The efficiency of water oxidation was determined through spectroelectrochemical experiments aimed at elucidating the electron density in the gold nanoparticles. A set-up similar to the water-splitting system was used to synthesize ammonia via nitrogen fixation using ruthenium instead of platinum as a co-catalyst. PMID- 26052420 TI - Dye-sensitized PS-b-P2VP-templated nickel oxide films for photoelectrochemical applications. AB - Moving from homogeneous water-splitting photocatalytic systems to photoelectrochemical devices requires the preparation and evaluation of novel p type transparent conductive photoelectrode substrates. We report here on the sensitization of polystyrene-block-poly-(2-vinylpyridine) (PS-b-P2VP) diblock copolymer-templated NiO films with an organic push-pull dye. The potential of these new templated NiO film preparations for photoelectrochemical applications is compared with NiO material templated by F108 triblock copolymers. We conclude that NiO films are promising materials for the construction of dye-sensitized photocathodes to be inserted into photoelectrochemical (PEC) cells. However, a combined effort at the interface between materials science and molecular chemistry, ideally funded within a Global Artificial Photosynthesis Project, is still needed to improve the overall performance of the photoelectrodes and progress towards economically viable PEC devices. PMID- 26052421 TI - Rational design of metal nitride redox materials for solar-driven ammonia synthesis. AB - Fixed nitrogen is an essential chemical building block for plant and animal protein, which makes ammonia (NH3) a central component of synthetic fertilizer for the global production of food and biofuels. A global project on artificial photosynthesis may foster the development of production technologies for renewable NH3 fertilizer, hydrogen carrier and combustion fuel. This article presents an alternative path for the production of NH3 from nitrogen, water and solar energy. The process is based on a thermochemical redox cycle driven by concentrated solar process heat at 700-1200 degrees C that yields NH3 via the oxidation of a metal nitride with water. The metal nitride is recycled via solar driven reduction of the oxidized redox material with nitrogen at atmospheric pressure. We employ electronic structure theory for the rational high-throughput design of novel metal nitride redox materials and to show how transition-metal doping controls the formation and consumption of nitrogen vacancies in metal nitrides. We confirm experimentally that iron doping of manganese nitride increases the concentration of nitrogen vacancies compared with no doping. The experiments are rationalized through the average energy of the dopant d-states, a descriptor for the theory-based design of advanced metal nitride redox materials to produce sustainable solar thermochemical ammonia. PMID- 26052422 TI - Hybrid photocathodes for solar fuel production: coupling molecular fuel production catalysts with solid-state light harvesting and conversion technologies. AB - Artificial photosynthesis is described as the great scientific and moral challenge of our time. We imagine a future where a significant portion of our energy is supplied by such technologies. However, many scientific, engineering and policy challenges must be addressed for this realization. Scientific challenges include the development of effective strategies to couple light absorption, electron transfer and catalysis for efficient conversion of light energy to chemical energy as well as the construction and study of structurally diverse assemblies to carry out these processes. In this article, we review recent efforts from our own research to develop a modular approach to interfacing molecular fuel-production catalysts to visible-light-absorbing semiconductors and discuss the role of the interfacing material as a protection layer for the catalysts as well as the underpinning semiconductor. In concluding, we briefly discuss the potential benefits of a globally coordinated project on artificial photosynthesis that interfaces teams of scientists, engineers and policymakers. Further, we offer cautions that such a large interconnected organization should consider. This article is inspired by, and draws largely from, an invited presentation given by the corresponding author at the Royal Society at Chicheley Hall, home of the Kavli Royal Society International Centre, Buckinghamshire on the themed meeting topic: 'Do we need a global project on artificial photosynthesis?' PMID- 26052423 TI - Principles of light harvesting from single photosynthetic complexes. AB - Photosynthetic systems harness sunlight to power most life on Earth. In the initial steps of photosynthetic light harvesting, absorbed energy is converted to chemical energy with near-unity quantum efficiency. This is achieved by an efficient, directional and regulated flow of energy through a network of proteins. Here, we discuss the following three key principles of this flow and of photosynthetic light harvesting: thermal fluctuations of the protein structure; intrinsic conformational switches with defined functional consequences; and environmentally triggered conformational switches. Through these principles, photosynthetic systems balance two types of operational costs: metabolic costs, or the cost of maintaining and running the molecular machinery, and opportunity costs, or the cost of losing any operational time. Understanding how the molecular machinery and dynamics are designed to balance these costs may provide a blueprint for improved artificial light-harvesting devices. With a multi disciplinary approach combining knowledge of biology, this blueprint could lead to low-cost and more effective solar energy conversion. Photosynthetic systems achieve widespread light harvesting across the Earth's surface; in the face of our growing energy needs, this is functionality we need to replicate, and perhaps emulate. PMID- 26052424 TI - The social acceptance of artificial photosynthesis: towards a conceptual framework. AB - Advancements in artificial photosynthesis have the potential to radically transform how societies convert and use energy. Their successful development, however, hinges not only on technical breakthroughs, but also acceptance and adoption by energy users. This article introduces a conceptual framework enabling analysts, planners and even investors to determine environments where artificial photosynthesis may thrive, and those where it may struggle. Drawn from work looking at the barriers and acceptance of solar photovoltaic and wind energy systems, the article proposes that social acceptance has multiple dimensions socio-political, community and market-that must be met holistically in order for investors and users to embrace new technologies. The article argues that any future market acceptance for artificial photosynthesis will depend upon the prevalence of nine factors, which create conducive environments; the lack of the conditions engenders environments where they will likely be rejected. The conditions are (i) strong institutional capacity; (ii) political commitment; (iii) favourable legal and regulatory frameworks; (iv) competitive installation and/or production costs; (v) mechanisms for information and feedback; (vi) access to financing; (vii) prolific community and/or individual ownership and use; (viii) participatory project siting; and (ix) recognition of externalities or positive public image. PMID- 26052425 TI - Multidisciplinary approaches to solar hydrogen. AB - This review summarizes three different approaches to engineering systems for the solar-driven evolution of hydrogen fuel from water: molecular, nanomaterials and biomolecular. Molecular systems have the advantage of being highly amenable to modification and detailed study and have provided great insight into photophysics, electron transfer and catalytic mechanism. However, they tend to display poor stability. Systems based on nanomaterials are more robust but also are more difficult to synthesize in a controlled manner and to modify and study in detail. Biomolecular systems share many properties with molecular systems and have the advantage of displaying inherently high efficiencies for light absorption, electron-hole separation and catalysis. However, biological systems must be engineered to couple modules that capture and convert solar photons to modules that produce hydrogen fuel. Furthermore, biological systems are prone to degradation when employed in vitro. Advances that use combinations of these three tactics also are described. Multidisciplinary approaches to this problem allow scientists to take advantage of the best features of biological, molecular and nanomaterials systems provided that the components can be coupled for efficient function. PMID- 26052427 TI - Sustainable fuel, food, fertilizer and ecosystems through a global artificial photosynthetic system: overcoming anticompetitive barriers. AB - This article discusses challenges that artificial photosynthetic (AP) systems will face when entering and competing in a global market characterized by established fossil fuel technology. It provides a perspective on the neoliberal principles underpinning much policy entrenching such environmentally destructive technology and outlines how competition law could aid overcoming these hurdles for AP development. In particular, it critiques the potential for competition law to promote a global AP initiative with greater emphasis on atmospheric carbon dioxide and nitrogen fixation (as well as solar-driven water splitting) to produce an equitable, globally distributed source of human food, fertilizer and biosphere sustainability, as well as hydrogen-based fuel. Some relevant strategies of competition law evaluated in this context include greater citizen consumer involvement in shaping market values, legal requirements to factor services from the natural environment (i.e. provision of clean air, water, soil pollution degradation) into corporate costs, reform of corporate taxation and requirements to balance maximization of shareholder profit with contribution to a nominated public good, a global financial transactions tax, as well as prohibiting horizontal cartels, vertical agreements and unilateral misuse of market power. PMID- 26052426 TI - Artificial photosynthesis: understanding water splitting in nature. AB - In the context of a global artificial photosynthesis (GAP) project, we review our current work on nature's water splitting catalyst. In a recent report (Cox et al. 2014 Science 345, 804-808 (doi:10.1126/science.1254910)), we showed that the catalyst-a Mn4O5Ca cofactor-converts into an 'activated' form immediately prior to the O-O bond formation step. This activated state, which represents an all Mn(IV) complex, is similar to the structure observed by X-ray crystallography but requires the coordination of an additional water molecule. Such a structure locates two oxygens, both derived from water, in close proximity, which probably come together to form the product O2 molecule. We speculate that formation of the activated catalyst state requires inherent structural flexibility. These features represent new design criteria for the development of biomimetic and bioinspired model systems for water splitting catalysts using first-row transition metals with the aim of delivering globally deployable artificial photosynthesis technologies. PMID- 26052428 TI - Biosolar cells: global artificial photosynthesis needs responsive matrices with quantum coherent kinetic control for high yield. AB - This contribution discusses why we should consider developing artificial photosynthesis with the tandem approach followed by the Dutch BioSolar Cells consortium, a current operational paradigm for a global artificial photosynthesis project. We weigh the advantages and disadvantages of a tandem converter against other approaches, including biomass. Owing to the low density of solar energy per unit area, artificial photosynthetic systems must operate at high efficiency to minimize the land (or sea) area required. In particular, tandem converters are a much better option than biomass for densely populated countries and use two photons per electron extracted from water as the raw material into chemical conversion to hydrogen, or carbon-based fuel when CO2 is also used. For the average total light sum of 40 mol m(-2) d(-1) for The Netherlands, the upper limits are many tons of hydrogen or carbon-based fuel per hectare per year. A principal challenge is to forge materials for quantitative conversion of photons to chemical products within the physical limitation of an internal potential of ca 2.9 V. When going from electric charge in the tandem to hydrogen and back to electricity, only the energy equivalent to 1.23 V can be stored in the fuel and regained. A critical step is then to learn from nature how to use the remaining difference of ca 1.7 V effectively by triple use of one overpotential for preventing recombination, kinetic stabilization of catalytic intermediates and finally generating targeted heat for the release of oxygen. Probably the only way to achieve this is by using bioinspired responsive matrices that have quantum classical pathways for a coherent conversion of photons to fuels, similar to what has been achieved by natural selection in evolution. In appendix A for the expert, we derive a propagator that describes how catalytic reactions can proceed coherently by a convergence of time scales of quantum electron dynamics and classical nuclear dynamics. We propose that synergy gains by such processes form a basis for further progress towards high efficiency and yield for a global project on artificial photosynthesis. Finally, we look at artificial photosynthesis research in The Netherlands and use this as an example of how an interdisciplinary approach is beneficial to artificial photosynthesis research. We conclude with some of the potential societal consequences of a large-scale roll out of artificial photosynthesis. PMID- 26052429 TI - Person-centered Therapeutics. AB - A clinician's effectiveness in treatment depends substantially on his or her attitude toward -- and understanding of -- the patient as a person endowed with self-awareness and the will to direct his or her own future. The assessment of personality in the therapeutic encounter is a crucial foundation for forming an effective working alliance with shared goals. Helping a person to reflect on their personality provides a mirror image of their strengths and weaknesses in adapting to life's many challenges. The Temperament and Character Inventory (TCI) provides an effective way to describe personality thoroughly and to predict both the positive and negative aspects of health. Strengths and weaknesses in TCI personality traits allow strong predictions of individual differences of all aspects of well-being. Diverse therapeutic techniques, such as diet, exercise, mood self-regulation, meditation, or acts of kindness, influence health and personality development in ways that are largely indistinguishable from one another or from effective allopathic treatments. Hence the development of well being appears to be the result of activating a synergistic set of mechanisms of well-being, which are expressed as fuller functioning, plasticity, and virtue in adapting to life's challenges. PMID- 26052430 TI - Vitamin D as an adjuvant in melanoma therapy. PMID- 26052431 TI - Metastasizing tenosynovial giant cell tumour, diffuse type/pigmented villonodular synovitis. AB - Tenosynovial giant cell tumour, diffuse type, also known under a variety of other terms including diffuse pigmented villonodular synovitis, tends to be locally aggressive and not infrequently can show multiple recurrences. The differential diagnosis with the extremely rare and somewhat controversial malignant variant of tenosynovial giant cell tumour, diffuse type, is challenging due to overlapping radiologic features of these two entities. Malignant tenosynovial giant cell tumour is defined by the presence of overtly malignant sarcomatous areas. We describe a very unusual case of a 63-year-old man affected by tenosynovial giant cell tumour, diffuse type of the knee that, despite absence of morphologic evidence of sarcomatous transformation, developed inguinal lymph node metastases following multiple surgical procedures. PMID- 26052432 TI - In Vitro Screening of Environmental Chemicals Identifies Zearalenone as a Novel Substrate of the Placental BCRP/ABCG2 Transporter. AB - The BCRP (ABCG2) transporter is responsible for the efflux of chemicals from the placenta to the maternal circulation. Inhibition of BCRP activity could enhance exposure of offspring to environmental chemicals leading to altered reproductive, endocrine, and metabolic development. The purpose of this study was to characterize environmental chemicals as potential substrates and inhibitors of the human placental BCRP transporter. The interaction of BCRP with a panel of environmental chemicals was assessed using the ATPase and inverted plasma membrane vesicle assays as well as a cell-based fluorescent substrate competition assay. Human HEK cells transfected with wild-type BCRP or the Q141K genetic variant, as well as BeWo placental cells that endogenously express BCRP were used to further test inhibitor and substrate interactions. To varying degrees, the eleven chemicals inhibited BCRP activity in activated ATPase membranes and inverted membrane vesicles. Further, genistein, zearalenone, and tributyltin increased the retention of the fluorescent BCRP substrate, Hoechst 33342, between 50-100% in BeWo cells. Additional experiments characterized the mycotoxin and environmental estrogen, zearalenone, as a novel substrate and inhibitor of BCRP in WT-BCRP and BeWo cells. Interestingly, the BCRP genetic variant Q141K exhibited reduced efflux of zearalenone compared to the wild-type protein. Taken together, screening assays and direct quantification experiments identified zearalenone as a novel human BCRP substrate. Additional in vivo studies are needed to directly determine whether placental BCRP prevents fetal exposure to zearalenone. PMID- 26052433 TI - Modification of PEGylated enzyme with glutaraldehyde can enhance stability while avoiding intermolecular crosslinking. AB - We demonstrate an enzyme stabilization approach whereby a model enzyme is PEGylated, followed by controlled chemical modification with glutaraldehyde. Using this stabilization strategy, size increases and aggregation due to intermolecular crosslinking are avoided. Immediately following synthesis, the PEGylated enzyme with and without glutaraldehyde modification possessed specific activities of 372.9 +/- 20.68 U/mg and 373.9 +/- 15.14 U/mg, respectively (vs. 317.7 +/- 19.31 U/mg for the native enzyme). The glutaraldehyde-modified PEGylated enzyme retains 73% original activity after 4 weeks at 37 degrees C (vs. 2% retention for control). PMID- 26052435 TI - A peculiar variety of indirect inguinal hernia (juxtacordal indirect inguinal hernia). AB - BACKGROUND: Indirect inguinal hernias are usually congenital, forming a sac in the core of the spermatic cord covered by the internal spermatic, cremasteric, and external spermatic fasciae(1-3). Direct inguinal hernias are acquired; the sac lies beside/behind the cord(1-3). A rare third type is a combination of indirect and direct sacs on both sides of inferior epigastric vessels(1-3). We describe a rare fourth type, juxtacordal indirect oblique inguinal hernia (Fig. 1), in which the sac emerges through a weakness in the deep inguinal ring, lateral to inferior epigastric vessels, and passes into the inguinal canal beside and in contact with the cord but outside of its covering fasciae. OBJECTIVE: Describes a very rare variety of inguinal hernia. DESIGN: Case reports. SETTING: Tikrit Teaching Hospital/Salahuddin/Iraq. PARTICIPANTS AND PRESENTATION: The first case; a 5-year-old male with right inguinal hernia, the second case; a 25 year-old man with right inguinal hernia, the third case; a 60-year-old man with right inguinal hernia. INTERVENTIONS: Surgery has been done electively for all. RESULTS AND DISCUSSION: Because the sac emerges through the deep inguinal ring and passes through the inguinal canal, it is an indirect type and because it passes beside the spermatic cord we call it juxtacordal hernia. Because of the thick extraperitoneal fat layer over the sac, we think this hernia is acquired. CONCLUSIONS: Knowing this type of hernia might reduce the risk of inferior epigastric vessels injury and lower the rate of recurrence. PMID- 26052434 TI - High-fat load: mechanism(s) of insulin resistance in skeletal muscle. AB - Skeletal muscle from sedentary obese patients is characterized by depressed electron transport activity, reduced expression of genes required for oxidative metabolism, altered mitochondrial morphology and lower overall mitochondrial content. These findings imply that obesity, or more likely the metabolic imbalance that causes obesity, leads to a progressive decline in mitochondrial function, eventually culminating in mitochondrial dissolution or mitoptosis. A decrease in the sensitivity of skeletal muscle to insulin represents one of the earliest maladies associated with high dietary fat intake and weight gain. Considerable evidence has accumulated to suggest that the cytosolic ectopic accumulation of fatty acid metabolites, including diacylglycerol and ceramides, underlies the development of insulin resistance in skeletal muscle. However, an alternative mechanism has recently been evolving, which places the etiology of insulin resistance in the context of cellular/mitochondrial bioenergetics and redox systems biology. Overnutrition, particularly from high-fat diets, generates fuel overload within the mitochondria, resulting in the accumulation of partially oxidized acylcarnitines, increased mitochondrial hydrogen peroxide (H2O2) emission and a shift to a more oxidized intracellular redox environment. Blocking H2O2 emission prevents the shift in redox environment and preserves insulin sensitivity, providing evidence that the mitochondrial respiratory system is able to sense and respond to cellular metabolic imbalance. Mitochondrial H2O2 emission is a major regulator of protein redox state, as well as the overall cellular redox environment, raising the intriguing possibility that elevated H2O2 emission from nutrient overload may represent the underlying basis for the development of insulin resistance due to disruption of normal redox control mechanisms regulating protein function, including the insulin signaling and glucose transport processes. PMID- 26052436 TI - The safety and adequacy of resection on hepatocellular carcinoma larger than 10 cm: A retrospective study over 10 years. AB - BACKGROUND/PURPOSE: Current treatment options for HCC>=10 cm (huge HCC) are limited. Otherwise, the margin status is known as a prognostic factor. Our aim was to determine the safety, effectiveness, and risk factors for overall survival and disease-free survival for these patients. METHODS: A total of 211 consecutive patients from 2000/08 to 2010/12 were enrolled. Characteristics of patients, tumors, and treatment were compared between the huge group (HCCs; >=10 cm, n = 23; 11%) and those with smaller group (HCC; <10 cm n = 188; 89%). Disease-free survival (DFS), overall survival (OS), and risk factors were analyzed. RESULTS: Median follow up was 37 months. Patients with huge HCC were more likely to be symptomatic, positive for preoperative portal vein thrombosis, longer surgical time, more blood loss and transfusions, and significantly shorter median OS and DFS. Both groups had similar postoperative mortality and morbidity rates. In the huge HCC, multivariate analysis identified two significant determinants of DFS (preoperative portal vein thrombosis on imaging and tumor-free margin less than 1 mm) and two significant determinants of OS (age over 80 and preoperative portal vein thrombosis). Even with positive margins, it still had no impact on OS. For DFS, 1 mm free margins appeared to be adequate. CONCLUSION: Tumor-free margin is an independent risk factor for recurrence but has no impact on OS. Surgical margin >1 mm is adequate in patients with tumors >=10 cm. Postoperative close follow up, especially of distant metastasis, and appropriate treatment of recurrence by a multidisciplinary approach may improve prognosis. PMID- 26052437 TI - Prosthetic rehabilitation of a patient after a partial mandibulectomy. AB - INTRODUCTION: The treatment of orofacial tumors may cause facial deformities by losses of structures that affect basic functions, i.e. feeding, speech, and the reduction of patient self-steam. PRESENTATION OF CASE: A white male patient was diagnosed with epidermoid cancer on the mandibular alveolar ridge with infiltration staging IV A. The patient was submitted to a mandibulectomy associated with a complete extraction of mandibular teeth. For rehabilitation, a conventional denture for the mandibular arch and a removable partial denture for the maxillary arch were fabricated. A correct occlusal adjustment and a satisfactory amount of alveolar bone was favorable for conventional dentures of the prostheses bases improve their retention and stability. After one year of follow-up, the patient was adapted to the prostheses, satisfied with their retention, and reported an improvement on his feeding. DISCUSSION: The prosthetic rehabilitation of patients after a partial mandibulectomy is essential for their self-steam. Conventional dentures may have their retention and stability improved if they are well fabricated, recorded and have a balanced occlusion. CONCLUSION: A correct occlusal adjustment and an adequate retention of the prostheses bases may improve their retention and stability. Patients without xerostomy and with a satisfactory amount of alveolar bone may have a favorable prognosis for conventional dentures. PMID- 26052438 TI - Diurnal variation in fecal concentrations of acid-detergent insoluble ash and alkaline-peroxide lignin from cattle fed bermudagrass hays of varying nutrient content. AB - BACKGROUND: The effect of time of fecal sampling on the accuracy of acid detergent insoluble ash (ADIA) and alkaline-peroxide lignin (APL) for the prediction of fecal output (FO) in cattle was evaluated. Eight ruminally cannulated cows (594 +/- 35.5 kg) were allocated randomly to 4 bermudagrass [Cynodon dactylon (L.) Pers.] hay diets markedly different in crude protein concentration (79-164 g/kg) with 2 replicates per diet for 3 periods. Cows were offered hay individually at 20 g DM/kg of body weight daily in equal feedings at 08:00 and 16:00 h for a 10-d adaptation period followed by 5-d of total fecal collection. Fecal grab samples also were taken each day during the fecal collection period at 06:00, 12:00, 18:00, and 24:00 h either directly from the rectum or from freshly voided feces. Samples were composited within cow and time across the 5 d total fecal collection period. Additionally, forage, ort, and fecal samples were analyzed for concentrations of APL and ADIA. RESULTS: Fecal concentrations of ADIA and APL were not affected by sampling time (P >= 0.22), even though diet affected (P < 0.01) fecal ADIA and APL concentrations. There were no diet * sampling time interactions (P >= 0.60). Estimates of FO and dry matter digestibility (DMD) from ADIA and APL were not affected (P >= 0.16) by sampling time or the diet * sampling time interaction (P >= 0.74). Estimates of FO and DMD from markers from different sampling times or all different combinations of sampling time were not different (P >= 0.72) from those of total collection among internal markers. CONCLUSION: Little variation in concentrations of ADIA and APL in daily fecal excretion across time increases flexibility in fecal grab sampling schedules for predicting FO and DMD. PMID- 26052439 TI - Medical malpractice, defensive medicine and role of the "media" in Italy. AB - BACKGROUND: For many years until now, Italy has been subjected to an inconsistent and contradictory media campaign. On one hand the "media" present us with bold and reassuring messages about the progress of medical science; on the other hand they are prone to kneejerk criticism every time medical treatment does not have the desired effect, routinely describing such cases as glaring examples of "malasanita", an Italian word of recent coinage used to denote medical malpractice. Newspaper reports of legal proceedings involving health treatment are frequently full of errors and lack any scientific basis. DATA SOURCES: The published data confirm the unsustainably high number of lawsuits against doctors and medical structures, accompanied by demands for compensation arising from true or alleged medical errors or mistakes blamed on the work of health structures. CONCLUSIONS AND IMPLICATIONS: Currently Italian citizens have a greater awareness of their right to health than in the past, and patients' expectations have risen. A discrepancy is emerging between the current state of medical science and the capacities of individual doctors and health structures. Lastly, there is a need for greater monitoring of the quality of health care services and a greater emphasis on health risk prevention. PMID- 26052440 TI - Effects of financial incentives for treatment supporters on tuberculosis treatment outcomes in Swaziland: a pragmatic interventional study. AB - BACKGROUND: Swaziland has the highest national incidence of tuberculosis (TB) in the world, with treatment success rates well below the 85 % international target. Treatment support as part of comprehensive TB services is a core component of the Stop TB Strategy. This study investigated the effects of financial incentives for treatment supporters on TB treatment outcomes in Swaziland. METHODS: This was a controlled study that compared treatment outcomes for patients with a treatment supporter who received or did not receive a financial incentive. RESULTS: The intervention group had a higher chance of treatment success as compared with the control group: 73 % (95 % confidence intervals [CIs] 66-80 %) versus 60 % (95 % CIs 57-64 %), respectively, p = 0.003. This improvement remained significant when treatment success rates were adjusted for differences in baseline characteristics, with the effect of incentivised treatment supporters on treatment outcomes having an odds ratio (OR) of 1.8. There was also a significant improvement in the death rate in the intervention group, as compared with the control group (10.6 versus 23.5 %, p = <0.001). CONCLUSION: Incentives provided to TB treatment supporters appear to significantly improve TB treatment outcomes. Incentivising treatment support may be appropriate as an effective addition to support and supervision measures (199 words). PMID- 26052441 TI - An unusual occurrence: a case of venous thromboembolism in pregnancy associated with heterotaxy syndrome. AB - BACKGROUND: Heterotaxy is a relatively uncommon congenital anomaly that is usually diagnosed incidentally on imaging studies in adults. We present an unusual case of venous thromboembolism in a 26 year old pregnant female with Heterotaxy syndrome. CASE PRESENTATION: A 26 year-old pregnant female at 13 weeks gestation suffered cardiac arrest with successful cardiac resuscitation and return of spontaneous circulation. The cardiac arrest was secondary to massive pulmonary embolism requiring thrombolytic therapy and stabilization of hemodynamics. She had extensive evaluation to determine the etiology for the pulmonary embolism and was noted to have an anatomic variation consistent with heterotaxy syndrome on imaging studies. After thrombolysis the patient was treated with UFH and then switched to enoxaparin without complication until 25 weeks of gestation when she experienced worsening abdominal pain with associated headaches, lightheadedness and elevated blood pressures needing elective induction of labor. The infant died shortly after delivery. The anticoagulation was continued for additional 3 months and she was subsequently placed on low dose aspirin to prevent recurrent venous thromboembolic episodes. She is currently stable on low dose aspirin and is into her third year after the venous thromboembolism without any recurrence. CONCLUSION: To our knowledge, this is the first reported case of venous thromboembolism in pregnancy associated with heterotaxy syndrome. A discussion on pathophysiology of venous thromboembolism in pregnancy and heterotaxy syndrome has been undertaken along with treatment approach in such situations. PMID- 26052442 TI - Hybrid heating systems optimization of residential environment to have thermal comfort conditions by numerical simulation. AB - The aim of this study is to determine optimum hybrid heating systems parameters, such as temperature, surface area of a radiant heater and vent area to have thermal comfort conditions. DOE, Factorial design method is used to determine the optimum values for input parameters. A 3D model of a virtual standing thermal manikin with real dimensions is considered in this study. Continuity, momentum, energy, species equations for turbulent flow and physiological equation for thermal comfort are numerically solved to study heat, moisture and flow field. K ERNG Model is used for turbulence modeling and DO method is used for radiation effects. Numerical results have a good agreement with the experimental data reported in the literature. The effect of various combinations of inlet parameters on thermal comfort is considered. According to Pareto graph, some of these combinations that have significant effect on the thermal comfort require no more energy can be used as useful tools. A better symmetrical velocity distribution around the manikin is also presented in the hybrid system. PMID- 26052444 TI - Adverse Effects of Medicines: Is the Omani population safe? PMID- 26052443 TI - Gene Expression Profiling of Ewing Sarcoma Tumors Reveals the Prognostic Importance of Tumor-Stromal Interactions: A Report from the Children's Oncology Group. AB - Relapse of Ewing sarcoma (ES) can occur months or years after initial remission and salvage therapy for relapsed disease is usually ineffective. Thus, there is great need to develop biomarkers that can predict which patients are at risk for relapse so that therapy and post-therapy evaluation can be adjusted accordingly. For the current study we performed whole genome expression profiling on two independent cohorts of clinically annotated ES tumors in an effort to identify and validate prognostic gene signatures. ES specimens were obtained from the Children's Oncology Group (COG) and whole genome expression profiling performed using Affymetrix Human Exon 1.0 ST arrays. Lists of differentially expressed genes between survivors and non-survivors were used to identify prognostic gene signatures. An independent cohort of tumors from the Euro-Ewing cooperative group was similarly analyzed as a validation cohort. Unsupervised clustering of gene expression data failed to segregate tumors based on outcome. Supervised analysis of survivors vs. non-survivors revealed a small number of differentially expressed genes and several statistically significant gene signatures. Gene specific enrichment analysis (GSEA) demonstrated that integrin and chemokine genes were associated with survival in tumors where stromal contamination was present. Tumors that did not harbor stromal contamination showed no association of any genes or pathways with clinical outcome. Our results reflect the challenges of performing RNA-based assays on archived bone tumor specimens. In addition, they reveal a key role for tumor stroma in determining ES prognosis. Future biologic and clinical investigations should focus on elucidating the contribution of tumor:microenvironment interactions on ES progression and response to therapy. Key words: ES, gene expression profiling, prognostic signature. PMID- 26052445 TI - (18)F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography in the Management of Metastatic Colorectal Cancer: Are we there yet? PMID- 26052446 TI - Adult Hepatoblastoma: What do we know? PMID- 26052448 TI - Ebolavirus and Haemorrhagic Syndrome. AB - The Ebola virus is a highly virulent, single-stranded ribonucleic acid virus which affects both humans and apes and has fast become one of the world's most feared pathogens. The virus induces acute fever and death, with haemorrhagic syndrome occurring in up to 90% of patients. The known species within the genus Ebolavirus are Bundibugyo, Sudan, Zaire, Reston and Tai Forest. Although endemic in Africa, Ebola has caused worldwide anxiety due to media hype and concerns about its international spread, including through bioterrorism. The high fatality rate is attributed to unavailability of a standard treatment regimen or vaccine. The disease is frightening since it is characterised by rapid immune suppression and systemic inflammatory response, causing multi-organ and system failure, shock and often death. Currently, disease management is largely supportive, with containment efforts geared towards mitigating the spread of the virus. This review describes the classification, morphology, infective process, natural ecology, transmission, epidemic patterns, diagnosis, clinical features and immunology of Ebola, including management and epidemic containment strategies. PMID- 26052447 TI - The Role of Damage-Associated Molecular Patterns (DAMPs) in Human Diseases: Part II: DAMPs as diagnostics, prognostics and therapeutics in clinical medicine. AB - This article is the second part of a review that addresses the role of damage associated molecular patterns (DAMPs) in human diseases by presenting examples of traumatic (systemic inflammatory response syndrome), cardiovascular (myocardial infarction), metabolic (type 2 diabetes mellitus), neurodegenerative (Alzheimer's disease), malignant and infectious diseases. Various DAMPs are involved in the pathogenesis of all these diseases as they activate innate immune machineries including the unfolded protein response and inflammasomes. These subsequently promote sterile autoinflammation accompanied, at least in part, by subsequent adaptive autoimmune processes. This review article discusses the future role of DAMPs in routine practical medicine by highlighting the possibility of harnessing and deploying DAMPs either as biomarkers for the appropriate diagnosis and prognosis of diseases, as therapeutics in the treatment of tumours or as vaccine adjuncts for the prophylaxis of infections. In addition, this article examines the potential for developing strategies aimed at mitigating DAMPs-mediated hyperinflammatory responses, such as those seen in systemic inflammatory response syndrome associated with multiple organ failure. PMID- 26052449 TI - Increasing Incidence of Infants with Low Birth Weight in Oman. AB - This review article provides an overview of the levels, trends and some possible explanations for the increasing rate of low birth weight (LBW) infants in Oman. LBW data from national health surveys in Oman, and published reports from Oman's Ministry of Health and the World Health Organization were collected and assessed between January and August 2014. Oman's LBW rate has been increasing since the 1980s. It was approximately 4% in 1980 and had nearly doubled (8.1%) by 2000. Since then, it has shown a slow but steady rise, reaching 10% in recent times. High rates of consanguinity, premature births, number of increased pregnancies at an older maternal age and changing lifestyles are some important factors related to the increasing rate of LBW in Oman. The underlying causes of this increase need to be understood and addressed in obstetric policies and practices in order to reduce the rate of LBW in Oman. PMID- 26052450 TI - The Burden of Asthma in Oman. AB - Asthma is a common lung disease worldwide, although its prevalence varies from country to country. Oman is ranked in the intermediate range based on results from the International Study of Asthma and Allergies in Childhood. A 2009 study revealed that the majority of asthmatic patients in Oman reported both daytime and nocturnal symptoms, while 30% of adults and 52% of children reported absences from work or school due to their symptoms. Despite these findings, there is little data available on the economic burden of asthma in Oman. The only accessible information is from a 2013 study which concluded that Oman's highest asthma-related costs were attributable to inpatient (55%) and emergency room (25%) visits, while asthma medications contributed to less than 1% of the financial toll. These results indicate a low level of asthma control in Oman, placing a large economic burden on healthcare providers. Therefore, educating asthmatic patients and their families should be prioritised in order to improve the management and related costs of this disease within Oman. PMID- 26052451 TI - Heavy Vehicle Crash Characteristics in Oman 2009-2011. AB - In recent years, Oman has seen a shift in the burden of diseases towards road accidents. The main objective of this paper, therefore, is to describe key characteristics of heavy vehicle crashes in Oman and identify the key driving behaviours that influence fatality risks. Crash data from January 2009 to December 2011 were examined and it was found that, of the 22,543 traffic accidents that occurred within this timeframe, 3,114 involved heavy vehicles. While the majority of these crashes were attributed to driver behaviours, a small proportion was attributed to other factors. The results of the study indicate that there is a need for a more thorough crash investigation process in Oman. Future research should explore the reporting processes used by the Royal Oman Police, cultural influences on heavy vehicle operations in Oman and improvements to the current licensing system. PMID- 26052452 TI - A Historical Tale of Two Lymphomas: Part I: Hodgkin lymphoma. PMID- 26052453 TI - The Controversies of Hyponatraemia in Hypothyroidism: Weighing the evidence. AB - Hyponatraemia is a common electrolyte disturbance, with moderate (serum sodium: 125-129 mmol/L) to severe (serum sodium: <=125 mmol/L) forms of the disease occurring in 4-15% of hospitalised patients. While it is relatively common, determining the underlying cause of this condition can be challenging and may require extensive laboratory investigations. To this end, it is important to ascertain the efficacy of laboratory tests in determining the cause of hyponatraemia. Up to 10% of patients with hypothyroidism also have hyponatraemia. Routine evaluation of thyroid function is often advocated in cases of low serum sodium. A review and discussion of the available literature is presented here to examine this recommendation. PMID- 26052454 TI - Underlying Factors Behind the Low Prevalence of Autism Spectrum Disorders in Oman: Sociocultural perspective. AB - Epidemiological surveys from various countries indicate an increased prevalence of autism spectrum disorders (ASD), leading researchers to debate whether there are now 'more affected' or 'more detected'. The epidemiology of ASD in developing countries, such as Oman, has generally indicated a lower prevalence compared to developed countries in the West. In Oman, the prevalence is low; however, this article highlights some of the factors that could contribute to the appearance of a low ASD rate: cross-cultural variations in the presentation of distress; a lack of reliable biological markers for diagnosing ASD, and a lack of health services for children with ASD, thus limiting the number of participants in epidemiological surveys. While the defining features of ASD have yet to be established, pilot studies in Oman indicate a substantial number of children with these disorders. Therefore, it is important that these discrepancies be addressed and the need for appropriate services for this patient population in Oman be highlighted. PMID- 26052455 TI - Predicting the Pathogenic Potential of BRCA1 and BRCA2 Gene Variants Identified in Clinical Genetic Testing. AB - OBJECTIVES: Missense variants are very commonly detected when screening for mutations in the BRCA1 and BRCA2 genes. Pathogenic mutations in the BRCA1 and BRCA2 genes lead to an increased risk of developing breast, ovarian, prostate and/or pancreatic cancer. This study aimed to assess the predictive capability of in silico programmes and mutation databases in assisting diagnostic laboratories to determine the pathogenicity of sequence-detectable mutations. METHODS: Between July 2011 and April 2013, an analysis was undertaken of 13 missense BRCA gene variants that had been detected in patients referred to the Genetic Health Services New Zealand (Northern Hub) for BRCA gene analysis. The analysis involved the use of 13 in silico protein prediction programmes, two in silico transcript analysis programmes and the examination of three BRCA gene databases. RESULTS: In most of the variants, the analysis showed different in silico interpretations. This illustrates the interpretation challenges faced by diagnostic laboratories. CONCLUSION: Unfortunately, when using online mutation databases and carrying out in silico analyses, there is significant discordance in the classification of some missense variants in the BRCA genes. This discordance leads to complexities in interpreting and reporting these variants in a clinical context. The authors have developed a simple procedure for analysing variants; however, those of unknown significance largely remain unknown. As a consequence, the clinical value of some reports may be negligible. PMID- 26052456 TI - Epidemiology of Diabetes Mellitus in Oman: Results from two decades of research. AB - OBJECTIVES: This study aimed to describe the epidemiology of diabetes mellitus over the past two decades in Oman, particularly in terms of its prevalence and incidence. In addition, the study sought to estimate the future incidence of diabetes in Oman. METHODS: Three national and three regional surveys conducted between 1991 and 2010 were analysed to obtain the age-adjusted prevalence and undiagnosed proportion of type 2 diabetes mellitus (T2DM) among Omani subjects aged >=20 years. Diabetes mellitus registers and published studies were used to determine incidence rates of both type 1 diabetes mellitus (T1DM) and T2DM in Oman. Linear regression was used to determine trends and projections for diabetes in 2050. RESULTS: The age-adjusted prevalence of T2DM in Oman varied from 10.4% to 21.1%, while the highest prevalence of impaired fasting glucose was found in males (35.1%). In comparison to men, higher incidence rates of T2DM were found in women (2.7 cases compared to 2.3 cases per 1,000 person-years, respectively). No significant trends were observed for the prevalence or incidence of T2DM in both genders. Undiagnosed T2DM was more common in men (range: 33-68%) than women (range: 27-53%). The results of this study show that by 2050, there will be an estimated 350,000 people with T2DM living in Oman (a 174% increase compared to estimates for 2015). CONCLUSION: Health authorities need to prioritise diabetes prevention and control in order to prevent or delay long-term complications and avert a potential epidemic of diabetes in Oman. PMID- 26052457 TI - Incidence and Risk Factors of Parenteral Nutrition-Associated Cholestasis in Omani Neonates: Single centre experience. AB - OBJECTIVES: Parenteral nutrition-associated cholestasis (PNAC) is one of the most challenging complications of prolonged parenteral nutrition (PN) in neonates. There is a lack of research investigating its incidence in newborn infants in Oman and the Arab region. Therefore, this study aimed to assess the incidence of PNAC and its risk factors in Omani neonates. METHODS: This retrospective study took place between January and April 2014. All neonates who received PN for >=14 days during a four-year period (June 2009 to May 2013) at the neonatal intensive care unit (NICU) in Sultan Qaboos University Hospital, Muscat, Oman, were enrolled. RESULTS: A total of 1,857 neonates were admitted to the NICU over the study period and 135 neonates (7.3%) received PN for >=14 days. Determining the incidence of PNAC was only possible in 97 neonates; of these, 38 (39%) had PNAC. The main risk factors associated with PNAC were duration of PN, duration of enteral starvation, gastrointestinal surgeries, blood transfusions and sepsis. Neonates with PNAC had a slightly higher incidence of necrotising enterocolitis in comparison to those without PNAC. CONCLUSION: This study found a PNAC incidence of 39% in Omani neonates. There were several significant risk factors for PNAC in Omani neonates; however, after logistic regression analysis, only total PN duration remained statistically significant. Preventive strategies should be implemented in NICUs so as to avoid future chronic liver disease in this population. PMID- 26052458 TI - The Association between Human Leukocyte Antigens and Hypertensive End-Stage Renal Failure among Yemeni Patients. AB - OBJECTIVES: Many studies have attempted to locate a connection between various genetic factors and the pathogenesis of certain diseases. A number of these have found human leukocyte antigens (HLAs) to be the most significant genetic factors affecting the susceptibility of an individual to a certain disease. The present case-control study aimed to determine the connection between class I and class II HLAs and cases of hypertensive end-stage renal failure (HESRF), as contrasted with healthy controls, in Yemen. METHODS: The study was carried out between March 2013 and March 2014 and included 50 HESRF patients attending the Urology & Nephrology Center at Al-Thawra University Hospital in Sana'a, Yemen, and 50 healthy controls visiting the same centre for kidney donation. Among both patients and controls, HLA class I (A, B and C) and class II (DRB1) genotypes were determined by polymerase chain reactions. RESULTS: There was an association (odds ratio: 4.0) with HLA-A9(24) and HESRF, although this was not statistically significant. A significant protective function was found for the HLA-CW3 and DRB1 8 genes against the development of HESRF. Although HLA-B14 was present in some patients (0.06) and not in the controls, this difference was not statistically significant enough to conclude that HLA-B14 plays a role in the genetic predisposition for end-stage renal disease development. There was a high frequency of HLA-A2, B5, CW6, DRB1-3, DRB1-4 and DRB1-13 in both patients and controls. CONCLUSION: Although no HLAs were found to play a highly significant role in genetic predisposition to HESRF, certain HLA genes could be considered as protective genes against HESRF development. PMID- 26052459 TI - Knowledge, Beliefs and Behaviours Regarding the Adverse Effects of Medicines in an Omani Population: Cross-sectional survey. AB - OBJECTIVES: This study aimed to assess the knowledge, beliefs and behaviours of an Omani population with regards to the adverse effects of medicines. METHODS: This cross-sectional survey was conducted between February and June 2012. A 17 item questionnaire was designed to assess three aspects: knowledge, beliefs and behaviours related to medicine safety. A total of 740 questionnaires were distributed in three representative governorates of Oman. Median total scores for the three sections were estimated. Associations with participants' demographic variables and medication histories were also assessed. RESULTS: A total of 618 participants completed the survey (response rate: 83.5%). Many participants (46.4%) believed that side-effects occurred only with high doses of medication and over 30% believed that they did not occur at all with traditional and over the-counter medicines. The median total score was 19 (interquartile range: 6) out of a maximum of 30. Inadequate knowledge, incorrect beliefs and good behaviours were observed among the participants. There was a significant association between certain demographic parameters (age, educational qualification, history of chronic use of medicines and employment status) and median total scores. Participants reported obtaining additional information on medication safety from various sources, with doctors as the most widely used source. CONCLUSION: Inadequate knowledge and incorrect beliefs among this Omani population indicate a need for interventions to improve public knowledge and address misconceptions regarding medication safety. These interventions could be initiated on both an individual and public scale, with patient interactions by healthcare professionals and mass education activities targeting the larger population. PMID- 26052460 TI - Lifestyles of Adult Omani Women: Cross-sectional study on physical activity and sedentary behaviour. AB - OBJECTIVES: This study aimed to investigate the lifestyles of adult Omani women with regards to physical activity (PA) levels and sedentary behaviour (SB). METHODS: The study was carried out between May and June 2013 and included a total of 277 healthy women aged 18-48 years from five governorates in Oman. Total, moderate and vigorous PA levels and walking were self-reported by participants using the short form of the International Physical Activity Questionnaire. SB (total sitting time and different types of sitting time) was self-reported using the Domain-Specific Sitting Time Questionnaire on both working and non-working days. PA levels and SB were also objectively measured among 86 of the participants using an accelerometer. RESULTS: The self-reported median +/- interquartile range (IQR) total PA was 1,516 +/- 3,392 metabolic equivalent of task minutes/week. The self-reported median +/- IQR total sitting time was 433 +/ 323 minutes/day and 470 +/- 423 minutes/day for working and non-working days, respectively. Sitting at work on working days and sitting during leisure activities on non-working days formed the greatest proportion of total sitting time. Overall, accelerometer results indicated that participants spent 62% of their time involved in SB, 35% in light PA and only 3% in moderate to vigorous PA. CONCLUSION: Sedentary lifestyles were common among the adult Omani women studied. Lack of PA and increased SB is known to increase the risk of metabolic syndrome and obesity. The use of accelerometers to monitor PA and SB among different groups in Oman is highly recommended in order to accurately assess the lifestyle risks of this population. PMID- 26052461 TI - Validity and Reliability of the Clinical Competency Evaluation Instrument for Use among Physiotherapy Students: Pilot study. AB - OBJECTIVES: The aim of this study was to determine the content validity, internal consistency, test-retest reliability and inter-rater reliability of the Clinical Competency Evaluation Instrument (CCEVI) in assessing the clinical performance of physiotherapy students. METHODS: This study was carried out between June and September 2013 at University Kebangsaan Malaysia (UKM), Kuala Lumpur, Malaysia. A panel of 10 experts were identified to establish content validity by evaluating and rating each of the items used in the CCEVI with regards to their relevance in measuring students' clinical competency. A total of 50 UKM undergraduate physiotherapy students were assessed throughout their clinical placement to determine the construct validity of these items. The instrument's reliability was determined through a cross-sectional study involving a clinical performance assessment of 14 final-year undergraduate physiotherapy students. RESULTS: The content validity index of the entire CCEVI was 0.91, while the proportion of agreement on the content validity indices ranged from 0.83-1.00. The CCEVI construct validity was established with factor loading of >=0.6, while internal consistency (Cronbach's alpha) overall was 0.97. Test-retest reliability of the CCEVI was confirmed with a Pearson's correlation range of 0.91-0.97 and an intraclass coefficient correlation range of 0.95-0.98. Inter-rater reliability of the CCEVI domains ranged from 0.59 to 0.97 on initial and subsequent assessments. CONCLUSION: This pilot study confirmed the content validity of the CCEVI. It showed high internal consistency, thereby providing evidence that the CCEVI has moderate to excellent inter-rater reliability. However, additional refinement in the wording of the CCEVI items, particularly in the domains of safety and documentation, is recommended to further improve the validity and reliability of the instrument. PMID- 26052462 TI - Heavy Metals in Seafood and Farm Produce from Uyo, Nigeria: Levels and health implications. AB - OBJECTIVES: This study aimed to obtain representative data on the levels of heavy metals in seafood and farm produce consumed by the general population in Uyo, Akwa Ibom State, Nigeria, a region known for the exploration and exploitation of crude oil. METHODS: In May 2012, 25 food items, including common types of seafood, cereals, root crops and vegetables, were purchased in Uyo or collected from farmland in the region. Dried samples were ground, digested and centrifuged. Levels of heavy metals (lead, cadmium, nickel, cobalt and chromium) were analysed using an atomic absorption spectrophotometer. Average daily intake and target hazard quotients (THQ) were estimated. RESULTS: Eight food items (millet, maize, periwinkle, crayfish, stock fish, sabina fish, bonga fish and pumpkin leaf) had THQ values over 1.0 for cadmium, indicating a potential health risk in their consumption. All other heavy metals had THQ values below 1.0, indicating insignificant health risks. The total THQ for the heavy metals ranged from 0.389 to 2.986. There were 14 items with total THQ values greater than 1.0, indicating potential health risks in their consumption. CONCLUSION: The regular consumption of certain types of farm produce and seafood available in Uyo, Akwa Ibom State, Nigeria, is likely adding to the body burden of heavy metals among those living in this region. PMID- 26052463 TI - Disclosure of Medical Errors in Oman: Public preferences and perceptions of current practice. AB - OBJECTIVES: This study aimed to provide insight into the preferences for and perceptions of medical error disclosure (MED) by members of the public in Oman. METHODS: Between January and June 2012, an online survey was used to collect responses from 205 members of the public across five governorates of Oman. RESULTS: A disclosure gap was revealed between the respondents' preferences for MED and perceived current MED practices in Oman. This disclosure gap extended to both the type of error and the person most likely to disclose the error. Errors resulting in patient harm were found to have a strong influence on individuals' perceived quality of care. In addition, full disclosure was found to be highly valued by respondents and able to mitigate for a perceived lack of care in cases where medical errors led to damages. CONCLUSION: The perceived disclosure gap between respondents' MED preferences and perceptions of current MED practices in Oman needs to be addressed in order to increase public confidence in the national health care system. PMID- 26052464 TI - Measuring Secondhand Smoke in Muscat, Oman. AB - OBJECTIVES: This study aimed to measure exposure to secondhand smoke (SHS) and assess venue compliance with the municipal Law against smoking indoors in public places in Muscat, Oman. METHODS: Following the selection of 30 public indoor venues within the Muscat governorate, the concentration of suspended SHS particulate matter (PM2.5) in the venues' indoor air was measured throughout July and August 2010. RESULTS: Almost all of the venues were found to be compliant with the smoke-free municipal, with the exception of a cafe that served waterpipes for smoking indoors. The concentration of PM2.5 in this venue showed an average level of 256 ug/m(3) which was 64 times the level of that found in the non-smoking venues. CONCLUSION: Aside from one cafe, the majority of the assessed indoor public venues abided by the smoke-free municipal law. However, the enforcement of policies banning smoking in indoor public recreational venues should be re-examined in order to protect member of the public in Oman from exposure to SHS. PMID- 26052465 TI - Estimates of Average Glandular Dose with Auto-modes of X-ray Exposures in Digital Breast Tomosynthesis. AB - OBJECTIVES: The aim of this research was to examine the average glandular dose (AGD) of radiation among different breast compositions of glandular and adipose tissue with auto-modes of exposure factor selection in digital breast tomosynthesis. METHODS: This experimental study was carried out in the National Cancer Society, Kuala Lumpur, Malaysia, between February 2012 and February 2013 using a tomosynthesis digital mammography X-ray machine. The entrance surface air kerma and the half-value layer were determined using a 100H thermoluminescent dosimeter on 50% glandular and 50% adipose tissue (50/50) and 20% glandular and 80% adipose tissue (20/80) commercially available breast phantoms (Computerized Imaging Reference Systems, Inc., Norfolk, Virginia, USA) with auto-time, auto filter and auto-kilovolt modes. RESULTS: The lowest AGD for the 20/80 phantom with auto-time was 2.28 milliGray (mGy) for two dimension (2D) and 2.48 mGy for three dimensional (3D) images. The lowest AGD for the 50/50 phantom with auto time was 0.97 mGy for 2D and 1.0 mGy for 3D. CONCLUSION: The AGD values for both phantoms were lower against a high kilovolt peak and the use of auto-filter mode was more practical for quick acquisition while limiting the probability of operator error. PMID- 26052466 TI - Rare Presentation of Aggressive T/Natural Killer Lymphoproliferative Disorder in a Leukaemic Phase in an Omani Patient. PMID- 26052467 TI - Porcelain Heart and Lung. PMID- 26052468 TI - Re: Antibiotic Prescribing Trends in an Omani Paediatric Population. PMID- 26052469 TI - Changes in N-acylethanolamine Pathway Related Metabolites in a Rat Model of Cerebral Ischemia/Reperfusion. AB - In mammals, the endocannabinoid signaling pathway provides protective cellular responses to ischemia. Previous work demonstrated increases in long-chain N acylethanolamines (NAE) in ischemia and suggested a protective role for NAE. Here, a targeted lipidomics approach was used to study comprehensive changes in the molecular composition and quantity of NAE metabolites in a rat model of controlled brain ischemia. Changes of NAE, its precursors, N acylphosphatidylethanolamines (NAPE), major and minor phospholipids, and free fatty acids (FFA) were quantified in response to ischemia. The effect of intraperitoneal injection of N-palmitoylethanolamine (NAE 16:0) prior to ischemia on NAE metabolite and phospholipid profiles was measured. While ischemia, in general, resulted in elevated levels of N-acyl 16:0 and18:0 NAE, NAPE, and FFA species, pretreatment with NAE 16:0 reduced infarct volume, neurological behavioral deficits in rats, and FFA content in ischemic tissues. Pretreatment with NAE 16:0 did not affect the profiles of other NAE metabolites. These studies demonstrate the utility of a targeted lipidomics approach to measure complex and concomitant metabolic changes in response to ischemia. They suggest that the neuroprotective effects of exogenous NAE 16:0 and the reduction in inflammatory damage may be mediated by factors other than gross changes in brain NAE levels, such as modulation of transcriptional responses. PMID- 26052471 TI - Assessing Measles Transmission in the United States Following a Large Outbreak in California. AB - The recent increase in measles cases in California may raise questions regarding the continuing success of measles control. To determine whether the dynamics of measles is qualitatively different in comparison to previous years, we assess whether the 2014-2015 measles outbreak associated with an Anaheim theme park is consistent with subcriticality by calculating maximum-likelihood estimates for the effective reproduction numbe given this year's outbreak, using the Galton Watson branching process model. We find that the dynamics after the initial transmission event are consistent with prior transmission, but does not exclude the possibilty that the effective reproduction number has increased. PMID- 26052470 TI - Differential Specificity of Interferon-alpha Inducible Gene Expression in Association with Human Immunodeficiency Virus and Hepatitis C Virus Levels and Declines in vivo. AB - OBJECTIVE: This study was aimed to correlate in vivo interferon (IFN) inducible gene (IFIG) expression and IFIG induction with viral-load (VL) and VL-kinetics of Human-Immunodeficiency-Virus (HIV) or Hepatitis-C-Virus (HCV) in HIV-positive patients treated with pegylated IFN-alpha-2a (PegIFNalpha). METHODS: HIV mono infected patients (N=8) and HIV/HCV co-infected patients (N=23, without HIV viremia) were treated with PegIFNalpha (180 MUg/week) for 12 and 48 weeks, respectively. Blood sampling for monitoring IFIG expression occurred at day_0 and week_3, _6 and _12 for HIV mono-infected patients vs. only at day_0 and week_48 for HIV/HCV co-infected subjects. IFIG expression (N=20) was measured in peripheral blood mononuclear cells by bDNA-assay. VL levels/changes in plasma were analyzed for correlation with IFIG expression/induction at/between selected time points. Overall, P<0.05 was considered significant. RESULTS: None of the 20 IFIG expression profiles at day_0 correlated significantly with HIV-VL at day_0. Expression at day_0 of 3 IFIG (APOBEC3G/OAS1/OAS2) correlated significantly (r>+0.42/P<0.05) with HCV-VL at day_0. The strongest antiviral effect [measured as median viral decline per week: DeltaVL/week (log10)] occurred in common against HIV and HCV between day_0 and week_3 during 12 weeks of continuous PegIFNalpha treatment in both cohorts. Expression at day_0 of 1 IFIG (APOBEC3A) correlated significantly (r<-0.71/P<0.05) with HIV-DeltaVL/week (log10) from day_0 to week_3. No significance was reached in correlations between expression values of 20 IFIG at day_0 and HCV-DeltaVL/week (log10) from day_0 to week_3. No significant correlation was detected between IFIG expression changes (DeltaIFIG=induction) from day_0 to week_3 and HIV-DeltaVL/week (log10) from day_0 to week_3. Interestingly, induction of 1 IFIG (DeltaISG20) from day_0 to week_48 was significantly associated (P<0.05) with permanent HCV clearance. CONCLUSION: This study demonstrates the differential specificity of PegIFNalpha mediated molecular actions by dissecting the kinetics of IFIG expression and induction, suggesting multiple, possibly non-overlapping mechanisms for antiviral effects against HCV and HIV. PMID- 26052472 TI - Effects of a Novel Dental Gel on Plaque and Gingivitis: A Comparative Study. AB - OBJECTIVES: The goal of this prospective, randomized, controlled, double-blinded study was to evaluate the effects of a novel dental gel on plaque and gingival health. The dental gel was designed to (1) break up and prevent re-accumulation of microbial biofilm, and (2) inhibit metal mediated inflammation. MATERIALS AND METHODS: Twenty-five subjects with moderate gingival inflammation (Loe and Silness Gingival Index >=2) and pocket depths <4 were randomly assigned to brush twice daily for 21 days with the test or the control dental gel. On Days 0, 7, 14 and 21, plaque levels (Quigley-Hein, Turesky Modification Plaque Index), gingival inflammation (Loe and Silness Gingival Index) and gingival bleeding (modified Sulcus Bleeding Index) were determined by one blinded, investigator using a pressure sensitive probe. RESULTS: After 3 weeks, all 3 clinical indices were significantly improved in both groups (P<0.05) and significantly lower in the test group (P<0.05). CONCLUSION: The novel dental gel formulation was provided effective plaque control and reduced gingival inflammation. CLINICAL RELEVANCE: A novel dentifrice formulation may be an effective tool for plaque removal and maintaining gingival health. PMID- 26052473 TI - Utilization of the National Health and Nutrition Examination (NHANES) Survey for Symptoms, Tests, and Diagnosis of Chronic Respiratory Diseases and Assessment of Second hand Smoke Exposure. AB - BACKGROUND: Respiratory diseases encompass a number of complex disorders that constitute a major cause of both morbidity and mortality worldwide with a major burden to the afflicted as well as the health care systems that care for them. Although the prevalence of chronic respiratory diseases (CRDs) has been decreasing in industrialized countries due to a decreasing number of smokers and stricter laws aimed at reducing exposure to secondhand smoke (SHS), the burden of CRDs in developing world populations is expected to worsen due to communicable disease prevention programs, aging populations, environmental air pollution, and continued tobacco smoke exposure. Although tobacco smoking has been shown to be significantly associated with many CRDs, evidence linking SHS exposure to different CRDs is mixed, especially with low levels of SHS exposure. METHODS: The National Health and Nutrition Examination Survey (NHANES) is a series of studies designed to assess the health and nutritional status of non-institutionalized adults and children in the United States (U.S.). In addition to being used to monitor the health of the U.S. population, NHANES data allow for research into prevalent health problems and their risk factors in the population, such with CRDs and SHS exposure. NHANES data can be utilized to explore a variety of issues related to the assessment of SHS exposure and its association to respiratory symptoms and illnesses. RESULTS: First, we provide a brief review of NHANES including its strengths and limitations. We then provide a summary of the variables and publically available population based data that can be used to study associations between SHS exposure and CRD symptoms, testing and diagnoses. CONCLUSION: Rich and cost effective, NHANES data provide a unique opportunity for research into the risk factors for CRDs in the U.S. population, particularly into the possible health effects of low levels of SHS exposure. PMID- 26052474 TI - Effect of emotional valence on episodic memory stages as indexed by event-related potentials. AB - Several investigations have shown that emotional events show superior recall than non-emotional ones. However, the cortical mechanisms underlying the episodic recall of emotional scenes are still poorly understood. Our main aim was to compare the magnitude of the Event-Related brain Potentials (ERP) old-new effect related to emotionally unpleasant, pleasant and neutral photographic images. As expected, correct recognition of all types of images elicited three topographically distinct ERP components sensitive to the classical old-new recognition effect. The results revealed that the behavioral performances were mainly sensitive to arousal, while the ERP old/new effect over posterior regions (300 - 1000 ms) was exclusively affected by unpleasantness. A later component (1000 - 1400 ms) showed an inverted old/ new effect at parietal sites, which was also sensitive to unpleasantness. These results imply that ERP reflecting episodic conscious recollection and post-retrieval monitoring are clearly affected both by valence and arousal. PMID- 26052475 TI - PTSD, Depression, Daily Stressors, and Treatment Pathways Among Urban Veterans. AB - Many veterans face various mental health challenges after separation. This study examines change over 14 months in mental health and related factors among 242 veterans returning to low-income predominately minority sections of New York City. Mental health treatment provided more than reductions in symptoms of PTSD and depression. It also resulted in reductions in substance use disorders and daily stresses. However, many veterans not in treatment are experiencing combat related concerns at subsyndromal levels. The findings highlight the need for low threshold community-based outreach programs for this population. PMID- 26052476 TI - Body Image in Adult Women: Moving Beyond the Younger Years. AB - In spite of copious literature investigating body dissatisfaction and its correlates in adolescents and young adult women, exploration of body image disturbances in adult women remains an underrepresented domain in the literature. Yet, there are many reasons to suspect that body image in adult women both may differ from and possibly be more complex than that of younger women. Adult women face myriad factors influencing body image beyond those delineated in the body image literature on adolescents and young adult women. For instance, aging related physiological changes shift the female body further away from the thin young-ideal, which is the societal standard of female beauty. Further, life priorities and psychological factors evolve with age as well. As such, adult women encounter changes that may differentially affect body image across the lifespan. This paper aims to provide an up-to-date review of the current literature on the relationship between body image and associated mental and physical health problems and behaviors in adult women. In addition, we explore factors that may influence body image in adult women. Lastly, we use this review to identify significant gaps in the existing literature with the aim of identifying critical targets for future research. PMID- 26052477 TI - Lamina Cribrosa in Glaucoma: Diagnosis and Monitoring. AB - The lamina cribrosa is the putative site of retinal ganglion cell axonal injury in glaucoma. Although histological studies have provided evidence of structural changes to the lamina cribrosa, even in early stages of glaucoma, until recently, the ability to evaluate the lamina cribrosa in vivo has been limited. Recent advances in optical coherence tomography, including enhanced depth and swept source imaging, have changed this, providing a means to image the lamina cribrosa. Imaging has identified general and localized configurational changes in the lamina of glaucomatous eyes, including posterior laminar displacement, altered laminar thickness, and focal laminar defects with spatial association with conventional structural and functional losses. In addition, although the temporal relationship between changes to the lamina cribrosa and glaucomatous retinal ganglion cell loss is yet to be elucidated, quantitative measurements of laminar microarchitecture have good reproducibility and offer the potential to serve as biomarkers for glaucoma diagnosis and progression. PMID- 26052478 TI - Height-based Indices of Pubertal Timing in Male Adolescents. AB - It is important to account for timing of puberty when studying the adolescent brain and cognition. The use of classical methods for assessing pubertal status may not be feasible in some studies, especially in male adolescents. Using data from a sample of 478 males from a longitudinal birth cohort, we describe the calculations of three independent height-based markers of pubertal timing: Age at Peak Height Velocity (APHV), Height Difference in Standard Deviations (HDSDS), and Percent Achieved of Adult Stature (PAAS). These markers correlate well with each other. In a separate cross-sectional study, we show that the PAAS marker correlates well with testosterone levels and self-reported pubertal-stage scores. We conclude by discussing key considerations for investigators when drawing upon these methods of assessing pubertal timing. PMID- 26052479 TI - Examining the Psychosis Continuum. AB - The notion that psychosis may exist on a continuum with normal experience has been proposed in multiple forms throughout the history of psychiatry. However, in recent years there has been an exponential increase in efforts aimed at elucidating what has been termed the 'psychosis continuum'. The present review seeks to summarize some of the more basic characteristics of this continuum and to present some of the recent findings that provide support for its validity. While there is still considerable work to be done, the emerging data holds considerable promise for advancing our understanding of both risk and resilience to psychiatric disorders characterized by psychosis. PMID- 26052482 TI - When is youths' debt to society paid off? Examining the long-term consequences of juvenile incarceration for adult functioning. AB - PURPOSE: To examine the long-term consequences of juvenile incarceration on functioning in adulthood (ages 27-33). METHODS: Propensity score analysis was used to compare incarcerated youth with those who were never incarcerated in a subsample of individuals who had experienced at least one police contact in adolescence. Data were drawn from the Seattle Social Development Project (SSDP), a multiethnic, gender balanced community sample. RESULTS: Youth who were incarcerated in adolescence were more likely to experience incarceration at ages 27, 30, or 33, more likely to meet criteria for alcohol abuse or dependence, and more likely to be receiving public assistance than similar youth who were never incarcerated. CONCLUSIONS: Results show that juvenile incarceration is not only ineffective at reducing criminal behavior later in life, but that there are also unintended consequences for incarceration beyond the criminal domain. Furthermore, it appears that once a youth becomes involved in the juvenile justice system, there is a higher likelihood that he/she will remain tethered to the criminal justice system through the transition to adulthood. Given these long term deleterious outcomes, it is recommended that suitable alternatives to juvenile incarceration that do not jeopardize public safety be pursued. PMID- 26052480 TI - Development of Lung Epithelium from Induced Pluripotent Stem Cells. AB - Considerable progress has been made in the field of in vitro development of alveolar epithelium from induced pluripotent stem cells. Patient specific derived alveolar cells could potentially populate tissue engineered lungs, provide a cell source for drug testing or function as a model for research into lung diseases. Induced to pluripotency through a variety of techniques, stem cells can be differentiated to alveolar epithelium through exposure to a variety of different culture conditions and growth media. The ultimate success of differentiated cells for translational medicine applications will depend on further advances in the understanding of the human lung developmental pathway, and successful application to in vitro culture. In this review will focus the major signaling pathways and molecules in lung development and the existing protocol for directed different ion of iPSC and hESC to cells resembling respiratory epithelium in vitro. PMID- 26052481 TI - Epigenetic Regulation of miRNAs and Breast Cancer Stem Cells. AB - MicroRNAs have emerged as important targets of chemopreventive strategies in breast cancer. We have found that miRNAs are dysregulated at an early stage in breast cancer, in non-malignant Ductal Carcinoma In Situ. Many dietary chemoprevention agents can act by epigenetically activating miRNA-signaling pathways involved in tumor cell proliferation and invasive progression. In addition, many miRNAs activated via chemopreventive strategies target cancer stem cell signaling and prevent tumor progression or relapse. Specifically, we have found that miRNAs regulate DCIS stem cells, which may play important roles in breast cancer progression to invasive disease. We have shown that chemopreventive agents can directly inhibit DCIS stem cells and block tumor formation in vivo, via activation of tumor suppressor miRNAs. PMID- 26052483 TI - Traumatic optic neuropathy-Clinical features and management issues. AB - Traumatic optic neuropathy (TON) is an uncommon cause of visual loss following blunt or penetrating head trauma, but the consequences can be devastating, especially in cases with bilateral optic nerve involvement. Although the majority of patients are young adult males, about 20% of cases occur during childhood. A diagnosis of TON is usually straightforward based on the clinical history and examination findings indicative of an optic neuropathy. However, the assessment can be difficult when the patient's mental status is impaired owing to severe trauma. TON frequently results in profound loss of central vision, and the final visual outcome is largely dictated by the patient's baseline visual acuities. Other poor prognostic factors include loss of consciousness, no improvement in vision after 48 hours, the absence of visual evoked responses, and evidence of optic canal fractures on neuroimaging. The management of TON remains controversial. Some clinicians favor observation alone, whereas others opt to intervene with systemic steroids, surgical decompression of the optic canal, or both. The evidence base for these various treatment options is weak, and the routine use of high-dose steroids or surgery in TON is not without any attendant risks. There is a relatively high rate of spontaneous visual recovery among patients managed conservatively, and the possible adverse effects of intervention therefore need to be even more carefully considered in the balance. PMID- 26052484 TI - Arthroscopic Excision of Acetabular Osteoid Osteoma: Computer Tomography-Guided Approach. AB - Osteoid osteoma is a benign osteoblastic tumor that occurs in the subcortical shaft and metaphysis of the long bones of the lower extremities; however, intra articular lesions are also possible. Intra-articular osteoid osteomas are rare, and clinical symptoms are often less specific and, thereby, may lead to misdiagnosis. The definitive treatment for osteoid osteoma is the excision of the nidus. We present the case of a 23-year-old man with a 4-year history of right anterior hip pain, subsequently diagnosed with a subarticular osteoid osteoma located in the right anterior acetabulum. Hip arthroscopic excision of the juxta articular osteoid osteoma is presented as an effective treatment, with the advantage of less potential damage to normal bone and cartilage, as well as the additional benefits available with hip arthroscopy. PMID- 26052485 TI - Direct Visualization of Existing Footprint and Outside-In Drilling of the Femoral Tunnel in Anterior Cruciate Ligament Reconstruction in the Knee. AB - Improper femoral tunnel placement in anterior cruciate ligament (ACL) reconstruction is a significant problem and may be a cause of ACL graft failure and abnormal kinematics, which may lead to late degenerative changes after reconstruction. Recently, there has been concern that the transtibial approach may contribute to nonanatomic placement of the femoral tunnel, resulting in abnormal knee kinematics. Tibial-independent techniques can provide more anatomic placement of the ACL graft, but these can be technically demanding. This technical note describes the senior author's technique to directly identify the femoral ACL remnant and use the center of the femoral ACL footprint and retrograde drilling to create an anatomic femoral socket for single-bundle reconstruction. This technique provides femoral tunnel placement based on identification of a patient-specific ACL footprint instead of averaged anatomic measurements from large groups. This technique has been shown to produce anatomic ACL graft position and orientation and restore more normal knee kinematics. PMID- 26052486 TI - Endoscopic Pubic Symphysectomy for Recalcitrant Osteitis Pubis. AB - Recalcitrant osteitis pubis presents a challenging problem for orthopaedic surgeons. Various surgical interventions have been described for treatment, including opening-wedge resection, symphysiodesis, and curettage. We propose that endoscopic pubic symphysectomy offers an effective method of treating such a challenging problem. This article describes in detail the technique used to perform endoscopic pubic symphysectomy, and a companion video demonstrating the procedure is included. Our experience suggests that removal of the interpubic fibrocartilaginous lamina and resection of approximately 1 cm of bone can successfully eliminate all sources of pain and dysfunction caused by the recalcitrant osteitis pubis. PMID- 26052487 TI - Arthroscopic-Assisted Fixation of Ideberg Type III Glenoid Fractures. AB - Operative treatment of scapular fractures with extension into the glenoid can be a challenging clinical scenario. Though traditionally addressed in an open fashion, the morbidity of this approach, complemented by advancements in arthroscopic technique and instrumentation, has led to increasing use of arthroscopic-assisted fixation. We describe our technique, including pearls and pitfalls, for minimally invasive fixation of Ideberg type III glenoid fractures. This approach minimizes morbidity, allows optimal visualization and reduction, and provides good functional results. PMID- 26052488 TI - All-Arthroscopic Reconstruction of the Acetabular Labrum by Capsular Augmentation. AB - The acetabular labrum plays an important role in hip joint stability and articular cartilage maintenance. As such, reconstitution of the labral complex is ideal. In cases in which the labrum is too degenerative to allow adequate reconstruction with current repair techniques, a capsular augmentation is a novel technique that can be used to restore the labral structure. Use of capsular augmentation enables preservation of the donor-tissue blood supply with local tissue transfer, without adding significant complexity to the procedure or significant donor-site morbidity. PMID- 26052489 TI - Subscapularis Tendon Repair Using Suture Bridge Technique. AB - The subscapularis tendon plays an essential role in shoulder function. Although subscapularis tendon tears are less common than other rotator cuff tears, tears of the subscapularis tendon have increasingly been recognized with the advent of magnetic resonance imaging and arthroscopy. A suture bridge technique for the treatment of posterosuperior rotator cuff tears has provided the opportunity to improve the pressurized contact area and mean footprint pressure. However, suture bridge fixation of subscapularis tendon tears appears to be technically challenging. We describe an arthroscopic surgical technique for suture bridge repair of subscapularis tendon tears that obtains ideal cuff integrity and footprint restoration. Surgery using such a suture bridge technique is indicated for large tears, such as tears involving the entire first facet or more, tears with a disrupted lateral sling, and combined medium to large supraspinatus/infraspinatus tears. PMID- 26052490 TI - The Spin Move: A Reliable and Cost-Effective Gowning Technique for the 21st Century. AB - Operating room efficiency (ORE) and utilization are considered one of the most crucial components of quality improvement in every hospital. We introduced a new gowning technique that could optimize ORE. The Spin Move quickly and efficiently wraps a surgical gown around the surgeon's body. This saves the operative time expended through the traditional gowning techniques. In the Spin Move, while the surgeon is approaching the scrub nurse, he or she uses the left heel as the fulcrum. The torque, which is generated by twisting the right leg around the left leg, helps the surgeon to close the gown as quickly and safely as possible. From 2003 to 2012, the Spin Move was performed in 1,725 consecutive procedures with no complication. The estimated average time was 5.3 and 7.8 seconds for the Spin Move and traditional gowning, respectively. The estimated time saving for the senior author during this period was 71.875 minutes. Approximately 20,000 orthopaedic surgeons practice in the United States. If this technique had been used, 23,958 hours could have been saved. The money saving could have been $14,374,800.00 (23,958 hours * $600/operating room hour) during the past 10 years. The Spin Move is easy to perform and reproducible. It saves operating room time and increases ORE. PMID- 26052491 TI - Arthroscopic Treatment of Popliteal Cyst: A Direct Posterior Portal by Inside-Out Technique for Intracystic Debridement. AB - Popliteal cysts are characterized by enlargement of the gastrocnemius semimembranosus bursa. The pathogenesis includes a valvular opening between the knee joint and the bursa, and associated intra-articular pathology may give rise to knee effusion. The mainstay of treatment is conservative. If popliteal cysts are symptomatic, analgesia, aspiration, and steroid injection therapy may be considered, but most recur rapidly. In the past, open excision was an option if they remained symptomatic, but the associated recurrence rate was high. One important reason was that the intra-articular pathology causing the knee effusion was not treated. We present an alternative minimally invasive arthroscopic treatment using dye (methylene blue) directly injected into the cyst, which will leak from the cyst into the joint, to identify the valvular opening. The thickened valve is opened using a basket forceps and then enlarged using a motorized shaver to disrupt the 1-way mechanism between the joint and bursa, as well as to establish an unobstructed freeway connection between them. We also present a safe technique to create a direct posterior portal. Intracystic debridement of the fibrous membrane, nodules, and septa through this portal will decrease the recurrence rate of the popliteal cyst. PMID- 26052492 TI - Arthroscopic Removal of a Polyethylene Glenoid Component in Total Shoulder Arthroplasty. AB - We present a technique for arthroscopic glenoid removal in a case of glenoid loosening after total shoulder arthroplasty (TSA). The presented technique is technically feasible and may be useful if 1-stage surgery with glenoid reimplantation is not indicated. To exclude low-grade infection, the presented technique allows for an intraoperative infection workup such as intraoperative cultures. However, glenoid loosening in TSA is a well-known problem and has been described before. The advantages of the presented technique include minimally invasive surgery, decreased pain, preservation of the subscapularis tendon, and assurance of exclusion of low-grade infection before reimplantation of a new glenoid implant. In this case a 73-year-old patient was treated with a TSA for severe osteoarthritis of the right shoulder in April 2014. Because of persistent anterior shoulder pain postoperatively, radiographic evaluation was performed and showed signs of glenoid loosening 6 months after surgery without any clinical signs of infection. To exclude low-grade infection, arthroscopy of the right shoulder was performed. Arthroscopy showed a totally loosened glenoid component leading to arthroscopic glenoid removal by use of a special forceps. PMID- 26052493 TI - Arthroscopically Assisted Reconstruction of Acute Acromioclavicular Joint Dislocations: Anatomic AC Ligament Reconstruction With Protective Internal Bracing-The "AC-RecoBridge" Technique. AB - An arthroscopically assisted technique for the treatment of acute acromioclavicular joint dislocations is presented. This pathology-based procedure aims to achieve anatomic healing of both the acromioclavicular ligament complex (ACLC) and the coracoclavicular ligaments. First, the acromioclavicular joint is reduced anatomically under macroscopic and radiologic control and temporarily transfixed with a K-wire. A single-channel technique using 2 suture tapes provides secure coracoclavicular stabilization. The key step of the procedure consists of the anatomic repair of the ACLC ("AC-Reco"). Basically, we have observed 4 patterns of injury: clavicular-sided, acromial-sided, oblique, and midportion tears. Direct and/or transosseous ACLC repair is performed accordingly. Then, an X-configured acromioclavicular suture tape cerclage ("AC Bridge") is applied under arthroscopic assistance to limit horizontal clavicular translation to a physiological extent. The AC-Bridge follows the principle of internal bracing and protects healing of the ACLC repair. The AC-Bridge is tightened on top of the repair, creating an additional suture-bridge effect and promoting anatomic ACLC healing. We refer to this combined technique of anatomic ACLC repair and protective internal bracing as the "AC-RecoBridge." A detailed stepwise description of the surgical technique, including indications, technical pearls and pitfalls, and potential complications, is given. PMID- 26052494 TI - Arthroscopic Technique of Capsular Plication for the Treatment of Hip Instability. AB - Atraumatic instability or microinstability of the hip is a recognized cause of groin pain and hip instability. Risk factors include female sex, ligamentous laxity, and borderline dysplasia. Arthroscopically, the joint may distract easily, and there may be associated ligamentum teres tears and laxity of the capsule on manual probing. The use of arthroscopic capsular plication in this cohort of patients has shown good to excellent results. Biomechanically, a capsular plication aims to create an imbrication and inferior shift of the capsule to augment the screw-home mechanism of the capsuloligamentous structures and thereby improve stability in extension and external rotation. The purpose of this article is to detail the step-by-step surgical technique of arthroscopic capsular plication, in addition to the indications, pearls, and pitfalls of the technique. PMID- 26052495 TI - All-Suture Transosseous Repair for Rotator Cuff Tear Fixation Using Medial Calcar Fixation. AB - We describe an all-suture transosseous repair technique used in the management of rotator cuff tears by means of an all-suture anchor secured on the intra articular side of the humeral calcar. The technique uses an anterior cruciate ligament guide to ensure accurate positioning of the tunnels, avoiding the articular cartilage and minimizing risk to the neurovascular structures. The distal end of the guide is inserted through a rotator interval portal and passed down to the axillary pouch. The proximal end of the guide is approximated to the greater tuberosity at the cuff footprint, and a complete transosseous tunnel is created with a 2.4-mm drill. An all-suture implant is inserted through this tunnel down to the calcar, and its deployment is visualized under arthroscopy. Gentle traction is applied to the anchor, resulting in a 4-mm concertina of the suture anchor that rests opposed to the medial cortex. The major advantage of this technique is the fixation strength gained from the biomechanically superior cortical bone of the calcar. Furthermore, this method permits greater preservation of bone surface area at the level of the footprint for a larger tendon-to-bone healing surface. This technique also provides an excellent alternative in revision situations. PMID- 26052496 TI - Arthroscopic Allograft Cartilage Transfer for Osteochondral Defects of the Talus. AB - Arthroscopic treatment of osteochondral defects is well established but has had mixed results in larger lesions and revision operations. Particulated allograft cartilage transfer may provide an arthroscopic option for lesions that would otherwise have been treated through open approaches or osteotomies. The procedure is performed under noninvasive distraction with standard arthroscopic portals. PMID- 26052497 TI - Anterior Cruciate Ligament Reconstruction Using a Bone-Patellar Tendon-Bone Autograft to Avoid Harvest-Site Morbidity in Knee Arthroscopy. AB - Although anterior cruciate ligament reconstruction using a bone-patellar tendon bone (BPTB) autograft has many advantages (e.g., high strength and solid fixation), there are also several complications (e.g., anterior knee pain or kneeling pain) due to harvest-site morbidity associated with the use of this graft type compared with the use of hamstring tendon. Therefore the ultimate goal of anterior cruciate ligament reconstruction using a BPTB graft is to minimize harvest-site morbidity. We have used a technique for harvesting central-third BPTB grafts that involves only a 3-cm-long, longitudinal, curved incision in the medial tibial tuberosity for both graft harvesting and fixation. The purpose of this report is to describe the technique, which can avoid the harvest-site morbidities associated with BPTB autografts during knee arthroscopy. We believe that this less invasive reconstruction may reduce the harvest-site morbidities associated with BPTB grafts because it allows for BPTB graft harvesting without incising the synovial bursa or paratenon and mitigates scarring and adhesion formation. PMID- 26052498 TI - Arthroscopic Saucerization and Repair of Discoid Lateral Meniscal Tear. AB - Meniscal tears are among the most commonly diagnosed knee injuries and often require surgical intervention. Understanding the types of meniscal tears and treatment options is paramount to caring for the young athlete. Sports medicine and arthroscopic physicians now recognize that meniscal preservation in the young athlete is essential to the long-term health and function of the knee. Although uncommon, the discoid lateral meniscus is more prone to injury because of its increased thickness and lack of blood supply. Because of the abnormal development, the peripheral attachments are frequently absent and instability often persists after a partial meniscectomy. If the instability is unrecognized during the initial treatment, a recurrence of pain and mechanical symptoms is likely and a subsequent subtotal meniscectomy may be the only treatment option. With increased awareness, arthroscopic saucerization accompanied by arthroscopically assisted inside-out meniscal repair is a preferable treatment option with an excellent outcome. PMID- 26052499 TI - The "Labral Bridge": A Novel Technique for Arthroscopic Anatomic Knotless Bankart Repair. AB - Arthroscopic Bankart repair with suture anchors is widely considered a mainstay for surgical treatment of anterior shoulder instability after recurrent anterior shoulder dislocations. Traditionally, the displaced capsulolabral complex is restored and firmly attached to the glenoid by placing multiple suture anchors individually from a 5- to 3-o'clock position. A variety of different techniques using different anchor designs and materials have been described. Knotless anchors are widely used nowadays for shoulder instability repair, providing a fast and secure way of labral fixation with favorable long-term outcomes. However, these techniques result in a concentrated point load of the reduced labrum to the glenoid at each suture anchor. We describe a technique, developed by the first author, using a 1.5-mm LabralTape (Arthrex, Naples, FL) in combination with knotless suture anchors (3.5-mm PEEK [polyether ether ketone] PushLock anchors; Arthrex), for hybrid fixation of the labrum. The LabralTape is used to secure the torn labrum to the glenoid between each suture anchor, thus potentially providing a more even pressure distribution. PMID- 26052500 TI - Arthroscopic Repair of Collateral Ligaments in Metacarpophalangeal Joints. AB - Although typically reported in thumb and small fingers, collateral ligament ruptures of the metacarpophalangeal (MCP) joints have been described in all digits. Traditional open repair requires a dissection that violates the sagittal band and may result in increased scarring and decreased hand function. Arthroscopic repair of MCP collateral ligaments has not been previously described. We present a new technique for repairing MCP collateral ligaments arthroscopically. PMID- 26052501 TI - Successful pregnancy outcome in paroxysmal nocturnal hemoglobinuria (PNH) following escalated eculizumab dosing to control breakthrough hemolysis. AB - Pregnancy in women with paroxysmal nocturnal hemoglobinuria (PNH) is associated with increased maternal and fetal morbidity and mortality. There is limited published experience regarding therapy of PNH during pregnancy. We describe a case of a 30 year old female with hypoplastic myelodysplastic syndrome and PNH. After two years of treatment with eculizumab, she became pregnant. She developed breakthrough hemolysis at 20 weeks gestation. Pharmacokinetic and pharmacodynamic studies demonstrated a subtherapeutic eculizumab level with absence of complement blockade. Escalation of her eculizumab dose successfully controlled hemolysis and restored therapeutic eculizumab level and activity. She delivered a healthy baby at 36 weeks. PMID- 26052502 TI - The role of global traditional and complementary systems of medicine in treating mental health problems. AB - Traditional and complementary systems of medicine (TCM) encompass a broad range of practices which are commonly embedded within contextual cultural milieu, reflecting community beliefs, experiences, religion and spirituality. Evidence from across the world, especially from low- and middle-income countries (LMIC), suggests that TCM is commonly used by a large number of persons with mental illness. Even though some overlap exists between the diagnostic approaches of TCM and conventional biomedicine (CB), there are major differences, largely reflecting differences in the understanding of the nature and etiology of mental disorders. However, treatment modalities employed by providers of TCM may sometimes fail to meet common understandings of human rights and humane care. Still, there are possibilities for collaboration between TCM and CB in the care of persons with mental illness. Research is required to clearly delineate the boundaries of such collaboration and to test its effectiveness in bringing about improved patient outcomes. PMID- 26052503 TI - High Prevalence of Malnutrition among the Above Thirteen with Primary Pyomyositis in Northern Uganda. AB - AIM: To determine the prevalence of malnutrition and its association with primary pyomyositis among patients and controls who were age and sex matched. STUDY DESIGN AND SETTING: A case-control study was conducted at Gulu Regional, Lacor, Kalongo, Kitgum and St. Joseph's Hospitals in Northern Uganda. STUDY DURATION: Study was conducted from September 2011 to November 2013. METHODS: Primary pyomyositis patients were consecutively recruited to these Hospitals and were age and sex-matched with controls selected during the same period. History, physical examinations, Body Mass Index (BMI), blood samples for haematology, biochemistry, clinical chemistry and muscle biopsy for histology were obtained. Those that did not meet the inclusion criteria were excluded. The study was approved by the Ethics and Review Committee of Gulu University Medical School. RESULTS: During the study period, 63 patients and 63 controls were recruited; 29 females and 34 males. Among primary pyomyositis patients, 59 (93.7%) had malnutrition while there were 2 in the control group, giving a prevalence of 3.2%.The matched analysis produced an aOR of 449.875 with a 95% CI (79.382, 2549.540; p<0.001) for malnutrition. Among the cases, 16 (25.4%) fulfilled the Clinical Case Definition (CCD) for AIDS, compared to 2 (3.2%) among the controls. The adjusted Odds ratio for the difference in fulfilling the CCD for AIDS between cases and controls was statistically significant aOR of 10.383 with a 95% CI (2.275, 47.397; p<0.001). CONCLUSION: Primary pyomyositis is a common health problem in Northern Uganda. It is evident that malnutrition is the most common risk factor in Primary pyomyositis especially among the above thirteen year olds in Northern Uganda. PMID- 26052505 TI - Clinical Impact of the Immunome in Lymphoid Malignancies: The Role of Myeloid Derived Suppressor Cells. AB - The better definition of the mutual sustainment between neoplastic cells and immune system has been translated from the bench to the bedside acquiring value as prognostic factor. Additionally, it represents a promising tool for improving therapeutic strategies. In this context, myeloid-derived suppressor cells (MDSCs) have gained a central role in tumor developing with consequent therapeutic implications. In this review, we will focus on the biological and clinical impact of the study of MDSCs in the settings of lymphoid malignancies. PMID- 26052507 TI - Psychotherapy Interventions for Managing Anxiety and Depressive Symptoms in Adult Brain Tumor Patients: A Scoping Review. AB - BACKGROUND: Adult brain tumor (BT) patients and longer-term survivors are susceptible to experiencing emotional problems, including anxiety and/or depression disorders, which may further compromise their quality-of-life (QOL) and general well-being. The objective of this paper is to review psychological approaches for managing anxiety and depressive symptoms in adult BT patients. A review of psychological interventions comprising mixed samples of oncology patients, and which included BT patients is also evaluated. The review concludes with an overview of a recently developed transdiagnostic psychotherapy program, which was specifically designed to treat anxiety and/or depressive symptoms in adult BT patients. METHODS: Electronic databases (PsycINFO, Medline, Embase, and Cochrane) were searched to identify published studies investigating psychological interventions for managing anxiety and depressive symptoms in adult BT patients. Only four randomized controlled trials (RCTs) were identified. RESULTS: Only one of the RCTs tested a psychosocial intervention, which was specifically developed for primary BT patients, and which was found to improve QOL including existential well-being as well as reducing depressive symptoms. A second study tested a combined cognitive rehabilitation and problem-solving intervention, although was not found to significantly improve mood or QOL. The remaining two studies tested multidisciplinary psychosocial interventions in heterogeneous samples of cancer patients (included BT patients) with advanced stage disease. Maintenance of QOL was found in both studies, although no secondary gains were found for improvements in mood. CONCLUSION: There is a notable paucity of psychological interventions for adult BT patients across the illness trajectory. Further research is required to strengthen the evidence base for psychological interventions in managing anxiety and depressive symptoms, and enhancing the QOL of distressed adults diagnosed with a BT. PMID- 26052506 TI - Editorial: Prostate Cancer: What We Know and What We Would Like to Know. PMID- 26052508 TI - Short-term effects of the whole-body vibration on the balance and muscle strength of type 2 diabetic patients with peripheral neuropathy: a quasi-randomized controlled trial study. AB - BACKGROUND: Patients with diabetes type 2 suffer from many complications such as peripheral neuropathy (PN). PN impairs postural stability and muscle strength. Therapeutic exercise may improve functional abilities of diabetic patients but they are unwilling to participate in exercise programs. Whole Body vibration (WBV) is a new somatosensory stimulation which is easy to use and time-efficient. The effects of WBV on balance and strength of diabetic patients had not been studied; therefore the aim of this study was to assess the effects of WBV in type 2 diabetes patients. METHODS: It was a quasi-RCT study performed between March 2011 and February 2013. Twenty patients were randomly assigned into either a whole body vibration group, or a control group. WBV group received vibration (frequency: 30 Hz, amplitude: 2 mm) twice a week for 6 weeks. Muscle strength, Timed Up & Go Test (TUGT) and Unilateral Stance Test and balance parameters were measured at baseline and after the intervention. RESULTS: WBV had significantly increased strength of tibialis anterior (P = 0.004) and quadriceps muscles (P = 0.05) after 6 weeks of training. TUGT time decreased significantly (P = 0.001) in the WBV group. CONCLUSIONS: Application of WBV enhanced muscles strength and balance in patients with diabetes type 2-induced peripheral neuropathy. The changes may be due to muscle tuning hypothesis and altered postural control strategies. TRIAL REGISTRATION: IRCT201106156806N1. PMID- 26052509 TI - School Feeding and Girls' Enrollment: The Effects of Alternative Implementation Modalities in Low-Income Settings in Sub-Saharan Africa. AB - BACKGROUND: School feeding interventions are implemented in nearly every country in the world, with the potential to support the education, health and nutrition of school children. In terms of impact on school participation, there is little evidence to show that different school feeding modalities have different effect sizes. OBJECTIVE: To examine the influence of different school feeding modalities on primary school enrollment, particularly for girls, in 32 countries across sub Saharan Africa. METHODS: An observational study involving a meta-analysis of published data was developed to examine program effect. Schools were divided according to the type and length of the program: those with existing programs, those that had had school feeding for less than 1 year, and a counterfactual including schools without a program but that were going to initiate school feeding within the survey year. The intervention consisted of two different types of school feeding: onsite meals alone or onsite meals plus take-home rations. Changes in enrollment, both total and disaggregated by grade and gender, over a 1 year period, were used to assess effects of school feeding. To control for pre program characteristics in the beneficiary population, data on covariates were also examined before the school feeding intervention began and after one year of implementation. Using this design a comparison of enrollment levels was made between the types of treatment schools and controls schools during the period school feeding was first introduced. Standard multiple regression models were used to analyze program effect. RESULTS: School feeding programs were found to have statistically significant increases in enrollment, with effect size of about 10%. The changes on enrollment varied by modality of school feeding provision and by gender, with onsite meals appearing to have stronger effects in the first year of treatment in the lower primary grades, and onsite combined with take-home rations also being effective post-year 1, particularly for girls that were receiving the extra take-home rations. CONCLUSION: School feeding programs had a positive impact on school enrollment. The operational nature of the survey data used in the meta-analysis, however, limits the robustness of the design and validity of the findings. Nevertheless, this analysis is the first to study possible links between enrollment and length of program duration using multivariable models, examining whether programs reach a saturation point or steady state beyond which school feeding may in fact have no further benefits on school enrollment. Further research is required to examine this issue in more detail. PMID- 26052510 TI - Bioinspired iterative synthesis of polyketides. AB - Diverse array of biopolymers and second metabolites (particularly polyketide natural products) has been manufactured in nature through an enzymatic iterative assembly of simple building blocks. Inspired by this strategy, molecules with inherent modularity can be efficiently synthesized by repeated succession of similar reaction sequences. This privileged strategy has been widely adopted in synthetic supramolecular chemistry. Its value also has been reorganized in natural product synthesis. A brief overview of this approach is given with a particular emphasis on the total synthesis of polyol-embedded polyketides, a class of vastly diverse structures and biologically significant natural products. This viewpoint also illustrates the limits of known individual modules in terms of diastereoselectivity and enantioselectivity. More efficient and practical iterative strategies are anticipated to emerge in the future development. PMID- 26052511 TI - Endophytic and epiphytic microbes as "sources" of bioactive agents. AB - Beginning with the report by Stierle and Strobel in 1993 on taxol((R)) production by an endophytic fungus (Stierle et al., 1993), it is possible that a number of the agents now used as leads to treatments of diseases in man, are not produced by the plant or invertebrate host from which they were first isolated and identified. They are probably the product of a microbe in, on or around the macroorganism. At times there is an intricate "dance" between a precursor produced by a microbe, and interactions within the macroorganism, or in certain cases, a fungus, that ends up with the production of a novel agent that has potential as a treatment for a human disease. This report will give examples from insects, plants, and marine invertebrates. PMID- 26052513 TI - Conditional Cripto overexpression in satellite cells promotes myogenic commitment and enhances early regeneration. AB - Skeletal muscle regeneration mainly depends on satellite cells, a population of resident muscle stem cells. Despite extensive studies, knowledge of the molecular mechanisms underlying the early events associated with satellite cell activation and myogenic commitment in muscle regeneration remains still incomplete. Cripto is a novel regulator of postnatal skeletal muscle regeneration and a promising target for future therapy. Indeed, Cripto is expressed both in myogenic and inflammatory cells in skeletal muscle after acute injury and it is required in the satellite cell compartment to achieve effective muscle regeneration. A critical requirement to further explore the in vivo cellular contribution of Cripto in regulating skeletal muscle regeneration is the possibility to overexpress Cripto in its endogenous configuration and in a cell and time specific manner. Here we report the generation and the functional characterization of a novel mouse model for conditional expression of Cripto, i.e., the Tg:DsRed (loxP/loxP) Cripto-eGFP mice. Moreover, by using a satellite cell specific Cre-driver line we investigated the biological effect of Cripto overexpression in vivo, and provided evidence that overexpression of Cripto in the adult satellite cell compartment promotes myogenic commitment and differentiation, and enhances early regeneration in a mouse model of acute injury. PMID- 26052512 TI - Novel roles for protein disulphide isomerase in disease states: a double edged sword? AB - Protein disulphide isomerase (PDI) is a multifunctional redox chaperone of the endoplasmic reticulum (ER). Since it was first discovered 40 years ago the functions ascribed to PDI have evolved significantly and recent studies have recognized its distinct functions, with adverse as well as protective effects in disease. Furthermore, post translational modifications of PDI abrogate its normal functional roles in specific disease states. This review focusses on recent studies that have identified novel functions for PDI relevant to specific diseases. PMID- 26052514 TI - Comparison of methods for the isolation of human breast epithelial and myoepithelial cells. AB - Two lineages, epithelial, and myoepithelial cells are the main cell populations in the normal mammary gland and in breast cancer. Traditionally, cancer research has been performed using commercial cell lines, but primary cell cultures obtained from fresh breast tissue are a powerful tool to study more reliably new aspects of mammary gland biology, including normal and pathological conditions. Nevertheless, the methods described to date have some technical problems in terms of cell viability and yield, which hamper work with primary mammary cells. Therefore, there is a need to optimize technology for the proper isolation of epithelial and myoepithelial cells. For this reason, we compared four methods in an effort to improve the isolation and primary cell culture of different cell populations of human mammary epithelium. The samples were obtained from healthy tissue of patients who had undergone mammoplasty or mastectomy surgery. We based our approaches on previously described methods, and incorporated additional steps to ameliorate technical efficiency and increase cell survival. We determined cell growth and viability by phase-contrast images, growth curve analysis and cell yield, and identified cell-lineage specific markers by flow cytometry and immunofluorescence in 3D cell cultures. These techniques allowed us to better evaluate the functional capabilities of these two main mammary lineages, using CD227/K19 (epithelial cells) and CD10/K14 (myoepithelial cells) antigens. Our results show that slow digestion at low enzymatic concentration combined with the differential centrifugation technique is the method that best fits the main goal of the present study: protocol efficiency and cell survival yield. In summary, we propose some guidelines to establish primary mammary epithelial cell lines more efficiently and to provide us with a strong research instrument to better understand the role of different epithelial cell types in the origin of breast cancer. PMID- 26052515 TI - Pioneering Robotic Liver Surgery in Germany: First Experiences with Liver Malignancies. AB - BACKGROUND: Minimally invasive liver surgery is growing worldwide with obvious benefits for the treated patients. These procedures maybe improved by robotic techniques, which add several innovative features. In Germany, we were the first surgical department implementing robotic assisted minimally invasive liver resections. MATERIAL AND METHODS: Between June 2013 and March 2015, we performed robotic based minimally invasive liver resections in nine patients with malignant liver disease. Five off these patients suffered from primary and four from secondary liver malignancies. We retrospectively analyzed the perioperative variables of these patients and the oncological follow up. RESULTS: Mean age of the patients was 63 years (range 45-71). One patient suffered from intrahepatic cholangiocellular, four from hepatocellular carcinoma, and four patients from colorectal liver metastases. In six patients, left lateral liver resection, in two cases single segment resection, and in one case minimally invasive guided liver ablation were performed. Five patients underwent previous abdominal surgery. Mean operation time was 312 min (range 115-458 min). Mean weight of the liver specimens was 182 g (range 62-260 g) and mean estimated blood loss was 251 ml (range 10-650 ml). The mean tumor size was 4.4 cm (range 3.5-5.5 cm). In all cases, R0 status was confirmed with a mean margin of 0.6 cm (range 0.1-1.5 cm). One patient developed small bowel fistula on postoperative day 5, which could be treated conservatively. No patient died. Mean hospital stay of the patients was 6 days (range 3-10 days). During a mean follow up of 12 months (range 1-21 months), two patients developed tumor recurrence. CONCLUSION: Robotic-based liver surgery is feasible in patients with primary and secondary liver malignancies. To achieve perioperative parameters comparable to open settings, the learning curve must be passed. Minor liver resections are good candidates to start this technique. But the huge benefits of robotic-based liver resections should be expected in extended procedures beyond minor liver resections with the currently available technology. PMID- 26052516 TI - Crystal structure of the magnetobacterial protein MtxA C-terminal domain reveals a new sequence-structure relationship. AB - Magnetotactic bacteria (MTB) are a diverse group of aquatic bacteria that have the magnetotaxis ability to align themselves along the geomagnetic field lines and to navigate to a microoxic zone at the bottom of chemically stratified natural water. This special navigation is the result of a unique linear assembly of a specialized organelle, the magnetosome, which contains a biomineralized magnetic nanocrystal enveloped by a cytoplasmic membrane. The Magnetospirillum gryphiswaldense MtxA protein (MGR_0208) was suggested to play a role in bacterial magnetotaxis due to its gene location in an operon together with putative signal transduction genes. Since no homology is found for MtxA, and to better understand the role and function of MtxA in MTBes magnetotaxis, we initiated structural and functional studies of MtxA via X-ray crystallography and deletion mutagenesis. Here, we present the crystal structure of the MtxA C-terminal domain and provide new insights into its sequence-structure relationship. PMID- 26052518 TI - The Causes and Consequences Explicit in Verbs. AB - Interpretation of a pronoun in one clause can be systematically affected by the verb in the previous clause. Compare Archibald angered Bartholomew because he... (he=Archibald) with Archibald criticized Bartholomew because he... (he=Bartholomew). While it is clear that meaning plays a critical role, it is unclear whether that meaning is directly encoded in the verb or, alternatively, inferred from world knowledge. We report evidence favoring the former account. We elicited pronoun biases for 502 verbs from seven Levin verb classes in two discourse contexts (implicit causality and implicit consequentiality), showing that in both contexts, verb class reliably predicts pronoun bias. These results confirm and extend recent findings about implicit causality and represent the first such study for implicit consequentiality. We discuss these findings in the context of recent work in semantics, and also develop a new, probabilistic generative account of pronoun interpretation. PMID- 26052517 TI - Evolution and intelligent design in drug development. AB - Sophisticated protein kinase networks, empowering complexity in higher organisms, are also drivers of devastating diseases such as cancer. Accordingly, these enzymes have become major drug targets of the twenty-first century. However, the holy grail of designing specific kinase inhibitors aimed at specific cancers has not been found. Can new approaches in cancer drug design help win the battle with this multi-faced and quickly evolving enemy? In this perspective we discuss new strategies and ideas that were born out of a recent breakthrough in understanding the molecular basis underlying the clinical success of the cancer drug Gleevec. An "old" method, stopped-flow kinetics, combined with old enzymes, the ancestors dating back up to about billion years, provides an unexpected outlook for future intelligent design of drugs. PMID- 26052519 TI - Widespread gene transfer in the central nervous system of cynomolgus macaques following delivery of AAV9 into the cisterna magna. AB - Adeno-associated virus serotype 9 (AAV9) vectors have recently been shown to transduce cells throughout the central nervous system of nonhuman primates when injected into the cerebrospinal fluid (CSF), a finding which could lead to a minimally invasive approach to treat genetic and acquired diseases affecting the entire CNS. We characterized the transduction efficiency of two routes of vector administration into the CSF of cynomolgus macaques-lumbar puncture, which is typically used in clinical practice, and suboccipital puncture, which is more commonly used in veterinary medicine. We found that delivery of vector into the cisterna magna via suboccipital puncture is up to 100-fold more efficient for achieving gene transfer to the brain. In addition, we evaluated the inflammatory response to AAV9-mediated GFP expression in the nonhuman primate CNS. We found that while CSF lymphocyte counts increased following gene transfer, there were no clinical or histological signs of immune toxicity. Together these data indicate that delivery of AAV9 into the cisterna magna is an effective method for achieving gene transfer in the CNS, and suggest that adapting this uncommon injection method for human trials could vastly increase the efficiency of gene delivery. PMID- 26052520 TI - Genetic barcode sequencing for screening altered population dynamics of hematopoietic stem cells transduced with lentivirus. AB - Insertional mutagenesis has been associated with malignant cell transformation in gene therapy protocols, leading to discussions about vector security. Therefore, clonal analysis is important for the assessment of vector safety and its impact on patient health. Here, we report a unique approach to assess dynamic changes in clonality of lentivirus transduced cells upon Sanger sequence analysis of a specially designed genetic barcode. In our approach, changes in the electropherogram peaks are measured and compared between successive time points, revealing alteration in the cell population. After in vitro validation, barcoded lentiviral libraries carrying IL2RG or LMO2 transgenes, or empty vector were used to transduce mouse hematopoietic (ckit+) stem cells, which were subsequently transplanted in recipient mice. We found that neither the empty nor IL2RG encoding vector had an effect on cell dynamics. In sharp contrast, the LMO2 oncogene was associated with altered cell dynamics even though hematologic counts remained unchanged, suggesting that the barcode could reveal changes in cell populations not observed by the frontline clinical assay. We describe a simple and sensitive method for the analysis of clonality, which could be easily used by any laboratory for the assessment of cellular behavior upon lentiviral transduction. PMID- 26052521 TI - Development of an inducible caspase-9 safety switch for pluripotent stem cell based therapies. AB - Induced pluripotent stem cell (iPSC) therapies offer a promising path for patient specific regenerative medicine. However, tumor formation from residual undifferentiated iPSC or transformation of iPSC or their derivatives is a risk. Inclusion of a suicide gene is one approach to risk mitigation. We introduced a dimerizable-"inducible caspase-9" (iCasp9) suicide gene into mouse iPSC (miPSC) and rhesus iPSC (RhiPSC) via a lentivirus, driving expression from either a cytomegalovirus (CMV), elongation factor-1 alpha (EF1alpha) or pluripotency specific EOS-C(3+) promoter. Exposure of the iPSC to the synthetic chemical dimerizer, AP1903, in vitro induced effective apoptosis in EF1alpha-iCasp9 expressing (EF1alpha)-iPSC, with less effective killing of EOS-C(3+)-iPSC and CMV iPSC, proportional to transgene expression in these cells. AP1903 treatment of EF1alpha-iCasp9 miPSC in vitro delayed or prevented teratomas. AP1903 administration following subcutaneous or intravenous delivery of EF1alpha-iPSC resulted in delayed teratoma progression but did not ablate tumors. EF1alpha iCasp9 expression was downregulated during in vitro and in vivo differentiation due to DNA methylation at CpG islands within the promoter, and methylation, and thus decreased expression, could be reversed by 5-azacytidine treatment. The level and stability of suicide gene expression will be important for the development of suicide gene strategies in iPSC regenerative medicine. PMID- 26052522 TI - DNA vaccination strategy targets epidermal dendritic cells, initiating their migration and induction of a host immune response. AB - The immunocompetence and clinical accessibility of dermal tissue offers an appropriate and attractive target for vaccination. We previously demonstrated that pDNA injection into the skin in combination with surface electroporation (SEP), results in rapid and robust expression of the encoded antigen in the epidermis. Here, we demonstrate that intradermally EP-enhanced pDNA vaccination results in the rapid induction of a host humoral immune response. In the dermally relevant guinea pig model, we used high-resolution laser scanning confocal microscopy to observe direct dendritic cell (DC) transfections in the epidermis, to determine the migration kinetics of these cells from the epidermal layer into the dermis, and to follow them sequentially to the immediate draining lymph nodes. Furthermore, we delineate the relationship between the migration of directly transfected epidermal DCs and the generation of the host immune response. In summary, these data indicate that direct presentation of antigen to the immune system by DCs through SEP-based in vivo transfection in the epidermis, is related to the generation of a humoral immune response. PMID- 26052523 TI - Pigtailed macaques as a model to study long-term safety of lentivirus vector mediated gene therapy for hemoglobinopathies. AB - Safely achieving long-term engraftment of genetically modified hematopoietic stem cells (HSCs) that maintain therapeutic transgene expression is the benchmark for successful application of gene therapy for hemoglobinopathies. We used the pigtailed macaque HSC transplantation model to ascertain the long-term safety and stability of a gamma-globin lentivirus vector. We observed stable gene-modified cells and fetal hemoglobin expression for 3 years. Retrovirus integration site (RIS) analysis spanning 6 months to 3.1 years revealed vastly disparate integration profiles, and dynamic fluctuation of hematopoietic contribution from different gene-modified HSC clones without evidence for clonal dominance. There were no perturbations of the global gene-expression profile or expression of genes within a 300 kb region of RIS, including genes surrounding the most abundantly marked clones. Overall, a 3-year long follow-up revealed no evidence of genotoxicity of the gamma-globin lentivirus vector with multilineage polyclonal hematopoiesis, and HSC clonal fluctuations that were not associated with transcriptome dysregulation. PMID- 26052524 TI - Role of specific endocytic pathways in electrotransfection of cells. AB - Electrotransfection is a technique utilized for gene delivery in both preclinical and clinical studies. However, its mechanisms are not fully understood. The goal of this study was to investigate specific pathways of endocytosis involved in electrotransfection. In the study, three different human cell lines (HEK293, HCT116, and HT29) were either treated with ice cold medium postelectrotransfection or endocytic inhibitors prior to electrotransfection. The inhibitors were pharmacological agents (chlorpromazine, genistein, and amiloride) or different small interfering RNA (siRNA) molecules that could knockdown expression of clathrin heavy chain (CLTC), caveolin-1, and Rab34, respectively. The reduction in gene expressions was confirmed with western blot analysis at 48 72h post-siRNA treatment. It was observed that treatments with either ice cold medium, chlorpromazine, or genistein resulted in significant reductions in electrotransfection efficiency (eTE) in all three cell lines, compared to the matched controls, but amiloride treatment had insignificant effects on eTE. For cells treated with siRNA, only CLTC knockdown resulted in eTE reduction for all three cell lines. Together, these data demonstrated that the clathrin-mediated endocytosis played an important role in electrotransfection. PMID- 26052525 TI - Efficient genome editing in hematopoietic stem cells with helper-dependent Ad5/35 vectors expressing site-specific endonucleases under microRNA regulation. AB - Genome editing with site-specific endonucleases has implications for basic biomedical research as well as for gene therapy. We generated helper-dependent, capsid-modified adenovirus (HD-Ad5/35) vectors for zinc-finger nuclease (ZFN)- or transcription activator-like effector nuclease (TALEN)-mediated genome editing in human CD34+ hematopoietic stem cells (HSCs) from mobilized adult donors. The production of these vectors required that ZFN and TALEN expression in HD-Ad5/35 producer 293-Cre cells was suppressed. To do this, we developed a microRNA (miRNA)-based system for regulation of gene expression based on miRNA expression profiling of 293-Cre and CD34+ cells. Using miR-183-5p and miR-218-5p based regulation of transgene gene expression, we first produced an HD-Ad5/35 vector expressing a ZFN specific to the HIV coreceptor gene ccr5. We demonstrated that HD-Ad5/35.ZFNmiR vector conferred ccr5 knock out in primitive HSC (i.e., long term culture initiating cells and NOD/SCID repopulating cells). The ccr5 gene disruption frequency achieved in engrafted HSCs found in the bone marrow of transplanted mice is clinically relevant for HIV therapy considering that these cells can give rise to multiple lineages, including all the lineages that represent targets and reservoirs for HIV. We produced a second HD-Ad5/35 vector expressing a TALEN targeting the DNase hypersensitivity region 2 (HS2) within the globin locus control region. This vector has potential for targeted gene correction in hemoglobinopathies. The miRNA regulated HD-Ad5/35 vector platform for expression of site-specific endonucleases has numerous advantages over currently used vectors as a tool for genome engineering of HSCs for therapeutic purposes. PMID- 26052527 TI - Increasing the minicircle DNA purity using an enhanced triplex DNA technology to eliminate DNA contaminants. AB - DNA vectors for human gene therapy have to meet the efficacy and safety requirements. Minicircles (MCs), a class of optimized DNA vectors free of plasmid backbone (PB) DNAs, have emerged as promising candidates because of their superior transgene expression profiles. However, the existence of impure DNAs, including the unrecombined MC producing plasmid (PP) and PB circle, in the MC products made using the current technologies exceed the safety limit. Here, we report the development of an enhanced triplex DNA (TriD) technology to eliminate almost all the impure DNAs from the MC products. To do this, a pair of optimized TriD forming sequences was placed to flank the kanamycin resistance gene in the PP. The MC products were incubated with a biotinylated TriD forming DNA oligonucleotide (olig), and the resulted TriDs were removed by binding to streptovidin-coated magnetic beads. Consequently, the residual impure DNAs were 0.03% or less in the final MC products. The reproducibility of this technique was confirmed with MCs of various transgene expression cassettes, sizes, and quantities, suggesting its great potential in making high quality MC for human gene therapy. PMID- 26052526 TI - Engineered dendritic cells from cord blood and adult blood accelerate effector T cell immune reconstitution against HCMV. AB - Human cytomegalovirus (HCMV) harmfully impacts survival after peripheral blood hematopoietic stem cell transplantation (PB-HSCT). Delayed immune reconstitution after cord blood (CB)-HSCT leads to even higher HCMV-related morbidity and mortality. Towards a feasible dendritic cell therapy to accelerate de novo immunity against HCMV, we validated a tricistronic integrase-defective lentiviral vector (coexpressing GM-CSF, IFN-alpha, and HCMV pp65 antigen) capable to directly induce self-differentiation of PB and CB monocytes into dendritic cells processing pp65 ("SmyleDCpp65"). In vitro, SmyleDCpp65 resisted HCMV infection, activated CD4(+) and CD8(+) T cells and expanded functional pp65-specific memory cytotoxic T lymphocytes (CTLs). CD34(+) cells obtained from PB and CB were transplanted into irradiated NOD.Rag1(-/-).IL2gammac(-/-) mice. Donor-derived SmyleDCpp65 administration after PB-HSCT stimulated peripheral immune effects: lymph node remodeling, expansion of polyclonal effector memory CD8(+) T cells in blood, spleen and bone marrow, and pp65-reactive CTL and IgG responses. SmyleDCpp65 administration after CB-HSCT significantly stimulated thymopoiesis. Expanded frequencies of CD4(+)/CD8(+) T cell precursors containing increased levels of T-cell receptor excision circles in thymus correlated with peripheral expansion of effector memory CTL responses against pp65. The comparative in vivo modeling for PB and CB-HSCT provided dynamic and spatial information regarding human T and B cell reconstitution. In vivo potency supports future clinical development of SmyleDCpp65. PMID- 26052528 TI - MD11-mediated delivery of recombinant eIF3f induces melanoma and colorectal carcinoma cell death. AB - The f subunit of the eukaryotic initiation factor 3 (eIF3f) is downregulated in several cancers and in particular in melanoma and pancreatic cancer cells. Its enforced expression by transient gene transfection negatively regulates cancer cell growth by activating apoptosis. With the aim to increase the intracellular level of eIF3f proteins and activate apoptosis in cancer cell lines, we developed a protein transfer system composed of a cell-penetrating peptide sequence fused to eIF3f protein sequence (MD11-eIF3f). To determine whether exogenously administered eIF3f proteins were able to compensate the loss of endogenous eIF3f and induce cancer cell death, we analyzed the therapeutic action of MD11-eIF3f in several tumor cells. We identified four cell lines respondent to eIF3f-treatment and we evaluated the antitumor properties of the recombinant proteins using dose- and time-dependent studies. Our results demonstrate that this protein delivery approach represents an innovative and powerful strategy for cancer treatment. PMID- 26052529 TI - Bilateral single-site intracerebral injection of a nonpathogenic herpes simplex virus-1 vector decreases anxiogenic behavior in MPS VII mice. AB - Genetic diseases of the brain usually have pathologic lesions distributed throughout, thus requiring global correction. Herpes simplex virus-1 (HSV-1) vectors may be especially useful for gene delivery in these disorders since they can spread trans-synaptically along neuronal pathways to distal sites from a localized injection. We have previously shown that a nonpathogenic HSV-1 (strain 1716), which is deleted in the ICP34.5 gene, and expressing the lysosomal enzyme beta-glucuronidase (GUSB) from the latency-associated transcript (LAT) promoter, spreads within the brains of GUSB-deficient mucopolysaccharidosis VII mice to reverse the pathognomonic storage lesions throughout the diseased brain. In this study, we tested the ability of the 1716 LAT-GUSB vector to improve behavioral deficits. The treatment significantly decreased anxiogenic behaviors associated with the mutation, as indicated by open-field behavior and decreased neophobia in a novel object-recognition task. The treated mice also exhibited an improvement in cognitive function associated with the cerebral cortex in a familiar object test. The results indicate the functional therapeutic potential of the 1716 LAT GUSB vector. PMID- 26052530 TI - High-throughput monitoring of integration site clonality in preclinical and clinical gene therapy studies. AB - Gene transfer to hematopoietic stem cells with integrating vectors not only allows sustained correction of monogenic diseases but also tracking of individual clones in vivo. Quantitative real-time PCR (qPCR) has been shown to be an accurate method to quantify individual stem cell clones, yet due to frequently limited amounts of target material (especially in clinical studies), it is not useful for large-scale analyses. To explore whether vector integration site (IS) recovery techniques may be suitable to describe clonal contributions if combined with next-generation sequencing techniques, we designed artificial ISs of different sizes which were mixed to simulate defined clonal situations in clinical settings. We subjected all mixes to either linear amplification-mediated PCR (LAM-PCR) or nonrestrictive LAM-PCR (nrLAM-PCR), both combined with 454 sequencing. We showed that nrLAM-PCR/454-detected clonality allows estimating qPCR-detected clonality in vitro. We then followed the kinetics of two clones detected in a patient enrolled in a clinical gene therapy trial using both, nrLAM PCR/454 and qPCR and also saw nrLAM-PCR/454 to correlate to qPCR-measured clonal contributions. The method presented here displays a feasible high-throughput strategy to monitor clonality in clinical gene therapy trials is at hand. PMID- 26052531 TI - Generation of a lentiviral vector producer cell clone for human Wiskott-Aldrich syndrome gene therapy. AB - We have developed a producer cell line that generates lentiviral vector particles of high titer. The vector encodes the Wiskott-Aldrich syndrome (WAS) protein. An insulator element has been added to the long terminal repeats of the integrated vector to limit proto-oncogene activation. The vector provides high-level, stable expression of WAS protein in transduced murine and human hematopoietic cells. We have also developed a monoclonal antibody specific for intracellular WAS protein. This antibody has been used to monitor expression in blood and bone marrow cells after transfer into lineage negative bone marrow cells from WAS mice and in a WAS negative human B-cell line. Persistent expression of the transgene has been observed in transduced murine cells 12-20 weeks following transplantation. The producer cell line and the specific monoclonal antibody will facilitate the development of a clinical protocol for gene transfer into WAS protein deficient stem cells. PMID- 26052532 TI - Multigenic lentiviral vectors for combined and tissue-specific expression of miRNA- and protein-based antiangiogenic factors. AB - Lentivirus-based gene delivery vectors carrying multiple gene cassettes are powerful tools in gene transfer studies and gene therapy, allowing coexpression of multiple therapeutic factors and, if desired, fluorescent reporters. Current strategies to express transgenes and microRNA (miRNA) clusters from a single vector have certain limitations that affect transgene expression levels and/or vector titers. In this study, we describe a novel vector design that facilitates combined expression of therapeutic RNA- and protein-based antiangiogenic factors as well as a fluorescent reporter from back-to-back RNApolII-driven expression cassettes. This configuration allows effective production of intron-embedded miRNAs that are released upon transduction of target cells. Exploiting such multigenic lentiviral vectors, we demonstrate robust miRNA-directed downregulation of vascular endothelial growth factor (VEGF) expression, leading to reduced angiogenesis, and parallel impairment of angiogenic pathways by codelivering the gene encoding pigment epithelium-derived factor (PEDF). Notably, subretinal injections of lentiviral vectors reveal efficient retinal pigment epithelium-specific gene expression driven by the VMD2 promoter, verifying that multigenic lentiviral vectors can be produced with high titers sufficient for in vivo applications. Altogether, our results suggest the potential applicability of combined miRNA- and protein-encoding lentiviral vectors in antiangiogenic gene therapy, including new combination therapies for amelioration of age-related macular degeneration. PMID- 26052533 TI - Inhalable delivery of AAV-based MRP4/ABCC4 silencing RNA prevents monocrotaline induced pulmonary hypertension. AB - The ATP-binding cassette transporter MRP4 (encoded by ABCC4) regulates membrane cyclic nucleotides concentrations in arterial cells including smooth muscle cells. MRP4/ABCC4 deficient mice display a reduction in smooth muscle cells proliferation and a prevention of pulmonary hypertension in response to hypoxia. We aimed to study gene transfer of a MRP4/ABCC4 silencing RNA via intratracheal delivery of aerosolized adeno-associated virus 1 (AAV1.shMRP4 or AAV1.control) in a monocrotaline-induced model of pulmonary hypertension in rats. Gene transfer was performed at the time of monocrotaline administration and the effect on the development of pulmonary vascular remodeling was assessed 35 days later. AAV1.shMRP4 dose-dependently reduced right ventricular systolic pressure and hypertrophy with a significant reduction with the higher doses (i.e., >10(11) DRP/animal) as compared to AAV1. CONTROL: The higher dose of AAV1.shMRP4 was also associated with a significant reduction in distal pulmonary arteries remodeling. AAV1.shMRP4 was finally associated with a reduction in the expression of ANF, a marker of cardiac hypertrophy. Collectively, these results support a therapeutic potential for downregulation of MRP4 for the treatment of pulmonary artery hypertension. PMID- 26052534 TI - Re-examination of regulatory opinions in Europe: possible contribution for the approval of the first gene therapy product Glybera. AB - The first commercially approved human gene therapy in the Western world is Glybera (alipogene tiparvovec), which is an adenoassociated viral vector encoding the lipoprotein lipase gene. Glybera was recommended for marketing authorization by the European Medicines Agency in 2012. The European Medicines Agency had only ever reviewed three marketing authorization applications for gene therapy medicinal products. Unlike in the case of Glybera, the applications of the first two products, Cerepro and Contusugene Ladenovec Gendux/Advexin, both of which were for cancer diseases, were withdrawn. In this report, we studied the European public assessment reports of the three gene therapy products. During the assessment process, Glybera was re-examined and reviewed for a fourth time. We therefore researched the re-examination procedure of the European Union regulatory process. Approximately 25% of the new medicinal products initially given negative opinions from the Committee for Medicinal Products for Human Use were ultimately approved after re-examination from 2009 to 2013. The indications of most medicines were changed during the re-examination procedure, and the products were later approved with a mode of approval. These results suggested that the re-examination system in the European Union contributed to the approval of both several new drugs and the first gene therapy product. PMID- 26052535 TI - Effectiveness of gene delivery systems for pluripotent and differentiated cells. AB - Human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC) assert a great future for the cardiovascular diseases, both to study them and to explore therapies. However, a comprehensive assessment of the viral vectors used to modify these cells is lacking. In this study, we aimed to compare the transduction efficiency of recombinant adeno-associated vectors (AAV), adenoviruses and lentiviral vectors in hESC, hiPSC, and the derived cardiomyocytes. In undifferentiated cells, adenoviral and lentiviral vectors were superior, whereas in differentiated cells AAV surpassed at least lentiviral vectors. We also tested four AAV serotypes, 1, 2, 6, and 9, of which 2 and 6 were superior in their transduction efficiency. Interestingly, we observed that AAVs severely diminished the viability of undifferentiated cells, an effect mediated by induction of cell cycle arrest genes and apoptosis. Furthermore, we show that the transduction efficiency of the different viral vectors correlates with the abundance of their respective receptors. Finally, adenoviral delivery of the calcium-transporting ATPase SERCA2a to hESC and hiPSC-derived cardiomyocytes successfully resulted in faster calcium reuptake. In conclusion, adenoviral vectors prove to be efficient for both differentiated and undifferentiated lines, whereas lentiviral vectors are more applicable to undifferentiated cells and AAVs to differentiated cells. PMID- 26052536 TI - A novel, long-lived, and highly engraftable immunodeficient mouse model of mucopolysaccharidosis type I. AB - Mucopolysaccharidosis type I (MPS I) is an inherited alpha-L-iduronidase (IDUA, I) deficiency in which glycosaminoglycan (GAG) accumulation causes progressive multisystem organ dysfunction, neurological impairment, and death. Current MPS I mouse models, based on a NOD/SCID (NS) background, are short-lived, providing a very narrow window to assess the long-term efficacy of therapeutic interventions. They also develop thymic lymphomas, making the assessment of potential tumorigenicity of human stem cell transplantation problematic. We therefore developed a new MPS I model based on a NOD/SCID/Il2rgamma (NSG) background. This model lives longer than 1 year and is tumor-free during that time. NSG MPS I (NSGI) mice exhibit the typical phenotypic features of MPS I including coarsened fur and facial features, reduced/abnormal gait, kyphosis, and corneal clouding. IDUA is undetectable in all tissues examined while GAG levels are dramatically higher in most tissues. NSGI brain shows a significant inflammatory response and prominent gliosis. Neurological MPS I manifestations are evidenced by impaired performance in behavioral tests. Human neural and hematopoietic stem cells were found to readily engraft, with human cells detectable for at least 1 year posttransplantation. This new MPS I model is thus suitable for preclinical testing of novel pluripotent stem cell-based therapy approaches. PMID- 26052537 TI - OTC Antioxidant Products for the Treatment of Cardiovascular and other Disorders: Popular Myth or Fact? PMID- 26052538 TI - Neonatal seizures and therapeutic hypothermia for hypoxic-ischemic encephalopathy. AB - Neonatal seizures are associated with morbidity and mortality. Hypoxic-ischemic encephalopathy (HIE) is the most common cause of seizures in newborns. Neonatal animal models suggest that therapeutic hypothermia can reduce seizures and epileptiform activity in the setting of hypoxia-ischemia, however data from human studies have conflicting results. In this research highlight, we will discuss the findings of our recent study that demonstrated a decreased seizure burden in term newborns with moderate HIE treated with hypothermia. PMID- 26052539 TI - Bacterial lipopolysaccharide induces a dose-dependent activation of neuroglia and loss of basal forebrain cholinergic cells in the rat brain. AB - In a rat model of neuroinflammation induced with a low-dose infusion lipopolysaccharide (5.0 ng/hr, LPS), we reported that brain arachidonic acid (ARA, 20:4 n-6), but not docosahexaenoic acid (DHA, 22:6n-3), metabolism is increased compared to control rats. To further characterize the impact LPS has on the induction of injury in this model, we quantified the dose-dependent activation of neuroglia and the loss of cholinergic cells in rats subjected to increasing doses of LPS. In this study, we found that LPS produced a statistically significant and linear dose-dependent increase in the percentage of activated CD11b-positive microglia ranging from 26% to 82% following exposure to doses ranging between 0.05 and 500 ng/hr, respectively. The percentage of activated GFAP-positive astrocytes also increased linearly and significantly from 35% to 91%. Significant astroglial scaring was evident at the lateral ventricular boarder of rats treated with 50 and 500 ng/hr LPS, but not evident in control treated rats or rats treated with lower doses of LPS. A dose-dependent decrease in the numbers of ChAT-positive cells in the basal forebrain of LPS-treated rats was found at higher doses of LPS (5, 50, and 500 ng/hr) but not at lower doses. The numbers of ChAT-positive cells within individual regions of the basal forebrain (medial septum and diagonal bands) and the composite basal forebrain were similar in their response. These data demonstrate that extremely low doses of LPS are sufficient to induce significant neuroglia activation while moderate doses above 5.0 ng/hr are required to induce cholinergic cell loss. PMID- 26052541 TI - Suppression of NF-kappaB signaling mitigates polyethylene wear particle-induced inflammatory response. AB - In end-stage arthritis patients, total joint replacement is a very effective surgical procedure. Nevertheless, the high revision rate after surgery remains a major concern. The wear particles generated from biomaterial-induced tissue responses may lead to chronic inflammation and local bone destruction (periprosthetic osteolysis). Several important signaling pathways are involved in wear particles induced inflammatory reactions, including the transcription factor NF-kappaB. We recently reported that RAW264.7 macrophage cell exposure to ultra high molecular weight polyethylene (UHMWPE) particles significantly increased the NF-kappaB activity in a generated NF-kappaB responsive luciferase reporter cell clone. The NF-kappaB activity induced by UHMWPE particles in a mouse RAW264.7 macrophage cell line, bone marrow derived macrophages, and human THP1 macrophage cell line, were suppressed by double strand decoy oligodeoxynucleotide (ODN) containing an NF-kappaB binding element. Macrophages exposure to UHMWPE particles with or without endotoxin induced pro-inflammatory cytokine and chemokine expression including TNF-alpha, MCP1, MIP1alpha, and others. Finally, the decoy ODN significantly suppressed the induced cytokine and chemokine expression in both murine and human macrophages, consequently reducing macrophage recruitment by cellular conditioned medium exposed to wear particles. These findings suggest that local suppression of inflammatory cytokine production via inhibition of NF kappaB activity with decoy ODN in total joint replacement patients could potentially be an effective strategy to alleviate wear particle-induced chronic inflammation. PMID- 26052540 TI - Novel Therapeutic Targets in Neuroinflammation and Neuropathic Pain. AB - There is abounding evidence that neuroinflammation plays a major role in the pathogenesis of neurodegeneration and neuropathic pain. Chemokine-induced recruitment of peripheral immune cells is a central feature in inflammatory neurodegenerative disorders. Immune cells, glial cells and neurons constitute an integral network that coordinates the immune response by releasing inflammatory mediators that in turn modulate inflammation, neurodegeneration and the signal transduction of pain, via interaction with neurotransmitters and their receptors. The chemokine monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand (MCP-1/CCL2) and its receptor C-C chemokine receptor (CCR2) play a major role in mediating neuroinflammation and targeting CCL2/CCR2 represents a promising strategy to limit neuroinflammation-induced neuropathy. In addition, the CCL2/CCR2 axis is also involved in mediating the pain response. Key cellular signaling events such as phosphorylation and subsequent activation of mitogen activated protein kinase (MAPK) p38 and its substrate MAPK-activated protein MAPKAP Kinase (MK) MK-2, regulate neuroinflammation, neuronal survival and synaptic activity. Further, MAPKs such as extracellular signal-regulated kinases (ERK), c-jun N-terminal kinase (JNK) and p38 play vital roles in mediating the pain signaling cascade and contribute to the maintenance of peripheral and central neuronal sensitization associated with chronic pain. This review outlines the rationale for developing therapeutic strategies against CCL2/CCR2 and MAPK signaling networks, identifying them as novel therapeutic targets for limiting neuroinflammation and neuropathic pain. PMID- 26052542 TI - Lung inflammation and damage induced by extracellular histones. AB - Despite decades of research, acute respiratory distress syndrome (ARDS) remains an important clinical challenge due to an incomplete understanding of the pathophysiological mechanisms. No FDA-approved drug therapy currently exists for treatment of humans with ARDS. There is accumulating evidence in rodents and humans suggesting that extracellular histones are strong drivers of inflammation and tissue damage. We recently described an important role for extracellular histones during acute lung injury (ALI) in mice (Bosmann et al., FASEB J. 27:5010 5021 (2013)). Extracellular histones were detected in bronchoalveolar lavage fluids (BALF) from patients with ARDS but not in BALF from non-ARDS patients in intensive care units. Extracellular histones were also detected in BALF from mice during experimental ALI. The presence of extracellular histones was dependent on the two C5a receptors (C5aR and C5L2) and availability of neutrophils. Extracellular histones were highly pro-inflammatory, and caused severe damage to respiratory function. Intratracheal instillation of histones resulted in pro inflammatory mediator production, epithelial cell damage, disturbances in alveolar-capillary gas exchange, lung consolidation, activation of the coagulation cascade, and in some cases, death. Antibody-mediated neutralization of extracellular histones attenuated C5a-induced ALI. Together, these data suggested a prominent role for extracellular histones in the pathophysiology of ALI. The predominant source of histones in ALI may be neutrophils that have been activated by C5a to form neutrophil extracellular traps (NETs). Therapeutic targeting of extracellular histones may provide a novel approach to combat ARDS in humans. PMID- 26052543 TI - Monoamine oxidase A (MAO-A): a signature marker of alternatively activated monocytes/macrophages. AB - Monocytes/macrophages are versatile cells centrally involved in host defense and immunity. Th1 cytokines induce a classical activation program in monocytes/macrophages leading to a proinflammatory M1 macrophage phenotype while Th2 cytokines IL-4 and IL-13 promote monocyte differentiation into an alternatively activated, anti-inflammatory M2 macrophage phenotype. Although monoamine oxidase A (MAO-A) is primarily known for its action in the nervous system, several recent studies have identified MAO-A as a signature marker of alternative activation of monocytes/macrophages. In this brief review we explore the signaling pathways/molecules that regulate MAO-A expression in alternatively activated monocytes/macrophages. We further discuss the contribution of MAO-A to the resolution of inflammation and identify potential therapeutic targets for controlling inflammation. Altogether this review provides deeper insight into the role of MAO-A in alternative activation of monocytes/macrophages and their participation in the inflammatory response. PMID- 26052544 TI - MFG-E8, a novel homeostatic regulator of osteoclastogenesis. AB - Although the glycoprotein MFG-E8 (milk fat globule-epidermal growth factor-factor 8) has been investigated extensively as an anti-inflammatory and homeostatic molecule, a possible role in bone homeostasis and disease was not addressed until recently. Our group has now shown that MFG-E8 is expressed by human and mouse osteoclasts and regulates their differentiation and function (Abe et al., J Immunol 2014;193:1383-1391). Whereas genetic deficiency or antibody-mediated neutralization of MFG-E8 enhances osteoclastogenesis and promotes inflammation induced bone loss in mice, local administration of recombinant MFG-E8 blocks bone loss. These findings establish MFG-E8 as a novel homeostatic regulator of osteoclastogenesis and suggest that MFG-E8 could be exploited therapeutically to treat disorders associated with inflammatory bone loss, such as periodontitis and rheumatoid arthritis. PMID- 26052545 TI - SHIPi Enhances Autologous and Allogeneic Hematolymphoid Stem Cell Transplantation. AB - Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometime untreatable, disease due to toxic conditioning regimens, graft vs. host disease and required use of mismatched bone marrow in some cases. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PC) and produces a suppressive microenvironment ideal for incoming grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach to creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) can mobilize functional HS-PC, accelerate hematologic recovery, and enhance donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize HSCT. PMID- 26052546 TI - Obesity Correlates With Glomerulomegaly But Is Not Associated With Kidney Dysfunction Early After Donation. AB - BACKGROUND: Body mass index (BMI) is a convenient measure used to assess obesity and is used to select candidates for kidney donation. Glomerulomegaly is an early indicator of obesity-related kidney disease. Whether obesity assessment by BMI best reflects underlying glomerulomegaly and is predictive of adverse changes in renal function postdonation is unclear. METHODS: We performed a retrospective study on a cohort of 1065 living donors at the Mayo Clinic in Rochester; obesity measures by BMI and by computed tomography were compared between 20 donors with largest to 20 donors with the smallest glomerular volumes (on implantation biopsy). In addition, the change in kidney function postdonation (mean 7 months) was compared across BMI groups (<25, 25-29, 30-34, >=35 kg/m2) in about 500 donors. RESULTS: We observed that larger glomerular volume was more strongly associated with BMI per standard deviation (SD) (odds ratio [OR] =5.0, P = 0.002) than waist circumference/height2 per SD (OR = 3.9, P = 0.02), visceral fat/height2 per SD (OR = 2.4, P = 0.02), subcutaneous fat/height2 per SD (OR = 2.0, P = 0.06), renal hilar fat/height2 per SD (OR = 1.6, P = 0.19), or peri/pararenal fat/height2 per SD (OR = 1.5, P = 0.23). Postdonation changes in glomerular filtration rate, blood pressure, and albuminuria were similar across BMI categories. CONCLUSIONS: The BMI outperforms various computed tomography measures of abdominal fat in detecting obesity-related glomerulomegaly. Despite this strong association with glomerulomegaly, short-term renal function outcomes are similar across BMI categories. Long-term follow-up is required to definitively define the impact of obesity on kidney function after donation. PMID- 26052547 TI - Vulnerability of synapses in the frontal cortex of mice developmentally exposed to an insecticide: Potential contribution to neuropsychiatric disease. AB - Increasingly, exposure to various chemicals found in our environment has been found to be a significant contributor to the risk of developing neurological disease, such as Parkinson disease, autism spectrum disorder, as well as other deficits in thought and function. Exposure to these compounds during critical periods of neurodevelopment, encompassing exposures that occur in utero, during infancy, childhood, and adolescence, represents a time period of nervous system growth that is uniquely vulnerable to disruption by environmental chemicals. Indeed, a contemporary hypothesis suggests that the pathological cascade associated with many common neurological disorders has its origin in disturbances of normal neurodevelopment. Moreover, alterations to the ontogeny of the synapse and neurotransmitter signaling during neurodevelopment may be a premier pathological event that underlies neuropsychiatric and neurodegenerative disease. To interrogate the impact of exposure to a ubiquitous environmental chemical, the pesticide, endosulfan, on development of neurotransmitter circuits, we coupled in vitro and in vivo platforms to evaluate its effect on the formation of GABAergic, glutamatergic, and dopaminergic pathways in the frontal cortex. With this approach we found exposure of cortical neurons, in vitro, exhibited a marked reduction in the length of their neurite process as well as the number of synaptic connections. Further investigation using an in vivo model of developmental exposure identified significant alterations to pre and postsynaptic proteins involved in neurotransmitter handling and signaling in each of the neurotransmitter systems investigated. These findings suggest that exposure to endosulfan during vulnerable periods of neurodevelopment can alter the normal development and potential function of neurotransmission in the frontal cortex. Interestingly, the alterations identified in our study closely mimic the pathological markers associated with schizophrenia, which shows disturbances in synaptic proteins important for GABAergic, glutamatergic, and dopaminergic signaling in the frontal cortex. These findings provide important support for the impact of exposure to environmental chemicals during neurodevelopment and risk for neurological disease. PMID- 26052548 TI - Effect of Sodium Fluoride on the endogenous MMP Activity of Dentin Matrices. AB - OBJECTIVES: This study evaluated the effect of incorporating increasing concentrations of sodium fluoride in incubation media, on the loss of dry mass and solubilization of collagen from demineralized dentin beams incubated for up to 7 days. The effect of fluoride on the inhibition of matrix-bound metalloproteinases (MMPs) was also measured. METHODS: Dentin beams were completely demineralized in 10% phosphoric acid. After baseline measurements of dry mass, the beams were divided into six groups (n=10) and incubated at 37 degrees C either in buffered media containing sodium fluoride (NaF) at 75, 150, 300, 450, 600 ppm or in fluoride-free media (control) for seven days. Following incubation, dry mass was re-measured. The incubation media was hydrolyzed with HCl for the quantitation of hydroxyproline (HYP) as an index of solubilization of collagen by endogenous dentin proteases. Increasing concentrations of fluoride were also evaluated for their ability to inhibit rhMMP-9. RESULTS: Addition of NaF to the incubation media produced a progressive significant reduction (p<0.05) in the loss of mass of dentin matrices, with all concentrations demonstrating significantly less mass loss than the control group. Significantly less HYP release from the dentin beams was found in the higher fluoride concentration groups, while fluoride concentrations of 75 and 150 ppm significantly reduced rhMMP-9 activity by 6.5% and 79.2%, respectively. CONCLUSIONS: The results of this study indicate that NaF inhibits matrix-bound MMPs and therefore may slow the degradation of dentin matrix by endogenous dentin MMPs. PMID- 26052549 TI - The Essential WalK Histidine Kinase and WalR Regulator Differentially Mediate Autolysis of Staphylococcus aureus RN4220. AB - The two-component regulatory system, WalR/WalK is necessary for growth of different gram-positive bacteria, including Staphylococcus aureus. In present study, we confirmed the essentiality of both the histidine kinase protein WalK and the response regulator WalR for growth using S. aureus RN4220 strain and demonstrated that the histidine kinase protein WalK and the response regulator WalR function differently in regulation of staphylococcal autolysis. The down regulation of walR expression effectively inhibited Triton X-100-induced lysis and had a weak impact on bacterial tolerance to penicillin induced cell lysis. In contrast, the down-regulation of walK expression had no influence on either Triton X-100- or penicillin-caused autolysis. Moreover, we determined the effect of WalR and WalK on bacterial hydrolase activity using a zymogram analysis. The results showed that the cell lysate of down-regulated walR expression mutant displayed several bands of decreased cell wall hydrolytic activities; however, the down-regulation of WalK had no dramatic impact on the hydrolytic activities. Furthermore, we examined the impact of WalR on the transcription of cidA associated with staphylococcal autolysis, and the results showed that the down regulation of WalR led to decreased transcription of cidA in the log phase of growth. Taken together, the above results suggest that the essential WalR response regulator and the essential WalK histidine kinase might differently control bacterial lysis in RN4220 strain. PMID- 26052550 TI - A new way to detect the danger: Lysosomal cell death induced by a bacterial ribosomal protein. AB - The death of immune cells in response to pathogens often dictates the outcome of an infection. In some contexts, pathogens specifically kill immune cells by producing highly potent toxins or by triggering host cell death pathways, thus ensuring successful infections. But for intracellular pathogens and viruses, the death of host cells normally is disastrous for their intracellular life cycle. Our recent experiments with the pathogen Legionella pneumophila revealed that the bacterial ribosomal protein RpsL is able to trigger lysosomal membrane permeabilization (LMP) and the subsequent macrophage cell death. Interestingly, a lysine to arginine mutation at the 88th residue, which also confers resistance to the antibiotic streptomycin, substantially impaired the cell death inducing activity of RpsL and allowed L. pneumophila to succeed in intracellular replication, suggesting the convergence of resistance mechanisms to innate immunity and antibiotics. The discovery of lysosomal cell death as an immune response to a bacterial ligand has expanded the spectrum of reactions that host cells can mount against bacterial infection; these observations provide a model to study the pathways that lead to the induction of LMP, a currently poorly understood cellular process involved in the development of many diseases. PMID- 26052551 TI - Retinal phagocytes in age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in industrial countries. Vision loss caused by AMD results from geographic atrophy (dry AMD) and/or choroidal neovascularization (wet AMD). Presently, the etiology and pathogenesis of AMD is not fully understood and there is no effective treatment. Oxidative stress in retinal pigment epithelial (RPE) cells is considered to be one of the major factors contributing to the pathogenesis of AMD. Also retinal glia, as scavengers, are deeply related with diseases and could play a role. Therefore, therapeutic approaches for microglia and Muller glia, as well as RPE, may lead to new strategies for AMD treatment. This review summarizes the pathological findings observed in RPE cells, microglia and Muller glia of AMD murine models. PMID- 26052552 TI - A mouse model of craniofacial bone lesion of tuberous sclerosis complex. AB - The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway plays critical roles in skeletal development. The impact and underlying mechanisms of its dysregulation in bone homeostasis is poorly defined. The best known and characterized mTOR signaling dysregulation in human disease is called Tuberous Sclerosis Complex (TSC). TSC is an autosomal dominant neurocutaneous syndrome with a high frequency (>66%) of osseous manifestations such as sclerotic lesions in the craniofacial region. TSC is caused by mutations of TSC1 or TSC2, the heterodimer protein inhibitor of mTORC1 signaling. The underlying mechanism of bone lesions in TSC is unclear. We generated a TSC mouse model with TSC1 deletion in neural crest derived (NCD) cells, which recapitulated the sclerotic craniofacial bone lesion in TSC patients. We demonstrated that TSC1 null NCD osteoblasts overpopulated the NCD bones and the resultant increased bone formation is responsible for the sclerotic bone phenotype. Mechanistically, osteoblast number increase is due to the hyperproliferation of osteoprogenitor cells at an early postnatal stage. Noteworthy, administration of rapamycin, an mTORC1 inhibitor at early postnatal stage can completely rescue the excess bone acquisition, but late treatment cannot. Altogether, our data suggested that enhanced mTORC1 signaling in NCD cells can enlarge the osteoprogenitor pool and lead to the excess bone acquisition, which is likely the underlying mechanism of sclerotic bone lesion observed in TSC patients. PMID- 26052556 TI - NIDA-Drug Addiction Treatment Outcome Study (DATOS) Relapse as a Function of Spirituality/Religiosity. AB - BACKGROUND: The connection between religion/spirituality and deviance, like substance abuse, was first made by Durkheim who defined socially expected behaviors as norms. He explained that deviance is due in large part to their absence (called anomie), and concluded that spirituality lowers deviance by preserving norms and social bonds. Impairments in brain reward circuitry, as observed in Reward Deficiency Syndrome (RDS), may also result in deviance and as such we wondered if stronger belief in spirituality practice and religious belief could lower relapse from drugs of abuse. METHODS: The NIDA Drug Addiction Treatment Outcome Study data set was used to examine post hoc relapse rates among 2,947 clients who were interviewed at 12 months after intake broken down by five spirituality measures. RESULTS: Our main findings strongly indicate, that those with low spirituality have higher relapse rates and those with high spirituality have higher remission rates with crack use being the sole exception. We found significant differences in terms of cocaine, heroin, alcohol, and marijuana relapse as a function of strength of religious beliefs (x2 = 15.18, p = 0.028; logistic regression = 10.65, p = 0.006); frequency of attending religious services (x2 = 40.78, p < 0.0005; logistic regression = 30.45, p < 0.0005); frequency of reading religious books (x2 = 27.190, p < 0.0005; logistic regression = 17.31, p < 0.0005); frequency of watching religious programs (x2 = 19.02, p = 0.002; logistic regression = ns); and frequency of meditation/prayer (x2 = 11.33, p = 0.045; logistic regression = 9.650, p = 0.002). Across the five measures of spirituality, the spiritual participants reported between 7% and 21% less alcohol, cocaine, heroin, and marijuana use than the non-spiritual subjects. However, the crack users who reported that religion was not important reported significantly less crack use than the spiritual participants. The strongest association between remission and spirituality involves attending religious services weekly, the one marker of the five that involves the highest social interaction/social bonding consistent with Durkheim's social bond theory. CONCLUSIONS: Stronger spiritual/religious beliefs and practices are directly associated with remission from abused drugs except crack. Much like the value of having a sponsor, for clients who abuse drugs, regular spiritual practice, particularly weekly attendance at the religious services of their choice is associated with significantly higher remission. These results demonstrate the clinically significant role of spirituality and the social bonds it creates in drug treatment programs. PMID- 26052558 TI - RETNA: From Requirements to Testing in a Natural Way. AB - Most problems in building and refining a system can be traced back to errors in requirements. Poorly organized requirements, most often in natural language are among the major causes of failures of software projects. In this paper, we present a requirements analysis tool called RETNA and the technology behind it. RETNA accepts natural language requirements, classifies them, interacts with the user to refine them, automatically translates natural language requirements to a logical format so that they can be validated and finally generates test cases from the requirements. PMID- 26052557 TI - Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction. AB - BACKGROUND: The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. METHODS: To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. RESULTS: While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. CONCLUSION: Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARSPREDXTM), the first test to accurately predict one's genetic risk for RDS. PMID- 26052559 TI - Restoration of Mitochondrial Gene Expression Using a Cloned Human Gene in Chinese Hamster Lung Cell Mutant. AB - BACKGROUND: Gal-32 is a Chinese hamster lung cell nuclear mutant that is unable to grow in galactose due to a defect in mitochondrial protein synthesis. Since the product of the Gal-32 gene was unknown, it was imperative to use phenotypic complementation to clone a human gene that corrected the Gal-32 mutation. RESULTS: Recessive Gal-32 cells were co-transformed with pSV2-neo plasmid DNA and recombinant DNA from a human genomic library containing the dominant human Gal+ gene and a chloramphenicol-resistance (camr ) gene present in the pSV13 vector. Primary transformants were selected by growth in galactose and the neomycin analog G418. In order to rescue the human Gal+ gene, a genomic library was constructed with primary transformant DNA and the pCV108 cosmid vector. The camr gene was used to identify clones with the nearby human sequences. DNA from two camr , Alu-hybridizing clones was able to transform the recessive Gal-32 cells to the Gal+ phenotype and to restore mitochondrial protein synthesis. CONCLUSION: These data demonstrate the isolation of two pCV108-transformant recombinant clones containing a human gene that complements the Chinese hamster Gal-32 mutation and restores galactose metabolism. PMID- 26052560 TI - Deformation-Invariant Sparse Coding for Modeling Spatial Variability of Functional Patterns in the Brain. AB - For a given cognitive task such as language processing, the location of corresponding functional regions in the brain may vary across subjects relative to anatomy. We present a probabilistic generative model that accounts for such variability as observed in fMRI data. We relate our approach to sparse coding that estimates a basis consisting of functional regions in the brain. Individual fMRI data is represented as a weighted sum of these functional regions that undergo deformations. We demonstrate the proposed method on a language fMRI study. Our method identified activation regions that agree with known literature on language processing and established correspondences among activation regions across subjects, producing more robust group-level effects than anatomical alignment alone. PMID- 26052561 TI - One or more elastographic methods for liver fibrosis assessment? PMID- 26052562 TI - Variable sonographic spectrum of parathyroid adenoma with a novel ultrasound finding: dual concentric echo sign. AB - AIMS: To review the detailed gray-scale and Doppler ultrasonography features of histologically proven parathyroid adenomas (PAs) evaluated with high-end ultrasonography devices and to present a novel ultrasonography finding called the dual concentric echo sign in PA with histopathologic correlation which was encountered during detailed analysis. MATERIAL AND METHODS: Fifty-six PAs with histopathological result were enrolled. The longest dimension, shape, distance to skin surface, internal echo and Doppler US features obtained with high-end US devices were evaluated. RESULTS: PAs had variable range of shape including oval, irregular, fusiform, lobulated, crescent-shaped, and nodular configuration. In nine patients the lesions were shown to have cystic components and calcifications were seen in four cases. Dual concentric echo sign was detected in 18% PAs. Histological reevaluation of this subgroup demonstrated significantly increased edema (p<0.01), and ectatic vessels (p=0.02) in the central part of the lesion compared to the rest of the PAs. CONCLUSIONS: The results of the study led to the conclusion that PAs have variable gray-scale and Doppler findings. Typical sonographic features like ovoid shape, homogeneously hypoechoic pattern may not be present in all PAs. Dual concentric echo sign which is a novel sonographic pattern may be suggestive of a PA. PMID- 26052563 TI - Columnar cell lesions of the breast: radiological features and histological correlation. AB - OBJECTIVE: This study aimed at investigating the characteristic imaging findings of the columnar cell lesions (CCLs) of the breast via mammography (MG), ultrasonography (US), and magnetic resonance imaging (MRI). MATERIALS AND METHODS: The MG, US and MRI findings of 72 patients with histopathological diagnosis of CCLs were retrospectively evaluated. Histopathologically, the CCLs were divided into those with and without atypia; the radiological findings of these two groups were compared with a Chi-square test. RESULTS: Sixty-nine patients underwent stereotaxic biopsy (MG-guided in 50 patients and US-guided in 19 patients) and 3 patients underwent US-guided core needle biopsy; all of these patients were diagnosed with CCLs based on a histological examination. The evaluation of the CCLs in patients that underwent MG-guided stereotaxic biopsy revealed that the most common type of microcalcifications were amorphous indistinct (52%, n= 26/50) and the most common microcalcification distribution pattern was clustered type (76%, n= 38/50). The ratio of CCLs with atypia was similar in patients with high-risk microcalcifications and in those with benign or intermediate-risk microcalcifications (OR: 1.13, 95% CI: 0.573-2.227, p: 0.475). On the other hand, those patients who underwent US-guided biopsies for the evaluation of CCLs had similar proportions of cystic or solid lesions, posterior acoustic shadowing and contour irregularities whether or not they had atypia (p: 0.584, 0.075, 0.187, respectively). Patients with atypia had a higher number of lesions greater than 1 cm via US as compared to those without atypia, but this difference was not statistically significant (p: 0.06). MRI findings were also similar in patients with and without atypia. CONCLUSIONS: MG revealed that clustered distribution patterns and amorphous- indistinct type microcalcifications were more commonly seen in patients with CCLs; however, there was no significant relationship between US or MRI findings and CCLs. In addition, the MG, US and MRI findings were similar in patients with CCLs that did or did not have histopathological characteristics of atypia. PMID- 26052564 TI - Ultrasonographic evaluation of the posterolateral radiohumeral plica in asymptomatic subjects and in patients with osteoarthritis. AB - AIMS: The aim of this study was to describe the morphological features of posterolateral radiohumeral (RH) plica in asymptomatic subjects and in patients with elbow osteoarthritis using ultrasonography (US). MATERIAL AND METHODS: The control group included a total of 100 healthy elbows (51 subjects) and the study group consisted of 22 elbows (22 patients) with osteoarthritis confirmed clinically and by imaging methods. The presence, length, height, thickness, cross sectional area, shape, and echogenicity of the posterolateral RH plica were evaluated in both groups. In addition, humeral and radial cartilage thicknesses were also measured. The clinical characteristics and radiographic findings of the study group were evaluated. RESULTS: The posterolateral RH plica was present in all elbows of the control group (100%) and in 15 (68%) of elbows in the study group (p<0.05). All sizes and cross sectional areas of the plica were statistically significantly lower in the elbows of the study group compared to the elbows of the control group (p<0.05 and p<0.001, respectively). The detected posterolateral RH plicae were triangularly shaped in both groups. The plica was hyperechoic in 95 elbows (95%) in the control group and 7 osteoarthritis elbows (46.7%) (p<0.001). The thicknesses of radial and humeral cartilage were also significantly higher in the control group (p<0.001). There were no statistically significant relationships between the radiographic scoring of the elbow osteoarthritis and US findings of the RH plica (all p>0.05). CONCLUSIONS: The posterolateral RH plica can be successfully evaluated using US. Based on these findings, it appears that osteoarthritis can result in a reduction of the RH plica and affect its morphological appearance. PMID- 26052565 TI - Effectiveness of bone marrow mononuclear cells delivered through a graft vessel for patients with previous myocardial infarction and chronic heart failure: an echocardiographic study of left ventricular remodeling. AB - AIMS: The graft of stem cells to treat ischemic cardiomyopathy is popular in many clinical trials. The aim of this study was to evaluate the effectiveness of isolated coronary artery bypass graft combined with bone marrow mononuclear cells (BMMNC) delivered through graft vessels to improve left ventricular remodeling of patients with previous myocardial infarction and chronic heart failure using echocardiography. MATERIAL AND METHODS: Patients with previous myocardial infarction and chronic heart failure were randomly allocated to one of the two groups: CABG only (18 patients), or CABG with BMMNC transplantation (24 patients). Echocardiographic parameters were measured on B-mode imaging, 3D imaging and color flow imaging. RESULTS Post-operative LVEDD (end-diastolic dimension of left ventricle), LVESD (end-systolic dimension of left ventricle), LVEDV (end-diastolic volume of left ventricle), LVESV (end-systolic volume of left ventricle), LVEDVI (LVEDV indexed to body surface area), LVESVI (LVESV indexed to body surface area), LV-mass (mass of left ventricle) and LV-massI (LV mass indexed to body surface area) were significantly improved compared with those obtained prior to operation in CABG+BMMNC group (al p<0.05). The same parameters were not significantly different pre- and postoperative in the CABG group (al p>0.05). Postoperative mitral regurgitation score was not significantly different from those prior to operation in both groups (al p>0.05). In Chi-square tests, LVEDD, LVESD, LVEDV, LVESV, LVEDVI, LVESVI, LV-mass, LV-massI were determinants of the left ventricular remodeling. CONCLUSION: The improvement of left ventricular remodeling in CABG+BMMNC group was better than in the CABG group and this improvement was verified by echocardiography. PMID- 26052566 TI - Carotid intima-media thickness and hemodynamic parameters: reproducibility of manual measurements with Doppler ultrasound. AB - AIMS: To evaluate the carotid ultrasound intra- and interobserver agreements in a common clinical scenario when making manual measurements of the intima-media thickness (IMT) and peak systolic (PSV) and end diastolic (EDV) velocities in the common (CCA) and the internal carotid (ICA) arteries. MATERIAL AND METHODS: Three different experienced operators performed two time-point carotid ultrasounds in 21 patients with cardiovascular risk factors. Each operator measured freehand the CCA IMT three consecutive times in each examination. The CCA and ICA hemodynamic parameters were acquired just once. For our purpose we took the average (IMTmean) and maximum (IMTmax) IMT values. Quantitative variables were analyzed with the t student, and ANOVA test. Agreements were evaluated with the Intraclass Correlation Coefficient (ICC). RESULTS: IMTmean intraobserver agreement was better on the left (ICC: 0.930-0.851-0.916, operators 1-2-3) than on the right (ICC: 0.789-0.580-0.673, operators 1-2-3). IMTmax agreements (Left ICC: 0.821 0.723-0.853, operators 1-2-3; Right ICC: 0.669-0.421-0.480, operators 1-2-3) were lower and more variable. Interobserver agreements for IMTmean (ICC: 0.852-0.860; first-second ultrasound) and IMTmax (ICC: 0.859-0.835; first-second ultrasound) were excellent on the left, but fair-good and more variable on the right (IMTmean; ICC: 0.680-0.809; first-second ultrasound; IMTmax; 0.694-0.799; first second ultrasound). Intraobserver agreements were fair-moderate for PSVs and good excellent for EDVs. Interobserver agreements were good-excellent for both PSVs and EDVs. Overall, 95% confidence intervals were narrower for the left IMTmean and CCA velocities. CONCLUSIONS: Intra and interobserver agreements in carotid ultrasound are variable. In order to improve carotid IMT agreements, IMTmean is preferable over IMTmax. PMID- 26052567 TI - The Daily Resistive Index measurement useful tool in the estimation of the optimal time interval between two Shock Wave Lithotripsy sessions. AB - OBJECTIVE: : To monitor the impact of Shock Wave Lithotripsy (SWL) on the renal resisive index (RI) and to investigate the potential of the RI measurement for the estimation of the optimal duration between 2 SWL sessions. MATERIAL AND METHODS: Thirty patients with single pelvis renalis stone were included. Participitants were grouped according to their age as group 1 (<40 years, mean age 36.2+/-3.9 years) and group 2 (>/=40 years, mean age 55.4+/-6.5 years). RI measurement was performed in of all patients prior to SWL. After SWL, RI was monitored daily until RI returned to their pre-SWL values. RESULTS: The mean stone size was 2 8.97+/-3.62 in group 1 and 10.08+/-4.67 mm in group 2 (p=0.077). Following SWL, the RI value of both goups increased and the higher RI value was measured at the 24th hour as compared with their pre-SWL values (p<0.001). In day 2 RI of the groups declined, but the differences were still statistically different from their pre-SWL RI values (p<0.001). However, on the third day, RI of group 1 was close to their pre-SWL level (p=0.143). But, in group 2, RI value returned to their pre-SWL limits on day 4 (p=0.229). CONCLUSIONS: RI measurement gives important data regarding SWL related acute renal trauma and should be used as an US marker for recovery after SWL. PMID- 26052568 TI - Prospective evaluation of the renal morphology and vascular resistance in patients with ankylosing spondylitis. AB - AIMS: To evaluate renal morphology, prevalence of urinary stone disease, renal perfusion and resistance to renal blood flow in patients with ankylosing spondylitis(AS). MATERIAL AND METHODS: Thirty-eight patients diagnosed with AS and with normal basal renal functions, together with 38 healthy individuals matched in terms of age, sex, blood lipid profile and body mass index, were included. Total cholesterol, triglyceride, urea, creatinine and glucose levels were measured in both groups, as well as vitamin D, erythrocyte sedimentation rate (ESR) and C-reactive protein in the AS group. Renal dimensions, parenchymal echogenicity, presence of stone and renal resistive index (RRI) from the interlobular artery level were measured, and correlations with clinical and laboratory parameters were assessed. RESULTS: Thirty-eight patients diagnosed with AS (age 42.4+/- 11.5, 24 male, 14 women) and a control group of 38 healthy individuals (age 41.7+/-10.8, 23 male, 15 female) were included in the study. Renal stone was present in 7 patients (18.4%) in the AS group and 4 subjects (10.5%) in the control group. There was no significant difference in prevalence of stone between the groups (p=0.516). RRI values were significantly higher in the patients with AS (0.63+/-0.06) compared with the control group (0.59+/-0.03, p=0.001). Significant correlations were determined between RRI and age, triglyceride level, body mass index and length of disease. CONCLUSIONS: Renal Doppler is an important examination in early diagnosis and monitoring of renal changes in AS patients since renal complications in AS develop in the chronic and follow a subclinical course. PMID- 26052569 TI - Ultrasonography of the metacarpophalangeal joints in healthy subjects using an 18 MHz transducer. AB - AIM: To evaluate the metacarpophalangeal (MCP) joints (MCP2 and 5) in healthy subjects by ultrasonography (US) using a high frequency transducer (18 MHz) and to verify the interobserver agreement. MATERIAL AND METHODS: We enrolled 50 healthy volunteers (37 women, age between 30-58 years, mean age 41.7 years, divided into 3 groups according to age: 30-39, 40-49, and 50-58 years). The subjects were successively evaluated by 4 rheumatologists: 2 experienced (team A) and 2 beginners (team B) in US. Seven dorsal and palmar longitudinal scanning positions and a supplementary scan for MCP cartilage were performed. The bone surface (erosions, osteophytes), the intra-articular content (synovial thickening and vascularization, 4 grade scale), and the aspect of the metacarpal head cartilage were analyzed. The anterior palmar recess was measured. The time for examination was recorded. RESULTS: Erosions were detected in 7% of joints by team A and 2% by team B (p<0.05, kappa agreement 0.567) in subjects over 40 years. The agreement by team A in the detection of the erosions was very good (kappa value 0.83). A moderate positive correlation was obtained between the presence of erosions and age (r= 0.401, p=0.004). Osteophytes were identified only on the dorsal scan in subjects over 50 years (in 3.5% of joints team A, 1.5% team B, p>0.05, kappa value 0.421). No grade 1 synovitis was observed by team A but 4 joints with grade 1 synovitis were identified by team B (p<0.05) from the dorsal scan. The dimensions of the palmar recess had large distribution (MCP 2 between 0.55-1.3 mm; MCP 5 between 0.6-1.2 mm). No statistical significant differences were obtained when comparing the dimensions of the two hands, the values obtained in age-groups (all p>0.05). No statistical significant correlations were obtained between the dimensions of palmar recess and the body mass index or dominant hand (all p>0.05). No pathological findings were found in the examination of the metacarpal head cartilage. Power Doppler investigation found the presence of grade 1 signal in 2.5% joints by team A and 1.5% by team B (p>0.05) only in the dorsal scans. The mean time for examination was 7.8+/-1.74 min in team A and 13.78+/-2.96 min in team B (p<0.05). CONCLUSIONS: In healthy subjects pathological findings are occasionally encountered, especially erosions and osteophytes. Using an 18 MHz transducer the aspect of grade 1 synovitis was not encountered in healthy non-inflammatory MCP joints. There is a permanent need for standardized training and examination in musculoskeletal US. PMID- 26052570 TI - Acoustic Radiation Force Impulse imaging for detecting thyroid nodules: a systematic review and pooled meta-analysis. AB - AIM: To investigate the diagnostic performance of shear wave velocity (SWV) using virtual touch tissue quantification (VTQ) of acoustic radiation force impulse imaging (ARFI) technology in differentiating malignant and benign thyroid nodules by conducting a meta-analysis. MATERIAL AND METHODS: The Cochrane library, Embase, Pubmed, and Web of Science were searched for relevant studies through December 2014. Studies evaluating the diagnostic accuracy of SWV in the identification of malignant and benign thyroid nodules by using VTQ of ARFI technology were selected. The cytology or histology was used as the reference standard. The pooled sensitivity, specificity, diagnostic odds ratio, likelihood ratio, and the area under the summary receiver operating characteristic (SROC) curve were used to examine the diagnostic accuracy of SWV. RESULTS: A total of 13 cohort studies involving 1617 thyroid nodules from 1451 patients were identified. Of 13 studies, one was a retrospective study and others were prospective studies. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio of SWV in differentiating malignant and benign thyroid nodules were 86.3% (95%CI: 78.2-91.7), 89.5% (95%CI: 83.3 93.6), 7.04 (95%CI: 4.40-11.26), 0.17 (95%CI: 0.10-0.31), and 46.66 (95%CI:19.47 111.81), respectively. The area under the SROC curve was 94% (95% CI: 92-96). CONCLUSIONS: This meta-analysis indicates that VTQ is useful in evaluating the stiffness of thyroid nodules and differentiating between malignant and benign nodules. Due to the high sensitivity, specificity, and diagnostic odds ratio, SWV can be considered as a useful complement for conventional ultrasonography. PMID- 26052571 TI - How useful are ARFI elastography cut-off values proposed by meta-analysis for predicting the significant fibrosis and compensated liver cirrhosis? AB - AIM: To evaluate how often do we "miss" chronic hepatitis C patients with at least significant fibrosis (F>/=2) and those with compensated cirrhosis, by using Acoustic Radiation Force Impulse (ARFI) elastography cut-off values proposed by meta-analysis. MATERIAL AND METHODS: Our study included 132 patients with chronic hepatitis C, evaluated by means of ARFI and liver biopsy (LB), in the same session. Reliable measurements were defined as: median value of 10 liver stiffness (LS) measurements with a success rate>/=60% and an interquartile range interval<30%. For predicting F>/=2 and F=4 we used the LS cut-offs proposed in the last published meta-analysis: 1.35 m/s and 1.87 m/s, respectively. RESULTS: Reliable LS measurements by means of ARFI were obtained in 117 patients (87.9%). In our study, 58 patients (49.6%) had LS values <1.35 m/s; from these 75.8% had F>/=2 in LB. From the 59 patients (50.4%) with LS values>/=1.35 m/s, only 6.8% had F0 or F1 in LB. Also, in our study, 88 patients (75.3%) had LS values <1.87 m/s; from these only 2.2 % had F4 in LB. From the 29 patients (24.7%) with LS values>/=1.87 m/s, 41.3% had F4 in LB. Both for prediction of at least significant fibrosis and liver cirrhosis, higher aminotransferases levels were associated with wrongly classified patients, in univariate and multivariate analysis. CONCLUSIONS: ARFI elastography had a very good positive predictive value (93.2%) for predicting the presence of significant fibrosis and excellent negative predictive value (97.8%) for excluding the presence of compensated liver cirrhosis. PMID- 26052572 TI - A new sign in the standard hip ultrasound image of the Graf method. AB - AIM: The aim of the study was to assess the usefulness of obtaining a 900 angle between the plane of the osteochondral plate and the surface of the transducer during standard hip ultrasonography according to Graf method. MATERIAL AND METHODS: In this retrospective study 1078 patients (2156 hips) were included examined between 2008 and 2014 for developmental dysplasia of the hip (DDH) ultrasound screening. The patients were divided in two groups. Group I consisted of 402 patients examined between January 2008 and December 2011 using the standard Graf method. Group II consisted of 676 patients examined from January 2012 to December 2014 using the Graf method with an additional criterion: 900 angle between the plane of the osteochondral plate and the surface of the transducer. RESULTS: We found more dysplastic patients in group I comparing to group II: 55 (13.7%) and 38 (5.6%) respectively. The difference in the incidence of patients diagnosed with DDH was highly significant (p<0.001). The mean alpha angle value in group I was 65.310, respectively 67.520 for group II (p<0.001). CONCLUSION: The new osteochondral plate sign has the potential to reduce the overdiagnosis of DDH and provide a better tailored approach to borderline hips. PMID- 26052573 TI - The utility of ultrasound for surgical spinal decompression. AB - Surgery is routinely performed to decompress the spinal cord. While a number of imaging modalities are currently used in the perioperative setting of surgical spinal cord decompression including computed tomography scan and magnetic resonance imaging, ultrasound (US) usage is relatively new. Therefore, only a few studies in the literature describe its value in the perioperative setting. US is a simple, safe, rapid, non-invasive, and inexpensive modality that constitutes a potential alternative when other modalities are not suitable or unavailable. It enables surgeons to generate high-resolution real-time images that can aid in diagnosing pathologies, guiding surgeries, and evaluating surgical outcomes. This review discusses the present literature and utility of pre-, intra-, and post operative US in patients undergoing surgical spinal decompression. We also delineate three cases in which US was utilized at King Saud University hospital, which is considered one of the first centers in our region to report the use of US to guide treatment in spine surgery. PMID- 26052574 TI - Contrast enhanced ultrasound of renal masses. A reappraisal of EFSUMB recommendations and possible emerging applications. AB - The main imagistic method for characterization of renal lesions is contrast enhanced computed tomography (CECT). Disadvantages of CECT are a contrast-induced nephropathy in patients with renal impairment, allergic reactions and high costs. Contrast-enhanced ultrasound (CEUS) evaluation of hepatic and non-hepatic lesions is a relatively new, but increasingly utilised, diagnostic method. In 2011 the European Federation of Societies of Ultrasound in Medicine and Biology (EFSUMB) updated the Guidelines and Recommendations on the Clinical Practice of CEUS and included in the recommendation the renal pathology. However, there are several possible new indications that have not been discussed (pyelocaliceal masses and renal vein thrombosis) and several issues that remain controversial such as the differentiation of benign and malignant tumours or the differentiation of lymphoma and metastasis. This study aims to review literature data, as well as reveal the latest findings in the field of renal CEUS. PMID- 26052575 TI - Endoscopic ultrasound for the characterization and staging of rectal cancer. Current state of the method. Technological advances and perspectives. AB - Endoscopic ultrasound is the most accurate type of examination for the assessment of rectal tumors. Over the years, the method has advanced from gray-scale examination to intravenous contrast media administration and to different types of elastography. The multimodal approach of tumors (transrectal, transvaginal) is adapted to each case. 3D ultrasound is useful for spatial representation and precise measurement of tumor formations, using CT/MR image reconstruction; color elastography is useful for tumor characterization and staging; endoscopic ultrasound using intravenous contrast agents can help study the amount of contrast agent targeted at the level of the tumor formations and contrast wash in/wash-out time, based on the curves displayed on the device. The transvaginal approach often allows better visualization of the tumor than the transrectal approach. Performing the procedure with the rectal ampulla distended with contrast agent may be seen as an optimization of the examination methodology. All these aspects are additional methods for gray-scale endoscopic ultrasound, capable of increasing diagnostic accuracy. This paper aims at reviewing the progress of transrectal and transvaginal ultrasound, generically called endoscopic ultrasound, for rectal tumor diagnosis and staging, with emphasis on the current state of the method and its development trends. PMID- 26052576 TI - The use of modern ultrasound tridimensional techniques for the evaluation of fetal cerebral midline structures- a practical approach. AB - Fetal central nervous system midline structures represent an essential landmark for the confirmation of normality or for the identification of severe pathology. The ultrasound examination of the fetal brain using modern 3D techniques allows the creation of high sensitivity reconstructions. The facility of 3D volume acquisition permits the identification of corpus callosum, median septum, cavum septi pellucid and cerebellar vermis even in difficult cases. The examination should rely on both static (3D) and dynamic acquisition (4D). The use of a practical ultrasound protocol in clinical settings ensures the visualization of the midline cerebral structures in the vast majorities of fetuses. In selected cases MRI can be performed. PMID- 26052577 TI - Characterization and staging of rectal tumors: endoscopic ultrasound versus MRI / CT. Pictorial essay. AB - Endoscopic ultrasound is recommended for rectal cancer staging. Transrectal ultrasound approach is able to overcome one of the limitations of this technique regarding circumferential rectal stenosis. Prior intrarectal administration of a small amount of fluid contrast agent optimizes the method, making it easier to distinguish the layers of the rectal wall and tumor formation. Endoscopic ultrasound focuses on the gray-scale mode. Additional procedures provide useful information for tumor assessment: Doppler ultrasound helps identify chaotic intratumoral vascularization; 3D ultrasound allows the assessment and accurate measurement of the tumor; elastography can identify focal tumor dysplasia within adenomas; contrast-enhanced ultrasound allows characterization of tumor microvasculature. Even if they are not as accurate in distinguishing rectal wall layers, cross-sectional imaging techniques (CT, MRI) can identify the anatomical relationships of advanced locoregional cancers, as well as possible distant metastasis. This paper aims at illustrating the main pathological aspects of endoscopic ultrasound multimodal examination useful for cancer staging. PMID- 26052578 TI - Ectopic cervical thymus as a rare cause of pediatric neck mass: the role of ultrasound and MRI in the diagnosis. Case report. AB - Ectopic cervical thymus (ECT) is an uncommon cause for cervical mass in the pediatric age group. Ultrasound and magnetic resonance imaging findings of the mass (located along the thymic descent pathway along the thymopharyngeal tract and has identical echostructure and signal intensities to the native thymus in the superior mediastinum) would lead to the diagnosis. The diagnosis is confirmed by fine needle aspiration biopsy or histopathology after resection. The management of ECT is a conservative follow up, except in symptomatic cases with tracheal compression and histologically confirmed neoplasia where surgery is indicated. We present the case of ECT presenting as a left upper neck mass in a 12 year old girl. PMID- 26052579 TI - Plastic reconstruction of fetal anatomy using three-dimensional ultrasound and magnetic resonance imaging scan data in a giant cervical teratoma. Case report. AB - Cervical teratoma is a rare congenital tumor that tends to be large and is usually solid/cystic. Estimation of the degree of tracheal compression or distortion allows multidisciplinary planning for delivery and neonatal resuscitation. We present a case of prenatal diagnosis of cervical teratoma at 29 weeks of gestation. The use of a physical model from 3D ultrasound and magnetic resonance imaging improved the understanding of spatial relationships of fetal anomaly and the adjacent structures, permitting better parent counselling. This technology can be used for educational purposes and as a method for parents to visualize their unborn baby. PMID- 26052580 TI - Pitfall in Echocardiography: infective endocarditis or valvular strand? Case report. AB - Lambl's excrescences are thin filiform mobile processes with thin attachment at valvular closure lines. In this case report we describe the transesophageal views of Lambl's excrescences; our case is meant to serve as a classic example of this commonly misinterpreted lesion. PMID- 26052581 TI - Ultrasound-guided drainage of walled-off pancreatic necrosis. Case report. AB - ERCP (endoscopic retrograde cholangiopancreatography) represents a safe endoscopic procedure and serious complications (perforation, haemorrhage, and acute pancreatitis) are usually uncommon. We present the case of a 38-year-old patient with gallstones in the common biliary duct who developed acute pancreatitis after ERCP. One month later a huge fluid collection with necrotic tissue in the right paracolic gutter was found, the fluid being drained by percutaneous drainage under ultrasonographic guiding. The particularity of the case is the post-ERCP pancreatitis, complicated with walled-off necrosis, resolved without surgical intervention by using percutaneous drainage. PMID- 26052582 TI - Clinical utility of echocardiography and magnetic resonance imaging for detecting cardiac complications in systemic sclerosis. A case report. AB - Systemic sclerosis (SSc) is a chronic autoimmune disease that beside the skin involvement it may affect the peripheral vessels and several organs, such as the lungs, the kidneys or the heart. Cardiac impairment usually becomes symptomatic in the late stages of the disease and is associated with poor prognosis. We report the case of a 80-year-old woman patient presenting symptoms of heart failure, subsequently diagnosed with limited SSc. The cardiac function was evaluated using a combined approach based on echocardiography, cardiac magnetic resonance imaging with late gadolinium enhancement. This case shows the fatal consequences of the late diagnosis of SSc. PMID- 26052583 TI - Trachea transplantation: from laboratory to patient. AB - Today, tracheal lesions occupying<30%of the trachea in children and<50%in adults can be treated with primary resection, followed by end-to-end anastomosis. However, lesions larger than this require a tracheal replacement, of which there are currently few options available. The recent advancement of tissue-engineering principles in tracheal research is quickly opening up new vistas for airway reconstruction and creating a very promising future for medical science. This review discusses the main criteria required for the development of a tissue engineered tracheal replacement. The criteria include: (a) appropriate cell types and sources; (b) biomolecules to direct the differentiation of the cells to the desired lineage; (c) a suitable scaffold for a cellular matrix; and (d) a bioreactor to facilitate cell attachment and proliferation and construct transport to theatre. Our group has designed and developed the world's first synthetic tracheal replacement, using a novel nanocomposite material, also developed in our laboratory. It was implanted clinically in June 2011 with a successful outcome. The application of tissue-engineering approaches to tracheal replacement development is the first step towards the much-anticipated 'off-the shelf' tissue-engineered technology, contributing extensively to the advancement in treatment and rehabilitation of patients afflicted with tracheal pathology. PMID- 26052584 TI - Lung-cancer immunotherapeutics on the horizon as Opdivo advances through Phase 2. PMID- 26052586 TI - Celldex hopeful about new immunotherapeutic against brain tumors. PMID- 26052585 TI - Clinical trials for Ebola vaccines staged in Africa, North America and Europe. PMID- 26052587 TI - Novel vaccine-adjuvant combination successful against bacterial diarrhea. PMID- 26052588 TI - In situ vaccination combined with radiotherapy promising for low-grade lymphoma. PMID- 26052589 TI - First ever Hepatitis C vaccine successfully finishes Phase 1 trial. PMID- 26052590 TI - Fast track designation for Novavax may bring H7N9 vaccine closer. PMID- 26052591 TI - Response. PMID- 26052592 TI - New NCCN Member Institution: Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute. PMID- 26052593 TI - NCCN publishes new guidelines for smoking cessation. PMID- 26052594 TI - 20 years of improving cancer care together - An NCCN roundtable discussion. PMID- 26052596 TI - Abstracts of the 12th Congress of the European Society of Contact Dermatitis (ESCD), 25-28 June, 2014, Barcelona, Spain. PMID- 26052595 TI - Molecular biomarkers in gastric cancer. AB - Gastric cancer (GC) represents a serious health problem on a global scale. Despite some recent advances in the field, the prognosis in metastatic GC remains poor. Even in localized disease the adjunctive therapies improve overall survival (OS) by only approximately 10%. A better understanding of molecular biology, which would lead to improved treatment options, is needed and is the basis for this review. Many potential biomarkers of prognostic significance have been identified, including ALDH, SHH, Sox9, HER2, EGFR, VEGF, Hippo/YAP, and MET. However, inhibition of only HER2 protein has led to a modest survival benefit. A new approach to GC treatment, which is a disease influenced by inflammation, is the exploitation of the immune system to fight disease. Two interesting targets/prognostic markers that bear further investigation in GC are PD1 and PDL, particularly given their success in the treatment of other inflammation/immune associated malignancies. PMID- 26052597 TI - The EHR in the room. PMID- 26052598 TI - Use of ciprofloxacin during breastfeeding. AB - QUESTION: My patient has a urinary tract infection and is currently breastfeeding her 9-week-old son. I would like to prescribe her ciprofloxacin. Should I be concerned about osteoarticular toxicity in the infant? ANSWER: Although there are concerns about the possible risk of osteoarticular toxicity with ciprofloxacin, the amounts excreted into breast milk are low and studies report no substantial increase in osteoarticular toxicity even with the systemic use of ciprofloxacin in neonates and children. Therefore, interrupting breastfeeding during ciprofloxacin treatment appears unnecessary. PMID- 26052599 TI - Home visits in family medicine residency: evaluation of 8 years of a training program. AB - PROBLEM ADDRESSED: There has been a decline in family physicians providing home visits to housebound patients. OBJECTIVE OF PROGRAM: To increase family medicine residents' exposure to home visits; their comfort and skills in providing home visits; and their willingness to provide home visits after graduation. PROGRAM DESCRIPTION: Between 2000 and 2010, each family practice resident at St Joseph's Health Centre Family Medicine Teaching Unit in Toronto, Ont, was assigned at least 1 housebound patient to care for longitudinally over 2 years; the rationale for this was to increase the sense of "ownership" and responsibility among residents for their assigned homebound patients. Starting in 2003, until the program's conclusion in 2010, residents were asked to fill out surveys before and after the program to assess their comfort with and confidence in providing home visits, as well as their satisfaction with the program. Survey responses were analyzed for changes over the course of residency training. A total of 85 residents completed the home visit teaching program between 2003 and 2010 inclusive. CONCLUSION: While residents' willingness to provide home visits did not increase over the course of residency, their confidence in making housecalls did increase. There was also a trend toward increased confidence among residents in working with community agencies. Thus, having home visit patients be a part of resident practices might play an important role in increasing the likelihood that future family physicians will continue to care for their patients when those patients are no longer ambulatory. PMID- 26052600 TI - Health care professionals' comprehension of the legal status of end-of-life practices in Quebec: study of clinical scenarios. AB - OBJECTIVE: To determine health care professionals' understanding of the current legal status of different end-of-life practices and their future legal status if medical aid in dying were legalized, and to identify factors associated with misunderstanding surrounding the current legal status. DESIGN: Cross-sectional survey using 6 clinical scenarios developed from a validated European questionnaire and from a validated classification of end-of-life practices. SETTING: Quebec. PARTICIPANTS: Health care professionals (physicians and nurses). MAIN OUTCOME MEASURES: Perceptions of the current legal status of the given scenarios and whether or not the practices would be authorized in the event that medical aid in dying were legalized. RESULTS: Among the respondents (n = 271, response rate 88.0%), more than 98% knew that the administration or prescription of lethal medication was currently illegal. However, 45.8% wrongly thought that it was not permitted to withdraw a potentially life-prolonging treatment at the patient's request, and this misconception was more common among nurses and professionals who had received their diplomas longer ago. Only 39.5% believed that, in the event that medical aid in dying were legalized, the use of lethal medication would be permitted at the patient's request, and 34.6% believed they would be able to give such medication to an incompetent patient upon a relative's request. CONCLUSION: Health care professionals knew which medical practices were illegal, but some wrongly believed that current permitted practices were not legal. There were various interpretations of what would or would not be allowed if medical aid in dying were legalized. Education on the clinical implications of end-of-life practice legislation should be promoted. PMID- 26052602 TI - The future potential of regenerative medicine for neural therapy and repair: introduction to the ASNTR special issue from the 2014 meeting. PMID- 26052601 TI - Giving curriculum planners an edge: using entrance surveys to design family medicine education. AB - OBJECTIVE: To pilot a survey of family medicine residents entering residency, describing their exposure to family medicine and their perspectives related to their future intentions to practise family medicine, in order to inform curriculum planners; and to test the methodology, feasibility, and utility of delivering a longitudinal survey to multiple residency programs. DESIGN: Pilot study using surveys. SETTING: Five Canadian residency programs. PARTICIPANTS: A total of 454 first-year family medicine residents were surveyed. MAIN OUTCOME MEASURES: Residents' previous exposure to family medicine, perspectives on family medicine, and future practice intentions. RESULTS: Overall, 70% of first-year residents surveyed responded (n = 317). Although only 5 residency programs participated, respondents included graduates from each of the medical schools in Canada, as well as international medical graduates. Among respondents, 92% felt positive or strongly positive about their choice to be family physicians. Most (73%) indicated they had strong or very strong exposure to family medicine in medical school, yet more than 40% had no or minimal exposure to key clinical domains of family medicine like palliative care, home care, and care of underserved groups. Similar responses were found about residents' lack of intention to practise in these domains. CONCLUSION: Exposure to clinical domains in family medicine could influence future practice intentions. Surveys at entrance to residency can help medical school and family medicine residency planners consider important learning experiences to include in training. PMID- 26052603 TI - Abstracts of the 2014 World Transplant Congress, July 28-31, San Francisco, CA. PMID- 26052604 TI - CardioPulse: pharmadisclosure: much activity, but little progress,with the European Society of Cardiology ahead of many. PMID- 26052605 TI - CardioPulse: cardiac imaging of adult cancer patients on chemotherapy. PMID- 26052606 TI - CardioPulse: drinking moderate amounts of alcohol is linked to reduced risk of heart failure. PMID- 26052607 TI - CardioPulse: the dilemmas in diagnosing left ventricular non-compaction in athletes. PMID- 26052608 TI - Beyond Ebola: worldly viruses close to home. In an era of easy travel, exotic illnesses can end up on your doorstep. PMID- 26052609 TI - Clinical and ultrasonic markers of postoperative complications of carotid endarterectomy in patients with cerebrovascular insufficiency. PMID- 26052610 TI - [Obituary]. PMID- 26052611 TI - Real-Time High-Resolution Tandem Mass Spectrometry Identifies Furan Derivatives in Exhaled Breath. AB - The identification of chemical compounds in exhaled human breath is promising in the search for new biomakers of diseases. However, the analytical techniques used nowadays are not capable of achieving a robust identification, especially in real time analysis. In this work, we show that real-time high-resolution tandem mass spectrometry (HRMS/MS) is suitable for the identification of biomarkers in exhaled breath. Using this approach, we identified a number of furan derivatives, compounds found in the exhalome whose nature and origin are not yet clearly understood. It is also shown that the combination of HRMS/MS with UHPLC allowed not only the identification of the furan derivatives but also the proper separation of their isomeric forms. PMID- 26052612 TI - Safety profile of a liquid formulation of deferiprone in young children with transfusion-induced iron overload: a 1-year experience. AB - BACKGROUND: Data on the use of deferiprone in young children with iron overload are limited. OBJECTIVE: To study the safety profile of a liquid formulation of deferiprone in chelating young children with transfusion-induced iron overload. PATIENTS AND METHODS: A daily dose of 50-100 mg/kg BW in three divided doses of oral deferiprone was given to young patients who had received at least ten packed red cell transfusions and achieved a serum ferritin level >1000 MUg/L during a 12 month period from 2011 to 2012. RESULTS: Nine children (four males) diagnosed with various types of thalassaemia (n = 8) and hereditary spherocytosis (n = 1) were enrolled. Their mean (SD) age was 4.5 (1.9) years. The patients received 15 20 ml/kg BW of packed red cell transfusions every 4-8 weeks from a mean (SD) age of 2.1 (1.7) years to maintain a pre-transfusion haematocrit at 27%. A mean (SD) total of packed red cells of 5132 (2725) ml were given within a mean (SD) duration of 2.4 (1.1) years before the study. During the 1-year study period, they received a mean (SD) total of packed red cells of 2194 (680) ml or 138 (50) ml/kg BW with a mean (SD) daily iron load of 0.29 (0.12) mg/kg BW. The pre treatment geometric mean of serum ferritin of 1863.8 MUg/L decreased to 1279.7 MUg/L after 1 year of treatment (P = 0.05). All patients tolerated the liquid formulation well and did not experience any gastro-intestinal discomfort, nausea or vomiting. CONCLUSION: The liquid formulation of deferiprone is safe in young children with transfusion-induced iron overload. PMID- 26052613 TI - A New Class of Nitroanilinic Dimer, the PNA O-Dimer: Electronic Structure and Emission Characteristics of O-Dimeric Aggregates. AB - p-Nitroaniline (PNA) has been reported as a "J" aggregate species. In retrospect, this communication confirms a radically different "oblique" orientation of the PNA units in all three solid, liquid, and gas phases of the dimer, the O-dimer. The nonvanishing transition dipole moments (TDM) associated with the allowed electronic excitations of the O-dimer, computed using electron-hole pair density distribution (EDD and HDD) analyses ascertained the two monomers to be inclined at slippage (theta) and polarization (alpha) angles of 18.5 degrees and 55.4 degrees , respectively. A detailed structure-property relationship of the PNA O dimeric aggregate was carried out using UV-vis absorption and matrix scan emission spectroscopy, supported by electronic structure calculations at DFT M062X/6-31G+(d,p) level using integral equation formalism polarizable continuum model (IEFPCM). The computed potential energy surface (PES) implied the global minimum of the PNA O-dimer stabilized by 4.8 kcal.mol(-1), owing to bifurcated intermolecular hydrogen bonding. In the excited PNA O-dimeric aggregate, an exchange of excitation energy between the monomeric units resulted in two distinct electronic states separated by an interaction energy of -1644 cm(-1). The TD-DFT computed excited state equilibrium structures of the PNA O-dimer corroborated the experimentally observed pronounced Stoke's shift to internal conversion following vibrational relaxation of the allowed electronic excited states. On the basis of the detailed structural analysis of PNA O-dimer, the observed energy shifts in optical absorption spectroscopy were evident within the framework of exciton coupling model. PMID- 26052614 TI - miR-22 and miR-29a Are Members of the Androgen Receptor Cistrome Modulating LAMC1 and Mcl-1 in Prostate Cancer. AB - The normal prostate as well as early stages and advanced prostate cancer (PCa) require a functional androgen receptor (AR) for growth and survival. The recent discovery of microRNAs (miRNAs) as novel effector molecules of AR disclosed the existence of an intricate network between AR, miRNAs and downstream target genes. In this study DUCaP cells, characterized by high content of wild-type AR and robust AR transcriptional activity, were chosen as the main experimental model. By integrative analysis of chromatin immunoprecipitation-sequencing (ChIP-seq) and microarray expression profiling data, miRNAs putatively bound and significantly regulated by AR were identified. A direct AR regulation of miR-22, miR-29a, and miR-17-92 cluster along with their host genes was confirmed. Interestingly, endogenous levels of miR-22 and miR-29a were found to be reduced in PCa cells expressing AR. In primary tumor samples, miR-22 and miR-29a were less abundant in the cancerous tissue compared with the benign counterpart. This specific expression pattern was associated with a differential DNA methylation of the genomic AR binding sites. The identification of laminin gamma 1 (LAMC1) and myeloid cell leukemia 1 (MCL1) as direct targets of miR-22 and miR-29a, respectively, suggested a tumor-suppressive role of these miRNAs. Indeed, transfection of miRNA mimics in PCa cells induced apoptosis and diminished cell migration and viability. Collectively, these data provide additional information regarding the complex regulatory machinery that guides miRNAs activity in PCa, highlighting an important contribution of miRNAs in the AR signaling. PMID- 26052616 TI - Correction to Nickerson et al. (2014). PMID- 26052615 TI - Adiponectin-SOGA Dissociation in Type 1 Diabetes. AB - CONTEXT: Circulating adiponectin is elevated in human type 1 diabetes (T1D) and nonobese diabetic (NOD) mice without the expected indications of adiponectin action, consistent with tissue resistance. OBJECTIVE: Adiponectin stimulates hepatocyte production of the suppressor of glucose from autophagy (SOGA), a protein that inhibits glucose production. We postulated that due to tissue resistance, the elevation of adiponectin in T1D should fail to increase the levels of a surrogate marker for liver SOGA, the circulating C-terminal SOGA fragment. MAIN OUTCOME MEASURES: Liver and plasma SOGA were measured in NOD mice (n = 12) by Western blot. Serum adiponectin and SOGA were measured in T1D and control (Ctrl) participants undergoing a three-stage insulin clamp for the Coronary Artery Calcification in T1D study (n = 20). Glucose turnover was measured using 6,6[(2)H2]glucose (n = 12). RESULTS: In diabetic NOD mice, the 13% 29% decrease of liver SOGA (P = .003) and the 30%-37% reduction of circulating SOGA (P < .001) were correlated (r = 0.826; P = .001). In T1D serum, adiponectin was 50%-60% higher than Ctrl, SOGA was 30%-50% lower and insulin was 3-fold higher (P < .05). At the low insulin infusion rate (4 mU/m(2).min), the resulting glucose appearance correlated negatively with adiponectin in T1D (r = -0.985, P = .002) and SOGA in Ctrl and T1D (r = -0.837, P = .001). Glucose disappearance correlated with adiponectin in Ctrl (r = -0.757, P = .049) and SOGA in Ctrl and T1D (r = -0.709, P = .010). At 40 mU/m(2).min, the lowered glucose appearance was similar in Ctrl and T1D. Glucose disappearance increased only in Ctrl (P = .005), requiring greater glucose infusion to maintain euglycemia (8.58 +/- 1.29 vs 3.09 +/- 0.87 mg/kg.min; P = .009). CONCLUSIONS: The correlation between liver and plasma SOGA in NOD mice supports the use of the latter as surrogate marker for liver concentration. Reduced SOGA in diabetic NOD mice suggests resistance to adiponectin. The dissociation between adiponectin and SOGA in T1D raises the possibility that restoring adiponectin signaling and SOGA might improve the metabolic response to insulin therapy. PMID- 26052618 TI - The latent structure of personality functioning: Investigating criterion a from the alternative model for personality disorders in DSM-5. AB - The alternative model for the classification of personality disorders (PD) in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) Section III comprises 2 major components: impairments in personality functioning (Criterion A) and maladaptive personality traits (Criterion B). In this study, we investigated the latent structure of Criterion A (a) within subdomains, (b) across subdomains, and (c) in conjunction with the Criterion B trait facets. Data were gathered as part of an online study that collected other-ratings by 515 laypersons and 145 therapists. Laypersons were asked to assess 1 of their personal acquaintances, whereas therapists were asked to assess 1 of their patients, using 135 items that captured features of Criteria A and B. We were able to show that (a) the structure within the Criterion A subdomains can be appropriately modeled using generalized graded unfolding models, with results suggesting that the items are indeed related to common underlying constructs but often deviate from their theoretically expected severity level; (b) the structure across subdomains is broadly in line with a model comprising 2 strongly correlated factors of self- and interpersonal functioning, with some notable deviations from the theoretical model; and (c) the joint structure of the Criterion A subdomains and the Criterion B facets broadly resembles the expected model of 2 plus 5 factors, albeit the loading pattern suggests that the distinction between Criteria A and B is somewhat blurry. Our findings provide support for several major assumptions of the alternative DSM-5 model for PD but also highlight aspects of the model that need to be further refined. PMID- 26052617 TI - Nondaily smokers' experience of craving on days they do not smoke. AB - Nondaily, or intermittent smokers (ITS), represent a growing pattern in adult smoking that needs to be explained by models of drug dependence. ITS regularly and voluntarily abstain from smoking, yet have difficulty quitting. We examine potential accounts of ITS' smoking by exploring their experience of craving and withdrawal on the days they abstain. For 3 weeks, 146 ITS and 194 daily smokers used the Ecological Momentary Assessment (EMA) to monitor craving, withdrawal, and smoking in real-time. ITS' craving (p < .001) and arousal (p < .001) were significantly lower on the 34.4% of days when they abstained (compared with days they smoked), and they experienced no increases in withdrawal symptoms. ITS who abstained for longer experienced lower craving, even on their first day of abstinence (p < .001). Within strata defined by longest duration of abstinence (1, 2-3, 4-6, >=7 days), craving did not change over time, demonstrating no increase as resumption of smoking approached. Craving increased only at the moment smoking resumed. Furthermore, duration of abstinence runs varied more within persons than across persons. These findings contradict the predictions of a model positing that craving recurs at fixed intervals. Findings are consistent with the hypothesis that ITS' smoking is cued or primed by particular stimuli rather than by temporal cycles. These analyses demonstrate that ITS do not experience increased craving or withdrawal on days they do not smoke, and show neither signs of classical dependence nor regular cycles of craving and smoking. PMID- 26052619 TI - A person-centered approach to examining heterogeneity and subgroups among survivors of sexual assault. AB - This study identified subgroups of female sexual assault survivors based on characteristics of their victimization experiences, validated the subgroup structure in a second cohort of women recruited identically to the first, and examined subgroups' differential associations with sexual risk/safety behavior, heavy episodic drinking (HED), psychological distress symptomatology, incarceration, transactional sex, and experiences with controlling and violent partners. The community sample consisted of 667 female survivors of adolescent or adult sexual assault who were 21 to 30 years old (M = 24.78, SD = 2.66). Eligibility criteria included having unprotected sex within the past year, other HIV/STI risk factors, and some experience with HED, but without alcohol problems or dependence. Latent class analyses (LCA) were used to identify subgroups of women with similar victimization experiences. Three groups were identified and validated across 2 cohorts of women using multiple-group LCA: contact or attempted assault (17% of the sample), incapacitated assault (52%), and forceful severe assault (31%). Groups did not differ in their sexual risk/safety behavior. Women in the forceful severe category had higher levels of anxiety, depression, and trauma symptoms; higher proportions of incarceration and transactional sex; and more experiences with controlling and violent partners than did women in the other 2 groups. Women in the forceful severe category also reported a higher frequency of HED than women in the incapacitated category. Different types of assault experiences appear to be differentially associated with negative outcomes. Understanding heterogeneity and subgroups among sexual assault survivors has implications for improving clinical care and contributing to recovery. PMID- 26052620 TI - Limitations of a morphological criterion of adaptive inference in the fossil record. AB - Experimental analyses directly inform how an anatomical feature or complex functions during an organism's lifetime, which serves to increase the efficacy of comparative studies of living and fossil taxa. In the mammalian skull, food material properties and feeding behaviour have a pronounced influence on the development of the masticatory apparatus. Diet-related variation in loading magnitude and frequency induce a cascade of changes at the gross, tissue, cellular, protein and genetic levels, with such modelling and remodelling maintaining the integrity of oral structures vis-a-vis routine masticatory stresses. Ongoing integrative research using rabbit and rat models of long-term masticatory plasticity offers unique insight into the limitations of functional interpretations of fossilised remains. Given the general restriction of the palaeontological record to bony elements, we argue that failure to account for the disparity in the hierarchical network of responses of hard versus soft tissues may overestimate the magnitude of the adaptive divergence that is inferred from phenotypic differences. Second, we note that the developmental onset and duration of a loading stimulus associated with a given feeding behaviour can impart large effects on patterns of intraspecific variation that can mirror differences observed among taxa. Indeed, plasticity data are relevant to understanding evolutionary transformations because rabbits raised on different diets exhibit levels of morphological disparity comparable to those found between closely related primate species that vary in diet. Lastly, pronounced variation in joint form, and even joint function, can also characterise adult conspecifics that differ solely in age. In sum, our analyses emphasise the importance of a multi-site and hierarchical approach to understanding determinants of morphological variation, one which incorporates critical data on performance. PMID- 26052621 TI - Spinal intraosseous epidural arteriovenous fistula with perimedullary drainage obliterated with Onyx embolization: case report. AB - The authors report an extremely rare case of spinal intraosseous epidural arteriovenous fistula (AVF) with perimedullary vein reflux causing symptoms of myelopathy. The intraosseous fistula tracts were completely obliterated with Onyx embolic agent, resulting in a total resolution of symptoms. The unique features of this case include the rare location of the fistula in the vertebral body and the association of the fistula with a compressive fracture. Imaging studies confirmed these hemodynamic findings and provided clarity and direct evidence regarding the association of epidural AVF formation with the vertebral compressive fracture. The authors also propose a possible disease evolution based on the previously adduced reflux-impending mechanism. PMID- 26052622 TI - Benefit of Retraining pKa Models Studied Using Internally Measured Data. AB - The ionization state of drugs influences many pharmaceutical properties such as their solubility, permeability, and biological activity. It is therefore important to understand the structure property relationship for the acid-base dissociation constant pKa during the lead optimization process to make better informed design decisions. Computational approaches, such as implemented in MoKa, can help with this; however, they often predict with too large error especially for proprietary compounds. In this contribution, we look at how retraining helps to greatly improve prediction error. Using a longitudinal study with data measured over 15 years in a drug discovery environment, we assess the impact of model training on prediction accuracy and look at model degradation over time. Using the MoKa software, we will demonstrate that regular retraining is required to address changes in chemical space leading to model degradation over six to nine months. PMID- 26052623 TI - Isolation of major phenolics from Launaea spinosa and their protective effect on HepG2 cells damaged with t-BHP. AB - CONTEXT: Some Launaea species (Asteraceae) are used traditionally to treat liver oxidative stress. OBJECTIVE: The present study investigates the protective effects of isolated compounds from Launaea spinosa Sch. Bip. (Asteraceae) against oxidative stress on t-BHP-induced HepG2 cells. MATERIALS AND METHODS: Major phenolic content from flowering aerial parts of L. spinosa was isolated and identified. The protective effects of isolated compounds (10 and 20 MUM) against oxidative stress induced by tert-butyl hydroperoxide (t-BHP) in HepG2 cells were investigated through the measurement of aspartate aminotransferase (AST), alanine transaminase (ALT), and superoxide dismutase (SOD) levels. RESULTS: A new phenolic compound identified as 2,3-diferulyl R,R-(+) methyl tartrate (6), in addition to five known metabolites, esculetin (1), esculetin-7-O-d-glucoside (cichoriin) (2), fertaric acid (3), acacetin-7-O-d-glucoside (4), and acacetin-7 O-d-glucuronic acid (5), were isolated. Oxidant-induced damage by 200 MUM t-BHP in HepG2 cells was inhibited by compounds 1, 4, and 5 (10 and 20 MUM), or quercetin (10 MUM; positive control). The protective effects of compounds 1, 4, and 5 were associated with decreasing in AST, ALT, and SOD levels. Compound 4 (20 MUM) decreased the AST level from 128.5 +/- 13.9 to 7.9 +/-1.8 U/mL. Meanwhile, compound 1 (20 MUM) decreased ALT activity from 20.3 +/- 7.0 to 7.6 +/- 2.4 U/mL, while compound 5 decreased SOD levels from 41.6 +/- 9.0 to 28.3 +/- 3.4 mU/mg. CONCLUSION: The major phenolic compounds isolated from L. spinosa displayed a significant cytoprotective effect against oxidative stress, leading to maintenance of the normal redox status of the cell. PMID- 26052624 TI - Long-term outcomes of transplant recipients referred for angiography for suspected transplant renal artery stenosis. AB - Our aim was to study the long-term outcomes of all transplant recipients who underwent angiography for suspected TRAS at our institution. The patients were divided into TRAS+ve and TRAS-ve groups based upon angiographically confirmed results. TRAS was confirmed in 58.1% of 74 patients with median time of 8.9 months. Primary angioplasty alone was performed in 56% of patients with TRAS, while the remaining had PTA with stent (PTAS). There was reduction in systolic and diastolic BP (165 +/- 19-136 +/- 15 mmHg and 82 +/- 14 mmHg to 68 +/- 12 mmHg; p < 0.05) and number of antihypertensive drugs (3.5 +/- 0.9-2.7 +/- 1.0; p < 0.05). Overall, graft survival and patient survival from time of transplant were similar in both groups. Graft function was similar for the patients with treated TRAS+ve as compared to TRAS-ve over time. Graft survival and patient survival when compared to an age- and year of transplant-matched cohort control group were also similar. In conclusion, angiography for suspected TRAS is more likely to yield a confirmatory result early in the transplant course as compared to late. Treatment of TRAS in these patients had sustained long-term graft function. Alternative etiologies of HTN and graft dysfunction should be sought for recipients further out from transplant. PMID- 26052625 TI - Biomimetic Catalytic and Sensing Cascades Built with Two Designer Bolaamphiphilic Self-Assemblies. AB - A system performing both a catalytic hydrolysis reaction and the direct optical monitoring of the product was created by the combination of two bolaamphiphile self-assemblies. Two bolaamphiphilic self-assemblies were applied as a biomimetic catalyst of p-nitrophenyl acetate (p-NPA) hydrolysis and an optical sensor probe that detects p-NPA hydrolysis through photoluminescence quenching by p nitrophenol (p-NP), the product of p-NPA hydrolysis. One bolaamphiphilic self assembly with a histidine moiety catalytically hydrolyzed the p-NPA substrate, and the other self-assembly of tyrosyl bolaamphiphile monitored the product of p NP by photoluminescence quenching. The progression of the reaction and quenching degree were adjusted by controlling the quantity of histidyl and tyrosyl self assemblies, respectively. The reaction and subsequent sensing cascade could be interrupted by a reducing agent. The addition of NaBH4 induced the chemical conversion of p-NP to p-aminophenol, which retarded photoluminescence quenching. Thus, it was demonstrated that hydrolysis of an organic substrate and subsequent monitoring of the hydrolysis reaction could be achieved through a combination of independent bolaamphiphilic self-assemblies. This study demonstrated the construction of a catalytic reaction and detection system incorporating designer biomimetic self-assemblies whose functionalities were devised to realize deliberate functions. PMID- 26052626 TI - Signs and Symptoms of Myofascial Pain: An International Survey of Pain Management Providers and Proposed Preliminary Set of Diagnostic Criteria. AB - OBJECTIVE: Myofascial Pain Syndrome (MPS) is highly prevalent in pain medicine, yet there is no "gold standard" or set of validated diagnostic criteria for clinical or research use. A survey collected clinician perspectives on MPS to foster the development of a formal case definition for empirical validation. DESIGN: International survey. METHODS: Clinician members of the International Association for the Study of Pain and the American Academy of Pain Medicine received a survey of the symptoms and signs of MPS and expected response to treatment. Write-in fields were available for each category and to suggest relevant diagnostic studies. RESULTS: Two hundred fourteen responses were received from 4,143 surveys mailed. The most essential components of MPS were tender spots that recreate symptoms when palpated. MPS was also associated with muscle stiffness, decreased range of motion of the affected joints, worsening symptoms with stress, palpable taut band or tender nodule, and referred pain with palpation of the tender spot. Diagnostic studies are reported to be useful for ruling out other pathology, but not to confirm the presence of the condition. CONCLUSIONS: These results were used to propose a set of preliminary diagnostic criteria; expert consensus for case definition and subsequent empirical validation are required for standardization in research and clinical management of MPS. PMID- 26052627 TI - Letter to the Editor: Neoadjuvant chemotherapy to maximize glioblastoma resection in the elderly. PMID- 26052628 TI - Anal incontinence among first time mothers - what happens in pregnancy and the first year after delivery? AB - INTRODUCTION: Pregnancy- and delivery-related factors affect postpartum anal incontinence. We aimed to explore changes in continence status among primiparas from late pregnancy through the first year postpartum. MATERIAL AND METHODS: In this prospective cohort study set in two Norwegian hospitals, 862 healthy primiparas completed questionnaires about the main outcome measure anal incontinence, including flatus incontinence and urgency, at three time points; late pregnancy, 6 and 12 months postpartum. Socioeconomic and delivery-related data were obtained from hospital records. Logistic regression analyses were applied to determine the association between continence status at 12 months postpartum, and continence status in late pregnancy, 6 months postpartum, demographic and delivery-related characteristics. RESULTS: Among the 189 (22%) primiparas reporting anal incontinence in late pregnancy, 34 (18%) had persistent anal incontinence 1 year later. Forty-eight (43%) of the 113 women incontinent at 6 months postpartum experienced persistent anal incontinence at 12 months. Eight percent of previously continent women reported new onset anal incontinence at 6 and 12 months after delivery. Occipitoposterior presentation was the only delivery-related factor increasing the risk of postpartum anal incontinence [odds ratio (OR) 1.8, 95% confidence interval (CI) 1.0-3.4]. Young age increased the risk of anal incontinence at 1 year after delivery, whereas incontinence in late pregnancy increased the risk of anal incontinence persisting through 6 and 12 months postpartum. CONCLUSION: In most first-time mothers with postpartum anal incontinence, the onset of anal incontinence was before delivery. Except for occipitoposterior presentation, no delivery-related factors increased the risk of postpartum anal incontinence. This may indicate that hormonal, mechanical or neuromuscular changes in pregnancy affect long-term anal incontinence more than vaginal delivery. PMID- 26052629 TI - Dexamethasone therapy for preventing delayed encephalopathy after carbon monoxide poisoning. AB - We investigated dexamethasone therapy for preventing delayed encephalopathy after carbon monoxide (CO) poisoning. Eighty healthy male rats were exposed to CO and randomly divided into four groups: hyperbaric oxygen treatment (H), treatment (D), combined hyperbaric and dexamethasone treatment (C), and a control (M) group in which the rats inhaled CO to coma in the hyperbaric oxygen chamber, then were removed without further treatment. Twelve rats were put into the hyperbaric oxygen chamber and treated with air for 60 min (N) group. An eight arm maze was used to evaluate cognitive and memory abilities of these mice. Serum myelin basic protein (MBP) levels were evaluated using ELISA, and magnetic resonance imaging was used to observe brain demyelination and morbidity associated with delayed encephalopathy. A sample of the hippocampus from each group was examined by light microscopy. Cognitive and memory functions decreased in the control group M. Three days after CO poisoning, the serum MBP level of each group increased significantly. On Day 10 after CO poisoning, the MBP levels in groups C and D decreased significantly, but returned to normal on Day 18. MBP levels in the M and H groups were elevated at all time points. Brain MRIs showed significant differences among C, D, H and control M groups. Hematoxylin & eosin staining of the hippocampus showed greater damage in the control M and H groups. Early dexamethasone treatment may be useful for preventing delayed encephalopathy after CO poisoning and may reduce serum MBP levels. PMID- 26052630 TI - Does evidence really matter? An exploratory analysis of the role of evidence in plea bargaining in felony drug cases. AB - The majority of cases in the United States are disposed of through plea bargaining; however, this important discretionary point has received relatively little attention from researchers compared with trial and jury proceedings, and other discretionary points such as arrest and sentencing. Additionally, although evidence is considered an important factor in determining case outcomes, its influence on prosecutors' decisions regarding plea offers is less clear. In this study, we examined the potential impact of evidentiary factors, as well as other legal and extralegal factors, on two plea bargaining decisions, plea-to-a-lesser charge offers and sentence offers, using data on felony drug cases processed by the New York County District Attorney's office. We found that prosecutors made more punitive charge offers when they had audio/video evidence, eyewitness identification(s), prerecorded buy money used by an undercover officer in a buy and-bust operation, or had recovered currency. Of all evidence factors analyzed, only the recovery of currency predicted sentence offers. By contrast, three other factors-defendants' detention status, the presence of multiple plea offers, and prior prison sentence-had a much greater impact on charge and sentence offers. Although additional research is needed, it is possible that evidence has a greater impact at the initial stages of a case, particularly on the decision about whether to accept a case for prosecution, than it does on subsequent prosecutorial decisions. PMID- 26052631 TI - Charge transport through a semiconductor quantum dot-ring nanostructure. AB - Transport properties of a gated nanostructure depend crucially on the coupling of its states to the states of electrodes. In the case of a single quantum dot the coupling, for a given quantum state, is constant or can be slightly modified by additional gating. In this paper we consider a concentric dot-ring nanostructure (DRN) and show that its transport properties can be drastically modified due to the unique geometry. We calculate the dc current through a DRN in the Coulomb blockade regime and show that it can efficiently work as a single-electron transistor (SET) or a current rectifier. In both cases the transport characteristics strongly depend on the details of the confinement potential. The calculations are carried out for low and high bias regime, the latter being especially interesting in the context of current rectification due to fast relaxation processes. PMID- 26052632 TI - Modified SuperCurve Method for Analysis of Reverse-Phase Protein Array Data. AB - Reverse-phase protein arrays (RPPAs) are widely used in biological and biomedical fields of study. One of the most popular analytic methods in RPPA data analysis is the SuperCurve method, which requires estimation of the background fluorescence level. This estimation is usually not accurate and has sample bias and spatial bias. Here, we propose a taking-the-difference method to overcome this problem. Briefly, for each two consecutive RPPA cycles, we subtract the later cycle from the earlier cycle, transforming the m-cycle data into m-1 cycle of data. This removes most of the background fluorescence noise. We then use the m-1 cycle of data to fit a new model accordingly derived from the SuperCurve model. To evaluate our proposed method, we compare the accuracy and precision between our proposed model and the original SuperCurve model by testing them on both real and simulated datasets. For both situations, our modified model shows improved results. The modified SuperCurve method is easy to perform and the taking-the-difference idea is recommended for application to all current methods of RPPA data analysis. PMID- 26052633 TI - Ionoregulatory Aspects of the Osmorespiratory Compromise during Acute Environmental Hypoxia in 12 Tropical and Temperate Teleosts. AB - In the traditional osmorespiratory compromise, as seen in the hypoxia-intolerant freshwater rainbow trout (Oncorhynchus mykiss), the branchial modifications that occur to improve O2 uptake during hypoxia result in unfavorable increases in the fluxes of ions and water. However, at least one hypoxia-tolerant freshwater species, the Amazonian oscar (Astronotus ocellatus), shows exactly the opposite: decreased branchial flux rates of ions, water, and nitrogenous wastes during acute hypoxia. In order to find out whether the two strategies were widespread, we used a standard 2-h normoxia, 2-h hypoxia (20%-30% saturation), 2-h normoxic recovery protocol to survey 10 other phylogenetically diverse tropical and temperate species. Unidirectional influx and efflux rates of Na(+) and net flux rates of K(+), ammonia, and urea-N were measured. The flux reduction strategy was seen only in one additional species, the Amazonian tambaqui (Colossoma macropomum), which is similarly hypoxia tolerant and lives in the same ion-poor waters as the oscar. However, five other species exhibited evidence of the increased flux rates typical of the traditional osmorespiratory compromise in the trout: the rosaceu tetra (Hyphessobrycon bentosi rosaceus), the moenkhausia tetra (Moenkhausia diktyota), the bluegill sunfish (Lepomis macrochirus), the zebra fish (Danio rerio), and the goldfish (Carassius auratus). Four other species exhibited no marked flux changes during hypoxia: the cardinal tetra (Paracheirodon axelrodi), the hemigrammus tetra (Hemigrammus rhodostomus), the pumpkinseed sunfish (Lepomis gibbosus), and the Atlantic killifish (Fundulus heteroclitus). Overall, a diversity of strategies exist; we speculate that these may be linked to differences in habitat and/or lifestyle. PMID- 26052634 TI - Reduction of Energetic Demands through Modification of Body Size and Routine Metabolic Rates in Extremophile Fish. AB - Variation in energy availability or maintenance costs in extreme environments can exert selection for efficient energy use, and reductions in organismal energy demand can be achieved in two ways: reducing body mass or metabolic suppression. Whether long-term exposure to extreme environmental conditions drives adaptive shifts in body mass or metabolic rates remains an open question. We studied body size variation and variation in routine metabolic rates in locally adapted populations of extremophile fish (Poecilia mexicana) living in toxic, hydrogen sulfide-rich springs and caves. We quantified size distributions and routine metabolic rates in wild-caught individuals from four habitat types. Compared with ancestral populations in nonsulfidic surface habitats, extremophile populations were characterized by significant reductions in body size. Despite elevated metabolic rates in cave fish, the body size reduction precipitated in significantly reduced energy demands in all extremophile populations. Laboratory experiments on common garden-raised fish indicated that elevated routine metabolic rates in cave fish likely have a genetic basis. The results of this study indicate that adaptation to extreme environments directly impacts energy metabolism, with fish living in cave and sulfide spring environments expending less energy overall during routine metabolism. PMID- 26052635 TI - The Behavior-Physiology Nexus: Behavioral and Physiological Compensation Are Relied on to Different Extents between Seasons. AB - Environmental variability occurring at different timescales can significantly reduce performance, resulting in evolutionary fitness costs. Shifts in thermoregulatory behavior, metabolism, and water loss via phenotypic plasticity can compensate for thermal variation, but the relative contribution of each mechanism and how they may influence each other are largely unknown. Here, we take an ecologically relevant experimental approach to dissect these potential responses at two temporal scales: weather transients and seasons. Using acclimation to cold, average, or warm conditions in summer and winter, we measure the direction and magnitude of plasticity of resting metabolic rate (RMR), water loss rate (WLR), and preferred body temperature (Tpref) in the lizard Cordylus oelofseni within and between seasons. In summer, lizards selected lower Tpref when acclimated to warm versus cold but had no plasticity of either RMR or WLR. By contrast, winter lizards showed partial compensation of RMR but no behavioral compensation. Between seasons, both behavioral and physiological shifts took place. By integrating ecological reality into laboratory assays, we demonstrate that behavioral and physiological responses of C. oelofseni can be contrasting, depending on the timescale investigated. Incorporating ecologically relevant scenarios and the plasticity of multiple traits is thus essential when attempting to forecast extinction risk to climate change. PMID- 26052636 TI - Seasonal Patterns and Relationships among Coccidian Infestations, Measures of Oxidative Physiology, and Immune Function in Free-Living House Sparrows over an Annual Cycle. AB - Temporal variation in oxidative physiology and its associated immune function may occur as a result of changes in parasite infection over the year. Evidence from field and laboratory studies suggests links between infection risk, oxidative stress, and the ability of animals to mount an immune response; however, the importance of parasites in mediating seasonal change in physiological makeup is still debated. Also, little is known about the temporal consistency of relationships among parasite infestation, markers of oxidative status and immune function in wild animals, and whether variation in oxidative measures can be viewed as a single integrated system. To address these questions, we sampled free living house sparrows (Passer domesticus) every 2 mo over a complete year and measured infestation with coccidian parasites as well as nine traits that reflect condition, oxidative physiology, and immune function. We found significant seasonal variation in coccidian infestation and in seven out of nine condition and physiological variables over the year. However, we found little support for parasite-mediated change in condition, oxidative physiology, and immune functions in house sparrows. In accordance with this, we found no temporal consistency in relationships between the intensity of infestation and physiology. Among measures of oxidative physiology, antioxidants (measured as the total antioxidant capacity and the concentration of uric acid in the plasma) and oxidative damage (measured through the level of malondialdehyde in plasma) positively and consistently covaried over the year, while no such associations were found for the rest of traits (body mass, total glutathione, and leukocyte numbers). Our results show that natural levels of chronic coccidian infection have a limited effect on the seasonal change of physiological traits, suggesting that the variation of the latter is probably more affected by short-term disturbances, such as acute infection and/or season-specific stress stimuli. PMID- 26052637 TI - Energy Expenditure of Free-Ranging Chicks of the Cape Gannet Morus capensis. AB - The Cape gannet Morus capensis, a large fish-eating seabird, is endemic to southern Africa. To study the energetics of nestling growth, we used the doubly labeled water technique to measure field metabolic rate (FMR) of nestlings, from hatchings to large partly feathered chicks (n = 17) at Malgas Island, Saldanha Bay, South Africa. At the same time, the growth rate of a large sample of chicks was measured (n = 338). These data, together with literature values on resting metabolic rate and body composition, were used to construct and partition the nestling energy budget. Nestling FMR (kJ d(-1)) increased with body mass according to FMR = 1.23m(0.923), r(2) = 0.944. Mass-specific FMR (FMRratio; kJ d( 1) g(-3/4)) was independent of chick age (r(2) = 0.20, P > 0.05); mean mass specific FMR was 4.11 +/- 1.28, n = 17. Peak daily-metabolized energy (DME), which represents the maximum rate at which parents must supply their nestlings, occurred at age 71 d and was 2,141 kJ d(-1). Between the ages 51 and 92 d (43% of the fledging period), the DME of Cape gannet chicks was equal to or surpassed 90% of adult FMR at the nest. Energy demand during this period of peak DME represented 58% of the total metabolized energy, which was estimated at 150.1 MJ for an average chick during a 97-d period, from hatching to fledging. Sensitivity analysis of the energy budget indicated that the model was robust; the biggest source of error (+/-15%) was for the mass-FMR equation used in the model. PMID- 26052638 TI - Does Exurban Housing Development Affect the Physiological Condition of Forest Breeding Songbirds? A Case Study of Ovenbirds (Seiurus aurocapillus) in the Largest Protected Area in the Contiguous United States. AB - Exurban development (low-density development in rural areas) can significantly alter wildlife community composition, but it is largely unknown whether it also affects wildlife at the individual level. We investigated individual-level impacts of exurban development in New York State's Adirondack Park by comparing the physiological condition of 62 male ovenbirds (Seiurus aurocapillus) breeding in forests with low-density housing development with those in contiguous forests. We used hematocrit (HCT) volume and plasma triglyceride (TRIG) levels to compare energetic condition, plasma uric acid (UA) and total plasma protein (TPP) levels to compare diet quality, and heterophil?lymphocyte ratios (H?L) to compare chronic stress. HCT was the only parameter to differ, with birds near houses exhibiting lower values. The comparable TRIG, UA, and TPP that we found between treatment types suggest that ovenbird food quality and availability are unaffected by exurban development in our study area. Similar H?L suggests that homeowner activities do not significantly change chronic stressors faced by breeding male ovenbirds. We also found no difference in body mass, body size, or age ratio to indicate that habitats in either treatment type were in higher demand or more difficult to acquire. Although our results suggest that exurban development does not reduce habitat quality for male ovenbirds in a way that affects their condition, we caution that it may still ultimately reduce fitness by attracting synanthropic predators. Further work is needed to better understand the impacts of exurban development on wildlife at all levels and provide science based information needed to meet conservation challenges in rapidly developing exurban areas. PMID- 26052640 TI - The Acid Test: pH Tolerance of the Eggs and Larvae of the Invasive Cane Toad (Rhinella marina) in Southeastern Australia. AB - Invasive cane toads are colonizing southeastern Australia via a narrow coastal strip sandwiched between unsuitable areas (Pacific Ocean to the east, mountains to the west). Many of the available spawning sites exhibit abiotic conditions (e.g., temperature, salinity, and pH) more extreme than those encountered elsewhere in the toad's native or already invaded range. Will that challenge impede toad expansion? To answer that question, we measured pH in 35 ponds in northeastern New South Wales and 8 ponds in the Sydney region, in both areas where toads occur (and breed) and adjacent areas where toads are likely to invade, and conducted laboratory experiments to quantify effects of pH on the survival and development of toad eggs and larvae. Our field surveys revealed wide variation in pH (3.9-9.8) among natural water bodies. In the laboratory, the hatching success of eggs was increased at low pH (down to pH 4), whereas the survival, growth, and developmental rates of tadpoles were enhanced by higher pH levels. We found that pH influenced metamorph size and shape (relative head width, relative leg length) but not locomotor performance. The broad tolerance range of these early life-history stages suggests that pH conditions in ponds will not significantly slow the toad's expansion southward. Indeed, toads may benefit from transiently low pH conditions, and habitat where pH in wetlands is consistently low (such as coastal heath) may enhance rather than reduce toad reproductive success. A broad physiological tolerance during embryonic and larval life has contributed significantly to the cane toad's success as a widespread colonizer. PMID- 26052639 TI - Glycerophospholipid Profiles of Bats with White-Nose Syndrome. AB - Pseudogymnoascus destructans is an ascomycetous fungus responsible for the disease dubbed white-nose syndrome (WNS) and massive mortalities of cave-dwelling bats. The fungus infects bat epidermal tissue, causing damage to integumentary cells and pilosebaceous units. Differences in epidermal lipid composition caused by P. destructans infection could have drastic consequences for a variety of physiological functions, including innate immune efficiency and water retention. While bat surface lipid and stratum corneum lipid composition have been described, the differences in epidermal lipid content between healthy tissue and P. destructans-infected tissue have not been documented. In this study, we analyzed the effect of wing damage from P. destructans infection on the epidermal polar lipid composition (glycerophospholipids [GPs] and sphingomyelin) of little brown bats (Myotis lucifugus). We hypothesized that infection would lead to lower levels of total lipid or higher oxidized lipid product proportions. Polar lipids from three damaged and three healthy wing samples were profiled by electrospray ionization tandem mass spectrometry. We found lower total broad lipid levels in damaged tissue, specifically ether-linked phospholipids, lysophospholipids, phosphatidylcholine, and phosphatidylethanolamine. Thirteen individual GP species from four broad GP classes were present in higher amounts in healthy tissue. Six unsaturated GP species were absent in damaged tissue. Our results confirm that P. destructans infection leads to altered lipid profiles. Clinical signs of WNS may include lower lipid levels and lower proportions of unsaturated lipids due to cellular and glandular damage. PMID- 26052641 TI - High Concentrations of Ketocarotenoids in Hepatic Mitochondria of Haemorhous mexicanus. AB - Vertebrates cannot synthesize carotenoid pigments de novo, so to produce carotenoid-based coloration they must ingest carotenoids. Most songbirds that deposit red carotenoids in feathers, bills, eyes, or skin ingest only yellow or orange dietary pigments, which they oxidize to red pigments via a ketolation reaction. It has been hypothesized that carotenoid ketolation occurs in the liver of vertebrates, but this hypothesis remains to be confirmed. To better understand the role of hepatocytes in the production of ketolated carotenoids in songbirds, we measured the carotenoid content of subcellular components of hepatocytes from wild male house finches (Haemorhous mexicanus) that were molting red, ketocarotenoid-containing feathers (e.g., 3-hydroxy-echinenone). We homogenized freshly collected livers of house finches and isolated subcellular fractions, including mitochondria. We found the highest concentration of ketocarotenoids in the mitochondrial fraction. These observations are consistent with the hypothesis that carotenoid pigments are oxidized on or within hepatic mitochondria, esterified, and then transported to the Golgi apparatus for secretory processing. PMID- 26052642 TI - Superoxide Anion Radical Production in the Tardigrade Paramacrobiotus richtersi, the First Electron Paramagnetic Resonance Spin-Trapping Study. AB - Anhydrobiosis is an adaptive strategy that allows withstanding almost complete body water loss. It has been developed independently by many organisms belonging to different evolutionary lines, including tardigrades. The loss of water during anhydrobiotic processes leads to oxidative stress. To date, the metabolism of free radicals in tardigrades remained unclear. We present a method for in vivo monitoring of free radical production in tardigrades, based on electron paramagnetic resonance and spin-trap DEPMPO, which provides simultaneous identification of various spin adducts (i.e., different types of free radicals). The spin trap can be easily absorbed in animals, and tardigrades stay alive during the measurements and during 24-h monitoring after the treatment. The results show that hydrated specimens of the tardigrade Paramacrobiotus richtersi produce the pure superoxide anion radical ((*)O2(-)). This is an unexpected result, as all previously examined animals and plants produce both superoxide anion radical and hydroxyl radical ((*)OH) or exclusively hydroxyl radical. PMID- 26052643 TI - Significantly Enhanced Visible Light Photoelectrochemical Activity in TiO2 Nanowire Arrays by Nitrogen Implantation. AB - Titanium oxide (TiO2) represents one of most widely studied materials for photoelectrochemical (PEC) water splitting but is severely limited by its poor efficiency in the visible light range. Here, we report a significant enhancement of visible light photoactivity in nitrogen-implanted TiO2 (N-TiO2) nanowire arrays. Our systematic studies show that a post-implantation thermal annealing treatment can selectively enrich the substitutional nitrogen dopants, which is essential for activating the nitrogen implanted TiO2 to achieve greatly enhanced visible light photoactivity. An incident photon to electron conversion efficiency (IPCE) of ~10% is achieved at 450 nm in N-TiO2 without any other cocatalyst, far exceeding that in pristine TiO2 nanowires (~0.2%). The integration of oxygen evolution reaction (OER) cocatalyst with N-TiO2 can further increase the IPCE at 450 nm to ~17% and deliver an unprecedented overall photocurrent density of 1.9 mA/cm(2), by integrating the IPCE spectrum with standard AM 1.5G solar spectrum. Systematic photoelectrochemical and electrochemical studies demonstrated that the enhanced PEC performance can be attributed to the significantly improved visible light absorption and more efficient charge separation. Our studies demonstrate the implantation approach can be used to reliably dope TiO2 to achieve the best performed N-TiO2 photoelectrodes to date and may be extended to fundamentally modify other semiconductor materials for PEC water splitting. PMID- 26052644 TI - Elevate and Uterine Preservation: Two-Year Results. AB - OBJECTIVE: To evaluate efficacy of the Elevate Anterior and Apical (EAA) in the repair of pelvic organ prolapse (POP) when performed after previous hysterectomy and with or without uterine preservation during POP surgery. MATERIALS AND METHODS: One hundred forty-two women with anterior vaginal prolapse and/or apical descent >= stage II were enrolled. The primary outcome was treatment failure defined as > stage II POP-Q during follow-up using the Last observed Failure Carried Forward method. Three sub-groups were analysed: baseline previous hysterectomy (N = 61); concomitant hysterectomy (N = 29), and preserved uterus/no hysterectomy (N = 51). Demographics, primary and secondary outcomes, and extrusion were compared between the groups. A P value less than 0.05 was considered statistically significant. RESULTS: Anatomic success shows significant and durable improvement at 24 months. The success for the apical compartment ranged between 93.8% and 100%. Success was slightly lower for the anterior compartment (70.8-89.1%). No statistically significant difference between the 3 subgroups. Age was the only patient characteristic to be found different between the 3 subgroups. In addition, there was no difference in overall intraoperative complications (P = 0.263). Mesh extrusion was found in all groups: 3 of 61 (4.9%) had previous hysterectomy; 4 of 29 (13.8%) had concomitant hysterectomy; and 1 of 51 (2.0%) had uterus preserved (P = 0.094). There appears to be a trend toward higher extrusion when a hysterectomy was performed with the EAA. CONCLUSIONS: Anatomic success and complications for the EAA do not appear to be significantly impacted when the uterus is removed before or during surgery or preserved. There may be a trend toward increased mesh extrusion when a hysterectomy is performed. However, larger cohort studies are needed to determine if concomitant hysterectomy impact extrusion. PMID- 26052645 TI - Lower Urinary Tract and Functional Bowel Symptoms in Women With Vulvar Diseases and Controls. AB - OBJECTIVES: This study aims to compare the prevalences of lower urinary tract symptoms (LUTS), irritable bowel syndrome (IBS) and constipation in women with vulvar diseases to those from the general population. METHODS: Three groups of women were recruited from the University of Michigan Gynecology Clinics, women with: (1) biopsy proven lichen sclerosus (LS), (2) non-LS vulvar diseases (vulvar controls, VC), and (3) presenting for annual examinations (AE). All patients completed self-administered surveys and validated pelvic floor symptom questionnaires. RESULTS: 317 subjects were enrolled: 101 with LS, 86 VCs, and 130 AEs. Compared to women in the VC and AE groups, LS subjects were older and of higher parity, and also had a higher prevalence of overactive bladder and urinary incontinence. The IBS was more common in the LS and VC groups compared to the AE group but no difference in constipation was seen. Similar results were found when all women with vulvar disease (LS and VC) were compared to the AEs. Age (adjusted odds ratio [OR], 1.28; P = 0.003) and IBS (adjusted OR, 3.05; P < 0.001) were the 2 variables predictive of overactive bladder. Urinary incontinence was predicted by age (adjusted OR, 1.35; P = 0.002), vulvar disease categorization (adjusted OR, 2.31; P = 0.004) and IBS (adjusted OR, 4.51; P < 0.001). CONCLUSIONS: We find a significantly greater prevalence of LUTS and IBS in women with vulvar disease compared to women presenting for annual gynecologic exams, but no difference in constipation. Similar rates of LUTS, IBS, and constipation were seen in women with LS and non-LS vulvar disease. PMID- 26052646 TI - Risk Factors for Surgical Site Infection in Patients Undergoing Sacral Nerve Modulation Therapy. AB - OBJECTIVES: The aim of this study was to identify risk factors for surgical site infection in patients undergoing sacral nerve modulation (SNM) surgery. METHODS: We conducted a retrospective cohort analysis of 290 patients undergoing a total of 669 SNM procedures between 2002 and 2012 by 2 fellowship-trained female pelvic medicine and reconstructive surgery attending physicians at the University of California-Irvine Medical Center. Infection was defined as a charted abnormal examination finding at the implantation site (erythema, induration, purulent discharge) resulting in prescription of antibiotics, hospitalization, or explantation. We extracted information from the medical record regarding possible risk factors for infection including age, body mass index, immunosuppression (diabetes mellitus, chronic steroid use, smoker, chemotherapy), number of procedures per patient, and number of days between stages 1 and 2. In addition, we compared infection rates before and after 2008 when a clinical practice change was made with the implementation of home chlorhexidine washing (CHW) prior to SNM surgery. RESULTS: Thirty infections occurred, 25 of which were managed with oral antibiotics. Nine required intravenous antibiotics, and 11 required removal of the implanted device. Three patients experienced infection on 2 separate occasions. Seventeen infections had culture data available. Nine of the patients who underwent explantation had wound cultures positive for methicillin-resistant Staphylococcus aureus.Thirteen of the 26 patients who developed infection had medical histories significant for immunosuppression. Three patients developed late-onset abscess formation at 234, 257, and 687 days after stage 2, respectively. The median time between the most recent SNM procedure and development of infection was 14 days (range, 6-88 days).Body mass index and immunosuppression were significant predictors of infection, whereas age, parity, indication for procedure, and number of days between stages 1 and 2 were not found to be independent predictors. Three hundred twenty-three procedures were performed prior to and 346 procedures were performed after institution of home CHW. Twenty-four (80%) of the 30 reported infections were prior to CHW, whereas only 6 infections (20%) occurred after this change in practice. Prior to institution of CHW, the infection rate was 7.4%, and after institution of CHW, it was 1.7% (P = 0.002). Of the 83 patients with compliance data available for CHW use, 71 reported using CHW, whereas 12 reported not using CHW. CONCLUSIONS: Surgical site infection is a significant risk of SNM surgery, although our infection rate is lower than previously reported. Chlorhexidine washing appears to reduce the risk of infection in this population. Because the majority of infections requiring explantation were methicillin-resistant S. aureus positive, prophylactic treatment for this organism should be considered as an additional strategy to reduce infection. Body mass index and immunosuppression appear to be independent risk factors for infection. PMID- 26052647 TI - Postoperative Delirium in Older Adults. PMID- 26052648 TI - The relationship between overt and in-situ lymphoma: a retrospective study of follicular and mantle cell lymphoma cases. PMID- 26052649 TI - A systematic method for search term selection in systematic reviews. AB - The wide variety of readily available electronic media grants anyone the freedom to retrieve published references from almost any area of research around the world. Despite this privilege, keeping up with primary research evidence is almost impossible because of the increase in professional publishing across disciplines. Systematic reviews are a solution to this problem as they aim to synthesize all current information on a particular topic and present a balanced and unbiased summary of the findings. They are fast becoming an important method of research across a number of fields, yet only a small number of guidelines exist on how to define and select terms for a systematic search. This article presents a replicable method for selecting terms in a systematic search using the semantic concept recognition software called leximancer (Leximancer, University of Queensland, Brisbane, Australia). We use this software to construct a set of terms from a corpus of literature pertaining to transborder interventions for drug control and discuss the applicability of this method to systematic reviews in general. This method aims to contribute a more 'systematic' approach for selecting terms in a manner that is entirely replicable for any user. PMID- 26052650 TI - Methods for documenting systematic review searches: a discussion of common issues. AB - INTRODUCTION: As standardized reporting requirements for systematic reviews are being adopted more widely, review authors are under greater pressure to accurately record their search process. With careful planning, documentation to fulfill the Preferred Reporting Items for Systematic Reviews and Meta-Analyses requirements can become a valuable tool for organizing a systematic review literature search and planning updates. METHODS: A working group of information specialists convened to discuss current practice and were informed by a Web-based survey of over 260 systematic review authors, trials search coordinators, librarians, and other information specialists conducted in February/March 2011. DISCUSSION: Survey responses provided insight into current practices and difficulties of reporting searches. These included a lack of time, tools, clear understanding of the requirements, and uncertainty about responsibility for documenting these elements. This paper will present some of the practical aspects of documenting the systematic literature search. Section 1 provides background information and rationale for this paper. Section 2 discusses issues and recommendations arising from survey results. Section 3 outlines specific elements to be recorded. Section 4 guides the reader through the information management process. Section 5 concludes with implications for future research and practice. These principles are applicable to any large literature search for systematic reviews, health technology assessments, and guideline development. PMID- 26052651 TI - Reporting quality of search methods in systematic reviews of HIV behavioral interventions (2000-2010): are the searches clearly explained, systematic and reproducible? AB - Systematic reviews are an essential tool for researchers, prevention providers and policy makers who want to remain current with the evidence in the field. Systematic review must adhere to strict standards, as the results can provide a more objective appraisal of evidence for making scientific decisions than traditional narrative reviews. An integral component of a systematic review is the development and execution of a comprehensive systematic search to collect available and relevant information. A number of reporting guidelines have been developed to ensure quality publications of systematic reviews. These guidelines provide the essential elements to include in the review process and report in the final publication for complete transparency. We identified the common elements of reporting guidelines and examined the reporting quality of search methods in HIV behavioral intervention literature. Consistent with the findings from previous evaluations of reporting search methods of systematic reviews in other fields, our review shows a lack of full and transparent reporting within systematic reviews even though a plethora of guidelines exist. This review underscores the need for promoting the completeness of and adherence to transparent systematic search reporting within systematic reviews. PMID- 26052652 TI - Critical reflections on realist review: insights from customizing the methodology to the needs of participatory research assessment. AB - Realist review has increased in popularity as a methodology for complex intervention assessment. Our experience suggests that the process of designing a realist review requires its customization to areas under investigation. To elaborate on this idea, we first describe the logic underpinning realist review and then present critical reflections on our application experience, organized in seven areas. These are the following: (1) the challenge of identifying middle range theory; (2) addressing heterogeneity and lack of conceptual clarity; (3) the challenge of appraising the quality of complex evidence; (4) the relevance of capturing unintended outcomes; (5) understanding the process of context, mechanism, and outcome (CMO) configuring; (6) incorporating middle-range theory in the CMO configuration process; and (7) using middle range theory to advance the conceptualization of outcomes - both visible and seemingly 'hidden'. One conclusion from our experience is that the degree of heterogeneity of the evidence base will determine whether theory can drive the development of review protocols from the outset, or will follow only after an intense period of data immersion. We hope that presenting a critical reflection on customizing realist review will convey how the methodology can be tailored to the often complex and idiosyncratic features of health research, leading to innovative evidence syntheses. PMID- 26052653 TI - Search wide, dig deep: literature searching for qualitative research. An analysis of the publication formats and information sources used for four systematic reviews in public health. AB - BACKGROUND: When literature searching for systematic reviews, it is good practice to search widely across different information sources. Little is known about the contributions of different publication formats (e.g. journal article and book chapter) and sources, especially for studies of people's views. METHOD: Studies from four reviews spanning three public health areas (active transport, motherhood and obesity) were analysed in terms of publication formats and the information sources they were identified from. They comprised of 229 studies exploring people's perceptions, beliefs and experiences ('views studies') and were largely qualitative. RESULTS: Although most (61%) research studies were published within journals, nearly a third (29%) were published as research reports and 5% were published in books. The remainder consisted of theses, conference papers and raw datasets. Two-thirds of studies (66%) were located in a total of 19 bibliographic databases, and 15 databases provided studies that were not identified elsewhere. PubMed was a good source for all reviews. Supplementary information sources were important for identifying studies in all publication formats. CONCLUSIONS: Undertaking sensitive searches across a range of information sources is essential for locating views studies in all publication formats. We discuss some benefits and challenges of utilising different information sources. PMID- 26052654 TI - Opportunities and challenges in using studies without a control group in comparative effectiveness reviews. AB - When examining the evidence on therapeutic interventions to answer a comparative effectiveness research question, one should consider all studies that are informative on the interventions' causal effects. "Single group studies" evaluate outcomes longitudinally in cohorts of subjects who are managed with a single treatment strategy. Because these studies are "missing" a direct, concurrent comparison group, they are typically deemed non-informative on comparative effectiveness. However, in principle, single group studies can provide information on causal treatment effects by extrapolating expected outcomes in the "missing" untreated arm. Single group studies rely on before-after, implicit, or historical comparisons as a proxy for an ideal comparison group. The validity of these comparisons must be carefully examined on a case-by-case basis. While in many cases, researchers will disagree on whether such extrapolations are reasonable; circumstances exist where such studies are generally acceptable as a source of evidence. This article provides an overview of issues related to the interpretation of single group studies with a focus on the assumptions required to support their consideration in comparative effectiveness reviews. We discuss the various settings in which single group studies are employed, common research designs that systematic reviewers need to interpret, and challenges associated with using these designs to inform comparative effectiveness questions. PMID- 26052655 TI - Bayesian network meta-analysis for unordered categorical outcomes with incomplete data. AB - We develop a Bayesian multinomial network meta-analysis model for unordered (nominal) categorical outcomes that allows for partially observed data in which exact event counts may not be known for each category. This model properly accounts for correlations of counts in mutually exclusive categories and enables proper comparison and ranking of treatment effects across multiple treatments and multiple outcome categories. We apply the model to analyze 17 trials, each of which compares two of three treatments (high and low dose statins and standard care/control) for three outcomes for which data are complete: cardiovascular death, non-cardiovascular death and no death. We also analyze the cardiovascular death category divided into the three subcategories (coronary heart disease, stroke and other cardiovascular diseases) that are not completely observed. The multinomial and network representations show that high dose statins are effective in reducing the risk of cardiovascular disease. PMID- 26052656 TI - Metal-organic frameworks derived CoxFe1-xP nanocubes for electrochemical hydrogen evolution. AB - Designing and developing active, cost-effective and stable electrocatalysts for hydrogen evolution reaction (HER) are still an ongoing challenge. Herein, we report the synthesis of binary transition metal phosphide (CoxFe1-xP) nanocubes with different Co and Fe ratios through a phosphidation process using metal organic frameworks (MOFs) as templates. MOF templates contribute well-defined nanocube architectural features after phosphidation, while a suitable phosphidation temperature could allow formation of a crystal structure and maintain the well-defined structure. The incorporation of a binary transition metal results in redistribution of the valence electrons in CoxFe1-xP. The changes imply anionic states of the P and Fe atoms, which act as active sites and thus have stronger electron-donating ability. When CoxFe1-xP nanocubes are employed as electrocatalysts, these characteristic features facilitate the performance of HER. Remarkably, Co0.59Fe0.41P nanocubes prepared at 450 degrees C afford a current density of 10 mA cm(-2) at a low overpotential of 72 mV in acidic conditions and 92 mV in alkaline conditions. Co0.59Fe0.41P nanocubes also exhibit a small Tafel slope of 52 mV decade(-1) in acidic conditions and 72 mV decade(-1) in alkaline conditions. Moreover, Co0.59Fe0.41P nanocubes show good stability in both acidic and alkaline conditions. Our method produces the highly active HER catalyst based on binary transition metal MOF templates, providing a new avenue for designing excellent electrocatalysts. PMID- 26052657 TI - Changes in daily substance use among people experiencing homelessness and mental illness: 24-month outcomes following randomization to Housing First or usual care. AB - AIMS: Housing First (HF) is an established intervention for people experiencing homelessness and mental illness. We compared daily substance use (DSU) between HF and treatment as usual (TAU). DESIGN: Two concurrent randomized controlled trials with 24-month follow-up. SETTING: Market rental apartments with support provided by Assertive Community Treatment (ACT) or Intensive Case Management (ICM); a single building with on-site supports (CONG); TAU in Vancouver, Canada. PARTICIPANTS: Inclusion criteria were current homelessness and mental illness. Participants were assessed as having either 'high needs' (HN; n = 297) or 'moderate needs' (MN; n = 200). MN participants were randomized to ICM (n = 100) or MN-TAU (n = 100). HN participants were randomized to ACT (n = 90), CONG (n = 107) or HN-TAU (n = 100). INTERVENTIONS AND COMPARATORS: All HF interventions included independent housing with support services, with an emphasis on promoting client choice and harm reduction in relation to substance use. TAU included existing services and support available to homeless adults with mental illness. MEASUREMENTS: DSU over 24 and 12 months was derived from the Maudsley Addiction Profile. Also measured were demographics, homelessness history, psychiatric diagnoses, symptom severity, comorbid illnesses and duration of stable housing. FINDINGS: Compared with HN-TAU, neither CONG [adjusted odds (AOR) ratio = 0.73, 95% confidence interval (CI) = 0.39-1.37] nor ACT (AOR = 1.22, 95% CI = 0.61 2.45) differed on DSU at 24 months, and MN-TAU did not differ from ICM (AOR = 0.78, 95% CI = 0.37-1.63). There were no differences at 12 months, when analyses were restricted to participants who indicated substance use at baseline, or when considering the duration of stable housing. CONCLUSIONS: Housing First, an intervention to support recovery for homeless people who have co-occurring mental illness and substance use disorders, did not reduce daily substance use compared with treatment as usual after 12 or 24 months. PMID- 26052658 TI - Lack of Oestrogenic Inhibition of the Nuclear Factor-kappaB Pathway in Somatolactotroph Tumour Cells. AB - Activation of nuclear factor (NF)-kappaB promotes cell proliferation and inhibits apoptosis. We have previously shown that oestrogens sensitise normal anterior pituitary cells to the apoptotic effect of tumour necrosis factor (TNF)-alpha by inhibiting NF-kappaB nuclear translocation. In the present study, we examined whether oestrogens also modulate the NF-kappaB signalling pathway and apoptosis in GH3 cells, a rat somatolactotroph tumour cell line. As determined by Western blotting, 17beta-oestradiol (E2 ) (10(-9) m) increased the nuclear concentration of NF-kappaB/p105, p65 and p50 in GH3 cells. However, E2 did not modify the expression of Bcl-xL, a NF-kappaB target gene. TNF-alpha induced apoptosis of GH3 cells incubated in either the presence or absence of E2 . Inhibition of the NF-kB pathway using BAY 11-7082 (BAY) (5 MUm) decreased the viability of GH3 cells and increased the percentage of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive GH3 cells. BAY also increased TNF-alpha-induced apoptosis of GH3 cells, an effect that was further increased by an inhibitor of the c-Jun N-terminal protein kinase pathway, SP600125 (10 MUm). We also analysed the role of the NF-kappaB signalling pathway on proliferation and apoptosis of GH3 tumours in vivo. The administration of BAY to nude mice bearing GH3 tumours increased the number of TUNEL-positive cells and decreased the number of proliferating GH3 cells. These findings suggest that GH3 cells lose their oestrogenic inhibitory action on the NF-kappaB pathway and that the pro-apoptotic effect of TNF-alpha on these tumour pituitary cells does not require sensitisation by oestrogens as occurs in normal pituitary cells. NF-kappaB was required for the survival of GH3 cells, suggesting that pharmacological inhibition of the NF-kappaB pathway could interfere with pituitary tumour progression. PMID- 26052659 TI - Spontaneous activity and stretch-induced contractile differentiation are reduced in vascular smooth muscle of miR-143/145 knockout mice. AB - AIM: Stretch is essential for maintaining the contractile phenotype of vascular smooth muscle cells, and small non-coding microRNAs are known to be important in this process. Using a Dicer knockout model, we have previously reported that microRNAs are essential for stretch-induced differentiation and regulation of L type calcium channel expression. The aim of this study was to investigate the importance of the smooth muscle-enriched miR-143/145 microRNA cluster for stretch induced differentiation of the portal vein. METHODS: Contractile force and depolarization-induced calcium influx were determined in portal veins from wild type and miR-143/145 knockout mice. Stretch-induced contractile differentiation was investigated by determination of mRNA expression following organ culture for 24 h under longitudinal load by a hanging weight. RESULTS: In the absence of miR 143/145, stretch-induced mRNA expression of contractile markers in the portal vein was reduced. This was associated with decreased amplitude of spontaneous activity and depolarization-induced contractile and intracellular calcium responses, while contractile responses to 5-HT were largely maintained. We found that these effects correlated with a reduced basal expression of the pore-forming subunit of L-type calcium channels and an increased expression of CaMKIIdelta and the transcriptional repressor DREAM. CONCLUSION: Our results suggest that the microRNA-143/145 cluster plays a role in maintaining stretch-induced contractile differentiation and calcium signalling in the portal vein. This may have important implications for the use of these microRNAs as therapeutic targets in vascular disease. PMID- 26052660 TI - Marine microbiology. Deep sequencing of the global oceans. PMID- 26052662 TI - Dispersing misconceptions and identifying opportunities for the use of 'omics' in soil microbial ecology. AB - Technological advances are enabling the sequencing of environmental DNA and RNA at increasing depth and with decreasing costs. Metagenomic and transcriptomic analysis of soil microbial communities and the assembly of 'population genomes' from soil DNA are therefore now feasible. Although the value of such 'omic' approaches is limited by the associated technical and bioinformatic difficulties, even if these obstacles were eliminated and 'perfect' metagenomes and metatranscriptomes were available, important conceptual challenges remain. This Opinion article considers these conceptual challenges in the context of the current use of omics in soil microbiology, but the main arguments presented are also relevant to the application of omics to marine, freshwater, gut or other environments. PMID- 26052665 TI - Bacterial pathogenesis. Message in a bottle. PMID- 26052661 TI - Bottlenecks in HIV-1 transmission: insights from the study of founder viruses. AB - HIV-1 infection typically results from the transmission of a single viral variant, the transmitted/founder (T/F) virus. Studies of these HIV-1 variants provide critical information about the transmission bottlenecks and the selective pressures acting on the virus in the transmission fluid and in the recipient tissues. These studies reveal that T/F virus phenotypes are shaped by stochastic and selective forces that restrict transmission and may be targets for prevention strategies. In this Review, we highlight how studies of T/F viruses contribute to a better understanding of the biology of HIV-1 transmission and discuss how these findings affect HIV-1 prevention strategies. PMID- 26052668 TI - Discovery of novel Bcr-Abl inhibitors with diacylated piperazine as the flexible linker. AB - Forty-two compounds (series 8, 9 and 10) incorporated with diacylated piperazine have been synthesized and evaluated as novel Bcr-Abl inhibitors based on 'six atom linker'. Five of them, 8d, 8h, 8l, 10m and 10p, displayed potent Bcr-Abl inhibitory activity comparable with Imatinib. Moreover, compounds 8e, 10q, 10s, and 10u were potent Bcr-Abl inhibitors with IC50 values at the sub-micromolecular level. Most compounds exhibited moderate to high antiproliferative activity against K562 cells. In particular, compound 9e was the most promising Bcr-Abl inhibitor. Docking studies revealed that the binding modes of these compounds were similar with Imatinib. These compounds could be considered as promising lead compounds for further optimization. PMID- 26052667 TI - Viral apoptotic mimicry. AB - As opportunistic pathogens, viruses have evolved many elegant strategies to manipulate host cells for infectious entry and replication. Viral apoptotic mimicry, defined by the exposure of phosphatidylserine - a marker for apoptosis - on the pathogen surface, is emerging as a common theme used by enveloped viruses to promote infection. Focusing on the four best described examples (vaccinia virus, dengue virus, Ebola virus and pseudotyped lentivirus), we summarize our current understanding of apoptotic mimicry as a mechanism for virus entry, binding and immune evasion. We also describe recent examples of non-enveloped viruses that use this mimicry strategy, and discuss future directions and how viral apoptotic mimicry could be targeted therapeutically. PMID- 26052669 TI - Mental Well-being Considerations in Preparation for Disaster Health Care: Learning From Deployment. AB - INTRODUCTION: The mental well-being of internationally deployed disaster-relief workers has become an issue of concern. The psychological consequences for the relief worker being exposed to trauma and threats have been well documented; however, the role of pre-deployment preparation in supporting mental well-being has not received due attention, despite research indicating the need for it. HYPOTHESIS/PROBLEM: This case series examines the experiences of deployed volunteers of one emergency-relief organization. The aim of this research was to identify the participants' interpretations of the appropriateness of the pre deployment preparation they had received in light of supporting their mental well being during and after deployment. The main research questions were: How appropriate was pre-deployment preparation in supporting mental well-being? What elements were lacking, and what else would be useful? METHODS: Using a hermeneutic phenomenological approach, thematic, semi-structured interviews were conducted with six deployed volunteers of an international emergency-relief organization. Data were analyzed using content analysis. RESULTS: The participants in this study regarded the pre-deployment preparation they had received, on the whole, as appropriate in supporting their mental well-being. The seven main themes identified as important and supportive of mental well-being were: (1) realistic expectations, (2) team building and support, (3) self awareness and self-care, (4) post-deployment support, (5) practical skills and creative solutions, (6) shared values and beliefs, and (7) safety and security. Specific areas identified as lacking within these themes included communication, self-care, post-deployment support, and safety and security. CONCLUSION: Themes identified as important for supporting mental well-being in this research largely were consistent with those in previous research. The generally positive experiences of the support received do not reflect results from existing research, where significant shortcomings in worker support have been expressed. However, important elements were also identified as lacking in this specific pre deployment preparation. PMID- 26052670 TI - Forebrain deletion of the dystonia protein torsinA causes dystonic-like movements and loss of striatal cholinergic neurons. AB - Striatal dysfunction plays an important role in dystonia, but the striatal cell types that contribute to abnormal movements are poorly defined. We demonstrate that conditional deletion of the DYT1 dystonia protein torsinA in embryonic progenitors of forebrain cholinergic and GABAergic neurons causes dystonic-like twisting movements that emerge during juvenile CNS maturation. The onset of these movements coincides with selective degeneration of dorsal striatal large cholinergic interneurons (LCI), and surviving LCI exhibit morphological, electrophysiological, and connectivity abnormalities. Consistent with the importance of this LCI pathology, murine dystonic-like movements are reduced significantly with an antimuscarinic agent used clinically, and we identify cholinergic abnormalities in postmortem striatal tissue from DYT1 dystonia patients. These findings demonstrate that dorsal LCI have a unique requirement for torsinA function during striatal maturation, and link abnormalities of these cells to dystonic-like movements in an overtly symptomatic animal model. PMID- 26052673 TI - Nitride-bridged triiron complex and its relevance to dinitrogen activation. AB - Using a simple metathesis approach, the triiron(II) tribromide complex Fe3Br3L (1) reacts with tetrabutylammonium azide to afford the monoazide dibromide analogue Fe3(Br)2(N3)L (2) in high yield. The inclusion of azide was confirmed by IR spectroscopy with a nu(N3) = 2082 cm(-1) as well as combustion analysis and X ray crystallography. Heating 2 in the solid state results in the complete loss of the azide vibration in the IR spectra and the isolation of the olive-green mononitride complex Fe3(Br)2(N)L (3). Solution magnetic susceptibility measurements support that the trimetallic core within 2 is oxidized upon generation of 3 (5.07 vs 3.09 MUB). Absorption maxima in the UV-visible-near-IR (NIR) spectra of 2 and 3 support the azide-to-nitride conversion, and a broad NIR absorption centered at 1117 nm is similar to that previously reported for the intervalence charge-transfer band for a mixed-valent nitridodiiron cluster. The cyclic voltammograms recorded for 3 are comparable to those of 1 with no reductive waves observed between ~0 and -2.5 V (vs Fc/Fc(+)), whereas a reversible one-electron redox process is observed for Fe3(NH2)3L (4). These results suggest that intercluster cooperativity is unlikely to predominate the dinitrogen reduction mechanism when 1 is treated with KC8 under N2. PMID- 26052671 TI - The unfolded protein response is required for dendrite morphogenesis. AB - Precise patterning of dendritic fields is essential for the formation and function of neuronal circuits. During development, dendrites acquire their morphology by exuberant branching. How neurons cope with the increased load of protein production required for this rapid growth is poorly understood. Here we show that the physiological unfolded protein response (UPR) is induced in the highly branched Caenorhabditis elegans sensory neuron PVD during dendrite morphogenesis. Perturbation of the IRE1 arm of the UPR pathway causes loss of dendritic branches, a phenotype that can be rescued by overexpression of the ER chaperone HSP-4 (a homolog of mammalian BiP/grp78). Surprisingly, a single transmembrane leucine-rich repeat protein, DMA-1, plays a major role in the induction of the UPR and the dendritic phenotype in the UPR mutants. These findings reveal a significant role for the physiological UPR in the maintenance of ER homeostasis during morphogenesis of large dendritic arbors. PMID- 26052672 TI - Mitochondrial Genomes of Giant Deers Suggest their Late Survival in Central Europe. AB - The giant deer Megaloceros giganteus is among the most fascinating Late Pleistocene Eurasian megafauna that became extinct at the end of the last ice age. Important questions persist regarding its phylogenetic relationship to contemporary taxa and the reasons for its extinction. We analyzed two large ancient cervid bone fragments recovered from cave sites in the Swabian Jura (Baden-Wurttemberg, Germany) dated to 12,000 years ago. Using hybridization capture in combination with next generation sequencing, we were able to reconstruct nearly complete mitochondrial genomes from both specimens. Both mtDNAs cluster phylogenetically with fallow deer and show high similarity to previously studied partial Megaloceros giganteus DNA from Kamyshlov in western Siberia and Killavullen in Ireland. The unexpected presence of Megaloceros giganteus in Southern Germany after the Ice Age suggests a later survival in Central Europe than previously proposed. The complete mtDNAs provide strong phylogenetic support for a Dama-Megaloceros clade. Furthermore, isotope analyses support an increasing competition between giant deer, red deer, and reindeer after the Last Glacial Maximum, which might have contributed to the extinction of Megaloceros in Central Europe. PMID- 26052674 TI - Cu4 Cluster Doped Monolayer MoS2 for CO Oxidation. AB - The catalytic oxidation of CO molecule on a thermodynamically stable Cu4 cluster doped MoS2 monolayer is investigated by density functional theory (DFT) where the reaction proceeds in a new formation order of COOOCO* (O2* + 2CO* -> COOOCO*), OCO* (COOOCO* -> CO2 + OCO*), and CO2 (OCO* -> CO2) desorption with the corresponding reaction barrier values of 0.220 eV, 0.370 eV and 0.119 eV, respectively. Therein, the rate-determining step is the second one. This low barrier indicates high activity of this system where CO oxidation could be realized at room temperature (even lower). As a result, the Cu4 doped MoS2 could be a candidate for CO oxidation with lower cost and higher activity without poisoning and corrosion problems. PMID- 26052675 TI - Two-year post-transplantation cytomegalovirus DNAemia in asymptomatic kidney transplant recipients: incidence, risk factors, and outcome. AB - BACKGROUND: The incidence and the impact of asymptomatic cytomegalovirus (CMV) DNAemia occurring after the first year post transplantation is unknown. METHODS: In this retrospective cross-sectional study, we analyzed the incidence, risk factors, and impact of 2-year post-transplantation asymptomatic CMV DNAemia (2YCD) on graft function. We included 892 consecutive asymptomatic kidney transplant recipients transplanted for at least 2 years and all were monitored using whole blood CMV quantitative nucleic acid amplification testing (CMV-QNAT). RESULTS: Twenty-eight patients displayed 2YCD (3.1%). Using multivariate analysis in 578 patients, we found that female gender (odds ratio [OR] = 2.57, P = 0.02), a past history of CMV drug-resistance mutation (OR = 8.73, P = 0.005), and corticosteroid use (OR = 2.37, P = 0.03) were independently associated with an increased risk of 2YCD. 2YCD was associated with an increased incidence of subsequent CMV disease over the year following its diagnosis (7% vs. 0.6%, P = 0.02). Patients with 2YCD also exhibited a declining estimated glomerular filtration rate more frequently (77%) than patients with a negative CMV-QNAT (56%, P = 0.02). CONCLUSION: 2YCD appears to be a rare entity, which appears to be associated with chronic graft dysfunction. PMID- 26052676 TI - Physical Characterization of Tobramycin Inhalation Powder: I. Rational Design of a Stable Engineered-Particle Formulation for Delivery to the Lungs. AB - A spray-dried engineered particle formulation, Tobramycin Inhalation Powder (TIP), was designed through rational selection of formulation composition and process parameters. This PulmoSphere powder comprises small, porous particles with a high drug load. As a drug/device combination, TOBI Podhaler enables delivery of high doses of drug per inhalation, a feature critical for dry powder delivery of anti-infectives for treatment of cystic fibrosis. The objective of this work was to characterize TIP on both the particle and molecular levels using multiple orthogonal physical characterization techniques. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), electron spectroscopy for chemical analysis (ESCA), and Raman measurements show that a TIP particle consists of two phases: amorphous, glassy tobramycin sulfate with a glass transition temperature of about 100 degrees C and a gel-phase phospholipid (DSPC) with a gel-to-liquid-crystal transition temperature of about 80 degrees C. This was by design and constituted a rational formulation approach to provide Tg and Tm values that are well above the temperatures used for long-term storage of TIP. Raman and ESCA data provide support for a core/shell particle architecture of TIP. Particle surfaces are enriched with a porous, hydrophobic coating that reduces cohesive forces, improving powder fluidization and dispersibility. The excellent aerosol dispersibility of TIP enables highly efficient delivery of fine particles to the respiratory tract. Collectively, particle engineering has enabled development of TOBI Podhaler, an approved inhaled drug product that meaningfully reduces the treatment burden to cystic fibrosis patients worldwide. PMID- 26052678 TI - 11-GHz waveguide Nd:YAG laser CW mode-locked with single-layer graphene. AB - We report stable, passive, continuous-wave (CW) mode-locking of a compact diode pumped waveguide Nd:YAG laser with a single-layer graphene saturable absorber. The depressed cladding waveguide in the Nd:YAG crystal is fabricated with an ultrafast laser inscription method. The saturable absorber is formed by direct deposition of CVD single-layer graphene on the output coupler. The few millimeter long cavity provides generation of 16-ps pulses with repetition rates in the GHz range (up to 11.3 GHz) and 12 mW average power. Stable CW mode-locking operation is achieved by controlling the group delay dispersion in the laser cavity with a Gires-Tournois interferometer. PMID- 26052677 TI - Coronary Computed Tomography Angiography Versus Radionuclide Myocardial Perfusion Imaging in Patients With Chest Pain Admitted to Telemetry: A Randomized Trial. AB - BACKGROUND: The role of coronary computed tomography angiography (CCTA) in the management of symptomatic patients suspected of having coronary artery disease is expanding. However, prospective intermediate-term outcomes are lacking. OBJECTIVE: To compare CCTA with conventional noninvasive testing. DESIGN: Randomized, controlled comparative effectiveness trial. (ClinicalTrials.gov: NCT00705458). SETTING: Telemetry-monitored wards of an inner-city medical center. PATIENTS: 400 patients with acute chest pain (mean age, 57 years); 63% women; 54% Hispanic and 37% African-American; and low socioeconomic status. INTERVENTION: CCTA or radionuclide stress myocardial perfusion imaging (MPI). MEASUREMENTS: The primary outcome was cardiac catheterization not leading to revascularization within 1 year. Secondary outcomes included length of stay, resource utilization, and patient experience. Safety outcomes included death, major cardiovascular events, and radiation exposure. RESULTS: Thirty (15%) patients who had CCTA and 32 (16%) who had MPI underwent cardiac catheterization within 1 year. Fifteen (7.5%) and 20 (10%) of these patients, respectively, did not undergo revascularization (difference, -2.5 percentage points [95% CI, -8.6 to 3.5 percentage points]; hazard ratio, 0.77 [CI, 0.40 to 1.49]; P = 0.44). Median length of stay was 28.9 hours for the CCTA group and 30.4 hours for the MPI group (P = 0.057). Median follow-up was 40.4 months. For the CCTA and MPI groups, the incidence of death (0.5% versus 3%; P = 0.12), nonfatal cardiovascular events (4.5% versus 4.5%), rehospitalization (43% versus 49%), emergency department visit (63% versus 58%), and outpatient cardiology visit (23% versus 21%) did not differ. Long-term, all-cause radiation exposure was lower for the CCTA group (24 versus 29 mSv; P < 0.001). More patients in the CCTA group graded their experience favorably (P = 0.001) and would undergo the examination again (P = 0.003). LIMITATION: This was a single-site study, and the primary outcome depended on clinical management decisions. CONCLUSION: The CCTA and MPI groups did not significantly differ in outcomes or resource utilization over 40 months. Compared with MPI, CCTA was associated with less radiation exposure and with a more positive patient experience. PRIMARY FUNDING SOURCE: American Heart Association. PMID- 26052679 TI - Comment on: Steroid-resistant kaposiform hemangioendothelioma: A retrospective study of 37 patients treated with vincristine and long-term follow-up. PMID- 26052680 TI - Unexpectedly Simple Synthesis of Benzazoles by tBuONa-Catalyzed Direct Aerobic Oxidative Cyclocondensation of o-Thio/Hydroxy/Aminoanilines with Alcohols under Air. AB - tBuONa-catalyzed direct aerobic oxidative cyclocondensation reactions of readily available alcohols and o-thio/hydroxy/aminoanilines under air have been developed and provide an efficient, practical, and green method for the synthesis of benzazoles. Mechanistic studies revealed that o-substituted anilines promote the initial aerobic alcohol-oxidation step, which explains the high reactivity and success of this unexpectedly simple and practical cyclocondensation method. PMID- 26052681 TI - ADRM1-amplified metastasis gene in gastric cancer. AB - The proteasome ubiquitin receptor ADRM1 has been shown to be a driver for 20q13.3 amplification in epithelial cancers including ovarian and colon cancer. We performed array-CGH on 16 gastric cancer cell lines and found 20q13.3 to be amplified in 19% with the minimal amplified region in gastric cancer cell line AGS spanning a 1 Mb region including ADRM1. Expression microarray analysis shows overexpression of only two genes in the minimal region, ADRM1 and OSBPL2. While RNAi knockdown of both ADRM1 and OSBPL2 led to a slight reduction in growth, only ADRM1 RNAi knockdown led to a significant reduction in migration and growth in soft-agar. Treatment of AGS cells with the ADRM1 inhibitor RA190 resulted in proteasome inhibition, but RNAi knockdown of ADRM1 did not. However, RNAi knockdown of ADRM1 led to a significant reduction in specific proteins including MNAT1, HRS, and EGFR. We hypothesize that ADRM1 may act in ADRM1-amplified gastric cancer to alter protein levels of specific oncogenes resulting in an increase in metastatic potential. Selective inhibition of ADRM1 independent of proteasome inhibition may result in a targeted therapy for ADRM1-amplified gastric cancer. In vivo models are now warranted to validate these findings. (c) 2015 Wiley Periodicals, Inc. PMID- 26052682 TI - Co-evolutionary analysis implies auxiliary functions of HSP110 in Plasmodium falciparum. AB - Plasmodium falciparum encounters frequent environmental challenges during its life cycle which makes productive protein folding immensely challenging for its metastable proteome. To identify the important components of protein folding machinery involved in maintaining P. falciparum proteome, we performed a proteome wide phylogenetic profiling across various species. We found that except HSP110, the parasite lost all other cytosolic nucleotide exchange factors essential for regulating HSP70 which is the centrum of the protein folding network. Evolutionary and structural analysis shows that besides its canonical interaction with HSP70, PfHSP110 has acquired sequence insertions for additional dynamic interactions. Molecular co-evolution profile depicts that the co-evolving proteins of PfHSP110 belong to distinct pathways like genetic variation, DNA repair, fatty acid biosynthesis, protein modification/trafficking, molecular motions, and apoptosis. These proteins exhibit unique physiochemical properties like large size, high iso-electric point, low solubility, and antigenicity, hence require PfHSP110 chaperoning to attain functional state. Co-evolving protein interaction network suggests that PfHSP110 serves as an important hub to coordinate protein quality control, survival, and immune evasion pathways in the parasite. Overall, our findings highlight potential accessory roles of PfHSP110 that may provide survival advantage to the parasite during its lifecycle and febrile conditions. The data also open avenues for experimental validation of auxiliary functions of PfHSP110 and their exploration for design of better antimalarial strategies. PMID- 26052683 TI - Metabolic engineering for the high-yield production of isoprenoid-based C5 alcohols in E. coli. AB - Branched five carbon (C5) alcohols are attractive targets for microbial production due to their desirable fuel properties and importance as platform chemicals. In this study, we engineered a heterologous isoprenoid pathway in E. coli for the high-yield production of 3-methyl-3-buten-1-ol, 3-methyl-2-buten-1 ol, and 3-methyl-1-butanol, three C5 alcohols that serve as potential biofuels. We first constructed a pathway for 3-methyl-3-buten-1-ol, where metabolite profiling identified NudB, a promiscuous phosphatase, as a likely pathway bottleneck. We achieved a 60% increase in the yield of 3-methyl-3-buten-1-ol by engineering the Shine-Dalgarno sequence of nudB, which increased protein levels by 9-fold and reduced isopentenyl diphosphate (IPP) accumulation by 4-fold. To further optimize the pathway, we adjusted mevalonate kinase (MK) expression and investigated MK enzymes from alternative microbes such as Methanosarcina mazei. Next, we expressed a fusion protein of IPP isomerase and the phosphatase (Idi1~NudB) along with a reductase (NemA) to diversify production to 3-methyl-2 buten-1-ol and 3-methyl-1-butanol. Finally, we used an oleyl alcohol overlay to improve alcohol recovery, achieving final titers of 2.23 g/L of 3-methyl-3-buten 1-ol (~70% of pathway-dependent theoretical yield), 150 mg/L of 3-methyl-2-buten 1-ol, and 300 mg/L of 3-methyl-1-butanol. PMID- 26052684 TI - The Braincase and Endosseous Labyrinth of Plioplatecarpus peckensis (Mosasauridae, Plioplatecarpinae), With Functional Implications for Locomotor Behavior. AB - Adaptations of mosasaurs to the aquatic realm have been extensively studied from the perspective of modifications to the post-cranial skeleton. In recent years, imaging techniques such as computed tomography have permitted the acquisition of anatomical data from previously inaccessible sources. An exquisitely preserved specimen of the plioplatecarpine mosasaur Plioplatecarpus peckensis presents an opportunity to examine the detailed structure of the braincase, as well as the form of the otic capsule endocast. These data elaborate upon previous descriptions of the braincase of Plioplatecarpus, and provide a detailed, three dimensional reconstruction of the osseous labyrinth for the first time. The otic capsule endocasts reveal that the size of the labyrinth relative to head size is comparable to that of other squamates, suggesting that labyrinth size was not a factor in increasing sensitivity. However, all three semicircular canals are tall and strongly arced to a degree comparable to, and even exceeding, that observed in arboreal and aquatic lizards. Comparison of the sensitivity of the canals in each of the three major axes of rotation suggests Plioplatecarpus peckensis may have been most sensitive to movements in the pitch axis. Although early mosasaurs were probably anguilliform swimmers, most are thought to have been subcarangiform to thunniform locomotors with a near-rigid body form and likely decreased maneuverability. The data from the labyrinth presented here add a potential new dimension to this model of locomotion for further consideration, wherein changes in orientation, such as pitch, may have been more common locomotor behaviors than previously thought. PMID- 26052685 TI - Humic acid adsorption onto cationic cellulose nanofibers for bioinspired removal of copper(II) and a positively charged dye. AB - Waste pulp residues are herein exploited for the synthesis of a sorbent for humic acid (HA), which is a major water pollutant. Cellulose pulp was etherified with a quaternary ammonium salt in water thereby introducing positive charges onto the surface of the pulp fibers, and subsequently mechanically disintegrated into high surface area cellulose nanofibers (CNF). CNF with three different charge contents were produced and their adsorption capacity towards HA was investigated with UV spectrophotometry, quartz crystal microbalance with dissipation, and zeta potential measurements. Substantial coverage of the CNF surface with HA in a wide pH range led to a reversal of the positive zeta-potentials of CNF suspensions. The HA adsorption capacity and the kinetics of HA uptake were found to be promoted by both acidic pH conditions and the surface charge content of CNF. It is suggested that HA adsorption onto CNF depends on electrostatic interactions between the two components, as well as on the conformation of HA. At pH ~ 6, up to 310 mg g(-1) of HA were adsorbed by the functionalized CNF, a substantially higher capacity than that of previously reported HA sorbents in the literature. It is further shown that CNF-HA complexes could be freeze-dried into "soil mimicking" porous foams having good capacity to capture Cu(II) ions and positive dyes from contaminated water. Thus, the most abundant natural polymer, i.e., cellulose could effectively bind the most abundant natural organic matter for environmental remediation purpose. PMID- 26052686 TI - Analysis of functional outcomes in patients with mandible reconstruction using vascularized fibular grafts. AB - BACKGROUNDS: Although a vascularized fibular graft (VFG) is the favored method for mandible reconstruction, only few functional reports have been published. In this study, surgical outcomes and functional results after mandible reconstruction were analyzed. PATIENTS AND METHODS: From 1999 through 2010, oromandibular defects after segmental mandibulectomy were reconstructed with VFG in 101 patients. Operative outcomes and subjective functional evaluation was performed. Of these, 44 patients could be evaluated for functional outcomes, and bite force was measured with an occlusal force meter in 24 patients. RESULTS: Major surgical complications required secondary revisional surgery developed in four patients. A normal diet was possible in 37 patients (84.1%), and a soft diet was possible in 7 patients (15.9%). Conversational ability was rated as excellent in 42 patients (95.5%). The mean bite force on the nonaffected side of the mandible was 187.7 N, and bite force decreased as the number of osteotomies in the VFG increased. Furthermore, bite force was significantly lower (P = 0.001) on the affected side (58.2 N), compared to nonaffected side (191.9 N). CONCLUSIONS: Although masticatory force decreases as the number of osteotomies increases, oral function after mandible reconstruction is satisfactory in most cases. Transfer of a VFG is a safe and reliable method for functional mandible reconstruction. (c) 2015 Wiley Periodicals, Inc. Microsurgery 37:101-104, 2017. PMID- 26052687 TI - Cognitive Tests to Detect Dementia: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Dementia is a global public health problem. The Mini-Mental State Examination (MMSE) is a proprietary instrument for detecting dementia, but many other tests are also available. OBJECTIVE: To evaluate the diagnostic performance of all cognitive tests for the detection of dementia. DATA SOURCES: Literature searches were performed on the list of dementia screening tests in MEDLINE, EMBASE, and PsychoINFO from the earliest available dates stated in the individual databases until September 1, 2014. Because Google Scholar searches literature with a combined ranking algorithm on citation counts and keywords in each article, our literature search was extended to Google Scholar with individual test names and dementia screening as a supplementary search. STUDY SELECTION: Studies were eligible if participants were interviewed face to face with respective screening tests, and findings were compared with criterion standard diagnostic criteria for dementia. Bivariate random-effects models were used, and the area under the summary receiver-operating characteristic curve was used to present the overall performance. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, and positive and negative likelihood ratios were the main outcomes. RESULTS: Eleven screening tests were identified among 149 studies with more than 49,000 participants. Most studies used the MMSE (n = 102) and included 10,263 patients with dementia. The combined sensitivity and specificity for detection of dementia were 0.81 (95% CI, 0.78-0.84) and 0.89 (95% CI, 0.87-0.91), respectively. Among the other 10 tests, the Mini-Cog test and Addenbrooke's Cognitive Examination-Revised (ACE-R) had the best diagnostic performances, which were comparable to that of the MMSE (Mini-Cog, 0.91 sensitivity and 0.86 specificity; ACE-R, 0.92 sensitivity and 0.89 specificity). Subgroup analysis revealed that only the Montreal Cognitive Assessment had comparable performance to the MMSE on detection of mild cognitive impairment with 0.89 sensitivity and 0.75 specificity. CONCLUSIONS AND RELEVANCE: Besides the MMSE, there are many other tests with comparable diagnostic performance for detecting dementia. The Mini-Cog test and the ACE-R are the best alternative screening tests for dementia, and the Montreal Cognitive Assessment is the best alternative for mild cognitive impairment. PMID- 26052688 TI - Correction: Sequential separation of ultra-trace U, Th, Pb, and lanthanides using a simple automatic system. AB - Correction for 'Sequential separation of ultra-trace U, Th, Pb, and lanthanides using a simple automatic system' by Yutaka Miyamoto, et al., Analyst, 2015, DOI: 10.1039/c5an00027k. PMID- 26052689 TI - Second-line chemotherapy for advanced biliary tract cancer after failure of the gemcitabine-platinum combination: A large multicenter study by the Association des Gastro-Enterologues Oncologues. AB - BACKGROUND: Few data are available on second-line chemotherapy (CT2) for advanced biliary tract cancer (ABTC). The aim of this multicenter study was to describe the CT2 regimens used, the response rates, and the outcomes of patients treated with various CT2 regimens. METHODS: Patients who received CT2 for ABTC at 17 French institutions after the failure of the gemcitabine-platinum combination were retrospectively studied. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Cox models were used for multivariate analyses. RESULTS: Among 603 patients who received first-line chemotherapy (CT1) for ABTC, 196 received CT2: 5-fluorouracil (5-FU) and irinotecan (n = 64), 5-FU and oxaliplatin (n = 21), 5-FU and cisplatin (n = 38), 5-FU or capecitabine (n = 40), sunitinib (n = 10), or other various regimens (n = 23). Among the 186 assessable patients, there were 22 partial responses and 70 stabilizations. After a median follow-up of 26.4 months, the median PFS and OS were 3.2 and 6.7 months, respectively. There was no significant difference in PFS or OS between CT2 regimens. Fluoropyrimidine-based doublet chemotherapy was not superior to fluoropyrimidine alone in terms of OS and PFS. In a multivariate analysis, a performance status of 0 to 1, disease control with CT1, and a carbohydrate antigen 19-9 (CA 19-9) level <= 400 IU/mL were significantly associated with longer PFS and OS. Grade 3 to 4 toxicity occurred in 32% of the patients. CONCLUSIONS: CT2 might provide disease control for selected patients with ABTC after the failure of gemcitabine-platinum, but the prognosis remains poor. No particular regimen seems superior to others, and this calls for new treatments. A good performance status, disease control with CT1, and a low level of CA 19-9 were associated with longer survival. PMID- 26052690 TI - On the Use of Optically Stimulated Luminescent Dosimeter for Surface Dose Measurement during Radiotherapy. AB - This study was carried out to investigate the suitability of using the optically stimulated luminescence dosimeter (OSLD) in measuring surface dose during radiotherapy. The water equivalent depth (WED) of the OSLD was first determined by comparing the surface dose measured using the OSLD with the percentage depth dose at the buildup region measured using a Markus ionization chamber. Surface doses were measured on a solid water phantom using the OSLD and compared against the Markus ionization chamber and Gafchromic EBT3 film measurements. The effect of incident beam angles on surface dose was also studied. The OSLD was subsequently used to measure surface dose during tangential breast radiotherapy treatments in a phantom study and in the clinical measurement of 10 patients. Surface dose to the treated breast or chest wall, and on the contralateral breast were measured. The WED of the OSLD was found to be at 0.4 mm. For surface dose measurement on a solid water phantom, the Markus ionization chamber measured 15.95% for 6 MV photon beam and 12.64% for 10 MV photon beam followed by EBT3 film (23.79% and 17.14%) and OSLD (37.77% and 25.38%). Surface dose increased with the increase of the incident beam angle. For phantom and patient breast surface dose measurement, the response of the OSLD was higher than EBT3 film. The in-vivo measurements were also compared with the treatment planning system predicted dose. The OSLD measured higher dose values compared to dose at the surface (Hp(0.0)) by a factor of 2.37 for 6 MV and 2.01 for 10 MV photon beams, respectively. The measurement of absorbed dose at the skin depth of 0.4 mm by the OSLD can still be a useful tool to assess radiation effects on the skin dermis layer. This knowledge can be used to prevent and manage potential acute skin reaction and late skin toxicity from radiotherapy treatments. PMID- 26052691 TI - Lean body mass, not FFA, predicts VLDL-TG secretion rate in healthy men. AB - OBJECTIVE: Triglyceride is a risk factor for cardiovascular disease. However, the impact of body composition and free fatty acid (FFA) levels on very-low-density lipoprotein triglyceride (VLDL-TG) secretion remains controversial. The aim was to identify predictors of VLDL-TG secretion in a data set compiled from seven previously published studies. METHODS: VLDL-TG kinetics was studied in 96 healthy men covering a wide span in body composition. A primed-constant infusion of ex vivo labeled [1-(14)C]-triolein VLDL-TG was used. Body composition was determined by dual X-ray absorptiometry and computed tomography scanning. Energy expenditure was measured by indirect calorimetry. Palmitate flux was measured by a [9,10 (3)H]-palmitate infusion. RESULTS: VLDL-TG secretion rate correlated significantly with body mass index (BMI), lean body mass (LBM), total fat mass, resting energy expenditure (REE), and insulin. A trend toward an inverse relationship between VLDL-TG secretion rate and FFA concentration was observed. In mixed model linear regression analysis, VLDL-TG secretion rate was positively associated with LBM (P = 0.03), and VLDL-TG clearance rate was inversely related to total fat mass (P < 0.01). CONCLUSIONS: LBM is a predictor of VLDL-TG secretion in healthy men, whereas FFA availability is not associated with VLDL-TG secretion. The work suggests reporting VLDL-TG secretion rates normalized for LBM when comparing subjects with differences in body composition. PMID- 26052692 TI - Detecting pan-cancer conserved microRNA modules from microRNA expression profiles across multiple cancers. AB - MicroRNAs (miRNAs) play an indispensable role in cancer initiation and progression. Different cancers have some common hallmarks in general. Analyzing miRNAs that consistently contribute to different cancers can help us to discover the relationship between miRNAs and traits shared by cancers. Most previous works focus on analyzing single miRNA. However, dysregulation of a single miRNA is generally not sufficient to contribute to complex cancer processes. In this study, we put emphasis on analyzing cooperation of miRNAs across cancers. We assume that miRNAs can cooperatively regulate oncogenic pathways and contribute to cancer hallmarks. Such a cooperation is modeled by a miRNA module referred to as a pan-cancer conserved miRNA module. The module consists of miRNAs which simultaneously regulate cancers and are significantly intra-correlated. A novel computational workflow for the module discovery is presented. Multiple modules are discovered from miRNA expression profiles using the method. The function of top two ranked modules are analyzed using the mRNAs which correlate to all the miRNAs in a module across cancers, inferring that the two modules function in regulating the cell cycle which relates to cancer hallmarks as self sufficiency in growth signals and insensitivity to antigrowth signals. Additionally, two novel miRNAs mir-590 and mir-629 are found to cooperate with well-known onco miRNAs in the modules to contribute to cancers. We also found that PTEN, which is a well known tumor suppressor that regulates the cell cycle, is a common target of miRNAs in the top-one module and cooperative control of PTEN can be a reason for the miRNAs' cooperation. We believe that analyzing the cooperative mechanism of the miRNAs in modules rather than focusing on only single miRNAs may help us know more about the complicated relationship between miRNAs and cancers and develop more effective treatment strategies for cancers. PMID- 26052693 TI - Liposome-Based in Vitro Evolution of Aminoacyl-tRNA Synthetase for Enhanced Pyrrolysine Derivative Incorporation. AB - Methanosarcina species pyrrolysyl-tRNA synthetase (PylRS) attaches Pyl to its cognate amber suppressor tRNA. The introduction of two mutations (Y384F and Y306A) into PylRS was previously shown to generate a mutant, designated LysZ-RS, that was able to attach N-benzyloxycarbonyl-L-lysine (LysZ) to its cognate tRNA. Despite the potential of LysZ derivatives, further LysZ-RS engineering has not been performed; consequently, we aimed to generate LysZ-RS mutants with improved LysZ incorporation activity through in vitro directed evolution. Using a liposome based in vitro compartmentalization (IVC) approach, we screened a randomly mutagenized gene library of LysZ-RS and obtained a mutant that showed increased LysZ incorporation activity both in vitro and in vivo. The ease and high flexibility of liposome-based IVC should enable the evolution of not only LysZ-RS that can attach various LysZ derivatives but also of other enzymes involved in protein translation. PMID- 26052694 TI - In-Silico Template Selection of In-Vitro Evolved Kalata B1 of Oldenlandia Affinis for Scaffolding Peptide-Based Drug Design. AB - Structural stability of Oldenlandia affinis cyclotide, kalata B1 of native (1NB1) and two mutants 2F2I ([P20D, V21K] kB1) and 2F2J ([W19K, P20N, V21K] kB1) was investigated. Single model analysis showed high number of intra-molecular interactions followed by more proportion of beta sheet contents in [P20D, V21K] kB1 as compared to that of native and the other mutant of kalata B1. Further, the modern conformational sampling approach, an alternate to classical molecular dynamics was introduced, which revealed that the [P20D, V21K] kB1 was identified as structurally stable one, substantiated by various structural events viz., root mean square deviation, root mean square fluctuation, and angular deviation by Ramachandran plot. Moreover, the statistically validated contours of polar surface area, hydrogen bond distribution and the distance of disulfide bridges also supported the priority of [P20D, V21K] kB1 with respect to stability. From this work, it is proposed that the [P20D, V21K] kB1 (2F2I) could be the best template for scaffolding peptide based drug design. PMID- 26052695 TI - Self-stigma of seeking treatment and being male predict an increased likelihood of having an undiagnosed eating disorder. AB - OBJECTIVE: To examine whether self-stigma of seeking psychological help and being male would be associated with an increased likelihood of having an undiagnosed eating disorder. METHOD: A multi-national sample of 360 individuals with diagnosed eating disorders and 125 individuals with undiagnosed eating disorders were recruited. Logistic regression was used to identify variables affecting the likelihood of having an undiagnosed eating disorder, including sex, self-stigma of seeking psychological help, and perceived stigma of having a mental illness, controlling for a broad range of covariates. RESULTS: Being male and reporting greater self-stigma of seeking psychological help was independently associated with an increased likelihood of being undiagnosed. Further, the association between self-stigma of seeking psychological help and increased likelihood of being undiagnosed was significantly stronger for males than for females. DISCUSSION: Perceived stigma associated with help-seeking may be a salient barrier to treatment for eating disorders-particularly among male sufferers. PMID- 26052696 TI - Can discrete joint action be synergistic? Studying the stabilization of interpersonal hand coordination. AB - The human perceptual-motor system is tightly coupled to the physical and informational dynamics of a task environment. These dynamics operate to constrain the high-dimensional order of the human movement system into low-dimensional, task-specific synergies-functional groupings of structural elements that are temporarily constrained to act as a single coordinated unit. The aim of the current study was to determine whether synergistic processes operate when coacting individuals coordinate to perform a discrete joint-action task. Pairs of participants sat next to each other and each used 1 arm to complete a pointer-to target task. Using the uncontrolled manifold (UCM) analysis for the first time in a discrete joint action, the structure of joint-angle variance was examined to determine whether there was synergistic organization of the degrees of freedom employed at the interpersonal or intrapersonal levels. The results revealed that the motor actions performed by coactors were synergistically organized at both the interpersonal and intrapersonal levels. More importantly, however, the interpersonal synergy was found to be significantly stronger than the intrapersonal synergies. Accordingly, the results provide clear evidence that coacting individuals can become temporarily organized to form single synergistic 2-person systems during performance of a discrete joint action. PMID- 26052697 TI - Synchronous imitation of continuous action sequences: The role of spatial and topological mapping. AB - What are the mapping mechanisms that enable people to synchronously imitate continuous action sequences observed in others? We investigated this question in 4 experiments that used a tapping task where participants synchronously performed alternating bimanual hand movements with a model presented in an egocentric or allocentric orientation. Their task was to tap in synchrony, with each hand matching the movements of the ipsilateral model hand as closely as possible. The results show that automatic establishment of topological mappings, where the performer's hand is mapped onto the model's anatomically matching hand even if the 2 are spatially misaligned, can interfere with maintaining spatial mappings (Experiments 1 and 2). The interference was particularly strong in musicians who have expertise in establishing topological mappings in continuous performance (Experiment 4). Adopting an unusual body posture greatly interfered with establishing spatial as well as topological mappings (Experiment 3). Together, the results suggest that synchronous imitation of continuous action sequences depends on flexible predictive models that simultaneously apply spatial and topological mapping constraints to enable an actor to act in synchrony with observed action sequences. PMID- 26052698 TI - Impact of Education on Weight in Newly Diagnosed Type 2 Diabetes: Every Little Bit Helps. AB - AIMS: Highly structured, intensive behavioral lifestyle interventions have been shown to be efficacious in research settings for type 2 diabetes management and weight loss. We sought to evaluate the benefit of participation in more limited counseling and/or education among individuals with newly diagnosed type 2 diabetes in more modest real-world clinical settings. METHODS: Electronic Health Records of newly diagnosed type 2 diabetes patients age 35-74 from a large ambulatory group practice were analyzed (n = 1,314). We examined participation in clinic-based lifestyle counseling/education and subsequent weight loss. RESULTS: Of the total cohort, 599 (45.6%) patients received counseling/education with (26.2%) and without (19.4%) medication, 298(22.7%) patients received a prescription for medication alone, and 417(31.7%) patients were only monitored. On average, those who participated in counseling/education attended 2.5 sessions (approximately 2-3 hours). The average weight loss of patients who received counseling/education alone during the follow-up period (up to three years post exposure to participation) was 6.3 lbs. (3.3% of body weight), and, if received with medication prescription, 8.1 lbs. (4.0% of body weight) (all at P<0.001). The weight loss associated with medication was only 3.5 lbs. (P<0.001). No significant weight change was observed in the monitoring only group. CONCLUSIONS: While efforts to improve both the short-term and long-term effectiveness of behavioral lifestyle interventions in real-world settings are ongoing, it is important for clinicians to continue to utilize less intensive, existing resources. Even relatively small "doses" of health education may help in promoting weight loss and may potentially reduce cardiometabolic risk. PMID- 26052699 TI - Validation and Reliability of a Classification Method to Measure the Time Spent Performing Different Activities. AB - The aim of this study was to validate the performance and reliability of results obtained from a classification model that measures time spent performing activities in confined (CE) and unrestricted (UE) environments. In CE, participants wore a pair of biaxial and/or triaxial accelerometers while performing pre-determined training activities classified as variants of lying down, dynamic standing, sitting, walking and running on two separate days. A classification model trained with activities performed in a specific order during the first day was developed to validate the activities performed in a random order on the second day (CE) and over 24 hours on a separate day (UE). The performance of the classification model was validated against triaxial accelerometers using six (x, y and step counts for arm and thigh) or eight (same as six features plus z axis) features. The reliability of the classification model was tested in both environments using six features. Results revealed an overall accuracy of 94% in CE and 90% in UE. The sensitivity in CE and UE was 94% and 95% for lying down, 88% and 80% for dynamic standing, 97% and 89% for sitting, 96% and 78% for walking and 90% and 64% for running, respectively. No significant differences were noted between performances obtained with six or eight features. Results were highly reproducible in both environments. The results obtained from the classification model were accurate and reproducible, and highlight the potential use of this approach in research to quantify the time spent performing different activities. PMID- 26052700 TI - Inhibition of Glycoprotein VI Clustering by Collagen as a Mechanism of Inhibiting Collagen-Induced Platelet Responses: The Example of Losartan. AB - Exposure of platelets to collagen triggers the formation of a platelet clot. Pharmacological agents capable of inhibiting platelet activation by collagen are thus of potential therapeutic interest. Thrombus formation is initiated by the interaction of the GPIb-V-IX complex with collagen-bound vWF, while GPVI interaction with collagen triggers platelet activation that is reinforced by ADP and thromboxane A2. Losartan is an angiotensin II (Ang II) type I receptor (AT1R) antagonist proposed to have an antiplatelet activity via the inhibition of both the thromboxane A2 (TXA2) receptor (TP) and the glycoprotein VI (GPVI). Here, we characterized in vitro the effects of losartan at different doses on platelet responses: losartan inhibited platelet aggregation and secretion induced by 1 MUg . mL(-1) and 10 MUg . mL(-1) of collagen with an IC50 of ~ 6 MUM. Losartan inhibited platelet responses induced by the GPVI specific collagen related peptide but not by the alpha2beta1 specific peptide. However, losartan did not inhibit the binding of recombinant GPVI to collagen, which is not in favor of a simple competition. Indeed, the clustering of GPVI observed in flow cytometry and using the Duolink methodology, was inhibited by losartan. The impact of a therapeutic dose of losartan (100 mg/day) on platelet responses was analyzed ex vivo in a double blind study. No statistically significant differences were observed between losartan-treated (n=25) and non-treated (n=30) patients in terms of collagen and U46619-induced platelet activation. These data indicate that in treated patients, losartan does not achieve a measurable antiplatelet effect but provide the proof of concept that inhibiting collagen-induced GPVI clustering is of pharmacological interest to obtain an antithrombotic efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00763893. PMID- 26052701 TI - Prevalence of Non-Tuberculosis Mycobacterial Infections among Tuberculosis Suspects in Iran: Systematic Review and Meta-Analysis. AB - INTRODUCTION: The infections due to Non-Tuberculosis Mycobacteria (NTM) are becoming an important health problem in many countries in the world. Globally, an increase in NTM infections has been reported from many countries around the world. However, limited information is available about the prevalence of NTM infections in Iran. MATERIAL AND METHODS: The data of the prevalence of NTM infections were collected from databases such as PubMed, Web of science, Cochrane Library, Embase, Scopus, Iranmedex, and Scientific Information Database. Comprehensive Meta-Analysis (V2.0, Biostat) software was used to analyze the data. RESULTS: The meta-analyses showed that the prevalence of NTM infections was 10.2% (95% confidence interval [95% CI] 6.3-15.9) among culture-positive cases of tuberculosis (TB) in Iran. The further stratified analyses indicated that the prevalence of NTM was higher in studies that were done after year 2000. Additionally, M. simiae (43.3% [95% CI 36.8-50.0]), M. intracellucar (27.3% [95% CI 0.7-95.5]) and M. fortuitum (22.7% [95% CI 16.1-30.9]) were the most prevalent NTM species, respectively. DISCUSSION: The relatively high prevalence of NTM infections (10.2%) among culture positive cases for TB underlines the need for greater enforcement of infection control strategies. Establishment of appropriate diagnostic criteria and management guidelines for NTM diseases and expanding the number and quality of regional reference laboratories may facilitate more accurate action for prevention and control of NTM infections in Iran. PMID- 26052702 TI - BIG3 Inhibits the Estrogen-Dependent Nuclear Translocation of PHB2 via Multiple Karyopherin-Alpha Proteins in Breast Cancer Cells. AB - We recently reported that brefeldin A-inhibited guanine nucleotide-exchange protein 3 (BIG3) binds Prohibitin 2 (PHB2) in cytoplasm, thereby causing a loss of function of the PHB2 tumor suppressor in the nuclei of breast cancer cells. However, little is known regarding the mechanism by which BIG3 inhibits the nuclear translocation of PHB2 into breast cancer cells. Here, we report that BIG3 blocks the estrogen (E2)-dependent nuclear import of PHB2 via the karyopherin alpha (KPNA) family in breast cancer cells. We found that overexpressed PHB2 interacted with KPNA1, KPNA5, and KPNA6, thereby leading to the E2-dependent translocation of PHB2 into the nuclei of breast cancer cells. More importantly, knockdown of each endogenous KPNA by siRNA caused a significant inhibition of E2 dependent translocation of PHB2 in BIG3-depleted breast cancer cells, thereby enhancing activation of estrogen receptor alpha (ERalpha). These data indicated that BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2, thereby leading to inhibition of KPNAs-mediated PHB2 nuclear translocation in the presence of E2 in breast cancer cells. Understanding this regulation of PHB2 nuclear import may provide therapeutic strategies for controlling E2/ERalpha signals in breast cancer cells. PMID- 26052703 TI - Valuation of Normal Range of Ankle Systolic Blood Pressure in Subjects with Normal Arm Systolic Blood Pressure. AB - SUBJECT: This study aimed to establish a normal range for ankle systolic blood pressure (SBP). METHODS: A total of 948 subjects who had normal brachial SBP (90 139 mmHg) at investigation were enrolled. Supine BP of four limbs was simultaneously measured using four automatic BP measurement devices. The ankle arm difference (An-a) on SBP of both sides was calculated. Two methods were used for establishing normal range of ankle SBP: the 99% method was decided on the 99% reference range of actual ankle BP, and the An-a method was the sum of An-a and the low or up limits of normal arm SBP (90-139 mmHg). RESULTS: Whether in the right or left side, the ankle SBP was significantly higher than the arm SBP (right: 137.1 +/- 16.9 vs 119.7 +/- 11.4 mmHg, P<0.05). Based on the 99% method, the normal range of ankle SBP was 94~181 mmHg for the total population, 84~166 mmHg for the young (18-44 y), 107~176 mmHg for the middle-aged(45-59 y) and 113~179 mmHg for the elderly (>= 60 y) group. As the An-a on SBP was 13 mmHg in the young group and 20 mmHg in both middle-aged and elderly groups, the normal range of ankle SBP on the An-a method was 103-153 mmHg for young and 110-160 mmHg for middle-elderly subjects. CONCLUSION: A primary reference for normal ankle SBP was suggested as 100-165 mmHg in the young and 110-170 mmHg in the middle-elderly subjects. PMID- 26052704 TI - Malaria in Pregnancy Is a Predictor of Infant Haemoglobin Concentrations during the First Year of Life in Benin, West Africa. AB - BACKGROUND: Anaemia is an increasingly recognized health problem in Africa, particularly in infants and pregnant women. Although malaria is known to be the main risk factor of anaemia in both groups, the consequences of maternal factors, particularly malaria in pregnancy (MiP), on infant haemoglobin (Hb) concentrations during the first months of life are still unclear. METHODS: We followed-up a cohort of 1005 Beninese pregnant women from the beginning of pregnancy until delivery. A subsample composed of the first 400 offspring of these women were selected at birth and followed until the first year of life. Placental histology and blood smear at 1st clinical antenatal visit (ANC), 2nd ANC and delivery were used to assess malaria during pregnancy. Infant Hb concentrations were measured at birth, 6, 9 and 12 months of age. A mixed multi level model was used to assess the association between MiP and infant Hb variations during the first 12 months of life. RESULTS: Placental malaria (difference mean [dm] = - 2.8 g/L, 95% CI [-5.3, -0.3], P = 0.03) and maternal peripheral parasitaemia at delivery (dm = - 4.6 g/L, 95% CI [-7.9, -1.3], P = 0.007) were the main maternal factors significantly associated with infant Hb concentrations during the first year of life. Poor maternal nutritional status and malaria infection during infancy were also significantly associated with a decrease in infant Hb. CONCLUSION: Antimalarial control and nutritional interventions before and during pregnancy should be reinforced to reduce specifically the incidence of infant anaemia, particularly in Sub-Saharan countries. PMID- 26052705 TI - Changes in Macrophage Gene Expression Associated with Leishmania (Viannia) braziliensis Infection. AB - Different Leishmania species cause distinct clinical manifestations of the infectious disease leishmaniasis. It is fundamentally important to understand the mechanisms governing the interaction between Leishmania and its host cell. Little is known about this interaction between Leishmania (Viannia) braziliensis and human macrophages. In this study, we aimed to identify differential gene expression between non-infected and L. (V) braziliensis-infected U937-derived macrophages. We deployed a whole human transcriptome microarray analysis using 72 hours post-infection samples and compared those samples with their non-infected counterparts. We found that 218 genes were differentially expressed between infected and non-infected macrophages. A total of 71.6% of these genes were down regulated in the infected macrophages. Functional enrichment analyses identified the steroid and sterol/cholesterol biosynthetic processes between regulatory networks down-regulated in infected macrophages. RT-qPCR further confirmed this down-regulation in genes belonging to these pathways. These findings contrast with those from studies involving other Leishmania species at earlier infection stages, where gene up-regulation for this metabolic pathway has been reported. Sterol biosynthesis could be an important biological process associated with the expression profile of macrophages infected by L. (V.) braziliensis. Differential transcriptional results suggest a negative regulation of the genetic regulatory network involved in cholesterol biosynthesis. PMID- 26052706 TI - Preliminary Observations of Population Genetics and Relatedness of the Broadnose Sevengill Shark, Notorynchus cepedianus, in Two Northeast Pacific Estuaries. AB - The broadnose sevengill shark, Notorynchus cepedianus, a common coastal species in the eastern North Pacific, was sampled during routine capture and tagging operations conducted from 2005-2012. One hundred and thirty three biopsy samples were taken during these research operations in Willapa Bay, Washington and in San Francisco Bay, California. Genotypic data from seven polymorphic microsatellites (derived from the related sixgill shark, Hexanchus griseus) were used to describe N. cepedianus genetic diversity, population structure and relatedness. Diversity within N. cepedianus was found to be low to moderate with an average observed heterozygosity of 0.41, expected heterozygosity of 0.53, and an average of 5.1 alleles per microsatellite locus. There was no evidence of a recent population bottleneck based on genetic data. Analyses of genetic differences between the two sampled estuaries suggest two distinct populations with some genetic mixing of sharks sampled during 2005-2006. Relatedness within sampled populations was high, with percent relatedness among sharks caught in the same area indicating 42.30% first-order relative relationships (full or half siblings). Estuary-specific familial relationships suggest that management of N. cepedianus on the U.S. West Coast should incorporate stock-specific management goals to conserve this ecologically important predator. PMID- 26052707 TI - The Role of Temporal Envelope and Fine Structure in Mandarin Lexical Tone Perception in Auditory Neuropathy Spectrum Disorder. AB - Temporal information in a signal can be partitioned into temporal envelope (E) and fine structure (FS). Fine structure is important for lexical tone perception for normal-hearing (NH) listeners, and listeners with sensorineural hearing loss (SNHL) have an impaired ability to use FS in lexical tone perception due to the reduced frequency resolution. The present study was aimed to assess which of the acoustic aspects (E or FS) played a more important role in lexical tone perception in subjects with auditory neuropathy spectrum disorder (ANSD) and to determine whether it was the deficit in temporal resolution or frequency resolution that might lead to more detrimental effects on FS processing in pitch perception. Fifty-eight native Mandarin Chinese-speaking subjects (27 with ANSD, 16 with SNHL, and 15 with NH) were assessed for (1) their ability to recognize lexical tones using acoustic E or FS cues with the "auditory chimera" technique, (2) temporal resolution as measured with temporal gap detection (TGD) threshold, and (3) frequency resolution as measured with the Q(10dB) values of the psychophysical tuning curves. Overall, 26.5%, 60.2%, and 92.1% of lexical tone responses were consistent with FS cues for tone perception for listeners with ANSD, SNHL, and NH, respectively. The mean TGD threshold was significantly higher for listeners with ANSD (11.9 ms) than for SNHL (4.0 ms; p < 0.001) and NH (3.9 ms; p < 0.001) listeners, with no significant difference between SNHL and NH listeners. In contrast, the mean Q(10dB) for listeners with SNHL (1.8 +/- 0.4) was significantly lower than that for ANSD (3.5 +/- 1.0; p < 0.001) and NH (3.4 +/- 0.9; p < 0.001) listeners, with no significant difference between ANSD and NH listeners. These results suggest that reduced temporal resolution, as opposed to reduced frequency selectivity, in ANSD subjects leads to greater degradation of FS processing for pitch perception. PMID- 26052709 TI - Breviscapine Injection Improves the Therapeutic Effect of Western Medicine on Angina Pectoris Patients. AB - To evaluate the beneficial and adverse effects of breviscapine injection in combination with Western medicine on the treatment of patients with angina pectoris. The Cochrane Central Register of Controlled Trials, Medline, Science Citation Index, EMBASE, the China National Knowledge Infrastructure, the Wanfang Database, the Chongqing VIP Information Database and the China Biomedical Database were searched to identify randomized clinical trials (RCTs) that evaluated the effects of Western medicine compared to breviscapine injection plus Western medicine on angina pectoris patients. The included studies were analyzed using RevMan 5.1.0 software. The literature search yielded 460 studies, wherein 16 studies matched the selection criteria. The results showed that combined therapy using Breviscapine plus Western medicine was superior to Western medicine alone for improving angina pectoris symptoms (OR=3.77, 95% Cl: 2.76~5.15) and also resulted in increased electrocardiogram (ECG) improvement (OR=2.77, 95% Cl: 2.16~3.53). The current evidence suggests that Breviscapine plus Western medicine achieved a superior therapeutic effect compared to Western medicine alone. PMID- 26052710 TI - Using the Fuzzy DEMATEL to Determine Environmental Performance: A Case of Printed Circuit Board Industry in Taiwan. AB - The method by which high-technology product manufacturers balance profits and environmental performance is of crucial concern for governments and enterprises. To examine the environmental performance of manufacturers, the present study applied Fuzzy-DEMATEL model to examine environmental performance of the PCB industry in Taiwan. Fuzzy theory was employed to examine the environmental performance criteria of manufacturers and analyse fuzzy linguistics. The fuzzy DEMATEL model was then employed to assess the direction and level of interaction between environmental performance criteria. The core environmental performance criteria which were critical for enhancing environmental performance of the PCB industry in Taiwan were identified and presented. The present study revealed that green design (a1), green material procurement (a2), and energy consumption (b3) constitute crucial reason criteria, the core criteria influencing other criteria, and the driving factors for resolving problems. PMID- 26052708 TI - Collagenase mRNA Overexpression and Decreased Extracellular Matrix Components Are Early Events in the Pathogenesis of Emphysema. AB - To describe the progression of parenchymal remodeling and metalloproteinases gene expression in earlier stages of emphysema, mice received porcine pancreatic elastase (PPE) instillation and Control groups received saline solution. After PPE instillation (1, 3, 6 hours, 3 and 21 days) we measured the mean linear intercept, the volume proportion of types I and III collagen, elastin, fibrillin and the MMP-1, -8, -12 and -13 gene expression. We observed an initial decrease in type I (at the 3rd day) and type III collagen (from the 6th hour until the 3rd day), in posterior time points in which we detected increased gene expression for MMP-8 and -13 in PPE groups. After 21 days, the type III collagen fibers increased and the type I collagen values returned to similar values compared to control groups. The MMP-12 gene expression was increased in earlier times (3 and 6 hours) to which we detected a reduced proportion of elastin (3 days) in PPE groups, reinforcing the already established importance of MMP-12 in the breakdown of ECM. Such findings will be useful to better elucidate the alterations in ECM components and the importance of not only metalloelastase but also collagenases in earlier emphysema stages, providing new clues to novel therapeutic targets. PMID- 26052711 TI - Breach of belongingness: Newcomer relationship conflict, information, and task related outcomes during organizational socialization. AB - Previous studies of newcomer socialization have underlined the importance of newcomers' information seeking for their adjustment to the organization, and the conflict literature has consistently reported negative effects of relationship conflict with coworkers. However, to date, no study has examined the consequences of relationship conflict on newcomers' information seeking. In this study, we examined newcomers' reactions when they have relationship conflict with their coworkers, and hence cannot obtain necessary information from them. Drawing upon belongingness theory, we propose a model that moves from breach of belongingness to its proximal and distal consequences, to newcomer information seeking, and then to task-related outcomes. In particular, we propose that second paths exist first coworker-centric and the other supervisor-centric-that may have simultaneous yet contrasting influence on newcomer adjustment. To test our model, we employ a 3-wave data collection research design with egocentric and Likert type multisource surveys among a sample of new software engineers and their supervisors working in India. This study contributes to the field by linking the literatures on relationship conflict and newcomer information seeking and suggesting that despite conflict with coworkers, newcomers may succeed in organizations by building relationships with and obtaining information from supervisors. PMID- 26052712 TI - Social media: A contextual framework to guide research and practice. AB - Social media are a broad collection of digital platforms that have radically changed the way people interact and communicate. However, we argue that social media are not simply a technology but actually represent a context that differs in important ways from traditional (e.g., face-to-face) and other digital (e.g., email) ways of interacting and communicating. As a result, social media is a relatively unexamined type of context that may affect the cognition, affect, and behavior of individuals within organizations. We propose a contextual framework that identifies the discrete and ambient stimuli that distinguish social media contexts from digital communication media (e.g., email) and physical (e.g., face to-face) contexts. We then use this contextual framework to demonstrate how it changes more person-centered theories of organizational behavior (e.g., social exchange, social contagion, and social network theories). These theoretical insights are also used to identify a number of practical implications for individuals and organizations. This study's major contribution is creating a theoretical understanding of social media features so that future research may proceed in a theory-based, rather than platform-based, manner. Overall, we intend for this article to stimulate and broadly shape the direction of research on this ubiquitous, but poorly understood, phenomenon. PMID- 26052713 TI - Extending the multifoci perspective: The role of supervisor justice and moral identity in the relationship between customer justice and customer-directed sabotage. AB - The multifoci perspective of justice proposes that individuals tend to target their (in)justice reactions toward the perceived source of the mistreatment. Empirical support for target-specific reactions, however, has been mixed. To explore theoretically relevant reasons for these discrepant results and address unanswered questions in the multifoci justice literature, the present research examines how different justice sources might interactively predict target specific reactions, and whether these effects occur as a function of moral identity. Results from a sample of North American frontline service employees (N = 314, Study 1) showed that among employees with lower levels of moral identity, low supervisor justice exacerbated the association between low customer justice and customer-directed sabotage, whereas this exacerbation effect was not observed among employees with higher levels of moral identity. This 3-way interaction effect was replicated in a sample of South Korean employees (N = 265, Study 2). PMID- 26052714 TI - Within-individual increases in innovative behavior and creative, persuasion, and change self-efficacy over time: A social-cognitive theory perspective. AB - Studies of innovative behavior (the generation, dissemination, and implementation of new ideas) have generally overlooked the agency perspective on this important type of performance behavior. Guided by social-cognitive theory, we propose a moderated mediation relationship to explain why and how employees become motivated to make things happen through their innovative endeavors. First, we propose that within-individual increases in organizational trust and perceived respect by colleagues promote within-individual increases in creative, persuasion, and change self-efficacy over time. Second, we propose that within individual increases in self-efficacy beliefs promote within-individual increases in idea generation, dissemination, and implementation over time. Finally, we propose that psychological collectivism (a between-individual variable) is a moderator, and that a higher level of psychological collectivism weakens the positive relationship between within-individual increases in self-efficacy beliefs and within-individual increases in innovative behavior. Repeated measures collected from 267 employees in Italy at 3 time points over an 8-month period generally support our proposed dynamic moderated mediation relationship. PMID- 26052715 TI - Postnatal Age Is a Critical Determinant of the Neonatal Host Response to Sepsis. AB - Neonates manifest a unique host response to sepsis even among other children. Preterm neonates may experience sepsis soon after birth or during often protracted birth hospitalizations as they attain physiologic maturity. We examined the transcriptome using genome-wide expression profiling on prospectively collected peripheral blood samples from infants evaluated for sepsis within 24 h after clinical presentation. Simultaneous plasma samples were examined for alterations in inflammatory mediators. Group designation (sepsis or uninfected) was determined retrospectively on the basis of clinical exam and laboratory results over the next 72 h from the time of evaluation. Unsupervised analysis showed the major node of separation between groups was timing of sepsis episode relative to birth (early, <3 d, or late, >=3 d). Principal component analyses revealed significant differences between patients with early or late sepsis despite the presence of similar key immunologic pathway aberrations in both groups. Unique to neonates, the uninfected state and host response to sepsis is significantly affected by timing relative to birth. Future therapeutic approaches may need to be tailored to the timing of the infectious event based on postnatal age. PMID- 26052717 TI - Association of parent-child relationships and executive functioning in South Asian adolescents. AB - OBJECTIVE: It is known that some environmental variables can significantly affect the development of executive functions (EF). The primary aim of this study was to analyze whether some family conditions, such as the adolescent's perception of the quality of parent-child relationships and the socioeconomic status (SES; assessed according to education, occupational status, and income) are significantly associated with EF test scores. METHODS: There were 370 Pakistani participants ranging in age 13 to 19 years who were selected and then individually administered the following tests taken from the Delis-Kaplan Executive Function System (D-KEFS): Trail Making Test (TMT), Design Fluency Test (DFT), Color Word Interference Test (CWIT), and Card Sorting Test (CST). In addition, a Parent-Child Relationship Scale (PCRS) also was administered. RESULTS: Results showed that perceived "neglect" in the PCRS was negatively associated with the 4 EF test scores. Parents' education and SES were positively associated with 3 EF measures: DFT, CWIT, and CST. Further correlational analyses revealed that inhibition (as measured with the CWIT) and problem-solving ability (as measured with the CST) were significantly associated with the perceived parent-child relationships. Some gender differences also were observed: males outperformed females on TMT, DFT, and CST, while females outperformed males in the CWIT. CONCLUSION: It was concluded that perceived parent-child relationships, SES, and parents' education are significantly associated with executive function test performance during adolescents. PMID- 26052718 TI - Action research regarding the optimisation of radiological protection for nurses during vascular interventional radiology. AB - The optimisation and decision-making processes for radiological protection have been broadened by the introduction of re-examination or feedback after introducing protective measures. In this study, action research was used to reduce the occupational exposure of vascular interventional radiology (IR) nurses. Four radiological protection improvement measures were continuously performed in cooperation with the researchers, nurses and stakeholders, and the nurses' annual effective doses were compared before and after the improvements. First, the dosimetry equipment was changed from one electronic personal dosimeter (EPD) to two silver-activated phosphate glass dosimeters (PGDs). Second, the nurses were educated regarding maintaining a safe distance from the sources of scattered and leakage radiation. Third, portable radiation shielding screens were placed in the IR rooms. Fourth, the x-ray units' pulse rates were reduced by half. On changing the dosimetry method, the two PGDs recorded a 4.4 fold greater dose than the single EPD. Educating nurses regarding radiological protection and reducing the pulse rates by half decreased their effective doses to one-third and two-fifths of the baseline dose, respectively. No significant difference in their doses was detected after the placement of the shielding screens. Therefore, the action research effectively decreased the occupational doses of the vascular IR nurses. PMID- 26052716 TI - Serum Amyloid A Stimulates PKR Expression and HMGB1 Release Possibly through TLR4/RAGE Receptors. AB - Serum amyloid A (SAA) proteins are known to be surrogate markers of sepsis, but their pathogenic roles remain poorly elucidated. Here we provide evidence to support a possible role of SAA as a pathogenic mediator of lethal sepsis. In a subset of septic patients for which serum high mobility group box 1 (HMGB1) levels paralleled the clinical scores, some anti-HMGB1 antibodies detected a 12 kDa protein belonging to the SAA family. In contrast to the most abundant SAA1, human SAA induced double-stranded RNA-activated protein kinase R (PKR) expression and HMGB1 release in the wild-type, but not toll-like receptor 4/receptor for advanced glycation end products (TLR4/RAGE)-deficient, macrophages. Pharmacological inhibition of PKR phosphorylation blocked SAA-induced HMGB1 release, suggesting an important role of PKR in SAA-induced HMGB1 release. In animal models of lethal endotoxemia and sepsis, recombinant SAA exacerbated endotoxemic lethality, whereas SAA-neutralizing immunoglobulins G (IgGs) significantly improved animal survival. Collectively, these findings have suggested SAA as an important mediator of inflammatory diseases. Highlights of this study include: human SAA is possibly only expressed in a subset of septic patients; SAA induces HMGB1 release via TLR4 and RAGE receptors; SAA supplementation worsens the outcome of lethal endotoxemia; whereas SAA neutralizing antibodies confer protection against lethal endotoxemia and sepsis. PMID- 26052719 TI - Preparation of robust polyamide microcapsules by interfacial polycondensation of p-phenylenediamine and sebacoyl chloride and plasticization with oleic acid. AB - Microcapsules produced by interfacial polycondensation of p-phenylenediamine (PPD) and sebacoyl chloride (SC) were studied. The products were characterized in terms of morphology, mean diameter and effectiveness of dodecane encapsulation. The use of Tween 20 as dispersion stabilizer, in comparison with polyvinyl alcohol (PVA), reduced considerably the mean diameter of the microcapsules and originated smoother wall surfaces. When compared to ethylenediamine (EDA), microcapsules produced with PPD monomer were more rigid and brittle, prone to fracture during processing and ineffective retention of the core liquid. The use of diethylenetriamine (DETA) cross-linker in combination with PPD did not decrease capsule fragility. On the other hand, addition of a small fraction of oleic acid to the organic phase remarkably improved wall toughness and lead to successful encapsulation of the core-oil. Oleic acid is believed to act as a plasticizer. Its incorporation in the polymeric wall was demonstrated by FTIR and (1)H-NMR. PMID- 26052720 TI - Mucoadhesive drug carrier based on functional-modified cellulose as poorly water soluble drug delivery system. AB - The purpose of this study was to design and characterise an oral mucoadhesive micellar drug carrier. In this regard, a mucoadhesive hydrophobic cationic aminocellulose was easily synthesised under mild homogeneous conditions with high yield. The cellulose derivative resulted in strongly improved mucoadhesive properties but was pH dependent. Furthermore, the hydrophobic anticancer drug camptothecin was successfully encapsulated into the mucoadhesive cellulose derivative micelles with spherical shape stability of 233 nm in diameter and low particle size distribution. The CPT-loaded nanocarriers provided high encapsulation efficiency about 86.4%. In vitro release, CPT-loaded cellulose derivative micelles showed a reduction in release rate compared with physically pure CPT solution. The release results also indicated that a sustained release of CPT to >80% over 4 d for pH 6.8 and 7.4. Therefore, mucoadhesive hydrophobic cationic aminocellulose micelles seem to be a promising carrier for various pharmaceutical applications especially for poorly water-soluble drug delivery system. PMID- 26052721 TI - Encapsulation of orange terpenes investigating a plasticisation extrusion process. AB - Extrusion is widely used for flavour encapsulation. However, there is a lack of process understanding. This study is aimed at improving the understanding of a counter rotating twin screw extrusion process. Orange terpenes as model flavour, maltodextrin and sucrose as matrix materials, and a water feed rate between 4.0% and 5.7% were applied. Product temperatures < 80 degrees C and specific mechanical energy inputs <260 Wh/kg resulted. Amorphous and partly crystalline samples were obtained. The loss of crystalline sucrose was linked to a dissolution process of the sugar in the available water amount. Melting of the excipients did not arise, resulting in a plasticisation extrusion process. Maximally 67% of the flavour was retained (corresponding to a 4.1% product flavour load). The flavour loss correlated with insufficient mixing during the process and flavour evaporation after extrusion. Based on these results, recommendations for an improved encapsulation process are given. PMID- 26052722 TI - Oral self-nanoemulsifying peptide drug delivery systems: impact of lipase on drug release. AB - It was the aim of this study to evaluate the impact of lipases on the release behaviour of a peptide drug from oral self-nanoemulsifying drug delivery systems. Octreotide was ion paired with the anionic surfactants deoxycholate, decanoate, oleate and dodecylsulphate. The lipophilic character of these complexes was characterised by determining the n-octanol/buffer pH 7.4 partition coefficient. In the following the most hydrophilic complex was incorporated in a likely lipase degradable self-nanoemulsifying drug delivery systems (SNEDDS) formulation containing a triglyceride (olive oil; Pharm.Eur.) and in a likely not lipase degradable SNEDDS containing lipids and surfactants without any ester bonds. After 1:100 dilutions in artificial intestinal fluid (AIF), the lipid droplets were characterised regarding size distribution. With these SNEDDS, drug release studies were performed in AIF with and without lipase. Results showed that the most hydrophobic complex can be formed with deoxycholate in an octreotide:anionic surfactant ratio of 1:5. Even 73.1 +/- 8.1% of it could be quantified in the n octanol phase. SNEDDS containing octreotide | olive oil | cremophor EL | propylene glycol (2|57|38|3) and octreotide | liquid paraffin | Brij 35 | propylene glycol | ethanol (2|66.5|25|5|1.5) showed after dilution in AIF, a mean droplet size of 232 +/- 53 nm and 235 +/- 50 nm, respectively. Drug release studies showed a sustained release of octreotide out of these formulations for at least 24 h, whereas > 80% of the drug was released within 2 h in the presence of lipase in the case of the triglyceride containing SNEEDS. In contrast the release profile from ester-free SNEDDS was not significantly altered (p < 0.05) due to the addition of lipase providing evidence for the stability of this formulation towards lipases. According to these results, SNEDDS could be identified as a useful tool for sustained oral peptide delivery taking an enzymatic degradation by intestinal lipases into considerations. PMID- 26052723 TI - Cinnamic acid derived compounds loaded into liposomes: antileishmanial activity, production standardisation and characterisation. AB - Synthetic compounds derived from cinnamic acid were tested in cultures containing the promastigote form of Leishmania amazonensis and the dimethylsulphoxide solution of B2 compound (2.0 mg/mL) led to a 92% decrease of leishmania in 96 h of treatment. Then, different liposomal systems (diameters ~200 nm) were prepared by the extrusion method in the presence and absence of compounds studied. DSC thermograms of the liposomes in the presence of these compounds caused changes in DeltaH, Tm and DeltaT1/2, compared to controls, indicating that there was an interaction of the compounds with the lipid bilayer. Assays with negatively charged liposomal systems containing these drugs in L. amazonensis cultures led to a 50-80% decrease in the number of leishmanias with a concentration to 100 times lower when compared to the B2 initial test. These liposomal systems are promoting more interaction and delivery of the compounds and proved to be an efficient, stable and promising system. PMID- 26052724 TI - Chitosan nanoparticles as adenosine carriers. AB - The objective of this research project was to evaluate the potential use of chitosan (CS) nanoparticles (NPs) as a drug delivery system for the molecule adenosine. Adenosine is an essential drug used for treating several health issues especially irregular heart rhythm. However, due to its extremely short half-life in vivo (<10 s), the effective delivery of adenosine in clinical applications is a significant challenge. In this research, adenosine was encapsulated into NPs formed by ionic gelation of CS. The encapsulation efficiency and loading capacity of 20% and 3% were obtained, respectively, by forming a complex between CS NPs and adenosine. The obtained CS NPs had a spherical shape in the size range of 260.6 +/- 20.1 nm. Spectrophotometry analysis of the adenosine released in vitro showed an initial burst release phase, a plateau phase, followed by a steady release over a week. PMID- 26052725 TI - Thyroid Status, Cardiac Function, and Mortality in Patients With Idiopathic Dilated Cardiomyopathy. AB - CONTEXT: Previous studies claiming a relationship between thyroid dysfunction and poor prognosis of heart failure (HF) had a major limitation in that they included patients with different etiologies. OBJECTIVE: With complete information of thyroid function profile from 458 consecutive patients with idiopathic dilated cardiomyopathy, we tested the hypothesis that thyroid status can independently influence mortality in patients with HF. Design, Patients, and Outcome Measure: The original cohort consisted of 572 consecutive patients with idiopathic dilated cardiomyopathy, and 458 patients remained at the end of follow-up. All patients took thyroid function tests and other regular examinations in hospital. The risk of mortality was evaluated based on free T3, TSH, and the whole thyroid function profile, respectively. RESULTS: The most frequent thyroid dysfunction was subclinical hypothyroidism (n = 41), followed by subclinical hyperthyroidism (n = 35), low-T3 syndrome (n = 17), and hypothyroidism (n = 12). Logistic analysis showed log-TSH and free T3 as independent predictors of exacerbated cardiac function (New York Heart Association stages III-IV vs New York Heart Association stages I-II). During the follow-up (17 +/- 8 mo), 111 cumulative deaths occurred. Hypothyroidism was the strongest predictor of mortality [hazard ratio (HR) 4.189; 95% confidence interval (CI) 2.118-8.283)], followed by low-T3 syndrome (HR 3.147; 95% CI 1.558-6.355) and subclinical hypothyroidism (HR 2.869; 95% CI 1.817 4.532). Subclinical hyperthyroidism showed no significant impact. CONCLUSIONS: We found a clear association between thyroid dysfunction and increased risk of mortality in idiopathic dilated cardiomyopathy with HF. These results suggest that monitoring thyroid function in HF patients is necessary, and further studies on the treatment of HF with thyroid dysfunction are needed. PMID- 26052726 TI - 1,25-Dihydroxyvitamin D Levels in Pediatric Intensive Care Units: Risk Factors and Association With Clinical Course. AB - CONTEXT: Multiple adult and some pediatric critical care studies have suggested that poor vitamin D status is associated with illness severity and outcome. The majority have evaluated vitamin D status through serum 25-hydroxyvitamin D [25(OH)D]. Critical illness-related organ dysfunction may result in impaired conversion of 25(OH)D to the active hormone 1,25-dihydroxyvitamin D [1,25(OH)2D]. Consequently 1,25(OH)2D levels could be an independent additive prognostic marker in the intensive care unit. OBJECTIVES: The distribution of 1,25(OH)2D levels, prevalence of low levels, investigation of risk factors, and tests for associations with markers of illness severity and outcome are reported. DESIGN, SETTING, AND PATIENTS: This was a secondary analysis of data and samples collected as part of a prospective cohort study in six Canadian pediatric intensive care units (PICUs). MAIN OUTCOME MEASURE: Admission blood 1,25(OH)2D concentrations were measured. RESULTS: The median cohort 1,25(OH)2D level was 93.3 pmol/L (interquartile range, 53.0-121.9) with 13% (95% confidence interval, 9-17) and 21% (95% confidence interval, 17-27) of patients having levels of <40 and <50 pmol/L, respectively. Low 1,25(OH)2D levels occurred more often in patients with low 25(OH)D and hepatic, renal, and parathyroid organ dysfunction. After adjustment for 25(OH)D, low 1,25(OH)2D levels were not associated with catecholamine or fluid administration, ventilation, PICU length of stay, or mortality. CONCLUSION: Critically ill children are at risk for low 1,25(OH)2D levels, particularly in the presence of established risk factors. However, the lack of association between the 1,25(OH)2D level and selected outcome measures, after controlling for 25(OH)D, does not suggest value in measuring this metabolite at the time of PICU admission. PMID- 26052727 TI - Physiological Levels of Melatonin Relate to Cognitive Function and Depressive Symptoms: The HEIJO-KYO Cohort. AB - CONTEXT: In contrast with randomized controlled trials, observational studies have suggested that physiological levels of melatonin are reduced in patients with dementia or depression, but the relationship has not been evaluated in large populations. OBJECTIVE: The objective was to determine the relationships between physiological levels of melatonin and cognitive function and depressive symptoms. DESIGN AND PARTICIPANTS: A cohort of 1105 community-dwelling elderly individuals was enrolled in this cross-sectional study (mean age, 71.8 +/- 7.1 y). MEASURES: Urinary 6-sulfatoxymelatonin excretion (UME) and Mini-Mental State Examination (MMSE; n = 935) and Geriatric Depression Scale (GDS; n = 1097) scores were measured as indices of physiological melatonin levels, cognitive function, and depressive symptoms, respectively. RESULTS: With increases in UME quartiles, the prevalence of cognitive impairment (MMSE score <= 26) and depressed mood (GDS score >= 6) significantly decreased (P for trend = .003 and .012, respectively). In multivariate logistic regression models, after adjusting for confounders such as age, gender, socioeconomic status, physical activity, and sleep/wake cycles, higher UME levels were significantly associated with lower odds ratios (ORs) for cognitive impairment and depressed mood (ORs: Q1 = 1.00; Q2 = 0.88 and 0.76; Q3 = 0.66 and 0.85; Q4 = 0.67 and 0.53; P for trend = .023 and .033, respectively). In addition, the highest UME group showed a significantly lower OR for depressed mood than the lowest UME group (Q4 vs Q1: OR, 0.53; 95% confidence interval, 0.32 0.89; P = .033). UME levels above the median value were significantly associated with a lower OR for cognitive impairment, even after further adjustment for depressive symptoms (OR = 0.74; 95% confidence interval, 0.55-0.99; P = .043). CONCLUSIONS: Significant associations of higher physiological melatonin levels with lower prevalence of cognitive impairment and depressed mood were revealed in a large general elderly population. The association between physiological melatonin levels and cognitive function was independent of depressive symptoms. PMID- 26052728 TI - Fibroblast Growth Factor 21 and Fetuin-A in Obese Adolescents With and Without Type 2 Diabetes. AB - CONTEXT: Hepatokines such as fetuin-A or fibroblast growth factor 21 (FGF21) are reasonable candidates affecting the pathophysiology of type 2 diabetes mellitus (T2DM). However, studies in humans at the onset of disease are scarce. OBJECTIVE: The objective of the study was to compare FGF21 and fetuin-A levels between adolescents with and without T2DM. DESIGN: This was a cross-sectional comparison of adolescents with and without T2DM. SETTING: The study was conducted at diabetes and obesity treatment centers. PATIENTS: Seventy-four predominantly Caucasian adolescents with T2DM aged 12-18 years and 74 body mass index (BMI)-, age-, and gender-matched controls participated in the study. INTERVENTION: There were no interventions. MAIN OUTCOME MEASURES: FGF21 and fetuin-A and their correlation to age, BMI, glycated hemoglobin, blood pressure, lipids, adiponectin, and leptin were measured. RESULTS: Adolescents with T2DM showed significant higher FGF21 serum concentrations compared with obese controls without T2DM [median 277 pg/mL (interquartile range [IQR] 161-586) vs 200 pg/mL (IQR 116-323), respectively, P = .009] and higher fetuin-A serum concentrations (median 0.30 g/L (IQR 0.27-0.33) vs 0.28 g/L (IQR 0.25-0.30), respectively, P = .005). In a multiple linear regression analysis, fetuin-A was positively associated with glycated hemoglobin [beta-coefficient 0.005 (95% confidence interval +/- 0.004), P = .013], negatively with adiponectin (beta-coefficient 0.004 (95% confidence interval +/-0.002, P = .006) but not with BMI, age, gender, ethnicity, or leptin. FGF21 was not associated with any parameter in multiple linear regression analysis. CONCLUSIONS: Increased FGF21 serum levels in obese adolescents with T2DM compared with obese adolescents without T2DM suggest a FGF21-resistant state in T2DM because FGF21 improves insulin sensitivity. The increase of fetuin-A levels in obese adolescents with T2DM supports the hypothesis that fetuin-A is involved in the pathogenesis of T2DM because this hepatokine leads to insulin resistance. PMID- 26052729 TI - Establishing a surgical skills laboratory and dissection curriculum for neurosurgical residency training. AB - Surgical education has been forced to evolve from the principles of its initial inception, in part due to external pressures brought about through changes in modern health care. Despite these pressures that can limit the surgical training experience, training programs are being held to higher standards of education to demonstrate and document trainee competency through core competencies and milestones. One of the methods used to augment the surgical training experience and to demonstrate trainee proficiency in technical skills is through a surgical skills laboratory. The authors have established a surgical skills laboratory by acquiring equipment and funding from nondepartmental resources, through institutional and private educational grants, along with product donations from industry. A separate educational curriculum for junior- and senior-level residents was devised and incorporated into the neurosurgical residency curriculum. The initial dissection curriculum focused on cranial approaches, with spine and peripheral nerve approaches added in subsequent years. The dissections were scheduled to maximize the use of cadaveric specimens, experimenting with techniques to best preserve the tissue for repeated uses. A survey of residents who participated in at least 1 year of the curriculum indicated that participation in the surgical skills laboratory translated into improved understanding of anatomical relationships and the development of technical skills that can be applied in the operating room. In addition to supplementing the technical training of surgical residents, a surgical skills laboratory with a dissection curriculum may be able to help provide uniformity of education across different neurosurgical training programs, as well as provide a tool to assess the progression of skills in surgical trainees. PMID- 26052730 TI - High prevalence of primary drug resistance in children with intrathoracic tuberculosis in India. AB - BACKGROUND: Drug susceptibility testing (DST) of Mycobacterium tuberculosis (Mtb) isolates is crucial for the effective treatment of tuberculosis. Data on DST patterns in Mtb isolates in childhood tuberculosis are scanty. AIMS: To determine drug resistance patterns in Mtb isolates from a paediatric TB cohort in North India. METHODS: 403 children aged 6 months to14 year with probable intrathoracic tuberculosis were enrolled prospectively. All were treatment-naive. 802 ambulatory-induced sputa (IS) and 787 gastric aspirate (GA) samples were cultured in BACTEC-MGIT960 system, and DST of the Mtb isolates was undertaken using the automated BACTEC-MGIT960 SIRE kit. RESULTS: Of the 403 children, 147 (36.4%) were culture-confirmed: 132 (89.8%) isolates were Mtb and 15 (10.2%) non-tuberculous mycobacteria (NTM). Five Mtb isolates were contaminated and the remaining 127 were subjected to in-vitro drug susceptibility testing against streptomycin, isoniazid, rifampicin and ethambutol. Twenty-six (20.47%) isolates were resistant to one or more drugs, seven (5.5%) were resistant to rifampicin singly or in combination, and 11 (8.7%) were resistant to isoniazid singly or in combination. Mono-resistance to isoniazid, rifampicin, streptomycin and ethambutol was detected in four (3.1%), one (0.8%), four (3.1%) and two (1.6%), respectively. Five children (3.9%) had MDR-TB; 101 (79.9%) children had Mtb isolates which were sensitive to all four drugs. CONCLUSIONS: The rifampicin and isoniazid resistance rates were much higher than those in the adult TB population in India. PMID- 26052731 TI - Factor structure and item level psychometrics of the Social Problem Solving Inventory-Revised: Short Form in traumatic brain injury. AB - Social problem-solving deficits characterise individuals with traumatic brain injury (TBI), and poor social problem solving interferes with daily functioning and productive lifestyles. Therefore, it is of vital importance to use the appropriate instrument to identify deficits in social problem solving for individuals with TBI. This study investigates factor structure and item-level psychometrics of the Social Problem Solving Inventory-Revised: Short Form (SPSI R:S), for adults with moderate and severe TBI. Secondary analysis of 90 adults with moderate and severe TBI who completed the SPSI-R:S was performed. An exploratory factor analysis (EFA), principal components analysis (PCA) and Rasch analysis examined the factor structure and item-level psychometrics of the SPSI R:S. The EFA showed three dominant factors, with positively worded items represented as the most definite factor. The other two factors are negative problem-solving orientation and skills; and negative problem-solving emotion. Rasch analyses confirmed the three factors are each unidimensional constructs. It was concluded that the total score interpretability of the SPSI-R:S may be challenging due to the multidimensional structure of the total measure. Instead, we propose using three separate SPSI-R:S subscores to measure social problem solving for the TBI population. PMID- 26052732 TI - Origin of the Individual Basicity of Corrole NH-Tautomers: A Quantum Chemical Study on Molecular Structure and Dynamics, Kinetics, and Thermodynamics. AB - Free-base corroles exist as individual NH-tautomers that may differ in their spectral and chemical properties. The present paper focuses on the origin of the basicity difference between two AB2-pyrimidinylcorrole NH-tautomers, which has been tentatively attributed to differences in the weak out-of-plane distortions of the pyrrolenic ring between two NH-tautomers. Using DFT-geometry optimizations, we show that the pyrroles involved in the NH-tautomerization process are approximately in-plane, whereas the other two pyrroles are tilted out of-plane in opposite directions. Alternative out-of-plane distortion patterns play a minor role, as revealed by ab initio molecular dynamics simulations. Given that the protonated corrole is a unique species, the energy difference between the two NH-tautomers equals the difference in protonation driving force between them. This energy difference increases with improved theoretical level of accounting for intermolecular interactions and dielectric screening of surface charges. The different charge distributions of the two NH-tautomers result in electrostatic potential distributions that effect a larger proton attraction in the case of the T1 tautomer than in the case of the T2 tautomer. In summary, our quantum chemical results show clearly a higher basicity of the T1 tautomer as compared to the T2 tautomer: The previously assumed pronounced out-of-plane tilt of the T1-nonprotonated nitrogen is verified by ab initio molecular dynamics simulations. Together with analysis of the electrostatic potential distribution we show that the nonprotonated nitrogen is not only tilted stronger but also significantly more accessible for protons in the case of T1 as compared to T2. Additionally, the thermodynamic basicity is higher for T1 than for T2. PMID- 26052733 TI - Abrupt Schottky Junctions in Al/Ge Nanowire Heterostructures. AB - In this Letter we report on the exploration of axial metal/semiconductor (Al/Ge) nanowire heterostructures with abrupt interfaces. The formation process is enabled by a thermal induced exchange reaction between the vapor-liquid-solid grown Ge nanowire and Al contact pads due to the substantially different diffusion behavior of Ge in Al and vice versa. Temperature-dependent I-V measurements revealed the metallic properties of the crystalline Al nanowire segments with a maximum current carrying capacity of about 0.8 MA/cm(2). Transmission electron microscopy (TEM) characterization has confirmed both the composition and crystalline nature of the pure Al nanowire segments. A very sharp interface between the ?111? oriented Ge nanowire and the reacted Al part was observed with a Schottky barrier height of 361 meV. To demonstrate the potential of this approach, a monolithic Al/Ge/Al heterostructure was used to fabricate a novel impact ionization device. PMID- 26052735 TI - Hydrogen-Bonded Multilayer Films Based on Poly(N-vinylamide) Derivatives and Tannic Acid. AB - Layer-by-layer (LbL) assembly based on hydrogen-bonding interactions is generating great interest for biomedical applications because it is composed of neutral polymers, while LbL assembly based on electrostatic interaction requires polycations which may induce toxicity issues. As a neutral polymer, poly(N vinylamide), which has low toxicity compared to poly(acrylamide), has the potential to fabricate LbL thin films via hydrogen-bonding interactions. Herein we report interpolymer complexes of poly(N-vinylamide)s and natural polyphenol tannic acid to form the multilayered thin film. Poly(N-vinylformamide) and poly(N vinylacetamide), which are water-soluble and insoluble in acetonitrile, could not form complexes with TA in water. On the other hand, N-alkylated poly(N vinylamide) such as poly(N-ethyl-N-vinylformamide) and poly(N-methyl-N vinylacetamide) was soluble in acetonitrile and allowed the LbL assembly to proceed with TA. Furthermore, the QCM frequency shift with films composed of poly(N-ethyl-N-vinylformamide) and TA were stable in water, while those of poly(N methyl-N-vinylacetamide) and TA were instable in water, possibly because formamide has lower steric hindrance compared to acetamide to allow stronger hydrogen-bonding interactions to take place. Thus, LbL assembly reactions with alkylated poly(N-vinylamide)s and TA were investigated and revealed that poly(N ethyl-N-formamide) and TA, which are water-soluble, effectively interacted with one another to generate water-stable hydrogen-bonded multilayered films. PMID- 26052734 TI - Determinants of Receptor- and Tissue-Specific Actions in Androgen Signaling. AB - The physiological androgens testosterone and 5alpha-dihydrotestosterone regulate the development and maintenance of primary and secondary male sexual characteristics through binding to the androgen receptor (AR), a ligand-dependent transcription factor. In addition, a number of nonreproductive tissues of both genders are subject to androgen regulation. AR is also a central target in the treatment of prostate cancer. A large number of studies over the last decade have characterized many regulatory aspects of the AR pathway, such as androgen dependent transcription programs, AR cistromes, and coregulatory proteins, mostly in cultured cells of prostate cancer origin. Moreover, recent work has revealed the presence of pioneer/licensing factors and chromatin modifications that are important to guide receptor recruitment onto appropriate chromatin loci in cell lines and in tissues under physiological conditions. Despite these advances, current knowledge related to the mechanisms responsible for receptor- and tissue specific actions of androgens is still relatively limited. Here, we review topics that pertain to these specificity issues at different levels, both in cultured cells and tissues in vivo, with a particular emphasis on the nature of the steroid, the response element sequence, the AR cistromes, pioneer/licensing factors, and coregulatory proteins. We conclude that liganded AR and its DNA response elements are required but are not sufficient for establishment of tissue specific transcription programs in vivo, and that AR-selective actions over other steroid receptors rely on relaxed rather than increased stringency of cis elements on chromatin. PMID- 26052736 TI - Letter to the Editor: Mobi-C cervical artificial disc. PMID- 26052737 TI - Efficient staining of actinomycetoma and eumycetoma grains using henna extract. AB - The use of natural, nontoxic, convenient and eco-friendly dyes for histopathological diagnosis avoids some of the synthetic dyes' hazards. I used an aqueous extract of henna at a concentration of 20 g/ml and acidified with acetic acid to stain mycetoma grains. Henna stained mycetoma grains orange-red to brown. The engulfed mycetoma grains within inflammatory cells stained well with henna extract compared to hematoxylin and eosin (H & E) and hexamine silver. PMID- 26052738 TI - Conjugated Polymer-Small Molecule Alloy Leads to High Efficient Ternary Organic Solar Cells. AB - Ternary organic solar cells are promising candidates for bulk heterojunction solar cells; however, improving the power conversion efficiency (PCE) is quite challenging because the ternary system is complicated on phase separation behavior. In this study, a ternary organic solar cell (OSC) with two donors, including one polymer (PTB7-Th), one small molecule (p-DTS(FBTTH2)2), and one acceptor (PC71BM), is fabricated. We propose the two donors in the ternary blend forms an alloy. A notable averaged PCE of 10.5% for ternary OSC is obtained due to the improvement of the fill factor (FF) and the short-circuit current density (J(sc)), and the open-circuit voltage (V(oc)) does not pin to the smaller V(oc) of the corresponding binary blends. A highly ordered face-on orientation of polymer molecules is obtained due to the formation of an alloy structure, which facilitates the enhancement of charge separation and transport and the reduction of charge recombination. This work indicates that a high crystallinity and the face-on orientation of polymers could be obtained by forming alloy with two miscible donors, thus paving a way to largely enhance the PCE of OSCs by using the ternary blend strategy. PMID- 26052739 TI - Electrocatalytic Hydrogen Evolution Reaction on Edges of a Few Layer Molybdenum Disulfide Nanodots. AB - The design and development of inexpensive highly efficient electrocatalysts for hydrogen production underpins several emerging clean-energy technologies. In this work, for the first time, molybdenum disulfide (MoS2) nanodots have been synthesized by ionic liquid assisted grinding exfoliation of bulk platelets and isolated by sequential centrifugation. The nanodots have a thickness of up to 7 layers (~4 nm) and an average lateral size smaller than 20 nm. Detailed structural characterization established that the nanodots retained the crystalline quality and low oxidation states of the bulk material. The small lateral size and reduced number of layers provided these nanodots with an easier path for the electron transport and plentiful active sites for the catalysis of hydrogen evolution reaction (HER) in acidic electrolyte. The MoS2 nanodots exhibited good durability and a Tafel slope of 61 mV dec(-1) with an estimated onset potential of -0.09 V vs RHE, which are considered among the best values achieved for 2H phase. It is envisaged that this work may provide a simplistic route to synthesize a wide range of 2D layered nanodots that have applications in water splitting and other energy related technologies. PMID- 26052740 TI - The impact of tertiary wastewater treatment on copper and zinc complexation. AB - Tightening quality standards for European waters has seen a move towards enhanced wastewater treatment technologies such as granulated organic carbon treatment and ozonation. Although these technologies are likely to be successful in degrading certain micro-organic contaminants, these may also destroy compounds which would otherwise complex and render metals significantly less toxic. This study examined the impact of enhanced tertiary treatment on the capacity of organic compounds within sewage effluents to complex copper and zinc. The data show that granulated organic carbon treatment removes a dissolved organic carbon (DOC) fraction that is unimportant to complexation such that no detrimental impact on complexation or metal bioavailability is likely to occur from this treatment type. High concentrations of ozone (>1 mg O3/mg DOC) are, however, likely to impact the complexation capacity for copper although this is unlikely to be important at the concentrations of copper typically found in effluent discharges or in rivers. Ozone treatment did not affect zinc complexation capacity. The complexation profiles of the sewage effluents show these to contain a category of non-humic ligand that appears unaffected by tertiary treatment and which displays a high affinity for zinc, suggesting these may substantially reduce the bioavailability of zinc in effluent discharges. The implication is that traditional metal bioavailability assessment approaches such as the biotic ligand model may overestimate zinc bioavailability in sewage effluents and effluent-impacted waters. PMID- 26052741 TI - Environmental Monitoring: Inferring the Diatom Index from Next-Generation Sequencing Data. AB - Diatoms are widely used as bioindicators for the assessment of water quality in rivers and streams. Classically, the diatom biotic indices are based on the relative abundance of morphologically identified species weighted by their autoecological value. Obtaining such indices is time-consuming, costly, and requires excellent taxonomic expertise, which is not always available. Here we tested the possibility to overcome these limitations using a next-generation sequencing (NGS) approach to identify and quantify diatoms found in environmental DNA and RNA samples. We analyzed 27 river sites in the Geneva area (Switzerland), in order to compare the values of the Swiss Diatom Index (DI-CH) computed either by microscopic quantification of diatom species or directly from NGS data. Despite gaps in the reference database and variations in relative abundance of analyzed species, the diatom index shows a significant correlation between morphological and molecular data indicating similar biological quality status for the majority of sites. This proof-of-concept study demonstrates the potential of the NGS approach for identification and quantification of diatoms in environmental samples, opening new avenues toward the routine application of genetic tools for bioassessment and biomonitoring of aquatic ecosystems. PMID- 26052742 TI - Group living in squamate reptiles: a review of evidence for stable aggregations. AB - How sociality evolves and is maintained remains a key question in evolutionary biology. Most studies to date have focused on insects, birds, and mammals but data from a wider range of taxonomic groups are essential to identify general patterns and processes. The extent of social behaviour among squamate reptiles is under-appreciated, yet they are a promising group for further studies. Living in aggregations is posited as an important step in the evolution of more complex sociality. We review data on aggregations among squamates and find evidence for some form of aggregations in 94 species across 22 families. Of these, 18 species across 7 families exhibited 'stable' aggregations that entail overlapping home ranges and stable membership in long-term (years) or seasonal aggregations. Phylogenetic analysis suggests that stable aggregations have evolved multiple times in squamates. We: (i) identify significant gaps in our understanding; (ii) outline key traits which should be the focus of future research; and (iii) outline the potential for utilising reproductive skew theory to provide insights into squamate sociality. PMID- 26052743 TI - Ultraviolet A1 phototherapy beyond morphea: experience in 83 patients. AB - BACKGROUND/PURPOSE: Ultraviolet A1 (UVA1) phototherapy has been used for over 15 years in the United States, primarily for the treatment of localized sclerosis and various sclerosing disorders. The objective was to describe use of UVA1 for dermatoses beyond localized sclerosis at two academic institutions. METHODS: Data from 83 patients treated with low- (20-40 J/cm(2) ), medium- (>40-80 J/cm(2) ), and high- (>80-120 J/cm(2) ) dose UVA1 phototherapy was retrospectively analyzed. The mean individual treatment dose (J/cm(2) ), the mean number of sessions, and the mean total dose (J/cm(2) ) were evaluated. Effectiveness was assessed by reviewing clinical examination notes from office visits. RESULTS: Good therapeutic efficacy was seen in patients with systemic sclerosis (SS, 16 patients), graft-versus-host disease (GVHD, 25 patients), and nephrogenic systemic fibrosis (NSF, 17 patients). A statistically significant a dose-response association was observed in the cases of SS, GVHD and NSF. Likelihood of clinical improvement from UVA1 phototherapy was very likely for medium- and high-dose regimens in SS, while this level of improvement was only observed in GVHD and NSF patients receiving high-dose UVA1. CONCLUSION: UVA1 phototherapy is effective and safe in the treatment of GVHD, NSF, SS, and mast cell disorders. High-dose regimens appear to be more effective than medium- and low-dose regimens for NSF and GVHD, while medium- and high-dose regimens outperform low-dose UVA1 in SS. PMID- 26052744 TI - The association between Polycystic Ovary Syndrome (PCOS) and metabolic syndrome: a statistical modelling approach. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) affects 12-21% of women. Women with PCOS exhibit clustering of metabolic features. We applied rigorous statistical methods to further understand the interplay between PCOS and metabolic features including insulin resistance, obesity and androgen status. DESIGN: Retrospective cross-sectional analysis. PATIENTS: Women with PCOS attending reproductive endocrine clinics in South Australia for the treatment of PCOS (n = 172). Women without PCOS (controls) in the same Australian region (n = 335) from the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), a national population based study (age- and BMI-matched within one standard deviation of the PCOS cohort). MEASUREMENTS: The factor structure for metabolic syndrome for women with PCOS and control groups was examined, specifically, the contribution of individual factors to metabolic syndrome and the association of hyperandrogenism with other metabolic factors. RESULTS: Women with PCOS demonstrated clustering of metabolic features that was not observed in the control group. Metabolic syndrome in the PCOS cohort was strongly represented by obesity (standardized factor loading = 0.95, P < 0.001) and insulin resistance factors (loading = 0.92, P < 0.001) and moderately by blood pressure (loading = 0.62, P < 0.001) and lipid factors (loading = 0.67, P = 0.002). On further analysis, the insulin resistance factor strongly correlated with the obesity (r = 0.70, P < 0.001) and lipid factors (r = 0.68, P < 0.001) and moderately with the blood pressure factor (loading = 0.43, P = 0.002). The hyperandrogenism factor was moderately correlated with the insulin resistance factor (r = 0.38, P < 0.003), but did not correlate with any other metabolic factors. CONCLUSIONS: PCOS women are more likely to display metabolic clustering in comparison with age- and BMI-matched control women. Obesity and insulin resistance, but not androgens, are independently and most strongly associated with metabolic syndrome in PCOS. PMID- 26052746 TI - Are Chronic and Episodic Migraine Distinct Neurophysiological Entities? More Research is Needed. PMID- 26052745 TI - Mortality in incident dementia - results from the German Study on Aging, Cognition, and Dementia in Primary Care Patients. AB - OBJECTIVE: Dementia is known to increase mortality, but the relative loss of life years and contributing factors are not well established. Thus, we aimed to investigate mortality in incident dementia from disease onset. METHOD: Data were derived from the prospective longitudinal German AgeCoDe study. We used proportional hazards models to assess the impact of sociodemographic and health characteristics on mortality after dementia onset, Kaplan-Meier method for median survival times. RESULTS: Of 3214 subjects at risk, 523 (16.3%) developed incident dementia during a 9-year follow-up period. Median survival time after onset was 3.2 years (95% CI = 2.8-3.7) at a mean age of 85.0 (SD = 4.0) years (>=2.6 life years lost compared with the general German population). Survival was shorter in older age, males other dementias than Alzheimer's, and in the absence of subjective memory complaints (SMC). CONCLUSION: Our findings emphasize that dementia substantially shortens life expectancy. Future studies should further investigate the potential impact of SMC on mortality in dementia. PMID- 26052747 TI - Glycosylphosphatidylinositol-anchored proteins as chaperones and co-receptors for FERONIA receptor kinase signaling in Arabidopsis. AB - The Arabidopsis receptor kinase FERONIA (FER) is a multifunctional regulator for plant growth and reproduction. Here we report that the female gametophyte expressed glycosylphosphatidylinositol-anchored protein (GPI-AP) LORELEI and the seedling-expressed LRE-like GPI-AP1 (LLG1) bind to the extracellular juxtamembrane region of FER and show that this interaction is pivotal for FER function. LLG1 interacts with FER in the endoplasmic reticulum and on the cell surface, and loss of LLG1 function induces cytoplasmic retention of FER, consistent with transport of FER from the endoplasmic reticulum to the plasma membrane in a complex with LLG1. We further demonstrate that LLG1 is a component of the FER-regulated RHO GTPase signaling complex and that fer and llg1 mutants display indistinguishable growth, developmental and signaling phenotypes, analogous to how lre and fer share similar reproductive defects. Together our results support LLG1/LRE acting as a chaperone and co-receptor for FER and elucidate a mechanism by which GPI-APs enable the signaling capacity of a cell surface receptor. PMID- 26052748 TI - Functional topography of the human entorhinal cortex. AB - Despite extensive research on the role of the rodent medial and lateral entorhinal cortex (MEC/LEC) in spatial navigation, memory and related disease, their human homologues remain elusive. Here, we combine high-field functional magnetic resonance imaging at 7 T with novel data-driven and model-based analyses to identify corresponding subregions in humans based on the well-known global connectivity fingerprints in rodents and sensitivity to spatial and non-spatial information. We provide evidence for a functional division primarily along the anteroposterior axis. Localising the human homologue of the rodent MEC and LEC has important implications for translating studies on the hippocampo-entorhinal memory system from rodents to humans. PMID- 26052750 TI - Highly Selective and Sensitive Luminescence Turn-On-Based Sensing of Al(3+) Ions in Aqueous Medium Using a MOF with Free Functional Sites. AB - A new metal-organic framework [Co(OBA)(DATZ)0.5(H2O)] {OBA = 4,4'-oxybis(benzoic acid) and DATZ = 3,5-diamino-1,2,4-triazole}, 1, was synthesized by hydrothermal reaction. Single-crystal X-ray data of 1 confirmed two-dimensional rhombus grid network topology with a free nitrogen site of triazole ring and two amine groups of each DATZ. Photoluminescence study of 1 in aqueous medium shows blue emission at 407 nm upon excitation at 283 nm. This emissive property was used for the sensing of Al(3+) ions in aqueous medium through very high luminescence turn-on (6.3-fold) along with the blue shifting (~24 nm) of the emission peak. However, luminescence studies in the presence of other common metal ions such as Mg(2+), Zn(2+), Ni(2+), Co(2+), Mn(2+), K(+), Na(+), Ca(2+), Cd(2+), Hg(2+), Cu(2+), Fe(2+), Fe(3+), and Cr(3+) in aqueous medium shows luminescence quenching in varying extent. Interestingly, the luminescence turn-on-based selectivity of Al(3+) ions in aqueous medium was achieved even in the presence of the highest quenchable metal ion, Fe(3+). Furthermore, very high sensitivity was observed in the case of Al(3+) ions with a limit of detection of Al(3+) of 57.5 ppb, which is significantly lower than the higher limit of U.S. Environmental Protection Agency recommendation of Al(3+) ion for drinking water (200 ppb). PMID- 26052749 TI - Functional subregions of the human entorhinal cortex. AB - The entorhinal cortex (EC) is the primary site of interactions between the neocortex and hippocampus. Studies in rodents and nonhuman primates suggest that EC can be divided into subregions that connect differentially with perirhinal cortex (PRC) vs parahippocampal cortex (PHC) and with hippocampal subfields along the proximo-distal axis. Here, we used high-resolution functional magnetic resonance imaging at 7 Tesla to identify functional subdivisions of the human EC. In two independent datasets, PRC showed preferential intrinsic functional connectivity with anterior-lateral EC and PHC with posterior-medial EC. These EC subregions, in turn, exhibited differential connectivity with proximal and distal subiculum. In contrast, connectivity of PRC and PHC with subiculum followed not only a proximal-distal but also an anterior-posterior gradient. Our data provide the first evidence that the human EC can be divided into functional subdivisions whose functional connectivity closely parallels the known anatomical connectivity patterns of the rodent and nonhuman primate EC. PMID- 26052751 TI - Reliability of a retrospective decade-based life-course alcohol consumption questionnaire administered in later life. AB - BACKGROUND AND AIMS: Retrospective measures of alcohol intake are becoming increasingly popular; however, the reliability of such measures remains uncertain. This study assessed the reliability of a retrospective decade-based life-course alcohol consumption questionnaire, based on the standardized Alcohol Use Disorder Identification Test-Consumption (AUDIT-C) administered in older age in a well-characterized cohort study. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: A retrospective alcohol life-grid was administered to 5980 participants (72% male, mean age 70 years) in the Whitehall II study covering frequency of drinking, number of drinks in a typical drinking day and frequency of consuming six or more drinks in a single drinking occasion in the teens (16-19 years) through to the 80s. A subsample of 385 individuals completed a repeat survey to determine test-retest reliability. Retrospective measures were also compared with prospectively ascertained information and used to predict objectively measured systolic blood pressure to test their predictive validity. FINDINGS: Across all decades of life, test-retest reliability was generally good (kappa range = 0.62-0.78 for frequency, 0.55-0.62 for usual number of drinks and 0.57-0.65 for frequency of consuming six or more drinks in a single occasion). The concordance between prospective and retrospective measures was consistently moderate to high. The life-grid method performed better than a single question in identifying life-time abstainers. Retrospective measures were also related to systolic blood pressure in the manner anticipated. CONCLUSION: A retrospective decade-based AUDIT-C grid administered in older age provides a relatively reliable measure of alcohol consumption across the life-course. PMID- 26052752 TI - A new role for alpha-ketoglutarate dehydrogenase complex: regulating metabolism through post-translational modification of other enzymes. AB - This Editorial highlights a study by Gibson et al. published in this issue of JNeurochem, in which the authors reveal a novel role for the alpha-ketoglutarate dehydrogenase complex (KGDHC) in post-translational modification of proteins. KGDHC may catalyze post-translational modification of itself as well as several other proteins by succinylation of lysine residues. The authors' report of an enzyme responsible for succinylation of key mitochondrial enzymes represents a major step toward our understanding of the complex functional metabolome. TCA, tricarboxylic acid; KG, alpha-ketoglutarate; KGDHC, alpha-ketoglutarate dehydrogenase complex; FUM, fumarase; MDH, malate dehydrogenase; ME, malic enzyme; GDH, glutamate dehydrogenase; AAT, aspartate aminotransferase; GS, glutamine synthetase; PAG, phosphate-activated glutaminase; SIRT3, silent information regulator 3; SIRT5, silent information regulator 5. PMID- 26052753 TI - Emotion Dysregulation and Affective Intensity Mediate the Relationship Between Childhood Abuse and Suicide-Related Behaviors Among Women with Bulimia Nervosa. AB - Self-harm and suicide attempts occur at elevated rates among individuals with bulimia nervosa, particularly among those who have experienced childhood abuse. This study investigated the potential mediating roles of emotion dysregulation and affective intensity in the relationship between these variables in 125 women with bulimia nervosa. Analyses revealed that emotion dysregulation mediated the relationship between sexual and emotional abuse with both self-harm and suicide attempts. Negative affective intensity mediated the relationship between abuse and suicide attempts. The findings may advance the understanding of mechanisms underlying suicide-related behaviors in women with bulimia nervosa who experienced abuse and suggest potential clinical targets. PMID- 26052755 TI - The evolving role of effusion cytology in the diagnosis of malignant mesothelioma. PMID- 26052756 TI - The role of biomedical scientists in research. PMID- 26052758 TI - Morphology Quiz: Cervical Cytology. PMID- 26052757 TI - Guidelines for the Cytopathologic Diagnosis of Epithelioid and Mixed-Type Malignant Mesothelioma: a secondary publication. AB - OBJECTIVE: To provide practical guidelines for the cytopathologic diagnosis of malignant mesothelioma. DATA SOURCES: Cytopathologists with an interest in the field involved in the International Mesothelioma Interest Group (IMIG) and the International Academy of Cytology (IAC) contributed to this update. Reference material includes peer-reviewed publications and textbooks. RATIONALE: This article is the result of discussions during and after the IMIG 2012 conference in Boston, followed by thorough discussions during the 2013 IAC meeting in Paris. Additional contributions have been obtained from cytopathologists and scientists who could not attend these meetings, with final discussions and input during the IMIG 2014 conference in Cape Town. PMID- 26052759 TI - Diet-induced obesity alters anabolic signalling in mice at the onset of skeletal muscle regeneration. AB - AIM: Obesity is classified as a metabolic disorder that is associated with delayed muscle regeneration following damage. For optimal skeletal muscle regeneration, inflammation along with extracellular matrix remodelling and muscle growth must be tightly regulated. Moreover, the regenerative process is dependent on the activation of myogenic regulatory factors (MRFs) for myoblast proliferation and differentiation. The purpose of this study was to determine how obesity alters inflammatory and protein synthetic signalling and MRF expression at the onset of muscle regeneration in mice. METHODS: Forty-eight male C57BL/6J mice (3 weeks old) were randomly assigned to either a high-fat diet (HFD, 60% fat) or a lean diet (10% fat) for 12 weeks. At 15 weeks, bupivacaine was injected into the tibialis anterior (TA) of the injured group (n = 5-8/group) and PBS was injected into the control (n = 5-6). The TA was excised 3 or 28 days after injection. RESULTS: We demonstrated impaired muscle regeneration in obese mice. The obese mice had reduced IL-6, MyoD and IGF-1 mRNA abundance compared to the lean mice (P < 0.05). Three days following muscle damage, TNF-alpha mRNA and protein levels of P-STAT3 and P-Akt were 14-fold, fourfold and fivefold greater in the lean mice respectively. However, there were no differences observed in the obese injured group compared to the uninjured group. Moreover, p70S6K1 was threefold greater in lean injured mice compared to uninjured but was reduced by 28% in the obese injured mice. CONCLUSION: Obese mice have impaired inflammatory and protein synthetic signalling that may negatively influence muscle regeneration. PMID- 26052761 TI - Images of the Month: An Unusual Cause of Pancreatic Cancer. PMID- 26052762 TI - Images of the Month: A Polypoid Lesion in the Portal Vein. PMID- 26052763 TI - Images of the Month: Gastric Pneumatosis Due to Sevelamer-Mediated Necrosis. PMID- 26052764 TI - Images of the Month: Herniation of the Liver Through an Incisional Lumbar Hernia. PMID- 26052765 TI - Video of the Month: EUS-Guided Choledochoduodenstomy With a Cautery-Equipped Lumen-Apposing Stent Allows Future Biliary Access in Patients With Type 2 Duodenal Obstruction. PMID- 26052770 TI - Serial Fecal Calprotectin and Lactoferrin Measurements for Early Diagnosis of Pouchitis After Proctocolectomy for Ulcerative Colitis: Is Pouchoscopy No Longer Needed? AB - This editorial discusses the role of serial measurements of fecal calprotectin or fecal lactoferrin for the early detection of pouchitis in patients with ulcerative colitis having undergone procto-colectomy with ileo-pouch-anal anastomosis. Furthermore, the role of fecal calprotectin and fecal lactoferrin for the monitoring of pouchitis is highlighted. PMID- 26052771 TI - Response to Magro et al. PMID- 26052772 TI - Response to Irwin et al. PMID- 26052773 TI - Herbal Medicines, a Prominent Component in Complementary and Alternative Medicine Use in Gastrointestinal Field. PMID- 26052774 TI - Unsedated Transnasal Endoscopy (uTNE): Not Quite Ready to Replace Sedated Esophagogastroduodenoscopy (sEGD). PMID- 26052775 TI - Response to Pasalar et al. PMID- 26052776 TI - Response to Syed et al. PMID- 26052777 TI - Treatment With Anakinra, a Recombinant IL-1 Receptor Antagonist, Unlikely to Induce Lasting Remission in Patients With CGD Colitis. PMID- 26052778 TI - Hospital Readmissions in Decompensated Cirrhosis. PMID- 26052780 TI - Corrigendum: Impact of Retroflexion Vs. Second Forward View Examination of the Right Colon on Adenoma Detection: A Comparison Study. PMID- 26052781 TI - Corrigendum: Oral Prolonged Release Beclomethasone Dipropionate and Prednisone in the Treatment of Active Ulcerative Colitis: Results From a Double-Blind, Randomized, Parallel Group Study. PMID- 26052782 TI - Addendum: BOB CAT: A Large-Scale Review and Delphi Consensus for Management of Barrett's Esophagus With No Dysplasia, Indefinite for, or Low-Grade Dysplasia. PMID- 26052783 TI - Spatial structure, host heterogeneity and parasite virulence: implications for vaccine-driven evolution. AB - Natural host-parasite interactions exhibit considerable variation in host quality, with profound consequences for disease ecology and evolution. For instance, treatments (such as vaccination) may select for more transmissible or virulent strains. Previous theory has addressed the ecological and evolutionary impact of host heterogeneity under the assumption that hosts and parasites disperse globally. Here, we investigate the joint effects of host heterogeneity and local dispersal on the evolution of parasite life-history traits. We first formalise a general theoretical framework combining variation in host quality and spatial structure. We then apply this model to the specific problem of parasite evolution following vaccination. We show that, depending on the type of vaccine, spatial structure may select for higher or lower virulence compared to the predictions of non-spatial theory. We discuss the implications of our results for disease management, and their broader fundamental relevance for other causes of host heterogeneity in nature. PMID- 26052784 TI - Exploring the link between clinical managers involvement in budgeting and performance: Insights from the Italian public health care sector. AB - BACKGROUND: The public health care sector has had an increase in initiatives, mostly inspired by New Public Management principles, aimed at assigning financial accountability to clinical managers. However, clinical managers might experience a scarce alignment between professional values and organizational requirements, which is a potentially important phenomena that may result in negative consequences on clinical managers' job performance. PURPOSES: Building on Psychological Ownership Theory and adopting a psychology-based management accounting research approach, we focus on the managerial (nonmedical) role the clinical manager fulfills and explore the budgetary participation-performance link via the indirect effects of job-based psychological ownership, role clarity, and clinical managers' affective commitment toward managerial roles. METHODOLOGY/APPROACH: The data were collected by a survey conducted in an Italian hospital. The research hypotheses were tested employing a path model. FINDINGS: Our study revealed new insights that shed some light on underexplored processes through which mental states mediate the participation-performance link. Among these latter, the findings demonstrate that (a) budgetary participation has a direct effect on job-based psychological ownership; (b) role clarity mediates participation- and job-based psychological ownership link; (c) role clarity and job-based psychological ownership partially mediate the participation-commitment link; and (d) job-based psychological ownership, role clarity, and commitment fully mediate the participation-performance link. PRACTICE IMPLICATIONS: From a managerial viewpoint, an understanding of how clinical managers' feelings of ownership toward managerial roles could be enhanced is imperative in health care because ownership accounts for important attitudinal and organizational consequences. Results suggest that health care organizations that invest in budgetary participation will directly and indirectly affect clinical managers' psychological ownership, and this, along with role clarity, motivates clinical managers' managerial work attitudes and performance. PMID- 26052785 TI - Does electronic health record use improve hospital financial performance? Evidence from panel data. AB - PURPOSE: The aim of this study was to examine the impact of electronic health record (EHR) adoption on hospital financial performance. METHODOLOGY/APPROACH: We constructed a longitudinal panel using data from the three secondary sources: (a) the 2007-2010 American Hospital Association (AHA) Annual Survey, (b) the 2007 2010 AHA Annual Survey Information Technology Supplement, and (c) the 2007-2011 Medicare Cost Reports from Centers for Medicare and Medicaid Services. Because potential financial benefits attributable to EHR adoption may take some time to accrue, we ran regressions with lags of 1 and 2 years that included hospital and year fixed effects to examine the relationship between the level of EHR adoption and three hospital financial performance measures. FINDINGS: A change in the level of EHR adoption was not associated with changes in operating margin or return on assets within hospitals. However, total margin was significantly improved, after 2 years, in hospitals that moved from no EHR to having a comprehensive EHR in all areas of their hospital (beta = 0.030, p < .034). On the other hand, hospitals that increased their level of EHR adoption but did not achieve hospital-wide comprehensive adoption did not experience changes in any financial performance measures examined. PRACTICE IMPLICATIONS: The improvements in total margin, as opposed to operating margin, are likely due to hospital incentive payments under the Health Information Technology for Economic and Clinical Health Act that are reflected in nonpatient revenues and therefore show up in total margin calculations. Thus, after 2 years of EHR adoption, hospital financial performance is observed to improve based only on meaningful use incentive payments. More research will be needed to determine whether EHR adoption impacts financial performance on a longer time horizon. PMID- 26052786 TI - Knowledge management, health information technology and nurses' work engagement. AB - BACKGROUND: Knowledge management (KM) extends the health information technology (HIT) literature by addressing its impact on creating knowledge by sharing and using the knowledge of health care professionals in hospitals. PURPOSE: The aim of the study was to provide insight into how HIT affects nurses' explicit and tacit knowledge of their ongoing work processes and work engagement. METHODOLOGY: Data were collected from 74 nurses in four wards of a Dutch hospital via a paper and-pencil survey using validated measurement instruments. In a quasiexperimental research design, HIT was introduced in the two experimental wards in contrast to the two control wards. At the time of the HIT introduction, a pretest was administered in all four wards and was followed by a posttest after 3 months. Data were analyzed via partial least squares modeling. RESULTS: Generally, nurses' tacit knowledge (i.e., their insight into and their capacity to make sense of the work processes) appears to be a significant and strong predictor of their work engagement. In contrast, nurses' explicit knowledge (i.e., information feedback about patients and tasks) only indirectly affects work engagement via its effect on tacit knowledge. Its effect on work engagement therefore depends on the mediating role of tacit knowledge. Interestingly, introducing HIT significantly affects only nurses' explicit knowledge, not their tacit knowledge or work engagement. PRACTICE IMPLICATIONS: Nurses' tacit and explicit knowledge needs to be systematically distinguished when implementing HIT/KM programs to increase work engagement in the workplace. Tacit knowledge (insight into work processes) appears to be pivotal, whereas efforts aimed only at improving available information will not lead to a higher level of work engagement in nurses' work environments. PMID- 26052787 TI - Overextension in verb conjunctions. AB - Hampton (1988) discovered that people are subject to overextension-they categorize some things as falling under a conjunction (e.g., they categorize chess as a sport which is also a game) but not as falling under both of the corresponding conjuncts (e.g., they do not categorize chess as a sport). Although subsequent literature has replicated this effect with a wider range of constructions than those originally used by Hampton, the research so far has been exclusively concerned with various forms of noun compounds. This article generalizes the previous findings to the domain of verb conjunctions. By using a novel paradigm for studying overextension effects, this study demonstrates a very strong overextension effect for conjunctions of gerunds (e.g., walking and smoking). The author discusses the implications of the new findings for available explanations of overextension. PMID- 26052788 TI - Syntactic predictability in the recognition of carefully and casually produced speech. AB - The present study investigated whether the recognition of spoken words is influenced by how predictable they are given their syntactic context and whether listeners assign more weight to syntactic predictability when acoustic-phonetic information is less reliable. Syntactic predictability was manipulated by varying the word order of past participles and auxiliary verbs in Dutch subordinate clauses. Acoustic-phonetic reliability was manipulated by presenting sentences either in a careful or a casual speaking style. In 3 eye-tracking experiments, participants recognized past participles more quickly when they occurred after their associated auxiliary verbs than when they preceded them. Response measures tapping into later stages of processing suggested that this effect was stronger for casually than for carefully produced sentences. These findings provide further evidence that syntactic predictability can influence word recognition and that this type of information is particularly useful for coping with acoustic phonetic reductions in conversational speech. We conclude that listeners dynamically adapt to the different sources of linguistic information available to them. PMID- 26052789 TI - Traditional Lower Blepharoplasty: Is Additional Support Necessary? A 30-Year Review. AB - BACKGROUND: Several refinements have been made in lower eyelid rejuvenation, and there is now strong belief that the traditional approach places too little emphasis on lower eyelid support. The purpose of this study was to retrospectively review the 30-year experience of the senior author (J.A.F.) performing primary lower blepharoplasty by the traditional approach and to determine the complication rate when lower lid-tightening procedures were not performed concomitantly. METHODS: A retrospective chart review of all traditional blepharoplasties performed by the senior author over the past 30 years was performed. The traditional approach was performed through an external, subciliary incision. Concomitant lower lid-tightening procedures were not performed. The authors determined the complication rate of the procedure, such as symptomatic lower eyelid malposition and chemosis. RESULTS: A total of 3014 patients underwent traditional lower blepharoplasties and, after applying the exclusion criteria, 2007 patients were studied. A postoperative complication was defined as the development of either chemosis or symptomatic lower eyelid malposition. Chemosis developed in only 1.2 percent of the patients (24 of 2007). Eight of the 2007 patients (0.4 percent) developed symptomatic lower eyelid malposition. CONCLUSIONS: This study proves that when performed meticulously and precisely, traditional lower blepharoplasty is safe and effective. Correction of preoperatively diagnosed lower lid laxity is essential; however, when lower eyelid tone is adequate, the authors believe that the routine addition of a tightening procedure for support or the routine use of combined internal and external approaches is unnecessary. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26052791 TI - Attenuation of MK-801-induced behavioral perseveration by typical and atypical antipsychotic pretreatment in rats. AB - The noncompetitive NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5-10-imine maleate (MK-801) has been shown to increase the probability of operant responding during extinction and reduce infralimbic prefrontal cortical activation, possibly modeling the cognitive dysfunction symptomology, and underlying cause, in patients with schizophrenia. The present study sought to determine if typical and/or atypical antipsychotics would attenuate the MK-801-induced behavioral perseveration and whether this would be associated with concomitant changes in phosphorylated ERK1/2 (pERK1/2) labeling in the infralimbic cortex (IL). Male, Long Evans rats were pretreated with the typical antipsychotic, Flupenthixol (0, 0.125, 0.25 or 0.5 mg/kg) or the atypical antipsychotic, aripiprazole (0, 0.3, 1.0, 3.0 mg/kg), then given 0.1 mg/kg MK-801 followed by a 60-min appetitive operant extinction session. Flupenthixol produced a dose-dependent decrease in MK-801-induced bar pressing behavior and locomotor activity and a dose-dependent increase in IL pERK1/2 labeling. Aripiprazole produced a U-shaped dose-response curve on MK-801-induced bar pressing behavior, a dose-dependent decrease in locomotor activity but no changes in IL pERK1/2 labeling. The attenuation of the MK-801-induced behavioral (bar pressing, locomotion) profile by Flupenthixol indicates a clear dopaminergic contribution to this behavior. The behavioral effect of aripiprazole may be due to its a) binding to presynaptic dopamine receptors at the midrange dose decreasing dopamine output and b) binding to postsynaptic dopamine receptors at the higher dose increasing dopamine tone. While both classes of antipsychotics can normalize perseverative behavioral symptoms, the underlying prefrontal cortical dysregulation seems to persist. PMID- 26052790 TI - Environmental enrichment as a therapy for autism: A clinical trial replication and extension. AB - Based on work done in animal models showing that autism-like symptoms are ameliorated following exposure to an enriched sensorimotor environment, we attempted to develop a comparable therapy for children with autism. In an initial randomized controlled trial, children with autism who received sensorimotor enrichment at home for 6 months had significant improvements in both their cognitive ability and the severity of their autism symptoms (Woo & Leon, 2013). We now report the outcomes of a similar randomized controlled trial in which children with autism, 3 to 6 years old, were randomly assigned to groups that received either daily sensorimotor enrichment, administered by their parents, along with standard care, or they received standard care alone. After 6 months, enriched children showed statistically significant gains in their IQ scores, a decline in their atypical sensory responses, and an improvement in their receptive language performance, compared to controls. Furthermore, after 6 months of enrichment therapy, 21% of the children who initially had been given an autism classification, using the Autism Diagnostic Observation Schedule, improved to the point that, although they remained on the autism spectrum, they no longer met the criteria for classic autism. None of the standard care controls reached an equivalent level of improvement. Finally, the outcome measures for children who received only a subset of sensory stimuli were similar to those receiving the full complement of enrichment exercises. Sensorimotor enrichment therapy therefore appears to be a cost-effective means of treating a range of symptoms for children with autism. PMID- 26052792 TI - Strength and fine dexterity recovery profiles after a primary motor cortex insult and effect of a neuronal cell graft. AB - The aim of this study was to set up (a) a large primary motor cortex (M1) lesion in rodent and (b) the conditions for evaluating a long-lasting motor deficit in order to propose a valid model to test neuronal replacement therapies aimed at improving motor deficit recovery. A mitochondrial toxin, malonate, was injected to induce extensive destruction of the forelimb M1 cortex. Three key motor functions that are usually evaluated following cerebral lesion in the clinic strength, target reaching, and fine dexterity-were assessed in rats by 2 tests, a forelimb grip strength test and a skilled reaching task (staircase) for reaching and dexterity. The potential enhancement of postlesion recovery induced by a neuronal cell transplantation was then explored and confirmed by histological analyses. Both tests showed a severe functional impairment 2 days post lesion, however, reaching remained intact. Deficits in forelimb strength were long lasting (up to 3 months) but spontaneously recovered despite the extensive lesion size. This natural grip strength recovery could be enhanced by cell therapy. Histological analyses confirmed the presence of grafted cells 3 months postgraft and showed partial tissue reconstruction with some living neuronal cells in the graft. In contrast, fine dexterity never recovered in the staircase test even after grafting. These results suggest that cell replacement was only partially effective and that the forelimb M1 area may be a node of the sensorimotor network, where compensation from secondary pathways could account for strength recovery but recovery of forelimb fine dexterity requires extensive tissue reconstruction. PMID- 26052793 TI - Alcohol gains access to appetitive learning through adolescent heavy drinking. AB - Adolescent heavy alcohol drinking increases the risk for alcohol use disorders in adulthood, yet mechanisms conferring increased risk are not well understood. We propose that adolescent alcohol drinking shapes alcohol's aversive or appetitive properties in adulthood. Alcohol normally drives aversive learning and alcohol predictive cues are avoided. We hypothesize that through adolescent heavy drinking alcohol gains access to appetitive learning. A primary consequence is that alcohol-predictive cues become valued and sought out. To test this hypothesis, we gave genetically heterogeneous, male Long Evans rats voluntary, chronic intermittent access to water or alcohol throughout adolescence and then identified moderate and heavy alcohol drinkers. After a short abstinence period, we assessed the aversive or appetitive properties of alcohol using flavor learning procedures. We compared alcohol to the known appetitive properties of sugar. Flavor learning in adult rats who were alcohol-naive or adolescent moderate alcohol drinkers revealed alcohol to be aversive and sugar to be appetitive. The same flavor learning procedures revealed both alcohol and sugar to be appetitive in adult rats who were adolescent heavy drinkers. The results demonstrate that alcohol gains access to neurobehavioral circuits for appetitive learning through adolescent heavy alcohol drinking. PMID- 26052795 TI - The medial prefrontal cortex and nucleus accumbens mediate the motivation for voluntary wheel running in the rat. AB - Voluntary wheel running in rats provides a preclinical model of exercise motivation in humans. We hypothesized that rats run because this activity has positive incentive salience in both the acquisition and habitual stages of wheel running and that gender differences might be present. Additionally, we sought to determine which forebrain regions are essential for the motivational processes underlying wheel running in rats. The motivation for voluntary wheel running in male and female Sprague-Dawley rats was investigated during the acquisition (Days 1-7) and habitual phases (after Day 21) of running using conditioned place preference (CPP) and the reinstatement (rebound) response after forced abstinence, respectively. Both genders displayed a strong CPP for the acquisition phase and a strong rebound response to wheel deprivation during the habitual phase, suggesting that both phases of wheel running are rewarding for both sexes. Female rats showed a 1.5 times greater rebound response than males to wheel deprivation in the habitual phase of running, while during the acquisition phase, no gender differences in CPP were found. We transiently inactivated the medial prefrontal cortex (mPFC) or the nucleus accumbens (NA), hypothesizing that because these regions are involved in the acquisition and reinstatement of self administration of both natural and pharmacological stimuli, they might also serve a role in the motivation to wheel run. Inactivation of either structure decreased the rebound response in the habitual phase of running, demonstrating that these structures are involved in the motivation for this behavior. PMID- 26052796 TI - Tetrabutylammonium iodide-catalyzed oxidative coupling of enamides with sulfonylhydrazides: synthesis of beta-keto-sulfones. AB - A facile synthetic route towards pharmaceutically interesting beta-keto-sulfone derivatives by tetrabutylammonium iodide (TBAI)/tert-butyl hydroperoxide (TBHP) mediated oxidative coupling of readily prepared enamides with economical sulfonylhydrazides is described. The corresponding beta-keto-sulfone compounds were obtained in moderate to good yields. The present method is metal-free and base-free and shows tolerance to a variety of functional groups. PMID- 26052794 TI - Auditory gap-in-noise detection behavior in ferrets and humans. AB - The precise encoding of temporal features of auditory stimuli by the mammalian auditory system is critical to the perception of biologically important sounds, including vocalizations, speech, and music. In this study, auditory gap-detection behavior was evaluated in adult pigmented ferrets (Mustelid putorius furo) using bandpassed stimuli designed to widely sample the ferret's behavioral and physiological audiogram. Animals were tested under positive operant conditioning, with psychometric functions constructed in response to gap-in-noise lengths ranging from 3 to 270 ms. Using a modified version of this gap-detection task, with the same stimulus frequency parameters, we also tested a cohort of normal hearing human subjects. Gap-detection thresholds were computed from psychometric curves transformed according to signal detection theory, revealing that for both ferrets and humans, detection sensitivity was worse for silent gaps embedded within low-frequency noise compared with high-frequency or broadband stimuli. Additional psychometric function analysis of ferret behavior indicated effects of stimulus spectral content on aspects of behavioral performance related to decision-making processes, with animals displaying improved sensitivity for broadband gap-in-noise detection. Reaction times derived from unconditioned head orienting data and the time from stimulus onset to reward spout activation varied with the stimulus frequency content and gap length, as well as the approach-to target choice and reward location. The present study represents a comprehensive evaluation of gap-detection behavior in ferrets, while similarities in performance with our human subjects confirm the use of the ferret as an appropriate model of temporal processing. PMID- 26052797 TI - Paraparesis From Upper Cervical Spinal Dural Arteriovenous Fistula. PMID- 26052798 TI - Critical steps in the isolation and expansion of adipose-derived stem cells for translational therapy. AB - Since the discovery of adipose-derived stem cells (ASCs), there have been high expectations of their putative clinical use. Recent advances support these expectations, and it is expected that the transition from pre-clinical and clinical studies to implementation as a standard treatment modality is imminent. However ASCs must be isolated and expanded according to good manufacturing practice guidelines and a basic assurance of quality, safety, and medical effectiveness is needed for authorisation by regulatory agencies, such as European Medicines Agency and US Food and Drug Administration. In this review, a collection of studies investigating the influence of different steps of the isolation and expansion protocol on the yield and functionality of ASCs has been presented in an attempt to come up with best recommendations that ensure potential beneficial clinical outcome of using ASCs in any therapeutic setting. If the findings confirm the initial observations of beneficial effects of ASCs, the path is paved for implementing these ASC-based therapies as standard treatment options. PMID- 26052799 TI - First results of an eye lens dosimetry survey in an interventional cardiology department. AB - The eye lens annual dose limit for exposed personnel to ionizing radiation has recently been revised by the ICRP--International Commission on Radiological Protection and the proposed new limit has been accepted by European legislation through the Council Directive 2013/59/EURATOM 2013. Among medical exposed personnel, the staff performing interventional cardiology are usually affected by relevant doses. For this reason a survey, employing dosemeters characterized in terms of H(p)(3), was performed in order to get the order of magnitude of the doses received by the eye lens, at least as a first guess.The survey showed that the annual dose limit can easily be reached if a proper radiation protection approach is not implemented. PMID- 26052800 TI - TAFRO syndrome: 2 cases and review of the literature. AB - Recently, more than ten cases of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome or Castleman-Kojima disease exhibiting such symptoms as thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly have been reported in Japan. We have found two cases of TAFRO syndrome and have reviewed another eighteen previously reported cases. Histological findings of the lymph nodes and levels of interleukin 6 (IL-6) and vascular endothelial growth factor in both serum/plasma and effusions are important characteristics for diagnosing this syndrome. PMID- 26052801 TI - Profiles of EQ-5D utility scores in the daily practice of Japanese patients with rheumatoid arthritis; Analysis of the IORRA database. AB - OBJECTIVE: Along with the advances of newly developed medical therapies in rheumatoid arthritis (RA), the number of pharmacoeconomical issues has been paid attention rapidly. For cost-utility analysis and determination of quality adjusted life years, measurement of the EuroQol 5-dimensional descriptive system (EQ-5D) is essential, and has been used in several clinical studies. However, EQ 5D utility measure in Japanese patients with RA, especially in daily practice has not been fully documented. We analyzed the distribution of EQ5D utility scores and investigated the relationship between other clinical measures based on our Institute of Rheumatology, Rheumatoid Arthritis (IORRA) database. METHOD: Among 5,284 outpatients who participated in the IORRA cohort study on October 2007, data from 5,043 patients who completed the EQ-5D questionnaire were cross sectionally analyzed. EQ-5D scores in each subgroup for baseline feature such as gender, age, disease activity score 28 (DAS28), and Japanese version of health assessment questionnaire (J-HAQ) were evaluated. For the evaluation of variables that influenced EQ-5D score, the contribution of each variable was evaluated by ANOVA. RESULTS: Average EQ-5D score was 0.76 in 5,284 patients (84% females, average age: 59.0 years, average disease duration: 12.4 years) whose average DAS28 was 3.3 and average J-HAQ was 0.74. EQ-5D scores were highly correlated with J-HAQ and DAS28, and were significantly lower in females and rheumatoid factor-positive patients. Older age, longer disease duration, higher DAS28, and higher J-HAQ were also significantly associated with lower EQ-5D scores. In multivariate analysis, the factor that most strongly influenced EQ-5D was J-HAQ (57.6%), followed by pain visual analog score (VAS; 12.5%). CONCLUSION: This study clearly demonstrated the distribution of EQ-5D score in the daily practice of RA patients, and provides important information for the pharmacoeconomical studies in rheumatology. PMID- 26052802 TI - Combined disease with pulmonary arterial hypertension and pulmonary venous hypertension revealed after treatment of heart failure with preserved ejection fraction in a case with primary Sjogren syndrome. AB - A 49-year-old woman with primary Sjogren syndrome initially developed pulmonary venous hypertension (PVH) due to heart failure with preserved ejection fraction. Endomyocardial biopsy specimens showed mild myocardial fibrosis. Pulmonary arterial hypertension (PAH) was revealed after the treatment with diuretics. During the treatment for PAH using upfront combination with pulmonary vasodilators and immunosuppressants, the patient developed combined disease with PAH and PVH. A careful hemodynamic assessment is necessary in such cases. PMID- 26052803 TI - The usefulness of a new triple combination treatment utilizing methotrexate, salazosulfapyridine, and bucillamine in rheumatoid arthritis. AB - OBJECTIVES: Combination treatment with methotrexate, salazosulfapyridine and bucillamine as an alternative to treatment with TNF-inhibiting biologics in rheumatoid arthritis was investigated. METHODS: Twenty-six facilities allied with the Japan Association of Rheumatologists in Private Practice participated in this study. One hundred and twelve patients enrolled in this study, all of whom were within 3 years of diagnosis with rheumatoid arthritis for whom treatment with one DMARD or a combination of two DMARDs had failed (DAS28 > 3.2). Patients chose their own treatment. The triple DMARDs combination group was comprised of 72 patients; the TNF-inhibiting biologics treatment group was comprised of 40 patients. RESULTS: DAS28 scores for the triple DMARDs combination group and the TNF-inhibiting biologics treatment groups were 4.84 +/- 0.96 and 5.23 +/- 1.26, and there was no significant difference between the two groups. From the 6th month, average disease activities of both groups were reduced, and there was no difference between the two groups at 12 months (DAS28, 3.39 +/- 1.43 and 3.05 +/- 1.43, p = 0.39). Furthermore, there was no significant difference in the degree of bone destruction between the two groups at 12 months. CONCLUSIONS: The triple DMARD combination therapy provided a new treatment option for those patients for whom treatment with biologics is difficult. PMID- 26052804 TI - Extracorporeal membrane oxygenation for cardiac arrest during moyamoya cerebral revascularization surgery: case report. AB - The authors describe the case of a 51-year-old man with bilateral moyamoya disease and prior strokes who developed an asystolic cardiac arrest while undergoing revascularization surgery under mild hypothermia. The patient was successfully treated with venoarterial (VA) extracorporeal membrane oxygenation (ECMO) after manual cardiopulmonary resuscitation (CPR) was unsuccessful for 45 minutes. ECMO is a cardiopulmonary support system that is indicated for respiratory failure in pediatric and adult patients. It is increasingly being used as an extension to mechanical CPR for patients who have suffered cardiac arrest if the underlying cause of cardiac arrest is thought to be reversible. Identifying which patients should be placed on emergency ECMO after cardiac arrest is controversial given its high morbidity and mortality. ECMO in neurosurgical settings has associated risks of intracranial hemorrhage and neurological compromise, while resource utilization is paramount given the high costs of this treatment. This paper is significant because it describes the use of ECMO in an unindicated setting. Limited data are available for ECMO usage after cardiac arrest with baseline cerebral ischemia. Furthermore, this paper raises important considerations for extracorporeal CPR use in a patient who had recently undergone craniotomy. The patient in this report remained on ECMO for 48 hours, after which he was successfully weaned. He developed a pericardial effusion and compartment syndrome from the ECMO but made a complete neurological recovery. Use of ECMO emergently in an appropriately chosen neurosurgical patient is safe, even in the setting of baseline cerebral ischemia and recent craniotomy. PMID- 26052806 TI - Erratum. PMID- 26052805 TI - Traumatic brain injury caregivers: A qualitative analysis of spouse and parent perspectives on quality of life. AB - The objective of this qualitative study was to examine how family caregivers of individuals with traumatic brain injury (TBI) describe their quality of life in the context of their caregiving role. Fifty-two caregivers of adults with moderate or severe TBI (n = 31 parents, n = 21 partners/spouses; 77% female; mean age = 57.96 years, range = 34-78 years) were recruited from three data collection sites to participate in focus groups. Thematic content analysis was used to identify two main meta-themes: Caregiver Role Demands and Changes in Person with TBI. Prominent sub-themes indicated that caregivers are (1) overburdened with responsibilities, (2) lack personal time and time for self-care, (3) feel that their life is interrupted or lost, (4) grieve the loss of the person with TBI, and (5) endorse anger, guilt, anxiety, and sadness. Caregivers identified a number of service needs. A number of sub-themes were perceived differently by partner versus parent caregivers. The day-to-day responsibilities of being a caregiver as well as the changes in the person with the TBI present a variety of challenges and sources of distress for caregivers. Although services that address instrumental as well as emotional needs of caregivers may benefit caregivers in general, the service needs of parent and partner caregivers may differ. PMID- 26052807 TI - Structure-activity study of N-((trans)-4-(2-(7-cyano-3,4-dihydroisoquinolin-2(1H) yl)ethyl)cyclohexyl)-1H-indole-2-carboxamide (SB269652), a bitopic ligand that acts as a negative allosteric modulator of the dopamine D2 receptor. AB - We recently demonstrated that SB269652 (1) engages one protomer of a dopamine D2 receptor (D2R) dimer in a bitopic mode to allosterically inhibit the binding of dopamine at the other protomer. Herein, we investigate structural determinants for allostery, focusing on modifications to three moieties within 1. We find that orthosteric "head" groups with small 7-substituents were important to maintain the limited negative cooperativity of analogues of 1, and replacement of the tetrahydroisoquinoline head group with other D2R "privileged structures" generated orthosteric antagonists. Additionally, replacement of the cyclohexylene linker with polymethylene chains conferred linker length dependency in allosteric pharmacology. We validated the importance of the indolic NH as a hydrogen bond donor moiety for maintaining allostery. Replacement of the indole ring with azaindole conferred a 30-fold increase in affinity while maintaining negative cooperativity. Combined, these results provide novel SAR insight for bitopic ligands that act as negative allosteric modulators of the D2R. PMID- 26052808 TI - Treatment of glabella skin necrosis following injection of hyaluronic acid filler using platelet-rich plasma. AB - Hyaluronic acid (HA) fillers have been widely used for soft-tissue augmentation. However, there can be various complications following HA filler injection. Skin necrosis is rare but one of the most disastrous side effects that, if not treated promptly and effectively, can result in permanent and potentially disfiguring scarring. Thus, early proper management is important. Herein we report a patient who experienced tissue necrosis of the glabellar area after receiving filler injections that was successfully treated using platelet-rich plasma and provide full follow-up clinical photographs. PMID- 26052809 TI - Laser and energy-based devices' complications in dermatology. AB - Laser dermatology is an ever-expanding part of the specialty used extensively for both aesthetic and medical conditions. Advances in laser technology have led to an expansion in the number of devices available, with as a consequence an increase in the total number of complications. Fortunately, the current technology has improved greatly which adds to the safety profile of such devices; nevertheless, thorough knowledge of laser complications and how to avoid them is paramount for any practitioner who uses such technology. PMID- 26052810 TI - Estimated beginning time of local anesthesia effectiveness in forced cold air application: A preliminary study. AB - BACKGROUND: The literature has reported that forced cold air anesthesia decreases the discomfort effect of various laser therapies. The aim of this preliminary study was to determine the average beginning time of the local anesthetic effect of the forced cold air application when it is applied to all body surfaces except the face. MATERIALS AND METHODS: A total of 52 participants (26 females and 26 males) were included in this study. During application of the forced cold air, the beginning time of local anesthesia effectiveness for each volunteer was determined by giving painful stimuli. The results were then analyzed statistically. RESULTS: The mean beginning time value of the local anesthesia was 52.88 (ranging between 30 and 60) seconds in the female group and 56.34 (ranging between 30 and 60) seconds in the male group. The mean beginning time value of the local anesthesia was 54.61 (ranging between 30 and 60) seconds in both genders. There was no statistical difference between the two groups (Z = - 0.834, p = 0.404). CONCLUSION: Forced cold air anesthesia-which is a quick, safe, cost effective, and practical local anesthesia method-seems to be useful and effective when used alone in laser treatment. PMID- 26052811 TI - Fractional CO2 laser treatment for a skin graft. AB - Skin grafts are widely used in reconstructive and plastic surgery, leaving an inevitable scar appearance on the body, affecting the quality of life of the patients. Fractional ablative lasers have become a leading procedure for the treatment of acne and burn scars. We report a case of a skin graft showing excellent improvement in overall appearance after three sessions of fractional CO2 laser. The undamaged tissue left between the microthermal treatment zones is responsible of collagen formation and reepithelialization. Remodeling and collagen formation are observed even 6 months after a fractional CO2 laser session. PMID- 26052812 TI - Histological and molecular analysis of the long-pulse 1,064-nm Nd:YAG laser irradiation on the ultraviolet-damaged skin of hairless mice: In association with pulse duration change. AB - BACKGROUND: Nonablative lasers have been widely used to improve photodamaged skin, although the mechanism underlying dermal collagen remodeling remains unclear. OBJECTIVE: To investigate the effects and the molecular mechanisms of long-pulse neodymium-doped yttrium aluminum garnet (Nd:YAG) laser irradiation on dermal collagen remodeling in association with different pulse durations. MATERIAL AND METHODS: Five hairless mice were pretreated with ultraviolet B irradiation for 8 weeks. The dorsal quadrant of each mouse was then irradiated twice at 1-week intervals at a pulse duration of 1 ms, 12 ms, or 50 ms, and a constant fluence of 20 J/cm(2). The levels of dermal collagen, mRNAs of procollagens, matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs), and various growth factors were analyzed after 4 weeks. RESULTS: Long-pulse Nd:YAG treatment increased the dermal collagen level. A substantial increase in the level of procollagens, MMPs, TIMPs, and various growth factors was also observed irrespective of pulse duration, with a trend toward maximal increase at a pulse duration of 12 ms. CONCLUSION: Long-pulse 1,064-nm Nd:YAG laser irradiation promotes wound-healing process, which is characterized by the induction of growth factor expression and subsequent increase in MMPs and TIMPs, followed by matrix remodeling as confirmed by new procollagen production. PMID- 26052813 TI - Comparative study between excimer light and topical antioxidant versus excimer light alone for treatment of vitiligo. AB - BACKGROUND: Vitiligo is an acquired idiopathic cutaneous disease characterized by pearly white patches of variable shapes and sizes. Various medical and surgical therapeutic options have been proposed to achieve repigmentation; phototherapy is one of the most efficient options. Topical therapies have been a mainstay of vitiligo treatment, with or without phototherapy. AIM OF THE WORK: To compare the efficacy of combined topical antioxidant hydrogel and excimer light versus excimer light alone in treating vitiligo. PATIENTS AND METHODS: Thirty patients were included in this comparative, prospective, randomized study. For each patient, at least 2-4 vitiliginous macules were randomly selected and treated while an untreated vitiliginous macule served as control. Lesions were divided into two groups: Group A received combination therapy of daily topical antioxidant plus excimer light, while Group B received only excimer light. Lesions were treated twice a week for a maximum of 24 sessions. Initial fluencies were adjusted individually according to the minimal erythema dose in vitiliginous skin. Efficacy based on repigmentation percentages were blindly evaluated by two independent physicians. RESULTS: Group A lesions showed significant efficacy than group B (p < 0.001), specially on treating UV-sensitive lesions with no side effects. CONCLUSION: Topical antioxidant and excimer light represents a valuable, effective therapy for localized vitiligo. PMID- 26052814 TI - D-SP5 Peptide-Modified Highly Branched Polyethylenimine for Gene Therapy of Gastric Adenocarcinoma. AB - Peptide-mediated targeting of tumors has become an effective strategy for cancer therapy. Retro-inverso peptides resist protease degradation and maintain their bioactivity. We used the retro-inverso peptide D(PRPSPKMGVSVS) (D-SP5) as a targeting ligand to develop gene therapy for gastric adenocarcinoma. D-SP5 has a higher affinity for human gastric adenocarcinoma (SGC7901) cells compared with that of its parental peptide, L(SVSVGMKPSPRP) (L-SP5). Polyethylenimine (PEI)/pDNA, polyethylene glycol (mPEG)-PEI/pDNA and D-SP5-PEG-PEI/pDNA were prepared for further study. Quantitative luciferase assays showed the transfection efficiency of D-SP5-PEG-PEI/pGL(4.2) was larger compared with that of mPEG-PEI/pGL(4.2). Flow cytometry assays revealed that the apoptosis rates of SGC7901 cells treated with D-SP5-PEG-PEI/pTRAIL were larger than mPEG-PEI/pTRAIL. Western blot assays indicated that the expression of tumor necrosis factor related apoptosis inducing ligand (TRAIL) protein in SGC7901 cells treated with D SP5-PEG-PEI/pTRAIL was higher compared with that in cells treated with mPEG PEI/pTRAIL. In vivo pharmacodynamics study revealed that D-SP5-PEG-PEI/pTRAIL could inhibit the growth of gastric adenocarcinoma SGC7901 xenografts in nude mice. Our results demonstrate that D-SP5-PEG-PEI is a safe and efficient gene delivery vector with potential applications in antitumor gene therapy. PMID- 26052815 TI - The influence of psychological symptoms on mental health literacy of college students. AB - Psychological problems, such as depression and anxiety, are common among college students, but few receive treatment for it. Mental health literacy may partially account for low rates of mental health treatment utilization. We report 2 studies that investigated mental health literacy among individuals with varying degrees of psychological symptoms, using cross-sectional online survey methodology. Study 1 involved 332 college students, of which 32% were categorized as high depressed using an established measure of depression, and mental health literacy for depression was assessed using a vignette. Logistic regression results showed that high depressed individuals were less likely to recognize depression compared to low depressed individuals, and depression recognition was associated with recommendations to seek help. Study 2 replicated and extended findings of Study 1 using a separate sample of 1,321 college students with varying degrees of psychological distress (32% no/mild distress, 55% moderate distress, and 13% serious distress) and examining mental health literacy for anxiety in addition to depression. Results indicated that compared to those with no/mild distress, those with moderate distress had lower recognition of depression, and those with moderate and serious distress were less likely to recommend help-seeking. In contrast, there were no differences in mental health literacy for anxiety, which was low across all participants. These findings suggest that psychological symptoms can impact certain aspects of mental health literacy, and these results have implications for targeting mental health literacy to increase mental health services utilization among individuals in need of help. (PsycINFO Database Record PMID- 26052816 TI - An exploratory study of nonsuicidal self-injury and suicidal behaviors in adolescent Latinas. AB - To date, there is little research to validate empirically differences between nonsuicidal self-injurious behavior (NSSI) and attempted suicide among Latina adolescents. Understanding the characteristics and contextual features of self harmful behaviors among Latina teens is a critical public health and social justice matter given the disproportionate rates of attempted suicide and anticipated population growth of this vulnerable group. In this article, we draw on an ecodevelopmental model to focus attention on factors in the sociocultural environment that shape suicidal behaviors and NSSIs. Through analysis of qualitative interviews conducted with girls who used NSSI (n = 18), attempted suicide (n = 29), used NSSI and attempted suicide (n = 8,) and had no reported lifetime history of self-harm (n = 28), we describe the sociocultural factors that shaped psychosocial vulnerabilities and gave rise to decisions to use NSSI or attempt suicide. Our analysis revealed that adolescents who engaged in NSSI perceived their negative feelings as something that could be controlled through self-injurious acts, whereas powerlessness was a theme underlying the emotional states of girls who attempted suicide. When NSSI ceased to function as a mechanism for control, girls came to sudden decisions to attempt suicide. Most teens identified specific, and often multiple, situations that induced intense affective states and shaped decisions to inflict self-harm. Two situational experiences emerged as particularly salient and promising for subsequent studies on self-harmful behaviors among Latina adolescents: transnational stress and bullying. We describe each of these and offer suggestions for future research and practice. PMID- 26052817 TI - Expressions of E2 and E7-HPV16 proteins in pre-malignant and malignant lesions of the uterine cervix. AB - Continuous production of the E7 protein from different types of high risk human papilloma virus (HPV) is required for progression of malignancy. We developed antibodies against HPV type 16 E7 and E2 proteins to evaluate their utility as markers for diagnosis during early stages of cervical cancer. Forty biopsies from uterine cervices were diagnosed as low grade intraepithelial lesion (LSIL), high grade intraepithelial lesion (HSIL), squamous carcinoma (SC), in situ adenocarcinoma (ISA) and invasive adenocarcinoma (AC), all of which were infected with HPV 16. Immunohistochemistry was used to investigate the expressions of E7 and E2 (both from HPV 16) and p16. P16 was expressed in eight of 12 LSILs, in all HSILs, in 16 of 18 SC and in all ACs. E2 was expressed in six of 12 LSILs. E7 was positive in eight of 12 LSILs and in all HSIL and carcinomas. The expressions of E2 and E7 of HPV16 related to p16 expression confirmed the value of the viral oncogenic proteins as complementary to histology and support the carcinogenic model of the uterine cervix, because HPVDNA integration into cellular DNA implies the destruction of the gene encoding E2, which suppresses the expression of the E6 and E7 oncoproteins. E2 from HPV16 could be marker for LSILs, while E7 could be a marker for progression of LSILs to HSILs in patients infected by HPV16, because viral typing has little positive predictive value. PMID- 26052818 TI - Critical Intermediates Reveal New Biosynthetic Events in the Enigmatic Colibactin Pathway. AB - Colibactin is a potent genotoxin that induces DNA double-strand breaks; it is produced by Escherichia coli strains harboring a pks+ island. However, the structure of this compound remains elusive. Here, using transformation-associated recombination (TAR) cloning to perform heterologous expression, we took advantage of the significantly increased yield of colibactin pathway-related compounds to determine and isolate a series of vital (pre)colibactin intermediates. The chemical structures of compounds 8, 10 and 11 were identified by NMR and MS(n) analyses. The new 1H-pyrrolo[3,4-c]pyridine-3,6(2H,5H)-dione- and thiazole containing compound 10 provides new insights regarding the biosynthetic pathway to (pre)colibactin and establishes foundations for future investigation of the intriguing (pre)colibactin structures and its modes of action. PMID- 26052820 TI - Persistent luminescence from Eu(3+) in SnO2 nanoparticles. AB - Persistent luminescence phosphors, which are capable of emitting light for a long time after ceasing excitation, have shown great promise in diverse areas as bioprobes, lighting and displays. Exploring new materials to realize efficient persistent luminescence is a goal of general concern. Herein, we report a novel persistent luminescence phosphor based on Eu(3+)-doped SnO2 nanoparticles (NPs). The afterglow decay behaviour, the trap depth distribution as well as the underlying mechanism for persistent luminescence of the NPs were comprehensively surveyed by means of thermoluminescence and temperature-dependent afterglow decay measurements. It was found that the thermal activation mechanism is responsible for the afterglow decay of the NPs with an inverse power-law exponent of 1.0 (or 1.7) in the temperature region below (or above) 220 K. In particular, the co existence of uniform and exponential distributions in trap depths may result in such a unique afterglow decay behaviour. These results reveal the great potential of SnO2 NPs as an excellent host material for Eu(3+) doping for the generation of efficient persistent luminescence. PMID- 26052821 TI - PI3K/AKT signaling inhibits NOTCH1 lysosome-mediated degradation. AB - The pathways of NOTCH and PI3K/AKT are dysregulated in about 60% and 48% of T cell acute lymphoblastic leukemia (T-ALL) patients, respectively. In this context, they interact and cooperate in controlling tumor cell biology. Here, we propose a novel mechanism by which the PI3K/AKT pathway regulates NOTCH1 in T ALL, starting from the evidence that the inhibition of PI3K/AKT signaling induced by treatment with LY294002 or transient transfection with a dominant negative AKT mutant downregulates NOTCH1 protein levels and activity, without affecting NOTCH1 transcription. We showed that the withdrawal of PI3K/AKT signaling was associated to NOTCH1 phosphorylation in tyrosine residues and monoubiquitination of NOTCH1 detected by Ubiquitin capture assay. Co-immunoprecipitation assay and colocalization analysis further showed that the E3 ubiquitin ligase c-Cbl interacts and monoubiquitinates NOTCH1, activating its lysosomal degradation. These results suggest that the degradation of NOTCH1 could represent a mechanism of control by which NOTCH1 receptors are actively removed from the cell surface. This mechanism is finely regulated by the PI3K/AKT pathway in physiological conditions. In pathological conditions characterized by PI3K/AKT hyperactivation, such as T-ALL, the excessive AKT signaling could lead to NOTCH1 signaling dysregulation. Therefore, a therapeutic strategy directed to PI3K/AKT in T-ALL could contemporaneously inhibit the dysregulated NOTCH1 signaling. (c) 2015 Wiley Periodicals, Inc. PMID- 26052822 TI - Correction: Intermolecular network analysis of the liquid and vapor interfaces of pentane and water: microsolvation does not trend with interfacial properties. AB - Correction for 'Intermolecular network analysis of the liquid and vapor interfaces of pentane and water: microsolvation does not trend with interfacial properties' by Yasaman Ghadar et al., Phys. Chem. Chem. Phys., 2014, 16, 12475 12487. PMID- 26052823 TI - Letter to the Editor: Smoking status in the ACDF versus 2-level total disc replacement study. PMID- 26052824 TI - Fluorescence Enhancement/Quenching Based on Metal Orbital Control: Computational Studies of a 6-Thienyllumazine-Based Mercury Sensor. AB - To understand the sensing behaviors of molecular fluorescent probes, lumazine (Lm) and 6-thienyllumazine (TLm) and their complexation with metal(II) ions ([(L)nM(H2O)m](2+), M = Cd(2+) and Hg(2+)) were examined by scalar relativistic density functional theory (DFT). A red shifting from L to [(L)nM(H2O)m](2+) was found. This is due to the metal affinity that stabilizes the LUMOs of [(L)nM(H2O)m](2+) greater than the HOMOs. Singlet excited-state structures of L and [(L)nM(H2O)m](2+) (M = Cd(2+) and Hg(2+)) were fully optimized using time dependent DFT (TDDFT). Their fluorescent emissions in aqueous solution were calculated to be 371 nm (Lm), 439 nm (cis-TLm), and 441 nm (trans-TLm), agreeing with experimental values of 380 nm for Lm and 452 nm for TLm. Theoretical support is presented for a sensing mechanism of photoinduced charge transfer of the L probe. The mechanism of the chelation-enhanced fluorescence (CHEF) and the chelating quenched fluorescence (CHQF) is explained. Fluorescence amplification (for Cd(2+)) is due to blocking of the nitrogen lone pair orbital due to the stabilizing interaction with the vacant s-orbital of the metal ion, while fluorescence quenching (Hg(2+)) results from the energy of the LUMO of the metal ion being between HOMO and LUMO of the sensor. Effects of structure rearrangements on the fluorescence spectra of the sensors are insignificant. This proposed mechanism of metal orbital controlled fluorescence enhancement/quenching suggests a development concept in the future design of fluorescent turn-on/off sensors. PMID- 26052825 TI - Activated protein C attenuates ischemia-reperfusion-induced acute lung injury. AB - Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions, such as lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax, or pleural effusion, cardiopulmonary bypass, etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues. Activated protein C (APC) manifests multiple activities with antithrombotic, profibrinolytic, and anti-inflammatory effects. We therefore conducted this study to determine the beneficial effects of APC in IR-induced ALI. IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ. The animals were divided into the control group, IR group, and IR+APC group. There were six adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary microvascular hyperpermeability, pulmonary edema and dysfuction, increased cytokines (tumor necrosis factor (TNF)-alpha, IL-17, CXCL 1), and neutrophils infiltration in lung tissues. Administration of APC significantly attenuated IR-induced ALI with improving microvascular permeability, pulmonary edema, pulmonary dysfunction, and suppression inflammatory response. The current study demonstrates the beneficial effects of APC in IR-induced ALI. This protective effect is possibly associated with the inhibition of TNF-alpha, IL-17A, CXCL1, and neutrophils infiltration in lung tissues. However, the current results were obtained in an animal model and it is still necessary to confirm these findings in human subjects. If we can demonstrate the benefits of APC to protect IR lung injury, we can postulate that APC is a potential therapeutic drug for lung preservation. PMID- 26052826 TI - miR-132 inhibits lipopolysaccharide-induced inflammation in alveolar macrophages by the cholinergic anti-inflammatory pathway. AB - OBJECTIVE: Although microRNA-132 (miR-132) has been shown to be involved in the inflammatory regulation, its role in sepsis-induced lung injury is unknown. We hypothesized that miR-132 attenuated lipopolysaccharide (LPS)-induced inflammation of alveolar macrophages by targeting acetylcholinesterase (AChE) and enhancing the acetylcholine (ACh)-mediated cholinergic anti-inflammatory response. METHODS: The LPS-treated rat alveolar macrophage cell line NR8383 was used as the inflammatory model. To assess the effect of miR-132, alveolar macrophages were transfected with miR-132 mimic or inhibitor. RESULTS: We found that miR-132 was upregulated in LPS-stimulated alveolar macrophages. Induction of AChE mRNA showed an inverse pattern with respect to AChE protein and activity, suggesting posttranscriptional regulation of AChE. Utilizing miR-132 mimic transfection, we found that overexpression of miR-132 enhanced the ACh-mediated cholinergic anti-inflammatory reaction by targeting AChE mRNA in LPS-treated alveolar macrophages. Blockage of miR-132 using miR-132 inhibitor reversed the Ach action upon LPS-induced release of inflammatory mediators and reduction in AchE protein/activity. Moreover, in the presence of ACh, upregulation of miR-132 suppressed LPS-induced nuclear translocation of NF-kappaB and production of STAT3 and phosphorylated STAT3, while downregulation of miR-132 enhanced the nuclear translocation of NF-kappaB. CONCLUSION: We propose that miR-132 functions as a negative regulator of the inflammatory response in alveolar macrophages by potentiating the cholinergic anti-inflammatory pathway, and represents a potential therapeutic leverage point in modulating inflammatory responses. PMID- 26052827 TI - Gadolinium chloride modulates bradykinin-induced pulmonary vasoconstriction and hypoxic pulmonary vasoconstriction during polymicrobial abdominal sepsis in rats. AB - BACKGROUND: Macrophages importantly contribute to sepsis-induced lung injury. As their impact on pulmonary endothelial injury and dysregulation of hypoxic pulmonary vasoconstriction (HPV) remains unclear, we assessed pulmonary endothelial dysfunction and HPV by macrophage inhibition via gadolinium chloride (GC) pre-treatment in rats with peritonitis (cecal ligation and puncture [CLP]). METHODS: The following four study groups were made: Group I: SHAM and group II: SHAM + GC (pre-treatment with NaCl 0.9% or GC 14 mg/kg body weight (b.w.) intravenously 24 hours prior to sham laparotomy); group III: CLP and group IV: CLP + GC (pre-treatment with NaCl 0.9% or GC 14 mg/kg b.w. 24 hours prior to induction of peritonitis). Exhaled nitric oxide (exNO), bradykinin-induced pulmonary vasoconstriction (=surrogate marker of endothelial dysfunction) and HPV were investigated in isolated and perfused lungs (n = 40). Using the same protocol wet to dry lung weight ratio and myeloperoxidase (MPO) activity were investigated in separate rats (n = 28). In additional rats (n = 12) of groups III and IV nitrite levels in alveolar macrophages (AM) were measured. RESULTS: In sepsis, GC pre-treatment significantly attenuated exNO levels, AM-derived nitrite levels, lung MPO activity, and restored blunted HPV, but severely enhanced endothelial dysfunction in healthy and septic animals. CONCLUSION: Macrophages exhibit a controversial role in sepsis-induced lung injury. The GC-induced restoration of inflammation parameters to sham levels is clearly limited by the negative impact on CLP-induced endothelial injury in this setting. The exact link between the GC-associated modulation of the NO pathway demonstrated and septic lung injury needs to be determined in future studies. PMID- 26052828 TI - Mast cell stabilization with sodium cromoglycate modulates pulmonary vessel wall remodeling during four-day hypoxia in rats. AB - AIM OF THE STUDY: In rats, the environment with low content of oxygen induces hypoxic pulmonary hypertension. Remodeling of pulmonary resistance arteries is particularly triggered by the mast cell degranulation products, e.g., rodent-like interstitial collagenase (matrix metalloproteinase 13). Administration of sodium cromoglycate leads to stabilization of mast cell granules, and thus to the modified remodeling process. MATERIALS AND METHODS: During four-day hypoxia, we treated rats with sodium cromoglycate. Pulmonary vascular remodeling was assessed as well as counts of periarterial pulmonary mast cells, both total and matrix metalloproteinase 13-positive ones. RESULTS: Four-day hypoxia induced remodeling of both resistance arteries and large conduit arteries. We have found increase in the tunica media thickness of resistance arteries. Tunica adventitia thickness of both resistance arteries and large conduit arteries with a diameter of over 300 MUm increased as well; the latter ones revealed increase in the number of vasa vasorum in their walls. Mast cell stabilization suppressed hypoxic pulmonary vascular remodeling in resistance pulmonary arteries. Four-day hypoxia led to changes in distribution of toluidine blue-detected and MMP-13 positive periarterial mast cells; this redistribution was also influenced by the administration of sodium cromoglycate. CONCLUSIONS: The number of pulmonary periarterial mast cells seemingly decreases during hypoxia due to their degranulation, which disables their identification. Large conduit arteries do not affect final blood pressure in the pulmonary vascular bed; however, their structure changes substantially under hypoxia. Such remodeling changes are not mediated by mast cell products only since they have occurred in spite of stabilization of mast cell granules. PMID- 26052829 TI - Synthetic lung surfactant reduces alveolar-capillary protein leakage in surfactant-deficient rabbits. AB - PURPOSE OF THE STUDY: Alveolar-capillary leakage of proteinaceous fluid impairs alveolar ventilation and surfactant function and decreases lung compliance in acute lung injury. We investigated the correlation between lung function and total protein levels in bronchoalveolar lavage fluid (BALF) of ventilated, lavaged surfactant-deficient rabbits treated with various clinical and synthetic lung surfactant preparations. MATERIALS AND METHODS: 109 ventilated, young adult New Zealand White rabbits underwent lung lavage to induce surfactant-deficiency (PaO2 <100 torr in 100% O2), were treated with a clinical surfactant or a synthetic surfactant preparation with surfactant protein B (SP-B) and/or surfactant protein C (SP-C) analogs, and mechanically ventilated for 120 min. Total protein levels in postmortem BALF were correlated with arterial PO2 (PaO2) and dynamic lung compliance values at 120 min post-surfactant treatment. RESULTS: Repeated lung lavages decreased mean PaO2 values from 540 to 58 torr and lung compliance from 0.64 to 0.33 mL/kg/cm H2O. Two hours after surfactant therapy and mechanical ventilation, mean PaO2 values had increased to 346 torr and lung compliance to 0.44 mL/kg/cm H2O. Eighty-six rabbits (79%) responded to surfactant therapy with an increase in PaO2 to values >200 torr. Fourteen non-responders received inactive surfactant preparations. BALF protein levels were inversely correlated with PaO2 and lung compliance (P < .001). Surfactant preparations containing both SP-B and SP-C proteins or peptide analogs outperformed single protein/peptide preparations. CONCLUSIONS: Clinical and synthetic surfactant therapy reduces alveolar-capillary protein leakage in surfactant-deficient rabbits. Surfactant preparations with both SP-B and SP-C (analogs) were more efficient than preparations with SP-B or SP-C alone. PMID- 26052831 TI - Mindfulness-based prevention for eating disorders: A school-based cluster randomized controlled study. AB - OBJECTIVE: Successful prevention of eating disorders represents an important goal due to damaging long-term impacts on health and well-being, modest treatment outcomes, and low treatment seeking among individuals at risk. Mindfulness-based approaches have received early support in the treatment of eating disorders, but have not been evaluated as a prevention strategy. This study aimed to assess the feasibility, acceptability, and efficacy of a novel mindfulness-based intervention for reducing the risk of eating disorders among adolescent females, under both optimal (trained facilitator) and task-shifted (non-expert facilitator) conditions. METHOD: A school-based cluster randomized controlled trial was conducted in which 19 classes of adolescent girls (N = 347) were allocated to a three-session mindfulness-based intervention, dissonance-based intervention, or classes as usual control. A subset of classes (N = 156) receiving expert facilitation were analyzed separately as a proxy for delivery under optimal conditions. RESULTS: Task-shifted facilitation showed no significant intervention effects across outcomes. Under optimal facilitation, students receiving mindfulness demonstrated significant reductions in weight and shape concern, dietary restraint, thin-ideal internalization, eating disorder symptoms, and psychosocial impairment relative to control by 6-month follow-up. Students receiving dissonance showed significant reductions in socio-cultural pressures. There were no statistically significant differences between the two interventions. Moderate intervention acceptability was reported by both students and teaching staff. DISCUSSION: Findings show promise for the application of mindfulness in the prevention of eating disorders; however, further work is required to increase both impact and acceptability, and to enable successful outcomes when delivered by less expert providers. PMID- 26052830 TI - A prospective study of adolescent eating in the absence of hunger and body mass and fat mass outcomes. AB - OBJECTIVE: Eating in the absence of hunger (EAH) refers to the consumption of palatable foods in a sated state. It has been proposed that EAH promotes excess weight gain in youth; yet there are limited prospective data to support this hypothesis. We examined whether EAH at baseline predicted increases in body mass (BMI and BMIz) and fat mass (kg) 1 year later among adolescent boys and girls. METHODS: EAH was assessed as adolescents' consumption of palatable snack foods following eating to satiety from an ad libitum lunch buffet. Parents also completed a questionnaire about their children's EAH. Body composition was assessed using air displacement plethysmography. RESULTS: Of 196 adolescents assessed for EAH at baseline, 163 (83%) were re-evaluated 1 year later. Accounting for covariates, which included respective baseline values for each dependent variable, race, height, age, sex, and pubertal stage, there were no significant associations between baseline observed or parent-reported EAH and change in adolescent BMI, BMIz, or fat mass. Results did not differ by sex, child weight status, or maternal weight status. CONCLUSIONS: No evidence was found to support the hypothesis that EAH is a unique endophenotype for adolescent weight or fat gain. PMID- 26052832 TI - In-depth study of the phase separation behaviour of a thermoresponsive ionic liquid and a poly(ionic liquid) in concentrated aqueous solution. AB - The temperature-induced phase transition behaviors of a thermoresponsive ionic liquid (tributylhexylphosphonium 3-sulfopropylmethacrylate, [P4,4,4,6][MC3S]) and its polymer (poly-tributylhexylphosphonium 3-sulfopropylmethacrylate, P[P4,4,4,6][MC3S]) have been investigated using DSC, optical microscopy, temperature-variable (1)H NMR, and FT-IR in combination with two-dimensional analysis methods, including perturbation correlation moving window (PCMW) and two dimensional correlation spectroscopy (2Dcos). We found that there exists a distribution gradient of water molecules in P[P4,4,4,6][MC3S] ranging from hydrophobic backbones to hydrophilic sulfonates. Linked together by covalent bonds, P[P4,4,4,6][MC3S] would form an "urchin-like" structure, which can improve its stability and strengthen the gradient distribution of water. Finally, 2Dcos was employed to elucidate the sequential order of chemical group motions during heating. It is concluded that both [P4,4,4,6][MC3S] and P[P4,4,4,6][MC3S] experience the anionic dominated phase transition process. Moreover, the driving force for the phase transitions is shown to be the dehydration of hydrophobic ester carbonyls. PMID- 26052833 TI - Significant enhancement of PEDOT thin film adhesion to inorganic solid substrates with EDOT-acid. AB - With its high conductivity, tunable surface morphology, relatively soft mechanical response, high chemical stability, and excellent biocompatibility, poly(3,4-ethylenedioxythiophene) (PEDOT) has become a promising coating material for a variety of electronic biomedical devices. However, the relatively poor adhesion of PEDOT to inorganic metallic and semiconducting substrates still poses challenges for long-term applications. Here, we report that 2,3-dihydrothieno(3,4 b)(1,4)dioxine-2-carboxylic acid (EDOT-acid) significantly improves the adhesion between PEDOT thin films and inorganic solid electrodes. EDOT-acid molecules were chemically bonded onto activated oxide substrates via the chemisorption of the carboxylic groups. PEDOT was then polymerized onto the EDOT-acid modified substrates, forming covalently bonded coatings. The adsorption of EDOT-acid onto the electrode surfaces was characterized by cyclic voltammetry (CV), contact angle measurements, atomic force microscopy, and X-ray photoelectron spectroscopy. The electrical properties of the subsequently coated PEDOT films were studied by electrochemical impedance spectroscopy and CV. An aggressive ultrasonication test confirmed the significantly improved adhesion and mechanical stability of the PEDOT films on electrodes with EDOT-acid treatment over those without treatment. PMID- 26052834 TI - Use of Elemental Sulfur or Selenium in a Novel One-Pot Copper-Catalyzed Tandem Cyclization of Functionalized Ynamides Leading to Benzosultams. AB - A novel and efficient [Cu]-catalyzed one-pot regio- and stereospecific synthesis of benzo[1,4,2]dithiazine 1,1-dioxides and benzo[1,4,2]thiaselenazine 1,1 dioxides by cyclization of functionalized ynamides with elemental sulfur/selenium has been developed. Its generality is elegantly illustrated by extension to benzodithiazepines and benzothiaselenazepines. Involvement of water in the reaction is demonstrated by the incorporation of (2)D at the olefinic site by using D2O in place of water. Selective oxidation at sulfur in benzo[1,4,2]dithiazine 1,1-dioxide by using mCPBA as the oxidizing agent is also described. PMID- 26052835 TI - Bis-N-heterocyclic Carbene Aminopincer Ligands Enable High Activity in Ru Catalyzed Ester Hydrogenation. AB - Bis-N-heterocyclic carbene (NHC) aminopincer ligands were successfully applied for the first time in the catalytic hydrogenation of esters. We have isolated and characterized a well-defined catalyst precursor as a dimeric [Ru2(L)2Cl3]PF6 complex and studied its reactivity and catalytic performance. Remarkable initial activities up to 283,000 h(-1) were achieved in the hydrogenation of ethyl hexanoate at only 12.5 ppm Ru loading. A wide range of aliphatic and aromatic esters can be converted with this catalyst to corresponding alcohols in near quantitative yields. The described synthetic protocol makes use of air-stable reagents available in multigram quantities, rendering the bis-NHC ligands an attractive alternative to the conventional phosphine-based systems. PMID- 26052836 TI - Cognitive Mechanisms underlying visual perspective taking in typical and ASC children. AB - Previous research has suggested that people with Autism Spectrum Conditions (ASC) may have difficulty with visual perspective taking (VPT) but it is not clear how this relates to different strategies that can be used in perspective taking tasks. The current study examined VPT in 30 children with autism and 30 verbal mental age matched typical children, in comparison to mental rotation (MR) abilities and body representation abilities. Using a similar paradigm to Hamilton, Brindley, and Frith [2009] all children completed three tasks: a VPT task in which children decided what a toy on a table would look like from a different points of view; a MR task in which the child decided what a toy would look like after it had been rotated; and a body posture matching task, in which children matched pictures of a body shown from different viewpoints. Results showed that children with ASC performed better than the typically developing children on the MR task, and at a similar level on the VPT task and body matching task. Importantly, in the typical children VPT performance was predicted by performance on the body matching task, whereas in the ASC children VPT performance was predicted by MR ability. These findings suggest that differences in VPT in ASC may be explained by the use of a spatial rotation strategy rather than the embodied egocentric transformation strategy used by typical children. PMID- 26052838 TI - Multiscale enhanced sampling of intrinsically disordered protein conformations. AB - In a recently developed multiscale enhanced sampling (MSES) technique, topology based coarse-grained (CG) models are coupled to atomistic force fields to enhance the sampling of atomistic protein conformations. Here, the MSES protocol is refined by designing more sophisticated Hamiltonian/temperature replica exchange schemes that involve additional parameters in the MSES coupling restraint potential, to more carefully control how conformations are coupled between the atomistic and CG models. A specific focus is to derive an optimal MSES protocol for simulating conformational ensembles of intrinsically disordered proteins (IDPs). The efficacy of the refined protocols, referred to as MSES-soft asymptote (SA), was evaluated using two model peptides with various levels of residual helicities. The results show that MSES-SA generates more reversible helix-coil transitions and leads to improved convergence on various ensemble conformational properties. This study further suggests that more detailed CG models are likely necessary for more effective sampling of local conformational transition of IDPs. (c) 2015 Wiley Periodicals, Inc. PMID- 26052837 TI - Intravenous Administration of Stable-Labeled N-Acetylcysteine Demonstrates an Indirect Mechanism for Boosting Glutathione and Improving Redox Status. AB - There is an increasing interest in using N-acetylcysteine (NAC) as a treatment for neurodegenerative disorders to increase glutathione (GSH) levels and its redox status. The purpose of this study was to characterize the biosynthesis of NAC to GSH using a novel stable isotope-labeled technique, and investigate the pharmacodynamics of NAC in vivo. Female wild-type mice were given a single intravenous bolus dose of 150 mg kg(-1) stable-labeled NAC. Plasma, red blood cells (RBC), and brain tissues were collected at predesignated time points. Stable-labeled NAC and its metabolite GSH (both labeled and unlabeled forms) were quantified in blood and brain samples. Molar ratios of the reduced and oxidized forms of GSH (GSH divided by glutathione disulfide, redox ratio) were also determined. The elimination phase half-life of NAC was approximately 34 min. Both labeled and unlabeled GSH in RBC were found to increase; however, the area under the curve above baseline (AUCb0-280 ) of labeled GSH was only 1% of the unlabeled form. These data indicate that NAC is not a direct precursor of GSH. In addition, NAC has prolonged effects in brain even when the drug has been eliminated from systemic circulation. PMID- 26052839 TI - Lentiviral Vector-Mediated FoxO1 Overexpression Inhibits Extracellular Matrix Protein Secretion Under High Glucose Conditions in Mesangial Cells. AB - Diabetic nephropathy is characterized by inordinate secretion of extracellular matrix (ECM) proteins from mesangial cells (MCs), which is tightly associated with excessive activation of TGF-beta signaling. The forkhead transcription factor O1 (FoxO1) protects mesangial cells from hyperglycemia-induced oxidative stress, which may be involved in ameliorating the redundant secretion of ECM proteins under high glucose conditions. Here, we reported that high glucose elevated the level of p-Akt to attenuate endogenous FoxO1 bioactivities in MCs, accompanied with decreases in the mRNA expressions of catalase (CAT) and superoxide dismutase 2 (SOD2). Meanwhile, the expressions of major ECM proteins FN and Col I-increased under high glucose conditions, in consistent with the activation of TGF-beta/Smad signaling. By contrast, overexpression of nucleus localized FoxO1 (insensitive to Akt phosphorylation) directly up-regulated the expressions of anti-oxidative enzymes, accompanied with inactivation of TGF beta/Smad3 pathway, as well as decreases of extracellular matrix proteins. Moreover, similar to those MCs overexpressed of nucleus-localized FoxO1 in high glucose conditions, MCs with down-regulation of FoxO1 by small interference-RNA under normal glucose conditions showed increased FN level and activated TGF beta/Smad3 pathway. Our findings link the anti-oxidative activity of FoxO1 and the TGF-beta-induced secretion of ECM proteins, indicating the novel role of FoxO1 in protecting MCs under high glucose conditions. PMID- 26052840 TI - The expanding role of somatostatin analogues in the treatment of neuroendocrine tumours: the CLARINET study. PMID- 26052841 TI - Outcome is unchanged by adding vincristine upfront to the Malawi 28-day protocol for endemic Burkitt lymphoma. AB - BACKGROUND: We previously reported a 28-day treatment protocol for children with endemic Burkitt lymphoma (BL) which included four doses of cyclophosphamide (CPM), intrathecal methotrexate and hydrocortisone (IT MTX/HC) at Queen Elizabeth Central Hospital (QECH) in Malawi which resulted in an Event-Free Survival (EFS) of 50% at 1 year. METHODS: In an attempt to improve survival whilst maintaining acceptable toxicity, brevity, low-cost and a standard treatment for all patients, four doses of vincristine (VCR) at 1.5 mg/m(2) were added to the backbone of CPM 40 mg/kg on day 1 and 60 mg/kg on days 8,18 and 28 and IT MTX /HC 12.5 mg on days 1,8,18 and 28. RESULTS: Seventy cytology confirmed cases of BL, 42 males and 28 females with a median age of 80 years, were treated with this protocol between January 2010 and April 2012. Four percent had St Jude Stage I disease; 29% Stage II; 30% Stage III and 37% Stage IV. Disease site in order of frequency was face (64%); abdomen (47%); CSF (26%) and paraspinal (17%). There were two on-treatment deaths. Sixty-three percent required antibiotics and 19% required blood transfusion. Eighty-one percent of patients achieved complete clinical remission at day 28. Overall predicted EFS at 1 year was 48%; 100% in Stage I, 83% in Stage II, 24% in Stage III and 32% in Stage IV disease. EFS was significantly worse in patients with Stage III/IV disease (P = 0.002) and paraplegia (P = 0.002). CONCLUSION: The addition of vincristine to the Malawi 28 day BL treatment protocol did not improve survival. PMID- 26052842 TI - Transnasal administration of a combination of dexmedetomidine, midazolam and butorphanol produces deep sedation in New Zealand White rabbits. AB - OBJECTIVE: To study the sedative and cardiorespiratory effects of transnasal (TN) administration of a combination of dexmedetomidine (DEX), midazolam (MID) and butorphanol (BUT) administered through a nasal catheter to rabbits undergoing diagnostic procedures. STUDY DESIGN: Descriptive cross-sectional experimental study. ANIMALS: Eight healthy New Zealand White rabbit does (12 +/- 1 months old, 3.5 +/- 0.3 kg). METHODS: DEX (0.1 mg kg(-1)), MID (2 mg kg(-1)) and BUT (0.4 mg kg(-1)) were mixed (DMB) in a syringe and applied to the rabbits' nasopharyngeal mucosa after the accurate catheterization of one nostril. The onset, duration and quality of effects including analgesia were scored using a numeric rating scale of sedation for rabbits. Continuous monitoring of vital parameters was performed via clinical and multiparametric recording. Physiological variables were explored using repeated measures anova for parametric data or Friedman's test for non parametric data. Tukey's or Dunn's post hoc multiple comparisons test was used depending on normality. The statistical significance was set at p < 0.05. RESULTS: Loss of the righting reflex, deep sedation and profound analgesia ensued simultaneously at 1.4 +/- 1.1 minutes after DMB administration. These effects lasted 45 minutes before subsiding into moderate sedation, which lasted for an additional 25 minutes. Residual central nervous system impairment persisted up to 100 minutes. Blood pressure dropped progressively over time by 50%, whereas respiratory frequency decreased by 70%, consistent with moderate hypoxemia and hypercarbia. CONCLUSION AND CLINICAL RELEVANCE: The TN route is a reliable and effective means for administration of DEX, MID and BUT to rabbits. The overall profound sedative effects and analgesic proprieties of the DMB combination can be selectively reversed depending on the needs of the procedure. Oxygen supplementation and careful monitoring are mandatory even in healthy subjects. The DMB protocol should be cautiously used in rabbits with cardiovascular or respiratory deficiencies. PMID- 26052844 TI - Neutral Poly/Per-Fluoroalkyl Substances in Air from the Atlantic to the Southern Ocean and in Antarctic Snow. AB - The oceanic scale occurrences of typical neutral poly/per-fluoroalkyl substances (PFASs) in the atmosphere across the Atlantic, as well as their air-snow exchange at the Antarctic Peninsula, were investigated. Total concentrations of the 12 PFASs (?PFASs) in gas phase ranged from 2.8 to 68.8 pg m(-3) (mean: 23.5 pg m( 3)), and the levels in snow were from 125 to 303 pg L(-1) (mean: 209 pg L(-1)). Fluorotelomer alcohols (FTOHs) were dominant in both air and snow. The differences of specific compounds to ?PFASs were not significant between air and snow. ?PFASs were higher above the northern Atlantic compared to the southern Atlantic, and the levels above the southern Atlantic <30 degrees S was the lowest. High atmospheric PFAS levels around the Antarctic Peninsula were the results of a combination of air mass, weak elimination processes and air-snow exchange of PFASs. Higher ratios of 8:2 to 10:2 to 6:2 FTOH were observed in the southern hemisphere, especially around the Antarctic Peninsula, suggesting that PFASs in the region were mainly from the long-range atmospheric transport. No obvious decrease of PFASs was observed in the background marine atmosphere after 2005. PMID- 26052843 TI - All-systolic non-ECG-gated myocardial perfusion MRI: Feasibility of multi-slice continuous first-pass imaging. AB - PURPOSE: To develop and test the feasibility of a new method for non-ECG-gated first-pass perfusion (FPP) cardiac MR capable of imaging multiple short-axis slices at the same systolic cardiac phase. METHODS: A magnetization-driven pulse sequence was developed for non-ECG-gated FPP imaging without saturation-recovery preparation using continuous slice-interleaved radial sampling. The image reconstruction method, dubbed TRACE, used self-gating based on reconstruction of a real-time image-based navigator combined with reference-constrained compressed sensing. Data from ischemic animal studies (n = 5) was used in a simulation framework to evaluate temporal fidelity. Healthy subjects (n = 5) were studied using both the proposed approach and the conventional method to compare the myocardial contrast-to-noise ratio (CNR). Patients (n = 2) underwent adenosine stress studies using the proposed method. RESULTS: Temporal fidelity of the developed method was shown to be sufficient at high heart-rates. The healthy volunteers studies demonstrated normal perfusion and no dark-rim artifacts. Compared with the conventional scheme, myocardial CNR for the proposed method was slightly higher (8.6 +/- 0.6 versus 8.0 +/- 0.7). Patient studies showed stress induced perfusion defects consistent with invasive angiography. CONCLUSION: The presented methods and results demonstrate feasibility of the proposed approach for high-resolution non-ECG-gated FPP imaging of 3 myocardial slices at the same systolic phase, and indicate its potential for achieving desirable image quality (high CNR and no dark-rim artifacts). PMID- 26052845 TI - Methodological approaches in conducting overviews: current state in HTA agencies. AB - OBJECTIVES: Overviews search for reviews rather than for primary studies. They might have the potential to support decision making within a shorter time frame by reducing production time. We aimed to summarize available instructions for authors intending to conduct overviews as well as the currently applied methodology of overviews in international Health Technology Assessment (HTA) agencies. METHODS: We identified 127 HTA agencies and scanned their websites for methodological handbooks as well as published overviews as HTA reports. Additionally, we contacted HTA agencies by e-mail to retrieve possible unidentified handbooks or other related sources. RESULTS: In total, eight HTA agencies providing methodological support were found. Thirteen HTA agencies were found to have produced overviews since 2007, but only six of them published more than four overviews. Overviews were mostly employed in HTA products related to rapid assessment. Additional searches for primary studies published after the last review are often mentioned in order to update results. CONCLUSIONS: Although the interest in overviews is rising, little methodological guidance for the conduct of overviews is provided by HTA agencies. Overviews are of special interest in the context of rapid assessments to support policy-making within a short time frame. Therefore, empirical work on overviews needs to be extended. National strategies and experience should be disclosed and discussed. PMID- 26052846 TI - Practicalities of using a modified version of the Cochrane Collaboration risk of bias tool for randomised and non-randomised study designs applied in a health technology assessment setting. AB - We describe our experience of using a modified version of the Cochrane risk of bias (RoB) tool for randomised and non-randomised comparative studies. OBJECTIVES: To assess time to complete RoB assessment. To assess inter-rater agreement. To explore the association between RoB and treatment effect size METHODS: Cochrane risk of bias assessment was performed on a sample of full text primary reports included in a systematic review comparing operative techniques for radical prostatectomy. Inter-rater agreement was assessed using the kappa statistic. RESULTS: Twenty-four studies were judged as high overall RoB, 13 were judged as low RoB and 11 were unclear. The weighted Kappa value was 0.35 indicating fair agreement. The median (range) time taken to rate each study was 30 min (10-49). The effect estimate for all studies was 0.61 (95% credible interval (CrI) 0.46-0.83) and 0.73 (95% CrI 0.29-1.75) for low risk studies. CONCLUSIONS: Although the process was time consuming, using a modified version of the RoB tool proved useful for demonstrating conservative effect estimates. That we only achieved a fair agreement between reviewers demonstrates the urgent need for further validation to improve inter-rater agreement. We suggest additional RoB levels could improve inter-rater reliability. PMID- 26052847 TI - Trial sequential methods for meta-analysis. AB - Statistical methods for sequential meta-analysis have applications also for the design of new trials. Existing methods are based on group sequential methods developed for single trials and start with the calculation of a required information size. This works satisfactorily within the framework of fixed effects meta-analysis, but conceptual difficulties arise in the random effects model. One approach applying sequential meta-analysis to design is 'trial sequential analysis', developed by Wetterslev, Thorlund, Brok, Gluud and others from the Copenhagen Trial Unit. In trial sequential analysis, information size is based on the required sample size of a single new trial, which, in the random effects model, is obtained by simply inflating it in comparison with fixed effects meta analysis. However, this is not sufficient as, depending on the amount of heterogeneity, a minimum of several new trials may be indicated, and the total number of new patients needed may be substantially reduced by planning an even larger number of small trials. We provide explicit formulae to determine the requisite minimum number of trials and their sample sizes within this framework, which also exemplify the conceptual difficulties referred to. We illustrate all these points with two practical examples, including the well-known meta-analysis of magnesium for myocardial infarction. PMID- 26052848 TI - Searching for grey literature for systematic reviews: challenges and benefits. AB - There is ongoing interest in including grey literature in systematic reviews. Including grey literature can broaden the scope to more relevant studies, thereby providing a more complete view of available evidence. Searching for grey literature can be challenging despite greater access through the Internet, search engines and online bibliographic databases. There are a number of publications that list sources for finding grey literature in systematic reviews. However, there is scant information about how searches for grey literature are executed and how it is included in the review process. This level of detail is important to ensure that reviews follow explicit methodology to be systematic, transparent and reproducible. The purpose of this paper is to provide a detailed account of one systematic review team's experience in searching for grey literature and including it throughout the review. We provide a brief overview of grey literature before describing our search and review approach. We also discuss the benefits and challenges of including grey literature in our systematic review, as well as the strengths and limitations to our approach. Detailed information about incorporating grey literature in reviews is important in advancing methodology as review teams adapt and build upon the approaches described. PMID- 26052849 TI - The impact of multiple endpoint dependency on Q and I(2) in meta-analysis. AB - A common assumption in meta-analysis is that effect sizes are independent. When correlated effect sizes are analyzed using traditional univariate techniques, this assumption is violated. This research assesses the impact of dependence arising from treatment-control studies with multiple endpoints on homogeneity measures Q and I(2) in scenarios using the unbiased standardized-mean-difference effect size. Univariate and multivariate meta-analysis methods are examined. Conditions included different overall outcome effects, study sample sizes, numbers of studies, between-outcomes correlations, dependency structures, and ways of computing the correlation. The univariate approach used typical fixed effects analyses whereas the multivariate approach used generalized least-squares (GLS) estimates of a fixed-effects model, weighted by the inverse variance covariance matrix. Increased dependence among effect sizes led to increased Type I error rates from univariate models. When effect sizes were strongly dependent, error rates were drastically higher than nominal levels regardless of study sample size and number of studies. In contrast, using GLS estimation to account for multiple-endpoint dependency maintained error rates within nominal levels. Conversely, mean I(2) values were not greatly affected by increased amounts of dependency. Last, we point out that the between-outcomes correlation should be estimated as a pooled within-groups correlation rather than using a full-sample estimator that does not consider treatment/control group membership. PMID- 26052850 TI - Learning by doing-teaching systematic review methods in 8 weeks. AB - OBJECTIVE: The objective of this paper is to describe the course "Systematic Reviews and Meta-analysis" at the Johns Hopkins Bloomberg School of Public Health. METHODS: A distinct feature of our course is a group project in which students, assigned to multi-disciplinary groups, conduct a systematic review. In class sessions comprise didactic lectures, hands-on exercises, demonstrations, discussion, and group work. Students also work outside of class to complete the systematic review. Students evaluated the course at the end of the term. We also surveyed students from 2004 to 2012 to learn more about the long-term impact of the course. RESULTS: The course has been offered to more than 800 students since 1995. In our view, aspects that worked well include the hands-on approach, students working in a multidisciplinary group, intensive interaction with the teaching team, moving to an online approach, and continuous updates of the course content. A persistent issue is the constraint of time. 193 of 211 (91%) survey participants reported that the course is currently useful or as having an impact on their work. CONCLUSIONS: Our experiences have led us to remain committed to a hands-on approach. Our course serves as a bridge between classroom learning and real-world practice, and provides an example of teaching systematic review. PMID- 26052851 TI - A multivariate model for the meta-analysis of study level survival data at multiple times. AB - Motivated by our meta-analytic dataset involving survival rates after treatment for critical leg ischemia, we develop and apply a new multivariate model for the meta-analysis of study level survival data at multiple times. Our data set involves 50 studies that provide mortality rates at up to seven time points, which we model simultaneously, and we compare the results to those obtained from standard methodologies. Our method uses exact binomial within-study distributions and enforces the constraints that both the study specific and the overall mortality rates must not decrease over time. We directly model the probabilities of mortality at each time point, which are the quantities of primary clinical interest. We also present I(2) statistics that quantify the impact of the between study heterogeneity, which is very considerable in our data set. PMID- 26052852 TI - Clinical trial registries are of minimal use for identifying selective outcome and analysis reporting. AB - OBJECTIVE: This study aimed to examine selective outcome reporting (SOR) and selective analysis reporting (SAR) in randomized controlled trials (RCTs) and to explore the usefulness of trial registries for identifying SOR and SAR. STUDY DESIGN AND SETTING: We selected one "index outcome" for each of three comparative effectiveness reviews (CERs) of pharmacotherapy and extracted data on this outcome from trial registries and from study publications. RESULTS: Among 50 RCTs published since 2005 and reporting the index outcome, only 50% were listed in registries; 90% of RCTs were assessed as having SOR or SAR. The index outcome in the registry was different from that in the publication in 75% of trials in two CERs, and not specified at all in the third. Reported outcomes and analyses were not consistent between the publication's methods section and the results section in 33% and 46% of the two CERs where the index outcome was a benefit. There were no statistically significant predictors of SOR and SAR in our small sample where some predictors lacked variability. CONCLUSION: The SOR and SAR were frequent in this pilot study, and the most common type of SOR was the publication of outcomes that were not pre-specified. Trial registries were of little use in identifying SOR and of no use in identifying SAR. PMID- 26052853 TI - Intra- and trans-generational effects of larval diet on susceptibility to an entomopathogenic fungus, Beauveria bassiana, in the greater wax moth, Galleria mellonella. AB - In addition to nutritional conditions experienced by individuals themselves, those experienced by their parents can affect their immune function. Here, we studied the intra- and trans-generational effects of larval diet on susceptibility to an entomopathogenic fungus, Beauveria bassiana, in the greater wax moth, Galleria mellonella. In the first part of the study, a split-brood design was used to compare the susceptibility of full sibs raised either on low- or on high-nutrition larval diet. In the second part of the study, a similar experimental design was employed to investigate the effects of maternal and paternal diet as well as their interaction on offspring's susceptibility. In the first part of the study, we found that individuals fed with high-nutrition diet had higher mortality from infection than individuals fed with low-nutrition diet. However, diet did not affect post-infection survival time. Conversely, in the second part of the study, maternal diet was found to have no significant effect on final mortality rate of offspring, but it affected survival time: larvae with high-nutrition maternal diet survived fewer days after infection than larvae with low-nutrition maternal diet. Paternal diet had no significant effect on offspring's susceptibility to the fungus, indicating that paternal effects are not as important as maternal effects in influencing immune function in this species. Our findings provide further indication that maternal nutrition affects immune function in insects, and suggest that the direct effects of nutrition on immunity may be different, yet parallel, to those caused by parental nutrition. PMID- 26052860 TI - Incidence of and risk factors for difficult ventilation via a supraglottic airway device in a population of 14,480 patients from South-East Asia. AB - Difficult airway practice guidelines include the use of a supraglottic airway device as part of the armamentarium to provide and maintain ventilation and oxygenation. We retrospectively reviewed 14 480 patients aged >= 18 years who underwent general anaesthesia. We identified 74 (0.5%) patients whose lungs were identified as having been difficult to ventilate via a supraglottic airway device, and 29 (0.2%) patients in whom device placement failed. Multivariate analysis identified four risk factors for difficult ventilation via a supraglottic airway device: male sex (OR 1.75, 95% CI 1.07-2.86, p = 0.02); age > 45 years (OR 1.70, 95% CI 1.01-2.86, p = 0.04); short thyromental distance (OR 4.35, 95% CI 2.31-8.17, p < 0.001); and limited neck movement (OR 2.75, 95% CI 1.02-7.44, p = 0.04). Adverse respiratory events including oxygen desaturation, hypercapnoea, laryngospasm, and bronchospasm occurred in 17 patients (22%). The incidence of difficult ventilation via a supraglottic airway device was 0.5% in a large cohort of South-East Asian patients. PMID- 26052861 TI - Correction: Registered report: Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. PMID- 26052862 TI - Insomnia Complaint Versus Sleep Diary Parameters: Predictions of Suicidal Ideation. AB - The purpose of this study was to determine which aspects of insomnia best predict suicidal ideation (SI). Participants were grouped according to whether they complained of insomnia and whether their sleep would be characterized as poor or good by applying quantitative criteria for insomnia to their sleep diary data. Analyses revealed that insomnia complaint was more strongly associated with SI than was poor sleep. These findings suggest that patients who complain of insomnia, regardless of the presence or absence of poor sleep, may be at greater risk for suicide than those who are content with their sleep. PMID- 26052863 TI - Questionnaire-based clinical research. PMID- 26052864 TI - Indirect Magnetic Exchange between o-Iminosemiquinonate Ligands Controlled by Apical Substituent in Pentacoordinated Gallium(III) Complexes. AB - A number of pentacoordinated gallium complexes iSQ2GaR (1-7) (R = Et (1), Me (2), N3 (3), Cl (4), Br (5), I (6), NCS (7)) where iSQ is a radical anion of 4,6-di tert-butyl-N-(2,6-diisopropylphenyl)-o-iminobenzoquinone were synthesized, and crystalline samples of 1-7 were characterized using magnetic susceptibility measurements. The character of magnetic exchange interaction between spins of o iminosemiquinonate radicals was found to be strongly influenced by the nature of the apical substituent. The antiferromagnetic coupling is predominant when the apical position is occupied by halogens or other tested inorganic anions, and the value of exchange interaction parameter varies from -99 to -176 K for R = I and NCS, respectively. In the case of alkyl groups the ferromagnetic exchange prevails and, as the result, the triplet ground state for pentacoordianted biradical compounds was observed. Compounds 1-7 demonstrate a biradical X-band EPR spectrum in frozen toluene matrix. The molecular structures of 4, 6, and 7 have been established by single-crystal X-ray analysis. A computational DFT UB3LYP/6-31G(d,p) study was performed on complexes 1-7 in order to understand the reason for changes in the magnetic behavior of the related diradical gallium compounds. The calculations showed that the magnetic behavior of the complexes with inorganic anions is conditioned by the presence of antiferromagnetic exchange channel formed as a consequence of overlapping between donor atomic orbitals of iminoquinone with pi-orbitals of halogen atoms (4-6) or nitrogen atom (3, 7). PMID- 26052865 TI - Exosomes in development, metastasis and drug resistance of breast cancer. AB - Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. PMID- 26052867 TI - Activation of angiotensin II type 1 receptors and contractile activity in human sigmoid colon in vitro. AB - AIM: To analyse the effects of angiotensin II (Ang II) on the contractility of human sigmoid colon, and to characterize the subtype(s) of receptor(s) involved and the related action mechanism. METHODS: The contractility of sigmoid colon circular muscle strips was recorded isometrically. RT-PCR and immunohistochemistry were used to reveal the eventual existence of a local renin angiotensin system (RAS) and the distribution of Ang II receptors. RESULTS: Transcripts encoding for the Ang II type 1 (AT1 ) and the Ang II type 2 (AT2 ) receptor subtypes and for the angiotensin-converting enzyme in the whole thickness muscular wall were observed. Ang II caused a concentration-dependent contractile response, which is antagonized by losartan, AT1 receptor antagonist, but not by PD123319, AT2 receptor antagonist. The joint application of losartan and PD123319 did not produce any additive effect. The contractile response to Ang II was partially reduced by tetrodotoxin, Na(+) voltage-gated neural channel blocker, and to some extent by SR48968, tachykinin NK2 receptor antagonist. However, hexamethonium, nicotinic receptor antagonist, atropine, cholinergic muscarinic receptor antagonist and SR140333, tachykinin NK1 receptor antagonist, were ineffective. Immunohistochemical analysis showed that AT1 receptors were expressed on the smooth muscle layers and myenteric plexus. CONCLUSION: Ang II positively modulates the spontaneous contractile activity of human sigmoid colon via activation of post-junctional and pre-junctional AT1 receptors, the latter located on the enteric nerves that modulate the release of tachykinins. The presence of the components of RAS in the human colon suggests that Ang II can be also locally generated to control colonic motility. PMID- 26052868 TI - Cognitive Behavioral Therapy for Chronic Insomnia: State of the Science Versus Current Clinical Practices. PMID- 26052866 TI - A Phase II, double-blind, randomized, parallel group, dose-finding study of the safety and tolerability of darexaban compared with warfarin in patients with non valvular atrial fibrillation: the oral factor Xa inhibitor for prophylaxis of stroke in atrial fibrillation study 2 (OPAL-2). AB - BACKGROUND: Darexaban (YM150) is a novel oral anticoagulant that directly inhibits factor Xa. OBJECTIVES: To investigate the optimal daily dose regimen of YM150 in subjects with non-valvular atrial fibrillation (NVAF). METHODS: In this multicenter, double-blind, double-dummy, randomized, parallel-group, dose confirmation study (NCT00938730), patients with NVAF were randomized to darexaban 15 mg bid, 30 mg qd, 30 mg bid, 60 mg qd, 60 mg bid or 120 mg qd, or warfarin qd. The primary endpoint was the incidence of adjudicated major and/or clinically relevant non-major bleeding events. Secondary endpoints included efficacy, pharmacodynamics, safety and tolerability. RESULTS: A total of 1297 patients were randomized and finally included in the trial (median age, 66 [range 30-89] years; 68.8% male): 981 completed treatment for a median of 28 weeks (interquartile range, 24-36). At daily doses of 30-60 mg, darexaban bid resulted in fewer bleeding events than darexaban qd. For darexaban 120 mg, the bid regimen produced more bleeding events than the qd regimen. Although few efficacy endpoints occurred, these decreased with increasing daily darexaban dose. Darexaban decreased plasma D-dimer levels (index of thrombogenesis) after 4 weeks of treatment by 21.5-33.8% compared with baseline, which was comparable with warfarin at the higher darexaban doses. Darexaban was well tolerated with no liver toxicity. CONCLUSIONS: In this Phase II study in patients with NVAF, a lower bleeding rate was observed in the 120 mg daily darexaban group compared with warfarin with a reduction in plasma D-dimer as marker for hemostasis. Further investigation of the optimal dose of darexaban for the prevention of stroke in patients with NVAF would need to be considered. PMID- 26052869 TI - Controlling for Socioeconomic Status in Pain Disparities Research: All-Else-Equal Analysis When "All Else" Is Not Equal. PMID- 26052870 TI - Communication--The Most Challenging Procedure. PMID- 26052871 TI - Treatment of solar urticaria using antihistamine and leukotriene receptor antagonist combinations tailored to disease severity. AB - BACKGROUND: Solar urticarial (SU) is characterized by erythema, whealing, and/or pruritus occurring minutes after sun exposure. Treatment is difficult and often unsatisfactory. OBJECTIVES: To determine the action spectra and minimal urticaria dose (MUD) and to tailor a treatment regimen graded according to disease severity in a series of patients with SU. PATIENTS AND METHODS: Eleven patients (seven females, four males, age range: 5-60 years) with a clinical history suggestive of SU, verified by photo-provocation tests to ultraviolet A (UVA), visible light, and/or UVB, were treated with various combinations of antihistamines and leukotriene receptor antagonist. RESULTS: All patients were sensitive to visible light (median MUD 50 J/cm(2)). Three patients were sensitive to UVA (median MUD 3.75 J/cm(2)), and one patient was sensitive to UVB (MUD of 0.03 J/cm(2)). Two patients experienced a spontaneous remission without treatment. One patient declined treatment. The remaining eight patients were managed by a combination of antihistamines (desloratidine, fexofenadine, cetirizine HCl) and a leukotriene receptor antagonist (montelukast). Seven of the 8 patients experienced a sustained remission of symptoms and signs following treatment. CONCLUSIONS: Photoprovocation for SU with determination of action spectra and MUD enables specifically tailored treatment regimens consisting of combinations of antihistamines and leukotriene receptor antagonist. PMID- 26052872 TI - An analysis of the psychometric properties of the translated versions of the European Organisation for the Research and Treatment of Cancer QLQ CX24 questionnaire in the two South African indigenous languages of Xhosa and Afrikaans. AB - This study evaluates the psychometric properties of the Xhosa and Afrikaans version, the European Organization for Research and Treatment of Cancer (EORTC) of the Quality of Life Questionnaire Cervical Cancer Module (QLQ-CX24). Translated Xhosa and Afrikaans versions, EORTC QLQ-CX24 and the core questionnaire (the EORTC QLQ-C30) were completed by 66 Xhosa and 142 Afrikaans speaking women newly diagnosed with cervical cancer. Construct reliability and validity of the EORTC QLQ-CX24 questionnaire were assessed via factor analysis, multi-trait scaling analyses and known group comparisons. The mean age was similar in the groups with a mean age of the Xhosa group (52 year) and Afrikaans group (49.2 year) (P = 0.25). The study groups had a high unemployment rate of, respectively, 52% (Xhosa) and 51% (Afrikaans) (P = 0.35). The Xhosa group had a statistically significant higher incidence of advanced stage (III and IV) disease (P = 0.006). Scale reliability was confirmed by Cronbach's alpha coefficients for internal consistency, which ranged from 0.73 to 0.81 (Xhosa) and 0.73 to 0.76 (Afrikaans). Clinical validity of both language versions was demonstrated by the ability to discriminate among different stages of cervical cancer. The translated Xhosa and Afrikaans versions of the EORTC QLQ-CX24 were found to be reliable and valid measure of quality of life of women with cervical cancer. PMID- 26052873 TI - The Use of Complementary and Alternative Medicine in Hospitalized Patients with Type 2 Diabetes Mellitus in Israel. AB - INTRODUCTION: The use of complementary and alternative medicine (CAM) has been on the rise in recent years in the general population, as well as among patients with chronic diseases such as diabetes mellitus. The aim of this study was to add information regarding the use of CAM in patients with type 2 diabetes mellitus (DM2) in Israel and explore possible interactions between CAM and prescription medication (PM). METHODS: This is a cross-sectional study based on questionnaires. The study included type 2 diabetic patients who were hospitalized in an internal medicine department at Assaf Harofeh Medical Center, Zerifin, Israel, between December 2013 and December 2014. Possible interactions between CAM and PM were evaluated by a clinical pharmacist and a clinical pharmacologist. RESULTS: Out of 111 diabetic patients, 23.4% used CAM. There was no significant difference between the consumers and nonconsumers in terms of age, education, income, smoking, or alcohol habits. Only 11 of the 26 CAM consumers informed their physician regarding the use. We found possible drug-herb interactions in 19 of the 26 CAM consumers. A major interaction was found between omega-3 and antiaggregants and was encountered in 7 (26.9%) of the CAM consumers. Other minor and major interactions were found with vitamin E, ginkgo-biloba, co-enzyme Q10, green tea, fenugreek seeds, pyridoxine, and dandelion. CONCLUSIONS: Since CAM consumption is on the rise, it is desirable to improve our knowledge concerning their potential effects and adverse effects, especially in conjunction with PM. Given the complexity of pharmaceutics in patients with chronic diseases, among them patients with DM, the use of supplementary medicine cannot be ignored. PMID- 26052874 TI - The effectiveness of clinician feedback in the treatment of depression in the community mental health system. AB - OBJECTIVE: We describe the development and evaluation of a clinician feedback intervention for use in community mental health settings. The Community Clinician Feedback System (CCFS) was developed in collaboration with a community partner to meet the needs of providers working in such community settings. METHOD: The CCFS consists of weekly performance feedback to clinicians, as well as a clinical feedback report that assists clinicians with patients who are not progressing as expected. Patients in the randomized sample (N = 100) were predominantly female African Americans, with a mean age of 39 years. RESULTS: Satisfaction ratings of the CCFS indicate that the system was widely accepted by clinicians and patients. A hierarchical linear models (HLM) analysis comparing rates of change across conditions controlling for baseline gender, age, and racial group indicated a moderate effect in favor of the feedback condition for symptom improvement, t(94) = 2.41, p = .017, d = .50. Thirty-six percent of feedback patients compared with only 13% of patients in the no-feedback condition demonstrated clinically significant change across treatment, chi2(1) = 6.13, p = .013. CONCLUSIONS: These results indicate that our CCFS is acceptable to providers and patients of mental health services and has the potential to improve the effectiveness of services for clinically meaningful depression in the community mental health setting. PMID- 26052875 TI - Adult attachment as a moderator of treatment outcome for generalized anxiety disorder: Comparison between cognitive-behavioral therapy (CBT) plus supportive listening and CBT plus interpersonal and emotional processing therapy. AB - OBJECTIVE: To determine whether baseline dimensions of adult insecure attachment (avoidant and anxious) moderated outcome in a secondary analysis of a randomized controlled trial comparing cognitive-behavioral therapy (CBT) plus supportive listening (CBT + SL) versus CBT plus interpersonal and emotional processing therapy (CBT + I/EP). METHOD: Eighty-three participants diagnosed with generalized anxiety disorder (GAD) were recruited from the community and assigned randomly to CBT + SL (n = 40) or to CBT + I/EP (n = 43) within a study using an additive design. PhD-level psychologists treated participants. Blind assessors evaluated participants at pretreatment, posttreatment, 6-month, 12-month, and 2 year follow-up with a composite of self-report and assessor-rated GAD symptom measures (Penn State Worry Questionnaire, Hamilton Anxiety Rating Scale, Clinician's Severity Rating). Avoidant and anxious attachment were assessed using self-reported dismissing and angry states of mind, respectively, on the Perceptions of Adult Attachment Questionnaire. RESULTS: Consistent with our prediction, at all assessments higher levels of dismissing styles in those who received CBT + I/EP predicted greater change in GAD symptoms compared with those who received CBT + SL for whom dismissiveness was unrelated to the change. At postassessment, higher angry attachment was associated with less change in GAD symptoms for those receiving CBT + I/EP, compared with CBT + SL, for whom anger was unrelated to change in GAD symptoms. Pretreatment attachment-related anger failed to moderate outcome at other time points and therefore, these moderation effects were more short-lived than the ones for dismissing attachment. CONCLUSIONS: When compared with CBT + SL, CBT + I/EP may be better for individuals with GAD who have relatively higher dismissing styles of attachment. PMID- 26052876 TI - Cyanine polyene reactivity: scope and biomedical applications. AB - Cyanines are indispensable fluorophores that form the chemical basis of many fluorescence-based applications. A feature that distinguishes cyanines from other common fluorophores is an exposed polyene linker that is both crucial to absorption and emission and subject to covalent reactions that dramatically alter these optical properties. Over the past decade, reactions involving the cyanine polyene have been used as foundational elements for a range of biomedical techniques. These include the optical sensing of biological analytes, super resolution imaging, and near-IR light-initiated uncaging. This review surveys the chemical reactivity of the cyanine polyene and the biomedical methods enabled by these reactions. The overarching goal is to highlight the multifaceted nature of cyanine chemistry and biology, as well as to point out the key role of reactivity based insights in this promising area. PMID- 26052879 TI - Arthur C Upton (1923-2015)--In Memoriam. PMID- 26052878 TI - Impaired Synaptic Development, Maintenance, and Neuromuscular Transmission in LRP4-Related Myasthenia. AB - IMPORTANCE: Congenital myasthenic syndromes (CMS) are heterogeneous disorders. Defining the phenotypic features, genetic basis, and pathomechanisms of a CMS is relevant to prognosis, genetic counseling, and therapy. OBJECTIVES: To characterize clinical, structural, electrophysiologic, and genetic features of a CMS and to search for optimal therapy. DESIGN, SETTINGS, AND PARTICIPANTS: Two sisters with CMS affecting the limb-girdle muscles were investigated between 2012 and 2014 at an academic medical center by clinical observation, in vitro analysis of neuromuscular transmission, cytochemical and electron microscopy studies of the neuromuscular junction, exome sequencing, expression studies in HEK293 and COS7 cells, and for response to therapy, and they were compared with 15 historical control participants. MAIN OUTCOMES AND MEASURES: We identified the disease gene and mutation, confirmed pathogenicity of the mutation by expression studies, and instituted optimal pharmacotherapy. RESULTS: Quantitative analysis of single EP regions was done for all 15 control participants and microelectrode studies of neuromuscular transmission and alpha-bgt binding sites per EP was conducted for 13 control participants. Examination of the older sister's intercostal muscle end plates (EPs) showed them to be abnormally small, with attenuated reactivities for the acetylcholine receptor and acetylcholinesterase. Most EPs had poorly differentiated or degenerate junctional folds, and some appeared denuded of nerve terminals. The amplitude of the EP potential (EPP), the miniature EPP, and the quantal content of the EPP were all markedly reduced. Exome sequencing identified a novel homozygous p.Glu1233Ala mutation in low density lipoprotein receptor-related protein 4 (LRP4), a coreceptor for agrin to activate muscle-specific tyrosine kinase (MuSK), which is required for EP development and maintenance. Expression studies indicate that the mutation compromises the ability of LRP4 to bind to, phosphorylate, and activate MuSK. Treatment with albuterol sulfate improved the patients' symptoms. A previously identified patient harboring 2 heterozygous mutations in LRP4 had structurally abnormal intercostal EPs but no identifiable defect of neuromuscular transmission at these EPs. CONCLUSIONS AND RELEVANCE: We identified a second CMS kinship harboring mutations in LRP4, identified the mechanisms that impair neuromuscular transmission, and mitigated the disease by appropriate therapy. PMID- 26052877 TI - Comorbidity Between Attention Deficit/Hyperactivity Disorder and Obsessive Compulsive Disorder Across the Lifespan: A Systematic and Critical Review. AB - The concept of comorbidity between attention deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) has been discussed for two decades. No review, however, has examined this question in light of the stark contrast in disorder-specific phenomenology and neurobiology. We review reported prevalence rates and the methodological, phenomenological, and theoretical issues concerning concomitant ADHD-OCD. Reported co-occurrence rates are highly inconsistent in the literature. Studies aimed at examining the potential for comorbidity have suffered from various methodological problems, including the existence of very few community samples, highly variable exclusionary criteria, and possible clinical misinterpretation of symptoms. Despite numerous studies suggesting an ADHD-OCD comorbidity, thus far etiological (i.e., genetic) backing has been provided only for a pediatric comorbidity. Additionally, inflated rates of ADHD-OCD co-occurrence may be mediated by the presence of tic disorders, and evidence of impaired neuronal maturational processes in pediatric OCD may lead to possibly transient phenotypical expressions that resemble ADHD symptomatology. Thus, clinicians are encouraged to consider the possibility that ADHD-like symptoms resulting from OCD-specific symptomatology may be misdiagnosed as ADHD. This suggestion may account for the lower co-occurrence rates reported in adolescents and adults and for the lack of a theoretical account for comorbidity in these age groups. Existing literature is summarized and critically reviewed, and recommendations are made for future research. PMID- 26052880 TI - Intrasylvian hematoma caused by ruptured middle cerebral artery aneurysms predicts recovery from poor-grade subarachnoid hemorrhage. AB - OBJECT: Intrasylvian hematoma (ISH) is a subtype of intracranial hematoma caused by aneurysmal rupture and often presents with a poor initial neurological grade; it is not well studied. The aim of this study was to elucidate outcomes of aneurysmal subarachnoid hemorrhage (SAH) with ISH. METHODS: Data for 97 patients with poor-grade SAH (World Federation of Neurosurgical Societies Grade IV or V) were retrospectively analyzed from a single-center, prospective, observational cohort database. Ultra-early surgical clipping, removal of hematoma, external decompression for brain swelling, and prevention of vasospasm by cisternal irrigation with milrinone were combined as an aggressive treatment. Characteristics and clinical courses of SAH with ISH were identified. The authors also evaluated any correlations between poor admission-grade SAH and ISH with good functional outcome. RESULTS: Patients with poor admission-grade SAH and with ISH were more likely to have initial cerebral edema (p < 0.001, Mann-Whitney U test), which significantly resolved overtime (p < 0.001, Mann-Whitney U-test). These patients had a better chance of functional survival (modified Rankin Scale scores of 1-3; OR 5.75; 95% CI 1.36-24.3; p = 0.017) at 6 months after hospital discharge, after adjustment for potential confounders such as younger age and better initial neurological grade by multivariable analysis. CONCLUSIONS: ISH predicted good functional recovery from poor-grade aneurysmal SAH. PMID- 26052881 TI - Assessment challenges in competency-based education: A case study in health professions education. AB - There is a growing demand for health sciences faculty with formal training in education. Addressing this need, the University of Michigan Medical School created a Master in Health Professions Education (UM-MHPE). The UM-MHPE is a competency-based education (CBE) program targeting professionals. The program is individualized and adaptive to the learner's situation using personal mentoring. Critical to CBE is an assessment process that accurately and reliably determines a learner's competence in educational domains. The program's assessment method has two principal components: an independent assessment committee and a learner repository. Learners submit evidence of competence that is evaluated by three independent assessors. The assessments are presented to an Assessment Committee who determines whether the submission provides evidence of competence. The learner receives feedback on the submission and, if needed, the actions needed to reach competency. During the program's first year, six learners presented 10 submissions for review. Assessing learners in a competency-based program has created challenges; setting standards that are not readily quantifiable is difficult. However, we argue it is a more genuine form of assessment and that this process could be adapted for use within most competency-based formats. While our approach is demanding, we document practical learning outcomes that assess competence. PMID- 26052882 TI - German MedicalTeachingNetwork (MDN) implementing national standards for teacher training. AB - BACKGROUND: An increasing demand for proof of professionalism in higher education strives for quality assurance (QA) and improvement in medical education. A wide range of teacher trainings is available to medical staff in Germany. Cross institutional approval of individual certificates is usually a difficult and time consuming task for institutions. In case of non-acceptance it may hinder medical teachers in their professional mobility. AIM: The faculties of medicine aimed to develop a comprehensive national framework, to promote standards for formal faculty development programmes across institutions and to foster professionalization of medical teaching. METHODS AND RESULTS: Addressing the above challenges in a joint approach, the faculties set up the national MedicalTeacherNetwork (MDN). Great importance is attributed to work out nationally concerted standards for faculty development and an agreed-upon quality control process across Germany. Medical teachers benefit from these advantages due to portability of faculty development credentials from one faculty of medicine to another within the MDN system. CONCLUSION: The report outlines the process of setting up the MDN and the national faculty development programme in Germany. Success factors, strengths and limitations are discussed from an institutional, individual and general perspective. Faculties engaged in similar developments might be encouraged to transfer the MDN concept to their countries. PMID- 26052883 TI - The degree of disparateness of event details modulates future simulation construction, plausibility, and recall. AB - Several episodic simulation studies have suggested that the plausibility of future events may be influenced by the disparateness of the details comprising the event. However, no study had directly investigated this idea. In the current study, we designed a novel episodic combination paradigm that varied the disparateness of details through a social sphere manipulation. Participants recalled memory details from three different social spheres. Details were recombined either within spheres or across spheres to create detail sets for which participants imagined future events in a second session. Across-sphere events were rated as significantly less plausible than within-sphere events and were remembered less often. The presented paradigm, which increases control over the disparateness of details in future event simulations, may be useful for future studies concerned with the similarity of the simulations to previous events and its plausibility. PMID- 26052884 TI - Design, synthesis, and anticonvulsant activity of new hybrid compounds derived from 2-(2,5-dioxopyrrolidin-1-yl)propanamides and 2-(2,5-dioxopyrrolidin-1 yl)butanamides. AB - The library of 27 new 1-(4-phenylpiperazin-1-yl)- or 1-(morpholin-4-yl)-(2,5 dioxopyrrolidin-1-yl)propanamides and (2,5-dioxopyrrolidin-1-yl)butanamides as potential new hybrid anticonvulsant agents was synthesized. These hybrid molecules join the chemical fragments of well-known antiepileptic drugs (AEDs) such as ethosuximide, levetiracetam, and lacosamide. Compounds 5, 10, 11, and 24 displayed the broad spectra of activity across the preclinical seizure models, namely, the maximal electroshock (MES) test, the subcutaneous pentylenetetrazole (scPTZ) test, and the six-hertz (6 Hz) model of pharmacoresistant limbic seizures. The highest protection was demonstrated by 11 (ED50 MES = 88.4 mg/kg, ED50 scPTZ = 59.9 mg/kg, ED50 6 Hz = 21.0 mg/kg). This molecule did not impair the motor coordination of animals in the chimney test even at high doses (TD50 > 1500 mg/kg), yielding superb protective indexes (PI MES > 16.97, PI PTZ > 25.04, PI 6 Hz > 71.43). As a result, 11 displayed distinctly better safety profile than clinically relevant AEDs ethosuximide, lacosamide, or valproic acid. PMID- 26052885 TI - Lived Experiences of Sex Life Difficulties in Men and Women with Early RA - The Swedish TIRA Project. AB - BACKGROUND: Men and women with rheumatoid arthritis (RA) experience restrictions in everyday life, in spite of the development of new medications. Recent research has described in detail how participation limitations are experienced in everyday life from a patient perspective. However, knowledge of how sex and intimate relationships are affected is still scarce. OBJECTIVES: The aim of the present study was to explore sex life experiences in relation to sexual function and sexual relationships in men and women with early RA. METHODS: The study formed part of TIRA-2 (the Swedish acronym for the prospective multicentre early arthritis project). The data collection included 45 interviews with 21 men and 24 women, aged 20-63, which were recorded and transcribed verbatim. The critical incident technique was used to collect data, and content analysis to categorize the results. RESULTS: Half the participants stated that RA affected their sex life. The general descriptions formed five categories: sex life and tiredness; sex life and ageing; emotional consequences of impaired sexual function; facilitators of sexual function and sexual relationships; and strain on the sexual relationship. CONCLUSIONS: Sex life is affected in early RA, in spite of new effective treatment strategies. New strategies of communication, assessment and self-managing interventions concerning the sex lives of patients with RA need to be implemented by a multidisciplinary healthcare team. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26052887 TI - Joint trajectories of cognitive functioning and challenging behavior for persons living with dementia in long-term care. AB - The current study examines the longitudinal relationship between dementia-related challenging behaviors (e.g., vocal disruption, physical aggression, repetitive behaviors, and restlessness) and cognitive functioning in the long-term care (LTC) context. A multivariate latent growth curve model within the structural equation modeling (SEM) framework was applied to data collected from 16,804 older adults upon admission to LTC and every 3 months for a period of 2.5 years. Increases in challenging behaviors were characterized by a significant positive linear and negative quadratic trend (i.e., a subtle leveling off at later assessment times), whereas increases in cognitive impairment were characterized by a positive linear trend. On average, individuals who were more cognitively impaired upon entry into LTC and who exhibited a steeper increase in cognitive impairment also exhibited more challenging behaviors at entry into LTC and a steeper increase in challenging behaviors, respectively. At the within-person level, individuals demonstrating an increase in cognitive impairment at a specific occasion were also more likely to demonstrate an increase in challenging behaviors at that same occasion; however, the magnitude of these effects was very small, suggesting limited practical implications. This study provides novel empirical evidence about the coevolution of cognitive impairment and challenging behaviors, going beyond prior research that has been either cross-sectional in nature, examined longitudinal change in only 1 variable, or simply looked at linear trends without attempting to explore the possibility of nonlinear change. Most importantly, this longitudinal examination of persons with dementia living in LTC has implications for how challenging behaviors can be better managed and for how new strategies can be implemented to prevent challenging behaviors. PMID- 26052886 TI - Spatial representations in older adults are not modified by action: Evidence from tool use. AB - Theories of embodied perception hold that the visual system is calibrated by both the body schema and the action system, allowing for adaptive action-perception responses. One example of embodied perception involves the effects of tool use on distance perception, in which wielding a tool with the intention to act upon a target appears to bring that object closer. This tool-based spatial compression (i.e., tool-use effect) has been studied exclusively with younger adults, but it is unknown whether the phenomenon exists with older adults. In this study, we examined the effects of tool use on distance perception in younger and older adults in 2 experiments. In Experiment 1, younger and older adults estimated the distances of targets just beyond peripersonal space while either wielding a tool or pointing with the hand. Younger adults, but not older adults, estimated targets to be closer after reaching with a tool. In Experiment 2, younger and older adults estimated the distance to remote targets while using either a baton or a laser pointer. Younger adults displayed spatial compression with the laser pointer compared to the baton, although older adults did not. Taken together, these findings indicate a generalized absence of the tool-use effect in older adults during distance estimation, suggesting that the visuomotor system of older adults does not remap from peripersonal to extrapersonal spatial representations during tool use. PMID- 26052888 TI - Comparative performance analyses of commercially available products for salivary collection and nucleic acid processing in the newborn. AB - Analysis of saliva for clinical monitoring and biomarker detection holds great promise for improving health care. Commercially available assays are not intended for use with neonates, however, and collection and processing of saliva for subsequent transcriptomic analysis presents unique challenges in this population. We compared RNA yield, quality, stability and RT-qPCR performance for two commonly used commercial systems: the Qiagen RNeasy Protect Saliva Mini Kit((r)) and the DNA Genotek Oragene*RNA((r)) assay. Two 10 MUl saliva samples were collected from ten newborns and stabilized for each assay. Total RNA was extracted following incubation for 3, 10, 15 or 20 days. Total RNA extracted from each assay was analyzed for integrity, quality and quantity using the Agilent BioAnalyzer 2100. RT-qPCR was performed for the reference gene, GAPDH, to assess subsequent performance of the extracted RNA. Although the DNA Genotek extraction protocol required nearly twice the time of the Qiagen protocol, RNA integrity did not differ between the kits. RNA concentration using the DNA Genotek assay, however, was 3,264 pg/MUl (range: 262 - 10,336 pg/MUl) compared to 822.4 pg/MUl (range: 0 - 1,856 pg/MUl) for the Qiagen protocol. Linear regression analysis showed a stronger correlation between the threshold cycle and RNA concentration using DNA Genotek (r(2) = 0.356) compared to Qiagen (r(2) = 0.0331). Our results suggest that although the Qiagen assay may reduce overall extraction time, RNA yield and performance in subsequent transcriptomic analysis is more robust using the DNA Genotek assay. PMID- 26052889 TI - This edition of the Journal starts off with a wonderful review. Introduction. PMID- 26052890 TI - Correction to Exploring the Mechanisms of the Reductase Activity of Neuroglobin by Site-Directed Mutagenesis of the Heme Distal Pocket. PMID- 26052891 TI - Neonatal admissions, quality of care and outcome: 4 years of inpatient audit data from The Gambia's teaching hospital. AB - BACKGROUND: National facility-based neonatal mortality audits are an important source of data to identify areas for improvement of service delivery and outcome of care. OBJECTIVES: To examine admissions to the neonatal unit, Edward Francis Small Teaching Hospital, Banjul, The Gambia and make recommendations for programme action to reduce mortality through improvements in the quality of care, particularly with respect to suspected neonatal infections. METHODS: Case notes were reviewed for all neonates admitted to the neonatal unit during a 5-year period (1 January 2009 to 31 December 2013) to assess outcome and quality of care. Data for 2009 were subsequently excluded because of the low proportion of records retrieved. RESULTS: Of the 4944 admissions between 1 January 2010 and 31 December 2013, 1734 infants (35%) died, with 57% of all deaths occurring within the first 48 hours of admission. There were 1267 early neonatal deaths (deaths occurring during the first 7 days of life), 67% of which occurred during the first 48 hours of life. Independent predictors of neonatal death in the multivariable analysis were; maternal lack of antenatal care, non-teaching hospital delivery, admission weight < 1500 g, abnormal blood glucose concentration ( < 2.6 mmol/L or >6.9 mmol/L) and hypothermia (axillary temperature < 36.5 C). Forty-eight per cent of newborns had point-of-admission hypothermia. Possible severe bacterial infection (pSBI) accounted for 44% (2166/4944) of admissions, prematurity/low birthweight for 27% (1340/4944) and intrapartum-related conditions for 20%. Only 5% (104/2166) of pSBI cases had at least one supportive investigation; 41 had a chest radiograph, 26 had a blood culture and 43 had a lumbar puncture. Although 94% of the newborns received intravenous antibiotics, 55% of those who did lacked clinical evidence of pSBI and had no diagnostic work-up. CONCLUSION: Priority areas for action include infection prevention and improved diagnosis and management. There is also scope to reduce hypothermia with feasible interventions particularly targeting preterm infants. Improved patient records and audit data with linked action and accountability are interventions which could prevent such deaths of newborns in The Gambia and other developing countries. PMID- 26052892 TI - The pilus usher controls protein interactions via domain masking and is functional as an oligomer. AB - The chaperone-usher (CU) pathway assembles organelles termed pili or fimbriae in Gram-negative bacteria. Type 1 pili expressed by uropathogenic Escherichia coli are prototypical structures assembled by the CU pathway. Biogenesis of pili by the CU pathway requires a periplasmic chaperone and an outer-membrane protein termed the usher (FimD). We show that the FimD C-terminal domains provide the high-affinity substrate-binding site but that these domains are masked in the resting usher. Domain masking requires the FimD plug domain, which serves as a switch controlling usher activation. We demonstrate that usher molecules can act in trans for pilus biogenesis, providing conclusive evidence for a functional usher oligomer. These results reveal mechanisms by which molecular machines such as the usher regulate and harness protein-protein interactions and suggest that ushers may interact in a cooperative manner during pilus assembly in bacteria. PMID- 26052894 TI - Increased NOD1, but not NOD2, activity in subcutaneous adipose tissue from patients with metabolic syndrome. AB - OBJECTIVE: Nucleotide-binding oligomerization domain (NOD) protein, as cytoplasmic receptor of the innate immune response, plays an important role in adipose inflammation and insulin resistance in obesity. Our objective was to examine adipose tissue (AT) NOD in nascent metabolic syndrome (MetS) patients and to investigate its association with MetS features. METHODS: Thirty-four MetS subjects and 31 controls were recruited. Fasting blood was collected, and abdominal subcutaneous AT was obtained by biopsy for NOD1/NOD2 expression and activity. RESULTS: MetS subjects showed significantly increased expression for NOD1 on adipose depots as compared to controls. In addition to increased expression of downstream signaling mediators RIPK2 and NF-kappaB p65 nuclear translocation, there was remarkably higher release of monocyte chemotactic protein1 (MCP-1), interleukin (IL)-6, and IL-8 in MetS versus controls following priming of the isolated adipocytes with NOD1 ligand iE-DAP. With regard to NOD2, the differences between the two groups were not significant in either basal state or after activation. Increased NOD1 positively correlated with waist circumference. NOD1 was also correlated with HbA1c and HOMA-IR. NOD1 positively correlated with serum levels of IL-6, MCP-1, and NF-kappaB activity. CONCLUSIONS: Activation of the innate immune pathway via NOD1 may be partially responsible for the increased systemic inflammation and insulin resistance in MetS. PMID- 26052893 TI - ATP binding drives substrate capture in an ECF transporter by a release-and-catch mechanism. AB - ECF transporters are a family of active transporters for vitamins. They are composed of four subunits: a membrane-embedded substrate-binding subunit (EcfS), a transmembrane coupling subunit (EcfT) and two ATP-binding-cassette ATPases (EcfA and EcfA'). We have investigated the mechanism of the ECF transporter for riboflavin from the pathogen Listeria monocytogenes, LmECF-RibU. Using structural and biochemical approaches, we found that ATP binding to the EcfAA' ATPases drives a conformational change that dissociates the S subunit from the EcfAA'T ECF module. Upon release from the ECF module, the RibU S subunit then binds the riboflavin transport substrate. We also find that S subunits for distinct substrates compete for the ATP-bound state of the ECF module. Our results explain how ECF transporters capture the transport substrate and reproduce the in vivo observations on S-subunit competition for which the family was named. PMID- 26052895 TI - A novel cobalt sodium phosphate hydroxide with the ellenbergerite topology: crystal structure and physical properties. AB - The novel phase Na2-xCo6(OH)3[HPO4][Hx/3PO4]3 (x~ 1.1) was prepared by hydrothermal synthesis at 553 K. Its crystal structure was determined using single-crystal X-ray diffraction data and refined against F(2) to R = 0.052, including positions of all hydrogen atoms. The compound crystallizes in the hexagonal space group P63mc, with unit-cell parameters a = 12.630(3) A, c = 5.017(1) A, V = 693.1(3) A(3), and Z = 2. The crystal structure is based on a 3D framework built from CoO6 octahedra and PO4 tetrahedra. Channels in the [001] direction accommodate columns of Na-centered octahedra sharing faces. The compound is a new structural representative of the topology shown by aluminosilicate mineral ellenbergerite and its numerous natural and synthetic varieties. Magnetic susceptibility measurements revealed a strong antiferromagnetic interaction and magnetic transition to low temperature spin canted phase at TN = 44 K. The physical properties of the title compound are found to be very similar to those of the structurally related arsenate Co1 xCo6(OH)3[H2x/3AsO4]3[HAsO4] and vanadate Co7(OH)2(H2O)[VO4]4. PMID- 26052896 TI - Contrasting environmental drivers of adult and juvenile growth in a marine fish: implications for the effects of climate change. AB - Many marine fishes have life history strategies that involve ontogenetic changes in the use of coastal habitats. Such ontogenetic shifts may place these species at particular risk from climate change, because the successive environments they inhabit can differ in the type, frequency and severity of changes related to global warming. We used a dendrochronology approach to examine the physical and biological drivers of growth of adult and juvenile mangrove jack (Lutjanus argentimaculatus) from tropical north-western Australia. Juveniles of this species inhabit estuarine environments and adults reside on coastal reefs. The Nino-4 index, a measure of the status of the El Nino-Southern Oscillation (ENSO) had the highest correlation with adult growth chronologies, with La Nina years (characterised by warmer temperatures and lower salinities) having positive impacts on growth. Atmospheric and oceanographic phenomena operating at ocean basin scales seem to be important correlates of the processes driving growth in local coastal habitats. Conversely, terrestrial factors influencing precipitation and river runoff were positively correlated with the growth of juveniles in estuaries. Our results show that the impacts of climate change on these two life history stages are likely to be different, with implications for resilience and management of populations. PMID- 26052897 TI - Bone Is a Major Target of PTH/PTHrP Receptor Signaling in Regulation of Fetal Blood Calcium Homeostasis. AB - The blood calcium concentration during fetal life is tightly regulated within a narrow range by highly interactive homeostatic mechanisms that include transport of calcium across the placenta and fluxes in and out of bone; the mechanisms of this regulation are poorly understood. Our findings that endochondral bone specific PTH/PTHrP receptor (PPR) knockout (KO) mice showed significant reduction of fetal blood calcium concentration compared with that of control littermates at embryonic day 18.5 led us to focus on bone as a possibly major determinant of fetal calcium homeostasis. We found that the fetal calcium concentration of Runx2 KO mice was significantly higher than that of control littermates, suggesting that calcium flux into bone had a considerable influence on the circulating calcium concentration. Moreover, Runx2:PTH double mutant fetuses showed calcium levels similar to those of Runx2 KO mice, suggesting that part of the fetal hypocalcemia in PTH KO mice was caused by the increment of the mineralized bone mass allowed by the formation of osteoblasts. Finally, Rank:PTH double mutant mice had a blood calcium concentration even lower than that of the either Rank KO or PTH KO mice alone at embryonic day 18.5. These observations in our genetic models suggest that PTH/PTHrP receptor signaling in bones has a significant role of the regulation of fetal blood calcium concentration and that both placental transport and osteoclast activation contribute to PTH's hypercalcemic action. They also show that PTH-independent deposition of calcium in bone is the major controller of fetal blood calcium level. PMID- 26052898 TI - Exercise Regulation of Marrow Fat in the Setting of PPARgamma Agonist Treatment in Female C57BL/6 Mice. AB - The contribution of marrow adipose tissue (MAT) to skeletal fragility is poorly understood. Peroxisome proliferator-activated receptor (PPAR)gamma agonists, associated with increased fractures in diabetic patients, increase MAT. Here, we asked whether exercise could limit the MAT accrual and increase bone formation in the setting of PPARgamma agonist treatment. Eight-week-old female C57BL/6 mice were treated with 20-mg/kg . d rosiglitazone (Rosi) and compared with control (CTL) animals. Exercise groups ran 12 km/d when provided access to running wheels (CTL exercise [CTL-E], Rosi-E). After 6 weeks, femoral MAT (volume of lipid binder osmium) and tibial bone morphology were assessed by microcomputer tomography. Rosi was associated with 40% higher femur MAT volume compared with CTL (P < .0001). Exercise suppressed MAT volume by half in CTL-E mice compared with CTL (P < .01) and 19% in Rosi-E compared with Rosi (P < .0001). Rosi treatment increased fat markers perilipin and fatty acid synthase mRNA by 4-fold (P < .01). Exercise was associated with increased uncoupling protein 1 mRNA expression in both CTL-E and Rosi-E groups (P < .05), suggestive of increased brown fat. Rosi increased cortical porosity (P < .0001) but did not significantly impact trabecular or cortical bone quantity. Importantly, exercise induction of trabecular bone volume was not prevented by Rosi (CTL-E 21% > CTL, P < .05; Rosi E 26% > Rosi, P < .01). In summary, despite the Rosi induction of MAT extending well into the femoral diaphysis, exercise was able to significantly suppress MAT volume and induce bone formation. Our results suggest that the impact of PPARgamma agonists on bone and marrow health can be partially mitigated by exercise. PMID- 26052899 TI - The Calcilytic Agent NPS 2143 Rectifies Hypocalcemia in a Mouse Model With an Activating Calcium-Sensing Receptor (CaSR) Mutation: Relevance to Autosomal Dominant Hypocalcemia Type 1 (ADH1). AB - Autosomal dominant hypocalcemia type 1 (ADH1) is caused by germline gain-of function mutations of the calcium-sensing receptor (CaSR) and may lead to symptomatic hypocalcemia, inappropriately low serum PTH concentrations and hypercalciuria. Negative allosteric CaSR modulators, known as calcilytics, have been shown to normalize the gain-of-function associated with ADH-causing CaSR mutations in vitro and represent a potential targeted therapy for ADH1. However, the effectiveness of calcilytic drugs for the treatment of ADH1-associated hypocalcemia remains to be established. We have investigated NPS 2143, a calcilytic compound, for the treatment of ADH1 by in vitro and in vivo studies involving a mouse model, known as Nuf, which harbors a gain-of-function CaSR mutation, Leu723Gln. Wild-type (Leu723) and Nuf mutant (Gln723) CaSRs were expressed in HEK293 cells, and the effect of NPS 2143 on their intracellular calcium responses was determined by flow cytometry. NPS 2143 was also administered as a single ip bolus to wild-type and Nuf mice and plasma concentrations of calcium and PTH, and urinary calcium excretion measured. In vitro administration of NPS 2143 decreased the intracellular calcium responses of HEK293 cells expressing the mutant Gln723 CaSR in a dose-dependent manner, thereby rectifying the gain-of-function associated with the Nuf mouse CaSR mutation. Intraperitoneal injection of NPS 2143 in Nuf mice led to significant increases in plasma calcium and PTH without elevating urinary calcium excretion. These studies of a mouse model with an activating CaSR mutation demonstrate NPS 2143 to normalize the gain-of-function causing ADH1 and improve the hypocalcemia associated with this disorder. PMID- 26052901 TI - Detection of Structural Changes upon One-Electron Oxidation and Reduction of Stilbene Derivatives by Time-Resolved Resonance Raman Spectroscopy during Pulse Radiolysis and Theoretical Calculations. AB - Stilbene (St) derivatives have been investigated for many years because of their interesting photochemical reactions such as cis-trans isomerization in the excited states and charged states and their relation to poly(p phenylenevinylene)s. To clarify their charged state properties, structural information is indispensable. In the present study, radical cations and radical anions of St derivatives were investigated by radiation chemical methods. Absorption spectra of radical ion states were obtained by transient absorption measurements during pulse radiolysis; theoretical calculations that included the solvent effect afforded reasonable assignments. The variation in the peak position was explained by using HOMO and LUMO energy levels. Structural changes upon one-electron oxidation and reduction were detected by time-resolved resonance Raman measurements during pulse radiolysis. Significant downshifts were observed with the CC stretching mode of the ethylenic groups, indicative of the decrease in the bonding order. It was confirmed that the downshifts observed with reduction were larger than those with oxidation. On the other hand, the downshift caused by oxidation depends significantly on the electron-donating or electron withdrawing nature of the substituents. PMID- 26052900 TI - Rapamycin protects against gentamicin-induced acute kidney injury via autophagy in mini-pig models. AB - Gentamicin may cause acute kidney injury. The pathogenesis of gentamicin nephrotoxicity is unclear. Autophagy is a highly conserved physiological process involved in removing damaged or aged biological macromolecules and organelles from the cytoplasm. The role of autophagy in the pathogenesis of gentamicin nephrotoxicity is unclear. The miniature pigs are more similar to humans than are those of rodents, and thus they are more suitable as human disease models. Here we established the first gentamicin nephrotoxicity model in miniature pigs, investigated the role of autophagy in gentamicin-induced acute kidney injury, and determined the prevention potential of rapamycin against gentamicin-induced oxidative stress and renal dysfunction. At 0, 1, 3, 5, 7 and 10 days after gentamicin administration, changes in autophagy, oxidative damage, apoptosis and inflammation were assessed in the model group. Compared to the 0-day group, gentamicin administration caused marked nephrotoxicity in the 10-day group. In the kidneys of the 10-day group, the level of autophagy decreased, and oxidative damage and apoptosis were aggravated. After rapamycin intervention, autophagy activity was activated, renal damage in proximal tubules was markedly alleviated, and interstitium infiltration of inflammatory cells was decreased. These results suggest that rapamycin may ameliorate gentamicin-induced nephrotoxicity by enhancing autophagy. PMID- 26052904 TI - Spanish Immunology on the move. PMID- 26052908 TI - Treatment ethics, quality of life and health economics in the management of hematopoietic malignancies in older patients. AB - The prevalence of diseases such as AML or myelodysplastic syndromes increases with the aging of the population. Only intensive chemotherapy or hematopoietic cell transplantation have curative potential. However, comorbid conditions may interfere with effective therapy. Although transplantation following low intensity conditioning is being carried out in patients even in their 70s, these are highly selected patients, and the data cannot be extrapolated to the population at large. Further, such a therapy in older individuals may be associated with considerable morbidity and the need for prolonged hospitalization and rehabilitation, stressing the system and draining family resources. As the focus of many older individuals is on quality of life, it is important to emphasize that, for various advanced malignancies, emerging data indicate that quality of life may be better and survival may be longer with palliative care. A re-assessment of treatment decisions in older patients is in order. We tend to 'oversell', and particularly older patients do not have a full understanding of the impact of the proposed therapy on their lives. Our conversations with these patients must include a discussion of supportive/palliative care and must address end-of-life issues. Talking about death may mean talking about life. PMID- 26052910 TI - Cord blood unit factors influencing transplant outcomes from the Asian multiethnic Singapore Cord Blood Bank. PMID- 26052909 TI - Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) is one of curative treatment options for patients with hematologic malignancies. Although GVHD mediated by the donor's T lymphocytes remains the most challenging toxicity of allo-HSCT, graft-versus-leukemia (GVL) effect targeting leukemic cells, has an important role in affecting the overall outcome of patients with AML. Here we comprehensively characterized the TCR repertoire in patients who underwent matched donor or haplo-cord HSCT using next-generation sequencing approach. Our study defines the functional kinetics of each TCRA and TCRB clone, and changes in T-cell diversity (with identification of CDR3 sequences) and the extent of clonal expansion of certain T-cells. Using this approach, our study demonstrates that higher percentage of cord-blood cells at 30 days after transplant was correlated with higher diversity of TCR repertoire, implicating the role of cord-chimerism in enhancing immune recovery. Importantly, we found that GVHD and relapse, exclusive of each other, were correlated with lower TCR repertoire diversity and expansion of certain T-cell clones. Our results highlight novel insights into the balance between GVHD and GVL effect, suggesting that higher diversity early after transplant possibly implies lower risks of both GVHD and relapse following the HSCT transplantation. PMID- 26052911 TI - Imatinib for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. PMID- 26052912 TI - A cross-sectional study on vision-related quality of life in patients with ocular GvHD. AB - Ocular GvHD affects about 40-60% of patients receiving bone marrow transplantation. Ocular complaints worsen quality of life (QoL), which, besides survival time, is a primary end point in a patient's follow-up. The aim of our study was to assess the ocular surface status and vision-related QoL (VRQoL) and explore the potential determinants in VRQoL in patients with chronic GvHD with ocular involvement. In this cross-sectional study, we investigated 40 patients with ocular GvHD after allogeneic hematopoietic stem cell transplantation assessing ocular symptoms and signs, VRQoL and ophthalmologic parameters. The median age was 52.1 years; 32.5% were females. Most of them presented a multiple organ involvement. Ophthalmological parameter examinations were on average abnormal. Corneal staining was severe/very severe in 25%; conjunctival staining in 10% of subjects. The worse QoL scores were on 'general vision', 'ocular pain', 'vision-specific mental health' and 'vision-specific role difficulties'. Both symptoms and sign scores indicate poor VRQoL. A lower VRQoL was related to schooling level, job position, underlying disease and extracorporeal photopheresis. Corneal staining, Schirmer and tear film breakup time were negatively associated to visual function-related subscales. An accurate ophthalmological and VRQoL assessment should be mandatory for a long time to promptly recognize early signs of ocular suffering, and to prevent irreversible ocular complications. PMID- 26052914 TI - Inflammatory bowel disease after allogeneic stem cell transplantation. PMID- 26052913 TI - Recommendations on hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential to cure patients with an inherited bone marrow failure syndrome (IBMFS). However, the procedure involves the risk of treatment-related mortality and may be associated with significant early and late morbidity. For these reasons, the benefits should be carefully weighed against the risks. IBMFS are rare, whereas case reports and small series in the literature illustrate highly heterogeneous practices in terms of indications for HSCT, timing, stem cell source and conditioning regimens. A consensus meeting was therefore held in Vienna in September 2012 on behalf of the European Group for Blood and Marrow Transplantation to discuss HSCT in the setting of IBMFS. This report summarizes the recommendations from this expert panel, including indications for HSCT, timing, stem cell source and conditioning regimen. PMID- 26052915 TI - IV pentamidine for primary PJP prophylaxis in adults undergoing allogeneic hematopoietic progenitor cell transplant. PMID- 26052916 TI - High-resolution HLA matching in unrelated donor transplantation in Switzerland: differential impact of class I and class II mismatches may reflect selection of nonimmunogenic or weakly immunogenic DRB1/DQB1 disparities. AB - Unrelated donor searches in Switzerland require high-resolution HLA typing for HLA-A/B/C/DRB1/DRB3,4/DQB1 loci. We evaluated this strategy accepting donors with ?9/10 match. Of 802 unrelated donor transplants in 2000-2013, 570 were 10/10 matched, 31 were DRB3/4 mismatched, 261 were single-allele mismatched and 13 had 2 allele mismatches. Of the 261 single-allele disparities, 60 concerned HLA-A/-B, 55 HLA-C and 73 HLA-DRB1/-DQB1 loci. Transplants were reduced intensity conditioning (289, 36%), marrow (187, 23%), EBMT risk score was low in 39, intermediate I in 331, intermediate II in 333 and high in 99 patients. Five-year survival was 48+/-4%. HLA affected survival in the multivariate model adjusted for risk score. HLA-A/-B and HLA-C mismatches had twice the mortality risks, whereas HLA-DRB1/-DQB1 mismatches were similar to matched transplants. HLA-DRB3/4 mismatches were associated with a nonsignificant increased mortality risk. HLA DRB3/4 mismatches had higher graft-versus-host disease and transplant-related mortality risks and lower relapse rates compared with matched transplants. We show significant effects of HLA class I, but not HLA class II, mismatches. The lack of impact of DRB1 disparities may be related to the lower immunogenicity of the DRB1*11:01/11:04 and DRB1*14:01/14:54 mismatches, representing 46% of DRB1 incompatibilities. These results support a matching algorithm that prioritizes mismatches considered as more permissive. PMID- 26052917 TI - Functional Identification of Target by Expression Proteomics (FITExP) reveals protein targets and highlights mechanisms of action of small molecule drugs. AB - Phenomenological screening of small molecule libraries for anticancer activity yields potentially interesting candidate molecules, with a bottleneck in the determination of drug targets and the mechanism of anticancer action. We have found that, for the protein target of a small-molecule drug, the abundance change in late apoptosis is exceptional compared to the expectations based on the abundances of co-regulated proteins. Based on this finding, a novel method to drug target deconvolution is proposed. In a proof of principle experiment, the method yielded known targets of several common anticancer agents among a few (often, just one) likely candidates identified in an unbiased way from cellular proteome comprising more than 4,000 proteins. A validation experiment with a different set of cells and drugs confirmed the findings. As an additional benefit, mapping most specifically regulated proteins on known protein networks highlighted the mechanism of drug action. The new method, if proven to be general, can significantly shorten drug target identification, and thus facilitate the emergence of novel anticancer treatments. PMID- 26052918 TI - Serum albumin level at diagnosis of diffuse large B-cell lymphoma: an important simple prognostic factor. AB - This study compared the value of several simple laboratory parameters with known prognostic models for predicting survival in patients with diffuse large B-cell lymphoma (DLBCL). The data of 157 adult patients with DLBCL diagnosed at Rabin Medical Center in 2004-2008 and treated with R-CHOP immunochemotherapy were retrospectively reviewed. Main clinical features of the cohort were as follows: mean age 63.0 years, 43% male, 63% stage III/IV disease, 28% ECOG performance status >2, 60% elevated lactate dehydrogenase level. Median duration of follow-up was 6.6 years. The NCCN-International Prognostic Index (IPI) was found to be a more powerful prognosticator than the IPI. Five-year overall survival (OS) was 69.6; 73.6% for patients with intermediate NCCN-IPI and 38.4% for patients with poor NCCN-IPI. On univariate analysis, pretreatment hemoglobin and albumin levels were significantly associated with survival. By albumin level, 5-year OS was 77.6 + 4% in patients with >3.5 g/dl and 53 + 7% in patients with <3.5 g/dl (p < 0.001); 5-year progression-free survival (PFS) was 69.9% and 50.9%, respectively (p = 0.002). By hemoglobin level, 5-year OS was 82.9 + 4.5% in patients with >12 g/dl and 58.8 + 5% in patients with <12 g/dl (p = 0.007); 5-year PFS was 75.5% and 54.1%, respectively (p = 0.008). On multivariate analysis with Cox regression, pretreatment albumin level was a significant independent predictor of OS. Furthermore, 5-year OS of patients with a high NCCN-IPI and albumin < 3.5 g/dl was 29.2% compared with 60% in patients with albumin > 3.5 g/dl (p = 0.022). In conclusion, pretreatment albumin level is a strong prognostic factor for OS in patients with DLBCL and can discriminate high-risk patients for good and poor prognosis. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26052919 TI - Multifunctional glucose biosensors from Fe3O4 nanoparticles modified chitosan/graphene nanocomposites. AB - Novel water-dispersible and biocompatible chitosan-functionalized graphene (CG) has been prepared by a one-step ball milling of carboxylic chitosan and graphite. Presence of nitrogen (from chitosan) at the surface of graphene enables the CG to be an outstanding catalyst for the electrochemical biosensors. The resulting CG shows lower ID/IG ratio in the Raman spectrum than other nitrogen-containing graphene prepared using different techniques. Magnetic Fe3O4 nanoparticles (MNP) are further introduced into the as-synthesized CG for multifunctional applications beyond biosensors such as magnetic resonance imaging (MRI). Carboxyl groups from CG is used to directly immobilize glucose oxidase (GOx) via covalent linkage while incorporation of MNP further facilitated enzyme loading and other unique properties. The resulting biosensor exhibits a good glucose detection response with a detection limit of 16 MUM, a sensitivity of 5.658 mA/cm(2)/M, and a linear detection range up to 26 mM glucose. Formation of the multifunctional MNP/CG nanocomposites provides additional advantages for applications in more clinical areas such as in vivo biosensors and MRI agents. PMID- 26052921 TI - Equilibrium and nonequilibrium dynamics of soft sphere fluids. AB - We use computer simulations to test the freezing-point scaling relationship between equilibrium transport coefficients (self-diffusivity, viscosity) and thermodynamic parameters for soft sphere fluids. The fluid particles interact via the inverse-power potential (IPP), and the particle softness is changed by modifying the exponent of the distance-dependent potential term. In the case of IPP fluids, density and temperature are not independent variables and can be combined to obtain a coupling parameter to define the thermodynamic state of the system. We find that the rescaled coupling parameter, based on its value at the freezing point, can approximately collapse the diffusivity and viscosity data for IPP fluids over a wide range of particle softness. Even though the collapse is far from perfect, the freezing-point scaling relationship provides a convenient and effective way to compare the structure and dynamics of fluid systems with different particle softness. We further show that an alternate scaling relationship based on two-body excess entropy can provide an almost perfect collapse of the diffusivity and viscosity data below the freezing transition. Next, we perform nonequilibrium molecular dynamics simulations to calculate the shear-dependent viscosity and to identify the distinct role of particle softness in underlying structural changes associated with rheological properties. Qualitatively, we find a similar shear-thinning behavior for IPP fluids with different particle softness, though softer particles exhibit stronger shear thinning tendency. By investigating the distance and angle-dependent pair correlation functions in these systems, we find different structural features in the case of IPP fluids with hard-sphere like and softer particle interactions. Interestingly, shear-thinning in hard-sphere like fluids is accompanied by enhanced translational order, whereas softer fluids exhibit loss of order with shear. Our results provide a systematic evaluation of the role of particle softness in equilibrium and nonequilibrium transport properties and their underlying connection with thermodynamic and structural properties. PMID- 26052922 TI - Uniform Doping of Titanium in Hematite Nanorods for Efficient Photoelectrochemical Water Splitting. AB - Doping elements in hematite nanostructures is a promising approach to improve the photoelectrochemical (PEC) water-splitting performance of hematite photoanodes. However, uniform doping with precise control on doping amount and morphology is the major challenge for quantitatively investigating the PEC water-splitting enhancement. Here, we report on the design and synthesis of uniform titanium (Ti) doped hematite nanorods with precise control of the Ti amount and morphology for highly effective PEC water splitting using an atomic layer deposition assisted solid-state diffusion method. We found that Ti doping promoted band bending and increased the carrier density as well as the surface state. Remarkably, these uniformly doped hematite nanorods exhibited high PEC performance with a pronounced photocurrent density of 2.28 mA/cm(2) at 1.23 V vs reversible hydrogen electrode (RHE) and 4.18 mA/cm(2) at 1.70 V vs RHE, respectively. Furthermore, as prepared Ti-doping hematite nanorods performed excellent repeatability and durability; over 80% of the as-fabricated photoanodes reproduced the steady photocurrent density of 1.9-2.2 mA/cm(2) at 1.23 V vs RHE at least 3 h in a strong alkaline electrolyte solution. PMID- 26052923 TI - One-Pot Synthesis of Pyrrolo[1,2-a]quinoxaline Derivatives via a Copper-Catalyzed Aerobic Oxidative Domino Reaction. AB - A copper-catalyzed process for the synthesis of pyrrolo[1,2-a]quinoxalines from readily available alpha-amino acids and 1-(2-halophenyl)-1H-pyrroles is described. Different functional groups were well tolerated to give the corresponding products. PMID- 26052924 TI - Probiotics in obstetrics and gynaecology. AB - Despite the great advances in modern medicine, our understanding of the most basic function of our complete genetic makeup is extremely poor. Our complete genetic make up is complemented by 100 trillion cells living within or on our body and is called the microbiome. Manipulation of the microbiome is in the embryological stages of investigation but promises great hope in targeting both pregnancy specific and general medical / gynaecological conditions. This review presents an undertanding of the microbiome manipulation with probiotics in women's health in 2015. PMID- 26052920 TI - Where hearing starts: the development of the mammalian cochlea. AB - The mammalian cochlea is a remarkable sensory organ, capable of perceiving sound over a range of 10(12) in pressure, and discriminating both infrasonic and ultrasonic frequencies in different species. The sensory hair cells of the mammalian cochlea are exquisitely sensitive, responding to atomic-level deflections at speeds on the order of tens of microseconds. The number and placement of hair cells are precisely determined during inner ear development, and a large number of developmental processes sculpt the shape, size and morphology of these cells along the length of the cochlear duct to make them optimally responsive to different sound frequencies. In this review, we briefly discuss the evolutionary origins of the mammalian cochlea, and then describe the successive developmental processes that lead to its induction, cell cycle exit, cellular patterning and the establishment of topologically distinct frequency responses along its length. PMID- 26052925 TI - Outcrossing potential between 11 important genetically modified crops and the Chilean vascular flora. AB - The potential impact of genetically modified (GM) crops on biodiversity is one of the main concerns in an environmental risk assessment (ERA). The likelihood of outcrossing and pollen-mediated gene flow from GM crops and non-GM crops are explained by the same principles and depend primarily on the biology of the species. We conducted a national-scale study of the likelihood of outcrossing between 11 GM crops and vascular plants in Chile by use of a systematized database that included cultivated, introduced and native plant species in Chile. The database included geographical distributions and key biological and agronomical characteristics for 3505 introduced, 4993 native and 257 cultivated (of which 11 were native and 246 were introduced) plant species. Out of the considered GM crops (cotton, soya bean, maize, grape, wheat, rice, sugar beet, alfalfa, canola, tomato and potato), only potato and tomato presented native relatives (66 species total). Introduced relative species showed that three GM groups were formed having: a) up to one introduced relative (cotton and soya bean), b) up to two (rice, grape, maize and wheat) and c) from two to seven (sugar beet, alfalfa, canola, tomato and potato). In particular, GM crops presenting introduced noncultivated relative species were canola (1 relative species), alfalfa (up to 4), rice (1), tomato (up to 2) and potato (up to 2). The outcrossing potential between species [OP; scaled from 'very low' (1) to 'very high' (5)] was developed, showing medium OPs (3) for GM-native relative interactions when they occurred, low (2) for GMs and introduced noncultivated and high (4) for the grape-Vitis vinifera GM-introduced cultivated interaction. This analytical tool might be useful for future ERA for unconfined GM crop release in Chile. PMID- 26052927 TI - The landscape of copy number variations in Finnish families with autism spectrum disorders. AB - Rare de novo and inherited copy number variations (CNVs) have been implicated in autism spectrum disorder (ASD) risk. However, the genetic underpinnings of ASD remain unknown in more than 80% of cases. Therefore, identification of novel candidate genes and corroboration of known candidate genes may broaden the horizons of determining genetic risk alleles, and subsequent development of diagnostic testing. Here, using genotyping arrays, we characterized the genetic architecture of rare CNVs (<1% frequency) in a Finnish case-control dataset. Unsurprisingly, ASD cases harbored a significant excess of rare, large (>1 Mb) CNVs and rare, exonic CNVs. The exonic rare de novo CNV rate (~22.5%) seemed higher compared to previous reports. We identified several CNVs in well-known ASD regions including GSTM1-5, DISC1, FHIT, RBFOX1, CHRNA7, 15q11.2, 15q13.2-q13.3, 17q12, and 22q11.21. Additionally, several novel candidate genes (BDKRB1, BDKRB2, AP2M1, SPTA1, PTH1R, CYP2E1, PLCD3, F2RL1, UQCRC2, LILRB3, RPS9, and COL11A2) were identified through gene prioritization. The majority of these genes belong to neuroactive ligand-receptor interaction pathways, and calcium signaling pathways, thus suggesting that a subset of these novel candidate genes may contribute to ASD risk. Furthermore, several metabolic pathways like caffeine metabolism, drug metabolism, retinol metabolism, and calcium-signaling pathway were found to be affected by the rare exonic ASD CNVs. Additionally, biological processes such as bradykinin receptor activity, endoderm formation and development, and oxidoreductase activity were enriched among the rare exonic ASD CNVs. Overall, our findings may add data about new genes and pathways that contribute to the genetic architecture of ASD. PMID- 26052928 TI - Integrated Framework for Assessing Impacts of CO2 Leakage on Groundwater Quality and Monitoring-Network Efficiency: Case Study at a CO2 Enhanced Oil Recovery Site. AB - This study presents a combined use of site characterization, laboratory experiments, single-well push-pull tests (PPTs), and reactive transport modeling to assess potential impacts of CO2 leakage on groundwater quality and leakage detection ability of a groundwater monitoring network (GMN) in a potable aquifer at a CO2 enhanced oil recovery (CO2 EOR) site. Site characterization indicates that failures of plugged and abandoned wells are possible CO2 leakage pathways. Groundwater chemistry in the shallow aquifer is dominated mainly by silicate mineral weathering, and no CO2 leakage signals have been detected in the shallow aquifer. Results of the laboratory experiments and the field test show no obvious damage to groundwater chemistry should CO2 leakage occur and further were confirmed with a regional-scale reactive transport model (RSRTM) that was built upon the batch experiments and validated with the single-well PPT. Results of the RSRTM indicate that dissolved CO2 as an indicator for CO2 leakage detection works better than dissolved inorganic carbon, pH, and alkalinity at the CO2 EOR site. The detection ability of a GMN was assessed with monitoring efficiency, depending on various factors, including the natural hydraulic gradient, the leakage rate, the number of monitoring wells, the aquifer heterogeneity, and the time for a CO2 plume traveling to the monitoring well. PMID- 26052926 TI - Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates. AB - BACKGROUND: Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides using a microarray gene expression profiling strategy. METHODS: To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7) treated with well-characterized pro-inflammatory (PIC) and non-inflammatory (NIC) compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA). RESULTS: Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes. CONCLUSIONS: In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior to entering clinical trials. Additional characterization of these genes can provide further insight into the cervicovaginal immunoinflammatory and mucosal-altering processes that facilitate or limit HIV transmission with implications for the design of prevention strategies. PMID- 26052930 TI - In Situ Monitoring of Electrooxidation Processes at Gold Single Crystal Surfaces Using Shell-Isolated Nanoparticle-Enhanced Raman Spectroscopy. AB - Identifying the intermediate species in an electrocatalytic reaction can provide a great opportunity to understand the reaction mechanism and fabricate a better catalyst. However, the direct observation of intermediate species at a single crystal surface is a daunting challenge for spectroscopic techniques. In this work, electrochemical shell-isolated nanoparticle-enhanced Raman spectroscopy (EC SHINERS) is utilized to in situ monitor the electrooxidation processes at atomically flat Au(hkl) single crystal electrode surfaces. We systematically explored the effects of crystallographic orientation, pH value, and anion on electrochemical behavior of intermediate (AuOH/AuO) species. The experimental results are well correlated with our periodic density functional theory calculations and corroborate the long-standing speculation based on theoretical calculations in previous electrochemical studies. The presented in situ electrochemical SHINERS technique offers a unique way for a real-time investigation of an electrocatalytic reaction pathway at various well-defined noble metal surfaces. PMID- 26052929 TI - Inhibition of IGF1R signaling abrogates resistance to afatinib (BIBW2992) in EGFR T790M mutant lung cancer cells. AB - Non-small cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation have benefited from treatment of reversible EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib. Acquisition of a secondary mutation in EGFR T790M is the most common mechanism of resistance to first generation EGFR TKIs, resulting in therapeutic failure. Afatinib is a second generation of EGFR TKI that showed great efficacy against tumors bearing the EGFR T790M mutation, but it failed to show the improvement on overall survival of lung cancer patients with EGFR mutations possibly because of novel acquired resistance mechanisms. Currently, there are no therapeutic options available for lung cancer patients who develop acquired resistance to afatinib. To identify novel resistance mechanism(s) to afatinib, we developed afatinib resistant cell lines from a parental human-derived NSCLC cell line, H1975, harboring both EGFR L858R and T790M mutations. We found that activation of the insulin-like growth factor 1 receptor (IGF1R) signaling pathway contributes to afatinib resistance in NSCLC cells harboring the T790M mutation. IGF1R knockdown not only significantly sensitizes resistant cells to afatinib, but also induces apoptosis in afatinib resistance cells. In addition, combination treatment with afatinib and linsitinib shows more than additive effects on tumor growth in in vivo H1975 xenograft. Therefore, these finding suggest that IGF1R inhibition or combination of EGFR-IGF1R inhibition strategies would be potential ways to prevent or potentiate the effects of current therapeutic options to lung cancer patients demonstrating resistance to either first or second generation EGFR TKIs. PMID- 26052931 TI - Localized thermal tumor destruction using dye-enhanced photothermal tumor therapy. AB - BACKGROUND AND OBJECTIVE: In an attempt to develop a new therapeutic approach for highly localized thermal destruction of tissue targets that lack natural pigmentation, the potential of in-vivo dye-enhanced photothermal therapy (PTT) was investigated. PTT involves the application of an exogenous absorber, which accumulates in metabolically active tissues, followed by non-invasive light irradiation, using appropriate wavelengths, exposure durations, and irradiances. The chromophore used, palladium(II) octabutoxynaphthalocyanine (PdNc(OBu)8 ), strongly absorbs in the near infrared wavelength range which thus permits good penetration depth of the exciting light. The predominant de-excitation routes of the chromophore are radiationless thermal processes. MATERIALS AND METHODS: Using a BALB/c mouse model with a subcutaneously implanted syngeneic EMT6 adenocarcinoma, 96-100 hours after intraperitoneal application of PdNc(OBu)8 , tumor, and surrounding tissue were irradiated with a 830 nm continuous wave diode laser applying 30 Wcm(-2) for 10-20 seconds. Treatment parameters were based on theoretical calculations. RESULTS: Histological evaluation of thermal effects on tumor and normal tissue showed that after PdNc(OBu)8 -enhanced photothermal treatment, highly localized and selective thermal damage of the tumors was achieved. The necrotic tumor area was invaded by inflammatory cells, including neutrophils, macrophages, mast cells, and lymphocytes, thus reflecting a prominent host immune response. In tumors treated with PTT for 15 or 20 seconds, respectively, only few surviving tumor cells were detected underneath the epidermis. Adjacent peripheral normal tissue including skin and muscle remained completely unaffected. CONCLUSION: This study highlights the potential of achieving irreversible thermal tissue damage closely localized to the target tissue when PdNc(OBu)8 is used in combination with continuous-wave light. PMID- 26052932 TI - The Structure-Dependent Electric Release and Enhanced Oxidation of Drug in Graphene Oxide-Based Nanocarrier Loaded with Anticancer Herbal Drug Berberine. AB - The aim of the current investigation is to explore graphene oxide (GO) special electric and electrochemical properties in modulating and tuning drug delivery in tumor special environment of electrophysiology. The electric-sensitive drug release and redox behavior of GO-bearing berberine (Ber) was studied. Drug release in cell potential was applied in a designed electrode system: tumor environment was simulated at pH 6.2 with 0.1 V pulse voltage, whereas the normal was at pH 7.4 with 0.2 V. Quite different from the pH-depended profile, the electricity-triggered behavior indicated a high correlation with the carriers' structure: GO-based nanocomposite showed a burst release on its special "skin effect," whereas the PEGylated ones released slowly owing to the electroviscous effect of polymer. Cyclic voltammetry was used to investigate the redox behaviors of colloid PEGylated GO toward absorbed Ber in pH 5.8 and 7.2 solutions. After drug loading, the oxidation of Ber was enhanced in a neutral environment, whereas the enhancement of PEG-GO was in an acidic one, which means a possible increased susceptibility of their biotransformation in vivo. The studies designed in this work may help to establish a kind of carrier system for the sensitive delivery and metabolic regulation of drugs according to the different electrophysiological environment in tumor therapy. PMID- 26052933 TI - Radiotherapy-related arterial intima thickening and plaque formation in childhood cancer survivors detected with very-high resolution ultrasound during young adulthood. AB - BACKGROUND: The aim of the study was to evaluate arterial morphology and function in a national cohort of long-term survivors of high-risk neuroblastoma (NBL) treated with high-dose chemotherapy and autologous hematopoietic stem cell transplantation with or without total body irradiation (TBI). METHODS AND RESULTS: Common carotid, femoral, brachial, and radial artery morphology were assessed with very-high-resolution vascular ultrasound (25-55 MHz), and carotid artery stiffness and brachial artery flow-mediated dilatation measured with conventional vascular ultrasound in 19 adult or pubertal (age 22.7 +/- 4.9 years, range 16-30) NBL survivors transplanted during 1984-1999 at the mean age of 2.5 +/- 1.0 years. Results were compared with 20 age- and sex-matched healthy controls. The cardiovascular risk assessment included history, body mass index, fasting plasma lipids, glucose, and 24-h ambulatory blood pressure (BP). The survivors had consistently smaller arterial lumens, increased carotid intima media thickness (IMT), plaque formation (N = 3), and stiffness, as well as increased radial artery intima thickness (N = 5) compared with the control group. Survivors displayed higher plasma triglyceride and cholesterol levels, and increased heart rate, as well as increased systolic and diastolic BPs. TBI (N = 10) and a low body surface area were independent predictors for decreased arterial lumen size and increased IMT. Three out of five survivors with subclinical intima thickening had arterial plaques. Plaques occurred only among TBI-treated survivors. CONCLUSIONS: Long-term childhood cancer survivors treated with TBI during early childhood display significant signs of premature arterial aging during young adulthood. PMID- 26052934 TI - Simian Immunodeficiency Virus Impacts MicroRNA-16 Mediated Post-Transcriptional Regulation of mu Opioid Receptor in CEM *174 Cells. AB - Although the mechanism which regulates transcription in the 5'-UTR of the mu opioid receptor gene (OPRM1) in lymphocytes has been well-studied, a question remains as to whether there is post-transcriptional regulation of OPRM1 gene in lymphocytes. In this study, the authors describe both the role played by miRNAs and the impact of SIVmac239 infection on post-transcriptional regulation of OPRM1 gene in CEM *174 cells. Our results show that miR-16 is able to bind the target site in the range of 8699-8719 nt from the stop codon in MOR-1 mRNA 3'-UTR and suppress the expression of OPRM1 gene. Mutation of this target site reduces the effect of miR-16. Morphine (1 uM) inhibits the expression of miR-16, and this effect is reversed by the antagonist naloxone. Thus, morphine may up-regulate receptor level by both stimulating OPRM1 gene transcription and stabilizing its mRNA. SIVmac239 infection results in an apparent elevation of miR-16 and gradual reduction of OPRM1 gene expression. The inverse correlation of elevated miR-16 and reduced OPRM1 gene expression under viral loading confirmed the effect of SIVmac239 on post-transcriptional regulation of OPRM1 gene in lymphocytes. The authors conclude that miR-16 is a primary factor in post-transcriptional regulation of OPRM1 gene. SIVmac239 upregulates miR-16 levels and consequently suppresses OPRM1 gene expression. This finding will be helpful for full understanding of the regulatory mechanism of OPRM1 gene in lymphocytes, as well as the synergistic mechanism of HIV infection and morphine addiction in the pathogenesis of AIDS. PMID- 26052935 TI - Association between single nucleotide polymorphisms of upstream transcription factor 1 (USF1) and susceptibility to papillary thyroid cancer. AB - BACKGROUND: Thyroid cancer, predominantly by papillary thyroid cancer (PTC), is a malignant tumour of endocrine system with increasing incidence rate worldwide. Upstream transcription factor 1 (USF1) regulates a variety of biological processes by transactivation of functional genes. In this study, we investigated the association between USF1 polymorphisms and PTC risk. MATERIAL & METHODS: A total of 334 patients with PTC, 186 patients with benign nodules (BN) and 668 healthy controls were enrolled in our study. Tag-SNPs were identified in Chinese Han in Beijing (CHB) from International HapMap Project Databases. Genomic DNAs were extracted by TaqMan Blood DNA kits. SNPs of USF1 were genotyped by TaqMan SNPs genotyping assay. Odds ratios (OR) and corresponding 95% confidence interval (CI) were used to assess the association between USF1 genetic variants and PTC risk. The statistical analyses were carried out with spss 13.0 software. RESULTS: Five tag-SNPs were retrieved to capture all the genetic variants of USF1. Among the five tag-SNPs, genetic variants in rs2516838, rs3737787 and rs2516839 have significant association with PTC risk. The rs2516838 polymorphisms dominant model (CG+GG vs CC: OR = 0.71; 95% CI: 0.52-0.97; P = 0.033) and allelic model (C vs G: OR = 0.031; 95% CI: 0.56-0.97; P = 0.031) indicated it may act as a protective factor against PTC. On the contrary, the results of rs3737787 polymorphisms: dominant model (CT+TT vs CC: OR = 1.55; 95%CI: 1.09-2.02; P = 0.001) and allelic model (C vs T: OR = 1.35; 95%CI: 1.10-1.64; P = 0.003), as well as the results of rs2516839 polymorphisms: dominant model (GA+AA vs GG: OR = 1.77; 95%CI: 1.31 2.38; P < 0.001) and allelic model (G vs A: OR = 1.36; 95%CI: 1.13-1.63; P = 0.014), revealed that they may act as risk factors for PTC. CONCLUSION: In this study, we found the SNPs of rs2516838 (mutant G alleles vs wild C alleles), rs3737787 (mutant T alleles vs wild C alleles) and rs2516839 (mutant A alleles vs wild G alleles) were significantly associated with PTC risk. Further large-scale studies with different ethnicities are still needed to validate our findings and explore the underlying mechanism of USF1 in PTC development. PMID- 26052936 TI - Quercus Suber L. Cork Extracts Induce Apoptosis in Human Myeloid Leukaemia HL-60 Cells. AB - Quercus suber L. cork contains a diversity of phenolic compounds, mostly low molecular weight phenols. A rising number of reports support with convergent findings that polyphenols evoke pro-apoptotic events in cancerous cells. However, the literature related to the anti-cancer bioactivity of Q. suber L. cork extractives (QSE) is still limited. Herein, we aim to describe the antitumor potential displayed by cork extractives obtained by different extraction methods in the human promyelocytic leukaemia cells. In order to quantify the effects of QSE on cancer cells viability, phosphatidylserine exposure, caspase-3 activity, mitochondrial membrane potential and cell cycle were evaluated. The results indicated that the QSE present a time-dependent and dose-dependent cytotoxicity in the human promyelocytic leukaemia cells. Such a noxious effect leads these leukaemia cells to their death through apoptotic processes by altering the mitochondrial outer membrane potential, activating caspase-3 and externalizing phosphatidylserine. However, cells cycle progression was not affected by the treatments. This study contributes to open a new way to use this natural resource by exploiting its anti-cancer properties. Moreover, it opens new possibilities of application of cork by-products, being more efficient in the sector of cork-based agriculture. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26052937 TI - Effect of Storage Temperature on Structure and Function of Cultured Human Oral Keratinocytes. AB - PURPOSE/AIMS: To assess the effect of storage temperature on the viability, phenotype, metabolism, and morphology of cultured human oral keratinocytes (HOK). MATERIALS AND METHODS: Cultured HOK cells were stored in HEPES- and sodium bicarbonate-buffered Minimum Essential Medium (MEM) at nine temperatures in approximately 4 degrees C increments from 4 degrees C to 37 degrees C for seven days. Cells were characterized for viability by calcein fluorescence, phenotype retention by immunocytochemistry, metabolic parameters (pH, glucose, lactate, and O2) within the storage medium by blood gas analysis, and morphology by scanning electron microscopy and light microscopy. RESULTS: Relative to the cultured, but non-stored control cells, a high percentage of viable cells were retained only in the 12 degrees C and 16 degrees C storage groups (85% +/- 13% and 68% +/- 10%, respectively). Expression of ABCG2, Bmi1, C/EBPdelta, PCNA, cytokeratin 18, and caspase-3 were preserved after storage in the 5 groups between 4 degrees C and 20 degrees C, compared to the non-stored control. Glucose, pH and pO2 in the storage medium declined, whereas lactate increased with increasing storage temperature. Morphology was best preserved following storage of the three groups between 12 degrees C, 16 degrees C, and 20 degrees C. CONCLUSION: We conclude that storage temperatures of 12 degrees C and 16 degrees C were optimal for maintenance of cell viability, phenotype, and morphology of cultured HOK. The storage method described in the present study may be applicable for other cell types and tissues; thus its significance may extend beyond HOK and the field of ophthalmology. PMID- 26052938 TI - Car Crashes and Central Disorders of Hypersomnolence: A French Study. AB - BACKGROUND: Drowsiness compromises driving ability by reducing alertness and attentiveness, and delayed reaction times. Sleep-related car crashes account for a considerable proportion of accident at the wheel. Narcolepsy type 1 (NT1), narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) are rare central disorders of hypersomnolence, the most severe causes of sleepiness thus being potential dangerous conditions for both personal and public safety with increasing scientific, social, and political attention. Our main objective was to assess the frequency of recent car crashes in a large cohort of patients affected with well-defined central disorders of hypersomnolence versus subjects from the general population. METHODS: We performed a cross-sectional study in French reference centres for rare hypersomnia diseases and included 527 patients and 781 healthy subjects. All participants included needed to have a driving license, information available on potential accident events during the last 5 years, and on potential confounders; thus analyses were performed on 282 cases (71 IH, 82 NT2, 129 NT1) and 470 healthy subjects. RESULTS: Patients reported more frequently than healthy subjects the occurrence of recent car crashes (in the previous five years), a risk that was confirmed in both treated and untreated subjects at study inclusion (Untreated, OR = 2.21 95%CI = [1.30-3.76], Treated OR = 2.04 95%CI = [1.26-3.30]), as well as in all disease categories, and was modulated by subjective sleepiness level (Epworth scale and naps). Conversely, the risk of car accidents of patients treated for at least 5 years was not different to healthy subjects (OR = 1.23 95%CI = [0.56-2.69]). Main risk factors were analogous in patients and healthy subjects. CONCLUSION: Patients affected with central disorders of hypersomnolence had increased risk of recent car crashes compared to subjects from the general population, a finding potentially reversed by long-term treatment. PMID- 26052939 TI - Capsid Mutated Adeno-Associated Virus Delivered to the Anterior Chamber Results in Efficient Transduction of Trabecular Meshwork in Mouse and Rat. AB - BACKGROUND: Adeno associated virus (AAV) is well known for its ability to deliver transgenes to retina and to mediate improvements in animal models and patients with inherited retinal disease. Although the field is less advanced, there is growing interest in AAV's ability to target cells of the anterior segment. The purpose of our study was to fully articulate a reliable and reproducible method for injecting the anterior chamber (AC) of mice and rats and to investigate the transduction profiles of AAV2- and AAV8-based capsid mutants containing self complementary (sc) genomes in the anterior segment of the eye. METHODOLOGY/PRINCIPLE FINDINGS: AC injections were performed in C57BL/6 mice and Sprague Dawley rats. The cornea was punctured anterior of the iridocorneal angle. To seal the puncture site and to prevent reflux an air bubble was created in the AC. scAAVs expressing GFP were injected and transduction was evaluated by immunohistochemistry. Both parent serotype and capsid modifications affected expression. scAAV2- based vectors mediated efficient GFP-signal in the corneal endothelium, ciliary non-pigmented epithelium (NPE), iris and chamber angle including trabecular meshwork, with scAAV2(Y444F) and scAAV2(triple) being the most efficient. CONCLUSIONS/SIGNIFICANCE: This is the first study to semi quantitatively evaluate transduction of anterior segment tissues following injection of capsid-mutated AAV vectors. scAAV2- based vectors transduced corneal endothelium, ciliary NPE, iris and trabecular meshwork more effectively than scAAV8-based vectors. Mutagenesis of surface-exposed tyrosine residues greatly enhanced transduction efficiency of scAAV2 in these tissues. The number of Y-F mutations was not directly proportional to transduction efficiency, however, suggesting that proteosomal avoidance alone may not be sufficient. These results are applicable to the development of targeted, gene-based strategies to investigate pathological processes of the anterior segment and may be applied toward the development of gene-based therapies for glaucoma and acquired or inherited corneal anomalies. PMID- 26052940 TI - ULK2 Ser 1027 Phosphorylation by PKA Regulates Its Nuclear Localization Occurring through Karyopherin Beta 2 Recognition of a PY-NLS Motif. AB - Uncoordinated 51-like kinase 2 (ULK2), a member of the serine/threonine kinase family, plays an essential role in the regulation of autophagy in mammalian cells. Given the role of autophagy in normal cellular homeostasis and in multiple diseases, improved mechanistic insight into this process may result in the development of novel therapeutic approaches. Here, we present evidence that ULK2 associates with karyopherin beta 2 (Kapbeta2) for its transportation into the nucleus. We identify a potential PY-NLS motif ((774)gpgfgssppGaeaapslRyvPY(795)) in the S/P space domain of ULK2, which is similar to the consensus PY-NLS motif (R/K/H)X(2-5)PY. Using a pull-down approach, we observe that ULK2 interacts physically with Kapbeta2 both in vitro and in vivo. Confocal microscopy confirmed the co-localization of ULK2 and Kapbeta2. Localization of ULK2 to the nuclear region was disrupted by mutations in the putative Kapbeta2-binding motif (P794A). Furthermore, in transient transfection assays, the presence of the Kapbeta2 binding site mutant (the cytoplasmic localization form) was associated with a substantial increase in autophagy activity (but a decrease in the in vitro serine phosphorylation) compared with the wild type ULK2. Mutational analysis showed that the phosphorylation on the Ser1027 residue of ULK2 by Protein Kinase A (PKA) is the regulatory point for its functional dissociation from Atg13 and FIP 200, nuclear localization, and autophagy. Taken together, our observations indicate that Kapbeta2 interacts with ULK2 through ULK2's putative PY-NLS motif, and facilitates transport from the cytoplasm to the nucleus, depending on its Ser1027 residue phosphorylation by PKA, thereby reducing autophagic activity. PMID- 26052941 TI - Diversity and Evolutionary History of Iron Metabolism Genes in Diatoms. AB - Ferroproteins arose early in Earth's history, prior to the emergence of oxygenic photosynthesis and the subsequent reduction of bioavailable iron. Today, iron availability limits primary productivity in about 30% of the world's oceans. Diatoms, responsible for nearly half of oceanic primary production, have evolved molecular strategies for coping with variable iron concentrations. Our understanding of the evolutionary breadth of these strategies has been restricted by the limited number of species for which molecular sequence data is available. To uncover the diversity of strategies marine diatoms employ to meet cellular iron demands, we analyzed 367 newly released marine microbial eukaryotic transcriptomes, which include 47 diatom species. We focused on genes encoding proteins previously identified as having a role in iron management: iron uptake (high-affinity ferric reductase, multi-copper oxidase, and Fe(III) permease); iron storage (ferritin); iron-induced protein substitutions (flavodoxin/ferredoxin, and plastocyanin/cytochrome c6) and defense against reactive oxygen species (superoxide dismutases). Homologs encoding the high affinity iron uptake system components were detected across the four diatom Classes suggesting an ancient origin for this pathway. Ferritin transcripts were also detected in all Classes, revealing a more widespread utilization of ferritin throughout diatoms than previously recognized. Flavodoxin and plastocyanin transcripts indicate possible alternative redox metal strategies. Predicted localization signals for ferredoxin identify multiple examples of gene transfer from the plastid to the nuclear genome. Transcripts encoding four superoxide dismutase metalloforms were detected, including a putative nickel-coordinating isozyme. Taken together, our results suggest that the majority of iron metabolism genes in diatoms appear to be vertically inherited with functional diversity achieved via possible neofunctionalization of paralogs. This refined view of iron use strategies in diatoms elucidates the history of these adaptations, and provides potential molecular markers for determining the iron nutritional status of different diatom species in environmental samples. PMID- 26052942 TI - Chemokine Transfer by Liver Sinusoidal Endothelial Cells Contributes to the Recruitment of CD4+ T Cells into the Murine Liver. AB - Leukocyte adhesion and transmigration are central features governing immune surveillance and inflammatory reactions in body tissues. Within the liver sinusoids, chemokines initiate the first crucial step of T-cell migration into the hepatic tissue. We studied molecular mechanisms involved in endothelial chemokine supply during hepatic immune surveillance and liver inflammation and their impact on the recruitment of CD4(+) T cells into the liver. In the murine model of Concanavalin A-induced T cell-mediated hepatitis, we showed that hepatic expression of the inflammatory CXC chemokine ligands (CXCL)9 and CXCL10 strongly increased whereas homeostatic CXCL12 significantly decreased. Consistently, CD4(+) T cells expressing the CXC chemokine receptor (CXCR)3 accumulated within the inflamed liver tissue. In histology, CXCL9 was associated with liver sinusoidal endothelial cells (LSEC) which represent the first contact site for T cell immigration into the liver. LSEC actively transferred basolaterally internalized CXCL12, CXCL9 and CXCL10 via clathrin-coated vesicles to CD4(+) T cells leading to enhanced transmigration of CXCR4(+) total CD4(+) T cells and CXCR3(+) effector/memory CD4(+) T cells, respectively in vitro. LSEC-expressed CXCR4 mediated CXCL12 transport and blockage of endothelial CXCR4 inhibited CXCL12-dependent CD4(+) T-cell transmigration. In contrast, CXCR3 was not involved in the endothelial transport of its ligands CXCL9 and CXCL10. The clathrin-specific inhibitor chlorpromazine blocked endothelial chemokine internalization and CD4(+) T-cell transmigration in vitro as well as migration of CD4(+) T cells into the inflamed liver in vivo. Moreover, hepatic accumulation of CXCR3(+) CD4(+) T cells during T cell-mediated hepatitis was strongly reduced after administration of chlorpromazine. These data demonstrate that LSEC actively provide perivascularly expressed homeostatic and inflammatory chemokines by CXCR4 and clathrin-dependent intracellular transport mechanisms thereby contributing to the hepatic recruitment of CD4(+) T-cell populations during immune surveillance and liver inflammation. PMID- 26052943 TI - Risk-Taking Behavior in a Computerized Driving Task: Brain Activation Correlates of Decision-Making, Outcome, and Peer Influence in Male Adolescents. AB - Increased propensity for risky behavior in adolescents, particularly in peer groups, is thought to reflect maturational imbalance between reward processing and cognitive control systems that affect decision-making. We used functional magnetic resonance imaging (fMRI) to investigate brain functional correlates of risk-taking behavior and effects of peer influence in 18-19-year-old male adolescents. The subjects were divided into low and high risk-taking groups using either personality tests or risk-taking rates in a simulated driving task. The fMRI data were analyzed for decision-making (whether to take a risk at intersections) and outcome (pass or crash) phases, and for the influence of peer competition. Personality test-based groups showed no difference in the amount of risk-taking (similarly increased during peer competition) and brain activation. When groups were defined by actual task performance, risk-taking activated two areas in the left medial prefrontal cortex (PFC) significantly more in low than in high risk-takers. In the entire sample, risky decision-specific activation was found in the anterior and dorsal cingulate, superior parietal cortex, basal ganglia (including the nucleus accumbens), midbrain, thalamus, and hypothalamus. Peer competition increased outcome-related activation in the right caudate head and cerebellar vermis in the entire sample. Our results suggest that the activation of the medial (rather than lateral) PFC and striatum is most specific to risk-taking behavior of male adolescents in a simulated driving situation, and reflect a stronger conflict and thus increased cognitive effort to take risks in low risk-takers, and reward anticipation for risky decisions, respectively. The activation of the caudate nucleus, particularly for the positive outcome (pass) during peer competition, further suggests enhanced reward processing of risk taking under peer influence. PMID- 26052944 TI - Efficacy of Hospital at Home in Patients with Heart Failure: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Heart failure (HF) is the commonest cause of hospitalization in older adults. Compared to routine hospitalization (RH), hospital at home (HaH)- substitutive hospital-level care in the patient's home--improves outcomes and reduces costs in patients with general medical conditions. The efficacy of HaH in HF is unknown. METHODS AND RESULTS: We searched MEDLINE, Embase, CINAHL, and CENTRAL, for publications from January 1990 to October 2014. We included prospective studies comparing substitutive models of hospitalization to RH in HF. At least 2 reviewers independently selected studies, abstracted data, and assessed quality. We meta-analyzed results from 3 RCTs (n = 203) and narratively synthesized results from 3 observational studies (n = 329). Study quality was modest. In RCTs, HaH increased time to first readmission (mean difference (MD) 14.13 days [95% CI 10.36 to 17.91]), and improved health-related quality of life (HrQOL) at both, 6 months (standardized MD (SMD) -0.31 [-0.45 to -0.18]) and 12 months (SMD -0.17 [-0.31 to -0.02]). In RCTs, HaH demonstrated a trend to decreased readmissions (risk ratio (RR) 0.68 [0.42 to 1.09]), and had no effect on all-cause mortality (RR 0.94 [0.67 to 1.32]). HaH decreased costs of index hospitalization in all RCTs. HaH reduced readmissions and emergency department visits per patient in all 3 observational studies. CONCLUSIONS: In the context of a limited number of modest-quality studies, HaH appears to increase time to readmission, reduce index costs, and improve HrQOL among patients requiring hospital-level care for HF. Larger RCTs are necessary to assess the effect of HaH on readmissions, mortality, and long-term costs. PMID- 26052946 TI - Developmental Expression and Hypoxic Induction of Hypoxia Inducible Transcription Factors in the Zebrafish. AB - The hypoxia inducible transcription factor (HIF) has been shown to coordinate the hypoxic response of vertebrates and is expressed in three different isoforms, HIF 1alpha, HIF-2alpha and HIF-3alpha. Knock down of either Hif-1alpha or Hif-2alpha in mice results in lethality in embryonic or perinatal stages, suggesting that this transcription factor is not only controlling the hypoxic response, but is also involved in developmental phenomena. In the translucent zebrafish embryo the performance of the cardiovascular system is not essential for early development, therefore this study was designed to analyze the expression of the three Hif isoforms during zebrafish development and to test the hypoxic inducibility of these transcription factors. To complement the existing zfHif-1alpha antibody we expressed the whole zfHif-2alpha protein and used it for immunization and antibody generation. Similarly, fragments of the zfHif-3alpha protein were used for immunization and generation of a zfHif-3alpha specific antibody. To demonstrate presence of the Hif-isoforms during development [between 1 day post fertilization (1 dpf) and 9 dpf] affinity-purified antibodies were used. Hif 1alpha protein was present under normoxic conditions in all developmental stages, but no significant differences between the different developmental stages could be detected. Hif-2alpha was also present from 1 dpf onwards, but in post hatching stages (between 5 and 9 dpf) the expression level was significantly higher than prior to hatching. Similarly, Hif-3alpha was expressed from 1 dpf onwards, and the expression level significantly increased until 5 dpf, suggesting that Hif 2alpha and Hif-3alpha play a particular role in early development. Hypoxic exposure (oxygen partial pressure = 5 kPa) in turn caused a significant increase in the level of Hif-1alpha protein even at 1 dpf and in later stages, while neither Hif-2alpha nor Hif-3alpha protein level were affected. In these early developmental stages Hif-1alpha therefore appears to be more important for the coordination of hypoxic responsiveness. PMID- 26052945 TI - The Toxic Effects of Pathogenic Ataxin-3 Variants in a Yeast Cellular Model. AB - Ataxin-3 (AT3) is a deubiquitinating enzyme that triggers an inherited neurodegenerative disorder, spinocerebellar ataxia type 3, when its polyglutamine (polyQ) stretch close to the C-terminus exceeds a critical length. AT3 variants carrying the expanded polyQ are prone to associate with each other into amyloid toxic aggregates, which are responsible for neuronal death with ensuing neurodegeneration. We employed Saccharomyces cerevisiae as a eukaryotic cellular model to better clarify the mechanism by which AT3 triggers the disease. We expressed three variants: one normal (Q26), one expanded (Q85) and one truncated for a region lying from the beginning of its polyQ stretch to the end of the protein (291Delta). We found that the expression of the expanded form caused reduction in viability, accumulation of reactive oxygen species, imbalance of the antioxidant defense system and loss in cell membrane integrity, leading to necrotic death. The truncated variant also exerted a qualitatively similar, albeit milder, effect on cell growth and cytotoxicity, which points to the involvement of also non-polyQ regions in cytotoxicity. Guanidine hydrochloride, a well-known inhibitor of the chaperone Hsp104, almost completely restored wild type survival rate of both 291Delta- and Q85-expressing strains. This suggests that AT3 aggregation and toxicity is mediated by prion forms of yeast proteins, as this chaperone plays a key role in their propagation. PMID- 26052947 TI - Very Preterm Infants Failing CPAP Show Signs of Fatigue Immediately after Birth. AB - OBJECTIVE: To investigate the differences in breathing pattern and effort in infants at birth who failed or succeeded on continuous positive airway pressure (CPAP) during the first 48 hours after birth. METHODS: Respiratory function recordings of 32 preterm infants were reviewed of which 15 infants with a gestational age of 28.6 (0.7) weeks failed CPAP and 17 infants with a GA of 30.1 (0.4) weeks did not fail CPAP. Frequency, duration and tidal volumes (VT) of expiratory holds (EHs), peak inspiratory flows, CPAP-level and FiO2-levels were analysed. RESULTS: EH incidence increased <6 minutes after birth and remained stable thereafter. EH peak inspiratory flows and VT were similar between CPAP fail and CPAP-success infants. At 9-12 minutes, CPAP-fail infants more frequently used smaller VTs, 0-9 ml/kg and required higher peak inspiratory flows. However, CPAP-success infants often used large VTs (>9 ml/kg) with higher peak inspiratory flows than CPAP-fail infants (71.8 +/- 15.8 vs. 15.5 +/- 5.2 ml/kg.s, p <0.05). CPAP-fail infants required higher FiO2 (0.31 +/- 0.03 vs. 0.21 +/- 0.01), higher CPAP pressures (6.62 +/- 0.3 vs. 5.67 +/- 0.26 cmH2O) and more positive pressure delivered breaths (45 +/- 12 vs. 19 +/- 9%) (p <0.05). CONCLUSION: At 9-12 minutes after birth, CPAP-fail infants more commonly used lower VTs and required higher peak inspiratory flow rates while receiving greater respiratory support. VT was less variable and larger VT was infrequently used reflecting early signs of fatigue. PMID- 26052948 TI - Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase Associated Neurodegeneration by Reducing Motor Coordination in Mice. AB - BACKGROUND: Pantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK) isoforms. PanK initiates the synthesis of coenzyme A (CoA), an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme. This evidence has led to the hypothesis that lower CoA might be the underlying cause of the neurodegeneration in PKAN patients; however, no mouse model of the disease is currently available to investigate the connection between neuronal CoA levels and neurodegeneration. Indeed, genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease. OBJECTIVE, METHODS, RESULTS AND CONCLUSIONS: Cellular CoA levels are tightly regulated by a balance between synthesis and degradation. CoA degradation is catalyzed by two peroxisomal nudix hydrolases, Nudt7 and Nudt19. In this study we sought to reduce neuronal CoA in mice through the alternative approach of increasing Nudt7-mediated CoA degradation. This was achieved by combining the use of an adeno-associated virus-based expression system with the synapsin (Syn) promoter. We show that mice with neuronal overexpression of a cytosolic version of Nudt7 (scAAV9-Syn-Nudt7cyt) exhibit a significant decrease in brain CoA levels in conjunction with a reduction in motor coordination. These results strongly support the existence of a link between CoA levels and neuronal function and show that scAAV9-Syn-Nudt7cyt mice can be used to model PKAN. PMID- 26052949 TI - Oceans apart, yet connected: Findings from a qualitative study on professional supervision in rural and remote allied health services. AB - OBJECTIVE: Improving the quality and safety of health care in Australia is imperative to ensure the right treatment is delivered to the right person at the right time. Achieving this requires appropriate clinical governance and support for health professionals, including professional supervision. This study investigates the usefulness and effectiveness of and barriers to supervision in rural and remote Queensland. DESIGN: As part of the evaluation of the Allied Health Rural and Remote Training and Support program, a qualitative descriptive study was conducted involving semi-structured interviews with 42 rural or remote allied health professionals, nine operational managers and four supervisors. The interviews explored perspectives on their supervision arrangements, including the perceived usefulness, effect on practice and barriers. RESULTS: Themes of reduced isolation; enhanced professional enthusiasm, growth and commitment to the organisation; enhanced clinical skills, knowledge and confidence; and enhanced patient safety were identified as perceived outcomes of professional supervision. Time, technology and organisational factors were identified as potential facilitators as well as potential barriers to effective supervision. CONCLUSIONS: This research provides current evidence on the impact of professional supervision in rural and remote Queensland. A multidimensional model of organisational factors associated with effective supervision in rural and remote settings is proposed identifying positive supervision culture and a good supervisor supervisee fit as key factors associated with effective arrangements. PMID- 26052950 TI - Designing and Testing of Novel Taxanes to Probe the Highly Complex Mechanisms by Which Taxanes Bind to Microtubules and Cause Cytotoxicity to Cancer Cells. AB - Our previous work identified an intermediate binding site for taxanes in the microtubule nanopore. The goal of this study was to test derivatives of paclitaxel designed to bind to this intermediate site differentially depending on the isotype of beta-tubulin. Since beta-tubulin isotypes have tissue-dependent expression--specifically, the betaIII isotype is very abundant in aggressive tumors and much less common in normal tissues--this is expected to lead to tubulin targeted drugs that are more efficacious and have less side effects. Seven derivatives of paclitaxel were designed and four of these were amenable for synthesis in sufficient purity and yield for further testing in breast cancer model cell lines. None of the derivatives studied were superior to currently used taxanes, however computer simulations provided insights into the activity of the derivatives. Our results suggest that neither binding to the intermediate binding site nor the final binding site is sufficient to explain the activities of the derivative taxanes studied. These findings highlight the need to iteratively improve on the design of taxanes based on their activity in model systems. Knowledge gained on the ability of the engineered drugs to bind to targets and bring about activity in a predictable manner is a step towards personalizing therapies. PMID- 26052952 TI - Are There Really Syntactic Complexity Effects in Sentence Production? A Reply to Scontras et al. (2015). PMID- 26052951 TI - Smoking and survival after breast cancer diagnosis in Japanese women: A prospective cohort study. AB - The results of previous studies investigating whether there is an association between active smoking and risk of death among breast cancer patients have been inconsistent. We investigated the association between active and passive smoking and risk of all-cause and breast cancer-specific death among female breast cancer patients in relation to menopausal and tumor estrogen/progesterone receptor (ER/PR) status. The present study included 848 patients admitted to a single hospital in Japan from 1997 to 2007. Active or passive smoking status was assessed using a self-administered questionnaire. The patients were followed until 31 December 2010. We used a Cox proportional-hazard model to estimate hazard ratios (HR). During a median follow-up period of 6.7 years, 170 all-cause and 132 breast cancer-specific deaths were observed. Among premenopausal patients, current smokers showed a non-significant higher risk of all-cause and breast cancer-specific death. A duration of smoking >21.5 years was positively associated with all-cause (HR = 3.09, 95% confidence interval [CI], 1.17-8.20) and breast cancer-specific death (HR = 3.35, 95% CI: 1.22-9.23, Ptrend = 0.035) among premenopausal patients. In premenopausal patients with ER+ or PR+ tumors, there was some suggestion that a longer duration of smoking was associated with higher risk of all-cause and breast cancer-specific death. Passive smoking demonstrated no significant risk. Our results suggest that a longer duration of active smoking is associated with an increased risk of all-cause and breast cancer-specific death among premenopausal patients, possibly with hormonal receptor-positive tumors. Breast cancer patients should be informed about the importance of smoking cessation. PMID- 26052953 TI - A finite mixture method for outlier detection and robustness in meta-analysis. AB - When performing a meta-analysis unexplained variation above that predicted by within study variation is usually modeled by a random effect. However, in some cases, this is not sufficient to explain all the variation because of outlier or unusual studies. A previously described method is to define an outlier as a study requiring a higher random effects variance and testing each study sequentially. An extension is described where the studies are considered to be a finite mixture of outliers and non-outliers, allowing any number of outlier studies and the use of standard mixture model techniques. The bootstrap likelihood ratio test is used to determine if there are any outliers present by comparing models with and without outliers, and the outlier studies are identified using posterior predicted probabilities. The estimation of the overall treatment effect is then determined including all observations but with the outliers down-weighted. This has the advantage that studies that are marginal outliers are still included in the meta-analysis but with an appropriate weighting. The method is applied to examples from meta-analysis and meta-regression. PMID- 26052954 TI - Methods for the joint meta-analysis of multiple tests. AB - Existing methods for meta-analysis of diagnostic test accuracy focus primarily on a single index test. We propose models for the joint meta-analysis of studies comparing multiple index tests on the same participants in paired designs. These models respect the grouping of data by studies, account for the within-study correlation between the tests' true-positive rates (TPRs) and between their false positive rates (FPRs) (induced because tests are applied to the same participants), and allow for between-study correlations between TPRs and FPRs (such as those induced by threshold effects). We estimate models in the Bayesian setting. We demonstrate using a meta-analysis of screening for Down syndrome with two tests: shortened humerus (arm bone), and shortened femur (thigh bone). Separate and joint meta-analyses yielded similar TPR and FPR estimates. For example, the summary TPR for a shortened humerus was 35.3% (95% credible interval (CrI): 26.9, 41.8%) versus 37.9% (27.7, 50.3%) with joint versus separate meta analysis. Joint meta-analysis is more efficient when calculating comparative accuracy: the difference in the summary TPRs was 0.0% (-8.9, 9.5%; TPR higher for shortened humerus) with joint versus 2.6% (-14.7, 19.8%) with separate meta analyses. Simulation and empirical analyses are needed to refine the role of the proposed methodology. PMID- 26052955 TI - Meta-analysis and the reversed Theorem of the Means. AB - Conventional meta-analysis estimators are weighted means of study measures, meant to estimate an overall population measure. For measures such as means, mean differences and risk differences, a weighted arithmetic mean is the conventional estimator. When the measures are ratios, such as odds ratios, logarithms of the study measures are most frequently used, and the back-transform is a weighted geometric mean, rather than the arithmetic mean. For numbers needed to treat, a weighted harmonic mean is the back-transform. The Theorem of the Means effectively states that unless all of the studies have an equal result, the arithmetic mean must be greater than the geometric mean, which must be greater than the harmonic mean. When the weights are fixed sampling weights, the inequalities are in the expected direction. However, when the weights are the usual reciprocal variance estimates, the inequalities go in the opposite direction. The use of reciprocal variance weights is therefore questioned as perhaps having a fundamental flaw. An example is shown of a meta-analysis of frequencies of two classes of drug-resistant HIV-1 mutations. PMID- 26052956 TI - Meta-analysis of a continuous outcome combining individual patient data and aggregate data: a method based on simulated individual patient data. AB - When some trials provide individual patient data (IPD) and the others provide only aggregate data (AD), meta-analysis methods for combining IPD and AD are required. We propose a method that reconstructs the missing IPD for AD trials by a Bayesian sampling procedure and then applies an IPD meta-analysis model to the mixture of simulated IPD and collected IPD. The method is applicable when a treatment effect can be assumed fixed across trials. We focus on situations of a single continuous outcome and covariate and aim to estimate treatment-covariate interactions separated into within-trial and across-trial effect. An illustration with hypertension data which has similar mean covariates across trials indicates that the method substantially reduces mean square error of the pooled within trial interaction estimate in comparison with existing approaches. A simulation study supposing there exists one IPD trial and nine AD trials suggests that the method has suitable type I error rate and approximately zero bias as long as the available IPD contains at least 10% of total patients, where the average gain in mean square error is up to about 40%. However, the method is currently restricted by the fixed effect assumption, and extension to random effects to allow heterogeneity is required. PMID- 26052957 TI - Exploration of heterogeneity in distributed research network drug safety analyses. AB - Distributed data networks representing large diverse populations are an expanding focus of drug safety research. However, interpreting results is difficult when treatment effect estimates vary across datasets (i.e., heterogeneity). In a previous study, risk estimates were generated for selected drugs and potential adverse outcomes. Analyses were replicated across eight distributed data sources using an identical analytic structure. To evaluate heterogeneity of risk estimates across data sources, the estimates were combined with summary-level data characterizing the population of each data source. Meta-analysis, meta regression, and plots of the influence on overall results versus contribution to heterogeneity were examined and used to illustrate an approach to heterogeneity assessment. Heterogeneity, as measured by the I-squared statistic, was high with variability across outcomes. Plots of the relationship between influence on overall results and contribution to heterogeneity suggest that certain datasets and characteristics were influential but there was variability dependent on the drug and outcome being assessed. Exploratory meta-regression identified many possible influential factors, but may be subject to ecological bias and false positive conclusions. Distributed data network drug safety analyses can produce heterogeneous risk estimates that may not be easily explained. Approaches illustrated here can be useful for research that is subject to similar problems with heterogeneity. PMID- 26052959 TI - Immune Dysfunction After Cardiac Surgery with Cardiopulmonary Bypass: Beneficial Effects of Maintaining Mechanical Ventilation. AB - Cardiac surgery with cardiopulmonary bypass (CPB) induces postoperative immunosuppression and impaired pulmonary function. Maintaining mechanical ventilation (MV) during CPB improves pulmonary function and diminishes postoperative systemic inflammation. However, there are no data about the influence of maintaining MV during CPB on postoperative immune dysfunction. METHODS: Fifty patients were prospectively divided into two groups: without MV during bypass (n = 25) and dead space MV with positive end-expiratory pressure (n = 25). PaO2 (arterial oxygen tension)/FIO2 (inspired oxygen fraction) ratio, CXCL10 (C-X-C motif chemokine 10), CCL2 (chemokine ligand 2), tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), human leukocyte antigen-DR antigen (HLA-DR), monocytic myeloid-derived suppressor cells (Mo-MDSCs, CD14HLA DR monocytes), and blood cell count were collected before and after surgery. RESULTS: Cardiopulmonary bypass induced a marked immunosuppression with a significant increase in plasmatic levels of TNF-alpha and IL-10 and a significant decrease in HLA-DR monocytic expression. The postoperative proportion of Mo-MDSCs was subsequently significantly increased. Maintaining MV during CPB significantly improved PaO2/FIO2 ratio and decreased postoperative plasmatic levels of TNF alpha and IL-10 compared with patients without MV during CPB. Furthermore, nonventilated patients had a lower lymphocyte count after surgery compared with patients with MV during CPB. CONCLUSION: Our study suggests that maintaining MV during CPB for cardiac surgery decreases postoperative immune dysfunction and could be an interesting strategy to diminish the occurrence of postoperative nosocomial infection without hampering the surgical procedure. However, these findings have to be confirmed in a clinical trial using the incidence of nosocomial infection as an endpoint. PMID- 26052958 TI - A scoping review of scoping reviews: advancing the approach and enhancing the consistency. AB - BACKGROUND: The scoping review has become an increasingly popular approach for synthesizing research evidence. It is a relatively new approach for which a universal study definition or definitive procedure has not been established. The purpose of this scoping review was to provide an overview of scoping reviews in the literature. METHODS: A scoping review was conducted using the Arksey and O'Malley framework. A search was conducted in four bibliographic databases and the gray literature to identify scoping review studies. Review selection and characterization were performed by two independent reviewers using pretested forms. RESULTS: The search identified 344 scoping reviews published from 1999 to October 2012. The reviews varied in terms of purpose, methodology, and detail of reporting. Nearly three-quarter of reviews (74.1%) addressed a health topic. Study completion times varied from 2 weeks to 20 months, and 51% utilized a published methodological framework. Quality assessment of included studies was infrequently performed (22.38%). CONCLUSIONS: Scoping reviews are a relatively new but increasingly common approach for mapping broad topics. Because of variability in their conduct, there is a need for their methodological standardization to ensure the utility and strength of evidence. PMID- 26052960 TI - EFFECTS OF HELIUM PRECONDITIONING ON INTESTINAL ISCHEMIA AND REPERFUSION INJURY IN RATS. AB - Intestinal ischemia-reperfusion (I/R) injury can occur in clinical settings such as organ transplantation, cardiopulmonary bypass and trauma. The noble gas helium attenuates I/R injury in a number of animal organs and thus may offer a strategy for reducing I/R-induced intestinal injury in clinical settings. In the present study, we used four different helium preconditioning (HPC) profiles to investigate the potential beneficial effect of HPC on I/R-induced intestinal injury. Male Sprague-Dawley rats were pretreated with three cycles of air breathing for 5 min combined with three cycles of breathing a 70% helium:30% oxygen mixture for either 2, 5, 10, or 15 min, after which they were subjected to 60-min intestinal ischemia and 60-min reperfusion. Sixty minutes after reperfusion, the intestinal tissues of the variously treated rats were analyzed using histology, immunohistochemistry, terminal dUTP nick-end labeling staining, myeloperoxidase activity assay, Western blotting, and enzyme-linked immunosorbent assay for tumor necrosis factor alpha and macrophage inflammatory protein 1alpha. Intestinal permeability was assayed by measuring fluorescein isothiocyanate dextran release in blood samples. The results showed that the HPC profile consisting of three cycles of 10 or 15 min of helium breathing and three cycles of 5 min of air breathing reduced I/R-induced intestinal injury, cell apoptosis, and the inflammatory response. However, the 2- or 5-min helium breathing did not confer any protective effects. It seems that longer helium episodes should be used in HPC profiles designed to attenuate intestinal I/R injury. PMID- 26052961 TI - PERIOPERATIVE PROGRAMMED DEATH 1 EXPRESSION ON CD4+ T CELLS PREDICTS THE INCIDENCE OF POSTOPERATIVE INFECTIOUS COMPLICATIONS. AB - INTRODUCTION: Programmed death 1 (PD-1) has been reported to be an immunoinhibitory receptor expressed by chronically stimulated T cells after T cell activation. The present study was designed to evaluate the relationship between perioperative PD-1 expression on CD4 T cells and the incidence of postoperative infectious complications in patients undergoing gastroenterological surgery. METHODS: One hundred one patients with gastroenterological disease were enrolled in this study. Blood samples were taken on the preoperative day (Pre) and the first postoperative day (POD1). We calculated the CD4 T-cell count and the PD-1 expression on CD4 T cells via flow cytometry. RESULTS: Postoperative infectious complications occurred in 30 of the 101 patients. The CD4 T-cell count was significantly lower in the patients who developed postoperative infectious complications at POD1 compared with the patients who did not. In addition, the PD 1 expression on CD4 T cells was significantly higher at Pre or POD1 in the patients who developed postoperative infectious complications. The preoperative PD-1 expression on CD4 T cells was found to be independently associated with postoperative infectious complications according to multivariate analysis. CONCLUSIONS: The perioperative CD4 T-cell count or PD-1 expression on CD4 T cells may be early predictive markers for the development of postoperative infectious complications. PMID- 26052962 TI - Mechanical comparison of monofilament nylon leader and orthopaedic wire for median sternotomy closure. AB - OBJECTIVES: To compare the mechanical properties of monofilament nylon leader and orthopaedic wire for median sternotomy closure in the dog. MATERIALS AND METHODS: Median sternotomy was performed in 14 canine cadaver sternums with the manubrium intact. The sternotomy was closed with either 80 lb monofilament nylon leader or 20G orthopaedic stainless steel wire in a peristernal figure of 8 pattern. Constructs were loaded in a servohydraulic material testing machine. Load at yield, maximum load, stiffness, displacement and mode of failure were compared between constructs subjected to a single cycle load to failure. RESULTS: No significant differences were found in load at yield, maximum load, stiffness or displacement between the monofilament nylon leader and the stainless steel wire constructs. No implant failure was evident in the stainless steel wire constructs. Four of the monofilament nylon leader constructs failed by pulling of the nylon through the crimp. CLINICAL SIGNIFICANCE: Monofilament nylon leader is mechanically comparable to stainless steel wire and potentially a suitable alternative for closure of median sternotomy in the dog. PMID- 26052963 TI - Genomics for Nursing Education and Practice: Measuring Competency. AB - BACKGROUND: Nurses lack genome literacy, skill, and self-confidence in applying genomics to health care. Standardized curricula and evaluation tools are needed for wide spread uptake and application of genome science in nursing education, practice, and research. AIM: To determine whether psychometrically robust survey instruments exist to assess knowledge, skills, attitudes, and self-confidence in applying genomic nursing competency among students and registered nurses. DESIGN: Psychometric systematic review. DATA SOURCES: Medline, CINAHL, Academic Search Elite, Web of Science, and ProQuest Dissertations were searched from 1995 to 2014, with an English language restriction. PROCEDURES: Critical analysis of the study elements and psychometric attributes was conducted after data were abstracted into analysis and synthesis tables. The synthesis assessed the design, methods, and measurement properties with a focus on reliability and validity using 16 criteria on a 4-point grading scale. FINDINGS: Twelve studies were included in a detailed review that focused on assessment of genomic nursing core competencies. Six studies met the inclusion criteria. In terms of psychometric quality of the instruments, one study scored high, two moderate, two low, and one very low. LINKING EVIDENCE TO ACTION: Most instruments assess self-perceived rather than objectively assessed competency. The highest quality instrument lacks clinical application. Knowledge-focused test questions based on up-to-date genome science that are relevant to practice need to be developed. PMID- 26052964 TI - Determinants of mammography screening participation among Turkish immigrant women in Germany--a qualitative study reflecting key informants' and women's perspectives. AB - Mammography screening programmes aiming to reduce mortality from breast cancer are implemented in most European countries. Immigrant women are less likely to participate than women of the respective autochthonous populations in several European countries but not in Germany. Qualitative, semi-structured interviews were conducted with 16 key informants and 10 Turkish immigrant women aged 50-69 years to analyse the factors influencing their screening participation in Germany. Interviews were analysed using summarising content analysis. The Theory of Planned Behaviour was used for structuring the results. Key informants stated poor German language skills and insufficient knowledge about breast cancer and screening as factors influencing screening participation. Immigrant women demonstrated basic knowledge about screening, but their attitudes towards screening varied. Information from the invitation letter of the screening programme was often filtered by family members. Key informants tended to emphasise barriers and system-related factors while the Turkish women focused more on factors on the individual level. Contrasting both perspectives is helpful for health professionals to critically assess their own views. Measures to improve screening participation need to address not only barriers but also take women's attitudes and norms into account, thus helping women to make an informed decision. PMID- 26052965 TI - Isoxazolidine-fused meso-tetraarylchlorins as key tools for the synthesis of mono and bis-annulated chlorins. AB - The microwave-assisted catalytic hydrogenation of the isoxazolidine-fused meso tetrakis(pentafluorophenyl)chlorin afforded directly a mono-annulated chlorin with a singular 1-methyl-2,3-dihydro-1H-benzo[b]azepine ring that resulted from the cleavage of the isoxazolidine N-O bond followed by an intramolecular nucleophilic aromatic substitution of an o-F atom. The subsequent treatment of the mono-annulated chlorin with NaH induced a second intramolecular nucleophilic aromatic substitution, generating a bis-annulated chlorin having an additional 2H pyran ring. PMID- 26052966 TI - Metal Domain Size Dependent Electrical Transport in Pt-CdSe Hybrid Nanoparticle Monolayers. AB - Thin films prepared of semiconductor nanoparticles are promising for low-cost electronic applications such as transistors and solar cells. One hurdle for their breakthrough is their notoriously low conductivity. To address this, we precisely decorate CdSe nanoparticles with platinum domains of one to three nanometers in diameter by a facile and robust seeded growth method. We demonstrate the transition from semiconductor to metal dominated conduction in monolayered films. By adjusting the platinum content in such solution-processable hybrid, oligomeric nanoparticles the dark currents through deposited arrays become tunable while maintaining electronic confinement and photoconductivity. Comprehensive electrical measurements allow determining the reigning charge transport mechanisms. PMID- 26052967 TI - Fecal Calprotectin in Ileal Crohn's Disease: Relationship with Magnetic Resonance Enterography and a Pathology Score. AB - BACKGROUND: Magnetic resonance enterography (MRE) is an effective method of assessing small bowel Crohn's disease (CD). Fecal calprotectin (FC) correlates well with endoscopic disease activity. We aimed to evaluate the correlation between FC and disease activity according to MRE and surgical pathology in small bowel CD. METHODS: One hundred twenty consecutive patients with ileal CD who underwent MRE assessment were included. Clinical data, C-reactive protein and FC, radiological and histological variables were obtained. Clinical activity was evaluated by the Harvey-Bradshaw Index and FC by enzyme-linked immunosorbent assay. MRE activity was assessed by means of the Magnetic Resonance Index of Activity score. Chiorean's score was used to grade pathological inflammation in surgical specimens. RESULTS: Seventy-five patients (62.5%) were in clinical remission (Harvey-Bradshaw Index < 5) and 45 (37.5%) had active disease (Harvey Bradshaw Index >= 5). The Magnetic Resonance Index of Activity score was significantly associated with FC levels (P < 0.01), with a moderate overall correlation (Spearman's r = 0.56, P < 0.001). FC reflected MRE inflammatory activity with an area under the receiver operating characteristic curve of 0.914 (confidence interval, 0.849-0.958; P < 0.001). A cutoff value of 166.50 MUg/g had 90% sensitivity, 74% specificity, 89% positive predictive value, and 76% negative predictive value for diagnosis of inflammation. Twenty-eight of 120 patients were operated. Surgical pathology showed a good agreement with FC for moderate (P = 0.03) and severe (P = 0.01) Chiorean's index. No relationship was detected for C reactive protein. CONCLUSIONS: FC correlates with the degree of MRE inflammatory activity and with surgical pathology damage in ileal CD. Thus, FC could be a surrogate marker of disease control used to select patients for MRE assessment and therapeutic adjustment. PMID- 26052968 TI - International Federation for Emergency Medicine point of care ultrasound curriculum. AB - To meet a critical and growing need for a standardized approach to emergency point of care ultrasound (PoCUS) worldwide, emergency physicians must be trained to deliver and teach this skill in an accepted and reliable format. Currently, there is no globally recognized, standard PoCUS curriculum that defines the accepted applications, as well as standards for training and practice of PoCUS by specialists and trainees in emergency medicine. To address this deficit, the International Federation for Emergency Medicine (IFEM) convened a sub-committee of international experts in PoCUS to outline a curriculum for training of specialists in emergency PoCUS. This curriculum document represents the consensus of recommendations by this sub-committee. The curriculum is designed to provide a framework for PoCUS education in emergency medicine. The focus is on the processes required to select core and enhanced applications, as well as the key elements required for the delivery of PoCUS training from introduction through to continuing professional development and skill maintenance. It is designed not to be prescriptive but to assist educators and emergency medicine leadership to advance PoCUS education in emergency medicine no matter the training venue. The content of this curriculum is relevant not just for communities with mature emergency medicine systems but in particular for developing nations or for nations seeking to develop PoCUS training programs within the current educational structure. We anticipate that there will be wide variability in how this curriculum is implemented and taught, reflecting the existing educational environment, resources and goals of educational programs. PMID- 26052969 TI - Thrombolysis for acute ischemic stroke: does it work?--the con position. PMID- 26052970 TI - CJEM and the changing landscape of medical education and knowledge translation. PMID- 26052971 TI - Don't know much about embryology... PMID- 26052972 TI - Validity of ultrasonography to diagnosing pneumothorax: a critical appraisal of two meta-analyses. AB - CLINICAL QUESTION: Can ultrasonography be used in lieu of chest radiography to diagnose pneumothorax? Articles chosen 1. Ding W, Shen Y, Yang J, et al. Diagnosis of pneumothorax by radiography and ultrasonography: a metaanalysis. Chest 2011;140:859-66. [Epub 2011 May 5] 2. Alrajhi K, Woo MY, Vaillancourt C. Test characteristics of ultrasonography for the detection of pneumothorax: a systematic review and meta-analysis. Chest 2012; 141:703-8 PMID- 26052973 TI - Improved neurologic outcomes after cardiac arrest with combined administration of vasopressin, steroids, and epinephrine compared to epinephrine alone. AB - CLINICAL QUESTION: Is a vasopressin, steroid, and epinephrine (VSE) protocol for in-hospital cardiac arrest resuscitation associated with better survival to hospital discharge with favourable neurologic outcome compared to epinephrine alone? Article chosen Mentzelopoulos S, Malachias S, Konstantopoulos D, et al. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA 2013;310:270 9. OBJECTIVE: To determine if a VSE protocol during cardiopulmonary resuscitation with hydrocortisone administration in patients with postresuscitative shock at 4 hours after return of spontaneous circulation would improve survival to hospital discharge with favourable neurologic outcome. PMID- 26052974 TI - Development and optimization of a noncontact optical device for online monitoring of jaundice in human subjects. AB - Jaundice is one of the notable markers of liver malfunction in our body, revealing a significant rise in the concentration of an endogenous yellow pigment bilirubin. We have described a method for measuring the optical spectrum of our conjunctiva and derived pigment concentration by using diffused reflection measurement. The method uses no prior model and is expected to work across the races (skin color) encompassing a wide range of age groups. An optical fiber based setup capable of measuring the conjunctival absorption spectrum from 400 to 800 nm is used to monitor the level of bilirubin and is calibrated with the value measured from blood serum of the same human subject. We have also developed software in the LabVIEW platform for use in online monitoring of bilirubin levels in human subjects by nonexperts. The results demonstrate that relative absorption at 460 and 600 nm has a distinct correlation with that of the bilirubin concentration measured from blood serum. Statistical analysis revealed that our proposed method is in agreement with the conventional biochemical method. The innovative noncontact, low-cost technique is expected to have importance in monitoring jaundice in developing/underdeveloped countries, where the inexpensive diagnosis of jaundice with minimally trained manpower is obligatory. PMID- 26052975 TI - Stressed podocytes - Bestrophin-3 is not just Bestrophin-3. PMID- 26052976 TI - Body dissatisfaction: Do associations with disordered eating and psychological well-being differ across race/ethnicity in adolescent girls and boys? AB - OBJECTIVE: This study examined whether body dissatisfaction, and its associations with disordered eating and psychological well-being, differ significantly across racial/ethnic groups of adolescents. METHOD: Cross-sectional analysis using data from a large, population-based study of adolescents participating in Eating and Activity in Teens, 2010 (EAT 2010) (N = 2,793; Mage = 14.4 years). The sample was socioeconomically and racially/ethnically diverse (81% racial/ethnic minority; 54% low or low-middle income). RESULTS: Body dissatisfaction differed significantly across racial/ethnic groups; Asian American girls and boys reported the most dissatisfaction with their bodies. Among boys, the relationship between body dissatisfaction and unhealthy weight control behaviors was moderated by race/ethnicity (p < .01), with a significantly weaker association for African American boys compared with those in other groups. Otherwise, the associations between body dissatisfaction and dieting and disordered eating did not vary significantly across racial/ethnic groups. Associations between body dissatisfaction and depressive symptoms and (boys') self-esteem differed significantly across racial/ethnic groups. CONCLUSION: In this study, with the exception of boys' unhealthy weight control behaviors, body dissatisfaction was associated with measures of dieting and disordered eating for youth across racial/ethnic groups. In addition, the association between body dissatisfaction and psychological well-being interacted significantly with adolescents' racial/ethnic backgrounds (with the exception of girls' self-esteem). Findings highlight specific racial/ethnic differences in the associations between body dissatisfaction and psychological well-being, and underscore the importance of addressing body dissatisfaction in youth of all racial/ethnic backgrounds. PMID- 26052978 TI - Cafestol-Type Diterpenoids from the Twigs of Tricalysia fruticosa with Potential Anti-inflammatory Activity. AB - Eight new cafestol-type diterpenoids, tricalysins A-H (1-8), along with five known analogues (9-13), were isolated from the twigs of Tricalysia fruticosa. The structures of 1-8 were elucidated by the application of spectroscopic methods. Inhibitory effects of the isolates on nitric oxide (NO) production in lipopolysaccaride-activated RAW 264.7 macrophages were evaluated, and compound 8 exhibited the most potent bioactivity, with an IC50 value of 6.6 +/- 0.4 MUM. It was shown further that compound 8 inhibits inflammatory responses via suppression of the expression of iNOS and reduction of the production of the pro-inflammatory cytokines IL-6 and TNF-alpha, resulting from activation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of MAPKs (ERK, JNK, and p38). PMID- 26052977 TI - Noninvasive Computed Tomography-based Risk Stratification of Lung Adenocarcinomas in the National Lung Screening Trial. AB - RATIONALE: Screening for lung cancer using low-dose computed tomography (CT) reduces lung cancer mortality. However, in addition to a high rate of benign nodules, lung cancer screening detects a large number of indolent cancers that generally belong to the adenocarcinoma spectrum. Individualized management of screen-detected adenocarcinomas would be facilitated by noninvasive risk stratification. OBJECTIVES: To validate that Computer-Aided Nodule Assessment and Risk Yield (CANARY), a novel image analysis software, successfully risk stratifies screen-detected lung adenocarcinomas based on clinical disease outcomes. METHODS: We identified retrospective 294 eligible patients diagnosed with lung adenocarcinoma spectrum lesions in the low-dose CT arm of the National Lung Screening Trial. The last low-dose CT scan before the diagnosis of lung adenocarcinoma was analyzed using CANARY blinded to clinical data. Based on their parametric CANARY signatures, all the lung adenocarcinoma nodules were risk stratified into three groups. CANARY risk groups were compared using survival analysis for progression-free survival. MEASUREMENTS AND MAIN RESULTS: A total of 294 patients were included in the analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into the Good, Intermediate, and Poor CANARY risk groups yielded distinct progression-free survival curves (P < 0.0001). This observation was confirmed in the unadjusted and adjusted (age, sex, race, and smoking status) progression-free survival analysis of all stage I cases. CONCLUSIONS: CANARY allows the noninvasive risk stratification of lung adenocarcinomas into three groups with distinct post-treatment progression-free survival. Our results suggest that CANARY could ultimately facilitate individualized management of incidentally or screen-detected lung adenocarcinomas. PMID- 26052979 TI - Developmental changes in misinterpretation of garden-path wh-questions in French. AB - This study explores (mis)interpretation of biclausal wh-questions by French speaking adults and children, aiming to investigate cross-linguistic differences in sentence revision mechanisms. Following previous work in Japanese the ambiguity of wh-questions was manipulated: In ambiguous questions, the fronted wh phrase could be associated with the first, main-clause verb or the second, embedded-clause verb, while in garden-path questions, an inserted filled-gap prepositional phrase (PP) blocked main-clause attachment. Importantly, French differs from Japanese in that the filled gap arises after the first verb-that is, after the wh-phrase has been interpreted within the main clause. Two story-based comprehension experiments were conducted to probe the effect of word order on revision performance. Adults and children frequently provided main-clause interpretations of ambiguous questions. In filled-gap questions, children displayed relatively acute sensitivity to the filled-gap in wh-argument questions (Experiment 2), but not in wh-adjunct questions (Experiment 1); adults showed surprisingly low sensitivity to it, frequently misinterpreting adjunct and argument questions. Acceptability ratings (Experiment 3) showed that adults systematically prefer in situ questions over wh-fronting questions. We conclude that timing of the error signal influences revision, and that whereas French speaking children prioritize syntactic cues, adults prioritize distributional information about the optionality of wh-fronting in French. PMID- 26052980 TI - Unexpected Spin-Crossover and a Low-Pressure Phase Change in an Iron(II)/Dipyrazolylpyridine Complex Exhibiting a High-Spin Jahn-Teller Distortion. AB - The synthesis of 4-methyl-2,6-di(pyrazol-1-yl)pyridine (L) and four salts of [FeL2]X2 (X(-) = BF4(-), 1; X(-) = ClO4(-), 2; X(-) = PF6(-), 3; X(-) = CF3SO3( ), 4) are reported. Powder samples of 1 and 2 both exhibit abrupt, hysteretic spin-state transitions on cooling, with T1/2? = 204 and T1/2? = 209 K (1), and T1/2? = 175 and T1/2? = 193 K (2). The 18 K thermal hysteresis loop for 2 is unusually wide for a complex of this type. Single crystal structures of 2 show it to exhibit a Jahn-Teller-distorted six-coordinate geometry in its high-spin state, which would normally inhibit spin-crossover. Bulk samples of 1 and 2 are isostructural by X-ray powder diffraction, and undergo a crystallographic phase change during their spin-transitions. At temperatures below T1/2, exposing both compounds to 10(-5) Torr pressure inside the powder diffractometer causes a reversible transformation back to the high-temperature crystal phase. Consideration of thermodynamic data implies this cannot be accompanied by a low > high spin-state change, however. Both compounds also exhibit the LIESST effect, with 2 exhibiting an unusually high T(LIESST) of 112 K. The salts 3 and 4 are respectively high-spin and low-spin between 3 and 300 K, with crystalline 3 exhibiting a more pronounced version of the same Jahn-Teller distortion. PMID- 26052981 TI - Neuroinflammation in Temporal Lobe Epilepsy Measured Using Positron Emission Tomographic Imaging of Translocator Protein. AB - IMPORTANCE: Neuroinflammation may play a role in epilepsy. Translocator protein 18 kDa (TSPO), a biomarker of neuroinflammation, is overexpressed on activated microglia and reactive astrocytes. A preliminary positron emission tomographic (PET) imaging study using carbon 11 ([11C])-labeled PBR28 in patients with temporal lobe epilepsy (TLE) found increased TSPO ipsilateral to seizure foci. Full quantitation of TSPO in vivo is needed to detect widespread inflammation in the epileptic brain. OBJECTIVES: To determine whether patients with TLE have widespread TSPO overexpression using [11C]PBR28 PET imaging, and to replicate relative ipsilateral TSPO increases in patients with TLE using [11C]PBR28 and another TSPO radioligand, [11C]DPA-713. DESIGN, SETTING, AND PARTICIPANTS: In a cohort study from March 2009 through September 2013 at the Clinical Epilepsy Section of the National Institute of Neurological Disorders and Stroke, participants underwent brain PET and a subset had concurrent arterial sampling. Twenty-three patients with TLE and 11 age-matched controls were scanned with [11C]PBR28, and 8 patients and 7 controls were scanned with [11C]DPA-713. Patients with TLE had unilateral temporal seizure foci based on ictal electroencephalography and structural magnetic resonance imaging. Participants with homozygous low-affinity TSPO binding were excluded. MAIN OUTCOMES AND MEASURES: The [11C]PBR28 distribution volume (VT) corrected for free fraction (fP) was measured in patients with TLE and controls using FreeSurfer software and T1-weighted magnetic resonance imaging for anatomical localization of bilateral temporal and extratemporal regions. Side-to-side asymmetry in patients with TLE was calculated as the ratio of ipsilateral to contralateral [11C]PBR28 and [11C]DPA-713 standardized uptake values from temporal regions. RESULTS: The [11C]PBR28 VT to fp ratio was higher in patients with TLE than in controls for all ipsilateral temporal regions (27%-42%; P < .05) and in contralateral hippocampus, amygdala, and temporal pole (approximately 30%-32%; P < .05). Individually, 12 patients, 10 with mesial temporal sclerosis, had asymmetrically increased hippocampal [11C]PBR28 uptake exceeding the 95% confidence interval of the controls. Binding of [11C]PBR28 was increased significantly in thalamus. Relative [11C]PBR28 and [11C]DPA-713 uptakes were higher ipsilateral than contralateral to seizure foci in patients with TLE ([11C]PBR28: 2%-6%; [11C]DPA 713: 4%-9%). Asymmetry of [11C]DPA-713 was greater than that of [11C]PBR28 (F = 29.4; P = .001). CONCLUSIONS AND RELEVANCE: Binding of TSPO is increased both ipsilateral and contralateral to seizure foci in patients with TLE, suggesting ongoing inflammation. Anti-inflammatory therapy may play a role in treating drug resistant epilepsy. PMID- 26052982 TI - Endoscopic transnasal approach for resection of locally aggressive tumors in the orbit. AB - OBJECT: In recent years, application of endoscopic transnasal surgery (ETS) has been expanded to orbital lesions, and preliminary results have started to be published for medially located soft mass lesions. However, reports on experience with endoscopic intraorbital surgery aimed at resection of invasive skull base tumors remains quite limited. This report presents the authors' experience with ETS for locally aggressive tumors involving the orbit. METHODS: ETS was performed for 15 cases of aggressive tumors involving the orbit: 5 meningiomas (meningothelial, n = 3; atypical, n = 1; anaplastic, n = 1), 4 chordomas, 2 chondrosarcomas, and 4 others (metastasis from systemic myxofibrosarcoma, schwannoma, inverted papilloma, and acinic cell carcinoma, n = 1 each). Among these, 9 tumors were located outside the periorbita and 6 inside the periorbita. In 6 intraperiosteal tumors, 5 were intraconal lesions, of which 3 arose in the muscle cone (anaplastic meningioma, optic sheath meningioma, and metastatic myxofibrosarcoma), and 2 meningothelial meningioma had invaded from the sphenoid ridge or the cavernous sinus into the muscle cone through the optic canal and the superior orbital fissure. A case of schwannoma originated around the cavernous sinus and pterygopalatine fossa and extended extraconally into the periorbita. Intraoperatively, ethmoid air cells and the lamina papyracea were removed, and extraperiosteal tumors were safely approached. For intraperiosteal tumors, the periorbita was widely opened, and the tumors were approached through the surgical window between the rectus and oblique muscles. RESULTS: Gross-total resection was achieved for 12 of the 15 tumors, including 2 intraconal lesions. After surgery, exophthalmos resolved in all 8 patients with this symptom, and diplopia resolved in 5 of 6 patients. Improvement of visual symptoms was reported by 4 of 5 patients with loss of visual acuity or constriction of the visual field. Postoperatively, 1 patient showed mild, transient worsening of existing facial dysesthesia, and another showed transient ptosis and mild hypesthesia of the forehead on the affected side. All those symptoms resolved within 3 months. No patients showed enophthalmos, worsening of diplopia or visual function, or impairment of olfaction after surgery. CONCLUSIONS: ETS appears acceptable as a less-invasive alternative for treating aggressive tumors involving the orbit. For extraperiosteal tumors, gross-total removal can generally be achieved without neurological complications. For intraperiosteal tumors, surgical indications should be carefully discussed, considering the relationship between the tumor and normal anatomy. Wide opening of the periorbital window is advocated to create a sufficient surgical pathway between the extraocular muscles, allowing a balance between functional preservation and successful tumor resection. PMID- 26052983 TI - Letter to the Editor: Operator doses in cone beam computed tomography. PMID- 26052985 TI - Diagnostic Delay in Rheumatoid Arthritis: A Qualitative Study of Symptom Interpretation Before the First Visit to the Doctor. AB - BACKGROUND: To prevent joint damage among patients with rheumatoid arthritis (RA), there is a need to minimize delays from the onset of symptoms until the initiation of appropriate therapy. The present study explored the factors that have an impact on the time it takes for Danish patients with RA to approach their general practitioner (GP) with joint pain, and also how GPs respond to patients' complaints. METHODS: The study was based on qualitative data collected using 11 semi-structured individual interviews. RESULTS: When symptoms were obvious to patients, there was a shorter delay between symptom onset and contacting their GP. In cases where symptoms gradually worsened or were difficult to interpret, there was a longer delay. Participants with a high degree of body awareness appeared to be good at detecting when something was not normal, and they responded quickly to their symptoms. For those who regarded the doctor as a resource to which they were entitled and who were not worried about getting a diagnosis there was a shorter delay. Diffuse symptoms seemed to confuse GPs and can contribute to physician delay in the investigation process. Similarly, the presence of other diseases can result in a prolonged period before referral to a rheumatologist. CONCLUSIONS: The nature and severity of symptoms are the deciding factors in their interpretation, by both the GP and the patient. Both the patient's disease recognition and his/her subsequent interaction with the doctor is influenced by the patient's body awareness and general attitude towards going to the doctor. The results showed that the greater the patient's body awareness, the better the disease recognition, the fewer barriers to contacting the GP and the shorter the delay in doing so. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26052986 TI - Preoperative Testing--A Bridge to Nowhere: A Teachable Moment. PMID- 26052989 TI - Managing biofilm by using dressings. AB - Biofilm is a thin layer containing masses of microorganisms; it has a gelatinous protective cover that is capable of attaching to virtually any surface. A wound provides the perfect medium for the growth of bacteria. In a wound, the organisms in the biofilm can obtain nutrients more easily than when they live on their own, and they are protected from many of the insults of daily life. This article will focus on these microorganisms and their ability to protect the colony against all attempts to remove it and the problems biofilm creates within a wound. PMID- 26052987 TI - Mechanistic Studies of the Radical S-Adenosyl-L-methionine Enzyme 4 Demethylwyosine Synthase Reveal the Site of Hydrogen Atom Abstraction. AB - TYW1 catalyzes the formation of 4-demethylwyosine via the condensation of N methylguanosine (m1G) with carbons 2 and 3 of pyruvate. In this study, labeled transfer ribonucleic acid (tRNA) and pyruvate were utilized to determine the site of hydrogen atom abstraction and regiochemistry of the pyruvate addition. tRNA containing a 2H-labeled m1G methyl group was used to identify the methyl group of m1G as the site of hydrogen atom abstraction by 5'-deoxyadenosyl radical. [2-13C1 3,3,3-2H3]Pyruvate was used to demonstrate retention of all the pyruvate protons, indicating that C2 of pyruvate forms the bridging carbon of the imidazoline ring and C3 the methyl. PMID- 26052990 TI - Providing cost-effective treatment of hard-to-heal wounds in the community through use of NPWT. AB - OBJECTIVE: The treatment of non-healing wounds accounts for a high proportion of wound care costs. Advanced technology treatments, such as negative pressure wound therapy (NPWT), could be cost-effective if they result in faster healing. The objective of this study is to assess the effect on healing and the cost effectiveness of a single-use NPWT (i.e PICO by Smith & Nephew) when used on hard to-heal wounds in a community setting. METHOD: This was a cohort case study in which wounds were treated with NWPT for 2 weeks. Wounds were assessed every 2-4 weeks to a healed state. The weekly cost of treatment prior to intervention, that is, the products used and nurse time, were compared with treatment costs associated with NWPT and after a return to standard treatment. RESULTS: The study included 9 patients with leg ulcers or pressure ulcers that had been slow healing or non-healing for at least 6 weeks. While treated with NPWT, the average weekly reduction in wound size was 21%. The wound size achieved with NPWT was reached on average 10 weeks earlier than predicted. The increased healing rate continued after PICO stopped and 5 wounds healed on average 8 weeks later. Frequency of dressing changes fell from 4 times weekly at baseline to 2 times a week with NPWT and to 1.8 after NPWT stopped. Weekly cost of treatment with NPWT was, on average, 1.6 times higher than the baseline, but fell to 3 times less when NPWT stopped owing to the reduction in dressing changes. The amount of change in healing rate was considerably higher than the increase in costs associated with NPWT. CONCLUSION: NWPT is a cost-effective treatment for hard-to-heal wounds. Wounds decreased in size and healed more quickly under NWPT treatment than under standard treatment. Additional NPWT costs can be quickly offset by faster healing and a shortened treatment period. PMID- 26052991 TI - Influence of psychosocial factors on coping and living with a venous leg ulcer. AB - This clinical focus and literature review describe the effect of psychosocial factors on coping and living with a venous leg ulcer (VLU). The associated stressors of living with a VLU include: pain, loss of self-esteem, and social isolation, with subsequent negative emotions that could potentially lead to anxiety and depression. The ability to cope with a VLU depends upon the individual, with some patients employing negative coping strategies such as denial, depending on the stage of the illness and level of acceptance reached (Husband, 2001; Brown, 2014). Psychosocial interventions by health professionals have been shown to reduce the stress of living with a VLU, to improve a patient's coping ability, and subsequently enhance wound healing. This article highlights the importance of holistic assessment and joint treatment planning, to incorporate patients' psychosocial needs and individual coping methods in order to reduce the associated stress of living with a VLU. PMID- 26052992 TI - Reviewing the benefits and harm of NPWT in the management of closed surgical incisions. AB - The use of negative pressure wound therapy (NPWT) for the treatment of open traumatic, non-traumatic, chronic wounds and coverage over skin grafts has increased in popularity over the past decade. Although the exact mechanism of the action of NPWT on wound healing is still an active area of research, evidence propose it is achieved by removing oedema, increasing blood circulation, reducing bacterial bio-burden, providing a moist wound-healing environment, and increasing granulation tissue formation. In recent years, there has been an emerging body of literature describing a novel application of NPWT on closed surgical wounds, especially on closed orthopaedic incisional (COI) wounds. It has been suggested that applying NPWT to a COI may decrease the incidence of surgical wound-healing complications, such as hematoma, seroma, infection, or dehiscence, and hasten the healing of the incision. This review will evaluate the potential effect on the reduction of postoperative closed wound complications and examine the benefits and harm of NPWT in the management of COI. PMID- 26052993 TI - A multicentre clinical evaluation of Cuticell Contact silicone wound contact layer in daily practice. AB - OBJECTIVE: To evaluate clinically the performance of Cuticell Contact, a silicone based primary contact wound dressing. BACKGROUND: Primary contact dressings that allow removal of exudate while protecting the wound bed during dressing changes are a key tool in wound management. Silicone dressings are of particular interest owing to their excellent conformability, pain-free dressing changes, and low toxicity. Cuticell Contact is a silicone-based wound dressing thought to provide these desirable benefits. METHOD: In this evaluation, 38 patients with 40 wounds of a variety of aetiologies and anatomical locations managed with Cuticell Contact and secondary dressings were observed in 8 centres across Germany and the Netherlands. The observation period ranged from 2-42 days (mean 21 days, median 18 days). At the end of the observation, Cuticell Contact was evaluated for permeability to exudate, nonadherence to the wound bed, pain at dressing change, and overall performance. The condition of the wound bed, wound surface area, and levels of exudate were recorded at baseline, at each dressing change, and at the end of the evaluation, along with the condition of the wound edge and peri-wound skin. RESULTS: Wounds managed with Cuticell Contact showed improvement in the wound bed as evidenced by an increase in wounds with complete granulation from 12.5% (n=40) to 26.5% (n=34), and wounds with partial or complete epithelialisation from 35% to 82.4%. Cuticell Contact was assessed at the end of the evaluation as nonadherent to the wound in 91.2% of cases (n=34), and 93.3% of dressing changes (n=104) were deemed pain free. Wound surface area decreased by a mean of 19.9%. Cuticell Contact was rated satisfactory for permeability to wound exudate in 82.4% of responses and overall satisfaction with the dressing performance was also 82.4%. CONCLUSION: Cuticell Contact is a soft silicone dressing that is easy to use, efficacious in supporting wound healing through protecting the wound bed, and facilitates atraumatic dressing changes. PMID- 26052994 TI - The Leg Club(r) experience of a husband-and-wife team. PMID- 26052997 TI - Can the outcome of the General Election affect wound care? PMID- 26052999 TI - Ruthenium indenylidene complexes bearing N-alkyl/N-mesityl-substituted N heterocyclic carbene ligands. AB - We report on the synthesis and characterization of second generation ruthenium indenylidene catalysts bearing unsymmetrical N-heterocyclic carbene (NHC) ligands denoted as RuCl2(3-phenyl-1-indenylidene)(1-mesityl-3-R-4,5-dihydroimidazol-2 ylidene)(PCy3), in which R is methyl 8a, octyl 8b or cyclohexyl 8c. The characterization of 8a-c was performed by NMR spectroscopy, elemental analysis, IR, HRMS and single-crystal X-ray diffraction analysis. In addition, the catalytic activity of the obtained initiators was evaluated in various representative metathesis reactions. The results reveal that the complexes 8a-c, bearing an N-alkyl side on the NHC, show a faster catalytic initiation than the reference complex 2. Complex 8a, which performs the best among the investigated indenylidene complexes, exhibits slower initiation but better overall efficiency than its benzylidene analogue 1c, especially in a low catalyst loading. PMID- 26052998 TI - Advances in wound debridement techniques. AB - Dead and devitalised tissue interferes with the process of wound healing. Debridement is a natural process that occurs in all wounds and is crucial to healing; it reduces the bacterial burden in a wound and promotes effective inflammatory responses that encourage the formation of healthy granulation tissue (Wolcott et al, 2009). Wound care should be part of holistic patient care. Recent advances in debridement techniques include: biosurgery, hydrosurgery, mechanical debridement, and ultrasound. Biosurgery and mechanical debridement can be practiced by nonspecialist nurses and can be provided in a patient's home, thus increasing the patient's access to debridement therapy and accelerating wound healing. PMID- 26053000 TI - The sweet spot of clinical intuitions: Predictors of the effects of context on impressions of conduct disorder symptoms. AB - How people interpret a mental disorder symptom has been shown to depend on the contextual life factors surrounding its presentation. Specifically, people are more likely to judge a symptom as clinically relevant if that symptom presents in a high-risk environment (e.g., child associates with deviant peers) relative to a low-risk environment (e.g., child associates with normative peer group). Importantly, not all symptoms are influenced by context to the same extent, and there is low agreement across people as to how this influence manifests. In this paper, we explore what factors predict the extent to which clinicians and laypeople interpret mental disorder symptoms as a function of diagnosis-congruent versus incongruent contextual information. We tested the impact of 2 statistical factors (prevalence and diagnosticity) and 2 more intuitive factors (diagnostic importance and abnormality) on the degree to which a symptom is interpreted differently in different contexts. Clinicians' impressions of the diagnosticity and importance of a symptom evidenced a curvilinear relationship with the use of context, with extremely important and unimportant as well as extremely diagnostic and nondiagnostic symptoms being less influenced by context. Laypeople showed a similar curvilinear relation between diagnosticity judgments and context effects. Additionally, clinicians showed a linear relationship between abnormality judgments and context use, with extremely abnormal symptoms being influenced less by context, whereas laypeople showed a curvilinear relationship between symptom abnormality and context use, with extremely abnormal and normal symptoms being influenced the most by context. We discuss implications of these findings for clinical diagnosis. (PsycINFO Database Record PMID- 26053001 TI - Evaluation of internal validity using modern test theory: Application to word association. AB - Word association tests (WATs) have been widely used to examine associative/semantic memory structures and shown to be relevant to behavior and its underpinnings. Despite successful applications of WATs in diverse research areas, few studies have examined psychometric properties of these tests or other open-ended cognitive tests of common use. Modern test theory models, such as item response theory (IRT) models, are well suited to evaluate interpretations of this class of test. In this evaluation, unidimensional IRT models were fitted to the data on the WAT designed to capture associative memory relevant to an important applied issue: casual sex in a sample of 1,138 adult drug offenders. Using association instructions, participants were instructed to generate the first behavior or action that came to mind in response to cues (e.g., "hotel/motel") that might elicit casual sex-related responses. Results indicate a multitude of evidence for the internal validity of WAT score interpretations. All WAT items measured a single latent trait of casual sex-related associative memory, strongly related to the latent trait, and were invariant across gender, ethnicity, age groups, and sex partner profiles. The WAT was highly informative at average-to high levels of the latent trait and also associated with risky sex behavior, demonstrating the usefulness of this class of test. The study illustrates the utility of the assessments in this at-risk population as well as the benefits of application of the modern test theory models in the evaluation of internal validity of open-ended cognitive test score interpretation. (PsycINFO Database Record PMID- 26053002 TI - Multifractal temporal correlations in circle-tracing behaviors are associated with the executive function of rule-switching assessed by the Trail Making Test. AB - Rule switching is 1 among a diverse set of executive functions whose delicate interactions allows us to coordinate behavior appropriately to changing contexts and demands. Clinical assessments such as the Trail Making Test (TMT) estimate flexibility of rule switching, but such assessments can be challenging to interpret. TMT scores are sums of many choice response times (RTs): More time spent reflects not simply manual motor speed and visual scanning but also fluctuation of attention to sequence and less flexible switching among rules to reject many inappropriate targets and instead select the single next appropriate target. A growing consensus recognizes that the aggregate of many choice RTs reflect multiplicative interaction of factors across multiple scales, among which manual motor speed, counting up sequence, and rule-switching are just a few. Multiplicative interactions entail first, fractal temporal correlations and, more importantly, variability of fractality within the same series, that is, "multifractality," The authors analyzed circle-tracing data to test whether tracing variance, degree of fractal temporal correlations, and multifractality correlate with TMT scores. Despite the absence of effects of variance, stronger temporal correlations indicated poorer Trails B performance, but multifractality moderated this relationship. These results suggest potential markers for predicting rule-switching ability from motor behavior. (PsycINFO Database Record PMID- 26053003 TI - Li1.2Mn0.54Ni0.13Co0.13O2-Encapsulated Carbon Nanofiber Network Cathodes with Improved Stability and Rate Capability for Li-Ion Batteries. AB - Li1.2Mn0.54Ni0.13Co0.13O2-encapsulated carbon nanofiber network cathode materials were synthesized by a facile electrospinning method. The microstructures, morphologies and electrochemical properties are characterized by X-ray diffraction (XRD), field-emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM), galvonostatic charge/discharge tests, cyclic voltammetry and electrochemical impedance spectroscopy (EIS), etc. The nanofiber decorated Li1.2Mn0.54Ni0.13Co0.13O2 electrode demonstrated higher coulombic efficiency of 83.5%, and discharge capacity of 263.7 mAh g(-1) at 1 C as well as higher stability compared to the pristine particle counterpart. The superior electrochemical performance results from the novel network structure which provides fast transport channels for electrons and lithium ions and the outer carbon acts a protection layer which prevents the inner oxides from reacting with HF in the electrolyte during charge discharge cycling. PMID- 26053005 TI - Femoral cement extraction in revision total hip arthroplasty--an in vitro study comparing computer-assisted freehand-navigated cement removal to conventional cement extraction. AB - BACKGROUND: Revision surgery of cemented femoral stems in total hip arthroplasty is gaining more and more importance, but cement removal in revision hip arthroplasty may be technically challenging. Conventional manual cement removal can be time consuming and be associated with complications such as cortical perforation, fracture, or bone loss. The aim of this study was to investigate the practicability of computer-navigated cement removal. MATERIAL AND METHODS: In an in vitro study, we examined the removal of the bone cement out of composite bones. To evaluate accuracy, the bones were scanned before and after cement removal with the ISO-C three-dimensional C-arm computed tomography system to determine the amount of unremoved cement and the loss of bone stock. The data of freehand-navigated cement removal is compared to conventionally extracted cement using levers and drills under X-ray control. RESULTS: The mean time for cement removal was 29 +/- 5 min for the conventional method and 32 +/- 8 min for the freehand-navigated cement removal. Here, excepting the preparatory examinations, the navigated cement removal only took 13 +/- 5 min. The measured temperature during polymerization was 36 +/- 5 degrees C and during navigated cement removal was 37 +/- 8 degrees C. In the distal part of the femur, cement removal was more accurate with the conventional method compared to the navigated one. CONCLUSION: The freehand-navigated cement removal, with the exception of the preparatory examinations, is time saving compared to the conventional method. However, a potential for technical development especially for the milling device and accuracy exist. PMID- 26053004 TI - A Systematic Review of Interventions Addressing Adherence to Anti-Diabetic Medications in Patients with Type 2 Diabetes--Components of Interventions. AB - BACKGROUND: Poor adherence to anti-diabetic medications contributes to suboptimal glycaemic control in patients with type 2 diabetes (T2D). A range of interventions have been developed to promote anti-diabetic medication adherence. However, there has been very little focus on the characteristics of these interventions and how effectively they address factors that predict non adherence. In this systematic review we assessed the characteristics of interventions that aimed to promote adherence to anti-diabetic medications. METHOD: Using appropriate search terms in Medline, Embase, CINAHL, International Pharmaceutical Abstracts (IPA), PUBmed, and PsychINFO (years 2000-2013), we identified 52 studies which met the inclusion criteria. RESULTS: Forty-nine studies consisted of patient-level interventions, two provider-level interventions, and one consisted of both. Interventions were classified as educational (n = 7), behavioural (n = 3), affective, economic (n = 3) or multifaceted (a combination of the above; n = 40). One study consisted of two interventions. The review found that multifaceted interventions, addressing several non-adherence factors, were comparatively more effective in improving medication adherence and glycaemic target in patients with T2D than single strategies. However, interventions with similar components and those addressing similar non-adherence factors demonstrated mixed results, making it difficult to conclude on effective intervention strategies to promote adherence. Educational strategies have remained the most popular intervention strategy, followed by behavioural, with affective components becoming more common in recent years. Most of the interventions addressed patient-related (n = 35), condition-related (n = 31), and therapy-related (n = 20) factors as defined by the World Health Organization, while fewer addressed health care system (n = 5) and socio-economic related factors (n = 13). CONCLUSION: There is a noticeable shift in the literature from using single to multifaceted intervention strategies addressing a range of factors impacting adherence to medications. However, research limitations, such as limited use of standardized methods and tools to measure adherence, lack of individually tailored adherence promoting strategies and variability in the interventions developed, reduce the ability to generalize the findings of the studies reviewed. Furthermore, this review highlights the need to develop multifaceted interventions which can be tailored to the individual patient's needs over the duration of their diabetes management. PMID- 26053006 TI - The relation of vitamin D status with metabolic syndrome in childhood and adolescence: an update. AB - Among children and adolescents, metabolic syndrome (MetS) is more common than previously believed. Hence, any information on the relation between vitamin D insufficiency/deficiency and insulin resistance (IR) in this population with risk of developing MetS is of great importance. This review analyzes and evaluates the existing evidence from cross-sectional, observational, and retrospective studies concerning the effect of vitamin D insufficiency/deficiency on MetS as a whole or on its various components. Most data show that insufficient vitamin D status is associated with increased prevalence of MetS or its individual components, mainly blood pressure and IR, often independent of overall obesity or abdominal adiposity. The implications of these findings could be associated with increased risk for developing cardiovascular disease and type 2 diabetes mellitus in later life. The very few randomized control trials examining any possible beneficial effects of vitamin D supplementation are also included. PMID- 26053007 TI - Reference intervals for 24 laboratory parameters determined in 24-hour urine collections. AB - BACKGROUND: Reference intervals for many laboratory parameters determined in 24-h urine collections are either not publicly available or based on small numbers, not sex specific or not from a representative sample. METHODS: Osmolality and concentrations or enzymatic activities of sodium, potassium, chloride, glucose, creatinine, citrate, cortisol, pancreatic alpha-amylase, total protein, albumin, transferrin, immunoglobulin G, alpha1-microglobulin, alpha2-macroglobulin, as well as porphyrins and their precursors (delta-aminolevulinic acid and porphobilinogen) were determined in 241 24-h urine samples of a population-based cohort of asymptomatic adults (121 men and 120 women). For 16 of these 24 parameters creatinine-normalized ratios were calculated based on 24-h urine creatinine. The reference intervals for these parameters were calculated according to the CLSI C28-A3 statistical guidelines. RESULTS: By contrast to most published reference intervals, which do not stratify for sex, reference intervals of 12 of 24 laboratory parameters in 24-h urine collections and of eight of 16 parameters as creatinine-normalized ratios differed significantly between men and women. For six parameters calculated as 24-h urine excretion and four parameters calculated as creatinine-normalized ratios no reference intervals had been published before. For some parameters we found significant and relevant deviations from previously reported reference intervals, most notably for 24-h urine cortisol in women. Ten 24-h urine parameters showed weak or moderate sex specific correlations with age. CONCLUSIONS: By applying up-to-date analytical methods and clinical chemistry analyzers to 24-h urine collections from a large population-based cohort we provide as yet the most comprehensive set of sex specific reference intervals calculated according to CLSI guidelines for parameters determined in 24-h urine collections. PMID- 26053008 TI - Assessing quality and functionality of DNA isolated from FFPE tissues through external quality assessment in tissue banks. AB - BACKGROUND: Biobanks are becoming increasingly important for assessment of disease risk as well as identification and validation of new diagnostic biomarkers and druggable targets. The validity of data obtained from biobanks is critically limited by the biomaterial quality of the biological samples. External quality assessment (EQA) programs suitable to comprehensively measure the biomaterial quality in archived materials are currently lacking. We report on quantitative assay designs for the analysis of both structural and functional integrity of DNAs that were applied in a first pilot EQA within the priority program on tumor tissue biobanking funded by the German Cancer Aid. METHODS: Participating biobanks isolated DNAs from a standardized set of 10 samples comprising sections of four different formalin-fixed paraffin-embedded tissues using their standard operating procedures. Isolated DNAs and analytical results were returned and analyzed centrally for nucleic acids yield, purity, fragmentation and amplificability at a quantitative level using dedicated assay designs. RESULTS: The amount of extracted DNA varied in isolates ranging between 1.5 MUg and 25.8 MUg. Quantification of DNA fragmentation and amplificability allowed to highlight considerable discrepancies in DNA quality. Amplicons yielded from the isolates of these identical EQA samples ranged from 105 to 411 bp suggesting differences between residual inhibitors of downstream enzymatic reactions. CONCLUSIONS: The quality of extraction of bioanalytes from biomaterial archives is heterogeneous even for stable biomolecules like DNA isolated with highly standardized methods. EQAs are appropriate tools to uncover strengths and weaknesses in biobanks in a systematic fashion. Biomaterial integrity is insufficiently reflected by standard methods, but needs to be assessed to improve biobank interoperability. Finally, our results also point towards the problem of measuring the quality of more delicate biomolecules like proteins or metabolites. PMID- 26053009 TI - The Laboratory Medicine and the care of patients infected by the Ebola virus. Experience in a reference hospital of Madrid, Spain. AB - The ongoing Ebola virus outbreak in several countries in West Africa was considered by the World Health Organisation (WHO) as a public health emergency of international concern. Healthcare providers must be prepared by organising specific procedures in our hospitals based on recommendations from national and international healthcare organisations. Two aims should be considered: appropriate medical care for patients with suspected or confirmed disease must be ensured, as must measures to prevent transmission to healthcare workers. The clinical laboratory plays an important role and must define and establish its own procedures in accordance with clinicians and integrated into those of the institution, starting with the definition of the organisation model in the laboratory to achieve those goals. In this review we present our experience based on the care of three patients with confirmed cases. We hope it will help other colleagues to plan for Ebola. PMID- 26053010 TI - Diagnostic performances of clinical laboratory tests using Triton X-100 to reduce the biohazard associated with routine testing of Ebola virus-infected patients. AB - BACKGROUND: Ebola virus, an enveloped virus, is the cause of the largest and most complex Ebola virus disease (EVD) outbreak in West Africa. Blood or body fluids of an infected person may represent a biohazard to laboratory workers. Laboratory tests of virus containing specimens should be conducted in referral centres at biosafety level 4, but based on the severity of clinical symptoms, basic laboratories might be required to execute urgent tests for patients suspected of EVD. The aim of this work was to compare the analytical performances of laboratory tests when Triton X-100, a chemical agent able to inactivate other enveloped viruses, was added to specimens. METHODS: Results of clinical chemistry, coagulation and haematology parameters on samples before and after the addition of 0.1% (final concentration) of Triton X-100 and 1 h of incubation at room temperature were compared. RESULTS: Overall, results showed very good agreement by all statistical analyses. Triton X-100 at 0.1% did not significantly affect the results for the majority of the analytes tested. CONCLUSIONS: Triton X 100 at 0.1% can be used to reduce the biohazard in performing laboratory tests on samples from patients with EVD without affecting clinical decisions. PMID- 26052984 TI - Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. AB - BACKGROUND: Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS: In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS: During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32). CONCLUSIONS: Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.). PMID- 26053011 TI - Accuracy and precision assessment of a new blood glucose monitoring system. AB - BACKGROUND: Blood glucose self-monitoring by individuals with diabetes is essential in controlling blood glucose levels. The International Organization for Standardization (ISO) introduced new standards for blood glucose monitoring systems (BGMS) in 2013 (ISO 15197: 2013). The CONTOUR PLUS(r) (CONTOUR PLUS) BGMS has been demonstrated to meet the 2013 ISO standards; however, no Chinese data on CONTOUR PLUS accuracy and precision have been published. METHODS: This study evaluated the accuracy and precision of CONTOUR PLUS BGMS in quantitative glucose testing of capillary and venous whole blood samples obtained from 363 patients at three different hospitals. RESULTS: Results of fingertip and venous blood glucose measurements by the CONTOUR PLUS system were compared with laboratory reference values to determine accuracy. Accuracy was 98.1% (96.06%-99.22%) for fingertip blood tests and 98.1% (96.02%-99.21%) for venous blood tests. Precision was evaluated across a wide range of blood glucose values (5.1-17.2 mmol/L), testing three blood samples repeatedly 15 times with the CONTOUR PLUS blood glucose meter using test strips from three lots. All within-lot results met ISO criteria (i.e., SD<0.42 mmol/L for blood glucose concentration <5.55 mmol/L; CV<7.5% for blood glucose concentration >=5.55 mmol/L). Between-lot variations were 1.5% for low blood glucose concentration, 2.4% for normal and 3.4% for high. CONCLUSIONS: Accuracy of both fingertip and venous blood glucose measurements by the CONTOUR PLUS system was >95%, confirming that the system meets ISO 15197: 2013 requirements. PMID- 26053012 TI - Comparison of capillary electrophoresis and high performance liquid chromatography for detection and quantification of hemoglobin New York. AB - BACKGROUND: Hemoglobin (Hb) New York [beta113 (G15) Val->Glu, GTG->GAG], also known as Hb Kaohsiung, is one of the most common Hb variants in South China. Currently, most used screening methods for hemoglobinopathies in South China are high performance liquid chromatography (HPLC) and capillary electrophoresis (CE). However, there is no study comparing the performance of CE and HPLC in the detection of Hb New York. METHODS: In total 15 samples (including 13 adult blood samples and 2 cord blood samples) with heterozygous Hb New York were analyzed by CE and HPLC. Levels of Hb New York, HbA2, Hb, mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were compared within the two groups. RESULTS: All 15 cases (100%) were detected by CE, whereas none was detected by HPLC. Mean values of Hb New York and HbA2 in adult heterozygous group were (43.82+/-2.47)% and (2.85+/-0.31)%, respectively; mean values for cord blood group were (7.95+/ 0.78)% and (0.30+/-0.14)%. CONCLUSIONS: CE allows the detection of Hb New York, while this variant is not separated from Hb A on HPLC. CE may be the preferred method for hemoglobinopathy screening in areas with high prevalence of Hb New York. PMID- 26053013 TI - Differentiation of acute pyelonephritis from other febrile states in children using urinary neutrophil gelatinase-associated lipocalin (uNGAL). AB - BACKGROUND: Acute pyelonephritis is a severe disease which is sometimes difficult to recognize based on clinical symptoms and routinely available diagnostic tests, especially in young children. The aim of this study was to assess the diagnostic value of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a biomarker of acute pyelonephritis. METHODS: In this case-control study we analyzed 134 children (median age 2.5 years) who were admitted to the Pediatric Clinic of University Hospital Centre Osijek, Croatia. Eighty of them had acute pyelonephritis, while 54 children had febrile state of different etiology including cystitis and they represented the control group. uNGAL, white blood cells, C-reactive protein, urinanalysis, urine culture, kidney ultrasound and a dimercaptosuccinic acid scintigraphic scan were done for each child. uNGAL was measured using chemiluminiscent microparticle immunoassay on ARHITECT i1000SR (Abbott Diagnostics, IL, USA). RESULTS: uNGAL values were significantly higher in children with acute pyelonephritis compared to the control groups (113.6 ng/mL vs. 10.2 ng/mL, p<0.001). A receiver operating characteristic curve comparison was done for tested parameters and encouraging results were obtained for uNGAL (AUC=0.952). A cut-off value of 29.4 ng/mL had 92.5% sensitivity and 90.7% specificity. We showed that uNGAL can also serve in differentiating acute pyelonephritis from cystitis (cut-off 38.5 ng/mL), and for differentiation of cystitis from febrile states with etiology other than urinary tract infection (UTI) (cut-off 20.4 ng/mL). CONCLUSIONS: uNGAL can be a useful diagnostic biomarker in acute pyelonephritis in children, but also in differentiating cystitis from febrile states other than UTI. PMID- 26053014 TI - Finasteride, not tamsulosin, increases severity of erectile dysfunction and decreases testosterone levels in men with benign prostatic hyperplasia. AB - BACKGROUND: 5alpha-reductase inhibitors (5alpha-RIs) (finasteride and dutasteride) have been proven useful in treatment of lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH). However, these inhibitors exert undesirable sexual side effects and, in some cases, these effects are persistent. There is considerable disagreement with regard to whether the adverse side effects resolve with continuous treatment. AIM: To investigate the long-term adverse effects of finasteride treatment in men with BPH on erectile function and to compare these adverse effects in men treated with the alpha1-adrenergic receptor blocker, tamsolusin. METHODS: In this retrospective registry study, a cohort of 470 men aged between 47 and 68 years (mean 57.78+/-4.81) were treated with finasteride (5 mg/day). A second cohort of 230 men aged between 52 and 72 years (mean 62.62+/-4.65) were treated with tamsulosin (0.4 mg). All men were followed up for 45 months. At intervals of 3 months and at each visit, plasma testosterone (T) levels and the international index of erectile function (IIEF EF) questionnaire scores were determined. RESULTS: Long-term treatment with finasteride therapy is associated with worsening of erectile dysfunction (ED) as shown by the significant decrease in the IIEF-EF scores in men treated with finasteride. No worsening of ED was observed in men treated with tamsulosin. The increase in ED due to finasteride did not resolve with continued treatment with finasteride. Most importantly, long-term finasteride therapy resulted in reduction in total T levels, contributing to a state of hypogonadism. On the contrary, no changes in T levels were noted in men treated with tamsolusin. CONCLUSION: Our findings suggest that in men with BPH, long-term finasteride therapy but not tamsulosin results in worsening of ED and reduces total T concentrations. Clinicians are urged to discuss the impact of 5alpha-RIs therapy on sexual function with their patients before commencing this therapy. PMID- 26053015 TI - An ethnopharmacological approach to the preliminary screening of native Australian herbal medicines for anticancer activity. AB - BACKGROUND: Five plants used traditionally by Australian Aboriginals and two edible native Australian fruits have been investigated for anticancer activity. The aim was to identify native Australian herbal medicines which displayed anticancer activity, with cytotoxicity to cancer cells but sparing or even proliferating normal immunological cells, and subsequently provide potentially new anticancer drug leads. METHODS: Extracts and derived fractions were assayed for cell viability against a multiple myeloma cell line, RPMI-8226, in comparison to the peripheral blood mononuclear cells (PBMC) representing normal human immunological cells. RESULTS: None of the crude extracts exhibited the desirable differential activity; however, following further fractionation of the Eremophila duttonii F. Muell. (Myoporaceae) extract, one fraction (termed F01) exhibited a greater cytotoxicity to the cancer cell line than to the normal cells. CONCLUSIONS: One fraction may potentially contain valuable compounds which may be useful for further investigation. This may focus on the identification of the bioavailable purified compounds present within these fractions or by detailed delineation of the related mechanisms of action. PMID- 26053016 TI - Quantification of the In Vitro Radiosensitivity of Mung Bean Sprout Elongation to 6MV X-Ray: A Revised Target Model Study. AB - In this study, a revised target model for quantifying the in vitro radiosensitivity of mung bean sprout elongation to 6-MV X-rays was developed. The revised target model, which incorporated the Poisson prediction for a low probability of success, provided theoretical estimates that were highly consistent with the actual data measured in this study. The revised target model correlated different in vitro radiosensitivities to various effective target volumes and was successfully confirmed by exposing mung beans in various elongation states to various doses of 6-MV X-rays. For the experiment, 5,000 fresh mung beans were randomly distributed into 100 petri dishes, which were randomly divided into ten groups. Each group received an initial watering at a different time point prior to X-ray exposure, resulting in different effective target volumes. The bean sprouts were measured 70 hr after X-ray exposure, and the average length of the bean sprouts in each group was recorded as an index of the mung bean in vitro radiosensitivity. Mung beans that received an initial watering either six or sixteen hours before X-ray exposure had the shortest sprout length, indicating that the maximum effective target volume was formed within that specific time period. The revised target model could be also expanded to interpret the "two-hit" model of target theory, although the experimental data supported the "one-hit" model. If the "two-hit" model was sustained, theoretically, the target size would be 2.14 times larger than its original size to produce the same results. PMID- 26053017 TI - Impairment of Colour Vision in Diabetes with No Retinopathy: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetics Study (SNDREAMS- II, Report 3). AB - PURPOSE: To assess impairment of colour vision in type 2 diabetics with no diabetic retinopathy and elucidate associated risk factors in a population-based cross-sectional study. METHODS: This is part of Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular-genetics Study (SN-DREAMS II) which was conducted between 2007-2010. FM 100 hue-test was performed in 253 subjects with no clinical evidence of diabetic retinopathy. All subjects underwent detailed ophthalmic evaluation including cataract grading using LOCS III and 45 degrees 4 field stereoscopic fundus photography. Various ocular and systemic risk factors for impairment of colour vision (ICV) were assessed in subjects with diabetes but no retinopathy. P value of < 0.05 was considered statistically significant. RESULTS: The mean age of the study sample was 57.08 +/- 9.21 (range: 44-86 years). Gender adjusted prevalence of ICV among subjects with diabetes with no retinopathy was 39.5% (CI: 33.5-45.5). The mean total error score in the study sample was 197.77 +/- 100 (range: 19-583). The risk factors for ICV in the study were women OR: 1.79 (1.00-3.18), increased resting heart rate OR: 1.04 (1.01 1.07) and increased intraocular pressure OR: 1.12 (1.00-1.24). Significant protective factor was serum high-density lipoprotein OR: 0.96 (0.93-0.99). CONCLUSIONS: Acquired ICV is an early indicator of neurodegenerative changes in the retina. ICV found in diabetic subjects without retinopathy may be of non vascular etiology. PMID- 26053018 TI - The Intranasal Application of Zanamivir and Carrageenan Is Synergistically Active against Influenza A Virus in the Murine Model. AB - BACKGROUND: Carrageenan is a clinically proven and marketed compound for the treatment of viral upper respiratory tract infections. As infections caused by influenza virus are often accompanied by infections with other respiratory viruses the combination of a specific anti-influenza compound with the broadly active antiviral polymer has huge potential for the treatment of respiratory infections. Thus, the combination of the specific anti-influenza drug Zanamivir together with carrageenan in a formulation suitable for intranasal application was evaluated in-vitro and in-vivo. PRINCIPAL FINDINGS: We show in-vitro that carrageenan and Zanamivir act synergistically against several influenza A virus strains (H1N1(09)pdm, H3N2, H5N1, H7N7). Moreover, we demonstrate in a lethal influenza model with a low pathogenic H7N7 virus (HA closely related to the avian influenza A(H7N9) virus) and a H1N1(09)pdm influenza virus in C57BL/6 mice that the combined use of both compounds significantly increases survival of infected animals in comparison with both mono-therapies or placebo. Remarkably, this benefit is maintained even when the treatment starts up to 72 hours post infection. CONCLUSION: A nasal spray containing carrageenan and Zanamivir should therefore be tested for prevention and treatment of uncomplicated influenza in clinical trials. PMID- 26053019 TI - HEPNet: A Knowledge Base Model of Human Energy Pool Network for Predicting the Energy Availability Status of an Individual. AB - HEPNet is an electronic representation of metabolic reactions occurring within human cellular organization focusing on inflow and outflow of the energy currency ATP, GTP and other energy associated moieties. The backbone of HEPNet consists of primary bio-molecules such as carbohydrates, proteins and fats which ultimately constitute the chief source for the synthesis and obliteration of energy currencies in a cell. A series of biochemical pathways and reactions constituting the catabolism and anabolism of various metabolites are portrayed through cellular compartmentalization. The depicted pathways function synchronously toward an overarching goal of producing ATP and other energy associated moieties to bring into play a variety of cellular functions. HEPNet is manually curated with raw data from experiments and is also connected to KEGG and Reactome databases. This model has been validated by simulating it with physiological states like fasting, starvation, exercise and disease conditions like glycaemia, uremia and dihydrolipoamide dehydrogenase deficiency (DLDD). The results clearly indicate that ATP is the master regulator under different metabolic conditions and physiological states. The results also highlight that energy currencies play a minor role. However, the moiety creatine phosphate has a unique character, since it is a ready-made source of phosphoryl groups for the rapid synthesis of ATP from ADP. HEPNet provides a framework for further expanding the network diverse age groups of both the sexes, followed by the understanding of energetics in more complex metabolic pathways that are related to human disorders. PMID- 26053020 TI - Exogenous Restoration of TUSC2 Expression Induces Responsiveness to Erlotinib in Wildtype Epidermal Growth Factor Receptor (EGFR) Lung Cancer Cells through Context Specific Pathways Resulting in Enhanced Therapeutic Efficacy. AB - Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC) cell lines resistant to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2 erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR. PMID- 26053022 TI - Immunization surveillance systems for pregnant women. PMID- 26053021 TI - Endogenous and Uric Acid-Induced Activation of NLRP3 Inflammasome in Pregnant Women with Preeclampsia. AB - Preeclampsia (PE) is a specific syndrome of pregnancy, characterized by hypertension and proteinuria. This pathology is associated with hyperuricemia and elevated serum levels of inflammatory cytokines. Uric acid crystals may activate an intracellular complex called inflammasome, which is important for processing and release of inflammatory cytokines. This study investigated the state of monocyte activation, both endogenous and stimulated with monosodium urate (MSU), by gene expression of NLRP1 and NLRP3 receptors as well as their association with inflammatory cytokines expression. Monocytes were obtained from peripheral blood of 23 preeclamptic pregnant women, 23 normotensive pregnant women (NT) and 23 healthy non-pregnant women (NP). Inflammasome activation was evaluated by the gene expression of NLRP1, NLRP3, caspase-1, IL-1beta, IL-18 and TNF-alpha by RT qPCR in unstimulated monocytes (endogenous expression), or after cell stimulation with MSU (stimulated expression). The concentration of cytokines was assessed by ELISA. In preeclamptic pregnant women, gene expression of NLRP1, NLRP3, caspase 1, IL-1beta and TNF-alpha by monocytes stimulated or not with MSU was significantly higher than in NT and NP groups. Stimulation of monocytes from preeclamptic and non-pregnant women with MSU induced increased gene expression of NLRP3, caspase-1 and TNF-alpha in relation to the endogenous expression in these groups, while this was not observed in the NT group. The cytokine determination showed that monocytes from women with PE produced higher endogenous levels of IL 1beta, IL-18 and TNF-alpha compared to the other groups, while the stimulus with MSU led to higher production of these cytokines in preeclamptic group than in the NT group. In conclusion, the results showed increased basal gene expression of NLRP1 and NLRP3 receptors in monocytes from PE group. These cells stimulation with MSU demonstrates that uric acid plays a role in NLRP3 inflammasome activation, suggesting the participation of this inflammatory complex in the pathogenesis of preeclampsia. PMID- 26053023 TI - Adverse event following immunization surveillance systems for pregnant women. PMID- 26053024 TI - The Effects of as-Needed Nalmefene on Patient-Reported Outcomes and Quality of Life in Relation to a Reduction in Alcohol Consumption in Alcohol-Dependent Patients. AB - BACKGROUND: The objective of this article was to investigate the effect of as needed nalmefene on health-related quality of life (HRQoL) in patients with alcohol dependence, and to relate changes in drinking behavior and status to HRQoL outcomes. METHODS: This post hoc analysis was conducted on a pooled subgroup of patients with at least a high drinking risk level (men: >60 g/day; women: >40 g/day) who participated in one of two randomized controlled 6-month studies, ESENSE 1 and ESENSE 2. Patients received nalmefene 18 mg or placebo on an as-needed basis, in addition to a motivational and adherence-enhancing intervention (BRENDA). At baseline and after 12 and 24 weeks questionnaires for the Medical Outcomes Study (MOS) 36-item Short-Form Health Survey (SF-36), European Quality of life-5 Dimensions (EQ-5D) and the Drinker Inventory of Consequences (DrInC-2R) were completed. RESULTS: The pooled population consisted of 667 patients (nalmefene: 335; placebo: 332), with no notable between-group differences in baseline patient demographics/characteristics. At week 24, nalmefene had a superior effect compared to placebo in improving SF-36 mental component summary scores (mean difference [95% CI], p-value: 3.09 [1.29, 4.89]; p=0.0008), SF-36 physical component summary scores (1.23 [0.15, 2.31]; p=0.026), EQ-5D utility index scores (0.03 [0.00, 0.06]; p=0.045), EQ-5D health state scores (3.46 [0.75, 6.17]; p=0.012), and DrInC-2R scores (-3.22 [-6.12, 0.33]; p=0.029). The improvements in SF-36 mental component summary scores at week 24, and the DrInC-2R total score change from baseline to week 24, were significantly correlated to reductions in heavy drinking days and total alcohol consumption at week 24. CONCLUSIONS: As-needed nalmefene significantly improved almost all patient-reported HRQoL measures included in SF-36 and EQ-5D compared with placebo. These HRQoL gains were significantly correlated to reduced drinking behavior, as determined by reductions in heavy drinking days and total alcohol consumption. PMID- 26053025 TI - ATP Binding and Hydrolysis Properties of ABCB10 and Their Regulation by Glutathione. AB - ABCB10 (ATP binding cassette sub-family B10) is a mitochondrial inner-membrane ABC transporter. ABCB10 has been shown to protect the heart from the impact of ROS during ischemia-reperfusion and to allow for proper hemoglobin synthesis during erythroid development. ABC transporters are proteins that increase ATP binding and hydrolysis activity in the presence of the transported substrate. However, molecular entities transported by ABCB10 and its regulatory mechanisms are currently unknown. Here we characterized ATP binding and hydrolysis properties of ABCB10 by using the 8-azido-ATP photolabeling technique. This technique can identify potential ABCB10 regulators, transported substrates and amino-acidic residues required for ATP binding and hydrolysis. We confirmed that Gly497 and Lys498 in the Walker A motif, Glu624 in the Walker B motif and Gly602 in the C-Loop motif of ABCB10 are required for proper ATP binding and hydrolysis activity, as their mutation changed ABCB10 8-Azido-ATP photo-labeling. In addition, we show that the potential ABCB10 transported entity and heme precursor delta-aminolevulinic acid (dALA) does not alter 8-azido-ATP photo-labeling. In contrast, oxidized glutathione (GSSG) stimulates ATP hydrolysis without affecting ATP binding, whereas reduced glutathione (GSH) inhibits ATP binding and hydrolysis. Indeed, we detectABCB10 glutathionylation in Cys547 and show that it is one of the exposed cysteine residues within ABCB10 structure. In all, we characterize essential residues for ABCB10 ATPase activity and we provide evidence that supports the exclusion of dALA as a potential substrate directly transported by ABCB10. Last, we show the first molecular mechanism by which mitochondrial oxidative status, through GSH/GSSG, can regulate ABCB10. PMID- 26053026 TI - Adverse Effects of High Concentrations of Fluoride on Characteristics of the Ovary and Mature Oocyte of Mouse. AB - Reproductive toxicity has been an exciting topic of research in reproductive biology in recent years. Soluble fluoride salts are toxic at high concentrations; their reproductive toxicity was assessed in this study by administering different fluoride salt concentrations to mice. Continuous feeding for five weeks resulted in damage to the histological architecture of ovaries. The expression of genes, including Dazl, Stra8, Nobox, Sohlh1, and ZP3 gene, associated with oocyte formation were much lower in the experimental group as compared with the control group. The number of in vitro fertilization of mature oocytes were also much lower in the experimental group as compared with control. Moreover, the fertility of female mice, as assessed by mating with normal male mice, was also lower in experimental compared with control groups. The expression of the oocyte-specific genes: Bmp15, Gdf9, H1oo, and ZP2, which are involved in oocyte growth and the induction of the acrosome reaction, decreased with the fluoride administration. DNA methylation and histone acetylation (H3K18ac and H3K9ac) are indispensable for germline development and genomic imprinting in mammals, and fluoride administration resulted in reduced levels of H3K9ac and H3K18ac in the experimental group as compared with the control group, as detected by immunostaining. Our results indicate that the administration of high concentrations of fluoride to female mice significantly reduced the number of mature oocytes and hampered their development and fertilization. Thus, this study lays a foundation for future studies on fluoride-induced reproductive disorders in women. PMID- 26053027 TI - Risk Factors Associated with Colorectal Cancer in a Subset of Patients with Mutations in MLH1 and MSH2 in Taiwan Fulfilling the Amsterdam II Criteria for Lynch Syndrome. AB - BACKGROUND AND AIM: Lynch syndrome, caused by germline mutations in mismatch repair genes, is a predisposing factor for colorectal cancer (CRC). This retrospective cohort study investigated the risk factors associated with the development of CRC in patients with MLH1 and MSH2 germline mutations. METHODS: In total, 301 MLH1 and MSH2 germline mutation carriers were identified from the Amsterdam criteria family registry provided by the Taiwan Hereditary Nonpolyposis Colorectal Cancer Consortium. A Cox proportional hazard model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to determine the association between the risk factors and CRC development. A robust sandwich covariance estimation model was used to evaluate family dependence. RESULTS: Among the total cohort, subjects of the Hakka ethnicity exhibited an increased CRC risk (HR = 1.62, 95% CI = 1.09-2.34); however, those who performed regular physical activity exhibited a decreased CRC risk (HR = 0.62, 95% CI = 0.41-0.88). The CRC risk was enhanced in MLH1 germline mutation carriers, with corresponding HRs of 1.72 (95% CI = 1.16-2.55) and 0.54 (95% CI = 0.34-0.83) among subjects of the Hakka ethnicity and those who performed regular physical activity, respectively. In addition, the total cohort with a manual occupation had a 1.56 times higher CRC risk (95% CI = 1.07-2.27) than did that with a skilled occupation. Moreover, MSH2 germline mutation carriers with blood group type B exhibited an increased risk of CRC development (HR = 2.64, 95% CI = 1.06-6.58) compared with those with blood group type O. CONCLUSION: The present study revealed that Hakka ethnicity, manual occupation, and blood group type B were associated with an increased CRC risk, whereas regular physical activity was associated with a decreased CRC risk in MLH1 and MSH2 germline mutation carriers. PMID- 26053028 TI - Oxidative stress: Determination of 4-hydroxy-2-nonenal by gas chromatography/mass spectrometry in human and rat plasma. AB - The lipid peroxidation product 4-hydroxynonenal (HNE) is a biomarker of oxidative stress which is essentially involved in the pathophysiology of many diseases. The analysis of HNE is challenging because this aldehyde is extremely reactive and thus unstable. Hence, we adopted a gas chromatography-mass spectrometry (GC-MS) method based on derivatization of HNE with pentafluorobenzyl-hydroxylamine-HCl followed by trimethylsilylation to trimethylsilyl ethers. Ions representative for a negative ion chemical ionization mode were recorded at m/z = 152 for HNE and at m/z = 162 for the deuterated analogon (HNE-d11) as internal standard. This excellent stable and precise GC-MS method was carefully validated for HNE, and showed good linearity (r(2) = 0.998), and high specificity and sensitivity. Within-day precisions were 4.4-6.1% and between-day precisions were 5.2-10.2%. Accuracies were between 99% and 104% for the whole calibration range (2.5-250 nmol/L) of HNE. To examine the versatility of this modified GC-MS method, we analyzed HNE in ethylenediaminetetraacetic acid (EDTA) plasma in a well-defined collective of migraine patients; recently published. The results underline our former observations that women with migraine are afflicted with increased levels of HNE. Patients with thyroidal dysfunction showed no significant HNE alterations. This was confirmed by normal HNE EDTA plasma levels in hyper- und hypothyroid Sprague-Dawley rats. Taken together, the GC-MS method presented herein is of excellent quality to record oxidative stress-related bioactive HNE levels. This is important for a reorientation of oxidative stress analytics in other human diseases first of atherosclerosis and cancer. PMID- 26053029 TI - Reaction Kinetics of Catechol (1,2-Benzenediol) and Guaiacol (2-Methoxyphenol) with Ozone. AB - The kinetic reactions of 1,2-benzenediol (catechol) and 2-methoxyphenol (guaiacol) with ozone were studied in a simulation chamber (8 m(3)) under dark conditions. The rate coefficients were measured at 294 +/- 2 K, atmospheric pressure and dry conditions (relative humidity, RH < 1%), except for 1,2 benzenediol where they were also measured as a function of relative humidity (RH = 1-80%). The concentrations of organic compounds were followed by a PTR-ToF-MS for a continuous monitoring of gas-phase species. The O3 rate coefficients were obtained using both the pseudo-first-order and relative rate methods. The values (in cm(3) molecule(-1) s(-1)) determined for catechol and guaiacol under dry conditions are (13.5 +/- 1.1) * 10(-18) and (0.40 +/- 0.31) * 10(-18), respectively. The rate coefficient of catechol was found to be independent of RH below 20% and above 60%, whereas for RH between 20% and 60% it decreases with increasing RH. The determined rate coefficients have been used to evaluate the atmospheric lifetime of each compound with respect to O3. To our knowledge, this study represents the first determination of the ozone rate coefficient with guaiacol and is also the first kinetic investigation for the influence of the relative humidity on the oxygenated aromatic ozonolysis. PMID- 26053030 TI - Presence of Plasmodium falciparum DNA in Plasma Does Not Predict Clinical Malaria in an HIV-1 Infected Population. AB - BACKGROUND: HIV-1 and Plasmodium falciparum malaria cause substantial morbidity in Sub-Saharan Africa, especially as co-infecting pathogens. We examined the relationship between presence of P. falciparum DNA in plasma samples and clinical malaria as well as the impact of atazanavir, an HIV-1 protease inhibitor (PI), on P. falciparum PCR positivity. METHODS: ACTG study A5175 compared two NNRTI-based regimens and one PI-based anti-retroviral (ARV) regimen in antiretroviral therapy naive participants. We performed nested PCR on plasma samples for the P. falciparum 18s rRNA gene to detect the presence of malaria DNA in 215 of the 221 participants enrolled in Blantyre and Lilongwe, Malawi. We also studied the closest sample preceding the first malaria diagnosis from 102 persons with clinical malaria and randomly selected follow up samples from 88 persons without clinical malaria. RESULTS: PCR positivity was observed in 18 (8%) baseline samples and was not significantly associated with age, sex, screening CD4+ T-cell count, baseline HIV-1 RNA level or co-trimoxazole use within the first 8 weeks. Neither baseline PCR positivity (p = 0.45) nor PCR positivity after initiation of antiretroviral therapy (p = 1.0) were significantly associated with subsequent clinical malaria. Randomization to the PI versus NNRTI ARV regimens was not significantly associated with either PCR positivity (p = 0.5) or clinical malaria (p = 0.609). Clinical malaria was associated with a history of tuberculosis (p = 0.006) and a lower BMI (p = 0.004). CONCLUSION: P. falciparum DNA was detected in 8% of participants at baseline, but was not significantly associated with subsequent development of clinical malaria. HIV PI therapy did not decrease the prevalence of PCR positivity or incidence of clinical disease. PMID- 26053031 TI - Identification of Pathogen Signatures in Prostate Cancer Using RNA-seq. AB - Infections of the prostate by bacteria, human papillomaviruses, polyomaviruses, xenotropic murine leukemia virus (MLV)-related gammaretroviruses, human cytomegaloviruses and other members of the herpesvirus family have been widely researched. However, many studies have yielded conflicting and controversial results. In this study, we systematically investigated the transcriptomes of human prostate samples for the unique genomic signatures of these pathogens using RNA-seq data from both western and Chinese patients. Human and nonhuman RNA-seq reads were mapped onto human and pathogen reference genomes respectively using alignment tools Bowtie and BLAT. Pathogen infections and integrations were analyzed in adherence with the standards from published studies. Among the nine pathogens (Propionibacterium acnes, HPV, HCMV, XMRV, BKV, JCV, SV40, EBV, and HBV) we analyzed, Propionibacterium acnes genes were detected in all prostate tumor samples and all adjacent samples, but not in prostate samples from healthy individuals. SV40, HCMV, EBV and low-risk HPVs transcripts were detected in one tumor sample and two adjacent samples from Chinese prostate cancer patients, but not in any samples of western prostate cancer patients; XMRV, BKV and JCV sequences were not identified in our work; HBV, as a negative control, was absent from any samples. Moreover, no pathogen integration was identified in our study. While further validation is required, our analysis provides evidence of Propionibacterium acnes infections in human prostate tumors. Noted differences in viral infections across ethnicity remain to be confirmed with other large prostate cancer data sets. The effects of bacterial and viral infections and their contributions to prostate cancer pathogenesis will require continuous research on associated pathogens. PMID- 26053032 TI - CYP2J2 overexpression ameliorates hyperlipidemia via increased fatty acid oxidation mediated by the AMPK pathway. AB - OBJECTIVE: The study aims to investigate the effect of cytochrome P450 2J2 (CYP2J2) overexpression on hyperlipidemia in mice and further to explore its effect on fatty acid oxidation in vivo and in vitro. METHODS: The effects and mechanisms of endothelial-specific CYP2J2 transgene (Tie2-CYP2J2-Tr) on lipid and fatty acid metabolism were investigated in high-fat diet (HFD) -treated mice. HepG2, LO2 cells, and HUVECs were exposed to 0.4 mM free fatty acid (FFA) for 24 h and used as a model to investigate the roles of CYP2J2 overexpression and epoxyeicosatrienoic acids (EETs) on fatty acid beta-oxidation in vitro. RESULTS: Tie2-CYP2J2-Tr mice had significantly lower plasma and liver triglycerides, lower liver cholesterol and fatty acids, and reduced HFD-induced lipid accumulation. CYP2J2 overexpression resulted in activation of the hepatic and endothelial AMPKalpha, increased ACC phosphorylation, and increased expression of CPT-1 and PPARalpha, which were all reduced by HFD treatment. In FFA-treated HepG2, LO2, and HUVECs, both CYP2J2 overexpression and EETs significantly decreased lipid accumulation and increased fatty acid oxidation via activating the AMPK and PPARalpha pathways. CONCLUSIONS: Endothelial-specific CYP2J2 overexpression alleviates HFD-induced hyperlipidemia in vivo. CYP2J2 ameliorates FFA-induced dyslipidemia via increased fatty acid oxidation mediated by the AMPK and PPARalpha pathways. PMID- 26053033 TI - Kruppel-like factor 4 signals through microRNA-206 to promote tumor initiation and cell survival. AB - Tumor cell heterogeneity poses a major hurdle in the treatment of cancer. Mammary cancer stem-like cells (MaCSCs), or tumor-initiating cells, are highly tumorigenic sub-populations that have the potential to self-renew and to differentiate. These cells are clinically important, as they display therapeutic resistance and may contribute to treatment failure and recurrence, but the signaling axes relevant to the tumorigenic phenotype are poorly defined. The zinc finger transcription factor Kruppel-like factor 4 (KLF4) is a pluripotency mediator that is enriched in MaCSCs. KLF4 promotes RAS-extracellular signal regulated kinase pathway activity and tumor cell survival in triple-negative breast cancer (TNBC) cells. In this study, we found that both KLF4 and a downstream effector, microRNA-206 (miR-206), are selectively enriched in the MaCSC fractions of cultured human TNBC cell lines, as well as in the aldehyde dehydrogenase-high MaCSC sub-population of cells derived from xenografted human mammary carcinomas. The suppression of endogenous KLF4 or miR-206 activities abrogated cell survival and in vivo tumor initiation, despite having only subtle effects on MaCSC abundance. Using a combinatorial approach that included in silico as well as loss- and gain-of-function in vitro assays, we identified miR 206-mediated repression of the pro-apoptotic molecules programmed cell death 4 (PDCD4) and connexin 43 (CX43/GJA1). Depletion of either of these two miR-206 regulated transcripts promoted resistance to anoikis, a prominent feature of CSCs, but did not consistently alter MaCSC abundance. Consistent with increased levels of miR-206 in MaCSCs, the expression of both PDCD4 and CX43 was suppressed in these cells relative to control cells. These results identify miR-206 as an effector of KLF4-mediated prosurvival signaling in MaCSCs through repression of PDCD4 and CX43. Consequently, our study suggests that a pluripotency factor exerts prosurvival signaling in MaCSCs, and that antagonism of KLF4-miR-206 signaling may selectively target the MaCSC niche in TNBC. PMID- 26053034 TI - The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERalpha expression and enhances hormonal therapy for breast cancer. AB - Estrogen receptor-alpha (ERalpha)-negative breast cancer is clinically aggressive and does not respond to conventional hormonal therapies. Strategies that lead to re-expression of ERalpha could sensitize ERalpha-negative breast cancers to selective ER modulators. FTY720 (fingolimod, Gilenya), a sphingosine analog, is the Food and Drug Administration (FDA)-approved prodrug for treatment of multiple sclerosis that also has anticancer actions that are not yet well understood. We found that FTY720 is phosphorylated in breast cancer cells by nuclear sphingosine kinase 2 and accumulates there. Nuclear FTY720-P is a potent inhibitor of class I histone deacetylases (HDACs) that enhances histone acetylations and regulates expression of a restricted set of genes independently of its known effects on canonical signaling through sphingosine-1-phosphate receptors. High-fat diet (HFD) and obesity, which is now endemic, increase breast cancer risk and have been associated with worse prognosis. HFD accelerated the onset of tumors with more advanced lesions and increased triple-negative spontaneous breast tumors and HDAC activity in MMTV-PyMT transgenic mice. Oral administration of clinically relevant doses of FTY720 suppressed development, progression and aggressiveness of spontaneous breast tumors in these mice, reduced HDAC activity and strikingly reversed HFD-induced loss of estrogen and progesterone receptors in advanced carcinoma. In ERalpha-negative human and murine breast cancer cells, FTY720 reactivated expression of silenced ERalpha and sensitized them to tamoxifen. Moreover, treatment with FTY720 also re-expressed ERalpha and increased therapeutic sensitivity of ERalpha-negative syngeneic breast tumors to tamoxifen in vivo more potently than a known HDAC inhibitor. Our work suggests that a multipronged attack with FTY720 is a novel combination approach for effective treatment of both conventional hormonal therapy-resistant breast cancer and triple-negative breast cancer. PMID- 26053035 TI - Which Kind of Provider's Operation Volumes Matters? Associations between CABG Surgical Site Infection Risk and Hospital and Surgeon Operation Volumes among Medical Centers in Taiwan. AB - BACKGROUND: Volume-infection relationships have been examined for high-risk surgical procedures, but the conclusions remain controversial. The inconsistency might be due to inaccurate identification of cases of infection and different methods of categorizing service volumes. This study takes coronary artery bypass graft (CABG) surgical site infections (SSIs) as an example to examine whether a relationship exists between operation volumes and SSIs, when different SSIs case identification, definitions and categorization methods of operation volumes were implemented. METHODS: A population-based cross-sectional multilevel study was conducted. A total of 7,007 patients who received CABG surgery between 2006 and 2008 from 19 medical centers in Taiwan were recruited. SSIs associated with CABG surgery were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9 CM) codes and a Classification and Regression Trees (CART) model. Two definitions of surgeon and hospital operation volumes were used: (1) the cumulative CABG operation volumes within the study period; and (2) the cumulative CABG operation volumes in the previous one year before each CABG surgery. Operation volumes were further treated in three different ways: (1) a continuous variable; (2) a categorical variable based on the quartile; and (3) a data-driven categorical variable based on k-means clustering algorithm. Furthermore, subgroup analysis for comorbidities was also conducted. RESULTS: This study showed that hospital volumes were not significantly associated with SSIs, no matter which definitions or categorization methods of operation volume, or SSIs case identification approaches were used. On the contrary, the relationships between surgeon's volumes varied. Most of the models demonstrated that the low-volume surgeons had higher risk than high-volume surgeons. CONCLUSION: Surgeon volumes were more important than hospital volumes in exploring the relationship between CABG operation volumes and SSIs in Taiwan. However, the relationships were not robust. Definitions and categorization methods of operation volume and correct identification of SSIs are important issues for future research. PMID- 26053036 TI - Candidate gene association studies and risk of Hodgkin lymphoma: a systematic review and meta-analysis. AB - To evaluate the contribution of association studies of candidate polymorphisms to inherited predisposition to Hodgkin lymphoma (HL), we conducted a systematic review and meta-analysis of published case-control studies. Of the variants examined more than once in candidate gene association studies, we identified 21 studies that reported on 12 polymorphic variants in 10 genes. Data were also extracted from a published genome wide association study to allow analysis of an additional 47 variants in a further 30 genes. Promising associations were seen in nine of the variants (p < 0.05). Given that the estimated false positive report probabilities (FPRPs) for all associations are high (i.e. FPRP > 0.2), these findings should be interpreted with caution. While studies of candidate polymorphisms may be an attractive means of identifying risk factors for HL, future studies should employ sample sizes adequately powered to identify variants having only modest effects on HL risk. Furthermore, because of aetiological heterogeneity within HL, stratification of genotyping according to age, tumour Epstein-Barr virus status and histology is essential. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26053037 TI - Can Neurotypical Individuals Read Autistic Facial Expressions? Atypical Production of Emotional Facial Expressions in Autism Spectrum Disorders. AB - The difficulties encountered by individuals with autism spectrum disorder (ASD) when interacting with neurotypical (NT, i.e. nonautistic) individuals are usually attributed to failure to recognize the emotions and mental states of their NT interaction partner. It is also possible, however, that at least some of the difficulty is due to a failure of NT individuals to read the mental and emotional states of ASD interaction partners. Previous research has frequently observed deficits of typical facial emotion recognition in individuals with ASD, suggesting atypical representations of emotional expressions. Relatively little research, however, has investigated the ability of individuals with ASD to produce recognizable emotional expressions, and thus, whether NT individuals can recognize autistic emotional expressions. The few studies which have investigated this have used only NT observers, making it impossible to determine whether atypical representations are shared among individuals with ASD, or idiosyncratic. This study investigated NT and ASD participants' ability to recognize emotional expressions produced by NT and ASD posers. Three posing conditions were included, to determine whether potential group differences are due to atypical cognitive representations of emotion, impaired understanding of the communicative value of expressions, or poor proprioceptive feedback. Results indicated that ASD expressions were recognized less well than NT expressions, and that this is likely due to a genuine deficit in the representation of typical emotional expressions in this population. Further, ASD expressions were equally poorly recognized by NT individuals and those with ASD, implicating idiosyncratic, rather than common, atypical representations of emotional expressions in ASD. PMID- 26053038 TI - Metabolic Changes in Masseter Muscle of Rats Submitted to Acute Stress Associated with Exodontia. AB - Clinical evidence has shown that stress may be associated with alterations in masticatory muscle functions. Morphological changes in masticatory muscles induced by occlusal alterations and associated with emotional stress are still lacking in the literature. The objective of this study was to evaluate the influence of acute stress on metabolic activity and oxidative stress of masseter muscles of rats subjected to occlusal modification through morphological and histochemical analyses. In this study, adult Wistar rats were divided into 4 groups: a group with extraction and acute stress (E+A); group with extraction and without stress (E+C); group without extraction and with acute stress (NO+A); and control group without both extraction and stress (NO+C). Masseter muscles were analyzed by Succinate Dehydrogenase (SDH), Nicotinamide Adenine Dinucleotide Diaphorase (NADH) and Reactive Oxygen Species (ROS) techniques. Statistical analyses and two-way ANOVA were applied, followed by Tukey-Kramer tests. In the SDH test, the E+C, E+A and NO+A groups showed a decrease in high desidrogenase activities fibers (P < 0.05), compared to the NO+C group. In the NADH test, there was no difference among the different groups. In the ROS test, in contrast, E+A, E+C and NO+A groups showed a decrease in ROS expression, compared to NO+C groups (P < 0.05). Modified dental occlusion and acute stress--which are important and prevalent problems that affect the general population--are important etiologic factors in metabolic plasticity and ROS levels of masseter muscles. PMID- 26053039 TI - A Pipeline for Screening Small Molecules with Growth Inhibitory Activity against Burkholderia cenocepacia. AB - Infections with the bacteria Burkholderia cepacia complex (Bcc) are very difficult to eradicate in cystic fibrosis patients due the intrinsic resistance of Bcc to most available antibiotics and the emergence of multiple antibiotic resistant strains during antibiotic treatment. In this work, we used a whole-cell based assay to screen a diverse collection of small molecules for growth inhibitors of a relevant strain of Bcc, B. cenocepacia K56-2. The primary screen used bacterial growth in 96-well plate format and identified 206 primary actives among 30,259 compounds. From 100 compounds with no previous record of antibacterial activity secondary screening and data mining selected a total of Bce bioactives that were further analyzed. An experimental pipeline, evaluating in vitro antibacterial and antibiofilm activity, toxicity and in vivo antibacterial activity using C. elegans was used for prioritizing compounds with better chances to be further investigated as potential Bcc antibacterial drugs. This high throughput screen, along with the in vitro and in vivo analysis highlights the utility of this experimental method to quickly identify bioactives as a starting point of antibacterial drug discovery. PMID- 26053040 TI - Analysis of HIV Correlated Factors in Chinese and Vietnamese Female Sex Workers in Hekou, Yunnan Province, a Chinese Border Region. AB - OBJECTIVES: To assess the prevalence and correlated factors of HIV-1 among Chinese and Vietnamese female sex workers (FSW) in the border county of Hekou, Yunnan province, China. METHODS: A cross-sectional survey was conducted collecting information on demographics, sexual behavior, medical history, and drug use. Blood samples were obtained to test for HIV/STIs. Multivariate logistic regression model was used to examine associations between factors and HIV-1 infection. RESULTS: Of 345 FSWs who participated in this study, 112 (32.5%) were Chinese and 233 (67.5) were Vietnamese. Vietnamese FSWs were significantly more likely to be HIV-1 positive (7.7%) compared with Chinese FSWs (0.9%) (p = 0.009). In multivariate analysis, sexual debut at age <= 16 (OR 3.8: 95% CI: 1.4, 10.6), last client's payment <150 RMB ($22 USD) (OR: 5.2, 95% CI; 1.7, 16.6), and HSV-2 (OR: 12.3; 95% CI: 1.6, 94.8) were significant for HIV-1 infection. CONCLUSIONS: Differences in HIV prevalence in Vietnamese and Chinese FSWs may be indicative of differential risk. It is important to characterize the nature of trans-border transmission in order to gain a better understanding of the potential impact on the international HIV epidemic. Understanding the correlated factors for HIV in Vietnamese and Chinese FSWs is important for designing interventions for this vulnerable population. PMID- 26053042 TI - One-Shot Double Amination of Sondheimer-Wong Diynes: Synthesis of Photoluminescent Dinaphthopentalenes. AB - Photoluminescent diamino-substituted dinaphthopentalenes were synthesized successfully by the treatment of in situ prepared dinaphthocyclooctadiyne with lithium amide. This reaction involves a series of transformations including the nucleophilic addition of the lithium amide to a triple bond of the cyclooctadiyne moiety, transannulation, protonation of the resulting pentalene anion, and the nucleophilic substitution of the pentalene core with the lithium amide. In this procedure, a novel double amination step plays a key role. When the diamino substituted dinaphthopentalenes were irradiated with UV light in toluene, fluorescence was observed at around 580 nm (PhiF < 0.03). PMID- 26053041 TI - Ancient DNA from South-East Europe Reveals Different Events during Early and Middle Neolithic Influencing the European Genetic Heritage. AB - The importance of the process of Neolithization for the genetic make-up of European populations has been hotly debated, with shifting hypotheses from a demic diffusion (DD) to a cultural diffusion (CD) model. In this regard, ancient DNA data from the Balkan Peninsula, which is an important source of information to assess the process of Neolithization in Europe, is however missing. In the present study we show genetic information on ancient populations of the South East of Europe. We assessed mtDNA from ten sites from the current territory of Romania, spanning a time-period from the Early Neolithic to the Late Bronze Age. mtDNA data from Early Neolithic farmers of the Starcevo Cris culture in Romania (Carcea, Gura Baciului and Negrilesti sites), confirm their genetic relationship with those of the LBK culture (Linienbandkeramik Kultur) in Central Europe, and they show little genetic continuity with modern European populations. On the other hand, populations of the Middle-Late Neolithic (Boian, Zau and Gumelnita cultures), supposedly a second wave of Neolithic migration from Anatolia, had a much stronger effect on the genetic heritage of the European populations. In contrast, we find a smaller contribution of Late Bronze Age migrations to the genetic composition of Europeans. Based on these findings, we propose that permeation of mtDNA lineages from a second wave of Middle-Late Neolithic migration from North-West Anatolia into the Balkan Peninsula and Central Europe represent an important contribution to the genetic shift between Early and Late Neolithic populations in Europe, and consequently to the genetic make-up of modern European populations. PMID- 26053043 TI - Fibroblasts Influence Survival and Therapeutic Response in a 3D Co-Culture Model. AB - In recent years, evidence has indicated that the tumor microenvironment (TME) plays a significant role in tumor progression. Fibroblasts represent an abundant cell population in the TME and produce several growth factors and cytokines. Fibroblasts generate a suitable niche for tumor cell survival and metastasis under the influence of interactions between fibroblasts and tumor cells. Investigating these interactions requires suitable experimental systems to understand the cross-talk involved. Most in vitro experimental systems use 2D cell culture and trans-well assays to study these interactions even though these paradigms poorly represent the tumor, in which direct cell-cell contacts in 3D spaces naturally occur. Investigating these interactions in vivo is of limited value due to problems regarding the challenges caused by the species-specificity of many molecules. Thus, it is essential to use in vitro models in which human fibroblasts are co-cultured with tumor cells to understand their interactions. Here, we developed a 3D co-culture model that enables direct cell-cell contacts between pancreatic, breast and or lung tumor cells and human fibroblasts/ or tumor-associated fibroblasts (TAFs). We found that co-culturing with fibroblasts/TAFs increases the proliferation in of several types of cancer cells. We also observed that co-culture induces differential expression of soluble factors in a cancer type-specific manner. Treatment with blocking antibodies against selected factors or their receptors resulted in the inhibition of cancer cell proliferation in the co-cultures. Using our co-culture model, we further revealed that TAFs can influence the response to therapeutic agents in vitro. We suggest that this model can be reliably used as a tool to investigate the interactions between a tumor and the TME. PMID- 26053044 TI - Cell proliferation by silk gut incorporating FGF-2 protein microcrystals. AB - Silk gut processed from the silk glands of the silkworm could be an ideal biodegradable carrier for cell growth factors. We previously demonstrated that polyhedra, microcrystals of Cypovirus 1 polyhedrin, can serve as versatile carrier proteins. Here, we report the generation of a transgenic silkworm that expresses polyhedrin together with human basic fibroblast growth factor (FGF-2) in its posterior silk glands to utilize silk gut as a proteinaceous carrier to protect and slowly release active cell growth factors. In the posterior silk glands, polyhedrin formed polyhedral microcrystals, and FGF-2 became encapsulated within the polyhedra due to a polyhedron-immobilization signal. Silk gut powder prepared from posterior silk glands containing polyhedron-encapsulated FGF-2 stimulated the phosphorylation of p44/p42 MAP kinase and induced the proliferation of serum-starved NIH3T3 cells by releasing bioactive FGF-2. Even after a one-week incubation at 25 degrees C, significantly higher biological activity of FGF-2 was observed for silk gut powder incorporating polyhedron encapsulated FGF-2 relative to silk gut powder with non-encapsulated FGF-2. Our results demonstrate that posterior silk glands incorporating polyhedron encapsulated FGF-2 are applicable to the preparation of biodegradable silk gut, which can protect and release FGF-2 that is produced in a virus- and serum-free expression system with significant application potential. PMID- 26053045 TI - Purified Human Synovium Mesenchymal Stem Cells as a Good Resource for Cartilage Regeneration. AB - Mesenchymal stem cells (MSCs) have the ability to differentiate into a variety of lineages and to renew themselves without malignant changes, and thus hold potential for many clinical applications. However, it has not been well characterized how different the properties of MSCs are depending on the tissue source in which they resided. We previously reported a novel technique for the prospective MSC isolation from bone marrow, and revealed that a combination of cell surface markers (LNGFR and THY-1) allows the isolation of highly enriched MSC populations. In this study, we isolated LNGFR(+) THY-1 (+) MSCs from synovium using flow cytometry. The results show that the synovium tissue contained a significantly larger percentage of LNGFR (+) THY-1 (+) MSCs. We examined the colony formation and differentiation abilities of bone marrow-derived MSCs (BM MSCs) and synovium-derived MSCs (SYN-MSCs) isolated from the same patients. Both types of MSCs exhibited a marked propensity to differentiate into specific lineages. BM-MSCs were preferentially differentiated into bone, while in the SYN MSC culture, enhanced adipogenic and chondrogenic differentiation was observed. These data suggest that the tissue from which MSCs are isolated should be tailored according to their intended clinical therapeutic application. PMID- 26053046 TI - Static Postural Stability in Women during and after Pregnancy: A Prospective Longitudinal Study. AB - This longitudinal study aimed to compare static postural stability in women between early pregnancy, advanced pregnancy, and at 2 and 6 months postpartum. Forty-five pregnant women were enrolled and 31 completed the protocol. Data were collected at 7-16 and 34-39 weeks gestation, and at 6-10 and 26-30 weeks postpartum. For each subject, the center of foot pressure path length and mean velocity (with directional subcomponents) were computed from 30-s long quiet standing trials on a stationary force plate with eyes open or closed. The body mass, stance width, and sleep duration within 24 h before testing were also recorded. Static postural stability was not different between pregnancy and postpartum, except for the anterior posterior sway tested in the eyes-closed condition, which was significantly increased in late pregnancy compared to that at 2 and 6 months postpartum. Pregnant/postpartum women's body mass weakly positively correlated with anterior-posterior sway in the eyes-closed condition and their stance width weakly positively correlated with the anterior-posterior sway in the eyes-open condition. No effect of sleep duration on postural sway was found. Our findings indicate that under visual deprivation conditions women in advanced pregnancy may have decreased static stability compared to their non pregnant state. PMID- 26053047 TI - Software-aided automatic laser optoporation and transfection of cells. AB - Optoporation, the permeabilization of a cell membrane by laser pulses, has emerged as a powerful non-invasive and highly efficient technique to induce transfection of cells. However, the usual tedious manual targeting of individual cells significantly limits the addressable cell number. To overcome this limitation, we present an experimental setup with custom-made software control, for computer-automated cell optoporation. The software evaluates the image contrast of cell contours, automatically designates cell locations for laser illumination, centres those locations in the laser focus, and executes the illumination. By software-controlled meandering of the sample stage, in principle all cells in a typical cell culture dish can be targeted without further user interaction. The automation allows for a significant increase in the number of treatable cells compared to a manual approach. For a laser illumination duration of 100 ms, 7-8 positions on different cells can be targeted every second inside the area of the microscope field of view. The experimental capabilities of the setup are illustrated in experiments with Chinese hamster ovary cells. Furthermore, the influence of laser power is discussed, with mention on post treatment cell survival and optoporation-efficiency rates. PMID- 26053048 TI - Production of a Highly Protease-Resistant Fungal alpha-Galactosidase in Transgenic Maize Seeds for Simplified Feed Processing. AB - Raffinose-family oligosaccharide (RFO) in soybeans is one of the major anti nutritional factors for poultry and livestocks. alpha-Galactosidase is commonly supplemented into the animal feed to hydrolyze alpha-1,6-galactosidic bonds on the RFOs. To simplify the feed processing, a protease-resistant alpha galactosidase encoding gene from Gibberella sp. strain F75, aga-F75, was modified by codon optimization and heterologously expressed in the embryos of transgentic maize driven by the embryo-specific promoter ZM-leg1A. The progenies were produced by backcrossing with the commercial inbred variety Zheng58. PCR, southern blot and western blot analysis confirmed the stable integration and tissue specific expression of the modified gene, aga-F75m, in seeds over four generations. The expression level of Aga-F75M reached up to 10,000 units per kilogram of maize seeds. In comparison with its counterpart produced in Pichia pastoris strain GS115, maize seed-derived Aga-F75M showed a lower temperature optimum (50 degrees C) and lower stability over alkaline pH range, but better thermal stability at 60 degrees C to 70 degrees C and resistance to feed pelleting inactivation (80 degrees C). This is the first report of producing alpha-galactosidase in transgenic plant. The study offers an effective and economic approach for direct utilization of alpha-galactosidase-producing maize without any purification or supplementation procedures in the feed processing. PMID- 26053049 TI - Langerhans Cells Facilitate UVB-Induced Epidermal Carcinogenesis. AB - UVB light is considered the major environmental inducer of human keratinocyte (KC) DNA mutations, including within the tumor-suppressor gene p53, and chronic exposure is associated with cutaneous squamous cell carcinoma formation. Langerhans cells (LCs) comprise a dendritic network within the suprabasilar epidermis, yet the role of LCs in UVB-induced carcinogenesis is largely unknown. Herein we show that LC-intact epidermis develops UVB-induced tumors more readily than LC-deficient epidermis. Although levels of epidermal cyclopyrimidine dimers following acute UVB exposure are equivalent in the presence or absence of LCs, chronic UVB-induced p53 mutant clonal islands expand more readily in association with LCs, which remain largely intact and are preferentially found in proximity to the expanding mutant KC populations. The observed LC facilitation of mutant p53 clonal expansion is completely alphabeta and gammadelta T-cell independent and is associated with increased intraepidermal expression of IL-22 and the presence of group 3 innate lymphoid cells. These data demonstrate that LCs have a key role in UVB-induced cutaneous carcinogenesis and suggest that LCs locally stimulate KC proliferation and innate immune cells that provoke tumor outgrowth. PMID- 26053050 TI - Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). AB - Drug survival reflects a drug's effectiveness, safety, and tolerability. We assessed the drug survival of biologics used to treat psoriasis in a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register (BADBIR)). The survival rates of the first course of biologics for 3,523 biologic-naive patients with chronic plaque psoriasis were compared using survival analysis techniques and predictors of discontinuation analyzed using a multivariate Cox proportional hazards model. Data for patients on adalimumab (n=1,879), etanercept (n=1,098), infliximab (n=96), and ustekinumab (n=450) were available. The overall survival rate in the first year was 77%, falling to 53% in the third year. Multivariate analysis showed that female gender (hazard ratio (HR) 1.22; 95% confidence interval (CI): 1.09-1.37), being a current smoker (HR 1.19; 95% CI: 1.03-1.38), and a higher baseline dermatology life quality index (HR 1.01; 95% CI: 1.00-1.02) were predictors of discontinuation. Presence of psoriatic arthritis (HR 0.82; 95% CI: 0.71-0.96) was a predictor for drug survival. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16 2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37-0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival. The results of this study will aid clinical decision making when choosing biologic therapy for psoriasis patients. PMID- 26053051 TI - Receptor Activator of NF-kappaB Ligand Promotes the Production of CCL17 from RANK+ M2 Macrophages. PMID- 26053052 TI - Effect of Testosterone on Neuronal Morphology and Neuritic Growth of Fetal Lamb Hypothalamus-Preoptic Area and Cerebral Cortex in Primary Culture. AB - Testosterone plays an essential role in sexual differentiation of the male sheep brain. The ovine sexually dimorphic nucleus (oSDN), is 2 to 3 times larger in males than in females, and this sex difference is under the control of testosterone. The effect of testosterone on oSDN volume may result from enhanced expansion of soma areas and/or dendritic fields. To test this hypothesis, cells derived from the hypothalamus-preoptic area (HPOA) and cerebral cortex (CTX) of lamb fetuses were grown in primary culture to examine the direct morphological effects of testosterone on these cellular components. We found that within two days of plating, neurons derived from both the HPOA and CTX extend neuritic processes and express androgen receptors and aromatase immunoreactivity. Both treated and control neurites continue to grow and branch with increasing time in culture. Treatment with testosterone (10 nM) for 3 days significantly (P < 0.05) increased both total neurite outgrowth (35%) and soma size (8%) in the HPOA and outgrowth (21%) and number of branch points (33%) in the CTX. These findings indicate that testosterone-induced somal enlargement and neurite outgrowth in fetal lamb neurons may contribute to the development of a fully masculine sheep brain. PMID- 26053053 TI - Meditative Movement Therapies and Health-Related Quality-of-Life in Adults: A Systematic Review of Meta-Analyses. AB - Poor health-related quality-of-life (HRQOL) is a significant public health issue while the use of meditative movement therapies has been increasing. The purpose of this investigation was to carry out a systematic review of previous meta analyses that examined the effects of meditative movement therapies (yoga, tai chi and qigong) on HRQOL in adults. Previous meta-analyses of randomized controlled trials published up through February, 2014 were included by searching nine electronic databases and cross-referencing. Dual-selection and data abstraction occurred. The Assessment of Multiple Systematic Reviews Instrument (AMSTAR) was used to assess methodological quality. Standardized mean differences that were pooled using random-effects models were included. In addition, 95% prediction intervals were calculated as well as the number needed-to-treat and percentile improvements. Of the 510 citations screened, 10 meta-analyses representing a median of 3 standardized mean differences in 82 to 528 participants (median = 270) with breast cancer, schizophrenia, low back pain, heart failure and diabetes, were included. Median methodological quality was 70%. Median length, frequency and duration of the meditative movement therapies were 12 weeks, 3 times per week, for 71 minutes per session. The majority of results (78.9%) favored statistically significant improvements (non-overlapping 95% confidence intervals) in HRQOL, with standardized mean differences ranging from 0.18 to 2.28. More than half of the results yielded statistically significant heterogeneity (Q <= 0.10) and large or very large inconsistency (I2 >= 50%). All 95% prediction intervals included zero. The number-needed-to-treat ranged from 2 to 10 while percentile improvements ranged from 9.9 to 48.9. The results of this study suggest that meditative movement therapies may improve HRQOL in adults with selected conditions. However, a need exists for a large, more inclusive meta analysis (PROSPERO Registration #CRD42014014576). PMID- 26053054 TI - 13C SPE MAS measurement of ligand concentration in compressible chromatographic beads. AB - A method for measuring the ligand concentration in heterogeneous materials like chromatography media is described. In this method, (13)C single pulse excitation magic angle spinning NMR experiment with broadband (1)H decoupling is used to determine the peak integrals for a butyl ligand in the spectrum of a dried chromatography medium. Within a carefully controlled protocol, those integrals compared with that of the internal reference compound dimethyl sulfone provide the required volume concentration with an accuracy of ca 2%. The effects of temperature, degree of hydration, and other experimental parameters are discussed. PMID- 26053056 TI - The ratio of oxidized and reduced forms of selected antioxidants as a possible marker of oxidative stress in humans. AB - Oxidative stress is an imbalance between reactive oxygen species exposure and the ability of organisms to detoxify the reactive intermediates and to repair the oxidative damage of biologically important molecules. Many clinical studies of oxidative stress unfortunately provide conflicting and contradictory results. The ability of antioxidant systems to adequately respond to oxidative stress can be used in laboratory diagnostics. In the present review, methods using the ratio of reduced and oxidized forms of uric acid, ascorbic acid, glutathione and coenzyme Q10 as suitable indicators of oxidative stress are discussed. From the mentioned publications it is evident that suitable sample preparation prior to analysis is crucial. PMID- 26053055 TI - Load Dependency of Postural Control--Kinematic and Neuromuscular Changes in Response to over and under Load Conditions. AB - INTRODUCTION: Load variation is associated with changes in joint torque and compensatory reflex activation and thus, has a considerable impact on balance control. Previous studies dealing with over (OL) and under loading (UL) used water buoyancy or additional weight with the side effects of increased friction and inertia, resulting in substantially modified test paradigms. The purpose of this study was to identify gravity-induced load dependency of postural control in comparable experimental conditions and to determine the underlying neuromuscular mechanisms. METHODS: Balance performance was recorded under normal loading (NL, 1 g), UL (0.16 g 0.38 g) and OL (1.8 g) in monopedal stance. Center of pressure (COP) displacement and frequency distribution (low 0.15-0.5 Hz (LF), medium 0.5-2 Hz (MF), high 2-6 Hz (HF)) as well as ankle, knee and hip joint kinematics were assessed. Soleus spinal excitability was determined by H/M-recruitment curves (H/M-ratios). RESULTS: Compared to NL, OL caused an increase in ankle joint excursion, COP HF domain and H/M-ratio. Concomitantly, hip joint excursion and COP LF decreased. Compared to NL, UL caused modulations in the opposite direction: UL decreased ankle joint excursions, COP HF and H/M-ratio. Collaterally, hip joint excursion and COP LF increased. COP was augmented both in UL and in OL compared to NL. CONCLUSION: Subjects achieved postural stability in OL and UL with greater difficulty compared to NL. Reduced postural control was accompanied by modified balance strategies and compensatory reflex activation. With increasing load, a shift from hip to ankle strategy was observed. Accompanying, COP frequency distribution shifted from LF to HF and spinal excitability was enhanced. It is suggested that in OL, augmented ankle joint torques are compensated by quick reflex-induced postural reactions in distal muscles. Contrarily, UL is associated with diminished joint torques and thus, postural equilibrium may be controlled by the proximal segments to adjust the center of gravity above the base of support. PMID- 26053057 TI - Women's use of herbal and alternative medicines for preconception care. AB - BACKGROUND: Use of complementary and alternative medicine (CAM), particularly herbal and alternative medicine supplements, for preconception care and fertility management is becoming increasingly common. AIMS: To determine the factors associated with the use of CAMs by women for preconception care. MATERIALS AND METHODS: 412 women who had visited an antenatal 'first visit' clinic situated at a Brisbane obstetric hospital or had visited a private ultrasound clinic in the same city for the purposes of a routinely indicated ultrasound scan in the first trimester were recruited into the study. Data were collected via a cross sectional questionnaire. RESULTS: Complementary and alternative medicines (not including multivitamins) were used during preconception by 8.3% of women attending for obstetric care. Approximately half (55.8%) of women taking herbal and alternative medicines ceased these medications on discovery of their pregnancy, though fewer (17.4%) ceased taking multivitamin supplements. Baseline characteristics (age, education and income) are not significantly different between CAM users and those who did not take CAMs preconception. The results of statistical analyses showed that only visiting a practitioner to check for health (OR = 2.00; 95% CI: 1.33, 3.00) and trying to lose weight prior to pregnancy (OR = 1.53; 95% CI: 1.00, 2.36) were the key predictors for women using CAM during preconception. CONCLUSIONS: Women do consume CAMs to enhance preconception care to a certain extent, though CAM users remain in the minority. CAM users also tend to cease use once pregnant. PMID- 26053058 TI - Suppressed Release of Clarithromycin from Tablets by Crystalline Phase Transition of Metastable Polymorph Form I. AB - The pharmaceutical properties of clarithromycin (CAM) tablets containing the metastable form I of crystalline CAM were investigated. Although the dissolution rate of form I was higher than that of stable form II, the release of CAM from form I tablet was delayed. Disintegration test and liquid penetration test showed that the disintegration of the tablet delayed because of the slow penetration of an external solution into form I tablet. Investigation by scanning electron microscopy revealed that the surface of form I tablet was covered with fine needle-shaped crystals following an exposure to the external solution. These crystals were identified as form IV crystals by powder X-ray diffraction. The phenomenon that CAM releases from tablet was inhibited by fine crystals spontaneously formed on the tablet surface could be applied to the design of sustained-release formulation systems with high CAM contents by minimizing the amount of functional excipients. PMID- 26053059 TI - Dynamics and yielding of binary self-suspended nanoparticle fluids. AB - Yielding and flow transitions in bi-disperse suspensions of particles are studied using a model system comprised of self-suspended spherical nanoparticles. An important feature of the materials is that the nanoparticles are uniformly dispersed in the absence of a solvent. Addition of larger particles to a suspension of smaller ones is found to soften the suspensions, and in the limit of large size disparities, completely fluidizes the material. We show that these behaviors coincide with a speeding-up of de-correlation dynamics of all particles in the suspensions and are accompanied by a reduction in the energy dissipated at the yielding transition. We discuss our findings in terms of ligand-mediated jamming and un-jamming of hairy particle suspensions. PMID- 26053060 TI - Mentoring ethnic minority counseling and clinical psychology students: A multicultural, ecological, and relational model. AB - The aim of the current study was to understand the role of race and culture in successful mentoring relationships in graduate school. We examined the practices of 9 faculty mentors working with 15 ethnic minority doctoral students in counseling and clinical psychology. Grounded theory was used to discern unifying patterns and to formulate a theory of multicultural mentoring. Five overall themes significant to multicultural mentoring emerged: (a) career support and guidance tailored for ethnic minorities, (b) relationality between mentors and proteges, (c) significance of contexts, (d) interconnections across contexts, and (e) multidirectionality of interactions between contexts. The 5 themes combined to form a multicultural, ecological, and relational model of mentoring. Our findings suggest that mentoring ethnic minority students can be successful, productive, and satisfying for both mentors and proteges when mentors possess the necessary skills, time, commitment, and multicultural competencies. Implications for doctoral programs in counseling and clinical psychology are discussed, along with recommendations for future research directions. PMID- 26053061 TI - The relationship of perceived campus culture to mental health help-seeking intentions. AB - Despite mental health issues being widespread on college campuses, the majority of college students do not seek help. Prior research suggests several individual factors that may be related to mental health help-seeking including age, gender, and prior treatment experience. However, there has been little work considering the broader role of the college environment on person-level predictors of mental health help-seeking, specifically the relationship with perceived campus culture. Thus, informed by the theory of planned behavior (Ajzen, 1991), the purpose of this study was to examine the relationship between perceived campus cultural perspectives on different personal processes, such as attitudes toward treatment, stigma, and treatment barriers that are believed to relate to mental health help seeking intentions. Participants were 212 undergraduate students from a large university in the southeastern United States. As hypothesized, we found a significant mediation relationship for personal attitudes in the relationship between perceived campus attitudes and help-seeking intentions. In contrast, analyses did not support mediation relationships for personal barriers or personal stigma. These findings suggest that perceived campus culture may serve an important role in personal mental health treatment beliefs. Campus mental health policies and prevention programming may consider targeting perceived campus culture as an important means for increasing personal positive beliefs toward mental health treatment. (PsycINFO Database Record PMID- 26053063 TI - What Difference Does Patient and Public Involvement Make and What Are Its Pathways to Impact? Qualitative Study of Patients and Researchers from a Cohort of Randomised Clinical Trials. AB - BACKGROUND: Patient and public involvement (PPI) is advocated in clinical trials yet evidence on how to optimise its impact is limited. We explored researchers' and PPI contributors' accounts of the impact of PPI within trials and factors likely to influence its impact. METHODS: Semi-structured qualitative interviews with researchers and PPI contributors accessed through a cohort of randomised clinical trials. Analysis of transcripts of audio-recorded interviews was informed by the principles of the constant comparative method, elements of content analysis and informant triangulation. RESULTS: We interviewed 21 chief investigators, 10 trial managers and 17 PPI contributors from 28 trials. The accounts of informants within the same trials were largely in agreement. Over half the informants indicted PPI had made a difference within a trial, through contributions that influenced either an aspect of a trial, or how researchers thought about a trial. According to informants, the opportunity for PPI to make a difference was influenced by two main factors: whether chief investigators had goals and plans for PPI and the quality of the relationship between the research team and the PPI contributors. Early involvement of PPI contributors and including them in responsive (e.g. advisory groups) and managerial (e.g. trial management groups) roles were more likely to achieve impact compared to late involvement and oversight roles (e.g. trial steering committees). CONCLUSION: Those seeking to enhance PPI in trials should develop goals for PPI at an early stage that fits the needs of the trial, plan PPI implementation in accordance with these goals, invest in developing good relationships between PPI contributors and researchers, and favour responsive and managerial roles for contributors in preference to oversight-only roles. These features could be used by research funders in judging PPI in trial grant applications and to inform policies to optimise PPI within trials. PMID- 26053062 TI - Variation in Gamma-Globin Expression before and after Induction with Hydroxyurea Associated with BCL11A, KLF1 and TAL1. AB - The molecular mechanisms governing gamma-globin expression in a subset of fetal hemoglobin (alpha2gamma2: HbF) expressing red blood cells (F-cells) and the mechanisms underlying the variability of response to hydroxyurea induced gamma globin expression in the treatment of sickle cell disease are not completely understood. Here we analyzed intra-person clonal populations of basophilic erythroblasts (baso-Es) derived from bone marrow common myeloid progenitors in serum free cultures and report the level of fetal hemoglobin production in F cells negatively correlates with expression of BCL11A, KLF1 and TAL1. We then examined the effects of hydroxyurea on these three transcription factors and conclude that a successful induction of gamma-globin includes a reduction in BCL11A, KLF1 and TAL1 expression. These data suggests that expression changes in this transcription factor network modulate gamma-globin expression in F-cells during steady state erythropoiesis and after induction with hydroxyurea. PMID- 26053065 TI - Role of EGFR expression levels in the regulation of integrin function by EGF. AB - Activation of beta1 integrins in dormant tumor cells has been linked to metastatic progression, suggesting that therapies designed to maintain beta1 integrins in an inactive state may be useful in the prevention of metastatic disease. Our earlier studies have demonstrated that EGF regulates the activation state of the alpha5beta1 integrin in EGFR overexpressing tumor cells through an ERK/p90RSK signaling pathway. Activation of this pathway by EGF resulted in the filamin A dependent inactivation of the alpha5beta1 integrin receptor for fibronectin. The current study was designed to address the role of EGFR overexpression in the regulation of alpha5beta1 integrin activation state by EGF. Lentiviral knockdown of EGFR coupled with limited dilution cloning was used to develop A431 squamous carcinoma cell lines expressing high, moderate, and low levels of EGFR. Inactivation of alpha5beta1 integrin by EGF was shown to correlate with both the level of EGFR expression and the extent of p90RSK phosphorylation, but not with the level of ERK phosphorylation, suggesting that high levels of EGFR promote alpha5beta1 integrin inactivation through sustained activation of p90RSK. Treatment of cells with EGFR kinase inhibitor resulted in a reactivation of the integrin which could be reversed with the phosphatase inhibitor, menadione. Taken together, these findings indicate that p90RSK may function to maintain dormancy in tumor cells expressing high levels of EGFR. (c) 2015 Wiley Periodicals, Inc. PMID- 26053066 TI - Metal-Organic Nanotube with Helical and Propeller-Chiral Motifs Composed of a C10 Symmetric Double-Decker Nanoring. AB - Coassembly of an achiral ferrocene-cored tetratopic pyridyl ligand (FcL) with AgBF4 in CH2Cl2/MeCN (7:3 v/v) containing chiral Bu4N(+) (+)- or (-) menthylsulfate (MS*(-)) results in the formation of an "optically active" metal organic nanotube (FcNT) composed of a C10-symmetric double-decker nanoring featuring 10 FcL units and 20 Ag(+) ions. The circular dichroism spectrum of FcNT along with its 2D X-ray diffraction (2D XRD) pattern indicates that the constituent metal-organic nanorings in FcNT stack one-handed helically on top of each other. A crystal structure of the dimeric double-decker model complex (Ag2(FcL')2) from a ditopic ferrocene ligand (FcL') and AgBF4 allowed for confirming the binding of MS*(-) onto the Ag(+) center of the complex. The results of detailed spectroscopic studies indicate that in its double-decker aromatic arrays, FcNT possibly possesses propeller-chiral twists in addition to the helically chiral structure, where the former is considerably more dynamic than the latter. Notably, both chiral structural motifs responded nonlinearly to an enantiomeric excess of MS*(-) (majority rule) though with no stereochemical influence on one another. PMID- 26053064 TI - TpUB05, a Homologue of the Immunodominant Plasmodium falciparum Protein UB05, Is a Marker of Protective Immune Responses in Cattle Experimentally Vaccinated against East Coast Fever. AB - INTRODUCTION: East Coast fever, a devastating disease of cattle, can be controlled partially by vaccination with live T. parva sporozoites. The antigens responsible for conferring immunity are not fully characterized. Recently it was shown that the P. falciparum immunodominant protein UB05 is highly conserved in T. parva, the causative agent of East Coast fever. The aim of the present investigation was to determine the role of the homologue TpUB05 in protective immunity to East Coast fever. METHODS: The cloning, sequencing and expression of TpUB05 were done according to standard protocols. Bioinformatics analysis of TpUB05 gene was carried out using algorithms found in the public domain. Polyclonal antiserum against recombinant TpUB05 were raised in rabbits and used for further analysis by Western blotting, ELISA, immunolocalization and in vitro infection neutralization assay. The ability of recombinant TpUB05 (r-TpUB05) to stimulate bovine PBMCs ex-vivo to produce IFN-gamma or to proliferate was tested using ELISpot and [3H]-thymidine incorporation assays, respectively. RESULTS: All the 20 cattle immunised by the infection and treatment method (ITM) developed significantly higher levels of TpUB05 specific antibodies (p<0.0001) compared to the non-vaccinated ones. Similarly, r-TpUB05 highly stimulated bovine PMBCs from 8/12 (67%) of ITM-immunized cattle tested to produce IFN-gamma and proliferate (p< 0.029) as compared to the 04 naive cattle included as controls. Polyclonal TpUB05 antiserum raised against r-TpUB05 also marginally inhibited infection (p < 0.046) of bovine PBMCs by T. parva sporozoites. In further experiments RT-PCR showed that the TpUB05 gene is expressed by the parasite. This was confirmed by immunolocalization studies which revealed TpUB05 expression by schizonts and piroplasms. Bioinformatics analysis also revealed that this antigen possesses two transmembrane domains, a N-glycosylation site and several O-glycosylation sites. CONCLUSION: It was concluded that TpUB05 is a potential marker of protective immunity in ECF worth investigating further. PMID- 26053067 TI - Increased Thymic Cell Turnover under Boron Stress May Bypass TLR3/4 Pathway in African Ostrich. AB - Previous studies revealed that thymus is a targeted immune organ in malnutrition, and high-boron stress is harmful for immune organs. African ostrich is the living fossil of ancient birds and the food animals in modern life. There is no report about the effect of boron intake on thymus of ostrich. The purpose of present study was to evaluate the effect of excessive boron stress on ostrich thymus and the potential role of TLR3/4 signals in this process. Histological analysis demonstrated that long-term boron stress (640 mg/L for 90 days) did not disrupt ostrich thymic structure during postnatal development. However, the numbers of apoptotic cells showed an increased tendency, and the expression of autophagy and proliferation markers increased significantly in ostrich thymus after boron treatment. Next, we examined the expression of TLR3 and TLR4 with their downstream molecular in thymus under boron stress. Since ostrich genome was not available when we started the research, we first cloned ostrich TLR3 TLR4 cDNA from thymus. Ostrich TLR4 was close to white-throated Tinamou. Whole avian TLR4 codons were under purify selection during evolution, whereas 80 codons were under positive selection. TLR3 and TLR4 were expressed in ostrich thymus and bursa of fabricius as was revealed by quantitative real-time PCR (qRT-PCR). TLR4 expression increased with age but significantly decreased after boron treatment, whereas TLR3 expression showed the similar tendency. Their downstream molecular factors (IRF1, JNK, ERK, p38, IL-6 and IFN) did not change significantly in thymus, except that p100 was significantly increased under boron stress when analyzed by qRT-PCR or western blot. Taken together, these results suggest that ostrich thymus developed resistance against long-term excessive boron stress, possibly by accelerating intrathymic cell death and proliferation, which may bypass the TLR3/4 pathway. In addition, attenuated TLRs activity may explain the reduced inflammatory response to pathogens under boron stress. PMID- 26053069 TI - Comparative Transcriptome Analysis Reveals the Influence of Abscisic Acid on the Metabolism of Pigments, Ascorbic Acid and Folic Acid during Strawberry Fruit Ripening. AB - A comprehensive investigation of abscisic acid (ABA) biosynthesis and its influence on other important phytochemicals is critical for understanding the versatile roles that ABA plays during strawberry fruit ripening. Using RNA-seq technology, we sampled strawberry fruit in response to ABA or nordihydroguaiaretic acid (NDGA; an ABA biosynthesis blocker) treatment during ripening and assessed the expression changes of genes involved in the metabolism of pigments, ascorbic acid (AsA) and folic acid in the receptacles. The transcriptome analysis identified a lot of genes differentially expressed in response to ABA or NDGA treatment. In particular, genes in the anthocyanin biosynthesis pathway were actively regulated by ABA, with the exception of the gene encoding cinnamate 4-hydroxylase. Chlorophyll degradation was accelerated by ABA mainly owing to the higher expression of gene encoding pheide a oxygenase. The decrease of beta-carotene content was accelerated by ABA treatment and delayed by NDGA. A high negative correlation rate was found between ABA and beta carotene content, indicating the importance of the requirement for ABA synthesis during fruit ripening. In addition, evaluation on the folate biosynthetic pathway indicate that ABA might have minor function in this nutrient's biosynthesis process, however, it might be involved in its homeostasis. Surprisingly, though AsA content accumulated during fruit ripening, expressions of genes involved in its biosynthesis in the receptacles were significantly lower in ABA-treated fruits. This transcriptome analysis expands our understanding of ABA's role in phytochemical metabolism during strawberry fruit ripening and the regulatory mechanisms of ABA on these pathways were discussed. Our study provides a wealth of genetic information in the metabolism pathways and may be helpful for molecular manipulation in the future. PMID- 26053068 TI - Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model. AB - INTRODUCTION: Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer's oxidative phosphorylation system. METHODS: Xenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2)]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content). RESULTS: Ketogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention. CONCLUSIONS: Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose that a ketogenic diet and/or calorie restriction should be further evaluated as a possible adjuvant therapy for patients undergoing treatment for neuroblastoma. PMID- 26053070 TI - Diagnostically challenging case of low-fat spindle cell lipoma. PMID- 26053071 TI - Incidence, Remission and Mortality of Convulsive Epilepsy in Rural Northeast South Africa. AB - BACKGROUND: Epilepsy is one of the most common neurological conditions globally, estimated to constitute 0.75% of the global burden of disease, with the majority of this burden found in low- and middle- income countries (LMICs). Few studies from LMICs, including much of sub-Saharan Africa, have described the incidence, remission or mortality rates due to epilepsy, which are needed to quantify the burden and inform policy. This study investigates the epidemiological parameters of convulsive epilepsy within a context of high HIV prevalence and an emerging burden of cardiovascular disease. METHODS: A cross-sectional population survey of 82,818 individuals, in the Agincourt Health and Socio-demographic Surveillance Site (HDSS) in rural northeast South Africa was conducted in 2008, from which 296 people were identified with active convulsive epilepsy. A follow-up survey was conducted in 2012. Incidence and mortality rates were estimated, with duration and remission rates calculated using the DISMOD II software package. RESULTS: The crude incidence for convulsive epilepsy was 17.4/100,000 per year (95%CI: 13.1 23.0). Remission was 4.6% and 3.9% per year for males and females, respectively. The standardized mortality ratio was 2.6 (95%CI: 1.7-3.5), with 33.3% of deaths directly related to epilepsy. Mortality was higher in men than women (adjusted rate ratio (aRR) 2.6 (95%CI: 1.2-5.4)), and was significantly associated with older ages (50+ years versus those 0-5 years old (RR 4.8 (95%CI: 0.6-36.4)). CONCLUSIONS: The crude incidence was lower whilst mortality rates were similar to other African studies; however, this study found higher mortality amongst older males. Efforts aimed at further understanding what causes epilepsy in older people and developing interventions to reduce prolonged seizures are likely to reduce the overall burden of ACE in rural South Africa. PMID- 26053073 TI - Orthostatic Changes in Hemodynamics and Cardiovascular Biomarkers in Dysautonomic Patients. AB - BACKGROUND: Impaired autonomic control of postural homeostasis results in orthostatic intolerance. However, the role of neurohormones in orthostatic intolerance has not been explained. METHODS: Six-hundred-and-seventy-one patients (299 males; 55 +/- 22 years) with unexplained syncope underwent head-up tilt (HUT) with serial blood sampling. Systolic blood pressure (SBP) and heart rate (HR) supine, after 3 min, and lowest BP/highest HR during HUT were recorded. Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine vasopressin (CT-proAVP), C-terminal- endothelin-1 (CT-proET-1), and mid-regional fragment of pro-atrial-natriuretic-peptide (MR-proANP) were determined at supine and 3 min of HUT. Multivariate-adjusted logistic regression model was applied to compare 1st (reference) with 4th quartile of 3 min and maximal DeltaSBP/DeltaHR (i.e. pronounced hypotension or tachycardia) vs. changes in neuroendocrine biomarkers, respectively. RESULTS: Higher resting CT-proET-1 predicted BP fall at 3 min (Odds ratio (OR) per 1 SD: 1.62, 95%CI 1.18-2.22; p = 0.003), and max BP fall during HUT (1.82, 1.28-2.61; p = 0.001). Higher resting CT-proAVP predicted BP fall at 3 min (1.33, 1.03-1.73; p = 0.03), which was also associated with increase in CT-proAVP (1.86, 1.38-2.51; p = 0.00005) and epinephrine (1.47, 1.12 1.92; p = 0.05) during HUT. Lower resting MR-proANP predicted tachycardia at 3 min (0.37, 0.24-0.59; p = 0.00003), and max tachycardia during HUT (0.47, 0.29 0.77; p = 0.002). Further, tachycardia during HUT was associated with increase in epinephrine (1.60, 1.15-2.21; p = 0.005), and norepinephrine (1.87, 1.38-2.53; p = 0.005). CONCLUSIONS: Resting CT-proET-1 and CT-proAVP are increased in orthostatic hypotension, while resting MR-proANP is decreased in postural tachycardia. Moreover, early BP fall during orthostasis evokes increase in CT proAVP and epinephrine, while postural tachycardia is associated with increase in norepinephrine and epinephrine. PMID- 26053072 TI - Oral delivery of Acid Alpha Glucosidase epitopes expressed in plant chloroplasts suppresses antibody formation in treatment of Pompe mice. AB - Deficiency of acid alpha glucosidase (GAA) causes Pompe disease in which the patients systemically accumulate lysosomal glycogen in muscles and nervous systems, often resulting in infant mortality. Although enzyme replacement therapy (ERT) is effective in treating patients with Pompe disease, formation of antibodies against rhGAA complicates treatment. In this report, we investigated induction of tolerance by oral administration of GAA expressed in chloroplasts. Because full-length GAA could not be expressed, N-terminal 410-amino acids of GAA (as determined by T-cell epitope mapping) were fused with the transmucosal carrier CTB. Tobacco transplastomic lines expressing CTB-GAA were generated through site-specific integration of transgenes into the chloroplast genome. Homoplasmic lines were confirmed by Southern blot analysis. Despite low-level expression of CTB-GAA in chloroplasts, yellow or albino phenotype of transplastomic lines was observed due to binding of GAA to a chloroplast protein that has homology to mannose-6 phosphate receptor. Oral administration of the plant-made CTB-GAA fusion protein even at 330-fold lower dose (1.5 MUg) significantly suppressed immunoglobulin formation against GAA in Pompe mice injected with 500 MUg rhGAA per dose, with several-fold lower titre of GAA specific IgG1 and IgG2a. Lyophilization increased CTB-GAA concentration by 30 fold (up to 190 MUg per g of freeze-dried leaf material), facilitating long-term storage at room temperature and higher dosage in future investigations. This study provides the first evidence that oral delivery of plant cells is effective in reducing antibody responses in ERT for lysosomal storage disorders facilitating further advances in clinical investigations using plant cell culture system or in vitro propagation. PMID- 26053074 TI - Far-field subwavelength imaging with near-field resonant metalens scanning at microwave frequencies. AB - A method for far-field subwavelength imaging at microwave frequencies using near field resonant metalens scanning is proposed. The resonant metalens is composed of switchable split-ring resonators (SRRs). The on-SRR has a strong magnetic coupling ability and can convert evanescent waves into propagating waves using the localized resonant modes. In contrast, the off-SRR cannot achieve an effective conversion. By changing the switch status of each cell, we can obtain position information regarding the subwavelength source targets from the far field. Because the spatial response and Green's function do not need to be measured and evaluated and only a narrow frequency band is required for the entire imaging process, this method is convenient and adaptable to various environment. This method can be used for many applications, such as subwavelength imaging, detection, and electromagnetic monitoring, in both free space and complex environments. PMID- 26053075 TI - Electronic Cigarette Topography in the Natural Environment. AB - This paper presents the results of a clinical, observational, descriptive study to quantify the use patterns of electronic cigarette users in their natural environment. Previously published work regarding puff topography has been widely indirect in nature, and qualitative rather than quantitative, with the exception of three studies conducted in a laboratory environment for limited amounts of time. The current study quantifies the variation in puffing behaviors among users as well as the variation for a given user throughout the course of a day. Puff topography characteristics computed for each puffing session by each subject include the number of subject puffs per puffing session, the mean puff duration per session, the mean puff flow rate per session, the mean puff volume per session, and the cumulative puff volume per session. The same puff topography characteristics are computed across all puffing sessions by each single subject and across all subjects in the study cohort. Results indicate significant inter subject variability with regard to puffing topography, suggesting that a range of representative puffing topography patterns should be used to drive machine-puffed electronic cigarette aerosol evaluation systems. PMID- 26053076 TI - Interprofessional Collaboration: What Makes This Real? PMID- 26053077 TI - Chemical Dependency and Nursing Students: A Complicated Process Calling for Nurse Educator Involvement. AB - Chemical use and dependency is a prevalent problem in society and among the members of the nursing profession. Nursing students, as the novice representatives of the profession, may be particularly vulnerable to chemical use. Nursing leaders in both educational institutions and practice settings must recognize highly vulnerable individuals, which nursing activities are most vulnerable, and interventions to assist and support the vulnerable individual while assuring a safe practice environment. As nurses, it is our responsibility, both ethically and legally, to provide a safe working environment not only for our patients but also for ourselves by reporting the behaviors of nurses who may be impaired through the proper channels according to your state's Nurse Practice Act. Through a united approach, nurse leaders from both the academic and practice environments should provide a safe and effective rehabilitation approach. PMID- 26053078 TI - The Effect of Self-Efficacy on Treatment. AB - Becker's (1974) Health Belief Model has been used successfully to address behavior change in chronic diseases, including smoking and alcohol dependence. This project applies the Health Belief Model to opiate addiction treatment, specifically medication-assisted treatment (MAT). The purpose of this study was to measure the relationship between self-efficacy and treatment outcomes for opiate-dependent clients on MAT. A convenience sample of 50 persons with addiction to opiates was admitted to an outpatient substance abuse treatment program for MAT and followed for a period of 6 months. Pretreatment and posttreatment self-efficacy scores were obtained using a modified General Self Efficacy Scale (GSE). Treatment outcomes were measured by the number of negative random monthly urine screens, attendance at group and individual counseling sessions, and retention in treatment for at least 6 months. Pretreatment and posttreatment self-efficacy scores were compared using a t test, and self efficacy scores were compared with client outcomes using Pearson's correlation. GSE scores showed improvement after 6 months in treatment (p <= .01). However, no statistically significant relationship was found between GSE scores and treatment outcomes. PMID- 26053079 TI - Alcohol Misuse Among Nursing Students. AB - BACKGROUND: The self-reported prevalence of alcohol use among U.S. college students decreased from 90.5% in 1980 to 79.2% in 2012. National efforts exist to reduce alcohol misuse among college students in the United States, yet little research addresses substance abuse among nursing students and even less addresses alcohol misuse. Alcohol misuse in nursing students may result in patient harm. PURPOSE: This scoping study describes the state of the science of alcohol misuse among nursing students, guided by the research question: "What is the current state of alcohol misuse among U.S. nursing students?" METHODS: Evidence was drawn from several scholarly sources. Articles were included if they addressed U.S. nursing students; alcohol misuse; substance abuse or chemical impairment; prevalence rates; and/or characteristics including nursing student behaviors, attitudes, and beliefs. Using thematic analysis, common themes were extracted, followed by hand coding those themes and using NVivo qualitative software. RESULTS: Six studies met inclusion criteria. Three themes, eight subthemes, and several gaps in knowledge were identified. The themes include "high prevalence exists," "necessity of supportive environments," and "hopelessness without policies." Subthemes include "root cause," "vulnerable population," "scholarship and substance use," "education," "identification of risk factors," "prevention and deterrents," "safety," "ethical and legal issues," and "consequences." CONCLUSIONS: On the basis of this analysis, several research questions were developed to explore alcohol misuse in this population. Alcohol was the most often used substance. Nursing students were unaware of a safe level of consumption and the potential negative health-related and professional effects associated with alcohol misuse. PMID- 26053080 TI - Mobile Phone Overuse Among Elementary School Students in Korea: Factors Associated With Mobile Phone Use as a Behavior Addiction. AB - This research was conducted to examine the relationships among mobile phone use, anxiety, and parental attitudes toward child-rearing in a convenience sample of 351 Grade 6 elementary school students. There were 157 boys and 194 girls. A mobile phone overuse questionnaire, the State-Trait Anxiety Inventory, and the Parental Attitude Inventory were used for data collection. The data were analyzed by the t test, analysis of variance, hierarchical regression, and descriptive analysis using SPSS WIN 18.0. Mobile phone use was greater in girls than in boys, and the difference was statistically significant. Mobile phone use was positively correlated with anxiety, and it was negatively correlated with parental child raising attitudes. Mobile phone use in girls was mainly affected by anxiety, and in boys, it was significantly affected by the maternal child-raising attitude. This research provides basic data for parent education, school policy, and prevention programs about mobile phone overuse that support mental health improvement in the individual, family, and community. PMID- 26053081 TI - Statewide Survey of Healthcare Professionals: Management of Patients With Chronic Noncancer Pain. AB - BACKGROUND: Increased availability of prescription opioids has caused serious problems with misuse, abuse, and increased rates of morbidity and mortality. In response, Washington State enacted a law to regulate pain management and opioid prescribing practices. OBJECTIVES: The purpose of this research was to investigate healthcare professionals' practices for the care of individuals with chronic noncancer pain (CNP) who received opioid therapy before the enactment of the Washington State law. METHODS: This descriptive study used a tailored design survey protocol with a 23-item questionnaire and stratified random sample of 1618 Washington State healthcare professionals. Topic areas assessed included prescribing patterns; use of best practices; consultation access; and provider education, satisfaction, and competence in prescribing opioids. RESULTS: Only 41% of the respondents provided care for patients with CNP. Of these, nearly all (96%) managed patients with prescription opioids. Most reported "always" obtaining, evaluating, and documenting the patient's health history (86%); reviewing the patient's history for substance abuse (77.8%); and conducting ongoing interviews (57.3%). Sixty percent of the respondents self-rated being not at all, somewhat, or moderately competent to prescribe opioids. Only 8.5% reported being very or extremely satisfied working with patients with CNP. CONCLUSIONS: The enactment of Washington State's pain management law mandates all providers to adopt management and prescribing practices for patients with CNP receiving opioid medications. This study determined that these practices were not universally adopted before the law. Evaluation of the effect of this law is essential to determine if it can serve as a model for other states. PERSPECTIVE: In 2010, Washington State enacted legislation on the management of CNP. The purpose of this study was to assess clinical practice among health professionals providing care to patients with CNP before implementation of the law and to discuss the potential impact of the regulation. PMID- 26053082 TI - Growing Old With Ice: A Review of the Potential Consequences of Methamphetamine Abuse in Australian Older Adults. AB - This review analyzes contemporary literature in the context of Australian aging methamphetamine users, service response, and challenges to provision of care to this population. The article focuses on Australian literature with comparisons made with trends arising from international scholarship. Searches of the CINAHL, ProQuest, and Scopus electronic journal databases were performed in early 2014 as part of a wider study investigating dual diagnosis in older adults. Methamphetamine abuse is common in individuals with comorbid mental illness. The literature presented in this review outlines potential neuropsychological and persistent psychiatric sequelae associated with the use of methamphetamine, along with a number of concerning behaviors prevalent in individuals with comorbid human immunodeficiency virus-positive status. Despite an abundance of literature discussing methamphetamine use in adult populations, this is the first review exploring methamphetamine use in the context of aging and older adult mental health. Contemporary literature suggests that methamphetamine dependence will be a significant challenge for services that cater to older adults, requiring further research to fully assess the impact this cohort will have on the healthcare system. PMID- 26053083 TI - Psychotherapy in Addictions Treatment: A Process for Learning Skills. PMID- 26053084 TI - Workforce Development: Strengthening Professional Identity. PMID- 26053085 TI - A New Formulation of Buprenorphine/Naloxone. PMID- 26053086 TI - An Interview With Lisa Clark, MSN. PMID- 26053088 TI - Childhood Physical and Sexual Abuse History and Leukocyte Telomere Length among Women in Middle Adulthood. AB - OBJECTIVE: Abuse victimization in childhood is associated with a variety of age related cardiometabolic diseases, but the mechanisms remain unknown. Telomeres, which form the protective caps at the ends of chromosomes, have been proposed as measures of biological age, and a growing body of research suggests that telomere attrition may help to explain relationships between stress and cardiometabolic degradation. We examined the association between childhood abuse victimization and leukocyte telomere length among 1,135 participants in the Nurses' Health Study II (NHSII). METHODS: The NHSII ascertained physical and sexual child abuse histories in 2001. Telomere length was measured in genomic DNA extracted from peripheral blood leukocytes collected between 1996 and 1999. The ratio of telomere repeat copy number to a single gene copy number (T/S) was determined by a modified version of the quantitative real-time PCR telomere assay. Telomere length was log-transformed and corrected for assay variation across batch. We regressed telomere length on childhood abuse exposure variables and covariates using linear regression. RESULTS: We observed a reduction in telomere length associated with moderate physical abuse versus no physical abuse, but there was no evidence of a dose-response relationship for increased severity of physical abuse. No associations were noted for sexual abuse. CONCLUSIONS: We found no evidence of an association between severity of childhood physical or sexual abuse and leukocyte telomere length in the NHSII. PMID- 26053089 TI - Above- and below-ground effects of plant diversity depend on species origin: an experimental test with multiple invaders. AB - Although many plant communities are invaded by multiple nonnative species, we have limited information on how a species' origin affects ecosystem function. We tested how differences in species richness and origin affect productivity and seedling establishment. We created phylogenetically paired native and nonnative plant communities in a glasshouse experiment to test diversity-productivity relationships and responsible mechanisms (i.e. selection or complementarity effects). Additionally, we tested how productivity and associated mechanisms influenced seedling establishment. We used diversity-interaction models to describe how species' interactions influenced diversity-productivity relationships. Communities with more species had higher total biomass than did monoculture communities, but native and nonnative communities diverged in root : shoot ratios and the mechanism responsible for increased productivity: positive selection effect in nonnative communities and positive complementarity effect in native communities. Seedling establishment was 46% lower in nonnative than in native communities and was correlated with the average selection effect. Interspecific interactions contributed to productivity patterns, but the specific types of interactions differed between native and nonnative communities. These results reinforce findings that the diversity-productivity mechanisms in native and nonnative communities differ and are the first to show that these mechanisms can influence seedling establishment and that different types of interactions influence diversity-productivity relationships. PMID- 26053090 TI - Effects of androstenedione exposure on fathead minnow (Pimephales promelas) reproduction and embryonic development. AB - High concentrations (300 ng/L) of androstenedione (A4) were identified in snowmelt runoff from fields fertilized with manure from livestock feeding operations in Wisconsin, USA. In fishes, A4 is an active androgen and substrate for biosynthesis of functional androgens (e.g., testosterone and 11 ketotestosterone) and estrogens (e.g., estradiol-17beta). Thus, A4 has the potential to be a powerful endocrine disruptor. This hypothesis was tested by exposing reproductively mature fathead minnows to 0.0 ng/L, 4.5 ng/L, 74 ng/L, and 700 ng/L A4 for 26 d in a flow-through system. Various reproductive endpoints were measured including fecundity, fertilization success, secondary sexual characteristics, gonadosomatic index (GSI), and hepatic vitellogenin messenger RNA (mRNA) expression. In addition, fertilized embryos from the reproduction assay were used in an embryonic development assay to assess A4 effects on development and hatchability. In males, A4 significantly increased Vtg mRNA expression (estrogenic effect), significantly reduced GSI, and had no effect on tubercle expression (p = 0.067). In females, A4 induced tubercle development (androgenic effect) with no effects on GSI. Fecundity was not significantly impacted. Exposure to A4 had no effect on fertilization, embryonic development, or hatchability. These data indicate that exogenous A4, at environmentally relevant concentrations, can significantly modulate the reproductive physiology of the fathead minnows in a sex-specific manner and that A4 should be monitored as an endocrine disruptor. PMID- 26053091 TI - NDRG4 is a novel oncogenic protein and p53 associated regulator of apoptosis in malignant meningioma cells. AB - Aggressive meningiomas exhibit high levels of recurrence, morbidity and mortality. When surgical and radiation options are exhausted, there is need for novel molecularly-targeted therapies. We have recently identified NDRG4 overexpression in aggressive meningiomas. NDRG4 is a member of the N-Myc Downstream Regulated Gene (NDRG) family of the alpha/beta hydrolase superfamily. We have demonstrated that NDRG4 downregulation results in decreased cell proliferation, migration and invasion. In follow up to our prior studies; here we demonstrate that the predominant form of cell death following NDRG4 silencing is apoptosis, utilizing Annexin-V flow cytometry assay. We show that apoptosis caused by p53 upregulation, phosphorylation at Ser15, BAX activation, Bcl-2 and BcL-xL downregulation, mitochondrial cytochrome c release and execution of caspases following NDRG4 depletion. Sub-cellular distribution of BAX and cytochrome c indicated mitochondrial-mediated apoptosis. In addition, we carried out the fluorescence cytochemical analysis to confirm mitochondrial-mediated apoptosis by changes in mitochondrial membrane potential (Psim), using JC-1 dye. Immunoprecipitation and immunofluorescence confirmed binding of NDRG4 to p53. In addition, we demonstrate that apoptosis is mitochondrial and p53 dependent. The proapoptotic effect of p53 was verified by the results in which a small molecule compound PFT-alpha, an inhibitor of p53 phosphorylation, is greatly protected against targeting NDRG4 induced apoptosis. These findings bring novel insight to the roles of NDRG4 in meningioma progression. A better understanding of this pathway and its role in meningioma carcinogenesis and cell biology is promising for the development of novel therapeutic targets for the management of aggressive meningiomas. PMID- 26053092 TI - Targeted next generation sequencing of parotid gland cancer uncovers genetic heterogeneity. AB - Salivary gland cancer represents a heterogeneous group of malignant tumors. Due to their low incidence and the existence of multiple morphologically defined subtypes, these tumors are still poorly understood with regard to their molecular pathogenesis and therapeutically relevant genetic alterations.Performing a systematic and comprehensive study covering 13 subtypes of salivary gland cancer, next generation sequencing was done on 84 tissue samples of parotid gland cancer using multiplex PCR for enrichment of cancer related gene loci covering hotspots of 46 cancer genes.Mutations were identified in 22 different genes. The most frequent alterations affected TP53, followed by RAS genes, PIK3CA, SMAD4 and members of the ERB family. HRAS mutations accounted for more than 90% of RAS mutations, occurring especially in epithelial-myoepithelial carcinomas and salivary duct carcinomas. Additional mutations in PIK3CA also affected particularly epithelial-myoepithelial carcinomas and salivary duct carcinomas, occurring simultaneously with HRAS mutations in almost all cases, pointing to an unknown and therapeutically relevant molecular constellation. Interestingly, 14% of tumors revealed mutations in surface growth factor receptor genes including ALK, HER2, ERBB4, FGFR, cMET and RET, which might prove to be targetable by new therapeutic agents. 6% of tumors revealed mutations in SMAD4.In summary, our data provide novel insight into the fundamental molecular heterogeneity of salivary gland cancer, relevant in terms of tumor classification and the establishment of targeted therapeutic concepts. PMID- 26053093 TI - Mutant AKT1-E17K is oncogenic in lung epithelial cells. AB - The hotspot E17K mutation in the pleckstrin homology domain of AKT1 occurs in approximately 0.6-2% of human lung cancers. In this manuscript, we sought to determine whether this AKT1 variant is a bona-fide activating mutation and plays a role in the development of lung cancer. Here we report that in immortalized human bronchial epithelial cells (BEAS-2B cells) mutant AKT1-E17K promotes anchorage-dependent and -independent proliferation, increases the ability to migrate, invade as well as to survive and duplicate in stressful conditions, leading to the emergency of cells endowed with the capability to form aggressive tumours at high efficiency. We provide also evidence that the molecular mechanism whereby AKT1-E17K is oncogenic in lung epithelial cells involves phosphorylation and consequent cytoplasmic delocalization of the cyclin-dependent kinase (cdk) inhibitor p27. In agreement with these results, cytoplasmic p27 is preferentially observed in primary NSCLCs with activated AKT and predicts poor survival. PMID- 26053094 TI - Ataxia-telangiectasia mutated (ATM) silencing promotes neuroblastoma progression through a MYCN independent mechanism. AB - Neuroblastoma, a childhood cancer with highly heterogeneous biology and clinical behavior, is characterized by genomic aberrations including amplification of MYCN. Hemizygous deletion of chromosome 11q is a well-established, independent marker of poor prognosis. While 11q22-q23 is the most frequently deleted region, the neuroblastoma tumor suppressor in this region remains to be identified. Chromosome bands 11q22-q23 contain ATM, a cell cycle checkpoint kinase and tumor suppressor playing a pivotal role in the DNA damage response. Here, we report that haploinsufficiency of ATM in neuroblastoma correlates with lower ATM expression, event-free survival, and overall survival. ATM loss occurs in high stage neuroblastoma without MYCN amplification. In SK-N-SH, CLB-Ga and GI-ME-N human neuroblastoma cells, stable ATM silencing promotes neuroblastoma progression in soft agar assays, and in subcutaneous xenografts in nude mice. This effect is dependent on the extent of ATM silencing and does not appear to involve MYCN. Our findings identify ATM as a potential haploinsufficient neuroblastoma tumor suppressor, whose inactivation mirrors the increased aggressiveness associated with 11q deletion in neuroblastoma. PMID- 26053095 TI - PP2A inhibitors arrest G2/M transition through JNK/Sp1- dependent down-regulation of CDK1 and autophagy-dependent up-regulation of p21. AB - Protein phosphatase 2A (PP2A) plays an important role in the control of the cell cycle. We previously reported that the PP2A inhibitors, cantharidin and okadaic acid (OA), efficiently repressed the growth of cancer cells. In the present study, we found that PP2A inhibitors arrested the cell cycle at the G2 phase through a mechanism that was dependent on the JNK pathway. Microarrays further showed that PP2A inhibitors induced expression changes in multiple genes that participate in cell cycle transition. To verify whether these expression changes were executed in a PP2A-dependent manner, we targeted the PP2A catalytic subunit (PP2Ac) using siRNA and evaluated gene expression with a microarray. After the cross comparison of these microarray data, we identified that CDK1 was potentially the same target when treated with either PP2A inhibitors or PP2Ac siRNA. In addition, we found that the down-regulation of CDK1 occurred in a JNK dependent manner. Luciferase reporter gene assays demonstrated that repression of the transcription of CDK1 was executed through the JNK-dependent activation of the Sp1 transcription factor. By constructing deletion mutants of the CDK1 promoter and by using ChIP assays, we identified an element in the CDK1 promoter that responded to the JNK/Sp1 pathway after stimulation with PP2A inhibitors. Cantharidin and OA also up-regulated the expression of p21, an inhibitor of CDK1, via autophagy rather than PP2A/JNK pathway. Thus, this present study found that the PP2A/JNK/Sp1/CDK1 pathway and the autophagy/p21 pathway participated in G2/M cell cycle arrest triggered by PP2A inhibitors. PMID- 26053096 TI - Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me-induced apoptosis in breast cancer cells. AB - The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-C28-methyl ester (CDDO-Me) is considered a promising anti-tumorigenic compound. In this study, we show that treatment with CDDO-Me induces progressive endoplasmic reticulum (ER)-derived vacuolation in various breast cancer cells and ultimately kills these cells by inducing apoptosis. We found that CDDO-Me-induced increases in intracellular Ca2+ levels, reflecting influx from the extracellular milieu, make a critical contribution to ER-derived vacuolation and subsequent cell death. In parallel with increasing Ca2+ levels, CDDO-Me markedly increased the generation of reactive oxygen species (ROS). Interestingly, there exists a reciprocal positive-regulatory loop between Ca2+ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me. In addition, CDDO-Me rapidly reduced the protein levels of c-FLIPL (cellular FLICE-inhibitory protein) and overexpression of c-FLIPL blocked CDDO-Me-induced cell death, but not vacuolation. These results suggest that c-FLIPL downregulation is a key contributor to CDDO-Me-induced apoptotic cell death, independent of ER-derived vacuolation. Taken together, our results show that ER-derived vacuolation via Ca2+ influx and ROS generation as well as caspase activation via c-FLIPL downregulation are responsible for the potent anticancer effects of CDDO-Me on breast cancer cells. PMID- 26053097 TI - C/EBPalpha-p30 protein induces expression of the oncogenic long non-coding RNA UCA1 in acute myeloid leukemia. AB - Accumulating evidences indicate that different long non-coding RNAs (lncRNAs) might play a relevant role in tumorigenesis, with their expression and function already associated to cancer development and progression. CCAAT/enhancer-binding protein-alpha (CEBPA) is a critical regulator of myeloid differentiation whose inactivation contributes to the development of acute myeloid leukemia (AML). Mutations in C/EBPalpha occur in around 10% of AML cases, leading to the expression of a 30-kDa dominant negative isoform (C/EBPalpha-p30). In this study, we identified the oncogenic urothelial carcinoma associated 1 (UCA1) lncRNA as a novel target of the C/EBPalpha-p30. We show that wild-type C/EBPalpha and C/EBPalpha-p30 isoform can bind the UCA1 promoter but have opposite effects on UCA1 expression. While wild-type C/EBPalpha represses, C/EBPalpha-p30 can induce UCA1 transcription. Notably, we also show that UCA1 expression increases in cytogenetically normal AML cases carrying biallelic CEBPA mutations. Furthermore, we demonstrate that UCA1 sustains proliferation of AML cells by repressing the expression of the cell cycle regulator p27kip1. Thus, we identified, for the first time, an oncogenic lncRNA functioning in concert with the dominant negative isoform of C/EBPalpha in AML. PMID- 26053098 TI - Identification and characterization of the gene expression profiles for protein coding and non-coding RNAs of pancreatic ductal adenocarcinomas. AB - Significant advances have been achieved in recent years in the identification of the genetic and the molecular alterations of pancreatic ductal adenocarcinoma (PDAC). Despite this, at present the understanding of the precise mechanisms involved in the development and malignant transformation of PDAC remain relatively limited. Here, we evaluated for the first time, the molecular heterogeneity of PDAC tumors, through simultaneous assessment of the gene expression profile (GEP) for both coding and non-coding genes of tumor samples from 27 consecutive PDAC patients. Overall, we identified a common GEP for all PDAC tumors, characterized by an increased expression of genes involved in PDAC cell proliferation, local invasion and metastatic capacity, together with a significant alteration of the early steps of the cellular immune response. At the same time, we confirm and extend on previous observations about the genetic complexity of PDAC tumors as revealed by the demonstration of two clearly distinct and unique GEPs (e.g. epithelial-like vs. mesenchymal-like) reflecting the alteration of different signaling pathways involved in the oncogenesis and progression of these tumors. Our results also highlight the potential role of the immune system microenvironment in these tumors, with potential diagnostic and therapeutic implications. PMID- 26053099 TI - NF-kappaB, p38 MAPK, ERK1/2, mTOR, STAT3 and increased glycolysis regulate stability of paricalcitol/dexamethasone-generated tolerogenic dendritic cells in the inflammatory environment. AB - Tolerogenic dendritic cells (tDCs) may offer an intervention therapy in autoimmune diseases or transplantation. Stable immaturity and tolerogenic function of tDCs after encountering inflammatory environment are prerequisite for positive outcome of immunotherapy. However, the signaling pathways regulating their stable tolerogenic properties are largely unknown. In this study, we demonstrated that human monocyte-derived tDCs established by using paricalcitol (analogue of vitamin D2), dexamethasone and monophosphoryl lipid A exposed for 24h to LPS, cytokine cocktail, polyI:C or CD40L preserved reduced expression of co-stimulatory molecules, increased levels of inhibitory molecules ILT-3, PDL-1 and TIM-3, increased TLR-2, increased secretion of IL-10 and TGF-beta, reduced IL 12 and TNF-alpha secretion and reduced T cell stimulatory capacity. tDCs further induced IL-10-producing T regulatory cells that suppressed the proliferation of responder T cells. In the inflammatory environment, tDCs maintained up-regulated indoleamine 2, 3 dioxygenase but abrogated IkappaB-alpha phosphorylation and reduced transcriptional activity of p65/RelA, RelB and c-Rel NF-kappaB subunits except p50. Mechanistically, p38 MAPK, ERK1/2, mTOR, STAT3 and mTOR-dependent glycolysis regulated expression of ILT-3, PDL-1 and CD86, secretion of IL-10 and T cell stimulatory capacity of tDCs in the inflammatory environment. Stability of tDCs in the inflammatory environment is thus regulated by multiple signaling pathways. PMID- 26053101 TI - Efficiency Enhancement of Inverted Structure Perovskite Solar Cells via Oleamide Doping of PCBM Electron Transport Layer. AB - An amphiphilic surfactant, oleamide, was applied to dope the PCBM electron transport layer (ETL) of inverted structure perovskite solar cells (ISPSCs), resulting in a dramatic efficiency enhancement. Under the optimized oleamide doping ratio of 5.0 wt %, the power conversion efficiency of the CH3NH3PbIxCl(3 x) perovskite-based ISPSC device is enhanced from 10.05% to 12.69%, and this is primarily due to the increases of both fill factor and short-circuit current. According to the surface morphology study of the perovskite/PCBM bilayer film, oleamide doping improves the coverage of PCBM ETL onto the perovskite layer, and this is beneficial for the interfacial contact between the perovskite layer and the Ag cathode and consequently the electron transport from perovskite to the Ag cathode. Such an improved electron transport induced by oleamide doping is further evidenced by the impedance spectroscopic study, revealing the prohibited electron-hole recombination at the interface between the perovskite layer and the Ag cathode. PMID- 26053100 TI - Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice. AB - Skeletal muscle aging is associated with a progressive decline in muscle mass and strength, a process termed sarcopenia. Evidence suggests that accumulation of mitochondrial dysfunction plays a causal role in sarcopenia, which could be triggered by impaired mitophagy. Mitochondrial function, mitophagy and mitochondrial morphology are interconnected aspects of mitochondrial biology, and may coordinately be altered with aging. However, mitochondrial morphology has remained challenging to characterize in muscle, and whether sarcopenia is associated with abnormal mitochondrial morphology remains unknown. Therefore, we assessed the morphology of SubSarcolemmal (SS) and InterMyoFibrillar (IMF) mitochondria in skeletal muscle of young (8-12wk-old) and old (88-96wk-old) mice using a quantitative 2-dimensional transmission electron microscopy approach. We show that sarcopenia is associated with larger and less circular SS mitochondria. Likewise, aged IMF mitochondria were longer and more branched, suggesting increased fusion and/or decreased fission. Accordingly, although no difference in the content of proteins regulating mitochondrial dynamics (Mfn1, Mfn2, Opa1 and Drp1) was observed, a mitochondrial fusion index (Mfn2-to-Drp1 ratio) was significantly increased in aged muscles. Our results reveal that sarcopenia is associated with complex changes in mitochondrial morphology that could interfere with mitochondrial function and mitophagy, and thus contribute to aging-related accumulation of mitochondrial dysfunction and sarcopenia. PMID- 26053102 TI - Quantitative MRI in a non-surgical model of cervical spinal cord injury. AB - Quantitative T2 (qT2), diffusion tensor imaging (DTI), and histology were used to investigate a cervical model of spinal cord injury (SCI) in the rat. While quantitative MRI can significantly increase the specificity in the presence of pathology, it must be validated for each type of injury or disease. In the case of traumatic SCI most models are difficult to image, either due to the location of the injury, or as a result of damage to surrounding tissues resulting from invasive surgical procedures. In this study a non-surgical cervical model of SCI, produced using a combination of focused ultrasound and microbubbles, was used to produce pathology similar to that seen in models of contusive and compressive injuries. qT2 and DTI were performed at 24 h and 1 and 2 weeks following injury, and compared with H&E and luxol fast blue histology. In the injured spinal cord, in addition to intra/extracellular (I/E) water and myelin water in white matter, qT2 revealed a large component with very short T2 of about 3 ms, which was highly correlated with the presence of hemorrhage in both gray and white matter at 24 h, and with the presence of hemosiderin in gray matter at 2 weeks following injury. The T2 of the I/E water peak was also elevated at 24 h in both gray and white matter, which was correlated with the presence of vacuolation/edema on histology. Cystic cavities were only seen at the 1 or 2 week timepoints, and were correlated with the presence of a water peak with T2 > 250 ms. No significant changes in diffusivity parameters were observed. Pathologies were often co-occurring, with opposite effects on the average T2 in a given voxel, reducing the visibility of injured tissue on standard T2 -weighted MR images. PMID- 26053103 TI - Comparison of different types of cardiac amyloidosis by cardiac magnetic resonance imaging. AB - OBJECTIVES: We sought to determine cardiac morphological and functional differences between light-chain (AL), mutant-type transthyretin (ATTRmt) and wild type TTR (ATTRwt) amyloidosis using contrast-enhancement cardiac magnetic resonance imaging (CE-CMR). Finally, we attempted to establish the diagnostic and prognostic impact of these findings. INTRODUCTION: The most common forms of cardiac amyloid are AL and ATTR amyloidosis, but the clinical courses of these variants are quite heterogeneous. While CE-CMR is used to evaluate patients with cardiac amyloidosis, its ability to predict prognosis in these patients is debatable. METHODS: About 130 patients with cardiac amyloidosis (AL, n = 62; ATTRmt, n = 30, ATTRwt, n = 33) were assessed by CE-CMR (cardiac morphology, cardiac function, late gadolinium enhancement). RESULTS: Left ventricular (LV) mass, basal and mid-ventricular maximal wall thickness, and thickness of the inter-atrial septum were higher in ATTRwt when compared to AL and ATTRmt amyloidosis. Tricuspid annular excursion was lower in ATTRwt amyloidosis than in AL amyloidosis. CE was observed in 94.6% of the patients (AL 80.6%; ATTRmt 90%; ATTRwt 87.9%) with significant differences in quality and intensity between the groups. Differentiation of amyloid types was achieved by combination of age, number of organs, the presence of inferolateral CE-CMR, thickness of inter-atrial septum and troponin T. Overall 1-year-survival rates were 93.3, 93.9 and 70.5% in ATTRwt, ATTRmt and AL amyloidosis, respectively. LV mass, mitral annular excursion and NT-proBNP in AL amyloidosis, LV mass maximal apical wall thickness and troponin T in ATTRwt amyloidosis, and finally NT-proBNP and renal function in ATTRmt amyloidosis were independent predictors of outcome. CONCLUSIONS: This study demonstrates that CE-CMR can highlight morphological and functional differences between different types of cardiac amyloidosis. In addition, CE-CMR and cardiac biomarkers provide useful prognostic information in patients with cardiac amyloidosis. PMID- 26053104 TI - Hepatocyte growth factor measurement in AL amyloidosis. AB - Hepatocyte growth factor (HGF) is a pro-angiogenic cytokine activated by tissue type plasminogen activator (tPA) that might play a role in the progression of multiple myeloma (MM). Preliminary studies indicated that serum HGF levels were higher in patients with AL amyloidosis (AL) compared to those with MM. The aim of the present study was to determine whether HGF is a relevant marker of diagnosis and prognosis in AL. HGF serum levels were measured at diagnosis in patients with monoclonal gammopathy (MG) without AL (76 controls), or with biopsy-proven systemic AL (69 patients). HGF serum levels were significantly higher in patients with AL compared to controls, respectively, 11.2 ng/mL [min: 0.95-max: 200.4] versus 1.4 ng/mL [min: 0.82-max: 6.2] (p < 0.0001). The threshold value of 2.2 ng/mL conferred optimal sensitivity (88%) and specificity (95%) to differentiate AL and monoclonal gammopathy of undetermined significance (MGUS) patients. Serum HGF concentrations were correlated positively with the severity of cardiac involvement and the serum level of monoclonal light chains. These data suggest that HGF measurement could be used in patients with MG to detect AL or to reinforce a clinical suspicion of AL and to guide indications for diagnostic tissue biopsies. PMID- 26053105 TI - Yeast red pigment modifies Amyloid beta growth in Alzheimer disease models in both Saccharomyces cerevisiae and Drosophila melanogaster. AB - The effect of yeast red pigment on amyloid-beta (Abeta) aggregation and fibril growth was studied in yeasts, fruit flies and in vitro. Yeast strains accumulating red pigment (red strains) contained less amyloid and had better survival rates compared to isogenic strains without red pigment accumulation (white strains). Confocal and fluorescent microscopy was used to visualise fluorescent Abeta-GFP aggregates. Yeast cells containing less red pigment had more Abeta-GFP aggregates despite the lower level of overall GFP fluorescence. Western blot analysis with anti-GFP, anti-Abeta and A11 antibodies also revealed that red cells contained a considerably lower amount of Abeta GFP aggregates as compared to white cells. Similar results were obtained with exogenous red pigment that was able to penetrate yeast cells. In vitro experiments with thioflavine and TEM showed that red pigment effectively decreased Abeta fibril growth. Transgenic flies expressing Abeta were cultivated on medium containing red and white isogenic yeast strains. Flies cultivated on red strains had a significant decrease in Abeta accumulation levels and brain neurodegeneration. They also demonstrated better memory and learning indexes and higher locomotor ability. PMID- 26053106 TI - Alectorioid Morphologies in Paleogene Lichens: New Evidence and Re-Evaluation of the Fossil Alectoria succini Magdefrau. AB - One of the most important issues in molecular dating studies concerns the incorporation of reliable fossil taxa into the phylogenies reconstructed from DNA sequence variation in extant taxa. Lichens are symbiotic associations between fungi and algae and/or cyanobacteria. Several lichen fossils have been used as minimum age constraints in recent studies concerning the diversification of the Ascomycota. Recent evolutionary studies of Lecanoromycetes, an almost exclusively lichen-forming class in the Ascomycota, have utilized the Eocene amber inclusion Alectoria succinic as a minimum age constraint. However, a re-investigation of the type material revealed that this inclusion in fact represents poorly preserved plant remains, most probably of a root. Consequently, this fossil cannot be used as evidence of the presence of the genus Alectoria (Parmeliaceae, Lecanorales) or any other lichens in the Paleogene. However, newly discovered inclusions from Paleogene Baltic and Bitterfeld amber verify that alectorioid morphologies in lichens were in existence by the Paleogene. The new fossils represent either a lineage within the alectorioid group or belong to the genus Oropogon. PMID- 26053107 TI - Endoscopic polypectomy in the clinic: a pilot cost-effectiveness analysis. AB - OBJECTIVE: The purpose of this pilot economic evaluation was to assess the cost effectiveness of the endoscopic polypectomy in the clinic (EPIC) procedure compared to formal endoscopic sinus surgery (ESS) for the treatment of select chronic rhinosinusitis (CRS) patients with nasal polyposis. DESIGN: Cost effectiveness analysis using a Markov decision tree model with a 30-year time horizon. The two comparative treatment groups were as follows: (i) EPIC and (ii) ESS. Costs and effects were discounted at a rate of 3.5%. A probabilistic sensitivity analysis was performed. SETTING: Economic perspective of the Canadian government third-party payer. PARTICIPANTS: CRS patients with nasal polyposis who have predominantly isolated symptoms of nasal obstruction with or without olfactory loss. MAIN OUTCOME MEASURES: Incremental cost per quality adjusted life year (QALY). RESULTS: Over a time period of 30 years, the reference case demonstrated that the ESS strategy cost a total of $21,345 and produced 13.17 QALYs while the EPIC strategy cost a total of $5591 and produced 12.93 QALYs. The ESS versus EPIC incremental cost-effectiveness ratio was $65,641/QALY. The probability that EPIC is cost-effective compared to ESS at a maximum willingness to-pay threshold of $30,000 and $50,000/QALY is 66% and 60%, respectively. CONCLUSIONS: Outcomes from this study have demonstrated that the EPIC procedure may be a cost-effective treatment strategy for 'select' patients with nasal polyposis. Data from this study were obtained from a small pilot trial, and we feel the results warrant a future randomised controlled trial to strengthen the outcomes. PMID- 26053108 TI - Measurement of entropy production in living cells under an alternating electric field--Deals with queries. PMID- 26053109 TI - Modulating mechanosensory afferent excitability by an atypical mGluR. AB - Mechanotransduction by proprioceptive sensory organs is poorly understood. Evidence was recently shown that muscle spindle and hair follicle primary afferents (lanceolates) constantly release glutamate from synaptic-like vesicles (SLVs) within the terminals. The secreted glutamate activates a highly unusual metabotropic glutamate receptor (mGluR) to modulate the firing rate (spindles) and SLV recycling (lanceolates). This receptor has yet to be isolated and sequenced. To further investigate this receptor's pharmacology, ligands selective for classical mGluRs have been recently characterised for their ability to alter stretch-evoked spindle firing and SLV endocytosis in these different endings. Here, it is described how the results of these screens facilitated the development of novel compounds to be used in the process of isolating and sequencing of this non-canonical mGluR. This study shows how the compounds were tested for their ability to alter stretch-evoked afferent firing in muscle spindles and SLV endocytosis in the lanceolate endings of hair follicles to ensure they maintained their ability to bind to the receptor. For the development of novel compounds, kainate was chosen as the parent ligand due to its potency and ease of chemical modification. Novel kainate derivatives were then synthesised and tested to find potent analogues suitable for 'click-chemistry', an established technique for relatively quick, cheap, stereospecific and high yield chemical modifications (Angewandte Chemie (International ed. in English), 40, 2001, pp2004). Of the novel kainate analogues developed, unfortunately ZCZ49 and ZCZ50 lost the ability to produce a significant change in spindle stretch evoked firing. However, ZCZ90 was as potent as kainate, increasing firing by a similar margin at 1 MUm (n = 8; P < 0.001). The addition of either a biotin or a fluorescein side group to ZCZ90, using the click-chemistry technique, did not affect the potency and hence these compounds will be used in further studies of the receptor. As well as the development of these compounds, the study found not only many similarities, but also some key differences between the two types of primary mechanosensory endings investigated. These differences must be taken into account in further study. However, they also present an intriguing opportunity for these receptors to be targeted selectively to modulate ending sensitivity as treatments for muscle spasm in multiple sclerosis and spinal cord injury, and possibly even baroreceptor firing to treat hypertension. PMID- 26053110 TI - Mesoporous ZnAl2O4: an efficient adsorbent for the removal of arsenic from contaminated water. AB - We report, for the first time, an efficient soft-templating strategy for the synthesis of mesoporous ZnAl2O4 using the supramolecular assembly of lauric acid (surfactant) as a template under alkaline pH conditions. A 50 : 50 (v/v) mixture of water-ethanol has been found to be a very efficient synthesis medium for the dissolution of inorganic precursors, retaining the supramolecular assembly of the lauric acid surfactant and adjusting the necessary pH of the synthesis gel, which are very crucial parameters to obtain the stable mesophase of zinc aluminate. This mesoporous ZnAl2O4 material has retained the mesophase upon calcination, showed good BET surface area and electron microscopic results revealed that the material is composed of tiny spherical nanoparticles of dimensions ca. 5-7 nm size. Mesoporous ZnAl2O4 showed very good adsorption efficiency for the removal of arsenic from contaminated water. An efficient synthesis strategy, high BET surface area, stable mesophase and good adsorption efficiency for AsO4(3-) from arsenic-contaminated water by the mesoporous ZnAl2O4 material have huge potential to be explored in the large scale purification of groundwater. PMID- 26053111 TI - Extracellular matrix biomimicry for the creation of investigational and therapeutic devices. AB - The extracellular matrix (ECM) is a web of fibrous proteins that serves as a scaffold for tissues and organs, and is important for maintaining homeostasis and facilitating cellular adhesion. Integrin transmembrane receptors are the primary adhesion molecules that anchor cells to the ECM, thus integrating cells with their microenvironments. Integrins play a critical role in facilitating cell matrix interactions and promoting signal transduction, both from the cell to the ECM and vice versa, ultimately mediating cell behavior. For this reason, many advanced biomaterials employ biomimicry by replicating the form and function of fibrous ECM proteins. The ECM also acts as a reservoir for small molecules and growth factors, wherein fibrous proteins directly bind and present these bioactive moieties that facilitate cell activity. Therefore biomimicry can be enhanced by incorporating small molecules into ECM-like substrates. Biomimetic ECM materials have served as invaluable research tools for studying interactions between cells and the surrounding ECM, revealing that cell-matrix signaling is driven by mechanical forces, integrin engagement, and small molecules. Mimicking pathological ECMs has also elucidated disease specific cell behaviors. For example, biomimetic tumor microenvironments have been used to induce metastatic cell behaviors, and have thereby shown promise for in vitro cancer drug testing and targeting. Further, ECM-like substrates have been successfully employed for autologous cell recolonization for tissue engineering and wound healing. As we continue to learn more about the mechanical and biochemical characteristics of the ECM, these properties can be harnessed to develop new biomaterials, biomedical devices, and therapeutics. PMID- 26053112 TI - Reply. PMID- 26053113 TI - Three-dimensional Laparoscopy: Does Improved Visualization Decrease the Learning Curve Among Trainees in Advanced Procedures? AB - PURPOSE: Complex laparoscopy is difficult to master because it involves 3 dimensional (3D) interpretation on a 2-dimensional (2D) viewing screen. The use of 3D technology has an uncertain effect on training surgeons. We aim to evaluate the effectiveness of 3D on learning and performing laparoscopic tasks. METHODS: Medical students without laparoscopic experience (novices) were evaluated doing inanimate object transfer and laparoscopic suturing. Tasks were repeated using 2D and 3D cameras with standard instruments. Time and error rates (missed attempts, dropped objects, and failure to complete the task) were recorded. RESULTS: Twenty nine novice medical students experienced a 45.5% decrease in the time to complete PEG transfer using 3D (mean 207 s with 2D vs. 113 s with 3D). Error rate was reduced to 50% (2D, 4 errors vs. 3D, 2 errors) and mean drop rate was reduced to 0. Similar decreases in suture time (46.5%) were seen (mean 403 s with 2D vs. 220 s with 3D). CONCLUSIONS: Our results indicate that 3D significantly improved visualization and ability to perform complex tasks in the skills laboratory setting. This technology may be very effective in teaching advanced laparoscopic skills in the era of work-hour restrictions. PMID- 26053114 TI - Pharmacokinetics and Toxicity of Tacrolimus Early After Heart and Lung Transplantation. AB - Annually, about 8000 heart and lung transplantations are successfully performed worldwide. However, morbidity and mortality still pose a major concern. Renal failure in heart and lung transplant recipients is an essential adverse cause of morbidity and mortality, often originating in the early postoperative phase. At this time of clinical instability, the kidneys are exposed to numerous nephrotoxic stimuli. Among these, tacrolimus toxicity plays an important role, and its pharmacokinetics may be significantly altered in this critical phase by fluctuating drug absorption, changed protein metabolism, anemia and (multi-) organ failure. Limited understanding of tacrolimus pharmacokinetics in these circumstances is hampering daily practice. Tacrolimus dose adjustments are generally based on whole blood trough levels, which widely vary early after transplantation. Moreover, whole blood trough levels are difficult to predict and are poorly related to the area under the concentration-time curve. Even within the therapeutic range, toxicity may occur. These shortcomings of tacrolimus monitoring may not hold for the unbound tacrolimus plasma concentrations, which may better reflect tacrolimus toxicity. This review focuses on posttransplant tacrolimus pharmacokinetics, discusses relevant factors influencing the unbound tacrolimus concentrations and tacrolimus (nephro-) toxicity in heart and lung transplantation patients. PMID- 26053115 TI - Roll-to-Roll Nanomanufacturing of Hybrid Nanostructures for Energy Storage Device Design. AB - A key limitation to the practical incorporation of nanostructured materials into emerging applications is the challenge of achieving low-cost, high throughput, and highly replicable scalable nanomanufacturing techniques to produce functional materials. Here, we report a benchtop roll-to-roll technique that builds upon the use of binary solutions of nanomaterials and liquid electrophoretic assembly to rapidly construct hybrid materials for battery design applications. We demonstrate surfactant-free hybrid mixtures of carbon nanotubes, silicon nanoparticles, MoS2 nanosheets, carbon nanohorns, and graphene nanoplatelets. Roll-to-roll electrophoretic assembly from these solutions enables the controlled fabrication of homogeneous coatings of these nanostructures that maintain chemical and physical properties defined by the synergistic combination of nanomaterials utilized without adverse effects of surfactants or impurities that typically limit liquid nanomanufacturing routes. To demonstrate the utility of this nanomanufacturing approach, we employed roll-to-roll electrophoretic processing to fabricate both positive and negative electrodes for lithium ion batteries in less than 30 s. The optimized full-cell battery, containing active materials of prelithiated silicon nanoparticles and MoS2 nanosheets, was assessed to exhibit energy densities of 167 Wh/kgcell(-1) and power densities of 9.6 kW/kgcell(-1). PMID- 26053116 TI - Surface Roughness Impacts on Granular Media Filtration at Favorable Deposition Conditions: Experiments and Modeling. AB - Column tests were conducted to investigate media roughness impacts on particle deposition in absence of an energy barrier (i.e., high ionic strength). Media/collector surface roughness consistently influenced colloid deposition in a nonlinear, nonmonotonic manner such that a critical roughness size associated with minimum particle deposition could be identified; this was confirmed using a convection-diffusion model. The results demonstrate that media surface roughness size alone is inadequate for predicting media roughness impacts on particle deposition; rather, the relative size relationship between the particles and media/collectors must also be considered. A model that quantitatively considers media surface roughness was developed that described experimental outcomes well and consistently with classic colloid filtration theory (CFT) for smooth surfaces. Dimensionless-scaling factors froughness and fPCIF were introduced and used to develop a model describing particle deposition rate (kd) and colloid attachment efficiency (alpha). The model includes fitting parameters that reflect the impact of critical system characteristics such as ionic strength, loading rate, hydrophobicity. Excellent agreement was found not only between the modeled outcomes for colloid attachment efficiency (alpha) and experimental results from the column tests, but also with experimental outcomes reported elsewhere. The model developed herein provides a framework for describing media surface roughness impacts on colloid deposition. PMID- 26053117 TI - Class I histone deacetylase inhibitors inhibit the retention of BRCA1 and 53BP1 at the site of DNA damage. AB - BRCA1 and 53BP1 antagonistically regulate homology-directed repair (HDR) and non homologous end-joining (NHEJ) of DNA double-strand breaks (DSB). The histone deacetylase (HDAC) inhibitor trichostatin A directly inhibits the retention of 53BP1 at DSB sites by acetylating histone H4 (H4ac), which interferes with 53BP1 binding to dimethylated histone H4 Lys20 (H4K20me2). Conversely, we recently found that the retention of the BRCA1/BARD1 complex is also affected by another methylated histone residue, H3K9me2, which can be suppressed by the histone lysine methyltransferase (HKMT) inhibitor UNC0638. Here, we investigate the effects of the class I HDAC inhibitors MS-275 and FK228 compared to UNC0638 on histone modifications and the DNA damage response. In addition to H4ac, the HDAC inhibitors induce H3K9ac and inhibit H3K9me2 at doses that do not affect the expression levels of DNA repair genes. By contrast, UNC0638 selectively inhibits H3K9me2 without affecting the levels of H3K9ac, H3K56ac or H4ac. Reflecting their effects on histone modifications, the HDAC inhibitors inhibit ionizing radiation induced foci (IRIF) formation of BRCA1 and BARD1 as well as 53BP1 and RIF1, whereas UNC0638 suppresses IRIF formation of BRCA1 and BARD1 but not 53BP1 and RIF1. Although HDAC inhibitors suppressed HDR, they did not cooperate with the poly(ADP-ribose) polymerase inhibitor olaparib to block cancer cell growth, possibly due to simultaneous suppression of NHEJ pathway components. Collectively, these results suggest the mechanism by that HDAC inhibitors inhibit both the HDR and NHEJ pathways, whereas HKMT inhibitor inhibits only the HDR pathway; this finding may affect the chemosensitizing effects of the inhibitors. PMID- 26053118 TI - Deletion of Fifteen Open Reading Frames from Modified Vaccinia Virus Ankara Fails to Improve Immunogenicity. AB - Modified vaccinia virus Ankara (MVA) is a highly attenuated strain of vaccinia virus, which has been used as a recombinant vaccine vector in many vaccine development programmes. The loss of many immunosuppressive and host-range genes resulted in a safe and immunogenic vaccine vector. However it still retains some immunomodulatory genes that may reduce MVA immunogenicity. Earlier reports demonstrated that the deletion of the A41L, B15R, C6L, or C12L open reading frames (ORFs) enhanced cellular immune responses in recombinant MVA (rMVA) by up to 2-fold. However, previously, we showed that deletion of the C12L, A44L, A46R, B7R, or B15R ORFs from rMVA, using MVA-BAC recombineering technology, did not enhance rMVA immunogenicity at either peak or memory cellular immune responses. Here, we extend our previous study to examine the effect of deleting clusters of genes on rMVA cellular immunogenicity. Two clusters of fifteen genes were deleted in one rMVA mutant that encodes either the 85A antigen of Mycobacterium tuberculosis or an immunodominant H2-Kd-restricted murine malaria epitope (pb9). The deletion mutants were tested in prime only or prime and boost vaccination regimens. The responses showed no improved peak or memory CD8+ T cell frequencies. Our results suggest that the reported small increases in MVA deletion mutants could not be replicated with different antigens, or epitopes. Therefore, the gene deletion strategy may not be taken as a generic approach for improving the immunogenicity of MVA-based vaccines, and should be carefully assessed for every individual recombinant antigen. PMID- 26053119 TI - Association Between Thoracic Spinal Cord Gray Matter Atrophy and Disability in Multiple Sclerosis. AB - IMPORTANCE: In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques. OBJECTIVES: To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels. DESIGN, SETTING, AND PARTICIPANTS: Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital. MAIN OUTCOMES AND MEASURES: Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates. RESULTS: Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume. CONCLUSIONS AND RELEVANCE: Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration. PMID- 26053120 TI - Peptoid-Substituted Hybrid Antimicrobial Peptide Derived from Papiliocin and Magainin 2 with Enhanced Bacterial Selectivity and Anti-inflammatory Activity. AB - Antimicrobial peptides (AMPs) are important components of the host innate immune system. Papiliocin is a 37-residue AMP purified from larvae of the swallowtail butterfly Papilio xuthus. Magainin 2 is a 23-residue AMP purified from the skin of the African clawed frog Xenopus laevis. We designed an 18-residue hybrid peptide (PapMA) incorporating N-terminal residues 1-8 of papiliocin and N terminal residues 4-12 of magainin 2, joined by a proline (Pro) hinge. PapMA showed high antimicrobial activity but was cytotoxic to mammalian cells. To decrease PapMA cytotoxicity, we designed a lysine (Lys) peptoid analogue, PapMA k, which retained high antimicrobial activity but displayed cytotoxicity lower than that of PapMA. Fluorescent dye leakage experiments and confocal microscopy showed that PapMA targeted bacterial cell membranes whereas PapMA-k penetrated bacterial cell membranes. Nuclear magnetic resonance experiments revealed that PapMA contained an N-terminal alpha-helix from Lys(3) to Lys(7) and a C-terminal alpha-helix from Lys(10) to Lys(17), with a Pro(9) hinge between them. PapMA-k also had two alpha-helical structures in the same region connected with a flexible hinge residue at Nlys(9), which existed in a dynamic equilibrium of cis and trans conformers. Using lipopolysaccharide-stimulated RAW264.7 macrophages, the anti-inflammatory activity of PapMA and PapMA-k was confirmed by inhibition of nitric oxide and inflammatory cytokine production. In addition, treatment with PapMA and PapMA-k decreased the level of ultraviolet irradiation-induced expression of genes encoding matrix metalloproteinase-1 (MMP-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) in human keratinocyte HaCaT cells. Thus, PapMA and PapMA-k are potent peptide antibiotics with antimicrobial and anti-inflammatory activity, with PapMA-k displaying enhanced bacterial selectivity. PMID- 26053121 TI - Global circulation patterns of seasonal influenza viruses vary with antigenic drift. AB - Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour. PMID- 26053122 TI - Hippocampal-prefrontal input supports spatial encoding in working memory. AB - Spatial working memory, the caching of behaviourally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. Although the prefrontal cortex and hippocampus are known to contribute jointly to successful spatial working memory, the anatomical pathway and temporal window for the interaction of these structures critical to spatial working memory has not yet been established. Here we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues in mice. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal-prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory. PMID- 26053124 TI - Mechanism of Oxygen Atom Transfer from Fe(V)(O) to Olefins at Room Temperature. AB - In biological oxidations, the intermediate Fe(V)(O)(OH) has been proposed to be the active species for catalyzing the epoxidation of alkenes by nonheme iron complexes. However, no study has been reported yet that elucidates the mechanism of direct O-atom transfer during the reaction of Fe(V)(O) with alkenes to form the corresponding epoxide. For the first time, we study the mechanism of O-atom transfer to alkenes using the Fe(V)(O) complex of biuret-modified Fe-TAML at room temperature. The second-order rate constant (k2) for the reaction of different alkenes with Fe(V)(O) was determined under single-turnover conditions. An 8000 fold rate difference was found between electron-rich (4-methoxystyrene; k2 = 216 M(-1) s(-1)) and electron-deficient (methyl trans-cinnamate; k2 = 0.03 M(-1) s( 1)) substrates. This rate difference indicates the electrophilic character of Fe(V)(O). The use of cis-stilbene as a mechanistic probe leads to the formation of both cis- and trans-stilbene epoxides (73:27). This suggests the formation of a radical intermediate, which would allow C-C bond rotation to yield both stereoisomers of stilbene-epoxide. Additionally, a Hammett rho value of -0.56 was obtained for the para-substituted styrene derivatives. Detailed DFT calculations show that the reaction proceeds via a two-step process through a doublet spin surface. Finally, using biuret-modified Fe-TAML as the catalyst and NaOCl as the oxidant under catalytic conditions epoxide was formed with modest yields and turnover numbers. PMID- 26053125 TI - A natural product, resveratrol, protects against high-glucose-induced developmental damage in chicken embryo. AB - Resveratrol, a famous plant-derived polyphenolic phytoalexin, has been considered to play physiological roles such as antioxidative, neuroprotective, and anticancer effects in adults. However, its antioxidative activity and neuroprotective effect were seldom discussed in the embryonic system. In this study, the effect of resveratrol on chicken embryo development under high glucose and its underlying mechanism of resveratrol were investigated. High glucose administrated to chicken embryo at embryonic Day 1 induced stillbirth, growth retardation, and impaired blood vessel development on yolk sac. However, resveratrol supplementation before glucose exposure showed significant effect on decreasing the death rate, developmental damage, and vessel injury. In addition, oxidative stress was caused by high-glucose exposure, and resveratrol could rescue this high-glucose-induced oxidative stress. Moreover, the neural developmental marker paired box 3 was significantly decreased by high glucose and recovered by resveratrol. Cell cycle-regulated gene expression was also intervened by resveratrol. This study had found an association between resveratrol and hyperglycemia-induced embryonic damage, which suggested a potential protective effect of resveratrol on gestational diabetes. PMID- 26053123 TI - HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. AB - Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine-1-phosphate (S1P) is a key regulator of lymphocyte egress. Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high density lipoprotein (HDL) particle, the immunological functions of the ApoM-S1P complex are unknown. Here we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow lymphocyte progenitors. Mice that lacked ApoM (Apom(-/-)) had increased proliferation of Lin(-) Sca-1(+) cKit(+) haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P1 suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P1 signalling in vivo. Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(-/-) mice developed more severe experimental autoimmune encephalomyelitis, characterized by increased lymphocytes in the central nervous system and breakdown of the blood brain barrier. Thus, the ApoM-S1P-S1P1 signalling axis restrains the lymphocyte compartment and, subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities. PMID- 26053126 TI - Thermal Decomposition of 2(3H) and 2(5H) Furanones: Theoretical Aspects. AB - The thermal decomposition reactions of 2(3H) and 2(5H) furanones and their methyl derivatives are explored. Theoretical calculations of the barriers, reaction enthalpies, and the properties of these and intermediate species are reported using the composite model chemistry CBS-QB3 and also the functional M06-2X allied to the 6-311++G(d,p) basis set. Thus, the bond dissociation enthalpies, ionization energies, and unimolecular chemical kinetic rate constants in the high pressure limit were computed. We show that flow reactor experiments that intimated that heating the 2(3H) furanone converts it to the isomeric 2(5H) furanone occurs via a 1 -> 2 H-transfer reaction to an open ring ketenoic aldehyde. The latter can then ring close to the other isomeric structure. The final products acrolein and carbon monoxide are only formed from 2(3H), and acrolein will further decompose to ethylene and CO. Comparable channels explain the interconversion of 5-methyl-2(3H) furanone to its 2(5H) isomer and to the formation of methyl vinyl ketone and CO. The influence of the methyl group at other positions on the ring is hardly of significance except in the case of 5 methyl-2(5H) furanone where a hydrogen atom transfer from the methyl group leads to the formation of a doubly unsaturated carboxylic compound, 2,4-pentadienoic acid. Studies of the UV photolysis of the parent compounds in both low temperature inert argon matrices and in solution are broadly in accord with the thermal findings insofar as product formation is concerned and with our theoretical calculations. The dominant features of the early decomposition chemistry of these compounds are simple hydrogen transfer and simultaneous ring opening reactions, which do however result in some quite unusual species. PMID- 26053127 TI - Carbazole-Based Boron Dipyrromethenes (BODIPYs): Facile Synthesis, Structures, and Fine-Tunable Optical Properties. AB - Carbazole-based BODIPYs were synthesized in three steps using an organometallic approach consisting of sequential Ir-catalyzed borylation, Suzuki-Miyaura coupling, and boron complexation. Various substituents were introduced into the carbazole moiety, and large substituent effects were confirmed by means of absorption spectroscopy, cyclic voltammetry, and DFT calculations. Dibenzocarbazoles were also converted into the corresponding BODIPYs. PMID- 26053128 TI - Molecular Dynamics Simulation of Conformational Transition and Frictional Performance Modulation of Densely Packed Self-Assembled Monolayers Based on Electrostatic Stimulation. AB - Self-assembled monolayers (SAMs) terminated with functional end groups such as polyethylene glycols (PEG) have attracted considerable attention because of their unique and flexible structure that exhibits conformational transition under electrostatic stimulation. Molecular dynamics simulations are used to investigate the conformational transition and associated modulation of frictional performance of densely packed PEG-terminated SAMs subjected to electrical field stimulation. Previously reported empirical potentials and atomic charges were used to model the intrachain bonds and electrostatic and interchain interactions. Simulation results indicate that significant conformational transition is generated because of the electrostatic forces. Under positive electrical fields, PEG groups are compressed and twisted into the helical form, "gauche" state, whereas under negative electrical fields, PEG groups are stretched into the straight form, "all trans" state. Such conformational transition may lead to substantial alteration of frictional response upon SAMs. By shallow penetration and sliding using a repulsive indenter, the SAMs under positive electrical fields exhibit a level of frictional response that is comparatively lower than those under zero and negative potentials, which may be attributed to reduced interchain space for deformation, limited conformational transition, and less energy absorption. The simulation results demonstrate that with appropriate selection of functional end groups attached to SAM backbone chains it is possible to modulate frictional performance of densely packed SAMs via electrostatic stimuli. PMID- 26053129 TI - Determine the difficulties of home care in children following haematopoietic stem cell transplantation. AB - The aim of this study was to determine the difficulties regarding the home care of children following haematopoietic stem cell transplantation (HSCT). The sample of the study includes the families of 73 children in a bone marrow transplant unit between 2010 and 2013, Turkey. Data were collected using a form included descriptive information and questions about the difficulties and complications of home care. Families were telephoned and problems they had encountered were recorded. Mann-Whitney U-test and the logistic regression analysis were used. The average age of the children was 10.65 +/- 5.03 years, the average age was 8.89 +/ 4.9 when HSCT was performed, and the average year after HSCT was 1.79 +/- 0.74. 41.1% of the children underwent transplantation with diagnoses of anaemia. Primary physical problems that were found after discharge from the hospital were fever (43.8%), decreased appetite (37%), rash (34.2%) and pain (26%). Socially, 43.8% of families reported that their children had difficulties with school. Primary difficulties regarding care and follow-up were reported as skin care (34.2%) and catheter care (33.3%). In the post-transplantation period, it is important to provide information about potential problems and care to patients and families in order to increase the quality of life. PMID- 26053130 TI - Letter to the Editor: Operator doses in cone beam computed tomography-a response from the authors. PMID- 26053131 TI - Reductive alkylation of active methylene compounds with carbonyl derivatives, calcium hydride and a heterogeneous catalyst. AB - A one-pot two-step reaction (Knoevenagel condensation - reduction of the double bond) has been developed using calcium hydride as a reductant in the presence of a supported noble metal catalyst. The reaction between carbonyl compounds and active methylene compounds such as methylcyanoacetate, 1,3-dimethylbarbituric acid, dimedone and the more challenging dimethylmalonate, affords the corresponding monoalkylated products in moderate to good yields (up to 83%) with minimal reduction of the starting carbonyl compounds. PMID- 26053132 TI - Antibacterial Nanofibrous Mats Composed of Eudragit for pH-Dependent Dissolution. AB - A pH-responsive nanofibrous mesh was prepared for the controlled release of antibiotics in response to pH changes. Eudragit EPO (EPO) and Eudragit L100 (L100) were injected through inner and outer needle and simultaneously electrospun through coaxial nozzles composed of inner and outer needles. Various amounts of EPO and L100 were coejected with tetracycline through the needle and simultaneously electrospun to the fibrous meshes. The mass erosion rates of the meshes at pH 6.0 gradually decreased as the amounts of EPO increased, whereas those at pH 2.0 showed negligible differences; these differences were confirmed by scanning electron microscopy and monitoring the dry weight changes. At pH 6.0, the fibrous structures of the meshes rapidly disappeared compared to those under acidic conditions because Eudragit L100 is localized to the shell of the nanofiber during the electrospinning process. Both the pH changes and the blend ratio of the two polymers significantly affected the tetracycline release; tetracycline was rapidly released from the meshes at pH 6.0, whereas the release rates were attenuated at pH 2.0. Tetracycline was released faster from the mesh at higher blend ratios of EPO for both pH values. The electrostatic interaction between EPO and L100 is expected to yield different release profiles of tetracycline. Consequently, higher amounts of encapsulated drugs were released from the mesh at neutral pH and successfully inhibited bacterial growth. PMID- 26053133 TI - When Medical Care Leads to Harm--Difficulty Finding Words: A Teachable Moment. PMID- 26053134 TI - Letter to the Editor: Vertebral artery pexy for microvascular decompression. PMID- 26053135 TI - Design of a micellized alpha-cyclodextrin based supramolecular hydrogel system. AB - In recent years supramolecular structures built from macrocyclic compounds have attracted tremendous interest due to the unique properties derived from dynamic self-assembly. Our study proposes a two-step mechanism to form a supramolecular hydrogel system: (1) the formation of micelles, and (2) micelle association with alpha-cyclodextrin (alpha-CD) due to threading of PEGMA in the alpha-CD cavity, forming inclusion complexes. Using this mechanism, a supramolecular hydrogel made from a tri-component copolymer PLLA/DMAEMA/PEGMA and alpha-CD was fabricated for the first time and characterized in terms of its structural, morphological, and rheological properties. PMID- 26053136 TI - Maternal zinc deficiency during pregnancy elevates the risks of fetal growth restriction: a population-based birth cohort study. AB - We investigated the association between maternal zinc level during pregnancy and the risks of low birth weight (LBW) and small for gestational age (SGA) infants in a large population-based birth cohort study. In this study, 3187 pregnant women were recruited. For serum zinc level, 2940 pregnant women were sufficient (>=56 MUg/dL) and 247 deficient (<56 MUg/dL). Of interest, 7.3% newborns were with LBW among subjects with low zinc level (RR: 3.48; 95% CI: 2.03, 5.96; P < 0.001). Adjusted RR for LBW was 3.41 (95% CI: 1.97, 5.91; P < 0.001) among subjects with low zinc level. Moreover, 15.0% newborns were with SGA among subjects with low zinc level (RR: 1.98; 95% CI: 1.36, 2.88; P < 0.001). Adjusted RR for SGA was 1.93 (95% CI: 1.32, 2.82; P < 0.001) among subjects with low zinc level. A nested case-control study within above cohort showed that maternal serum zinc level was lower in SGA cases as compared with controls. By contrast, maternal serum C-reactive protein, TNF-alpha and IL-8 levels were significantly higher in SGA cases than that of controls. Moreover, nuclear NF-kappaB p65 was significantly up-regulated in placentas of SGA cases as compared with controls. Taken together, maternal zinc deficiency during pregnancy elevates the risks of LBW and SGA infants. PMID- 26053137 TI - Sonographic assessment of abdominal fat distribution during the first year of infancy. AB - BACKGROUND: Longitudinal data regarding the fat distribution in the early postnatal period is sparse. METHODS: We performed ultrasonography (US) as a noninvasive approach to investigate the development of abdominal subcutaneous (SC) and preperitoneal (PP) fat depots in infants <=1 y and compared longitudinal US data with skinfold thickness (SFT) measurements and anthropometry in 162 healthy children at 6 wk, 4 mo, and 1 y postpartum. RESULTS: US was found to be a reproducible method for the quantification of abdominal SC and PP adipose tissue (AT) in this age group. Thickness of SC fat layers significantly increased from 6 wk to 4 mo and decreased at 1 y postpartum, whereas PP fat layers continuously increased. Girls had a significantly higher SC fat mass compared to boys, while there was no sex-specific difference in PP fat thickness. SC fat layer was strongly correlated with SFT measurements, while PP fat tissue was only weakly correlated with anthropometric measures. CONCLUSION: US is a feasible and reproducible method for the quantification of abdominal fat mass in infants <=1 y of age. PP and SC fat depots develop differentially during the first year of life. PMID- 26053139 TI - Ototoxicity in retinoblastoma survivors treated with carboplatin based chemotherapy: A cross-sectional study of 116 patients. PMID- 26053138 TI - Effects of temporary low-dose galactose supplements in children aged 5-12 y with classical galactosemia: a pilot study. AB - BACKGROUND: Classical galactosemia is caused by severe galactose-1-phosphate uridyltransferase deficiency. Despite life-long galactose-restriction, many patients experience long-term complications. Intoxication by galactose and its metabolites as well as over-restriction of galactose may contribute to the pathophysiology. We provided temporary low-dose galactose supplements to patients. We assessed tolerance and potential beneficial effects with clinical monitoring and measurement of biochemical, endocrine, and IgG N-glycosylation profiles. METHODS: We enrolled 26 patients (8.6 +/- 1.9 y). Thirteen were provided with 300 mg of galactose/day followed by 500 mg for 2 wk each (13 patient controls). RESULTS: We observed no clinical changes with the intervention. Temporary mild increase in galactose-1-phosphate occurred, but renal, liver, and bone biochemistry remained normal. Patients in the supplementation group had slightly higher leptin levels at the end of the study than controls. We identified six individuals as "responders" with an improved glycosylation pattern (decreased G0/G2 ratio, P < 0.05). There was a negative relationship between G0/G2 ratio and leptin receptor sOb-R in the supplementation group (P < 0.05). CONCLUSION: Temporary low-dose galactose supplementation in children over 5 y is well tolerated in the clinical setting. It leads to changes in glycosylation in "responders". We consider IgG N-glycan monitoring to be useful for determining individual optimum galactose intake. PMID- 26053140 TI - Costs of Rapid HIV Screening in an Urban Emergency Department and a Nearby County Jail in the Southeastern United States. AB - Emergency departments and jails provide medical services to persons at risk for HIV infection and are recommended venues for HIV screening. Our main objective in this study was to analyze the cost per new HIV diagnosis associated with the HIV screening program in these two venues. The emergency department's parallel testing program was conducted at Grady Memorial Hospital in Atlanta, Georgia starting in 2008; the jail's integrated testing program began at the Fulton County (GA) Jail in 2011. The two sites, four miles apart from one another, employed the same rapid HIV test. Ascertainment that cases were new differed by site; only the jail systematically checked identities against health department HIV registries. The program in the emergency department used dedicated HIV test counselors and made 242 diagnoses over a 40-month period at a cost of $2,981 per diagnosis. The jail program used staff nurses, and found 41 new HIV cases over 10.5 months at a cost of $6,688 per new diagnosis. Differences in methods for ascertainment of new diagnoses, previously undiagnosed HIV sero-positivity, and methodologies used for assessing program costs prevent concluding that one program was more economical than the other. Nonetheless, our findings show that testing in both venues yielded many new diagnoses, with the costs within the range reported in the literature. PMID- 26053141 TI - Course of neurological soft signs in first-episode schizophrenia: Relationship with negative symptoms and cognitive performances. AB - This prospective study examined the course of neurological soft signs (NSS) in patients with first-episode schizophrenia and its relationship with negative symptoms and cognitive functions. One hundred and forty-five patients with first episode schizophrenia were recruited, 29 were classified as having prominent negative symptoms. NSS and neuropsychological measures were administered to all patients and 62 healthy controls at baseline. Patients were then followed-up prospectively at six-month intervals for up to a year. Patients with prominent negative symptoms exhibited significantly more motor coordination signs and total NSS than patients without prominent negative symptoms. Patients with prominent negative symptoms performed worse than patients without negative symptoms in working memory functions but not other fronto-parietal or fronto-temporal functions. Linear growth model for binary data showed that the prominent negative symptoms were stable over time. Despite general improvement in NSS and neuropsychological functions, the prominent negative symptoms group still exhibited poorer motor coordination and higher levels of NSS, as well as poorer working memory than patients without prominent negative symptoms. Two distinct subtypes of first-episode patients could be distinguished by NSS and prominent negative symptoms. PMID- 26053142 TI - Heat, Acid and Chemically Induced Unfolding Pathways, Conformational Stability and Structure-Function Relationship in Wheat alpha-Amylase. AB - Wheat alpha-amylase, a multi-domain protein with immense industrial applications, belongs to alpha+beta class of proteins with native molecular mass of 32 kDa. In the present study, the pathways leading to denaturation and the relevant unfolded states of this multi-domain, robust enzyme from wheat were discerned under the influence of temperature, pH and chemical denaturants. The structural and functional aspects along with thermodynamic parameters for alpha-amylase unfolding were probed and analyzed using fluorescence, circular dichroism and enzyme assay methods. The enzyme exhibited remarkable stability up to 70 degrees C with tendency to aggregate at higher temperature. Acid induced unfolding was also incomplete with respect to the structural content of the enzyme. Strong ANS binding at pH 2.0 suggested the existence of a partially unfolded intermediate state. The enzyme was structurally and functionally stable in the pH range 4.0 9.0 with 88% recovery of hydrolytic activity. Careful examination of biophysical properties of intermediate states populated in urea and GdHCl induced denaturation suggests that alpha-amylase unfolding undergoes irreversible and non coincidental cooperative transitions, as opposed to previous reports of two-state unfolding. Our investigation highlights several structural features of the enzyme in relation to its catalytic activity. Since, alpha-amylase has been comprehensively exploited for use in a range of starch-based industries, in addition to its physiological significance in plants and animals, knowledge regarding its stability and folding aspects will promote its biotechnological applications. PMID- 26053143 TI - The antisaccade task: Vector inversion contributes to a statistical summary representation of target eccentricities. AB - Antisaccades require the top-down suppression of a stimulus-driven prosaccade (i.e., response suppression) and the inversion of a target's spatial location to mirror-symmetrical space (i.e., vector inversion). Moreover, recent work has shown that antisaccade amplitudes are characterized by a statistical summary representation (SSR) of the target eccentricities included in a stimulus-set--a result suggesting that antisaccades are supported via the same relative visual information as perceptions. The present investigation sought to determine whether response suppression and the disruption of real-time control or vector inversion contribute to a SSR in oculomotor control. Participants completed pro- and antisaccades (target eccentricities of 10.5 degrees , 15.5 degrees , and 20.5 degrees ) in blocks of trials that differed with regard to the frequency that individual target eccentricities were presented. The manipulation of target eccentricity frequency was used to determine whether the most frequently presented target within a stimulus-set (i.e., the SSR) influences saccade amplitudes. Moreover, we disrupted the real-time control of prosaccades by requiring participants to suppress their response for a brief visual delay (i.e., 2000 ms: so-called delay prosaccade). As expected, antisaccades and delay prosaccades produced equivalent reaction times. In turn, amplitudes for delay prosaccades were refractory to the manipulation of target eccentricity frequency, whereas antisaccades were biased in the direction of the most frequently presented target within a stimulus-set. Accordingly, we propose that vector inversion contributes to the mediation of target eccentricities via a SSR and that such a phenomenon provides convergent evidence that a relative visual percept mediates antisaccades. PMID- 26053144 TI - Not all summary statistics are made equal: Evidence from extracting summaries across time. AB - Over the past 15 years, a number of behavioral studies have shown that the human visual system can extract the average value of a set of items along a variety of feature dimensions, often with great facility and accuracy. These efficient representations of sets of items are commonly referred to as summary representations, but very little is known about whether their computation constitutes a single unitary process or if it involves different mechanisms in different domains. Here, we asked participants to report the average value of a set of items presented serially over time in four different feature dimensions. We then measured the contribution of different parts of the information stream to the reported summaries. We found that this temporal weighting profile differs greatly across domains. Specifically, summaries of mean object location (Experiment 1) were influenced approximately 2.5 times more by earlier items than by later items. Summaries of mean object size (Experiment 1), mean facial expression (Experiment 2), and mean motion direction (Experiment 3), however, were more influenced by later items. These primacy and recency effects show that summary representations computed across time do not incorporate all items equally. Furthermore, our results support the hypothesis that summary representations operate differently in different feature domains, and may be subserved by distinct mechanisms. PMID- 26053146 TI - Child exposure to serious life events, COMT, and aggression: Testing differential susceptibility theory. AB - Both genetic and environmental factors contribute to individual differences in aggression. Catechol-O-methyltransferase Val158Met (COMT), a common, functional polymorphism, has been implicated in aggression and aggression traits, as have childhood experiences of adversity. It is unknown whether these effects are additive or interactional and, in the case of interaction, whether they conform to a diathesis-stress or differential susceptibility model. We examined Gene * Environment interactions between COMT and serious life events on measures of childhood aggression and contrasted these 2 models. The sample was composed of community children (N = 704); 355 were boys, and the mean age was 54.8 months (SD = 3.0). The children were genotyped for COMT rs4680 and assessed for serious life events and by teacher-rated aggression. Regression analysis showed no main effects of COMT and serious life events on aggression. However, a significant interactive effect of childhood serious life events and COMT genotype was observed: Children who had faced many serious life events and were Val homozygotes exhibited more aggression (p = .02) than did their Met-carrying counterparts. Notably, in the absence of serious life events, Val homozygotes displayed significantly lower aggression scores than did Met carriers (p = .03). When tested, this constellation of findings conformed to the differential susceptibility hypothesis: In this case, Val homozygotes are more malleable to the effect of serious life events on aggression and not simply more vulnerable to the negative effect of having experienced many serious life events. PMID- 26053145 TI - Resting-state brain connectivity after surgical and behavioral weight loss. AB - OBJECTIVE: Changes in food-cue neural reactivity associated with behavioral and surgical weight loss interventions have been reported. Resting functional connectivity represents tonic neural activity that may contribute to weight loss success. This study explores whether intervention type is associated with differences in functional connectivity after weight loss. METHODS: Fifteen participants with obesity were recruited prior to adjustable gastric banding surgery. Thirteen demographically matched participants with obesity were selected from a separate behavioral diet intervention. Resting-state functional magnetic resonance imaging was collected 3 months after surgery/behavioral intervention. ANOVA was used to examine post-weight loss differences between the two groups in connectivity to seed regions previously identified as showing differential cue reactivity after weight loss. RESULTS: Following weight loss, behavioral dieters exhibited increased connectivity between left precuneus/superior parietal lobule (SPL) and bilateral insula pre- to postmeal and bariatric patients exhibited decreased connectivity between these regions pre- to postmeal (P(corrected) <0.05). CONCLUSIONS: Behavioral dieters showed increased connectivity pre- to postmeal between a region associated with processing of self-referent information (precuneus/SPL) and a region associated with interoception (insula) whereas bariatric patients showed decreased connectivity between these regions. This may reflect increased attention to hunger signals following surgical procedures and increased attention to satiety signals following behavioral diet interventions. PMID- 26053148 TI - Are persistent early onset child conduct problems predicted by the trajectories and initial levels of discipline practices? AB - In the present investigation we focused on 2 broad sets of questions: Do parental overreactivity, laxness, and corporal punishment show evidence of normative change in early to middle childhood? Are persistently elevated child conduct problems (CPs) associated with deviations from normative changes in, as well as high initial levels of, discipline practices? Four hundred fifty-three couples with 3- to 7-year-old children were recruited via random digit dialing and studied at 3 annual assessments. Parents completed questionnaire measures of all study constructs. Normative declines were found in maternal corporal punishment and laxness. Maternal overreactivity showed a normative increase. For fathers, only corporal punishment showed evidence of a normative decline. The declines in mothers' corporal punishment and laxness, and in fathers' corporal punishment, exhibited little variability. In contrast, the trajectories of maternal overreactivity were significantly variable. High-increasing CPs were more common than low-stable CPs in families with greater increases in maternal overreactivity. High-increasing CPs were also more common in families with greater initial maternal overreactivity and corporal punishment. Yet in no case did discipline practices significantly distinguish children on high-increasing versus high-decreasing CPs trajectories. In tests of alternative models, child effects were found for all parenting variables, suggesting reciprocal causation. The findings are discussed relative to etiological models of CPs and implications for preventive intervention. PMID- 26053147 TI - The developmental costs and benefits of children's involvement in interparental conflict. AB - Building on empirical documentation of children's involvement in interparental conflicts as a weak predictor of psychopathology, we tested the hypothesis that involvement in conflict more consistently serves as a moderator of associations between children's emotional reactivity to interparental conflict and their psychological problems. In Study 1, 263 early adolescents (M age = 12.62 years), mothers, and fathers completed surveys of family and child functioning at 2 measurement occasions spaced 2 years apart. In Study 2, 243 preschool children (M age = 4.60 years) participated in a multimethod (i.e., observations, structured interview, surveys) measurement battery to assess family functioning, children's reactivity to interparental conflict, and their psychological adjustment. Across both studies, latent difference score analyses revealed that involvement moderated associations between emotional reactivity and children's increases in psychological (i.e., internalizing and externalizing) problems. Children's emotional reactivity to interparental conflict was a significantly stronger predictor of their psychological maladjustment when they were highly involved in the conflicts. In addition, the developmental benefits and costs of involvement varied as a function of emotional reactivity. Involvement in interparental conflict predicted increases in psychological problems for children experiencing high emotional reactivity and decreases in psychological problems when they exhibited low emotional reactivity. We interpret the results in the context of the new formulation of emotional security theory (e.g., Davies & Martin, 2013) and family systems models of children's parentification (e.g., Byng-Hall, 2002). PMID- 26053149 TI - Relevance of a neurophysiological marker of attention allocation for children's learning-related behaviors and academic performance. AB - Learning-related behaviors are important for school success. Socioeconomic disadvantage confers risk for less adaptive learning-related behaviors at school entry, yet substantial variability in school readiness exists within socioeconomically disadvantaged populations. Investigation of neurophysiological systems associated with learning-related behaviors in high-risk populations could illuminate resilience processes. This study examined the relevance of a neurophysiological measure of controlled attention allocation, amplitude of the P3b event-related potential, for learning-related behaviors and academic performance in a sample of socioeconomically disadvantaged kindergarteners. The sample consisted of 239 children from an urban, low-income community, approximately half of whom exhibited behavior problems at school entry (45% aggressive/oppositional; 64% male; 69% African American, 21% Hispanic). Results revealed that higher P3b amplitudes to target stimuli in a go/no-go task were associated with more adaptive learning-related behaviors in kindergarten. Furthermore, children's learning-related behaviors in kindergarten mediated a positive indirect effect of P3b amplitude on growth in academic performance from kindergarten to 1st grade. Given that P3b amplitude reflects attention allocation processes, these findings build on the scientific justification for interventions targeting young children's attention skills in order to promote effective learning-related behaviors and academic achievement within socioeconomically disadvantaged populations. PMID- 26053150 TI - Achievement, motivation, and educational choices: A longitudinal study of expectancy and value using a multiplicative perspective. AB - Drawing on the expectancy-value model, the present study explored individual and gender differences in university entry and selection of educational pathway (e.g., science, technology, engineering, and mathematics [STEM] course selection). In particular, we examined the multiplicative effects of expectancy and task values on educational outcomes during the transition into early adulthood. Participants were from a nationally representative longitudinal sample of 15-year-old Australian youths (N = 10,370). The results suggest that (a) both math self-concept and intrinsic value interact in predicting advanced math course selection, matriculation results, entrance into university, and STEM fields of study; (b) prior reading achievement has negative effects on advanced math course selection and STEM fields through math motivational beliefs; and (c) gender differences in educational outcomes are mediated by gender differences in motivational beliefs and prior academic achievement, while the processes underlying choice of educational pathway were similar for males and females. PMID- 26053151 TI - Dual polarization of microglia isolated from mixed glial cell cultures. AB - Microglia are versatile immune effector cells of the CNS and are sensitive to various stimuli. The different methods used to isolate microglia may affect some of their characteristics, such as their polarization state. The influence of cell sorting methods on the polarization state of microglia has never been studied. Mixed glial culture system (MGCS) and magnetic activated cell sorting (MACS) are two methods that are commonly used to purify microglia. This study compares the immunological states between microglia isolated by MGCS and microglia isolated by MACS. We show that microglia isolated by MGCS exhibit a stronger immune-activated state than microglia isolated by MACS. They present an elevated phagocytic ability and high levels of markers associated with classical activation (M1) and alternative activation (M2). In addition, high levels of M1-type and M2-type chemokine (C-C motif) ligand 2 and transforming growth factor-beta1 were detected in the culture medium of mixed glial cells. Our results show that microglia isolated by MGCS are in an immune-activated state, whereas microglia isolated by MACS appear to be closer to their primary in vivo state. Therefore, the immune status of microglia, depending on the protocol used to purify them, should be carefully considered in neuropathology research. PMID- 26053152 TI - Characterization of the molecular genetic pathology in patients with 11beta hydroxylase deficiency. AB - OBJECTIVE: Steroid 11beta-hydroxylase (CYP11B1) deficiency (11OHD) is the second most common form of congenital adrenal hyperplasia. Nonclassic or mild 11OHD appears to be a rare condition. Our study assessed the residual CYP11B1 function of detected mutations, adding to the spectrum of mild 11OHD, and illustrates the variability of the clinical presentation of 11OHD. PATIENTS AND METHODS: Five patients presented with mild to moderate 11OHD. Two women presented with mild hirsutism and in one case with secondary amenorrhoea. Two men presented with precocious pseudopuberty, gynaecomastia and elevated blood pressure. One 46,XX female patient was diagnosed with virilization of the external genitalia 2 years after birth. Direct DNA sequencing was carried out to perform CYP11B1 mutation analysis. The CYP11B1 mutations were functionally characterized using an in vitro expression system. RESULTS: CYP11B1-inactivating mutations were detected in all patients. Two novel missense mutations (p.P42L and p.A297V) and the previously characterized p.R143W mutation had residual CYP11B1 activities between 10% and 27%. A novel p.L382R and the previously uncharacterized p.G444D mutation both caused complete loss of CYP11B1 enzymatic activity. CONCLUSION: Mutations causing partial impairment of 11beta-hydroxylase activity (residual activity of 10% or above) are associated with a less severe clinical presentation of 11OHD, which can be classified as a nonclassic form. Our data demonstrate that patients with nonclassic 11OHD can present with androgen excess, precocious pseudopuberty and increased blood pressure. Timely diagnosis of nonclassic 11OHD and consequently initiation of personalized treatment is essential to prevent co-morbidities caused by androgen excess and hypertension. PMID- 26053153 TI - Organ Weight Measured at Autopsy in Critically Ill Children. AB - We determined whether organ weights at autopsy are correlated with disease acuity leading to pediatric intensive care unit (ICU) admission and death. The weights of heart, lungs, kidneys, liver, spleen, and brain were recorded in 68 pediatric ICU cases. For each organ, weight Z scores were calculated based on reference values previously established in large cohorts of deceased children by Kayser (any organ), or Dekaban and Sadowsky (brain only). Organ weight Z scores in pediatric ICU patients were severely increased (median [range] for heart, +3.2 [ 6.3 to +37.7]; lungs, +3.0 [-8.6 to +38.1]; kidneys, +3.6 [-10.0 to +56.3]; liver, +4.2 [-14.9 to +70.5]; and spleen, +1.3 [-11.5 to +155.8]). Conversely, the brain weight Z score was lower compared to any other organ using either set of reference values: Kayser, -1.1 (-10.5 to +10.6; P < 0.0001); Dekaban and Sadowsky, -0.2 (-7.4 to +7.7; P < 0.0001). Pediatric ICU cases were subdivided based on disease acuity: (1) previously healthy with an acute illness (n = 11), (2) chronic disease due to congenital malformations (n = 29), and (3) chronic disease without any detectable malformation (n = 28). Organ weight Z scores were similar among subgroups with the exception of the brain, which was statistically decreased in chronic disease pathologies (groups 2 and 3). Overall, this study demonstrates the heterogenous distribution of organ weights at autopsy in critically ill children; the weight of heart, lungs, kidneys, and liver, being most frequently increased. The brain is relatively smaller in chronic disease pathologies of pediatric ICU patients. PMID- 26053154 TI - Effect of Furniture Weight on Carrying, Lifting, and Turning of Chairs and Desks among Elementary School Children. AB - Rearranging furniture in elementary school classrooms encourages classroom activities. In elementary schools in Indonesia and some other developing countries, usually only one style of furniture is used for all children, and the furniture is heavy and oversized for younger children. This affects their ability to carry it. The objective of this study is to investigate the effects of elementary school furniture weight and children's age on performance of three carrying tasks (carrying a chair, lifting and turning a chair on a desk, and carrying both a chair and a desk together), from the ergonomics point of view. A total of 42 schoolchildren (ages 6-9; 17 Indonesian, 25 Japanese) participated in this study. Two types of Japanese chairs (Chair A and B, weight: 3.2 kg and 3.9 kg), one type of Indonesian chair (Chair C, weight: 5.0 kg), and two types of desks (height: 58 cm and 68 cm) were used. Indonesian chairs took significantly longer time to carry than the two Japanese chairs, and there was a significant negative relationship between age and task time for Chairs B and C, but not Chair A. Success rates for lifting and turning the chair declined as age decreased and chair weight increased, but were not significantly influenced by desk height. Success rates for carrying a chair and desk together significantly decreased with heavier furniture. Children aged six showed an extremely low success rate in almost all conditions. In conclusion, children's ability to carry furniture is affected by their age and furniture characteristics, especially weight. In order to encourage classroom activities in elementary school, school furniture should be of appropriate weight. Supervision for younger children is required during classroom furniture arrangement. PMID- 26053155 TI - Resolution-enhanced 2D NMR of complex mixtures by non-uniform sampling. AB - NMR is a powerful tool for the analysis of complex mixtures and the identification of individual components. Two-dimensional (2D) NMR potentially offers a wealth of information, but resolution is often sacrificed in order to contain experimental times. We explore the use of non-uniform sampling (NUS) to increase substantially the resolution of 2D NMR spectra of complex mixtures of small molecules, with no increase in experimental time. Two common pulse sequences for metabolomics applications are analysed, HSQC and TOCSY. Specific attention is paid to sensitivity in resolution-enhanced NUS spectra, using the signal-to-maximum-noise ratio as a metric. With a careful choice of sampling schedule and reconstruction algorithm, resolution in the (13) C dimension for HSQC is increased by a factor of at least 32, with no loss in sensitivity and no spurious peaks. For TOCSY, multiplets can be resolved in the indirect dimension in a reasonable experimental time. These properties should increase the usefulness of 2D NMR for metabolomics applications by, for example, increasing the chances of metabolite identification. PMID- 26053156 TI - Intracerebroventricular administration of leptin increase physical activity but has no effect on thermogenesis in cold-acclimated rats. AB - Most small homotherms display low leptin level in response to chronic cold exposure. Cold-induced hypoleptinemia was proved to induce hyperphagia. However, it is still not clear whether hypoleptinemia regulates energy expenditure in cold condition. We try to answer this question in chronic cold-acclimated rats. Results showed that 5-day intracerebroventricular(ICV) infusion of leptin (5 MUg/day) had no effects on basal and adaptive thermogenesis and uncoupling protein 1 expression. Physical activity was increased by leptin treatment. We further determined whether ghrelin could reverse the increasing effect of leptin on physical activity. Coadministration of ghrelin (1.2 MUg/day) completely reversed the effect of leptin on physical activity. Collectively, this study indicated the regulation of leptin on energy expenditure during cold acclimation may be mainly mediated by physical activity but not by thermogenesis. Our study outlined behavioral role of leptin during the adaptation to cold, which adds some new knowledge to promote our understanding of cold-induced metabolic adaptation. PMID- 26053157 TI - Chemopreventive opportunities to control basal cell carcinoma: Current perspectives. AB - Basal cell carcinoma (BCC) is a major health problem with approximately 2.8 million new cases diagnosed each year in the United States. BCC incidences have continued to rise due to lack of effective chemopreventive options. One of the key molecular characteristics of BCC is the sustained activation of hedgehog signaling through inactivating mutations in the tumor suppressor gene patch (Ptch) or activating mutations in Smoothened. In the past, several studies have addressed targeting the activated hedgehog pathway for the treatment and prevention of BCC, although with toxic effects. Other studies have attempted BCC chemoprevention through targeting the promotional phase of the disease especially the inflammatory component. The compounds that have been utilized in pre-clinical and/or clinical studies include green and black tea, difluoromethylornithine, thymidine dinucleotide, retinoids, non-steroidal anti-inflammatory drugs, vitamin D3, and silibinin. In this review, we have discussed genetic and epigenetic modifications that occur during BCC development as well as the current state of BCC pre-clinical and clinical chemoprevention studies. PMID- 26053158 TI - A General Approach to Sequence-Controlled Polymers Using Macrocyclic Ring Opening Metathesis Polymerization. AB - A new and general strategy for the synthesis of sequence-defined polymers is described that employs relay metathesis to promote the ring opening polymerization of unstrained macrocyclic structures. Central to this approach is the development of a small molecule "polymerization trigger" which when coupled with a diverse range of sequence-defined units allows for the controlled, directional synthesis of sequence controlled polymers. PMID- 26053159 TI - Development and validation of a sensitive liquid chromatographic-tandem mass spectrometric method for the simultaneous analysis of granisetron and 7-hydroxy granisetron in human plasma and urine samples: application in a clinical pharmacokinetic study in pregnant subject. AB - A liquid chromatography-tandem mass spectrometric method for the quantification of granisetron and its major metabolite, 7-hydroxy granisetron in human plasma and urine samples was developed and validated. Respective stable isotopically labeled granisetron and 7-hydroxy granisetron were used as internal standards (IS). Chromatography was performed using an Xselect HSS T3 analytical column with a mobile phase of 20% acetonitrile in water (containing 0.2 mM ammonium formate and 0.14% formic acid, pH 4) delivered in an isocratic mode. Tandem mass spectrometry operating in positive electrospray ionization mode with multiple reaction monitoring was used for quantification. The standard curves were linear in the concentration ranges of 0.5-100 ng/mL for granisetron and 0.1-100 ng/mL for 7-hydroxy granisetron in human plasma samples, and 2-2000 ng/mL for granisetron and 2-1000 ng/mL for 7-hydroxy granisetron in human urine samples, respectively. The accuracies were >85% and the precision as determined by the coefficient of variations was <10%. No significant matrix effects were observed for granisetron or 7-hydroxy granisetron in either plasma or urine samples. Granisetron was stable under various storage and experimental conditions. This validated method was successfully applied to a pharmacokinetic study after intravenous administration of 1 mg granisetron to a pregnant subject. PMID- 26053160 TI - The use of 'mother and baby gifts' (MBGs) to increase uptake of supervised births in the Milne Bay Province of Papua New Guinea. AB - Improving access to supervised birth reduces mortality in developing countries. In the Milne Bay Province of Papua New Guinea, many women do not deliver at local health centres (HCs) because they feel 'shy' at presenting in an impoverished state and not having baby's clothes, and the state of facilities associated with HCs was poor. To overcome this, women were offered 'mother and baby gifts' (MBGs) at the time of delivery. We found subsequent increases in the rate of supervised birth in all HCs surveyed. PMID- 26053161 TI - Transient improvement of urticaria induces poor adherence as assessed by Morisky Medication Adherence Scale-8. AB - Poor adherence to medication is a major public health challenge. Here, we aimed to determine the adherence to oral and topical medications and to analyze underlying associated factors using the translated Japanese version of Morisky Medication Adherence Scale-8 regarding urticaria treatment. Web-based questionnaires were performed for 3096 registered dermatological patients, along with a subanalysis of 751 registered urticaria patients in this study. The adherence to oral medication was significantly associated with the frequency of hospital visits. Variables that affected the adherence to topical medication included age and experience of drug effectiveness. The rate of responses that "It felt like the symptoms had improved" varied significantly among the dermatological diseases treated with oral medications. Dermatologists should be aware that adherence to the treatment of urticaria is quite low. Regular visits and active education for patients with urticaria are mandatory in order to achieve a good therapeutic outcome by increasing the adherence. PMID- 26053163 TI - Reserves in Context: Planning for Leakage from Protected Areas. AB - When protected areas reduce threats within their boundaries, they often displace a portion of these threats into adjacent areas through a process known as 'leakage', undermining conservation objectives. Using theoretical models and a case study of terrestrial mammals in Indonesia, we develop the first theoretical explanation of how leakage impacts conservation actions, and highlight conservation strategies that mitigate these impacts. Although leakage is a socio economic process, we demonstrate that its negative impacts are also affected by the distribution of species, with leakage having larger impacts in landscapes with homogeneous distribution of species richness. Moreover, leakage has a greater negative effect when conservation strategies are implemented opportunistically, even creating the potential for perversely negative consequences from protected area establishment. Leakage thereby increases the relative benefits of systematic conservation planning over opportunism, especially in areas with high leakage and heterogeneously distributed species. Although leakage has the potential to undermine conservation actions, conservation planning can minimize this risk. PMID- 26053162 TI - The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. AB - Various neurodegenerative diseases are characterized by the accumulation of amyloidogenic proteins such as tau, alpha-synuclein, and amyloid-beta. Prior to the formation of these stable aggregates, intermediate species of the respective proteins-oligomers-appear. Recently acquired data have shown that oligomers may be the most toxic and pathologically significant to neurodegenerative diseases such as Alzheimer's and Parkinson's. The covalent modification of these oligomers may be critically important for biological processes in disease. Ubiquitin and small ubiquitin-like modifiers are the commonly used tags for degradation. While the modification of large amyloid aggregates by ubiquitination is well established, very little is known about the role ubiquitin may play in oligomer processing and the importance of the more recently discovered sumoylation. Many proteins involved in neurodegeneration have been found to be sumoylated, notably tau protein in brains afflicted with Alzheimer's. This evidence suggests that while the cell may not have difficulty recognizing dangerous proteins, in brains afflicted with neurodegenerative disease, the proteasome may be unable to properly digest the tagged proteins. This would allow toxic aggregates to develop, leading to even more proteasome impairment in a snowball effect that could explain the exponential progression in most neurodegenerative diseases. A better understanding of the covalent modifications of oligomers could have a huge impact on the development of therapeutics for neurodegenerative diseases. This review will focus on the proteolysis of tau and other amyloidogenic proteins induced by covalent modification, and recent findings suggesting a relationship between tau oligomers and sumoylation. PMID- 26053164 TI - Photocatalytic generation of hydrogen by core-shell WO3/BiVO4 nanorods with ultimate water splitting efficiency. AB - Efficient photocatalytic water splitting requires effective generation, separation and transfer of photo-induced charge carriers that can hardly be achieved simultaneously in a single material. Here we show that the effectiveness of each process can be separately maximized in a nanostructured heterojunction with extremely thin absorber layer. We demonstrate this concept on WO3/BiVO4+CoPi core-shell nanostructured photoanode that achieves near theoretical water splitting efficiency. BiVO4 is characterized by a high recombination rate of photogenerated carriers that have much shorter diffusion length than the thickness required for sufficient light absorption. This issue can be resolved by the combination of BiVO4 with more conductive WO3 nanorods in a form of core shell heterojunction, where the BiVO4 absorber layer is thinner than the carrier diffusion length while it's optical thickness is reestablished by light trapping in high aspect ratio nanostructures. Our photoanode demonstrates ultimate water splitting photocurrent of 6.72 mA cm(-2) under 1 sun illumination at 1.23 V(RHE) that corresponds to ~90% of the theoretically possible value for BiVO4. We also demonstrate a self-biased operation of the photoanode in tandem with a double junction GaAs/InGaAsP photovoltaic cell with stable water splitting photocurrent of 6.56 mA cm(-2) that corresponds to the solar to hydrogen generation efficiency of 8.1%. PMID- 26053165 TI - Sex Differences in Drosophila melanogaster Heterochromatin Are Regulated by Non Sex Specific Factors. AB - The eukaryotic genome is assembled into distinct types of chromatin. Gene-rich euchromatin has active chromatin marks, while heterochromatin is gene-poor and enriched for silencing marks. In spite of this, genes native to heterochromatic regions are dependent on their normal environment for full expression. Expression of genes in autosomal heterochromatin is reduced in male flies mutated for the noncoding roX RNAs, but not in females. roX mutations also disrupt silencing of reporter genes in male, but not female, heterochromatin, revealing a sex difference in heterochromatin. We adopted a genetic approach to determine how this difference is regulated, and found no evidence that known X chromosome counting elements, or the sex determination pathway that these control, are involved. This suggested that the sex chromosome karyotype regulates autosomal heterochromatin by a different mechanism. To address this, candidate genes that regulate chromosome organization were examined. In XX flies mutation of Topoisomerase II (Top2), a gene involved in chromatin organization and homolog pairing, made heterochromatic silencing dependent on roX, and thus male-like. Interestingly, Top2 also binds to a large block of pericentromeric satellite repeats (359 bp repeats) that are unique to the X chromosome. Deletion of X heterochromatin also makes autosomal heterochromatin in XX flies dependent on roX and enhances the effect of Top2 mutations, suggesting a combinatorial action. We postulate that Top2 and X heterochromatin in Drosophila comprise a novel karyotype-sensing pathway that determines the sensitivity of autosomal heterochromatin to loss of roX RNA. PMID- 26053167 TI - Symptomatic Gallbladder Sludge and its Relationship to Subsequent Biliary Events. PMID- 26053168 TI - Cow's Milk Protein Allergy Causing Persistent Elevation of Antitissue Transglutaminase Antibodies in a Child With Celiac Disease. PMID- 26053166 TI - Transcriptomic Analysis Reveals Possible Influences of ABA on Secondary Metabolism of Pigments, Flavonoids and Antioxidants in Tomato Fruit during Ripening. AB - Abscisic acid (ABA) has been proven to be involved in the regulation of climacteric fruit ripening, but a comprehensive investigation of its influence on ripening related processes is still lacking. By applying the next generation sequencing technology, we conducted a comparative analysis of the effects of exogenous ABA and NDGA (Nordihydroguaiaretic acid, an inhibitor of ABA biosynthesis) on tomato fruit ripening. The high throughput sequencing results showed that out of the 25728 genes expressed across all three samples, 10388 were identified as significantly differently expressed genes. Exogenous ABA was found to enhance the transcription of genes involved in pigments metabolism, including carotenoids biosynthesis and chlorophyll degradation, whereas NDGA treatment inhibited these processes. The results also revealed the crucial role of ABA in flavonoids synthesis and regulation of antioxidant system. Intriguingly, we also found that an inhibition of endogenous ABA significantly enhanced the transcriptional abundance of genes involved in photosynthesis. Our results highlighted the significance of ABA in regulating tomato ripening, which provided insight into the regulatory mechanism of fruit maturation and senescence process. PMID- 26053169 TI - Abdominal Paracentesis Drainage Does Not Increase Infection in Severe Acute Pancreatitis: A Prospective Study. AB - GOALS: To demonstrate the relationship between abdominal paracentesis drainage (APD) and infectious complications in moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP) patients. BACKGROUND: The effectiveness of APD for SAP was demonstrated in our previous study. However, the relationship between APD and infectious complications has not been fully elucidated. STUDY: We conducted a prospective cohort study of 255 patients with MSAP or SAP. The patients were divided into 2 groups: patients with acute pancreatitis who underwent APD (group 1) and patients with acute pancreatitis who did not undergo APD (group 2). Four types of infectious complications were evaluated: bacteremia, infected necrosis, pneumonia, and sepsis. The pathogens responsible for infectious complications were analyzed. The need for percutaneous catheter drainage and mortality were also compared between the 2 groups. RESULTS: A total of 255 patients were included with analogous baseline features. The rate of overall infectious complications in group 1 was 38.1%, which was lower than that in group 2 (52.7%, P=0.019). This difference was mainly based on infected necrosis (12.7% and 23.3% in groups 1 and 2, respectively, P=0.034). The microbial spectrum was similar in the 2 groups. Percutaneous catheter drainage was used less frequent in group 1 (18.3%) than in group 2 (31.8%, P=0.014). The infection-related mortality in groups 1 and 2 was 6.5% and 8.5%, respectively, and there was no significant difference (P=0.457). CONCLUSION: Our results indicate that APD did not increase the infectious complications and infection related mortality compared with the strategy without APD in patients with MSAP or SAP. PMID- 26053170 TI - A Novel Sleep Positioning Device Reduces Gastroesophageal Reflux: A Randomized Controlled Trial. AB - GOAL: We hypothesized that sleeping left-side down with the head/torso elevated reduces recumbent gastroesophageal reflux (GER). BACKGROUND: Previous studies show that sleeping with head of bed elevated or on wedge reduces GER and lying left-side down reduces GER versus right-side down and supine. No prior studies have evaluated the potential compounding effects of lying in an inclined position combined with lateral positioning on GER. STUDY: We evaluated a sleep-positioning device (SPD) consisting of an inclined base and body pillow that maintains lateral position while elevating the head/torso. This was a single institution, randomized controlled trial involving 20 healthy volunteers receiving 4 six-hour impedance-pH tests. After placement of reflux probe, subjects returned home, ate standardized meal, and lay down in randomly assigned positions: SPD right-side down (SPD-R), SPD left-side down (SPD-L), standard wedge any position (W), or flat any position (F). A wireless accelerometer documented position during each study. Number of reflux episodes (RE) and esophageal acid exposure (EAE) were calculated over 6 hours. RESULTS: Significantly less EAE occurred during sleeping SPD-L versus sleeping W, SPD-R, and F. The most EAE occurred during sleeping SPD R despite use of the positioning device. RE were significantly less SPD-L than SPD-R. Patients sleeping SPD-L and SPD-R spent the majority of first 2 hours and greater than half of 6 hours in assigned position. Patients sleeping W and F averaged more time supine than right or left. CONCLUSIONS: The sleep positioning device maintains recumbent position effectively. Lying left-side down, it reduces recumbent esophageal acid exposure. PMID- 26053171 TI - Inoculation of Transgenic Resistant Potato by Phytophthora infestans Affects Host Plant Choice of a Generalist Moth. AB - Pathogen attack and the plant's response to this attack affect herbivore oviposition preference and larval performance. Introduction of major resistance genes against Phytophthora infestans (Rpi-genes), the cause of the devastating late blight disease, from wild Solanum species into potato changes the plant pathogen interaction dynamics completely, but little is known about the effects on non-target organisms. Thus, we examined the effect of P. infestans itself and introduction of an Rpi-gene into the crop on host plant preference of the generalist insect herbivore, Spodoptera littoralis (Lepidoptera: Noctuidae). In two choice bioassays, S. littoralis preferred to oviposit on P. infestans inoculated plants of both the susceptible potato (cv. Desiree) and an isogenic resistant clone (A01-22: cv. Desiree transformed with Rpi-blb1), when compared to uninoculated plants of the same genotype. Both cv. Desiree and clone A01-22 were equally preferred for oviposition by S. littoralis when uninoculated plants were used, while cv. Desiree received more eggs compared to the resistant clone when both were inoculated with the pathogen. No significant difference in larval and pupal weight was found between S. littoralis larvae reared on leaves of the susceptible potato plants inoculated or uninoculated with P. infestans. Thus, the herbivore's host plant preference in this system was not directly associated with larval performance. The results indicate that the Rpi-blb1 based resistance in itself does not influence insect behavior, but that herbivore oviposition preference is affected by a change in the plant-microbe interaction. PMID- 26053172 TI - Recently evolved diversity and convergent radiations of rainforest mahoganies (Meliaceae) shed new light on the origins of rainforest hyperdiversity. AB - Tropical rainforest hyperdiversity is often suggested to have evolved over a long time-span (the 'museum' model), but there is also evidence for recent rainforest radiations. The mahoganies (Meliaceae) are a prominent plant group in lowland tropical rainforests world-wide but also occur in all other tropical ecosystems. We investigated whether rainforest diversity in Meliaceae has accumulated over a long time or has more recently evolved. We inferred the largest time-calibrated phylogeny for the family to date, reconstructed ancestral states for habitat and deciduousness, estimated diversification rates and modeled potential shifts in macro-evolutionary processes using a recently developed Bayesian method. The ancestral Meliaceae is reconstructed as a deciduous species that inhabited seasonal habitats. Rainforest clades have diversified from the Late Oligocene or Early Miocene onwards. Two contemporaneous Amazonian clades have converged on similar ecologies and high speciation rates. Most species-level diversity of Meliaceae in rainforest is recent. Other studies have found steady accumulation of lineages, but the large majority of plant species diversity in rainforests is recent, suggesting (episodic) species turnover. Rainforest hyperdiversity may best be explained by recent radiations from a large stock of higher level taxa. PMID- 26053173 TI - A comparative study of the modeled effects of atrazine on aquatic plant communities in midwestern streams. AB - Potential effects of atrazine on the nontarget aquatic plants characteristic of lower-order streams in the Midwestern United States were previously assessed using the Comprehensive Aquatic System Model (CASMATZ ). Another similar bioenergetics-based, mechanistic model, AQUATOX, was examined in the present study, with 3 objectives: 1) to develop an AQUATOX model simulation similar to the CASMATZ model reference simulation in describing temporal patterns of biomass production by modeled plant populations, 2) to examine the implications of the different approaches used by the models in deriving plant community-based levels of concern (LOCs) for atrazine, and 3) to determine the feasibility of implementing alternative ecological models to assess ecological impacts of atrazine on lower-order Midwestern streams. The results of the present comparative modeling study demonstrated that a similar reference simulation to that from the CASMATZ model could be developed using the AQUATOX model. It was also determined that development of LOCs and identification of streams with exposures in excess of the LOCs were feasible with the AQUATOX model. Compared with the CASMATZ model results, however, the AQUATOX model consistently produced higher estimates of LOCs and generated non-monotonic variations of atrazine effects with increasing exposures. The results of the present study suggest an opportunity for harmonizing the treatments of toxicity and toxicity parameter estimation in the CASMATZ and the AQUATOX models. Both models appear useful in characterizing the potential impacts of atrazine on nontarget aquatic plant populations in lower-order Midwestern streams. The present model comparison also suggests that, with appropriate parameterization, these process-based models can be used to assess the potential effects of other xenobiotics on stream ecosystems. PMID- 26053174 TI - Correction: Characterization of Calmodulin-Free Murine Inducible Nitric-Oxide Synthase. PMID- 26053175 TI - An empirical comparison of heterogeneity variance estimators in 12 894 meta analyses. AB - Heterogeneity in meta-analysis is most commonly estimated using a moment-based approach described by DerSimonian and Laird. However, this method has been shown to produce biased estimates. Alternative methods to estimate heterogeneity include the restricted maximum likelihood approach and those proposed by Paule and Mandel, Sidik and Jonkman, and Hartung and Makambi. We compared the impact of these five methods on the results of 12,894 meta-analyses extracted from the Cochrane Database of Systematic Reviews. We compared the methods in terms of the following: (1) the extent of heterogeneity, expressed as an I(2) statistic; (2) the overall effect estimate; (3) the precision of the overall effect estimate; and (4) p-values testing the no effect hypothesis. Results suggest that, in some meta-analyses, I(2) estimates differ by more than 50% when different heterogeneity estimators are used. Conclusions naively based on statistical significance (at a 5% level) were discordant for at least one pair of estimators in 7.5% of meta-analyses, indicating that the choice of heterogeneity estimator could affect the conclusions of a meta-analysis. These findings imply that using a single estimate of heterogeneity may lead to non-robust results in some meta analyses, and researchers should consider using alternatives to the DerSimonian and Laird method. PMID- 26053176 TI - Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients. AB - Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women's Interagency HIV Study, who reported NVP use for >1 month from 2003-2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized <= 74%, 75%-94% or >= 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2-26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity. PMID- 26053178 TI - Conductivity Enhancement of PEDOT:PSS Films via Phosphoric Acid Treatment for Flexible All-Plastic Solar Cells. AB - Highly conductive polymer films on plastic substrates are desirable for the application of flexible electronics. Here, we report the conductivity of poly(3,4 ethylenedioxythiophene): poly(styrenesulfonate) ( PEDOT: PSS) can be enhanced to 1460 S/cm via phosphoric acid (H3PO4) treatment. The conductivity enhancement is associated with the partial removal of PSS from the film. The H3PO4 treatment is compatible with plastic substrates, while sulfuric acid (H2SO4) can easily damage the plastic substrate. With the flexible electrode of poly(ether sulfone) (PES)/H3PO4-treated PEDOT: PSS, we have demonstrated flexible all-plastic solar cells (PES/H3PO4-treated PEDOT: PSS/PEI/P3HT:ICBA/EG-PEDOT:PSS). The cells exhibit an open-circuit voltage of 0.84 V, a fill factor of 0.60, and a power conversion efficiency of 3.3% under 100 mW/cm(2) white light illumination. PMID- 26053177 TI - Resveratrol Upregulates Cardiac SDF-1 in Mice with Acute Myocardial Infarction through the Deacetylation of Cardiac p53. AB - AIMS: We previously demonstrated that resveratrol (RSV) administration causes cardiac stromal cell-derived factor (SDF)-1 upregulation and can enhance the mobilization of stem cells in mice with acute myocardial infarction (AMI). However, the upstream signal transduction involved in SDF-1 regulation in the setting of AMI and RSV administration remains unclear. Because RSV is a sirtuin 1 (SIRT1) activator and SIRT proteins act as deacetylases, we investigated the role of SIRT1 in SDF-1 upregulation and its subsequent effects. METHODS AND RESULTS: In vitro experiments with H9C2 cardiomyocytes under hypoxia and serum-deprivation conditions showed that p53 acted upstream of SDF-1. RSV could not regulate SDF-1 effectively after SIRT1 silencing, indicating that it is dependent on SIRT1. Subsequently, male C57BL/6 mice were divided into four groups: 1) sham, 2) MI, 3) MI+RSV, and 4) MI+RSV plus nicotinamide, an inhibitor of the deacetylase activity of SIRT (MI+RSV+NAM). Compared with the sham mice, AMI caused a slight increase in the cardiac p53 level and resulted in significant SIRT1 downregulation and p53 acetylation or activation. Compared with the MI mice, MI+RSV administration improved the cardiac SDF-1 level and reversed the reduction of SIRT1 and the activation of p53. Furthermore, we observed less cardiac dysfunction in MI+RSV mice and determined that NAM abolished the effects of RSV. CONCLUSIONS: RSV enhances cardiac SDF-1 excretion after AMI partially through a SIRT1 normalization/p53 inactivation pathway. PMID- 26053179 TI - High Prevalence of HIV Infection and Bisexual Networks among a Sample of Men Who Have Sex with Men in Eastern China. AB - OBJECTIVE: To examine homosexual and heterosexual behaviors, behavioral networks and HIV infection among men who have sex with men (MSM) in Eastern China. METHODS: A cross-sectional survey was conducted among MSM in 2013 in a rural prefecture of Zhejiang province. Participants were interviewed for their sexual behaviors and sexual networks and were tested for HIV infection. RESULTS: A total of 620 MSM from gay bath houses and bars participated in the survey. Of them, 58.2% aged 18 to 39 years and 49.5% were currently married with a female. The age of first homosexual contact was 26.7 years on average, ranging from 12 to 66 years. 91.0% had multiple male sex partners and 86.1% also had female sex partners in lifetime. 70 (11.3%) of the participants were tested HIV-positive. A total of 620 independent egocentric sexual networks involving 620 study participants and 1,971 reported sexual partners in the past 12 months were constructed, including 70 networks for the 70 HIV-positive participants with their 221 sexual partners and 550 networks for the 550 HIV-negative participants with their 1,750 sexual partners. The median network degree was 3 (IQR 2-4) overall and was not different between HIV-positive participants (Median: 3; IQR: 2-4) and HIV-negative participants (Median: 3; IQR: 2-4) (Mann-Whitney test, Z= 0.015, P=0.998). The proportion of networks with a multiple male sexual partnership was 63.7% overall, 62.8% for HIV-positive participants and 63.8% for HIV-negative participants (chi2=0.025, P=0.875). The proportion of networks with both male and female sexual partners was 44.8% overall, 47.1% for HIV-positive participants and 44.5% for HIV-negative participants (chi2=0.169, P=0.681). Consistent condom use and knowledge of HIV infection status were rare within the network partners. CONCLUSIONS: The currently high HIV prevalence and complicated bisexual networks among MSM in the study area provides enhanced evidence for developing tailored prevention strategies for HIV transmission among and beyond the MSM population. PMID- 26053180 TI - Tracks through the genome to physiological events. AB - NEW FINDINGS: What is the topic of this review? We discuss tools available to access genome-wide data sets that harbour cell-specific, brain region-specific and tissue-specific information on exon usage for several species, including humans. In this Review, we demonstrate how to access this information in genome databases and its enormous value to physiology. What advances does it highlight? The sheer scale of protein diversity that is possible from complex genes, including those that encode voltage-gated ion channels, is vast. But this choice is critical for a complete understanding of protein function in the most physiologically relevant context. Many proteins of great interest to physiologists and neuroscientists are structurally complex and located in specialized subcellular domains, such as neuronal synapses and transverse tubules of muscle. Genes that encode these critical signalling molecules (receptors, ion channels, transporters, enzymes, cell adhesion molecules, cell-cell interaction proteins and cytoskeletal proteins) are similarly complex. Typically, these genes are large; human Dystrophin (DMD) encodes a cytoskeletal protein of muscle and it is the largest naturally occurring gene at a staggering 2.3 Mb. Large genes contain many non-coding introns and coding exons; human Titin (TTN), which encodes a protein essential for the assembly and functioning of vertebrate striated muscles, has over 350 exons and consequently has an enormous capacity to generate different forms of Titin mRNAs that have unique exon combinations. Functional and pharmacological differences among protein isoforms originating from the same gene may be subtle but nonetheless of critical physiological significance. Standard functional, immunological and pharmacological approaches, so useful for characterizing proteins encoded by different genes, typically fail to discriminate among splice isoforms of individual genes. Tools are now available to access genome-wide data sets that harbour cell-specific, brain region-specific and tissue-specific information on exon usage for several species, including humans. In this Review, we demonstrate how to access this information in genome databases and its enormous value to physiology. PMID- 26053181 TI - MicroRNA-106b inhibits osteoclastogenesis and osteolysis by targeting RANKL in giant cell tumor of bone. AB - Giant cell tumor (GCT) of bone consists of three major cell types: giant cells, monocytic cells, and stromal cells. From microarray analysis, we found that miR 106b was down-regulated in GCT clinical samples and further determined by fluorescence in situ hybridization. In addition, the expression of novel potential target of miR-106b, RANKL, was elevated in GCT along with previously determined targets in other tumors such as IL-8, MMP2 and TWIST. In a RANKL 3'UTR luciferase reporter assays, agomiR-106b repressed the luciferase activity and the effect was eliminated when the targeting site in the reporter was mutated, suggesting a direct regulation of miR-106b on RANKL mRNA. Moreover, overexpression of miR-106b in GCTSCs through TALEN-mediated site-specific knockin clearly inhibited osteoclastogenesis and osteolysis. By grafting the GCT onto the chick CAM, we confirmed the inhibitory effect of miR-106b on RANKL expression and giant cell formation. Furthermore, in an OVX mouse model, silencing of miR-106b increased RANKL protein expression and promoted bone resorption, while up regulation of miR-106b inhibited bone resorption. These results suggest that miR 106b is a novel suppressor of osteolysis by targeting RANKL and some other cytokines, which indicates that miR-106b may be a potential therapeutic target for the treatment of GCT. PMID- 26053182 TI - Targeting the Hedgehog signaling pathway in cancer: beyond Smoothened. AB - An essential role for Hedgehog (Hh) signaling in human cancer has been established beyond doubt. At present, targeting Hh signaling has mainly been investigated with SMO inhibitors. Unfortunately, resistance against currently used SMO inhibitors has already been observed in basal cell carcinoma (BCC) patients. Therefore, the use of Hh inhibitors targeting the signaling cascade more downstream of SMO could represent a more promising strategy. Furthermore, besides the classical canonical way of Hh signaling activation, non-canonical activation of the GLI transcription factors by multiple important signaling pathways (e.g. MAPK, PI3K, TGFbeta) has also been described, pinpointing the importance of targeting the transcription factors GLI1/2. The most promising agent in this context is probably the GLI1/2 inhibitor GANT61 which has been investigated preclinically in numerous tumor types in the last few years. In this review, the emerging role of Hh signaling in cancer is critically evaluated focusing on the potential of targeting Hh signaling more downstream of SMO, i.e. at the level of the GLI transcription factors. Furthermore, the working mechanism and therapeutic potential of the most extensively studied GLI inhibitor in human cancer, i.e. GANT61, is discussed in detail. In conclusion, GANT61 appears to be highly effective against human cancer cells and in xenograft mouse models, targeting almost all of the classical hallmarks of cancer and could hence represent a promising treatment option for human cancer. PMID- 26053183 TI - Progesterone receptor loss identifies luminal-type local advanced breast cancer with poor survival in patients who fail to achieve a pathological complete response to neoadjuvant chemotherapy. AB - The aim of this study was to investigate the potential of progesterone receptor (PgR) as a biomarker for differentiating estrogen receptor (ER)-positive patients who fail to achieve a pathological complete response to neoadjuvant chemotherapy (NCT) with different prognoses. A total of 327 consecutive, locally advanced breast cancer patients with ER-positive disease were included in this study. According to their HER-2 and Ki-67 status, the patients were classified into the Luminal-A or Luminal-B subtype. We evaluated the clinical and pathological response to NCT and relapse or death occurring during follow-up according to PgR status in the different luminal subtypes. In the Luminal-B subtype, patients with PgR- tumors had a relatively higher pathological complete response (pCR) rate (29.5% vs. 4.7% pCR, P < 0.001) and Miller-Payne grades (45.5% vs. 23.5% of grade 4-5, P = 0033) compared to PgR+ tumors. In Luminal-B patients with residual tumor after NCT, PgR loss was also independently correlated with poor relapse-free survival (P = 0.017; HR = 0.430; PgR- as a reference) and overall survival (P = 0.013; HR = 0.355; PgR- as a reference). However, in the Luminal-A subtype, there were no statistically significant differences between PgR+ and PgR- disease in response to NCT or survival. Our findings have demonstrated the prognostic value of PgR loss in the neoadjuvant setting, indicating that ER+/PgR- Luminal-B tumors warrant further attention due to their high risk of relapse after primary treatment. PMID- 26053184 TI - Leptin stimulates migration and invasion and maintains cancer stem-like properties in ovarian cancer cells: an explanation for poor outcomes in obese women. AB - The evidence linking obesity with ovarian cancer remains controversial. Leptin is expressed at higher levels in obese women and stimulates cell migration in other epithelial cancers. Here, we explored the clinical impact of overweight/obesity on patient prognosis and leptin's effects on the metastatic potential of ovarian cancer cells. We assessed clinical outcomes in 70 ovarian cancer patients (33 healthy weight and 37 overweight) that were validated with an external cohort from The Cancer Genome Atlas (TCGA) database. Progression-free and overall survival rates were significantly decreased in overweight patients. Similarly, a worse overall survival rate was found in TCGA patients expressing higher leptin/OB-Rb levels. We explored serum and ascites leptin levels and OB-Rb expression in our cohort. Serum and ascites leptin levels were higher in overweight patients experiencing worse survival. OB-Rb was more highly expressed in ascites and metastases than in primary tumors. Leptin exposure increased cancer cell migration/invasion through leptin-mediated activation of JAK/STAT3, PI3/AKT and RhoA/ROCK and promoted new lamellipodial, stress-fiber and focal adhesion formation. Leptin also contributed to the maintenance of stemness and the mesenchymal phenotype in ovarian cancer cells. Our findings demonstrate that leptin stimulated ovarian cancer cell migration and invasion, offering a potential explanation for the poor prognosis among obese women. PMID- 26053185 TI - Inhaled aztreonam lysine versus inhaled tobramycin in cystic fibrosis. An economic evaluation. AB - RATIONALE: Pseudomonas aeruginosa infection is a significant cause of morbidity and mortality in patients with cystic fibrosis and is associated with a high economic burden. A recently published comparator trial demonstrated that outcomes in patients with cystic fibrosis with chronic P. aeruginosa infections switched from tobramycin solution for inhalation to aztreonam lysine for inhalation were better than those of patients who continued on tobramycin. OBJECTIVES: To compare overall costs of treatment of chronic inhaled tobramycin and aztreonam lysine in patient with cystic fibrosis who have chronic Pseudomonas infection, taking differences in outcomes into account. METHODS: A cost-effectiveness analysis with a 3-year time horizon was performed to simulate the economic consequences of either treatment from the perspective of a third party payer in the United States. We extrapolated results from the comparator trial and used data regarding clinical outcomes, quality of life, and costs from published literature and proprietary databases. A Markov structure was used to consider transitions between health states, defined principally by levels of percent predicted of FEV1. Extensive scenario and probabilistic sensitivity analyses were performed. MEASUREMENTS AND MAIN RESULTS: Use of aztreonam lysine for inhalation was associated with an average cost saving of $41,947 per patient over 3 years, as well as greater quality-adjusted life-years and total life-years. Scenario analyses demonstrated that these findings were robust to changes in key assumptions. CONCLUSIONS: It appears, with high likelihood, that the use of aztreonam solution for inhalation is associated with cost savings, an increase in quality-adjusted life-years, and improved clinical outcomes among patients with extensive prior use of tobramycin solution for inhalation who are naive to inhaled aztreonam lysine. PMID- 26053186 TI - Mercapturic Acids Derived from the Toxicants Acrolein and Crotonaldehyde in the Urine of Cigarette Smokers from Five Ethnic Groups with Differing Risks for Lung Cancer. AB - The Multiethnic Cohort epidemiology study has clearly demonstrated that, compared to Whites and for the same number of cigarettes smoked, African Americans and Native Hawaiians have a higher risk for lung cancer whereas Latinos and Japanese Americans have a lower risk. Acrolein and crotonaldehyde are two important constituents of cigarette smoke which have well documented toxic effects and could play a role in lung cancer etiology. Their urinary metabolites 3 hydroxypropylmercapturic acid (3-HPMA) and 3-hydroxy-1-methylpropylmercapturic acid (HMPMA), respectively, are validated biomarkers of acrolein and crotonaldehyde exposure. We quantified levels of 3-HPMA and HMPMA in the urine of more than 2200 smokers from these five ethnic groups, and also carried out a genome wide association study using blood samples from these subjects. After adjusting for age, sex, creatinine, and total nicotine equivalents, geometric mean levels of 3-HPMA and HMPMA were significantly different in the five groups (P < 0.0001). Native Hawaiians had the highest and Latinos the lowest geometric mean levels of both 3-HPMA and HMPMA. Levels of 3-HPMA and HMPMA were 3787 and 2759 pmol/ml urine, respectively, in Native Hawaiians and 1720 and 2210 pmol/ml urine in Latinos. These results suggest that acrolein and crotonaldehyde may be involved in lung cancer etiology, and that their divergent levels may partially explain the differing risks of Native Hawaiian and Latino smokers. No strong signals were associated with 3-HPMA in the genome wide association study, suggesting that formation of the glutathione conjugate of acrolein is mainly non enzymatic, while the top significant association with HMPMA was located on chromosome 12 near the TBX3 gene, but its relationship to HMPMA excretion is not clear. PMID- 26053188 TI - Exploratory Study Examining Clinical Measures of Adiposity Risk for Predicting Obesity in Adolescents with Physical Disabilities. AB - OBJECTIVE: The purposes of this study were to assess the accuracy of clinical measures for predicting adiposity when compared with a criterion standard of body fat percentage measured by dual-energy X-ray absorptiometry and to determine the most appropriate cut points for classifying obesity for each measure in adolescents with physical disability. DESIGN: Body mass index, triceps skinfolds, and waist, arm, and leg circumferences were collected on 29 adolescents aged 14 17 yrs with spinal cord injury, cerebral palsy, or spina bifida. Percentage of body fat was measured using dual-energy X-ray absorptiometry. Multiple linear regression models were used to assess the ability of measures to predict percentage of body fat. Receiver operating characteristic curves were used to identify optimal cut points for each measure. RESULTS: Although all clinical measures correlated with body fat as measured by dual-energy X-ray absorptiometry, current cut points are not adequate in this group. Using a body mass index of 20 kg/m (boys) and 19 kg/m (girls) was optimal but still misclassified a significant number of participants as nonobese in this group. Using the optimal cut points for waist circumference, which were 83 cm (boys) and 78 cm (girls), was the best predictor. CONCLUSIONS: Body mass index, triceps skinfolds, and waist, leg, and arm circumferences are valid measures for estimating obesity in adolescents with physical disability, but further research is needed to validate disability-specific cut points. PMID- 26053187 TI - Gait Efficiency on an Uneven Surface Is Associated with Falls and Injury in Older Subjects with a Spectrum of Lower Limb Neuromuscular Function: A Prospective Study. AB - OBJECTIVE: The objective of this study was to determine which gait measures on smooth and uneven surfaces predict falls and fall-related injuries in older subjects with diabetic peripheral neuropathy. DESIGN: Twenty-seven subjects (12 women) with a spectrum of peripheral nerve function ranging from normal to moderately severe diabetic peripheral neuropathy walked on smooth and uneven surfaces, with gait parameters determined by optoelectronic kinematic techniques. Falls and injuries were then determined prospectively over the following year. RESULTS: Seventeen subjects (62.9%) fell and 12 (44.4%) sustained a fall-related injury. As compared with nonfallers, the subject group reporting any fall, as well as the subject group reporting fall-related injury, demonstrated decreased speed, greater step width (SW), shorter step length (SL), and greater SW-to-SL ratio (SW:SL) on both surfaces. Uneven surface SW:SL was the strongest predictor of falls (pseudo-r = 0.65; P = 0.012) and remained so with inclusion of other relevant variables into the model. Post hoc analysis comparing injured with noninjured fallers showed no difference in any gait parameter. CONCLUSION: SW:SL on an uneven surface is the strongest predictor of falls and injuries in older subjects with a spectrum of peripheral neurologic function. Given the relationship between SW:SL and efficiency, older neuropathic patients at increased fall risk appear to sacrifice efficiency for stability on uneven surfaces. PMID- 26053189 TI - Aerobic Interval Training Elicits Different Hemodynamic Adaptations Between Heart Failure Patients with Preserved and Reduced Ejection Fraction. AB - OBJECTIVE: This investigation explored how aerobic interval training influences central or peripheral hemodynamic response(s) to exercise in patients with heart failure (HF) with preserved ejection fraction (HFpEF) or those with HF with reduced ejection fraction (HFrEF). DESIGN: One hundred twenty HF patients were divided into four groups: HFpEF and HFrEF with aerobic interval training (3-min intervals at 40% and 80% VO2peak for 30 mins/day, 3 days/wk for 12 wks) and general health care groups. Exercise hemodynamics in the heart, frontal cerebral lobe, and vastus lateralis muscle, and oxygenation in the frontal cerebral lobe and vastus lateralis muscle were measured before and after the intervention. RESULTS: Aerobic interval training significantly (1) improved pumping function with enhanced peak cardiac power index in the HFrEF group and improved diastolic function with reduction of the E/E' ratio in the HFpEF group, (2) increased blood distribution to the frontal cerebral lobe/vastus lateralis muscle and O2 extraction by vastus lateralis muscle during exercise in the HFpEF group compared with the HFrEF group, (3) heightened VO2peak in both HFpEF and HFrEF groups and lowered the VE/VCO2 slope in the HFpEF group, and (4) increased the Short Form-36 physical/mental component scores and decreased the Minnesota Living with Heart Failure questionnaire score in both HFpEF and HFrEF groups. CONCLUSIONS: Aerobic interval training effectively enhances cardiac hemodynamic response to exercise in HFrEF patients while increasing the delivery/use of O2 to exercising skeletal muscles and frontal cerebral lobe tissues in HFpEF patients, thereby improving global/disease-specific quality-of-life measures in these HF patients. PMID- 26053190 TI - Ultrasound imaging facilitated the detection of a double crush radial nerve injury. PMID- 26053191 TI - Efficacy of Ultrasound in the Diagnosis of Biceps Tendon Dislocation. PMID- 26053192 TI - Prehabilitation--Is It Worth Our While? PMID- 26053193 TI - Re: handheld dynamometry for plantar flexors? PMID- 26053194 TI - Synthesizing Porous NaTi2(PO4)3 Nanoparticles Embedded in 3D Graphene Networks for High-Rate and Long Cycle-Life Sodium Electrodes. AB - Sodium ion batteries attract increasing attention for large-scale energy storage as a promising alternative to the lithium counterparts in view of low cost and abundant sodium source. However, the large ion radius of Na brings about a series of challenging thermodynamic and kinetic difficulties to the electrodes for sodium-storage, including low reversible capacity and low ion transport, as well as large volume change. To mitigate or even overcome the kinetic problems, we develop a self-assembly route to a novel architecture consisting of nanosized porous NASICON-type NaTi2(PO4)3 particles embedded in microsized 3D graphene network. Such architecture synergistically combines the advantages of a 3D graphene network and of 0D porous nanoparticles. It greatly increases the electron/ion transport kinetics and assures the electrode structure integrity, leading to attractive electrochemical performance as reflected by a high rate capability (112 mAh g(-1) at 1C, 105 mAh g(-1) at 5C, 96 mAh g(-1) at 10C, 67 mAh g(-1) at 50C), a long cycle-life (capacity retention of 80% after 1000 cycles at 10C), and a high initial Coulombic efficiency (>79%). This nanostructure design provides a promising pathway for developing high performance NASICON-type materials for sodium storage. PMID- 26053195 TI - Determining the stability of complete blood count parameters in stored blood samples using the SYSMEX XE-5000 automated haematology analyser. AB - INTRODUCTION: In this study, changes that occur in various blood parameters as determined by the Sysmex XE-5000 analyser upon storage of blood samples for 72 h were investigated. METHODS: Blood specimens (200) were processed through the SYSMEX XE-5000 haematology analyser within 4 h of collection. Each specimen was distributed into two aliquots and one stored at 4 degrees C and the other at room temperature (25 +/- 1 degrees C). Both stored aliquots were retested after 24, 48 and 72 h. The mean, mean per cent change and mean absolute difference between the value at 4 h and each time point for all parameters were calculated. RESULTS: Among CBC parameters tested, the white cell count, red cell count and haemoglobin levels were found to be stable for up to 72 h. The mean cell volume and haematocrit changed significantly following 24-h storage at room temperature. Reticulocytes were stable for 72 h under both storage conditions. Among the differential parameters, results of the monocyte count displayed significant change after 24-h storage at room temperature. CONCLUSION: The data presented suggest that clinically reliable results for some CBC parameters can be obtained from specimens that are stored at 4 degrees C for up to 72 h. PMID- 26053197 TI - P-S bond cleavage in reactions of thiophosphinidene-bridged dimolybdenum complexes with [Co2(CO)8] to give phosphinidene-bridged heterometallic derivatives. AB - The thiophosphinidene complex [Mo2Cp2(MU-kappa(2):kappa(1),eta(6)-SPMes*)(CO)2] (Mes* = 2,4,6-C6H2(t)Bu3) reacted with [Co2(CO)8] at room temperature or below to give several of the following phosphinidene-bridged products, depending on reaction conditions: the MoCo complexes [CoMoCp(MU-kappa(1):kappa(1),eta(6) PMes*)(CO)3] and [CoMoCp(MU-PMes*)(CO)5] (Co-Mo = 2.972(1) A), the MoCo3 cluster [Co3MoCp(MU3-PMes*)(CO)9] (Co-Mo = 2.664(1), 2.810(1) A), and the sulphido bridged tetranuclear complexes [Co2Mo2Cp2(MU-kappa(1):kappa(1):kappa(1),eta(4) PMes*)(MU3-S)(CO)7] and [Co3MoCp(MU-kappa(1):kappa(1):kappa(1),eta(4)-PMes*)(MU3 S)(CO)8]. In contrast, the thiophosphinidene complex [Mo2Cp2(MU kappa(2):kappa(1),eta(4)-SPMes*)(CO)3] reacted with the same cobalt reagent selectively to give the above Mo2Co2 complex in very high yield. The latter could be decarbonylated photochemically to give [Co2Mo2Cp2(MU kappa(1):kappa(1):kappa(1),eta(6)-PMes*)(MU3-S)(CO)6] (Co-Co = 2.435(3), Co-Mo = 2.769(2), 2.798(2) A), after an eta(4)- to eta(6)-haptotropic rearrangement of the aryl ring of the phosphinidene ligand that could be reversed upon reaction with CO. The related complex [Mo2Cp2(MU-kappa(2):kappa(1),eta(4) SPMes*)(CO)2(CN(t)Bu)], however, displayed poor selectivity towards the cobalt dimer and yielded a mixture of CoMo complexes [CoMoCp(MU-PMes*)(CO)5] and [CoMoCp(MU-PMes*)(CO)3(CN(t)Bu)2], and the tetranuclear sulphido-bridged ones [Co2Mo2Cp2(MU-kappa(1):kappa(1):kappa(1),eta(4)-PMes*)(MU3-S)(CO)6(CN(t)Bu)] (Co Co = 2.533(1), Co-Mo = 2.7485(9), 2.770(1) A) and [Co3MoCp(MU kappa(1):kappa(1):kappa(1),eta(4)-PMes*)(MU3-S)(CO)7(CN(t)Bu)] (Co-Co = 2.4120(7) to 2.5817(7) A). This reduction in selectivity might have an electronic origin rather than a steric origin, since the related but cationic substrate [Mo2Cp2{MU kappa(2):kappa(1),eta(5)-SP(C6H3(t)Bu3)}(CO)2(CN(t)Bu)]BAr [Ar' = 3,5-C6H3(CF3)2] reacted with [Co2(CO)8] more selectively to give the sulphido-bridged Co2Mo2 complex [Co2Mo2Cp2{MU-kappa(1):kappa(1):kappa(1),eta(5)-P(C6H3(t)Bu3)}(MU3 S)(CO)6(CN(t)Bu)]BAr, along with small amounts of the Co3Mo complex [Co3MoCp{MU kappa(1):kappa(1):kappa(1),eta(5)-P(C6H3(t)Bu3)}(MU3-S)(CO)7(CN(t)Bu)]BAr (Co-Co = 2.414(2) to 2.560(2) A). The structure of the new complexes was analyzed on the basis of the corresponding X-ray diffraction and spectroscopic data, and likely reaction pathways were discussed on the basis of the above results and some additional experiments. PMID- 26053196 TI - Comparative brain morphology of Neotropical parrots (Aves, Psittaciformes) inferred from virtual 3D endocasts. AB - Psittaciformes are a very diverse group of non-passerine birds, with advanced cognitive abilities and highly developed locomotor and feeding behaviours. Using computed tomography and three-dimensional (3D) visualization software, the endocasts of 14 extant Neotropical parrots were reconstructed, with the aim of analysing, comparing and exploring the morphology of the brain within the clade. A 3D geomorphometric analysis was performed, and the encephalization quotient (EQ) was calculated. Brain morphology character states were traced onto a Psittaciformes tree in order to facilitate interpretation of morphological traits in a phylogenetic context. Our results indicate that: (i) there are two conspicuously distinct brain morphologies, one considered walnut type (quadrangular and wider than long) and the other rounded (narrower and rostrally tapered); (ii) Psittaciformes possess a noticeable notch between hemisphaeria that divides the bulbus olfactorius; (iii) the plesiomorphic and most frequently observed characteristics of Neotropical parrots are a rostrally tapered telencephalon in dorsal view, distinctly enlarged dorsal expansion of the eminentia sagittalis and conspicuous fissura mediana; (iv) there is a positive correlation between body mass and brain volume; (v) psittacids are characterized by high EQ values that suggest high brain volumes in relation to their body masses; and (vi) the endocranial morphology of the Psittaciformes as a whole is distinctive relative to other birds. This new knowledge of brain morphology offers much potential for further insight in paleoneurological, phylogenetic and evolutionary studies. PMID- 26053198 TI - Burden of dose escalation with tumour necrosis factor inhibitors in rheumatoid arthritis: a systematic review of frequency and costs. AB - OBJECTIVES: Optimising therapy to minimise disease activity is the goal for treating rheumatoid arthritis (RA) today. In refractory disease requiring biologics, the ability to modify therapy may be limited. In the case of the most widely used biologics, the TNF inhibitors (TNFi), dose escalation consisting of increasing the dose and/or shortening the interval between doses is often reported. METHODS: We systematically searched PubMed, EMBASE, Cochrane and Centre of Disseminated Reviews for reports of dose escalation of TNFi in RA and the economic effects of such a practice. RESULTS: Of 41 publications, 36 reported dose escalation and a weighted proportion of dose escalators was calculated for each drug. The proportion of dose escalators varied widely (adalimumab 7.5% to 36%, etanercept 0% to 22%, and infliximab 0% to 80%) due to a variety of methods for defining dose escalation. Based on 33 studies, the weighted proportion of dose escalators was adalimumab 14.9%, etanercept 4.9% and infliximab 41.7%. Six studies reported economic data comparing dose escalators with non-dose escalators. Adalimumab drug costs increased 27% to 43%, with total costs increasing 28% to 34%; infliximab drug costs increased 14% to 71%, RA-related costs increased 25% to 54% and total costs increased 14% to 34% and etanercept drug costs increased 3.2% to 19%, RA-related costs increased 4.5% and total costs increased 2.2% to 15%. CONCLUSIONS: Escalating the dose of TNFi in inadequate responders in RA is widespread, occurring most frequently with infliximab and least with etanercept. This practice not only increases drug costs, but also RA related and total costs. PMID- 26053199 TI - Image-guided surgery using multimodality strategy and molecular probes. AB - The ultimate goal of cancer surgery is to maximize the excision of tumorous tissue with minimal damage to the collateral normal tissues, reduce the postoperative recurrence, and improve the survival rate of patients. In order to locate tumor lesions, highlight tumor margins, visualize residual disease in the surgical wound, and map potential lymph node metastasis, various imaging techniques and molecular probes have been investigated to assist surgeons to perform more complete tumor resection. Combining imaging techniques with molecular probes is particularly promising as a new approach for image-guided surgery. Considering inherent limitations of different imaging techniques and insufficient sensitivity of nonspecific molecular probes, image-guided surgery with multimodality strategy and specific molecular probes appears to be an optimal choice. In this article, we briefly describe typical imaging techniques and molecular probes followed by a focused review on the current progress of multimodal image-guided surgery with specific molecular navigation. We also discuss optimal strategy that covers all stages of image-guided surgery including preoperative scanning of tumors, intraoperative inspection of surgical bed and postoperative care of patients. PMID- 26053200 TI - Ovalbumin-specific IgE/total IgE ratio improves the prediction of tolerance development in egg-allergic children aged >=5 years. PMID- 26053201 TI - BRAF Mutations in Canine Cancers. AB - Activating mutations of the BRAF gene lead to constitutive activation of the MAPK pathway. Although many human cancers carry the mutated BRAF gene, this mutation has not yet been characterized in canine cancers. As human and canine cancers share molecular abnormalities, we hypothesized that BRAF gene mutations also exist in canine cancers. To test this hypothesis, we sequenced the exon 15 of BRAF, mutation hot spot of the gene, in 667 canine primary tumors and 38 control tissues. Sequencing analysis revealed that a single nucleotide T to A transversion at nucleotide 1349 occurred in 64 primary tumors (9.6%), with particularly high frequency in prostatic carcinoma (20/25, 80%) and urothelial carcinoma (30/45, 67%). This mutation results in the amino acid substitution of glutamic acid for valine at codon 450 (V450E) of canine BRAF, corresponding to the most common BRAF mutation in human cancer, V600E. The evolutional conservation of the BRAF V600E mutation highlights the importance of MAPK pathway activation in neoplasia and may offer opportunity for molecular diagnostics and targeted therapeutics for dogs bearing BRAF-mutated cancers. PMID- 26053202 TI - Skin substitute-assisted repair shows reduced dermal fibrosis in acute human wounds validated simultaneously by histology and optical coherence tomography. AB - Skin substitutes are heterogeneous biomaterials designed to accelerate wound healing through provision of replacement extracellular matrix. Despite growing evidence for their use in chronic wounds, the role of skin substitutes in acute wound management and their influence on fibrogenesis remains unclear. Skin substitute characteristics including biocompatibility, porosity, and elasticity strongly influence cellular behavior during wound healing. Thus, we hypothesize that structural and biomechanical variation between biomaterials may induce differential scar formation after cutaneous injury. The following human prospective cohort study was designed to investigate this premise. Four 5-mm full thickness punch biopsies were harvested from 50 volunteers. In all cases, site 1 healed by secondary intention, site 2 was treated with collagen-GAG scaffold (CG), and decellularised dermis (DCD) was applied to site 3 while tissue extracted from site 4 was replaced (autograft). Healing tissue was assessed weekly with optical coherence tomography (OCT), before being excised on days 7, 14, 21, or 28 depending on study group allocation for later histological and immunohistochemical evaluation. Extracted RNA was used in microarray analysis and polymerase chain reaction of highlighted genes. Autograft treatment resulted in minimal fibrosis confirmed immunohistochemically and with OCT through significantly lower collagen I levels (p = 0.047 and 0.03) and reduced mean grayscale values (p = 0.038 and 0.015), respectively. DCD developed intermediate scar formation with partial rete ridge reformation and reduced fasiculonodular fibrosis. It was uniquely associated with late up-regulation of matrix metalloproteinases 1 and 3, oncostatin M, and interleukin-10 (p = 0.007, 0.04, 0.019, 0.019). Regenerated dermis was significantly thicker in DCD and autografts 28 days post-injury compared with control and CG samples (p = 0.003 and < 0.0001). In conclusion, variable fibrotic outcomes were observed in skin substitute-treated wounds with reduced scarring in autograft and DCD samples compared with controls. OCT enabled concurrent assessment of wound morphology and quantification of dermal fibrosis. PMID- 26053203 TI - Dorsal Plating of Unstable Scaphoid Fractures and Nonunions. AB - Achieving stable fixation of displaced acute and chronic nonunited scaphoid fractures continues to be a challenge for the treating surgeon. The threaded compression screw has been the mainstay of treatment of these fractures for the last 3 decades; however, persistent nonunion after screw fixation has prompted development of new techniques. Recent results of volar buttress plating have been promising. We describe a novel technique of dorsal scaphoid plating. In contrast to volar plating, the dorsal plate is biomechanically more favorable as it utilizes the tension side of the scaphoid bone for dynamic compression. Dorsal scaphoid plating provides a more stable construct than the traditional Herbert screw and mitigates the need for vascular or corticocancellous bone grafting in most cases. PMID- 26053204 TI - New Strategies in the Treatment of Unilateral Sporadic Retinoblastoma. PMID- 26053205 TI - Beating Cilia and Whipping Flagella: More Than Meets the Eye. PMID- 26053208 TI - Erratum for "Reliability and Application Variability of a Commercially Available Infrared Videonystagmography Unit". PMID- 26053207 TI - Clinical Insights Into Foveal Morphology in Albinism. AB - PURPOSE: A hallmark of albinism is foveal hypoplasia. However, literature suggests variable foveal development. This study evaluates the association between ocular phenotype and foveal morphology to demonstrate the broad structural and functional spectrum. METHODS: Best-corrected visual acuity (BCVA), nystagmus, angle kappa, stereoacuity, iris transillumination, macular melanin presence, foveal avascular zone, and annular reflex were recorded in 14 patients with albinism. Spectral-domain optical coherence tomography provided macular images. RESULTS: The clinical phenotype was broad, with BCVA varying from 20/20 to 20/100. Better BCVA was associated with a preserved foveal avascular zone, annular macular reflex, stereoacuity, and macular melanin. Imaging demonstrated a continuum of foveal development correlating with BCVA. Individuals with a rudimentary pit had normal inner and outer segment lengthening and better BCVA. CONCLUSIONS: The spectrum of ocular structure and visual function in albinism is broad, suggesting a possible diagnosis of albinism in a patient with an even more normal clinical presentation. PMID- 26053209 TI - Comparison of the Efficacy of Medial Rectus Recession and Lateral Rectus Resection for Treatment of Divergence Insufficiency. AB - PURPOSE: Surgical approaches for divergence insufficiency esotropia include medial rectus recession and lateral rectus resection. A retrospective chart review compared the efficacy of each. METHODS: Eighteen patients older than 50 years with divergence insufficiency esotropia who were operated on between 2005 and 2012 by two surgeons were reviewed. RESULTS: Nine patients underwent medial rectus recession and nine underwent lateral rectus resection. The average distance esotropia decreased from 19.75 to 3.2 prism diopters in the medial rectus recession group (P = .001) and from 17.7 to 2.6 prism diopters in the lateral rectus resection group (P = .0002). The disparity between distance and near alignment decreased from 7.3 to 3.4 in the medial rectus recession group (P = .019) and from 9 to 5.4 prism diopters in the lateral rectus resection group (P = .004). CONCLUSIONS: Both medial rectus recession and lateral rectus resection are effective treatment for divergence insufficiency, with both decreasing distance-near disparity. PMID- 26053210 TI - Goniotomy for Steroid-Induced Glaucoma: Clinical and Tonographic Evidence to Support Therapeutic Goniotomy. AB - PURPOSE: To report the surgical results of goniotomy for corticosteroid-induced glaucoma and to provide evidence to support its use as initial surgical therapy. METHODS: The medical records of 5 patients with a history of goniosurgery for steroid-induced glaucoma were reviewed. Preoperative and postoperative clinical findings were reviewed, including the topical use of steroids, tonometric and gonioscopic findings, goniosurgery, and postoperative results. In addition, tonography was performed on one patient to document the improved facility of outflow following successful goniosurgery. RESULTS: Surgical success was achieved in all patients, with intraocular pressures less than 18 mm Hg without the use of medication for an average follow-up period of 11.5 years (range: 9 months to 30 years). A normal postoperative facility of outflow (C = 0.30 mm3/min/mm Hg) was determined in one patient. No complications of surgery were experienced. CONCLUSION: Goniotomy is an effective procedure for persistent steroid-induced glaucoma, and should be considered for initial surgical treatment. PMID- 26053212 TI - Pediatric Experience in Surgical Treatment of Acquired Esotropia Associated With High Myopia. PMID- 26053213 TI - Scheimpflug Imaging of Bilateral Ectopia Lentis and the Wrinkled Anterior Lens Capsule in Marfan's Syndrome. PMID- 26053211 TI - Ocular Neuromyotonia and Myasthenia Gravis. PMID- 26053214 TI - Evaluation of an educational activity in the oral health of students. AB - OBJECTIVE: To investigate the influence of educational activity in the school environment based on prescriptive and subjective oral health indicators. METHODS: Cross-sectional, comparative study involving students between 9 and 12 years of age, from schools that have educational activities and those that do not, designated schools A and B. The oral health indicators used were the Simplified Oral Hygiene Index (OHI-S) and the Community Periodontal Index (CPITN). Knowledge and attitudes with regard to oral health were evaluated using a structured questionnaire. RESULTS: A total of 289 schoolchildren took part, 50.5% from school A and 49.5% from school B, in the town of Montes Claros, in the Brazilian state of Minas Gerais. In school A, the schoolchildren's OHI-S was satisfactory for 9.6%, normal for 78.8% and deficient for 11.6%, while in school B, the respective percentages were 3.5%, 17.5% and 79% (chi-squared, P < 0.001). The students in school A showed better CPITN results, namely lack of bleeding for 61.6%, the presence of bleeding for 29.5% and presence of tartar for 8.9%, while in school B, the respective results were 25.2%, 45.5% and 29.4% (chi-squared, P < 0.001). Students in school A achieved more correct answers in questions that evaluated knowledge of oral health. The account of daily use of dental floss in school A was 21.7% and in B, 3.6% (chi-squared, P < 0.001). CONCLUSION: It is believed that educational activity in the school environment had a positive effect on oral health conditions, the consolidation of knowledge and incorporation of oral hygiene habits. PMID- 26053215 TI - Locked 2'-Deoxy-2',4'-Difluororibo Modified Nucleic Acids: Thermal Stability, Structural Studies, and siRNA Activity. AB - 2'-Deoxy-2',4'-difluorouridine (2',4'-diF-rU) was readily incorporated into DNA and RNA oligonucleotides via standard solid phase synthesis protocols. NMR and thermal denaturation (Tm) data of duplexes was consistent with the 2',4'-diF-rU nucleotides adopting a rigid North (RNA-like) sugar conformation, as previously observed for the nucleoside monomer. The impact of this modification on Tm is neutral when incorporated within RNA:RNA duplexes, mildly destabilizing when located in the RNA strand of a DNA:RNA duplex, and highly destabilizing when inserted in the DNA strand of DNA:RNA and DNA:DNA duplexes. Molecular dynamics calculations suggest that the destabilization effect in DNA:DNA and DNA:RNA duplexes is the result of structural distortions created by A/B junctions within the helical structures. Quantum mechanics calculations suggest that the "neutral" effect imparted to A-form duplexes is caused by alterations in charge distribution that compensate the stabilizing effect expected for a pure North puckered furanose sugar. 2',4'-diF-RNA modified siRNAs were able to trigger RNA interference with excellent efficiency. Of note, incorporation of a few 2',4'-diF rU residues in the middle of the guide (antisense) strand afforded siRNAs that were more potent than the corresponding siRNAs containing LNA and 2'-F-ANA modifications, and as active as the 2'-F-RNA modified siRNAs. PMID- 26053216 TI - Human Serum from Urban and Rural Adolescents and Their Mothers Shows Exposure to Polychlorinated Biphenyls Not Found in Commercial Mixtures. AB - Although polychlorinated biphenyls are no longer sold as commercial mixtures, they are still being produced through modern manufacturing processes. We have previously shown that non-Aroclor PCB 11 is prevalent in indoor and outdoor air and sediment and detected in human serum. Here we report the prevalence of non Aroclor PCB congeners (<=0.20 wt % in Aroclor) in human serum collected from urban and rural adolescents and their mothers. We hypothesized that additional non-Aroclor congeners are present in serum. Sera were extracted and detected for 209 PCBs using gas chromatography-tandem mass spectrometry. A list of 70 non Aroclor PCB congeners was determined by measurement of original Aroclors. PCB 11, 14, 35, and 209 are the major dominating and most frequently detected congeners. PCB 14 and 35 have not been previously reported for environmental matrices. Adolescents have significantly lower total non-Aroclor PCB concentrations than mothers in East Chicago (p < 0.001) and Columbus Junction (p = 0.008). There are significant differences in non-Aroclor PCBs between East Chicago community and Columbus Junction community (p < 0.001). Non-Aroclor PCBs represent an average of 10% (and up to 50%) of total PCBs measured in serum. An average of 50% (and up to 100%) of these concentrations may be attributed to aryl azo and phthalocyanine paint pigments. PMID- 26053218 TI - The Future of Research in Multiple Sclerosis. PMID- 26053217 TI - Impact of deep brain stimulation on pharyngo-esophageal motility: a randomized cross-over study. AB - BACKGROUND: Bilateral subthalamic nucleus (STN) stimulation is used to alleviate Parkinson's disease (PD) motor symptoms. Recently, it has been shown that this therapeutic also increased gut cholinergic contractions. We therefore investigated the effect of STN stimulation on esophageal motility in an interventional randomized study. METHODS: Sixteen humans PD patients (4 women, 12 men; age: 62.4 +/- 9.3-years old) who underwent STN stimulation for at least 6 months were randomly evaluated with either stimulator turned OFF then ON, or inversely. Esophageal high resolution manometry was performed at the end of each ON and OFF period, with a 5 min resting period followed by ten swallows of 5 mL. KEY RESULTS: During the ON, an increase in the distal contractility index was found (OFF: 1750 +/- 629 vs ON: 2171 +/- 755 mmHg/cm/s; p = 0.03), with no difference in the distal front velocity. A decrease in the integrative relaxation pressure of the lower esophageal sphincter (LES) was noted (OFF: 11.1 +/- 1.8 mmHg vs ON: 7.2 +/- 1.8 mmHg; p < 0.05) in ON. The LES resting pressure remained unchanged during the two periods. This resulted in a decrease in the intrabolus pressure (p = 0.03). No difference was observed for the upper esophageal sphincter, nor the pharyngeal contraction amplitude and velocity. CONCLUSIONS & INFERENCES: In conclusion, STN stimulation in PD patients increased esophageal body contractions and enhanced the LES opening. This suggests that the nigrostriatal-striatonigral loop is involved in the control of esophageal motility. PMID- 26053219 TI - Synthesis and Characterization of Hybrid Polymer/Lipid Expansile Nanoparticles: Imparting Surface Functionality for Targeting and Stability. AB - The size, drug loading, drug release kinetics, localization, biodistribution, and stability of a given polymeric nanoparticle (NP) system depend on the composition of the NP core as well as its surface properties. In this study, novel, pH responsive, and lipid-coated NPs, which expand in size from a diameter of approximately 100 to 1000 nm in the presence of a mildly acidic pH environment, are synthesized and characterized. Specifically, a combined miniemulsion and free radical polymerization method is used to prepare the NPs in the presence of PEGylated lipids. These PEGylated-lipid expansile NPs (PEG-L-eNPs) combine the swelling behavior of the polymeric core of expansile NPs with the improved colloidal stability and surface functionality of PEGylated liposomes. The surface functionality of PEG-L-eNPs allows for the incorporation of folic acid (FA) and folate receptor-targeting. The resulting hybrid polymer/lipid nanocarriers, FA PEG-L-eNPs, exhibit greater in vitro uptake and potency when loaded with paclitaxel compared to nontargeted PEG-L-eNPs. PMID- 26053223 TI - Compromised hematopoiesis and increased DNA damage following non-lethal ionizing radiation of a human hematopoietic system reconstituted in immunodeficient mice. PMID- 26053220 TI - The kinetochore encodes a mechanical switch to disrupt spindle assembly checkpoint signalling. AB - The spindle assembly checkpoint (SAC) is a unique signalling mechanism that responds to the state of attachment of the kinetochore to spindle microtubules. SAC signalling is activated by unattached kinetochores, and it is silenced after these kinetochores form end-on microtubule attachments. Although the biochemical cascade of SAC signalling is well understood, how kinetochore-microtubule attachment disrupts it remained unknown. Here we show that, in budding yeast, end on microtubule attachment to the kinetochore physically separates the Mps1 kinase, which probably binds to the calponin homology domain of Ndc80, from the kinetochore substrate of Mps1, Spc105 (KNL1 orthologue). This attachment-mediated separation disrupts the phosphorylation of Spc105, and enables SAC silencing. Additionally, the Dam1 complex may act as a barrier that shields Spc105 from Mps1. Together these data suggest that the protein architecture of the kinetochore encodes a mechanical switch. End-on microtubule attachment to the kinetochore turns this switch off to silence the SAC. PMID- 26053221 TI - Molecular mechanism of vinculin activation and nanoscale spatial organization in focal adhesions. AB - Focal adhesions (FAs) link the extracellular matrix to the actin cytoskeleton to mediate cell adhesion, migration, mechanosensing and signalling. FAs have conserved nanoscale protein organization, suggesting that the position of proteins within FAs regulates their activity and function. Vinculin binds different FA proteins to mediate distinct cellular functions, but how vinculin's interactions are spatiotemporally organized within FAs is unknown. Using interferometric photoactivation localization super-resolution microscopy to assay vinculin nanoscale localization and a FRET biosensor to assay vinculin conformation, we found that upward repositioning within the FA during FA maturation facilitates vinculin activation and mechanical reinforcement of FAs. Inactive vinculin localizes to the lower integrin signalling layer in FAs by binding to phospho-paxillin. Talin binding activates vinculin and targets active vinculin higher in FAs where vinculin can engage retrograde actin flow. Thus, specific protein interactions are spatially segregated within FAs at the nanoscale to regulate vinculin activation and function. PMID- 26053222 TI - The Population-Based Risk of Need for Coronary Revascularization According to the Presence of Type 2 Diabetes Mellitus and History of Coronary Heart Disease in the Korean Population. AB - BACKGROUND: Whether diabetic patients without a history of coronary heart disease (CHD) have the same risk of CHD events as non-diabetic patients with a history of CHD remains controversial. This study aimed to determine whether type 2 diabetes mellitus (T2DM) is a coronary heart disease (CHD) equivalent in the need for coronary revascularization procedures (RVs) in the Korean population. METHODOLOGY/PRINCIPAL FINDINGS: We followed 2,168,698 subjects who had oral anti diabetic drugs (OADs)-taking T2DM in 2008 and/or CHD in 2007-2008 (i.e., recent CHD). We used systematic datasets from the nationwide claims database of the Health Insurance Review and Assessment service of Korea, which is representative of the whole population of Korea, from January 2007 to December 2012. The primary study endpoint was the development of need for RVs (i.e., incident CHD) after January 2009 among three groups based on their status of T2DM and recent CHD, i.e., T2DM only, recent CHD only, and both T2DM and recent CHD. After adjustment for age and sex, patients with recent CHD only had 2.14 times the risk of incident CHD (95% CI, 2.11-2.18, P<0.001) compared with patients with T2DM only. Patients with both T2DM and recent CHD demonstrated approximately 2-fold increased risk of incident CHD compared with subjects with recent CHD only (95% CI, 1.75-1.82), while 4-fold increased risk compared with subjects with T2DM only (95% CI, 3.71-3.87). The risk of incident CHD also differed according to sex and age. CONCLUSIONS/SIGNIFICANCE: This analysis of data from the nationwide claims database revealed that T2DM did not have a recent CHD equivalent risk in the Korean population. These results suggest that an appropriate strategy for the CHD risk stratification in diabetic patients should be adopted to manage this population. PMID- 26053224 TI - SNP in pre-miR-1666 decreases mature miRNA expression and is associated with chicken performance. AB - Polymorphisms in miRNA genes could potentially alter various biological processes by influencing the processing and (or) target selection of miRNAs. The rs14120863 (C > G) mutation, which we characterized in a Gushi-Anka F2 resource population, resides in the precursor region of miR-1666. Association analysis with chicken carcass and growth traits showed that the SNP was significantly associated with carcass weight, evisceration weight, breast muscle weight, leg muscle weight, and body weight at 8 weeks of age, as well as some body size indexes including shank girth, chest breadth, breast bone length, and body slanting length, in the Gushi Anka F2 resource population. Quantitative RT-PCR results showed that miR-1666 expression levels in muscle tissues differed within various genotypes. Experiment in DF1 cells further confirmed that the SNP in miR-1666 could significantly alter mature miRNA production. Subsequently, using dual-luciferase report assay, we verified that miR-1666 could perform its function through targeting of the CBFB gene. In conclusion, the SNP in the precursor of miR-1666 could significantly reduce mature miR-1666 production. It may further affect the function of miR-1666 through the target gene CBFB, hence it is associated with chicken growth traits. PMID- 26053225 TI - Group Additive Kinetics for Hydrogen Transfer Between Oxygenates. AB - Hydrogen abstraction reactions involving oxygenates in gaseous phase play an important role in many biomass-related conversion processes. In this work, group additivity is used to provide Arrhenius parameters in a temperature range of 300 2500 K for hydrogen abstractions between oxygenate compounds such as alcohols, ethers, esters, acids, ketones, diketones, aldehydes, hydroxyperoxides, alkyl peroxides, and unsaturated ethers and ketones. The group additive values for Arrhenius parameters of hydrogen transfer reactions of the type O--H--C and O--H- O are derived from CBS-QB3 calculations in the high-pressure limit. From a total set of 118 reactions, 43 group additivity values are determined. Inclusion of an additional 37 corrections accounting for cross-resonance effects in the transition state further improves the accuracy of the model. For a set of 25 ab initio calculated and 60 experimental rate coefficients, group additive modeling reproduces rate coefficients within a mean factor of deviation of ~3. Hence, the developed group additive models can be reliably used for an accurate and fast prediction of the kinetics of hydrogen abstractions involving oxygenates. PMID- 26053226 TI - Toward the Synthesis of Fluorinated Analogues of HCV NS3/4A Serine Protease Inhibitors Using Methyl alpha-Amino-beta-fluoro-beta-vinylcyclopropanecarboxylate as Key Intermediate. AB - Synthesis of fluorocyclopropyl building blocks, which constitute the core of various therapeutic agents against the hepatitis C virus, is described. The relevant methyl alpha-amino-beta-fluoro-beta-vinylcyclopropanecarboxylate has been used as a key intermediate for the total synthesis of a fluorinated analogue of Simeprevir (TMC 435), a HCV NS3/4A protease inhibitor. PMID- 26053227 TI - Differential gene expression of three nitric oxide synthases is consistent with increased nitric oxide in the hindbrain of broilers with cold-induced pulmonary hypertension. AB - Quantitative real-time PCR and Griess reaction were conducted to evaluate gene expression of nitric oxide synthases (eNOS, nNOS and iNOS) and nitric oxide (NO) production in the hindbrain, midbrain, forebrain of chickens with cold-induced pulmonary hypertension. The ratio of the right to total ventricular weight of heart as an indication of pulmonary hypertension was increased in the cold stress groups of chickens at 42 d of age. In the pulmonary hypertensive chickens, production of NO was increased in the hindbrain but was unchanged in the forebrain and midbrain. Relative gene expression of eNOS and nNOS was upregulated in the three segments of brain, whereas the iNOS transcript was downregulated in the forebrain and midbrain of the cold-induced pulmonary hypertensive chickens. It is concluded that in the chickens with cold-induced pulmonary hypertension, variations of nNOS, eNOS and iNOS gene expression would lead to overproduction of NO in the hindbrain, whereas the variations in the expression of these genes did not result in an elevation of NO in the forebrain and midbrain. It is suggested that high levels of NO in the hindbrain excites neural mechanisms involved in pulmonary hypertension. PMID- 26053228 TI - Electric Interfacial Layer of Modified Cellulose Nanocrystals in Aqueous Electrolyte Solution: Predictions by the Molecular Theory of Solvation. AB - The X-ray crystal structure-based models of Ialpha cellulose nanocrystals (CNC), both pristine and containing surface sulfate groups with negative charge 0-0.34 e/nm(2) produced by sulfuric acid hydrolysis of softwood pulp, feature a highly polarized "crystal-like" charge distribution. We perform sampling using molecular dynamics (MD) of the structural relaxation of neutral pristine and negatively charged sulfated CNC of various lengths in explicit water solvent and then employ the statistical mechanical 3D-RISM-KH molecular theory of solvation to evaluate the solvation structure and thermodynamics of the relaxed CNC in ambient aqueous NaCl solution at a concentration of 0.0-0.25 mol/kg. The MD sampling induces a right-hand twist in CNC and rearranges its initially ordered structure with a macrodipole of high-density charges at the opposite faces into small local spots of alternating charge at each face. This surface charge rearrangement observed for both neutral and charged CNC significantly affects the distribution of ions around CNC in aqueous electrolyte solution. The solvation free energy (SFE) of charged sulfated CNC has a minimum at a particular electrolyte concentration depending on the surface charge density, whereas the SFE of neutral CNC increases linearly with NaCl concentration. The SFE contribution from Na(+) counterions exhibits behavior similar to the NaCl concentration dependence of the whole SFE. An analysis of the 3D maps of Na(+) density distributions shows that these model CNC particles exhibit the behavior of charged nanocolloids in aqueous electrolyte solution: an increase in electrolyte concentration shrinks the electric interfacial layer and weakens the effective repulsion between charged CNC particles. The 3D-RISM-KH method readily treats solvent and electrolyte of a given nature and concentration to predict effective interactions between CNC particles in electrolyte solution. We provide CNC structural models and a modeling procedure for studies of effective interactions and the formation of ordered phases of CNC suspensions in electrolyte solution. PMID- 26053229 TI - Comment on: Childhood cancer and exposure to corona ions from power lines: an epidemiological study. PMID- 26053230 TI - The impact of validation and invalidation on aggression in individuals with emotion regulation difficulties. AB - For individuals with difficulty regulating their emotions, aggression has been found to be a particularly problematic interpersonal behavior. Invalidation (i.e., rejection of one's emotional experience) is thought to play a role in the etiology of disorders of emotion regulation, and it may be a trigger for aggressive behaviors. The present study experimentally manipulated validation and invalidation after a sad mood induction among individuals with few versus many difficulties regulating their emotions. Subsequent aggression was measured using an in-laboratory behavioral task. Results indicate that, among individuals with many difficulties regulating their emotions, validation led to significantly less aggression than did invalidation. However, among individuals with few difficulties regulating their emotions, aggressive behaviors were generally low and did not differ after validation as compared with invalidation. The findings suggest that validation of emotional experiences may help to prevent aggressive behaviors among individuals with difficulties regulating their emotions. PMID- 26053231 TI - Double-headed nucleotides introducing thymine nucleobases in the major groove of nucleic acid duplexes. AB - Four different double-headed nucleosides each combining two thymine nucleobases with different linkers were synthesised. The 5-position of 2'-deoxyuridine was connected to the N1-position of a thymine through either m- or p-disubstituted phenyl or phenylacetylene linkers by the use of Suzuki or Sonogashira couplings. When introduced into oligonucleotides, the thermal stability of dsDNA and DNA : RNA duplexes were determined and structural information was obtained from CD- and fluorescence spectroscopy. Also the recognition of abasic sites was studied. In general, the more stable duplexes were obtained with m- rather than p substitution and with phenylacetylene rather than phenyl linkers. PMID- 26053232 TI - Comparison of Traditional 2-AB Fluorescence LC-MS/MS and Automated LC-MS for the Comparative Glycan Analysis of Monoclonal Antibodies. AB - Monoclonal antibody therapeutics are a heterogeneous mixture of glycoforms. Multiple methods exist for defining the glycan composition and relative abundance of species present. In the current report, two MS-based methods were compared for their ability to both identify glycans and monitor differences in the glycoprofile. Gross changes in the glycoprofile can be identified either by visual inspection of fluorescence profiles and correlated to glycan identities when coupled with online MS/MS (LC-F-MS/MS) or through extracted ion chromatograms using LC-MS. In the present study, both an LC-F-MS/MS method and an automated LC-MS label free approach were able to identify minor differences in low abundance glycoforms, and data indicate a disparity in glycosylation between the analyzed batches of US and foreign-sourced mAb X. Thus, either method may be useful in characterizing monoclonal antibody therapeutics products and could serve as a potential screening test for understanding process, comparability, similarity, and possibly detecting counterfeit agents. PMID- 26053233 TI - CPAP, Surfactant, or Both for the Preterm Infant: Resolving the Dilemma. PMID- 26053234 TI - Data encoding based on the shape of the ferroelectric domains produced by using a scanning probe microscope tip. AB - Ferroelectric materials are broadly considered for information storage due to the extremely high storage and information processing densities they enable. To date, ferroelectric based data storage has invariably relied on the formation of cylindrical domains, allowing for binary information encoding. Here we demonstrate and explore the potential of high-density encoding based on the domain morphology. We explore the domain morphogenesis during the tip-induced polarization switching by sequences of positive and negative pulses in a lithium niobate single-crystal and demonstrate the principles of information coding by the shape and size of the domains. We applied cross-correlation and neural network approaches for recognition of the switching sequence by the shape of the resulting domains and established optimal parameters for domain shape recognition. These studies both provide insight into the highly non-trivial mechanism of domain switching and potentially establish a new paradigm for multilevel information storage and content retrieval memory devices. Furthermore, this approach opens a pathway to exploration of domain switching mechanisms via shape analysis. PMID- 26053235 TI - Combined use of diffusion tensor tractography and multifused contrast-enhanced FIESTA for predicting facial and cochlear nerve positions in relation to vestibular schwannoma. AB - OBJECT: The authors assessed whether the combined use of diffusion tensor tractography (DTT) and contrast-enhanced (CE) fast imaging employing steady-state acquisition (FIESTA) could improve the accuracy of predicting the courses of the facial and cochlear nerves before surgery. METHODS: The population was composed of 22 patients with vestibular schwannoma in whom both the facial and cochlear nerves could be identified during surgery. According to DTT, depicted fibers running from the internal auditory canal to the brainstem were judged to represent the facial or vestibulocochlear nerve. With regard to imaging, the authors investigated multifused CE-FIESTA scans, in which all 3D vessel models were shown simultaneously, from various angles. The low-intensity areas running along the tumor from brainstem to the internal auditory canal were judged to represent the facial or vestibulocochlear nerve. RESULTS: For all 22 patients, the rate of fibers depicted by DTT coinciding with the facial nerve was 13.6% (3/22), and that of fibers depicted by DTT coinciding with the cochlear nerve was 63.6% (14/22). The rate of candidates for nerves predicted by multifused CE FIESTA coinciding with the facial nerve was 59.1% (13/22), and that of candidates for nerves predicted by multifused CE-FIESTA coinciding with the cochlear nerve was 4.5% (1/22). The rate of candidates for nerves predicted by combined DTT and multifused CE-FIESTA coinciding with the facial nerve was 63.6% (14/22), and that of candidates for nerves predicted by combined DTT and multifused CE-FIESTA coinciding with the cochlear nerve was 63.6% (14/22). The rate of candidates predicted by DTT coinciding with both facial and cochlear nerves was 0.0% (0/22), that of candidates predicted by multifused CE-FIESTA coinciding with both facial and cochlear nerves was 4.5% (1/22), and that of candidates predicted by combined DTT and multifused CE-FIESTA coinciding with both the facial and cochlear nerves was 45.5% (10/22). CONCLUSIONS: By using a combination of DTT and multifused CE FIESTA, the authors were able to increase the number of vestibular schwannoma patients for whom predicted results corresponded with the courses of both the facial and cochlear nerves, a result that has been considered difficult to achieve by use of a single modality only. Although the 3D image including these prediction results helped with comprehension of the 3D operative anatomy, the reliability of prediction remains to be established. PMID- 26053236 TI - Construction of a smart microgel glutathione peroxidase mimic based on supramolecular self-assembly. AB - In an effort to construct smart artificial glutathione peroxidase (GPx) featuring high catalytic activity in an efficient preparation process, an artificial microgel GPx (PPAM-ADA-Te) has been prepared using a supramolecular host-guest self-assembly technique. Herein, 6,6'-telluro-bis(6-deoxy-beta-cyclodextrin) (CD Te-CD) was selected as a tellurium-containing host molecule, which also served as the crosslinker for the scaffold of the supramolecular microgel. And an adamantane-containing block copolymer (PPAM-ADA) was designed and synthesized as a guest building block copolymer. Subsequently, PPAM-ADA-Te was constructed through the self-assembly of CD-Te-CD and PPAM-ADA. The formation of this self assembled construct was confirmed by dynamic light scattering, NMR, SEM and TEM. Notably, PPAM-ADA-Te not only exhibits a significant temperature responsive catalytic activity, but also features the characteristic saturation kinetics behaviour similar to that of a natural enzyme catalyst. We demonstrate in this paper that both the hydrophobic microenvironment and the crosslinker in this supramolecular microgel network played significant roles in enhancing and altering the temperature responsive catalytic behaviour. The successful construction of PPAM-ADA-Te not only provides a novel method for the preparation of microgel artificial GPx with high catalytic activity but also provides properties suitable for the future development of intelligent antioxidant drugs. PMID- 26053237 TI - Nanophase diagram of binary eutectic Au-Ge nanoalloys for vapor-liquid-solid semiconductor nanowires growth. AB - Although the vapor-liquid-solid growth of semiconductor nanowire is a non equilibrium process, the equilibrium phase diagram of binary alloy provides important guidance on the growth conditions, such as the temperature and the equilibrium composition of the alloy. Given the small dimensions of the alloy seeds and the nanowires, the known phase diagram of bulk binary alloy cannot be expected to accurately predict the behavior of the nanowire growth. Here, we developed a unified model to describe the size- and dimensionality-dependent equilibrium phase diagram of Au-Ge binary eutectic nanoalloys based on the size dependent cohesive energy model. It is found that the liquidus curves reduce and shift leftward with decreasing size and dimensionality. Moreover, the effects of size and dimensionality on the eutectic composition are small and negligible when both components in binary eutectic alloys have the same dimensionality. However, when two components have different dimensionality (e.g. Au nanoparticle-Ge nanowire usually used in the semiconductor nanowires growth), the eutectic composition reduces with decreasing size. PMID- 26053238 TI - Shape and surface chemistry effects on the cytotoxicity and cellular uptake of metallic nanorods and nanospheres. AB - Metallic nanoparticles (such as gold and silver) have been intensely studied for wound healing applications due to their ability to be easily functionalized, possess antibacterial properties, and their strong potential for targeted drug release. In this study, rod-shaped silver nanorods (AgNRs) and gold nanorods (AuNRs) were fabricated by electron beam physical vapor deposition (EBPVD), and their cytotoxicity toward human skin fibroblasts were assessed and compared to sphere-shaped silver nanospheres (AgNSs) and gold nanospheres (AuNSs). Results showed that the 39.94 nm AgNSs showed the greatest toxicity with fibroblast cells followed by the 61.06 nm AuNSs, ~556 nm * 47 nm (11.8:1 aspect ratio) AgNRs, and the ~534 nm * 65 nm (8.2:1 aspect ratio) AuNRs demonstrated the least amount of toxicity. The calculated IC50 (50% inhibitory concentration) value for the AgNRs exposed to fibroblasts was greater after 4 days of exposure (387.3 MUg mL(-1)) compared to the AgNSs and AuNSs (4.3 and 23.4 MUg mL(-1), respectively), indicating that these spherical metallic nanoparticles displayed a greater toxicity to fibroblast cells. The IC50 value could not be measured for the AuNRs due to an incomplete dose response curve. The reduced cell toxicity with the presently developed rod-shaped nanoparticles suggests that they may be promising materials for use in numerous biomedical applications. PMID- 26053239 TI - Universal freezing of quantum correlations within the geometric approach. AB - Quantum correlations in a composite system can be measured by resorting to a geometric approach, according to which the distance from the state of the system to a suitable set of classically correlated states is considered. Here we show that all distance functions, which respect natural assumptions of invariance under transposition, convexity, and contractivity under quantum channels, give rise to geometric quantifiers of quantum correlations which exhibit the peculiar freezing phenomenon, i.e., remain constant during the evolution of a paradigmatic class of states of two qubits each independently interacting with a non dissipative decohering environment. Our results demonstrate from first principles that freezing of geometric quantum correlations is independent of the adopted distance and therefore universal. This finding paves the way to a deeper physical interpretation and future practical exploitation of the phenomenon for noisy quantum technologies. PMID- 26053240 TI - Decision-making of Prefrontal Patients with the Iowa Gambling Task: Unexpected Spared Performances and Preliminary Evidence for the Need of Alternative Measures. AB - OBJECTIVE: Human decision-making is a growing area of research most commonly associated with the Iowa Gambling Task (IGT), which was first developed to assess patients with prefrontal cortex (PFC) damage. The IGT is now considered an appropriate task to predict behavioral disorders in various clinical populations. However, several studies have questioned the validity and reliability of the task, arguing that its particular payoff scheme may influence the decision-making process in terms of sensitivity to gain-loss frequency (GLF) rather than long term outcome (the basic assumption of IGT). Despite the potential significance of this assertion for the diagnosis of decision-making deficits, few studies have addressed the influence of GLF on IGT performances in clinical populations, and there is no study to date that involves patients with prefrontal lobe damage. METHOD: We tested 17 patients with PFC damage and 17 matched healthy controls with the IGT to analyze influence in choice behavior of both long-term outcomes and GLF. RESULTS: There was a difference between groups in the GLF score, but none between groups in the long-term outcome variable (the traditional measure). Our findings demonstrate that only control subjects seemed able to consider both long-term outcome and GLF. CONCLUSIONS: The discussion focuses on the contribution of empirical data, which may have implications for the clinical assessment of decision-making ability with the IGT. PMID- 26053241 TI - Understanding mid-level representations in visual processing. AB - It is clear that early visual processing provides an image-based representation of the visual scene: Neurons in Striate cortex (V1) encode nothing about the meaning of a scene, but they do provide a great deal of information about the image features within it. The mechanisms of these "low-level" visual processes are relatively well understood. We can construct plausible models for how neurons, up to and including those in V1, build their representations from preceding inputs down to the level of photoreceptors. It is also clear that at some point we have a semantic, "high-level" representation of the visual scene because we can describe verbally the objects that we are viewing and their meaning to us. A huge number of studies are examining these "high-level" visual processes each year. Less well studied are the processes of "mid-level" vision, which presumably provide the bridge between these "low-level" representations of edges, colors, and lights and the "high-level" semantic representations of objects, faces, and scenes. This article and the special issue of papers in which it is published consider the nature of "mid-level" visual processing and some of the reasons why we might not have made as much progress in this domain as we would like. PMID- 26053242 TI - Assessment from Functional Perspectives: Using Sensorimotor Control in the Hand as an Outcome Indicator in the Surgical Treatment of Carpal Tunnel Syndrome. AB - To investigate whether sensorimotor control of the hand could be an outcome indicator after carpal tunnel release (CTR), this work examined changes in the results of patients' manual tactile test (MTT), pinch-holding-up activity (PHUA), two-point discrimination (2PD) and Semmes-Weinstein monofilament (SWM) tests. Participants included 30 predominantly sensory neuropathy CTS patients, as confirmed by a nerve conduction study. The MTT, precision pinch performance in PHUA and traditional sensibility (2PD and SWM) tests were used to examine different aspects of sensory status at the time-points of two weeks before operation and one month post-operation, with a single-blind design. The results showed significant improvements in the sensory function as detected by the 2PD and SWM tests (p<0.001) and sensorimotor function as detected by the MTT (p<0.001) and PHUA test (p<0.05) for patients receiving CTR. The responsiveness of the SWM, MTT and PHUA tests (effect size>0.5, p<0.01) are better than that of two-point discrimination test (effect size<0.5, p<0.001). However, pinch strength saw a decline compared to baseline with a moderate effect sizes (effect size = 0.7, p<0.001). This cohort study found that the MTT and PHUA test can both meet all the statistical criteria with regard to assessing treatment outcomes for patients with CTS. In addition, the results of this work provide clinicians with the information that the sensorimotor functions of the hands, as assessed by MTT and PHUA, are responsive to clinical changes due to CTR. PMID- 26053243 TI - Modulation of extracellular signal-related kinase, cyclin D1, glial fibrillary acidic protein, and vimentin expression in estradiol-pretreated astrocyte cultures treated with competence and progression growth factors. AB - The present study seeks to elucidate the interactions between the "competence" growth factor basic fibroblast growth factor (bFGF) and/or estrogen 17beta estradiol and the "progression" growth factors epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and insulin (INS) on DNA labeling and also cyclin D1, extracellular signal-related kinase 1/2 (ERK1/2), glial fibrillary acidic protein (GFAP), and vimentin expression in astroglial cultures under different experimental conditions. Pretreatment for 24 hr with bFGF and subsequent exposure for 36 hr to estradiol (E2 ) and EGF, IGF-I, or INS stimulated DNA labeling in the last 12 hr, especially when the cultures were treated with progression growth factors. bFGF pretreatment and subsequent treatment with E2 for 36 hr stimulated DNA labeling. The 36-hr E2 treatment alone did not significantly decrease DNA labeling, but contemporary addition of E2 with two or three growth factors stimulated DNA labeling remarkably. When E2 was coadded with growth factors, a significantly increased DNA labeling was observed, demonstrating an astroglial synergistic mitogenic effect evoked by contemporary treatment with growth factors in the presence of estrogens. Cyclin D1 expression was markedly increased when astrocyte cultures were pretreated for 36 hr with E2 and subsequently treated with two or three competence and progression growth factors. A highly significant increase of ERK1/2 expression was observed after all the treatments (EGF, bFGF, INS, IGF-I alone or in combination with two or three growth factors). GFAP and vimentin expression was markedly increased when the cultures were treated with two or three growth factors. In conclusion, our data demonstrate estradiol-growth factor cross-talk during astroglial cell proliferation and differentiation in culture. PMID- 26053244 TI - Effects of dietary fat profile on gut permeability and microbiota and their relationships with metabolic changes in mice. AB - OBJECTIVE: To distinguish the effects of dietary fat profile on gut parameters and their relationships with metabolic changes and to determine the capacity of n 3 fatty acids to modify gut variables in the context of diet-induced metabolic dysfunctions. METHODS: Mice received control or high-fat diets emphasizing saturated (HFD-sat), n-6 (HFD-n6), or n-3 (HFD-n3) fatty acids for 8 weeks. In another cohort, mice that were maintained on HFD-sat received n-3-rich fish oil or resolvin D1 supplementation. RESULTS: HFD-sat and HFD-n6 induced similar weight gain, but only HFD-sat increased index of insulin resistance (HOMA-IR), colonic permeability, and mesenteric fat inflammation. Hydrogen sulfide-producing bacteria were one of the major groups driving the diet-specific changes in gut microbiome, with the overall microbial profile being associated with changes in body weight, HOMA-IR, and gut permeability. In mice maintained on HFD-sat, fish oil and resolvin D1 restored barrier function and reduced inflammation in the colon but were unable to normalize HOMA-IR. CONCLUSIONS: Different dietary fat profiles led to distinct intestinal and metabolic outcomes that are independent of obesity. Interventions targeting inflammation successfully restored gut health but did not reverse systemic aspects of diet-induced metabolic dysfunction, implicating separation between gut dysfunctions and disease-initiating and/or maintaining processes. PMID- 26053245 TI - Distraction by emotional sounds: Disentangling arousal benefits and orienting costs. AB - Unexpectedly occurring task-irrelevant stimuli have been shown to impair performance. They capture attention away from the main task leaving fewer resources for target processing. However, the actual distraction effect depends on various variables; for example, only target-informative distractors have been shown to cause costs of attentional orienting. Furthermore, recent studies have shown that high arousing emotional distractors, as compared with low arousing neutral distractors, can improve performance by increasing alertness. We aimed to separate costs of attentional orienting and benefits of arousal by presenting negative and neutral environmental sounds (novels) as oddballs in an auditory visual distraction paradigm. Participants categorized pictures while task irrelevant sounds preceded visual targets in two conditions: (a) informative sounds reliably signaled onset and occurrence of visual targets, and (b) noninformative sounds occurred unrelated to visual targets. Results confirmed that only informative novels yield distraction. Importantly, irrespective of sounds' informational value participants responded faster in trials with high arousing negative as compared with moderately arousing neutral novels. That is, costs related to attentional orienting are modulated by information, whereas benefits related to emotional arousal are independent of a sound's informational value. This favors a nonspecific facilitating cross-modal influence of emotional arousal on visual task performance and suggests that behavioral distraction by noninformative novels is controlled after their motivational significance has been determined. PMID- 26053246 TI - Seeing the world through rose-colored glasses: People who are happy and satisfied with life preferentially attend to positive stimuli. AB - Given the many benefits conferred by trait happiness and life satisfaction, a primary goal is to determine how these traits relate to underlying cognitive processes. For example, visual attention acts as a gateway to awareness, raising the question of whether happy and satisfied people attend to (and therefore see) the world differently. Previous work suggests that biases in selective attention are associated with both trait negativity and with positive affect states, but to our knowledge, no previous work has explored whether trait-happy individuals attend to the world differently. Here, we employed eye tracking as a continuous measure of sustained overt attention during passive viewing of displays containing positive and neutral photographs to determine whether selective attention to positive scenes is associated with measures of trait happiness and life satisfaction. Both trait measures were significantly correlated with selective attention for positive (vs. neutral) scenes, and this general pattern was robust across several types of positive stimuli (achievement, social, and primary reward), and not because of positive or negative state affect. Such effects were especially prominent during the later phases of sustained viewing. This suggests that people who are happy and satisfied with life may literally see the world in a more positive light, as if through rose-colored glasses. Future work should investigate the causal relationship between such attention biases and one's happiness and life satisfaction. PMID- 26053247 TI - Anxiety, not anger, induces inflammatory activity: An avoidance/approach model of immune system activation. AB - Psychological stressors reliably trigger systemic inflammatory activity as indexed by levels of proinflammatory cytokines. This experiment demonstrates that one's specific emotional reaction to a stressor may be a significant determinant of whether an inflammatory reaction occurs in response to that stressor. Based on extant correlational evidence and theory, a causal approach was used to determine whether an avoidant emotion (anxiety) triggers more inflammatory activity than an approach emotion (anger). In an experimental design (N = 40), a 3-way Emotion Condition * Time * Analyte interaction revealed that a writing-based anxiety induction, but not a writing-based anger induction, increased mean levels of interferon-gamma (IFN- gamma) and interleukin-1beta (IL-1beta), but not interleukin-6 (IL-6) in oral mucous, F(2, 54) = 4.64, p = .01, etap(2) = .15. Further, self-reported state anxiety predicted elevated levels of proinflammatory cytokines, all DeltaR(2) >.06, ps <.04, but self-reported state anger did not. These results constitute the first evidence to our knowledge that specific negative emotions can differentially cause inflammatory activity and support a theoretical model explaining these effects based on the avoidance or approach motivations associated with emotions. PMID- 26053249 TI - Parathyroid surgery: correlation between pre-operative localization studies and surgical outcomes. AB - OBJECTIVE: Pre-operative imaging techniques have enabled minimally invasive parathyroid surgery to supersede the traditional approach to hyperparathyroidism (HPT) surgery, which included cervical exploration. Cervical ultrasound (US) and sestamibi scan (MIBI) are commonly performed, but the results of these localization tests do not always match. This study correlated surgical outcomes with pre-operative localization findings, including matched positive US and MIBI studies, one positive study (US or MIBI), conflicting studies or negative results. DESIGN: Retrospective medical record review. PATIENTS: A hundred and sixty nine consecutive patients who underwent parathyroidectomy from January 2005 to December 2012. MEASUREMENTS: Correlation between surgical outcomes and pre operative localization tests. RESULTS: All patients (134F/35M, 59.6 +/- 13.5 years of age) had primary HPT. US and MIBI localization studies matched in 76%, whereas 10.7% had positive MIBI only and 8.3% US only. Studies were negative in 3.6% and contradictory in 1.8%. Minimally invasive parathyroidectomy was performed in 87% of the matched group and 89% of the MIBI-only group. Surgical success rate, defined as postoperative normalization of calcium and PTH levels, was similar in patients with a single positive study (MIBI or US) vs double matched studies (MIBI and US). Patients were followed up for 6 weeks. Overall, pathology was consistent with adenoma in 95%. DISCUSSION: Parathyroidectomy success rate was similar in patients with primary HPT and MIBI-only or US-only positive localization studies compared to those with matched US/MIBI studies. The results support a clinical algorithm in which positive results from one imaging technique, either MIBI or US, are sufficient to refer a patient for parathyroid surgery. PMID- 26053248 TI - Thymic Atrophy and Apoptosis of CD4+CD8+ Thymocytes in the Cuprizone Model of Multiple Sclerosis. AB - Previous studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first time, how cuprizone feeding affects the thymus, the organ of T-cell maturation and selection. We found that even one week of cuprizone treatment induced significant thymic atrophy, affecting the cortex over the medulla. Fluorescent microscopy and flow-cytometric analyses of thymi from cuprizone- and vehicle-treated mice indicated that eradication of the cluster of the differentiation-4 (CD4)-CD8 double-positive T-cell subset was behind the substantial cell loss. This result was confirmed with CD3-CD4-CD8 triple-staining experiments. Ultrastructurally, we observed degraded as well as enlarged mitochondria, myelin-bodies, large lipid droplets, and large lysosomes in the thymi of cuprizone-treated mice. Some of these features were similar to those in physiological and steroid-induced accelerated aging. According to our results, apoptosis was mainly of mitochondrial origin mediated by both caspase-3- and apoptosis inducing factor mediated mechanisms. Additionally, mitogen activated protein kinase activation and increased pro-apoptotic B cell lymphoma-2 family protein expression were the major underlying processes. Our results do not indicate a functional relationship between cuprizone-induced thymus involution and the absence of inflammatory responses or the selective demyelination observed in the cuprizone model. On the other hand, due to the reversible nature of cuprizone's deleterious effects, the cuprizone model could be valuable in studying thymus regeneration as well as remyelination processes. PMID- 26053251 TI - Editorial: Shrinks: The Untold Story of Psychiatry, by Jeffrey A. Lieberman, M.D., with Ogi Ogas: A Critical Discussion. PMID- 26053250 TI - Epigenetic memory gained by priming with osteogenic induction medium improves osteogenesis and other properties of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are highly plastic cells that are able to transdifferentiate or dedifferentiate under appropriate conditions. In the present study, we reported here that after in vitro induction of osteogenic differentiation, MSCs could be reverted to a primitive stem cell population (dedifferentiated osteogenic MSCs, De-Os-MSCs) with improved cell survival, colony formation, osteogenic potential, migratory capacity and increased expression of Nanog, Oct4 and Sox2. Most importantly, our results showed great superiority of the De-Os-MSCs over untreated MSCs in ectopic bone formation in vivo. Furthermore, Nanog-knockdown in MSCs could reverse these enhanced properties in De-Os-MSCs in vitro, indicating a central role of Nanog in the transcriptional network. In addition, epigenetic regulations including DNA methylation and histone modifications may play important roles in regulating the de-osteogenic differentiation process. And we found decreased methylation and promoter accrual of activating histone marks, such as H3K4me3 and H4ac on both Nanog and Oct4 gene promoters. Taken together, our study demonstrated that epigenetic memory in De-Os-MSCs gained by priming with osteogenic induction medium favored their differentiation along osteoblastic lineage with improved cell survival and migratory abilities, which may have application potential in enhancing their regenerative capacity in mammals. PMID- 26053253 TI - A multinuclear magnetic resonance study of fluoro derivatives of hydroxybenzaldehydes. PMID- 26053252 TI - The actions of neurotensin in rat bladder detrusor contractility. AB - This study assessed the expression, distribution and function of neurotensin (NTs) and two main neurotensin receptors (NTSR), NTSR1 and NTSR2 in normal rat urinary bladders. NTs is primarily located in the suburothelium and the interstitium of smooth muscle bundles. The NTSR1 and NTSR2 receptor subtypes are found to co-localize with smooth muscle cells (SMCs). NTs not only can directly act on bladder SMCs to induce intracellular calcium mobilization by activating the phospholipase C/inositol triphosphate (PLC/IP3) pathway, promoting extracellular calcium influx through a non-selective cation channels, but may be also involved in the modulation of the cholinergic system. Nowadays, the selective antimuscarinic drugs (solifenacin) and the selective beta 3-adrenergic agonist (mirabegron) are used as the first-line pharmacotherapy for overactive bladder (OAB), but without satisfactory treatment benefits in some patients. This study provided evidence suggesting that bladder NTs may play an important role in the regulation of micturition. Further research is needed to investigate the effects of NTs on bladder contractility and the underlying mechanism, which might reveal that the administration of NTSR antagonists can potentially relieve the symptoms of OAB by coordination with antimuscarinic pharmacotherapy. PMID- 26053254 TI - Metal-Free Preparation of Linear and Cross-Linked Polydicyclopentadiene. AB - Metal-free ring-opening metathesis polymerization (ROMP) utilizes organic photoredox mediators as alternatives to traditional metal-based ROMP initiators to allow the preparation of polymers without residual metal contamination. Herein we report studies exploring the use of endo-dicyclopentadiene (DCPD), a common ROMP monomer, to form linear polyDCPD and copolymers with norbornene. Subsequent cross-linking of the linear polyDCPD using thiol-ene chemistry allows for a completely metal-free preparation of cross-linked polyDCPD. Furthermore, the examination of a number of structurally related monomers offers insights into mechanistic details of this polymerization and demonstrates new monomers that can be utilized for metal-free ROMP. PMID- 26053255 TI - ONION: Functional Approach for Integration of Lipidomics and Transcriptomics Data. AB - To date, the massive quantity of data generated by high-throughput techniques has not yet met bioinformatics treatment required to make full use of it. This is partially due to a mismatch in experimental and analytical study design but primarily due to a lack of adequate analytical approaches. When integrating multiple data types e.g. transcriptomics and metabolomics, multidimensional statistical methods are currently the techniques of choice. Typical statistical approaches, such as canonical correlation analysis (CCA), that are applied to find associations between metabolites and genes are failing due to small numbers of observations (e.g. conditions, diet etc.) in comparison to data size (number of genes, metabolites). Modifications designed to cope with this issue are not ideal due to the need to add simulated data resulting in a lack of p-value computation or by pruning of variables hence losing potentially valid information. Instead, our approach makes use of verified or putative molecular interactions or functional association to guide analysis. The workflow includes dividing of data sets to reach the expected data structure, statistical analysis within groups and interpretation of results. By applying pathway and network analysis, data obtained by various platforms are grouped with moderate stringency to avoid functional bias. As a consequence CCA and other multivariate models can be applied to calculate robust statistics and provide easy to interpret associations between metabolites and genes to leverage understanding of metabolic response. Effective integration of lipidomics and transcriptomics is demonstrated on publically available murine nutrigenomics data sets. We are able to demonstrate that our approach improves detection of genes related to lipid metabolism, in comparison to applying statistics alone. This is measured by increased percentage of explained variance (95% vs. 75-80%) and by identifying new metabolite-gene associations related to lipid metabolism. PMID- 26053256 TI - Concordance of maternal and paternal decision-making and its effect on choice for vaginal birth after caesarean section. AB - BACKGROUND: The proportion of women who plan for a repeat elective caesarean section (CS) is one of the major determinants of the overall rate of CS, and programs aiming to reduce the rate of CS have not been greatly successful. To date, there appear to have been no large studies directly addressing paternal influences on decision-making regarding vaginal birth after caesarean (VBAC). This study aimed to compare the reactions of fathers and mothers to the prospect of VBAC. METHODS: Couples were recruited from three Australian hospitals and were eligible with a singleton pregnancy, a normal morphology ultrasound, and where there was no condition in the new pregnancy that would preclude a vaginal birth. Questionnaires were scheduled for 20 weeks' gestation, 32-36 weeks' gestation and six weeks postnatal and were sent separately to each partner. RESULTS: Seventy five couples completed the full sets of questionnaires during the study period. In total, 31 women (41%) ultimately attempted vaginal delivery, and 44 (59%) were delivered by planned CS. When the paternal rating of risk fell between the second and third trimesters, the couple were likely to attempt VBAC (P < 0.05). Where the maternal rating of importance was 3 or less, 92% had a planned CS compared to 63% for the same paternal scores (P = 0.02). CONCLUSION: This study suggests that interventions that improve the paternal perceptions of risk during a pregnancy might increase the chance that a couple will attempt VBAC. PMID- 26053257 TI - Ammonia-oxidising bacteria not archaea dominate nitrification activity in semi arid agricultural soil. AB - Ammonia-oxidising archaea (AOA) and bacteria (AOB) are responsible for the rate limiting step in nitrification; a key nitrogen (N) loss pathway in agricultural systems. Dominance of AOA relative to AOB in the amoA gene pool has been reported in many ecosystems, although their relative contributions to nitrification activity are less clear. Here we examined the distribution of AOA and AOB with depth in semi-arid agricultural soils in which soil organic matter content or pH had been altered, and related their distribution to gross nitrification rates. Soil depth had a significant effect on gene abundances, irrespective of management history. Contrary to reports of AOA dominance in soils elsewhere, AOA gene copy numbers were four-fold lower than AOB in the surface (0-10 cm). AOA gene abundance increased with depth while AOB decreased, and sub-soil abundances were approximately equal (10-90 cm). The depth profile of total archaea did not mirror that of AOA, indicating the likely presence of archaea without nitrification capacity in the surface. Gross nitrification rates declined significantly with depth and were positively correlated to AOB but negatively correlated to AOA gene abundances. We conclude that AOB are most likely responsible for regulating nitrification in these semi-arid soils. PMID- 26053258 TI - Simultaneous separation and sensitive detection of naringin and naringenin in nanoparticles by chromatographic method indicating stability and photodegradation kinetics. AB - A simple, sensitive, precise and linear method by liquid chromatography was established for simultaneous determination and quantification of naringin and naringenin in polymeric nanoparticles. The method results in excellent separation in <11 min and with a peak purity of both flavonoids. The analyses were performed using a C18 column (4.6 * 150 mm, 5 um), at a 1 mL/min flow rate. The mobile phase consisted of a gradient of acetonitrile-water (pH 4.0; v/v) at a temperature of 25 degrees C. The nanoparticles were prepared according to the method of interfacial deposition of a pre-formed polymer. The method were validated in compliance with guidelines, and was found to be linear in the 1-40 ug/mL concentration range for both naringin and naringenin (r > 0.99). Repeatability was determined at three concentration levels, obtaining an RSD (%) <0.9%, and the accuracy of the method was >98%. The photodegradation kinetics was determined for naringin; the coefficient that best represents degradation was of first order and naringenin presented a zero-order kinetics. To our knowledge, a rapid and sensitive method for naringin and naringenin in polymeric nanoparticles has not been published elsewhere and this method is applicable to simultaneous evaluation of flavonoids. PMID- 26053259 TI - Associations of intramyocellular lipid in vastus lateralis and biceps femoris with blood free fatty acid and muscle strength differ between young and elderly adults. AB - The present study aimed to determine relationships between intramyocellular lipid and biochemical profiles or muscle strength in elderly (n = 15; mean age, 71 years) and young (n = 15; mean age, 21 years) male and female adults. Levels of intramyocellular lipid in the vastus lateralis and biceps femoris muscles were determined using 1 H-magnetic resonance spectroscopy. Fasting blood samples were collected to measure levels of glucose, insulin, haemoglobin A1c, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, free fatty acid, triglyceride, adiponectin, and high-sensitivity C reactive protein. Muscle strength was assessed as maximal voluntary contraction during isometric knee extension. Muscle cross-sectional area in the vastus lateralis was measured using magnetic resonance imaging. Specific force (N cm-2 ) indicating force generation capacity was calculated as muscle strength (N) divided by the muscle cross-sectional area of the vastus lateralis (cm2 ). The intramyocellular lipid content was similar in both muscles in both groups. The intramyocellular lipid content in the biceps femoris significantly correlated with serum free fatty acid levels (r = 0.62, P<0.05), and that in the vastus lateralis significantly and inversely correlated with specific force (r = -0.58, P<0.05) in the young, but not in the elderly adults. The relationship between the intramyocellular lipid content in the thigh muscles and biochemical profiles, or specific force differed between elderly and young adults. Age-associated changes in morphology, function and metabolic factors apparently influence intramyocellular lipid metabolism in the thigh muscles. PMID- 26053260 TI - Reference Values for Real Time Three-Dimensional Echocardiography-Derived Left Ventricular Volumes and Ejection Fraction: Review and Meta-Analysis of Currently Available Studies. AB - INTRODUCTION: Current guidelines recommend three-dimensional echocardiography (3DE) as the reference technique to assess left ventricular (LV) volumes and ejection fraction (EF). We performed a meta-analysis to identify normative reference values by real time 3DE in healthy subjects. METHODS: We searched MEDLINE and the Cochrane Library databases using the key search terms three dimensional echocardiography, volumes, and healthy. Data were pooled using random effects meta-analysis, and source of variation was investigated using meta regression. After selection, 13 articles were included (2806 subjects). Four studies were conducted in children and young adolescents; one study provided data in an independent pediatric subgroup. RESULTS: In adults, pooled mean value for LV EDV was 98.4 mL (95%CI, 87-110 mL), while LV ESV mean value was 37.0 mL (95%CI, 32-42 mL). LV EF mean value was 62.9% (95%CI 61.7-64.2%). Male subjects showed a significant increase in both LV EDV index (mean difference 5.3 mL/m(2) ; P < 0.001) and LV ESV index (mean difference 3.3 mL/m(2) ; P < 0.001). LV EF was significantly higher in female subjects (P = 0.003). In pediatric studies, LV EDV pooled mean value was 53.1 mL (95%CI, 38.1-68 mL), while for LV ESV, it was 19.8 mL (95%CI, 14.8-24.8 mL); LV EF mean value was 63.3% (95%CI, 61.6-65%). Significant heterogeneity and inconsistency were noted among studies. Age, systolic blood pressure, and heart rate were identified as a source of between studies variation for LV volumes. Body surface area was a predictor of nonindexed LV volumes. CONCLUSIONS: Data from available studies of normative values for 3DE were summarized. Our findings may increase the generalizability of LV normative data by 3DE. PMID- 26053261 TI - Nested radiations and the pulse of angiosperm diversification: increased diversification rates often follow whole genome duplications. AB - Our growing understanding of the plant tree of life provides a novel opportunity to uncover the major drivers of angiosperm diversity. Using a time-calibrated phylogeny, we characterized hot and cold spots of lineage diversification across the angiosperm tree of life by modeling evolutionary diversification using stepwise AIC (MEDUSA). We also tested the whole-genome duplication (WGD) radiation lag-time model, which postulates that increases in diversification tend to lag behind established WGD events. Diversification rates have been incredibly heterogeneous throughout the evolutionary history of angiosperms and reveal a pattern of 'nested radiations' - increases in net diversification nested within other radiations. This pattern in turn generates a negative relationship between clade age and diversity across both families and orders. We suggest that stochastically changing diversification rates across the phylogeny explain these patterns. Finally, we demonstrate significant statistical support for the WGD radiation lag-time model. Across angiosperms, nested shifts in diversification led to an overall increasing rate of net diversification and declining relative extinction rates through time. These diversification shifts are only rarely perfectly associated with WGD events, but commonly follow them after a lag period. PMID- 26053262 TI - Predictors of Future Suicide Attempts Among Individuals Referred to Psychiatric Services in the Emergency Department: A Longitudinal Study. AB - This study examined which factors predict future suicide attempts (SAs) among people referred to psychiatric services in the emergency department (ED). It included consecutive adult (age >18 years) presentations (N = 6919) over a 3-year period to the two tertiary care hospitals in Manitoba, Canada. Medical professionals assessed each individual on 19 candidate risk factors. Stepwise logistic regression and receiver operating characteristic curves examined the association between the baseline variables and future SAs within the next 6 months. A total of 104 individuals re-presented to the ED with future SAs. Of the 19 baseline variables, only two independently accounted for the variance in future attempts. High-risk scores using this two-item model were associated with elevated odds of future SA (odds ratio, 3.22; 95% confidence interval, 1.62-6.42; p < 0.01), but this was tempered by a low positive predictive value. Further evaluation is required to determine if this two-item tool could help identify people requiring more comprehensive risk assessment referred to psychiatry in the ED. PMID- 26053263 TI - Pervasive Genotypic Mosaicism in Founder Mice Derived from Genome Editing through Pronuclear Injection. AB - Genome editing technologies, especially the Cas9/CRISPR system, have revolutionized biomedical research over the past several years. Generation of novel alleles has been simplified to unprecedented levels, allowing for rapid expansion of available genetic tool kits for researchers. However, the issue of genotypic mosaicism has become evident, making stringent analyses of the penetrance of genome-edited alleles essential. Here, we report that founder mice, derived from pronuclear injection of ZFNs or a mix of guidance RNAs and Cas9 mRNAs, display consistent genotypic mosaicism for both deletion and insertion alleles. To identify founders with greater possibility of transmitting the mutant allele through the germline, we developed an effective germline genotyping method. The awareness of the inherent genotypic mosaicism issue with genome editing will allow for a more efficient implementation of the technologies, and the germline genotyping method will save valuable time and resources. PMID- 26053264 TI - Genome-wide identification of chromium stress-responsive micro RNAs and their target genes in tobacco (Nicotiana tabacum) roots. AB - Tobacco easily accumulates certain heavy metals in leaves and thus poses a potential threat to human health. To systematically dissect Cr-responsive microRNAs (miRNAs) and their targets at the global level, 4 small RNA libraries were constructed from the roots of Cr-treated (Cr) and Cr-free (control) for 2 contrasting tobacco genotypes,Yunyan2 (Cr-sensitive) and Guiyan1 (Cr-tolerant). Using high-throughput-sequencing-technology, the authors identified 53 conserved and 29 novel miRNA families. Comparative genomic analysis of 41 conserved Cr responsive miRNA families revealed that 11 miRNA families showed up-regulation in Guiyan1 but unaltered in Yunyan2, and 17 miRNA families were up-regulated only in Yunyan2 under Cr stress. Only 1 family, miR6149, was down-regulated in Yunyan2 but remained unchanged in Guiyan1. Of the 29 novel miRNA families, 14 expressed differently in the 2 genotypes under Cr stress. Based on a high-throughput degradome sequencing homology search, potential targets were predicted for the 41 conserved and 14 novel Cr-responsive miRNA families. Clusters of Orthologous Groups functional category analysis revealed that some of these predicted target transcripts of miRNAs are responsive to biotic and abiotic stresses. Furthermore, the expression patterns of many Cr-responsive miRNAs were validated by stem-loop real-time transcription polymerase chain reaction. The results of the present study provide valuable information and a framework for understanding the function of miRNAs in Cr tolerance. PMID- 26053265 TI - Low-Frequency Fluctuations of the Resting Brain: High Magnitude Does Not Equal High Reliability. AB - The amplitude of low-frequency fluctuation (ALFF) measures low-frequency oscillations of the blood-oxygen-level-dependent signal, characterizing local spontaneous activity during the resting state. ALFF is a commonly used measure for resting-state functional magnetic resonance imaging (rs-fMRI) in numerous basic and clinical neuroscience studies. Using a test-retest rs-fMRI dataset consisting of 21 healthy subjects and three repetitive scans, we found that several key brain regions with high ALFF intensities (or magnitude) had poor reliability. Such regions included the posterior cingulate cortex, the medial prefrontal cortex in the default mode network, parts of the right and left thalami, and the primary visual and motor cortices. The above finding was robust with regard to different sample sizes (number of subjects), different scanning parameters (repetition time) and variations of test-retest intervals (i.e., intra scan, intra-session, and inter-session reliability), as well as with different scanners. Moreover, the qualitative, map-wise results were validated further with a region-of-interest-based quantitative analysis using "canonical" coordinates as reported previously. Therefore, we suggest that the reliability assessments be incorporated in future ALFF studies, especially for the brain regions with a large ALFF magnitude as listed in our paper. Splitting single data into several segments and assessing within-scan "test-retest" reliability is an acceptable alternative if no "real" test-retest datasets are available. Such evaluations might become more necessary if the data are collected with clinical scanners whose performance is not as good as those that are used for scientific research purposes and are better maintained because the lower signal-to-noise ratio may further dampen ALFF reliability. PMID- 26053267 TI - Leaf Lateral Asymmetry in Morphological and Physiological Traits of Rice Plant. AB - Leaf lateral asymmetry in width and thickness has been reported previously in rice. However, the differences between the wide and narrow sides of leaf blade in other leaf morphological and physiological traits were not known. This study was conducted to quantify leaf lateral asymmetry in leaf width, leaf thickness, specific leaf weight (SLW), leaf nitrogen (N) concentration based on dry weight (Nw) and leaf area (Na), and chlorophyll meter reading (SPAD). Leaf morphological and physiological traits of the two lateral halves of the top three leaves at heading stage were measured on 23 rice varieties grown in three growing seasons in two locations. Leaf lateral asymmetry was observed in leaf width, leaf thickness, Nw, Na, and SPAD, but not in SLW. On average, the leaf width of the wide side was about 17% higher than that of the narrow side. The wide side had higher leaf thickness than the narrow side whereas the narrow side had higher Nw, Na, and SPAD than the wide side. We conclude that the narrow side of leaf blade maintained higher leaf N status than the wide side based on all N-related parameters, which implies a possibility of leaf lateral asymmetry in photosynthetic rate in rice plant. PMID- 26053268 TI - Letter to the Editor: An Important Use of a National Joint Registry. PMID- 26053266 TI - The Effect of Quercetin on the Osteogenesic Differentiation and Angiogenic Factor Expression of Bone Marrow-Derived Mesenchymal Stem Cells. AB - Bone marrow-derived mesenchymal stem cells (BMSCs) are widely used in regenerative medicine in light of their ability to differentiate along the chondrogenic and osteogenic lineages. As a type of traditional Chinese medicine, quercetin has been preliminarily reported to promote osteogenic differentiation in osteoblasts. In the present study, the effects of quercetin on the proliferation, viability, cellular morphology, osteogenic differentiation and angiogenic factor secretion of rat BMSCs (rBMSCs) were examined by MTT assay, fluorescence activated cell sorter (FACS) analysis, real-time quantitative PCR (RT-PCR) analysis, alkaline phosphatase (ALP) activity and calcium deposition assays, and Enzyme-linked immunosorbent assay (ELISA). Moreover, whether mitogen activated protein kinase (MAPK) signaling pathways were involved in these processes was also explored. The results showed that quercetin significantly enhanced the cell proliferation, osteogenic differentiation and angiogenic factor secretion of rBMSCs in a dose-dependent manner, with a concentration of 2 MUM achieving the greatest stimulatory effect. Moreover, the activation of the extracellular signal-regulated protein kinases (ERK) and p38 pathways was observed in quercetin-treated rBMSCs. Furthermore, these induction effects could be repressed by either the ERK inhibitor PD98059 or the p38 inhibitor SB202190, respectively. These data indicated that quercetin could promote the proliferation, osteogenic differentiation and angiogenic factor secretion of rBMSCs in vitro, partially through the ERK and p38 signaling pathways. PMID- 26053269 TI - Authors' Responses. PMID- 26053270 TI - Pharmacokinetics of Novel Plant Cell-Expressed Taliglucerase Alfa in Adult and Pediatric Patients with Gaucher Disease. AB - Taliglucerase alfa is a beta-glucocerebrosidase enzyme replacement therapy approved in the United States, Israel, and other countries for treatment of Type 1 Gaucher disease in adults, and is the first approved plant cell--expressed recombinant protein. In this report, taliglucerase alfa pharmacokinetics were assessed in adult and pediatric patients with Gaucher disease from separate multicenter trials of 30 Units/kg and 60 Units/kg doses infused every 2 weeks. Serial blood samples were obtained from adult patients following single-dose administration on day 1 (n = 26) and multiple doses at week 38 (n = 29), and from pediatric patients following administration of multiple doses of taliglucerase alfa for 10-27 months (n = 10). In both adult and pediatric patients, maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time zero to last measureable concentration (AUC0-t), and from time zero to infinity (AUC0-infinity) were higher after 60 Units/kg dose than 30 Units/kg dose. No tendency for accumulation or change in taliglucerase alfa pharmacokinetic parameters over time from day 1 to week 38 was observed with repeated doses of 30 or 60 Units/kg in adults. After multiple doses, mean (range) dose-normalized pharmacokinetic parameters were similar for adult versus pediatric patients receiving 60 Units/kg: Cmax expressed in ng/mL/mg was 42.4 (14.5-95.4) in adults and 46.6 (34.4-68.4) in pediatric patients, AUC0 t expressed in ng * h/mL/mg was 63.4 (26.3-156) in adults and 63.9 (39.8-85.1) in pediatric patients, t1/2 expressed in minutes was 34.8 (11.3-104) in adults and 31.5 (18.0-42.9) in pediatric patients and total body clearance expressed in L/h was 19.9 (6.25-37.9) in adults and 17.0 (11.7-24.9) in pediatric patients. These pharmacokinetic data extend the findings of taliglucerase alfa in adult and pediatric patients. TRIAL REGISTRATION: ClinicalTrials.gov. NCT00376168 (in adults); NCT01411228 (in children). PMID- 26053271 TI - Assessment of the Annual Additional Effective Doses amongst Minamisoma Children during the Second Year after the Fukushima Daiichi Nuclear Power Plant Disaster. AB - An assessment of the external and internal radiation exposure levels, which includes calculation of effective doses from chronic radiation exposure and assessment of long-term radiation-related health risks, has become mandatory for residents living near the nuclear power plant in Fukushima, Japan. Data for all primary and secondary children in Minamisoma who participated in both external and internal screening programs were employed to assess the annual additional effective dose acquired due to the Fukushima Daiichi nuclear power plant disaster. In total, 881 children took part in both internal and external radiation exposure screening programs between 1st April 2012 to 31st March 2013. The level of additional effective doses ranged from 0.025 to 3.49 mSv/year with the median of 0.70 mSv/year. While 99.7% of the children (n = 878) were not detected with internal contamination, 90.3% of the additional effective doses was the result of external radiation exposure. This finding is relatively consistent with the doses estimated by the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR). The present study showed that the level of annual additional effective doses among children in Minamisoma has been low, even after the inter-individual differences were taken into account. The dose from internal radiation exposure was negligible presumably due to the success of contaminated food control. PMID- 26053273 TI - Tiny cause with huge impact: polar instability through strong magneto-electric elastic coupling in bulk EuTiO3. AB - EuTiO3 exhibits strong magneto-electric coupling at the onset of antiferromagnetic order below TN = 5.7 K. The dielectric permittivity drops at TN by 7% and recovers to normal values with increasing magnetic field. This effect is shown to stem from tiny lattice effects as seen in magnetostriction data which directly affect the soft optic mode and its polarizability coordinate. By combining experimental results with theory we show that marginal changes in the lattice parameter of the order of 0.01% have a more than 1000% effect on the transverse optic soft mode of ETO and thus easily induce a ferroelectric instability. PMID- 26053274 TI - Novel ZnO/Fe2O3 Core-Shell Nanowires for Photoelectrochemical Water Splitting. AB - A facile and simple fabrication of Fe2O3 as a shell layer on the surface of ZnO nanowires (NW) as a core-shell nanoelectrode is applied for the photoelectrochemical (PEC) splitting of water. An ZnO NW array of core diameter ~80 nm was grown on a fluorine-doped tin-oxide (FTO) substrate with a hydrothermal method; subsequent deposition and annealing achieved a shell structure of the Fe2O3 layer of thickness a few nm. Fe2O3 in the alpha phase and ZnO in the wurtzite phase were identified as the structures of the shell and core, respectively, through analysis with X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The ZnO/Fe2O3 core-shell NW showed an excellent PEC response to the oxidation of water, and also benefited from a negative shift of onset potential because of an n/n heterojunction structure. A detailed energy diagram of the ZnO/Fe2O3 core-shell NW was investigated with a Mott-Schottky analysis. This novel core-shell nanostructure can hence not only exhibit a great potential for the solar generation of hydrogen, but also offer a blueprint for the future design of photocatalysts. PMID- 26053272 TI - Photodynamic Inactivation of Candida albicans with Imidazoacridinones: Influence of Irradiance, Photosensitizer Uptake and Reactive Oxygen Species Generation. AB - The increasing applicability of antifungal treatments, the limited range of available drug classes and the emergence of drug resistance in Candida spp. suggest the need for new treatment options. To explore the applicability of C. albicans photoinactivation, we examined nine structurally different imidazoacridinone derivatives as photosensitizing agents. The most effective derivatives showed a >10(4)-fold reduction of viable cell numbers. The fungicidal action of the three most active compounds was compared at different radiant powers (3.5 to 63 mW/cm2), and this analysis indicated that 7 mW/cm2 was the most efficient. The intracellular accumulation of these compounds in fungal cells correlated with the fungicidal activity of all 9 derivatives. The lack of effect of verapamil, an inhibitor targeting Candida ABC efflux pumps, suggests that these imidazoacridinones are not substrates for ABC transporters. Thus, unlike azoles, a major class of antifungals used against Candida, ABC transporter mediated resistance is unlikely. Electron paramagnetic resonance (EPR)-spin trapping data suggested that the fungicidal light-induced action of these derivatives might depend on the production of superoxide anion. The highest generation rate of superoxide anion was observed for 1330H, 1610H, and 1611. Singlet oxygen production was also detected upon the irradiation of imidazoacridinone derivatives with UV laser light, with a low to moderate yield, depending on the type of compound. Thus, imidazoacridinone derivatives examined in the present study might act via mixed type I/type II photodynamic mechanism. The presented data indicate lack of direct correlation between the structures of studied imidazoacridinones, cell killing ability, and ROS production. However, we showed for the first time that for imidazoacridinones not only intracellular accumulation is necessary prerequisite of lethal photosensitization of C. albicans, but also localization within particular cellular structures. Our findings present IA derivatives as efficient antifungal photosensitizers with a potential to be used in local treatment of Candida infection. PMID- 26053275 TI - Suppression of multidrug resistance by rosiglitazone treatment in human ovarian cancer cells through downregulation of FZD1 and MDR1 genes. AB - Multidrug resistance (MDR) is a major obstacle in the successful treatment of ovarian cancer. One of the most common causes of MDR is overexpression of P glycoprotein (P-gp), encoded by the MDR1 gene. The MDR1 gene is a direct target of the Wnt/beta-catenin signaling pathway, which plays an important role in ovarian cancer. Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands have been found to protect against development of cancer through the Wnt/beta-catenin pathway. To investigate the effect of PPARgamma ligands on MDR1/P-gp expression, we treated a MDR ovarian cancer cell subline, A2780/Taxol, with different concentrations of rosiglitazone (Rosi), a member of the synthetic PPARgamma ligands. Rosi downregulated FZD1 and MDR1/P-gp expression in a concentration-dependent manner. In addition, nuclear beta-catenin levels and its transcriptional activity decreased significantly. In conclusion, Rosi may reverse MDR of ovarian cancer cells by downregulating the Wnt/beta-catenin pathway with the suppression of FZD1. PMID- 26053276 TI - Suberoylanilide hydroxamic acid synergistically enhances the antitumor activity of etoposide in Ewing sarcoma cell lines. AB - Ewing sarcomas (ES) are highly malignant tumors arising in bone and soft tissues. Given the poor outcome of affected patients with primary disseminated disease or at relapse, there is a clear need for new targeted therapies. The HDAC inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA, Vorinostat) inhibits ES tumor growth and induces apoptosis in vitro and in vivo. Thus, SAHA may be considered a novel treatment. However, it is most likely that not a single agent but a combination of agents with synergistic mechanisms will help improve the prognosis in high-risk ES patients. Therefore, the aim of the present study was to assess a putative synergistic effect of SAHA in combination with conventional chemotherapeutic agents. The antitumor activity of SAHA in combination with conventional chemotherapeutics (doxorubicin, etoposide, rapamycin, topotecan) was assessed using an MTT cell proliferation assay on five well-characterized ES cell lines (CADO-ES-1, RD-ES, TC-71, SK-ES-1, SK-N-MC) and a newly established ES cell line (DC-ES-15). SAHA antagonistically affected the antiproliferative effect of doxorubicin and topotecan in the majority of the ES cell lines, but synergistically enhanced the antiproliferative activity of etoposide. In functional analyses, pretreatment with SAHA significantly increased the effects of etoposide on apoptosis and clonogenicity. The in-vitro analyses presented in this work show that SAHA synergistically enhances the antitumor activity of etoposide in ES cells. Sequential treatment with etoposide combined with SAHA may represent a new therapeutic approach in ES. PMID- 26053277 TI - Drug-induced RAF dimerization is independent of RAS mutation status and does not lead to universal MEK dependence for cell survival in head and neck cancers. AB - Treatments for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) have limited efficacy. One potential therapeutic target for HNSCC is the RAS/RAF/MEK/ERK cascade, which is one of the major signaling pathways for HNSCC cell survival. In HNSCC, RAS can be activated either by HRAS mutation or by upstream signaling. The ABL inhibitor nilotinib acts as a weak RAF inhibitor that induces RAF dimerization and subsequent activation of MEK/ERK in other cancer cell lines with activated RAS, leading to an unexpected dependence on MEK/ERK for cell survival. We hypothesized that nilotinib and the MEK inhibitor MEK162 would be synergistic in HNSCC cell lines owing to the frequent activation of RAS. We treated HNSCC cell lines with nilotinib and performed immunoblotting and cell viability experiments. We used an orthotopic mouse model to assess synergistic effects in vivo. Nilotinib induced significant BRAF-CRAF heterodimerization and ERK activation irrespective of RAS mutation status. In cell-viability assays, nilotinib synergized with MEK162. MEK162 alone induced G1 arrest that was minimally enhanced by nilotinib. In the mouse model, treatment with MEK162 alone or combined with nilotinib led to tumor growth inhibition. In HNSCC, nilotinib induced RAF dimerization is independent of RAS mutation status, but this dimerization does not lead to MEK dependence for cell survival in all HNSCC cell lines. MEK inhibition alone leads to decreased proliferation both in vitro and in vivo. Although nilotinib has some synergistic effects with MEK162, other agents may be more effective against HNSCC when combined with MEK162. PMID- 26053278 TI - CDK4/6 inhibitors in breast cancer. AB - Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated. The early pan-CDK inhibitor flavopiridol and subsequent preclinical and clinical development of selective CDK4/6 inhibitors are described. Ongoing studies in breast cancer with novel CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) are explored. A literature search of these topics was performed through PubMed. Abstracts from major oncology meetings were also reviewed. Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs. Considerable resources are being devoted towards exploring the efficacy of these drugs in combination with endocrine therapies, an approach that has yielded encouraging results and accelerated approval by the US Food and Drugs Administration for one of these agents (palbociclib). The results of confirmatory phase 3 trials are, however, awaited. We discuss further therapy combinations in development and highlight potential areas for caution including the potential for antagonistic interactions with cytotoxic chemotherapies. PMID- 26053279 TI - Carboplatin, methotrexate, vinblastine, and epirubicin (M-VECa) as salvage treatment in patients with advanced bladder cancer: a phase II study. AB - The primary objective of this study was to determine the activity and safety of carboplatin, methotrexate, vinblastine, and epirubicin (the M-VECa regimen) in patients with advanced bladder cancer after failure of at least one chemotherapy line. Treatment consisted of carboplatin 250 mg/m on day 1, methotrexate 30 mg/m on days 1 and 22, vinblastine 3 mg/m on days 2 and 22, and epirubicin 50 mg/m on day 2 every 28 days until disease progression or death. Response rate was the main end-point. Twenty-five patients were enrolled: the median age was 67 years (range 42-83) and there were 14 patients aged at least 70 years (56%). Fourteen patients had previously received vinflunine as a second-line treatment. Complete remission occurred in one patient (4%), partial remission in five patients (20%), and stable disease in eight patients (32%). The overall response rate was 24% [95% confidence interval (CI), 9.3-45.1%] and the overall disease control rate was 56% (95% CI, 34.9-75.5%). The median progression-free survival was 5.1 months (95% CI, 3.9-6.4) and the median overall survival was 9.5 months (95% CI, 7.1 11.2). Treatment was well tolerated: grade 3 neutropenia was documented in five patients and grade 3 nausea and vomiting in two patients. The M-VECa regimen seems to be feasible as second-line or third-line treatment in patients with advanced bladder cancer who have been pretreated with one or more chemotherapy lines, and may achieve encouraging results in terms of disease control rate, progression-free survival, and overall survival. PMID- 26053280 TI - Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients. AB - Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic. PMID- 26053281 TI - Tolerability of cabazitaxel in patients with metastatic castration-resistant prostate cancer progressing after docetaxel and abiraterone acetate: a single institution experience. AB - Both abiraterone acetate (AA) and cabazitaxel (Cbz) have been shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel (D). Although no standard sequencing has been established as yet, Cbz has recently been proven to be active after AA. However, to date, few data are available on its safety in this setting. Therefore, the primary endpoint of this study was to investigate Cbz tolerability in mCRPC patients treated previously with D and AA. From April 2011 to the present, 43 mCRPC patients received AA after D at our institution. Of these, 22 patients were subsequently treated with Cbz and were evaluable for toxicity in the present retrospective study. Cbz was administered at a dose of 25 mg/m plus 10 mg oral prednisone every 3 weeks. Adverse events (AEs) were reported using the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. Despite the advanced stage of disease and frailty of our study population, there were no unexpected side effects. The most common AEs were hematologic. Neutropenia was observed in nine (40.9%) patients and of grade>=3 in six (27.2%). No febrile neutropenia occurred. The most common nonhematologic AEs were diarrhea and asthenia, reported in eight (36.3%) and in five (22.7%) patients, respectively. In this setting, Cbz toxicity seems to be manageable and comparable with second-line Cbz. Therefore, our results seem to support the safety of Cbz as a third-line treatment for mCRPC patients. PMID- 26053282 TI - Metabolic aspects of high-altitude adaptation in Tibetans. AB - NEW FINDINGS: What is the topic of this review? The topic of this review is how Tibetans have adapted genetically to high altitude, particularly with reference to altitude-induced changes in metabolism. What advances does it highlight? It highlights recent work on metabolic phenotyping in Tibetans and demonstrates that selected genetic haplotypes influence their metabolism of fats and glucose. Recent studies have identified genes involved in high-altitude adaptation in Tibetans. Three of these genes (EPAS1, EGLN1 and PPARA) are associated with decreased haemoglobin levels compared with non-Tibetans living at altitude. Consistent with the phenotype, EGLN1 in Tibetans has a gain-of-function mutation that confers a higher affinity for oxygen, hence less sensitivity to hypoxia. Considering the demands imposed upon metabolism in meeting energy demands despite limitations on fuel oxidation, we hypothesized that other selected genes might alter metabolism to allow adaptation to altitude despite the desensitization of the upstream hypoxia sensing caused by the EGLN1 mutation that results in the failure to sense hypoxia. A shift in fuel preference to glucose oxidation and glycolysis at the expense of fatty acid oxidation would provide adaptation to decreased oxygen availability. Measurements of serum metabolites from Tibetans living at high altitude are consistent with this hypothesis; the EPAS1 haplotype is significantly associated with increased lactate levels (suggesting increased anaerobic metabolism), and the PPARA haplotype and serum free fatty acids are positively related (suggesting decreased fat oxidation). These data suggest that the high-altitude adaptations may offer protection from diabetes at high altitude but increase the risk of diabetes at lower elevations and/or with adoption of a non-traditional diet. It should also be considered in future work in the field that because iron is a cofactor for EGLN1, there may be significant associations of phenotypes with the significant degrees of variation seen in tissue iron among human populations. PMID- 26053283 TI - Pulmonary Gas Exchange and Exercise Capacity in Adults Born Preterm. AB - RATIONALE: Preterm birth, and its often-required medical interventions, can result in respiratory and gas exchange deficits into childhood. However, the long term sequelae into adulthood are not well understood. OBJECTIVES: To determine exercise capacity and pulmonary gas exchange efficiency during exercise in adult survivors of preterm birth. METHODS: Preterm (n = 14), very low birth weight (<1,500 g) adults (20-23 yr) and term-born, age-matched control subjects (n = 16) performed incremental exercise on a cycle ergometer to volitional exhaustion while breathing one of two oxygen concentrations: normoxia (fraction of inspired oxygen, 0.21) or hypoxia (fraction of inspired oxygen, 0.12). MEASUREMENTS AND MAIN RESULTS: Ventilation, mixed expired gases, arterial blood gases, power output, and oxygen consumption were measured during rest and exercise. We calculated the alveolar-to-arterial oxygen difference to determine pulmonary gas exchange efficiency. Preterm subjects had lower power output at volitional exhaustion than did control subjects in normoxia (150 +/- 10 vs. 180 +/- 10 W; P = 0.01), despite similar normoxic oxygen consumption. However, during hypoxic exercise, there was no difference in power output at volitional exhaustion between the two groups (116 +/- 10 vs. 135 +/- 10 W; P = 0.11). Preterm subjects also exhibited a more acidotic, acid-base balance throughout exercise compared with control subjects. In contrast to other studies, adults born preterm, as a group developed a wider alveolar-to-arterial oxygen difference and lower PaO2 than did control subjects during normoxic but not hypoxic exercise. CONCLUSIONS: This study demonstrates that pulmonary gas exchange efficiency is lower in some adult survivors of preterm birth during exercise compared with control subjects. The gas exchange inefficiency, when present, is accompanied by low arterial blood oxygen tension. Preterm subjects also exhibit reduced power output. Overall, our findings suggest potential long-term consequences of extreme preterm birth and very low birth weight on cardiopulmonary function. PMID- 26053284 TI - Standardization of Research-Quality Anthropometric Measurement of Infants and Implementation in a Multicenter Study. AB - Malnutrition is one of the earliest clinical manifestations of cystic fibrosis (CF) and is associated with poorer pulmonary and cognitive outcomes and survival later in life. Infant growth can be a responsive measure for clinical research in this age group if obtained and characterized accurately. We report here the methods to standardize and implement research-quality anthropometric measurement of infants with cystic fibrosis in the Baby Observational Nutrition Study multicenter trial. PMID- 26053285 TI - Efficacy and safety of off-label use of rituximab in refractory lupus: data from the Italian Multicentre Registry. AB - OBJECTIVES: To evaluate the efficacy and safety of rituximab (RTX) in patients with systemic lupus erythematosus (SLE) refractory to standard therapy in the clinical practice setting. METHODS: 145 SLE patients (ACR criteria) were treated with RTX in 11 Italian Centres: 118 with two infusions (1 g), two weeks apart; 27 with 4 infusions (375 mg/m2), one week apart, followed in 10 cases by two further doses, after 1 and 2 months. Systemic complete response (CR) was defined as European Consensus Lupus Activity Measurement (ECLAM) score <=1 and partial response (PR) as 1< ECLAM <=3. Renal CR (RCR) and renal PR (RPR) were defined according to EULAR recommendations for management of lupus nephritis. RESULTS: Data from 134 (92.4%) patients were available. The mean+/-SD follow-up was 27.3+/ 18.5 months. After the first course of RTX, CR or PR were observed in 85.8% and CR in 45.5% of cases; RCR or RPR in 94.1% and RCR in 30.9% of patients after 12 month follow-up. Disease flares occurred in 35.1% and renal flares in 31.2% of patients during observational period. Among patients retreated, CR or PR were observed in 84.4% and CR in 57.8% of cases. Adverse events, infections, and infusion reactions occurred after first RTX course in 23.8%, 16.4%, and 3.8% of patients and after retreatment in 33.3%, 22.2% and 11.1%, respectively. No severe infusion reactions or deaths occurred. CONCLUSIONS: Data from Italian multicentre RTX Registry confirmed the efficacy and safety of RTX in SLE patients refractory to standard treatment in clinical practice setting. PMID- 26053286 TI - Adjuvants in micro- to nanoscale: current state and future direction. AB - Adjuvants have been used in vaccines for over 70 years to promote long-lived and sterilizing immunity. Since then, various adjuvant systems were developed by combining nanotechnology with natural and/or synthetic immunomodulatory molecules. These systems are biocompatible, immunogenic, and possess higher antigen carrying capacity. This article showcases advancements made in the adjuvant systems formulations, their synthesis routes, and the improvement of these adjuvants have brought in response to combat against ongoing global health threats such as malaria, hepatitis C, universal influenza, and human immunodeficiency virus. This review also highlights the interaction of adjuvants with the delivery of antigens to cells and unfolds mechanism of actions. In addition, this review discusses the physicochemical factors responsible for the efficient interaction of nanoadjuvants with antigen receptors to develop more effective, less reactogenic, and multifunctional systems for the next generation vaccines. PMID- 26053287 TI - A computational analysis of the apparent nido vs. hypho conflict: are we dealing with six- or eight-vertex open-face diheteroboranes? AB - A series of computational studies have been undertaken to investigate the electronic structures and bonding schemes for six hetero-substituted borane cages, all of which have been presented in the literature as potential hypho structures. The six species are hypho-7,8-[C2B6H13](-) (1a), hypho-7,8-[CSB6H11]( ) (1b), hypho-7,8-[S2B6H9](-) (1c), hypho-7,8-[NSB6H11] (1d), exo-7-Me-hypho-7,8 [NCB6H12] (1e), and endo-7-Me-hypho-7,8-[NCB6H12] (1f) and the so-called mno rule has been applied to each of them. As no structural data are known for the carbathia-, azathia-, and dithiahexaboranes, we have also applied the ab initio/GIAO/NMR structural tool for 1b-1d, with 1c having been prepared for this purpose. We conclude that an mno count of 10 means that 1a, 1b, 1d, 1e, and 1f should be termed pseudo-nido or pseudo-hypho. Only 1c can be considered to be correctly termed hypho-7,8-[S2B6H9](-). PMID- 26053289 TI - What is urticaria? Expert opinion from the 1st Global Urticaria Forum. PMID- 26053288 TI - No Enhancement of 24-Hour Visuomotor Skill Retention by Post-Practice Caffeine Administration. AB - Caffeine is widely consumed throughout the world and appears to indirectly facilitate learning and memory through effects on attention and motivation. Animal work indicates that post-training caffeine administration augments inhibitory avoidance memory, spatial memory, and object memory. In humans, post training caffeine administration enhances the ability to discern between familiar images and new, similar images. However, the effect of post-training caffeine administration on motor memory has not been examined. Therefore, we tested two groups of low caffeine consumers (average weekly consumption <=500 mg) in a double-blind, placebo-controlled study involving acquisition of a continuous isometric visuomotor tracking skill. On Day 1, subjects completed 5 blocks (150 repetitions) of training on the continuous isometric visuomotor skill and subsequently ingested either 200 mg of caffeine or placebo. On day 2, subjects completed an additional 5 blocks of training. Day 1 mean performance and performance variability were both similar between groups, suggesting that both groups acquired the motor skill similarly. For mean performance on Day 2, patterns of re-learning, mean performance learning magnitudes, mean performance learning rates, and mean performance retention magnitudes were all similar between groups. For performance variability on Day 2, there was a small trend towards increased variability in the caffeine group during re-learning, but performance variability learning magnitudes and performance variability retention magnitudes did not differ between groups. Because motor skill acquisition can also be conceptualized as a reduction in performance variability, these results suggest that there may be a small negative effect of post-practice caffeine administration on memory of a newly-learned visuomotor skill. Overall, we found no evidence to suggest that post-training caffeine administration enhances 24 hour retention of a newly-learned continuous visuomotor skill, and these results support the notion that memory-enhancing effects of post-training caffeine ingestion may be task-specific. PMID- 26053290 TI - An individualized diagnostic approach based on guidelines for chronic urticaria (CU). AB - Chronic urticaria (CU), defined as the spontaneous or inducible appearance of hives, angioedema or both for 6 weeks or more, presents with a number of subtypes which all substantially impair patients' quality of life (QoL). International urticaria guidelines give clear recommendations on workup and treatment but the occurrence of CU with multiple causes and triggers (sometimes with more than one subtype occurring in a single patient) presents challenges for an individualized assessment by physicians. This review summarizes recent guidance on the classification, diagnosis and assessment of CU subtypes and discusses how currently available patient assessment tools and laboratory tests can be used in clinical practice as part of an individualized patient management plan. PMID- 26053291 TI - Diagnostic dilemmas in chronic urticaria. AB - The European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA(2) LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) recently published updated recommendations for the classification, diagnosis and management of chronic urticaria (CU). This article discusses several cases of CU that provide examples of how the recommendations in the guidelines can be implemented in the diagnosis of chronic spontaneous urticaria (CSU) (also called chronic idiopathic urticaria [CIU]), chronic inducible urticaria (CINDU) or CU with comorbidities. PMID- 26053292 TI - Management and treatment of chronic urticaria (CU). AB - Developments increasing our understanding of chronic urticaria have resulted in the simplification and improvement of available treatments. Currently, many treatments target mast cell mediators, but we can now disrupt mast cell activation with the anti-IgE antibody omalizumab, which has markedly advanced the treatment landscape for patients with difficult-to-treat urticaria. Current guidelines provide a framework for the management and treatment of patients with CU but, as each patient is different, knowledge and experience of specialist dermatologists and allergists are key to effective pharmacotherapy. This article reviews the different therapeutic options for patients with chronic spontaneous urticaria (also called chronic idiopathic urticaria) or chronic inducible urticaria and discusses management of special populations or special circumstances related to CU. PMID- 26053293 TI - Treatment dilemmas in chronic urticaria. AB - The European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA(2) LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) recently published updated recommendations for the classification, diagnosis and management of chronic urticaria (CU). This article discusses several case histories that provide examples of how these recommendations can be implemented in the treatment of CU in a variety of real life patients. PMID- 26053294 TI - Chronic urticaria: tools to aid the diagnosis and assessment of disease status in daily practice. AB - This article focuses on practical considerations for the optimal management of chronic urticaria (CU) with regard to the tools and instruments that are currently available to assist in the diagnosis and assessment of this condition before and during treatment. PMID- 26053295 TI - Health Status and Risk Factors among Adolescent Survivors One Month after the 2014 Ludian Earthquake. AB - BACKGROUND: An earthquake struck Ludian in Yunnan Province (China) on 3 August 2014, resulting in 3143 injuries, 617 deaths, and 112 missing persons. Our study aimed at estimating the health status and associated determinants among adolescent survivors after the Ludian earthquake. METHODS: A cross-sectional survey of 845 was conducted at the Ludian No. 1 Middle School. Descriptive statistics, t-tests, ANOVA and stepwise linear regression analysis were used for data analysis. RESULTS: The mean scores on the physical component summary (PCS) and mental component summary (MCS) were 46.23 (SD=7.10) and 36.34 (SD=7.09), respectively. Lower PCS scores in the aftermath of an earthquake were associated with being trapped or in danger, being female, being an ethnic minority, injury to self and house damage, while lower MSC scores were associated with fear during the earthquake, Han ethnicity, death in the family, not being involved in the rescue and low household income. CONCLUSIONS: In our study, significant associations between demographic, socio-economic, and trauma-related experiences variables and overall physical and mental health of adolescent survivors were presented. The results of this study help expand our knowledge of health status among adolescent survivors after the Ludian earthquake. PMID- 26053296 TI - Clear Skies and Grey Areas: Flight Attendants' Secondhand Smoke Exposure and Attitudes toward Smoke-Free Policy 25 Years since Smoking was Banned on Airplanes. AB - Our objective was to provide descriptive data on flight attendant secondhand smoke (SHS) exposure in the work environment, and to examine attitudes toward SHS exposure, personal health, and smoke-free policy in the workplace and public places. Flight attendants completed a web-based survey of self-reported SHS exposure and air quality in the work environment. We assessed the frequency and duration of SHS exposure in distinct areas of the workplace, attitudes toward SHS exposure and its health effects, and attitudes toward smoke-free policy in the workplace as well as general public places. A total of 723 flight attendants participated in the survey, and 591 responded to all survey questions. The mean level of exposure per flight attendant over the past month was 249 min. The majority of participants reported being exposed to SHS always/often in outdoor areas of an airport (57.7%). Participants who worked before the in-flight smoking ban (n=240) were more likely to support further smoking policies in airports compared to participants who were employed after the ban (n=346) (76.7% versus 60.4%, p-value<0.01). Flight attendants are still being exposed to SHS in the workplace, sometimes at concerning levels during the non-flight portions of their travel. Flight attendants favor smoke-free policies and want to see further restrictions in airports and public places. PMID- 26053297 TI - Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. AB - Capsaicin bestows spiciness by activating TRPV1 channel with exquisite potency and selectivity. Although a capsaicin-bound channel structure was previously resolved by cryo-EM at 4.2- to 4.5-A resolution, capsaicin was registered as a small electron density, reflecting neither its chemical structure nor specific ligand-channel interactions--important details required for mechanistic understanding. We obtained the missing atomic-level details by iterative computation and confirmed them by systematic site-specific functional tests. We observed that the bound capsaicin takes a 'tail-up, head-down' configuration. The vanillyl and amide groups form specific interactions to anchor its bound position, while the aliphatic tail may sample a range of conformations, making it invisible in cryo-EM images. Capsaicin stabilizes TRPV1's open state by 'pull-and contact' interactions between the vanillyl group and the S4-S5 linker. Our study provides a structural mechanism for the agonistic function of capsaicin and its analogs, and demonstrates an effective approach to obtain atomic-level information from cryo-EM structures. PMID- 26053299 TI - Biomaterials: Recipe for squid beak. PMID- 26053298 TI - Infiltration of chitin by protein coacervates defines the squid beak mechanical gradient. AB - The beak of the jumbo squid Dosidicus gigas is a fascinating example of how seamlessly nature builds with mechanically mismatched materials. A 200-fold stiffness gradient begins in the hydrated chitin of the soft beak base and gradually increases to maximum stiffness in the dehydrated distal rostrum. Here, we combined RNA-Seq and proteomics to show that the beak contains two protein families. One family consists of chitin-binding proteins (DgCBPs) that physically join chitin chains, whereas the other family comprises highly modular histidine rich proteins (DgHBPs). We propose that DgHBPs play multiple key roles during beak bioprocessing, first by forming concentrated coacervate solutions that diffuse into the DgCBP-chitin scaffold, and second by inducing crosslinking via an abundant GHG sequence motif. These processes generate spatially controlled desolvation, resulting in the impressive biomechanical gradient. Our findings provide novel molecular-scale strategies for designing functional gradient materials. PMID- 26053300 TI - The Conundrum of Unnecessary Preoperative Testing. PMID- 26053301 TI - Pathophysiology of gastroesophageal reflux disease: new understanding in a new era. AB - BACKGROUND: The prevalence of gastroesophageal reflux disease (GERD) has increased in the last decades and it is now one of the most common chronic diseases. Throughout time our insight in the pathophysiology of GERD has been characterized by remarkable back and forth swings, often prompted by new investigational techniques. Even today, the pathophysiology of GERD is not fully understood but it is now recognized to be a multifactorial disease. Among the factors that have been shown to be involved in the provocation or increase of reflux, are sliding hiatus hernia, low lower esophageal sphincter pressure, transient lower esophageal sphincter relaxation, the acid pocket, obesity, increased distensibility of the esophagogastric junction, prolonged esophageal clearance, and delayed gastric emptying. Moreover, multiple mechanisms influence the perception of GERD symptoms, such as the acidity of the refluxate, its proximal extent, the presence of gas in the refluxate, duodenogastroesophageal reflux, longitudinal muscle contraction, mucosal integrity, and peripheral and central sensitization. Understanding the pathophysiology of GERD is important for future targets for therapy as proton pump inhibitor-refractory GERD symptoms remain a common problem. PURPOSE: In this review we provide an overview of the mechanisms leading to reflux and the factors influencing perception, in the light of historical developments. It is clear that further research remains necessary despite the recent advances in the understanding of the pathophysiology of GERD. PMID- 26053302 TI - Pivotal role of ATP in macrophages fast tracking wound repair and regeneration. AB - Chronic wounds occurring during aging or diabetes pose a significant burden to patients. The classical four-phase wound healing process has a 3-6 day lag before granulation starts to appear and it requires an intermediate step of activation of resident fibroblasts during the remodeling phase for production of collagen. This brief communication discusses published articles that demonstrate how the entire wound healing process can be fast tracked by intracellular ATP delivery, which triggers a novel pathway where alternatively activated macrophages play absolutely critical and central roles. This novel pathway involves an increase in proinflammatory cytokines (TNF, IL-1beta, IL-6) and a chemokine (MCP-1) release. This is followed by activation of purinergic receptor (a family of plasma membrane receptors found in almost all mammalian cells), production of platelets and platelet microparticles, and activation of ATP-dependent chromatin remodeling enzymes. The end result is a massive influx and in situ proliferation of macrophages, increases in vascular endothelial growth factors that promote neovascularization, and most prominently, the direct production of collagen. PMID- 26053303 TI - Re-Examining the Agentic Shift: The Sense of Agency Influences the Effectiveness of (Self)Persuasion. AB - In the present study we investigated whether differences in the sense of agency influenced the effectiveness of both direct persuasion and self-persuasion techniques. By manipulating both the delay and contingency of the outcomes of actions, participants were led to experience either a low or high sense of agency. Participants were subsequently presented with arguments as to why a clean local environment is important (direct persuasion), or were asked to generate those arguments themselves (self-persuasion). Subsequently, participants' cleanliness attitudes and willingness to participate in a campus cleanup were measured. The results show that techniques of direct persuasion influenced attitudes and volunteering behavior under conditions of low rather than high agency, whereas techniques of self-persuasion were most effective under conditions of high rather than low agency. The present findings therefore show how recent experiences of agency, a state based experience of control, can influence the effectiveness of both external and internal persuasion techniques. PMID- 26053304 TI - Indirect CO2 Emission Implications of Energy System Pathways: Linking IO and TIMES Models for the UK. AB - Radical changes to current national energy systems-including energy efficiency and the decarbonization of electricity-will be required in order to meet challenging carbon emission reduction commitments. Technology explicit energy system optimization models (ESOMs) are widely used to define and assess such low carbon pathways, but these models only account for the emissions associated with energy combustion and either do not account for or do not correctly allocate emissions arising from infrastructure, manufacturing, construction and transport associated with energy technologies and fuels. This paper addresses this shortcoming, through a hybrid approach that estimates the upstream CO2 emissions across current and future energy technologies for the UK using a multiregional environmentally extended input-output model, and explicitly models the direct and indirect CO2 emissions of energy supply and infrastructure technologies within a national ESOM (the UK TIMES model). Results indicate the large significance of nondomestic indirect emissions, particularly coming from fossil fuel imports, and finds that the marginal abatement cost of mitigating all emissions associated with UK energy supply is roughly double that of mitigating only direct emissions in 2050. PMID- 26053305 TI - A salutogenic patient-centred perspective of improved oral health behaviour - a descriptive phenomenological interview study. AB - A salutogenic perspective was applied in the study when investigating the patient's perspective of what it means to move in the direction towards health in the treatment of periodontitis. OBJECTIVES: The study aimed at describing the lived experience of improved oral health-related behaviour. METHOD: The descriptive phenomenological method was chosen for collection and analysis of data. Patients were selected from a private general dental clinic. RESULTS: The results described the patient-centred perspective in the general structure held together by eight constituents: (i) change is increased successively, (ii) a changed view on self-care at the start of change, (iii) improved self-care includes understanding and automatic routine, (iv) motivating challenges and feedback are perceived as strengthening, (v) having good thoughts and being satisfied with one's own capacity, (vi) experiencing trust and participation along with an expert, (vii) negative experiences and limitations precedes the change and (viii) relating yourself to past time, present time, future and other people. CONCLUSION: The complex pattern of interconnected external and internal components in the results calls for the need of a holistic perspective of the change process and for the clinician to practise flexibility. PMID- 26053306 TI - Differential Modulation of Cellular Bioenergetics by Poly(L-lysine)s of Different Molecular Weights. AB - Poly(L-lysine)s (PLLs), and related derivatives, have received considerable attention as nonviral vectors. High molecular weight PLLs (H-PLLs) are superior transfectants compared with low Mw PLLs (L-PLLs), but suggested to be more cytotoxic. Through a pan-integrated metabolomic approach using Seahorse XF technology, we studied the impact of PLL size on cellular bioenergetic processes in two human cell lines. In contrast to L-PLLs (1-5 kDa), H-PLLs (15-30 kDa) were more detrimental to both mitochondrial oxidative phosphorylation (OXPHOS) and glycolytic activity resulting in considerable intracellular ATP depletion, thereby initiating necrotic-type cell death. The cellular differences to polycation sensitivity were further related to the mitochondrial state, where the impact was substantial on cells with hyperpolarized mitochondria. These medium throughput approaches offer better opportunities for understanding inter-related intracellular and cell type-dependent processes instigating a bioenergetics crisis, thus, aiding selection (from available libraries) and improved design of safer biodegradable polycations for nucleic acid compaction and cell type specific delivery. PMID- 26053307 TI - Postglacial recolonization in a cold climate specialist in western Europe: patterns of genetic diversity in the adder (Vipera berus) support the central marginal hypothesis. AB - Understanding the impact of postglacial recolonization on genetic diversity is essential in explaining current patterns of genetic variation. The central marginal hypothesis (CMH) predicts a reduction in genetic diversity from the core of the distribution to peripheral populations, as well as reduced connectivity between peripheral populations. While the CMH has received considerable empirical support, its broad applicability is still debated and alternative hypotheses predict different spatial patterns of genetic diversity. Using microsatellite markers, we analysed the genetic diversity of the adder (Vipera berus) in western Europe to reconstruct postglacial recolonization. Approximate Bayesian Computation (ABC) analyses suggested a postglacial recolonization from two routes: a western route from the Atlantic Coast up to Belgium and a central route from the Massif Central to the Alps. This cold-adapted species likely used two isolated glacial refugia in southern France, in permafrost-free areas during the last glacial maximum. Adder populations further from putative glacial refugia had lower genetic diversity and reduced connectivity; therefore, our results support the predictions of the CMH. Our study also illustrates the utility of highly variable nuclear markers, such as microsatellites, and ABC to test competing recolonization hypotheses. PMID- 26053308 TI - Radiofrequency Ablation Using a Multiple-Electrode Switching System for Lung Tumors with 2.0-5.0-cm Maximum Diameter: Phase II Clinical Study. AB - PURPOSE: To prospectively evaluate the safety and effectiveness of radiofrequency ablation (RFA) by using a multiple-electrode switching system to treat 2.0-5.0-cm lung tumors. MATERIALS AND METHODS: The institutional review board approved this prospective phase II study. Written informed consent was obtained from all patients. Between September 2009 and July 2011, RFA using two or three radiofrequency (RF) electrodes and a multiple-electrode switching system was performed for malignant lung tumors with a maximum tumor diameter of 2.0-5.0 cm in nonsurgical candidates. The primary endpoint was safety, as evaluated using the Common Terminology Criteria for Adverse Events. Patients were observed for at least 1 year. Local tumor progression and overall survival were analyzed with the Kaplan-Meier method. RESULTS: Thirty-three patients (26 men, seven women; mean age, 70.5 years +/- 10.0; age range, 46-87 years) with 35 lung tumors with a mean maximum diameter of 3.0 cm +/- 0.7 (standard deviation; range, 2.0-4.4 cm) underwent treatment in 35 sessions. No procedure-related death or grade 4 adverse events (AEs) occurred. Grade 3 AEs occurred in four patients (12%), with pleural effusion requiring chest tube placement in two patients, pneumothorax requiring pleural adhesion in one patient, and pulmonary hemorrhage requiring pulmonary artery coil embolization in one patient. Grade 2 AEs were detected in 13 patients (39%). The 1-year local tumor progression and overall survival rates were 12.7% (95% confidence interval [CI]: 1.0, 25.5) and 81.2% (95% CI: 67.6, 94.8). CONCLUSION: RFA with a multiple-electrode switching system may be a safe therapeutic option with which to treat 2.0-5.0-cm lung cancer tumors. PMID- 26053309 TI - Abnormal Intrinsic Brain Activity Patterns in Patients with End-Stage Renal Disease Undergoing Peritoneal Dialysis: A Resting-State Functional MR Imaging Study. AB - PURPOSE: To analyze the spontaneous brain activity patterns in patients with end stage renal disease (ESRD) undergoing peritoneal dialysis (PD) by using resting state functional magnetic resonance (MR) imaging with an amplitude of low frequency fluctuations (ALFF) algorithm. MATERIALS AND METHODS: This study received institutional review board approval, and all subjects gave informed consent. Forty-four patients with ESRD, 24 of whom were undergoing PD (PD group; eight women; mean age, 34 years +/- 8) and 20 who were not undergoing PD or hemodialysis (nondialysis group; six women; mean age, 37 years +/- 9) and 24 healthy control subjects (eight women; mean age, 32 years +/- 9 years) were included. All subjects underwent neuropsychologic tests, and patients with ESRD underwent laboratory testing. ALFF values were compared among the three groups. The relationship between ALFF values and clinical markers was investigated by using multiple regression analysis. RESULTS: Patients in both the PD and nondialysis groups showed lower ALFF values in default mode network regions than did healthy control subjects (P < .01, false discovery rate corrected). Patients in the PD group showed lower ALFF values than did those in the nondialysis group in the left superior parietal lobe (1.51 +/- 0.21 vs 2.01 +/- 0.40), left inferior parietal lobe (0.99 +/- 0.16 vs 1.13 +/- 0.22) and left precuneus (1.45 +/- 0.39 vs 1.77 +/- 0.41) (P < .01, corrected with simulation software). In patients in the PD group, neuropsychologic test scores correlated with ALFF values of the middle temporal gyrus and the parietal and occipital lobe, serum urea and creatinine levels negatively correlated with ALFF in some default mode network regions, and hemoglobin positively correlated with ALFF in the bilateral precuneus, precentral, and supplementary motor areas (P < .01 corrected). CONCLUSION: Patients with ESRD who were undergoing PD showed more severe spontaneous brain activity abnormalities that correlate with cognitive impairments than did patients who were not undergoing dialysis. Elevated serum urea, creatinine, and lowered hemoglobin levels affect spontaneous brain activity in patients with ESRD. PMID- 26053310 TI - Advanced High-Grade Serous Ovarian Cancer: Frequency and Timing of Thoracic Metastases and the Implications for Chest Imaging Follow-up. AB - PURPOSE: To study the frequency, timing, and associations of thoracic metastases in advanced (stage III and IV) high-grade serous ovarian cancer (HGSC) to help optimize the use of cross-sectional chest imaging. MATERIALS AND METHODS: This institutional review board-approved retrospective study with waived informed consent included 186 consecutive patients with pathologically proven advanced HGSC after primary cytoreduction (mean age +/- standard deviation, 60 years +/- 9.7) who underwent imaging at our tertiary cancer institution from January 2012 to December 2012 with at least 1 year of follow-up, unless there was thoracic metastasis or death. Electronic medical records and all available imaging studies were reviewed to record patient and tumor characteristics, frequency and timing of abdominal and thoracic metastases, and visibility of the first thoracoabdominal metastasis on abdominal images. Patient and tumor characteristics associated with thoracic metastases were studied by using univariate and multivariate Cox proportional analysis. RESULTS: After median follow-up of 57 months (interquartile range [IQR], 38-93), 175 patients (94%) developed metastatic disease; each had abdominal disease, and 76 (41%) had thoracic metastases. The first thoracoabdominal metastasis was visible on abdominal images in all 175 patients. The thoracic metastasis-free interval was longer than the abdominal disease-free interval (median, 85 months [IQR, 28-131] vs 14 months [IQR, 7-27], respectively; P < .0001). Presence of disease on abdominal images (hazard ratio, 2.56; 95% confidence interval: 1.35, 4.76) was the only factor independently associated with thoracic metastases. CONCLUSION: Thoracic metastases in advanced HGSC rarely occur before abdominal disease, and first thoracoabdominal metastases are invariably visible on abdominal images. Therefore, cross-sectional chest imaging may be deferred until development of abdominal disease, with minimal risk of missing thoracic metastases. PMID- 26053311 TI - Endocannabinoid and nitric oxide interaction mediates food intake in neonatal chicken. AB - The aim of the current study was to investigate the interaction of the nitric oxide and cannabinoidergic systems on feeding behaviour in neonatal chicken. A total of 6 experiments were designed to evaluate the interaction between cannabinoidergic and nitrergic systems on food intake in 3-h food-deprived (FD3) neonatal chickens. In Experiment 1, chickens received intracerebroventricular (ICV) injections of saline, 2-arachidonoylglycerol (2-AG) (a CB1 receptor agonist, 2 ug), l-arginine (nitric oxide precursor, 200 nmol) and co administration of 2-AG + l-arginine. In Experiment 2, ICV injection of saline, 2 AG (2 ug), l-NAME (a nitric oxide synthesis inhibitor, 100 nmol) and their combination (2-AG + l-NAME) were applied to the birds. In Experiment 3, injections were saline, CB65 (a CB2 receptor agonist, 1.25 ug), l-arginine (200 nmol) and CB65 + l-arginine. In Experiment 4, birds received ICV injection of saline, CB65 (1.25 ug), l-NAME (100 nmol) and CB65 + l-NAME. In Experiment 5, chickens were ICV injected with saline, l-arginine (800 nmol), SR141716A (a selective CB1 receptor antagonist, 6.25 ug) and l-arginine + SR141716A. In Experiment 6, birds were injected with saline, l-arginine (800 nmol), AM630 (a selective CB2 receptor antagonist, 5 ug) and l-arginine + AM630. Cumulative food intake was recorded until 2-h post injection. ICV injection of CB1 and CB2 receptor agonists increased food intake. Co-injection of 2-AG + l-NAME increased the hyperphagic effects of CB1 receptors. CB2 receptor-induced food intake was not affected by co-administration of CB65 + l-NAME. l-Arginine decreased food intake and this effect was amplified by co-injection of l-arginine + SR141716A. However; CB2 receptor antagonists had no effect on l-arginine-induced hypophagia. The results suggest that there is an interaction between endogenous nitric oxide and the cannabinoidergic system on feeding behaviour which is mediated via CB1 receptors in the neonatal chicken. PMID- 26053312 TI - Generation of amphidiploids from hybrids of wheat and related species from the genera Aegilops, Secale, Thinopyrum, and Triticum as a source of genetic variation for wheat improvement. AB - We aim to improve diversity of domesticated wheat by transferring genetic variation for important target traits from related wild and cultivated grass species. The present study describes the development of F1 hybrids between wheat and related species from the genera Aegilops, Secale, Thinopyrum, and Triticum and production of new amphidiploids. Amphidiploid lines were produced from 20 different distant relatives. Both colchicine and caffeine were successfully used to double the chromosome numbers. The genomic constitution of the newly formed amphidiploids derived from seven distant relatives was determined using genomic in situ hybridization (GISH). Altogether, 42 different plants were analysed, 19 using multicolour GISH separating the chromosomes from the A, B, and D genomes of wheat, as well as the distant relative, and 23 using single colour GISH. Restructuring of the allopolyploid genome, both chromosome losses and aneuploidy, was detected in all the genomes contained by the amphidiploids. From the observed chromosome numbers there is an indication that in amphidiploids the B genome of wheat suffers chromosome losses less frequently than the other wheat genomes. Phenotyping to realize the full potential of the wheat-related grass germplasm is underway, linking the analyzed genotypes to agronomically important target traits. PMID- 26053313 TI - Palladium-Catalyzed Enantioselective Three-Component Synthesis of alpha Substituted Amines. AB - The first general palladium-catalyzed, enantioselective three-component synthesis of alpha-arylamines starting from sulfonamides, aldehydes, and arylboronic acids has been developed. These reactions generate a wide array of alpha-arylamines with high yields and enantioselectivities. Notably, this process is tolerant to air and moisture, providing an operationally simple approach for the synthesis of chiral alpha-arylamines. PMID- 26053314 TI - Fast Electron Transfer Exchange at Self-Assembled Monolayers of Organometallic Ruthenium(II) sigma-Arylacetylide Complexes. AB - A new series of ruthenium organometallic carbon-rich complexes, exhibiting fast electron transfer kinetics combined to a low oxidation potential, was synthesized for self-assembled monolayer (SAM) formation on gold surfaces. The molecules consist of highly conjugated ruthenium(II) mono(sigma-arylacetylide) or bis(sigma arylacetylide) complexes functionalized with different bridge units with specific (protected) anchoring groups that possess high affinity for gold, such as thiol, carbodithioate, and isocyanide. Single component and mixed SAMs were prepared and fully characterized by wettability studies, infrared reflection absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS), and electrochemical analyses. By applying the Laviron's formalism, fast electron transfer kinetics (~10(4) s(-1)) were found at the derived self-assemblies while no significant effect could have been evidenced with variation of the bridging unit and of the anchoring moiety. Interestingly, a hexyl aliphatic spacer in the bridging unit with a thiol group and dilution with suitable nonelectroactive thiols lead to better SAM organization and packing, in comparison with undiluted complexes with shorter spacers. Such features make these compounds suitable alternatives to the widely used ferrocene center as redox-active building blocks for reversible charge storage devices. PMID- 26053315 TI - Reply to 'Comment on: Childhood cancer and exposure to corona ions from power lines: an epidemiological study'. PMID- 26053316 TI - Characterizing Thalamocortical Disturbances in Cervical Spondylotic Myelopathy: Revealed by Functional Connectivity under Two Slow Frequency Bands. AB - BACKGROUND AND PURPOSE: Recent advanced MRI studies on cervical spondylotic myelopathy (CSM) revealed alterations of sensorimotor cortex, but the disturbances of large-scale thalamocortical systems remains elusive. The purpose of this study was to characterizing the CSM-related thalamocortical disturbances, which were associated with spinal cord structural injury, and clinical measures. METHODS: A total of 17 patients with degenerative CSM and well-matched control subjects participated. Thalamocortical disturbances were quantified using thalamus seed-based functional connectivity in two distinct low frequencies bands (slow-5 and slow-4), with different neural manifestations. The clinical measures were evaluated by Japanese Orthopaedic Association (JOA) score system and Neck Disability Index (NDI) questionnaires. RESULTS: Decreased functional connectivity was found in the thalamo-motor, -somatosensory, and -temporal circuits in the slow-5 band, indicating impairment of thalamo-cortical circuit degeneration or axon/synaptic impairment. By contrast, increased functional connectivity between thalami and the bilateral primary motor (M1), primary and secondary somatosensory (S1/S2), premotor cortex (PMC), and right temporal cortex was detected in the slow-4 band, and were associated with higher fractional anisotropy values in the cervical cord, corresponding to mild spinal cord structural injury. CONCLUSIONS: These thalamocortical disturbances revealed by two slow frequency bands inform basic understanding and vital clues about the sensorimotor dysfunction in CSM. Further work is needed to evaluate its contribution in central functional reorganization during spinal cord degeneration. PMID- 26053318 TI - Why humans build fires shaped the same way. AB - Here we see why humans unwittingly build fires that look the same: edifices of fuel, as tall as they are wide. The pile of fuel is permeable, air invades it by natural convection and drives the combustion. I show that the hottest pile of burning fuel occurs when the height of the pile is roughly the same as its base diameter. Future studies may address the shape effect of wind, material type, and packing. Key is why humans of all eras have been relying on this design of fire "unwittingly". The reason is that the heat flow from fire facilitates the movement and spreading of human mass on the globe. PMID- 26053317 TI - Identification of G Protein-Coupled Receptors (GPCRs) in Primary Cilia and Their Possible Involvement in Body Weight Control. AB - Primary cilia are sensory organelles that harbor various receptors such as G protein-coupled receptors (GPCRs). We analyzed subcellular localization of 138 non-odorant GPCRs. We transfected GPCR expression vectors into NIH3T3 cells, induced ciliogenesis by serum starvation, and observed subcellular localization of GPCRs by immunofluorescent staining. We found that several GPCRs whose ligands are involved in feeding behavior, including prolactin-releasing hormone receptor (PRLHR), neuropeptide FF receptor 1 (NPFFR1), and neuromedin U receptor 1 (NMUR1), localized to the primary cilia. In addition, we found that a short form of dopamine receptor D2 (DRD2S) is efficiently transported to the primary cilia, while a long form of dopamine receptor D2 (DRD2L) is rarely transported to the primary cilia. Using an anti-Prlhr antibody, we found that Prlhr localized to the cilia on the surface of the third ventricle in the vicinity of the hypothalamic periventricular nucleus. We generated the Npy2r-Cre transgenic mouse line in which Cre-recombinase is expressed under the control of the promoter of Npy2r encoding a ciliary GPCR. By mating Npy2r-Cre mice with Ift80 flox mice, we generated Ift80 conditional knockout (CKO) mice in which Npy2r-positive cilia were diminished in number. We found that Ift80 CKO mice exhibited a body weight increase. Our results suggest that Npy2r-positive cilia are important for body weight control. PMID- 26053319 TI - Gordon L. Amidon: Very Sustained Drug Absorption. PMID- 26053320 TI - A laboratory-based test of the relation between adolescent alcohol use and panic relevant responding. AB - A burgeoning literature supports a link between alcohol use and panic-spectrum problems (e.g., panic attacks, disorder) among adolescents, but the direction of influence has yet to be properly examined. From a theoretical perspective, panic spectrum problems may increase risk for problematic drinking via affect regulation efforts (e.g., self-medication), and problematic consumption also may increase or initiate panic-relevant responding (e.g., learning or kindling models). The objective of the current investigation was to examine the role of prior alcohol use in predicting panic-relevant responding, as well as panic symptom history in predicting the desire to consume alcohol, in the context of either a voluntary hyperventilation or a low-arousal task. Participants were community-recruited adolescents aged 12-17 years (n = 92, Mage = 15.42, SD = 1.51; 39.1% girls). Results indicated that prior alcohol use predicted panic relevant responding among those undergoing the hyperventilation task (but not the low-arousal task), and that this finding was robust to the inclusion of theoretically relevant covariates (i.e., age, sex, negative affectivity). However, panic symptom history did not predict the desire to consume alcohol as a function of either the hyperventilation or low-arousal condition. This work sheds further light on the nature of the relation between panic-spectrum problems and problematic alcohol use in adolescence. Specifically, the current findings suggest that frequent alcohol use may increase panic vulnerability among adolescents, whereas acute panic symptoms may not elicit the immediate (self reported) desire to drink. PMID- 26053321 TI - Exposure to female fertility pheromones influences men's drinking. AB - Research has shown that humans consciously use alcohol to encourage sexual activity. In the current study, we investigated whether decision making about alcohol use and sex can be cued outside of awareness by recently revealed sexual signaling mechanisms. Specifically, we examined if males exposed without their knowledge to pheromones emitted by fertile females would increase their alcohol consumption, presumably via neurobehavioral information pathways that link alcohol to sex and mating. We found that men who smelled a T-shirt worn by a fertile female drank significantly more (nonalcoholic) beer, and exhibited significantly greater approach behavior toward female cues, than those who smelled a T-shirt worn by a nonfertile female. These findings reveal previously unknown influences on human alcohol consumption, augment the research base for pheromone cuing of sexual behavior in humans, and raise the possibility that other, as yet unknown, pathways of behavioral influence may be operating hidden from view. PMID- 26053322 TI - Application of an alcohol clamp paradigm to examine inhibitory control, subjective responses, and acute tolerance in late adolescence. AB - Individual differences in acute alcohol effects on cognitive control and subjective responses--and acute tolerance to these effects--are implicated in the risk for heavy drinking and alcohol-related harms. Few studies have examined these effects in drinkers under age 21. Additionally, studies of acute tolerance typically involve bolus oral alcohol administration, such that estimates of tolerance are confounded with blood alcohol concentration (BAC) limb. The current study examined cognitive control and subjective responses in young heavy drinkers (n = 88; M = 19.8 years old, SD = 0.8) during a single-session alcohol clamp protocol. Participants completed an intravenous alcohol session comprising an ascending limb (0 to 80 mg% in 20 min) and a BAC plateau (80 mg% for 80 min). Serial assessments included a cued go/no-go task and measures of stimulation, sedation, and craving. Relevant individual difference factors (attention-deficit hyperactivity disorder [ADHD] symptoms and sensation seeking) were examined as moderators. Multilevel modeling demonstrated that response inhibition worsened following initial rise in BAC and showed increasing impairment during the BAC plateau. ADHD symptoms and sensation seeking moderated this effect. Significant within-person associations between stimulation and craving were evident on the ascending limb only. Participants with higher ADHD symptoms reported steeper increases in stimulation during the ascending limb. These findings provide initial information about subjective and behavioral responses during pseudoconstant BAC, and potential moderators of these outcomes, in late adolescence. Additional studies with placebo-controlled designs are necessary to confirm these findings. PMID- 26053323 TI - Brief and extended alcohol-cue-exposure effects on craving and attentional bias. AB - Past research has shown that underage college-student drinkers (UCSDs) report increased subjective craving and exhibit stronger attentional biases to alcohol following alcohol-cue exposure. To date, less research has examined whether momentary decreases in alcohol craving are associated with reductions in attentional bias. One experimental manipulation that has been used to produce within-session decreases in alcohol craving is to extend the duration of laboratory-based alcohol-cue exposure protocols. The aim of this study was to examine the effects of both brief and extended alcohol-cue exposure on subjective craving and attentional bias among UCSDs. Eighty participants were randomized either to a group that received a short, in vivo, alcohol-cue-exposure period (short-exposure group [SE], 2 3-min blocks) or to a group that received a long exposure period (long-exposure group [LE], 6 3-min blocks). Both groups completed a visual probe task before and after cue exposure to assess changes in attentional bias. Analyses revealed no group differences in mean craving or mean attentional bias before or after cue exposure. Further, exploratory analyses revealed no sex differences in our measures of craving or attentional bias. For Group LE, but not Group SE, within-session changes in craving positively predicted within-session changes in attentional bias. However, further analyses revealed that this relationship was significant only for women in the LE group. Implications for treatments that aim to reduce craving and/or attentional bias are discussed. PMID- 26053325 TI - Coexistence of different droplet generating instabilities: new breakup regimes of a liquid filament. AB - The coexistence of multiple droplet breakup instabilities in a Step emulsification geometry is studied. A liquid filament, which is confined in one dimension by channel walls and surrounded by a co-flowing immiscible continuous phase, decays into droplets when subject to a sudden release of confinement. Depending on the filament aspect ratio and liquid flow rates, an unexpectedly rich variety of droplet breakup regimes is found. All of these breakup regimes are composed of two basic instabilities, i.e. a step- and a jet-instability, that coexist in various combinations on the same filament. Surprisingly, even an asymmetric breakup regime is found, producing droplet families of significantly different diameters, while the filament is subject to a fully symmetric flow field. We suggest key physical principles explaining the spontaneous symmetry breaking and the transitions between individual droplet breakup regimes. The particular ability to produce distinct droplet families from a single filament is demonstrated to allow for simultaneous concentration and encapsulation of particles into one droplet family while excess bulk liquid is released into another family of droplets. PMID- 26053324 TI - Effect of a Gluten-Free Diet on Cortical Excitability in Adults with Celiac Disease. AB - INTRODUCTION: An imbalance between excitatory and inhibitory synaptic excitability was observed in de novo patients with celiac disease (CD) in a previous study with Transcranial Magnetic Stimulation (TMS), suggesting a subclinical involvement of GABAergic and glutamatergic neurotransmission in asymptomatic patients. The aim of this investigation was to monitor the eventual changes in the same cohort of patients, evaluated after a period of gluten-free diet. METHODS: Patients were re-evaluated after a median period of 16 months during which an adequate gluten-free diet was maintained. Clinical, cognitive and neuropsychiatric assessment was repeated, as well as cortical excitability by means of single- and paired-pulse TMS from the first dorsal interosseous muscle of the dominant hand. RESULTS: Compared to baseline, patients showed a significant decrease of the median resting motor threshold (from 35% to 33%, p<0.01). The other single-pulse (cortical silent period, motor evoked potentials latency and amplitude, central motor conduction time) and paired-pulse TMS measures (intracortical inhibition and intracortical facilitation) did not change significantly after the follow-up period. Antibodies were still present in 7 subjects. DISCUSSION: In patients under a gluten-free diet, a global increase of cortical excitability was observed, suggesting a glutamate-mediated functional reorganization compensating for disease progression. We hypothesize that glutamate receptor activation, probably triggered by CD-related immune system dysregulation, might result in a long-lasting motor cortex hyperexcitability with increased excitatory post-synaptic potentials, probably related to phenomena of long-term plasticity. The impact of the gluten-free diet on subclinical neurological abnormalities needs to be further explored. PMID- 26053326 TI - Poly(ethylene glycol)-containing hydrogels modulate alpha-defensin release from polymorphonuclear leukocytes and monocyte recruitment. AB - Polymorphonuclear leukocytes (PMNs) release granule proteins as the first line of defense against bacteria and set up chemotactic gradients that result in monocyte infiltration to the site of injury. Although well established, the role of biomaterials in regulating adherent PMN degranulation and subsequent PMN-monocyte paracrine interactions is less clear. The aim of this study was to determine how biomaterials affect the degranulation of selected biomarkers and downstream monocyte adhesion and transendothelial migration. Poly(ethylene glycol) (PEG) containing hydrogels (PEG and an interpenetrating network of PEG and gelatin) promote the release of the alpha-defensins human neutrophil peptides 1-3, but not azurocidin or monocyte chemotactic protein-1. Although human neutrophil peptides 1-3 are monocyte chemoattractants, no subsequent effects on monocyte transmigration are observed in static conditions. Under flow conditions, monocyte adhesion on human umbilical vein endothelial cells stimulated with tumor necrosis factor-alpha is elevated in the presence of granule proteins from PMNs adherent on polydimethylsiloxane, but not from PMNs cultured on PEG hydrogels. These results suggest that PEG promotes PMN antimicrobial capacity without enhanced monocyte recruitment. PMID- 26053327 TI - Atomistic and Coarse Grain Topologies for the Cofactors Associated with the Photosystem II Core Complex. AB - Electron transfers within and between protein complexes are core processes of the electron transport chains occurring in thylakoid (chloroplast), mitochondrial, and bacterial membranes. These electron transfers involve a number of cofactors. Here we describe the derivation of molecular mechanics parameters for the cofactors associated with the function of the photosystem II core complex: plastoquinone, plastoquinol, heme b, chlorophyll A, pheophytin, and beta carotene. Parameters were also obtained for ubiquinol and ubiquinone, related cofactors involved in the respiratory chain. Parameters were derived at both atomistic and coarse grain (CG) resolutions, compatible with the building blocks of the GROMOS united-atom and Martini CG force fields, respectively. Structural and thermodynamic properties of the cofactors were compared to experimental values when available. The topologies were further tested in molecular dynamics simulations of the cofactors in their physiological environment, e.g., either in a lipid membrane environment or in complex with the heme binding protein bacterioferritin. PMID- 26053328 TI - Unpacking University-Community Partnerships to Advance Scholarship of Practice. AB - Today, more than ever, occupational therapists are engaged in close partnerships with community organizations and community settings such as service agencies, refugee and immigrant enclaves, and faith-based organizations, to name a few, for the purpose of engaging in scholarship of practice. However, we know little about the views of community partners regarding the development and sustainability of university-community partnerships. The purpose of this article is twofold: First, we will describe a pilot study in which we gathered qualitative data from community partners engaged in scholarship of practice with faculty and students, regarding their views about benefits of partnerships, challenges, and characteristics of sustainable partnerships. Second, based on this pilot study and extensive experience of the authors, we propose a revised version of a partnerships model available in the literature. We illustrate the model through examples of the authors' collective experiences developing and sustaining successful university-community partnerships. PMID- 26053329 TI - Aromatic Methoxylation and Hydroxylation by Organometallic High-Valent Nickel Complexes. AB - Herein we report the synthesis and reactivity of several organometallic Ni(III) complexes stabilized by a modified tetradentate pyridinophane ligand containing one phenyl group. A room temperature stable dicationic Ni(III)-disolvento complex was also isolated, and the presence of two available cis coordination sites in this complex offers an opportunity to probe the C-heteroatom bond formation reactivity of high-valent Ni centers. Interestingly, the Ni(III)-dihydroxide and Ni(III)-dimethoxide species can be synthesized, and they undergo aryl methoxylation and hydroxylation that is favored by addition of oxidant, which also limits the beta-hydride elimination side reaction. Overall, these results provide strong evidence for the involvement of high-valent organometallic Ni species, possibly both Ni(III) and Ni(IV) species, in oxidatively induced C heteroatom bond formation reactions. PMID- 26053330 TI - Biomimetic Intrafibrillar Mineralization of Type I Collagen with Intermediate Precursors-loaded Mesoporous Carriers. AB - Limited continuous replenishment of the mineralization medium is a restriction for in-situ solution-based remineralization of hypomineralized body tissues. Here, we report a process that generated amine-functionalized mesoporous silica nanoparticles for sustained release of biomimetic analog-stabilized amorphous calcium phosphate precursors. Both two-dimensional and three-dimensional collagen models can be intrafibrillarly mineralized with these released fluidic intermediate precursors. This represents an important advance in the translation of biomineralization concepts into regimes for in-situ remineralization of bone and teeth. PMID- 26053331 TI - An Effective Way to Optimize the Functionality of Graphene-Based Nanocomposite: Use of the Colloidal Mixture of Graphene and Inorganic Nanosheets. AB - The best electrode performance of metal oxide-graphene nanocomposite material for lithium secondary batteries can be achieved by using the colloidal mixture of layered CoO2 and graphene nanosheets as a precursor. The intervention of layered CoO2 nanosheets in-between graphene nanosheets is fairly effective in optimizing the pore and composite structures of the Co3O4-graphene nanocomposite and also in enhancing its electrochemical activity via the depression of interaction between graphene nanosheets. The resulting CoO2 nanosheet-incorporated nanocomposites show much greater discharge capacity of ~1750 mAhg(-1) with better cyclability and rate characteristics than does CoO2-free Co3O4-graphene nanocomposite (~1100 mAhg(-1)). The huge discharge capacity of the present nanocomposite is the largest one among the reported data of cobalt oxide-graphene nanocomposite. Such a remarkable enhancement of electrode performance upon the addition of inorganic nanosheet is also observed for Mn3O4-graphene nanocomposite. The improvement of electrode performance upon the incorporation of inorganic nanosheet is attributable to an improved Li(+) ion diffusion, an enhanced mixing between metal oxide and graphene, and the prevention of electrode agglomeration. The present experimental findings underscore an efficient and universal role of the colloidal mixture of graphene and redoxable metal oxide nanosheets as a precursor for improving the electrode functionality of graphene-based nanocomposites. PMID- 26053333 TI - Organocatalytic asymmetric Michael addition of 1-acetylcyclohexene and 1 acetylcyclopentene to nitroolefins. AB - Enantioselective organocatalytic Michael addition reactions of 1 acetylcyclohexene, 1-acetylcyclopentene and 1-acetylcyclobutene to nitroolefins have been developed. This is the first report where an alpha-branched enone has been activated by an amine catalyst for the asymmetric Michael addition reaction to an electrophile. The Michael products have also been cyclized to bicyclic compounds. PMID- 26053332 TI - Comparative analysis of Meissner's corpuscles in the fingertips of primates. AB - Meissner's corpuscles (MCs) are tactile mechanoreceptors found in the glabrous skin of primates, including fingertips. These receptors are characterized by sensitivity to light touch, and therefore might be associated with the evolution of manipulative abilities of the hands in primates. We examined MCs in different primate species, including common marmoset (Callithrix jacchus, n = 5), baboon (Papio anubis, n = 2), rhesus macaque (Macaca mulatta, n = 3), chimpanzee (Pan troglodytes, n = 3), bonobo (Pan paniscus, n = 1) and human (Homo sapiens, n = 8). Fingertips of the first, second and fourth digits were collected from both hands of specimens, dissected and histologically stained using hematoxylin and eosin. The density (MCs per 1 mm(2) ) and the size (cross-sectional diameter of MCs) were quantified. Overall, there were no differences in the densities of MCs or their size among the digits or between the hands for any species examined. However, MCs varied across species. We found a trend for higher densities of MCs in macaques and humans compared with chimpanzees and bonobos; moreover, apes had larger MCs than monkeys. We further examined whether the density or size of MCs varied as a function of body mass, measures of dexterity and dietary frugivory. Among these variables, only body size accounted for a significant amount of variation in the size of MCs. PMID- 26053334 TI - Resolution of precocious puberty following resection of fourth ventricular medulloblastoma: case report. AB - Medulloblastoma is a malignant embryonal tumor that arises in the cerebellum and invades the fourth ventricle, often resulting in obstructive hydrocephalus. Patients typically present with symptoms related to increased intracranial pressure and cerebellar dysfunction. The authors report a rare case of classic medulloblastoma with central precocious puberty (CPP) as its only presenting symptom. A 7-year-old boy with no prior history of medulloblastoma presented with Tanner Stage IV testicular enlargement and a 4-month history of acne and pubic hair. Laboratory tests of blood samples demonstrated highly elevated luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone. Admission MRI of the brain revealed a mass in the posterior fossa, which bordered and compressed the fourth ventricle. The patient also exhibited mild lateral and third ventriculomegaly. Surgical options were discussed with the neurosurgical department. A suboccipital craniotomy and C-1 laminectomy were performed. A large mass was seen arising from the inferior surface of the vermis, and lying within the fourth ventricle. Gross-total microsurgical resection of the mass was performed. Histopathological investigation characterized the tumor as classic medulloblastoma. Follow-up laboratory tests of blood samples demonstrated a reduction of LH, FSH, and testosterone back to prepubertal levels. The patient then began radiation and chemotherapy. This report demonstrates that mild obstructive hydrocephalus due to a posterior fossa tumor may present with unexpected symptoms, such as CPP. To the authors' knowledge, precocious puberty has not yet been associated with medulloblastoma, although it has been found with other posterior fossa tumors. Extensive imaging of the CNS for patients presenting with CPP is recommended. PMID- 26053335 TI - Anti-obesity and metabolic efficacy of the beta3-adrenergic agonist, CL316243, in mice at thermoneutrality compared to 22 degrees C. AB - OBJECTIVE: Mice are typically housed at environmental temperatures below thermoneutrality, whereas humans live near thermoneutrality. This difference affects energy physiology and, potentially, anti-obesity drug efficacy. Here beta3-adrenergic agonist treatment at thermoneutrality (30 degrees C) versus room temperature (22 degrees C) is compared. METHODS: Male C57BL/6J mice were singly housed at 30 degrees C or 22 degrees C and treated with vehicle or CL316243, a beta3-agonist, for 4 weeks. Food intake, energy expenditure, body and adipose weight, brown adipose activity, white adipose browning, and glucose tolerance were evaluated. CL316243 treatment was studied in both chow- and high-fat diet fed mice. RESULTS: Mice at 30 degrees C, compared to 22 degrees C, had reduced food intake, metabolic rate, and brown adipose activity, as well as increased adiposity. At both temperatures, CL316243 treatment increased brown adipose activation and energy expenditure and improved glucose tolerance. At 30 degrees C, CL316243 increased energy expenditure disproportionately to changes in food intake, thus reducing adiposity, while at 22 degrees C these changes were matched, yielding unchanged adiposity. CONCLUSIONS: CL316243 treatment can have beneficial metabolic effects in the absence of adiposity changes. In addition, the interaction between environmental temperature and CL316243 treatment is different from the interaction between environmental temperature and 2,4 dinitrophenol treatment reported previously, suggesting that each drug mechanism must be examined to understand the effect of environmental temperature on drug efficacy. PMID- 26053336 TI - Future perspectives in OrbitrapTM-high-resolution mass spectrometry in food analysis: a review. AB - A literature search from 2007 to 2014 was conducted to identify publications where principally LC-OrbitrapTM-high-resolution mass spectrometry (HRMS) has been employed in food analysis. Of a total of 212 relevant references, only 22 papers were from 2007-10, but in subsequent years there has been a steady growth in publications with 38-55 relevant papers being published each year from 2011 to 2014. In the food safety area, over 50% of the published papers were equally divided between pesticides, veterinary drug residues and natural toxins (including mycotoxins) focused primarily on multi-analyte target analysis. LC Orbitrap-HRMS was also found to be increasingly important for the analysis of bioactive substances, principally phenolic compounds in foods. A number of studies reported for the first time the identification of new fungal metabolites, predominantly various conjugated forms of known mycotoxins. Novel process contaminants were also identified by LC-Orbitrap-HRMS, as were various substances used for food adulteration and bioactive substances in herbal products and dietary supplements. Untargeted analysis is seen as a major future trend where HRMS plays a significant role. Retrospective analysis of scanned high-resolution mass spectra in conjunction with relevant databases can provide new insights. Metabolomics is also being increasingly used where foods are being profiled through fingerprinting using HRMS. All evidence points towards future growth in the number of applications of HRMS in food safety and quality, as the power of this technique gains wider recognition. PMID- 26053337 TI - Exploring the Effects of Different Types of Surfactants on Zebrafish Embryos and Larvae. AB - Currently, surfactants are widely distributed in the environment. As organic pollutants, their toxicities have drawn extensive attention. In this study, the effects of anionic [sodium dodecyl sulphate (SDS)], cationic [dodecyl dimethyl benzyl ammonium chloride (1227)] and non-ionic [fatty alcohol polyoxyethylene ether (AEO)] surfactants on zebrafish larval behaviour were evaluated. Five behavioural parameters were recorded using a larval rest/wake assay, including rest total, number of rest bouts, rest bouts length, total activity and waking activity. The results revealed that 1227 and AEO at 1 MUg/mL were toxic to larval locomotor activity and that SDS had no significant effects. Moreover, we tested the toxicities of the three surfactants in developing zebrafish embryos. AEO exposure resulted in smaller head size, smaller eye size and shorter body length relative to SDS and 1227. All three surfactants incurred concentration-dependent responses. Furthermore, in situ hybridisation indicated that smaller head size may be associated with a decreased expression of krox20. The altered expression of ntl demonstrated that the developmental retardation stemmed from inhibited cell migration and growth. These findings provide references for ecotoxicological assessments of different types of surfactants, and play a warning role in the application of surfactants. PMID- 26053338 TI - DNA Marker Transmission and Linkage Analysis in Populations Derived from a Sugarcane (Saccharum spp.) x Erianthus arundinaceus Hybrid. AB - Introgression of Erianthus arundinaceus has been the focus of several sugarcane breeding programs in the world, because the species has desirable traits such as high biomass production, vigour, ratooning ability and good resistance to environmental stresses and disease. In this study four genetic maps were constructed for two intergeneric populations. The first population (BC1) was generated from a cross between an Erianthus/Saccharum hybrid YC96-40 and a commercial sugarcane variety CP84-1198. The second population (BC2) was generated from a cross between YCE01-116, a progeny of the BC1 cross and NJ57-416, a commercial sugarcane cultivar. Markers across both populations were generated using 35 AFLP and 23 SSR primer pairs. A total of 756 and 728 polymorphic markers were scored in the BC1 and BC2 populations, respectively. In the BC1 population, a higher proportion of markers was derived from the Erianthus ancestor than those from the Saccharum ancestor Badila. In the BC2 population, both the number and proportion of markers derived from Erianthus were approximately half of those in the BC1 population. Linkage analysis led to the construction of 38, 57, 36 and 47 linkage groups (LGs) for YC96-40, CP84-1198, YCE01-116, and NJ57-416, encompassing 116, 174, 97 and 159 markers (including single dose, double dose and bi-parental markers), respectively. These LGs could be further placed into four, five, five and six homology groups (HGs), respectively, based on information from multi-allelic SSR markers and repulsion phase linkages detected between LGs. Analysis of repulsion phase linkage indicated that Erianthus behaved like a true autopolyploid. PMID- 26053339 TI - Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. AB - BACKGROUND: Vitamin D toxicity, often considered rare, can be life-threatening and associated with substantial morbidity, if not identified promptly. OBJECTIVE: To describe clinical and biochemical features, risk factors and management of patients with vitamin D toxicity seen between January 2011 and January 2013. METHODOLOGY: Patients presenting with vitamin D toxicity, between January 2011 and January 2013, at single tertiary care centre in Delhi-NCR, India, were included. Evaluation included detailed clinical history and biochemical tests including serum calcium, phosphorus, creatinine, intact parathyroid hormone and 25-hydroxyvitamin D (25(OH)D). RESULTS: Sixteen patients with vitamin D toxicity could be identified. Clinical manifestations included nausea, vomiting, altered sensorium, constipation, pancreatitis, acute kidney injury and weight loss. Median (range) age was 64.5 (42-86) years. Median (range) serum 25(OH)D level and median (range) serum total serum calcium level were 371 (175-1161) ng/ml and 13.0 (11.1-15.7) mg/dl, respectively. Overdose of vitamin D caused by prescription of mega-doses of vitamin D was the cause of vitamin D toxicity in all cases. Median (range) cumulative vitamin D dose was 3,600,000 (2,220,000-6,360,000) IU. CONCLUSION: Our data demonstrate an emergence of vitamin D toxicity as an increasingly common cause of symptomatic hypercalcaemia. Irrational use of vitamin D in mega-doses resulted in vitamin D toxicity in all cases. Awareness among healthcare providers regarding the toxic potential of high doses of vitamin D and cautious use of vitamin D supplements is the key to prevent this condition. PMID- 26053340 TI - Cross-modal effects of auditory magnitude on visually guided grasping. AB - Recent research has established the role of objects' semantic properties in the planning of motor actions with respect to these objects. It has been shown that visual numerical magnitude affects visuomotor control in a similar direction to the effect of physical size: The larger the numerical value, the larger the grip aperture even when physical size remains invariant. The relationship has been attributed to a common mechanism, in particular to a neural network within the parietal lobe, which mediates the processing of magnitude across different domains. In this study, we show that the effect of magnitude on grasping is not limited to visual numerical information and is in fact cross-modal in nature; presentations of auditory signals of different types of auditory-based magnitudes affected visually guided actions in two different experiments. In Experiment 1, symbolic representations of magnitudes (numerals) affected initial grasping trajectories. In Experiment 2, a nonsymbolic presentation of magnitude, i.e., tone duration, had similar effects on grasping trajectories. We conclude that different types of magnitude representations are processed by a common mechanism that cooperates with visuomotor control. PMID- 26053342 TI - Utility of Isovolumic Contraction Peak Velocity for Evaluation of Adult Patient Status after Transcatheter Closure of Atrial Septal Defect. AB - BACKGROUND: Transcatheter closure is a well-established treatment for patients with atrial septal defect (ASD), but long-term outcome prognostic factors for adults have not been fully identified yet. METHODS: Forty-nine consecutive patients (age 57 +/- 17 years, 59% female), who underwent transcatheter closure of ASD, were the subjects of this study. Transthoracic echocardiography was performed before and midterm after the procedure (6 +/- 1 months). Isovolumic contraction peak velocity (IVV) was measured at the lateral site of the tricuspid annulus using spectral tissue Doppler imaging, and DeltaIVV was determined as the absolute change at midterm follow-up. Long-term unfavorable outcome events, tracked for 19 +/- 9 months, were prespecified as primary end points comprising newly developed atrial fibrillation, cerebral infarction, and heart failure. RESULTS: Symptomatic improvement, defined as an improvement in New York Heart Association functional class by one grade or more at midterm after the procedure, was observed in 24 patients (49%), and the remaining 25 (51%) were classified as not symptomatically improved. DeltaIVV was significantly larger for patients with symptomatic improvement than for those without (from 11.5 +/- 4.3 cm/s to 14.2 +/ 3.7 cm/s vs. from 11.8 +/- 4.1 cm/s to 12.5 +/- 2.9 cm/s; P = 0.045). An important finding of the multivariate Cox proportional-hazards analysis was that only DeltaIVV was independently associated with cardiovascular events (HR: 0.701; 95% CI 0.537-0.916; P = 0.01). Kaplan-Meier analysis showed that more patients with enhanced DeltaIVV presented with favorable long-term outcome than those with diminished DeltaIVV (log-rank P = 0.0001). CONCLUSIONS: IVV, which is a less volume-sensitive parameter, can be useful for comprehensive evaluation of ASD patients referred for transcatheter closure. PMID- 26053343 TI - Change in Corporal Punishment Over Time in a Representative Sample of Canadian Parents. AB - Corporal punishment is a controversial form of discipline. Although its prevalence appears high, legal reforms and public education efforts to limit corporal punishment may be resulting in a decrease in its prevalence and frequency of use. This study drew on Canadian nationally representative data to understand the social change that might be happening and to characterize parents who continue to use corporal punishment. The study relied on cross-sectional data from Cycles 1 (1994) to 8 (2008) of the Canadian National Longitudinal Survey of Children and Youth to examine parental reports of corporal punishment for children ages 2-11 years. Analyses were conducted separately for 2- to 5-, 6- to 9-, and 10- to 11-year-olds, and sociodemographics associated with corporal punishment were examined. A significant decrease in the prevalence and frequency of corporal punishment use was observed across time for all age groups. Child sex, parent age, employment status, family structure, household size, immigration status, ethnicity, and religion significantly distinguished parents who use corporal punishment from those who do not, but there was variability across the age groups. Effect sizes question the relevance of the observed decrease in corporal punishment from an applied perspective. Approximately 25% of Canadian parents still use corporal punishment with children ages 2-11 years; therefore, it remains an issue that merits continued attention. Certain child, parent, and family characteristics seem to characterize parents who use corporal punishment, but other more dynamic variables may be important to consider, such as parental stress and their attitudes toward corporal punishment. PMID- 26053341 TI - Nonintubated Surfactant Application vs Conventional Therapy in Extremely Preterm Infants: A Randomized Clinical Trial. AB - IMPORTANCE: Treatment of respiratory distress syndrome in premature infants with continuous positive airway pressure (CPAP) preserves surfactant and keeps the lung open but is insufficient in severe surfactant deficiency. Traditional surfactant administration is related to short periods of positive pressure ventilation and implies the risk of lung injury. CPAP with surfactant but without any positive pressure ventilation may work synergistically. This randomized trial investigated a less invasive surfactant application protocol (LISA). OBJECTIVE: To test the hypothesis that LISA increases survival without bronchopulmonary dysplasia (BPD) at 36 weeks' gestational age in extremely preterm infants. DESIGN, SETTING, AND PARTICIPANTS: The Nonintubated Surfactant Application trial was a multicenter, randomized, clinical, parallel-group study conducted between April 15, 2009, and March 25, 2012, in 13 level III neonatal intensive care units in Germany. The final follow-up date was June 21, 2012. Participants included 211 of 558 eligible (37.8%) spontaneously breathing preterm infants born between 23.0 and 26.8 weeks' gestational age with signs of respiratory distress syndrome. In an intention-to-treat design, infants were randomly assigned to receive surfactant either via a thin endotracheal catheter during CPAP-assisted spontaneous breathing (intervention group) or after conventional endotracheal intubation during mechanical ventilation (control group). Analysis was conducted from September 6, 2012, to June 20, 2013. INTERVENTION: LISA via a thin catheter. MAIN OUTCOMES AND MEASURES: Survival without BPD at 36 weeks' gestational age. RESULTS: Of 211 infants who were randomized, 104 were randomized to the control group and 107 to the LISA group. Of the infants who received LISA, 72 (67.3%) survived without BPD compared with 61 (58.7%) of those in the control group. The reduction in absolute risk was 8.6% (95% CI, -5.0% to 21.9%; P = .20). Intervention group infants were less frequently intubated (80 infants [74.8%] vs 103 [99.0%]; P < .001) and required fewer days of mechanical ventilation. Significant reductions were seen in pneumothorax (5 of 105 intervention group infants [4.8%] vs 13 of 103 12.6%]; P = .04) and severe intraventricular hemorrhage (11 infants [10.3%] vs 23 [22.1%]; P = .02), and the combined survival without severe adverse events was increased in the intervention group (54 infants [50.5%] vs 37 [35.6%]; P = .02; absolute risk reduction, 14.9; 95% CI, 1.4 to 28.2). CONCLUSIONS AND RELEVANCE: LISA did not increase survival without BPD but was associated with increased survival without major complications. Because major complications are related to lifelong disabilities, LISA may be a promising therapy for extremely preterm infants. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN64011614. PMID- 26053344 TI - Number of deployments, relationship satisfaction and perpetration of partner violence among U.S. Navy members. AB - The present brief report examined whether number of deployments, relationship satisfaction, and the interaction between number of deployments and relationship satisfaction predicted Navy members' reports of perpetrating physical partner violence. Participants were 80 U.S. Navy members assigned to an Arleigh Burke class destroyer anticipating an 8-month deployment after Operation Enduring Freedom/Operation Iraqi Freedom. The effect that the number of deployments had on perpetrating physical partner violence diminished as relationship satisfaction increased. Results suggest the importance of designing domestic violence intervention and treatment efforts toward those who report high levels of deployment and low relationship satisfaction. PMID- 26053346 TI - Correction to Hawkins and Erickson (2015). PMID- 26053345 TI - "The best is always yet to come": Relationship stages and processes among young LGBT couples. AB - Limited research has examined relationship development among lesbian, gay, bisexual, and transgender (LGBT) couples in emerging adulthood. A better understanding of LGBT couples can inform the development of relationship education programs that reflect their unique needs. The following questions guided this study: (a) What are the stages and processes during young LGBT couples' relationship development? and (b) How do these compare with existing literature on heterosexual adults? A secondary goal was to explore similarities and differences between couples assigned male (MAAB) and female at birth (FAAB). Thirty-six couples completed interviews on their relationship history. Qualitative analyses showed that relationship stages and processes were similar to past research on heterosexuals, but participants' subjective experiences reflected their LGBT identities and emerging adulthood, which exerted additional stress on the relationship. These factors also affected milestones indicative of commitment among heterosexual adults (e.g., introducing partner to family). Mixed methods analyses indicated that MAAB couples described negotiating relationship agreements and safe sex in more depth than FAAB couples. Relationship development models warrant modifications to consider the impact of sexual and gender identity and emerging adulthood when applied to young LGBT couples. These factors should be addressed in interventions to promote relationship health among young LGBT couples. PMID- 26053347 TI - Effects of change in arthritis severity on spouse well-being: The moderating role of relationship closeness. AB - The severity of a patient's illness may be detrimental for the psychological well being of the spouse, especially for those in a particularly close relationship. Using 2 waves of data collected from a sample of 152 knee osteoarthritis (OA) patients and their spouses, we examined associations between change in patients' illness severity and change in 3 indicators of spouses' well-being (positive affect, depressive symptoms, and life satisfaction) over a 6-month period. We also tested the hypothesis that spouses' perceived relationship closeness with the patient would moderate these associations. Consistent with our prediction, a high level of relationship closeness exacerbated the negative impact of increases in patient illness severity on spouses' positive affect and depressive symptoms over 6 months. Spouses' life satisfaction declined when patients became more ill, regardless of level of relationship closeness. Our findings highlight the value of examining change in illness as a predictor of change in spouse well-being and the potential downside of relationship closeness for couples living with chronic illness. PMID- 26053348 TI - Predictors of relationship dissolution in lesbian, gay, and heterosexual adoptive parents. AB - Little work has examined relationship dissolution or divorce in adoptive parents or same-sex parent couples. The current study examined predictors of relationship dissolution across the first 5 years of parenthood among a sample of heterosexual, lesbian, and gay male adoptive couples. Of the 190 couples in the study, 15 (7.9%) dissolved their relationships during the first 5 years of adoptive parenthood. Specifically, 7 of 57 lesbian couples (12.3%), 1 of 49 gay male couples (2.0%), and 7 of 84 heterosexual couples (8.3%) dissolved their unions. Results of our logistic regression analysis revealed that the odds of relationship dissolution were significantly higher for (a) couples who adopted a noninfant (i.e., older child); (b) participants who reported feeling less prepared for the adoption, 3 months postadoptive placement; and (c) couples in which both partners reported very low or very high preadoption levels of relationship maintenance behaviors. Findings have implications for adoption professionals seeking to support same-sex and heterosexual prospective adopters, as well as societal debates and policy regarding same-sex relationships and parenting. (PsycINFO Database Record PMID- 26053349 TI - Socioeconomic status, parenting, and externalizing problems in African American single-mother homes: A person-oriented approach. AB - African American youth, particularly those from single-mother homes, are overrepresented in statistics on externalizing problems. The family is a central context in which to understand externalizing problems; however, reliance on variable-oriented approaches to the study of parenting, which originate from work with intact, middle-income, European American families, may obscure important information regarding variability in parenting styles among African American single mothers, and in turn, variability in youth outcomes as well. The current study demonstrated that within African American single-mother families: (a) a person-, rather than variable-, oriented approach to measuring parenting style may further elucidate variability; (b) socioeconomic status may provide 1 context within which to understanding variability in parenting style; and (c) 1 marker of socioeconomic status, income, and parenting style may each explain variability in youth externalizing problems; however, the interaction between income and parenting style was not significant. Findings have potential implications for better understanding the specific contexts in which externalizing problems may be most likely to occur within this at-risk and underserved group. PMID- 26053350 TI - Fostering parents' emotion regulation through a sibling-focused experimental intervention. AB - In this study, we assessed whether an intervention designed to improve children's sibling relationships, the More Fun with Sisters and Brothers program (MFWSB), may also help parents manage their emotions more effectively. Families with at least 2 children between the ages of 4 and 8 years were randomly assigned to an intervention (n = 50) or wait-list control (n = 34) group. Parents completed pre- and posttest questionnaires on sibling warmth and agonism, their emotion regulation during sibling conflict, and their global emotion regulation styles. Program participation had a direct effect on 3 of the 4 emotion regulation outcomes for mothers. Mothers in the intervention versus control group reported lower levels of dysregulation and suppression and higher levels of reappraisal at posttest, controlling for pretest regulation scores. Additionally, path models examining posttest responses showed that participation in MFWSB led to lower levels of maternal and paternal negative reactivity in the sibling context via lower levels of sibling agonism, controlling for pretest levels of negative reactivity. Alternate path models, with parents' emotion regulation as mechanisms linking MFWSB and sibling relationship quality, were tested but not supported. Results highlight the value of a sibling-focused intervention for promoting parents' abilities to regulate their emotions. PMID- 26053351 TI - What makes siblings different? The development of sibling differences in academic achievement and interests. AB - To illuminate processes that contribute to the development of sibling differences, this study examined cross-lagged links between parents' beliefs about sibling differences in academic ability and differences between siblings' grade point averages (GPAs), and cross-lagged links between differences in siblings' GPAs and sibling differences in academic interests. Data were collected from mothers, fathers, firstborn youth (M age at Time 1 = 15.71, SD = 1.07), and secondborn youth (M age at Time 1 = 13.18, SD = 1.29) from 388 European American families on 3 annual occasions. Findings revealed that, after controlling for siblings' average grades and prior differences in performance, parents' beliefs about sibling differences in academic ability predicted differences in performance such that youth rated by parents as relatively more competent than their sibling earned relatively higher grades the following year. Siblings' relative school performance, however, did not predict parents' beliefs about differences between siblings' competencies. Further, after controlling for average interests and grades, sibling differences in GPA predicted differences in siblings' interests such that youth who had better grades than their siblings reported relatively stronger academic interests the following year. Differences in interest, however, did not predict sibling differences in GPA. Findings are discussed in terms the role of sibling dynamics in family socialization. PMID- 26053352 TI - Morphological aspects of blister aneurysms and nuances for surgical treatment. AB - OBJECT: Blister aneurysms of the supraclinoid part of the internal carotid artery (ICA) are known for their high morbidity and mortality rates related to treatment, regardless of whether the treatment is surgical or endovascular. However, this grim prognosis is based on results that indiscriminately group all blister aneurysms together without taking into account the heterogeneous appearance of these lesions. The goal of this study was 2-fold: to determine whether different blister aneurysm morphologies present different pitfalls, which would then require different surgical strategies, as well as to determine whether there are identifiable subgroups of these types of aneurysms based on morphology. METHODS: The authors reviewed the charts, cerebral catheter angiograms, surgical reports, and intraoperative videos of all ICA blister aneurysms treated surgically at the Centre Hospitalier de l'Universite de Montreal from 2005 to 2012 to investigate whether there was a relationship between morphology and pitfalls, and whether different surgical strategies had been used according to these pitfalls. During this review process the authors noted 4 distinct morphological aspects. These 4 aspects led to a review of the English and French literature on blister aneurysms in which imaging was available, to determine whether other cases could also be classified into the same 4 subgroups based on these morphological aspects. RESULTS: The retrospective review of the authors' series of 10 patients allowed a division into 4 distinct subtypes: Type I (classic), Type II (berry-like), Type III (longitudinal), and Type IV (circumferential). These subtypes may at times be progressive stages in the arterial anomaly, and could represent a continuum. Each subtype described in this paper presented its own pitfalls and required specific surgical adaptations. Upon reviewing the literature the authors retained 35 studies involving a total of 61 cases of blister aneurysms, and all cases were able to be classified into 1 of these 4 distinct subtypes. CONCLUSIONS: Although they share some common characteristics, blister aneurysms may be divided into distinct subtypes, suggestive of a continuum. Such a classification with a detailed description of each type of blister aneurysm would allow for better recognition to anticipate complications during intervention and better assess the different treatment strategies according to the subtypes. PMID- 26053353 TI - Fully automatic assignment of small molecules' NMR spectra without relying on chemical shift predictions. AB - We present a method for the automatic assignment of small molecules' NMR spectra. The method includes an automatic and novel self-consistent peak-picking routine that validates NMR peaks in each spectrum against peaks in the same or other spectra that are due to the same resonances. The auto-assignment routine used is based on branch-and-bound optimization and relies predominantly on integration and correlation data; chemical shift information may be included when available to fasten the search and shorten the list of viable assignments, but in most cases tested, it is not required in order to find the correct assignment. This automatic assignment method is implemented as a web-based tool that runs without any user input other than the acquired spectra. PMID- 26053354 TI - Abnormal body mass index at diagnosis in patients with Ewing sarcoma is associated with inferior tumor necrosis. AB - BACKGROUND: Abnormal body mass index (BMI) in cancer patients at diagnosis has been associated with lower survival rates. The degree of tumor necrosis after induction chemotherapy in Ewing sarcoma (EWS) is highly associated with treatment failure. We analyzed the effect of BMI on tumor necrosis in children and young adults undergoing induction treatment for EWS. PROCEDURE: Retrospective review of BMI and tumor necrosis in children and young adults with EWS. Patients were grouped into normal and abnormal BMI groups. Multivariate logistic regression and multivariate Cox regression were used to evaluate the impact of BMI on tumor necrosis, recurrence of disease, and survival. RESULTS: Fifty patients who underwent resection of the tumor were eligible. Of them, 32 (64%) and 18 (36%) had normal and abnormal BMI, respectively. Poor histologic response (PR), defined as tumor necrosis of less than 90%, was achieved in 35 (70%) patients. When comparing abnormal to normal BMI, there were more cases of PR [9 (50%) vs. 6 (19%) (P = 0.025)], more relapses [8 (44%) vs. 8 (25%) (P = 0.164)], and more deaths [10 (57%) vs. 7 (22%) (P = 0.040)], respectively. Abnormal BMI was independently associated with PR (OR 4.33, 95% CI 1.12-19.14 P = 0.034) and worse overall survival (HR 2.76, 95% CI 1.19-9.99 P = 0.022), while it had no impact on event free survival. CONCLUSIONS: The association between abnormal BMI and lower survival in EWS is presumed to be due to PR to chemotherapy. These findings stress the significance of BMI on treatment response in malignant diseases. PMID- 26053356 TI - Plant contributions to our understanding of sex chromosome evolution. AB - A minority of angiosperms have male and female flowers separated in distinct individuals (dioecy), and most dioecious plants do not have cytologically different (heteromorphic) sex chromosomes. Plants nevertheless have several advantages for the study of sex chromosome evolution, as genetic sex determination has evolved repeatedly and is often absent in close relatives. I review sex-determining regions in non-model plant species, which may help us to understand when and how (and, potentially, test hypotheses about why) recombination suppression evolves within young sex chromosomes. I emphasize high throughput sequencing approaches that are increasingly being applied to plants to test for non-recombining regions. These data are particularly illuminating when combined with sequence data that allow phylogenetic analyses, and estimates of when these regions evolved. Together with comparative genetic mapping, this has revealed that sex-determining loci and sex-linked regions evolved independently in many plant lineages, sometimes in closely related dioecious species, and often within the past few million years. In reviewing recent progress, I suggest areas for future work, such as the use of phylogenies to allow the informed choice of outgroup species suitable for inferring the directions of changes, including testing whether Y chromosome-like regions are undergoing genetic degeneration, a predicted consequence of losing recombination. PMID- 26053355 TI - Disrupted resting-state attentional networks in T2DM patients. AB - Although Type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for dementia, the neural mechanisms that underlie cognitive impairment in T2DM remain unclear. This study uses resting-state functional magnetic resonance imaging (fMRI) to examine attention network alterations in T2DM and their relationships to impaired cognitive performance. Data-driven independent component analysis was applied to resting-state fMRI data from 38 T2DM patients and 32 healthy controls to identify the dorsal attention network (DAN) and ventral attention network (VAN). Correlations were then determined among the resting-state functional connectivity (rsFC), clinical data, and neuropsychological scores. The T2DM patients exhibited decreased rsFC in the left middle frontal gyrus (MFG) and bilateral inferior parietal lobe (IPL) of the DAN, as well as the left IPL and right MFG/IFG of the VAN. In addition, the rsFC of the left MFG was inversely correlated with the Trail Making Test-B scores; the rsFC of the left IPL was positively correlated with the Digit Span Test scores but negatively correlated with HbA1c; and the rsFC in the right precuneus was positively associated with cognitive performance (without Bonferroni correction). In conclusion, T2DM affects resting-state attentional networks, which may be related to reduced attention and a hyperglycemic state. PMID- 26053357 TI - Efficacy of antiviral prophylaxis in HBsAg-negative, anti-HBc positive patients undergoing hematopoietic stem cell transplantation. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) reactivation can occur in persons who are hepatitis B surface antigen (HBsAg)-negative but hepatitis B core antibody (anti-HBc) positive, especially following hematopoietic stem cell transplantation (HSCT). However, evidence supporting the routine use of prophylactic antiviral agents for such patients is scarce. The aim of this study was to compare the frequency of HBV reactivation between prophylactic and non-prophylactic groups in patients who underwent HSCT. METHODS: This retrospective cohort study included 315 HBsAg-negative, anti-HBc positive patients who received autologous or allogenic stem cell transplantation from January 2008 to December 2013. Patients were categorized into prophylactic and non-prophylactic groups. The primary endpoint was the incidence of HBV reactivation. RESULTS: Median follow-up duration was 21.4 months. Antiviral prophylaxis was not given to 219 patients, and 96 received prophylaxis. The median duration of prophylaxis was 7.0 months. HBV reactivated in 12 patients (prophylactic group, 4; non-prophylactic group, 8). The median time to reactivation was 20.5 months after starting chemotherapy. All patients who reactivated were promptly and successfully treated with rescue antiviral agents. The risk of reactivation did not differ between prophylactic and non-prophylactic groups (P = 0.061) but was increased significantly by the allogenic type of HSCT and the loss of recipient's antibodies against HBsAg (anti HBs). CONCLUSIONS: Short-term antiviral prophylaxis appears insufficient to decrease the risk of HBV reactivation. Therefore, either prophylaxis longer than 24 months or careful monitoring of HBV DNA combined with on-demand antiviral treatment may prove more effective than the routine short-term prophylaxis given to these patients. PMID- 26053358 TI - Regioselective Cross-Couplings of Coumarins and Flavones with Ethers via C(sp(3)) H Functionalization. AB - Coumarin and flavone derivatives are highly valuable molecules in drug discovery. Here, two new regioselective cross-dehydrogenation couplings of coumarins and flavones with different ethers via C(sp(3))-H functionalization processes were developed, generating new ether-substituted derivatives not previously reported. These reactions proceeded well via radical mechanisms and provided the corresponding products in good yields. PMID- 26053359 TI - Selection bias correction for species sensitivity distribution modeling and hazardous concentration estimation. AB - The species sensitivity distribution (SSD) has been an important development in ecotoxicology, and despite numerous concerns having been raised over many years, it remains the preferred (and often mandated) technique for establishing "safe" concentrations of contaminants in receiving water bodies by jurisdictions around the world. Although universally recognized as a crucial prerequisite for the statistical validity of the procedure, the assumption of random selection of species for SSD modeling is invariably violated. It is shown in the present study that, under very minimal assumptions, nonrandom species selection can result in hazardous concentration estimation errors of a factor of 20 or more. Importantly, if the toxicity data are biased toward the more sensitive species, then the conventional practice of using the lower confidence interval limit for the estimated hazardous concentration may be compensating in the wrong direction. PMID- 26053360 TI - LC/MS/MS determination and pharmacokinetic study of iridoid glycosides monotropein and deacetylasperulosidic acid isomers in rat plasma after oral administration of Morinda officinalis extract. AB - Morinda officinalis is a famous traditional Chinese medicine containing iridoid glycoside compounds, such as monotropein and deacetylasperulosidic acid. The aim of the study was to develop a novel and sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of the two isomeric iridoid glycosides and then evaluate their pharmacokinetic properties in rats. Selected-reaction monitoring mode was employed for quantification of two analytes in rat plasma. The calibration curves were linear over their respective concentration range with correlation coefficient >0.995 for both analytes. Precision for monotropein and deacetylasperulosidic acid ranged from 2.5 to 11.9% relative standard deviation, and the accuracy of two analytes was -2.0-3.7 and 6.4-10.7% relative error, respectively. This method was successfully applied in pharmacokinetic study after oral administration of M. officinalis extract in rats. The results provided a basis for further research on the bioactivity of M. officinalis. PMID- 26053361 TI - Probiotics in neonatal intensive care - back to the future. AB - Survival of extremely preterm and critically ill neonates has improved significantly over the last few decades following advances in neonatal intensive care. These include antenatal glucocorticoids, surfactant, continuous positive airway pressure support, advanced gentle modes of ventilation and inhaled nitric oxide. Probiotic supplementation is a recent significant milestone in the history of neonatal intensive care. Very few, if any, interventions match the ability of probiotics to significantly reduce the risk of death and definite necrotising enterocolitis while facilitating enteral feeds in high-risk preterm neonates. Probiotics also have a potential to benefit neonates with surgical conditions with significant gastrointestinal morbidity. Current evidence for the benefits of probiotic supplementation for neonates in an intensive care unit is reviewed. The mechanisms for the benefits of probiotics in this population are discussed, and guidelines for clinicians are provided in the context of the regulatory framework in Australia. PMID- 26053362 TI - How Do Work Engagement, Workaholism, and the Work-to-Family Interface Affect Each Other? A 7-Year Follow-Up Study. AB - OBJECTIVE: To investigate the long-term relationships between work engagement, workaholism, work-to-family enrichment, and work-to-family conflict (WFC). METHODS: We used structural equation modeling and the three-wave 7-year follow-up data of 1580 Finnish dentists to test our hypotheses. RESULTS: Work engagement and work-to-family enrichment mutually predicted each other, and work engagement also negatively predicted WFC. Workaholism predicted WFC, but not vice versa. Work engagement and workaholism were unrelated over time. CONCLUSIONS: The results indicate that beyond its suggested benefits for organizations, work engagement may boost the positive interaction between work and family, whereas workaholism is likely to lead to WFC over time. It is valuable for organizations to distinguish work engagement from workaholism and to enhance the former while preventing the latter to have sustainably hardworking working employees with happy home lives. PMID- 26053363 TI - Systemic Inflammation Associated With World Trade Center Dust Exposures and Airway Abnormalities in the Local Community. AB - BACKGROUND: Destruction of the World Trade Center (WTC) towers on September 11, 2001, released massive dust, gas, and fumes with environmental exposures for community members. Many community members have lower respiratory symptoms (LRSs) that began after September 11, 2001, and remain persistent. We evaluated whether systemic inflammation measured by C-reactive protein was associated with WTC dust exposures, persistent LRS, and lung function. METHODS: Community members self referred for the treatment of symptoms related to September 11, 2001. C-reactive protein and lung function measurements, including spirometry and forced oscillation tests (impulse oscillometry system), were included as routine analyses in patients (2007 to 2012). RESULTS: Increased C-reactive protein levels were associated with the type of WTC dust exposure, LRS, reduced spirometry, and increased forced oscillation measurements (n = 724). CONCLUSIONS: Ongoing systemic inflammation measured years after the event was associated with WTC dust exposures, persistent LRS, and abnormal lung function in a community cohort. These findings have implications for treatment and surveillance. PMID- 26053364 TI - Factors Associated With Presenteeism and Psychological Distress Using a Theory Driven Approach. AB - OBJECTIVE: To test a model of presenteeism on the basis of established and emerging theories separated into organizational and individual factors that could be mediated by psychological distress. METHODS: This was a Web survey of 2371 employees (response rate of 48%) of a provincial government agency. We assessed theories with validated measures for organizational and individual factors. RESULTS: Psychological distress was negatively associated to presenteeism, when controlling for sex, short-term work absence in the last year, and social desirability. Both individual and organizational factors were related to psychological distress. The most important factors included the presence of stress events in the preceding 6 months, extrinsic efforts (interruptions, work requirements), self-esteem as a worker, and internal amotivation. CONCLUSIONS: By identifying modifiable factors, our results suggest that the implementation of a work organization structure that promotes stimulation and accomplishment would reduce psychological distress and further presenteeism. PMID- 26053365 TI - Racial and Ethnic Disparities in Health Among Employees at Large Firms. AB - OBJECTIVES: To determine whether race/ethnic disparities in the prevalence of chronic health conditions exist among an employed population. METHODS: We measured racial and ethnic differences in health across a national sample of workers in 46 large US businesses. We examined 15 chronic conditions for six ethnic/racial groups: African American, Hispanic, white, Asian/Pacific Islander, Native American, and Two or More Races. We identified the presence of each condition, using health care claims data. We report unadjusted and adjusted prevalence statistics for each race and ethnic group, controlling for confounding variables. RESULTS: Native Americans and African Americans had a significantly higher prevalence for almost half of the conditions studied compared to one or more other group. CONCLUSIONS: Employers should be cautious when initiating programs that may unfairly discriminate against employee groups with inherent medical conditions associated with certain race and ethnic groups. PMID- 26053366 TI - The Employee Absenteeism Costs of Rheumatoid Arthritis: Evidence From US National Survey Data. AB - OBJECTIVE: To estimate indirect costs associated with rheumatoid arthritis (RA). METHODS: This was a retrospective study using 1996-2006 US Medical Expenditure Panel Survey data. Employed individuals were aged 18 to 65 years. A two-part model estimated the probability of time lost from work and annual number of workdays missed due to illness. RESULTS: Sixty-seven percent (209/312) of RA individuals missed work versus 58% (52,046/89,734) of those without RA (P = 0.0007). Among individuals who missed work, those with RA missed more workdays annually than those without RA ((Equation is included in full-text article.)= 13.659, 9.879, respectively; P = 0.008). Incremental per capita costs in annual lost workdays between those with and without RA were $596. Estimated national indirect costs of RA-related absenteeism were $252 million annually. CONCLUSIONS: Individuals with RA have higher probabilities of missing work and missing workdays than those without RA. PMID- 26053367 TI - Measuring the Effects of Screening Programs in Asymptomatic Employees: Detection of Hypertension Through Worksite Screenings. AB - OBJECTIVE: To evaluate the effectiveness of workplace screenings on identification, subsequent follow-up, and treatment of patients with undiagnosed hypertension. METHODS: Claims data and screening values for 31,281 individuals from 21 self-insured employer groups were combined with zip code-level information and analyzed using multilevel logit models. RESULTS: Up to 17.6% of individuals without a previous indication of hypertension in the administrative data exhibited high blood pressure (140/90 or greater) at screening. In the month following workplace screening, significant increases were noted, using administrative claims, in the number of new diagnoses for hypertension (odds ratio: 1.81; P < 0.0001) and new prescriptions for antihypertensive drugs (odds ratio: 2.27; P < 0.0001), primarily among individuals with high blood pressure at screening. CONCLUSIONS: Workplace screening programs offer a potential approach to identify undiagnosed hypertension in employees and ensuing therapeutic management. PMID- 26053370 TI - Prostate Cancer and PFOA. PMID- 26053371 TI - A Letter in Response to Olsen et al. PMID- 26053372 TI - Response to Prostate Cancer and PFOA. PMID- 26053373 TI - Using Causal Models for the Calculation of Direct and Indirect Effects: An Example From Occupational Health. PMID- 26053374 TI - How to Improve Your Paper With a Cost of Illness Analysis: Providing an Example on Bullying Among Social Care Workers in Elder Care. PMID- 26053375 TI - Photosynthetic Response of Soybean to Microclimate in 26-Year-Old Tree-Based Intercropping Systems in Southern Ontario, Canada. AB - In order to study the effect of light competition and microclimatic modifications on the net assimilation (NA), growth and yield of soybean (Glycine max L.) as an understory crop, three 26-year-old soybean-tree (Acer saccharinum Marsh., Populus deltoides X nigra, Juglans nigra L.) intercropping systems were examined. Tree competition reduced photosynthetically active radiation (PAR) incident on soybeans and reduced net assimilation, growth and yield of soybean. Soil moisture of 20 cm depth close (< 3 m) to the tree rows was also reduced. Correlation analysis showed that NA and soil water content were highly correlated with growth and yield of soybean. When compared with the monoculture soybean system, the relative humidity (RH) of the poplar-soybean, silver maple-soybean, and black walnut-soybean intercropped systems was increased by 7.1%, 8.0% and 5.9%, soil water content was reduced by 37.8%, 26.3% and 30.9%, ambient temperature was reduced by 1.3 degrees C, 1.4 degrees C and 1.0 degrees C, PAR was reduced by 53.6%, 57.9% and 39.9%, and air CO2 concentration was reduced by 3.7MUmol.mol( 1), 4.2MUmol.mol(-1) and 2.8MUmol.mol(-1), respectively. Compared to the monoculture, the average NA of soybean in poplar, maple and walnut treatments was also reduced by 53.1%, 67.5% and 46.5%, respectively. Multivariate stepwise regression analysis showed that PAR, ambient temperature and CO2 concentration were the dominant factors influencing net photosynthetic rate. PMID- 26053376 TI - Bicontinuous Structure of Li3V2(PO4)3 Clustered via Carbon Nanofiber as High Performance Cathode Material of Li-Ion Batteries. AB - In this work, the composite structure of Li3V2(PO4)3 (LVP) nanoparticles with carbon nanofibers (CNF) is designed. The size and location of LVP particles, and the degree of graphitization and diameter of carbon nanofibers, are optimized by electrospinning and heat treatment. The bicontinuous morphologies of LVP/CNF are dependent on the carbonization of PVP and simultaneous growing of LVP, with the fibers shrunk and the LVP crystals grown toward the outside. LVP nanocystals clustered via carbon nanofibers guarantee improving the diffusion ability of Li(+), and the carbon fiber simultaneously guarantees the effective electron conductivity. Compared with the simple carbon-coated LVP and pure LVP, the particle-clustered structure guarantees high rate capability and long-life cycling stability of NF-LVP as cathode for LIBs. At 20 C rate in the range 3.0 4.3 V, NF-LVP delivers the initial capacity of 122.6 mAh g(-1) close to the theoretical value of 133 mAh g(-1), and maintains 97% of the initial capacity at the 1000th cycle. The bead-like structure of cathode material clustered via carbon nanofibers via electrospinning will be further applied to high-performance LIBs. PMID- 26053377 TI - Static and dynamic strain coupling behaviour of ferroic and multiferroic perovskites from resonant ultrasound spectroscopy. AB - Resonant ultrasound spectroscopy (RUS) provides a window on the pervasive influence of strain coupling at phase transitions in perovskites through determination of elastic and anelastic relaxations across wide temperature intervals and with the application of external fields. In particular, large variations of elastic constants occur at structural, ferroelectric and electronic transitions and, because of the relatively long interaction length provided by strain fields in a crystal, Landau theory provides an effective formal framework for characterizing their form and magnitude. At the same time, the Debye equations provide a robust description of dynamic relaxational processes involving the mobility of defects which are coupled with strain. Improper ferroelastic transitions driven by octahedral tilting in KMnF3, LaAlO3, (Ca,Sr)TiO3, Sr(Ti,Zr)O3 and BaCeO3 are accompanied by elastic softening of tens of % and characteristic patterns of acoustic loss due to the mobility of twin walls. RUS data for ferroelectrics and ferroelectric relaxors, including BaTiO3, (K,Na)NbO3,Pb(Mg1/3Nb2/3)O3 (PMN), Pb(Sc1/2Ta1/2)O3 (PST), (Pb(Zn1/3Nb2/3)O3)0.955(PbTiO3)0.045 (PZN-PT) and (Pb(In1/2Nb1/2)O3)0.26(Pb(Mg1/3Nb2/3)O3)0.44(PbTiO3)0.30 (PIN-PMN-PT) show similar patterns of softening and attenuation but also have precursor softening associated with the development of polar nano regions. Defect-induced ferroelectricity occurs in KTaO3, without the development of long range ordering. By way of contrast, spin-lattice coupling is much more variable in strength, as reflected in a greater range of softening behaviour for Pr0.48Ca0.52MnO3 and Sm0.6Y0.4MnO3 as well as for the multiferroic perovskites EuTiO3,BiFeO3, Bi0.9Sm0.1FeO3, Bi0.9Nd0.1FeO3, (BiFeO3)0.64(CaFeO2.5)0.36, (Pb(Fe0.5Ti0.5)O3)0.4(Pb(Zr0.53Ti0.47)O3)0.6. A characteristic feature of transitions in which there is a significant Jahn-Teller component is softening as the transition point is approached from above, as illustrated by PrAlO3, and this is suppressed by application of an external magnetic field in the colossal magnetoresistive manganite Pr0.48Ca0.52MnO3 or by reducing grain size in La0.5Ca0.5MnO3. Spin state transitions for Co(3+) in LaCoO3, NdCoO3 and GdCoO3 produce changes in the shear modulus that scale with a spin state order parameter, which is itself coupled with the order parameter(s) for octahedral tilting in a linear-quadratic manner. A new class of phase transitions in perovskites, due to orientational or conformational ordering of organic molecules on the crystallographic A-site of metal organic frameworks, is illustrated for [(CH3)2NH2]Co(HCOO)3 and [(CH2)3NH2]Mn(HCOO)3 which also display elastic and anelastic anomalies due to the influence of intrinsic and extrinsic strain relaxation behaviour. PMID- 26053378 TI - High levels of positive end-expiratory pressure preserve diaphragmatic contractility during acute respiratory distress syndrome in rats. AB - NEW FINDINGS: What is the central question of this study? Higher levels of positive end-expiratory pressure (PEEP) have recently been used in patients with acute respiratory distress syndrome (ARDS). In normal physiological conditions, the ability of the diaphragm to generate pressure is reduced when the lung volume is elevated beyond its functional residual capacity. It is unknown whether higher levels of PEEP will have a negative impact on diaphragmatic contraction in the presence of the pathophysiology of ARDS. What is the main finding and its importance? Mechanical ventilation with higher levels of PEEP reduced lung injury, improved diaphragmatic contractility and increased the expression of both dihydropyridine receptor and ryanodine receptor in the diaphragms of rats with ARDS. Higher levels of positive end-expiratory pressure (PEEP) have recently been used in patients with acute respiratory distress syndrome (ARDS). In normal physiological conditions, the ability of the diaphragm to generate pressure is reduced when the lung volume is elevated beyond its functional residual capacity. Thus, it is critical to understand whether higher levels of PEEP will have a negative impact on diaphragmatic contraction in the presence of the pathophysiology of ARDS. This study was designed to determine whether higher levels of PEEP reduce diaphragmatic contractility in a rat model of ARDS generated using i.p. lipopolysaccharide. Forty rats were randomly assigned to the following five groups: a control group with no special treatment; an ARDS group with no mechanical ventilation; and three ARDS groups with mechanical ventilation with PEEP at 0, 5 or 10 cmH2 O, respectively. We found that mechanical ventilation with PEEP reduced lung injury, improved diaphragmatic contractility and increased the expression of both dihydropyridine receptor and ryanodine receptor in the diaphragms of rats with ARDS. These changes were most significant at a PEEP of 10 cmH2 O among all applied levels of PEEP. In conclusion, using a rat ARDS model, this study confirmed that diaphragmatic contractility was preserved by mechanical ventilation with high levels of PEEP. PMID- 26053379 TI - A New Method for Rapid Screening of End-Point PCR Products: Application to Single Genome Amplified HIV and SIV Envelope Amplicons. AB - PCR is the most widely applied technique for large scale screening of bacterial clones, mouse genotypes, virus genomes etc. A drawback of large PCR screening is that amplicon analysis is usually performed using gel electrophoresis, a step that is very labor intensive, tedious and chemical waste generating. Single genome amplification (SGA) is used to characterize the diversity and evolutionary dynamics of virus populations within infected hosts. SGA is based on the isolation of single template molecule using limiting dilution followed by nested PCR amplification and requires the analysis of hundreds of reactions per sample, making large scale SGA studies very challenging. Here we present a novel approach entitled Long Amplicon Melt Profiling (LAMP) based on the analysis of the melting profile of the PCR reactions using SYBR Green and/or EvaGreen fluorescent dyes. The LAMP method represents an attractive alternative to gel electrophoresis and enables the quick discrimination of positive reactions. We validate LAMP for SIV and HIV env-SGA, in 96- and 384-well plate formats. Because the melt profiling allows the screening of several thousands of PCR reactions in a cost-effective, rapid and robust way, we believe it will greatly facilitate any large scale PCR screening. PMID- 26053380 TI - Carriers of Mitochondrial DNA Macrohaplogroup N Lineages Reached Australia around 50,000 Years Ago following a Northern Asian Route. AB - BACKGROUND: The modern human colonization of Eurasia and Australia is mostly explained by a single-out-of-Africa exit following a southern coastal route throughout Arabia and India. However, dispersal across the Levant would better explain the introgression with Neanderthals, and more than one exit would fit better with the different ancient genomic components discovered in indigenous Australians and in ancient Europeans. The existence of an additional Northern route used by modern humans to reach Australia was previously deduced from the phylogeography of mtDNA macrohaplogroup N. Here, we present new mtDNA data and new multidisciplinary information that add more support to this northern route. METHODS: MtDNA hypervariable segments and haplogroup diagnostic coding positions were analyzed in 2,278 Saudi Arabs, from which 1,725 are new samples. Besides, we used 623 published mtDNA genomes belonging to macrohaplogroup N, but not R, to build updated phylogenetic trees to calculate their coalescence ages, and more than 70,000 partial mtDNA sequences were screened to establish their respective geographic ranges. RESULTS: The Saudi mtDNA profile confirms the absence of autochthonous mtDNA lineages in Arabia with coalescence ages deep enough to support population continuity in the region since the out-of-Africa episode. In contrast to Australia, where N(xR) haplogroups are found in high frequency and with deep coalescence ages, there are not autochthonous N(xR) lineages in India nor N(xR) branches with coalescence ages as deep as those found in Australia. These patterns are at odds with the supposition that Australian colonizers harboring N(xR) lineages used a route involving India as a stage. The most ancient N(xR) lineages in Eurasia are found in China, and inconsistently with the coastal route, N(xR) haplogroups with the southernmost geographical range have all more recent radiations than the Australians. CONCLUSIONS: Apart from a single migration event via a southern route, phylogeny and phylogeography of N(xR) lineages support that people carrying mtDNA N lineages could have reach Australia following a northern route through Asia. Data from other disciplines also support this scenario. PMID- 26053382 TI - Association of Perioperative Plasma Neutrophil Gelatinase-Associated Lipocalin Levels with 3-Year Mortality after Cardiac Surgery: A Prospective Observational Cohort Study. AB - BACKGROUND: Higher levels of plasma neutrophil gelatinase-associated lipocalin (pNGAL) are an early marker of acute kidney injury and are associated with increased risk of short-term adverse outcomes. The independent association between pNGAL and long-term mortality is unknown. METHODS: In this prospective observational cohort study, we studied 1191 adults who underwent cardiac surgery between 2007 and 2009 at 6 centers in the TRIBE-AKI cohort. We measured the pNGAL on the pre-operative and first 3 post-operative days and assessed the relationship of peri-operative pNGAL concentrations with all-cause mortality. RESULTS: During a median follow-up of 3.0 years, 139 participants died (50/1000 person-years). Pre-operative levels of pNGAL were associated with 3-year mortality (unadjusted HR 1.96, 95% CI 1.34,2.85) and the association persisted after adjustment for pre-operative variables including estimated glomerular filtration rate (adjusted HR 1.48, 95% CI 1.04-2.12). After adjustment for pre- and intra-operative variables, including pre-operative NGAL levels, the highest tertiles of first post-operative and peak post-operative pNGAL were also independently associated with 3-year mortality risk (adjusted HR 1.31, 95% CI 1.0 1.7 and adjusted HR 1.78, 95% CI 1.2-2.7, respectively). However, after adjustment for peri-operative changes in serum creatinine, there was no longer an independent association between the first post-operative and peak post-operative pNGAL and long-term mortality (adjusted HR 0.98,95% CI 0.79-1.2 for first pNGAL and adjusted HR 1.19, 95% CI 0.87-1.61 for peak pNGAL). CONCLUSIONS: Pre operative pNGAL levels were independently associated with 3-year mortality after cardiac surgery. While post-operative pNGAL levels were also associated with 3 year mortality, this relationship was not independent of changes in serum creatinine. These findings suggest that while pre-operative pNGAL adds prognostic value for mortality beyond routinely available serum creatinine, post-operative pNGAL measurements may not be as useful for this purpose. PMID- 26053383 TI - Controlled Rewarming after Hypothermia: Adding a New Principle to Renal Preservation. AB - Early graft dysfunction due to preservation/reperfusion injury still represents a notable issue after kidney transplantation, affecting long term prognosis of graft viability. One trigger of postischemic cell dysfunction could be recognized in the abrupt temperature shift from hypo- to normothermia, leading to mitochondrial dysfunction and proapoptotic signal transduction. Here we propose a technique to cope with this "rewarming injury" by interposing a period of gentle warming up by hypo- to subnormothermic machine perfusion of the isolated graft prior to warm reperfusion. Porcine kidneys were subjected either to 18 hours of hypothermic machine preservation (HMP) or 18 hours static cold storage + 3 hours of gentle, machine controlled oxygenated rewarming (COR). Functional integrity was evaluated in both groups by subsequent normothermic reperfusion in vitro. The functional benefit of COR was documented by an approximately twofold increase in renal clearances of creatinine as well as urea upon warm reperfusion, compared to controls. This was accompanied with a notable mitigation of postischemic mitochondrial dys-homeostasis. COR significantly improved renal oxygen consumption and maintained total NAD tissue content upon reperfusion. Mitochondrial initiation of cellular apoptosis, as evidenced by activation of caspase 9 was also largely prevented after COR but not in controls. The concept of gentle regenerative graft rewarming could become a valuable adjunct in renal transplantation. PMID- 26053384 TI - Regular theta-firing neurons in the nucleus incertus during sustained hippocampal activation. PMID- 26053385 TI - Clinical and Cost-Effectiveness of Procalcitonin Test for Prodromal Meningococcal Disease-A Meta-Analysis. AB - BACKGROUND: Despite vaccines and improved medical intensive care, clinicians must continue to be vigilant of possible Meningococcal Disease in children. The objective was to establish if the procalcitonin test was a cost-effective adjunct for prodromal Meningococcal Disease in children presenting at emergency department with fever without source. METHODS AND FINDINGS: Data to evaluate procalcitonin, C-reactive protein and white cell count tests as indicators of Meningococcal Disease were collected from six independent studies identified through a systematic literature search, applying PRISMA guidelines. The data included 881 children with fever without source in developed countries.The optimal cut-off value for the procalcitonin, C-reactive protein and white cell count tests, each as an indicator of Meningococcal Disease, was determined. Summary Receiver Operator Curve analysis determined the overall diagnostic performance of each test with 95% confidence intervals. A decision analytic model was designed to reflect realistic clinical pathways for a child presenting with fever without source by comparing two diagnostic strategies: standard testing using combined C-reactive protein and white cell count tests compared to standard testing plus procalcitonin test. The costs of each of the four diagnosis groups (true positive, false negative, true negative and false positive) were assessed from a National Health Service payer perspective. The procalcitonin test was more accurate (sensitivity=0.89, 95%CI=0.76-0.96; specificity=0.74, 95%CI=0.4-0.92) for early Meningococcal Disease compared to standard testing alone (sensitivity=0.47, 95%CI=0.32-0.62; specificity=0.8, 95% CI=0.64-0.9). Decision analytic model outcomes indicated that the incremental cost effectiveness ratio for the base case was L-8,137.25 (US $ -13,371.94) per correctly treated patient. CONCLUSIONS: Procalcitonin plus standard recommended tests, improved the discriminatory ability for fatal Meningococcal Disease and was more cost effective; it was also a superior biomarker in infants. Further research is recommended for point-of-care procalcitonin testing and Markov modelling to incorporate cost per QALY with a life-time model. PMID- 26053386 TI - 18F- fluoride PET/CT assessment in patients fulfilling the clinical arm of the ASAS criteria for axial spondyloarthritis. A comparative study with ankylosing spondylitis. PMID- 26053387 TI - Assembly of a large cerium(III)-containing tungstotellurites(IV) nanocluster: [Ce10Te8W88O298(OH)12(H2O)40]18-. AB - A large lanthanide-containing tungstotellurites(iv) nanocluster Na18[Ce10Te8W88O298(OH)12(H2O)40].54H2O () was synthesized by combining cerium linkers and TeO3(2-) heteroanion templates. The macroanion in consists of two identical [Te4W42O144(OH)6Ce4(H2O)13](14-) subunits and two triangle-shaped {W2O5Ce(H2O)7} linkers. PMID- 26053388 TI - Fetal Behavioural Responses to Maternal Voice and Touch. AB - BACKGROUND: Although there is data on the spontaneous behavioural repertoire of the fetus, studies on their behavioural responses to external stimulation are scarce. AIM, METHODS: The aim of the current study was to measure fetal behavioural responses in reaction to maternal voice; to maternal touch of the abdomen compared to a control condition, utilizing 3D real-time (4D) sonography. Behavioural responses of 23 fetuses (21st to 33rd week of gestation; N = 10 in the 2nd and N = 13 in the 3rd trimester) were frame-by-frame coded and analyzed in the three conditions. RESULTS: Results showed that fetuses displayed more arm, head, and mouth movements when the mother touched her abdomen and decreased their arm and head movements to maternal voice. Fetuses in the 3rd trimester showed increased regulatory (yawning), resting (arms crossed) and self-touch (hands touching the body) responses to the stimuli when compared to fetuses in the 2nd trimester. CONCLUSION: In summary, the results from this study suggest that fetuses selectively respond to external stimulation earlier than previously reported, fetuses actively regulated their behaviours as a response to the external stimulation, and that fetal maturation affected the emergence of these differential responses to the environment. PMID- 26053390 TI - Regulation of Gene Editing Activity Directed by Single-Stranded Oligonucleotides and CRISPR/Cas9 Systems. AB - Single-stranded DNA oligonucleotides (ssODNs) can direct the repair of a single base mutation in human genes. While the regulation of this gene editing reaction has been partially elucidated, the low frequency with which repair occurs has hampered development toward clinical application. In this work a CRISPR/Cas9 complex is employed to induce double strand DNA breakage at specific sites surrounding the nucleotide designated for exchange. The result is a significant elevation in ssODN-directed gene repair, validated by a phenotypic readout. By analysing reaction parameters, we have uncovered restrictions on gene editing activity involving CRISPR/Cas9 complexes. First, ssODNs that hybridize to the non transcribed strand direct a higher level of gene repair than those that hybridize to the transcribed strand. Second, cleavage must be proximal to the targeted mutant base to enable higher levels of gene editing. Third, DNA cleavage enables a higher level of gene editing activity as compared to single-stranded DNA nicks, created by modified Cas9 (Nickases). Fourth, we calculated the hybridization potential and free energy levels of ssODNs that are complementary to the guide RNA sequences of CRISPRs used in this study. We find a correlation between free energy potential and the capacity of single-stranded oligonucleotides to inhibit specific DNA cleavage activity, thereby indirectly reducing gene editing activity. Our data provide novel information that might be taken into consideration in the design and usage of CRISPR/Cas9 systems with ssODNs for gene editing. PMID- 26053391 TI - Effect of dietary supplementation of rutin on lactation performance, ruminal fermentation and metabolism in dairy cows. AB - The effect of long-term dietary supplementation with rutin on the lactation performance, ruminal fermentation and metabolism of dairy cows were investigated in this study. Twenty multiparous Chinese Holstein cows were randomly divided into four groups, and each was offered a basal diet supplemented with 0, 1.5, 3.0 or 4.5 mg rutin/kg of diet. The milk yield of the cows receiving 3.0 and 4.5 mg rutin/kg was higher than that of the control group, and the milk yield was increased by 10.06% and 3.37% (p < 0.05). On the basis of that finding, the cows supplemented with 0 or 3.0 mg rutin/kg of diet were used to investigate the effect of rutin supplementation on blood metabolites and hormone levels. Compared with the control group, the serum blood urea nitrogen (BUN) concentration of the 3.0 mg rutin/kg group is significantly decreased (p < 0.05). In another trial, four adult cows with permanent rumen fistula and duodenal cannulae were attributed in a self-control design to investigate the peak occurrence of rutin and quercetin in different parts of the gastrointestinal tract, ruminal fermentation and microbial population in dairy cows. The cows supplemented with 3.0 mg rutin/kg in the diet differed from the control period. Samples of rumen fluid, duodenal fluid and blood were collected at 1, 2, 3, 4, 5, 6, 7 and 8 h after morning feeding. Compared to the control group, the pH, ammonia nitrogen concentration, number and protein content of rumen protozoa and blood urea nitrogen were lower, but the concentration of total volatile fatty acid (TVFA), microbial crude protein (MCP) and serum lysozyme content were higher for the cows fed the rutin diets. The addition of 3.0 mg rutin/kg to diets for a long term tended to increase the milk yield and improve the metabolism and digestibility of the dairy cows. PMID- 26053392 TI - Copyright and Bedside Cognitive Testing: Why We Need Alternatives to the Mini Mental State Examination. PMID- 26053393 TI - Hydrogen Production by the Thermophilic Bacterium Thermotoga neapolitana. AB - As the only fuel that is not chemically bound to carbon, hydrogen has gained interest as an energy carrier to face the current environmental issues of greenhouse gas emissions and to substitute the depleting non-renewable reserves. In the last years, there has been a significant increase in the number of publications about the bacterium Thermotoga neapolitana that is responsible for production yields of H2 that are among the highest achievements reported in the literature. Here we present an extensive overview of the most recent studies on this hyperthermophilic bacterium together with a critical discussion of the potential of fermentative production by this bacterium. The review article is organized into sections focused on biochemical, microbiological and technical issues, including the effect of substrate, reactor type, gas sparging, temperature, pH, hydraulic retention time and organic loading parameters on rate and yield of gas production. PMID- 26053394 TI - Specific Colon Cancer Cell Cytotoxicity Induced by Bacteriophage E Gene Expression under Transcriptional Control of Carcinoembryonic Antigen Promoter. AB - Colorectal cancer is one of the most prevalent cancers in the world. Patients in advanced stages often develop metastases that require chemotherapy and usually show a poor response, have a low survival rate and develop considerable toxicity with adverse symptoms. Gene therapy may act as an adjuvant therapy in attempts to destroy the tumor without affecting normal host tissue. The bacteriophage E gene has demonstrated significant antitumor activity in several cancers, but without any tumor-specific activity. The use of tumor-specific promoters may help to direct the expression of therapeutic genes so they act against specific cancer cells. We used the carcinoembryonic antigen promoter (CEA) to direct E gene expression (pCEA-E) towards colon cancer cells. pCEA-E induced a high cell growth inhibition of human HTC-116 colon adenocarcinoma and mouse MC-38 colon cancer cells in comparison to normal human CCD18co colon cells, which have practically undetectable levels of CEA. In addition, in vivo analyses of mice bearing tumors induced using MC-38 cells showed a significant decrease in tumor volume after pCEA-E treatment and a low level of Ki-67 in relation to untreated tumors. These results suggest that the CEA promoter is an excellent candidate for directing E gene expression specifically toward colon cancer cells. PMID- 26053395 TI - Engraftment of Prevascularized, Tissue Engineered Constructs in a Novel Rabbit Segmental Bone Defect Model. AB - The gold standard treatment of large segmental bone defects is autologous bone transfer, which suffers from low availability and additional morbidity. Tissue engineered bone able to engraft orthotopically and a suitable animal model for pre-clinical testing are direly needed. This study aimed to evaluate engraftment of tissue-engineered bone with different prevascularization strategies in a novel segmental defect model in the rabbit humerus. Decellularized bone matrix (Tutobone) seeded with bone marrow mesenchymal stromal cells was used directly orthotopically or combined with a vessel and inserted immediately (1-step) or only after six weeks of subcutaneous "incubation" (2-step). After 12 weeks, histological and radiological assessment was performed. Variable callus formation was observed. No bone formation or remodeling of the graft through TRAP positive osteoclasts could be detected. Instead, a variable amount of necrotic tissue formed. Although necrotic area correlated significantly with amount of vessels and the 2-step strategy had significantly more vessels than the 1-step strategy, no significant reduction of necrotic area was found. In conclusion, the animal model developed here represents a highly challenging situation, for which a suitable engineered bone graft with better prevascularization, better resorbability and higher osteogenicity has yet to be developed. PMID- 26053396 TI - Efficient Synthesis of Peptide and Protein Functionalized Pyrrole-Imidazole Polyamides Using Native Chemical Ligation. AB - The advancement of DNA-based bionanotechnology requires efficient strategies to functionalize DNA nanostructures in a specific manner with other biomolecules, most importantly peptides and proteins. Common DNA-functionalization methods rely on laborious and covalent conjugation between DNA and proteins or peptides. Pyrrole-imidazole (Py-Im) polyamides, based on natural minor groove DNA-binding small molecules, can bind to DNA in a sequence specific fashion. In this study, we explore the use of Py-Im polyamides for addressing proteins and peptides to DNA in a sequence specific and non-covalent manner. A generic synthetic approach based on native chemical ligation was established that allows efficient conjugation of both peptides and recombinant proteins to Py-Im polyamides. The effect of Py-Im polyamide conjugation on DNA binding was investigated by Surface Plasmon Resonance (SPR). Although the synthesis of different protein-Py-Im polyamide conjugates was successful, attenuation of DNA affinity was observed, in particular for the protein-Py-Im-polyamide conjugates. The practical use of protein-Py-Im-polyamide conjugates for addressing DNA structures in an orthogonal but non-covalent manner, therefore, remains to be established. PMID- 26053397 TI - Vanadium Compounds as Pro-Inflammatory Agents: Effects on Cyclooxygenases. AB - This paper discusses how the activity and expression of cyclooxygenases are influenced by vanadium compounds at anticancer concentrations and recorded in inorganic vanadium poisonings. We refer mainly to the effects of vanadate (orthovanadate), vanadyl and pervanadate ions; the main focus is placed on their impact on intracellular signaling. We describe the exact mechanism of the effect of vanadium compounds on protein tyrosine phosphatases (PTP), epidermal growth factor receptor (EGFR), PLCgamma, Src, mitogen-activated protein kinase (MAPK) cascades, transcription factor NF-kappaB, the effect on the proteolysis of COX-2 and the activity of cPLA2. For a better understanding of these processes, a lot of space is devoted to the transformation of vanadium compounds within the cell and the molecular influence on the direct targets of the discussed vanadium compounds. PMID- 26053398 TI - Detection of Serum Protein Biomarkers for the Diagnosis and Staging of Hepatoblastoma. AB - The present study aimed to identify serum biomarkers for the detection of hepatoblastoma (HB). Serum samples were collected from 71 HB patients (stage I, n = 19; stage II, n = 19, stage III, n = 19; and stage IV, n = 14) and 23 age- and sex-matched healthy children. Differential expression of serum protein markers were screened using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS), and the target proteins were isolated and purified using HPLC and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS), SEQUEST, and bioinformatics analysis. Differential protein expression was confirmed by enzyme-linked immunosorbent analysis (ELISA). SELDI-TOF-MS screening identified a differentially expressed protein with an m/z of 9348 Da, which was subsequently identified as Apo A-I; its expression was significantly lower in the HB group as compared to the normal control group (1546.67 +/- 757.81 vs. 3359.21 +/- 999.36, respectively; p < 0.01). Although the expression level decreased with increasing disease stage, pair-wise comparison revealed significant differences in Apo A-I expression between the normal group and the HB subgroups (p < 0.01). ELISA verified the reduced expression of Apo A-I in the HB group. Taken together, these results suggest that Apo A-I may represent a serum protein biomarker of HB. Further studies will assess the value of using Apo A-I expression for HB diagnosis and staging. PMID- 26053399 TI - Single Cell Electrical Characterization Techniques. AB - Electrical properties of living cells have been proven to play significant roles in understanding of various biological activities including disease progression both at the cellular and molecular levels. Since two decades ago, many researchers have developed tools to analyze the cell's electrical states especially in single cell analysis (SCA). In depth analysis and more fully described activities of cell differentiation and cancer can only be accomplished with single cell analysis. This growing interest was supported by the emergence of various microfluidic techniques to fulfill high precisions screening, reduced equipment cost and low analysis time for characterization of the single cell's electrical properties, as compared to classical bulky technique. This paper presents a historical review of single cell electrical properties analysis development from classical techniques to recent advances in microfluidic techniques. Technical details of the different microfluidic techniques are highlighted, and the advantages and limitations of various microfluidic devices are discussed. PMID- 26053400 TI - The Stable Level of Glutamine synthetase 2 Plays an Important Role in Rice Growth and in Carbon-Nitrogen Metabolic Balance. AB - Glutamine synthetase 2 (GS2) is a key enzyme involved in the ammonium metabolism in plant leaves. In our previous study, we obtained GS2-cosuppressed plants, which displayed a normal growth phenotype at the seedling stage, while at the tillering stage they showed a chlorosis phenotype. In this study, to investigate the chlorosis mechanism, we systematically analyzed the plant growth, carbon nitrogen metabolism and gene expressions between the GS2-cosuppressed rice and wild-type plants. The results revealed that the GS2-cosuppressed plants exhibited a poor plant growth phenotype and a poor nitrogen transport ability, which led to nitrogen accumulation and a decline in the carbon/nitrogen ratio in the stems. Interestingly, there was a higher concentration of soluble proteins and a lower concentration of carbohydrates in the GS2-cosuppressed plants at the seedling stage, while a contrasting result was displayed at the tillering stage. The analysis of the metabolic profile showed a significant increase of sugars and organic acids. Additionally, gene expression patterns were different in root and leaf of GS2-cosuppressed plants between the seedling and tillering stage. These results indicated the important role of a stable level of GS2 transcription during normal rice development and the importance of the carbon-nitrogen metabolic balance in rice growth. PMID- 26053401 TI - Toll-like receptors 2 and 4 modulate the contractile response induced by serotonin in mouse ileum: analysis of the serotonin receptors involved. AB - BACKGROUND: Microbiota through toll-like receptors (TLR) may regulate gastrointestinal motility by activating neuroendocrine mechanisms. We evaluated the influence of TLR2 and TLR4 in the spontaneous contractions and serotonin (5 HT)-induced motor response in mouse ileum, and the 5-HT receptors involved. METHODS: Muscle contractility studies to evaluate the spontaneous intestinal motility and the response to 5-HT were performed in the ileum from wild type (WT), TLR2(-/-), TLR4(-/-), and TLR2/4 double knockout (DKO) mice. 5-HT receptor expression was determined by real-time PCR. KEY RESULTS: The amplitude of spontaneous contractions in ileum was higher in TLR2(-/-), TLR4(-/-), and TLR2/4 DKO mice with respect to WT. 5-HT evoked concentration-dependent contractile responses in the ileum from TLR2(-/-) and TLR4(-/-) mice similar to WT. However, in ileum from TLR2/4 DKO, 5-HT did not induce any contractile response. Expression of 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT3 receptors resulted increased in ileum from TLR4(-/-) and TLR2/4 DKO. Expression of the 5-HT4 receptor was diminished in TLR2(-/-) and TLR2/4 DKO. High levels of 5-HT7 receptor expression were found in TLR2/4 DKO but not in TLR2(-/-) or TLR4(-/-). In WT and TLR4(-/-), 5-HT2, 5-HT3, 5-HT4, and 5-HT7 receptor antagonists reduced the contractile response evoked by 5-HT. In TLR2(-/-) mice, 5-HT4 antagonist did not reduce the 5 HT response. In TLR2/4 DKO mice, only 5-HT4 and 5-HT7 receptor antagonists reduced the relaxing response induced by 5-HT. CONCLUSIONS & INFERENCES: TLR2 and TLR4 signaling may modulate the spontaneous contractions and the serotonin contractile response by acting on 5-HT2, 5-HT3, 5-HT4, and 5-HT7 receptors. PMID- 26053402 TI - Representation of retrieval confidence by single neurons in the human medial temporal lobe. AB - Memory-based decisions are often accompanied by an assessment of choice certainty, but the mechanisms of such confidence judgments remain unknown. We studied the response of 1,065 individual neurons in the human hippocampus and amygdala while neurosurgical patients made memory retrieval decisions together with a confidence judgment. Combining behavioral, neuronal and computational analysis, we identified a population of memory-selective (MS) neurons whose activity signaled stimulus familiarity and confidence, as assessed by subjective report. In contrast, the activity of visually selective (VS) neurons was not sensitive to memory strength. The groups further differed in response latency, tuning and extracellular waveforms. The information provided by MS neurons was sufficient for a race model to decide stimulus familiarity and retrieval confidence. Together, our results indicate a trial-by-trial relationship between a specific group of neurons and declared memory strength in humans. We suggest that VS and MS neurons are a substrate for declarative memories. PMID- 26053403 TI - Polygenic risk scores for schizophrenia and bipolar disorder predict creativity. AB - We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 * 10(-6) and 3.8 * 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots. PMID- 26053405 TI - Peroxide-based oxygen generating topical wound dressing for enhancing healing of dermal wounds. AB - Oxygen generating biomaterials represent a new trend in regenerative medicine that aims to generate and supply oxygen at the site of requirement, to support tissue healing and regeneration. To enhance the healing of dermal wounds, we have developed a highly portable, in situ oxygen generating wound dressings that uses sodium percarbonate (SPO) and calcium peroxide (CPO) as chemical oxygen sources. The dressing continuously generated oxygen for more than 3 days, after which it was replaced. In the in vivo testing on porcine full-thickness porcine wound model, the SPO/CPO dressing showed enhanced wound healing during the 8 week study period. Quantitative measurements of wound healing related parameters, such as wound closure, reepithelialization, epidermal thickness and collagen content of dermis showed that supplying oxygen topically using the SPO/CPO dressing significantly accelerated the wound healing. An increase in neovascularization, as determined using Von Willebrand factor (vWF) and CD31 staining, was also observed in the presence of SPO/CPO dressing. This novel design for a wound dressing that contains oxygen generating biomaterials (SPO/CPO) for supplying topical oxygen, may find utility in treating various types of acute to chronic wounds. PMID- 26053404 TI - Comprehensive Analysis of Disease-Related Genes in Chronic Lymphocytic Leukemia by Multiplex PCR-Based Next Generation Sequencing. AB - BACKGROUND: High resolution molecular studies have demonstrated that the clonal acquisition of gene mutations is an important mechanism that may promote rapid disease progression and drug resistance in chronic lymphocytic leukemia (CLL). Therefore, the early and sensitive detection of such mutations is an important prerequisite for future predictive CLL diagnostics in the clinical setting. MATERIAL & METHODS: Here, we describe a novel, target-specific next generation sequencing (NGS) approach, which combines multiplex PCR-based target enrichment and library generation with ultra-deep high-throughput parallel sequencing using a MiSeq platform. We designed a CLL specific target panel, covering hotspots or complete coding regions of 15 genes known to be recurrently mutated and/or related to B-cell receptor signaling. RESULTS: High-throughput sequencing was performed using as little as 40 ng of peripheral blood B-cell DNA from 136 CLL patients and a dilution series of two ATM- or TP53-mutated cell lines, the latter of which demonstrated a limit of mutation detection below 5%. Using a stringent functional assessment algorithm, 102 mutations in 8 genes were identified in CLL patients, including hotspot regions of TP53, SF3B1, NOTCH1, ATM, XPO1, MYD88, DDX3X and the B-cell receptor signaling regulator PTPN6. The presence of mutations was significantly associated with an advanced disease status und molecular markers of an inferior prognosis, such as an unmutated IGHV mutation status or positivity for ZAP70 by flow cytometry. CONCLUSION: In summary, targeted sequencing using an amplicon based library technology allows a resource efficient and sensitive mutation analysis for diagnostic or exploratory purposes and facilitates molecular subtyping of patient sets with adverse prognosis. PMID- 26053406 TI - Optimal Ozone Control with Inclusion of Spatiotemporal Marginal Damages and Electricity Demand. AB - Marginal damage (MD), or damage per ton of emission, is a policy metric used for effective pollution control and reducing the corresponding adverse health impacts. However, for a pollutant such as NOx, the MD varies by the time and location of the emissions, a complication that is not adequately accounted for in the currently implemented economic instruments. Policies accounting for MD information would aim to encourage emitters with large MDs to reduce their emissions. An optimization framework is implemented to account for NOx spatiotemporal MDs calculated through adjoint sensitivity analysis and to simulate power plants' behavior under emission and simplified electricity constraints. The results from a case study of U.S. power plants indicate that time-specific MDs are high around noon and low in the evening. Furthermore, an emissions reduction of about 40% and a net benefit of about $1200 million can be gained for this subset of power plants if a larger fraction of the electricity demand is supplied by power plants at low-damage times and in low-damage locations. The results also indicate that the consideration of temporal effects in NOx control policies results in a comparable net benefit to the consideration of spatial or spatiotemporal effects, thus providing a promising option for policy development. PMID- 26053407 TI - Dental flossing behaviour and its determinants among students in a suburb area of Tehran-Iran: using Transtheoretical Model. AB - OBJECTIVES: Oral health problems are a global concern particularly among underprivileged groups. This study aimed to use TTM model to assess the flossing behaviour and its determinants among students in a suburb area and compare the flossing behaviour between boys and girls using TTM. METHODS: Cluster sampling was employed to recruit 653 high school students from eight schools in Tehran suburban area, Iran. Two self-administrated questionnaires: (i) stage of change questionnaire and (ii) TTM constructs questionnaire including demographic features, decisional balance (perceived benefits and barriers), self-efficacy and process of change were used to assess the flossing behaviour and its psychological determinants. The statistical analysis of the data included Kruskal Wallis test, t-test, anova, Spearman correlation and binary logistic regression using SPSS ver15 software. RESULTS: In this study, 301 (46.1%) and 352 (53.9%) of participants were women and men, respectively. Nearly half of the students (51.4%) were in precontemplation stage with the rest distributed among the other stages of flossing behaviour change. There was no statistically significant difference between genders regarding the stages of change (P < 0.05). Flossing behaviour is related to TTM constructs such as self-efficacy, perceived benefits, low perceived barriers and process of changes. CONCLUSION: According to the results of this study, TTM is useful in determining the stages of interdental cleaning behaviour among students. However, further interventional researches are suggested to support the potential for eventual use of the TTM as a framework for understanding the determinants of interdental cleaning behaviour. PMID- 26053408 TI - Colloidal synthesis of single-layer MSe2 (M = Mo, W) nanosheets via anisotropic solution-phase growth approach. AB - The generation of single-layer 2-dimensional (2D) nanosheets has been challenging, especially in solution-phase, since it requires highly anisotropic growth processes that exclusively promote planar directionality during nanocrystal formation. In this study, we discovered that such selective growth pathways can be achieved by modulating the binding affinities of coordinating capping ligands to the edge facets of 2D layered transition-metal chalcogenides (TMCs). Upon changing the functional groups of the capping ligands from carboxylic acid to alcohol and amine with accordingly modulated binding affinities to the edges, the number of layers of nanosheets is controlled. Single layer MSe2 (M = Mo, W) TMC nanosheets are obtained with the use of oleic acid, while multilayer nanosheets are formed with relatively strong binding ligands such as oleyl alcohol and oleylamine. With the choice of appropriate capping ligands in the 2D anisotropic growth regime, our solution-based synthetic method can serve a new guideline for obtaining single-layer TMC nanosheets. PMID- 26053409 TI - Longevity Sticker Shock: The One Remaining Obstacle to Widespread Credentialed Support for Rejuvenation Biotechnology. PMID- 26053411 TI - Decreased patency rates following endoscopic vein harvest in coronary artery bypass surgery. AB - OBJECTIVES: Endoscopic vein harvest has gained widespread use in coronary artery bypass surgery. However, potential negative mid- and long-term effects following endoscopic vein harvest have been described. We aimed to compare long-term clinical outcomes following endoscopic and open vein graft harvesting. DESIGN: This study was a clinical follow-up with additional computed tomographic coronary angiography among 126 first-time bypass patients originally included in a randomized study comparing early leg wound complications and cosmetic results. Deceased patients were retrospectively followed up. RESULTS: Follow-up was complete, but information on clinical endpoints was not available in all patients. A total of 111 patients were alive at follow-up. Median observation time was 6.3 (range: 0.2-9.1) years including three in-hospital deaths. Vein graft failure was significantly higher in the endoscopic vein harvest (EVH) group (13 of 31; 42%) compared with the open vein harvest (OVH) group (2 of 32, 6%) (P = 0.001). However, this difference was not reflected by differences in recurrence of angina (P = 0.44), myocardial infarction (P = 0.11), and all-cause mortality (P = 0.15). CONCLUSIONS: Using a median follow-up time of 6.3 years significantly more vein graft failures were identified following EVH compared with OVH without any differences in long-term clinical outcomes. PMID- 26053410 TI - Screening of Probiotic Candidates in Human Oral Bacteria for the Prevention of Dental Disease. AB - The oral cavity in healthy subjects has a well-balanced microbiota that consists of more than 700 species. However, a disturbance of this balance, with an increase of harmful microbes and a decrease of beneficial microbes, causes oral disorders such as periodontal disease or dental caries. Nowadays, probiotics are expected to confer oral health benefits by modulating the oral microbiota. This study screened new probiotic candidates with potential oral health benefits and no harmful effects on the oral cavity. We screened 14 lactobacillus strains and 36 streptococcus strains out of 896 oral isolates derived from healthy subjects. These bacteria did not produce volatile sulfur compounds or water-insoluble glucan, had higher antibacterial activity against periodontal bacteria, and had higher adherence activity to oral epithelial cells or salivary-coated hydroxyapatite in vitro. We then evaluated the risk of primary cariogenicity and infective endocarditis of the selected oral isolates. As a result, Lactobacillus crispatus YIT 12319, Lactobacillus fermentum YIT 12320, Lactobacillus gasseri YIT 12321, and Streptococcus mitis YIT 12322 were selected because they showed no cariogenic potential in an artificial mouth system and a lower risk of experimental infective endocarditis in a rat model. These candidates are expected as new probiotics with potential oral health benefits and no adverse effects on general health. PMID- 26053412 TI - Relationship between oxidative stress parameters and asymptomatic organ damage in hypertensive patients without diabetes mellitus. AB - OBJECTIVE: We aimed to evaluate the levels of oxidative stress (OS) parameters such as total antioxidant status or TAS, total oxidant status (TOS), OS index (OSI), paraoxonase 1 (PON1), arylesterase, and total thiol in hypertensive patients with and without asymptomatic organ damage (AOD), and to determine the relationship between these parameters and AOD. DESIGN: Sixty-six patients (21 men, 45 women) with AOD and 66 patients without AOD (21 men, 45 women) were enrolled in the study. Serum OS parameters were measured by colorimetric method. RESULTS: The OSI levels were found to be higher while PON1, PON1/high-density lipoprotein, and arylesterase levels were found to be lower in patients with AOD compared with those in the patients without AOD. Stepwise regression analysis showed high 24-h mean systolic blood pressure, OSI, and low arylesterase level to be independent predictors of AOD. CONCLUSION: OS level was found to be higher in hypertensive patients with AOD compared with the patients without AOD. However, it is not clear whether increased OS leads to AOD or AOD increases the level of OS. For this purpose, OS level needs to be decreased by antioxidant therapies and patients need to be followed up for a longer duration. PMID- 26053413 TI - Rhodium(III)-Catalyzed Oxidative Annulation of 7-Azaindoles and Alkynes via Double C-H Activation. AB - Rhodium(III)-catalyzed double C-H activation involving N-directed ortho C-H activation and subsequent roll-over C-H activation of the heterocycle ring has been developed to form complex 7-azaindole derivatives in moderate to excellent yields. A broad scope of 7-azaindoles and internal alkynes has been demonstrated in this oxidative annulation reaction. PMID- 26053415 TI - The Influence of Minimalist Footwear on Knee and Ankle Load during Depth Jumping. AB - Plyometric training is used by athletes to promote strength and explosive power. However plyometric activities such as depth jumping are associated with a high incidence of injuries. This study examined the influence of minimalist and conventional footwear on the loads experienced by the patellofemoral joint and Achilles tendon. Patellofemoral and Achilles tendon forces were obtained from ten male participants using an eight-camera 3D motion capture system and force platform data as they completed depth jumps in both footwear conditions. Differences between footwear were calculated using paired t-tests. The results show that the minimalist footwear were associated with significantly lower patellofemoral contact force/pressure and also knee abduction moment. It is therefore recommended, based on these observations, that those who are susceptible to knee pain should consider minimalist footwear when performing plyometric training. PMID- 26053416 TI - Synergy in Extraction System Chemistry: Combining Configurational Entropy, Film Bending, and Perturbation of Complexation. AB - Iron-uranium selectivity in liquid-liquid extraction depends not only on the mole fraction of extractants, but also on the nature of the diluent used, even if the diluent has no complexation interaction with the extracted ions. Modeling strong nonlinearity is difficult to parametrize without a large number of parameters, interpreted as "apparent constants". We determine in this paper the synergy curve versus mole fraction of HDEHP-TOPO (di(2-ethylexyl) phosphoric acid/tri-n-octyl phosphine oxide) and compare the free energy of aggregation to the free energy of extraction in various diluents. There is always a concomitant maximum of the two quantities, but with a gradual influence on intensity. The diluent is wetting the chains of the reverse aggregates responsible of the extraction. We show here that the intensity of the unexplained synergy peak is strongly dependent on the "penetrating" or "nonpenetrating" nature of the diluent. This experimental determination allows us to attribute the synergy to a combination of entropic effects favoring extraction, opposed to perturbation of the first coordination sphere by penetration as well as surfactant film bending energy. PMID- 26053418 TI - Characterisation of Stress-Induced Aggregate Size Distributions and Morphological Changes of a Bi-Specific Antibody Using Orthogonal Techniques. AB - A critical step in monoclonal antibody (mAb) screening and formulation selection is the ability of the mAb to resist aggregation following exposure to environmental stresses. Regulatory authorities welcome not only information on the presence of micron-sized particles, but often any information on sub-visible particles in the size range obtained by orthogonal sizing techniques. The present study demonstrates the power of combining established techniques such as dynamic light scattering (DLS) and micro-flow imaging (MFI), with novel analyses such as raster image correlation spectroscopy (RICS) that offer to bridge existent particle sizing gaps in this area. The influence of thermal and freeze-thaw stress treatments on particle size and morphology was assessed for a bi-specific antibody (mAb2). Aggregation of mAb2 was confirmed to be concentration- and treatment-dependent following thermal stress and freeze-thaw cycling. Particle size and count data show concentration- and treatment-dependent behaviour of aggregate counts, morphological descriptors and particle size distributions. Complementarity in particle size output was observed between all approaches utilised, where RICS bridged the analytical size gap (~0.5-5 MUm) between DLS and MFI. Overall, this study highlights the potential of orthogonal image analyses such as RICS (analytical size gap) and MFI (particle morphology) for formulation screening. PMID- 26053420 TI - Combining individual participant and aggregated data in a meta-analysis with correlational studies. AB - This paper presents methods for combining individual participant data (IPD) with aggregated study level data (AD) in a meta-analysis of correlational studies. Although medical researchers have employed IPD in a wide range of studies, only a single example exists in the social sciences. New policies at the National Science Foundation requiring grantees to submit data archiving plans may increase social scientists' access to individual level data that could be combined with traditional meta-analysis. The methods presented here extend prior work on IPD to meta-analyses using correlational studies. The examples presented illustrate the synthesis of publicly available national datasets in education with aggregated study data from a meta-analysis examining the correlation of socioeconomic status measures and academic achievement. The major benefit of the inclusion of the individual level is that both within-study and between-study interactions among moderators of effect size can be estimated. Given the potential growth in data archives in the social sciences, we should see a corresponding increase in the ability to synthesize IPD and AD in a single meta-analysis, leading to a more complete understanding of how within-study and between-study moderators relate to effect size. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053419 TI - Application of Enhanced Sampling Monte Carlo Methods for High-Resolution Protein Protein Docking in Rosetta. AB - The high-resolution refinement of docked protein-protein complexes can provide valuable structural and mechanistic insight into protein complex formation complementing experiment. Monte Carlo (MC) based approaches are frequently applied to sample putative interaction geometries of proteins including also possible conformational changes of the binding partners. In order to explore efficiency improvements of the MC sampling, several enhanced sampling techniques, including temperature or Hamiltonian replica exchange and well-tempered ensemble approaches, have been combined with the MC method and were evaluated on 20 protein complexes using unbound partner structures. The well-tempered ensemble method combined with a 2-dimensional temperature and Hamiltonian replica exchange scheme (WTE-H-REMC) was identified as the most efficient search strategy. Comparison with prolonged MC searches indicates that the WTE-H-REMC approach requires approximately 5 times fewer MC steps to identify near native docking geometries compared to conventional MC searches. PMID- 26053421 TI - Evidence-based sample size estimation based upon an updated meta-regression analysis. AB - A traditional meta-analysis examines the overall effectiveness of an intervention by producing a pooled estimate of treatment efficacy. In contrast to this, a meta regression model seeks to determine whether a study-level covariate (X) is a plausible source of heterogeneity in a set of treatment effects. Upon performing such an analysis, the results may suggest the presence of a meaningful amount of variation in the treatment effects because of the covariate; however, the current set of trials may not provide sufficient statistical power for such a conclusion. The proposed approach provides quantitative insight into the amount of support that a new trial may provide to the hypothesis that X is a meaningful source of variation in an updated meta-regression model, which includes both the previously completed and the proposed trial. This empirical algorithm allows examination of the potential feasibility of a planned study of various sizes to further support or refute the hypothesis that X is a statistically significant source of variation. A detailed example illustrates the sample size estimation algorithm for both a planned individually or cluster randomized trial to investigate the now commonly accepted impact of geographical latitude on the observed effectiveness of the Bacillus Calmette-Guerin vaccine in the prevention of tuberculosis. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053422 TI - Automating network meta-analysis. AB - Mixed treatment comparison (MTC) (also called network meta-analysis) is an extension of traditional meta-analysis to allow the simultaneous pooling of data from clinical trials comparing more than two treatment options. Typically, MTCs are performed using general-purpose Markov chain Monte Carlo software such as WinBUGS, requiring a model and data to be specified using a specific syntax. It would be preferable if, for the most common cases, both could be derived from a well-structured data file that can be easily checked for errors. Automation is particularly valuable for simulation studies in which the large number of MTCs that have to be estimated may preclude manual model specification and analysis. Moreover, automated model generation raises issues that provide additional insight into the nature of MTC. We present a method for the automated generation of Bayesian homogeneous variance random effects consistency models, including the choice of basic parameters and trial baselines, priors, and starting values for the Markov chain(s). We validate our method against the results of five published MTCs. The method is implemented in freely available open source software. This means that performing an MTC no longer requires manually writing a statistical model. This reduces time and effort, and facilitates error checking of the dataset. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053423 TI - Unsolved issues of mixed treatment comparison meta-analysis: network size and inconsistency. AB - Indirect comparisons and mixed treatment comparison (MTC) meta-analyses are increasingly used in medical research. These methods allow a simultaneous analysis of all relevant interventions in a connected network even if direct evidence regarding two interventions is missing. The framework of MTC meta analysis provides a flexible approach for complex networks. However, this method has yet some unsolved problems, in particular the choice of the network size and the assessment of inconsistency. In this paper, we describe the practical application of MTC meta-analysis by using a data set on antidepressants. We focus on the impact of the size of the chosen network and the assumption of consistency. A larger network is based on more evidence but may show inconsistencies, whereas a smaller network contains less evidence but may show no clear inconsistencies. A choice is required which network should be used in practice. In summary, MTC meta-analysis represents a promising approach; however, clear application standards are still lacking. Especially, standards for the identification of inconsistency and the way to deal with potential inconsistency are required. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053424 TI - Network meta-analysis, electrical networks and graph theory. AB - Network meta-analysis is an active field of research in clinical biostatistics. It aims to combine information from all randomized comparisons among a set of treatments for a given medical condition. We show how graph-theoretical methods can be applied to network meta-analysis. A meta-analytic graph consists of vertices (treatments) and edges (randomized comparisons). We illustrate the correspondence between meta-analytic networks and electrical networks, where variance corresponds to resistance, treatment effects to voltage, and weighted treatment effects to current flows. Based thereon, we then show that graph theoretical methods that have been routinely applied to electrical networks also work well in network meta-analysis. In more detail, the resulting consistent treatment effects induced in the edges can be estimated via the Moore-Penrose pseudoinverse of the Laplacian matrix. Moreover, the variances of the treatment effects are estimated in analogy to electrical effective resistances. It is shown that this method, being computationally simple, leads to the usual fixed effect model estimate when applied to pairwise meta-analysis and is consistent with published results when applied to network meta-analysis examples from the literature. Moreover, problems of heterogeneity and inconsistency, random effects modeling and including multi-armed trials are addressed. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053425 TI - Article Alerts: Items from 2011, Part I. AB - The print component of this fifth 'Article Alerts' installment comprises 100 articles published in 2011. Since the preceding installment, more than 1,100 items disseminated before 1994 have been added to the archive component. To improve access, searching, and other aspects of users' experience, items from the print and archive components are being added to an online library. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053414 TI - Comparative analyses of clinical and environmental populations of Cryptococcus neoformans in Botswana. AB - Cryptococcus neoformans var. grubii (Cng) is the most common cause of fungal meningitis, and its prevalence is highest in sub-Saharan Africa. Patients become infected by inhaling airborne spores or desiccated yeast cells from the environment, where the fungus thrives in avian droppings, trees and soil. To investigate the prevalence and population structure of Cng in southern Africa, we analysed isolates from 77 environmental samples and 64 patients. We detected significant genetic diversity among isolates and strong evidence of geographic structure at the local level. High proportions of isolates with the rare MATa allele were observed in both clinical and environmental isolates; however, the mating-type alleles were unevenly distributed among different subpopulations. Nearly equal proportions of the MATa and MATalpha mating types were observed among all clinical isolates and in one environmental subpopulation from the eastern part of Botswana. As previously reported, there was evidence of both clonality and recombination in different geographic areas. These results provide a foundation for subsequent genomewide association studies to identify genes and genotypes linked to pathogenicity in humans. PMID- 26053427 TI - Effects of excluded volume and hydrodynamic interaction on the deformation, orientation and motion of ring polymers in shear flow. AB - A ring polymer is a classical model to explore the behaviors of biomacromolecules. Compared with its linear counterpart in shear flow, the ring polymer should be more sensitive to excluded volume and hydrodynamic interaction attributed to the absence of chain ends. We carried out multiparticle collision dynamics combined with molecular dynamics simulation to study the effects of excluded volume and hydrodynamic interaction on the behaviors of ring polymers in shear flow. The results show that in the absence of the strong excluded volume interaction, the ring polymer prefers a two-strand linear conformation with high deformation and orientation in the flow-gradient plane, and the tank-treading motion is nearly negligible. Ring polymers without excluded volume show no significant difference from linear polymers in the scaling exponents for the deformation, orientation and tumbling motion. We also observed that the hydrodynamic interaction could efficiently slow down the relaxation of ring polymers while the scaling exponents against the Weissenberg number have rarely been affected. PMID- 26053426 TI - Role of Staphylococcus aureus Virulence Factors in Inducing Inflammation and Vascular Permeability in a Mouse Model of Bacterial Endophthalmitis. AB - Staphylococcus (S.) aureus is a common causative agent of bacterial endophthalmitis, a vision threatening complication of eye surgeries. The relative contribution of S. aureus virulence factors in the pathogenesis of endophthalmitis remains unclear. Here, we comprehensively analyzed the development of intraocular inflammation, vascular permeability, and the loss of retinal function in C57BL/6 mouse eyes, challenged with live S. aureus, heat killed S. aureus (HKSA), peptidoglycan (PGN), lipoteichoic acid (LTA), staphylococcal protein A (SPA), alpha-toxin, and Toxic-shock syndrome toxin 1 (TSST1). Our data showed a dose-dependent (range 0.01 MUg/eye to 1.0 MUg/eye) increase in the levels of inflammatory mediators by all virulence factors. The cell wall components, particularly PGN and LTA, seem to induce higher levels of TNF-alpha, IL-6, KC, and MIP2, whereas the toxins induced IL-1beta. Similarly, among the virulence factors, PGN induced higher PMN infiltration. The vascular permeability assay revealed significant leakage in eyes challenged with live SA (12-fold) and HKSA (7.3-fold), in comparison to other virulence factors (~2-fold) and controls. These changes coincided with retinal tissue damage, as evidenced by histological analysis. The electroretinogram (ERG) analysis revealed a significant decline in retinal function in eyes inoculated with live SA, followed by HKSA, SPA, and alpha-toxin. Together, these findings demonstrate the differential innate responses of the retina to S. aureus virulence factors, which contribute to intraocular inflammation and retinal function loss in endophthalmitis. PMID- 26053428 TI - Rationalization of specific structure formation in electrospinning process: Study on nano-fibrous PCL- and PLGA-based scaffolds. AB - Formation of specific structures on poly-E-caprolactone (PCL) and poly lactide-co glycolide (PLGA) based electrospun mats is rationalized and the effect of interactive parameters; high voltage and flow rate on unique surface topography is evaluated. By increasing the collecting time in electrospinning process and enhancing fiber to fiber repulsion, surface characteristics of mats changes from nano- to micro-topography. In this study surface topography of the fabricated mats based on PCL and PLGA were assessed using AFM and SEM techniques to display the distinct phenomenon occurs on collected random fibers. In this research the rationale behind the formation of bump and flower like structures on fibrous mats was discussed. Because of great potential application of the fabricated substrates in the fields of medical purposes, cell-matrix interaction was evaluated and in vitro biological test with human dermal fibroblast and mouse L929 fibroblast cells was performed to study the cell responses to different roughness of nano-fibers collected at different time intervals. Our results show that after 7 days, cell proliferation is improved on PCL collected at 40 min in the case of human fibroblast cells and on PCL collected in 70 min in the case of L929 mouse fibroblast cells. PMID- 26053429 TI - Monte Carlo Planning Method Estimates Planning Horizons during Interactive Social Exchange. AB - Reciprocating interactions represent a central feature of all human exchanges. They have been the target of various recent experiments, with healthy participants and psychiatric populations engaging as dyads in multi-round exchanges such as a repeated trust task. Behaviour in such exchanges involves complexities related to each agent's preference for equity with their partner, beliefs about the partner's appetite for equity, beliefs about the partner's model of their partner, and so on. Agents may also plan different numbers of steps into the future. Providing a computationally precise account of the behaviour is an essential step towards understanding what underlies choices. A natural framework for this is that of an interactive partially observable Markov decision process (IPOMDP). However, the various complexities make IPOMDPs inordinately computationally challenging. Here, we show how to approximate the solution for the multi-round trust task using a variant of the Monte-Carlo tree search algorithm. We demonstrate that the algorithm is efficient and effective, and therefore can be used to invert observations of behavioural choices. We use generated behaviour to elucidate the richness and sophistication of interactive inference. PMID- 26053430 TI - Validation of the Safe at Home Screening with Adults Who Have Acquired Brain Injury. AB - The Safe at Home Screening (SAH) is an occupational therapy assessment tool designed to quickly assess home safety awareness and skills through the use of mock hazardous situations in a kitchen setting. The SAH has been standardized on community-dwelling adults. This research project involves psychometric analyses using the SAH on a sample of adults with acquired brain injuries (ABI; N = 31), and compares their SAH outcome scores with those of the Kohlman Evaluation of Living Skills (KELS). The scores on the two tests were found to be moderately correlated. An aspect of content validity was explored by asking the clients' occupational therapists to make predictions about their clients' functioning in the realm of home safety. Correlations between the expert opinions of potential client scores and actual SAH test scores were moderate. PMID- 26053432 TI - Multiple Redox Modes in the Reversible Lithiation of High-Capacity, Peierls Distorted Vanadium Sulfide. AB - Vanadium sulfide VS4 in the patronite mineral structure is a linear chain compound comprising vanadium atoms coordinated by disulfide anions [S2](2-). (51)V NMR shows that the material, despite having V formally in the d(1) configuration, is diamagnetic, suggesting potential dimerization through metal metal bonding associated with a Peierls distortion of the linear chains. This is supported by density functional calculations, and is also consistent with the observed alternation in V-V distances of 2.8 and 3.2 A along the chains. Partial lithiation results in reduction of the disulfide ions to sulfide S(2-), via an internal redox process whereby an electron from V(4+) is transferred to [S2](2-) resulting in oxidation of V(4+) to V(5+) and reduction of the [S2](2-) to S(2-) to form Li3VS4 containing tetrahedral [VS4](3-) anions. On further lithiation this is followed by reduction of the V(5+) in Li3VS4 to form Li3+xVS4 (x = 0.5 1), a mixed valent V(4+)/V(5+) compound. Eventually reduction to Li2S plus elemental V occurs. Despite the complex redox processes involving both the cation and the anion occurring in this material, the system is found to be partially reversible between 0 and 3 V. The unusual redox processes in this system are elucidated using a suite of short-range characterization tools including (51)V nuclear magnetic resonance spectroscopy (NMR), S K-edge X-ray absorption near edge spectroscopy (XANES), and pair distribution function (PDF) analysis of X-ray data. PMID- 26053431 TI - Yeast Assay Highlights the Intrinsic Genomic Instability of Human PML Intron 6 over Intron 3 and the Role of Replication Fork Proteins. AB - Human acute promyelocytic leukemia (APL) is characterized by a specific balanced translocation t(15;17)(q22;q21) involving the PML and RARA genes. In both de novo and therapy-related APL, the most frequent PML breakpoints are located within intron 6, and less frequently in intron 3; the precise mechanisms by which these breakpoints arise and preferentially in PML intron 6 remain unsolved. To investigate the intrinsic properties of the PML intron sequences in vivo, we designed Saccharomyces cerevisiae strains containing human PML intron 6 or intron 3 sequences inserted in yeast chromosome V and measured gross chromosomal rearrangements (GCR). This approach provided evidence that intron 6 had a superior instability over intron 3 due to an intrinsic property of the sequence and identified the 3' end of intron 6 as the most susceptible to break. Using yeast strains invalidated for genes that control DNA replication, we show that this differential instability depended at least upon Rrm3, a DNA helicase, and Mrc1, the human claspin homolog. GCR induction by hydrogen peroxide, a general genotoxic agent, was also dependent on genetic context. We conclude that: 1) this yeast system provides an alternative approach to study in detail the properties of human sequences in a genetically controlled situation and 2) the different susceptibility to produce DNA breaks in intron 6 versus intron 3 of the human PML gene is likely due to an intrinsic property of the sequence and is under replication fork genetic control. PMID- 26053433 TI - Non-coding RNAs derived from an alternatively spliced REST transcript (REST-003) regulate breast cancer invasiveness. AB - RE1-Silencing Transcription factor (REST) has a well-established role in regulating transcription of genes important for neuronal development. Its role in cancer, though significant, is less well understood. We show that REST downregulation in weakly invasive MCF-7 breast cancer cells converts them to a more invasive phenotype, while REST overexpression in highly invasive MDA-MB-231 cells suppresses invasiveness. Surprisingly, the mechanism responsible for these phenotypic changes does not depend directly on the transcriptional function of REST protein. Instead, it is driven by previously unstudied mid-size (30-200 nt) non-coding RNAs (ncRNAs) derived from the first exon of an alternatively spliced REST transcript: REST-003. We show that processing of REST-003 into ncRNAs is controlled by an uncharacterized serine/arginine repeat-related protein, SRRM3. SRRM3 expression may be under REST-mediated transcriptional control, as it increases following REST downregulation. The SRRM3-dependent regulation of REST 003 processing into ncRNAs has many similarities to recently described promoter associated small RNA-like processes. Targeting ncRNAs that control invasiveness could lead to new therapeutic approaches to limit breast cancer metastasis. PMID- 26053434 TI - Biorealistic cardiac cell culture platforms with integrated monitoring of extracellular action potentials. AB - Current platforms for in vitro drug development utilize confluent, unorganized monolayers of heart cells to study the effect on action potential propagation. However, standard cell cultures are of limited use in cardiac research, as they do not preserve important structural and functional properties of the myocardium. Here we present a method to integrate a scaffolding technology with multi electrode arrays and deliver a compact, off-the-shelf monitoring platform for growing biomimetic cardiac tissue. Our approach produces anisotropic cultures with conduction velocity (CV) profiles that closer resemble native heart tissue; the fastest impulse propagation is along the long axis of the aligned cardiomyocytes (CVL) and the slowest propagation is perpendicular (CVT), in contrast to standard cultures where action potential propagates isotropically (CVL ~ CVT). The corresponding anisotropy velocity ratios (CVL/CVT = 1.38 - 2.22) are comparable with values for healthy adult rat ventricles (1.98 - 3.63). The main advantages of this approach are that (i) it provides ultimate pattern control, (ii) it is compatible with automated manufacturing steps and (iii) it is utilized through standard cell culturing protocols. Our platform is compatible with existing read-out equipment and comprises a prompt method for more reliable CV studies. PMID- 26053435 TI - Jaw myology and bite force of the monk parakeet (Aves, Psittaciformes). AB - Psittaciform birds exhibit novelties in jaw bone structure and musculature that are associated with strong bite forces. These features include an ossified arcus suborbitalis and the muscles ethmomandibularis and pseudomasseter. We analyse the jaw musculature of the monk parakeet (Myiopsitta monachus) to enable future studies aimed at understanding craniofacial development, morphology, function and evolution. We estimate bite force based on muscle dissections, physiological cross-sectional area and skull biomechanical modelling. We also compare our results with available data for other birds and traced the evolutionary origin of the three novel diagnostic traits. Our results indicate that, in Myiopsitta, (i) the arcus suborbitalis is absent and the orbit is ventrally closed by an elongate processus orbitalis and a short ligamentum suborbitale; (ii) the ethmomandibularis muscle is a conspicuous muscle with two bellies, with its origin on the anterior portion of the septum interorbitale and insertion on the medial aspect of the mandible; (iii) the pseudomasseter muscle consists of some fibers arising from the m. adductor mandibulae externus superficialis, covering the lateral surface of the arcus jugalis and attaches by an aponeurotic sheet on the processus orbitalis; (iv) a well-developed adductor mandibulae complex is present; (v) the bite force estimation relative to body mass is higher than that calculated for other non-psittaciform species; and (vi) character evolution analysis revealed that the absence of the arcus suborbitalis and the presence of the m. pseudomassseter are the ancestral conditions, and mapping is inconclusive about presence of one or two bellies of the m. ethmomandibularis. PMID- 26053436 TI - Cerebellar cavernous malformation in pediatric patients: defining clinical, neuroimaging, and therapeutic characteristics. AB - OBJECT: Cerebellar cavernous malformations (CCMs) have not been specifically described in the pediatric age group. Authors of this study, after considering the published literature, describe the characteristic clinical, radiological, and surgical features of CCM in children. METHOSDS: Patients younger than 18 years of age who were known to have CCM and had undergone surgery between 1992 and 2014 at the authors' institution were reviewed. Pediatric CCM cases reported in the literature (case reports and cases included in series on CMs in the pediatric age group) were also analyzed for specific features of this entity. RESULTS: Four male patients and 1 female patient (2.5-14 years of age) with CCM presented acutely with severe headache followed by cerebellar dysfunction. In all patients, neuroimaging (cranial CT and MRI) demonstrated hemorrhagic cerebellar lesions with heterogeneous T1 and T2 signal intensities and hyperintense blooming on susceptibility-weighted imaging. The lesions reached large sizes exhibiting spherical, cystic, and often "pseudotumoral" morphology. In 3 patients, developmental venous anomalies (DVAs) were found. In 4 of the 5 patients, the CCMs and hematomas were totally removed. All patients had a clinically excellent functional outcome without surgical complication and with complete resolution of their presenting symptoms. CONCLUSIONS: Cerebellar CMs occur in all pediatric age groups and display characteristic clinical and imaging features. In children, CCMs reach large sizes and can result in massive hemorrhage, often leading to a possible diagnosis of hemorrhage into a tumor. An associated DVA is quite common. Surgery is a safe and efficient treatment option with excellent outcomes in patients. PMID- 26053437 TI - Treatment by Therapeutic Magnetic Resonance (TMRTM) increases fibroblastic activity and keratinocyte differentiation in an in vitro model of 3D artificial skin. AB - This study investigated the effect of extremely low-frequency pulsed electromagnetic fields (PEMFs) on skin wound healing in an in vitro dermal-like tissue. In this study, fibroblast and endothelial cells were utilized for the in vitro reconstruction of dermal-like tissues treated for various times up to 21 days with PEMFs. The effects of PEMFs on cell proliferation (MTT test), cell ageing (beta-galactosidase test, ROS production), gene expression, the quality of the extracellular matrix and the amount of fibroblast growth factors were analysed. The high quality of the dermis products in the presence of PEMFs at the end of the study was confirmed through the high degree of organization of keratinocytes, which were subsequently seeded on the aforementioned in vitro reconstructed dermis. The cells organized themselves in well-defined multi-layers and were better organized compared with the epidermis present on the dermis that was obtained without PEMF treatment. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26053438 TI - Phase Modulation in Rydberg Dressed Multi-Wave Mixing processes. AB - We study the enhancement and suppression of different multi-waving mixing (MWM) processes in a Rydberg-EIT rubidium vapor system both theoretically and experimentally. The nonlinear dispersion property of hot rubidium atoms is modulated by the Rydberg-Rydberg interaction, which can result in a nonlinear phase shift of the relative phase between dark and bright states. Such Rydberg induced nonlinear phase shift can be quantitatively estimated by the lineshape asymmetry in the enhancedand suppressed MWM processes, which can also demonstrate the cooperative atom-light interaction caused by Rydberg blockaded regime. Current study on phase shift is applicable to phase-sensitive detection and the study of strong Rydberg-Rydberg interaction. PMID- 26053439 TI - Robust Performance of Marginal Pacific Coral Reef Habitats in Future Climate Scenarios. AB - Coral reef ecosystems are under dual threat from climate change. Increasing sea surface temperatures and thermal stress create environmental limits at low latitudes, and decreasing aragonite saturation state creates environmental limits at high latitudes. This study examines the response of unique coral reef habitats to climate change in the remote Pacific, using the National Center for Atmospheric Research Community Earth System Model version 1 alongside the species distribution algorithm Maxent. Narrow ranges of physico-chemical variables are used to define unique coral habitats and their performance is tested in future climate scenarios. General loss of coral reef habitat is expected in future climate scenarios and has been shown in previous studies. This study found exactly that for most of the predominant physico-chemical environments. However, certain coral reef habitats considered marginal today at high latitude, along the equator and in the eastern tropical Pacific were found to be quite robust in climate change scenarios. Furthermore, an environmental coral reef refuge previously identified in the central south Pacific near French Polynesia was further reinforced. Studying the response of specific habitats showed that the prevailing conditions of this refuge during the 20th century shift to a new set of conditions, more characteristic of higher latitude coral reefs in the 20th century, in future climate scenarios projected to 2100. PMID- 26053442 TI - A New Association Between Castleman Disease and Immune-Mediated Cerebellitis. PMID- 26053443 TI - Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease. PMID- 26053444 TI - Glucocerebrosidase Gene Mutation and Preclinical Markers of Parkinson Disease Reply. PMID- 26053445 TI - Diagnosing Encephalitis, Not Otherwise Specified. PMID- 26053446 TI - Diagnosing Encephalitis, Not Otherwise Specified. PMID- 26053447 TI - Diagnosing Encephalitis, Not Otherwise Specified-Reply. PMID- 26053448 TI - In Memoriam: Jean Lindenmann (1924-2015): A Circuitous Interfering Power in Neurology. PMID- 26053449 TI - Are Meteorological Conditions within the First Trimester of Pregnancy Associated with the Risk of Severe Pre-Eclampsia? AB - BACKGROUND: Severe pre-eclampsia (SPE) is the second cause of maternal death in developed countries. The literature suggests different risk factors for early- and late-onset pre-eclampsia. SPE is usually related to the early-onset type. Pre eclampsia rate exhibits seasonal variation. However, the weather-SPE association is still unknown. We examined the associations between maternal exposure to meteorological parameters after conception and SPE. METHODS: From 2008 to 2011, all deliveries of women living in the Yvelines area, France, have been prospectively registered. Meteorological measurements from weather stations scattered inside Yvelines were averaged on two exposure windows: early-pregnancy (30 days after conception) and first-trimester (90 days after conception). The relationship between SPE and season of conception was also examined. Hierarchical complementary log-log regression models were used to estimate the weather-SPE association. RESULTS: SPE was diagnosed in 526 (0.8%) out of 63,633 singleton pregnancies. Increasing temperature or sunshine across both windows was associated with increased SPE risk. Early-pregnancy minimum temperature showed the strongest effect with adjusted odds ratio (OR) per 1 degree Celsius: 1.03 [95% confidence interval (CI) 1.01, 1.04]. The risk of SPE was higher when conception was in summer as compared to winter (OR 1.53, 95% CI 1.27, 1.85). Effect estimates showed only small variations in sensitivity analyses. CONCLUSIONS: Our findings of a weather impact during early pregnancy on SPE may provide a new clue for understanding the causes of pre-eclampsia. Further investigation into the biologic mechanisms for this finding is required. PMID- 26053455 TI - Noninvasive Ventilation With vs Without Early Surfactant to Prevent Chronic Lung Disease in Preterm Infants: A Systematic Review and Meta-analysis. AB - IMPORTANCE: Controversy exists regarding which of the 2 major strategies currently used to prevent chronic lung disease (CLD) in preterm infants is optimal: noninvasive continuous positive airway pressure (NCPAP) or intubate surfactant-extubate (INSURE). Preterm infants often require surfactant administration because of respiratory distress syndrome. OBJECTIVE: To evaluate whether early INSURE or NCPAP alone is more effective in preventing CLD, death, or both. DATA SOURCES: We searched the MEDLINE, EMBASE, Cochrane Controlled Trials Register, and Cumulative Index to Nursing and Allied Health Literature databases from their inception to January 2, 2015, along with conference proceedings and trial registrations. STUDY SELECTION: Randomized clinical trials that compared early INSURE with NCPAP alone in preterm infants who had never been intubated before the study entry were selected. Among 1761 initially identified articles, 9 trials (1551 infants) were included. DATA EXTRACTION AND SYNTHESIS: Duplicate study selection and data extraction were performed. Meta-analysis was conducted using random-effects models with quality-of-evidence assessment according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. MAIN OUTCOMES AND MEASURES: Seven main outcomes were selected a priori to be assessed according to GRADE, including a composite outcome of CLD and/or death, CLD alone, death alone, air leakage, severe intraventricular hemorrhage, neurodevelopmental impairment, and a composite outcome of death and/or neurodevelopmental impairment. RESULTS: There were no statistically significant differences between early INSURE and NCPAP alone for all outcomes assessed. However, the relative risk (RR) estimates appeared to favor early INSURE over NCPAP alone, with a 12% RR reduction in CLD and/or death (RR, 0.88; 95% CI, 0.76-1.02; risk difference [RD], -0.04; 95% CI, -0.08 to 0.01; moderate quality of evidence), a 14% decrease in CLD (RR, 0.86; 95% CI, 0.71 1.03; RD, -0.03; 95% CI, -0.06 to 0.01; moderate quality of evidence), and a 50% decrease in air leakage (RR, 0.50; 95% CI, 0.24-1.07; RD, -0.03; 95% CI, -0.06 to 0.00; very low quality of evidence). The sample size was less than the optimal information size. CONCLUSIONS AND RELEVANCE: Currently, no evidence suggests that either early INSURE or NCPAP alone is superior to the other. INSURE does not appear to increase CLD and/or death, CLD alone, and air leakage and may reduce these adverse outcomes compared with NCPAP alone. Further adequately powered trials are required. PMID- 26053456 TI - A New Method for Direct Three-Dimensional Measurement of Left Atrial Appendage Dimensions during Transesophageal Echocardiography. AB - AIMS: Currently, two-dimensional transesophageal echocardiography (2DTEE) at a cut-plane angulation of 135 degrees is the recommended method to size maximal left atrial appendage (LAA) orifice diameter before introducing a percutaneous LAA closure device. We compared real time three-dimensional TEE (RT3DTEE) and 2DTEE for measuring LAA dimensions versus computed tomography (CT) as gold standard. METHODS AND RESULTS: We prospectively studied 30 consecutive patients who underwent a routine TEE examination, using QLAB 10.0 Application on EPIQ7 iE33 3D echo machine between December 2012 and December 2013. All patients underwent 64-slice CT before pulmonary vein isolation or for workup of pulmonary embolism. LAA measurements were compared between 135 2DTEE and RT3DTEE. Results were compared with CT measurements. Using RT3DTEE, larger LAA diameters were measured versus 2DTEE (23.5 +/- 3.9 vs. 24.5 +/- 4.7 mm). In seven patients (23.3%), the measurements in 135 degrees 2DTEE were smaller than the cut-plane angulation with maximal orifice diameter. RT3DTEE measurements of LAA were not different from CT regarding number of lobes, area of orifice, and maximal diameter. LAA volume could not be measured directly using RT3DTEE. No difference was found between LAA depth using RT3DTEE (19.5 +/- 2.3 mm) vs. CT (19.6 +/- 2.3, P = NS) and 2DTEE (19.4 +/- 2.2 mm) vs. CT (P = NS). However, RT3DTEE (24.5 +/- 4.7 mm) vs. CT (24.6 +/- 5, P = NS) was more accurate in measuring maximal LAA diameter compared to 2DTEE (23.5 +/- 3.9 mm) vs. CT (P < 0.01). CONCLUSION: RT3DTEE method is more accurate than 2DTEE for assessment of maximal LAA orifice diameter. Bedsides, RT3DTEE LAA measurements are not statistically different from CT. Thus, RT3DTEE may facilitate LAA closure procedure by choosing the appropriate device size. PMID- 26053457 TI - Association between in-hospital adverse events and mortality for patients with brain tumors. AB - OBJECT: The Agency for Healthcare Research and Quality patient safety indicators (PSIs) and the Centers for Medicare and Medicaid Services hospital-acquired conditions (HACs) are administrative data-based metrics. The use of these outcomes as standard performance measures has been discussed in previous studies. With the objective of determining the applicability of these events as performance metrics among patients undergoing brain tumor surgery, this study had 2 aims: 1) to evaluate the association between PSIs, HACs, and in-hospital mortality rates; and 2) to determine a correlation between hospital volume, PSIs, and HACs. METHODS: Patients with brain tumors treated between 1998 and 2009 were captured in the Nationwide Inpatient Sample database. Hospitals were categorized into groups according to surgical volume. Associations between PSIs, HACs, and in hospital mortality rates were studied. Factors associated with a PSI, HAC, and mortality were evaluated in a multivariate setting. RESULTS: A total of 444,751 patients with brain tumors underwent surgery in 1311 hospitals nationwide. Of these, 7.4% of patients experienced a PSI, 0.4% an HAC, and 1.9% died during their hospitalization. The occurrence of a PSI was strongly associated with mortality. Patients were 7.6 times more likely to die (adjusted odds ratio [aOR] 7.6, CI 6.7-8.7) with the occurrence of a PSI in a multivariate analysis. Moderate to strong associations were found between HACs, PSIs, and hospital volume. Patients treated at the highest-volume hospitals compared with the lowest volume ones had reduced odds of a PSI (aOR 0.9, CI 0.8-1.0) and HAC (aOR 0.5, CI 0.5-0.08). CONCLUSIONS: Patient safety-related adverse events were strongly associated with in-hospital mortality. Moderate to strong correlations were found between PSIs, HACs, and hospital procedural volume. Patients treated at the highest-volume hospitals had consistently lower rates of mortality, PSIs, and HACs compared with those treated at the lowest-volume facilities. PMID- 26053459 TI - Paroxysmal cold hemoglobinuria due to an IgA Donath-Landsteiner antibody. AB - Paroxysmal cold hemoglobinuria (PCH) is an autoimmune hemolytic anemia (AIHA) characterized by the presence of a Donath-Landsteiner (D-L) antibody. PCH occurs most commonly in young children and is associated with acute, often self-limited hemolytic anemia. The D-L antibody is classically a biphasic IgG anti-P autoantibody identified by the D-L test. Rare case reports confirm the existence of IgM D-L antibodies. We report the case of a 2-year-old male diagnosed with acute AIHA and found to have PCH caused by an IgA D-L antibody. The clinical course and treatment of this condition, which has not been reported previously, are described. PMID- 26053458 TI - Novel PI3K/AKT targeting anti-angiogenic activities of 4-vinylphenol, a new therapeutic potential of a well-known styrene metabolite. AB - The pneumo- and hepato-toxicity of 4-vinylphenol (4VP), a styrene metabolite, has been previously reported. Nevertheless, the present study reported the novel anti angiogenic activities of 4VP which was firstly isolated from the aqueous extract of a Chinese medicinal herb Hedyotis diffusa. Our results showed that 4VP at non toxic dose effectively suppressed migration, tube formation, adhesion to extracellular matrix proteins, as well as protein and mRNA expressions of metalloproteinase-2 of human endothelial cells (HUVEC and HMEC-1). Investigation of the signal transduction revealed that 4VP down-regulated PI3K/AKT and p38 MAPK. Besides, 4VP interfered with the phosphorylation of ERK1/2, the translocation and expression of NFkappaB. In zebrafish embryo model, the new blood vessel growth was significantly blocked by 4VP (6.25-12.5 MUg/mL medium). The VEGF-induced blood vessel formation in Matrigel plugs in C57BL/6 mice was suppressed by 4VP (20-100 MUg/mL matrigel). In addition, the blood vessel number and tumor size were reduced by intraperitoneal 4VP (0.2-2 mg/kg) in 4T1 breast tumor-bearing BALB/c mice, with doxorubicin as positive control. Together, the in vitro and in vivo anti-angiogenic activities of 4VP were demonstrated for the first time. These findings suggest that 4VP has great potential to be further developed as an anti-angiogenic agent. PMID- 26053460 TI - BAHD or SCPL acyltransferase? What a dilemma for acylation in the world of plant phenolic compounds. AB - Phenolic compounds are secondary metabolites involved in several plant growth and development processes, including resistance to biotic and abiotic stresses. The biosynthetic pathways leading to the vast diversity of plant phenolic products often include an acylation step, with phenolic compounds being the donor or acceptor molecules. To date, two acyltransferase families using phenolic compounds as acceptor or donor molecules have been described, with each using a different 'energy-rich' acyl donor. BAHD-acyltransferases, named after the first four biochemically characterized enzymes of the group, use acyl-CoA thioesters as donor molecules, whereas SCPL (Serine CarboxyPeptidase Like)-acyltransferases use 1-O-beta-glucose esters. Here, common and divergent specifications found in the literature for both enzyme families were analyzed to answer the following questions. Are both acyltransferases involved in the synthesis of the same molecule (or same group of molecules)? Are both acyltransferases recruited in the same plant? How does the subcellular localization of these enzymes impact metabolite trafficking in plant cells? PMID- 26053461 TI - Assessment of acute kidney injury at hospital admission in cirrhosis: estimating baseline serum creatinine is not the answer. PMID- 26053462 TI - Fostering a Quality of Care Culture in Community-Based Palliative Care: What Will It Take? PMID- 26053463 TI - Fate of polychlorinated biphenyls in a contaminated lake ecosystem: combining equilibrium passive sampling of sediment and water with total concentration measurements of biota. AB - Equilibrium sampling devices can be applied to study and monitor the exposure and fate of hydrophobic organic chemicals on a thermodynamic basis. They can be used to determine freely dissolved concentrations and chemical activity ratios and to predict equilibrium partitioning concentrations of hydrophobic organic chemicals in biota lipids. The authors' aim was to assess the equilibrium status of polychlorinated biphenyls (PCBs) in a contaminated lake ecosystem and along its discharge course using equilibrium sampling devices for measurements in sediment and water and by also analyzing biota. The authors used equilibrium sampling devices (silicone rubber and polyethylene [PE]) to determine freely dissolved concentrations and chemical activities of PCBs in the water column and sediment porewater and calculated for both phases the corresponding equilibrium concentrations and chemical activities in model lipids. Overall, the studied ecosystem appeared to be in disequilibrium for the studied phases: sediment, water, and biota. Chemical activities of PCBs were higher in sediment than in water, which implies that the sediment functioned as a partitioning source of PCBs and that net diffusion occurred from the sediment to the water column. Measured lipid-normalized PCB concentrations in biota were generally below equilibrium lipid concentrations relative to the sediment (CLip ?Sed ) or water (CLip ?W ), indicating that PCB levels in the organisms were below the maximum partitioning levels. The present study shows the application versatility of equilibrium sampling devices in the field and facilitates a thermodynamic understanding of exposure and fate of PCBs in a contaminated lake and its discharge course. PMID- 26053464 TI - Determination of glucosamine and its derivatives released from photocrosslinked gelatin hydrogels using HPLC. AB - A simple, accurate and validated reverse-phase high-performance liquid chromatography (HPLC)/UV method is developed for the determination of glucosamine hydrochloride (GlcN), N-acetyl-glucosamine (NAG) and N-acryloyl-glucosamine (AGA) released from photocrosslinked gelatin hydrogels. The HPLC separation was achieved on a Shimadzu InertSustain amino column (250 * 4.6 mm, 5 um particle size) at room temperature using a mobile phase of acetonitrile-phosphate buffer (75:25, v/v, pH 6.0) at a flow rate of 1.0 mL/min and UV detection of 194 nm. The method was validated for specificity, linearity, limit of detection and quantification, accuracy, precision, extraction recovery and solution stability. The calibration curves were with excellent linearity, with correlation coefficients (R(2)) >0.999 for all three drugs. The intra- and inter-day variation was <3.10% and the relative error was between -1.43 and 1.78%. The extraction recovery results ranged from 94.62 to 99.33%, demonstrating the absence of matrix effect. The sample and standard solutions were stable for more than 2 months. The method was successfully used for the analysis of released properties of drugs physically encapsulated and chemically crosslinked in the gelatin hydrogels. PMID- 26053465 TI - A randomised clinical trial to assess satisfaction with the levonorgestrel- releasing intrauterine system inserted at caesarean section compared to postpartum placement. AB - BACKGROUND: Insertion of levonorgestrel-releasing intrauterine system (LNG-IUS) at caesarean section (CS) provides contraception prior to resumption of ovulation or sexual activity. Patient satisfaction with insertion at CS has not previously been studied. AIMS: The aim of this study was to compare patient satisfaction with LNG-IUS inserted at the time of lower uterine segment CS to six weeks postpartum. MATERIALS AND METHODS: Open-label randomised controlled trial. Women booked for elective CS were randomised to LNG-IUS insertion either at the time of CS (study group) or at six weeks postpartum (control group). The primary outcome measure was patient satisfaction. Outcomes were measured at six weeks, three months and six months postpartum. RESULTS: Forty-eight women were randomised into two treatment groups. Twenty-five women were randomised to have LNG-IUS inserted at the time of CS, 23 of whom had the planned intervention and two had the LNG IUS inserted postpartum. Twenty-three women were randomised to the control group, four of whom withdrew prior to treatment. The 44 remaining women contributed to data analysis. Patient satisfaction was high and similar in both groups. At six months postpartum, 90.5% of the study group were very satisfied or somewhat satisfied compared with 88.2% of the control group. CONCLUSIONS: Patient satisfaction is high with LNG-IUS insertion at CS and not different to that with delayed insertion. LNG-IUS insertion may be an option for women who find postpartum contraception difficult to access. PMID- 26053466 TI - Professional Demands and Job Satisfaction in Orthopaedic Trauma: An OTA Member Survey. AB - OBJECTIVES: The goal of this study was to examine the factors that affect career satisfaction in orthopaedic traumatologists. We hypothesize that the level of stress and career satisfaction in orthopaedic traumatology would be affected by increased number of call nights and work hours. DATA SOURCES: A 30-question survey was emailed to members of the OTA. The survey evaluated 5 critical areas: training/experience, practice characteristics, demands, stress management strategies, and satisfaction. STUDY SELECTION: After approval by the OTA research committee, all active and associate US members of the OTA were contacted. DATA EXTRACTION: The survey was open to the OTA members from July through November of 2012. DATA SYNTHESIS: Of 1031 members of the OTA, 263 members responded for an overall response rate of 25.5%. Most respondents were fellowship-trained (218, 82.9%) and predominantly young (<5 years in practice, 34.4%) or established surgeons (>15 years in practice, 28.5%). Most surgeons were married (229, 87.1%) and have not been divorced (226, 85.9%). Career satisfaction was statistically improved by belonging to larger practice (P = 0.016), decreased by work for more hours per week (P = 0.001), and improved by taking more call (P = 0.014). CONCLUSIONS: Career satisfaction among orthopaedic trauma surgeons was extremely high. Our results indicate that young surgeons may improve their job satisfaction and potentially prolong their career by limiting the numbers of hours worked, taking a consistent number of calls and joining a larger group. LEVEL OF EVIDENCE: Prognostic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 26053470 TI - A new phase of phosphorus: the missed tricycle type red phosphorene. AB - We predict a new two-dimensional allotrope of phosphorus, which we call red phosphorene, by restructuring the segments of the previously proposed blue and black phosphorenes. Its atomic and electronic structures as well as the thermodynamic and dynamic stabilities are systematically studied by first principles calculations. The results indicate that the red phosphorene is dynamically stable and possesses remarkably thermodynamical stability comparable to that of the black one. Because of the sp(3)-hybridization and the formation of a localized lone pair, red phosphorene is a semiconductor with an indirect band gap of about 1.96 eV, which can be effectively modulated by in-plane strains due to its wave-like configuration. We find that the red, black and blue phosphorenes show evident distinction in their layer thicknesses, surface work functions, and possible colors, based on which one can distinguish them in future experiments. PMID- 26053467 TI - Tangential Bicortical Locked Fixation Improves Stability in Vancouver B1 Periprosthetic Femur Fractures: A Biomechanical Study. AB - OBJECTIVES: The biomechanical difficulty in fixation of a Vancouver B1 periprosthetic fracture is purchase of the proximal femoral segment in the presence of the hip stem. Several newer technologies provide the ability to place bicortical locking screws tangential to the hip stem with much longer lengths of screw purchase compared with unicortical screws. This biomechanical study compares the stability of 2 of these newer constructs to previous methods. METHODS: Thirty composite synthetic femurs were prepared with cemented hip stems. The distal femur segment was osteotomized, and plates were fixed proximally with either (1) cerclage cables, (2) locked unicortical screws, (3) a composite of locked screws and cables, or tangentially directed bicortical locking screws using either (4) a stainless steel locking compression plate system with a Locking Attachment Plate (Synthes) or (5) a titanium alloy Non-Contact Bridging system (Zimmer). Specimens were tested to failure in either axial or torsional quasistatic loading modes (n = 3) after 20 moderate load preconditioning cycles. Stiffness, maximum force, and failure mechanism were determined. RESULTS: Bicortical constructs resisted higher (by an average of at least 27%) maximum forces than the other 3 constructs in torsional loading (P < 0.05). Cables constructs exhibited lower maximum force than all other constructs, in both axial and torsional loading. The bicortical titanium construct was stiffer than the bicortical stainless steel construct in axial loading. CONCLUSIONS: Proximal fixation stability is likely improved with the use of bicortical locking screws as compared with traditional unicortical screws and cable techniques. In this study with a limited sample size, we found the addition of cerclage cables to unicortical screws may not offer much improvement in biomechanical stability of unstable B1 fractures. PMID- 26053471 TI - A Molecular Dynamics Study on Controlling the Self-Assembly of beta-Sheet Peptides with Designer Nanorings. AB - Recently, a rational approach for constructing beta-barrel protein mimics by the self-assembly of peptide-based building blocks has been demonstrated. We performed molecular dynamics simulations of nanoring formation by means of the self-assembly of designed beta-sheet-forming peptides. Several factors contributing to the stability of the nanoring structures with respect to size were investigated. Our simulations predicted that an optimal nanoring size may be achieved by minimizing repulsions due to steric hindrance between bulky groups while maintaining favorable hydrogen-bond interactions between neighboring beta sheet chains. It was shown that mutations in a test peptide, in which all or half of the tryptophan residues were replaced by phenylalanine, could enable the assembly of stable nanoring structures with smaller pore sizes. Insights into the fundamental factors driving the formation of peptide-based nanostructures are expected to facilitate the design of novel functional bionanostructures. PMID- 26053472 TI - Placental volume and uterine artery Doppler evaluation at 11 + 0 to 13 + 6 weeks' gestation in pregnancies conceived with in-vitro fertilization: comparison between autologous and donor oocyte recipients. AB - OBJECTIVE: To compare first-trimester uterine artery pulsatility index (UtA-PI) and three-dimensional (3D) placental volume in pregnancies conceived through in vitro fertilization (IVF) using autologous or donor oocytes and pregnancies conceived naturally, and to relate these measurements to the development of pre eclampsia (PE). METHODS: UtA-PI and placental volume were measured at 11 + 0 to 13 + 6 weeks of gestation in 416 IVF pregnancies (307 with autologous and 109 with donor oocytes) and in 498 spontaneously conceived pregnancies. We recruited nulliparous women with singleton pregnancy. The measured mean UtA-PI and placental volume values were converted to multiples of the expected normal median (MoM), adjusted for gestational age. MoM values of IVF pregnancies were compared with MoM values of the naturally conceived pregnancies and related to PE development. RESULTS: Placental volume was significantly reduced in IVF pregnancies (K = 169.3; P < 0.0001) compared with natural pregnancies. No difference was found in UtA-PI MoM between the two groups. Among IVF pregnancies, significantly lower placental volumes were seen in those that received donor oocytes when compared with those with autologous oocytes (z = 3.89; P < 0.001). In IVF pregnancies that developed PE, lower values of placental volume were demonstrated with respect to normotensive pregnancies (donor: U = 6.8; P = 0.009; autologous: U = 5.1; P = 0.023), whereas no difference was found in UtA-PI. Multivariate logistic regression analysis demonstrated that placental volume (odds ratio (OR), 1.97 (95% CI, 1.33-2.27)) and donor oocytes in IVF pregnancy (OR, 2.24 (95% CI, 1.5-2.83)) were independent predictors of PE, whereas autologous oocytes in IVF pregnancy were not found to be significant in the model. CONCLUSIONS: First-trimester placental volume, as assessed by 3D ultrasound, is reduced in IVF pregnancies and this reduction is more marked in those involving donor oocyte recipients. The relative decrease in placental volume in IVF pregnancies that developed PE suggests an etiological mechanism different from uterine perfusion in such patients. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26053473 TI - Matching Solid-State to Solution-Phase Photoluminescence for Near-Unity Down Conversion Efficiency Using Giant Quantum Dots. AB - Efficient, stable, and narrowband red-emitting fluorophores are needed as down conversion materials for next-generation solid-state lighting that is both efficient and of high color quality. Semiconductor quantum dots (QDs) are nearly ideal color-shifting phosphors, but solution-phase efficiencies have not traditionally extended to the solid-state, with losses from both intrinsic and environmental effects. Here, we assess the impacts of temperature and flux on QD phosphor performance. By controlling QD core/shell structure, we realize near unity down-conversion efficiency and enhanced operational stability. Furthermore, we show that a simple modification of the phosphor-coated light-emitting diode device-incorporation of a thin spacer layer-can afford reduced thermal or photon flux quenching at high driving currents (>200 mA). PMID- 26053474 TI - Pros and Cons of Opioids and Prediction of Sustained Use Provides Long-awaited Answers With Clarity. PMID- 26053475 TI - Self-immolative spacers: kinetic aspects, structure-property relationships, and applications. AB - Self-immolative spacers are covalent assemblies tailored to correlate the cleavage of two chemical bonds after activation of a protective part in a precursor: Upon stimulation, the protective moiety is removed, which generates a cascade of disassembling reactions leading to the temporally sequential release of smaller molecules. Originally introduced to overcome limitations for drug delivery, self-immolative spacers have gained wide interest in medicinal chemistry, analytical chemistry, and material science. For most applications, the kinetics of the disassembly of the activated self-immolative spacer governs functional properties. This Review addresses kinetic aspects of self-immolation. It provides information for selecting a particular self-immolative motif for a specific demand. Moreover, it should help researchers design kinetic experiments and fully exploit the rich perspectives of self-immolative spacers. PMID- 26053476 TI - H Rodney Withers (1932-2015). PMID- 26053477 TI - Prognostic role of FDG-PET/CT in differentiated thyroid carcinoma: Where are we now? PMID- 26053478 TI - Hemithoracic radiation therapy after extrapleural pneumonectomy for malignant pleural mesothelioma: Applicable to all and by all? PMID- 26053480 TI - Merkel Cell Carcinoma Analysis of Outcomes: A 30-Year Experience. AB - BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with poor prognosis. Limited data exists to guide treatment decisions. Here we report on our institutional experience and outcomes treating patients with MCC. METHODS: A database search (1984-2014) of patients treated at the University of Wisconsin Hospital and Clinics was used to identify patients with histologically confirmed MCC. Patient, tumor, and treatment characteristics were examined via review of medical records. Statistical analyses were performed to assess outcomes and associated prognostic factors. RESULTS: A total of 87 patients with MCC were identified with a median follow-up of 17 months (mean: 38, range: 0-210 months). Two and five-year overall survival rates were 53.9% and 32.8%, respectively. Recurrence was documented in 31.0% of patients (85.2% locoregional, 48.1% distant and 33.3% both). Patients with a history of immunosuppression exhibited significantly worse survival (hazard ratio, 2.01; 95% CI, 1.1-3.7) when compared to immune-competent individuals. The head and neck region was the most common location of primary lesion (N=49) followed by the extremities (N=31). Upper extremity primaries predicted significantly better overall survival (hazard ratio, 0.48; 95% CI, 0.23-0.99) while lower extremity primaries did not have significantly better results (hazard ratio, 0.5; 95% CI, 0.21-1.2) in comparison to head and neck site of primary. Nodal involvement (hazard ratio, 2.95; 95% CI, 1.5-5.79) was also a negative prognostic factor associated with poor overall survival when compared with clinically node negative patients. Primary tumor size > 2 cm (hazard ratio, 1.76; 95% CI, 0.91-3.4) was not associated with survival. CONCLUSIONS: This study highlights the role of various factors in determining prognosis of Merkel cell carcinoma; history of immunosuppression, nodal involvement, and head/neck primary predicted worse overall survival. These findings suggest that improvements in both distant and locoregionally directed therapies might play an important role in control of MCC and identify areas for future study. PMID- 26053481 TI - Adherence with Dosing Guideline in Patients with Impaired Renal Function at Hospital Discharge. AB - OBJECTIVES: To determine the prevalence, determinants, and potential clinical relevance of adherence with the Dutch dosing guideline in patients with impaired renal function at hospital discharge. DESIGN: Retrospective cohort study between January 2007 and July 2011. SETTING: Academic teaching hospital in the Netherlands. SUBJECTS: Patients with an estimated glomerular filtration rate (eGFR) between 10-50 ml/min/1.73 m(2) at discharge and prescribed one or more medicines of which the dose is renal function dependent. MAIN OUTCOME MEASURES: The prevalence of adherence with the Dutch renal dosing guideline was investigated, and the influence of possible determinants, such as reporting the eGFR and severity of renal impairment (severe: eGFR<30 and moderate: eGFR 30-50 ml/min/1.73 m(2)). Furthermore, the potential clinical relevance of non-adherence was assessed. RESULTS: 1327 patients were included, mean age 67 years, mean eGFR 38 ml/min/1.73 m(2). Adherence with the guideline was present in 53.9% (n=715) of patients. Reporting the eGFR, which was incorporated since April 2009, resulted in more adherence with the guideline: 50.7% vs. 57.0%, RR 1.12 (95% CI 1.02 1.25). Adherence was less in patients with severe renal impairment (46.0%), compared to patients with moderate renal impairment (58.1%, RR 0.79; 95% CI 0.70 0.89). 71.4% of the cases of non-adherence had the potential to cause moderate to severe harm. CONCLUSION: Required dosage adjustments in case of impaired renal function are often not performed at hospital discharge, which may cause harm to the majority of patients. Reporting the eGFR can be a small and simple first step to improve adherence with dosing guidelines. PMID- 26053482 TI - Advanced allied health assistants: an emerging workforce. AB - OBJECTIVE: Nationally and internationally there is work underway to continue to advance the scope of practice of allied health assistants (AHA). The advanced role requires additional training and competency development, as well as significant clinical experience. To build on the evidence relating to advanced scope AHAs, ACT Health undertook a project to explore the potential for the development of the local AHA workforce. This paper provides an overview of the project. METHODS: The potential for advanced AHAs in the Australian Capital Territory (ACT) was assessed using literature reviews, consultation with other services working with advanced AHAs and interviews with local allied health managers and assistants. RESULTS: A role for advanced AHAs within the ACT workforce was recommended, along with the need to further develop the AHA governance structure and AHA training packages and to undertake more research into the AHA workforce. CONCLUSION: AHAs make a positive contribution to the delivery of effective, responsive, consumer-focused healthcare. The advanced AHA role provides further opportunities to enhance the flexibility of allied health services while also providing a career structure for this growing workforce. PMID- 26053484 TI - Thermochromism and switchable paramagnetism of cobalt(II) in thiocyanate ionic liquids. AB - Temperature-dependent switching of paramagnetism of a cobalt(II) complex is observed in an ionic liquid solution. Paramagnetic and thermochromic switching occur simultaneously due to a reversible change in coordination. This reversible switching is possible in the ionic liquid solution, which enables mobility of thiocyanate anions by remaining mobile at low temperatures and acts as an anion reservoir. PMID- 26053483 TI - ROS Production via P2Y1-PKC-NOX2 Is Triggered by Extracellular ATP after Electrical Stimulation of Skeletal Muscle Cells. AB - During exercise, skeletal muscle produces reactive oxygen species (ROS) via NADPH oxidase (NOX2) while inducing cellular adaptations associated with contractile activity. The signals involved in this mechanism are still a matter of study. ATP is released from skeletal muscle during electrical stimulation and can autocrinely signal through purinergic receptors; we searched for an influence of this signal in ROS production. The aim of this work was to characterize ROS production induced by electrical stimulation and extracellular ATP. ROS production was measured using two alternative probes; chloromethyl-2,7- dichlorodihydrofluorescein diacetate or electroporation to express the hydrogen peroxide-sensitive protein Hyper. Electrical stimulation (ES) triggered a transient ROS increase in muscle fibers which was mimicked by extracellular ATP and was prevented by both carbenoxolone and suramin; antagonists of pannexin channel and purinergic receptors respectively. In addition, transient ROS increase was prevented by apyrase, an ecto-nucleotidase. MRS2365, a P2Y1 receptor agonist, induced a large signal while UTPyS (P2Y2 agonist) elicited a much smaller signal, similar to the one seen when using ATP plus MRS2179, an antagonist of P2Y1. Protein kinase C (PKC) inhibitors also blocked ES-induced ROS production. Our results indicate that physiological levels of electrical stimulation induce ROS production in skeletal muscle cells through release of extracellular ATP and activation of P2Y1 receptors. Use of selective NOX2 and PKC inhibitors suggests that ROS production induced by ES or extracellular ATP is mediated by NOX2 activated by PKC. PMID- 26053485 TI - Brown Adipose Tissue Response Dynamics: In Vivo Insights with the Voltage Sensor 18F-Fluorobenzyl Triphenyl Phosphonium. AB - Brown adipose tissue (BAT) thermogenesis is an emerging target for prevention and treatment of obesity. Mitochondria are the heat generators of BAT. Yet, there is no noninvasive means to image the temporal dynamics of the mitochondrial activity in BAT in vivo. Here, we report a technology for quantitative monitoring of principal kinetic components of BAT adaptive thermogenesis in the living animal, using the PET imaging voltage sensor 18F-fluorobenzyltriphenylphosphonium (18F FBnTP). 18F-FBnTP targets the mitochondrial membrane potential (DeltaPsim)--the voltage analog of heat produced by mitochondria. Dynamic 18F-FBnTP PET imaging of rat's BAT was acquired just before and during localized skin cooling or systemic pharmacologic stimulation, with and without administration of propranolol. At ambient temperature, 18F-FBnTP demonstrated rapid uptake and prolonged steady state retention in BAT. Conversely, cold-induced mitochondrial uncoupling resulted in an immediate washout of 18F-FBnTP from BAT, which was blocked by propranolol. Specific variables of BAT evoked activity were identified and quantified, including response latency, magnitude and kinetics. Cold stimulation resulted in partial washout of 18F-FBnTP (39.1%+/-14.4% of basal activity). The bulk of 18F-FBnTP washout response occurred within the first minutes of the cold stimulation, while colonic temperature remained nearly intact. Drop of colonic temperature to shivering zone did not have an additive effect. The beta3 adrenergic agonist CL-316,243 elicited 18F-FBnTP washout from BAT of kinetics similar to those caused by cold stimulation. Thus, monitoring DeltaPsim in vivo using 18F-FBnTP PET provides insights into the kinetic physiology of BAT. 18F FBnTP PET depicts BAT as a highly sensitive and rapidly responsive organ, emitting heat in short burst during the first minutes of stimulation, and preceding change in core temperature. 18F-FBnTP PET provides a novel set of quantitative metrics highly important for identifying novel therapeutic targets at the mitochondrial level, for developing means to maximize BAT mass and activity, and assessing intervention efficacy. PMID- 26053487 TI - Searching for Joy in Residency by Listening to Our Patients. PMID- 26053486 TI - Podocalyxin Is a Marker of Poor Prognosis in Pancreatic Ductal Adenocarcinoma. AB - AIM OF THE STUDY: Podocalyxin-like 1 is a transmembrane glyco-protein whose overexpression associates in many cancers with poor prognosis and unfavorable clinicopathological characteristics. Until now, its prognostic value has never been studied in pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to investigate podocalyxin expression in PDAC by a novel monoclonal antibody and a commercially available polyclonal antibody. PATIENTS AND MATERIALS: With tissue microarrays and immuno-histochemistry, podocalyxin expression evaluation involved 168 PDAC patients. The associations of the podocalyxin tumor expression with clinicopathological variables were explored by Fisher's exact test and the linear-by-linear test. Survival analyses were by Kaplan-Meier analysis and the Cox proportional hazard model. RESULTS: The polyclonal antibody revealed membranous podocalyxin expression in 73 (44.0%) specimens and the monoclonal antibody was highly expressed in 36 (21.8%) cases. Membranous expression by the polyclonal antibody was associated with T classification (p=0.045) and perineural invasion (p=0.005), and high expression by the mono-clonal antibody with poor differentiation (p=0.033). High podocalyxin expression associated significantly with higher risk of death from PDAC by both the polyclonal antibody (hazard ratio (HR) = 1.62; 95% confidence interval (CI) 1.12-2.33; p=0.01) and the monoclonal antibody (HR = 2.10, 95% CI 1.38-3.20; p<0.001). The results remained significant in multivariate analysis, adjusted for age, gender, stage, lymph node ratio (>=/< 20%), and perivascular invasion (respectively as HR = 2.03; 95% CI 1.32-3.13, p=0.001; and as HR = 2.36; 95% CI 1.47-3.80, p<0.001). CONCLUSION: We found podocalyxin to be an independent factor for poor prognosis in PDAC. To our knowledge, this is the first such report of its prognostic value. PMID- 26053488 TI - Overview of Methods for the Direct Molar Mass Determination of Cellulose. AB - The purpose of this article is to provide the reader with an overview of the methods used to determine the molecular weights of cellulose. Methods that employ direct dissolution of the cellulose polymer are described; hence methods for investigating the molecular weight of cellulose in derivatized states, such as ethers or esters, only form a minor part of this review. Many of the methods described are primarily of historical interest since they have no use in modern cellulose chemistry. However, older methods, such as osmometry or ultracentrifuge experiments, were the first analytical methods used in polymer chemistry and continue to serve as sources of fundamental information (such as the cellulose structure in solution). The first part of the paper reviews methods, either absolute or relative, for the estimation of average molecular weights. Regardless of an absolute or relative approach, the outcome is a molecular weight average (MWA). In the final section, coupling methods are described. The primary benefit of performing a pre-separation step on the molecules is the discovery of the molecular weight distribution (MWD). Here, size exclusion chromatography (SEC) is unquestionably the most powerful and most commonly-applied method in modern laboratories and industrial settings. PMID- 26053489 TI - Discovery of Novel Small Molecule Anti-HCV Agents via the CypA Inhibitory Mechanism Using O-Acylation-Directed Lead Optimization. AB - In this work, the relationship between cyclophilin A (CypA) and HCV prompted us to screen a series of small molecule CypA inhibitors which were previously reported by our group. Among them, compound 1, discovered as a non immunosuppressive anti-HCV agent with an EC50 value of 0.67 MUM in a virus assay, was selected for further study. Subsequent chemical modification by O-acylation led to a novel class of molecules, among which compound 25 demonstrated the most potent anti-HCV activity in the virus assay (EC50 = 0.19 MUM), but low cytotoxicity and hERG cardiac toxicity. The following studies (a solution stability assay and a simple pharmacokinetic test together with a CypA enzyme inhibition assay) preliminarily indicated that 25 was a prodrug of 1. To the best of our knowledge, 25 is probably the most potent currently reported small molecule anti-HCV agent acting via the CypA inhibitory mechanism. Consequently, our study has provided a new potential small molecule for curing HCV infection. PMID- 26053490 TI - Biological Activity and Molecular Structures of Bis(benzimidazole) and Trithiocyanurate Complexes. AB - 1-(1H-Benzimidazol-2-yl)-N-(1H-benzimidazol-2-ylmethyl)methanamine (abb) and 2 (1H-benzimidazol-2-ylmethylsulfanylmethyl)-1H-benzimidazole (tbb) have been prepared and characterized by elemental analysis. These bis(benzimidazoles) have been further used in combination with trithiocyanuric acid for the preparation of complexes. The crystal and molecular structures of two of them have been solved. Each nickel atom in the structure of trinuclear complex [Ni3(abb)3(H2O)3(MU ttc)](ClO4)3.3H2O.EtOH (1), where ttcH3 = trithiocyanuric acid, is coordinated with three N atoms of abb, the N,S donor set of ttc anion and an oxygen of a water molecule. The crystal of [(tbbH2)(ttcH2)2(ttcH3)(H2O)] (2) is composed of a protonated bis(benzimidazole), two ttcH2 anions, ttcH3 and water. The structure is stabilized by a network of hydrogen bonds. These compounds were primarily synthesized for their potential antimicrobial activity and hence their possible use in the treatment of infections caused by bacteria or yeasts (fungi). The antimicrobial and antifungal activity of the prepared compounds have been evaluated on a wide spectrum of bacterial and yeast strains and clinical specimens isolated from patients with infectious wounds and the best antimicrobial properties were observed in strains after the use of ligand abb and complex 1, when at least 80% growth inhibition was achieved. PMID- 26053491 TI - Non-Conventional Yeasts Whole Cells as Efficient Biocatalysts for the Production of Flavors and Fragrances. AB - The rising consumer requests for natural flavors and fragrances have generated great interest in the aroma industry to seek new methods to obtain fragrance and flavor compounds naturally. An alternative and attractive route for these compounds is based on bio-transformations. In this review, the application of biocatalysis by Non Conventional Yeasts (NCYs) whole cells for the production of flavor and fragrances is illustrated by a discussion of the production of different class of compounds, namely Aldehydes, Ketones and related compounds, Alcohols, Lactones, Terpenes and Terpenoids, Alkenes, and Phenols. PMID- 26053492 TI - Corrigendum. PMID- 26053493 TI - Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma. AB - BACKGROUND AND PURPOSE: Despite surgery, radiotherapy (RT) and temozolomide (TMZ), the prognosis of glioblastoma (GBM) patients remains dismal. Normally prescribed with the aim to lower blood pressure, angiotensin-II (Ang-II) inhibitors were reported to reduce angiogenesis and tumour growth in several tumour models including one glioma. Thus whether treatment with Ang-II inhibitors could be associated with a better clinical outcome in GBM patients was investigated. METHODS: A series of 81 consecutive patients, homogeneously treated with RT and TMZ for a newly diagnosed, supratentorial GBM, were analysed. The objective of this retrospective study was to assess the impact of angiotensin converting enzyme inhibitors (ACEIs) and Ang-II receptor 1 blockers (ARBs) on functional independence, progression-free survival (PFS) and overall survival (OS). RESULTS: Amongst the 81 GBM patients analysed, 26 were already treated for high blood pressure (seven with ACEIs and 19 with ARBs). The number of patients who remained functionally independent at 6 months after RT was higher in the group of patients treated with Ang-II inhibitors compared to the other patients (85% vs. 56%, P = 0.01). In patients treated with Ang-II inhibitors, PFS was 8.7 months (vs. 7.2 months in the other patients) and OS was 16.7 months (vs. 12.9 months). The use of Ang-II inhibitors was a significant prognostic factor for both PFS (P = 0.04) and OS (P = 0.04) in multivariate analysis. CONCLUSION: Treatment with Ang-II inhibitors in combination with RT and TMZ might improve clinical outcome in GBMs. Prospective trials are needed to test this hypothesis. PMID- 26053494 TI - Recurrent somatic mutations in regulatory regions of human cancer genomes. AB - Aberrant regulation of gene expression in cancer can promote survival and proliferation of cancer cells. Here we integrate whole-genome sequencing data from The Cancer Genome Atlas (TCGA) for 436 patients from 8 cancer subtypes with ENCODE and other regulatory annotations to identify point mutations in regulatory regions. We find evidence for positive selection of mutations in transcription factor binding sites, consistent with these sites regulating important cancer cell functions. Using a new method that adjusts for sample- and genomic locus specific mutation rates, we identify recurrently mutated sites across individuals with cancer. Mutated regulatory sites include known sites in the TERT promoter and many new sites, including a subset in proximity to cancer-related genes. In reporter assays, two new sites display decreased enhancer activity upon mutation. These data demonstrate that many regulatory regions contain mutations under selective pressure and suggest a greater role for regulatory mutations in cancer than previously appreciated. PMID- 26053495 TI - Statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls. AB - Determining whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders. Colocalization methods disentangle shared and distinct causal variants. However, existing approaches require independent data sets. Here we extend two colocalization methods to allow for the shared-control design commonly used in comparison of genome-wide association study results across diseases. Our analysis of four autoimmune diseases--type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis--identified 90 regions that were associated with at least one disease, 33 (37%) of which were associated with 2 or more disorders. Nevertheless, for 14 of these 33 shared regions, there was evidence that the causal variants differed. We identified new disease associations in 11 regions previously associated with one or more of the other 3 disorders. Four of eight T1D-specific regions contained known type 2 diabetes (T2D) candidate genes (COBL, GLIS3, RNLS and BCAR1), suggesting a shared cellular etiology. PMID- 26053496 TI - CTCF/cohesin-binding sites are frequently mutated in cancer. AB - Cohesin is present in almost all active enhancer regions, where it is associated with transcription factors. Cohesin frequently colocalizes with CTCF (CCCTC binding factor), affecting genomic stability, expression and epigenetic homeostasis. Cohesin subunits are mutated in cancer, but CTCF/cohesin-binding sites (CBSs) in DNA have not been examined for mutations. Here we report frequent mutations at CBSs in cancers displaying a mutational signature where mutations in A*T base pairs predominate. Integration of whole-genome sequencing data from 213 colorectal cancer (CRC) samples and chromatin immunoprecipitation sequencing (ChIP-exo) data identified frequent point mutations at CBSs. In contrast, CRCs showing an ultramutator phenotype caused by defects in the exonuclease domain of DNA polymerase E (POLE) displayed significantly fewer mutations at and adjacent to CBSs. Analysis of public data showed that multiple cancer types accumulate CBS mutations. CBSs are a major mutational hotspot in the noncoding cancer genome. PMID- 26053497 TI - Variation in NRT1.1B contributes to nitrate-use divergence between rice subspecies. AB - Asian cultivated rice (Oryza sativa L.) consists of two main subspecies, indica and japonica. Indica has higher nitrate-absorption activity than japonica, but the molecular mechanisms underlying that activity remain elusive. Here we show that variation in a nitrate-transporter gene, NRT1.1B (OsNPF6.5), may contribute to this divergence in nitrate use. Phylogenetic analysis revealed that NRT1.1B diverges between indica and japonica. NRT1.1B-indica variation was associated with enhanced nitrate uptake and root-to-shoot transport and upregulated expression of nitrate-responsive genes. The selection signature of NRT1.1B-indica suggests that nitrate-use divergence occurred during rice domestication. Notably, field tests with near-isogenic and transgenic lines confirmed that the japonica variety carrying the NRT1.1B-indica allele had significantly improved grain yield and nitrogen-use efficiency (NUE) compared to the variety without that allele. Our results show that variation in NRT1.1B largely explains nitrate-use divergence between indica and japonica and that NRT1.1B-indica can potentially improve the NUE of japonica. PMID- 26053499 TI - Treatment-Limiting Complications of Percutaneous Spinal Cord Stimulator Implants: A Review of Eight Years of Experience From an Academic Center Database. AB - OBJECTIVE: The study aims to evaluate the long-term implant survival and complications of spinal cord stimulation (SCS) leading to surgical revision or explant in patients treated for chronic noncancer pain. MATERIALS AND METHODS: This is a retrospective study of all patients who underwent a percutaneous spinal cord stimulation trial followed by implant in an academic Pain Medicine division by four practitioners from 2007 to 2013, with follow-up data through April 2014. RESULTS: A total of 345 patients were considered candidates for dorsal column stimulation and underwent a trial. Two hundred thirty-four patients were implanted with an implant-to-trial ratio of 67-86% across various chronic pain entities (postlaminectomy syndrome, complex regional pain syndrome, small-fiber peripheral neuropathy, abdominal/pelvic pain, nonsurgical candidates with lumbosacral neuropathy, and neuropathic pain not otherwise specified), with the exception of nonsurgical candidates with lumbosacral neuropathy who had an implant ratio of 43%. The complication rate was 34.6%, with the hardware related being the most common reason, comprising 74.1% of all complications. The revision and explant rates were 23.9% each. The most common reason for explant was loss of therapeutic effect (41.1%). CONCLUSIONS: SCS is an effective treatment for chronic noncancer pain. It is a minimally invasive procedure, safe, and with good long-term outcomes. However, the surgical revision and explant rates are relatively high. As the use of SCS continues to grow, research into the causes of and risk factors for SCS-related complications is paramount to decrease complication rates in the future. PMID- 26053498 TI - Whole-genome fingerprint of the DNA methylome during human B cell differentiation. AB - We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation. PMID- 26053500 TI - Properties of a Glutamatergic Synapse Controlling Information Output from Retinal Bipolar Cells. AB - One general categorization of retinal ganglion cells is to segregate them into tonically or phasically responding neurons, each conveying discrete aspects of the visual scene. Although best identified in the output signals of the retina, this distinction is initiated at the first synapse: between photoreceptors and the dendrites of bipolar cells. In this study we found that the output synapses of bipolar cells also contribute to separate these pathways. Both transient and sustained ganglion cells can produce maintained spike activity, but bipolar cell glutamate release exhibits a divergence that corresponds to the response characteristics of the ganglion cells. Comparing light intensity coding in the sustained and transient ON pathways revealed that they shared the intensity spectrum. The transient pathway had greater sensitivity but smaller dynamic range, and switched from intensity coding to event detection at light levels where sustained pathway sensitivity began to rise. The distinctive properties of the sustained pathway depended upon inhibition and shifted toward those of the transient pathway in the absence of inhibition. The transient system was comparatively unaffected by the loss of inhibition and this was due to the concomitant activation of perisynaptic NMDA receptors. Overall, the properties of bipolar cell dendritic and axon terminals both contribute to the formation of key aspects of the sustained/transient dichotomy normally associated with ganglion cells. PMID- 26053501 TI - Source Apportionment of Polycyclic Aromatic Hydrocarbons in Central European Soils with Compound-Specific Triple Isotopes (delta(13)C, Delta(14)C, and delta(2)H). AB - This paper reports the first study applying a triple-isotope approach for source apportionment of polycyclic aromatic hydrocarbons (PAHs). The (13)C/(12)C, (14)C/(12)C, and (2)H/(1)H isotope ratios of PAHs were determined in forest soils from mountainous areas of the Czech Republic, European Union. Statistical modeling applying a Bayesian Markov chain Monte Carlo (MCMC) framework to the environmental triple isotope PAH data and an end-member PAH isotope database allowed comprehensive accounting of uncertainties and quantitative constraints on the PAH sources among biomass combustion, liquid fossil fuel combustion, and coal combustion at low and high temperatures. The results suggest that PAHs in this central European region had a clear predominance of coal combustion sources (75 +/- 6%; uncertainties represent 1 SD), mainly coal pyrolysis at low temperature (~650 degrees C; 61 +/- 8%). Combustion of liquid fossil fuels and biomass represented 16 +/- 3 and 9 +/- 3% of the total PAH burden (?PAH14), respectively. Although some soils were located close to potential PAH point sources, the source distribution was within a narrow range throughout the region. These observation based top-down constraints on sources of environmental PAHs provide a reference for both improved bottom-up emission inventories and guidance for efforts to mitigate PAH emissions. PMID- 26053502 TI - Investigating the Influence of Visual Function and Systemic Risk Factors on Falls and Injurious Falls in Glaucoma Using the Structural Equation Modeling. AB - PURPOSE: To investigate the relationship between visual function and the risks of falling and injurious falls in subjects with primary open angle glaucoma (POAG). METHODS: Questionnaires were conducted in 365 POAG patients to assess history of falls and falls with injury and general patient health. Structural equation modeling (SEM) was used to investigate the relationship between visual function, as measured by a patient's binocular integrated visual field and visual acuity (VA), general health and the risks of falling and injurious falls. RESULTS: Among the 365 subjects, 55 subjects experienced falls in the past year. A significant difference was observed in worse-eye VA between the faller and non-faller groups (p = 0.03). SEM of fallers obtained a Root Mean Square Error of Approximation (RMSEA) of 0.035 and a Comparative Fit Index (CFI) of 0.99. The 95% confidence intervals (CI) of regression coefficients from this model suggested better VA and worse VA were significant risk factors for falling. Among the 55 fallers, 22 subjects experienced an associated injury. There was a significant difference in gender between the non-injurious and injurious faller groups (p = 0.002). SEM of injurious fallers obtained a RMSEA of 0.074 and a CFI of 0.97. In this SEM model, the 95% CI of regression coefficients suggested gender and average total deviation values in the lower peripheral visual field were significant risk factors for an injurious fall. CONCLUSIONS: This study suggests that worse-eye and better-eye VAs are associated with falls. Furthermore, patients with inferior visual field loss and females were found to be at greater risk of injurious falls. PMID- 26053503 TI - Evaluation of a hydrophobic gel adhering to the gingiva in comparison with a standard water-soluble 1% chlorhexidine gel after scaling and root planing in patients with moderate chronic periodontitis. A randomized clinical trial. AB - OBJECTIVES: To evaluate the clinical, microbiological and enzymatic activity of a hydrophobic chlorhexidine-based gingiva-adhering gel containing herbal ingredients, compared with a commercially available 1% chlorhexidine water soluble gel, during non-surgical therapy of moderate chronic periodontitis. METHODS: A total of 34 subjects participated in this 6-month blinded randomized parallel controlled trial (ISRCTN35210084). After scaling and root planing (SRP), test group received the gel, by rubbing on the gingiva, once every second day, for 14 days. The control group received the control gel twice daily. Clinical parameters considered were the approximal plaque index, simplified oral hygiene index, modified gingival index, bleeding on probing, probing depth and clinical attachment level (primary outcome), assessed at baseline, 3 and 6 months, together with the frequency of detection of Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis (P.g.), Prevotella intermedia, Treponema denticola (T.d.), Tannerella forsythia (T.f.), and activity of neutrophil elastase and myeloperoxidase (secondary outcomes). RESULTS: At 3 and 6 months, all clinical parameters improved significantly, without significant intergroup differences, except OHI-S, which improved at 3 months (P < 0.05). Microbiological data resulted in no significant intergroup differences at baseline and 6 months. At 3 months, significant differences for P.g., T.f. and T.d. were noted. A significant reduction of neutrophil elastase after 3 and 6 months was observed (P < 0.005), without significant intergroup differences. For myeloperoxidase, significant reductions were noted in both groups (P < 0.005 and P < 0.05), but no significant intergroup differences. The tested product seemed to have an increased efficacy, due to longer persistence on the gingiva, with reduced application frequency. CONCLUSIONS: Both products had a relatively similar influence on the clinical, microbiological and enzymatic outcomes at 3 and 6 months after SRP. PMID- 26053504 TI - Observing the growth of metal-organic frameworks by in situ liquid cell transmission electron microscopy. AB - Liquid cell transmission electron microscopy (LCTEM) can provide direct observations of solution-phase nanoscale materials, and holds great promise as a tool for monitoring dynamic self-assembled nanomaterials. Control over particle behavior within the liquid cell, and under electron beam irradiation, is of paramount importance for this technique to contribute to our understanding of chemistry and materials science at the nanoscale. However, this type of control has not been demonstrated for complex, organic macromolecular materials, which form the basis for all biological systems and all of polymer science, and encompass important classes of advanced porous materials. Here we show that by controlling the liquid cell membrane surface chemistry and electron beam conditions, the dynamics and growth of metal-organic frameworks (MOFs) can be observed. Our results demonstrate that hybrid organic/inorganic beam-sensitive materials can be analyzed with LCTEM and, at least in the case of ZIF-8 dynamics, the results correlate with observations from bulk growth or other standard synthetic conditions. Furthermore, we show that LCTEM can be used to better understand how changes to synthetic conditions result in changes to particle size. We anticipate that direct, nanoscale imaging by LCTEM of MOF nucleation and growth mechanisms may provide insight into controlled MOF crystal morphology, domain composition, and processes influencing defect formation. PMID- 26053505 TI - Lexical Characteristics of Anticipatory and Consummatory Anhedonia in Schizophrenia: A Study of Language in Spontaneous Life Narratives. AB - OBJECTIVES: The extent to which anticipatory anhedonia (an important determinant of outcome in schizophrenia) is determined by interpersonal characteristics, cognitive biases, or even artifacts of measurement remains unclear. The present study aims to provide understanding cognitive, affective and phenomenological characteristics of this construct by examining the lexical characteristics of life narratives with schizophrenia with computerized lexical analysis. METHOD: A total of 41 individuals with a diagnosis of schizophrenia or schizoaffective disorder completed the Indiana Psychiatric Illness Interview, and the lexical characteristics of these narratives were examined for their relationships to both anticipatory and consummatory anhedonia. RESULTS: Results revealed that relatively higher levels of both anticipatory and consummatory anhedonia were linked with fewer past-related words and by lesser use of first-person plural pronouns. CONCLUSIONS: This may suggest anhedonia is linked to diminished access to past narrative episodes and a lesser sense of shared important moments with others. PMID- 26053506 TI - Identification of metals from osteoblastic ST-2 cell supernatants as novel OGR1 agonists. AB - Ovarian cancer G-protein-coupled receptor 1 (OGR1) is a G-protein-coupled receptor (GPCR), which has previously been identified as a receptor for protons. It has been reported in this and previous studies that OGR1 expression was markedly up-regulated during osteoclast differentiation. We predicted the possibility of other molecules activating OGR1 in neutral pH, and that osteoblasts might release OGR1 agonistic molecules and activate OGR1 expressed in osteoclasts such as RANKL. We screened for cell supernatants and organ extracts and discovered OGR1 agonistic activity in ST-2 osteoblastic cell supernatants and pancreatic tissues. Finally, we partially purified and identified essential metals, Fe, Zn, Co, Ni and Mn, as novel OGR1 agonists. These OGR1 agonistic metals induce intracellular Gq-coupled inositol phosphate signals in OGR1 expressing cells and primary osteoclasts through OGR1. We also confirmed that these OGR1 agonistic metals activated OGR1 through the same residues which act with protons. Here, we demonstrate that metals, Fe, Zn, Co, Ni and Mn are the novel OGR1 agonists, which can singly activate OGR1 in neutral pH. PMID- 26053507 TI - Structural insights of PA-824 derivatives: ligand-based 3D-QSAR study and design of novel PA824 derivatives as anti-tubercular agents. AB - With the purpose of designing novel chemical entities with improved inhibitory potencies against drug-resistant Mycobacterium tuberculosis, the 3D- quantitative structure-activity relationship (QSAR) studies were carried out on biphenyl analogs of the tuberculosis (TB) drug, PA-824. Anti-mycobacterial activity (MABA) was considered for the 3D-QSAR studies using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The best CoMFA and CoMSIA models were found statistically significant with cross-validated coefficients (q(2)) of 0.784 and 0.768, respectively, and conventional coefficients (r(2)) of 0.823 and 0.981, respectively. The cross validated and the external validation results revealed that both the CoMFA and CoMSIA models possesses high accommodating capacities and they would be reliable for predicting the pMIC values of new PA-824 derivatives. Based on the models and structural insights, a series of new PA-824 derivatives were designed and the anti-mycobacterial activities of the designed compounds were predicted based on the best 3D-QSAR model. The predicted data results suggest the designed compounds are more potent than existed ones. PMID- 26053508 TI - Antagonistic molecular interactions of photosynthetic pigments with molecular disease targets: a new approach to treat AD and ALS. AB - Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) are progressive neurodegenerative diseases that affect the neurons in the brain and the spinal cord. Neuroinflamation and apoptosis are key players in the progressive damage of the neurons in AD and ALS. Currently, there is no drug to offer complete cure for both these diseases. Riluzole is the only available drug that can prolong the life time of the ALS patients for nearly 3 months. Molecules that offer good HIT to the molecular targets of ALS will help to treat AD and ALS patients. P53 kinase receptor (4AT3), EphA4 (3CKH) and histone deacetylase (3SFF) are the promising disease targets of AD and ALS. This paper discusses on a new approach to combat neurodegenerative diseases using photosynthetic pigments. The docking studies were performed with the Autodock Vina algorithm to predict the binding of the natural pigments such as beta carotene, chlorophyll a, chlorophyll b, phycoerythrin and phycocyanin on these targets. The beta carotene, phycoerythrin and phycocyanin had higher binding energies indicating the antagonistic activity to the disease targets. These pigments serve as a potential therapeutic molecule to treat neuroinflammation and apoptosis in the AD and ALS patients. PMID- 26053509 TI - Insulin stimulates integrin-linked kinase in UMR-106 cells: potential role of heparan sulfate on syndecan-1. AB - Insulin plays a wide variety of physiological actions in osteoblast cells such as differentiation and gene expression. Integrins are transmembrane heterodimeric proteins consisting of alpha and beta subunits which transduce signals from extracellular matrix into the cell. The integrin-mediated signals regulate gene expression, differentiation and survival of osteoblast. In the present study, we explored to determine if insulin could regulate integrin-linked kinase (ILK) signaling in osteoblast like UMR-106 cells. Insulin rapidly stimulated ILK activity in a time-dependent manner with maximal activity observed at 60 min. The insulin's ability to stimulate ILK was almost completely abolished when the cells were pre-incubated with heparinase III (HepIII), suggesting the heparan sulfates attached to syndecan-1 play an important role in the activation of ILK in response to insulin. Interestingly, insulin also activated Akt activity by phosphorylation, whereas pre-treatment of HepIII failed to interfere Akt activation by insulin. In contrast, HepIII pre-treatment inhibited alkaline phosphatase stimulation and collagen synthesis in response to insulin. These results strongly suggest that heparan sulfates on the syndecan-1 and/or shedding of syndecan-1 play a significant role in regulating ILK by insulin, and thereby regulating alkaline phosphatase and collagen synthesis in osteoblast cells. PMID- 26053510 TI - Protection of curcumin against amyloid-beta-induced cell damage and death involves the prevention from NMDA receptor-mediated intracellular Ca2+ elevation. AB - Alzheimer's disease (AD) is one of the common neurodegenerative diseases and amyloid-beta (Abeta) is thought to be a key molecule contributing to AD pathology. Recently, curcumin is supposed to be beneficial to AD treatment. This study investigates the inhibitory effects of curcumin on Abeta-induced cell damage and death involving NMDA receptor-mediated intracellular Ca(2+) elevation in human neuroblastoma SH-SY5Y cells. Cells were impaired significantly in Abeta damaged group compared with the control group, and cell viability was decreased while the released LDH from the cytosol was increased. Curcumin promotes cell growth and decreases cell impairment induced by Abeta. Curcmin attenuates Abeta induced elevation of the ratio of cellular glutamate/gamma-aminobutyric acid (GABA) with a concentration-dependent manner. Curcumin inhibits Abeta-induced increase of cellular Ca(2+) and depresses Abeta-induced phosphorylations of both NMDA receptor and cyclic AMP response element-binding protein (CREB) and activating transcription factor 1 (ATF-1). These results indicated that curcumin inhibits Abeta-induced neuronal damage and cell death involving the prevention from intracellular Ca(2+) elevation mediated by the NMDA receptor. PMID- 26053511 TI - Effects of dihydroxy gymnemic triacetate (DGT) on expression of apoptosis associated proteins in human prostate cancer cell lines (PC3). AB - Prostate cancer is the most common malignancies among men. The present study is aimed at the investigation of dihydroxy gymnemic triacetate (DGT) from Gymnema sylvestre on mitochondrial apoptotic pathway and cell cycle arrest. Treatment of DGT resulted in a dose-dependent inhibition of growth of PC-3 cells. The cell cycle arrest was observed at the G2/M phase and accumulation of apoptotic cells was observed in DGT-treated prostate cancer cell lines. The occurrence of apoptosis in these cells was observed by DNA fragmentation. These events were associated with increased levels of pro-apoptotic proteins Bax, Bad and reduced levels of the antiapoptotic proteins Bcl-2, Bcl-xL and Mcl-1. DGT also induces the activation of caspase-9 and caspase-3. The above results, clearly, suggest that DGT induces apoptosis by the intrinsic pathways which could be very useful for the treatment of prostate cancer. PMID- 26053512 TI - Spinorphin inhibits membrane depolarization- and capsaicin-induced intracellular calcium signals in rat primary nociceptive dorsal root ganglion neurons in culture. AB - OBJECTIVE: Spinorphin is a potential endogenous antinociceptive agent although the mechanism(s) of its analgesic effect remain unknown. We conducted this study to investigate, by considering intracellular calcium concentrations as a key signal for nociceptive transmission, the effects of spinorphin on cytoplasmic Ca(2+) ([Ca(2+)]i) transients, evoked by high-K(+) (30 mM) depolariasation or capsaicin, and to determine whether there were any differences in the effects of spinorphin among subpopulation of cultured rat dorsal root ganglion (DRG) neurons. METHODS: DRG neurons were cultured on glass coverslips following enzymatic digestion and mechanical agitation, and loaded with the calcium sensitive dye fura-2 AM (1 uM). Intracellular calcium responses in individual DRG neurons were quantified using standard fura-2 based ratiometric calcium imaging technique. All data were analyzed by using unpaired t test, p < 0.05 defining statistical significance. RESULTS: Here we found that spinorphin inhibited cytoplasmic Ca(2+) ([Ca(2+)]i) transients, evoked by depolarization and capsaicin selectively in medium and small cultured rat DRG neurons. Spinorphin (10-300 uM) inhibited the Ca(2+) signals in concentration dependant manner in small- and medium diameter DRG neurons. Capsaicin produced [Ca(2+)]i responses only in small and medium-sized DRG neurons, and pre-treatment with spinorphin significantly attenuated these [Ca(2+)]i responses. CONCLUSION: Results from this study indicates that spinorphin significantly inhibits [Ca(2+)]i signaling, which are key for the modulation of cell membrane excitability and neurotransmitter release, preferably in nociceptive subtypes of this primary sensory neurons suggesting that peripheral site is involved in the pain modulating effect of this endogenous agent. PMID- 26053513 TI - Muscarinic drugs regulate the PKG-II-dependent phosphorylation of M3 muscarinic acetylcholine receptors at plasma membranes from airway smooth muscle. AB - Muscarinic agonists induce the activation of the airway smooth muscle (ASM) leading to smooth muscle contraction, important in asthma. This activation is mediated through M2/M3 muscarinic acetylcholine receptors (mAChRs). Muscarinic receptor activity, expressed as [(3)H]QNB binding at plasma membranes from bovine tracheal smooth muscle (BTSM), increased with cGMP and was augmented significantly cGMP plus ATP but diminished with the PKG-II inhibitor, Sp-8-pCPT cGMPS. The [(3)H]-QNB binding was accelerated by okadaic acid, (OKA), a protein phosphatase (PPase) inhibitor. These two results indicated the involvement of a membrane-bound PPase. Moreover, a cGMP-dependent-[(32)P]gammaATP phosphorylation of plasma membranes from BTSM was stimulated at low concentrations of muscarinic agonist carbamylcholine (CC). However, higher amounts of CC produced a significant decrement of [(32)P]-labeling. A selective M3mAChR antagonist, 4-DAMP produced a dramatic inhibition of the basal and CC-dependent [(32)P]-labeling. The [(32)P] labeled membrane sediments were detergent solubilized and immunoprecipitated with specific M2/M3mAChR antibodies. The M3mAChR immuno precipitates exhibited the highest cGMP-dependent [(32)P]-labeling, indicating it is a PKG-II substrate. Experiments using synthetic peptides from the C-terminal of the third intracellular loop (i3) of both M2mAChR (356-369) and M3mAChR (480 493) as external PKG-II substrates resulted in the i3M3-peptide being heavily phosphorylated. These results indicated that PKG-II phosphorylated the M3mAChR at the i3M3 domain ((480)MSLIKEKK(485)), suggesting that Ser(481) may be the target. Finally, this phosphorylation site seems to be regulated by a membrane-bound PPase linked to muscarinic receptor. These findings are important to understand the role of M3mAChR in the patho-physiology of ASM involved in asthma and COPD. PMID- 26053514 TI - Evidence of a Genetic Basis for Differences in Parasitization Success between Strains of Avetianella longoi (Siscaro). AB - When the cerambycid, Phoracantha recurva, invaded California in the mid 1990's a parasitoid wasp was imported from its native range in Australia as part of a biological control program. The wasp was later identified to be Avetianella longoi, which had already been released years earlier to control the congener longhorned beetle, Phoracantha semipunctata. Despite being recognized as the same species, the two wasps exhibited differential success on P. recurva eggs, indicating the presence of two separate strains. Here we determine if the differentiating factor between the two strains of A. longoi is a heritable genetic trait. All four pairings between the two strains were conducted, resulting in two homogenous and two heterogeneous crosses. All crosses except one produced viable F1 female offspring. F1 females were allowed to oviposit on P. recurva eggs and the survival of their offspring was compared to determine if survival can be affected by paternal contributions. The result was that the offspring of females with fathers from the second introduced strain showed significantly increased survival compared to F1 females with parents from the first introduced strain. This increased survival demonstrated that there is a heritable dominant trait that is associated with increased survival on P. recurva host eggs. PMID- 26053516 TI - Production of a Cloned Buffalo (Bubalus bubalis) Calf from Somatic Cells Isolated from Urine. AB - This study was aimed at isolation of cells from urine and skin on the ventral part of the tails of healthy adult female buffaloes (Bubalus bubalis), an area rarely exposed to solar radiation, establishment of the cells in culture, and their use as donor cells for production of buffalo embryos by handmade cloning (HMC). The blastocyst rate and total cell number of urine- and tail skin-derived embryos were similar to those of control embryos derived from ear skin cells; however, their apoptotic index was lower (p<0.05) than that of control blastocysts. The global level of histone H3 acetylated at lysine 9 (H3K9ac) was similar in the three types of donor cells and in urine- and tail skin-derived HMC blastocysts and in vitro-fertilized (IVF) blastocysts (controls). The global level of histone H3 trimethylated at lysine 27 (H3K27me3) in the cells was in the order (p<0.05) urine>=tail skin>ear skin-derived cells, whereas in blastocysts, it was higher (p<0.05) in urine- and tail skin-derived HMC blastocysts than that in IVF blastocysts. The expression level of CASPASE3, CASPASE9, P53, DNMT1, DNMT3a, OCT4, and NANOG, which was similar in HMC blastocysts of three the groups, was lower (p<0.05) than that in IVF blastocysts, whereas that of HDAC1 was similar among the four groups. Following transfer of urine-derived embryos (n=10) to five recipients (two embryos/recipient), one of the recipients delivered a normal calf that is now 5 weeks old. PMID- 26053515 TI - Transdifferentiation of Fibroblasts by Defined Factors. AB - Cellular differentiation is usually considered to be an irreversible process during development due to robust lineage commitment. Feedback and feed-forward loops play a significant role in maintaining lineage-specific gene expression processes in various cell types, and, in turn, factors secreted by cells may regulate the homeostatic balance of these cycles during development and differentiation. The output of biological responses is controlled by such mechanisms in many regulatory pathways through gene networks involved in transcription, RNA metabolism, signal transduction, micromolecular synthesis, and degradation. The pluripotent stage during cellular conversion may be avoided through ectopic expression of lineage-specific factors. Lineage-specific transcription factors produced during development may strengthen cell type specific gene expression patterns. Cellular phenotypes are further stabilized by epigenetic modifications. This reprogramming approach could have important implications for disease modeling and regenerative and personalized medicine. PMID- 26053517 TI - Application Of Small Molecules Favoring Naive Pluripotency during Human Embryonic Stem Cell Derivation. AB - In mice, inhibition of both the fibroblast growth factor (FGF) mitogen-activated protein kinase kinase/extracellular-signal regulated kinase (MEK/Erk) and the Wnt signaling inhibitor glycogen synthase-3beta (GSK3beta) enables the derivation of mouse embryonic stem cells (mESCs) from nonpermissive strains in the presence of leukemia inhibitory factor (LIF). Whereas mESCs are in an uncommitted naive state, human embryonic stem cells (hESCs) represent a more advanced state, denoted as primed pluripotency. This burdens hESCs with a series of characteristics, which, in contrast to naive ESCs, makes them not ideal for key applications such as cell-based clinical therapies and human disease modeling. In this study, different small molecule combinations were applied during human ESC derivation. Hereby, we aimed to sustain the naive pluripotent state, by interfering with various key signaling pathways. First, we tested several combinations on existing, 2i (PD0325901 and CHIR99021)-derived mESCs. All combinations were shown to be equally adequate to sustain the expression of naive pluripotency markers. Second, these conditions were tested during hESC derivation. Overall, the best results were observed in the presence of medium supplemented with 2i, LIF, and the noncanonical Wnt signaling agonist Wnt5A, alone and combined with epinephrine. In these conditions, outgrowths repeatedly showed an ESC progenitor-like morphology, starting from day 3. Culturing these "progenitor cells" did not result in stable, naive hESC lines in the current conditions. Although Wnt5A could not promote naive hESC derivation, we found that it was sustaining the conversion of established hESCs toward a more naive state. Future work should aim to distinct the effects of the various culture formulations, including our Wnt5A-supplemented medium, reported to promote stable naive pluripotency in hESCs. PMID- 26053518 TI - Stem Cell-Derived Bioactive Materials Accelerate Development of Porcine In Vitro Fertilized Embryos. AB - Stem cells show the capability to proliferate in an undifferentiated state with long-term self-renewal, which gives the cells advantages for use as bioactive material (BM) for embryo culture in vitro. The objective of this experiment was to investigate the effect of two BMs-human adipose tissue-derived mesenchymal stem cell BM (hAT-MSC-BM) and human embryonic stem cell-derived BM (hESC-BM)-on porcine embryo development compared to commonly used bovine serum albumin (BSA) or serum treatment groups. In vitro-fertilized (IVF) embryos were cultured in PZM 5 with 4 mg/mL BSA until day 4 and equally divided into four groups. Starting from day 4 (until day 6), each group was treated with the following protein additives: 4 mg/mL BSA (control), 10% fetal bovine serum (FBS), 10% hAT-MSC-BM, or 10% hESC-BM. Our results show FBS- and two other BM-treated groups showed significant increases in blastocyst formation rate, hatching rate, and total cell number compared with the control group (p<0.05). The hAT-MSC-BM and hESC-BM treatment groups presented better-quality embryo development, especially from the middle expanding stage to hatching. In particular, the hAT-MSC-BM-treated group showed the highest developmental potential of all groups and formed the most expanding-stage blastocysts. The relative expression of reprogramming-related transcription factor (POU5F1, SOX2, DPPA5, and CDH1), antioxidant (PRDX5), and apoptosis (BCL2L1 and BIRC5) genes also increased in two types of BMs compared to the control. In addition, we investigated the protein synthesis of the tight junction- and gap junction-related genes, connexin 43 and zonula occludens-1 (ZO 1); these increased more than in the control. These results demonstrate that stem cell-derived BMs accelerate porcine preimplantation embryo development and that the BMs would be helpful in the development of preimplantation embryos. PMID- 26053519 TI - Epigenetic Modification of Cloned Embryos Improves Nanog Reprogramming in Pigs. AB - Incomplete reprogramming of pluripotent genes in cloned embryos is associated with low cloning efficiency. Epigenetic modification agents have been shown to enhance the developmental competence of cloned embryos; however, the effect of the epigenetic modification agents on pluripotent gene reprogramming remains unclear. Here, we investigated Nanog reprogramming and the expression patterns of pluripotent transcription factors during early embryo development in pigs. We found that compared with fertilized embryos, cloned embryos displayed higher methylation in the promoter and 5'-untranslated region and lower methylation in the first exon of Nanog. When 5-aza-2'-deoxycytidine (5-aza-dC) or trichostatin A (TSA) enhanced the development of porcine cloned embryos, Nanog methylation reprogramming was also improved, similar to that detected in fertilized counterparts. Furthermore, our results showed that the epigenetic modification agents improved the expression levels of Oct4 and Sox2 and effectively promoted Nanog transcription in cloned embryos. In conclusion, our results demonstrated that the epigenetic modification agent 5-aza-dC or TSA improved Nanog methylation reprogramming and the expression patterns of pluripotent transcription factors, thereby resulting in the enhanced expression of Nanog and high development of porcine cloned embryos. This work has important implications in the improvement of cloning efficiency. PMID- 26053520 TI - Generation of Induced Pluripotent Stem Cells from Bovine Epithelial Cells and Partial Redirection Toward a Mammary Phenotype In Vitro. AB - In contrast to adult stem cells, induced pluripotent stem cells (iPSCs) can be grown robustly in vitro and differentiated into virtually any tissue, thus providing an attractive alternative for biomedical applications. Although iPSC technology is already being used in human biomedicine, its potential in animal production has not been investigated. Herein, we investigated the potential application of iPSCs in dairy production by generating bovine iPSCs and establishing their ability to generate mammary epithelial tissue. iPSCs were derived by retrovirus-mediated expression of murine Oct4, Sox2, Klf4, and c-Myc in mammary epithelium and dermal fibroblasts. The resulting reprogrammed cells stained positive for alkaline phosphatase and showed renewed expression of pluripotency genes, including Lin28, Rex1, Oct4, Sox2, and Nanog. In addition, injection of epithelial- or fibroblast-derived reprogrammed cells into nonobese diabetic (NOD/NOD) mice resulted in the formation of teratomas containing differentiated derivatives of the three germ layers, including cartilage, membranous ossification, stratified squamous epithelial tissue, hair follicles, neural pinwheels, and different types of glandular tissue. Finally, mammary epithelium-derived iPSCs could be induced to differentiate back to a mammary phenotype characterized by epithelial cells expressing cytokeratin 14 (CK14), CK18, and smooth muscle actin (SMA) as a result of treatment with 10 nM progesterone. This study reports for the first time the generation of iPSCs from bovine epithelial cells and demonstrates the potential of using iPSCs technology for generating bovine mammary tissue in vitro. PMID- 26053521 TI - Conversion of Adipose Tissue-Derived Mesenchymal Stem Cells to Neural Stem Cell Like Cells by a Single Transcription Factor, Sox2. AB - Adipose tissue is an attractive source of easily accessible adult candidate cells for regenerative medicine. Adipose tissue-derived mesenchymal stem cells (ADSCs) have multipotency and strong proliferation and differentiation capabilities in vitro. However, as mesodermal multipotent stem cells, whether the ADSCs can convert into induced neural stem cells (NSCs) has so far not been demonstrated. In this study, we found that normally the naive ADSCs cultured as either monolayer or spheres in NSC medium did not express Sox2 and Pax6 genes and proteins, and could not differentiate to neuron-like cells. However, when we introduced the Sox2 gene into ADSCs by retrovirus, they exhibited a typical NSC like morphology, and could be passaged continuously, and expressed NSC specific markers Sox2 and Pax6. In addition, the ADSC-derived NSC-like cells displayed the ability to differentiate into neuron-like cells when switched to the differentiation culture medium, expressing neuronal markers, including Tuj1 and MAP2 genes and proteins. Our results suggest the ADSCs can be converted into induced NSC-like cells with a single transcription factor Sox2. This finding could provide another alternative cell source for cell therapy of neurological disorders. PMID- 26053522 TI - Runx1 and Runx3 Are Downstream Effectors of Nanog in Promoting Osteogenic Differentiation of the Mouse Mesenchymal Cell Line C3H10T1/2. AB - Previously, we reported that the transcription factor Nanog, which maintains the self-renewal of embryonic stem cells (ESCs), promotes the osteogenic differentiation of the mouse mesenchymal cell line C3H10T1/2 through a genome reprogramming process. In the present study, to clarify the mechanism underlying the multipotency of mesenchymal stem cells (MSCs) and to develop a novel approach to bone regenerative medicine, we attempted to identify the downstream effectors of Nanog in promoting osteogenic differentiation of mouse mesenchymal cells. We demonstrated that Runx1 and Runx3 are the downstream effectors of Nanog, especially in the early and intermediate osteogenic differentiation of the mouse mesenchymal cell line C3H10T1/2. PMID- 26053523 TI - Macroevolutionary persistence of heritable endosymbionts: acquisition, retention and expression of adaptive phenotypes in Spiroplasma. AB - The phylogenetic incongruence between insects and their facultative maternally transmitted endosymbionts indicates that these infections are generally short lived evolutionarily. Therefore, long-term persistence of many endosymbionts must depend on their ability to colonize and spread within new host species. At least 17 species of Drosophila are infected with endosymbiotic Spiroplasma that have various phenotypic effects. We transinfected five strains of Spiroplasma from three divergent clades into Drosophila neotestacea to test their capacity to spread in a novel host. A strain that causes male killing in Drosophila melanogaster (its native host) also does so in D. neotestacea, even though these host species diverged 40-60 mya. A strain native to D. neotestacea (designated sNeo) and the two other strains of the poulsonii clade of Spiroplasma confer resistance to wasp parasitism, suggesting that this trait may be ancestral within this clade of Spiroplasma. Conversely, no strain other than sNeo conferred resistance to the sterilizing effects of nematode parasitism, suggesting that nematode resistance is a recently derived condition. The apparent addition of nematode resistance to a Spiroplasma lineage that already confers resistance to wasp parasitism suggests endosymbionts can increase the repertoire of traits conducive to their spread. The capacity of an endosymbiont to undergo maternal transmission and express adaptive phenotypes in novel hosts, without requiring a period of host-symbiont co-evolution, enables the spread of such symbionts immediately after the colonization of a new host. This could be critical for the macroevolutionary persistence of facultative endosymbionts whose sojourn times within individual host species are relatively brief. PMID- 26053524 TI - Sulfenylation of beta-Diketones Using C-H Functionalization Strategy. AB - Sulfenylation of beta-diketones is challenging as beta-diketones undergo deacylation after sulfenylation in the reaction medium. The sulfenylation of beta diketones without deacylation under metal-free conditions at ambient temperature via a cross dehydrogenative coupling (CDC) strategy is reported. The resultant products can be further manipulated to form alpha,alpha-disubstituted beta diketones and pyrazoles. PMID- 26053525 TI - Association of Pre-miRNA-499 rs3746444 and Pre-miRNA-146a rs2910164 Polymorphisms and Susceptibility to Behcet's Disease. AB - MiRNAs and NFKB1 are well-known immune response and inflammation regulators. MiRNA gene polymorphisms may affect miRNA biogenesis and function and, may thus, lead to changes in the expression of hundreds of genes such as NFKB1. The aim of this study was to investigate the association of Behcet's disease (BD) with NFKB1 rs28362491, pre-miRNA-146a rs2910164, and pre-miRNA-499 rs3746444 polymorphisms, as well as the analysis of their single and combined effects on its susceptibility in a Turkish population. These polymorphisms were analyzed by using the polymerase chain reaction-restriction fragment length polymorphism method in 100 BD patients and 145 healthy control subjects. The results were analyzed statistically using Pearson chi-square (chi(2)) test and Fisher's exact test (two sided). According to genotype analysis, the frequencies of ins/ins genotype and ins allele of rs28362491 were considerably higher in BD patients. Also, miRNA-499 rs3746444 homozygous (TT) genotypes exibited a significantly higher risk in patients with BD (odds ratios [OR]=3.0, 95% confidence intervals [95% CI]=1.284-7.007, p=0.017). Moreover, the frequency of T allele of rs3746444 was a risk factor for BD (OR=1.562, 95% CI=1.087-2.24, p=0.015). In addition, significant differences were found between the groups concerning miRNA-146a rs2910164 polymorphism. Homozygous CC genotype and C allele of rs2910164 polymorphism were found to be protective factors against BD. The results of the combined genotype analysis showed no notable differences between the multiple comparisons of rs28362491-rs2910164 and of rs28362491-rs3746444 in patients and control groups. Our data demonstrate that homozygous CC genotype and C allele of rs2910164 polymorphism are protective factors against BD, but rs3746444 and rs28362491 polymorphisms in miRNA-499 and in NFKB1 promoter are involved in the genetic susceptibility of BD. In addition, TT and ins/ins genotypes may influence certain proinflammatory cytokines and, may thus, play a role in the pathogenesis of BD. PMID- 26053526 TI - Stabilization of Polar Step Edges on Calcite (10.4) by the Adsorption of Congo Red. AB - In this work, we present the stabilization of polar step edges along the [010] direction of calcite (10.4) by the presence of a water-soluble organic molecule, namely Congo Red. While characteristic etch pits are observed on the surface in the absence of the additive, no etch pits can be found in the presence of the additive. Using atomic force microscopy, we can directly follow the restructuring of the surface. Upon addition of Congo Red, the charge-neutral step edges confining the characteristic etch pits vanish, while polar step edges along the [010] direction appear on the surface, which are entirely decorated by well ordered molecular islands of the additive. After the restructuring has taken place, the surface exclusively exhibits these polar step edges. Our results give direct evidence of the fact that these polar step edges become thermodynamically favored when Congo Red is present. PMID- 26053527 TI - New opportunities for European radiation protection research. PMID- 26053528 TI - The endonasal endoscopic harvest and anatomy of the buccal fat pad flap for closure of skull base defects. AB - OBJECTIVES/HYPOTHESIS: Extirpation via expanded endonasal approaches (EEA) to the skull base can result in defects requiring vascularized rotational flap reconstruction. The buccal fat pad (BFP) is a vascularized graft described in open skull base resections, but its harvest and adequacy of vascular supply have not been examined for use with EEA. STUDY DESIGN: A transfacial cadaveric dissection was carried forth in a latex-injected specimen to characterize the BFP blood supply. Then a cadaveric dissection series was performed involving the endoscopic harvest and rotation of 10 buccal fat pads in five cadaveric specimens to assess defect coverage. METHODS: An endoscopic medial maxillectomy combined with an anterior maxillotomy was performed prior to endoscopic harvest in cadaveric specimens. The BFP was rotated to assess its capability to reconstruct seven possible ventral skull base defects. Finally, the BFP vascular anatomy was further characterized following harvest and transposition. RESULTS: The BFP reconstructed defects at the greater sphenoid wing, inferior and superior clivus, sella, planum, and bilateral ethmoids in all cadaveric specimens. In some cases it covered two sites concurrently. CONCLUSIONS: The BFP pedicled rotational flap is a potential alternate flap following EEA in select cases. LEVEL OF EVIDENCE: NA PMID- 26053529 TI - DNA interaction of europium(III) complex containing 2,2'-bipyridine and its antimicrobial activity. AB - The interaction of native fish salmon DNA (FS-DNA) with [Eu(bpy)3Cl2(H2O)]Cl, where bpy is 2,2'-bipyridine, is studied at physiological pH in Tris-HCl buffer by spectroscopic methods, viscometric techniques as well as circular dichroism (CD). These experiments reveal that Eu(III) complex has interaction with FS-DNA. Moreover, binding constant and binding site size have been determined. The value of Kb has been defined 2.46 +/- .02 * 10(5) M(-1). The thermodynamic parameters are calculated by Van't Hoff equation, the results show that the interaction of the complex with FS-DNA is an entropically driven phenomenon. CD spectroscopy followed by viscosity as well as fluorescence and UV--Vis measurements indicate that the complex interacts with FS-DNA via groove binding mode. Also, the synthesized Eu(III) complex has been screened for antimicrobial activities. PMID- 26053530 TI - Self-initiated helping behaviors and recovery in severe mental illness: Implications for work, volunteerism, and peer support. AB - OBJECTIVE: Despite recent interest in peer support workers in recovery-oriented services, little is known about how helping behaviors may affect recovery from severe mental illness outside of formal peer support roles. The current study is a mixed-methods approach to understanding naturalistic helping behaviors and their relationship with recovery outcomes among persons with serious mental illness. METHODS: Forty-six participants with schizophrenia-spectrum disorders completed a narrative interview and standardized measures of recovery, symptoms, hope, patient activation, quality of life, medication adherence, insight, and illness management. Interviews were coded using emergent, thematic analysis. The study compared individuals who (unprompted) mentioned helping behaviors in their interview to those who did not on recovery-related outcomes. RESULTS: Sixteen participant narratives (35%) described self-initiated helping behaviors. Themes included a desire to tell others their story, teach others recovery-promoting skills, become a peer support worker, give back to society, and be more active family members. Those who discussed helping others in narrative interviews scored significantly higher on measures of recovery, illness management, patient activation, hope, quality of life, medication adherence, and insight and scored significantly lower on measures of overall symptoms, as well as negative, positive, and cognitive symptoms, than did those who did not discuss helping behaviors. The groups did not differ on hostility or emotional discomfort symptoms. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Findings indicate associations between helping others and improved scores on measures of recovery outcomes. Potential implications include focusing on meaningful work/volunteerism and expanding roles for peer support in recovery-oriented services. PMID- 26053531 TI - Establishing a recovery orientation in mental health services: Evaluating the Recovery Self-Assessment (RSA) in a Swedish context. AB - OBJECTIVE: Although there has been an emphasis on developing knowledge regarding recovery in Sweden, it is unclear to what extent this has been translated into a recovery orientation in the provision of mental health services. Instruments, which present the components of recovery as measurable dimensions of change, may provide a framework for program development. Involving users is an essential factor in the utilization of such tools. The purpose of this study was to evaluate the psychometric properties of the Recovery Self-Assessment (RSA) measure and its potential for being utilized in a Swedish context. METHODS: The sample consisted of 78 participants from 6 community mental health services targeting people with serious mental illnesses in a municipality in Sweden. They completed the RSA at the study baseline and two weeks later. User panels participated in the translation and administration of the RSA and the reporting of results. RESULTS: The Swedish version of the RSA had good face and content validity, satisfactory internal consistency, and a moderate to good level of stability in test-retest reliability. The user panels contributed to establishing validity and as collaborators in the study. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Establishing the RSA as a valid and reliable instrument with which to focus on the recovery orientation of services is a first step in beginning to study the types of interventions that may effect and contribute to recovery oriented practice in Sweden. PMID- 26053532 TI - Faculty perceptions of accommodations, strategies, and psychiatric advance directives for university students with mental illnesses. AB - OBJECTIVE: Universities across the country struggle with the legal and ethical dilemmas of how to respond when a student shows symptoms of serious mental illness. This mixed-method study provides information on faculty knowledge of mental health problems in students, their use of available accommodations and strategies, and their willingness to accept psychiatric advance directives (PADs) as helpful interventions for managing student crises. METHOD: Participants were 168 faculty members at a large, public, Southern university. A web-based survey was used to collect quantitative self-report data as well as qualitative data in the form of open-ended questions. Quantitative data are presented with descriptive statistics. Qualitative data were analyzed using thematic analysis. RESULTS: The majority of faculty surveyed have an overall supportive stance and are willing to provide accommodations to students with a mental illness. The most common advantage faculty see in a PAD is support of student autonomy and choice, and the primary concern voiced about PADs is that students with mental illness will have poor judgment regarding the contents of the PADs they create. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: PADs may be effective recovery tools to help university students with mental illnesses manage crises and attain stability and academic success. For PADs to be effective, university faculty and administration will need to understand mental illnesses, the strategies students need to manage mental health crises, and how PADs can play a role in supporting students. PMID- 26053534 TI - Effect of the Amount and Particle Size of Wheat Fiber on the Physicochemical Properties and Gel Morphology of Starches. AB - Effects of added wheat fiber, with different levels and particle sizes, on the physicochemical properties and gel morphology of wheat starch and mung bean starch were investigated, using rapid visco analyzer (RVA), texture analyzer (TPA) and scanning electron microscopy (SEM). Each starch was added with wheat fiber at 10, 20, 30 and 40% (weight basis, g/100g), and different sizes of 60, 100 and 180 mesh, respectively. The peak viscosity (PV) of starches with wheat fiber were higher than the control. Starches had the highest PV with 40%, 60 mesh wheat fiber. The starches with wheat fiber showed higher hardness when compared to the control. Wheat starch and mung bean starch, with 40%, 60 mesh wheat fiber, had the highest hardnesses of 147.78 and 1032.11 g, respectively. SEM showed that the dense honeycomb structure of starch gel was diminished with increasing wheat fiber. Additionally, the number of internal pores was reduced, and a large lamellar structure was formed. PMID- 26053533 TI - The impact of adverse child and adult experiences on recovery from serious mental illness. AB - OBJECTIVE: The purpose of this study was to compare effects of adverse childhood experiences and adverse adult experiences on recovery from serious mental illnesses. METHODS: As part of a mixed-methods study of recovery from serious mental illnesses, we interviewed and administered questionnaires to 177 members of a not-for-profit health plan over a 2-year period. Participants had a diagnosis of bipolar disorder, affective psychosis, schizophrenia, or schizoaffective disorder. Data for analyses came from standardized self-reported measures; outcomes included recovery, functioning, quality of life, and psychiatric symptoms. Adverse events in childhood and adulthood were evaluated as predictors. RESULTS: Child and adult exposures to adverse experiences were high, at 91% and 82%, respectively. Cumulative lifetime exposure to adverse experiences (childhood plus adult experiences) was 94%. In linear regression analyses, adverse adult experiences were more important predictors of outcomes than adverse childhood experiences. Adult experiences were associated with lower recovery scores, quality of life, mental and physical functioning and social functioning and greater psychiatric symptoms. Emotional neglect in adulthood was associated with lower recovery scores. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Early and repeated exposure to adverse events was common in this sample of people with serious mental illnesses. Adverse adult experiences were stronger predictors of worse functioning and lower recovery levels than were childhood experiences. Focusing clinical attention on adult experiences of adverse or traumatic events may result in greater benefit than focusing on childhood experiences alone. PMID- 26053535 TI - An introduction to methodological issues when including non-randomised studies in systematic reviews on the effects of interventions. AB - BACKGROUND: Methods need to be further developed to include non-randomised studies (NRS) in systematic reviews of the effects of health care interventions. NRS are often required to answer questions about harms and interventions for which evidence from randomised controlled trials (RCTs) is not available. Methods used to review randomised controlled trials may be inappropriate or insufficient for NRS. AIM AND METHODS: A workshop was convened to discuss relevant methodological issues. Participants were invited from important stakeholder constituencies, including methods and review groups of the Cochrane and Campbell Collaborations, the Cochrane Editorial Unit and organisations that commission reviews and make health policy decisions. The aim was to discuss methods for reviewing evidence when including NRS and to formulate methodological guidance for review authors. WORKSHOP FORMAT: The workshop was structured around four sessions on topics considered in advance to be most critical: (i) study designs and bias; (ii) confounding and meta-analysis; (iii) selective reporting; and (iv) applicability. These sessions were scheduled between introductory and concluding sessions. SUMMARY: This is the first of six papers and provides an overview. Subsequent papers describe the discussions and conclusions from the four main sessions (papers 2 to 5) and summarise the proposed guidance into lists of issues for review authors to consider (paper 6). Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 26053536 TI - Issues relating to study design and risk of bias when including non-randomized studies in systematic reviews on the effects of interventions. AB - Non-randomized studies may provide valuable evidence on the effects of interventions. They are the main source of evidence on the intended effects of some types of interventions and often provide the only evidence about the effects of interventions on long-term outcomes, rare events or adverse effects. Therefore, systematic reviews on the effects of interventions may include various types of non-randomized studies. In this second paper in a series, we address how review authors might articulate the particular non-randomized study designs they will include and how they might evaluate, in general terms, the extent to which a particular non-randomized study is at risk of important biases. We offer guidance for describing and classifying different non-randomized designs based on specific features of the studies in place of using non-informative study design labels. We also suggest criteria to consider when deciding whether to include non-randomized studies. We conclude that a taxonomy of study designs based on study design features is needed. Review authors need new tools specifically to assess the risk of bias for some non-randomized designs that involve a different inferential logic compared with parallel group trials. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053537 TI - Issues relating to confounding and meta-analysis when including non-randomized studies in systematic reviews on the effects of interventions. AB - BACKGROUND: Confounding caused by selection bias is often a key difference between non-randomized studies (NRS) and randomized controlled trials (RCTs) of interventions. KEY METHODOLOGICAL ISSUES: In this third paper of the series, we consider issues relating to the inclusion of NRS in systematic reviews on the effects of interventions. We discuss whether potential biases from confounding in NRS can be accounted for, the limitations of current methods for attempting to do so, the different contexts of NRS and RCTs, the problems these issues create for reviewers, and a research agenda for the future. GUIDANCE: Reviewers who are considering whether or not to include NRS in meta-analyses must weigh a number of factors. Including NRS may allow a review to address outcomes or pragmatic implementations of an intervention not studied in RCTs, but it will also increase the workload for the review team, as well as their required technical repertoire. Furthermore, the results of a synthesis involving NRS will likely be more difficult to interpret, and less certain, relative to the results of a synthesis involving only randomized studies. When both randomized and non-randomized evidence are available, we favor a strategy of including NRS and RCTs in the same systematic review but synthesizing their results separately. CONCLUSION: Including NRS will often make the limitations of the evidence derived from RCTs more apparent, thereby guiding inferences about generalizability, and may help with the design of the next generation of RCTs. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053538 TI - Issues relating to selective reporting when including non-randomized studies in systematic reviews on the effects of healthcare interventions. AB - BACKGROUND: Selective outcome and analysis reporting (SOR and SAR) occur when only a subset of outcomes measured and analyzed in a study is fully reported, and are an important source of potential bias. KEY METHODOLOGICAL ISSUES: We describe what is known about the prevalence and effects of SOR and SAR in both randomized controlled trials (RCTs) and non-randomized studies (NRS), and the effects of SOR and SAR on summary effect estimates and conclusions in systematic reviews of the effectiveness of healthcare interventions. GUIDANCE: Review authors should always suspect SOR and SAR in reviews that include NRS, assess primary studies for the risk of bias, and make reasonable attempts to retrieve study protocols or other documentation developed before study recruitment began. There are clues that may suggest SOR or SAR in NRS, including differences between the methods and results sections of the publication, study funder, and differences between study protocol or registration information and the study report. CONCLUSION: Existing evidence about reporting biases in primary studies comes almost exclusively from methodological reviews of RCTs. The prevalence and impact of SOR and SAR in NRS are likely even greater than in RCTs but it is difficult to identify and confirm selective reporting in NRS. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053539 TI - Non-randomized studies as a source of complementary, sequential or replacement evidence for randomized controlled trials in systematic reviews on the effects of interventions. AB - The terms applicability, generalizability, external validity and transferability are related, sometimes used interchangeably and have in common that they lack a clear and consistent definition in the classic epidemiological literature. However, all of these terms generally describe one overarching theme: whether or not available research evidence can be directly utilized to answer the healthcare questions at hand, ideally supported by a judgment about the degree of confidence for this utilization. This concept has been called directness. The objectives of this paper were to delineate how non-randomized studies (NRS) inform judgments in relation to directness and the concepts that it encompasses in the context of systematic reviews. We will briefly review what is known and describe the theoretical and practical issues as well as offer guidance to those tackling the challenges of judging directness and using research evidence to answer healthcare questions with evidence from NRS. In particular, we suggest a framework in which authors can use NRS as a complement, sequence or replacement for randomized controlled trials (RCTs) by focusing on judgments about the population, intervention, comparison and outcomes. Authors of systematic reviews will use NRS to complement judgments about the inconsistencies, the rationale and credibility of subgroup analysis, the baseline risk estimates for the determination of absolute benefits and downsides, and the directness of surrogate outcomes. This evidence includes contextual or supplementary evidence. Authors of systematic review and other summaries of the evidence use NRS as sequential evidence to provide evidence when insufficient evidence is available for an outcome from RCTs, but NRS evidence is available (e.g., long-term harms). Use of evidence from NRS may also serve to replace RCT evidence when NRS provide equivalent (or potentially higher) confidence in the evidence (i.e. quality) compared to indirect evidence from RCTs. These judgments will be made in the context of other domains that influence the overall quality of the body of evidence, including the risk of bias, publication bias (i.e. limitations in the detailed study design and execution), inconsistency, imprecision and factors that increase our confidence in effects. This article will support systematic reviewers in their interaction with decision makers, that is, those who use the systematic review to develop guidelines, address health policy makers, and make clinical decisions, by making these judgments transparent. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 26053540 TI - Checklists of methodological issues for review authors to consider when including non-randomized studies in systematic reviews. AB - BACKGROUND: There is increasing interest from review authors about including non randomized studies (NRS) in their systematic reviews of health care interventions. This series from the Ottawa Non-Randomized Studies Workshop consists of six papers identifying methodological issues when doing this. AIM: To format the guidance from the preceding papers on study design and bias, confounding and meta-analysis, selective reporting, and applicability/directness into checklists of issues for review authors to consider when including NRS in a systematic review. CHECKLISTS: Checklists were devised providing frameworks to describe/assess: (1) study designs based on study design features; (2) risk of residual confounding and when to consider meta-analysing data from NRS; (3) risk of selective reporting based on the Cochrane framework for detecting selective outcome reporting in trials but extended to selective reporting of analyses; and (4) directness of evidence contributed by a study to aid integration of NRS findings into summary of findings tables. SUMMARY: The checklists described will allow review groups to operationalize the inclusion of NRS in systematic reviews in a more consistent way. The next major step is extending the existing Cochrane Risk of Bias tool so that it can assess the risk of bias to NRS included in a review. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 26053541 TI - Reconstructing 2 x 2 contingency tables from odds ratios using the Di Pietrantonj method: difficulties, constraints and impact in meta-analysis results. AB - A problem that is frequently encountered during the systematic review process is when studies that meet the inclusion criteria do not provide the appropriate numerical estimates to include in a meta-analysis. For dichotomous outcomes, a method has been suggested by Di Pietrantonj for reconstructing the 2 * 2 table when the Odds Ratio (OR), the Standard Error (SE(lnOR)) and the sample sizes are provided. The method produces two possible 2 * 2 tables; and to select the correct one, the Control Group Risk (CGR) is used. As CGR is typically unknown and only rounded figures of the OR and SE(lnOR) are provided, the accuracy of the reconstruction method varies. In this paper, we evaluate the performance of the method using simulated and empirical data. Small studies with large OR and CGR away from 50% are reconstructed satisfactorily, and the use of SE(lnOR) rounded to the third decimal rather than the second one improves the performance of the method. However, when CGR is unknown, its estimation from other studies is problematic as it exhibits high heterogeneity. Inclusion of an incorrectly reconstructed table in the meta-analysis may result in different summary effects. Reviewers that consider applying the method should be cautious about its impact in the meta-analysis. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053542 TI - Counter-effect of Brownian and elastic forces on the liquid-to-solid transition of microgel suspensions. AB - Suspensions of microgel particles undergo a transition from liquid-like to solid like mechanics upon increase of the microgel packing fraction. We study the opposed effects of the microgel softness and size on this transition. We tune the softness of the microgels by varying their polymer crosslinking density, while we simultaneously and independently vary their size and the contribution of Brownian particle motion by investigating two sets of colloidal-scale microgels synthesized by precipitation polymerization, along with one set of granular-scale microgels prepared by droplet-templated polymerization in microfluidic devices. We find that the microgel packing fraction at which the liquid-to-solid transition occurs depends on both the size and the softness of the microgel particles: small and soft microgels undergo this transition at much larger packing fractions than stiff microgels of the same size and than larger microgels with the same softness. This work suggests a systematic strategy to quantitatively predict this transition. PMID- 26053543 TI - Development of a novel frontal bone defect mouse model for evaluation of osteogenesis efficiency. AB - The skull defect model is the existing representative osteogenesis model. The skull defect model involves monitoring osteogenesis patterns at the site of a skull defect, which has the advantages that identical defects can be induced across individual experimental animals and the results can be quantitatively evaluated. However, it can damage the cerebrum because it requires a complex surgery performed on the parietal bone. This study aims to develop a new osteogenesis model that compensates for the weak points of the existing model. Male 8-week-old imprinting control region mice were put under inhalational anesthesia, and the surgery area was disinfected with 70% ethanol prior to the creation of a 5-mm incision along the sagittal line between the glabella with a pair of scissors. The incised area was opened and, after we checked the positions of the inferior cerebral vein and the sagittal suture, a 21-gauge needle was used to make two symmetrical holes with respect to the sagittal suture 3 mm below the inferior cerebral vein and 2 mm on either side of the sagittal suture. After images were obtained using micro-computed tomography, the degree of osteogenesis was quantitatively analyzed. In addition, mRNA extracted from the site of the defect confirmed a significant increase in mRNA levels of collagen 1a, alkaline phosphatase, bone sialoprotein, osteocalcin, and Runx2, known markers for osteoblasts. The promotion of osteogenesis could be observed at the site of the defect, by histological analysis. PMID- 26053544 TI - Vesicles Formation by Zwitterionic Micelle and Poly-L-lysine: Solvation and Rotational Relaxation Study. AB - The stable unilamellar vesicles formation, having large potential applications in biological as well as biomedical fields, has been investigated in aqueous solution composed of a zwitterionic surfactant, N-hexadecyl-N,N-dimethylammonio-1 propanesulfonate (SB-16), and water-soluble cationic poly(amino acid), poly-L lysine (PLL). Dynamic light scattering (DLS), transmission electron microscopy (TEM), and other optical spectroscopic techniques revealed the transformation of SB-16 micelles in aqueous solutions into stable unilamellar vesicles above a certain concentration (0.008 to 0.1% w/v) of PLL. Solvation and rotational dynamics of coumarin 480 (C-480) give the information on hydration behavior around the headgroup regions of SB-16 micelle and SB-16/PLL vesicle. It was observed that the hydration nature around the headgroup regions of SB-16/PLL vesicular system is higher than the head group regions of micellar system. Thus, PLL permits more water molecules in the headgroup regions of vesicular system. PMID- 26053545 TI - Immediate and Early Loading of Hydrothermally Treated, Hydroxyapatite-Coated Dental Implants: 2-Year Results from a Prospective Clinical Study. AB - This investigation was undertaken to determine if multithreaded implants partially coated with plasma-sprayed hydroxyapatite (HA) could be effectively loaded earlier than 3-6 months after placement. Forty-eight patients (22 men, 26 women) were enrolled in the study and received 48 implants. The population was divided into 2 groups: A implants (n = 23) were loaded immediately on the day of surgery and group B implants (n = 19) were loaded 3 weeks after surgery. Cone beam computerized tomography (CBCT) scans were taken preoperatively to aid in treatment planning. Bone density was evaluated by tactile feedback during surgery. Insertion torque was recorded at time of implant placement. Resonance frequency analysis, performed on the day of surgery, at the time of loading, and at 6, 12, and 24 months, was used to record implant stability according to the unit's implant stability quotient (Osstell ISQ). Standardized radiographs were taken at time of implant placement and at 6, 12, and 24 months to measure crestal bone stability. Bone level changes were measured by software (Image J). Bone quality was judged as either type 1 (n = 1), 2 (n = 31), 3 (n = 15), or 4 (n = 1). There were no failures in the group A (survival = 100%, n = 23/23) and 1 failure in group B (survival = 94.7%, n = 18/19). After 2 years in function, cumulative mean radiographic bone loss was 0.75 +/- 0.50mm (maxillae: 0.92 +/- 0.49 mm, n = 14; mandibles: 0.67 +/- 0.49 mm, n = 28). No differences in bone levels were noted between implants placed in previously augmented and nonaugmented sites, and there were no periodontal or soft tissue complications. After 2 years in function, implants partially coated with plasma-sprayed and hydrothermally treated HA were clinically predictable when restored in occlusion immediately after or within 3 weeks of implant placement. PMID- 26053547 TI - Lipid Membrane Deformation Accompanied by Disk-to-Ring Shape Transition of Cholesterol-Rich Domains. AB - During vesicle budding or endocytosis, biomembranes undergo a series of lipid- and protein-mediated deformations involving cholesterol-enriched lipid rafts. If lipid rafts of high bending rigidities become confined to the incipient curved membrane topology such as a bud-neck interface, they can be expected to reform as ring-shaped rafts. Here, we report on the observation of a disk-to-ring shape morpho-chemical transition of a model membrane in the absence of geometric constraints. The raft shape transition is triggered by lateral compositional heterogeneity and is accompanied by membrane deformation in the vertical direction, which is detected by height-sensitive fluorescence interference contrast microscopy. Our results suggest that a flat membrane can become curved simply by dynamic changes in local chemical composition and shape transformation of cholesterol-rich domains. PMID- 26053546 TI - Differential MicroRNA Expression in Human Macrophages with Mycobacterium tuberculosis Infection of Beijing/W and Non-Beijing/W Strain Types. AB - OBJECTIVES: The role of microRNAs in association with Mycobacterium tuberculosis (MTB) infection and the immunology regulated by microRNAs upon MTB infection have not been fully unravelled. We examined the microRNA profiles of THP-1 macrophages upon the MTB infection of Beijing/W and non-Beijing/W clinical strains. We also studied the microRNA profiles of the host macrophages by microarray in a small cohort with active MTB disease, latent infection (LTBI), and from healthy controls. RESULTS: The results revealed that 14 microRNAs differentiated infections of Beijing/W from non-Beijing/W strains (P<0.05). A unique signature of 11 microRNAs in human macrophages was identified to differentiate active MTB disease from LTBI and healthy controls. Pathway analyses of these differentially expressed miRNAs suggest that the immune-regulatory interactions involving TGF beta signalling pathway take part in the dysregulation of critical TB processes in the macrophages, resulting in active expression of both cell communication and signalling transduction systems. CONCLUSION: We showed for the first time that the Beijing/W TB strains repressed a number of miRNAs expressions which may reflect their virulence characteristics in altering the host response. The unique signatures of 11 microRNAs may deserve further evaluation as candidates for biomarkers in the diagnosis of MTB and Beijing/W infections. PMID- 26053548 TI - Predicting Species Distributions Using Record Centre Data: Multi-Scale Modelling of Habitat Suitability for Bat Roosts. AB - Conservation increasingly operates at the landscape scale. For this to be effective, we need landscape scale information on species distributions and the environmental factors that underpin them. Species records are becoming increasingly available via data centres and online portals, but they are often patchy and biased. We demonstrate how such data can yield useful habitat suitability models, using bat roost records as an example. We analysed the effects of environmental variables at eight spatial scales (500 m - 6 km) on roost selection by eight bat species (Pipistrellus pipistrellus, P. pygmaeus, Nyctalus noctula, Myotis mystacinus, M. brandtii, M. nattereri, M. daubentonii, and Plecotus auritus) using the presence-only modelling software MaxEnt. Modelling was carried out on a selection of 418 data centre roost records from the Lake District National Park, UK. Target group pseudoabsences were selected to reduce the impact of sampling bias. Multi-scale models, combining variables measured at their best performing spatial scales, were used to predict roosting habitat suitability, yielding models with useful predictive abilities. Small areas of deciduous woodland consistently increased roosting habitat suitability, but other habitat associations varied between species and scales. Pipistrellus were positively related to built environments at small scales, and depended on large-scale woodland availability. The other, more specialist, species were highly sensitive to human-altered landscapes, avoiding even small rural towns. The strength of many relationships at large scales suggests that bats are sensitive to habitat modifications far from the roost itself. The fine resolution, large extent maps will aid targeted decision-making by conservationists and planners. We have made available an ArcGIS toolbox that automates the production of multi-scale variables, to facilitate the application of our methods to other taxa and locations. Habitat suitability modelling has the potential to become a standard tool for supporting landscape-scale decision making as relevant data and open source, user-friendly, and peer-reviewed software become widely available. PMID- 26053549 TI - Alpha or beta human chorionic gonadotropin knockdown decrease BeWo cell fusion by down-regulating PKA and CREB activation. AB - The aim of the present study is to delineate the role of human chorionic gonadotropin (hCG) in trophoblast fusion. In this direction, using shRNA lentiviral particles, alpha- and beta-hCG silenced 'BeWo' cell lines were generated. Treatment of both alpha- and beta-hCG silenced BeWo cells with either forskolin or exogenous hCG showed a significant reduction in cell fusion as compared with control shRNA treated cells. Studies by qRT-PCR, Western blotting and immunofluorescence revealed down-regulation of fusion-associated proteins such as syncytin-1 and syndecan-1 in the alpha- and beta-hCG silenced cells. Delineation of downstream signaling pathways revealed that phosphorylation of PKA and CREB were compromised in the silenced cells whereas, no significant changes in p38MAPK and ERK1/2 phosphorylation were observed. Moreover, beta-catenin activation was unaffected by either alpha- or beta-hCG silencing. Further, inhibition of PKA by H89 inhibitor led to a significant decrease in BeWo cell fusion but had no effect on beta-catenin activation suggesting the absence of non canonical beta-catenin stabilization via PKA. Interestingly, canonical activation of beta-catenin was associated with the up-regulation of Wnt 10b expression. In summary, this study establishes the significance of hCG in the fusion of trophoblastic BeWo cells, but there may be additional factors involved in this process. PMID- 26053550 TI - Do nuclear-encoded core subunits of mitochondrial complex I confer genetic susceptibility to schizophrenia in Han Chinese populations? AB - Schizophrenia is one of the most prevalent psychiatric disorders with complex genetic etiology. Accumulating evidence suggests that energy metabolism and oxidative stress play important roles in the pathophysiology of schizophrenia. Dysfunction of mitochondrial respiratory chain and altered expression of complex I subunits were frequently reported in schizophrenia. To investigate whether nuclear-encoded core subunit genes of mitochondrial complex I are associated with schizophrenia, we performed a genetic association study in Han Chinese. In total, 46 tag single nucleotide polymorphisms (SNPs) from 7 nuclear-encoded core genes of mitochondrial complex I were genotyped in 918 schizophrenia patients and 1042 healthy controls. We also analyzed these SNPs in a large sample mainly composed of Europeans through using the available GWAS datasets from the Psychiatric Genomics Consortium (PGC). No significant associations were detected between these SNPs and schizophrenia in Han Chinese and the PGC data set. However, we observed nominal significant associations of 2 SNPs in the NDUFS1 gene and 4 SNPs in the NDUFS2 gene with early onset schizophrenia (EOS), but none of these associations survived the Bonferroni correction. Taken together, our results suggested that common SNPs in the nuclear-encoded core subunit genes of mitochondrial complex I may not confer genetic susceptibility to schizophrenia. PMID- 26053552 TI - Copper-catalyzed efficient direct amidation of 2-methylquinolines with amines. AB - A novel Cu-catalyzed direct amidation of 2-methylquinolines with amines is described. This method afforded an efficient approach for the synthesis of biologically important aromatic amides from readily available coupling partners using molecular oxygen as the oxidant. PMID- 26053551 TI - A Common Cancer Risk-Associated Allele in the hTERT Locus Encodes a Dominant Negative Inhibitor of Telomerase. AB - The TERT-CLPTM1L region of chromosome 5p15.33 is a multi-cancer susceptibility locus that encodes the reverse transcriptase subunit, hTERT, of the telomerase enzyme. Numerous cancer-associated single-nucleotide polymorphisms (SNPs), including rs10069690, have been identified within the hTERT gene. The minor allele (A) at rs10069690 creates an additional splice donor site in intron 4 of hTERT, and is associated with an elevated risk of multiple cancers including breast and ovarian carcinomas. We previously demonstrated that the presence of this allele resulted in co-production of full length (FL)-hTERT and an alternatively spliced, INS1b, transcript. INS1b does not encode the reverse transcriptase domain required for telomerase enzyme activity, but we show here that INS1b protein retains its ability to bind to the telomerase RNA subunit, hTR. We also show that INS1b expression results in decreased telomerase activity, telomere shortening, and an increased telomere-specific DNA damage response (DDR). We employed antisense oligonucleotides to manipulate endogenous transcript expression in favor of INS1b, which resulted in a decrease in telomerase activity. These data provide the first detailed mechanistic insights into a cancer risk-associated SNP in the hTERT locus, which causes cell type-specific expression of INS1b transcript from the presence of an additional alternative splice site created in intron 4 by the risk allele. We predict that INS1b expression levels cause subtle inadequacies in telomerase-mediated telomere maintenance, resulting in an increased risk of genetic instability and therefore of tumorigenesis. PMID- 26053553 TI - Raised intracranial pressure and nonsyndromic sagittal craniosynostosis. PMID- 26053555 TI - Targeted delivery of AAV-transduced mesenchymal stromal cells to hepatic tissue for ex vivo gene therapy. AB - Adeno-associated virus (AAV)-mediated gene therapy holds great promise if challenges related to vector neutralization by pre-existing antibodies are circumvented. The use of autologous or allogeneic cells to shield the vector might offer the possibility of successful gene transfer in such a situation. In the present study, we evaluated the feasibility of AAV-transduced mesenchymal stromal cells (MSCs) as a vehicle for hepatic gene transfer in a murine liver injury model. In our initial studies to determine the most suitable vector, we observed that AAV1 (91%) and AAV6 (72%) serotypes are highly efficient in transducing MSCs. Subsequently, we generated a transient liver injury model to analyse the efficacy of MSCs homing to the liver, as well as their hepatic gene transfer efficiency; our data show that administration of acetaminophen (500 mg/kg) served as a cue for the homing of MSCs to the liver. Furthermore, sex mismatched transplantation of AAV1-infected MSCs demonstrated a 3.5-fold (day 7) and 2.2-fold (day 28) higher hepatic gene transfer efficiency. To further corroborate this, we estimated the donor cell Y chromosome copies in the liver of recipient female mice. Our data revealed a 12.7-fold increase in average genome copies of male MSCs in the livers of recipient mice with injury compared to control, 60 days after transplantation. However, in vivo administration of AAV transduced MSCs in the presence of neutralization antibodies (intravenous immunoglobulin, IVIG) was not beneficial. This is possibly due to the clearance of transplanted MSCs by circulating IVIG and underscores the need to develop suitable in vivo models to study such a mode of gene transfer. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26053554 TI - Establishment of Trophectoderm Cell Lines from Buffalo (Bubalus bubalis) Embryos of Different Sources and Examination of In Vitro Developmental Competence, Quality, Epigenetic Status and Gene Expression in Cloned Embryos Derived from Them. AB - Despite being successfully used to produce live offspring in many species, somatic cell nuclear transfer (NT) has had a limited applicability due to very low (>1%) live birth rate because of a high incidence of pregnancy failure, which is mainly due to placental dysfunction. Since this may be due to abnormalities in the trophectoderm (TE) cell lineage, TE cells can be a model to understand the placental growth disorders seen after NT. We isolated and characterized buffalo TE cells from blastocysts produced by in vitro fertilization (TE-IVF) and Hand made cloning (TE-HMC), and compared their growth characteristics and gene expression, and developed a feeder-free culture system for their long-term culture. The TE-IVF cells were then used as donor cells to produce HMC embryos following which their developmental competence, quality, epigenetic status and gene expression were compared with those of HMC embryos produced using fetal or adult fibroblasts as donor cells. We found that although TE-HMC and TE-IVF cells have a similar capability to grow in culture, significant differences exist in gene expression levels between them and between IVF and HMC embryos from which they are derived, which may have a role in the placental abnormalities associated with NT pregnancies. Although TE cells can be used as donor cells for producing HMC blastocysts, their developmental competence and quality is lower than that of blastocysts produced from fetal or adult fibroblasts. The epigenetic status and expression level of many important genes is different in HMC blastocysts produced using TE cells or fetal or adult fibroblasts or those produced by IVF. PMID- 26053556 TI - Decreased elimination clearance of midazolam by doxorubicin through reductions in the metabolic activity of hepatic CYP3A in rats. AB - 1. We examined the effects of doxorubicin (DOX) on the expression level and metabolic activity of CYP3A in the liver as well as on the pharmacokinetics of midazolam (MDZ), a probe for CYP3A, in rats. Changes in the hepatic status of DOX treated rats were confirmed. 2. Serum levels of the biomarkers of hepatic impairment were elevated by the DOX treatment, which was consistent with the results obtained from a histopathological evaluation of the liver. 3. No significant difference was observed in the expression of proteins for hepatic CYP3A1 and CYP3A2 between the DOX and control groups. The metabolic production of 1'-hydroxylated and 4'-hydroxylated MDZ by hepatic microsomes was significantly lower in DOX-treated rats than in control rats. 4. The area under the curve (AUC) and the half-life (t1/2) of intravenously administered MDZ were significantly increased, and the total clearance (CLtot) and the elimination rate constant at the terminal phase (ke) were significantly decreased without significant changes in the volume of distribution at a steady state (Vdss). 5. These results indicated that a DOX-induced depression in the metabolic activity, but not expression level of CYP3A contributed to a decrease in the elimination clearance of MDZ, and also that reduced CYP3A function may be associated with the hepatotoxicity of DOX. PMID- 26053557 TI - Mechanism-based inhibition of CYPs and RMs-induced hepatoxicity by rutaecarpine. AB - 1. Rutaecarpine, a quinolone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is one of the main active components used in a variety of clinical applications, including the treatment of hypertension and arrhythmia. However, its hepatotoxicity has also been reported in recent years. 2. Reactive metabolites (RMs) play a vital role in drug-induced liver injury. Rutaecarpine has a secondary amine structure that may be activated to RMs. The aim of the study was to investigate the inhibition of rutaecarpine on CYPs and explore the possible relationship between RMs and potential hepatotoxicity. 3. A cell counting kit-8 cytotoxicity assay indicated that rutaecarpine can decrease the primary rat hepatocyte viability, increase lactate dehydrogenase and reactive oxygen species, reduce JC-1, and cause cell stress and membrane damage. The indexes were significantly restored by adding ABT, an inhibitor of CYPs. A cocktail assay showed that CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 can be inhibited by rutaecarpine in human liver microsomes. The IC50 values of CYP1A2 with and without NADPH were 2.2 and 7.4 MUM, respectively, which presented a 3.3 shift. The results from a metabolic assay indicated that three mono-hydroxylated metabolites and two di-hydroxylated metabolites were identified and two GSH conjugates were also trapped. 4. Rutaecarpine can inhibit the activities of CYPs and exhibit a potential mechanism-based inhibition on CYP1A2. RMs may cause herb drug interactions, providing important information for predicting drug-induced hepatotoxicity. PMID- 26053558 TI - In vitro glucuronidation of aprepitant: a moderate inhibitor of UGT2B7. AB - 1. Aprepitant, an oral antiemetic, commonly used in the prevention of chemotherapy-induced nausea and vomiting, is primarily metabolized by CYP3A4. Aprepitant glucuronidation has yet to be evaluated in humans. The contribution of human UDP-glucuronosyltransferase (UGT) isoforms to the metabolism of aprepitant was investigated by performing kinetic studies, inhibition studies and correlation analyses. In addition, aprepitant was evaluated as an inhibitor of UGTs. 2. Glucuronidation of aprepitant was catalyzed by UGT1A4 (82%), UGT1A3 (12%) and UGT1A8 (6%) and Kms were 161.6 +/- 15.6, 69.4 +/- 1.9 and 197.1 +/- 28.2 uM, respectively. Aprepitant glucuronidation was significantly correlated with both UGT1A4 substrates anastrazole and imipramine (rs = 0.77, p < 0.0001 for both substrates; n = 44), and with the UGT1A3 substrate thyroxine (rs = 0.58, p < 0.0001; n = 44). 3. We found aprepitant to be a moderate inhibitor of UGT2B7 with a Ki of ~10 uM for 4-MU, morphine and zidovudine. Our results suggest that aprepitant can alter clearance of drugs primarily eliminated by UGT2B7. Given the likelihood for first-pass metabolism by intestinal UGT2B7, this is of particular concern for oral aprepitant co-administered with oral substrates of UGT2B7, such as zidovudine and morphine. PMID- 26053559 TI - Interspecies variation in phase I metabolism of bufalin in hepatic microsomes from mouse, rat, dog, minipig, monkey, and human. AB - 1. Bufalin (BF), one of the major bioactive compounds in traditional Chinese medicine (TCM) Chansu, has been found with various pharmacological and toxicological effects. This study aims to investigate the species differences in phase I metabolism of BF in hepatic microsomes from human and five common experimental animals. 2. Metabolite profiling demonstrated that two major metabolites were formed in liver microsomes from human and animal species in NADPH-generating system. Two major metabolites were identified as 5beta-hydroxyl bufalin and 3-keto-bufalin, with the help of authentic standards. CYP3A was assigned as the main isoform involved in both 5beta-hydroxylation and 3-oxidation in all studied liver microsomes. The apparent kinetic parameters including substrate affinity and catalytic efficiency for 5beta-hydroxylation and 3 oxidation of BF were also determined. 3. In summary, CYP3A mediated 5beta hydroxylation and 3-oxidation were two major metabolic pathways of BF in hepatic microsomes from human and five studied animals, but kinetic analysis demonstrated that the intrinsic clearances of these two metabolic pathways were much different among various species. The qualitative and quantitative interspecies study indicated that minipig exhibited the similar metabolic profile, kinetic behaviors and intrinsic metabolic clearances of BF phase I biotransformation in comparison with that of human. PMID- 26053560 TI - Coherent Generation of Photo-Thermo-Acoustic Wave from Graphene Sheets. AB - Many remarkable properties of graphene are derived from its large energy window for Dirac-like electronic states and have been explored for applications in electronics and photonics. In addition, strong electron-phonon interaction in graphene has led to efficient photo-thermo energy conversions, which has been harnessed for energy applications. By combining the wavelength independent absorption property and the efficient photo-thermo energy conversion, here we report a new type of applications in sound wave generation underlined by a photo thermo-acoustic energy conversion mechanism. Most significantly, by utilizing ultrafast optical pulses, we demonstrate the ability to control the phase of sound waves generated by the photo-thermal-acoustic process. Our finding paves the way for new types of applications for graphene, such as remote non-contact speakers, optical-switching acoustic devices, etc. PMID- 26053561 TI - ALK-positive primary cutaneous T-cell-lymphoma (CTCL) with unusual clinical presentation and aggressive course. AB - Anaplastic lymphoma kinase (ALK) expression is uncommon in primary cutaneous T cell-lymphomas (CTCL). We report the case of a patient who was initially diagnosed with small plaque parapsoriasis, and eventually developed an unusual manifestation of CTCL 6 years later. The disease was characterized by aggressively ulcerating plaques and tumors of the entire skin. Histopathology revealed monoclonal proliferation of atypical T-lymphocytes and CD30-positive blasts with expression of ALK and identification of an ATIC-ALK fusion protein. Extensive staging confirmed the primary cutaneous origin of the lymphoma. After failure of several conventional treatments including polychemotherapy, the patient finally achieved remission after receiving brentuximab-vedotin, alemtuzumab and subsequent allogeneic stem cell transplantation. In the following, the patient developed inflammatory cutaneous lesions that pathologically showed no evidence for lymphoma relapse or classical cutaneous graft-versus-host disease. The patient responded to immunosuppression, but finally died from multi-organ failure due to sepsis 8 months after stem cell transplantation. This is a rare instance of ALK positivity in a CTCL, most likely resembling CD30+ transformed mycosis fungoides, because it was not typical for cutaneous anaplastic large cell lymphoma (ALCL). In contrast to its role in systemic ALCL as favorable prognostic marker, ALK expression here was associated with an aggressive course. PMID- 26053562 TI - [Capitate Non-Union: One of the Causes of Carpal Tunnel Syndrome]. AB - We report on a carpal tunnel syndrome in a 50-year-old woman, presumably caused in part by a 35-year-old asymptomatic capitate non-union. The carpal tunnel was released and a large exostosis removed. 3 weeks after the operation the patient was free of symptoms. PMID- 26053564 TI - High Quality Monolayer Graphene Synthesized by Resistive Heating Cold Wall Chemical Vapor Deposition. PMID- 26053563 TI - Gestational Weight Gain Trend and Population Attributable Risks of Adverse Fetal Growth Outcomes in Ohio. AB - BACKGROUND: The trend of gestational weight gain (GWG) in relation to the Institute of Medicine (IOM) guidelines and the population attributable risks (PARs) of GWG on fetal growth outcomes remain unclear. METHODS: We analysed Ohio birth certificates from 2006 to 2012 to examine GWG trend by prepregnancy body mass index, to calculate the risk of small- and large-for-gestational age (SGA and LGA), and macrosomia (birthweight >4000 g or >4500 g) infants, and to estimate the PARs of GWG below or above the guidelines. RESULTS: Of 869,531 women who delivered singleton live births at 22-44 weeks of gestation, 4.5% were underweight, 48.9% were normal weight, 23.9% were overweight, and 22.7% were obese before pregnancy. About 36.5% of underweight, 52.6% of normal weight, 72.5% of overweight, and 62.4% of obese women gained weight above the guidelines, with only slight changes from 2006 to 2012. Also, 34.9% of underweight, 20.1% of normal weight, 16.3% of overweight, and 27.0% of obese women gained weight below the guidelines. The PAR of GWG below or above the guidelines was -13% for SGA, 32.6% for LGA, 28.1% for macrosomia >4000 g, and 48.3% for macrosomia >4500 g, mostly driven by currently GWG above the guidelines in normal weight, overweight, and obese women. CONCLUSIONS: A high percentage of pregnant women gained weight outside of the current IOM GWG guidelines; however, changes from 2006 to 2012 were small. GWG above the IOM guidelines significantly contributed to a large proportion of LGA and macrosomic infants in the general population. PMID- 26053565 TI - Effects of Breastfeeding on Obesity and Intelligence: Causal Insights From Different Study Designs. PMID- 26053566 TI - Comparison between Regional and Local Pulse-Wave Velocity Data. AB - BACKGROUND: Gold standard for pulse-wave velocity (PWV) measurement is determination of the carotid-femoral cfPWV, reflecting regional aortic PWV. Nevertheless, in several echocardiographic laboratories, PWV is measured locally, most commonly at the common carotid artery (CCA). The aim of this study was to compare regional and local PWV values in healthy volunteers. METHODS: The study population consisted of 22 prospectively enrolled healthy subjects, mean age 38.7 +/- 11.1 years, 50% male. For regional PWV measurement, we evaluated cfPWV with a standard echo scanner. Regional PWV was measured at the CCA, with semiautomated dedicated software (MyLab, EsaOte, Italy). RESULTS: cfPWV and local PWV values correlated significantly with high Pearson correlation coefficient (0.62, P = 0.002). Mean regional cfPWV (9.29 +/- 3.73 m/s), however, was significantly higher than mean local PWV value (5.96 +/- 1.08 m/s) (P < 0.001). The difference persisted in the subgroup analysis using different cfPWV cutoff values (10, 9, 8, and 7 m/s), except for subjects with cfPWV <=7 m/s, where regional and local PWV values were similar. CONCLUSION: In a group of healthy volunteers, regional and local PWV values showed a good correlation. However, regional PWV was significantly higher than local PWV. These findings should be carefully taken into account when using this technique in the clinical setting. PMID- 26053567 TI - Letter to the Editor: Nickel allergy and aneurysm clips. PMID- 26053568 TI - Coping with intimate partner violence: Qualitative findings from the study of dynamics of husband to wife abuse. AB - INTRODUCTION: Coping can be defined as an individual's efforts to manage a problem. In Intimate Partner Violence (IPV), coping depends heavily on relationship context, circumstances, and resource availability. The range of coping strategies utilized by women experiencing violence are not fully understood. METHOD: Two hundred female patients who screened positive for verbal or physical abuse were recruited from 6 primary care clinics in San Antonio. Subjects were instructed to complete a baseline survey, which included the COPE scale, as well as daily telephone reports, weekly contact with research staff, and an end-of-study survey. A total of 42 women completed an in-depth qualitative interview at the end of 3 months. RESULTS: Using a template approach to qualitative analysis, interview transcripts were analyzed and coded. "Coping" as a theme emerged independently and was categorized into 14 subcategories, according to the COPE scale; the most commonly endorsed themes from interviews were "avoidance" and "active coping." Previously undescribed methods of coping with IPV were also discovered using this approach, including "preventing escalation" and "ignoring." DISCUSSION: In a qualitative study of women living with IPV, coping emerged as an independent theme. We found that the women used methods not listed on the COPE standardized scale at least as often as more traditional categories. It is important for family medicine clinicians to be aware of the wide variety of coping mechanisms to best address safety planning. PMID- 26053569 TI - The tri-optic: Next step for Collaborative Family Health Care. AB - C. J. Peek, PhD, is a descriptive psychologist, someone trained to organize and define the implicit structure of a discipline. Dr. Peek applies his training to name and organize the content of Collaborative Family Health Care (CFHC) and to examine our next developmental steps. In Dr. Peek's article (see record 2015 25290-002), the reader will find a clear examination of the CFHC organizing principles, visionary components, 20 years of planning, CFHC core competencies, and outcomes. According to Seaburn (see record 2015-10057-002), the impetus for Peek's work comes with the passing last year of Donald A. Bloch, MD, the principle person who envisioned our discipline, founded our organization, and launched this journal. PMID- 26053570 TI - Don Bloch's vision for Collaborative Family Health Care: Progress and next steps. AB - BACKGROUND: Don Bloch is the central figure in the origin story for the field of collaborative family health care; the journal Families, Systems, & Health; and for the Collaborative Family Healthcare Association (CFHA). He exerted extraordinary intellectual and practical leadership for all 3. He convened a national working session in 1994 that took stock of the field and set out next steps, one of which was to create the interprofessional organization dedicated to collaborative family health care that is now CFHA. PURPOSE: As part of honoring Don Bloch's contributions to the field and this journal, this article sets out tenets of his original vision and traces next steps toward this vision generated by national groups between 1994 and 2014, showing what is the same or different over these 20 years, and especially what this means for the field going forward. METHOD: Precepts of Don Bloch's original vision are drawn from his writings, including the briefing papers he prepared for the national Wingspread group convened in 1994, which also set out next steps for the field. These steps are then compared with next developmental steps for the field generated by CFHA conference attendees in 2004 and again in 2014, after reviewing the history of the organization and the field. CONCLUSION: Much of Don Bloch's vision has remained relevant to health care transformation, with a number of areas showing significant accomplishment and acceptance, whereas others remain aspirational, and a few others arguably being more difficult to achieve now than when Don articulated them. PMID- 26053571 TI - Don Bloch's vision: A commentary. AB - Comments on the article "Don Bloch's vision for Collaborative Family Health Care: Progress and next steps" by C. J. Peek (see record 2015-25290-002). Every visionary deserves a skilled integrator and synthesizer such as C. J. Peek. Don would have been impressed with this concise account of the evolution of his own ideas and those of his colleagues in the Collaborative Family Health Care Association, which is Don's greatest legacy-a participatory, visionary, nonguild membership organization. Don Bloch's ecosystemic perspective was all about flattening hierarchies conceptually, clinically, and organizationally. His emphasis on families was also connected to this flattening of hierarchies. Inclusion of families creates more potential for true partnership because the patient needs a team as much as the clinician needs one. The current author wants to hold up the issues of hierarchies, power, and guilds. PMID- 26053572 TI - Inspiration and instruction: Commentary on C. J. Peek's study of Don Bloch's legacy. AB - Comments on the article "Don Bloch's vision for Collaborative Family Health Care: Progress and next steps" by C. J. Peek (see record 2015-25290-002). C. J. offers us a breathtaking, magnificent gift, itself made from gifts. He has taken something good-Don's seminal contributions- and by showing them off in their properly revealed context, like a stone in a setting, has multiplied their value and created something new in its own right. Make no mistake: this article is a work of serious research, conducted according to the methods of the longest running research tradition of all-historical research, and specifically, comparative historical research (Turner, 2014). PMID- 26053573 TI - Unrounding the corners of collaborative family health care. AB - C. J. Peek has done us two lasting services with this beautiful summary. He has reminded us of Don Bloch's contributions to the beginning of collaborative family health care, and he has catalogued the elements of Don's vision for the field. Don's vision was for "collaborative family health care." Although we have made a great deal of progress developing collaborative health care that he would endorse, the full vision including the family as a basic unit of care and of understanding in health care is still ahead of us. The requirement of the inclusion of the family in the formulation of the patient-centered medical home may provide the impetus for a full realization of the "unrounded corners" version of Don's vision. PMID- 26053574 TI - Advancing family involvement in collaborative health care: Next steps. AB - Comments on the article "Don Bloch's vision for Collaborative Family Health Care: Progress and next steps" by C. J. Peek (see record 2015-25290-002). C. J. Peek has provided us with a masterful integration of Don Bloch's vision of collaborative family health care and the evolution over the past 20 years of the field. The current author was very fortunate to be part of the initial meeting at Wingspread in 1994. As a family systems-oriented community and public health trained psychiatrist, my primary focus over 30 years has been on families facing chronic illness and disability and collaborative care efforts in specialty, primary, rehabilitation, and palliative care medicine. In my view, the ability of the health care consumer (patient and his or her family members) and professional worlds to collaborate in a more egalitarian and less hierarchical and wary manner remains a significant constraint to progress. PMID- 26053575 TI - Building the science: Join us. AB - Comments on the article "Don Bloch's vision for Collaborative Family Health Care: Progress and next steps" by C. J. Peek (see record 2015-25290-002). As Peek points out, Don Bloch's vision is alive and well. Teams of health and behavioral health professionals are now working in concert with a shared biopsychosocial frame of reference to improve care and health. You have the opportunity to be involved and move science forward. Seek out like-minded colleagues and expect your system to collect process and outcome metrics. Learn and disseminate your knowledge so that we can provide the outstanding services we all deserve. PMID- 26053576 TI - Open communication: Recommendations for enhancing communication among primary care and mental health providers, services, and systems. AB - Comments on the article "Please break the silence: Parents' views on communication between pediatric primary care and mental health providers" by Greene et al. (see record 2015-14521-001). The article highlights the need to improve communication between primary care and mental health care providers to better serve children and families. The report reaffirms that parents understand the value and necessity of collaborative care, as evidenced by the identification of gaps in consistency of bidirectional communication between providers in traditional and separate practice settings and the desire for improved care coordination. PMID- 26053584 TI - Integrated behavioral health: The train has left the station. Where to next? AB - It's time for the final push to make integrated behavioral health (IBH) the way primary care (and indeed all medical care) is practiced in the United States. Too many of our patients are still suffering from the fragmentation in our health system. Team-based care that includes integrated behavioral health care has the best chance of achieving the Triple Aims of a transformed and efficient health care delivery system that delivers better care, better health, and lower cost for all Americans. (PsycINFO Database Record PMID- 26053585 TI - Parents' Education Shapes, but Does Not Originate, the Disability Representations of Their Children. AB - The present research tested whether children's disability representations are influenced by cultural variables (e.g., social activities, parent education, custom complex variables) or by cognitive constraints. Four questionnaires were administered to a sample of 76 primary school aged children and one of their parents (n = 152). Questionnaires included both open-ended and closed-ended questions. The open-ended questions were created to collect uncensored personal explanations of disability, whereas the closed-ended questions were designed to elicit a response of agreement for statements built on the basis of the three most widespread disability models: individual, social, and biopsychosocial. For youngest children (6-8 years old), people with disabilities are thought of as being sick. This early disability representation of children is consistent with the individual model of disability and independent from parents' disability explanations and representations. As children grow older (9-11 years old), knowledge regarding disability increases and stereotypical beliefs about disability decrease, by tending to espouse their parents representations. The individual model remains in the background for the adults too, emerging when the respondents rely on their most immediately available mental representation of disability such as when they respond to an open-ended question. These findings support that the youngest children are not completely permeable to social representations of disability likely due to cognitive constraints. Nevertheless, as the age grows, children appear educable on perspectives of disability adhering to a model of disability representation integral with social context and parent perspective. PMID- 26053586 TI - Microwave synthesis and actuation of shape memory polycaprolactone foams with high speed. AB - Microwave technology is a highly effective approach to fast and uniform heating. This article investigates that the microwave heating as a novel method is used to rapidly foam and actuate biocompatible and biodegradable shape memory crosslinked polycaprolactone (c-PCL) foams. The optical microscope proves that the resulting c-PCL foams have homogenous pore structure. Mechanical behavior and shape memory performance of c-PCL foams are investigated by static materials testing. Shape recovery ratio is approximately 100% and the whole recovery process takes only 98 s when trigged by microwave. Due to the unique principle of microwave heating, the recovery speed of c-PCL foams in microwave oven is several times faster than that in hot water and electric oven. Hence compared to the traditional heating methods, microwave is expected to bring more advantages to modern industry and scientific research in the field of smart materials and structures. PMID- 26053587 TI - Renal medullary carcinoma and sickle cell trait: A systematic review. AB - Sickle cell trait (SCT) carries a small risk of renal medullary carcinoma (RMC). We conducted a systematic literature review and reported new four RMC cases (total N = 217). Eighty eight percent had SCT and 8% had sickle cell disease; 50% were children. Males had 2.4* risk than females. Isolated hematuria or in combination with abdominal or flank pain was the presenting sign in 66% cases. Tumor-related mortality was 95%. Four non-metastatic patients were long-term disease-free survivors. Although risk appears to be very low, individuals with SCT should be informed about the low risk of RMC with the hope of early diagnosis. Hematuria should prompt immediate investigation. PMID- 26053588 TI - Health disparities in liver disease in sub-Saharan Africa. AB - Disparities in health reflect the differences in the incidence, prevalence, burden of disease and access to care determined by socio-economic and environmental factors. With liver disease, these disparities are exacerbated by a combination of limited awareness and preventable causes of morbidity and mortality in addition to the diagnostic and management costs. Sub-Saharan Africa, comprising 11% of the world's population, disproportionately has 24% of the global disease burden, yet allocates <1% of global spend on health. It has 3% of the global healthcare workforce with a mean of 0.8 healthcare workers per 1000 population. Barriers to healthcare access are many and compounded by limited civil registration data, socio-economic inequalities, discrepancies in private and public healthcare services and geopolitical strife. The UN 2014 report on the Millennium Development Goals suggest that sub-Saharan Africa will probably not meet several goals, however with HIV/AIDS and Malaria (goal 6), many successes have been achieved. A 2010 Global Burden of Disease study demonstrated that cirrhosis mortality in sub-Saharan Africa doubled between 1980 and 2010. Aetiologies included hepatitis B (34%), hepatitis C (17%), alcohol (18%) and unknown in 31%. Hepatitis B, C and alcohol accounted for 47, 23 and 20% of hepatocellular carcinoma respectively. In 10%, the underlying aetiology was not known. Liver disease reflects the broader disparities in healthcare in sub Saharan Africa. However, many of these challenges are not insurmountable as vaccines and new therapies could comprehensively deal with the burden of viral hepatitis. Access to and affordability of therapeutics remains the major barrier. PMID- 26053589 TI - UVCB substances: methodology for structural description and application to fate and hazard assessment. AB - Substances of unknown or variable composition, complex reaction products, or biological materials (UVCBs) have been conventionally described in generic terms. Commonly used substance identifiers are generic names of chemical classes, generic structural formulas, reaction steps, physical-chemical properties, or spectral data. Lack of well-defined structural information has significantly restricted in silico fate and hazard assessment of UVCB substances. A methodology for the structural description of UVCB substances has been developed that allows use of known identifiers for coding, generation, and selection of representative constituents. The developed formats, Generic Simplified Molecular-Input Line Entry System (G SMILES) and Generic Graph (G Graph), address the need to code, generate, and select representative UVCB constituents; G SMILES is a SMILES-based single line notation coding fixed and variable structural features of UVCBs, whereas G Graph is based on a workflow paradigm that allows generation of constituents coded in G SMILES and end point-specific or nonspecific selection of representative constituents. Structural description of UVCB substances as afforded by the developed methodology is essential for in silico fate and hazard assessment. Data gap filling approaches such as read-across, trend analysis, or quantitative structure-activity relationship modeling can be applied to the generated constituents, and the results can be used to assess the substance as a whole. The methodology also advances the application of category-based data gap filling approaches to UVCB substances. PMID- 26053591 TI - INFORMed choices: facilitating shared decision-making in health care. AB - A clinical audit was undertaken before and after the introduction of a five minute video presentation as an adjunct to the clinical consultation in the setting of ruptured membranes at term. The video framed clinical information using an INFORM structure: providing Information, Facts, Options, Reasons, Meaning. Subsequently, women were more likely to report that information was unbiased, based on facts and evidence that they were involved in the decision making and overall satisfied with the information provided. PMID- 26053590 TI - Dietary, supplement, and adipose tissue tocopherol levels in relation to prostate cancer aggressiveness among African and European Americans: The North Carolina Louisiana Prostate Cancer Project (PCaP). AB - BACKGROUND: Controversies remain over the safety and efficacy of vitamin E (i.e., alpha-tocopherol) supplementation use for the prevention of prostate cancer (CaP); however, associations of different tocopherol forms and CaP aggressiveness have yet to be examined. METHODS: This study examined whether food intake of tocopherols, vitamin E supplement use, and adipose tissue biomarkers of tocopherol were associated with CaP aggressiveness among African-American (AA, n = 1,023) and European-American (EA, n = 1,079) men diagnosed with incident CaP. Dietary tocopherols were estimated from a food frequency questionnaire, supplement use from questionnaire/inventory, and biomarkers from abdominal adipose samples measured using high-performance liquid chromatography. Odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated from logistic regression comparing high-aggressive CaP to low/intermediate aggressive CaP, adjusting for covariates. RESULTS: Dietary intakes of alpha-and delta-tocopherol were related inversely to CaP aggressiveness among EAs [OR (95%CI), highest versus lowest quartile: alpha-tocopherol, 0.34 (0.17-0.69), P(trend) = 0.006; delta-tocopherol, 0.45 (0.21-0.95) P(trend) = 0.007]. Inverse associations between dietary and supplemental alpha-tocopherol and CaP aggressiveness were observed among AAs, though these did not reach statistical significance [OR (95%CI), highest versus lowest quartile: dietary alpha-tocopherol, 0.58 (0.28 1.19), P(trend) = 0.20; supplemental alpha-tocopherol, 0.64 (0.31-1.21) P(trend) = 0.15]. No significant association was observed between adipose tocopherol levels and CaP aggressiveness [OR (95%CI), highest versus lowest quartiles of alpha-tocopherol for EAs 1.43 (0.66-3.11) and AAs 0.66 (0.27-1.62)]. CONCLUSIONS: The inverse associations observed between dietary sources of tocopherols and CaP aggressiveness suggests a beneficial role of food sources of these tocopherols in CaP aggressiveness. PMID- 26053592 TI - Esophageal pH Monitoring in Children: A Simple Mathematical Formula for pH Probe Positioning. AB - Correct pH probe placement is vital for the precision of esophageal pH monitoring. This study aimed at finding the optimal formula for placement of pH probe in the locus proposed by the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition European Pediatric Impedance Working Group, that is, 2 vertebrae above the diaphragm. An analysis of data regarding 353 children ages 0-18 years in whom the position of the pH sensor was determined radiographically revealed that a mathematical formula (3.2 + 0.2 * body length or height, centimeter) could guide the probe to within 1/12 of thoracic spine length of the desired location in 71.7% of all of the patients. PMID- 26053593 TI - The structure of H2TiO3-a short discussion on "Lithium recovery from salt lake brine by H2TiO3". AB - A short discussion on the structure of H2TiO3 presented in the article entitled Lithium recovery from salt lake brine by H2TiO3 (R. Chitrakar, Y. Makita, K. Ooi and A. Sonoda, Dalton Trans., 2014, 43, 8933) is presented. In our opinion, it is not correct to identify the phase of H2TiO3 as monoclinic. The XRD pattern of H2TiO3 differs substantially from that of Li2TiO3. XRD pattern simulation shows that the peak (1[combining macron]33) and the peak (2[combining macron]06) cannot be fully collapsed or substantially decrease in intensity by substitution of Li(+) with H(+) if H2TiO3 shares a similar space group and lattice parameters with Li2TiO3. A direct verification of a similar structure by N. V. Tarakina and co-workers may aid the confirmation of the structure. The layered double hydroxide type with the 3R1 sequence of oxygen layers is more reasonable for H2TiO3 and can be described as a stacking of charge-neutral metal oxyhydroxide slabs [(OH)2OTi2O(OH)2]. PMID- 26053594 TI - A combined theoretical and experimental investigation of uranium dioxide under high static pressure. AB - We have investigated the behavior of uranium dioxide (UO2) under high static pressure using a combination of experimental and theoretical techniques. We have made Raman spectroscopic measurements up to 87 GPa, electrical transport measurements up to 50 GPa from 10 K to room temperature, and optical transmission measurements up to 28 GPa. We have also carried out theoretical calculations within the GGA + U framework. We find that Raman frequencies match to a large extent, theoretical predictions for the cotunnite (Pnma) structure above 30 GPa, but at higher pressures some behavior is not captured theoretically. The Raman measurements also imply that the low-pressure fluorite phase coexists with the cotunnite phase up to high pressures, consistent with earlier reports. Electrical transport measurements show that the resistivity decreases by more than six orders of magnitude with increasing pressure up to 50 GPa but that the material never adopts archetypal metallic behavior. Optical transmission spectra show that while UO2 becomes increasingly opaque with increasing pressure, a likely direct optical band gap of more than 1 eV exists up to at least 28 GPa. Together with the electrical transport measurements, we conclude that the high pressure electrical conductivity of UO2 is mediated by variable-range hopping. PMID- 26053595 TI - Bioconjugation of Serum Albumin to a Maleimide-appended Porphyrin/Cyclodextrin Supramolecular Complex as an Artificial Oxygen Carrier in the Bloodstream. AB - HemoCD is an inclusion complex of per-O-methylated beta-cyclodextrin dimer and an iron(II) porphyrin, which forms a stable O2 complex in water. Therefore, hemoCD has the potential for use as a synthetic O2 carrier in mammalian blood. In this study, a hemoCD derivative having a maleimide group (Mal-hemoCD) was conjugated to a Cys residue of serum albumin via a Michael addition reaction in order to increase the circulation time of the O2 carrier. The O2 -binding affinities (P1/2 [Torr]) and half-lives (t1/2 [h]) of the O2 adducts at pH 7.4 and 25 degrees C were determined to be 9 Torr and 23 h for Mal-hemoCD, and 10 Torr and 14 h for albumin-conjugated hemoCD (Alb-hemoCD). Our pharmacokinetic study revealed that renal excretion of Alb-hemoCD was effectively suppressed and that half of injected Alb-hemoCD remained in blood at 3 h after injection. It is noteworthy that Mal-hemoCD also had a long circulation time because of the bioconjugation reaction that occurred during circulation in the bloodstream. PMID- 26053596 TI - Mid-gestation brain Doppler and head biometry in fetuses with congenital heart disease predict abnormal brain development at birth. AB - OBJECTIVES: Fetuses with congenital heart disease (CHD) show evidence of abnormal brain development before birth, which is thought to contribute to adverse neurodevelopment during childhood. Our aim was to evaluate whether brain development in late pregnancy can be predicted by fetal brain Doppler, head biometry and the clinical form of CHD at the time of diagnosis. METHODS: This was a prospective cohort study including 58 fetuses with CHD, diagnosed at 20-24 weeks' gestation, and 58 normal control fetuses. At the time of diagnosis, we recorded fetal head circumference (HC), biparietal diameter, middle cerebral artery pulsatility index (MCA-PI), cerebroplacental ratio (CPR) and brain perfusion by fractional moving blood volume. We classified cases into one of two clinical types defined by the expected levels (high or low) of placental (well oxygenated) blood perfusion, according to the anatomical defect. All fetuses underwent subsequent 3T-magnetic resonance imaging (MRI) at 36-38 weeks' gestation. RESULTS: Abnormal prenatal brain development was defined by a composite score including any of the following findings on MRI: total brain volume < 10(th) centile, parietoccipital or cingulate fissure depth < 10(th) centile or abnormal metabolic profile in the frontal lobe. Logistic regression analysis demonstrated that MCA-PI (odds ratio (OR), 12.7; P = 0.01), CPR (OR, 8.7; P = 0.02) and HC (OR, 6.2; P = 0.02) were independent predictors of abnormal neurodevelopment; however, the clinical type of CHD was not. CONCLUSIONS: Fetal brain Doppler and head biometry at the time of CHD diagnosis are independent predictors of abnormal brain development at birth, and could be used in future algorithms to improve counseling and targeted interventions. Copyright (c) 2015 ISUOG. Published by John Wiley & Sons Ltd. PMID- 26053597 TI - Bioinspired Surface for Surgical Graspers Based on the Strong Wet Friction of Tree Frog Toe Pads. AB - Soft tissue damage is often at risk during the use of a surgical grasper, because of the strong holding force required to prevent slipping of the soft tissue in wet surgical environments. Improvement of wet friction properties at the interface between the surgical grasper and soft tissue can greatly reduce the holding force required and, thus, the soft tissue damage. To design and fabricate a biomimetic microscale surface with strong wet friction, the wet attachment mechanism of tree frog toe pads was investigated by observing their epithelial cell structure and the directionally dependent friction on their toe pads. Using these observations as inspiration, novel surface micropatterns were proposed for the surface of surgical graspers. The wet friction of biomimetic surfaces with various types of polygon pillar patterns involving quadrangular pillars, triangular pillars, rhomboid pillars, and varied hexagonal pillars were tested. The hexagonal pillar pattern exhibited improved wet frictional performance over the modern surgical grasper jaw pattern, which has conventional macroscale teeth. Moreover, the deformation of soft tissue in the bioinspired surgical grasper with a hexagonal pillar pattern is decreased, compared with the conventional surgical grasper. PMID- 26053598 TI - National Association of Clinical Nurse Specialists news: President's message. PMID- 26053599 TI - Meeting the challenges of children's health. PMID- 26053600 TI - Maximizing smart pump technology to enhance patient safety. PMID- 26053601 TI - A review of the Child and Adolescent Social Support Scale for Healthy Behaviors. AB - Assessing an instrument's psychometric properties to determine appropriateness for use can be a challenging process. Dissecting the statistical terminology may be even more perplexing. There are several instruments that evaluate adolescents' perceived social support, but a fairly new instrument related to this construct assesses not only the availability of social support but also support for healthy behaviors in this population. The Child and Adolescent Social Support Scale for Healthy Behaviors, first published in 2013, demonstrates adequate initial reliability and validity. The purpose of this article is to review the psychometric properties of the Child and Adolescent Social Support Scale for Healthy Behaviors and potential uses of the instrument. PMID- 26053602 TI - Looking "fit and thin" to win: diuretic drug abuse in and outside the arena. PMID- 26053603 TI - Overcoming "financial phobia". PMID- 26053604 TI - Prevention of pressure ulcers in the intensive care unit: a randomized trial of 2 viscoelastic foam support surfaces. AB - AIMS AND OBJECTIVES: The aim of this study is to compare whether differences exist between 2 viscoelastic foam support surfaces in the development of new pressure ulcers. BACKGROUND: There is evidence to support the use of viscoelastic foam over standard hospital foam to reduce pressure. A comparative effectiveness study was done to compare 2 viscoelastic foam support surfaces. DESIGN: A randomized controlled trial was carried out. METHOD: The study was performed in 2 intensive care units between October 1, 2008, and January 4, 2010. Patients (n = 105) admitted to intensive care unit were randomly assigned to viscoelastic foam 1 (n = 53) or viscoelastic foam 2 support surface (n = 52). RESULTS: In total, 42.8% of all patients developed a new pressure ulcer of stage 1 or worse. By stages, pressure ulcer incidence was 28.6%, 13.3%, and 1.0% for stages 1, 2, and 3, respectively. There was no significant difference in pressure ulcer incidence between the viscoelastic foam 1 and 2 groups (X2 = 0.07, df = 1, P > .05). CONCLUSIONS: No difference was found between 2 different viscoelastic foam surfaces in the prevention of pressure ulcers in patients treated in intensive care. RELEVANCE TO CLINICAL PRACTICE: Pressure ulcer incidence in critically ill patients remains high. Nurses must compare current products for effectiveness and develop innovative systems, processes, or devices to deliver best practices. PMID- 26053605 TI - Strategies to improve nurse knowledge of delirium: a call to the adult gerontology clinical nurse specialist. AB - PURPOSE/OBJECTIVES: The purpose of this article is to discuss the role of the adult-gerontology clinical nurse specialist in addressing the problem of delirium in hospitalized older adults through strategies to improve nurse knowledge. BACKGROUND: Delirium is a significant issue in hospitalized older adults. This acute confusional state can adversely impact older adults in various ways. Delirium has been implicated in (1) poor physical, cognitive, and psychological outcomes, (2) prolonged hospitalizations, (3) increased costs of care, (4) need for continued postacute care, and (5) patient and provider stress. To prevent delirium, nurses must possess the knowledge to identify risk factors and institute preventive strategies. Once a change in mental status occurs, it is critical that nurses recognize delirium and the steps necessary to provide safe, effective care. Nurses are the major providers of bedside care; however, multiple studies have identified a lack of nurse knowledge regarding delirium. The adult gerontology clinical nurse specialist can be instrumental in fostering knowledge on this important issue. DESCRIPTION: Multiple interventions can be conducted by the adult-gerontology clinical nurse specialist with acute care nurses to increase delirium knowledge. A review of the literature revealed strategies that might be used in the hospital setting. Before educational endeavors, it is crucial to assess baseline nurse knowledge of delirium. Educational strategies can then include use of standardized delirium assessment tools, implementation of the Geriatric Resource Nurse model, fostering geriatric case studies and simulations, conducting geriatric grand rounds, and development of structured delirium educational programs. Exploring the patient experience, post delirium, can provide an invaluable, first-hand account of the acute confusional state. This information can impact nurse knowledge as well as patient safety and well being. Geriatric certification and professional organizational involvement can be encouraged. Numerous online geriatric resources can be shared with nurses to enhance knowledge of delirium. OUTCOME: Improved nurse knowledge will assist in preventing/decreasing incidents of delirium and thwart the negative outcomes associated with delirium occurrence in hospitalized older adults. IMPLICATIONS: Nurse knowledge can be measured and patient care assessed to determine the effectiveness of the proposed educational strategies. CONCLUSION: The goal of the identified adult-gerontology clinical nurse specialist-led educational initiatives is to improve knowledge of delirium, which will assist nurses in providing evidence-based, safe, appropriate care to all hospitalized older adults. PMID- 26053606 TI - Implementing the dynamic appraisal of situational aggression in mental health units. AB - PURPOSE: The aims of this study are to explain the intervention of implementing a structured violence risk assessment procedure in mental health inpatient units using the Ottawa Model of Research Use (OMRU) as a guiding framework and to consider nurses' perspectives of its clinical utility and implementation process. BACKGROUND: Patient aggression toward staff is a global concern in mental health units. The limited extant literature exploring the use of structured violence risk assessments in mental health units, although small and inconsistent, reveals some positive impacts on the incidence of aggression and staff's use of restrictive interventions. RATIONALE: Although numerous violence risk assessment instruments have been developed and tested, their systematic implementation and use are still limited. DESCRIPTION OF THE PROJECT: A project titled "Safer Working Management" (111298) was conducted in a Finnish hospital district, across 3 mental health units. The 6 steps of OMRU were followed during implementation of the Dynamic Appraisal of Situational Aggression (DASA). OUTCOME: Nurses' views toward structured violence risk assessment procedures varied. Although implementation of the DASA was seen as a useful method to increase discussions with patients and nursing staff, some staff preferred their own clinical judgment for assessment of violence risk. CONCLUSION: It is possible to use a specific model to promote the implementation of risk assessment instruments in mental health units. However, the complex mental health inpatient environment and the difficulties in understanding and managing aggressive patients present challenges for the implementation of structured violence risk assessment methods. IMPLICATIONS: The OMRU provides a tool for clinical nurse specialists to guide implementation process in mental health units. Clinical nurse specialists must promote training for staff regarding use of new innovations, such as the DASA. Implementation processes should be reviewed so that clinical nurse specialists can lead and support mental health staff to properly use structured violence risk assessment measures. PMID- 26053607 TI - Epic arts programs in Cambodia, China, and the United Kingdom bring to life the humanizing power of the arts. PMID- 26053608 TI - Survey design research: a tool for answering nursing research questions. AB - The clinical nurse specialist is in a unique position to identify and study clinical problems in need of answers, but lack of time and resources may discourage nurses from conducting research. However, some research methods can be used by the clinical nurse specialist that are not time-intensive or cost prohibitive. The purpose of this article is to explain the utility of survey methodology for answering a number of nursing research questions. The article covers survey content, reliability and validity issues, sample size considerations, and methods of survey delivery. PMID- 26053610 TI - Elucidation of Pathways for NO Electroreduction on Pt(111) from First Principles. AB - The mechanism of nitric oxide electroreduction on Pt(111) is investigated using a combination of first principles calculations and electrokinetic rate theories. Barriers for chemical cleavage of N-O bonds on Pt(111) are found to be inaccessibly high at room temperature, implying that explicit electrochemical steps, along with the aqueous environment, play important roles in the experimentally observed formation of ammonia. Use of explicit water models, and associated determination of potential-dependent barriers based on Bulter-Volmer kinetics, demonstrate that ammonia is produced through a series of water-assisted protonation and bond dissociation steps at modest voltages (<0.3 V). In addition, the analysis sheds light on the poorly understood formation mechanism of nitrous oxide (N2 O) at higher potentials, which suggests that N2 O is not produced through a Langmuir-Hinshelwood mechanism; rather, its formation is facilitated through an Eley-Rideal-type process. PMID- 26053611 TI - Transient Sulfate Aerosols as a Signature of Exoplanet Volcanism. AB - Geological activity is thought to be important for the origin of life and for maintaining planetary habitability. We show that transient sulfate aerosols could be a signature of exoplanet volcanism and therefore of a geologically active world. A detection of transient aerosols, if linked to volcanism, could thus aid in habitability evaluations of the exoplanet. On Earth, subduction-induced explosive eruptions inject SO2 directly into the stratosphere, leading to the formation of sulfate aerosols with lifetimes of months to years. We demonstrate that the rapid increase and gradual decrease in sulfate aerosol loading associated with these eruptions may be detectable in transit transmission spectra with future large-aperture telescopes, such as the James Webb Space Telescope (JWST) and European Extremely Large Telescope (E-ELT), for a planetary system at a distance of 10 pc, assuming an Earth-like atmosphere, bulk composition, and size. Specifically, we find that a signal-to-noise ratio of 12.1 and 7.1 could be achieved with E-ELT (assuming photon-limited noise) for an Earth analogue orbiting a Sun-like star and M5V star, respectively, even without multiple transits binned together. We propose that the detection of this transient signal would strongly suggest an exoplanet volcanic eruption, if potential false positives such as dust storms or bolide impacts can be ruled out. Furthermore, because scenarios exist in which O2 can form abiotically in the absence of volcanic activity, a detection of transient aerosols that can be linked to volcanism, along with a detection of O2, would be a more robust biosignature than O2 alone. PMID- 26053613 TI - The Australian 75+ Health Assessment: could it detect early functional decline better? AB - OBJECTIVE: The aim of the present study was to identify opportunities to improve the reach and impact of the Australian Medicare 75+ Health Assessment (75+HA) to detect early functional decline (FD). METHODS: A comparison of two published review articles produced two outputs: (1) assessments identified in the systematic review that underpinned the 75+HA items were ranked for evidence of effectiveness and compared with the volume of research into assessment areas identified by a recent review on indicators of early FD; and (2) items in the 75+HA were compared with those in the recent review. RESULTS: The review underpinning the 75+HA found 19 assessment areas, with strongest evidence of effectiveness for vision/hearing, teeth/oral, balance/gait, cognitive and service use. The more recent review reported on six domains (eight subdomains) of FD assessment: physical and cognitive elements of the performance capacity domain were the least well assessed, whereas the most comprehensively assessed domains were health service use, performance capacity (mental subdomain), participation (motivation/volition subdomain) and demographics. The 75+HA addresses only some items related to early FD as identified by the recent literature. CONCLUSION: Reassessment of the 75+HA with a view to including current evidence-based assessments for early FD is recommended. Updating the 75+HA items with ways to detect FD earlier may increase its relevance to Australia's ageing population. PMID- 26053612 TI - Molecular prey identification in Central European piscivores. AB - Diet analysis is an important aspect when investigating the ecology of fish eating animals and essential for assessing their functional role in food webs across aquatic and terrestrial ecosystems. The identification of fish remains in dietary samples, however, can be time-consuming and unsatisfying using conventional morphological analysis of prey remains. Here, we present a two-step multiplex PCR system, comprised of six assays, allowing for rapid, sensitive and specific detection of fish DNA in dietary samples. This approach encompasses 78 fish and lamprey species native to Central European freshwaters and enables the identification of 31 species, six genera, two families, two orders and two fish family clusters. All targeted taxa were successfully amplified from 25 template molecules, and each assay was specific when tested against a wide range of invertebrates and vertebrates inhabiting aquatic environments. The applicability of the multiplex PCR system was evaluated in a feeding trial, wherein it outperformed morphological prey analysis regarding species-specific prey identification in faeces of Eurasian otters. Additionally, a wide spectrum of fish species was detected in field-collected faecal samples and regurgitated pellets of Common Kingfishers and Great Cormorants, demonstrating the broad applicability of the approach. In conclusion, this multiplex PCR system provides an efficient, easy to use and cost-effective tool for assessing the trophic ecology of piscivores in Central Europe. Furthermore, the multiplex PCRs and the primers described therein will be applicable wherever DNA of the targeted fish species needs to be detected at high sensitivity and specificity. PMID- 26053614 TI - Ru-Ag and Ru-Au dicarbene complexes from an abnormal carbene ruthenium system. AB - Reaction of [Ru(OAc)2(PPh3)2] with a P-functionalized imidazolium bromide easily affords a cationic abnormal carbene Ru system. Metalation with Ag2O yields a Ru Ag complex containing an anionic dicarbene ligand, while subsequent transmetalation with Au(tht)Cl leads to the corresponding Ru-Au system. The bimetallic complexes were characterized by single crystal X-ray diffraction and are the first examples of complexes bearing anionic dicarbene ligands connecting two different d-block elements. PMID- 26053615 TI - Trends in Pulmonary Function Testing Before Noncardiothoracic Surgery. PMID- 26053616 TI - NF-kappaBp65 and Expression of Its Pro-Inflammatory Target Genes Are Upregulated in the Subcutaneous Adipose Tissue of Cachectic Cancer Patients. AB - Cancer cachexia, of which the most notable symptom is severe and rapid weight loss, is present in the majority of patients with advanced cancer. Inflammatory mediators play an important role in the development of cachexia, envisaged as a chronic inflammatory syndrome. The white adipose tissue (WAT) is one of the first compartments affected in cancer cachexia and suffers a high rate of lipolysis. It secretes several cytokines capable of directly regulating intermediate metabolism. A common pathway in the regulation of the expression of pro inflammatory cytokines in WAT is the activation of the nuclear transcription factor kappa-B (NF-kappaB). We have examined the gene expression of the subunits NF-kappaBp65 and NF-kappaBp50, as well as NF-kappaBp65 and NF-kappaBp50 binding, the gene expression of pro-inflammatory mediators under NF-kappaB control (IL 1beta, IL-6, INF-gamma, TNF-alpha, MCP-1), and its inhibitory protein, nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkappaB-alpha). The observational study involved 35 patients (control group, n = 12 and cancer group, n = 23, further divided into cachectic and non-cachectic). NF-kappaBp65 and its target genes expression (TNF-alpha, IL-1beta, MCP-1 and IkappaB-alpha) were significantly higher in cachectic cancer patients. Moreover, NF-kappaBp65 gene expression correlated positively with the expression of its target genes. The results strongly suggest that the NF-kappaB pathway plays a role in the promotion of WAT inflammation during cachexia. PMID- 26053617 TI - Prebiotics Modulate the Effects of Antibiotics on Gut Microbial Diversity and Functioning in Vitro. AB - Intestinal bacteria carry out many fundamental roles, such as the fermentation of non-digestible dietary carbohydrates to produce short chain fatty acids (SCFAs), which can affect host energy levels and gut hormone regulation. Understanding how to manage this ecosystem to improve human health is an important but challenging goal. Antibiotics are the front line of defence against pathogens, but in turn they have adverse effects on indigenous microbial diversity and function. Here, we have investigated whether dietary supplementation--another method used to modulate gut composition and function--could be used to ameliorate the side effects of antibiotics. We perturbed gut bacterial communities with gentamicin and ampicillin in anaerobic batch cultures in vitro. Cultures were supplemented with either pectin (a non-fermentable fibre), inulin (a commonly used prebiotic that promotes the growth of beneficial bacteria) or neither. Although antibiotics often negated the beneficial effects of dietary supplementation, in some treatment combinations, notably ampicillin and inulin, dietary supplementation ameliorated the effects of antibiotics. There is therefore potential for using supplements to lessen the adverse effects of antibiotics. Further knowledge of such mechanisms could lead to better therapeutic manipulation of the human gut microbiota. PMID- 26053618 TI - A Protein Extract from Chicken Reduces Plasma Homocysteine in Rats. AB - The present study aimed to evaluate effects of a water-soluble protein fraction of chicken (CP), with a low methionine/glycine ratio, on plasma homocysteine and metabolites related to homocysteine metabolism. Male Wistar rats were fed either a control diet with 20% w/w casein as the protein source, or an experimental diet where 6, 14 or 20% w/w of the casein was replaced with the same amount of CP for four weeks. Rats fed CP had reduced plasma total homocysteine level and markedly increased levels of the choline pathway metabolites betaine, dimethylglycine, sarcosine, glycine and serine, as well as the transsulfuration pathway metabolites cystathionine and cysteine. Hepatic mRNA level of enzymes involved in homocysteine remethylation, methionine synthase and betaine-homocysteine S methyltransferase, were unchanged, whereas cystathionine gamma-lyase of the transsulfuration pathway was increased in the CP treated rats. Plasma concentrations of vitamin B2, folate, cobalamin, and the B-6 catabolite pyridoxic acid were increased in the 20% CP-treated rats. In conclusion, the CP diet was associated with lower plasma homocysteine concentration and higher levels of serine, choline oxidation and transsulfuration metabolites compared to a casein diet. The status of related B-vitamins was also affected by CP. PMID- 26053619 TI - Hyponatremia Predicts New-Onset Cardiovascular Events in Peritoneal Dialysis Patients. AB - BACKGROUND AND AIM: Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients on peritoneal dialysis (PD). Hyponatremia was recently shown to be a modifiable factor that is strongly associated with increased mortality in PD patients. However, the clinical impact of hyponatremia on CV outcomes in these patients is unclear. METHODS: To determine whether a low serum sodium level predicts the development of CV disease, we carried out a prospective observational study of 441 incident patients who started PD between January 2000 and December 2005. Time-averaged serum sodium (TA-Na) levels were determined to investigate the ability of hyponatremia to predict newly developed CV events in these patients. RESULTS: During a mean follow-up of 43.2 months, 106 (24.0%) patients developed new CV events. The cumulative incidence of new-onset CV events after the initiation of PD was significantly higher in patients with TA-Na levels <= 138 mEq/L than in those with a TA-Na > 138 mEq/L. After adjustment for multiple potentially confounding covariates, an increase in TA-Na level was found to be associated with a significantly lower risk of CV events (subdistribution hazard ratio per 1 mEq/L increase, 0.90; 95% confidence interval, 0.83-0.96; p = 0.003). Patients with a TA-Na <= 138 mEq/L had a 2.31-fold higher risk of suffering a CV event. CONCLUSIONS: These results provide evidence of a clear association between low serum sodium and new-onset CV events after dialysis initiation in PD patients. Whether the correction of hyponatremia for this indication provides additional protection for the development of CV disease in these patients remains to be addressed in interventional studies. PMID- 26053621 TI - Donor double common bile duct in living donor liver transplantation. PMID- 26053620 TI - Protective Effects of Clenbuterol against Dexamethasone-Induced Masseter Muscle Atrophy and Myosin Heavy Chain Transition. AB - BACKGROUND: Glucocorticoid has a direct catabolic effect on skeletal muscle, leading to muscle atrophy, but no effective pharmacotherapy is available. We reported that clenbuterol (CB) induced masseter muscle hypertrophy and slow-to fast myosin heavy chain (MHC) isoform transition through direct muscle beta2 adrenergic receptor stimulation. Thus, we hypothesized that CB would antagonize glucocorticoid (dexamethasone; DEX)-induced muscle atrophy and fast-to-slow MHC isoform transition. METHODOLOGY: We examined the effect of CB on DEX-induced masseter muscle atrophy by measuring masseter muscle weight, fiber diameter, cross-sectional area, and myosin heavy chain (MHC) composition. To elucidate the mechanisms involved, we used immunoblotting to study the effects of CB on muscle hypertrophic signaling (insulin growth factor 1 (IGF1) expression, Akt/mammalian target of rapamycin (mTOR) pathway, and calcineurin pathway) and atrophic signaling (Akt/Forkhead box-O (FOXO) pathway and myostatin expression) in masseter muscle of rats treated with DEX and/or CB. RESULTS AND CONCLUSION: Masseter muscle weight in the DEX-treated group was significantly lower than that in the Control group, as expected, but co-treatment with CB suppressed the DEX induced masseter muscle atrophy, concomitantly with inhibition of fast-to-slow MHC isoforms transition. Activation of the Akt/mTOR pathway in masseter muscle of the DEX-treated group was significantly inhibited compared to that of the Control group, and CB suppressed this inhibition. DEX also suppressed expression of IGF1 (positive regulator of muscle growth), and CB attenuated this inhibition. Myostatin protein expression was unchanged. CB had no effect on activation of the Akt/FOXO pathway. These results indicate that CB antagonizes DEX-induced muscle atrophy and fast-to-slow MHC isoform transition via modulation of Akt/mTOR activity and IGF1 expression. CB might be a useful pharmacological agent for treatment of glucocorticoid-induced muscle atrophy. PMID- 26053622 TI - Reading from a Head-Fixed Display during Walking: Adverse Effects of Gaze Stabilization Mechanisms. AB - Reading performance during standing and walking was assessed for information presented on earth-fixed and head-fixed displays by determining the minimal duration during which a numerical time stimulus needed to be presented for 50% correct naming answers. Reading from the earth-fixed display was comparable during standing and walking, with optimal performance being attained for visual character sizes in the range of 0.2 degrees to 1 degrees . Reading from the head fixed display was impaired for small (0.2-0.3 degrees ) and large (5 degrees ) visual character sizes, especially during walking. Analysis of head and eye movements demonstrated that retinal slip was larger during walking than during standing, but remained within the functional acuity range when reading from the earth-fixed display. The detrimental effects on performance of reading from the head-fixed display during walking could be attributed to loss of acuity resulting from large retinal slip. Because walking activated the angular vestibulo-ocular reflex, the resulting compensatory eye movements acted to stabilize gaze on the information presented on the earth-fixed display but destabilized gaze from the information presented on the head-fixed display. We conclude that the gaze stabilization mechanisms that normally allow visual performance to be maintained during physical activity adversely affect reading performance when the information is presented on a display attached to the head. PMID- 26053623 TI - Teaching This Class Drives Me Nuts!--Examining the Person and Context Specificity of Teacher Emotions. AB - Teachers' emotions are critically important for the quality of classroom instruction, and they are key components of teachers' psychological well-being. Past research has focused on individual differences between teachers, whereas within-teacher variation across contexts has rarely been considered. As such, the present research addresses the long-standing yet unresolved person-situation debate pertaining to the emotional experiences of teachers. In two diary studies (N = 135, 70% female, and N = 85, 28% female), we examined the role of person, academic subject, and group of students for teacher emotions; focusing on three of the most salient emotions found in teachers: enjoyment, anger, and anxiety. Findings from multi-level analysis confirmed the person specificity of enjoyment, anger, and, in particular, anxiety. In addition, underscoring the existence of within-teacher variability, findings supported that teachers' emotions considerably varied depending on the subject and group of students taught, particularly so for enjoyment and anger. Implications of the person and context specificity of teacher emotions are discussed in relation to assessments and intervention programs aiming to improve teachers' emotional lives in the classroom. PMID- 26053624 TI - Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF mediated apoptosis of fibro/adipogenic progenitors. AB - Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure. Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown. Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process. We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs). In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor beta1 (TGF-beta1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells. Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-beta1 and reduce muscle fibrosis in mdx mice. Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-beta rich environment favors fibrotic degeneration of the muscle during chronic injury. PMID- 26053626 TI - Successful Discontinuation of Systemic Opioids After Implantation of an Intrathecal Drug Delivery System. AB - INTRODUCTION: An implantable drug delivery system (IDDS) provides an alternate route of opioid administration for patients with chronic pain. We collected data on systemic opioid use before and after IDDS implantation; patients who successfully discontinued systemic opioids; and physician support of discontinuation. METHODS: This was a single-center, retrospective chart review of 99 consecutive patients who used IDDSs for at least six months. Data collection included pre/postimplant systemic opioid use and pain scores, and patient demographic and clinical characteristics. RESULTS: The study population averaged 67 years of age, was 68% women, and 77% were Medicare beneficiaries. Ninety-five percent of patients had low back pain, and 86% had limb pain. The majority (81%) had pain for >5 years. Failed treatments included epidural injections (74%), lumbar spine surgery (46%), spinal cord stimulation (14%), and facet joint injections (11%), with 84% also reporting significant systemic opioid side effects. All patients taking long-acting opioids discontinued these within one month of implant. Total systemic opioid elimination was accomplished by 68% of patients at one month postimplant, 84% at one year, and 92% at five years. At one month postimplant, 60% of patients reported decreased pain (mean change: -4.07), and at one year, 64% did (mean change: -3.42). CONCLUSIONS: IDDS can provide significant and lasting pain relief and an alternate route of delivery compared with systemic opioids with their associated side-effects. We demonstrated that systemic opioid elimination could be accomplished after IDDS implantation in the majority of cases through appropriate patient selection, monitoring, and participation. PMID- 26053625 TI - Activation of HIF-1alpha and LL-37 by commensal bacteria inhibits Candida albicans colonization. AB - Candida albicans colonization is required for invasive disease. Unlike humans, adult mice with mature intact gut microbiota are resistant to C. albicans gastrointestinal (GI) colonization, but the factors that promote C. albicans colonization resistance are unknown. Here we demonstrate that commensal anaerobic bacteria-specifically clostridial Firmicutes (clusters IV and XIVa) and Bacteroidetes-are critical for maintaining C. albicans colonization resistance in mice. Using Bacteroides thetaiotamicron as a model organism, we find that hypoxia inducible factor-1alpha (HIF-1alpha), a transcription factor important for activating innate immune effectors, and the antimicrobial peptide LL-37 (CRAMP in mice) are key determinants of C. albicans colonization resistance. Although antibiotic treatment enables C. albicans colonization, pharmacologic activation of colonic Hif1a induces CRAMP expression and results in a significant reduction of C. albicans GI colonization and a 50% decrease in mortality from invasive disease. In the setting of antibiotics, Hif1a and Camp (which encodes CRAMP) are required for B. thetaiotamicron-induced protection against C. albicans colonization of the gut. Thus, modulating C. albicans GI colonization by activation of gut mucosal immune effectors may represent a novel therapeutic approach for preventing invasive fungal disease in humans. PMID- 26053628 TI - U.S. Air Quality and Health Benefits from Avoided Climate Change under Greenhouse Gas Mitigation. AB - We evaluate the impact of climate change on U.S. air quality and health in 2050 and 2100 using a global modeling framework and integrated economic, climate, and air pollution projections. Three internally consistent socioeconomic scenarios are used to value health benefits of greenhouse gas mitigation policies specifically derived from slowing climate change. Our projections suggest that climate change, exclusive of changes in air pollutant emissions, can significantly impact ozone (O3) and fine particulate matter (PM2.5) pollution across the U.S. and increase associated health effects. Climate policy can substantially reduce these impacts, and climate-related air pollution health benefits alone can offset a significant fraction of mitigation costs. We find that in contrast to cobenefits from reductions to coemitted pollutants, the climate-induced air quality benefits of policy increase with time and are largest between 2050 and 2100. Our projections also suggest that increasing climate policy stringency beyond a certain degree may lead to diminishing returns relative to its cost. However, our results indicate that the air quality impacts of climate change are substantial and should be considered by cost-benefit climate policy analyses. PMID- 26053627 TI - Natural Selection and Functional Potentials of Human Noncoding Elements Revealed by Analysis of Next Generation Sequencing Data. AB - Noncoding DNA sequences (NCS) have attracted much attention recently due to their functional potentials. Here we attempted to reveal the functional roles of noncoding sequences from the point of view of natural selection that typically indicates the functional potentials of certain genomic elements. We analyzed nearly 37 million single nucleotide polymorphisms (SNPs) of Phase I data of the 1000 Genomes Project. We estimated a series of key parameters of population genetics and molecular evolution to characterize sequence variations of the noncoding genome within and between populations, and identified the natural selection footprints in NCS in worldwide human populations. Our results showed that purifying selection is prevalent and there is substantial constraint of variations in NCS, while positive selectionis more likely to be specific to some particular genomic regions and regional populations. Intriguingly, we observed larger fraction of non-conserved NCS variants with lower derived allele frequency in the genome, indicating possible functional gain of non-conserved NCS. Notably, NCS elements are enriched for potentially functional markers such as eQTLs, TF motif, and DNase I footprints in the genome. More interestingly, some NCS variants associated with diseases such as Alzheimer's disease, Type 1 diabetes, and immune-related bowel disorder (IBD) showed signatures of positive selection, although the majority of NCS variants, reported as risk alleles by genome-wide association studies, showed signatures of negative selection. Our analyses provided compelling evidence of natural selection forces on noncoding sequences in the human genome and advanced our understanding of their functional potentials that play important roles in disease etiology and human evolution. PMID- 26053629 TI - Immunology of metal allergies. AB - Allergic contact hypersensitivity to metal allergens is a common health concern worldwide, greatly impacting affected individuals with regard to both quality of life and their ability to work. With an estimated 15-20 % of the Western population hypersensitive to at least one metal allergen, sensitization rates for metallic haptens by far outnumber those reported for other common triggers of allergic contact dermatitis such as fragrances and rubber. Unfortunately, the prevalence of metal-induced hypersensitivity remains high despite extensive legislative efforts to ban/reduce the content of allergy-causing metals in recreational and occupational products. Recently, much progress has been made regarding the perception mechanisms underlying the inflammatory responses to this unique group of contact allergens. This review summarizes recent advances in our understanding of this enigmatic disease. Particular emphasis is put on the mechanisms of innate immune activation and T cell activation by common metal allergens such as nickel, cobalt, palladium, and chromate. PMID- 26053630 TI - Antimicrobial Resistance Profiles of Campylobacter spp. Isolated from Broiler Chicken Meat of Estonian, Latvian and Lithuanian Origin at Estonian Retail Level and from Patients with Severe Enteric Infections in Estonia. AB - The resistance patterns of Campylobacter spp. isolated from retail broiler chicken meat originating either from Estonia, Lithuania or Latvia collected in Estonia were determined. Additionally, in collaboration with the laboratories of several Estonian hospitals, antimicrobial susceptibility patterns were determined for Campylobacter isolates from patients with severe Campylobacter enteric infections. The isolates were identified at the species level by the PCR method. Respectively, 88.8% of the isolates were C. jejuni, and 11.2% were C. coli. In total, 126 Campylobacter isolates of broiler chicken meat and human origin were tested for minimal inhibitory concentrations (MICs) with the broth microdilution VetMIC(TH) method (National Veterinary Institute; Uppsala, Sweden) for a total of six antimicrobials. Resistance to one or more antimicrobials was detected in 62 (63.3%) of Campylobacter broiler chicken meat isolates and in 20 (71.4%) of human origin isolates. Large proportions of the broiler chicken meat isolates were resistant to ciprofloxacin (60.2%). Multidrug resistance (i.e. to three or more unrelated antimicrobials) was detected in five (5.1%) C. jejuni isolates. Among the human isolates, 20 (71.4%) were resistant to fluoroquinolones, and two (7.1%) C. jejuni isolates exhibited multidrug resistance. The chicken meat isolates of Estonian origin were the most susceptible. However, a high proportion of fluoroquinolone-resistant C. jejuni isolates were found in Latvian and Lithuanian products. The results of this study indicate that the problems caused by the inappropriate use of antimicrobials extend beyond the country in which a food originates; therefore, both domestic and international interventions and agreements are required to implement common policies on antimicrobial usage and to minimize the emergence of Campylobacter drug resistance. PMID- 26053631 TI - Unsupervised lineage-based characterization of primate precursors reveals high proliferative and morphological diversity in the OSVZ. AB - Generation of the primate cortex is characterized by the diversity of cortical precursors and the complexity of their lineage relationships. Recent studies have reported miscellaneous precursor types based on observer classification of cell biology features including morphology, stemness, and proliferative behavior. Here we use an unsupervised machine learning method for Hidden Markov Trees (HMTs), which can be applied to large datasets to classify precursors on the basis of morphology, cell-cycle length, and behavior during mitosis. The unbiased lineage analysis automatically identifies cell types by applying a lineage-based clustering and model-learning algorithm to a macaque corticogenesis dataset. The algorithmic results validate previously reported observer classification of precursor types and show numerous advantages: It predicts a higher diversity of progenitors and numerous potential transitions between precursor types. The HMT model can be initialized to learn a user-defined number of distinct classes of precursors. This makes it possible to 1) reveal as yet undetected precursor types in view of exploring the significant features of precursors with respect to specific cellular processes; and 2) explore specific lineage features. For example, most precursors in the experimental dataset exhibit bidirectional transitions. Constraining the directionality in the HMT model leads to a reduction in precursor diversity following multiple divisions, thereby suggesting that one impact of bidirectionality in corticogenesis is to maintain precursor diversity. In this way we show that unsupervised lineage analysis provides a valuable methodology for investigating fundamental features of corticogenesis. PMID- 26053632 TI - The Cytosolic Iron-Sulfur Cluster Assembly Protein MMS19 Regulates Transcriptional Gene Silencing, DNA Repair, and Flowering Time in Arabidopsis. AB - MMS19 is an essential component of the cytoplasmic iron-sulfur (Fe-S) cluster assembly complex in fungi and mammals; the mms19 null mutant alleles are lethal. Our study demonstrates that MMS19/MET18 in Arabidopsis thaliana interacts with the cytoplasmic Fe-S cluster assembly complex but is not an essential component of the complex. We find that MMS19 also interacts with the catalytic subunits of DNA polymerases, which have been demonstrated to be involved in transcriptional gene silencing (TGS), DNA repair, and flowering time regulation. Our results indicate that MMS19 has a similar biological function, suggesting a functional link between MMS19 and DNA polymerases. In the mms19 null mutant, the assembly of Fe-S clusters on the catalytic subunit of DNA polymerase alpha is reduced but not blocked, which is consistent with the viability of the mutant. Our study suggests that MMS19 assists the assembly of Fe-S clusters on DNA polymerases in the cytosol, thereby facilitating transcriptional gene silencing, DNA repair, and flowering time control. PMID- 26053634 TI - The animal gut as a melting pot for horizontal gene transfer. AB - In this minireview, we examine horizontal gene transfer (HGT) events in the mammalian gastrointestinal tract and their role in the evolutionary adaptation of microorganisms to the gut environment. We explore the notion of the mammalian gut as a melting pot of genetic exchange, resulting in the large extent of HGT occurrence. PMID- 26053633 TI - Laparoscopic Nephrectomy versus Open Nephrectomy for Patients with Autosomal Dominant Polycystic Kidney Disease: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: To compare efficacy and safety of laparoscopicnephrectomy (LN) versus open nephrectomy (ON) in the management of autosomal dominant polycystic kidney disease (ADPKD), we conducted a systematic review and meta-analysis. METHODS: A systematic search of the electronic databases PubMed, Scopus, and the Cochrane Library was performed up to October 2014. This systematic review was performed based on observational comparative studies that assessed the two techniques. The weighted mean difference (WMD) and risk ratio (RR), with their corresponding 95% confidence interval (CI), were calculated to compare continuous and dichotomous variables, respectively. RESULTS: Seven studies were identified, including 195 cases (118 LN/77 ON). Although LN was associated with longer operative time (WMD 30.236, 95%CI 14.541 -45.932, P<0.001) and the specimen might not have been resected as heavy as the ON group (WMD -986.516, 95%CI -1883.24--89.795, P = 0.031), patients in this group might benefit from a shorter length of hospital stay (WMD -3.576, 95%CI 4.976--2.176, P <0.001), less estimated blood loss (WMD 180.245, 95%CI -317.939--42.556, P = 0.010), and lower need of transfusion (RR 0.345, 95%CI 0.183-0.650, P = 0.001). The LN group also had less overall complications (RR 0.545, 95%CI 0.329-0.903, P = 0.018). The need of narcotic analgesics between the two groups might have no significant difference (WMD 54.66, 95%CI -129.76-20.44, P = 0.154). CONCLUSION: LN for giant symptomatic ADPKD was feasible, safe and efficacious. Morbidity was significantly reduced compared with the open approach. For an experienced laparoscopist, LN might be a better alternative. PMID- 26053635 TI - Predictable Technique to Register Retruded Contact Position (RCP) Using a Disposable Jaw Relation Recording Device. AB - The dental literature presents various definitions and techniques to describe and register centric relation (CR) or centric occlusion (CO). Briefly reviewing the literature in relation to CR, this article proposes the use of the term retruded contact position (RCP), clinically defined as retruded, unstrained, repeatable position and where the mandibular movements start when a Gothic arch tracing is used. With this clinical definition, a technique can be easily selected that meets all the requirements of such position. The article discusses the use of a jaw recorder that is an intraorally graphic recording device that results in a tracing of mandibular movements in one plane, with the apex of the tracing indicating the retruded, unstrained, and repeatable relationship. The intersection of the arcs produced by the right and left working movement form the apex of the Gothic arch tracing. Several clinical situations using the jaw recorder are described. Clinicians can now quickly and accurately record RCP, balance complete, partial, or implant dentures, and orthopedically reposition the mandible. The technique achieves highly reliable and reproducible results. PMID- 26053636 TI - Diagnostically Driven Planning and Execution of an All-on-4 Treatment Concept. AB - The All-on-4 treatment concept offers advantages to patients seeking full-arch immediate function, including reduced treatment time and costs, improved esthetics, and high patient satisfaction. The biomechanical basis and clinical success of the All-on-4 concept have been validated by numerous scientific and clinical studies. Nevertheless, relatively few clinicians have successfully implemented this extraordinary service for their patients. This article introduces specific planning and treatment protocols advanced by the authors that are intended to: reduce surgical and restorative chairtime; circumvent surgical site disruption; improve the durability and esthetics of the provisional restoration; optimize patient comfort and convenience; and increase clinical implementation compared to first-generation protocols. PMID- 26053637 TI - Assessing Treatment Options Based on Expected Long-Term Results: Case Report Demonstrates 6-Year Outcomes. AB - A patient whose chief concern was the esthetics of her anterior teeth presented for a second opinion after it had been recommended that crowns be placed throughout her mouth. Examination revealed numerous defective and some fractured restorations with recurring caries. With treatment goals including creating and maintaining a healthy periodontal environment, leveling the occlusal plane, and decreasing biomechanical risk, the treatment plan incorporated an interdisciplinary approach that utilized orthodontics, a Kois deprogrammer, and implant therapy. Demonstrating 6-year outcomes, this report discusses use of a method to assess treatment options based on expected long-term results. PMID- 26053638 TI - A Review of the Positive Influence of Crown Contours on Soft-Tissue Esthetics. AB - Successful crown restorations duplicate the natural tooth in hue, chroma, value, maverick colors, and surface texture. Equally important is the visual harmony of the facial and proximal soft-tissue contours, which requires the collaborative skills of the restorative dentist, periodontist, and dental technician. The treatment team must understand the biologic structures adjacent to natural dentition and dental implants. This report describes the potential for specifically designed restorative contours to dictate the optimal gingival profile for tooth-supported and implant-supported crowns. Showing several cases, the article explains how esthetic soft-tissue contours enhance the definitive crown restoration, highlights the importance of clinical evaluation of adjacent biologic structures, and discusses keys to predicting when the proximal papilla has the potential to return to a favorable height and shape. PMID- 26053639 TI - Regeneration in Periodontics: Collagen-A Review of Its Properties and Applications in Dentistry. AB - Collagen is the most abundant protein in mammals, also making it the most important component of the body structurally and functionally. Collagen provides cell occlusiveness, biocompatibility, and resorbability. It is chemotactic for regenerative cells and may enhance the migration and attachment of fibroblasts through its space-making ability. Collagen also has the advantage of being a hemostatic agent with weak immunogenicity, easy manipulation, and the ability to augment tissue thickness. Additionally, upon breakdown through the resorption process, its byproducts are utilized by the host to form native tissue. Further, these proteins are elastic and enhance repair, properties that make the material useful for various biomedical applications. This review highlights and discusses some of the important aspects of collagen as a biomaterial in dentistry. PMID- 26053640 TI - Evaluation of Salivary Transcriptome Markers for the Early Detection of Oral Squamous Cell Cancer in a Prospective Blinded Trial. AB - BACKGROUND: Oral squamous cell cancer (OSCC) is often diagnosed in late stages. Informative biomarkers could play a key role in early diagnosis. Prior case control studies identified discriminatory salivary mRNA markers for OSCC. The National Cancer Institute (NCI) recommends prospective-specimencollection, retrospective-blinded-evaluation (PRoBE) design study for rigorous biomarker identification and validation. METHODS: A PRoBE design study enrolled 170 patients with lesions suspicious for OSCC. Saliva was collected before performing oral biopsy. Six pre-specified oral-cancer-associated mRNAs (IL1beta, IL8, OAZ1, SAT, S100P, and DUSP1) and five housekeeping mRNAs (MT-ATP6, RPL30, RPL37A, RPL0, and RPS17) were measured by quantitative polymerase chain reaction (PCR) without knowledge of tissue diagnosis. A pre-specified multi-marker panel from prior NCI Early Detection Research Network (EDRN) studies was evaluated in this new PRoBE dataset. Individual marker cycle thresholds (Ct) from PCR were also compared in cancer versus control, and new discriminatory models were generated. RESULTS: The EDRN model was validated based on pre-specified statistical analysis plan. Ct values of individual mRNAs reflect an approximately twofold to nearly fourfold increase in concentration in invasive OSCC (P less than 0.01 for all). A new model from this intended-use population with incorporation of housekeeping genes demonstrates a maximal sum of sensitivity and specificity of 150.7% with an area under the receiver operating characteristic (ROC) curve of over 0.85. CONCLUSION: The validation of six pre-specified individual salivary transcriptome markers of OSCC and a pre-specified multi-marker model in a new prospective population supports the robustness of these markers and the multi-marker methodology. New models generated in this intended-use population have the potential to further enhance the decision process for early biopsy. Lesions at very low risk for cancer could be identified noninvasively as could those at significantly increased risk. Further study is necessary to assure effective implementation of this technology into routine clinical practice. PMID- 26053641 TI - Today's Endodontic Therapy Driven By Advances in Technology, Changes in Thinking. PMID- 26053642 TI - Thermoresponsive Chiral to Nonchiral Ordering Transformation in the Nematic Liquid-Crystal Phase of Rodlike Viruses: Turning the Survival Strategy of a Virus into Valuable Material Properties. AB - The current work investigates the thermoresponsive in situ chiral to nonchiral ordering transformation of a rodlike virus in the naturally assembled state-the chiral nematic liquid crystal (CLC) phase. We take this as an elegant example of reconfigurable self-assembly, through which it is possible to realize in situ transformation from one assembled state to another without disrupting the preformed assembly in general or going through a secondary assembling procedure of the disassembled building blocks. The detailed investigation presented here reveals many unique characteristics of the thermoresponsive 3D chiral ordering of rodlike viruses induced by heat stress. The chiral to nonchiral ordering transformation is highly reversible in the temperature range of up to 60 degrees C and can be repeated many times. There exists a critical temperature around 40 degrees C which is independent of the ionic strength and virus concentration. Such reconfigurable ordering in the CLC phase stems from the intrinsic structure change of constituent coat proteins without disrupting the structural integrity of the virus, as revealed by three analytical techniques targeting levels ranging from the molecular, secondary conformation of the constituent proteins to the whole single virus, respectively. Such structural flexibility, also termed polymorphism, is relative to the survival strategies of a biological organism such as the virus and can be transformed into very precious material properties. The potential of the virus-based CLC phase as the chiral matrix to regulate chiro optical properties of gold nanorods is also presented. PMID- 26053643 TI - Molecular spectrum of PIK3CA gene mutations in patients with nonsmall-cell lung cancer in Turkey. AB - AIMS: The aim of the present study was to obtain the first data for the phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) mutation frequency among nonsmall-cell lung cancer (NSCLC) patients in Turkey. All exons of the PIK3CA gene were investigated by sequence analysis in 40 NSCLC tumor tissue samples. RESULTS: The 1634A>C mutation, which has previously been identified in many cancers including NSCLC, was identified in three tumor tissue samples in the present study. Interestingly, a second mutation (1658_1659delGTinsC) was also identified in these patients. The concurrence of these two mutations has been reported as the Cowden syndrome, which is known to be a cancer predisposition syndrome. This finding is important since it may be an indicator of the underlying cancer predisposition syndrome in NSCLC patients. Moreover, four novel mutations were identified in the present study. However, in vitro studies are required to evaluate the effects of these mutations on kinase activation. CONCLUSIONS: The high frequency of PIK3CA mutations exerts important clinical implications for targeted therapy. This finding indicates that therapeutic agents targeting the phosphatidylinositol 3-kinase (PI3K) would be beneficial in the NSCLC subpopulation. PMID- 26053644 TI - Negative Regulation of TGFbeta Signaling by Stem Cell Antigen-1 Protects against Ischemic Acute Kidney Injury. AB - Acute kidney injury, often caused by an ischemic insult, is associated with significant short-term morbidity and mortality, and increased risk of chronic kidney disease. The factors affecting the renal response to injury following ischemia and reperfusion remain to be clarified. We found that the Stem cell antigen-1 (Sca-1), commonly used as a stem cell marker, is heavily expressed in renal tubules of the adult mouse kidney. We evaluated its potential role in the kidney using Sca-1 knockout mice submitted to acute ischemia reperfusion injury (IRI), as well as cultured renal proximal tubular cells in which Sca-1 was stably silenced with shRNA. IRI induced more severe injury in Sca-1 null kidneys, as assessed by increased expression of Kim-1 and Ngal, rise in serum creatinine, abnormal pathology, and increased apoptosis of tubular epithelium, and persistent significant renal injury at day 7 post IRI, when recovery of renal function in control animals was nearly complete. Serum creatinine, Kim-1 and Ngal were slightly but significantly elevated even in uninjured Sca-1-/- kidneys. Sca-1 constitutively bound both TGFbeta receptors I and II in cultured normal proximal tubular epithelial cells. Its genetic loss or silencing lead to constitutive TGFbeta receptor-mediated activation of canonical Smad signaling even in the absence of ligand and to KIM-1 expression in the silenced cells. These studies demonstrate that by normally repressing TGFbeta-mediated canonical Smad signaling, Sca-1 plays an important in renal epithelial cell homeostasis and in recovery of renal function following ischemic acute kidney injury. PMID- 26053645 TI - Comparison of two proanthocyanidin cross-linked recombinant human collagen peptide (RHC) - chitosan scaffolds. AB - Cross-linking plays an important role in tissue engineering, which involves the alternative of cross-linker and the way of components interaction. We compared two proanthocyanidin (PA) cross-linked recombinant human collagen-peptide - chitosan scaffolds: immerse cross-linking (I-CLS) and premix cross-linking (P CLS). Both of the scaffolds presented homogeneous pore structure with mean pore size of 110-115 MUm. The swelling ratio was decreased to 29.6 in I-CLS, but increased to 37.1 in P-CLS while porosity of the two scaffolds was reduced about 8% comparing to 94.3% before cross-linking. The cross-linked scaffolds exhibited enhanced resistance to enzyme degradation and improved compressive modulus (I-CLS > P-CLS). The scaffolds transformed from elastic region to plastic region until the strain reached 60%, and the stress was 40.5, 133.2 and 84.1 kPa of uncross linking scaffold, I-CLS and P-CLS individually. Thermal stability indicated molecular bonding between PA and the scaffold components, simultaneously, Fourier transform infrared spectroscopy mainly presented hydrogen bonding between the protein amide carbonyl and the phenolic hydroxyl with a particular transform due to pyrrolidine rings of proline in P-CLS. Both of the I-CLS and P-CLS could promote human umbilical vein endothelial cells attachment and proliferation. The characterization suggested in situ biodegradable application of P-CLS, while a potential long-term utilization of I-CLS in tissue engineering. PMID- 26053646 TI - Collectivistic coping strategies for distress among Polynesian Americans. AB - Previous research has shown that psychological services designed to assist clients in coping with stressful or traumatic events are more effective when aligned with clients' cultural values, practices, and worldviews. However, limited research is available regarding the preferred coping strategies of Polynesian Americans. In examining collectivistic coping styles and their association with previous distress among 94 Polynesian Americans, we found that participants were highly likely to use family support and religion/spirituality to buffer the initial and residual effects of impairment attributable to distressing events, and private emotional outlets, such as psychotherapy, very infrequently. The use of private emotional outlets was associated with lower impairment from distress, although family support was much more predictive of lower impairment and positive psychological well-being. Mental health professionals can align their services with the cultural values of Polynesian Americans by accounting for collectivistic coping styles and family dynamics. PMID- 26053647 TI - FDA's draft guidance on laboratory-developed tests increases clinical and economic risk to adoption of pharmacogenetic testing. PMID- 26053648 TI - FDA oversight of laboratory-developed tests will facilitate adoption of pharmacogenetic testing into routine clinical care. PMID- 26053650 TI - Effect of Chalcogens on Electronic and Photophysical Properties of Vinylene-Based Diketopyrrolopyrrole Copolymers. AB - Three vinylene linked diketopyrrolopyrrole based donor-acceptor (D-A) copolymers have been synthesized with phenyl, thienyl, and selenyl units as donors. Optical and electronic properties were investigated with UV-vis absorption spectroscopy, cyclic voltammetry, near edge X-ray absorption spectroscopy, organic field effect transistor (OFET) measurements, and density functional theory (DFT) calculations. Optical and electrochemical band gaps decrease in the order phenyl, thienyl, and selenyl. Only phenyl-based polymers are nonplanar, but the main contributor to the larger band gap is electronic, not structural effects. Thienyl and selenyl polymers exhibit ambipolar charge transport but with higher hole than electron mobility. Experimental and theoretical results predict the selenyl system to have the best transport properties, but OFET measurements prove the thienyl system to be superior with p-channel mobility as high as 0.1 cm(2) V(-1) s(-1). PMID- 26053651 TI - Meta-analysis inside and outside particle physics: two traditions that should converge? AB - The use of meta-analysis in medicine and epidemiology really took off in the 1970s. However, in high-energy physics, the Particle Data Group has been carrying out meta-analyses of measurements of particle masses and other properties since 1957. Curiously, there has been virtually no interaction between those working inside and outside particle physics. In this paper, we use statistical models to study two major differences in practice. The first is the usefulness of systematic errors, which physicists are now beginning to quote in addition to statistical errors. The second is whether it is better to treat heterogeneity by scaling up errors as do the Particle Data Group or by adding a random effect as does the rest of the community. Besides fitting models, we derive and use an exact test of the error-scaling hypothesis. We also discuss the other methodological differences between the two streams of meta-analysis. Our conclusion is that systematic errors are not currently very useful and that the conventional random effects model, as routinely used in meta-analysis, has a useful role to play in particle physics. The moral we draw for statisticians is that we should be more willing to explore 'grassroots' areas of statistical application, so that good statistical practice can flow both from and back to the statistical mainstream. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053652 TI - Meta-analysis inside and outside particle physics: convergence using the path of least resistance? AB - In this note, we explain how the method proposed by Hartung and Knapp provides a compromise between conventional meta-analysis methodology and 'unconstrained averaging', as used by the Particle Data Group. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 26053653 TI - Synthesizing regression results: a factored likelihood method. AB - Regression methods are widely used by researchers in many fields, yet methods for synthesizing regression results are scarce. This study proposes using a factored likelihood method, originally developed to handle missing data, to appropriately synthesize regression models involving different predictors. This method uses the correlations reported in the regression studies to calculate synthesized standardized slopes. It uses available correlations to estimate missing ones through a series of regressions, allowing us to synthesize correlations among variables as if each included study contained all the same variables. Great accuracy and stability of this method under fixed-effects models were found through Monte Carlo simulation. An example was provided to demonstrate the steps for calculating the synthesized slopes through sweep operators. By rearranging the predictors in the included regression models or omitting a relatively small number of correlations from those models, we can easily apply the factored likelihood method to many situations involving synthesis of linear models. Limitations and other possible methods for synthesizing more complicated models are discussed. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053654 TI - Random-effects meta-analysis of time-to-event data using the expectation maximisation algorithm and shrinkage estimators. AB - Meta-analysis of time-to-event data has proved difficult in the past because consistent summary statistics often cannot be extracted from published results. The use of individual patient data allows for the re-analysis of each study in a consistent fashion and thus makes meta-analysis of time-to-event data feasible. Time-to-event data can be analysed using proportional hazards models, but incorporating random effects into these models is not straightforward in standard software. This paper fits random-effects proportional hazards models by treating the random effects as missing data and applying the expectation-maximisation algorithm. This approach has been used before by using Markov chain Monte Carlo methods to perform the expectation step of the algorithm. In this paper, the expectation step is simplified, without sacrificing accuracy, by approximating the expected values of the random effects using simple shrinkage estimators. This provides a robust method for fitting random-effects models that can be implemented in standard statistical packages. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053655 TI - Using meta-analysis to inform the design of subsequent studies of diagnostic test accuracy. AB - An individual diagnostic accuracy study rarely provides enough information to make conclusive recommendations about the accuracy of a diagnostic test; particularly when the study is small. Meta-analysis methods provide a way of combining information from multiple studies, reducing uncertainty in the result and hopefully providing substantial evidence to underpin reliable clinical decision-making. Very few investigators consider any sample size calculations when designing a new diagnostic accuracy study. However, it is important to consider the number of subjects in a new study in order to achieve a precise measure of accuracy. Sutton et al. have suggested previously that when designing a new therapeutic trial, it could be more beneficial to consider the power of the updated meta-analysis including the new trial rather than of the new trial itself. The methodology involves simulating new studies for a range of sample sizes and estimating the power of the updated meta-analysis with each new study added. Plotting the power values against the range of sample sizes allows the clinician to make an informed decision about the sample size of a new trial. This paper extends this approach from the trial setting and applies it to diagnostic accuracy studies. Several meta-analytic models are considered including bivariate random effects meta-analysis that models the correlation between sensitivity and specificity. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26053656 TI - Robust variance estimation in meta-regression with binary dependent effects. AB - Dependent effect size estimates are a common problem in meta-analysis. Recently, a robust variance estimation method was introduced that can be used whenever effect sizes in a meta-analysis are not independent. This problem arises, for example, when effect sizes are nested or when multiple measures are collected on the same individuals. In this paper, we investigate the robustness of this method in small samples when the effect size of interest is the risk difference, log risk ratio, or log odds ratio. This simulation study examines the accuracy of 95% confidence intervals constructed using the robust variance estimator across a large variety of parameter values. We report results for both estimations of the mean effect (intercept) and of a slope. The results indicate that the robust variance estimator performs well even when the number of studies is as small as 10, although coverage is generally less than nominal in the slope estimation case. Throughout, an example based on a meta-analysis of cognitive behavior therapy is used for motivation. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 26053657 TI - Combining study outcome measures using dominance adjusted weights. AB - Weighting of studies in meta-analysis is usually implemented by using the estimated inverse variances of treatment effect estimates. However, there is a possibility of one study dominating other studies in the estimation process by taking on a weight that is above some upper limit. We implement an estimator of the heterogeneity variance that takes advantage of dominance adjusted weights. The performance of this estimator is compared with that of the commonly used estimator in meta-analysis, the DerSimonian-Laird estimator. Two test procedures for the overall treatment effect are proposed that are based on the quadratic form associated with the proposed heterogeneity variance estimator. An example is given to illustrate the application of these procedures. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 26053658 TI - Bayesian meta-analysis of coefficient alpha. AB - The current paper describes and illustrates a Bayesian approach to the meta analysis of coefficient alpha. Alpha is the most commonly used estimate of the reliability or consistency (freedom from measurement error) for educational and psychological measures. The conventional approach to meta-analysis uses inverse variance weights to combine information from independent studies to provide an overall estimate. The Bayesian approach provides similar estimates to the conventional approach if a diffuse prior is used. However, the Bayesian approach also provides 'shrunken' local estimates of reliability in each context. The amount of shrinkage depends upon both the variability in the underlying populations and the sampling variance of the local estimates. Advantages of the approach are the estimation of individual studies adjusted for sampling error and the application of meta-analytic results to new local studies in which the local study 'borrows strength' from the meta-analysis. The ability to borrow strength for the new local studies is particularly useful in applied work in which the estimate of the local parameter is of primary interest. The approach is illustrated by the analysis of studies of the reliability of the General Ethnicity Questionnaire - Abridged, a measure of identification with the culture of one's heritage and the culture of one's host country. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 26053659 TI - A Water Stable Magnesium MOF That Conducts Protons over 10(-2) S cm(-1). AB - From the outset of the study of MOFs as proton conductors, both conductivity and hydrolytic robustness of the materials have needed to be improved. Here, we report a layered magnesium carboxyphosphonate framework, PCMOF10, that shows an extremely high proton conductivity value of 3.55 * 10(-2) S.cm(-1) at 70 degrees C and 95% RH. Moreover, PCMOF10 is water stable owing to strong Mg phosphonate bonding. The 2,5-dicarboxy-1,4-benzenediphosphonic acid (H6L) linker anchors a robust backbone and has hydrogen phosphonate groups that interact with the lattice water to form an efficient proton transfer pathway. PMID- 26053660 TI - Thermally-induced transition of lamellae orientation in block-copolymer films on 'neutral' nanoparticle-coated substrates. AB - Block-copolymer orientation in thin films is controlled by the complex balance between interfacial free energies, including the inter-block segregation strength, the surface tensions of the blocks, and the relative substrate interactions. While block-copolymer lamellae orient horizontally when there is any preferential affinity of one block for the substrate, we recently described how nanoparticle-roughened substrates can be used to modify substrate interactions. We demonstrate how such 'neutral' substrates can be combined with control of annealing temperature to generate vertical lamellae orientations throughout a sample, at all thicknesses. We observe an orientational transition from vertical to horizontal lamellae upon heating, as confirmed using a combination of atomic force microscopy (AFM), neutron reflectometry (NR) and rotational small-angle neutron scattering (RSANS). Using molecular dynamics (MD) simulations, we identify substrate-localized distortions to the lamellar morphology as the physical basis of the novel behavior. In particular, under strong segregation conditions, bending of horizontal lamellae induce a large energetic cost. At higher temperatures, the energetic cost of conformal deformations of lamellae over the rough substrate is reduced, returning lamellae to the typical horizontal orientation. Thus, we find that both surface interactions and temperature play a crucial role in dictating block-copolymer lamellae orientation. Our combined experimental and simulation findings suggest that controlling substrate roughness should provide a useful and robust platform for controlling block-copolymer orientation in applications of these materials. PMID- 26053661 TI - Maternal HIV-1 envelope-specific antibody responses and reduced risk of perinatal transmission. AB - Despite the wide availability of antiretroviral drugs, more than 250,000 infants are vertically infected with HIV-1 annually, emphasizing the need for additional interventions to eliminate pediatric HIV-1 infections. Here, we aimed to define humoral immune correlates of risk of mother-to-child transmission (MTCT) of HIV 1, including responses associated with protection in the RV144 vaccine trial. Eighty-three untreated, HIV-1-transmitting mothers and 165 propensity score matched nontransmitting mothers were selected from the Women and Infants Transmission Study (WITS) of US nonbreastfeeding, HIV-1-infected mothers. In a multivariable logistic regression model, the magnitude of the maternal IgG responses specific for the third variable loop (V3) of the HIV-1 envelope was predictive of a reduced risk of MTCT. Neutralizing Ab responses against easy-to neutralize (tier 1) HIV-1 strains also predicted a reduced risk of peripartum transmission in secondary analyses. Moreover, recombinant maternal V3-specific IgG mAbs mediated neutralization of autologous HIV-1 isolates. Thus, common V3 specific Ab responses in maternal plasma predicted a reduced risk of MTCT and mediated autologous virus neutralization, suggesting that boosting these maternal Ab responses may further reduce HIV-1 MTCT. PMID- 26053662 TI - Harnessing endogenous stem/progenitor cells for tendon regeneration. AB - Current stem cell-based strategies for tissue regeneration involve ex vivo manipulation of these cells to confer features of the desired progenitor population. Recently, the concept that endogenous stem/progenitor cells could be used for regenerating tissues has emerged as a promising approach that potentially overcomes the obstacles related to cell transplantation. Here we applied this strategy for the regeneration of injured tendons in a rat model. First, we identified a rare fraction of tendon cells that was positive for the known tendon stem cell marker CD146 and exhibited clonogenic capacity, as well as multilineage differentiation ability. These tendon-resident CD146+ stem/progenitor cells were selectively enriched by connective tissue growth factor delivery (CTGF delivery) in the early phase of tendon healing, followed by tenogenic differentiation in the later phase. The time-controlled proliferation and differentiation of CD146+ stem/progenitor cells by CTGF delivery successfully led to tendon regeneration with densely aligned collagen fibers, normal level of cellularity, and functional restoration. Using siRNA knockdown to evaluate factors involved in tendon generation, we demonstrated that the FAK/ERK1/2 signaling pathway regulates CTGF-induced proliferation and differentiation of CD146+ stem/progenitor cells. Together, our findings support the use of endogenous stem/progenitor cells as a strategy for tendon regeneration without cell transplantation and suggest this approach warrants exploration in other tissues. PMID- 26053663 TI - Selenoprotein P influences colitis-induced tumorigenesis by mediating stemness and oxidative damage. AB - Patients with inflammatory bowel disease are at increased risk for colon cancer due to augmented oxidative stress. These patients also have compromised antioxidant defenses as the result of nutritional deficiencies. The micronutrient selenium is essential for selenoprotein production and is transported from the liver to target tissues via selenoprotein P (SEPP1). Target tissues also produce SEPP1, which is thought to possess an endogenous antioxidant function. Here, we have shown that mice with Sepp1 haploinsufficiency or mutations that disrupt either the selenium transport or the enzymatic domain of SEPP1 exhibit increased colitis-associated carcinogenesis as the result of increased genomic instability and promotion of a protumorigenic microenvironment. Reduced SEPP1 function markedly increased M2-polarized macrophages, indicating a role for SEPP1 in macrophage polarization and immune function. Furthermore, compared with partial loss, complete loss of SEPP1 substantially reduced tumor burden, in part due to increased apoptosis. Using intestinal organoid cultures, we found that, compared with those from WT animals, Sepp1-null cultures display increased stem cell characteristics that are coupled with increased ROS production, DNA damage, proliferation, decreased cell survival, and modulation of WNT signaling in response to H2O2-mediated oxidative stress. Together, these data demonstrate that SEPP1 influences inflammatory tumorigenesis by affecting genomic stability, the inflammatory microenvironment, and epithelial stem cell functions. PMID- 26053664 TI - Outcomes of acute leukemia patients transplanted with naive T cell-depleted stem cell grafts. AB - BACKGROUND: Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT). In mice, naive T cells (TN) cause more severe GVHD than memory T cells (TM). We hypothesized that selective depletion of TN from human allogeneic peripheral blood stem cell (PBSC) grafts would reduce GVHD and provide sufficient numbers of hematopoietic stem cells and TM to permit hematopoietic engraftment and the transfer of pathogen-specific T cells from donor to recipient, respectively. METHODS: In a single-arm clinical trial, we transplanted 35 patients with high risk leukemia with TN-depleted PBSC grafts following conditioning with total body irradiation, thiotepa, and fludarabine. GVHD prophylactic management was with tacrolimus immunosuppression alone. Subjects received CD34-selected PBSCs and a defined dose of TM purged of CD45RA+ TN. Primary and secondary objectives included engraftment, acute and chronic GVHD, and immune reconstitution. RESULTS: All recipients of TN-depleted PBSCs engrafted. The incidence of acute GVHD was not reduced; however, GVHD in these patients was universally corticosteroid responsive. Chronic GVHD was remarkably infrequent (9%; median follow-up 932 days) compared with historical rates of approximately 50% with T cell-replete grafts. TM in the graft resulted in rapid T cell recovery and transfer of protective virus-specific immunity. Excessive rates of infection or relapse did not occur and overall survival was 78% at 2 years. CONCLUSION: Depletion of TN from stem cell allografts reduces the incidence of chronic GVHD, while preserving the transfer of functional T cell memory. TRIAL REGISTRATION: ClinicalTrials.gov (NCT 00914940). PMID- 26053665 TI - Neural crest-derived SEMA3C activates endothelial NRP1 for cardiac outflow tract septation. AB - In mammals, the outflow tract (OFT) of the developing heart septates into the base of the pulmonary artery and aorta to guide deoxygenated right ventricular blood into the lungs and oxygenated left ventricular blood into the systemic circulation. Accordingly, defective OFT septation is a life-threatening condition that can occur in both syndromic and nonsyndromic congenital heart disease. Even though studies of genetic mouse models have previously revealed a requirement for VEGF-A, the class 3 semaphorin SEMA3C, and their shared receptor neuropilin 1 (NRP1) in OFT development, the precise mechanism by which these proteins orchestrate OFT septation is not yet understood. Here, we have analyzed a complementary set of ligand-specific and tissue-specific mouse mutants to show that neural crest-derived SEMA3C activates NRP1 in the OFT endothelium. Explant assays combined with gene-expression studies and lineage tracing further demonstrated that this signaling pathway promotes an endothelial-to-mesenchymal transition that supplies cells to the endocardial cushions and repositions cardiac neural crest cells (NCCs) within the OFT, 2 processes that are essential for septal bridge formation. These findings elucidate a mechanism by which NCCs cooperate with endothelial cells in the developing OFT to enable the postnatal separation of the pulmonary and systemic circulation. PMID- 26053666 TI - The Clinical Features and Bacteriological Characterizations of Bone and Joint Tuberculosis in China. AB - Bone and Joint tuberculosis (BJTB) constitutes about 10% of total extra-pulmonary TB cases. Since the BJTB is a paucibacillary condition, there has been no systematic study on the bacterial characterization, especially the epidemiological feature. Here we collected the mycobacterial clinical isolates, analyzed the clinical features and the bacteriological characteristics from 113 BJTB cases reported in China. The mean age of the cases was 40.33 years while most of the patients fell into the 20-29 year age group; local pain was the most common onset symptom of BJTB cases; mean time from symptom onset to BJTB diagnosis was 13.16 months. 31 isolates were defined as drug resistant, including 15 multidrug resistant (MDR) and 2 extensively drug resistant (XDR) isolates according to the drug susceptibility test outcomes; after spoligotyping, 87.6% (99/113) isolates were categorized as Beijing family. In contrast to the isolates from pulmonary tuberculosis patients, here the MIRU-VNTR assay did not find anything significant. A prolonged time span for BJTB diagnosis highlights the requirement of paying further attention to BJTB infection in China. This study provides essential insights into the demographic and microbial characteristics of BJTB cases in China. PMID- 26053668 TI - LMNB1-related autosomal-dominant leukodystrophy: Clinical and radiological course. AB - OBJECTIVE: Duplication of the LMNB1 gene encoding lamin B1 causes adult-onset autosomal-dominant leukodystrophy (ADLD) starting with autonomic symptoms, which are followed by pyramidal signs and ataxia. Magnetic resonance imaging (MRI) of the brain reveals characteristic findings. This is the first longitudinal study on this disease. Our objective is to describe the natural clinical and radiological course of LMNB1-related ADLD. METHODS: Twenty-three subjects in two families with LMNB1 duplications were studied over two decades with clinical assessment and MRI of the brain and spinal cord. They were 29 to 70 years old at their first MRI. Repeated MRIs were performed in 14 subjects over a time period of up to 17 years. RESULTS: Pathological MRI findings were found in the brain and spinal cord in all examinations (i.e., even preceding clinical symptoms). MRI changes and clinical symptoms progressed in a definite order. Autonomic dysfunction appeared in the fifth to sixth decade, preceding or together with gait and coordination difficulties. Motor signs developed ascending from spastic paraplegia to tetraplegia and pseudobulbar palsy in the seventh decade. There were clinical, radiological, and neurophysiological signs of myelopathy. Survival lasted more than two decades after clinical onset. INTERPRETATION: LMNB1-related ADLD is a slowly progressive neurological disease. MRI abnormalities of the brain and spinal cord can precede clinical symptoms by more than a decade and are extensive in all symptomatic patients. Spinal cord involvement is a likely contributing factor to early autonomic symptoms and spastic paraplegia. PMID- 26053667 TI - Mutational Analysis of Intracellular Loops Identify Cross Talk with Nucleotide Binding Domains of Yeast ABC Transporter Cdr1p. AB - The ABC transporter Cdr1 protein (Cdr1p) of Candida albicans, which plays a major role in antifungal resistance, has two transmembrane domains (TMDs) and two nucleotide binding domains (NBDs) that are interconnected by extracellular (ECLs) and intracellular (ICLs) loops. To examine the communication interface between the NBDs and ICLs of Cdr1p, we subjected all four ICLs to alanine scanning mutagenesis, replacing each of the 85 residues with an alanine. The resulting ICL mutant library was analyzed by biochemical and phenotypic mapping. Only 18% of the mutants from this library displayed enhanced drug susceptibility. Most of the drug-susceptible mutants displayed uncoupling between ATP hydrolysis and drug transport. The two drug-susceptible ICL1 mutants (I574A and S593A) that lay within or close to the predicted coupling helix yielded two chromosomal suppressor mutations that fall near the Q-loop of NBD2 (R935) and in the Walker A motif (G190) of NBD1. Based on a 3D homology model and kinetic analysis of drug transport, our data suggest that large distances between ICL residues and their respective chromosomal suppressor mutations rule out a direct interaction between them. However, they impact the transport cycle by restoring the coupling interface via indirect downstream signaling. PMID- 26053669 TI - New technologies for essential newborn care in under-resourced areas: what is needed and how to deliver it. AB - Globally, the largest contributors to neonatal mortality are preterm birth, intrapartum complications and infection. Many of these deaths could be prevented by providing temperature stability, respiratory support, hydration and nutrition; preventing and treating infections; and diagnosing and treating neonatal jaundice and hypoglycaemia. Most neonatal health-care technologies which help to accomplish these tasks are designed for high-income countries and are either unavailable or unsuitable in low-resource settings, preventing many neonates from receiving the gold standard of care. There is an urgent need for neonatal health care technologies which are low-cost, robust, simple to use and maintain, affordable and able to operate from various power supplies. Several technologies have been designed to meet these requirements or are currently under development; however, unmet technology needs remain. The distribution of an integrated set of technologies, rather than separate components, is essential for effective implementation and a substantial impact on neonatal health. Close collaboration between stakeholders at all stages of the development process and an increased focus on implementation research are necessary for effective and sustainable implementation. PMID- 26053670 TI - Parenting style influences bullying: a longitudinal study comparing children with and without behavioral problems. AB - BACKGROUND: More optimal parenting has been linked with lower rates of bullying. However, it is not clear whether parenting can alter the trajectories of bullying among children diagnosed with ADHD or ODD as well as those who are not so diagnosed. This study examined whether parenting at age 4-5 years was associated with changes in bullying over the next 4 years among children with Attention deficit/Hyperactivity Disorder (ADHD) with and without comorbid Oppositional Defiant Disorder (ODD) relative to children without these disorders. METHOD: Children from the New York metropolitan area (n = 162) were prospectively studied over six annual assessment points between preschool and 9 years of age. Parenting was assessed by laboratory observations of the parent and child; teachers rated child bullying, and parents reported on children's diagnostic status (Neither ADHD nor ODD, ADHD but not ODD, both ADHD and ODD). RESULTS: Children with comorbid ADHD and ODD were more likely to bully than the other two groups. Hierarchical linear modeling revealed a fall in bullying over five years. Diagnostic status was significantly associated with initial levels of bullying. Irrespective of diagnostic group, children receiving more parent support for child autonomy at age 4 to 5 years showed a significantly greater decline in bullying than those provided with little support for autonomy. There was no longitudinal link between parent negative affect, emotionally supportive parenting and quality of parent-child interactions with bullying. CONCLUSIONS: Greater parent support for child autonomy at age 4-5 years is related to reduced bullying. Interventions that encourage parent support for child autonomy at the time of entry into school may reduce bullying during early school years. PMID- 26053671 TI - Endoscopic endonasal approach to the lateral orbital apex: case report. AB - Although the medial and inferior orbital apex are considered safely accessible using the endonasal endoscopic approach, the lateral apex has been considered unsafe to access since the optic nerve lies between the surgeon and the pathology. The authors present the case of a 4-year-old girl with recurrent rhabdomyosarcoma attached to the lateral rectus muscle located lateral and inferior to the optic nerve in the orbital apex. The tumor was totally resected through an endoscopic endonasal transmaxillary transpterygoidal approach using a 45 degrees endoscope. A gross-total resection was achieved, and the patient's vision was unchanged. This procedure is a safe, minimal-access alternative to open procedures in selected cases and provides evidence that increases the applicability of the endonasal endoscopic approach to reach the lateral compartment of the orbital apex. PMID- 26053672 TI - Base catalyzed synthesis of bicyclo[3.2.1]octane scaffolds. AB - The base-catalyzed reaction of achiral 1,3-cyclopentanediones tethered to activated olefins afforded in high yields bicyclo[3.2.1]octane-6,8-dione or bicyclo[3.2.1]octane-6-carboxylate derivatives bearing respectively three or five stereogenic centers. The course of the reaction is closely related to the reaction time and to the base involved in the reaction. PMID- 26053673 TI - Mouse DRG Cell Line with Properties of Nociceptors. AB - In vitro cell lines from DRG neurons aid drug discovery because they can be used for early stage, high-throughput screens for drugs targeting pain pathways, with minimal dependence on animals. We have established a conditionally immortal DRG cell line from the Immortomouse. Using immunocytochemistry, RT-PCR and calcium microfluorimetry, we demonstrate that the cell line MED17.11 expresses markers of cells committed to the sensory neuron lineage. Within a few hours under differentiating conditions, MED17.11 cells extend processes and following seven days of differentiation, express markers of more mature DRG neurons, such as NaV1.7 and Piezo2. However, at least at this time-point, the nociceptive marker NaV1.8 is not expressed, but the cells respond to compounds known to excite nociceptors, including the TRPV1 agonist capsaicin, the purinergic receptor agonist ATP and the voltage gated sodium channel agonist, veratridine. Robust calcium transients are observed in the presence of the inflammatory mediators bradykinin, histamine and norepinephrine. MED17.11 cells have the potential to replace or reduce the use of primary DRG culture in sensory, pain and developmental research by providing a simple model to study acute nociception, neurite outgrowth and the developmental specification of DRG neurons. PMID- 26053674 TI - Analyzing Beach Recreationists' Preferences for the Reduction of Jellyfish Blooms: Economic Results from a Stated-Choice Experiment in Catalonia, Spain. AB - Jellyfish outbreaks and their consequences appear to be on the increase around the world, and are becoming particularly relevant in the Mediterranean. No previous studies have quantified tourism losses caused by jellyfish outbreaks. We used a stated-choice questionnaire and a Random Utility Model to estimate the amount of time respondents would be willing to add to their journey, in terms of reported extra travel time, in order to reduce the risk of encountering jellyfish blooms in the Catalan coast. The estimation results indicated that the respondents were willing to spend on average an additional 23.8% of their travel time to enjoy beach recreation in areas with a lower risk of jellyfish blooms. Using as a reference the opportunity cost of time, we found that the subsample of individuals who made a trade-off between the disutility generated by travelling longer in order to lower the risk of jellyfish blooms, and the utility gained from reducing this risk, are willing to pay on average ?3.20 per beach visit. This estimate, combined with the respondents' mean income, yielded annual economic gains associated with reduction of jellyfish blooms on the Catalan coast around ?422.57 million, or about 11.95% of the tourism expenditures in 2012. From a policy-making perspective, this study confirms the importance of the economic impacts of jellyfish blooms and the need for mitigation strategies. In particular, providing daily information using social media applications or other technical devices may reduce these social costs. The current lack of knowledge about jellyfish suggests that providing this information to beach recreationists may be a substantially effective policy instrument for minimising the impact of jellyfish blooms. PMID- 26053675 TI - High-dose recombinant human bone morphogenetic protein-2 impacts histological and biomechanical properties of a cervical spine fusion segment: results from a sheep model. AB - The 'off-label' use of high-dose recombinant human bone morphogenetic protein-2 (rhBMP-2) in lumbar and cervical fusion leads to heterotopic bone formation and vertebral osteolysis. These radiographically assessed side-effects in patients were frequently associated with an over-dosage of BMP-2. However, little is so far known about the histological, functional or biomechanical tissue consequences of over-dosage of rhBMP-2 in these specific clinical situations. We hypothesized that a high dose of rhBMP-2 in cervical spinal fusion could induce substantial alterations in bone, leading to mechanical impairment. An anterior cervical spinal fusion (C3-C4 ACDF) model in 16 sheep (aged > 2.5 years; n = 8/group) was used to quantify the consequences of a high rhBMP-2 dose (6 mg rhBMP-2) on fusion tissue compared to the 'gold standard' of autologous, cancellous bone graft. The fusion site was assessed by radiography after 0, 8 and 12 weeks. Biomechanical non-destructive testing and (immuno)histological and histomorphometrical analyses were performed 12 weeks postoperatively. Although high-dose rhBMP-2 treatment led to an advanced radiological fusion result compared to autograft treatment, heterotopic bone formation and vertebral bone resorption were induced simultaneously. Histological evaluation unveiled highly active bone-forming processes ventral to the fusion segment after 12 weeks, while radiolucent areas showed still a partial loss of regular trabecular structure, with rare signs of remodelling and restoration. Despite qualitative alteration of the trabecular bone structure within the fusion site, the massive anterior heterotopic bone formation led to a substantial increase in mechanical stiffness compared to the autograft group. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26053676 TI - High risk HPV testing in the triage of repeat ASC-US and LSIL. AB - INTRODUCTION: The purpose of this study was to evaluate the real-life performance of high-risk (HR) HPV testing in the triage of repeat atypical squamous cells of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesions (LSIL). MATERIAL AND METHODS: In 2004-2012, 127 women with repeat ASC-US and 118 women with LSIL were triaged with HPV testing using either a Hybrid Capture 2((r)) or Abbott RealTime((r)) HR-HPV test. The patient charts were retrospectively reviewed for performance of the tests. RESULTS: In the repeat ASC US group, 40.9% of the women were positive for HR-HPV. The prevalence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was 8.7%. The sensitivity of the HR-HPV testing for detection of CIN2+ was 90.9% (95% Cl 58.7-98.5%), with a specificity of 63.8% (95%CI 54.4-72.5%). In women >=30 years old, the specificity was 70.4%, whereas in younger women it was only 27.8%. The negative predictive value to predict CIN3 was 100% (95% CI 95.2-100.0%). Of the women with LSIL, 68.6% were positive for HR-HPV and the prevalence of CIN2+ was 14.4%. The sensitivity of HR-HPV testing for detection of CIN2+ was 94.1% (95% CI 71.2 99.0%), and the specificity 35.6% (95% CI 26.4-45.8%), respectively. The negative predictive value to predict CIN3 was 100% (95% CI 90.4-100.0%). CONCLUSION: HR HPV testing seems to be beneficial in the triage of repeat ASC-US in women >=30 years old, but a high prevalence of HR-HPV infection combined with poor specificity limit the use of HPV testing in the case of LSIL. PMID- 26053678 TI - Dendrimers in Nanoscale Confinement: The Interplay between Conformational Change and Nanopore Entrance. AB - Hyperbranched dendrimers are nanocarriers for drugs, imaging agents, and catalysts. Their nanoscale confinement is of fundamental interest and occurs when dendrimers with bioactive payload block or pass biological nanochannels or when catalysts are entrapped in inorganic nanoporous support scaffolds. The molecular process of confinement and its effect on dendrimer conformations are, however, poorly understood. Here, we use single-molecule nanopore measurements and molecular dynamics simulations to establish an atomically detailed model of pore dendrimer interactions. We discover and explain that electrophoretic migration of polycationic PAMAM dendrimers into confined space is not dictated by the diameter of the branched molecules but by their size and generation-dependent compressibility. Differences in structural flexibility also rationalize the apparent anomaly that the experimental nanopore current read-out depends in nonlinear fashion on dendrimer size. Nanoscale confinement is inferred to reduce the protonation of the polycationic structures. Our model can likely be expanded to other dendrimers and be applied to improve the analysis of biophysical experiments, rationally design functional materials such as nanoporous filtration devices or nanoscale drug carriers that effectively pass biological pores. PMID- 26053677 TI - APOE-epsilon4 Allele Altered the Rest-Stimulus Interactions in Healthy Middle Aged Adults. AB - The apolipoprotein E-epsilon4 allele is a well-known genetic risk factor for late onset Alzheimer's disease, which also impacts the cognitive functions and brain network connectivity in healthy middle-aged adults without dementia. Previous studies mainly focused on the effects of apolipoprotein E-epsilon4 allele on single index using task or resting-state fMRI. However, how these evoked and spontaneous BOLD indices interact with each other remains largely unknown. Therefore, we evaluated the 'rest-stimulus interaction' between working-memory activation and resting-state connectivity in middle-aged apolipoprotein E epsilon4 carriers (n=9) and non-carriers (n=8). Four n-back task scans (n = 0, 1, 2, 3) and one resting-state scan were acquired at a 3T clinical MRI scanner. The working-memory beta maps of low-, moderate-, and high-memory loads and resting state connectivity maps of default mode, executive control, and hippocampal networks were derived and compared between groups. Apolipoprotein E-epsilon4 carriers presented declined working-memory activation in the high-memory load across whole brain regions and reduced hippocampal connectivity compared with non carriers. In addition, disrupted rest-stimulus interactions were found in the right anterior insula and bilateral parahippocampal regions for middle-aged adults with apolipoprotein E-epsilon4 allele. The rest-stimulus interaction improved the detectability of network integrity changes in apolipoprotein E epsilon4 carriers, demonstrating the disrupted intrinsic connectivity within the executive-functional regions and the modulated memory-encoding capability within hippocampus-related regions. PMID- 26053680 TI - Low glycaemic diet and metformin therapy: a new approach in male subjects with acne resistant to common treatments. AB - Acne is a common and complex skin disease, with a very complex pathogenesis. Although in women the relationship between acne and insulin resistance is well known, in particular in women with PCOS, in males this relationship has been poorly investigated. In total, 20 subjects with an altered metabolic profile were considered for this study and randomized as follows: 10 patients were treated with metformin plus a hypocaloric diet for 6 months (group A), while 10 patients did not receive any treatment with metformin and were only followed up (group B). All patients of group A, after 6 months of metformin therapy, had a statistically significant improvement compared with patients in group B. Our study reveals the importance of diet and insulin resistance in acne pathogenesis, and underlines the possible use of metformin and diet as possible adjuvant therapy for male patients with acne. PMID- 26053679 TI - Effect of Antihelminthic Treatment on Vaccine Immunogenicity to a Seasonal Influenza Vaccine in Primary School Children in Gabon: A Randomized Placebo Controlled Trial. AB - BACKGROUND: Helminth infections are a major public health problem, especially in the tropics. Infected individuals have an altered immune response with evidence that antibody response to vaccination is impaired. Hence, treatment of helminth infections before vaccination may be a simple intervention to improve vaccine immunogenicity. In the present study we investigated whether a single-dose antihelminthic treatment influences antibody responses to a seasonal influenza vaccine in primary school children living in Gabon, Central Africa. METHODS: In this placebo-controlled double-blind trial conducted in Gabon the effect of a single-dose antihelminthic treatment with 400 mg albendazole versus a placebo one month prior to immunization with a seasonal influenza vaccine was investigated. Antiviral antibody titers against all three vaccine strains were assessed by haemagglutination inhibition (HI) test at baseline (Day 0; vaccination) and four weeks (Day 28) as well as 12 weeks (Day 84) following vaccination. Vaccine specific memory B-cell response was measured at Day 0 and Day 84 by vaccine specific Enzyme-linked Immunospot (ELISpot) assay. The trial is registered with the Pan African Clinical Trials Registry (PACTR) (PACTR201303000434188). RESULTS: 98 school children aged 6-10 years were randomly allocated to receive either antihelminthic treatment or placebo and were vaccinated one month after the treatment. The prevalence of helminths at baseline was 21%. Vaccine-specific HI titers against at least one of the three vaccine strains increased at Day 28 and Day 84 in all participants. HI titers against both influenza A strains as well as memory B-cell response were modestly higher in the antihelminthic treated group compared to the placebo group but the difference was not statistically significant. Total but not specific IgA was elevated in the antihelminthic treated group compared to the control group at Day 28. CONCLUSION: In our setting antihelminthic treatment had no significant effect on influenza vaccine immunogenicity. A trend towards better antiviral and vaccine immunogenicity in the antihelminthic treated group encourages studies to be conducted with alternative treatment schedules or in populations with a higher helminth burden. PMID- 26053681 TI - Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury. AB - Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants. Responses to peripheral mechanical sensory stimulation were significantly improved in transplanted animals. Transganglionic tracing showed host sensory axons only in the spinal cord dorsal horn of treated animals. Immunohistochemical analysis confirmed that sensory fibers had grown through the bridge and showed robust survival and differentiation of the transplants. Section of the repaired dorsal roots distal to the transplant completely abolished the behavioral improvement. This demonstrates that hNP transplants promote recovery of sensorimotor functions after dorsal root avulsion, and that these effects are mediated by spinal ingrowth of host sensory axons. These results provide a rationale for the development of novel stem cell-based strategies for functionally useful bridging of the peripheral and central nervous system. PMID- 26053683 TI - [Adenectomy]. PMID- 26053682 TI - Genomic Analysis and Surveillance of the Coronavirus Dominant in Ducks in China. AB - The genetic diversity, evolution, distribution, and taxonomy of some coronaviruses dominant in birds other than chickens remain enigmatic. In this study we sequenced the genome of a newly identified coronavirus dominant in ducks (DdCoV), and performed a large-scale surveillance of coronaviruses in chickens and ducks using a conserved RT-PCR assay. The viral genome harbors a tandem repeat which is rare in vertebrate RNA viruses. The repeat is homologous to some proteins of various cellular organisms, but its origin remains unknown. Many substitutions, insertions, deletions, and some frameshifts and recombination events have occurred in the genome of the DdCoV, as compared with the coronavirus dominant in chickens (CdCoV). The distances between DdCoV and CdCoV are large enough to separate them into different species within the genus Gammacoronavirus. Our surveillance demonstrated that DdCoVs and CdCoVs belong to different lineages and occupy different ecological niches, further supporting that they should be classified into different species. Our surveillance also demonstrated that DdCoVs and CdCoVs are prevalent in live poultry markets in some regions of China. In conclusion, this study shed novel insight into the genetic diversity, evolution, distribution, and taxonomy of the coronaviruses circulating in chickens and ducks. PMID- 26053685 TI - Parental Consent for the Use of Residual Newborn Screening Bloodspots: Respecting Individual Liberty vs Ensuring Public Health. PMID- 26053687 TI - The poor patient with diabetes 'should live like a saint'. PMID- 26053686 TI - The Risk of Gestational Diabetes Mellitus Following Bereavement: A Cohort Study from Denmark and Sweden. AB - BACKGROUND: We investigated whether bereavement of a close family member - a source of severe psychological stress exposure - the year before pregnancy is associated with gestational diabetes mellitus (GDM). METHODS: We studied pregnant women with livebirths in Denmark during 1994-2008 and with births in Sweden during 1987-2006 (n = 2,569,446). We obtained data on death of women's parents, siblings, and older children, and on demographic and health- and pregnancy related factors through linkage between nationwide registers. RESULTS: In multivariable models, death of a close relative the year before pregnancy was associated with a 14% increased odds of GDM [95% confidence intervals (CIs) 1.03, 1.26]. The odds ratios corresponding to the loss of a child, parent, and sibling were 1.51 (95% CI: 1.17, 1.95), 1.12 (95% CI: 1.00, 1.25), and 0.68 (95% CI: 0.40, 1.25), respectively. Deaths due to cardiovascular diseases or diabetes were more closely related to the risk of GDM than other types of deaths. We found no association between unnatural deaths and the risk of GDM. CONCLUSIONS: Death of a close relative the year before pregnancy was associated with a modestly increased GDM risk. Our findings according to the relative's cause of death suggest that differences in screening for GDM among exposure groups and residual confounding by familial factors related to metabolic and cardiovascular diseases may have contributed to this association. If there is a causal stress effect on GDM in this predominantly Nordic population, it is most likely small. PMID- 26053688 TI - Angiographic dimple of profound significance in cases of aneurysmal subarachnoid hemorrhage: report of 2 cases. AB - The occurrence of an angiographic dimple or irregularity due to indentation of the contrast column by an intraluminal thrombus at the dome of a ruptured aneurysm is not uncommon and does not draw much clinical attention. However, an angiographic dimple at the base of the ruptured aneurysm or division of the parent artery can signify a rupture point close to the dimple and an intraluminal thrombus, which has utmost clinical significance as it is close to the parent artery and necessitates a different treatment strategy from rupture of the aneurysm dome. The author reports on 2 cases of an angiographic dimple following subarachnoid hemorrhage (SAH) and subsequent surgical exploration. In the first patient, a 57-year-old-woman, angiography revealed a basal dimple in a superiorly directed anterior communicating artery aneurysm. A pterional craniotomy was performed, which revealed a bilobed aneurysm harboring a superiorly directed unruptured lobule and inferiorly directed ruptured lobule. An intraluminal thrombus in the inferiorly directed lobule apparently obscured the lobule and caused the appearance of the basal dimple on the angiograms. In the second patient, a 40-year-old man who had been transferred to the author's institution because of an angiographic evaluation that did not show any aneurysm despite SAH in the basal cisterns, initial angiography revealed a subtle dimple on the superior wall of the anterior communicating artery (ACoA). On follow-up angiography, a very small aneurysm was seen at the site of the dimple. A craniotomy then revealed a very small ruptured and thrombosed aneurysm on the superior wall of the ACoA. PMID- 26053689 TI - Analysis of 24-h recovery of transfused stored RBCs in recipient mice of distinct genetic backgrounds. AB - BACKGROUND AND OBJECTIVES: Human studies have demonstrated substantial donor-to donor variation in refrigerated RBC storage with respect to several variables, including 24-h post-transfusion RBC recovery. However, the human studies leading to these observations are mostly performed using autologous transfusions of stored RBCs, thereby avoiding issues of infectious disease transmission and alloimmunization. Accordingly, one cannot distinguish whether variability in 24-h RBC recovery is due to alterations in RBC storage, differences in phagocytic activity of the recipient's reticuloendothelial system or both. Similar to humans, genetically distinct inbred mouse strains have substantial differences in RBC storage biology, including 24-h post-transfusion RBC recovery. MATERIALS AND METHODS: In this report, we juxtaposed 24-h recoveries in 15 distinct inbred strains of mice, holding the RBC donor constant to isolate transfusion recipient variation as an independent variable. Strains were chosen for differences in baseline reticulocyte count and haemoglobin, which may correlate to RBC life span and turnover. RESULTS: Unlike large differences observed in storage of RBCs obtained from different strains of mice, only subtle strain-to-strain differences were observed regarding 24-h post-transfusion RBC recoveries. CONCLUSIONS: These findings indicate that the murine strains examined are not likely to be useful in sorting out mechanisms of clearance of stored RBCs, and suggest that such mechanisms may be generally conserved in the strains of mice analysed. PMID- 26053690 TI - Automated Detection of Vessel Abnormalities on Fluorescein Angiogram in Malarial Retinopathy. AB - The detection and assessment of intravascular filling defects is important, because they may represent a process central to cerebral malaria pathogenesis: neurovascular sequestration. We have developed and validated a framework that can automatically detect intravascular filling defects in fluorescein angiogram images. It first employs a state-of-the-art segmentation approach to extract the vessels from images and then divide them into individual segments by geometrical analysis. A feature vector based on the intensity and shape of saliency maps is generated to represent the level of abnormality of each vessel segment. An AdaBoost classifier with weighted cost coefficient is trained to classify the vessel segments into normal and abnormal categories. To demonstrate its effectiveness, we apply this framework to 6,358 vessel segments in images from 10 patients with malarial retinopathy. The test sensitivity, specificity, accuracy, and area under curve (AUC) are 74.7%, 73.5%, 74.1% and 74.2% respectively when compared to the reference standard of human expert manual annotations. This performance is comparable to the agreement that we find between human observers of intravascular filling defects. Our method will be a powerful new tool for studying malarial retinopathy. PMID- 26053692 TI - Response to The reduced CO(2+) -binding ability of ischaemia-modified albumin is unlikely to be because of oxidative modification of the N-terminus". PMID- 26053691 TI - Cognitive dysfunction in children with brain tumors at diagnosis. AB - BACKGROUND: Survivors of brain tumors have a high risk for a wide range of cognitive problems. These dysfunctions are caused by the lesion itself and its surgical removal, as well as subsequent treatments (chemo- and/or radiation therapy). Multiple recent studies have indicated that children with brain tumors (BT) might already exhibit cognitive problems at diagnosis, i.e., before the start of any medical treatment. The aim of the present study was to investigate the baseline neuropsychological profile in children with BT compared to children with an oncological diagnosis not involving the central nervous system (CNS). METHODS: Twenty children with BT and 27 children with an oncological disease without involvement of the CNS (age range: 6.1-16.9 years) were evaluated with an extensive battery of neuropsychological tests tailored to the patient's age. Furthermore, the child and his/her parent(s) completed self-report questionnaires about emotional functioning and quality of life. In both groups, tests were administered before any therapeutic intervention such as surgery, chemotherapy, or irradiation. Groups were comparable with regard to age, gender, and socioeconomic status. RESULTS: Compared to the control group, patients with BTs performed significantly worse in tests of working memory, verbal memory, and attention (effect sizes between 0.28 and 0.47). In contrast, the areas of perceptual reasoning, processing speed, and verbal comprehension were preserved at the time of measurement. CONCLUSION: Our results highlight the need for cognitive interventions early in the treatment process in order to minimize or prevent academic difficulties as patients return to school. PMID- 26053693 TI - Molecular markers in bladder cancer: Novel research frontiers. AB - Bladder cancer (BC) is a heterogeneous disease encompassing distinct biologic features that lead to extremely different clinical behaviors. In the last 20 years, great efforts have been made to predict disease outcome and response to treatment by developing risk assessment calculators based on multiple standard clinical-pathological factors, as well as by testing several molecular markers. Unfortunately, risk assessment calculators alone fail to accurately assess a single patient's prognosis and response to different treatment options. Several molecular markers easily assessable by routine immunohistochemical techniques hold promise for becoming widely available and cost-effective tools for a more reliable risk assessment, but none have yet entered routine clinical practice. Current research is therefore moving towards (i) identifying novel molecular markers; (ii) testing old and new markers in homogeneous patients' populations receiving homogeneous treatments; (iii) generating a multimarker panel that could be easily, and thus routinely, used in clinical practice; (iv) developing novel risk assessment tools, possibly combining standard clinical-pathological factors with molecular markers. This review analyses the emerging body of literature concerning novel biomarkers, ranging from genetic changes to altered expression of a huge variety of molecules, potentially involved in BC outcome and response to treatment. Findings suggest that some of these indicators, such as serum circulating tumor cells and tissue mitochondrial DNA, seem to be easily assessable and provide reliable information. Other markers, such as the phosphoinositide-3-kinase (PI3K)/AKT (serine-threonine kinase)/mTOR (mammalian target of rapamycin) pathway and epigenetic changes in DNA methylation seem to not only have prognostic/predictive value but also, most importantly, represent valuable therapeutic targets. Finally, there is increasing evidence that the development of novel risk assessment tools combining standard clinical pathological factors with molecular markers represents a major quest in managing this poorly predictable disease. PMID- 26053694 TI - Complex contaminant mixtures in multistressor Appalachian riverscapes. AB - Runoff from watersheds altered by mountaintop mining in the Appalachian region (USA) is known to pollute headwater streams, yet regional-scale assessments of water quality have focused on salinization and selenium. The authors conducted a comprehensive survey of inorganic contaminants found in 170 stream segments distributed across a spectrum of historic and contemporary human land use. Principal component analysis identified 3 important dimensions of variation in water chemistry that were significantly correlated with contemporary surface mining (principal component 1: elevated dominant ions, sulfate, alkalinity, and selenium), coal geology and legacy mines (principal component 2: elevated trace metals), and residential development (principal component 3: elevated sodium and chloride). The combination of these 3 dominant sources of pollutants produced a complex stream-to-stream patchwork of contaminant mixtures. Seventy-five percent of headwater streams (catchments < 5 km(2) ) had water chemistries that could be classified as either reference (49%), development only (18%), or mining only (8%). Only 21% of larger streams (catchments > 5 km(2) ) were classified as having reference chemistries, and chemistries indicative of combined mining and development contaminants accounted for 47% of larger streams (compared with 26% of headwater streams). Extreme degradation of larger streams can be attributed to accumulation of contaminants from multiple human land use activities that include contemporary mountaintop mining, underground mining, abandoned mines, and untreated domestic wastewater. Consequently, water quality improvements in this region will require a multicontaminant remediation approach. PMID- 26053695 TI - The Characteristics and Function of S100A7 Induction in Squamous Cell Carcinoma: Heterogeneity, Promotion of Cell Proliferation and Suppression of Differentiation. AB - S100A7 is highly expressed in squamous cell carcinomas (SCC) and is related to the terminal differentiation of keratinocytes. However, its characteristic and function in SCC is not very known. In this present study, we used immunohistochemistry to examine the expression of S100A7 in 452 SCC specimens, including the lung, esophagus, oral cavity, skin, cervix, bladder, and three SCC cell lines. We found that S100A7-positive staining showed significant heterogeneity in six types of SCC specimen and three SCC cell lines. Further examination found that S100A7-positive cells and its expression at mRNA and protein levels could be induced in HCC94, FaDu, and A-431 cells both in vitro and in vivo using immunohistochemistry, real-time PCR, and Western blotting. Notably, the upregulation of squamous differentiation markers, including keratin-4, keratin-13, TG-1, and involucrin, also accompanied S100A7 induction, and a similar staining pattern of S100A7 and keratin-13 was found in HCC94 cells both in vitro and in vivo. Further study revealed that the overexpression of S100A7 significantly increased proliferation and inhibited squamous differentiation in A 431 cells both in vitro and in vivo. Conversely, silencing S100A7 inhibited cell growth and survival and increased the expression of keratin-4, keratin-13, TG-1, and involucrin in HCC94 cells. Therefore, these results demonstrate that S100A7 displays heterogeneous and inducible characteristic in SCC and also provide novel evidence that S100A7 acts as a dual regulator in promoting proliferation and suppressing squamous differentiation of SCC. PMID- 26053696 TI - The predictive value of ERG protein expression for development of castration resistant prostate cancer in hormone-naive advanced prostate cancer treated with primary androgen deprivation therapy. AB - BACKGROUND: Biomarkers predicting response to primary androgen deprivation therapy (ADT) and risk of castration-resistant prostate cancer (CRPC) is lacking. We aimed to analyse the predictive value of ERG expression for development of CRPC. METHODS: In total, 194 patients with advanced and/or metastatic prostate cancer (PCa) treated with first-line castration-based ADT were included. ERG protein expression was analysed in diagnostic specimens using immunohistochemistry (anti-ERG, EPR3864). Time to CRPC was compared between ERG subgroups using multiple cause-specific Cox regression stratified on ERG-status. Risk reclassification and time-dependent area under the ROC curves were used to assess the discriminative ability of ERG-status. Time to PSA-nadir, proportion achieving PSA-nadir <=0.2 ng/ml, and risk of PCa-specific death were secondary endpoints. RESULTS: Median follow-up was 6.8 years (IQR: 4.9-7.3). In total, 105 patients (54.1%) were ERG-positive and 89 (45.9%) were ERG-negative. No difference in risk of CRPC was observed between ERG subgroups (P = 0.51). Median time to CRPC was 3.9 years (95%CI: 3.2-5.1) and 4.5 years (95%CI: 2.3-not reached) in the ERG-positive and ERG-negative group, respectively. Compared to a model omitting ERG-status, the ERG-stratified model showed comparable AUC values 1 year (77.6% vs. 78.0%, P = 0.82), 2 years (71.7% vs. 71.8%, P = 0.85), 5 years (68.5% vs. 69.9%, P = 0.32), and 8 years (67.9% vs. 71.4%, P = 0.21) from ADT initiation. No differences in secondary endpoints were observed. CONCLUSIONS: ERG expression was not associated with risk of CRPC suggesting that ERG is not a candidate biomarker for predicting response to primary ADT in patients diagnosed with advanced and/or metastatic PCa. PMID- 26053697 TI - Emotional intelligence is associated with reduced insula responses to masked angry faces. AB - High levels of emotional intelligence (EI) have been associated with increased success in the workplace, greater quality of personal relationships, and enhanced wellbeing. Evidence suggests that EI is mediated extensively by the interplay of key emotion regions including the amygdala, insula, and ventromedial prefrontal cortex, among others. The insula, in particular, is important for processing interoceptive and somatic cues that are interpreted as emotional responses. We investigated the association between EI and functional brain responses within the aforementioned neurocircuitry in response to subliminal presentations of social threat. Fifty-four healthy adults completed the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) and underwent functional magnetic brain imaging while viewing subliminal presentations of faces displaying anger, using a backward masked facial affect paradigm to minimize conscious awareness of the expressed emotion. In response to masked angry faces, the total MSCEIT scores correlated negatively with a cluster of activation located within the left insula, but not with activation in any other region of interest. Considering the insula's role in the processing of interoceptive emotional cues, the results suggest that greater EI is associated with reduced emotional visceral reactivity and/or more accurate interoceptive prediction when confronted with stimuli indicative of social threat. PMID- 26053698 TI - Extending or creating a new brand: evidence from a study on event-related potentials. AB - Brand strategy is a critical problem in new product promotion. In relation to this, producers typically have two main options, namely, brand extension and new brand creation. The current study investigated the neural basis of evaluating these brand strategies at the brain level by using event-related potentials. The experiment used a word-pair paradigm, in which the first word was either a famous beverage brand name or a newly created brand, and the second word was a product name from one of the two product categories (beverage or household appliance). Therefore, four conditions existed as follows: a famous beverage brand paired with a beverage product (BB) or with a household appliance (BH) and a newly created brand paired with a beverage product (NB) or with a household appliance (NH). Behavioral results showed that brand extension obtained a higher acceptance rate than new brand creation under the beverage product category; however, a lower acceptance rate was observed under the household appliance category. Moreover, at the brain level, BB elicited lower N400 mean amplitude than the new brand product NB, whereas BH led to higher N400 amplitude than the new brand product NH. These results showed that the likelihood of accepting a product depended on the association between the brand name and product name, and that the N400 could serve as an index of brand strategy evaluation. In addition, this study also confirmed that brand extension is not always the best brand strategy; an inappropriate extension sometimes performed worse than the creation of a new brand. PMID- 26053699 TI - Processing of motion stimuli by cells in the optic tectum of chickens. AB - The ability to detect motion is crucial for the survival of animals. In the avian optic tectum, motion-sensitive output neurons in the stratum griseum centrale have large dendritic fields and receive direct retinal input at their distal dendrites (bottlebrush endings). It has been hypothesized that the activation of each ending elicits a burst in the neuron. Thus, an object moving across the receptive field would lead to a fixed number of bursts, independent of movement speed. However, experimental confirmation of this hypothesis is still missing. We measured the response of tectal neurons to moving stimuli in vivo and found that in 'fast-bursting' units (~500 Hz within burst), the number of bursts was independent of stimulus speed. These results indicate that the number of bursts might indeed be related to the sequential activation of the bottlebrush endings by visual stimuli. PMID- 26053700 TI - A novel approach for mechanical tissue characterization indicates decreased elastic strength in brain areas affected by experimental thromboembolic stroke. AB - As treatment of ischemic stroke remains a challenge with respect to the failure of numerous neuroprotective attempts, there is an ongoing need for better understanding of pathophysiological mechanisms causing tissue damage. Although ischemic outcomes have been studied extensively at the cellular and molecular level using histological and biochemical methods, properties of ischemia-affected brain tissue with respect to mechanical integrity have not been addressed so far. As a novel approach, this study used fluorescence-based detection of regions affected by experimental thromboembolic stroke in combination with scanning force microscopy to examine mechanical alterations in selected rat brain areas. Twenty five hours after onset of ischemia, a decreased elastic strength in the striatum as the region primarily affected by ischemia was found compared with the contralateral nonaffected hemisphere. Additional intrahemispheric analyses showed decreased elastic strength in the ischemic border zone compared with the more severely affected striatum. In conclusion, these data strongly indicate a critical alteration in mechanical tissue integrity caused by focal cerebral ischemia. Further, on the basis of data that have been obtained in relation to the ischemic border zone, a shell-like pattern of mechanical tissue damage was found in good accordance with the penumbra concept. These findings might enable the development of specific therapeutic interventions to protect affected areas from critical loss of mechanical integrity. PMID- 26053701 TI - Infantile mitochondrial disorder associated with subclinical hypothyroidism is caused by a rare mitochondrial DNA 8691A>G mutation: a case report. AB - Mitochondrial diseases, ~15% of cases, are because of mitochondrial DNA mutations. This study reported a case of an 11-month-old male infant with mitochondrial disease characteristics and subclinical hypothyroidism (a high thyrotropin level). Laboratory tests were all normal and the enzymatic activities of mitochondrial respiratory chain enzyme complexes I-IV were normal. However, thyroid tests showed abnormal results, and complex V showed a deficiency activity of 52.8% of the low limit of healthy individuals (normal activity is >60.7%). The patient experienced convulsions, and the 24-h ambulatory electroencephalography results showed abnormalities, but the electromyography results were normal. Axial brain MRI showed abnormal dysplasia over the white matter myelination in the bilateral horn of the lateral ventricle. Furthermore, DNA sequencing data showed a novel mutation at 8691A>G of the mitochondrial ATPase 6 gene. This case adds to the growing literature of mitochondrial disorders caused by mitochondrial ATPase 6 mutations. PMID- 26053702 TI - Reduced noise susceptibility in littermate offspring from heterozygous animals of the German waltzing guinea pig. AB - The German waltzing guinea pig is a spontaneously mutated strain with severe auditory and vestibular impairment caused by a so far unknown genetic mutation. The animals are born deaf and show a circling behavior. The heterozygote animals of this guinea pig strain have functionally normal hearing and balance. However, these animals have, in earlier studies, shown an increased resistance to noise compared with normal wild-type guinea pigs. In the present study, we explored the functional hearing with auditory brainstem response thresholds before and at different time points after noise exposure. Symptom-free littermates from heterozygote couples of the German waltzing guinea pigs were exclusively used for the study, which, after the hearing test, were sent back for breeding to confirm their genotype (i.e. heterozygote or normal). The aim of this paper was to ascertain that the previously shown reduced susceptibility to noise trauma in the heterozygote animals of the German waltzing guinea pig was also evident when littermates were used as control animals. The findings are important for further analysis of the heterozygote animals of this strain and for future investigations of the underlying mechanisms behind the diverse susceptibility to exposures of loud sound. PMID- 26053703 TI - Muscle biopsy and UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene mutation analysis in two Chinese patients with distal myopathy with rimmed vacuoles. AB - Distal myopathy with rimmed vacuoles is an autosomal recessive genetic disease characterized by weakness of the anterior compartment of the lower limbs, sparing the quadriceps muscle, and rimmed vacuoles in muscle biopsies. The disease is caused by a mutation in the UDP-N-acetylglucosamine 2-epimerase/N acetylmannosamine kinase (GNE) gene located on chromosome 9p13.3. We present two cases of Chinese patients with progressive lower extremity weakness. Clinical presentation, laboratory evaluation, electrodiagnostic testing, muscle pathology, and genetic analysis are described. Patient 1 was found to have heterozygous missense mutations (p.C13S and p.G576R) in the GNE gene and patient 2 had a homozygous missense mutation (p.C13S). The mutation p.C13S has been reported previously in China, Japan, and South Korea; however, the mutation p.G576R has not been described previously. PMID- 26053704 TI - Telemedicine versus WhatsApp: from tradition to evolution. PMID- 26053705 TI - Resonance local phonon mode and electron spin-lattice relaxation of formate-type free radicals studied by electron spin echo in Cd(HCOO)2.2H2O crystal. AB - The results of X-band electron spin resonance (ESR) and electron spin echo (ESE) measurements for free radicals generated in Cd(HCOO)2.2H2O single crystal are presented. From ESR spectra analysis the radicals were identified as CO2(-) after x-ray irradiation and as HOCO after gamma-ray irradiation. The room temperature g factors are: g|| = 1.9969 and g? = 2.0024 for CO2(-) and g1 = 2.0087, g2 = 2.0029 and g3 = 1.9960 for HOCO. Axial g-tensor symmetry for CO2(-) is due to fast reorientation of the radical molecule around the g||-axis. Assignment of HOCO is confirmed by hyperfine splitting (Amax = 0.4 mT) from a single distant proton. Spin lattice relaxation rate was determined from ESE measurements in temperature range 4-250 K. Both radicals relax via local resonance mode lying within acoustic phonon branch. The existing theories of electron spin-lattice relaxation via local resonance mode are critically reviewed and compared with experimental data. A new approximation is proposed giving local mode energy homega(R) = 56 cm(-1) for CO2(-) and homega(R) = 44 cm(-1) for the HOCO-radical. PMID- 26053706 TI - Complete Remission of Metastatic Neuroendocrine Paragastric Carcinoma After "Neoadjuvant" Peptide Receptor Radionuclide Therapy and Surgery. AB - A 48-year-old man presenting with upper abdominal pain was diagnosed with neuroendocrine tumor after biopsy of a paragastric mass with multiple liver metastases. (68)Ga-DOTATATE PET/CT showed intense uptake in the paragastric tumor and in multiple liver metastases not allowing primary surgery. Two cycles with cumulative 14.6 GBq (177)Lu-DOTATATE were given resulting in a considerable improvement. Subsequent surgery resulted in a complete remission as demonstrated by (68)Ga-DOTATATE PET/CT. Usually, peptide receptor radionuclide (PRRT) therapy is considered a palliative treatment. Few patients demonstrate a very favorable response allowing resection of the primary tumor after downstaging metastatic disease burden. PMID- 26053707 TI - Whole-Body Pediatric Neuroblastoma Imaging: 123I-mIBG and Beyond. AB - Pediatric cancer imaging stands to benefit from higher tumor detection sensitivity without ionizing radiation exposure. A prospective protocol compared diagnostic I-metaiodobenzylguanidine (I-mIBG) with whole-body diffusion-weighted MRI (DWI) to validate adjunctive methods of identifying small-volume oligometastatic neuroblastoma tumor deposits. Dual-modality imaging (I-mIBG and DWI) was obtained within a 3- and 25-day window at baseline and again at one year in the first enrolled patient. MRI was able to define the full extent of metastatic disease foci with improved resolution. These findings may provide critical information for definitive locoregional surgery and radiotherapy for high-risk neuroblastoma treatment. PMID- 26053708 TI - 18F-Fluciclovine PET/CT for the Detection of Prostate Cancer Relapse: A Comparison to 11C-Choline PET/CT. AB - PURPOSE: In recent years, a new PET compound (anti-3-(18)F-FACBC or (18)F fluciclovine) was tested for the detection of prostate cancer relapse. Despite very promising results, only preliminary data were available with regard to the comparison to (11)C-choline. The aim of this study was to compare the detection rate of (18)F-FACBC and (11)C-choline in patients presenting a biochemical relapse. PATIENTS AND METHODS: Fifty patients radically treated for prostate cancer and presenting with rising prostate-specific antigen (PSA) levels were consecutively and prospectively enrolled. All the patients were out of hormonal therapy and underwent both (11)C-choline PET/CT and (18)F-fluciclovine PET/CT within 1 week. The results were compared in terms of detection rate on a patient and lesion basis. Furthermore, a more detailed analysis regarding local, lymph node, and bone relapse was performed. RESULTS: On a patient-based analysis, (18)F fluciclovine detection turned out to be significantly superior to (11)C-choline (P < 0.000001). This result was also true on lesion, lymph node, bone lesion, and local relapse analysis (P < 0.0001 in all the cases). There was no significant difference in terms of target to background of positive lesions between (11)C choline and (18)F-fluciclovine. When the patients were divided into groups with different PSA levels, (18)F-fluciclovine had a superior detection rate for low, intermediate, and high PSA levels. CONCLUSIONS: In our experimental conditions, (18)F-fluciclovine provided a statistically significant better performance in terms of lesion detection rate as compared with (11)C-choline. However, more studies are required to evaluate the clinical significance of these results in terms of sensitivity, specificity, and accuracy. PMID- 26053709 TI - Monitoring the Effect of Immunotherapy in Autoimmune Limbic Encephalitis Using 18F-FDG PET. AB - A 70-year-old woman with a history of autoimmune hepatitis and renal cell carcinoma presented with subacute cognitive impairment. A brain MRI revealed mild leukoaraiosis, whereas brain F-FDG PET/CT showed diffuse cerebral hypometabolism that resembled some of the patterns described in limbic encephalitis and neurodegenerative diseases. With the suspicion of autoimmune encephalitis, the patient received immunotherapy with dramatic improvement of cognitive function and metabolic normalization at the 2-month follow-up on brain F-FDG PET/CT. Our results demonstrate that brain F-FDG PET/CT might be a useful tool in the assessment of patients with autoimmune encephalitis. PMID- 26053710 TI - Assessing Cutaneous Psoriasis Activity Using FDG-PET: Nonattenuation Corrected Versus Attenuation Corrected PET Images. AB - Psoriasis is a chronic inflammatory skin condition characterized by well circumscribed erythematous plaques with thick silvery scale. Infiltration of inflammatory cells such as lymphocytes, neutrophils, and macrophages and epidermal cell proliferation within psoriatic lesions may result in selective FDG accumulation. We present a 55-year-old patient with a 30-year history of psoriasis. Nonattenuation corrected PET/CT images demonstrated significant cutaneous FDG uptake corresponding to clinically apparent psoriatic lesions. However, in attenuation corrected (AC) FDG-PET images, the signal was substantially diminished and minimally detectable. Nonattenuation corrected FDG PET images may be useful and preferable to AC images in assessing skin inflammation in psoriasis. PMID- 26053711 TI - Staging of High-Risk Endometrial Cancer With PET/CT and Sentinel Lymph Node Mapping. AB - PURPOSE: The aim of this study was to evaluate the role of PET/CT and sentinel lymph node (SLN) biopsy in staging high-risk endometrial cancer patients (G2 and deep myometrial invasion, G3, serous clear cell carcinoma or carcinosarcoma) in early clinical stage. PATIENTS AND METHODS: From January 2006 to December 2012, high-risk early-stage endometrial cancer patients performing PET/CT scan followed by surgery (systematic pelvic +/- aortic lymphadenectomy) were included. From December 2010, SLN mapping with Tc-albumin nanocolloid and blue dye cervical injection was included in our clinical practice and additionally performed. Histological findings were used as the reference standard. RESULTS: Ninety-three patients were included, of which 22 of 93 had both PET/CT and SLN biopsy. The median number of dissected lymph nodes (LNs) was 28. Nineteen women (20.4%) had pelvic LN metastases; 14 were correctly identified by PET/CT. Among 5 false negative cases, 3 occurred after the introduction of SLN mapping due to detection of micrometastases by ultrastaging. On overall patient-based analysis, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of PET/CT for pelvic LN metastases were 73.7%, 98.7%, 93.6%, 93.3%, 93.6%, respectively. CONCLUSIONS: PET/CT demonstrated moderate sensitivity and high specificity in detecting pelvic LN metastases; its high positive predictive value (93.3%) is useful to refer patients to appropriate debulking surgery. Sentinel LN mapping and histological ultrastaging increased the identification of metastases (incidence, 18.3%-27.3%) not detectable by PET/CT because of its spatial resolution. The combination of both modalities is promising for nodal staging purpose. PMID- 26053712 TI - Impact of 18F-Choline PET/CT in the Decision-Making Strategy of Treatment Volumes in Definitive Prostate Cancer Volumetric Modulated Radiation Therapy. AB - INTRODUCTION: Aim of the study is to evaluate the impact of Cho-PET/CT in decision-making strategy of patients with localized prostate cancer (PC) eligible to definitive radiotherapy (RT). MATERIALS AND METHODS: Sixty patients Cho-PET/CT before RT were prospectively enrolled. All patients were treated with volumetric modulated arc therapy with simultaneous integrated boost in 28 fractions. Androgen deprivation therapy was prescribed according to National Comprehensive Cancer Network (NCCN) risk classification. Therapeutic strategy based on the Cho PET/CT evaluation was compared with the strategy that would have been proposed in case of PET not available and/or not strictly indicated, according to international and national PC guidelines. RESULTS: Cho-PET/CT was positive in 57 cases (95%): T in 45 (79%); T in combination with N in 8 (14%); and M (bone) in combination with T or N, or both, in 4 (7%). After Cho-PET/CT, patients were stratified as follows: 26 (43%) low risk, 10 (16%) intermediate risk, and 24 (41%) high risk. Cho-PET/CT shifted treatment indication in 13 cases (21%). The changes regarding radiation treatment volumes were as follows: 6 intermediate risk (10%) shifted to high risk and consequently were irradiated on prostate, seminal vesicles, and pelvic nodes PTVs; in 7 high risk (11%), the Cho-PET/CT showed bone and/or N uptake, and consequently, a simultaneous integrated boost on PET positive sites was prescribed. CONCLUSIONS: Cho-PET/CT seems to be a promising diagnostic tool in patients who are candidates for radical RT and supporting the decision making in treatment planning, in particular in intermediate-high risk. PMID- 26053713 TI - PET/CT Fusion Scan Prevents Futile Laparotomy in Early Stage Pancreatic Cancer. AB - BACKGROUND: Surgical resection with negative margins is the only curative approach for pancreatic cancer. A paucity of data exists in using PET/CT scan as staging workup in resectable pancreatic cancer. The aim of this study is to determine if PET/CT prevents futile laparotomy by detecting occult metastatic disease in patients with resectable or borderline resectable pancreatic cancer. METHODS: Patients were included using institutional PET/CT data base incorporating National Oncologic PET Registry with diagnosis of resectable or borderline resectable pancreatic cancer from 2005 to 2012. Clinical, radiographic, and pathologic characteristics were evaluated. The impact of PET/CT on patient management was estimated by calculating the percentage of patients whose treatment plan was altered secondary to PET/CT. RESULTS: We identified 285 patients with early stage pancreatic cancer who received PET/CT as part of initial staging workup. Upon initial workup (CT + EUS), 62% of patients were considered resectable, and 38% were borderline resectable. Addition of PET/CT scan changed the management in 10.9% (n = 31) of the patients (95% CI, 8%-15%). Metastatic lesions were confirmed with biopsy in 19 patients (61%). The proportion of change in treatment plan was significantly higher in patients who were initially considered to have borderline resectable compared with resectable malignancy (17% vs 7%, P = 0.019). In 199 patients who underwent surgery, 18.1% (n = 36) were found to have metastatic disease intraoperatively. CONCLUSIONS: PET/CT helped improve detection of occult metastases, ultimately sparing these patients a potentially unnecessary surgery. The role of PET/CT scan should be validated in prospective study. PMID- 26053714 TI - Metastatic Malignant Fibrous Histiocytoma in the Stomach: Imaging With 18F-FDG PET/CT. AB - Metastatic malignant fibrous histiocytoma (MFH) in the stomach is extremely rare. We report a 73-year-old man with MFH in the left popliteal fossa that metastasized to the stomach. Whole-body F-FDG PET/CT showed abnormal tracer uptakes in the stomach, which was subsequently confirmed as metastatic MFH. PMID- 26053715 TI - Sentinel Node Mapping in Melanoma of the Back: SPECT/CT Helps Discriminate "True" and "False" in-Transit Lymph Nodes. AB - A 32-year-old man with melanoma on the right paramedian region of the lower back underwent lymphoscintigraphy for radioguided sentinel node (SN) biopsy. Planar imaging showed the presence of 2 sites of radioactivity accumulation corresponding to an axillary SN and to an "in-transit" SN, located on the right side of the upper trunk. A further "hot spot" placed on the left paramedian region of the lower back was identified by planar lymphoscintigraphy. This last finding could be mistaken for another "in-transit" SN, but SPECT/CT demonstrated it was actually a nonspecific radiopharmaceutical accumulation at the level of the right renal pelvis. PMID- 26053716 TI - Orbital IgG4-Related Disease Detected by 11C-Methionine PET/CT. AB - A 64-year-old man presented with a complaint of left exophthalmos. Whole-body F FDG PET/CT showed increased uptake in the soft tissue masses in the orbits, peripancreas, and left renal hilum. C-methionine (MET) PET/CT of the head and neck showed increased uptake in the orbits, and the SUVmax of the left orbital lesion was 7.0. The patient was finally diagnosed as IgG4-related disease by the results of increased serum IgG4 and the biopsy of the orbital lesion. Although C MET is generally considered as a tumor-specific tracer, fibrous tissues of IgG4 related disease may be visualized by C-MET PET/CT. PMID- 26053717 TI - Focal 99mTc-DMSA Uptake in Lung Parenchyma Without Structural Alterations on SPECT/CT. AB - Static renal scintigraphy with Tc-DMSA is commonly used for the evaluation of renal morphology and function. Extrarenal uptake of Tc-DMSA is a rare finding described previously on sites such as bone metastasis, hemangioma, and splenic amyloidosis. We report a case with Tc-DMSA activity in the lungs. PMID- 26053718 TI - Combined 18F-NaF and 18F-FDG PET/CT in the Evaluation of Sarcoma Patients. AB - PURPOSE: The combined administration of F-NaF and F-FDG in a single PET/CT scan has the potential to improve patient convenience and cancer detection. Here we report the use of this approach for patients with sarcomas. PATIENTS AND METHODS: This is a retrospective review of 21 patients (12 men, 9 women; age, 19-66 years) with biopsy-proven sarcomas who had separate F-NaF PET/CT, F-FDG PET/CT, and combined F-NaF/F-FDG PET/CT scans for evaluation of malignancy. Two board certified nuclear medicine physicians and 1 board-certified musculoskeletal radiologist were randomly assigned to review the scans. Results were analyzed for sensitivity and specificity, using linear regression and receiver operating characteristics. RESULTS: A total of 13 patients had metastatic disease on F-NaF PET/CT, F-FDG PET/CT, and combined F-NaF/F-FDG PET/CT. Skeletal disease was more extensive on the F-NaF PET/CT scan than on the F-FDG PET/CT in 3 patients, whereas in 1 patient, F-FDG PET/CT showed skeletal disease and the F-NaF PET/CT was negative. Extraskeletal lesions were detected on both F-FDG and combined F NaF/F-FDG PET/CT in 20 patients, with 1 discordant finding in the lung. CONCLUSIONS: The combined F-NaF/F-FDG PET/CT scan allows for accurate evaluation of sarcoma patients. Further evaluation of this proposed imaging modality is warranted to identify the most suitable clinical scenarios, including initial treatment strategy and evaluation of response to therapy. PMID- 26053719 TI - Clinical Impact of Preoperative Sentinel Lymph Node Imaging With SPECT/CT in the Management of Interscapular Malignant Melanoma. AB - A 31-year-old male patient with a biopsy-proven cutaneous malignant melanoma located in the interscapular area was referred to lymphoscintigraphy for preoperative sentinel lymph node mapping. Anterior and posterior planar images showed 3 hot spots suggesting left axillary sentinel nodes. Herein, we reported the contribution of preoperative SPECT/CT-guided sentinel lymph node excision on accurate staging, management, prognostic evaluation, and determination of the proper surgical positioning preoperatively. PMID- 26053720 TI - 18F-FDG PET/CT Follow-up of Rosai-Dorfman Disease. AB - Rosai-Dorfman disease (RDD) or sinus histiocytosis is a rare histiocytic disorder characterized by massive lymphadenopathy and with extranodal involvement in 25% to 43% of cases. The clinical course of RDD is unpredictable with episodes of exacerbation and remissions that can last many years, and treatment strategies can be different according to organ involvement. We report a case of a 42-year old woman with extranodal disease followed for almost 10 years from the diagnosis who underwent seven (18)F-FDG PET/CT. PET/CT has proven to be a useful method for the management of this patient, mainly for the staging, follow-up, and evaluation of treatment results. PMID- 26053721 TI - Intrapancreatic Accessory Spleen Mimicking Neuroendocrine Tumor on 68Ga-DOTATATE PET/CT. AB - Besides well-known physiologic uptake of Ga-DOTATATE in spleen, pituitary gland, pancreatic head, adrenals, kidney, and urinary bladder, sometimes unusual areas of uptake are found. We report a case of a 53-year-old woman who had vague pain in abdomen for which abdominal CT was done showing a contrast-enhancing lesion in the pancreatic tail. It was suspected to be of neuroendocrine origin and Ga DOTATATE PET/CT showed a corresponding focal uptake. Spleen-preserving pancreatic tail resection was performed. Pathology revealed the diagnosis of an accessory intrapancreatic spleen (AIPS). PMID- 26053722 TI - Giant Cell Tumor of the Tendon Sheath With Discordant Metabolism as a False Positive on Staging of Mantle Cell Lymphoma. AB - A baseline F-FDG PET/CT scan in a patient with mantle cell lymphoma showed diffuse minimally FDG-avid lymphadenopathy and splenomegaly. There was also a focus of uptake in the left subscapularis muscle without a CT correlate. A post chemotherapy scan showed interval decrease in size, and resolution of FDG uptake, of the lymph nodes and spleen. Persistent activity was seen in the subscapularis muscle. Posttreatment biopsy of the FDG-avid lesion showed a benign giant cell tumor of tendon sheath. This case illustrates that a lesion with a markedly discordant SUV should raise suspicion for a second process. PMID- 26053723 TI - Development of Malignant Melanoma of the Orbit in Previous Radiation Field. AB - We present a case of a 40-year-old woman with a history of retinoblastoma in the left eye treated with enucleation and radiation therapy as an infant who recently developed worsening pain and exophthalmos in her right eye. Multimodality imaging demonstrated an enhancing, FDG-avid mass in the medial right orbit with associated bone destruction and extension into the ethmoid sinus. Pathologic analysis after excision showed a highly undifferentiated tumor consistent with melanoma. Although development of malignant melanoma in an irradiated field is rare, it should be considered in the differential, especially in childhood cancer survivors at increased risk of second malignant neoplasms. PMID- 26053724 TI - Reversal of Severe and Refractory Humoral Hypercalcemia With 177Lu-Octreotate Peptide Receptor Radionuclide Therapy for Neuroendocrine Tumor of the Pancreas. AB - A 48-year-old Caucasian male patient with newly diagnosed neuroendocrine tumor of the pancreas with multiple liver metastases developed severe and refractory hypercalcemia. Complementary investigations were compatible with humoral hypercalcemia with high parathyroid hormone-related peptide (PTHrP) levels. Hypercalcemia was refractory to medical treatments for more than 2 years. Serum calcium returned to normal values only after 4 cycles of peptide receptor radionuclide therapy with Lu-octreotate, with concomitant reduction of PTHrP level and tumor regression. The use of radionuclide therapy could be an option for the management of severe humoral hypercalcemia in patients with inoperable metastatic pancreatic neuroendocrine tumor. PMID- 26053725 TI - A New Portable Hybrid Camera for Fused Optical and Scintigraphic Imaging: First Clinical Experiences. AB - PURPOSE: Although portable gamma cameras (PGCs) have been helpful to depict sentinel nodes (SNs), sometimes nuclear physicians or surgeons have difficulties to interpret PGC images because of the lack of anatomical information. The aim of the present study was to develop and clinically test the prototype of a new portable hybrid camera (PHC), which adds optical to gamma-imaging. METHODS: In 2 hospitals, the existing PGC (Sentinella S102; Oncovision) was upgraded with an optical module (BB2-08S2C-25; Point Grey Research) to build a PHC. Preoperative PHC overview images (positioned at 15 cm distance) and close-up image (position at <5 cm distance) were obtained from 25 patients (12 melanoma, 2 oral cavity, and 11 breast cancer) after conventional lymphoscintigraphy. Errors in the optical image coregistration were evaluated with a 5-mm accuracy for each patient. RESULTS: Conventional lymphoscintigraphy and the close-up PHC images depicted 55 SNs in total. In the PHC overview images, the optical module offered fused optical and gamma-imaging indicating the image field of view and anatomical SN locations. Average optical image coregistration errors were 1.0 cm (range, 0 2.0 cm). CONCLUSIONS: Fused optical and gamma-imaging with the prototype PHC is technically feasible and helpful for the image interpretation. The optical image visualizes the gamma-image field of view, enabling SN localization in an anatomical context in a preoperative setting; however, for the operating room, the use of its optical component needs to be additionally adjusted. PMID- 26053726 TI - 68Ga DOTATATE PET/CT is an Accurate Imaging Modality in the Detection of Culprit Tumors Causing Osteomalacia. AB - OBJECTIVES: Tumor-induced osteomalacia (TIO) is generally caused by small benign mesenchymal tumors producing fibroblast growth factor-23 (FGF-23). The only curative therapy of the disease is resection of the causative tumors. However, these tumors are extremely difficult to detect using conventional imaging modalities. This research was undertaken to evaluate efficacy of (68)Ga DOTATATE PET/CT in this clinical setting. METHODS: Images of (68)Ga DOTATATE PET/CT and clinical charts from 54 patients with clinically suspected TIO were retrospectively reviewed. The image findings were compared with the results of histopathological examinations and clinical follow-ups. RESULTS: (68)Ga DOTATATE PET/CT scans were positive in 44 patients, among which, 33 had surgery to remove the lesions. Postsurgical pathological examination confirmed causative tumors in 32 patients whose symptoms diminished promptly, and the serum phosphate levels became normal, which confirmed the diagnoses of TIO. Eleven patients with positive (68)Ga DOTATATE PET/CT did not have surgery. These 11 patients continued to have symptoms and hypophosphatemia but were not included in the final analysis because of lack of evidence to confirm or exclude TIO. Ten patients had negative (68)Ga DOTATATE PET/CT scans. All of these10 patients responded to conservative therapy and had normal serum phosphate levels in the follow-up, which excluded TIO. Therefore, the (68)Ga DOTATATE PET/CT imaging had a sensitivity of 100% (32/32) and a specificity of 90.9% (10/11). The overall accuracy of (68)Ga DOTATATE PET/CT scan in the detection of tumors responsible for osteomalacia is 97.7% (42/43). CONCLUSIONS: (68)Ga DOTATATE PET/CT scan is an accurate imaging modality in the detection of tumors causing TIO. PMID- 26053727 TI - Lymph Node Metastasis from Tall-Cell Thyroid Cancer Negative on 18F-FDG PET/CT and Detected by 18F-Choline PET/CT. AB - A 77-year-old woman underwent thyroidectomy and (131)I remnant ablation for tall cell differentiated cancer (DTC) of the left lobe. Detectable Tg levels (4.1 MUg/L) under TSH suppression, with undetectable serum Tg-antibody levels, prompted neck ultrasonography, which revealed a lymph node in the left laterocervical region and in the right retroclavicular region. (18)F-FDG PET/CT showed uptake by the left lymph node. (18)F-choline PET/CT showed increased uptake by both lymph nodes. Histopathology revealed DTC solid metastasis in the left lymph node and solid and cystic metastasis in the right one. (18)F-choline PET/CT can locate virulent DTC recurrence, thereby increasing (18)F-FDG PET/CT information. PMID- 26053728 TI - 18F-FDG PET/CT in Hepatosplenic Gamma-Delta T-Cell Lymphoma. AB - Hepatosplenic T-cell lymphoma (HSTCL) is a rare and often difficult-to-diagnose subtype of lymphoma that can occur in the chronically immunosuppressed patient. We present the typical FDG PET/CT findings of HSTCL in a renal transplant recipient. The whole-body metabolic and morphologic information provided by FDG PET/CT can be of great additional value in establishing this diagnosis, thus allowing for a timely start of treatment. PMID- 26053729 TI - Metastatic Prostate Carcinoma Presenting as a Superscan on 68Ga-PSMA PET/CT. AB - We describe the finding of a metastatic superscan detected by Ga-PSMA PET/CT imaging. A 63-year-old man with metastatic prostate carcinoma underwent Ga-PSMA PET/CT imaging for staging and evaluation of the most appropriate therapeutic option. Images demonstrated diffuse and extensive skeletal uptake in the axial and appendicular skeleton, corresponding to the typical red marrow distribution. Intense soft tissue uptake was also seen in the prostate and multiple pelvic and abdominal lymph nodes. PMID- 26053730 TI - PET/CT in a Patient Diagnosed With Dandy-Walker Syndrome. AB - The Dandy-Walker syndrome (DWS) is a rare congenital posterior fossa malformation characterized by aplasia or hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle, and enlargement of the posterior fossa. We present a 52-year-old Caucasian man diagnosed with gastrointestinal stromal tumor and submitted to 18F-FDG PET/CT as a staging procedure. The patient was previously diagnosed with DWS in brain CT scan. PET/CT images revealed an ametabolic large cyst in the posterior fossa and hypoplasia of cerebellar vermis. The case is presented with the aim to show the appearance of this syndrome on PET/CT study. PMID- 26053731 TI - SPECT Myocardial Blood Flow Quantitation Concludes Equivocal Myocardial Perfusion SPECT Studies to Increase Diagnostic Benefits. AB - Recently, myocardial blood flow quantitation with dynamic SPECT/CT has been reported to enhance the detection of coronary artery disease in human. This advance has created important clinical applications to coronary artery disease diagnosis and management for areas where myocardial perfusion PET tracers are not available. We present 2 clinical cases that undergone a combined test of 1-day rest/dipyridamole-stress dynamic SPECT and ECG-gated myocardial perfusion SPECT scans using an integrated imaging protocol and demonstrate that flow parameters are capable to conclude equivocal myocardial perfusion SPECT studies, therefore increasing diagnostic benefits to add value in making clinical decisions. PMID- 26053732 TI - Risk of ultrasound-detected neonatal brain abnormalities in intrauterine growth restricted fetuses born between 28 and 34 weeks' gestation: relationship with gestational age at birth and fetal Doppler parameters. AB - OBJECTIVE: To estimate the value of gestational age at birth and fetal Doppler parameters in predicting the risk of neonatal cranial abnormalities in intrauterine growth-restricted (IUGR) fetuses born between 28 and 34 weeks' gestation. METHODS: Fetal Doppler parameters including umbilical artery (UA), middle cerebral artery (MCA), aortic isthmus, ductus venosus and myocardial performance index were evaluated in a cohort of 90 IUGR fetuses with abnormal UA Doppler delivered between 28 and 34 weeks' gestation and in 90 control fetuses matched for gestational age. The value of gestational age at birth and fetal Doppler parameters in predicting the risk of ultrasound-detected cranial abnormalities (CUA), including intraventricular hemorrhage, periventricular leukomalacia and basal ganglia lesions, was analyzed. RESULTS: Overall, IUGR fetuses showed a significantly higher incidence of CUA than did control fetuses (40.0% vs 12.2%, respectively; P < 0.001). Within the IUGR group, all predictive variables were associated individually with the risk of CUA, but fetal Doppler parameters rather than gestational age at birth were identified as the best predictor. MCA Doppler distinguished two groups with different degrees of risk of CUA (48.5% vs 13.6%, respectively; P < 0.01). In the subgroup with MCA vasodilation, presence of aortic isthmus retrograde net blood flow, compared to antegrade flow, allowed identification of a subgroup of cases with the highest risk of CUA (66.7% vs 38.6%, respectively; P < 0.05). CONCLUSION: Evaluation of fetal Doppler parameters, rather than gestational age at birth, allows identification of IUGR preterm fetuses at risk of neonatal brain abnormalities. PMID- 26053733 TI - All-Aqueous Electrosprayed Emulsion for Templated Fabrication of Cytocompatible Microcapsules. AB - Encapsulation of biomolecules and cells in hydrogel capsules via emulsion templating frequently induces an irreversible loss of bioactivity, because of the use of nonaqueous solvents. Here, we introduce an all-aqueous electrospray (AAE) approach to generate aqueous two-phase emulsion droplets, and we use them as templates to fabricate microcapsules with preserved cell viability. The approach allows formation of monodisperse microparticles with tunable sizes, variable compositions, and interior architectures in a mild gelation process. This technique potentially benefits a variety of new biomedical applications, such as delivery of bioactive proteins, transplantation of living cells, and assembly of cell-mimicking structures. PMID- 26053734 TI - Encapsulation of Halocarbons in a Tetrahedral Anion Cage. AB - Caged supramolecular systems are promising hosts for guest inclusion, separation, and stabilization. Well-studied examples are mainly metal-coordination-based or covalent architectures. An anion-coordination-based cage that is capable of encapsulating halocarbon guests is reported for the first time. This A4L4-type (A=anion) tetrahedral cage, [(PO4)4L4](12-), assembled from a C3-symmetric tris(bisurea) ligand (L) and phosphate ion (PO4(3-)), readily accommodates a series of quasi-tetrahedral halocarbons, such as the Freon components CFCl3, CF2Cl2, CHFCl2, and C(CH3)F3, and chlorocarbons CH2Cl2, CHCl3, CCl4, C(CH3)Cl3, C(CH3)2Cl2, and C(CH3)3Cl. The guest encapsulation in the solid state is confirmed by crystal structures, while the host-guest interactions in solution were demonstrated by NMR techniques. PMID- 26053735 TI - Nearly Forty Years after Viking: Are We Ready for a New Life-Detection Mission? PMID- 26053736 TI - Tailoring three-dimensional architectures by rolled-up nanotechnology for mimicking microvasculatures. AB - Artificial microvasculature, particularly as part of the blood-brain barrier, has a high benefit for pharmacological drug discovery and uptake regulation. We demonstrate the fabrication of tubular structures with patterns of holes, which are capable of mimicking microvasculatures. By using photolithography, the dimensions of the cylindrical scaffolds can be precisely tuned as well as the alignment and size of holes. Overlapping holes can be tailored to create diverse three-dimensional configurations, for example, periodic nanoscaled apertures. The porous tubes, which can be made from diverse materials for differential functionalization, are biocompatible and can be modified to be biodegradable in the culture medium. As a proof of concept, endothelial cells (ECs) as well as astrocytes were cultured on these scaffolds. They form monolayers along the scaffolds, are guided by the array of holes and express tight junctions. Nanoscaled filaments of cells on these scaffolds were visualized by scanning electron microscopy (SEM). This work provides the basic concept mainly for an in vitro model of microvasculature which could also be possibly implanted in vivo due to its biodegradability. PMID- 26053737 TI - Improving public health surveillance of chlamydia: analysis of population-level positivity trends. AB - Background Chlamydia remains Australia's most frequently notified communicable disease; however, interpretation of notification data is difficult without knowledge of testing practices. This study examined the value of reporting positivity trends. METHODS: Tasmanian population-level chlamydia laboratory tests and notification data from 2001 to 2010 were compared. RESULTS: Notifications, tests and positivity increased, most significantly in males and females aged 15 29 years. CONCLUSIONS: Analysis of chlamydia positivity trends can inform the development, monitoring and evaluation of prevention and control activities and improves the interpretation of notification trends. After allowing for testing effort, an increase in chlamydia infections in young people was found. PMID- 26053738 TI - Bioactive comparison of main components from unripe fruits of Rubus chingii Hu and identification of the effective component. AB - Dried and unripe fruit of Rubus chingii Hu, known as "Fu-pen-zi" in Chinese, has been used as a food and tonic in China for a long time. In order to analyze its effective ingredients, polysaccharides, flavonoids, saponins and alkaloids were extracted from the unripe fruits and their contents were determined. The in vitro antioxidant, anticomplementary and anticancer activities against human lung adenocarcinoma A549 cells of the four major constituents were investigated. Results showed that total flavonoids exhibited an obvious antioxidant activity, which was very close to ascorbic acid. The anticomplementary and anticancer activities of flavonoids were also the best among the four chemical compositions. Therefore, extraction process optimization of flavonoids was conducted using response surface methodology. The optimal conditions were as follows: extraction temperature 72.8 degrees C, ethanol concentration 30.67%, extraction time 2.66 h, and a liquid/solid ratio of 19.54 : 1. In addition, total flavonoids were subsequently separated by column chromatography and the major flavonoid was identified as tiliroside. Further experimental data revealed that tiliroside treatment could suppress the proliferation and induced the apoptosis of A549 cells. PMID- 26053740 TI - Reporting of Limitations of Observational Research. PMID- 26053739 TI - Protective Effects of Ferulic Acid on High Glucose-Induced Protein Glycation, Lipid Peroxidation, and Membrane Ion Pump Activity in Human Erythrocytes. AB - Ferulic acid (FA) is the ubiquitous phytochemical phenolic derivative of cinnamic acid. Experimental studies in diabetic models demonstrate that FA possesses multiple mechanisms of action associated with anti-hyperglycemic activity. The mechanism by which FA prevents diabetes-associated vascular damages remains unknown. The aim of study was to investigate the protective effects of FA on protein glycation, lipid peroxidation, membrane ion pump activity, and phosphatidylserine exposure in high glucose-exposed human erythrocytes. Our results demonstrated that FA (10-100 MUM) significantly reduced the levels of glycated hemoglobin (HbA1c) whereas 0.1-100 MUM concentrations inhibited lipid peroxidation in erythrocytes exposed to 45 mM glucose. This was associated with increased glucose consumption. High glucose treatment also caused a significant reduction in Na+/K+-ATPase activity in the erythrocyte plasma membrane which could be reversed by FA. Furthermore, we found that FA (0.1-100 MUM) prevented high glucose-induced phosphatidylserine exposure. These findings provide insights into a novel mechanism of FA for the prevention of vascular dysfunction associated with diabetes. PMID- 26053741 TI - Gay and Bisexual Men's Perceptions of the Donation and Use of Human Biological Samples for Research: A Qualitative Study. AB - Human biological samples (biosamples) are increasingly important in diagnosing, treating and measuring the prevalence of illnesses. For the gay and bisexual population, biosample research is particularly important for measuring the prevalence of human immunodeficiency virus (HIV). By determining people's understandings of, and attitudes towards, the donation and use of biosamples, researchers can design studies to maximise acceptability and participation. In this study we examine gay and bisexual men's attitudes towards donating biosamples for HIV research. Semi-structured telephone interviews were conducted with 46 gay and bisexual men aged between 18 and 63 recruited in commercial gay scene venues in two Scottish cities. Interview transcripts were analysed thematically using the framework approach. Most men interviewed seemed to have given little prior consideration to the issues. Participants were largely supportive of donating tissue for medical research purposes, and often favourable towards samples being stored, reused and shared. Support was often conditional, with common concerns related to: informed consent; the protection of anonymity and confidentiality; the right to withdraw from research; and ownership of samples. Many participants were in favour of the storage and reuse of samples, but expressed concerns related to data security and potential misuse of samples, particularly by commercial organisations. The sensitivity of tissue collection varied between tissue types and collection contexts. Blood, urine, semen and bowel tissue were commonly identified as sensitive, and donating saliva and as unlikely to cause discomfort. To our knowledge, this is the first in-depth study of gay and bisexual men's attitudes towards donating biosamples for HIV research. While most men in this study were supportive of donating tissue for research, some clear areas of concern were identified. We suggest that these minority concerns should be accounted for to develop inclusive, evidence-informed research protocols that balance collective benefits with individual concerns. PMID- 26053742 TI - Ecological Diversity in South American Mammals: Their Geographical Distribution Shows Variable Associations with Phylogenetic Diversity and Does Not Follow the Latitudinal Richness Gradient. AB - The extent to which the latitudinal gradient in species richness may be paralleled by a similar gradient of increasing functional or phylogenetic diversity is a matter of controversy. We evaluated whether taxonomic richness (TR) is informative in terms of ecological diversity (ED, an approximation to functional diversity) and phylogenetic diversity (AvPD) using data on 531 mammal species representing South American old autochthonous (marsupials, xenarthrans), mid-Cenozoic immigrants (hystricognaths, primates) and newcomers (carnivorans, artiodactyls). If closely related species are ecologically more similar than distantly related species, AvPD will be a strong predictor of ED; however, lower ED than predicted from AvPD may be due to species retaining most of their ancestral characters, suggesting niche conservatism. This pattern could occur in tropical rainforests for taxa of tropical affinity (old autochthonous and mid Cenozoic immigrants) and in open and arid habitats for newcomers. In contrast, higher ED than expected from AvPD could occur, possibly in association with niche evolution, in arid and open habitats for taxa of tropical affinity and in forested habitats for newcomers. We found that TR was a poor predictor of ED and AvPD. After controlling for TR, there was considerable variability in the extent to which AvPD accounted for ED. Taxa of tropical affinity did not support the prediction of ED deficit within tropical rainforests, rather, they showed a mosaic of regions with an excess of ED interspersed with zones of ED deficit within the tropics; newcomers showed ED deficit in arid and open regions. Some taxa of tropical affinity showed excess of ED in tropical desert areas (hystricognaths) or temperate semideserts (xenarthrans); newcomers showed excess of ED at cold-temperate latitudes in the Northern Hemisphere. This result suggests that extreme climatic conditions at both temperate and tropical latitudes may have promoted niche evolution in mammals. PMID- 26053744 TI - The Effect of a Mutation in the Thyroid Stimulating Hormone Receptor (TSHR) on Development, Behaviour and TH Levels in Domesticated Chickens. AB - The thyroid stimulating hormone receptor (TSHR) has been suggested to be a "domestication locus" in the chicken, due to a strong selective sweep over the gene found in domesticated chickens, differentiating them from their wild ancestor the Red Junglefowl (RJF). We investigated the effect of the mutation on development (incubation time), behaviour and thyroid hormone levels in intercross chickens homozygous for the mutation (d/d), wild type homozygotes (w/w) or heterozygotes (d/w). This allowed an assessment of the effect of genotype at this locus against a random mix of RJF and WL genotypes throughout the rest of the genome, controlling for family effects. The d/d genotype showed a longer incubation time, less fearful behaviours, lower number of aggressive behaviours and decreased levels of the thyroid hormone T4, in comparison to the w/w genotype. The difference between TSHR genotypes (d/d vs. w/w) in these respects mirrors the differences in development and behaviour between pure domesticated White Leghorns and pure RJF chickens. Higher individual T3 and T4 levels were associated with more aggression. Our study indicates that the TSHR mutation affects typical domestication traits, possibly through modifying plasma levels of thyroid hormones, and may therefore have been important during the evolution of the domestic chicken. PMID- 26053745 TI - GTRF: a game theory approach for regulating node behavior in real-time wireless sensor networks. AB - The selfish behaviors of nodes (or selfish nodes) cause packet loss, network congestion or even void regions in real-time wireless sensor networks, which greatly decrease the network performance. Previous methods have focused on detecting selfish nodes or avoiding selfish behavior, but little attention has been paid to regulating selfish behavior. In this paper, a Game Theory-based Real time & Fault-tolerant (GTRF) routing protocol is proposed. GTRF is composed of two stages. In the first stage, a game theory model named VA is developed to regulate nodes' behaviors and meanwhile balance energy cost. In the second stage, a jumping transmission method is adopted, which ensures that real-time packets can be successfully delivered to the sink before a specific deadline. We prove that GTRF theoretically meets real-time requirements with low energy cost. Finally, extensive simulations are conducted to demonstrate the performance of our scheme. Simulation results show that GTRF not only balances the energy cost of the network, but also prolongs network lifetime. PMID- 26053743 TI - Expression of Vesicular Glutamate Transporter 2 (vGluT2) on Large Dense-Core Vesicles within GnRH Neuroterminals of Aging Female Rats. AB - The pulsatile release of GnRH is crucial for normal reproductive physiology across the life cycle, a process that is regulated by hypothalamic neurotransmitters. GnRH terminals co-express the vesicular glutamate transporter 2 (vGluT2) as a marker of a glutamatergic phenotype. The current study sought to elucidate the relationship between glutamate and GnRH nerve terminals in the median eminence--the site of GnRH release into the portal capillary vasculature. We also determined whether this co-expression may change during reproductive senescence, and if steroid hormones, which affect responsiveness of GnRH neurons to glutamate, may alter the co-expression pattern. Female Sprague-Dawley rats were ovariectomized at young adult, middle-aged and old ages (~4, 11, and 22 months, respectively) and treated four weeks later with sequential vehicle + vehicle (VEH + VEH), estradiol + vehicle (E2 + VEH), or estradiol + progesterone (E2+P4). Rats were perfused 24 hours after the second hormone treatment. Confocal microscopy was used to determine colocalization of GnRH and vGluT2 immunofluorescence in the median eminence. Post-embedding immunogold labeling of GnRH and vGluT2, and a serial electron microscopy (EM) technique were used to determine the cellular interaction between GnRH terminals and glutamate signaling. Confocal analysis showed that GnRH and vGluT2 immunofluorescent puncta were extensively colocalized in the median eminence and that their density declined with age but was unaffected by short-term hormone treatment. EM results showed that vGluT2 immunoreactivity was extensively associated with large dense core vesicles, suggesting a unique glutamatergic signaling pathway in GnRH terminals. Our results provide novel subcellular information about the intimate relationship between GnRH terminals and glutamate in the median eminence. PMID- 26053746 TI - Visual privacy by context: proposal and evaluation of a level-based visualisation scheme. AB - Privacy in image and video data has become an important subject since cameras are being installed in an increasing number of public and private spaces. Specifically, in assisted living, intelligent monitoring based on computer vision can allow one to provide risk detection and support services that increase people's autonomy at home. In the present work, a level-based visualisation scheme is proposed to provide visual privacy when human intervention is necessary, such as at telerehabilitation and safety assessment applications. Visualisation levels are dynamically selected based on the previously modelled context. In this way, different levels of protection can be provided, maintaining the necessary intelligibility required for the applications. Furthermore, a case study of a living room, where a top-view camera is installed, is presented. Finally, the performed survey-based evaluation indicates the degree of protection provided by the different visualisation models, as well as the personal privacy preferences and valuations of the users. PMID- 26053747 TI - Magnetic-particle-sensing based diagnostic protocols and applications. AB - Magnetic particle-labeled biomaterial detection has attracted much attention in recent years for a number of reasons; easy manipulation by external magnetic fields, easy functionalization of the surface, and large surface-to-volume ratio, to name but a few. In this review, we report on our recent investigations into the detection of nano-sized magnetic particles. First, the detection by Hall magnetic sensor with lock-in amplifier and alternative magnetic field is summarized. Then, our approach to detect sub-200 nm diameter target magnetic particles via relatively large micoro-sized "columnar particles" by optical microscopy is described. Subsequently, we summarize magnetic particle detection based on optical techniques; one method is based on the scattering of the magnetically-assembled nano-sized magnetic bead chain in rotating magnetic fields and the other one is based on the reflection of magnetic target particles and porous silicon. Finally, we report recent works with reference to more familiar industrial products (such as smartphone-based medical diagnosis systems and magnetic removal of unspecific-binded nano-sized particles, or "magnetic washing"). PMID- 26053748 TI - Matching the best viewing angle in depth cameras for biomass estimation based on poplar seedling geometry. AB - In energy crops for biomass production a proper plant structure is important to optimize wood yields. A precise crop characterization in early stages may contribute to the choice of proper cropping techniques. This study assesses the potential of the Microsoft Kinect for Windows v.1 sensor to determine the best viewing angle of the sensor to estimate the plant biomass based on poplar seedling geometry. Kinect Fusion algorithms were used to generate a 3D point cloud from the depth video stream. The sensor was mounted in different positions facing the tree in order to obtain depth (RGB-D) images from different angles. Individuals of two different ages, e.g., one month and one year old, were scanned. Four different viewing angles were compared: top view (0 degrees ), 45 degrees downwards view, front view (90 degrees ) and ground upwards view (-45 degrees ). The ground-truth used to validate the sensor readings consisted of a destructive sampling in which the height, leaf area and biomass (dry weight basis) were measured in each individual plant. The depth image models agreed well with 45 degrees , 90 degrees and -45 degrees measurements in one-year poplar trees. Good correlations (0.88 to 0.92) between dry biomass and the area measured with the Kinect were found. In addition, plant height was accurately estimated with a few centimeters error. The comparison between different viewing angles revealed that top views showed poorer results due to the fact the top leaves occluded the rest of the tree. However, the other views led to good results. Conversely, small poplars showed better correlations with actual parameters from the top view (0 degrees ). Therefore, although the Microsoft Kinect for Windows v.1 sensor provides good opportunities for biomass estimation, the viewing angle must be chosen taking into account the developmental stage of the crop and the desired parameters. The results of this study indicate that Kinect is a promising tool for a rapid canopy characterization, i.e., for estimating crop biomass production, with several important advantages: low cost, low power needs and a high frame rate (frames per second) when dynamic measurements are required. PMID- 26053749 TI - Design and development of nEMoS, an all-in-one, low-cost, web-connected and 3D printed device for environmental analysis. AB - The Indoor Environmental Quality (IEQ) refers to the quality of the environment in relation to the health and well-being of the occupants. It is a holistic concept, which considers several categories, each related to a specific environmental parameter. This article describes a low-cost and open-source hardware architecture able to detect the indoor variables necessary for the IEQ calculation as an alternative to the traditional hardware used for this purpose. The system consists of some sensors and an Arduino board. One of the key strengths of Arduino is the possibility it affords of loading the script into the board's memory and letting it run without interfacing with computers, thus granting complete independence, portability and accuracy. Recent works have demonstrated that the cost of scientific equipment can be reduced by applying open-source principles to their design using a combination of the Arduino platform and a 3D printer. The evolution of the 3D printer has provided a new means of open design capable of accelerating self-directed development. The proposed nano Environmental Monitoring System (nEMoS) instrument is shown to have good reliability and it provides the foundation for a more critical approach to the use of professional sensors as well as for conceiving new scenarios and potential applications. PMID- 26053752 TI - Using a Smart City IoT to Incentivise and Target Shifts in Mobility Behaviour--Is It a Piece of Pie? AB - Whilst there is an increasing capability to instrument smart cities using fixed and mobile sensors to produce the big data to better understand and manage transportation use, there still exists a wide gap between the sustainability goals of smart cities, e.g., to promote less private car use at peak times, with respect to their ability to more dynamically support individualised shifts in multi-modal transportation use to help achieve such goals. We describe the development of the tripzoom system developed as part of the SUNSET-SUstainable social Network SErvices for Transport-project to research and develop a mobile and fixed traffic sensor system to help facilitate individual mobility shifts. Its main novelty was its ability to use mobile sensors to classify common multiple urban transportation modes, to generate information-rich individual and group mobility profiles and to couple this with the use of a targeted incentivised marketplace to gamify travel. This helps to promote mobility shifts towards achieving sustainability goals. This system was trialled in three European country cities operated as Living Labs over six months. Our main findings were that we were able to accomplish a level of behavioural shifts in travel behaviour. Hence, we have provided a proof-of-concept system that uses positive incentives to change individual travel behaviour. PMID- 26053750 TI - QD-Based FRET Probes at a Glance. AB - The unique optoelectronic properties of quantum dots (QDs) give them significant advantages over traditional organic dyes, not only as fluorescent labels for bioimaging, but also as emissive sensing probes. QD sensors that function via manipulation of fluorescent resonance energy transfer (FRET) are of special interest due to the multiple response mechanisms that may be utilized, which in turn imparts enhanced flexibility in their design. They may also function as ratiometric, or "color-changing" probes. In this review, we describe the fundamentals of FRET and provide examples of QD-FRET sensors as grouped by their response mechanisms such as link cleavage and structural rearrangement. An overview of early works, recent advances, and various models of QD-FRET sensors for the measurement of pH and oxygen, as well as the presence of metal ions and proteins such as enzymes, are also provided. PMID- 26053751 TI - Generation of Red-Shifted Cameleons for Imaging Ca2+ Dynamics of the Endoplasmic Reticulum. AB - Cameleons are sophisticated genetically encoded fluorescent probes that allow quantifying cellular Ca2+ signals. The probes are based on Forster resonance energy transfer (FRET) between terminally located fluorescent proteins (FPs), which move together upon binding of Ca2+ to the central calmodulin myosin light chain kinase M13 domain. Most of the available cameleons consist of cyan and yellow FPs (CFP and YFP) as the FRET pair. However, red-shifted versions with green and orange or red FPs (GFP, OFP, RFP) have some advantages such as less phototoxicity and minimal spectral overlay with autofluorescence of cells and fura-2, a prominent chemical Ca2+ indicator. While GFP/OFP- or GFP/RFP-based cameleons have been successfully used to study cytosolic and mitochondrial Ca2+ signals, red-shifted cameleons to visualize Ca2+ dynamics of the endoplasmic reticulum (ER) have not been developed so far. In this study, we generated and tested several ER targeted red-shifted cameleons. Our results show that GFP/OFP based cameleons due to miss-targeting and their high Ca2+ binding affinity are inappropriate to record ER Ca2+ signals. However, ER targeted GFP/RFP-based probes were suitable to sense ER Ca2+ in a reliable manner. With this study we increased the palette of cameleons for visualizing Ca2+ dynamics within the main intracellular Ca2+ store. PMID- 26053753 TI - Review of Research Status and Development Trends of Wireless Passive LC Resonant Sensors for Harsh Environments. AB - Measurement technology for various key parameters in harsh environments (e.g., high-temperature and biomedical applications) continues to be limited. Wireless passive LC resonant sensors offer long service life and can be suitable for harsh environments because they can transmit signals without battery power or wired connections. Consequently, these devices have become the focus of many current research studies. This paper addresses recent research, key technologies, and practical applications relative to passive LC sensors used to monitor temperature, pressure, humidity, and harmful gases in harsh environments. The advantages and disadvantages of various sensor types are discussed, and prospects and challenges for future development of these sensors are presented. PMID- 26053754 TI - Signal-to-Noise Enhancement of a Nanospring Redox-Based Sensor by Lock-in Amplification. AB - A significant improvement of the response characteristics of a redox chemical gas sensor (chemiresistor) constructed with a single ZnO coated silica nanospring has been achieved with the technique of lock-in signal amplification. The comparison of DC and analog lock-in amplifier (LIA) AC measurements of the electrical sensor response to toluene vapor, at the ppm level, has been conducted. When operated in the DC detection mode, the sensor exhibits a relatively high sensitivity to the analyte vapor, as well as a low detection limit at the 10 ppm level. However, at 10 ppm the signal-to-noise ratio is 5 dB, which is less than desirable. When operated in the analog LIA mode, the signal-to-noise ratio at 10 ppm increases by 30 dB and extends the detection limit to the ppb range. PMID- 26053755 TI - An Efficient Adaptive Angle-Doppler Compensation Approach for Non-Sidelooking Airborne Radar STAP. AB - In this study, the effects of non-sidelooking airborne radar clutter dispersion on space-time adaptive processing (STAP) is considered, and an efficient adaptive angle-Doppler compensation (EAADC) approach is proposed to improve the clutter suppression performance. In order to reduce the computational complexity, the reduced-dimension sparse reconstruction (RDSR) technique is introduced into the angle-Doppler spectrum estimation to extract the required parameters for compensating the clutter spectral center misalignment. Simulation results to demonstrate the effectiveness of the proposed algorithm are presented. PMID- 26053756 TI - Using K-Nearest Neighbor Classification to Diagnose Abnormal Lung Sounds. AB - A reported 30% of people worldwide have abnormal lung sounds, including crackles, rhonchi, and wheezes. To date, the traditional stethoscope remains the most popular tool used by physicians to diagnose such abnormal lung sounds, however, many problems arise with the use of a stethoscope, including the effects of environmental noise, the inability to record and store lung sounds for follow-up or tracking, and the physician's subjective diagnostic experience. This study has developed a digital stethoscope to help physicians overcome these problems when diagnosing abnormal lung sounds. In this digital system, mel-frequency cepstral coefficients (MFCCs) were used to extract the features of lung sounds, and then the K-means algorithm was used for feature clustering, to reduce the amount of data for computation. Finally, the K-nearest neighbor method was used to classify the lung sounds. The proposed system can also be used for home care: if the percentage of abnormal lung sound frames is > 30% of the whole test signal, the system can automatically warn the user to visit a physician for diagnosis. We also used bend sensors together with an amplification circuit, Bluetooth, and a microcontroller to implement a respiration detector. The respiratory signal extracted by the bend sensors can be transmitted to the computer via Bluetooth to calculate the respiratory cycle, for real-time assessment. If an abnormal status is detected, the device will warn the user automatically. Experimental results indicated that the error in respiratory cycles between measured and actual values was only 6.8%, illustrating the potential of our detector for home care applications. PMID- 26053757 TI - Inhibitory Effect of Aqueous Extracts from Marine Sponges on the Activity and Expression of Gelatinases A (MMP-2) and B (MMP-9) in Rat Astrocyte Cultures. AB - The aim of this study was to evaluate whether water soluble compounds present in aqueous extracts from seven Mediterranean demosponges exert biological activity towards matrix metalloproteinases (MMPs), which represent important pathogenic factors of human diseases. Aqueous extracts were tested on LPS-activated cultured rat astrocytes, and levels and expression of MMP-2 and MMP-9 were assessed by zymography and RT-PCR, respectively. Our results demonstrated that the studied extracts contain water soluble compounds able to inhibit MMP-2 and MMP-9 activity and expression. We also compared the anti-MMP activities present in aqueous extracts from wild and reared specimens of Tethya aurantium and T. citrina. The results obtained revealed that the reared sponges maintain the production of bioactive compounds with inhibitory effect on MMP-2 and MMP-9 for all the duration of the rearing period. Taken together, our results indicate that the aqueous extracts from the selected Mediterranean demosponges possess a variety of water-soluble bioactive compounds, which are able to inhibit MMPs at different levels. The presence of biological activity in aqueous extracts from reared specimens of T. aurantium and T. citrina strongly encourage sponge aquaculture as a valid option to supply sponge biomass for drug development on a large scale. PMID- 26053758 TI - The Source Parameters of Echolocation Clicks from Captive and Free-Ranging Yangtze Finless Porpoises (Neophocaena asiaeorientalis asiaeorientalis). AB - The clicks of Yangtze finless porpoises (Neophocaena asiaeorientalis asiaeorientalis) from 7 individuals in the tank of Baiji aquarium, 2 individuals in a netted pen at Shishou Tian-e-zhou Reserve and 4 free-ranging individuals at Tianxingzhou were recorded using a broadband digital recording system with four element hydrophones. The peak-to-peak apparent source level (ASL_pp) of clicks from individuals at the Baiji aquarium was 167 dB re 1 MUPa with mean center frequency of 133 kHz, -3dB bandwidth of 18 kHz and -10 dB duration of 58 MUs. The ASL_pp of clicks from individuals at the Shishou Tian-e-zhou Reserve was 180 dB re 1 MUPa with mean center frequency of 128 kHz, -3dB bandwidth of 20 kHz and -10 dB duration of 39 MUs. The ASL_pp of clicks from individuals at Tianxingzhou was 176 dB re 1 MUPa with mean center frequency of 129 kHz, -3dB bandwidth of 15 kHz and -10 dB duration of 48 MUs. Differences between the source parameters of clicks among the three groups of finless porpoises suggest these animals adapt to their echolocation signals depending on their surroundings. PMID- 26053759 TI - In Vivo and in Vitro Isomer-Specific Biotransformation of Perfluorooctane Sulfonamide in Common Carp (Cyprinus carpio). AB - Biotransformation of PFOS-precursors (PreFOS) may contribute significantly to the level of perfluorooctanesulfonate (PFOS) in the environment. Perfluorooctane sulfonamide (PFOSA) is one of the major intermediates of higher molecular weight PreFOS. Its further degradation to PFOS could be isomer specific and thereby explain unexpected high percentages of branched (Br-) PFOS isomers observed in wildlife. In this study, isomeric degradation of PFOSA was concomitantly investigated by in vivo and in vitro tests using common carp as an animal model. In the in vivo tests branched isomers of PFOSA and PFOS were eliminated faster than the corresponding linear (n-) isomers, leading to enrichment of n-PFOSA in the fish. In contrast, Br-PFOS was enriched in the fish, suggesting that Br-PFOSA isomers were preferentially metabolized to Br-PFOS over n-PFOSA. This was confirmed by the in vitro test. The exception was 1m-PFOSA, which could be the most difficult to be metabolized due to its alpha-branched structure, resulting in the deficiency of 1m-PFOS in the fish. The in vitro tests indicated that the metabolism mainly took place in the fish liver instead of its kidney, and it was mainly a Phase I reaction. The results may help to explain the special PFOS isomer profile observed in wildlife. PMID- 26053760 TI - Grain rotation and lattice deformation during photoinduced chemical reactions revealed by in situ X-ray nanodiffraction. AB - In situ X-ray diffraction (XRD) and transmission electron microscopy (TEM) have been used to investigate many physical science phenomena, ranging from phase transitions, chemical reactions and crystal growth to grain boundary dynamics. A major limitation of in situ XRD and TEM is a compromise that has to be made between spatial and temporal resolution. Here, we report the development of in situ X-ray nanodiffraction to measure high-resolution diffraction patterns from single grains with up to 5 ms temporal resolution. We observed, for the first time, grain rotation and lattice deformation in chemical reactions induced by X ray photons: Br(-) + hv -> Br + e(-) and e(-) + Ag(+) -> Ag(0). The grain rotation and lattice deformation associated with the chemical reactions were quantified to be as fast as 3.25 rad s(-1) and as large as 0.5 A, respectively. The ability to measure high-resolution diffraction patterns from individual grains with a temporal resolution of several milliseconds is expected to find broad applications in materials science, physics, chemistry and nanoscience. PMID- 26053761 TI - The role of quasi-plasticity in the extreme contact damage tolerance of the stomatopod dactyl club. AB - The structure of the stomatopod dactyl club--an ultrafast, hammer-like device used by the animal to shatter hard seashells--offers inspiration for impact tolerant ceramics. Here, we present the micromechanical principles and related micromechanisms of deformation that impart the club with high impact tolerance. By using depth-sensing nanoindentation with spherical and sharp contact tips in combination with post-indentation residual stress mapping by Raman microspectroscopy, we show that the impact surface region of the dactyl club exhibits a quasi-plastic contact response associated with the interfacial sliding and rotation of fluorapatite nanorods, endowing the club with localized yielding. We also show that the subsurface layers exhibit strain hardening by microchannel densification, which provides additional dissipation of impact energy. Our findings suggest that the club's macroscopic size is below the critical size above which Hertzian brittle cracks are nucleated. PMID- 26053762 TI - Liquid-crystalline ordering of antimicrobial peptide-DNA complexes controls TLR9 activation. AB - Double-stranded DNA (dsDNA) can trigger the production of type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by binding to endosomal Toll-like receptor 9 (TLR9; refs 1-5). It is also known that the formation of DNA-antimicrobial peptide complexes can lead to autoimmune diseases via amplification of pDC activation. Here, by combining X-ray scattering, computer simulations, microscopy and measurements of pDC IFN production, we demonstrate that a broad range of antimicrobial peptides and other cationic molecules cause similar effects, and elucidate the criteria for amplification. TLR9 activation depends on both the inter-DNA spacing and the multiplicity of parallel DNA ligands in the self assembled liquid-crystalline complex. Complexes with a grill-like arrangement of DNA at the optimum spacing can interlock with multiple TLR9 like a zipper, leading to multivalent electrostatic interactions that drastically amplify binding and thereby the immune response. Our results suggest that TLR9 activation and thus TLR9-mediated immune responses can be modulated deterministically. PMID- 26053763 TI - Subnanometre ligand-shell asymmetry leads to Janus-like nanoparticle membranes. AB - Self-assembly of nanoparticles at fluid interfaces has emerged as a simple yet efficient way to create two-dimensional membranes with tunable properties. In these membranes, inorganic nanoparticles are coated with a shell of organic ligands that interlock as spacers and provide tensile strength. Although curvature due to gradients in lipid-bilayer composition and protein scaffolding is a key feature of many biological membranes, creating gradients in nanoparticle membranes has been difficult. Here, we show by X-ray scattering that nanoparticle membranes formed at air/water interfaces exhibit a small but significant ~6 A difference in average ligand-shell thickness between their two sides. This affects surface-enhanced Raman scattering and can be used to fold detached free standing membranes into tubes by exposure to electron beams. Molecular dynamics simulations elucidate the roles of ligand coverage and mobility in producing and maintaining this asymmetry. Understanding this Janus-like membrane asymmetry opens up new avenues for designing nanoparticle superstructures. PMID- 26053764 TI - Budget Constraints Affect Male Rats' Choices between Differently Priced Commodities. AB - Demand theory can be applied to analyse how a human or animal consumer changes her selection of commodities within a certain budget in response to changes in price of those commodities. This change in consumption assessed over a range of prices is defined as demand elasticity. Previously, income-compensated and income uncompensated price changes have been investigated using human and animal consumers, as demand theory predicts different elasticities for both conditions. However, in these studies, demand elasticity was only evaluated over the entirety of choices made from a budget. As compensating budgets changes the number of attainable commodities relative to uncompensated conditions, and thus the number of choices, it remained unclear whether budget compensation has a trivial effect on demand elasticity by simply sampling from a different total number of choices or has a direct effect on consumers' sequential choice structure. If the budget context independently changes choices between commodities over and above price effects, this should become apparent when demand elasticity is assessed over choice sets of any reasonable size that are matched in choice opportunities between budget conditions. To gain more detailed insight in the sequential choice dynamics underlying differences in demand elasticity between budget conditions, we trained N=8 rat consumers to spend a daily budget by making a number of nosepokes to obtain two liquid commodities under different price regimes, in sessions with and without budget compensation. We confirmed that demand elasticity for both commodities differed between compensated and uncompensated budget conditions, also when the number of choices considered was matched, and showed that these elasticity differences emerge early in the sessions. These differences in demand elasticity were driven by a higher choice rate and an increased reselection bias for the preferred commodity in compensated compared to uncompensated budget conditions, suggesting a budget context effect on relative valuation. PMID- 26053765 TI - Viability and stability of Escherichia coli and enterococci populations in fecal samples upon freezing. AB - We studied the survival of Escherichia coli and enterococci populations in fecal samples of 7 host species after storage at -20 and -80 degrees C for 30 days. Composite fecal samples were collected from cows, chickens, horses, pigs, dogs, birds, and humans, and bacteria were enumerated before and after storage. Twenty eight colonies of each bacterial species were typed before and after storage and the strains were assigned to different biochemical phenotypes (BPTs). A significant reduction in the number of E. coli was observed in all samples stored at -20 degrees C but in only 3 of those samples stored at -80 degrees C. However, the numbers of enterococci were similar in most stored samples (except cow and birds). The number and the distribution of E. coli and enterococci BPTs in fresh samples did not vary significantly from those stored at either temperature. Furthermore, the population structure of E. coli and enterococci did not change significantly after storage at -80 degrees C, this was always the case for those samples stored at -20 degrees C. We conclude that for those studies investigating E. coli or enterococci population structure, short-term storage (<= 30 days) of fecal samples in a glycerol broth at -80 degrees C is a preferable option. PMID- 26053766 TI - Chemical Bath Deposition of Aluminum Oxide Buffer on Curved Surfaces for Growing Aligned Carbon Nanotube Arrays. AB - Direct growth of vertically aligned carbon nanotube (CNT) arrays on substrates requires the deposition of an aluminum oxide buffer (AOB) layer to prevent the diffusion and coalescence of catalyst nanoparticles. Although AOB layers can be readily created on flat substrates using a variety of physical and chemical methods, the preparation of AOB layers on substrates with highly curved surfaces remains challenging. Here, we report a new solution-based method for preparing uniform layers of AOB on highly curved surfaces by the chemical bath deposition of basic aluminum sulfate and annealing. We show that the thickness of AOB layer can be increased by extending the immersion time of a substrate in the chemical bath, following the classical Johnson-Mehl-Avrami-Kolmogorov crystallization kinetics. The increase of AOB thickness in turn leads to the increase of CNT length and the reduction of CNT curviness. Using this method, we have successfully synthesized dense aligned CNT arrays of micrometers in length on substrates with highly curved surfaces including glass fibers, stainless steel mesh, and porous ceramic foam. PMID- 26053767 TI - News from the pediatric anesthesia societies. PMID- 26053769 TI - How to best induce anesthesia in infants with pyloric stenosis? PMID- 26053770 TI - Staying away from the edge - cerebral oximetry guiding blood pressure management. PMID- 26053771 TI - Response to the letter of Dr. B Haydar. PMID- 26053772 TI - Craniosynostosis reconstruction in patients with cyanotic heart defects-risk factors for venous air embolism and overview of preventative strategies. PMID- 26053773 TI - Implementation of Google Glass technology in patient care: evaluating its potential benefits and pitfalls. PMID- 26053774 TI - Total intravenous anesthesia with dexmedetomidine and ketamine in children. PMID- 26053775 TI - Drowning eye sign-massive hydrocephalus. PMID- 26053776 TI - Inspired-expired oxygen gap: an alternative method for oxygen saturation monitoring in a patient with an undiagnosed hemoglobinopathy. PMID- 26053778 TI - Updating Classifications of Ceramic Dental Materials: A Guide to Material Selection. AB - The indications for and composition of today's dental ceramic materials serve as the basis for determining the appropriate class of ceramics to use for a given case. By understanding the classifications, composition, and characteristics of the latest all-ceramic materials, which are presented in this article in order of most to least conservative, dentists and laboratory technicians can best determine the ideal material for a particular treatment. PMID- 26053777 TI - Identification of AII amacrine, displaced amacrine, and bistratified ganglion cell types in human retina with antibodies against calretinin. AB - Antibodies against calretinin are markers for one type of rod pathway interneuron (AII amacrine cell) in the retina of some but not all mammalian species. The AII cells play a crucial role in night-time (scotopic) vision and have been proposed as a target for optogenetic restoration of vision in retinal disease. In the present study we aimed to characterize the AII cells in human retina. Postmortem human donor eyes were obtained with ethical approval and processed for calretinin immunofluorescence. Calretinin-positive somas in the inner nuclear and the ganglion cell layer were filled with the lipophilic dye DiI. The large majority (over 80%) of calretinin-immunoreactive cells is located in the inner nuclear layer, is immunopositive for glycine transporter 1, and shows the typical morphology of AII amacrine cells. In addition, a small proportion of calretinin positive cells in the inner nuclear layer and in the ganglion cell layer is glutamic acid decarboxylase-positive and shows the morphology of widefield amacrine cells (stellate, semilunar, and thorny amacrine cells). About half of the calretinin cells in the ganglion cell layer are bistratified ganglion cells resembling the small bistratified (presumed blue-ON/yellow-OFF) and the G17 ganglion cell previously described in primates. We conclude that in human retina, antibodies against calretinin can be used to identify AII amacrine cells in the inner nuclear layer as well as widefield amacrine and small bistratified ganglion cells in the ganglion cell layer. PMID- 26053779 TI - Three Serious Drug Interactions that Every Dentist Should Know About. AB - Patients with complex medical and drug histories are becoming more commonplace in dental practice. This article reviews three serious adverse drug interactions that are well supported by the literature and can impact dental practice. Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the renal excretion of lithium and lead to lithium toxicity. Metronidazole and fluconazole inhibit the metabolism of warfarin by blocking cytochrome P-450 2C9 (CYP-2C9), the major metabolic pathway of warfarin, with the end result being dramatic increases in patients' international normalized ratios (INRs) and potentially fatal bleeding. Propranolol and other nonselective beta-adrenergic blocking agents can inhibit the vasodilatory effect of epinephrine in dental local anesthetic solutions, leading to hypertensive reactions and a concomitant reflex bradycardia. It is important for clinicians to recognize and avoid these serious drug interactions. By doing so, they will provide the safest and best treatment for their patients. PMID- 26053780 TI - Systematic Treatment Using a Direct Deprogrammer to Resolve Long-Standing Problems in a Phobic Patient. AB - In this case, a patient who had been responsible and regularly sought good care was disappointed with previous dental work and felt let down and angry in the face of worsening oral health. She presented in the author's office with trepidation and distrust in the profession. Through the use of a Kois deprogrammer, which was immediately fabricated chairside, the patient experienced rapid relief from long-standing discomfort, then proceeded to accept a comprehensive solution to her dental problems. In addition to discussing the case, this article details instructions for the fabrication of this immediate appliance. PMID- 26053781 TI - Diffuse Large B-Cell Lymphoma of the Gingiva in a Patient on Long-Term Use of Methotrexate Being Treated for Psoriasis. AB - An 81-year-old male patient presented with a large gingival ulcer of 2 months' duration. He had been taking methotrexate, a potent anti inflammatory/immunosuppressant, for the past 50 years to treat psoriasis. A biopsy revealed diffuse large B-cell lymphoma Epstein-Barr virus positive. Remission occurred after discontinuing the medication. Clinicians noting a non healing ulcer in the mucosal or keratinized tissue of the oral cavity of a patient on immunosuppressants should perform a biopsy examination to rule out lymphoma or other malignancy. PMID- 26053782 TI - Defining Periodontitis for "Person-Centered Care". PMID- 26053783 TI - Case Presentations Demonstrating Periodontal Treatment Variation: PEARL Network. AB - BACKGROUND: Variation in periodontal terminology can affect the diagnosis and treatment plan as assessed by practicing general dentists in the Practitioners Engaged in Applied Research and Learning (PEARL) Network. General dentists participating in the PEARL Network are highly screened, credentialed, and qualified and may not be representative of the general population of dentists. METHODS: Ten randomized case presentations ranging from periodontal health to gingivitis, to mild, moderate, and severe periodontitis were randomly presented to respondents. Descriptive comparisons were made between these diagnosis groups in terms of the treatment recommendations following diagnosis. RESULTS: PEARL practitioners assessing periodontal clinical scenarios were found to either over- or under-diagnose the case presentations, which affected treatment planning, while the remaining responses concurred with respect to the diagnosis. The predominant diagnosis was compared with that assigned by two practicing periodontists. There was variation in treatment based on the diagnosis for gingivitis and the lesser forms of periodontitis. CONCLUSION: Data suggests that a lack of clarity of periodontal terminology affects both diagnosis and treatment planning, and terminology may be improved by having diagnosis codes, which could be used to assess treatment outcomes. CLINICAL IMPLICATIONS: This article provides data to support best practice for the use of diagnosis coding and integration of dentistry with medicine using ICD-10 terminology. PMID- 26053784 TI - Composite Restorations: Wheels of Progress Continue to Turn. PMID- 26053786 TI - Catalytic enantioselective synthesis of planar-chiral cyclic amides based on a Pd catalyzed asymmetric allylic substitution reaction. AB - The highly enantioselective synthesis of planar-chiral nine-membered cyclic amides was achieved by the Pd-catalyzed asymmetric allylic cyclization of achiral linear precursors in the presence of a catalytic amount of chiral ligand. PMID- 26053787 TI - The science, applications, and ethical concerns surrounding low copy number DNA analysis. PMID- 26053785 TI - Long-term response to renal ischaemia in the human kidney after partial nephrectomy: results from a prospective clinical trial. AB - OBJECTIVE: To assess the 1-year renal functional changes in patients undergoing partial nephrectomy with intra-operative renal biopsies. PATIENTS AND METHODS: A total of 40 patients with a single renal mass deemed fit for a partial nephrectomy were recruited prospectively between January 2009 and October 2010. We performed renal biopsies of normal renal parenchyma and collected serum markers before, during and after surgically induced renal clamp ischaemia during the partial nephrectomy. We then followed patients clinically with interval serum creatinine and physical examination. RESULTS: Peri-operative data from 40 patients showed a transient increase in creatinine levels which did not correlate with ischaemia time. Renal ultrastructural changes were generally mild and included mitochondrial swelling, which resolved at the post-perfusion biopsy. A total of 37 patients had 1-year follow-up data. Creatinine at 1 year increased by 0.121 mg/dL, which represents a 12.99% decrease in renal function from baseline (preoperative creatinine 0.823 mg/dL, estimated glomerular filtration rate = 93.9 mL/min/1.73 m(2) ). The only factors predicting creatinine change on multivariate analysis were patient age, race and ischaemia type, with cold ischaemia being associated with higher creatinine level. Importantly, the duration of ischaemia did not show any significant correlation with renal function change, either as a continuous variable (P = 0.452) or as a categorical variable (P = 0.792). CONCLUSIONS: Our data suggest that limited ischaemia is generally well tolerated in the setting of partial nephrectomy and does not directly correspond to long term renal functional decline. For surgeons performing partial nephrectomy, the kidney can be safely clamped to ensure optimum oncological outcomes. PMID- 26053788 TI - Gambling and gambling-related problems in France. AB - AIMS: To provide an overview of the gambling landscape and gambling-related problems in France, including the history, legislation, gambling policy and epidemiological data on excessive gambling. METHOD: A literature review, using Medline, PsycInfo and Toxibase/OFDT databases, based on the systematic monitoring of scientific literature since 2008 (including French and international papers). RESULTS: Since 1776 and the creation of the royal lottery, state monopoly has been the main pillar of gambling policy in France. Increases in gambling venues and opportunities, growing evidence of gambling-related problems, pressures from the European Commission and the growth of on-line gambling have led to major changes in this policy: while land-based gambling remains mainly in the form of a state monopoly, on-line gambling was partially liberalized in 2010, and regulation authorities were established. The first epidemiological survey was conducted in 2010. Rates of problematic gambling in France are within the average of other European countries. Treatment has begun to be made available within addiction centres. CONCLUSION: A majority of on-line gamblers in France use legal websites, which was one of the initial goals of liberalization. Recent studies confirm that the prevalence of problem gambling in France is far higher among on line gamblers than among land-based gamblers; however, this difference cannot be attributed only to greater addictiveness of on-line gambling. PMID- 26053789 TI - Potential of biocompatible regenerated silk fibroin/sodium N-lauroyl sarcosinate hydrogels. AB - Hydrogels are becoming widely used in biomaterial applications. The available methods for the preparation of these materials are continually growing. The gelation time (GT) of silk protein fibroin is difficult to control by physical methods. The cross-linkers used in available chemical techniques are likely to impact the biocompatibility of the resultant materials. In this paper, we demonstrate that the addition of sodium N-lauroyl sarcosinate (an amino-acid based surfactant) accelerates the formation of hydrogels from fibroin. GT, turbidity variations, changes of viscoelasticity during the gelation process, and the mechanical properties of the products are measured. The secondary structure was probed by Fourier transform infrared spectroscopy, X-ray diffraction and the morphologies of the products were investigated by scanning electron microscopy. Transformations in the beta-sheet content were monitored by the fluorescence of Thioflavine T and circular dichroism measurements. The relationship between the surface tension of sodium N-lauroyl sarcosinate and the GT was also explained. To investigate cell compatibility, fibroblast cells were seeded onto the surface of the hydrogels. The results indicate that the sodium N-lauroyl sarcosinate/fibroin GT can be controlled. This blend-hydrogel demonstrates excellent cell compatibility, good compression strength, and outstanding compression-recovery characteristics. Sodium N-lauroyl sarcosinate/silk fibroin hydrogels containing beta-sheets have considerable potential as replacement materials in addressing the tissue defects involved with repair surgery. PMID- 26053790 TI - Tactile processing in children and adolescents with obsessive-compulsive disorder. AB - Many obsessive-compulsive disorder (OCD) patients experience sensory phenomena, such as bodily sensations and "just-right" perceptions accompanying compulsions. We studied tactile processing in OCD by psychophysical experiments targeting the somatosensory cortex. Thirty-two children and adolescents with OCD (8 tic related, 19 with sensory phenomena (SP)) and their sex- and age-matched controls participated in the study. After clinical assessments, two questionnaires were completed for sensory problems (Sensory Profile and Touch Inventory for Elementary-School-Aged Children). The psychophysical experiments consisted of five tasks: simple reaction time, choice reaction time, dynamic (detection) threshold, amplitude discrimination, and amplitude discrimination with single site adaptation. The tactile stimuli were sinusoidal mechanical vibrations (frequency: 25 Hz) applied on the fingertips. Just-noticeable differences (JNDs) were found in amplitude discrimination tasks. There was no difference between the OCD group and controls in detection thresholds. However, the OCD group (especially young males) had worse amplitude discrimination (i.e., higher JNDs) than controls. Young OCD participants had reduced adaptation than young controls. Tic-related OCD participants and those with SP had higher detection thresholds than those without. Additionally, the OCD group reported more problems than controls in the Emotional/Social subset of the Sensory Profile questionnaire. The discrimination results show altered tactile processing in OCD at suprathreshold levels. This can be explained by a scaling factor modifying the sensory signal with decreasing slope at higher input levels to achieve normal Weber fractions internally. Quadratic discriminant analysis gave the best positive (76%) and negative (60%) predictive values for classifying individuals (into "OCD" or "control" groups) based on psychophysical data alone. PMID- 26053792 TI - Dynamics and rheology of nonpolar bijels. AB - Bicontinuous, interfacially jammed, emulsion gels (bijels) are a novel class of materials composed of two immiscible phases with interpenetrating domains that are stabilized by a monolayer of colloidal particles at the interface. However, existing bijel systems so far all consist of at least one polar fluid, which is believed to be essential to induce electrostatic repulsion for stabilizing interfacial particles. It is not known whether two nonpolar fluids can form a bijel. Here, we experimentally achieve a bijel using styrene trimer and low molecular weight polybutene-two nonpolar fluids that are similar to polymer blends, which are important in technical applications. By combining laser scanning confocal microscopy, cryo-SEM and rheology measurement, we systematically investigate the dynamics and rheology of this nonpolar bijel. In contrast to previous studies on polar bijels, we observe the formation of localized regions of high particle concentration or "particle patches" on the interface which assemble during coarsening. We also provide the first quantitative relation between the morphology of a bijel, the interfacial particle coverage and the shear modulus during bijel coarsening. Moreover, we reveal a previously unnoticed increase in the elastic modulus of bijels that can be attributed to the rearrangement of interfacial particles at long time scales. In addition, we also found a hydrophobic particle framework that survives after the direct remixing of the nonpolar bijel. Our study provides important insights into the formation of bijels and is the first step to explore the missing link between polar bijels and particle-stabilized bicontinuous polymer blends. PMID- 26053791 TI - The Cell Adhesion Molecules Roughest, Hibris, Kin of Irre and Sticks and Stones Are Required for Long Range Spacing of the Drosophila Wing Disc Sensory Sensilla. AB - Most animal tissues and organ systems are comprised of highly ordered arrays of varying cell types. The development of external sensory organs requires complex cell-cell communication in order to give each cell a specific identity and to ensure a regular distributed pattern of the sensory bristles. This involves both long and short range signaling mediated by either diffusible or cell anchored factors. In a variety of processes the heterophilic Irre Cell Recognition Module, consisting of the Neph-like proteins: Roughest, Kin of irre and of the Nephrin like proteins: Sticks and Stones, Hibris, plays key roles in the recognition events of different cell types throughout development. In the present study these proteins are apically expressed in the adhesive belt of epithelial cells participating in sense organ development in a partially exclusive and asymmetric manner. Using mutant analysis the GAL4/UAS system, RNAi and gain of function we found an involvement of all four Irre Cell Recognition Module-proteins in the development of a highly structured array of sensory organs in the wing disc. The proteins secure the regular spacing of sensory organs showing partial redundancy and may function in early lateral inhibition events as well as in cell sorting processes. Comparisons with other systems suggest that the Irre Cell Recognition module is a key organizer of highly repetitive structures. PMID- 26053793 TI - The Effect of Cataract on Early Stage Glaucoma Detection Using Spatial and Temporal Contrast Sensitivity Tests. AB - BACKGROUND: To investigate the effect of cataract on the ability of spatial and temporal contrast sensitivity tests used to detect early glaucoma. METHODS: Twenty-seven glaucoma subjects with early cataract (mean age 60 +/- 10.2 years) which constituted the test group were recruited together with twenty-seven controls (cataract only) matched for age and cataract type from a primary eye care setting. Contrast sensitivity to flickering gratings at 20 Hz and stationary gratings with and without glare, were measured for 0.5, 1.5 and 3 cycles per degree (cpd) in central vision. Perimetry and structural measurements with the Heidelberg Retinal Tomograph (HRT) were also performed. RESULTS: After considering the effect of cataract, contrast sensitivity to stationary gratings was reduced in the test group compared with controls with a statistically significant mean difference of 0.2 log units independent of spatial frequency. The flicker test showed a significant difference between test and control group at 1.5 and 3 cpd (p = 0.019 and p = 0.011 respectively). The percentage of glaucoma patients who could not see the temporal modulation was much higher compared with their cataract only counterparts. A significant correlation was found between the reduction of contrast sensitivity caused by glare and the Glaucoma Probability Score (GPS) as measured with the HRT (p<0.005). CONCLUSIONS: These findings indicate that both spatial and temporal contrast sensitivity tests are suitable for distinguishing between vision loss as a consequence of glaucoma and vision loss caused by cataract only. The correlation between glare factor and GPS suggests that there may be an increase in intraocular stray light in glaucoma. PMID- 26053795 TI - The Cover Page. PMID- 26053796 TI - Neurosciences Education: From 'Gurukul' to e-Learning. PMID- 26053797 TI - Snakebite in India today. PMID- 26053798 TI - Electrophysiologic evaluation of snake bite. PMID- 26053794 TI - Prevention and Immunotherapy of Secondary Murine Alveolar Echinococcosis Employing Recombinant EmP29 Antigen. AB - Alveolar echinococcosis (AE) is caused by infection with the larval stage of the tapeworm Echinococcus multilocularis. An increasing understanding of immunological events that account for the metacestode survival in human and murine AE infection prompted us to undertake explorative experiments tackling the potential of novel preventive and/or immunotherapeutic measures. In this study, the immunoprotective and immunotherapeutic ability of recombinant EmP29 antigen (rEmP29) was assessed in mice that were intraperitoneally infected with E. multilocularis metacestodes. For vaccination, three intraperitoneal injections with 20MUg rEmP29 emulsified in saponin adjuvants were applied over 6 weeks. 2 weeks after the last boost, mice were infected, and at 90 days post-infection, rEmP29-vaccinated mice exhibited a median parasite weight that was reduced by 75% and 59% when compared to NaCl- or saponin-treated control mice, respectively. For immunotherapeutical application, the rEmP29 (20MUg) vaccine was administered to experimentally infected mice, starting at 1 month post-infection, three times with 2 weeks intervals. Mice undergoing rEmP29 immunotherapy exhibited a median parasite load that was reduced by 53% and 49% when compared to NaCl- and saponin treated control mice, respectively. Upon analysis of spleen cells, both, vaccination and treatment with rEmP29, resulted in low ratios of Th2/Th1 (IL 4/IFN-gamma) cytokine mRNA and low levels of mRNA coding for IL-10 and IL-2. These results suggest that reduction of the immunosuppressive environment takes place in vaccinated as well as immunotreated mice, and a shift towards a Th1 type of immune response may be responsible for the observed increased restriction of parasite growth. The present study provides the first evidence that active immunotherapy may present a sustainable route for the control of AE. PMID- 26053799 TI - Stepping to reorganize the damaged brain: Does the journey lead to a destination? PMID- 26053800 TI - Is it possible to facilitate neural plasticity for enhancing post chronic stroke recovery? PMID- 26053801 TI - Surgery for acromegaly. PMID- 26053802 TI - Decoding the V3 segment of the vertebral artery... PMID- 26053803 TI - Cerebral venous thrombosis: An Indian perspective. AB - Cerebral venous thrombosis (CVT) is an uncommon cause of stroke with extremely varied clinical presentations, predisposing factors, imaging findings, and outcomes, and thus can be extremely challenging to diagnose. Accurate and prompt diagnosis of CVT is crucial because timely and appropriate therapy can reverse the disease process and significantly reduce the risk of acute complications and long-term squel. In this article, we have reviewed the epidemiology, causative factors, clinical features, diagnosis and treatment of CVT from an Indian perspective. Over the last decade, a change in trends in the causative factors has been noted from India. PMID- 26053804 TI - Brain abscess: Heuristics, principles, pathobiology, practice. AB - Brain abscess is an uncommon but a compelling reality in neurosurgical practice. Its focal, local, and systemic manifestations conceal its infective and obsessive nature. There are many a lesson that a brain abscess, as a bio-phenomenon, offers to the medical fraternity in general and the neurosurgeons, in particular. From Skt. puyati = to stink, comes the word "pus," meaning something foul, putrid, or rotten. From ab = away, and cedre = to go, comes the term "abscess" which is but nature's ingenious way of creating a fluid-filled cavity that will eventually rupture to an exterior to get rid of the non-self contents and proceed to healing. A brain abscess is special in the sense that it is, in general, more solid than fluid for reasons the human body and brain know best. PMID- 26053805 TI - Publication performance and research output of Neurology and Neurosurgery training institutes in India: A 5-year analysis. AB - CONTEXT: Scientific publications are a reflection of the quality of the clinical and academic work being carried out in an institute. Training in the process of research and scientific writing are important components of the residency curriculum. AIMS: The publication performance and research output of institutes training residents in neurology and neurosurgery were evaluated. SETTING AND DESIGN: Internet-based study. METHODS: This study was based on the data available on the websites of the Medical Council of India and the National Board of Examinations. The PubMed search interface was used to determine the publication output of institutes over the past 5 years (2010-2014). Google Scholar was used to determine the citation performance of each paper. The publication parameters were normalized to the number of faculty members in each institute as listed on the institutional web page. The normalized publication performance for an institute was computed by comparing the figures for that institute with the national average. RESULTS: Institutes could be ranked on several criteria. There was a high degree of clustering of output from the top 5% of the institutes. About 13% of the neurology intake and 30.9% of neurosurgery intake over the past 5 years has been into the institutes that have not published a single paper during this period. CONCLUSIONS: This evaluation of the publication performance and research output of neurology and neurosurgery training institutes would serve as a baseline data for future evaluations and comparisons. The absence of any publication and research output from several training institutes is a matter of concern. PMID- 26053806 TI - Rehabilitation interventions to improve locomotor outcome in chronic stroke survivors: A prospective, repeated-measure study. AB - OBJECTIVE: To ascertain whether rehabilitation interventions improve locomotion beyond 6 months post stroke. Site: The Neurological Rehabilitation Department of a university tertiary research hospital. STUDY DESIGN: Prospective, repeated measure study. PATIENTS: Patients with first episode of supra-tentorial stroke of more than 6 months duration. INTERVENTION: Twenty sessions of task-specific interventions consisting of lower limb resistive exercises and treadmill gait training to locomotor abilities (90 min/day, 5 days/week for 4 weeks). Evaluations were performed at the beginning and end of training and at a follow up of 3 months. OUTCOME MEASURES: Stroke severity (Scandinavian Stroke Scale - SSS), balance (Berg Balance scale - BBS), ambulation (Functional Ambulation Category), walking ability (speed 10-m walk test - WS) and functional ability (Barthel Index - BI). RESULTS: Forty patients (32 men and eight women; age range: 22-65 years; mean post-stroke duration of 18.90 +/- 12.76 months) were included in the study. Thirty-two (80.0%) patients completed their training and 28 (70.0%) patients reported at a follow up of 3-months. At the beginning, the end of training and at follow-up, the mean SSS scores were 41.71, 44.09, and 43.96; the BBS scores were 36.28, 46.75 and 46.82; the WS scores were 0.41, 0.53 and 0.51; and the BI scores were 77.34, 89.06 and 92.32, respectively. All outcome measures showed statistically significant improvement (P < 0.001) at the end of training and at follow-up. CONCLUSION: Rehabilitation interventions significantly improve locomotor outcome even in the chronic phase following a stroke. PMID- 26053807 TI - Adverse effects of antiepileptic drugs and quality of life in pediatric epilepsy. AB - BACKGROUND: In pediatric epilepsy, health-related quality of life (HRQOL) may be affected across the physical, psychological, social, and school domains. Studies have shown that antiepileptic drugs (AEDs) could have a significant negative impact on HRQOL, but these findings are scarce and inconsistent. AIM: To evaluate the influence that the adverse effects of AEDs have on HRQOL in pediatric epilepsy. MATERIALS AND METHODS: A total of 75 children with epilepsy and at least one parent participated in this study. The Pediatric Quality of Life Inventory (PedsQL) was utilized to assess the HRQOL, while the Adverse Event Profile (AEP) was used to assess the presence and severity of the adverse effects of AEDs. RESULTS: Assessing the children's ratings, the AEP score significantly influenced the PedsQL based psychosocial functioning score (P < 0.02; partial c2 = 0.07); and, assessing the parents' ratings, the AEP score significantly influenced both the PedsQL based physical functioning score (P < 0.02; partial c2 = 0.07) as well as the PedsQL psychosocial functioning score (P < 0.001, partial c2 = 0.30). CONCLUSION: The frequency and severity of AED-related adverse effects could significantly predict the lowered levels of HRQOL among children with epilepsy, in particular having a large impact on their psychosocial functioning. PMID- 26053808 TI - Clinical profile and outcome of patients with acromegaly according to the 2014 consensus guidelines: Impact of a multi-disciplinary team. AB - AIM: The diagnosis and treatment of acromegaly, a rare and possibly curable disease, has undergone a paradigm shift in the past few decades. Our aim was to study the changing trends in clinical presentation, management and outcome of the disease in the last fifteen years. METHODOLOGY: 271 consecutive patients with acromegaly treated at the Departments of Endocrinology and Neurosurgery, PGIMER, Chandigarh, between 2000 and 2014, were included in the study. Clinical and hormonal profiles, comorbidities, treatment modalities, outcome and mortality data were evaluated. The cure rate was assessed according to the present consensus criteria. RESULTS: The gender distribution was equal with the mean age (+/-SD) of 37.1 +/- 12.3 years at diagnosis. The average lag period to diagnosis was 4.7 +/- 4.2 years. The most common presenting manifestations were acral enlargement and headache followed by visual deficits. The overall mortality rate was 5%, with the perioperative mortality being 1.5%. The most prevalent comorbidities in our series were hypertension (17.7%), diabetes mellitus (16.2%), arthropathy (11.8%) and obstructive sleep apnea (10.3%). Overall, 2 patients in our series suffered from extra-pituitary neoplasms and 12 patients had apoplexy as the presenting manifestation. As per the present consensus criteria, cure rate in our series was 28.5%. The cure rate was only 7.9% when many surgeons were operating. It increased to 25.5% when surgeries were being performed by one surgeon exclusively; and, when a sub-specialty clinic exclusively for pituitary diseases was set up, the cure rates improved upto 56%. CONCLUSION: Acromegaly has wide-ranging manifestations from acral enlargement to altered sensorium; incidental diagnosis was not prevalent in our series. Majority of the cases were due to the presence of a pituitary macroadenoma. Better cure rate can be achieved only when a dedicated group of multi-disciplinary team is involved. PMID- 26053809 TI - Acute ischemic stroke with tandem/terminal ICA occlusion - CT perfusion based case selection for mechanical recanalization. AB - BACKGROUND: Rapid reperfusion in a patient with a favorable penumbral pattern is crucial to achieving a good outcome in acute ischemic stroke. Recanalization rates for tandem and terminal internal carotid artery (ICA) occlusion are better with endovascular management as compared with intravenous tissue plasminogen activator (IV-tPA) alone. We hypothesize that tissue-based selection would enable the identification of the ideal patient most suited for reperfusion therapy. We present our series of patients who developed tandem or terminal ICA occlusion and were selected for endovascular management based on their computed tomography (CT) perfusion (CTP) imaging. RESULTS: In this prospective study, 14 (29.16%) of the 48 patients treated by endovascular intervention between January 2011 and March 2014 had either tandem or terminal ICA occlusion. In the tandem group, thrombolysis in cerebral infarction (TICI) 2b/3 reperfusion and a good outcome was observed in five (71.42%, n = 7) and six patients (85.71%, n = 6), respectively. Among the terminal ICA occlusion group, TICI 2b/3 reperfusion and a good outcome was observed in three (42.8%, n = 7) and two patients (28.5%, n = 7), respectively. In patients with early reperfusion, a strong correlation with a median difference of one, in cerebral blood volume (CBV) Alberta Stroke Program Early CT Score (ASPECTS) on CBV map and post-procedure 24-h non-contrast CT, was noted. The median imaging-to-puncture and puncture-to -meaningful reperfusion time was 70 and 68.5 min, respectively, and, overall, good outcomes were seen in 57.1% of the patients. CONCLUSION: The cerebral blood volume (CBV) core estimation reliably predicted the final infarct volume. The key reasons for the significantly better outcomes seen in our cohort were the stringent perfusion imaging-based patient selection and the rapid reperfusion. PMID- 26053810 TI - Comparative study of electrophysiological changes in snake bites. AB - AIMS: To study and compare the electrophysiological changes in neuroparalytic or vasculotoxic snakebites. MATERIALS AND METHODS: 40 patients who had a definite history of snakebite, either vasculotoxic or neuroparalytic, were selected. They were grouped as Group A, 20 patients having a neuroparalytic snakebite with definite envenomation at the time of admission, and Group B, 20 patients having a vasculotoxic snakebite with definite envenomation at the time of admission. All patients underwent a detailed clinical examination, all relevant investigations and nerve conduction studies according to protocol. RESULTS: In this study, we noticed that the motor nerve conduction amplitude, conduction velocity and distal latency were within normal limits in both the groups. On RNS (repetitive nerve stimulation study) of facial and median nerves, a decremental response was seen in 13 (65%) patients in facial nerve and in 7 (35%) patients in median nerve in Group A; while, the same response was seen in 8 (40%) patients in facial nerve and 3 (15%) patients in median nerve in Group B. A post exercise decremental response was seen in 13 (65%) patients in median nerve and 16 (80%) patients in facial nerve in Group A; and, in 3 (15%) patients in median nerve and 8 (40%) patients in facial nerve in Group B. CONCLUSIONS: In our study, we noticed that the decremental response on RNS was not only present in neuroparalytic snake bite (post-synaptic neuromuscular blockade) but also in vasculotoxic snakebite [pre synaptic neuromuscular blockade] (seen in Russel's viper). PMID- 26053811 TI - Risk stratification of vertebral artery vulnerability during surgery for congenital atlanto-axial dislocation with or without an occipitalized atlas. AB - CONTEXT: Variability in dimensions and course of vertebral artery (VA) makes it vulnerable to injury during surgery for congenital atlanto-axial dislocation (AAD) with or without an occipitalized atlas. AIMS: This prospective study attempts to define anatomical variations that render VA at the craniovertebral junction (CVJ) vulnerable to injury during transoral decompression and posterior stabilization procedures; and, to propose a classification that helps in preoperative risk stratification. SETTINGS AND DESIGN: A prospective study. MATERIALS AND METHODS: 104 patients (65 with AAD; 39 controls) underwent a three dimensional multiplanar computed tomographic angiogram to study anatomical variations in VA size, course, and anomalous medial deviation as well as in the type of axial isthmus and rotational deformity/tilt at the CVJ. The VA/foramen transversarium diameter; "stretched loop" sign of VA; and C1-2 facet joint angle were also assessed. STATISTICAL ANALYSIS USED: A medial VA deviation that brought it in close proximity to the trajectory of the surgical approach was evaluated (P <= 0.05 significant). RESULTS: An increased predisposition to VA injury was present in 23 (35.4%) patients (persistent first intersegmental artery [n = 20; 30%]; fenestrated VA [n = 1; 1.53%], and low-lying posterior inferior cerebellar artery [n = 2; 3.0%]) where VA crossed the C1-2 facet joint; 8 (12%) with an anomalous medial deviation; 12 (18%) with a high-riding VA at C2 and a narrow axial isthmus; and 13 (20%) with rotation/tilt at the CVJ. A normal score of 5 was obtained in 21 patients; and a score of 6-9 (that progressively indicated an increased vulnerability of VA to iatrogenic injury) in 44 patients. The "AAD with an occipitalized atlas" group was associated with a significant medial deviation of VA (right: P = 0.00 and left: P = 0.001). CONCLUSIONS: A preoperative detailed risk assessment of anatomical variations in the size and course of VA at the CVJ significantly reduces chances of its iatrogenic injury. PMID- 26053812 TI - Dorsal ectopic breast in a case of spinal dysraphism: A rare entity. AB - An ectopic breast, that is present at a distance from the embryonic milk line, is an uncommon condition in the normal population. We describe a case with the presence of a breast in the dorsal region occurring in a patient with meningomyelocele and split cord malformation type I. A dorsally situated breast in a case of split cord malformation has never been reported previously in the literature. This case report highlights that an ectopic breast could be a marker of occult spinal dysraphism. This lesion should be corrected only after appropriate radiological investigations ascertain the underlying pathology. PMID- 26053813 TI - First reported case of Charcot Marie Tooth disease type 4C in a child from India with SH3TC2 mutation but absent spinal deformities. AB - Charcot Marie Tooth (CMT) disease is a group of hereditary motor sensory neuropathies with significant genetic heterogeneity. This disorder has been scarcely reported in the Indian literature. Here, we report a case of the rare but relatively more severe autosomal recessive CMT type 4C disease with a few features that are distinct from its regular presentation. Our patient was proven to have one of the common mutations in the SH3TC2 gene, which has so far not been described in Indian patients. PMID- 26053814 TI - P53 stratification reveals the prognostic utility of matrix metalloproteinase-9 protein expression in glioblastoma. AB - BACKGROUND: Despite the conventional acceptance of the matrix metalloproteinases (MMP)-2 and MMP-9, as markers of invasion in glioblastoma (GBM), there is no large body of evidence supporting their role as prognostic markers. Since the co expression of MMPs with p53 was noted to be prognostic in other cancers, we evaluated the protein expression of MMP-2 and MMP-9 in GBM and explored their prognostic relevance with respect to p53 expression. MATERIALS AND METHODS: Tumor tissues from a uniformly treated cohort of 132 GBM patients were examined for MMP 2, MMP-9, and p53 protein expression by immunohistochemistry (IHC). Survival analyses were performed by Cox-regression and Kaplan-Meier (KM) survival analysis. P53 IHC-based stratification of all GBM cases was performed, and subgroup-specific expression of MMP-2 and MMP-9 was correlated with survival. RESULTS: MMP-2 and MMP-9 were expressed in p53 positive as well as p53 negative GBM tumors. MMP-2 and MMP-9 protein expressions had no correlation with prognosis. MMP-9 expression, however, emerged as a strong independent predictor of poor survival in p53 positive GBMs on both Cox-regression analysis (P = 0.036) and KM survival analysis (P = 0.008). Further, even on multivariate analysis, MMP 9 remained strongly associated with poor prognosis (P = 0.010). CONCLUSIONS: MMP 9 expression strongly associates with poor prognosis in p53 positive GBMs, but the absence of such correlation in p53 negative GBMs, skews the overall relation of this molecule with prognosis. The study highlights that the dual positivity of MMP-9 and p53 is of prognostic relevance in GBM. PMID- 26053815 TI - Endoscopic endonasal transplanum transtuberculum approach for retrochiasmatic craniopharyngiomas: Operative nuances. AB - The surgical treatment of craniopharyngiomas is challenging. An optimal surgical approach is extremely important to achieve complete removal of the tumor, which is often the goal of treatment. Conventionally, the endoscopic transsphenoidal approach is used for resection of craniopharyngiomas that are essentially confined to the sellar cavity, or have smaller suprasellar extension. However, the tumors located in the retrochiasmatic space are difficult to remove surgically due to a poor access. Traditionally, various transcranial microsurgical routes have been employed with limited success for resection of retrochiasmatic craniopharyngiomas. The transcranial approaches generally do not provide adequate exposure of the tumors originating in the space under the optic chiasm and nerves. Recently, the extended endonasal endoscopic surgical route, obtained by removal of the tuberculum sellae and planum sphenoidale, has been used with great success in the surgical management of tumors lying ventral to the optic chiasm, including craniopharyngiomas. It offers a direct midline access to the retrochiasmatic space and provides excellent visualization of the undersurface of the optic chiasm. It also allows extracapsular dissection using binostril-bimanual technique and facilitates complete removal of these formidable tumors. In this report, we describe step-by-step, the technical details of the endonasal endoscopic transplanum transtuberculum approach with emphasis on the operative nuances for removal of retrochiasmatic craniopharyngiomas. PMID- 26053816 TI - Department of Neurology, King George's Medical University, Lucknow: The journey continues. AB - King George Medical University is one of the oldest and most prestigious medical universities of India. The Department of Neurology has trained many illustrious neurologists who are offering yeoman's service to the nation. This brief review traces the history and milestones of the department and its current areas of focus. PMID- 26053817 TI - A to Z in neurointerventional surgery: A primer for residents. AB - Neurointerventional surgery has evolved rapidly over the last two-and-a-half decades. It is now the treatment of choice for many neurovascular conditions, and its techniques and indications are rapidly expanding. It is the need of the hour that residents in training programs should familiarize themselves with the basic concepts of neurointerventional surgery. There are no set guidelines regarding neuroendovascular training of residents in India. The current article provides an insight into the basic concepts of neurointerventional surgery for residents in training. PMID- 26053818 TI - A summary of some of the recently published, seminal papers in Neuroscience. PMID- 26053819 TI - Vigabatrin-induced reversible changes on magnetic resonance imaging of the brain. PMID- 26053820 TI - Ophthalmic artery occlusion with total ophthalmoplegia following spinal surgery. PMID- 26053821 TI - A novel minimally invasive endoscopic repair in a case of spontaneous CSF rhinorrhea with persistent craniopharyngeal canal. PMID- 26053822 TI - Megaencephalic leukoencephalopathy with subcortical cysts in a young Bengali girl. PMID- 26053823 TI - Cavernous sinus syndrome due to skull base metastasis: A rare presentation of hepatocellular carcinoma. PMID- 26053824 TI - "Fungimitosis": Invasive fulminant Aspergillus brain infection mimicking gliomatosis cerebri. PMID- 26053825 TI - Quadrigeminal cistern lipoma revisited. PMID- 26053826 TI - Hemifacial spasm associated with the vertebral artery fenestration. PMID- 26053827 TI - Wall-eyed bilateral internuclear ophthalmoplegia. PMID- 26053828 TI - Hypokalemic paralysis as a primary presentation of Fanconi's syndrome and distal renal tubular acidosis in a patient with primary Sjogren's syndrome. PMID- 26053829 TI - A rare case of an aberrant innominate vein causing posttracheostomy haemorrhage. PMID- 26053830 TI - Multiple glioblastoma: A diagnostic challenge and controversies in management. PMID- 26053831 TI - Diffusion restriction in fulminant subacute sclerosing panencephalitis: Report of an unusual finding. PMID- 26053832 TI - Bilateral isolated basal ganglia bleed: An atypical presentation of Japanese encephalitis. PMID- 26053833 TI - Post ventriculo-peritoneal shunt chronic calcified hematoma or an abscess: A dilemma. PMID- 26053834 TI - "Owl eye sign": Anterior spinal artery syndrome. PMID- 26053835 TI - Magnetic nanoparticle tagged stem cell transplantation in spinal cord injury: A promising approach for targeted homing of cells at the lesion site. PMID- 26053836 TI - Platelet PI3Kgamma Contributes to Carotid Intima-Media Thickening under Severely Reduced Flow Conditions. AB - Studies have begun to focus on the emerging function of platelets as immune and inflammatory cells that initiate and accelerate vascular inflammation. Phosphoinositide 3-kinase gamma (PI3Kgamma) is critically involved in a number of inflammatory and autoimmune diseases. This study aims to investigate the contribution of platelet PI3Kgamma to vascular remodeling under flow severely reduced conditions. Mouse partial left carotid artery ligation with adoptive transfer of activated, washed wild-type or PI3Kgamma-/- platelets was used as the model. Intima-media area, leukocyte recruitment, and proinflammatory mediator expression were assessed. In vitro PI3Kgamma-/- platelets were used to verify the effect of PI3Kgamma on platelet activation, interaction with leukocytes, and endothelial cells. Mice injected with activated platelets showed a significant increase in intima-media thickening, recruitment of neutrophils (at 3 d) and macrophages (at 21 d), and intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor alpha, and interleukin-6 expression (at 3 d) in the flow-reduced area. These effects were abrogated by platelet PI3Kgamma deficiency. Circulating platelet-leukocyte aggregates were reduced in PI3Kgamma-/- mice after partial ligation. In vivo data confirmed that PI3Kgamma mediated Adenine di-Phosphate -induced platelet activation through the Akt and p38 MAP kinase signaling pathways. Moreover, platelet PI3Kgamma deficiency reduced platelet-leukocyte aggregation and platelet-endothelial cell (EC) interaction. These findings indicate that platelet PI3Kgamma contributes to platelet-mediated vascular inflammation and carotid intima-media thickening after flow severely reduced. Platelet PI3Kgamma may be a new target in the treatment of vascular diseases. PMID- 26053837 TI - Prognostic Significance of Initial Serum Albumin and 24 Hour Daily Protein Excretion before Treatment in Multiple Myeloma. AB - Renal failure is a common morbidity in multiple myeloma (MM). Although proteinuria has been increasingly reported in malignancies, it is not routinely used to refine risk estimates of survival outcomes in patients with MM. Here we aimed to investigate initial serum albumin and 24-hour daily protein excretion (24-h DPE) before treatment as prognostic factors in patients with MM. We conducted a retrospective analysis of 102 patients with myeloma who were ineligible for haematopoietic stem cell transplantation between October 2000 and December 2012. Initial proteinuria was assessed before treatment by quantitative analysis of 24-hour urine samples. The demographic and laboratory characteristics, survival outcome, and significance of pre-treatment 24-h DPE and albumin in the new staging system of MM were analyzed. Pre-treatment proteinuria (>300 mg/day) was present in 66 patients (64.7%). The optimal cut-off value of 24 h DPE before treatment was 500 mg/day. Analysis of the time-dependent area under the curve showed that the serum albumin and 24-h DPE before treatment were better than 24-h creatinine clearance rate and beta2-microglobulin. A subgroup analysis showed that an initial excess proteinuria (24-h DPE >= 500 mg) was associated with poor survival status (17.51 vs. 34.24 months, p = 0.002). Furthermore, initial serum albumin was an independent risk factor on multivariate analysis (<2.8 vs. >= 2.8, hazard ratio = 0.486, p = 0.029). Using the A-DPE staging system, there was a significant survival difference among patients with stage I, II, and III MM (p < 0.001). Initial serum albumin and 24-h DPE before treatment showed significant prognostic factors in patients with MM, and the new A-DPE staging system may be utilized instead of the International Staging System. Its efficacy should be evaluated by further large prospective studies. PMID- 26053838 TI - Proteomic Analysis of Duodenal Tissue from Escherichia coli F18-Resistant and Susceptible Weaned Piglets. AB - Diarrhea and edema disease in weaned piglets due to infection by Escherichia coli F18 is a leading cause of economic loss in the pig industry. Resistance to E. coli F18 depends on expression of receptors on intestinal epithelial cells, and individual immunity. This study was conducted in Sutai pig E. coli F18-resistant and -susceptible full sib-pair individuals, identified on the basis of resource populations and verification of adhesion assays. The molecular mechanism underlying E. coli F18 resistance was investigated through analysis of the expression of E. coli F18 receptor associated and innate immunity proteins, using proteomics and bioinformatics techniques. Two-dimensional electrophoresis analysis revealed a total of 20 differentially expressed proteins in E. coli F18 resistant and -susceptible groups (10 upregulated and 10 downregulated). A total of 16 differentially expressed proteins were identified by MALDI TOF/TOF mass spectral analysis. According to gene ontology and pathway analysis, differentially expressed proteins were mainly involved in cell adhesion, immune response and other biologically relevant functions. Network analysis of interactions between differentially expressed proteins indicated a likelihood of their involvement in E. coli F18 infection. The expression levels of several important proteins including actin beta (ACTB), vinculin (VCL), heat stress proteins (HSPs) and transferrin (TF) in E. coli F18-resistant and -susceptible individuals were verified by Western blotting, supporting the identification of ACTB, VCL, HSPs and TF as promising candidate proteins for association with E. coli F18 susceptibility. PMID- 26053839 TI - The relationship between subjective sleep disturbance, sleep quality, and emotion regulation difficulties in a sample of college students reporting trauma exposure. AB - Sleep disturbance and poor sleep quality has been associated with trauma exposure and posttraumatic stress disorder (PTSD) symptoms; however, the associated emotional consequences of sleep disturbance have not been examined within this context (i.e., emotional reactivity, emotion modulation). The current study examined the relationship between sleep disturbance, poor sleep quality, and emotion regulation difficulties. In a sample of college students reporting exposure to at least 1 traumatic event, online survey methodology was used to assess PTSD symptom severity (PTSS), sleep disturbances, including PTSD-specific sleep disturbances, and emotion regulation difficulties. After controlling for PTSS, sleep disturbance and poor sleep quality domains were related to both global and specific difficulties in emotion regulation domains. The findings suggest that sleep disturbance and emotion regulation difficulties associated with PTSD may not be a mere extension of the clinical picture of PTSD. Sleep disturbances following trauma exposure may contribute to emotion regulation difficulties and exacerbate negative consequences. Future research should examine the effects of treatments that simultaneously address sleep disturbances and PTSD symptoms on emotion regulation processes. PMID- 26053840 TI - Clinical treatment selection for posttraumatic stress disorder: Suggestions for researchers and clinical trainers. AB - Posttraumatic stress disorder (PTSD) disrupts the lives of many Veterans and their families, and multiple treatment options exist. Two evidence-based psychotherapies (EBPs)-cognitive processing therapy (CPT) and prolonged exposure (PE)-are specifically identified by Veterans Affairs (VA) and Department of Defense clinical practice guidelines as first-line treatments. Despite the strong emphasis on training clinicians to provide these EBPs, several questions remain unaddressed. We sought to answer 3 main questions: What associated clinical features are clinicians considering as they select PE or CPT to treat a given patient? What exclusionary criteria are clinicians using? How helpful do clinicians find the extant literature on comorbid conditions and associated clinical features when making treatment decisions? We contacted mental health clinicians who were VA-trained in CPT and PE and requested participation in this online survey. We (a) identified several associated factors that clinicians use to help select between these treatments, (b) determined which associated factors or comorbidities clinicians identified as exclusionary criteria for CPT or PE, and (c) evaluated the perceived utility of research to practicing clinicians. We discuss factors for which clinicians reached a consensus, areas of discrepancy (e.g., substance use), and factors for which further research guidance would be beneficial (e.g., dissociation). Findings imply that VA efforts at disseminating best treatment practices and current PTSD research have been effective. Additionally, findings can help inform treatment guidelines and clinical trainings, as well as highlight gaps in research identified by clinicians. PMID- 26053841 TI - Less is less: a systematic review of graph use in meta-analyses. AB - Graphs are an essential part of scientific communication. Complex datasets, of which meta-analyses are textbook examples, benefit the most from visualization. Although a number of graph options for meta-analyses exist, the extent to which these are used was hitherto unclear. A systematic review on graph use in meta analyses in three disciplines (medicine, psychology, and business) and nine journals was conducted. Interdisciplinary differences, which are mirrored in the respective journals, were revealed, that is, graph use correlates with external factors rather than methodological considerations. There was only limited variation in graph types (with forest plots as the most important representatives), and diagnostic plots were very rare. Although an increase in graph use over time could be observed, it is unlikely that this phenomenon is specific to meta-analyses. There is a gaping discrepancy between available graphic methods and their application in meta-analyses. This may be rooted in a number of factors, namely, (i) insufficient dissemination of new developments, (ii) unsatisfactory implementation in software packages, and (iii) minor attention on graphics in meta-analysis reporting guidelines. Using visualization methods to their full capacity is a further step in using meta-analysis to its full potential. PMID- 26053842 TI - Confidence intervals for the between-study variance in random effects meta analysis using generalised Cochran heterogeneity statistics. AB - Statistical inference is problematic in the common situation in meta-analysis where the random effects model is fitted to just a handful of studies. In particular, the asymptotic theory of maximum likelihood provides a poor approximation, and Bayesian methods are sensitive to the prior specification. Hence, less efficient, but easily computed and exact, methods are an attractive alternative. Here, methodology is developed to compute exact confidence intervals for the between-study variance using generalised versions of Cochran's heterogeneity statistic. If some between-study is anticipated, but it is unclear how much, then a pragmatic approach is to use the reciprocals of the within-study standard errors as weights when computing the confidence interval. PMID- 26053843 TI - 'Clustering' documents automatically to support scoping reviews of research: a case study. AB - BACKGROUND: Scoping reviews of research help determine the feasibility and the resource requirements of conducting a systematic review, and the potential to generate a description of the literature quickly is attractive. AIMS: To test the utility and applicability of an automated clustering tool to describe and group research studies to improve the efficiency of scoping reviews. METHODS: A retrospective study of two completed scoping reviews was conducted. This compared the groups and descriptive categories obtained by automatically clustering titles and abstracts with those that had originally been derived using traditional researcher-driven techniques. RESULTS: The clustering tool rapidly categorised research into themes, which were useful in some instances, but not in others. This provided a dynamic means to view each dataset. Interpretation was challenging where there were potentially multiple meanings of terms. Where relevant clusters were unambiguous, there was a high precision of relevant studies, although recall varied widely. CONCLUSIONS: Policy-relevant scoping reviews are often undertaken rapidly, and this could potentially be enhanced by automation depending on the nature of the dataset and information sought. However, it is not a replacement for researcher-developed classification. The possibilities of further applications and potential for use in other types of review are discussed. PMID- 26053844 TI - Survey of the methods and reporting practices in published meta-analyses of test performance: 1987 to 2009. AB - We performed a survey of meta-analyses of test performance to describe the evolution in their methods and reporting. Studies were identified through MEDLINE (1966-2009), reference lists, and relevant reviews. We extracted information on clinical topics, literature review methods, quality assessment, and statistical analyses. We reviewed 760 publications reporting meta-analyses of test performance, published between 1987 and 2009. Eligible reviews included a median of 18 primary studies that were used in quantitative analyses. Most common clinical areas were cardiovascular disease (21%) and oncology (25%); most common test categories were imaging (44%) and biomarker tests (28%). Assessment of verification and spectrum bias, blinding, prospective study design, and consecutive patient recruitment became more common over time (p < 0.001 comparing reviews published through 2004 vs 2005 onwards). These changes coincided with the increasing use of checklists to guide assessment of methodological quality. Heterogeneity tests were used in 58% of meta-analyses; subgroup or regression analyses were used in 57%. Random effects models were employed in 57% of meta analyses (38% through 2004 vs 72% 2004-onwards; p < 0.001). Use of bivariate models of sensitivity and specificity increased in recent years (21% in 2008-2009 vs 7% in earlier years; p < 0.001). Methods employed in meta-analyses of test performance have improved with the introduction of quality assessment checklists and the development of more sophisticated statistical methods. PMID- 26053845 TI - Quality assessment of comparative diagnostic accuracy studies: our experience using a modified version of the QUADAS-2 tool. AB - Assessing the quality of included studies is a vital step in undertaking a systematic review. The recently revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool (QUADAS-2), which is the only validated quality assessment tool for diagnostic accuracy studies, does not include specific criteria for assessing comparative studies. As part of an assessment that included comparative diagnostic accuracy studies, we used a modified version of QUADAS-2 to assess study quality. We modified QUADAS-2 by duplicating questions relating to the index test, to assess the relevant potential sources of bias for both the index test and comparator test. We also added review-specific questions. We have presented our modified version of QUADAS-2 and outlined some key issues for consideration when assessing the quality of comparative diagnostic accuracy studies, to help guide other systematic reviewers conducting comparative diagnostic reviews. Until QUADAS is updated to incorporate assessment of comparative studies, QUADAS-2 can be used, although modification and careful thought is required. It is important to reflect upon whether aspects of study design and methodology favour one of the tests over another. PMID- 26053846 TI - Special issue on inclusion of non-randomized studies in systematic reviews. PMID- 26053847 TI - Synergistic Effect between Ultra-Small Nickel Hydroxide Nanoparticles and Reduced Graphene Oxide sheets for the Application in High-Performance Asymmetric Supercapacitor. AB - Nanoscale electrode materials including metal oxide nanoparticles and two dimensional graphene have been employed for designing supercapacitors. However, inevitable agglomeration of nanoparticles and layers stacking of graphene largely hamper their practical applications. Here we demonstrate an efficient co ordination and synergistic effect between ultra-small Ni(OH)2 nanoparticles and reduced graphene oxide (RGO) sheets for synthesizing ideal electrode materials. On one hand, to make the ultra-small Ni(OH)2 nanoparticles work at full capacity as an ideal pseudocapacitive material, RGO sheets are employed as an suitable substrate to anchor these nanoparticles against agglomeration. As a consequence, an ultrahigh specific capacitance of 1717 F g(-1) at 0.5 A g(-1) is achieved. On the other hand, to further facilitate ion transfer within RGO sheets as an ideal electrical double layer capacitor material, the ultra-small Ni(OH)2 nanoparticles are introduced among RGO sheets as the recyclable sacrificial spacer to prevent the stacking. The resulting RGO sheets exhibit superior rate capability with a high capacitance of 182 F g(-1) at 100 A g(-1). On this basis, an asymmetric supercapacitor is assembled using the two materials, delivering a superior energy density of 75 Wh kg(-1) and an ultrahigh power density of 40 000 W kg(-1). PMID- 26053848 TI - Culture-Dependent and -Independent Methods Capture Different Microbial Community Fractions in Hydrocarbon-Contaminated Soils. AB - Bioremediation is a cost-effective and sustainable approach for treating polluted soils, but our ability to improve on current bioremediation strategies depends on our ability to isolate microorganisms from these soils. Although culturing is widely used in bioremediation research and applications, it is unknown whether the composition of cultured isolates closely mirrors the indigenous microbial community from contaminated soils. To assess this, we paired culture-independent (454-pyrosequencing of total soil DNA) with culture-dependent (isolation using seven different growth media) techniques to analyse the bacterial and fungal communities from hydrocarbon-contaminated soils. Although bacterial and fungal rarefaction curves were saturated for both methods, only 2.4% and 8.2% of the bacterial and fungal OTUs, respectively, were shared between datasets. Isolated taxa increased the total recovered species richness by only 2% for bacteria and 5% for fungi. Interestingly, none of the bacteria that we isolated were representative of the major bacterial OTUs recovered by 454-pyrosequencing. Isolation of fungi was moderately more effective at capturing the dominant OTUs observed by culture-independent analysis, as 3 of 31 cultured fungal strains ranked among the 20 most abundant fungal OTUs in the 454-pyrosequencing dataset. This study is one of the most comprehensive comparisons of microbial communities from hydrocarbon-contaminated soils using both isolation and high-throughput sequencing methods. PMID- 26053849 TI - Ontogenetic Shape Change in the Chicken Brain: Implications for Paleontology. AB - Paleontologists have investigated brain morphology of extinct birds with little information on post-hatching changes in avian brain morphology. Without the knowledge of ontogenesis, assessing brain morphology in fossil taxa could lead to misinterpretation of the phylogeny or neurosensory development of extinct species. Hence, it is imperative to determine how avian brain morphology changes during post-hatching growth. In this study, chicken brain shape was compared at various developmental stages using three-dimensional (3D) geometric morphometric analysis and the growth rate of brain regions was evaluated to explore post hatching morphological changes. Microscopic MRI (MUMRI) was used to acquire in vivo data from living and post-mortem chicken brains. The telencephalon rotates caudoventrally during growth. This change in shape leads to a relative caudodorsal rotation of the cerebellum and myelencephalon. In addition, all brain regions elongate rostrocaudally and this leads to a more slender brain shape. The growth rates of each brain region were constant and the slopes from the growth formula were parallel. The dominant pattern of ontogenetic shape change corresponded with interspecific shape changes due to increasing brain size. That is, the interspecific and ontogenetic changes in brain shape due to increased size have similar patterns. Although the shape of the brain and each brain region changed considerably, the volume ratio of each brain region did not change. This suggests that the brain can change its shape after completing functional differentiation of the brain regions. Moreover, these results show that consideration of ontogenetic changes in brain shape is necessary for an accurate assessment of brain morphology in paleontological studies. PMID- 26053850 TI - The Golgi-Localized gamma-Ear-Containing ARF-Binding (GGA) Proteins Alter Amyloid beta Precursor Protein (APP) Processing through Interaction of Their GAE Domain with the Beta-Site APP Cleaving Enzyme 1 (BACE1). AB - Proteolytic processing of amyloid-beta precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) is the initial step in the production of amyloid beta (Abeta), which accumulates in senile plaques in Alzheimer's disease (AD). Essential for this cleavage is the transport and sorting of both proteins through endosomal/Golgi compartments. Golgi-localized gamma-ear-containing ARF-binding (GGA) proteins have striking cargo-sorting functions in these pathways. Recently, GGA1 and GGA3 were shown to interact with BACE1, to be expressed in neurons, and to be decreased in AD brain, whereas little is known about GGA2. Since GGA1 impacts Abeta generation by confining APP to the Golgi and perinuclear compartments, we tested whether all GGAs modulate BACE1 and APP transport and processing. We observed decreased levels of secreted APP alpha (sAPPalpha), sAPPbeta, and Abeta upon GGA overexpression, which could be reverted by knockdown. GGA-BACE1 co-immunoprecipitation was impaired upon GGA-GAE but not VHS domain deletion. Autoinhibition of the GGA1-VHS domain was irrelevant for BACE1 interaction. Our data suggest that all three GGAs affect APP processing via the GGA-GAE domain. PMID- 26053851 TI - Characterizing HSF1 Binding and Post-Translational Modifications of hsp70 Promoter in Cultured Cortical Neurons: Implications in the Heat-Shock Response. AB - Causes of lower induction of Hsp70 in neurons during heat shock are still a matter of debate. To further inquire into the mechanisms regulating Hsp70 expression in neurons, we studied the activity of Heat Shock Factor 1 (HSF1) and histone posttranslational modifications (PTMs) at the hsp70 promoter in rat cortical neurons. Heat shock induced a transient and efficient translocation of HSF1 to neuronal nuclei. However, no binding of HSF1 at the hsp70 promoter was detected while it bound to the hsp25 promoter in cortical neurons during heat shock. Histone PTMs analysis showed that the hsp70 promoter harbors lower levels of histone H3 and H4 acetylation in cortical neurons compared to PC12 cells under basal conditions. Transcriptomic profiling data analysis showed a predominant usage of cryptic transcriptional start sites at hsp70 gene in the rat cerebral cortex, compared with the whole brain. These data support a weaker activation of hsp70 canonical promoter. Heat shock increased H3Ac at the hsp70 promoter in PC12 cells, which correlated with increased Hsp70 expression while no modifications occurred at the hsp70 promoter in cortical neurons. Increased histone H3 acetylation by Trichostatin A led to hsp70 mRNA and protein induction in cortical neurons. In conclusion, we found that two independent mechanisms maintain a lower induction of Hsp70 in cortical neurons. First, HSF1 fails to bind specifically to the hsp70 promoter in cortical neurons during heat shock and, second, the hsp70 promoter is less accessible in neurons compared to non-neuronal cells due to histone deacetylases repression. PMID- 26053852 TI - Reference Values of Grip Strength Measured with a Jamar Dynamometer in 1526 Adults with Intellectual Disabilities and Compared to Adults without Intellectual Disability. AB - AIM: The aim of this study was to investigate grip strength in a large sample of people with intellectual disabilities, to establish reference values for adults with intellectual disabilities (ID) and compare it to adults without intellectual disability. METHODS: This study analysed pooled baseline data from two independent studies for all 1526 adults with ID: Special Olympics Funfitness Spain (n = 801) and the Dutch cross-sectional study 'Healthy aging and intellectual disabilities' (n = 725). RESULTS: The grip strength result of people with ID across gender and age subgroups is presented with CI95% values from higher 25.5-31.0 kg in male younger to lower 4.3-21.6 kg in female older. CONCLUSION: This study is the first to present grip strength results of a large sample of people with ID from 20-90 years of age. This study provides reference values for people with ID for use in clinical practice. PMID- 26053853 TI - The effects of a low-salt diet on the efficacy of different antihypertensive drug regimens. AB - The objective of this study was to compare the antihypertensive effects of 3 types of antihypertensive drug regimens between different salt intake levels. The 180 patients with mild to moderate primary hypertension participating in this randomized, controlled clinical trial were randomly allocated to a low-salt diet (LSD) group or a non-low-salt diet (NLSD) group. Each group included 3 subgroups: a losartan 100 mg subgroup, a losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg subgroup, and an irbesartan 150 mg/HCTZ 12.5 mg subgroup. The LSD group received a diet in which the sodium content was strictly controlled (2.3 g/day). After 2 months, the office blood pressure (BP), the 24-hour mean BP, and the morning BP were significantly reduced (P <= .01) in each group. No significant differences were observed between the 3 LSD subgroups (P > .05). In the NLSD group, the losartan 50 mg/HCTZ 12.5 mg subgroup, and the irbesartan 150 mg/HCTZ 12.5 mg subgroup exhibited identical antihypertensive efficacy (P > .05), and these groups were significantly different from the losartan 100 mg subgroup(P <= .05). The BP of the patients who received the LSD was further decreased compared with those who received the NLSD (P <= .05). Therefore, we concluded that this LSD exerts synergistic BP-reducing effects. PMID- 26053854 TI - EEG Changes Due to Experimentally Induced 3G Mobile Phone Radiation. AB - The aim of this study was to investigate whether a 15-minute placement of a 3G dialing mobile phone causes direct changes in EEG activity compared to the placement of a sham phone. Furthermore, it was investigated whether placement of the mobile phone on the ear or the heart would result in different outcomes. Thirty-one healthy females participated. All subjects were measured twice: on one of the two days the mobile phone was attached to the ear, the other day to the chest. In this single-blind, cross-over design, assessments in the sham phone condition were conducted directly preceding and following the mobile phone exposure. During each assessment, EEG activity and radiofrequency radiation were recorded jointly. Delta, theta, alpha, slowbeta, fastbeta, and gamma activity was computed. The association between radiation exposure and the EEG was tested using multilevel random regression analyses with radiation as predictor of main interest. Significant radiation effects were found for the alpha, slowbeta, fastbeta, and gamma bands. When analyzed separately, ear location of the phone was associated with significant results, while chest placement was not. The results support the notion that EEG alterations are associated with mobile phone usage and that the effect is dependent on site of placement. Further studies are required to demonstrate the physiological relevance of these findings. PMID- 26053855 TI - Amino Acid Derivatives as Palmitoylethanolamide Prodrugs: Synthesis, In Vitro Metabolism and In Vivo Plasma Profile in Rats. AB - Palmitoylethanolamide (PEA) has antinflammatory and antinociceptive properties widely exploited in veterinary and human medicine, despite its poor pharmacokinetics. Looking for prodrugs that could progressively release PEA to maintain effective plasma concentrations, we prepared carbonates, esters and carbamates at the hydroxyl group of PEA. Chemical stability (pH 7.4) and stability in rat plasma and liver homogenate were evaluated by in vitro assays. Carbonates and carbamates resulted too labile and too resistant in plasma, respectively. Ester derivatives, prepared by conjugating PEA with various amino acids, allowed to modulate the kinetics of PEA release in plasma and stability in liver homogenate. L-Val-PEA, with suitable PEA release in plasma, and D-Val-PEA, with high resistance to hepatic degradation, were orally administered to rats and plasma levels of prodrugs and PEA were measured at different time points. Both prodrugs showed significant release of PEA, but provided lower plasma concentrations than those obtained with equimolar doses of PEA. Amino-acid esters of PEA are a promising class to develop prodrugs, even if they need further chemical optimization. PMID- 26053856 TI - Differential Expression Profile of Chicken Embryo Fibroblast DF-1 Cells Infected with Cell-Adapted Infectious Bursal Disease Virus. AB - RNA-Seq was used to unveil the transcriptional profile of DF-1 cells at the early stage of caIBDV infection. Total RNAs were extracted from virus-infected cells at 0, 6 and 12 hpi. RNA-Seq datasets of respective samples mapped to 56.5-57.6% of isoforms in the reference genome Galgal4.73. At 6 hpi, 23 isoforms underwent an elevated expression, while 128 isoforms were up-regulated and 5 were down regulated at 12 hpi in the virus-infected group. Besides, 10 isoforms were exclusively expressed in the virus-infected cells. Though no significant change was detected in cytokine and interferon expression levels at the first 12 hours of infection, modulations of the upstream regulators were observed. In addition to the reported regulatory factors including EIF2AK2, MX, OAS*A, GBP7 and IFIT, IBDV infection also triggered a IFIT5-IRF1/3-RSAD5 pathway in the DF-1 cells which potentially restricted the viral replication cycle in the early infection stage. Over-expression of LIPA and CH25H, together with the suppression of STARD4, LSS and AACS genes implied a modulation of membrane fluidity and lipid raft arrangement in the infected cells. Alternative splicing of the EFR3 homolog A gene was also through to be involved in the lipid membrane regulation, and these cumulative responses projected an inhibition of viral endocytosis. Recognition of viral RNA genomes and intermediates was presumably enhanced by the elevated levels of IFIH1, DHX58 and TRIM25 genes which possess properties on detecting viral dsRNA. On the other hand, the caIBDV arrested the host's apoptotic process by inducing the expression of apoptosis inhibitors including NFKBIA/Z, TNFAIP2/3 and ITA at the first 12 hours of infection. In conclusion, the differential expression landscape demonstrated with RNA-Seq provides a comprehensive picture on the molecular interactions between host cells and virus at the early stage of infection. PMID- 26053857 TI - Epigenetic Modifications of the PGC-1alpha Promoter during Exercise Induced Expression in Mice. AB - The transcriptional coactivator, PGC-1alpha, is known for its role in mitochondrial biogenesis. Although originally thought to exist as a single protein isoform, recent studies have identified additional promoters which produce multiple mRNA transcripts. One of these promoters (promoter B), approximately 13.7 kb upstream of the canonical PGC-1alpha promoter (promoter A), yields alternative transcripts present at levels much lower than the canonical PGC-1alpha mRNA transcript. In skeletal muscle, exercise resulted in a substantial, rapid increase of mRNA of these alternative PGC-1alpha transcripts. Although the beta2-adrenergic receptor was identified as a signaling pathway that activates transcription from PGC-1alpha promoter B, it is not yet known what molecular changes occur to facilitate PGC-1alpha promoter B activation following exercise. We sought to determine whether epigenetic modifications were involved in this exercise response in mouse skeletal muscle. We found that DNA hydroxymethylation correlated to increased basal mRNA levels from PGC-1alpha promoter A, but that DNA methylation appeared to play no role in the exercise induced activation of PGC-1alpha promoter B. The level of the activating histone mark H3K4me3 increased with exercise 2-4 fold across PGC-1alpha promoter B, but remained unaltered past the canonical PGC-1alpha transcriptional start site. Together, these data show that epigenetic modifications partially explain exercise-induced changes in the skeletal muscle mRNA levels of PGC-1alpha isoforms. PMID- 26053858 TI - Pre-Slaughter Stress Affects Ryanodine Receptor Protein Gene Expression and the Water-Holding Capacity in Fillets of the Nile Tilapia. AB - Current study evaluated the effect of pre-slaughter stress on serum cortisol levels, pH, colorimetry, water-holding capacity (WHC) and gene expression of ryanodine receptors (RyR1 and RyR3) in the Nile tilapia. A 3x4 factorial scheme experiment was conducted comprising three densities (100, 200, 400 kg/m3) with four transportation times (60, 120, 180, and 240 minutes).Transportation times alone reduced cortisol levels up to 180 minutes, followed by increased WHC and mRNA expression, RyR1 and RyR3 (200 kg/m3 density). No effect of density x transportation time interacted on the evaluated parameters. Results provided the first evidence that pre-slaughter stress affected ryanodine gene expression receptors and, consequently, the water-holding capacity in tilapia fillets. PMID- 26053859 TI - Relationship between differentially expressed mRNA and mRNA-protein correlations in a xenograft model system. AB - Differential mRNA expression studies implicitly assume that changes in mRNA expression have biological meaning, most likely mediated by corresponding changes in protein levels. Yet studies into mRNA-protein correspondence have shown notoriously poor correlation between mRNA and protein expression levels, creating concern for inferences from only mRNA expression data. However, none of these studies have examined in particular differentially expressed mRNA. Here, we examined this question in an ovarian cancer xenograft model. We measured protein and mRNA expression for twenty-nine genes in four drug-treatment conditions and in untreated controls. We identified mRNAs differentially expressed between drug treated xenografts and controls, then analysed mRNA-protein expression correlation across a five-point time-course within each of the four experimental conditions. We evaluated correlations between mRNAs and their protein products for mRNAs differentially expressed within an experimental condition compared to those that are not. We found that differentially expressed mRNAs correlate significantly better with their protein product than non-differentially expressed mRNAs. This result increases confidence for the use of differential mRNA expression for biological discovery in this system, as well as providing optimism for the usefulness of inferences from mRNA expression in general. PMID- 26053860 TI - A Distinct Perisynaptic Glial Cell Type Forms Tripartite Neuromuscular Synapses in the Drosophila Adult. AB - Previous studies of Drosophila flight muscle neuromuscular synapses have revealed their tripartite architecture and established an attractive experimental model for genetic analysis of glial function in synaptic transmission. Here we extend these findings by defining a new Drosophila glial cell type, designated peripheral perisynaptic glia (PPG), which resides in the periphery and interacts specifically with fine motor axon branches forming neuromuscular synapses. Identification and specific labeling of PPG was achieved through cell type specific RNAi-mediated knockdown (KD) of a glial marker, Glutamine Synthetase 2 (GS2). In addition, comparison among different Drosophila neuromuscular synapse models from adult and larval developmental stages indicated the presence of tripartite synapses on several different muscle types in the adult. In contrast, PPG appear to be absent from larval body wall neuromuscular synapses, which do not exhibit a tripartite architecture but rather are imbedded in the muscle plasma membrane. Evolutionary conservation of tripartite synapse architecture and peripheral perisynaptic glia in vertebrates and Drosophila suggests ancient and conserved roles for glia-synapse interactions in synaptic transmission. PMID- 26053861 TI - Genetic Tools for the Analysis of Drosophila Stomatogastric Nervous System Development. AB - The Drosophila stomatogastric nervous system (SNS) is a compact collection of neurons that arises from the migration of neural precursors. Here we describe genetic tools allowing functional analysis of the SNS during the migratory phase of development. We constructed GAL4 lines driven by fragments of the Ret promoter, which yielded expression in a subset of migrating neural SNS precursors and also included a distinct set of midgut associated cells. Screening of additional GAL4 lines driven by fragments of the Gfrl/Munin, forkhead, twist and goosecoid (Gsc) promoters identified a Gsc fragment with expression from initial selection of SNS precursors until the end of embryogenesis. Inhibition of EGFR signaling using three identified lines disrupted the correct patterning of the frontal and recurrent nerves. To manipulate the environment traveled by SNS precursors, a FasII-GAL4 line with strong expression throughout the entire intestinal tract was identified. The transgenic lines described offer the ability to specifically manipulate the migration of SNS precursors and will allow the modeling and in-depth analysis of neuronal migration in ENS disorders such as Hirschsprung's disease. PMID- 26053863 TI - Could the Extended Phenotype Extend to the Cellular and Subcellular Levels in Insect-Induced Galls? AB - Neo-ontogenesis of plant galls involves redifferentiation of host plant tissues to express new phenotypes, when new cell properties are established via structural-functional remodeling. Herein, Psidium cattleianum leaves and Nothotrioza cattleiani galls are analyzed by developmental anatomy, cytometry and immunocytochemistry of cell walls. We address hypothesis-driven questions concerning the organogenesis of globoid galls in the association of P. cattleianum-N. cattleianum, and P. myrtoides-N. myrtoidis. These double co generic systems represent good models for comparing final gall shapes and cell lineages functionalities under the perspective of convergent plant-dependent or divergent insect-induced characteristics. Gall induction, and growth and development are similar in both galls, but homologous cell lineages exhibit divergent degrees of cell hypertrophy and directions of elongation. Median cortical cells in P. cattleianum galls hypertrophy the most, while in P. myrtoides galls there is a centrifugal gradient of cell hypertrophy. Cortical cells in P. cattleianum galls tend to anisotropy, while P. myrtoidis galls have isotropically hypertrophied cells. Immunocytochemistry evidences the chemical identity and functional traits of cell lineages: epidermal cells walls have homogalacturonans (HGAs) and galactans, which confer rigidity to sites of enhanced cell division; oil gland cell walls have arabinogalactan proteins (AGPs) that help avoiding cell death; and parenchyma cell walls have HGAs, galactans and arabinans, which confer porosity. Variations in such chemical identities are related to specific sites of hypertrophy. Even though the double co-generic models have the same macroscopic phenotype, the globoid morphotype, current analyses indicate that the extended phenotype of N. cattleiani is substantiated by cellular and subcellular specificities. PMID- 26053862 TI - Lack of a Functioning P2X7 Receptor Leads to Increased Susceptibility to Toxoplasmic Ileitis. AB - BACKGROUND: Oral infection of C57BL/6J mice with the protozoan parasite Toxoplasma gondii leads to a lethal inflammatory ileitis. PRINCIPAL FINDINGS: Mice lacking the purinergic receptor P2X7R are acutely susceptible to toxoplasmic ileitis, losing significantly more weight than C57BL/6J mice and exhibiting much greater intestinal inflammatory pathology in response to infection with only 10 cysts of T. gondii. This susceptibility is not dependent on the ability of P2X7R deficient mice to control the parasite, which they accomplish just as efficiently as C57BL/6J mice. Rather, susceptibility is associated with elevated ileal concentrations of pro-inflammatory cytokines, reactive nitrogen intermediates and altered regulation of elements of NFkappaB activation in P2X7R-deficient mice. CONCLUSIONS: Our data support the thesis that P2X7R, a well-documented activator of pro-inflammatory cytokine production, also plays an important role in the regulation of intestinal inflammation. PMID- 26053864 TI - Synthesis of DNA fragments containing 2'-deoxy-4'-selenonucleoside units using DNA polymerases: comparison of dNTPs with O, S and Se at the 4'-position in replication. AB - 4'-SelenoDNA fragments were synthesized for the first time using 4' selenothymidine triphosphate (SeTTP) by taking advantage of its bioequivalence against DNA polymerases. DNA fragments each with a homologous element (O, S or Se) at the 4'-position of the thymidine units were effectively amplified using KOD Dash DNA polymerase. PMID- 26053865 TI - Inverted U-Shaped Relationship between Central Venous Pressure and Intra Abdominal Pressure in the Early Phase of Severe Acute Pancreatitis: A Retrospective Study. AB - OBJECTIVE: Many studies have indicated that intra-abdominal pressure (IAP) is positively correlated with central venous pressure (CVP) in severe cases. However, although elevated IAP is common in patients with severe acute pancreatitis (SAP), its relationship with CVP remains unclear. Our study aimed to investigate the association of IAP with CVP in early-phase SAP patients. METHODS: In total, 116 SAP patients were included in this retrospective study. On the first day of hospitalization, blood samples were collected for biochemical examination and cytokine concentration monitoring. Additionally, a urinary catheter and right subclavian vein catheter were inserted for IAP and CVP measurement, respectively. Other routine clinical data were also recorded. RESULTS: Within 24 hours after hospitalization, CVP fluctuated and increased with increasing IAP up to 15.7 mmHg (P = 0.054) but decreased with increasing IAP when the IAP was > 15.7 mmHg (P < 0.001). After adjusting for abdominal perfusion pressure (APP) and mean arterial pressure (MAP), a similar distribution was observed. An inverted U-shaped trend between IAP and CVP was also present in the groups classified according to the patient's sex, local complications, ascites, and serum amylase levels. CONCLUSIONS: CVP and IAP have an inverted U-shaped relationship, with a peak at an IAP of 15.7 mmHg in the early phase of SAP. After this peak, CVP decreases as IAP increases. These results have crucial implications for clinical fluid resuscitation in SAP patients. In particular, because one CVP value might be correlated with different IAP values in patients with the same CVP, the volume of fluid needed might be different. PMID- 26053866 TI - Understanding Public Perceptions of the HPV Vaccination Based on Online Comments to Canadian News Articles. AB - BACKGROUND: Given the variation in human papillomavirus (HPV) vaccine coverage across Canada, and debate regarding delivery of HPV vaccines in Catholic schools, we studied online comments on Canadian news websites to understand public perceptions of HPV and HPV vaccine. METHODS: We searched English- and French language Canadian news websites for 2012 articles that contained the terms "HPV" or "human papillomavirus." Articles about HPV vaccinations that contained at least one comment were included. Two researchers independently coded comments, analyzing them for emerging themes. RESULTS: We identified 3073 comments from 1198 individuals in response to 71 news articles; 630 (52.6%) individuals expressed positive sentiments about HPV vaccination (2.5 comments/individual), 404 (33.7%) were negative (3.0 comments/individual), 34 (2.8%) were mixed (1.5 comments/individual) and 130 (10.8%) were neutral (1.6 comments/individual). Vaccine-supportive commenters believed the vaccine is safe and effective. Common themes in negative comments included concerns regarding HPV vaccine safety and efficacy, distrust of pharmaceutical companies and government, and belief that school-age children are too young for HPV vaccine. Many comments focused on whether the Catholic Church has the right to inform health policy for students, and discussion often evolved into debates regarding HPV and sexual behaviour. We noted that many individuals doubted the credibility of vaccine safety information. CONCLUSION: The majority of commenters do not appear to be against HPV vaccination, but public health messaging that focuses on both the vaccine's safety profile, and its use as a means to prevent cancer rather than sexually transmitted HPV infection may facilitate its acceptance. PMID- 26053867 TI - Reasons for delays in treatment of bacterial sexually transmissible infections in remote Aboriginal communities in Australia: a qualitative study of healthcentre staff. AB - Background Remote Aboriginal communities in Australia experience high rates of bacterial sexually transmissible infections (STIs). To control the transmission and decrease the risk of complications, frequent STI testing combined with timely treatment is required, yet significant delays in treatment have been reported. Perceived barriers to timely treatment for asymptomatic patients in remote communities were explored. METHODS: A qualitative study was undertaken as part of the STRIVE (STIs in Remote communities, ImproVed and Enhanced primary health care) project; a cluster randomised controlled trial of a sexual health quality improvement program. During 2012, we conducted 36 in-depth interviews with staff in 22 clinics in remote Australia. RESULTS: Participants included registered nurses (72%) and Aboriginal health practitioners (28%). A key barrier to timely treatment was infrequent transportation of specimens to laboratories often hundreds of kilometres away from clinics. Within clinics, there were delays checking and actioning test results, and under-utilisation of systems to recall patients. Participants also described difficulties in physically locating patients due to: (i) high mobility between communities; and (ii) low levels of community knowledge created by high staff turnover. Participants also suggested strategies to overcome some barriers such as dedicated clinical time to follow-up recalls and taking treatment out to patients. CONCLUSIONS: Participants identified barriers to timely STI treatment in remote Aboriginal communities, and systems to address some of the barriers. Innovative strategies such as point-of care testing or increased support for actioning results, coupled with incentives to individual patients to attend for results, may also assist in decreasing the time to treatment. PMID- 26053868 TI - Detoxification of Organophosphate Poisoning Using Nanoparticle Bioscavengers. AB - Organophosphate poisoning is highly lethal as organophosphates, which are commonly found in insecticides and nerve agents, cause irreversible phosphorylation and inactivation of acetylcholinesterase (AChE), leading to neuromuscular disorders via accumulation of acetylcholine in the body. Direct interception of organophosphates in the systemic circulation thus provides a desirable strategy in treatment of the condition. Inspired by the presence of AChE on red blood cell (RBC) membranes, we explored a biomimetic nanoparticle consisting of a polymeric core surrounded by RBC membranes to serve as an anti organophosphate agent. Through in vitro studies, we demonstrated that the biomimetic nanoparticles retain the enzymatic activity of membrane-bound AChE and are able to bind to a model organophosphate, dichlorvos, precluding its inhibitory effect on other enzymatic substrates. In a mouse model of organophosphate poisoning, the nanoparticles were shown to improve the AChE activity in the blood and markedly improved the survival of dichlorvos-challenged mice. PMID- 26053869 TI - Posterior odontoid process angulation in pediatric Chiari I malformation: an MRI morphometric external validation study. AB - OBJECT Osseous anomalies of the craniocervical junction are hypothesized to precipitate the hindbrain herniation observed in Chiari I malformation (CM-I). Previous work by Tubbs et al. showed that posterior angulation of the odontoid process is more prevalent in children with CM-I than in healthy controls. The present study is an external validation of that report. The goals of our study were 3-fold: 1) to externally validate the results of Tubbs et al. in a different patient population; 2) to compare how morphometric parameters vary with age, sex, and symptomatology; and 3) to develop a correlative model for tonsillar ectopia in CM-I based on these measurements. METHODS The authors performed a retrospective review of 119 patients who underwent posterior fossa decompression with duraplasty at the Monroe Carell Jr. Children's Hospital at Vanderbilt University; 78 of these patients had imaging available for review. Demographic and clinical variables were collected. A neuroradiologist retrospectively evaluated preoperative MRI examinations in these 78 patients and recorded the following measurements: McRae line length; obex displacement length; odontoid process parameters (height, angle of retroflexion, and angle of retroversion); perpendicular distance to the basion-C2 line (pB-C2 line); length of cerebellar tonsillar ectopia; caudal extent of the cerebellar tonsils; and presence, location, and size of syringomyelia. Odontoid retroflexion grade was classified as Grade 0, > 90 degrees ; Grade I,85 degrees -89 degrees ; Grade II, 80 degrees 84 degrees ; and Grade III, < 80 degrees . Age groups were defined as 0-6 years, 7-12 years, and 13-17 years at the time of surgery. Univariate and multivariate linear regression analyses, Kruskal-Wallis 1-way ANOVA, and Fisher's exact test were performed to assess the relationship between age, sex, and symptomatology with these craniometric variables. RESULTS The prevalence of posterior odontoid angulation was 81%, which is almost identical to that in the previous report (84%). With increasing age, the odontoid height (p < 0.001) and pB-C2 length (p < 0.001) increased, while the odontoid process became more posteriorly inclined (p = 0.010). The pB-C2 line was significantly longer in girls (p = 0.006). These measurements did not significantly correlate with symptomatology. Length of tonsillar ectopia in pediatric CM-I correlated with an enlarged foramen magnum (p = 0.023), increasing obex displacement (p = 0.020), and increasing odontoid retroflexion (p < 0.001). CONCLUSIONS Anomalous bony development of the craniocervical junction is a consistent feature of CM-I in children. The authors found that the population at their center was characterized by posterior angulation of the odontoid process in 81% of cases, similar to findings by Tubbs et al. (84%). The odontoid process appeared to lengthen and become more posteriorly inclined with age. Increased tonsillar ectopia was associated with more posterior odontoid angulation, a widened foramen magnum, and an inferiorly displaced obex. PMID- 26053871 TI - Optical signatures of intrinsic electron localization in amorphous SiO2. AB - We measure and analyse the optical absorption spectra of three silica glass samples irradiated with 1 MeV electrons at 80 K, where self-trapped holes are stable, and use ab initio calculations to demonstrate that these spectra contain a signature of intrinsic electron traps created as counterparts to the holes. In particular, we argue that optical absorption bands peaking at 3.7, 4.7, and 6.4 eV belong to strongly localised electrons trapped at precursor sites in amorphous structure characterized by strained Si-O bonds and O-Si-O angles greater than 132 degrees . These results are important for our understanding of the properties of silica glass and other silicates as well as the reliability of electronic and optical devices and for luminescence dating. PMID- 26053870 TI - Latent profile analysis of neuropsychological measures to determine preschoolers' risk for ADHD. AB - BACKGROUND: Hyperactive/Inattentive preschool children show clear evidence of neuropsychological dysfunction. We examined whether patterns and severity of test scores could reliably identify subgroups of preschoolers with differential risk for ADHD during school-age. METHOD: Typically developing (TD: n = 76) and Hyperactive/Inattentive (HI: n = 138) 3-4 year olds were assessed annually for 6 years (T1-T6). Latent profile analysis (LPA) was used to form subgroups among the HI group based on objective/neuropsychological measures (NEPSY, Actigraph and Continuous Performance Test). Logistic regression assessed the predictive validity of empirically formed subgroups at risk for ADHD diagnosis relative to the TD group and to each other from T2 to T6. RESULTS: Latent profile analysis yielded two subgroups of HI preschoolers: (a) selectively weak Attention/Executive functions, and (b) pervasive neuropsychological dysfunction across all measures. Both subgroups were more likely to have ADHD at all follow up time-points relative to the TD group (OR range: 11.29-86.32), but there were no significant differences between the LPA-formed subgroups of HI children at any time-point. CONCLUSIONS: Objective/neuropsychological measures distinguish HI preschoolers from their TD peers, but patterns and severity of neuropsychological dysfunction do not predict risk for ADHD during school-age. We hypothesize that trajectories in at-risk children are influenced by subsequent environmental and neurodevelopmental factors, raising the possibility that they are amenable to early intervention. PMID- 26053872 TI - Transmission and Demographic Dynamics of Coxsackievirus B1. AB - The infectious activity of coxsackievirus B1 (CV-B1) in Taiwan was high from 2008 to 2010, following an alarming increase in severe neonate disease in the United States (US). To examine the relationship between CV-B1 strains isolated in Taiwan and those from other parts of the world, we performed a phylodynamic study using VP1 and partial 3Dpol (414 nt) sequences from 22 strains of CV-B1 isolated in Taiwan (1989-2010) and compared them to sequences from strains isolated worldwide. Phylogenetic trees were constructed by neighbor-joining, maximum likelihood, and Bayesian Monte Carlo Markov Chain methods. Four genotypes (GI-IV) in the VP1 region of CV-B1 and three genotypes (GA-C) in the 3Dpol region of enterovirus B were identified and had high support values. The phylogenetic analysis indicates that the GI and GIII strains in VP1 were geographically distributed in Taiwan (1993-1994) and in India (2007-2009). On the other hand, the GII and GIV strains appear to have a wider spatiotemporal distribution and ladder-like topology A stair-like phylogeny was observed in the VP1 region indicating that the phylogeny of the virus may be affected by different selection pressures in the specified regions. Further, most of the GI and GII strains in the VP1 tree were clustered together in GA in the 3D tree, while the GIV strains diverged into GB and GC. Taken together, these data provide important insights into the population dynamics of CV-B1 and indicate that incongruencies in specific gene regions may contribute to spatiotemporal patterns of epidemicity for this virus. PMID- 26053873 TI - Overexpression of Lamin B Receptor Results in Impaired Skin Differentiation. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a rare segmental progeroid disorder commonly caused by a point mutation in the LMNA gene that results in the increased activation of an intra-exonic splice site and the production of a truncated lamin A protein, named progerin. In our previous work, induced murine epidermal expression of this specific HGPS LMNA mutation showed impaired keratinocyte differentiation and upregulated lamin B receptor (LBR) expression in suprabasal keratinocytes. Here, we have developed a novel transgenic animal model with induced overexpression of LBR in the interfollicular epidermis. LBR overexpression resulted in epidermal hypoplasia, along with the downregulation and mislocalization of keratin 10, suggesting impaired keratinocyte differentiation. Increased LBR expression in basal and suprabasal cells did not coincide with increased proliferation. Similar to our previous report of HGPS mice, analyses of gammaH2AX, a marker of DNA double-strand breaks, revealed an increased number of keratinocytes with multiple foci in LBR-overexpressing mice compared with wild-type mice. In addition, suprabasal LBR-positive cells showed densely condensed and peripherally localized chromatin. Our results show a moderate skin differentiation phenotype, which indicates that upregulation of LBR is not the sole contributor to the HGPS phenotype. PMID- 26053875 TI - Methylobacterium Species Promoting Rice and Barley Growth and Interaction Specificity Revealed with Whole-Cell Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF/MS) Analysis. AB - Methylobacterium species frequently inhabit plant surfaces and are able to utilize the methanol emitted from plants as carbon and energy sources. As some of the Methylobacterium species are known to promote plant growth, significant attention has been paid to the mechanism of growth promotion and the specificity of plant-microbe interactions. By screening our Methylobacterium isolate collection for the high growth promotion effect in vitro, we selected some candidates for field and pot growth tests for rice and barley, respectively. We found that inoculation resulted in better ripening of rice seeds, and increased the size of barley grains but not the total yield. In addition, using whole-cell matrix-assister laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF/MS) analysis, we identified and classified Methylobacterium isolates from Methylobacterium-inoculated rice plants. The inoculated species could not be recovered from the rice plants, and in some cases, the Methylobacterium community structure was affected by the inoculation, but not with predomination of the inoculated species. The isolates from non-inoculated barley of various cultivars grown in the same field fell into just two species. These results suggest that there is a strong selection pressure at the species level of Methylobacterium residing on a given plant species, and that selection of appropriate species that can persist on the plant is important to achieve growth promotion. PMID- 26053876 TI - Cognition of and Demand for Education and Teaching in Medical Statistics in China: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Although a substantial number of studies focus on the teaching and application of medical statistics in China, few studies comprehensively evaluate the recognition of and demand for medical statistics. In addition, the results of these various studies differ and are insufficiently comprehensive and systematic. OBJECTIVES: This investigation aimed to evaluate the general cognition of and demand for medical statistics by undergraduates, graduates, and medical staff in China. METHODS: We performed a comprehensive database search related to the cognition of and demand for medical statistics from January 2007 to July 2014 and conducted a meta-analysis of non-controlled studies with sub-group analysis for undergraduates, graduates, and medical staff. RESULTS: There are substantial differences with respect to the cognition of theory in medical statistics among undergraduates (73.5%), graduates (60.7%), and medical staff (39.6%). The demand for theory in medical statistics is high among graduates (94.6%), undergraduates (86.1%), and medical staff (88.3%). Regarding specific statistical methods, the cognition of basic statistical methods is higher than of advanced statistical methods. The demand for certain advanced statistical methods, including (but not limited to) multiple analysis of variance (ANOVA), multiple linear regression, and logistic regression, is higher than that for basic statistical methods. The use rates of the Statistical Package for the Social Sciences (SPSS) software and statistical analysis software (SAS) are only 55% and 15%, respectively. CONCLUSION: The overall statistical competence of undergraduates, graduates, and medical staff is insufficient, and their ability to practically apply their statistical knowledge is limited, which constitutes an unsatisfactory state of affairs for medical statistics education. Because the demand for skills in this area is increasing, the need to reform medical statistics education in China has become urgent. PMID- 26053877 TI - Borrelia miyamotoi Disease in the Northeastern United States: A Case Series. AB - BACKGROUND: The first recognized cases of Borrelia miyamotoi disease (BMD) in North America were reported in the northeastern United States in 2013. OBJECTIVE: To further describe the clinical spectrum and laboratory findings for BMD. DESIGN: Case series. SETTING: Patients presenting to primary care offices, emergency departments, or urgent care clinics in 2013 and 2014. PARTICIPANTS: Acutely febrile patients from the northeastern United States in whom the treating health care providers suspected and ordered testing for tick-transmitted infections. MEASUREMENTS: Whole-blood polymerase chain reaction (PCR) testing was performed for the presence of specific DNA sequences of common tickborne infections (including BMD). Serologic testing for B. miyamotoi was performed using a recombinant glycerophosphodiester phosphodiesterase (rGlpQ) protein. Clinical records were analyzed to identify the major features of acute disease. RESULTS: Among 11,515 patients tested, 97 BMD cases were identified by PCR. Most of the 51 case patients on whom clinical histories were reviewed presented with high fever, chills, marked headache, and myalgia or arthralgia. Twenty-four percent were hospitalized. Elevated liver enzyme levels, neutropenia, and thrombocytopenia were common. At presentation, 16% of patients with BMD were seropositive for IgG and/or IgM antibody to B. miyamotoi rGlpQ. Most (78%) had seropositive convalescent specimens. Symptoms resolved after treatment with doxycycline, and no chronic sequelae or symptoms were observed. LIMITATION: Findings were based on specimens submitted for testing to a reference laboratory, and medical records of only 51 of the 97 case patients with BMD were reviewed. CONCLUSION: Patients with BMD presented with nonspecific symptoms, including fever, headache, chills, myalgia, and arthralgia. Laboratory confirmation of BMD was possible by PCR on blood from acutely symptomatic patients who were seronegative at presentation. Borrelia miyamotoi disease may be an emerging tickborne infection in the northeastern United States. PRIMARY FUNDING SOURCE: IMUGEN. PMID- 26053874 TI - Molecular Phylogeny of Grassland Caterpillars (Lepidoptera: Lymantriinae: Gynaephora) Endemic to the Qinghai-Tibetan Plateau. AB - Gynaephora (Lepidoptera Erebidae: Lymantriinae) is a small genus, consisting of 15 nominated species, of which eight species are endemic to the Qinghai-Tibetan Plateau (QTP). In this study, we employed both mitochondrial and nuclear loci to infer a molecular phylogeny for the eight QTP Gynaephora spp. We used the phylogeny to estimate divergence dates in a molecular dating analysis and to delimit species. This information allowed us to investigate associations between the diversification history of the eight QTP species and geological and climatic events. Phylogenetic analyses indicated that the eight QTP species formed a monophyletic group with strong supports in both Bayesian and maximum likelihood analyses. The low K2P genetic distances between the eight QTP species suggested that diversification occurred relatively quickly and recently. Out of the eight species, five species were highly supported as monophyletic, which were also recovered by species delimitation analyses. Samples of the remaining three species (G. aureata, G. rouergensis, and G. minora) mixed together, suggesting that further studies using extensive population sampling and comprehensive morphological approaches are necessary to clarify their species status. Divergence time estimation results demonstrated that the diversification and speciation of Gynaephora on the QTP began during the late Miocene/early Pliocene and was potentially affected by the QTP uplift and associated climate changes during this time. PMID- 26053879 TI - Synthesis and Anticonvulsant Activity Evaluation of 4-Phenyl-[1,2,4]triazolo[4,3 a]quinazolin-5(4H)-one and Its Derivatives. AB - A series of 4-(substituted-phenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones (6a-x) with triazole and other heterocyclic substituents (7-14) were synthesized and the compounds were evaluated for their anticonvulsant activity and neurotoxicity by maximal electroshock (MES) and rotarod neurotoxicity tests. Among the compounds studied, 6o and 6q showed wide margins of safety with protective indices (PIs) that were much higher than those of currently used drugs (PI6o > 25.5, PI6q > 26.0). Compounds 6o and 6q showed significant oral activity against MES-induced seizures in mice, with ED50 values of 88.02 and 94.6 mg/kg, respectively. The two compounds were also found to have potent activity against seizures that were induced by pentylenetetrazole and bicuculline. PMID- 26053878 TI - Comparative Transcriptome Analysis of White and Purple Potato to Identify Genes Involved in Anthocyanin Biosynthesis. AB - INTRODUCTION: The potato (Solanum tuberosum) cultivar 'Xin Daping' is tetraploid with white skin and white flesh, while the cultivar 'Hei Meiren' is also tetraploid with purple skin and purple flesh. Comparative transcriptome analysis of white and purple cultivars was carried out using high-throughput RNA sequencing in order to further understand the mechanism of anthocyanin biosynthesis in potato. METHODS AND RESULTS: By aligning transcript reads to the recently published diploid potato genome and de novo assembly, 209 million paired end Illumina RNA-seq reads from these tetraploid cultivars were assembled on to 60,930 transcripts, of which 27,754 (45.55%) are novel transcripts and 9393 alternative transcripts. Using a comparison of the RNA-sequence datasets, multiple versions of the genes encoding anthocyanin biosynthetic steps and regulatory transcription factors were identified. Other novel genes potentially involved in anthocyanin biosynthesis in potato tubers were also discovered. Real time qPCR validation of candidate genes revealed good correlation with the transcriptome data. SNPs (Single Nucleotide Polymorphism) and indels were predicted and validated for the transcription factors MYB AN1 and bHLH1 and the biosynthetic gene anthocyanidin 3-O-glucosyltransferase (UFGT). CONCLUSIONS: These results contribute to our understanding of the molecular mechanism of white and purple potato development, by identifying differential responses of biosynthetic gene family members together with the variation in structural genes and transcription factors in this highly heterozygous crop. This provides an excellent platform and resource for future genetic and functional genomic research. PMID- 26053880 TI - Congenital malignant melanoma and cutaneous metastases treated with diphencyprone. PMID- 26053881 TI - Large-scale preparation of graphene by high temperature insertion of hydrogen into graphite. AB - Experimental evidence for high temperature diffusion of hydrogen into the interlayer space of graphite is provided. This process is discussed as a possible method for the rapid production of high-quality, inexpensive graphene in large quantities, which could lead to the widespread application of graphene. It was found that hydrogen cations, dissolved in molten LiCl, can be discharged on cathodically polarized graphite rods, which then intercalate into the graphite structure, leading to the peeling of graphite to produce graphene. The graphene nanosheets produced displayed a single-crystalline structure with a lateral size of several hundred nanometers and a high degree of crystallinity and thermal stability. The method introduced could be scaled up to produce industrial quantities of high-quality graphene. PMID- 26053882 TI - The Relationship between Diabetes Self-efficacy and Diabetes Self-care in American Indians and Alaska Natives. AB - The objective of the present study was to investigate how American Indian/Alaska Natives' (AI/ANs') attitudes and beliefs might influence how they experience and manage diabetes, with particular attention paid to their attitudes about disease causality. An AI/AN sample of 119 participants completed an anonymous survey that examined the impact of judgments of personal responsibility for disease onset, anger, self-blame, social support, and diabetes self-efficacy on diabetes self care. Our primary model was tested using structural equation modeling. Results indicated that, while many participants considered themselves almost entirely responsible for their disease onset, this judgment did not predict anger. Anger was strongly related to self-blame and social support, while diabetes self efficacy was strongly related to diabetes self-care. These psychosocial variables accounted for 70% of the variability in self-reported disease management. PMID- 26053883 TI - ADHD Symptoms in American Indian/Alaska Native Boys and Girls. AB - Despite the commonality of attention-deficit/hyperactivity disorder (ADHD), the diagnostic criteria are based largely on research with European American boys. Much less research is available regarding the prevalence of ADHD in other groups, specifically American Indian/Alaska Native (AI/AN) children. Moreover, research on sex differences in ADHD has typically not included AI/AN children. The current study examined parent- and teacher-reported ADHD symptoms in 72 AI children from one region in the Southern U.S., with a focus on sex differences. Data showed that AI children may have more pronounced sex differences in ADHD symptomology than is found in studies with primarily European American children. Implications, limitations, and future directions are discussed. PMID- 26053884 TI - American Indian Substance Abuse Prevention Efforts: A Review of Programs, 2003 2013. AB - The purpose of the review was to assess substance abuse prevention (SAP) efforts in American Indian and Alaska Native (AI/AN) communities from 2003-2013. In the past, many SAP programs were unable to meet the unique cultural needs of AI/AN communities adequately. It has been suggested that a disconnect may exist between the theories that are used to guide development of prevention programs in AI/AN communities and culturally appropriate theoretical constructs of AI/AN worldviews. To explore this possible disconnect further, Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to assess a total of 18 articles (N = 31 programs) on program location and method, participant characteristics, described program cultural elements, use of theory, program outcomes, program measures, and future recommendations. Results indicated that SAP programs in AI/AN communities vary widely in their use of theory, implementation strategies, view and definition of cultural constructs, overall evaluational rigor, and reporting methods. Future research is needed to integrate appropriate theory and cultural elements into SAP programs to tie them to measurable outcomes for AI/AN communities. PMID- 26053885 TI - Momentary assessment of contextual influences on affective response during physical activity. AB - OBJECTIVE: Higher positive and lower negative affective response during physical activity may reinforce motivation to engage in future activity. However, affective response during physical activity is typically examined under controlled laboratory conditions. This research used ecological momentary assessment (EMA) to examine social and physical contextual influences on momentary affective response during physical activity in naturalistic settings. METHOD: Participants included 116 adults (mean age = 40.3 years, 73% female) who completed 8 randomly prompted EMA surveys per day for 4 days across 3 semiannual waves. EMA surveys measured current activity level, social context, and physical context. Participants also rated their current positive and negative affect. Multilevel models assessed whether momentary physical activity level moderated differences in affective response across contexts controlling for day of the week, time of day, and activity intensity (measured by accelerometer). RESULTS: The Activity Level * Alone interaction was significant for predicting positive affect (beta = -0.302, SE = 0.133, p = .024). Greater positive affect during physical activity was reported when with other people (vs. alone). The Activity Level * Outdoors interaction was significant for predicting negative affect (beta = -0.206, SE = 0.097, p = .034). Lower negative affect during physical activity was reported outdoors (vs. indoors). CONCLUSIONS: Being with other people may enhance positive affective response during physical activity, and being outdoors may dampen negative affective response during physical activity. PMID- 26053887 TI - Ocular Inflammation in the Setting of Concomitant Systemic Autoimmune Conditions in an Older Male Population. AB - PURPOSE: This retrospective cross-sectional study was designed to investigate the frequency and types of inflammatory ocular manifestations of specific systemic autoimmune diseases in a South Florida Veterans Affairs Hospital population. METHODS: Demographic and medical diagnosis information was extracted from the Veterans Administration database for 1225 patients. These patients were seen in Miami and Broward Veterans Affairs hospitals between April 18, 2008, and April 17, 2013, and were diagnosed with at least 1 of the following: systemic lupus erythematosus, sarcoid, rheumatoid arthritis, polymyalgia rheumatica, Takayasu arteritis, giant cell arteritis, Kawasaki disease, polyarteritis nodosa, Buerger disease, Henoch-Schonlein purpura, Behcet syndrome, granulomatosis with polyangiitis, other polyarteritis nodosa-associated vasculitides, or arteritis not otherwise specified. RESULTS: Of 1225 patients, 618 were seen in the VA eye clinic and 25 were diagnosed with concomitant inflammatory ocular conditions. Uveitis was the most common, and included 8 cases of anterior, 1 anterior intermediate, 1 intermediate, 2 panuveitis, and 3 unspecified. Other manifestations included 7 cases of keratitis and 2 each of scleritis, episcleritis, and acute ischemic optic neuropathy. The overall frequency of inflammatory ocular disease was 2%. The diseases associated with the highest frequency of ocular involvement were granulomatosis with polyangiitis (1/8), sarcoid (9/198), giant cell arteritis (2/68), and rheumatoid arthritis (11/576). Of these 25 patients, 9 were diagnosed with eye disease before systemic disease. CONCLUSIONS: In this population, ocular manifestations were rarely the presenting feature of systemic disease, but autoimmune disorders are an important underlying cause of inflammatory eye disease that should be considered on first evaluation, even in this "nontraditional," predominantly male, autoimmune disease population. PMID- 26053886 TI - Increased Risk of Depressive Disorder following Cholecystectomy for Gallstones. AB - BACKGROUND: Prior studies indicate a possible association between depression and cholecystectomy, but no study has compared the risk of post-operative depressive disorders (DD) after cholecystectomy. This retrospective follow-up study aimed to examine the relationship between cholecystectomy and the risk of DD in patients with gallstones in a population-based database. METHODS: Using ambulatory care data from the Longitudinal Health Insurance Database 2000, 6755 patients who received a first-time principal diagnosis of gallstones at the emergency room (ER) were identified. Among them, 1197 underwent cholecystectomy. Each patient was then individually followed-up for two years to identify those who were later diagnosed with DD. Cox proportional hazards regressions were performed to estimate the risk of developing DD between patients with gallstone who did and those who did not undergo cholecystectomy. RESULTS: Of 6755 patients with gallstones, 173 (2.56%) were diagnosed with DD during the two-year follow-up. Among patients who did and those who did not undergo cholecystectomy, 3.51% and 2.36% later developed depressive disorder, respectively. After adjusting for the patient's sex, age and geographic location, the hazard ratio (HR) of DD within two years of gallstone diagnosis was 1.43 (95% CI, 1.02-2.04) for patients who underwent cholecystectomy compared to those who did not. Females, but not males, had a higher the adjusted HR of DD (1.61; 95% CI, 1.08-2.41) for patients who underwent cholecystectomy compared to those who did not. CONCLUSIONS: There is an association between cholecystectomy and subsequent risk of DD among females, but not in males. PMID- 26053888 TI - Investigation on Spin Dependent Transport Properties of Core-Shell Structural Fe3O4/ZnS Nanocomposites for Spintronic Application. AB - The core-shell structural Fe3O4/ZnS nanocomposites with controllable shell thickness were well-fabricated via seed-mediate growth method. Structural and morphological characterizations reveal the direct deposition of crystalline II-VI compound semiconductor ZnS shell layer on Fe3O4 particles. Spin dependent electrical transport is studied on Fe3O4/ZnS nanocomposites with different shell thickness, and a large magnetoresistance (MR) ratio is observed under the magnetic field of 1.0 T at room temperature and 100 K for the compacted sample by Fe3O4/ZnS nanocomposites, which is 50% larger than that of sample with pure Fe3O4 particles, indicating that the enhanced MR is contributed from the spin injection between Fe3O4 and ZnS layer. PMID- 26053889 TI - Homology modeling of larger proteins guided by chemical shifts. AB - We describe an approach to the structure determination of large proteins that relies on experimental NMR chemical shifts, plus sparse nuclear Overhauser effect (NOE) data if available. Our alignment method, POMONA (protein alignments obtained by matching of NMR assignments), directly exploits pre-existing bioinformatics algorithms to match experimental chemical shifts to values predicted for the crystallographic database. Protein templates generated by POMONA are subsequently used as input for chemical shift-based Rosetta comparative modeling (CS-RosettaCM) to generate reliable full-atom models. PMID- 26053890 TI - Quantifying domain-ligand affinities and specificities by high-throughput holdup assay. AB - Many protein interactions are mediated by small linear motifs interacting specifically with defined families of globular domains. Quantifying the specificity of a motif requires measuring and comparing its binding affinities to all its putative target domains. To this end, we developed the high-throughput holdup assay, a chromatographic approach that can measure up to 1,000 domain motif equilibrium binding affinities per day. After benchmarking the approach on 210 PDZ-peptide pairs with known affinities, we determined the affinities of two viral PDZ-binding motifs derived from human papillomavirus E6 oncoproteins for 209 PDZ domains covering 79% of the human 'PDZome'. We obtained sharply sequence dependent binding profiles that quantitatively describe the PDZome recognition specificity of each motif. This approach, applicable to many categories of domain ligand interactions, has wide potential for quantifying the specificities of interactomes. PMID- 26053891 TI - Bilateral lesions in a specific subregion of posterior insular cortex impair conditioned taste aversion expression in rats. AB - The gustatory cortex (GC) is widely regarded for its integral role in the acquisition and retention of conditioned taste aversions (CTAs) in rodents, but large lesions in this area do not always result in CTA impairment. Recently, using a new lesion mapping system, we found that severe CTA expression deficits were associated with damage to a critical zone that included the posterior half of GC in addition to the insular cortex (IC) that is just dorsal and caudal to this region (visceral cortex). Lesions in anterior GC were without effect. Here, neurotoxic bilateral lesions were placed in the anterior half of this critical damage zone, at the confluence of the posterior GC and the anterior visceral cortex (termed IC2 ), the posterior half of this critical damage zone that contains just VC (termed IC3), or both of these subregions (IC2 + IC3). Then, pre and postsurgically acquired CTAs (to 0.1 M NaCl and 0.1 M sucrose, respectively) were assessed postsurgically in 15-minute one-bottle and 96-hour two-bottle tests. Li-injected rats with histologically confirmed bilateral lesions in IC2 exhibited the most severe CTA deficits, whereas those with bilateral lesions in IC3 were relatively normal, exhibiting transient disruptions in the one-bottle sessions. Groupwise lesion maps showed that CTA-impaired rats had more extensive damage to IC2 than did unimpaired rats. Some individual differences in CTA expression among rats with similar lesion profiles were observed, suggesting idiosyncrasies in the topographic representation of information in the IC. Nevertheless, this study implicates IC2 as the critical zone of the IC for normal CTA expression. PMID- 26053892 TI - Enhanced response and sensitivity of self-corrugated graphene sensors with anisotropic charge distribution. AB - We introduce a high-performance molecular sensor using self-corrugated chemically modified graphene as a three dimensional (3D) structure that indicates anisotropic charge distribution. This is capable of room-temperature operation, and, in particular, exhibiting high sensitivity and reversible fast response with equilibrium region. The morphology consists of periodic, "cratered" arrays that can be formed by condensation and evaporation of graphene oxide (GO) solution on interdigitated electrodes. Subsequent hydrazine reduction, the corrugated edge area of the graphene layers have a high electric potential compared with flat graphene films. This local accumulation of electrons interacts with a large number of gas molecules. The sensitivity of 3D-graphene sensors significantly increases in the atmosphere of NO2 gas. The intriguing structures have several advantages for straightforward fabrication on patterned substrates, high performance graphene sensors without post-annealing process. PMID- 26053893 TI - Rotational thromboelastometry-guided blood product management in major spine surgery. AB - OBJECT Major spinal surgery in adult patients is often associated with significant intraoperative blood loss. Rotational thromboelastometry (ROTEM) is a functional viscoelastometric method for real-time hemostasis testing. In this study, the authors sought to characterize the coagulation abnormalities encountered in spine surgery and determine whether a ROTEM-guided, protocol-based approach to transfusion reduced blood loss and blood product use and cost. METHODS A hospital database was used to identify patients who had undergone adult deformity correction spine surgery with ROTEM-guided therapy. All patients who received ROTEM-guided therapy (ROTEM group) were matched with historical cohorts whose coagulation status had not been evaluated with ROTEM but who were treated using a conventional clinical and point-of-care laboratory approach to transfusion (Conventional group). Both groups were subdivided into 2 groups based on whether they had received intraoperative tranexamic acid (TXA), the only coagulation-modifying medication administered intraoperatively during the study period. In the ROTEM group, 26 patients received TXA (ROTEM-TXA group) and 24 did not (ROTEM-nonTXA group). Demographic, surgical, laboratory, and perioperative transfusion data were recorded. Data were analyzed by rank permutation test, adapted for the 1:2 ROTEM-to-Conventional matching structure, with p < 0.05 considered significant. RESULTS Comparison of the 2 groups in which TXA was used showed significantly less fresh-frozen plasma (FFP) use in the ROTEM-TXA group than in the Conventional-TXA group (median 0 units [range 0-4 units] vs 2.5 units [range 0-13 units], p < 0.0002) but significantly more cryoprecipitate use (median 1 unit [range 0-4 units] in the ROTEM-TXA group vs 0 units [range 0-2 units] in the Conventional-TXA group, p < 0.05), with a nonsignificant reduction in blood loss (median 2.6 L [range 0.9-5.4 L] in the ROTEM-TXA group vs 2.9 L [0.7-7.0 L] in the Conventional-TXA group, p = 0.21). In the 2 groups in which TXA was not used, the ROTEM-nonTXA group showed significantly less blood loss than the Conventional-nonTXA group (median 1 L [range 0.2-6.0 L] vs 1.5 L [range 1.0-4.5 L], p = 0.0005), with a trend toward less transfusion of packed red blood cells (pRBC) (median 0 units [range 0-4 units] vs 1 unit [range 0-9 units], p = 0.09]. Cryoprecipitate use was increased and FFP use decreased in response to ROTEM analysis identifying hypofibrinogenemia as a major contributor to ongoing coagulopathy. CONCLUSIONS In major spine surgery, ROTEM-guided transfusion allows for standardization of transfusion practices and early identification and treatment of hypofibrinogenemia. Hypofibrinogenemia is an important cause of the coagulopathy encountered during these procedures and aggressive management of this complication is associated with less intraoperative blood loss, reduced transfusion requirements, and decreased transfusion-related cost. PMID- 26053894 TI - General Strategy to Introduce pH-Induced Allostery in DNA-Based Receptors to Achieve Controlled Release of Ligands. AB - Inspired by naturally occurring pH-regulated receptors, here we propose a rational approach to introduce pH-induced allostery into a wide range of DNA based receptors. To demonstrate this we re-engineered two model DNA-based probes, a molecular beacon and a cocaine-binding aptamer, by introducing in their sequence a pH-dependent domain. We demonstrate here that we can finely tune the affinity of these model receptors and control the load/release of their specific target molecule by a simple pH change. PMID- 26053896 TI - Stage I mycosis fungoides: frequent association with a favourable prognosis but disease progression and disease-specific mortality may occur. PMID- 26053895 TI - Metastases to the kidney: a comprehensive analysis of 151 patients from a tertiary referral centre. AB - OBJECTIVE: To describe the presentation, treatment and outcomes of patients with metastatic tumours to the kidney treated at a tertiary referral centre. PATIENTS AND METHODS: We retrospectively identified 151 patients diagnosed with a primary non-renal malignancy with renal metastasis. Clinical, radiographic and pathological characteristics were assessed. Overall survival (OS) was calculated using Kaplan-Meier methods. RESULTS: The median patient age was 56.7 years. The most common presenting symptoms were flank pain (30%), haematuria (16%) and weight loss (12%). Most primary cancers were carcinomas (80.8%). The most common primary tumour sites were lung (43.7%), colorectal (10.6%), head and neck (6%), breast (5.3%), soft tissue (5.3%) and thyroid (5.3%). Renal metastases were typically solitary (77.5%). Concordance between radiologist and clinician imaging assessment was 54.0%. Three ablations and 48 nephrectomies were performed. For non-surgical patients, renal metastasis diagnosis was made with fine-needle aspiration or biopsy. The median OS from primary tumour diagnosis was 3.08 years and the median OS from time of metastatic diagnosis was 1.13 years. For patients treated with surgery, median OS from primary tumour diagnosis was 4.81 years, and OS from metastatic diagnosis was 2.24 years. CONCLUSIONS: Metastases to the kidney are a rare entity. Survival appears to be longer in patients who are candidates for and are treated with surgery. Surgical intervention in carefully selected patients with oligometastatic disease and good performance status should be considered. A multidisciplinary approach with input from urologists, oncologists, radiologists and pathologists is needed to achieve the optimum outcomes for this specific patient population. PMID- 26053897 TI - Simulation of Observed PCBs and Pesticides in the Water Column during the North Atlantic Bloom Experiment. AB - The dynamics of persistent organic pollutants in the oceans are not well constrained, in particular during a bloom formation and collapse. Polychlorinated biphenyls (PCBs) and some pesticides were measured in air, water, and zooplankton tracking the North Atlantic Bloom in May 2008. Lower weight PCBs were entering the water column from the atmosphere during the main bloom period but reached equilibrium after the bloom collapsed. The PCBs in the lipids of zooplankton Calanus were in equilibrium with those in the dissolved phase. A Lagrangian box model was developed to simulate the dissolved phase PCBs and pesticides by including the following processes: air-water exchange, reversible sorption to POC, changes in mixed layer depth, removal by sinking particles, and degradation. Results suggest that sorption to (sinking) POC was the dominant removal process for hydrophobic pollutants from seawater. Statistical test suggested simulated results were not significantly different from observed values for hydrophobic pollutants (p,p'-DDE). PMID- 26053899 TI - NICE guidelines for use of implantable cardioverter defibrillators. PMID- 26053898 TI - Excess Metabolic Syndrome Risks Among Women Health Workers Compared With Men. AB - Metabolic syndrome is associated with higher rates of cardiovascular morbidity and mortality. Although significant disparities in the risks of metabolic syndrome by occupation type and sex are well documented, the factors associated with metabolic syndrome in low- to middle-income countries remain unclear. These gaps in evidence identify the need for patterns of metabolic syndrome among hospital personnel of both sexes in Nigeria. A total of 256 hospital workers comprising 32.8% men were studied. The mean age of the participants was 42.03 +/- 9.4 years. Using International Diabetic Federation criteria, the prevalence of metabolic syndrome was 24.2%. Women were substantially and significantly more likely to be identified with metabolic syndrome compared with men (34.9% vs 2.4%, respectively; P=.0001). This study identified metabolic syndrome among health workers with over one third of women with metabolic syndrome compared with <10% of men. These results support the implementation of lifestyle modification programs for management of metabolic syndrome in the health care workplace. PMID- 26053900 TI - Will social media make or break medical conferences? PMID- 26053902 TI - Systemic manifestations of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease is a complex multisystem disease with comorbidities and systemic manifestations that affect respiratory symptoms, exacerbation frequency and mortality. This article gives an overview of these systemic manifestations and their importance, and offers strategies for managing them. PMID- 26053903 TI - Heart failure: not a single organ disease but a multisystem syndrome. AB - Heart failure is not simply a single organ disease; rather it is a complex multi system clinical syndrome, with impairment of endocrine, haematological, musculoskeletal, renal, respiratory and vascular systems, which influence morbidity and mortality. PMID- 26053904 TI - A guide to oral ulceration for the medical physician. AB - Oral ulceration is a common finding yet its classification, diagnosis and management remain a challenge for many hospital physicians. This article discusses the different types of oral ulceration and how to investigate and manage them. PMID- 26053905 TI - Imaging of extremity soft tissue masses: pitfalls in diagnosis. AB - Soft tissue sarcomas are rare tumours which can be clinically difficult to differentiate from more common benign lesions. Imaging plays a fundamental role in diagnosis, but in some cases it can be difficult to differentiate benign from malignant conditions. This article reviews potential pitfalls in soft tissue sarcoma imaging. PMID- 26053906 TI - Clinical handover: the importance, problems and educational interventions to improve its practice. AB - The clinical handover is a complex area of advanced communication in medicine and is becoming increasingly recognized as a situation where good communication is needed to ensure patient safety. This article outlines its importance and the need to make improvements. PMID- 26053907 TI - Use of a care bundle to reduce mortality following emergency laparotomy. AB - Emergency laparotomy is a common intra-abdominal procedure with outcomes recognized to be poor. Efforts are being made to improve these outcomes, both nationally and internationally. This article describes the methodology of a successfully implemented collaborative quality improvement project that improved outcomes following emergency laparotomy in four NHS trusts. PMID- 26053908 TI - Surgery at the Battle of Waterloo. PMID- 26053909 TI - Takayasu's arteritis in an active man: burnt out or quiescent? PMID- 26053910 TI - Varicella pneumonia. PMID- 26053911 TI - The importance of taking a thorough history. PMID- 26053912 TI - A common autoimmune disease with rare organ involvement. PMID- 26053913 TI - Protecting the confidentiality of medical records in the theatre environment. PMID- 26053915 TI - To beta-block or not? PMID- 26053916 TI - Paraproteinaemia. PMID- 26053917 TI - Dealing with encounters being recorded by patients. PMID- 26053918 TI - Screening for lung cancer. PMID- 26053919 TI - How to manage gynaecology on call. PMID- 26053920 TI - LGBT People and the Work Ahead in Bioethics. PMID- 26053922 TI - Adjunctive Treatment of Periodontal Disease with Self-Adhesive Hydrogel Wound Dressing: Case Series. AB - Periodontal disease (periodontitis) is a common inflammatory condition affecting the deep, supporting tissues around teeth. While specific bacteria in plaque biofilm initiate the disease process, host immuno-inflammatory responses are responsible for the majority of tissue destruction. Conventional methods for controlling periodontitis include mechanical removal of the biofilm-with or without surgical access-and the adjunctive use of chemotherapeutics (antimicrobials or host modulators). PerioPatchTM is an approved device product that has been developed as an oral adhesive barrier for promoting healing in inflamed oral/gingival tissues and reducing pain, irritation, and the symptoms of inflammation. In this case series, which documented the adjunctive benefits of PerioPatch therapy in patients with chronic periodontitis, 9 patients who presented with generalized moderate to severe chronic periodontitis were treated with scaling and root planing plus adjunctive PerioPatch devices. Patients applied the devices to identified areas with periodontal pocketing (>= 6 mm at baseline) twice daily at Day 1, then once daily for Days 2 to 7. Three of the patients additionally applied devices to the treatment sites on Days 15 to 21. Patients were evaluated for changes in probing parameters at 4 to 6 weeks. RESULTS: Clinical examinations performed at baseline and post-treatment indicated consistent pocket depth reductions (mean 2.8 mm) and resolution of bleeding on probing (94%). Patients complied with the application schedule and reported no adverse effects. The authors conclude that within the confines of this case series, the PerioPatch is a novel but simple device that can be used adjunctively with scaling and root planing for the management of chronic periodontitis. PMID- 26053921 TI - Playing with Strangers: Which Shared Traits Attract Us Most to New People? AB - Homophily, the tendency for individuals to associate with those who are most similar to them, has been well documented. However, the influence of different kinds of similarity (e.g. relating to age, music taste, ethical views) in initial preferences for a stranger have not been compared. In the current study, we test for a relationship between sharing a variety of traits (i.e. having different kinds of similarity) with a stranger and the perceived likeability of that stranger. In two online experiments, participants were introduced to a series of virtual partners with whom they shared traits, and subsequently carried out activities designed to measure positivity directed towards those partners. Greater numbers of shared traits led to linearly increasing ratings of partner likeability and ratings on the Inclusion of Other in Self scale. We identified several consistent predictors of these two measures: shared taste in music, religion and ethical views. These kinds of trait are likely to be judged as correlates of personality or social group, and may therefore be used as proxies of more in-depth information about a person who might be socially more relevant. PMID- 26053923 TI - The Effect of Chemical Amendments Used for Phosphorus Abatement on Greenhouse Gas and Ammonia Emissions from Dairy Cattle Slurry: Synergies and Pollution Swapping. AB - Land application of cattle slurry can result in incidental and chronic phosphorus (P) loss to waterbodies, leading to eutrophication. Chemical amendment of slurry has been proposed as a management practice, allowing slurry nutrients to remain available to plants whilst mitigating P losses in runoff. The effectiveness of amendments is well understood but their impacts on other loss pathways (so-called 'pollution swapping' potential) and therefore the feasibility of using such amendments has not been examined to date. The aim of this laboratory scale study was to determine how the chemical amendment of slurry affects losses of NH3, CH4, N2O, and CO2. Alum, FeCl2, Polyaluminium chloride (PAC)- and biochar reduced NH3 emissions by 92, 54, 65 and 77% compared to the slurry control, while lime increased emissions by 114%. Cumulative N2O emissions of cattle slurry increased when amended with alum and FeCl2 by 202% and 154% compared to the slurry only treatment. Lime, PAC and biochar resulted in a reduction of 44, 29 and 63% in cumulative N2O loss compared to the slurry only treatment. Addition of amendments to slurry did not significantly affect soil CO2 release during the study while CH4 emissions followed a similar trend for all of the amended slurries applied, with an initial increase in losses followed by a rapid decrease for the duration of the study. All of the amendments examined reduced the initial peak in CH4 emissions compared to the slurry only treatment. There was no significant effect of slurry amendments on global warming potential (GWP) caused by slurry land application, with the exception of biochar. After considering pollution swapping in conjunction with amendment effectiveness, the amendments recommended for further field study are PAC, alum and lime. This study has also shown that biochar has potential to reduce GHG losses arising from slurry application. PMID- 26053924 TI - Changes in testosterone related to body composition in late midlife: Findings from the 1946 British birth cohort study. AB - OBJECTIVE: Randomized trials in men with testosterone deficiency have provided evidence of short-term effects of testosterone therapy on muscle and fat mass but it is unclear whether this persists over a longer period or how testosterone affects women. We examined whether the midlife decline in testosterone relates to fat and lean mass in both sexes. METHODS: Data were collected from 440 men and 560 women participating in the 1946 British birth cohort study with testosterone measured at 53 and/or 60-64 years. Fat and appendicular lean mass were measured at 60-64 years using dual-energy X-ray absorptiometry. RESULTS: Mean free testosterone concentrations were lower at 60-64 than 53 years, by 26% in both sexes. At both ages testosterone was negatively associated with fat mass in men and positively associated in women. A larger decline in free testosterone was associated with higher fat mass in men but with lower fat mass among women. In contrast, declines in testosterone were not associated with lean mass in either sex. CONCLUSIONS: Our findings suggest sex-divergent relationships between testosterone and fat mass and their distribution but do not support the hypothesis that midlife declines in testosterone lead to lower lean mass. PMID- 26053925 TI - Hydrogen Peroxide Induce Human Cytomegalovirus Replication through the Activation of p38-MAPK Signaling Pathway. AB - Human cytomegalovirus (HCMV) is a major risk factor in transplantation and AIDS patients, which induces high morbidity and mortality. These patients infected with HCMV experience an imbalance of redox homeostasis that cause accumulation of reactive oxygen species (ROS) at the cellular level. H2O2, the most common reactive oxygen species, is the main byproduct of oxidative metabolism. However, the function of H2O2 on HCMV infection is not yet fully understood and the effect and mechanism of N-acetylcysteine (NAC) on H2O2-stimulated HCMV replication is unclear. We, therefore, examined the effect of NAC on H2O2-induced HCMV production in human foreskin fibroblast cells. In the present study, we found that H2O2 enhanced HCMV lytic replication through promoting major immediate early (MIE) promoter activity and immediate early (IE) gene transcription. Conversely, NAC inhibited H2O2-upregulated viral IE gene expression and viral replication. The suppressive effect of NAC on CMV in an acute CMV-infected mouse model also showed a relationship between antioxidants and viral lytic replication. Intriguingly, the enhancement of HCMV replication via supplementation with H2O2 was accompanied with the activation of the p38 mitogen-activated protein kinase pathway. Similar to NAC, the p38 inhibitor SB203580 inhibited H2O2-induced p38 phosphorylation and HCMV upregulation, while upregulation of inducible ROS was unaffected. These results directly relate HCMV replication to H2O2, suggesting that treatment with antioxidants may be an attractive preventive and therapeutic strategy for HCMV. PMID- 26053929 TI - Developing clinical skills bundles. AB - BACKGROUND: This article describes an innovative method of learning clinical skills. A care bundle is defined as a small set of evidence-based interventions that, when implemented together, results in significantly better patient outcomes than when implemented individually. Care bundles improve the consistency of standards of care delivered, and hence reduce harm. CONTEXT: In 2007 The Scottish Clinical Skills Strategy identified the use of simulation-based education to ensure all health care staff can deliver a consistently high standard of clinical skills practice throughout the National Health Service in Scotland (NHS Scotland). INNOVATION: Clinical skills bundles were developed to underpin a number of evidence-based care bundles. Grouping the clinical skills together and learning them as a clinical skills bundle may improve the reliability of skills delivery for each care bundle. Three groups were recruited and asked to identify a consensus of the essential technical and non-technical skills for clinical skills bundle for a central venous catheter (CVC) maintenance care bundle. As a pilot, six clinical skills bundle workshops were held for junior doctors, nursing and medical students, and clinical skills educators. The aims of the workshops were to introduce the concepts of clinical skills bundles and to give participants a chance to practice the underpinning clinical skills bundle for a care bundle using simulation. The majority of participants rated the workshop as excellent or good. Self-reported learning included refreshing their clinical skills in a different context. Care bundles improve the consistency of standards of care delivered IMPLICATION: Learning skills together as a bundle may enhance the reliability of clinical skills performance for care bundles, and may also reinforce the use of care bundles. PMID- 26053926 TI - The Emerging Roles of Viroporins in ER Stress Response and Autophagy Induction during Virus Infection. AB - Viroporins are small hydrophobic viral proteins that oligomerize to form aqueous pores on cellular membranes. Studies in recent years have demonstrated that viroporins serve important functions during virus replication and contribute to viral pathogenicity. A number of viroporins have also been shown to localize to the endoplasmic reticulum (ER) and/or its associated membranous organelles. In fact, replication of most RNA viruses is closely linked to the ER, and has been found to cause ER stress in the infected cells. On the other hand, autophagy is an evolutionarily conserved "self-eating" mechanism that is also observed in cells infected with RNA viruses. Both ER stress and autophagy are also known to modulate a wide variety of signaling pathways including pro-inflammatory and innate immune response, thereby constituting a major aspect of host-virus interactions. In this review, the potential involvement of viroporins in virus induced ER stress and autophagy will be discussed. PMID- 26053930 TI - Letter to the Editor: Correlation of diffusion tensor imaging and intraoperative macrostimulation. PMID- 26053931 TI - Dual recollection in episodic memory. AB - In the mainstream memory literature, recollection is conceptualized as a univariate process that involves conscious reinstatement of contextual details that accompanied earlier events. That conception predominates in several domains other than basic memory research-such as cognitive development, cognitive neuroscience, dementia, and forensic interviewing. According to the dual recollection hypothesis, however, there are 2 distinct forms of recollection: conscious reinstatement of contextual details (context recollection) and conscious reinstatement of target events per se (target recollection). We review existing lines of evidence that favor the dual-recollection hypothesis, and we describe a source-monitoring paradigm with an accompanying model that separates the 2 recollections from each other and from familiarity. Some experiments are reported whose aims were to determine how measures of target and context recollection react to a series of theoretically motivated manipulations and to assess the validity of the modeling tool that supplies those measurements. The manipulations produced a series of single and double dissociations between target recollection, context recollection, and familiarity, and subsequent state-trace analyses revealed that the 3 retrieval processes were jointly independent. Fit analyses showed that the model gave acceptable accounts of the data of all experiments, but that fit was unacceptable when either the target recollection process or the context recollection process was removed from the model. PMID- 26053927 TI - Protein-Protein Interactions of Viroporins in Coronaviruses and Paramyxoviruses: New Targets for Antivirals? AB - Viroporins are members of a rapidly growing family of channel-forming small polypeptides found in viruses. The present review will be focused on recent structural and protein-protein interaction information involving two viroporins found in enveloped viruses that target the respiratory tract; (i) the envelope protein in coronaviruses and (ii) the small hydrophobic protein in paramyxoviruses. Deletion of these two viroporins leads to viral attenuation in vivo, whereas data from cell culture shows involvement in the regulation of stress and inflammation. The channel activity and structure of some representative members of these viroporins have been recently characterized in some detail. In addition, searches for protein-protein interactions using yeast two hybrid techniques have shed light on possible functional roles for their exposed cytoplasmic domains. A deeper analysis of these interactions should not only provide a more complete overview of the multiple functions of these viroporins, but also suggest novel strategies that target protein-protein interactions as much needed antivirals. These should complement current efforts to block viroporin channel activity. PMID- 26053932 TI - Lotus-like effect for metal filings recovery and particle removal on heated metal surfaces using Leidenfrost water droplets. AB - A "lotus-like" effect is applied to demonstrate the ability of the Leidenfrost water droplets to recover Cu particles on a heated Al substrate. Cu particles on the heated surface adhere to the rim of the Leidenfrost droplets and eventually coat the droplets' surface to form an aggregation. When Fe filings are added to the Cu particles, the aggregated mixture can then be collected using a strong rare earth magnet (NdFeB) upon evaporation of the water. We also show that the Leidenfrost effect can be effectively utilized to recover both hydrophobic (dust and activated carbon) and hydrophilic (SiO2 and MgO) particles from heated Al surfaces without any topographical modification or surfactant addition. Our results show that hydrophobic and hydrophilic materials can be collected with >92% and >96% effectiveness on grooved and smooth Al surfaces, respectively. Furthermore, we observed no significant differences in the amount of material collected above the Leidenfrost point within the tested temperature range (240 degrees C vs. 340 degrees C) as well as when the Al sheet was replaced with a Cu sheet as the substrate. However, we did observe that the Leidenfrost droplets were able to collect a greater amount of material when the working liquid was water than when it was ethanol. Our findings show promise in the development of an effective precious coinage metal filings recovery technology for application in the mint industry, as well as the self-cleaning of metallic and semiconductor surfaces where manual cleaning is not amenable. PMID- 26053933 TI - Core-Shell Upconversion Nanoparticle@Metal-Organic Framework Nanoprobes for Luminescent/Magnetic Dual-Mode Targeted Imaging. AB - Core-shell upconversion nanoparticle@metal-organic framework (UCNP@MOF) nanostructures are constructed by coating hexagonal NaYF4 :Yb,Er nanoparticle (NP) cores with amino-functionalized iron carboxylate MOF shells. These nanostructures combine the near-infrared optical property of the UCNP cores and the T2 -magnetic response (MR) imaging property of the MOF shells. After surface modification, the core-shell nanostructures are demonstrated as high-resolution nanoprobes for targeted luminescence/MR imaging both in vitro and in vivo. PMID- 26053934 TI - Ligand-Assisted Gold-Catalyzed Cross-Coupling with Aryldiazonium Salts: Redox Gold Catalysis without an External Oxidant. AB - Gold-catalyzed C(sp)-C(sp(2)) and C(sp(2))-C(sp(2)) cross-coupling reactions are accomplished with aryldiazonium salts as the coupling partner. With the assistance of bpy ligand, gold(I) species were oxidized to gold(III) by diazonium without any external oxidants. Monitoring the reaction with NMR and ESI-MS provided strong evidence for the nitrogen extrusion followed by Au(III) reductive elimination as the key step. PMID- 26053935 TI - Female genital cosmetic surgery: beyond a mechanistic view of sexual satisfaction. PMID- 26053936 TI - Drying of Durum Wheat Pasta and Enriched Pasta: A Review of Modeling Approaches. AB - Models on drying of durum wheat pasta and enriched pasta were reviewed to identify avenues for improvement according to consumer needs, product formulation and processing conditions. This review first summarized the fundamental phenomena of pasta drying, mass transfer, heat transfer, momentum, chemical changes, shrinkage and crack formation. The basic equations of the current models were then presented, along with methods for the estimation of pasta transport and thermodynamic properties. The experimental validation of these models was also presented and highlighted the need for further model validation for drying at high temperatures (>-100 degrees C) and for more accurate estimation of the pasta diffusion and mass transfer coefficients. This review indicates the need for the development of mechanistic models to improve our understanding of the mass and heat transfer mechanisms involved in pasta drying, and to consider the local changes in pasta transport properties and relaxation time for more accurate description of the moisture transport near glass transition conditions. The ability of current models to describe dried pasta quality according to the consumers expectations or to predict the impact of incorporating ingredients high in nutritional value on the drying of these enriched pasta was also discussed. PMID- 26053937 TI - NK cells expressing the B cell antigen CD19: Expanding the phenotypical characterization and the potential consequences from misinterpretation of this subset population. PMID- 26053938 TI - Look-back study on recipients of Parvovirus B19 (B19V) DNA-positive blood components. AB - BACKGROUND AND OBJECTIVES: To assess the relevance of Parvovirus B19 (B19V) DNA at low to intermediate concentrations in blood donors for the recipients of their blood components. MATERIAL AND METHODS: We studied recipients of B19V DNA positive blood components [red blood cell concentrates (RBCs), pooled platelet concentrates and fresh frozen plasma]. This included archived pretransfusion samples as well as follow-up samples investigated by ELISA or NAT and genome sequence analysis. RESULTS: In 132 out of 424 recipients, we could detect no anti B19V IgG before transfusion. In 67 out of 132 sero-negative recipients, a follow up sample was available. Sixty-five of these received blood components from donors with <10(4) IU B19V DNA/ml plasma and had no evidence of transfusion transmitted (TT)-B19V infection. Homology in genome sequences in donor and recipient provided evidence for a TT-B19V infection in two recipients. Both patients received RBC containing 3.4 * 10(6) and 1.8 * 10(4) IU B19V DNA/ml plasma, respectively. The anti-B19V IgG titres in the donors were 2 and 76 IU/ml plasma, respectively. The antibodies in the second donor were directed against capsid proteins and are thus considered as potential neutralizing antibodies. CONCLUSIONS: TT-B19V infections through blood components with low (<10(4) IU/ml plasma) B19V DNA concentrations did not occur in our study. One of the TT-B19V infections occurred from RBC with intermediate B19V DNA concentration despite the presence of potential neutralizing antibodies in the donor, but its clinical significance was low. PMID- 26053939 TI - The complete mitochondrial genome of banana shrimp Fenneropenaeus merguiensis with phylogenetic consideration. AB - The complete mitochondrial genome sequence of Fenneropenaeus merguiensis was determined by shotgun assembly method. The complete mitochondrial DNA sequence is a circular molecule with 16,023 bp in length including 13 protein-coding genes, 22 transfer RNA genes, 2 rRNA genes and a control region. The gene arrangements are consistent with the pan crustacean ground pattern. The molecular analyses provided robust evidence for the monophyly of Fenneropenaeus, but Litopenaeus was not monophyletic. Phylogenetic analyses robustly supported the fact that genus Penaeus s.l. contains the two lineages: Marsupenaeus and Penaeus s.s+ Fenneropenaeus + Litopenaeus + Farfantepenaeus. PMID- 26053940 TI - The complete chloroplast genome of Cinnamomum kanehirae Hayata (Lauraceae). AB - The complete chloroplast genome of Cinnamomum kanehirae (Hayata), the first to be completely sequenced of Lauraceae family, is presented in this study. The total genome size is 152,700 bp, with a typical circular structure including a pair of inverted repeats (IRa/b) of 20,107 bp of length separated by a large single-copy region (LSC) and a small single-copy region (SSC) of 93,642 bp and 18,844 bp of length, respectively. The overall GC content of the genome is 39.1%. The nucleotide sequence shows 91% identities with Liriodendron tulipifera in the Magnoliaceae. In total, 123 annotated genes consisted of 79 coding genes, eight rRNA genes, and 36 tRNA genes. Among all 79 coding genes, seven genes (rpoC1, atpF, rpl2, ndhB, ndhA, rps16, and rpl2) contain one intron, while two genes (ycf3 and clpP) contain two introns. The maximum likelihood phylogenetic analysis revealed that C. kanehirae chloroplast genome is closely related to Calycanthus fertilis within Laurales order. PMID- 26053941 TI - Serum serotonin reduced the expression of hepatic transporter Mrp2 and P-gp via regulating nuclear receptor CAR in PI-IBS rats. AB - Hepatic transporters and drug metabolizing enzymes (DMEs) play important roles in the pharmacological effects and (or) side-effects of many drugs, and are regulated by several mediators, including neurotransmitters. This work aimed to investigate whether serum levels of 5-hydroxytryptamine (5-HT) affected the expression of hepatic transporters or DMEs. The expression of hepatic transporters was assessed using the Western-blot technique in a 2,4,6 trinitrobenzenesulfonic-acid-induced rat model of post-infectious irritable bowel syndrome (PI-IBS), in which serum levels of 5-HT were significantly elevated. To further clarify the underlying mechanism, the 5-HT precursor 5-hydroxytryptophan (5-HTP) and the 5-HT depleting agent parachlorophenylalanine (pCPA) were applied to adjust serum levels of 5-HT. Serum levels of 5-HT were measured using LC MS/MS; the expression of hepatic transporters, DMEs, and nuclear receptors were examined by Western-blot technique. Our results showed that in PI-IBS rats the expression of multidrug resistance protein 2 (Mrp2) was significantly decreased, while colonic enterochromaffin cell density and serum levels of 5-HT were all significantly increased. Moreover, 5-HTP treatment significantly increased serum levels of 5-HT and decreased the expression of Mrp2 and glycoprotein P (P-gp), whereas treatment with pCPA markedly decreased serum levels of 5-HT and increased the expression of Mrp2 and P-gp. Our results indicated that serum 5-HT regulates the expression of Mrp2 and P-gp, and the underlying mechanism may be related to the altered expression of the nuclear receptor constitutive androstane receptor (CAR). PMID- 26053942 TI - Facile One-Step Synthesis of Three-Dimensional Pd-Ag Bimetallic Alloy Networks and Their Electrocatalytic Activity toward Ethanol Oxidation. AB - The three-dimensional palladium networks and palladium-silver bimetallic alloy networks were synthesized at room temperature on a large scale using a rapid and simple strategy. The results revealed that the morphology of the networks is not affected by the composition. We demonstrated that the as-prepared unsupported networks exhibited excellent electrochemical activity and stability toward ethanol oxidation reaction in alkaline media due to the formation of palladium silver alloys as well as the porous nanostructures. The results indicate that the well-defined three-dimensional palladium-silver bimetallic alloy networks are promising catalysts for fuel cells. PMID- 26053943 TI - Occupational Deprivation or Occupational Adaptation of Mexican Americans on Renal Dialysis. AB - The aim of this study was to explore the occupational changes and perceptions experienced by Mexican Americans with end-stage renal disease (ESRD) and their families living with dialysis. In-depth interviews were conducted with 17 Mexican Americans with ESRD and 17 family members. The participants with ESRD described altered or lost activity patterns, capacities and freedoms. With a heightened awareness of death, the family members made altered occupational choices, which were consistent with their cultural values. Changes in the physical body, adhering to the dialysis regimen and environmental restrictions created barriers to occupational participation. These findings suggest that living with dialysis facilitate occupational deprivation among individuals with ESRD and adaption among the family members within cultural alignments. This phenomenon could affect the design of occupational therapy intervention and call for research on the role of occupation therapy services with this population. PMID- 26053944 TI - Reply. PMID- 26053945 TI - Assessing key assumptions of network meta-analysis: a review of methods. AB - BACKGROUND: Homogeneity and consistency assumptions underlie network meta analysis (NMA). Methods exist to assess the assumptions but they are rarely and poorly applied. We review and illustrate methods to assess homogeneity and consistency. METHODS: Eligible articles focussed on indirect comparison or NMA methodology. Articles were sought by hand-searching and scanning references (March 2013). Assumption assessment methods described in the articles were reviewed, and applied to compare anti-malarial drugs. RESULTS: 116 articles were included. Methods to assess homogeneity were: comparing characteristics across trials; comparing trial-specific treatment effects; using hypothesis tests or statistical measures; applying fixed-effect and random-effects pair-wise meta analysis; and investigating treatment effect-modifiers. Methods to assess consistency were: comparing characteristics; investigating treatment effect modifiers; comparing outcome measurements in the referent group; node-splitting; inconsistency modelling; hypothesis tests; back transformation; multidimensional scaling; a two-stage approach; and a graph-theoretical method. For the malaria example, heterogeneity existed for some comparisons that was unexplained by investigating treatment effect-modifiers. Inconsistency was detected using node splitting and inconsistency modelling. It was unclear whether the covariates explained the inconsistency. CONCLUSIONS: Presently, we advocate applying existing assessment methods collectively to gain the best understanding possible regarding whether assumptions are reasonable. In our example, consistency was questionable; therefore the NMA results may be unreliable. PMID- 26053946 TI - A standardized mean difference effect size for multiple baseline designs across individuals. AB - Single-case designs are a class of research methods for evaluating treatment effects by measuring outcomes repeatedly over time while systematically introducing different condition (e.g., treatment and control) to the same individual. The designs are used across fields such as behavior analysis, clinical psychology, special education, and medicine. Emerging standards for single-case designs have focused attention on methods for summarizing and meta analyzing findings and on the need for effect sizes indices that are comparable to those used in between-subjects designs. In the previous work, we discussed how to define and estimate an effect size that is directly comparable to the standardized mean difference often used in between-subjects research based on the data from a particular type of single-case design, the treatment reversal or (AB)(k) design. This paper extends the effect size measure to another type of single-case study, the multiple baseline design. We propose estimation methods for the effect size and its variance, study the estimators using simulation, and demonstrate the approach in two applications. PMID- 26053947 TI - Methodological quality of meta-analyses: matched-pairs comparison over time and between industry-sponsored and academic-sponsored reports. AB - CONTEXT: Meta-analyses are regularly used to inform healthcare decisions. Concerns have been expressed about the quality of meta-analyses and, in particular, about those supported by the pharmaceutical industry. OBJECTIVE: The objective of this study is to compare the quality of pharmaceutical-industry supported meta-analyses with academic meta-analyses and of meta-analyses published before and after companies started to disclose their data. DATA SOURCES: We identified industry-supported meta-analyses by searching the Scopus bibliographic database, using author affiliations. We matched each industry supported meta-analysis with an academic meta-analysis using high-level MeSH terms in PubMed. STUDY SELECTION: We included meta-analyses of randomized trials assessing the efficacy or safety of any pharmaceutical intervention in humans, published in 2002-2004 or 2008-2009. Cochrane reviews were excluded. Two individuals independently selected papers, with discrepancies resolved by two further individuals. ASSESSMENT: We developed and piloted a quality-assessment tool, consisting of 43 questions in four domains, with a key summary question covering each domain. Two individuals independently assessed each meta-analysis. RESULTS: We examined 126 meta-analysis publications in 63 matched pairs. The average quality was low, with fewer than 50% adequate in three of the four domains. Industry-supported meta-analyses less often demonstrated adequate methods for locating studies and assessing their quality (odds ratio 0.44, 95% confidence interval 0.21 to 0.92), for analysing the included studies (0.52, 0.25 to 1.06), for undertaking meta-analyses (0.82, 0.40 to 1.68) and in reaching sound conclusions (0.62, 0.30 to 1.28). Quality generally improved over time, particularly for some aspects of industry reports. CONCLUSIONS: Academic meta analysis papers are generally of higher quality than industry-supported ones. This is largely due to less detailed reporting in industry-supported meta analyses and a tendency for them to take the included studies at face value, probably arising from the implicit assumption that these studies already have high methodological standards to meet licensing requirements. The improved quality over time does not appear to be due to the use of data disclosed by industry. The main limitations of this study are the small sample of papers and the subjective nature of some of the assessment processes. PMID- 26053948 TI - A tool to assess the quality of a meta-analysis. AB - BACKGROUND: Because meta-analyses are increasingly prevalent and cited in the medical literature, it is important that tools are available to assess their methodological quality. When performing an empirical study of the quality of published meta-analyses, we found that existing tools did not place a strong emphasis on statistical and interpretational issues. METHODS: We developed a quality-assessment tool using existing materials and expert judgment as a starting point, followed by multiple iterations of input from our working group, piloting, and discussion. After having used the tool for our empirical study, agreement for four key items in the tool was measured using weighted kappa coefficients. RESULTS: Our tool contained 43 items divided into four key areas (data sources, analysis of individual studies, meta-analysis methods, and interpretation), and each area ended with a summary question. We also produced guidance for completing the tool. Agreement between raters was fair to moderate. CONCLUSIONS: The tool should usefully inform subsequent initiatives to develop quality-assessment tools for meta-analysis. We advocate use of consensus between independent raters when assessing statistical appropriateness and adequacy of interpretation in meta-analyses. PMID- 26053950 TI - Physiological measurements corroborate symptomatic improvement after therapeutic leukapheresis in a pregnant woman with chronic myelogenous leukemia. AB - Therapeutic leukapheresis can control the white blood cell count (WBC) of pregnant women with chronic myelogenous leukemia (CML) who have hyperleukocytosis without leukostasis. The medical justification for this treatment has not been objectively documented. We report a 27-year-old woman, diagnosed with CML at 10 week gestation, who developed severe dyspnea on exertion. A workup that included chest CT and echocardiography with a bubble study detected no cardiopulmonary pathology to explain her symptoms, and thus she was referred for leukapheresis. Prior to her first leukapheresis, which lowered her WBC from 154 * 10(3) /MUL to 133 * 10(3) /MUL, her oxygen saturation (SpO2 ) on room air decreased from 98 to 93% during 100 feet of slow ambulation and she was dyspneic. Just after the leukapheresis, her dyspnea on exertion was much improved and her SpO2 remained at 98% with repeat ambulation. Spirometry and lung volume studies obtained before and after her first leukapheresis demonstrated 32 and 31% improvements in forced vital capacity and forced expiratory volume in 1 s respectively, a 25% increase in functional residual capacity, and a 142% improvement in expiratory reserve volume. Residual volume decreased by almost 20%. Three times in a week, leukapheresis was continued until her WBC was controlled with interferon alpha-2b approximately 4 weeks later. Her dyspnea had completely resolved. She gave birth by elective caesarean section to a healthy boy at 32 weeks. Corroboration of symptom relief by leukapheresis with physiological data may justify such treatment in pregnant patients with CML. J. Clin. Apheresis 31:393-397, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26053951 TI - Clinical Analysis of the HBV Infection Status of 135 Patients with Diffuse Large B Cell Lymphoma Treated with R-CHOP or CHOP/CHOP-Like Chemotherapy. AB - OBJECTIVES: This study aimed to determine the HBV infection status of 135 patients with DLBCL (diffuse large B cell lymphoma), to analyze the overall survival (OS) and progression-free survival (PFS) of the different HBV infection status groups, and to discuss the relationship between HBV serological test results and the prognosis of DLBCL patients. METHODS: A retrospective analysis was performed of the clinical data, HBV serological test results, and PFS/OS of 135 DLBCL patients who were initially diagnosed and treated with more than 3 cycles of an R-CHOP/CHOP/CHOP-like regimen at our center from January 1, 2008 to December 31, 2012. RESULTS: The patients in the HBV infection group were older at disease onset (>=60 years old) and were more likely to present with stage 3-4 disease compared with the HBV-free group (P = 0.030 and P = 0.025, respectively). Approximately 50% of the patients with an active HBV infection required a reduction in the chemotherapy dose, and 66.7% of the patients in this group received more than 1 line of therapy; these rates were significantly higher than those in the no infection group (P = 0.003 and P = 0.011, respectively). Although HBV infection had no obvious influence on the outcome of first-line therapy, patients with an inactive infection had a higher relapse/progression rate within 3 months after a CR/PR than patients with an active infection (14/20 vs. 1/12, P = 0.001). The PFS at 1 year, 3 years and OS rates at 1 year, 3 years were significantly lower in the active HBV infection group than in the HBV-free group (P = 0.008, P = 0.002, P = 0.004, and P = 0.002, respectively). The PFS rates at 1 year and 3 year in HBV-free group were higher than those in the HBV infection group (80.5% and 52.9% P = 0.001, 78.1% and 44.4% P = 0.002). The lymphoma related mortality rates were 2.7% in the no infection group, 19.2% in the HBV infection group (P = 0.004), and 28.6% in the active HBV infection group (P = 0.001). Among the patients treated with MabThera, the PFS in the HBV infection group was 11 months in the HBV infection group and 67 months in the infection free group (P = 0.000). A Cox regression model of PFS revealed that age >=60 years and HBV infection were independent prognostic factors (age: P = 0.019, HR = 2.002, 95% CI 1.123-3.567; HBV infection: P = 0.026, HR = 0.494, 95% CI 0.265 0.919). CONCLUSION: Compared with the patients in HBV-free group, those in the HBV infection group were older at disease onset, and the active infection patients presented with more advanced disease and had a lower PFS at 1, 3 years as well as a lower OS at 3 years. The patients in the inactive infection group had a higher progression/relapse rate within 3 months after a CR/PR than those in the active infection group. HBV infection was an unfavorable factor for PFS in the MabThera group. An age >=60 years and HBV infection were independent unfavorable prognostic factors for PFS. PMID- 26053952 TI - Projected changes in erythemal and vitamin D effective irradiance over northern hemisphere high latitudes. AB - Simulations of the monthly mean noon UV index and the effective dose for the production of vitamin D in the human skin have been performed for local noon for the latitude band 55 degrees N-85 degrees N using a radiative transfer model. The magnitude and spatial distribution of the changes estimated for the two quantities between the past (1955-1965 mean), the present (2010-2020 mean) and the future (2085-2095 mean) are discussed and the main drivers for these changes are identified. The irradiance simulations are based on simulations and projections of total ozone, surface reflectivity and aerosol optical depth derived from models used in the fifth phase of the Coupled Model Intercomparison Project (CMIP-5). The cloud modification factor is also derived from the CMIP-5 models and used to account for the effects of cloudiness. Simulations have been derived for two socioeconomic scenarios: the moderate RCP 4.5 and the extreme RCP 8.5. For the future, the two quantities are projected to be generally lower than in the past and the present, mainly due to the projected super-recovery of stratospheric ozone and reduced surface reflectivity. Although the greatest changes are projected over the Arctic Ocean and do not directly affect humans, the changes over land are also important. Over land, the greatest changes are found in northern Asia, Greenland and the north-east shores of Canada and Alaska. The greatest reductions over land are projected for April under all skies, locally reaching ~30% for the noon UV index and ~50% for the noon effective UV dose for the production of vitamin D. PMID- 26053954 TI - Early presentation of symptomatic individuals is critical in controlling sexually transmissible infections. AB - Two papers in this issue by Williams et al. and Scott et al. describe the sexual risks and health-seeking behaviour of young Indigenous Australians. Their sexual risks and health-seeking behaviours are similar to the general Australian population, yet their risk of past sexually transmissible infections (STIs) is higher. These findings are consistent with previous findings and suggest that access to health care, and not sexual risk, remain critical to STI control in remote Indigenous communities. PMID- 26053953 TI - The Efficacy and Clinical Safety of Various Analgesic Combinations for Post Operative Pain after Third Molar Surgery: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: To run a systematic review and meta-analysis of randomized clinical trials aiming to answer the clinical question "which analgesic combination and dosage is potentially the most effective and safe for acute post-operative pain control after third molar surgery?". MATERIALS AND METHODS: A systematic search of computer databases and journals was performed. The search and the evaluations of articles were performed by 2 independent reviewers in 3 rounds. Randomized clinical trials related to analgesic combinations for acute post-operative pain control after lower third molar surgery that matched the selection criteria were evaluated to enter in the final review. RESULTS: Fourteen studies with 3521 subjects, with 10 groups (17 dosages) of analgesic combinations were included in the final review. The analgesic efficacy were presented by the objective pain measurements including sum of pain intensity at 6 hours (SPID6) and total pain relief at 6 hours (TOTPAR6). The SPID6 scores and TOTPAR6 scores of the reported analgesic combinations were ranged from 1.46 to 6.44 and 3.24 - 10.3, respectively. Ibuprofen 400mg with oxycodone HCL 5mg had superior efficacy (SPID6: 6.44, TOTPAR6: 9.31). Nausea was the most common adverse effect, with prevalence ranging from 0-55%. Ibuprofen 200mg with caffeine 100mg or 200mg had a reasonable analgesic effect with fewer side effects. CONCLUSION: This systematic review and meta-analysis may help clinicians in their choices of prescribing an analgesic combination for acute post-operative pain control after lower third molar surgery. It was found in this systematic review Ibuprofen 400mg combined with oxycodone HCL 5mg has superior analgesic efficacy when compared to the other analgesic combinations included in this study. PMID- 26053955 TI - Viability and neuronal differentiation of neural stem cells encapsulated in silk fibroin hydrogel functionalized with an IKVAV peptide. AB - Three-dimensional (3D) porous scaffolds combined with therapeutic stem cells play vital roles in tissue engineering. The adult brain has very limited regeneration ability after injuries such as trauma and stroke. In this study, injectable 3D silk fibroin-based hydrogel scaffolds with encapsulated neural stem cells were developed, aiming at supporting brain regeneration. To improve the function of the hydrogel towards neural stem cells, silk fibroin was modified by an IKVAV peptide through covalent binding. Both unmodified and modified silk fibroin hydrogels were obtained, through sonication, with mechanical stiffness comparable to that of brain tissue. Human neural stem cells were encapsulated in both hydrogels and the effects of IKVAV peptide conjugation on cell viability and neural differentiation were assessed. The silk fibroin hydrogel modified by IKVAV peptide showed increased cell viability and an enhanced neuronal differentiation capability, which contributed to understanding the effects of IKVAV peptide on the behaviour of neural stem cells. For these reasons, IKVAV-modified silk fibroin is a promising material for brain tissue engineering. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26053956 TI - Use of Preoperative Testing and Physicians' Response to Professional Society Guidance. AB - IMPORTANCE: The value of routine preoperative testing before most surgical procedures is widely considered to be low. To improve the quality of preoperative care and reduce waste, 2 professional societies released guidance on use of routine preoperative testing in 2002, but researchers and policymakers remain concerned about the health and cost burden of low-value care in the preoperative setting. OBJECTIVE: To examine the long-term national effect of the 2002 professional guidance from the American College of Cardiology/American Heart Association and the American Society of Anesthesiologists on physicians' use of routine preoperative testing. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of nationally representative data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey to examine adults in the United States who were evaluated during preoperative visits from January 1, 1997, through December 31, 2010. A quasiexperimental, difference-in difference (DID) approach evaluated whether the publication of professional guidance in 2002 was associated with changes in preoperative testing patterns, adjusting for temporal trends in routine testing, as captured by testing patterns in general medical examinations. MAIN OUTCOMES AND MEASURES: Physician orders for outpatient plain radiography, hematocrit, urinalysis, electrocardiogram, and cardiac stress testing. RESULTS: During the 14-year period, the average annual number of preoperative visits in the United States increased from 6.8 million in 1997-1999 to 9.8 million in 2002-2004 and 14.3 million in 2008-2010. After accounting for temporal trends in routine testing, we found no statistically significant overall changes in the use of plain radiography (11.3% in 1997-2002 to 9.9% in 2003-2010; DID, -1.0 per 100 visits; 95% CI, -4.1 to 2.2), hematocrit (9.4% in 1997-2002 to 4.1% in 2003-2010; DID, 1.2 per 100 visits; 95% CI, -2.2 to 4.7), urinalysis (12.2% in 1997-2002 to 8.9% in 2003-2010; DID, 2.7 per 100 visits; 95% CI, -1.7 to 7.1), or cardiac stress testing (1.0% in 1997-2002 to 2.0% in 2003-2010; DID, 0.7 per 100 visits; 95% CI, -0.1 to 1.5) after the publication of professional guidance. However, the rate of electrocardiogram testing fell (19.4% in 1997-2002 to 14.3% in 2003-2010; DID, -6.7 per 100 visits; 95% CI, -10.6 to -2.7) in the period after the publication of guidance. CONCLUSIONS AND RELEVANCE: The release of the 2002 guidance on routine preoperative testing was associated with a reduced incidence of routine electrocardiogram testing but not of plain radiography, hematocrit, urinalysis, or cardiac stress testing. Because routine preoperative testing is generally considered to provide low incremental value, more concerted efforts to understand physician behavior and remove barriers to guideline adherence may improve health care quality and reduce costs. PMID- 26053957 TI - Physical supports from liver cancer cells are essential for differentiation and remodeling of endothelial cells in a HepG2-HUVEC co-culture model. AB - Blood vessel remodeling is crucial in tumor growth. Growth factors released by tumor cells and endothelium-extracellular matrix interactions are highlighted in tumor angiogenesis, however the physical tumor-endothelium interactions are highly neglected. Here, we report that the physical supports from hepatocellular carcinoma, HepG2 cells, are essential for the differentiation and remodeling of endothelial cells. In a HepG2-HUVEC co-culture model, endothelial cells in direct contact with HepG2 cells could differentiate and form tubular structures similar to those plated on matrigel. By employing HepG2 cell sheet as a supportive layer, endothelial cells formed protrusions and sprouts above it. In separate experiments, fixed HepG2 cells could stimulate endothelial cells differentiation while the conditioned media could not, indicating that physical interactions between tumor and endothelial cells were indispensable. To further investigate the endothelium-remodeling mechanisms, the co-culture model was treated with inhibitors targeting different angiogenic signaling pathways. Inhibitors targeting focal adhesions effectively inhibited the differentiation of endothelial cells, while the growth factor receptor inhibitor displayed little effect. In conclusion, the co-culture model has provided evidences of the essential role of cancer cells in the differentiation and remodeling of endothelial cells, and is a potential platform for the discovery of new anti angiogenic agents for liver cancer therapy. PMID- 26053958 TI - Intervention study for smoking cessation in Spanish college students: pragmatic randomized controlled trial. AB - AIM: To evaluate the effectiveness of a nurse intervention aimed at helping college student smokers quit smoking. DESIGN: Single-blind, pragmatic randomized controlled trial which compares a multi-component intervention, tailored specifically to college students, with a brief advice session with a 6-month follow-up. SETTINGS: This study was conducted at the University of Navarra, Spain. PARTICIPANTS: A total of 255 college student smokers (age range = 18-24 years) were randomized to an intervention group (n = 133) or to a control group (n = 122). INTERVENTION: A multi-component intervention based on the Theory of Triadic Influence of Flay was developed. The intervention consisted of a 50 minute motivational interview conducted by a nurse and online self-help material. The follow-up included a reinforcing e-mail and group therapy. MEASUREMENTS: The primary outcome was self-reported abstinence, with biochemical verification at 6 months. The secondary outcomes consisted of the mean number of cigarettes smoked per day, self-reported attempts to quit smoking and stage of change at 6 months. FINDINGS: At the 6-month follow-up, the smoking cessation incidence was 21.1% in the intervention group compared with 6.6% in the control group (difference = 14.5 confidence interval = 6.1-22.8; relative risk = 3.41, 95% confidence interval = 1.62-7.20). The difference in the mean number of cigarettes at 6 months was significantly different (difference = -2.2, confidence interval = -3.6 to -0.9). CONCLUSIONS: A multi-component intervention tailored to college students and managed by a nurse is effective in increasing smoking cessation among college students. PMID- 26053959 TI - Comparison of chemotherapeutic agents as a myeloablative conditioning with total body irradiation for pediatric acute lymphoblastic leukemia: A study from the pediatric ALL working group of the Japan Society for Hematopoietic Cell Transplantation. AB - BACKGROUND: As a partner of total body irradiation (TBI) in hematopoietic stem cell transplantation (HSCT) for pediatric acute lymphoblastic leukemia (ALL), various cytotoxic agents are used, but the optimal combination is still unclear. PROCEDURE: We retrospectively analyzed 767 children who received TBI-based myeloablative allogeneic HSCT in complete remission (CR), using nationwide registry data of the Japan Society for Hematopoietic Cell Transplantation. Combinations of chemotherapy were categorized as follows: cyclophosphamide (CY) (n = 74), melphalan (L-PAM) (n = 139), CY + etoposide (VP16) (n = 408), CY + cytarabine (AraC) (n = 73), and others (n = 73). RESULTS: Event-free survival (EFS) at 5 years after HSCT was 62.2% for CY, 71.4% for L-PAM, 67.6% for CY + VP16, 52.6% for CY + AraC, and 59.1% for others (P = 0.009). Further detailed comparison of LPAM and CY + VP16 demonstrated superior EFS for LPAM (83.2 +/- 6.7%), with a marked difference compared with CY + VP16 (66.7 +/- 4.9%) when limited to HSCT from a matched related donor (MRD), and this result was reproduced regardless of disease status (CR1 or CR2). However, EFS for CY + VP16 (68.3 +/- 2.8%) was comparable to that for LPAM (64.5 +/- 5.7%, P = 0.37) in HSCT from alternative donors, because higher non-relapse mortality attenuated the advantage of LPAM. CONCLUSIONS: For pediatric ALL in remission, LPAM could provide superior EFS for HSCT from MRD; however, compared to LPAM, CY + VP16 has similar EFS for HSCT from an alternative donor. PMID- 26053960 TI - Focusing on Plates: Controlling Guided Waves using Negative Refraction. AB - Elastic waves are guided along finite structures such as cylinders, plates, or rods through reflection, refraction, and mode conversion at the interfaces. Such wave propagation is ubiquitous in the world around us, and studies of elastic waveguides first emerged in the later part of the 19(th) century. Early work on elastic waveguides revealed the presence of backward propagating waves, in which the phase velocity and group velocity are anti-parallel. While backward wave propagation exists naturally in very simple finite elastic media, there has been remarkably little attention paid to this phenomenon. Here we report the development of a tunable acoustic lens in an isotropic elastic plate showing negative refraction over a finite acoustic frequency bandwidth. As compared to engineered acoustic materials such as phononic crystals and metamaterials, the design of the acoustic lens is very simple, with negative refraction obtained through thickness changes rather than internal periodicity or sub-wavelength resonant structures. A new class of acoustic devices, including resonators, filters, lenses, and cloaks, may be possible through topography optimization of elastic waveguide structures to exploit the unique properties of backward waves. PMID- 26053961 TI - Comparative Secretome Analysis of Trichoderma reesei and Aspergillus niger during Growth on Sugarcane Biomass. AB - BACKGROUND: Our dependence on fossil fuel sources and concern about the environment has generated a worldwide interest in establishing new sources of fuel and energy. Thus, the use of ethanol as a fuel is advantageous because it is an inexhaustible energy source and has minimal environmental impact. Currently, Brazil is the world's second largest producer of ethanol, which is produced from sugarcane juice fermentation. However, several studies suggest that Brazil could double its production per hectare by using sugarcane bagasse and straw, known as second-generation (2G) bioethanol. Nevertheless, the use of this biomass presents a challenge because the plant cell wall structure, which is composed of complex sugars (cellulose and hemicelluloses), must be broken down into fermentable sugar, such as glucose and xylose. To achieve this goal, several types of hydrolytic enzymes are necessary, and these enzymes represent the majority of the cost associated with 2G bioethanol processing. Reducing the cost of the saccharification process can be achieved via a comprehensive understanding of the hydrolytic mechanisms and enzyme secretion of polysaccharide-hydrolyzing microorganisms. In many natural habitats, several microorganisms degrade lignocellulosic biomass through a set of enzymes that act synergistically. In this study, two fungal species, Aspergillus niger and Trichoderma reesei, were grown on sugarcane biomass with two levels of cell wall complexity, culm in natura and pretreated bagasse. The production of enzymes related to biomass degradation was monitored using secretome analyses after 6, 12 and 24 hours. Concurrently, we analyzed the sugars in the supernatant. RESULTS: Analyzing the concentration of monosaccharides in the supernatant, we observed that both species are able to disassemble the polysaccharides of sugarcane cell walls since 6 hours post-inoculation. The sugars from the polysaccharides such as arabinoxylan and beta-glucan (that compose the most external part of the cell wall in sugarcane) are likely the first to be released and assimilated by both species of fungi. At all time points tested, A. niger produced more enzymes (quantitatively and qualitatively) than T. reesei. However, the most important enzymes related to biomass degradation, including cellobiohydrolases, endoglucanases, beta-glucosidases, beta-xylosidases, endoxylanases, xyloglucanases, and alpha-arabinofuranosidases, were identified in both secretomes. We also noticed that the both fungi produce more enzymes when grown in culm as a single carbon source. CONCLUSION: Our work provides a detailed qualitative and semi-quantitative secretome analysis of A. niger and T. reesei grown on sugarcane biomass. Our data indicate that a combination of enzymes from both fungi is an interesting option to increase saccharification efficiency. In other words, these two fungal species might be combined for their usage in industrial processes. PMID- 26053962 TI - Evaluation of CYP3A-mediated drug-drug interactions with romidepsin in patients with advanced cancer. AB - Two multicenter, single-arm, single-infusion, open-label studies were conducted to evaluate the effect of ketoconazole (a strong CYP3A inhibitor) or rifampin (a strong CYP3A inducer) daily for 5 days on the pharmacokinetics (PK) and safety of romidepsin (8 mg/m(2) intravenous 4-hour infusion for the ketoconazole study or a 14 mg/m(2) intravenous 4-hour infusion for the rifampin study) in patients with advanced cancer. Romidepsin coadministered with ketoconazole (400 mg) or rifampin (600 mg) was not bioequivalent to romidepsin alone. With ketoconazole, the mean romidepsin AUC and Cmax were increased by approximately 25% and 10%, respectively. With rifampin, the mean romidepsin AUC and Cmax were unexpectedly increased by approximately 80% and 60%, respectively; this is likely because of inhibition of active liver uptake. For both studies, romidepsin clearance and volume of distribution were decreased, terminal half-life was comparable, and median Tmax was similar. Overall, the safety profile of romidepsin was not altered by coadministration with ketoconazole or rifampin, except that a higher incidence and greater severity of thrombocytopenia was observed when romidepsin was given with rifampin. The use of romidepsin with rifampin and strong CYP3A inducers should be avoided. Toxicity related to romidepsin exposure should be monitored when romidepsin is given with strong CYP3A inhibitors. PMID- 26053963 TI - Treatment of a cerebral pial arteriovenous fistula in a patient with sickle cell disease-related moyamoya syndrome: case report. AB - Sickle cell disease (SCD) is an autosomal recessive hematological disorder, characterized by sickling of the red blood cells in response to a hypoxic stress and vaso-occlusive crises. It is associated with moyamoya-like changes on cerebral angiographic imaging in 43% of patients. Cerebral aneurysms, arteriovenous malformations, and dural arteriovenous fistulas (AVFs) have been described in association with SCD and moyamoya disease. However, the description of a pial AVF (pAVF) in a patient with SCD and/or moyamoya formation has not yet been reported. The authors present the case of a 15-year-old boy with SCD associated moyamoya disease harboring a pAVF who developed a de novo venous aneurysm 8 months after undergoing indirect superficial temporal artery-middle cerebral artery (MCA) bypass that was complicated by bilateral ischemia of the MCA territory. The pAVF was successfully treated with transarterial embolization using Onyx. The authors describe the possible pathophysiological mechanisms and management strategies for this rare occurrence. PMID- 26053965 TI - Microfluidic pumping, routing and metering by contactless metal-based electro osmosis. AB - Over the past decade, many microfluidic platforms for fluid processing have been developed in order to perform on-chip fluidic manipulations. Many of these methods, however, require expensive and bulky external supporting equipment, which are not typically applicable for microsystems requiring portability. We have developed a new type of portable contactless metal electro-osmotic micropump capable of on-chip fluid pumping, routing and metering. The pump operates using two pairs of gallium metal electrodes, which are activated using an external voltage source, and separated from a main flow channel by a thin micron-scale PDMS membrane. The thin contactless membrane allows for field penetration and electro-osmotic (EO) flow within the microchannel, but eliminates electrode damage and sample contamination commonly associated with traditional DC electro osmotic pumps that utilize electrodes in direct contact with the working fluid. The maximum flow rates and pressures generated by the pump using DI water as a working buffer are 10 nL min(-1) and 30 Pa, respectively. With our current design, the maximum operational conductivity where fluid flow is observed is 0.1 mS cm(-1). Due to the small size and simple fabrication procedure, multiple micropump units can be integrated into a single microfluidic device for automated on-chip routing and sample metering applications. We experimentally demonstrated the ability to quantify micropump electro-osmotic flowrate and pressure as a function of applied voltage, and developed a mathematical model capable of predicting the performance of a contactless micropump for a given external load and internal hydrodynamic microchannel resistance. Finally, we showed that by activating specific pumps within a microchannel network, our micropumps are capable of routing microchannel fluid flow and generating plugs of solute. PMID- 26053964 TI - Rapamycin inhibition of eosinophil differentiation attenuates allergic airway inflammation in mice. AB - BACKGROUND AND OBJECTIVE: The mammalian target of rapamycin (mTOR) signalling pathway regulates immune responses, and promotes cell growth and differentiation. Inhibition of mTOR with rapamycin modulates allergic asthma, while the underlying molecular mechanisms remain elusive. Here, we demonstrate that rapamycin, effectively inhibits eosinophil differentiation, contributing to its overall protective role in allergic airway inflammation. METHODS: Rapamycin was administered in a mouse model of ovalbumin-induced allergic airway inflammation, and the eosinophil differentiation was analysed in vivo and in vitro. RESULTS: Rapamycin significantly attenuated allergic airway inflammation and markedly decreased the amount of eosinophils in local airways, peripheral blood and bone marrow, independently of levels of interleukin-5 (IL-5). In vitro colony forming unit assay and liquid culture demonstrated that rapamycin directly inhibited IL-5 induced eosinophil differentiation. In addition, rapamycin reduced the production of IL-6 and IL-13 by eosinophils. Rapamycin was also capable of reducing the eosinophil levels in IL-5 transgenic NJ.1638 mice, again regardless of the constitutive high levels of IL-5. Interestingly, rapamycin inhibition of eosinophil differentiation in turn resulted in an accumulation of eosinophil lineage-committed progenitors in bone marrow. CONCLUSIONS: Altogether these results clearly demonstrate a direct inhibitory role of rapamycin in eosinophil differentiation and function, and reemphasize the importance of rapamycin and possibly, mTOR, in allergic airway disease. PMID- 26053966 TI - Just Noticeable Differences and Weber Fraction of Oral Thickness Perception of Model Beverages. AB - Rheological properties of beverages contribute considerably to texture perception. When developing new beverages, it is important to have knowledge on the smallest differences of viscosity which a consumer can discriminate. Thickness is the sensory attribute most commonly used to describe the viscosity of beverages. The aim of this study was to determine the Just Noticeable Differences (JNDs) of oral thickness perception and the Weber fraction (K) of Newtonian model stimuli (maltodextrin solutions). JNDs were determined using the method of constant stimuli with 5 reference stimuli ranging in viscosity from 10 to 100 mPa?s. JNDs increased with increasing viscosity of the reference stimulus. The Weber fraction (K) for oral thickness perception of model beverages was K = 0.26 for the studied viscosity range. The Weber fraction for oral thickness perception is comparable to Weber fractions reported in literature for perception of kinesthetic food firmness and spreadability, creaminess, sourness, and bitterness perception. This demonstrates that the human sensitivity towards oral discrimination of thickness of liquid stimuli is comparable to the human sensitivity towards discrimination of specific texture properties and specific taste stimuli. PRACTICAL APPLICATION: Changes in the viscosity of beverages can cause changes in thickness perception. The changes in thickness perception can be accompanied by differences in other sensory properties such as sweetness and creaminess which might be undesirable when reformulating beverages or developing new products. Knowledge on the differences by which viscosity of beverages can be modified to create a difference in sensory perception is currently lacking. This study quantified the Just Noticeable Difference (the minimal difference that can be detected between 2 stimuli) for thickness perception of beverages. This knowledge helps food industry to reformulate beverages while maintaining sensory properties. PMID- 26053967 TI - Borrelia miyamotoi: The Newest Infection Brought to Us by Deer Ticks. PMID- 26053968 TI - Micronutrient deficiencies in normal and overweight infants in a low socio economic population in north-east Brazil. AB - BACKGROUND: Micronutrient deficiencies are the most prevalent form of malnutrition worldwide. Although commonly related to underweight, micronutrient deficiencies can occur in both normal and overweight children in medium- and low income populations undergoing nutritional transition. OBJECTIVE: To describe haemoglobin and micronutrient levels in infants from a low-income area in Brazil in relation to their weight-for-length Z-score. METHODS: A cross-sectional survey was undertaken of 2-11-month-old infants in Laranjeiras, a small urban community in North-east-Brazil between April 2009 and February 2010. Anthropometry and assays for haemoglobin, ferritin, plasma zinc, copper and selenium and erythrocyte zinc and copper concentrations were investigated. RESULTS: The total number of full-term infants born in the study period was 222, of whom 153 were available for the study. Three (2%) children were wasted, 98 (66%) were of normal weight, 37 (25%) were at risk of overweight and 11 (7%) were overweight or obese. Nearly all (97%) children had at least one micronutrient deficiency, 102 (67%) had anaemia, 86 (58%) and 100 (67%) had plasma and erythrocyte zinc deficiency, respectively, and 7 (5%) and 113 (76%) had plasma and erythrocyte copper deficiency, respectively. 138 (91%) children had selenium deficiency. Except for plasma zinc, the proportion of infants with micronutrient deficiencies did not differ by weight-for-length status. CONCLUSIONS: The increased risk of overweight and micronutrient deficiencies in this population highlights the need to address the double burden of excess weight with micronutrient deficiencies in medium- and low-income settings. PMID- 26053969 TI - Stepwise assembly of a cross-linked free-standing nanoparticle sheet with controllable shape. AB - In this paper, we report a free-standing thin lamella consisting of nanoparticles with controllable shape. A self-assembly technique is utilized to obtain this sheet in a step by step fashion with nanoparticles and polymer single crystals as the basic building blocks. Inside the thin lamella, nanoparticles are not only immobilized on the surface of a polymer single crystal, which functions as a template, but also interconnected by a bifunctional crosslinker, i.e. 1,6-hexane dithiol. As a consequence, the nanoparticle lamella is crosslinked and cannot be destructed by solvent and heat treatment. This fabrication strategy is generally applicable and can be applied to a variety of different nanoparticles with various properties, including catalytically active platinum nanoparticles, superparamagnetic iron oxide nanoparticles or luminescent quantum dots, and different types of polymer single crystals, such as hexagonal polycaprolactone and square-shaped polyethylene glycol ones. Based on the abundant properties originating from both nanoparticles and polymer single crystals, we have demonstrated that the resulting ensemble can function as recyclable catalytically active materials or magnetically responsive luminescent materials. PMID- 26053970 TI - Doxycycline-induced hypoglycaemia. AB - Tetracyclines, including doxycycline, are widely used drugs that form an integral part of daily prescribing, and serious adverse reactions (SARs) are rarely reported. The frequency of hypoglycaemia complicating tetracycline treatment remains unknown, and is not a recognized complication. We describe an 80-year-old man with a history of insulin-dependent diabetes who was recruited into a large research study, and subsequently experienced the unexpected SAR of hypoglycaemia following treatment with doxycycline. PMID- 26053971 TI - Experimental approaches to vascularisation within tissue engineering constructs. AB - Tissue engineering opens up a new area to restore the function of damaged tissue or replace a defective organ. Common strategies in tissue engineering to repair and form new tissue containing a functional vascular network include the use of cells, growth factors, extracellular matrix proteins, and biophysical stimuli. Yet, formation of well-distributed, interconnected, and stable vascular network still remains challenging. In addition, anastomoses with host vasculature upon implantation and long-time survival of the new blood vessel in vivo are other critical issues to be addressed. This paper presents a brief review of recent advances in vascularization in vitro as well as in vivo for tissue engineering, along with suggestions for future research. PMID- 26053972 TI - Exogenous Sodium Pyruvate Stimulates Adipogenesis of 3T3-L1 Cells. AB - We investigated the effects of exogenous sodium pyruvate (SP) on adipocyte differentiation, lipid accumulation, and the mRNA expression levels of adipogenesis-related genes in 3T3-L1 pre-adipocytes. Differentiation of pre adipocytes was induced by MDI (3-isobutyl-1-methylxanthine: IBMX, dexamethasone: DEX, and insulin), in the presence or absence of SP. Adipogenesis was stimulated by SP in a concentration-dependent manner. SP also induced the expression of genes encoding aP2, GLUT4, and adiponectin, but had no effect on cell proliferation. Exogenous glucose did not promote adipogenesis or lipid accumulation. 2-deoxy-D-glucose inhibited adipogenesis initiated by MDI, but failed to influence the effects of SP on adipogenesis, whereas 3-bromopyruvate inhibited adipogenesis regardless of whether SP was present. The pro-adipogenic properties of SP were limited to the early events of adipogenesis. To determine whether SP mimics the adipogenic action of dexamethasone or insulin, we examined the effects of SP on adipogenesis with combinations of IBMX, DEX, and insulin. SP did not improve incomplete lipid accumulation observed in cells grown under IBMX , DEX-, or insulin-free conditions. Insulin-stimulated ERK1/2 phosphorylation was diminished by SP, while phosphorylation of Akt was increased, correlating with increased glucose uptake in response to insulin. We also observed that SP stimulated immediate early expression of C/EBPbeta and C/EBPdelta. The PPARgamma antagonist GW9662 inhibited adipogenesis. Our findings highlight the adipogenic function of exogenous SP by stimulating early events of adipogenesis. PMID- 26053973 TI - Experimental quantum annealing: case study involving the graph isomorphism problem. AB - Quantum annealing is a proposed combinatorial optimization technique meant to exploit quantum mechanical effects such as tunneling and entanglement. Real-world quantum annealing-based solvers require a combination of annealing and classical pre- and post-processing; at this early stage, little is known about how to partition and optimize the processing. This article presents an experimental case study of quantum annealing and some of the factors involved in real-world solvers, using a 504-qubit D-Wave Two machine and the graph isomorphism problem. To illustrate the role of classical pre-processing, a compact Hamiltonian is presented that enables a reduced Ising model for each problem instance. On random N-vertex graphs, the median number of variables is reduced from N(2) to fewer than N log2 N and solvable graph sizes increase from N = 5 to N = 13. Additionally, error correction via classical post-processing majority voting is evaluated. While the solution times are not competitive with classical approaches to graph isomorphism, the enhanced solver ultimately classified correctly every problem that was mapped to the processor and demonstrated clear advantages over the baseline approach. The results shed some light on the nature of real-world quantum annealing and the associated hybrid classical-quantum solvers. PMID- 26053974 TI - ACE-inhibitor-related angioedema. PMID- 26053975 TI - Dehiscent high jugular bulb attached to the tympanic membrane. PMID- 26053976 TI - A rare case of pleomorphic adenoma of the nasal septum. PMID- 26053977 TI - Cricotracheal resection. PMID- 26053978 TI - Neuropathic pain from a nasal valve suspension suture. PMID- 26053979 TI - Improvement in allergic and nonallergic rhinitis: A secondary benefit of adenoidectomy in children. AB - Chronic rhinitis (CR) is a common disorder in children. Allergic rhinitis (AR) is a risk factor for CR, and children with AR tend to suffer more from hypertrophic adenoids than do patients with nonallergic rhinitis (NAR). Few studies have addressed the issue of alleviating symptoms of pediatric CR or AR following adenoidectomy alone. We conducted a retrospective chart review to determine whether CR in children improves after adenoidectomy and whether children with AR will benefit more than those with NAR. Charts of 47 children who had undergone adenoidectomy for nasal obstruction and chronic middle ear effusion were reviewed. AR and NAR subgroups were classified based on symptoms, signs, blood IgE, and nasal smear (allergic criteria). Hypertrophic adenoids were graded using the adenoid-to-nasopharyngeal ratio (ANr >0.8). A questionnaire was used to assess the change in chronic rhinitis postoperatively. Improvement in CR was reported in 37 of 47 (79%) children. Patients with AR improved to a higher extent than those with NAR (12 of 14 [86%] vs. 25 of 33 [76%], respectively), but the difference was not statistically significant. A total of 41 lateral postoperative nasopharyngeal x-rays were obtained. The x-rays revealed that 20 of 26 (77%) of patients with ANr >0.8 had complete and 4 of 26 (15%) had partial resolution of symptoms of CR for a total resolution rate of 92%, compared to only a 53% resolution in the ANr <0.8 subgroup (6 of 15 and 2 of 15 patients, respectively [p <0.05]). The correlation between adenoid size and resolution of CR was not related to any of the AR/NAR subgroups. We conclude that symptoms of CR may improve after adenoidectomy in children who are experiencing nasal obstruction and chronic otitis media with effusion. Clinical improvement did not differ between AR and NAR patients, and was more prominent in children with hypertrophic adenoids (ANr >0.8). PMID- 26053980 TI - Th1 and Th2 cytokine gene expression in atopic and nonatopic patients with nasal polyposis. AB - The pathogenesis of nasal polyps has been debated for many years. The lymphocytes that infiltrate nasal polyps have been identified as predominantly memory T cells in an activated state, and these cells produce a mixed cytokine pattern of T1 helper (Th1) and T2 helper (Th2) cells. We conducted a prospective study to compare the expression levels of some Th1 and Th2 cytokines in atopic and nonatopic patients. Our study population consisted of 75 adults-42 men and 33 women (mean age: 38 yr)-with nasal polyposis. Patients with an allergy were distinguished from those without an allergy on the basis of the history, the results of skin-prick testing, and measurement of total IgE serum concentrations. Based on these criteria, patients were divided into two groups: atopic (n = 38) and nonatopic (n = 37). Levels of cytokine gene expression in the atopic patients were compared with those of the nonatopic patients by real-time polymerase chain reaction. Statistical analysis found no significant differences in the rate of interleukin (IL) 10 and IL-12 gene expression between the allergic and nonallergic patients. On the other hand, rates of interferon gamma and IL-4 gene expression were significantly higher in the atopic patients (p = 0.03 and p = 0.02, respectively). Our research suggests that an imbalance of Th1 and Th2 cells plays an important role in the pathophysiology of nasal polyps. Although nasal polyposis is a multifactorial disease associated with several different etiologic factors, chronic persistent inflammation is undoubtedly a major factor, regardless of the specific etiology. PMID- 26053981 TI - Laryngeal findings and acoustic changes in light cigar smokers. AB - The aim of this prospective study was to look at the laryngeal findings and acoustic changes in light cigar smokers in comparison to nonsmokers, in the setting of a voice clinic. A total of 22 cigar smokers and 19 nonsmokers used as controls were enrolled in the study. Demographic data included age, number of years smoking, number of cigars per week, history of allergy, and history of reflux. The confounding effects of allergy and reflux were accounted for in the control group. Subjects underwent laryngeal endoscopy and acoustic analysis. On laryngeal endoscopy, the most common laryngeal finding was thick mucus. There was no significant difference in the prevalence of any of the laryngeal findings in cigar smokers vs. CONTROLS: In comparison with the control group, both the fundamental frequency and habitual pitch were significantly lower in cigar smokers (p value = 0.034 and 0.004, respectively). We conclude that cigar smokers have lower fundamental frequency and habitual pitch compared to nonsmokers. PMID- 26053982 TI - Duplication of the right internal jugular vein: A case report. AB - We present a case of duplication of the right internal jugular vein (IJV) in a patient who underwent neck dissection as part of the management of carcinoma of the larynx. The patient was a 63-year-old man who presented to the otolaryngology department with a 7-month history of hoarseness and a 3-week history of noisy breathing. Flexible endoscopy detected a transglottic tumor that had extended beyond the vocal folds. The patient underwent a total laryngectomy and bilateral selective neck dissection at levels II-VI. Intraoperatively, the right IJV was noted to be duplicated. The duplicate segment was approximately 10 cm in length, and it rejoined the normal vein before the normal vein joined the subclavian vein. PMID- 26053983 TI - Intraductal infusion of steroids in patients with Sjogren syndrome to treat painful salivary swelling: Report of 2 cases. AB - Painful salivary swelling in patients with Sjogren syndrome presents the clinician with a difficult-to-manage condition, and treatment options are limited. We report 2 cases that demonstrate the utility of a clinic-based intraductal corticosteroid infusion for the treatment of painful salivary swelling associated with Sjogren syndrome. Steroid infusion is a cost-effective, simple-to-perform, well-tolerated gland-sparing procedure that may yield good clinical results in selected patients. PMID- 26053984 TI - Maxillary myxoma: A case report and review. AB - An odontogenic myxoma is a rare, benign tumor that is found almost exclusively in the facial bones, usually the mandible. The diagnosis poses a challenge because its features overlap with those of other benign and malignant neoplasms. We present an unusual case of odontogenic myxoma that involved the maxilla, and we review the clinical, radiographic, and histologic characteristics of this case. Even though it is benign, odontogenic myxoma can be locally invasive and cause significant morbidity. Complete surgical excision is the treatment of choice, but it can be challenging because of the tumor's indistinct margins. PMID- 26053985 TI - Juvenile nasopharyngeal angiofibroma staging: An overview. AB - Staging of tumors is very important in treatment and surgical decision making, as well as in predicting disease recurrence and prognosis. This review focuses on the different available classifications of juvenile nasopharyngeal angiofibroma (JNA) and their impact on the evaluation, management, and prognosis of JNA. The literature was reviewed, and publications on JNA staging were examined. Our MEDLINE search of the entire English-language literature found no review article on the current available staging systems for JNA. In this article, we review the common JNA classification systems that have been published, and we discuss some of their advantages and disadvantages. The most commonly used staging systems for JNA are the Radkowski and the Andrews-Fisch staging systems. However, some newer staging systems that are based on advances in technology and surgical approaches the Onerci, INCan, and UPMC systems-have shown promising utility, and they will probably gain popularity in the future. PMID- 26053986 TI - Internal auditory canal osteoma: Case report and review of the literature. AB - We report a case of internal auditory canal osteoma and discuss this entity's etiology, natural history, and treatment options. The internal auditory canal osteoma is a rare entity with only a few reports published in the medical literature. Its diagnosis is based on two complementary imaging modalities: thin slice computed tomography and magnetic resonance imaging. No consensus exists regarding the treatment of this entity, and treatment should be tailored to each patient depending on that patient's initial complaints, as well as his or her medical findings. PMID- 26053987 TI - Anaplastic large-cell lymphoma presenting as a nasopharyngeal mass and cervical lymphadenopathy. AB - Cervical lymphadenopathy in adults has a broad differential diagnosis, including bacterial and viral infections, Kikuchi-Fujimoto disease, systemic lupus erythematosus, and various neoplasms. Many of its etiologies share similar symptomatology and presentations, which complicates the diagnosis. A thorough history and a comprehensive physical examination, to include nasopharyngoscopy and imaging as indicated by the specific case, are key to determining the origin of the lymphadenopathy and to avoid a missed or delayed diagnosis. Based on our review of the literature, we present the second reported case of anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma presenting in an adult with an obstructing adenoid/nasopharyngeal mass and lymphadenopathy. The mass, which occurred in a 19-year-old woman of Asian descent, caused nasal airway obstruction in the setting of cervical lymphadenopathy that was initially ascribed to mononucleosis. PMID- 26053988 TI - Use of fluoroscopic guidance to remove a migrating esophageal foreign body. AB - Ingested foreign bodies that migrate extraluminally are rare. In such cases, exploration of the neck via an external approach is the recommended procedure to remove the object. However, locating such a foreign body can be a difficult task. We report what we believe is the first adult case of fluoroscopically guided localization of an accidentally ingested foreign body that had migrated into the soft tissues of the neck. We also review the other methods used to locate a migrating foreign body. PMID- 26053989 TI - A novel method for reconstruction of severe caudal nasal septal deviation: Marionette septoplasty. AB - We conducted a retrospective study to compare open and endonasal (closed) approaches to extracorporeal reconstruction of severe caudal septal deviations. From January 1, 2010, through December 31, 2013, 78 patients with severe caudal septal deviation underwent corrective surgery at our hospital. Of this group, 33 patients (mean age: 32 yr) underwent extracorporeal septoplasty via an open approach, and 45 patients (mean age: 35 yr) underwent treatment with a new procedure that we developed: subtotal extracorporeal septoplasty through a closed approach, which we call "marionette septoplasty." In addition to demographic data, we compiled information on surgical time, the duration of postoperative edema, the degree of postoperative pain, and differences between pre- and postoperative nasal function and tip support in both groups. We found that our marionette septoplasty procedure required significantly less surgical time and resulted in a significantly shorter duration of postoperative edema than did open septoplasty, while there was no statistically significant difference between the two procedures in the degree of pain. Following surgery, nasal function in both groups improved significantly, without any significant difference between the two. Finally, we documented improved tip support in all 78 patients. Our results show that marionette septoplasty produces the same functional results as does open septoplasty while requiring less surgical time and shortening the healing period. PMID- 26053990 TI - Sleep problems of adolescents: A detailed survey. AB - We investigated the sleep problems and sleep habits of adolescents at three public primary schools and two high schools. Our study included 428 Turkish school children (244 girls and 184 boys). We used a questionnaire to determine the time they went to sleep at night; waking time in the morning; incidence of nightmares, snoring, daytime sleepiness, and intrafamilial physical trauma; concentration difficulty in class; and school success. The students were divided into age-related groups (group 1 = 11 to 13 years of age; group 2 = 14 to 15 years; group 3 = 16 to 18 years). The time they went to sleep was mostly between 10 and 11 p.m. in groups 1 and 2, and 11 to 12 p.m. in group 3. Difficulty in falling asleep was reported by 16.8 to 19.6% of the students in the three groups. Difficulty in waking up in the morning was reported by 12.7% of group 1, 16.0% of group 2, and 16.8% of group 3. Snoring was present in 12.1% of females and 22.0% of males. The occurrence of one nightmare in the preceding 3 months was reported by 11.3% of the students; 17.9% of the students reported having nightmares several times. Daytime sleepiness was present in 65.1%, and concentration difficulty was present in 56.8% of the students. We conclude that difficulty in falling asleep, snoring, and daytime sleepiness may be seen in adolescents who are in both primary and high schools. Watching inappropriate programs and movies on television and intrafamilial physical trauma may cause nightmares and sleeping problems in these adolescents. Students and families should be educated about the importance of sleep in academic performance. Countries' public health policies should address sleep problems and related educational activities. PMID- 26053991 TI - Nonossifying fibroma (metaphyseal fibrous defect) of the mandible in a 15-year old boy. AB - We describe a rare case of nonossifying fibroma of the mandible in a 15-year-old boy who presented with a left mandibular swelling. Conventional imaging showed an expansile radiolucent lesion involving the angle and the body of the left mandible. The lesion was curetted, and a miniplate was implanted at the excision site. Microscopic examination of the removed specimen revealed a cellular lesion characterized by a proliferation of uniform spindle-shaped cells in a vague but prominent storiform pattern, which represented the classic appearance of nonossifying fibroma. Three months later, radiography detected a fracture of the implantation plate. The area was re-explored with curettage of the soft tissue, which on microscopy demonstrated findings similar to the initial curettage findings. Follow-up radiology revealed satisfactory healing of the jaw, and no further recurrence was seen 2 years after the initial surgery. We present this case to highlight the importance of recognizing nonossifying fibroma in the mandible, which can be easily confused with more common mandibular lesions. PMID- 26053992 TI - Bezold abscess. PMID- 26053993 TI - Maggot infestation of an ulcerated neck wound. PMID- 26053994 TI - General anaesthetic agents do not influence persistent pain after breast cancer surgery: A prospective nationwide cohort study. AB - BACKGROUND: It has recently been suggested that propofol exerts a protective effect on the occurrence of persistent pain after breast cancer surgery. We analysed data from a subcohort taken from a multicentre study to validate this information. OBJECTIVE: The objective of this article is to study the role of the agent used for maintenance of general anaesthesia on the occurrence of persistent pain, with adjustment for multiple pre and peri-operative variables using the generalised linear model. DESIGN: A prospective cohort study. SETTING: Four French university hospitals. PATIENTS: Three hundred and twenty-eight and 362 patients with full dataset, depending on the studied outcome. INTERVENTION: Questionnaires sent at the third and the sixth month after surgery. MAIN OUTCOME MEASURES: The risk of persistent postsurgical neuropathic pain (defined by the DN4 questionnaire) within 6 months after surgery, and the intensity of persistent pain at the sixth month. RESULTS: Axillary lymph node harvesting and previous history of peripheral neuropathy were independent risk factors of persistent postsurgical neuropathic pain, although older age was protective. The same independent risk factors, but not age, explained the intensity of persistent postsurgical pain at the sixth month after surgery. We did not find any effect of the general anaesthetic, whether halogenated agent or propofol, using either unadjusted or adjusted analyses based on covariates or propensity score. CONCLUSION: There does not appear to be a role for the anaesthetic protocol in the occurrence of persistent postsurgical pain. Other already well established hypotheses were confirmed. TRIAL REGISTRATION: ClinicalTrials.gov (ref. NCT00812734). PMID- 26053996 TI - Bioelectronics: Injection and unfolding. PMID- 26053995 TI - Syringe-injectable electronics. AB - Seamless and minimally invasive three-dimensional interpenetration of electronics within artificial or natural structures could allow for continuous monitoring and manipulation of their properties. Flexible electronics provide a means for conforming electronics to non-planar surfaces, yet targeted delivery of flexible electronics to internal regions remains difficult. Here, we overcome this challenge by demonstrating the syringe injection (and subsequent unfolding) of sub-micrometre-thick, centimetre-scale macroporous mesh electronics through needles with a diameter as small as 100 MUm. Our results show that electronic components can be injected into man-made and biological cavities, as well as dense gels and tissue, with >90% device yield. We demonstrate several applications of syringe-injectable electronics as a general approach for interpenetrating flexible electronics with three-dimensional structures, including (1) monitoring internal mechanical strains in polymer cavities, (2) tight integration and low chronic immunoreactivity with several distinct regions of the brain, and (3) in vivo multiplexed neural recording. Moreover, syringe injection enables the delivery of flexible electronics through a rigid shell, the delivery of large-volume flexible electronics that can fill internal cavities, and co-injection of electronics with other materials into host structures, opening up unique applications for flexible electronics. PMID- 26053999 TI - Strain and Hole Gas Induced Raman Shifts in Ge-Si(x)Ge(1-x) Core-Shell Nanowires Using Tip-Enhanced Raman Spectroscopy. AB - We report tip-enhanced and conventional Raman spectroscopy studies of Ge Si0.5Ge0.5 core-shell nanowires in which we observe two distinct Ge-Ge vibrational mode Raman peaks associated with vibrations in the Ge nanowire core and at the Ge-Si0.5Ge0.5 interface at which a quantum-confined hole gas is formed. Tip enhanced Raman measurements show dramatically increased sensitivity to the modes at the Ge-Si0.5Ge0.5 interface and a shift in position of this mode due to plasmonic field localization at the tip apex and the resulting change in phonon self-energy caused by increased coupling between phonons and intervalence band carrier transitions. PMID- 26053997 TI - Comparative analysis of glucagonergic cells, glia, and the circumferential marginal zone in the reptilian retina. AB - Retinal progenitors in the circumferential marginal zone (CMZ) and Muller glia derived progenitors have been well described for the eyes of fish, amphibians, and birds. However, there is no information regarding a CMZ and the nature of retinal glia in species phylogenetically bridging amphibians and birds. The purpose of this study was to examine the retinal glia and investigate whether a CMZ is present in the eyes of reptilian species. We used immunohistochemical analyses to study retinal glia, neurons that could influence CMZ progenitors, the retinal margin, and the nonpigmented epithelium of ciliary body of garter snakes, queen snakes, anole lizards, snapping turtles, and painted turtles. We compare our observations on reptile eyes to the CMZ and glia of fish, amphibians, and birds. In all species, Sox9, Pax6, and the glucocorticoid receptor are expressed by Muller glia and cells at the retinal margin. However, proliferating cells were found only in the CMZ of turtles and not in the eyes of anoles and snakes. Similar to eyes of chickens, the retinal margin in turtles contains accumulations of GLP1/glucagonergic neurites. We find that filamentous proteins, vimentin and GFAP, are expressed by Muller glia, but have different patterns of subcellular localization in the different species of reptiles. We provide evidence that the reptile retina may contain nonastrocytic inner retinal glial cells, similar to those described in the avian retina. We conclude that the retinal glia, glucagonergic neurons, and CMZ of turtles appear to be most similar to those of fish, amphibians, and birds. PMID- 26053998 TI - Distinct inter-hemispheric dysconnectivity in schizophrenia patients with and without auditory verbal hallucinations. AB - Evidence from behavioral, electrophysiological and diffusion-weighted imaging studies suggest that schizophrenia patients suffer from deficiencies in bilateral brain communication, and this disruption may be related to the occurrence of auditory verbal hallucinations (AVH). To increase our understanding of aberrant inter-hemispheric communication in relation to AVH, we recruited two groups of first-episode schizophrenia patients: one group with AVH (N = 18 AVH patients) and one without hallucinations (N = 18 Non-AVH patients), and 20 healthy controls. All participants received T1 structural imaging and resting-state fMRI scanning. We adopted a newly developed index, voxel-mirrored homotopic connectivity (VMHC), to quantitatively describe bilateral functional connectivity. The whole-brain VMHC measure was compared among the three groups and correlation analyses were conducted between symptomology scores and neurological measures. Our findings suggest all patients shared abnormalities in parahippocampus and striatum. Aberrant bilateral connectivity of default mode network (DMN), inferior frontal gyrus and cerebellum only showed in AVH patients, whereas aberrances in superior temporal gyrus and precentral gyrus were specific to Non-AVH patients. Meanwhile, inter-hemispheric connectivity of DMN correlated with patients' symptomatology scores. This study corroborates that schizophrenia is characterized by inter-hemispheric dysconnectivity, and suggests the localization of such abnormalities may be crucial to whether auditory verbal hallucinations develop. PMID- 26054000 TI - Prostate biopsy decisions: one-size-fits-all approach with total PSA is out and a multivariable approach with the Prostate Health Index is in. PMID- 26054001 TI - A systematic review of terms used to describe hidradenitis suppurativa. PMID- 26054002 TI - Molybdenum Hydride and Dihydride Complexes Bearing Diphosphine Ligands with a Pendant Amine: Formation of Complexes with Bound Amines. AB - CpMo(CO)(PNP)H complexes (PNP = (R2PCH2)2NMe, R = Et or Ph) were synthesized by displacement of two CO ligands of CpMo(CO)3H by the PNP ligand; these complexes were characterized by IR and variable temperature (1)H and (31)P NMR spectroscopy. CpMo(CO)(PNP)H complexes are formed as mixture of cis- and trans isomers. The structures of both cis-CpMo(CO)(P(Et)N(Me)P(Et))H and trans CpMo(CO)(P(Ph)N(Me)P(Ph))H were determined by single crystal X-ray diffraction. Electrochemical oxidation of CpMo(CO)(P(Et)N(Me)P(Et))H and CpMo(CO)(P(Ph)N(Me)P(Ph))H in CH3CN are both irreversible at slow scan rates and quasireversible at higher scan rates, with E1/2 = -0.36 V (vs Cp2Fe(+/0)) for CpMo(CO)(P(Et)N(Me)P(Et))H and E1/2 = -0.18 V for CpMo(CO)(P(Ph)N(Me)P(Ph))H. Hydride abstraction from CpMo(CO)(PNP)H with [Ph3C](+)[A](-) (A = B(C6F5)4 or BAr(F)4; [Ar(F) = 3,5-bis(trifluoromethyl)phenyl]) afforded "tuck-in" [CpMo(CO)(kappa(3)-PNP)](+) complexes that feature the amine bound to the metal. Displacement of the kappa(3) Mo-N bond by CD3CN gives [CpMo(CO)(PNP)(CD3CN)](+). The kinetics of this reaction were studied by (31)P{(1)H} NMR spectroscopy for [CpMo(CO)(kappa(3)-P(Et)N(Me)P(Et))](+), providing the activation parameters DeltaH(?) = 21.6 +/- 2.8 kcal/mol, DeltaS(?) = -0.3 +/- 9.8 cal/(mol K), Ea = 22.1 +/- 2.8 kcal/mol. Protonation of CpMo(CO)(P(Et)N(Me)P(Et))H affords the Mo dihydride complex [CpMo(CO)(kappa(2)-P(Et)N(Me)P(Et))(H)2](+), which loses H2 to generate [CpMo(CO)(kappa(3)-P(Et)N(Me)P(Et))](+) at room temperature. Our results show that the pendant amine has a strong driving force to form stable "tuck-in" [CpMo(CO)(kappa(3)-PNP)](+) complexes, and also promotes hydrogen elimination from [CpMo(CO)(PNP)(H)2](+) complexes by formation of a Mo-N dative bond. CpMo(CO)(dppp)H (dppp = 1,3-bis(diphenylphosphino)propane) was studied as a Mo diphosphine analogue without a pendant amine, and the product of protonation of this complex gives [CpMo(CO)(dppp)(H)2](+). PMID- 26054003 TI - Tuning the Photophysical Properties of Ru(II) Monometallic and Ru(II),Rh(III) Bimetallic Supramolecular Complexes by Selective Ligand Deuteration. AB - A series of three new complexes of the design [(TL)2Ru(BL)](2+), two new complexes of the design [(TL)2Ru(BL)Ru(TL)2](4+), and three new complexes of the design [(TL)2Ru(BL)RhCl2(TL)](3+) (TL = bpy or d8-bpy; BL = dpp or d10-dpp; TL = terminal ligand; BL = bridging ligand; bpy = 2,2'-bipyridine; dpp = 2,3-bis(2 pyridyl)pyrazine) were synthesized and the (1)H NMR spectroscopy, electrochemistry, electronic absorbance spectroscopy, and photophysical properties studied. Incorporation of deuterated ligands into the molecular architecture simplifies the (1)H NMR spectra, allowing for complete (1)H assignment of [(d8-bpy)2Ru(dpp)](PF6)2 and partial assignment of [(bpy)2Ru(d10 dpp)](PF6)2. The electrochemistry for the deuterated and nondeuterated species showed nearly identical redox properties. Electronic absorption spectroscopy of the deuterated and nondeuterated complexes are superimposable with the lowest energy transition being Ru(dpi) -> BL(pi*) charge transfer in nature (BL = dpp or d10-dpp). Ligand deuteration impacts the excited-state properties with an observed increase in the quantum yield of emission (Phi(em)) and excited-state lifetime (tau) of the Ru(dpi) -> d10-dpp(pi*) triplet metal-to-ligand charge transfer ((3)MLCT) excited state when dpp is deuterated, and a decrease in the rate constant for nonradiative decay (knr). Choice of ligand deuteration between bpy and dpp strongly impacts the observed photophysical properties with BL = d10 dpp complexes showing an enhanced Phi(em) and tau, providing further support that the lowest electronic excited state populated via UV or visible excitation is the photoactive Ru(dpi) -> dpp(pi*) CT excited state. The Ru(II),Rh(III) complex incorporating the deuterated BL shows increased hydrogen production compared to the variants incorporating the protiated BL, while demonstrating identical dynamic quenching behaviors in the presence of sacrificial electron donor. PMID- 26054005 TI - Patient reported outcomes of the -clinical use of a proprietary topical dry mouth product. AB - PURPOSE: To present patient reported changes in oral symptoms in response to an open-label product trial conducted in patients self-identifying as having Sjogren's syndrome. METHODS: A survey was conducted in conjunction with the Sjogren's Syndrome Foundation and 151 foundation members completed a survey rating their common oral symptoms, based upon the Vanderbilt Head and Neck Symptom Survey before and after use of the trial products, including rinse, lozenges, gel, and spray. RESULTS: Subjects reported multiple oral symptoms with the highest rated symptoms involving dry mouth with 80% of symptoms showing statistically significant reduction from pre- to posttest. The largest symptom reductions were in dry mouth symptoms and dietary problems. CONCLUSIONS: Symptoms of dry mouth were improved with use of MedActive(r) products. Increased ease of taking oral medications also was reported. Improvement in mouth/throat pain was noted. Subjects reported considerable effect of the test product upon dry mouth and oral symptoms. PMID- 26054006 TI - MFAP5 is related to obesity-associated adipose tissue and extracellular matrix remodeling and inflammation. AB - OBJECTIVE: Low-grade inflammation is involved in adipose tissue (AT) and extracellular matrix (ECM) remodeling and induces deposition of ECM proteins in AT. We have previously shown that MFAP5 (microfibrillar-associated protein 5) expression decreases in AT after weight loss. The aim of this study was to investigate MFAP5 localization in human AT and gene expression in adipocytes and the role of MFAP5 in adipocyte metabolism and inflammation. METHODS: MFAP5 protein localization and gene expression were studied with immunohistochemistry and quantitative reverse transcriptase PCR (RT-qPCR) in human subcutaneous AT and cultured Simpson-Golabi-Behmel syndrome (SGBS) adipocytes, respectively. The effect of MFAP5 knock-down by siRNA on gene expression and insulin action was examined with RT-qPCR, western blot, and insulin-stimulated glucose uptake. The effect of different cytokines on MFAP5 gene and protein expression was investigated in cultured human SGBS preadipocytes. RESULTS: MFAP5 protein was highly expressed in AT, and gene expression decreased during adipocyte differentiation in SGBS cells. Treatment of preadipocytes with TNFalpha and TGFbeta1 increased MFAP5 gene and protein expression. Furthermore, MFAP5 knock down decreased the expression of genes involved in inflammation. CONCLUSIONS: Our results demonstrate that factors involving low-grade inflammation modulate MFAP5 expression and that the modified expression of MFAP5 may further regulate AT inflammation. PMID- 26054007 TI - Method for Derivatization and Detection of Chemical Weapons Convention Related Sulfur Chlorides via Electrophilic Addition with 3-Hexyne. AB - Sulfur monochloride (S2Cl2) and sulfur dichloride (SCl2) are important precursors of the extremely toxic chemical warfare agent sulfur mustard and classified, respectively, into schedule 3.B.12 and 3.B.13 of the Chemical Weapons Convention (CWC). Hence, their detection and identification is of vital importance for verification of CWC. These chemicals are difficult to detect directly using chromatographic techniques as they decompose and do not elute. Until now, the use of gas chromatographic approaches to follow the derivatized sulfur chlorides is not reported in the literature. The electrophilic addition reaction of sulfur monochloride and sulfur dichloride toward 3-hexyne was explored for the development of a novel derivatization protocol, and the products were subjected to gas chromatography-mass spectrometric (GC-MS) analysis. Among various unsaturated reagents like alkenes and alkynes, symmetrical alkyne 3-hexyne was optimized to be the suitable derivatizing agent for these analytes. Acetonitrile was found to be the suitable solvent for the derivatization reaction. The sample preparation protocol for the identification of these analytes from hexane spiked with petrol matrix was also optimized. Liquid-liquid extraction followed by derivatization was employed for the identification of these analytes from petrol matrix. Under the established conditions, the detection and quantification limits are 2.6 MUg/mL, 8.6 MUg/mL for S2Cl2 and 2.3 MUg/mL, 7.7 MUg/mL for SCl2, respectively, in selected ion monitoring (SIM) mode. The calibration curve had a linear relationship with y = 0.022x - 0.331 and r(2) = 0.992 for the working range of 10 to 500 MUg/mL for S2Cl2 and y = 0.007x - 0.064 and r(2) = 0.991 for the working range of 10 to 100 MUg/mL for SCl2, respectively. The intraday RSDs were between 4.80 to 6.41%, 2.73 to 6.44% and interday RSDs were between 2.20 to 7.25% and 2.34 to 5.95% for S2Cl2 and SCl2, respectively. PMID- 26054008 TI - Asystolic Cardiac Arrest of Unknown Duration in Profound Hypothermia and Polysubstance Overdose: A Case Report of Complete Recovery. AB - BACKGROUND: Opioid addiction and overdose is a serious problem worldwide. Fatal overdoses from opioids are responsible for numerous deaths and are increasing, especially if taken in combination with other psychoactive substances. Combined with environmental exposure, opioid overdose can cause profound hypothermia. Opioid abuse and other drugs of abuse impair thermoregulation, leading to severe hypothermia. Both drug overdose and severe hypothermia can cause cardiac arrest. CASE REPORT: We report a case of 20-year-old man with history of polysubstance abuse presenting with severe hypothermia and asystole of unknown duration with return of spontaneous circulation (ROSC) achieved after 28 minutes of cardiopulmonary resuscitation (CPR). Urine toxicology was positive for cocaine, heroin, and benzodiazepine, along with positive blood alcohol level. The patient was rewarmed using non-invasive techniques. Hospital course was complicated by acute renal failure (ARF), severe rhabdomyolysis, severe hyperkalemia, ST elevation myocardial infarction (STEMI), shock liver, coagulopathy, and aspiration pneumonia. CONCLUSIONS: Survival with full cardiovascular and neurologic recovery after a cardiac arrest caused by drug overdose in the setting of severe hypothermia is still possible, even if the cardiac arrest is of unknown or prolonged duration. Patients with severe hypothermia experiencing cardiac arrest/hemodynamic instability can be rewarmed using non-invasive methods and may not necessarily need invasive rewarming techniques. PMID- 26054009 TI - Diagnosing Nodular Regenerative Hyperplasia of the Liver Is Thwarted by Low Interobserver Agreement. AB - BACKGROUND AND AIMS: Nodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH. METHODS: Liver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index. RESULTS: After review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (kappa = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (kappa = 0.45). CONCLUSIONS: The interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone. PMID- 26054010 TI - Letter to the Editor: Endovascular treatment of wide-necked aneurysms. PMID- 26054012 TI - Correction: Structural bases for mechano-responsive properties in molecular gels of (R)-12-hydroxy-N-(omega-hydroxyalkyl)octadecanamides. Rates of formation and responses to destructive strain. AB - Correction for "Structural bases for mechano-responsive properties in molecular gels of (R)-12-hydroxy-N-(omega-hydroxyalkyl)octadecanamides. Rates of formation and responses to destructive strain" by V. Ajay Mallia and Richard G. Weiss, Soft Matter, 2015, DOI: 10.1039/C5SM00353A. PMID- 26054011 TI - Up-Regulation of the Biosynthesis and Release of Substance P through Wnt/beta Catenin Signaling Pathway in Rat Dorsal Root Ganglion Cells. AB - To examine regulatory effects of beta-catenin on the biosynthesis and release of substance P, a rat chronic constriction injury (CCI) model and a rat dorsal root ganglion (DRG) cell culture model were used in the present study. The CCI treatment significantly induced the overall expression of beta-catenin (158 +/- 6% of sham) in the ipsilateral L5 DRGs in comparison with the sham group (109 +/- 4% of sham). The CCI-induced aberrant expression of beta-catenin was significantly attenuated by oral administration of diclofenac (119 +/- 6% of the sham value; 10 mg/kg). Importantly, aberrant nuclear accumulation of beta-catenin in cultured DRG cells resulted in up-regulation of the PPT-A mRNA expression and the substance P release. The up-regulation of both the PPT-A mRNA expression and the substance P release by either a GSK-3beta inhibitor TWS119 (10 MUM) or a Wnt signaling agonist Wnt-3a (100 ng/ml) were significantly abolished by an inhibitor of cyclooxygenase-2 (COX-2; NS-398, 1 MUM). Collectively, these data suggest that nociceptive input-activated beta-catenin signaling plays an important role in regulating the biosynthesis and release of substance P, which may contribute to the inflammation responses related to chronic pain. PMID- 26054013 TI - Sexual Dysfunctions in Men and Women with Inflammatory Bowel Disease: The Influence of IBD-Related Clinical Factors and Depression on Sexual Function. AB - INTRODUCTION: Inflammatory bowel disease (IBD) is likely to have an impact on sexual function because of its symptoms, like diarrhea, fatigue, and abdominal pain. Depression is commonly reported in IBD and is also related to impaired sexual function. This study aimed to evaluate sexual function and its association with depression among patients with IBD compared with controls. METHODS: IBD patients registered at two hospitals participated. The control group consisted of a general practitioner practice population. The web-based questionnaire included the Female Sexual Function Index (FSFI) for women and the International Index of Erectile Function (IIEF) for men. Other variables evaluated were depression, disease activity, IBD-related quality of life, body image, and fatigue. RESULTS: In total, 168 female and 119 male patients were available for analysis (response rate 24%). Overall, patients with IBD did not significantly differ in prevalence of sexual dysfunctions from controls: female patients 52%, female controls 44%, male patients and male controls both 25%. However, men and women with an active disease scored significantly lower than patients in remission and controls, indicating impaired sexual functioning during disease activity. Significant associations were found between active disease, fatigue, depressive mood, quality of life, and sexual function for both male and female patients. The association between disease activity and sexual function was totally mediated by depression. CONCLUSION: Male and female IBD patients with an active disease show impaired sexual function relative to patients in remission and controls. Depression is the most important determinant for impaired sexual function in IBD. PMID- 26054014 TI - Association between cerebral palsy and microscopically verified placental infarction in extremely preterm infants. AB - INTRODUCTION: Previously, cerebral palsy has been associated with placental infarctions diagnosed macroscopically by midwifes. However, the risk of misclassification of infarctionsis is high without a histological verification. Therefore, the objective of this study was to study placental histopathology in relation to developmental outcome at 2.5 years corrected age in a population born extremely preterm. MATERIAL AND METHODS: A prospective cohort study was carried out at Karolinska University Hospital, Stockholm, Sweden on a population of 139 live born infants delivered <27 gestational weeks during 2004-2007. A senior perinatal pathologist, who was blinded to outcome data, evaluated all placental slides microscopically. Neuromotor and sensory functions of the children were evaluated. Bayley Scales of Infant and Toddler Development-III (Bayley-III) were used to assess development at corrected age 2.5 years. The outcome data were evaluated without reference to obstetrical and pathology data. The primary outcome measure was neurological and developmental status at 2.5 years of corrected age. This was measured as diagnosis of cerebral palsy, visual impairment, hearing impairment as well as performance on Bayley-III scales evaluating cognitive, language and motor functions. RESULTS: Two out of seven children with placental infarction were diagnosed with cerebral palsy compared with one child of 51 without placental infarction (p = 0.036). For developmental outcome according to Bayley-III at 2.5 years no statistically significant associations with placental pathology were found. CONCLUSION: A possible association between placental infarction, verified by microscopic examination, and cerebral palsy has been identified in this extremely preterm population. PMID- 26054016 TI - Relationship of menstrual cycle and vaginal infection in female rhesus macaques challenged with repeated, low doses of SIVmac251. AB - Varying susceptibility during menstrual cycling could be a factor for S(H)IV infection risk in female rhesus macaques. We retrospectively determined vaginal SIV infection time points relative to the menstrual cycle in a group of rhesus macaques (n=11) enrolled in an HIV transmission trial. Eight of nine rhesus macaques became infected around menstruation time. PMID- 26054017 TI - Outcome of allogeneic hematopoietic stem cell transplantation for cytogenetically normal AML and identification of high-risk subgroup using WT1 expression in association with NPM1 and FLT3-ITD mutations. AB - According to recent guidelines, cytogenetically normal acute myeloid leukemia (CN AML) is divided into four molecular subgroups based on nucleophosmin-1 (NPM1) and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations. All subgroups except for isolated NPM1mut are associated with poor prognosis. We retrospectively analyzed 223 patients with CN AML, 156 of whom were treated with standard chemotherapy. For postremission therapy, patients with available donors underwent allogeneic (allo) hematopoietic stem cell transplantation (HSCT) and the rest were treated with autologous HSCT or chemotherapy alone. We first compared the 4 conventional molecular subgroups, and then created another 4 subgroups based on WT1 expression: isolated NPM1mut, NPM1wt/FLT3-ITD-neg with low WT1 or high WT1, and FLT3-ITD-pos CN AML. We finally evaluated 89 patients who were treated with allo HSCT and achieved complete remission after standard chemotherapy. FLT3-ITD CN AML showed the worst outcome irrespective of NPM1mut, and isolated NPM1mut CN AML showed no significant differences compared with NPM1wt/FLT3-ITD-neg CN AML. In contrast, two newly stratified low-risk subgroups (NPM1wt/FLT3-ITD-neg with low WT1 and isolated NPM1mut CN AML) showed higher remission rates with superior overall survival (OS) compared with the other two high-risk subgroups, which showed a higher relapse rate even after allo HSCT. Further analysis showed that higher pre-HSCT expression of WT1 resulted in a higher relapse rate and poorer OS after allo HSCT. For CN AML, a risk-adapted approach using allo HSCT with novel agents should be evaluated with stratification specified by WT1. (c) 2015 Wiley Periodicals, Inc. PMID- 26054018 TI - Screening of carcinoma metastasis by flow cytometry: A study of 238 cases. AB - BACKGROUND: Malignant epithelial cells may be detected in different specimens, by immunophenotyping using flow cytometry (FCM). CD326 (epithelial-specific antigen, clone Ber-Ep4) was used to identify epithelial cells, CD45 to discriminate between leucocytes (positive for this antigen) and non-hematological cells (negative for this antigen), and CD33 to identify monocytes/macrophages. This combination is particularly useful in effusions to characterize large cells and distinguish between monocyte/macrophages (CD45+ CD33+ CD326-), mesothelial cells (CD45 +/- (dim) CD33 - CD326-) and epithelial cells (CD45 - CD33 - CD326 +). We evaluated the efficiency of flow cytometry to detect malignant epithelial cells in 238 fresh samples, including effusions, lymph node biopsies, fine needle aspirates, bone marrow aspirates, cerebrospinal fluid, among others. These are specimens expected to lack epithelial cells. FCM results were then compared to the results of smear and cell block morphology, as well as immunocytochemistry on paraffin wax embedded cell blocks, when available. Final diagnosis was the gold standard and a very good sensitivity (96.7%) and specificity (99.3%) were obtained. We concluded that the detection of CD326 positive cells using FCM is strongly indicative of the presence of carcinoma cells. (c) 2015 International Clinical Cytometry Society. PMID- 26054019 TI - Prospective Validation of Central Line-Days Derived From an Electronic Medical Record System. AB - Validation of the number of central line-days by hospitals is required by the National Healthcare Safety Network. A prospective study that compared a daily report of such days generated by an electronic medical record with observational audits by nurses revealed that the report was 100% sensitive and 99.9% specific. PMID- 26054020 TI - MiR-199a-5p is negatively associated with malignancies and regulates glycolysis and lactate production by targeting hexokinase 2 in liver cancer. AB - Cancer cells possess a unique metabolic phenotype that allows them to preferentially utilize glucose through aerobic glycolysis. This phenomenon is referred to as the "Warburg effect." Accumulating evidence suggests that microRNAs (miRNAs), a class of small noncoding regulatory RNAs, interact with oncogenes/tumor suppressors and induce such metabolic reprograming in cancer cells. To systematically study the metabolic roles of miRNAs in cancer cells, we developed a gain-of-function miRNA screen in HeLa cells. Subsequent investigation of the characterized miRNAs indicated that miR-199a-5p acts as a suppressor for glucose metabolism. Furthermore, miR-199a-5p is often down-regulated in human liver cancer, and its low expression level was correlated with a low survival rate, large tumor size, poor tumor differentiation status, high tumor-node metastasis stage and the presence of tumor thrombus of patients. MicroRNA-199a-5p directly targets the 3'-untranslated region of hexokinase 2 (HK2), an enzyme that catalyzes the irreversible first step of glycolysis, thereby suppressing glucose consumption, lactate production, cellular glucose-6-phosphate and adenosine triphosphate levels, cell proliferation, and tumorigenesis of liver cancer cells. Moreover, HK2 is frequently up-regulated in liver cancer tissues and associated with poor patient outcomes. The up-regulation of hypoxia-inducible factor-1alpha under hypoxic conditions suppresses the expression of miR-199a-5p and promotes glycolysis, whereas reintroduction of miR-199a-5p interferes with the expression of HK2, abrogating hypoxia-enhanced glycolysis. CONCLUSION: miR-199a-5p/HK2 reprograms the metabolic process in liver cancer cells and provides potential prognostic predictors for liver cancer patients. PMID- 26054021 TI - A three-component reaction for rapid access to underexplored 1,3-thiazine-2 thiones. AB - Driven by the shortage of known effective possibilities for the synthesis of 4 hydroxy-3,4-dihydro-2H-1,3-thiazine-2-thiones on the one hand and the promising potential of these structures as novel drug candidates on the other hand, synthetic access to 4-hydroxy-3,4-dihydro-2H-1,3-thiazine-2-thiones was developed. The desired products could be synthesized effectively and facilely starting from beta-chlorovinyl aldehydes with the aid of a new MCR (multicomponent reaction). Furthermore, the 4-hydroxy-3,4-dihydro-2H-1,3-thiazine 2-thiones are shown to be appropriate substrates in the preparation of diverse annulated polycyclic systems. PMID- 26054022 TI - Potential uses of Bayesian networks as tools for synthesis of systematic reviews of complex interventions. AB - Bayesian networks (BNs) are tools for representing expert knowledge or evidence. They are especially useful for synthesising evidence or belief concerning a complex intervention, assessing the sensitivity of outcomes to different situations or contextual frameworks and framing decision problems that involve alternative types of intervention. Bayesian networks are useful extensions to logic maps when initiating a review or to facilitate synthesis and bridge the gap between evidence acquisition and decision-making. Formal elicitation techniques allow development of BNs on the basis of expert opinion. Such applications are useful alternatives to 'empty' reviews, which identify knowledge gaps but fail to support decision-making. Where review evidence exists, it can inform the development of a BN. We illustrate the construction of a BN using a motivating example that demonstrates how BNs can ensure coherence, transparently structure the problem addressed by a complex intervention and assess sensitivity to context, all of which are critical components of robust reviews of complex interventions. We suggest that BNs should be utilised to routinely synthesise reviews of complex interventions or empty reviews where decisions must be made despite poor evidence. PMID- 26054023 TI - Robust variance estimation with dependent effect sizes: practical considerations including a software tutorial in Stata and spss. AB - Methodologists have recently proposed robust variance estimation as one way to handle dependent effect sizes in meta-analysis. Software macros for robust variance estimation in meta-analysis are currently available for Stata (StataCorp LP, College Station, TX, USA) and spss (IBM, Armonk, NY, USA), yet there is little guidance for authors regarding the practical application and implementation of those macros. This paper provides a brief tutorial on the implementation of the Stata and spss macros and discusses practical issues meta analysts should consider when estimating meta-regression models with robust variance estimates. Two example databases are used in the tutorial to illustrate the use of meta-analysis with robust variance estimates. PMID- 26054024 TI - Pinpointing needles in giant haystacks: use of text mining to reduce impractical screening workload in extremely large scoping reviews. AB - In scoping reviews, boundaries of relevant evidence may be initially fuzzy, with refined conceptual understanding of interventions and their proposed mechanisms of action an intended output of the scoping process rather than its starting point. Electronic searches are therefore sensitive, often retrieving very large record sets that are impractical to screen in their entirety. This paper describes methods for applying and evaluating the use of text mining (TM) technologies to reduce impractical screening workload in reviews, using examples of two extremely large-scale scoping reviews of public health evidence (choice architecture (CA) and economic environment (EE)). Electronic searches retrieved >800,000 (CA) and >1 million (EE) records. TM technologies were used to prioritise records for manual screening. TM performance was measured prospectively. TM reduced manual screening workload by 90% (CA) and 88% (EE) compared with conventional screening (absolute reductions of ~430 000 (CA) and ~378 000 (EE) records). This study expands an emerging corpus of empirical evidence for the use of TM to expedite study selection in reviews. By reducing screening workload to manageable levels, TM made it possible to assemble and configure large, complex evidence bases that crossed research discipline boundaries. These methods are transferable to other scoping and systematic reviews incorporating conceptual development or explanatory dimensions. PMID- 26054025 TI - Techniques for identifying cross-disciplinary and 'hard-to-detect' evidence for systematic review. AB - Driven by necessity in our own complex review, we developed alternative systematic ways of identifying relevant evidence where the key concepts are generally not focal to the primary studies' aims and are found across multiple disciplines-that is, hard-to-detect evidence. Specifically, we sought to identify evidence on community engagement in public health interventions that aim to reduce health inequalities. Our initial search strategy used text mining to identify synonyms for the concept 'community engagement'. We conducted a systematic search for reviews on public health interventions, supplemented by searches of trials databases. We then used information in the reviews' evidence tables to gather more information about the included studies than was evident in the primary studies' own titles or abstracts. We identified 319 primary studies cited in reviews after full-text screening. In this paper, we retrospectively reflect on the challenges and benefits of the approach taken. We estimate that more than a quarter of the studies that were identified would have been missed by typical searching and screening methods. This identification strategy was highly effective and could be useful for reviews of broad research questions, or where the key concepts are unlikely to be the main focus of primary research. PMID- 26054026 TI - Meta-regression approximations to reduce publication selection bias. AB - Publication selection bias is a serious challenge to the integrity of all empirical sciences. We derive meta-regression approximations to reduce this bias. Our approach employs Taylor polynomial approximations to the conditional mean of a truncated distribution. A quadratic approximation without a linear term, precision-effect estimate with standard error (PEESE), is shown to have the smallest bias and mean squared error in most cases and to outperform conventional meta-analysis estimators, often by a great deal. Monte Carlo simulations also demonstrate how a new hybrid estimator that conditionally combines PEESE and the Egger regression intercept can provide a practical solution to publication selection bias. PEESE is easily expanded to accommodate systematic heterogeneity along with complex and differential publication selection bias that is related to moderator variables. By providing an intuitive reason for these approximations, we can also explain why the Egger regression works so well and when it does not. These meta-regression methods are applied to several policy-relevant areas of research including antidepressant effectiveness, the value of a statistical life, the minimum wage, and nicotine replacement therapy. PMID- 26054027 TI - Assessing baseline imbalance in randomised trials: implications for the Cochrane risk of bias tool. AB - A key component of the Cochrane Collaboration's risk of bias tool for critically evaluating randomised trials is the consideration of whether baseline characteristics of the treatment groups being compared are systematically different. Considered under the domain of 'selection bias', this is currently evaluated by looking at the methods of randomisation and specifically at the generation of the randomised allocation sequence and the concealment of this sequence during the process of randomisation. Assessment of the actual similarity of baseline variables across groups in demographic and clinical characteristics is seldom performed. Even when performed, the link with selection bias is sometimes not considered. Methods of randomisation and allocation concealment are often poorly reported in published trials, yet baseline data tables are presented in a large majority of trial reports. In this article, we propose that assessment of trial baseline data should form a key and prominent part of selection bias judgements when using the risk of bias tool. We outline the possible benefits from using this approach, including reduced uncertainty in systematic review conclusions, reduced risk of chance findings being ascribed to treatment effects and better use of available evidence by a more considered approach to evaluating studies using imperfect randomisation and allocation methods. PMID- 26054028 TI - Two-by-two table contradicts study's conclusions on tongue colour. PMID- 26054029 TI - Intermittent catheterisation for long-term bladder management (abridged cochrane review). AB - AIMS: To review the evidence on strategies to reduce UTI, other complications or improve satisfaction in intermittent catheter (IC) users by comparing: (1) one catheter design, material or technique versus another; (2) sterile technique versus clean; or (3) single-use (sterile) or multiple-use (clean) catheters. METHODS: We searched Cochrane Incontinence Group Specialised Trials Register, MEDLINE, EMBASE, CINAHL, ERIC, reference lists, and conference proceedings to November 2013. We contacted other investigators for unpublished data or clarification. Trial screening, assessment and data abstraction were all in accordance with the Cochrane handbook. RESULTS: Thirty one trials (13 RCTs and 18 randomized crossover trials), addressed the inclusion criteria comparing method or design and UTI/bacteriuria, other complications or participant assessed outcomes. Studies varied widely in follow-up, UTI definition and attrition; in some, data could not be combined. Where there were data, confidence intervals were wide and hence clinically important differences could neither be reliably identified nor ruled out. CONCLUSIONS: Current research evidence is weak and design issues are significant. It has not yet been established whether incidence of UTI, other complications such as haematuria, or user satisfaction are affected by sterile or clean technique, coated or uncoated catheters, single or multiple use catheters or by any other strategy. For people using IC, choice of catheter will depend on personal preference, cost, portability, and ease of use. Individuals should discuss the catheter options with their healthcare practitioner. Cost-effectiveness analysis and use of the standard definition of UTI are essential in any proposed clinical trial. PMID- 26054030 TI - Nodulation Characterization and Proteomic Profiling of Bradyrhizobium liaoningense CCBAU05525 in Response to Water-Soluble Humic Materials. AB - The lignite biodegradation procedure to produce water-soluble humic materials (WSHM) with a Penicillium stain was established by previous studies in our laboratory. This study researched the effects of WSHM on the growth of Bradyrhizobium liaoningense CCBAU05525 and its nodulation on soybean. Results showed that WSHM enhanced the cell density of CCBAU05525 in culture, and increased the nodule number, nodule fresh weight and nitrogenase activity of the inoculated soybean plants. Then the chemical compounds of WSHM were analyzed and flavonoid analogues were identified in WSHM through tetramethyl ammonium hydroxide (TMAH)-py-GC/MS analysis. Protein expression profiles and nod gene expression of CCBAU05525 in response to WSHM or genistein were compared to illustrate the working mechanism of WSHM. The differently expressed proteins in response to WSHM were involved in nitrogen and carbon metabolism, nucleic acid metabolism, signaling, energy production and some transmembrane transports. WSHM was found more effective than genistein in inducing the nod gene expression. These results demonstrated that WSHM stimulated cell metabolism and nutrient transport, which resulted in increased cell density of CCBAU05525 and prepared the bacteria for better bacteroid development. Furthermore, WSHM had similar but superior functions to flavone in inducing nod gene and nitrogen fixation related proteins expression in CCBAU05525. PMID- 26054032 TI - Rotational self-diffusion in suspensions of charged particles: simulations and revised Beenakker-Mazur and pairwise additivity methods. AB - We present a comprehensive joint theory-simulation study of rotational self diffusion in suspensions of charged particles whose interactions are modeled by the generic hard-sphere plus repulsive Yukawa (HSY) pair potential. Elaborate, high-precision simulation results for the short-time rotational self-diffusion coefficient, D(r), are discussed covering a broad range of fluid-phase state points in the HSY model phase diagram. The salient trends in the behavior of D(r) as a function of reduced potential strength and range, and particle concentration, are systematically explored and physically explained. The simulation results are further used to assess the performance of two semi analytic theoretical methods for calculating D(r). The first theoretical method is a revised version of the classical Beenakker-Mazur method (BM) adapted to rotational diffusion which includes a highly improved treatment of the salient many-particle hydrodynamic interactions. The second method is an easy-to implement pairwise additivity (PA) method in which the hydrodynamic interactions are treated on a full two-body level with lubrication corrections included. The static pair correlation functions required as the only input to both theoretical methods are calculated using the accurate Rogers-Young integral equation scheme. While the revised BM method reproduces the general trends of the simulation results, it significantly underestimates D(r). In contrast, the PA method agrees well with the simulation results for D(r) even for intermediately concentrated systems. A simple improvement of the PA method is presented which is applicable for large concentrations. PMID- 26054031 TI - Statin Therapy and Risk of Acute Memory Impairment. AB - IMPORTANCE: Reports on the association between statins and memory impairment are inconsistent. OBJECTIVE: To assess whether statin users show acute decline in memory compared with nonusers and with users of nonstatin lipid-lowering drugs (LLDs). DESIGN, SETTING, AND PARTICIPANTS: Using The Health Improvement Network database during January 13, 1987, through December 16, 2013, a retrospective cohort study compared 482,543 statin users with 2 control groups: 482,543 matched nonusers of any LLDs and all 26,484 users of nonstatin LLDs. A case-crossover study of 68,028 patients with incident acute memory loss evaluated exposure to statins during the period immediately before the outcome vs 3 earlier periods. Analysis was conducted from July 7, 2013, through January 15, 2015. RESULTS: When compared with matched nonusers of any LLDs (using odds ratio [95% CI]), a strong association was present between first exposure to statins and incident acute memory loss diagnosed within 30 days immediately following exposure (fully adjusted, 4.40; 3.01-6.41). This association was not reproduced in the comparison of statins vs nonstatin LLDs (fully adjusted, 1.03; 0.63-1.66) but was also present when comparing nonstatin LLDs with matched nonuser controls (adjusted, 3.60; 1.34-9.70). The case-crossover analysis showed little association. CONCLUSIONS AND RELEVANCE: Both statin and nonstatin LLDs were strongly associated with acute memory loss in the first 30 days following exposure in users compared with nonusers but not when compared with each other. Thus, either all LLDs cause acute memory loss regardless of drug class or the association is the result of detection bias rather than a causal association. PMID- 26054033 TI - PSOFuzzySVM-TMH: identification of transmembrane helix segments using ensemble feature space by incorporated fuzzy support vector machine. AB - Membrane protein is a central component of the cell that manages intra and extracellular processes. Membrane proteins execute a diversity of functions that are vital for the survival of organisms. The topology of transmembrane proteins describes the number of transmembrane (TM) helix segments and its orientation. However, owing to the lack of its recognized structures, the identification of TM helix and its topology through experimental methods is laborious with low throughput. In order to identify TM helix segments reliably, accurately, and effectively from topogenic sequences, we propose the PSOFuzzySVM-TMH model. In this model, evolutionary based information position specific scoring matrix and discrete based information 6-letter exchange group are used to formulate transmembrane protein sequences. The noisy and extraneous attributes are eradicated using an optimization selection technique, particle swarm optimization, from both feature spaces. Finally, the selected feature spaces are combined in order to form ensemble feature space. Fuzzy-support vector Machine is utilized as a classification algorithm. Two benchmark datasets, including low and high resolution datasets, are used. At various levels, the performance of the PSOFuzzySVM-TMH model is assessed through 10-fold cross validation test. The empirical results reveal that the proposed framework PSOFuzzySVM-TMH outperforms in terms of classification performance in the examined datasets. It is ascertained that the proposed model might be a useful and high throughput tool for academia and research community for further structure and functional studies on transmembrane proteins. PMID- 26054034 TI - The Human Shoulder Suspension Apparatus: A Causal Explanation for Bilateral Asymmetry and a Fresh Look at the Evolution of Human Bipedality. AB - The combination of large mastoid processes and clavicles is unique to humans, but the biomechanical and evolutionary significance of their special configuration is poorly understood. As part of the newly conceptualized shoulder suspension apparatus, the mastoid processes and clavicles are shaped by forces exerted by the musculo-fascial components of the cleidomastoid and clavotrapezius muscles as they suspend the shoulders from the head. Because both skeletal elements develop during infancy in tandem with the attainment of an upright posture, increased manual dexterity, and the capacity for walking, we hypothesized that the same forces would have shaped them as the shoulder suspension apparatus evolved in ancestral humans in tandem with an upright posture, increased manual dexterity, and bipedality with swinging arms. Because the shoulder suspension apparatus is subjected to asymmetrical forces from handedness, we predicted that its skeletal features would grow asymmetrically. We used this prediction to test our hypothesis in a natural experiment to correlate the size of the skeletal features with the forces exerted on them. We (1) measured biomechanically relevant bony features within the shoulder suspension apparatus in 101 male human specimens (62 of known handedness); and (2) modeled and analyzed the forces within the shoulder suspension apparatus from X-ray CT data. We identified eight right-handed characters and demonstrated the causal relationship between these right-handed characters and the magnitude and direction of forces acting on them. Our data suggest that the presence of the shoulder suspension apparatus in humans was a necessary precondition for human bipedality. PMID- 26054036 TI - Plasticity in striatopallidal projection neurons mediates the acquisition of habitual actions. AB - In instrumental conditioning, newly acquired actions are generally goal-directed and are mediated by the relationship between the action and its consequences or outcome. With continued training, however, the performance of such actions can become automatic, reflexive or habitual and under the control of antecedent stimuli rather than their consequences. Recent evidence suggests that habit learning is mediated by plasticity in the dorsolateral striatum (DLS). To date, however, no direct evidence of learning-related plasticity associated with overtraining has been reported in this region, nor is it known whether, or which, specific cell types are involved in this learning process. The striatum is primarily composed of two classes of spiny projection neurons, the striatonigral and striatopallidal spiny projection neurons, which express dopamine D1 and D2 receptors, and control direct and indirect pathways, respectively. Here we found evidence of a post-synaptic depression in DLS striatopallidal projecting neurons in the indirect pathway during habit learning in mice. Moreover, this training induced depression occluded post-synaptic depression induced by co-activation of D2 receptors and transient receptor potential vanilloid 1 (TRPV1) channels, implying that this pathway is involved in habit learning. This hypothesis was further tested by disrupting this signal pathway by knocking out TRPV1 channels, resulting in compromised habit learning. Our findings suggest that post-synaptic plasticity at D2 neurons in the DLS mediates habit learning and, by implicating an interaction between the D2 receptor and TRPV1 channel activity, provide a potential drug target for influencing habitual action control. PMID- 26054035 TI - Internalization of silver nanoparticles into mouse spermatozoa results in poor fertilization and compromised embryo development. AB - Silver nanoparticles (AgNPs) have many features that make them attractive as medical devices, especially in therapeutic agents and drug delivery systems. Here we have introduced AgNPs into mouse spermatozoa and then determined the cytotoxic effects of AgNPs on sperm function and subsequent embryo development. Scanning electron microscopy and transmission electron microscopy analyses showed that AgNPs could be internalized into sperm cells. Furthermore, exposure to AgNPs inhibited sperm viability and the acrosome reaction in a dose-dependent manner, whereas sperm mitochondrial copy numbers, morphological abnormalities, and mortality due to reactive oxygen species were significantly increased. Likewise, sperm abnormalities due to AgNPs internalization significantly decreased the rate of oocyte fertilization and blastocyst formation. Blastocysts obtained from AgNPs treated spermatozoa showed lower expression of trophectoderm-associated and pluripotent marker genes. Overall, we propose that AgNPs internalization into spermatozoa may alter sperm physiology, leading to poor fertilization and embryonic development. Such AgNPs-induced reprotoxicity may be a valuable tool as models for testing the safety and applicability of medical devices using AgNPs. PMID- 26054037 TI - Meta-analysis comparing higher and lower dose radiotherapy for palliation in locally advanced lung cancer. PMID- 26054038 TI - Response to "A meta-analysis comparing higher and lower dose radiotherapy for palliation in locally advanced lung cancer". PMID- 26054041 TI - Social networks and substance use among at-risk emerging adults living in disadvantaged urban areas in the southern United States: a cross-sectional naturalistic study. AB - BACKGROUND AND AIMS: Substance use and risk-taking are common during emerging adulthood, a transitional period when peer influences often increase and family influences decrease. Investigating relationships between social network features and substance use can inform community-based prevention programs. This study investigated whether substance use among emerging adults living in disadvantaged urban areas was influenced by peer and family social network messages that variously encouraged and discouraged substance use. DESIGN: Cross-sectional, naturalistic field study. SETTING AND PARTICIPANTS: Lower-income neighborhoods in Birmingham, Alabama, USA with 344 participants (110 males, 234 females, ages 15 25 years; mean = 18.86 years), recruited via respondent-driven sampling. MEASUREMENTS: During structured interviews conducted in community locations, the Alcohol, Smoking and Substance Involvement Screening Test assessed substance use and related problems. Predictor variables were network characteristics, including presence of substance-using peers, messages from friends and family members about substance use and network sources for health information. FINDINGS: Higher substance involvement was associated with friend and family encouragement of use and having close peer network members who used substances (Ps < 0.001). Peer discouragement of substance use was associated with reduced risk (b = - 1.46, P < 0.05), whereas family discouragement had no protective association. CONCLUSIONS: Social networks appear to be important in both promoting and preventing substance use in disadvantaged young adults in the United States. PMID- 26054042 TI - Evaluation of disease-mediated therapeutic protein-drug interactions between an anti-interleukin-6 monoclonal antibody (sirukumab) and cytochrome P450 activities in a phase 1 study in patients with rheumatoid arthritis using a cocktail approach. AB - This therapeutic protein-drug interaction study evaluated the disease-mediated effect of sirukumab (anti-interleukin 6 [anti-IL-6] monoclonal antibody) on the pharmacokinetics of the cytochrome P450 (CYP) probe substrates midazolam (CYP3A), omeprazole (CYP2C19), warfarin (CYP2C9), and caffeine (CYP1A2) in patients with active rheumatoid arthritis (RA). Twelve patients with C-reactive protein (CRP) >= 8.0 mg/L at screening received oral administration of a CYP probe cocktail consisting of 0.03 mg/kg midazolam, 10 mg warfarin + 10 mg vitamin K (equivalent to 5 mg S-warfarin), 20 mg omeprazole, and 100 mg caffeine 1 week before and 1, 3, and 6 weeks after a single subcutaneous dose of 300 mg sirukumab. The results showed that the pharmacokinetics of midazolam, omeprazole, and S-warfarin were nonequivalent before and after the administration of a single dose of 300 mg sirukumab. Area under the plasma concentration-time curve (AUC0- infinity ) for midazolam, omeprazole, and S-warfarin was reduced by 30%-35%, 37%-45%, and 18% 19%, respectively, after sirukumab administration. Caffeine AUC0-infinity was increased by 20%-34% after sirukumab administration. The effect of sirukumab on CYP substrates was sustained for at least 6 weeks. No new adverse drug reactions related to the administration of sirukumab were observed in this study. These results suggest that sirukumab may reverse IL-6-mediated suppression of CYP3A, CYP2C9, and CYP2C19 activities in patients with active RA. PMID- 26054043 TI - Flaccid pustules and vesicles in a middle-aged woman. PMID- 26054044 TI - Relapse and outcome patterns of patients with central nervous system mixed malignant germ cell tumors treated without irradiation: Findings from the third international central nervous system (CNS) germ cell tumor (GCT) study. AB - OBJECTIVES: To evaluate patterns of relapse and outcome in patients newly diagnosed with CNS Mixed Malignant GCT (MMGCT) treated initially with chemotherapy alone. METHODS: A retrospective chart review was conducted using all 25 patients enrolled on the International CNS GCT Study III, with at least 7 years follow-up for all surviving patients. RESULTS: Thirteen patients at diagnosis had CNS MMGCT by pathology and tumor markers (n = 11), or tumor markers alone (n = 2). Twelve received chemotherapy alone, one additionally receiving focal irradiation prior to relapse. Six patients (46%) relapsed (mean of 30.5 months; range 6-59 months), two beyond and four within the primary site alone. Three patients relapsed early (6-23 months from diagnosis), two with alpha fetoprotein elevations and one without tumor markers assessed; all three expired of progressive disease at 2-10 months following initial relapse. Three patients relapsed late (37-59 months) without AFP elevations, one with pathologically pure germinoma, two with mild beta-human chorionic gonadotropin elevations; these patients survive disease-free at 86+, 94+, and 126+ months following additional treatment. CONCLUSIONS: Patients with CNS MMGCT relapsing following chemotherapy alone display two distinct patterns of recurrence and outcome; patients relapsing early possess MMGCT elements and have a dismal prognosis, while patients relapsing late do so with pure germinomatous elements and have an excellent outcome. Current cooperative group studies utilizing more localized fields of irradiation should monitor closely the patterns of relapse and outcome; late recurrences with germinomatous elements might be avoided by initial use of low dose larger field irradiation in select patients. PMID- 26054045 TI - Molecular Origin of Strength and Stiffness in Bamboo Fibrils. AB - Bamboo, a fast-growing grass, has a higher strength-to-weight ratio than steel and concrete. The unique properties of bamboo come from the natural composite structure of fibers that consists mainly of cellulose microfibrils in a matrix of intertwined hemicellulose and lignin called lignin-carbohydrate complex (LCC). Here, we have used atomistic simulations to study the mechanical properties of and adhesive interactions between the materials in bamboo fibers. With this aim, we have developed molecular models of lignin, hemicellulose and LCC structures to study the elastic moduli and the adhesion energies between these materials and cellulose microfibril faces. Good agreement was observed between the simulation results and experimental data. It was also shown that the hemicellulose model has stronger mechanical properties than lignin while lignin exhibits greater tendency to adhere to cellulose microfibrils. The study suggests that the abundance of hydrogen bonds in hemicellulose chains is responsible for improving the mechanical behavior of LCC. The strong van der Waals forces between lignin molecules and cellulose microfibril is responsible for higher adhesion energy between LCC and cellulose microfibrils. We also found out that the amorphous regions of cellulose microfibrils are the weakest interfaces in bamboo fibrils. Hence, they determine the fibril strength. PMID- 26054046 TI - Repeatability of Mice Consumption Discrimination of Wheat (Triticum aestivum L.) Varieties across Field Experiments and Mouse Cohorts. AB - Whole grain wheat (Triticum aestivum L.) foods can provide critical nutrients for health and nutrition in the human diet. Potential flavor differences among varieties can be examined using consumption discrimination of the house mouse (Mus musculus L.) as a model system. This study examines consistency and repeatability of the mouse model and potentially, wheat grain flavor. A single elimination tournament design was used to measure relative consumption preference for hard red spring and hard white spring varieties across all 3 experiments in combination with 2 mouse cohorts. Fifteen replicate mice were used in 24-h trials to examine differences in preference among paired wheat varieties until an overall "winner" was established as the most highly preferred variety of wheat. In all 3 experiment-cohort combinations, the same varieties were preferred as the "winner" of both the hard red spring and hard white spring wheat varieties, Hollis and BR 7030, respectively. Despite the consistent preference for these varieties across experiments, the degree (magnitude) to which the mice preferred these varieties varied across experiments. For the hard white spring wheat varieties, the small number of varieties and confounding effects of experiment and cohort limited our ability to accurately gauge repeatability. Conversely, for the hard red spring wheat varieties, consumption preferences were consistent across experiments and mice cohorts. The single-elimination tournament model was effective in providing repeatable results in an effort to more fully understand the mouse model system and possible flavor differences among wheat varieties. PRACTICAL APPLICATION: The mouse model system used here is effective in identifying wheat varieties that may be more or less desirable to humans in whole wheat foods. The system identifies consistent differences across different mouse cohorts and crop years. PMID- 26054047 TI - Alternatives to Hazard Ratios for Comparing the Efficacy or Safety of Therapies in Noninferiority Studies. AB - A noninferiority study is often used to investigate whether a treatment's efficacy or safety profile is acceptable compared with an alternative therapy regarding the time to a clinical event. The empirical quantification of the treatment difference for such a study is routinely based on the hazard ratio (HR) estimate. The HR, which is not a relative risk, may be difficult to interpret clinically, especially when the underlying proportional hazards assumption is violated. The precision of the HR estimate depends primarily on the number of observed events but not directly on exposure times or sample size of the study population. If the event rate is low, the study may require an impractically large number of events to ensure that the prespecified noninferiority criterion for the HR is attainable. This article discusses deficiencies in the current approach for the design and analysis of a noninferiority study. Alternative procedures are provided, which do not depend on any model assumption, to compare 2 treatments. For a noninferiority safety study, the patients' exposure times are more clinically important than the observed number of events. If the patients' exposure times are long enough to evaluate safety reliably, then these alternative procedures can effectively provide clinically interpretable evidence on safety, even with relatively few observed events. These procedures are illustrated with data from 2 studies. One explores the cardiovascular safety of a pain medicine; the second examines the cardiovascular safety of a new treatment for diabetes. These alternative strategies to evaluate safety or efficacy of an intervention lead to more meaningful interpretations of the analysis results than the conventional strategy that uses the HR estimate. PMID- 26054048 TI - Vertical split-ring resonator based anomalous beam steering with high extinction ratio. AB - Metasurfaces created artificially with metal nanostructures that are patterned on surfaces of different media have shown to possess "unusual" abilities to manipulate light. Limited by nanofabrication difficulties, so far most reported works have been based on 2D metal structures. We have recently developed an advanced e-beam process that allowed for the deposition of 3D nanostructures, namely vertical split-ring resonators (VSRRs), which opens up another degree of freedom in the metasurface design. Here we explore the functionality of beam steering with phase modulation by tuning only the vertical dimension of the VSRRs and show that anomalous steering reflection of a wide range of angles can be accomplished with high extinction ratio using the finite-difference-time-domain simulation. We also demonstrate that metasurfaces made of 3D VSRRs can be made with roughly half of the footprint compared to that of 2D nano-rods, enabling high density integration of metal nanostructures. PMID- 26054049 TI - Effect of reducing portion size at a compulsory meal on later energy intake, gut hormones, and appetite in overweight adults. AB - OBJECTIVE: Larger portion sizes (PS) are associated with greater energy intake (EI), but little evidence exists on the appetitive effects of PS reduction. This study investigated the impact of reducing breakfast PS on subsequent EI, postprandial gastrointestinal hormone responses, and appetite ratings. METHODS: In a randomized crossover design (n = 33 adults; mean BMI 29 kg/m(2) ), a compulsory breakfast was based on 25% of gender-specific estimated daily energy requirements; PS was reduced by 20% and 40%. EI was measured at an ad libitum lunch (240 min) and snack (360 min) and by weighed diet diaries until bed. Blood was sampled until lunch in 20 participants. Appetite ratings were measured using visual analogue scales. RESULTS: EI at lunch (control: 2,930 +/- 203; 20% reduction: 2,853 +/- 198; 40% reduction: 2,911 +/- 179 kJ) and over the whole day except breakfast (control: 7,374 +/- 361; 20% reduction: 7,566 +/- 468; 40% reduction: 7,413 +/- 417 kJ) did not differ. Postprandial PYY, GLP-1, GIP, insulin, and fullness profiles were lower and hunger, desire to eat, and prospective consumption higher following 40% reduction compared to control. Appetite ratings profiles, but not hormone concentrations, were associated with subsequent EI. CONCLUSIONS: Smaller portions at breakfast led to reductions in gastrointestinal hormone secretion but did not affect subsequent energy intake, suggesting small reductions in portion size may be a useful strategy to constrain EI. PMID- 26054050 TI - Metabolic Suppression of a Drug-Resistant Subpopulation in Cancer Spheroid Cells. AB - Inhibition of metabolic features which distinguish cancer cells from their non malignant counterparts is a promising approach to cancer treatment. Energy support for drug extrusion in multidrug resistance (MDR) is a potential target for metabolic inhibition. Two major sources of ATP-based metabolic energy are partial (glycolysis) and complete (mitochondrial oxidative phosphorylation) oxidation of metabolic fuels. In cancer cells, the balance between them tends to be shifted toward glycolysis; this shift is considered to be characteristic of the cancer metabolic phenotype. Numerous earlier studies, conducted with cells cultured in a monolayer (2-D model), suggested inhibition of glycolytic ATP production as an efficient tool to suppress MDR in cancer cells. Yet, more recent work challenged the appropriateness of the 2-D model for such studies and suggested that a more clinically relevant approach would utilize a more advanced cellular model such as a 3-D model. Here, we show that the transition from the 2 D model (cultured monolayer) to a 3-D model (cultured spheroids) introduces essential changes into the concept of energetic suppression of MDR. The 3-D cell organization leads to the formation of a discrete cell subpopulation (not formed in the 2-D model) with elevated MDR transport capacity. This subpopulation has a specific metabolic phenotype (mixed glycolytic/oxidative MDR support) different from that of cells cultured in the 2-D model. Finally, the shift to the oxidative phenotype becomes greater when the spheroids are grown under conditions of lactic acidosis that are typical for solid tumors. The potential clinical significance of these findings is discussed. PMID- 26054051 TI - Bayesian-based deconvolution fluorescence microscopy using dynamically updated nonstationary expectation estimates. AB - Fluorescence microscopy is widely used for the study of biological specimens. Deconvolution can significantly improve the resolution and contrast of images produced using fluorescence microscopy; in particular, Bayesian-based methods have become very popular in deconvolution fluorescence microscopy. An ongoing challenge with Bayesian-based methods is in dealing with the presence of noise in low SNR imaging conditions. In this study, we present a Bayesian-based method for performing deconvolution using dynamically updated nonstationary expectation estimates that can improve the fluorescence microscopy image quality in the presence of noise, without explicit use of spatial regularization. PMID- 26054052 TI - The importance of assessing priorities of reproductive health concerns among adolescent and young adult patients with cancer. AB - Visions for the future are a normal developmental process for adolescents and young adults (AYAs) with and without cancer, and these visions often include expectations of sexual and romantic relationships. AYA cancer survivors indicate reproductive health is an issue of great importance and more attention is needed in the health care setting throughout the cancer experience, beginning at diagnosis. Various practice guidelines are predominately focused on fertility; are intended to influence survivorship care plans; and do not encompass the broad scope of reproductive health that includes romantic partnering, friendships, body image, sexuality, sexual identity, fertility, contraception, and more. Although interventions to reduce reproductive health-related sequelae from treatment are best approached as an evolving process, practitioners are not certain of the priorities of these various reproductive health content areas. Strategies incongruent with the reproductive health priorities of AYAs will likely thwart adequate follow-up care and foster feelings of isolation from the treatment team. Research is needed to identify these priorities and ensure discussions of diverse content areas. This review explored various domains of reproductive health and emphasized how understanding the priorities of the AYA cancer cohort will guide future models of care. PMID- 26054053 TI - Lipocalin-2 (NGAL/LCN2), a "help-me" signal in organ inflammation. PMID- 26054055 TI - Estimating variability in grain legume yields across Europe and the Americas. AB - Grain legume production in Europe has recently come under scrutiny. Although legume crops are often promoted to provide environmental services, European farmers tend to turn to non-legume crops. It is assumed that high variability in legume yields explains this aversion, but so far this hypothesis has not been tested. Here, we estimate the variability of major grain legume and non-legume yields in Europe and the Americas from yield time series over 1961-2013. Results show that grain legume yields are significantly more variable than non-legume yields in Europe. These differences are smaller in the Americas. Our results are robust at the level of the statistical methods. In all regions, crops with high yield variability are allocated to less than 1% of cultivated areas. Although the expansion of grain legumes in Europe may be hindered by high yield variability, some species display risk levels compatible with the development of specialized supply chains. PMID- 26054054 TI - Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development. AB - Receptor occupancy (RO) assays are designed to quantify the binding of therapeutics to their targets on the cell surface and are frequently used to generate pharmacodynamic (PD) biomarker data in nonclinical and clinical studies of biopharmaceuticals. When combined with the pharmacokinetic (PK) profile, RO data can establish PKPD relationships, which are crucial for informing dose decisions. RO is commonly measured by flow cytometry on fresh blood specimens and is subject to numerous technical and logistical challenges. To ensure that reliable and high quality results are generated from RO assays, careful assay design, key reagent characterization, data normalization/reporting, and thorough planning for implementation are of critical importance during development. In this article, the authors share their experiences and perspectives in these areas and discuss challenges and potential solutions when developing and implementing a flow cytometry-based RO method in support of biopharmaceutical drug development. PMID- 26054057 TI - Comparison Study for Whitney (Raviart-Thomas)-Type Source Models in Finite Element-Method-Based EEG Forward Modeling. AB - This study concentrates on finite-element-method (FEM)-based electroencephalography (EEG) forward simulation in which the electric potential evoked by neural activity in the brain is to be calculated at the surface of the head. The main advantage of the FEM is that it allows realistic modeling of tissue conductivity inhomogeneity. However, it is not straightforward to apply the classical model of a dipolar source with the FEM, due to its strong singularity and the resulting irregularity. The focus of this study is on comparing different methods to cope with this problem. In particular, we evaluate the accuracy of Whitney (Raviart-Thomas)-type dipole-like source currents compared to two reference dipole modeling methods: the St. Venant and partial integration approach. Common to all these methods is that they enable direct approximation of the potential field utilizing linear basis functions. In the present context, Whitney elements are particularly interesting, as they provide a simple means to model a divergence-conforming primary current vector field satisfying the square integrability condition. Our results show that a Whitney type source model can provide simulation accuracy comparable to the present reference methods. It can lead to superior accuracy under optimized conditions with respect to both source location and orientation in a tetrahedral mesh. For random source orientations, the St. Venant approach turns out to be the method of choice over the interpolated version of the Whitney model. The overall moderate differences obtained suggest that practical aspects, such as the focality, should be prioritized when choosing a source model. PMID- 26054056 TI - Three-Dimensional Visualization of Developing Neurovascular Architecture in the Craniofacial Region of Embryonic Mice. AB - Recent studies have highlighted the mechanism of vascular and axonal guidance to ensure proper morphogenesis and organogenesis. We aimed to perform global mapping of developing neurovascular networks during craniofacial development of embryonic mice. To this end, we developed histology-based three-dimensional (3D) reconstructions using paraffin-embedded serial sections obtained from mouse embryos. All serial sections were dual-immunolabeled with Pecam1 and Pgp9.5/Gap43 cocktail antibodies. All immunolabeled serial sections were digitized with virtual microscopy to acquire high spatial resolution images. The 3D reconstructs warranted superior positional accuracy to trace the long-range connectivity of blood vessels and individual cranial nerve axons. It was feasible to depict simultaneously the details of angiogenic sprouting and axon terminal arborization and to assess quantitatively the locoregional proximity between blood vessels and cranial nerve axons. Notably, 3D views of the craniofacial region revealed the following: Branchial arch arteries and blood capillary plexi were formed without accompanying nerves at embryonic day (E) 9.5. Cranial nerve axons began to grow into the branchial arches, developing a labyrinth of small blood vessels at E10.5. Vascular remodeling occurred, and axon terminals of the maxillary, mandibular, chorda tympani, and hypoglossal nerve axons had arborized around the lateral lingual swellings at E11.5. The diverged patterning of trigeminal nerves and the arterial branches from the carotid artery became congruent at E11.5. The overall results support the advantage of dual-immunolabeling and 3D reconstruction technology to document the architecture and wiring of the developing neurovascular networks in mouse embryos. PMID- 26054058 TI - Ballistocardiogram as Proximal Timing Reference for Pulse Transit Time Measurement: Potential for Cuffless Blood Pressure Monitoring. AB - GOAL: We tested the hypothesis that the ballistocardiogram (BCG) waveform could yield a viable proximal timing reference for measuring pulse transit time (PTT). METHODS: From 15 healthy volunteers, we measured PTT as the time interval between BCG and a noninvasively measured finger blood pressure (BP) waveform. To evaluate the efficacy of the BCG-based PTT in estimating BP, we likewise measured pulse arrival time (PAT) using the electrocardiogram (ECG) as proximal timing reference and compared their correlations to BP. RESULTS: BCG-based PTT was correlated with BP reasonably well: the mean correlation coefficient (r ) was 0.62 for diastolic (DP), 0.65 for mean (MP), and 0.66 for systolic (SP) pressures when the intersecting tangent method was used as distal timing reference. Comparing four distal timing references (intersecting tangent, maximum second derivative, diastolic minimum, and systolic maximum), PTT exhibited the best correlation with BP when the systolic maximum method was used (mean r value was 0.66 for DP, 0.67 for MP, and 0.70 for SP). PTT was more strongly correlated with DP than PAT regardless of the distal timing reference: mean r value was 0.62 versus 0.51 (p = 0.07) for intersecting tangent, 0.54 versus 0.49 (p = 0.17) for maximum second derivative, 0.58 versus 0.52 (p = 0.37) for diastolic minimum, and 0.66 versus 0.60 (p = 0.10) for systolic maximum methods. The difference between PTT and PAT in estimating DP was significant (p = 0.01) when the r values associated with all the distal timing references were compared altogether. However, PAT appeared to outperform PTT in estimating SP ( p = 0.31 when the r values associated with all the distal timing references were compared altogether). CONCLUSION: We conclude that BCG is an adequate proximal timing reference in deriving PTT, and that BCG based PTT may be superior to ECG-based PAT in estimating DP. SIGNIFICANCE: PTT with BCG as proximal timing reference has potential to enable convenient and ubiquitous cuffless BP monitoring. PMID- 26054060 TI - Cognitive Behavioral Therapy for Chronic Insomnia: A Systematic Review and Meta analysis. AB - BACKGROUND: Because psychological approaches are likely to produce sustained benefits without the risk for tolerance or adverse effects associated with pharmacologic approaches, cognitive behavioral therapy for insomnia (CBT-i) is now commonly recommended as first-line treatment for chronic insomnia. PURPOSE: To determine the efficacy of CBT-i on diary measures of overnight sleep in adults with chronic insomnia. DATA SOURCES: Searches of MEDLINE, EMBASE, PsycINFO, CINAHL, the Cochrane Library, and PubMed Clinical Queries from inception to 31 March 2015, supplemented with manual screening. STUDY SELECTION: Randomized, controlled trials assessing the efficacy of face-to-face, multimodal CBT-i compared with inactive comparators on overnight sleep in adults with chronic insomnia. Studies of insomnia comorbid with medical, sleep, or psychiatric disorders were excluded. DATA EXTRACTION: Study characteristics, quality, and data were assessed independently by 2 reviewers. Main outcome measures were sleep onset latency (SOL), wake after sleep onset (WASO), total sleep time (TST), and sleep efficiency (SE%). DATA SYNTHESIS: Among 292 citations and 91 full-text articles reviewed, 20 studies (1162 participants [64% female; mean age, 56 years]) were included. Approaches to CBT-i incorporated at least 3 of the following: cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation. At the posttreatment time point, SOL improved by 19.03 (95% CI, 14.12 to 23.93) minutes, WASO improved by 26.00 (CI, 15.48 to 36.52) minutes, TST improved by 7.61 (CI, -0.51 to 15.74) minutes, and SE% improved by 9.91% (CI, 8.09% to 11.73%). Changes seemed to be sustained at later time points. No adverse outcomes were reported. LIMITATION: Narrow inclusion criteria limited applicability to patients with comorbid insomnia and other sleep problems, and accuracy of estimates at later time points was less clear. CONCLUSION: CBT-i is an effective treatment for adults with chronic insomnia, with clinically meaningful effect sizes. PRIMARY FUNDING SOURCE: None. (PROSPERO registration number: CRD42012002863). PMID- 26054059 TI - Structural and Dynamic Features of F-recruitment Site Driven Substrate Phosphorylation by ERK2. AB - The F-recruitment site (FRS) of active ERK2 binds F-site (Phe-x-Phe-Pro) sequences found downstream of the Ser/Thr phospho-acceptor on cellular substrates. Here we apply NMR methods to analyze the interaction between active ERK2 (ppERK2), and a 13-residue F-site-bearing peptide substrate derived from its cellular target, the transcription factor Elk-1. Our results provide detailed insight into previously elusive structural and dynamic features of FRS/F-site interactions and FRS-driven substrate phosphorylation. We show that substrate F site engagement significantly quenches slow dynamics involving the ppERK2 activation-loop and the FRS. We also demonstrate that the F-site phenylalanines make critical contacts with ppERK2, in contrast to the proline whose cis-trans isomerization has no significant effect on F-site recognition by the kinase FRS. Our results support a mechanism where phosphorylation of the disordered N terminal phospho-acceptor is facilitated by its increased productive encounters with the ppERK2 active site due to docking of the proximal F-site at the kinase FRS. PMID- 26054061 TI - Species interactions determine the spatial mortality patterns emerging in plant communities after extreme events. AB - Gap disturbance is assumed to maintain species diversity by creating environmental heterogeneity. However, little is known about how interactions with neighbours, such as competition and facilitation, alter the emerging gap patterns after extreme events. Using a spatially explicit community model we demonstrate that negative interactions, especially intraspecific competition, greatly promote both average gap size and gap-size diversity relative to positive interspecific interaction. This suggests that competition would promote diversity maintenance but also increase community invasibility, as large gaps with a wide size variety provide more diverse niches for both local and exotic species. Under interspecific competition, both gap metrics interestingly increased with species richness, while they were reduced under intraspecific competition. Having a wider range of species interaction strengths led to a smaller average gap size only under intraspecific competition. Increasing conspecific clumping induced larger gaps with more variable sizes under intraspecific competition, in contrast to interspecific competition. Given the range of intraspecific clumping in real communities, models or experiments based on randomly synthesized communities may yield biased estimates of the opportunities for potential colonizers to fill gaps. Overall, our "static" model on gap formation offers perspectives to better predict recolonization opportunity and thus community secondary succession under extreme event regimes. PMID- 26054062 TI - Biomechanically Constrained Surface Registration: Application to MR-TRUS Fusion for Prostate Interventions. AB - In surface-based registration for image-guided interventions, the presence of missing data can be a significant issue. This often arises with real-time imaging modalities such as ultrasound, where poor contrast can make tissue boundaries difficult to distinguish from surrounding tissue. Missing data poses two challenges: ambiguity in establishing correspondences; and extrapolation of the deformation field to those missing regions. To address these, we present a novel non-rigid registration method. For establishing correspondences, we use a probabilistic framework based on a Gaussian mixture model (GMM) that treats one surface as a potentially partial observation. To extrapolate and constrain the deformation field, we incorporate biomechanical prior knowledge in the form of a finite element model (FEM). We validate the algorithm, referred to as GMM-FEM, in the context of prostate interventions. Our method leads to a significant reduction in target registration error (TRE) compared to similar state-of-the-art registration algorithms in the case of missing data up to 30%, with a mean TRE of 2.6 mm. The method also performs well when full segmentations are available, leading to TREs that are comparable to or better than other surface-based techniques. We also analyze robustness of our approach, showing that GMM-FEM is a practical and reliable solution for surface-based registration. PMID- 26054063 TI - No-reference image sharpness assessment in autoregressive parameter space. AB - In this paper, we propose a new no-reference (NR)/blind sharpness metric in the autoregressive (AR) parameter space. Our model is established via the analysis of AR model parameters, first calculating the energy- and contrast-differences in the locally estimated AR coefficients in a pointwise way, and then quantifying the image sharpness with percentile pooling to predict the overall score. In addition to the luminance domain, we further consider the inevitable effect of color information on visual perception to sharpness and thereby extend the above model to the widely used YIQ color space. Validation of our technique is conducted on the subsets with blurring artifacts from four large-scale image databases (LIVE, TID2008, CSIQ, and TID2013). Experimental results confirm the superiority and efficiency of our method over existing NR algorithms, the stateof the-art blind sharpness/blurriness estimators, and classical full-reference quality evaluators. Furthermore, the proposed metric can be also extended to stereoscopic images based on binocular rivalry, and attains remarkably high performance on LIVE3D-I and LIVE3D-II databases. PMID- 26054064 TI - Image Quality Assessment Using Human Visual DOG Model Fused With Random Forest. AB - Objective image quality assessment (IQA) plays an important role in the development of multimedia applications. Prediction of IQA metric should be consistent with human perception. The release of the newest IQA database (TID2013) challenges most of the widely used quality metrics (e.g., peak-to-noise ratio and structure similarity index). We propose a new methodology to build the metric model using a regression approach. The new IQA score is set to be the nonlinear combination of features extracted from several difference of Gaussian (DOG) frequency bands, which mimics the human visual system (HVS). Experimental results show that the random forest regression model trained by the proposed DOG feature is highly correspondent to the HVS and is also robust when tested by available databases. PMID- 26054065 TI - Inner and inter label propagation: salient object detection in the wild. AB - In this paper, we propose a novel label propagation-based method for saliency detection. A key observation is that saliency in an image can be estimated by propagating the labels extracted from the most certain background and object regions. For most natural images, some boundary superpixels serve as the background labels and the saliency of other superpixels are determined by ranking their similarities to the boundary labels based on an inner propagation scheme. For images of complex scenes, we further deploy a threecue-center-biased objectness measure to pick out and propagate foreground labels. A co-transduction algorithm is devised to fuse both boundary and objectness labels based on an inter propagation scheme. The compactness criterion decides whether the incorporation of objectness labels is necessary, thus greatly enhancing computational efficiency. Results on five benchmark data sets with pixelwise accurate annotations show that the proposed method achieves superior performance compared with the newest state-of-the-arts in terms of different evaluation metrics. PMID- 26054066 TI - Fast image interpolation via random forests. AB - This paper proposes a two-stage framework for fast image interpolation via random forests (FIRF). The proposed FIRF method gives high accuracy, as well as requires low computation. The underlying idea of this proposed work is to apply random forests to classify the natural image patch space into numerous subspaces and learn a linear regression model for each subspace to map the low-resolution image patch to high-resolution image patch. The FIRF framework consists of two stages. Stage 1 of the framework removes most of the ringing and aliasing artifacts in the initial bicubic interpolated image, while Stage 2 further refines the Stage 1 interpolated image. By varying the number of decision trees in the random forests and the number of stages applied, the proposed FIRF method can realize computationally scalable image interpolation. Extensive experimental results show that the proposed FIRF(3, 2) method achieves more than 0.3 dB improvement in peak signal-to-noise ratio over the state-of-the-art nonlocal autoregressive modeling (NARM) method. Moreover, the proposed FIRF(1, 1) obtains similar or better results as NARM while only takes its 0.3% computational time. PMID- 26054067 TI - Adaptive Metric Learning for Saliency Detection. AB - In this paper, we propose a novel adaptive metric learning algorithm (AML) for visual saliency detection. A key observation is that the saliency of a superpixel can be estimated by the distance from the most certain foreground and background seeds. Instead of measuring distance on the Euclidean space, we present a learning method based on two complementary Mahalanobis distance metrics: 1) generic metric learning (GML) and 2) specific metric learning (SML). GML aims at the global distribution of the whole training set, while SML considers the specific structure of a single image. Considering that multiple similarity measures from different views may enhance the relevant information and alleviate the irrelevant one, we try to fuse the GML and SML together and experimentally find the combining result does work well. Different from the most existing methods which are directly based on low-level features, we devise a superpixelwise Fisher vector coding approach to better distinguish salient objects from the background. We also propose an accurate seeds selection mechanism and exploit contextual and multiscale information when constructing the final saliency map. Experimental results on various image sets show that the proposed AML performs favorably against the state-of-the-arts. PMID- 26054068 TI - Continuous Depth Map Reconstruction From Light Fields. AB - In this paper, we investigate how the recently emerged photography technology- the light field--can benefit depth map estimation, a challenging computer vision problem. A novel framework is proposed to reconstruct continuous depth maps from light field data. Unlike many traditional methods for the stereo matching problem, the proposed method does not need to quantize the depth range. By making use of the structure information amongst the densely sampled views in light field data, we can obtain dense and relatively reliable local estimations. Starting from initial estimations, we go on to propose an optimization method based on solving a sparse linear system iteratively with a conjugate gradient method. Two different affinity matrices for the linear system are employed to balance the efficiency and quality of the optimization. Then, a depth-assisted segmentation method is introduced so that different segments can employ different affinity matrices. Experiment results on both synthetic and real light fields demonstrate that our continuous results are more accurate, efficient, and able to preserve more details compared with discrete approaches. PMID- 26054069 TI - Double Line Image Rotation. AB - This paper proposes a fast algorithm for rotating images while preserving their quality. The new approach rotates images based on vertical or horizontal lines in the original image and their rotated equation in the target image. The proposed method is a one-pass method that determines a based-line equation in the target image and extracts all corresponding pixels on the base-line. Floating-point multiplications are performed to calculate the base-line in the target image, and other line coordinates are calculated using integer addition or subtraction and logical justifications from the base-line pixel coordinates in the target image. To avoid a heterogeneous distance between rotated pixels in the target image, each line rotates to two adjacent lines. The proposed method yields good performance in terms of speed and quality according to the results of an analysis of the computation speed and accuracy. PMID- 26054070 TI - Tensor Dictionary Learning for Positive Definite Matrices. AB - Sparse models have proven to be extremely successful in image processing and computer vision. However, a majority of the effort has been focused on sparse representation of vectors and low-rank models for general matrices. The success of sparse modeling, along with popularity of region covariances, has inspired the development of sparse coding approaches for these positive definite descriptors. While in earlier work, the dictionary was formed from all, or a random subset of, the training signals, it is clearly advantageous to learn a concise dictionary from the entire training set. In this paper, we propose a novel approach for dictionary learning over positive definite matrices. The dictionary is learned by alternating minimization between sparse coding and dictionary update stages, and different atom update methods are described. A discriminative version of the dictionary learning approach is also proposed, which simultaneously learns dictionaries for different classes in classification or clustering. Experimental results demonstrate the advantage of learning dictionaries from data both from reconstruction and classification viewpoints. Finally, a software library is presented comprising C++ binaries for all the positive definite sparse coding and dictionary learning approaches presented here. PMID- 26054072 TI - Control of a Wheelchair in an Indoor Environment Based on a Brain-Computer Interface and Automated Navigation. AB - The concept of controlling a wheelchair using brain signals is promising. However, the continuous control of a wheelchair based on unstable and noisy electroencephalogram signals is unreliable and generates a significant mental burden for the user. A feasible solution is to integrate a brain-computer interface (BCI) with automated navigation techniques. This paper presents a brain controlled intelligent wheelchair with the capability of automatic navigation. Using an autonomous navigation system, candidate destinations and waypoints are automatically generated based on the existing environment. The user selects a destination using a motor imagery (MI)-based or P300-based BCI. According to the determined destination, the navigation system plans a short and safe path and navigates the wheelchair to the destination. During the movement of the wheelchair, the user can issue a stop command with the BCI. Using our system, the mental burden of the user can be substantially alleviated. Furthermore, our system can adapt to changes in the environment. Two experiments based on MI and P300 were conducted to demonstrate the effectiveness of our system. PMID- 26054071 TI - Upper Body-Based Power Wheelchair Control Interface for Individuals With Tetraplegia. AB - Many power wheelchair control interfaces are not sufficient for individuals with severely limited upper limb mobility. The majority of controllers that do not rely on coordinated arm and hand movements provide users a limited vocabulary of commands and often do not take advantage of the user's residual motion. We developed a body-machine interface (BMI) that leverages the flexibility and customizability of redundant control by using high dimensional changes in shoulder kinematics to generate proportional control commands for a power wheelchair. In this study, three individuals with cervical spinal cord injuries were able to control a power wheelchair safely and accurately using only small shoulder movements. With the BMI, participants were able to achieve their desired trajectories and, after five sessions driving, were able to achieve smoothness that was similar to the smoothness with their current joystick. All participants were twice as slow using the BMI however improved with practice. Importantly, users were able to generalize training controlling a computer to driving a power wheelchair, and employed similar strategies when controlling both devices. Overall, this work suggests that the BMI can be an effective wheelchair control interface for individuals with high-level spinal cord injuries who have limited arm and hand control. PMID- 26054073 TI - Compensating for Tissue Changes in an Ultrasonic Power Link for Implanted Medical Devices. AB - Ultrasonic power transfer using piezoelectric devices is a promising wireless power transfer technology for biomedical implants. However, for sub-dermal implants where the separation between the transmitter and receiver is on the order of several acoustic wavelengths, the ultrasonic power transfer efficiency (PTE) is highly sensitive to the distance between the transmitter and receiver. This sensitivity can cause large swings in efficiency and presents a serious limitation on battery life and overall performance. A practical ultrasonic transcutaneous energy transfer (UTET) system design must accommodate different implant depths and unpredictable acoustic changes caused by tissue growth, hydration, ambient temperature, and movement. This paper describes a method used to compensate for acoustic separation distance by varying the transmit (Tx) frequency in a UTET system. In a benchtop UTET system we experimentally show that without compensation, power transfer efficiency can range from 9% to 25% as a 5 mm porcine tissue sample is manipulated to simulate in situ implant conditions. Using an active frequency compensation method, we show that the power transfer efficiency can be kept uniformly high, ranging from 20% to 27%. The frequency compensation strategy we propose is low-power, non-invasive, and uses only transmit-side measurements, making it suitable for active implanted medical device applications. PMID- 26054074 TI - Experimental Study on the Perception Characteristics of Haptic Texture by Multidimensional Scaling. AB - Recent works regarding real texture perception demonstrate that physical factors such as stiffness and spatial period play a fundamental role in texture perception. This research used a multidimensional scaling (MDS) analysis to further characterize and quantify the effects of the simulation parameters on haptic texture rendering and perception. In a pilot experiment, 12 haptic texture samples were generated by using a 3-degrees-of-freedom (3-DOF) force-feedback device with varying spatial period, height, and stiffness coefficient parameter values. The subjects' perceptions of the virtual textures indicate that roughness, denseness, flatness and hardness are distinguishing characteristics of texture. In the main experiment, 19 participants rated the dissimilarities of the textures and estimated the magnitudes of their characteristics. The MDS method was used to recover the underlying perceptual space and reveal the significance of the space from the recorded data. The physical parameters and their combinations have significant effects on the perceptual characteristics. A regression model was used to quantitatively analyze the parameters and their effects on the perceptual characteristics. This paper is to illustrate that haptic texture perception based on force feedback can be modeled in two- or three dimensional space and provide suggestions on improving perception-based haptic texture rendering. PMID- 26054075 TI - MLPNN Training via a Multiobjective Optimization of Training Error and Stochastic Sensitivity. AB - The training of a multilayer perceptron neural network (MLPNN) concerns the selection of its architecture and the connection weights via the minimization of both the training error and a penalty term. Different penalty terms have been proposed to control the smoothness of the MLPNN for better generalization capability. However, controlling its smoothness using, for instance, the norm of weights or the Vapnik-Chervonenkis dimension cannot distinguish individual MLPNNs with the same number of free parameters or the same norm. In this paper, to enhance generalization capabilities, we propose a stochastic sensitivity measure (ST-SM) to realize a new penalty term for MLPNN training. The ST-SM determines the expectation of the squared output differences between the training samples and the unseen samples located within their Q -neighborhoods for a given MLPNN. It provides a direct measurement of the MLPNNs output fluctuations, i.e., smoothness. We adopt a two-phase Pareto-based multiobjective training algorithm for minimizing both the training error and the ST-SM as biobjective functions. Experiments on 20 UCI data sets show that the MLPNNs trained by the proposed algorithm yield better accuracies on testing data than several recent and classical MLPNN training methods. PMID- 26054076 TI - Synchronization of Memristor-Based Coupling Recurrent Neural Networks With Time Varying Delays and Impulses. AB - Synchronization of an array of linearly coupled memristor-based recurrent neural networks with impulses and time-varying delays is investigated in this brief. Based on the Lyapunov function method, an extended Halanay differential inequality and a new delay impulsive differential inequality, some sufficient conditions are derived, which depend on impulsive and coupling delays to guarantee the exponential synchronization of the memristor-based recurrent neural networks. Impulses with and without delay and time-varying delay are considered for modeling the coupled neural networks simultaneously, which renders more practical significance of our current research. Finally, numerical simulations are given to verify the effectiveness of the theoretical results. PMID- 26054077 TI - A Novel Brain Networks Enhancement Model (BNEM) for BOLD fMRI Data Analysis With Highly Spatial Reproducibility. AB - Independent component analysis aiming at detecting the functional connectivity among discrete cortical brain regions has been extensively used to explore the functional magnetic resonance imaging data. Although the independent components (ICs) were with relatively high quality, the noise embedding in ICs has a great impact on the true active/inactive region inference and the reproducibility, in postprocessing stage, e.g., the extraction of statistical parametrical maps (SPMs). In this paper, a novel brain network enhancement model (BNEM) is proposed, which mainly consists of two key techniques: 1) 3-D wavelet noise filter (3DWNF) for the meaningful ICs, which greatly suppresses noise and enforces the real activation inference of SPMs; and 2) a spatial reproducibility enhancement algorithm (SREA), aiming to improve the reproducibility of SPMs. The simulated experiment demonstrated that the postfiltering signals by 3DWNF were with higher correlation and less normalized mean square error to the ground truths than the prefiltering ones; SREA could further enhance the quality of most postfiltering ones, preserving the consistency with 3DWNF. The real data experiments also revealed that 1) 3DWNF could lead to more accurate preservation of the true positive voxels by correctly identifying the high proportionally misclassified voxels of the nonenhanced SPMs; 2) SREA could further improve the classification accuracy of the active/inactive voxels of SPMs corresponding to the 3DWNF denoised ICs; and 3) both 3DWNF and SREA contribute to the reproducibility enhancement of the reproduced SPMs by BNEM. Thus, BNEM is expected to have wide applicability in the neuroscience and clinical domain. PMID- 26054078 TI - Leveraging Multiscale Hessian-Based Enhancement With a Novel Exudate Inpainting Technique for Retinal Vessel Segmentation. AB - Accurate vessel detection in retinal images is an important and difficult task. Detection is made more challenging in pathological images with the presence of exudates and other abnormalities. In this paper, we present a new unsupervised vessel segmentation approach to address this problem. A novel inpainting filter, called neighborhood estimator before filling, is proposed to inpaint exudates in a way that nearby false positives are significantly reduced during vessel enhancement. Retinal vascular enhancement is achieved with a multiple-scale Hessian approach. Experimental results show that the proposed vessel segmentation method outperforms state-of-the-art algorithms reported in the recent literature, both visually and in terms of quantitative measurements, with overall mean accuracy of 95.62% on the STARE dataset and 95.81% on the HRF dataset. PMID- 26054079 TI - Covariation of depressive mood and spontaneous physical activity in major depressive disorder: toward continuous monitoring of depressive mood. AB - The objective evaluation of depressive mood is considered to be useful for the diagnosis and treatment of depressive disorders. Thus, we investigated psychobehavioral correlates, particularly the statistical associations between momentary depressive mood and behavioral dynamics measured objectively, in patients with major depressive disorder (MDD) and healthy subjects. Patients with MDD ( n = 14) and healthy subjects ( n = 43) wore a watch-type computer device and rated their momentary symptoms using ecological momentary assessment. Spontaneous physical activity in daily life, referred to as locomotor activity, was also continuously measured by an activity monitor built into the device. A multilevel modeling approach was used to model the associations between changes in depressive mood scores and the local statistics of locomotor activity simultaneously measured. We further examined the cross validity of such associations across groups. The statistical model established indicated that worsening of the depressive mood was associated with the increased intermittency of locomotor activity, as characterized by a lower mean and higher skewness. The model was cross validated across groups, suggesting that the same psychobehavioral correlates are shared by both healthy subjects and patients, although the latter had significantly higher mean levels of depressive mood scores. Our findings suggest the presence of robust as well as common associations between momentary depressive mood and behavioral dynamics in healthy individuals and patients with depression, which may lead to the continuous monitoring of the pathogenic processes (from healthy states) and pathological states of MDD. PMID- 26054080 TI - Entropy Measurement for Biometric Verification Systems. AB - Biometric verification systems are designed to accept multiple similar biometric measurements per user due to inherent intrauser variations in the biometric data. This is important to preserve reasonable acceptance rate of genuine queries and the overall feasibility of the recognition system. However, such acceptance of multiple similar measurements decreases the imposter's difficulty of obtaining a system-acceptable measurement, thus resulting in a degraded security level. This deteriorated security needs to be measurable to provide truthful security assurance to the users. Entropy is a standard measure of security. However, the entropy formula is applicable only when there is a single acceptable possibility. In this paper, we develop an entropy-measuring model for biometric systems that accepts multiple similar measurements per user. Based on the idea of guessing entropy, the proposed model quantifies biometric system security in terms of adversarial guessing effort for two practical attacks. Excellent agreement between analytic and experimental simulation-based measurement results on a synthetic and a benchmark face dataset justify the correctness of our model and thus the feasibility of the proposed entropy-measuring approach. PMID- 26054081 TI - Local Laplacian Coding From Theoretical Analysis of Local Coding Schemes for Locally Linear Classification. AB - Local coordinate coding (LCC) is a framework to approximate a Lipschitz smooth function by combining linear functions into a nonlinear one. For locally linear classification, LCC requires a coding scheme that heavily determines the nonlinear approximation ability, posing two main challenges: 1) the locality making faraway anchors have smaller influences on current data and 2) the flexibility balancing well between the reconstruction of current data and the locality. In this paper, we address the problem from the theoretical analysis of the simplest local coding schemes, i.e., local Gaussian coding and local student coding, and propose local Laplacian coding (LPC) to achieve the locality and the flexibility. We apply LPC into locally linear classifiers to solve diverse classification tasks. The comparable or exceeded performances of state-of-the-art methods demonstrate the effectiveness of the proposed method. PMID- 26054082 TI - Inverse-Free Extreme Learning Machine With Optimal Information Updating. AB - The extreme learning machine (ELM) has drawn insensitive research attentions due to its effectiveness in solving many machine learning problems. However, the matrix inversion operation involved in the algorithm is computational prohibitive and limits the wide applications of ELM in many scenarios. To overcome this problem, in this paper, we propose an inverse-free ELM to incrementally increase the number of hidden nodes, and update the connection weights progressively and optimally. Theoretical analysis proves the monotonic decrease of the training error with the proposed updating procedure and also proves the optimality in every updating step. Extensive numerical experiments show the effectiveness and accuracy of the proposed algorithm. PMID- 26054083 TI - In memoriam: Edward B. Singleton (1920-2015). PMID- 26054084 TI - In memoriam: Jimmy Frank Howell (1932-2014). PMID- 26054085 TI - In memoriam: Joseph K. Perloff (1924-2014). PMID- 26054086 TI - [Diabetes and cancer - epidemiologic evidence]. PMID- 26054087 TI - [A role of new molecular-target drugs for hematologic malignancies]. PMID- 26054088 TI - [Brentuximab vedotin (replased/refractory Hodgkin lymphoma and CD30 positive non Hodgkin lymphoma]. PMID- 26054089 TI - [Mogamulizumab for the treatment of ATL and PTCL]. PMID- 26054090 TI - [Novel monoclonal antibodies for chronic lymphocytic leukemia - ofatumumab, alemtuzumab]. PMID- 26054091 TI - [New treatment option for patient with CML-bosutinib]. PMID- 26054092 TI - Abstracts of the European Journal of Physiology. PMID- 26054093 TI - EMS 3.0: the benefits of a data-driven world. PMID- 26054095 TI - Abstracts of the IAFP 2014 Meeting, Indianapolis, Indiana. PMID- 26054094 TI - Forgotten women doctors. PMID- 26054096 TI - Cardiovascular devices; reclassification of nonroller-type cardiopulmonary bypass blood pumps for cardiopulmonary and circulatory bypass; effective date of requirement for premarket approval for nonroller-type cardiopulmonary bypass blood pumps for temporary ventricular support. Final order. AB - The Food and Drug Administration (FDA) is issuing a final order to reclassify nonroller-type cardiopulmonary bypass blood pump (NRP) devices for cardiopulmonary and circulatory bypass, a preamendments class III device, into class II (special controls), and to require the filing of a premarket approval application (PMA) for NRP devices for temporary ventricular support. FDA is also revising the title and identification of the regulation for NRP devices in this order. PMID- 26054097 TI - Stroke. PMID- 26054098 TI - Improvements in palliative and end of life care require a new approach to change. Author's reply. PMID- 26054099 TI - Dress code PMID- 26054100 TI - Raising the index of suspicion for constrictive pericarditis PMID- 26054101 TI - Of poppies and men - from trench nephritis to Gulf War syndrome. PMID- 26054102 TI - Premenstrual syndrome: management and pathophysiology. AB - Premenstrual syndrome (PMS) is triggered by hormonal events ensuing after ovulation. The symptoms can begin in the early, mid, or late luteal phase and are not associated with defined concentrations of any specific gonadal or non-gonadal hormone. Women with PMS experience affective or somatic symptoms that cause severe dysfunction in social or occupational realms. Although evidence for a hormonal abnormality has not been established, the symptoms of the premenopausal disorders are related to the production of progesterone by the ovary. The progesterone metabolites may bind to a neurosteroid-binding site on the membrane of the neurotransmitters. Thus, ovulation suppression is an area of focus for diagnostic and treatment options. Many treatment studies have focused on suppression of ovulation with gonadotropin-releasing hormone analogs (GnRHa), high doses of transdermal estrogen, and bilateral oophorectomy all have positive evidence as treatment options for prevention of PMS. However, because of these limitations and their substantial intensive care, these do not appear to be appropriate methods for conventional treatment of PMS. Serotonergic antidepressants, selective serotonin reuptake inhibitors, are well-established, highly effective, and first-line pharmacologic therapy. PMID- 26054103 TI - Relevance of parathyroid hormone (PTH), vitamin 25(OH)D3, calcitonin (CT), bone metabolic markers, and bone mass density (BMD) in 860 female cases. AB - OBJECTIVE: To study the relevance of PTH, 25(OH)D3, CT, bone resorption markers C terminal telopeptide of type I (CTX-1), and tartrate-resistant acid phosphatase (TRACP), bone formation markers bone gla protein (BGP), bone alkaline phosphatase (BALP) with the femoral neck BMD in females. MATERIALS AND METHODS: PTH, 25(OH)D3, CT, CTX-1, TRACP, BGP, and BALP were detected by an enzyme immunoassay analyzer and femoral neck BMD were measured by a BMD detector. The results of 860 females were divided into several groups according to standard of five-year age intervals. SPSS 13.0 software was used for statistical analysis. RESULTS: The measured values of PTH, 25(OH) D3 and CT had no differences in 35-50 age group. The measured values of 25(OH) D3 began to decline after the age of 50, and 25(OH)D3 had positive relevance with BMD. The values of CT were decreased in the age groups from 65 to 79 years old, and were significant positive correlated with BMD. The CTX-1 and TRACP had negative relevance with BMD in 35-45 age group and BGP and BALP had positive relevance with BMD in 35-45 age group. The BGP, BALP increased significantly in 50-60 age group, and CTX-1, TRACP, BGP, and BALP had negative relevance with BMD in 50-60 age group. BGP and BALP began to decline and had positive relevance with BMD after the age of 65, and CTX-1 and TRACP had negative relevance with BMD after the age of 65. CONCLUSIONS: PTH, 25(OH)D3, CT, CTX-1, TRACP, BGP, and BALP were the important technical means for monitoring the level of bone metabolism and the diagnosis and differential diagnosis of osteoporosis. PMID- 26054104 TI - First trimester termination of pregnancy: methods in comparison between two European university hospitals. AB - PURPOSE OF INVESTIGATION: To compare methods, epidemiological features, and legislations of first trimester termination of pregnancy in two European Union University Hospital: Szeged, Hungary, (UHS) and Rome, Italy (UHR). MATERIALS AND METHODS: The study included 195 women in UHS and 197 women in UHR undergoing a termination of pregnancy, The method used in UHR was electric vacuum aspiration, while in UHS it is chosen according to the patients' features. RESULTS: Mean gestational week at the time of interruption was 8.21 +/- 0.12 SD for UHS and 9.00 +/- 0.08 SD for UHR (p = 0.000 1). Previous artificial termination of pregnancy was 0.40 +/- 0.05 SD for UHR, and 0.77 +/- 0.07 SD for UHS (p = 0.0001). Foreign women were 32.5% in UHR and 0.5% in UHS. Incidence of side effects was 1% for UHS and 0.5% for UHR. Parity was 2.54 +/- 0.12 SD for UHR and 3.00 +/- 0.14 SD for UHS (p = 0.01). CONCLUSIONS: The methods for interruption resulted safe and effective. Antibiotic prophylaxis, routinely provided in UHR, turned out to be effective to pre- vent post-operative infections. Cervical priming with Laminaria is safe, but patient's hospitalization is required. Different legislations may account for some epidemiological differences between the two hospitals. PMID- 26054105 TI - A different technique for the closure of trocar sites. AB - This study aims to present a different technique for the closure of trocar sites in laparoscopic surgeries. MATERIALS AND METHODS: Retrospective records of cases who received the new closure technique were collected. Multifilament synthetic absorbable suture was used in this technique, with no additional tools. RESULTS: This technique was applied in a total of ten cases, which included myomectomy, hysterectomy, sacrocolpopexy, and ectopic pregnancy. No intraoperative and postoperative complications were seen in any of the cases. CONCLUSION: This new and relatively easy-to-use technique can be used as an alternative technique for the closure of trocar sites in laparoscopy. PMID- 26054106 TI - Hysterosalpingography versus hysterscopy in intrauterine pathology research of infertile patients. AB - BACKGROUND: The objective of the present paper is to confirm the validity and reliability of hysterosalpingography (HSG) in intrauterine pathology research of infertile female patients by comparing the hysteroscopy (HC) findings to a "gold standard" test. AIM: To analyze HSG and HC findings in infertility patients. MATERIALS AND METHODS: The research was conducted as a prospective study at the Gynecological and Obstetrics Clinic "Narodni front" in Belgrade. RESULTS: HSG indicated pathological findings in 72.5% of patients whereas HC revealed abnormalities of uterine cavity in 77.5%. In 12.5% of patients, HSG demonstrated a normal uterine cavity, and HC confirmed pathological findings, while in 7.5% of patients with filling defects and irregular shapes on HSG images, HC reported normal findings. In 22.5% of patients normal finding as well as endometrial polyps were reported; congenital malformations (anomalies) were found in 32.5%, submucosal myomas in 12.5% and Asherman's syndrome in 10%. CONCLUSION: HC finding was crucial in final diagnosing. PMID- 26054107 TI - An analysis of the main reasons that perimenopausal and postmenopausal women in China have for seeking outpatient treatment and factors influencing their symptoms: a single-center survey. AB - OBJECTIVE: To explore the main reasons that perimenopausal and postmenopausal women have for seeking treatment and factors influencing their symptoms in order to provide (peri-) menopausal women with better healthcare treatments. MATERIALS AND METHODS: Interviews were conducted with 357 (peri-) menopausal women who sought outpatient treatment at The Sixth People's Hospital, Shanghai Jiaotong University from July 1, 2010 to March 31, 2012. The survey includes general questions and an evaluation of (peri-) menopausal symptoms using the modified Kupperman index score. RESULTS: The average age of the women who took part in the study was 51.47 years old (standard deviation = 5.18). Of the women, 47.6% were perimenopausal, 34.7% were early postmenopausal, and 17.7% were late postmenopausal. The age of natural menopause was between 39 and 56 years, and the average natural menopause age was 49.3 years (standard deviation = 4.0). The incidence of (peri-) menopausal symptoms was 91%. Age, education level, and chronic diseases were associated with menopausal symptoms. The main reasons for seeking treatment were hot flushes, insomnia, bone and joint pains, mood swings, and palpitations. CONCLUSIONS: The main reasons for Chinese (peri-) menopausal women seeking treatment were hot flushes, insomnia, bone and joint pains, mood swings, and palpitations; age, education level, and chronic diseases are the main factors that influencing the (peri-) menopausal symptoms. PMID- 26054108 TI - Single uroflow study as a tool in predicting the possibility of abnormal voiding symptoms after the administration of antimuscarinic agents in treating overactive bladder syndrome. AB - PURPOSE OF STUDY: The aim of this study was to evaluate the efficacy of uroflowmetry in predicting the possibility of abnormal voiding symptoms following antimuscarinic treatment for overactive bladder syndrome (OAB) in Taiwanese women. MATERIALS AND METHODS: A retrospective study was conducted on women with OAB. Forty-five women with abnormal voiding patterns shown by urodynamic study comprised the main group and 38 women with normal voiding patterns comprised the control group. All patients were prescribed two mg tolterodine once daily for one week. Follow-up on complaints of abnormal voiding symptoms was done one week later. RESULTS: One woman in control group and 12 women in main group complained of abnormal voiding symptoms. There was a significant difference in the occurrence of abnormal voiding symptoms after antimuscarinic administration between main study group and control group (26.7 % vs 2.6 %, p = 0.02). CONCLUSIOn: Uroflowmetry is a non-invasive and simple tool to predict the occurrence of abnormal voiding symptoms after antimuscarinic use. PMID- 26054109 TI - Decreased Bcl-6 and increased Blimp-1 in the peritoneal cavity of patients with endometriosis. AB - PURPOSE OF INVESTIGATION: The authors investigated the expression patterns of interleukin (IL)-lbeta and tumor necrosis factor (TNF)-alpha, cytokines associated with peritoneal inflammatory reactions, and of B cell leukemia lymphoma (Bcl)-6 and B lymphocyte inducer of maturation program (Blimp)-1, transcriptional factors associated with immunoglobulin (Ig) production; the concentrations of Igs, and their correlation, in patients with and without endometriosis. MATERIALS AND METHODS: The authors analyzed the peritoneal fluid of 98 patients, 46 with endometriosis, and 52 with benign tumors. RESULTS: IL-1 and TNF-alpha mRNAs and IgG and IgA concentrations were higher in the endometriosis group, but the differences were not statistically significant. However, Bcl-6 mRNA level was significantly lower and Blimp-1 mRNA level was significantly higher in the endometriosis group with significant correlations among transcriptional factors, Igs, and cytokines (p < 0.05). CONCLUSION: Peritoneal immune responses in patients with endometriosis may be due to increased IgG and IgA concentrations, as well as to changes in expression of proinflammatory cytokines and transcriptional factors. PMID- 26054110 TI - Prevalence of menopausal related symptoms and their impact on quality of life among Egyptian women. AB - OBJECTIVE: To assess the prevalence of menopausal-related symptoms and to evaluate their impact on quality of life (QoL) among a sample of menopausal women from Egypt. MATERIALS AND METHODS: A cross-sectional hospital-based study conducted at the Gynecology department, Suez Canal University, Ismailia - Egypt. A total 1,214 women aged 40 - 70 years were recruited and studied using an interview questionnaire. The questionnaire contains four main items: socio demographic data, menstruation status assessment, modified Menopausal Rating Scale (MRS), and World Health Organization Quality of Life (WHOQOL-BREF) questionnaire. RESULTS: Mean age was 48.1 +/- 10.3 years, with 26.6% of the studied participants were illiterates. According to menstruation status, 40.9% of the studied women were postmenopausal, 41.4% were premenopausal, while 17.7% were perimenopausal. Most of the studied participants have mild/moderate somatic symptoms. Mild/moderate depressive mode, irritability, and anxiety have been reported in 63%, 58.4%, and 58.2% of women, respectively. Postmenopausal women have significantly higher scores on MRS except for urogenital score that was higher in perimenopausal women. They also had significantly lower QoL score in all subscales of WHOQOL-BREF except for psychological domain that was lowest among perimenopausal women. MRS total score has significant negative correlation to all domains of WHOQOL questionnaire. CONCLUSION: Postmenopausal women have higher prevalence of menopausal symptoms that significantly affect their quality of life more than pre- and perimenopausal women. Those in the transition period (perimenopausal) have higher prevalence of psychological symptoms with higher impact on their psychological welfare. PMID- 26054111 TI - Genetic variation in COX-2 -1195 and the risk of endometriosis and adenomyosis. AB - AIM: Ths study aims to explore the relationship between COX-2 gene polymorphism and the hereditary susceptibility or endoomeyriosis and adenomyosis. MATERIALS AND METHODS: Gene polymorphism in COX-2 gene was genotyped in 170 cases of endometriosis, 150 cases of adenomyosis, and 240 matched non-endometriosis and non-adenomyosis controls. RESULTS: Genotypic frequencies of GG, AG, and AA in COX 2 locus in endometriosis and adenomyosis were 16.5%, 51.2%, 32.4% and 16.0%, 49.3%, 34.7%, respectively. They were both significantly different from those in the control group (24.6%, 53.3%, and 22.1%) (p < 0.05). An allele frequency in endometriosis and adenomyosis were significantly higher than that in the control group. The risk of endometriosis or adenomyosis for those carrying two A alleles were 2.19 and 2.41 times to non-A genotype. CONCLUSION: Genetic variation of G to A at -1195 locus in the promoter region of COX-2 gene increases the risk of endometriosis and adenomyosis, and the genetic susceptibility of these two diseases are similar. PMID- 26054112 TI - IVF/ICSI frozen replacement cycles; every cycle? Opinion expressed after a systematic review of the literature. AB - OBJECTIVE: To determine whether in vitro fertilization (IVF), frozen replacement cycles offer better outcomes than fresh cycles in order to support, or not, a possible shift towards total replacement of fresh IVF/intracytoplasmic sperm injection (ICSI) cycles from frozen elective transfers (FETs). STUDY DESIGN: Systematic review; opinion paper. RESULTS: Initial results seem to support a shift in current practice towards frozen cycles. CONCLUSION: Initial results may support replacement all fresh IVF/ICSI cycles with FETs, as this could be a safer and equally effective strategy. However, robust evidence from randomized controlled trials is needed if this will be generally applied. PMID- 26054113 TI - A pilot survey on obstetric complications in pregnant women with a history of repeated embryo implantation failure and those undergoing single local endometrial injury. AB - PURPOSE OF INVESTIGATION: To assess if a history of repeated implantation failure (RIF) or local endometrial injury (LEI) for RIF affects the pregnancy course in women who conceived in the subsequent in vitro fertilization (IVF) embryo/blastocyst transfer (ET/BT) cycle. MATERIALS AND METHODS: Of 42 pregnant women with a history of three consecutive failed ET/BT cycles with negative pregnancy tests, 11 patients had a clinical pregnancy in the immediate subsequent ET/BT cycle following (the RIF group), whereas 31 patients had a clinical pregnancy in the subsequent ET/BT cycle following single curettage LEI in the proliferative phase of the preceding spontaneous cycle (the RIF/LEI group). Information on the obstetric complications were retrieved from medical records and compared with that of women who had a live birth in the first ET/BT attempt (the control group). Results: The clinical pregnancy rate, ongoing pregnancy rate, and live birth rate were significantly higher in the RIF/LEI group than in the RIF group (p < 0.010). There were no significant differences in the incidence of pregnancy of unknown location, ectopic pregnancy, miscarriage, stillbirth, preterm birth, premature rupture of the membranes, placenta previa, placental abruption, preeclampsia, pregnancy-induced hypertension, gestational diabetes, fetal growth restriction, caesarean section, and blood transfusion were similar between the three groups (p > 0.31). CONCLUSION: In this pilot survey, neither a history of RIF nor LEI intervention for RIF increased the incidence of obstetric complications in the women who conceived in the subsequent ET/BT cycle. PMID- 26054114 TI - Fear of childbirth in women with normal pregnancy evolution. AB - PURPOSE OF INVESTIGATION: The authors aimed to research the prevalence of fear of childbirth (FOC) in women with a positive birth experience and some factors associated with FOC. MATERIALS AND METHODS: The study sample consisted of 817 women with positive birth experience within the last month of their pregnancy from February 2012 to May 2013. The data were collected with a questionnaire form including women's demographic-obstetric information and the Turkish form of Wijma Delivery Expectancy Questionnaire. Whether it was a planned pregnancy and their preferable delivery method for the current pregnancy were recorded. RESULTS: The total number of women with FOC was found to be 128 (15.6%). None of the patients had severe FOC. Fear of labour pain was found as the major cause for preferring cesarean section (73.5%). FOC was associated with preferring delivery methods (OR 5.91, 95% CI 3.96-8.84). FOC was associated with pregnancy planning status (OR 2.4, 95% CI 1.66-3.58). CONCLUSION: Fear of childbirth may be seen to some extent in women with a positive birth experience. However even with woman's positive birth experience, it is important to avoid severe FOC. The pregnancy planning status should be evaluated in the early stages of pregnancy and maternal education programs may be offered to reduce FOC level. PMID- 26054115 TI - Fetal loss after amniocentesis: analysis of a single center's 7,957 cases in China. AB - PURPOSE OF INVESTIGATION: The fetal loss rate after amniocentesis was different in previous reports. Instead of using the fetal loss rate reported by others when facing the counseling couples, the present authors sought to estimate our institution-specific fetal loss rate after amniocentesis. MATERIALS AND METHODS: The study included 7,957 Chinese women in singleton pregnancy that had an amniocentesis in mid-trimester between 18-26 weeks of gestation in Shengjing Hospital for any indication. All clinical data, fetal karyotype, and pregnancy outcome were collected for analysis in the present study. RESULTS: The number of abnormal karyotypes detected in this study were 436 (5.48%). The loss follow-up rate was 0.45%. The total fetal loss rate after amniocentesis was 4.09 % including 3.23% elective termination of pregnancy and 0.86% unintended fetal loss. The potentially procedure-related fetal loss rate was lower than 0.59%. The potentially procedure-related fetal loss rate was found to be significantly associated with maternal age (> 35 years), previous fetal loss history, and abnormal vaginal bleeding in this pregnancy. CONCLUSION: 5.48% of women with amniocentesis have abnormal karyotypes and the proportion of women with major chromosomal abnormalities was even 2.20%; on the contrary, the fetal loss rate related to the procedure was lower than 0.59%. PMID- 26054116 TI - Epidemiological, clinical, and virological characteristics of women with genital warts in Greece. AB - This is a prospective study of the epidemiological, clinical, and virological characteristics of cases of genital warts in a Greek University Hospital. The women completed a questionnaire regarding their medical and sexual history and underwent cervical cytology, HPV DNA typing, mRNA testing, colposcopy, Chlamydia testing, and proctoscopy. Univariate and multivariate analyses were performed. The most commonly detected types were type 6 (36.1%) and 16 (24.3%). E6/E7 mRNA testing was positive in 21.5%. Concurrent cervical intraepithelial neoplasia grade 2 or worse was found in 11.1% and intra-anal warts in 10.4%. For chlamydial infection the number of sexual partners was a significant predictor. Women with warts infected with types 6 and 11 constituted only 37.5% of the total. This could have a negative effect on the efficacy of vaccination in reducing the incidence of the disease. Based on the present findings the authors recommend cytology and colposcopy for all women with genital warts. PMID- 26054117 TI - Vaginal bilateral cervical lips suture in combination with intrauterine Foley catheter to arrest postpartum hemorrhage. AB - Vaginal bilateral cervical lips suture allows retention of intrauterine Foley catheter in women with a dilated cervix. This novel indication for vaginal bilateral cervix suture may be a useful adjunct to intrauterine balloon tamponade in the management of postpartum hemorrhage. OBJECTIVE: To describe an effective, minimally invasive surgical technique for avoiding intrauterine balloon tamponade prolapse. MATERIALS AND METHODS: This procedure was performed in the delivery room with or without bladder retraction. The cervix was grasped with two ring forceps and firmly pulled outward, two cm horizontal suture of the cervical lips was made at both the three and nine o'clock positions, which were placed two cm as close to the cervix external os, without transversing the cervicovesical reflection anteriorly and the pouch of Douglas posteriorly, then one or more Foley catheters were inserted through the cervix and inflated with saline 60-80 ml each. RESULTS: The balloons remained in place and hemorrhage abated in all nine cases. CONCLUSION: vaginal bilateral cervical lips suture can prevent intrauterine balloon prolapse, which may be a useful adjunct to intrauterine balloon tamponade in management of postpartum hemorrhage. PMID- 26054118 TI - The importance of size of cervical ectopy to predict postcoital bleeding: is there any cut-off value? AB - OBJECTIVE: To investigate the relationship between size of cervical ectopy and existence of postcoital bleeding (PCB) in non-symptomatic women. MATERIALS AND METHODS: Study population were recruited from women ages 18-65 years, sexually active who applied to the present outpatient department. They were asked whether they had had postcoital bleeding in the last three months. After ful visualization of the cervix, the existence of ectopy was noted and measured. The smears were taken from all patients with endobrushes. RESULTS: The authors found a relationship between the size of ectopy and PCB. In the prediction of PCB, the lesion's size (of both antero-posterior and transverse diameters) of 3.5 mm as the cut off level, sensitivity, and specificity were found to be 70% and 76%, respectively. CONCLUSION: The full visualization of the cervix is important because of the relationship between the existence of ectopy and PCB. PMID- 26054119 TI - Efficacy of chlortetracycline treatment on vulvar non-neoplastic epithelial disorders. AB - OBJECTIVE: To observe the effectiveness of chlortetracycline (aureomycin) treatment on vulval white lesions and to explore its possible pathogenesis. MATERIALS AND METHODS: From January 2001 to April 2011, 194 patients with vulvar non-neoplastic epithelial disorders were divided into three groups according to therapy regimens received, ie, chlortetracycline treatment group (72 cases), chlortetracycline + beclomethasone treatment group (66 cases), and beclomethasone treatment group (56 cases); their local changes of vulvar lesions were observed and efficacy of these treatment profiles was evaluated after one year. RESULTS: Effective rates of chlortetracycline group, chlortetracycline + clobetasol group and clobetasol groups were 86.1% (62/72), 87.9% (58/66), and 62.5% (35/56), respectively. There was a significant difference among these three groups (Hc = 10.7766,p = 0.0046), the curative rate of clobetasol group was markedly lower than that of the former two groups (p = 0.0072 and p = 0.0019), but was not statistical significant (p = 0.6077) when compared between the former groups. CONCLUSION: The occurrence of vulvar non-neoplastic epithelial disorders may be associated with chlamydia and mycoplasma infection, the chlortetracycline is an effective drug for this illness, the mechanism of which might be related to killing pathogens directly and inhibiting inflammatory mediators. PMID- 26054120 TI - A new surgical approach for the management of severe postpartum hemorrhage due to uterine atony: preliminary results in 27 cases. AB - PURPOSE OF INVESTIGATION: To demonstrate a new suturing technique that effectively reduces severe postpartum hemorrhage secondary to uterine atony. MATERIALS AND METHODS: The study consisted of 27 patients with persistent postpartum bleeding due to uterine atony which was unresponsive to medical treatment. The patients were treated with infinity compression sutures that passed through entire uterine wall on which the placenta was located and were knotted within uterine cavity. Demographic properties, complications, operative results are demonstrated. RESULTS: Uterine bleeding was controlled in 26 of 27 cases (%96.3). Total abdominal hysterectomy was performed in only one patient who had persistent incision site bleeding and disseminated intravascular coagulation. CONCLUSION: Uterine atony is an emergency and early intervention is necessary. As indicated by the preliminary results, the new technique effectively stopped bleeding in 96.3% of cases; no other techniques were carried out additionally. The technique is promising with properties as easy applicability, safety, and absence of major complications. A larger study is needed for further comparison of operative results. PMID- 26054121 TI - Influence of regularity of checkups during pregnancy on prevalence of asymptomatic bacteriuria and maternal behaviors regarding urinary infection prevention. AB - PURPOSE OF INVESTIGATION: T0 investigate how the regularity of checkups in pregnancy influences maternal behavior regarding habits in prevention of urinary tract infection (UTI), the level of information, and finally the prevalence of asymptomatic bacteriuria (AB). MATERIALS AND METHODS: This study included 223 women with regular and 220 women with irregular checkups in pregnancy were given the questionnaire on the following issues: frequency of sexual intercourses during pregnancy, the regularity of bathing and changing of underwear, the direction of washing the genital region after urinating, the regularity of antenatal visits to gynecologist, and the subjective experience concerning the quality of the information received by the healthcare provider. RESULTS: AB was present significantly more frequent in group of participants with irregular controls during pregnancy compared to group with regular checkups in pregnancy. The prevalence of AB was higher in those women who had irregular prenatal checkups. Maternal behaviors related with the risk of urinary infections are more frequent among women with irregular prenatal care. CONCLUSION: Results of the present study emphasize the importance of regular prenatal care in AB prevention. PMID- 26054122 TI - Intimate partner violence among Egyptian pregnant women: incidence, risk factors, and adverse maternal and fetal outcomes. AB - AIMS: To assess incidence and risk factors of intimate partner violence (IPV) during pregnancy among a sample of women from Egypt and to evaluate its impact on maternal and fetal adverse health outcomes. MATERIALS AND METHODS: After obtaining ethical approval, a total of 1,857 women aged 18 - 43 years completed the study and were investigated using an interview questionnaire. The questionnaire contains five main items: demographic characteristics of women, intimate partner characteristics, assessment of IPV during current pregnancy, and assessment of maternal as well as fetal/neonatal adverse outcomes. Women were also examined to detect signs of violence and identify injuries. RESULTS: Exposure to IPV during pregnancy was reported among 44.1% of the studied women. Emotional violence was the most common form. Women exposed to violence were of younger age, higher parity, and lower educational level. Their partners were older, less educated, and more likely to be addicted to drugs and alcohol. Women were also found to have significantly higher incidence of adverse pregnancy outcomes (miscarriage, preterm labor, and premature rupture of membrane), and fetal/neonatal adverse outcomes (fetal distress, fetal death, and low birth weight). A total of 297 cases had been exposed to physical violence (15.9%) vs 32.6% and 10% exposed to emotional and sexual violence, respectively. The most common form of physical violence was kicking. CONCLUSION: Violence during pregnancy is prevalent among Egyptian women. Exposure to violence was a significant risk factor for multiple adverse maternal and fetal health outcomes. PMID- 26054123 TI - Plasma pentraxin 3 levels in preeclamptic patients. AB - The authors evaluated plasma pentraxin 3 (PTX 3) levels in preeclamptic patients and determined the relationship between albuminuria and plasma PTX 3 levels. During a period of one year, 29 patients with severe or mild preeclampsia and 49 healthy pregnant women were included in the cross-sectional study. The two groups were compared each other with PTX 3 levels. The relationship between PTX 3 levels and urea, creatinine, AST, ALT, CRP, LDH, platelet count, and spot urine protein/creatinine rate were evaluated. PTX 3 level was significantly high in the preeclamptic group (p < 0.05). No significant correlation was found between serum PTX 3 level and urea, creatinine, AST, ALT, CRP, LDH, platelet, and spot urine protein/creatinine rate (p > 0.05). PTX 3 is a biochemical parameter that shows endothelial dysfunction. The authors believe that PTX 3 can be a valuable parameter to predict preeclampsia according to the significantly high PTX 3 levels in preeclamptic patients. PMID- 26054124 TI - Levonorgestrel-releasing intrauterine device use as an alternative to surgical therapy for uterine leiomyoma. AB - OBJECTIVE: To evaluate the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of leiomyoma related menorrhagia and to assess the effect of LNG-IUS on uterine, leiomyoma, and ovarian volume. MATERIALS AND METHODS: In this prospective before and after study, LNG-IUS was inserted in 38 women with myoma-related menorrhagia. The patients were evaluated for serum levels of hemoglobin, hematocrit and uterine, leiomyoma, and ovarian volume at the time of insertion and at six months. RESULTS: Significant reduction in the Pictorial Blood Loss Assessment Chart (PBAC) score and increases in serum hemoglobin levels and in amenorrhea was observed within three months. However, there was no statistically significant reduction in the myoma and uterine volume. Ovarian volume, also, did not changed significantly. CONCLUSION: The use of LNG IUS is effective in reducing menorrhagia associated with leiomyomas with improvement in hemoglobin levels and may be a simple and effective alternative to surgical treatment of leiomyoma-related abnormal uterine bleeding (AUB-L) without significant influence on the volume of leiomyoma and ovarian and uterine volume. PMID- 26054125 TI - Scorpion stings in pregnant women: an analysis of 11 cases and review of literature. AB - Scorpion sting is one of the most important public health problem in many regions of the world. But there is not enough medical data about scorpion stings in pregnant women in the literature. The aim of this study was to describe the clinical findings and treatment modalities of scorpion stings in pregnant women. This study was performed in the Southeast Region of Turkey, retrospectively. Eleven pregnants were studied, totally. All of the patients were detected as class I according to the scorpion envenomization system. They were in different weeks of gestation. Local pain, hyperemia, swelling, and itching were the most frequent complaint in these cases. None of our patients received antivenom, and all of them were treated, symptomatically. Complication of pregnancy was observed in none of them. PMID- 26054126 TI - Microparticles hyperactivity in a case of intrauterine growth restriction. AB - A case of a residual intrauterine fetal growth is described in a primiparous woman, aged 33 years, undergoing the 37th week of pregnancy. The patient was admitted to the outpatient department of the present clinic complaining of decreased fetal movement in the past few days. The cardiotocography (CTG) was non reactive, with reduced variability for a period of more than 30 minutes. The evaluation of the activity of microparticles (MPs) showed a value of 48.90 nM, which was 21.26 times higher than the mean of normal women of comparable pregnancy age (2.31 +/- 1.95 nM) and 18.11 times higher than that of the average women who had intrauterine growth retardation (2.70 +/- 2.63 nM). The reasons for this increase in the activity of the MPs are discussed in this case report. PMID- 26054127 TI - A case of prenatally diagnosed Uhl's anomaly. AB - BACKGROUND: Uhl's anomaly is an extremely rare cardiac defect characterized by absence of the myocardium of the right ventricle. Until now, only three cases have been diagnosed or have showed suspicious diagnosis in prenatal period. CASE: A 28-year-old nulliparous woman was referred to the present hospital for counseling the risk of drug medication. The authors found dilatation of the right ventricle and thinning of the right ventricular wall in the fetus at 25 weeks gestation. No other structural abnormalities were found concerning the great arteries and all heart valves demonstrated normal function. Uhl's anomaly was suspected on fetal echocardiography and it was confirmed postnatally by echocardiography and computed tomography (CT). The infant showed stable condition during neonatal period and is doing well in the ambulatory care after three-years follow up: CONCLUSION: Although the outcomes of Uhl's anomaly are generally unfavorable, the duration of survival shows wide variation according to the cardiac function. To estimate the postnatal outcomes, it is highly recommended to perform the accurate differential diagnosis by using fetal echocardiography during pregnancy. PMID- 26054128 TI - Increased nuchal translucency and diaphragmatic hernia. A case report. AB - Increased nuchal translucency (NT) thickness is present in 40% of fetuses with diaphragmatic hernia, including 80% of those that result in neonatal death and in 20% of the survivors. A 33-year-old nulliparous woman had first trimester scan at 12 weeks. The fetus had a NT of 2.3 mm, normal ductus venosus (DV), and tricuspid doppler and present nasal bone. Pregnancy-associated plasma protein A (PAPP-A) was 0.59 MoM and beta-human chorionic gonadotropin (b-hCG) 2.56 MoM. The couple did not opt for chorionic villous sampling (CVS) and repeat ultrasound examination was advised. At 18 weeks, ultrasound revealed left sided diaphragmatic hernia. The couple consented for termination of the pregnancy. The molecular test showed normal karyotype and male gender. In such cases with intrathoracic herniation of abdominal viscera, the increased NT may be the consequence of venous congestion due to mediastinal compression. The prolonged compression of the lungs causes pulmonary hypoplasia. Increased NT with normal fetal karyotype is associated with structural fetal anomalies like diaphragmatic hernia and screening at 16-18 weeks is imperative. PMID- 26054129 TI - Sonographic diagnosis of complete uterine inversion: an unusual case. AB - Complete puerperal uterine inversion is an uncommon but potentially life threatening obstetric emergency. It generally occurs as an obstetrical complication in the postpartum period and can present in acute, subacute, and chronic forms depending on the time interval after delivery. Maternal mortality has been reported to be as high as 15%, mainly because of life associated threatening blood loss and shock. Early diagnosis and treatment are essential, but diagnosis of this is not simple. This is a report of unusual case of complete uterine inversion diagnosed by accurate ultrasound leading to prompt potentially life-saving treatment. PMID- 26054130 TI - Viper bite during pregnancy: case report. AB - Viper bites in pregnant women have rarely been reported thus far. Moreover, there is no consensus regarding the treatment of such cases. In this paper, the authors report the successful treatment of viper bite during pregnancy without using antivenom. PMID- 26054131 TI - Successful management of a second-trimester post-abortion hemorrhage with the Bakri balloon tamponade. AB - Hemorrhage after abortion is rare but it is a significant cause of abortion related mortality and morbidity. Conservative management of hemorrhage is gaining popularity. The authors describe a case which a uterine tamponade balloon which was successfully used to control second-trimester post-abortion hemorrhage. PMID- 26054132 TI - The outcome of pregnancy in a woman affected by Takayasu arteritis: case report and review of literature. AB - Takayasu arteritis (TA) is a chronic non-specific inflammatory vascular disease, of which the cause is not very clear. The disease is more severe in females. Furthermore, during the entire pregnancy, it is of great harm to the mother and child. The formation of blood clots is harmful to the mother and thrombosis is dangerous to the fetus and can lead to its death. Hence, prevention with control of perioperative hemodynamic changes during the pregnancy is an effective method to prevent heart failure, embolism, and thrombosis. PMID- 26054133 TI - Live birth after transfer of vitrified-warmed blastocyst derived from ICSI with frozen-thawed sperm: case report. AB - OBJECTIVE: A live birth after transfer of vitrified-warmed blastocyst derived from intracytoplasmic sperm injection (ICSI) with frozen-thawed sperm of a male cancer patient is described. MATERIALS AND METHODS: A case report from a tertiary center for assisted reproductive technologies. The 35-year-old male patient had been diagnosed with testicular tumor nine years ago. He had unilateral orchiectomy operation after the diagnosis. Four years after the first operation, he was diagnosed with another testicular tumor in the other testis. He admitted to our center with the demand of sperm preservation before the second surgery. The sperm samples were cryopreserved and stored in liquid nitrogen until required. The patient had no chemotherapy or radiotherapy after the operations. After he completed his oncologic follow up, ICSI was decided with his frozen samples. Although the couple failed to conceive with the fresh cycle, the remaining embryos were frozen and revealed a pregnancy in the subsequent frozen thawed cycle. RESULTS: A healthy female infant with a birth weight of 3,700 g was born by cesarean section at 38th weeks of the gestation. CONCLUSION: Giving detailed information about fertility-saving management in male patients is important in those who wish to bear children. However, both the patients and physicians should be cautious that preservation should be performed before surgery and/or adjuvant therapy. In this respect, assited reproductive technology (ART) and related facilities yield chance of pregnancy in such population. PMID- 26054134 TI - Abdominal wall desmoid tumor during pregnancy: case report and literature review. AB - Desmoid tumors are fibromatous lesions that are the result of abnormal proliferation of myofibroblasts. Despite its benign microscopic appearance and non-metastasizing behavior, tumor infiltrates surrounding tissues and has a high risk of recurrence. Pregnancy-associated desmoid tumors are very rare and optimal management of this tumor is not well established. The authors report a case of a 31-year-old pregnant woman with a large desmoid tumor, which increased rapidly in size and caused worsening symptom of dyspnea. The tumor was successfully removed during a caesarian section, which resulted in an anterior abdominal wall defect. Reconstruction of the abdominal wall defect was performed with a polypropylene mesh. The postoperative recovery of the patient was uneventful. After a follow-up of 44 months, the patient was found to be well and there was no evidence of local recurrence. The authors also reviewed the literature on the world's experience with this tumor and its management during pregnancy.Twelve desmoid tumors arising during pregnancy were reported in the existing literature; the managements were varied and has yet to be defined. PMID- 26054135 TI - [Impacts on pregnancy outcome treated with acupuncture and moxibustion in IVF-ET patients]. AB - OBJECTIVE: To observe the impacts on endometrial and pregnancy outcomes treated with acupuncture and moxibustion in the patients of in vitro fertilization-embryo transfer (IVF-ET) and explore the application value, of acupuncture and moxibustion in IVF-ET treatment. METHODS: One hundred and fourteen patients of IVF-ET treated with standard long-term program at luteal phase were randomized into an observation group and a control group, 57 cases in each one. In the observation group, at the beginning of ovulatory induction, moxibustion was applied to Shenque (CV 8) and acupuncture was to Zhongji (CV 3), Guanyuan (CV 4), Qihai (CV 6), Zigong (EX-CA 1), Xuebai (SP 10), etc. till the transfer time for one session of treatment. Totally, 3 sessions were required. In the control group, no intervention of acupuncture and moxibustion was applied. The endometrial morphology, subendometrial blood flow index, the levels of serum estradiol (E2), progesterone (P) and luteinizing hormone (LH) on the day of injection of human chorionic gonadotropin (hCG), the dosage and time of gonadotropin (Gn), oocyte count, high-quality embryo number, embryo cultivation rate and clinical pregnant rate were observed in the two groups. RESULTS: The A type endometrial proportion on hCG day and high-quality embryo rate in the observation group were higher than those in the control group, indicating the significant differences (both P< 0.05). The difference in endometrial thickness on hCG day was not significant between the two groups (P> 0.05). In the observation group, endometrial hemodynamic index (peak systolic blood velocity/end-diastolic blood velocity, S/D), resistive index (RI) and pulse index (PI) were lower than those in the control group (P<0. 01, P<0. 05). The levels of serum E2 and P on hCG day in the observation group were higher than those in the control group (both P<0. 05). The differences were not significant in Gn dose, Gn medication time, numbers of follicles >1. 6 cm on hCG day, oocyte count, embryo cultivation rate and clinical pregnancy rate and LH level on hCG day between the two groups (all P>0. 05). CONCLUSION: In IVF-ET treatment, acupuncture and moxibustion affect estrogen level on hCG day, improve high-quality embryo rate, endometrial blood flow state and morphology so that the endometrial receptivity is increased and the method is expected to be the assistant therapeutic approach for the improvement of IVF-ET outcome. PMID- 26054136 TI - [Analgesic effect on primary dysmenorrheal treated with conventional and sham acupuncture at San-yinjiao (SP 6)]. AB - OBJECTIVE: To observe the difference in the analgesic effect on primary dysmenorrheal between acupuncture and sham acupuncture at Sanyinjiao (SP 6) during menstrual pain and evaluate the impact of psychological effect on acupuncture analgesia. METHODS: Sixty subjects were randomized into an acupuncture group and a sham acupuncture group, 30 cases in each one. The conventional acupuncture and sham acupuncture were applied to Sanyinjiao (SP 6) on bilateral sides when menstrual pain began to attack and needles were retained for 30 min each time. Three menstrual cycles were required. The visual analogue scale (VAS) was adopted to determine the scores before and 0. 5 h, 1 h, 3 h, 6 h and 12 h after acupuncture during menstrual pain in each cycle separately. RESULTS: In the acupuncture group, VAS score at each time point after acupuncture was reduced as compared with that at the previous one during menstrual pain in each menstrual cycle, indicating the significant difference (all P<0. 05). In the sham acupuncture group, the scores in 6 h and 12 h of acupuncture were reduced as compared with the previous one, indicating the significant difference (all P<0. 05). After acupuncture, VAS score at each time point in the acupuncture group was lower than that in the sham acupuncture group (all P<0. 05). CONCLUSION: The conventional acupuncture at Sanyinjiao (SP 6) achieves the significant analgesic effect on primary dysmenorrheal. The psychological placebo effect of sham acupuncture has no obvious impact on acupuncture analgesia. PMID- 26054137 TI - [Efficacy on endometriosis treated with electroacupuncture]. AB - OBJECTIVE: To compare the difference in the clinical efficacy on endometriosis (EM) between electroacupuncture (EA) and western medication. METHODS: Seventy-two EM patients were divided into an EA group and a western medication group according to visiting departments, 36 cases in each one. In the EA group, acupuncture was applied to Qihai (CV 6), Guanyuan (CV 4), Zhongji (CV 3), Zigong (EX-CA 1), Diji (SP 8), Sanyinjiao (SP 6), Hegu (LI 4) and Taichong (LR 3). After qi arrival, G6805-I pulse electronic apparatus was attached to bilateral Zigong (EX-CA 1), Guanyuan (CV 4) and Zhongji (CV 3), with continuous wave, 70 Hz in frequency, 3 mA in intensity. The EA was given once every two days. In the western medication group, mifepristone tablets were prescribed for oral administration, 12. 5 mg per treatment, once a day, for 6 months. The pain degree was observed before and after treatment and the clinical efficacy and recurrence rate were evaluated in the two groups. The enzyme-linked immunoassay (ELISA) was adopted to determine the tumor marker serum CA125 before and after treatment in the two groups. RESULTS: The total effective rate was 94. 4% (34/36) in the EA group and was 91. 7% (33/36) in the western medication group, without significant difference (P>0. 05). The pain score after treatment was lower than that before treatment in the two groups (both P< 0. 01), but the score after treatment in the EA group was lower than that in the western medication group (P<0. 05). Serum CA125 was reduced after treatment in the patients of the two groups (both P<0. 01), and serum CA125 after treatment in the EA group was lower than that in the western medication group (P<0. 05). In the follow-up visit of one year, the reoccurrence rate was 17. 6% (6/34) in the EA group and was 33. 3% (11/33) in the western medication group, indicating the significant difference (P<0. 05). CONCLUSION: EA achieves the significant clinical efficacy and the reoccurrence rate in 1 year in the EA group is obviously lower than that in the western medication group. This therapy could be promoted in clinical practice of acupuncture and moxibustion. PMID- 26054138 TI - [Mild and moderate female stress urinary incontinence treated with transcutaneous acupoint electrical stimulation: a randomized controlled trial]. AB - OBJECTIVE: To compare the difference in the clinical efficacy on mild and moderate female stress urinary incontinence (FSUI) between transcutaneous acupoint electrical stimulation and oral administration of midodrine hydrochloride tablets. METHODS: Ninety cases of mild and moderate FSUI were randomized into an observation group and a control group, 45 cases in each one. In the observation group, the transcutaneous acupoint electrical stimulation was applied to Ciliao (BL 32), Shenshu (BL 23), Zigong (EX-CA 1), Guanyuan (CV 4) and Qihai (CV 6), once a day. In the control group, midodrine hydrochloride tablets were prescribed for oral administration, 2. 5 mg per treatment, three times each day. The duration of treatment was 4 weeks. The score of international consultation on incontinence questionnaire-urinary incontinence short form (ICI-Q SF) and leakage of urine in 1 h urinal pad test were observed before and after treatment in the patients of the two groups, and the efficacy was compared between the two groups. RESULTS: The score of ICI-Q-SF and leakage of urine in urinal pad test after treatment were all improved apparently as compared with those before treatment in the two groups (all P<0. 01), and the results in the observation group were better than those in the control group (both P<0. 01). The total effective rate was 86. 7% (39/45) in the observation group, which was better than 68. 9% (31/45, P<0. 05) in the control group. CONCLUSION: The transcutaneous acupoint electrical stimulation achieves the better efficacy on FSUI as compared with the oral administration of midodrine hydrochloride tablets. This therapy effectively improves the patient's urine control ability and reduces leakage of urine. PMID- 26054139 TI - [BO's abdominal acupuncture for obese type-2 diabetes mellitus]. AB - OBJECTIVE: To observe the clinical efficacy of BO's abdominal acupuncture for obese type-2 diabetes mellitus (T2DM). METHODS: Sixty patients of obese T2DM were randomly divided into an acupuncture group and a medication group, 30 cases in each one. Patients in the medication group were treated with basic treatment combined with oral administration of regular antidiabetics, three weeks as one session. Patients in the acupuncture group, based on the medication group, were treated with abdominal acupuncture at Yinqiguiyuan [Zhongwan (CV 12), Xiawan (CV 10), Qihai (CV 6), Guanguan (CV 4)], Fusiguan [Huaroumen (ST 24), Wailing (TE 5)], Tianshu (ST 25), Daheng (SP 15), Qixue (KI 13), etc.; the treatment was given three times per week, 3 weeks as one session. The systolic blood pressure (SBP), diastolic blood pressure (DBP), body weight, waist circumference (WC), hip circumference, body mass index (BI) were observed before and after treatment in the two groups, and fasting plasma glucose (FPG), fasting insulin (FINS), 2-hours postprandial blood glucose by oral glucose tolerance test (OGTT) and insulin, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), HOMA-IR of insulin resistance index were calculated and adverge events were recorded. RESULTS: Compared before the treatment, SBP, WC, body weight, BMI, FPG, OG-TT2hBG, FINS, GTT2h insulin, HOMA-IR, TC and LDL-C in the acupuncture group were all significantly reduced (all P <0. 05), while FPG, OGTT2H insulin and TG were increased in the medication group (all P<0. 05)'. The differences of reducing SBP, WC, FPG, OGTT2H insulin, HOMA-IR, TC, TG and LDL-C were statistically significant between the two groups (all P<0. 05). The total effective rate was 93. 3% (28/30) in the acupuncture group, which was significantly superior to 23. 3% (7/30) in the medication group (P<0. 01). CONCLUSION: BO's abdominal acupuncture has obvious clinical efficacy for obese type-2 diabetes mellitus, featuring in lowering blood pressure, reducing weight, decreasing blood glucose, im- proving insulin resistance and lowering lipid, which has no adverse effects and is worthy of clinical popularization and application. PMID- 26054140 TI - [Clinical controlled trial on chronic nephritis albuminuria treated with acupuncture and moxibustion at DONG's extra points, "Xiasanhuana"]. AB - OBJECTIVE: Io compare the difference on the clinical efficacy in treatment of chronic nephritis albuminuria between acupuncture and moxibustion at "Xiasanhuang", DONG's extra points and benazepril hydrochloride so as to provide the effective therapeutic method for the treatment of chronic nephritis albuminuria. Methods One hundred and six cases of nephritis albuminuria were randomized into an acupuncture and moxibustion group and a western medication group, 53 cases in each one. In the acupuncture and moxibustion group, acupuncture and moxibustion were applied to "Xiasanhuang" (Tianhuang fuxue namely "shenguan", "Dihuang", "Renhuang"), once a day, the interval of 2 days once every 10 treatments. In the western medication group, benazepril hydrochloride was prescribed for oral administration, 5 to 10 mg each time, once a day. The treatment of 2 months made, one session in the two groups. After 1 session treatment, the clinical efficacy, red blood cell count (RBC) of urinary sediment, 24 h urine protein quantitation and creatinine clearance rate (Ccr) before and after treatment were observed in the two groups. RESULTS: The total effective rate was 84. 9% (45/53) in the acupuncture and moxibustion group, superior to 52. 8% (28/53) in the western medication group (P<0. 01). After treatment, RBC of urinary sediment and 24 h urine protein quantitation were reduced as compared with those before treatment (P< 0. 01, P<0. 05), and the results in the acupuncture and moxibustion group were lower than those in the western medication group (P<0. 05, P<0. 01). After treatment, Ccr in the acupuncture and moxibustion group was higher than that before treatment (P<0. 05) and higher than that in the western medication group (P<0. 05). Ccr was not different significantly before and after treatment in the western medication group (P>0. 05). CONCLUSION: Acupuncture and moxibustion at DONG's extra points (Xiasanhuang) reduce proteinuria and improve kidney, function in patients of chronic nephritis and the efficacy is better than that with benazepril hydrochloride. PMID- 26054141 TI - [Efficacy of acupuncture on moderate and severe allergic rhinitis]. AB - OBJECTIVE: To observe the efficacy and safety of acupuncture therapy on moderate and severe allergic rhinitis via the comparison evaluation of western medicine. METHODS: Sixty cases of moderate and severe allergic rhinitis were divided into an acupuncture group (30 cases) and a western medicine group (30 cases). In the acupuncture group, the main acupoints included Yingxiang (LI 20), Shangxing (GV 23), Fengchi (GB 20), Quchi (LI 11), Xuehai (SP 10), Feishu (BL 13), Geshu (BL 17), Pishu (BL 20), etc. The supplementary points were selected according to syndrome differentiation. In the western medicine group, budesonide nasal spray and cetirizine tablets were prescribed. All the cases were treated for 8 weeks in the two groups. Separately, before treatment, in 4 weeks and 8 weeks of treatment, the scores of clinical symptoms and physical signs were observed and the clinical efficacy and safety were compared between the two groups. RESULTS: In 4 weeks and 8 weeks of treatment, the scores of symptoms such as sneezing, nasal discharge, nasal obstruction, nasal itching, eye itching and turbinate hypertrophy, the score of physical signs and total score were all reduced apparently as compared with those before treatment (all P<0. 05). The differences were not significant between the acupuncture group and the western medicine group (all P>0. 05). The total effective rates were 90. 0% (27/30) and 93. 4% (28/30) in the acupuncture group after 4 and 8 weeks of treatment, and were 76. 6% (23/30) and 80. 0% (24/30) in the western medicine group separately, without significant difference in comparison (all P>0. 05). CONCLUSION: Acupuncture achieves the similar efficacy on moderate and severe allergic rhinitis as western medicine. It is the safe therapy and has no apparent adverse reactions. PMID- 26054142 TI - [Efficacy on nervous tinnitus of kidney deficiency treated with Zhuang medicine at Qineihuan point and conventional acupuncture therapy]. AB - OBJECTIVE: To compare the difference of the clinical efficacy in treatment of nervous tinnitus of kidney deficiency between the combined therapy of Zhuang medicine at Qineihuan point combined with the conventional acupuncture and simple conventional acupancture. METHODS: Sixty patients were randomized into an observation group and a control group, 30 cases in each one. In the control group, the conventional acupuncture was applied to Taixi (KI 3), Zhaohai (KI 6), Tinggong (SI 19) and Waiguan (TE 5), etc. and the needles were retained for 30 min. In the observation group, on the basic treatment as the control group, Zhuang medicine acupuncture at Qineihuan point was added. The treatment was given once every day, 10 treatments made one session and there were 2 days of interval between the sessions. In 3 sessions of treatment, the changes of tinnitus were observed and the clinical efficacy was evaluated. RESULTS: After treatment, tinnitus score and tinnitus grade were all improved as compared with those before treatment in the two groups (all P<0. 05) and the results in the observation group were better than those in the control group (all P<0. 05). The curative and remarkably effective rate was 63. 3% (19/30) and the total effective rate was 93. 3% (28/30) in the observation group, better than 30. 0% (9/30) and 73. 3% (22/30) in the control group (both P<0. 05). CONCLUSION: The combined therapy of Zhuang medicine at Qineihuan point and conventional acupuncture achieves the better efficacy on nervous tinnitus of kidney deficiency as compared with the simple conventional acupuncture. PMID- 26054143 TI - [Rules analysis of acupoint selection on perimenopausal syndrome treated with acupuncture and moxibustion]. AB - With the keywords of "acupuncture" "acupuncture and moxibustion" "perimenopausal syndrome" "rules of acupoint selection", the clinical literature in recent 10 years regarding perimenopausal syndrome treated with acupuncture and moxibustion was searched from China National Knowledge Infrastructure(CNKI). One hundred and ninety-seven relevant articles were acquired,and after excluding, total 67 articles were in accord with research criterion. With method of artificial count, acupoints selected in the inclusive articles were counted. Frequencies of main acupoints, matching acupoints,meridial distributions and locations of the acupoints selected were calculated,and then rules on main acupoints, matching acupoints, meridial distributions and acupoints locations were analyzed. The result indicates that the acupoints with higher selection frequency on perimenopausal syndrome treated with acupuncture and moxibustion are Sanyinjiao(SP 6), Baihui(GV 20),Taichong(LR 3) Shenshu(BL 23), Guanyuan(CV 4), Shenmen(HT 7),Taixi(KI 3), Zusanli(ST 36), Pishu(BL 20) and Ganshu(BL 18), and the meridians are mainly concentrated on governor vessel, bladder meridian, kidney meridian,stomach meridian, conception vessel and spleen meridian,and the distribution of acupoints are mostly concentrated on the 4 limbs and the back and waist. PMID- 26054144 TI - [Correlation between heel vessel and human balance function]. AB - The heel vessel belongs to the eight extra meridians in human meridian system, which is closely related to the human motion function. Balance function plays an essential role in successful completion of activities in daily life, so the physiological function and pathology of heel vessel as well as human balance function are analyzed, and from the aspect of running course of heel vessel and syndrome, the correlation between heel vessel and human balance function is explored, and the application status of acupoints related to heel vessel for balance dysfunction is introduced. It is believed that heel vessel is closely related to human balance function, especially the motion regulation mechanisms of balance function, and it is hoped that new ideas and methods can be provided for acupuncture treatment for the balance function disorders. PMID- 26054145 TI - [Effects of electroacupuncture on proteasomes of substantia nigra in rats with Parkinson's disease]. AB - OBJECTIVE: To explore the effects and action mechanism of electroacupuncture (EA) on Parkinson's disease (PD). METHODS: Forty-eight healthy male SD rats were randomly divided into a normal group, a sham operation group, a model group and an EA group, 12 rats in each one. Rats in the model group and EA group were treated with subcutaneous injection of rotenone (1mg/kg, dissolved in dimethyl sulfoxide and 0. 9 % normal saline) on neck and back for 40 days to establish rat model. Rats in the sham operation group were treated with injection of identical dose of dimethyl sulfoxide and 0. 9 %o normal saline at identical location which did not contain rotenone. After model establishment, rats in the EA group were treated with EA at "Fengfu" (GV 16) and "Taichong" (LR 3) with continuous wave (2 Hz, 1 mA), which was given 20 min per time, once a day for consecutive 28 days. Rats in the remaining groups were treated with fixation and immobilization without any other intervention. The rats behavioristics changes were observed and scored; immunohisto-chemistry was adopted to test the expression of tyrosine hydroxylase (TH); fluorescence spectrometry was used to detect the activities of 20 S beta1, beta2, beta5; western blot method was applied to measure the expression of 20S proteasome and its a subunit. RESULTS: Compared with the normal group and sham operation group, there was significant change of behavioristics in the model group, and TH positive neuron counting was obviously reduced; after treatment, the behavioristics score in the EA group was lower than that in the model group (P<0. 05), and TH positive neuron counting was significantly increased (P<0. 05). Compared with the normal group and sham operation group, the activities of 20 S beta1, beta2, beta5 in model group were significantly reduced (all P<0. 01), and those in the EA group were higher than those in the model group (P<0. 01). Compared with the normal group and sham operation group, the expression of 20S proteasome and its a subunit was reduced in the model group, and that in the EA group was higher than that in the model group (P<0. 05). CONCLUSION: EA could improve the loss of dopaminergic neurons induced by rotenone to prevent and treat PD, which is likely to be related with protecting the activity and expression of proteasomes in substantia nigra. PMID- 26054146 TI - [Analgesic effect of electroacupuncture on gastric ulcer rats with liver depression syndrome]. AB - OBJECTIVE: To explore the analgesic effect and action mechanism of electroacupuncture (EA) on gastric ulcer rats with liver-depression syndrome. METHODS: Through open-field experimental method, 45 qualified SPF-grade male SD rats were selected and divided into a blank group, a model group and an EA group according to random number table method, 15 rats in each group. The model of gastric ulcer rats with liver-depression syndrome was established in the model group and the EA group by using chronic unpredictable stimulation combined with acetic acid burning method. Rats in the blank group did not receive intervention. Rats in the model group were treated with fixation and immobilization for 13 days. Rats in the EA group were treated with EA at "Liangqiu" (ST 34) and "Ganshu" (BL 18); EA voltage was 2 V; disperse-dense wave was selected with 4 Hz of disperse wave and 15 Hz of dense wave, and the intensity of EA was according to the slight vibration of local skin and; muscles; the needles were retained for 20 min, once a day for consecutive 6 days; there was an interval of 1 day' and the treatment was given for 2 weeks. The general condition, open-field experimental result and gastric ulcer index were observed; the western blotting method was applied to measure the expression of vanilloid receptor subtype 1 (VR1) in hypothalamus and gastric antral mucosal, and ELISA method was applied to test the expression of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in hippocampus. RESULTS: After model establishment, the general behavior condition in the model group was inferior to that in the blank group, which was obviously improved after EA. The range of motion in the model group was less than that in the blank group (P<0.01) while that in the EA group was higher than that in the model group (P<0.01). The ulcer inhibition rate was. 54.95%, and the ulcer index in the EA group was lower than that in the model group (P<0.01). Compared with; the blank group, the expression of VR1 in hypothalamus and gastric antral mucosal in the model group was increased (P<0.05); compared with the model group, the expression of VR1 in the EA group was reduced (P<0.05). Compared with the blank group, the expression of 5-HT an NE in hippocampus in the model group was significantly reduced (both P<0.01); compared with the model group, the expression of 5-HT and NE in the EA group was increased (both P<0.01). CONCLUSION: EA at "Liangqiu" (ST 34) and "Ganshu" (BL 18) has certain analgesic effect in gastric ulcer rats with liver-depression syndrome, which is likely to be related with lowering the contents of VR1 in hypothalamus and gastric antral mucosal and increasing the content of 5-HT and NE in hippocampus. PMID- 26054147 TI - [Clinical research of lung resection surgery with microinjection acupuncture and drug anesthesia instead of traditional acupuncture anesthesia]. AB - OBJECTIVE: To explore the feasibility and safety on lung resection surgery with the combined method of microinjection acupuncture (MIA) and intravenous anesthesia instead of compound traditional acupuncture and drug anesthesia (ADA). METHODS: Ninety cases of lung resection surgery were randomized into a general anesthesia group, a MIA group and a ADA group, 30 cases in each one. In the general anesthesia group, before surgery, the intramuscular injection of atropine 0. 5 mg was used; during surgery, the anesthesia induction was followed with intravenous injection of fentanyl citrate, propofol and rocuronium bromide and the dosage was increased accordingly; after surgery, the analgesia pump was applied. In the MIA group, on the basis of general anesthesia, before anesthesia induction, the acupoint catgut embedding was applied to Jiaji (EX-B 2) of T4 , T6 and T, , Feishui (BL 13), Xinshu (BL 15) and Geshu (BL 17) on the affected side and bilateral Quchi (LI 11) and Zusanli (ST 36); after surgery, the analgesia pump was applied. In the ADA group, on the basis of general anesthesia, before! anesthesia induction, electroacupuncture (EA) was applied to Hegu (LI 4), Neiguan (PC 6) , Houxi (SI 3) and Zhigou (TE 6) for 30 min; during surgery, EA and intravenous medication were combined at the same acupoints as those before surgery; after surgery, moxibustion and the analgesia pump were applied in combination for analgesia. In each group, the biological indices were monitored during surgery at 11 time points named T. (before anesthesia I induction), T1 (intubation in general anesthesia induction), T2 (skin incision), T3 (rib exposure in muscular incision) T. (chest open), T, (lung removal), T6 (drainage tube implantation), T7 (chest closure), T (muscular stitching), T, (skin stitching) and T0 (extubation). The actual dosage of anesthetics during surgery and the, dosage of fentanyl citrate in analgesia pump were quantified after surgery. Results (1) In the MIA group and ADA group, the increased dosage of fentanyl citrate was less than that in the general anesthesia group [(1. 23+/-0. 28) ug . kg-1 . h-1 vs (2. 4+/-0. 54ug. kg-1 . h-1, (1. 1+/-0. 38ug . kg-1 . h-1 vs (2. 4+/-0. 54ug. kg-1 . h-1 , both P<0. 05]. The increased dosage of propofol and rocuronium bromide was not different during surgery among the groups (all P>0. 05). (2) In the MIA group and ADA group, after surgery, the increased dosage of fentanyl citrate was less than that in the general anesthesia group [(11. 0+/ 1. 04)ug/kg vs (15. 4+/-1. 52ug/kg, (11. 5+/-1. 38ug/kg vs (15. 4+/-1. 52ug/kg, both P<0. 05], reducing by 25% in comparison. (3) The differences in heart rate and blood pressure at 11 time points during surgery were not significant among the three groups (all P>0. 05). CONCLUSION: n The combined method of MIA and intravenous anesthesia significantly reduces the dosage of intravenous anesthetics during and after lung resection surgery as compared with ADA, presenting the similar analgesic effect as simple intravenous medication and the good safety. The combined method of MIA and intravenous anesthesia is much PMID- 26054148 TI - [Rejection reactions after acupoint embedding with chromic catgut: case report and discussion]. AB - Four cases of rejection reactions after acupoint embedding with chromic catgut as well as the diagnosis and treatment course were reported to reveal the importance of rejection reaction and its generality. Besides, the cause and mechanism were discussed. By combining the treatment experience, it was recommended to replace the catgut with third-generation absorbable medical suture, which could prompt execution of standardized manipulation of acupoint embedding. PMID- 26054149 TI - [Case of cerebral infarction after cerebral hemorrhage]. PMID- 26054150 TI - [Questionnaire investigation on cost-effectiveness analysis of acupuncture for migraine]. AB - OBJECTIVE: By using questionnaire method to understand the evaluation regarding cost-effectiveness of acupuncture for migraine in both doctors and patients. METHODS: By using questionnaire method, questionnaires for doctors and patients were made respectively; by using network platform, two sets of questionnaires were publicly released, which were filled in online. The results were real-time background collected and then analyzed. RESULTS: Totally 696 effective questionnaires for patients and 114 questionnaires for doctors were collected. The results indicated that (1)the direct cost (including treatment fee and material fee) for preventive treatment of migraine was 109 yuan per time in regular acupuncture, 152 yuan per time in regular acupuncture + electroacupuncture (EA) and 238 yuan per time in acupoint catgut embedding. The travelling expense was 42 yuan per time within the city and 193 yuan per time between cities. The indirect cost included cost for loss of working time (208 yuan per time), cost for treatment time (acupoint catgut embedding: 10 to 30 min per time, once one to three weeks; the remaining two treatments: 20 to 50 min per time, once to 5 times every week), time cost for arriving and departing hospital (1 to 3 hours per time within the city and 4 hours per time between cities). From the angle of treatment course, acupoint catgut embedding reduced the treatment frequency, leading to a lower total cost. (2)A mong the reasons to select different acupuncture methods to treat migraine, the results of patient questionnaire indicated that the focus in the patients who selected acupoint catgut embedding was different from that in the patients who selected two other treatments. The main advantage of acupoint catgut embedding was superior and lasting efficacy with low cost. The results of doctor questionnaire indicated the main reason to select acupoint catgut embedding was "lasting efficacy after single treatment" (87. 5%) and "lower frequency of treatment" (75. 0%). (3) The main reason to obstruct the popularization of acupoint catgut embedding was this method was not widely known. CONCLUSION: The acupoint catgut embedding is one ideal preventive treatment for migraine, which has higher cost-effectiveness, however, currently it is not widely applied. In future advertisement and training program should be strengthened to perform targeted popularization of acupoint catgut embedding for migraine. PMID- 26054151 TI - [Discussion on "abdominal as well, back such as cake"]. PMID- 26054152 TI - [Science of Meridians, Collaterals and Acupoints--Exploration on teaching method of meridian syndromes]. AB - Meridian syndromes are the required basic knowledge for mastering Science of Meridians, Collaterals and Acupoints but have not brought the adequate attention on the teaching program. The writers discovered' that the content of this section occupied a decisive role for developing the students' clinical thinking ability and, stimulating their interests to learn classical TCM theories. It's necessary to enhance the importance on meridian syndromes during teaching program. The teaching program was discussed in three aspects, named workshop pattern, competitive pattern and multimedia pattern. This teaching method may improve students' interests in the study on classical TCM theories, deepen the understanding on knowledge and motivate students' learning autonomy so that the teaching quality can be improved. PMID- 26054153 TI - [Case of eosinophilic gastroenteritis]. PMID- 26054154 TI - [Acupuncture theory of promoting blood circulation and removing stasis and its clinical application]. AB - The effects and methods of acupuncture on promoting blood circulation and removing stasis and its importance for modern clinical acupuncture are explored and explained. The acupuncture theory of promoting blood circulation and removing stasis in Internal Canon of Yellow Emperor and the ancient medical scholars' knowledge of acupuncture for promoting blood circulation and removing stasis are traced, and then the principles and characteristics of acupuncture for promoting blood circulation and removing stasis are explored and summarized. The methods and common tools of prompting blood circulation and removing stasis of modern clinical acupuncture are summed up as well. It is considered that the treatment principles and methods of acupuncture for prompting blood and removing stasis deserve to be paid attention to and applied by all departments of clinical acupuncture. PMID- 26054155 TI - [Theory analysis and clinical application of spirit-regulating and pain-relieving acupuncture method]. AB - The theoretical foundation and scientific connotation of spirit-regulating and pain-relieving acupuncture method as well as its clinical application for pain are discussed. During spirit regulation, attention should be paid on regulating heart and brain, while acupoints should be selected mainly from the Heart Meridian, Pericardium Meridian and Governor Vessel. It has significant efficacy for refractory pain in clinical treatment. Spirit-regulating and pain-relieving acupuncture method is development of acupuncture treating spirit, and it is an important method for pain in clinic. Improvement on sensitization of pain center and brain function is considered as one of the mechanisms in spirit-regulating and pain-relieving acupuncture method. PMID- 26054156 TI - [Acupuncture and stress]. AB - The relationship between acupuncture and stress is discussed from three aspects, including is it possible for acupuncture stimulation to be a stressor, whether acupuncture will start stress reaction, and whether acupuncture effects contain some stress factors. It is believed that correct acupuncture manipulation will not cause stress response, however, under some circumstances, such as inaccurate manipulation, improper treatment or patients who are very nervous but do not receive effective intervention, acupuncture is likely to cause stress response. Acupuncture-induced stress response is totally different from acupuncture anti stress. The possible stress factors in acupuncture effect are explored, which can provide a new angle for the research on action mechanism of acupuncture. From the view of stress to review acupuncture treatment, there are three enlightenments: emphasizing on communication between doctors and patients, avoiding over-pursuit of deqi and focusing on analysis of the body constitution. PMID- 26054157 TI - [Design and application of silver needle-knife]. AB - A silver needle-knife which has the dual function of silver needle and needle knife is designed. The main components of this silver needle-knife are approximately 50% silver and approximately 50% nichrome. The silver needle-knife is composed of five parts, including needle-knife tail, spiral handle; steering handle, needle-knife body and needle-knife edge. It converges the advantages of needle-knife and silver needle, which can cut loose of diseased tissue and peel adhesion of lesions, but also be heated with moxa cone and thermal therapeutic instrument, and connect with electroacupuncture apparatus. It has the function of warming channel and removing coldness, dispelling wind and eliminating dampness, resolving spasm and relieving pain, dredging the channel and so on. Due to the spiral handle and the steering handle, the operation is easier, which reduces the blindness of cutting and increase the safety. It is mainly used for soft tissue injury, rheumatism and rheumatoid arthritis, as well as degenerative diseases of spine and joint, and it has obvious efficacy on some internal medical diseases. PMID- 26054158 TI - [Acupoint injection for 21 cases of trigeminal neuralgia]. PMID- 26054159 TI - [Syndrome differentiation and treatment according to meridians for 49 cases of lumbar intervertebral disc protrusion]. PMID- 26054160 TI - [Acupuncture combined with Western medicine for angina of coronary artery disease: a systematic review]. AB - The effectiveness and safety of acupuncture combined with western medicine for angina of coronary artery disease are evaluated. Databases including Pubmed, Embase, Cochrane Library, CBMDisk,. CNKI, Wanfang, Chinese Clinical Trial Registry, etc. are searched with search time from beginning of the database establishment to January of 2014. As a result, totally 15 articles of acupuncture for angina of coronary artery disease that met the inclusive criteria were collected, involving 11 researches and 1 232 patients. The results of Meta analysis indicate that based on regular western medicine, additional use of acupuncture could further improve symptoms of angina, increase efficacy of electrocardiogram (ECG) and reduce the dosage of nitroglycerin, in the meanwhile the hemorheology could be ameliorated, and the contents of C reactive protein (CRP), malondialdehyde (MDA), lipid peroxide (LPO), endothelin (ET) could be reduced, while the contents of superoxide dismutase (SOD) and nitric oxide (NO) could be increased; besides, the occurrence rate of cardiovascular event could be reduced without causing obvious adverse events. Except for certain outcomes (including dynamic ECG and blood viscosity) those have no statistical significance between treatment group and control group, the differences of remaining outcomes are: statistically significant. It is believed that acupuncture combined with regular treatment of western medicine are effective treatment plan for angina of coronary artery disease, which are superior to regular treatment of western medicine, but the results of this systematic review be taken with caution, and more clinical trials with high quality are looking forward to be included into Meta-analysis to increase the level of evidence. PMID- 26054161 TI - [Case of severe eczema]. PMID- 26054162 TI - [Research progress of needles with knife-edge for carotid cardiac syndrome]. AB - According to topographic anatomy, pathogenesis and by retrieving, summarizing and analyzing literature regarding needle-knife and needles with knife-edge for carotid cardiac syndrome, it is found out that clinical misdiagnosis rate of carotid cardiac syndrome is considerably high. Needle-knife and needles with knife-edge could significantly improve the clinical symptoms of carotid cardiac syndrome, showing characteristic and advantage in treatment, but it is deficient in technique standard and efficacy criteria that should be united and authoritative. Researches regarding pathogenesis of carotid cardiac syndrome are not systematic. Clinical observation regarding long-term efficacy and relapse of needle-knife and needles with knife-edge treatment is rare. It is believed that the awareness on carotid cardiac syndrome should be increased to reduce misdiagnosis; scientific and standardized technique standard and efficacy criteria should be established; systematic and comprehensive researches regarding mechanism of needle-knife and needles with knife-edge for carotid cardiac syndrome should be launched; besides, clinical discussion regarding its long-term efficacy should start to provide a better clinical guideline. PMID- 26054163 TI - [Image of the month. Importance of infant's head circumference monitoring]. PMID- 26054164 TI - [How I treat ... Osgood-Schlatter disease]. AB - Osgood-Schlatter disease (osteochondosis of the tibial tubercle) is a common and benign disease which usually affects sportpracticing teenagers during their adolescence. Traditionally, its treatment includes total restriction from sport during several months. The latest recommendations, however, are more lenient and adapt all restriction of such practice to the level of pain experienced by the patient. Indeed, this pathology is unlikely to generate any complication and potential sequelae should be surgically managed once the patient has reached adulthood. PMID- 26054165 TI - [Management of hypophosphatemia: a case report]. AB - Hypophosphatemia is defined by a serum phosphate level lower than 0.8 mmol/l. If hypophosphatemia is chronically maintained, it is associated with muscular, osteous, neurological or cardio-respiratory disorders. We describe a patient with isolated hypophosphatemia, detail the mechanisms of phosphate homeostasis, and envisage the differential diagnosis of hypophosphatemia. Furthermore, we propose a sequential decisional algorithm based on basic biological tests and few complementary investigations. Treatment options are reviewed. PMID- 26054166 TI - [Epithelioid hemangioma, a rare bone tumor]. AB - A case of pathological hip fracture associated with an epithelioid hemangioma is reported. Epithelioid hemangioma is a benign tumor, rarely localized in a bone. When the tumor is found on the skeleton, it generally involves a long bone. X-ray does not permit the differenciation of epithelioid hemangioma from other, malignant, vascular tumors. Therefore, the diagnosis requires surgery. Although no consensus treatment guidelines exist, the curettage--filling is most often proposed. PMID- 26054167 TI - [50 Hz electric and magnetic fields and health: which message to the public?]. AB - Scientific data of effects of 50 Hz electric and magnetic fields on health are inconclusive. This uncertainty raises numerous questions. In this paper, significant key concepts are described to better understand the potential effects of electric and magnetic fields on health. Everyday life exposure values are included, as well as courses of action to be taken in front of a patient asking questions on health effects of 50 Hz electric and magnetic fields. PMID- 26054168 TI - [Rosacea]. AB - Rosacea is a common centro-facial dermatosis with a high socio-esthetic impact. Different subtypes are distinguished, classified into grades according to their severity. This classification is essential for therapeutic management. In general, rosacea remains difficult to treat as its pathophysiology is still not entirely understood. Future research is needed for a better understanding of this disease and the development of targeted treatments. PMID- 26054169 TI - [Isolated superior ophthalmic vein thrombosis due to tamoxifen]. AB - Superior ophthalmic vein thrombosis is a rare entity, which may lead to serious vision complications. We report the unusual observation of a 78-year-old patient who developed exophtalmos, chemosis, and blurred vision due to isolated superior ophthalmic vein thrombosis. This rare complication is likely due to tamoxifen therapy. In contrast with published data, in the present case, cessation of tamoxifen therapy did not improve ocular symptoms. PMID- 26054170 TI - [Spondylodiscitis in children: a review. A propos of two cases]. AB - Spondylodiscitis is defined as an infection of the intervertebral disc and the adjacent vertebral bodies. It represents, at the most, 2-4% of osteoarticular infections in children and its clinical presentation is often insidious. The specific condition of the young child (isolated discitis) is explained by some anatomical peculiarities. We report two cases of spondylodiscitis in children of different ages and review the pediatric characteristics, the role of imaging, the bacteriological diagnosis and the management of this disease. PMID- 26054171 TI - [Management of febrile neutropenia in cancer patients]. AB - The incidence of cancer is raising and the treatments are increasingly aggressive. Consequently, general practitioners, emergency departments, hematologists and oncologists are regularly facing a severe side-effect of cytotoxic therapy, febrile neutropenia (FN). FN is a serious complication of chemotherapy because it can be quickly fatal and causes a temporary or definitive cessation of treatment. In this article, we summarize the latest recommendations for the management of patients with FN under anti-cancer treatments. PMID- 26054172 TI - [Idiopathic bilateral patellar tendon rupture]. AB - In the absence of systemic disease, specific treatment or sport tendonitis, simultaneous bilateral patellar tendon rupture is rare. Often missed on the first glance, it represents a diagnostic difficulty that should not be overlooked at the initial medical visit. The loss of active extension of the lower limb and a radiographic patella alta, even in a bilateral context, should raise suspicion of this diagnosis. It is then necessary to search for predisposing causes and to evoke the differential, or frequently associated, diagnoses. The present report illustrates these diagnostic difficulties and summarizes some clinical considerations that might help to avoid neglecting these different elements at the first medical visit (positive diagnosis, associated lesions, favouring factors). PMID- 26054173 TI - [Albiglutide (Eperzan): a new once-weekly agonist of glucagon-like peptide-1 receptors]. AB - Albiglutide (Eperzan) is a new once-weekly agonist of Glucagon-Like Peptide-1 (GLP-1) receptors that is indicated in the treatment of type 2 diabetes. Two doses are available, 30 mg and 50 mg, to be injected subcutaneously once a week. It has been extensively evaluated in the HARMONY programme of eight large randomised controlled trials that were performed at different stages of type 2 diabetes, in comparison with placebo or an active comparator. The endocrine and metabolic effects of albiglutide are similar to those of other GLP-1 receptor agonists: stimulation of insulin secretion (incretin effect) and inhibition of glucagon secretion, both in a glucose-dependent manner, retardation of gastric emptying and increase of satiety. These effects lead to a reduction in glycated haemoglobin (HbA(1c)) levels, combined with a weight reduction. The overall tolerance profile is good. Albiglutide is currently reimbursed in Belgium after failure (HbA(1c) > 7.5%) of and in combination with a dual therapy with metformin and a sulfonylurea as well as in combination with a basal insulin (with or without oral antidiabetic drugs). To avoid hypoglycaemia, a reduction in the dose of sulfonylurea or insulin may be recommended. A once-weekly administration should increase patient's acceptance of injectable therapy and improve compliance. PMID- 26054174 TI - [Depression as a common complication of systemic lupus erythematosus]. AB - Systemic lupus erythematosus (SLE) is an inflammatory disease with multiple and disabling consequences, including the psychological status. The prevalence of major depressive episodes among patients suffering from SLE is significantly higher than in healthy people, or people suffering from other inflammatory diseases. While it is obvious that its chronic disease status with a frequently pejorative ending, as well as the number of treatments it requires, are contributing factors, it is likely that due to its pathogenic mechanisms, SLE causes direct injury to the brain, leading to a depressive symptomatology. Numerous hypotheses are under consideration. We shall review them all, recall a few epidemiologic features, add histology and medical imaging contributions and discuss the importance of setting up a fitting therapy for such patients. PMID- 26054175 TI - Crossover clinical investigation of a whitening chewing gum for inhibiting dental stain formation in conjunction with tooth brushing. AB - OBJECTIVE: The purpose of this clinical investigation was to evaluate the effectiveness of a marketed whitening chewing gum compared to a no-gum control in preventing the formation of extrinsic stains on the teeth of stain-forming subjects when chewed over a 12-week period of regular unsupervised use in conjunction with daily tooth brushing. METHODS: This was a single-center, examiner-blind, randomized, 12-week crossover clinical trial. Stain-forming (after smoking or drinking coffee or tea) adults, starting with a stain-free baseline, either chewed the test gum (Orbit White) unsupervised four times per day, 15 minutes/chew, or used no gum along with daily brushing with a commercially available toothbrush and dentifrice for 12 weeks. At the crossover, all procedures were repeated with subjects assigned the opposite treatment. Extrinsic stain was measured at six and 12 weeks by both the Lobene Stain Index (LSI) and the Modified Lobene Stain Index (MLSI) using separate experienced examiners. RESULTS: After 12 weeks, LSI stain scores showed a significant 25% reduction (p = 0.0008) in new stain formation for subjects using the test chewing gum along with tooth brushing versus tooth brushing alone (no-gum control). The corresponding MLSI stain scores demonstrated a 36% reduction (p < 0.0001) in the formation of extrinsic stain on the teeth. CONCLUSION: The overall findings of this clinical study demonstrated that regular use of Orbit White chewing gum, soon after smoking or drinking coffee or tea, will supplement daily tooth brushing in preventing unsightly stains from forming on the anterior teeth compared to brushing alone. PMID- 26054176 TI - U.S. Food and Drug Administration and American Dental Association: ensuring oral care product safety for the public. PMID- 26054177 TI - Placebo-controlled clinical trial evaluating 9.5% hydrogen peroxide high-adhesion whitening strips. AB - OBJECTIVE: To evaluate the effectiveness and tolerability of an experimental 9.5% hydrogen peroxide whitening strip relative to a placebo control over a three-week period. METHODS: In this parallel-design, double-blind clinical trial, 54 adult volunteers were randomized to an experimental 9.5% hydrogen peroxide whitening strip or placebo strip balancing for age and baseline tooth color, and received treatment. Strips were worn on the maxillary arch 30 minutes daily for 20 days. Efficacy was measured objectively as L*a*b* color change from digital images at Days 4, 7, 15, and 21. RESULTS: As early as Day 4 and at all subsequent visits, the 9.5% strip group experienced significant (p < 0.004) color improvement relative to placebo for b* and L* color parameters. The amount of color improvement increased with continuing peroxide strip use. Mean +/- SE between group differences in Ab* were -0.6 +/- 0.16, -0.8 +/- 0.15, -1.6 +/- 0.19, and 1.9 +/- 0.20 at Days 4, 7, 15, and 21, respectively. Similar results were noted for AL*. Minor tooth sensitivity was the most common adverse event, as reported by 12% of subjects in the 9.5% strip group and 11% of subjects in the placebo group. No subjects discontinued treatment due to an adverse event. CONCLUSION: This placebo-controlled clinical trial demonstrated that an experimental 9.5% hydrogen peroxide strip yielded significant tooth whitening relative to a placebo strip as early as after three days of product use. PMID- 26054178 TI - The effect of zinc lactate and magnolia bark extract added tablets on volatile sulfur-containing compounds in the oral cavity. AB - OBJECTIVE: A controlled, clinical, double-blind study was conducted to assess the efficacy of sugar-free tablets containing zinc lactate and magnolia bark extract (MBE) on oral volatile sulfur-containing compounds (VSC) versus placebo tablets for two hours. METHODS: In order to join the study, subjects had to have at least 24 teeth, no report of oral and systemic diseases, and no removable dentures. All 128 eligible participants had to avoid any professional oral hygiene, refrain from taking medicines for two weeks, be not menstruating, and not brush their teeth and tongue, smoke, drink alcohol, coffee or tea, eat onion, garlic, or licorice for a six-hour period before the visit and during the test. Moreover, to join the protocol, they had to show a VSC score of >= 75 ppb at the baseline measurement. Each qualified subject was placed in the test or the control group using a table of random numbers. The test tablet (0.7 g) contained 0.17 mg of zinc, in the form of zinc lactate, and 0.84 mg magnolia bark extract; the control tablet was identical, but without these active agents. The OralChroma2 device was utilized to evaluate total oral VSC. Their levels were recorded at baseline, after eight minutes of sucking two tablets in succession, after one hour, and after two hours. Data were analyzed with SPSS software and the level of significance was set at alpha = 0.05. RESULTS: One hundred subjects completed the trial (50 in the control group and 50 in the test group); 52 men and 48 women, mean age 38. None reported problems linked to zinc lactate or magnolia bark extract. The mean percentage reduction from baseline at the end of eight minutes of tablet sucking was 39% in the control group (p < 0.001) and 62% in the test group (p < 0.001); one hour later it was 6% in the control group and 30% in the test group (p < 0.001), and two hours later it was 2% in the control group and 18% in the test group (p < 0.001). The comparisons between the two groups after baseline adjustment showed a statistically significant difference in reductions of VSC between the test and the control tablets at the end of the sucking period (p < 0.01), after one hour (p < 0.001), and after two hours (p < 0.05). CONCLUSION: Tablets containing zinc lactate and magnolia bark extract can statistically significantly reduce the oral VSC levels for over two hours and were statistically significantly more effective than a control tablet. PMID- 26054179 TI - Comparison of the incipient lesion enamel fluoride uptake from various prescription and OTC fluoride toothpastes and gels. AB - OBJECTIVE: The objective of this in vitro study was to compare the fluoride uptake into incipient enamel lesions of a novel 970 ppm F- ion SnF2 over-the counter (OTC) gel (Enamelon Preventive Treatment Gel) and a novel 1150 ppm F- ion OTC toothpaste (Enamelon), each delivering amorphous calcium phosphate (ACP), to the uptake from two different prescription strength, 5000 ppm F- ion dentifrices containing tri-calcium phosphate (TCP) and a prescription 900 ppm F- ion paste containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP). METHODS: The test procedure followed method #40 in the US-FDA Anticaries Drug Products for OTC Human Use, Final Monograph testing procedures. Eight sets of twelve incisor enamel cores were mounted in Plexiglas rods and the exposed surfaces were polished. The indigenous fluoride levels of each specimen were determined prior to treatment. The treatments were performed using slurries of a negative control (water) and the following products applied to a set of sound enamel cores: 5000 ppm F- ion, sodium fluoride (NaF) prescription (Rx) dentifrice "A" containing TCP; 5000 ppm F- ion, NaF Rx dentifrice "B" containing TCP; 900 ppm F- ion, NaF Rx paste with CPP-ACP; 1150 ppm F- ion, NaF OTC toothpaste; 1150 ppm F- ion, stannous fluoride (SnF2) OTC toothpaste delivering ACP (Enamelon); 1100 ppm F- ion, SnF2 OTC toothpaste; and 970 ppm F- ion, SnF2 OTC gel delivering ACP (Enamelon Preventive Treatment Gel). The twelve specimens of each group were immersed into 25 ml of their assigned slurry with constant stirring (350 rpm) for 30 minutes. Following treatment, one layer of enamel was removed from each specimen and analyzed for fluoride and calcium. The pre-treatment fluoride (indigenous) level of each specimen was subtracted from the post-treatment value to determine the change in enamel fluoride due to the test treatment. RESULTS: The increase in the average fluoride uptake for treated enamel cores was: 10,263 +/- 295 ppm for the 970 ppm F- ion, Enamelon Preventive Treatment Gel; 7,016 +/- 353 ppm for the 1150 ppm F- ion Enamelon Toothpaste; 4,138 +/- 120 ppm for the 5000 ppm F- ion, NaF prescription dentifrice "A" with TCP; 3801 +/- 121 ppm for the 5000 ppm F- ion, NaF prescription dentifrice "B" with TCP; 2,647 +/- 57 ppm for the 1100 ppm F- ion, SnF2 OTC toothpaste; 1470 +/- 40 ppm for the 1150 ppm F- ion, NaF OTC toothpaste; and 316 +/- 9 ppm for the 900 ppm F- ion, NaF paste with CPP-ACP. The differences among all the products tested were statistically significant (p < 0.05), except for the two 5000 ppm F- ion products with TCP that were not statistically different from one another, and the 900 ppm F ion, NaF paste with CPP-ACP that was not statistically different from the negative water control. CONCLUSION: The Enamelon products (970 ppm and 150 ppm F ion, SnF2OTC dentifrices) delivering ACP provide statistically significantly more fluoride to incipient enamel lesions than two prescription strength 5000 ppm F- ion toothpastes containing TCP, the 900 ppm F- ion prescription paste containing CPP ACP, and the other OTC toothpastes compared in this study. PMID- 26054180 TI - Comparison of the enamel solubility reduction from Various prescription and OTC fluoride toothpastes and gels. AB - OBJECTIVE: The purpose of this in vitro study was to determine if a novel 970 ppm F ion SnF2OTC gel (Enamelon Preventive Treatment Gel) and a 1150 ppm F- ion SnF2OTC Enamelon Toothpaste, each delivering amorphous calcium phosphate (ACP), can significantly reduce the effect of an acid challenge to enamel as compared to two prescription (Rx) strength 5000 ppm F- ion (NaF) dentifrices containing tri calcium phosphate (TCP), and an Rx 900 ppm F- ion (NaF) paste with casein phosphopeptide-amorphous calcium phosphate (CPP-ACP). The effect will be determined by measuring the resistance of enamel specimens to an acid challenge before and after treatment with the test dentifrices. METHODS: The procedure used in this study was the FDA Test Method #33 for the determination of the effect of different test dentifrices on enamel solubility reduction. Twelve sets of three extracted human teeth were unprotected and etched prior to treatment with 0.1 M lactic acid buffer solution. The amount of phosphate dissolved from the teeth was quantified via measuring the phosphate in the retained lactate buffer solution with phosphorous analysis (pre-treatment phosphorous levels). The teeth sets were then exposed to the following treatments (diluted 1:3 parts in preheated [37 degrees C] distilled water): 5000 ppm F- ion, sodium fluoride (NaF) Rx dentifrice containing TCP; 5000 ppm F- ion, NaF Rx dentifrice; 900 ppm F- ion, NaF Rx paste with CPP-ACP; 1150 ppm F- ion, stannous fluoride (SnF2) OTC toothpaste delivering ACP Enamelon Toothpaste; and 970 ppm F- ion, SnF2 OTC gel delivering ACP (Enamelon Preventive Treatment Gel). The teeth sets were rinsed with distilled water and then exposed to 0.1 M buffered lactic acid solution. The amount of phosphate in the lactic acid buffer was determined for a second time (post treatment phosphorous levels). The percent of enamel solubility reduction was then computed as the difference between the amount of phosphorous in the pre- and post-treatment lactic acid solutions divided by the amount of phosphorous in the pre-treatment solution, and multiplied by 100. RESULTS: The percent reduction in enamel solubility recorded in this study was as follows: 60.14 +/- 0.79 for the Enamelon Toothpaste; 56.91 +/- 1.05 for the Enamelon Preventive Treatment Gel; 18.78 +/- 3.20 for the 5000 ppm F- ion, NaF prescription dentifrice "A' with TCP; 6.84 +/- 1.20 for the 900 ppm F- ion, NaF paste with CPP-ACP; 5.82 +/- 3.10 for the 5000 ppm F- ion, NaF prescription dentifrice "B" with TCP; and -5.45 +/- 1.86 for the negative control. The differences between all the products tested were statistically significant (p < 0.05), except for the Enamelon products that were not statistically different. The 900 ppm F- ion, NaF paste with CPP-ACP and the 5000 ppm F- ion, NaF toothpaste results were also not statistically different. CONCLUSION: The Enamelon products (970 ppm and 1150 ppm F- ion, SnF2 OTC dentifrices) delivering ACP were statistically significantly more effective in reducing enamel solubility than two Rx strength 5000 ppm F- ion NaF toothpastes containing TCP and the Rx 900 ppm F- ion NaF paste containing CPP-ACP. PMID- 26054181 TI - Efficacy of two different toothbrush heads on a sonic power toothbrush compared to a manual toothbrush on established gingivitis and plaque. AB - OBJECTIVE: To evaluate the efficacy of a power toothbrush with distinct multi directional cleaning action using two different heads (Colgate ProClinical C200 toothbrush with either a triple clean head or a sensitive head) as compared to a manual flat-trim toothbrush (Oral B Indicator toothbrush) on supragingival plaque and established gingivitis. METHODS: This examiner-blind, randomized, controlled, three-treatment, parallel-group clinical research study assessed plaque removal via the comparison of pre- to post-brushing after a single use and again after four weeks of use, using the Rustogi Modified Navy Plaque Index. This study also assessed gingivitis at four weeks using the Loe-Silness Gingival Index. Qualifying adult male and female subjects from the central New Jersey, USA area reported to the study site after refraining from any oral hygiene procedures for 24 hours, and from eating, drinking, and smoking for four hours. Following an examination for plaque and gingivitis, they were randomized into three balanced groups. Subjects were instructed to brush their teeth for two minutes under supervision with their assigned toothbrush and a commercially available toothpaste (Colgate Cavity Protection toothpaste), after which they were again evaluated for plaque. Subjects were dismissed from the study site with the toothpaste and their assigned toothbrush to use at home twice daily for the next four weeks. They reported to the study site after four weeks of product use, at which time they were evaluated for plaque and gingivitis. RESULTS: One hundred twenty (120) enrolled subjects complied with the protocol and completed the clinical study. The results of the study indicated that all three test products provided statistically significant reductions in pre-brushing to post-brushing plaque scores for whole mouth and interproximal sites after a single use. For gingival margin plaque sites, only the Colgate ProClinical C200 toothbrush, with either the triple clean head or the sensitive head, provided statistically significant reductions in pre- to post-brushing plaque scores. After four weeks of product use, all three test products provided statistically significant reductions in baseline to four-week whole mouth and interproximal site plaque scores, but only the Colgate ProClinical C200 toothbrush, with either the triple clean head or the sensitive head, provided a statistically significant reduction in plaque scores at gingival margin sites. All three test products provided statistically significant reductions in gingival and gingivitis severity index scores after four weeks of product use. Relative to the manual toothbrush group, after a single tooth brushing the Colgate ProClinical C200 toothbrush, with either the triple clean head or sensitive head, provided statistically significantly greater reductions in whole mouth plaque index scores (51.9% and 59.3%, respectively), in gingival margin plaque index scores (700% and 650%, respectively), and interproximal plaque index scores (64.2% and 60.4%, respectively). Relative to the manual toothbrush group, after four weeks of use the Colgate ProClinical C200 toothbrush, with either the triple clean head or sensitive head, provided statistically significantly greater reductions in whole mouth plaque index scores (78.6%, and 82.1%, respectively), in gingival margin plaque index scores (3700% and 3400%, respectively), and interproximal plaque index scores (50.8% and 52.5%, respectively). Relative to the manual toothbrush group, after four weeks of use the Colgate ProClinical C200 toothbrush, with either the triple clean head or sensitive head, provided statistically significantly greater reductions in gingival index scores of 900% and 833%, respectively, and in gingivitis severity index scores of 466.7% and 600%, respectively. All statistically significant reductions were at the p <= 0.05 level. There were no statistically significant differences between the scores of the Colgate ProClinical C200 toothbrush with triple clean head and the scores of the Colgate ProClinical C200 toothbrush with sensitive head at any comparison time point. CONCLUSION: The Colgate ProClinicaI C200 toothbrush, with either a triple clean head or a sensitive head, provides statistically significant and clinically relevant levels of efficacy in the removal of supragingival dental plaque in the whole mouth, at the gingival margin, and interproximally after a single tooth brushing and after four weeks of use, as well as a statistically significantly greater level of efficacy in the reduction of gingivitis and gingival bleeding when compared to a manual flat-trim toothbrush. PMID- 26054182 TI - Salivary pH after a glucose rinse: effect of a new mucoadhesive spray (Cariex) based on sodium bicarbonate and xylitol. AB - OBJECTIVE: This study evaluated whether sodium bicarbonate applied on the oral mucosa through a new mucoadhesive spray (Cariex) could control a drop in salivary pH after a glucose rinse, and therefore enhance the buffering potential of saliva. METHODS: A sample of 50 healthy adults was selected. At day 1, the measurement of salivary pH was performed in the lower fornix in correspondence with the lower molars. Each subject rinsed with 10 ml of a 10% glucose solution and then pH was monitored continually for 40 minutes. At day 2, the same experimental procedure was repeated and three shots of the spray were administered on the oral mucosa. The tested spray is composed of sodium bicarbonate, xylitol, and excipients. RESULTS: Without the mucoadhesive spray, salivary pH became significantly lower following the glucose rinse (p < 0.01). Following the spray, the time in which the pH remained lower than 6.0 was reduced statistically significantly (p < 0.01). A continual rise of salivary pH was observed for the 40 minutes in which the pH recording was performed. Conclusions: The use of a sodium bicarbonate spray on the mucosa was shown to control the lowering of salivary pH following carbohydrate consumption, and might therefore add to the prevention of caries and dental erosion. PMID- 26054183 TI - An in vitro comparison of the effects of various air polishing powders on enamel and selected esthetic restorative materials. AB - OBJECTIVE: The purpose of this study was to investigate the effects of each of the commercially available air polishing powders on the surface characterization of human enamel, hybrid composite, and glass ionomer using a highly standardized protocol. The air polishing powders utilized in the study included aluminum trihydroxide, calcium carbonate, calcium sodium phosphosilicate, glycine, and sodium bicarbonate. METHODS: The hybrid composite and glass ionomer cement were mixed and photo light-cured for 40 seconds according to manufacturer's directions, and formed in a specially prepared mold that was coated using a Teflon aerosolized spray. The enamel samples were prepared by removing sections of human enamel from extracted unerupted third molars using a water-cooled, slow speed diamond rotary saw. The enamel sections were approximately one centimeter in diameter and 3 mm thick. The enamel sections were flattened using a series of silicon carbide grit papers (600, 800, and 1200 grit) mounted on a rotating polishing wheel. A flat polished enamel surface, at least 5 mm in size, was produced and embedded in the hybrid composite material used for testing purposes, resulting in a sample approximately 10 mm in diameter and 2 mm thick. The restorative material samples were wet-polished to produce a uniform smooth surface and to remove the resin-rich surface layer, using the same series of silicon carbide grit papers used on the enamel (600, 800, and 1200 grit). The 1200 grit abrasive paper used is equivalent to a dental polishing disc commonly used to finish dental restorations. All samples were stored in distilled water at 37 degrees C prior to testing. Each of the three types of samples was treated with each air polishing powder for one, two, and five seconds. A test group of five samples each of hybrid composite, glass ionomer cement, and enamel was fabricated for each of the six types of abrasive powder and three-time exposures for the air polishing treatment, resulting in a total of 270 samples. The treatment samples were exposed to the air polishing powders for the three periods of time using a custom mounting jig and shutter device that was fabricated to standardize the air polishing treatments. The air polishing handpiece was placed in a mounting jig that positioned the tip of the handpiece at an 80 angle from the sample surface. The exposure to the air polishing air, water, and polishing powder was regulated by an articulated metal plate positioned between the tip and the test sample. The holder for the test sample kept the sample in a constant circular motion to simulate clinical use of the air polishing handpiece. A custom computer program was developed to activate a stepper motor that rotated the metal plate away from the sample for the controlled exposure times of one, two, and five seconds before the plate moved back to intercept the polishing spray mixture. RESULTS: The effect of the air polishing application on the surfaces of the tooth enamel and restorative materials was evaluated for changes in surface roughness and surface topography. The average surface roughness value was evaluated with a contact profilometer prior to and after the air polishing treatment. Changes in the surface characterization of each sample due to air polishing treatment were recorded using scanning electron microscopy. Epoxy resin replicas of representative test samples were made for evaluating under the scanning electron microscope. Samples were sputter-coated with gold palladium and the scanning electron photomicrographs were taken at a magnification of 25X and at a 45 degrees angle. Based on evaluation with the contact profilometer, there were statistically significant interactions between the type of powder and material, type of power and time, and type of material and time. The SEM photomicrographs were used to evaluate the clinical significance of the effects of the air polishing on each type of material. The SEM photomicrographs provided a visual quantitative analysis of the effects of air polishing powders on the restorative materials and the enamel. Any disruption of the surface characterization was considered to be clinically significant and represented volumetric loss and violation of the integrity of the restorative materials and/or enamel. CONCLUSIONS: Based on the results of this study, the air polishing powders that are compatible with use on hybrid composite and glass ionomer cements are EMS glycine and EMS sodium bicarbonate. The air polishing powders that are compatible for use on enamel include EMS glycine, Dentsply sodium bicarbonate, and EMS sodium bicarbonate. PMID- 26054184 TI - A profilometry-based dentifrice abrasion Method for V8 brushing machines. Part I: Introduction to RDA-PE. AB - OBJECTIVE: This paper describes the development and standardization of a profilometry-based method for assessment of dentifrice abrasivity called Radioactive Dentin Abrasivity - Profilometry Equivalent (RDA-PE). METHODS: Human dentine substrates are mounted in acrylic blocks of precise standardized dimensions, permitting mounting and brushing in V8 brushing machines. Dentin blocks are masked to create an area of "contact brushing." Brushing is carried out in V8 brushing machines and dentifrices are tested as slurries. An abrasive standard is prepared by diluting the ISO 11609 abrasivity reference calcium pyrophosphate abrasive into carboxymethyl cellulose/glycerin, just as in the RDA method. Following brushing, masked areas are removed and profilometric analysis is carried out on treated specimens. Assessments of average abrasion depth (contact or optical profilometry) are made. RESULTS: Inclusion of standard calcium pyrophosphate abrasive permits a direct RDA equivalent assessment of abrasion, which is characterized with profilometry as Depth test/Depth control x 100. Within the test, the maximum abrasivity standard of 250 can be created in situ simply by including a treatment group of standard abrasive with 2.5x number of brushing strokes. RDA-PE is enabled in large part by the availability of easy to-use and well-standardized modern profilometers, but its use in V8 brushing machines is enabled by the unique specific conditions described herein. CONCLUSION: RDA-PE permits the evaluation of dentifrice abrasivity to dentin without the requirement of irradiated teeth and infrastructure for handling them. In direct comparisons, the RDA-PE method provides dentifrice abrasivity assessments comparable to the gold industry standard RDA technique. PMID- 26054185 TI - Randomized clinical trial of the efficacy of dentifrices containing 1.5% arginine, an insoluble calcium compound and 1450 ppm fluoride over two years. AB - OBJECTIVE: A double blind, randomized, unsupervised, parallel-group clinical trial was conducted on over 5,500 children in Sichuan Province, China. This clinical trial compared the anti-caries efficacy of two test dentifrices to that of a control dentifrice. METHODS: The test dentifrices contained 1.5% arginine, 1450 ppm fluoride as sodium monofluorophosphate (MFP), and an insoluble calcium compound (either dicalcium phosphate or calcium carbonate). The positive control dentifrice contained 1450 ppm fluoride as sodium fluoride (NaF), in a silica base. The children were randomly assigned one of the toothpastes, and children residing in the same household were assigned the same dentifrice to use at home, twice a day. RESULTS: Three calibrated dentists examined the children at baseline, as well as after one and two years of product use. After one year of product use, there were no statistically significant differences among the three groups with respect to decayed, missing, and filled teeth (DMFT) or to decayed, missing, and filled surfaces (DMFS). After two years of product use, subjects in the two test groups using the dentifrices containing 1.5% arginine, 1450 ppm fluoride as MFP, and an insoluble calcium compound had a statistically significant reduction in DMFT increments of 20.5% and in DMFS increments of 19.6% when compared to subjects in the group using the positive control dentifrice. After two years, there were no statistically significant differences with respect to DMFT or DMFS between the two groups using the dentifrices containing 1.5% arginine, 1450 ppm fluoride as MFP, and an insoluble calcium compound. CONCLUSION: The use of the two test dentifrices demonstrated significant reductions in decayed, missing, and filled teeth and surfaces, however there was no statistically significant different between the two test dentifrices clinically after two years of using the toothpastes. The results of this two-year clinical investigation support the conclusion that dentifrices containing 1.5% arginine, an insoluble calcium compound, and 1450 ppm fluoride as MFP provide superior protection against caries lesion cavitation compared to a positive control dentifrice containing only 1450 ppm fluoride as NaF. PMID- 26054186 TI - Dental hygienists' evaluation of the usability research study of the Colgate ProClinical A1500 electric toothbrush. AB - OBJECTIVE: To determine the user experiences among patients of a new electric toothbrush vs. a manual toothbrush. METHODS: Five dental hygienists were selected to review videotapes demonstrating patient use of their manual toothbrush and the Colgate ProClinical A1500 electric toothbrush. A total of 14 users were videotaped during the three-week duration of this observational study. The dental hygienists were asked to review four assigned user videotapes and then complete a four-page questionnaire sheet for each of them. Each patient participant was reviewed by at least two dental hygienists. RESULTS: The results provide an understanding that there may be differences in the length of time that patients brush their teeth with their manual toothbrush vs. this electric toothbrush. The users of the electric toothbrush appeared to brush in a more concentrated and focused tooth brushing pattern vs. the manual brush. The users did become accustomed to using this electric toothbrush over time and felt an improvement in cleaning efficacy with the product. The observations from the five dental hygienists were consistent with the results of a previously published usability study. CONCLUSION: The Colgate ProClinical A1500 electric toothbrush, relative to a manual toothbrush, provided an improved brushing experience for the fourteen users whose brushing techniques were evaluated by five dental hygienists who reviewed their videotapes from the usability study. PMID- 26054187 TI - In vitro study of the diagnostic performance of the Spectra Caries Detection Aid. AB - OBJECTIVE: The Spectra Caries Detection Aid is a fluorescent camera (FC) caries detector device that has been demonstrated to detect occlusal caries extending into dentin with good sensitivity and specificity. This in vitro study examined the diagnostic performance of this device with the goal of defining the numerical reading that best indicates that a tooth has dentin caries. METHODS: Ninety extracted human third molars, that either appeared clinically intact or had early occlusal caries, were used. Teeth were photographed then analyzed using the Spectra Caries detector. Following Spectra readings, the teeth were sectioned perpendicular to the long axis of the tooth. Cuts were made in such a way as to expose the dentino-enamel junction below the pits and fissures. The sectioned teeth were scored as being caries-free, having enamel caries, or dentin caries. Using each tooth's Spectra reading and histological diagnosis, the sensitivity and specificity for various potential dentin caries cut-off values were calculated. Also, the receiver operator curve (ROC) was plotted and the area under the curve calculated. RESULTS: At the manufacture's recommended cut-off for dentin caries diagnosis of 2, the sensitivity is 0.68 and the specificity is 0.78. At a lower cut-off value in the study reported here of 1.8, it was observed that the sensitivity is higher at 0.87, but that the specificity is lower at 0.7. The overall diagnostic performance of the Spectra is good with an ROC area under the curve of 0.82. CONCLUSION: Although lower cut-off values may have higher sensitivity, the use of the manufacture's established cut-off of 2 will result in fewer instances where dentin caries will be diagnosed incorrectly. The use of higher thresholds will discourage restorative treatment of early lesions that are best managed by sealants or other preventive approaches. PMID- 26054188 TI - Flexural strength and flexural fatigue properties of resin-modified glass ionomers. AB - OBJECTIVE: To determine the physical properties of several resin-modified glass ionomers (RMGIs) by means of flexural strength and flexural fatigue testing, and to compare them to conventional glass ionomer cements (GICs) and flowable composite resins. METHODS: RMGI samples were fabricated according to ISO 4049 standard. Rectangular specimens were produced using a polytetrafluoroethylene (PTFE) mold with dimensions of 2 x 2 x 25 mm. Flexural strength and flexural fatigue were measured by means of the 3-point bending tests using an Instron universal testing machine at 0.75 mm/min and 0.03 Hz for 100 cycles, respectively. Flexural stress, load, and displacement were recorded for all tests. Data were statistically compared (ANOVA, SNK, p < 0.05). Statistical data analysis for flexural fatigue was achieved through the least frequent events method (failures versus non-failures). The following RMGIs, flowable composites, and GICs were tested: 1) Activa Bioactive-Restorative; 2) Activa Bioactive Base/Liner; 3) Tetric EvoFlow; 4) Beautifil Flow Plus; 5) Geristore; 6) Fuji Filling LC; 7) Fuji Lining LC; 8) Ketac Nano; 9) Fuji Triage; 10) Ketac Nano; and 11) Vitrebond Plus. RESULTS: The flexural strength of Activa-enhanced RMGIs was statistically significantly greater than all other RMGIs and GICs (p < 0.001). The flexural fatigue of Activa-enhanced RMGIs and flowable composites was significantly greater than all other materials (p < 0.00 1). The flexural fatigue of the Activa-enhanced RMGIs was comparable to the two flowable composites tested. CONCLUSION: The Activa-enhanced RMGIs demonstrated comparable flexural strength and flexural fatigue to flowable composites. Activa-enhanced RMGIs and flowable composites demonstrated flexural strength and flexural fatigue significantly greater than all other tested materials. PMID- 26054189 TI - Ergonomics and toothbrushes. PMID- 26054190 TI - [Effect of electroacupuncture of "Guanyuan" (CV 4) on Wnt-beta-catenin signaling in osteoporosis rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture of "Guanyuan" (CV 4) on bone miner density, bone biomechanics, serum osteocalcin (BGP) and alkaline phosphatase (ALP) contents, and femoral osteoblastic Wnt-beta-catenin signaling in postmenopausal osteoporosis (PMOP) rats. METHODS: Forty female SD rats were randomly divided into sham operation (sham), model, EA-CV 4, and EA-non-acupoint (below the costal region) groups (n = 10 in each group). The PMOP model was established by performing an ovariectomy in the rats of the later 3 groups. EA (2 Hz, 1 mA) was applied to CV 4 for 20 min, once daily for one month, with one day's break between every 10 days. After the treatment, serum BGP and ALP contents were detected using ELISA, the right femoral bone miner density and biomechanics (maximum load, breakage load) were measured using a Dual Energy X Ray Bone Densitometer and a Universal Material Testing Instrument, respectively. The expression levels of Wnt 3 a mRNA, beta-catenin mRNA and the bone-specific factors runt-related transcription factor 2 (Runx 2) mRNA of the femoral bone tissue were determined by real time RT-PCR. RESULTS: HE staining results suggested EA of "Guanyuan" (CV 4) can improve the morphological changes (trabeculae) of osteoporosis in ovariectomized rats. Compared with the control group, femoral maximum load and breakage load, bone density and serum BGP and ALP contents, femoral Wnt 3 a mRNA, beta-catenin and Runx 2 mRNA expression levels, and femoral Wnt 3 a.and beta-catenin immunoactivity were significantly down regulated in the ovariectomized rats (model group) (P < 0.05). Following EA treatment, all the decreased levels of femoral maximum load and breakage load, bone density and serum BGP and ALP, femoral Wnt 3 a mRNA and protein, beta catenin mRNA and protein and Runx 2 mRNA expression were obviously reversed in the EA-CV 4 group (P < 0.05) rather than in the non-acupoint group (P > 0.05). CONCLUSION: EA of CV 4 can improve the femoral biomechanics, increase bone density in OVX rats, which are associated to its effects in up-regulating levels of serum BGP and ALP, femoral Wnt 3 a mRNA and protein, beta-catenin mRNA and protein and Runx 2 mRNA expression, suggesting an involment of improved bone metabolism and activation of osteoblastic Wnt-beta-catenin signaling. PMID- 26054191 TI - [Effect of Electroacupuncture stimulation of acupoints of the Pericardium Meridian on serum NGF and Nogo-A contents and cerebral NGF and Nogo-A expression in cerebral ischemia rats]. AB - OBJECTIVE: To observe the effect of Electroacupuncture (EA) stimulation of "Tianquan"(PC 2), "Quze" (PC 3), "Neiguan" (PC 6), "Daling" (PC 7) of the Pericardium Meridian on cerebral angiogenesis in cerebral ischemia (CI) rats, so as to reveal its mechanisms underlying improvement of stroke. METHODS: A total of 50 SD rats were equally randomized into normal control, sham, model, EA Pericardium-Meridian acupoints (EA-PCM) and EA-Lung-Meridian acupoint (EA-LUM) groups. The CI model was established by occlusion of the middle cerebral artery. EA (2-4 V, 20 Hz) was applied to PC 2, PC 3, PC 6, PC 7 and "Tianfu"(LU 3), "Chize" (LU 5), "Lieque" (LU 7), "Taiyuan" (LU 9) of the Lung Meridian for 30 min, once at time-points of 0 h, 6 h, 24 h, 48 h and 72 h, respectively after modeling. Serum nerve growth factor (NGF) and Nogo protein-A (Nogo-A) contents were assayed by enzyme linked immunosorbent assay (ELISA), and cerebral NGF and Nogo-A immunoactivity levels in the ischemic cerebral tissue were detected by immunohistochemistry. RESULTS: (1) Compared to the normal control group, serum NGF and Nogo-A contents, and cerebral NGF immunoactivity level in the model group were significantly increased (P < 0.01). Following EA interventions, serum and cerebral NGF levels were further significantly up-regulated in the EA-PCM and EA LUM groups (P < 0.01), while serum Nogo-A contents were down-regulated in the two EA groups (P < 0.01). The effect of EA-PCM was markedly superior to that of EA LUM in up-regulating serum and cerebral NGF levels and down-regulating serum No- go-A level (P < 0.01). No significant differences were found between the normal control and sham groups in serum and cerebral NGF and Nogo-A levels (P > 0.05) , and among the 5 groups in cerebral Nogo-A levels (P > 0.05). CONCLUSION: EA stimulation of acupoints of both Pericardium Meridian and Lung Meridian can up regulate serum NGF, cerebral NGF expression and down-regulate serum Nogo-A in CI rats, and the effect of Pericardium Meridian is markedly superior to that of Lung Meridian, suggesting a possible better nerve repair effect of EA-PCM acupoints on ischemic brain. PMID- 26054192 TI - [Effect of electroacupuncture and moxibustion pretreatment on expression of cerebral micro- RNAs and Aquaporin protein-4 in cerebral infarction rats]. AB - OBJECTIVE: The present study aimed at observing the effect of moxibustion pretreatment on the expression of cerebral microRNAs and Aquaporin protein-4 (AQP 4) in rats with cerebral ischemia and reperfusion (CI/R), so as to reveal its mechanism underlying improvement of cerebral infarction. METHODS: A total of 130 Wistar rats were randomly divided into blank control (n = 10), CI/R model (n = 30), electroacupuncture (EA, n = 30), moxibustion (n = 30), Aspirin groups (n = 30). Before modeling, EA (2 Hz/5 Hz, 1-2 mA) or moxibustion was applied to "Baihui" (GV 20), "Fengfu" (GV 16) and "Dazhui" (GV 14) for 20 min, once daily for 7 days. The rats of the Asprin group were treated by intragastric administration of Aspirin (10 mg/kg, 1 mg/mL) , once daily for 7 days before modeling. The CI/R model was established by occlusion of the bilateral carotid arteries. The expression levels of cerebral miRNAs and AQP 4 were detected by real-time PCR and Western blot, respectively. RESULTS: Compared with the blank control group, the expression levels of cerebral miRNA 290 and miRNA 494 were significantly reduced, while that of AQP 4 was obviously up-regulated in the model group (P < 0.01). After pretreatment with EA and moxibustion, the relative expression levels of miRNA 290 and miRNA 494 were significantly higher in the EA, moxibustion and Aspirin pretreatment groups than in the model group (P < 0.01), while cortical AQP 4 expression levels were significantly lower in the EA, moxibustion and Aspirin pretreatment groups than in the model group (P < 0. 01, P < 0.05). The effects of both EA and moxibustion groups were significantly superior to those of Aspirin pretreatment group in up-regulating expression of miRNA 290 and miRNA 494 and down-regulating expression of AQP 4 (P < 0.01, P < 0.05). In addition, the EA pretreatment was markedly superior to moxibustion pretreatment in the aforementioned effects (P < 0.05). CONCLUSION EA pretreatment of GV 14, GV 16 and GV 20 can effectively up-regulate cerebral cortical miRNA 290 and miRNA 494 and down-regulate AQP 4 in CI/R rats, which may contribute to its effect in preventing the cerebral tissue from ischemia/reperfusion injury. PMID- 26054193 TI - [Effect of moxibustion with ignited Zhuang-medicine medicated-thread on interstitial cells of Cajal in gastric antrum in diabetic gastroparesis rats]. AB - OBJECTIVE: To observe the effect of Zhuang-medicine medicated-thread moxibustion therapy on interstitial cells of Cajal (ICC) in the gastric antrum of diabetic gastroparesis (DGP) rats, so as to investigate its mechanism underlying improving DGP. METHODS: Sprague-Dawley (SD) male rats were randomly divided into 3 groups: control (n = 30) , model (n = 30) and moxibustion (n = 30). The DGP model was established by intraperitoneal injection of streptozotocin (STZ) and by feeding the rats with high fat-sugar forage. Zhuang-medicine medicated-thread moxibustion was applied to "Zhongwan" (CV 12), bilateral "Pishu" (BL 20), "Weishu" (BL 21), "Neiguan" (PC 6) and "Zusanli" (ST 36) once per day, for 3 weeks except weekends. The gastrointestinal propulsion rate and weight of stool in 24 h were determined, and c-kit (a marker for ICC) expression of the gastric antrum tissue was measured by immunohistochemistry. RESULTS: The stool weight was significantly higher in the model group than in the control group (P < 0.01), but the rate of gastrointestinal propulsion and the rate of c-kit immunoreaction (IR) positive cells in the gastric antrum tissue were significantly lower in the model group than in the control group (P < 0.01). After moxibustion, the increased stool weight and the decreased gastrointestinal propulsion rate and decreased c-kit IR positive cell rate were reversed (P < 0.01). CONCLUSION: Zhuang-medicine medicated-thread moxibustion therapy can improve gastrointestinal function in DGP rats, which may be associated with its effect in up-regulating the expression of c-kit IR-positive ICC. PMID- 26054194 TI - [Effect of electroacupuncture intervention combined with polysaccharide of Gastrodia elata Blume on expression of nestin and stem cell factor around the ischemic locus of frontal lobe cortex in local cerebral ischemia rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA), Polysaccharide of Gastrodia elata Blume (PGB), and EA + PGB on the expression of Nestin and stem cell factor (SCF) in the frontal lobe cortex around the ischemic loci of cerebral ischemia (CI) rats, so as to explore its mechanisms underlying improvement of CI. METHODS: A total of 40 Sprague-Dawley adult rats were randomly divided into normal control, CI model, EA intervention, PGB intervention and EA + PGB groups (n = 8 in each group). The CI model was prepared by middle cerebral artery occlusion. EA (2 Hz, 2 V) was applied to "Baihui" (GV 20) and left "Zusanli" (ST 36) for 30 min, once daily for 14 days. Rats of the PGB and EA + PGB groups were treated by gastrogavage of PGB at a dose of 100 mg/kg, once daily for 14 successive days. The expression of Nestin and SCF in the frontal lobe around the ischemic loci of the frontal lobe was detected by immunohistochemistry. RESULTS: Compared with the normal control group, the expression levels of regional cerebral cortical Nestin and SCF proteins were significantly increased in the model group (P < 0.05). After the treatment, the expression levels of Nestin and SCF were significantly further up-regulated in the EA, PGB and EA + PGB groups in comparison with the model group (P < 0.05). CONCLUSION: EA combined with PGB can significantly up-regulate the expression of Nestin and SCF in the frontal lobe around the ischemic loci in cerebral ischemia rats, which may contribute to their function in improving CI. PMID- 26054195 TI - [Effects of electroacupuncture preconditioning on expression of nitric oxide synthase and glial fibrillary acidic protein in cortex of focal cerebral ischemia reperfusion rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) preconditioning on the expression of neuronal nitric oxide synthase (nNOS), inducible nitric synthase (iNOS) and glial fibrilliary acidic protein (GFAP) in the cortex of focal cerebral ischemia-reperfusion (CI/R) rats so as to explore its underlying mechanism in the protection of ischemic cerebral tissue. METHODS: Twenty-four Sprague-Dawley rats were randomized into sham operation (sham), model, and EA preconditioning groups (n = 8 in each group). The CI/R model was induced by intraluminal middle cerebral artery occlusion .(MCAO) with a nylon monofilament suture. Before modeling, EA (2 Hz/15 Hz, 3 V) was applied to "Baihui"(GV 20) and "Dazhui"(GV 14) for 30 min, once daily for 7 consecutive days. The neurologic impairment score was assessed by using Longa standards and the survival number of neurons in the local ischemic cerebral cortex was determined after Nissl staining, and the expression of nNOS, iNOS and GFAP in the cerebral cortex was detected using immunohistochemistry. RESULTS: Compared with the sham operation group, the neurological deficit score of the rats in the model group was significantly increased (P < 0.01), and the number of survival neurons of the ischemic cortex was obviously decreased (P < 0.01), and the expression levels of nNOS, iNOS and GFAP were significantly increased in the model group (P < 0.01). In the EA preconditioning group , the neurological deficit score, the expression levels of nNOS and iNOS were significantly down-regulated (P < 0.01), while the number of the survival neurons and GFAP expression level in the ischemic cerebral cortex were obviously higher in the EA preconditioning group in compared with the model group (P < 0.01). CONCLUSION: EA preconditioning can protect the ischemic cerebral cortex tissue from injury in CI/R rats, which may be related to its effects in down-regulating the expression of nNOS and iNOS, and up-regulating the expression of GFAP. PMID- 26054196 TI - [Effects of acupotomy intervention on regional pathological changes and expression of carti- lage-mechanics related proteins in rabbits with knee osteoarthritis]. AB - OBJECTIVE: To observe the effect of acupotomy (needle-knife) therapy on local pathological changes and cartilage-mechanics related protein expression in rabbits with knee osteoarthritis (KOA) so as to study its mechanisms underlying improving KOA. METHODS: Forty New Zealand rabbits were randomly divided into normal control group, model group, acupotomy group, and electroacupuncture (EA) group (n = 10 in each group). The KOA model was established by immobilization of the left knee-joint (modified Videman method) for 6 weeks. After modeling, acupotomy relaxing was applied to the lateral collateral ligament and patellar ligament of the left knee-joint, once a week for 3 times, and EA (2 Hz/100 Hz, 3 mA) was applied to the left "Yanglingquan" (GB 34), "Yinlingquan" (SP 9), "Neixiyan" (EX-LE 4) and "Waixiyan" (ST 35) for 20 min, 3 times a week for three weeks. The expression levels of Integrin beta1, type II collagen (Col-II), matrix metalloproteinase (MMP)-3 and Aggrecan proteins of the cartilage tissue of the left femoral medial and external condyles were observed by Western blot. Pathological changes of the knee-joint by X-ray scanning and those of the femoral condyle tissue were evaluated by Mankin's scores under light microscope after H. E. staining. RESULTS: X-ray showed successful modeling, and pathological changes of the articular cartilage belonged to the early and moderate lesion of knee osteoarthritis. The Mankin's score was significantly higher in the model group than in the control group (P < 0.01) , and after the treatment, the Mankin's scores were significantly decreased in the acupotomy. group (P < 0.01), rather than in the EA group (P > 0.05). The results of Western blot showed that after modeling, the expression levels of Integrin beta 1, Col-II and Aggrecan proteins of the femoral articular cartilage were considerably decreased (P < 0.01), while that of MMP-3 protein was significantly increased (P < 0.01). Compared with the model group, the decreased expression levels of Integrin beta 1, Col-II and Aggrecan proteins in the acupotomy group and Integrin beta 1 protein in the EA group were notably up-regulated (P < 0.01 , P < 0.05), and MMP-3 expression in the acupotomy group was significantly down-regulated (P < 0.01). No significant changes were found in the EA group in the expression levels of Col-II , Aggrecan and MMP-3 proteins compared with the model group (P > 0.05). CONCLUSION: Acupotomy intervention can relieve KOA-induced injury of the knee-joint in KOA rats, which is associated with its actions in raising expression levels of Integrin beta 1, Col-II and Aggrecan proteins and in lowering the expression of MMP-3 proteins in the articular cartilage, probably by adjusting the mechanics related signal pathway of the articular chondrocytes. PMID- 26054197 TI - [Effect of low-frequency electroacupuncture intervention on oxidative stress and glucose metabolism in rats with polycystic ovary syndrome]. AB - OBJECTIVE: To observe the effect of low-frequency electroacupuncture (EA) treatment on oxidative stress and metabolism disorder in polycystic ovary syndrome (PCOS) rats, so as to study its underlying mechanisms in improving PCOS. METHODS: Thirty female SD rats were randomized into control group, model group and EA group (n = 10 in each group). The PCOS model was established by subcutaneous injection of testosterone propionate (1 mg/100 g, 10 mg/mL) for 8 weeks. EA (2 Hz) was applied to "Zhongwan" (CV 12) , "Guanyuan" (CV 4) and bilateral "Sanyinjiao" (SP 6) or "Housanli" (ST 36) for 30 min, once daily (except weekends) for 5 weeks. Serum testosterone (T) , sex hormone-binding globulin (SHBG) and fasting serum insulin (FINS) contents were detected by ELISA, serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were assayed by thiobarbituric acid (TBA) and xanthine oxidation (XTO) methods, respectively, and fasting blood glucose (FBG) was determined by roche glucose meter. In addition, homeostasis model assessment for insulin resistance (HOMA-IR) and modified B cell function index (MBCI) were calculated. RESULTS: Compared with the control group, serum T, FBG, FINS, HOMA-IR, and serum MDA levels were significantly increased in the model group (P < 0.01), while serum SHBG, MBCI and SOD levels were considerably decreased in the model group (P < 0.01). Following EA treatment, all the increased serum T, FBG, FINS, HOMA-IR, and serum MDA levels, and the decreased serum SHBG, MBCI and SOD levels were reversed obviously (P < 0.05, P < 0.01). CONCLUSION: EA treatment may normalize insulin sensitivity, ameliorate insulin resistance and hyperinsulinemia in PCOS rats, probably by regulating the function of pancreatic islets beta cell and by reducing oxidative stress and free androgen. PMID- 26054198 TI - [Effects of acupuncture stimulation of different acupoint groups on sleeping latency, serum and hippocampal TNF-alpha and IL-25 contents in rats with gastric mucosal injury]. AB - OBJECTIVE: To observe the effect of acupuncture intervention on gastric ulcer (GU) and sleeping quality from the viewpoint of brain-gut axis which plays an important role in the regulation of many vital functions in the body. METHODS: Forty male Wistar rats were randomized into normal control, GU model, acupuncture of "Zhongwan"(CV 12)-"Zusanli"(ST 36, gastric function regulating acupoints), acupuncture of "Shenmai" (BL 62)-"Zhaohai" (KI 6, sleep-promotion acupoints), and acupuncture of CV 12-ST 36+ BL 62-KI 6 (combined treatment) groups, with 8 rats in each group. GU model was established by intragastric perfusion of dehydrated alcohol (1 mL/rat), and sleep model established by intraperitoneal injection of pentobarbital sodium (40 mg/kg) after the last treatment. The abovementioned acupoints were punctured with filiform needles and stimulated by manipulating the needle for about 30 s, once every 5 min during 20 min of needle retention. The treatment was conducted once daily for five days. The contents of tumor necrosis factor-alpha (TNF-alpha) and interleukin-25(IL-25) in the serum and hippocampal tissues were detected by ELISA. RESULTS: Compared with the normal control group, the gastric ulcer index score, barbiturate-induced sleeping time, and TNF-alpha and IL-25 contents in both serum and hippocampus were significantly increased in the model group (P < 0.01). Following acupuncture treatment, in comparison with the model group, the gastric ulcer index score, barbiturate-induced sleeping time, and TNF-alpha and IL-25 contents in both serum and hippocampus were significantly down-regulated in the CV 12-ST 36, BL 62-KI 6 and combined treatment groups (P < 0.01, P < 0.05). The effects of the CV 12-ST 36 and combined treatment groups were remarkably superior to those of the BL 62-KI 6 group in down-regulating ulcer index score, serum IL-25, and hippocampal TNF alpha and IL-25 contents (P < 0.01, P < 0.05). In addition, the effects of the BL 62-KI 6 and combined treatment groups was considerably better than that of the CV 12-ST 36 group in shortening barbiturate-induced sleeping time (P < 0.01, P < 0.05). The effect of the combined treatment group was markedly better than that of the CV 12-ST 36 and BL 62-KI 6 groups in lowering serum TNF-alpha content (P < 0.05). CONCLUSION: Acupuncture stimulation of CV 12, ST 36, KI 6 and BL 62 can relieve the gastric mucosal lesion, and shorten barbiturate-induced sleeping time in gastric ulcer rats, which may be related to its effects in reducing TNF-alpha and IL-25 contents in the serum and hippocampus tissues, suggesting a correlation between the gastrointestinal disorder and sleeping. PMID- 26054199 TI - [Effect of twirling-reinforcing-reducing needling manipulations on contents of serum acetylcholine and arterial NOS and cGMP in stress-induced hypertension rats]. AB - OBJECTIVE: To observe the effect of twirling-reinforcing or reducing needling manipulations on plasma acetylcholine (Ach) content and expression of nitric oxide synthetase (NOS) and cyclic guanosine monophosphate (cGMP) in thoracic artery tissue in stress-induced hypertension rats. METHODS: A total of 60 male rats were randomly divided into blank control, model, acupuncture (no-needle manipulation) , twirling-reinforcing needling and twirling-reducing needling groups (n = 12 in each group). The stress hypertension model was established by giving the animals with noise and electric shock stimulation (paw), twice a day for 15 days. Acupuncture stimulation was applied to bilateral "Taichong" (LR 3) for 1 min, followed by retaining the needles for 20 min. The treatment was conducted once daily for 7 days. Systolic blood pressure of the rat's tail was detected with non-invasive method and plasma Ach, and NOS and cGMP contents in the thoracic artery tissue were measured using ELISA method. RESULTS: Compared with the control group, the systolic blood pressure was significantly higher in the model group after 15 days' stress stimulation (P < 0.01), while the contents of plasma Ach, arterial NOS and cGMP were markedly down-regulated (P < 0.01). Following 7 days' acupuncture interventions, the increased blood pressure was down-regulated in the no-needle-manipulation, twirling-reinforcing needling and twirling-reducing needling groups (P < 0.05, P < 0.01); and the decreased Ach and NOS in the 3 treatment groups, and cGMP levels in the twirling-reinforcing and twirling-reducing needling groups were remarkably up-regulated (P < 0.01, P < 0.05). No significant change of arterial cGMP content was found in the no-needle manipulation group (P > 0.05). The effect of the twirling-reducing needling was superior to that of no-needle-manipulation and twirling-reinforcing needling in lowering blood pressure and raising plasma Ach content (P < 0.05, P < 0.01). CONCLUSION: The twirling-reducing needling of acupuncture has a significant anti hypertensive effect in stress hypertension rats, which may be associated with its effects in raising blood Ach, and arterial NOS and cGMP levels. PMID- 26054200 TI - [Effect of electroacupunctu-e intervention on serum IL-17 and IL-23 contents in rheumatoid arthritis rats]. AB - OBJECTIVE: To observe the influence of electroacupuncture (EA) stimulation of "Zusanli" (ST 36) and "Kunlun" (BL 60) on serum and knee-joint IL-17 and IL-23 contents in rheumatoid arthritis (RA) rats so as to study its underlying mechanism in improving RA. METHODS: Male Wistar rats were randomly allocated to normal control, RA model, EA and Prednisolone groups (n = 8 in each group). The RA model was established by intra-planta injection of incomplete Freund's adjuvant and type II collagen. EA (2 Hz/100 Hz,1-2 mA)was applied to bilateral "Zusanli"(ST 36) and "Kunlun"(BL 60) for 30 min, once daily for 10 days. The rats' ankle diameter was measured, and IL-17 and IL-23 contents in the serum and the knee-joint cavity were assayed by ELISA and Western blot, respectively. RESULTS: In comparison with the normal control group, the rats' ankle diameter, serum IL-17 and IL-23 contents and knee-joint IL-17 and IL-23 protein expression levels were significantly increased in the model group (P < 0.05). After EA and Prednisolone treatment, compared with the model group, all the rats' ankle diameter, serum IL-17 and IL-23 contents and knee-joint IL-17 and IL-23 protein expression levels were decreased remarkably (P < 0.05). No obvious differences were found between the EA and Prednisolone groups in the aforementioned indexes (P > 0.05), except IL-17 protein expression level (being markedly lower in the Prednisolone group than in the EA group). CONCLUSION: EA intervention can reduce inflammatory reaction of the ankle-joint in RA rats, which may be related to its effects in down-regulating serum and knee-joint IL-17 and IL-23 levels. PMID- 26054201 TI - [Effects of different-frequency-electroacupuncture and moxibustion stimulation of "Neiguan" (PC 6) on arrhythmia in rabbits]. AB - OBJECTIVE: To observe the effect of different-frequency-electroacupuncture (EA) and moxibustion stimulation on rabbits' arrhythmias. METHODS: Newzealand rabbits were randomly divided into arrhythmia model (n = 18), EA-3 Hz (n = 19), EA-20 Hz (n = 19), EA-100 Hz (n = 18) and moxibustion (n = 18) groups. The arrhythmia model was induced by intravenous injection of 25 MUg/kg aconitine. EA (3 Hz, 20 Hz or 100 Hz, 3.5-4 V) or moxibustion was applied to bilateral "Neiguan" (PC 6) for 20 min and electrocardiogram (ECG) of the standard limb lead II was recorded by using a Biosignal Processing Instrument. The concentration of serum hypersensitive C reactive protein (hs-CRP) content was detected by using ELISA method. RESULTS: Following EA intervention, the duration of aconitine-induced arrhythmia was significantly shorter in both EA-20 Hz and EA-100 Hz groups than in the model group (P < 0.05, P < 0.01), and the serum hs-CRP level in the EA-20 Hz group was significantly lower than that of the model group ( P < 0.05). No significant changes were found in the duration of arrhythmia in both EA-3 Hz and moxibustion groups, and in the serum hs-CRP level in the EA-3 Hz, EA-100.Hz and the moxibustion groups (P > 0. 05). CONCLUSION: EA stimulation of PC 6 at 20 Hz and 100 Hz has an anti-arrhythmic effect in aconitine-induced arrhythmia rabbits. PMID- 26054202 TI - [Effects of electroacupuncture intervention on changes of quality of ovum and pregnancy out- come in patients with polycystic ovarian syndrome]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) treatment on the quality of ovum, stem cell factor(SCF) and the pregnancy outcome in patients with polycystic ovarian syndrome (PCOS), so as to explore its mechanism underlying improving pregnancy rate. METHODS: A total of 200 PCOS patients undergoing in vitro fertilization-embryo transplantation (IVF-ET) were randomly divided into control (medication) group (n = 98) and EA group (n = 102). For patients of the EA group who were undergoing controlled ovarian hyperstimulation, EA stimulation (5 Hz/20 Hz, 15-20 V) was applied to bilateral Shenshu (BL 23), Qihai (CV6), bilateral Zusanli (ST 36)-Sanyinjiao (SP 6), and bilateral Neiguan (PC6)-Zigong (EX-CA 1) for 30 min, once daily till accepting embryo transplant. Patients of the medication group were treated with controlled ovarian hyperstimulation using Diane-35, Decepepty, Gonadotrophin, human Chorionic Gonadotrophin, etc. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), estradiol (E2, and progesterone (P) contents were detected using chemiluminescent method. SCF contents in the serum and follicular fluid were assayed by ELISA. The number of retrieved oocytes, fertilization rate, cleavage rate, high quality embryo rate, ovarian hyperstimulation syndrome (OHSS) incidence rate, cycle cancellation rate, clinical pregnancy rate, early abortion rate, Gn dosage and administration duration, and the correlation between the high quality embryo rate and SOF level were determined. RESULTS: Comparison between the two groups showed that the high quality embryo rate, and serum and follicular fluid SCF contents were significantly higher in the EA group than in the medication group (P < 0.05, P < 0.01), while the dosage and administration duration of Gn were significantly lower in the EA group than in the medication group (P < 0.05). A positive correlation was found between the high quality embryo rate and the SCF level in both follicular fluid and serum (P < 0.01). No significant differences were found between the two groups in the number of retrieved oocytes, fertilization rate, cleavage rate, clinical pregnancy rate, OHSS incidence rate, cycle cancellation rate, early abortion rate, serum LH, E2 and P contents (P > 0.05). CONCLUSION: EA can improve the high quality embryo rate, which may be related to its effect in increasing serum and follicular fluid SCF levels. PMID- 26054203 TI - [Clinical trials of treatment of acute facial paralysis with pain by blood letting plus acupuncture in patients]. AB - OBJECTIVE: To observe the clinical therapeutic effect of blood-letting plus acupuncture intervention for acute facial paralysis with pain (damp-heat type of liver and gallbladder). METHODS: A total of 120 cases of acute facial paralysis with pain were randomly and equally divided into control group and treatment group. Patients of the control group were treated by simple acupuncture therapy only, and patients of the treatment group treated by acupuncture plus bloodletting at the ipsilateral Yangbai(GB 14) and Quanliao (SI 18), and Dazhui (GV 14) and Yifeng (TE 17), alternatively. Shallow-acupuncture stimulation of ipsilateral Cuanzhu (BL 2), Sizhukong (TE 23), Sibai (ST 2), Dicang (ST 4), Jiache (ST 6), Yingxiang (SP 9), and bilateral Hegu (LI 4), Yanglingquan (GB 34) and Xingjian (LR 2) was administered for 30 min, once daily for one month. The patients' facial pain degree was evaluated by visual analogue scale (VAS), and the pain duration during acute stage was recorded. The facial nerve function and facial nerve function recovery (grade II) time were determined by using Sunnybrook Facial Grading scale and House-Brackmann (HB) grading scale, respectively. RESULTS: In comparison with pre-treatment, the post-aurem pain scores after the first treatment and after the acute stage were significantly decreased, and the facial nerve function scores after the treatment were significantly increased in both control and treatment groups (P < 0.01), and the effects of the treatment group were significantly superior to those of the control group (P < 0.01). The post-aurem pain duration and the time of facial nerve function recovery (HB) of the treatment group were considerably lower than those of the control group (P < 0.01). Of the 58 and 59 facial palsy patients in the control and treatment groups, 16 (27.6%) and 24 (40.7%) were cured, 18 (31.0%) and 23 (39.0%) experienced marked improvement, 15 (25.9%) and 10 (16.9%) were improved, and 9 (15.5%) and 2 (3.4%) were failed, with the effective rate being 85.0% and 96.6%, respectively. CONCLUSION: Bloodletting combined acupuncture is effective in the treatment of acute facial paralysis with pain. PMID- 26054204 TI - [On Ziwuliuzhu (midnight-noon ebb-flow) needling of acupuncture theory and rigidification process of acupuncture theory in the Jin and Yuan Dynasties]. AB - The Ziwuliuzhu (midnight-noon ebb-flow) needling of acupuncture theory was generally considered to be a representative perfect example of traditional acupuncture theory. It is created in the Jin and Yuan Dynasties, and has been being frequently cited thereafter. It is mainly derived from and inherits the theory of Wuxing (five-elements) doctrine of traditional Chinese culture in ancient China, for which the Wushu-points, five specific acupoints on the distal ends of the arm and leg, i. e., Jing (Well-points), Xing (Spring-point), Shu (stream-point), Jing (river-point) and He (sea-point) to match the Wuxing so as to calculate their open time according to the Heavenly Stems and Earthly Branches designating the years, months, days and hours in ancient China. Although it has been repeatedly copied in Chinese medical books, this theory was not really used by clinical acupuncturists in the Jin, Yuan and following dynasties. The present theory came up in the special time, primarily being derived from the combination of medical and Confucian theories in the Song Dynasty. Nowadays, we should thoroughly make known its connotations, and do not make heedless affirmation and clinical validation. PMID- 26054205 TI - [Our viewpoints on Deqi in the later ages after birth of classical works "The Yellow Emperor's Internal Classic" and "Canon of Difficult Medical Problems"]. AB - In our previous paper, we analyzed "Deqi" in book Huangdi Neijing (The Yellow Emperor's Internal Classic) and Nanjing (Canon of Difficult Medical Problems) from "Zhishen"(Treating mentality) and Tiaoqi (Regulating qi). In the present paper, the authors discuss the connotations of "Deqi" and related events in the later ages of the abovementioned two classic books to the later stage of the Qing Dynasty when involves about 20 classical works as Zhenjiu Dacheng ( The Great Compendium of Acupuncture and Moxibustion), Zhenjing Zhinan (Guide to the classics of Acupuncture), Zhenjiu Daquan (A Complete Works of Acupuncture and Moxibustion) etc. from 1) close association between "Deqi" and patients' mental activity; 2) how to wait for arrival of qi if the needling does not induce "Deqi" for the time being; 3) how to identify "qi-arrival" and then, performing suitable manipulations; 4) Deqi and shallow- or deep-needling; 5) putting more emphasis on patients' feeling and reactions, rather than the practitioners perception beneath the needle which is described in book Huangdi Neijing; and 6) not withdrawing the acupuncture needles if qi does not arrive. Generally, in the later ages, the connotations of Deqi are enriched greatly. PMID- 26054206 TI - [Clinical application regularity of Fengfu (GV 16) acupoint: research on ancient Chinese medical literature]. AB - OBJECTIVE: To sum up the application regularity of Fengfu (GV 16) acupoint in clinical practice through studying the ancient literature from the early stage of the Qin Dynasty to the Qing Dynasty. METHODS: Chinese ancient medical literature relevant to Fengfu (GV 16) was searched to establish a database containing information of clinical indications of GV 16, supplementary acupoints, relevant needling techniques, moxibustion methods, etc. RESULTS: A total of 277 articles about Fengfu (GV 16) for 61 types of clinical disorders or diseases involving internal medicine, surgery, paediatrics, five sense organs, etc. were obtained from 2,200 ancient Chinese medical books. Fengfu (GV 16) alone was most frequently used for treatment of disorders caused by exogenous factors, such as common cold, neck pain, headache, epilepsy, mania, dizziness, throat dumb, leg foot problems, etc. , with the auxiliary acupoint being Fengchi (GB 20). In addition, 147 articles relevant to needling and moxibustion stimulation of GV 16 (7 types of methods) were found. CONCLUSION: Fengfu (GV 16) is mainly used for local problems in the human body, and also for problems occurred along the meridian trace, aiming at the pathogenesis. When employed, GV 16 is often stimulated by acupuncture needle. PMID- 26054207 TI - Introduction. Drugs are at the centre of a complexly entangled web of science, politics, economics and culture. PMID- 26054208 TI - Cold drugs. Circulation, production and intelligence of antibiotics in post-WWII years. AB - The paper details how the earliest antibiotics were subject to a strict control during the earliest phase of the Cold War. Because of antibiotics strategic and economic value, Anglo-American Governments restricted circulation of scientists, techno-scientific know-how and technology related to penicillin production, as well as closely controlling the circulation of the drugs in the Communist countries. These efforts are documented by archival documents, testifying how drugs were actual instruments of propaganda and political strategies, affecting pharmaceutical development both in the Western and the Eastern bloc. PMID- 26054209 TI - Patents, antibiotics, and autarky in Spain. AB - Patents on antibiotics were introduced in Spain in 1949. Preliminary research reveals diversification in the types of antibiotics: patents relating to penicillin were followed by those relating to streptomycin, erythromycin and tetracycline. There was also diversification in the firms that applied for patents: while Merck & Co. Incorporated and Schenley Industries Inc. were the main partners with Spanish antibiotics manufacturers in the late 1940s, this industrial space also included many others, such as Eli Lilly & Company, Abbott Laboratories, Chas. Pfizer & Co. Incorporated, and American Cyanamid Company in the mid-1970s. The introduction of these drugs in Spain adds new elements to a re evaluation of the autarkic politics of the early years of the Franco dictatorship. PMID- 26054210 TI - Biological warfare warriors, secrecy and pure science in the Cold War: how to understand dialogue and the classifications of science. AB - This paper uses a case study from the Cold War to reflect on the meaning at the time of the term 'Pure Science'. In 1961, four senior scientists from Britain's biological warfare centre at Porton Down visited Moscow both attending an International Congress and visiting Russian microbiological and biochemical laboratories. The reports of the British scientists in talking about a limited range of topics encountered in the Soviet Union expressed qualities of openness, sociologists of the time associated with pure science. The paper reflects on the discourses of "Pure Science", secrecy and security in the Cold War. Using Bakhtin's approach, I suggest the cordial communication between scientists from opposing sides can be seen in terms of the performance, or speaking, of one language among several at their disposal. Pure science was the language they were allowed to share outside their institutions, and indeed political blocs. PMID- 26054211 TI - Penicillin and the reconstruction of Japan. AB - This paper explores postwar American strategies regarding penicillin in Japan. Perceived as both an American gift and a symbol of reconstruction, penicillin played a singular role in Washington's postwar policies towards Europe and Japan. Washington encouraged US pharmaceutical companies to penetrate Europe but sought to protect intra-European trade. In Japan, however, importing penicillin from the US or establishing private American factories was forbidden. Jackson W. Foster implemented a smaller-scale, military-directed version of the US's wartime penicillin project. In this paper, it is argued that the MacArthur administration aimed to boost Japanese penicillin production and transfer American industrial culture to Japan. This was initially a major success. However, the Japanese pharmaceutical industry failed to break down barriers to market entry established by first movers and, consequently, was uncompetitive throughout the twentieth century. This paper regards the American penicillin project in Japan as a factor in the weakness of the postwar Japanese pharmaceutical industry. PMID- 26054212 TI - Sera-therapy, exile and Franco's regime. The survival strategy of the Ravetllat Pla Institute in postwar Spain. AB - The aim of this paper is to analyse the scientific and commercial survival strategy of the Ravetllat-Pla Institute after the Spanish Civil War. Founded in 1923 by Ramon Pla (1880-1956) and Joaquim Ravetllat (1872-1923), it produced two sera: 'Hemo-antitoxin' and the 'Ravetllat-Pla serum'. When the Civil War ended and Ramon Pla was forced into exile, management of this laboratory was taken over by his daughter, Nuia Pla Monseny (1918- 2011) who had to deal with an extremely difficult economic, political and commercial situation. In this paper, I analyse the means by which the Institute survived. These involved the Institute's ability to construct different political symbols from 'Hemo-antitoxin'. I study how Franco's repression influenced this survival strategy and Ramon Pla's role in exile. I also analyse the part played in this scientific and commercial process by the Institute's scientific and commercial network in Chile. PMID- 26054213 TI - 'Clueless about contraception': the introduction and circulation of the contraceptive pill in state-socialist Poland (1960s-1970s). AB - This paper discusses the introduction of the pill into the state-socialist Polish market in the late 1960s and its circulation over the following decade. Abortion, legalised for socio-economic reasons in 1956, had been available practically on demand since 1959, and there were no legal obstacles to contraception. The pill first appeared in Poland in the early 1960s, but was not widely available in pharmacies until 1969, when the local pharmaceutical industry began production. Throughout the 1970s, only two brands were widely available: Femigen and Angravid. The pill played a marginal role in family planning during the 1960s and 1970s in Poland, with cycle-observation, backed by the possibility of a legal abortion, being the main resource for birth control. This was due to structural limits to the distribution of the pill on a centrally-planned market closed to Western pharmaceutical companies, cultural patterns of sexual behaviour, and the availability of abortion. PMID- 26054214 TI - Controlling the production and distribution of drugs in communist Poland. AB - Between 1944 and 1989--the period of communist power in Poland--the national pharmaceutical market experienced several dramatic changes. The country was a prodigious importer of drugs following the Second World War, with a large portion of the medicine received being donated by various aid organisations. In the 1960s, Poland became a significant exporter of drugs to the Eastern Bloc countries, but dropped down the list of meaningful producers again after the post 1989 transformation. For four and a half decades the pharmaceutical market in Poland had been a scene of political and ideological struggle. The companies, owned and controlled by the state, were poorly managed, being neither innovative nor competitive. This fact, along with the state's irrational and inconsequent drug policy, caused an almost permanent shortage in drug supplies for patients: ironic for a socialist system in which universal and free health care was a basic principle. PMID- 26054215 TI - When 'drugs' become 'drugs': issues of pharmaceutical abuse in France from the 1960s to the 1990s. AB - Since the 1970s, media frenzies about drug addiction have focused mainly on illicit drugs taken by rebellious or marginalised addicts, relegating iatrogenic drug abuse, and policies and problems linked to psychotropic pharmaceuticals available by prescription or over-the-counter to the shadows. In this article I go beyond the division between illicit drugs and medicines still configuring both public representations and historiography: using archival materials from the 1960s-1990s in France, I highlight some blind spots in drug history. Firstly I demonstrate the role of pharmaceutical abuse in the career of addicts, and then examine regulation policies, which are the dark side, however complementary, of drug policies and prohibition. Finally, I analyse the role of physicians and pharmacists in this control, and discuss the various professional debates relating to the legal supply of psychoactive drugs. In all these issues, the frame of the Cold War context will also be highlighted. PMID- 26054216 TI - The long postwar and the politics of penicillin: early circulation and smuggling in Spain, 1944-1954. AB - In this paper I explore the early circulation of penicillin. I review the early distribution in Spain of a scarce product, reflect on the available sources about the illegal penicillin trade and discuss some cases of smuggling. I argue the early distribution of penicillin involved time and geography, a particular chronology of post Second World War geopolitics. Penicillin practices and experiences belong to this period, in a dictatorship that tolerated smuggling and illegal trade of other products, some, like penicillin, produced in neighbouring countries. As a commodity that crossed borders, penicillin, transiting between the law and hidden trade, between countries and social domains--between war fronts and from a war front to an urban site to be sold--reveals practices of the early years of prosperity in the 1950s. These transits were permanent tests of a society based on taxes and exchanges, law and bureaucracy, control, discipline and the creation of standards. PMID- 26054217 TI - The fabbrica della penicillina in postwar Italy: an institutionalist approach. AB - This paper focuses on the motives and long-term effects of the momentous decision to build a world-class biomedical research laboratory, the International Center for Chemical Microbiology, at the Istituto Superiore di Sanita in Rome, rather than develop domestic production of penicillin to meet the needs of a destitute postwar Italy. An institutionalist approach will provide a richer vision of the intersections of scientific and national political history in postwar Italy and the Cold War. The Center failed in its modernising mission due to an insular mentality producing an 'enclosure effect' against the State, the healthcare system and the pharmaceutical industry. The absence of a scientific base together with an economic policy of 'liberal protectionism' that placed premiums on import tariffs and the licensing of foreign products explains the path dependency of the pharmaceutical industry during the postwar years and its demise in the 1960s. PMID- 26054218 TI - [LUCCHETTA F. (ed), Ibn al-Gazzar, Book of care and health of children. Venice, Filippi Editore, 2010]. PMID- 26054219 TI - [MAZZARELLO P., The herb of the queen. The story of a miraculous decoction. Turin, Bollati Boringhieri, 2013]. PMID- 26054220 TI - [On the situation of African swine fever and the biological characterization of recent virus isolates]. AB - African swine fever (ASF), a disease notifiable to the World Organization of Animal Health (OIE), is characterized by severe, unspecific clinical signs and high mortality rates. Hosts for ASF virus (ASFV) are only members of the family Suidae and soft ticks of the genus Ornithodoros. Currently, no vaccine is available and therefore, the control is primarily based on strict sanitary measures. The most important part is the early detection of the disease within affected animal holdings and the fast and reliable confirmation by laboratory diagnosis. Infections of domestic pigs and European wild boar with recent Armenian, Sardinian, Lithuanian or Kenyan ASFV isolates lead to severe, acute disease courses with the predominant symptom of high fever (> 41 degrees C) accompanied by further unspecific clinical signs such as lethargy, loss of appetite, diarrhoea, respiratory symptoms, and an increased bleeding tendency. In experimental infection studies the mortality rate reached 100%. The most prominent pathomorphological findings included ebony-colored gastrohepatic lymph nodes, lung oedema, petechiae in the renal cortex, and oedema of the gallbladder wall. In the light of the current epidemiological situation with endemic ASFV infections on Sardinia, outbreaks in Russia and several Eastern EU Member States there is a risk for an introduction in further, previously unaffected EU countries including Germany. Hence, appropriate sample materials (serum, blood, spleen) of domestic pigs with unspecific clinical symptoms or pathomorphological findings should be examined for both ASFV and classical swine fever virus. PMID- 26054221 TI - Fascioloides magna--epizootiology in a deer farm in Germany. AB - After initial observations of suspicious cases in 2009, the occurrence of Fascioloides (F.) magna in deer of a deer farm located in northeastern Bavaria, Germany, at the border to the Czech Republic was confirmed in autumn 2011. In March 2012, the deer were treated for fascioloidosis with triclabendazole. To monitor the epizootiology of fascioloidosis in the farm, 80-100 faecal samples were examined for Fascioloides eggs at monthly intervals from June 2012 to June 2013 inclusive. In addition, livers of 27 red deer and one sika deer collected during winter 2012/2013 were examined for gross lesions suspicious for F. magna infection and 21 of the 28 livers were dissected for F. magna recovery. Fascioloides eggs were recorded in 63 (4.9%) of 1280 faecal samples (range 0.4 to 355 eggs per gram). Both, number of Fascioloides-egg positive samples and egg counts were low during the first eight months of the study but increased notably since February 2013. While Fascioloides egg-positive faecal samples were obtained from red deer (46/948,4.9%) and fallow deer (17/166, 10.2%), no Fascioloides eggs were demonstrated in the 166 samples obtained from sika deer. Livers of five red deer and the sika deer showed gross lesions characteristic for fascioloidosis, and F. magna were recovered from three of the five affected red deer livers (range, five to seven flukes). Results of this study confirm that F. magna is endemic in the deer farm, and measures should be implemented to minimize the transmission of the parasite. PMID- 26054222 TI - Emerging cases of chlamydial abortion in sheep and goats in Croatia and Bosnia and Herzegovina. AB - In a recent lambing season (2012/2013), the seroprevalence of ovine chlamydiosis was monitored in small ruminant abortion cases in Croatia. Blood samples of 93 sheep and 69 goats were examined. In addition, 50 sheep and 61 goat samples were tested using molecular methods. Furthermore, 14 sheep blood samples, one goat blood sample and one sheep placenta sample from Bosnia and Herzegovina (BIH) were also tested as a part of inter-laboratory cooperation. Overall high seroprevalence was detected in sheep, 19.6% with the ELISA IDEXX kit and 20.5% with the ClVTEST kit. Seroprevalence in goats was 11.4%. In BIH, four sheep and one goat blood sample were seropositive for chlamydiosis. The disease causing agent, Chlamydia abortus (C. abortus) was confirmed using molecular methods in two sheep flocks in continental Croatia and in one sheep flock in BIH. In this study, C. abortus infection in sheep was identified for the first time in Croatia using species specific molecular methods. Ovine chlamydiosis is present in national sheep and goat flocks in Croatia and BIH. Thus should be subject to ongoing controls in the case of abortion. A combination of serological and molecular methods should be used for optimal laboratory diagnostics of C. abortus. PMID- 26054223 TI - SAT2 foot and mouth disease (FMD) outbreak in a mixed farm in Egypt. AB - A dairy farm keeping Holstein cattle and buffaloes in the Menoufia Governorate was investigated during and after the last Foot and Mouth Disease (FMD) outbreak in Egypt (starting February 2012) to determine the impact of the outbreak on animals as well as to assess some factors that might have helped to spread the disease in the investigated farm. All animals were vaccinated against FMD with the locally produced bivalent vaccine containing O1 and A/Egy/2006 strains two months before the onset of the outbreak. Laboratory examination of the samples collected from diseased and dead animals' revealed detection of a newly emerged serotype of FMD (SAT2). Although, all buffaloes (8/8) in the herd were infected (100%), none of them died, while lactating Holstein cattle showed varying morbidity rates along the period of the outbreak with peak rates in March followed by April, May and June. Crud mortality and case fatality rates among cattle peaked during April 2012 to reach 9.3 and 21.7%, respectively. Calves were the most affected animals with the highest morbidities and mortalities. The high prevalence of the disease among all animal categories in the investigated farm is attributed to the lack of previous immunity through vaccination against the new serotype of the virus. In addition, the hygienic and biosecurity measures in the farm were unsatisfactory with respect to prevention of introduction and spread of the disease between the farm units. The prevalent weather conditions during the outbreak might have played a role in spread of the FMDv, especially ambient temperature, humidity and wind movement. PMID- 26054224 TI - [Analysis of the impact of animal health parameters on the average daily net gain in pigs for fattening]. AB - According to regulation (EC) No. 854/2004 all pigs slaughtered in Austria are subject to a routine meat inspection at the slaughterhouse in order to detect pathological-anatomical organ alterations due to disease. This mandatory meat inspection constitutes an important contribution to ensure food safety and the resulting post-mortem findings provide a possibility to process optimization by reporting the routinely recorded results to the producers. We analyzed the impact of 18 post-mortem findings on the average daily net gain of 6119 pigs. All findings were recorded at an Austrian slaughterhouse within a quality assurance system. A linear mixed model (LMM) was applied incorporating the farm of origin as random effect in order to take non-observed farm specific risk factors (e. g. feed management, housing system, hygiene status) into account. As a result the expected average daily net gain of 490 g could be estimated and several post mortem findings could be identified as significant factors (at the significance level 0.05) affecting the average daily net gain. The expected average daily net gain decreases significantly for pigs with at least one of the post-mortem findings arthritis (-64 g), abscess (-32 g), severe pneumonia (-13 g), visceralis pleuritis (-7 g) and hepatitis (-9 g). The expected average daily net gain increases by 5 g for pigs with post-mortem finding bursitis. The estimated random farm effect indicates the relevant impact of the farm environment on the average daily net gain. The results reinforce that there is still a great potential to improve efficiency in fattening, although the quality assurance system was implemented twelve years ago. PMID- 26054225 TI - Detection of porcine circovirus type 2 and its association with PMWS in wild boars and domestic pigs in Germany: a histopathological, immunohistochemical and molecular biological study. AB - Beside domestic pigs wild boars can also be affected by postweaning multisystemic wasting syndrome (PMWS). For the first time a nationwide survey of wild boars (n = 356) and domestic pigs (n = 340) was carried out in Germany by histopathology, immunohistochemistry (IHC) and quantitative PCR (qPCR). Whereas 102/340 domestic pigs were immunoreactive for PCV2 antigen in at least one examined tissue, only 8/356 wild boars reacted positively. Similar findings could be found in qPCR: all domestic pigs showed viral DNA in at least one tissue, while in the examined tissues of 170 wild boars PCV2-DNA was not detectable. The specimens were examined histologically for histiocytosis and depletion of lymphocytes, both typical for PMWS. Based on these findings, six wild boars and 69 domestic pigs were assumed to be affected by PMWS. PMID- 26054226 TI - Toxigenic Corynebacterium ulcerans isolated from a free-roaming red fox (Vulpes vulpes). AB - Corynebacterium (C.) ulcerans could be isolated from the spleen of a red fox (Vulpes vulpes) that had been found dead in the state of Baden-Wurttemberg, Germany. Pathohistological examination suggested that the fox had died of distemper, as was confirmed by PCR. The isolate was identified biochemically, by MALDI-TOF MS, FT-IR and by partial 16S rRNA, rpoB and tox gene sequencing. Using the Elek test the C. ulcerans isolate demonstrated diphtheria toxin production. FT-IR and sequencing data obtained from the C. ulcerans isolate from the red fox showed higher similarity to isolates from humans than to those from wild game. PMID- 26054227 TI - [Efficacy of siRNA on feline leukemia virus replication in vitro]. AB - Feline leukemia virus (FeLV) can lead to severe clinical signs in cats. Until now, there is no effective therapy for FeLV-infected cats. RNA interference-based antiviral therapy is a new concept. Specific small interfering RNA (siRNA) are designed complementary to the mRNA of a target region, and thus inhibit replication. Several studies have proven efficacy of siRNAs in inhibiting virus replication. The aim of this study was to evaluate the inhibitory potential of siRNAs against FeLV replication in vitro. siRNAs against the FeLV env gene and the host cell surface receptor (feTHTR1) which is used by FeLV-A for entry as well as siRNA that were not complementary to the FeLV or cat genome, were tested. Crandell feline kidney cells (CrFK cells) were transfected with FeLV-A/Glasgow-1. On day 13, infected cells were transfected with siRNAs. As control, cells were mock-transfected or treated with azidothymidine (AZT) (5 MUg/ml). Culture supernatants were analyzed for FeLV RNA using quantitative real-time RT-PCR and for FeLV p27 by ELISA every 24 hours for five days. All siRNAs significantly reduced viral RNA and p27 production, starting after 48 hours. The fact that non complementary siRNAs also inhibited virus replication may lead to the conclusion that unspecific mechanisms rather than specific binding lead to inhibition. PMID- 26054228 TI - [Investigation of the presence of the etiological agents of malignant catarrhal fever in clinically healthy ruminants in zoological gardens]. AB - Malignant catarrhal fever (MCF) is an infectious disease in even-toed ungulates including domestic cattle and wild living ruminants, which repeatedly also occurred in zoological gardens in Europe. The goal of the study presented here was to determine whether wild ruminants--here in the sense of non-domesticated ruminant species in zoological collections--normally not known as carriers of MCF viruses, may carry and shed these viruses and thus might play a possible role as source of infection. To this end, swap samples from eye, nose, and rectum, and also some blood samples, collected from different ruminant species in 11 zoological gardens and animal parks in the years 2007 to 2009 were examined with real-time polymerase chain reaction (rt-PCR) for the presence of the genome of viruses known to cause MCF most frequently: alcelaphine herpesvirus 1 (AIHV-1), ovine herpesvirus 2 (OvHV-2), caprine herpesvirus 2 (CpHV-2) and malignant catarrhal fever virus--white-tailed deer (MCFV-WTD) The results of this investigation showed the presence of the genomes of one--or more--of these MCF viruses in five of the contributing institutions. A total of 28 samples (12.84%) proved to be positive. In no case, the presence of the AIHV-1 genome was detected. For the first time, the presence of the MCFV-WTD genome was demonstrated in goats, indicating a carrier state of this animal species. PMID- 26054229 TI - [Lactational incidences of common diseases in dairy herds in Schleswig-Holstein (Germany): effect of first test-day milk yield, herd milk yield and number of lactation]. AB - It was the aim of this study to record common diseases in dairy cows in Schleswig Holstein, Germany, and to describe associations between lactation number (LN: 1, 2, > 2), first test-day milk yield (TD1: < 30 kg, >= 30 kg) and herd milk yield (HM: <= 7500 kg, > 7500 kg), the latter parameter serving as a proxy for herd management (extensive vs. intensive). Data of 98 dairy herds (6439 lactations) were processed on cow level using mixed logistic regression models with LN< TD1, HM and calving season as fixed effects and herd as random effect. Lactational incidences were as follows: hypocalcaemia (5.0%), dystocia (13.2%), retained placental membranes (7.2%), clinical metritis/endometritis (4.9%), clinical mastitis (15.3%), subclinical mastitis (61.9%), ketosis (1.6%), displaced abomasum (0.4%), lameness (15.4%). Number of lactation (2, > 2 vs. 1) was a risk factor for hypocalcaemia (OR 3.715, 23.047), retained placental membranes (OR 1.764, 2.479), clinical mastitis (> 2 vs. 1 OR 2.118), subclinical mastitis (OR 1.668,4.397), ketosis (> 2 vs. 1 OR 3.936) and lameness (OR 1.275, 2.070). Older cows had a lower risk for dystocia (OR 0.373, 0.357). TD1 (>= 30 kg) was not a risk factor of disease except for subclinical mastitis in first parity animals (OR 1.319). Herd milk yield (> 7500 kg) was a risk factor for clinical metritis/endometritis (OR 1.971), displaced abomasum (OR 7.764), lameness (OR 1.618) and hypocalcaemia (cows with high TD1 [OR 2.273]). In conclusion, not individual milk yield, but herd milk yield as an indicator of differences in intensity of herd management as well as number of lactation seemed to influence the frequency of common diseases in dairy cows. PMID- 26054230 TI - Analysis of risk factors for infections with gastrointestinal nematodes, Eimeria spp. and lungworms in German organic sheep farms. AB - The aim of this study was to determine the risk factors influencing the occurrence of parasitic infections in organic sheep farms in Germany. Therefore, 635 pooled faecal samples from sheep kept on 20 organic farms were collected and examined by standard parasitological analyses for gastrointestinal nematodes (GINs), Eimeria species (spp.) and liver flukes (Fasciola hepatica). Additionally, 128 double-pooled samples were analysed for lungworm larvae. In 60.5% of all samples, parasite stadiums were detected, and 38.3% of the double pooled samples were lungworm-positive. Production period, months and year of sampling had significant effects on infections with GINs (p < 0.05). The prevalence of GIN infection was lowest in 'dairy'(40.0%) when compared with'meat'sheep (65.4%). The odds of being infected with Eimeria spp. was influenced by the month (p < 0.05). The number of ewes on a farm, the primary purpose or the grazing area showed no significant effects. Infections with lungworms occurred in tendency more often 'after' lambing period. PMID- 26054231 TI - [Investigations on the acute, carrageenan-induced inflammatory reaction and pharmacology of orally administered sodium salicylate in turkeys]. AB - The complex mechanisms of acute inflammation have been subject to veterinary investigations since a long time. However, knowledge on the role of specific inflammatory mediators, as well as pharmacokinetics (PK) and -dynamics (PD) of non-steroidal anti-inflammatory drugs (NSAID) in birds is limited. The objective of this work therefore was to establish a modified tissue cage-model to investigate the acute, carrageenan-mediated inflammatory response, as well as plasma and exudate-kinetics and the antiphlogistic effect of orally administered sodium salicylate on the elicited inflammatory reaction in turkeys. Within the class Aves, comparable studies have so far only been published in chicken. Following bilateral subcutaneous implantation of carrageenan-treated synthetic sponges in the lateral thoracic region, sodium salicylate was administered orally at a dose of 50 mg/kg body weight (BW; therapy group) twice daily on three consecutive days, while a control group received drinking water as a placebo (n = 24 per group). Combined PK and PD of sodium salicylate were evaluated on the basis of salicylate- and prostaglandin (PG) E2-plasma- and -exudate concentrations, exudate volumes, as well as leukocyte exudate counts. Sodium salicylate was readily absorbed from the gastrointestinal tract and accumulated in the inflammatory exudate. At 4, 6, and 10 h after first application, sodium salicylate significantly reduced PG E2-concentrations in the inflammatory exudate when compared to the control group, whereas leukocyte exudate counts increased over time in both study groups, unaffected by sodium salicylate The described modified tissue cage-model can be beneficial for further research on the pathophysiology of avian inflammatory processes and the investigation of the combined pharmacodynamics and -kinetics of drugs in birds of adequate size. PMID- 26054232 TI - Death of a South American fur seal (Arctocephalus australis) after the ingestion of toads--evaluation of toad poisoning by toxicological analysis. AB - Animals in zoological gardens are at risk of severe and even lethal poisoning when they accidentally ingest toads. Here we report the case of an eleven month old male South American fur seal (Arctocephalus australis) which was found dead in its outdoor enclosure in the zoo of Dortmund, Germany. Autopsy revealed the presence of two adult, partly digested common toads (Bufo bufo) in the stomach. Toxicological analysis of the stomach content using high performance liquid chromatography coupled to time-of-flight mass spectrometry (LC-TOF MS) proved the presence of bufadienolides, the major cardiotoxic components of toad poisons. Using electrochemical luminescens immunoassay (ECLIA) compounds equivalent to digitoxin were detected in the blood sample confirming the absorption of toad poison components from the intestines into the circulation potentially leading to cardiac failure. In zoological gardens special precautions are necessary to protect non-native animals from encountering toads and the risk of poisoning, particularly in early spring, the spawning period of the toads. PMID- 26054233 TI - S6K1 controls autophagosome maturation in autophagy induced by sulforaphane or serum deprivation. AB - It is well established that mTORC1 suppresses autophagy by phosphorylation and inactivation of proteins involved in autophagosome formation. However, the role of its substrate, p70S6 kinase1 (S6K1), in autophagy is quite controversial. In some models S6K1 activity correlates with autophagy suppression, however, some other studies show that S6K1 promotes rather than inhibits this process. Here, we investigated the role of S6K1 in prostate cancer cells (PC-3) and non-cancerous, mouse embryonic fibroblasts (MEF), either treated with autophagy inducer sulforaphane, an isothiocyanate derived from cruciferous plants, or deprived of serum. Our results indicate that constitutively active S6K1 decreases the level of LC3 processing and foci formation by autophagosomal vacuoles in cells treated with sulforaphane. On the other hand, presence of S6K1 is necessary for autophagosome maturation under conditions of autophagy induced by either sulforaphane or serum deprivation. Diminished level of S6K1 or lack of S6 kinases results in both, accumulation of autophagosomes and drop in the autophagolysosome number, and thus disturbs autophagy flux under stress conditions. Moreover, lack of S6 kinases reduces cell survival under stress conditions. PMID- 26054234 TI - Factors affecting patient valuations of caries prevention: Using and validating the willingness to pay method. AB - OBJECTIVES: Determining the value of, or strength of preference for health care interventions is useful for policy makers in planning health care services. Willingness to pay (WTP) is an established economic technique to determine the strength of preferences for interventions by eliciting monetary valuations from individuals in hypothetical situations. The objective of this study was to elicit WTP values for a dental preventive intervention and to analyze the factors affecting these as well as investigating the validity of the WTP method. METHODS: Patients aged 40 years plus attending dental practices in the UK and Germany were recruited on a consecutive basis over one month. Participants received information about a novel root caries prevention intervention. They then completed a questionnaire including a WTP task. Where the coating was indicated, patients were offered this for a payment and acceptance was recorded. Analysis included econometric modelling and comparison of expected (based on stated WTP) versus actual behaviour. RESULTS: The mean WTP for the coating was L96.41 (standard deviation 60.61). Econometric models showed that no demographic or dental history factors were significant predictors of WTP. 63% of the sample behaved as expected when using stated WTP to predict whether they would buy the coating. The remainder were split almost equally between those expected to pay but who did not and those who were expected to refuse but paid. CONCLUSIONS: Values for a caries preventive intervention had a large and unpredictable variance. In comparing hypothetical versus real preferences both under- and over valuation occurs. CLINICAL SIGNIFICANCE: Wide and unpredictable variation in valuations for prevention may mean that there are difficult policy questions around what resource should be allocated to dental prevention and how to target this resource. PMID- 26054235 TI - Effect of chemical interaction on the bonding strengths of self-etching adhesives to deproteinised dentine. AB - OBJECTIVES: The present study examined (1) the chemical interaction between three self-etching adhesives and sodium hypochlorite (NaOCl)-deproteinised dentine, and (2) the influence of NaOCl treatment on bond strength of self-etching adhesives with/without adhesive functional monomers to dentine. METHODS: Caries-free dentine disks (control) and those treated with 5.25% NaOCl for 60s were prepared. Xeno V (no functional monomers), G-Bond (containing 4-MET) or S3 Bond (containing 10-MDP) were applied to the NaOCl-treated dentine and either left without further treatment, or rinsed with 100% ethanol or distilled water. Attenuated total reflection (ATR) spectroscopy and field-emission scanning electron microscopy (FE SEM) were used to evaluate the affinity of functional monomers with deproteinised dentine. Chemical interaction between the functional monomers and deproteinised dentine was evaluated using thin-film X-ray diffraction (TF-XRD). Microtensile bond strength (MTBS) was used to evaluate the mechanical property of the adhesives, either immediately or after thermo-cycling (5-55 degrees C) for 10,000 cycles. RESULTS: According to the ATR and FE-SEM results, G-Bond and S3 Bond showed stronger affinity to deproteinised dentine than Xeno V even after rinsing with water. TF-XRD showed that chemical interaction between S3 Bond and deproteinised dentine occurred by formation of 10-MDP-Ca salt. Both deproteinisation and thermo-cycling adversely affected the MTBS of Xeno V (P<0.05) but deproteinisation had no significant influence on S3 Bond. CONCLUSIONS: When bonding to NaOCl-treated dentine, self-etch adhesives containing functional monomers (10-MDP) can maintain immediate and aged bond strengths after 10,000 thermal cycles. PMID- 26054236 TI - Neuropsychological function, anxiety, depression and pain impact in fibromyalgia patients. AB - Cognitive deficits have a significant impact on the daily performance of fibromyalgia patients. This paper analyzes executive functioning and decision making performance, and the relationships between these functions and pain, anxiety, depression and medication in fibromyalgia patients. A group of fibromyalgia patients (FG) (n = 85) was compared with a healthy control group (CG) (n = 85) in their performance in the Wisconsin Card Sorting Test (WCST) and the Iowa Gambling Task (IGT). In the WCST, results showed a percentage of non perseverative errors significantly higher in the CG than in the FG (p = .026), the other variables (percentage of perseverative errors, number of categories and failures to maintain set) showed no significant differences. In relation to decision-making (IGT), once the rules had been learnt, the FG made fewer advantageous choices than the CG, but these differences were not statistically significant (p = .325). In the FG, pain severity (p = .010) and impact on daily activities (p = .016) interfered with decision-making, unlike anxiety, depression or medication, which did no relate to it. In executive function, pain and impact on daily activities were associated with the percentage of perseverative errors (p = .051) and the number of categories (p = .031), whereas pain severity was related to failures to maintain set (p = .039), indicative of increased distractibility and poor attentional ability. In conclusion, FG showed normal performance in executive functioning and decision-making. Moreover, pain was associated with neuropsychological functioning whereas anxiety, depression and medication were not. PMID- 26054237 TI - Aqueous Solution-Deposited Gallium Oxide Dielectric for Low-Temperature, Low Operating-Voltage Indium Oxide Thin-Film Transistors: A Facile Route to Green Oxide Electronics. AB - We reported a novel aqueous route to fabricate Ga2O3 dielectric at low temperature. The formation and properties of Ga2O3 were investigated by a wide range of characterization techniques, revealing that Ga2O3 films could effectively block leakage current even after annealing in air at 200 degrees C. Furthermore, all aqueous solution-processed In2O3/Ga2O3 TFTs fabricated at 200 and 250 degrees C showed mobilities of 1.0 and 4.1 cm2 V(-1) s(-1), on/off current ratio of ~10(5), low operating voltages of 4 V, and negligible hysteresis. Our study represents a significant step toward the development of low cost, low-temperature, and large-area green oxide electronics. PMID- 26054238 TI - A receptor like kinase gene with expressional responsiveness on Xanthomonas oryzae pv. oryzae is essential for Xa21-mediated disease resistance. AB - BACKGROUND: Leucine-rich repeat receptor-like kinases (LRR-RLKs) represent a large class of proteins in regulating plant development and immunity. The LRR-RLK XA21 confers resistance to the bacterial disease caused by the pathogen of Xanthomonas oryzae pv. oryzae (Xoo). Several XA21 binding proteins have been characterized, however the early events governing XA21 signaling have not been fully elucidated. RESULTS: Here we report the identification of one LRR-RLK gene (XIK1) whose expression is induced rapidly upon the infection with the pathogen of Xoo. Expression pattern analysis reveals that XIK1 is preferentially expressed in reproductive leaves and panicles, and that expression is associated with plant development. By using RNA interference (RNAi), we silenced the expression of XIK1 in rice with Xa21 and found that reduced expression of XIK1 compromised disease resistance mediated by XA21. In addition, we found that the expression of the downstream marker genes of pathogen associated molecular pattern (PAMP) triggered immunity (PTI) in rice was compromised in Xa21 plants silenced for XIK1. CONCLUSION: Our study reveals that the LRR-RLK gene XIK1 is Xoo-responsive and positively regulates Xa21-mediated disease resistance. PMID- 26054239 TI - Forward screening for seedling tolerance to Fe toxicity reveals a polymorphic mutation in ferric chelate reductase in rice. AB - BACKGROUND: Rice contains the lowest grain Fe content among cereals. One biological limiting factor is the tolerance of rice to Fe toxicity. Reverse and forward genetic screenings were used to identify tolerance to Fe toxicity in 4,500 M4 lines irradiated by fast neutrons (FN). FINDINGS: Fe-tolerant mutants were successfully isolated. In the forward screen, we selected five highly tolerant and four highly intolerant mutants based on the response of seedlings to 300 ppm Fe. Reverse screening based on the polymorphic coding sequence of seven Fe homeostatic genes detected by denaturing high performance liquid chromatography (dHPLC) revealed MuFRO1, a mutant for OsFRO1 (LOC_Os04g36720). The MuFRO1 mutant tolerated Fe toxicity in the vegetative stage and had 21-30% more grain Fe content than its wild type. All five highly Fe-tolerant mutants have the same haplotype as the MuFRO1, confirming the important role of OsFRO1 in Fe homeostasis in rice. CONCLUSIONS: FN radiation generated extreme Fe-tolerant mutants capable of tolerating different levels of Fe toxicity in the lowland rice environment. Mutants from both reverse and forward screens suggested a role for OsFRO1 in seedling tolerance to Fe toxicity. The MuFRO1 mutant could facilitate rice production in the high-Fe soil found in Southeast Asia. PMID- 26054240 TI - Genetic analysis of flag leaf size and candidate genes determination of a major QTL for flag leaf width in rice. AB - BACKGROUND: Flag leaf is the most essential organ for photosynthesis in rice and its size plays an important role in rice breeding for ideal plant-type. Flag leaf size affect photosynthesis to a certain extent, thereby influencing rice production. Several genes controlling leaf size and shape have been identified with mutants. Although a number of quantitative trait loci (QTLs) for leaf size and shape have been detected on 12 chromosomes with different populations of rice, few of them were cloned. RESULTS: The pair-wise correlation analysis was conducted on length, width and length-width ratio of the flag leaf, and yield per plant in the core recombinant inbred lines of Liang-You-Pei-Jiu (LYP9) developed in Hainan and Hangzhou. There were significant correlations among the three flag leaf size and shape traits. Interestingly, a positive correlation was found between flag leaf width and yield per plant. Based on the high-resolution linkage map we constructed before, 43 QTLs were detected for three flag leaf size and shape traits and yield per plant, among which 31 QTLs were unreported so far. Seven QTLs were identified common in two environments. And qFLW7.2, a new major QTL for flag leaf width, was fine mapped within 27.1 kb region on chromosome 7. Both qFLW7.2 and qPY7 were located in the interval of 45.30 ~ 53.34 cM on chromosome 7, which coincided with the relationship between yield per plant (PY) and flag leaf width (FLW). CONCLUSION: qFLW7.2, which explained 14% of the phenotypic variation, increased flag leaf width with 93-11 allele. Two candidate genes were selected based on sequence variation and expression difference between two parents, which facilitated further QTL cloning and molecular breeding in super rice. PMID- 26054242 TI - Delving deeper into technological innovations to understand differences in rice quality. AB - Increasing demand for better quality rice varieties, which are also more suited to growth under sub-optimal cultivation conditions, is driving innovation in rice research. Here we have used a multi-disciplinary approach, involving SNP-based genotyping together with phenotyping based on yield analysis, metabolomic analysis of grain volatiles, and sensory panel analysis to determine differences between two contrasting rice varieties, Apo and IR64. Plants were grown under standard and drought-induced conditions. Results revealed important differences between the volatile profiles of the two rice varieties and we relate these differences to those perceived by the sensory panel. Apo, which is the more drought tolerant variety, was less affected by the drought condition concerning both sensory profile and yield; IR64, which has higher quality but is drought sensitive, showed greater differences in these characteristics in response to the two growth conditions. Metabolomics analyses using GCxGC-MS, followed by multivariate statistical analyses of the data, revealed a number of discriminatory compounds between the varieties, but also effects of the difference in cultivation conditions. Results indicate the complexity of rice volatile profile, even of non-aromatic varieties, and how metabolomics can be used to help link changes in aroma profile with the sensory phenotype. Our outcomes also suggest valuable multi-disciplinary approaches which can be used to help define the aroma profile in rice, and its underlying genetic background, in order to support breeders in the generation of improved rice varieties combining high yield with high quality, and tolerance of both these traits to climate change. PMID- 26054241 TI - Functional diversity of jasmonates in rice. AB - Phytohormone jasmonates (JA) play essential roles in plants, such as regulating development and growth, responding to environmental changes, and resisting abiotic and biotic stresses. During signaling, JA interacts, either synergistically or antagonistically, with other hormones, such as salicylic acid (SA), gibberellin (GA), ethylene (ET), auxin, brassinosteroid (BR), and abscisic acid (ABA), to regulate gene expression in regulatory networks, conferring physiological and metabolic adjustments in plants. As an important staple crop, rice is a major nutritional source for human beings and feeds one third of the world's population. Recent years have seen significant progress in the understanding of the JA pathway in rice. In this review, we summarize the diverse functions of JA, and discuss the JA interplay with other hormones, as well as light, in this economically important crop. We believe that a better understanding of the JA pathway will lead to practical biotechnological applications in rice breeding and cultivation. PMID- 26054243 TI - Pyramiding of three bacterial blight resistance genes for broad-spectrum resistance in deepwater rice variety, Jalmagna. AB - BACKGROUND: Jalmagna is a popular deepwater rice variety with farmers of India because of its good yield under waterlogged condition. However, the variety is highly susceptible to bacterial blight (BB) disease. The development of resistant cultivars has been the most effective and economical strategy to control the disease under deepwater situation. Three resistance genes (xa5 + xa13 + Xa21) were transferred from Swarna BB pyramid line, using a marker-assisted backcrossing (MAB) breeding strategy, into the BB-susceptible elite deepwater cultivar, Jalmagna. RESULTS: Molecular marker integrated backcross breeding program has been employed to transfer three major BB resistance genes (Xa21, xa13 and xa5) into Jalmagna variety. During backcross generations, markers closely linked to the three genes were used to select plants possessing these resistance genes and markers polymorphic between donor and recurrent parent were used to select plants that have maximum contribution from the recurrent parent genome. A selected BC3F1 plant was selfed to generate homozygous BC3F2 plants with different combinations of BB resistance genes. The three-gene pyramid and two gene pyramid lines exhibited high levels of resistance against the BB pathogen. Under conditions of BB infection, the three-gene pyramided lines exhibited a significant yield advantage over Jalmagna. The selected pyramided lines showed all agro-morphologic traits of Jalmagna without compromising the yield. CONCLUSION: The three major BB resistance genes pyramided lines exhibited high level of resistance and are expected to provide durable resistance under deep water situation where control through chemicals is less effective. High similarity in agro-morphologic traits and absence of antagonistic effects for yield and other characters were observed in the best pyramided lines. PMID- 26054244 TI - Effectiveness of percutaneous vertebroplasty in cases of vertebral metastases. AB - PURPOSE AND OBJECTIVES: To assess the effectiveness of percutaneous vertebroplasty (PV) in patients with vertebral collapse due to metastases. MATERIALS AND METHODS: PV procedures performed on 95 vertebras in 52 patients with primary malignancy were retrospectively evaluated. Vertebral metastases, primary malignancies of the patients, pain before and after PV on a visual analogue scale (VAS), amount of polymethylmethacrylate (PMMA) cement applied to the vertebral body during PV, PMMA cement leakage and vertebral approaches were evaluated. RESULTS: VAS scores of 43 patients (in total 79 vertebras) were evaluated. Median VAS scores of patients declined from 8 (4-10) before PV to 3 (0 7) within one day after the procedure, to 2 (0-9) one week after the procedure and eventually to 2 (0-9) 3months after the procedure (p<0.001). PMMA amount applied to the vertebral body during PV varied between 1.5-9mL (average+/-SD 4.91+/-1.61). There was no significant statistical correlation between PMMA amounts and VAS scores within one day after, 1week after and 3months after the PV procedure (p>0.05). CONCLUSION: PV is a simple, effective, reliable, easy to perform and minimally invasive procedure in patients with painful vertebral metastases. PMID- 26054245 TI - Transcatheter arterial embolization for acute nonvariceal upper gastrointestinal bleeding: Indications, techniques and outcomes. AB - Over the past three decades, transcatheter arterial embolization has become the first-line therapy for the management of acute nonvariceal upper gastrointestinal bleeding that is refractory to endoscopic hemostasis. Advances in catheter-based techniques and newer embolic agents, as well as recognition of the effectiveness of minimally invasive treatment options, have expanded the role of interventional radiology in the treatment of bleeding for a variety of indications. Transcatheter arterial embolization is a fast, safe, and effective minimally invasive alternative to surgery, when endoscopic treatment fails to control acute bleeding from the upper gastrointestinal tract. This article describes the role of arterial embolization in the management of acute nonvariceal upper gastrointestinal bleeding and summarizes the literature evidence on the outcomes of endovascular therapy in such a setting. PMID- 26054246 TI - Ruptured visceral artery aneurysms. AB - Visceral artery aneurysms are rare but their estimated mortality due to rupture ranges between 25 and 70%. Treatment of visceral artery aneurysm rupture is usually managed by interventional radiology. Specific embolization techniques depend on the location, affected organ, locoregional arterial anatomy, and interventional radiologist skill. The success rate following treatment by interventional radiology is greater than 90%. The main complication is recanalization of the aneurysm, showing the importance of post-therapeutic monitoring, which should preferably be performed using MR imaging. PMID- 26054248 TI - Chemiluminescence and the Nox1-Nox2-Nox4 Triple Knockout. PMID- 26054247 TI - Modular synthesis and biological activity of pyridyl-based analogs of the potent Class I Histone Deacetylase Inhibitor Largazole. AB - The formation of a series of analogs containing a pyridine moiety in place of the natural thiazole heterocycle, based on the potent, naturally occurring HDAC inhibitor Largazole has been accomplished. The synthetic strategy was designed modularly to access multiple inhibitors with different aryl functionalities containing both the natural depsipeptide and peptide isostere variant of the macrocycle. The cytotoxicity and biochemical activity of the library of HDAC inhibitors is described herein. PMID- 26054249 TI - Symptom CheckList-90-R: proposed scales in a probability sample of adolescents from the general population. AB - To provide questionnaires for clinical assessment with scales adapted for adolescents would benefit clinical practice as well as research. The aim of this paper is to report normative data for adolescents on the SCL-90-R using a probability sample from the community. The participants were 1,663 adolescents, 845 girls and 818 boys, with an average age of 14.26 (SD = 1.36). They were selected through stratified cluster sampling with groups randomly selected from schools. Sampling error was estimated at 4% with a 95.5% confidence level. Cohen's d effect sizes are reported for age-group. We found significant differences across participants according to gender and age on SCL-90-R Global Scores and Symptom Dimensions. Thus, we provide normative data, divided according to age and gender. PMID- 26054250 TI - Prevention of thromboembolism in myeloma: expanding the tool-box of assays to predict the risk? PMID- 26054251 TI - How metamer mismatching decreases as the number of colour mechanisms increases with implications for colour and lightness constancy. AB - Metamer mismatching has been previously found to impose serious limitations on colour constancy. The extent of metamer mismatching is shown here to be considerably smaller for trichromats than for dichromats, and maximal for monochromats. The implications for achromatic colour perception are discussed. PMID- 26054252 TI - Bottlenecks in the implementation of essential screening tests in antenatal care: Syphilis, HIV, and anemia testing in rural Tanzania and Uganda. AB - OBJECTIVE: To identify and compare implementation bottlenecks for effective coverage of screening for syphilis, HIV, and anemia in antenatal care in rural Tanzania and Uganda; and explore the underlying determinants and perceived solutions to overcome these bottlenecks. METHODS: In this multiple case study, we analyzed data collected as part of the Expanded Quality Management Using Information Power (EQUIP) project between November 2011 and April 2014. Indicators from household interviews (n=4415 mothers) and health facility surveys (n=122) were linked to estimate coverage in stages of implementation between which bottlenecks can be identified. Key informant interviews (n=15) were conducted to explore underlying determinants and analyzed using a framework approach. RESULTS: Large differences in implementation were found within and between countries. Availability and effective coverage was significantly lower for all tests in Uganda compared with Tanzania. Syphilis screening had the lowest availability and effective coverage in both countries. The main implementation bottleneck was poor availability of tests and equipment. Key informant interviews validated these findings and perceived solutions included the need for improved procurement at the central level. CONCLUSION: Our findings reinforce essential screening as a missed opportunity, caused by a lack of integration of funding and support for comprehensive antenatal care programs. PMID- 26054253 TI - Maladaptive family dysfunction and parental death as risk markers of childhood abuse in women. AB - This study aims to examine the prevalence and characteristics of physical, emotional and sexual childhood abuse. It also examines whether other non-abuse types of childhood adversities related to maladaptive family functioning and separations during childhood can be used as markers for the presence of childhood abuse. Participants (N = 237) were women at 2-3 days after delivery that completed the Spanish-validated version of the Early Trauma Inventory Self Report (ETI-SR; Bremner, Bolus, & Mayer, 2007; Plaza et al., 2011), designed to assess the presence of childhood adversities. Results show that 29% of the women had experienced some type of childhood abuse, and 10% more than one type. Logistic regression analyses indicate that childhood parental death is a risk marker for childhood emotional abuse (OR: 3.77; 95% CI: 1.327-10.755; p <.013), childhood parental substance abuse is a risk marker for childhood sexual (OR: 3.72; 95% CI: 1.480-9.303; p < .005) and physical abuse (OR: 2.610; 95% CI: 1.000-6.812; p < .05) and that childhood family mental illness is a risk marker for childhood emotional (OR: 2.95; 95% CI: 1.175-7.441; p < .021) and sexual abuse (OR: 2.55; 95% CI: 1.168-5.580; p < .019). The high prevalence of childhood abuse indicates a need for assessment during the perinatal period. Screening for childhood family mental illness, parental substance abuse, and parental death - all identified risk factors for reporting childhood abuse - can help to identify women that should be assessed specifically regarding abuse. PMID- 26054254 TI - Age differences among older adults in the use of emotion regulation strategies. What happens among over 85s and centenarians? AB - OBJECTIVE: Past research on emotion regulation strategies has concluded that older adults use more passive strategies than young adults. However, we found scarce research in this field focusing on the oldest old (i.e. those aged 85 and over). The aim of this study was to analyze whether or not differences exist in the way older adults aged 85 and over (centenarians included) use emotion regulation strategies, in comparison with younger age groups (65-74 and 75-84 years old). METHOD: Participants were 257 older adults from Spain, all aged between 65 and 104. The sample was divided into four age groups: 65-74; 75-84; 85 94; and 95-104 years old. Participants completed the Strategy Questionnaire after reading each of the vignettes designed to elicit feelings of either sadness or anger. The questionnaire measures four types of regulation strategies: Passive, Express, Solve and Seek. RESULTS: The 85-94 age group and centenarians were found to use proactive (Express, Seek) and Solve strategies less in comparison with younger age groups when regulating sadness and anger. In contrast, an increased use of Passive strategies was observed in the regulation of both emotions in the 85-94 age group. Significant differences were also found between centenarians and younger age groups in the use of Passive strategies for sadness, although not for anger. CONCLUSION: Age differences were observed in the use of emotion regulation strategies, with older age groups using proactive strategies less and passive strategies more. PMID- 26054255 TI - Charge transfer, bonding conditioning and solvation effect in the activation of the oxygen reduction reaction on unclustered graphitic-nitrogen-doped graphene. AB - The monodentate associative chemisorption of molecular oxygen on unclustered graphitic-nitrogen-doped graphene requires two nitrogen dopants per activated molecule. Significant charge transfers from regions corresponding to distant nitrogen-dopants, the presence of a nitrogen-dopant adjacent to the carbon atom acting as an active site, which favours its transition from a sp(2) hybridization state to sp(3), and the solvation effect turn the investigated mechanism to a favourable process. PMID- 26054257 TI - Effects of o-phenylenediamine on methylglyoxal generation from monosaccharide: Comment on "correlation of methylglyoxal with acrylamide formation in fructose/asparagine Maillard reaction model system". AB - Methylglyoxal (MG), a reactive carbonyl compound, has recently garnered much attention because of its ability to modify proteins over time and yield advanced glycation end products (AGEs) that are thought to contribute to the development of diabetes mellitus and its complications. In a recent paper published in Food Chemistry by Yuan et al. [Yuan, Y., Zhao, G. H., Hu, X. S., Wu, J. H., Liu, J., & Chen, F. (2007a). Correlation of methylglyoxal with acrylamide formation in fructose/asparagines Maillard reaction model system. Food Chemistry, 108(3), 885 890] authors showed a high correlation between methylglyoxal formation and acrylamide formation. However, in their study, model systems of aqueous fructose/asparagines (Fru/Asn) and fructose/asparagines/o-phenylenediamine (Fru/Asn/OPD) heating at 150 degrees C were used. The validity of these models relies on the assumption that OPD will only serve the role of a trapping agent for MG. In this short communication, we would like to call to attention that MG can also have a strong catalytic effect in the generation of MG from fructose. Therefore, it is concluded that the concentration of MG obtained in Fru/Asn/OPD model system cannot correspond to the total amount of MG formed by Maillard reaction of Fru and Asn as claimed by Yuan et al. [Yuan, Y., Zhao, G. H., Hu, X. S., Wu, J. H., Liu, J., & Chen, F. (2007a). Correlation of methylglyoxal with acrylamide formation in fructose/asparagines Maillard reaction model system. Food Chemistry, 108(3), 885-890, Yuan, Y., Zhao, G. H., Hu X. S., Wu, J. H., Liu, J., & Chen. F. (2007b). High correlation of methylglyoxal with acrylamide formation in glucose/asparagine Maillardreaction model. European Food Research and Technology. doi:10.1007/s00217-007-0658-0]. PMID- 26054256 TI - Association between Several Persistent Organic Pollutants in Serum and Adipokine Levels in Breast Milk among Lactating Women of Korea. AB - Exposure to several persistent organic pollutants (POPs) has been linked to alteration of lipid metabolism. Adipokines, such as leptin and adiponectin, are hormones that play roles in lipid metabolism, and have been suggested as markers of health effects that may lead to obesity. To date, only serum adipokines have been associated with POPs exposure. In the present study, for the first time, the associations between leptin and adiponectin in breast milk, and several POPs in serum were investigated among 82 lactating Korean women between 25 and 46 years of age. Breast milk adipokines are important because adipokine intake of infant through breastfeeding may influence the growth of infants. The median concentrations of leptin and adiponectin in skimmed milk of the Korean lactating women were 17.9 ng/L and 16.5 MUg/L, respectively. Leptin concentrations in breast milk were negatively associated with ?hexachlorohexane (HCH), oxychlordane, ?chlordane, or 2,2',4,4',5,5'-hexachlorobiphenyl (CB 153) levels in maternal serum. Linear relationships between adiponectin and POPs concentrations were not observed, however, nonmonotonic relationship which showed generally positive associations was suggested for p,p'-dichlorodiphenyltrichloroethane (DDT) and ?chlordane in quartile analysis. Our observations show that POPs at the current level of exposure may be associated with the alteration of lipid metabolism among lactating women. Implication of adipokine transfer to breastfed infants is of concern and deserves further investigation. PMID- 26054258 TI - Evaluation of plant products from the Legnicko-Glogowski region for their contamination with arsenic. AB - Contents of arsenic were determined in plant products originating from the region of two copperworks, Glogow and Legnica. Analyses were carried out by means of atomic absorption spectrometry, using an MHS-10 unit for hydride generation (acetylene/argon), after wet mineralisation of samples. The maximum permissible level of arsenic was not exceeded in any of the examined samples of cereals, potatoes, carrots, beetroots, cabbages, tomatoes, apples and pears, originating from the regions under scrutiny. PMID- 26054259 TI - Effect of storage on biochemical and microbiological parameters of edible truffle species. AB - The effects of different storage treatments on the most common edible truffle species, such as Tuber magnatum and Tuber borchii (white truffles), Tuber melanosporum and Tuber aestivum (black truffles), were analysed. Biochemical and microbiological profiles were monitored, in order to evaluate possible alterations during truffle preservation. After harvesting, some fresh samples were kept at 4 degrees C for 30days, other samples were frozen at -20 degrees C for one month, thawed and preserved at 4 degrees C; the remainder were autoclaved. The biochemical parameters studied were sugar and protein content, the activity of some enzymes involved in the central metabolism of the fungi and the electrophoretic pattern of soluble proteins. Total mesophilic bacteria were also counted. The results obtained showed that the storage at 4 degrees C is the treatment that best preserves the biochemical and microbiological characteristics of fresh truffles. Black truffles were more resistant to biochemical spoilage than the white ones, while T. magnatum was the most resistant to microbial spoilage. PMID- 26054260 TI - Extractable oil in microcapsules prepared by spray-drying: Localisation, determination and impact on oxidative stability. AB - Aim of the present study was to investigate the localisation of the extractable oil in spray-dried microencapsulated fish oil prepared under different spray drying conditions and to investigate the impact on lipid oxidation upon storage. Confocal laser scanning microscopy, scanning electron microscopy and different extraction procedures revealed that the extractable oil in microencapsulated fish oil is mainly located on the surface and in oil droplets close to the surface. Consequently, different methods for determination of the different fractions are proposed. Lipid oxidation as determined by hydroperoxide content or anisidine value was higher in microcapsules with 50% oil load spray-dried at 210/90 degrees C, propanal content was increased in samples with 30% oil load spray-dried at 210/90 degrees C. The differences in stability could only partly be explained by the varying amount of extractable oil. It is concluded that the surface oil protects other fractions of the extractable oil and that the extractable oil cannot be used to predict shelf-life of microencapsulated oils. PMID- 26054261 TI - Raman spectroscopy study of the structural effect of microbial transglutaminase on meat systems and its relationship with textural characteristics. AB - Raman spectroscopy and texture analysis (TPA) studies were carried out to determine the effect of adding different levels of microbial transglutaminase (MTGase) to meat systems. This addition produced a significant (p<0.05) increase in hardness, springiness and cohesiveness in the meat systems. Raman spectroscopy analysis revealed the occurrence of secondary structural changes in meat proteins due to MTGase. Modifications in the amide I (1650-1680cm(-1)) and amide III (1200 1300cm(-1)) regions indicated a significant (p<0.05) decrease in alpha-helix content, accompanied by a significant (p<0.05) increase in beta-sheets and turns due to the addition of the enzyme to meat systems. Significant (p<0.05) correlations were found between these secondary structural changes in meat proteins and the textural properties (hardness, adhesiveness, springiness and cohesiveness) of meat systems. PMID- 26054262 TI - Influence of added bean flour (Phaseolus vulgaris L.) on some physical and nutritional properties of wheat flour tortillas. AB - Composite flours containing 15%, 25%, or 35% of small red, black, pinto, or navy bean flours (BF) and wheat were made into tortillas. Dough rheology, firmness, cohesiveness, rollability, and some physical properties of tortillas were negatively affected as BF concentration increased regardless of bean cultivar. Nutritionally, all bean tortillas had significantly higher levels of crude protein, total phenols, 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3 ethylbenzothiazoline-6-sulphonic acid) (ABTS(+)) in vitro antioxidant activity (AA) and antinutritional compounds such as phytic acid (PA) and trypsin inhibitors (TI) than the wheat control. Tortillas to which 35% of small red, pinto and black BF was added had the highest levels of phenols, which were significantly correlated with both DPPH (r=0.99) and ABTS(+) (r=0.99) AA. Compared to raw flours, PA and TI were reduced from 37.37% to 43.78% and from 50% to 66%, respectively, in the tortillas. Overall analysis indicated that tortillas with acceptable texture and improved nutritional profile were produced at 25% substitution. PMID- 26054263 TI - Comparative study on acid-induced gelation of myosin from Atlantic cod (Gardus morhua) and burbot (Lota lota). AB - Physicochemical and rheological properties of myosin from Atlantic cod and burbot during acid-induced gelation at room temperature (22-23 degrees C) by d-gluconic acid-delta-lactone (GDL) were monitored. Turbidity and particle size of both myosins increased and salt soluble content decreased when pH decreased, suggesting the formation of protein aggregates caused by acidification. The formation of disulphide bonds in myosin gelation was induced by acid. Ca(2+) ATPase activity of myosin decreased (p<0.05), while surface hydrophobicity increased during acidification (p<0.05). Furthermore, the decreases in maximum transition temperature (Tmax) and the denaturation enthalpies (DeltaH) were found in both myosins. During acidification, the increases in storage modulus (G') and loss modulus (G") of myosin were observed (p<0.05), revealing the formation of elastic gel matrix. Thus, gelation of myosin from Atlantic cod and burbot could take place under acidic pH via denaturation and aggregation. However, myosin from Atlantic cod was generally more favourable to gelation than was burbot myosin. PMID- 26054264 TI - Rind of the rambutan, Nephelium lappaceum, a potential source of natural antioxidants. AB - The rind of rambutan, which is normally discarded was found to contain extremely high antioxidant activity when assessed using several methods. Although having a yield of only 18%, the ethanolic rambutan rind extract had a total phenolic content of 762+/-10mg GAE/g extract, which is comparable to that of a commercial preparation of grape seed extract. Comparing the extract's pro-oxidant capabilities with vitamin C, alpha-tocopherol, grape seed and green tea, the rind had the lowest pro-oxidant capacity. In addition, the extract at 100MUg/ml was seen to limit oxidant-induced cell death (DPPH at 50MUM) by apoptosis to an extent similar to that of grape seed. The extracts were not cytotoxic to normal mouse fibroblast cells or splenocytes while the powderised rind was seen to have heavy metals contents far below the permissible levels for nutraceuticals. Our study for the first time reveals the high phenolic content, low pro-oxidant capacity and strong antioxidant activity of the extract from rind of Nephelium lappaceum. This extract, either alone or in combination with other active principles, can be used in cosmetic, nutraceutical and pharmaceutical applications. PMID- 26054265 TI - Isolation and evaluation of the radical-scavenging activity of the antioxidants in the leaves of an edible plant, Mallotus japonicus. AB - The antioxidative properties of a hot water extract of the leaves of Mallotus japonicus were evaluated. The extract had a high phenolic content and strong antioxidative activity, compared with green tea, rooibos tea, and red wine. Six phenolic compounds were isolated as antioxidative components by HPLC. They were identified as mallotinic acid, mallotusinic acid, corilagin, geraniin, rutin, and ellagic acid. These antioxidative compounds were subjected to DPPH radical scavenging, superoxide radical-scavenging, and hydroxyl radical-scavenging assays, and compared with other antioxidative compounds. Four of the compounds, mallotinic acid, mallotusinic acid, corilagin and geraniin, exhibited much stronger antioxidative activity than gallic acid, rutin, ellagic acid, quercetin, and chlorogenic acid, and were as active as epigallocatechin gallate (EGCG), a strong antioxidant in green tea. Mallotus japonicus leaves are an excellent source of strong natural antioxidative materials. PMID- 26054266 TI - Optimization of lipase-catalyzed enantioselective esterification of (+/-)-menthol in ionic liquid. AB - Response surface methodology was successfully applied to optimize lipase catalyzed enantioselective esterification of (+/-)-menthol. The effects of various reaction conditions, including reaction time, temperature, enzyme loading, substrate molar ratio and water activity, were investigated. A Central Composite Rotatable Design was employed to search for the optimal conversion of (+/-)-menthol and enantiomeric excess. A quadratic polynomial regression model was used to analyze the experimental data at a 95% confidence level (p<0.05). The analysis confirmed that reaction temperature, enzyme loading and reaction time were the significant factors affecting the conversion of (+/-)-menthol. Moreover, reaction temperature, enzyme loading, substrate molar ratio and reaction time were found to affect the enantiomeric excess significantly. The coefficient of determination of these two models was found to be 0.980 and 0.967, respectively. Two sets of optimum reaction conditions were established and the verified experimental trials were performed for validating the optimum points. Under the optimum conditions, the conversion of (+/-)-menthol and the enantiomeric ratio exceeded 53% and 40%, respectively. PMID- 26054267 TI - Marination of deep-water pink shrimp with rosemary extract and the determination of its shelf-life. AB - The effect of the antioxidant activity of rosemary extract on marinated deep water pink shrimp (Parapenaeus longirostris Lucas, 1846) stored at 1 degrees C was investigated. Chemical, physical, instrumental, microbiological and sensory analyses were performed to investigate the quality changes and to determine the shelf-life of marinated shrimps. Chemical composition of the shrimp was determined and no significant difference (P>0.05) was found between the control group (without rosemary extract) and the experimental group (with rosemary extract). Both groups contained 2% citric acid. There was no significant difference (P>0.05) between the sensory analysis of control and experimental groups on storage days 0, 15, 30, 45 and 60 while rancidity was noted by the panelists in the control group on day 75. The TBA value of the control group reached the consumption limit on day 75 but it was still 'very good' for the experimental group. Although the bacterial load of both groups were lower than the consumption limits on storage day 75, TBA value limited the shelf-life of the control group but the experimental group was still of good quality for consumption after 75 days. PMID- 26054268 TI - Variation of lipid class composition in Nitzschia laevis as a response to growth temperature change. AB - The lipid composition and the distribution of fatty acids in the lipid pool were determined in eicosapentaenoic acid (EPA)-producing microalga (Nitzschia laevis) grown under different temperatures. Both the relative amounts of lipid classes and the degree of fatty acid unsaturation in various lipid species were not greatly changed under tested growth conditions. Higher temperature up to 23 degrees C benefited the growth of N. laevis but only had a slight influence on EPA and lipid contents. Further increasing the culture temperature caused a serious inhibition of both the cell growth and fatty acid biosynthesis. Under all temperatures tested, triacylglycerol (TAG) was the predominant lipid constituent (64.5-69.1% of total lipid) and was highly saturated. Lower temperature favored the formation of polar lipids. The highest content of phosphatidylcholine (PC), the major phospholipids component, was reached at 15 degrees C (10.9% of total lipid). In sharp contrast to TAG, PC was highly unsaturated and contained a higher amount of EPA under lower temperature. The highest EPA content in polar lipid was achieved at 19 degrees C. The results from this investigation suggested that the low temperature could improve the distribution of polyunsaturated fatty acids in phospholipids, though it could not significantly influence their amount, especially in PC. PMID- 26054269 TI - Heat treatment enhances the NO-suppressing and peroxynitrite-intercepting activities of kumquat (Fortunella margarita Swingle) peel. AB - In Taiwan, folk remedies containing dried kumquats (Fortunella margarita Swingle) are used to cure inflammatory respiratory disorders. The induction of inducible nitric oxide (NO) synthase in inflammatory cells and increased airway production of NO and peroxynitrite, its derivative, are key events in such disorders. Although heat is known to affect the antioxidant activity of citrus peels, the effects of dehydration and heating on NO suppression and on the interception of peroxynitrite are unclear. We determined the NO-suppressing activities of freeze dried, oven-dried, and heat-treated kumquat extracts by measuring their inhibition of NO production in lipopolysaccharide-activated RAW 264.7 macrophages. Furthermore, we evaluated the attenuation of peroxynitrite-mediated nitrotyrosine formation in albumin. Heating, but not oven drying, enhanced the ability of kumquat peels to suppress NO and intercept peroxynitrite, as compared with freeze drying. However, heat treatment and oven drying of kumquat flesh attenuated these activities; these effects were at least partially attributed to heat-susceptible ascorbate. PMID- 26054270 TI - ACE-inhibitory and antioxidant properties of potato (Solanum tuberosum). AB - Proteins were isolated from potato tubers (Solanum tuberosum) at different physiological states, and by-products from the potato industry were used to evaluate their ACE-inhibitory and radical-scavenging potencies. Protein isolates and by-products were autolysed or hydrolysed by alcalase, neutrase and esperase. Hydrolysis increased the inhibition of the angiotensin-converting enzyme (ACE) and the radical-scavenging activity. The ACE-inhibitory potencies of the hydrolysates were high (IC50=0.018-0.086) and the by-product fractions showed ACE inhibition also before hydrolysis. All samples exhibited low radical-scavenging activity, and hydrolysis for 2h with proteases was needed to produce an increase in the activity. Ultrafiltration through 10-3kDa membranes efficiently separated the ACE-inhibitory compounds into permeate fractions. The results of this study suggest that potato is a promising source for the production of bioactive compounds as ingredients for developing functional foods with a beneficial impact on cardiovascular health. PMID- 26054271 TI - Total and dialyzable levels of manganese from duplicate meals and influence of other nutrients: Estimation of daily dietary intake. AB - Both total and dialyzable Mn levels were determined in 108 duplicate meals during 36 consecutive days. Both mineral fractions were measured by a graphite furnace atomic absorption spectrometry (GFAAS) method previously optimized. A total mean Mn fraction of 1.03+/-0.49mg was found in the meals. The Mn supplied by the meals is directly and significantly (p<0.001) correlated with macronutrient content (carbohydrates, fibre and protein). The mean Mn fraction dialyzed through the dialysis membrane was 0.23+/-0.17mg (22.0+/-8.93% as bioaccessible fraction). The total and dialyzable Mn fractions found for breakfasts were significantly lower (p<0.001). Nevertheless, the Mn bioavailabilities expressed as the percentage of dialyzable element, were not significantly different among the three primary meals (breakfast, lunch and dinner). A significant correlation between the total and the dialyzable fraction of Mn in meals was found (p<0.001, r=0.78, r(2)=0.61). The dialyzed element fractions present in meals were significantly correlated mainly with carbohydrates, protein and several amino acid levels (p <0.01). Foods with higher carbohydrate and therefore energy contents, e.g. cereals, legumes, vegetables and fruits, would be primary sources of bioaccessible Mn in the diet. The bioaccessibility of Mn was only significant influenced by energy, carbohydrates and Se levels present in meals. The mean Mn daily dietary intake (DDI) was 3.05+/-0.61mgday(-1). PMID- 26054272 TI - Supplemental inulin does not enhance iron bioavailability to Caco-2 cells from milk- or soy-based, probiotic-containing, yogurts but incubation at 37 degrees C does. AB - The in vitro effects of supplemental inulin (4%) on iron (Fe) availability in two different probiotic-containing yogurts were examined. Milk or soy-based yogurts, with and without inulin, were incubated (37 degrees C) for 48h or without any incubation before comparison by an in vitro gastrointestinal digestion/Caco-2 cell culture model was used to assess iron bioavailability. The dialysable Fe fraction, cell ferritin formation, and cell associated Fe were monitored. Supplemental inulin decreased dialysable Fe only in non-incubated milk-based yogurt. In both yogurts incubation by itself increased dialysable Fe, and inulin increased the latter only in soy-based yogurt. Cellular ferritin concentration were higher after exposure to non-incubated milk-based than soy-based yogurt, although, after incubation the latter induced the highest ferritin formation. These data suggest that inulin does not have a direct effect on Fe bioavailability in the small intestine, and that probiotic bacteria play an enhancing role on Fe bioavailability. PMID- 26054273 TI - Inhibitory effect of wheat bran feruloyl oligosaccharides on oxidative DNA damage in human lymphocytes. AB - The present work assessed the protective effect of feruloyl oligosaccharides (FOs), the ferulic acid ester of oligosaccharides from wheat bran, against oxidative DNA damage in normal human peripheral blood lymphocytes induced by hydrogen peroxide (H2O2). The DNA damage was measured by using the single cell gel electrophoresis assay (comet assay). Lymphocytes were subjected to DNA damage by exposure to a range of H2O2 concentrations (10-200MUmol/l). H2O2, at a concentration of 200MUmol/l, resulted in nearly all cells being highly damaged. FOs showed no cytotoxicity and genotoxicity to normal human lymphocytes at the tested concentrations (10-500MUmol/l). In addition, DNA damage in human lymphocytes induced by 100MUmol/l H2O2 was inhibited by FOs in a concentration dependent fashion with 91.1% inhibition of lymphocyte DNA damage at 500MUmol/l as compared with the control. The results suggest that water-soluble FOs from wheat bran are able to enhance the ability of human lymphocytes to resist H2O2 induced oxidative damage. PMID- 26054274 TI - Antimicrobial activity of lactic acid and copper on growth of Salmonella and Escherichia coli O157:H7 in laboratory medium and carrot juice. AB - Outbreaks of food-borne pathogens, such as Escherichia coli O157:H7 and Salmonella, continue to draw public attention to food safety. Several reports have demonstrated the efficacy of using natural ingredients to control the growth of food-borne pathogens. The objective of this study was to investigate antimicrobial effects of lactic acid and copper, alone and in combination, on the survival and growth of Salmonella spp. and E. coli O157:H7 in laboratory medium and carrot juice. Survival and growth of 38 Salmonella spp. and six E. coli O157:H7 strains were compared when grown in brain heart infusion (BHI) broth and carrot juice under conditions including either lactic acid (0.2%) alone, copper sulfate (50ppm) alone or the combination of the two. The growth inhibition was negligible when copper sulfate was added to BHI broth and carrot juice. Lactic acid (0.2%) retarded the growth of bacterial strains. However, the growth of bacterial strains was significantly inhibited when both lactic acid and copper were in BHI broth and carrot juice within the time frame of this study. These findings indicated that lactic acid, in combination with copper sulfate, could be used to inhibit the growth of pathogens. Natural ingredients, such as lactic acid and low dose of copper ions, can be used to improve the safety of food products. PMID- 26054275 TI - Antioxidant activity and water-holding capacity of canola protein hydrolysates. AB - Canola protein hydrolysates were prepared using commercial enzymes, namely Alcalase, an endo-peptidase and Flavourzyme with both endo- and exo-peptidase activities. The hydrolysates so prepared were effective as antioxidants in model systems, mainly by scavenging of free radicals and acting as reducing agents. This effect was concentration-dependent and also influenced by the type of enzyme employed in the process. The hydrolysate prepared using flavourzyme showed the highest antioxidant activity among all samples, whereas the hydrolysates prepared by combination of Alcalase and Flavourzyme did not differ significantly (P>0.05) in antioxidant effectiveness from that produced by Alcalase alone. The hydrolysates were also found to be effective in enhancing water-holding capacity and cooking yield in a meat model system. Their capability in improving the cooking yield of meat was in the order of Flavourzyme hydrolysates>combination hydrolysates>Alcalase hydrolysates. These results suggest that canola protein hydrolysates can be useful in terms of their functionality and as functional food ingredients and that their composition determines their functional properties and thus their potential application in the food and feed industries. PMID- 26054276 TI - Evolution of red wine anthocyanins during malolactic fermentation, postfermentative treatments and ageing with lees. AB - A comparative study was conducted on nine batches of wine, from the same initial wine, subjected to malolactic fermentation and ageing in barrels, under different technological conditions: Malolactic fermentation in barrel or in tank, with or without wine clarification, ageing with or without lees and stirring or no stirring of the lees. Samples were taken of the initial wine, of the wine at the end of malolactic fermentation, of the wines after clarifying treatments, and after 3, 6, 9, 12 and 14 months of ageing in the barrel, making a total of 48 wines. As a result of the anthocyanin analysis of all the wines studied, a total of 21 different anthocyanin compounds were detected, which can be classified into four groups: simple glucosides, acetyl glucosides, cinnamoyl glucosides and pyroanthocyanins. During MLF, it was shown that the effect of the container used seems to be more important than the metabolic activity of the bacteria responsible for the process. From application of the LSD test, significant differences were found in the concentrations of all the anthocyanin compounds identified due to ageing time and significant differences were also revealed for most anthocyanin compounds in relation to the manufacturing method, especially the presence or absence of lees. PMID- 26054277 TI - Antioxidant and nitric oxide production inhibitory activities of galacturonyl hydroxamic acid. AB - The self-prepared pectin hydroxamic acid has been reported to have antioxidant activities [Yang, S. S., Cheng, K. D., Lin, Y. S., Liu, Y. W., & Hou, W. C. (2004). Pectin hydroxamic acids exhibit antioxidant activities in vitro. Journal of Agricultural and Food Chemistry, 52, 4270-4273]. In this study, the galacturonic acid (GalA), the monomer unit of the pectin polymer, was esterified with acidic methanol (1N HCl) at 4 degrees C with gentle stirring for 5days to get galacturonic acid methyl ester which was further reacted with alkaline hydroxylamine to get galacturonyl hydroxamic acid (GalA-NHOH). The GalA-NHOH was used to test the antioxidant and antiradical activities in the comparison with GalA. The scavenging activities of GalA-NHOH against DPPH radicals (half inhibition concentration, IC50, was 82MUM), hydroxyl radicals detected by electron spin resonance (IC50 was 0.227nM in the comparison with Trolox of 0.433MUM), superoxide radicals (IC50 was 830MUM) were determined. The protection activities of GalA-NHOH against hydroxyl radicals-mediated calf thymus DNA damages, linoleic acid peroxidation and peroxynitrite-mediated dihydrorhodamine 123 oxidations were also investigated. It was found that the GalA-NHOH exhibited dose-dependently antioxidant activity and few or none was found in GalA. The GalA NHOH was used to evaluate the suppressed activity of nitric oxide (NO) productions of RAW264.7 cells in the presence of lipopolysaccharide (LPS, 100ng/ml) as inducers. It was found that GalA-NHOH (0.02-0.1mg/ml) could dose dependently suppress the NO productions (expressed as nitrite concentrations) in RAW264.7 cells without significant cytotoxicity. PMID- 26054278 TI - Stabilization of alpha-lipoic acid by complex formation with chitosan. AB - alpha-Lipoic acid (ALA) is an essential cofactor in mitochondrial multi-enzyme complexes related to energy production. However, it is unstable under light or heat, and its decomposition is accompanied by an unpleasant odor. Therefore, its stabilization by complex formation with the cationic polymer chitosan (CS) was investigated. The ALA dissolved in demineralized water was efficiently adsorbed on the precipitated insoluble CS particles, and an ALA-CS complex was obtained. The amount of ALA adsorbed on CS was affected by the CS species and the quantity ratio of ALA to CS. The ALA from the ALA-CS complex was released immediately by changing the pH. When ALA was incubated at 65 degrees C, it melted and polymerized. In addition, some decomposition of ALA was also observed in the physical mixture of ALA with CS. However, the ALA-CS complex did not decompose at all under the same conditions. Thus, the stabilization of ALA was achieved by complex formation with CS. CS is useful as a material for the stabilization of ALA, leading to its clinical use. PMID- 26054279 TI - Response surface methodology for autolysis parameters optimization of shrimp head and amino acids released during autolysis. AB - Protein hydrolysates were prepared from the head waste of Penaens vannamei, a China seawater major shrimp by autolysis method. Autolysis conditions (viz., temperature, pH and substrate concentration) for preparing protein hydrolysates from the head waste proteins were optimized by response surface methodology (RSM) using a central composite design. Model equation was proposed with regard to the effect of temperature, pH and substrate concentration. Substrate concentration at 23% (w/v), pH at 7.85 and temperature at 50 degrees C were found to be the optimal conditions to obtain a higher degree of hydrolysis close to 45%. The autolysis reaction was nearly finished in the initial 3h. The amino acid compositions of the autolysis hydrolysates prepared using the optimized conditions in different time revealed that the hydrolysates can be used as a functional food ingredient or flavor enhancer. Endogenous enzymes in the shrimp heads had a strong autolysis capacity (AC) for releasing threonine, serine, valine, isoleucine, tyrosine, histidine and tryptophan. Endogenous enzymes had a relatively lower AC for releasing cystine and glycine. PMID- 26054280 TI - Volatile compounds suitable for rapid detection as quality indicators of cold smoked salmon (Salmo salar). AB - Volatile compounds in cold smoked salmon products were identified by gas chromatography to study their suitability for rapid detection as indicators to predict sensory quality evaluated by quantitative descriptive analysis. Smoked salmon odour contributed by guaiacol, boiled potato- and mushroom-like odours characteristic for fish lipid degradation and sweet odours associated with the microbial metabolites 3-methyl-butanal and 3-hydroxybutanone were the most intense odours. Other key volatiles were present in high levels but contributed less to the odours. These included furan-like compounds originating from the smoking, spoilage compounds like ethanol, 3-methyl-1-butanol, 2-butanone, and acetic acid along with oxidatively derived compounds like 1-penten-3-ol, hexanal, nonanal and decanal. Partial least square regression models based on data from storage studies of cold smoked salmon from Iceland and Norway verified that selected key volatile compounds performed better as predictors to explain variation in sensory attributes (smoked, sweet/sour rancid and off odour and flavour) than traditional chemical and microbial variables. PMID- 26054281 TI - Discrimination of teas with different degrees of fermentation by SPME-GC analysis of the characteristic volatile flavour compounds. AB - As tea is traded all over the world, it is necessary for both customs officers and business investigators to develop an easy and reliable method to discriminate teas from each other. A total of 56 kinds of various green, Oolong, and black teas were collected from different countries and markets, and their catechin contents and volatile flavour compounds (VFC) were compared by analyses, using HPLC and solid-phase microextraction-gas chromatograph (SPME-GC). It was found that neither total catechin nor individual catechin contents in green and Oolong teas were significantly different among the samples investigated, but the fermentation processes altered the profiles of tea VFC. Because many of the individual VFC did not change in response to the fermentation levels, several VFC in combination might be more reliable than a single compound to identify broader ranges of teas. A total concentration of five VFC, trans-2-hexenal, benzaldehyde, methyl-5-hepten-2-one, methyl salicylate, and indole, was shown to be able to discriminate clearly unfermented and fermented teas, while that of trans-2 hexenal and methyl salicylate together supplied an index to differentiate semi- and fully-fermented teas. In addition, the SPME-GC analysis was also able to distinguish real jasmine teas from fake jasmine teas based on the disappearance of some grassy/green odorants. PMID- 26054282 TI - GC-MS quantification of fatty acid profile including trans FA in the locally manufactured margarines of Pakistan. AB - Ten margarine brands of Pakistan were analyzed for their fatty acid composition with emphasis on trans fatty acids (TFA) using GC-MS. Saturated, cis monounsaturated and polyunsaturated fatty acids were present at 24.2-58.1, 5.7 35.4 and 3.8-37.4% of total fatty acids, respectively. Among the saturated fatty acids, palmitic acid (16.9-33.8%) was dominant in all analyzed margarine brands and its higher amount indicates that palm oil was a major contributor in the margarine manufacturing. Among samples tested only one contained a low level of TFA (2.2%) while the rest contained very high amounts of TFA (11.5-34.8%) which clearly shows that hydrogenated oils were used in the formulation of margarines. Fatty acid profiles demonstrated that all samples belong to the hard margarine category containing high amounts of trans and saturated fatty acids which is an alarming issue for the health of consumers. PMID- 26054283 TI - Determination of oxytetracycline in tomatoes by HPLC using fluorescence detection. AB - An analytical method for the determination of oxytetracycline (OTC) in tomatoes was developed and validated. Liquid-liquid extraction (LLE) and a solid-phase extraction (SPE) were used for sample preparation. Reversed-phase high performance liquid chromatography (RP-HPLC) using a C18 column and a mobile phase containing MeOH: calcium chloride, disodium ethylenediaminetetraacetate (EDTA) and sodium acetate, pH 7.3 (30:70, v/v), with fluorescence detection at 390nm excitation and 512nm emission, was used for separation and quantitation of OTC. The method was validated through the following performance criteria: linearity and linear range, sensitivity, selectivity, intra-day and inter-day precision, detection and quantitation limits and accuracy. Limit of quantitation show that the method developed is suitable for the determination of OTC at a level below the maximum residue limits established by the Brazilian legislations (250MUgkg( 1)). Of 40 samples analyzed, none contained OTC above the limit of quantitation. PMID- 26054284 TI - Characterisation of anthocyanins in red cabbage using high resolution liquid chromatography coupled with photodiode array detection and electrospray ionization-linear ion trap mass spectrometry. AB - The aim of this work was to analyse and tentatively identify anthocyanin species in red cabbage using HPLC/DAD-ESI/Qtrap MS. The extraction was realized by using a pressurized liquid technique and the separation of the pigments was achieved by a high resolution liquid chromatography system with a 1.8MUm particles C-18 column. Photodiode array detection was employed to determine the UV/Vis spectral characteristic of the pigments. Electrospray ionization-linear ion trap mass spectrometry allowed the specific determination of the fragmentation patterns of the anthocyanins, by performing different ion scan modes. Twenty four anthocyanins were separated and identified, all having cyanidin as aglycon, represented as mono- and/or di-glycoside, and acylated, or not, with aromatic and aliphatic acids. Nine anthocyanins were identified for the first time in red cabbage. PMID- 26054285 TI - Changes in free-radical scavenging ability of kombucha tea during fermentation. AB - Kombucha tea is a fermented tea beverage produced by fermenting sugared black tea with tea fungus (kombucha). Free-radical scavenging abilities of kombucha tea prepared from green tea (GTK), black tea (BTK) and tea waste material (TWK) along with pH, phenolic compounds and reducing power were investigated during fermentation period. Phenolic compounds, scavenging activity on DPPH radical, superoxide radical (xanthine-xanthine oxidase system) and inhibitory activity against hydroxyl radical mediated linoleic acid oxidation (ammonium thiocyanate assay) were increased during fermentation period, whereas pH, reducing power, hydroxyl radical scavenging ability (ascorbic acid-iron EDTA) and anti-lipid peroxidation ability (thiobarbituric assay) were decreased. From the present study, it is obvious that there might be some chances of structural modification of components in tea due to enzymes liberated by bacteria and yeast during kombucha fermentation which results in better scavenging performance on nitrogen and superoxide radicals, and poor scavenging performance on hydroxyl radicals. PMID- 26054286 TI - Analysis of azaarenes in pan fried meat and its gravy by liquid chromatography with fluorescence detection. AB - A method for analysis of six azaarenes (benzo[h]quinoline, benzo[a]acridine, benzo[c]acridine, dibenzo[a,c]acridine, dibenzo[a,j]acridine and dibenzo[a,h]acridine) in thermally treated high-protein food has been described. The clean-up procedure used based on alkaline hydrolysis, tandem solid phase extraction on columns filled with Extrelut - diatomaceous earth and cation exchanger (propyl sulfonic acid), enabled a selective isolation of carcinogenic compounds belonging to benzoacridines and dibenzoacridines from samples of cooked meat and its gravy. The isolated fractions of aza-PAHs were analysed by high performance liquid chromatography with fluorescence detection. The detection limits for the azaarenes were between 0.0001ng and 0.005ng loaded on column. The recoveries for the four-ring and five-ring azaarenes were from 55% to 67%. Two types of dishes prepared from pork by pan-frying were investigated. Total contents of the benzoacridines and dibenzoacridines determined in cooked meat were 1.57 and 2.50ng/g in collar and chop samples, respectively; their gravies contained 0.34 and 0.59ng of these azaarenes per g of cooked meat. PMID- 26054287 TI - Sterigmatocystin presence in typical Latvian grains. AB - Ninety five samples of different Latvian grains (wheat, buckwheat, barley, oats and rye) from the year 2006 and 120 samples from the year 2007 were analyzed for Aspergillus ssp. mycotoxin-sterigmatocystin (STC) content. 13.7% of the analyzed 2006 year samples were positive for STC with the concentration levels ranging from <0.7 to 83MUg/kg and 35% of the analyzed 2007 year samples were positive for STC with the concentration levels ranging from <1 to 47MUg/kg. A previously developed sensitive LC - Electrospray Positive Ionization - MS/MS method was applied for the analysis of STC in grains. Method includes sample extraction with acetonitrile/water solution, solid phase extraction (SPE) on Strata X SPE column, separation on reversed phase C18 column and STC detection by LC-MS/MS. PMID- 26054289 TI - The Students' Perceptions of School Success Promoting Strategies Inventory (SPSI): development and validity evidence based studies. AB - Students' perceptions about school success promotion strategies are of great importance for schools, as they are an indicator of how students perceive the school success promotion strategies. The objective of this study was to develop and analyze the validity evidence based of The Students' Perceptions of School Success Promoting Strategies Inventory (SPSI), which assesses both individual students' perceptions of their school success promoting strategies, and dimensions of school quality. A structure of 7 related factors was found, which showed good adjustment indices in two additional different samples, suggesting that this is a well-fitting multi-group model (p < .001). All scales presented good reliability values. Schools with good academic results registered higher values in Career development, Active learning, Proximity, Educational Technologies and Extra-curricular activities (p < .05). SPSI showed to be adequate to measure within-schools (students within schools) dimensions of school success. In addition, there is preliminary evidence for its adequacy for measuring school success promotion dimensions between schools for 4 dimensions. This study supports the validity evidence based of the SPSI (validity evidence based on test content, on internal structure, on relations to other variables and on consequences of testing). Future studies should test for within- and between level variance in a bigger sample of schools. PMID- 26054290 TI - Outcomes of Transfemoral Transcatheter Aortic Valve Implantation in Patients With Previous Coronary Bypass. AB - Patients with previous coronary artery bypass grafting (CABG) are considered to be at increased perioperative risk for a redo cardiac operation. In the era of transcatheter aortic valve implantation (TAVI), these patients constitute a considerable portion of those with severe aortic stenosis referred for TAVI. We evaluated the impact of previous CABG on transfemoral TAVI outcomes. Patients with severe symptomatic aortic stenosis (n = 515) who underwent transfemoral TAVI were divided according to the presence of history of CABG. Patients with previous valvular surgery were excluded (n = 12). TAVI clinical end points and adverse events were considered according to the Valve Academic Research Consortium 2 definitions. Survival was estimated using Cox regression models at the enter mode with the dependent variable defined as all-cause mortality. Of the total 503 patients who underwent TAVI, 91 (18.1%) had previous CABG. At baseline, patients with previous CABG were younger (80.8 vs 83.1 years, p <0.001), mostly men (85% vs 35%, p <0.001), had more cardiac and vascular co-morbidities, higher mean logistic EuroSCORE (32.8 vs 22; p <0.001), lower ejection fraction (53% vs 56%, p <0.001), and lower AV gradients and larger valve area. At a mean follow-up of 636 days, the overall Valve Academic Research Consortium 2-adjudicated end points did not differ. No differences in mortality were observed at 30 days, 6 months, and 1 year after TAVI (hazard ratio 1.34, p = 0.55, Cox regression). We conclude that patients with previous CABG who underwent TAVI do not have increased risk of periprocedural complications or mortality, although having distinct clinical features compared with the total TAVI population. PMID- 26054291 TI - High-performance organic field-effect transistors based on single-crystalline microribbons of a two-dimensional fused heteroarene semiconductor. AB - A novel two-dimensional organic semiconductor material [1]benzothieno[3,2 b][1]benzothieno[2,1-b:3,4-b':6,5-b'':7,8-b''']tetra(benzothiophene) (BTBTTBT) which largely extends the scope of the pi-conjugated framework of heteroarene through "H" configuration was synthesized and its thermal, optical and electrochemical properties were investigated. This 2D molecule enables the easy growth of single-crystalline microribbons by the physical vapor transport method, which were evidenced by XRD, SEM and TEM. The single-crystalline OFET devices were fabricated based on the individual BTBTTBT microribbon and the remarkable high mobility of 17.9 cm(2) V(-1) s(-1) and on/off ratios of over 10(7) could be achieved. PMID- 26054292 TI - Antimicrobial susceptibility and oxymino-beta-lactam resistance mechanisms in Salmonella enterica and Escherichia coli isolates from different animal sources. AB - The impact of extended-spectrum beta-lactamases (ESBLs) and plasmid-mediated AmpC beta-lactamases (PMAbetas) of animal origin has been a public health concern. In this study, 562 Salmonella enterica and 598 Escherichia coli isolates recovered from different animal species and food products were tested for antimicrobial resistance. Detection of ESBL-, PMAbeta-, plasmid-mediated quinolone resistance (PMQR)-encoding genes and integrons was performed in isolates showing non-wild type phenotypes. Susceptibility profiles of Salmonella spp. isolates differed according to serotype and origin of the isolates. The occurrence of cefotaxime non-wild-type isolates was higher in pets than in other groups. In nine Salmonella isolates, blaCTX-M (n = 4), blaSHV-12 (n = 1), blaTEM-1 (n = 2) and blaCMY-2 (n = 2) were identified. No PMQR-encoding genes were found. In 47 E. coli isolates, blaCTX-M (n = 15), blaSHV-12 (n = 2), blaCMY-2 (n = 6), blaTEM type (n = 28) and PMQR-encoding genes qnrB (n = 2), qnrS (n = 1) and aac(6')-Ib cr (n = 6) were detected. To the best of our knowledge, this study is the first to describe the presence of blaCMY-2 (n = 2) and blaSHV-12 (n = 1) genes among S. enterica from broilers in Portugal. This study highlights the fact that animals may act as important reservoirs of isolates carrying ESBL-, PMAbeta- and PMQR encoding genes that might be transferred to humans through direct contact or via the food chain. PMID- 26054294 TI - The unholy trinity: The Dark Triad, coercion, and Brunswik-Symmetry. AB - Psychopathy, Narcissism, and Machiavellianism (the Dark Triad) have each been hypothesized as predictors of socially deviant behavior including sexual coercion, but the three traits also covary significantly with one another. The purpose of this study was to examine several alternative Multisample Structural Equation Models (MSEMs) exploring the relations between the Dark Triad and Sexually Coercive Behavior, testing whether any or all of the three specific "Dark Personality" traits uniquely contributed to predicting sexually coercive behavior. Self-report questionnaires measuring Primary and Secondary Psychopathy, Narcissism, Machiavellianism, and Sexually Coercive Behavior were administered to a sample of undergraduates. The relative fit of each of the MSEMs to the data was examined by means of hierarchically nested model comparisons. The most parsimonious yet explanatory model identified was one in which a single common factor composed of the three Dark Triad indicators explained the relationships among the Dark Triad traits and Sexually Coercive Behavior without any direct contributions from the specific Dark Triad indicators. Results indicate that the three Dark Triad traits, controlling for the common factor, do not differentially predict Sexually Coercive Behavior. These results are interpreted with respect to the principle of Brunswik-Symmetry. PMID- 26054293 TI - A novel cysteine desulfurase influencing organosulfur compounds in Lentinula edodes. AB - Organosulfur compounds are the basis for the unique aroma of Lentinula edodes, and cysteine sulfoxide lyase (C-S lyase) is the key enzyme in this trait. The enzyme from Alliium sativum has been crystallized and well-characterized; however, there have been no reports of the characterization of fungi C-S lyase at the molecular level. We identified a L. edodes C-S lyase (Lecsl), cloned a gene of Csl encoded Lecsl and then combined modeling, simulations, and experiments to understand the molecular basis of the function of Lecsl. Our analysis revealed Lecsl to be a novel cysteine desulfurase and not a type of cysteine sulfoxide lyase. The pyridoxal-5-phosphate (PLP) molecule bonded tightly to Lecsl to form a Lecsl-PLP complex. Moreover, the Lecsl had one active center that served to bind two kinds of substrates, S-methyl-L-cysteine sulfoxide and L-cysteine, and had both cysteine sulfoxide lyase and cysteine desulfurase activity. We found that the amino acid residue Asn393 was essential for the catalytic activity of Lecsl and that the gene Csl encoded a novel cysteine desulfurase to influence organosulfur compounds in L. edodes. Our results provide a new insight into understanding the formation of the unique aroma of L. edodes. PMID- 26054295 TI - Cellulose gel dispersion: From pure hydrogel suspensions to encapsulated oil-in water emulsions. AB - Cellulose hydrogel particles were fabricated from molecularly-dissolved cellulose/IL solutions. The characteristics of the formed hydrogels (cellulose content, particles' size and porosity) were determined as a function of cellulose concentration in the precursor solutions. There is a significant change in the hydrogel structure when the initial cellulose solution concentration increases above about 7-9%wt. These changes include increase of the cellulose content in the hydrogel, and decrease in its pore size. The finest cellulose particle dispersions can be obtained using low concentration cellulose/IL solutions (cellulose concentration in dispersion less than 2%wt.) or hydrogels (concentration less than 1%wt.) in a dispersing medium consisting of IL with no more than 20%wt. water. Stable paraffin oil-in-water emulsions are achieved by mixing oil and water with cellulose/IL solutions. The optimal conditions for obtaining the finest particles (about 20MUm in diameter) are attained using cellulose solutions of concentration between 0.7 and 4%wt. at temperature of 70 degrees C and oil/cellulose mass ratios between 1 and 1.5. PMID- 26054296 TI - Low bilirubin levels are an independent risk factor for diabetic retinopathy and nephropathy in Japanese patients with type 2 diabetes. PMID- 26054297 TI - Interpreting physicochemical experimental data sets. AB - With the wealth of experimental physicochemical data available to chemoinformaticians from the literature, commercial, and company databases an increasing challenge is the interpretation of such datasets. Subtle differences in experimental methodology used to generate these datasets can give rise to variations in physicochemical property values. Such methodology nuances will be apparent to an expert experimentalist but not necessarily to the data analyst and modeller. This paper describes the differences between common methodologies for measuring the four most important physicochemical properties namely aqueous solubility, octan-1-ol/water distribution coefficient, pK(a) and plasma protein binding highlighting key factors that can lead to systematic differences. Insight is given into how to identify datasets suitable for combining. PMID- 26054299 TI - Postural effects on pulmonary gas exchange abnormalities in severe obesity before and after bariatric surgery. AB - BACKGROUND: We hypothesized that in morbid obesity, pulmonary gas exchange abnormalities will worsen when supine and that bariatric surgery (BS) will mitigate this effect. METHODS: Gas exchange was investigated in 19 morbidly obese and 8 non-obese, age-matched control females, spontaneously breathing ambient air, both upright and supine, before and one year after BS. RESULTS: In control non-obese individuals, no postural changes in arterial blood gases (ABGs) were observed. While obese subjects had more altered PaO2, SaO2 and AaPO2 values than controls (P<0.05 each) when upright, the values unexpectedly remained unchanged when supine. This was also the case in the subset of 6 normoxemic obese but the remaining 13 hypoxemic individuals actually improved ABGs when supine: PaO2 (by +2.7+/-1.3 mmHg, P=0.06), SaO2 (by +1.5+/-0.6%), pH (by +0.01+/-0.01) and AaPO2 (by -3.4+/-1.4 mmHg); and cardiac output increased (by +0.4+/-0.2 L.min-1) (P<0.05 each). After BS, PaO2 (from 75.5+/-2.4 to 89.4+/-2.4 mmHg), AaPO2 (from 27.0+/-2.0 to 15.4+/-2.1 mmHg) (P<0.05 each), and pulmonary gas exchange were improved compared to before BS when upright, but ABGs worsened when supine (PaO2, by -4.6+/-1.7 mmHg; AaPO2, by +4.2+/-1.6 mmHg) (P<0.05 each). CONCLUSIONS: Before BS, ABGs are not altered in normoxemic obese subjects moving from upright to supine, even improving in those with hypoxemia when supine. After successful BS, pulmonary gas exchange improved when upright in all subjects but ABGs deteriorated when supine. However, the important clinical observation is the lack of gas exchange deterioration when supine, which may have implications for critical care and anesthesia settings. PMID- 26054298 TI - Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells. AB - Recruitment of monocytes in the liver is a key pathogenic feature of hepatic inflammation in nonalcoholic steatohepatitis (NASH), but the mechanisms involved are poorly understood. Here, we studied migration of human monocytes in response to supernatants obtained from liver cells after inducing lipoapoptosis with saturated free fatty acids (FFA). Lipoapoptotic supernatants stimulated monocyte migration with the magnitude similar to a monocyte chemoattractant protein, CCL2 (MCP-1). Inhibition of c-Jun NH2-terminal kinase (JNK) in liver cells with SP600125 blocked migration of monocytes in a dose-dependent manner, indicating that JNK stimulates release of chemoattractants in lipoapoptosis. Notably, treatment of supernatants with Apyrase to remove ATP potently inhibited migration of THP-1 monocytes and partially blocked migration of primary human monocytes. Inhibition of the CCL2 receptor (CCR2) on THP-1 monocytes with RS102895, a specific CCR2 inhibitor, did not block migration induced by lipoapoptotic supernatants. Consistent with these findings, lipoapoptosis stimulated pathophysiological extracellular ATP (eATP) release that increased supernatant eATP concentration from 5 to ~60 nM. Importantly, inhibition of Panx1 expression in liver cells with short hairpin RNA (shRNA) decreased supernatant eATP concentration and inhibited monocyte migration, indicating that monocyte migration is mediated in part by Panx1-dependent eATP release. Moreover, JNK inhibition decreased supernatant eATP concentration and inhibited Pannexin1 activation, as determined by YoPro-1 uptake in liver cells in a dose-dependent manner. These results suggest that JNK regulates activation of Panx1 channels, and provide evidence that Pannexin1-dependent pathophysiological eATP release in lipoapoptosis is capable of stimulating migration of human monocytes, and may participate in the recruitment of monocytes in chronic liver injury induced by saturated FFA. PMID- 26054300 TI - Health-related quality of life of children with attention-deficit/hyperactivity disorder versus children with diabetes and healthy controls. AB - The impact of attention-deficit/hyperactivity disorder (ADHD) on health-related quality of life (HRQoL) is reported to be similar to that of other mental health and physical disorders. In this cross-sectional study, we hypothesized that children with ADHD and children with type 1 diabetes mellitus (T1DM) would have significantly worse HRQoL compared with healthy children, and that better clinical status in ADHD and T1DM would be associated with better HRQoL. Children were recruited from three outpatient services in Scotland. Responses to two frequently used validated HRQoL instruments, the Paediatric Quality of Life Inventory (PedsQL) and Child Health and Illness Profile-child edition (CHIP-CE), were obtained from parents/carers and children (6-16 years) with/without ADHD or T1DM. Child and parent/carer-completed HRQoL measurements were evaluated for 213 children with ADHD, 58 children with T1DM and 117 healthy children (control group). Significantly lower self and parent/carer ratings were observed across most PedsQL (P < 0.001) and CHIP-CE (P < 0.05) domains (indicating reduced HRQoL) for the ADHD group compared with the T1DM and control groups. Parent/carer and child ratings were significantly correlated for both measures of HRQoL (PedsQL total score: P < 0.001; CHIP-CE all domains: P < 0.001), but only with low-to moderate strength. Correlation between ADHD severity and HRQoL was significant with both PedsQL and CHIP-CE for all parent/carer (P < 0.01) and most child (P < 0.05) ratings; more ADHD symptoms were associated with poorer HRQoL. These data demonstrate that ADHD has a significant impact on HRQoL (as observed in both parent/carer and child ratings), which seems to be greater than that for children with T1DM. PMID- 26054301 TI - Secondary total vagina reconstruction after total pelvic exenteration using the transverse musculocutaneous gracilis flap. PMID- 26054302 TI - Comparison of perioperative outcomes of autologous breast reconstruction surgeries. PMID- 26054303 TI - Development of nNOS-positive neurons in the rat sensory ganglia after capsaicin treatment. AB - To gain a better understanding of the neuroplasticity of afferent neurons during postnatal ontogenesis, the distribution of neuronal nitric oxide synthase (nNOS) immunoreactivity was studied in the nodose ganglion (NG) and Th2 and L4 dorsal root ganglia (DRG) from vehicle-treated and capsaicin-treated female Wistar rats at different ages (10-day-old, 20-day-old, 30-day-old, and two-month-old). The percentage of nNOS-immunoreactive (IR) neurons decreased after capsaicin treatment in all studied ganglia in first 20 days of life, from 55.4% to 36.9% in the Th2 DRG, from 54.6% to 26.1% in the L4 DRG and from 37.1% to 15.0% in the NG. However, in the NG, the proportion of nNOS-IR neurons increased after day 20, from 11.8% to 23.9%. In the sensory ganglia of all studied rats, a high proportion of nNOS-IR neurons bound isolectin B4. Approximately 90% of the sensory nNOS-IR neurons bound to IB4 in the DRG and approximately 80% in the NG in capsaicin-treated and vehicle-treated rats. In 10-day-old rats, a large number of nNOS-IR neurons also expressed TrkA, and the proportion of nNOS(+)/TrkA(+) neurons was larger in the capsaicin-treated rats compared with the vehicle treated animals. During development, the percentage of nNOS(+)/TrkA(+) cells decreased in the first month of life in both groups. The information provided here will also serve as a basis for future studies investigating mechanisms of sensory neuron development. PMID- 26054304 TI - Temporary prenatal hyperglycemia leads to postnatal neuronal 'glucose-resistance' in the chicken hypothalamus. AB - Prenatal exposures may have a distinct impact for long-term health. Exposure to maternal 'diabesity' during pregnancy increases offspring 'diabesity' risk, e.g. by malprogramming the central nervous regulation of body weight, food intake and metabolism. Critical mechanisms and concrete disrupting factors still remain unclear. Due to the independent development, from the mother, the chicken embryo could provide a valuable model to distinctively establish causal factors. Aim of this study was to determine effects of temporary prenatal hyperglycemia on postnatal hypothalamic neuronal glucose sensitivity in the chicken. To induce hyperglycemia in chicken embryos, 0.5 ml glucose solution (concentration 30 mmol/l) were daily administered via catheter into a vessel of the chorioallantoic egg membrane from days 14 to 17 of incubation. On day 21 of postnatal age, body weight, body fat content, blood glucose, neuroelectrophysiological glucose sensitivity as well as glucose transporter expression were determined in hypothalamic brain slices. No significant changes in morphometric and metabolic parameters were observed. However, strongly decreased neuronal glucose sensitivity and glucose transporter expression occurred, indicating prenatally acquired hypothalamic 'glucose-resistance'. In conclusion, temporary late prenatal hyperglycemia induces lasting changes in central glucose sensing. The prenatally glucose-treated chicken provides a valuable new model for investigating early central nervous origins of 'diabesity' and related disorders. PMID- 26054305 TI - Brain activity during source memory retrieval in young, middle-aged and old adults. AB - We investigated neurofunctional changes associated with source memory decline across the adult life span using functional magnetic resonance imaging (fMRI). Young, middle-aged and old adults carried out a natural/artificial judgment of images of common objects that were randomly presented in one of the quadrants of the screen. At retrieval, the images were displayed at the center of the screen and the participants judged whether each image was new or old and, if old, they indicated in which quadrant of the screen the image had originally been presented. Comparing the items associated with correct versus incorrect source judgments revealed that no regions showed greater activity in young adults than in middle-aged adults; however, in young and middle-aged adults the activity in the left hippocampus and left anterior temporal cortex was of greater magnitude than in the older adults. Several regions also exhibited greater activity in young adults than in old adults. These results suggest that in middle age the recollection neural network, assessable by fMRI, is still preserved. PMID- 26054306 TI - MoS2 ultrathin nanosheets obtained under a high magnetic field for lithium storage with stable and high capacity. AB - A new strategy, namely a high magnetic field-induced method, has been designed to enhance lithium storage properties of MoS2 ultrathin nanosheets. The MoS2 ultrathin nanosheets obtained under 8 T exhibit improved cycling stability at high currents, better rate performance and reduced electrochemical impedance, compared to MoS2 ultrathin nanosheets obtained without a high magnetic field. PMID- 26054307 TI - Diffusion on networked systems is a question of time or structure. AB - Network science investigates the architecture of complex systems to understand their functional and dynamical properties. Structural patterns such as communities shape diffusive processes on networks. However, these results hold under the strong assumption that networks are static entities where temporal aspects can be neglected. Here we propose a generalized formalism for linear dynamics on complex networks, able to incorporate statistical properties of the timings at which events occur. We show that the diffusion dynamics is affected by the network community structure and by the temporal properties of waiting times between events. We identify the main mechanism--network structure, burstiness or fat tails of waiting times--determining the relaxation times of stochastic processes on temporal networks, in the absence of temporal-structure correlations. We identify situations when fine-scale structure can be discarded from the description of the dynamics or, conversely, when a fully detailed model is required due to temporal heterogeneities. PMID- 26054308 TI - To the Editor--Myocardial tissue characterization by cardiovascular magnetic resonance. PMID- 26054309 TI - Assessing the appropriateness of ICD use "appropriately". PMID- 26054310 TI - The Concealment of Significant Pelvic Injuries on Computed Tomography Evaluation by Pelvic Compression Devices. AB - BACKGROUND: Fractures of the pelvis and acetabulum are relatively rare, with a reported incidence of 3% to 8% of all adult fractures, but occur in approximately 20% of all polytrauma cases. They have high associated morbidity (40% to 50%) and mortality (5% to 30%). It is recommended that an external compression splint be applied in the presence of a suspected pelvic fracture before transfer and definitive investigation and management. CASE REPORT: Two cases are presented in which these recommendations were met and the patients underwent computed tomography (CT) scanning upon arrival to the emergency department at a major trauma center with the pelvic binder in situ. In both these cases, CT scanning failed to identify a significant pelvic injury, which was concealed by the pelvic external compression belt. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: When there is high clinical indication of pelvic injury, whether related to mechanism of injury or clinical findings, despite a CT scan where no bony injury is identified, obtaining plain pelvic x-ray studies out of the pelvic compression device to avoid overlooking or neglecting a significant pelvic injury would be prudent. PMID- 26054311 TI - Renal Agenesis: A Bedside Sonographic Finding in a Patient with Flank Pain. PMID- 26054312 TI - Ultrasound Diagnosis of Adult Intussusception. PMID- 26054313 TI - Pilot Validation of a Brief Screen Tool for Substance Use Detection in Emergency Care. AB - BACKGROUND: Screening and brief intervention for substance use in health care systems is recommended to identify and intervene with patients who abuse alcohol and other substances. However, there is limited research on the utility of short, single-item questions to identify illicit substance users. OBJECTIVE: Pilot validation of two single-item screening questions to detect illicit substance use, one for marijuana and one for other illicit drugs. The goal was to identify sensitive, time-efficient screening questions that can be easily integrated into busy health care settings. METHODS: A cross-sectional design was used. At intake, along with questions for tobacco and alcohol, nurses administered two brief screen questions to adult patients seen in designated areas in a large urban medical center. After patients were triaged to rooms, health educators (blind to brief screen responses) administered the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) as the reference standard. RESULTS: On the ASSIST, 14% and 9% of participants reported risky marijuana and illicit (nonmarijuana) drug use, respectively. Sensitivity values for the marijuana and street drug questions were 72% (95% confidence interval [CI] 67% to 78%) and 40% (95% CI 32% to 48%), respectively. Specificity values for the marijuana and street drug questions were 96% (95% CI 95% to 97%) and 99% (95% CI 98% to 99%), respectively. Values differed minimally as a function of patient characteristics. CONCLUSIONS: It is important to use validated questions to identify substance misuse so that individuals are not missed in the screening process. It is the possible that administration protocols play a role in detection rates. Future research is needed to identify easy-to-administer drug use screening questions. PMID- 26054316 TI - Location of motor fibers within branches of the recurrent laryngeal nerve with extralaryngeal terminal bifurcation; Functional identification by intraoperative neuromonitoring. AB - BACKGROUND: Extralaryngeal terminal bifurcation (ETB) of the recurrent laryngeal nerve (RLN) is an anatomic variation that threatens the safety of thyroid operation. Therefore, it is important to identify motor function in nerve branches to preserve appropriate motor activity. Intraoperative neuromonitoring (IONM) is an accepted procedure to identify motor function of the RLN. METHODS: We established the operative anatomy of RLNs with ETB in 47 patients. The main trunk, bifurcation point, and the branches were identified and exposed completely during thyroid operation. The location of motor fibers within nerve branches was investigated by identifying motor function via IONM. Wave amplitudes were recorded after electrophysiologic stimulation. RESULTS: A total of 61 RLNs had ETBs with anterior and posterior branches. Bifurcation occurred early along the pre-arterial (proximal) segment in 13% of bifid RLNs. IONM showed motor function in all anterior branches. IONM identified motor activity in 4 (18%) posterior branches of 22 right, 3 (8%) posterior branches of 39 left, and 7 (12%) posterior branches of all 61 RLNs with ETB. The rate of recorded wave amplitudes of motor function in seven posterior branches was between 14 and 78% of those of corresponding anterior branches. CONCLUSION: In the RLN, the anterior branch always and the posterior branch uncommonly contain motor fibers. Wave amplitude analysis showed that motor function in the posterior branch is weaker than that in the anterior branch. On the basis of the location of motor fibers in both branches, total exposure and preservation of anatomy and function of all branches of the RLN is mandatory for complication-free thyroid surgery. Electrophysiologic testing may be as an important adjunct to visualization of the nerve with anatomic variation. PMID- 26054317 TI - Adherence to surgical antibiotic prophylaxis remains a challenge despite multifaceted interventions. AB - BACKGROUND: Adherence to prophylactic antibiotics guidelines is challenging and poorly documented. We hypothesized that a multiphase, multifaceted quality improvement initiative would engage relevant stakeholders, address known barriers to adoption, and improve overall adherence. METHODS: From 2011 to 2014, a series of interventions were introduced in the pediatric operating rooms. After each interventional period, prospective assessments were performed to record the antibiotic type, dose, timing, and redosing according to the guidelines. Perioperative factors that may influence guideline adherence were analyzed. Spearman's rank correlation, analysis of variance, and chi(2) tests were performed. RESULTS: A total of 1,052 operations were observed, and 629 (60%) required prophylactic antibiotics. Adherence to all 4 guideline components remained unchanged (54-55%, P = .38). Redosing significantly improved (7-53%, P = .02), but correct type decreased (98-70%, P < .01). The percentage of cases in which only one antibiotic guideline component was missed remained unchanged (35 34%, P = .46). Adherence to guidelines was not significantly associated with American Society of Anesthesiologists class, surgical specialty, patient weight, anesthesia provider, or surgical wound class. CONCLUSION: Despite multiple interventions to improve antibiotic prophylaxis, overall adherence did not improve. Most interventions were directed at the point of administration in the operating room; future implementation strategies should focus on the perioperative setting. PMID- 26054318 TI - Gastroesophageal reflux disease in the obese: Pathophysiology and treatment. AB - Obesity is a condition that has increased all over the world in the last 3 decades. Overweight and gastroesophageal reflux disease (GERD) are related. GERD may have different causative factors in the obese compared with lean individuals. This review focuses on the proper treatment for GERD in the obese based on its pathophysiology. Increased abdominal pressure may play a more significant role in obese subjects with GERD than the defective esophagogastric barrier usually found in nonobese individuals. A fundoplication may be used to treat GERD in these individuals; however, outcomes may be not as good as in nonobese patients and it does not act on the pathophysiology of the disease. All bariatric techniques may ameliorate GERD symptoms owing to a decrease in abdominal pressure secondary to weight loss. However, some operations may lead to a disruption of natural anatomic antireflux mechanisms or even lead to slow gastric emptying and/or esophageal clearance and thus be a refluxogenic procedure. Roux-en-Y gastric bypass decreases both acid and bile reflux from the stomach into the esophagus. On the other hand, gastric banding is a refluxogenic operation, and sleeve gastrectomy may show different outcomes based on the anatomy of the gastric tube. PMID- 26054319 TI - Usefulness of operative planning based on 3-dimensional CT cholangiography for biliary malignancies. AB - BACKGROUND: The complexity of hepatic hilar anatomy is an obstacle to precise diagnosis of tumor spread and appropriate operative planning for biliary malignancies. Three-dimensional (3D) cholangiography and angiography may overcome this obstacle and facilitate curative resection. The objective of this study was to evaluate the impact of 3D CT cholangiography on operative planning and outcomes of biliary malignancies. METHODS: From 2009 to 2014, 3DCT cholangiography was performed on 49 patients with biliary malignancies requiring major hepatic resection and extrahepatic bile duct resection. The 3D cholangiogram was merged with 3D angiography and portography to create an all-in one 3D image of the hepatic hilum. The cutting line of the bile duct and the type of liver resection were determined based on the spatial relationship between tumor spread and the landmark vessels. The necessity of vascular reconstruction was also evaluated. Preoperative imaging and operative findings were compared. Operative curability was compared with that of the historical cohort before the introduction of 3D cholangiography. RESULTS: Histologic examination of the bile duct stump showed a negative margin in 39 (80%), carcinoma in situ in 7 (14%), and invasive cancer (IC) in 3 patients (6%) on the first cutting. The IC-free rate (94%) on the first cutting was superior to that in the historical cohort (80%; P = .02). The necessity for portal and arterial reconstruction was predicted with 98 and 94% accuracy, respectively. CONCLUSION: We found 3D cholangiography to provide accurate information about hilar anatomy and plays a role in facilitating adequate operative planning. PMID- 26054320 TI - TRPA1 mediates the effects of hypothermia on the monocyte inflammatory response. AB - INTRODUCTION: Hypothermia is a well-known risk factor for postoperative complications because it prolongs the monocyte inflammatory response. The purpose of this study was to investigate whether temperature-activated ion channels (transient receptor protein channels [TRP] A1 and V1) mediate the effects of temperature on monocytes. METHODS: Primary human monocytes were isolated and stimulated with lipopolysaccharide at 32 degrees C or 39 degrees C. RNA was isolated for analysis of microRNA (miR)-155 expression, and cytokines in the supernatant were measured with an enzyme-linked immunosorbent assay. Specific inhibitors of TRPA1 (HC- 030031) and a specific activator of TRPV1 (capsaicin) were used to block or activate TRPA1 and TRPV1, respectively. Statistical analysis was performed using the Wilcoxon signed-rank test. RESULTS: TRPM8 mRNA was not expressed in primary human monocytes, whereas TRPA1 and TRPV1 were expressed. TRPV1 mRNA expression was suppressed at 32 degrees C but not at 39 degrees C. TRPA1 was induced strongly at 32 degrees C and 39 degrees C. Immunofluorescence microscopy confirmed that monocytes express TRPA1 and TRPV1 on their cell surface. Interleukin-10 secretion was increased by blocking TRPA1 (77.8 +/- 3 2.8 pg/mL) and activating TRPA1 (79.4 +/- 16.1 pg/mL) after 24 hours at 32 degrees C (control 37.4 +/- 17.1 pg/mL, P < .05). At 36 hours, tumor necrosis factor secretion was decreased after TRPA1 blockade (2,321 +/- 439 pg/mL) and TRPV1 activation (2,137 +/- 411 pg/mL) compared with control (2,567 +/ 495 pg/mL, P < .05). Furthermore, miR-155 expression also was suppressed at 24 hours by TRPA1 blockade and TRPV1 activation (both P < .05). Silencing of TRPA1 normalized monocyte IL-10 secretion at 32 degrees C. CONCLUSION: These results demonstrate that hypothermia mediates its effects on monocytes through TRPA1. Blockade of TRPA1 or activation of TRPV1 may be used to modify the effects of hypothermia on the monocyte inflammatory response. PMID- 26054321 TI - Intramuscular and subcutaneous forearm parathyroid autograft hyperplasia in renal dialysis patients: A retrospective cohort study. AB - BACKGROUND: Intramuscular and subcutaneous forearm parathyroid autograft are proved to have compatible short-term outcome. However, long-term clinical courses have not been studied. METHODS: A single-surgeon retrospective cohort study of parathyroid autograft hyperplasia from August 1998 to January 2013 was performed. According to the location of their parathyroid autograft, patients were divided into an Intramuscular group and a Subcutaneous group. Clinical parameters were analyzed to assess the risk factors and clinical course of autograft hyperplasia. RESULTS: There were 888 consecutive patients who underwent total parathyroidectomy with forearm autotransplantation for renal hyperparathyroidism during the period. The median age at the time of total parathyroidectomy with forearm autotransplantation was 54.2 years (range, 12-86) and the median follow up time was 4.0 years (range 0.1-16). Autograftectomy was performed on 29 of 888 patients. The incidence of autograftectomy was 15 of 65 in the Intramuscular group and 14 of 823 in the Subcutaneous group; the incidence of repeated autograftectomy was 4 of 65 in the Intramuscular group and 1 of 823 in the Subcutaneous group. The cumulative frequency of autograftectomy was greater in the Intramuscular group than that in the Subcutaneous group (11.6 vs 3.1% at 6 years, P < .001). The location of the autograft was the only significant factor affecting the autograftectomy frequency (P = .002). The Intramuscular group reoperation patients experienced a longer period between their first operation and the autograftectomy (6.6 vs 3.3 years, P = .003), longer operating times (79 vs 37 minutes, P = .002), and a greater level of pre-autograftectomy systemic intact parathyroid hormone (1,044 vs 559 ng/L, P = .014) than the Subcutaneous group. CONCLUSION: Intramuscular parathyroid autotransplantation results in a high incidence of autograftectomy, repeated autograftectomy, and a high cumulative frequency of autograftectomy. PMID- 26054322 TI - Practice administration training needs of recent general surgery graduates. AB - INTRODUCTION: Practice administration education and experience during surgery residency are variable among residency programs. To better understand these issues, a survey of recent General Surgery residency (GS) graduates was compared with the results from a survey of GS program directors (PD). METHODS: All GS graduates completing residency from 2009 to 2013 (n = 5,512) were surveyed to assess opinions regarding the desire for more instruction during residency in practice administration. General surgeons were defined as those not pursuing fellowship training; specialist surgeons (SS) completed additional training after their GS residency. Separately, all GS residency PDs were surveyed regarding practice administration education in their programs. RESULTS: A total of 3,354 responded to the GS graduate survey (response rate = 61%). GS comprised 26% of the respondents. The vast majority of all respondents desired more training in practice administration. There were no significant differences in the degree to which instruction was desired among GS, SS, residency program type, or current practice setting. The GS PD response rate was 68% (171/252 programs). Only 28% of programs included practice administration in the residency curriculum. CONCLUSION: Practice administration education is highly desired by GS and SS graduates. Our findings indicate a clear need for a curriculum in practice administration during residency. PMID- 26054323 TI - Early impact of the 2011 ACGME duty hour regulations on surgical outcomes. AB - BACKGROUND: In 2011, the Accreditation Council for Graduate Medical Education (ACGME) implemented additional restrictions on resident work hours. Although the impact of these restrictions on the education of surgical trainees has been examined, the effect on patient safety remains poorly understood. METHODS: We used national Medicare Claims data for patients undergoing general (n = 1,223,815) and vascular (n = 475,262) surgery procedures in the 3 years preceding the duty hour changes (January, 2009-June, 2011) and the 18 months thereafter (July, 2011-December, 2012). Hospitals were stratified into quintiles by teaching intensity using a resident to bed ratio. We utilized a difference-in-differences analytic technique, using nonteaching hospitals as a control group, to compare risk-adjusted 30-day mortality, serious morbidity, readmission, and failure to rescue (FTR) rates before and after the duty hour changes. RESULTS: After duty hour reform, no changes were seen in the measured outcomes when comparing teaching with nonteaching hospitals. Even when stratifying by teaching intensity, there were no differences. For example, at the highest intensity teaching hospitals (resident/bed ratio of >= 0.6), mortality rates before and after the duty hour changes were 4.2% and 4.0%, compared with 4.7% and 4.4% for nonteaching hospitals (relative risk [RR], 0.98; 95% CI, 0.89-1.07). Similarly, serious complication (RR, 1.02; 95% CI, 0.98-1.06), FTR (RR, 0.95; 95% CI, 0.87-1.04), and readmission (odds ratio, 1.00; 95% CI, 0.96-1.03) rates were unchanged. CONCLUSION: In Medicare beneficiaries undergoing surgery at teaching hospitals, outcomes have not improved since the 2011 ACGME duty hour regulations. PMID- 26054324 TI - Genome-wide survey and expression analysis of the PUB family in Chinese cabbage (Brassica rapa ssp. pekinesis). AB - U-box proteins are widely distributed among eukaryotic organisms and show a higher prevalence in plants than in other organisms. Plant U-box (PUB) proteins play crucial regulatory roles in various developmental and physiological processes. Previously, 64 and 77 PUB genes have been identified in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), respectively. In this study, 101 putative PUB genes were identified in the Chinese cabbage (Brassica rapa ssp. pekinensis line Chiifu-401-42) genome and compared with other 15 representative plants. By specific protein domains and a phylogenetic analysis, the B. rapa PUB (BrPUB) gene family was subdivided into 10 groups. Localization of BrPUB genes showed an uneven distribution on the ten chromosomes of B. rapa. The orthologous and co-orthologous PUB gene pairs were identified between B. rapa and A. thaliana. RNA-seq transcriptome data of different tissues revealed tissue specific and differential expression profiles of the BrPUBs, and quantitative real-time PCR analysis showed inverse gene expression patterns of the BrPUB-ARMs in response to cold and heat stresses. Altogether, the identification, classification, phylogenetic analysis, chromosome distribution, conserved motifs, and expression patterns of BrPUBs were predicted and analysed. Importantly, this study of BrPUBs provides a rich resource that will aid in the determination of PUB functions in plant development. PMID- 26054325 TI - The Expected Net Present Value of Developing Weight Management Drugs in the Context of Drug Safety Litigation. AB - BACKGROUND: Following withdrawals, failures, and significant litigation settlements, drug product launches in the anti-obesity category slowed despite a large and growing unmet need. Litigation concerns, a more risk-averse regulatory policy, and the difficulty of developing a product with a compelling risk-benefit profile in this category may have limited innovators' expected return on investment and restricted investment in this therapeutic area. OBJECTIVE: The objective of the study was to estimate perceived manufacturer risk associated with product safety litigation and increased development costs vs. revenue expectations on anticipated return on investment and to determine which scenarios might change a manufacturer's investment decision. METHODS: Expected net present value of a weight-management drug entering pre-clinical trials was calculated for a range of scenarios representing evolving expectations of development costs, revenue, and litigation risk over the past 25 years. These three factors were based on published estimates, historical data, and analogs from other therapeutic areas. RESULTS: The main driver in expected net present value calculations is expected revenue, particularly if one assumes that litigation risk and demand are positively correlated. Changes in development costs associated with increased regulatory concern with potential safety issues for the past 25 years likely did not impact investment decisions. CONCLUSIONS: Regulatory policy and litigation risk both played a role in anti-obesity drug development; however, product revenue-reflecting efficacy at acceptable levels of safety-was by far the most important factor. To date, relatively modest sales associated with recent product introductions suggest that developing a product that is sufficiently efficacious with an acceptable level of safety continues to be the primary challenge in this market. PMID- 26054326 TI - Preventing Obesity in the USA: Impact on Health Service Utilization and Costs. AB - BACKGROUND: With more than two-thirds of the US population overweight or obese, the obesity epidemic is a major threat for population health and the financial sustainability of the healthcare service. Whether, and to what extent, effective prevention interventions may offer the opportunity to 'bend the curve' of rising healthcare costs is still an object of debate. OBJECTIVE: This study evaluates the potential economic impact of a set of prevention programmes, including education, counselling, long-term drug treatment, regulation (e.g. of advertising or labelling) and fiscal measures, on national healthcare expenditure and use of healthcare services in the USA. STUDY DESIGN AND METHOD: The study was carried out as a retrospective evaluation of alternative scenarios compared with a 'business as usual' scenario. An advanced econometric approach involving the use of logistic regression and generalized linear models was used to calculate the number of contacts with key healthcare services (inpatient, outpatient, drug prescriptions) and the associated cost. Analyses were carried out on the Medical Expenditure Panel Survey (1997-2010). RESULTS: In 2010, prevention interventions had the potential to decrease total healthcare expenditure by up to $US2 billion. This estimate does not include the implementation costs. The largest share of savings is produced by reduced use and costs of inpatient care, followed by reduced use of drugs. Reduction in expenditure for outpatient care would be more limited. Private insurance schemes benefit from the largest savings in absolute terms; however, public insurance schemes benefit from the largest cost reduction per patient. People in the lowest income groups show the largest economic benefits. CONCLUSION: Prevention interventions aimed at tackling obesity and associated risk factors may produce a significant decrease in the use of healthcare services and expenditure. Savings become substantial when a long-term perspective is taken. PMID- 26054328 TI - Janus subcompartmentalized microreactors. AB - We report on Janus subcompartmentalized assemblies with enzyme loaded liposomes entrapped within a polymer carrier capsule - Janus subcompartmentalized microreactors. The concept is based on the use of Pickering emulsions and the subsequent deposition of interacting liposomes and polymer layers. We demonstrate the adjustment of the size of the Janus domains and the control over the amount of trapped liposomes using multiple liposome deposition steps. The obtained Janus capsosomes feature a distinct liposome domain within a closed polymeric hydrogel shell. The assembly of functional Janus microreactors using trypsin as cargo within the liposomal subcompartments is shown by performing locally confined enzymatic encapsulated catalysis. The presented assemblies with spatial control over the position of their liposomal subunits are a fascinating first step towards artificial cells with polarity. PMID- 26054327 TI - Autonomic Regulation Therapy in Heart Failure. AB - Autonomic regulation therapy (ART) is a rapidly emerging therapy in the management of congestive heart failure secondary to systolic dysfunction. Modulation of the cardiac neuronal hierarchy can be achieved with bioelectronics modulation of the spinal cord, cervical vagus, baroreceptor, or renal nerve ablation. This review will discuss relevant preclinical and clinical research in ART for systolic heart failure. Understanding mechanistically what is being stimulated within the autonomic nervous system by such device-based therapy and how the system reacts to such stimuli is essential for optimizing stimulation parameters and for the future development of effective ART. PMID- 26054329 TI - Intracranial pial fistulas in pediatric population. Clinical features and treatment modalities. AB - PURPOSE: The purpose of the study is to describe the clinical manifestations and treatment modalities of patients having intracranial pial arteriovenous fistulas (PAVFs). METHODS: We retrospectively analyzed the cases of PAVFs from January 2004 to December 2013. Medical charts, diagnostic images, surgical, and endovascular reports were reviewed retrospectively during each of the procedures and follow-up. We recorded patient demographics, clinical presentation, treatment modalities, and outcome. RESULTS: Ten patients with single PAVFs were identified, one of them with multiple holes. The median age was 7.5 years old (20 days to 14 years). Six patients were male (60% of cases). Four PAVFs were localized in the posterior fossa, and six were supratentorial (60%). Two patients had intracranial bleeding, three presented seizures, one was studied for chronic headaches, three manifested by growth retardation, one had hydrocephalus, and one had a congestive heart failure (CHF) and vein of Galen aneurysmal malformation (VGAM). The latter did not improve after embolization and died few days later. Endovascular therapy was used in eight, whereas two patients were surgically managed. Total occlusion of the fistula was achieved in all cases. CONCLUSIONS: PAVF affects pediatric population at different ages with miscellaneous clinical manifestations. Endovascular treatment is safe and effective when the venous side of the fistula can be occluded. PMID- 26054332 TI - Lipid profiles of adipose and muscle tissues in mouse models of juvenile onset of obesity without high fat diet induction: a Fourier transform infrared (FT-IR) spectroscopic study. AB - The current study aims to determine lipid profiles in terms of the content and structure of skeletal muscle and adipose tissues to better understand the characteristics of juvenile-onset spontaneous obesity without high fat diet induction. For the purposes of this study, muscle (longissimus, quadriceps) and adipose (inguinal, gonadal) tissues of 10-week-old male DBA/2J and Berlin fat mouse inbred (BFMI) lines (BFMI856, BFMI860, BFMI861) fed with a standard breeding diet were used. Biomolecular structure and composition was determined using attenuated total reflection Fourier transform (ATR FT-IR) spectroscopy, and muscle triglyceride content was further quantified using high-performance liquid chromatography (HPLC) coupled with an evaporative light scattering detector (ELSD). The results revealed a loss of unsaturation in BFMI860 and BFMI861 lines in both muscles and inguinal adipose tissue, together with a decrease in the hydrocarbon chain length of lipids, especially in the BFMI860 line in muscles, suggesting an increased lipid peroxidation. There was an increase in saturated lipid and triglyceride content in all tissues of BFMI lines, more profoundly in longissimus muscle, where the increased triglyceride content was quantitatively confirmed by HPLC-ELSD. Moreover, an increase in the metabolic turnover of carbohydrates in muscles of the BFMI860 line was observed. The results demonstrated that subcutaneous (inguinal) fat also displayed considerable obesity induced alterations. Taken together, the results revealed differences in lipid structure and content of BFMI lines, which may originate from different insulin sensitivity levels of the lines, making them promising animal models for spontaneous obesity. The results will contribute to the understanding of the generation of insulin resistance in obesity without high fat diet induction. PMID- 26054333 TI - Optical absorption measurements of hydrogen chloride at high temperature and high concentration in the presence of water using a tunable diode laser system for application in pyrohydrolysis non-ferrous industrial process control. AB - A tunable diode laser (TDL) was used to measure hydrogen chloride (HCl) spectra at 5747 cm(-1) (1.74 MUm) and temperatures of 25-950 degrees C in a quartz cell. The purpose was to evaluate the capability of monitoring HCl concentration under pyrohydrolysis conditions using a near-infrared (NIR) laser. These conditions are characterized by 20-40% HCl, 2-40% H2O, and the presence of metal chloride vapors at temperatures of 600-1000 degrees C. Spectral peak area measurements of HCl-N2 mixtures at atmospheric pressure and a path length of 8.1 cm showed linear absorption behavior between concentrations of 5-95% and temperatures of 25-950 degrees C. Results from the addition of 2-40% water (H2O) indicate that the HCl peak area relationships are not affected for temperatures of 350-950 degrees C. Evaporating NiCl2 within the cell did not show spectral interference effects with HCl between 650 and 850 degrees C. The results from this work indicate that a near-infrared optical sensor is capable of measuring high HCl concentrations at high temperatures in the presence of high H2O content during pyrohydrolysis process conditions. PMID- 26054330 TI - Genetic risk of subsequent esophageal cancer in lymphoma and breast cancer long term survival patients: a pilot study. AB - The occurrence of a second primary esophageal carcinoma (EC) in long-term cancer survivors may represent a late effect of previous radio-chemotherapeutic treatment. To identify the genetic factors that could increase this risk, we analyzed nine variants within ERCC1, XPD, XRCC1 and XRCC3 DNA repair pathway genes, and GSTP1, TP53 and MDM2 genes in 61 patients who received radio chemotherapy for a prior lymphoma or breast cancer; 29 of them had a second primary EC. This cohort consists of 22 esophageal squamous cell carcinoma (ESCC) and 7 esophageal adenocarcinoma (EADC) patients. A validation cohort of 154 patients with sporadic EC was also included. The XPD Asp312Asn (rs1799793) was found to be associated with the risk of developing second primary ESCC (P=0.015). The resultant variant was also involved in the onset of sporadic ESCC (P=0.0018). To know in advance who among long-term cancer survivors have an increased risk of EC could lead to a more appropriate follow-up strategy. PMID- 26054334 TI - The phylogeographic structure of Hydrilla verticillata (Hydrocharitaceae) in China and its implications for the biogeographic history of this worldwide distributed submerged macrophyte. AB - BACKGROUND: Aquatic vascular plants are a distinctive group, differing from terrestrial plants in their growth forms and habitats. Among the various aquatic plant life forms, the evolutionary processes of freshwater submerged species are most likely distinct due to their exclusive occurrence in the discrete and patchy aquatic habitats. Using the chloroplast trnL-F region sequence data, we investigated the phylogeographic structure of a submerged macrophyte, Hydrilla verticillata, the single species in the genus Hydrilla, throughout China, in addition to combined sample data from other countries to reveal the colonisation and diversification processes of this species throughout the world. RESULTS: We sequenced 681 individuals from 123 sampling locations throughout China and identified a significant phylogeographic structure (NST > GST, p < 0.01), in which four distinct lineages occurred in different areas. A high level of genetic differentiation among populations (global FST = 0.820) was detected. The divergence of Hydrilla was estimated to have occurred in the late Miocene, and the diversification of various clades was dated to the Pleistocene epoch. Biogeographic analyses suggested an East Asian origin of Hydrilla and its subsequent dispersal throughout the world. CONCLUSIONS: The presence of all four clades in China indicates that China is most likely the centre of Hydrilla genetic diversity. The worldwide distribution of Hydrilla is due to recent vicariance and dispersal events that occurred in different clades during the Pleistocene. Our findings also provide useful information for the management of invasive Hydrilla in North America. PMID- 26054335 TI - Predicting postoperative complications of head and neck squamous cell carcinoma in elderly patients using random forest algorithm model. AB - BACKGROUND: Head and Neck Squamous Cell Carcinoma (HNSCC) has a high incidence in elderly patients. The postoperative complications present great challenges within treatment and they're hard for early warning. METHODS: Data from 525 patients diagnosed with HNSCC including a training set (n = 513) and an external testing set (n = 12) in our institution between 2006 and 2011 was collected. Variables involved are general demographic characteristics, complications, disease and treatment given. Five data mining algorithms were firstly exploited to construct predictive models in the training set. Subsequently, cross-validation was used to compare the different performance of these models and the best data mining algorithm model was then selected to perform the prediction in an external testing set. RESULTS: Data from 513 patients (age > 60 y) with HNSCC in a training set was included while 44 variables were selected (P < 0.05). Five predictive models were constructed; the model with 44 variables based on the Random Forest algorithm demonstrated the best accuracy (89.084%) and the best AUC value (0.949). In an external testing set, the accuracy (83.333%) and the AUC value (0.781) were obtained by using the random forest algorithm model. CONCLUSIONS: Data mining should be a promising approach used for elderly patients with HNSCC to predict the probability of postoperative complications. Our results highlighted the potential of computational prediction of postoperative complications in elderly patients with HNSCC by using the random forest algorithm model. PMID- 26054336 TI - Long-lasting insecticidal nets in Zambia: a cross-sectional analysis of net integrity and insecticide content. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) are a mainstay of malaria prevention in Africa. More LLINs are available now than in any time previously due to increases in funding for malaria control. LLINs are expected to last three to five years before they need to be replaced. Reports of nets lasting less than three years are frequent in Zambia, which, if true, will increase the number of LLINs needed to maintain universal coverage. METHODS: This study collected nets distributed during mass distribution campaigns. One net was collected from each participating home in 12 districts in 2010 and all nets were examined for holes. One household member was surveyed about net use and care. RESULTS: The study collected 713 polyester nets with a median age of 31 months (range 27-44 months, interquartile (IQR) range: 29-36 months), median number of holes was 17 (IQR: 5 33), and median total hole size was 88.3 sq cm (IQR: 14.5-360.4). The median total number of holes did differ by age of the net, from 27-44 months, but not in a linear fashion. The difference in the number of holes in the newest and oldest nets was not statistically significant. The mean deltamethrin level for all nets was 23 mg/sq m (>=8 mg/sq m is considered effective). There was a larger total hole area in the lower half of the nets (repeat measures ANOVA, F=228.43, df=2, p<0.0001) compared to the upper half and roof of the net. Only 8.7% of nets had evidence of repairs. CONCLUSIONS: At 27-30 months, LLINs already had a large total hole surface area that was equivalent to the oldest nets observed. Nets were often tucked under reed mats which may explain the finding that the largest hole area was found in the lower half of the net. Studies need to be conducted prospectively to determine when physical deterioration occurs and why nets are discarded. Re-enforcing the lower half of the sides of LLINs may help decrease holes. PMID- 26054337 TI - Prophylactic plasma and platelet transfusion in the critically Ill patient: just useless and expensive or even harmful? AB - It is still common practice to correct abnormal standard laboratory test results, such as increased INR or low platelet count, prior to invasive interventions, such as tracheostomy, central venous catheter insertion or liver biopsy, in critically ill patients. Data suggest that 30-90 % of plasma transfused for these indications is unnecessary and puts the patient at risk. Plasma transfusion is associated with a high risk of transfusion-associated adverse events such as transfusion-associated circulatory overload (TACO), transfusion-related lung injury (TRALI), transfusion-related immunomodulation (TRIM), and anaphylaxis/allergic reactions. Therefore, the avoidance of inappropriate plasma transfusion bears a high potential of improving patient outcomes. The prospective study by Durila et al., published recently in BMC Anesthesiology, provides evidence that tracheostomies can be performed without prophylactic plasma transfusion and bleeding complications in critically ill patients despite increased INR in case of normal thromboelastometry (ROTEM) results. Thromboelastometry-based restrictive transfusion management helped avoid unnecessary plasma and platelet transfusion, and should reduce the incidence of transfusion-related adverse events and transfusion-associated hospital costs. Therefore, the authors believe that thromboelastometry-based strategies should be implemented to optimize patient blood management in perioperative medicine. PMID- 26054338 TI - A folded and immunogenic IgE-hyporeactive variant of the major allergen Phl p 1 produced in Escherichia coli. AB - BACKGROUND: Group 1 grass pollen allergens are a major cause of allergic disease. Specific immunotherapy involving controlled administration of allergens can be used as a disease-modifying treatment for such disease. Recombinant allergen variants with reduced IgE binding capacity may be used as component in such vaccines, as they may induce fewer treatment side effects than materials currently in use. A mutated variant of the immunodominant C-terminal domain of the group 1 grass pollen allergen Phl p 1 was recently established through an approach that used a set of human monoclonal IgE as a guide to identify mutations that disturbed IgE-allergen interactions. Further analysis of this domain is required to establish its potential for use in treatment. METHODS: GST-tagged wild-type and mutated C-terminal domains of Phl p 1 were produced in Escherichia coli TUNER(DE3). The products were purified by affinity chromatography on immobilized glutathione. GST was removed by enzymatic cleavage and tag-free products were purified by size exclusion chromatography. Products were assessed by SDS-PAGE, circular dichroism spectroscopy, differential scanning fluorimetry and dynamic light scattering. Rats were immunized with GST-tagged and tag-free mutated C-terminal domain of Phl p 1. Antigen-binding properties of induced antibodies were assessed by immunochemical analysis. RESULTS: The mutated domain has a structure very similar to that of the wild-type domain as determined by circular dichroism, but a reduced thermal stability. Immunization of rats demonstrates that this IgE-hyporeactive domain, despite its three sequence modifications (K8A, N11A, D55A), is able to induce antibodies that substantially block the binding of allergic subjects' IgE to the wild-type allergen. CONCLUSIONS: It is concluded that this IgE-hyporeactive molecule can be produced in folded form and that it is able to induce an antibody response that efficiently competes with IgE recognition of Phl p 1. These findings suggest that it, or a further evolved variant thereof, is a candidate for use as a component in specific immunotherapy against grass pollen allergy. PMID- 26054339 TI - Widespread rescue of Y-linked genes by gene movement to autosomes. AB - A new study provides evidence that gene transposition from sex chromosomes to autosomes is a conserved phenomenon across mammalian species that rescues dosage sensitive genes. PMID- 26054342 TI - Is aging a failure or a conquest of natural selection? PMID- 26054340 TI - The importance of claudin-7 palmitoylation on membrane subdomain localization and metastasis-promoting activities. AB - BACKGROUND: Claudin-7 (cld7), a tight junction (TJ) component, is also found basolaterally and in the cytoplasm. Basolaterally located cld7 is enriched in glycolipid-enriched membrane domains (GEM), where it associates with EpCAM (EpC). The conditions driving cld7 out of TJ into GEM, which is associated with a striking change in function, were not defined. Thus, we asked whether cld7 serines or palmitoylation affect cld7 location and protein, particularly EpCAM, associations. RESULTS: HEK cells were transfected with EpCAM and wild type cld7 or cld7, where serine phopsphorylation or the palmitoylation sites (AA184, AA186) (cld7(mPalm)) were mutated. Exchange of individual serine phosphorylation sites did not significantly affect the GEM localization and the EpCAM association. Instead, cld7(mPalm) was poorly recruited into GEM. This has consequences on migration and invasiveness as palmitoylated cld7 facilitates integrin and EpCAM recruitment, associates with cytoskeletal linker proteins and cooperates with MMP14, CD147 and TACE, which support motility, matrix degradation and EpCAM cleavage. On the other hand, only cld7(mPalm) associates with TJ proteins. CONCLUSION: Cld7 palmitoylation prohibits TJ integration and fosters GEM recruitment. Via associated molecules, palmitoylated cld7 supports motility and invasion. PMID- 26054343 TI - Aging is neither a failure nor an achievement of natural selection. AB - In contraposition to the view of aging as a stochastic time-dependent accumulation of damage, phenoptotic theories of aging postulate that senescence may provide supra-individual advantages, and therefore it might have been promoted by natural selection. We reason that although programmed aging theories are subjectively appealing because they convey a cure for aging, they also raise a number of objections that need to be dealt with, before we may be entitled to contemplate aging as an adaptive function evolved through natural selection. As an alternative view, we present metabolism as an endless source of by-products and errors causing cellular damage. Although this damage accumulation event is a spontaneous entropy-driven process, its kinetics can be genetically and environmentally modulated, giving place to the wide range of lifespans we observe. Mild forms of damage may be accumulating during a long enough period of time to allow reproduction before the fatal failure happens. Hence, aging would be a stochastic process out of the reach of natural selection. However, those genetic pathways influencing the rate of aging and consequently determining longevity may be targets of natural selection and may contribute to shaping the optimal strategy according to the ecological context. In this sense, short- and long-lived organisms represent two extreme strategies that, in terms of biological fitness, can perform equally well, each within its own niche. PMID- 26054341 TI - Combined inhibition of the cell cycle related proteins Wee1 and Chk1/2 induces synergistic anti-cancer effect in melanoma. AB - BACKGROUND: Malignant melanoma has an increasing incidence rate and the metastatic disease is notoriously resistant to standard chemotherapy. Loss of cell cycle checkpoints is frequently found in many cancer types and makes the cells reliant on compensatory mechanisms to control progression. This feature may be exploited in therapy, and kinases involved in checkpoint regulation, such as Wee1 and Chk1/2, have thus become attractive therapeutic targets. METHODS: In the present study we combined a Wee1 inhibitor (MK1775) with Chk1/2 inhibitor (AZD7762) in malignant melanoma cell lines grown in vitro (2D and 3D cultures) and in xenografts models. RESULTS: Our in vitro studies showed that combined inhibition of Wee1 and Chk1/2 synergistically decreased viability and increased apoptosis (cleavage of caspase 3 and PARP), which may be explained by accumulation of DNA-damage (increased expression of gamma-H2A.X)--and premature mitosis of S-phase cells. Compared to either inhibitor used as single agents, combined treatment reduced spheroid growth and led to greater tumour growth inhibition in melanoma xenografts. CONCLUSIONS: These data provide a rationale for further evaluation of the combination of Wee1 and Chk1/2 inhibitors in malignant melanoma. PMID- 26054344 TI - Early life events can shape aging and longevity. AB - There is increasing evidence that nutritional and hormonal signals during development can influence longevity. It was reported that mice subjected to mild calorie restriction only during the preweaning period live longer than control animals. In long-lived hypopituitary dwarf mice, longevity can be reduced by growth hormone replacement therapy during pre- and peri-pubertal period. These findings suggest that trajectory of aging is importantly influenced by the availability of nutrients and the levels of anabolic hormones during development. PMID- 26054345 TI - Physiological and comparative evidence fails to confirm an adaptive role for aging in evolution. AB - The longstanding debate about whether aging may have evolved for some adaptive reason is generally considered to pit evolutionary theory against empirical observations consistent with aging as a programmed aspect of organismal biology, in particular conserved aging genes. Here I argue that the empirical evidence on aging mechanisms does not support a view of aging as a programmed phenomenon, but rather supports a view of aging as the dysregulation of complex networks that maintain organismal homeostasis. The appearance of programming is due largely to the inadvertent activation of existing pathways during the process of dysregulation. It is argued that aging differs markedly from known programmed biological phenomena such as apoptosis in that it is (a) very heterogeneous in how it proceeds, and (b) much slower than it would need to be. Furthermore, the taxonomic distribution of aging across species does not support any proposed adaptive theories of aging, which would predict that aging rate would vary on a finer taxonomic scale depending on factors such as population density. Thus, while there are problems with the longstanding non-adaptive paradigm, current evidence does not support the notion that aging is programmed or that it may have evolved for adaptive reasons. PMID- 26054346 TI - Solving the programmed/non-programmed aging conundrum. AB - For more than 150 years there has been some level of scientific argument regarding whether aging in humans and other mammals is purposely genetically programmed because living too long produces an evolutionary disadvantage, or whether aging in mammals is non-programmed because there is no such disadvantage. Although for many decades it was very widely thought that programmed aging in mammals was theoretically impossible, new evolutionary mechanics theories and new discoveries support programmed mammal aging as well as programmed lifespan limitation in non-mammals. The emergence of modern programmed aging theories has created a schism in the bioscience community regarding the programmed/ non programmed issue. Because the two theories have radically different predictions regarding the fundamental nature of aging and consequently the nature of highly age-related diseases like cancer, stroke, and heart disease, resolving this issue is critical to medical research. This article summarizes the evolutionary mechanics basis of modern programmed and non-programmed aging theories, describes some of the many ancillary circumstances that continue to prevent resolution of this issue, and recommends steps that could be taken to rapidly resolve the programmed/ non-programmed conundrum. PMID- 26054347 TI - Is the evolutionary programmed/ non-programmed aging argument moot? AB - There are two modern evolutionary theories of mammal senescence: Programmed theories contend that mammals purposely limit their lifespans because doing so creates an evolutionary advantage. Non-programmed theories contend that each mammal specie only needs a particular lifespan and therefore only evolved and retained the capability for attaining that lifespan. Arguments over the evolutionary nature of aging have now existed for more than 150 years and for reasons described here may never be definitively resolved. The programmed/ non programmed question is critical to medical research because the theories have grossly different predictions regarding the biological mechanisms associated with the aging process and therefore, the nature of age-related diseases and conditions. This article describes and compares two approaches for avoiding the need to obtain resolution on the evolutionary basis of senescence in order to identify and characterize the biological mechanisms responsible for aging and therefore the nature of highly age-related diseases. PMID- 26054348 TI - Towards an evidence-based model of aging. AB - The modern synthesis or evolutionary theory of aging assumes that aging results from the accumulation of errors or damages at the cellular level through the inadequacies of an organism's repair and maintenance machinery. The demonstration of cellular and organic rejuvenation requires the hypothesis that aging is the result of irreparable damage to be rejected. I will propose basic principles of mammalian aging based only on experimental data, without imposing the constraints of evolutionary theory. Consideration of the results of experiment suggests that fundamental assumptions about cell and organ aging being autonomous process, and about the centrality of cellular aging in organismic aging are wrong. The derived principles indicate that exogenous control of age-phenotype at cellular and higher levels of biological organization is possible. PMID- 26054349 TI - Non-programmed versus programmed aging paradigm. AB - There are two opposite paradigms to explain aging, here precisely defined as "age related progressive mortality increase, i.e. fitness decline, in the wild". The first maintains that natural selection is unable to maintain fitness as age increases. The second asserts that, in particular ecological conditions, natural selection favors specific mechanisms for limiting the lifespan. The predictions derived from the two paradigms are quite different and often opposing. A series of empirical data and certain theoretical considerations (non-universality of aging; great inter-specific variation of aging rates; effects of caloric restriction on lifespan; damage of aging for the senescing individual but its advantage in terms of supra-individual selection; existence of fitness decline in the wild; proportion of deaths due to intrinsic mortality inversely related to extrinsic mortality, when various species are compared; impossibility of explaining the age-related fitness decline as a consequence of genes that are harmful at a certain age; age-related progressive decline of cell turnover capacities; on/off cell senescence; gradual cell senescence) are compared with the predictions of the two paradigms and their compatibility with each paradigm is considered. The result is that the abovementioned empirical data and theoretical considerations strongly contradict and falsify in many ways all theories belonging to the first paradigm. On the contrary, they are consistent or compatible with the predictions of the second paradigm. PMID- 26054350 TI - Chronographic theory of development, aging, and origin of cancer: role of chronomeres and printomeres. AB - It is supposed that the development and aging of multicellular animals and humans are controlled by a special form of the clock mechanism - a chronograph. The development of animals and their aging are interconnected by the program of the species lifespan that has been selected in the evolution of each species to fit the resources of its ecological niche. The theory is based on the idea about a controlled loss by the neurons in the brain of hypothetical organelles - chronomeres that represent themselves small DNA molecules, which are amplificates of the segments of chromosomal DNA. A regular mode of the process of chronomere losses by neurons is provided by a pacemaker localized in the pineal gland and activated at least once per lunar month. Neurons, consecutively losing their chronomeres, are organized in the brain in the temporal relay race. Analogues of chronomeres, namely printomeres, are supposed to exist in dividing non-neuronal cells. Printomeres are not involved in a performance of temporal function, instead they are responsible for the maintenance in dividing cells of their memory about the state of differentiation. A critical shortening or loss of a printomere in a dividing cell leads to a cellular senescence, whereas telomere shortening is a bystander of this process. Thus, aging of a multicellular organism is associated with the loss of chronomeres, whereas senescence of dividing cells is associated with the loss of regulatory RNAs encoded by printomeres. If the cells that have lost their printomeres are environmentally forced to divide, they can transform into cancer cells. PMID- 26054351 TI - The interrelationship between disease and ageing and the implications for longevity. AB - Ageing is generally viewed as a detrimental phenotype; with age comes increasing susceptibility to disease and frailty. Recent data also suggests that disease can result in an increase in ageing phenotypes suggesting a positive feedback loop. It is clear that lifespan can be modified genetically and by interventions in certain organisms but the mechanisms by which this is achieved have not yet been fully elucidated, as indeed is the case for the ageing process itself. Because of the intimate relationship between disease, ageing and ultimately lifespan it is difficult to dissect the effects of individual changes. As we learn more about individual pathways and allelic variants influencing ageing and disease we can begin to unravel the influence of natural selection on these processes. PMID- 26054352 TI - Aging as an evolvability-increasing program which can be switched off by organism to mobilize additional resources for survival. AB - During the last decade, several pieces of convincing evidence were published indicating that aging of living organisms is programmed, being a particular case of programmed death of organism (phenoptosis). Among them, the following observations can be mentioned. (1) Species were described that show negligible aging. In mammals, the naked mole rat is the most impressive example. This is a rodent of mouse size living at least 10-fold longer than a mouse and having fecundity higher than a mouse and no agerelated diseases. (2) In some species with high aging rate, genes responsible for active organization of aging by poisoning of the organism with endogenous metabolites have been identified. (3) In women, standard deviations divided by the mean are the same for age of menarche (an event controlled by the ontogenetic program) and for age of menopause (an aging-related event). (4) Inhibitors of programmed cell death (apoptosis and necrosis) retard and in certain cases even reverse the development of age-dependent pathologies. (5) In aging species, the rate of aging is regulated by the individual which responds by changes in this rate to changes in the environmental conditions. In this review, we consider point (5) in detail. Data are summarized suggesting that inhibition of aging rate by moderate food restriction can be explained assuming that such restriction is perceived by the organism as a signal of future starvation. In response to this dramatic signal, the organism switches off such an optional program as aging, mobilizing in such a way additional reserves for survival. A similar explanation is postulated for geroprotective effects of heavy muscle work, a lowering or a rise in the external temperature, small amounts of metabolic poisons (hormesis), low doses of radiation, and other deleterious events. On the contrary, sometimes certain positive signals can prolong life by inhibiting the aging program in individuals who are useful for the community (e.g., geroprotective psychological factors). Similarly, dangerous individuals can be eliminated by programmed death due to operation of progeric psychological factors. The interplay of all these signals results in the final decision of the organism concerning its aging - to accelerate or to decelerate this process. Thus, paradoxically, such an originally counterproductive program as aging appears to be useful for the individual since this program can be switched off by the individual for a certain period of time, an action that thereby increases its resources in crucial periods of life. PMID- 26054353 TI - Aging as an optimization between cellular maintenance requirements and evolutionary constraints. AB - During the last decade, our understanding of the molecular mechanisms regulating the cellular environment has made significant advances. With the new dynamical description of the functionalities of the cell, several processes known to play a crucial role in the onset of aging such as cell senescence, the increase of ROS level and telomere shortening appear to be a consequence of the disruption of a systemic dynamical equilibrium established within the cellular environment. In this short review, I discuss how these new features provide us with a way to improve the current evolutionary theory of aging and help to clarify the role played by aging within the context of the evolution. PMID- 26054354 TI - A parameter estimation method for fluorescence lifetime data. AB - BACKGROUND: When modeling single-molecule fluorescence lifetime experimental data, the analysis often involves fitting a biexponential distribution to binned data. When dealing with small sample sizes, there is the potential for convergence failure in numerical optimization, for convergence to local optima resulting in physically unreasonable parameter estimates, and also for overfitting the data. RESULTS: To avoid the problems that arise in small sample sizes, we have developed a gamma conversion method to estimate the lifetime components. The key idea is to use a gamma distribution for initial numerical optimization and then convert the gamma parameters to biexponential ones via moment matching. A simulation study is undertaken with 30 unique configurations of parameter values. We also performed the same analysis on data obtained from a fluorescence lifetime experiment using the fluorophore Cy3. In both the simulation study and the real data analysis, fitting the biexponential directly led to a large number of data sets whose estimates were physically unreasonable, while using the gamma conversion yielded estimates consistently close to the true values. CONCLUSIONS: Our analysis shows that using numerical optimization methods to fit the biexponential distribution directly can lead to failure to converge, convergence to physically unreasonable parameter estimates, and overfitting the data. The proposed gamma conversion method avoids these numerical difficulties, yielding better results. PMID- 26054355 TI - Road traffic fatalities in Greece have continued to fall during the financial crisis. PMID- 26054356 TI - Beneficial Regulation of Metabolic Profiles by Black Raspberries in Human Colorectal Cancer Patients. AB - Dietary intervention of freeze-dried black raspberries (BRBs) in a group of human colorectal cancer patients has demonstrated beneficial effects, including proapoptosis, antiproliferation, and antiangiogenesis. The aim of this study was to investigate BRB-mediated metabolite changes from this same cohort of patients. Twenty-eight colorectal cancer patients were given 60 g BRB powder daily for 1 to 9 weeks. Urine and plasma specimens were collected before and after BRB intervention. A mass spectrometry-based nontargeted metabolomic analysis was conducted on each specimen. A total of more than 400 metabolites were annotated in each specimen. Of these 34 and 6 metabolites were significantly changed by BRBs in urine and plasma, respectively. Increased levels of 4-methylcatechol sulfate in both post-BRB urine and post-BRB plasma were significantly correlated with a higher level of apoptotic marker (TUNEL) in post-BRB tumors. One tricarboxylic acid (TCA) cycle metabolites, cis-aconitate, was increased in post BRB urine. Furthermore, BRB-derived polyphenols were absorbed and metabolized to various benzoate species, which were significantly increased in post-BRB specimens. Increased benzoate levels were positively correlated with enhanced levels of amino acid metabolite. These results suggest that BRBs induce significant metabolic changes and affect energy generating pathways.This study supports the hypothesis that BRBs might be beneficial to colorectal cancer patients through the regulation of multiple metabolites. PMID- 26054357 TI - Tobacco smoking is causally associated with antipsychotic medication use and schizophrenia, but not with antidepressant medication use or depression. AB - BACKGROUND: Tobacco smoking is more common among patients with schizophrenia and depression than among healthy individuals. We tested the hypothesis that high tobacco smoking intensity is causally associated with antipsychotic medication use, schizophrenia, antidepressant medication use and/or depression in the general population, and compared results with those for chronic obstructive pulmonary disease. METHODS: We used self-reported smoking intensity in cigarettes/day and a polymorphism in the CHRNA3 gene cluster (rs1051730) associated with smoking intensity, on 63,296 20-100-year-old individuals from the Danish general population; 23,282 were never-smokers and 40,014 ever-smokers. For schizophrenia, we compared our results with those in the Psychiatric Genomics Consortium. RESULTS: In smokers, heterozygotes (CT) and homozygotes (TT) for rs1051730 genotype had higher smoking intensity compared with non-carriers (CC). Furthermore, in ever-smokers homozygotes had increased risk of antipsychotic medication with an odds ratio (OR) of 1.16 [95% confidence interval (CI) 1.02 1.31] compared with non-carriers, whereas in never-smokers the corresponding OR was 1.07 (0.87-1.31) (P-interaction: 0.60). Correspondingly, ORs were 1.60 (0.74 3.47) and 1.02 (0.11-9.10) for schizophrenia (P-interaction: 0.85), 1.02 (0.93 1.13) and 0.99 (0.85-1.15) for antidepressant medication (P-interaction: 0.87), 0.85 (0.66-1.10) and 1.26 (0.87-1.83) for depression (P-interaction: 0.30) and 1.31 (1.16-1.47) and 0.89 (0.58-1.36) for chronic obstructive pulmonary disease (P-interaction: 0.16). Odds ratios per rs1051730 allele for schizophrenia and antipsychotic medication use in ever-smokers in the general population were 1.22 (95% CI: 0.84-1.79) and 1.06 (1.00-1.12). In the Psychiatric Genomics Consortium, the corresponding OR for schizophrenia was 1.06 (1.04-1.08) in ever- and never smokers combined. CONCLUSION: Our data suggest that tobacco smoking could influence the development of psychotic conditions causally, whereas an influence on depression seems unlikely. PMID- 26054358 TI - Clinical Validation of the "Sedentary Lifestyle" Nursing Diagnosis in Secondary School Students. AB - This study clinically validated the nursing diagnosis of "sedentary lifestyle" (SL) among 564 Brazilian adolescents. Measures of diagnostic accuracy were calculated for defining characteristics, and Mantel-Haenszel analysis was used to identify related factors. The measures of diagnostic accuracy showed that the following defining characteristics were statistically significant: "average daily physical activity less than recommended for gender and age," "preference for activity low in physical activity," "nonengagement in leisure time physical activities," and "diminished respiratory capacity." An SL showed statistically significant associations with the following related factors: insufficient motivation for physical activity; insufficient interest in physical activity; insufficient resources for physical activity; insufficient social support for physical activity; attitudes, beliefs, and health habits that hinder physical activity; and insufficient confidence for practicing physical exercises. The study highlighted the four defining characteristics and six related factors for making decisions related to SL among adolescents. PMID- 26054359 TI - Multiple-choice tests: polytomous IRT models misestimate item information. AB - Likert-type items and polytomous models are preferred over yes-no items and dichotomous models for the measurement of attitudes, because a broader range of response categories provides superior item and test information functions. Yet, for ability assessment with multiple-choice tests, the dichotomous three parameter logistic model (3PLM) is often chosen. Because multiple-choice responses are polytomous before they are categorized as correct or incorrect, a polytomous characterization might render more efficient tests. Early studies suggested that the nominal response model (NRM) is advantageous in this respect. We investigate the reasons for those results and the outcomes of a polytomous characterization based on the multiple-choice model (MCM). An empirical data set is used to compare polytomous (NRM and MCM) and dichotomous (3PLM) characterizations of a test. The results revealed superior item and test information functions from polytomous models. Yet, close inspection suggests that these outcomes are artifactual and two simulation studies confirmed this point. These studies revealed a structural inadequacy of the NRM for multiple-choice items and that the MCM characterization outperforms the 3PLM characterization only when distractor endorsement frequencies vary non-monotonically with ability, although this feature is rarely observed in empirical data sets. PMID- 26054360 TI - EHME: a new word database for research in Basque language. AB - This article presents EHME, the frequency dictionary of Basque structure, an online program that enables researchers in psycholinguistics to extract word and nonword stimuli, based on a broad range of statistics concerning the properties of Basque words. The database consists of 22.7 million tokens, and properties available include morphological structure frequency and word-similarity measures, apart from classical indexes: word frequency, orthographic structure, orthographic similarity, bigram and biphone frequency, and syllable-based measures. Measures are indexed at the lemma, morpheme and word level. We include reliability and validation analysis. The application is freely available, and enables the user to extract words based on concrete statistical criteria 1 , as well as to obtain statistical characteristics from a list of words PMID- 26054361 TI - Interpersonal self-support and attentional disengagement from emotional faces. AB - Prior studies have shown that interpersonal self-support is related to emotional symptoms. The present study explored the relationship between interpersonal self support and attentional disengagement from emotional faces. A spatial cueing task was administrated to 21 high and 24 low interpersonal self-support Chinese undergraduate students to assess difficulty in shifting away from emotional faces. The Sidak corrected multiple pairwise tests revealed that the low interpersonal self-support group had greater response latencies on negative faces than neutral faces or positive faces in the invalid cues condition, F(2, 41) = 5.68, p < .01, eta2 = .22. In addition, in the invalid cues condition, the low interpersonal self-support group responded more slowly than the high interpersonal self-support group to negative faces, F(1, 42) = 7.63, p < .01, eta2 = .15, the 95% confidence interval for difference of reaction time from 16.30 to 104.70. The results support our hypotheses that low interpersonal self support is related to difficulty disengaging from negative emotional information and suggest that interpersonal self-support may refer to emotional dispositions, especially negative emotional dispositions. PMID- 26054362 TI - Factor structure of the Self-Regulation Questionnaire (SRQ) at Spanish universities. AB - The Self-Regulation Questionnaire (SRQ) has been used in psychology research during the last decade. The instrument has been used in a variety of life domains: psychological well-being, dispositional happiness, depressive symptoms and career adaptability. This investigation studies the factor structure and internal consistency of the SRQ, extracting a short version in the Spanish context and examining its relation to academic variables (self-regulated learning and grades). The analysis started from a version with 63 items, representing seven conceptual dimensions. This version was administered to a sample of 834 students from Education and Psychology. The data from the above-mentioned sample were randomly divided into two sets, each containing 50% of the students (n = 417): exploratory and confirmatory. In the exploratory sample, exploratory factor analysis findings suggested a more parsimonious measurement model, with 17 items and 4 first-order factors. The confirmatory sample was used in the confirmatory factor analysis. The results show evidence for the internal consistency of the Short Self-Regulation Questionnaire (SSRQ) in the Spanish context, with indices greater than .90 and errors around .05. Regarding academic variables, both versions are related to self-regulated learning (r = .40, p < .01) and students' grades (r = .15, p < .01). Differences from other studies done in North America are discussed, as well as similarities to a study from North-West University (in South Africa). PMID- 26054363 TI - Post-traumatic headaches correlate with migraine symptoms in youth with concussion. AB - OBJECTIVE: The term "post-traumatic migraine" (PTM) has been used to describe post-traumatic headaches (PTHs) that have associated migraine features, but studies of this relationship are lacking. The objective of the present study was to determine whether PTH correlates strongly with migraine symptoms among youth with concussion. METHODS: Twenty-three symptoms were analyzed from a retrospective cohort of 1953 pediatric patients with concussion. A principal component analysis (PCA) with oblique Promax rotation was conducted to explore underlying symptom relationships in the full cohort and in subcohorts stratified by the presence (n = 414) or absence (n = 1526) of premorbid headache. RESULTS: The mean patient age was 14.1 years; 63% were male. Headache was the most common postconcussion symptom, acknowledged by 69.4% of patients. When considering the full cohort, the PCA demonstrated clustering of headache with photophobia, phonophobia, nausea, dizziness, and neck pain. Similar clustering was present among patients without premorbid headaches. Repeating the analysis in the patients with preconcussion headaches led to elimination of neck pain from the cluster. CONCLUSIONS: PTH correlates strongly with other migraine symptoms among youth with concussion, regardless of premorbid headaches. This clustering of migraine symptoms supports the existence of PTM as a distinct clinical entity in some patients. PMID- 26054364 TI - Correlation between habituation of visual-evoked potentials and magnetophosphene thresholds in migraine: A case-control study. AB - INTRODUCTION: In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality. METHODS: We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman's correlation. RESULTS: In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants. CONCLUSIONS: We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation. PMID- 26054365 TI - Cistrome of the aldosterone-activated mineralocorticoid receptor in human renal cells. AB - Aldosterone exerts its effects mainly by activating the mineralocorticoid receptor (MR), a transcription factor that regulates gene expression through complex and dynamic interactions with coregulators and transcriptional machinery, leading to fine-tuned control of vectorial ionic transport in the distal nephron. To identify genome-wide aldosterone-regulated MR targets in human renal cells, we set up a chromatin immunoprecipitation (ChIP) assay by using a specific anti-MR antibody in a differentiated human renal cell line expressing green fluorescent protein (GFP)-MR. This approach, coupled with high-throughput sequencing, allowed identification of 974 genomic MR targets. Computational analysis identified an MR response element (MRE) including single or multiple half-sites and palindromic motifs in which the AGtACAgxatGTtCt sequence was the most prevalent motif. Most genomic MR-binding sites (MBSs) are located >10 kb from the transcriptional start sites of target genes (84%). Specific aldosterone-induced recruitment of MR on the first most relevant genomic sequences was further validated by ChIP quantitative (q)PCR and correlated with concomitant and positive aldosterone activated transcriptional regulation of the corresponding gene, as assayed by RT qPCR. It was notable that most MBSs lacked MREs but harbored DNA recognition motifs for other transcription factors (FOX, EGR1, AP1, PAX5) suggesting functional interaction. This work provides new insights into aldosterone MR mediated renal signaling and opens relevant perspectives for mineralocorticoid related pathophysiology. PMID- 26054366 TI - Excess aldosterone is a critical danger signal for inflammasome activation in the development of renal fibrosis in mice. AB - High levels of aldosterone impair renal function by activating proinflammatory and profibrotic pathways. However, the molecular mechanism underlying aldosterone induced inflammation and fibrosis is unknown. Inflammasome activation contributes to chronic kidney disease. We hypothesized that aldosterone induces renal tubulointerstitial inflammation and fibrosis by activating the inflammasome. Infusing wild-type mice with aldosterone (0.25 mg/kg/d) caused tubulointerstitial damage, increased expression of inflammasome components, caspase 1 activation, and overproduction of IL-1beta and IL-18. These changes were suppressed by eplerenone treatment (100 mg/kg/d) in wild-type mice or in mice deficient in apoptosis-associated speck-like protein with a caspase-recruitment domain (ASC). Caspase 1-positive and F4/80-positive cells colocalized in the interstitium. Bone marrow transplantation using ASC-deficient mice indicated that inflammasome activation in macrophages mediated aldosterone-induced renal fibrosis. IL-18 was detected in culture supernatants of macrophages treated with aldosterone, and mitochondria-derived reactive oxygen species activated the inflammasome in these macrophages. Our results indicate that exposure of macrophages to high levels of aldosterone resulted in the activation of inflammasomes via the mitochondria derived reactive oxygen species. Thus, inflammasome activation in macrophages may serve as a new therapeutic target for chronic kidney disease. PMID- 26054367 TI - Parathyroid-specific deletion of dicer-dependent microRNAs abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia. AB - MicroRNAs (miRNAs) down-regulate gene expression and have vital roles in biology but their functions in the parathyroid are unexplored. To study this, we generated parathyroid-specific Dicer1 knockout (PT-Dicer(-/-) ) mice where parathyroid miRNA maturation is blocked. Remarkably, the PT-Dicer(-/-) mice did not increase serum parathyroid hormone (PTH) in response to acute hypocalcemia compared with the >5-fold increase in controls. PT-Dicer(-/-) glands cultured in low-calcium medium secreted 5-fold less PTH at 1.5 h than controls. Chronic hypocalcemia increased serum PTH >4-fold less in PT-Dicer(-/-) mice compared with control mice with no increase in PTH mRNA levels and parathyroid cell proliferation compared with the 2- to 3-fold increase in hypocalcemic controls. Moreover, uremic PT-Dicer(-/-) mice increased serum PTH and FGF23 significantly less than uremic controls. Therefore, stimulation of the parathyroid by both hypocalcemia and uremia is dependent upon intact dicer function and miRNAs. In contrast, the PT-Dicer(-/-) mice responded normally to activation of the parathyroid calcium-sensing receptor (Casr) by both hypercalcemia and a calcimimetic that decreases PTH secretion, demonstrating that they are dicer independent. Therefore, miRNAs are essential for the response of the parathyroid to both acute and chronic hypocalcemia and uremia, the major stimuli for PTH secretion. PMID- 26054369 TI - Naive Tests of Basic Local Independence Model's Invariance. AB - The basic local independence model (BLIM) is a probabilistic model for knowledge structures, characterized by the property that lucky guess and careless error parameters of the items are independent of the knowledge states of the subjects. When fitting the BLIM to empirical data, a good fit can be obtained even when the invariance assumption is violated. Therefore, statistical tests are needed for detecting violations of this specific assumption. This work provides an extension to theoretical results obtained by de Chiusole, Stefanutti, Anselmi, and Robusto (2013), showing that statistical tests based on the partitioning of the empirical data set into two (or more) groups are not adequate for testing the BLIM's invariance assumption. A simulation study confirms the theoretical results. PMID- 26054370 TI - Dysfunctional uterine bleeding as an early sign of polycystic ovary syndrome during adolescence. AB - Excessive uterine bleeding during the early years after menarche can be worrisome to the girl and her parents. The most prevalent diagnosis set is Dysfunctional uterine bleeding (DUB), after thorough examination and exclusion of other causes of abnormal uterine bleeding. The aim of this article was to review our knowledge and share our experience as tertiary reference center of pediatric-adolescent gynecology in Greece. We conducted a review of current literature using Pubmed and MedLine as our primary databases, as well as providing commentary considering work up, treatment and follow-up of our DUB patients. Insufficient progesterone production and subsequent abnormal shedding of the endometrium appears to orchestrate the pathophysiology of DUB in adolescence. Hypothalamic-pituitary ovarian (HPO) axis immaturity right after menarche, is usually the most plausible cause. Nevertheless, it is necessary to exclude other, possibly even life threatening causes. Complete work up including physical examination, laboratory and imaging studies (complete blood count, b-HCG, hormonal levels and ultrasonography) is needed, and appropriate treatment with combined oral contraceptives is administered accordingly. Although menstrual disorders are very common in early adolescence, a severe episode of DUB should always be thoroughly attended by any physician. Follow-up should be offered in all young patients due to high incidence of recurrence or subsequent development of endocrine disorders such as Polycystic Ovary Syndrome (PCOS). PMID- 26054372 TI - Current hypotheses of lithium's mechanism of action as a neuropsychiatric medication. PMID- 26054374 TI - Immunochemotherapy in Waldenstrom macroglobulinemia - still the backbone of treatment. PMID- 26054375 TI - Well-to-Wheels Greenhouse Gas Emissions of Canadian Oil Sands Products: Implications for U.S. Petroleum Fuels. AB - Greenhouse gas (GHG) regulations affecting U.S. transportation fuels require holistic examination of the life-cycle emissions of U.S. petroleum feedstocks. With an expanded system boundary that included land disturbance-induced GHG emissions, we estimated well-to-wheels (WTW) GHG emissions of U.S. production of gasoline and diesel sourced from Canadian oil sands. Our analysis was based on detailed characterization of the energy intensities of 27 oil sands projects, representing industrial practices and technological advances since 2008. Four major oil sands production pathways were examined, including bitumen and synthetic crude oil (SCO) from both surface mining and in situ projects. Pathway average GHG emissions from oil sands extraction, separation, and upgrading ranged from ~6.1 to ~27.3 g CO2 equivalents per megajoule (in lower heating value, CO2e/MJ). This range can be compared to ~4.4 g CO2e/MJ for U.S. conventional crude oil recovery. Depending on the extraction technology and product type output of oil sands projects, the WTW GHG emissions for gasoline and diesel produced from bitumen and SCO in U.S. refineries were in the range of 100-115 and 99-117 g CO2e/MJ, respectively, representing, on average, about 18% and 21% higher emissions than those derived from U.S. conventional crudes. WTW GHG emissions of gasoline and diesel derived from diluted bitumen ranged from 97 to 103 and 96 to 104 g CO2e/MJ, respectively, showing the effect of diluent use on fuel emissions. PMID- 26054373 TI - Glutaminolysis and autophagy in cancer. AB - The remarkable metabolic differences between cancer cells and normal cells result in the potential for targeted cancer therapy. The upregulation of glutaminolysis provides energetic advantages to cancer cells. The recently described link between glutaminolysis and autophagy, mediated by MTORC1, may constitute an attractive target for therapeutic strategies. A combination of therapies targeting simultane-ously cell signaling, cancer metabolism, and autophagy can solve therapy resistance and tumor relapse problems, commonly observed in patients treated with most of the current targeted therapies. In this review we summarize the mechanistic link between glutaminolysis and autophagy, and discuss the impacts of these processes on cancer progression and the potential for therapeutic intervention. PMID- 26054376 TI - NOX4 NADPH Oxidase-Dependent Mitochondrial Oxidative Stress in Aging-Associated Cardiovascular Disease. AB - AIMS: Increased oxidative stress and vascular inflammation are implicated in increased cardiovascular disease (CVD) incidence with age. We and others demonstrated that NOX1/2 NADPH oxidase inhibition, by genetic deletion of p47phox, in Apoe(-/-) mice decreases vascular reactive oxygen species (ROS) generation and atherosclerosis in young age. The present study examined whether NOX1/2 NADPH oxidases are also pivotal to aging-associated CVD. RESULTS: Both aged (16 months) Apoe(-/-) and Apoe(-/-)/p47phox(-/-) mice had increased atherosclerotic lesion area, aortic stiffness, and systolic dysfunction compared with young (4 months) cohorts. Cellular and mitochondrial ROS (mtROS) levels were significantly higher in aortic wall and vascular smooth muscle cells (VSMCs) from aged wild-type and p47phox(-/-) mice. VSMCs from aged mice had increased mitochondrial protein oxidation and dysfunction and increased vascular cell adhesion molecule 1 expression, which was abrogated with (2-(2,2,6,6 Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO) treatment. NOX4 expression was increased in the vasculature and mitochondria of aged mice and its suppression with shRNA in VSMCs from aged mice decreased mtROS levels and improved function. Increased mtROS levels were associated with enhanced mitochondrial NOX4 expression in aortic VSMCs from aged subjects, and NOX4 expression levels in arterial wall correlated with age and atherosclerotic severity. Aged Apoe(-/-) mice treated with MitoTEMPO and 2-(2 chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine 3,6(2H,5H)-dione had decreased vascular ROS levels and atherosclerosis and preserved vascular and cardiac function. INNOVATION AND CONCLUSION: These data suggest that NOX4, but not NOX1/2, and mitochondrial oxidative stress are mediators of CVD in aging under hyperlipidemic conditions. Regulating NOX4 activity/expression and using mitochondrial antioxidants are potential approaches to reducing aging-associated CVD. PMID- 26054377 TI - Changes in racial categorization over time and health status: an examination of multiracial young adults in the USA. AB - OBJECTIVE: Multiracial (two or more races) American health related to racial stability over the life course is a pressing issue in a burgeoning multi-ethnic and multicultural global society. Most studies on multiracial health are cross sectional and thus focus on racial categorization at a single time point, so it is difficult to establish how health indicators change for multiracials over time. Accordingly the central aim of this paper was to explore if consistency in racial categories over time is related to self-rated health for multiracial young adults in the USA. METHODS: Data were drawn from the National Longitudinal Study of Adolescent Health (Add Health) survey (N = 7957). Weighted multivariate logistic regression was used to exam health status in early adulthood between individuals who switched racial categories between Waves 1 and 3 compared to those who remained in the same racial categories. RESULTS: There were significant differences in report of self-rated health when comparing consistent monoracial adults with multiracial adults who switch racial categories over time. Diversifying (switching from one category to many categories) multiracial respondents are less likely to report fair/poor self-rated health compared to single-race minority young adults in the fully adjusted model (OR = 0.20; 95% CI [0.06-0.60]). CONCLUSION: These results demonstrate the importance of critically examining changes in racial categories as related to health status over time. Furthermore, these results demonstrate how the switch in racial categories during adolescence can explain some variations in health status during young adulthood. PMID- 26054378 TI - Deiters' Nucleus. Its Role in Cerebellar Ideogenesis : The Ferdinando Rossi Memorial Lecture. AB - Otto Deiters (1834-1863) was a promising neuroscientist who, like Ferdinando Rossi, died too young. His notes and drawings were posthumously published by Max Schultze in the book "Untersuchungen uber Gehirn und Ruckenmark." The book is well-known for his dissections of nerve cells, showing the presence of multiple dendrites and a single axon. Deiters also made beautiful drawings of microscopical sections through the spinal cord and the brain stem, the latter showing the lateral vestibular nucleus which received his name. This nucleus, however, should be considered as a cerebellar nucleus because it receives Purkinje cell axons from the vermal B zone in its dorsal portion. Afferents from the labyrinth occur in its ventral part. The nucleus gives rise to the lateral vestibulospinal tract. The cerebellar B module of which Deiters' nucleus is the target nucleus was used in many innovative studies of the cerebellum on the zonal organization of the olivocerebellar projection, its somatotopical organization, its microzones, and its role in posture and movement that are the subject of this review. PMID- 26054379 TI - Peripheral Neuropathy in Spinocerebellar Ataxia Type 1, 2, 3, and 6. AB - Spinocerebellar ataxias (SCAs) are characterized by autosomal dominantly inherited progressive ataxia but are clinically heterogeneous due to variable involvement of non-cerebellar parts of the nervous system. Non-cerebellar symptoms contribute significantly to the burden of SCAs, may guide the clinician to the underlying genetic subtype, and might be useful markers to monitor disease. Peripheral neuropathy is frequently observed in SCA, but subtype specific features and subclinical manifestations have rarely been evaluated. We performed a multicenter nerve conduction study with 162 patients with genetically confirmed SCA1, SCA2, SCA3, and SCA6. The study proved peripheral nerves to be involved in the neurodegenerative process in 82 % of SCA1, 63 % of SCA2, 55 % of SCA3, and 22 % of SCA6 patients. Most patients of all subtypes revealed affection of both sensory and motor fibers. Neuropathy was most frequently of mixed type with axonal and demyelinating characteristics in all SCA subtypes. However, nerve conduction velocities of SCA1 patients were slower compared to other genotypes. SCA6 patients revealed less axonal damage than patients with other subtypes. No influence of CAG repeat length or biometric determinants on peripheral neuropathy could be identified in SCA1, SCA3, and SCA6. In SCA2, earlier onset and more severe ataxia were associated with peripheral neuropathy. We proved peripheral neuropathy to be a frequent site of the neurodegenerative process in all common SCA subtypes. Since damage to peripheral nerves is readily assessable by electrophysiological means, nerve conduction studies should be performed in a longitudinal approach to assess these parameters as potential progression markers. PMID- 26054380 TI - Mechanisms underlying 3-bromopyruvate-induced cell death in colon cancer. AB - 3-Bromopyruvate (3BP) is an energy-depleting drug that inhibits Hexokinase II activity by alkylation during glycolysis, thereby suppressing the production of ATP and inducing cell death. As such, 3BP can potentially serve as an anti tumorigenic agent. Our previous research showed that 3BP can induce apoptosis via AKT /protein Kinase B signaling in breast cancer cells. Here we found that 3BP can also induce colon cancer cell death by necroptosis and apoptosis at the same time and concentration in the SW480 and HT29 cell lines; in the latter, autophagy was also found to be a mechanism of cell death. In HT29 cells, combined treatment with 3BP and the autophagy inhibitor 3-methyladenine (3-MA) exacerbated cell death, while viability in 3BP-treated cells was enhanced by concomitant treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone (z VAD-fmk) and the necroptosis inhibitor necrostatin (Nec)-1. Moreover, 3BP inhibited tumor growth in a SW480 xenograft mouse model. These results indicate that 3BP can suppress tumor growth and induce cell death by multiple mechanisms at the same time and concentration in different types of colon cancer cell by depleting cellular energy stores. PMID- 26054381 TI - Automatic Cardiac Self-Gating of Small-Animal PET Data. AB - PURPOSE: The cardiac gating signal (CGS) in positron emission tomography (PET) studies is usually obtained from an electrocardiography (ECG) monitor. In this work, we propose a method to obtain the CGS in small-animal PET using the acquired list-mode data without using any hardware or end-user input. PROCEDURES: The CGS was obtained from the number of coincidences over time acquired in the lines-of-response connected with the cardiac region. This region is identified in the image as its value changes with frequencies in the range of 3 to 12 Hz. The procedure was tested in a study with 29 Wistar rats and 6 mice injected with 2 deoxy-2-[(18)F]fluoro-D-glucose, which underwent a 45-min single-bed list-mode PET scan of the heart syncronized with an ECG. The estimated signals and the reconstructed images using eight-gated frames were compared with the ones obtained using the ECG signal from the monitor. RESULTS: The differences of the PET-based CGS with respect to the ECG relative to the duration of the heartbeats were 5.6 % in rats and 11.0 % in mice. The reconstructed gated images obtained from the proposed method do not differ qualitatively with respect to the ones obtained with the ECG. The quantitative analysis of both set of images were performed measuring the volume of the left ventricle (LV) of the rats in the end of-systole and end-of-diastole phase. The differences found in these parameters between both methods were below 12.1 % in the ESV and 9.3 % in the EDV with a 95 % confidence interval, which are comparable to the accuracy (7 %) of the method used for segmenting the LV. CONCLUSION: The proposed method is able to provide a valid and accurate CGS in small-animal PET list-mode data. PMID- 26054382 TI - Molecular Simulation of Cell Membrane Deformation by Picosecond Intense Electric Pulse. AB - The application of pulsed electric field is emerging as a new technique for cancer therapy. The irreversible electroporation is the major bioelectric effect to induce cell death. The pulsed electric field is transferred to target deep tissue non-invasively and precisely when the pulse duration is in picosecond regime. In this proposed work, the intense electric field with 100 ps pulse width is used for irreversible electroporation. If the electric field strength increases, the pore in the cell membrane enlarges, causing a loss of membrane intactness and the direct killing of cancer cells. This phenomenon is explored by molecular dynamics simulation. The electric field in the range of 0.8-5 V/nm is used for membrane dynamics. The membrane deformation occurs at the electric field of 5 V/nm. Picosecond pulsed electric field has a wealth of ultra-band spectrum, with extended time and enhanced spatial resolution and low signal distortion. The ultra-wide band antenna is used as a pulse delivery system for non-invasive skin cancer therapy. PMID- 26054383 TI - Role of Ratings of Perceived Exertion during Self-Paced Exercise: What are We Actually Measuring? AB - Ratings of perceived exertion (RPE) and effort are considered extremely important in the regulation of intensity during self-paced physical activity. While effort and exertion are slightly different constructs, these terms are often used interchangeably within the literature. The development of perceptions of both effort and exertion is a complicated process involving numerous neural processes occurring in various regions within the brain. It is widely accepted that perceptions of effort are highly dependent on efferent copies of central drive which are sent from motor to sensory regions of the brain. Additionally, it has been suggested that perceptions of effort and exertion are integrated based on the balance between corollary discharge and actual afferent feedback; however, the involvement of peripheral afferent sensory feedback in the development of such perceptions has been debated. As such, this review examines the possible difference between effort and exertion, and the implications of such differences in understanding the role of such perceptions in the regulation of pace during exercise. PMID- 26054384 TI - Biomarkers and prognostic indicators in pulmonary arterial hypertension. AB - Our understanding of the pathophysiology of pulmonary arterial hypertension (PAH) has increased substantially in the past decades. More accurate diagnosis and increased options for treatment have given researchers the opportunity to better explore the response to medical therapy and prognosis. As a result, the use of biomarkers and prognostic indicators for this devastating disease has been widely investigated. Biomarkers and prognostic indicators have also been more frequently incorporated into the design of new clinical trials. This approach has helped the pulmonary hypertension (PH) community step forward in the search for effective treatments for PAH. However, no single biomarker has shown significant superiority in predicting prognosis or patient response and an integrative approach is necessary to understand which combination of markers should be used in each of the clinical scenarios that characterize the management of PAH. PMID- 26054385 TI - Factors affecting timing of closure and non-reversal of temporary ileostomies. AB - BACKGROUND: Although stoma closure is considered a simple surgical intervention, the interval between construction and reversal is often prolonged, and some ileostomies may never be reversed. We evaluated possible predictors for non reversal and prolonged interval between construction and reversal. MATERIAL AND METHODS: In a cohort study of ileostomy patients treated in a large teaching hospital, we collected data from the surgical complication and enterostomal therapists' registries between January 2001 and December 2011. Parameters responsible for morbidity, mortality, length of stay and time interval between construction and reversal were analysed. RESULTS: Of 485 intentionally temporary ileostomies, 359 were reversed after a median of 5.6 months (IQR 3.8-8.9 months), while 126 (26%) remained permanent. End ileostomy and intra-abdominal abscess independently delayed reversal. Age, end ileostomy, higher body mass index and preoperative radiotherapy were independent factors for non-reversal. Median duration of hospitalisation for reversal was 7.0 days (5-13 days). Morbidity and mortality were 31 and 0.9%, respectively. In 20 patients (5.5%), re-ileostomy was necessary. CONCLUSIONS: A substantial number of ileostomies that are intended to be temporary will never be reversed. If reversed, the interval between construction and reversal is longer than anticipated, while morbidity after reversal and duration of hospitalisation are considerable. Besides a temporary ileostomy, there are two other options: no diversion or a permanent colostomy. Shared decision-making is to be preferred in these situations. PMID- 26054388 TI - Mechanochemistry in Polymers with Supramolecular Mechanophores. AB - Mechanochemistry is a burgeoning field of materials science. Inspired by nature, many scientists have looked at different ways to introduce weak bonds into polymeric materials to impart them with function and in particular mechano responsiveness. In the following sections, the incorporation of some of the weakest bonds, i.e. non-covalent bonds, into polymeric solids is being surveyed. This review covers sequentially pi-pi interactions, H-bonding and metal-ligand coordination bonds and tries to highlight some of the advantages and limitations of such systems, while providing some key perspective of what may come next in this tantalizing field. PMID- 26054386 TI - Stage-specific frequency and prognostic significance of aneuploidy in patients with sporadic colorectal cancer--a meta-analysis and current overview. AB - PURPOSE: Aneuploidy has long been suggested as an independent prognostic marker for colorectal cancer (CRC) patients and could thus aid for individualized medicine. However, due to a large spectrum of deviating studies, expert panels do not recommend ploidy assessment. In order to clarify a potential bias of stage specific frequency of aneuploidy, we now conducted a meta-analysis combined with a systematic review regarding aneuploidy and prognosis. METHODS: A systematic, web-based search process retrieved 1935 studies published in English between 1990 and 2011. The defined endpoint for the meta-analysis was an increase in aneuploidy frequency between early- (Dukes A, B and UICC I, II; n = 3632 samples) and late-stage (Dukes C, D and UICC III, IV; n = 3440 samples) colorectal carcinomas. RESULTS: Of 1935 studies initially identified, 17 image (2130 patients) and 20 (7023 patients) flow cytometric studies were analyzed in detail. The meta-analysis (7072 patients) revealed late-stage CRC to be more frequently aneuploid than early-stage CRC (odds ratio 1.51, 95 % CI 1.37-1.67; p = 0.0007). Independent of tumor stage, the overall range of aneuploidy was 39 to 81 % (median 58 %), and altogether, 21 (54.1 %) studies described a significant prognostic impact of aneuploidy for overall, disease-specific, and recurrence free survival, respectively. CONCLUSIONS: A substantial number of studies showed a prognostic importance of aneuploidy in CRC. Furthermore, the higher frequency of aneuploidy in late-stage CRC implies an increase in genomic instability with CRC progression, indicating aneuploidy to be also a stage-specific prognostic marker. PMID- 26054387 TI - A prognostic analysis of 895 cases of stage III colon cancer in different colon subsites. AB - PURPOSE: Stage III colon cancer is currently treated as an entity with a unified therapeutic principle. The aim of the retrospective study is to explore the clinicopathological characteristics and outcomes of site-specific stage III colon cancers and the influences of tumor location on prognosis. METHODS: Eight hundred ninety-five patients with stage III colon cancer treated with radical operation and subsequent adjuvant chemotherapy (5-fluorouracil/oxaliplatin) were divided into seven groups according to colon segment (cecum, ascending colon, hepatic flexure, transverse colon, splenic flexure, descending colon, and sigmoid colon). Expression of excision repair cross-complementing group 1 (ERCC1) and thymidylate synthase (TS) was examined by immunohistochemistry. We assessed if differences exist in patient characteristics and clinic outcomes between the seven groups. RESULTS: There were significant differences in tumor differentiation (P < 0.001), T stage (P < 0.001), N stage (P < 0.001), American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) stage (P < 0.001), metachronous liver metastasis (P < 0.001), metachronous lung metastasis (P < 0.001), and ERCCI expression (P < 0.001) between the seven groups. Both 5-year recurrence-free survival (RFS) and 5-year overall survival (OS) exhibited significant differences (both P < 0.001) with survival gradually decreasing from cecum to sigmoid colon. Cox regression analyses identified that tumor location was an independent prognostic factor for RFS and OS. CONCLUSIONS: Stage III colon cancer located proximally carried a poorer survival than that located distally. Different efficacies of FOLFOX adjuvant chemotherapy may be an important factor affecting survival of site-specific stage III colon cancers. PMID- 26054389 TI - Factors Associated with Non-disclosure of HIV Status in a Cohort of Childbearing HIV-Positive Women in Ukraine. AB - Ukraine has one of the largest populations of persons living with HIV in Europe. Data on 2019 HIV-positive married or cohabiting women enrolled in a postnatal cohort from 2007 to 2012 were analysed to investigate prevalence and factors associated with self-reported non-disclosure of HIV status. Median age at enrolment was 27.5 years, with two-thirds diagnosed during their most recent pregnancy. Almost all had received antenatal antiretroviral therapy and 24 % were taking it currently. One-tenth (n = 198) had not disclosed their HIV status to their partner and 1 in 20 (n = 93) had disclosed to no-one. Factors associated with non-disclosure were: unmarried status (AOR 2.99 (95 % CI 1.51-5.92), younger age at leaving full-time education (AOR 0.41 (95 % CI 0.19-0.88) for >=19 years vs <=16 years) and lack of knowledge of partner's HIV status (AOR 2.01 (95 % CI 1.09-3.66). Further work is needed to support disclosure in some groups and to explore relationships between disclosure and psychological factors in this setting, including depression, lack of support and perception of stigma. PMID- 26054390 TI - Attitudes and Acceptability on HIV Self-testing Among Key Populations: A Literature Review. AB - HIV self-testing (HIVST) is a potential strategy to overcome disparities in access to and uptake of HIV testing, particularly among key populations (KP). A literature review was conducted on the acceptability, values and preferences among KP. Data was analyzed by country income World Bank classification, type of specimen collection, level of support offered and other qualitative aspects. Most studies identified were from high-income countries and among men who have sex with men (MSM) who found HIVST to be acceptable. In general, MSM were interested in HIVST because of its convenient and private nature. However, they had concerns about the lack of counseling, possible user error and accuracy. Data on the values and preferences of other KP groups regarding HIVST is limited. This should be a research priority, as HIVST is likely to become more widely available, including in resource-limited settings. PMID- 26054391 TI - Attitudes Towards Power in Relationships and Sexual Concurrency Within Heterosexual Youth Partnerships in Baltimore, MD. AB - Sexual concurrency may increase risk for HIV/STIs among youth. Attitudes about gender roles, including power balances within sexual partnerships, could be a driver. We examined this association among Baltimore youth (N = 352), aged 15-24. Data were collected from February, 2011 to May, 2013. We examined whether index concurrency in male-reported partnerships (N = 221) and sex partner's concurrency in female-reported partnerships (N = 241) were associated with youth's attitudes towards relationship power. Males with more equitable beliefs about power were less likely to report index concurrency. Females with more equitable beliefs were more likely to report sex partner's concurrency. The relationship was significant in main and casual partnerships among females and main partnerships among males. The strongest associations were detected among middle-socioeconomic status (SES) males and low-SES and African American females. Implementing interventions that recognize the complex relationship between socioeconomic context, partner dynamics, gender, and sexual behavior is an important step towards reducing HIV/STI risk among youth. PMID- 26054393 TI - Continuous enhancement of iturin A production by Bacillus subtilis with a stepwise two-stage glucose feeding strategy. AB - BACKGROUND: The lipopeptide antibiotic iturin A is an attractive biopesticide with the potential to replace chemical-based pesticides for controlling plant pathogens. However, its industrial fermentation has not been realized due to the high production costs and low product concentrations. This study aims to enhance iturin A production by performing a novel fermentation process with effective glucose feeding control using rapeseed meal as a low-cost nitrogen source. RESULTS: We demonstrated that continuous and significant enhancement of iturin A production could be achieved by a novel two-stage glucose-feeding strategy with a stepwise decrease in feeding rate. Using this strategy, the ratio of spores to total cells could be maintained at a desirable/stable level of 0.80-0.86, and the reducing sugar concentration could be controlled at a low level of 2-3 g/L so that optimal substrate balance could be maintained throughout the feeding phase. As a result, the maximum iturin A concentration reached 1.12 g/L, which was two fold higher than that of batch culture. CONCLUSIONS: This is the first report which uses control of the glucose supply to improve iturin A production by fed batch fermentation and identifies some important factors necessary to realize industrial iturin A production. This approach may also enhance the production of other useful secondary metabolites by Bacillus subtilis. PMID- 26054392 TI - Natural selection on HFE in Asian populations contributes to enhanced non-heme iron absorption. AB - BACKGROUND: HFE, a major regulator of iron (Fe) homeostasis, has been suggested to be under positive selection in both European and Asian populations. While the genetic variant under selection in Europeans (a non-synonymous mutation, C282Y) has been relatively well-studied, the adaptive variant in Asians and its functional consequences are still unknown. Identifying the adaptive HFE variants in Asians will not only elucidate the evolutionary history and the genetic basis of population difference in Fe status, but also assist the future practice of genome-informed dietary recommendation. RESULTS: Using data from the International HapMap Project, we confirmed the signatures of positive selection on HFE in Asian populations and identified a candidate adaptive haplotype that is common in Asians (52.35-54.71%) but rare in Europeans (5.98%) and Africans (4.35%). The T allele at tag SNP rs9366637 (C/T) captured 95.8% of this Asian common haplotype. A significantly reduced HFE expression was observed in individuals carrying T/T at rs9366637 compared to C/C and C/T, indicating a possible role of gene regulation in adaptation. We recruited 57 women of Asian descent and measured Fe absorption using stable isotopes in those homozygous at rs9366637. We observed a 22% higher absorption in women homozygous for the Asian common haplotype (T/T) compared to the control genotype (C/C). Additionally, compared with a group of age-matched Caucasian women, Asian women exhibited significantly elevated Fe absorption. CONCLUSIONS: Our results indicate parallel adaptation of HFE gene in Europeans and Asians with different genetic variants. Moreover, natural selection on HFE may have contributed to elevated Fe absorption in Asians. This study regarding population differences in Fe homeostasis has significant medical impact as high Fe level has been linked to an increased disease risk of metabolic syndromes. PMID- 26054394 TI - The regional myocardial infarction registry of Saxony-Anhalt (RHESA) in Germany - rational and study protocol. AB - BACKGROUND: In 2012 the age-standardized acute myocardial infarction (AMI) mortality rate was in the federal state Saxony-Anhalt 67 deaths per 100.000 whereas in Germany the AMI-rate was 47 deaths per 100.000. The rate in Saxony Anhalt was therefore 43 % above the national average. Many factors may explain this above-average AMI mortality rate: First, the prevalence of cardiovascular risk factors (e.g. arterial hypertension, diabetes mellitus, smoking) in Saxony Anhalt is the highest among all the Federal States of Germany. Second, structural health care for patients with AMI is potentially deficient (e.g. insufficient number of percutaneous coronary intervention-centers or deficits in the pre hospital logistics of care). Third, the pre- and in-hospital process quality of health care for patients with AMI is possibly insufficient (e.g. time to reperfusion therapy). In July 2013 we established the regional myocardial infarction registry of Saxony-Anhalt (Regionales Herzinfarktregister in Sachsen Anhalt, RHESA). RHESA is a population-based registry in the eastern part of Germany. Aims of RHESA are to calculate the AMI morbidity and mortality rates. Furthermore we study the factors that may potentially influence these rates in Saxony-Anhalt. METHODS: RHESA is a population-based registry of patients with fatal or non-fatal AMI that was established in July 2013. The registry population comprises inhabitants aged 25 years or more of the city of Halle (Saale) (n = 179.000) and inhabitants of the rural district Altmark (n = 165.000) in the federal state Saxony-Anhalt, Germany. DISCUSSION: The main objectives of RHESA are to provide detailed estimates of the burden of AMI in Saxony-Anhalt which is the federal state with the highest AMI mortality rate in Germany and to investigate factors that influence morbidity and mortality rates due to AMI. Data collected in RHESA enable us to assess different levels of quality of health care of patients with AMI (structural, process and outcome). RHESA provides for the first time estimates of the burden of AMI in Saxony-Anhalt, and therefore contributes considerably to an improvement of the German Health Monitoring that strives for a more valid extrapolation of the nationwide morbidity and mortality rates of AMI. PMID- 26054395 TI - Cultural landscapes of the Araucaria Forests in the northern plateau of Santa Catarina, Brazil. AB - BACKGROUND: The Araucaria Forest is associated with the Atlantic Forest domain and is a typical ecosystem of southern Brazil. The expansion of Araucaria angustifolia had a human influence in southern Brazil, where historically hunter gatherer communities used the pinhao, araucaria's seed, as a food source. In the north of the state of Santa Catarina, the Araucaria Forest is a mosaic composed of cultivation and pasture inserted between forest fragments, where pinhao and erva-mate are gathered; some local communities denominate these forest ecotopes as caivas. Therefore, the aim of this study is to understand how human populations transform, manage and conserve landscapes using the case study of caivas from the Araucaria Forests of southern Brazil, as well as to evaluate the local ecological knowledge and how these contribute to conservation of the Araucaria Forest. METHODS: This study was conducted in the northern plateau of the state of Santa Catarina, Brazil in local five communities. To assess ethnoecological perceptions the historical use and management of caivas, semi structured interviews, checklist interviews and guided tours were conducted with family units. RESULTS: In total 28 family units participated in the study that had caivas on their properties. During the course of the study two main perceptions of the ecotope caiva were found, there is no consensus to the exact definition; perception of caivas is considered a gradient. In general caivas are considered to have the presence of cattle feeding on native pasture, with denser forest area that is managed, and the presence of specific species. Eleven management practices within caivas were found, firewood collection, cattle grazing, trimming of the herbaceous layer, and erva-mate extraction were the most common. Caivas are perceived and defined through the management practices and native plant resources. All participants stated that there have been many changes to the management practices within caivas and to the caiva itself. CONCLUSIONS: These areas still remain today due to cultural tradition, use and management of plant resources. Through this cultural tradition of maintaining caivas the vegetation of the Araucaria Forest has been conserved associated to the use of the Araucaria Forests native plant resources. PMID- 26054397 TI - Dendritic cells change IL-27 production pattern during childhood. AB - BACKGROUND: Interleukin-27 (IL-27) has been described to be highly expressed during the very first days after birth, but secretion of IL-27 by dendritic cells during the course of childhood has not been described. FINDINGS: In our present study we enrolled children (n = 55) in the range from 1 day of to 18 years of age and asked for a small whole blood sample. The capacity of dendritic cells to produce IL-27 during childhood was measured after whole blood culture with or without inflammatory stimuli. Results support recent findings of high IL-27 levels after birth and lowest levels in adults. Interestingly, we detected an interim peak production level at early adolescence. CONCLUSION: These data hint to prominent roles of IL-27 at the very start of post-natal life. Furthermore, a link has been given to so far not described immunological events during puberty. PMID- 26054396 TI - Drosophila Imp iCLIP identifies an RNA assemblage coordinating F-actin formation. AB - BACKGROUND: Post-transcriptional RNA regulons ensure coordinated expression of monocistronic mRNAs encoding functionally related proteins. In this study, we employ a combination of RIP-seq and short- and long-wave individual-nucleotide resolution crosslinking and immunoprecipitation (iCLIP) technologies in Drosophila cells to identify transcripts associated with cytoplasmic ribonucleoproteins (RNPs) containing the RNA-binding protein Imp. RESULTS: We find extensive binding of Imp to 3' UTRs of transcripts that are involved in F actin formation. A common denominator of the RNA-protein interface is the presence of multiple motifs with a central UA-rich element flanked by CA-rich elements. Experiments in single cells and intact flies reveal compromised actin cytoskeletal dynamics associated with low Imp levels. The former shows reduced F actin formation and the latter exhibits abnormal neuronal patterning. This demonstrates a physiological significance of the defined RNA regulon. CONCLUSIONS: Our data imply that Drosophila Imp RNPs may function as cytoplasmic mRNA assemblages that encode proteins which participate in actin cytoskeletal remodeling. Thus, they may facilitate coordinated protein expression in sub cytoplasmic locations such as growth cones. PMID- 26054398 TI - Risk adjustment in aging societies. AB - BACKGROUND: In Switzerland, age is the predominant driver of solidarity transfers in risk adjustment (RA). Concerns have been voiced regarding growing imbalances in cost sharing between young and old insured due to demographic changes (larger fraction of elderly >65 years and rise in average age). Particularly young adults aged 19-25 with limited incomes have to shoulder increasing solidarity burdens. Between 1996 and 2011, monthly intergenerational solidarity payments for young adults have doubled from CHF 87 to CHF 182, which corresponds to the highest absolute transfer increase of all age groups. RESULTS: By constructing models for age-specific RA growth and for calculating the lifetime sum of RA transfers we investigated the causes and consequences of demographic changes on RA payments. The models suggest that the main driver for RA increases in the past was below average health care expenditure (HCE) growth in young adults, which was only half as high (average 2% per year) compared with older adults (average 4% per year). Shifts in age group distributions were only accountable for 2% of the CHF 95 rise in RA payments. Despite rising risk adjustment debts for young insured the balance of lifetime transfers remains positive as long as HCE growth rates are greater than the discount rate used in this model (3%). Moreover, the life-cycle model predicts that the lifetime rate of return on RA payments may even be further increased by demographic changes. Nevertheless, continued growth of RA contributions may overwhelm vulnerable age groups such as young adults. We therefore propose methods to limit the burden of social health insurance for specific age groups (e.g. young adults in Switzerland) by capping solidarity payments. CONCLUSIONS: Taken together, our mathematical modelling framework helps to gain a better understanding of how demographic changes interact with risk adjustment and how redistribution of funds between age groups can be controlled without inducing further selection incentives. Those methods can help to construct more equitable systems of health financing in light of population aging. PMID- 26054399 TI - The impact of reference pricing and extension of generic substitution on the daily cost of antipsychotic medication in Finland. AB - OBJECTIVE: To assess the impact of reference pricing and extension of generic substitution on the daily cost of antipsychotic drugs in Finland during the first year after its launch. Furthermore, the additional impact of reference pricing on prior implemented generic substitution is assessed. METHODS: A retrospective analysis was performed between 2006 and 2010. A segmented linear regression analysis of interrupted time series was used to estimate changes in the levels and trends in the cost of one day of treatment. Of the study drugs, clozapine belonged to generic substitution already at the start of the study period while olanzapine and quetiapine were included in generic substitution alongside with reference pricing in 2009. Risperidone was included in generic substitution in 2008, before reference pricing. RESULTS: A substantial decrease in the daily cost of all four antipsychotic substances was seen after one year of the implementation of reference pricing and the extension of generic substitution. The impact ranged from -29.9% to -66.3%, and it was most substantial on the daily cost of olanzapine. Also in the daily cost of risperidone a substantial decrease of -43.3% was observed. However, most of these savings, -32.6%, were generated by generic substitution which had been adopted prior. CONCLUSIONS: Reference pricing and the extension of generic substitution produced substantial savings on antipsychotic medication costs during the first year after its launch, but the intensity of the impact differed between active substances. Furthermore, our results suggest that the additional cost savings from reference pricing after prior implemented generic substitution, are comparatively low. PMID- 26054400 TI - Methods for measuring horizontal equity in health resource allocation: a comparative study. AB - ?: There are many existing methodologies on measuring health equity, while seldom has method aiming at health resource allocation. We collected 6 method of measuring equity in health resource allocation. This paper presents key contents of methods on measuring horizontal equity in health service allocation, yet each method has its advantages and disadvantages as well as range of application, which may help researchers or government to make wise decision when choosing appropriate method for measuring equity. Through comparative analysis, we concluded that socioeconomic factors were considered in concentration index; although the Lorenz curve and Gini-coefficient are widely used, which exist uncertainty and incompleteness; overall inequality can be decomposed by Theil index, which is of significance for the planning of urban and rural areas; preferences on a certain class can be set artificially by Atkinson index; it is easy for Chi-square to analyze aided with statistical software; specific regional differences can be calculated by index of dissimilarity. CLASSIFICATION CODES: I1. PMID- 26054401 TI - Requirements for benefit assessment in Germany and England - overview and comparison. AB - BACKGROUND: This study compared the methodological requirements for early health technology appraisal (HTA) by the Federal Joint Committee/Institute for Quality and Efficiency in Health Care (G-BA/IQWiG; Germany) and the National Institute for Health and Care Excellence (NICE; England). METHODS: The following aspects were examined: guidance texts on methodology and information sources for the assessment; clinical study design and methodology; statistical analysis, quality of evidence base, extrapolation of results (modeling), and generalisability of study results; and categorisation of outcome. RESULTS: There is some degree of similarity regarding basic methodological elements such as selection of information sources (e.g. preference of randomised controlled studies, RCTs) and quality assessment of the available evidence. Generally, the approach taken by NICE seems to be more open and less restrictive as compared with G-BA/IQWiG. Any kind of potentially relevant evidence is requested, including data from non-RCTs. Surrogate endpoints are also accepted more readily, if they are reasonably likely to predict clinical benefit. Modeling is expected to be performed wherever possible and appropriate, e.g. for study duration, patient population, choice of comparator, and type of outcomes. The resulting uncertainty is quantified through sensitivity analyses before making a recommendation regarding reimbursement. By contrast, G-BA/IQWiG bases its assessment and quantification of the additional benefit largely, if not exclusively, on evidence of the highest level and quality and on measurements of "hard" clinical endpoints. This more conservative approach rather firmly dismisses evidence from non-RCTs and measurements of surrogate endpoints that have not or only partly been validated. Moreover, neither qualitative extrapolation nor quantitative modeling of data is done. CONCLUSIONS: Methodological requirements differed mainly in the acceptance of low-level evidence, surrogate endpoints, and data modeling. Some of the discrepancies may be explained, at least in part, by differences in the health care system and procedural aspects (e.g. timing of assessment). PMID- 26054402 TI - Macro-level factors impacting geographic disparities in cancer screening. AB - OBJECTIVES: Examine how differences in state regulatory environments predict geographic disparities in the utilization of cancer screening. DATA SOURCES/SETTING: 100% Medicare fee-for-service population data from 2001-2005 was developed as multi-year breast (BC) and colorectal cancer (CRC) screening utilization rates in each county in the US. STUDY DESIGN: A comprehensive set of supply and demand predictors are used in a multilevel model of county-level cancer screening utilization in the context of state regulatory markets. States dictate insurance mandates/regulations and whether alternative providers (nurse practitioners) can provide preventive care services supplied by MDs. Controlling statistically for the supply of both types of providers, we study the joint effects of two private insurance regulations: one mandating that insureds with serious or chronic health conditions may receive continuity of care from their established physician(s) after changing health insurance plans, and another mandating that external grievance review is an option for all health plan coverage/denial decisions. These private insurance plan regulations are expected to affect the degree of beneficial spillovers from managed care practices, which may have increased area-wide cancer screening rates. PRINCIPAL FINDINGS: The two private insurance regulations under study were significant predictors impacted by local market conditions. Managed care spillovers in local markets were significantly associated with higher BC screening rates, but only in states lacking the two forms of regulation under study. Spillovers were significantly associated with higher CRC cancer screening rates everywhere, but much higher in the unregulated states. Area poverty dampened screening rates, but less so for CRC screening in the states with these regulations. CONCLUSIONS: Two state insurance regulations that empowered consumers with more autonomy to make informed utilization decisions varied across states, and exhibited significant associations with screening rates, which varied with the degree of managed care penetration or poverty in the state's counties. Beneficial spillover effects from managed care practices and negative influences from area poverty are not uniform across the United States. Both variables had stronger associations with CRC than BC screening utilization, as did state regulatory variables. CRC screening by endoscopy was more subject to market and regulatory factors than BC screening. PMID- 26054403 TI - Prospective association between objective measures of childhood motor coordination and sedentary behaviour in adolescence and adulthood. AB - BACKGROUND: Higher levels of gross motor coordination are positively associated with physical activity in childhood, but little is known about how they relate to sedentary behaviour. The aim of this study was to investigate the longitudinal association between gross motor coordination at childhood and sedentary behaviour in adolescence and adulthood. METHODS: Data were from the 1970 British Cohort Study (the age 10, 16, and 42-year surveys). At age 10 the participant's mother provided information on how often participants watched TV and played sports and a health visitor administered several tests to assess gross motor coordination. At aged 16 and 42-years participants reported their daily screen and TV time, respectively, and physical activity status. We examined associations between gross motor coordination at age 10 with sedentary behaviour and physical activity at age 16 and 42, using logistic regression. RESULTS: In multivariable models, higher levels of gross motor coordination were associated with lower odds of high screen time (n = 3073; OR 0.79, 95% CI 0.64, 0.98) at 16-years although no associations with physical activity were observed (OR 1.16, 95% CI 0.93, 1.44). Similar associations were observed with TV time in adulthood when participants were aged 42, and in addition high gross motor coordination was also associated with physical activity participation (n = 4879; OR 1.18, 95 % CI 1.02, 1.36). CONCLUSIONS: Intervention efforts to increase physical activity participation and reduce sedentary behaviour over the life course may be best targeted towards children with low gross motor coordination. PMID- 26054404 TI - Inappropriate Drug Use in People with Cognitive Impairment and Dementia: A Systematic Review. AB - The aim of this systematic review was to identify, assess and summarize studies about potentially inappropriate drug use (IDU) in cognitive impairment and dementia and to present findings about whether cognitive impairment and dementia are associated with IDU. The search was made in Medline/PubMed using free terms in the title or abstract. The inclusion criteria were: English language, published until 1 March 2014, original quantitative study and assessment of overall IDU with a consensus based summarized measure. Exclusion criteria were: focus on specific patient group (other than cognitive impairment or dementia), focus on specific drug class and failure to present a prevalence measure of IDU or an effect estimate (i.e. odds ratio). Of the initial 182 studies found in Medline, 22 articles fulfilled the criteria. Most studies used the Beers criteria for assessment of IDU. Prevalence of IDU among individuals with cognitive impairment or dementia ranged from 10.2% to 56.4% and was higher in nursing home settings than in community-dwelling samples. Most studies reported a lower likelihood of IDU in case of cognitive impairment or dementia. To conclude, IDU is highly prevalent among persons with cognitive impairment and dementia, although these conditions seem to be associated with a lower probability of IDU. This might reflect an awareness among clinicians of cautious prescribing to this vulnerable group of patients. More studies on large cohorts of persons with cognitive impairment and dementia are needed to draw conclusions about optimal drug prescribing to this frail group of older persons. PMID- 26054406 TI - Multiscale approach for studying melting transitions in CuPt nanoparticles. AB - A multiscale approach, based on the combination of CALPHAD and molecular dynamics (MD) simulation, is applied in order to understand the melting transition taking place in CuPt nanoalloys. We found that in systems containing up to 1000 atoms, the morphology adopted by the nanoparticles causes the icosahedral CuPt to melt at temperatures 100 K below that of the other morphologies, if the chemical composition contains less than 30% of Pt. We show that the solid-to-liquid transition in CuPt nanoparticles of a radius equal to or greater than 3 nm could be studied using classical tools. PMID- 26054405 TI - Cohort profile: cholangiocarcinoma screening and care program (CASCAP). AB - BACKGROUND: Cholangiocarcinoma (CCA) is an extremely aggressive cancer that is usually fatal. Although globally morbidity and mortality are increasing, knowledge of the disease remains limited. The Mekong region of Southeast Asia, and particularly the northeast of Thailand, has by far the highest incidence of CCA worldwide with 135.4 per 100,000 among males and 43.0 per 100,000 among females being reported in Khon Kaen Province. Most patients are first seen during late stage disease with 5-year survival being less than 10%. Starting in 1984, control and prevention strategies have been focused on health education. Although early detection can substantially increase 5-year survival, there are currently no strategies to increase early diagnosis. METHODS/DESIGN: The Cholangiocarcinoma Screening and Care Program (CASCAP) is a prospective cohort study comprising two cohorts- the screening and the patient cohorts. For the screening cohort, ultrasound examination will be carried out regularly at least annually to determine whether there is current bile duct and/or liver pathology so that the optimal screening program for early diagnosis can be established. This cohort is expected to include at least 150,000 individuals coming from high-risk areas for CCA. For the patient cohort, it is estimated that about 25,000 CCA patients will be included during the 5-year recruitment period. All CCA patients will be treated according to routine clinical care and followed so that effective surgical treatment can be formulated. This cohort is indeed a conventional cancer registry. Thus, CASCAP is an ongoing project in which the number of participants changes dynamically. DISCUSSIONS: This is the first project on CCA that involves screening the at risk population at the community level. At the time of preparing this report, a total of 85,927 individuals have been enrolled in the screening cohort, 55.0% of whom have already undergone ultrasound screening, and 2661 CCA cases have been enrolled in the patient cohort. Among the participants of the screening, whose mean age was 53.8+/-9.8 years, 55.6% were female, 77.5% attained primary school as the highest level of education, 79.9% were farmers, 29.9%, reported having relatives with CCA, 89.1% had eaten uncooked fish, and 42.2% of those who had been tested for liver fluke were found to be infected. PMID- 26054407 TI - Validation of the SAMe-TT2R2 score in a nationwide population of nonvalvular atrial fibrillation patients on vitamin K antagonists. AB - The SAMe-TT2R2 score has been proposed to identify patients with non valvular atrial fibrillation (AF) who maintain a high average time in therapeutic range (TTR) on vitamin K antagonists treatment (VKA). This score has been validated in several studies, either monocentric or including very selected populations in a specialised setting. Our objective was to validate this score in a nationwide cohort of AF patients. From November 2013 to March 2014 we included in this study the first 10 patients with AF on VKA consecutively seen in 120 outpatient cardiology clinics in Spain. The SAMe-TT2R2 score was calculated for each patient and TTR in the preceding six months was estimated by Rosendaal method. A total of 1,056 patients were recruited (mean age 73.6 +/- 9.8 years, 42% female). Mean value of TTR was 63.8 +/- 25.9% (median 66.8%, interquartile range 45.6%-85.4%). We found a progressive decline in mean TTR from a score of 0 (67.5% +/- 24.6%) to >= 4 (52.7 +/- 28.7%, p < 0.01). The score was able to discriminate which patients had a good anticoagulation control (TTR >= 65%) with a C-statistic of 0.57 (95 %CI 0.53-0.60, p < 0.0005). A SAMe-TT2R2 score of 0-1 was associated with a good anticoagulation control with a sensitivity, specificity, positive and negative predictive values of 64%, 48%, 58% and 54%, respectively; and the odds ratio of having a TTR< 65% if the score was >= 2 was 1.64 (95% confidence interval 1.33-1.95, p < 0.001). In conclusion, in this nationwide population with AF on VKA, the SAMe-TT2R2 score had a significant, although moderate, ability to identify patients with a good anticoagulation control. PMID- 26054408 TI - Overt and subtle discrimination, subjective well-being and physical health related quality of life in an obese sample. AB - Obesity represents a serious health issue affecting millions of people in Western industrialized countries. The severity of the medical problems it causes is paralleled by the fact that obesity has become a social stigma that affects the psychological health-related quality of life of individuals with weight problems. Our study, with 111 obese patients of a Spanish hospital, focused specifically on how overt and subtle discrimination is related to subjective well-being (affect balance and life satisfaction) and physical health-related quality of life. It was shown that overt (r = -.28, p < .01 with affect balance; r = -.26, p < .01 with life satisfaction) and subtle discrimination (r = -.28, p < .01 with affect balance; r = -.27, p < .01 with life satisfaction) were negatively linked with subjective well-being, and that there was a negative correlation between overt discrimination and physical health-related quality of life (r = -.26, p < .01). Additionally, it was found that overt discrimination was a mediator variable in the relationship between physical health-related quality of life and subjective well-being using the Baron and Kenny procedure. Finally, it is discussed the relationship between discrimination, subjective well-being and physical health related quality of life in obese people. PMID- 26054409 TI - Attitudes towards same-sex marriage in Portugal: predictors and scale validation. AB - The goal of the present research was to validate a Portuguese version of Pearl and Galupo's (2007) Attitudes toward Same-Sex Marriage Scale (ATSM). Participants were 1,402 heterosexual men and women that completed an on-line questionnaire. The final 15-item scale formed a single factor showing high internal consistency (alpha = .95). This one factor structure was backed-up by a confirmatory factorial analysis. In a general way, the results indicate a clearly positive attitude toward same-sex marriage (overall mean was 63.79, SD = 12.66, above the scale mid-point, t(1401) = 55.55, p < .001). Furthermore, analysis of the scale's predictors demonstrates how a left-wing orientation (beta = .22, p < .001) and the level of denial of deservingness for lesbian/gay discrimination (beta = .30, p < .001) prove to be the best predictors of attitudes towards same-sex marriage. On the whole, these results indicate that the Portuguese ATSM version is a reliable instrument for carrying out scientific research and measuring and monitoring public opinion on this subject. PMID- 26054410 TI - Magnetic resonance imaging for prostate cancer: what the urologist needs to know. AB - The use of magnetic resonance imaging (MRI) for prostate cancer imaging has been an area of burgeoning research activity with a goal of finding imaging characteristics that will allow for improved diagnosis and surveillance of prostate cancer. This article will review the MRI sequences currently used for imaging the prostate and describe the scoring and reporting system used by radiologists for prostate MRI known as the Prostate Imaging Reporting and Data System (PI-RADS). Current research regarding the role of prostate MRI for patients without prior biopsy, with prior negative biopsy and elevated PSA, and on active surveillance protocols will also be reviewed. PMID- 26054411 TI - Novel biomarkers and genomic tests in prostate cancer: a critical analysis. AB - The aim of this review is to critically analyze the current state of research in selected biomarkers and genomic-based tests for prostate cancer (PCa) diagnosis, staging, prognostication, and monitoring. Although in Western societies, PCa is the most common solid malignancy and the second leading cause of cancer death in men, the vast majority of men with PCa are diagnosed with clinically localized disease. The widespread use of prostate-specific antigen (PSA) testing, on one hand, has resulted in earlier PCa detection at a potentially more curable stage, but on the other hand has led to an increase in the rate of negative biopsies, as well as overdetection and overtreatment of potentially indolent tumors that would not have become life-threatening to a patient. A multitude of molecular tests and algorithms has been developed to enhance diagnostic accuracy, improve pretreatment and post-treatment patient risk stratification, and identify aggressive versus indolent disease to facilitate therapeutic decision-making. PSA and derivatives (PSA kinetics, PSA density, percentage of free PSA) as well as algorithms based on PSA and PSA isoforms measurements (prostate health index, four-kallikrein score), urinary molecular biomarkers-based tests (Prostate Cancer Antigen 3, and the Michigan Health System Prostate Score) and selected genomic/proteomic tests now commercially available for disease prognostication (such as Confirm MDx, Prostate Core Mitomic Test, Oncotype DX, Prolaris, ProMark, and Decipher) are herein discussed to inform the readers about current and future clinical applications and their limitations. Finally, we briefly touch upon potential biomarkers predictive of response to therapy, such as androgen receptor splice variant AR-V7, and detection and quantification of circulating tumor cells in the blood stream. PMID- 26054412 TI - Active surveillance in prostate cancer: a critical review. AB - The aim of this paper was to examine the eligibility criteria, surveillance protocols and oncological outcomes of published active surveillance (AS) series. We also assessed the evidence for utility of novel tools for optimal risk stratification and surveillance of men suitable for AS. A non-systematic literature search of the Medline, Embase, and Scopus databases was performed in April 2015 using medical subject headings and free-text protocol. The search was conducted by applying free-text protocol with the following search terms: "active surveillance", "prostate cancer", "prostatic neoplasm", "watchful waiting", "low risk prostate cancer" and "very low risk prostate cancer". The definition of insignificant disease remains debatable as criteria for patient selection vary among studies. Tools for better selection of candidates and monitoring of the disease process have evolved since the conception of AS, including new biomarkers like phi, mpMRI and alternate biopsy strategies. AS is a sound strategy for reducing overtreatment of men with low-risk, and potentially selected men with intermediate-risk prostate cancer and shorter life expectancy, without compromising overall and cancer specific survival. More data are needed on the optimal integration of the new tools on AS paradigms and on the long-term health impact of AS in different populations. PMID- 26054413 TI - How Search for Meaning Interacts with Complex Categories of Meaning in Life and Subjective Well-Being? AB - This study sought to assess how the search for meaning interacts with crisis of meaning and with different categories of meaning in life (meaningfulness, crisis of meaning, existential indifference, and existential conflict). Furthermore, the moderation role of search for meaning between the relation of categories of meaning and subjective well-being (SWB) was also evaluated. Participants included 3,034 subjects (63.9% women) ranging in age from 18 to 91 (M = 33.90; SD = 15.01) years old from 22 Brazilian states. Zero-order correlations and a factorial MANOVA were implemented. Positive low correlations were found for search for meaning and crisis of meaning (r = .258; p < .001). Search for meaning presented a small-effect size moderation effect on the relation of the different categories of meaning with subjective happiness, F(6, 3008) = 2.698, p < .05; eta2 = .004, but not for satisfaction with life, F(6, 3008) = .935, p = .47; eta2 = .002. The differences on the levels of subjective happiness of those inserted in existential indifferent and conflicting categories differ depending on the levels of search for meaning. Further directions for future studies are proposed. PMID- 26054414 TI - Facile redox state manipulation in Cu(I) frameworks by utilisation of the redox active tris(4-(pyridin-4-yl)phenyl)amine ligand. AB - The incorporation of a redox-active tris(4-(pyridine-4-yl)phenyl)amine (NPy3) ligand into the Cu(I) coordination frameworks [CuNPy3NO3.solvent]n and [CuNPy3Cl.solvent]n has been shown to facilitate redox state switching in the materials. In both cases, the initial Cu(II) metal centre was reduced in situ during the solvothermal synthesis under relatively mild conditions where the use of chloride and nitrate counterions resulted in significantly different structures. Solid state electrochemical and Vis/NIR spectroelectrochemical experiments facilitated the characterisation and manipulation of the accessible redox states, demonstrating the highly tunable nature of the spectral properties a property of significant interest in the design of advanced materials. PMID- 26054415 TI - Electrospun porous carbon nanofiber@MoS2 core/sheath fiber membranes as highly flexible and binder-free anodes for lithium-ion batteries. AB - Self-standing membranes of porous carbon nanofiber (PCNF)@MoS2 core/sheath fibers have been facilely obtained through a combination of electrospinning, high temperature carbonization and the solvothermal reaction. PCNF fibers with porous channels are used as building blocks for the construction of hierarchical PCNF@MoS2 composites where thin MoS2 nanosheets are uniformly distributed on the PCNF surface. Thus, a three-dimensional open structure is formed, which provides a highly conductive pathway for rapid charge-transfer reactions, as well as greatly improving the surface active sites of MoS2 for fast lithiation/delithiation of Li(+) ions. The highly flexible PCNF@MoS2 composite membrane electrode exhibits synergistically improved electrochemical performance with a high specific capacity of 954 mA h g(-1) upon the initial discharge, a high rate capability of 475 mA h g(-1) even at a high current density of 1 A g( 1), and good cycling stability with almost 100% retention after 50 cycles, indicating its potential application as a binder-free anode for high-performance lithium-ion batteries. PMID- 26054416 TI - Assessing personal initiative among vocational training students: development and validation of a new measure. AB - Personal initiative characterizes people who are proactive, persistent and self starting when facing the difficulties that arise in achieving goals. Despite its importance in the educational field there is a scarcity of measures to assess students' personal initiative. Thus, the aim of the present study was to develop a questionnaire to assess this variable in the academic environment and to validate it for adolescents and young adults. The sample comprised 244 vocational training students. The questionnaire showed a factor structure including three factors (Proactivity-Prosocial behavior, Persistence and Self-Starting) with acceptable indices of internal consistency (ranging between alpha = .57 and alpha =.73) and good convergent validity with respect to the Self-Reported Initiative scale. Evidence of external validity was also obtained based on the relationships between personal initiative and variables such as self-efficacy, enterprising attitude, responsibility and control aspirations, conscientiousness, and academic achievement. The results indicate that this new measure is very useful for assessing personal initiative among vocational training students. PMID- 26054417 TI - Sex cord-stromal tumors of the ovary: a comprehensive review and update for radiologists. AB - Ovarian sex cord-stromal tumors are infrequent and represent approximately 7% of all primary ovarian tumors. This histopathologic ovarian tumor group differs considerably from the more prevalent epithelial ovarian tumors. Although sex cord stromal tumors present in a broad age group, the majority tend to present as a low-grade disease that usually follows a nonaggressive clinical course in younger patients. Furthermore, because the constituent cells of these tumors are engaged in ovarian steroid hormone production (e.g., androgens, estrogens, and corticoids), sex cord-stromal tumors are commonly associated with various hormone mediated syndromes and exhibit a wide spectrum of clinical features ranging from hyperandrogenic virilizing states to hyperestrogenic manifestations. The World Health Organization sex cord-stromal tumor classification has recently been revised, and currently these tumors have been regrouped into the following clinicopathologic entities: pure stromal tumors, pure sex cord tumors, and mixed sex cord-stromal tumors. Moreover, some entities considered in the former classification (e.g., stromal luteoma, stromal tumor with minor sex cord elements, and gynandroblastoma) are no longer considered separate tumors in the current classification. Herein, we discuss and revise the ultrasonography, computed tomography, and magnetic resonance imaging characteristics of the different histopathologic types and clinicopathologic features of sex cord stromal tumors to allow radiologists to narrow the differential diagnosis when facing ovarian tumors. PMID- 26054418 TI - Efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus and lupus nephritis who are refractory to conventional therapy. AB - OBJECTIVES: To evaluate the efficacy and safety of rituximab in Japanese patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) who are refractory to conventional immunosuppressive therapy. METHODS: Eligible patients received rituximab at a dose of 1,000 mg at days 1, 15, 169, and 183, and were followed for 53 weeks after the first dose of rituximab. Overall disease activity was assessed monthly using a British Isles Lupus Assessment Group activity index. Patients with LN (Upr/Ucr >= 1.0 at study entry) were identified and their renal responses were evaluated according to the criteria proposed by the American College of Rheumatology (ACR) and the Lupus Nephritis Assessment with Rituximab (LUNAR) study. RESULTS: A total of 34 patients were enrolled and received at least one dose of rituximab. Decrease in disease activity was achieved in 16 (76.5%) out of 34 patients. In 17 patients with LN, response rates of 58.8% and 52.9% by ACR and LUNAR criteria, respectively, were seen. Successful steroid tapering was achieved in association with disease remission. Rituximab was well tolerated, and most adverse drug reactions were grade 1-2 in severity. CONCLUSIONS: Rituximab is effective for treatment of Japanese patients with SLE and LN refractory to conventional therapy. PMID- 26054419 TI - Differential plasma microRNAs expression in juvenile idiopathic arthritis. AB - OBJECTIVES: To identify potential novel biomarkers for juvenile idiopathic arthritis (JIA), we evaluated the correlation between plasma expression levels of specific miRNAs and disease characteristics of JIA. METHODS: Differentially expressed miRNAs in JIA plasma were identified by microarray analysis. Five candidate plasma miRNAs with differential expression were further evaluated by qRT-PCR. The correlation between the expression of candidate plasma miRNAs and clinical parameters of JIA patients was assessed. RESULTS: The expression of miR 16, miR-146a, and miR-223 was higher, and miR-132 was lower, in the plasma of JIA patients as compared with healthy subjects and juvenile ankylosing spondylitis patients (p < 0.05). Plasma miR-16 concentrations were considerably higher for polyarticular JIA patients than oligoarticular JIA patients and correlated with the juvenile arthritis magnetic resonance imaging scores for the hip and plasma interleukin-6 or IL-6 levels. Additionally, miR-146a levels correlated directly with the Juvenile Arthritis Disease Activity Scores in 27 joints, the swollen joint count, the limited joint count, and the juvenile arthritis magnetic resonance imaging scores for the hip, but correlated inversely with plasma tumor necrosis factor-alpha or TNF-alpha levels. CONCLUSIONS: This study demonstrates that the expression of plasma miRNAs correlates with JIA disease and suggests that plasma miR-16 and miR-146a have potential novel value for JIA diagnosis. PMID- 26054420 TI - Quality of life in Japanese female patients with systemic lupus erythematosus: Evaluation using the Short Form 36 Health Survey. AB - OBJECTIVE: Aspects of health-related quality of life (HRQoL) are important for assessing perceived health status and treatment burden. We evaluated HRQoL using Short Form 36 Health Survey (SF-36) and factors associated with HRQoL. METHODS: We collected basic and lifestyle-related, clinical, and treatment characteristics among 119 female Japanese patients with systemic lupus erythematosus (SLE). Odds ratios (ORs) and their 95% confidence intervals were assessed for associations between HRQoL and selected factors. RESULTS: Irregularity of sleep was significantly associated with risk of lower role physical (RP) (OR = 8.27), vitality (VT) (OR = 8.45), and role emotional (OR = 10.7) domains. Compared with clerical work, non-clerical work was significantly associated with risk of lower RP (OR = 7.39), and unemployment was significantly associated with risk of lower VT (OR = 41.0). Daily soybean intake was associated with improved General Health or GH (OR = 0.17). Compared with Systemic Lupus Collaborative Clinics Damage Index (SDI) = 0, SDI > 2 was associated with risk of lower PF (OR = 7.88), RP (OR = 4.29), and bodily pain (OR = 3.06) domains. CONCLUSION: Reduced HRQoL was observed in our SLE patients. Interventions addressing sleep and work disturbances, as well as daily soybean consumption, could alter the HRQoL of SLE patients. PMID- 26054421 TI - Universal RNA-degrading enzymes in Archaea: Prevalence, activities and functions of beta-CASP ribonucleases. AB - beta-CASP ribonucleases are widespread in all three domains of life. They catalyse both 5'-3' exoribonucleolytic RNA trimming and/or endoribonucleolytic RNA cleavage using a unique active site coordinated by two zinc ions. These fascinating enzymes have a key role in 3' end processing in Eukarya and in RNA decay and ribosomal RNA maturation in Bacteria. The recent recognition of beta CASP ribonucleases as major players in Archaea is an important contribution towards identifying RNA-degrading enzymes in the third domain of life. Three beta CASP orthologous groups, aCPSF1, aCPSF2, aCPSF1b, are closely related to the eukaryal CPSF73 termination factor and one, aRNase J, is ortholog of the bacterial RNase J. The endo- and 5'-3' exoribonucleolytic activities carried by archaeal beta-CASP enzymes are strictly conserved throughout archaeal phylogeny suggesting essential roles in maturation and/or degradation of RNA. The recent progress in understanding the prevalence, activities and functions of archaeal beta-CASP ribonucleases is the focus of this review. The current status of our understanding of RNA processing pathways in Archaea is covered in light of this new knowledge on beta-CASP ribonucleases. PMID- 26054422 TI - Tackling Social Cognition in Schizophrenia: A Randomized Feasibility Trial. AB - BACKGROUND: Social cognition difficulties in schizophrenia are seen as a barrier to recovery. Intervention tackling problems in this domain have the potential to facilitate functioning and recovery. Social Cognition and Interaction Training (SCIT) is a manual-based psychological therapy designed to improve social functioning in schizophrenia. AIMS: The aim of this study is to evaluate the feasibility and acceptability of a modified version of SCIT for inpatient forensic wards. The potential benefits of the intervention were also assessed. METHOD: This study is a randomized single blind controlled design, with participants randomized to receive SCIT (N = 21) or treatment as usual (TAU; N = 15). SCIT consisted of 8-week therapy sessions twice per week. Participants were assessed at week 0 and one week after the intervention on measures of social cognition. Feasibility was assessed through group attendance and attrition. Participant acceptability and outcome was evaluated through post-group satisfaction and achievement of social goals. RESULTS: The intervention was well received by all participants and the majority reported their confidence improved. The SCIT group showed a significant improvement in facial affect recognition compared to TAU. Almost all participants agreed they had achieved their social goal as a result of the intervention. CONCLUSIONS: It is feasible to deliver SCIT in a forensic ward setting; however, some adaptation to the protocol may need to be considered in order to accommodate for the reduced social contact within forensic wards. Practice of social cognition skills in real life may be necessary to achieve benefits to theory of mind and attributional style. PMID- 26054423 TI - Diabetes Self-Management Education and Support in Type 2 Diabetes: A Joint Position Statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. PMID- 26054424 TI - Amphotericin B Resistance in Aspergillus terreus Is Overpowered by Coapplication of Pro-oxidants. AB - AIMS: Invasive fungal infections have significantly increased over the past decades in immunocompromised individuals and high-risk patients. Amphotericin B (AmB) exerts a powerful and broad activity against a vast array of fungi and has a remarkably low rate of microbial resistance. However, most isolates of Aspergillus terreus developed an intrinsic resistance against AmB, and during this study, we characterized the mode of action of this polyene antifungal drug in more detail in resistant (ATR) and rare susceptible (ATS) clinical isolates of A. terreus. RESULTS: We illustrate that AmB treatment changes cellular redox status and promotes the generation of high levels of reactive oxygen species (ROS) in ATS. In contrast, ATR isolates were able to cope better with AmB-induced oxidative stress. INNOVATION: Most importantly, we demonstrate in this study that coapplication of anti- and pro-oxidants significantly affects AmB efficacy in an antithetic manner--antioxidants and ROS-scavenging agents increase AmB tolerance in susceptible strains, while pro-oxidants render formerly resistant isolates considerably susceptible to the antifungal drug also in vivo in a Galleria animal model. CONCLUSION: Thereby, our study provides novel therapeutic options to treat formerly resistant fungal strains by a combination of AmB and pro-oxidant compounds. PMID- 26054425 TI - Sex differences in knee loading in recreational runners. AB - Patellofemoral pain is the most common chronic pathology in recreational runners. Female runners are at greater risk of developing patellofemoral pain, although the exact mechanism behind this is not fully understood. This study aimed to determine whether female recreational runners exhibit distinct knee loading compared to males. Fifteen males and 15 females recreational runners underwent 3D running analysis at 4.0 ms(-1)+/-5%. Sagittal/coronal joint moments, patellofemoral contact forces (PTF) and pressures (PCP) were compared between sexes. The results show that females exhibited significantly greater knee extension (p<0.008, peta(2)=0.27: males=3.04; females=3.47 N m kg(-1)) and abduction (p<0.008, peta(2)=0.28: males=0.54; females=0.82 N m kg(-1)) moments as well as PTF (p<0.008, peta(2)=0.29: males=3.25; females=3.84 B.W.) and PCP (p<0.008, peta(2)=0.26: males=7.96; females=9.27 MPa) compared to males. Given the proposed relationship between knee joint loading and patellofemoral pathology, the current investigation provides insight into the incidence of patellofemoral pain in females. PMID- 26054426 TI - Mechanical trapping of the nucleus on micropillared surfaces inhibits the proliferation of vascular smooth muscle cells but not cervical cancer HeLa cells. AB - The interaction between cells and the extracellular matrix on a topographically patterned surface can result in changes in cell shape and many cellular functions. In the present study, we demonstrated the mechanical deformation and trapping of the intracellular nucleus using polydimethylsiloxane (PDMS)-based microfabricated substrates with an array of micropillars. We investigated the differential effects of nuclear deformation on the proliferation of healthy vascular smooth muscle cells (SMCs) and cervical cancer HeLa cells. Both types of cell spread normally in the space between micropillars and completely invaded the extracellular microstructures, including parts of their cytoplasm and their nuclei. We found that the proliferation of SMCs but not HeLa cells was dramatically inhibited by cultivation on the micropillar substrates, even though remarkable deformation of nuclei was observed in both types of cells. Mechanical testing with an atomic force microscope and a detailed image analysis with confocal microscopy revealed that SMC nuclei had a thicker nuclear lamina and greater expression of lamin A/C than those of HeLa cells, which consequently increased the elastic modulus of the SMC nuclei and their nuclear mechanical resistance against extracellular microstructures. These results indicate that the inhibition of cell proliferation resulted from deformation of the mature lamin structures, which might be exposed to higher internal stress during nuclear deformation. This nuclear stress-induced inhibition of cell proliferation occurred rarely in cancer cells with deformable nuclei. PMID- 26054427 TI - Protein-protein interaction identification using a hybrid model. AB - BACKGROUND: Most existing systems that identify protein-protein interaction (PPI) in literature make decisions solely on evidence within a single sentence and ignore the rich context of PPI descriptions in large corpora. Moreover, they often suffer from the heavy burden of manual annotation. METHODS: To address these problems, a new relational-similarity (RS)-based approach exploiting context in large-scale text is proposed. A basic RS model is first established to make initial predictions. Then word similarity matrices that are sensitive to the PPI identification task are constructed using a corpus-based approach. Finally, a hybrid model is developed to integrate the word similarity model with the basic RS model. RESULTS: The experimental results show that the basic RS model achieves F-scores much higher than a baseline of random guessing on interactions (from 50.6% to 75.0%) and non-interactions (from 49.4% to 74.2%). The hybrid model further improves F-score by about 2% on interactions and 3% on non-interactions. CONCLUSION: The experimental evaluations conducted with PPIs in well-known databases showed the effectiveness of our approach that explores context information in PPI identification. This investigation confirmed that within the framework of relational similarity, the word similarity model relieves the data sparseness problem in similarity calculation. PMID- 26054428 TI - An empirical evaluation of supervised learning approaches in assigning diagnosis codes to electronic medical records. AB - BACKGROUND: Diagnosis codes are assigned to medical records in healthcare facilities by trained coders by reviewing all physician authored documents associated with a patient's visit. This is a necessary and complex task involving coders adhering to coding guidelines and coding all assignable codes. With the popularity of electronic medical records (EMRs), computational approaches to code assignment have been proposed in the recent years. However, most efforts have focused on single and often short clinical narratives, while realistic scenarios warrant full EMR level analysis for code assignment. OBJECTIVE: We evaluate supervised learning approaches to automatically assign international classification of diseases (ninth revision) - clinical modification (ICD-9-CM) codes to EMRs by experimenting with a large realistic EMR dataset. The overall goal is to identify methods that offer superior performance in this task when considering such datasets. METHODS: We use a dataset of 71,463 EMRs corresponding to in-patient visits with discharge date falling in a two year period (2011-2012) from the University of Kentucky (UKY) Medical Center. We curate a smaller subset of this dataset and also use a third gold standard dataset of radiology reports. We conduct experiments using different problem transformation approaches with feature and data selection components and employing suitable label calibration and ranking methods with novel features involving code co-occurrence frequencies and latent code associations. RESULTS: Over all codes with at least 50 training examples we obtain a micro F-score of 0.48. On the set of codes that occur at least in 1% of the two year dataset, we achieve a micro F-score of 0.54. For the smaller radiology report dataset, the classifier chaining approach yields best results. For the smaller subset of the UKY dataset, feature selection, data selection, and label calibration offer best performance. CONCLUSIONS: We show that datasets at different scale (size of the EMRs, number of distinct codes) and with different characteristics warrant different learning approaches. For shorter narratives pertaining to a particular medical subdomain (e.g., radiology, pathology), classifier chaining is ideal given the codes are highly related with each other. For realistic in-patient full EMRs, feature and data selection methods offer high performance for smaller datasets. However, for large EMR datasets, we observe that the binary relevance approach with learning-to-rank based code reranking offers the best performance. Regardless of the training dataset size, for general EMRs, label calibration to select the optimal number of labels is an indispensable final step. PMID- 26054429 TI - Analysis of lasalocid residues in grease and fat using liquid chromatography-mass spectrometry. AB - A method for the determination of lasalocid, an antibiotic and coccidiostat, in grease and fat is described. The manufacture of lasalocid produces a grease-like residue as a waste byproduct. Recently this byproduct has been shown to have been illegally introduced into the animal feed chain. Therefore, a quantitative and confirmatory procedure to analyse for lasalocid in this matrix is needed. A portion of grease/oil sample was extracted into hexane-washed acetonitrile, and a portion of the extract was then applied to a carboxylic acid solid-phase extraction (SPE) column for concentration and clean-up. The SPE column was washed with additional hexane-washed acetonitrile and ethyl acetate/methanol, after which lasalocid was eluted with 10% ammoniated methanol. The eluate was evaporated to dryness, redissolved in (1:1) acetonitrile-water and filtered through a PTFE syringe filter. Confirmation and quantitation of lasalocid in the final extract employed a triple quadrupole LC-MS/MS. The method was applied to grease and oil samples containing from 0.02 to 34,000 mg kg(-1) of lasalocid. PMID- 26054430 TI - Confetti-like depigmentation: A potential sign of rapidly progressing vitiligo. AB - BACKGROUND: Confetti-like depigmentation was noted in patients reporting recent worsening of vitiligo. OBJECTIVE: We sought to determine if confetti-like depigmentation is a marker of rapidly progressing vitiligo. METHODS: Review of patient records and images of patients from a vitiligo registry resulted in 7 patients with 12 images that fit inclusion criteria and were evaluated for percent depigmentation by 3 independent reviewers. The Vitiligo Disease Activity Score and the Koebner Phenomenon in Vitiligo Score in an additional cohort of patients with confetti-like lesions were compared with patients who had vitiligo without confetti-like lesions. RESULTS: The mean percentage of depigmentation at baseline was 19.2%, which increased to 43.9% in images obtained at a mean of 16 weeks of follow-up. Vitiligo Disease Activity Score and Koebner Phenomenon in Vitiligo Score were significantly higher in the patients with confetti-like lesions compared with those without confetti-like lesions. A skin biopsy specimen of a confetti-like lesion in 1 patient revealed an inflammatory infiltrate in the papillary dermis with CD8(+) T cells localized to the dermoepidermal junction. LIMITATIONS: Small, single-center retrospective review and lack of full-body photographs are limitations. CONCLUSIONS: A confetti-like pattern of depigmentation may be a negative prognostic indicator for patients with rapidly progressing vitiligo. Further, prospective studies to evaluate this physical finding should be performed. PMID- 26054431 TI - Updates in adult-onset Still disease: Atypical cutaneous manifestations and associations with delayed malignancy. AB - Adult-onset Still disease (AOSD) is a systemic inflammatory disorder that is clinically characterized by a heterogeneous constellation of symptoms and signs. Though an evanescent eruption is the classic cutaneous finding, recent literature has highlighted atypical rashes associated with Still disease. A second emerging concept in presentations of AOSD is its association with malignancy. This review focuses on these concepts: the clinical spectrum of atypical skin manifestations and AOSD as a paraneoplastic phenomenon. PubMed-MEDLINE was screened for peer reviewed articles describing atypical presentations of AOSD and cases associated with malignancy. Erythematous, brown or violaceous, persistent papules and plaques were the most common cutaneous finding (28/30 [93%]). Linear configurations were also rarely described. Of these patients, 81% concurrently had the typical evanescent skin eruption. There were 31 patients with associated malignancies, most commonly breast cancer and lymphoma. The diagnosis of malignancy did not precede or immediately follow a clinical presentation otherwise consistent with AOSD in a considerable subset of patients (42%). Understanding the cutaneous spectrum of AOSD and heightened awareness for its delayed association with malignancy may lead to improved recognition of cutaneous variants and reinforce the need for diagnostic evaluation and long-term follow-up for malignancy in patients with this clinical presentation. PMID- 26054432 TI - Prevalence of undiagnosed psoriatic arthritis among psoriasis patients: Systematic review and meta-analysis. AB - BACKGROUND: Skin psoriasis precedes the onset of psoriatic arthritis (PsA) in 84% of patients with psoriasis. Dermatologists have an important role to screen psoriasis patients for PsA. The efficiency of PsA screening remains unknown. OBJECTIVE: We sought to determine the point prevalence of undiagnosed PsA in patients with psoriasis using a systematic search of the literature and meta analysis. METHODS: PubMed, Cochrane, and Embase database searches yielded 394 studies for review. No study aimed to determine the prevalence of undiagnosed PsA in patients with psoriasis. We assumed that the prevalence of newly diagnosed PsA in patients with psoriasis at the time they seek medical care could be a sound estimate of this value. Seven epidemiological studies and 5 studies on PsA screening questionnaires allowed us to clearly identify patients with newly diagnosed PsA and were selected for review. RESULTS: The prevalence of undiagnosed PsA was 15.5% when all studies were considered and 10.1% when only epidemiological studies were considered. LIMITATIONS: Data were obtained from studies not designed to address the question at hand. Heterogeneity was high (I(2) = 96.86%), and therefore a random effects model was used. CONCLUSION: The high prevalence of undiagnosed PsA in patients with psoriasis adds to the recommendation that dermatologists need to screen all patients with psoriasis for PsA. PMID- 26054433 TI - Experience with Holter monitoring during propranolol therapy for infantile hemangiomas. AB - BACKGROUND: Although adverse events in children treated with propranolol have proven rare, the appropriate methods of assessing cardiovascular risk and monitoring for toxicity when the medication is used for infantile hemangiomas remain unclear. OBJECTIVE: We sought to analyze Holter monitor reports of otherwise healthy patients on propranolol for infantile hemangiomas to determine the incidence of sustained arrhythmias and to evaluate the utility of Holter monitoring in the outpatient setting. METHODS: We retrospectively reviewed the charts of patients with infantile hemangioma who underwent 24-hour Holter monitoring after initiation or dose escalation of propranolol between 2011 and 2014. RESULTS: In all, 43 patients aged 1.8 to 36.2 months, with 44 Holter monitor reports, were included in the study. No sustained arrhythmias were revealed. The treatment plan was not altered in any patient based on the Holter monitor report. LIMITATIONS: This was a retrospective study design. CONCLUSION: Our study suggests that Holter monitoring may be unnecessary in otherwise healthy patients with infantile hemangioma older than 12 weeks who are treated with propranolol in the outpatient setting. PMID- 26054434 TI - Towards a "Golden Standard" for computing globin stability: Stability and structure sensitivity of myoglobin mutants. AB - Fast and accurate computation of protein stability is increasingly important for e.g. protein engineering and protein misfolding diseases, but no consensus methods exist for important proteins such as globins, and performance may depend on the type of structural input given. This paper reports benchmarking of six protein stability calculators (POPMUSIC 2.1, I-Mutant 2.0, I-Mutant 3.0, CUPSAT, SDM, and mCSM) against 134 experimental stability changes for mutations of sperm whale myoglobin. Six different high-resolution structures were used to test structure sensitivity that may impair protein calculations. The trend accuracy of the methods decreased as I-Mutant 2.0 (R=0.64-0.65), SDM (R=0.57-0.60), POPMUSIC2.1 (R=0.54-0.57), I-Mutant 3.0 (R=0.53-0.55), mCSM (R=0.35-0.47), and CUPSAT (R=0.25-0.48). The mean signed errors increased as SDM3,927 vs. 6,550, p = 0.037) and provided hours (200 vs. 333 hours per year, p = 0.037). CONCLUSIONS: The intervention was cost neutral and does not seem to have affected health-related quality of life for the 1-year study, which may be because the follow-up period was too short. The intervention seems to have reduced hours and cost of informal care and help required with instrumental activities of daily living. This suggests that the intervention provides relief to informal caregivers. PMID- 26054489 TI - Effectiveness of laparoscopic Roux-en-Y gastric bypass on obese class I type 2 diabetes mellitus patients. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) can dramatically improve type 2 diabetes mellitus (T2D) in obese class II and III patients. There is increasing evidence that shows bariatric surgery can also ameliorate T2D in patients with BMI between 30 kg/m(2) and 35 kg/m(2) (obese class I). OBJECTIVE: To compare the effectiveness of LRYGB on T2D in obese class I patients with that of obese class II and III T2D patients. SETTING: University Hospital, China METHODS: A prospective study was performed in the authors' center from March 2010 to July 2011. Forty-two consecutive obese patients were included in the study. Anthropometric and metabolism parameters were compared between obese class II and III patients and obese class I patients before and after LRYGB. RESULTS: No patients were lost to follow up. After 36 months, metabolic parameters significantly improved in both groups. Partial remission rates between the 2 groups at each time point (12 months, 24 months, and 36 months) were comparable. Obese class II and III patients had higher complete remission rates at 12 months and 24 months, but no difference was observed at 36 months. CONCLUSION: Both obese class II and III patients and obese class I T2D patients showed significant improvement in multiple parameters after LRYGB. Obese class II and III patients had a higher complete remission rate than obese class I patients. Standardized remission criteria are needed to make outcomes form different centers comparable. Large prospective studies are needed and long-term outcomes have to be observed to better evaluate effectiveness of LRYGB on obese class I T2D patients. PMID- 26054490 TI - Can far-IR action spectroscopy combined with BOMD simulations be conformation selective? AB - The combination of conformation selective far-IR/UV double resonance spectroscopy with Born-Oppenheimer molecular dynamics (BOMD) simulations is presented here for the structural characterization of the Ac-Phe-Pro-NH2 peptide in the far-infrared spectral domain, i.e. for radiation below 800 cm(-1). Two conformers have been shown to be present in the experiment, namely a conformer with a gamma-turn fold (C7 interaction) and a beta-turn fold (C10 interaction). The combined experimental and theoretical work presented here aims to provide spectral features typical of each conformer in this far-IR domain. The simulated BOMD far IR spectra agree well with the experimental spectra and allow direct assignment of the observed bands. These assignments show that the 400-550 cm(-1) spectral domain is conformer selective, allowing us to distinguish the H-bond signature of the gamma-turn from the beta-turn. PMID- 26054491 TI - Empirically supported treatments for panic disorder with agoraphobia in a Spanish psychology clinic. AB - The aim of this work is to study the sociodemographic and clinical characteristics of patients diagnosed with Panic Disorder with Agoraphobia (PD/Ag), as well as the characteristics of the treatment and its results and cost in a University Psychology Clinic. Fifty patients demanded psychological assistance for PD/Ag; 80% were women, with an average age of 29.22 years (SD = 9.03). Mean number of evaluation sessions was 3.26 (SD = 1.03), and of treatment sessions, 13.39 (SD = 9.237). Of the patients, 83.33% were discharged (that is, questionnaire scores were below the cut-off point indicated by the authors, and no PD/Ag was observed at readministration of the semistructured interview), 5.5% refused treatment, and 11% were dropouts. The average number of treatment sessions of patients who achieved therapeutic success was 15.13 (SD = 8.98). Effect sizes (d) greater than 1 were obtained in all the scales. Changes in all scales were significant (p < .05). The estimated cost of treatment for patients who achieved therapeutic success was 945.12?. The treatment results are at least similar to those of studies of efficacy and effectiveness for PD/Ag. The utility of generalizing treatments developed in research settings to a welfare clinic is discussed. PMID- 26054492 TI - Distance to the object and social representations: replication and further evidences. AB - Distance to the object is a new approach that highlights the complex nature of the link between groups and social representations. It is composed of three elements: knowledge, involvement, and level of practices associated with the social object. This study aims to replicate a previous study that has demonstrated the validity of distance to the object in order to explore social representations of cannabis. We carried out a research on the social representations of cocaine. Respondents (n = 200) completed a questionnaire including opinions related to cocaine and constitutive elements of the distance to cocaine. The regression analysis on the representational dimensions revealed a significant effect of the distance variable on two dimensions (social facilitator, addiction and social dangerousness). The groups that were "distant" from the object showed stronger adherence to the normative component than to the functional component of SR, in opposition to those who were "close" to the object. The concept of distance to the object is thus heuristic as it offers an integrative grid of reading that permits to understand and highlight the link individuals maintain with a social representation. PMID- 26054493 TI - Wnt1-overexpressing skeletal myoblasts as an improved cell therapy for cardiac repair following myocardial infarction. AB - AIM: Recent findings highlight the critical role of the Wnt signaling pathway in cardiac repair and stem cell regulation. Our previous study shows that lithium chloride (LiCl) optimizes skeletal myoblast (SkM) for transplantation by mimicking the Wnt/beta-catenin signaling activities. In this study, we evaluate the therapeutic potential of SkMs genetically modified with Wnt1gene (Wnt1 SkMs) in a rat model with myocardial infarction (MI). METHODS: We harvested neonatal SkMs using Wistar rats (1-3-day old) transfected with p-EGFP-C3-Wnt1 plasmid. RT PCR and immunofluorescence showed a higher expression of Wnt1 in the Wnt1 SkMs. We observed that Wnt1 SkMs increased connexin 43 (Cx43) expression, reduced apoptosis induced by hydrogen peroxide (H2O2) and decreased caspase-3 expression via the canonical Wnt signaling pathways compared to the empty vector transfected SkMs (control SkMs). For in vivo studies, the myocardial infarction model was developed in the Wistar rats. The rats were grouped to receive 100 MUL basal DMEM without cells or containing 1.5*106SkMs and Wnt1 SkMs. Histological studies revealed improved survival of SkMs, reduced cardiomyocytes apoptosis, and upregulated expression of Cx43 in Wnt1 SkMs therapy group. Echocardiography monitored four weeks after therapy showed improvement of the left ventricular function in rats treated with Wnt1SkMs compared to other groups. CONCLUSION: Transplantation of Wnt1 SkMs improves rat myocardial function and enhances anti apoptotic properties of both SkMs and cardiomyocytes and upregulation of tissue Cx43 after infarction via the canonical Wnt/beta-catenin signaling activities. PMID- 26054494 TI - Differences between Alcoholics and Cocaine Addicts Seeking Treatment. AB - This study explored the characteristics of a representative sample of patients who were addicted to either alcohol or cocaine, comparing the profiles of both types of drug users. A sample of 234 addicted patients (109 alcoholics and 125 cocaine addicts) who sought outpatient treatment in a Spanish clinical centre was assessed. Data on socio-demographic, consumption, psychopathological and maladjustment characteristics were collected using the European Addiction Severity Index (EuropASI), the Symptom Checklist-90-Revised (SCL-90-R) and the Millon Clinical Multiaxial Inventory (MCMI-II). Demographically, differences were observed with regard to age (alcoholics were older than cocaine addicts; t = 12.2, p = .001), employment (the alcoholic group had more labor problems; chi 2 = 6.2, p = .045) and family consequences (worse in alcoholics; t = 2.3, p = .025). The EuropASI results showed statistically significant differences in addiction severity, with alcoholics showing a greater severity than cocaine addicts. In terms of psychopathology, alcoholics presented more associated symptomatology than cocaine addicts. According to these results, patients with alcohol dependence have a different profile from patients with cocaine dependence, resulting in different repercussions for important areas of their lives. These differences should be taken into account when standard treatments for addiction are implemented. PMID- 26054495 TI - Macroscopic quantum tunnelling in spin filter ferromagnetic Josephson junctions. AB - The interfacial coupling of two materials with different ordered phases, such as a superconductor (S) and a ferromagnet (F), is driving new fundamental physics and innovative applications. For example, the creation of spin-filter Josephson junctions and the demonstration of triplet supercurrents have suggested the potential of a dissipationless version of spintronics based on unconventional superconductivity. Here we demonstrate evidence for active quantum applications of S-F-S junctions, through the observation of macroscopic quantum tunnelling in Josephson junctions with GdN ferromagnetic insulator barriers. We show a clear transition from thermal to quantum regime at a crossover temperature of about 100 mK at zero magnetic field in junctions, which present clear signatures of unconventional superconductivity. Following previous demonstration of passive S-F S phase shifters in a phase qubit, our result paves the way to the active use of spin filter Josephson systems in quantum hybrid circuits. PMID- 26054496 TI - Relative Validity of a Diet History Questionnaire Against a Four-Day Weighed Food Record among Older Men in Australia: The Concord Health and Ageing in Men Project (CHAMP). AB - OBJECTIVES: To evaluate the relative validity of the diet history questionnaire (DHQ) used in the Concord Health and Ageing in Men Project (CHAMP) against a four day weighed food record (4dWFR) as the reference method. DESIGN AND MEASUREMENTS: Detailed DHQ followed by a 4dWFR were completed between July 2012 and October of 2013. SETTING: Burwood, Canada Bay and Strathfield in Sydney, Australia. PARTICIPANTS: Fifty six community- dwelling men aged 75 years and over (mean=79 years). RESULTS: DHQ estimates of intakes were generally higher than estimates from 4dWFR. Differences between the two methods were generally less than 20% with the exception of beta-carotene (37%). Fixed and proportional biases were only present for retinol, beta-carotene, magnesium, phosphorus and percentage of energy from protein; however, 95% limits of agreement were in some cases wide. Pearson correlation coefficient of log-transformed unadjusted values ranged from 0.15 (zinc) to 0.70 (alcohol), and from 0.06 (iron) to 0.63 (thiamin) after energy-adjustment. Spearman's correlation coefficients ranged from 0.16 (zinc) to 0.80 (alcohol) before energy adjustment, and from 0.15(zinc) to 0.81(alcohol) after energy adjustment. CONCLUSION: Our findings suggest that the DHQ used in CHAMP to measure the nutritional intake of its participants is appropriate to this age group and provides reasonably similar results to the 4dWFR for the majority of nutrients analysed. PMID- 26054497 TI - Self- Perception of Body Weight Status in Older Dutch Adults. AB - INTRODUCTION: OBJECTIVES: The prevalence of obesity is highest in older persons and a correct self-perception of body weight status is necessary for optimal weight control. The aim of this study was to determine self-perception of, and satisfaction with, body weight status, and to compare current versus ideal body image in a large, nationally representative sample of older people. Furthermore, determinants of misperception were explored. DESIGN: A cross-sectional study. SETTING: The Longitudinal Aging Study Amsterdam (LASA), conducted in a population based sample in the Netherlands. PARTICIPANTS: 1295 men and women aged 60-96 years. MEASUREMENTS: Body weight status was assessed using measured weight and height. Self-perceived body weight status, satisfaction with body weight and current and ideal body image were also assessed. Multiple logistic regression analysis was used to investigate the association of age, educational level and objectively measured BMI with underestimation of body weight status. RESULTS: The prevalence of obesity was 19.9% in men and 29.3% in women. The agreement between objective and self-perceived body weight status was low (Kappa < 0.2). Among overweight and obese persons, 42.1% of men and 44.1% of women were (very) dissatisfied with their body weight status and >99% of obese participants desired to be thinner (ideal body image < current image). Only 4.4% of obese men and 12.3% of obese women perceived their body weight status correctly. Higher age (women), lower educational level (men) and higher BMI (all) were associated with greater underestimation of body weight status. CONCLUSION: Many older persons misperceive their body weight status. Future actions to improve body weight perception in older persons are necessary to increase the impact of public health campaigns focussing on a healthy body weight in old age. PMID- 26054498 TI - Dehydration in the Elderly: A Review Focused on Economic Burden. AB - BACKGROUND: Dehydration is the most common fluid and electrolyte problem among elderly patients. It is reported to be widely prevalent and costly to individuals and to the health care system. The purpose of this review is to summarize the literature on the economic burden of dehydration in the elderly. METHOD: A comprehensive search of several databases from database inception to November 2013, only in English language, was conducted. The databases included Pubmed and ISI Web of Science. The search terms "dehydration" / "hyponaremia" / "hypernatremia" AND "cost" AND "elderly" were used to search for comparative studies of the economic burden of dehydration. A total of 15 papers were identified. RESULTS: Dehydration in the elderly is an independent factor of higher health care expenditures. It is directly associated with an increase in hospital mortality, as well as with an increase in the utilization of ICU, short and long term care facilities, readmission rates and hospital resources, especially among those with moderate to severe hyponatremia. CONCLUSIONS: Dehydration represents a potential target for intervention to reduce healthcare expenditures and improve patients' quality of life. PMID- 26054499 TI - Lean Mass Appears to Be More Strongly Associated with Bone Health than Fat Mass in Urban Black South African Women. AB - OBJECTIVES: To examine the association between body composition (fat mass, lean mass and body mass index, BMI) and bone health (bone mineral density, BMD and fracture risk) in urban black South African women. DESIGN: A cross sectional study examining associations between body composition, dietary intake (food frequency questionnaire), habitual physical activity (Activity energy expenditure (AEE) measured using an accelerometer with combined heart rate monitor and physical activity questionnaire) and bone health (BMD using dual-energy X ray absorptiometry, DXA and fracture risk). SETTING: Urban community dwellers from Ikageng in the North-West Province of South Africa. PARTICIPANTS: One hundred and eighty nine (189) healthy postmenopausal women aged >=43 years. RESULTS: Fat mass and lean mass were significantly associated with BMD and fracture risk when adjusted for potential confounders. However, lean mass and not fat mass remained significantly associated with femoral neck BMD (beta = 0.49, p <0.001), spine BMD (beta = 0.48, p< 0.0001) and hip BMD (beta = 0.59, p< 0.0001). Lean mass was also negatively associated with fracture risk (beta = -0.19 p =0.04) when both lean and fat mass were in the same model. CONCLUSION: Lean mass and fat mass were positively associated with femoral neck, spine and hip BMDs and negatively associated with fracture risk in urban black South African women. Our finding suggests that increasing lean mass rather than fat mass is beneficial to bone health. Our study emphasises the importance of positive lifestyle changes, intake of calcium from dairy and adequate weight to maintain and improve bone health of postmenopausal women. PMID- 26054500 TI - Health and Social Factors Associated with Nutrition Risk: Results from Life and Living in Advanced Age: A Cohort Study in New Zealand (LiLACS NZ). AB - OBJECTIVES: To establish the prevalence of high nutrition risk and associated health and social risk factors for New Zealand Maori and non-Maori in advanced age. DESIGN: A cross sectional analysis of inception cohorts to LiLACS NZ. SETTING: Bay of Plenty and Lakes region of the North Island, New Zealand. PARTICIPANTS: 255 Maori and 400 non- Maori octogenarians. MEASUREMENTS: Nutrition risk was assessed using a validated questionnaire Seniors in the Community: Risk Evaluation for Eating and Nutrition (SCREEN II). Demographic, social, physical and health characteristics were established using an interviewer administered questionnaire. Health related quality of life (HRQOL) was assessed with the SF 12, depressive symptoms using the GDS-15. RESULTS: Half (49%) of Maori and 38% of non-Maori participants were at high nutrition risk (SCREEN II score <49). Independent risk factors were for Maori younger age (p=0.04), lower education (p=0.03), living alone (p<0.001), depressive symptoms (p=0.01). For non- Maori high nutrition risk was associated with female gender (p=0.005), living alone (p=0.002), a lower physical health related quality of life (p=0.02) and depressive symptoms (p=0.002). CONCLUSION: Traditional risk factors apply to both Maori and non-Maori whilst education as indicative of low socioeconomic status is an additional risk factor for Maori. High nutrition risk impacts health related quality of life for non-Maori. Interventions which socially facilitate eating are especially important for women and for Maori to maintain cultural practices and could be initiated by routine screening. PMID- 26054501 TI - Vitamin E: Curse or Benefit in Alzheimer's Disease? A Systematic Investigation of the Impact of alpha-, gamma- and delta-Tocopherol on Abeta Generation and Degradation in Neuroblastoma Cells. AB - OBJECTIVES: The E vitamins are a class of lipophilic compounds including tocopherols, which have high antioxidative properties. Because of the elevated lipid peroxidation and increased reactive oxidative species in Alzheimer's disease (AD) many attempts have been made to slow down the progression of AD by utilizing the antioxidative action of vitamin E. Beside the mixed results of these studies nothing is known about the impact of vitamin E on the mechanisms leading to amyloid-beta production and degradation being responsible for the plaque formation, one of the characteristic pathological hallmarks in AD. Here we systematically investigate the influence of different tocopherols on Abeta production and degradation in neuronal cell lines. MEASUREMENTS: Beside amyloid beta level the mechanisms leading to Abeta production and degradation are examined. RESULTS: Surprisingly, all tocopherols have shown to increase Abeta level by enhancing the Abeta production and decreasing the Abeta degradation. Abeta production is enhanced by an elevated activity of the involved enzymes, the beta- and gamma-secretase. These secretases are not directly affected, but tocopherols increase their protein level and expression. We could identify significant differences between the single tocopherols; whereas alpha-tocopherol had only minor effects on Abeta production, delta-tocopherol showed the highest potency to increase Abeta generation. Beside Abeta production, Abeta clearance was decreased by affecting IDE, one of the major Abeta degrading enzymes. CONCLUSIONS: Our results suggest that beside the beneficial antioxidative effects of vitamin E, tocopherol has in respect to AD also a potency to increase the amyloid-beta level, which differ for the analysed tocopherols. We therefore recommend that further studies are needed to clarify the potential role of these various vitamin E species in respect to AD and to identify the form which comprises an antioxidative property without having an amyloidogenic potential. PMID- 26054502 TI - Diet, Alcohol Consumption and Cognitive Disorders in Central Africa: A Study from the EPIDEMCA Program. AB - Western research into dementia has focused on finding effective means of prevention, particularly through nutrition. To date, however, little is known about the relationship between diet and cognitive disorders in Africa, where the number of people with dementia is expected to increase most over the coming decades. The objective of the study was to investigate the relationship between diet and alcohol intake and cognitive disorders among elderly people in Central Africa. Between 2011 and 2012, a cross-sectional multicentre population-based study was carried out in rural and urban areas of the Central African Republic (CAR) and the Republic of Congo (ROC). Participants aged >=65 years were interviewed using the Community Screening Interview for Dementia (CSI-D). Elderly people who performed poorly (COGSCORE<=24.5/30) were clinically assessed by neurologists and underwent further psychometric testing. DSM-IV and Petersen criteria were required for a diagnosis of dementia or mild cognitive impairment (MCI), respectively. A food frequency questionnaire assessed the intakes of dairy products, fruit, vegetables, starches, legumes, oleaginous foods, meat or fish, eggs and sweet foods over the previous three days. We also collected data on alcohol intake. Sociodemographic, vascular, and psychological factors were documented. Multivariate multinomial logistic regression models were used to estimate the associations. In fully adjusted models, a lower consumption of oleaginous foods was associated with MCI (OR=3.7 [1.4-9.9]) and dementia (OR=2.8 [1.0-7.7]) in a rural area of CAR. Alcohol consumption was associated with reduced probability of dementia in CAR (OR=0.3 [0.1-0.8]). In ROC, food groups and alcohol intake were not associated with MCI or dementia. In conclusion, our study provides new data about the association between diet and cognitive disorders in Africa. Further studies should investigate the relationship between diet and cognitive disorders at the level of specific foods rather than food groups. PMID- 26054503 TI - Relationship between Plasma Ghrelin Levels and Sarcopenia in Elderly Subjects: A Cross-Sectional Study. AB - OBJECTIVE: The aim of this study was to investigate the relationship between plasma ghrelin levels and sarcopenia in elderly people. DESIGN: Cross-sectional study. SETTING: Health consortium medical centers in the Maresme region, Barcelona (Spain). PARTICIPANTS: Two groups of subjects: persons >=70 years (elderly group) and persons 25-65 years (young adults). MEASUREMENTS: Sarcopenia, diagnosed according to the EWGSOP definition, fasting and postprandial plasma ghrelin levels, body composition, hand grip, Barthel score, and frailty using Fried criteria. RESULTS: Fifty-five elderly subjects and 33 young adults were recruited. In both age groups, mean ghrelin levels were significantly higher in women than in men. However, mean ghrelin levels were similar in elderly and young men (716 vs. 752 pg mL-1, P = 0.763) as well as in elderly and young women (859 vs. 995 pg mL-1, P = 0.190). In the elderly group, subjects with sarcopenia showed significantly lower ghrelin levels than those without sarcopenia (650 vs. 899 pg mL-1, P = 0.036), but these differences disappeared when stratifying by gender. Elderly subjects without sarcopenia had the same ghrelin levels as young adults (899.3 vs. 899.6 pg mL-1). In young women, ghrelin levels correlated with fat free mass (rs = 0.58, P = 0.007) and muscular mass (rs = 0.54, P = 0.015) but these correlations were not observed in men nor in elderly women. CONCLUSION: This cross-sectional study does not allow a definitive conclusion about the relationship between ghrelin levels and sarcopenia. Further large prospective studies are needed to test this hypothesis. PMID- 26054504 TI - Implementing Frailty Screening, Assessment, and Sustained Intervention: The experience of the Gerontopole. AB - Despite its interest, frailty is not yet adequately implemented in the everyday clinical practice. Frailty is characterized by an initial functional loss which 1) still allows the individual to be independent in the daily life (although with some difficulties), and 2) may be reversed by targeted interventions. In the present article, we discuss: Why frailty is clinically relevant? Why frailty has not yet been implemented in daily clinical practice? How to implement frailty into clinical practice following the Gerontopole experience? Intervention to be effective must be targeted, strong, and maintained. PMID- 26054505 TI - French Multicenter Evaluation of the Appropriateness of Admission to the Emergency Department of the Over-80s. AB - BACKGROUND: Persons over 80 represents 40% of patients in French emergency services. We assessed the appropriateness of these admissions and sought to identify risk factors for inappropriate hospital stays. METHODS: The appropriateness of admission was assessed in a prospective, cross-sectional, multicenter study in eight hospitals in France by means of the Appropriateness Evaluation Protocol (French version, AEPf) during two non-consecutive periods of four weeks in 2010. We analyzed admission of patients aged 80 and over who were admitted to the hospital after a stay in the emergency department of the same hospital. Demographics and morbidity factors were recorded as were administrative hospitalization data to identify risk factors associated with inappropriate admissions. We also evaluated the economic impact of inappropriate admissions. For cost analysis, all variables were obtained from anonymized hospital reports of a diagnosis-related group system used for funding of the hospitals by health insurance. RESULTS: During two different periods, 1577 patients were included. 139 (8.8%) hospital admissions were inappropriate according to explicit criteria of the AEPf, but 18 of these (1.1%) were in fact considered appropriate by the physician responsible for the admission, leading to 121 (7.7%) inappropriate admissions. Multivariate logistic regression showed that patients with heart disease were less often subject to inappropriate admission (odds ratio OR= 0.36 [0.23; 0.56], p < 0.001), as also were patients who usually lived in a nursing home (OR = 0.53 [0.30; 0.87], p = 0.018) and patients with higher Acute Physiology Scores (OR = 0.97 [0.95; 0.99], p < 0.001). Inappropriate admission increased when patients had a syndrome as the main diagnosis (OR = 1.81 [1.81; 2.83], p = 0.010). By contrast, cognitive functions, gait and balance disturbance or falls, behavioral disorders and method of transport to the emergency department did not change the probability of inappropriateness. The median cost of the hospital stay of an older patient was 3 606.5 [2 498.1; 4 994.2] euros for inappropriate admissions. CONCLUSION: Inappropriate emergency admissions of older patients were infrequent. None of the geriatric syndromes were linked with the phenomenon and principle causes were severity of illness, mention of a cardiac disease, unclear pattern of consultation and institutionalized way of life. PMID- 26054506 TI - The H.U.G.E. Formula (Hematocrit, Urea, Sex) for Screening Chronic Kidney Disease (CKD) in an Age-Stratified General Population. AB - OBJECTIVES: AIM: To evaluate the screening power of the HUGE formula for the detection of chronic kidney disease (CKD) in a Spanish population sample obtained from the HERMEX study, a survey of cardiovascular risk factors carried out in the region of Extremadura, stratified by age. DESIGN AND METHODS: This was an observational, cross-sectional, population-based study. The final sample included 2,813 subjects selected from Health Care System records. Anthropometric data and cardiovascular risk factors were recorded. Hematocrit, urea, creatinine and microalbuminuria were analyzed, after which the HUGE formula was applied. Renal function, assessed as eGFR based on serum creatinine, was estimated following the MDRD-4 formula. RESULTS: Using the HUGE formula, the estimated prevalence of CKD was 2.2% (men 2.2%, women 2.1%). The prevalence of CKD increased with age (5.0% in persons aged 60- 70 years and 9.6% in individuals over 70 years of age, p < 0.001) whereas with the MDRD formula the prevalence values were 9.8% and 15.5% respectively. The HUGE formula was seen to be highly specific (0.99). CKD was more common in persons >70 years, obese subjects, hypertensive patients, dyslipidemic subjects and those with microalbuminuria. Multivariate analysis revealed an independent negative association of CKD as the dependent variable with SBP, serum triglyceride levels and microalbuminuria. CONCLUSIONS: The HUGE formula allows the prediction of CKD in the general population to be honed without relying on serum creatinine levels. This method was found to have a higher specificity than the MDRD-4 formula. Moreover, it could reduce the excessively extensive diagnostic suspicion of CKD in women. PMID- 26054507 TI - A Study of the Applicability of GFR Evaluation Equations for an Elderly Chinese Population. AB - OBJECTIVES: This study screened current GFR evaluation equations that showed high accuracy for elderly populations and evaluated the applicability of these equations for an elderly Chinese population. MEASUREMENTS: A standard dual plasma sampling method (DPSM) of estimating 99mTc-diethylene triamine penta-acetic acid clearance was used to determine measured GFR (mGFR). RESULTS: Comprehensive information was received for a total of 151 elderly individuals, with a mean mGFR of 65.39 +/- 24.19 ml/min/1.73 m2. For the overall samples, the accuracy (P30), bias, absolute bias and interquartile ranges (IQRs) of the CKD2 (cystatin C(CysC) serum creatinine(SCr)), CKD-EPI(CysC-SCr), Cockcroft-Gault(CG), CKD2(CysC), CKD EPI(CysC), and Hoek equations were superior to c-aGFR3, c-aGFR4 and Grubb equation, Bland-Altman analysis also demonstrated a consistent result. Among elderly subjects with mGFR>=60 ml/min/1.73 m2, the CKD2 (CysC-SCr) and CKD-EPI (CysC-SCr) equations showed significantly higher correlations and accuracy than the other examined equations. Among elderly subjects with mGFR<60 ml/min/1.73 m2, only the CG equation showed an accuracy (P30) of greater than 70% and demonstrated higher precision than the other examined equations. CONCLUSION: For the elderly population, the CG, CKD2, CKD-EPI, and Hoek equations exhibited good accuracy. The CKD2(CysC-SCr) equation and CKD-EPI(CysC-SCr) equation demonstrated relatively high accuracy for evaluating elderly subjects with mGFR>=60 ml/min/1.73 m2, whereas the CG equation was more suitable for evaluating elderly subjects with mGFR<60 ml/min/1.73 m2. PMID- 26054508 TI - Predictors of Long-Term Mortality in Oldest Old Patients (90+) Hospitalized to Medical Wards via the Emergency Department: The SAFES Cohort. AB - OBJECTIVES: To identify risk factors for long-term mortality in patients aged 90 years and over who are admitted to hospital through the emergency department. DESIGN: Prospective cohort study (SAFES cohort; Sujet Age Fragile - Evaluation Suivi). SETTING: 8 university teaching hospitals and one regional, non-academic hospital in France. PARTICIPANTS: Among 1306 patients in the SAFES cohort, 291 patients aged 90 or over were included. MEASUREMENTS: At inclusion, we recorded socio-demographic data (age, sex, level of education, living alone or in an institution, number of children, presence of helper/caregiver), and data from geriatric evaluation (dependence status, risk of depression, dementia, delirium, nutritional status, walking disorders, risk of falls, comorbidities, risk of pressure sores). Vital status at 36 months was obtained from the treating physician, the general practitioner, administrative registers, or during follow up consultations. RESULTS: Among 291 patients included, 190 (65.3%) had died at 36 months. Risk factors for mortality at 36 months identified by multivariate analysis were risk of malnutrition (HR 1.6, 95%CI 1.1-2.3, p=0.004) and delirium (HR 1.6, 95%CI 1.1-2.3, p=0.01). CONCLUSION: Risk of malnutrition and presence of delirium are risk factors for mortality at 36 months in subjects aged 90 years and over hospitalized through the emergency department. PMID- 26054509 TI - Letter to the editor: Is there a Future for ONS in Acute Geriatric Wards? PMID- 26054510 TI - The catechol-o-methyltransferase Val158Met polymorphism modulates the intrinsic functional network centrality of the parahippocampal cortex in healthy subjects. AB - The influence of catechol-o-methyltransferase (COMT) Val(158)Met on brain activation and functional connectivity has been widely reported. However, voxel wise effects of this genotype on resting-state brain networks remain unclear. Here, we used resting-state fMRI and eigenvector centrality to examine the effects of COMT Val(158)Met genotypes on the connection patterns of the brain network and working memory (WM) in healthy, young Val/Val and Met carrier subjects. There were significant differences in the performance level on the 2 back WM task between the different COMT genotypes: Val/Val individuals exhibited a higher correct rate compared to the Met carriers. A two-sample t test was used to examine the differences in the eigenvector centrality maps, using age and gender as covariates of no interest, between the Val/Val and Met carriers. We found that the Val/Val individuals exhibited significantly higher eigenvector centrality compared to the Met carriers in the left parahippocampal cortex. Furthermore, a significantly positive correlation between the mean eigenvector centrality of the significant cluster and the correct rate of the 2-back WM task was observed. By using a voxel-wise data-driven method, our findings may provide plausible implications regarding individual differences in the genetic contribution of COMT Val158Met to the brain network and cognition. PMID- 26054511 TI - Assessing the relationship between environmental factors and malaria vector breeding sites in Swaziland using multi-scale remotely sensed data. AB - Many entomological studies have analyzed remotely sensed data to assess the relationship between malaria vector distribution and the associated environmental factors. However, the high cost of remotely sensed products with high spatial resolution has often resulted in analyses being conducted at coarse scales using open-source, archived remotely sensed data. In the present study, spatial prediction of potential breeding sites based on multi-scale remotely sensed information in conjunction with entomological data with special reference to presence or absence of larvae was realized. Selected water bodies were tested for mosquito larvae using the larva scooping method, and the results were compared with data on land cover, rainfall, land surface temperature (LST) and altitude presented with high spatial resolution. To assess which environmental factors best predict larval presence or absence, Decision Tree methodology and logistic regression techniques were applied. Both approaches showed that some environmental predictors can reliably distinguish between the two alternatives (existence and non-existence of larvae). For example, the results suggest that larvae are mainly present in very small water pools related to human activities, such as subsistence farming that were also found to be the major determinant for vector breeding. Rainfall, LST and altitude, on the other hand, were less useful as a basis for mapping the distribution of breeding sites. In conclusion, we found that models linking presence of larvae with high-resolution land use have good predictive ability of identifying potential breeding sites. PMID- 26054512 TI - Predicting frequency distribution and influence of sociodemographic and behavioral risk factors of Schistosoma mansoni infection and analysis of co infection with intestinal parasites. AB - Geospatial analysis was used to study the epidemiology of Schistosoma mansoni, intestinal parasites and co-infections in an area (Ilha das Flores) in Sergipe, Brazil. We collected individually georeferenced sociodemographic, behavioral and parasitological data from 500 subjects, analyzed them by conventional statistics, and produced risk maps by Kernel estimation. The prevalence rates found were: S. mansoni (24.0%), Trichuris trichiura (54.8%), Ascaris lumbricoides (49.2%), Hookworm (17.6%) and Entamoeba histolytica (7.0%). Only 59/500 (11.8%) individuals did not present any of these infections, whereas 279/500 (55.8%) were simultaneously infected by three or more parasites. We observed associations between S. mansoni infection and various variables such as male gender, being rice farmer or fisherman, low educational level, low income, water contact and drinking untreated water. The Kernel estimator indicated that high-risk areas coincide with the poorest regions of the villages as well as with the part of the villages without an adequate sewage system. We also noted associations between both A. lumbricoides and hookworm infections with low education and low income. A. lumbricoides infection and T. trichiura infection were both associated with drinking untreated water and residential open-air sewage. These findings call for an integrated approach to effectively control multiple parasitic infections. PMID- 26054513 TI - Estimating population and livestock density of mobile pastoralists and sedentary settlements in the south-eastern Lake Chad area. AB - Mobile pastoralists provide major contributions to the gross domestic product in Chad, but little information is available regarding their demography. The Lake Chad area population is increasing, resulting in competition for scarce land and water resources. For the first time, the density of people and animals from mobile and sedentary populations was assessed using randomly defined sampling areas. Four sampling rounds were conducted over two years in the same areas to show population density dynamics. We identified 42 villages of sedentary communities in the sampling zones; 11 (in 2010) and 16 (in 2011) mobile pastoralist camps at the beginning of the dry season and 34 (in 2011) and 30 (in 2012) camps at the end of the dry season. A mean of 64.0 people per km2 (95% confidence interval, 20.3-107.8) were estimated to live in sedentary villages. In the mobile communities, we found 5.9 people per km2 at the beginning and 17.5 people per km2 at the end of the dry season. We recorded per km2 on average 21.0 cattle and 31.6 small ruminants in the sedentary villages and 66.1 cattle and 102.5 small ruminants in the mobile communities, which amounts to a mean of 86.6 tropical livestock units during the dry season. These numbers exceed, by up to five times, the published carrying capacities for similar Sahelian zones. Our results underline the need for a new institutional framework. Improved land use management must equally consider the needs of mobile communities and sedentary populations. PMID- 26054514 TI - Mapping of the environmental contamination of Toxoplasma gondii by georeferencing isolates from chickens in an endemic area in Southeast Rio de Janeiro State, Brazil. AB - The environmental contamination of Toxoplasma gondii in an endemic area in Brazil was mapped by georeferencing isolates from chickens in farms in the Southeast of the state of Rio de Janeiro. Tissue samples obtained from 153 adult chickens were analyzed by the mouse bioassay for T. gondii infection. These animals were reared free-range on 51 farms in the municipalities of Rio Bonito and Marica. The ArcGIS kernel density estimator based on the frequency of T. gondii-positive chickens was used to map the environmental contamination with this parasite. A questionnaire was applied to obtain data on the presence and management of cats and the type of water consumed. Of the farms studied, 64.7% were found to be located in areas of low to medium presence of T. gondii, 27.5% in areas with a high or very high contamination level and 7.8% in non-contaminated areas. Additionally, 70.6% kept cats, 66.7% were near water sources and 45.0% were in or near dense vegetation. Humans used untreated water for drinking on 41.2% of the farms, while all animals were given untreated water. The intensity of environmental T. gondii contamination was significantly higher on farms situated at a distance >500 m from water sources (P=0.007) and near (<=500 m) dense vegetation (P=0.003). Taken together, the results indicate a high probability of T. gondii infection of humans and animals living on the farms studied. The kernel density estimator obtained based on the frequency of chickens testing positive for T. gondii in the mouse bioassay was useful to map environmental contamination with this parasite. PMID- 26054515 TI - Spatio-temporal analysis of fox rabies cases in Germany 2005-2006. AB - Aiming to achieve new insights into rabies dynamics, this paper is the first to investigate fox rabies in Germany from a space-time pattern perspective. Based on a locally restricted dataset covering a fourteen month period, our findings indicate a strongly aggregated spatiotemporal point pattern resulting from an inhomogeneous stochastic process. In contrast to spatial or temporal approaches or cellular automata, our analysis focuses on the disease dynamics in time and space in a continuous time domain. Our findings confirm existing theories regarding fox rabies control highlighting the potential risk of urban areas and the need for effective rabies vaccination. PMID- 26054516 TI - American cutaneous leishmaniasis cases in the metropolitan region of Manaus, Brazil: association with climate variables over time. AB - A temporal series of the normalized difference vegetation index (NDVI) and other environmental parameters covering the years 2002- 2009 was used for the study of the potential association between the climate and the number of cases of American cutaneous leishmaniasis (CL) in Manaus Metropolitan Region (MMR), State of Amazonas, Brazil. The results show that CL has a marked seasonality and a strong linkage with local climate conditions. Dry and warm conditions favor the vector, while the maximum number of CL cases occurs during the following wet season. This has a clear relation to the El Nino/La Nina Southern Oscillation (ENSO) and the results presented here show that uncharacteristic dry conditions in the MMR follow El Nino after a lag period of 3 months, while wet conditions follow La Nina, again after a lag period of 3 months. El Nino brings dry conditions with warming of the land surface leading to increased growth of trees and bushes as indicated by rising NDVI values, eventually producing increased numbers of CL cases, with a peak of new cases occurring 4 to 5 months later. La Nina, on the other hand, produces wet and cool weather, which is less favorable for the leishmaniasis vector and therefore results in comparatively lower number of CL cases. Since these seasonal climate changes affect the dynamics of the CL vector, and thus the number of CL cases, a close watch of the ENSO phenomenon and the weather type it brings should be useful for monitoring and control of CL in the MMR. PMID- 26054517 TI - Spatial abundance and human biting rate of Anopheles arabiensis and Anopheles funestus in savannah and rice agro-ecosystems of Central Tanzania. AB - This study was carried out to determine the spatial variations in malaria mosquito abundance and human biting rate in five villages representing rice irrigation and savannah ecosystems in Kilosa District, central Tanzania. The study involved five villages namely Tindiga and Malui (wetland/rice irrigation), Twatwatwa and Mbwade (dry savannah) and Kimamba (wet savannah). Indoor mosquitoes were sampled using Centers for Disease Control and Prevention light traps in three houses in each village. Anopheles gambiae s.l. molecular identification was carried out using polymerase chain reaction (PCR). A total of 936 female mosquitoes were collected. About half (46.9%) were malaria mosquitoes (Anopheles gambiae s.l.=28.6%; An. funestus= 18.3%). A total of 161 (60.1%) of the morphologically identified An. gambiae s.l. (268) and subjected to PCR analysis for speciation were genotyped as An. arabiensis. The An. funestus complex mosquitoes were composed of An. funestus funestus and An. rivulorum at the 5:1 ratio. On average, 17.9 Anopheles mosquitoes were collected per village per day. Two-thirds (62.8%) of the malaria mosquitoes were collected in Malui (rice agro ecosystem) and the lowest number (2.3%) in Twatwatwa (dry savannah ecosystem). The biting rate per person per night for An. arabiensis+An. funestus s.s. was highest in Malui (46.0) and lowest in Twatwatwa (1.67). The parity rate of the An. funestus mosquitoes was lower compared to that of An. arabiensis and none of the mosquitoes was infected with malaria sporozoites. In conclusion, An. arabiensis is the most abundant malaria vector in Kilosa district and its variation is related to the ecological system. The heterogeneity in malaria mosquito abundance and human biting rate could be used to guide selection of locally appropriated control interventions. PMID- 26054518 TI - Sandwich mapping of schistosomiasis risk in Anhui Province, China. AB - Schistosomiasis mapping using data obtained from parasitological surveys is frequently used in planning and evaluation of disease control strategies. The available geostatistical approaches are, however, subject to the assumption of stationarity, a stochastic process whose joint probability distribution does not change when shifted in time. As this is impractical for large areas, we introduce here the sandwich method, the basic idea of which is to divide the study area (with its attributes) into homogeneous subareas and estimate the values for the reporting units using spatial stratified sampling. The sandwich method was applied to map the county-level prevalence of schistosomiasis japonica in Anhui Province, China based on parasitological data collected from sample villages and land use data. We first mapped the county-level prevalence using the sandwich method, then compared our findings with block Kriging. The sandwich estimates ranged from 0.17 to 0.21% with a lower level of uncertainty, while the Kriging estimates varied from 0 to 0.97% with a higher level of uncertainty, indicating that the former is more smoothed and stable compared to latter. Aside from various forms of reporting units, the sandwich method has the particular merit of simple model assumption coupled with full utilization of sample data. It performs well when a disease presents stratified heterogeneity over space. PMID- 26054519 TI - Diagnostic approaches to malaria in Zambia, 2009-2014. AB - Malaria is an important health burden in Zambia with proper diagnosis remaining as one of the biggest challenges. The need for reliable diagnostics is being addressed through the introduction of rapid diagnostic tests (RDTs). However, without sufficient laboratory amenities in many parts of the country, diagnosis often still relies on non-specific, clinical symptoms. In this study, geographical information systems were used to both visualize and analyze the spatial distribution and the risk factors related to the diagnosis of malaria. The monthly reported, district-level number of malaria cases from January 2009 to December 2014 were collected from the National Malaria Control Center (NMCC). Spatial statistics were used to reveal cluster tendencies that were subsequently linked to possible risk factors, using a non-spatial regression model. Significant, spatio-temporal clusters of malaria were spotted while the introduction of RDTs made the number of clinically diagnosed malaria cases decrease by 33% from 2009 to 2014. The limited access to road network(s) was found to be associated with higher levels of malaria, which can be traced by the expansion of health promotion interventions by the NMCC, indicating enhanced diagnostic capability. The capacity of health facilities has been strengthened with the increased availability of proper diagnostic tools and through retraining of community health workers. To further enhance spatial decision support systems, a multifaceted approach is required to ensure mobilization and availability of human, infrastructural and technological resources. Surveillance based on standardized geospatial or other analytical methods should be used by program managers to design, target, monitor and assess the spatio-temporal dynamics of malaria diagnostic resources country-wide. PMID- 26054520 TI - Earth observation in support of malaria control and epidemiology: MALAREO monitoring approaches. AB - Malaria affects about half of the world's population, with the vast majority of cases occuring in Africa. National malaria control programmes aim to reduce the burden of malaria and its negative, socioeconomic effects by using various control strategies (e.g. vector control, environmental management and case tracking). Vector control is the most effective transmission prevention strategy, while environmental factors are the key parameters affecting transmission. Geographic information systems (GIS), earth observation (EO) and spatial modelling are increasingly being recognised as valuable tools for effective management and malaria vector control. Issues previously inhibiting the use of EO in epidemiology and malaria control such as poor satellite sensor performance, high costs and long turnaround times, have since been resolved through modern technology. The core goal of this study was to develop and implement the capabilities of EO data for national malaria control programmes in South Africa, Swaziland and Mozambique. High- and very high resolution (HR and VHR) land cover and wetland maps were generated for the identification of potential vector habitats and human activities, as well as geoinformation on distance to wetlands for malaria risk modelling, population density maps, habitat foci maps and VHR household maps. These products were further used for modelling malaria incidence and the analysis of environmental factors that favour vector breeding. Geoproducts were also transferred to the staff of national malaria control programmes in seven African countries to demonstrate how EO data and GIS can support vector control strategy planning and monitoring. The transferred EO products support better epidemiological understanding of environmental factors related to malaria transmission, and allow for spatio-temporal targeting of malaria control interventions, thereby improving the cost-effectiveness of interventions. PMID- 26054521 TI - Comparing the perception with the reality of walking in a hilly environment: an accessibility method applied to a University campus in Hong Kong. AB - The influence of hilliness on walking behavior could be a consequence of the real effect of the local topography, but individual perception of the difficulties associated with walking in a hilly environment may also be important. Previous studies have found that people's perceptions do not necessarily match well with the realities of walking in hilly environments. There are a few methods that can be used to visualize the geography of that difference for use by urban planners and public health practitioners. A walking accessibility measure that allows comparison of perception and reality is proposed and implemented in this study. We note that difficulties in calculating accessibility measures in the present context arise primarily from problems with data quality, three-dimensional pedestrian network modelling and the adequacy of accessibility methods for describing and predicting walking behavior. We present practical strategies for addressing these issues using geographic information systems. Our method is illustrated by calculating accessibility for a hilly university campus in Hong Kong. Walking behaviors on, and people's perceptions of, this hilly environment were obtained through walking diaries and a survey. The article concludes with suggested directions for the future development of walking accessibility measures along with some ideas about their applicability to the practice of planning and designing a walkable environment. PMID- 26054522 TI - Spatio-temporal cluster detection of chickenpox in Valencia, Spain in the period 2008-2012. AB - Chickenpox is a highly contagious airborne disease caused by Varicella zoster, which affects nearly all non-immune children worldwide with an annual incidence estimated at 80-90 million cases. To analyze the spatiotemporal pattern of the chickenpox incidence in the city of Valencia, Spain two complementary statistical approaches were used. First, we evaluated the existence of clusters and spatio temporal interaction; secondly, we used this information to find the locations of the spatio-temporal clusters via the space-time permutation model. The first method used detects any aggregation in our data but does not provide the spatial and temporal information. The second method gives the locations, areas and time frame for the spatio-temporal clusters. An overall decreasing time trend, a pronounced 12-monthly periodicity and two complementary periods were observed. Several areas with high incidence, surrounding the center of the city were identified. The existence of aggregation in time and space was observed, and a number of spatio-temporal clusters were located. PMID- 26054523 TI - The spatial distribution of Schistosoma mansoni infection in four regions of western Cote d'Ivoire. AB - Schistosomiasis poses a considerable public health burden in sub- Saharan Africa and a sound understanding of the spatial distribution facilitates to better target control interventions. The objectives of this study were i) to assess the prevalence of Schistosoma mansoni among school-aged children in four regions of western Cote d'Ivoire; ii) to determine demographic, climatic and environmental factors that influence the distribution of S. mansoni; and iii) to map and predict the distribution of S. mansoni in non-sampled locations. Parasitological surveys were carried out in 264 schools from June to December 2011. In each school, we aimed to examine 50 children for S. mansoni infection using duplicate Kato-Katz thick smears. Schools were georeferenced using a hand-held global positioning system receiver. Demographic data were obtained from readily available school lists, while climatic and environmental data were extracted from open-access remote sensing databases. Multivariable, binary non-spatial models and a Bayesian geostatistical logistic regression model were used to identify demographic, climatic and environmental risk factors for S. mansoni infection. Risk maps were developed based on observed S. mansoni prevalences and using Bayesian geostatistical models to predict prevalences at non-sampled locations. Overall, 12,462 children provided a sufficiently large stool sample to perform at least one Kato-Katz thick smear. The observed overall prevalence of S. mansoni infection was 39.9%, ranging from 0 to 100% at the unit of the school. Bayesian geostatistical analysis revealed that age, sex, altitude and difference between land surface temperature at day and night were significantly associated with S. mansoni infection. The S. mansoni risk map presented here is being been used by the national schistosomiasis control programme for spatial targeting of praziquantel and other interventions. PMID- 26054524 TI - Ghrelin accelerates the growth and osteogenic differentiation of rabbit mesenchymal stem cells through the ERK1/2 pathway. AB - BACKGROUND: Mesenchymal stem cells (MSCs) can differentiate into chondroblasts, adipocytes, or osteoblasts under appropriate stimulation. Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHSR), stimulates growth hormone (GH) secretion, and has both orexigenic and adipogenic effects. This study sought to understand the potential involvement of members of MAPK serine/threonine kinases in the ghrelin-induced growth of rabbit MSCs ( rBMSC). METHODS: We applied various concentrations of ghrelin to cultured rBMSC and observed the growth rate of the cells by MTT, changes in the phosphorylation state of ERK1/2, JNK and p38, and the expression levels of ALP, Runx2, and Osterix by wetern blot. RESULTS: We found that the growth and osteogenic differentiation of ghrelin-treated rBMSC are promoted primarily by phosphorylated ERK1/2, and that this phosphorylation, as well p38 phosphorylation, is mediated by GHSR. CONCLUSIONS: Our study suggests that ghrelin promotes the growth and osteogenic differentiation of rBMSC primarily through the ERK1/2 pathway. PMID- 26054525 TI - Anti-hyperlipidemic and anti-atherosclerotic effects of Pinus eldarica Medw. nut in hypercholesterolemic rabbits. AB - BACKGROUND: Previous studies suggest that chemical constituents present in Pinus eldarica Medw (P. eldarica) nut possess antioxidant properties that may positively influence lipid profile. The present study was conducted to evaluate the efficacy of P. eldarica nut on the experimental atherosclerosis development in hypercholesterolemic rabbits. METHODS: Forty male 6 months old white New Zealand rabbits (1.8-2 kg) were randomly assigned into five equal groups. One group was kept as control (normal) group, fed on standard rabbit diet and other 4 groups were fed on high cholesterol diet (HCD). Out of four HCD groups one group was kept as control (HCD) and other three groups were treated with different doses (50, 100 and 200 mg/kg/day) of P. eldarica nut for 8 weeks. Percentage of aortic wall area changes as indication of atherosclerosis development and fasting blood cholesterol, LDL, HDL and triglyceride levels were determined in all groups. RESULTS: The results indicate that fasting blood cholesterol and aortic atherosclerotic involvements in 200 mg/kg/day and 100 mg/kg/day P. eldarica nut extract treated groups significantly decreased as compared to the high cholesterol-diet control group. CONCLUSION: P. eldarica nut lowers blood cholesterol level and aortic atherosclerotic involvement in hypercholesterolemic rabbits. PMID- 26054526 TI - Mercaptosilane-assisted synthesis of sub-nanosized Pt particles within hierarchically porous ZSM-5/SBA-15 materials and their enhanced hydrogenation properties. AB - A novel catalyst that consists of sub-nanosized Pt particles within hierarchically porous ZSM-5/SBA-15 materials was synthesized. This catalyst exhibited high stability and a hierarchically porous structure of a micro mesoporous composite and possessed a high density of active sites by confinement of sub-nanosized Pt particles within small-pore zeolites, showing high catalytic properties for the hydrogenation of 1,3-butadiene and cyclooctadiene at room temperature. PMID- 26054527 TI - A remotely piloted aircraft system in major incident management: concept and pilot, feasibility study. AB - BACKGROUND: Major incidents are complex, dynamic and bewildering task environments characterised by simultaneous, rapidly changing events, uncertainty and ill-structured problems. Efficient management, communication, decision-making and allocation of scarce medical resources at the chaotic scene of a major incident is challenging and often relies on sparse information and data. Communication and information sharing is primarily voice-to-voice through phone or radio on specified radio frequencies. Visual cues are abundant and difficult to communicate between teams and team members that are not co-located. The aim was to assess the concept and feasibility of using a remotely piloted aircraft (RPA) system to support remote sensing in simulated major incident exercises. METHODS: We carried out an experimental, pilot feasibility study. A custom-made, remotely controlled, multirotor unmanned aerial vehicle with vertical take-off and landing was equipped with digital colour- and thermal imaging cameras, a laser beam, a mechanical gripper arm and an avalanche transceiver. We collected data in five simulated exercises: 1) mass casualty traffic accident, 2) mountain rescue, 3) avalanche with buried victims, 4) fisherman through thin ice and 5) search for casualties in the dark. RESULTS: The unmanned aerial vehicle was remotely controlled, with high precision, in close proximity to air space obstacles at very low levels without compromising work on the ground. Payload capacity and tolerance to wind and turbulence were limited. Aerial video, shot from different altitudes, and remote aerial avalanche beacon search were streamed wirelessly in real time to a monitor at a ground base. Electromagnetic interference disturbed signal reception in the ground monitor. CONCLUSION: A small remotely piloted aircraft can be used as an effective tool carrier, although limited by its payload capacity, wind speed and flight endurance. Remote sensing using already existing remotely piloted aircraft technology in pre hospital environments is feasible and can be used to support situation assessment and information exchange at a major incident scene. Regulations are needed to ensure the safe use of unmanned aerial vehicles in major incidents. Ethical issues are abundant. PMID- 26054528 TI - A derivation of the Polytomous Rasch model based on the most probable distribution method. AB - Boltzmann's most probable distribution method is applied to derive the Polytomous Rasch model as the distribution accounting for the maximum number of possible outcomes in a test while introducing latent traits, item characteristics, and thresholds as constraints to the system. Affinities and similarities of the present result with other derivations of the model are discussed in light of the conceptual frameworks of statistical physics and of the principle of maximum entropy. PMID- 26054529 TI - Patients' and physicians' satisfaction with a pharmacist managed anticoagulation program in a family medicine clinic. AB - BACKGROUND: A pharmacist managed anticoagulation service was initiated in a multi physician family medicine clinic in December 2006. In order to determine the patient and physician satisfaction with the service, a study was designed to describe the patients' satisfaction with the warfarin education and management they received from the pharmacist, and to describe the physicians' satisfaction with the level of care provided by the pharmacist for patients taking warfarin. A self-administered survey was completed by both eligible patients receiving warfarin and physicians prescribing warfarin between December 2006 and May 2008. The patient survey collected information on patient demographics, satisfaction with warfarin education and daily warfarin management. The physician survey collected data about the satisfaction with patient education and daily anticoagulation management by the pharmacist. RESULTS: Seventy-six of 94 (81%) patients completed the survey. Fifty-nine percent were male with a mean age of 65 years (range 24-90). Ninety-six percent agreed/strongly agreed the pharmacist did a good job teaching the importance of warfarin adherence, the necessity of INR testing and the risks of bleeding. Eighty-five percent agreed/strongly agreed the risk of blood clots was well explained, 79% felt the pharmacist did a good job teaching about dietary considerations and 77% agreed/strongly agreed the pharmacist explained when to see a doctor. All patients felt the pharmacist gave clear instructions on warfarin dosing and INR testing. Four of nine physicians (44%) completed the survey. All agreed/strongly agreed the pharmacist was competent in the care provided, were confident in the care their patients received, would like the pharmacist to continue the service, and would recommend this program to other clinics. CONCLUSIONS: Patients and family physicians were satisfied with the pharmacist managed anticoagulation program and recommended continuation of the program. These results support the role of the pharmacist in the management of anticoagulation in a multi-physician family medicine clinic. PMID- 26054530 TI - Characterizing Sleep Issues Using Twitter. AB - BACKGROUND: Sleep issues such as insomnia affect over 50 million Americans and can lead to serious health problems, including depression and obesity, and can increase risk of injury. Social media platforms such as Twitter offer exciting potential for their use in studying and identifying both diseases and social phenomenon. OBJECTIVE: Our aim was to determine whether social media can be used as a method to conduct research focusing on sleep issues. METHODS: Twitter posts were collected and curated to determine whether a user exhibited signs of sleep issues based on the presence of several keywords in tweets such as insomnia, "can't sleep", Ambien, and others. Users whose tweets contain any of the keywords were designated as having self-identified sleep issues (sleep group). Users who did not have self-identified sleep issues (non-sleep group) were selected from tweets that did not contain pre-defined words or phrases used as a proxy for sleep issues. RESULTS: User data such as number of tweets, friends, followers, and location were collected, as well as the time and date of tweets. Additionally, the sentiment of each tweet and average sentiment of each user were determined to investigate differences between non-sleep and sleep groups. It was found that sleep group users were significantly less active on Twitter (P=.04), had fewer friends (P<.001), and fewer followers (P<.001) compared to others, after adjusting for the length of time each user's account has been active. Sleep group users were more active during typical sleeping hours than others, which may suggest they were having difficulty sleeping. Sleep group users also had significantly lower sentiment in their tweets (P<.001), indicating a possible relationship between sleep and pyschosocial issues. CONCLUSIONS: We have demonstrated a novel method for studying sleep issues that allows for fast, cost effective, and customizable data to be gathered. PMID- 26054531 TI - Enhanced caveolin-1 expression increases migration, anchorage-independent growth and invasion of endometrial adenocarcinoma cells. AB - BACKGROUND: Caveolin-1 (CAV1) has been implicated both in tumor suppression and progression, whereby the specific role appears to be context dependent. Endometrial cancer is one of the most common malignancies of the female genital tract; however, little is known about the role of CAV1 in this disease. METHODS: Here, we first determined by immunohistochemistry CAV1 protein levels in normal proliferative human endometrium and endometrial tumor samples. Then using two endometrial cancer cell lines (ECC: Ishikawa and Hec-1A) we evaluated mRNA and protein levels of CAV1 by real time qPCR and Western blot analysis, respectively. The role of CAV1 expression in ECC malignancy was further studied by either inducing its expression in endometrial cancer cells with the tumor promotor 12-O tetradecanoyl-phorbol-13-acetate (4beta-TPA) or decreasing expression using short hairpin RNA constructs, and then evaluating the effects of these changes on ECC proliferation, transmigration, matrigel invasion, and colony formation in soft agar. RESULTS: Immunohistochemical analysis of endometrial epithelia revealed that substantially higher levels of CAV1 were present in endometrial tumors than the normal proliferative epithelium. Also, in Ishikawa and Hec-1A endometrial cancer cells CAV1 expression was readily detectable. Upon treatment with 4beta TPA CAV1 levels increased and coincided with augmented cell transmigration, matrigel invasion, as well as colony formation in soft agar. Reduction of CAV1 expression using short-hairpin RNA constructs ablated these effects in both cell types whether treated or not with 4beta-TPA. Alternatively, CAV1 expression appeared not to modulate significantly proliferation of these cells. CONCLUSION: Our study shows that elevated CAV1, observed in patients with endometrial cancer, is linked to enhanced malignancy of endometrial cancer cells, as evidenced by increased migration, invasion and anchorage-independent growth. PMID- 26054532 TI - Impact of post-implant dosimetric parameters on the quality of life of patients treated with low-dose rate brachytherapy for localised prostate cancer: results of a single-institution study. AB - BACKGROUND: To assess the relationship between dosimetric parameters and the quality of life (QL) outcomes of patients with low-intermediate-risk localised prostate cancer (LPC) treated with low-dose-rate brachytherapy (LDR-BT). MATERIALS AND METHODS: We evaluated the participants in two consecutive prospective studies of the QL of patients treated with LDR-BT for LPC. QL was evaluated by means of a patient-completed questionnaire assessing non functional [physical (PHY) and psychological (PSY) well-being, physical autonomy (POW), social relationships (REL)] and functional scales [urinary (URI), rectal (REC), and sexual (SEX) function]; a scale for erectile function (ERE) was included in the second study. Urethra (D10 <= 210 Gy) and rectal wall constraints (V100 <= 0.5 cc) were used for pre-planning dosimetry and were assessed with post planning computerized tomography one month later for each patient. RESULTS: QL was assessed in 251 LPC patients. Dosimetry did not influence the non-functional scales. As expected, a progressive impairment in sexual and erectile function was reported one month after LDR-BT, and became statistically significant after the third year. Rectal function significantly worsened after LDR-BT, but the differences progressively decreased after the 1-year assessment. Overall urinary function significantly worsened immediately after LDR-BT and then gradually improved over the next three years. Better outcomes were reported for V100 rectal wall volumes of <= 0.5 cc and D10 urethra values of <= 210 Gy. CONCLUSIONS: The findings of this study show that dosimetric parameters influence only functional QL outcomes while non-functional outcomes are only marginally influenced. PMID- 26054533 TI - High-dose single-fraction IMRT versus fractionated external beam radiotherapy for patients with spinal bone metastases: study protocol for a randomized controlled trial. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT)using intensity-modulated radiotherapy (IMRT) can be a safe modality for treating spinal bone metastasis with enhanced targeting accuracy and an effective method for achieving good tumor control and a rigorous pain response. METHODS/DESIGN: This is a single-center, prospective randomized controlled trial to evaluate pain relief after RT and consists of two treatment groups with 30 patients in each group. One group will receive single-fraction intensity-modulated RT with 1 * 24 Gy, and the other will receive fractionated RT with 10 * 3 Gy. The target parameters will be measured at baseline and at 3 and 6 months after RT. DISCUSSION: The aim of this study is to evaluate pain relief after RT in patients with spinal bone metastases by means of two different techniques: stereotactic body radiation therapy and fractionated RT. The primary endpoint is pain relief at the 3-month time-point after RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02358720 (June 2, 2015). PMID- 26054534 TI - The in vitro and in vivo evaluation of fenofibrate with a self- microemulsifying formulation. AB - Fenofibrate is virtually insoluble in water and is highly lipophilic, which leads to poor oral bioavailability. The purpose of this approach is to develop self microemulsifying drug delivery system (SMEDDS) for oral bioavailability enhancement of fenofibrate. The in vitro dissolution test and pharmacokinetic behavior in beagle dogs were conducted to assess the formulation of fenofibrate in selfmicroemulsifying systems. The concentrations of fenofibrate were determined by HPLC. A crossover fashion study was performed in six fasted beagle dogs with SMEDDS formulation and commercial capsules. The results showed that SMEDDS formulation provides a good drug release with more than 90% of fenofibrate dissoluted from self-emulsifying formulations while less than 10% from the commercial capsules was released within 20min. The mean particle size of SMEDDS formulation after dispersion was about 33.7nm In pharmacokinetic parameters of SMEDDS formulation, the area under the plasma concentration-time curve (AUC) was significantly higher and was approximately 7-fold greater than that obtained when commercial capsule of the same dose of fenofibrate was administered. Also, the maximum absorption was advanced (2h to 1.25h) with SMEDDS formulation. The self microemulsifying drug delivery systems can significantly increase fenofibrate dissolution in vitro and absorption in vivo. PMID- 26054535 TI - The role of tomatine adjuvant in antigen delivery for cross- presentation. AB - The aim of this study was to investigate the use of tomatine adjuvant to deliver soluble antigen for crosspresentation by bone marrow-derived dendritic cells (BMDCs). BMDCs were incubated with tomatine adjuvantovalbumin (OVA) complex and analyzed for antigen uptake by flow cytometry. Adjuvant-induced cell death was examined in situ by terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay. To elucidate the effect of antigen internalization on tomatine adjuvant-mediated antigen presentation, BMDCs were treated with several endocytosis inhibitors, and antigen presentation was analyzed by B3Z activity assay. Our data indicated that tomatine adjuvant enhanced antigen internalization by antigen presenting cells (APCs) and induced significant cell death and leukocyte infiltration at the injection sites. In vitro tomatine adjuvant treatment of BMDCs activated Ova/K(b) restricted B3Z T cell hybridomas, whereas this activation was impaired by pretreatment with brefeldin A, cytochalasin B, wortmannin, or ZnCl2. Our results demonstrated the role of tomatine adjuvant in antigen delivery to antigen presenting cells (APCs) and suggested the involvement of phagocytosis and PI3K signaling during the delivery of soluble antigens in the context of MHC class I. PMID- 26054536 TI - Characterization of novel composite alginate chitosan-carrageenan nanoparticles for encapsulation of BSA as a model drug delivery system. AB - The objective of this research project was to develop a nanoparticle drug delivery system using the biopolymer chitosan as the base component. The nanoparticles were produced through ionotropic gelation by flush mixing chitosan with counterions carrageenan and alginate. The nanoparticles were generated under a range of conditions to determine the effect of pH, chitosan concentration, carrageenan concentration, and alginate concentration on the nanoparticle characteristics of particle diameter, zeta potential, and particle size distribution. The encapsulation and controlled release of BSA from chitosan nanoparticles was also evaluated. The encapsulation of BSA was used as a model system for the controlled drug delivery from composite nanoparticles. The release profile indicated an initial burst in the first few hours of the trial, followed by a slower steady release over time. According to Korsmeyer-Peppas model, the release profile followed fickian diffusion. PMID- 26054537 TI - Immune Sensitization and Mortality in Wait-Listed Kidney Transplant Candidates. AB - Cardiovascular mortality is the leading cause of death in ESRD. Whereas innate and adaptive immunity have established roles in cardiovascular disease, the role of humoral immunity is unknown. We conducted a retrospective cohort study in first-time adult kidney transplant candidates (N=161,308) using data from the Scientific Registry of Transplant Recipients and the Centers for Medicare and Medicaid Services to evaluate whether anti-human leukocyte antigen antibodies, measured as panel reactive antibodies (PRAs), are related to mortality in ESRD. Relationships between time-varying PRAs and all-cause or cardiovascular mortality were assessed using Cox proportional hazards models. The analysis was repeated in subcohorts of candidates at lower risk for significant comorbidities, activated on the waiting list after 2007, or unsensitized at activation. Competing risks analyses were also conducted. Fully adjusted models showed increased hazard ratios (HRs [95% confidence intervals]) for all-cause mortality (HR, 1.02 [95% CI, 0.99 to 1.06]; HR, 1.11 [95% CI,1.07 to 1.16]; and HR,1.21 [95% CI,1.15 to 1.27]) and cardiovascular mortality (HR, 1.05 [95% CI,1.00 to 1.10]; HR,1.11 [95% CI,1.05 to 1.18]; and HR,1.21 [95% CI,1.12 to 1.31]) in PRA 1%-19%, PRA 20%-79%, and PRA 80%-100% categories compared with PRA 0%, respectively. Associations between PRA and the study outcomes were accentuated in competing risks models and in lower-risk patients and persisted in other subcohorts. Our findings suggest that PRA is an independent predictor of mortality in wait-listed kidney transplant candidates. The mechanisms by which PRA confers an incremental mortality risk in sensitized patients, and the role of transplantation in modifying this risk, warrant further study. PMID- 26054538 TI - Surveillance of gammadelta T Cells Predicts Cytomegalovirus Infection Resolution in Kidney Transplants. AB - Cytomegalovirus (CMV) infection in solid-organ transplantation is associated with increased morbidity and mortality, particularly if a CMV mutant strain with antiviral resistance emerges. Monitoring CMV-specific T cell response could provide relevant information for patient care. We and others have shown the involvement of Vdelta2(neg) gammadelta T cells in controlling CMV infection. Here, we assessed if Vdelta2(neg) gammadelta T cell kinetics in peripheral blood predict CMV infection resolution and emergence of a mutant strain in high-risk recipients of kidney transplants, including 168 seronegative recipients receiving organs from seropositive donors (D+R-) and 104 seropositive recipients receiving antithymocyte globulins (R+/ATG). Vdelta2(neg) gammadelta T cell percentages were serially determined in patients grafted between 2003 and 2011. The growing phase of Vdelta2(neg) gammadelta T cells was monitored in each infected patient, and the expansion rate during this phase was estimated individually by a linear mixed model. A Vdelta2(neg) gammadelta T cell expansion rate of ?0.06% per day predicted the growing phase. The time after infection at which an expansion rate of 0.06% per day occurred was correlated with the resolution of CMV DNAemia (r=0.91; P<0.001). At 49 days of antiviral treatment, Vdelta2(neg) gammadelta T cell expansion onset was associated with recovery, whereas absence of expansion was associated with recurrent disease and DNAemia. The appearance of antiviral resistant mutant CMV strains was associated with delayed Vdelta2(neg) gammadelta T cell expansion (P<0.001). In conclusion, longitudinal surveillance of Vdelta2(neg) gammadelta T cells in recipients of kidney transplants may predict CMV infection resolution and antiviral drug resistance. PMID- 26054539 TI - CKD Stimulates Muscle Protein Loss Via Rho-associated Protein Kinase 1 Activation. AB - In patients with CKD, muscle wasting is common and is associated with morbidity and mortality. Mechanisms leading to loss of muscle proteins include insulin resistance, which suppresses Akt activity and thus stimulates protein degradation via the ubiquitin-proteasome system. However, the specific factors controlling CKD-induced suppression of Akt activity in muscle remain undefined. In mice with CKD, the reduction in Akt activity in muscle exceeded the decrease in upstream insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activity, suggesting that CKD activates other pathways that suppress Akt. Furthermore, a CKD-induced increase uncovered caspase-3 activity in muscle in these mice. In C2C12 muscle cells, activated caspase-3 cleaves and activates Rho-associated protein kinase 1 (ROCK1), which enhances the activity of phosphatase and tensin homolog (PTEN) and reduces Akt activity. Notably, constitutive activation of ROCK1 also led to increased caspase-3 activity in vitro. In mice with either global ROCK1 knockout or muscle-specific PTEN knockout, CKD-associated muscle proteolysis was blunted. These results suggest ROCK1 activation in CKD and perhaps in other catabolic conditions can promote loss of muscle protein via a negative feedback loop. PMID- 26054540 TI - Association of Body Mass Index with Patient-Centered Outcomes in Children with ESRD. AB - Obesity is associated with less access to transplantation among adults with ESRD. To examine the association between body mass index at ESRD onset and survival and transplantation in children, we performed a retrospective analysis of children ages 2-19 years old beginning RRT from 1995 to 2011 using the US Renal Data System. Among 13,172 children, prevalence of obesity increased from 14% to 18%, whereas prevalence of underweight decreased from 12% to 9% during this period. Over a median follow-up of 7.0 years, 10,004 children had at least one kidney transplant, and 1675 deaths occurred. Risk of death was higher in obese (hazard ratio [HR], 1.17; 95% confidence interval [95% CI], 1.03 to 1.32) and underweight (HR, 1.26; 95% CI, 1.09 to 1.47) children than children with normal body mass indices. Obese and underweight children were less likely to receive a kidney transplant (HR, 0.92; 95% CI, 0.87 to 0.97; HR, 0.83; 95% CI, 0.78 to 0.89, respectively). Obese children had lower odds of receiving a living donor transplant (odds ratio, 0.85; 95% CI, 0.74 to 0.98) if the transplant occurred within 18 months of ESRD onset. Adjustment for transplant in a time-dependent Cox model attenuated the higher risk of death in obese but not underweight children (HR, 1.09; 95% CI, 0.96 to 1.24). Lower rates of kidney transplantation may, therefore, mediate the higher risk of death in obese children with ESRD. The increasing prevalence of obesity among children starting RRT may impede kidney transplantation, especially from living donors. PMID- 26054541 TI - RORgammat(+)Foxp3(+) Cells are an Independent Bifunctional Regulatory T Cell Lineage and Mediate Crescentic GN. AB - Cells expressing both the regulatory T cell (Treg)-inducing transcription factor Foxp3 and the Th17 transcription factor RORgammat have been identified (biTregs). It is unclear whether RORgammat(+)Foxp3(+) biTregs belong to the Th17-specific Treg17 cells, represent intermediates during Treg/Th17 transdifferentiation, or constitute a distinct cell lineage. Because the role of biTregs in inflammatory renal disease is also unknown, we studied these cells in the nephrotoxic nephritis (NTN) model of acute crescentic GN. Induction of NTN resulted in rapid renal and systemic expansion of biTregs. Notably, analyses of the biTreg expression profile revealed production of both anti-inflammatory (IL-10, IL-35) and proinflammatory (IL-17) cytokines. Additionally, biTregs expressed a signature of surface molecules and transcription factors distinct from those of Th17 cells and conventional Tregs (cTregs), and biTregs were identified in Treg17 deficient mice. Finally, fate reporter and cell transfer studies confirmed that biTregs are not Treg/Th17 transdifferentiating cells. Therapeutic transfer of biTregs suppressed the development of nephritis to an extent similar to that observed with transferred cTregs, but in vitro studies indicated different mechanisms of immunosuppression for biTregs and cTregs. Intriguingely, as predicted from their cytokine profile, endogenous biTregs displayed additional proinflammatory functions in NTN that were abrogated by cell-specific deletion of RORgammat. In summary, we provide evidence that RORgammat(+)Foxp3(+) biTregs are a novel and independent bifunctional regulatory T cell lineage distinct from cTregs, Treg17 cells, and Th17 cells. Furthermore, biTregs appear to contribute to crescentic GN and hence may be novel therapeutic targets. PMID- 26054542 TI - Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism. AB - Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1(flox/flox)) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic appearing tubules. Expression of epithelial polarity markers beta-catenin and E cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-alpha (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism. PMID- 26054543 TI - Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling. AB - Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs. PMID- 26054544 TI - Proximal Tubules Have the Capacity to Regulate Uptake of Albumin. AB - Evidence from multiple studies supports the concept that both glomerular filtration and proximal tubule (PT) reclamation affect urinary albumin excretion rate. To better understand these roles of glomerular filtration and PT uptake, we investigated these processes in two distinct animal models. In a rat model of acute exogenous albumin overload, we quantified glomerular sieving coefficients (GSC) and PT uptake of Texas Red-labeled rat serum albumin using two-photon intravital microscopy. No change in GSC was observed, but a significant decrease in PT albumin uptake was quantified. In a second model, loss of endogenous albumin was induced in rats by podocyte-specific transgenic expression of diphtheria toxin receptor. In these albumin-deficient rats, exposure to diphtheria toxin induced an increase in albumin GSC and albumin filtration, resulting in increased exposure of the PTs to endogenous albumin. In this case, PT albumin reabsorption was markedly increased. Analysis of known albumin receptors and assessment of cortical protein expression in the albumin overload model, conducted to identify potential proteins and pathways affected by acute protein overload, revealed changes in the expression levels of calreticulin, disabled homolog 2, NRF2, angiopoietin-2, and proteins involved in ATP synthesis. Taken together, these results suggest that a regulated PT cell albumin uptake system can respond rapidly to different physiologic conditions to minimize alterations in serum albumin level. PMID- 26054546 TI - Structured training in assessment increases confidence amongst basic life support instructors. AB - AIM: Assessment skills are often neglected in resuscitation training and it has been shown that the ERC BLS/AED instructor course may be insufficient to prepare candidates for an assessment role. We have introduced an Assessment Training Programme (ATP) to improve assessors' decision making. In this article we present our ATP and an observational study of candidates' confidence levels upon completing both an ERC BLS/AED instructor course and our ATP. METHODS: Forty seven candidates undertook the ERC instructor course and 20 qualified ERC BLS/AED instructors undertook the ATP. Pre- and post-course questionnaires were completed. Confidence was assessed on ten-point Visual Analogue Scales (VAS). RESULTS: Overall confidence on the ERC BLS/AED instructor course rose from 5.9 (SD 1.8) to 8.7 (SD 1.4) (P < 0.001). A more modest improvement was witnessed on the ATP, rising from 8.2 (SD 1.4) to 9.6 (SD 0.5) (P < 0.001). Upon completion of their respective courses, assessors (mean 9.6, SD 0.5) were significantly more confident at assessing than instructors (mean 8.7, SD 0.5) (P<0.001). Confidence in assessing individual algorithm components was similar on both courses. On the post-course questionnaire those on the ATP remained significantly more confident at assessing borderline candidates compared to instructors (P < 0.001), with no difference for clear pass (P = 0.067) or clear fail (P = 0.060) candidates. CONCLUSION: The ATP raises the confidence of assessing BLS/AED candidates to a level above that of the ERC instructor course alone. We advocate that resuscitation organisations consider integrating an ATP into their existing training structure. PMID- 26054545 TI - Practice effects distort translational validity estimates for a Neurocognitive Battery. AB - INTRODUCTION: With the globalization of biomedical research and the advent of "precision medicine," there is increased need for translation of neuropsychological tests, such as computerized batteries that can be incorporated in large-scale genomic studies. Estimates of translational validity are obtained by administering the test in the original and the translated versions to bilingual individuals. We investigated the translation of a neuropsychological battery from English to Arabic and how practice effects influence translational validity estimates. METHODS: The Penn computerized neurocognitive battery (Penn CNB) includes tests that were validated with functional neuroimaging and provides measures of accuracy and speed of performance in several cognitive domains. To develop an Arabic version of the CNB, the English version was translated into Arabic, then back translated and revised. The Arabic and the original English versions were administered in a randomized crossover design to bilingual participants (N = 22). RESULTS: Performance varied by cognitive domain, but generally improved at the second session regardless of the language of the initial test. When performance on the English and Arabic version was compared, significant positive correlations were detected for accuracy in 8/13 cognitive domains and for speed in 4/13 domains (r = .02 to .97). When the practice estimates using linear models were incorporated, the translational validity estimates improved substantially (accuracy, r = .50-.96, speed, r = .63-.92, all correlations, p = .05 or better). CONCLUSION: While crossover designs control for order effects on average performance, practice effects, regardless of language, still need to be removed to obtain estimates of translational validity. When practice effect is controlled for, the Arabic and English versions of the Penn CNB are well correlated, and the Arabic version is suitable for use in research. PMID- 26054547 TI - Achieving Site-Specificity in Multistep Colloidal Synthesis. AB - We show that partial inhibition of the emerging Ag domain can be achieved by controlling the growth dynamics. With the symmetry broken by the "fresh" surface, sequentially growth gives (Au sphere)-(Ag wire)-(Ag plate) triblock nanostructures. This new understanding opens doors to sophisticated synthetic designs, broadening the horizon of our search for functional architectures. PMID- 26054548 TI - Association of body fat composition and obstructive sleep apnea in the elderly: A longitudinal study. AB - OBJECTIVE: Obesity and aging are considered risk factors for developing sleep apnea syndrome (OSA). The aim of this study was to determine the association between body fat composition and OSA in healthy elderly subjects examined in a 7 year longitudinal study. METHODS: A total of 209 elderly with unrecognized OSA aged 68.3 +/- 0.8 years underwent a clinical, ambulatory nocturnal respiratory recording, and anthropometric as well as body fat composition assessment by dual energy X-ray absorptiometry (DEXA) at baseline and follow-up. RESULTS: At study entry, 50.3% of the population showed an apnea+hypopnea index (AHI) <15 with a mean AHI of 16.8 +/- 11. At follow-up, a reduction of OSA cases (42%) was evident with a mean AHI of 14.6 +/- 10.2. The DEXA data demonstrated that body mass and total lean mass were reduced at follow-up, while central and peripheral fat mass showed a slight increase. Correlation analysis between the changes in DEXA measurements versus the changes in AHI and the indices of nocturnal hypoxemia showed an absence of a statistical correlation. CONCLUSIONS: The lack of correlation between the DEXA measurement changes and the changes in the AHI confirm our previous data on the absence of a central fat mass effect on OSA in the elderly. PMID- 26054549 TI - Buying health: assessing the impact of a consumer-side vegetable subsidy on purchasing, consumption and waste. AB - OBJECTIVE: To measure the impact of a reimbursement-based consumer subsidy on vegetable expenditures, consumption and waste. DESIGN: Two-arm randomized controlled trial; two-week baseline observation period, three-week intervention period. Participants' vegetable expenditures, consumption and waste were monitored using receipts collection and through an FFQ. During the intervention period, the treatment group received reimbursement of up to 50 US dollars ($) for purchased vegetables. SETTING: Participants were solicited from Palo Alto, CA, USA using materials advertising a 'consumer behavior study' and a small participation incentive. To prevent selection bias, solicitation materials did not describe the specific behaviour being evaluated. SUBJECTS: One hundred and fifty potential participants responded to the solicitations and 144 participants enrolled in the study; 138 participants completed all five weekly surveys. RESULTS: Accounting for the control group (n 69) and the two-week baseline period, the intervention significantly impacted the treatment group's (n 69) vegetable expenditures (+$8.16 (sd 2.67)/week, P<0.01), but not vegetable consumption (+1.3 (sd 1.2) servings/week, P=0.28) or waste (-0.23 (sd 1.2) servings/week, P=0.60). CONCLUSIONS: The consumer subsidy significantly increased participants' vegetable expenditures, but not consumption or waste, suggesting that this type of subsidy might not have the effects anticipated. Reimbursement based consumer subsidies may therefore not be as useful a policy tool for impacting vegetable consumption as earlier studies have suggested. Moreover, moderation analysis revealed that the subsidy's effect on participants' vegetable expenditures was significant only in men. Additional research should seek to determine how far reaching gender-specific effects are in this context. Further research should also examine the effect of a similar consumer subsidy on high risk populations and explore to what extent increases in participants' expenditures are due to the purchase of more expensive vegetables, purchasing of vegetables during the study period that were consumed outside the study period, or a shift from restaurant vegetable consumption to grocery vegetable consumption. PMID- 26054550 TI - Food allergy emergency preparedness in Illinois schools: rural disparity in guideline implementation. PMID- 26054551 TI - Progression of Irreversible Airflow Limitation in Asthma: Correlation with Severe Exacerbations. AB - BACKGROUND: Severe exacerbations of asthma are periods of excess functional and pathological changes in the airways that have been proposed to induce airway remodeling. OBJECTIVE: The objective of this study was to explore whether severe exacerbations are correlated with the decline in post-bronchodilator forced expiratory volume in 1 second (FEV1) and loss of bronchodilator reversibility (BDR). METHODS: We examined the changes in FEV1 and BDR in 140 nonsmoking patients with well-controlled asthma at baseline and correlated these changes with the frequency of severe asthma exacerbations. RESULTS: A 3-year follow-up assessment was completed in 128 patients. A total of 28 (21.9%) patients experienced at least 1 severe exacerbation with a mean rate of 0.16 year(-1). The exacerbation rate was significantly correlated with an annual rate of decline in FEV1 (rho = 0.49, P < .0001). Both patients with 1 exacerbation and those with 2 or more exacerbations had greater declines in FEV1 than patients with no exacerbations (no exacerbation, 13.6 mL/year; 1 exacerbation, 41.3 mL/year; 2 or more exacerbations, 58.3 mL/year; P < .01 and P < .0001, respectively). The changes in BDR from baseline to the end of the study in patients who did or did not experience an exacerbation were -1.2% and 0.1%, respectively (P < .0005). The changes in BDR were significantly correlated with the annual rates of change in FEV1 (r = 0.40, P < .0001). CONCLUSION: The occurrence of severe exacerbations of asthma is correlated with the progression of irreversible airflow limitation over time. This suggests that asthma exacerbations could have the long-term adverse consequences of structural and functional changes in the airways. PMID- 26054552 TI - A Practical Guide to Patch Testing. AB - Contact dermatitis is a common disease seen by allergists, dermatologists, and primary care physicians. The gold standard for diagnosing allergic contact dermatitis (ACD) is patch testing and is indicated in any patient with a chronic, pruritic, eczematous, or lichenified dermatitis if underlying or secondary ACD is suspected. Patients with acute generalized dermatitis who have extensive eczema on the back, are on immunosuppressant medications, and have applied topical corticosteroids, topical calcineurin inhibitors, or ultraviolet radiation to the patch test (PT) site may have suppressed PT reactions. The procedure of patch testing is not a difficult one to perform, but the interpretation of the PT needs some critical components, including having an appropriate level of suspicion for the diagnosis of ACD, testing the relevant allergens in their proper vehicle and concentration, and the necessary experience to properly interpret the results. Careful history and physical examination must be correlated with the result of the PT to establish clinical relevance. Once the PT is completed, allergens are identified, and relevance has been established, educating the patient about the avoidance of exposure is critical. The Joint Task Force of the American Academy of Allergy, Asthma and Immunology and American College of Allergy, Asthma and Immunology has developed updated practice parameters for contact dermatitis and patch testing, and their recommendations will be discussed (Fonacier LF, Bernstein DI, Pacheco K, Holness DL. Contact dermatitis: a practice parameter update 2015. J Allergy Clin Immunol Pract 2015; 3(3S):S1-S40.). PMID- 26054553 TI - Similar Efficacy with Omalizumab in Chronic Idiopathic/Spontaneous Urticaria Despite Different Background Therapy. AB - BACKGROUND: Data from the 3 omalizumab pivotal trials in patients with chronic idiopathic urticaria/chronic spontaneous urticaria (CIU/CSU) represent the largest database of patients reported to date with refractory disease (omalizumab, n = 733; placebo, n = 242). OBJECTIVE: The objective of this study was to compare results from ASTERIA I and II, which included only approved doses of H1-antihistamine as background therapy based on regulatory authority requirements, to those from GLACIAL, which permitted higher doses of H1 antihistamines as well as other types of background therapy, in a post hoc analysis. METHODS: Efficacy data from the placebo, omalizumab 150-mg, and omalizumab 300-mg treatment arms of ASTERIA I and II were pooled and analyzed (n = 162 and n = 160, respectively). The 300-mg treatment arm analyses were compared with the analysis of data from GLACIAL (n = 252) using analysis of covariance models. The key efficacy endpoint was change from baseline to week 12 in mean weekly itch severity score (ISS); other endpoints were also evaluated. Safety data were pooled from all 3 studies. RESULTS: Mean ISS was significantly reduced from baseline at week 12 in the pooled ASTERIA I and II omalizumab 150- and 300 mg treatment arms and in the GLACIAL omalizumab 300-mg arm. The weekly ISS reduction magnitude at week 12 was similar between the omalizumab 300-mg groups in the ASTERIA I and II pooled and GLACIAL studies. Similar treatment effect sizes were observed across multiple endpoints. Omalizumab was well tolerated and the adverse-event profile was similar regardless of background therapy for CIU/CSU. The overall safety profile was generally consistent with omalizumab therapy in allergic asthma. CONCLUSION: Omalizumab 300 mg was safe and effective in reducing CIU/CSU symptoms regardless of background therapy. PMID- 26054554 TI - Morphokinetics as a predictor of self-correction to diploidy in tripronucleated intracytoplasmic sperm injection-derived human embryos. AB - OBJECTIVE: To describe, in morphokinetic terms, a tripronucleated embryo (TPN) population according to ploidy and to explore the value of such variables for predicting ploidy. DESIGN: Experimental. SETTING: In vitro fertilization laboratory. PATIENT(S): Seventy-nine TPN embryos obtained after intracytoplasmic sperm injection (TPN-ICSI) were cultured in a time-lapse incubator for 6 days. INTERVENTION(S): Ploidy determinations were carried out for 35 TPN-ICSI at the cleavage and/or blastocyst stage. Their morphokinetics were then retrospectively compared. MAIN OUTCOME MEASURE(S): Direct (cleavage time from 2- to 8-cell stages) and indirect (cell cycle duration and blastomere synchrony at cleavage) morphokinetic variables; ploidy determination by FISH; in vitro development to the blastocyst stage. RESULT(S): TPN-ICSI cleaved later than bipronucleated control embryos (BPN). Diploid TPN displayed morphokinetic behavior closer to BPN than triploid TPN regarding almost all of the direct and indirect morphokinetic variables measured. Variable t5 was found to be a predictable variable of ploidy in TPN. CONCLUSION(S): TPN-ICSI are not homogeneous in ploidy, cleavage, or morphokinetic terms. Diploid, but nontriploid, TPN are morphokinetically similar to diploid BPN. The ploidy of TPN can be predicted by variable t5. PMID- 26054555 TI - Putative role for insulin resistance in depression risk in polycystic ovary syndrome. AB - OBJECTIVE: To evaluate whether insulin resistance is associated with depression risk in women with polycystic ovary syndrome (PCOS), independent of other factors, including body mass index (BMI). DESIGN: Cross-sectional. SETTING: Tertiary university center. PATIENT(S): A total of 301 women, aged 14-52 years, with PCOS by Rotterdam criteria, consecutively examined between 2006 and 2013. INTERVENTION(S): Complete history and physical examinations, including endovaginal ultrasounds, dermatologic assessments, completion of Beck Depression Inventory Fast Screen (BDI-FS), and serum testing. MAIN OUTCOME MEASURE(S): Scores >4 on BDI-FS indicated a positive screen for depression. Scores were further subdivided into mild (5-8), moderate (9-12), and severe (>12) depression risk. Insulin resistance was assessed using the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR). RESULT(S): A total of 131 women (44%) were at risk for depression, determined by positive BDI-FS screening. These patients had higher BMI (32.3 vs. 28.5), and elevated insulin resistance, assessed by HOMA-IR (5.2 vs. 2.6), compared with patients with negative depression screening. In a stratified analysis by BMI category, obese women with positive depression screens had elevated HOMA-IR, compared with obese women with normal BDI-FS scores (7.4 vs. 4.1). In a multivariate logistic regression analysis, HOMA-IR was independently related to the odds of depression risk after controlling for age, ethnicity, BMI, and exercise (odds ratio: 1.07). CONCLUSION(S): Depression is common in PCOS. After controlling for confounders in multivariate regression analyses, we found HOMA-IR to be significantly associated with depression risk. Our data suggest a complex interplay among insulin resistance, obesity, and depression in PCOS, warranting additional investigation. Mental health assessment is indicated in comprehensive care of patients with PCOS. PMID- 26054556 TI - Total levels, localization patterns, and proportions of sperm exhibiting phospholipase C zeta are significantly correlated with fertilization rates after intracytoplasmic sperm injection. AB - OBJECTIVE: To study the relationship of total levels, localization patterns, and proportions of sperm exhibiting phospholipase C zeta, with fertilization rates after in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). DESIGN: Laboratory study; controls vs. patients after IVF (n = 27) or ICSI (n = 17) treatment. SETTING: Fertility center. PATIENT(S): A total of 44 semen samples, subjected to either IVF or ICSI treatment. Oocyte collection, ICSI or IVF, determination of sperm concentration and motility, and immunocytochemical analyses of phospholipase C zeta (PLCzeta). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Percentages of sperm exhibiting PLCzeta. RESULT(S): Significant positive correlation between ICSI fertilization rates and total levels, localization patterns, and the proportion (percentage) of sperm exhibiting PLCzeta. Total levels, localization patterns, and the proportion of sperm exhibiting PLCzeta are correlated with fertilization rates for ICSI, but not for IVF. CONCLUSION(S): Evaluating total levels, localization patterns, and proportions of PLCzeta may represent a useful diagnostic tool for clinical purposes in men for whom IVF is not advised or has previously failed. This clinical study further supports the fundamental role of PLCzeta in the oocyte activation process. PMID- 26054557 TI - Lupinus mutabilis: Composition, Uses, Toxicology, and Debittering. AB - Lupinus mutabilis has protein (32.0-52.6 g/100 g dry weight) and lipid (13.0-24.6 g/100 g dry weight) contents similar to soya bean (Glycine max). The Omega3, Omega6, and Omega9 contents are 1.9-3.0, 26.5-39.6, and 41.2-56.2 g/100 g lipid, respectively. Lupins can be used to fortify the protein content of pasta, bread, biscuits, salads, hamburgers, sausages, and can substitute milk and soya bean. Specific lupin protein concentrates or isolates display protein solubility (>90%), water-absorption capacity (4.5 g/g dry weight), oil-absorption capacity (3.98 g/g), emulsifying capacity (2000 mL of oil/g), emulsifying stability (100%, 60 hours), foaming capacity (2083%), foaming stability (78.8%, 36 hours), and least gelation concentration (6%), which are of industrial interest. Lupins contain bitter alkaloids. Preliminary studies on their toxicity suggest as lethal acute dose for infants and children 10 mg/kg bw and for adults 25 mg/kg bw. However, alkaloids can also have medical use for their hypocholesterolemic, antiarrhythmic, and immunosuppressive activity. Bitter lupins can be detoxified by biological, chemical, or aqueous processes. The shortest debittering process requires one hour. This review presents the nutritional composition of lupins, their uses (as food, medicine, and functional protein isolates), toxicology, and debittering process scenarios. It critically evaluates the data, infers conclusions, and makes suggestions for future research. PMID- 26054558 TI - Comprehensive analytical methodology to determine hydrocarbons in marine waters using extraction disks coupled to glass fiber filters and compound-specific isotope analyses. AB - Solid-phase extraction of both aliphatic (AHs) and aromatic polycyclic hydrocarbons (PAHs) from seawater samples was evaluated using a GFF filter stacked upon an octadecyl bonded silica (C18) disk. Stable-isotope measurements were developed on hydrocarbons extracted from both GFF and C18-disks in order to characterize the source of hydrocarbons. A clear partition of hydrocarbon compounds between the dissolved and the particulate phase was highlighted. PAHs showed a higher affinity with the dissolved phase (recoveries efficiency of 48 71%) whereas AHs presented strong affinity with the particulate phase (up to 76% of extraction efficiency). Medium volumes of seawater samples were tested and no breakthrough was observed for a 5L sample. Isotopic fractionation was investigated within all analytical steps but none was evidenced. This method has been applied to harbor seawater samples and very low AH and PAH concentrations were achieved. Due to the low concentration levels of hydrocarbons in the samples, the source of hydrocarbons was determined by molecular indices rather than isotopic measurements and a pyrolytic origin was evidenced. The aliphatic profile also revealed the presence of long-chain linear alkylbenzenes (LABs). The methodology presented here would better fit to polluted coastal environments affected by recent oil spills. PMID- 26054559 TI - Broad spectrum analysis of polar and apolar organic compounds in submicron atmospheric particles. AB - A method for the quantitative analysis of organic compounds on submicron particulate matter (PM1) collected on quartz filters was developed. The compounds analyzed encompassed C22-C35 alkanes, polycyclic aromatic hydrocarbons (PAHs), quinones, levoglucosan, cis-pinonic acid and short chain dicarboxylic acids such as malonic, succinic, glutaric, adipic, suberic, azelaic, malic and phthalic acids. The method included extraction with a pressure liquid extraction system, sample filtration though glass fibre filter, fractionation by high performance liquid chromatography and subsequent analysis by gas chromatography coupled to mass spectrometry. The study of the extraction efficiency of different solvent mixtures showed that DCM:MeOH 1:1 was the one providing the highest recoveries for all compounds. Extraction temperatures of 100 degrees C provided better results than 60 degrees C or 80 degrees C. This method provided comparable extraction efficiency and qualitative and quantitative data to those involving Soxhlet extraction. Method recoveries for alkanes, most PAH, quinones and polar compounds calculated from spiked real samples were 52-72%, 78-101%, 50-62% and 76 104%, respectively, reproducibilities were 2-28%, 7-29%, 10-27% and 5-28%, respectively, limits of quantification were 0.01-0.1ng/m(3), 0.01-0.27ng/m(3), 0.04ng/m(3) and 0.32-2.8ng/m(3), respectively, which affords the quantification of a broad number of primary and secondary organic constituents of submicron aerosols. PMID- 26054560 TI - Protein adsorption to poly(ethylenimine)-modified Sepharose FF: V. Complicated effects of counterions. AB - In the previous studies on protein adsorption to poly(ethylenimine) (PEI)-grafted Sepharose FF resins, a critical ionic capacity (600mmol/L) of PEI-Sepharose resins was found for the adsorption of bovine serum albumin (BSA), above which both protein capacity and uptake rate increased drastically. In this work, the influence of counterions on the PEI-Sepharose resin with an ionic capacity of 683mmol/L (FF-PEI-L680) was investigated with sodium salts of SCN(-), Cl(-), HPO4(2-) and SO4(2-). Linear gradient elution, batch adsorption and breakthrough experiments showed that counterion preference, effective pore diffusion coefficient (De) and dynamic binding capacity (DBC) values increased in the order of SCN(-), Cl(-), HPO4(2-) and SO4(2-), while static adsorption capacity decreased in this order. It is considered that higher counterion preference of the ion exchange groups resulted in lower protein binding strength and adsorption capacity, while the De value increased due to the enhanced "chain delivery" effect (a kind of surface diffusion). Besides, the DBC value was mainly dependent on De value. In particular, SO4(2-) was the most favorable counterion for the PEI Sepharose resin, which gave rise to the highest De value (De/D0=1.17, D0 is protein diffusivity in free solution) and DBC value (118mg/mL at a residence time of 2min). Moreover, the effects of counterions on BSA adsorption to DEAE Sepharose FF and Q Sepharose FF, which were non-grafted resins, were also studied for comparisons. It was found that the counterion preferences of the two non grafted resins were different from each other and also different from that of FF PEI-L680. The different counterion preferences were attributed to the differences in the ion-exchange ligand chemistries. In addition, the De values for DEAE Sepharose FF and Q Sepharose FF kept unchanged. The low counterion sensitivity of De values could be interpreted as the lack of "chain delivery" effect for the non grafted resins. The results indicate that protein adsorption and chromatographic performance with PEI-Sepharose can be improved by proper counterions. For the four counterions tested, SO4(2-) was the most favorable for providing the best adsorption and elution outcomes with FF-PEI-L680. PMID- 26054561 TI - Understanding and diminishing the extra-column band broadening effects in supercritical fluid chromatography. AB - Supercritical fluid chromatography, where a low-viscosity mobile phase such as carbon dioxide is used, proves to be an excellent technique for fast and efficient separations, especially when sub-2MUm particles are used. However, to achieve high velocities when using these small particles, and in order to stay within the flow rate range of current SFC-instruments, narrow columns (e.g. 2.1mm ID) must be used. Unfortunately, state-of-the-art instrumentation is limiting the full separation power of these narrower columns due to significant extra-column band broadening effects. The present work identifies and quantifies the different contributions to extra-column band broadening in SFC such as the influence of the sample solvent, injection volume, extra-column volumes and detector cell volume/design. When matching the sample solvent to the mobile phase in terms of elution strength and polarity (e.g. using hexane/ethanol/isopropanol 85/10/5vol%) and lowering the injection volume to 0.4MUL, the plate count can be increased from 7600 to 21,300 for a low-retaining compound (k'=2.3) on a 2.1mm*150mm column (packed with 1.8MUm particles). The application of a water/acetonitrile mixture as sample solvent was also investigated. It was found that when the volumetric ratio of water/acetonitrile was optimized, only a slightly lower plate count was measured compared to the hexane-based solvent when minimizing injection and extra column volume. This confirms earlier results that water/acetonitrile can be used if water-soluble samples are considered or when a less volatile solvent is preferred. Minimizing the ID of the connection capillaries from 250 to 65MUm, however, gives no further improvement in obtained efficiency for early-eluting compounds when a standard system configuration with optimized sample solvent was used. When switching to a state-of-the-art detector design with reduced (dispersion) volume (1.7-0.6MUL), an increase in plate count is observed (from 11,000 to 14,000 plates on a 2.1mm*100mm column with 1.8MUm particles for k'=3) even when 250MUm tubing was used. Using this detector cell and decreasing the ID of the tubing from 250 to 120MUm resulted in an additional increase to 17,300 plates. Further decreasing the tubing ID (e.g. 65MUm) appeared to have no observable influence on the obtained plate count. PMID- 26054562 TI - Evolution and molecular epidemiology of streptococci. PMID- 26054563 TI - Implication of Nitrate in Drinking Water in Kawauchi Village, Fukushima. PMID- 26054564 TI - Novel therapeutic core-shell hydrogel scaffolds with sequential delivery of cobalt and bone morphogenetic protein-2 for synergistic bone regeneration. AB - Enabling early angiogenesis is a crucial issue in the success of bone tissue engineering. Designing scaffolds with therapeutic potential to stimulate angiogenesis as well as osteogenesis is thus considered a promising strategy. Here, we propose a novel scaffold designed to deliver angiogenic and osteogenic factors in a sequential manner to synergize the bone regeneration event. Hydrogel fibrous scaffolds comprised of a collagen-based core and an alginate-based shell were constructed. Bone morphogenetic protein 2 (BMP2) was loaded in the core, while the shell incorporated Co ions, enabled by the alginate crosslinking in CoCl2/CaCl2 solution. The incorporation of Co ions was tunable by altering the concentration of Co ions in the crosslinking solution. The incorporated Co ions, that are known to play a role in angiogenesis, were released rapidly within a week, while the BMP2, acting as an osteogenic factor, was released in a highly sustainable manner over several weeks to months. The release of Co ions significantly up-regulated the in vitro angiogenic properties of cells, including the expression of angiogenic genes (CD31, VEGF, and HIF-1alpha), secretion of VEGF, and the formation of tubule-like networks. However, BMP2 did not activate the angiogenic processes. Osteogenesis was also significantly enhanced by the release of Co ions as well as BMP2, characterized by higher expression of osteogenic genes (OPN, ALP, BSP, and OCN), and OCN protein secretion. An in vivo study on the designed scaffolds implanted in rat calvarium defect demonstrated significantly enhanced bone formation, evidenced by new bone volume and bone density, due to the release of BMP2 and Co ions. This is the first study using Co ions as an angiogenic element together with the osteogenic factor BMP2 within scaffolds, and the results demonstrated the possible synergistic role of Co ions with BMP2 in the bone regeneration process, suggesting a novel potential therapeutic scaffold system. STATEMENT OF SIGNIFICANCE: This is the first report that utilizes Co ion as a pro-angiogenic factor in concert with osteogenic factor BMP-2 in the fine-tuned core-shell hydrogel fiber scaffolds, and ultimately achieves osteo/angiogenesis of MSCs and bone regeneration through the sequential delivery of both biofactors. This novel approach facilitates a new class of therapeutic scaffolds, aiming at successful bone regeneration with the help of angiogenesis. PMID- 26054565 TI - Impact of influenza A (H3N2) seasonal outbreak on the pattern of vaccination uptake in healthcare workers. PMID- 26054566 TI - Biomarkers for personalized medicine in GI cancers. AB - Gastrointestinal malignancies are a major health care challenge due to the high incidence and overall poor outcome. A biomarker is a molecular characteristic of a tumor that may be utilized in the initial risk assessment and the subsequent management of the patient. This review focuses on the most pertinent prognostic and predictive biomarkers used in the clinical management of gastric, pancreas, and colon cancer. The available assays, limitations and clinical use for each biomarker are reviewed. The clinical trials evaluating novel biomarkers in GI cancers are discussed. PMID- 26054567 TI - Politics of science: Progress toward prevention of the dementia-Alzheimer's syndrome. AB - There exist many challenges hampering the discovery and development of effective interventions to prevent dementia. Three major trends have now intersected to influence the emerging interest in disease modifying therapies that may delay or halt dementia. The three crucial factors shaping this current focus are: (1) the emergence of the longevity revolution and the impact of a aging society, (2) the effects of the US Federal investment in research in advancing knowledge about the neurobiology of aging and dementia, and (3) the problem of US legislators and health policy makers to balance the allocation of evermore scarce research funding resources. The purpose of this essay is to provide a survey of the politics of science and to describe efforts to correctly manage the high level of expectations of both the patient and research communities. The perspective offered reviews the history and evolution of the ideas to treat or prevent dementia and Alzheimer's disease as a national strategic goal. The aim is to evaluate the interplay between science and formulation of public policy for setting research priority. We use the history of developing US National Institute of Aging's extramural research programs on brain aging and Alzheimer's disease (Khachaturian, 2006; 2007) as an initial case study. PMID- 26054568 TI - Exploring the various aspects of the pathological role of vascular endothelial growth factor (VEGF) in diabetic retinopathy. AB - Diabetic retinopathy, a sight-threatening microvascular complication of diabetes mellitus, is initiated by retinal endothelial dysfunction and succeeded by various pathological events, eventually resulting in vision-loss. These events are regulated by numerous mediators, including vascular endothelial growth factor (VEGF), which induces the progression of various events characterizing diabetic retinopathy, such as neovascularization and macular edema. VEGF is physiologically required for regulating proliferation and assembling of endothelial cells, during vasculogenesis, as well as for their maintenance and survival throughout the lifetime of blood vessels. However, various pathological conditions are induced in the body during diabetes (such as ischemia, oxidative stress and overactivation of protein kinase C), which upregulate the expression of VEGF, thereby deviating it from its physiological role and leading to various pathological demonstrations such as angiogenesis, increased permeability of endothelium, decreased inhibition of pro-apoptotic proteins and activation of various other inflammatory mediators. Such events disrupt vascular homeostasis and play key roles in the pathophysiology of diabetic retinopathy. Hence, acknowledging various VEGF-mediated pathways helps in understanding the deeper aspects related to progression of this disorder. Targeting and inhibiting VEGF mediated disease progression might provide an effective alternative therapy and hence prove beneficial in the treatment of diabetic retinopathy. PMID- 26054570 TI - [Not Available]. PMID- 26054569 TI - Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner. AB - Ilexgenin A is a natural triterpenoid with beneficial effects on lipid disorders. This study aimed to investigate the effects of ilexgenin A on endothelial homeostasis and its mechanisms. Palmitate (PA) stimulation induced endoplasmic reticulum stress (ER stress) and subsequent thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in endothelial cells, leading to endothelial dysfunction. Ilexgenin A enhanced LKB1-dependent AMPK activity and improved ER stress by suppression of ROS-associated TXNIP induction. However, these effects were blocked by knockdown of AMPKalpha, indicating AMPK is essential for its action in suppression of ER stress. Meanwhile, ilexgenin A inhibited NLRP3 inflammasome activation by down-regulation of NLRP3 and cleaved caspase-1 induction, and thereby reduced IL-1beta secretion. It also inhibited inflammation and apoptosis exposed to PA insult. Consistent with these results in endothelial cells, ilexgenin A attenuated ER stress and restored the loss of eNOS activity in vascular endothelium, and thereby improved endothelium-dependent vasodilation in rat aorta. A further analysis in high-fat fed mice showed that oral administration of ilexgenin A blocked ER stress/NLRP3 activation with reduced ROS generation and increased NO production in vascular endothelium, well confirming the beneficial effect of ilexgenin A on endothelial homeostasis in vivo. Taken together, these results show ER stress-associated TXNIP/NLRP3 inflammasome activation was responsible for endothelial dysfunction and ilexgenin A ameliorated endothelial dysfunction by suppressing ER-stress and TXNIP/NLRP3 inflammasome activation with a regulation of AMPK. This finding suggests that the application of ilexgenin A is useful in the management of cardiovascular diseases in obesity. PMID- 26054571 TI - Differentiation of squamous cell carcinoma and inverted papilloma using non invasive MR perfusion imaging. AB - OBJECTIVES: To investigate the diagnostic value of tumour blood flow (TBF) obtained with pseudocontinuous arterial spin labelling for the differentiation of squamous cell carcinoma (SCC) and inverted papilloma (IP) in the nasal or sinonasal cavity. METHODS: We retrospectively analysed the cases of 33 patients with SCC and 8 patients with IP in the nasal or sinonasal cavity. Pseudocontinuous arterial spin labelling scanning was performed for all patients using a 3.0-T MR unit. Quantitative TBF values were measured by two neuroradiologists by respectively delineating the whole-tumour regions of interest, and the mean of them was determined as TBF value in each patient. Additionally, the presence of imaging findings of convoluted cerebriform pattern (CCP) on MR T2 weighted images was determined in all patients. As a subgroup analysis, patients with IP were divided into aggressive and non-aggressive IPs depending on their progression range. First, an intraclass correlation coefficient (ICC) of TBF values between two neuroradiologists was determined. Next, a statistical comparison of the TBF value by a Mann-Whitney U test between the patients with SCC and IP was performed. Additionally, the comparison by an ANOVA with a post hoc test of Tukey's method among the SCC, non-aggressive IP and aggressive IP groups was also performed. If significance was observed, the diagnostic accuracy to differentiate SCCs from IPs was calculated. Diagnostic accuracy by CCP findings alone and by the combination of CCP findings and TBF were also assessed. RESULTS: The ICC of TBF values between two neuroradiologists was 0.82. The mean TBF values in the patients with SCC, all patients with IP, those with aggressive IP and those with non-aggressive IP were 141.2 +/- 33.1, 77.8 +/- 31.5, 109.4 +/- 16.7 and 58.8 +/- 19.9 ml 100 g-1 min-1, respectively. A significant difference was observed between SCC and IP (p < 0.001), SCC and non aggressive IP (p < 0.01) and non-aggressive IP and aggressive IP (p < 0.01). The diagnostic accuracy values obtained with receiver operating characteristic curve analysis for the differentiation of SCC from IP and for SCC from non-aggressive IP were 0.90 and 0.92, respectively. The diagnostic accuracy was elevated (0.95 from 0.88) by adding the TBF value to CCP findings. CONCLUSIONS: The pseudocontinuous arterial spin labelling technique can be a useful non-invasive diagnostic tool to differentiate SCC from IP in nasal or sinonasal cavity. PMID- 26054572 TI - Effect of exposure parameters and voxel size on bone structure analysis in CBCT. AB - OBJECTIVE: To evaluate the effect of exposure parameters and voxel size on bone structure analysis in dental CBCT. METHODS: 20 cylindrical bone samples underwent CBCT scanning (3D Accuitomo 170; J. Morita, Kyoto, Japan) using three combinations of tube voltage (kV) and tube current-exposure time product (mAs), corresponding with a CT dose index of 3.4 mGy: 90 kV and 62 mAs, 73 kV and 108.5 mAs, and 64 kV and 155 mAs. Images were reconstructed with a voxel size of 0.080 mm. In addition, the 90 kV scan was reconstructed at voxel sizes of 0.125, 0.160, 0.200, 0.250 and 0.300 mm. The following parameters were measured: bone surface (BS) and bone volume (BV) per total volume (TV), fractal dimension, connectivity density, anisotropy, trabecular thickness (Tb. Th.) and trabecular spacing (Tb. Sp.), structure model index (SMI), plateness, branches, junctions, branch length and triple points. RESULTS: For most parameters, there was no significant effect of the kV value. For BV/TV, "90 kV" differed significantly from the other kV settings; for SMI, "64 vs 73 kV" was significant. For BS/TV, fractal dimension, connectivity density, branches, junctions and triple points values incrementally decreased at larger voxel sizes, whereas an increase was seen for Tb. Th., Tb. Sp., SMI and branch length. For anisotropy and plateness, no (or little) effect of voxel size was seen; for BV/TV, the effect was inconsistent. CONCLUSIONS: Most bone structure parameters are not affected by the kV if the radiation dose is constant. Parameters dealing with the trabecular structure are heavily affected by the voxel size. PMID- 26054574 TI - Blood test for Down's syndrome is safe and effective, say researchers. PMID- 26054573 TI - A coagulase-negative and non-haemolytic strain of Staphylococcus aureus for investigating the roles of SrtA in a murine model of bloodstream infection. AB - Sortase A (SrtA) is a cysteine transpeptidase and virulence factor from Staphylococcus aureus (S. aureus) that catalyses the attachment and display of surface proteins on the cell wall, thereby mediating bacterial adhesion to host tissues, host-cell entry and evasion of the immune response. As a result, SrtA has become an important target in the development of therapies for S. aureus infections. In this study, we used the new reference strain S. aureus Newman D2C to investigate the role of SrtA in a murine model of bloodstream infection, when the impact of coagulase and haemolysin is excluded. The results suggested that deletion of SrtA reduced the bacterial burden on the heart, liver and kidneys by blunting the host proinflammatory cytokine response at an early point in infection. Kidneys, but not heart or liver, formed abscesses on the sixth day following non-lethal infection, and this effect was diminished by SrtA mutation. These findings indicate that SrtA is a determining virulence factor in lethality and formation of renal abscesses in mice followed by S. aureus bloodstream infection. We have thus established a convenient in vitro and mouse model for developing SrtA-targeted therapeutic strategies. PMID- 26054575 TI - Perceptions regarding medication administration errors among hospital staff nurses of South Korea. AB - OBJECTIVE: To identify reasons for medication administration errors (MAEs) and why they are unreported, and estimate the percentage of MAEs actually reported among hospital nurses. DESIGN: A cross-sectional survey design. SETTING: Three university hospitals in three South Korean provinces. PARTICIPANTS: A total of 312 hospital staff nurses were included in this study. MAIN OUTCOME: Medication administration errors. RESULTS: Actual MAEs were experienced by 217 nurses (69.6%) during their clinical career, whereas 149 nurses (47.8%) perceived that MAEs only occur less than 20% rate. MAEs occurred mostly during intravenous (IV) administrations. Nurses perceived that the most common reasons for MAEs were inadequate number of nurses in each working shift (4.88 +/- 1.05) and administering drugs with similar names or labels (4.49 +/- 0.94). The most prevalent reasons for unreported MAEs included fears of being blamed (4.36 +/- 1.10) and having too much emphasis on MAEs as a measure of nursing care quality (4.32 +/- 1.02). The three most frequent errors perceived by nurses for non-IV related MAEs included administering medications to the incorrect patients and incorrect medication doses and drug choices. The three most frequent IV related MAEs included incorrect infusion rates, patients and medication doses. CONCLUSIONS: Nurse-staffing adequacy could be helpful to prevent MAEs among nurses as well ongoing education, and training regarding safe medication administration using the problem-based simulation education. In addition, encouraging nurses to identify and report work related errors in a non-punitive milieu will increase error reporting. PMID- 26054576 TI - Disseminated Mycobacterium avium complex infection in a child with partial dominant interferon gamma receptor 1 deficiency in India. AB - Mendelian susceptibility to mycobacterial disease (MSMD) is a rare condition characterized by clinical disease caused by weakly virulent mycobacteria. All genes mutated in MSMD patients are involved in IFN-gamma immunity. Autosomal partial dominant (PD) interferon-gamma receptor 1 (IFN-gammaR1) deficiency is the most frequent abnormality affecting the group of MSMD patients leading to impaired response of IFN-gamma. We describe here a patient from India with disseminated infection due to Mycobacterium avium intracellulare (MAC) including multifocal osteomyelitis and BCG disease. A heterozygous mutation in exon 6 of IFNGR1 gene was identified, conferring an autosomal PD IFN-gammaR1 deficiency. Patient had recurrence of mycobacterial disease during antibiotic therapy for which subcutaneous IFN-gamma was added as a modality of treatment for resistant MAC infection. PMID- 26054577 TI - A novel mouse model of diabetes mellitus using unilateral nephrectomy. AB - Diabetes mellitus (DM) is a major cause of morbidity and mortality worldwide, and its complications are prominent public health issues. Many experimental models of streptozotocin (STZ)-induced and high-fat diet (HF)-induced DM have been used to study this disease. Studies have indicated that unilateral nephrectomy (UN) accelerates the development of diabetic nephropathy. We hypothesized that UN stimulates HF and STZ combination-induced DM in mice. Seventy-two female C57BL/6J mice were divided into four treatment groups: HF; HF + STZ120 (HF and STZ, 120 mg/kg); UN + HF + STZ120 (UN, HF and STZ, 120 mg/kg); and HF + STZ200 (HF and STZ, 200 mg/kg). Onset of DM, survival rate, blood pressure, urine glucose level, and pancreatic histology were investigated. Additionally, renal function was evaluated in the UN + HF + STZ120 group after STZ injection. DM was induced in the UN + HF + STZ120 and HF + STZ200 groups within one week. The UN + HF + STZ120 group had lower mortality than the HF + STZ200 group and greater pancreatic destruction than the HF and HF + STZ120 groups. Two weeks after STZ injection, blood pressure was not significantly different among the groups. Nephrotoxicity associated with the combination of UN and STZ was not observed. In conclusion, the combination of these three techniques--UN, HF and STZ induced DM rapidly and effectively. PMID- 26054578 TI - A Case of Lichen Sclerosus et Atrophicus With Distinct Erythematous Borders. AB - BACKGROUND: Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory and fibrosing condition that mostly affects the genital mucosa. Nongenital skin may be affected either in isolation or in association with genital involvement. A distinct, brightly red border may be seen but is poorly documented in major dermatology texts. In the case presented, such a border was noted in all of the patient's very extensive lesions. OBJECTIVE: To draw attention to this clinical manifestation and to stimulate future observations as to its clinical and prognostic significance. METHODS AND RESULTS: A 67-year-old woman presented with disseminated LSA with genital involvement. All the lesions had a distinct red border. A review of major textbooks available to the authors revealed that the presence of a marginal erythema is regularly not mentioned. CONCLUSION: An erythematous border to LSA may be a notable feature. Its frequency and clinical significance remain to be determined. PMID- 26054579 TI - Relationship between DNA degradation ratios and the number of loci detectable by STR kits in extremely old seminal stain samples. AB - The relationships between DNA degradation ratios and the number of detected loci were explored in extremely old seminal stains evaluated using three short tandem repeat (STR) kits: the AmpFlSTR(r) IdentifilerTM PCR Amplification Kit (Identifiler), the AmpFlSTR(r) YfilerTM PCR Amplification Kit (Yfiler), and the AmpFlSTR(r) MiniFilerTM PCR Amplification Kit (MiniFiler). DNA degradation ratios based on 41, 129, and 305bp DNA fragments were calculated (129:41 and 305:41), and the relationships between the ratios and storage duration were also explored. Using the Identifiler kit, the number of loci detected was strongly correlated with the 129:41 ratio (r=0.887), whereas the correlation with the 305:41 ratio was moderate (r=0.656). Using the Yfiler kit, the DYS385 amplicon was detected in all samples, suggesting that DYS385 may be resistant to degradation. The number of detected loci was strongly correlated with the 129:41 ratio (r=0.768), and moderately so with the 305:41 ratio (r=0.515). MiniFiler detected at least seven loci in all samples. In samples that did not yield full profiles, the undetected loci were D7S820 and D21S11, or D21S11 only, suggesting that these loci might be easily degraded. The number of loci detected using STR kits correlated with the DNA degradation ratios. In particular, the 129:41 ratio was particularly useful for estimating the number of loci detectable by STR kits. On the other hand, we suggest that storage duration cannot be accurately estimated using DNA degradation ratios; these ratios were not strongly correlated with storage duration (129:41; r=-0.698, 305:41; r=-0.550). However, the ratios may allow the identification of samples that have been stored for more than 40years. PMID- 26054580 TI - Performance evaluation of four 25-hydroxyvitamin D assays to measure 25 hydroxyvitamin D2. AB - OBJECTIVES: The ability of current immunoassays to accurately measure equimolar amounts of 25(OH)D2 and 25(OH)D3 has been recently questioned. This study determined serum 25(OH)D2, 25(OH)D3 and total serum 25(OH)D concentrations in healthy vitamin D2-supplemented subjects by isotope dilution liquid chromatography mass spectrometry (ID-LC-MS/MS); and, evaluated the ability of the Siemens, DiaSorin, Roche, and Abbott Vitamin D Total assays to monitor total serum 25(OH)D concentrations compared to an ID-LC-MS/MS method traceable to the National Institute of Standards and Technology (NIST), and that has achieved certification from the Centers for Disease Control and Prevention (CDC) Vitamin D Standardization Certification Program (VDSCP). DESIGN AND METHODS: Twenty (20) healthy adults, with no history of prior vitamin D supplementation were administered oral vitamin D2 (2400IU/day for 6months). Serum samples (140) from baseline and monthly blood draws were tested. RESULTS: After one month, the mean serum 25(OH)D2 concentrations rose from 0.8 to 43.6nmol/L, whereas 25(OH)D3 concentrations declined from 84.0 to 63.4nmol/L; total serum 25(OH)D concentrations rose from 86.6 to 107.0nmol/L. The overall mean bias to ID-LC MS/MS was -7.1% for the Siemens ADVIA Centaur assay, -15.3% for the DiaSorin LIAISON assay; -8.4% for the Roche ELECSYS assay and -16.3% for the Abbott ARCHITECT assay. Correlation coefficients (r) were 0.94, 0.79, 0.74, and 0.73; the mean bias for baseline [25(OH) D3-containing] versus six-month [25(OH)D2- and 25(OH)D3-containing] samples was -13.4% and -5.7%; -3.5% and 20.3%, 9.6% and 12.1%, and 0.2% and -17.8%, respectively. CONCLUSIONS: The bias results obtained for the Siemens ADVIA Centaur assay and Roche ELECSYS assay were slightly lower than those for the DiaSorin LIAISON assay and the Abbott ARCHITECT assay, but all 25(OH)D assays demonstrated acceptable performance. PMID- 26054581 TI - Developing a reference measurement procedure for free glycerol in human serum by two-step gas chromatography-isotope dilution mass spectrometry. AB - BACKGROUND: Free glycerol in human serum is measured in clinical laboratories using enzymatic methods, which can be affected by interferences from biological samples. These methods are not applicable when stable isotopic tracers are used to determine lipid kinetics. Hence, a reference measurement procedure for free glycerol in human serum is needed. METHODS: A reference measurement procedure based on two-step gas chromatography-isotope dilution mass spectrometry (GC-IDMS) was developed for the measurement of free glycerol in human serum. This procedure involved spiking with (13)C3-glycerol, protein precipitation and cation exchange SPE, followed by two-step derivatization with 1-butylboronic acid and N-methyl-N trimethylsilyltrifluoroacetamide. Tripalmitin certified reference material (CRM) was used as the calibration standard to ensure metrological traceability. RESULTS: Good precision and accuracy were obtained as demonstrated by relative standard deviation (RSD) of 1.51%-3.33%, with average recoveries over 98%. The relative measurement uncertainty was below 3% with major contributions from the concentration of glycerol calibration solution, choice of ion pair, linear regression, and measurement precision. CONCLUSIONS: With good accuracy and precision, as well as clear metrological traceability, the developed GC-IDMS procedure is useful in producing traceable and accurate measurement of free glycerol in human serum. PMID- 26054582 TI - The relationship between elevated red cell distribution width and long-term outcomes among patients with atrial fibrillation. AB - OBJECTIVES: Red cell distribution width (RDW) is associated with the incidence of atrial fibrillation (AF). The aim of this study was to evaluate the relationship between elevated RDW and long-term clinical outcomes among patients with AF. DESIGN AND METHODS: We prospectively observed 300 consecutive patients with AF (50.3% males, mean age 62.6 +/- 12.9 years) between February 2009 and October 2011. Baseline RDW levels and clinical data were collected. The primary clinical outcomes of interest included all-cause mortality and the incidence of major adverse events (MAEs). RESULTS: During a median follow-up period of 3.2 years, 60 deaths and 92 MAEs were recorded. From the lowest to the highest RDW quartile, an increased risk of mortality (2.76, 3.98, 8.40 and 13.77 per 100 person-years, respectively) and an incidence of MAEs (6.46, 8.18, 13.79 and 20.27 per 100 person-years, respectively) were noted. In a multivariate Cox regression analysis, RDW was independently associated with both all-cause mortality (hazard ratio (HR): 1.024; 95% confidence interval (CI): 1.012-1.036, P < 0.001) and MAEs (HR: 1.012; 95% CI: 1.002-1.023, P = 0.023). A receiver operating characteristic (ROC) analysis revealed that RDW predicted both mortality and MAEs with areas under the ROC curves (AUCs) of 0.682 (P < 0.001) and 0.617 (P = 0.001); the best cutoff points were 13.85% and 13.55%, respectively. CONCLUSIONS: Elevated RDW is an independent predictor of long-term adverse clinical outcomes, including all cause mortality and MAEs, among patients with AF. PMID- 26054583 TI - Primary stent placement for hepatic artery stenosis after liver transplantation. AB - OBJECTIVE: Significant hepatic artery stenosis (HAS) after orthotopic liver transplantation (OLT) can lead to thrombosis, with subsequent liver failure in 30% of patients. Although operative intervention or retransplantation has been the traditional solution, endovascular therapy has emerged as a less invasive treatment strategy. Prior smaller studies have been conflicting in the relative efficacy of percutaneous transluminal angioplasty (PTA) vs primary stent placement for HAS. METHODS: This was a single-center retrospective review of all endovascular interventions for HAS after OLT during a 54-month period (August 2009-December 2013). Patients with ultrasound imaging with evidence of severe HAS (peak systolic velocity >400-450 cm/s, resistive index <0.5) underwent endovascular treatment with primary stent placement or PTA. Outcomes calculated were technical success, primary and primary assisted patency rates, reinterventions, and complications. RESULTS: Sixty-two interventions for HAS were performed in 42 patients with a mean follow-up of 19.1 +/- 15.2 months. During the study period, 654 OLTs were performed. Of 61 patients diagnosed with HAS, 42 underwent an endovascular intervention. The rate of endovascularly treated HAS was 6.4% (42 of 654). Primary technical success was achieved in 95% (59 of 62) of the interventions. Initial treatment was with PTA alone in 17 or primary stent in 25. Primary patency rates after initial stent placement were 87%, 76.5%, 78%, and 78% at 1, 6, 12, and 24 months, respectively, compared with initial PTA rates of 64.7%, 53.3%, 40%, and 0% (P = .19). There were 20 reinterventions in 14 patients (eight stents, six PTAs). The time to the initial reintervention was 51 days in patients with PTA alone vs 105.8 days for those with an initial stent (P = .16). Overall primary assisted patency was 93% at 24 months. Major complications were one arterial rupture and two hepatic artery dissections. The long-term risk of hepatic artery thrombosis in the entire patient cohort was 3.2%. CONCLUSIONS: HAS after OLT can be treated endovascularly with high technical success and excellent primary assisted patency. This series represents the largest reported cohort of endovascular interventions for HAS to date. Initial use of a stent showed a strong trend toward decreasing the need for reintervention. Avoidance of hepatic artery thrombosis is possible in >95% of patients with endovascular treatment and close follow-up. PMID- 26054586 TI - Discussion. PMID- 26054585 TI - Angiogenic properties of human placenta-derived adherent cells and efficacy in hindlimb ischemia. AB - OBJECTIVE: Human placenta-derived adherent cells (PDACs) are a culture-expanded, undifferentiated mesenchymal-like population from full-term placental tissue and were previously shown to possess anti-inflammatory and immunomodulatory properties. PDACs (formulated as PDA-002) are in clinical trials for peripheral arterial disease with diabetic foot ulcer. In the current study, we examined their angiogenic and tissue reparative properties. METHODS: The effects of PDACs on survival and tube formation of human umbilical vein endothelial cells (HUVECs) were tested using conditioned media and noncontact coculture. Angiogenic effects were assessed in the chick chorioallantoic membrane assay. Hindlimb ischemia (HLI) was induced in mice and rats by femoral artery transection, and blood flow and blood vessel density were monitored in vivo by laser Doppler and angiography in the ischemic and control limbs. Tissue damage and regeneration in HLI were examined in histologic sections of quadriceps muscle stained with hematoxylin and eosin, and newly synthesized blood vessels were detected by indoxyl-tetrazolium staining for alkaline phosphatase. RESULTS: PDACs enhanced the survival of serum starved HUVECs and stimulated HUVEC tube formation, and in the chick chorioallantoic membrane assay, PDACs stimulated blood vessel formation. In HLI, intramuscular administration of PDACs resulted in improved blood flow and vascular density, and in quadriceps muscle, tissue regeneration and increased numbers of blood vessels were observed. CONCLUSIONS: PDACs exhibited various activities consistent with angiogenesis and tissue repair, supporting the continued investigation of this cell therapy as treatment for vascular disease related indications. PMID- 26054584 TI - Systemic inflammation as a predictor of clinical outcomes after lower extremity angioplasty/stenting. AB - OBJECTIVE: The activation state of the systemic inflammatory milieu has been proposed as a critical regulator of vascular repair after injury. We evaluated the early inflammatory response after endovascular intervention for symptomatic peripheral arterial disease to determine its association with clinical success or failure. METHODS: Blood samples were obtained from 14 patients undergoing lower extremity angioplasty/stenting and analyzed using high-throughput gene arrays, multiplex serum protein analyses, and flow cytometry. RESULTS: Time-dependent plasma protein and monocyte phenotype analyses demonstrated endovascular revascularization had a modest influence on the overall activation state of the systemic inflammatory system, with baseline variability exceeding the perturbations induced by the intervention. In contrast, specific time-dependent changes in the monocyte genome are evident in the initial 28 days, predominately in those genes associated with leukocyte extravasation. Investigating the relationship between inflammation and the 1-year success or failure of the intervention showed no single plasma protein was correlated with outcome, but a more comprehensive cluster analysis revealed a clear pattern of protein expression that was closely related to the clinical phenotype. Corresponding examination of the monocyte genome identified a gene subset at 1 day postprocedure that was predictive of clinical outcome, with most of these genes active in cell-cycle signaling. CONCLUSIONS: Although the global influence of angioplasty/stenting on systemic inflammation was modest, circulating cytokine and monocyte genome analyses support a pattern of early inflammation that is associated with ultimate intervention success vs failure. Molecular profiles incorporating genes involved in monocyte cell-cycle progression and homing, or proinflammatory cytokines, or both, offer the most promise for the development of class prediction tools for clinical application. PMID- 26054587 TI - Patency of renal and visceral vessels after open thoracoabdominal aortic replacement. AB - OBJECTIVE: In thoracoabdominal aortic aneurysms (TAAAs), a paradigm shift is observed from open surgery toward total endovascular aortic repair using fenestrated and branched endografts. Whereas outcome after open replacement in terms of mortality and paraplegia has been evaluated extensively, no studies exist addressing long-term patency of visceral and renal vessels. To enable comparison of target vessel patency between open and endovascular treatment, we analyzed our series of open TAAA replacements. METHODS: Our vascular surgery database was screened for patients who received open TAAA replacement between 1998 and 2012, and patient records were analyzed retrospectively. All available imaging scans (computed tomography and magnetic resonance angiography: preoperative, postoperative, and follow-up) were evaluated for graft and vessel patency. RESULTS: We identified 62 patients (mean age, 66 +/- 10 years; 40 men) who had been operated on for aneurysms of Crawford types I (8), II (13), III (13), and IV (24) and Safi type V (4). A total of 181 vessels were revascularized by either patch inclusion (n = 147) or selective revascularization (bypass or transposition, n = 34); 48 survived the procedure, resulting in a number of vessels available for follow-up of 154 (patch, 126; selective revascularization, 28). The respective patency rates for overall, patch, and selective revascularization were 95.2%, 94.2%, and 100% at 5 years and 83.7%, 81.3%, and 100% at 10 years, respectively. In addition, a trend for better performance of selective revascularization (bypass or transposition) was evident as all vessel occlusions were observed in cases of patch inclusion, whereas all selectively revascularized vessels were patent. The respective patency rates for the celiac trunk, superior mesenteric artery, and left and right renal artery were 100%, 97.5%, 92.3%, and 90.3% at 5 years. CONCLUSIONS: In our series of open thoracoabdominal aortic replacement, excellent patency rates for revascularized renal and visceral vessels were observed during long-term follow-up. We were able to provide a reference value of long-term target vessel patency that can and should be taken into account to judge the efficacy of endovascular repair in TAAA. PMID- 26054588 TI - Late aortic remodeling persists in the stented segment after endovascular repair of acute complicated type B aortic dissection. AB - OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) for acute complicated type B aortic dissection (AD) promotes early positive aortic remodeling. However, little is known about the long-term effect of TEVAR on the dissected aorta, which is the goal of this study. METHODS: Between August 2005 and August 2009, 31 patients with complicated type B AD were treated with TEVAR and had >1-year follow-up imaging. Computed tomography angiograms obtained at 1 month, 1 year, and long term (average, 42 months) were compared with baseline scans. The largest diameters of the stented thoracic aorta, stented true lumen, and stented false lumen were recorded at each time point, as were the values in the unstented distal thoracic aorta and the abdominal aorta. Changes over time were evaluated by a mixed effect analysis of variance model of repeated measures. RESULTS: The average age of the cohort was 56 years, and 74% were male. Indications for TEVAR were as follows: 61% malperfusion, 32% refractory hypertension, 45% impending rupture, and 32% persistent pain; 58% had more than one indication. All patients were treated in the acute phase within 7 days of the initial presentation. The average length of aorta covered was 19 cm. Observation of the stented segment over time showed that the maximum diameter of the stented thoracic aorta was stable (P = NS), the diameter of the stented true lumen increased (P < .001), and the diameter of the stented false lumen decreased (P < .001); 84% had complete false lumen obliteration across the stented aortic segment. Observation of the uncovered thoracic aorta over time showed that the maximum diameter increased (P = .014), as did the visceral segment of the aorta (P < .001). The average growth of the visceral segment was 31% in patients with a patent false lumen vs 3% in those with a thrombosed false lumen (P = .004). One patient had aneurysmal degeneration of the false lumen and required an additional endograft at 18 months. CONCLUSIONS: TEVAR of acute AD promotes long-term remodeling across the stented segment, with false lumen obliteration in 84% of patients. However, false lumen obliteration beyond the stented segment appears necessary to prevent late aneurysmal degeneration of the distal aorta. PMID- 26054589 TI - Human urine kininogenase attenuates balloon-induced intimal hyperplasia in rabbit carotid artery through transforming growth factor beta1/Smad2/3 signaling pathway. AB - OBJECTIVE: Effective treatments against restenosis after percutaneous transluminal angioplasty and stenting are largely lacking. Human tissue kallikrein gene transfer has been shown to be able to attenuate neointima formation induced by balloon catheter. As a tissue kallikrein in vivo, human urinary kininogenase (HUK) is widely used to prevent ischemia-reperfusion injury. However, the effects of HUK on neointima formation have not been explored. We therefore investigated whether HUK could alleviate balloon catheter-induced intimal hyperplasia in rabbits fed with high-fat diets. METHODS: The effects of HUK on neointima and atherosclerosis formation were analyzed by hematoxylin-eosin staining and immunohistochemical staining in balloon-injured carotid arteries of rabbits. Local inflammatory response was evaluated by detecting the gene expression of tumor necrosis factor alpha and interleukin 1beta with real-time quantitative polymerase chain reaction plus the invasion of macrophages with immunohistochemical staining. Western blotting was employed to investigate the effects of HUK on activities of endothelial nitric oxide synthase (eNOS), transforming growth factor beta1 (TGF-beta1), and Smad signaling pathway. The long-term effect of HUK on intimal hyperplasia of the injured carotid artery was assessed by angiography. RESULTS: Quantitative image analysis showed that intravenous administration of HUK for 14 days significantly decreased the intimal areas and intima area/media area ratios (day 14, 54% decrease in intimal area and 58% decrease in intima area/media area ratios; day 28, 63% and 85%). Significant decreases were also noted in macrophage foam cell-positive area after 7-day or 14 day administration of HUK (day 7, 69% decrease in intimal area and 78% decrease in media area; day 14, 79% and 60%; day 28, 68% and 44%). Actin staining for smooth muscle cells in neointima at 2 months showed similar results (vascular smooth muscle cell-positive area of neointima, 28.21% +/- 5.58% vs 43.78% +/- 8.36%; P < .05). Real-time quantitative polymerase chain reaction or Western blot analysis showed that HUK reduced expression of tumor necrosis factor alpha, interleukin 1beta, TGF-beta1, and p-Smad2/3 but increased the expression of p eNOS. Angiography analysis showed that 14-day administration of HUK significantly decreased the degree of stenosis (26.8% +/- 7.1% vs 47.9% +/- 5.7%; P < .01) at 2 months after balloon injury. CONCLUSIONS: Our results indicate that HUK is able to attenuate atherosclerosis formation and to inhibit intimal hyperplasia by downregulating TGF-beta1 expression and Smad2/3 phosphorylation, upregulating eNOS activity. HUK may be a potential therapeutic agent to prevent stenosis after vascular injury. PMID- 26054590 TI - Characteristics that define high risk in carotid endarterectomy from the Vascular Study Group of New England. AB - OBJECTIVE: The Stenting with Angioplasty and Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial compared carotid endarterectomy (CEA) to carotid artery stenting (CAS) among high-risk patients using a model of risk that has not been validated by previous publications. The objective of our study was to determine the accuracy of this high-risk model and to determine the true risk factors that result in patients being at high risk for CEA. METHODS: Prospectively collected data for 3098 CEAs between 2003 and 2011 at 20 Vascular Surgery Group of New England (VSGNE) centers were used. SAPPHIRE general inclusion criteria and primary outcomes were assessed. Factors that were associated with the primary outcome by analysis of variance (P < .10) and not linearly dependent, as determined by a Pearson correlation analysis, were further assessed for an independent association by multivariate logistic regression. A risk index model was developed for these significant predictors to accurately define high-risk CEA. RESULTS: The average patient age was 69.9 +/- 9.5 years, 60% were male, and 45.7% were asymptomatic. The 1-year composite outcome event rate, defined as postoperative myocardial infarction and stroke or death, was 14.2%. Multivariate analysis (P < .05) found the following independently significant risk factors: age in years (95% confidence interval [CI], 1.0-1.1; P < .001), preadmission living in a nursing home (95% CI, 1.2-6.6; P = .020), congestive heart failure (95% CI, 1.4-2.8; P < .001), diabetes mellitus (DM; 95% CI, 1.1-1.3; P < .001), chronic obstructive pulmonary disease (95% CI, 1.2-1.5; P < .001), any previous cerebrovascular disease (95% CI, 1.1-1.9; P = .003), and contralateral internal carotid artery stenosis (95% CI, 1.0-1.2; P = .001). Three of the SAPPHIRE high-risk criteria-abnormal stress test, recurrent stenosis after CEA, and previous radiotherapy to the neck-were not independently associated with an adverse outcome. Independently significant risk factors not included in the SAPPHIRE criteria are inclusion of ages <80 years, preadmission living in a nursing home, DM, contralateral carotid stenosis, and any previous cerebrovascular accident. The risk index predictors are age in years (40-49: 0 points; 50-59: 2 points; 60-69: 4 points; 70-79: 6 points; 80-89: 8 points), living in a nursing home (4 points), any cardiovascular disease (2 points), congestive heart failure (5 points), chronic obstructive pulmonary disease (3 points), DM (2 points), degree of contralateral stenosis (<50%: 0 points; 50% 69%: 1 point; 70%-near occlusion: 2 points; occlusion: 3 points). High-risk CEA is defined as >13 points, representing adverse outcome rate of 22.5%. CONCLUSIONS: SAPPHIRE and other previously reported high-risk CAS inclusion criteria do not include all of the factors found to be independently associated with outcomes. Further studies are required to determine whether CAS is inferior to CEA in high-risk patients using a validated model of risk. In addition, this preoperative assessment includes novel criteria that can be used to stratify risks. PMID- 26054591 TI - Incidence and prognosis of vascular complications after percutaneous placement of left ventricular assist device. AB - OBJECTIVE: Mechanical assist devices have found an increasingly important role in high-risk interventional cardiac procedures. The Impella (Abiomed Inc, Danvers, Mass) is a percutaneous left ventricular assist device inserted through the femoral artery under fluoroscopic guidance and positioned in the left ventricular cavity. This study was undertaken to assess the incidence of vascular complications and associated morbidity and mortality that can occur with Impella placement. METHODS: We used a prospective database to review patients who underwent placement of an Impella left ventricular assist device in our tertiary referral center from July 2010 to December 2013. Patient demographics, comorbidities, interventional complications, and 30-day mortality were recorded. RESULTS: The study included 90 patients (60% male). Mean age was 66 years (range, 17-97 years). Hypertension was found in 69% of the patients, 37% were diabetic, 57% had a history of tobacco abuse, and 65% had chronic renal insufficiency. The median preprocedure cardiac ejection fraction was 30%. Most (87%) had undergone coronary artery intervention. Cardiogenic shock was documented in 67 patients (74%). The Impella was placed for an average of 1 day (range, 0-5 days). At least one vascular complication occurred in 15 patients (17%). Acute limb ischemia occurred in 12 patients; of whom four required an amputation and six required open or endovascular surgery. Other complications included groin hematomas and one pseudoaneurysm. All-patient 30-day mortality was 50%, which was not significantly associated with vascular complications. Female sex and cardiogenic shock at the time of insertion were associated with vascular complications (P = .043 and P = .018, respectfully). CONCLUSIONS: Vascular complications are common with placement of the Impella percutaneous left ventricular assist device (17%) and are related to emergency procedures. Vascular complications in this high-risk patient population frequently lead to withdrawal of care. These data provide quality improvement targets for left ventricular assist device programs. PMID- 26054592 TI - The end-to-end anastomosis of John B. Murphy. PMID- 26054593 TI - Two Decades of Environmental Surveillance in the Vicinity of a Waste Incinerator: Human Health Risks Associated with Metals and PCDD/Fs. AB - The concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), as well as the levels of a number of heavy metals, have been periodically measured in samples of soil and vegetation collected around a municipal solid waste incinerator (MSWI) in Tarragona (Catalonia, Spain) for approximately 20 years. Since 2007, the levels of the above-mentioned pollutants have also been determined in air samples by means of either active or passive samplers. In the present study, data regarding the environmental impact of the MSWI, in terms of PCDD/Fs and heavy metals, are updated. The temporal trends of these pollutants were evaluated by comparison with data from previous surveys. In the current survey (2013-2014), mean concentrations of PCDD/Fs in soil, vegetation, and air were 0.63 ng I-TEQ/g, 0.07 ng I-TEQ/g, and 10.1 fg WHO TEQ/m(3), respectively. Decreases of 47 and 35 % of PCDD/Fs in soil and vegetation, respectively, were observed in relation to the background study (1999). Regarding air samples, a slight temporal decrease of the PCDD/F levels was also found with the remaining concentrations staying nearly constant through time. With respect to metals, notable fluctuations in the concentrations were noted, being dependent on each specific environmental monitor. Overall, the current exposure to PCDD/Fs and metals does not mean any additional health risks for the population living near the facility. In conclusion, the results of the present study show that the environmental impact of the Tarragona MSWI is not significant, in terms of PCDD/Fs and heavy metals, after >20 years of continuous operation. PMID- 26054594 TI - Neuroendocrine and Eosinophilic Granule Cells in the Gills of Tilapia, Oreochromis niloticus: Effects of Waterborne Copper Exposure. AB - The contamination of aquatic ecosystems with copper (Cu) poses a serious threat to aquatic organisms. Although the histopathological changes caused by Cu in fish gills are well documented, knowledge about the impact of this metal in gill specific cell types, such as neuroendocrine cells (NECs) and eosinophilic granule cells (EGCs), is still limited. In the present work, Nile tilapia (Oreochromis niloticus) were exposed for 21 days to nominal concentrations of Cu (40 and 400 ug L(-1)). Stereological methods were used to estimate the volumetric density of both NECs and EGCs in fish gill filament after 3, 7, 14, and 21 days of exposure. The results showed that Cu significantly increased the relative volume of NECs, whereas the relative volume of EGCs decreased. NECs were more affected by Cu in the first 7 days of exposure, during which a greater increase in their relative volume was observed. The Cu exposure induced a progressive decrease in the relative volume of EGCs, which reached statistical significance after 14 days of exposure. An exception was observed in subepithelial EGCs with a slight increase in their relative volume after 3 days of exposure. Our findings confirm that Cu can modulate both neuroendocrine and immune systems and becomes immunotoxic after a prolonged exposure. PMID- 26054595 TI - Exercise interventions in polypathological aging patients that coexist with diabetes mellitus: improving functional status and quality of life. AB - In elderly populations, diabetes is associated with reduced muscle strength, poor muscle quality, and accelerated loss of muscle mass. In addition, diabetes mellitus increases risk for accelerated aging and for the development of frailty syndrome. This disease is also associated with a polypathological condition, and its complications progressively affect quality of life and survival. Exercise interventions, including resistance training, represent the cornerstones of diabetes management, especially in patients at severe functional decline. This review manuscript aimed to describe the beneficial effects of different exercise interventions on the functional capacity of elderly diabetics, including those at polypathological condition. The SciELO, Science Citation Index, MEDLINE, Scopus, SPORTDiscus, and ScienceDirect databases were searched from 1980 to 2015 for articles published from original scientific investigations. In addition to the beneficial effects of exercise interventions on glycemic control, and on the cardiovascular risk factors associated with diabetes, physical exercise is an effective intervention to improve muscle strength, power output, and aerobic power and functional capacity in elderly diabetic patients. Thus, a combination of resistance and endurance training is the most effective exercise intervention to promote overall physical fitness in these patients. In addition, in diabetic patients with frailty and severe functional decline, a multicomponent exercise program including strength and power training, balance exercises, and gait retraining may be an effective intervention to reduce falls and improve functional capacity and quality of life in these patients. PMID- 26054596 TI - Erlotinib Pretreatment Improves Photodynamic Therapy of Non-Small Cell Lung Carcinoma Xenografts via Multiple Mechanisms. AB - Aberrant expression of the epidermal growth factor receptor (EGFR) is a common characteristic of many cancers, including non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma, and ovarian cancer. Although EGFR is currently a favorite molecular target for the treatment of these cancers, inhibition of the receptor with small-molecule inhibitors (i.e., erlotinib) or monoclonal antibodies (i.e., cetuximab) does not provide long-term therapeutic benefit as standalone treatment. Interestingly, we have found that addition of erlotinib to photodynamic therapy (PDT) can improve treatment response in typically erlotinib-resistant NSCLC tumor xenografts. Ninety-day complete response rates of 63% are achieved when erlotinib is administered in three doses before PDT of H460 human tumor xenografts, compared with 16% after PDT-alone. Similar benefit is found when erlotinib is added to PDT of A549 NCSLC xenografts. Improved response is accompanied by increased vascular shutdown, and erlotinib increases the in vitro cytotoxicity of PDT to endothelial cells. Tumor uptake of the photosensitizer (benzoporphyrin derivative monoacid ring A; BPD) is increased by the in vivo administration of erlotinib; nevertheless, this elevation of BPD levels only partially accounts for the benefit of erlotinib to PDT. Thus, pretreatment with erlotinib augments multiple mechanisms of PDT effect that collectively lead to large improvements in therapeutic efficacy. These data demonstrate that short-duration administration of erlotinib before PDT can greatly improve the responsiveness of even erlotinib-resistant tumors to treatment. Results will inform clinical investigation of EGFR-targeting therapeutics in conjunction with PDT. PMID- 26054598 TI - Pregnancy outcomes of overweight and obese women aged 35 years or older - A registry-based study in Finland. AB - OBJECTIVE: To compare pregnancy outcomes of overweight and obese pregnant women aged 35 years or older to women aged less than 35 years old. METHODS: A registry based study covering years 2004-2008 including data on women >=35 years (N=45,718) compared to those <35 years (N=203,930) and their pre-pregnancy body mass index (BMI) (<25, 25-29 and >=30). In multivariable modelling, the main outcome measures were preterm delivery (<28 weeks, 28-31weeks and 32-36 weeks), low Apgar scores at 5min, small-for-gestational age (SGA), foetal death, asphyxia, Caesarean section, induction, preeclampsia, blood transfusion, admission to a neonatal intensive care unit (NICU), shoulder dystocia, and large for gestational age (LGA). RESULTS: Maternal overweight and obesity along with advanced maternal age (AMA) significantly increased the risks of preterm delivery, preeclampsia, foetal death, LGA and Caesarean as compared to women of average weight aged <35 years. When comparing overweight and obese women aged >=35 years to normal weight women of the same age, the rates of preeclampsia, preterm delivery <28 weeks, LGA and low Apgar score were significantly increased. When observing overweight and obese women <35 years as a reference group, the risks of preterm delivery and foetal death were significantly increased. CONCLUSIONS: The risks were increased by maternal age>=35 years and both obesity and overweight. The combined effect of AMA and either overweight or obesity appeared to be a high risk state particularly for stillbirth and preterm delivery. PMID- 26054597 TI - Neuroblastoma Arginase Activity Creates an Immunosuppressive Microenvironment That Impairs Autologous and Engineered Immunity. AB - Neuroblastoma is the most common extracranial solid tumor of childhood, and survival remains poor for patients with advanced disease. Novel immune therapies are currently in development, but clinical outcomes have not matched preclinical results. Here, we describe key mechanisms in which neuroblastoma inhibits the immune response. We show that murine and human neuroblastoma tumor cells suppress T-cell proliferation through increased arginase activity. Arginase II is the predominant isoform expressed and creates an arginine-deplete local and systemic microenvironment. Neuroblastoma arginase activity results in inhibition of myeloid cell activation and suppression of bone marrow CD34(+) progenitor proliferation. Finally, we demonstrate that the arginase activity of neuroblastoma impairs NY-ESO-1-specific T-cell receptor and GD2-specific chimeric antigen receptor-engineered T-cell proliferation and cytotoxicity. High arginase II expression correlates with poor survival for patients with neuroblastoma. The results support the hypothesis that neuroblastoma creates an arginase-dependent immunosuppressive microenvironment in both the tumor and blood that leads to impaired immunosurveillance and suboptimal efficacy of immunotherapeutic approaches. PMID- 26054599 TI - Transitions: Athanasios Koukopoulos [AthetaalphanualphasigmaiotaOmicronsigma kappaOmicronupsilonkappaomicronpiOmicronupsilonlambdaOmicronsigma], M.D. (1931 2013). PMID- 26054600 TI - Glial-specific gene alterations associated with manic behaviors. AB - BACKGROUND: Glial dysfunction has been purported to be important to the pathophysiology of bipolar illness. However, manic behavior has not been previously demonstrated to result as a consequence of glial pathology. The aim of the current study was to assess the behaviors of the glial-specific sodium pump alpha2 subunit (ATP1A2) knockout (KO) heterozygote mice to determine if a glial specific abnormality can produce manic-like behavior. METHODS: Activity and behavior of hemideficient sodium pump alpha2 KO mice and wild-type (WT) littermates (C57BL6/Black Swiss background) were examined at baseline, following forced swimming stress and restraint stress and after 3 days of sleep deprivation. RESULTS AND DISCUSSION: At baseline, the 24-h total distance traveled and center time were significantly greater in KO mice, but there were no behavioral differences with sweet water preference or with inactivity time during forced swim or tail suspension tests. After restraint stress or forced swimming stress, there were no differences in activity. Three days of sleep deprivation utilizing the inverted flowerpot method induced a significant increase in the distance traveled by the KO versus WT mice in the 30-min observation period (p=0.016). Lithium pretreatment has no effect on WT animals versus their baseline but significantly reduces hyperactivity induced by sleep deprivation in KO. Knockout of the glial-specific alpha2 isoform is associated with some manic behaviors compared to WT littermates, suggesting that glial dysfunction could be associated with mania. PMID- 26054601 TI - National asset map for clinical trials launched. PMID- 26054603 TI - Controversy over Doctors of BC vote. PMID- 26054604 TI - More hospitals Choosing Wisely. PMID- 26054605 TI - External validation of the Hospital-patient One-year Mortality Risk (HOMR) model for predicting death within 1 year after hospital admission. AB - BACKGROUND: Predicting long-term survival after admission to hospital is helpful for clinical, administrative and research purposes. The Hospital-patient One-year Mortality Risk (HOMR) model was derived and internally validated to predict the risk of death within 1 year after admission. We conducted an external validation of the model in a large multicentre study. METHODS: We used administrative data for all nonpsychiatric admissions of adult patients to hospitals in the provinces of Ontario (2003-2010) and Alberta (2011-2012), and to the Brigham and Women's Hospital in Boston (2010-2012) to calculate each patient's HOMR score at admission. The HOMR score is based on a set of parameters that captures patient demographics, health burden and severity of acute illness. We determined patient status (alive or dead) 1 year after admission using population-based registries. RESULTS: The 3 validation cohorts (n = 2,862,996 in Ontario, 210 595 in Alberta and 66,683 in Boston) were distinct from each other and from the derivation cohort. The overall risk of death within 1 year after admission was 8.7% (95% confidence interval [CI] 8.7% to 8.8%). The HOMR score was strongly and significantly associated with risk of death in all populations and was highly discriminative, with a C statistic ranging from 0.89 (95% CI 0.87 to 0.91) to 0.92 (95% CI 0.91 to 0.92). Observed and expected outcome risks were similar (median absolute difference in percent dying in 1 yr 0.3%, interquartile range 0.05%-2.5%). INTERPRETATION: The HOMR score, calculated using routinely collected administrative data, accurately predicted the risk of death among adult patients within 1 year after admission to hospital for nonpsychiatric indications. Similar performance was seen when the score was used in geographically and temporally diverse populations. The HOMR model can be used for risk adjustment in analyses of health administrative data to predict long-term survival among hospital patients. PMID- 26054606 TI - Proposed reforms delay Quebec's Bill 20. PMID- 26054607 TI - Social accountability and the supply of physicians for remote rural Canada. PMID- 26054608 TI - Ebola lessons guide International Health Regulations review. PMID- 26054609 TI - Doctors of BC will vote again for president-elect. PMID- 26054610 TI - Venom anaphylaxis. PMID- 26054611 TI - CIHR "dismantling" Aboriginal health research. PMID- 26054612 TI - Room 23. PMID- 26054613 TI - Spatial asymmetries in connectivity influence colonization-extinction dynamics. AB - Movement has broad implications for many areas of biology, including evolution, community and population ecology. Movement is crucial in metapopulation ecology because it facilitates colonization and reduces the likelihood of local extinction via rescue effects. Most metapopulation modeling approaches describe connectivity using pair-wise Euclidean distances resulting in the simplifying assumption of a symmetric connectivity pattern. Yet, assuming symmetric connectivity when populations show net asymmetric movement patterns may result in biased estimates of colonization and extinction, and may alter interpretations of the dynamics and conclusions regarding the viability of metapopulations. Here, we use a 10-year time series on a wind-dispersed orchid Lepanthes rupestris that anchors its roots in patches of moss growing on trees or boulders along streams, to test for the role of connectivity asymmetries in explaining the colonization extinction dynamics of this orchid in a network of 975 patches. We expected that wind direction could highly alter dispersal direction in this orchid. To account for this potential asymmetry, we modified the connectivity measure traditionally used in metapopulation models to allow for asymmetric effective distances between patches and subsequently estimated colonization and extinction probabilities using a dynamic occupancy modeling approach. Asymmetric movement was prevalent in the L. rupestris metapopulation and incorporating potential dispersal asymmetries resulted in higher colonization estimates in larger patches and more accurate models. Accounting for dispersal asymmetries may reveal connectivity effects where they were previously assumed to be negligible and may provide more reliable conclusions regarding the role of connectivity in patch dynamics. PMID- 26054614 TI - Biodegradation of Various Aromatic Compounds by Enriched Bacterial Cultures: Part A-Monocyclic and Polycyclic Aromatic Hydrocarbons. AB - Present study focused on the screening of bacterial consortium for biodegradation of monocyclic aromatic hydrocarbon (MAH) and polycyclic aromatic hydrocarbons (PAHs). Target compounds in the present study were naphthalene, acenaphthene, phenanthrene (PAHs), and benzene (MAH). Microbial consortia enriched with the above target compounds were used in screening experiments. Naphthalene-enriched consortium was found to be the most efficient consortium, based on its substrate degradation rate and its ability to degrade other aromatic pollutants with significantly high efficiency. Substrate degradation rate with naphthalene enriched culture followed the order benzene > naphthalene > acenaphthene > phenanthrene. Chryseobacterium and Rhodobacter were discerned as the predominant species in naphthalene-enriched culture. They are closely associated to the type strain Chryseobacterium arthrosphaerae and Rhodobacter maris, respectively. Single substrate biodegradation studies with naphthalene (PAH) and benzene (MAH) were carried out using naphthalene-enriched microbial consortium (NAPH). Phenol and 2-hydroxybenzaldehyde were identified as the predominant intermediates during benzene and naphthalene degradation, respectively. Biodegradation of toluene, ethyl benzene, xylene, phenol, and indole by NAPH was also investigated. Monod inhibition model was able to simulate biodegradation kinetics for benzene, whereas multiple substrate biodegradation model was able to simulate biodegradation kinetics for naphthalene. PMID- 26054615 TI - Comparative Profiling of MicroRNAs in Male and Female Rhipicephalus sanguineus. AB - Rhipicephalus sanguineus is an ectoparasite of medical and veterinary significance, which can transmit a number of pathogens including Babesia canis, Ehrlichia canis, and Rickettsia conorii. MicroRNAs (miRNAs) are recognized as regulators in sex differentiation in dioecious species. We here investigated and compared the miRNA profiles of male and female adults of R. sanguineus by combining Solexa deep sequencing with bioinformatics platform and quantitative real-time PCR. A total of 11.88 and 16.09 million raw reads were obtained from male and female R. sanguineus, respectively. By mapping to the reference genome, 59 and 76 miRNA candidates from the female and male parasite were obtained, with 19 of each consistent with known Ixodes scapularis miRNAs deposited in the miRBase database. Besides, 51 miRNAs were shared by the two genders, and 8 and 25 were female and male specific, respectively. The number of predicted targets of the identified miRNAs ranged from 1 to 383 with an average of 176. Functional analysis showed that a number of predicted targets corresponded to transcription, splicing, and translation factors, elongation factors, and growth factors which were essential for the development of the parasite. Enrichment analysis revealed that some functions of the predicted targets were higher in female than in male, such as antioxidant and electron carrier. The present study firstly described the global profiling of miRNAs in male and female R. sanguineus and identified a number of gender-specific miRNAs, which are likely to participate in the sex differentiation/maintenance process and provide novel resources for better understanding of the biology of the parasite, and may further lead to effective control of the parasite and diseases it causes. PMID- 26054616 TI - Biodegradation of Various Aromatic Compounds by Enriched Bacterial Cultures: Part B--Nitrogen-, Sulfur-, and Oxygen-Containing Heterocyclic Aromatic Compounds. AB - Present study focused on the biodegradation of various heterocyclic nitrogen, sulfur, and oxygen (NSO) compounds using naphthalene-enriched culture. Target compounds in the study were pyridine, quinoline, benzothiophene, and benzofuran. Screening studies were carried out using different microbial consortia enriched with specific polycyclic aromatic hydrocarbon (PAH) and NSO compounds. Among different microbial consortia, naphthalene-enriched culture was the most efficient consortium based on high substrate degradation rate. Substrate degradation rate with naphthalene-enriched culture followed the order pyridine > quinoline > benzofuran > benzothiophene. Benzothiophene and benzofuran were found to be highly recalcitrant pollutants. Benzothiophene could not be biodegraded when concentration was above 50 mg/l. It was observed that 2-(1H)-quinolinone, benzothiophene-2-one, and benzofuran-2,3-dione were formed as metabolic intermediates during biodegradation of quinoline, benzothiophene, and benzofuran, respectively. Quinoline-N and pyridine-N were transformed into free ammonium ions during the biodegradation process. Biodegradation pathways for various NSO compounds are proposed. Monod inhibition model was able to simulate single substrate biodegradation kinetics satisfactorily. Benzothiophene and benzofuran biodegradation kinetics, in presence of acetone, was simulated using a generalized multi-substrate model. PMID- 26054617 TI - Production of Novel VHH Nanobody Inhibiting Angiogenesis by Targeting Binding Site of VEGF. AB - Vascular endothelial growth factor (VEGF) is one of the key players in angiogenesis and is considered as one of the major targets in cancer therapy. VEGF is secreted by the cancerous cells to form new vessels that carry oxygen and nutrients to the tumor, allowing it to grow beyond 1-2 mm. Cancerous cells spread using these veins and cause malignancy. Therefore, neutralization of VEGF could prevent tumor growth and malignancy, and nowadays, antibodies are widely used for such purpose. Among antibody fragments, nanobodies possess unique characteristics which make them appropriate tools for cancer therapy. In this study, the receptor binding region of VEGF was used to produce a nanobody using phage display technology. A camel was immunized with the recombinant VEGF, and VHH fragments were amplified using nested PCR on lymphocyte complementary DNA (cDNA). The highest binding affinity was achieved after three rounds of panning. Twenty-four clones were tested by monoclonal phage ELISA, and the clone with the highest affinity (VA12) was selected for soluble expression of nanobody. VA12 was tested under various physicochemical conditions and showed considerable stability in extreme temperatures, pH, and various urea concentrations. Stability of VA12 under such conditions is considered as an advantage over the prevailing antibodies. PMID- 26054618 TI - Identification and Characterization of Two Endogenous beta-Glucosidases from the Termite Coptotermes formosanus. AB - Coptotermes formosanus is a well-known wood-feeding termite that can degrade lignocellulose polysaccharides efficiently with its unique multi-enzyme catalysis system. beta-glucosidase (BG) is one of the important cellulases in its enzyme system. However, there may present multiple endogenous BGs in termite digestive system for various properties and functions. This study aims to characterize two BG homologs and reveal their potential coordinative effect. In this study, two endogenous BG homologs (CfGlu1B and CfGlu1C) from C. formosanus showed different substrate specificity. CfGlu1B favors cellobiose while CfGlu1C favors sucrose. Besides, CfGlu1C exhibited higher alkali resistance than CfGlu1B. Kinetic analysis revealed that CfGlu1B enzyme's activity toward p-NP-beta-D glucopyranoside (p-NPG) was higher than that of CfGlu1C, and the difference mainly attributes to the turnover number (K cat). In addition, the activity assay showed significant synergistic action of CfGlu1B and CfGlu1C in degrading D lactosum. For effect of metals, Cu(2+) inhibited both enzymes and Ca(2+) increased the activity of CfGlu1C but not CfGlu1B. Site-directed mutagenesis analysis indicated that both enzymes lost activities when residues E190 of CfGlu1B and E168 of CfGlu1C were mutated to alanine, respectively, which were essential active centers of the GHF1 enzymes. Moreover, mutation H252N increased the activity of enzyme CfGlu1C by 2.1-fold. This study implies interesting possibilities for better practical biotechnological use in green energy production. PMID- 26054619 TI - Extra- vs. intramedullary treatment of pertrochanteric fractures: a biomechanical in vitro study comparing dynamic hip screw and intramedullary nail. AB - INTRODUCTION: Due to the demographic trend, pertrochanteric fractures of the femur will gain increasing importance in the future. Both extra- and intramedullary implants are used with good results in the treatment of these fractures. New, angular stable extramedullary implants promise increased postoperative stability even with unstable fractures. Additional trochanteric plates are intended to prevent secondary impaction, varisation and shortening of the fracture, as well as medialisation of the femoral shaft. The aim of this study was to perform a biomechanical comparison of both procedures regarding their postoperative stability and failure mechanisms. MATERIALS AND METHODS: Twelve fresh-frozen human femurs were randomized into two groups based on the volumetric bone mineral density (vBMD). Standardized pertrochanteric fractures (AO31-A2.3) were generated and treated either with an angular stable dynamic hip screw (DHS) or an intramedullary nail (nail). Correct implant position and the tip-apex distance (TAD) were controlled postoperatively using X-ray. Specimens were mounted in a servohydraulic testing machine and an axial loading was applied according to a single-leg stance model. Both groups were biomechanically compared with regard to native and postoperative stiffness, survival during cyclic testing, load to failure, and failure mechanisms. RESULTS: TAD, vBMD, and native stiffness were similar for both groups. The stiffness decreased significantly from native to postoperative state in all specimens (p < 0.001). The postoperative stiffness of both groups varied non-significantly (p = 0.275). The failure loads for specimens treated with the nail were significantly higher than for those treated with the DHS (8480.8 +/- 1238.9 N vs. 2778.2 +/- 196.8 N; p = 0.008). CONCLUSIONS: Extra- and intramedullary osteosynthesis showed comparable results as regards postoperative stiffness and survival during cyclic testing. Since the failure load of the nail was significantly higher in the tested AO31 A2.3 fracture model, we conclude that intramedullary implants should be preferred in these, unstable, fractures. PMID- 26054621 TI - Temperature-induced structural transitions in self-assembling magnetic nanocolloids. AB - With the help of a unique combination of density functional theory and computer simulations, we discover two possible scenarios, depending on concentration, for the hierarchical self-assembly of magnetic nanoparticles on cooling. We show that typically considered low temperature clusters, i.e. defect-free chains and rings, merge into more complex branched structures through only three types of defects: four-way X junctions, three-way Y junctions and two-way Z junctions. Our accurate calculations reveal the predominance of weakly magnetically responsive rings cross-linked by X defects at the lowest temperatures. We thus provide a strategy to fine-tune magnetic and thermodynamic responses of magnetic nanocolloids to be used in medical and microfluidics applications. PMID- 26054620 TI - Extreme multifunctional proteins identified from a human protein interaction network. AB - Moonlighting proteins are a subclass of multifunctional proteins whose functions are unrelated. Although they may play important roles in cells, there has been no large-scale method to identify them, nor any effort to characterize them as a group. Here, we propose the first method for the identification of 'extreme multifunctional' proteins from an interactome as a first step to characterize moonlighting proteins. By combining network topological information with protein annotations, we identify 430 extreme multifunctional proteins (3% of the human interactome). We show that the candidates form a distinct sub-group of proteins, characterized by specific features, which form a signature of extreme multifunctionality. Overall, extreme multifunctional proteins are enriched in linear motifs and less intrinsically disordered than network hubs. We also provide MoonDB, a database containing information on all the candidates identified in the analysis and a set of manually curated human moonlighting proteins. PMID- 26054622 TI - Dynamic assessment: the Spanish version of the Application of Cognitive Functions Scale. AB - For the last 30 years, the sphere of educational assessment has been giving consideration to methodology that would focus on the processes more than on the final results obtained. Dynamic Assessment has appeared within this context, making it possible to assess a child's ability to improve on a certain task after receiving mediated training. One of the techniques developed to assess the learning potential of preschoolers is the Application of Cognitive Functions Scale (ACFS: Lidz & Jepsen, 2003). The objective of this study was to verify the criterion validity of the Spanish version of the ACFS which was applied to 87 children in the second year of preschool, at which time a learning potential index was obtained for each child. Two years later, the children were reassessed with respect to intelligence, metacognition and scholastic aptitudes. Results showed that learning potential presented evidences of predictive validity regarding to the progression showed on the Kaufman Brief Intelligence Test's (K BIT: Kaufman & Kauffman, 1994) matrices subtest (p = .04, eta2 = .04) and on the evaluation subtest of the metacognition questionnaire (p = .02, eta2 = .05). Results also showed significant differences between groups on the visual perceptive aptitude subtest (p = .01) in favor of the children classified as learners. PMID- 26054623 TI - How Do US Gastroenterologists Use Over-the-Counter and Prescription Medications in Patients With Gastroesophageal Reflux and Chronic Constipation? AB - BACKGROUND: The aim of this study was to assess how US gastroenterologists perceive and utilize over-the-counter (OTC) and prescription medications for gastroesophageal reflux disease (GERD) and chronic constipation (CC). METHODS: A total of 3,600 randomly selected American Gastroenterological Association (AGA) members were mailed a 27-question survey that assessed their perceptions and use of OTC and prescription medications. The chi(2) test and Student's t-test were utilized for bivariate analysis. RESULTS: A total of 830 gastroenterologists (23.1%) completed the survey. For the typical acid reflux patient, 50% of gastroenterologists recommended OTC proton pump inhibitors (PPIs), 13% recommended an OTC histamine2 receptor antagonist, whereas 33% recommended a prescription PPI. However, in the typical CC patient, 97% of gastroenterologists initially utilized OTC treatments. The vast majority of gastroenterologists felt that OTC brand name and store brand PPIs (76%) and polyethylene glycol (PEG 3350; 90%) were equally effective. Despite this, a minority "always" or "very often" directed their patients to purchase a store brand PPI (35%) or laxative (40%). In addition, gastroenterologists tended to underestimate the cost savings associated with store brand medicines and had limited knowledge regarding the regulation of store brands. CONCLUSIONS: Among US gastroenterologists, OTC medications now dominate primary therapy of GERD and CC. Despite feeling that name brand and store brand PPIs and laxatives are equally effective, the majority of gastroenterologists recommend brand name medicines and underestimate the cost savings associated with store brands. In this age of accountable care, greater efforts to help physicians and patients to better utilize their health-care dollars is warranted. PMID- 26054625 TI - Non-suicidal self injury, psychopathology and attachment: a study with university students. AB - Conducted with a community sample, this study first tested the hypothesis that the constant association of Non-Suicidal Self Injury (NSSI) with various psychopathological states may be overrepresented because many of the studies reporting these associations used clinical samples. Secondly, the study aimed to test the emotional regulation model of NSSI by exploring the functions, the affective antecedents and consequences of NSSI episodes and to understand this emotion regulation role of NSSI in the light of Attachment Theory by differentiating self-injurers and non-self-injurers on relevant romantic attachment dimensions. A third purpose of this study was to test the hypothesis that individuals currently performing NSSI could be differentiated on these dimensions from those who had ceased engaging in NSSI. Pursuing these purposes, 518 university students (171 males and 347 females), aged 17 to 62 years old completed the Self-Injury Questionnaire - Treatment Related (Claes & Vandereycken, 2007), the Brief Symptom Inventory (Derogatis, 1982) and the Adult Attachment Scale (Collins & Read, 1990). Individuals with NSSI scored significantly higher on all BSI subscales (all p < .001). Results also revealed the existence of significant differences between participants with and without NSSI on Anxiety (Z = -2.92, p < .01) and Comfort with Proximity (Z = -3.18, p < .01), and significant differences between past self-injurers and current self injurers on Trust in Others (Z = -2.40, p < .05). These results are discussed by linking NSSI and Attachment Theory literatures. PMID- 26054624 TI - Second-Look Colonoscopies and the Impact on Capacity in FIT-Based Colorectal Cancer Screening. AB - OBJECTIVES: Fecal immunochemical testing (FIT) and colonoscopy are tandem procedures in colorectal cancer (CRC) screening. A positive FIT predicts advanced neoplasia (AN) that requires endoscopic detection and removal. En bloc or piecemeal resection of AN is associated with a significant rate of residual or recurrent neoplasia. Second-look colonoscopies are indicated to assess completeness of removal of AN. These colonoscopies can make a substantial demand on colonoscopy capacity and health-care system. This study is the first to evaluate the demand and risk factors for second-look colonoscopy in FIT CRC screening. METHODS: All colonoscopies after a positive FIT, in subjects aged 50 74 years approached for 3 rounds of FIT screening, were prospectively registered. Second-look colonoscopies were defined as any colonoscopy within 1 year following a colonoscopy after positive FIT. RESULTS: Out of 1,215 FIT-positive screenees undergoing colonoscopy, 105 (8.6%) patients underwent a second-look colonoscopy, of whom 30 (2.5%) underwent more than one colonoscopy (range 2-9), leading to a total of 149 (12.3%) additional colonoscopies. Main reasons for second-look colonoscopies were assessment of complete AN removal (41.9%) and need for additional polypectomy (34.3%). Risk factors were advanced adenomas and poor bowel preparation (P<0.001). High fecal hemoglobin concentration was the only predictor of a second-look colonoscopy before index colonoscopy (P<0.001). CONCLUSIONS: Second-look colonoscopies have substantial impact on colonoscopy resources, increasing the demand with 12%. The main reasons for these second-look colonoscopies were previous incomplete polypectomy and control of completeness of removal of neoplastic lesions. A high fecal hemoglobin concentration as measured by FIT can help to identify patients at risk of a second-look colonoscopy. PMID- 26054626 TI - Proteomics analysis of metabolically engineered yeast cells and medium-chained hydrocarbon biofuel precursors synthesis. AB - Recently, various biofuels have been synthesized through metabolic engineering approaches to meet the exploding energy demands. Hydrocarbon biofuels, energy equivalent to petroleum-based fuels, are identified as promising replacements for petroleum. Metabolically engineered Saccharomyces cerevisiae capable of synthesize precursors of medium-chained hydrocarbons is proposed in this study. The hydroperoxide pathway introduced in S. cerevisiae consisted of lipoxygenase (LOX) and hydroperoxide lyase (HPL) from almond, which catalyzes linoleic acid to 3(Z)-nonenal, the precursor for medium-chained hydrocarbon biofuels. Proteomics study showed that 31 proteins displayed different expression levels among four functional strains and most of them were related to carbohydrate metabolism and protein synthesis, suggested prospective capabilities of energy generation and exogenous protein synthesis. Biotransformation efficiency studies carried out by GC-FID were in accordance with the expectations. The highest yield of 3(Z) nonenal was up to 1.21 +/- 0.05 mg/L with the carbon recovery of up to 12.4%. PMID- 26054628 TI - Syntheses, structures, photoluminescence and photocatalysis of chiral 3D Cd(II) frameworks from achiral mixed flexible ligands by spontaneous resolution. AB - Unprecedented two homochiral Cd(ii) enantiomers [Cd(dtba)(bpp)]n (1: 1P and 1M) (H2dtba = 2,2'-dithiodibenzoic acid, bpp = 1,3-bis(4-pyridyl)propane), were obtained by self-assembly with mixed achiral flexible ligands. Single-crystal X ray diffraction analysis reveals that complexes 1P and 1M crystallize in trigonal space groups P3121 and P3221, respectively. The compounds are optically active, and their UV spectra in the solid state showed Cotton effects in the opposite directions. Compounds 1P and 1M present the examples of three-interpenetrating chiral frameworks with triangular and quasi-heart-like threefold helical chiral channels, chair-like twofold helical chiral channels and one type of threefold double-helical chain. The 3D metal-organic framework can be regarded as a bcu type topology with the symbol of 8(6). The photoluminescent properties of compound 1 have been studied. Remarkably, compound 1 exhibits good photocatalytic activity for degradation of dyes under the simulated sunlight irradiation in the pH = 3 aqueous solution. PMID- 26054627 TI - Characterization of a Self-renewing and Multi-potent Cell Population Isolated from Human Minor Salivary Glands. AB - Adult stem cells play an important role in maintaining tissue homeostasis. Although these cells are found in many tissues, the presence of stem cells in the human minor salivary glands is not well explored. Using the explant culture method, we isolated a population of cells with self-renewal and differentiation capacities harboring that reside in the human minor salivary glands, called human minor salivary gland mesenchymal stem cells (hMSGMSCs). These cells show embryonic stem cell and mesenchymal stem cell phenotypes. Our results demonstrate that hMSGMSCs have the potential to undergo mesodermal, ectodermal and endodermal differentiation in conditioned culture systems in vitro. Furthermore, in vivo transplantation of hMSGMSCs into SCID mice after partial hepatectomy shows that hMSGMSCs are able to survive and engraft, characterized by the survival of labeled cells and the expression of the hepatocyte markers AFP and KRT18. These data demonstrate the existence of hMSGMSCs and suggest their potential in cell therapy and regenerative medicine. PMID- 26054629 TI - Stereoselective Pd-catalyzed etherification and asymmetric synthesis of furanomycin and its analogues from a chiral aziridine. AB - A chiral aziridine was utilized for the synthesis of the anti-bacterial natural amino acid L-(+)-furanomycin, and its analogues including 5'-epi-furanomycin and norfuranomycin. Key steps of this synthesis are the stereoselective Pd-catalyzed etherification for diallyl ethers and ring closing metathesis. PMID- 26054630 TI - Self-determination, behavioral engagement, disaffection, and academic performance: a mediational analysis. AB - The present study examined the role of behavioral engagement and disaffection as mediators between self-determination and academic performance. Participants were 545 secondary students (53.4% girls) aged 12 to 19 years. Variables were assessed in the Spanish language classroom over a nine-month period. Students estimated their self-determination, and their teachers assessed student engagement, disaffection, and performance. Structural equation models corroborated the hypotheses: the types of self-determination differentially predicted engagement (R 2 = .39) and disaffection (R 2 = .24), and were progressively more adaptive the higher the autonomy; self-determination, behavioral engagement, and disaffection predicted performance (R 2 = .43); engagement and disaffection partially mediated the relationship from external regulation (beta = -.097; p < .002; Confidence Interval = -.177, -.051), identified regulation (beta = .109; p < .006; CI = .054, .165), and intrinsic motivation (beta = .139; p < .002; CI = .086, .206) to performance. The implications of these findings for current theory and educational intervention are discussed. PMID- 26054631 TI - Surprise Questions for Survival Prediction in Patients With Advanced Cancer: A Multicenter Prospective Cohort Study. AB - BACKGROUND: Predicting the short-term survival in cancer patients is an important issue for patients, family, and oncologists. Although the prognostic accuracy of the surprise question has value in 1-year mortality for cancer patients, the prognostic value for short-term survival has not been formally assessed. The primary aim of the present study was to assess the prognostic value of the surprise question for 7-day and 30-day survival in patients with advanced cancer. PATIENTS AND METHODS: The present multicenter prospective cohort study was conducted in Japan from September 2012 through April 2014, involving 16 palliative care units, 19 hospital-based palliative care teams, and 23 home-based palliative care services. RESULTS: We recruited 2,425 patients and included 2,361 for analysis: 912 from hospital-based palliative care teams, 895 from hospital palliative care units, and 554 from home-based palliative care services. The sensitivity, specificity, positive predictive value, and negative predictive value of the 7-day survival surprise question were 84.7% (95% confidence interval [CI], 80.7%-88.0%), 68.0% (95% CI, 67.3%-68.5%), 30.3% (95% CI, 28.9%-31.5%), and 96.4% (95% CI, 95.5%-97.2%), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for the 30-day surprise question were 95.6% (95% CI, 94.4%-96.6%), 37.0% (95% CI, 35.9%-37.9%), 57.6% (95% CI, 56.8%-58.2%), and 90.4% (95% CI, 87.7%-92.6%), respectively. CONCLUSION: Surprise questions are useful for screening patients for short survival. However, the high false-positive rates do not allow clinicians to provide definitive prognosis prediction. IMPLICATIONS FOR PRACTICE: The findings of this study indicate that clinicians can screen patients for 7- or 30-day survival using surprise questions with 90% or more sensitivity. Clinicians cannot provide accurate prognosis estimation, and all patients will not always die within the defined periods. The screened patients can be regarded as the subjects to be prepared for approaching death, and proactive discussion would be useful for such patients. PMID- 26054632 TI - The Prevalence and Impact of Hyperglycemia and Hyperlipidemia in Patients With Advanced Cancer Receiving Combination Treatment With the Mammalian Target of Rapamycin Inhibitor Temsirolimus and Insulin Growth Factor-Receptor Antibody Cixutumumab. AB - BACKGROUND: Cixutumumab (a humanized monoclonal antibody against insulin-like growth factor-1 receptor [IGF-1R]) and the mammalian target of rapamycin (mTOR) inhibitor temsirolimus were combined in a phase I study of patients with advanced cancer. We investigated the prevalence of metabolic toxicities, their management, and impact on outcome. METHODS: The temsirolimus dose was 25 mg or 37.5 mg i.v. weekly with escalating doses of cixutumumab (3, 5, or 6 mg/kg i.v. weekly). No patients with diabetes or hyperlipidemia at baseline were eligible until the expansion cohort. We assessed metabolic derangements in our patient cohort, their management, and their association with tumor shrinkage, time to progression (TTP) and overall survival (OS). RESULTS: Of the 57 patients analyzed, hyperglycemia was seen in 36 (63%) (grade 1-2: 33 [58%]; grade 3-4: 3 [5%]). The median blood sugar level (fasting and nonfasting) across cohorts was 149 mg/dL (upper limit of normal: 110 mg/dL). No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma or pancreatitis during treatment. Median maximum triglyceride, cholesterol, and low-density lipoprotein levels achieved were 247 mg/dL (range: 65-702 mg/dL), 243 mg/dL (range: 103-424 mg/dL), and 153 mg/dL (range 50-375 mg/dL), respectively. Higher glucose levels were associated with more RECIST tumor shrinkage (r = -.30 [95% confidence interval: -.52, -.03; p = .03]). There was no association between metabolic toxicities of the mTOR and IGF-1R combination and TTP or OS. CONCLUSION: The combination of temsirolimus and cixutumumab was safe and resulted in manageable metabolic toxicities. More tumor shrinkage was seen in patients who developed these adverse events. Although perhaps limited by the small number of patients, no significant association was discerned between hyperglycemia, hypertriglyceridemia, or hypercholesterolemia and TTP or OS. IMPLICATIONS FOR PRACTICE: Results of this study show that the combination of temsirolimus and cixutumumab is safe. The most common side effects, hyperglycemia and hyperlipidemia, are tolerable and manageable. This combination of therapies should not be withheld from diabetic patients and patients with high cholesterol levels. Collaboration between oncologist and endocrinologist allows for individualized treatment and better control of these adverse events, with few dose interruptions and reductions. Supportive care and close monitoring is needed. Those patients who develop hyperglycemia or hypercholesterolemia may benefit more from the drug. PMID- 26054633 TI - Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor Treatment and Salvage Chemotherapy in EGFR-Mutated Elderly Pulmonary Adenocarcinoma Patients. AB - BACKGROUND: Lung cancer is frequently a disease of elderly patients. However, these patients are often treated less actively owing to a higher comorbidity rate and poor performance status. The efficacy of different treatments in elderly patients with epidermal growth factor receptor (EGFR)-mutated lung cancer is still unknown. MATERIALS AND METHODS: We retrospectively reviewed the records of our pulmonary adenocarcinoma patients treated between 2010 and 2013. Data on patient age, type of tumor EGFR mutation, response to first-line EGFR-tyrosine kinase inhibitor (TKI) treatment, type of salvage chemotherapy, and efficacy of EGFR-TKI and salvage chemotherapy were collected. RESULTS: In all, 473 of 1,230 stage IV adenocarcinoma patients had an EGFR mutation, and 330 of them received first-line TKI treatment. Of the 330 patients, 160 were >=70 years old (elderly group) and 170 were <70 years old (younger group). The response rate and progression-free survival (PFS) with first-line TKI treatment were not significantly different. The elderly group had shorter median survival. A total of 107 patients received salvage chemotherapy after first-line EGFR-TKI treatment: 45 in the elderly group and 62 in the younger group. Their response rate and PFS were not significantly different; however, the younger group had longer median survival. Additional subgroup analysis showed that younger patients who received platinum-based chemotherapy or combination chemotherapy had better median survival than did the elderly patients. The PFS was longer among younger patients receiving a platinum-based regimen than that among the elderly patients. CONCLUSION: Elderly patients with disease progression after first-line EGFR-TKI treatment can receive chemotherapy and have a response rate similar to that of younger patients. IMPLICATIONS FOR PRACTICE: The aim of the present study was to investigate the efficacy of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients and the outcomes of subsequent salvage chemotherapy after disease progression. The most important finding was that elderly patients with disease progression after first-line EGFR TKI treatment can receive salvage chemotherapy and have a response rate similar to that of younger patients who received salvage chemotherapy. PMID- 26054635 TI - A simple but highly efficient multi-formyl phenol-amine system for fluorescence detection of peroxide explosive vapour. AB - A simple, highly stable, sensitive and selective fluorescent system for peroxide explosives was developed via an aromatic aldehyde oxidation reaction. The high efficiency arises from its higher HOMO level and multiple H-bonding. The sensitivity is obtained to be 0.1 ppt for H2O2 and 0.2 ppb for TATP. PMID- 26054634 TI - Ribosome profiling reveals translation control as a key mechanism generating differential gene expression in Trypanosoma cruzi. AB - BACKGROUND: Due to the absence of transcription initiation regulation of protein coding genes transcribed by RNA polymerase II, posttranscriptional regulation is responsible for the majority of gene expression changes in trypanosomatids. Therefore, cataloging the abundance of mRNAs (transcriptome) and the level of their translation (translatome) is a key step to understand control of gene expression in these organisms. RESULTS: Here we assess the extent of regulation of the transcriptome and the translatome in the Chagas disease causing agent, Trypanosoma cruzi, in both the non-infective (epimastigote) and infective (metacyclic trypomastigote) insect's life stages using RNA-seq and ribosome profiling. The observed steady state transcript levels support constitutive transcription and maturation implying the existence of distinctive posttranscriptional regulatory mechanisms controlling gene expression levels at those parasite stages. Meanwhile, the downregulation of a large proportion of the translatome indicates a key role of translation control in differentiation into the infective form. The previously described proteomic data correlate better with the translatomes than with the transcriptomes and translational efficiency analysis shows a wide dynamic range, reinforcing the importance of translatability as a regulatory step. Translation efficiencies for protein families like ribosomal components are diminished while translation of the transialidase virulence factors is upregulated in the quiescent infective metacyclic trypomastigote stage. CONCLUSIONS: A large subset of genes is modulated at the translation level in two different stages of Trypanosoma cruzi life cycle. Translation upregulation of virulence factors and downregulation of ribosomal proteins indicates different degrees of control operating to prepare the parasite for an infective life form. Taking together our results show that translational regulation, in addition to regulation of steady state level of mRNA, is a major factor playing a role during the parasite differentiation. PMID- 26054636 TI - Hepatitis C Virus Disease Progression in People Who Inject Drugs: Protocol for a Systematic Review and Meta-Analysis. AB - BACKGROUND: Most hepatitis C virus (HCV) infections in the United States occur following non-sterile injection drug use. However, the majority of people who inject drugs (PWID) with chronic HCV are not currently receiving care. OBJECTIVE: This paper presents our protocol for the systematic review and meta-analysis of data on the natural history of HCV among PWID and will inform modeling of the impact and cost-effectiveness of HCV management among this population. This study is conducted as part of the HCV Synthesis Project, which is funded to develop recommendations for HCV control strategies in the United States. METHODS: This protocol describes the methods used for a systematic review and meta-analysis of published and unpublished data on the natural history of HCV among PWID including viral clearance, fibrosis progression, and the incidence of compensated cirrhosis (CC), decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver related mortality. RESULTS: Final results are anticipated by December 2016. CONCLUSIONS: Methods used for the synthesis of data on disease progression among HCV mono-infected PWID are presented. Data from the systematic review and meta analysis will be used to inform simulations of the natural history of HCV and to model the effects of prevention and treatment strategies to reduce disease burden and the associated costs to society and individual patients. PMID- 26054637 TI - High-level expression, purification, and enzymatic characterization of truncated human plasminogen (Lys531-Asn791) in the methylotrophic yeast Pichia pastoris. AB - BACKGROUND: Plasmin is a serine protease that plays a critical role in fibrinolysis, which is a process that prevents blood clots from growing and becoming problematic. Recombinant human microplasminogen (rhMUPlg) is a derivative of plasmin that solely consists of the catalytic domain of human plasmin and lacks the five kringle domains found in the native protein. Developing an industrial production method that provides high yields of this protein with high purity, quality, and potency is critical for preclinical research. RESULTS: The human microplasminogen gene was cloned into the pPIC9K vector, and the recombinant plasmid was transformed into Pichia pastoris strain GS115. The concentration of plasmin reached 510.1 mg/L of culture medium. Under fermentation conditions, the yield of rhMUPlg was 1.0 g/L. We purified rhMUPlg to 96% purity by gel-filtration and cation-exchange chromatography. The specific activity of rhMUPlg reached 23.6 U/mg. The K m of substrate hydrolysis by recombinant human microplasmin was comparable to that of human plasmin, while rhMUPlm had higher k cat /Km values than plasmin. The high purity and activity of the rhMUPlg obtained here will likely prove to be a valuable tool for studies of its application in thrombotic diseases and vitreoretinopathies. CONCLUSIONS: Reliable rhMUPlg production (for use in therapeutic applications) is feasible using genetically modified P. pastoris as a host strain. The successful expression of rhMUPlg in P. pastoris lays a solid foundation for its downstream application. PMID- 26054638 TI - Quantitative susceptibility mapping in superficial hemosiderosis of the central nervous system. PMID- 26054639 TI - Who Gets Head Trauma or Recruited in Mild Traumatic Brain Injury Research? AB - Mild traumatic brain injury (mTBI) is a public health problem. Outcome from mTBI is heterogeneous in part due to pre-injury individual differences that typically are not well described or understood. Pre-injury health characteristics of all consecutive patients (n=3023) who underwent head computed tomography due to acute head trauma in the emergency department of Tampere University Hospital, Finland, between August 2010 and July 2012 were examined. Patients were screened to obtain a sample of working age adults with no pre-injury medical or mental health problems who had sustained a "pure" mTBI. Of all patients screened, 1990 (65.8%) fulfilled the mTBI criteria, 257 (8.5%) had a more severe TBI, and 776 (25.7%) had a head trauma without obvious signs of brain injury. Injury-related data and participant-related data (e.g., age, sex, diagnosed diseases, and medications) were collected from hospital records. The most common pre-injury diseases were circulatory (39.4%-43.2%), neurological (23.7%-25.2%), and psychiatric (25.8% 27.5%) disorders. Alcohol abuse was present in 18.4%-26.8%. The most common medications were for cardiovascular (33.1%-36.6%), central nervous system (21.4% 30.8%), and blood clotting and anemia indications (21.5%-22.6%). Of the screened patients, only 2.5% met all the enrollment criteria. Age, neurological conditions, and psychiatric problems were the most common reasons for exclusion. Most of the patients sustaining an mTBI have some pre-injury diseases or conditions that could affect clinical outcome. By excluding patients with pre existing conditions, the patients with known risk factors for poor outcome remain poorly studied. PMID- 26054640 TI - Cardiac stress reactions and perseverance: Diminished reactivity is associated with study non-completion. AB - Blunted cardiovascular stress reactions may be a marker for poor behavioral regulation. The present study examined the association between heart rate reactivity and perseverance, operationalized as the failure to complete a subsequent follow-up assessment. The heart rate (using electrocardiography), cardiac output (using Doppler echocardiography) and blood pressure (using a semi- automatic sphygmomanometer) of 176 high school students were measured before and during exposure to a standard 10-min mental arithmetic stress. A year later, all participants were contacted to complete a simple and undemanding on-line assessment. Despite repeated promptings, 44 failed to do so. Diminished heart rate and cardiac output stress reactions predicted failure to complete the follow up. This result adds to the emerging characterization of those who exhibit blunted stress reactions by revealing associated deficiencies in perseverance. It may also have prognostic implications for the completion of multi-session interventions, as well as for selection bias in stress reactivity studies with follow-up designs. PMID- 26054641 TI - Evolutionary dynamics of rhomboid proteases in Streptomycetes. AB - BACKGROUND: Proteolytic enzymes are ubiquitous and active in a myriad of biochemical pathways. One type, the rhomboids are intramembrane serine proteases that release their products extracellularly. These proteases are present in all forms of life and their function is not fully understood, although some evidence suggests they participate in cell signaling. Streptomycetes are prolific soil bacteria with diverse physiological and metabolic properties that respond to signals from other cells and from the environment. In the present study, we investigate the evolutionary dynamics of rhomboids in Streptomycetes, as this can shed light into the possible involvement of rhomboids in the complex lifestyles of these bacteria. RESULTS: Analysis of Streptomyces genomes revealed that they harbor up to five divergent putative rhomboid genes (arbitrarily labeled families A-E), two of which are orthologous to rhomboids previously described in Mycobacteria. Characterization of each of these rhomboid families reveals that each group is distinctive, and has its own evolutionary history. Two of the Streptomyces rhomboid families are highly conserved across all analyzed genomes suggesting they are essential. At least one family has been horizontally transferred, while others have been lost in several genomes. Additionally, the transcription of the four rhomboid genes identified in Streptomyces coelicolor, the model organism of this genus, was verified by reverse transcription. CONCLUSIONS: Using phylogenetic and genomic analysis, this study demonstrates the existence of five distinct families of rhomboid genes in Streptomycetes. Families A and D are present in all nine species analyzed indicating a potentially important role for these genes. The four rhomboids present in S. coelicolor are transcribed suggesting they could participate in cellular metabolism. Future studies are needed to provide insight into the involvement of rhomboids in Streptomyces physiology. We are currently constructing knock out (KO) mutants for each of the rhomboid genes from S. coelicolor and will compare the phenotypes of the KOs to the wild type strain. PMID- 26054642 TI - Adenosine A2AR blockade prevents neuroinflammation-induced death of retinal ganglion cells caused by elevated pressure. AB - BACKGROUND: Elevated intraocular pressure (IOP) is a major risk factor for glaucoma, a degenerative disease characterized by the loss of retinal ganglion cells (RGCs). There is clinical and experimental evidence that neuroinflammation is involved in the pathogenesis of glaucoma. Since the blockade of adenosine A2A receptor (A2AR) confers robust neuroprotection and controls microglia reactivity in the brain, we now investigated the ability of A2AR blockade to control the reactivity of microglia and neuroinflammation as well as RGC loss in retinal organotypic cultures exposed to elevated hydrostatic pressure (EHP) or lipopolysaccharide (LPS). METHODS: Retinal organotypic cultures were either incubated with LPS (3 MUg/mL), to elicit a pro-inflammatory response, or exposed to EHP (+70 mmHg), to mimic increased IOP, for 4 or 24 h, in the presence or absence of the A2AR antagonist SCH 58261 (50 nM). A2AR expression, microglial reactivity and neuroinflammatory response were evaluated by immunohistochemistry, quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). RGC loss was assessed by immunohistochemistry. In order to investigate the contribution of pro-inflammatory mediators to RGC loss, the organotypic retinal cultures were incubated with rabbit anti-tumour necrosis factor (TNF) (2 MUg/mL) and goat anti interleukin-1beta (IL-1beta) (1 MUg/mL) antibodies. RESULTS: We report that the A2AR antagonist (SCH 58261) prevented microglia reactivity, increase in pro inflammatory mediators as well as RGC loss upon exposure to either LPS or EHP. Additionally, neutralization of TNF and IL-1beta prevented RGC loss induced by LPS or EHP. CONCLUSIONS: This work demonstrates that A2AR blockade confers neuroprotection to RGCs by controlling microglia-mediated retinal neuroinflammation and prompts the hypothesis that A2AR antagonists may be a novel therapeutic option to manage glaucomatous disorders. PMID- 26054644 TI - Evaluating immune responses after sipuleucel-T therapy. AB - Following FDA approval of sipuleucel-T in 2010 for metastatic castration resistant prostate cancer (mCRPC), several studies have described the effect of sipuleucel-T on peripheral immune responses. Retrospective associations have also been made with immune responses and survival. A recently published study by Fong et al. was the first to characterize the immune response of sipuleucel-T in the tumor microenvironment. The findings of this study have been hypothesis generating, yet it remains unclear whether the peri-tumor immune response described is predictive of survival. Increasing evidence suggests that radiographic or PSA progression does not accurately reflect survival with sipuleucel-T and other immunotherapies. Finding an immune biomarker which can accurately reflect clinical benefit and validating it prospectively offers the potential for a predictive indicator of response in an area where none currently exists. PMID- 26054643 TI - Urinary 8-iso-prostaglandin F2alpha as a marker of metabolic risks in the general Japanese population: The ROAD study. AB - OBJECTIVE: To determine whether 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) is a reliable biomarker of the accumulation of metabolic risks [e.g., overweight, hypertension, impaired glucose tolerance (IGT), and dyslipidemia]. METHODS: This was a cross-sectional study of the baseline characteristics of a Japanese general population cohort study: Research on Osteoarthritis/Osteoporosis Against Disability (ROAD). Of 1,690 participants, 1,527 fulfilled all questionnaires and examinations. Free and conjugated urinary 8-iso-PGF2alpha levels and metabolic syndrome (MetS) components including blood pressure, HbA1c, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C were analyzed. The data were analyzed by ANCOVA, multiple regression analysis, and multinomial logistic analysis. RESULTS: 8-iso-PGF2alpha was significantly associated with HbA1c and significantly inversely associated with total cholesterol and non-HDL C. Notably, IGT with an HbA1c cut-off of 5.5% was significantly associated with 8 iso-PGF2alpha level in participants aged <=50 years. Multinomial logistic regression analysis revealed 8-iso-PGF2alpha level was significantly associated with a greater number of MetS risks present; this association was stronger in younger participants. In participants aged >=71 years, 8-iso-PGF2alpha was significantly associated with a greater number of MetS risks with higher IGT cut offs. CONCLUSIONS: Urinary 8-iso-PGF2alpha can be a reliable marker of IGT and the accumulation of MetS risks, especially in younger people. PMID- 26054646 TI - The role of the local retail food environment in fruit, vegetable and sugar sweetened beverage consumption in Brazil. AB - OBJECTIVE: To examine the relationship between the local retail food environment and consumption of fruits and vegetables (FV) and sugar-sweetened beverages (SSB) in Sao Paulo, Brazil, as well as the moderation effects of income in the studied relationships. DESIGN: Cross-sectional study design that drew upon neighbourhood- and individual-level data. For each participant, community (density and proximity) and community food environment (availability, variety, quality and price) measures of FV and SSB were assessed in retail food stores and specialized fresh produce markets within 1.6 km of their homes. Poisson generalized estimating equations (GEE) were used to model the associations of food consumption with food environment measures, adjusted by individual-level characteristics. SETTING: Sao Paulo, Brazil. SUBJECTS: Adults (n 1842) residing in the same census tracts (n 52) in Sao Paulo, Brazil as those where the neighbourhood-level measures were taken. RESULTS: FV availability in neighbourhoods was associated with regular FV consumption (>=5 times/week; prevalence ratio=1.41; 95 % CI 1.19, 1.67). Regular FV consumption prevalence was significantly lower among lower-income individuals living in neighbourhoods with fewer supermarkets and fresh produce markets (P-interaction <0.05). A greater variety of SSB was associated with a 15 % increase in regular SSB consumption (>=5 times/week) prevalence, after adjustment for confounding variables. CONCLUSIONS: Our findings suggest that the local retail food environment is associated with FV and SSB consumption in a Brazilian urban sample. PMID- 26054645 TI - Complement regulator CD46: genetic variants and disease associations. AB - Membrane cofactor protein (MCP; CD46) is an ubiquitously expressed complement regulatory protein that protects host cells from injury by complement. This type I membrane glycoprotein serves as a cofactor for the serine protease factor I to mediate inactivation of C3b and C4b deposited on host cells. More than 60 disease associated mutations in MCP have now been identified. The majority of the mutations are linked to a rare thrombotic microangiopathic-based disease, atypical hemolytic uremic syndrome (aHUS), but new putative links to systemic lupus erythematosus, glomerulonephritis, and pregnancy-related disorders among others have also been identified. This review summarizes our current knowledge of disease-associated mutations in this complement inhibitor. PMID- 26054647 TI - Authentication of Botanical Origin in Herbal Teas by Plastid Noncoding DNA Length Polymorphisms. AB - The aim of this study was to develop a DNA barcode assay to authenticate the botanical origin of herbal teas. To reach this aim, we tested the efficiency of a PCR-capillary electrophoresis (PCR-CE) approach on commercial herbal tea samples using two noncoding plastid barcodes, the trnL intron and the intergenic spacer between trnL and trnF. Barcode DNA length polymorphisms proved successful in authenticating the species origin of herbal teas. We verified the validity of our approach by sequencing species-specific barcode amplicons from herbal tea samples. Moreover, we displayed the utility of PCR-CE assays coupled with sequencing to identify the origin of undeclared plant material in herbal tea samples. The PCR-CE assays proposed in this work can be applied as routine tests for the verification of botanical origin in herbal teas and can be extended to authenticate all types of herbal foodstuffs. PMID- 26054648 TI - Use of a real-size 3D-printed model as a preoperative and intraoperative tool for minimally invasive plating of comminuted midshaft clavicle fractures. AB - BACKGROUND: Open reduction and plate fixation is the standard operative treatment for displaced midshaft clavicle fracture. However, sometimes it is difficult to achieve anatomic reduction by open reduction technique in cases with comminution. METHODS: We describe a novel technique using a real-size three dimensionally (3D) printed clavicle model as a preoperative and intraoperative tool for minimally invasive plating of displaced comminuted midshaft clavicle fractures. A computed tomography (CT) scan is taken of both clavicles in patients with a unilateral displaced comminuted midshaft clavicle fracture. Both clavicles are 3D printed into a real-size clavicle model. Using the mirror imaging technique, the uninjured side clavicle is 3D printed into the opposite side model to produce a suitable replica of the fractured side clavicle pre-injury. RESULTS: The 3D printed fractured clavicle model allows the surgeon to observe and manipulate accurate anatomical replicas of the fractured bone to assist in fracture reduction prior to surgery. The 3D-printed uninjured clavicle model can be utilized as a template to select the anatomically precontoured locking plate which best fits the model. The plate can be inserted through a small incision and fixed with locking screws without exposing the fracture site. Seven comminuted clavicle fractures treated with this technique achieved good bone union. CONCLUSIONS: This technique can be used for a unilateral displaced comminuted midshaft clavicle fracture when it is difficult to achieve anatomic reduction by open reduction technique. Level of evidence V. PMID- 26054649 TI - Improving communication and recall of information in paediatric diabetes consultations: a qualitative study of parents' experiences and views. AB - BACKGROUND: Parents of non-adolescent children with type 1 diabetes are responsible for most of their child's diabetes management tasks. Consultations are used to provide diabetes education, review clinical progress and promote diabetes management tasks. This study explored parents' experiences of, and views about, their child's diabetes consultations. The objective was to identify ways in which consultations could be improved to aid communication, understanding and knowledge retention. METHODS: In-depth interviews with 54 parents of children (aged <=12 years) with type 1 diabetes. Data were analysed using an inductive thematic approach. RESULTS: Parents' accounts revealed structural and contextual factors which could hinder effective communication and knowledge acquisition during consultations. Most reported feeling anxious going into consultations and worrying about being reprimanded by health professionals if their child's glycaemic control had not improved. As a consequence, many parents highlighted problems concentrating and assimilating information during consultations. In extreme cases, worries about being reprimanded led parents to omit or fabricate information when discussing their child's treatment or even to their cancelling appointments. Many parents described wanting opportunities to speak to health professionals alone because young children could be distracting and/or they did not want to raise distressing issues in front of their child. Parents described the benefits of receiving clinical advice from health professionals familiar with their family circumstances and disliking attending busy clinics and seeing different health professionals on each occasion. Parents also highlighted the benefits of receiving treatment recommendations in a written form after the consultation. DISCUSSION AND CONCLUSIONS: This study has highlighted unrecognised and undocumented aspects of the consultation which may result in parents leaving uncertain about the main issues discussed and with questions unanswered and support needs unaddressed. Structural and contextual changes to consultations are recommended to improve concentration, knowledge acquisition and retention. These include: sending letters/written summaries after consultations highlighting key decisions, providing opportunities for parents to consult health professionals without their child being present, encouraging parents to ask more questions during consultations, having procedures in place to promote continuity of care and providing parents with consistent and non-contradictory advice. PMID- 26054650 TI - An accurate test for homogeneity of odds ratios based on Cochran's Q-statistic. AB - BACKGROUND: A frequently used statistic for testing homogeneity in a meta analysis of K independent studies is Cochran's Q. For a standard test of homogeneity the Q statistic is referred to a chi-square distribution with K-1 degrees of freedom. For the situation in which the effects of the studies are logarithms of odds ratios, the chi-square distribution is much too conservative for moderate size studies, although it may be asymptotically correct as the individual studies become large. METHODS: Using a mixture of theoretical results and simulations, we provide formulas to estimate the shape and scale parameters of a gamma distribution to fit the distribution of Q. RESULTS: Simulation studies show that the gamma distribution is a good approximation to the distribution for Q. CONCLUSIONS: Use of the gamma distribution instead of the chi-square distribution for Q should eliminate inaccurate inferences in assessing homogeneity in a meta-analysis. (A computer program for implementing this test is provided.) This hypothesis test is competitive with the Breslow-Day test both in accuracy of level and in power. PMID- 26054651 TI - Pathogenesis and Treatment of Callus in the Diabetic Foot. AB - Diabetic foot is one of the most common long term complications of diabetes. The risk of developing a foot ulcer is significantly increased when a patient presents with a callus. Callus develops due to various reasons, of which, the most important in people with diabetes is peripheral neuropathy. Motor neuropathy leads to deformity and sensory neuropathy causes lack of sensation, which results in persistent abnormal pressure on the foot. The cells of skin react to it by increasing keratinization and turns into a callus, which predisposes to foot ulceration. However, there is a lack of research in the field of callus. The link between hyperkeratosis, insulin and hyperglycaemia is not fully explored. There is also a lack of research on the relationship between genetic defects of hyperkeratosis, and the risk of developing a diabetic foot ulcer. There is scope for further research in this area, such as exploring whether development of callus is an individual risk factor, and whether glycaemic control or its treatment has any relationship with callus formation. The research around the genetic defects of hyperkeratosis may lead to identification of those, with diabetes, who may have increased risk of developing a foot ulcer. PMID- 26054652 TI - Activated NMDA receptor imaging: a step forward in epilepsy. PMID- 26054653 TI - Modulatory effects of 1,25-dihydroxyvitamin D3 on eye disorders: A critical review. AB - Many studies have shown that the presence of 1,25-dihydroxyvitamin D3 in the eye is able to modulate inflammatory responses. In fact, it has been demonstrated that topical administration of vitamin D3 inhibits Langerhans cells migration from the central cornea, corneal neovascularization, and production of cytokines (i.e., interleukin-1-6-8) in experimental animals. Moreover, both in vitro and in vivo studies have demonstrated that vitamin D is a potent inhibitor of retinal neovascularization. It has been shown that calcitriol, the biologically active form of vitamin D, inhibits angiogenesis both in cultured endothelial cells and in retinas from guinea pigs with retinoblastoma or oxygen-induced ischemic retinopathy. In addition, it seems that this compound is able to prevent the progression from early to neovascular age-related macular degeneration (AMD) and, at the same time, to down-regulate the characteristic inflammatory cascade at the retinal pigment epithelium-choroid interface due to its anti-inflammatory and immunomodulatory capabilities. Furthermore, 1,25-dihydroxyvitamin D3 and its analogue, 2-methylene-19-nor-1,25-dihydroxyvitamin D3, are able to modulate intraocular pressure (IOP) through gene expression. Several studies have suggested a role in glaucoma and diabetic retinopathy therapies for vitamin D3. In conclusion, this review summarizes our current knowledge on the potential use of vitamin D3 in the protection and treatment of ocular diseases in ophthalmology. PMID- 26054654 TI - Sarcocystis spp. Infection in two Red Panda Cubs (Ailurus fulgens). AB - Two neonatal male red panda (Ailurus fulgens) littermates were submitted for necropsy examination. One animal was found dead with no prior signs of illness; the other had a brief history of laboured breathing. Post-mortem examination revealed disseminated protozoal infection. To further characterize the causative agent, transmission electron microscopy (TEM), immunohistochemistry (IHC), polymerase chain reaction (PCR) and amplification and nucleic acid sequencing were performed. IHC was negative for Toxoplasma gondii and Neospora caninum, but was positive for a Sarcocystis spp. TEM of cardiac muscle and lung revealed numerous intracellular apicomplexan protozoa within parasitophorous vacuoles. PCR and nucleic acid sequencing of partial 18S rRNA and the internal transcribed spacer (ITS)-1 region confirmed a Sarcocystis spp. that shared 99% sequence homology to Sarcocystis neurona and Sarcocystis dasypi. This represents the first report of sarcocystosis in red pandas. The histopathological, immunohistochemical, molecular and ultrastructural findings are supportive of vertical transmission resulting in fatal disseminated disease. PMID- 26054655 TI - The Promotion of Executive Functioning in a Brazilian Public School: A Pilot Study. AB - Studies have highlighted the role of early Executive Functioning (EF) interventions with regard to preventing behavioral and mental health problems. In this sense, interventions to promote EF have been developed and tested; however, in Latin America, evidence of early EF-related interventions is still limited. We developed a program for EF promotion in children and applied it to first-grade students. Sixty-eight six-year-old children and their five teachers were divided into an experimental group (EG) and a control group (CG). EG teachers administered the Intervention Program for Self-regulation and Executive Functions in a classroom context. The results of the ANCOVAs showed that children in the EG had significantly better performance in measures of cognitive flexibility (Trail Making Test for Preschoolers; p = .05), attention (Cancellation Attention Test - errors in the Part 3; p = .027), inhibition (Simon Task - interference score in the part 1; p = .008 and interference reaction time in the part 2; p = .010), and planning (CHEXI - planning scale; p = .041) than those in the CG. The results show that EF can be promoted using classroom intervention in public schools. These results expand previous findings for Latin America. PMID- 26054656 TI - Do Emotional Appeals in Public Service Advertisements Influence Adolescents' Intention to Reduce Consumption of Sugar-Sweetened Beverages? AB - Mass media campaigns are a commonly used approach to reduce sugary drink consumption, which is linked to obesity in children and adolescents. The present study investigated the direct and mediated effects of emotional appeals in public service advertisements (PSAs) that aired between 2010 and 2012 on adolescents' intention to reduce their sugar-sweetened beverage (SSB) consumption. An online randomized experiment was conducted with a national sample of adolescent respondents ages 13 to 17 years old (N = 805). Participants were randomly assigned to 1 of 4 conditions. Three experimental conditions represented PSAs with different emotional appeals: humor, fear, and nurturance, plus a fourth control condition. The outcome was adolescents' intention to cut back on SSBs. The direct effect of fear appeals on intention was mediated through adolescents' perception of the PSAs' argument strength; perceived argument strength was also the key mediator for the indirect effects of humor and nurturance on intention. Several hypothesized mediators influenced by the appeals were not associated with intention. This is the first study to test the effect of persuasive emotional appeals used in SSB-related PSAs. The perceived strength of the PSAs' arguments is important to consider in the communication of messages designed to reduce SSB consumption. PMID- 26054657 TI - Sarcopenia evaluated by fat-free mass index in patients with chronic heart failure. PMID- 26054658 TI - Surgical duration and risk of Urinary Tract Infection: An analysis of 1,452,369 patients using the National Surgical Quality Improvement Program (NSQIP). AB - INTRODUCTION: While the relationship between surgical duration and post-operative morbidity has been well-studied in specific procedures for specific complications, there is a paucity of literature that addresses whether longer surgeries increase the risk of Urinary Tract Infection (UTI). We have performed the first study to elucidate the relationship between increasing surgical duration and UTI events across surgical specialties via the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. METHODS: Patients, who received general anesthesia, were stratified into quintiles by a calculated z-score for their anesthesia time based on the standard deviation and mean of their respective current procedural terminology (CPT) code. Z-score analysis standardized interprocedural differences in anesthesia time. Multivariate regression analysis was employed to evaluate the independent association of anesthesia time with risk of UTI. Multiple sub-analyses were performed to evaluate the robustness of our results. RESULTS: 22,305 patients (1.5%) experienced a UTI. Compared to the mean procedural duration as represented by the 3rd quintile, procedures of longer duration were independently associated with increased risk of UTI (OR, 1.156 (95% CI 1.104-1.21); OR, 1.758 (95% CI 1.682-1.838)) while procedures of shorter duration were associated with reduced risk (OR, .928 (95% CI .873-.987); OR, .955 (95% CI .906-1.007)). CONCLUSIONS: Our findings suggest that increasing surgical duration may independently worsen the risk of post-operative UTI pan-surgically. We hope that our results will help guide decision making regarding the safety of combination procedures as well as improve pre-operative risk stratification. PMID- 26054659 TI - National trends and complication rates after bilateral mastectomy and immediate breast reconstruction from 2005 to 2012. AB - BACKGROUND: This study's purpose was to examine the national rate of breast cancer patients undergoing bilateral mastectomy (BM) and immediate breast reconstruction (IBR) and their associated complication rates. METHODS: Using the National Surgical Quality Improvement Program database, breast cancer patients undergoing mastectomy between 2005 and 2012 were identified. Rates in BM and IBR as well as associated complication rates were evaluated. Logistic regression was used to identify predictors of BM, IBR, and complications. RESULTS: A total of 56,905 breast cancer patients underwent mastectomy. The rate of BM tripled (9.14% vs 25.44%, P < .0001) and the rate of IBR increased by 50% (29.73% vs 44.68%, P < .0001). Complication rates were higher in patients undergoing BM compared with unilateral mastectomy (11.49% vs 9.52%, P < .0001) and in patients undergoing IBR compared with mastectomy alone (11.62% vs 8.91%, P < .0001). White race and age less than 40 years were predictors of patients undergoing BM and IBR. CONCLUSIONS: The rates of BM and associated IBR have increased significantly since 2005 despite higher complication rates. Further research is needed to understand the reasons for these trends. PMID- 26054660 TI - Virtual operating room for team training in surgery. AB - BACKGROUND: We proposed to develop a novel virtual reality (VR) team training system. The objective of this study was to determine the feasibility of creating a VR operating room to simulate a surgical crisis scenario and evaluate the simulator for construct and face validity. METHODS: We modified ICE STORM (Integrated Clinical Environment; Systems, Training, Operations, Research, Methods), a VR-based system capable of modeling a variety of health care personnel and environments. ICE STORM was used to simulate a standardized surgical crisis scenario, whereby participants needed to correct 4 elements responsible for loss of laparoscopic visualization. The construct and face validity of the environment were measured. RESULTS: Thirty-three participants completed the VR simulation. Attendings completed the simulation in less time than trainees (271 vs 201 seconds, P = .032). Participants felt the training environment was realistic and had a favorable impression of the simulation. All participants felt the workload of the simulation was low. CONCLUSIONS: Creation of a VR-based operating room for team training in surgery is feasible and can afford a realistic team training environment. PMID- 26054661 TI - Characterization of fish gelatin-gum arabic complex coacervates as influenced by phase separation temperature. AB - The rheological and structural characteristics of fish gelatin (FG)-gum arabic (GA) complex coacervate phase, separated from an aqueous mixture of 1% FG and 1% GA at pH 3.5, were investigated as influenced by phase separation temperature. Decreasing the phase separation temperature from 40 to 10 degrees C lead to: (1) the formation of a coacervate phase with a larger volume fraction and higher biopolymer concentrations, which is more viscous, more structural resistant at low shear rates, more shear-thinning at high shear rates, and more condensed in microstructure, (2) a solid-like elastic behavior of the phase separated at 10 degrees C at a high oscillatory frequency, (3) the increase in gelling and melting temperatures of the coacervate phase (3.7-3.9 degrees C and 6.2-6.9 degrees C, respectively), (4) the formation of a more rigid and thermo-stable coacervate gel. The coacervate phase is regarded as a homogeneously networked biopolymer matrix dispersed with water vacuoles and its gel as a weak physical gel reinforced by FG-GA attractive electrostatic interactions. PMID- 26054662 TI - Depolymerization of polysaccharides from Opuntia ficus indica: Antioxidant and antiglycated activities. AB - The extraction, purification and degradation of polysaccharides from Opuntia ficus indica cladodes, as well as the evaluation of their antioxidant and antiglycated activities in vitro were investigated. The optimization of the extraction showed that extraction by ultrasound at 40 degrees C presented the best carbohydrates yield. The degradation of the extracted polysaccharides was achieved by free radical depolymerization with H2O2 in the presence of copper(II) acetate for various reaction times. Sugar contents were determined by colorimetric assays. The macromolecular characteristics of the different isolated and degraded carbohydrates were carried by size exclusion chromatography (SEC/MALS/VD/DRI). These experiments showed that all samples are polysaccharides, which are probably pectins and that molecular weight (Mw) has decreased from 6,800,000 to 14,000 g/mol after 3 h of depolymerization without changing the structure. Preliminary antioxidant and antiglycated tests indicated that degraded polysaccharides for 2 and 3 h showed even better antioxidant and antiglycated activities. PMID- 26054663 TI - A semi-rational approach to obtain an ionic liquid tolerant bacterial laccase through pi-type interactions. AB - Laccases are particularly promising enzymes for biotechnology and bioremediation purposes. They are among the most effective enzymes capable of catalyzing the degradation of phenolic compounds with poor water solubility. The technological utility of lacasses can be enhanced greatly by their use in ionic liquids rather than in conventional organic solvents or in their natural aqueous reaction media. In the current study, a laccase from Bacillus HR03 has been engineered through a semi rational method. By screening a library of 450 clones, Glu188Tyr and Glu188Phe showed a distinct improvement in thermal stability and ionic liquid tolerance. In comparison with the wild type, selected mutants exhibited higher kcat/Km against ABTS in the imidazolium based ionic liquids, (1-ethyl-3-methyl imidazolium chloride [EMIm][Cl], butyl-3-methyl imidazolium chloride [BMIm][Cl] and hexyl-3-methyl imidazolium chloride [HMIm][Cl]). Glu188Tyr had a catalytic efficiency, two times greater when compared to the wild type in [HMIm][Cl]. Far UV circular dichroism (CD) exhibited no significant changes in the secondary structure of the mutants and wild type. Glu188Tyr revealed a more compact structure using Near-UV CD and fluorescence spectroscopy that could account for its high thermal stability. According to bioinformatic analysis, pi-pi and anion pi interactions played the dominant role in stabilizing both variants. PMID- 26054664 TI - Bacteriocinogenic potential of a probiotic strain Bacillus coagulans [BDU3] from Ngari. AB - Bacteriocin producing strain BDU3 was isolated from a traditional fermented fish of Manipur Ngari. The strain BDU3 was identified as Bacillus coagulans by phenotypic and genotypic characterization. The BDU3 produced novel bacteriocin, which showed an antimicrobial spectrum toward a wide spectrum of food borne, and closely related pathogens with a MIC that ranged between 0.5 and 2.5 MUg/mL. The isolate was able to tolerate pH as low as 2.0 and up to 0.2% bile salt concentration. Three step purification was employed to increase the specific activity of the antimicrobial compound. The fractions were further chromatographed by Rp-HPLC C-18 column and the purified bacteriocin had a specific activity of ~8500 AU/mg. However, the potency of bacteriocin was susceptible to digestion with Proteinase K, Pepsin, SDS, EDTA and Urea. Molecular mass of purified bacteriocin was found to be 1.4 kDa using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF). The functional group was revealed by FTIR analysis. The cytotoxicity assay (MTT) using purified bacteriocin showed 2 times lower EC50 values compared to SDS. This is the smaller bacteriocin ever reported before from B. coagulans with greater antimicrobial potency with lower cytotoxicity. This bacteriocin raises the possibilities to be used as a biopreservative in food industries. PMID- 26054665 TI - Targeting protein kinase and DNA molecules by diimine-phthalate complexes in antiproliferative activity. AB - The serendipitous discovery of the anticancer drug cisplatin cemented medicinal inorganic chemistry as an independent discipline in 1960s. DNA and protein kinases are one of the major intracellular targets of many anticancer drugs. It is thus highly desirable to develop metal complexes, either by interacting with DNA or to target alternative cellular machinery such as protein kinases to provide a more effective means of monitoring disease progression. In this study we report the synthesis and characterization of few novel Cu(II) and Zn(II) Knoevenagel condensed metallointercalators incorporating phthalic acid. The intercalation behavior of the complexes with DNA is confirmed by spectral and analytical experiments. Due to the promising performance of DNA interaction efficacy of Cu(II) complexes 1-4, their in vitro and in vivo anticancer properties are explored on various cancerous cell lines which reveal that they exhibit substantial anticancer activity without affecting the normal cells. It is found that the complex 1 induces apoptosis in Hep G2 cells. Theoretically, DFT is used to optimize the Cu(II) complexes 1-4 to explore their quantum mechanical properties and to carry out affinity studies against cyclin dependant kinase 2 (CDK2) to understand atomic level interactions. Further, the complex-receptor stability is confirmed by molecular dynamics. PMID- 26054667 TI - The effect and mechanism of miR196a in HepG2 cell. AB - AIM: To explore the role of miR-196a on the regulatory mechanism in hepatocelluar carcinoma. METHODS: The antisense RNA of microRNA-196a was synthesized and cloned into the vector. HepG2 cells were infected by inhibiting miR196a vector. The HepG2 cells were divided into miR196a lower expression group, NC group and N group in vitro. The expression of the targets of miR-196a was detected by qPCR. Cell growth was analyzed by cck8 assay. The invasion was detected by transwell method. Apoptosis was detected by annexinV/PI. The P53, caspase-3, HOXB9, HOXB8 mRNA and their protein was detected by qPCR and Western-blot. RESULTS: (1) The expression level of miR-196a was less than normal (41%). (2) The proliferation of HepG2 was also markedly suppressed in inhibiting miR196a at the 24 h point than normal about 72.29+/-2.51% (P<0.01). (3) The number of cells that migrated through the chamber of miR196a inhibiting group is less than normal and NC (P<0.01). (4) The cell apoptosis in miR196a inhibiting group is more than NC and normal group (P<0.05). HOXB8 mRNA and protein expression, in HepG2 cell line miR196a inhibiting group is significantly less than normal, NC (P<0.05). Caspase 3 mRNA and protein expression is maximum in three groups (P<0.05). In three groups there was no significant difference in the expression of P53 mRNA and protein and HOXB9mRNA. CONCLUSIONS: Our results demonstrate that miR-196a can effect the proliferation, the apoptosis and migration of HepG2 cell lines by gene HOXB8, caspase-3 regulation. However, there is no correlation between miRNA196a and P53 and HOXB9. PMID- 26054666 TI - The DAF-7/TGF-beta signaling pathway regulates abundance of the Caenorhabditis elegans glutamate receptor GLR-1. AB - Transforming growth factor-beta (TGF-beta) family signaling pathways have roles in both neuronal development and the regulation of synaptic function. Here we identify a novel role for the Caenorhabditis elegans DAF-7/TGF-beta signaling pathway in the regulation of the AMPA-type glutamate receptor GLR-1. We found that the abundance of GLR-1 increases at synapses in the ventral nerve cord (VNC) of animals with loss-of-function mutations in multiple DAF-7/TGF-beta pathway components including the TGF-beta ligand DAF-7, the type I receptor DAF-1, and the Smads DAF-8 and DAF-14. The GLR-1 defect can be rescued by expression of daf 8 specifically in glr-1-expressing interneurons. The effect on GLR-1 was specific for the DAF-7 pathway because mutations in the DBL-1/TGF-beta family pathway did not increase GLR-1 levels in the VNC. Immunoblot analysis indicates that total levels of GLR-1 protein are increased in neurons of DAF-7/TGF-beta pathway mutants. The increased abundance of GLR-1 in the VNC of daf-7 pathway mutants is dependent on the transcriptional regulator DAF-3/Smad suggesting that DAF-3 dependent transcription controls GLR-1 levels. Furthermore, we found that glr-1 transcription is increased in daf-7 mutants based on a glr-1 transcriptional reporter. Together these results suggest that the DAF-7/TGF-beta signaling pathway functions in neurons and negatively regulates the abundance of GLR-1, in part, by controlling transcription of the receptor itself. Finally, DAF-7/TGF beta pathway mutants exhibit changes in spontaneous locomotion that are dependent on endogenous GLR-1 and consistent with increased glutamatergic signaling. These results reveal a novel mechanism by which TGF-beta signaling functions in the nervous system to regulate behavior. PMID- 26054668 TI - Clinical outcomes of chronic kidney disease patients treated with everolimus eluting stents (EES) and paclitaxel-eluting stents (PES). AB - BACKGROUND: The target lesion revascularization of paclitaxel-eluting stents (PES) has been reported to be lower than that of sirolimus-eluting stents in patients on hemodialysis (HD). However, the comparison of PES and second generation drug-eluting stents in CKD patients has not been fully investigated. We compared clinical outcomes of everolimus-eluting stents (EES) and PES in CKD patients. METHODS: Hundred and forty seven CKD patients (eGFR<60mLmin(-1)1.73m( 2)) treated with PES (n=74, from May 2007 to December 2009) and EES (n=73, from January 2010 to January 2013) were enrolled in the study. Major adverse cardiac events (MACEs) were defined as death, non-fatal myocardial infarction, and ischemia driven target lesion revascularization. RESULTS: The incidence of 36 month MACE was significantly lower in EES, non-HD group compared to PES, non HD group (0% in EES group and 13.5% in PES group, respectively, P<0.01). There was no significant difference in MACE between EES and PES in HD patients (5.4% in PES group and 5.5% in EES group, P=0.98). In multivariate analysis, PES group and PES ISR were independent factors for worse incidence of MACE. CONCLUSIONS: In CKD patients, PES was associated with worse clinical outcomes in non-HD patients as compared with EES. PMID- 26054669 TI - Short term exposure to ethyl pyruvate has long term anti-inflammatory effects on microglial cells. AB - Ethyl pyruvate (EP) has been increasingly appreciated as an anti-inflammatory and neuroprotective agent with potent pharmacological properties relevant for treatment of various CNS disorders. Microglial cells seem to be particularly sensitive to its effects. In this study, microglial cells were exposed to EP for relatively short periods (10-120min) and inflammatory properties of the cells were determined after 24h of cultivation. Application of EP in the short-term periods inhibited production of interleukin-6, tumor necrosis factor and nitric oxide in microglial cells. At the same time, the effects on cell viability, reactive oxygen species generation and expression of F4/80 and CD40 of microglial cells were minor. NFkappaB activation was not affected by EP in the cells during the short exposures, thus implying that the observed effect of EP on cytokine and nitric oxide generation was performed in NFkappaB independent way. Importantly, effects of the short term EP treatment on microglial cells were detected by a real time cell analysis, as well. The observed ability of EP to affect microglial cell function after relatively short time of exposure is relevant for its therapeutic potential against inflammatory disorders of the CNS. PMID- 26054670 TI - Trastuzumab-cisplatin conjugates for targeted delivery of cisplatin to HER2 overexpressing cancer cells. AB - Cisplatin is widely used for the treatment of numerous types of cancer, while its application is limited by the adverse side effects for its poor selectivity. Trastuzumab is a highly targeting protein to HER2 protein, and it is usually combined with paclitaxel or cisplatin for the treatment of HER2-overexpressing breast cancer. In the present work, we used trastuzumab as a targeting carrier for platinum drug delivery. In ELISA assays and immunofluorescence study, Tmab-1 exhibited high and specific binding affinity to HER2 protein and HER2 overexpressing SK-BR-3 cells. In cytotoxicity test, Tmab-1 showed promising antiproliferative activity to SK-BR-3 cells, while it hardly inhibited the growth of MCF-7 cells and MDA-MB-231 cells. The cell cycle arrest study showed Tmab-1 induced the cell cycle arrest mainly at G2/M phase. This work indicates that trastuzumab is an effective and potential targeting carrier for drug delivery. PMID- 26054671 TI - Atorvastatin delays the glucose clearance rate in hypercholesterolemic rabbits. AB - The administration of statin might increase the risk of new-onset diabetes in hypercholesterolemic patients based on the recent clinical evidence. However, the causal relationship must be clarified and confirmed in animal experiments. Therefore, we mimicked hypercholesterolemia by feeding rabbits a high-cholesterol diet (HCD) and performed 16 weeks of atorvastatin administration to investigate the effect of statin on glucose metabolism. The intravenous glucose tolerance test showed that plasma glucose levels in the statin-treated rabbits were consistently higher and that there was a slower rate of glucose clearance from the blood than in HCD rabbits. The incremental area under the curve for glucose in the statin-treated rabbits was also significantly larger than in the HCD rabbits. However, there was no significant difference between the two groups in the intravenous insulin tolerance test. The glucose-lowering ability of exogenous insulin was not impaired by statin treatment in hypercholesterolemic rabbits. The administration of a single dose of statin did not affect glucose metabolism in normal rabbits. The statin also significantly increased the levels of high density lipoprotein cholesterol, alanine aminotransferase and aspartate transaminase and decreased plasma levels of total cholesterol, triglycerides and low-density lipoprotein cholesterol in the hypercholesterolemic rabbits, whereas it did not affect plasma levels of glucose and insulin. The current results showed that atorvastatin treatment resulted in a significant delay of glucose clearance in hypercholesterolemic rabbits, and this rabbit model could be suitable for studying the effects of statin on glucose metabolism. PMID- 26054672 TI - Chemopreventive role of anthocyanins in atherosclerosis via activation of Nrf2 ARE as an indicator and modulator of redox. AB - Anthocyanins have been reported to induce the expression of enzymes involved in both cellular antioxidant defenses and attenuating inflammation-associated pathogenesis. Induction of such enzymes by edible anthocyanin largely accounts for their atherosclerosis chemo-protective activities. Nuclear factor erythroid 2 related factor 2 (Nrf2) plays an essential role in the coordinated induction of those genes encoding redox-responsive and cellular defense antioxidant enzyme termed antioxidant response element (ARE). Current studies have revealed that Nrf2-ARE signaling is involved in attenuating inflammation-associated pathogenesis such as atherosclerosis. Conversely, reduction in Nrf2 signaling leads to enhanced susceptibility to oxidative stress and inflammatory tissue injuries. The activation of Nrf2-ARE might inhibit the production of pro inflammatory mediator including cyclooxygenase-2, chemokines, cytokines, cell adhesion molecules, and induction nitric oxide synthase. This review highlights the gene expression induced by dietary anthocyanin via Nrf2 signaling on redox regulated transcription factor in atherosclerosis disorders. PMID- 26054673 TI - Lapatinib enhances the cytotoxic effects of doxorubicin in MCF-7 tumorspheres by inhibiting the drug efflux function of ABC transporters. AB - Increasing evidences indicate that cancer stem cells are resistant to chemotherapy due to their cell quiescence and the expression of ATP-binding cassette (ABC) transporters. In this study, we utilized tumorsphere cultures to seek better strategies to overcome chemoresistance since tumorsphere cultures have been used widely for the enrichment of cancer stem cells. We found that tumorspheres generated from MCF-7 human breast cancer cells exhibited high proportions of quiescent cells and expressed MDR-1 at elevated levels, leading to resistance to 5-fluorouracil, paclitaxel, and doxorubicin. Because the expression of EGFR/HER2 was increased in MCF-7 tumorspheres, we assessed the combinational effect of the dual ErbB1/ErbB2 inhibitor, lapatinib, with doxorubicin in tumorspheres. The results showed that inhibition of EGFR/HER2 signaling by lapatinib sensitized MCF-7 tumorspheres to doxorubicin by inhibiting the expression of the ABC transporters, MDR-1 and BCRP, and thus, enhancing the intracellular accumulation of doxorubicin. These findings suggest that combinations of lapatinib and cytotoxic anticancer drugs may offer an advantage for treating the drug-resistant cancers. PMID- 26054674 TI - Interferon-beta gene transfer induces a strong cytotoxic bystander effect on melanoma cells. AB - A local gene therapy scheme for the delivery of type I interferons could be an alternative for the treatment of melanoma. We evaluated the cytotoxic effects of interferon-beta (IFNbeta) gene lipofection on tumor cell lines derived from three human cutaneous and four canine mucosal melanomas. The cytotoxicity of human IFNbeta gene lipofection resulted higher or equivalent to that of the corresponding addition of the recombinant protein (rhIFNbeta) to human cells. IFNbeta gene lipofection was not cytotoxic for only one canine melanoma cell line. When cultured as monolayers, three human and three canine IFNbeta lipofected melanoma cell lines displayed a remarkable bystander effect. As spheroids, the same six cell lines were sensitive to IFNbeta gene transfer, two displaying a significant multicell resistance phenotype. The effects of conditioned IFNbeta-lipofected canine melanoma cell culture media suggested the release of at least one soluble thermolabile cytotoxic factor that could not be detected in human melanoma cells. By using a secretion signal-free truncated human IFNbeta, we showed that its intracellular expression was enough to induce cytotoxicity in two human melanoma cell lines. The lower cytoplasmatic levels of reactive oxygen species detected after intracellular IFNbeta expression could be related to the resistance displayed by one human melanoma cell line. As IFNbeta gene transfer was effective against most of the assayed melanomas in a way not limited by relatively low lipofection efficiencies, the clinical potential of this approach is strongly supported. PMID- 26054675 TI - MiR-498 regulated FOXO3 expression and inhibited the proliferation of human ovarian cancer cells. AB - Ovarian cancer is one of the most common human malignancies and the fifth leading cause of cancer deaths in women. Thus, improved approaches for detection of ovarian cancer are urgently needed. Recently, microRNAs (miRNAs) have been suggested to be closely associated with ovarian cancer tumorigenesis. In the current study, our study showed that expression of miR-498 was markedly downregulated in ovarian cancer cells and ovarian cancer tissues compared with human ovary surface epithelial cells (HOSE) and the matched tumor adjacent normal tissues (ANT). Ectopic expression of miR-498 suppressed cell proliferation of ovarian cancer cells, while i miR-498-in showed the opposite effect. Furthermore, upregulation of miR-498 in ovarian cancer cells resulted in blocking of their entry into the S transitional phase, which was caused by downregulation of the CDK regulator cyclin D1 and upregulation of cyclin-dependent kinase inhibitor p27. Additionally, we identified FOXO3 as a direct target of miR-498. Moreover, we demonstrated that miR-498 upregulated FOXO3 expression by directly targeting the FOXO3 3'-untranslated region. Thus, our findings suggested that miR-498 acted as a new tumor suppressor by targeting the FOXO3 gene and inhibiting cell proliferation of ovarian cancer. PMID- 26054676 TI - Involvement of miR-485-5p in hepatocellular carcinoma progression targeting EMMPRIN. AB - EMMPRIN plays important roles in cancer development, which includes EMMPRIN 1, 2, 3, and 4 isoforms. EMMPRIN2 is the main component in human cancers, but its regulation by miRNAs is still unclear. In this study, we will investigate the mechanism of EMMPRIN regulation in hepatocellular carcinoma (HCC) by miRNAs. Through RT-PCR, we found that EMMPRIN2 was the main isoform in HCC cells. EMMPRIN2 was down-regulated significantly by predicted miRNAs and miR-485-5p was one of the miRNA that regulated EMMPRIN in HCC cell lines. It was verified that EMMPRIN was a target gene of miR-485-5p by using luciferase analysis assay. We found that miR-485-5p was significantly downregulated in HCC tissues and that its expression was inversely correlated with the TNM stage and metastasis in HCC samples. Results of cellular functions in HCC showed that miR-485-5p could inhibit cell proliferation and metastasis. Additionally, miR-485-5p overexpression suppressed HCC growth in vivo by down-regulation of EMMPRIN. Our study for the first time demonstrated that miR-485-5p represses HCC invasive and metastatic capacities by targeting EMMPRIN expression. PMID- 26054677 TI - MicroRNA-126 inhibits cell proliferation in gastric cancer by targeting LAT-1. AB - MicroRNA-126 (miR-126) is a pivotal post-transcriptional regulator, which has been validated as a suppressor in gastric cancer (GC). However, the downstream of its tumor inhibiting function has not been totally clear. L-type amino-acid transporter 1 (LAT-1) is a novel member of system L-type transporters involving in cell proliferation, and we have previously validated that LAT-1 played a role of promotor in GC. In this study, we further detected and confirmed that LAT-1 was exactly targeted by miR-126 in GC. We found LAT-1 was significantly downregulated in GC MKN-45 cell lines by using miR-126 mimics, along with an impairment on cell proliferation and cell cycle. Additionally, by overexpressing LAT-1 in MKN-45 cells which was firstly treated with miR-126 mimics, the ability of cell proliferation in MKN-45 cells was definitely rescued. Thus, our results suggests and consolidates the standpoint that miR-126 plays a pivotal role in GC suppressing the process of GC cell, and this function is at least partly taken to implement by miR-126s's post-transcriptional effect on LAT-1. This might provide us likely potential biomarkers and targets for GC prevention, diagnosis and therapeutic treatment. PMID- 26054678 TI - Using the comet and micronucleus assays for genotoxicity studies: A review. AB - Physical, chemical and biological agents can act in the DNA, resulting in mutation involved in cancer. Thus, genotoxic tests are required by regulatory agencies in order to evaluate potential risk of cancer. Among these tests, the comet assay (CA) and micronucleus assay (MNA) are the most commonly used. However, there are different protocols and recommendations already published. This is the first review, after the inclusion of CA in S2R1 guidance and OECD 489, which summarizes the main technical recommendations of both CA and MNA. PMID- 26054679 TI - Systematic gene microarray analysis of the lncRNA expression profiles in human uterine cervix carcinoma. AB - The human uterine cervix carcinoma is one of the most well-known malignancy reproductive system cancers, which threatens women health globally. However, the mechanisms of the oncogenesis and development process of cervix carcinoma are not yet fully understood. Long non-coding RNAs (lncRNAs) have been proved to play key roles in various biological processes, especially development of cancer. The function and mechanism of lncRNAs on cervix carcinoma is still rarely reported. We selected 3 cervix cancer and normal cervix tissues separately, then performed lncRNA microarray to detect the differentially expressed lncRNAs. Subsequently, we explored the potential function of these dysregulated lncRNAs through online bioinformatics databases. Finally, quantity real-time PCR was carried out to confirm the expression levels of these dysregulated lncRNAs in cervix cancer and normal tissues. We uncovered the profiles of differentially expressed lncRNAs between normal and cervix carcinoma tissues by using the microarray techniques, and found 1622 upregulated and 3026 downregulated lncRNAs (fold-change>2.0) in cervix carcinoma compared to the normal cervical tissue. Furthermore, we found HOXA11-AS might participate in cervix carcinogenesis by regulating HOXA11, which is involved in regulating biological processes of cervix cancer. This study afforded expression profiles of lncRNAs between cervix carcinoma tissue and normal cervical tissue, which could provide database for further research about the function and mechanism of key-lncRNAs in cervix carcinoma, and might be helpful to explore potential diagnosis factors and therapeutic targets for cervix carcinoma. PMID- 26054680 TI - The new esters derivatives of betulin and betulinic acid in epidermoid squamous carcinoma treatment - In vitro studies. AB - BACKGROUND: Betulinic acid and betulin are triterpenes with documented cytotoxic properties toward various cell lines. Unfortunately both betulinic acid and its metabolic precursor, betulin, are very poorly soluble in aqueous buffers, thus their bioavailability and bio-distribution are insufficient in terms of medical applications. OBJECTIVE: To investigate the specific anticancer role of the newly synthesized betulin derivatives in human epidermoid carcinoma cells. METHODS: In the present study we synthesized five amino acid esters of betulin. For the synthesis we selected alanine (Boc-l-Ala-OH, negative control) and four basic amino acids - natural lysine (Boc-l-Lys(Boc)-OH) and three its unnatural derivatives (Boc-l-Dap(Boc)-OH, Boc-l-Dab(Boc)-OH, and Boc-l-Orn(Boc)-OH). Boc protected amino acids were most convenient for the synthesis. All new esters have one (betulin-l-Ala-NH2) or two free amino groups which significantly increase their solubility in water and facilitate their transport through the cell membrane. It is worth noting that the biological activity of new esters of betulin is positive correlated with the length of the side chain of l-amino acid. The highest biological activity displayed compound containing lysine side chain (Lys, -CH2-CH2-CH2-CH2-NH2). Considering the biological activity, other derivatives can be set in the following series: Orn (-CH2-CH2-CH2-NH2)>Dab (-CH2 CH2-NH2)>Dap (-CH2-NH2)>Ala (CH3)>betulin. New betulin esters were tested in normal human keratinocytes (HaCaT) and human epidermoid carcinoma cells (A431). To assess cytotoxicity, MTT test was performed after 24, 48 and 72h of incubation with the test compounds at a concentration range of 0.75-100MUM. In case of apoptotic activity, a TUNEL method and comet assay were performed. Additionally expression of caspase-3 and PARP1 was evaluated immunocytochemically. RESULTS: The highest cytotoxicity in cells induced skin cancer new compounds, particularly compound containing a lysine side chain (IC50=7MUM) and ornithine (IC50=10MUM). The highest number of apoptotic cells was observed in case incubation with compound containing Orn, Dab and Dap side chain. CONCLUSIONS: The new betulin ester derivatives display enhanced antitumor activity compared to their non modified precursors. It is worth emphasizing their specific toxicity against epidermoid carcinoma cells. PMID- 26054681 TI - Association of seven thrombotic pathway gene CpG-SNPs with coronary heart disease. AB - OBJECTIVES: Coronary heart disease (CHD) has been considered a thromboembolic arterial diseases. The aim of this case-control study was to explore whether the CpG-SNPs of the thrombotic pathway genes contributed to the risk of CHD. METHODS AND MATERIALS: A total of 784 CHD patients and 738 healthy controls were recruited in the current association study, which evaluated 7 CpG-SNPs of the thrombotic pathway genes. The CpG-SNPs included THBS4 rs17878919, CYP2C19 rs12773342, P2RY12 rs1491974, ITGA2 rs26680, FGB rs2227389, F7 rs510317 and F5 rs2269648. SNP genotyping was performed with a Sequenom Mass Spectrometry Genetic Analyzer. RESULTS: Our results demonstrated that CYP2C19 rs12773342 polymorphism was significantly associated with CHD in the recessive model (chi(2)=5.41, df=1, P=0.020, OR=1.455, 95% CI=1.060-1.996). A breakdown analysis by age showed that the association of CYP2C19 rs12773342 with CHD was mainly found in individuals aged 55-65 (genotype: chi(2)=7.93, df=2, P=0.019; allele: chi(2)=4.45, df=1, P=0.035). In addition, we also observed a significant association between F7 rs510317 polymorphism and CHD in males (genotype: chi(2)=7.24, df=2, P=0.027). There was no significant association with CHD for the remaining CpG-SNPs. CONCLUSION: Our results supported that the CYP2C19 rs12773342 and F7 rs510317 polymorphisms were associated with CHD in the Han Chinese population. PMID- 26054682 TI - FOXP1 and SPINK1 reflect the risk of cirrhosis progression to HCC with HBV infection. AB - BACKGROUND: Hepatocellular carcinoma (HCC) deriving from cirrhosis with HBV infection harbors higher morbidity and poor prognosis. The diagnosis of HCC at its early stage is essential for improving the effect of treatment and survival rate of patients. METHOD: Affymetrix GeneChip was practiced to establish gene expression profile and significance analysis of microarray (SAM) as well as prediction analysis of microarray (PAM) was utilized to screen candidate marker genes in tissue of carcinoma and para-cancerous with cirrhosis from 15 hepatitis B virus (HBV) related HCC patients. RESULT: Total 497 differential genes were selected by microarray (fold change >2; P value<0.01). Then 162 significant genes were determined by SAM (fold change -1.46 to 1.28). A number of 8-genes showing "poor risk signature" was validated with threshold of 6.2, which was associated with cirrhosis progressing to HCC. Only 3 down-regulated and 2 up-regulated predictor genes had statistical difference in HCC and cirrhosis groups by RT-PCR (P value<0.01). Forkhead box protein 1 (FOXP1) and serine protease inhibitor Kazal-type 1 (SPINK1) proteins were found significantly increased in carcinoma tissues than para-cancerous cirrhotic tissues by IH and WB. CONCLUSION: Over expression of FOXP1 and SPINK1 may participate in the carcinogenesis of HBV related cirrhosis. They could use as potential biomarkers for diagnosing early HCC. PMID- 26054683 TI - Increased expression of LncRNA BANCR is associated with clinical progression and poor prognosis in gastric cancer. AB - Long non-coding RNAs (lncRNAs), emerging non-coding RNAs, have been proved to serve as a critical role in the proliferation, metastasis apoptosis of gastric cancer. However little is known about the clinical significance of BRAF-activated non-coding RNA (BANCR) in gastric cancer. The aim of our study is to identify the clinical value of BANCR in gastric cancer patients. Expression of BANCR was analyzed in one hundred and eighty-four gastric cancer samples using Real-time PCR. In our results, the expression of BANCR was increased in gastric cancer tissues compared with paired adjacent normal tissues. Moreover, high expression of BANCR was positively associated with clinical stage, tumor depth, lymph node metastasis and distant metastasis in gastric cancer patients. In survival analysis, high expression of BANCR was an independent unfavorable prognostic factor in gastric cancer patients. In summary, overexpression of BANCR acts as an unfavorable prognostic biomarker in gastric cancer patients. PMID- 26054684 TI - Long non-coding RNA PANDAR correlates with poor prognosis and promotes tumorigenesis in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide. Long non-coding RNAs (lncRNAs) are new-found non-coding RNAs longer than 200 nucleotides, and have emerged as important players in tumorigenesis. However, the clinical significance and molecular mechanism of lncRNAs in HCC remain largely elusive. The aim of this study was to determine the expression pattern and clinical value of PANDAR, a novel lncRNA, in HCC. qRT-PCR was conducted in tissues and cell lines. Then, associations between PANDAR expression and clinicopathological features of HCC patients were further analyzed. Next, ROC curve was constructed to evaluate diagnostic values. Finally, effects of PANDAR on HCC cell phenotypes were verified. PANDAR was overexpressed in HCC tissues and cell lines. Moreover, its expression level was significantly correlated with liver cirrhosis, HBsAg, AFP, tumor nodule, vascular invasion and TNM stage. PANDAR overexpression was associated with poorer survival and shorter recurrence. Importantly, the area under the ROC curve of PANDAR was up to 0.9564. Furthermore, PANDAR knockdown significantly repressed cell proliferation, colony formation and cycle progression of HCC in vitro. PANDAR was a powerful tumor biomarker, which highlighted its potential clinical utility as a promising prognostic biomarker and therapeutic target. PMID- 26054685 TI - miR-892a regulated PPP2R2A expression and promoted cell proliferation of human colorectal cancer cells. AB - Colorectal cancer (CRC) is one of the most common malignancy cancers in the world. Aberrant microRNA expression is involved in human diseases including cancer. In the present study, we investigated the miR-892a's role in CRC cell proliferation. We found that miR-892a was frequently upregulated in human colorectal cancer tissues and cell lines compared with the matched tumor adjacent tissues and normal colonic cell line FHC. Overexpression of miR-892a promoted cell proliferation and colony formation of CRC. Bioinformatics analysis further revealed PPP2R2A was identified as a potential miR-892a. Overexpression of miR 892a-in SW480 cells reduced PPP2R2A protein expression. Subsequently, data from luciferase reporter assays showed that PPP2R2A 3'-untranslated region (3'-UTR) carried the directly binding site of miR-892a. Furthermore, siRNA-mediated silencing of PPP2R2A blocked the inhibitory effect of miR-892a-in on CRC cell growth. In sum, our data provided compelling evidence that overexpression of miR 892a may provide a selective growth promotion for CRC cells by direct suppression of PPP2R2A expression. PMID- 26054686 TI - Oridonin triggers apoptosis in colorectal carcinoma cells and suppression of microRNA-32 expression augments oridonin-mediated apoptotic effects. AB - Oridonin, a bioactive diterpenoid isolated from Rabdosia rubescens, has been found to exhibit various anti-tumor effects. In this work, to investigate its pharmacological effects on human colorectal carcinoma HCT-116 and LoVo cells, cell proliferation and apoptosis were respectively evaluated by 3-[4,5 dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assay, annexin V FITC, and propidium iodide (PI) staining. Western blotting was used to detect the expression levels of Bim, Bax, Bcl-2, cytosolic cytochrome c, procaspase-9, cleaved caspase-9, procaspase-3, and caspase-3 proteins. Caspase-Glo-9 and Caspase-Glo-3 assays were applied to determine caspase-9 and caspase-3 activity. MicroRNA-32 (miR-32) expression level was detected by real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The in vivo anti-tumor effects of oridonin were evaluated using cell lines HCT-116 and LoVo xenograft model. The results indicated that oridonin effectively inhibited cell proliferation and induced apoptosis in HCT-116 and LoVo cells in a concentration dependent manner. Oridonin treatment upregulated the expression levels of Bim, Bax, cytosolic cytochrome c, cleaved caspase-9 and cleaved caspase-3 proteins, downregulated the expression levels of Bcl-2, procaspase-9 and procaspase-3 proteins, and meanwhile obviously activated caspase-9 and caspase-3 in a dose dependent manner in HCT-116 and LoVo cells. The results of qRT-PCR demonstrated that oridonin treatment significantly decreased miR-32 expression, and furthermore, suppression of miR-32 expression by miR-32 inhibitors augmented oridonin-mediated inhibitory and apoptotic effects in HCT-116 and LoVo cells. In vivo results indicated that oridonin administration through intraperitoneal injection suppressed tumor growth in nude mice. Therefore, these findings suggest that oridonin maybe is a potential candidate for colorectal cancer treatment. PMID- 26054687 TI - Sirtuin-4 (SIRT4) is downregulated and associated with some clinicopathological features in gastric adenocarcinoma. AB - BACKGROUND: Several members of the SIRT family (SIRT1-7), which are a highly conserved family of NAD(+)-dependent enzymes, play an important role in tumor formation. Recently, several studies have suggested that SIRT4 can regulate glutamine metabolism yet have tumor suppressor function too. However, our understanding of SIRT4 expression and its association with the clinicopathological parameters remains poor. METHOD: We evaluated SIRT4 protein expression levels in gastric adenocarcinoma and corresponding normal gastric tissue by immunohistochemical staining on a tissue microarray that included 75 gastric adenocarcinoma patients. We also determined the association between SIRT4 expression levels and selected clinicopathological parameters in gastric adenocarcinoma. RESULTS: We found that the expression level of SIRT4 in gastric adenocarcinoma was significantly lower than the corresponding normal tissue levels (P=0.003). Besides, lower SIRT4 levels were observed in pathological grade (P=0.002), depth of tumor invasion (P=0.034), positive lymph node numbers (P=0.005) and UICC stage (P=0.002). CONCLUSIONS: Our results support the notion that SIRT4 behaves as a tumor suppressor at the human tissue protein level. In addition, our data indicate that SIRT4 might be closely involved in the process of gastric adenocarcinoma development and it might potentially serve as a diagnostic biomarker and therapeutic target in gastric adenocarcinoma. PMID- 26054688 TI - Prolonged adjuvant capecitabine chemotherapy improved survival of stage IIIA gastric cancer after D2 gastrectomy. AB - GOALS: This study aims to investigate the safety and efficacy of prolonged adjuvant capecitabine chemotherapy on survival of gastric cancer after D2 gastrectomy. BACKGROUND: Inadequate evidence is available on optimal duration of chemotherapy and the number of administered cycles is generally based on patient responsiveness and individual tolerability as well as physician preferences. STUDY: We randomly assigned 307 gastric cancer patients after D2 gastrectomy between January 2006 and December 2010 to XELOX group and Prolonged group. XELOX consisted of a 2-h intravenous infusion of oxaliplatin 130mg/mg on day 1 and oral capecitabine 1000mg/m(2) twice daily on days 1-14 of a 3-week cycle for eight cycles in half a year. In Prolonged group, patients underwent extra oral capecitabine 1000mg/m(2) twice daily on days 1-14 of a 3-week cycle for eight cycles after eight cycles of XELOX. The disease-free survival and overall survival were compared. RESULTS: Significant differences were found in 3-year disease-free survival (Prolonged group 56.6%, XELOX group 48.4%, P=0.0357). Subgroup analysis by TNM staging showed that patients with stage IIIA gastric cancer in the Prolonged group had significantly higher DFS (50.00% vs 40.96, P=0.0178) and OS (71.95% vs 57.83, P=0.0230) than that of patients in the XELOX group. No grade 4 adverse effects or treatment-related deaths were reported. More patients in the Prolonged group experienced hand-foot syndrome than in the XELOX group. CONCLUSIONS: Prolonged capecitabine chemotherapy prevents improves the prognosis of patients with stage IIIA gastric cancer after D2 gastrectomy. PMID- 26054689 TI - Self-assembled betulinic acid protects doxorubicin induced apoptosis followed by reduction of ROS-TNF-alpha-caspase-3 activity. AB - Doxorubicin (DOX) is a well-known drug used to treat a wide range of solid tumor and hematological malignancies, but the use of this drug is now restricted owing to its severe side effects, including normal cellular toxicity. This study was conducted to evaluate the potency of self-assembled betulinic acid (SA-BA) against DOX induced chemotherapeutic toxicity in human peripheral blood lymphocytes (PBLs). The isolated betulinic acid from the bark of Ziziphus jujuba tree was purified by column chromatography and characterized by FT-IR, XRD, (1)H NMR and self-assembly property was investigated by SEM imaging. DOX treatment produced significant reduction of viability of PBLs mainly by lowering cellular anti-oxidant pool and elevating the reactive oxygen species level. Pre-treatment with SA-BA followed by DOX exposure for 24h protected the PBLs from DOX induced oxidative stress. Potent anti-apoptotic role of SA-BA was also confirmed by FACS analysis and western blot assay. Severe inflammation is one of the major concerns in DOX treatment. We found that pre-treatment with SA-BA on PBLs significantly protected the PBLs from DOX induced inflammation. Thus, our finding confirms that SA-BA can be used to ameliorate the cytotoxic effects of DOX, which can be a helpful strategy during DOX mediated chemotherapy in cancer patients. PMID- 26054690 TI - miR-217 targeting Wnt5a in osteosarcoma functions as a potential tumor suppressor. AB - Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults, however roles of microRNAs (miRNAs) in OS is still unclear. miR-217 is recently widely studied in various cancers, but not including OS. This study is aimed to investigate the expression and cellular function of miR-217 in OS. The data showed that miR-217 expression was consistently lower in OS tissues and cell lines than the normal controls. Restoration of miR-217 expression in MG-63 and U2OS cells could inhibit cell proliferation, migration and invasion, and induced apoptosis. Bioinformatic prediction suggested that Wnt5a is a target gene of miR 217. Using luciferase assay, mRNA and protein expression analysis, it was verified that Wnt5a was a target gene of miR-217 in OS cells. Restored expression of Wnt5a weakened miR-217-mediated suppression of tumor progression. Taken together, our data indicate that miR-217 functions as a tumor suppressor in OS by suppressing Wnt5a expression. PMID- 26054691 TI - The STAT3-regulated long non-coding RNA Lethe promote the HCV replication. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) are a class of RNAs that do not code protein but play important roles in diverse biological processes. In recent years, with the application of high-throughput sequencing, a great deal of lncRNAs associated with virus infections have been discovered and intensively studied, but there are few studies about the relationship between lncRNAs and HCV replication. METHODS: We identify that several lncRNAs can be upregulated and downregulated by phosphorylated STAT3 by using human PCR array method. And among these lncRNAs, lnc-Lethe was involved in the HCV replication. Transfection of siRNA Lethe partially blocked the replication of HCV in Huh7 cells. RESULTS: In the present study, we have established that phosphorylated STAT3 can promote the HCV replication. Data also indicated that when transfected with siRNA Lethe, the expression levels of PKR, OAS and IRF1, which were all ISGs, were all up regulated. CONCLUSIONS: Based on our findings from Lethe knockdown, we have identified that Lethe, which was upregulated by activated STAT3, may promoting the replication of HCV through a negative regulatory mechanism of type I IFN response. PMID- 26054692 TI - Knockdown of ST6Gal-I inhibits the growth and invasion of osteosarcoma MG-63 cells. AB - The upregulation of alpha-2,6-sialyltranferase 1 (ST6Gal-I) has been observed in several malignant tumors, including colon, ovarian and liver cancers, where its expression correlates with the invasion and metastasis of these tumors. However, the roles and molecular mechanisms by which ST6Gal-I mediates the growth and invasion of osteosarcoma cells still remain poorly unknown. In this study, we investigated the expression of ST6Gal-I in osteosarcoma MG-63 and Saos-2 cells which have different metastatic potential, and found that ST6Gal-I was highly expressed in MG-63 cells compared to Saos-2 cells. Downregulation of ST6Gal-I by shRNA in MG-63 cells significantly inhibited their malignant behaviors, including in cell proliferation and soft agar colony formation, as well as migration and invasion properties. In addition, we found that ST6Gal-I knockdown inhibited the expression levels of N-cadherin, vimentin, a-SMA, MMP-2, MMP-9 and VEGF. Together, our results suggest a role for ST6Gal-I to promote the growth and invasion of osteosarcoma cells through modulation of EMT-related molecules, and might be a promising marker for the prognosis and therapy of osteosarcoma. PMID- 26054693 TI - Increased 17beta-hydroxysteroid dehydrogenase type 1 levels in primary cervical cancer. AB - Infections with oncogenic human papillomavirus (HPV) strains are recognized as the major risk factor for developing malignant lesions in the uterine cervix. However, several findings have demonstrated cooperation between HPV infection and 17beta-estradiol (E2) in cervical carcinogenesis. The 17beta-hydroxysteroid dehydrogenase type 1 (HSD17B1) is the enzyme involved in the transformation of estrone (E1) into E2. In this study, we identified the HSD17B1 transcript and protein in HeLa, SiHa, Ca Ski and C-33A cervical cancer cells. These cells were able to convert E1 to E2 in a time-dependent manner. Moreover, we identified the HSD17B1 transcript and protein in primary cancerous tissues (n=28) and in histologically unchanged tissues (n=25). We did not observe significant differences (P=0.33) between the HSD17B1 transcript levels in cancerous tissues and histologically unchanged tissues. However, we found an overrepresentation of the HSD17B1 protein in cancerous tissues compared with histologically unchanged tissues (P<0.001). This overrepresentation of the HSD17B1 protein in primary cervical cancerous tissues may be responsible for the local conversion of E1 to E2. PMID- 26054694 TI - Rational drug discovery design approaches for treating Parkinson's disease. AB - INTRODUCTION: Parkinson's disease (PD) is a severe progressive neurodegenerative disorder. As yet, no therapeutic agent can prevent the characteristic neuronal cell loss in PD brain. The introduction of levodopa to the clinic several decades ago has greatly mitigated the symptomatic burden in PD patients. But the discovery of neuroprotective and disease-modifying therapies has lagged behind, becoming one of the most desired prizes in the drug discovery arms race for neurodegenerative disorders, including PD. AREAS COVERED: In this review, the author provides an overview of the rational drug discovery approaches that are designed to prevent the onset or alter the course of the disease, and/or target its non-motor symptoms. EXPERT OPINION: Largely due to the intertwined etiology that is a hallmark of PD's pathology, neuroprotective drug discovery is challenging, while very limited targeting strategies exist for the non-motor symptoms that afflict sufferers of PD. Rational approaches toward PD neurotherapeutics should target previously identified or emerging pathological pathways that are discovered in the course of investigating the underlying mechanisms in PD disease progression. Each of these pathways contributes to events that ultimately lead to the complex disease burden seen in PD and can form the basis for rational and highly targeted drug development. PMID- 26054695 TI - Comparing the inhibitory thresholds of dairy manure co-digesters after prolonged acclimation periods: Part 1--Performance and operating limits. AB - Co-digestion has been used to improve biogas yields and the long-term stability of anaerobic digesters compared to mono-digestion; however, less is known about the ultimate inhibition from co-substrates at their maximum loading rates and mixing ratios because these limits cannot be practically tested by existing facilities. Here, we performed a controlled experiment with long operating periods to ensure sufficient acclimation with the goal to observe ultimate inhibition and the full benefit that can be gained from co-digestion. The three substrates: 1) food waste (FW); 2) alkaline hydrolysate (AH); and 3) crude glycerol (GY) were individually co-digested with dairy manure (MN) for more than 900 days using continuously stirred anaerobic reactors at mesophilic temperatures. Food waste caused no reduction in performance or stability when co digested with manure up to a total organic loading rate (OLR) of 3.9 g volatile solids (VS).L(-1).Day(-1) (MN:FW = 51:49; VS basis), resulting in a specific methane yield (SMY) of 297 +/- 3 mL CH4.g VS(-1) for the combined wastes. Alkaline hydrolysate was co-digested with manure up to a total OLR of 2.7 g VS.L( 1).Day(-1) (MN:AH = 75:25) with a corresponding SMY of 299 +/- 6 mL CH4.g VS(-1). However, the free ammonia concentration reached levels previously reported as inhibitory, and may have led to the observed accumulation of volatile fatty acids at higher loading rates. Crude glycerol co-digestion resulted in an optimum SMY of 549 +/- 25 mL CH4.g VS(-1) at a total OLR of 3.2 g VS.L(-1).Day(-1) (MN:GY = 62:38). Stable digestion beyond this level was prohibited by an accumulation of long-chain fatty acids and foaming. These results can be used to implement effective co-digestion strategies. Co-substrates that possess similar inhibiting characteristics should be monitored to prevent severe instability at high loading rates and mixing ratios. PMID- 26054696 TI - Simultaneous effect of initial moisture content and airflow rate on biodrying of sewage sludge. AB - The simultaneous effect of initial moisture content (initial Mc) and air-flow rate (AFR) on biodrying performance was evaluated. For the study, a 3(2) factorial design, whose factors were AFR (1, 2 and 3 L/min kg(TS)) and initial Mc (59, 68 and 78% w.b.), was used. Using energy and water mass balance the main routes of water removal, energy use and efficiencies were determined. The results show that initial Mc has a stronger effect on the biodrying than the AFR, affecting the air outlet temperature and improving the water removal, with higher maximum temperatures obtained around 68% and the lowest maximum matrix temperature obtained at initial Mc = 78%.Through the water mass balance it was found that the main mechanism for water removal was the aeration, with higher water removal at intermediate initial Mc (68%) and high AFR (3 L/min kg(TS)). The energy balance indicated that bioreaction is the main energy source for water evaporation, with higher energy produced at intermediate initial Mc (68%). Finally, it was found that low values of initial Mc (59%) improve biodrying efficiency. PMID- 26054698 TI - Ultrasonic cleaning: An historical perspective. AB - The development of ultrasonic cleaning dates from the middle of the 20th century and has become a method of choice for a range of surface cleaning operations. The reasons why this has happened and the methods of assessing the efficiency of ultrasonic cleaning baths are reviewed. PMID- 26054697 TI - Parenting Stress Related to Behavioral Problems and Disease Severity in Children with Problematic Severe Asthma. AB - Our study examined parenting stress and its association with behavioral problems and disease severity in children with problematic severe asthma. Research participants were 93 children (mean age 13.4 +/- 2.7 years) and their parents (86 mothers, 59 fathers). As compared to reference groups analyzed in previous research, scores on the Parenting Stress Index in mothers and fathers of the children with problematic severe asthma were low. Higher parenting stress was associated with higher levels of internalizing and externalizing behavioral problems in children (Child Behavior Checklist). Higher parenting stress in mothers was also associated with higher airway inflammation (FeNO). Thus, although parenting stress was suggested to be low in this group, higher parenting stress, especially in the mother, is associated with more airway inflammation and greater child behavioral problems. This indicates the importance of focusing care in this group on all possible sources of problems, i.e., disease exacerbations and behavioral problems in the child as well as parenting stress. PMID- 26054699 TI - Genetics and ethics in Latin America. PMID- 26054700 TI - Dorsoventral patterning by the Chordin-BMP pathway: a unified model from a pattern-formation perspective for Drosophila, vertebrates, sea urchins and Nematostella. AB - Conserved from Cnidarians to vertebrates, the dorsoventral (DV) axis is patterned by the Chordin-BMP pathway. However, the functions of the pathway's components are very different in different phyla. By modeling it is shown that many observations can be integrated by the assumption that BMP, acting as an inhibitory component in more ancestral systems, became a necessary and activating component for the generation of a secondary and antipodal-located signaling center. The different realizations seen in vertebrates, Drosophila, sea urchins and Nematostella allow reconstruction of a chain of modifications during evolution. BMP-signaling is proposed to be based on a pattern-forming reaction of the activator-depleted substrate type in which BMP-signaling acts via pSmad as the local self-enhancing component and the depletion of the highly mobile BMP Chordin complex as the long-ranging antagonistic component. Due to the rapid removal of the BMP/Chordin complex during BMP-signaling, an oriented transport and "shuttling" results, although only ordinary diffusion is involved. The system can be self-organizing, allowing organizer formation even from near homogeneous initial situations. Organizers may regenerate after removal. Although connected with some losses of self-regulation, for large embryos as in amphibians, the employment of maternal determinants is an efficient strategy to make sure that only a single organizer of each type is generated. The generation of dorsoventral positional information along a long-extended anteroposterior (AP) axis cannot be achieved directly by a single patch-like organizer. Nature found different solutions for this task. Corresponding models provide a rationale for the well known reversal in the dorsoventral patterning between vertebrates and insects. PMID- 26054701 TI - Doctor is charged with manslaughter over woman who died after abortion. PMID- 26054702 TI - High Oxygen Concentration Increases the Abundance and Activity of Bacterial Rather than Archaeal Nitrifiers in Rice Field Soil. AB - Oxygen is considered as a limiting factor for nitrification in rice paddy soil. However, little is known about how the nitrifying microbial community responds to different oxygen concentrations at community and transcript level. In this study, soil and roots were harvested from 50-day-old rice microcosms and were incubated for up to 45 days under two oxygen concentrations: 2 % O(2) and 20 % O(2) (ambient air). Nitrification rates were measured from the accumulation of nitrite plus nitrate. The population dynamics of bacterial (AOB) and archaeal (AOA) ammonia oxidizers was determined from the abundance (using quantitative PCR (qPCR)) and composition (using terminal restriction fragment length polymorphism and cloning/sequencing) of their amoA genes, that of nitrite oxidizers (NOB) by quantifying the nxrA gene of Nitrobacter spp. and the 16S rRNA gene of Nitrospira spp. The activity of the nitrifiers was determined by quantifying the copy numbers of amoA and nxrA transcripts (using RT-qPCR). Different oxygen concentrations did not affect the community compositions of AOB, AOA, and NOB, which however were different between surface soil, bottom soil, and rice roots. However, nitrification rates were higher under ambient air than 2 % O(2), and abundance and transcript activities of AOB, but not of AOA, were also higher. Abundance and transcript copy numbers of Nitrobacter were also higher at ambient air. These results indicate that AOB and NOB, but not AOA, were sensitive to oxygen availability. PMID- 26054703 TI - High-Throughput Sequencing Reveals Drastic Changes in Fungal Communities in the Phyllosphere of Norway Spruce (Picea abies) Following Invasion of the Spruce Bud Scale (Physokermes piceae). AB - The aim of this study was to assess the diversity and composition of fungal communities in damaged and undamaged shoots of Norway spruce (Picea abies) following recent invasion of the spruce bud scale (Physokermes piceae) in Lithuania. Sampling was done in July 2013 and included 50 random lateral shoots from ten random trees in each of five visually undamaged and five damaged 40-50 year-old pure stands of P. abies. DNA was isolated from 500 individual shoots, subjected to amplification of the internal transcribed spacer of fungal ribosomal DNA (ITS rDNA), barcoded and sequenced. Clustering of 149,426 high-quality sequences resulted in 1193 non-singleton contigs of which 1039 (87.1 %) were fungal. In total, there were 893 fungal taxa in damaged shoots and 608 taxa in undamaged shoots (p < 0.0001). Furthermore, 431 (41.5 %) fungal taxa were exclusively in damaged shoots, 146 (14.0 %) were exclusively in undamaged shoots, and 462 (44.5 %) were common to both types of samples. Correspondence analysis showed that study sites representing damaged and undamaged shoots were separated from each other, indicating that in these fungal communities, these were largely different and, therefore, heavily affected by P. piceae. In conclusion, the results demonstrated that invasive alien tree pests may have a profound effect on fungal mycobiota associated with the phyllosphere of P. abies, and therefore, in addition to their direct negative effect owing physical damage of the tissue, they may also indirectly determine health, sustainability and, ultimately, distribution of the forest tree species. PMID- 26054704 TI - AAPL Practice Guideline for the Forensic Assessment. PMID- 26054705 TI - Digital histology quantification of intra-hepatic fat in patients undergoing liver resection. AB - BACKGROUND: High intra-hepatic fat (IHF) content is associated with insulin resistance, visceral adiposity, and increased morbidity and mortality following liver resection. However, in clinical practice, IHF is assessed indirectly by pre operative imaging [for example, chemical-shift magnetic resonance (CS-MR)]. We used the opportunity in patients undergoing liver resection to quantify IHF by digital histology (D-IHF) and relate this to CT-derived anthropometrics, insulin related serum biomarkers, and IHF estimated by CS-MR. METHODS: A reproducible method for quantification of D-IHF using 7 histology slides (inter- and intra rater concordance: 0.97 and 0.98) was developed. In 35 patients undergoing resection for colorectal cancer metastases, we measured: CT-derived subcutaneous and visceral adipose tissue volumes, Homeostasis Model Assessment of Insulin Resistance (HOMA-IR), fasting serum adiponectin, leptin and fetuin-A. We estimated relative IHF using CS-MR and developed prediction models for IHF using a factor-clustered approach. RESULTS: The multivariate linear regression models showed that D-IHF was best predicted by HOMA-IR (Beta coefficient(per doubling): 2.410, 95% CI: 1.093, 5.313) and adiponectin (beta(per doubling): 0.197, 95% CI: 0.058, 0.667), but not by anthropometrics. MR-derived IHF correlated with D-IHF (rho: 0.626; p = 0.0001), but levels of agreement deviated in upper range values (CS-MR over-estimated IHF: regression versus zero, p = 0.009); this could be adjusted for by a correction factor (CF: 0.7816). CONCLUSIONS: Our findings show IHF is associated with measures of insulin resistance, but not measures of visceral adiposity. CS-MR over-estimated IHF in the upper range. Larger studies are indicated to test whether a correction of imaging-derived IHF estimates is valid. PMID- 26054706 TI - Axillary lymph node dissection versus sentinel lymph node biopsy alone for early breast cancer with sentinel node metastasis: A meta-analysis. AB - BACKGROUND: In early breast cancer patients with sentinel node metastasis, the effect of axillary lymph node dissection (ALND) is controversial. The purpose of this study is to compare the safety and efficacy of sentinel lymph node biopsy (SLNB) alone versus ALND in patients with early breast cancer and sentinel node metastasis. METHODS: We searched PubMed, Embase, Web of Science, and Cochrane Library databases from 1965 to February 2014. All data were analyzed using Review Manager Software 5.2. RESULTS: 12 studies, which included 130,575 patients from five randomized controlled trials and seven observational studies, met our inclusion criteria. 26,870 early breast cancer patients underwent SLNB alone and 103,705 underwent ALND. Patients underwent ALND had more paresthesia (risk ratio [RR] 0.26, 95% confidence interval [CI] 0.20-0.33; p < 0.01) and lymphedema (RR 0.28, 95% CI 0.20-0.41; p < 0.01) than those had SLNB alone. There were no significant differences in overall survival (hazard ratio [HR] 0.95, 95% CI 0.85 1.06; p = 0.35), disease-free survival (HR 1.00, 95% CI 0.98-1.02, p = 0.96), and locoregional recurrence (RR 0.92, 95% CI 0.59-1.44; p = 0.73). CONCLUSION: Current evidence indicates that axillary dissection may be omitted in early breast cancer patients with sentinel lymph metastasis. PMID- 26054707 TI - Myrtucommulone-A treatment decreases pluripotency- and multipotency-associated marker expression in bladder cancer cell line HTB-9. AB - Cancer and stem cells exhibit similar features, including self-renewal, differentiation and immortality. The expression of stem-cell-related genes in cancer cells is demonstrated to be potentially correlated with cancer cell behaviour, affecting both drug response and tumor recurrence. There is an emerging body of evidence that subpopulations of tumors carry a distinct molecular sign and are selectively resistant to chemotherapy. Therefore, it is important to find novel therapeutic agents that could suppress the stem-like features of cancer cells while inhibiting their proliferation. Myrtucommulone-A (MC-A) is an active compound of a nonprenylated acylphloroglucinol isolated from the leaves of myrtle. Here we have investigated the potential of MC-A in inhibiting the expression of self-renewal regulatory factors and cancer stem cell markers in a bladder cancer cell line HTB-9. We used RT-PCR, immunocytochemistry, flow cytometry and western blotting to examine the expression of pluripotency- and multipotency-associated markers with or without treatment with MC-A. Treatment with MC-A not only decreased cancer cell viability and proliferation but also resulted in a decrease in the expression of pluripotency- and multipotency-associated markers such as NANOG, OCT-4, SOX-2, SSEA-4, TRA-1-60, CD90, CD73 and CD44. MC-A treatment was also observed to decrease the sphere forming ability of HTB-9 cells. In summary, this study provides valuable information on the presence of stem-cell marker expression in HTB-9 cells and our results imply that MC-A could be utilized to target cancer cells with stem-like characteristics. PMID- 26054708 TI - Assessment of Military Cultural Competence: A Pilot Study. AB - OBJECTIVE: Cultural competence is widely considered a cornerstone of patient care. Efforts to improve military cultural competency have recently gained national attention. Assessment of cultural competence is a critical component to this effort, but no assessment of military cultural competence currently exists. METHODS: An assessment of military cultural competence (AMCC) was created through broad input and consensus. Careful review of previous cultural competency assessment designs and analysis techniques was considered. The AMCC was organized into three sections: skills, attitudes, and knowledge. In addition to gathering data to determine absolute responses from groups with different exposure levels to the military (direct, indirect, and none), paired questions were utilized to assess relative competencies between military culture and culture in general. RESULTS: Piloting of the AMCC revealed significant differences between military exposure groups. Specifically, those with personal military exposure were more likely to be in absolute agreement that the military is a culture, were more likely to screen for military culture, and had increased knowledge of military culture compared to those with no military exposure. Relative differences were more informative. For example, all groups were less likely to agree that their personal culture could be at odds with military culture as compared to other cultures. Such perceptions could hinder asking difficult questions and thus undermine care. CONCLUSION: The AMCC is a model for the measurement of the skills, attitudes, and knowledge related to military cultural competence. With further validity testing, the AMCC will be helpful in the critical task of measuring outcomes in ongoing efforts to improve military cultural competence. The novel approach of assessing variance appears to reduce bias and may also be helpful in the design of other cultural competency assessments. PMID- 26054709 TI - The Protective Effect of Bafilomycin A1 Against Cobalt Nanoparticle-Induced Cytotoxicity and Aseptic Inflammation in Macrophages In Vitro. AB - Co ions released due to corrosion of Co nanoparticles (CoNPs) in the lysosomes of macrophages may be a factor in the particle-induced cytotoxicity and aseptic inflammation accompanying metal-on-metal (MOM) hip prosthesis failure. Here, we show that CoNPs are easily dissolved under a low pH, simulating the acidic lysosomal environment. We then used bafilomycin A1 to change the pH inside the lysosome to inhibit intracellular corrosion of CoNPs and then investigated its protective effects against CoNP-induced cytotoxicity and aseptic inflammation on murine macrophage RAW264.7 cells. XTT {2,3-bis (2-methoxy-4-nitro-5-sulfophenyl) 5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide} assays revealed that bafilomycin A1 can significantly decrease CoNP-induced cytotoxicity in RAW264.7 cells. Enzyme-linked immunosorbent assays showed that bafilomycin A1 can significantly decrease the subtoxic concentration of CoNP-induced levels of pro inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6), but has no effect on anti-inflammatory cytokines (transforming growth factor-beta and interleukin-10) in RAW264.7 cells. We studied the protective mechanism of bafilomycin A1 against CoNP-induced effects in RAW264.7 cells by measuring glutathione/oxidized glutathione (GSH/GSSG), superoxide dismutase, catalase, and glutathione peroxidase levels and employed scanning electron microscopy, transmission electron microscopy, and energy dispersive spectrometer assays to observe the ultrastructural cellular changes. The changes associated with apoptosis were assessed by examining the pAKT and cleaved caspase 3 levels using Western blotting. These data strongly suggested that bafilomycin A1 can potentially suppress CoNP-induced cytotoxicity and aseptic inflammation by inhibiting intracellular corrosion of CoNPs and that the reduction in Co ions released from CoNPs may play an important role in downregulating oxidative stress in RAW264.7 cells. PMID- 26054710 TI - Association between leptin gene expression in subcutaneous adipose tissue and circulating leptin levels in obese patients with psoriasis. AB - Numerous reports have shown that psoriasis is associated with obesity and leptin. However, few reports are available on the association between serum leptin levels and leptin gene expression in SAT of psoriasis patients. To clarify this point, we examined serum leptin levels and expression levels of leptin messenger RNA (mRNA) in subcutaneous adipose tissue (SAT) of psoriasis patients. 17 psoriasis vulgaris patients and 6 non-obese control patients who underwent skin surgery were enrolled in this study. We measured serum leptin levels. SAT samples in psoriasis patients were taken from beneath the lesional psoriatic skin at the time of skin biopsy. Leptin mRNA expression in SAT was measured using quantitative real-time reverse transcription polymerase chain reaction (real-time RT-PCR) amplification. Leptin mRNA expression showed a positive correlation with serum leptin levels and BMI. We classified psoriasis patients into two groups according to BMI: the group of non-obese psoriasis patients (BMI < 25, n = 7), and the group of obese psoriasis patients (BMI >= 25, n = 10). PASI score, serum leptin levels and Leptin mRNA expression in SAT were significantly higher in the obese psoriasis patients than in the non-obese psoriasis patients. Leptin mRNA expression in SAT was correlated with circulating levels of leptin, the severity of psoriasis, and obesity in psoriasis patients. Serum leptin levels and leptin mRNA expression levels in SAT of non-obese psoriasis patients were not significantly different from those of non-obese controls. The altered secretion of leptin by SAT may be related to the severity of psoriasis. PMID- 26054711 TI - Pharmacokinetics of rituximab in a pediatric patient with therapy-resistant nephrotic syndrome. AB - BACKGROUND: Rituximab (RTX) has recently been introduced as a second-line therapy for nephrotic syndrome in children. Studies show that RTX given during the nephrotic state may be less effective than treatment during a non-nephrotic state, possibly due to loss of RTX in the urine. CASE-DIAGNOSIS/TREATMENT: We describe a 10-year-old boy with steroid-resistant nephrotic syndrome (SRNS) treated with RTX during a phase of active non-selective proteinuria. The serum half-life of RTX in this patient was less than 1 day compared to 20 days in patients without protein losses. Urinary clearance was at least 25 %, compared to approximately 0 % in control patients. However, RTX loss in the urine, as well as in pleural effusion and ascites, only partly explains the rapid drop in the serum RTX concentration of this patient. CONCLUSIONS: Serum half-life of RTX can be extremely short, partly due to excessive urinary losses in therapy-resistant nephrotic syndrome with non-selective proteinuria, as seen in our patient. These findings may help to explain the poor results of RTX treatment in patients with active proteinuria. PMID- 26054712 TI - Urinary excretion of polyols and sugars in children with chronic kidney disease. AB - BACKGROUND: The urinary concentrations of monosaccharides and polyols are used for diagnosing inborn errors of metabolism and renal tubular disorders. Reference values are age-related and depend on the method of detection. However, the influence of the renal function is often still neglected. In this study we examined the urinary excretion of monosaccharides and polyols in children with various degrees of chronic kidney disease (CKD), but with no known metabolic or renal tubular disorders. CASE DIAGNOSIS/TREATMENT: In 25 patients with CKD stage 1-5, urinary concentrations of 18 monosaccharides and polyols were measured by gas chromatography-mass spectrometry (GC-MS) in random urinary samples and were compared with age-related reference values. Serum creatinine was measured at the time of the urine sample, and the height-independent estimated glomerular filtration rate (eGFR-Pottel) was calculated. Urinary excretions of monosaccharides and polyols were above the reference values in 8-88% of all patients. A significant difference between CKD stage 1-2 compared with CKD stage 3-5 was found for allose, arabitol and sorbitol (p < 0.05) and for arabinose, fucose, myoinositol, ribitol, xylitol, and xylose (p < 0.01). CONCLUSIONS: We show that the excretion of polyols and sugars depends on eGFR, which warrants a cautious interpretation of the results in patients with CKD. PMID- 26054713 TI - Pleuro-peritoneal or pericardio-peritoneal leak in children on chronic peritoneal dialysis-A survey from the European Paediatric Dialysis Working Group. AB - BACKGROUND: Pleural or pericardial effusions secondary to pleuro-peritoneal fistula (PPF) and pericardio-peritoneal fistula (PcPF) are rare but serious complications of peritoneal dialysis (PD). METHODS: We conducted a 10-year survey across all participating centres in the European Paediatric Dialysis Working Group to review the incidence, diagnostic techniques, therapeutic options and outcome of children on chronic PD with PPF and/or PcPF. RESULTS: Of 1506 children on PD there were ten cases (8 of PPF, 1 each of PcPF and PPF + PcPF), with a prevalence of 0.66%. The median age at presentation was 1.5 [inter-quartile range (IQR) 0.4-2.4] years, and nine children were <3 years. The time on PD before onset of symptoms was 4.3 (IQR 1.3-19.8) months. Eight children had herniae and seven had abdominal surgery in the preceding 4 weeks. Symptoms at presentation were respiratory distress, reduced ultrafiltration and tachycardia. PD was stopped in all children; three were managed conservatively and thoracocentesis was performed in seven (with pleurodesis in 3). PD was restarted in only three children, in two of them with success. CONCLUSION: In conclusion, PPF and PcPF are rare in children on chronic PD, but are associated with significant morbidity, requiring a change of dialysis modality in all cases. Risk factors for PPF development include age of <3 years, herniae and recent abdominal surgery. PMID- 26054714 TI - Long-term renal outcomes of childhood-onset global and segmental diffuse proliferative lupus nephritis. AB - BACKGROUND: Data on global (IV-G) and segmental (IV-S) diffuse proliferative lupus nephritis (DPLN) in children are lacking. METHODS: To determine the clinicopathology and prognosis of DPLN subclasses IV-G and IV-S, we analyzed the clinical, laboratory, and demographic data of 56 children aged <18 years diagnosed with DPLN [36 (64.3%) with IV-G; 20 (35.7%) with IV-S] between 2004 and 2013. Clinical endpoints were: (1) complete remission (CR), (2) chronic kidney disease [CKD; defined as estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) or end-stage renal disease (ESRD)], and (3) death. RESULTS: Proteinuria and the activity index were higher in patients with IV-G (p < 0.05). Global endocapillary proliferation and leukocyte exudation were predominant in IV G patients, whereas segmental endocapillary proliferation was predominant in patients with IV-S (p < 0.005). CR rates in IV-G and IV-S patients were 50 and 60%, respectively (p = 0.47). Renal survival rates, defined as an eGFR of >=60 mL/min/1.73 m(2), were 93, 78, and 64% at 1, 5, and 10 years, respectively. Patient survival rates at 1, 5, and 10 years were 98, 96, and 91%, respectively. Patient and renal survival rates were similar in both subclasses. CONCLUSIONS: Although patients with IV-G and IV-S displayed some clinical and histopathological disparities, renal outcomes were similar. The majority of children with DPLN reached adulthood but accrued significant renal damage. Treatment regimens which can slow the progression of CKD are needed. PMID- 26054715 TI - Rapid urine preparation prior to identification of uropathogens by MALDI-TOF MS. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-ToF MS) has been introduced in clinical routine microbiology laboratories. For the rapid diagnosis of urinary tract infections, culture-independent methods prior MALDI-mediated identification have been described. Here, we describe a comparison of three of these methods based on their performance of bacterial identification and their potential as a routine tool for microbiology labs : (i) differential centrifugation, (ii) urine filtration and (iii) a 5-h bacterial cultivation on solid culture media. For 19 urine samples, all methods were directly compared and correct bacterial species identification by MALDI was used as performance indicator. A higher percentage of correct MALDI identification was obtained after filtration (78.9 %) and the growth-based method (84.2 %) as compared to differential centrifugation (68.4 %). Additional testing of 76 mono microbial specimens (bacteriuria > 10(5) CFU/mL) confirmed the good performance of short growth with a 90.8 % correct MALDI score, with a potentially better fit to the routine workflow of microbiology labs. PMID- 26054716 TI - Prolonging culture to 15 days improves bacterial detection in bone and joint infections. AB - Since the optimal incubation period of cultures for diagnosis of bone and joint infections is still a matter of debate, the present study aimed to evaluate the effects of different incubation periods (5 and 15 days) on microbial isolation. Samples from 387 patients with bone and joint infections (including prosthetic ones) were analyzed from March 2012 to February 2014. In 197 patients (51 %) growth was obtained within 48 hrs, while in 124 (32 %) and 66 (17 %) patients cultures yielded positive results within and after 5 days of incubation, respectively. Of 449 microorganisms isolated, 247 grew within 48 hrs, 131 within the first 5 days of incubation while 71 were isolated after 5 days. Staphylococcus aureus was the most frequently isolated pathogen within 48 hrs, while Propionibacteria were prevalently isolated after 5 days of incubation. Interestingly, about 25 % of microorganisms isolated after 5 days of incubation were coagulase-negative staphylococci. Extending incubation period of broth cultures improves isolation rates of pathogens involved in bone and joint infections thus improving management of these infections. PMID- 26054718 TI - The fluoro-less and contrast-less peripheral endovascular intervention: a concept for the future today. AB - INTRODUCTION: Percutaneous endovascular revascularization requires fluoroscopic guidance and radiopaque contrast use. This approach becomes problematic, especially in patients with advanced renal disease or allergies to iodinated contrast medium. The direct (exposure) and indirect (lead garment) burden of radiation affects patients and operators alike. PURPOSE: We propose a completely contrast-free, fluoroscopy-free approach to endovascular diagnostic arterial imaging and percutaneous intervention using available technologies, and outline a timeframe for its implementation. PROJECT DESCRIPTION/METHODOLOGY: Ultrasound imaging of the leg creates a roadmap of the vessel and identifies the lesion of interest. Device-based sensors using a low-powered electromagnetic field allow for wiring of the vessel. This is followed by the use of intravascular ultrasonography and near infrared spectroscopy to characterize the lesion dimensions and composition. After completion of the diagnostic phase of the process, the interventional portion with deployment of an angioplasty balloon and/or stent is performed using the electromagnetic field-guided sensors. FEASIBILITY: The project uses already available technologies. BENEFITS/ANTICIPATED OUTCOMES: This project demonstrates the real potential of performing endovascular peripheral intervention without fluoroscopy or contrast in a practical, user-friendly way with the currently available technology. The prospects in renal function preservation and radiation avoidance for both patients and operators are extremely attractive. PMID- 26054721 TI - Expression of the N2 fixation gene operon of Paenibacillus sp. WLY78 under the control of the T7 promoter in Escherichia coli BL21. AB - OBJECTIVE: To investigate the transcription and translation and nitrogenase activity of the nine N2-fixing-gene (nif) operon (nifBHDKENXhesAnifX) of Paenibacillus sp. WLY78 under the control of the T7 promoter in Escherichia coli BL21 under different conditions. RESULTS: The Paenibacillus nif operon under the control of the T7 promoter is significantly transcribed and effectively translated in E. coli BL21 when grown in medium containing organic N compounds (yeast extract and Tryptone) or NH4+ by using RT-PCR and Western blot analysis. Transcription and translation of foreign nif genes in E. coli are not inhibited by environmental organic or inorganic N compounds or O2. However, contrary to transcription and translation, nitrogenase activity is 4% lower in the recombinant E. coli 78-32 compared to the native Paenibacillus sp. WLY78. CONCLUSION: The Paenibacillus nif operon under the control of T7 promoter enables E. coli BL21 to synthesize active nitrogenase. This study shows how the nif gene operon can be transferred to non-N2-fixing bacteria or to eukaryotic organelles. PMID- 26054719 TI - Batf3 maintains autoactivation of Irf8 for commitment of a CD8alpha(+) conventional DC clonogenic progenitor. AB - The transcription factors Batf3 and IRF8 are required for the development of CD8alpha(+) conventional dendritic cells (cDCs), but the basis for their actions has remained unclear. Here we identified two progenitor cells positive for the transcription factor Zbtb46 that separately generated CD8alpha(+) cDCs and CD4(+) cDCs and arose directly from the common DC progenitor (CDP). Irf8 expression in CDPs required prior autoactivation of Irf8 that was dependent on the transcription factor PU.1. Specification of the clonogenic progenitor of CD8alpha(+) cDCs (the pre-CD8 DC) required IRF8 but not Batf3. However, after specification of pre-CD8 DCs, autoactivation of Irf8 became Batf3 dependent at a CD8alpha(+) cDC-specific enhancer with multiple transcription factor AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3(-/-) mice that were specified toward development into pre-CD8 DCs failed to complete their development into CD8alpha(+) cDCs due to decay of Irf8 autoactivation and diverted to the CD4(+) cDC lineage. PMID- 26054720 TI - Identification of cDC1- and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow. AB - Mouse conventional dendritic cells (cDCs) can be classified into two functionally distinct lineages: the CD8alpha(+) (CD103(+)) cDC1 lineage, and the CD11b(+) cDC2 lineage. cDCs arise from a cascade of bone marrow (BM) DC-committed progenitor cells that include the common DC progenitors (CDPs) and pre-DCs, which exit the BM and seed peripheral tissues before differentiating locally into mature cDCs. Where and when commitment to the cDC1 or cDC2 lineage occurs remains poorly understood. Here we found that transcriptional signatures of the cDC1 and cDC2 lineages became evident at the single-cell level from the CDP stage. We also identified Siglec-H and Ly6C as lineage markers that distinguished pre-DC subpopulations committed to the cDC1 lineage (Siglec-H(-)Ly6C(-) pre-DCs) or cDC2 lineage (Siglec-H(-)Ly6C(+) pre-DCs). Our results indicate that commitment to the cDC1 or cDC2 lineage occurs in the BM and not in the periphery. PMID- 26054722 TI - Biotransformation of 20(S)-protopanaxatriol by Mucor racemosus and the anti cancer activities of some products. AB - OBJECTIVE: To produce new derivatives of 20(S)-protopanaxatriol by fungal biotransformation. RESULT: Biotransformation of 20(S)-protopanaxatriol (1) by Mucor racemosus AS 3.205 afforded six products. Their structures were elucidated on the basis of extensive spectroscopic analyses. M. racemosus could selectively catalyze dehydrogenation at C-12 and further hydroxylation at C-7, C-11, and C 15, as well as rearrangement of double bond at C-26. Two of these new compounds exhibited potent inhibitory activity against SH-SY5Y and HepG2 cell lines. CONCLUSION: Biotransformation by M. racemosus AS 3.205 was an effective approach to produce new derivatives of 20(S)-protopanaxatriol. PMID- 26054723 TI - Hepatocellular carcinoma-derived exosomes promote motility of immortalized hepatocyte through transfer of oncogenic proteins and RNAs. AB - Exosomes are increasingly recognized as important mediators of cell-cell communication in cancer progression through the horizontal transfer of RNAs and proteins to neighboring or distant cells. Hepatocellular carcinoma (HCC) is a highly malignant cancer, whose metastasis is largely influenced by the tumor microenvironment. The possible role of exosomes in the interactions between HCC tumor cell and its surrounding hepatic milieu are however largely unknown. In this study, we comprehensively characterized the exosomal RNA and proteome contents derived from three HCC cell lines (HKCI-C3, HKCI-8 and MHCC97L) and an immortalized hepatocyte line (MIHA) using Ion Torrent sequencing and mass spectrometry, respectively. RNA deep sequencing and proteomic analysis revealed exosomes derived from metastatic HCC cell lines carried a large number of protumorigenic RNAs and proteins, such as MET protooncogene, S100 family members and the caveolins. Of interest, we found that exosomes from motile HCC cell lines could significantly enhance the migratory and invasive abilities of non-motile MIHA cell. We further demonstrated that uptake of these shuttled molecules could trigger PI3K/AKT and MAPK signaling pathways in MIHA with increased secretion of active MMP-2 and MMP-9. Our study showed for the first time that HCC-derived exosomes could mobilize normal hepatocyte, which may have implication in facilitating the protrusive activity of HCC cells through liver parenchyma during the process of metastasis. PMID- 26054724 TI - Jealousy and violence in dating relationships: gender-related differences among a Spanish sample. AB - The present study analyzes violent behavior (psychological, physical, and sexual violence) that may occur in dating relationships. Data was collected from couples of adolescents and young adults in a sample of 579 students from the region of Madrid, consisting of 319 females and 260 males aged between 12 and 22 years. A novel aspect of this study compared with the great majority of published studies is analysis of a) the frequency of violent behaviors (and not only their presence or absence) to study significant mean differences and b) potential gender and age related differences in the patterns of violence. Results indicate the high prevalence of violence in Spanish dating relationships. Specifically, females carry out more mild physical (p < .001) and psychological violence (p < .05), whereas males perpetrate more sexual violence (p < .001). However, with regard to victimization, no significant gender related differences in frequency were found between boys and girls in any type of violence. With regard to age, young adolescents perform (p < .05) and suffer (p < .01) significantly more jealous behavior, whereas the young adults of our sample commit and suffer more sexual violence (p < .05). Directions for future research are outlined, mainly concerning instruments used that ought to be more sensitive to the reality being measured. PMID- 26054725 TI - Defective Number Sense or Impaired Access? Differential Impairments in Different Subgroups of Children With Mathematics Difficulties. AB - Developmental dyscalculia (DD) is a specific learning disability in mathematics that affects around 6% of the population. Currently, the core deficit of DD remains unknown. While the number sense deficit hypothesis suggests that the core deficit of DD lies in the inability to represent nonsymbolic numerosity, the access deficit hypothesis suggests that the origin of this disability lies in the inability to associate numbers with the underlying magnitude representation. The present study compared the performance of DDs with their low-achieving (LA) and normally achieving peers in nonsymbolic numerosity processing and number magnitude mapping over 1 year (from kindergarten to 1st grade). The results demonstrated differential impairments in different subgroups of children with mathematics difficulties. While DDs showed deficits in both nonsymbolic numerosity processing and number-magnitude mapping, LAs showed deficit only in the number-magnitude mapping. Furthermore, the deficit in number-magnitude mapping among the DD group was partially explained by their number sense deficit. The number sense deficit hypothesis is supported. Theoretical and practical implications are discussed. PMID- 26054726 TI - Metacognitive Strategies. AB - This study assessed the effect of metacognitive instruction on the spelling and word reading of Hebrew-speaking children with specific language impairment (SLI). Participants were 67 kindergarteners with SLI in a supported learning context. Children were classified into three spelling instruction groups: (a) metalinguistic instruction (ML), (b) ML that integrates metacognitive strategies (MCML), and (c) a control group. Letter naming, letter sounding, word spelling, and word recognition were assessed at pretest and posttest. Findings from spelling and reading tests as well as interviews indicated that both the ML and MCML groups made statistically significant gains in all measures, whereas the control group did not. However, children with SLI who received training in metacognitive strategies significantly outperformed those who received ML alone in spelling and reading skills. This study provides evidence that children with SLI benefit from applying of metacognitive strategies to spelling practices when acquiring early spelling and reading skills. PMID- 26054727 TI - A novel protein-based subunit Shigella vaccine candidate. PMID- 26054728 TI - GRace: a MATLAB-based application for fitting the discrimination-association model. AB - The Implicit Association Test (IAT) is a computerized two-choice discrimination task in which stimuli have to be categorized as belonging to target categories or attribute categories by pressing, as quickly and accurately as possible, one of two response keys. The discrimination association model has been recently proposed for the analysis of reaction time and accuracy of an individual respondent to the IAT. The model disentangles the influences of three qualitatively different components on the responses to the IAT: stimuli discrimination, automatic association, and termination criterion. The article presents General Race (GRace), a MATLAB-based application for fitting the discrimination association model to IAT data. GRace has been developed for Windows as a standalone application. It is user-friendly and does not require any programming experience. The use of GRace is illustrated on the data of a Coca Cola-Pepsi Cola IAT, and the results of the analysis are interpreted and discussed. PMID- 26054729 TI - [On the interdisciplinary S3 guidelines for the treatment of chronic idiopathic tinnitus]. AB - INTRODUCTION: Tinnitus is a frequent symptom, which, particularly in combination with comorbidities, can result in a severe disease-related burden. Chronic idiopathic tinnitus (CIT) is the most frequent type of tinnitus. A considerable number of treatment strategies are used to treat CIT-for many of which there is no evidence of efficacy. In order to enable scientific evidence-based treatment of CIT, German interdisciplinary S3 guidelines have recently been constructed for the first time. Here we present a short form of these S3 guidelines. MATERIALS AND METHODS: The guidelines were constructed based on a meta-analysis of the treatment of chronic tinnitus performed by the authors. Additionally, a systematic literature search was performed in the PubMed and Cochrane Library databases. Furthermore, a systematic search for international guidelines was performed in Google, as well as in the Guidelines International Network and National Guideline Clearinghouse (USA) database. Evidence was classified according to the Oxford Centre for Evidence-Based Medicine system. RESULTS: According to the guidelines, alongside counselling, manualized structured tinnitus-specific cognitive behavioral therapy (tCBT) with a validated treatment manual is available as evidence-based therapy. In addition, the guidelines recommend concurrent treatment of comorbidities, including drug-based treatment, where appropriate. Particularly important is treatment of anxiety and depression. Where a psychic or psychiatric comorbidity is suspected, further diagnosis and treatment should be performed by an appropriately qualified specialist (psychiatrist, neurologist, psychosomatic medicine consultant) or psychological psychotherapist. In cases accompanied by deafness or hearing loss bordering on deafness, cochlear implants may be indicated. CONCLUSION: No recommendations can be made for drug-based treatment of CIT, audiotherapy, transcranial magnetic or electrical stimulation, specific forms of acoustic stimulation or music therapy; or such recommendations must remain open due to the lack of available evidence. Polypragmatic tinnitus treatment with therapeutic strategies for which there is no evidence of efficacy from controlled studies is to be refused. PMID- 26054730 TI - [Differential indication of active middle ear implants]. AB - INTRODUCTION: Hearing aids (HA) provide adequate support for many patients with hearing loss, but not all. Around one third of 10.000 patients provided with hearing aids in the Abbreviated Profile of Hearing Aid Benefit felt no actual benefit when using the hearing aid, although they demonstrated the necessary hearing improvement on speech audiometry. Epidemiological data show bad compliance, especially in older people. Only one in three hearing aid owners wears their device regularly. For this subpopulation of patients active middle ear implants (AMEIs) have been used since 1998. In the present review, the current indications for AMEIs are presented. MATERIAL AND METHODS: A selective literature search in PubMed, as well as a guideline search at the Arbeitsgemeinschaft der Wissenschaftlichen Fachgesellschaften e. V. (German Association of Scientific Societies), was carried out. RESULTS: The present review shows that when there is an adequate indication the hearing capacity of patients can be thoroughly rehabilitated and thus their quality of life improved with the help of AMEIs. Although most commercially available systems have a satisfactory risk profile, increased extrusion rates, malfunctioning and facial paresis have been reported in older implant series. The advantages of AMEIs include increased hearing gain, reduced feedback, increased hearing quality, increased speech discrimination in the presence of background noise, and an absence of occlusion. CONCLUSIONS: The audiological indication for AMEIs in primary care is usually controversial, since the functional hearing gain and increase in speech discrimination may be small compared with modern conventional hearing aids. AMEIs thus play a main role in the secondary care of patients who do not have sufficient benefit or who have side effects after having a conventional hearing aid fitted. PMID- 26054731 TI - Early Triassic wrinkle structures on land: stressed environments and oases for life. AB - Wrinkle structures in rocks younger than the Permian-Triassic (P-Tr) extinction have been reported repeatedly in marine strata, but rarely mentioned in rocks recording land. Here, three newly studied terrestrial P-Tr boundary rock succession in North China have yielded diverse wrinkle structures. All of these wrinkles are preserved in barely bioturbated shore-shallow lacustrine siliciclastic deposits of the Liujiagou Formation. Conversely, both the lacustrine siliciclastic deposits of the underlying Sunjiagou Formation and the overlying Heshanggou Formation show rich bioturbation, but no wrinkle structures or other microbial-related structures. The occurrence of terrestrial wrinkle structures in the studied sections reflects abnormal hydrochemical and physical environments, presumably associated with the extinction of terrestrial organisms. Only very rare trace fossils occurred in the aftermath of the P-Tr extinction, but most of them were preserved together with the microbial mats. This suggests that microbial mats acted as potential oases for the surviving aquatic animals, as a source of food and oxygen. The new finds suggests that extreme environmental stresses were prevalent both in the sea and on land through most of the Early Triassic. PMID- 26054732 TI - A psychrotolerant strain of Serratia marcescens (MTCC 4822) produces laccase at wide temperature and pH range. AB - A psychrotolerant bacterial strain of Serratia marcescens, originally isolated from a glacial site in Indian Himalayan Region (IHR), has been investigated for laccase production under different culture conditions. The bacterial strain was found to grow between 4 to 45 degrees C (opt. 25 degrees C) and 3 to 14 pH (opt. 5 pH) on prescribed growth medium, coinciding with production of laccase in laccase producing medium. However, the production of laccase was more consistent toward alkaline pH. Laccase enzyme was partially purified using gel filtration chromatography. The molecular mass of laccase was determined ~53 kDa on native PAGE. The Km and Vmax values were determined to be 0.10 mM and 50.00 MUM min(-1), respectively, with ABTS. Inoculum size (4.0% v/v at 1.5 O.D.) resulted in significantly higher production of laccase. Carbon and nitrogen sources also affected the laccase production significantly. All the carbon sources enhanced laccase production, xylose being the best enhancer (P < 0.01). Among nitrogen sources, organic sources were found to act as inhibitors (P < 0.01), and among the in-organic sources only sodium nitrate enhanced the laccase production. Low molecular weight organic solvents significantly (P < 0.01) enhanced laccase production up to 24 h of incubation with a decline in later incubation period. Production of laccase by the psychrotolerant bacterium in wide range of temperature and pH is likely to have inference in biotechnological processes. PMID- 26054733 TI - Catalytic and hydrodynamic properties of styrene monooxygenases from Rhodococcus opacus 1CP are modulated by cofactor binding. AB - Styrene monooxygenases (SMOs) are flavoenzymes catalyzing the epoxidation of styrene into styrene oxide. SMOs are composed of a monooxygenase (StyA) and a reductase (StyB). The latter delivers reduced FAD to StyA on the expense of NADH. We identified Rhodococcus opacus 1CP as the first microorganism to possess three different StyA isoforms occurring in two systems StyA1/StyA2B and StyA/StyB, respectively. The hydrodynamic properties of StyA isozymes were found to be modulated by the binding of the (reduced) FAD cofactor. StyA1 and SyA2B mainly occur as dimers in their active forms while StyA is a monomer. StyA1 showed the highest epoxidation activity and excellent enantioselectivity in aromatic sulfoxidation. The hydrodynamic and biocatalytic properties of SMOs from strain 1CP are of relevance for investigation of possible industrial applications. PMID- 26054734 TI - Substrate stereoselectivity of poly(Asp) hydrolase-1 capable of cleaving beta amide bonds as revealed by investigation of enzymatic hydrolysis of stereoisomeric beta-tri(Asp)s. AB - We previously reported that poly(Asp) hydrolase-1 (PahZ1KP-2) from Pedobacter sp. KP-2 selectively, but not completely, cleaved the amide bonds between beta-Asp units in thermally synthesized poly(Asp) (tPAA). In the present study, the enzymatic hydrolysis of stereoisomeric beta-tri(Asp)s by PahZ1KP-2 was investigated to clarify the substrate stereoselectivity of PahZ1KP-2 in the hydrolysis of tPAA. The results suggest the following structural features of PahZ1KP-2 at its substrate binding site: (1) the active site contains four subsites (2, 1, -1, and -2), three of which need to be occupied by Asp units for cleavage to occur; (2) for the hydrolysis to proceed, subsite 1 should be occupied by an L-Asp unit, whereas the other three subsites may accept both L- and D-Asp units; (3) for the two central subsites between which cleavage occurs, the (L-Asp)-(D-Asp) sequence is the most favorable for cleavage. PMID- 26054735 TI - Engineering alternative isobutanol production platforms. AB - A synthetic inducible operon (IbPSO) expressing alsS, ilvC, ilvD and kivD genes encoding a pathway capable to transform pyruvate into 2-isobutyraldehyde has been designed and two recombinant plasmids named pIZIbPSO and p424IbPSO were constructed. The IbPSO containing plasmids can generate in a single transformation event new recombinant isobutanol producer strains and are useful for testing as suitable hosts wild type bacteria in different culture media. In this way we found that Shimwellia blattae (p424IbPSO) was able to produce in flasks up to 6 g l(-1) of isobutanol using glucose as carbon source. Moreover, for the first time, we have demonstrated that isobutanol can be produced from sucrose using Escherichia coli W (ATCC9367) transformed with pIZIbPSO. These robust recombinant strains were also able to produce isobutanol from a raw carbon source like hydrolysed lignocellulosic biomass. PMID- 26054736 TI - Fast and reliable production, purification and characterization of heat-stable, bifunctional enzyme chimeras. AB - Degradation of complex plant biomass demands a fine-regulated portfolio of glycoside hydrolases. The LE (LguI/Eco81I)-cloning approach was used to produce two enzyme chimeras CB and BC composed of an endoglucanase Cel5A (C) from the extreme thermophilic bacterium Fervidobacterium gondwanense and an archaeal beta glucosidase Bgl1 (B) derived from a hydrothermal spring metagenome. Recombinant chimeras and parental enzymes were produced in Escherichia coli and purified using a two-step affinity chromatography approach. Enzymatic properties revealed that both chimeras closely resemble the parental enzymes and physical mixtures, but Cel5A displayed lower temperature tolerance at 100 degrees C when fused to Bgl1 independent of the conformational order. Moreover, the determination of enzymatic performances resulted in the detection of additive effects in case of BC fusion chimera. Kinetic measurements in combination with HPLC-mediated product analyses and site-directed mutation constructs indicated that Cel5A was strongly impaired when fused at the N-terminus, while activity was reduced to a slighter extend as C-terminal fusion partner. In contrast to these results, catalytic activity of Bgl1 at the N-terminus was improved 1.2-fold, effectively counteracting the slightly reduced activity of Cel5A by converting cellobiose into glucose. In addition, cellobiose exhibited inhibitory effects on Cel5A, resulting in a higher yield of cellobiose and glucose by application of an enzyme mixture (53.1%) compared to cellobiose produced from endoglucanase alone (10.9%). However, the overall release of cellobiose and glucose was even increased by catalytic action of BC (59.2%). These results indicate possible advantages of easily produced bifunctional fusion enzymes for the improved conversion of complex polysaccharide plant materials. PMID- 26054737 TI - A bodipy based dual functional probe for the detection of hydrogen sulfide and H2S induced apoptosis in cellular systems. AB - A bodipy based dual functional probe 1 has been designed and synthesized, which selectively detects H2S as well as monitors H2S induced apoptosis in cells. PMID- 26054738 TI - How to get the desired reduction voltage in a single framework! Metallacarborane as an optimal probe for sequential voltage tuning. AB - An appealingly wide set of redox couples ranging from -1.74 to -0.35 V based on a metallabisdicarbollide derivative, [M(C2B9H11-yIy)2](-) (M = Co, Fe), each being distinguished from the former by near 0.15 V and all having the same structure have been demonstrated. The redox active methyl viologen moiety ([MV](2+)) has been used as a benchmark. PMID- 26054739 TI - RNA nucleosides as chiral sensing agents in NMR spectroscopy. AB - The study reports chiral sensing properties of RNA nucleosides. Adenosine, guanosine, uridine and cytidine are used as chiral derivatizing agents to differentiate chiral 1 degrees -amines. A three component protocol has been adopted for complexation of nucleosides and amines. The chiral differentiating ability of nucleosides is examined for different amines based on the (1)H NMR chemical shift differences of diastereomers (Deltadelta(R,S)). Enantiomeric differentiation has been observed at multiple chemically distinct proton sites. Adenosine and guanosine exhibit large chiral differentiation (Deltadelta(R,S)) due to the presence of a purine ring. The diastereomeric excess (de) measured by using adenosine is in good agreement with the gravimetric values. PMID- 26054740 TI - Tower of London: planning development in children from 6 to 13 years of age. AB - Executive Function is a multidimensional construct that includes a wide range of cognitive abilities that allow solving goal-directed behaviors efficiently. Its development begins in early childhood and continues through adolescence. A key aspect of Executive Function is planning, defined as the capacity to generate and organize the necessary step sequence to carry out a goal-directed behavior. The aim of this study was to assess the development of planning in children. The Tower of London task was used in 270 children aged 6, 8, 11, and 13 years. The results showed that the time required to generate and organize the plan to solve a goal-directed problem increases as the difficulty of the problem increases, and that older children need less time to solve problems with a certain level of difficulty than younger children F(15, 1330) = 8.787; MSE = 1.441; p < .01; eta2 =.090. These results are in line with the findings that planning develops through childhood and even during the first years of adolescence. PMID- 26054741 TI - Quantitative determination of fluoride in pure water using luminescent europium complexes. AB - Two luminescent probes [Eu.L1-2]+ are reported for the rapid detection of fluoride in water. Probes [Eu.L1-2]+ exhibit exceptional enhancements in Eu emission in the presence of fluoride, permitting its selective determination within the environmentally relevant concentration range (20-210 MUM). PMID- 26054743 TI - Small but Mighty: Cell Size and Bacteria. AB - Our view of bacteria is overwhelmingly shaped by their diminutive nature. The most ancient of organisms, their very presence was not appreciated until the 17th century with the invention of the microscope. Initially, viewed as "bags of enzymes," recent advances in imaging, molecular phylogeny, and, most recently, genomics have revealed incredible diversity within this previously invisible realm of life. Here, we review the impact of size on bacterial evolution, physiology, and morphogenesis. PMID- 26054744 TI - ERK1/2 has an essential role in B cell receptor- and CD40-induced signaling in an in vitro model of germinal center B cell selection. AB - Germinal center (GC) B cells undergo apoptosis after B cell receptor (BCR) ligation, unless they receive CD40-mediated survival signal from helper T cells. In the present study, we used a human follicular lymphoma cell line HF1A3, as an in vitro model to study the selection process in germinal centers. We show here that BCR ligation led to immediate ERK1/2 activation and phosphorylations of its downstream targets, Bim EL/L and Bcl-2 (at Ser70) which resulted in short-term survival. On the other hand, during the late phase of BCR signaling, ERK1/2 phosphorylation was inhibited which resulted in apoptosis. In addition, CD40 signaling led to sustained ERK1/2 activation and up-regulation of Bcl-xL in BCR primed HF1A3 GC B cells. In conclusion, MEK-ERK pathway and Bcl-2 family proteins are crucial players in BCR-mediated survival/apoptosis and CD40-mediated survival. PMID- 26054745 TI - The Role of Thalamic Damage in Mild Traumatic Brain Injury. AB - There is growing alarm in the United States about an epidemiologically large occurrence of mild traumatic brain injury with serious long lasting consequences. Although conventional imaging has been unable to identify damage capable of explaining its organic origin or discerning patients at risk of developing long term or permanently disabling neurological impairment, most disease models assume that diffuse axonal injury in white matter must be present but is difficult to resolve. The few histopathological investigations conducted, however, show only limited evidence of such damage, which cannot account for the stereotypical globalized nature of symptoms generally reported in patients. This review examines recent proposals that in addition to white matter, the thalamus may be another important further site of injury. Although its possible role still remains largely under-investigated, evidence from experimental human and animal models, as well as simulational and analytical representations of mild head injury and other related conditions, suggest that this strategically vital region of the brain, which has reciprocal projections to the entire cerebral cortex, could feasibly play an important role in understanding pathology and predicting outcome. PMID- 26054742 TI - Schwann cell myelination. AB - Myelinated nerve fibers are essential for the rapid propagation of action potentials by saltatory conduction. They form as the result of reciprocal interactions between axons and Schwann cells. Extrinsic signals from the axon, and the extracellular matrix, drive Schwann cells to adopt a myelinating fate, whereas myelination reorganizes the axon for its role in conduction and is essential for its integrity. Here, we review our current understanding of the development, molecular organization, and function of myelinating Schwann cells. Recent findings into the extrinsic signals that drive Schwann cell myelination, their cognate receptors, and the downstream intracellular signaling pathways they activate will be described. Together, these studies provide important new insights into how these pathways converge to activate the transcriptional cascade of myelination and remodel the actin cytoskeleton that is critical for morphogenesis of the myelin sheath. PMID- 26054746 TI - Expression and regulative function of tissue inhibitor of metalloproteinase 3 in the goat ovary and its role in cultured granulosa cells. AB - Tissue inhibitor of metalloproteinase 3 (TIMP3) played a key role in female reproduction. However, its expression and function in goat are still unclear. In the present study, the full-length cDNA of goat TIMP3 was cloned from adult goat ovary; meanwhile, we demonstrated that putative TIMP3 protein shared a highly conserved amino acid sequence with known mammalian homologs. Real-time PCR results showed that TIMP3 was widely expressed in the tissues of adult goat. In the ovary, increasing expression of TIMP3 mRNA was discovered during the growth process of follicle and corpus luteum. Immunohistochemistry results suggested that TIMP3 protein existed in oocytes of all types of follicles, corpus luteum and granulosa and theca cells of primary, secondary, and antral but not primordial follicles. In vitro, human chorionic gonadotropin (hCG) stimulated the expression of TIMP3 in goat granulosa cells. hCG-induced TIMP3 mRNA expression was reduced by the inhibitors of protein kinase A, protein kinase C, MAPK kinase, or p38 kinase. Functionally, over-expression of TIMP3 significantly increased apoptosis and decreased the viability of cultured granulosa cells. Knockdown of TIMP3 could decrease hCG-induced progesterone secretion and the mRNA abundance of key steroidogenic enzymes (StAR, p450scc and HSD3B) as well as ECM proteins (DCN and FN). These findings provided evidence that the hCG induced expression of TIMP3 may play an important role in regulating goat granulosa cell survival and steroidogenesis. PMID- 26054747 TI - Dihydromyricetin stimulates irisin secretion partially via the PGC-1alpha pathway. AB - Irisin, derived from FNDC5, is an exercise-induced myokine that can stimulate the 'browning' of white adipose tissue, which is regulated by peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC-1alpha). Dihydromyricetin (DHM), a natural flavonoid, exerts its activities through PGC-1alpha activation. Here, we explored whether DHM could mimic the effects of exercise on irisin secretion. DHM administration increased circulating irisin in rats and humans. Notably, the serum irisin level had a greater correlation to the level of circulating DHM than to the amount of exercise. DHM treatment upregulated PGC 1alpha and FNDC5 expression, enhanced energy metabolism, as evidenced by NMR based metabonomics analysis, and partially abolished the suppressive effects of Pgc-1alpha siRNA on FNDC5 expression. These results suggest that DHM can stimulate irisin secretion partially via the PGC-1alpha pathway. As a potent exercise mimetic, DHM is expected to benefit patients suffering from metabolic diseases, especially those who cannot undergo rigorous exercise. PMID- 26054748 TI - Weight gain and inflammation regulate aromatase expression in male adipose tissue, as evidenced by reporter gene activity. AB - Obesity and white adipose tissue (WAT) inflammation are associated with enhanced aromatization in women, but little is known about the regulation of aromatase (CYP19A1) gene expression in male WAT. We investigated the impact of weight gain and WAT inflammation on the regulation of CYP19A1 in males, by utilizing the hARO Luc aromatase reporter mouse model containing a >100-kb 5'-region of the human CYP19A1 gene. We show that hARO-Luc reporter activity is enhanced in WAT of mice with increased adiposity and inflammation. Dexamethasone and TNFalpha, as well as forskolin and phorbol 12-myristate 13-acetate, upregulate hARO-Luc activity, suggesting the involvement of promoters I.4 and I.3/II. Furthermore, we show that diet enriched with antioxidative plant polyphenols attenuates WAT inflammation and hARO-Luc activity in obese males. In conclusion, our data suggest that obesity-associated WAT inflammation leads to increased peripheral CYP19A1 expression in males, and that polyphenol-enriched diet may have the potential to attenuate excessive aromatization in WAT of obese men. PMID- 26054749 TI - Resveratrol attenuates high glucose-induced oxidative stress and cardiomyocyte apoptosis through AMPK. AB - BACKGROUND: Diabetic cardiomyopathy (DCM) suggests a direct cellular insult to myocardium. Hyperglycemia-induced oxidative stress and apoptosis have been implicated in the pathogenesis of DCM. NADPH oxidase is a major source of reactive oxygen species (ROS) generation in cardiomyocytes. Resveratrol, a naturally occurring polyphenol, has shown beneficial effects on some cardiovascular complications associated with diabetes. OBJECTIVES: We aimed to examine the role of resveratrol on high glucose-induced NADPH oxidase-derived ROS production and cardiac apoptosis, together with modulation of protein signaling pathways in cardiomyocytes. METHODS: Primary cultures of neonatal rat cardiomyocytes were exposed to 30 mmol/L high glucose with or without resveratrol. Cell viability, apoptosis, superoxide formation, NADPH oxidase activity and its subunits expression, antioxidant enzymes activities, as well as the potential regulatory molecules AMPK, Akt and GSK-3beta were assessed in cardiac cells. RESULTS: Elevated ROS production induced by 30 mmol/L high glucose was inhibited with the addition of resveratrol in primary cultured neonatal rat cardiomyocytes. Consistently, resveratrol markedly suppressed the increased activity of NADPH oxidase and Rac1, as well as the enhanced expression of p67(phox), p47(phox), and gp91(phox) induced by high glucose. Lipid peroxidation, SOD, catalase, GSH-px activity and GSH content was reversed in the presence of resveratrol. Moreover, the expression of pro-apoptotic protein Bax was down regulated while anti-apoptotic protein Bcl-2 was up regulated. And cardiac cell injury and apoptosis were markedly rescued by resveratrol. In addition, resveratrol significantly increased phosphorylation of AMP-activated protein kinase (AMPK) at Thr172 in cardiomyocytes exposed to high glucose. Compound C, the pharmacologic inhibitor of AMPK, could mostly abrogate roles of resveratrol on cardiomyocytes in high glucose. In contrast, Akt and GSK-3beta were little influenced by resveratrol. CONCLUSIONS: Our data demonstrated that resveratrol protected cardiomyocytes against high glucose-induced apoptosis through suppression NADPH oxidase-derived ROS generation and maintenance endogenous antioxidant defenses. And the protective effects of resveratrol are mostly mediated by AMPK related pathway. PMID- 26054750 TI - 1,25-Dihydroxyvitamin D3 and extracellular calcium promote mineral deposition via NPP1 activity in a mature osteoblast cell line MLO-A5. AB - While vitamin D supplementation is common, the anabolic mechanisms that improve bone status are poorly understood. Under standard mineralising conditions including media ionised calcium of 1.1 mM, 1,25-dihydroxyvitamin D3 (1,25D) enhanced differentiation and mineral deposition by the mature osteoblast/pre osteocyte cell line, MLO-A5. This effect was markedly increased with a higher ionised calcium level (1.5 mM). Gene expression analyses revealed that 1,25D induced mineral deposition was associated with induction of Enpp1 mRNA, coding for nucleotide pyrophosphatase phosphodiesterase 1 (NPP1) and NPP1 protein levels. Since MLO-A5 cells express abundant alkaline phosphatase that was not further modified by 1,25D treatment or exposure to increased calcium, this finding suggested that the NPP1 production of pyrophosphate (PPi) may provide alkaline phosphatase with substrate for the generation of inorganic phosphate (Pi). Consistent with this, co-treatment with Enpp1 siRNA or a NPP1 inhibitor, PPADS, abrogated 1,25D-induced mineral deposition. These data demonstrate that 1,25D stimulates osteoblast differentiation and mineral deposition, and interacts with the extracellular calcium concentration. 1,25D regulates Enpp1 expression, which presumably, in the context of adequate tissue non-specific alkaline phosphatase activity, provides Pi to stimulate mineralisation. Our findings suggest a mechanism by which vitamin D with adequate dietary calcium can improve bone mineral status. PMID- 26054751 TI - ABC294640, a sphingosine kinase 2 inhibitor, enhances the antitumor effects of TRAIL in non-small cell lung cancer. AB - Evidences suggest that tumor microenvironment may play an important role in cancer drug resistance. Sphingosine kinase 2 (SphK2) is proposed to be the key regulator of sphingolipid signaling. This study is aimed to investigate whether the combination of molecular targeting therapy using a specific inhibitor of SphK2 (ABC294640), with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can enhance the apoptosis of non-small cell lung cancer (NSCLC) cells. Our results revealed that NSCLC cells' sensitivity to TRAIL is correlated with the level of SphK2. Compared with TRAIL alone, the combination therapy enhanced the apoptosis induced by TRAIL, and knockdown of SphK2 by siRNA presented a similar effect. Combination therapy with ABC294640 increased the activity of caspase-3/8 and up-regulated the expression of death receptors (DR). Additional investigations revealed that translocation of DR4/5 to the cell membrane surface was promoted by adding ABC294640. However, expression of anti-apoptosis proteins such as Bcl(-)2 and IAPs was not significantly modified by this SphK2 inhibitor. Overall, this work demonstrates that SphK2 may contribute to the apoptosis resistance in NSCLC, thus indicating a new therapeutic target for resistant NSCLC cells. PMID- 26054752 TI - Shaping fat distribution: New insights into the molecular determinants of depot- and sex-dependent adipose biology. AB - OBJECTIVE: To review recent advances in understanding the cellular mechanisms that regulate fat distribution. METHODS: In this review, new insights into depot and sex differences in the developmental origins and growth of adipose tissues as revealed by studies that use new methods, including lineage tracing, are highlighted. RESULTS: Variations in fat distribution during normal growth and in response to alterations in nutritional or hormonal status are driven by intrinsic differences in cells found in each adipose depot. Adipose progenitor cells and preadipocytes in different anatomical adipose tissues derive from cell lineages that determine their capacity for proliferation and differentiation. As a result, rates of hypertrophy and hyperplasia during growth and remodeling vary among depots. The metabolic capacities of adipose cells are also determined by variations in the expression of key transcription factors and non-coding RNAs. These developmental events are influenced by sex chromosomes and hormonal and nutrient signals that determine the adipogenic, metabolic, and functional properties of each depot. CONCLUSIONS: These new developments in the understanding of fat distribution provide a sound basis for understanding the association of body shape and health in men and women with and without obesity. PMID- 26054753 TI - The distribution and evolution of Arabidopsis thaliana cis natural antisense transcripts. AB - BACKGROUND: Natural antisense transcripts (NATs) are regulatory RNAs that contain sequence complementary to other RNAs, these other RNAs usually being messenger RNAs. In eukaryotic genomes, cis-NATs overlap the gene they complement. RESULTS: Here, our goal is to analyze the distribution and evolutionary conservation of cis-NATs for a variety of available data sets for Arabidopsis thaliana, to gain insights into cis-NAT functional mechanisms and their significance. Cis-NATs derived from traditional sequencing are largely validated by other data sets, although different cis-NAT data sets have different prevalent cis-NAT topologies with respect to overlapping protein-coding genes. A. thaliana cis-NATs have substantial conservation (28-35% in the three substantive data sets analyzed) of expression in A. lyrata. We examined evolutionary sequence conservation at cis NAT loci in Arabidopsis thaliana across nine sequenced Brassicaceae species (picked for optimal discernment of purifying selection), focussing on the parts of their sequences not overlapping protein-coding transcripts (dubbed 'NOLPs'). We found significant NOLP sequence conservation for 28-34% NATs across different cis-NAT sets. This NAT NOLP sequence conservation versus A. lyrata is generally significantly correlated with conservation of expression. We discover a significant enrichment of transcription factor binding sites (as evidenced by CHIP-seq data) in NOLPs compared to randomly sampled near-gene NOLP-like DNA , that is linked to significant sequence conservation. Conversely, there is no such evidence for a general significant link between NOLPs and formation of small interfering RNAs (siRNAs), with the substantial majority of unique siRNAs arising from the overlapping portions of the cis-NATs. CONCLUSIONS: In aggregate, our results suggest that many cis-NAT NOLPs function in the regulation of conserved promoter/regulatory elements that they 'over-hang'. PMID- 26054754 TI - Repurposing FDA approved drugs against the human fungal pathogen, Candida albicans. AB - BACKGROUND: The high cost and prolonged timeline of new drug discovery and development are major roadblocks to creating therapies for infectious diseases. Candida albicans is an opportunistic fungal pathogen that is the most common cause of fatal fungal infections in humans and costs $2-4 billion dollars to treat in the US alone. METHODS: To accelerate drug discovery, we screened a library of 1581 existing FDA approved drugs, as well as drugs approved abroad, for inhibitors of C. albicans. The screen was done on YPD yeast growth media as well as on the serum plate assay developed in this study. RESULTS: We discovered that fifteen drugs, all which were originally approved for treating various infectious and non-infectious diseases, were able to kill Candida albicans. Additionally, one of those drugs, Octodrine, displays wide-spectrum anti microbial activity. Compared to other selected anti-Candida drugs, Octodrine was shown to be one of the most effective drugs in killing serum-grown Candida albicans without significantly affecting the survival of host macrophages and skin cells. CONCLUSIONS: This approach is useful for the discovery of economically viable new therapies against infectious diseases. PMID- 26054755 TI - MOARF, an Integrated Workflow for Multiobjective Optimization: Implementation, Synthesis, and Biological Evaluation. AB - We describe the development and application of an integrated, multiobjective optimization workflow (MOARF) for directed medicinal chemistry design. This workflow couples a rule-based molecular fragmentation scheme (SynDiR) with a pharmacophore fingerprint-based fragment replacement algorithm (RATS) to broaden the scope of reconnection options considered in the generation of potential solution structures. Solutions are ranked by a multiobjective scoring algorithm comprising ligand-based (shape similarity) biochemical activity predictions as well as physicochemical property calculations. Application of this iterative workflow to optimization of the CDK2 inhibitor Seliciclib (CYC202, R-roscovitine) generated solution molecules in desired physicochemical property space. Synthesis and experimental evaluation of optimal solution molecules demonstrates CDK2 biochemical activity and improved human metabolic stability. PMID- 26054756 TI - Non-linear education gradient across the nutrition transition: mothers' overweight and the population education transition. AB - OBJECTIVE: Previous studies found that developed and developing countries present opposite education-overweight gradients but have not considered the dynamics at different levels of national development. An inverted U-shaped curve is hypothesized to best describe the education-overweight association. It is also hypothesized that as the nutrition transition unfolds within nations the shape of education-overweight curve changes. DESIGN: Multilevel logistic regression was used to estimate the moderating effect of the nutrition transition at the population level on the education-overweight gradient. At the individual level, a non-linear estimate of the education association was used to assess the optimal functional form of the association across the nutrition transition. SETTING: Twenty-two administrations of the Demographic and Health Survey, collected at different time points across the nutrition transition in nine Latin American/Caribbean countries. SUBJECTS: Mothers of reproductive age (15-49 years) in each administration (n 143 258). RESULTS: In the pooled sample, a non-linear education gradient on mothers' overweight was found; each additional year of schooling increases the probability of being overweight up to the end of primary schooling, after which each additional year of schooling decreases the probability of overweight. Also, as access to diets high in animal fats and sweeteners increases over time, the curve's critical point moves to lower education levels, the detrimental positive effect of education diminishes, and both occur as the overall risk of overweight increases with greater access to harmful diets. CONCLUSIONS: Both hypotheses were supported. As the nutrition transition progresses, the education-overweight curve shifts steadily to a negative linear association with a higher average risk of overweight; and education, at increasingly lower levels, acts as a 'social vaccine' against increasing risk of overweight. These empirical patterns fit the general 'population education transition' curve hypothesis about how education's influences on health risks are contextualized across population transitions. PMID- 26054757 TI - Baseline of visceral fat area and decreased body weight correlate with improved pulmonary function after Roux-en-Y gastric bypass in Chinese obese patients with BMI 28-35 kg/m2 and type 2 diabetes: a 6-month follow-up. AB - BACKGROUND: Associations between demographic data and pulmonary function have not been adequately examined in patients that underwent Roux-en-Y Gastric Bypass (RYGB). This study was designed to examine changes in body fat distribution and metabolic parameters after RYGB and whether these changes correlated with improved lung function. METHODS: A retrospective review of 32 ethnic Chinese with obesity with body mass index (BMI) 28-35 kg/m(2) and type 2 diabetes (T2DM) was conducted, focusing on metabolic outcomes and pulmonary function 6 months after RYGB. RESULTS: Forced expiratory volume during first second (FEV1), percentage of forced expiratory volume during first second (FEV1 [%pred]), forced vital capacity (FVC), and percentage of forced vital capacity (FVC [%pred]) all improved significantly after RYGB. These increases all were negatively correlated with decreases in body weight and visceral fat area (VFA). The improvements of FEV1, FEV1 [%pred] and FVC were also negatively correlated with baseline of body weight and VFA. Furthermore, increases in FEV1 and FVC were independently associated with baseline of VFA (beta = -0.003, P = 0.000; beta = -0.004, P = 0.002, respectively). CONCLUSIONS: The baseline of VFA and weight loss induced by RYGB independently correlated with improved pulmonary function in Chinese patients. PMID- 26054758 TI - Developing a programme theory to explain how primary health care teams learn to respond to intimate partner violence: a realist case-study. AB - BACKGROUND: Despite the progress made on policies and programmes to strengthen primary health care teams' response to Intimate Partner Violence, the literature shows that encounters between women exposed to IPV and health-care providers are not always satisfactory, and a number of barriers that prevent individual health care providers from responding to IPV have been identified. We carried out a realist case study, for which we developed and tested a programme theory that seeks to explain how, why and under which circumstances a primary health care team in Spain learned to respond to IPV. METHODS: A realist case study design was chosen to allow for an in-depth exploration of the linkages between context, intervention, mechanisms and outcomes as they happen in their natural setting. The first author collected data at the primary health care center La Virgen (pseudonym) through the review of documents, observation and interviews with health systems' managers, team members, women patients, and members of external services. The quality of the IPV case management was assessed with the PREMIS tool. RESULTS: This study found that the health care team at La Virgen has managed 1) to engage a number of staff members in actively responding to IPV, 2) to establish good coordination, mutual support and continuous learning processes related to IPV, 3) to establish adequate internal referrals within La Virgen, and 4) to establish good coordination and referral systems with other services. Team and individual level factors have triggered the capacity and interest in creating spaces for team leaning, team work and therapeutic responses to IPV in La Virgen, although individual motivation strongly affected this mechanism. Regional interventions did not trigger individual and/ or team responses but legitimated the workings of motivated professionals. CONCLUSIONS: The primary health care team of La Virgen is involved in a continuous learning process, even as participation in the process varies between professionals. This process has been supported, but not caused, by a favourable policy for integration of a health care response to IPV. Specific contextual factors of La Virgen facilitated the uptake of the policy. To some extent, the performance of La Virgen has the potential to shape the IPV learning processes of other primary health care teams in Murcia. PMID- 26054760 TI - Corrigendum: targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. PMID- 26054759 TI - Inactivation of Escherichia coli O157:H7 and Listeria monocytogenes in biofilms by pulsed ultraviolet light. AB - BACKGROUND: The inactivation of biofilms formed by pathogenic bacteria on ready to-eat and minimally processed fruits and vegetables by nonthermal processing methods is critical to ensure food safety. Pulsed ultraviolet (PUV) light has shown promise in the surface decontamination of liquid, powdered, and solid foods. In this study, the antimicrobial efficacy of PUV light treatment on nascent biofilms formed by Escherichia coli O157:H7 and Listeria monocytogenes on the surfaces of food packaging materials, such as low-density polyethylene (LDPE), and fresh produce, such as lettuce (Lactuca sativa) leaves, was investigated. RESULTS: The formation of biofilms on Romaine lettuce leaves and LDPE films was confirmed by crystal violet and Alcian blue staining methods. Inactivation of cells in the biofilm was determined by standard plating procedures, and by a luminescence-based bacterial cell viability assay. Upon PUV treatment of 10 s at two different light source to sample distances (4.5 and 8.8 cm), viable cell counts of L. monocytogenes and E. coli O157:H7 in biofilms on the lettuce surface were reduced by 0.6-2.2 log CFU mL(-1) and 1.1-3.8 log CFU mL(-1), respectively. On the LDPE surface, the efficiency of inactivation of biofilm-encased cells was slightly higher. The maximum values for microbial reduction on LDPE were 2.7 log CFU mL(-1) and 3.9 log CFU mL(-1) for L. monocytogenes and E. coli O157:H7, respectively. Increasing the duration of PUV light exposure resulted in a significant (P < 0.05) reduction in biofilm formation by both organisms. The results also revealed that PUV treatment was more effective at reducing E. coli biofilms compared with Listeria biofilms. A moderate increase in temperature (~7-15 degrees C) was observed for both test materials. CONCLUSIONS: PUV is an effective nonthermal intervention method for surface decontamination of E. coli O157:H7 and L. monocytogenes on fresh produce and packaging materials. PMID- 26054762 TI - Issues deserve attention in encapsulating probiotics: Critical review of existing literature. AB - Probiotic bacteria are being increasingly added to food for developing products with health-promoting properties. However, the efficacy of probiotics in commercial products is often questioned due to the loss of their viability during shelf storage and in human gastrointestinal tracts. Encapsulation of probiotics has been expected to provide protection to probiotics, but not many commercial products contain encapsulated and viable probiotic cells owing to various reasons. To promote the development and application of encapsulation technologies, this paper has critically reviewed previous publications with a focus on the areas where studies have fallen short, including insufficient consideration of structural effects of encapsulating material, general defects in encapsulating methods and issues in evaluation methodologies and risk assessments for application. Corresponding key issues that require further studies are highlighted. Some emerging trends in the field, such as current treads in encapsulating material and recently advanced encapsulation techniques, have also been discussed. PMID- 26054761 TI - The treatment of vasopressin V2-receptor antagonists in cirrhosis patients with ascites: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Ascites is the most common complication of cirrhosis. It may lead to the consequence of poor prognosis and the deterioration of quality of life. Asopressin V2 receptor antagonists is a kind of vaptans, and it has been proved to be effective in hyponatremia patients. We conducted a meta-analysis about treatment of vaptans in cirrhosis patients with ascites. METHODS: Following our selection criteria, we collected a total of 14 studies containing 16 randomized controlled trials (2620 patients) from a series of database about the treatment with vaptans for cirrhosis with ascites patients. The included studies compared the treatment effect of lixivaptan (VPA 985), or RMJ-351647, or satavaptan, or tolvaptan with placebo. RESULTS: The included vaptans (asopressin V2 receptor antagonists) showed significant effect of increasing the serum sodium concentration for cirrhosis patients (WMD = 2.11 mmol/L, p < 0.00001). Patients also could acquire significant improvement of ascites, as this kind of aquaretics can significantly reduce ascites patients' weight (WMD = -1.53, p < 0.00001), abdominal girth (WMD = -2.04, p < 0.00001), and the ratio of worsening ascites (RR = 0.51, p = 0.001). Though the drug did not produce more total adverse events (RR = 1.04, p = 0.09) and the total serious events (RR = 1.04, p = 0.42), the emergence of excessive correction of serum sodium concentrations (>145 mmol/L) was more frequently noted in patients under the employment of vaptans (RR = 2.14, 95 % CI [1.45, 3.16], p = 0.0001). Whether with the administration of vaptans for short-term or long-term, no survival benefit was detected from the selected studies. CONCLUSIONS: Asopressin V2 receptor antagonists could play an effective and safe role in symptomatic treatment for cirrhosis patients with ascites, especially for refractory ascites patients who presented insufficient response to conventional diuretics. PMID- 26054763 TI - MAPPING CHROMOSOME NEIGHBORHOODS. AB - The discovery of topologically associating domains (TADs) changed the way researchers think about gene expression and chromosome structure. Jeffrey Perkel takes a closer look into these "chromosome neighborhoods." PMID- 26054764 TI - Three-dimensional migration of neutrophils through an electrospun nanofibrous membrane. AB - The study of immune cell migration is important for understanding the immune system network, which is associated with the response to foreign cells. Neutrophils act against foreign cells before any other immune cell, and they must be able to change shape and squeeze through narrow spaces in the extracellular matrix (ECM) during migration to sites of infection. Conventional in vitro migration assays are typically performed on two-dimensional substrates that fail to reproduce the three-dimensional (3-D) nature of the ECM. Here we present an in vitro method to simulate the 3-D migration of neutrophils using an electrospun nanofibrous membrane, which is similar to the ECM in terms of morphology. We examined the properties of neutrophil movement and the effects of gravity and the presence of IL-8, which has been widely used as a chemotactic attractant for neutrophils. The number of neutrophils passing through the nanofibrous membrane were higher, and their movement was more active in the presence of IL-8. Also, we confirmed that neutrophils could migrate against gravity toward IL-8 through a nanofibrous membrane. PMID- 26054765 TI - Rapid method for the isolation of mammalian sperm DNA. AB - The unique DNA packaging of spermatozoa renders them resistant to DNA isolation techniques used for somatic cells, requiring alternative methods that are slow and labor intensive. Here we present a rapid method for isolating high-quality sperm DNA. Isolated human sperm cells were homogenized with 0.2 mm steel beads for 5 min at room temperature in the presence of guanidine thiocyanate lysis buffer supplemented with 50 mM tris(2-carboxyethyl)phosphine (TCEP). Our method yielded >90% high-quality DNA using 3 different commercially available silica based spin columns. DNA yields did not differ between immediate isolation (2.84 ± 0.04 pg/cell) and isolation after 2 weeks of homogenate storage at room temperature (2.91 ± 0.13 pg/cell). DNA methylation analyses revealed similar methylation levels at both time points for three imprinted loci. Our protocol has many advantages: it is conducted at room temperature; lengthy proteinase K (ProK) digestions are eliminated; the reducing agent, TCEP, is odorless and stable at room temperature; nucleic acids are stabilized, allowing storage of homogenate; and it is adaptable for other mammalian species. Taken together, the benefits of our improved method have important implications for settings where sample processing constraints exist. PMID- 26054766 TI - Combined in vitro transcription and reverse transcription to amplify and label complex synthetic oligonucleotide probe libraries. AB - Oligonucleotide microarrays allow the production of complex custom oligonucleotide libraries for nucleic acid detection-based applications such as fluorescence in situ hybridization (FISH). We have developed a PCR-free method to make single-stranded DNA (ssDNA) fluorescent probes through an intermediate RNA library. A double-stranded oligonucleotide library is amplified by transcription to create an RNA library. Next, dye- or hapten-conjugate primers are used to reverse transcribe the RNA to produce a dye-labeled cDNA library. Finally the RNA is hydrolyzed under alkaline conditions to obtain the single-stranded fluorescent probes library. Starting from unique oligonucleotide library constructs, we present two methods to produce single-stranded probe libraries. The two methods differ in the type of reverse transcription (RT) primer, the incorporation of fluorescent dye, and the purification of fluorescent probes. The first method employs dye-labeled reverse transcription primers to produce multiple differentially single-labeled probe subsets from one microarray library. The fluorescent probes are purified from excess primers by oligonucleotide-bead capture. The second method uses an RNA:DNA chimeric primer and amino-modified nucleotides to produce amino-allyl probes. The excess primers and RNA are hydrolyzed under alkaline conditions, followed by probe purification and labeling with amino-reactive dyes. The fluorescent probes created by the combination of transcription and reverse transcription can be used for FISH and to detect any RNA and DNA targets via hybridization. PMID- 26054767 TI - RiboTag is a flexible tool for measuring the translational state of targeted cells in heterogeneous cell cultures. AB - Primary neuronal cultures are a useful tool for measuring pharmacological- and transgene-regulated gene expression; however, accurate measurements can be confounded by heterogeneous cell types and inconsistent transfection efficiency. Here we describe our adaptation of a ribosomal capture strategy that was designed to be used in transgenic mice expressing tagged ribosomal subunits (RiboTag) in specific cell types, thereby allowing measurement of translating RNAs from desired cell types within complex tissues. Using this strategy we were able to isolate and analyze neuron-specific RNA despite the presence of glia by co transfecting experimental plasmids with plasmids that selectively express RiboTag in neurons. RiboTag immunoprecipitation was capable of recovering high integrity RNA from small numbers of transfected cells that can then be interrogated by a variety of methods (e.g., RT-qPCR, PCR array, RNA-Seq) and compared with basal RNA expression of the entire culture. Additionally, we demonstrate how co transfection of RiboTag with small hairpin RNA (shRNA) constructs can validate and accurately assess the degree of gene expression knockdown, and how RiboTag can be used to measure receptor-mediated gene regulation with transiently expressed designer receptors exclusively activated by designer drugs (DREADDs). RiboTag co-transfection represents a convenient and powerful tool to isolate RNA from a specific subset of cultured cells with a variety of applications for experiments in vitro. PMID- 26054768 TI - A newly established culture method highlights regulatory roles of retinoic acid on morphogenesis and calcification of mammalian limb cartilage. AB - During mammalian embryogenesis, sclerotome-derived chondrocytes in the limb bud are arranged into a complicated bone shape with specific areas undergoing hypertrophy and calcification, creating a region-specific mineralized pattern in the cartilage. To follow chondrogenesis progression in vitro, we isolated limb cartilage from mice on embryonic day 13 (E13) and cultured it at the air-liquid interface after microsurgical removal of the ectoderm/epidermis. Explants underwent proper morphogenesis, giving rise to complete templates for limb bones in vitro. We found that region-specific calcification patterns resembling limbs of prepartum mature embryos could be induced in explants using culture medium containing high concentrations of CaCl2 (Ca), ascorbic acid (AA), and beta glycerophosphoric acid (BGP). In this culture system, excess amounts of all-trans retinoic acid (RA) severely disrupted morphogenesis and calcification patterns in limb cartilage. These effects were more pronounced in forearms than in phalanges. Although dissociated, the nascent chondrocytes in culture did not give rise to cartilage units even though augmented calcification was induced in these cell aggregates in the presence of RA. Taken together, our newly established culture system revealed that RA independently regulates three-dimensional morphogenesis and calcification. PMID- 26054769 TI - STITCHER: A web resource for high-throughput design of primers for overlapping PCR applications. AB - Overlapping PCR is routinely used in a wide number of molecular applications. These include stitching PCR fragments together, generating fluorescent transcriptional and translational fusions, inserting mutations, making deletions, and PCR cloning. Overlapping PCR is also used for genotyping by traditional PCR techniques and in detection experiments using techniques such as loop-mediated isothermal amplification (LAMP). STITCHER is a web tool providing a central resource for researchers conducting all types of overlapping PCR experiments with an intuitive interface for automated primer design that's fast, easy to use, and freely available online (http://ohalloranlab.net/STITCHER.html). STITCHER can handle both single sequence and multi-sequence input, and specific features facilitate numerous other PCR applications, including assembly PCR, adapter PCR, and primer walking. Field PCR, and in particular, LAMP, offers promise as an on site tool for pathogen detection in underdeveloped areas, and STITCHER includes off-target detection features for pathogens commonly targeted using LAMP technology. PMID- 26054770 TI - A streamlined ribosome profiling protocol for the characterization of microorganisms. AB - Ribosome profiling is a powerful tool for characterizing in vivo protein translation at the genome scale, with multiple applications ranging from detailed molecular mechanisms to systems-level predictive modeling. Though highly effective, this intricate technique has yet to become widely used in the microbial research community. Here we present a streamlined ribosome profiling protocol with reduced barriers to entry for microbial characterization studies. Our approach provides simplified alternatives during harvest, lysis, and recovery of monosomes and also eliminates several time-consuming steps, in particular size selection steps during library construction. Furthermore, the abundance of rRNAs and tRNAs in the final library is drastically reduced. Our streamlined workflow enables greater throughput, cuts the time from harvest to the final library in half (down to 3-4 days), and generates a high fraction of informative reads, all while retaining the high quality standards of the existing protocol. PMID- 26054771 TI - Probiotics for the treatment of upper and lower respiratory-tract infections in children: systematic review based on randomized clinical trials. AB - OBJECTIVES: Evaluate the effect of probiotics on the symptoms, duration of disease, and the occurrence of new episodes of upper and lower respiratory infections in healthy children. SOURCES: In order to identify eligible randomized controlled trials, two reviewers accessed four electronic databases [MEDLINE/PubMed, Scopus (Elsevier), Web of Science, and Cochrane (Cochrane VHL)], as well as ClinicalTrials.gov until January 2015. Descriptors were determined by using the Medical Subject Headings tool, following the same search protocol. SUMMARY OF THE FINDINGS: Studies showed to be heterogeneous regarding strains of probiotics, the mode of administration, the time of use, and outcomes. The present review identified 11 peer-reviewed, randomized clinical trials, which analyzed a total of 2417 children up to 10 incomplete years of age. In the analysis of the studies, reduction in new episodes of disease was a favorable outcome for the use of probiotics in the treatment of respiratory infections in children. It is noteworthy that most of these studies were conducted in developed countries, with basic sanitation, health care, and strict, well-established and well-organized guidelines on the use of probiotics. Adverse effects were rarely reported, demonstrating probiotics to be safe. CONCLUSIONS: Despite the encouraging results - reducing new episodes of respiratory infections - the authors emphasize the need for further research, especially in developing countries, where rates of respiratory infections in children are higher when compared to the high per capita-income countries identified in this review. PMID- 26054772 TI - Adverse perinatal outcomes for advanced maternal age: a cross-sectional study of Brazilian births. AB - OBJECTIVES: To investigate the risk of adverse perinatal outcomes in women aged >=41 years relatively to those aged 21-34. METHODS: Approximately 8.5 million records of singleton births in Brazilian hospitals in the period 2004-2009 were investigated. Odds ratios were estimated for preterm and post-term births, for low Apgar scores at 1 min and at 5 min, for asphyxia, for low birth weight, and for macrosomia. RESULTS: For pregnant women >=41, increased risks were identified for preterm births, for post-term births (except for primiparous women with schooling >=12 years), and for low birth weight. When comparing older vs. younger women, higher educational levels ensure similar risks of low Apgar score at 1 min (for primiparous mothers and term births), of low Apgar score at 5 min (for term births), of macrosomia (for non-primiparous women), and of asphyxia. CONCLUSION: As a rule, older mothers are at higher risk of adverse perinatal outcomes, which, however, may be mitigated or eliminated, depending on gestational age, parity, and, especially, on the education level of the pregnant woman. PMID- 26054773 TI - Translation, cultural adaptation, and validation of the celiac disease DUX (CDDUX). AB - OBJECTIVE: To translate, cross-culturally adapt, and validate a specific questionnaire for the evaluation of celiac children and adolescents, the celiac disease DUX (CDDUX). METHODS: The steps suggested by Reichenheim and Moraes (2007) were followed to obtain conceptual, item, semantic, operational, and measurement equivalences. Four pediatric gastroenterologists; a researcher with tool validation background; three English teachers; and 33 celiac patients, aged 8-18 years, and their caregivers participated in the study. The scores of celiac patients and those obtained from their caregivers were compared. Among the patients, the scores were compared in relation to gender and age. RESULTS: All items were considered relevant to the construct and good semantic equivalence of the version was acquired. During measurement equivalence, the exploratory factor analysis showed appropriate weight of all items and good internal consistency, with Cronbach's alpha of 0.81. Significant difference was found among the final scores of children and their caregivers. There was no difference among the final scores in relation to gender or age. CONCLUSION: The questionnaire was translated and adapted according to all the proposed steps, with all equivalences adequately met. It is a valid tool to access the QoL of celiac children and adolescents in the translated language. PMID- 26054774 TI - Clinical and laboratory description of a series of cases of acute viral myositis. AB - OBJECTIVE: Describe the clinical and laboratory profile, follow-up, and outcome of a series of cases of acute viral myositis. METHOD: A retrospective analysis of suspected cases under observation in the emergency department was performed, including outpatient follow-up with the recording of respiratory infection and musculoskeletal symptoms, measurement of muscle enzymes, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), transaminases (AST and ALT), blood count, C reactive protein, and erythrocyte sedimentation rate in the acute phase and during follow-up until normalization. RESULTS: Between 2000 and 2009, 42 suspected cases were identified and 35 (27 boys) were included. The median age was 7 years and the diagnosis was reported in 89% in the first emergency visit. The observed respiratory symptoms were cough (31%), rhinorrhea (23%), and fever (63%), with a mean duration of 4.3 days. Musculoskeletal symptoms were localized pain in the calves (80%), limited ambulation (57%), gait abnormality (40%), and muscle weakness in the lower limbs (71%), with a mean duration of 3.6 days. There was significant increase in CPK enzymes (5507+/-9180U/L), LDH (827+/-598U/L), and AST (199+/-245U/L), with a tendency to leukopenia (4590+/-1420) leukocytes/mm(3). The complete recovery of laboratory parameters was observed in 30 days (median), and laboratory and clinical recurrence was documented in one case after 10 months. CONCLUSION: Typical symptoms with increased muscle enzymes after diagnosis of influenza and self-limited course of the disease were the clues to the diagnosis. The increase in muscle enzymes indicate transient myotropic activity related to seasonal influenza, which should be considered, regardless of the viral identification, possibly associated with influenza virus or other respiratory viruses. PMID- 26054775 TI - Portuguese Validation of the Consideration of Future Consequences Scale. AB - The Consideration of Future Consequences Scale (CFC-S) is a measure of the extent to which individuals reflect and are influenced by the immediate as well as by the distant outcomes of current behavior. It's composed by 12 items, grouped into two subscales (future and immediate). This study aims to explore the factor structure, psychometric properties and construct validity of the Portuguese version of the CFC-S in 5 samples, composed by 527 participants with ages between 13 and 71. A 2 factor structure has been found through Confirmatory Factor Analysis among several tested models. Item 5 has been eliminated in order to achieve better fit indices (chi2 df = 3.88, CFI = .90, GFI = .95, RMSEA = .07) and improve internal consistency. Both CFC subscales presented strong correlations with several psychological phenomena (Sensation Seeking, Self Esteem, Temporal Extension and Time Perspective) and main effects among groups of age and criminal record (for CFC-I, p < .001, for CFC-F, p < .001). These results allow us to support CFC as an efficient psychological evaluation instrument and as an important metric for individual differences in the study of temporal orientation. PMID- 26054776 TI - [Selective enrichment of Pseudomonas spp. in the rhizoplane of different plant species]. AB - In contrast to rhizobia-legume symbiosis, the specificity for root colonization by pseudomonads seems to be less strict. However, several studies about bacterial diversity in the rhizosphere highlight the influence of plant species on the selective enrichment of certain microorganisms from the bulk soil community. In order to evaluate the effect that different crops have on the structure of pseudomonad community on the root surface, we performed plant trap experiments, using surface-disinfected maize, wheat or soybean seeds that were sown in pots containing the same pristine soil as substrate. Rhizoplane suspensions were plated on a selective medium for Pseudomonas, and pooled colonies served as DNA source to carry out PCR-RFLP community structure analysis of the pseudomonads specific marker genes oprF and gacA. PCR-RFLP profiles were grouped by plant species, and were distinguished from those of bulk soil samples. Partial sequencing of 16S rDNA genes of some representative colonies of Pseudomonas confirmed the selective enrichment of distinctive genotypes in the rhizoplane of each plant species. These results support the idea that the root systems of agricultural crops such as soybean, maize and wheat, select differential sets of pseudomonads from the native microbial repertoire inhabiting the bulk soil. PMID- 26054777 TI - Older Adults' Use of Online and Offline Sources of Health Information and Constructs of Reliance and Self-Efficacy for Medical Decision Making. AB - We know little about older adults' use of online and offline health information sources for medical decision making despite increasing numbers of older adults who report using the Internet for health information to aid in patient-provider communication and medical decision making. Therefore we investigated older adult users and nonusers of online and offline sources of health information and factors related to medical decision making. Survey research was conducted using random digit dialing of Florida residents' landline telephones. The Decision Self Efficacy Scale and the Reliance Scale were used to measure relationships between users and nonusers of online health information. Study respondents were 225 older adults (age range = 50-92 years, M = 68.9, SD = 10.4), which included users (n = 105) and nonusers (n = 119) of online health information. Users and nonusers differed in frequency and types of health sources sought. Users of online health information preferred a self-reliant approach and nonusers of online health information preferred a physician-reliant approach to involvement in medical decisions on the Reliance Scale. This study found significant differences between older adult users and nonusers of online and offline sources of health information and examined factors related to online health information engagement for medical decision making. PMID- 26054778 TI - Vitamin D3 supplementation increases insulin level by regulating altered IP3 and AMPA receptor expression in the pancreatic islets of streptozotocin-induced diabetic rat. AB - Pancreatic islets, particularly insulin-secreting beta cells, share common characteristics with neurons. Glutamate is one of the major excitatory neurotransmitter in the brain and pancreas, and its action is mediated through glutamate receptors. In the present work, we analysed the role of vitamin D3 in the modulation of AMPA receptor subunit and their functional role in insulin release. Radio receptor binding study in diabetic rats showed a significant increase in AMPA receptor density. Insulin AMPA colabelling study showed an altered AMPA GluR2 and GluR4 subunit expression in the pancreatic beta cells. We also found lowered IP3 content and decreased IP3 receptor in pancreas of diabetic rats. The alterations in AMPA and IP3 receptor resulted in reduced cytosolic calcium level concentration, which further blocks Ca(2+)-mediated insulin release. Vitamin D3 supplementation restored the alteration in vitamin D receptor expression, AMPA receptor density and AMPA and IP3 receptor expression in the pancreatic islets that helps to restore the calcium-mediated insulin secretion. Our study reveals the antidiabetic property of vitamin D3 that is suggested to have therapeutic role through regulating glutamatergic function in diabetic rats. PMID- 26054779 TI - Fever, Jaundice, Abdominal Pain, Skin Lesions, and Dark Urine for 2 Days. PMID- 26054780 TI - Adherence to Vitamin D Recommendations Among US Infants Aged 0 to 11 Months, NHANES, 2009 to 2012. PMID- 26054781 TI - A Critical Review of the Marketing Claims of Infant Formula Products in the United States. AB - A highly competitive infant formula market has resulted in direct-to-consumer marketing intended to promote the sale of modified formulas that claim to ameliorate common infant feeding problems. The claims associated with these marketing campaigns are not evaluated with reference to clinical evidence by the Food and Drug Administration. We aimed to describe the language of claims made on formula labels and compare it with the evidence in systematic reviews. Of the 22 product labels we identified, 13 product labels included claims about colic and gastrointestinal symptoms. There is insufficient evidence to support the claims that removing or reducing lactose, using hydrolyzed or soy protein or adding pre /probiotics to formula benefits infants with fussiness, gas, or colic yet claims like "soy for fussiness and gas" encourage parents who perceive their infants to be fussy to purchase modified formula. Increased regulation of infant formula claims is warranted. PMID- 26054782 TI - Parapneumonic Effusion in Children: An Up-to-Date Review. PMID- 26054783 TI - Marijuana Exposure Among Children Younger Than Six Years in the United States. AB - This study investigates marijuana exposures among children <6 years old in the United States using data from the National Poison Data System. From 2000 through 2013, there were 1969 marijuana exposures among children <6 years old and an exposure rate of 5.90 per million children. The mean age of an exposed child was 1.81 years (median = 1.58 years). The majority of the children were exposed through ingestion (75.0%), and 18.5% of exposures required admission to a health care facility. The rate of marijuana exposure was significantly (2.82 times) higher in states where its use was legalized prior to 2000 compared with states where its use is not legal. Because more states are likely to pass legislation legalizing medical and recreational use of marijuana, increased efforts to establish child-focused safety requirements regarding packaging of commercially sold marijuana products are needed to help prevent more children from being exposed to this schedule I substance. PMID- 26054784 TI - Quantitative proteomic analysis of paired colorectal cancer and non-tumorigenic tissues reveals signature proteins and perturbed pathways involved in CRC progression and metastasis. AB - Modern proteomics has proven instrumental in our understanding of the molecular deregulations associated with the development and progression of cancer. Herein, we profile membrane-enriched proteome of tumor and adjacent normal tissues from eight CRC patients using label-free nanoLC-MS/MS-based quantitative proteomics and advanced pathway analysis. Of the 948 identified proteins, 184 proteins were differentially expressed (P<0.05, fold change>1.5) between the tumor and non tumor tissue (69 up-regulated and 115 down-regulated in tumor tissues). The CRC tumor and non-tumor tissues clustered tightly in separate groups using hierarchical cluster analysis of the differentially expressed proteins, indicating a strong CRC-association of this proteome subset. Specifically, cancer associated proteins such as FN1, TNC, DEFA1, ITGB2, MLEC, CDH17, EZR and pathways including actin cytoskeleton and RhoGDI signaling were deregulated. Stage specific proteome signatures were identified including up-regulated ribosomal proteins and down-regulated annexin proteins in early stage CRC. Finally, EGFR(+) CRC tissues showed an EGFR-dependent down-regulation of cell adhesion molecules, relative to EGFR(-) tissues. Taken together, this study provides a detailed map of the altered proteome and associated protein pathways in CRC, which enhances our mechanistic understanding of CRC biology and opens avenues for a knowledge driven search for candidate CRC protein markers. PMID- 26054785 TI - [Persistant pneumothorax in a polytraumatized patient]. PMID- 26054786 TI - Intensive care medicine and organ donation. Beyond our usual frontiers. PMID- 26054787 TI - [The de Winter ST-T pattern: An equivalent to acute coronary syndrome with ST segment elevation]. PMID- 26054788 TI - An oral DNA vaccine against infectious haematopoietic necrosis virus (IHNV) encapsulated in alginate microspheres induces dose-dependent immune responses and significant protection in rainbow trout (Oncorrhynchus mykiss). AB - Administered by intramuscular injection, a DNA vaccine (pIRF1A-G) containing the promoter regions upstream of the rainbow trout interferon regulatory factor 1A gene (IRF1A) driven the expression of the infectious hematopoietic necrosis virus (IHNV) glycoprotein (G) elicited protective immune responses in rainbow trout (Oncorhynchus mykiss). However, less laborious and cost-effective routes of DNA vaccine delivery are required to vaccinate large numbers of susceptible farmed fish. In this study, the pIRF1A-G vaccine was encapsulated into alginate microspheres and orally administered to rainbow trout. At 1, 3, 5, and 7 d post vaccination, IHNV G transcripts were detected by quantitative real-time PCR in gills, spleen, kidney and intestinal tissues of vaccinated fish. This result suggested that the encapsulation of pIRF1A-G in alginate microparticles protected the DNA vaccine from degradation in the fish stomach and ensured vaccine early delivery to the hindgut, vaccine passage through the intestinal mucosa and its distribution thought internal and external organs of vaccinated fish. We also observed that the oral route required approximately 20-fold more plasmid DNA than the injection route to induce the expression of significant levels of IHNV G transcripts in kidney and spleen of vaccinated fish. Despite this limitation, increased IFN-1, TLR-7 and IgM gene expression was detected by qRT-PCR in kidney of vaccinated fish when a 10 MUg dose of the oral pIRF1A-G vaccine was administered. In contrast, significant Mx-1, Vig-1, Vig-2, TLR-3 and TLR-8 gene expression was only detected when higher doses of pIRF1A-G (50 and 100 MUg) were orally administered. The pIRF1A-G vaccine also induced the expression of several markers of the adaptive immune response (CD4, CD8, IgM and IgT) in kidney and spleen of immunized fish in a dose-dependent manner. When vaccinated fish were challenged by immersion with live IHNV, evidence of a dose-response effect of the oral vaccine could also be observed. Although the protective effects of the oral pIRF1A-G vaccine after a challenge with IHNV were partial, significant differences in cumulative percent mortalities among the orally vaccinated fish and the unvaccinated or empty-plasmid vaccinated fish were observed. Similar levels of protection were obtained after the intramuscular administration of 5 MUg of pIRF1A-G or after the oral administration of a high dose of pIRF1A-G vaccine (100 MUg); with 70 and 56 relative percent survival values, respectively. When fish were vaccinated with alginate microspheres containing high doses of the pIRF1A-G vaccine (50 or 100 MUg), a significant increase in the production of anti-IHNV antibodies was detected in serum samples of the vaccinated fish compared with that in unvaccinated fish. At 10 days post-challenge, IHNV N gene expression was nearly undetectable in kidney and spleen of orally vaccinated fish which suggested that the vaccine effectively reduced the amount of virus in tissues of vaccinated fish that survived the challenge. In conclusion, our results demonstrated a significant increase in fish immune responses and resistance to an IHNV infection after the oral administration of increasing concentrations of a DNA vaccine against IHNV encapsulated into alginate microspheres. PMID- 26054789 TI - Maintaining older brain functionality: A targeted review. AB - The unprecedented growth in the number of older adults in our society is accompanied by the exponential increase in the number of elderly people who will suffer cognitive decline and dementia in the next decades. This will create an enormous cost for governments, families and individuals. Brain plasticity and its role in brain adaptation to the process of aging is influenced by other changes as a result of co-morbidities, environmental factors, personality traits (psychosocial variables) and genetic and epigenetic factors. This review summarizes recent findings obtained mostly from interventional studies that aim to prevent and/or delay age-related cognitive decline in healthy adults. There are a multitude of such studies. In this paper, we focused our review on physical activity, computerized cognitive training and social enhancement interventions on improving cognition, physical health, independent living and wellbeing of older adults. The methodological limitations of some of these studies, and the need for new multi-domain synergistic interventions, based on current advances in neuroscience and social-brain theories, are discussed. PMID- 26054791 TI - When ageing meets the blues: Are current antidepressants effective in depressed aged patients? AB - "I had to wait 110 years to become famous. I wanted to enjoy it as long as possible.", Jeanne Louise Calment (1875-1997). This review summarizes current knowledge of the effects of antidepressant drugs in elderly patients (double blind placebo (n=27) or active comparator-controlled clinical trials (n=21) indexed in Pubmed in depressed patients aged >=60) and in aged mice (>=9 months) and middle-aged rats (>=14 months) on depression-related symptoms and cognitive performances. Finally, other potential therapeutic targets for treating depression-related disorders in elderly patients are also addressed (neurogenesis, GABAB receptor, 5-HT4 receptor, mTOR signaling). Overall, the very few published preclinical studies (n=12 in total) in middle-aged and aged rodents seem to suggest that selective serotonin reuptake inhibitors (SSRIs) may be less effective than tricyclic antidepressant drugs (TCAs) in ameliorating depression like behavior and cognitive functions. On the other hand, results from clinical trials suggest that there is not a marked difference in efficacy and safety profiles of current marketed classes of antidepressant drugs. PMID- 26054792 TI - Contribution of brain or biological reserve and cognitive or neural reserve to outcome after TBI: A meta-analysis (prior to 2015). AB - Brain/biological (BR) and cognitive/neural reserve (CR) have increasingly been used to explain some of the variability that occurs as a consequence of normal ageing and neurological injuries or disease. However, research evaluating the impact of reserve on outcomes after adult traumatic brain injury (TBI) has yet to be quantitatively reviewed. This meta-analysis consolidated data from 90 studies (published prior to 2015) that either examined the relationship between measures of BR (genetics, age, sex) or CR (education, premorbid IQ) and outcomes after TBI or compared the outcomes of groups with high and low reserve. The evidence for genetic sources of reserve was limited and often contrary to prediction. APOE ?4 status has been studied most, but did not have a consistent or sizeable impact on outcomes. The majority of studies found that younger age was associated with better outcomes, however most failed to adjust for normal age-related changes in cognitive performance that are independent of a TBI. This finding was reversed (older adults had better outcomes) in the small number of studies that provided age-adjusted scores; although it remains unclear whether differences in the cause and severity of injuries that are sustained by younger and older adults contributed to this finding. Despite being more likely to sustain a TBI, males have comparable outcomes to females. Overall, as is the case in the general population, higher levels of education and pre-morbid IQ are both associated with better outcomes. PMID- 26054793 TI - How is working memory content consciously experienced? The 'conscious copy' model of WM introspection. AB - We address the issue of how visual information stored in working memory (WM) is introspected. In other words, how do we become aware of WM content in order to consciously examine or manipulate it? Influential models of WM have suggested that WM representations are either conscious by definition, or directly accessible for conscious inspection. We propose that WM introspection does not operate on the actual memory trace but rather requires a new representation to be created for the conscious domain. This conscious representation exists in addition and in parallel to the actual memory representation. The existence of such a separate representation is revealed by and reflected in the qualitatively different functional characteristics between the actual memory trace and its conscious experience, and their distinct interactions within external visual input. Our model differs from state-based models in that WM introspection does not involve a change in the state of WM content, but rather involves the creation of a new, second representation existing in parallel to the original memory trace. PMID- 26054794 TI - Affective agnosia: Expansion of the alexithymia construct and a new opportunity to integrate and extend Freud's legacy. AB - We describe a new type of agnosia consisting of an impairment in the ability to mentally represent or know what one is feeling. Freud the neurologist coined the term "agnosia" in 1891 before creating psychoanalysis in 1895 but the term has not been previously applied to the domain of affective processing. We propose that the concept of "affective agnosia" advances the theory, measurement and treatment of what is now called "alexithymia," meaning "lack of words for emotion." We trace the origin of the alexithymia construct and discuss the strengths and limitations of extant research. We review evidence that the ability to represent and put emotions into words is a developmental achievement that strongly influences one's ability to experience, recognize, understand and use one's own emotional responses. We describe the neural substrates of emotional awareness and affective agnosia and compare and contrast these with related conditions. We then describe how this expansion of the conceptualization and measurement of affective processing deficits has important implications for basic emotion research and clinical practice. PMID- 26054795 TI - Probing the mechanisms of drug release from amorphous solid dispersions in medium soluble and medium-insoluble carriers. AB - The objective of the current study is to mechanistically differentiate the dissolution and supersaturation behaviors of amorphous drugs from amorphous solid dispersions (ASDs) based on medium-soluble versus medium-insoluble carriers under nonsink dissolution conditions through a direct head-to-head comparison. ASDs of indomethacin (IND) were prepared in several polymers which exhibit different solubility behaviors in acidic (pH1.2) and basic (pH7.4) dissolution media. The selected polymers range from water-soluble (e.g., PVP and Soluplus) and water insoluble (e.g., ethylcellulose and Eudragit RL PO) to those only soluble in an acidic or basic dissolution medium (e.g., Eudragit E100, Eudragit L100, and HPMCAS). At 20wt.% drug loading, DSC and powder XRD analysis confirmed that the majority of incorporated IND was present in an amorphous state. Our nonsink dissolution results confirm that whether the carrier matrix is medium soluble determines the release mechanism of amorphous drugs from ASD systems which has a direct impact on the rate of supersaturation generation, thus in turn affecting the evolution of supersaturation in amorphous systems. For example, under nonsink dissolution conditions, the release of amorphous IND from medium-soluble carriers is governed by a dissolution-controlled mechanism leading to an initial surge of supersaturation followed by a sharp decline in drug concentration due to rapid nucleation and crystallization. In contrast, the dissolution of IND ASD from medium-insoluble carriers is more gradual as drug release is regulated by a diffusion-controlled mechanism by which drug supersaturation is built up gradually and sustained over an extended period of time without any apparent decline. Since several tested carrier polymers can be switched from soluble to insoluble by simply changing the pH of the dissolution medium, the results obtained here provide unequivocal evidence of the proposed transition of kinetic solubility profiles from the same ASD system induced by changes in the drug release mechanism in dissolution medium of a different pH. PMID- 26054796 TI - Significance of Extraction Forces in Kidney Stone Basketing. AB - INTRODUCTION: Ureteroscopic stone extraction devices are effective tools in the management of urolithiasis, but on occasion, their improper use can cause injury to the ureter. Avulsion and perforation of the ureter as a result of excessive forces on the extraction device are some of the more serious complications of this treatment. MATERIALS AND METHODS: In this article, avulsion and perforation forces were measured by two different test setups. Eleven clinicians were asked to apply three ranges of forces (safe, cautious, and dangerous). RESULTS: The output force measurements were recorded and plotted for further analysis. The maximal average perforation forces were 7.13+/-2.36 N in the benchtop tests and 7.07+/-2.20 N in the ex-vivo porcine tests (P=0.54). The maximal average avulsion forces were measured to be 10.14+/-2.01 N in the benchtop tests. Although the average forces were similar in the proximal and distal parts of the ureter (P=0.27), higher values were recorded for the distal part. The operative time was noted to be significantly different in the safe and cautious force regions (P=0.006). The average forces were higher in the benchtop tests compared with the porcine ureter tests. The extraction forces were measured and were noted to be significantly different for attending physicians and residents. The results suggest the need for force feedback training for residents. CONCLUSION: The findings can be used to design a "smart device" that can provide visual force feedback to clinicians while they are operating, leading to improved patient outcome. PMID- 26054790 TI - Negative affective states and cognitive impairments in nicotine dependence. AB - Smokers have substantial individual differences in quit success in response to current treatments for nicotine dependence. This observation may suggest that different underlying motivations for continued tobacco use across individuals and nicotine cessation may require different treatments in different individuals. Although most animal models of nicotine dependence emphasize the positive reinforcing effects of nicotine as the major motivational force behind nicotine use, smokers generally report that other consequences of nicotine use, including the ability of nicotine to alleviate negative affective states or cognitive impairments, as reasons for continued smoking. These states could result from nicotine withdrawal, but also may be associated with premorbid differences in affective and/or cognitive function. Effects of nicotine on cognition and affect may alleviate these impairments regardless of their premorbid or postmorbid origin (e.g., before or after the development of nicotine dependence). The ability of nicotine to alleviate these symptoms would thus negatively reinforce behavior, and thus maintain subsequent nicotine use, contributing to the initiation of smoking, the progression to dependence and relapse during quit attempts. The human and animal studies reviewed here support the idea that self medication for pre-morbid and withdrawal-induced impairments may be more important factors in nicotine addiction and relapse than has been previously appreciated in preclinical research into nicotine dependence. Given the diverse beneficial effects of nicotine under these conditions, individuals might smoke for quite different reasons. This review suggests that inter-individual differences in the diverse effects of nicotine associated with self-medication and negative reinforcement are an important consideration in studies attempting to understand the causes of nicotine addiction, as well as in the development of effective, individualized nicotine cessation treatments. PMID- 26054797 TI - Cribriform-morular variant of papillary thyroid carcinoma: a study of 3 cases featuring the PIK3CA mutation. AB - The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is an unusual neoplasm with a considerably important association with familial adenomatous polyposis in young women, characterized by a peculiar histologic morphology with mixed cribriform, papillary, solid, tall columnar, and morular patterns. However, it can also occur sporadically. The molecular pathogenesis of sporadic CMV-PTC is not completely understood. We report cases of 3 patients with sporadic CMV-PTC with PIK3CA mutations. Using sequencing analyses and immunohistochemistry, we examined KRAS, BRAF, PIK3CA, and CTNNB1 mutations and related proteins, including beta-catenin, PTEN, CD10, estrogen receptor, progesterone receptor, cytokeratin 19, and cyclin D1 in 3 CMV-PTCs. The 3 patients were teenaged girls. The tumors were solitary and encapsulated without cervical lymph node metastasis. They showed no recurrence for more than 6 years after the operation. Three tumors were diffusely positive for beta-catenin, cyclin D1, and PTEN. The biphasic immunohistochemical patterns between the morular and nonmorular components were identified; the nonmorular components were positive for estrogen receptor, progesterone receptor, and cytokeratin 19, whereas the morular components showed CD10 positivity. All tumors harbored the same mutation in exon 9, codon 545 of the PIK3CA gene (p.E545A), whereas the KRAS, BRAF, and CTNNB1 mutations were not detected. This is the first study identifying the PIK3CA mutation specifically in sporadic CMV-PTC. The presence of the PIK3CA mutation and the wild-type KRAS, BRAF, CTNNB1 genes, and the intact PTEN expression in 3 sporadic CMV-PTCs may suggest the possible contribution of the PIK3CA mutation in its tumorigenesis. PMID- 26054798 TI - Letter to the editor response. PMID- 26054800 TI - Arabidopsis AINTEGUMENTA mediates salt tolerance by trans-repressing SCABP8. AB - The Arabidopsis AINTEGUMENTA (ANT) gene, which encodes an APETALA2 (AP2)-like transcription factor, controls plant organ cell number and organ size throughout shoot development. ANT is thus a key factor in the development of plant shoots. Here, we have found that ANT plays an essential role in conferring salt tolerance in Arabidopsis. ant-knockout mutants presented a salt-tolerant phenotype, whereas transgenic plants expressing ANT under the 35S promoter (35S:ANT) exhibited more sensitive phenotypes under high salt stress. Further analysis indicated that ANT functions mainly in the shoot response to salt toxicity. Target gene analysis revealed that ANT bound to the promoter of SOS3-LIKE CALCIUM BINDING PROTEIN 8 (SCABP8), which encodes a putative Ca(2+) sensor, thereby inhibiting expression of SCABP8 (also known as CBL10). It has been reported that the salt sensitivity of scabp8 is more prominent in shoot tissues. Genetic experiments indicated that the mutation of SCABP8 suppresses the ant-knockout salt-tolerant phenotype, implying that ANT functions as a negative transcriptional regulator of SCABP8 upon salt stress. Taken together, the above results reveal that ANT is a novel regulator of salt stress and that ANT binds to the SCABP8 promoter, mediating salt tolerance. PMID- 26054799 TI - TORC2 mediates the heat stress response in Drosophila by promoting the formation of stress granules. AB - The kinase TOR is found in two complexes, TORC1, which is involved in growth control, and TORC2, whose roles are less well defined. Here, we asked whether TORC2 has a role in sustaining cellular stress. We show that TORC2 inhibition in Drosophila melanogaster leads to a reduced tolerance to heat stress, whereas sensitivity to other stresses is not affected. Accordingly, we show that upon heat stress, both in the animal and Drosophila cultured S2 cells, TORC2 is activated and is required for maintaining the level of its known target, Akt1 (also known as PKB). We show that the phosphorylation of the stress-activated protein kinases is not modulated by TORC2 nor is the heat-induced upregulation of heat-shock proteins. Instead, we show, both in vivo and in cultured cells, that TORC2 is required for the assembly of heat-induced cytoprotective ribonucleoprotein particles, the pro-survival stress granules. These granules are formed in response to protein translation inhibition imposed by heat stress that appears to be less efficient in the absence of TORC2 function. We propose that TORC2 mediates heat resistance in Drosophila by promoting the cell autonomous formation of stress granules. PMID- 26054801 TI - Pharmaceutical quality assessment. PMID- 26054802 TI - Solvent and pH Effects of Coumarin-Terminated Monolayer on Silver Particles. AB - A coumarin-terminated self-assembled monolayer on silver particles (C-SAM) from the reduction of silver ions in the presence of compound 3 was successfully prepared by utilizing phase transfer method, and analyzed by FTIR, SEM-EDS, UV Visible and a particle sizer. The fluorescence behavior of coumarin termini was carried out in ethanol and chloroform with emission wavelength determined at 386 nm, suggesting an interaction between the carbonyl group and the solvent media. The dispersion was then investigated in acidic and basic conditions, showing a direct proportional correlation between the emission and the pH of the aqueous. These results were consistent for interpreting hydrogen bonds, particularly between the carbonyl group with either proton of the alcohol (C=O----H-O-R) or positive species in acidic conditions (C=O----H(+)). The interactions were possible only when the coumarin terminal rearranged in the monolayer and the carbonyl exerted towards the solvent media, while the rest of the molecules were separated from the solvents. PMID- 26054803 TI - Comparisons of node-based and element-based approaches of assigning bone material properties onto subject-specific finite element models. AB - Subject-specific finite element (FE) models can be generated from computed tomography (CT) datasets of a bone. A key step is assigning material properties automatically onto finite element models, which remains a great challenge. This paper proposes a node-based assignment approach and also compares it with the element-based approach in the literature. Both approaches were implemented using ABAQUS. The assignment procedure is divided into two steps: generating the data file of the image intensity of a bone in a MATLAB program and reading the data file into ABAQUS via user subroutines. The node-based approach assigns the material properties to each node of the finite element mesh, while the element based approach assigns the material properties directly to each integration point of an element. Both approaches are independent from the type of elements. A number of FE meshes are tested and both give accurate solutions; comparatively the node-based approach involves less programming effort. The node-based approach is also independent from the type of analyses; it has been tested on the nonlinear analysis of a Sawbone femur. The node-based approach substantially improves the level of automation of the assignment procedure of bone material properties. It is the simplest and most powerful approach that is applicable to many types of analyses and elements. PMID- 26054804 TI - Evaluating the effect of increasing ceramic content on the mechanical properties, material microstructure and degradation of selective laser sintered polycaprolactone/beta-tricalcium phosphate materials. AB - Orthopaedic scaffold materials were fabricated from polycaprolactone (PCL) and composite PCL-beta-tricalcium phosphate (PCL/beta-TCP) powders using selective laser sintering (SLS). Incorporating beta-TCP particles is desirable to promote osteogenesis. The effects of increasing beta-TCP content on the material's mechanical properties and microstructure were evaluated. The wt% of beta-TCP and PCL particle sizes were found to influence material microstructure and mechanical properties, with increasing ceramic content causing a small but significant increase in stiffness but significant reductions in strength. Degradation of materials was achieved using accelerated ageing methods. The influence of beta TCP content on degradation at 7 weeks was evaluated through changes in mechanical properties and microstructure, and the ceramic particles were found to reduce elastic modulus and increase strength. The results of this study highlight the influence of ceramic content on mechanical properties and degradation behaviour of PCL/beta-TCP SLS materials, and indicate that these changes must be considered in the design of scaffolds for critical-sized defects. PMID- 26054805 TI - Development of a non-invasive diagnostic technique for acetabular component loosening in total hip replacements. AB - Current techniques for diagnosing early loosening of a total hip replacement (THR) are ineffective, especially for the acetabular component. Accordingly, new, accurate, and quantifiable methods are required. The aim of this study was to investigate the viability of vibrational analysis for accurately detecting acetabular component loosening. A simplified acetabular model was constructed using a Sawbones((r)) foam block. By placing a thin silicone layer between the acetabular component and the Sawbones block, 2- and 4-mm soft tissue membranes were simulated representing different loosening scenarios. A constant amplitude sinusoidal excitation with a sweep range of 100-1500 Hz was used. Output vibration from the model was measured using an accelerometer and an ultrasound probe. Loosening was determined from output signal features such as the number and relative strength of observed harmonic frequencies. Both measurement methods were sufficient to measure the output vibration. Vibrational analysis reliably detected loosening corresponding to both 2 and 4 mm tissue membranes at driving frequencies between 100 and 1000 Hz (p < 0.01) using the accelerometer. In contrast, ultrasound detected 2-mm loosening at a frequency range of 850-1050 Hz (p < 0.01) and 4-mm loosening at 500-950 Hz (p < 0.01). PMID- 26054806 TI - Effect of different radial hole designs on pullout and structural strength of cannulated pedicle screws. AB - Cannulated pedicle screws are designed for bone cement injection to enhance fixation strength in severely osteoporotic spines. However, the screws commonly fracture during insertion. This study aims to evaluate how different positions/designs of radial holes may affect the pullout and structural strength of cannulated pedicle screws using finite element analysis. Three different screw hole designs were evaluated under torsion and bending conditions. The pullout strength for each screw was determined by axial pullout failure testing. The results showed that when the Von Mises stress reached the yield stress of titanium alloy the screw with four radial holes required a greater torque or bending moment than the nine and twelve hole screws. In the pullout test, the strength and stiffness of each screw with cement augmentation showed no significant differences, but the screw with four radial holes had a greater average pullout strength, which probably resulted from the significantly greater mean maximum lengths of cement augmentation. Superior biomechanical responses, with lower stress around the radial holes and greater pullout strength, represented by cannulated pedicle screw with four radial holes may worth recommending for clinical application. PMID- 26054807 TI - Biomechanical properties of the Marfan's aortic root and ascending aorta before and after personalised external aortic root support surgery. AB - Marfan syndrome is an inherited systemic connective tissue disease which may lead to aortic root disease causing dilatation, dissection and rupture of the aorta. The standard treatment is a major operation involving either an artificial valve and aorta or a complex valve repair. More recently, a personalised external aortic root support (PEARS) has been used to strengthen the aorta at an earlier stage of the disease avoiding risk of both rupture and major surgery. The aim of this study was to compare the stress and strain fields of the Marfan aortic root and ascending aorta before and after insertion of PEARS in order to understand its biomechanical implications. Finite element (FE) models were developed using patient-specific aortic geometries reconstructed from pre and post-PEARS magnetic resonance images in three Marfan patients. For the post-PEARS model, two scenarios were investigated-a bilayer model where PEARS and the aortic wall were treated as separate layers, and a single-layer model where PEARS was incorporated into the aortic wall. The wall and PEARS materials were assumed to be isotropic, incompressible and linearly elastic. A static load on the inner wall corresponding to the patients' pulse pressure was applied. Results from our FE models with patient-specific geometries show that peak aortic stresses and displacements before PEARS were located at the sinuses of Valsalva but following PEARS surgery, these peak values were shifted to the aortic arch, particularly at the interface between the supported and unsupported aorta. Further studies are required to assess the statistical significance of these findings and how PEARS compares with the standard treatment. PMID- 26054808 TI - Analysis and measurement of dielectrophoretic manipulation of particles and lymphocytes using rail-type electrodes. AB - A particle manipulation and sorting device using the dielectrophoretic (DEP) force is described in this study. The device consists of "ladder-type", "flip type" and "oblique rail-type" electrode regions. The ladder-type and rail-type electrodes can generate a DEP force distribution that captures the particles, the DEP force of which is negative, in the area located at the center of the electrodes. The ladder-type electrode can align the particles with equal spacing in the streamwise direction. Using the flip-type electrode, which pushes the particles away, in combination with these electrodes, the direction of the particle and timing can be selected with high accuracy, reliability, and response. In the first half of this study, a numerical simulation is carried out to calculate the particle motion and evaluate the performance of the ladder-type electrode. Several models are used to investigate the influences of the non uniformity of the electric field and the electric interaction of the surface charges and polarizations. Experiments are then carried out to demonstrate the motions of the particles and the sorting reliability. The trajectories and the probability density functions of the particles at the inlet and outlet of the electrode region showed that by using these electrodes the particles can be aligned, sorted, and guided accurately. PMID- 26054809 TI - Anti-inflammatory effects of ginsenoside Rg1 and its metabolites ginsenoside Rh1 and 20(S)-protopanaxatriol in mice with TNBS-induced colitis. AB - Ginsenoside Rg1, one of the main constituents of Panax ginseng, exhibits anti inflammatory effect. In a preliminary study, it was observed that ginsenoside Rg1 was metabolized to 20(S)-protopanaxtriol via ginsenosides Rh1 and F1 by gut microbiota. We further investigated the anti-inflammatory effects of ginsenoside Rg1 and its metabolites in vitro and in vivo. Ginsenosides Rg1, Rh1, and 20(S) protopanaxtriol inhibited the activation of NF-kappaB activation, phosphorylation of transforming growth factor beta-activated kinase 1 and interleukin (IL)-1 receptor-associated kinase, and expression of tumor necrosis factor-alpha and IL 1beta in lipopolysaccharide (LPS)-stimulated macrophages. They also inhibited the binding of LPS to toll-like receptor 4 on the macrophages. Orally administered ginsenoside Rg1, Rh1, or 20(S)-protopanaxtriol inhibited 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colon shortening, myeloperoxidase activity, and expression of IL-1beta, IL-17, and tumor necrosis factor-alpha in mice with TNBS induced colitis. They did not only inhibit TNBS-induced NF-kappaB activation, but also restored TNBS-induced Th17/Treg imbalance. They restored IL-10 and Foxp3 expression. Moreover, they inhibited Th17 cell differentiation in vitro. Of these metabolites, in vitro and in vivo anti-inflammatory effect of 20(S) protopanaxtriol was the most potent, followed by Rh1. These findings suggest that ginsenoside Rg1 is metabolized to 20(S)-protopanaxtriol via ginsenosides Rh1 and F1 and these metabolites particularly 20(S)-protopanaxtriol, may ameliorate inflammatory disease such as colitis by inhibiting the binding of LPS to TLR4 on macrophages and restoring the Th17/Treg imbalance. PMID- 26054810 TI - Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. AB - Painful diabetic neuropathy is a common complication of diabetes mellitus, which often makes the patients suffer from severe hyperalgesia and allodynia. Thus far, the treatment of painful diabetic neuropathy remains unsatisfactory. Metformin, which is the first-line drug for type-2 diabetes, has been proved to attenuate hyperexcitability in sensory neurons linked to chemotherapy-induced neuropathic pain, highlighting its potential in alleviating pain related with painful diabetic neuropathy. The present study was designed to investigate the potential beneficial effect of metformin on hyperalgesia and allodynia in diabetic rats. The mechanical sensitivity, heat nociception, and cold allodynia were examined. The levels of malondialdehyde, superoxide dismutase, and advanced glycation end products in the blood were measured. The expression of adenosine monophosphate activated protein kinase (AMPK) phosphorylation and AMPK target genes were examined in the sciatic nerves of the animals. It was found that metformin was capable of attenuating diabetes-induced mechanical hyperalgesia, heat hyperalgesia and cold allodynia. In addition, metformin was capable of decreasing malondialdehyde and glycation end-products levels in blood, as well as increasing superoxide dismutas activity, indicating the inhibitory effect of metformin against diabetes-induced oxidative stress. Further studies showed that metformin could activate AMPK and increase the AMPK target genes in sciatic nerves in diabetic rats. In conclusion, metformin is able to attenuate diabetes-induced hyperalgesia and allodynia, which might be associated its anti-oxidative effect through AMPK pathway. Metformin might be used as an effective drug, especially with fewer side effects, for abnormal sensation in painful diabetic neuropathy. PMID- 26054812 TI - Equine Pathology and Diagnostics for the Practicing Veterinarian. PMID- 26054811 TI - Interobserver variation in classification of malleolar fractures. AB - OBJECTIVE: Classification of malleolar fractures is a matter of debate. In the ideal situation, a classification system is easy to use, shows good inter- and intraobserver agreement, and has implications for treatment or research. MATERIAL AND METHODS: Interobserver study. Four observers distributed 100 X-rays to the Weber, AO and Lauge-Hansen classification. In case of a trimalleolar fracture, the size of the posterior fragment was measured. Interobserver agreement was calculated with Cohen's kappa. Agreement on the size of the posterior fragment was calculated with the intraclass correlation coefficient. RESULTS: Moderate agreement was found with all classification systems: the Weber (K = 0.49), AO (K = 0.45) and Lauge-Hansen (K = 0.47). Interobserver agreement on the presence of a posterior fracture was substantial (K = 0.63). Estimation of the size of the fragment showed moderate agreement (ICC = 0.57). CONCLUSION: Classification according to the classical systems showed moderate interobserver agreement, probably due to an unclear trauma mechanism or the difficult relation between the level of the fibular fracture and syndesmosis. Substantial agreement on posterior malleolar fractures is mostly due to small (<5 %) posterior fragments. A classification system that describes the presence and location of fibular fractures, presence of medial malleolar fractures or deep deltoid ligament injury, and presence of relevant and dislocated posterior malleolar fractures is more useful in the daily setting than the traditional systems. In case of a trimalleolar fracture, a CT scan is in our opinion very useful in the detection of small posterior fragments and preoperative planning. PMID- 26054813 TI - A qualitative analysis of factors influencing middle school students' use of skills taught by a violence prevention curriculum. AB - This study examined factors that influenced the use of skills taught in a school based universal violence prevention program. Interviews were conducted with 91 students from two urban schools (83% were African American and 12% multiracial) and 50 students from a nearby county school (52% were White, 32% African American, and 12% multiracial). About half the sample (54%) was male. All had been in sixth grade classrooms where the Second Step (Committee for Children, 1997b) violence prevention curriculum had been implemented earlier in the school year or in the preceding school year. Qualitative analysis of interview transcripts suggested that participants' use of intervention skills was influenced by their beliefs and values, perceived relevance and effectiveness of the skill, issues related to enacting the behavior, and contextual factors. These findings highlight the need for a more intensive and comprehensive effort to address barriers and supports that influence the relevance and impact of school based violence prevention programs. PMID- 26054814 TI - Ecodevelopmental predictors of early initiation of alcohol, tobacco, and drug use among Hispanic adolescents. AB - The purpose of this cross-sectional study was to test the transactional relationships of risk and protective factors that influence initiation of alcohol, tobacco, and drug use among Hispanic youth. Ecodevelopmental theory was used to identify factors at multiple ecological levels with a focus on four school-level characteristics (i.e. school socioeconomic status, school climate, school acculturation, and school ethnic composition). A sample of 741 Hispanic adolescents (M age=13.9, SD=.67) and their caregivers were recruited from 18 participating middle schools in Miami-Dade County, FL. Structural equation modeling was used to test the hypothesized ecodevelopmental model of early substance use, accounting for school clustering effects. Results provided strong support for the model (CFI=.95; RMSEA=.03). School SES was indirectly related to the likelihood of starting substance use through perceived peer use norms (beta=.03, p<.02). Similarly, school climate had an indirect effect on substance use initiation through family functioning and perceptions of peer use norms (beta=-.03, p<.01). Neither school ethnic composition nor school acculturation had indirect effects on initiation of substance use. Results highlight the importance of the interplay of risk and protective factors at multiple ecological levels that impact early substance use initiation. Further, findings underscore the key role of school level characteristics on the initiation of substance use and present opportunities for intervention. PMID- 26054815 TI - Increasing teacher treatment integrity of behavior support plans through consultation and implementation planning. AB - School psychologists commonly provide intervention services to children through consultation with teachers. Data suggest, however, that many teacher consultees struggle to implement these interventions. There are relatively few evidence based strategies for promoting teacher consultees' intervention implementation. The purpose of this study was to evaluate Implementation Planning as a strategy for increasing the adherence and quality with which teacher consultees implemented behavior support plans. Implementation Planning involves adapting intervention steps to the implementation context, providing detailed logistical planning, as well as identifying implementation barriers and developing strategies to address them. Results indicated that teachers' implementation adherence levels increased and quality levels increased with corresponding decreases in variability, compared to standard behavioral consultation. Implications for future research on treatment integrity are discussed. PMID- 26054816 TI - The research impact of school psychology faculty. AB - Hirsch's (2005) h index has become one of the most popular indicators of research productivity for higher education faculty. However, the h index varies across academic disciplines so empirically established norms for each discipline are necessary. To that end, the current study collected h index values from Scopus and Google Scholar databases for 401 tenure-track faculty members from 109 school psychology training programs. Male faculty tended to be more senior than female faculty and a greater proportion of the male faculty held professorial rank. However, female faculty members outnumbered males at the assistant and associate professor ranks. Although strongly correlated (rho=.84), h index values from Google Scholar were higher than those from Scopus. h index distributions were positively skewed with many faculty having low values and a few faculty having high values. Faculty in doctoral training programs exhibited significantly larger h index values than faculty in specialist training programs and there were univariate differences in h index values across academic rank and sex, but sex differences were not significant after taking seniority into account. It was recommended that the h index be integrated with peer review and diverse other indicators when considering individual merit. PMID- 26054817 TI - Maximizing the potential of early childhood education to prevent externalizing behavior problems: A meta-analysis. AB - Early childhood education (ECE) programs offer a promising mechanism for preventing early externalizing behavior problems and later antisocial behavior; yet, questions remain about how to best maximize ECE's potential. Using a meta analytic database of 31 studies, we examined the overall effect of ECE on externalizing behavior problems and the differential effects of 3 levels of practice, each with increasing specificity and intensity aimed at children's social and emotional development. In short, we found that each successive level of programs did a better job than the prior level at reducing externalizing behavior problems. Level 1 programs, or those without a clear focus on social and emotional development, had no significant effects on externalizing behavior problems relative to control groups (ES=.13 SD, p<.10). On the other hand, level 2 programs, or those with a clear but broad focus on social and emotional development, were significantly associated with modest decreases in externalizing behavior problems relative to control groups (ES=-.10 SD, p<.05). Hence, level 2 programs were significantly better at reducing externalizing behavior problems than level 1 programs (ES=-.23 SD, p<.01). Level 3 programs, or those that more intensively targeted children's social and emotional development, were associated with additional significant reductions in externalizing behavior problems relative to level 2 programs (ES=-.26 SD, p<.05). The most promising effects came from level 3 child social skills training programs, which reduced externalizing behavior problems half of a standard deviation more than level 2 programs (ES= .50 SD, p<.05). PMID- 26054818 TI - Current controlled drug regulation in Taiwan. AB - In order to strengthen the management system of medical and scientific use of controlled drugs, Taiwan government referred to the three major drug control treaties of United Nation to formulate the "Controlled Drugs Act" in 1999. There are three kinds of system to manage controlled drugs, including (1) Schedule Management, (2) Licensing Regulation Management and (3) Diversion Control Management, such as the reporting and auditing systems. In this article, the management system of controlled drugs will be discussed thoroughly. Under the "Controlled Drugs Act", the controlled drugs are scheduled by the tendency of their habitual use, drug dependency, abuse, and social hazard. If violating the rule, the administrative sanction is applied. Cases of violations will also be given in this article. PMID- 26054819 TI - The case of chronic hepatitis B treatment with tenofovir: an update for nephrologists. AB - Tenofovir is a nucleotide acting both as an inhibitor of human immunodeficiency (HIV) reverse transcriptase and as a competitor for hepatitis B virus (HBV) RNA directed DNA polymerase. Approved worldwide in 2001, tenofovir is used as a component of highly active antiretroviral therapy (HAART) in patients with HIV infection. Since 2008, it has also been indicated for treatment of chronic HBV infection or HIV/HBV co-infection. The aim of the treatment consists in suppressing viral replication, thus reducing hepatic complications and improving patient survival. Furthermore, tenofovir could represent an effective therapeutic option in lamivudine-resistant HBV patients. Tenofovir is eliminated unchanged through urine via glomerular filtration (80%) and proximal tubular secretion (20%). Thus, alterations in renal clearance may interfere with tenofovir pharmacokinetics and systemic drug concentrations, modifying the therapeutic response. Hence, a renal overload of tenofovir in patients with a pre-existing kidney impairment could result in a worsening of renal function. Following a brief introduction on HBV infection and its therapeutic options, we review the latest evidence, to our knowledge, on renal toxicity of tenofovir in HBV patients and on drug management. PMID- 26054820 TI - Erratum to: Management of CKD-MBD in non-dialysis patients under regular nephrology care: a prospective multicenter study. PMID- 26054821 TI - Sulodexide alone or in combination with low doses of everolimus inhibits the hypoxia-mediated epithelial to mesenchymal transition in human renal proximal tubular cells. AB - BACKGROUND: Prolonged cold ischemia time, the period from the start of perfusion with cold preservation fluid after cessation of circulation due to arterial clamping until transplantation in the recipient, could induce epithelial-to mesenchymal transition (EMT) in renal tubular cells, a process associated with chronic graft damage. In this context, everolimus (EVE) and sulodexide (SUL) could potentially slow down this process. METHODS: To assess whether SUL (50 MUg/ml), EVE (at 5, 10, 100 nM) or their combination were able to inhibit EMT in human renal epithelial proximal tubular cells (HK-2) reoxygenated after 24 h under hypoxic conditions, we used classical biomolecular strategies. RESULTS: Hypoxia induced upregulation of alpha smooth muscle actin (alpha-SMA), fibronectin (FN) and vimentin at gene-expression and alpha-SMA and FN at protein levels. However, the addition, after reoxygenation, of SUL plus low-dose EVE (5 nM) to the cell culture reversed this condition. Moreover, SUL and EVE were able to inhibit the hypoxia-induced Akt phosphorylation in HK2 cells and their morphological changes. Similarly, SUL was able to reverse the hyper-expression of EMT markers induced by high EVE dosage (100 nM) in cells cultured under both normoxic and hypoxic conditions. CONCLUSIONS: Our data reveal, for the first time, that sulodexide, alone or combined to low doses of everolimus, may hinder EMT in renal cells following hypoxia or minimize fibrotic complications due to high dosage of mammalian target of rapamycin inhibitors. PMID- 26054823 TI - Mechanical labor induction in the obese population: a secondary analysis of a prospective randomized trial. AB - OBJECTIVE: The objective of this study was to estimate the influence of maternal body mass index (BMI) on progress and outcomes of labor induction using mechanical devices. METHODS: This study was a secondary analysis of data collected during the Cook Catheter vs. Foley Catheter study, a series of prospective randomized trials of women requiring cervical ripening for labor induction. The duration, characteristics, and outcomes of labor were analyzed after stratification by BMI categories. Outcomes assessed included time from device insertion to delivery, successful ripening, cesarean delivery rates, and any maternal and neonatal adverse events. RESULTS: One hundred and eighty-one patients were stratified according to BMI categories, with 102 study participants classified as normal weight (BMI <=30) and 79 as obese (BMI >30). Maternal satisfaction from the induction process was significantly lower in the obese group compared to the normal weight group (5.95 +/- 3.14 vs. 7.58 +/- 2.7, respectively, in a 1-10 scale, p = 0.009). The cesarean delivery rate was similar in the normal weight and the obese groups (17.6 vs. 25.3 %, respectively, p = 0.27). No statistical differences were found in all other outcomes evaluated, including a sub-analysis of the different mechanical devices. CONCLUSIONS: During the process of mechanical cervical ripening, maternal satisfaction, but not objective obstetrical parameters, was influenced by increased maternal BMI. The trial is registered at ClinicalTrials.gov, no: NCT00604487. Trial registry name is "Induction of Labor in Patients with Unfavorable Cervical Conditions." PMID- 26054822 TI - Eosinophilic Gastroenteritis and Colitis: a Comprehensive Review. AB - Eosinophilic gastrointestinal disorders, including eosinophilic esophagitis, gastroenteritis, and colitis, refer to a spectrum of clinical diseases that present with variable degrees of infiltration of the gastrointestinal tract by eosinophils in the absence of other known causes of tissue eosinophilia. Clinical symptoms and laboratory findings are usually non-specific and may or may not be accompanied by peripheral blood eosinophilia. The extent of eosinophilic infiltration of the gastrointestinal wall varies from mucosal to transmural and serosal involvement. Diagnosis requires presence of gastrointestinal symptoms, demonstration of gastrointestinal eosinophilia by biopsy, and exclusion of other known causes of tissue eosinophilia. Many studies have pointed toward the eosinophil as the major offender; however, the exact functional role of the eosinophil in the pathogenesis of eosinophilic gastrointestinal disorders remains unclear. The roles of T-helper-2 cytokines and other mediators, such as eotaxin-1 and interleukin-5, have gained significant importance in the pathobiology of eosinophilic gastrointestinal disorders. Current understanding of treatment is based on case reports and a few case series, as there is a lack of large prospective studies. Steroids are currently the mainstay of therapy, but the roles of other drugs such as leukotriene inhibitors, mast cell stabilizers, interleukin-5 inhibitors, and anti-immunoglobulin E, along with other targets in the immune pathway, are currently being explored. PMID- 26054824 TI - Tanshinone IIA inhibits the proliferation, migration and invasion of ectopic endometrial stromal cells of adenomyosis via 14-3-3zeta downregulation. AB - BACKGROUND: Adenomyosis is a specific subtype of endometriosis and recent evidences have indicated that Tanshinone IIA (TSIIA) might be a potential therapeutic option for endometriosis. Meanwhile, endometrial stromal cells (ESCs) of adenomyosis might play crucial roles in the progression of this disease, emphasizing the importance of targeting ESCs in the treatment of adenomyosis. Furthermore, previous evidences also implicated that deregulated 14-3-3zeta expression might be associated with therapeutic effects of certain drugs. AIM OF THE STUDY: The aim of this study is to evaluate the potential involvement of 14-3 3zeta in the process of TSIIA-treated adenomyosis. MATERIALS AND METHODS: Ectopic endometrial stromal cells (EESCs) were isolated from a total of 3 patients with adenomyosis. Cells were treated with TSIIA and infected with 14-3-3zeta overexpressing adenovirus, the expression level of 14-3-3zeta was determined by western blotting (WB), cell viability was detected by Cell Counting Kit-8 (CCK8), cell invasion and migration was evaluated by transwell assay, and cell apoptosis was detected by flow cytometry. RESULTS: TSIIA could decrease cell viability, induce cell apoptosis, and inhibit cell migration and invasion in EESCs. Mechanistically, TSIIA markedly reduced the expression of 14-3-3zeta in EESCs, and overexpression of 14-3-3zeta could restore the ability of cell viability, migration and invasion, but has no effect on cell apoptosis. CONCLUSIONS: TSIIA could be a promising novel therapeutic agent for adenomyosis, via inducing cell apoptosis, inhibiting cell viability, migration and invasion in EESCs. Furthermore, the effects of cell viability, migration and invasion were mediated in 14-3-3zeta-dependent manner while that of cell apoptosis was mediated in 14-3 3zeta-independent manner. PMID- 26054825 TI - Continuous or cyclic contraceptives for endometriosis: a question still without an answer. PMID- 26054826 TI - Reply to: Continuous or cyclic contraceptives for endometriosis: a question still without an answer. PMID- 26054827 TI - Daily indoor-to-outdoor temperature and humidity relationships: a sample across seasons and diverse climatic regions. AB - The health consequences of heat and cold are usually evaluated based on associations with outdoor measurements collected at a nearby weather reporting station. However, people in the developed world spend little time outdoors, especially during extreme temperature events. We examined the association between indoor and outdoor temperature and humidity in a range of climates. We measured indoor temperature, apparent temperature, relative humidity, dew point, and specific humidity (a measure of moisture content in air) for one calendar year (2012) in a convenience sample of eight diverse locations ranging from the equatorial region (10 degrees N) to the Arctic (64 degrees N). We then compared the indoor conditions to outdoor values recorded at the nearest airport weather station. We found that the shape of the indoor-to-outdoor temperature and humidity relationships varied across seasons and locations. Indoor temperatures showed little variation across season and location. There was large variation in indoor relative humidity between seasons and between locations which was independent of outdoor airport measurements. On the other hand, indoor specific humidity, and to a lesser extent dew point, tracked with outdoor, airport measurements both seasonally and between climates, across a wide range of outdoor temperatures. These results suggest that, in general, outdoor measures of actual moisture content in air better capture indoor conditions than outdoor temperature and relative humidity. Therefore, in studies where water vapor is among the parameters of interest for examining weather-related health effects, outdoor measurements of actual moisture content can be more reliably used as a proxy for indoor exposure than the more commonly examined variables of temperature and relative humidity. PMID- 26054828 TI - Phylogeny and Evolution of Multiple Common Carp (Cyprinus carpio L.) Populations Clarified by Phylogenetic Analysis Based on Complete Mitochondrial Genomes. AB - Common carp (Cyprinus carpio L.) is one of the oldest, most widely farmed commercially important freshwater fish in the world. However, many undetermined phylogenetic relationships and origins of common carp lineages remain, which are obstacles to conservation and genetic breeding of this species. Phylogenetic analyses based on molecular tools are helpful to distinguish the origin of species, understand and clarify their evolutionary history, and provide a genetic basis for selective breeding. In this study, we demonstrated a method to extract complete mitochondrial genome sequences from whole-genome resequencing data using the Illumina platform. The complete mitochondrial genome sequences of 26 individuals representing nine strains were obtained and subjected to a phylogenetic analysis. We reconstructed the phylogenetic topologies of the nine strains and analyzed the haplotypes. Results from both analyses suggested that the genome sequences belonged to two distinct subspecies from Europe and East Asia. We also estimated the time of divergence of the nine strains, which was up to 100 KYA. The phylogenetic results clarified the breeding history of Songpu mirror carp and suggest that this species may be hybrid of paternal European mirror carp and maternal Xingguo red carp. The results also support a previous hypothesis that koi may have originated from or have close ancestry with Oujiang color carp in China. PMID- 26054829 TI - Quinine, Malaria, and the Cinchona Bureau: Marketing Practices and Knowledge Circulation in a Dutch Transoceanic Cinchona-Quinine Enterprise (1920s-30s). AB - In this study, we will show how a Dutch pharmaceutical consortium of cinchona producers and quinine manufacturers was able to capitalize on one of the first international public health campaigns to fight malaria, thereby promoting the sale of quinine, an antimalarial medicine. During the 1920s and 1930s, the international markets for quinine were controlled by this Dutch consortium, which was a transoceanic cinchona-quinine enterprise centered in the Cinchona Bureau in the Netherlands. We will argue that during the interwar period, the Cinchona Bureau became the decision-making center of this Dutch cinchona-quinine pharmaceutical enterprise and monopolized the production and trade of an essential medicine. In addition, we will argue that capitalizing on the international public health campaign in the fight against malaria by the Dutch cinchona-quinine enterprise via the Cinchona Bureau can be regarded as an early example of corporate colonization of public health by a private pharmaceutical consortium. Furthermore, we will show how commercial interests prevailed over scientific interests within the Dutch cinchona-quinine consortium, thus interfering with and ultimately curtailing the transoceanic circulation of knowledge in the Dutch empire. PMID- 26054830 TI - Acute coronary syndromes: Should routine oxygen therapy be AVOIDed in normoxic patients with STEMI? PMID- 26054831 TI - Antiplatelet therapy: Defining the optimal duration of DAPT after PCI with DES. PMID- 26054832 TI - Device therapy: Where next in cardiogenic shock owing to myocardial infarction? PMID- 26054833 TI - Structural evidences for a secondary gold binding site in the hydrophobic box of lysozyme. AB - A new crystal structure is reported here for the adduct formed in the reaction between NH4 [Au(Sac)2], AuSac2, a cytotoxic homoleptic gold(I) complex with the saccharinate ligand, and the model protein hen egg white lysozyme. To produce this adduct, AuSac2 breaks down and releases both saccharinate ligands. The resulting Au(I) ions bind the protein to ND1 and NE2 atoms of His15 but also to SD atom of the zero-solvent accessible Met105 side chain, which is located in the protein hydrophobic box. The unexpected existence of this secondary gold(I) binding site is confirmed by spectroscopic and spectrometric measurements in solution. PMID- 26054834 TI - Stable p-type properties of single walled carbon nanotubes by electrochemical doping. AB - We report a highly stable p-type doping for single walled carbon nanotubes using an electrochemical method. The Raman spectroscopy showed the upshift of the G band when the applied potential increased. Furthermore, the carbon core level shifted as much as 0.14 eV in binding energy of XPS measurement, which is an evidence of p-type doping with a Fermi level change. The highly doped SWCNTs at an applied potential of 1.5 V during the electrochemical doping process showed long time stability, as long as 28 days. PMID- 26054835 TI - Psychopathological factors that can influence academic achievement in early adolescence: a three-year prospective study. AB - This three-phase prospective study investigated psychosocial factors predicting or associated with academic achievement. An initial sample of 1,514 school-age children was assessed with screening tools for emotional problems (Screen for Childhood Anxiety and Related Emotional Disorders; Leyton Obsessional Inventory Child Version; Children's Depression Inventory). The following year, 562 subjects (risk group/without risk group) were re-assessed and attention deficit/hyperactivity disorder (ADHD) was assessed. Two years later, 242 subjects were followed, and their parents informed about their academic achievement. Results showed that early depression (phase 1 B = -.130, p = .001; phase 1 + phase 2 B = -.187, p < .001), persistent anxiety symptoms (phase 1 + phase 2 B = 1.721, p = .018), and ADHD were predictors of lower academic achievement (phase 1 + phase 2 B = -3.415, p = .005). However, some anxiety symptoms can improve academic achievement (Social phobia B = .216, p = .018; Generalized anxiety B = .313, p < .001). Socio-economic status (SES) was positively related to academic achievement. We can conclude that in the transition period to adolescence, school health professionals and teachers need to consider the emotional issues of students to avoid unwanted academic outcomes. PMID- 26054836 TI - Contrasting ABA, AAB and ABC renewal in a free operant procedure. AB - One experiment used a free operant procedure with rats to compare ABA, AAB and ABC renewal by using a within-subject testing procedure. All rats were first trained to press a lever for food in context A. Lever pressing was then extinguished in either context A or context B. For rats in the groups ABA and ABC extinction took place in context B, while the rats in group AAB received extinction in the same context in which acquisition took place (context A). Finally, all rats were tested for renewal in two sessions. One extinction session was carried out in the same extinction context and another session in a different context. Rats in the group ABA were tested in context B and in context A; rats in the group AAB were tested in contexts A and B, whereas the group ABC was tested in contexts B and C. The results of the ANOVA showed context renewal since all groups had higher rates of responding when they were tested outside the extinction context, F(2, 21) = 15.32, p = .001, etap 2 = .59; however, AAB and ABC renewal was lesser than ABA renewal, F(1, 21) = 16.70, p = .0001, etap 2 = .61. PMID- 26054837 TI - The Effects of Time on Task in Response Selection--An ERP Study of Mental Fatigue. AB - Long lasting involvement in a cognitive task leads to mental fatigue. Substantial efforts have been undertaken to understand this phenomenon. However, it has been demonstrated that some changes with time on task are not only related to mental fatigue. The present study intends to clarify these effects of time on task unrelated to mental fatigue on response selection processes at the behavioural and electrophysiological level (using event-related potentials, ERPs). Participants had to perform a Simon task for more than 3 hours and rated their experienced mental fatigue and motivation to continue with the task at several time points during the experiment. The results show that at the beginning of the experiment some unspecific modulations of training and adaptation are evident. With time on task participants' ability to resolve response conflict appears to become impaired. The results reveal that time on task effects cannot be completely explained by mental fatigue. Instead, it seems that an interplay of adaptation at the beginning and motivational effects in the course of a task modulate performance and neurophysiological parameters. In future studies it will be important to account for the relative contribution of adaptation and motivation parameters when time on task effects are investigated. PMID- 26054838 TI - [Modern drug therapy in cardiovascular intensive care medicine]. AB - Vasoactive drugs and inotropes are important in the hemodynamic management of patients with cardiogenic shock despite modest volume administration. Currently, the concept of cardiac relief is pursued in the treatment of acute heart failure. In this article we present the use of different drugs in the intensive care unit for acute heart failure and cardiogenic shock. In acute heart failure catecholamines are only used during the transition from heart failure to cardiogenic shock. Here, the therapeutic concept of ventricular unloading is more sought after. This can be achieved by the use of diuretics, nitrates, levosimendan (inodilatator), or in the future serelaxin. The hemodynamic management in cardiogenic shock occurs after moderate volume administration with dobutamine to increase inotropy. If no adequate perfusion pressures are achieved, norepinephrine can be administered as a vasopressor. If there is still no sufficient increase in cardiac output, the inodilatator levosimendan can be used. Levosimendan instead of phosphodiesterase inhibitors in this case is preferable. The maxim of hemodynamic management in cardiogenic shock is the transient use of inotropes and vasopressors in the lowest dose possible and only for as long as necessary. This means that one should continuously check whether the dose can be reduced. There are no mortality data demonstrating the utility of hemodynamic monitoring based on objective criteria-but it makes sense to use inotropes and vasopressors sparingly. PMID- 26054840 TI - Negative magnetophoresis in diluted ferrofluid flow. AB - We report magnetic manipulation of non-magnetic particles suspended in diluted ferrofluid. Diamagnetic particles were introduced into a circular chamber to study the extent of their deflection under the effect of a non-uniform magnetic field of a permanent magnet. Since ferrofluid is a paramagnetic medium, it also experiences a bulk magnetic force that in turn induces a secondary flow opposing the main hydrodynamic flow. Sheath flow rate, particle size, and magnetic field strength were varied to examine this complex behaviour. The combined effect of negative magnetophoresis and magnetically induced secondary flow leads to various operation regimes, which can potentially find applications in separation, trapping and mixing of diamagnetic particles such as cells in a microfluidic system. PMID- 26054841 TI - Copper catalysed direct amidation of methyl groups with N-H bonds. AB - An efficient copper catalyzed direct aerobic oxidative amidation of methyl groups of azaarylmethanes with N-H bonds producing amides is successfully developed, which can produce primary, secondary and tertiary amides, including those with functional groups. This reaction represents a straightforward method for the preparation of amides from the readily available hydrocarbon starting materials. PMID- 26054839 TI - Enhanced viability and neural differential potential in poor post-thaw hADSCs by agarose multi-well dishes and spheroid culture. AB - Human adipose-derived stem cells (hADSCs) are potential adult stem cells source for cell therapy. But hADSCs with multi-passage or cryopreservation often revealed poor growth performance. The aim of our work was to improve the activity of poor post-thaw hADSCs by simple and effective means. We describe here a simple method based on commercially available silicone micro-wells for creating hADSCs spheroids to improve viability and neural differentiation potential on poor post thaw hADSCs. The isolated hADSCs positively expresse d CD29, CD44, CD105, and negatively expressed CD34, CD45, HLA-DR by flow cytometry. Meanwhile, they had adipogenic and osteogenic differentiation capacity. The post-thaw and post spheroid hADSCs from poor growth status hADSCs showed a marked increase in cell proliferation by CKK-8 analysis, cell cycle analysis and Ki67/P27 quantitative polymerase chain reaction (qPCR) analysis. They also displayed an increase viability of anti-apoptosis by annexin v and propidium iodide assays and mitochondrial membrane potential assays. After 3 days of neural induction, the neural differentiation potential of post-thaw and post-spheroid hADSCs could be enhanced by qPCR analysis and western blotting analysis. These results suggested that the spheroid formation could improve the viability and neural differentiation potential of bad growth status hADSCs, which is conducive to ADSCs research and cell therapy. PMID- 26054842 TI - Context variations and pluri-methodological issues concerning the expression of a social representation: the example of the Gypsy community. AB - Within the social representations' field of research, the "mute zone" hypothesis considers that some objects are characterized by counternormative content that people usually do not express in standard conditions of production. Within the framework of this approach, this study aims to explore the variations in the expression about the Gypsy community following the manipulation of different contexts and the issues associated with a pluri-methodological approach of data analysis. Indeed, two methodologies have been combined. The participants were asked to express themselves in public or in private. In addition, the identity of the experimenter was also manipulated as she presented herself as a Gypsy or not. Then, through a set of analyses based on a methodological triangulation approach, we were able to observe a recurrent modulation of the participants' answers. These analyses highlighted a greater incidence of the expression of counternormative elements when the context of expression was private and especially when the experimenter did not present herself as a Gypsy (p < .01, eta p 2 = .06). These results will be discussed in terms of the contribution of the methodologies employed and their comparison within the framework of the study of counternormative content. PMID- 26054843 TI - The Montreal Cognitive Assessment as a preliminary assessment tool in general psychiatry: Validity of MoCA in psychiatric patients. AB - OBJECTIVE: The aim of the presented research was to obtain the initial data regarding the validity of Montreal Cognitive Assessment (MoCA) in diagnosing cognitive impairment in psychiatrically hospitalized patients. METHOD: The results in MoCA obtained from 221 patients were analyzed in terms of proportional participation of patients with particular diagnosis in three result ranges. In 67 patients, additional version of the scale was also used. Comparative analysis of average results in particular diagnostic groups (organically based disorders, disorders due to psychoactive substance use, psychotic disorders, neurotic disorders and personality disorders) was also carried out, as well as an analysis of the scale's accuracy as a diagnostic test in detecting organic disorders. RESULTS: The reliability of the test measured with between tests correlation coefficient rho=0.92 (P=.000). Significant differences between particular diagnoses groups were detected (J-T=13736; P=.000). The cutoff points of 23 turned out to have a satisfactory sensitivity and specificity (0.82 and 0.70, respectively) in diagnosing organically based disorders. The area below the receiver operating characteristic curve (AUC=0.854; P=.000) suggests that MoCA has a satisfactory value as a classifier. CONCLUSION: The initial data suggest MoCA's high value in prediction of future diagnosis of organically based disorders. The initial results obtained in particular group of diagnoses support construct validity of the method. PMID- 26054844 TI - Corrigendum. PMID- 26054845 TI - Temperature matters with rodent metabolic studies. PMID- 26054846 TI - Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet-B-induced carcinogenesis. AB - We previously reported that deficiency in the gene encoding the catalytic subunit of protein phosphatase 6 (Ppp6c) predisposes mouse skin tissue to papilloma formation initiated by DMBA. Here, we demonstrate that Ppp6c loss acts as a tumor promoter in UVB-induced squamous cell carcinogenesis. Following UVB irradiation, mice with Ppp6c-deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice. Time course experiments showed that following UVB irradiation, Ppp6c-deficient keratinocytes upregulated expression of p53, PUMA, BAX, and cleaved caspase-3 proteins. UVB-induced tumors in Ppp6c-deficient keratinocytes exhibited a high frequency of both p53- and gammaH2AX-positive cells, suggestive of DNA damage. Epidemiological and molecular data strongly suggest that UVB from sunlight induces p53 gene mutations in keratinocytes and is the primary causative agent of human skin cancers. Our analysis suggests that PP6 deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB-induced mutated p53. Understanding PP6 function in preventing UV-induced tumorigenesis could suggest strategies to prevent and treat this condition. PMID- 26054847 TI - A prostate cancer-targeted polyarginine-disulfide linked PEI nanocarrier for delivery of microRNA. AB - Recent advances in efficient microRNA (miRNA) delivery techniques using prostate cancer-targeted nanoparticles offer critical information for understanding the functional role of miRNAs in vivo, and for supporting targeted gene therapy in terms of treating miRNA-associated prostate cancer. Here, we report the polyarginine peptide (R11)-labeled non-toxic SSPEI nanomaterials capable of prostate cancer-specific miR-145 delivery to prostate cancer in vivo where they display full bioactivity at completely nontoxic concentrations. The R11-labeled BPEI-SS (R11-SSPEI) nanocarrier showed less toxicity in prostate cancer, and electrostatic interaction of R11-SSPEI with miR-145 exhibited optimal transfection efficacy. The R11-SSPEI/miR-145 polymer could be specifically uptaken in prostate cancer using FAM-miR-145 mixed with R11-SSPEI. The functional action of miR-145 oligomers released from polyplexes was evaluated by a reporter vector containing a miR-145-binding sequence, and showed a significantly reduced reporter signal in a dose-dependent manner. More importantly, in a peritoneal mouse tumor model, the systemic administration of the R11-SSPEI/FAM-miR-145 complex leads to the delivery of miR-145 into the tumors, dramatically inhibiting tumor growth and prolonged survival time. Hence, we establish a novel and prostate cancer-specific targeting system for the systemic in vivo application of microRNAs through R11-SSPEI complexation as a powerful tool for future therapeutic use. PMID- 26054848 TI - Nuf2 is required for chromosome segregation during mouse oocyte meiotic maturation. AB - Nuf2 plays an important role in kinetochore-microtubule attachment and thus is involved in regulation of the spindle assembly checkpoint in mitosis. In this study, we examined the localization and function of Nuf2 during mouse oocyte meiotic maturation. Myc6-Nuf2 mRNA injection and immunofluorescent staining showed that Nuf2 localized to kinetochores from germinal vesicle breakdown to metaphase I stages, while it disappeared from the kinetochores at the anaphase I stage, but relocated to kinetochores at the MII stage. Overexpression of Nuf2 caused defective spindles, misaligned chromosomes, and activated spindle assembly checkpoint, and thus inhibited chromosome segregation and metaphase-anaphase transition in oocyte meiosis. Conversely, precocious polar body extrusion was observed in the presence of misaligned chromosomes and abnormal spindle formation in Nuf2 knock-down oocytes, causing aneuploidy. Our data suggest that Nuf2 is a critical regulator of meiotic cell cycle progression in mammalian oocytes. PMID- 26054849 TI - Sodium content on processed foods for snacks. AB - OBJECTIVE: To assess the Na content reported on the labels of processed foods sold in Brazil that are usually consumed as snacks by children and adolescents. DESIGN: Cross-sectional study that assessed Na content and serving size reporting on processed food labels. SETTING: A supermarket that is part of a large chain in Brazil. SUBJECTS: All foods available for sale at the study's location and reported in the literature as snacks present in the diets of Brazilian children and adolescents. RESULTS: Of the 2945 processed foods, 87 % complied with the reference serving sizes, although variability in reporting was observed in most of the food subgroups. In addition, 21 % of the processed foods had high Na levels (>600 mg/100 g) and 35 % had medium Na levels (>120 and <=600 mg/100 g). The meats, oils, fats and seeds groups as well as the prepared dishes had higher percentages of foods classified as high Na (81 %, 58 % and 53 %, respectively). CONCLUSIONS: Most of the processed foods had high or medium Na content. We emphasize the importance of revising Brazilian nutrition labelling legislation to standardize reference serving sizes to avoid variation. Besides, we point out the potential for reducing Na levels in most processed foods, as evidenced by the variability in Na content within subgroups. Finally, we have identified the need to develop a method to classify Na levels in processed foods with specific parameters for children and adolescents. PMID- 26054850 TI - Developmental origin of age-related coronary artery disease. AB - AIM: Age and injury cause structural and functional changes in coronary artery smooth muscle cells (caSMCs) that influence the pathogenesis of coronary artery disease. Although paracrine signalling is widely believed to drive phenotypic changes in caSMCs, here we show that developmental origin within the fetal epicardium can have a profound effect as well. METHODS AND RESULTS: Fluorescent dye and transgene pulse-labelling techniques in mice revealed that the majority of caSMCs are derived from Wt1(+), Gata5-Cre(+) cells that migrate before E12.5, whereas a minority of cells are derived from a later-emigrating, Wt1(+), Gata5 Cre(-) population. We functionally evaluated the influence of early emigrating cells on coronary artery development and disease by Gata5-Cre excision of Rbpj, which prevents their contribution to coronary artery smooth muscle cells. Ablation of the Gata5-Cre(+) population resulted in coronary arteries consisting solely of Gata5-Cre(-) caSMCs. These coronary arteries appeared normal into early adulthood; however, by 5-8 months of age, they became progressively fibrotic, lost the adventitial outer elastin layer, were dysfunctional and leaky, and animals showed early mortality. CONCLUSION: Taken together, these data reveal heterogeneity in the fetal epicardium that is linked to coronary artery integrity, and that distortion of the coronaries epicardial origin predisposes to adult onset disease. PMID- 26054851 TI - Enhanced recovery after surgery: The patient, the team, and the society. PMID- 26054853 TI - Osteoprotegerin in breast cancer: beyond bone remodeling. AB - Osteoprotegerin (OPG) is a secreted protein and member of the Tumor Necrosis Factor (TNF) Receptor superfamily. OPG has been well characterized as a regulator of bone metabolism which acts by blocking osteoclast maturation and preventing bone breakdown. Given this role, early studies on OPG in breast cancer focused on the administration of OPG in order to prevent the osteolysis observed with bone metastases. However OPG is also produced by the breast tumor cells themselves. Research focusing on OPG produced by breast tumor cells has revealed actions of OPG which promote tumor progression. In vitro studies into the role of OPG produced by breast tumor cells have demonstrated that OPG can block TNF-related apoptosis inducing ligand (TRAIL)-mediated apoptosis. Furthermore, in vivo studies show that OPG expression by breast tumors can promote tumor growth and metastasis. In addition it has been shown that OPG stimulates endothelial cell survival and tube formation thus it may indirectly promote breast tumor progression through impacting angiogenesis. This article will present a summary of the data concerning the tumor-promoting effects of OPG in breast cancer. PMID- 26054852 TI - The venomous cocktail of the vampire snail Colubraria reticulata (Mollusca, Gastropoda). AB - BACKGROUND: Hematophagy arose independently multiple times during metazoan evolution, with several lineages of vampire animals particularly diversified in invertebrates. However, the biochemistry of hematophagy has been studied in a few species of direct medical interest and is still underdeveloped in most invertebrates, as in general is the study of venom toxins. In cone snails, leeches, arthropods and snakes, the strong target specificity of venom toxins uniquely aligns them to industrial and academic pursuits (pharmacological applications, pest control etc.) and provides a biochemical tool for studying biological activities including cell signalling and immunological response. Neogastropod snails (cones, oyster drills etc.) are carnivorous and include active predators, scavengers, grazers on sessile invertebrates and hematophagous parasites; most of them use venoms to efficiently feed. It has been hypothesized that trophic innovations were the main drivers of rapid radiation of Neogastropoda in the late Cretaceous. We present here the first molecular characterization of the alimentary secretion of a non-conoidean neogastropod, Colubraria reticulata. Colubrariids successfully feed on the blood of fishes, throughout the secretion into the host of a complex mixture of anaesthetics and anticoagulants. We used a NGS RNA-Seq approach, integrated with differential expression analyses and custom searches for putative secreted feeding-related proteins, to describe in detail the salivary and mid-oesophageal transcriptomes of this Mediterranean vampire snail, with functional and evolutionary insights on major families of bioactive molecules. RESULTS: A remarkably low level of overlap was observed between the gene expression in the two target tissues, which also contained a high percentage of putatively secreted proteins when compared to the whole body. At least 12 families of feeding-related proteins were identified, including: 1) anaesthetics, such as ShK Toxin-containing proteins and turripeptides (ion-channel blockers), Cysteine-rich secretory proteins (CRISPs), Adenosine Deaminase (ADA); 2) inhibitors of primary haemostasis, such as novel vWFA domain-containing proteins, the Ectonucleotide pyrophosphatase/phosphodiesterase family member 5 (ENPP5) and the wasp Antigen-5; 3) anticoagulants, such as TFPI-like multiple Kunitz-type protease inhibitors, Peptidases S1 (PS1), CAP/ShKT domain-containing proteins, Astacin metalloproteases and Astacin/ShKT domain-containing proteins; 4) additional proteins, such the Angiotensin-Converting Enzyme (ACE: vasopressive) and the cytolytic Porins. CONCLUSIONS: Colubraria feeding physiology seems to involve inhibitors of both primary and secondary haemostasis, anaesthetics, a vasoconstrictive enzyme to reduce feeding time and tissue-degrading proteins such as Porins and Astacins. The complexity of Colubraria venomous cocktail and the divergence from the arsenal of the few neogastropods studied to date (mostly conoideans) suggest that biochemical diversification of neogastropods might be largely underestimated and worth of extensive investigation. PMID- 26054854 TI - The translation termination factor eRF1 (Sup45p) of Saccharomyces cerevisiae is required for pseudohyphal growth and invasion. AB - Mutations in the essential genes SUP45 and SUP35, encoding yeast translation termination factors eRF1 and eRF3, respectively, lead to a wide range of phenotypes and affect various cell processes. In this work, we show that nonsense and missense mutations in the SUP45, but not the SUP35, gene abolish diploid pseudohyphal and haploid invasive growth. Missense mutations that change phosphorylation sites of Sup45 protein do not affect the ability of yeast strains to form pseudohyphae. Deletion of the C-terminal part of eRF1 did not lead to impairment of filamentation. We show a correlation between the filamentation defect and the budding pattern in sup45 strains. Inhibition of translation with specific antibiotics causes a significant reduction in pseudohyphal growth in the wild-type strain, suggesting a strong correlation between translation and the ability for filamentous growth. Partial restoration of pseudohyphal growth by addition of exogenous cAMP assumes that sup45 mutants are defective in the cAMP dependent pathway that control filament formation. PMID- 26054855 TI - Coaggregation of Candida albicans, Actinomyces naeslundii and Streptococcus mutans is Candida albicans strain dependent. AB - Microbial interactions are necessarily associated with the development of polymicrobial oral biofilms. The objective of this study was to determine the coaggregation of eight strains of Candida albicans with Actinomyces naeslundii and Streptococcus mutans. In autoaggregation assays, C. albicans strains were grown in RPMI-1640 and artificial saliva medium (ASM) whereas bacteria were grown in heart infusion broth. C. albicans, A. naeslundii and S. mutans were suspended to give 10(6), 10(7) and 10(8) cells mL(-1) respectively, in coaggregation buffer followed by a 1 h incubation. The absorbance difference at 620 nm (DeltaAbs) between 0 h and 1 h was recorded. To study coaggregation, the same protocol was used, except combinations of microorganisms were incubated together. The mean DeltaAbs% of autoaggregation of the majority of RPMI-1640-grown C. albicans was higher than in ASM grown. Coaggregation of C. albicans with A. naeslundii and/or S. mutans was variable among C. albicans strains. Scanning electron microscopy images showed that A. naeslundii and S. mutans coaggregated with C. albicans in dual- and triculture. In conclusion, the coaggregation of C. albicans, A. naeslundii and S. mutans is C. albicans strain dependent. PMID- 26054857 TI - Factors influencing mortality in a captive breeding population of Loggerhead Shrike, Eastern subspecies (Lanius ludovicianus ssp.) in Canada. AB - BACKGROUND: The Loggerhead Shrike, Eastern subspecies (Lanius ludovicianus ssp.) (LOSH) is a predatory songbird native to Eastern North America. It is estimated that there are fewer than 55 breeding pairs of this subspecies in North America. Captive breeding plays a critical role in preventing the extirpation of this subspecies from its Canadian range. Unfortunately, high numbers of unexplained deaths among young birds in the captive breeding population threatened the success of this program. This paper describes fledgling mortality in the captive breeding population, and seeks to identify factors associated with fledgling survival and, ultimately, to identify steps to mitigate fledgling mortality. RESULTS: Over the study period (2006-2011) at two breeding sites, 696 LOSH were fledged. Among these, 68 % (n = 474) were released, 10 % (n = 69) were retained in the captive breeding population, and 22 % (n = 155) died. Fledgling survival declined from 99 % in 2006 to 44 % in 2011. The odds of survival were significantly lower for fledglings that were part of a second clutch. As the number of fledglings in a clutch increased, the odds of surviving increased significantly. As the breeding female aged from one to four years of age, there was a marked increase in the odds of a fledgling surviving, which then subsequently declined as females aged further. CONCLUSIONS: Based on our analyses, clutch number (first or second), number of fledglings in the brood, and age of breeding females were significant predictors of fledgling survival. Long term breeding management decisions will have to balance the need to increase the number of individuals and breeding pairs in the wild by releasing large numbers of young, against the need to maintain a genetically viable captive population, until the wild population is large enough to be self-sustaining. PMID- 26054856 TI - Neuroprotective effects of Liriope platyphylla extract against hydrogen peroxide induced cytotoxicity in human neuroblastoma SH-SY5Y cells. AB - BACKGROUND: Oxidative stress is involved in neuronal cell death and mitochondrial dysfunction in neurodegenerative diseases. Liriope platyphylla (LP) has been suggested to have anti-inflammation, anti-bacterial, and anti-cancer effects. However, whether LP exerts neuroprotective effects on neuronal cells is unknown. METHODS: The present study was performed to investigate the neuroprotective effects of LP extract (LPE) against hydrogen peroxide (H2O2)-induced injury in human neuroblastoma cells SH-SY5Y. To test neuroprotective effects of LPE, we performed cell viability assay, flow cytometry analysis and western blot analysis. In addition, mitochondrial membrane potential (MMP) and oxidative stress were performed to evaluate the anti-apoptotic and anti-oxidant effects. RESULTS: LPE pretreatment conferred significant protection against the H2O2 induced decrease of SH-SY5Y cell viability. H2O2-induced increases of intracellular oxidative stress and mitochondrial dysfunction were attenuated by LPE pretreatment. Therefore, LPE pretreatment prevented SH-SY5Y cell injury. Treatment with H2O2 significantly induced poly(ADP ribose) polymerase (PARP) and caspase-3 cleavage, which was blocked by LPE. We found that p38 activation was involved in the neuroprotective effects of LPE. CONCLUSIONS: Current findings suggest that LPE exerts neuroprotective effects against H2O2-induced apoptotic cell death by modulating p38 activation in SH-SY5Y cells. Therefore, LPE has potential anti-apoptotic effects that may be neuroprotective in neurodegenerative diseases and aging-related dementia. PMID- 26054858 TI - Diagnosis and Management of Latent Tuberculosis Infection. AB - The post-2015 World Health Organization global tuberculosis strategy recognizes that elimination requires a focus on reducing the pool of latently infected individuals, an estimated 30% of the global population, from which future tuberculosis cases would be generated. Tackling latent tuberculosis infection requires the identification and treatment of asymptomatic individuals to reduce the risk of progression to active disease. Diagnosis of latent tuberculosis infection is based on the detection of an immune response to Mycobacterium tuberculosis antigens using either the tuberculin skin test or interferon-gamma release assays. Current treatment requires the use of antibiotics for at least 3 months. In this article, we review the current knowledge of the natural history, immunology, and pathogenesis of latent tuberculosis, describe key population groups for screening and risk assessment, discuss clinical management in terms of diagnosis and preventative treatment, and identify areas for future research. PMID- 26054859 TI - Global risk factor rankings: the importance of age-based health loss inequities caused by alcohol and other risk factors. AB - BACKGROUND: Achieving health equity is a priority of the World Health Organization; however, there is a scant amount of literature on this topic. As the underlying influences that determine health loss caused by risk factors are age-dependent, the aim of this paper is to examine how the risk factor rankings for health loss differ by age. METHODS: Rankings were based on data obtained from the 2010 Global Burden of Disease study. Health loss (as measured by Disability Adjusted Life Years lost) by risk factor was estimated using Population Attributable Fractions, years of life lost due to premature mortality, and years lived with disability, which were calculated for 187 countries, 20 age groups and both sexes. Uncertainties of the risk factor rankings were estimated using 1,000 simulations taken from posterior distributions RESULTS: The top risk factors by age were: household air pollution for neonates 0-6 days of age [95% uncertainty interval (UI): 1 to 1]; suboptimal breast feeding for children 7-27 days of age (95% UI: 1-1); childhood underweight for children 28 days to less than 1 year of age and 1-4 years of age (95% UI: 1-2 and 1-1, respectively); iron deficiency for children and youth 5-14 years of age (95% UI: 1-1); alcohol use for people 15-49 years of age (95% UI: 1-2); and dietary risks for people 50 years of age and older (95% UI: 1-1). Rankings of risk factors varied by sex among the older age groups. Alcohol and smoking were the most important risk factors among men 15 years of age and older, and high body mass and intimate partner violence were some of the most important risk factors among women 15 years of age and older. CONCLUSIONS: Our analyses confirm that the relative importance of risk factors is age-dependent. Therefore, preventing harms caused by various modifiable risk factors using interventions that target people of different ages should be a priority, especially since easily implemented and cost-effective public health interventions exist. PMID- 26054860 TI - Enhancing dendritic cell immunotherapy for melanoma using a simple mathematical model. AB - BACKGROUND: The immunotherapy using dendritic cells (DCs) against different varieties of cancer is an approach that has been previously explored which induces a specific immune response. This work presents a mathematical model of DCs immunotherapy for melanoma in mice based on work by Experimental Immunotherapy Laboratory of the Medicine Faculty in the Universidad Autonoma de Mexico (UNAM). METHOD: The model is a five delay differential equation (DDEs) which represents a simplified view of the immunotherapy mechanisms. The mathematical model takes into account the interactions between tumor cells, dendritic cells, naive cytotoxic T lymphocytes cells (inactivated cytotoxic cells), effector cells (cytotoxic T activated cytotoxic cells) and transforming growth factor beta cytokine (T G F-beta). The model is validated comparing the computer simulation results with biological trial results of the immunotherapy developed by the research group of UNAM. RESULTS: The results of the growth of tumor cells obtained by the control immunotherapy simulation show a similar amount of tumor cell population than the biological data of the control immunotherapy. Moreover, comparing the increase of tumor cells obtained from the immunotherapy simulation and the biological data of the immunotherapy applied by the UNAM researchers obtained errors of approximately 10 %. This allowed us to use the model as a framework to test hypothetical treatments. The numerical simulations suggest that by using more doses of DCs and changing the infusion time, the tumor growth decays compared with the current immunotherapy. In addition, a local sensitivity analysis is performed; the results show that the delay in time " tau", the maximal growth rate of tumor "r" and the maximal efficiency of tumor cytotoxic cells rate "aT" are the most sensitive model parameters. CONCLUSION: By using this mathematical model it is possible to simulate the growth of the tumor cells with or without immunotherapy using the infusion protocol of the UNAM researchers, to obtain a good approximation of the biological trials data. It is worth mentioning that by manipulating the different parameters of the model the effectiveness of the immunotherapy may increase. This last suggests that different protocols could be implemented by the Immunotherapy Laboratory of UNAM in order to improve their results. PMID- 26054861 TI - Food adulteration: Sources, health risks, and detection methods. AB - Adulteration in food has been a concern since the beginning of civilization, as it not only decreases the quality of food products but also results in a number of ill effects on health. Authentic testing of food and adulterant detection of various food products is required for value assessment and to assure consumer protection against fraudulent activities. Through this review we intend to compile different types of adulterations made in different food items, the health risks imposed by these adulterants and detection methods available for them. Concerns about food safety and regulation have ensured the development of various techniques like physical, biochemical/immunological and molecular techniques, for adulterant detection in food. Molecular methods are more preferable when it comes to detection of biological adulterants in food, although physical and biochemical techniques are preferable for detection of other adulterants in food. PMID- 26054862 TI - Contemporary practice among pediatric surgeons in the use of bowel preparation for elective colorectal surgery: A survey of the American Pediatric Surgical Association. AB - PURPOSE: The goal of this study was to characterize contemporary practice among pediatric surgeons in the use of mechanical bowel preparation (MBP) and oral antibiotics (OA) for elective colorectal surgery. METHODS: A survey of the American Pediatric Surgical Association membership was conducted to characterize variation in the use of MBP and OA for commonly performed elective colorectal procedures in children. RESULTS: Three-hundred thirteen members completed the survey. The most common approach used was MBP alone (31.1%), followed by diet modification only (26.8%), MBP combined with OA (19.6%), no preparation or dietary modification (12.2%), and OA alone (5.4%). The most common MBP used was a polyethylene glycol-based solution (92.6%), and the most common OA approach was neomycin combined with erythromycin (55.9%). Although MBP alone was the preferred approach among pediatric surgeons, the greatest relative change reported over time was in the adoption of dietary modifications only or no preparation at all. CONCLUSIONS: Significant variation exists in the use of bowel preparation among pediatric surgeons. Although use of MBP alone remains the preferred approach for most procedures, an increasing number of surgeons report abandoning this approach in favor of dietary modification alone or no preparation at all. PMID- 26054863 TI - Factorial Structure and Measurement Invariance of the PANAS in Spanish Older Adults. AB - Developmental theories suggest age-related changes in the structure of affect. Paradoxically, the internal structure of the Positive and Negative Affect Schedule (PANAS; Watson, Clark, & Tellegen, 1988) has not been tested in Spanish older adults by means of confirmatory factor analysis (CFA) despite it is the most widely used measure of emotional well-being in later life. The aim of this study was to examine competing models of the internal structure of the Spanish version of the PANAS, its measurement invariance, reliability, and external validity. Participants were a representative sample of 585 community-dwelling people aged 60 and over, who also completed depression, loneliness and life satisfaction measures. Results showed that the orthogonal two-factor model with correlated errors (RMSEA = .057, 90% CI [.051, .063], SRMR = .084, CFI = .97, NNFI = .97) was the best fitting solution. Measurement invariance analyses confirmed that the two-independent factor structure can be used across young-old and very old people, as well as in both males and females. It showed good reliability (PA: alpha = .93, NA: alpha = .83), criterion, convergent and discriminant validity (p < .01). Our discussion highlights the role of age and culture in the experience and expression of emotions. PMID- 26054864 TI - FERTILITY PATTERN AND FITNESS OF THE SPANISH-MEXICAN COLONISTS OF CALIFORNIA (1742-1876). AB - The analysis of fertility in colonizing populations is of great interest, since its individuals experience a major environmental change, and fertility rates can reflect the level of adaptation of the population to its new conditions. Using Northrop's genealogical compilations, this paper examines the fertility pattern of California's early Spanish-Mexican colonists between 1742 and 1876, their fitness levels and their trend across time throughout the colonizing period. A total of 197 women from 599 compiled families who had completed their reproductive period and had at least one child were analysed. The correlations among variables were also analysed in order to infer the relationship between longevity and fertility, and the influence of fertility determinants. The results show a natural fertility pattern, with a very young age at marriage and birth of first child (17.2 and 19.1 years respectively), and also a young age at last childbirth (38.8 years). The population's fitness showed greater values than for contemporary European populations, with 8 of 9.2 children surviving to adulthood, in comparison with 55% of newborns in Finland for the same period, suggesting a good adaptation of the population to their new environmental conditions. No relationship between fertility and lifespan was observed, as has been reported by other authors and in opposition to classical theories. A temporal trend in the number of children, consisting of three different phases, was observed, in accordance with the stability of living conditions in the region. PMID- 26054865 TI - Hydrogel Spacer Prospective Multicenter Randomized Controlled Pivotal Trial: Dosimetric and Clinical Effects of Perirectal Spacer Application in Men Undergoing Prostate Image Guided Intensity Modulated Radiation Therapy. AB - PURPOSE: Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation. METHODS AND MATERIALS: Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months. RESULTS: Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 +/- 3.9 mm and 1.6 +/- 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption. CONCLUSIONS: Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols. PMID- 26054866 TI - An outbreak of multi-drug resistant Escherichia coli urinary tract infection in an elderly population: a case-control study of risk factors. AB - BACKGROUND: Prevention of infection due to multi-drug resistant organisms is particularly challenging because of the spread of resistant bacteria beyond hospitals into the community, including nursing homes. This study aimed to identify risk factors for the acquisition of a multidrug resistant (MDR) Escherichia coli in a local outbreak. METHODS: Study participants were all aged over 65 years. Cases had the MDR E. coli isolated from a routine urine sample, and controls had a urine sample submitted to the laboratory in the same time period but the MDR E. coli was not isolated. Information from clinical records was used to identify risk factors both in the hospital and the community setting for acquisition of the MDR E. coli. RESULTS: 76 cases and 156 controls were identified and included in the study. In a multivariate analysis, risk factors statistically significantly associated with acquisition of the MDR E. coli were female gender (adjusted OR 3.2; 95 % confidence interval 1.5-6.9), level of care (high dependency OR 7.5; 2.2-25.7) compared with living independently), and in hospital prescription of antimicrobials to which the MDR E. coli was resistant (OR 5.6; 2.5-12.9). CONCLUSIONS: The major risk factors for the acquisition of a MDR E. coli were found to be residence in a nursing home and in-hospital prescription of antimicrobials to which the MDR E. coli was resistant. This emphasises that prevention of transmission of MDROs within a community needs to involve both hospitals and also other healthcare organizations, in this case nursing homes. PMID- 26054867 TI - Social Marketing in Malaysia: Cognitive, Affective, and Normative Mediators of the TAK NAK Antismoking Advertising Campaign. AB - Antismoking mass media campaigns are known to be effective as part of comprehensive tobacco control programs in high-income countries, but such campaigns are relatively new in low- and middle-income countries and there is a need for strong evaluation studies from these regions. This study examines Malaysia's first national antismoking campaign, TAK NAK. The data are from the International Tobacco Control Malaysia Survey, which is an ongoing cohort survey of a nationally representative sample of adult smokers (18 years and older; N = 2,006). The outcome variable was quit intentions of adult smokers, and the authors assessed the extent to which quit intentions may have been strengthened by exposure to the antismoking campaign. The authors also tested whether the impact of the campaign on quit intentions was related to cognitive mechanisms (increasing thoughts about the harm of smoking), affective mechanisms (increasing fear from the campaign), and perceived social norms (increasing perceived social disapproval about smoking). Mediational regression analyses revealed that thoughts about the harm of smoking, fear arousal, and social norms against smoking mediated the relation between TAK NAK impact and quit intentions. Effective campaigns should prompt smokers to engage in both cognitive and affective processes and encourage consideration of social norms about smoking in their society. PMID- 26054868 TI - Management of nonfunctioning pituitary incidentaloma. AB - Prevalence of pituitary incidentaloma is variable: between 1.4% and 27% at autopsy, and between 3.7% and 37% on imaging. Pituitary microincidentalomas (serendipitously discovered adenoma <1cm in diameter) may increase in size, but only 5% exceed 10mm. Pituitary macroincidentalomas (serendipitously discovered adenoma>1cm in diameter) show increased size in 20-24% and 34-40% of cases at respectively 4 and 8years' follow-up. Radiologic differential diagnosis requires MRI centered on the pituitary gland. Initial assessment of nonfunctioning (NF) microincidentaloma is firstly clinical, the endocrinologist looking for signs of hypersecretion (signs of hyperprolactinemia, acromegaly or Cushing's syndrome), followed up by systematic prolactin and IGF-1 assay. Initial assessment of NF macroincidentaloma is clinical, the endocrinologist looking for signs of hormonal hypersecretion or hypopituitarism, followed up by hormonal assay to screen for hypersecretion or hormonal deficiency and by ophthalmologic assessment (visual acuity and visual field) if and only if the lesion is near the optic chiasm (OC). NF microincidentaloma of less than 5mm requires no surveillance; those of>=5mm are not operated on but rather monitored on MRI at 6months and then 2years. Macroincidentaloma remote from the OC is monitored on MRI at 1year, with hormonal exploration (for anterior pituitary deficiency), then every 2years. When macroincidentaloma located near the OC is managed by surveillance rather than surgery, MRI is recommended at 6months, with hormonal and visual exploration, then annual MRI and hormonal and visual assessment every 6months. Surgery is indicated in the following cases: evolutive NF microincidentaloma, NF macroincidentaloma associated with hypopituitarism or showing progression, incidentaloma compressing the OC, possible malignancy, non-compliant patient, pregnancy desired in the short-term, or context at risk of apoplexy. PMID- 26054869 TI - Are Morphologic Parameters Actually Correlated with the Rupture Status of Anterior Communicating Artery Aneurysms? AB - OBJECTIVE: The aim of this study was to identify whether computed tomography based morphologic parameters actually are correlated with the rupture status of anterior communicating artery aneurysms (ACoAAs). METHODS: A total of 167 patients with ACoAAs were treated in our neurosurgery department from May 2010 to May 2015, and the morphologic and clinical characteristics of 80 of them (50 ruptured and 30 unruptured) were analyzed retrospectively. Morphologic parameters were evaluated on the basis of 3-dimensional computed tomography angiograms and included neck diameter, maximum height, perpendicular height, aspect ratio, size ratio, aneurysm angle, vessel angle, flow angle, parent-daughter angle, aneurysm shape, number of aneurysms, variation of the A1 segment, and the direction of the aneurysm dome. RESULTS: The chi(2) test revealed that the anterior direction was associated with ACoAA rupture. The independent sample t-tests revealed that the parent-daughter angle and the size ratio were associated with ACoAA rupture. However, the binary logistic regression revealed that the size ratio was the strongest factor associated with ACoAA rupture. CONCLUSIONS: The anterior direction, parent-daughter angle, and size ratio between ruptured and unruptured ACoAAs were found to be statistically significant; they may be implicated in the rupture of ACoAAs, but the size ratio was the strongest factor that was correlated with rupture of ACoAAs based on binary logistic regression. PMID- 26054870 TI - Validation of a New Clinico-Radiological Grading for Compound Head Injury: Implications on the Prognosis and the Need for Surgical Intervention. AB - BACKGROUND: Lack of risk stratification among patients with varying severities of compound head injury has resulted in too-inconsistent and conflicting results to support any management strategy over another. The purpose of this study was to validate a new clinico-radiological grading scheme with implications on outcome and the need for surgical debridement. METHODS: Patients who sustained an external compound head injury with no serious systemic injury and no pre established infection and who continued the entire treatment were studied prospectively for their proposed grade of compound injury in relation to infective complications, unfavorable Glasgow Outcome Scale (GOS), delayed seizures, mortality, and hospital stay for 3 months. Appropriate univariate and multivariate analyses were performed. RESULTS: Among a total of 344 patients, 182 (53%) had no dural violation or midline shift (Grade 1), 56 (16%) had cerebrospinal fluid leak or pneumocephalus (Grade 2), 34 (10%) had exposed brain (Grade 3), 47 (14%) had midline shift (Grade 4), and 25 (7%) had both exposed brain and midline shift (Grade 5). Each successive grade of compound injury had significant incremental impact on all the outcome measures studied. Infective complications in Grades 1 to 5 were noted among 7%, 9%, 27%, 28%, and 36% of patients, respectively (P < 0.001). There was a significant difference in unfavorable GOS (23% vs. 56%, odds ratio [OR] 4.3, P < 0.001) and mortality (17% vs. 42%, OR 3.5, P < 0.001) between Grades 1-2 and Grades 3-5. Delayed seizures were noted in 4%, 4%, 9%, 13%, and 16% of patients in Grades 1-5 (P = 0.04). The median hospital stay was 1, 3, 6, 6, and 8 days, respectively (P < 0.001). All patients in Grades 4-5 (72) underwent surgery. Only 32 of 182 (18%) patients in Grade 1, 9 of 56 (16%) patients in Grade 2, and 23 of 34 (68%) patients in Grade 3 underwent surgical debridement, whereas the rest were managed conservatively. Patients who were managed conservatively had significantly lower infective complications (3% vs. 25%, OR 9.67, P < 0.001) in Grade 1, and (2% vs. 44%, OR 36.8, P = 0.002) in Grade 2, compared with those who underwent surgical debridement. In multivariate analysis, the proposed grade had significant independent association with infection (P < 0.001), unfavorable GOS (P = 0.01), delayed seizures (P = 0.001), and hospital stay (P < 0.001), and each successive grade had significant incremental impact on both infective complications and unfavourable GOS, independent of GCS and other prognostic factors. CONCLUSION: The new grading scheme appears to be of practical clinical significance. It shows significant statistical associations with the rates of infection, unfavorable neurologic outcome, delayed seizures, mortality, and duration of hospital stay. The incremental impact of each successive grade on infective complications and unfavorable GOS was independent of GCS and other prognostic factors. Conservative management had significantly lower infection compared to surgical debridement, at least in patients with Grades 1 and 2. PMID- 26054871 TI - Risk Factors for Surgical Site Infection After Spinal Surgery: A Meta-Analysis. AB - BACKGROUND: Surgical-site infection (SSI) after spinal surgery is the most common complication, which results in greater morbidity, mortality, and health care costs. Identifying risk factors of SSI is an important point for preventive strategies to reduce the incidence of SSI. The aim of this meta-analysis is to investigate the most important risk factors for SSI after spinal surgery. METHODS: PubMed, Embase, and Web of Science were systematically searched to identify cohort or case-control studies that investigated the risk factors for SSI following spinal surgery. A fixed-effects or random-effects model was used to pool the estimates, depending on the heterogeneity among the included studies. Heterogeneity between the studies was assessed by I2 and Cochran's Q test. RESULTS: Twelve studies with a total of 13,476 patients met the inclusion criteria were included in this meta-analysis. Of them, 1 was a nested case control studies, 7 were case-control studies, and 4 were cohort studies. The most important predictors of SSI were diabetes (risk ratio [RR] = 2.22, 95% confidence interval [95% CI] 1.38-3.60; P = 0.001), prolonged operative times (>3 hours) (RR = 2.16, 95% CI 1.12-4.19; P = 0.009), body mass index more than 35 (RR = 2.36, 95% CI 1.47-3.80; P = 0.000), and posterior approach (RR = 1.22, 95% CI 1.05 1.41; P = 0.009). CONCLUSION: Diabetes, prolonged operative times (>3 hours), body mass index more than 35, posterior approach, and number of intervertebral levels (>=7) are associated with an increased risk of SSI after spinal surgery. Almost all these risk factors are in line with the known risk factors for SSI in patients who underwent spinal surgery. PMID- 26054872 TI - Neural correlates of multiple object tracking strategies. AB - Amazingly, human observers can track four independently moving targets. The present study investigated the neural correlates of multiple-object tracking (MOT). Based on previous work we used a modified MOT-task to which subjects exhibited different behaviors. One half of the subjects showed slower RTs and higher error rates with increasing correspondence between tracked items and a probe consisting of 4 highlighted items presented after the tracking. The other half of the subjects had better performance when the probe fully matched the tracked items. Here we sought to investigate the neural representation of the two divergent behavior types. Using multivariate pattern analysis we observed two partly overlapping functional networks associated with the different behaviors. Subjects that responded fast and accurate to full-congruity trials predominantly showed a functional pattern for the full-congruity condition that was very different from patterns associated with any of the partly congruent conditions. This "deviant" pattern was observed in frontal, parietal and extrastriate visual brain areas. In the group of subjects with decreasing performance for increasing target-probe congruity these same regions exhibited a very different functional relationship, in which increasing congruities were associated with linearly changing neural activity patterns. Early low-tier visual areas exclusively exhibited the linear classification pattern while area LO and the primary motor cortex exclusively showed the deviant pattern across all subjects. The coexistence of both networks in groups with different behaviors provides the neural basis for a flexible behavior that can be flexibly adjusted as a function of the strategy employed in the task. PMID- 26054873 TI - Adaptation to shifted interaural time differences changes encoding of sound location in human auditory cortex. AB - The auditory system infers the location of sound sources from the processing of different acoustic cues. These cues change during development and when assistive hearing devices are worn. Previous studies have found behavioral recalibration to modified localization cues in human adults, but very little is known about the neural correlates and mechanisms of this plasticity. We equipped participants with digital devices, worn in the ear canal that allowed us to delay sound input to one ear, and thus modify interaural time differences, a major cue for horizontal sound localization. Participants wore the digital earplugs continuously for nine days while engaged in day-to-day activities. Daily psychoacoustical testing showed rapid recalibration to the manipulation and confirmed that adults can adapt to shifted interaural time differences in their daily multisensory environment. High-resolution functional MRI scans performed before and after recalibration showed that recalibration was accompanied by changes in hemispheric lateralization of auditory cortex activity. These changes corresponded to a shift in spatial coding of sound direction comparable to the observed behavioral recalibration. Fitting the imaging results with a model of auditory spatial processing also revealed small shifts in voxel-wise spatial tuning within each hemisphere. PMID- 26054874 TI - Functional connections between optic flow areas and navigationally responsive brain regions during goal-directed navigation. AB - Recent computational models suggest that visual input from optic flow provides information about egocentric (navigator-centered) motion and influences firing patterns in spatially tuned cells during navigation. Computationally, self-motion cues can be extracted from optic flow during navigation. Despite the importance of optic flow to navigation, a functional link between brain regions sensitive to optic flow and brain regions important for navigation has not been established in either humans or animals. Here, we used a beta-series correlation methodology coupled with two fMRI tasks to establish this functional link during goal directed navigation in humans. Functionally defined optic flow sensitive cortical areas V3A, V6, and hMT+ were used as seed regions. fMRI data was collected during a navigation task in which participants updated position and orientation based on self-motion cues to successfully navigate to an encoded goal location. The results demonstrate that goal-directed navigation requiring updating of position and orientation in the first person perspective involves a cooperative interaction between optic flow sensitive regions V3A, V6, and hMT+ and the hippocampus, retrosplenial cortex, posterior parietal cortex, and medial prefrontal cortex. These functional connections suggest a dynamic interaction between these systems to support goal-directed navigation. PMID- 26054875 TI - Structural brain correlates of associative memory in older adults. AB - Associative memory involves binding two or more items into a coherent memory episode. Relative to memory for single items, associative memory declines greatly in aging. However, older individuals vary substantially in their ability to memorize associative information. Although functional studies link associative memory to the medial temporal lobe (MTL) and prefrontal cortex (PFC), little is known about how volumetric differences in MTL and PFC might contribute to individual differences in associative memory. We investigated regional gray matter volumes related to individual differences in associative memory in a sample of healthy older adults (n=54; age=60years). To differentiate item from associative memory, participants intentionally learned face-scene picture pairs before performing a recognition task that included single faces, scenes, and face scene pairs. Gray-matter volumes were analyzed using voxel-based morphometry region-of-interest (ROI) analyses. To examine volumetric differences specifically for associative memory, item memory was controlled for in the analyses. Behavioral results revealed large variability in associative memory that mainly originated from differences in false-alarm rates. Moreover, associative memory was independent of individuals' ability to remember single items. Older adults with better associative memory showed larger gray-matter volumes primarily in regions of the left and right lateral PFC. These findings provide evidence for the importance of PFC in intentional learning of associations, likely because of its involvement in organizational and strategic processes that distinguish older adults with good from those with poor associative memory. PMID- 26054877 TI - Identifying neuronal oscillations using rhythmicity. AB - Neuronal oscillations are a characteristic feature of neuronal activity and are typically investigated through measures of power and coherence. However, neither of these measures directly reflects the distinctive feature of oscillations: their rhythmicity. Rhythmicity is the extent to which future phases can be predicted from the present one. Here, we present lagged coherence, a frequency indexed measure that quantifies the rhythmicity of neuronal activity. We use this method to identify the sensorimotor alpha and beta rhythms in ongoing magnetoencephalographic (MEG) data, and to study their attentional modulation. Using lagged coherence, the sensorimotor rhythms become visible in ongoing activity as local rhythmicity peaks that are separated from the strong posterior activity in the same frequency bands. In contrast, using conventional power analyses, the sensorimotor rhythms cannot be identified in ongoing data, nor can they be separated from the posterior activity. We go on to show that the attentional modulation of these rhythms is also evident in lagged coherence and moreover, that in contrast to power, it can be visualised even without an experimental contrast. These findings suggest that the rhythmicity of neuronal activity is better suited to identify neuronal oscillations than the power in the same frequency band. PMID- 26054876 TI - Evaluation of machine learning algorithms for treatment outcome prediction in patients with epilepsy based on structural connectome data. AB - The objective of this study is to evaluate machine learning algorithms aimed at predicting surgical treatment outcomes in groups of patients with temporal lobe epilepsy (TLE) using only the structural brain connectome. Specifically, the brain connectome is reconstructed using white matter fiber tracts from presurgical diffusion tensor imaging. To achieve our objective, a two-stage connectome-based prediction framework is developed that gradually selects a small number of abnormal network connections that contribute to the surgical treatment outcome, and in each stage a linear kernel operation is used to further improve the accuracy of the learned classifier. Using a 10-fold cross validation strategy, the first stage in the connectome-based framework is able to separate patients with TLE from normal controls with 80% accuracy, and second stage in the connectome-based framework is able to correctly predict the surgical treatment outcome of patients with TLE with 70% accuracy. Compared to existing state-of-the art methods that use VBM data, the proposed two-stage connectome-based prediction framework is a suitable alternative with comparable prediction performance. Our results additionally show that machine learning algorithms that exclusively use structural connectome data can predict treatment outcomes in epilepsy with similar accuracy compared with "expert-based" clinical decision. In summary, using the unprecedented information provided in the brain connectome, machine learning algorithms may uncover pathological changes in brain network organization and improve outcome forecasting in the context of epilepsy. PMID- 26054878 TI - Risk factors for resistance in urinary tract infections in women in general practice: A cross-sectional survey. AB - OBJECTIVES: In 2012 and 2013, a cross-sectional survey was conducted in women visiting a general practitioner for a urinary tract infection (UTI) to i) describe the patterns of antibiotic resistance of Enterobacteriaceae involved in community-acquired UTIs and ii) identify the factors associated with UTIs due to a multi-drug-resistant Enterobacteriaceae (MDREB). METHODS: Urine analyses were performed systematically for all adult women presenting with signs of UTI. Characteristics of women with UTI due to MDREB were compared to those with UTI due to non-MDREB. Weighted logistic regressions were performed to adjust for the sampling design of the survey. RESULTS: Significant factors associated with MDREB included the use of penicillin by the patient in the last three months (OR = 3.1; [1.2-8.0]); having provided accommodation in the previous 12 months to a resident from a country at high risk for drug resistance (OR = 4.0; [1.2-15.1]); and the consumption of raw meat within the previous three months (OR = 0.3; [0.1-0.9]). CONCLUSIONS: In the community, antibiotic use and exposure to a person returning from an area with a high risk of drug resistance are associated with UTIs due to MDREB. The potentially protective role of raw meat consumption warrants further study. PMID- 26054879 TI - Ganglioside GD1a suppresses LPS-induced pro-inflammatory cytokines in RAW264.7 macrophages by reducing MAPKs and NF-kappaB signaling pathways through TLR4. AB - Gangliosides, sialic acid-containing glycosphingolipids, have been considered to be involved in the development, differentiation, and function of nervous systems in vertebrates. However, the mechanisms for anti-inflammation caused by gangliosides are not clear. In this paper, we investigated the anti-inflammation effects of ganglioside GD1a by using RAW264.7 macrophages. Our data demonstrated that treatment of macrophages with lipopolysaccharide significantly increased the production of NO and pro-inflammatory cytokines. GD1a suppressed the induction of iNOS and COX-2 mRNA and protein expression and secretory pro-inflammatory cytokines in culture medium, such as TNFalpha, IL-1alpha and IL-1beta. In addition, LPS-induced phosphorylation of mitogen-activating protein kinases and IkappaBalpha degradation followed by translocation of the NF-kappaB from the cytoplasm to the nucleus were attenuated after GD1a treatment. Furthermore, GD1a probably inhibited LPS binding to macrophages and LPS-induced accumulation between TLR4 and MyD88. Taken together, the results demonstrated that ganglioside GD1a inhibited LPS-induced inflammation in RAW 264.7 macrophages by suppressing phosphorylation of mitogen-activating protein kinases and activation of NF-kappaB through repressing the Toll-like receptor 4 signaling pathway. PMID- 26054880 TI - Quercetin protects against perfluorooctanoic acid-induced liver injury by attenuating oxidative stress and inflammatory response in mice. AB - The aim of the present study was to investigate the protective effect of quercetin (Que) against perfluorooctanoic acid (PFOA)-induced liver injury in mice and its possible mechanisms of action. Mice were intragastrically administered PFOA (10mg/kg/day) alone or in combination with Que (75 mg/kg/day) for 14 consecutive days. The hepatic injury was evaluated by measuring morphological changes, liver function, oxidative stress, inflammatory response and hepatocellular apoptosis. Compared with mice treated with PFOA alone, simultaneous supplementation of Que significantly decreased serum levels of liver injury indicators alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase and total bile acids. Moreover, Que treatment inhibited the production of oxidative stress biomarkers malondialdehyde, hydrogen peroxide and 8-hydroxy-2'-deoxyguanosine, reduced the levels of proinflammatory cytokines interleukin 6, cyclooxygenase-2 and C-reactive protein, and decreased the number of TUNEL-positive cells in the liver of PFOA-treated mice. These results combined with liver histopathology demonstrated that Que exhibited a potential protective effect against PFOA-induced liver damage via mechanisms involving the attenuation of oxidative stress, alleviation of inflammation and inhibition of hepatocellular apoptosis. PMID- 26054881 TI - Randomized, double-blind, placebo-controlled pilot trial of reduced coenzyme Q10 for Parkinson's disease. AB - INTRODUCTION: Mitochondrial complex I deficiencies have been found in post-mortem brains of patients with Parkinson's disease (PD). Coenzyme Q10 (CoQ10) is the electron acceptor found in complexes I and II, and is a potent antioxidant. A recent trial of the oxidized form of CoQ10 for PD failed to show benefits; however, the reduced form of CoQ10 (ubiquinol-10) has shown better neuroprotective effects in animal models. METHODS: Randomized, double-blind, placebo-controlled, parallel-group pilot trials were conducted to assess the efficacy of ubiquinol-10 in Japanese patients with PD. Participants were divided into two groups: PD experiencing wearing off (Group A), and early PD, without levodopa (with or without a dopamine agonist) (Group B). Participants took 300 mg of ubiquinol-10 or placebo per day for 48 weeks (Group A) or 96 weeks (Group B). RESULTS: In Group A, total Unified Parkinson's Disease Rating Scale (UPDRS) scores decreased in the ubiquinol-10 group (n = 14; mean +/- SD [-4.2 +/- 8.2]), indicating improvement in symptoms. There was a statistically significant difference (p < 0.05) compared with the placebo group (n = 12; 2.9 +/- 8.9). In Group B, UPDRS increased in the ubiquinol-10 group (n = 14; 3.9 +/- 8.0), as well as in the placebo group (n = 8; 5.1 +/- 10.3). CONCLUSIONS: This is the first report showing that ubiquinol-10 may significantly improve PD with wearing off, as judged by total UPDRS scores, and that ubiquinol-10 is safe and well tolerated. PMID- 26054882 TI - Impaired peripheral vasoconstrictor response to orthostatic stress in patients with multiple system atrophy. AB - BACKGROUND AND PURPOSE: Most patients with multiple system atrophy (MSA) develop autonomic dysfunction; however, orthostatic hypotension is not always present. Failure of the vasoconstrictor response is thought to be responsible for orthostatic hypotension, but the degree of impairment of this response in patients with MSA is unclear. We assessed autonomic function in patients with MSA by evaluating the vasoconstrictive response during a head-up tilt test and determining its relationship to orthostatic hypotension. As an additional examination, the efficacy of norepinephrine in treating orthostatic hypotension was also assessed. METHODS: The study included 82 patients with MSA and 28 controls. Measures of total peripheral resistance were obtained during a head-up tilt test. Norepinephrine was administered to the patients lacking a vasoconstrictive response to evaluate its ability to treat orthostatic hypotension. RESULTS: At a 60 degrees tilt, orthostatic hypotension occurred in 47.6% of the patients and 0% of controls. Reduction in total peripheral resistance from baseline at a 60 degrees tilt was observed in 69.5% of the patients and 0% of controls. In patients with MSA, changes in systolic blood pressure from the baseline at a 60 degrees tilt correlated positively with changes in the total peripheral resistance (r = 0.69, p < 0.0001). Norepinephrine prevented the reduction of total peripheral resistance and development of orthostatic hypotension. CONCLUSIONS: A large number of patients with MSA with and without orthostatic hypotension have an impaired peripheral vasoconstrictive response, suggesting a high frequency of cardiovascular dysautonomia with an associated risk of developing orthostatic hypotension. A norepinephrine infusion was effective for treating orthostatic hypotension. PMID- 26054883 TI - Interleukin-6 mediates enhanced thrombus development in cerebral arterioles following a brief period of focal brain ischemia. AB - OBJECTIVE: The cerebral microvasculature is rendered more vulnerable to thrombus formation following a brief (5.0 min) period of focal ischemia. This study examined the contribution of interleukin-6 (IL-6), a neuroprotective and prothrombotic cytokine produced by the brain, to transient ischemia-induced thrombosis in cerebral arterioles. APPROACH & RESULTS: The middle cerebral artery of C57BL/6J mice was occluded for 5 min, followed by 24h of reperfusion (MCAo/R). Intravital fluorescence microscopy was used to monitor thrombus development in cerebral arterioles induced by light/dye photoactivation. Thrombosis was quantified as the time of onset of platelet aggregation on the vessel wall and the time for complete blood flow cessation. MCAo/R in wild type (WT) mice yielded an acceleration of thrombus formation that was accompanied by increased IL-6 levels in plasma and in post-ischemic brain tissue. The exaggerated thrombosis response to MCAo/R was blunted in WT mice receiving an IL-6 receptor-blocking antibody and in IL-6 deficient (IL-6(-/-)) mice. Bone marrow chimeras, produced by transplanting IL-6(-/-) marrow into WT recipients, did not exhibit protection against MCAo/R-induced thrombosis. CONCLUSIONS: The increased vulnerability of the cerebral vasculature to thrombus development after MCAo/R is mediated by IL 6, which is likely derived from brain cells rather than circulating blood cells. These findings suggest that anti-IL-6 therapy may reduce the likelihood of cerebral thrombus development after a transient ischemic attack. PMID- 26054885 TI - Peripheral to central: Organ interactions in stroke pathophysiology. AB - Stroke is associated with a high risk of disability and mortality, and with the exception of recombinant tissue-type plasminogen activator for acute stroke, most treatments have proven ineffective. Clinical translation of promising experimental therapeutics is limited by inadequate stroke models and a lack of understanding of the mechanisms underlying acute stroke and how they affect outcome. Bidirectional communication between the ischemic brain and peripheral immune system modulates stroke progression and tissue repair, while epidemiological studies have provided evidence of an association between organ dysfunction and stroke risk. This crosstalk can determine the fate of stroke patients and must be taken into consideration when investigating the pathophysiological mechanisms and therapeutic options for stroke. This review summarizes the current evidence for interactions between the brain and other organs in stroke pathophysiology in basic and clinic studies, and discusses the role of these interactions in the progression and outcome of stroke and how they can direct the development of more effective treatment strategies. PMID- 26054884 TI - Neurotrophin selectivity in organizing topographic regeneration of nociceptive afferents. AB - Neurotrophins represent some of the best candidates to enhance regeneration. In the current study, we investigated the effects of artemin, a member of the glial derived neurotrophic factor (GDNF) family, on sensory axon regeneration following a lumbar dorsal root injury and compared these effects with that observed after either NGF or GDNF expression in the rat spinal cord. Unlike previously published data, artemin failed to induce regeneration of large-diameter myelinated sensory afferents when expressed within either the spinal cord or DRG. However, artemin or NGF induced regeneration of calcitonin gene related peptide positive (CGRP(+)) axons only when expressed within the spinal cord. Accordingly, artemin or NGF enhanced recovery of only nociceptive behavior and showed a cFos distribution similar to the topography of regenerating axons. Artemin and GDNF signaling requires binding to different co-receptors (GFRalpha3 or GFRalpha1, respectively) prior to binding to the signaling receptor, cRet. Approximately 70% of DRG neurons express cRet, but only 35% express either co-receptor. To enhance artemin induced regeneration, we co-expressed artemin with either GFRalpha3 or GDNF. Co expression of artemin and GFRalpha3 only slightly enhanced regeneration of IB4(+) non-peptidergic nociceptive axons, but not myelinated axons. Interestingly, this co-expression also disrupted the ability of artemin to produce topographic targeting and lead to significant increases in cFos immunoreactivity within the deep dorsal laminae. This study failed to demonstrate artemin-induced regeneration of myelinated axons, even with co-expression of GFRalpha3, which only promoted mistargeted regeneration. PMID- 26054886 TI - Repetitive head trauma, chronic traumatic encephalopathy and tau: Challenges in translating from mice to men. AB - Chronic traumatic encephalopathy (CTE) is a neurological and psychiatric condition marked by preferential perivascular foci of neurofibrillary and glial tangles (composed of hyperphosphorylated-tau proteins) in the depths of the sulci. Recent retrospective case series published over the last decade on athletes and military personnel have added considerably to our clinical and histopathological knowledge of CTE. This has marked a vital turning point in the traumatic brain injury (TBI) field, raising public awareness of the potential long-term effects of mild and moderate repetitive TBI, which has been recognized as one of the major risk factors associated with CTE. Although these human studies have been informative, their retrospective design carries certain inherent limitations that should be cautiously interpreted. In particular, the current overriding issue in the CTE literature remains confusing in regard to appropriate definitions of terminology, variability in individual pathologies and the potential case selection bias in autopsy based studies. There are currently no epidemiological or prospective studies on CTE. Controlled preclinical studies in animals therefore provide an alternative means for specifically interrogating aspects of CTE pathogenesis. In this article, we review the current literature and discuss difficulties and challenges of developing in-vivo TBI experimental paradigms to explore the link between repetitive head trauma and tau-dependent changes. We provide our current opinion list of recommended features to consider for successfully modeling CTE in animals to better understand the pathobiology and develop therapeutics and diagnostics, and critical factors, which might influence outcome. We finally discuss the possible directions of future experimental research in the repetitive TBI/CTE field. PMID- 26054887 TI - [The temporary black henna tattoos: complications observed in Burkina Faso]. PMID- 26054888 TI - [Management of STEMI: A network consolidated by clinical research]. PMID- 26054889 TI - [Frey syndrome (auriculo-temporal syndrome)]. PMID- 26054890 TI - The impact of obesity on the relationship between epicardial adipose tissue, left ventricular mass and coronary microvascular function. AB - PURPOSE: Epicardial adipose tissue (EAT) has been linked to coronary artery disease (CAD) and coronary microvascular dysfunction. However, its injurious effect may also impact the underlying myocardium. This study aimed to determine the impact of obesity on the quantitative relationship between left ventricular mass (LVM), EAT and coronary microvascular function. METHODS: A total of 208 (94 men, 45 %) patients evaluated for CAD but free of coronary obstructions underwent quantitative [(15)O]H2O hybrid positron emission tomography (PET)/CT imaging. Coronary microvascular resistance (CMVR) was calculated as the ratio of mean arterial pressure to hyperaemic myocardial blood flow. RESULTS: Obese patients [body mass index (BMI) > 25, n = 133, 64 % of total] had more EAT (125.3 +/- 47.6 vs 93.5 +/- 42.1 cc, p < 0.001), a higher LVM (130.1 +/- 30.4 vs 114.2 +/- 29.3 g, p < 0.001) and an increased CMVR (26.6 +/- 9.1 vs 22.3 +/- 8.6 mmHg*ml( 1)*min(-1)*g(-1), p < 0.01) as compared to nonobese patients. Male gender (beta = 40.7, p < 0.001), BMI (beta = 1.61, p < 0.001), smoking (beta = 6.29, p = 0.03) and EAT volume (beta = 0.10, p < 0.01) were identified as independent predictors of LVM. When grouped according to BMI status, EAT was only independently associated with LVM in nonobese patients. LVM, hypercholesterolaemia and coronary artery calcium score were independent predictors of CMVR. CONCLUSION: EAT volume is associated with LVM independently of BMI and might therefore be a better predictor of cardiovascular risk than BMI. However, EAT volume was not related to coronary microvascular function after adjustments for LVM and traditional risk factors. PMID- 26054891 TI - Cardiovascular Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics for the Clinical Practitioner. AB - Current clinical cardiovascular practice requires a clinician to have a strong foundation in multiple aspects of pharmacology. Modern cardiovascular regimens are complex, and optimal management, application of evolving guidelines, and adoption of new therapies build off a more basic understanding of pharmacokinetics and pharmacodynamics. In addition, it is likely time to add a third pillar into this discussion, the expanding field of pharmacogenomics referring to the genetic influences on drug response. This field has increasing applications in medicine and clearly holds significant promise for cardiovascular disease management. Awareness of pharmacogenomic advances and the fundamentals of pharmacokinetics and pharmacodynamics can help the clinician more easily deliver great care. Here we attempt to briefly summarize and simplify key concepts of pharmacokinetics, pharmacodynamics, and pharmacogenomics relevant to the cardiovascular disease practitioner. PMID- 26054892 TI - Proteomic analysis of immunogenic proteins from salivary glands of Aedes aegypti. AB - Humans develop anti-salivary proteins after arthropod bites or exposure to insect salivary proteins. This reaction indicates that vector bites have a positive effect on the host immune response, which can be used as epidemiological markers of exposure to the vector. Our previous study identified two immunogenic proteins with molecular weights of 31 kDa and 56 kDa from salivary gland extract (SGE) of Aedes aegypti that cross-reacted with serum samples from Dengue Hemorrhagic Fever (DHF) patients and healthy people in an endemic area (Indonesia). Serum samples from individuals living in non-endemic area (sub-tropical country) and infants did not show the immunogenic reactions. The objective of this research was to identify two immunogenic proteins, i.e., 31 and 56 kDa by using proteomic analysis. In this study, proteomic analysis resulted in identification of 13 proteins and 7 proteins from the 31 kDa- and 56 kDa-immunogenic protein bands, respectively. Among those proteins, the D7 protein (Arthropode Odorant-Binding Protein, AOBP) was the most abundant in 31-kDa band, and apyrase was the major protein of the 56-kDa band. PMID- 26054893 TI - [Prospective observational study of insulin detemir in patients with poorly controlled type 2 diabetes mellitus initiating insulin therapy for the first time (SOLVE Study)]. AB - OBJECTIVE: Describe the experience in the primary care setting with insulin detemir in patients with poorly controlled type2 diabetes mellitus that need to add-on insulin to their oral antidiabetic drug therapy. METHODS: Prospective observational study of 6 months of follow up, performed in 10 countries. In Spain, participating sites were only from the primary care setting. Eligible patients were those with poorly controlled type2 diabetes mellitus adding-on once daily insulin detemir to their existing oral antidiabetic therapy in the month prior to their enrollment. The change of Hb1Ac and of weight at the end of the study and the incidence of hypoglycemia and adverse reactions, were analyzed. We report the results obtained in the Spanish cohort. RESULTS: Overall 17,374 patients were included, 973 in Spain [mean age 64.8 years (SE 12); duration of diabetes 9.4 years (SE 6.2); Hb1Ac 8.9% (DE 1.4)]. In the sample analyzed for efficacy (n=474) the mean change of Hb1Ac was -1.6% (95%CI: -1.75 to -1.42; P<.001), mean change of weight was -2.9 kg (95%CI: -3.72 to -2.08; P<.001). Only one episode of severe hypoglycemia was reported, which was also the only serious adverse reaction reported in the study. The incidence rate of non-severe hypoglycemia was 2.44 events/patient-year. CONCLUSIONS: In this cohort of patients with type 2 diabetes mellitus receiving newly initiated insulin therapy, once-daily detemir improved the glycemic control, with low incidence of hypoglycemia and a significant reduction of the weight. PMID- 26054894 TI - Infantile basal ganglia stroke after mild head trauma. PMID- 26054895 TI - Ischemic stroke after pellet embolization. PMID- 26054896 TI - Self-reported memory complaints: Implications from a longitudinal cohort with autopsies. PMID- 26054897 TI - To revitalize neurology we need to address physician burnout. PMID- 26054898 TI - Clinical Reasoning: A 66-year-old man with recurrent multi-territory infarcts. PMID- 26054899 TI - Teaching NeuroImages: Spontaneous spinal epidural hematoma with spot sign positivity. PMID- 26054901 TI - Letter to the editor. PMID- 26054902 TI - The relationships of the pulmonary arteries to lung lesions aid in differential diagnosis using computed tomography. AB - The improvement of the resolution of rapid scanning in multidetector computed tomography (CT) has an increased accuracy that allows for the demonstration of the relationship of the pulmonary arteries and lung lesions, even in the peripheral lung. The purpose of this study is to evaluate the relationship between the pulmonary arteries and lung lesions by CT, and to use this relationship to distinguish between benign and malignant lung lesions. The relationships of the lung lesions and the adjacent pulmonary artery were recorded as encasement, displacement, penetration, in the margin, and disconnection. Statistical analyses were then performed to evaluate the relationship of the pulmonary arteries to each lesion with a focus toward the possibility of malignancy and the degree of pulmonary arterial encasement in the lesion. The relationship between the pulmonary arteries and lung lesions had a statistically significant difference between benignancy and malignancy (P < 0.001). Inter observer agreement was substantial (kappa = 0.639; 95% CI: 0.518-0.719). The average degrees of pulmonary arterial encasement in benign and malignant lesions were 52.1% +/- 27.3% and 71.8% +/- 18.8%, respectively (P = 0.011). The ROC curve showed that the degree of pulmonary arterial encasement had a moderate discriminating ability in diagnosing lung carcinoma, and the area under the curve was 0.738. The best cutoff value was 44.4%. The relationships of the pulmonary arteries to lung lesions and the degree of pulmonary arterial encasement could be used in differentiating benignancy from malignancy not only for central lung lesions but also peripheral lung lesions. PMID- 26054903 TI - Multifocal osteolytic lesions of the skull: a primary cavernous hemangioma mimicking a neoplastic invasive lesion. AB - Intraosseous cavernous hemangioma is a rare cause of osteolytic lesions of the skull, and its multifocal type is even more infrequent. This tumor is difficult to accurately diagnose by imaging and can be confused with osteolytic Langerhan's cell histiocytosis or other neoplasms. Here we present a case of multifocal intraosseous cavernous hemangioma of the skull treated with surgical intervention in our hospital five years ago. A review of related literatures and case reports is also provided to help clarify the diagnosis and devise treatment regimens. In light of the difficulties of early diagnosis, early en bloc surgical removal is recommended. PMID- 26054900 TI - Turning Over a New Leaf: Cannabinoid and Endocannabinoid Modulation of Immune Function. AB - Cannabis is a complex substance that harbors terpenoid-like compounds referred to as phytocannabinoids. The major psychoactive phytocannabinoid found in cannabis ?(9)-tetrahydrocannabinol (THC) produces the majority of its pharmacological effects through two cannabinoid receptors, termed CB1 and CB2. The discovery of these receptors as linked functionally to distinct biological effects of THC, and the subsequent development of synthetic cannabinoids, precipitated discovery of the endogenous cannabinoid (or endocannabinoid) system. This system consists of the endogenous lipid ligands N- arachidonoylethanolamine (anandamide; AEA) and 2 arachidonylglycerol (2-AG), their biosynthetic and degradative enzymes, and the CB1 and CB2 receptors that they activate. Endocannabinoids have been identified in immune cells such as monocytes, macrophages, basophils, lymphocytes, and dendritic cells and are believed to be enzymatically produced and released "on demand" in a similar fashion as the eicosanoids. It is now recognized that other phytocannabinoids such as cannabidiol (CBD) and cannabinol (CBN) can alter the functional activities of the immune system. This special edition of the Journal of Neuroimmune Pharmacology (JNIP) presents a collection of cutting edge original research and review articles on the medical implications of phytocannabinoids and the endocannabinoid system. The goal of this special edition is to provide an unbiased assessment of the state of research related to this topic from leading researchers in the field. The potential untoward effects as well as beneficial uses of marijuana, its phytocannabinoid composition, and synthesized cannabinoid analogs are discussed. In addition, the role of the endocannabinoid system and approaches to its manipulation to treat select human disease processes are addressed. PMID- 26054904 TI - A giant? Think of genetics: growth hormone-producing adenomas in the young are almost always the result of genetic defects. PMID- 26054905 TI - Castleman disease mimicking nodal recurrence of thyroid cancer. AB - A 54-year-old woman who had undergone total thyroidectomy and radioactive iodine treatment for papillary thyroid cancer presented with elevated stimulated thyroglobulin levels and negative I-131 scan. Ultrasonography revealed suspicious lateral neck lymph nodes, which were FDG-avid. Neck dissection led to a diagnosis of Castleman disease. PMID- 26054906 TI - Transporters, chaperones, and P-type ATPases controlling grapevine copper homeostasis. AB - With more copper and copper-containing compounds used as bactericides and fungicides in viticulture, copper homeostasis in grapevine (Vitis) has become one of the serious environmental crises with great risk. To better understand the regulation of Cu homeostasis in grapevine, grapevine seedlings cultured in vitro with different levels of Cu were utilized to investigate the tolerance mechanisms of grapevine responding to copper availability at physiological and molecular levels. The results indicated that Cu contents in roots and leaves arose with increasing levels of Cu application. With copper concentration increasing, malondialdehyde (MDA) content increased in roots and leaves and the activities of superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) increased to protect the plant itself from damage. The expression patterns of 19 genes, encoding transporters, chaperones, and P-type ATPases involved in copper homeostasis in root and leaf of grapevine seedling under various levels of Cu(2+) were further analyzed. The expression patterns indicated that CTr1, CTr2, and CTr8 transporters were significantly upregulated in response both to Cu excess and deficiency. ZIP2 was downregulated in response to Cu excess and upregulated under Cu-deficient conditions, while ZIP4 had an opposite expression pattern under similar conditions. The expression of chaperones and P-type ATPases in response to Cu availability in grapevine were also briefly studied. PMID- 26054908 TI - ATP as a cotransmitter in the autonomic nervous system. AB - The role of adenosine 5'-triphosphate (ATP) as a major intracellular energy source is well-established. In addition, ATP and related nucleotides have widespread extracellular actions via the ionotropic P2X (ligand-gated cation channels) and metabotropic P2Y (G protein-coupled) receptors. Numerous experimental techniques, including myography, electrophysiology and biochemical measurement of neurotransmitter release, have been used to show that ATP has several major roles as a neurotransmitter in peripheral nerves. When released from enteric nerves of the gastrointestinal tract it acts as an inhibitory neurotransmitter, mediating descending muscle relaxation during peristalsis. ATP is also an excitatory cotransmitter in autonomic nerves; 1) It is costored with noradrenaline in synaptic vesicles in postganglionic sympathetic nerves innervating smooth muscle preparations, such as the vas deferens and most arteries. When coreleased with noradrenaline, ATP acts at postjunctional P2X1 receptors to evoke depolarisation, Ca(2+) influx, Ca(2+) sensitisation and contraction. 2) ATP is also coreleased with acetylcholine from postganglionic parasympathetic nerves innervating the urinary bladder and again acts at postjunctional P2X1 receptors, and possibly also a P2X1+4 heteromer, to elicit smooth muscle contraction. In both cases the neurotransmitter actions of ATP are terminated by dephosphorylation by extracellular, membrane-bound enzymes and soluble nucleotidases released from postganglionic nerves. There are indications of an increased contribution of ATP to control of blood pressure in hypertension, but further research is needed to clarify this possibility. More promising is the upregulation of P2X receptors in dysfunctional bladder, including interstitial cystitis, idiopathic detrusor instability and overactive bladder syndrome. Consequently, these roles of ATP are of great therapeutic interest and are increasingly being targeted by pharmaceutical companies. PMID- 26054910 TI - Barriers and facilitators to uptake of the school-based HPV vaccination programme in an ethnically diverse group of young women. AB - BACKGROUND: To identify the barriers and facilitators to uptake of the HPV vaccine in an ethnically diverse group of young women in the south west of England. METHODS: Three school-based vaccination sessions were observed. Twenty three young women aged 12 to 13 years, and six key informants, were interviewed between October 2012 and July 2013. Data were analysed using thematic analysis and the Framework method for data management. RESULTS: The priority given to preventing cervical cancer in this age group influenced whether young women received the HPV vaccine. Access could be affected by differing levels of commitment by school staff, school nurses, parents and young women to ensure parental consent forms were returned. Beliefs and values, particularly relevant to minority ethnic groups, in relation to adolescent sexual activity may affect uptake. Literacy and language difficulties undermine informed consent and may prevent vaccination. CONCLUSIONS: The school-based HPV vaccination programme successfully reaches the majority of young women. However, responsibility for key aspects remain unresolved which can affect delivery and prevent uptake for some groups. A multi-faceted approach, targeting appropriate levels of the socio ecological model, is required to address procedures for consent and cultural and literacy barriers faced by minority ethnic groups, increase uptake and reduce inequalities. PMID- 26054911 TI - Does government spending help to promote healthy behavior in the population? Evidence from 27 European countries. AB - BACKGROUND: The aim of this study was to examine if government spending is associated with an individual's decision to participate in physical activity and sport which is regarded as healthy behavior given the positive health effects documented in previous research. METHODS: Individual-level data (n = 25 243) containing socio-demographic information are combined with national-level data on government spending (5-year average) in 27 European countries. Given the hierarchical data structure, i.e. individuals are nested within countries; multi level analyses are applied. RESULTS: The multi-level models show that it is mainly education spending that has a significant positive association with participation in sport of various regularities. Health spending has some association with participation in other physical activity and sport of a lower regularity. CONCLUSIONS: While health spending can be considered a relevant policy tool for increasing sport participation rates, education spending is required more since the effects are larger and it affects both physical activity and sport. This suggests that health spending will have most effect combined with earlier influences from education spending. PMID- 26054909 TI - Advances in targeted therapies for hepatocellular carcinoma in the genomic era. AB - Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents. PMID- 26054912 TI - Aspects of dietary carbohydrate intake are not related to risk of colorectal polyps in the Tennessee Colorectal Polyp Study. AB - PURPOSE: High digestible carbohydrate intakes can induce hyperglycemia and hyperinsulinemia and collectively have been implicated in colorectal tumor development. Our aim was to explore the association between aspects of dietary carbohydrate intake and risk of colorectal adenomas and hyperplastic polyps in a large case-control study. METHODS: Colorectal polyp cases (n = 1,315 adenomas only, n = 566 hyperplastic polyps only and n = 394 both) and controls (n = 3,184) undergoing colonoscopy were recruited between 2003 and 2010 in Nashville, Tennessee, USA. Dietary intakes were estimated by a 108-item food frequency questionnaire. Unconditional logistic regression analysis was applied to determine odds ratios (OR) and corresponding 95 % confidence intervals (CI) for colorectal polyps according to dietary carbohydrate intakes, after adjustment for potential confounders. RESULTS: No significant associations were detected for risk of colorectal adenomas when comparing the highest versus lowest quartiles of intake for total sugars (OR 1.03; 95 % CI 0.84-1.26), starch (OR 1.01; 95 % CI 0.81-1.26), total or available carbohydrate intakes. Similar null associations were observed between dietary carbohydrate intakes and risk of hyperplastic polyps, or concurrent adenomas and hyperplastic polyps. CONCLUSION: In this US population, digestible carbohydrate intakes were not associated with risk of colorectal polyps, suggesting that dietary carbohydrate does not have an etiological role in the early stages of colorectal carcinogenesis. PMID- 26054913 TI - Bone cancer incidence by morphological subtype: a global assessment. AB - PURPOSE: To better understand the relevance of environmental factors to the changing patterns of bone cancer subtypes, we examine the incidence of osteosarcoma (OS), Ewing sarcoma (ES), and chondrosarcoma (CS) using data from cancer incidence in five continents. METHODS: Age-specific and age-standardized incidence rates (ASRs) per 100,000 person-years were computed and stratified by country (n = 43), subtype, and sex during 2003-2007. Temporal patterns of ASRs were examined during 1988-2007 (12 countries). Age-period-cohort models were fitted for the USA and UK by subtype. RESULTS: For most countries, OS represented 20-40 % of all bone cancers, ES < 20 %, while CS proportions varied more considerably. Overall ASRs of bone cancers were 0.8-1.2/100,000 in men and 0.5 1.0 in women (0.20-0.35/100,000 for OS and 0.10-0.30/100,000 for CS in both men and women, and <0.10-0.25/100,000 in men and 0.05-0.25/100,000 in women for ES). The age-specific incidence rates revealed a bimodal peak of OS, one peak of ES in childhood, and a more heterogeneous pattern for CS. The overall bone cancer incidence trends are generally flat, but more heterogeneous for ES and CS. A declining OS incidence was observed in the UK and USA (men), an increase in CS in the UK and USA (female), and an apparent increase in ES, followed by a leveling off in successive US and UK cohorts. CONCLUSION: Monitoring bone cancer incidence trends with data assembled from a geographically broader range of registries may generate hypotheses about additional risk factors and ensure that high-risk populations are not overlooked in cancer control efforts. PMID- 26054914 TI - Validation of clinical prognostic indices for diffuse large B-cell lymphoma in the National Cancer Data Base. AB - BACKGROUND: Accurate risk stratification is necessary for epidemiologic and outcomes research in diffuse large B-cell lymphoma (DLBCL). We evaluated performance characteristics of the clinically derived International Prognostic Index (IPI) and revised IPI (R-IPI) with a regression model-based score using the National Cancer Data Base. METHODS: We studied DLBCL patients diagnosed in 2004 2011, divided into derivation and validation cohorts. The model-based score was calculated from a Cox model incorporating variables routinely recorded by cancer registries. Calibration and discrimination of the indices with regard to overall survival were evaluated in the validation cohort. RESULTS: The IPI was recorded in 19,511 of 119,942 patients, of whom 79 % received chemotherapy. Both clinical indices provided good survival discrimination (5-year estimate range 33-74 % for the IPI, and 41-87 % for the R-IPI), but explained only 16 % of variation in survival. Survival predictions among chemotherapy-treated patients were similar to estimates from published clinical cohorts. The model-based score had significantly better discrimination characteristics (5-year survival estimate range 22-87 %) and explained 23 % of variation in survival. CONCLUSIONS: We validated the IPI and R-IPI as recorded by cancer registries to provide robust risk stratification in the general population with DLBCL, but a prognostic model using raw registry data provides superior performance. Explicit recording of prognostic factors is preferable to abstracting coarsened clinical indices for the purpose of population-based epidemiologic research. Considering low variation of survival explained by the standard clinical variables, incorporating molecular markers into registry data is necessary to improve risk stratification. PMID- 26054915 TI - First principles study on stability and hydrogen adsorption properties of Mg/Ti interface. AB - The hydrogenation and stability properties of the Mg/Ti interface are studied by first-principles calculations. The strain of lattice and movement of ions were imposed to search for a stable Mg/Ti interface. The anti-symmetrical configuration was found to be the most stable. The easiest transition pathway from anti-symmetrical to symmetrical configuration may be through the diagonal direction with no energy barrier. The hydrogen adsorption at distinguished positions in the Mg/Ti interface is investigated. The negative hydrogen adsorption energy reaches -0.991 eV at the top site in the interface, which will highly favor the thermodynamic stability of the Mg/Ti interface. The electronic structure is studied and it was found that the Ti acts as a hydrogen atom 'capturer' and strong interactions between H and its surrounding Ti and Mg atoms are expected. Thus, inserting Ti layers could create an interfacial zone where the adsorptions of hydrogen atoms may get stabilized and therefore improve the hydrogen storage properties of Mg. PMID- 26054916 TI - India makes strides in some, but not all, health goals, finds WHO. PMID- 26054917 TI - Cognitive impairment in Parkinson's disease: more than a frontostriatal dysfunction. AB - Cognitive deficit in Parkinson's disease has been traditionally considered as being mainly related to executive dysfunction secondary to frontostriatal affectation. However, this traditional consideration has recently been challenged. Forty-three nondemented PD patients (mean age = 59.19; SD = 9.64) and twenty control group subjects (mean age = 60.85; SD = 12.26) were studied. They were assessed on a wide range of cognitive functions. Patients showed motor slowing (p = .012), along with alterations in visuoperceptive (p = .001), visuospatial (p = .007) and visuoconstructive functions (p = .017), as well as in visual span (direct: p = .008; inverse: p = .037). Regarding executive functions, differences were not observed in classical measures for verbal fluency (phonetic: p = .28; semantic: p = .27) or in response inhibition (Stroop test: p = .30), while execution was altered in other prefrontal tasks (Wisconsin Test: p = .003; action fluency: p = .039). Patients showed altered performance in verbal learning processes (p = .005) and delayed memory (free: p = .032; cued: p = .006), visuospatial learning (p = .016) and linguistic functions (naming: p < .001; comprehension: p = .007). Poor performance in visuospatial memory is predicted by deficits in working memory and visuospatial perception. Taken together, the observed alterations not only suggest prefrontal affectation, but also temporal and parietal systems impairment. Thus, cognitive dysfunction in nondemented PD patients cannot be exclusively explained by frontostriatal circuit affectation and the resulting executive dysfunction. PMID- 26054918 TI - Health-related quality of life and social support in adolescents with type 1 diabetes. AB - This study investigated the correlations between health-related quality of life and social support in adolescents with type 1 diabetes (T1DM). Participants were 102 adolescents between 12 and 17 years old, who were patients of a healthcare program in the city of Porto Alegre, south of Brazil. Two questionnaires, the KIDSCREEN-52 and the Brazilian version of Social Support Appraisals, were used to evaluate health-related quality of life and social support. Results showed good quality of life and social support levels. Strong correlations were verified between social support and three of the KIDSCREEN-52 dimensions: psychological well-being (r = .63; p < .01); peers and social support (r = .67; p < .01) and school environment (r = .64; p < .01). Analysis of linear regression showed that gender, age and social support are variables associated with health-related quality of life, explaining 52.6% of variance. Results revealed the impact of the disease to young people, and can help to find strategies to improve care in these cases. PMID- 26054919 TI - Social identity, passion and well-being in university students, the mediating effect of passion. AB - Research on positive emotions associated with the performance of an activity, such as work or study, has increased exponentially in recent years. Passion is understood as an attitude and intense emotion in the performance of an activity, and it has shown both positive and negative consequences for well-being. A link between social identity and positive emotions through social category membership has been described. The aim of this work is to study the relationship between social identity, the dimensions of passion and the positive impact on university responses. A quasi-experimental design was used on a sample of 266 university students from different Spanish universities (Universidad Nacional de Educacion a Distancia, Universidad Miguel Hernandez and Universidad de Alicante). Descriptive analyzes were performed on the study's variables using SPSS 18. Structural equation modeling was carried out with AMOS 18 and the mediational analysis with MODMED macro developed by Preacher, Rucker, and Hayes (2007). The results show that the identity of the studies had an indirect effect on positive responses mediated by passion for the studies (RMSEA = .07; CFI = .97; NFI = .96; TLI = .92). It is observed that the harmonious and obsessive dimensions of passion differ in the mediating effect on happiness and satisfaction with studies. Practical and theoretical implications for well-being are discussed. PMID- 26054920 TI - Autophagy in autoimmune disease. AB - Autophagy is a protective and life-sustaining process in which cytoplasmic components are packaged into double-membrane vesicles and targeted to lysosomes for degradation. This process of cellular self-digestion is an essential stress response and is cytoprotective by removing damaged organelles and proteins that threaten the cell's survival. Key outcomes include energy generation and recycling of metabolic precursors. In the immune system, autophagy regulates processes such as antigen uptake and presentation, removal of pathogens, survival of short- and long-lived immune cells, and cytokine-dependent inflammation. In all cases, a window of optimal autophagic activity appears critical to balance catabolic, reparative, and inflammation-inducing processes. Dysregulation of autophagosome formation and autophagic flux can have deleterious consequences, ranging from a failure to "clean house" to the induction of autophagy-induced cell death. Abnormalities in the autophagic pathway have been implicated in numerous autoimmune diseases. Genome-wide association studies have linked polymorphisms in autophagy-related genes with predisposition for tissue destructive inflammatory disease, specifically in inflammatory bowel disease and systemic lupus erythematosus. Although the precise mechanisms by which dysfunctional autophagy renders the host susceptible to continuous inflammation remain unclear, autophagy's role in regulating the long-term survival of adaptive immune cells has recently surfaced as a defect in multiple sclerosis and rheumatoid arthritis. Efforts are underway to identify autophagy-inducing and autophagy-suppressing pharmacologic interventions that can be added to immunosuppressive therapy to improve outcomes of patients with autoimmune disease. PMID- 26054922 TI - Pyrimidine containing furanose derivative having antifungal, antioxidant, and anticancer activity. AB - BACKGROUND: A series of 6-(substituted aldehyde)-3,4-dihydro-1-(tetrahydro-3,4 dihydroxy-5-(hydroxymethyl) furan-2-yl)-4-phenylpyrimidine-2(1H)-one derivative (6A-6P) was synthesized from the 6-(substituted aldehyde)-4-phenylpyrimidine 2(1H)-one derivative (5A-5P) through following reaction mechanisms Claisen Schmidt, Cyclization, and Satos fusion. The structures of the synthesized compounds were elucidated by I.R.,(1)H-NMR, elemental analysis, and mass spectroscopic techniques. RESULT: The synthesized compounds were screened for in vitro antifungal activity at 25, 50, 100, and 200 MUg/ml concentrations. Among them, compounds 6P, 6D, and 6M exhibited significant antifungal activity that was carried out by cup plate method against fungal strain which was collected from IMTECH Chandigarh, India, against standard drug fluconazole. Compounds have been further evaluated by measuring zone of inhibition and percent inhibition. The synthesized compounds were screened for in vitro antioxidant activity using the DPPH assay, based on the AAI and antioxidant activity unit (AAU), using a combination relation between DPPH concentration and absorbance. The antioxidant strength of compounds was compared against ascorbic acid. Among them, compounds 6K, 6F, 6E, 6G, 6H, and 6M exhibited significant antioxidant activity and 6J have less active compound. The data of these synthesized compounds were submitted to the National Institute of Health, USA, under the drug discovery program of National Cancer Institute (NCI) and screened for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell lines. The selected compounds have shown potent significant anticancer activity in the NCI 60 cell line screening. CONCLUSION: A new series of pyrimidine analogues that contain furanose moiety were synthesized by Satos fusion and characterized. The synthesized compounds screened for their in vitro antioxidant, antifungal activity, as well as anticancer activity given by the derivative which has chloro, methoxy, nitro, and chloro substitution having furanose contain pyrimidine derivative that showed the most potent activity. PMID- 26054921 TI - The role of individual inheritance in tumor progression and metastasis. AB - Metastasis, the dissemination and growth of tumor cells at secondary sites, is the primary cause of patient mortality from solid tumors. Metastasis is an extremely complex, inefficient process requiring contributions of not only the tumor cell but also local and distant environmental factors, at both the cellular and molecular level. Variation in the function of any of the steps in the metastatic cascade may therefore have profound implications for the ultimate course of the disease. In addition to the somatic and cellular heterogeneity that can affect cancer outcome, an individual's specific ancestry or genetic background can also significantly influence metastatic progression. These inherited variants not only encoded for metastatic susceptibility but also provided a window to study critical factors that are not easily accessible with current technologies. Furthermore, investigations into inherited metastatic susceptibility enable identification of important molecular and cellular processes that are not subject to mutation and are consequently not detectable by standard cancer genome sequencing strategies. Incorporation of inherited variation into metastasis research therefore provides methods to more comprehensively investigate the etiology of the lethal consequences of tumor progression. PMID- 26054923 TI - Application of different fertilizers on morphological traits of dill (Anethum graveolens L.). AB - BACKGROUND: The aim of this study was to evaluate the effects of nitroxin biofertilizer and chemical fertilizer on the growth, yield, and essential oil composition of dill. The experiment was conducted under field condition in randomized complete block design with three replications and two factors. RESULTS: The first factor was the concentrations of nitroxin biofertilizer (0%, 50%, and 100%) of the recommended amount (1 l of biological fertilizer for 30 kg of seed). The second factor was the following chemical fertilizer treatments: no fertilizer (control) and 50 and 100 kg ha(-1) urea along with 300 kg ha(-1) ammonium phosphate. Different characteristics such as plant height, number of umbel per plant, number of umbellet per umbel, number of grain per umbellet, 1,000 seed weight, grain yield, biological yield, and oil percentage were recorded. According to the results, the highest height, biological yield, and grain yield components (except harvest index) were obtained on biological fertilizer. The results showed the highest essential oil content detected in biological fertilizer and chemical fertilizer. Identification of essential oil composition showed that the content of carvone increased with the application of biofertilizers and chemical fertilizers. The results indicated that the application of biofertilizers enhanced yield and other plant criteria in this plant. CONCLUSIONS: Generally, it seems that the use of biofertilizers or combinations of biofertilizer and chemical fertilizer could improve dill performance in addition to reduction of environmental pollution. PMID- 26054924 TI - FeCl3 mediated synthesis of substituted indenones by a formal [2+2] cycloaddition/ring opening cascade of o-keto-cinnamates. AB - A novel FeCl3 mediated formal [2+2] cycloaddition/ring opening cascade of o-keto cinnamates was developed for the synthesis of indenones. The reaction tolerates a broad range of functional groups, including bromide, chloride, amide, acid and ester groups. PMID- 26054925 TI - One-pot three-component domino protocol for the synthesis of novel pyrano[2,3 d]pyrimidines as antimicrobial and anti-biofilm agents. AB - A simple and facile synthesis of a series of novel pyrano[2,3-d]pyrimidines has been achieved successfully via the one-pot three-component reaction of 2-amino-7 methyl-5-oxo-4-phenyl-4,5-dihydropyrano[4,3-b]pyran-3-carbonitriles, DMF-DMA and arylamines in the presence of 1-butyl-3-methylhydrogensulphate [Bmim]HSO4 ionic liquid. This method has several advantages such as high yields, clean reaction, simple methodology and short reaction times. The synthesized compounds were evaluated for their antimicrobial activity against Gram-positive, Gram-negative and different Candida strains. Among the derivatives screened, compounds 4c, 4d, 4h and 4l were found to be active against both bacterial and Candida strains with MIC values ranging from 3.9 to 31.2 MUg mL(-1). In addition, compound 4l showed a good minimum bactericidal concentration, minimum fungicidal concentration and anti-biofilm activities. Furthermore, the mode of the antifungal action for the promising compound 4l was evaluated in C. albicans MTCC 1637 through an ergosterol biosynthesis inhibition process. PMID- 26054926 TI - Microscale extraction and phase separation using a porous capillary. AB - We report the use of a porous polytetrafluoroethylene capillary for the inline separation of liquid-liquid segmented flows, based on the selective wetting and permeation of the porous capillary walls by one of the liquids. Insertion of a narrow flow restriction at the capillary outlet allows the back pressure to be tuned for multiple liquid-liquid combinations and flow conditions. In this way, efficient separation of aqueous-organic, aqueous-fluorous and organic-fluorous segmented flows can be readily achieved over a wide range of flow rates. The porous-capillary-separator enables the straightforward regeneration of a continuous flow from a segmented flow, and may be applied to various applications, including inline analysis, biphasic reactions, and purification. As a demonstration of the latter, we performed a simple inline aqueous-organic extraction of the pH indicator 2,6-dichloroindophenol. An aqueous solution of the conjugate base was mixed with hydrochloric acid in continuous flow to protonate the indicator and render it organic-soluble. The indicator was then extracted from the aqueous feed into chloroform using a segmented flow. The two liquids were finally separated inline using a porous PTFE capillary, with the aqueous phase emerging as a continuous stream from the separator outlet. UV-visible absorption spectroscopy showed the concentration of indicator in the outflowing aqueous phase to be less than one percent of its original value, confirming the efficacy of the extraction and separation process. PMID- 26054927 TI - The aftereffect of perceived duration is contingent on auditory frequency but not visual orientation. AB - Recent sensory history plays a critical role in duration perception. It has been established that after adapting to a particular duration, the test durations within a certain range appear to be distorted. To explore whether the aftereffect of perceived duration can be constrained by sensory modality and stimulus feature within a modality, the current study applied the technique of simultaneous sensory adaptation, by which observers were able to simultaneously adapt to two durations defined by two different stimuli. Using both simple visual and auditory stimuli, we found that the aftereffect of perceived duration is modality specific and contingent on auditory frequency but not visual orientation of the stimulus. These results demonstrate that there are independent timers responsible for the aftereffects of perceived duration in each sensory modality. Furthermore, the timer for the auditory modality may be located at a relatively earlier stage of sensory processing than the timer for the visual modality. PMID- 26054928 TI - Spiritual and Non-spiritual Needs Among German Soldiers and Their Relation to Stress Perception, PTDS Symptoms, and Life Satisfaction: Results from a Structural Equation Modeling Approach. AB - In an anonym cross-sectional survey (using standardized questionnaires) among 1092 German soldiers, we found that 21 % regard their faith as a "strong hold in difficult times." Only a few had specific religious needs. Rather, a consistent theme from the participants was the need to communicate their own fears, worries and desire to attain states of inner peace. "Soldiers" stress perception and posttraumatic stress disorder symptoms were associated particularly with existential and Inner Peace Needs. Structural equation modeling indicated that stress perception has a negative influence on soldiers' life satisfaction, which in turn gives rise to specific unmet spiritual needs. These specific needs may indicate psycho-emotional problems which could be supported very early to prevent health affections and service failure. PMID- 26054929 TI - Post-transcriptional modifications and "Calmodulation" of voltage-gated calcium channel function: Reflections by two collaborators of David T Yue. AB - This review article is written to specially pay tribute to David T. Yue who was an outstanding human being and an excellent scientist who exuded passion and creativity. He exemplified an inter-disciplinary scientist who was able to cross scientific boundaries effortlessly in order to provide amazing understanding on how calcium channels work. This article provides a glimpse of some of the research the authors have the privilege to collaborate with David and it attempts to provide the thinking behind some of the research done. In a wider context, we highlight that calcium channel function could be exquisitely modulated by interaction with a tethered calmodulin. Post-transcriptional modifications such as alternative splicing and RNA editing further influence the Ca(2+)-CaM mediated processes such as calcium dependent inhibition and/or facilitation. Besides modifications of electrophysiological and pharmacological properties, protein interactions with the channels could also be influenced in a splice-variant dependent manner. PMID- 26054930 TI - Differences in the behavior and ecology of wild type medaka (Oryzias latipes complex) and an orange commercial variety (himedaka). AB - Genetic disturbance in wild populations of medaka (Oryzias latipes complex) has been mainly caused by the introduction of the orange-red commercial variety medaka (himedaka) in Japan. To examine whether survival, reproduction, and species recognition would be influenced by this difference in body coloration, we conducted three laboratory experiments (predatory pressure, mate choice, schooling behavior) using wild type medaka and himedaka. In the predation experiment using dark chub (Candidia temminckii) as a predator, himedaka were predated upon more often than wild type medaka. However, individuals did not choose mates or select schooling groups based on himedaka or wild type medaka phenotypes. The results indicate that himedaka receive higher predation pressure but are able to easily mate with wild type medaka in a natural environment. To conserve the genetic diversity of wild medaka populations, we need to control the risk of genetic disturbance caused by himedaka. PMID- 26054931 TI - Comparative transcriptional profiling analysis of developing melon (Cucumis melo L.) fruit from climacteric and non-climacteric varieties. AB - BACKGROUND: In climacteric fruit-bearing species, the onset of fruit ripening is marked by a transient rise in respiration rate and autocatalytic ethylene production, followed by rapid deterioration in fruit quality. In non-climacteric species, there is no increase in respiration or ethylene production at the beginning or during fruit ripening. Melon is unusual in having climacteric and non-climacteric varieties, providing an interesting model system to compare both ripening types. Transcriptomic analysis of developing melon fruits from Vedrantais and Dulce (climacteric) and Piel de sapo and PI 161375 (non climacteric) varieties was performed to understand the molecular mechanisms that differentiate the two fruit ripening types. RESULTS: Fruits were harvested at 15, 25, 35 days after pollination and at fruit maturity. Transcript profiling was performed using an oligo-based microarray with 75 K probes. Genes linked to characteristic traits of fruit ripening were differentially expressed between climacteric and non-climacteric types, as well as several transcription factor genes and genes encoding enzymes involved in sucrose catabolism. The expression patterns of some genes in PI 161375 fruits were either intermediate between. Piel de sapo and the climacteric varieties, or more similar to the latter. PI 161375 fruits also accumulated some carotenoids, a characteristic trait of climacteric varieties. CONCLUSIONS: Simultaneous changes in transcript abundance indicate that there is coordinated reprogramming of gene expression during fruit development and at the onset of ripening in both climacteric and non-climacteric fruits. The expression patterns of genes related to ethylene metabolism, carotenoid accumulation, cell wall integrity and transcriptional regulation varied between genotypes and was consistent with the differences in their fruit ripening characteristics. There were differences between climacteric and non climacteric varieties in the expression of genes related to sugar metabolism suggesting that they may be potential determinants of sucrose content and post harvest stability of sucrose levels in fruit. Several transcription factor genes were also identified that were differentially expressed in both types, implicating them in regulation of ripening behaviour. The intermediate nature of PI 161375 suggested that classification of melon fruit ripening behaviour into just two distinct types is an over-simplification, and that in reality there is a continuous spectrum of fruit ripening behaviour. PMID- 26054932 TI - Design and characterization of a new peptide vector for short interfering RNA delivery. AB - RNA interference holds tremendous potential as one of the most powerful therapeutic strategies. However, the properties of short interfering RNA (siRNA), such as hydrophilicity, negative charge, and instability in serum have limited its applications; therefore, significant efforts have been undertaken to improve its cellular uptake. Cell penetrating peptides have been utilized to deliver various biologically active molecules, such as proteins, liposomes, nanoparticles, peptide nucleic acids, and recently small interfering RNAs. Here, we introduce a new cell penetrating peptide GL1(Ac-GLWRAWLWKAFLASNWRRLLRLLR-NH2) to improve the intracellular uptake of siRNA. This peptide consists of four tryptophan residues that facilitated its binding with the cell membrane, five arginine residues and one lysine residue which are positively charged at physiological pH, which induced the formation of peptide-siRNA complexes and enhanced the affinity of the peptide and cell membrane. Moreover, GL1 adopted helical secondary structure due to the altered distribution of polar and nonpolar residues in the sequence. In this study, we investigated the effect of peptide/siRNA molar ratio on the particle size, surface charge, secondary structure, and uptake efficiency. The results showed that GL1 formed stable complexes with siRNA mainly through electrostatic interaction and hydrophobic interaction, and the complexes displayed a spherical shape with the size of ~100 nm and positive surface charge. Utilizing the techniques of fluorescence microscopy and flow cytometry, the intracellular localization of Cy3-labeled GAPDH siRNA was visualized and the cellular uptake was quantified. It is worth noting that in the serum free environment, compared to Lipofectamine 2000, GL1 achieved higher cellular uptake of siRNA (~95%); in the presence of serum, GL1 retained the same level of siRNA cellular uptake (~84%) as Lipofectamine 2000. In addition, the viability of cells treated by GL1 in all studied molar ratios was >85%, which was significantly higher than that treated by Lipofectamine 2000 (~70%). Taken together, the peptide GL1 demonstrated promise as a siRNA delivery system. PMID- 26054933 TI - Characterization of the Local Structure in Liquid Water by Various Order Parameters. AB - A wide range of geometric order parameters have been suggested to characterize the local structure of liquid water and its tetrahedral arrangement, but their respective merits have remained elusive. Here, we consider a series of popular order parameters and analyze molecular dynamics simulations of water, in the bulk and in the hydration shell of a hydrophobic solute, at 298 and 260 K. We show that these parameters are weakly correlated and probe different distortions, for example the angular versus radial disorders. We first combine these complementary descriptions to analyze the structural rearrangements leading to the density maximum in liquid water. Our results reveal no sign of a heterogeneous mixture and show that the density maximum arises from the depletion in interstitial water molecules upon cooling. In the hydration shell of the hydrophobic moiety of propanol, the order parameters suggest that the water local structure is similar to that in the bulk, with only a very weak depletion in ordered configurations, thus confirming the absence of any iceberg-type structure. Finally, we show that the main structural fluctuations that affect water reorientation dynamics in the bulk are angular distortions, which we explain by the jump hydrogen-bond exchange mechanism. PMID- 26054934 TI - Preferences for food and nutritional supplements among adult people living with HIV in Malawi. AB - OBJECTIVE: To elucidate the factors influencing food intake and preferences for potential nutritional supplements to treat mild and moderate malnutrition among adult people living with HIV (PLHIV). DESIGN: Qualitative research using in-depth interviews with a triangulation of participants and an iterative approach to data collection. SETTING: The study was conducted in a health clinic of rural Chilomoni, a southern town of Blantyre district, Malawi. SUBJECTS: Male and female participants, aged 18-49 years (n 24), affected by HIV; health surveillance assistants of Chilomoni clinic (n 8). RESULTS: Six themes emerged from the in-depth interviews: (i) PLHIV perceived having a poor-quality diet; (ii) health challenges determine the preferences of PLHIV for food; (iii) liquid thick, soft textures and subtle natural colours and flavours are preferred; (iv) preferred organoleptic characteristics of nutritional supplements resemble those of local foods; (v) food insecurity may contribute to intra-household sharing of nutritional supplements; and (vi) health surveillance assistants and family members influence PLHIV's dietary behaviours. No differences by sex were found. The emergent themes were corroborated by health surveillance assistants through participant triangulation. CONCLUSIONS: In this setting, a thickened liquid supplement, slightly sweet and sour, may be well accepted. A combination of quantitative and qualitative methods for data collection should follow to further develop the nutritional supplement and to fine tune the organoleptic characteristics of the product to the taste and requirements of PLHIV. Results of the present study provide a first approach to elucidate the factors influencing food intake and preferences for potential nutritional supplements among adult PLHIV. PMID- 26054935 TI - Social media users have different experiences, motivations, and quality of life. AB - While the number of individuals participating in internet-based social networks has continued to rise, it is unclear how participating in social networks might influence quality of life (QOL). Individuals differ in their experiences, motivations for, and amount of time using internet-based social networks, therefore, we examined if individuals differing in social network user experiences, motivations and frequency of social network also differed in self reported QOL. Two-hundred and thirty-seven individuals (aged 18-65) were recruited online using the online platform Mechanical Turk (MTurk). All participants completed a web-based survey examining social network use and the World Health Organization Quality of Life Scale Abbreviated Version (WHOQOL-Bref) to assess QOL. Individuals who reported positive associations with the use of social networks demonstrated higher QOL while those reporting negative associates demonstrated lower QOL. Moreover, individuals using social networks to stay connected to friends demonstrated higher QOL while those using social networking for dating purposes reported lower QOL. Frequency of social network use did not relate to QOL. These results suggest that QOL differs among social network users. Thus, participating in social networking may be a way to either promote or detract from QOL. PMID- 26054936 TI - Web-based phenotyping for Tourette Syndrome: Reliability of common co-morbid diagnoses. AB - Collecting phenotypic data necessary for genetic analyses of neuropsychiatric disorders is time consuming and costly. Development of web-based phenotype assessments would greatly improve the efficiency and cost-effectiveness of genetic research. However, evaluating the reliability of this approach compared to standard, in-depth clinical interviews is essential. The current study replicates and extends a preliminary report on the utility of a web-based screen for Tourette Syndrome (TS) and common comorbid diagnoses (obsessive compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD)). A subset of individuals who completed a web-based phenotyping assessment for a TS genetic study was invited to participate in semi-structured diagnostic clinical interviews. The data from these interviews were used to determine participants' diagnostic status for TS, OCD, and ADHD using best estimate procedures, which then served as the gold standard to compare diagnoses assigned using web-based screen data. The results show high rates of agreement for TS. Kappas for OCD and ADHD diagnoses were also high and together demonstrate the utility of this self report data in comparison previous diagnoses from clinicians and dimensional assessment methods. PMID- 26054937 TI - Antifungal activity of berberine hydrochloride and palmatine hydrochloride against Microsporum canis -induced dermatitis in rabbits and underlying mechanism. AB - BACKGROUND: Phellodendron amurense, exhibits antifungal activity mainly by bioactive components including berberine hydrochloride and palmatine hydrochloride. This study was conducted to evaluate the antifungal effects of berberine hydrochloride, palmatine hydrochloride, and a mixture of both substances against Microsporum canis in vivo and in vitro. METHODS: The minimal inhibitory concentrations (MICs) of monomers and clotrimazole were determined using 1.5 % tryptic soy agar. The effects of these drugs on Microsporum canis growth was detected by determining dry weight. Transmission electron microscopy (TEM) was performed to observe the effect of chemicals on cell ultrastructure. Differential mRNA expressions of eight genes of M. canis treated with berberine or palmatine or their combination at different time points were determined by real-time PCR. NADH enzyme concentration was also detected. Clinical evaluation via in-vivo antifungal assay was also performed. Skin histology PAS staining was also carried out. RESULTS: Results showed that MICs of berberine, palmatine and clotrimazole were 1, 1, and 0.015 mg/mL, respectively. No significant difference was observed among the growth curves of the three groups before 18 h was reached. TEM showed that these drugs could destroy the cell membrane and organelles of M. canis at different time points. After 30 h of incubation, relative mRNA expressions of the genes in the combined group were significantly higher than those in the other groups including the clotrimazole group (P < 0.05); Palmatine initially induced the mRNA up-regulation of PGAL4, FSH1, PQ-LRP, NADH1 and NDR in M. canis; by contrast, berberine maintained a high expression level of these genes to shorten fungal life cycle and eradicate M. canis. Clinical results showed that combined treatment was more effective than single administration of each monomer or clotrimazole. Hence, berberine mixed with palmatine significantly elicited antifungal activities and could be used to treat M. canis in rabbits. CONCLUSION: These results provide a comprehensive view of the mechanism of berberine and palmatine in anti-M. canis activity. PMID- 26054938 TI - Low-frequency stimulation of the pedunculopontine nucleus affects gait and the neurotransmitter level in the ventrolateral thalamic nucleus in 6-OHDA Parkinsonian rats. AB - The pedunculopontine nucleus (PPN) is connected to spinal, cerebellar and cerebral motor control structures and can be activated with external electrodes. Intrinsic cholinergic neuronal degeneration in the PPN is associated with postural instabilities and gait disturbances (PIGD) in advanced Parkinson's disease (PD). Clinical studies have demonstrated that PPN stimulation may improve PIGD. We investigated this claim and the underlying mechanisms using the 6 hydroxydopamine (6-OHDA) hemilesion model of PD. In this study, gait-related parameters, including the base of support (BOS), stride length, and maximum contact area, were analyzed via CatWalk gait analysis following PPN-low frequency stimulation (LFS) of rats with unilateral 6-OHDA lesions. Additionally, neurotransmitter concentrations in the ventrolateral thalamic nucleus (VL) were measured by microdialysis and liquid chromatography-mass spectrometry (LC-MS). Our data revealed that unilateral 6-OHDA lesions of the medial forebrain bundle (MFB) induced significant gait deficits. PPN-LFS significantly improved the BOS (hindlimb) and maximum contact area (impaired forelimb) scores, whereas no other gait parameters were significantly affected. Unilateral 6-OHDA MFB lesions significantly decreased acetylcholine (ACh) and moderately decreased noradrenaline (NA) concentrations in the VL. PPN-LFS mildly reversed the ACh loss in the VL in the lesioned rats but did not alter the NA levels. Taken together, our data indicate that PPN-LFS is useful for treating gait deficits of PD and that these effects are probably mediated by a rebalancing of ACh levels in the PPN-VL pathway. Thus, our findings provide possible insight into the mechanisms underlying PIGD in PD. PMID- 26054939 TI - GABAergic regulation of spontaneous spike patterns in the developing rabbit retina. AB - Spontaneous retinal waves play a critical role in the establishment of precise neuronal connections in the developing visual system. Retinal waves in mammals progress through three distinct developmental stages prior to eye opening. Using multielectrode array (MEA) recording from the rabbit retina, this study found characteristic changes in the spontaneous spike pattern in the ganglion cell layer during the transition from stage II to stage III retinal waves. These changes led to an increased diversity in the spatiotemporal pattern of the spontaneous activity, consistent with a potential role of stage III retinal waves in the establishment of diverse, cell type-specific neuronal connectivity during visual system development. The study also showed that GABAergic inhibition, predominantly mediated by GABAA receptors, was critical in breaking down large waves of ganglion cell spiking into spatially restricted and temporally diverse spike patterns at stage III, suggesting an important role of amacrine cells in shaping the diverse spontaneous activity patterns of developing ganglion cells. PMID- 26054940 TI - Impact of meteorological and environmental factors on the spatial distribution of Fasciola hepatica in beef cattle herds in Sweden. AB - BACKGROUND: Fasciola hepatica is a parasite with a significant impact on ruminant livestock production. Previous studies in north-west Europe have described its geographical distribution and determined potential predictors of fasciolosis using geographical information system (GIS) and regression modelling. In Sweden, however, information about the distribution of fasciolosis is limited. This study examined the geographical distribution of F. hepatica and identified high-risk areas for beef cattle in Sweden and sought to characterise potential predictors. Beef cattle serum samples were collected during winter 2006-2007 from 2135 herds which were examined for F. hepatica antibodies by enzyme-linked immunosorbent assay (ELISA). Fasciolosis distribution maps were created using GIS based on postcode location of seropositive herds. Spatial scan analysis (SaTScan) was performed to determine high-risk areas. Using datasets on animal density, temperature, precipitation and Corine land cover data, including soil type and soil mineral concentrations in Sweden, bivariate and multiple logistic regression analyses were carried out in R software to reveal potential predictors of F. hepatica infection. RESULTS: Overall herd seroprevalence of F. hepatica in beef cattle was 9.8 % (95 % CI: 8.6-11.1). An irregular spatial distribution of F. hepatica, with two main clusters, was observed in south-west Sweden. The most northerly occurrence of F. hepatica in the world was documented. The final model explained 15.8 % of the variation in F. hepatica distribution in study herds. Absence of coniferous forest was the variable with the highest predictive value. Precipitation in July-September, Dystric Cambisol, Dystric Regosol, and P and Cu concentrations in soil were other negative predictors. Beef cattle herd density, Dystric Leptosol and Fe concentration were positive predictors. CONCLUSIONS: The spatial distribution of F. hepatica in Swedish beef cattle herds is influenced by multi-factorial effects. Interestingly, absence of coniferous forest, herd density, specific soil type and concentration of some soil minerals are more important predictors than climate factors. PMID- 26054941 TI - Dietary polyphenols against metabolic disorders: How far have we progressed in the understanding of the molecular mechanisms of action of these compounds? AB - The aim of this review was to critically assess the evidence supporting the metabolic and anti-inflammatory effects attributed to polyphenols and the potential mechanisms of action underlying these effects. The metabolic and anti inflammatory properties of polyphenols and polyphenol-rich products have been shown mostly in rodents. These compounds appear to share multiple mechanisms of action at different body sites (gastrointestinal tract, microbiota, host organs) and the responsible molecules may be the original plant compounds, the microbial metabolites and (or) the host derived conjugates. Polyphenols may modify digestion and absorption of nutrients, microbiota composition and metabolism, and host tissue metabolic pathways but none of these mechanisms have been fully demonstrated in vivo and thus, more and better designed studies are needed. Furthermore, human clinical trials show inconsistent evidence of the metabolic and inflammation regulatory properties of polyphenols. Some of the principal limitations of these studies as well as recommendations to further progress in the understanding of the metabolic effects and mechanisms of action of polyphenols are discussed. PMID- 26054942 TI - Nonmedical Prescription Opioid Use in Childhood and Early Adolescence Predicts Transitions to Heroin Use in Young Adulthood: A National Study. AB - OBJECTIVES: To examine the relationship between nonmedical use of prescription opioids and heroin initiation from childhood to young adulthood, and to test whether certain ages, racial/ethnic, and income groups were at higher risk for this transition. STUDY DESIGN: Among a nationally representative sample of US adolescents assessed in the 2004-2011 National Surveys on Drug Use and Health cross-sectional surveys (n = 223,534 respondents aged 12-21 years), discrete-time hazard models were used to estimate the age-specific hazards of heroin initiation associated with prior history of nonmedical use of prescription opioids. Interactions were estimated between prior history of nonmedical use of prescription opioids and age of nonmedical use of prescription opioid initiation, race/ethnicity, and income. RESULTS: A prior history of nonmedical use of prescription opioids was strongly associated with heroin initiation (hazard ratio 13.12, 95% CI 10.73, 16.04). Those initiating nonmedical use of prescription opioids at ages 10-12 years had the highest risk of transitioning to heroin use; the association did not vary by race/ethnicity or income group. CONCLUSIONS: Prior use of nonmedical use of prescription opioids is a strong predictor of heroin use onset in adolescence and young adulthood, regardless of the user's race/ethnicity or income group. Primary prevention of nonmedical use of prescription opioids in late childhood may prevent the onset of more severe types of drug use such as heroin at later ages. Moreover, because the peak period of heroin initiation occurs at ages 17-18 years, secondary efforts to prevent heroin use may be most effective if they focus on young adolescents who already initiated nonmedical use of prescription opioids. PMID- 26054944 TI - Estimation of life expectancy and the expected years of life lost among heroin users in the era of opioid substitution treatment (OST) in Taiwan. AB - BACKGROUND: Opioid substitution treatment (OST) has been implemented in Taiwan since 2006. We estimated the life expectancy (LE) and expected years of life lost (EYLL) in a cohort of heroin users stratified by OST for comparison. METHODS: A total of 1283 heroin users recruited from 2006 to 2008 were linked to the National Mortality Registry until the end of 2011. Among them, 983 received OST, while 300 did not. Kaplan-Meier estimation for survival was performed, and it was extrapolated to 50 years to obtain the LE using a semi-parametric method. We further estimated the EYLL for both cohorts by subtracting their life expectancies from the age- and sex-matched referents of the general population. Cause-specific standardized mortality ratios (SMRs) were calculated and compared with the national cohort to validate the representativeness of this sample. RESULTS: After extrapolation to 50 years of survival, the estimated average LE and EYLL were 27.4 and 10.6 for OST subjects, respectively, while those of the non-OST were 20.2 and 18.4 years. The all-cause mortality rates (per 1000 person years) in the observational period for the OST and non-OST group were 15.5 and 23.9, respectively, representing a 7.5- and 10.2-fold SMR compared to the general population, indicating a high representativeness for our sample. But SMR of suicide mortality elevated 16.2 and 3.1 folds in OST and non-OST group, respectively. CONCLUSIONS: OST saves 7.8 EYLL more than non-OST after accounting for lead time bias. Effective suicide prevention programs could enhance its life saving effect, especially among those co-morbid with depressive disorders. PMID- 26054943 TI - Corticospinal Tract Injury Precedes Thalamic Volume Reduction in Preterm Infants with Cystic Periventricular Leukomalacia. AB - OBJECTIVES: To measure both fractional anisotropy (FA) values in the corticospinal tracts (CSTs) and volume of the thalami in preterm infants with cystic periventricular leukomalacia (c-PVL) and to compare these measurements with control infants. STUDY DESIGN: Preterm infants with c-PVL and controls with magnetic resonance imaging data acquired between birth and term equivalent age (TEA) were retrospectively identified in 2 centers. Tractography of the CST and segmentation of the thalamus were performed, and values from infants with c-PVL and controls were compared. RESULTS: Thirty-three subjects with c-PVL and 31 preterm controls were identified. All had at least 1 scan up to TEA, and multiple scans were performed in 31 infants. A significant difference in FA values of the CST was found between cases and controls on the scans both before and at TEA. Absolute thalamic volumes were significantly reduced at TEA but not on the earlier scans. Data acquired in infancy showed lower FA values in infants with c PVL. CONCLUSIONS: Damage to the CST can be identified on the early scan and persists, whereas the changes in thalamic volume develop in the weeks between the early and term equivalent magnetic resonance imaging. This may reflect the difference between acute and remote effects of the extensive injury to the white matter caused by c-PVL. PMID- 26054945 TI - Waterpipe tobacco smoking: The critical need for cessation treatment. AB - BACKGROUND: Waterpipe use has spread globally, and has substantial negative health effects and nicotine dependence potential. A growing literature addresses cessation-related experiences of waterpipe users, but this literature has not been summarized nor is guidance available on developing and testing cessation interventions. METHOD: Authors gathered key empirical papers on waterpipe cessation-related topics, including observational studies about users' perceived ability to quit, interest in quitting, quit rates, and cessation trials. Based on this review, recommendations are made to guide the development and rigorous evaluation of waterpipe cessation interventions. RESULTS: Many users want to quit and make quit attempts, but are unsuccessful at doing so on their own; therefore, developing and testing waterpipe cessation interventions should be a priority for global tobacco control efforts. Early efforts have tested waterpipe cessation interventions designed for, or adapted from, cigarette smoking programs. CONCLUSIONS: Waterpipe-specific cessation programs that address unique features of waterpipe smoking (e.g., its cultural significance, social uses, and intermittent use pattern) and characteristics and motivations of users who want to quit are needed. Recommendations are provided to move waterpipe cessation intervention development forward. PMID- 26054946 TI - Resettlement experiences and resilience in refugee youth in Perth, Western Australia. AB - BACKGROUND: In Australia, the two major pathways of refugee entry are the United Nations High Commissioner for Refugees resettlement programme and irregular maritime arrivals (IMAs) seeking asylum. The Australian Government's policies towards IMAs since July 2013 are controversial, uncompromising and consistently harsh, with asylum seekers held in detention centres for prolonged periods. Refugees and asylum seekers have distinct and unique stressors that make resettlement difficult. METHODS: This exploratory study examines resettlement experiences for refugee youth in Western Australia using the psychosocial conceptual framework and qualitative methods. Focus group discussions and key informant interviews were undertaken with verbatim transcripts analysed using thematic analysis to identify themes. RESULTS: Themes documented that language and its impact, and experience with education, health, and social activities, support structures provided to youth and supporting future aspirations as critical to successful resettlement. This exploratory study contributes to developing a broader understanding of the resettlement experiences of refugee youth, drawing on their current and past experiences, cultural differences and mechanisms for coping. CONCLUSION: Fluency in English language, especially spoken, was a facilitator of successful resettlement. Our results align with previous studies documenting that support programs are vital for successful resettlement. Although faced with immense difficulties refugee youth are resilient, want to succeed and have aspirations for the future. Strategies and recommendations suggested by refugee youth themselves could be used for developing interventions to assist successful resettlement. PMID- 26054947 TI - Development of Listening Comprehension Tests with Narrative and Expository Texts for Portuguese Students. AB - This investigation aimed to develop and collect psychometric data for two tests assessing listening comprehension of Portuguese students in primary school: the Test of Listening Comprehension of Narrative Texts (TLC-n) and the Test of Listening Comprehension of Expository Texts (TLC-e). Two studies were conducted. The purpose of study 1 was to construct four test forms for each of the two tests to assess first, second, third and fourth grade students of the primary school. The TLC-n was administered to 1042 students, and the TLC-e was administered to 848 students. The purpose of study 2 was to test the psychometric properties of new items for the TLC-n form for fourth graders, given that the results in study 1 indicated a severe lack of difficult items. The participants were 260 fourth graders. The data were analysed using the Rasch model. Thirty items were selected for each test form. The results provided support for the model assumptions: Unidimensionality and local independence of the items. The reliability coefficients were higher than .70 for all test forms. The TLC-n and the TLC-e present good psychometric properties and represent an important contribution to the learning disabilities assessment field. PMID- 26054948 TI - Imidazole-containing phthalazine derivatives inhibit Fe-SOD performance in Leishmania species and are active in vitro against visceral and mucosal leishmaniasis--CORRIGENDUM. PMID- 26054949 TI - Erratum to: Endogenous CCL2 neutralization restricts HIV-1 replication in primary human macrophages by inhibiting viral DNA accumulation. PMID- 26054950 TI - Introduction to the Supplement. PMID- 26054951 TI - Cross-Validation of FITNESSGRAM(r) Health-Related Fitness Standards in Hungarian Youth. AB - PURPOSE: The purpose of this study was to cross-validate FITNESSGRAM(r) aerobic and body composition standards in a representative sample of Hungarian youth. METHOD: A nationally representative sample (N = 405) of Hungarian adolescents from the Hungarian National Youth Fitness Study (ages 12-18.9 years) participated in an aerobic capacity assessment via treadmill test to maximum to determine peak oxygen consumption (VO2peak) and a bioelectrical impedance assessment to estimate percent body fat (%BF). Additionally, metabolic syndrome status was assessed via finger-stick blood sample. Youth were categorized into Healthy Fitness Zone (HFZ) and Needs Improvement (NI) groups based on Fitnessgram standards. Prevalence of metabolic syndrome was calculated and logistic regression was used to estimate odds of metabolic syndrome. RESULTS: Hungarian youth were generally fit with a low prevalence of metabolic syndrome. Approximately 69% to 77% of boys and 55% to 57% of girls were classified into the HFZ based on %BF and VO2peak. Youth in the NI health risk zones for VO2peak and %BF were 4 times to 5 and 2 times to 3 times more likely to have metabolic syndrome than children in the lower-risk groups, respectively. CONCLUSIONS: Fitnessgram standards for aerobic capacity and body composition were associated with metabolic syndrome status, though odds ratios were larger for VO2peak than for %BF and varied by sex. Even though these standards were developed in U.S. youth, they can be applied in Hungary and still provide a criterion-referenced indication of fitness. PMID- 26054952 TI - Agreement and Diagnostic Performance of FITNESSGRAM(r), International Obesity Task Force, and Hungarian National BMI Standards. AB - PURPOSE: This study examined agreement between all 3 standards (as well as relative diagnostic associations with metabolic syndrome) using a representative sample of youth from the Hungarian National Youth Fitness Study. METHOD: Body mass index (BMI) was assessed in a field sample of 2,352 adolescents (ages 10 18.5 years) and metabolic syndrome status was assessed in a laboratory subsample of 373 youth. All youth were categorized into weight status groups based on the FITNESSGRAM(r), International Obesity Task Force (IOTF), and Hungarian growth standards. Classification agreement was compared between all pairs of standards via cross-tabulation. Logistic regression was used to estimate the odds of metabolic syndrome by weight status. RESULTS: The 3 BMI standards agreed on >= 88% of cases, with better agreement on girls' standards than boys' standards. Kappa values ranged from .65 to .89. Using the Hungarian standards over the Fitnessgram or IOTF standards resulted in 5% to 10% more youth being classified as normal weight. The overweight/obesity groups were 4 times to 6 times more likely to have metabolic syndrome than those classified as normal weight regardless of the classification standards. These odds ratios increased to 8 times to 17 times when comparing the normal-weight/overweight groups to the obesity category. Odds ratios for boys tended to be slightly larger than those for girls. CONCLUSIONS: All 3 standards provide similar information about weight status and metabolic syndrome classification. To more easily facilitate international comparisons, it may be of greater benefit to use the IOTF standards, which also had better agreement with the U.S. Fitnessgram thresholds. PMID- 26054953 TI - Establishing Normative Reference Values for Handgrip Among Hungarian Youth. AB - PURPOSE: The purpose of this study was to examine age- and sex-related variation in handgrip strength and to determine reference values for the Hungarian population. METHOD: A sample of 1,086 Hungary youth (aged 11-18 years old; 654 boys and 432 girls) completed a handgrip strength assessment using a handheld dynamometer. Quantile regression was used to compute separate models for boys and girls and included a linear, cubic, and quadratic term for age to account for nonlinear patterns. These terms were tested for statistical significance using the Wald statistical test with p < .05. Age- and sex-specific centiles were generated and the 50th percentile was used to describe the overall patterns in handgrip strength. RESULTS: The linear, cubic, and quadratic terms for age fitted the data well for boys (p < .05), while both linear and quadratic terms for age were statistically significant for girls (p < .05). The 50th percentile values resulted in 21.4 kg, 21.7 kg, 25.0 kg, 30.0 kg, 35.4 kg, 40.0 kg, 42.6 kg, and 42.0 kg for boys aged 11 to 18 years old, respectively. The same percentile resulted in 20.0 kg, 19.5 kg, 19.6 kg, 20.3 kg, 21.6 kg, 23.5 kg, 26.1 kg, and 29.2 kg for girls aged 11 to 18 years old, respectively. CONCLUSIONS: Muscle strength as determined by handgrip has distinct age-related patterns in boys and girls. We have accounted for biological age differences and developed norm referenced values that can be used to interpret handgrip assessment scores obtained from school-aged children in Hungary. PMID- 26054954 TI - Overview of the Hungarian National Youth Fitness Study. AB - The 2012 Public Act on Education in Hungary made daily physical education (PE) a mandatory part of the school day starting in the 2012-2013 school year. This directive was linked to a significant reorganization of the Hungarian education system including a new National Core Curriculum that regulates the objectives and contents of PE. The Hungarian School Sport Federation (HSSF) recognized the opportunity and created the Strategic Actions for Health-Enhancing Physical Education or Testneveles az Egeszsegfejlesztesben Strategiai Intezkedesek (TESI) project. Physical fitness assessments have been a traditional part of the Hungarian PE program; however, the TESI plan called for the use of a new health related battery and assessment system to usher in a new era of fitness education in the country. The HSSF enlisted the Cooper Institute to assist in building an infrastructure for full deployment of a national student fitness assessment program based on the FITNESSGRAM(r) in Hungarian schools. The result is a new software-supported test battery, namely the Hungarian National Student Fitness Test (NETFIT), which uses health-related, criterion-referenced youth fitness standards. The NETFIT system now serves as a compulsory fitness assessment for all Hungarian schools. This article details the development process for the test battery and summarizes the aims and methods of the Hungarian National Youth Fitness Study. PMID- 26054955 TI - Establishing Normative Reference Values for Standing Broad Jump Among Hungarian Youth. AB - PURPOSE: The purpose of this study was to examine age and sex trends in anaerobic power assessed by a standing broad jump and to determine norm-referenced values for youth in Hungary. METHOD: A sample of 2,427 Hungarian youth (1,360 boys and 1,067 girls) completed the standing broad jump twice, and the highest distance score was recorded. Quantile regression was used to fit standing broad jump trends across linear and quadratic functions of age. Statistical significance was determined with bootstrap confidence intervals and the Wald test with p < .05. Age-by-sex specific centiles were generated and the 50th percentile was used to describe the overall patterns. RESULTS: Standing broad jump scores increased steadily in boys from age 11 through 18 years with a discrete plateau at the end of adolescence. Girls' standing broad jump scores of those who performed above the median increased with age and plateaued later in the adolescence. Both linear and quadratic age terms were statistically significant predictors of standing broad jump trends across age (p < .05), but the relations varied depending on the percentile. The 50th percentile values resulted in 147.0 cm, 162.0 cm, 175.0 cm, 186.0 cm, 195.0 cm, 202.0 cm, 207.0 cm, and 210.0 cm for boys aged 11 to 18 years old, respectively, and 140.0 cm, 143.9 cm, 147.3 cm, 150.0 cm, 152.1 cm, 153.7 cm, 154.6 cm, and 155.0 cm for girls aged 11 to 18 years old, respectively. CONCLUSIONS: This study provides normative reference charts that take into account age and sex differences in standing broad jump performance. The proposed reference values can be used to interpret standing broad jump scores in Hungarian youth. PMID- 26054956 TI - Health-Related Physical Fitness in Hungarian Youth: Age, Sex, and Regional Profiles. AB - PURPOSE: The purpose of this study was to examine region, age, and sex profiles of physical fitness in Hungarian youth. METHOD: A sample of 2,602 Hungarian youth aged 10 to 18 years old completed a series of physical fitness field tests: the Progressive Aerobic Cardiorespiratory Endurance Run (PACER) fitness test, body mass index (BMI), percent body fat (%BF), waist circumference (WC), curl-ups (CU), pushups (PU), trunk extension (TE), back-saver sit-and-reach (SR), handgrip (HG), and standing broad jump. Physical fitness scores were classified using FITNESSGRAM(r) standards, and trends for region, age, and sex were examined using logistic regression. The outcome variable represented the likelihood that a child would meet the recommended levels of fitness for health. RESULTS: Achievement rates varied considerably by region, age, and sex. The likelihood of achieving the Healthy Fitness Zone (HFZ) varied among Hungarian regions and on all the assessments (p < .05) with exception of the CU, PU, and HG tests (p > .05). The likelihood of achieving the HFZ was linearly related with age based on PACER, BMI, WC, %BF, CU, and SR scores (p < .05). There were statistically significant gender differences and boys were more likely to achieve the HFZ based on PACER, WC, CU, PU, TE, and SR scores (p < .05). CONCLUSIONS: The likelihood of achieving the recommended levels of fitness for youth varies between regions in Hungary, in most cases decreases with age, and tends to be higher in boys. This study is one of the few that provides evidence of regional, age, and sex patterns of health-related fitness using a representative sample of youth. PMID- 26054957 TI - Agreement Between Omron 306 and Biospace InBody 720 Bioelectrical Impedance Analyzers (BIA) in Children and Adolescents. AB - PURPOSE: The purpose of this study was to test the convergent validity of Omron 306 using Biospace InBody 720. METHOD: A total of 267 participants (145 boys; aged 10.4-17.9 years) completed testing during a single session. Each measure provided percent body fat (%BF), while the InBody 720 included fat-free mass (FFM). The validity was examined using the Pearson correlation. Limits of agreement (LOA) and multiple linear regression were also used to determine the impact of both age and FFM on the associations between the 2 measures. RESULTS: The 2 measures of %BF were correlated by .63 (p < .001) in boys and .89 (p < .001) in girls. The mean difference (i.e., InBody - Omron) for %BF in boys was - 4.7% with a lower LOA of - 20.5% and upper LOA of 11.2%. The same comparison for girls resulted in a difference of 3.0% with a lower LOA of - 10% and upper LOA of 4%. Examination of the residuals obtained from multiple linear regression indicated that FFM was the only statistically significant predictor of differences in boys (betaFFM = - 0.25 +/- 0.08%, p = .001). There were no significant associations for girls. CONCLUSIONS: Findings indicate that estimates of %BF obtained from Omron in boys exceed estimates from InBody 720. Disagreement was evident in younger boys with lower levels of FFM. Girls' %BF was closer between the 2 bioelectrical impedance analyzer measures (less residual) with age and FFM not explaining the disagreement. Overall, the 2 measures were not equivalent. PMID- 26054958 TI - Cross-Validation of a PACER Prediction Equation for Assessing Aerobic Capacity in Hungarian Youth. AB - PURPOSE: The purpose of this article was to evaluate the validity of the Progressive Aerobic Cardiovascular and Endurance Run (PACER) test in a sample of Hungarian youth. METHOD: Approximately 500 participants (aged 10-18 years old) were randomly selected across Hungary to complete both laboratory (maximal treadmill protocol) and field assessments (PACER) of aerobic capacity. Agreement between lab- and PACER-derived peak oxygen consumption (VO2) was examined using linear regression and 2-sided equivalence testing techniques, respectively. The impact of agreement on the classification accuracy of peak VO2 estimates into FITNESSGRAM(r) fitness zones was determined with kappa statistics. RESULTS: The final sample resulted in a total of 167 boys and 143 girls (N = 310). Analyses revealed that lab and PACER VO2 shared 13% to 18% of their variance (R(2)boys = .13, R(2)girls = .18) and that limits of agreement ranged from - 39.9 mL/kg/min to +37.6 mL/kg/min depending on the sex. The absolute error values were 14% for boys and 16% for girls; however, the average peak VO2 estimates from the PACER were within the 10% equivalence region for girls (37.2 mL/kg/min to 45.4 mL/kg/min), but not for boys (45.2 mL/kg/min to 55.2 mL/kg/min). When lab and PACER VO2 were categorized according to Fitnessgram zones, agreement was fair for both sexes (boys, Kappa = .25, and girls, Kappa = .31). CONCLUSIONS: Although the correlations between measured and predicted peak VO2 were lower than expected, the magnitude of error observed in the PACER is similar to past ranges of error observed in other studies (10%-15%), but the large individual error should be considered when interpreting individual results from this field-based measure of aerobic capacity. There was reasonable classification agreement between lab estimates and the PACER test for classification into the various fitness standards. PMID- 26054959 TI - Associations Between Attitudes Toward Physical Education and Aerobic Capacity in Hungarian High School Students. AB - PURPOSE: The purpose of this study was to create a physical education (PE) attitude scale and examine how it is associated with aerobic capacity (AC). METHOD: Participants (n = 961, aged 15-20 years) were randomly selected from 26 Hungarian high schools. AC was estimated from performance on the Progressive Aerobic Cardiovascular and Endurance Run test, and the attitude scale had 31 items measured on a Likert scale that ranged from 1 to 5. Principal component analysis was used to examine the structure of the questionnaire while several 2 way analyses of variance and multiple linear regression (MLR) were computed to examine trends in AC and test the association between component scores obtained from the attitude scale and AC, respectively. RESULTS: Five components were identified: health orientation in PE (C1), avoid failure in PE (C2), success orientation in PE (C3), attitude toward physical activity (C4), and cooperation and social experience in PE (C5). There was a statistically significant main effect for sex on C3 (p < .05), C4 (p < .001), and C5 (p < .05) indicating that boys' scores were higher than girls. The Sex * Age interaction was also statistically significant (p < .05) and follow-up comparisons revealed sex differences in C5 for 15-year-old participants. Girls showed statistically significant higher values than boys in C5 at the age of 16 years. MLR results revealed that component scores were significantly associated with AC (p < .05). Statistically significant predictors included C1, C2, C3, and C4 for boys and C2 and C4 for girls. CONCLUSION: The 5-component scale seems to be suitable for measuring students' attitudes toward PE. The design of the study does not allow for direct associations between attitudes and AC but suggests that these 2 might be related. PMID- 26054960 TI - Misconceptions and Misattributions About Traumatic Brain Injury: An Integrated Conceptual Framework. AB - The objective of the present narrative review was to provide a conceptual framework to address common misconceptions in the field of traumatic brain injury (TBI) and enhance clinical and research practices. This framework is based on review of the literature on TBI knowledge and beliefs. The comprehensive search of the literature included seminal and current texts as well as relevant articles on TBI knowledge and education, misconceptions, and misattributions. Reviewed materials ranged from 1970 to 2013 and were obtained from PubMed and PubMed Central online research databases. Research findings from the reviewed literature were integrated with existing social and cognitive psychological concepts to develop a framework that includes: (1) the identification antecedents of TBI related misconceptions and misattribution; (2) understanding of how inaccurate beliefs form and persist as the result of pre- and postinjury cognitive operations such as informational cascades and attribution biases; and (3) a discussion of ways in which these beliefs can result in consequences in all domains of a survivor's life, including physical and mental health, stigma, and discrimination. This framework is intended to serve as a first stage of development of a model that will improve treatment endeavors and service delivery to individuals with TBI and their families. PMID- 26054962 TI - Battery related cobalt and REE flows in WEEE treatment. AB - In batteries associated with waste electrical and electronic equipment (WEEE), battery systems can be found with a higher content of valuable and critical raw materials like cobalt and rare earth elements (REE) relative to the general mix of portable batteries. Based on a material flow model, this study estimates the flows of REE and cobalt associated to WEEE and the fate of these metals in the end-of-life systems. In 2011, approximately 40 Mg REE and 325 Mg cobalt were disposed of with WEEE-batteries. The end-of-life recycling rate for cobalt was 14%, for REE 0%. The volume of waste batteries can be expected to grow, but variation in the battery composition makes it difficult to forecast the future secondary raw material potential. Nevertheless, product specific treatment strategies ought to be implemented throughout the stages of the value chain. PMID- 26054961 TI - Angptl4 is upregulated under inflammatory conditions in the bone marrow of mice, expands myeloid progenitors, and accelerates reconstitution of platelets after myelosuppressive therapy. AB - BACKGROUND: Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines which are produced locally and at multiple sites throughout the body. METHODS: Using microarray studies, we found that Angptl4 is upregulated in the BM during systemic inflammation. RESULTS: Recombinant murine Angptl4 (rmAngptl4) stimulated the proliferation of myeloid colony-forming units (CFUs) in vitro. Upon repeated in vivo injections, rmAngptl4 increased BM progenitor cell frequency and this was paralleled by a relative increase in phenotypically defined granulocyte-macrophage progenitors (GMPs). Furthermore, in vivo treatment with rmAngptl4 resulted in elevated platelet counts in steady-state mice while allowing a significant acceleration of reconstitution of platelets after myelosuppressive therapy. The administration of rmAngptl4 increased the number of CD61(+)CD41(low)-expressing megakaryocytes (MK) in the BM of steady-state and in the spleen of transplanted mice. Furthermore, rmAngptl4 improved the in vitro differentiation of immature MKs from hematopoietic stem and progenitor cells. Mechanistically, using a signal transducer and activator of transcription 3 (STAT3) reporter knockin model, we show that rmAngptl4 induces de novo STAT3 expression in immature MK which could be important for the effective expansion of MKs after myelosuppressive therapy. CONCLUSION: Whereas the definitive role of Angptl4 in mediating the effects of lipopolysaccharide (LPS) on the BM has to be demonstrated by further studies involving multiple cytokine knockouts, our data suggest that Angptl4 plays a critical role during hematopoietic, especially megakaryopoietic, reconstitution following stem cell transplantation. PMID- 26054963 TI - Alkali activation of recovered fuel-biofuel fly ash from fluidised-bed combustion: Stabilisation/solidification of heavy metals. AB - Recovered fuel-biofuel fly ash from a fluidized bed boiler was alkali-activated and granulated with a sodium-silicate solution in order to immobilise the heavy metals it contains. The effect of blast-furnace slag and metakaolin as co-binders were studied. Leaching standard EN 12457-3 was applied to evaluate the immobilisation potential. The results showed that Ba, Pb and Zn were effectively immobilised. However, there was increased leaching after alkali activation for As, Cu, Mo, Sb and V. The co-binders had minimal or even negative effect on the immobilisation. One exception was found for Cr, in which the slag decreased leaching, and one was found for Cu, in which the slag increased leaching. A sequential leaching procedure was utilized to gain a deeper understanding of the immobilisation mechanism. By using a sequential leaching procedure it is possible fractionate elements into watersoluble, acid-soluble, easily-reduced and oxidisable fractions, yielding a total 'bioavailable' amount that is potentially hazardous for the environment. It was found that the total bioavailable amount was lower following alkali activation for all heavy metals, although the water soluble fraction was higher for some metals. Evidence from leaching tests suggests the immobilisation mechanism was chemical retention, or trapping inside the alkali activation reaction products, rather than physical retention, adsorption or precipitation as hydroxides. PMID- 26054964 TI - Comparing mesophilic and thermophilic anaerobic digestion of chicken manure: Microbial community dynamics and process resilience. AB - While methane fermentation is considered as the most successful bioenergy treatment for chicken manure, the relationship between operational performance and the dynamic transition of archaeal and bacterial communities remains poorly understood. Two continuous stirred-tank reactors were investigated under thermophilic and mesophilic conditions feeding with 10%TS. The tolerance of thermophilic reactor on total ammonia nitrogen (TAN) was found to be 8000mg/L with free ammonia (FA) 2000mg/L compared to 16,000mg/L (FA1500mg/L) of mesophilic reactor. Biomethane production was 0.29 L/gVSin in the steady stage and decreased following TAN increase. After serious inhibition, the mesophilic reactor was recovered successfully by dilution and washing stratagem compared to the unrecoverable of thermophilic reactor. The relationship between the microbial community structure, the bioreactor performance and inhibitors such as TAN, FA, and volatile fatty acid was evaluated by canonical correspondence analysis. The performance of methanogenic activity and substrate removal efficiency were changed significantly correlating with the community evenness and phylogenetic structure. The resilient archaeal community was found even after serious inhibition in both reactors. Obvious dynamics of bacterial communities were observed in acidogenic and hydrolytic functional bacteria following TAN variation in the different stages. PMID- 26054965 TI - Nomenclatural changes should not be based on equivocally supported phylogenies: Reply to Yang et al. 2015. AB - Phylogenies produced by Yang et al. 2015 provide reasonably well-supported hypotheses of relationships among 11 proposed tribes of cyprinine fishes and present an interesting hypothesis about the origin of a number of polyploid cyprinine lineages. However, support for relationships within some of the tribes is equivocal. Herein we address the treatment of African diploid and tetraploid cyprinine genera within tribe Smiliogastrini. More specifically, we reject the revalidation of Enteromius based on the evidence presented and discuss the ramifications of the proposed revalidation. PMID- 26054966 TI - Caregivers consequences of care among patients with eating disorders, depression or schizophrenia. AB - BACKGROUND: The consequences of caring for a person with a mental illness can impose a substantial burden. Few studies have compared this burden among caregivers of patients with eating disorders and other mental illnesses. The objective of this study was to compare caregiver consequences in eating disorders (ED) with caregiver consequences in depression and schizophrenia, assessed with the same instrument, the Involvement Evaluation Questionnaire (IEQ). Another aim was to identify factors that may predict these consequences. METHODS: We conducted a cross-sectional study involving 251 caregivers of ED patients; 252 caregivers of patients with depression; and 151 caregivers of patients with schizophrenia. Caregivers completed the Involvement Evaluation Questionnaire EU Version (IEQ-EU). Descriptive statistics, ANOVA, and Chi-square were applied to examine the inter-variable relationships. Consequences- indexes were also computed. RESULTS: In all samples, worrying was the most commonly reported consequence of caregiving. Predictive variables for a high level of caregiver burden included being a mother or partner of the person being cared for (p = <.01), and being a caregiver of a patient with ED. CONCLUSIONS: The burden of caregiving is higher among caregivers of patients with eating disorders patients than among caregivers of patients with depression or schizophrenia. Our findings suggest that caregivers of patients with an ED could benefit from providing adequate assessment and support. PMID- 26054967 TI - Cystic fibrosis lung disease and concomitant endometriosis: The final blow of interferon-gamma? PMID- 26054968 TI - Assessment of the Validity and Reproducibility of the Pap Smear in Mexico: Necessity of a Paradigm Shift. AB - BACKGROUND AND AIMS: An assessment was performed of the quality of Pap readings in 19 cytology laboratories (CLs) in Mexico from the Cervical Cancer Screening Program. METHODS: Nine CLs were affiliated with the Health Ministry (SSA), and ten were affiliated with the Mexican Social Security Institute (IMSS). Two sets of 200 cervical cytology specimens were prepared, one set for each institution. Fourteen percent of the specimens were positive and six were inappropriate for diagnosis (3%). All cervical cytology specimens were processed in the cytopathology laboratory at the General Hospital of Mexico, and histopathology was available for each positive case. RESULTS: Thirty percent of the SSA reading centers had a sensitivity of at least 80%; however, not one of the ten IMSS laboratories evaluated reached this figure. Some reading centers had a sensitivity <65%, meaning that nearly half of the specimens with a cytology consistent with cervical neoplasm were not identified. DISCUSSION: Given these results, it is a priority to effect a paradigm shift combining various screening tests to improve adherence to standards and enhanced cost-effectiveness of the early detection of cervicouterine cancer (CC) in Mexico. PMID- 26054969 TI - Accuracy of the surface electromyography RMS processing for the diagnosis of myogenous temporomandibular disorder. AB - Due to the multifactor etiology of temporomandibular disorder (TMD), the precise diagnosis remains a matter of debate and validated diagnostic tools are needed. The aim was to determine the accuracy of surface electromyography (sEMG) activity, assessed in the amplitude domain by the root mean square (RMS), in the diagnosis of TMD. One hundred twenty-three volunteers were evaluated using the Research Diagnostic Criteria for Temporomandibular Disorders and distributed into two groups: women with myogenous TMD (n=80) and women without TMD (n=43). The volunteers were then submitted to sEMG evaluation of the anterior temporalis, masseter and suprahyoid muscles at rest and during maximum voluntary teeth clenching (MVC) on parafilm. The accuracy, sensitivity and specificity of the muscle activity were analyzed. Differences between groups were found in all muscles analyzed at rest as well as in the masseter and suprahyoid muscles during MVC on parafilm. Moderate accuracy (AUC: 0.74-0.84) of the RMS sEMG was found in all muscles regarding the diagnosis of TMD at rest and in the suprahyoid muscles during MVC on parafilm. Moreover, sensitivity ranging from 71.3% to 80% and specificity from 60.5% to 76.6%. In contrast, RMS sEMG did not exhibit acceptable degrees of accuracy in the other masticatory muscles during MVC on parafilm. It was concluded that the RMS sEMG is a complementary tool for clinical diagnosis of the myogenous TMD. PMID- 26054970 TI - Lost without trace: oximetry signal dropout in preterm infants. AB - Oxygen saturation (SpO2) signal dropout leaves caregivers without a reliable measure to guide oxygen therapy. We studied SpO2 dropout in preterm infants on continuous positive airway pressure, noting the SpO2 values at signal loss and recovery and thus the resultant change in SpO2, and the factors influencing this parameter. In 32 infants of median gestation 26 weeks, a total of 3932 SpO2 dropout episodes were identified (1.1 episodes/h). In the episodes overall, SpO2 decreased by 1.1%, with the SpO2 change influenced by starting SpO2 (negative correlation), but not dropout duration. For episodes starting in hypoxia (SpO2 <85%), SpO2 recovered at a median of 3.2% higher than at SpO2 dropout, with a downward trajectory in a quarter of cases. We conclude that after signal dropout SpO2 generally recovers in a relative normoxic range. Blind FiO2 adjustments are thus unlikely to be of benefit during most SpO2 dropout episodes. PMID- 26054971 TI - Oral glucose during targeted neonatal echocardiography: is it useful? PMID- 26054972 TI - Dietary habits of invasive Ponto-Caspian gobies in the Croatian part of the Danube River basin and their potential impact on benthic fish communities. AB - Invasive Ponto-Caspian (P-C(1)) gobies have recently caused dramatic changes in fish assemblage structures throughout the Danube basin. While their presence in the Croatian part of the basin has been noted and distribution studied, their dietary habits and impacts on native fish communities have, until now, been unknown. In 2011, 17 locations in the Sava River Basin were sampled for fish and 15 for benthic invertebrates. Fish population monitoring data, available for nine seasons (2003-2006 and 2010-2014) and 12 locations, were used to analyse the impacts of P-C gobies on benthic fish abundance. Gut content analysis indicates that the monkey goby Neogobius fluviatilis diet is very diverse, but dominated by Trichoptera, Chironomidae, Bivalvia and Odonata. The diet overlaps considerably with the round goby Neogobius melanostomus diet, although Gastropoda are dominant in the latter's diet. Small fish and Gammarus sp. dominate the bighead goby Ponticola kessleri diet. Comparison of gut content with the prey available in the environment indicates that monkey and round gobies exhibit preference for Trichoptera, Megaloptera and Coleoptera, and bighead goby for Trichoptera, Gammarus sp. and Pisces. P-C gobies in the Sava River are spreading upstream, towards the reaches with lower fish diversity. Analyses indicate potentially positive impacts of P-C gobies' presence on some fish populations: round and bighead goby on Balkan golden loach Sabanejewia balcanica and monkey goby on common carp Cyprinus carpio, crucian carp Carassius carassius, burbot Lota lota and Balkan loach Cobitis elongata. However, there are also indications that bighead and round goby could adversely impact the native chub Squalius cephalus and zingel Zingel zingel populations, respectively. As P-C gobies are still in the expansionary period of invasion and the ecosystem still adapting to new circumstances, continued monitoring of fish population dynamics in the Sava basin is needed to determine the outcome and impacts of this invasion. PMID- 26054973 TI - Estimation of intestinal protein digestibility of protein supplements for ruminants using a three-step enzymatic in vitro procedure. AB - This study included 33 samples with main focus on unprotected or rumen-protected rapeseed and soybean feedstuffs, which were analysed using an enzymatic in vitro procedure (EIVP) in order to determine intestinal crude protein (CP) digestibility (IPD) of ruminally undegraded CP. The EIVP involved the sequential digestion of samples with a protease from Streptomyces griseus, pepsin-HCl and pancreatin. Briefly, the EIVP started with determination of true protein. Feeds were incubated for 18 h in a buffer solution at a constant ratio (41 U/g) of S. griseus protease activity to feed true protein. The dried residues were incubated in pepsin-HCl solution for 1 h, and residues from this step were incubated in pancreatin solution for 24 h. Results appeared to have lower IPD dimensions than literature data of previous studies. In addition, a negative correlation became apparent between acid detergent fibre and IPD, as well as a positive correlation between CP, true protein and IPD. The EIVP in its current, strictly standardised form can be applied to develop a database that can be used for protein evaluation systems for establishing tabular values of IPD. Nevertheless, future studies may be hindered since sufficient reference values, i.e. in vivo data, are completely missing. PMID- 26054975 TI - TSPAN1 functions as an oncogene in gastric cancer and is downregulated by miR 573. AB - Tetraspanin 1 (TSPAN1) has been reported to be upregulated in gastric cancer (GC). However, whilst TSPAN1 is positively correlated with clinical stage and negatively correlated with survival rates, its function in GC remains elusive. Here we show that expression of TSPAN1 is significantly higher in GC tissues compared to non-cancerous tissues. Furthermore, we demonstrate that RNAi-mediated down-regulation of TSPAN1 expression markedly blocks GC cell proliferation, cell cycle progression and invasive activity. We identified TSPAN1 as a novel target gene of miR-573. Overexpression of miR-573 suppressed proliferation and invasion of GC cells by down-regulation of TSPAN1 expression. Restoration of TSPAN1 rescued the effects of miR-573 overexpression. Therefore, our findings suggest that the miR-573/TSPAN1 axis is important in the control of gastric carcinogenesis. PMID- 26054976 TI - Energizing eukaryotic cell-free protein synthesis with glucose metabolism. AB - Eukaryotic cell-free protein synthesis (CFPS) is limited by the dependence on costly high-energy phosphate compounds and exogenous enzymes to power protein synthesis (e.g., creatine phosphate and creatine kinase, CrP/CrK). Here, we report the ability to use glucose as a secondary energy substrate to regenerate ATP in a Saccharomyces cerevisiae crude extract CFPS platform. We observed synthesis of 3.64+/-0.35 MUg mL(-1) active luciferase in batch reactions with 16 mM glucose and 25 mM phosphate, resulting in a 16% increase in relative protein yield (MUg protein/$ reagents) compared to the CrP/CrK system. Our demonstration provides the foundation for development of cost-effective eukaryotic CFPS platforms. PMID- 26054977 TI - On the demultiplexing of chromosome capture conformation data. AB - How to describe the multiple chromosome structures that underlie interactions among genome loci and how to quantify the occurrence of these structures in a cell population remain important challenges to solve, which can be addressed via a proper demultiplexing of chromosome capture conformation related data. Here, we first aim to review two main methodologies that have been proposed to tackle this problem: restrained-based methods, in which the resulting chromosome structures stem from the multiple solutions of a distance satisfaction problem; and thermodynamic-based methods, in which the structures stem from the simulation of polymer models. Next, we propose a novel demultiplexing method based on a matrix decomposition of contact maps. To this end, we extend the notion of topologically associated domains (TADs) by introducing that of statistical interaction domains (SIDs). SIDs can overlap and occur in a cell population at certain frequencies, and we propose a simple method to estimate these frequency values. As an application, we show that SIDs that measure 100kb to tens of Mb long occur both frequently and specifically in the human genome. PMID- 26054978 TI - Identification of nuclear localization signals within the human BCOR protein. AB - Mutations in the BCL-6 corepressor (BCOR) gene, which encodes a transcriptional corepressor, were described to cause oculofaciocardiodental syndrome (MIM 300166). The purpose of this study was to localize the classical nuclear localization signals (NLSs) of the BCOR using reported human BCOR mutations with comparable phenotypes. The genotype-phenotype correlation among the mutations could not be clearly explained; however, the classical NLSs were identified at two possible sites; RVDRKRKVSGD at aa1131-1141 (NLS1) and LKAKRRRVSK at aa1158 1167 (NLS2). In addition, according to our results, NLS2 displayed a more efficient nuclear import function than NLS1. PMID- 26054979 TI - A novel semi-automatic segmentation method for volumetric assessment of the colon based on magnetic resonance imaging. AB - PURPOSE: To develop a novel semi-automatic segmentation method for quantification of the colon from magnetic resonance imaging (MRI). METHODS: Fourteen abdominal T2-weighted and dual-echo Dixon-type water-only MRI scans were obtained from four healthy subjects. Regions of interest containing the colon were outlined manually on the T2-weighted images. Segmentation of the colon and feces was obtained using k-means clustering and image registration. Regional colonic and fecal volumes were obtained. Inter-observer agreement between two observers was assessed using the Dice similarity coefficient as measure of overlap. RESULTS: Colonic segmentations showed wide variation in volume and morphology between subjects. Colon volumes of the four healthy subjects for both observers were (median [interquartile range]) ascending colon 200 mL [169.5-260], transverse 200.5 mL [113.5-242.5], descending 148 mL [121.5-178.5], sigmoid-rectum 277 mL [192-345], and total 819 mL [687-898.5]. Overlap agreement for the total colon segmentation between the two observers was high with a Dice similarity coefficient of 0.91 [0.84-0.94]. The colon volume to feces volume ratio was on average 0.7. CONCLUSION: Regional colon volumes were comparable to previous findings using fully manual segmentation. The method showed good agreement between observers and may be used in future studies of gastrointestinal disorders to assess colon and fecal volume and colon morphology. Novel insight into morphology and quantitative assessment of the colon using this method may provide new biomarkers for constipation and abdominal pain compared to radiography which suffers from poor reliability. PMID- 26054980 TI - The value of dynamic magnetic resonance imaging in interdisciplinary treatment of pelvic floor dysfunction. AB - PURPOSE: The purpose of this study was to determine the value of dynamic pelvic floor MRI relative to standard clinical examinations in treatment decisions made by an interdisciplinary team of specialists in a center for pelvic floor dysfunction. METHODS: 60 women were referred for dynamic pelvic floor MRI by an interdisciplinary team of specialists of a pelvic floor center. All patients were clinically examined by an urologist, gynecologist, a proctological, and colorectal surgeon. The specialists assessed individually and in consensus, whether (1) MRI provides important additional information not evident by physical examination and in consensus whether (2) MRI influenced the treatment strategy and/or (3) changed management or the surgical procedure. RESULTS: MRI was rated essential to the treatment decision in 22/50 cases, leading to a treatment change in 13 cases. In 12 cases, an enterocele was diagnosed by MRI but was not detected on physical exam. In 4 cases an enterocele and in 2 cases a rectocele were suspected clinically but not confirmed by MRI. In 4 cases, MRI proved critical in assessment of rectocele size. Vaginal intussusception detected on MRI was likewise missed by gynecologic exam in 1 case. CONCLUSION: MRI allows diagnosis of clinically occult enteroceles, by comprehensively evaluating the interaction between the pelvic floor and viscera. In nearly half of cases, MRI changed management or the surgical approach relative to the clinical evaluation of an interdisciplinary team. Thus, dynamic pelvic floor MRI represents an essential component of the evaluation for pelvic floor disorders. PMID- 26054981 TI - Pre-operative CT predictors associated with 30-day adverse events in patients with appendiceal inflammatory masses who underwent immediate appendectomies. AB - PURPOSE: To retrospectively evaluate pre-operative CT predictors that are associated with 30-day adverse events in patients who underwent immediate appendectomies for appendiceal inflammatory masses. METHODS: This retrospective study was approved by our institutional review board, and the requirement for informed consent was waived. One hundred forty-four consecutive patients who underwent immediate appendectomies and were diagnosed with appendiceal inflammatory masses by pre-operative CT from January 2005 to December 2013 at a tertiary hospital were included. The main outcome measure was 30-day adverse events. Patient demographics and data for inflammatory markers including leukocyte counts, segmented neutrophils, and C-reactive protein levels were collected by a single radiologist. Pre- and post-operative CT findings were evaluated for features of appendiceal inflammatory masses, associated findings, and post-operative adverse events by two radiologists in a blinded fashion with consensus to assess surgical and pathologic results, post-operative outcomes, and original CT interpretations. Appendiceal inflammatory masses were defined as complicated appendicitis with a phlegmon or an abscess that was identified on pre operative CT exam. Factors associated with 30-day adverse events were assessed using logistic regression analysis. RESULTS: A total of 22 (15%) of the 144 patients (mean age [+/-SD] 44.6 +/- 22.0 years, range 3-97 years) experienced 30 day adverse events: ten intra-abdominal abscesses, three wound infections, two cases of peritonitis, two small bowel obstructions, two intra-abdominal abscesses with peritonitis, one intra-abdominal abscess with wound infection, one intra abdominal abscess with small bowel obstruction, and one case of peritonitis with small bowel obstruction. In univariate analysis, the presence of appendicolith (odds ratio [OR] 2.49, p = 0.048) and high-grade obstruction (OR 3.79; p = 0.01) were associated with adverse events. High-grade obstruction (adjusted OR 3.05; p = 0.04) was the only independent pre-operative predictor associated with 30-day adverse events in patients with appendiceal inflammatory masses. CONCLUSIONS: High-grade obstruction was an independent pre-operative CT predictor associated with 30-day adverse events in patients who underwent immediate appendectomies for appendiceal inflammatory masses. PMID- 26054982 TI - Interactive X-ray and proton therapy training and simulation. AB - PURPOSE: External beam X-ray therapy (XRT) and proton therapy (PT) are effective and widely accepted forms of treatment for many types of cancer. However, the procedures require extensive computerized planning. Current planning systems for both XRT and PT have insufficient visual aid to combine real patient data with the treatment device geometry to account for unforeseen collisions among system components and the patient. METHODS: The 3D surface representation (S-rep) is a widely used scheme to create 3D models of physical objects. 3D S-reps have been successfully used in CAD/CAM and, in conjunction with texture mapping, in the modern gaming industry to customize avatars and improve the gaming realism and sense of presence. We are proposing a cost-effective method to extract patient specific S-reps in real time and combine them with the treatment system geometry to provide a comprehensive simulation of the XRT/PT treatment room. RESULTS: The X3D standard is used to implement and deploy the simulator on the web, enabling its use not only for remote specialists' collaboration, simulation, and training, but also for patient education. CONCLUSIONS: An objective assessment of the accuracy of the S-reps obtained proves the potential of the simulator for clinical use. PMID- 26054983 TI - Multimodal image-guided prostate fusion biopsy based on automatic deformable registration. AB - PURPOSE: Transrectal ultrasound (TRUS)-guided random prostate biopsy is, in spite of its low sensitivity, the gold standard for the diagnosis of prostate cancer. The recent advent of PET imaging using a novel dedicated radiotracer, [Formula: see text]-labeled prostate-specific membrane antigen (PSMA), combined with MRI provides improved pre-interventional identification of suspicious areas. This work proposes a multimodal fusion image-guided biopsy framework that combines PET MRI images with TRUS, using automatic segmentation and registration, and offering real-time guidance. METHODS: The prostate TRUS images are automatically segmented with a Hough transform-based random forest approach. The registration is based on the Coherent Point Drift algorithm to align surfaces elastically and to propagate the deformation field calculated from thin-plate splines to the whole gland. RESULTS: The method, which has minimal requirements and temporal overhead in the existing clinical workflow, is evaluated in terms of surface distance and landmark registration error with respect to the clinical ground truth. Evaluations on agar-gelatin phantoms and clinical data of 13 patients confirm the validity of this approach. CONCLUSION: The system is able to successfully map suspicious regions from PET/MRI to the interventional TRUS image. PMID- 26054984 TI - [Haut Conseil de la sante publique (HCSP). Management of single or multiple pertussis cases]. PMID- 26054985 TI - A proposed solution to integrating cognitive-affective neuroscience and neuropsychiatry in psychiatry residency training: The time is now. AB - Despite increasing recognition of the importance of a strong neuroscience and neuropsychiatry education in the training of psychiatry residents, achieving this competency has proven challenging. In this perspective article, we selectively discuss the current state of these educational efforts and outline how using brain-symptom relationships from a systems-level neural circuit approach in clinical formulations may help residents value, understand, and apply cognitive affective neuroscience based principles towards the care of psychiatric patients. To demonstrate the utility of this model, we present a case of major depressive disorder and discuss suspected abnormal neural circuits and therapeutic implications. A clinical neural systems-level, symptom-based approach to conceptualize mental illness can complement and expand residents' existing psychiatric knowledge. PMID- 26054986 TI - Modified Virtual Colonoscopy in the Diagnosis and Quantification of Bowel and Disseminated Endometriosis. AB - This article describes the basic technology and technique behind modified virtual colonoscopy (MVC). It is accompanied by images illustrating the possibility of MVC to advance the imaging for endometriosis beyond the current modalities of magnetic resonance imaging (MRI) and ultrasound. A quantification system is described that will ultimately make staging and multicenter prospective scientific studies possible for rectogenital and disseminated endometriosis. PMID- 26054987 TI - The Efficiency of a Modified Real-time Wireless Brain Electric Activity Calculator to Reveal the Subliminal Psychological Instability of Surgeons that Possibly Leads to Errors in Surgical Procedures. AB - We know that experienced endoscopic surgeons, despite having extensive training, may make a rare but fatal mistake. Prof. Takeshi Ohdaira developed a device visualizing brain action potential to reflect the latent psychological instability of the surgeon. The Ohdaira system consists of three components: a real-time brain action potential measurement unit, a simulated abdominal cavity, and an intra-abdominal monitor. We conducted two psychological stress tests by using an artificial laparoscopic simulator and an animal model. There were five male subjects aged between 41 to 61 years. The psychological instability scores were considered to reflect, to some extent, the number of years of experience of the surgeon in medical care. However, very high inter-individual variability was noted. Furthermore, we discovered the following: 1) bleeding during simulated laparoscopic surgery--an episode generally considered to be psychological stress for the surgeon--did not form the greatest psychological stress; 2) the greatest psychological stress was elicited at the moment when the surgeon became faced with a setting in which his anatomical knowledge was lacking or a setting in which he presumed imminent bleeding; and 3) the excessively activated action potential of the brain possibly leads to a procedural error during surgery. A modified brain action potential measurement unit can reveal the latent psychological instability of surgeons that possibly leads to errors in surgical procedures. PMID- 26054988 TI - Shared Decision-Making in Surgery. AB - Medical treatment of patients always entails the risk of undesired complications or side effects. This is particularly poignant in surgery as both the disease to be treated and the surgical intervention to be performed can be life threatening. Hence, it is essential to inform a surgical patient in detail about the expectations desired, but also the possible undesired outcomes and complications, especially when new surgical techniques are introduced. Apart from communication about available evidence regarding treatment options, the patient's preference needs to be invoked to make sure the surgeon's advice matches the patient's preference. Shared decision-making (SDM) invokes the bidirectional communication between physicians and patients required to involve the patient's preference in the eventual treatment choice. SDM is considered as an essential part of evidence based medicine as it helps determine whether the available evidence on the possible benefits and harms of treatment options match the patient's characteristics and preferences. This paper will exemplify what SDM is, why it is important, and how it can be performed in surgical practice. Several tools to facilitate SDM are presented. PMID- 26054989 TI - Advances in the Surgical Treatment of Gastroschisis. AB - Gastroschisis (GS) is a structural defect of the anterior abdominal wall, usually diagnosed antenatally, that occurs with a frequency of approximately 4 per 10,000 pregnancies. Babies born with GS require neonatal intensive care and surgical management of the abdominal wall defect soon after birth. Although contemporary survival rates for GS are over 90%, these babies are at risk for significant morbidity, and require 4 to 6 weeks of costly, resource-intensive care in specialized neonatal units. Much consideration has been given to how best to treat the abdominal wall defect of GS. The traditional approach, necessitated by a need to establish enteral feeding as quickly as possible, consists of early postnatal visceral reduction and sutured abdominal closure. Advances in neonatal nutritional support have enabled the development of surgical approaches, which permit gradual visceral reduction and delayed abdominal closure. In cases where early visceral reduction cannot be achieved, delayed closure enabled by the initial placement of a prosthetic silo has been a live-saving alternative. The development of preformed silos has simplified their use and led to an interest in treating all cases with a delayed closure philosophy. Most recently, a sutureless technique of abdominal closure has been reported, which has the benefit of avoiding general anesthesia and offers other outcome improvements over sutured closure of the defect. The debate over primary closure versus silo placement and delayed closure continues to receive much attention. The goal of this article is to review historical aspects of gastroschisis closure, and then focus on current surgical techniques, including the innovative sutureless closure, with an analysis of the comparative clinical effectiveness of these approaches to treatment of the abdominal wall defect in GS. PMID- 26054990 TI - Catheter for Cleaning Surgical Optics During Surgical Procedures: A Possible Solution for Residue Buildup and Fogging in Video Surgery. AB - Currently, there is a tendency to perform surgical procedures via laparoscopic or thoracoscopic access. However, even with the impressive technological advancement in surgical materials, such as improvement in quality of monitors, light sources, and optical fibers, surgeons have to face simple problems that can greatly hinder surgery by video. One is the formation of "fog" or residue buildup on the lens, causing decreased visibility. Intracavitary techniques for cleaning surgical optics and preventing fog formation have been described; however, some of these techniques employ the use of expensive and complex devices designed solely for this purpose. Moreover, these techniques allow the cleaning of surgical optics when they becomes dirty, which does not prevent the accumulation of residue in the optics. To solve this problem we have designed a device that allows cleaning the optics with no surgical stops and prevents the fogging and residue accumulation. The objective of this study is to evaluate through experimental testing the effectiveness of a simple device that prevents the accumulation of residue and fogging of optics used in surgical procedures performed through thoracoscopic or laparoscopic access. Ex-vivo experiments were performed simulating the conditions of residue presence in surgical optics during a video surgery. The experiment consists in immersing the optics and catheter set connected to the IV line with crystalloid solution in three types of materials: blood, blood plus fat solution, and 200 mL of distilled water and 1 vial of methylene blue. The optics coupled to the device were immersed in 200 mL of each type of residue, repeating each immersion 10 times for each distinct residue for both thirty and zero degrees optics, totaling 420 experiments. A success rate of 98.1% was observed after the experiments, in these cases the device was able to clean and prevent the residue accumulation in the optics. PMID- 26054992 TI - Topical Agents and Dressings for Pilonidal Sinus Wound Healing by Secondary Intention: A Scoping Review. AB - Pilonidal disease (PD) is a chronic and debilitating condition. The overall aim of the scoping review is to map and summarize a wide range of evidence to examine which topical agent or dressing is effective in promoting pilonidal wound healing by secondary intention. Review of this cumulative body of evidence will inform care and guide dressing selection for PD related wounds and delineate future research priorities based on identified knowledge gaps and clinical practice issues. Overall, there is some evidence to suggest that topical applications of hydrogel, silver, honey, zinc, selected foam materials, negative pressure wound therapy, platelet rich plasma, and plant extracts may promote wound healing. Topical treatment using polyhexamethylene biguanide and silver may be beneficial in reducing bacterial burden. Finally, silver, honey, and hydrocolloid dressings may help alleviate wound related pain. However, evidence remains insufficient in light of methodological limitations and biases of the studies. PMID- 26054993 TI - Gentian Violet and Methylene Blue Polyvinyl Alcohol Foam Antibacterial Dressing as a Viable Form of Autolytic Debridement in the Wound Bed. AB - The objective of this article is to describe the results of a comparative porcine study that evaluated the effectiveness of a gentian violet and methylene blue (GV/MB) polyvinyl alcohol (PVA) antibacterial foam dressing in debriding eschar. The authors performed an in vivo, preclinical study on eschar-covered porcine wounds. Two clinical case studies are also included. Test products, GV/MB antibacterial foam dressing, collagenase ointment, collagenase ointment plus GV/MB antibacterial foam dressing, medical-grade honey, and moist gauze dressing (control), were applied to porcine wounds using a split-back study design. The percent of eschar removal and wound closure were measured and recorded at time points up to 14 days. Statistically significant reduction in eschar was observed with GV/MB dressing and with GV/MB dressing with collagenase. By day 14, the wounds with GV/MB dressing alone and GV/MB dressing with collagenase had eschar covering less than 25% of the wound bed area compared with collagenase alone, medical grade honey, or moist gauze control, which showed eschar still covering over 75% of the wound bed area. Autolytic debridement activity of GV/MB foam dressings was evident in the porcine eschar study, as well as in the cases described. PMID- 26054994 TI - Oxy-MatTM Mattress System Development Utilizing Simultaneous Measurement of Interface Pressure and Deep Tissue Oxygen Saturation. AB - The development and management of pressure ulcers (PUs) among hospital and nursing home patients is one of the greatest preventable challenges to healthcare worldwide. For over 50 years, pressure mapping and subjective comfort has been the primary indicators for mattress selection. Our research demonstrates that mattress/patient interface pressure and relative blood/oxygen perfusion do not inversely correlate and pressure is not a meaningful, real-time indicator of tissue ischemia and risk of pressure ulcer development. Developed in our research is a real-time sensor system to simultaneously measure and record these parameters over the anatomical sites at risk for PUs. Measurements focused on the heel, sacrum, trochanter, ischium, scapula and occipital. A modified pressure mapping system is used for interface pressure measurements and integrated with multiple near-infrared sensors to measure specific deep tissue hemoglobin saturated oxygen or rSO2. Testing and mattress design development was done during the period of 2008 to present. Over 200 human tests of commercially available mattresses were conducted in supine, 30 degree, and 70 degree positions, ranging in times of up to four hours. During this time period, we utilized 20 test subjects-eight female and 12 male-with ages ranging from 18 to 65 years. The result of this proprietary off-loading device evaluation and design system shows that the new Oxy-MatTM (Off-Loading Technologies, Tarrytown, NY) Non-Powered Mattress System consistently provides optimized tissue perfusion as measured by natural deep tissue oxygen saturation levels. In extensive laboratory and clinical evaluations, the Oxy-MatTM was shown to be functionally superior to CMS Group 2 powered mattresses. Another outcome of our research was that a powered mattress system may not be appropriate for most sensate and semi-ambulatory patients. Further research is underway. PMID- 26054995 TI - Structural Endoscopic Techniques to Treat Obesity: A Review. AB - The prevalence of overweight and obesity increased significantly during the past decades, affecting now approximately 30% of people worldwide. Bariatric surgery has proven to be the most effective treatment modality for obesity in the long term. However, current surgical procedures are accompanied by a substantial risk of complications. Several endoluminal techniques have been developed to achieve weight loss in obese patients and claim to be as effective as surgery but safer. The aim of this review is to evaluate the efficacy and safety of endoscopic bariatric procedures that provide structural changes in anatomy and physiology of the gastrointestinal tract. A comprehensive search was conducted using online databases and the references of the selected articles. All studies included in this review show excess weight loss in the short-term to medium-term, which ranges from 24% to 58%. Seven serious adverse events were reported. Therefore, we conclude that endoscopic bariatric procedures providing structural changes show relatively low complication rates and promising short-term weight loss and effect on obesity-related comorbidities. Long-term results in large study populations are necessary before these techniques can be incorporated in the standard treatment of obesity. PMID- 26054996 TI - Reduced Port Distal Gastrectomy With a Multichannel Port Plus One Puncture (POP). AB - BACKGROUND: This report describes the techniques and outcomes of reduced port distal gastrectomy (RPDG) with a multichannel port plus one puncture (POP) for gastric cancer patients. PATIENTS AND METHODS: A total of eight patients underwent a RPDG using the E?Z AccessTM/LAPPROTECTORTM (Hakko Co. Ltd., Tokyo, Japan) oval type devices with POP by a single surgeon. The median age of the patients was 66 years (range 48-75 years), and their median BMI was 22.3 kg/m2 (range 17.7-26.8 kg/m2). One (12.5 %) of eight patients was female. A thin caliber trocar MiniPortTM (Covidien, New Haven, CT) was inserted at the left upper quadrant by puncture without incision. An assistant used Endo ReliefTM (Hope Denshi Co. Ltd., Chiba, Japan) needlescopic forceps. In three cases, the pre-bent forceps (KTY-I, Adachi Industry Co. Ltd., Gifu, Japan) was introduced for surgeon's left hand. After the liver was retracted with a 2-0 Prolene suture, a distal subtotal resection of the stomach with D1+ or D2 lymph node dissection was performed. The Roux-en-Y method or Billroth-I anastomosis was used for reconstruction. The short-term patient outcomes were investigated to evaluate the feasibility of RPDG with POP. RESULTS: We employed this technique without the use of additional trocars in every patient except one. No conversion to laparotomy was observed. Both the Endo ReliefTM forceps and prebent forceps were useful to maintain countertraction and keep triangulation. The median length of the operation was 374 (range, 268-420) minutes, and the median estimated blood loss was 45 (range, 5-180) ml. The median number of dissected lymph nodes was 32 (range 22-46). Neither major postoperative complications, such as anastomotic leakage and stricture, nor postoperative mortality were observed. The mean length of the hospital stay was 1,5 days. The umbilical wound was indistinct. CONCLUSION: RPDG with POP using a needlescopic device procedure is feasible in terms of patient safety and curability. PMID- 26054997 TI - Continuous Intraoperative Neuromonitoring (C-IONM) Technique with the Automatic Periodic Stimulating (APS) Accessory for Conventional and Endoscopic Thyroid Surgery. AB - One of the most important trends in intraoperative neural monitoring (IONM) in thyroid surgery is currently the real-time monitoring of the vagus nerve (VN) in order to prevent recurrent laryngeal nerve (RLN) iatrogenic damages. Notably, continuous intraoperative neuromonitoring (C-IONM) seems to be superior to intermitted intraoperative neural monitoring (I-IONM) because it enhances standardization by permanent vagus nerve (VN) stimulation, and it provides entire and constant RLN function monitoring as the surgeon dissects and removes the thyroid gland. It also has to be highlighted that the surgical maneuvers for the automatic periodic stimulating (APS) placement must be accurate and standardized in order to avoid a potential iatrogenic morbidity on the VN function. We recommend the experienced surgeon be very careful in each step, with cautious dissection. With this review article we provide a comprehensive analyses of C IONM technique with the APS accessory for conventional and endoscopic thyroid surgery. PMID- 26054998 TI - Endoscopic Therapeutic Option for Weight Loss and Control of Type 2 Diabetes: the Duodenal-Jejunal Bypass Liner. AB - For a long time, obesity has been known as a risk factor for cardiovascular disease, which is one of the main causes of death in developed countries. This risk is due to the coexistence of other factors associated with obesity, such as hypertension, dyslipidemia, nonalcoholic fatty liver disease, and abnormalities in glycemic metabolism. Obesity is also a major risk factor for type 2 diabetes, and it is not surprising that the global prevalence of this disease continues to increase. Surgical intervention is now the most effective modality to treat severe obesity and its comorbidities. However, endoluminal interventions performed entirely through the gastrointestinal tract by using endoscopic devices offer the potential for an outpatient weight loss procedure that may be safer, less invasive, and more cost-effective, compared with current surgical approaches. Given the emerging role of endoscopic procedures in the treatment of obesity and rapid changes in endoscopic technologies and techniques, this review considers the current state of endoscopic management of obesity and type 2 diabetes. Endoscopic techniques attempt to mimic some of the anatomic features of bariatric surgery and rely on gastric restriction and duodenal exclusion. The endoscopic placement of the duodenal-jejunal bypass liner in morbidly obese patients induces significant weight loss. Additionally, early studies reported significant improvements in several parameters of glucose homeostasis in morbidly obese patients with type 2 diabetes. In this article we will review the available results obtained with the duodenal-jejunal bypass liner. PMID- 26054999 TI - Laparoscopic Cholecystectomy for a Patient with Left-sided Gallbladder. AB - A 47-year-old man who presented with epigastric pain after a meal was diagnosed with biliary sludge present in the gallbladder. Endoscopic retrograde cholangiopancreatography showed normal anatomy of the biliary tree. During the exploratory phase of a laparoscopic cholecystectomy using four ports positioned as usual, surgeons observed a left-sided gallbladder. A review of the preoperative imaging by computed tomography confirmed a round ligament connected to the right portal umbilical portion. It also established that the gallbladder was located to the left of the round ligament, and attached to the left lateral segment of the liver. Laparoscopic cholecystectomy was performed successfully in this patient with the usual port site and careful dissection with a normograde approach. The patient was discharged on the second postoperative day with an uneventful course. Prior identification of a left-sided gallbladder is possible with cautious attention. In particular, it is important for the surgeon to be aware of unusual alterations in the portal and biliary anatomy associated with this anomaly to safely complete a laparoscopic cholecystectomy. PMID- 26055000 TI - Detecting Incisional Hernia at Clinical and Radiological Examination. AB - PURPOSE: In clinical studies, incisional hernia is usually diagnosed by clinical examination. No other modality has been proven an aid in the diagnosis. The aim was to investigate the correlation between findings at clinical examination and at computed tomography when detecting incisional hernia after midline incisions. METHODS: Patients underwent clinical examination by three surgeons. Computed tomography was performed in both the supine position and in the prone position and was examined by three radiologists. The correlation between investigators and methods were estimated by calculating the Fleiss Kappa values. RESULTS: Twenty four patients were assessed. For the clinical examination, the Kappa was 0.81. For computed tomography with the patient in the supine position, the Kappa was 0.94 and in the prone position it was 0.89. The Kappa for clinical examination and computed tomography combined was 0.80. CONCLUSIONS: At clinical examination, incisional hernia can be defined as any detectable defect in the abdominal wall with intra-abdominal contents protruding beyond the aponeurosis. The same definition can be used at computed tomography with the addition that any visible hernia sac is also regarded an incisional hernia. With this definition, there is very good agreement between investigators at clinical investigation and at computed tomography in the prone or in the supine position. The highest agreement among investigators is achieved with computed tomography in the supine position. In clinical studies, clinical examination seems adequate for diagnosing herniation but in overweight patients a CT-scan may be a further aid. PMID- 26055001 TI - Value-based Clinical Quality Improvement (CQI) for Patients Undergoing Abdominal Wall Reconstruction. AB - Patients with complex ventral/incisional hernias often undergo an abdominal wall reconstruction (AWR). These operations have a high cost of care and often result in a long hospital stay and high complication rates. Using the principles of clinical quality improvement (CQI), several attempts at process improvement were implemented in one hernia program over a 3-year period. For consecutive cases of patients undergoing abdominal wall reconstruction, process improvement attempts included the use of a long-term resorbable synthetic mesh (TIGR(r) Resorbable Matrix, Novus Scientific, Uppsala, Sweden) in place of a biologic mesh, the use of the transversus abdominis release approach in place of an open or endoscopic component separation (external oblique release) technique, and the use of a preoperative transversus abdominis plane (TAP) block using a long-acting local anesthetic (Exparel(r), Pacira Pharmaceutical, Parsippany, NJ) as a part of perioperative multi-modal pain management and an enhanced recovery program. After over 60 cases, improvement in materials costs and postoperative outcomes were documented. No mesh-related complications occurred and no mesh removal was required. In this real-world, value-based application of CQI, several attempts at process improvement led to decreased costs and improved outcomes for patients who underwent abdominal wall reconstruction for complex ventral/incisional hernias. Value-based CQI could be a tool for improved health care value globally. PMID- 26055002 TI - Resection of Ileoinguinal and Ileohypogastric Nerves Combined with Gluing in Modified Lichtenstein Repair. AB - We conducted a cohort trial to investigate the relevance of resection of the ilioinguinal and iliohypogastric nerves in combination with mesh fixation with BioGlueTM (CryoLife(r) Inc., Kennsaw, Georgia) in modified Lichtenstein repair to the development of chronic pain and hernia recurrence.1 In all, 430 patients underwent Lichtenstein repair. In 247 patients the mesh was fixed by means of glue, and in 183 patients it was fixed with conventional sutures. In all cases the inguinal nerves N. ilioinguinalis and N. iliohypogastricus were located and resected after identification to prevent nerve reaction to the mesh. The pain intensity was measured with a numeric analogous scale (NAS) 24 hours after surgery. All complications were recorded with a follow-up of up to 5 years. There was a significantly lower pain intensity level in the gluing group compared with the suture group 24 hours after surgery (0.016 t test). The level was 3.8+/-2.4 in bilateral hernia and 3.3+/-2.1 in unilateral hernia in the gluing group. It was 4.7+/-3.3 in unilateral and 3.7+/-2.2 in bilateral hernia in the suture group. The cut-suture time was lower in the gluing group. There were no severe pain syndromes (NAS>=4) in the gluing group and only 1.1% in the suture group. There was a higher incidence of non-bacterial wound infections in the gluing group (3.6%) than in the suture group (1.1%). The rate of recurrence after 5 years amounted to 2.0% in the gluing group and 2.2% in the suture group. The technique of using BioGlueTM for mesh fixation combined with systematic nerve dissection reduces acute and chronic postoperative pain after modified Lichtenstein repair. Only 2 of 430 patients suffered from severe chronic pain. Combined gluing and systematic resection of the inguinal nerves is more comfortable than standard Lichtenstein repair. PMID- 26055003 TI - Mid-Term Follow Up of TAPP Hernia Repair Without Staples and Glue: An Audit of the Data. AB - Groin hernia repair by using the laparoscopic transabdominal preperitoneal (TAPP) repair approach presents lower post-operative pain with a quicker return to normal patient activity compared to the open technique. Nevertheless, the long learning curve, general anaesthesia, and increased costs due to devices are the arguments against TAPP. Currently, the only mesh fixation techniques are those using glue or tacks. We report the audit of two years follow-up about our experience using a self-gripping lightweight mesh Parietex ProGripTM (Covidien, Trevoux, France). The records of 39 patients for the first 50 procedures were reported. We registered wound infection, hematoma, seroma, neuralgia, numbness, and recurrence. In our opinion, TAPP procedure with ProGripTM mesh is a feasible procedure without using fixation devices; costs, chronic pain and recovery are improved. Moreover, in the medium-term follow-up, we are able to reduce foreign body sensation and numbness. PMID- 26055004 TI - Long-term Outcome on the use of the VentralightTM ST Hernia Patch in Laparoscopic Ventral Hernia Repair. AB - BACKGROUND: Laparoscopic ventral hernia repair (LVHR) is a common procedure in abdominal surgery. Use of mesh has become the gold standard in the last decade because of significantly fewer recurrences. Subsequently, the attention shifted to reduce mesh related complications in the short- and long-term as well as to facilitate its handling and positioning. In continuation of our previous study, we conducted a final analysis about the use of the VentralightTM ST hernia patch (Davol Inc, Subsidary of C. R. Bard, Inc. Warwick, RI). METHODS: Prospectively collected data of 61 consecutive patients (men/women: 44/17) from July 2011 to October 2013 were analysed in this final study. Patients were evaluated clinically at four time points in total. At the final clinical check- up, 97% of the total study population was reassessed. The primary outcome parameter was recurrence. Secondary outcome parameters were described in terms of mesh related complications, pain scores, and quality of life. RESULTS: Mean follow-up time was 23 months (range 16-44). Mean length of hospital stay was four days (range 2-17). There were no operative complications. Two patients (both>80 years old) died more than one year after the procedure because of a cardiovascular event. One morbidly obese patient (2%) treated for a recurrent incisional hernia showed a second recurrence at the last follow-up visit. A clinical significant seroma was observed in two patients (3%) one month postoperatively. At last follow-up, two patients (3%) reported persistent mild discomfort at one specific spot. There was a significant reduction in the visual analogue scale (VAS) scores at the last follow-up visit compared to preoperative scores (3.01 vs. 0.27; P<0.01). Quality of life measurements using the SF-36 questionnaire showed good results. CONCLUSION: This final analysis of long-term follow-up results on the use of the VentralightTM ST hernia patch in laparoscopic ventral hernia repair confirms our preliminary findings of the previous two reports. Use of the VentralightTM ST hernia patch is associated with good short- and long-term outcomes and can be considered as safe and feasible in LVHR. PMID- 26055005 TI - Correlation of Computed Tomography Measured Presacral Thickness with Body Mass Index. AB - Sacral colpopexy is often chosen as a reliable approach that effectively resolves vaginal vault prolapse. Advancements in minimally invasive technology, robotic and laparoscopic surgery, have helped facilitate surgical dissection and operation when performing this procedure. An increased presacral thickness can potentially present a surgical challenge when operating in the presacral space. We hypothesize that there is a correlation between body mass index and presacral thickness. Computed Tomography (CT) images of 241 patients were reviewed in this retrospective study. The presacral thickness was measured by taking the cross sectional distance from the sacral promontory to the upper aspect of the iliac arteries. The corresponding demographic information of age, body mass index (BMI), and comorbidities were evaluated using univariate analysis, linear regression, and multiple regression analysis. The mean age was 56.6 years, and BMI was 27.6. The mean presacral thickness measurement based on the CT scan was 21.08 mm. Univariate linear regression models demonstrated a positive correlation between presacral thickness and BMI and a negative correlation with age. When adjusting for both age and BMI on multivariate analysis, a positive correlation with hypertension was found. The surgeon should be aware of this potential change in anatomy when operating in the presacral space. PMID- 26055006 TI - Morphologic Evaluation of Post-implanted Monofilament Polypropylene Mesh Utilizing a Novel Technique with Scanning Electron Microscopy Quantification. AB - Polypropylene mesh has been shown to shrink up to 50%; however, little is known about other changes that may occur while it is implanted. It is unclear whether such changes have clinical impact; nonetheless, knowledge of such can ultimately affect the technique of implantation and may affect outcomes. The objective of this study was to evaluate surgically explanted mesh after two years implantation for evidence of change in morphology using scanning electron microscopy (SEM). Secondly, we describe a novel technique for quantifying such changes with intentions for future validation. SEM imaging was conducted and mesh changes were visualized. SEM images revealed deep surface cracks both transverse and longitudinal, flaking and peeling of fibers, as well as fibrosis. Microstructural quantification of cracks was also completed. The fraction of transverse cracked area to whole surface area was 24.2%. Average crack length range was 0.58 to 71.46 um and average crack thickness range was 0.99 to 25.46 um. Polypropylene mesh is subject to structural changes after surgical implantation. It is important to investigate how these processes impact clinical outcomes. Validated techniques of quantifying such changes can prove useful in future research and aid in development of the ideal graft. PMID- 26055007 TI - Preliminary Outcomes of a New, Safe, Tension-free Vaginal Tape Trocar. AB - The aim of this study is to introduce a new, safe, tension-free vaginal tape (TVT) trocar. Twenty-eight women with stress urinary incontinence who underwent a TVT procedure with a new trocar during a 6-month period were prospectively enrolled in this study. All the operations were performed by the same surgeon who developed the trocar. The trocar has two buttons, which make the tip of the device sharp or blunt. Median age of the study population was 52 years (range, 30 76 years), median number of vaginal deliveries was 3 (range, 1-10). And 57.1% of women were at menopause. Median body mass index was 30.0 kg/m2 (range, 23.8-35.2 kg/m2). Preoperative median Valsalva leak point pressure was 78 cmH2O (range, 50 94 cmH2O), while the median maximum urethral closure pressure was 50 cmH2O (range, 14-74 cmH2O). Concomitant prolapse surgery was present in 23 women (82.1%). At the 6-month postoperative visit, objective and subjective cure rates were 89.3% for each. No serious intraopeartive or postoperative complication such as bladder, intestine, or major vessel injury occured. Only 3 women (10.7%) needed blood transfusion, and 2 women (7.1%) had postoperative voiding difficulty. Due to the modifiable tip, this new sling trocar seems safer than the conventional trocars. But large studies are necessary to prove this assumption. Due to the modifiable tip, this new sling trocar seems safer than the conventional trocars. But large studies are necessary to prove this assumption. PMID- 26055008 TI - Office-Based HE-TUMT Costs Less than Medication over Four Years in Treating Benign Prostatic Hyperplasia. AB - OBJECTIVES: Benign prostatic hyperplasia (BPH) can cause lower urinary tract symptoms (LUTS). Medications are first line treatment for mild-moderate BPH. Office-based minimally invasive therapies (MITs) are also acceptable early treatment options but comparisons of MIT to medications are limited. MIT may be equally effective and less costly compared to long-term medical therapy. We compared data from a medication trial to pooled data of high-energy transurethral microwave therapy (HE-TUMT) to evaluate differences in outcomes and costs between the modalities. STUDY DESIGN: Covariate-adjusted comparison of treatments from independent clinical trials. MATERIALS AND METHODS: Data from Medical Therapy of Prostatic Symptoms (MTOPS) study arms were compared to Urologix pooled data from seven HE-TUMT studies at 25 centers. Improvements in voiding symptoms and quality of life (QoL) were determined and a repeated measure logistic regression analysis to control for baseline covariates was performed. Cost data were collected using published outcomes, Medicare 2013 national averages, and discount online pharmacy prices. RESULTS: HE-TUMT provided significant improvement in voiding symptoms and QoL compared to all MTOPS arms through two years. At four years, all therapies maintain similar improvements when adjusting for baseline covariates. Four year cumulative costs of HE-TUMT ($3,620) were less than combination medical therapy ($7,200). CONCLUSIONS: HE-TUMT provides better improvement of LUTS compared to medication for two years. At four years, all therapies provide comparable improvement but HE-TUMT is less expensive with better QoL. This suggests that HE TUMT is an excellent alternative to medical therapy that should be routinely discussed and offered during detailed management of BPH. PMID- 26055009 TI - Successful Valve Prolapse Repair for Ischemic Mitral Regurgitation: Combined Papillary Muscle Approximation and Mitral Chordae System Replacement. AB - Mitral valve prolapse occurs in 33.6% of patients undergoing surgery for ischemic mitral regurgitation (IMR). In the context of IMR, reparative strategy cannot disregard the underlying mechanism of pathogenesis and the progressive geometric alteration affecting left ventricle and papillary muscles. We present a case of extended mitral prolapse of the posteromedial commissure and A3 concomitant to chordal injury after inferior myocardial infarction. We propose a combined sequential approach including papillary muscle approximation and a mitral chordae system replacement. PMID- 26055010 TI - An Evolving Understanding of the Genetic Causes of Abdominal Aortic Aneurysm Disease. AB - Aneurysms of the abdominal aorta (AAA) are relatively common - affecting as many as 8% of men and 1% of women over the age of 65. AAAs are characterized by a 50% increase in the diameter of the aneurysmal aorta compared with the normal vessel. Degeneration of structural components of the aortic wall is believed to be central in the pathogenesis of AAAs. The exact mechanism of degeneration is not well characterized, although degradation of elastin and collagen has been clearly shown. At least six genetic variants have been associated with AAA in genome-wide association studies: CDKN2BAS1, DAB2IP, LDLR, LRP1, SORT1, and IL6R. These variants reach genome-wide significance; however, they have not been replicated in multiple cohorts, nor have they been clearly shown to be disease causative. AAA is a challenging disease for investigation because it is most often asymptomatic and generally has a late disease onset, making it difficult to diagnose. Determination of the genetic mechanism behind aneurysm formation, progression, and rupture crosses disciplines requiring input from multiple fields of study, larger patient cohorts, and the evolving modalities of genetic testing. PMID- 26055011 TI - Novel Techniques in Video-assisted Thoracic Surgery (VATS) Lobectomy. AB - Twenty years ago, thoracic surgery witnessed the leap from thoracotomy to the first video-assisted thoracic surgery (VATS) lobectomy. Gradually VATS lobectomy has become widely accepted and practiced worldwide. As the idea of less-invasive, fewer, and smaller incisions is taken up by surgeons, thoracic surgery has witnessed the progress of the conventional three-port VATS lung resection to two port VATS and finally the birth of uniportal VATS lobectomy. Incisions have also become much smaller over the years, such as those seen in total port access lobectomy or microlobectomy. A modified version of the uniportal VATS lobectomy through the subxiphoid incision has also recently been used. The movement toward less-invasive surgery has no doubt driven the innovation of sophisticated instruments and technology to cope with the demanding need of working through a restricted incision. Reported outcomes and results of these new developments are encouraging. PMID- 26055012 TI - Recent Advancements in Infrapopliteal Revascularization. AB - Infrapopliteal arterial disease is a challenging problem to treat. A shift toward an endovascular treatment approach over surgical bypass has occurred over recent years. Although current standard percutaneous transluminal balloon and bare metal stents are employed, their durability and outcomes are questionable. A number of endovascular advancements in the treatment of infrapopliteal (IP) arterial disease have recently been made. We review the recent literature for new atherectomy, stent, and balloon technologies. PMID- 26055013 TI - Mechanochemical Endovenous Occlusion of Varicose Veins Using the ClariVein(r) Device. AB - INTRODUCTION: In the last decade, minimally invasive endothermal ablation techniques have replaced surgery for the treatment of superficial venous insufficiency to reduce postoperative complications and recovery time and to improve quality of life. To avoid the risks of nerve damage and need for tumescent anesthesia to improve patient comfort, an alternative heatless technique has been introduced recently. METHODS: Endovenous mechanochemical occlusion using the ClariVein(r) catheter (Vascular Insights LLC, Quincy, MA) is a new technique combining mechanical injury to the venous endothelium coupled with simultaneous catheter-guided infusion of a liquid sclerosant. This produces irreversible damage to the endothelium resulting in fibrosis of the vein. RESULTS: The technique is related to a low complication rate and a success rate of 96% at two years and sustained quality of life improvement. This closure rate is comparable to endothermal techniques, but significantly less postoperative pain and earlier return to normal activities and work has been reported with endovenous mechanochemical occlusion. CONCLUSION: Mechanochemical occlusion using ClariVein(r) has proven to be safe and effective and has several advantages compared to endothermal techniques. The possibility of retrograde ablation of distal SSV insufficiency in C6 ulceration is considered a significant advantage. Randomized comparative studies with long-term follow up will continue to define the definite place of mechanochemical occlusion. PMID- 26055014 TI - Abdominal Aortic Aneurysm Repair Using NellixTM EndoVascular Aneurysm Sealing. AB - Since the dawn of endovascular aortic aneurysm repair (EVAR), starting from its initial report in 1991, there has been a significant evolution in stent graft design and delivery systems. Complications, mostly endoleaks, and re-intervention rates after EVAR remain amongst the most challenging aspects in comparison with traditional open repair. The use of a sac-anchoring endograft changes the approach of aneurysm exclusion. The NellixTM EndoVascular Aneurysm Sealing system (Endologix Inc., Irvine, CA) consists of balloon expandable stents surrounded by endobags that are filled with a polymer thereby sealing the aneurysm. By sealing the aneurysm sac instead of exclusion with only proximal and distal fixation, the risk of stent migration and endoleaks is theoretically diminished. Current investigational use is aimed to confirm clinical success, decreased complication, and secondary intervention rates compared to conventional endovascular repair. PMID- 26055015 TI - What's New in Venous Thromboembolic Prophylaxis Following Total Knee and Total Hip Arthroplasty? An Update. AB - Venous thromboembolic disease (VTED) (deep venous thrombosis and pulmonary embolism) is a considerable source of morbidity and mortality following lower extremity total joint arthroplasty. The purpose of this review was to: (1) evaluate the most recent updated guidelines on thromboprophylaxis; and to (2) provide an overview and update of current modalities of VTED prophylaxis, such as pharmacological agents and mechanical compression. Although the AAOS and ACCP guidelines have not changed since the last review, the SCIP guidelines have focused on implementing the concepts proposed by each of these organizations. Specifically, the use of aspirin has been highlighted as an acceptable chemoprophylactic agent. Warfarin and low molecular weight heparin remain widely used, but maintaining therapeutic levels of warfarin remains a challenge, and LWMH has not shown itself to be superior to any of the other chemoprophylactic agents. The newer oral anticoagulants, such as factor Xa inhibitors and direct thrombin inhibitors, may have superior efficacy, but their safety profile must be studied further. Additionally, the use of mechanical prophylaxis continues to rise in popularity because of their ability to minimize bleeding complications. Future research should emphasize the development of prophylactic modalities that maximize efficacy while minimizing the risk of adverse events. PMID- 26055016 TI - A review of ligament augmentation with the InternalBraceTM: the surgical principle is described for the lateral ankle ligament and ACL repair in particular, and a comprehensive review of other surgical applications and techniques is presented. AB - This article reviews the surgical decision-making considerations when preparing to undertake an anatomic ligament repair with augmentation using the InternalBraceTM. Lateral ankle ligament stabilization of the Brostrom variety and ACL repair in particular are used to illustrate its application. The InternalBraceTM supports early mobilization of the repaired ligament and allows the natural tissues to progressively strengthen. The principle established by this experience has resulted in its successful application to other distal extremity ligaments including the deltoid, spring, and syndesmosis complex. Knee ligament augmentation with the InternalBraceTM has been successfully applied to all knee ligaments including anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (MCL), lateral collateral ligament (LCL), anterolateral ligament (ALL), and patellofemoral ligament (PFL). The surgical technique and early results will be reviewed including multi-ligament presentations. Upper limb experience with acromioclavicular (AC) joint augmentation and ulnar collateral ligament (UCL) repair of the elbow with the InternalBraceTM will also be discussed. This article points to a change in orthopaedic practice positioning reconstruction as a salvage procedure that has additional surgical morbidity and should be indicated only if the tissues fail to heal adequately after augmentation and repair. PMID- 26055017 TI - Repeat Manipulation Under Anesthesia For Persistent Stiffness After Total Knee Arthroplasty Achieves Functional Range of Motion. AB - Poor range of motion may decrease a patient's ability to participate in activities of daily living after total knee arthroplasty. Manipulation under anesthesia has been shown to improve range of motion; however, some patients have persistent stiffness even after manipulation. The goal of this study was to evaluate the outcomes and complications of patients who underwent a second manipulation under anesthesia for persistent stiffness after total knee arthroplasty. The review of surgical records of two joint arthroplasty surgeons identified 226 knees in 210 patients who underwent a manipulation under anesthesia for poor range of motion after total knee arthroplasty. Of these patients, 16 patients underwent a second manipulation under anesthesia. For patients undergoing two manipulations under anesthesia procedures, at latest follow up (mean 539 days), mean extension improved from 10.50 degrees to 2.50 degrees (p=0.001) and mean flexion improved from 87.50 degrees to 112.69 degrees (p=0.001) respectively. SF-12 scores were available for 12 of 16 knees with a mean score of 34.42. Two of 16 patients (12.5%) experienced a complication. Three of 16 (18.8%) patients who underwent a second manipulation required a revision arthroplasty procedure. In conclusion, a second manipulation under anesthesia can achieve functional range of motion that is sustained after total knee arthroplasty. PMID- 26055018 TI - The Use of an Electronic System for Soft Tissue Balancing in Primary Total Knee Arthroplasties: Clinical and Radiological Evaluation. AB - The eLibra(r) Dynamic Knee Balancing System (Synvasive Technology, Zimmer, Warsaw, IN) is an instrument designed to address the flexion stability during a TKA. It provides an objective measurement of the soft-tissue forces in the two compartments before the final cuts are made, allowing to obtain patient-specific rotational orientation of the femoral component. Between March 2010 and March 2012, the eLibra(r) system was used during the implantation of 75 TKAs in 75 patients at the author's institution. Preoperative and postoperative clinical assessment were evaluated using the Knee Society Score (KSS) and the Visual Analogical Scale (VAS). Radiographic evaluation was performed with weight-bearing radiographs in antero-posterior and lateral views in order to study the presence of radiolucencies. In a sample of 20 patients, representative of the population studied, the rotation of the femoral component was measured by two independent observers using the C-arm Cone Beam CT scan (XperCT/Allura FD20 angiography system; Philips, Best, Netherlands). At a mean follow-up of 42.3 months (29-54 months), three patients died from causes not related to the surgery. We had one case of aseptic loosening three years after surgery. None of the patients reported complications peri- or postoperatively. Clinical evaluation showed an improvement in KSS scoring, from preoperative means of 48.35 and 47.53 points for clinical and functional aspects, respectively, to postoperative means of 88.03 and 91.2 points, respectively (p<0.001 for both aspects). The current study demonstrates that the use of the eLibra(r) device is simple and reproducible. It could help surgeons objectively quantify ligament balance and perform soft tissue guided resection in a reproducible way, resulting in better post-operative stability and reduced complications. The use of the postoperative cone beam computed tomography (CBCT), in a representative sample of patients, revealed a specific and optimal orientation of the femoral component with a mean of 2.18 degrees of external rotation. PMID- 26055019 TI - What Outcome Metrics Do the Various Knee Rating Systems for Assessment of Outcomes Following Total Knee Arthroplasty Measure? A Systematic Review of Literature. AB - Multiple scoring systems have been developed for the assessment of outcomes following total knee arthroplasty. However, few studies have comprehensively evaluated each scoring system to analyze the various outcome variables and their individual weightings toward generations of the final score. A systematic search of four electronic databases were performed from January 1960 to August, 2013 to identify studies that reported on knee scores and to sub-categorize the outcomes measured based on subjective, objective, rehabilitative, and quality of life outcomes. We also evaluated the outcome metrics that each of these systems measured to identify the relative impact of these variables toward the final score. We identified 45 different outcome metrics in 46 rating scales. Pain (80%), stiffness (13%), and swelling (13%) were the three most common subjective outcomes measured in the scoring systems, while measurements of range-of-motion (57%), flexion contracture (39%), and coronal plane deformity (35%) were the most often reported objective outcome variables. Of all the variables measured, we found that pain (mean weighted score, 26 points; range, 0 to 50 points), range-of motion (mean weighted score, 11 points; range, 0 to 50 points), distance walked (mean weighted score, 7 points; range, 0 to 30 points), ability to climb stairs (mean weighted score, 6 points; range, 0 to 20 points), ability to rise from sitting position (mean weighted score, 4 points; range, 0 to 20 points), and presence of a flexion contracture (mean weighted score, 4 points, range, 0 to 20 points) had the greatest impact on the final score standardized to 100 points. Currently, few rating scales exist that assess all aspects of functional, rehabilitative, and quality of life outcomes including patient satisfaction within the realms of a single scoring system. Further research is needed to determine the optimal combination and weightings of the individual outcomes metrics to better evaluate overall outcomes following total knee arthroplasty and to develop a more comprehensive scoring system. PMID- 26055020 TI - Groin Pain in Athletes: A Review of Diagnosis and Management. AB - INTRODUCTION: Groin pain is a common symptom in athletes, particularly in sports requiring sudden changes in speed and direction and those involving kicking. Despite a high prevalence of groin pain in this patient cohort, the diagnosis and management of the underlying pathological processes remains a challenge for surgeons and radiologists alike. AIM: The aim of this paper is to review the imaging findings and management of the common pathological processes which produce groin pain in athletes. MATERIALS AND METHODS: The anatomy of the groin region will be defined as a basis for further discussion. The common pathological processes underlying groin pain such as adductor dysfunction, rectus abdominus injury, osteitis pubis, and femuro-acetabular impingement will then be reviewed and correlating radiological imaging findings presented. Current management options will also be considered. CONCLUSION: This paper will aid surgeons and radiologists in navigating the challenging diagnostic and management dilemma of groin pain in athletes. PMID- 26055021 TI - Robotic-Arm Assisted Surgery in Total Hip Arthroplasty. AB - Complications following total hip arthroplasty (THA), such as dislocation, component loosening and wear, continue to be common indications for revision surgery. Multiple studies have attributed some of these problems to poor acetabular cup alignment and placement outside of the purported radiographic safe zone. In addition, it has been shown that conventional manually performed acetabular cup placement may not lead to optimal alignment, regardless of surgical experience. Additionally, incorrect leg length and offset can lead to dissatisfaction and instability. Therefore, robotic-arm assisted surgery has been introduced to improve accuracy of cup placement and leg length, and to offset with the aim of reducing the risk of hip instability and improving satisfaction after primary THA. Our aim was to prospectively review the use of robotic-arm assisted surgery in 224 patients and to assess whether the pre-operatively determined radiographic targets were achieved post-operatively and the proportion of acetabular cups outside of the safe zone. Pre-determined anteversion and inclination were 15 and 40 degrees, respectively. Our results have shown that the use of robotic-arm assisted surgery resulted in a post-operative mean inclination of 40 degrees (range, 34 to 51 degrees) and a mean anteversion of 16 degrees (range, 9 to 25 degrees). Ninety-nine percent of the patients remained within the pre-designated safe zone. Evidence has shown that robotic-arm assisted surgery may have improved accuracy in cup placement when compared to conventional surgery and possibly to computer-assisted surgery. When compared to the literature on robotic-arm assisted surgery, our results were comparable. We believe that this surgical technique may aid in reducing post-operative THA complications, such as aseptic loosening and dislocations, but further prospective studies are needed to evaluate clinical outcomes and long-term results. PMID- 26055022 TI - Rating Systems to Assess the Outcomes After Total Knee Arthroplasty. AB - INTRODUCTION: To assess the success of a total knee arthroplasty (TKA), scoring systems have been developed to provide a straightforward method of evaluating the outcomes of patients following surgery. Fully evaluating these outcomes is a challenging and time consuming task, and these simplistic measures often do not provide a complete picture of a patient's recovery. Therefore, we evaluated different scoring systems to determine the most effective method of assessing the outcomes of patients undergoing total knee arthroplasty. MATERIALS AND METHODS: We evaluated all knee scoring systems currently available in literature, and a total of 46 questionnaires met our inclusion and exclusion criteria. We then identified all the metrics assessed in the questionnaires (n=48) and subdivided them into objective, subjective, rehabilitative, and quality of life outcome measures. We identified the three most commonly referenced questionnaires (the Knee Society Scores, the Knee Osteoarthritis and Outcomes Scores, and the Western Ontario and McMaster Score-WOMAC) and assessed multiple permutations of these with other scoring systems to identify the combinations that would most comprehensively and efficiently evaluate the outcomes of patients undergoing TKA. RESULTS: Of the 48 metrics, we identified four subjective, eight objective, 20 rehabilitation, and 16 quality of life metrics. On permutation of the three most referenced scoring systems, the KSS and the KOOS together yielded the greatest coverage of the above metrics (79%). When the KSS, KOOS, and WOMAC, respectively, were combined with the Lower Extremity Function Scale (LEFS) and Short Form 36 (SF-36), they yielded 77, 73, and 60% coverage of the metrics and 35, 39, and 37% redundancy, respectively. CONCLUSION: Surgeons and researchers have attempted to fully evaluate the outcomes of patients undergoing TKA. The proposed combinations may provide a more comprehensive way to cost-effectively evaluate outcomes. Further analysis is required before attempting to create newer knee scoring systems. PMID- 26055023 TI - Efficacy of Different Rotator Cuff Repair Techniques. AB - The purpose of this review article is to describe the currently used techniques for rotator cuff repair and after treatment. The literature was searched for the different surgical techniques and additional treatment including: [1] full arthroscopic and arthroscopic assisted rotator cuff repair, [2] acromioplasty as an additional treatment to rotator cuff repair, [3] the use of plasma rich platelets (PRP) after rotator cuff repair, [4] the single and double row fixation techniques, [5] long head of the biceps brachii tenotomy or tenodesis with rotator cuff repair, [6] scaffolds in rotator cuff surgery, and [7] early motion or immobilization after rotator cuff repair. The rationale, the results, and the scientific evidence were reported for the eligible procedures. PMID- 26055024 TI - Standardized Questionnaire Time Burden for Practitioners and Patients. AB - INTRODUCTION: Many questionnaires are used to assess patient-reported outcomes, but there are few studies assessing the time to complete these questionnaires. The purpose of this study was to: (1) evaluate how much time it takes to complete the most commonly used patient-reported outcome questionnaires; (2) calculate the potential variation for time of completion; and (3) assess the potential role of demographics. MATERIALS AND METHODS: After literature review, nine different questionnaires were chosen based on the frequency of citation. Each patient was given one questionnaire and time to complete was recorded. Mean times were compared and statistical analysis was performed on patients based on age>=55 years, gender, and education level. RESULTS: The mean time of completion for each questionnaire is listed from shortest to longest: University of California Los Angeles (UCLA) activity score, Lower Extremity Activity Scale (LEAS), Hospital for Special Surgery Score (HSS), Lower Extremity Functional Scale (LEFS), Oxford Knee Score-12 (OKS-12), Knee Society Scores (KSS), Western Ontario and McMaster Universities Arthritis Index (WOMAC), Short Form-36 (SF-36), and the Knee Injury and Osteoarthritis Outcome Score (KOOS). The coefficients of variation were smallest in SF-36 and WOMAC while it was the largest in the UCLA activity score. Age of >=55 years was associated with a longer time to complete the questionnaires. There was no association found between gender or education level. DISCUSSION: It is possible that if it takes longer to complete certain questionnaires, then the answers given may not accurately reflect the patient's condition. Future studies should focus on the accuracy of the respondents' answers to each questionnaire as well as the accuracy after filling out multiple questionnaires at a single patient office visit. PMID- 26055025 TI - Constrained Implants in Total Knee Replacement. AB - Total knee replacement (TKR) is a successful procedure for pain relief and functional restoration in patients with advanced osteoarthritis. The number of TKRs is increasing, and this has led to an increase in revision surgeries. The key to long-term success in both primary and revision TKR is stability, as well as adequate and stable fixation between components and underlying bone. In the vast majority of primary TKRs and in some revision cases, a posterior cruciate retaining or a posterior cruciate substituting device can be used. In some primary cases with severe deformity or ligamentous instability and in most of the revision cases, a more constrained implant is required. The purpose of this paper is to review the literature concerning the use of condylar constrained knee (CCK) and rotating hinge (RH) implants in primary and revision cases focusing on the indications and results. According to this review, although excellent and very good results have been reported, there are limitations of the existing literature concerning the indications for the use of constrained implants, the absence of long-term results, and the limited comparative studies. PMID- 26055026 TI - Up-to-date Review and Cases Report on Chondral Defects of Knee Treated by ACI Technique: Clinical-instrumental and Histological Results. AB - The limited regenerative potential of a full thickness defect of the knee joint cartilage has certainly conditioned the development of therapeutic strategies that take into account all the aspects of the healing process. The most common treatments to repair chondral and osteochondral lesions are bone marrow stimulation, osteochondral autograft transplantation, autologous matrix-induced chondrogenesis, and autologous chondrocyte implantation. We like to emphasize the difference between a chondral and an osteochondral lesion because the difference is sometimes lost in the literature. In the context of treatment of injuries of the knee joint cartilage, the second-generation autologous chondrocyte transplant is a consolidated surgical method alternative to other techniques. Our experience with the transplantation of chondrocytes has had exceptional clinical results. We report 2 complete cases of a group of 22 in knee and ankle. These 2 cases had histological and instrumental evaluation. We cannot express conclusions, but can only make considerations, stating that, with the clinical functional result being equal, we obtained an excellent macroscopic result in both cases of second look. Autologous chondrocyte implantation (ACI) is a multiple surgical procedure with expensive chondrocyte culture, but even with this limitation, we think that it must be the choice in treating chondral lesions, especially in young patients. PMID- 26055027 TI - Treatment of Tendon Injuries of the Lower Limb with Growth Factors Associated with Autologous Fibrin Scaffold or Collagenous Scaffold. AB - Tendon injuries are an increasing problem in orthopedics as we are faced with a growing demand in sports and recreation and an aging population. Tendons have poor spontaneous regenerative capacity, and often, complete recovery after injury is not achieved. Once injured, tendons do not completely re-acquire the biological and biomechanical properties of normal tendons due to the formation of adhesions and scarring, and often these abnormalities in the arrangement and structure are risk factors for re-injury. These problems associated with the healing of tendon injuries are a challenge for clinicians and surgeons. This study examined 9 cases of subcutaneous injuries including quadriceps tendon (2 cases), patellar tendon (1 case), and Achilles tendon (6 cases), incomplete and complete, treated consecutively. The surgical technique has provided, as appropriate, the termino-terminal tenorraphy, techniques of plastics of rotation flap, reinsertion with suture anchors, and in one case tendon augmentation with cadaver tissue. In cases where we needed mechanical support to the suture, we used preloaded growth factors on porcine collagen scaffold; in cases where we needed only one biological support, we used fibrin scaffold. PMID- 26055028 TI - Can Sequentially-irradiated and Annealed Highly Cross-linked Polyethylene Inserts Thinner than Eight-millimeters Be Utilized in Total Knee Arthroplasty? AB - The routine use of highly cross-linked ultra-high molecular weight polyethylene (UHMWPE) has remained controversial secondary to the possibility of decreased material properties when compared to conventional UHMWPE. The aim of the present study was to evaluate if thin, sequentially-irradiated, and annealed highly cross linked UHMWPE tibial inserts would have improved wear properties, while maintaining mechanical integrity, compared to conventional UHMWPE during biomechanical testing under aligned and malaligned conditions. Polyethylene inserts (4.27 and 6.27 mm) manufactured from GUR 1020-UHMWPE were cyclically loaded to analyze for wear. All wear scars were visually examined after loading using scanning electron microscopy (SEM). Volume loss was plotted versus cycle count with linear regression analysis yielding wear rates. There was no statistical difference in wear between both thicknesses for all testing conditions. During aligned condition testing, the volumetric wear rate for sequentially-irradiated and annealed polyethylene thicknesses of 4.27 and 6.27 mm was 4.0 and 4.4 mm3/million cycles; and during malaligned conditions, it was 13.9 and 15.1 mm3/million cycles. For conventional polyethylene during aligned conditions, the volumetric wear rate was 33.0 and 22.8 mm3/million cycles; and during malaligned conditions it was 50.0 and 50.8 mm3/million cycles. By SEM evaluation, condylar wear surfaces for conventional and sequentially-irradiated and annealed polyethylene displayed surface ripples typical of adhesive wear. There were no observed visible differences between the wear scars for conventional compared to sequentially-irradiated and annealed polyethylene with no evidence of fatigue failure. This study demonstrated no differences between polyethylenes with thicknesses of 4.27 and 6.27 mm. This strengthens the conclusion that sequentially-irradiated and annealed highly cross-linked UHMWPE can be utilized in total knee arthroplasty. The successful wear properties of 4.27 mm liners could mean that smaller tibial resections leading to bone stock preservation could be utilized in patients undergoing total knee arthroplasty, although further in-vivo studies are needed. PMID- 26055029 TI - In-Hospital Mortality Following Open and Closed Long Bone Fracture: A Comparative Study. AB - BACKGROUND: Open fracture is a serious orthopaedic injury that can lead to significant patient morbidity and mortality. There is limited data on the mortality risk for open compared to closed long bone fracture. METHODS: The Nationwide Inpatient Sample was used to identify all patients who were admitted with a long bone fracture in the United States between 1998 and 2010. Cox proportional hazards regression modeling was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of mortality. RESULTS: After adjusting for age, gender, race, insurance, and comorbidities, the HR of mortality was 2.89 (95% CI, 2.56-3.28; p<0.001) for open compared to closed fracture. Stratified by anatomical site, the HR of mortality for open compared to fracture was 3.43 for femur (95% CI, 2.78-4.23; p<0.001), 2.81 for tibia or fibula (95% CI, 2.17-3.64; p<0.001), 2.54 for humerus (95% CI, 1.81-3.56; p<0.001), and 1.56 for radius or ulna (95% CI, 1.10-2.23; p=0.014). CONCLUSIONS: This data suggests that open fracture carries a worse prognosis compared to closed fracture at the same anatomical site. PMID- 26055030 TI - Molded Articulating Cement Spacers for Two-Stage Treatment of Infected THA and TKA. AB - Articulating spacers have been reported to promote greater range of motion, preserve bone, facilitate reimplantation, and enhance functional recovery, as well as provide a vehicle for local administration of antibiotics. The purpose of this study was to review patients treated at our center for deep hip and knee infection with two-staged exchange using molded, articulating antibiotic-laden cement spacers following debridement. A query of our practice registry revealed 84 patients (84 hips) and 177 patients (182 knees) diagnosed with deep infection after THA and TKA respectively, and treated with two-staged exchange using molded articulating cement spacers. Mean follow-up was three years in both groups. Second-stage reimplantation was accomplished in 81 hips, and reinfection occurred in 11 of those (14%), with three responding to a single irrigation and debridement (I&D) procedure, one undergoing two I&Ds, one chronically infected diabetic patient treated with one-stage exchange to cemented components, five patients undergoing multiple procedures including repeat two-staged exchange in four, and one patient declining further treatment. Harris hip score at most recent averaged 69. Second-stage reimplantation was accomplished in 177 knees, and reinfection occurred in 28 of those (16%). Range of motion improved from 93 degrees preoperatively to 101 degrees at most recent, Knee Society clinical scores improved from 46 to 76, and functional scores improved from 32 to 47. Treatment of deep infection after total joint arthroplasty using molded, articulating antibiotic-laden acrylic cement spacers was successful in eradicating infection in 83% of hips (70 of 84) and 82% of knees (149 of 182) at an average of three years after reimplantation. PMID- 26055031 TI - Patient Compliance with Preoperative Disinfection Protocols for Lower Extremity Total Joint Arthroplasty. AB - INTRODUCTION: Infection after total joint arthroplasty has been most attributed to bacterial wound contamination from skin flora. To address this, the CDC recommends bathing with an antiseptic agent the night prior to the operative day. However, despite these measures, the incidence of infections has not been reduced markedly. It is important to have measures in place to ensure proper patient education about infections and disinfection protocols to optimize compliance. Our purpose was to evaluate compliance with preoperative disinfection protocols at our institution and to identify measures which may improve adherence. MATERIALS AND METHODS: Between 2007 and 2011, we reviewed a database at our institution for all patients who underwent primary or revision total hip (n=2,458) and knee (n=2,293) arthroplasty. All of these patients were instructed to follow a chlorhexidine cloth disinfection protocol at the time of surgical scheduling or during their preoperative evaluation. To verify compliance, patients were instructed to remove adhesive stickers from the cloth packages at the time of disinfection and to affix them to the instruction sheet presented on the day of surgery. This was documented in the patient medical records. A database was generated to identify those patients who were compliant (n=1,035) or non compliant (n=3,716). Following this period, if patients did not use chlorhexidine as instructed, the staff ensured one application was received pre-operatively. RESULTS: Approximately 78% of patients (3,716 out of 4,751 patients) were noncompliant. When evaluating the demographic between the two groups, we found that age and gender distributions were not significantly different. DISCUSSION: While preoperative decolonization protocols may reduce surgical site infections, their efficacy is limited by patient compliance and comprehension. Providing patients with thorough instructions about preoperative disinfection protocols and information about the importance of infection burden is more likely to improve patient adherence. PMID- 26055032 TI - Selective Patellar Resurfacing: A Literature Review. AB - Whether to resurface the patella during total knee arthroplasty (TKA) remains a controversial topic among orthopaedic surgeons, and we are still no closer to identifying which technique provides the best outcomes. Advocates for patellar resurfacing have adopted this technique in order to avoid the potential for post operative anterior knee pain that may be associated with the need for future reoperations. However, reports have indicated that patellar resurfacing may be associated with increased complications such as patellar implant loosening, fracture, osteonecrosis, tendon injury, wear, and instability. More recently, studies have highlighted possible patient-specific and surgical factors, such as weight, body mass index, degree of chondromalacia, and patellar alignment, which may influence functional outcomes, and thus surgical decision making. However, currently there are minimal clear guidelines to help surgeons decide whether or not to resurface the patella. Our aim was to assess the current literature and present the evidence for and against patellar resurfacing, as well as to assess factors that may aid in deciding which procedure is more suitable for the specific patient. Ultimately, we believe there is a need for further research to identify the most appropriate candidates for patellar resurfacing. PMID- 26055033 TI - Role of EVICEL Fibrin Sealant to Assist Hemostasis in Cranial and Spinal Epidural Space: A Neurosurgical Clinical Study. AB - A variety of techniques have been used to stop venous bleeding from the cranial and spinal epidural space. These generally consist of packing with oxidized regenerated cellulose, fibrillar collagen, and so forth, and in cranial surgery, tack-up sutures. Bipolar coagulation may also be used to control bleeding from spinal venous plexus, but it may bear the risk of healthy nervous tissue injury: dissipation of heat from the tips of the bipolar forceps may induce thermal injury to adjacent neural structures. Quick and safe hemostasis reduces the duration of surgery. Efficient control of bleeding is also a prerequisite for the realization of the planned therapeutic procedure, that is, the result of surgery, and can thereby reduce perioperative morbidity. Fibrin sealant is safely used to increase hemostasis and to treat cerebrospinal leakage. Between January 2014 and March 2015, the authors used injection of fibrin sealant (EVICEL(r), Johnson & Johnson Wound Management, Somerville, NJ) into the cranial and spinal epidural space to assist in hemostasis in 97 patients. EVICEL injection was used in 81 cases of cranial surgery and 16 cases of spinal surgery. When the venous bleeding continued from the epidural space after packing with classical hemostatic agents, fibrin sealant was used to stop venous bleeding. When arterial bleeding was present, fibrin sealant was not used. In all cases, the results were judged to be excellent with stoppage of epidural bleeding, or good with mild persistent oozing. During the 10-minute observation period, no patients treated with EVICEL required additional hemostatic measures. No complications related to the fibrin glue were encountered. PMID- 26055034 TI - Minimally Invasive Lateral Interbody Fusion in the Treatment of Scoliosis Associated with Myelomeningocele. AB - INTRODUCTION: Surgical correction of spinal deformity in myelomeningocele is associated with high rates of pseudarthrosis and implant failure. The anterior fusion is traditionally a wide exposure from the thorax to the sacrum. We report minimally invasive lateral interbody fusion (MILIF) to address the issue of fusion between vertebrae with marginal posterior elements while minimizing the morbidity of an open approach. MATERIALS AND METHODS: We performed a single center, retrospective review of patients with myelomeningocele and severe scoliosis who underwent posterior spinal fusion (PSF) and staged MILIF for anterior fusion of the thoracolumbar/lumbar spine. We identified four patients with high risk of curve progression who met the following inclusion criteria: diagnosis of myelomeningocele, severe scoliosis (Cobb angle>70 degrees ), PSF using greater than 80% pedicle screws, age greater than 10 years at time of surgery, and a minimum follow-up of two years. Radiographic, clinical, and complication data were reviewed. RESULTS: All four patients achieved fusion (100%). The average age at index surgery was 12.8 years (range, 11-16) and follow up was 3.2 years (range, 2-4.9). The average preoperative coronal Cobb angle measured 111 degrees (range, 74-140 degrees ). The average postoperative Cobb angle at follow-up measured 37 degrees (range, 23-42 degrees ). The MILIF procedure was performed an average of six months after the index procedure. After anterior fusion, all patients spent one day in the pediatric ICU and an average of 5.5 days in the hospital (range, 4-7). One patient (25%) developed a postoperative wound infection after PSF which required irrigation and debridement in the operating room. CONCLUSION: MILIF as an adjunct to posterior spinal fusion for severe scoliosis associated with myelomeningocele may provide acceptable fusion rates, curve correction, maintenance of correction at mid-term follow-up, and be associated with less morbidity than the traditional anterior approach. PMID- 26055035 TI - A Clinico-pathologic Study of Oxidized Cellulose as Topical Hemostatic Agent in Neurosurgery. AB - Hemostasis is extremely important in neurosurgical procedures to prevent major postoperative bleedings and their catastrophic consequences. Emoxicel TAF Retilight (Bioster, a.s., Czech Republic) is a sterile, resorbable, hemostatic reticulum, mainly used to stop capillary and venous bleeding. The textile form of the hemostatic material allows, in several cases, perfect adjustment to the varied shape of the surgical cavities and of the epidural space to which it adheres when wet. Hemostatic effect is rapid, and complete hemostasis can be achieved in several minutes after application. This topical hemostatic agent is biocompatible, biodegradable, and highly resorbable. It has a hemostatic and antimicrobic effect. The main aim of this study was to verify the efficacy, broadness of use, and safety of this topical hemostatic in neurosurgical procedures. A total of 43 cases were included, 18 cranial and 25 spinal, and in only one case a postoperative epidural bleeding was reported. A histopathologic study of the hemostatic was performed. No allergic reactions were reported. Emoxicel was useful not only in stopping minor bleeding, but also for bleeding prevention in the postoperative period. PMID- 26055036 TI - [Inability to walk in a 41-year-old man]. PMID- 26055037 TI - [ANCA vasculitis: Is it time to change the standard of care for maintenance?]. PMID- 26055038 TI - A Novel Single-Nucleotide Deletion (c.1020delA) in NSUN2 Causes Intellectual Disability in an Emirati Child. AB - Intellectual disability (ID) is a major public health burden on most societies with significant socioeconomic costs. It has been shown that genetic mutations in numerous genes are responsible for a proportion of hereditary forms of ID. NOP2/Sun transfer RNA (tRNA) methyltransferase family member 2 encoded by NSUN2 gene is a highly conserved protein and has been shown to cause autosomal recessive ID type 5 (MRT5). In this study, we recruited an Emirati consanguineous family with a patient diagnosed with ID. Whole-exome sequencing revealed a homozygous variant c.1020delA in NSUN2 gene. The variants segregated in an autosomal recessive mode of inheritance in the family. This variant is novel and causes a frameshift and premature stop codon. At the messenger RNA (mRNA) level, relative expression analysis showed a decreased level of NSUN2 mRNA in the affected child compared to a healthy individual. Mutation prediction analysis and clinical investigation confirmed the pathogenic nature of the identified variant. We therefore conclude that c.1020delA mutation in NSUN2 is most likely the cause of ID in our patient. PMID- 26055039 TI - Impact of tonsillectomy combined with steroid pulse therapy on immunoglobulin A nephropathy depending on histological classification: a multicenter study. AB - BACKGROUND: In addition to corticosteroids and inhibition of the renin angiotensin-aldosterone system, tonsillectomy with steroid pulse therapy (TSP) may have a beneficial impact on the clinical course of IgA nephropathy (IgAN). However, there is still much uncertainty regarding the indications for therapy, treatment protocol, and therapeutic options for IgAN. METHODS: In this multicenter retrospective cohort study, we enrolled 284 patients with biopsy proven IgAN who received TSP or corticosteroid therapy or conservative therapy. The effects of TSP on clinical remission (CR) were evaluated after a median follow-up period of 4.1 years in relation to histological classifications. RESULTS: Among the 284 participants, 161 patients received TSP. During the observation time, 141 patients (49.6%) achieved CR, with a median time to remission of 397 days. In multivariate Cox regression analyses, TSP had an impact on achieving CR in only the group with histological grade 3 defined as glomerulosclerosis, crescent formation or adhesion to Bowman's capsule in 10-30% of all biopsied glomeruli, or mild cellular infiltration in the interstitium (hazard ratio (HR) 4.29, 95% confidence interval (95%CI) 1.88-11.19, P < 0.001). TSP independently contributed to a higher incidence of CR, particularly in the patient group showing evident mesangial hypercellularity (HR 2.54, 95%CI 1.38 5.08, P = 0.002). CONCLUSIONS: TSP may have a beneficial effect on the clinical course in IgAN patients with mild to moderate glomerular and interstitial lesions, particularly with distinct mesangial cell proliferation. PMID- 26055040 TI - Death by band-aid: fatal misuse of transdermal fentanyl patch. AB - We present a case of fatal intoxication by the application of a transdermal fentanyl patch upon a superficial bleeding abrasion of a 2-year-old girl. The grandmother discovered the body of the child in bed at approximately 7 a.m. External examination revealed a properly developed, nourished, and hydrated child, with some vomit in the nostrils and inside the mouth. There was no evidence of trauma besides small contusions and abrasions on the knees, with a patch placed over the largest abrasion. Closer inspection revealed that this was transdermal fentanyl patch. Internal examination and microscopic analysis revealed regurgitation of stomach content, cerebral and pulmonary edema, and liver congestion. Toxicology analysis revealed trace levels of fentanyl in the blood just above the limit of detection (2 ng/mL), while concentrations in the urine, liver, and kidney were approximately 102, 28, and 10 ng/mL, respectively. Investigation discovered that the child injured her knee while playing the evening before. The grandmother applied the patch to cover the injury, unaware that she had used a fentanyl transdermal patch instead of simple band-aid. Although fatal intoxications are uncommon among young children in high-income countries, it is of major interest to raise awareness of such events especially since a great majority of these are preventable. The presented case points at the need for more thorough education of users and more strict rules in prescribing and handling of this potent medicine. As well, we find this case to be a useful contribution to the evaluation of postmortem fentanyl concentrations in fatal intoxication in a small child. PMID- 26055041 TI - Electrochemical and microbial monitoring of multi-generational electroactive biofilms formed from mangrove sediment. AB - Electroactive biofilms were formed from French Guiana mangrove sediments for the analysis of bacterial communities' composition. The electrochemical monitoring of three biofilm generations revealed that the bacterial selection occurring at the anode, supposedly leading microbial electrochemical systems (MESs) to be more efficient, was not the only parameter to be taken into account so as to get the best electrical performance (maximum current density). Indeed, first biofilm generations produced a stable current density reaching about 18 A/m(2) while second and third generations produced current densities of about 10 A/m(2). MES bacterial consortia were characterized thanks to molecular biology techniques: DGGE and MiSeq(r) sequencing (Illumina(r)). High-throughput sequencing data statistical analysis confirmed preliminary DGGE data analysis, showing strong similarities between electroactive biofilms of second and third generations, but also revealing both selection and stabilization of the biofilms. PMID- 26055044 TI - Brain changes in T1DM--a microvascular complication? PMID- 26055047 TI - Celastrol identified as a leptin sensitizer and potential novel treatment for obesity. PMID- 26055048 TI - Porous one-dimensional Mo2C-amorphous carbon composites: high-efficient and durable electrocatalysts for hydrogen generation. AB - Porous one-dimensional Mo2C-amorphous carbon composites, fabricated by in situ solid state reactions, are exhibited as effective and high-performance electrocatalysts towards the hydrogen evolution reaction (HER). The morphological and structural characteristics of the Mo2C based electrocatalysts were analyzed by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). The analyses showed that they had various advantages for the HER, including a high crystallinity, porous and tubular characteristics and good conductivity. The porous one-dimensional Mo2C-amorphous carbon composites with a larger content of Mo2C and moderate thickness of the carbon layers exhibited superior catalytic activities for HER to most of the Mo2C based electrocatalysts recently reported. PMID- 26055046 TI - Bariatric and metabolic surgery: a shift in eligibility and success criteria. AB - The obesity epidemic, combined with the lack of available and effective treatments for morbid obesity, is a scientific and public health priority. Worldwide, bariatric and metabolic surgeries are increasingly being performed to effectively aid weight loss in patients with severe obesity, as well as because of the favourable metabolic effects of the procedures. The positive effects of bariatric surgery, especially with respect to improvements in type 2 diabetes mellitus, have expanded the eligibility criteria for metabolic surgery to patients with diabetes mellitus and a BMI of 30-35 kg/m(2). However, the limitations of BMI, both in the diagnosis and follow-up of patients, need to be considered, particularly for determining the actual adiposity and fat distribution of the patients following weight loss. Understanding the characteristics shared by bariatric and metabolic surgeries, as well as their differential aspects and outcomes, is required to enhance patient benefits and operative achievements. For a holistic approach that focuses on the multifactorial effects of bariatric and metabolic surgery to be possible, a paradigm shift that goes beyond the pure semantics is needed. Such a shift could lead to profound clinical implications for eligibility criteria and the definition of success of the surgical approach. PMID- 26055050 TI - Wolfgang Kohler's The Mentality of Apes and the animal psychology of his time. AB - In 1913, the Anthropoid Station for psychological and physiological research in chimpanzees and other apes was founded by the Royal Prussian Academy of Sciences (Berlin) near La Orotava, Tenerife. Eugene Teuber, its first director, began his work at the Station with several studies of anthropoid apes' natural behavior, particularly chimpanzee body language. In late 1913, the psychologist Wolfgang Kohler, the second and final director of the Station, arrived in Tenerife. During his stay in the Canary Islands, Kohler conducted a series of studies on intelligent behavior in chimpanzees that would become classics in the field of comparative psychology. Those experiments were at the core of his book Intelligenzprufungen an Menschenaffen (The Mentality of Apes), published in 1921. This paper analyzes Kohler's experiments and notions of intelligent behavior in chimpanzees, emphasizing his distinctly descriptive approach to these issues. It also makes an effort to elucidate some of the theoretical ideas underpinning Kohler's work. The ultimate goal of this paper is to assess the historical significance of Kohler's book within the context of the animal psychology of his time. PMID- 26055049 TI - Abeta25-35 Suppresses Mitochondrial Biogenesis in Primary Hippocampal Neurons. AB - Mitochondrial biogenesis is involved in the regulation of mitochondrial content, morphology, and function. Impaired mitochondrial biogenesis has been observed in Alzheimer's disease. Amyloid-beta (Abeta) has been shown to cause mitochondrial dysfunction in cultured neurons, but its role in mitochondrial biogenesis in neurons remains poorly defined. AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) are key energy-sensing molecules regulating mitochondrial biogenesis. In addition, peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC-1alpha), the master regulator of mitochondrial biogenesis, is a target for SIRT1 deacetylase activity. In this study, we investigated the effects of Abeta25 35 on mitochondrial biogenesis in cultured hippocampal neurons and the underlying mechanisms. In primary hippocampal neurons, we found that 24-h incubation with Abeta25-35 suppressed both phosphorylations of AMPK and SIRT1 expression and increased PGC-1alpha acetylation expression. In addition, Abeta25-35 also resulted in a decrease in mitochondrial DNA copy number, as well as decreases in the expression of mitochondrial biogenesis factors (PGC-1alpha, NRF 1, NRF 2, and Tfam). Taken together, these data show that Abeta25-35 suppresses mitochondrial biogenesis in hippocampal neurons. Abeta25-35-induced impairment of mitochondrial biogenesis may be associated with the inhibition of the AMPK-SIRT1-PGC-1alpha pathway. PMID- 26055051 TI - Effect of a mindfulness program on stress, anxiety and depression in university students. AB - Two of the problems that currently affect a large proportion of university students are high levels of anxiety and stress experienced in different situations, which are particularly high during the first years of their degree and during exam periods. The present study aims to investigate whether mindfulness training can bring about significant changes in the manifestations of depression, anxiety, and stress of students when compared to another group undergoing a physical activity program and a control group. The sample consisted of 125 students from the Bachelor of Education Program. The measuring instrument used was the Abbreviated Scale of Depression, Anxiety and Stress (DASS-21). The results indicate that the effects of reducing the identified variables were higher for the mindfulness group than for the physical education group and for the control group F(2) = 5.91, p = .004, eta2 = .106. The total scores for all variables related to the mindfulness group decreased significantly, including an important stress reduction t(29) = 2.95, p = .006, d = .667. Mindfulness exercises and some individual relaxing exercises involving Physical Education could help to reduce manifestations of stress and anxiety caused by exams in students. PMID- 26055052 TI - Arrestins: Critical Players in Trafficking of Many GPCRs. AB - Arrestins specifically bind active phosphorylated G protein-coupled receptors (GPCRs). Receptor binding induces the release of the arrestin C-tail, which in non-visual arrestins contains high-affinity binding sites for clathrin and its adaptor AP2. Thus, serving as a physical link between the receptor and key components of the internalization machinery of the coated pit is the best characterized function of non-visual arrestins in GPCR trafficking. However, arrestins also regulate GPCR trafficking less directly by orchestrating their ubiquitination and deubiquitination. Several reports suggest that arrestins play additional roles in receptor trafficking. Non-visual arrestins appear to be required for the recycling of internalized GPCRs, and the mechanisms of their function in this case remain to be elucidated. Moreover, visual and non-visual arrestins were shown to directly bind N-ethylmaleimide-sensitive factor, an important ATPase involved in vesicle trafficking, but neither molecular details nor the biological role of these interactions is clear. Considering how many different proteins arrestins appear to bind, we can confidently expect the elucidation of additional trafficking-related functions of these versatile signaling adaptors. PMID- 26055054 TI - Rhodopsin Trafficking and Mistrafficking: Signals, Molecular Components, and Mechanisms. AB - Rhodopsin is a seven-transmembrane G protein-coupled receptor (GPCR) and is the main component of the photoreceptor outer segment (OS), a ciliary compartment essential for vision. Because the OSs are incapable of protein synthesis, rhodopsin must first be synthesized in the inner segments (ISs) and subsequently trafficked across the connecting cilia to the OSs where it participates in the phototransduction cascade. Rapid turnover of the OS necessitates a high rate of synthesis and efficient trafficking of rhodopsin to the cilia. This cilia targeting mechanism is shared among other ciliary-localized GPCRs. In this review, we will discuss the process of rhodopsin trafficking from the IS to the OS beginning with the trafficking signals present on the protein. Starting from the endoplasmic reticulum and the Golgi apparatus within the IS, we will cover the molecular components assisting the biogenesis and the proper sorting. We will also review the confirmed binding and interacting partners that help target rhodopsin toward the connecting cilium as well as the cilia-localized components which direct proteins into the proper compartments of the OS. While rhodopsin is the most critical and abundant component of the photoreceptor OS, mutations in the rhodopsin gene commonly lead to its mislocalization within the photoreceptors. In addition to covering the trafficking patterns of rhodopsin, we will also review some of the most common rhodopsin mutants which cause mistrafficking and subsequent death of photoreceptors. Toward the goal of understanding the pathogenesis, three major mechanisms of aberrant trafficking as well as putative mechanisms of photoreceptor degeneration will be discussed. PMID- 26055055 TI - Intracellular Trafficking of Neuropeptide Y Receptors. AB - The multireceptor multiligand system of neuropeptide Y receptors and their ligands is involved in the regulation of a multitude of physiological and pathophysiological processes. Specific expression patterns, ligand-binding modes, and signaling properties contribute to the complex network regulating distinct cellular responses. Intracellular trafficking processes are important key steps that are regulated in context with accessory proteins. These proteins exert their influence by interacting directly or indirectly with the receptors, causing modification of the receptors, or operating as scaffolds for the assembly of larger signaling complexes. On the intracellular receptor faces, sequence specific motifs have been identified that play an important role in this process. Interestingly, it is also possible to influence the receptor internalization by modification of the peptide ligand. PMID- 26055053 TI - Regulation of GPCR Trafficking by Ubiquitin. AB - G protein-coupled receptor (GPCR)-promoted signaling mediates cellular responses to a variety of stimuli involved in diverse physiological processes. In addition, GPCRs are also the largest class of target for many drugs used to treat a variety of diseases. Despite the role of GPCR signaling in health and disease, the molecular mechanisms governing GPCR signaling remain poorly understanding. Classically, GPCR signaling is tightly regulated by GPCR kinases and beta arrestins, which act in a concerted fashion to govern GPCR desensitization and also GPCR trafficking. Ubiquitination has now emerged as an important posttranslational modification that has multiple roles, either directly or indirectly, in governing GPCR trafficking. Recent studies have revealed a mechanistic link between GPCR phosphorylation, beta-arrestins, and ubiquitination. Here, we review recent developments in our understanding of how ubiquitin regulates GPCR trafficking within the endocytic pathway. PMID- 26055056 TI - Insights into Serotonin Receptor Trafficking: Cell Membrane Targeting and Internalization. AB - Serotonin receptors (5-HTRs) mediate both central and peripheral control on numerous physiological functions such as sleep/wake cycle, thermoregulation, food intake, nociception, locomotion, sexual behavior, gastrointestinal motility, blood coagulation, and cardiovascular homeostasis. Six families of the G-protein coupled receptors comprise most of serotonin receptors besides the conserved 5 HT3R Cys-loop type which belongs to the family of Cys-loop ligand-gated cation channel receptors. Many of these receptors are targets of pharmaceutical drugs, justifying the importance for elucidating their coupling, signaling and functioning. Recently, special interest has been focused on their trafficking inside cell lines or neurons in conjunction with their interaction with partner proteins. In this review, we describe the trafficking of 5-HTRs including their internalization, desensitization, or addressing to the plasma membrane depending on specific mechanisms which are peculiar for each class of serotonin receptor. PMID- 26055057 TI - Calcium-Sensing Receptor: Trafficking, Endocytosis, Recycling, and Importance of Interacting Proteins. AB - The cloning of the extracellular calcium-sensing receptor (CaSR) provided a new paradigm in G-protein-coupled receptor (GPCR) signaling in which principal physiological ligand is a cation, namely, extracellular calcium (Ca(o)(2+)). A wealth of information has accumulated in the past two decades about the CaSR's structure and function, its contribution to pathology in disorders of calcium in humans, and CaSR-based therapeutics. The CaSR unlike many other GPCRs must function in the presence of its ligand, thus understanding the mechanisms such as anterograde trafficking and endocytic pathways of this receptor are complex and fallen behind other classical GPCRs. Factors controlling CaSR signaling include various proteins affecting the expression of the CaSR as well as modulation of its trafficking to and from the cell surface. The dimeric cell-surface CaSR links to various heterotrimeric G-proteins (G(q/11), G(i/o), G(12/13), and G(s)) to regulate intracellular second messengers, lipid kinases, various protein kinases, and transcription factors that are part of the machinery enabling the receptor to modulate the functions of the wide variety of cells in which it is expressed. This chapter describes key features of CaSR structure and function and discusses novel mechanisms by which the level of cell-surface receptor expression can be regulated including forward trafficking during biosynthesis, desensitization, internalization and recycling from the cell surface, and degradation. These processes are impacted by its interactions with several proteins in addition to signaling molecules per se (i.e., G-proteins, protein kinases, inositol phosphates, etc.) and include small molecular weight G-proteins (Sar1, Rabs, ARF, P24A, RAMPs, filamin A, 14-3-3 proteins, calmodulin, and caveolin-1). Moreover, CaSR signaling seems compartmentalized in cell-type-specific manner, and caveolin and filamin A likely act as scaffolds that bind signaling components and other key cellular elements (e.g., the cytoskeleton) to facilitate the interaction of the receptor with its signaling pathways. Regulatory mechanisms are still evolving to understand how defects in trafficking of CaSR contribute to pathology in disorders of calcium homeostasis. PMID- 26055058 TI - Trafficking of beta-Adrenergic Receptors: Implications in Intracellular Receptor Signaling. AB - beta-Adrenergic receptors (betaARs), prototypical G-protein-coupled receptors, play a pivotal role in regulating neuronal and cardiovascular responses to catecholamines during stress. Agonist-induced receptor endocytosis is traditionally considered as a primary mechanism to turn off the receptor signaling (or receptor desensitization). However, recent progress suggests that intracellular trafficking of betaAR presents a mean to translocate receptor signaling machinery to intracellular organelles/compartments while terminating the signaling at the cell surface. Moreover, the apparent multidimensionality of ligand efficacy in space and time in a cell has forecasted exciting pathophysiological implications, which are just beginning to be explored. As we begin to understand how these pathways impact downstream cellular programs, this will have significant implications for a number of pathophysiological conditions in heart and other systems, that in turn open up new therapeutic opportunities. PMID- 26055059 TI - Postendocytic Sorting of Adrenergic and Opioid Receptors: New Mechanisms and Functions. AB - The endocytic pathway tightly regulates the activity of G protein-coupled receptors (GPCRs). Much of our understanding of this relationship between GPCR endocytic trafficking and signaling comes from studies done on catecholamine and opioid receptors. After ligand-induced endocytosis, a key sorting step in the endosome determines whether receptors are recycled back to the cell surface, leading to recovery of signaling, or are degraded in the lysosome, leading to desensitization. Recycling of GPCRs, unlike that of many other proteins, is an active process driven by specific sequences on the receptor and proteins that interact with this sequence. Recent data suggest that sequence-dependent recycling plays complex roles in regulating both the timing and location of GPCR signaling. This chapter will describe our current understanding of the mechanisms regulating GPCR sorting in the endosome and discuss emerging ideas on their role in GPCR signaling, focusing on adrenergic and opioid receptors as prototypes. PMID- 26055060 TI - alpha2 Adrenergic Receptor Trafficking as a Therapeutic Target in Antidepressant Drug Action. AB - Antidepressant drugs remain poorly understood, especially with respect to pharmacological mechanisms of action. This lack of knowledge results from the extreme complexity inherent to psychopharmacology, as well as to a corresponding lack of knowledge regarding depressive disorder pathophysiology. While the final analysis is likely to be multifactorial and heterogeneous, compelling evidence exists for upregulation of brain alpha2 adrenergic receptors (ARs) in depressed patients. This evidence has sparked a line of research into actions of a particular antidepressant drug class, the tricyclic antidepressants (TCAs), as direct ligands at alpha(2A)ARs. Our findings, as outlined herein, demonstrate that TCAs function as arrestin-biased ligands at alpha(2A)ARs. Importantly, TCA induced alpha(2A)AR/arrestin recruitment leads to receptor endocytosis and downregulation of alpha(2A)AR expression with prolonged exposure. These findings represent a novel mechanism linking alpha(2)AR trafficking with antidepressant pharmacology. PMID- 26055062 TI - Temperature-Sensitive Intracellular Traffic of alpha2C-Adrenergic Receptor. AB - alpha(2C)-Adrenergic receptor (alpha(2C)-AR) is the least characterized adrenergic receptor subtype and still very little is known about the intracellular traffic properties and pathophysiological roles of this receptor. alpha(2C)-AR has an atypical subcellular localization. At 37 degrees C, in the vascular smooth muscle cells and in fibroblasts, the receptor is poorly localized at the plasma membrane and accumulates inside the cell. Exposure to lower temperatures stimulates alpha(2C)-AR transport to the cell surface. This particular intracellular trafficking of alpha(2C)-AR is significant in the pathology of Raynaud phenomenon. In this brief review, I will present general information on the tissue distribution and cellular localization of alpha(2C)-AR. Also, I will discuss the mechanisms involved in the receptor transport by focusing on the trafficking motifs and on the molecular chaperones. PMID- 26055061 TI - Regulation of alpha2B-Adrenerigc Receptor Export Trafficking by Specific Motifs. AB - Intracellular trafficking and precise targeting to specific locations of G protein-coupled receptors (GPCRs) control the physiological functions of the receptors. Compared to the extensive efforts dedicated to understanding the events involved in the endocytic and recycling pathways, the molecular mechanisms underlying the transport of the GPCR superfamily from the endoplasmic reticulum (ER) through the Golgi to the plasma membrane are relatively less well defined. Over the past years, we have used alpha(2B)-adrenergic receptor (alpha(2B)-AR) as a model to define the factors that control GPCR export trafficking. In this chapter, we will review specific motifs identified to mediate the export of nascent alpha(2B)-AR from the ER and the Golgi and discuss the possible underlying mechanisms. As these motifs are highly conserved among GPCRs, they may provide common mechanisms for export trafficking of these receptors. PMID- 26055063 TI - N-Terminal Signal Peptides of G Protein-Coupled Receptors: Significance for Receptor Biosynthesis, Trafficking, and Signal Transduction. AB - Signal sequences play a key role during the first steps of the intracellular transport of G protein-coupled receptors (GPCRs). They are involved in targeting of the nascent chains to the membrane of the endoplasmic reticulum (ER) and initiate integration of the newly synthesized receptors into this compartment. Two classes of signal sequences are known: N-terminal signal peptides, which are usually cleaved-off following ER insertion and internal signal sequences, the so called signal anchor sequences, which form part of the mature proteins. About 5 10% of the GPCRs contain N-terminal signal peptides; the vast majority possesses signal anchor sequences. The reason why only a subset of GPCRs require signal peptides for ER targeting/insertion was addressed in the past decade by a limited number of studies indicating that the presence of signal peptides facilitates N tail translocation at the ER membrane. Interestingly, recent work showed that signal peptides of GPCRs do not only serve "classical" functions in the early secretory pathway. Uncleaved pseudo signal peptides may regulate receptor densities in the plasma membrane, receptor dimerization, and G protein coupling selectivity. On the other hand, even cleaved and released peptides may have post ER functions. In this review, we summarize the current knowledge about cleavable signal peptides of GPCRs and address also the question whether these sequences may serve as future drug targets in pharmacology. PMID- 26055064 TI - Regulation of GPCR Anterograde Trafficking by Molecular Chaperones and Motifs. AB - G protein-coupled receptors (GPCRs) make up a superfamily of integral membrane proteins that respond to a wide variety of extracellular stimuli, giving them an important role in cell function and survival. They have also proven to be valuable targets in the fight against various diseases. As such, GPCR signal regulation has received considerable attention over the last few decades. With the amplitude of signaling being determined in large part by receptor density at the plasma membrane, several endogenous mechanisms for modulating GPCR expression at the cell surface have come to light. It has been shown that cell surface expression is determined by both exocytic and endocytic processes. However, the body of knowledge surrounding GPCR trafficking from the endoplasmic reticulum to the plasma membrane, commonly known as anterograde trafficking, has considerable room for growth. We focus here on the current paradigms of anterograde GPCR trafficking. We will discuss the regulatory role of both the general and "nonclassical private" chaperone systems in GPCR trafficking as well as conserved motifs that serve as modulators of GPCR export from the endoplasmic reticulum and Golgi apparatus. Together, these topics summarize some of the known mechanisms by which the cell regulates anterograde GPCR trafficking. PMID- 26055065 TI - Trafficking of GPCRs. Preface. PMID- 26055066 TI - The subcellular distribution of cyclin-D1 and cyclin-D3 within human islet cells varies according to the status of the pancreas donor. AB - AIMS/HYPOTHESIS: In humans, the rate of beta cell proliferation declines rapidly during the postnatal period and remains low throughout adult life. Recent studies suggest that this may reflect the distribution of cell cycle regulators which, unusually, are located in the cytosolic compartment of beta cells in islets isolated from adults. In the present work, we examined whether the localisation of cyclin-D molecules is also cytosolic in the islet cells of pancreatic samples studied in situ. METHODS: Immunohistochemical approaches were employed to examine the subcellular localisation of cyclin-D1, -D2 and -D3 in human pancreatic samples recovered either from heart-beating donors or post mortem. Immunofluorescence methods were used to reveal the cellular localisation of cyclin-D1 and -D3. RESULTS: The distribution of cyclin-D2 was invariably cytosolic in islet cells, whereas the localisation of cyclin-D1 and -D3 varied according to the status of the donor. In pancreatic sections from heart-beating donors these molecules were primarily nuclear. By contrast, in samples collected post mortem, they were mainly cytosolic. Cyclin-D1 was detected only in beta cells whereas cyclin-D3 was detected in both alpha and beta cells. The proportion of donors who were immunopositive for cyclin-D1 declined from 71% in controls to 30% in those with type 1 diabetes. Cyclin-D3 was present in the islets of the majority of donors in both groups. CONCLUSIONS/INTERPRETATION: The subcellular localisation of cyclin-D molecules varies according to the status of the donor. Both cyclin-D1 and -D3 can be found in the nuclei of human islet cells in situ. PMID- 26055067 TI - Relationship of fibroblast growth factor 21 with baseline and new on-study microvascular disease in the Fenofibrate Intervention and Event Lowering in Diabetes study. AB - AIMS/HYPOTHESIS: Baseline circulating fibroblast growth factor 21 (FGF21) levels can predict total cardiovascular disease events in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. This paper describes the relationship of baseline FGF21 levels and new on-study microvascular disease in patients with type 2 diabetes from the FIELD study. METHODS: Baseline FGF21 levels were measured in plasma by enzyme-linked immunosorbent assay in 9697 study participants. Total microvascular disease was defined as the presence of any nephropathy, retinopathy, neuropathy and/or microvascular amputation. The relationship between FGF21 levels and microvascular disease was assessed by multivariable logistic regression. RESULTS: Higher baseline FGF21 levels were found in patients with baseline total microvascular disease (p<0.001). The association remained significant after adjusting for potential confounding factors (OR [95% CI] 1.13 [1.08, 1.19] per SD increase in log e -transformed FGF21 levels, p<0.001). Of 6465 patients without baseline total microvascular disease, 1517 developed new on-study total microvascular disease over 5 years of follow-up. Higher baseline FGF21 levels were associated with a higher risk of new on-study total microvascular disease after adjusting for potential confounding factors (OR [95% CI] 1.09 [1.02, 1.16] per SD increase in log e -transformed FGF21 levels, p=0.01). Addition of FGF21 levels in a model of new on-study total microvascular disease with established risk factors significantly, but modestly, increased the integrated discrimination improvement and the net reclassification improvement (both p < 0.01). CONCLUSIONS/INTERPRETATION: Higher baseline FGF21 levels are seen in patients with type 2 diabetes and established microvascular disease, and predict the future development of new microvascular disease. PMID- 26055068 TI - Different kinds of infants' smiles in the first six months and contingency to maternal affective behavior. AB - Infants' smiling is considered an expression of affection, and an index of cognitive and socio-emotional development. Despite research advances in this area, there is much to explore on the ontogeny of smiling, its meaning and the context in which it is manifested early in life. This study aimed at: (a) investigating smiling patterns in these different developmental moments in early infancy, (b) analyzing patterns of association between babies' smiles and their mothers' affective behaviors, and (c) verifying whether babies can answer contingently, with smiles, to mothers' affective behaviors. Participants were sixty Brazilian mother-infant dyads. Infants in three age levels (one, three, and five months of age) and their mothers were observed. They were videotaped at home, during 20 minutes in free sessions. The results indicate increase in frequency of infants' smiling instances across ages (F(2, 59) = 9.18, p < .05), variations in the frequency of maternal behaviors accompanying the variations in infants' smiling (F(2, 59) = 6.03, p < .05), correlations between infants' smiling and mothers' affective behaviors, and contingency between the behaviors of both mothers and infants. It was verified a strong association between mothers' behavior and their babies' smiles, emphasizing the importance of affective interactions in early stages of development. PMID- 26055069 TI - Surgical outcomes of a civil war in a neighbouring country. AB - OBJECTIVES: The civil war in Syria began on 15 March 2011, and many of the injured were treated in the neighbouring country of Turkey. This study reports the surgical outcomes of this war, in a tertiary centre in Turkey. METHODS: 159 patients with civilian war injuries in Syria who were admitted to the General Surgery Department in the Research and Training Hospital of the Medical School of Mustafa Kemal University, Hatay, Turkey, between 2011 and 2012 were analysed regarding the age, sex, injury type, history of previous surgery for the injury, types of abdominal injuries (solid or luminal organ), the status of isolated abdominal injuries or multiple injuries, mortality, length of hospital stay and injury severity scoring. RESULTS: The median age of the patients was 30.05 (18-66 years) years. Most of the injuries were gunshot wounds (99 of 116 patients, 85.3%). Primary and previously operated patients were transferred to our clinic in a median time of 6.28+/-4.44 h and 58.11+/-44.08 h, respectively. Most of the patients had intestinal injuries; although a limited number of patients with colorectal injuries were treated with primary repair, stoma was the major surgical option due to the gross peritoneal contamination secondary to prolonged transport time. Two women and 21 men died. The major cause of death was multiorgan failure secondary to sepsis (18 patients). CONCLUSIONS: In the case of civil war in the bordering countries, it is recommended that precautions are taken, such as transformation of nearby civilian hospitals into military ones and employment of experienced trauma surgeons in these hospitals to provide effective medical care. Damage control procedures can avoid fatalities especially before the lethal triad of physiological demise occurs. Rapid transport of the wounded to the nearest medical centre is the key point in countries neighbouring a civil war. PMID- 26055070 TI - The design, synthesis, and biological evaluation of novel YC-1 derivatives as potent anti-hepatic fibrosis agents. AB - 1-Benzyl-3-(substituted aryl)-5-methylfuro[3,2-c]pyrazole (YC-1) is a well-known synthetic compound with various satisfactory pharmacological activities, such as the activation of soluble guanylate cyclase (sGC) and the inhibition of hypoxia induced factor-1alpha (HIF-1alpha). Recently, YC-1 has been demonstrated to have a potent activity on anti-fibrotic activity. However, the mechanism underlying its anti-fibrotic activity is still largely unknown. To this end, we presented here the design and synthesis of YC-1 and its novel derivatives, as well as the evaluation of their anti-fibrotic effects on activated human hepatic stellate cells (HSCs) LX-2. Moreover, the possible underlying mechanism of anti-fibrotic activity was also investigated for the first time by means of a CCK-8 assay, cell apoptosis analysis, and western blot analysis. Our study revealed that YC-1 and its derivatives suppressed activated LX-2 cell viability and induced cell apoptosis in a time- and dose-dependent manner. Western blot data demonstrated that these derivatives not only decreased the expression of alpha-smooth muscle actin (alpha-SMA), but also increased the expression of caspase-3, resulting in cell apoptosis. These findings strongly indicated that YC-1 and its derivatives, especially AC, could significantly inhibit LX-2 cell activation and induce LX-2 cell apoptosis by inhibiting alpha-SMA protein expression and promoting caspase-3 expression, respectively. In summary, our findings suggested that YC-1 derivatives might be potential agents for hepatic fibrosis therapy. PMID- 26055071 TI - A perfusion-capable microfluidic bioreactor for assessing microbial heterologous protein production. AB - We present an integrated microfluidic bioreactor for fully continuous perfusion cultivation of suspended microbial cell cultures. This system allowed continuous and stable heterologous protein expression by sustaining the cultivation of Pichia pastoris over 11 days. This technical capability also allowed testing the impact of perfusion conditions on protein expression. This advance should enable small-scale models for process optimization in continuous biomanufacturing. PMID- 26055073 TI - Differential effects of temperature on the feeding kinematics of the tadpoles of two sympatric anuran species. AB - Temperature impacts ectotherm performance by influencing many biochemical and physiological processes. When well adapted to their environment, ectotherms should perform most efficiently at the temperatures they most commonly encounter. In the present study, we tested how differences in temperature affects the feeding kinematics of tadpoles of two anuran species: the benthic tadpole of Rhinella schneideri and the nektonic tadpole of Trachycephalus typhonius. Benthic and nektonic tadpoles have segregated distributions within ponds and thus tend to face different environmental conditions, such as temperature. Muscle contractile dynamics, and thus whole organism performance, is primarily temperature dependent for ectotherms. We hypothesized that changes in mean temperatures would have differential effects on the feeding kinematics of these two species. We conducted a laboratory experiment in which we used high-speed videography to record tadpoles foraging at cold and warm temperatures. In general, tadpoles filmed at warm temperatures opened their jaws faster, attained maximum gape earlier, and exhibited shorter gape cycles than tadpoles in cold temperatures, irrespective of species. We also found species x temperature interactions regarding the closing phase velocity, and the percentage of time it takes tadpoles to achieve maximum gape and to start closing their jaws. These interactions could indicate that these two co-occurring species differ in their sensitivity to differences in water temperature and have temperature-dependent feeding strategies that maximize feeding performance in their preferred environment. PMID- 26055072 TI - Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus. AB - The acute neurotoxicity of oligomeric forms of amyloid-beta 1-42 (Abeta) is implicated in the pathogenesis of Alzheimer's disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Abeta, an event that could be important during the early stages of the disease. We show that oligomerised Abeta induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSC(A)) when applied intracellularly. This effect is dependent on postsynaptic Ca(2+) and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca(2+)-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSC(A). These results suggest that a primary neuronal response to intracellular Abeta oligomers is the rapid synaptic insertion of CP-AMPARs. PMID- 26055074 TI - In-situ tumor vaccination: Bringing the fight to the tumor. AB - After decades of development in the shadow of traditional cancer treatment, immunotherapy has come into the spotlight. Treatment of metastatic tumors with monoclonal antibodies to T cell checkpoints like programed cell death 1 (PD-1) or its ligand, (PD-L1), have resulted in significant clinical responses across multiple tumor types. However, these therapies fail in the majority of patients with solid tumors, in particular those who lack PD1(+)CD8(+) tumor-infiltrating lymphocytes within their tumors. Intratumoral "in situ vaccination" approaches seek to enhance immunogenicity, generate tumor infiltrating lymophcytes (TIL) and drive a systemic anti-tumor immune response, directed against "unvaccinated," disseminated tumors. Given the emerging picture of intratumoral immunotherapy as safe and capable of delivering systemic efficacy, it is anticipated that these approaches will become integrated into future multi-modality therapy. PMID- 26055075 TI - Associations of maternal weight status prior and during pregnancy with neonatal cardiometabolic markers at birth: the Healthy Start study. AB - BACKGROUND: Maternal obesity increases adult offspring risk for cardiovascular disease; however, the role of offspring adiposity in mediating this association remains poorly characterized. OBJECTIVE: To investigate the associations of maternal pre-pregnant body mass index (maternal BMI) and gestational weight gain (GWG) with neonatal cardiometabolic markers independent of fetal growth and neonatal adiposity. METHODS: A total of 753 maternal-infant pairs from the Healthy Start study, a large multiethnic pre-birth observational cohort were used. Neonatal cardiometabolic markers included cord blood glucose, insulin, glucose-to-insulin ratio (Glu/Ins), total and high-density lipoprotein cholesterol (HDL-c), triglycerides, free fatty acids and leptin. Maternal BMI was abstracted from medical records or self-reported. GWG was calculated as the difference between the first pre-pregnant weight and the last weight measurement before delivery. Neonatal adiposity (percent fat mass) was measured within 72 h of delivery using whole-body air-displacement plethysmography. RESULTS: In covariate adjusted models, maternal BMI was positively associated with cord blood insulin (P=0.01) and leptin (P<0.001) levels, and inversely associated with cord blood HDL-c (P=0.05) and Glu/Ins (P=0.003). Adjustment for fetal growth or neonatal adiposity attenuated the effect of maternal BMI on neonatal insulin, rendering the association nonsignificant. However, maternal BMI remained associated with higher leptin (P<0.0011), lower HDL-c (P=0.02) and Glu/Ins (P=0.05), independent of neonatal adiposity. GWG was positively associated with neonatal insulin (P=0.02), glucose (P=0.03) and leptin levels (P<0.001) and negatively associated with Glu/Ins (P=0.006). After adjusting for neonatal adiposity, GWG remained associated with higher neonatal glucose (P=0.02) and leptin levels (P=0.02) and lower Glu/Ins (P=0.048). CONCLUSIONS: Maternal weight prior and/or during pregnancy is associated with neonatal cardiometabolic makers including leptin, glucose and HDL-c at delivery, independent of neonatal adiposity. Our results suggest that intrauterine exposure to maternal obesity influences metabolic processes beyond fetal growth and fat accretion. PMID- 26055077 TI - Building sustainable neuroscience capacity in Africa: the role of non-profit organisations. AB - While advances in neuroscience are helping to improve many aspects of human life, inequalities exist in this field between Africa and more scientifically-advanced continents. Many African countries lack the infrastructure and appropriately trained scientists for neuroscience education and research. Addressing these challenges would require the development of innovative approaches to help improve scientific competence for neuroscience across the continent. In recent years, science-based non-profit organisations (NPOs) have been supporting the African neuroscience community to build state-of-the-art scientific capacity for sustainable education and research. Some of these contributions have included: the establishment of training courses and workshops to introduce African scientists to powerful-yet-cost-effective experimental model systems; research infrastructural support and assistance to establish research institutes. Other contributions have come in the form of the promotion of scientific networking, public engagement and advocacy for improved neuroscience funding. Here, we discuss the contributions of NPOs to the development of neuroscience in Africa. PMID- 26055076 TI - Longitudinal investigation of adenovirus 36 seropositivity and human obesity: the Cardiovascular Risk in Young Finns Study. AB - BACKGROUND/OBJECTIVES: Adenovirus-36 (Adv-36) infection is associated with exaggerated adipogenesis in cell culture and the development of obesity in animal models and humans, but a causal relationship remains unproven. Our objective was to determine whether serological evidence of Adv-36 infection in childhood and/or adulthood is associated with adult obesity. SUBJECTS/METHODS: Paired plasma concentrations of Adv-36 antibodies were measured by a novel enzyme-linked immunosorbent assay in a subgroup (n=449) of the Cardiovascular Risk in Young Finns Study in childhood (mean age 11.9 years) and adulthood (mean age 41.3 years). The study group included (1) individuals who had maintained normal-weight status (2) those who became obese adults from a normal-weight status in childhood and (3) those that were overweight/obese as a child and obese as an adult. RESULTS: Mean (s.d.) time between baseline and follow-up was 29.4 (3.2) years (range 21-31 years). A total of 24.4% of individuals who were normal weight throughout life were seropositive for Adv-36 during child and/or adulthood as compared with 32.3% of those who became obese adults (P=0.11). Those who became obese in adulthood were more likely to be Adv-36 seropositive as adults compared with those who maintained normal weight (21.3% vs. 11.6%, P=0.02). This difference was mediated by a decline in Adv-36 seropositivity between child and adulthood in those maintaining normal weight. No differences were observed in body mass index across the life course, nor in waist circumference in adult life, between those who were Adv-36 seronegative or seropositive at any age. CONCLUSIONS: Individuals who gained weight across the life course were more likely to be Adv-36 seropositive in adult life than those who did not gain weight. However, analysis of change in weight status in relation to Adv-36 positivity did not support a causal role for Adv-36 in the development of obesity. PMID- 26055078 TI - Are active and passive smoking associated with cardiometabolic risk factors in adolescents? The CASPIAN-III Study. AB - BACKGROUND: Smoking is an important risky behavior in adolescents worldwide. Active and passive smoking have adverse health effects at public and individual levels. OBJECTIVE: This study aimed to evaluate the association of active and passive smoking with cardiometabolic risk factors in a national sample of Iranian adolescents. METHODS: Participants consisted of 5625 students, aged 10-18 years, studied in the third survey of a national school-based surveillance system. Participants were classified into three groups based on smoking pattern: active smoker, passive smoker, and exposure to smoke (active or passive or both of them). Considering the Adult Treatment Panel III criteria modified for the paediatric age group, metabolic syndrome (MetS) was defined as the co-existence of three out of five components of abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and depressed high density cholesterol (HDL-C) levels. RESULTS: The mean (SD) age of participants was 14.7 (2.4) years. Mean level of HDL-C was significantly lower in all types of smoking compared to non-smokers. Low HDL-C and MetS had significant association with active smoking (OR 2.10, 95% CI 1.33-3.31 and OR 5.24, 95% CI 2.41-11.37), passive smoking (OR 1.19, 95% CI 1.01-1.43 and OR 1.79, 95% CI 1.09-2.96), and smoking exposure (OR 1.20, 95% CI 1.01-1.43 and OR 2.02, 95% CI 1.22-3.31), respectively. CONCLUSION: This study confirms that both smoking and exposure to smoke are associated with an increased risk of MetS and some of the cardiometabolic risk factors in adolescents. Preventive measures against passive smoking should be considered as a health priority in the paediatric age groups. PMID- 26055079 TI - Enantio- and diastereoselective asymmetric allylic alkylation catalyzed by a planar-chiral cyclopentadienyl ruthenium complex. AB - We report asymmetric allylic alkylation of allylic chloride with beta-diketones as the prochiral carbon nucleophiles using a planar-chiral Cp'Ru catalyst. The reaction proceeds under mild conditions; the resulting chiral products containing vicinal tertiary stereocenters are obtained with high regio-, diastereo-, and enantioselectivities. These chiral products can then be transformed into a chiral diol by controlling the four stereocentres. PMID- 26055080 TI - Allostasis and Resilience of the Human Individual Metabolic Phenotype. AB - The urine metabotype of 12 individuals was followed over a period of 8-10 years, which provided the longest longitudinal study of metabolic phenotypes to date. More than 2000 NMR metabolic profiles were analyzed. The majority of subjects have a stable metabotype. Subjects who were exposed to important pathophysiological stressful conditions had a significant metabotype drift. When the stress conditions ceased, the original metabotypes were regained, while an irreversible stressful condition resulted in a permanent metabotype change. These results suggest that each individual occupies a well-defined region in the broad metabolic space, within which a limited degree of allostasis is permitted. The insurgence of significant stressful conditions causes a shift of the metabotype to another distinct region. The spontaneous return to the original metabolic region when the stressful conditions are removed suggests that the original metabotype has some degree of resilience. In this picture, precision medicine should aim at reinforcing the patient's metabolic resilience, that is, his or her ability to revert to his or her specific metabotype rather than to a generic healthy one. PMID- 26055081 TI - Illustration of Cost Saving Implications of Lower Extremity Nerve Decompression to Prevent Recurrence of Diabetic Foot Ulceration. AB - The US diabetic foot ulcer (DFU) incidence is 3-4% of 22.3 million diagnosed diabetes cases plus 6.3 million undiagnosed, 858 000 cases total. Risk of recurrence after healing is 30% annually. Lower extremity multiple nerve decompression (ND) surgery reduces neuropathic DFU (nDFU) recurrence risk by >80%. Cost effectiveness of hypothetical ND implementation to minimize nDFU recurrence is compared to the current $6.171 billion annual nDFU expense. A literature review identified best estimates of annual incidence, recurrence risk, medical management expense, and noneconomic costs for DFU. Illustrative cost/benefit calculations were performed assuming widespread application of bilateral ND after wound healing to the nDFU problem, using Center for Medicare Services mean expense data of $1143/case for unilateral lower extremity ND. Calculations use conservative, evidence-based cost figures, which are contemporary (2012) or adjusted for inflation. Widespread adoption of ND after nDFU healing could reduce annual DFU occurrences by at least 21% in the third year and 24% by year 5, representing calculated cost savings of $1.296 billion (year 3) to $1.481 billion (year 5). This scenario proffers significant expense reduction and societal benefit, and represents a minimum 1.9* return on the investment cost for surgical treatment. Further large cost savings would require reductions in initial DFU incidence, which ND might achieve by selective application to advanced diabetic sensorimotor polyneuropathy (DSPN). By minimizing the contribution of recurrences to yearly nDFU incidence, ND has potential to reduce by nearly $1 billion the annual cost of DFU treatment in the United States. PMID- 26055082 TI - Effect of Continuous Glucose Monitoring Accuracy on Clinicians' Retrospective Decision Making in Diabetes: A Pilot Study. AB - BACKGROUND: The use of continuous glucose monitoring (CGM) in clinical decision making in diabetes could be limited by the inaccuracy of CGM data when compared to plasma glucose measurements. The aim of the present study is to investigate the impact of CGM numerical accuracy on the precision of diabetes treatment adjustments. METHOD: CGM profiles with maximum 5-day duration from 12 patients with type 1 diabetes treated with a basal-bolus insulin regimen were processed by 2 CGM algorithms, with the accuracy of algorithm 2 being higher than the accuracy of algorithm 1, using the median absolute relative difference (MARD) as the measure of accuracy. During 2 separate and similar occasions over a 1-month interval, 3 clinicians reviewed the processed CGM profiles, and adjusted the dose level of basal and prandial insulin. The precision of the dosage adjustments were defined in terms of the interclinician agreement and the intraclinician reproducibility of the decisions. The Cohen's kappa coefficient was used to assess the precision of the decisions. The study was based on retrospective and blind CGM data. RESULTS: For the interclinician agreement, in the first occasion, the kappa of algorithm 1 was .32, and that of algorithm 2 was .36. For the interclinician agreement, in the second occasion, the kappas of algorithms 1 and 2 were .17 and .22, respectively. For the intraclinician reproducibility of the decisions, the kappas of algorithm 1 were .35, .22, and .80 and the kappas of algorithm 2 were .44, .52, and .32, for the 3 clinicians, respectively. For the interclinician agreement, the relative kappa change from algorithm 1 to algorithm 2 was 86.06%, and for the intraclinician reproducibility, the relative kappa change from algorithm 1 to algorithm 2 was 53.99%. CONCLUSIONS: Results indicated that the accuracy of CGM algorithms might potentially affect the precision of the CGM-based insulin adjustments for type 1 diabetes patients. However, a larger study with several clinical centers, with higher number of clinicians and patients is required to validate the impact of CGM accuracy on decisions precision. PMID- 26055083 TI - Expansion of the HSFY gene family in pig lineages : HSFY expansion in suids. AB - BACKGROUND: Amplified gene families on sex chromosomes can harbour genes with important biological functions, especially relating to fertility. The Y-linked heat shock transcription factor (HSFY) family has become amplified on the Y chromosome of the domestic pig (Sus scrofa), in an apparently independent event to an HSFY expansion on the Y chromosome of cattle (Bos taurus). Although the biological functions of HSFY genes are poorly understood, they appear to be involved in gametogenesis in a number of mammalian species, and, in cattle, HSFY gene copy number may correlate with levels of fertility. RESULTS: We have investigated the HSFY family in domestic pig, and other suid species including warthog, bushpig, babirusa and peccaries. The domestic pig contains at least two amplified variants of HSFY, distinguished predominantly by presence or absence of a SINE within the intron. Both these variants are expressed in testis, and both are present in approximately 50 copies each in a single cluster on the short arm of the Y. The longer form has multiple nonsense mutations rendering it likely non functional, but many of the shorter forms still have coding potential. Other suid species also have these two variants of HSFY, and estimates of copy number suggest the HSFY family may have amplified independently twice during suid evolution. CONCLUSIONS: The HSFY genes have become amplified in multiple species lineages independently. HSFY is predominantly expressed in testis in domestic pig, a pattern conserved with cattle, in which HSFY may play a role in fertility. Further investigation of the potential associations of HSFY with fertility and testis development may be of agricultural interest. PMID- 26055084 TI - Ontogeny, tissue distribution and expression analysis of IgZ in rohu, Labeo rohita in response to various stimuli. AB - This study reports presence of IgZ transcripts, its ontogeny, tissue distribution and expression following various stimulations/infections in rohu. The derived rohu IgZ sequence clustered together with IgZ of Ctenopharyngodon idella and Cyprinus carpio in phylogenetic analysis. IgZ expression was detected at early developmental stages with higher expression at 1 day post-fertilization, and higher in anterior kidney and lower in skin tissues of juveniles. An inductive expression of IgZ was observed during both Edwardsiella tarda and Dactylogyrus catlaius infections in skin and/or gill tissues. In ConA treated HKLs, the response was prominent at 72 h post-stimulation where as in ConA-PMA treatment, it was higher during early time points. Increased expression of IgZ was found between 24 and 96 hps with formalin-killed Aeromonas hydrophila where as in poly I:C treated HKLs, the level increased at 96 hps. It seems to be the first report describing the functional existence of IgZ in rohu carp. PMID- 26055085 TI - Determinants of gestational night blindness in pregnant women from Rio de Janeiro, Brazil. AB - OBJECTIVE: To describe the prevalence and determinants of gestational night blindness in pregnant women receiving care in a hospital in Rio de Janeiro, Brazil. DESIGN: Cross-sectional study of pregnant and postpartum women receiving care in a public hospital in Rio de Janeiro from 1999 to 2001 (group I; n 225) or from 2005 to 2008 (group II; n 381). Night blindness was identified through a standardized and validated interview (WHO, 1996). The determinants of gestational night blindness were identified through a hierarchical logistic regression model. SETTING: Public maternity hospital in Rio de Janeiro, RJ, Brazil. SUBJECTS: Adult pregnant and postpartum women (n 606), aged >=20 years. RESULTS: The prevalence of gestational night blindness was 9.9 %. The final model revealed that not living in the South Zone of Rio de Janeiro (distal level: adjusted OR=1.846; 95 % CI 1.002, 3.401), belonging to group I (intermediate level: adjusted OR=2.183; 95 % CI 1.066, 4.471) and for the proximal level, having a history of abortion (adjusted OR=2.840; 95 % CI 1.134, 7.115) and having anaemia during the first and second trimesters of pregnancy (adjusted OR=3.776; 95 % CI 1.579, 9.029) were determinants of gestational night blindness. CONCLUSION: Gestational night blindness should be assessed for during the prenatal care of all pregnant women, especially those living in deprived areas of the city and/or who have a history of abortion or anaemia. Nutritional monitoring is recommended during pregnancy to control gestational night blindness. PMID- 26055086 TI - Recent developments in high-quality drying of vegetables, fruits, and aquatic products. AB - Fresh foods like vegetables, fruits, and aquatic products have high water activity and they are highly heat-sensitive and easily degradable. Dehydration is one of the most common methods used to improve food shelf-life. However, drying methods used for food dehydration must not only be efficient and economic but also yield high-quality products based on flavor, nutrients, color, rehydration, uniformity, appearance, and texture. This paper reviews some new drying technologies developed for dehydration of vegetables, fruits, and aquatic products. These include: infrared drying, microwave drying, radio frequency drying, electrohydrodynamic drying, etc., as well as hybrid drying methods combining two or more different drying techniques. A comprehensive review of recent developments in high-quality drying of vegetables, fruits and aquatic products is presented and recommendations are made for future research. PMID- 26055087 TI - Molecular profiling and functional insights of rock bream (Oplegnathus fasciatus) thioredoxin reductase 3-like molecule: investigation of its transcriptional modulation in response to live pathogen stress. AB - The thioredoxin (Trx) system plays a significant role in cellular antioxidative defense by dismutating the surpluses of reactive oxygen species. Thus, the role of thioredoxin reductase (TrxR) cannot be ignored, owing to its participation in initiating the Trx enzyme cascade. Here, we report the identification and molecular characterization of a teleostean TrxR (RbTrxR-3) ortholog that showed high similarity with the TrxR-3 isoforms of other vertebrates. The complete RbTrxR-3 coding sequence comprised 1800 nucleotides, encoding a 600-amino acid protein with a predicted molecular mass of ~66 kDa. RbTrxR-3 consisted of 16 exons separated by 15 introns and had a total length of 12,658 bp. In silico analysis of the RbTrxR-3 protein sequence revealed that it possesses typical TrxR domain architecture. Moreover, using multiple sequence alignment and pairwise sequence alignment strategies, we showed that RbTrxR-3 has high overall sequence similarity to other teleostean TrxR-3 proteins, including highly conserved active site residues. Phylogenetic reconstruction of RbTrxR-3 affirmed its close evolutionary relationship with fish TrxR-3 orthologs, as indicated by its clustering pattern. RbTrxR-3 transcriptional analysis, performed using quantitative polymerase chain reaction (qPCR), showed that RbTrxR-3 was ubiquitously distributed, with the highest level of mRNA expression in the blood, followed by the gill, and liver. Live bacterial and viral stimuli triggered the modulation of RbTrxR-3 basal transcription in liver tissues that correlated temporally with that of its putative substrate, rock bream thioredoxin1 under the same conditions of pathogenic stress. Finally, resembling the typical function of TrxR protein, purified recombinant RbTrxR-3 showed detectable dose-dependent thiol reductase activity against 5,5'-dithiobis (2-nitrobenzoic) acid. Taken together, these results suggest that RbTrxR-3 plays a role in the host Trx system under conditions of oxidative and pathogenic stress. PMID- 26055088 TI - Variation within three apoptosis associated genes as potential risk factors for Achilles tendinopathy in a British based case-control cohort. AB - Achilles tendon pathology (ATP) is a degenerative condition which exhibits excessive tenocyte apoptosis. Tumour necrosis factor receptor 1 (TNFR1), caspase 3 (CASP3) and caspase-8 (CASP8) are important regulators of apoptosis. To date, the effects of variation within the genes for TNFR1 and CASP3 as risk factors for ATP have not been described. There is evidence that two single nucleotide polymorphisms (SNPs) within the CASP8 gene are associated with ATP, but only in populations from the Southern Hemisphere. The primary aim of this study was to determine whether SNPs within the TNFRSF1A and CASP3 genes were associated with ATP in British Caucasians. We additionally sought to determine whether copy number variation (CNV) within the CASP8 gene was associated with ATP. We recruited 262 (131 ATP cases and 131 asymptomatic controls) Caucasian participants for this genetic association study and used quantitative PCR with chi-squared (chi(2)) tests and ANOVA to detect significant associations. For our entire cohort, we found no association between the TNFRSF1A rs4149577 (p=0.561), CASP3 rs1049253 (p=0.643) and CASP8 variants (p=0.219) and ATP. Likewise, when we tested potential interactions between gender, genotype and the risk of ATP, we found no association with the variants investigated. In conclusion, the TNFRSF1A, CASP3 and CASP8 gene variants were not associated with ATP in British Caucasians. PMID- 26055089 TI - Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease. AB - The hepatitis C virus (HCV) infection is a primary cause of chronic hepatitis which eventually progresses to cirrhosis and in some instances might advance to hepatocellular carcinoma. According to the WHO report, HCV infects 130-150 million people globally and every year 350,000 to 500,000 people die from hepatitis C virus infection. Great achievement has been made in viral treatment evolution, after the development of HCV NS3/4A protease inhibitor (Boceprevir). However, efficacy of Boceprevir is compromised by the emergence of drug resistant variants. The molecular principle behind drug resistance of the protease mutants such as (V36M, T54S and R155K) is still poorly understood. Therefore in this study, we employed a series of computational strategies to analyze the binding of antiviral drug, Boceprevir to HCV NS3/4A protease mutants. Our results clearly demonstrate that the point mutations (V36M, T54S and R155K) in protease are associated with lowering of its binding affinity with Boceprevir. Exhaustive analysis of the simulated Boceprevir-bound wild and mutant complexes revealed variations in hydrophobic interactions, hydrogen bond occupancy and salt bridge interactions. Also, substrate envelope analysis scrutinized that the studied mutations reside outside the substrate envelope which may affect the Boceprevir affinity towards HCV protease but not the protease enzymatic activity. Furthermore, structural analyses of the binding site volume and flexibility show impairment in flexibility and stability of the binding site residues in mutant structures. In order to combat Boceprevir resistance, renovation of binding interactions between the drug and protease may be valuable. The structural insight from this study reveals the mechanism of the Boceprevir resistance and the results can be valuable for the design of new PIs with improved efficiency. PMID- 26055090 TI - Ischemic postconditioning provides cardioprotective and antiapoptotic effects against ischemia-reperfusion injury through iNOS inhibition in hyperthyroid rats. AB - Ischemic postconditioning (IPost) is a strategy to provide protection against ischemia-reperfusion (IR) injury. The cardioprotective effects of IPost in cases of ischemic heart disease along with co-morbidities like hyperthyroidism remain unknown. The aim of this study was to investigate the effects of IPost on expression of eNOS, iNOS, Bax, and Bcl-2 genes in hyperthyroid male rats, subjected to myocardial IR. Hyperthyroidism was induced by adding thyroxine to drinking water for a period of 21 days. Using the Langendorff device hearts were perfused, then subjected to a 30-minute global ischemia which was followed by 120 min of reperfusion; subsequently IPost was induced immediately after ischemia. Results indicated that following IR, expression of eNOS and Bcl-2 decreased, whereas expression of iNOS and Bax increased in both the control and hyperthyroid groups. In hyperthyroid animals, IPost significantly increased expression of eNOS by 3.19 fold and Bcl-2 by 3.66 fold; it also decreased expression of Bax by 51%, and reduced IR-induced DNA laddering pattern and infarct size (45.7 +/- 1.82% vs. 59.3 +/- 1.83%, p<0.05) in the presence of aminoguanidine (AG), a selective iNOS inhibitor. In conclusion, IPost per se could not provide cardioprotection against myocardial ischemia in hyperthyroid rats, a loss of which however was restored by the combination of IPost and iNOS inhibition that acts by a decrease in Bax and an increase in both eNOS and Bcl-2 expression. PMID- 26055091 TI - Human cytomegalovirus microRNA miR-US25-1-5p inhibits viral replication by targeting multiple cellular genes during infection. AB - MicroRNAs (miRNAs) play important roles in regulating various cellular processes in plants, animals, and viruses. This mechanism is also utilized by human cytomegalovirus (HCMV) in the process of infection and pathogenesis. The HCMV encoded miRNA, hcmv-miR-US25-1-5p, was highly expressed during lytic and latent infections, and was found to inhibit viral replication. Identification of functional target genes of this microRNA is important in that it will enable a better understanding of the function of hcmv-miR-US25-1-5p during HCMV infection. In the present study, 35 putative cellular transcript targets of hcmv-miR-US25-1 5p were identified. Down-regulation of the targets YWHAE, UBB, NPM1, and HSP90AA1 by hcmv-miR-US25-1-5p was validated by luciferase reporter assay and Western blot analysis. In addition, we showed that hcmv-miR-US25-1-5p could inhibit viral replication by interacting with these targets, the existence of which may impact virus replication directly or indirectly. PMID- 26055092 TI - Corrigendum: Polymerization of Ethylene by Silica-Supported Dinuclear Cr(III) Sites through an Initiation Step Involving C-H Bond Activation. PMID- 26055093 TI - Analysis of glycation induced protein cross-linking inhibitory effects of some antidiabetic plants and spices. AB - BACKGROUND: Protein cross-linking which occurs towards the latter part of protein glycation is implicated in the development of chronic diabetic complications. Glycation induced protein cross-linking inhibitory effects of nine antidiabetic plants and three spices were evaluated in this study using a novel, simple, electrophoresis based method. METHODS: Methanol extracts of thirteen plants including nine antidiabetic plants and three spices were used. Lysozyme and fructose were incubated at 37 degrees C in the presence or absence of different concentrations of plant extracts up to 31 days. Standard glycation inhibitor aminoguanidine and other appropriate controls were included. A recently established sodium dodecyl polyacrylamide gel electrophoresis (SDS-PAGE) method was used to detect the products of protein cross-linking in the incubation mixtures. RESULTS: High molecular weight protein products representing the dimer, trimer and tetramer of lysozyme were detected in the presence of fructose. Among the nine antidiabetic plants, seven showed glycation induced protein cross linking inhibitory effects namely Ficus racemosa (FR) stem bark, Gymnema sylvestre (GS) leaves, Musa paradisiaca (MP) yam, Phyllanthus debilis (PD) whole plant, Phyllanthus emblica (PE) fruit, Pterocarpus marsupium (PM) latex and Tinospora cordifolia (TC) leaves. Inhibition observed with Coccinia grandis (CG) leaves and Strychnos potatorum (SP) seeds were much low. Leaves of Gymnema lactiferum (GL), the plant without known antidiabetic effects showed the lowest inhibition. All three spices namely Coriandrum sativum (CS) seeds, Cinnamomum zeylanicum (CZ) bark and Syzygium aromaticum (SA) flower buds showed cross-link inhibitory effects with higher effects in CS and SA. PD, PE, PM, CS and SA showed almost complete inhibition on the formation of cross-linking with 25 MUg/ml extracts. CONCLUSIONS: Methanol extracts of PD, PE, PM, CS and SA have shown promising inhibitory effects on glycation induced protein cross-linking. PMID- 26055095 TI - Teacher Support Resources, Need Satisfaction and Well-Being. AB - Based on Job Demands-Resources Model (JD-R), this study examines the relationships among teacher support resources, psychological need satisfaction, engagement and burnout in a sample of 282 Spanish secondary school teachers. Nine teacher psychological needs were identified based on the study of Bess and on the Self-Determination Theory (SDT). Self-report questionnaires were used to measure the constructs selected for this study and their interrelationships were examined by structural equation modeling. The results reveal a good model fit to the data (NNFI = .88; CFI = .90; GFI = .90; RMSEA = .061). The analyses indicate a positive and significant effect of latent variable Psychological Need Satisfaction on engagement (beta = .74, p < .05), and a negative and significant effect on burnout (beta = -.78, p <= .05). Furthermore, the results show the mediator role played by Psychological Need Satisfaction in the relationship between teacher support resources and both engagement and burnout (additional paths did not improve the model fit: Deltachi2(2) = 2.428, p = .29). Finally, practical implications of these findings are discussed. PMID- 26055094 TI - Is there an association between adolescent sleep restriction and obesity. AB - OBJECTIVE: This is the first prospective study of the reciprocal association between sleep restriction and weight among adolescents. Evidence on sleep duration and obesity in youth is sparse and the results have been equivocal. METHODS: Data are from a community-based, two-wave cohort study. The setting was a metropolitan area with a population of over 4 million. The cohort consisted of 4175 youths 11-17 at baseline and 3134 of these followed up a year later. Obesity was defined as body mass index >95th percentile for children of the same age and sex. Sleep restriction was defined as 6 or fewer hours of sleep per night on weeknights or on both weekends and weeknights. Covariates examined were age, gender, family income and depression. RESULTS: Results clearly demonstrated that there was no association between sleep restriction and obesity at baseline. In prospective analyses, sleep restriction did not increase future risk of obesity, nor did obesity increase risk of future sleep restriction. CONCLUSIONS: These findings call into question previous research based primarily on cross-sectional data suggesting a positive correlation between sleep restriction and obesity. However, the results for adolescents in this study are supported by one study of adolescents and by studies of adults using prospective designs. At this point, there appears to be little evidence for a temporal relation between sleep duration and obesity among adults or adolescents. PMID- 26055096 TI - Methicillin-Resistant Staphylococcus aureus: More Attention Should Be Paid in Mainland China. PMID- 26055097 TI - GeneStoryTeller: a mobile app for quick and comprehensive information retrieval of human genes. AB - In the last few years, mobile devices such as smartphones and tablets have become an integral part of everyday life, due to their software/hardware rapid development, as well as the increased portability they offer. Nevertheless, up to now, only few Apps have been developed in the field of bioinformatics, capable to perform fast and robust access to services. We have developed the GeneStoryTeller, a mobile application for Android platforms, where users are able to instantly retrieve information regarding any recorded human gene, derived from eight publicly available databases, as a summary story. Complementary information regarding gene-drugs interactions, functional annotation and disease associations for each selected gene is also provided in the gene story. The most challenging part during the development of the GeneStoryTeller was to keep balance between storing data locally within the app and obtaining the updated content dynamically via a network connection. This was accomplished with the implementation of an administrative site where data are curated and synchronized with the application requiring a minimum human intervention. PMID- 26055098 TI - An Ebola virus-centered knowledge base. AB - Ebola virus (EBOV), of the family Filoviridae viruses, is a NIAID category A, lethal human pathogen. It is responsible for causing Ebola virus disease (EVD) that is a severe hemorrhagic fever and has a cumulative death rate of 41% in the ongoing epidemic in West Africa. There is an ever-increasing need to consolidate and make available all the knowledge that we possess on EBOV, even if it is conflicting or incomplete. This would enable biomedical researchers to understand the molecular mechanisms underlying this disease and help develop tools for efficient diagnosis and effective treatment. In this article, we present our approach for the development of an Ebola virus-centered Knowledge Base (Ebola-KB) using Linked Data and Semantic Web Technologies. We retrieve and aggregate knowledge from several open data sources, web services and biomedical ontologies. This knowledge is transformed to RDF, linked to the Bio2RDF datasets and made available through a SPARQL 1.1 Endpoint. Ebola-KB can also be explored using an interactive Dashboard visualizing the different perspectives of this integrated knowledge. We showcase how different competency questions, asked by domain users researching the druggability of EBOV, can be formulated as SPARQL Queries or answered using the Ebola-KB Dashboard. PMID- 26055099 TI - A general concept for consistent documentation of computational analyses. AB - The ever-growing amount of data in the field of life sciences demands standardized ways of high-throughput computational analysis. This standardization requires a thorough documentation of each step in the computational analysis to enable researchers to understand and reproduce the results. However, due to the heterogeneity in software setups and the high rate of change during tool development, reproducibility is hard to achieve. One reason is that there is no common agreement in the research community on how to document computational studies. In many cases, simple flat files or other unstructured text documents are provided by researchers as documentation, which are often missing software dependencies, versions and sufficient documentation to understand the workflow and parameter settings. As a solution we suggest a simple and modest approach for documenting and verifying computational analysis pipelines. We propose a two-part scheme that defines a computational analysis using a Process and an Analysis metadata document, which jointly describe all necessary details to reproduce the results. In this design we separate the metadata specifying the process from the metadata describing an actual analysis run, thereby reducing the effort of manual documentation to an absolute minimum. Our approach is independent of a specific software environment, results in human readable XML documents that can easily be shared with other researchers and allows an automated validation to ensure consistency of the metadata. Because our approach has been designed with little to no assumptions concerning the workflow of an analysis, we expect it to be applicable in a wide range of computational research fields. PMID- 26055100 TI - dbHiMo: a web-based epigenomics platform for histone-modifying enzymes. AB - Over the past two decades, epigenetics has evolved into a key concept for understanding regulation of gene expression. Among many epigenetic mechanisms, covalent modifications such as acetylation and methylation of lysine residues on core histones emerged as a major mechanism in epigenetic regulation. Here, we present the database for histone-modifying enzymes (dbHiMo; http://hme.riceblast.snu.ac.kr/) aimed at facilitating functional and comparative analysis of histone-modifying enzymes (HMEs). HMEs were identified by applying a search pipeline built upon profile hidden Markov model (HMM) to proteomes. The database incorporates 11,576 HMEs identified from 603 proteomes including 483 fungal, 32 plants and 51 metazoan species. The dbHiMo provides users with web based personalized data browsing and analysis tools, supporting comparative and evolutionary genomics. With comprehensive data entries and associated web-based tools, our database will be a valuable resource for future epigenetics/epigenomics studies. PMID- 26055101 TI - kpath: integration of metabolic pathway linked data. AB - In the last few years, the Life Sciences domain has experienced a rapid growth in the amount of available biological databases. The heterogeneity of these databases makes data integration a challenging issue. Some integration challenges are locating resources, relationships, data formats, synonyms or ambiguity. The Linked Data approach partially solves the heterogeneity problems by introducing a uniform data representation model. Linked Data refers to a set of best practices for publishing and connecting structured data on the Web. This article introduces kpath, a database that integrates information related to metabolic pathways. kpath also provides a navigational interface that enables not only the browsing, but also the deep use of the integrated data to build metabolic networks based on existing disperse knowledge. This user interface has been used to showcase relationships that can be inferred from the information available in several public databases. PMID- 26055102 TI - BioAcoustica: a free and open repository and analysis platform for bioacoustics. AB - We describe an online open repository and analysis platform, BioAcoustica (http://bio.acousti.ca), for recordings of wildlife sounds. Recordings can be annotated using a crowdsourced approach, allowing voice introductions and sections with extraneous noise to be removed from analyses. This system is based on the Scratchpads virtual research environment, the BioVeL portal and the Taverna workflow management tool, which allows for analysis of recordings using a grid computing service. At present the analyses include spectrograms, oscillograms and dominant frequency analysis. Further analyses can be integrated to meet the needs of specific researchers or projects. Researchers can upload and annotate their recordings to supplement traditional publication. PMID- 26055103 TI - Summertime dosage-dependent hypersensitivity to an angiotensin II receptor blocker. AB - BACKGROUND: Summertime dips in blood pressure (BP), both in normotensive and hypertensive subjects, are well known. However, the dips are small and are not related to particular forms or doses of antihypertensive medication. Nevertheless it is the practice in some quarters to decrease antihypertensive medication in summer, and/or to increase in winter. Large scale studies being inconclusive, there are calls for long-term examination of the relationship between environmental temperature and blood pressure in single individuals under medication. CASE PRESENTATION: While analyzing data from a subject whose BP had been controlled for a decade with the angiotensin-II receptor blocker losartan, an extreme, dosage-dependent, summertime dip came to light. Downward dosage adjustment appeared essential and may have prevented hypotension-related pathology. CONCLUSION: The benefits of aggressive medication (the "J curve" phenomenon) being debated, the possibility of seasonal hypersensitivity, perhaps explicable in terms of differential signaling by countervailing receptors, should be taken into account when considering dosage adjustments in hypertensive subjects. PMID- 26055105 TI - Bone and Spinal Muscular Atrophy. AB - Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disease, leading to progressive denervation atrophy in the involved skeletal muscles. Bone status has been poorly studied. We assessed bone metabolism, bone mineral density (BMD) and fractures in 30 children (age range 15-171 months) affected by SMA types 2 and 3. Eighteen children (60%) had higher than normal levels of CTx (bone resorption marker); 25-OH vitamin D was in the lower range of normal (below 20 ng/ml in 9 children and below 12 ng/ml in 2). Lumbar spine BMAD (bone mineral apparent density) Z-score was below -1.5 in 50% of children. According to clinical records, four children had sustained four peripheral fractures; on spine X-rays, we observed 9 previously undiagnosed vertebral fractures in 7 children. There was a significant inverse regression between PTH and 25-OH D levels, and a significant regression between BMC and BMAD values and the scores of motor functional tests. Even if this study could not establish the pathogenesis of bone derangements in SMA, its main findings - reduced bone density, low 25OH vitamin D levels, increased bone resorption markers and asymptomatic vertebral fractures also in very young patients - strongly suggest that even young subjects affected by SMA should be considered at risk of osteopenia and even osteoporosis and fractures. PMID- 26055104 TI - Infection of ectocervical tissue and universal targeting of T-cells mediated by primary non-macrophage-tropic and highly macrophage-tropic HIV-1 R5 envelopes. AB - BACKGROUND: HIV-1 variants carrying non-macrophage-tropic HIV-1 R5 envelopes (Envs) are predominantly transmitted and persist in immune tissue even in AIDS patients who have highly macrophage-tropic variants in the brain. Non-macrophage tropic R5 Envs require high levels of CD4 for infection contrasting with macrophage-tropic Envs, which can efficiently mediate infection of cells via low CD4. Here, we investigated whether non-macrophage-tropic R5 Envs from the acute stage of infection (including transmitted/founder Env) mediated more efficient infection of ectocervical explant cultures compared to non-macrophage-tropic and highly macrophage-tropic R5 Envs from late disease. RESULTS: We used Env+ pseudovirions that carried a GFP reporter gene to measure infection of the first cells targeted in ectocervical explant cultures. In straight titrations of Env+ pseudovirus supernatants, mac-tropic R5 Envs from late disease mediated slightly higher infectivities for ectocervical explants although this was not significant. Surprisingly, explant infection by several T/F/acute Envs was lower than for Envs from late disease. However, when infectivity for explants was corrected to account for differences in the overall infectivity of each Env+ pseudovirus (measured on highly permissive HeLa TZM-bl cells), non-mac-tropic early and late disease Env+ pseudoviruses mediated significantly higher infection. This observation suggests that cervical tissue preferentially supports non-mac-tropic Env+ viruses compared to mac-tropic viruses. Finally, we show that T-cells were the main targets for infection regardless of whether explants were stimulated with T-cell or monocyte/macrophage cytokines. There was no evidence of macrophage infection even for pseudovirions carrying highly mac-tropic Envs from brain tissue or for the highly mac-tropic, laboratory strain, BaL, which targeted T cells in the explant tissue. CONCLUSIONS: Our data support ectocervical tissue as a favorable environment for non-mac-tropic HIV-1 R5 variants and emphasize the role of T-cells as initial targets for infection even for highly mac-tropic variants. PMID- 26055106 TI - Uncoupling protein-1 is protective of bone mass under mild cold stress conditions. AB - Brown adipose tissue (BAT), largely controlled by the sympathetic nervous system (SNS), has the ability to dissipate energy in the form of heat through the actions of uncoupling protein-1 (UCP-1), thereby critically influencing energy expenditure. Besides BAT, the SNS also strongly influences bone, and recent studies have demonstrated a positive correlation between BAT activity and bone mass, albeit the interactions between BAT and bone remain unclear. Here we show that UCP-1 is critical for protecting bone mass in mice under conditions of permanent mild cold stress for this species (22 degrees C). UCP-1-/- mice housed at 22 degrees C showed significantly lower cancellous bone mass, with lower trabecular number and thickness, a lower bone formation rate and mineralising surface, but unaltered osteoclast number, compared to wild type mice housed at the same temperature. UCP-1-/- mice also displayed shorter femurs than wild types, with smaller cortical periosteal and endocortical perimeters. Importantly, these altered bone phenotypes were not observed when UCP-1-/- and wild type mice were housed in thermo-neutral conditions (29 degrees C), indicating a UCP-1 dependent support of bone mass and bone formation at the lower temperature. Furthermore, at 22 degrees C UCP-1-/- mice showed elevated hypothalamic expression of neuropeptide Y (NPY) relative to wild type, which is consistent with the lower bone formation and mass of UCP-1-/- mice at 22 degrees C caused by the catabolic effects of hypothalamic NPY-induced SNS modulation. The results from this study suggest that during mild cold stress, when BAT-dependent thermogenesis is required, UCP-1 activity exerts a protective effect on bone mass possibly through alterations in central NPY pathways known to regulate SNS activity. PMID- 26055107 TI - Bone defect regeneration and cortical bone parameters of type 2 diabetic rats are improved by insulin therapy. AB - Zucker Diabetic Fatty (ZDF) rats represent an established model of type 2 diabetes mellitus (T2DM) and display several features of human diabetic bone disease, including impaired osteoblast function, decreased bone strength, and delayed bone healing. Here, we determined whether glycemic control by insulin treatment prevents skeletal complications associated with diabetes. Subcritical femur defects were created in diabetic (fa/fa) and non-diabetic (+/+) ZDF rats. Diabetic rats were treated once daily with long-lasting insulin glargin for 12weeks for glycemic control. Insulin treatment successfully maintained serum levels of glycated hemoglobin, while untreated diabetic rats showed a 2-fold increase. Trabecular and cortical bone mass measured by MUCT were decreased in diabetic rats. Insulin treatment increased bone mass of the cortical, but not of the trabecular bone compartment. Dynamic histomorphometry revealed a lower bone formation rate at the trabecular and periosteal cortical bone in diabetic animals and decreased serum procollagen type 1 N-terminal propeptide (P1NP, -49%) levels. Insulin treatment partially improved these parameters. In T2DM, serum levels of tartrate-resistant acid phosphatase (TRAP, +32%) and C-terminal telopeptide (CTX, +49%) were increased. Insulin treatment further elevated TRAP levels, but did not affect CTX levels. While diabetes impaired bone defect healing, glycemic control with insulin fully reversed these negative effects. In conclusion, insulin treatment reversed the adverse effects of T2DM on bone defect regeneration in rats mainly by improving osteoblast function and bone formation. This article is part of a Special Issue entitled Bone and diabetes. PMID- 26055109 TI - Response to: Bone alkaline phosphatase levels do not necessarily cause hypermineralization per se. PMID- 26055108 TI - New insights into the biology of osteocalcin. AB - Osteocalcin is among the most abundant proteins in bone and is produced exclusively by osteoblasts. Initially believed to be an inhibitor of bone mineralization, recent studies suggest a broader role for osteocalcin that extends to the regulation of whole body metabolism, reproduction, and cognition. Circulating undercarboxylated osteocalcin, which is regulated by insulin, acts in a feed-forward loop to increase beta-cell proliferation as well as insulin production and secretion, while skeletal muscle and adipose tissue respond to osteocalcin by increasing their sensitivity to insulin. Osteocalcin also acts in the brain to increase neurotransmitter production and in the testes to stimulate testosterone production. At least one putative receptor for osteocalcin, Gprc6a, is expressed by adipose, skeletal muscle, and the Leydig cells of the testes and appears to mediate osteocalcin's effects in these tissues. In this review, we summarize these new discoveries, which suggest that the ability of osteocalcin to function both locally in bone and as a hormone depends on a novel post translational mechanism that alters osteocalcin's affinity for the bone matrix and bioavailability. This article is part of a Special Issue entitled Bone and diabetes. PMID- 26055110 TI - A Plasmid-Borne System To Assess the Excision and Integration of Staphylococcal Cassette Chromosome mec Mediated by CcrA and CcrB. AB - Resistance to methicillin and other beta-lactam antibiotics in staphylococci is due to mecA, which is carried on a genomic island, staphylococcal cassette chromosome mec (SCCmec). The chromosomal excision and integration of SCCmec are mediated by the site-specific recombinase CcrAB or CcrC, encoded within this element. A plasmid-borne system was constructed to assess the activities of CcrA and CcrB in the excision and integration of SCCmec in Escherichia coli and Staphylococcus aureus. The excision frequency in E. coli mediated by CcrAB from methicillin-resistant S. aureus (MRSA) strain N315 was only 9.2%, while the integration frequency was 31.4%. In S. aureus the excision and integration frequencies were 11.0% and 18.7%, respectively. Truncated mutants identified the N-terminal domain of either CcrB or CcrA to be necessary for both integration and excision, while the C-terminal domain was important for recombination efficiency. Site-directed mutagenesis of the N-terminal domain identified S11 and R79 of CcrA and S16, R89, T149, and R151 of CcrB to be residues essential for catalytic activities, and the critical location of these residues was consistent with a model of the tertiary structure of the N terminus of CcrA and CcrB. Furthermore, CcrAB and CcrC, cloned from a panel of 6 methicillin-resistant S. aureus strains and 2 methicillin-resistant Staphylococcus epidermidis strains carrying SCCmec types II, IV, and V, also catalyzed integration at rates 1.3 to 10 times higher than the rates at which they catalyzed excision, similar to the results from N315. The tendency of SCCmec integration to be favored over excision may explain the low spontaneous excision frequency seen among MRSA strains. IMPORTANCE: Spontaneous excision of the genomic island (SCCmec) that encodes resistance to beta-lactam antibiotics (methicillin resistance) in staphylococci would convert a methicillin-resistant strain to a methicillin-susceptible strain, improving therapy of difficult-to-treat infections. This study characterizes a model system by which the relative frequencies of excision and integration can be compared. Using a plasmid-based model for excision and integration mediated by the recombinases CcrA and CcrB, integration occurred at a higher frequency than excision, consistent with the low baseline excision frequency seen in most strains. This model system can now be used to study conditions and drugs that may raise the SCCmec excision frequency and generate strains that are beta-lactam susceptible. PMID- 26055111 TI - Bacterial Signal Transduction by Cyclic Di-GMP and Other Nucleotide Second Messengers. AB - The first International Symposium on c-Di-GMP Signaling in Bacteria (22 to 25 March 2015, Harnack-Haus, Berlin, Germany)brought together 131 molecular microbiologists from 17 countries to discuss recent progress in our knowledge of bacterial nucleotide second messenger signaling. While the focus was on signal input, synthesis, degradation, and the striking diversity of the modes of action of the current second messenger paradigm, i.e., cyclic di-GMP (c-di-GMP), "classics" like cAMP and (p)ppGpp were also presented, in novel facets, and more recent "newcomers," such as c-di-AMP and c-AMP-GMP, made an impressive appearance. A number of clear trends emerged during the 30 talks, on the 71 posters, and in the lively discussions, including (i)c-di-GMP control of the activities of various ATPases and phosphorylation cascades, (ii) extensive cross talk between c-di-GMP and other nucleotide second messenger signaling pathways, and (iii) a stunning number of novel effectors for nucleotide second messengers that surprisingly include some long-known master regulators of developmental pathways. Overall, the conference made it amply clear that second messenger signaling is currently one of the most dynamic fields within molecular microbiology,with major impacts in research fields ranging from human health to microbial ecology. PMID- 26055112 TI - Structures of Capsular Polysaccharide Serotypes 35F and 35C of Streptococcus pneumoniae Determined by Nuclear Magnetic Resonance and Their Relation to Other Cross-Reactive Serotypes. AB - The structures of Streptococcus pneumoniae capsular polysaccharides (CPSs) are essential for defining the antigenic as well as genetic relationships between CPS serotypes. The four serotypes that comprise CPS serogroup 35 (i.e., types 35F, 35A, 35B, and 35C) are known to cross-react with genetically related type 20, 29, 34, 42, or 47F. While the structures of CPS serotype 35A (CPS35A) and CPS35B are known, those of CPS35F and CPS35C are not. In the present study, the serotypes of CPS35F and CPS35C were characterized by high-resolution heteronuclear magnetic resonance (NMR) spectroscopy and glycosyl composition analyses to reveal the following repeat unit structures: [Formula: see text] where OAc indicates O acetylated. Importantly, CPS35F, the immunizing serotype for the production of group 35 serum, more closely resembles CPS34 and CPS47F than other members of serogroup 35. Moreover, CPS35C is distinct from either CPS35F or CPS35B but closely related to CPS35A and identical to de-O-acetylated CPS42. The findings provide a comprehensive view of the structural and genetic relations that exist between the members of CPS serogroup 35 and other cross-reactive serotypes. IMPORTANCE: Cross-reactions of diagnostic rabbit antisera with Streptococcus pneumoniae capsular polysaccharide serotypes are generally limited to members of the same serogroup. Exceptions do, however, occur, most notably among a group of nonvaccine serotypes that includes the members of serogroup 35 (i.e., types 35F, 35A, 35B, and 35C) and other genetically related types. The presently determined structures of S. pneumoniae serotypes 35F and 35C complete the structural characterization of serogroup 35 and thereby provide the first comprehensive description of how different members of this serogroup are related to each other and to types 29, 34, 42, and 47F. The structural and genetic features of these serotypes suggest the existence of three distinct capsular polysaccharide subgroups that presumably emerged by immune selection in the human host. PMID- 26055113 TI - The RNA Helicase DeaD Stimulates ExsA Translation To Promote Expression of the Pseudomonas aeruginosa Type III Secretion System. AB - The Pseudomonas aeruginosa type III secretion system (T3SS) is a primary virulence factor important for phagocytic avoidance, disruption of host cell signaling, and host cell cytotoxicity. ExsA is the master regulator of T3SS transcription. The expression, synthesis, and activity of ExsA is tightly regulated by both intrinsic and extrinsic factors. Intrinsic regulation consists of the well-characterized ExsECDA partner-switching cascade, while extrinsic factors include global regulators that alter exsA transcription and/or translation. To identify novel extrinsic regulators of ExsA, we conducted a transposon mutagenesis screen in the absence of intrinsic control. Transposon disruptions within gene PA2840, which encodes a homolog of the Escherichia coli RNA-helicase DeaD, significantly reduced T3SS gene expression. Recent studies indicate that E. coli DeaD can promote translation by relieving inhibitory secondary structures within target mRNAs. We report here that PA2840, renamed DeaD, stimulates ExsA synthesis at the posttranscriptional level. Genetic experiments demonstrate that the activity of an exsA translational fusion is reduced in a deaD mutant. In addition, exsA expression in trans fails to restore T3SS gene expression in a deaD mutant. We hypothesized that DeaD relaxes mRNA secondary structure to promote exsA translation and found that altering the mRNA sequence of exsA or the native exsA Shine-Dalgarno sequence relieved the requirement for DeaD in vivo. Finally, we show that purified DeaD promotes ExsA synthesis using in vitro translation assays. Together, these data reveal a novel regulatory mechanism for P. aeruginosa DeaD and add to the complexity of global regulation of T3SS. IMPORTANCE: Although members of the DEAD box family of RNA helicases are appreciated for their roles in mRNA degradation and ribosome biogenesis, an additional role in gene regulation is now emerging in bacteria. By relaxing secondary structures in mRNAs, DEAD box helicases are now thought to promote translation by enhancing ribosomal recruitment. We identify here an RNA helicase that plays a critical role in promoting ExsA synthesis, the central regulator of the Pseudomonas aeruginosa type III secretion system, and provide additional evidence that DEAD box helicases directly stimulate translation of target genes. The finding that DeaD stimulates exsA translation adds to a growing list of transcriptional and posttranscriptional regulatory mechanisms that control type III gene expression. PMID- 26055114 TI - Diversity of Cyclic Di-GMP-Binding Proteins and Mechanisms. AB - Cyclic di-GMP (c-di-GMP) synthetases and hydrolases (GGDEF, EAL, and HD-GYP domains) can be readily identified in bacterial genome sequences by using standard bioinformatic tools. In contrast, identification of c-di-GMP receptors remains a difficult task, and the current list of experimentally characterized c di-GMP-binding proteins is likely incomplete. Several classes of c-di-GMP-binding proteins have been structurally characterized; for some others, the binding sites have been identified; and for several potential c-di-GMP receptors, the binding sites remain to be determined. We present here a comparative structural analysis of c-di-GMP-protein complexes that aims to discern the common themes in the binding mechanisms that allow c-di-GMP receptors to bind it with (sub)micromolar affinities despite the 1,000-fold excess of GTP. The available structures show that most receptors use their Arg and Asp/Glu residues to bind c-di-GMP monomers, dimers, or tetramers with stacked guanine bases. The only exception is the EAL domains that bind c-di-GMP monomers in an extended conformation. We show that in c-di-GMP-binding signature motifs, Arg residues bind to the O-6 and N-7 atoms at the Hoogsteen edge of the guanine base, while Asp/Glu residues bind the N-1 and N 2 atoms at its Watson-Crick edge. In addition, Arg residues participate in stacking interactions with the guanine bases of c-di-GMP and the aromatic rings of Tyr and Phe residues. This may account for the presence of Arg residues in the active sites of every receptor protein that binds stacked c-di-GMP. We also discuss the implications of these structural data for the improved understanding of the c-di-GMP signaling mechanisms. PMID- 26055115 TI - ABC Transporter Required for Intercellular Transfer of Developmental Signals in a Heterocystous Cyanobacterium. AB - In the filamentous cyanobacterium Anabaena, patS and hetN encode peptide-derived signals with many of the properties of morphogens. These signals regulate the formation of a periodic pattern of heterocysts by lateral inhibition of differentiation. Here we show that intercellular transfer of the patS- and hetN dependent developmental signals from heterocysts to vegetative cells requires HetC, a predicted ATP-binding cassette transporter (ABC transporter). Relative to the wild type, in a hetC mutant differentiation resulted in a reduced number of heterocysts that were incapable of nitrogen fixation, but deletion of patS or hetN restored heterocyst number and function in a hetC background. These epistasis results suggest that HetC is necessary for conferring self-immunity to the inhibitors on differentiating cells. Nine hours after induction of differentiation, HetC was required for neither induction of transcription of patS nor intercellular transfer of the patS-encoded signal to neighboring cells. Conversely, in strains lacking HetC, the patS- and hetN-encoded signals were not transferred from heterocyst cells to adjacent vegetative cells. The results support a model in which the patS-dependent signal is initially transferred between vegetative cells in a HetC-independent fashion, but some time before morphological differentiation of heterocysts is complete, transfer of both signals transitions to a HetC-dependent process. IMPORTANCE: How chemical cues that regulate pattern formation in multicellular organisms move from one cell to another is a central question in developmental biology. In this study, we show that an ABC transporter, HetC, is necessary for transport of two developmental signals between different types of cells in a filamentous cyanobacterium. ABC transporters are found in organisms as diverse as bacteria and humans and, as the name implies, are often involved in the transport of molecules across a cellular membrane. The activity of HetC was shown to be required for signaling between heterocysts, which supply fixed nitrogen to the organism, and other cells, as well as for conferring immunity to self-signaling on developing heterocysts. PMID- 26055116 TI - Members of the PpaA/AerR Antirepressor Family Bind Cobalamin. AB - PpaA from Rhodobacter sphaeroides is a member of a family of proteins that are thought to function as antirepressors of PpsR, a widely disseminated repressor of photosystem genes in purple photosynthetic bacteria. PpaA family members exhibit sequence similarity to a previously defined SCHIC (sensor containing heme instead of cobalamin) domain; however, the tetrapyrrole-binding specificity of PpaA family members has been unclear, as R. sphaeroides PpaA has been reported to bind heme while the Rhodobacter capsulatus homolog has been reported to bind cobalamin. In this study, we reinvestigated tetrapyrrole binding of PpaA from R. sphaeroides and show that it is not a heme-binding protein but is instead a cobalamin-binding protein. We also use bacterial two-hybrid analysis to show that PpaA is able to interact with PpsR and activate the expression of photosynthesis genes in vivo. Mutations in PpaA that cause loss of cobalamin binding also disrupt PpaA antirepressor activity in vivo. We also tested a number of PpaA homologs from other purple bacterial species and found that cobalamin binding is a conserved feature among members of this family of proteins. IMPORTANCE: Cobalamin (vitamin B12) has only recently been recognized as a cofactor that affects gene expression by interacting in a light-dependent manner with transcription factors. A group of related antirepressors known as the AppA/PpaA/AerR family are known to control the expression of photosynthesis genes in part by interacting with either heme or cobalamin. The specificity of which tetrapyrroles that members of this family interact with has, however, remained cloudy. In this study, we address the tetrapyrrole-binding specificity of the PpaA/AerR subgroup and establish that it preferentially binds cobalamin over heme. PMID- 26055117 TI - Evidence that Autophosphorylation of the Major Sporulation Kinase in Bacillus subtilis Is Able To Occur in trans. AB - Entry into sporulation in Bacillus subtilis is governed by a multicomponent phosphorelay, a complex version of a two-component system which includes at least three histidine kinases (KinA to KinC), two phosphotransferases (Spo0F and Spo0B), and a response regulator (Spo0A). Among the three histidine kinases, KinA is known as the major sporulation kinase; it is autophosphorylated with ATP upon starvation and then transfers a phosphoryl group to the downstream components in a His-Asp-His-Asp signaling pathway. Our recent study demonstrated that KinA forms a homotetramer, not a dimer, mediated by the N-terminal domain, as a functional unit. Furthermore, when the N-terminal domain was overexpressed in the starving wild-type strain, sporulation was impaired. We hypothesized that this impairment of sporulation could be explained by the formation of a nonfunctional heterotetramer of KinA, resulting in the reduced level of phosphorylated Spo0A (Spo0A~P), and thus, autophosphorylation of KinA could occur in trans. To test this hypothesis, we generated a series of B. subtilis strains expressing homo- or heterogeneous KinA protein complexes consisting of various combinations of the phosphoryl-accepting histidine point mutant protein and the catalytic ATP-binding domain point mutant protein. We found that the ATP-binding-deficient protein was phosphorylated when the phosphorylation-deficient protein was present in a 1:1 stoichiometry in the tetramer complex, while each of the mutant homocomplexes was not phosphorylated. These results suggest that ATP initially binds to one protomer within the tetramer complex and then the gamma-phosphoryl group is transmitted to another in a trans fashion. We further found that the sporulation defect of each of the mutant proteins is complemented when the proteins are coexpressed in vivo. Taken together, these in vitro and in vivo results reinforce the evidence that KinA autophosphorylation is able to occur in a trans fashion. IMPORTANCE: Autophosphorylation of histidine kinases is known to occur by either the cis (one subunit of kinase phosphorylating itself within the multimer) or the trans (one subunit of the multimer phosphorylates the other subunit) mechanism. The present study provided direct in vivo and in vitro evidence that autophosphorylation of the major sporulation histidine kinase (KinA) is able to occur in trans within the homotetramer complex. While the physiological and mechanistic significance of the trans autophosphorylation reaction remains obscure, understanding the detailed reaction mechanism of the sporulation kinase is the first step toward gaining insight into the molecular mechanisms of the initiation of sporulation, which is believed to be triggered by unknown factors produced under conditions of nutrient depletion. PMID- 26055119 TI - The complexities of charitable giving. PMID- 26055118 TI - Characterization of an Unconventional Rhodopsin from the Freshwater Actinobacterium Rhodoluna lacicola. AB - Rhodopsin-encoding microorganisms are common in many environments. However, knowing that rhodopsin genes are present provides little insight into how the host cells utilize light. The genome of the freshwater actinobacterium Rhodoluna lacicola encodes a rhodopsin of the uncharacterized actinorhodopsin family. We hypothesized that actinorhodopsin was a light-activated proton pump and confirmed this by heterologously expressing R. lacicola actinorhodopsin in retinal producing Escherichia coli. However, cultures of R. lacicola did not pump protons, even though actinorhodopsin mRNA and protein were both detected. Proton pumping in R. lacicola was induced by providing exogenous retinal, suggesting that the cells lacked the retinal cofactor. We used high-performance liquid chromatography (HPLC) and oxidation of accessory pigments to confirm that R. lacicola does not synthesize retinal. These results suggest that in some organisms, the actinorhodopsin gene is constitutively expressed, but rhodopsin based light capture may require cofactors obtained from the environment. IMPORTANCE: Up to 70% of microbial genomes in some environments are predicted to encode rhodopsins. Because most microbial rhodopsins are light-activated proton pumps, the prevalence of this gene suggests that in some environments, most microorganisms respond to or utilize light energy. Actinorhodopsins were discovered in an analysis of freshwater metagenomic data and subsequently identified in freshwater actinobacterial cultures. We hypothesized that actinorhodopsin from the freshwater actinobacterium Rhodoluna lacicola was a light-activated proton pump and confirmed this by expressing actinorhodopsin in retinal-producing Escherichia coli. Proton pumping in R. lacicola was induced only after both light and retinal were provided, suggesting that the cells lacked the retinal cofactor. These results indicate that photoheterotrophy in this organism and others may require cofactors obtained from the environment. PMID- 26055120 TI - The shifting landscape of safety pharmacology in 2015. AB - The relative importance of the discipline of safety pharmacology (which integrates physiology, pharmacologyand toxicology) has evolved since the incorporation of the Safety Pharmacology Society (SPS) as an entity on August 10, 2000. Safety pharmacology (SP), as a synthesis of these other fields of knowledge, is concerned with characterizing the safety profile (or potential undesirable pharmacodynamic effects) of new chemical entities (NCEs) and biologicals. Initially focused on the issue of drug-induced QT prolongation it has developed into an important discipline over the past 15years with expertise beyond its initial focus on torsades de pointes (TdP). It has become a repository for interrogation of models for drug safety studies and innovative non-clinical model development, validation and implementation. Thus, while safety pharmacology consists of the triumvirate obligatory cardiovascular, central nervous system (CNS) and respiratory system core battery studies it also involves assessing drug effects on numerous other physiological systems (e.g., ocular, auditory, renal, gastrointestinal, blood, immune) leveraging emerging new technologies in a wide range of non-clinical drug safety testing models. As with previous editorials that preface the themed issue on safety pharmacology methods published in the Journal of Pharmacological and Toxicological Methods (JPTM), we highlight here the content derived from the most recent (2014) SPS meeting held in Washington, DC. The dynamics of the discipline remain fervent and method development, extension and refinement are reflected in the content. This issue of the JPTM continues the tradition of providing a publication summary of articles (reviews, commentaries and methods) with impact on the discipline of safety pharmacology. PMID- 26055121 TI - Editorial overview: Theory and simulation. PMID- 26055122 TI - Internet-delivered cognitive control training as a preventive intervention for remitted depressed patients: Protocol for a randomized controlled trial. AB - BACKGROUND: Preventing recurrence of depression forms an important challenge for current treatments. Cognitive control impairments often remain present during remission of depression, putting remitted depressed patients at heightened risk for new depressive episodes by disrupting emotion regulation processes. Importantly, research indicates that cognitive control training targeting working memory functioning shows potential in reducing maladaptive emotion regulation and depressive symptomatology in clinically depressed patients and at-risk student samples. The current study aims to test the effectiveness of cognitive control training as a preventive intervention in a remitted depressed sample, exploring effects of cognitive control training on rumination and depressive symptomatology, along with indicators of adaptive emotion regulation and functioning. METHODS/DESIGN: We present a double blind randomized controlled design. Remitted depressed adults will complete 10 online sessions of a cognitive control training targeting working memory functioning or a low cognitive load training (active control condition) over a period of 14 days. Effects of training on primary outcome measures of rumination and depressive symptomatology will be assessed pre-post training and at three months follow-up, along with secondary outcome measure adaptive emotion regulation. Long-term effects of cognitive control training on broader indicators of functioning will be assessed at three months follow-up (secondary outcome measures). DISCUSSION: This study will provide information about the effectiveness of cognitive control training for remitted depressed adults in reducing vulnerability for depression. Furthermore, this study will address key questions concerning the mechanisms underlying the effects of cognitive control training, will take into account the subjective experience of the patients (including a self-report measure for cognitive functioning), and explore whether these effects extend to broad measures of functioning such as Quality of Life and disability. TRIAL REGISTRATION: This study is registered with ClinicalTrials.Gov, number NCT02407652 . PMID- 26055123 TI - Suppression of porcine reproductive and respiratory syndrome virus proliferation by glycyrrhizin. AB - Glycyrrhizin is a natural component extracted from the roots of Glycyrrhiza glabra. In this study, we investigated the antiviral activity of glycyrrhizin against porcine reproductive and respiratory syndrome virus (PRRSV), an Arterivirus that has been devastating the swine industry worldwide since the late 1980s. Our results showed that treatment with glycyrrhizin significantly reduced PRRSV proliferation and PRRSV-encoded protein expression in a dose-dependent manner. Mechanistically, glycyrrhizin mainly inhibits the penetration stage, and has little effect on the steps of adsorption or release of PRRSV in its life cycle. Furthermore, we were able to exclude a direct inhibitory action of glycyrrhizin on PRRSV particles. Given these results, glycyrrhizin may be a candidate component for a novel porcine reproductive and respiratory syndrome (PRRS) control strategy. PMID- 26055124 TI - Red ginseng represses hypoxia-induced cyclooxygenase-2 through sirtuin1 activation. AB - BACKGROUND: Korean red ginseng (KRG) is a traditional herbal medicine made by steaming and drying the fresh ginseng, leading to chemical transformation of some components by heat. It ameliorates various inflammatory diseases and strengthens the endocrine, immune, and central nervous systems. The cyclooxygenase-2 (COX 2)/prostaglandin E2 pathway in hypoxic cancer cells has important implications for stimulation of inflammation and tumorigenesis. PURPOSE: In this study we examined the effects and the mechanism underlying Korean red ginseng water extract (KRG-WE) inhibition of hypoxia-induced COX-2 in human distal lung epithelial A549 cells. STUDY DESIGN: The effect of the KRG on suppression of hypoxia-induced COX-2 in A549 cells were determined by Western blot and/or qRT PCR. The anti-invasive effect of KRG-WE was evaluated on A549 cells using matrigel invasion assay. The activation of glucocorticoid receptor (GR) and sirtuin1 (Sirt1) was examined by using specific inhibitors. RESULTS: We first observed that hypoxia induced COX-2 protein and mRNA levels and promoter activity were suppressed by KRG-WE. Second, we observed that hypoxia-induced cell migration is dramatically reduced by KRG-WE. Third, we found that the effect of KRG-WE was not antagonized by the GR antagonist RU486 implying that the effect is mediated other than GR pathway. Finally, we demonstrated that inhibition of Sirt1 abolished the effect of KRG-WE on hypoxia-induced COX-2 suppression and cell invasion indicating that the suppression is mediated by Sirt1. CONCLUSION: Taken together, KRG-WE inhibits the hypoxic induction of COX-2 expression and cell invasion through Sirt1 activation. Our results imply that KRG-WE could be effective for suppression of inflammation under hypoxia. PMID- 26055125 TI - Lemon verbena (Lippia citriodora) polyphenols alleviate obesity-related disturbances in hypertrophic adipocytes through AMPK-dependent mechanisms. AB - BACKGROUND: There is growing evidence that natural products, mostly plant-derived polyphenols, are important in the relationship between nutrients and health in humans. PURPOSE: We aimed to investigate if verbascoside (VB) and other lemon verbena polyphenols could ameliorate obesity-induced metabolic disturbances, as well as their putative mechanism. STUDY DESIGN: We used an insulin-resistant hypertrophic 3T3-L1-adipocyte model to test the effects of VB or lemon verbena extract on triglyceride accumulation, inflammation and oxidative stress and a murine model of diet-induced obesity to assess the in vivo metabolic response. RESULTS: Polyphenols decreased triglyceride accumulation, the generation of reactive oxygen species (ROS) and restored mitochondrial membrane potential in adipocytes. The underlying mechanisms seemed to occur via ROS-mediated downregulation of nuclear factor kappa-B transcription factor (NF-kappaB) and peroxisome proliferator-activated receptor gamma (PPAR-gamma)-dependent transcriptional upregulation of adiponectin. We also observed a potent activation of AMP-activated protein kinase (AMPK), the mRNA expression upregulation of PPAR alpha and the mRNA expression downregulation of fatty acid synthase. Experiments in mice suggested a significant improvement in fat metabolism. CONCLUSION: Decreased lipogenesis, enhanced fatty acid oxidation and the activation of the energy sensor AMPK, probably through activating transcriptional factors, are involved in the observed beneficial effects. VB effects were less potent than those observed with the extract, so a potential synergistic, multi-targeted action is proposed. The polypharmacological effects of plant-derived polyphenols from lemon verbena may have the potential for clinical applications in obesity. PMID- 26055126 TI - Selective inhibitory effects of machilin A isolated from Machilus thunbergii on human cytochrome P450 1A and 2B6. AB - BACKGROUND: The bark of Machilus thunbergii (Lauraceae) has been used as a folk medicine to treat abdominal pain and distension, and leg edema in Korea. Machilin A (MA), a lignan isolated from Machilus thunbergii, exhibits several biological activities including anti-oxidant and stimulatory effects on cell differentiation and proliferation. PURPOSE: Potential drug-interactions with MA via inhibition of cytochrome P450 (CYP) activity in human liver microsomes (HLMs), have not been investigated. STUDY DESIGN: The inhibitory effects of MA on the activities of CYPs were investigated using cocktail probe substrates in pooled HLMs and on human recombinant cDNA-expressed CYP isoforms. METHODS: The nine CYP-specific substrates were incubated in HLM or recombinant cDNA-expressed CYP 1A1, 1A2 and 2B6 with MA. After incubation, the samples were injected onto a C18 column for liquid chromatography-tandem mass spectrometry analysis. To investigate the binding poses between MA and CYP, we carried out structure-based docking simulations by using software and scripts written in-house (ALIS-DOCK; Automatic pLatform for Iterative Structure-based DOCKing). RESULTS: MA strongly inhibited CYP1A2-mediated phenacetin O-deethylation and CYP2B6-mediated bupropion hydroxylation with IC50 values of 3.0 and 3.9 uM, respectively, while it did not significantly inhibit other CYPs. A Dixon plot indicated that MA competitively inhibits CYP1A2 and CYP2B6 with Ki values of 0.71 and 4.1 uM, respectively. CONCLUSION: Overall, this was the first investigation of the inhibitory effects of MA on CYP1A2 and CYP2B6 in HLMs, and it has identified that MA acts via competitive inhibition. PMID- 26055127 TI - Supramolecular interaction of 6-shogaol, a therapeutic agent of Zingiber officinale with human serum albumin as elucidated by spectroscopic, calorimetric and molecular docking methods. AB - BACKGROUND: 6-Shogaol, one of the main bioactive constituents of Zingiber officinale has been shown to possess various therapeutic properties. Interaction of a therapeutic compound with plasma proteins greatly affects its pharmacokinetic and pharmacodynamic properties. PURPOSE: The present investigation was undertaken to characterize the interaction between 6-shogaol and the main in vivo transporter, human serum albumin (HSA). METHODS: Various binding characteristics of 6-shogaol-HSA interaction were studied using fluorescence spectroscopy. Thermal stability of 6-shogaol-HSA system was determined by circular dichroism (CD) and differential scanning calorimetric (DSC) techniques. Identification of the 6-shogaol binding site on HSA was made by competitive drug displacement and molecular docking experiments. RESULTS: Fluorescence quench titration results revealed the association constant, Ka of 6 shogaol-HSA interaction as 6.29 +/- 0.33 * 10(4) M(-1) at 25 oC. Values of the enthalpy change (-11.76 kJ mol(-1)) and the entropy change (52.52 J mol(-1) K( 1)), obtained for the binding reaction suggested involvement of hydrophobic and van der Waals forces along with hydrogen bonds in the complex formation. Higher thermal stability of HSA was noticed in the presence of 6-shogaol, as revealed by DSC and thermal denaturation profiles. Competitive ligand displacement experiments along with molecular docking results suggested the binding preference of 6-shogaol for Sudlow's site I of HSA. CONCLUSION: All these results suggest that 6-shogaol binds to Sudlow's site I of HSA through moderate binding affinity and involves hydrophobic and van der Waals forces along with hydrogen bonds. PMID- 26055128 TI - Effects of high phenolic olive oil on cardiovascular risk factors: A systematic review and meta-analysis. AB - BACKGROUND: Cardiovascular diseases are the world's leading cause of death. Prevention by nutrition is an easy and effective approach especially by advising foods with nutraceutic properties like high phenolic olive oil (HPOO). AIM: The aim of this review was to systematically access and meta-analyse the effects of HPOO on risk factors of the cardiovascular system and thusly to evaluate its use as a nutraceutical in prevention. DATA SYNTHESIS: Medline/PubMed, EMBase, the Cochrane Library, CAMbase and CAM-QUEST were searched through July 2013. Randomized controlled trials (RCTs) comparing high vs. low (resp. non) phenolic olive oils in either healthy participants or patients with cardiovascular diseases were included. For study appraisal the Cochrane Collaboration's risk of bias tool was used. Main outcomes were blood pressure, serum lipoproteins and oxidation markers. Standardized mean differences (SMD) and 95% confidence intervals (CI) were calculated and analysed by the generic inverse variance methods using a random effects model. Eight cross over RCTs comparing ingestion (21-90 d) of high vs. low (resp. non) phenolic olive oils with a total of 355 subjects were included. RESULTS: There were medium effects for lowering systolic blood pressure (n = 69; SMD -0.52; CI -0.77/-0.27; p < 0.01) and small effects for lowering oxLDL (n = 300; SMD -0.25; CI [-0.50/0.00]; p = 0.05). No effects were found for diastolic blood pressure (n = 69; SMD -0.20; CI -1.01/0.62; p = 0.64); malondialdehyde (n = 71; SMD -0.02; CI [-0.20/0.15]; p = 0.79), total cholesterol (n = 400; SMD -0.05; CI [-0.16/0.05]; p = 0.33); HDL (n = 400; SMD 0.03; CI [-0.14/0.08]; p = 0.62); LDL (n = 400; SMD -0.03; CI [-0.15/0.09]; p = 0.61); and triglycerides (n = 360; SMD 0.02; CI [-0.22/0.25]; p = 0.90). LIMITATIONS: The small number of studies/participants limits this review. CONCLUSIONS: HPOO provides small beneficial effects on systolic blood pressure and serum oxidative status (oxLDL). HPOO should be considered as a nutraceutical in cardiovascular prevention. PMID- 26055129 TI - Kinsenoside-mediated lipolysis through an AMPK-dependent pathway in C3H10T1/2 adipocytes: Roles of AMPK and PPARalpha in the lipolytic effect of kinsenoside. AB - BACKGROUND: Currently, more than one-third of the global population is overweight or obese, which is a risk factor for major causes of death including cardiovascular disease, numerous cancers, and diabetes. Kinsenoside, a major active component of Anoectochilus formosanus exhibits antihyperglycemic, antihyperliposis, and hepatoprotective effects and can be used to prevent and manage obesity. PURPOSE: This study examined the catabolic effects of kinsenoside on lipolysis in adipocytes transformed from C3H10T1/2 cells. STUDY DESIGN/METHODS: The lipolytic effect of kinsenoside in C3H10T1/2 adipocytes was evaluated by oil-red O staining and glycerol production. The underlying mechanisms were assessed by Western blots, chromatin immunoprecipitation (IP), Co IP, EMSA and siRNAs verification. RESULTS: We demonstrated that kinsenoside increased both adipose triglyceride lipase (ATGL)-mediated lipolysis, which was upregulated by AMP-activated protein kinase (AMPK) activation, and the hydrolysis of triglycerides to glycerol and fatty acids that require transportation into mitochondria for further beta-oxidation. We also demonstrated that kinsenoside increased the phosphorylation of peroxisome proliferator-activated receptor alpha (PPARalpha) and CRE-binding protein (CREB), and the protein levels of silent information regulator T1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) and carnitine palmitoyltransferase I (CPT1) through an AMPK-dependent mechanism. SIRT1 deacetylated PGC-1alpha, facilitating AMPK-mediated PGC-1alpha phosphorylation and increasing the interaction of PPARalpha with its coactivator, PGC-1alpha. This interaction elevated the expression of CPT1, a shuttle for the mitochondrial transport of fatty acids, in kinsenoside-treated cells. In addition, AMPK-phosphorylation mediated CREB activation caused kinsenoside-mediated PGC-1alpha upregulation. CONCLUSION: AMPK activation not only elevated ATGL expression for lipolysis but also induced CPT1 expression for further mitochondrial translocation of fatty acids. The results suggested that the mechanism underlying the catabolic effects of kinsenoside on lipolysis and increased CPT1 induction was mediated through an AMPK-dependent pathway. PMID- 26055130 TI - Detection of pyrrolizidine alkaloids in German licensed herbal medicinal teas. AB - BACKGROUND: Because of the hepatotoxic, mutagenic, and cancerogenic effects of pyrrolizidine alkaloids (PAs) the German Federal Institute for Risk Assessment (BfR) recommends not to exceed a daily PA intake of 0.007 ug/kg body weight (0.42 ug/60 kg adult). In a recent study conducted by the BfR, up to 5647 ug PA/kg dried herbal material were detected in tea products marketed as food. PURPOSE: The present study aimed at elucidating whether medicinal teas licensed or registered as medicinal products contain PAs as well. STUDY DESIGN: One hundred sixty-nine different commercially available medicinal teas, i.e. 19 nettle (Urtica dioica L.), 12 fennel (Foeniculum vulgare Mill.), 14 chamomile (Matricaria recutita L.), 11 melissa (Melissa officinalis L.) and 4 peppermint (Mentha piperita L.) teas as well as 109 tea mixtures were analyzed for the presence of 23 commercially available PAs. METHOD: LC/MS was used for the determination of the PAs RESULTS: In general, the total PA contents ranging 0 5668 ug/kg. Thirty percent of the tested single-ingredient tea products and 56.9% of the tested medicinal tea mixtures were found to contain PA concentrations above the limit of quantification (LOQ) of 10 ug/kg. In 11 medicinal teas PA contents >300 ug/kg dry herb were determined thus exceeding the recommended limit for PA intake by BfR. In addition three products of the investigated tea mixtures revealed extremely high PA contents of 4227, 5137, and 5668 ug/kg. Generally, single-ingredient tea products contained much less or even no detectable amounts of PAs when compared to the tea mixtures. PAs in the range between 13 and 1080 ug/kg were also detected in five analyzed aqueous herbal infusions of the medicinal tea mixture products with the highest PA content. Two out of the five investigated herbal infusions exceeded the recommended BfR limit for PA intake. CONCLUSION: This study demonstrates clearly that also medicinal teas licensed as medicinal products may partly contain high amounts of PAs exceeding current recommendations. For that reason manufacturers are advised to carry out more rigorous quality control tests devoted to the detection of PAs. This is very important to minimize PAs in medicinal teas accounting for possible additional exposure of the consumer to PAs from other food sources (e.g. honey). PMID- 26055131 TI - The in vitro antimicrobial activity of Cymbopogon essential oil (lemon grass) and its interaction with silver ions. AB - BACKGROUND: It is well known that Cymbopogon (lemon grass) essential oil exhibits antimicrobial activity while the efficacy of silver ions as a disinfectant is equally well reported. HYPOTHESIS: The antimicrobial activity of CEO and Ag(+) and their synergistic combinations will be useful in improving the current treatment strategies for various infections. STUDY DESIGN: In the present study, we determined the chemical composition and in vitro antimicrobial activity of six different Cymbopogon essential oils (CEO's) alone and in combination with silver ions (Ag(+)) against two Gram-positive (Staphylococcus aureus and Enterococcus faecalis), two Gram-negative (Escherichia coli and Moraxella catarrhalis) and two yeast species (Candida albicans and Candida tropicalis). The nature of potential interactions was determined by fractional inhibitory concentration indices (FICIs) for CEO's and Ag(+) calculated from microdilution assays and time-kill curves. RESULTS: Gas chromatography-mass spectrometry results confirmed the presence of nerol, geranial and geraniol as major volatile compounds. Minimum inhibitory concentration (MIC) values confirmed that all the tested pathogens are variably susceptible to both CEO's as well as Ag(+). The MIC of CEO's and Ag(+) against all the tested pathogens ranged from 0.032 mg/ml to 1 mg/ml and 0.004 and 0.064 mg/ml respectively, whereas when assayed in combination the FICI values were drastically reduced to range between 0.258 and 2.186, indicating synergy, additive and indifferent interactions. The most prominent interaction was observed between Cymbopogon flexuosus essential oil and Ag(+) against C. albicans with ?FIC = 0.254. The synergistic interactions were further confirmed through the construction of isobolograms and time-kill plots. Transmission electron microscopy showed disturbance in the cell envelope upon the concomitant treatment of CEO's and Ag(+), which ultimately leads to cell death. CONCLUSION: Results suggest that CEO's and Ag(+) when used in combination offers an opportunity to the formulation scientist to produce novel combinations acting synergistically in the continued quest to control important infectious pathogens. PMID- 26055132 TI - Synergistic mutual potentiation of antifungal activity of Zuccagnia punctata Cav. and Larrea nitida Cav. extracts in clinical isolates of Candida albicans and Candida glabrata. AB - BACKGROUND: Zuccagnia punctata Cav. (Fabaceae) and Larrea nitida Cav. (Zygophyllaceae) are indistinctly or jointly used in traditional medicine for the treatment of fungal-related infections. Although their dichloromethane (DCM) extract have demonstrated moderate antifungal activities when tested on their own, antifungal properties of combinations of both plants have not been assessed previously. PURPOSE: The aim of this study was to establish with statistical rigor whether Z. punctata (ZpE) and L. nitida DCM extract (LnE) interact synergistically against the clinically important fungi Candida albicans and Candida glabrata and to characterize the most synergistic combinations. STUDY DESIGN: For synergism assessment, the statistical-based Boik's design was applied. Eight ZpE-LnE fixed-ratio mixtures were prepared from four different months of 1 year and tested against Candida strains. Lphi (Loewe index) of each mixture at different fractions affected (phi) allowed for the finding of the most synergistic combinations, which were characterized by HPLC fingerprint and by the quantitation of the selected marker compounds. METHODS: Lphi and confidence intervals were determined in vitro with the MixLow method, once the estimated parameters from the dose-response curves of independent extracts and mixtures, were obtained. Markers (four flavonoids for ZpE and three lignans for LnE) were quantified in each extract and their combinations, with a valid HPLC-UV method. The 3D-HPLC profiles of the most synergistic mixtures were obtained by HPLC-DAD. RESULTS: Three over four IC50ZpE/IC50LnE fixed-ratio mixtures displayed synergistic interactions at effect levels phi > 0.5 against C. albicans. The dosis of the most synergistic (Lphi = 0.62) mixture was 65.96 ug/ml (ZpE = 28%; LnE = 72%) containing 8 and 36% of flavonoids and lignans respectively. On the other hand, one over four IC50ZpE/IC50LnE mixtures displays synergistic interactions at phi > 0.5 against C. glabrata. The dosis of the most synergistic (Lphi = 0.67) mixture was 168.23 ug/ml (ZpE = 27%; LnE = 73%) with 9.7 and 31.6% of flavonoids and lignans respectively. CONCLUSIONS: Studies with the statistical based MixLow method, allowed for the finding of the most ZpE-LnE synergistic mixtures, giving support to a proper joint use of both antifungal herbs in traditional medicine. PMID- 26055133 TI - Protective effect of Artemisia asiatica (Pamp.) Nakai ex Kitam ethanol extract against cisplatin-induced apoptosis of human HaCaT keratinocytes: Involvement of NF-kappa B- and Bcl-2-controlled mitochondrial signaling. AB - BACKGROUND: Oral mucositis is a common adverse effect of antineoplastic chemotherapy limiting sufficient dose of chemoregimen. Numerous attempts to mitigate chemotherapy-induced oral mucositis have failed to identify an appropriate treatment. HYPOTHESIS: We hypothesize that Artemisia asiatica (Pamp.) Nakai ex Kitam ethanol extract (Aa-EE) would mitigate cisplatin-induced cytotoxicity to oral mucosal epithelial cells. STUDY DESIGN: In vitro experimental study. METHODS: Cell viability and wound healing assay were performed. Apoptosis, mitochondrial membrane potential (MMP) change, and changes in apoptosis-related signaling were demonstrated in human primary keratinocyte (HaCaT). RESULTS: Cisplatin inhibited HaCaT cell proliferation and migration. Aa EE protected against these effects. Cisplatin treatment of HaCaT cells caused apoptosis and changes in MMP. Aa-EE inhibited cisplatin-induced apoptosis, and stabilized the cisplatin-induced loss of MMP. Western blots revealed that Aa-EE reduced the expression of cytochrome c and cleaved caspase-3 and inhibited nuclear translocation of nuclear factor-kappa B (NF-kappaB), compared with the levels observed after cisplatin treatment, whereas Bcl-2 expression was increased by Aa-EE. CONCLUSION: Collectively, our results suggest that Aa-EE protects HaCaT cells by inhibiting cisplatin-induced mitochondrial damage associated with Bcl-2 activity and by inhibiting nuclear translocation of NF-kappaB. PMID- 26055134 TI - Pancreatic Resection for Side-Branch Intraductal Papillary Mucinous Neoplasm (SB IPMN): a Contemporary Single-Institution Experience. AB - BACKGROUND: Given the malignant potential of main duct intraductal papillary mucinous neoplasm (M-IPMN), surgical resection is generally indicated. With regard to side-branch intraductal papillary mucinous neoplasm (SB-IPMN), resection vs. observation is a topic of debate. Further review of SB-IPMN is necessary to clarify appropriate management. The primary focus of this project is to determine the incidence of malignant final pathology for patients undergoing surgery for isolated SB-IPMN with non-malignant fine-needle aspiration (FNA) cytology. We also sought to describe the relationship between factors considered in the international consensus guidelines and final pathologic outcome. METHODS: The study is a retrospective review of all patients who underwent surgical resection for intraductal papillary mucinous neoplasm (IPMN) from 2002 to 2013 at our institution. Patients with a preoperative diagnosis of isolated SB-IPMN and FNA results for non-malignant cytology were selected among this surgical cohort for further analysis of preoperative clinical characteristics and outcomes. RESULTS: A total of 137 patients undergoing resection for IPMN were identified. Of these, 81 patients (59%) had a component of M-IPMN or invasive disease on FNA, leaving 66 (46%) patients with SB-IPMN and non-malignant cytology. Invasive adenocarcinoma was found in 8/66 (12%) patients and high-grade dysplasia (HGD) in 4/66 (8%) patients. The mean [SD] diameter of benign SB-IPMN was 2.0 cm [1.1] (range 0.3-5.7) vs. that of HGD/invasive disease which was 3.1 cm [1.3] (range 1.5-6.0; P = 0.014). Of the 12 patients found to have HGD or invasive disease, symptoms, mural nodules, and septations were found in 7 (58%), 5 (42%), and 6 (50%), respectively. Tumor staging were as follows: IA (2), IB (2), 2A (4), and 2B (1). CONCLUSION: With proper selection criteria, SB-IPMN is associated with a low rate of invasive pancreatic ductal adenocarcinoma at the time of resection. Nevertheless, given the demonstrated incidence of malignancy, appropriate operative candidates should undergo resection. PMID- 26055135 TI - Extended Versus Standard Lymphadenectomy for Pancreatic Head Cancer: Meta Analysis of Randomized Controlled Trials. AB - INTRODUCTION: The evidence for improved prognostic assessment and long-term survival for extended pancreatoduodenectomy (EPD) compared to standard pancreatoduodenectomy (SPD) in patients with carcinoma of the head of the pancreas has not been considered from only randomized controlled trials (RCTs). METHODS: The aim of this study was to conduct a systematic review and meta analysis of the outcomes comparing SPD and EPD in RCTs. Searches were performed on MEDLINE, Embase and Cochrane databases using MeSH keyword combinations: 'pancreatic cancer', 'pancreaticoduodenectomy', 'extended', 'randomized' and 'lymphadenectomy'. RCTs published up to 2014 were included. Overall post operative survival, morbidity, 30-day mortality and length of hospital stay were the outcomes assessed. RESULTS: Five eligible RCTs with 546 participants were included (EPD = 276 and SPD = 270). EPD was associated with a significantly higher number of excised lymph nodes (LNs) compared to SPD (mean difference = 15.73, 95% confidence interval (CI) = 9.41-22.04; P < 0.00001; I(2) = 88%). LN metastasis was detected in 58-68 and 55-70% of patients who had EPD and SPD, respectively. EPD did not improve overall survival (hazard ratio (HR) = 0.88, 95% CI = 0.75-1.03; P = 0.11) but did worsen post-operative morbidity compared to SPD (risk ratio (RR) = 1.23; 95% CI = 1.01-1.50; P = 0.004; I(2) = 9%). There were no differences in the 30-day mortality (RR = 0.81; 95% CI = 0.32-2.06; P = 0.66; I(2) = 0%) or length of hospital stay (mean difference = 1.39, 95% CI = -2.31 to 5.09; P = 0.46; I(2) = 67%). CONCLUSION: SPD is associated with reduced morbidity, but equivalent long-term benefits compared to patients undergoing EPD. PMID- 26055136 TI - Postoperative Mortality Among Patients With Inflammatory Bowel Diseases: A Systematic Review and Meta-analysis of Population-Based Studies. AB - BACKGROUND & AIMS: There have been varying reports of mortality after intestinal resection for the inflammatory bowel diseases (IBDs). We performed a systematic review and meta-analysis of population-based studies to determine postoperative mortality after intestinal resection in patients with IBD. METHODS: We searched Medline, EMBASE, and PubMed, from 1990 through 2015, to identify 18 articles and 3 abstracts reporting postoperative mortality among patients with IBD. The studies included 67,057 patients with ulcerative colitis (UC) and 75,971 patients with Crohn's disease (CD), from 15 countries. Mortality estimates stratified by emergent and elective surgeries were pooled separately for CD and UC using a random-effects model. To assess changes over time, the start year of the study was included as a continuous variable in a meta-regression model. RESULTS: In patients with UC, postoperative mortality was significantly lower among patients who underwent elective (0.7%; 95% confidence interval [CI], 0.6%-0.9%) vs emergent surgery (5.3%; 95% CI, 3.8%-7.4%). In patients with CD, postoperative mortality was significantly lower among patients who underwent elective (0.6%; 95% CI, 0.2%-1.7%) vs emergent surgery (3.6%; 95% CI, 1.8%-6.9%). Postoperative mortality did not differ for elective (P = .78) or emergent (P = .31) surgeries when patients with UC were compared with patients with CD. Postoperative mortality decreased significantly over time for patients with CD (P < .05) but not UC (P = .21). CONCLUSIONS: Based on a systematic review and meta-analysis, postoperative mortality was high after emergent, but not elective, intestinal resection in patients with UC or CD. Optimization of management strategies and more effective therapies are necessary to avoid emergent surgeries. PMID- 26055137 TI - Endoscopic Submucosal Dissection Using Head-mounted Display. PMID- 26055139 TI - Virus infection in HLA-haploidentical hematopoietic stem cell transplantation: incidence in the context of immune recovery in two different transplantation settings. AB - We retrospectively compared the incidence of virus infections and outcome in the context of immune reconstitution in two different HLA-haploidentical transplantation (haplo-HSCT) settings. The first was a combined T-cell-replete and T-cell-deplete approach using antithymocyte globulin (ATG) prior to transplantation in patients with hematological diseases (cTCR/TCD group, 28 patients; median age 31 years). The second was a T-cell-replete (TCR) approach using high-dose posttransplantation cyclophosphamide (TCR/PTCY group, 27 patients; median age 43 years). The incidence of herpesvirus infection was markedly lower in the TCR/PTCY (22 %) than in the cTCR/TCD group (93 %). Recovery of CD4+ T cells on day +100 was faster in the TCR/PTCY group. CMV reactivation was 30 % in the TCR/PTCY compared to 57 % in the cTCR/TCD group, and control with antiviral treatment was superior after TCR/PTCY transplantation (100 vs 50 % cTCR/TCD). Twenty-five percent of the patients in the cTCR/TCD group but no patient in the TCR/PTCY group developed PTLD. While 1-year OS was not different (TCR/PTCY 59 % vs cTCR/TCD 39 %; p = 0.28), virus infection-related mortality (VIRM) was significantly lower after TCR/PTCY transplantation (1-year VIRM, 0 % TCR/PTCY vs 29 % cTCR/TCD; p = 0.009). On day +100, predictors of better OS were lymphocytes >300/MUl, CD3+ T cells >200/MUl, and CD4+ T cells >150/MUl, whereas the application of steroids >1 mg/kg was correlated with worse outcome. Our results suggest that by presumably preserving antiviral immunity and allowing fast immune recovery of CD4+ T cells, the TCR approach using posttransplantation cyclophosphamide is well suited to handle the important issue of herpesvirus infection after haplo-HSCT. PMID- 26055138 TI - MicroRNA214 Is Associated With Progression of Ulcerative Colitis, and Inhibition Reduces Development of Colitis and Colitis-Associated Cancer in Mice. AB - BACKGROUND & AIMS: Persistent activation of the inflammatory response contributes to the development of inflammatory bowel diseases, which increase the risk of colorectal cancer. We aimed to identify microRNAs that regulate inflammation during the development of ulcerative colitis (UC) and progression to colitis associated colon cancer (CAC). METHODS: We performed a quantitative polymerase chain reaction analysis to measure microRNAs in 401 colon specimens from patients with UC, Crohn's disease, irritable bowel syndrome, sporadic colorectal cancer, or CAC, as well as subjects without these disorders (controls); levels were correlated with clinical features and disease activity of patients. Colitis was induced in mice by administration of dextran sodium sulfate (DSS), and carcinogenesis was induced by addition of azoxymethane; some mice also were given an inhibitor of microRNA214 (miR214). RESULTS: A high-throughput functional screen of the human microRNAome found that miR214 regulated the activity of nuclear factor-kappaB. Higher levels of miR214 were detected in colon tissues from patients with active UC or CAC than from patients with other disorders or controls and correlated with disease progression. Bioinformatic and genome-wide profile analyses showed that miR214 activates an inflammatory response and is amplified through a feedback loop circuit mediated by phosphatase and tensin homolog (PTEN) and PDZ and LIM domain 2 (PDLIM2). Interleukin-6 induced signal transducer and activator of transcription 3 (STAT3)-mediated transcription of miR214. A miR214 chemical inhibitor blocked this circuit and reduced the severity of DSS-induced colitis in mice, as well as the number and size of tumors that formed in mice given azoxymethane and DSS. In fresh colonic biopsy specimens from patients with active UC, the miR214 inhibitor reduced inflammation by increasing levels of PDLIM2 and PTEN. CONCLUSIONS: Interleukin-6 up-regulates STAT3-mediated transcription of miR214 in colon tissues, which reduces levels of PDLIM2 and PTEN, increases phosphorylation of AKT, and activates nuclear factor-kappaB. The activity of this circuit correlates with disease activity in patients with UC and progression to colorectal cancer. PMID- 26055140 TI - Predicting the other in cooperative interactions. AB - Recent research has shown that a collection of neurons in dorsal anterior cingulate cortex of rhesus monkeys may specifically encode the choice selection of an interaction partner. This raises interesting and important questions as to the nature of Theory of Mind processes in social interactive decision-making, with potential societal implications. PMID- 26055141 TI - miR-449b rs10061133 and miR-4293 rs12220909 polymorphisms are associated with decreased esophageal squamous cell carcinoma in a Chinese population. AB - Esophageal cancer is one of the most aggressive cancers in the world, 70% of which are from China and esophageal squamous cell carcinoma (ESCC) is the major histopathological form (>90%). The single nucleotide polymorphisms (SNPs) in mature sequence of microRNA (miRNA) (mmSNPs) could cause the alteration of microRNA expression and contribute to the susceptibility of cancers. To evaluate the association between mmSNPs and ESCC, a case-control study including 773 patients with ESCC and 882 gender- and age-matched controls was carried out to investigate the association of five mmSNPs (miR-449b rs10061133, miR-4293 rs12220909, miR-608 rs4919510, miR-627 rs2620381, and miR-646 rs6513497) with ESCC susceptibility. As a result, two SNPs, miR-449b rs10061133 and miR-4293 rs12220909, were associated with decreased ESCC risk. For miR-449b rs10061133 A>G, individuals carrying GG genotype had an odds ratio (OR) of 0.77 (95% confidence interval (95% CI) 0.62-0.97) compared with individuals with AA genotype. In the recessive model, the GG genotype also showed a protective effect on ESCC (OR = 0.78, 95% CI 0.63-0.97). For miR-4293 rs12220909 G>C, the heterozygous genotype GC was associated with a decreased ESCC risk (OR = 0.77, 95% CI 0.61-0.97) compared with GG genotype. The C allele conferred 23% decrease in ESCC risk compared with the G allele in the allelic model (95% CI 0.63-0.93). In the dominant model, the GC/CC genotypes decreased the risk of ESCC (adjusted OR = 0.77, 95% CI 0.61-0.96). This study provides the first evidence that miR 449b rs10061133 and miR-4293 rs12220909 are associated with ESCC risk in Chinese population. PMID- 26055142 TI - Downregulation of TRIM21 contributes to hepatocellular carcinoma carcinogenesis and indicates poor prognosis of cancers. AB - The aim of our work is to clarify the clinical implication and functional role of tripartite motif 21 (TRIM21) in hepatocellular carcinoma (HCC). We validated that TRIM21 was downregulated in liver cancer samples by immunohistochemical (IHC) staining. We also demonstrated that its downregulation was associated with several clinicopathologic features such as tumor numbers, T stage, Barcelona Clinic Liver Cancer (BCLC) stage, and Cancer of the Liver Italian Program (CLIP) stage of HCC patients. Importantly, the expression of TRIM21 in tumor samples is significantly correlated with the prognosis of the patients. We further silenced TRIM21 in HCC cell HepG2 and LM3 and confirmed that TRIM21 silencing will promote cancer cell proliferation (CCK-8 assay), colony forming (plate colony-forming assay), migration (transwell assay), and the ability of antiapoptosis (annexin V FITC/PI staining) in vitro. Then, we predicted gene sets influenced by TRIM21 by using bioinformatic tools. For the first time, we prove that TRIM21 is a potential tumor suppressor in HCC and its low expression indicates poor prognosis. Our findings provide useful insight into the mechanism of HCC origin and progression and offer clues to novel HCC therapies. PMID- 26055143 TI - Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients' outcome. AB - Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients' survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer. PMID- 26055144 TI - Overexpression of Wnt7alpha protein predicts poor survival in patients with colorectal carcinoma. AB - Wnt7alpha (wingless-type MMTV integration site family, member 7A) is a secreted glycoprotein that plays a critical role in tumorigenesis and development by controlling cell proliferation and differentiation. Whether Wnt7alpha has the properties of an oncogene or not is an interesting issue because of its diverse expression in different tumors. In the present study, Wnt7alpha protein expression was evaluated through immunohistochemistry and Western blot analysis. Univariate and multivariate analyses were applied to explore the associations between Wnt7alpha staining score and various clinical parameters, including overall survival (OS) and disease-free survival (DFS), and a total of 212 patients with colorectal cancer (CRC) were surveyed. Wnt7alpha was strongly expressed in most CRC tissues but weakly expressed in adjacent normal mucosa, colorectal adenomas, and colonic polyps. High levels of Wnt7alpha expression were strongly associated with tumor size (P = 0.006), lymph node involvement (P < 0.001), and the international tumor-node-metastasis (TNM) stage (P = 0.005). Patients with strong Wnt7alpha expression showed significantly poorer OS and DFS than patients with weak Wnt7alpha expression (P < 0.0001, both). Multivariate Cox analysis confirmed that Wnt7alpha protein expression and TNM stage are independent factors of adverse OS and DFS in CRC patients. Taken together, our results present evidence that Wnt7alpha overexpression is associated with an unfavorable prognosis and that positive Wnt7alpha, in addition to TNM stage, may be an independent prognosis factor influencing OS and DFS prediction in CRC patients. PMID- 26055146 TI - The Symmetry of Adverse Local Tissue Reactions in Patients with Bilateral Simultaneous and Sequential ASR Hip Replacement. AB - The purpose of this study was to evaluate whether patients with bilateral metal on-metal (MoM) hip replacements have symmetric adverse local tissue reactions (ALTRs) at follow-up. An MRI of both hips was performed at a mean time of six years after surgery in 43 patients. The prevalence and severity of ALTRs were found to be similar in simultaneous hips but differences were observed in sequential hips. The order and timing of sequential hip arthroplasties did not affect the severity of ALTRs. Thus, in addition to metal ion exposure from an earlier MoM implant other factors may also play a role in the progression of ALTRs. Bilateral implants should be given special consideration in risk stratification algorithms for management of patients with MoM hip arthroplasty. PMID- 26055147 TI - Differential uptake of recent Papanicolaou testing by HPV vaccination status among young women in the United States, 2008-2013. AB - BACKGROUND: A positive association between recent Papanicolaou (Pap) test uptake and initiation of HPV vaccination among U.S. women has been reported. However, it is unknown whether recent Pap testing by HPV vaccination status varies by race/ethnicity. Discerning racial/ethnic variations is important given the higher prevalence of HPV types other than 16 and 18 in some racial/ethnic groups. We assessed whether uptake of recent Pap testing differed among women aged 21-30 years who had not initiated the HPV vaccination series versus those who had and whether this pattern differed by sociodemographic factors. METHODS: 2008, 2010, and 2013 National Health Interview Survey data were used to generate weighted prevalence estimates and 95% confidence intervals (CIs) (n=7095). Adjusted predicted marginal models were used to generate adjusted prevalence ratios (aPRs) to assess the relationship between recent Pap test uptake and HPV vaccination series initiation by race/ethnicity. RESULTS: The uptake of recent Pap testing among those who had not initiated the HPV vaccination series was significantly lower (81.0%) compared to those who had initiated vaccination (90.5%) (aPR=0.93, 95% CI: 0.90-0.96). This finding was consistent across most sociodemographic factors, though not statistically significant for Blacks, Hispanics, those with lower levels of education, or those with higher levels of income. CONCLUSION: Young women who had not initiated HPV vaccination were less likely to have had a recent Pap test compared to women who had initiated vaccination. Concerted efforts are needed to increase uptake of recommended cervical cancer screening and HPV vaccination among young women. PMID- 26055148 TI - Oxysterols and related sterols: Chemical, biochemical and biological aspects. PMID- 26055149 TI - Rapid Increase in Neural Conduction Time in the Adult Human Auditory Brainstem Following Sudden Unilateral Deafness. AB - Individuals with sudden unilateral deafness offer a unique opportunity to study plasticity of the binaural auditory system in adult humans. Stimulation of the intact ear results in increased activity in the auditory cortex. However, there are no reports of changes at sub-cortical levels in humans. Therefore, the aim of the present study was to investigate changes in sub-cortical activity immediately before and after the onset of surgically induced unilateral deafness in adult humans. Click-evoked auditory brainstem responses (ABRs) to stimulation of the healthy ear were recorded from ten adults during the course of translabyrinthine surgery for the removal of a unilateral acoustic neuroma. This surgical technique always results in abrupt deafferentation of the affected ear. The results revealed a rapid (within minutes) reduction in latency of wave V (mean pre = 6.55 ms; mean post = 6.15 ms; p < 0.001). A latency reduction was also observed for wave III (mean pre = 4.40 ms; mean post = 4.13 ms; p < 0.001). These reductions in response latency are consistent with functional changes including disinhibition or/and more rapid intra-cellular signalling affecting binaurally sensitive neurons in the central auditory system. The results are highly relevant for improved understanding of putative physiological mechanisms underlying perceptual disorders such as tinnitus and hyperacusis. PMID- 26055150 TI - Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin. AB - Cyclodextrins are simple yet powerful molecules widely used in medicinal formulations and industry for their ability to stabilize and solubilize guest compounds. However, recent evidence shows that 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) causes severe hearing loss in mice, selectively killing outer hair cells (OHC) within 1 week of subcutaneous drug treatment. In the current study, the impact of HPbetaCD on auditory physiology and pathology was explored further as a function of time and route of administration. When administered subcutaneously or directly into cerebrospinal fluid, single injections of HPbetaCD caused up to 60 dB threshold shifts and widespread OHC loss in a dose dependent manner. Combined dosing caused no greater deficit, suggesting a common mode of action. After drug treatment, OHC loss progressed over time, beginning in the base and extending toward the apex, creating a sharp transition between normal and damaged regions of the cochlea. Administration into cerebrospinal fluid caused rapid ototoxicity when compared to subcutaneous delivery. Despite the devastating effect on the cochlea, HPbetaCD was relatively safe to other peripheral and central organ systems; specifically, it had no notable nephrotoxicity in contrast to other ototoxic compounds like aminoglycosides and platinum-based drugs. As cyclodextrins find expanding medicinal applications, caution should be exercised as these drugs possess a unique, poorly understood, ototoxic mechanism. PMID- 26055151 TI - Expression of 3-phosphoinositide-dependent protein kinase 1 in colorectal cancer as a potential therapeutic target. AB - 3-Phosphoinositide-dependent protein kinase 1 (PDK1) is centrally involved in cancer progression, including proliferation, apoptosis and invasion. However, its expression pattern and possible cellular functions in human colorectal cancer remain unclear. In the present study, we show that PDK1 expression is up regulated at both mRNA and protein levels in colorectal cancer clinical specimens and cell lines. Transient knockdown of PDK1 suppresses cellular growth, induces cellular apoptosis and causes abnormal cell cycle distribution. Meanwhile, decreased PDK1 level is closely associated with reduced Akt/cyclin D1 activity. Activating AKT activity and reintroducing cyclin D1 expression significantly compromised the oncogenic activity induced by PDK1. Together, our findings elucidate a key role for PDK1 in colorectal cellular functions trigged by the Akt/cyclin D1 pathway, thus providing a novel insight of PDK1 in colorectal carcinogenesis. PMID- 26055152 TI - Using the Theory of Planned Behaviour to examine enrolled nursing students' intention to care for patients with alcohol dependence: A survey study. AB - BACKGROUND: Nurses are often the first point of contact for patients hospitalized due to alcohol-related causes. Alcohol dependence is highly stigmatized and as a result healthcare professionals often have low behavioural intentions, meaning low willingness to care for these patients. This can have a direct influence on quality of care. OBJECTIVES: The purpose of this study was to explore enrolled nursing students' intention to care for patients with alcohol dependence and the antecedents, preliminary factors, that predict this within the Theory of Planned Behaviour; specifically attitudes, subjective norms, self-efficacy and controllability. DESIGN: The study was a cross-sectional survey using the Theory of Planned Behaviour. SETTING: Two Technical and Further Education South Australia campuses across metropolitan Adelaide. PARTICIPANTS: n=86 enrolled nursing students completed the survey (62% response rate). METHODS: Enrolled nursing students' intention, attitudes, subjective norms, self-efficacy and controllability were measured using a Theory of Planned Behaviour Questionnaire. The Short Alcohol and Alcohol Problems Perception Questionnaire investigated attitudes in more detail and a short knowledge scale assessed alcohol-related knowledge. RESULTS: Subjective norms and attitudes had a significant, positive effect on intention to care within the final model, accounting for 22.6% of the variance, F2,83=12.12, p<0.001. Subjective norms were the strongest predictor. External factors such as age, previous alcohol training and alcohol-related knowledge held direct paths to antecedents of intention. CONCLUSIONS: Subjective norms were the strongest predictor of intention to care for patients with alcohol dependence, followed by attitudes. The study provides an understanding of enrolled nursing students' intention to care for alcohol dependent patients. These findings can assist in developing tailored alcohol training for students, to increase attitudes and foster behavioural change, in order to improve the quality of care for these patients. PMID- 26055153 TI - Excited delirium: A psychiatric review. AB - The term 'excited delirium' (ED) is used to explain sudden and unexpected restraint-related deaths. Since the 1990s, ED has often been identified as the principal cause of death in restrained individuals, rather than the restraint procedure itself. Forensic pathologists and psychiatrists attach different meanings to the term delirium. For psychiatrists, delirium is a specific technical term, which implies a grave and potentially life-threatening underlying physical illness. If a patient dies during a bout of delirium, psychiatrists assume that there will be autopsy evidence to demonstrate the primary underlying organic cause. Conversely, pathologists appear to be using the term ED to refer to restraint-related deaths in either highly disturbed cocaine users or psychiatric patients in a state of extreme agitation. In these cases, there is no underlying physical disorder other than a terminal cardiac arrhythmia. As the term ED has different meanings for psychiatrists and for pathologists, it would be helpful for these two professional groups to develop a mutually agreed terminology. PMID- 26055154 TI - Long-term outcome in a case of shaken baby syndrome. AB - Shaken baby syndrome is one of the most common causes of disability and death in infants younger than one year of age. The syndrome is the result of major mechanical forces affecting the head and central nervous system. The outcome for surviving children is often poor, with both physical and mental disabilities. Multicystic encephalomalacia has been reported as a finding after such shaking. The present case involves a one-month-old boy who was brought to hospital by his father because of somnolence and feeding aversion. Radiological imaging revealed subdural haematomas, and fundoscopy found retinal haemorrhages. During police interrogation, the father confessed to having shaken the infant. Cranial ultrasonography subsequently showed increasing damage of the brain; the boy's general condition worsened. Eight weeks after admission, he died due to renal insufficiency. Upon autopsy, the brain was atrophic, with massive pseudocystic changes of the parenchyma. The case presented impressively shows the possible serious outcome of an admitted incident of shaking and emphasises the importance of an accurate education of parents about its severe and possible lethal consequences. PMID- 26055155 TI - Methods for the directed evolution of proteins. AB - Directed evolution has proved to be an effective strategy for improving or altering the activity of biomolecules for industrial, research and therapeutic applications. The evolution of proteins in the laboratory requires methods for generating genetic diversity and for identifying protein variants with desired properties. This Review describes some of the tools used to diversify genes, as well as informative examples of screening and selection methods that identify or isolate evolved proteins. We highlight recent cases in which directed evolution generated enzymatic activities and substrate specificities not known to exist in nature. PMID- 26055156 TI - Determinants of the rate of protein sequence evolution. AB - The rate and mechanism of protein sequence evolution have been central questions in evolutionary biology since the 1960s. Although the rate of protein sequence evolution depends primarily on the level of functional constraint, exactly what determines functional constraint has remained unclear. The increasing availability of genomic data has enabled much needed empirical examinations on the nature of functional constraint. These studies found that the evolutionary rate of a protein is predominantly influenced by its expression level rather than functional importance. A combination of theoretical and empirical analyses has identified multiple mechanisms behind these observations and demonstrated a prominent role in protein evolution of selection against errors in molecular and cellular processes. PMID- 26055158 TI - From the big five to the general factor of personality: a dynamic approach. AB - An integrating and dynamic model of personality that allows predicting the response of the basic factors of personality, such as the Big Five Factors (B5F) or the general factor of personality (GFP) to acute doses of drug is presented in this paper. Personality has a dynamic nature, i.e., as a consequence of a stimulus, the GFP dynamics as well as each one of the B5F of personality dynamics can be explained by the same model (a system of three coupled differential equations). From this invariance hypothesis, a partial differential equation, whose solution relates the GFP with each one of the B5F, is deduced. From this dynamic approach, a co-evolution of the GFP and each one of the B5F occurs, rather than an unconnected evolution, as a consequence of the same stimulus. The hypotheses and deductions are validated through an experimental design centered on the individual, where caffeine is the considered stimulus. Thus, as much from a theoretical point of view as from an applied one, the models here proposed open a new perspective in the understanding and study of personality like a global system that interacts intimately with the environment, being a clear bet for the high level inter-disciplinary research. PMID- 26055159 TI - What type of nanoscopic environment does a cationic fluorophore experience in room temperature ionic liquids? AB - In the presence of a cationic fluorophore (rhodamine 6G) whose absorption has a significant spectral overlap with the emission of a room temperature ionic liquid (RTIL), the emission of the latter gets quenched, and the quenching has been shown to be dynamic in nature. It has been shown that resonance energy transfer (RET) indeed happens between the RTIL (donor) and rhodamine 6G (cationic acceptor), and RET is the reason for the quenching of the RTIL emission. The spectral and temporal aspects of the RET (between neat RTILs as the donors and rhodamine 6G as the acceptor) were closely studied by steady-state and picosecond time-resolved fluorescence spectroscopy. The influence of the alkyl chain length of the cation, size of the anion, excitation wavelength and concentration of the acceptor on the RET dynamics were also investigated. The energy transfer time (obtained from the rise time of the acceptor) was noted to vary from 2.5 ns to 4.1 ns. By employing the Forster formulation, the donor-acceptor distance was obtained, and its magnitude was found to vary between 31.8 and 37.1 A. The magnitude of the donor-acceptor distance was shown to be independent of the alkyl chain length of the cation but dependent on the size of the anion of the RTIL. Moreover, the donor-acceptor distance was observed to be independent of the excitation wavelength or concentration of the acceptor. It was shown that the Forster formulation can possibly account for the mechanism and hence can explain the experimental observables in the RET phenomenon. Following the detailed experiments and rigorous analysis, a model has been put forward, which can successfully explain the nanoscopic environment that a cationic fluorophore experiences in an RTIL. Moreover, the nanoscopic environment experienced by the cationic probe has been noted to be different from that experienced by a neutral fluorophore. PMID- 26055157 TI - Reconstructing ancient genomes and epigenomes. AB - Research involving ancient DNA (aDNA) has experienced a true technological revolution in recent years through advances in the recovery of aDNA and, particularly, through applications of high-throughput sequencing. Formerly restricted to the analysis of only limited amounts of genetic information, aDNA studies have now progressed to whole-genome sequencing for an increasing number of ancient individuals and extinct species, as well as to epigenomic characterization. Such advances have enabled the sequencing of specimens of up to 1 million years old, which, owing to their extensive DNA damage and contamination, were previously not amenable to genetic analyses. In this Review, we discuss these varied technical challenges and solutions for sequencing ancient genomes and epigenomes. PMID- 26055160 TI - Dynamic changes in replication timing and gene expression during lineage specification of human pluripotent stem cells. AB - Duplication of the genome in mammalian cells occurs in a defined temporal order referred to as its replication-timing (RT) program. RT changes dynamically during development, regulated in units of 400-800 kb referred to as replication domains (RDs). Changes in RT are generally coordinated with transcriptional competence and changes in subnuclear position. We generated genome-wide RT profiles for 26 distinct human cell types, including embryonic stem cell (hESC)-derived, primary cells and established cell lines representing intermediate stages of endoderm, mesoderm, ectoderm, and neural crest (NC) development. We identified clusters of RDs that replicate at unique times in each stage (RT signatures) and confirmed global consolidation of the genome into larger synchronously replicating segments during differentiation. Surprisingly, transcriptome data revealed that the well accepted correlation between early replication and transcriptional activity was restricted to RT-constitutive genes, whereas two-thirds of the genes that switched RT during differentiation were strongly expressed when late replicating in one or more cell types. Closer inspection revealed that transcription of this class of genes was frequently restricted to the lineage in which the RT switch occurred, but was induced prior to a late-to-early RT switch and/or down regulated after an early-to-late RT switch. Analysis of transcriptional regulatory networks showed that this class of genes contains strong regulators of genes that were only expressed when early replicating. These results provide intriguing new insight into the complex relationship between transcription and RT regulation during human development. PMID- 26055161 TI - A novel mitochondrial genome architecture in thrips (Insecta: Thysanoptera): extreme size asymmetry among chromosomes and possible recent control region duplication. AB - BACKGROUND: Multipartite mitochondrial genomes are very rare in animals but have been found previously in two insect orders with highly rearranged genomes, the Phthiraptera (parasitic lice), and the Psocoptera (booklice/barklice). RESULTS: We provide the first report of a multipartite mitochondrial genome architecture in a third order with highly rearranged genomes: Thysanoptera (thrips). We sequenced the complete mitochondrial genomes of two divergent members of the Scirtothrips dorsalis cryptic species complex. The East Asia 1 species has the single circular chromosome common to animals while the South Asia 1 species has a genome consisting of two circular chromosomes. The fragmented South Asia 1 genome exhibits extreme chromosome size asymmetry with the majority of genes on the large, 14.28 kb, chromosome and only nad6 and trnC on the 0.92 kb mini-circle chromosome. This genome also features paralogous control regions with high similarity suggesting a very recent origin of the nad6 mini-circle chromosome in the South Asia 1 cryptic species. CONCLUSIONS: Thysanoptera, along with the other minor paraenopteran insect orders should be considered models for rapid mitochondrial genome evolution, including fragmentation. Continued use of these models will facilitate a greater understanding of recombination and other mitochondrial genome evolutionary processes across eukaryotes. PMID- 26055162 TI - Is Using Threshold-Crossing Method and Single Type of Features Sufficient to Achieve Realistic Application of Seizure Prediction? AB - Objective This study aims to verify whether the simple threshold-crossing method can work well enough to achieve the realistic application of seizure prediction on the basis of a large public database, and examines how a more complex classifier can improve prediction performance. It also verified whether the combination of multiple types of features with a complex classifier can improve prediction performance. Method Phase synchronization and spectral power features were extracted from electroencephalogram recordings. The threshold-crossing method and a support vector machine (SVM) were used to identify preictal and interictal samples. Based on the type of selected features and the manner of classification, 5 different methods were conducted on 19 patients. The performances of these methods were directly compared and tested using a random predictor. In-sample optimization problems were avoided in the feature and parameter selection procedure to obtain credible results. Results The threshold crossing method could only obtain satisfying prediction results for approximately half of the selected patients. The SVM classifier could significantly improve prediction performance compared with the threshold-crossing method for both types of features. Although the average performance was further improved when both types of features were combined with the SVM classifier, the improvement was insignificant. Conclusion A complex classifier, such as the SVM, is recommended in a realistic prediction device, although it will increase the complexity of the device. Indeed, the simple threshold-crossing method performs well enough for some of the patients. The combination of phase synchronization and spectral power features is unnecessary because of the increased computation complexity. PMID- 26055163 TI - In Memoriam: Shur-Tzu (Su) Chen, a pioneer in tumor suppressor WWOX for neuroscience. PMID- 26055164 TI - Pain-related attitudes and functioning in elderly primary care patients. AB - This study examined the associations between specific pain-related beliefs and both mental health and pain interference in elderly patients with chronic pain. A total of 139 patients completed validated questionnaires assessing pain domains (i.e., intensity, duration and location), psychological functioning, pain interference and demographic variables. Pain-related beliefs were related with poorer mental health (Disability = -.27; Harm = -.23; Solicitude = -.24; Control = .18; Emotion = -.29) and greater interference in daily activities (Disability =.41; Harm =.13; Solicitude =.29; Control = -.31). Our findings are consistent with a biopsychosocial model of chronic pain which goes beyond physical variables in an attempt to understand and promote patients' adjustment to chronic pain problems. PMID- 26055165 TI - On-chip lysis of mammalian cells through a handheld corona device. AB - On-chip lysis is required in many lab-on-chip applications involving cell studies. In these applications, the complete disruption of the cellular membrane and a high lysis yield is essential. Here, we present a novel approach to lyse cells on-chip through the application of electric discharges from a corona handheld device. The method only requires a microfluidic chip and a low-cost corona device. We demonstrate the effective lysis of BHK and eGFP HCT 116 cells in the sub-second time range using an embedded microelectrode. We also show cell lysis of non-adherent K562 leukemia cells without the use of an electrode in the chip. Cell lysis has been assessed through the use of bright-field microscopy, high-speed imaging and cell-viability fluorescence probes. The experimental results show effective cell lysis without any bubble formation or significant heating. Due to the simplicity of both the components involved and the lysis procedure, this technique offers an inexpensive lysis option with the potential for integration into lab-on-a-chip devices. PMID- 26055166 TI - Assessment of the Altitudinal Atmospheric Metal(loid) Deposition in a Mountainous City by Mosses. AB - Samples of moss (Haplocladium microphyllum) were collected at different elevations on a mountain and four representative sites in Guiyang City, and the concentrations of metal(loid)s were determined by ICP-MS. The altitudinal deposition of soil-originated metals differed from that of anthropogenic metal(loid)s. The concentrations of soil-related elements decreased with elevation, indicating that these elements tend to deposit at lower elevations and their impact on the higher elevations is less. The concentrations of anthropogenic elements varied only slightly with elevation, indicating that the atmospheric deposition of these elements did not vary largely with elevation. The results of this study showed that the mosses at different locations may serve to indicate a vertical gradient of atmospheric metal(loid) deposition. PMID- 26055167 TI - Concentrations of Heavy Metals in Sardinella gibbosa (Bleeker, 1849) from the Coast of Balochistan, Pakistan. AB - The concentrations of cadmium, iron, lead, manganese, nickel, and zinc in muscle tissue samples taken from Goldstripe sardinella (Sardinella gibbosa Bleeker, 1849) caught off the coast of Balochistan, Pakistan, in 2009 were determined. The samples were analyzed using a Perkin Elmer AAnalyst 700 flame atomic absorption spectrophotometer. The mean Cd, Fe, Mn, Ni, Pb, and Zn concentrations in the muscle samples were 0.65+/-0.05 ug g(-1), 23.39+/-1.97 ug g(-1), 4.35+/-0.22 ug g(-1), 0.61+/-0.07 ug g(-1), 0.39+/-0.04 ug g(-1), and 6.59+/-0.33 ug g(-1), respectively. The Cd, Fe, Pb, and Zn concentrations did not exceed the regulatory limits, but the Mn concentrations were high enough to potentially pose health risks to humans consuming S. gibbosa. Therefore, the Mn concentrations in S. gibbosa from the Balochistan coast should be monitored regularly. PMID- 26055168 TI - MERGING conventional and complementary medicine in a clinic department - a theoretical model and practical recommendations. AB - BACKGROUND: Today, the increasing demand for complementary medicine encourages health care providers to adapt and create integrative medicine departments or services within clinics. However, because of their differing philosophies, historical development, and settings, merging the partners (conventional and complementary medicine) is often difficult. It is necessary to understand the similarities and differences in both cultures to support a successful and sustainable integration. The aim of this project was to develop a theoretical model and practical steps that are based on theories from mergers in business to facilitate the implementation of an integrative medicine department. METHODS: Based on a literature search and expert discussions, the cultures were described and model domains were developed. These were applied to two case studies to develop the final model. Furthermore, a checklist with practical steps was devised. RESULTS: Conventional medicine and complementary medicine have developed different corporate cultures. The final model, which should help to foster integration by bridging between these cultures, is based on four overall aspects: culture, strategy, organizational tools and outcomes. Each culture is represented by three dimensions in the model: corporate philosophy (core and identity of the medicine and the clinic), patient (all characteristics of the professional team's contact with the patient), and professional team (the characteristics of the interactions within the professional team). CONCLUSION: Overall, corporate culture differs between conventional and complementary medicine; when planning the implementation of an integrative medicine department, the developed model and the checklist can support better integration. PMID- 26055169 TI - Blood-feeding ectoparasites as developmental stressors: Does corticosterone mediate effects of mite infestation on nestling growth, immunity and energy availability? AB - How resources are distributed to growth and self-maintenance early in life is likely to impact survival and reproduction. Early resource allocation decisions may be particularly critical in altricial birds, as they have rapid developmental trajectories, and may be highly susceptible to environmental factors that can perturb development. The aim of this study was to determine if blood-feeding ectoparasites act as developmental stressors in European starling (Sturnus vulgaris) nestlings, driving a trade-off between growth and immunity. We hypothesized that because ectoparasites compete for resources they would induce growth-immunity trade-offs in parasitized nestlings. We also tested the hypothesis that changes in plasma corticosterone mediate the effects of ectoparasites on growth and immunity. Throughout development we assessed between nest variation in ectoparasite density, measured growth, and a variety of blood parameters, including plasma corticosterone. We also assessed immune function across development. We found that nestlings from nests with high levels of ectoparasites were smaller, had elevated blood glucose, lower hematocrit levels, and appeared to engage in compensatory growth prior to fledging. They also had elevated innate immune responses early, but reduced responses later relative to nestlings from nests with low levels of ectoparasites. Plasma corticosterone was not affected by ectoparasite load, but did increase with nestling age. Overall, we find evidence that ectoparasites are developmental stressors that affect growth-immunity trade-offs, but their effects do not appear to be mediated by changes in circulating levels of corticosterone. PMID- 26055170 TI - Repeatability of Cerebral Perfusion Using Dynamic Susceptibility Contrast MRI in Glioblastoma Patients. AB - OBJECTIVES: This study evaluates the repeatability of brain perfusion using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) with a variety of post-processing methods. METHODS: Thirty-two patients with newly diagnosed glioblastoma were recruited. On a 3-T MRI using a dual-echo, gradient echo spin-echo DSC-MRI protocol, the patients were scanned twice 1 to 5 days apart. Perfusion maps including cerebral blood volume (CBV) and cerebral blood flow (CBF) were generated using two contrast agent leakage correction methods, along with testing normalization to reference tissue, and application of arterial input function (AIF). Repeatability of CBV and CBF within tumor regions and healthy tissues, identified by structural images, was assessed with intra-class correlation coefficients (ICCs) and repeatability coefficients (RCs). Coefficients of variation (CVs) were reported for selected methods. RESULTS: CBV and CBF were highly repeatable within tumor with ICC values up to 0.97. However, both CBV and CBF showed lower ICCs for healthy cortical tissues (up to 0.83), healthy gray matter (up to 0.95), and healthy white matter (WM; up to 0.93). The values of CV ranged from 6% to 10% in tumor and 3% to 11% in healthy tissues. The values of RC relative to the mean value of measurement within healthy WM ranged from 22% to 42% in tumor and 7% to 43% in healthy tissues. These percentages show how much variation in perfusion parameter, relative to that in healthy WM, we expect to observe to consider it statistically significant. We also found that normalization improved repeatability, but AIF deconvolution did not. CONCLUSIONS: DSC-MRI is highly repeatable in high-grade glioma patients. PMID- 26055171 TI - [(18)F]-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography of LAPC4-CR Castration-Resistant Prostate Cancer Xenograft Model in Soft Tissue Compartments. AB - Preclinical xenograft models have contributed to advancing our understanding of the molecular basis of prostate cancer and to the development of targeted therapy. However, traditional preclinical in vivo techniques using caliper measurements and survival analysis evaluate the macroscopic tumor behavior, whereas tissue sampling disrupts the microenvironment and cannot be used for longitudinal studies in the same animal. Herein, we present an in vivo study of [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) designed to evaluate the metabolism within the microenvironment of LAPC4-CR, a unique murine model of castration-resistant prostate cancer. Mice bearing LAPC4-CR subcutaneous tumors were administered [(18)F]-FDG via intravenous injection. After a 60-minute distribution phase, the mice were imaged on a PET/CT scanner with submillimeter resolution; and the fused PET/CT images were analyzed to evaluate tumor size, location, and metabolism across the cohort of mice. The xenograft tumors showed [(18)F]-FDG uptake that was independent of tumor size and was significantly greater than uptake in skeletal muscle and liver in mice (Wilcoxon signed-rank P values of .0002 and .0002, respectively). [(18)F] FDG metabolism of the LAPC4-CR tumors was 2.1 +/- 0.8 ID/cm(3)*wt, with tumor to muscle ratio of 7.4 +/- 4.7 and tumor to liver background ratio of 6.7 +/- 2.3. Noninvasive molecular imaging techniques such as PET/CT can be used to probe the microenvironment of tumors in vivo. This study showed that [(18)F]-FDG-PET/CT could be used to image and assess glucose metabolism of LAPC4-CR xenografts in vivo. Further work can investigate the use of PET/CT to quantify the metabolic response of LAPC4-CR to novel agents and combination therapies using soft tissue and possibly bone compartment xenograft models. PMID- 26055172 TI - Breast DCE-MRI Kinetic Heterogeneity Tumor Markers: Preliminary Associations With Neoadjuvant Chemotherapy Response. AB - The ability to predict response to neoadjuvant chemotherapy for women diagnosed with breast cancer, either before or early on in treatment, is critical to judicious patient selection and tailoring the treatment regimen. In this paper, we investigate the role of contrast agent kinetic heterogeneity features derived from breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for predicting treatment response. We propose a set of kinetic statistic descriptors and present preliminary results showing the discriminatory capacity of the proposed descriptors for predicting complete and non-complete responders as assessed from pre-treatment imaging exams. The study population consisted of 15 participants: 8 complete responders and 7 non-complete responders. Using the proposed kinetic features, we trained a leave-one-out logistic regression classifier that performs with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 under the ROC. We compare the predictive value of our features against commonly used MRI features including kinetics of the characteristic kinetic curve (CKC), maximum peak enhancement (MPE), hotspot signal enhancement ratio (SER), and longest tumor diameter that give lower AUCs of 0.71, 0.66, 0.64, and 0.54, respectively. Our proposed kinetic statistics thus outperform the conventional kinetic descriptors as well as the classifier using a combination of all the conventional descriptors (i.e., CKC, MPE, SER, and longest diameter), which gives an AUC of 0.74. These findings suggest that heterogeneity based DCE-MRI kinetic statistics could serve as potential imaging biomarkers for tumor characterization and could be used to improve candidate patient selection even before the start of the neoadjuvant treatment. PMID- 26055173 TI - The Value of Proton Magnetic Resonance Spectroscopy in High-Intensity Focused Ultrasound Treatment of Experimental Liver Cancer. AB - High-intensity focused ultrasound (HIFU) is a rapidly developing, non-invasive technique for local treatment of solid tumors that produce coagulative tumor necrosis. This study is aimed to investigate the feasibility of proton magnetic resonance spectroscopy (MRS) on early assessing treatment of HIFU ablation in rabbit with VX2 liver tumor. HIFU ablation was performed on normal liver and VX2 tumor in rabbit, and MRS was performed on normal liver and VX2 tumor before and 2 days after 100% HIFU ablation or 80% ablation in tumor volume. Choline (Cho) and choline/lipid (Cho/Lip) ratios between complete and partial HIFU ablation of tumor were compared. Tissues were harvested and sequentially sliced to confirm the necrosis. In normal liver, the Cho value liver was not obviously changed after HIFU (P > .05), but the Cho/Lip ratio was decreased (P < .05). Cho in liver VX2 tumor was much higher than that in normal liver (P < .001). Cho and Cho/Lip ratio were significantly decreased in tumor after complete HIFU ablation and partial HIFU ablation, and the Cho value in complete HIFU tumor ablation did not show any difference from that in normal liver after HIFU (P > .05); however, the Cho value in partial ablation was still higher than that in normal liver before or in tumor after complete HIFU treatment due to the residual part of tumors, and Cho/Lip ratio is lower than that in complete HIFU treatment (P < .001). The changes in MRS parameters were consistent with histopathologic changes of the tumor tissues after treatment. MRS could differentiate the complete tumor necrosis from residual tumor tissue, when combined with magnetic resonance imaging. We conclude that MRS may be applied as an important, non-invasive biomarker for monitoring the thoroughness of HIFU ablation. PMID- 26055174 TI - Cutaneous Angiosarcoma of Head and Neck: A New Predictive Score for Locoregional Metastasis. AB - OBJECTIVES: Cutaneous angiosarcoma of head and neck (cAS-HN) is a malignant neoplasm with deficient data on prognostic factors. The aim of this study is to present our monocenter database on cAS-HN so far and a new predictive score for locoregional metastasis (LRM). METHODS: Retrospectively, tumor characteristics and outcome of 103 consecutive patients with cAS-HN were analyzed. The main predictors of LRM (identified by univariate and multivariate statistics) were combined to a LRM risk score. The prognostic values of stratification into high-, medium-, and low-risk groups concerning disease-specific survival (DSS), distant metastasis (DM), and progression-free survival (PFS) were evaluated. RESULTS: LRM (n = 29) and control (n = 74) groups differed significantly concerning several tumor characteristics and outcome (DM, PFS, and DSS). Patients developing LRM showed 3-, 5-, and 10-year survival rates of 32%, 16%, and 11% (mean DSS time of 36.7 months [95% confidence interval (CI) 20.5-52.8]) compared to 81%, 73%, and 69% (mean DSS time of 292.4 months [95% CI 208.4-376.5]) in controls without LRM (P < .001). The main predictors were American Joint Committee on Cancer (AJCC) stage, tumor extent, and origin of the primary tumor. The LRM risk score revealed significant higher values for the LRM group [7.14 (SD 1.46) vs 4.88 (SD 1.89), P < .001]. The high-risk group showed significantly higher risk for DM and more unfavorable DSS and PFS. CONCLUSION: The LRM risk score is a simple way to estimate the risk for LRM and DM, to stage patients, and to determine treatment options. PMID- 26055175 TI - Understanding Heterogeneity and Permeability of Brain Metastases in Murine Models of HER2-Positive Breast Cancer Through Magnetic Resonance Imaging: Implications for Detection and Therapy. AB - OBJECTIVES: Brain metastases due to breast cancer are increasing, and the prognosis is poor. Lack of effective therapy is attributed to heterogeneity of breast cancers and their resulting metastases, as well as impermeability of the blood-brain barrier (BBB), which hinders delivery of therapeutics to the brain. This work investigates three experimental models of HER2+ breast cancer brain metastasis to better understand the inherent heterogeneity of the disease. We use magnetic resonance imaging (MRI) to quantify brain metastatic growth and explore its relationship with BBB permeability. DESIGN: Brain metastases due to breast cancer cells (SUM190-BR3, JIMT-1-BR3, or MDA-MB-231-BR-HER2) were imaged at 3 T using balanced steady-state free precession and contrast-enhanced T1-weighted spin echo sequences. The histology and immunohistochemistry corresponding to MRI were also analyzed. RESULTS: There were differences in metastatic tumor appearance by MRI, histology, and immunohistochemistry (Ki67, CD31, CD105) across the three models. The mean volume of an MDA-MB-231-BR-HER2 tumor was significantly larger compared to other models (F2,12 = 5.845, P < .05); interestingly, this model also had a significantly higher proportion of Gd impermeable tumors (F2,12 = 22.18, P < .0001). Ki67 staining indicated that Gd impermeable tumors had significantly more proliferative nuclei compared to Gd permeable tumors (t[24] = 2.389, P < .05) in the MDA-MB-231-BR-HER2 model. CD31 and CD105 staining suggested no difference in new vasculature patterns between permeable and impermeable tumors in any model. CONCLUSION: Significant heterogeneity is present in these models of brain metastases from HER2+ breast cancer. Understanding this heterogeneity, especially as it relates to BBB permeability, is important for improvement in brain metastasis detection and treatment delivery. PMID- 26055176 TI - Targeting Polo-Like Kinases: A Promising Therapeutic Approach for Cancer Treatment. AB - Polo-like kinases (Plks) are a family of serine-threonine kinases that regulate multiple intracellular processes including DNA replication, mitosis, and stress response. Plk1, the most well understood family member, regulates numerous stages of mitosis and is overexpressed in many cancers. Plk inhibitors are currently under clinical investigation, including phase III trials of volasertib, a Plk inhibitor, in acute myeloid leukemia and rigosertib, a dual inhibitor of Plk1/phosphoinositide 3-kinase signaling pathways, in myelodysplastic syndrome. Other Plk inhibitors, including the Plk1 inhibitors GSK461364A, TKM-080301, GW843682, purpurogallin, and poloxin and the Plk4 inhibitor CFI-400945 fumarate, are in earlier clinical development. This review discusses the biologic roles of Plks in cell cycle progression and cancer, and the mechanisms of action of Plk inhibitors currently in development as cancer therapies. PMID- 26055177 TI - Imaging and Therapy of Pancreatic Cancer with Phosphatidylserine-Targeted Nanovesicles. AB - Pancreatic cancer remains one of the most intractable cancers, with a dismal prognosis reflected by a 5-year survival of ~6%. Since early disease symptoms are undefined and specific biomarkers are lacking, about 80% of patients present with advanced, inoperable tumors that represent a daunting challenge. Despite many clinical trials, no single chemotherapy agent has been reliably associated with objective response rates above 10% or median survival longer than 5 to 7 months. Although combination chemotherapy regimens have in recent years provided some improvement, overall survival (8-11 months) remains very poor. There is therefore a critical need for novel therapies that can improve outcomes for pancreatic cancer patients. Here, we present a summary of the current therapies used in the management of advanced pancreatic cancer and review novel therapeutic strategies that target tumor biomarkers. We also describe our recent research using phosphatidylserine-targeted saposin C-coupled dioleoylphosphatidylserine nanovesicles for imaging and therapy of pancreatic cancer. PMID- 26055178 TI - Background Parenchymal Enhancement of the Contralateral Normal Breast: Association with Tumor Response in Breast Cancer Patients Receiving Neoadjuvant Chemotherapy. AB - PURPOSE: This study investigated the association between background parenchymal enhancement (BPE) and pathologic response to neoadjuvant chemotherapy (NAC). METHODS: A total of 46 patients diagnosed with invasive breast cancer were analyzed. Each patient had three magnetic resonance imaging (MRI) studies, one pre-treatment and two follow-up (F/U) MRI studies. BPE was measured as the averaged enhancement of the whole fibroglandular tissues. The pre-treatment BPE and the changes in the F/U MRI were compared between patients achieving pathologic complete response (pCR) versus those not. Subgroup analyses based on age, estrogen receptor (ER), and human epidermal growth factor receptor 2 (HER2) status of their cancers were also performed. RESULTS: The pre-treatment BPE was higher in the pCR group than that in the non-pCR group. Compared to baseline, BPE at F/U-1 was significantly decreased in the pCR group but not in the non-pCR group. In subgroup analysis based on age, these results were seen only in the younger group (<55 years old), not in the older group (>=55 years old). Older patients had a significantly lower pre-treatment BPE than younger patients. In analysis based on molecular biomarkers, a significantly decreased BPE at F/U-1 was only found in the ER-negative pCR group but not in the non-pCR, nor in the ER positive groups. CONCLUSIONS: A higher pre-treatment BPE showing a significant decrease early after starting NAC was related to pCR in pre/peri-menopausal patients. PMID- 26055179 TI - Drug-Resistant Urothelial Cancer Cell Lines Display Diverse Sensitivity Profiles to Potential Second-Line Therapeutics. AB - Combination chemotherapy with gemcitabine and cisplatin in patients with metastatic urothelial cancer of the bladder frequently results in the development of acquired drug resistance. Availability of cell culture models with acquired resistance could help to identify candidate treatments for an efficient second line therapy. Six cisplatin- and six gemcitabine-resistant cell lines were established. Cell viability assays were performed to evaluate the sensitivity to 16 different chemotherapeutic substances. The activity of the drug transporter ATP-binding cassette transporter, subfamily B, member 1 (ABCB1, a critical mediator of multidrug resistance in cancer) was evaluated using fluorescent ABCB1 substrates. For functional assessment, cells overexpressing ABCB1 were generated by transduction with a lentiviral vector encoding for ABCB1, while zosuquidar was used for selective inhibition. In this study, 8 of 12 gemcitabine- or cisplatin resistant cell lines were cross-resistant to carboplatin, 5 to pemetrexed, 4 to methotrexate, 3 to oxaliplatin, 5-fluorouracil, and paclitaxel, and 2 to cabazitaxel, larotaxel, docetaxel, topotecan, doxorubicin, and mitomycin c, and 1 of 12 cell lines was cross-resistant to vinflunine and vinblastine. In one cell line with acquired resistance to gemcitabine (TCC-SUP(r)GEMCI(20)), cross resistance seemed to be mediated by ABCB1 expression. Our model identified the vinca alkaloids vinblastine and vinflunine, in Europe an already approved second line therapeutic for metastatic bladder cancer, as the most effective compounds in urothelial cancer cells with acquired resistance to gemcitabine or cisplatin. These results demonstrate that this in vitro model can reproduce clinically relevant results and may be suitable to identify novel substances for the treatment of metastatic bladder cancer. PMID- 26055181 TI - Benefits of applying a proxy eligibility period when using electronic health records for outcomes research: a simulation study. AB - BACKGROUND: Electronic health records (EHRs) can provide valuable data for outcomes research. However, unlike administrative claims databases, EHRs lack eligibility tables or a standard way to define the benefit coverage period, which could lead to underreporting of healthcare utilization or outcomes, and could result in surveillance bias. We tested the effect of using a proxy eligibility period (eligibility proxy) when estimating a range of health resource utilization and outcomes parameters under varying degrees of missing encounter data. METHODS: We applied an eligibility proxy to create a benchmark cohort of chronic obstructive pulmonary disease (COPD) patients with 12 months of follow-up, with the assumption of no missing encounter data. The benchmark cohort provided parameter estimates for comparison with 9,000 simulated datasets representing 10 90% of COPD patients (by 10th percentiles) with between 1 and 11 months of continuous missing data. Two analyses, one for datasets using an eligibility proxy and one for those without an eligibility proxy, were performed on the 9,000 datasets to assess estimator performance under increasing levels of missing data. Estimates for each study variable were compared with those from the benchmark dataset, and performance was evaluated using bias, percentage change, and root mean-square error. RESULTS: The benchmark dataset contained 6,717 COPD patients, whereas the simulated datasets where the eligibility proxy was applied had between 671 and 6,045 patients depending on the percentage of missing data. Parameter estimates had better performance when an eligibility proxy based on the first and last month of observed activity was applied. This finding was consistent across a range of variables representing patient comorbidities, symptoms, outcomes, health resource utilization, and medications, regardless of the measures of performance used. Without the eligibility proxy, all evaluated parameters were consistently underestimated. CONCLUSION: In a large COPD patient population, this study demonstrated that applying an eligibility proxy to EHR data based on the earliest and latest months of recorded activity minimized the impact of missing data in outcomes research and improved the accuracy of parameter estimates by reducing surveillance bias. This approach may address the problem of missing data in a wide range of EHR outcomes studies. PMID- 26055180 TI - Pitfalls and Limitations of Diffusion-Weighted Magnetic Resonance Imaging in the Diagnosis of Urinary Bladder Cancer. AB - Adequately selecting a therapeutic approach for bladder cancer depends on accurate grading and staging. Substantial inaccuracy of clinical staging with bimanual examination, cystoscopy, and transurethral resection of bladder tumor has facilitated the increasing utility of magnetic resonance imaging to evaluate bladder cancer. Diffusion-weighted imaging (DWI) is a noninvasive functional magnetic resonance imaging technique. The high tissue contrast between cancers and surrounding tissues on DWI is derived from the difference of water molecules motion. DWI is potentially a useful tool for the detection, characterization, and staging of bladder cancers; it can also monitor posttreatment response and provide information on predicting tumor biophysical behaviors. Despite advancements in DWI techniques and the use of quantitative analysis to evaluate the apparent diffusion coefficient values, there are some inherent limitations in DWI interpretation related to relatively poor spatial resolution, lack of cancer specificity, and lack of standardized image acquisition protocols and data analysis procedures that restrict the application of DWI and reproducibility of apparent diffusion coefficient values. In addition, inadequate bladder distension, artifacts, thinness of bladder wall, cancerous mimickers of normal bladder wall and benign lesions, and variations in the manifestation of bladder cancer may interfere with diagnosis and monitoring of treatment. Recognition of these pitfalls and limitations can minimize their impact on image interpretation, and carefully applying the analyzed results and combining with pathologic grading and staging to clinical practice can contribute to the selection of an adequate treatment method to improve patient care. PMID- 26055182 TI - Aging of Stem and Progenitor Cells: Mechanisms, Impact on Therapeutic Potential, and Rejuvenation. AB - It was once suggested that adult or tissue-specific stem cells may be immortal; however, several recently published data suggest that their efficacy is limited by natural aging in common with most other somatic cell types. Decreased activity of stem cells in old age raises questions as to whether the age of the donor should be considered during stem cell transplantation and at what age the donor stem cells should be harvested to ensure the largest possible number of viable, functional, and non-altered stem cells. Although stem cells remain active into old age, changes in stem cells and their microenvironments inhibit their regenerative potential. The impact of aging on stem cell populations differs between tissues and depends on a number intrinsic and extrinsic factors, including systemic changes associated with immune system alterations. In this review, we describe key mechanisms of stem and progenitor cell aging and techniques that are currently used to identify signs of stem cells aging. Furthermore, we focus on the impact of aging on the capacity for proliferation, differentiation, and clinical use of stem cells. Finally, we detail the aging of embryonic, mesenchymal, and induced pluripotent stem cells, with particular emphasis on aging mechanisms and rejuvenation. PMID- 26055183 TI - Maternal anxiety following delivery, early infant temperament and mother's confidence in caregiving. AB - A mother's emotional state is a well-known environmental factor that relates to the development of infant temperament. However, some relevant issues have not yet been fully explored. The current study examines the influence of determined maternal, contextual and perinatal variables on infant temperament and the mother's confidence in caregiving during the first weeks of life. A prospective study was carried out in three-hundred and seventeen newborns and their mothers. Perinatal and socio-demographic variables were recorded. The mother's anxiety and mood were measured in the first days after childbirth and again at 8 weeks. Infant temperament and the mother's confidence in caregiving were measured at 8 weeks. A mother's postpartum anxiety following delivery was the best predictor for most of the variables of infant temperament, including infant irritability (p = .001), and other child variables like infant sleep (p = .0003) and nursing difficulty (p = .001). Contextual-family variables, such as the number of people at home (p = .0024) and whether they were primiparous (p = .001), were the best predictors for a mother's confidence in caregiving. Support was found for an early effect of maternal anxiety on infant temperament. The results have clinical implications for postnatal psychological interventions. PMID- 26055185 TI - Comparative Pessimism or Optimism: Depressed Mood, Risk-Taking, Social Utility and Desirability. AB - Comparative optimism can be defined as a self-serving, asymmetric judgment of the future. It is often thought to be beneficial and socially accepted, whereas comparative pessimism is correlated with depression and socially rejected. Our goal was to examine the social acceptance of comparative optimism and the social rejection of comparative pessimism in two dimensions of social judgment, social desirability and social utility, considering the attributions of dysphoria and risk-taking potential (studies 2 and 3) on outlooks on the future. In three experiments, the participants assessed either one (study 1) or several (studies 2 and 3) fictional targets in two dimensions, social utility and social desirability. Targets exhibiting comparatively optimistic or pessimistic outlooks on the future were presented as non-depressed, depressed, or neither (control condition) (study 1); non-depressed or depressed (study 2); and non-depressed or in control condition (study 3). Two significant results were obtained: (1) social rejection of comparative pessimism in the social desirability dimension, which can be explained by its depressive feature; and (2) comparative optimism was socially accepted on the social utility dimension, which can be explained by the perception that comparatively optimistic individuals are potential risk-takers. PMID- 26055184 TI - Transition metal-free one-pot synthesis of nitrogen-containing heterocycles. AB - One-pot heterocyclic synthesis is an exciting research area as it can open routes for the development of otherwise complex transformations in organic synthesis. Heterocyclic compounds show wide spectrum of applications in medicinal chemistry, chemical biology, and materials science. These heterocycles can be generated very efficiently through highly economical and viable routes using one-pot synthesis. In particular, the metal-free one-pot synthetic protocols are highly fascinating due to several advantages for the industrial production of heterocyclic frameworks. This comprehensive review is devoted to the transition metal-free one pot synthesis of nitrogen-containing heterocycles from the period 2010-2013. PMID- 26055186 TI - Feeding critically ill patients the right 'whey': thinking outside of the box. A personal view. AB - Atrophy of skeletal muscle mass is an almost universal problem in survivors of critical illness and is associated with significant short- and long-term morbidity. Contrary to common practice, the provision of protein/amino acids as a continuous infusion significantly limits protein synthesis whereas intermittent feeding maximally stimulates skeletal muscle synthesis. Furthermore, whey-based protein (high in leucine) increases muscle synthesis compared to soy or casein based protein. In addition to its adverse effects on skeletal muscle synthesis, continuous feeding is unphysiological and has adverse effects on glucose and lipid metabolism and gastrointestinal function. I propose that critically ill patients' be fed intermittently with a whey-based formula and that such an approach is likely to be associated with better glycemic control, less hepatic steatosis and greater preservation of muscle mass. This paper provides the scientific basis for my approach to intermittent feeding of critically ill patients. PMID- 26055187 TI - Long-term survival and quality of life after intensive care for patients 80 years of age or older. AB - BACKGROUND: Comparison of survival and quality of life in a mixed ICU population of patients 80 years of age or older with a matched segment of the general population. METHODS: We retrospectively analyzed survival of ICU patients >=80 years admitted to the Haukeland University Hospital in 2000-2012. We prospectively used the EuroQol-5D to compare the health-related quality of life (HRQOL) between survivors at follow-up and an age- and gender-matched general population. Follow-up was 1-13.8 years. RESULTS: The included 395 patients (mean age 83.8 years, 61.0 % males) showed an overall survival of 75.9 (ICU), 59.5 (hospital), and 42.0 % 1 year after the ICU. High ICU mortality was predicted by age, mechanical ventilator support, SAPS II, maximum SOFA, and multitrauma with head injury. High hospital mortality was predicted by an unplanned surgical admission. One-year mortality was predicted by respiratory failure and isolated head injury. We found no differences in HRQOL at follow-up between survivors (n = 58) and control subjects (n = 179) or between admission categories. Of the ICU non-survivors, 63.2 % died within 2 days after ICU admission (n = 60), and 68.3 % of these had life-sustaining treatment (LST) limitations. LST limitations were applied for 71.3 % (n = 114) of the hospital non-survivors (ICU 70.5 % (n = 67); post-ICU 72.3 % (n = 47)). CONCLUSIONS: Overall 1-year survival was 42.0 %. Survival rates beyond that were comparable to those of the general octogenarian population. Among survivors at follow-up, HRQOL was comparable to that of the age and sex-matched general population. Patients admitted for planned surgery had better short- and long-term survival rates than those admitted for medical reasons or unplanned surgery for 3 years after ICU admittance. The majority of the ICU non-survivors died within 2 days, and most of these had LST limitation decisions. PMID- 26055189 TI - Asymmetric synthesis of 3-substituted tetrahydro-2-benzazepines. AB - The enantiomerically and diastereomerically pure tricyclic oxazolidine cis-10 was prepared in a five step synthesis starting with 1-bromo-2-iodobenzene. Me3SiCN and allylSiMe3 reacted with cis-10 in the presence of TiCl4 to form the nitrile (3S)-11 and the allyl derivative (3S)-12 with high diastereoselectivity. The hydrogenolytic removal of the chiral auxiliary failed, since the endocyclic benzyl-N-bond was cleaved simultaneously. Therefore the N-(hydroxyethyl)amide of (3S)-12 was transformed into the enamide 27, which was hydrolyzed to afford the secondary amide 28. The enamide strategy to remove the chiral auxiliary from (3S) 11 led to complete racemization due to fast deprotonation in alpha-position of the cyano moiety. Two pairs of enantiomers 30a-b/ent-30a-b with prototypical sigma substituents at the N-atom were prepared. The low sigma1 affinity of the tetrahydro-2-benzazepines (ent-30b, Ki = 407 nM) is attributed to the short distance between the two lipophilic aromatic moieties. PMID- 26055188 TI - Functional characterization of salicylate hydroxylase from the fungal endophyte Epichloe festucae. AB - Epichloe spp. are symbiotic fungal endophytes of many cool season grasses. The presence of the fungal endophytes often confers insect, drought, and disease tolerance to the host grasses. The presence of the fungal endophytes within the host plants does not elicit host defense responses. The molecular basis for this phenomenon is not known. Epichloe festucae, the endophyte of Festuca rubra, expresses a salicylate hydroxylase similar to NahG from the bacterium Pseudomonas putida. Few fungal salicylate hydroxylase enzymes have been reported. The in planta expression of an endophyte salicylate hydroxylase raised the possibility that degradation of plant-produced salicylic acid is a factor in the mechanism of how the endophyte avoids eliciting host plant defenses. Here we report the characterization of the E. festucae salicylate hydroxylase, designated Efe-shyA. Although the fungal enzyme has the expected activity, based on salicylic acid levels in endophyte-free and endophyte-infected plants it is unlikely that expression of the endophyte salicylate hydroxylase is a factor in the lack of a host defense response to the presence of the fungal endophyte. PMID- 26055190 TI - A Dictionary Approach to Electron Backscatter Diffraction Indexing. AB - We propose a framework for indexing of grain and subgrain structures in electron backscatter diffraction patterns of polycrystalline materials. We discretize the domain of a dynamical forward model onto a dense grid of orientations, producing a dictionary of patterns. For each measured pattern, we identify the most similar patterns in the dictionary, and identify boundaries, detect anomalies, and index crystal orientations. The statistical distribution of these closest matches is used in an unsupervised binary decision tree (DT) classifier to identify grain boundaries and anomalous regions. The DT classifies a pattern as an anomaly if it has an abnormally low similarity to any pattern in the dictionary. It classifies a pixel as being near a grain boundary if the highly ranked patterns in the dictionary differ significantly over the pixel's neighborhood. Indexing is accomplished by computing the mean orientation of the closest matches to each pattern. The mean orientation is estimated using a maximum likelihood approach that models the orientation distribution as a mixture of Von Mises-Fisher distributions over the quaternionic three sphere. The proposed dictionary matching approach permits segmentation, anomaly detection, and indexing to be performed in a unified manner with the additional benefit of uncertainty quantification. PMID- 26055192 TI - Molecular Portrait of Breast-Cancer-Derived Cell Lines Reveals Poor Similarity with Tumors. AB - Breast-cancer-derived cell lines are an important sample source for cancer proteomics and can be classified on the basis of transcriptomic analysis into subgroups corresponding to the molecular subtypes observed in mammary tumors. This study describes a tridimensional fractionation method that allows high sequence coverage and proteome-wide estimation of protein expression levels. This workflow has been used to conduct an in-depth quantitative proteomic survey of five breast cancer cell lines matching all major cancer subgroups and shows that despite their different classification, these cell lines display a very high level of similarity. A proteome-wide comparison with the RNA levels observed in the same samples showed very little to no correlation. Finally, we demonstrate that the proteomes of in vitro models of breast cancer display surprisingly little overlap with those of clinical samples. PMID- 26055191 TI - Exaggerated blood pressure response to dynamic exercise despite chronic refractory hypotension: results of a human case study. AB - BACKGROUND: Chronic refractory hypotension is a rare but significant mortality risk in renal failure patients. Such aberrant physiology usually deems patient unfit for renal transplant surgery. Exercise stimulates the mechano chemoreceptors in the skeletal muscle thereby modulating the sympathetic effects on blood pressure regulation. The haemodynamic response to dynamic exercise in such patients has not been previously investigated. We present a case with severe chronic hypotension who underwent exercise testing before and after renal transplantation, with marked differences in blood pressure response to exercise. CASE PRESENTATION: A 40-year old haemodialysis-dependent patient with a 2 year history of refractory hypotension (<=80/50 mmHg) was referred for living donor renal transplantation at our tertiary centre. Each dialysis session was often less than 2 h and 30 min due to symptomatic hypotension. As part of the cardiovascular assessment, she underwent haemodynamic evaluation with cardiopulmonary exercise testing. Blood pressure normalized during unloaded pedalling but was exaggerated at maximal workload whereby it rose from 82/50 mmHg to a peak of 201/120 mmHg. Transthoracic echocardiography, tonometric measure of central vascular compliance and myocardial perfusion scan were normal. She subsequently underwent an antibody-incompatible renal transplantation and was vasopressor reliant for 14 days during the post-operative period. Eight weeks following transplant, resting blood pressure was normal and a physiological exercise-haemodynamic response was observed during a repeat cardiopulmonary exercise testing. CONCLUSION: This case highlights the potential therapeutic role of unloaded leg cycling exercise during dialysis session to correct chronic hypotension, allowing patients to have greater tolerance to fluid shift. It also adds to existing evidence that sympathetic dysfunction is reversible with renal transplant. Furthermore chronic hypotension with preserved exercise-haemodynamic response and cardiovascular reserve should not preclude these patients from renal transplant surgery. PMID- 26055193 TI - David Sackett and the birth of Evidence Based Medicine: How to Practice and Teach EBM. PMID- 26055194 TI - Food structure: Its formation and relationships with other properties. AB - Food materials are complex in nature as it has heterogeneous, amorphous, hygroscopic and porous properties. During processing, microstructure of food materials changes which significantly affects other properties of food. An appropriate understanding of the microstructure of the raw food material and its evolution during processing is critical in order to understand and accurately describe dehydration processes and quality anticipation. This review critically assesses the factors that influence the modification of microstructure in the course of drying of fruits and vegetables. The effect of simultaneous heat and mass transfer on microstructure in various drying methods is investigated. Effects of changes in microstructure on other functional properties of dried foods are discussed. After an extensive review of the literature, it is found that development of food structure significantly depends on fresh food properties and process parameters. Also, modification of microstructure influences the other properties of final product. An enhanced understanding of the relationships between food microstructure, drying process parameters and final product quality will facilitate the energy efficient optimum design of the food processor in order to achieve high-quality food. PMID- 26055195 TI - Activation of Hypocretin-1/Orexin-A Neurons Projecting to the Bed Nucleus of the Stria Terminalis and Paraventricular Nucleus Is Critical for Reinstatement of Alcohol Seeking by Neuropeptide S. AB - BACKGROUND: Environmental conditioning is a major trigger for relapse in abstinent addicts. We showed that activation of the neuropeptide S (NPS) system exacerbates reinstatement vulnerability to cocaine and alcohol via stimulation of the hypocretin-1/orexin-A (Hcrt-1/Ox-A) system. METHODS: Combining pharmacologic manipulations with immunohistochemistry techniques, we sought to determine how NPS and Hcrt-1/Ox-A systems interact to modulate reinstatement of alcohol seeking in rats. RESULTS: Intrahypothalamic injection of NPS facilitated discriminative cue-induced reinstatement of alcohol seeking. This effect was blocked by the selective Hcrt-1/Ox-A antagonist SB334867 microinjected into the hypothalamic paraventricular nucleus (PVN) or into the bed nucleus of the stria terminalis (BNST) but not into the ventral tegmental area or the locus coeruleus. Combining double labeling and confocal microscopy analyses, we found that NPS-containing axons are in close apposition to hypothalamic Hcrt-1/Ox-A positive neurons, a significant proportion of which express NPS receptors, suggesting a direct interaction between the two systems. Retrograde tracing experiments showed that intra-PVN or intra-BNST red fluorobead unilateral injection labeled bilaterally Hcrt-1/Ox-A somata, suggesting that NPS could recruit two distinct neuronal pathways. Confirming this assumption, intra-BNST or PVN Hcrt-1/Ox-A injection enhanced alcohol seeking similarly to hypothalamic NPS injection but to a lesser degree. CONCLUSIONS: Results suggest that the Hcrt-1/Ox-A neurocircuitry mediating the facilitation of cue-induced reinstatement by NPS involves structures critically involved in stress regulation such as the PVN and the BNST. These findings open to the tempting hypothesis of a role of the NPS system in modulating the interactions between stress and environmental conditioning factors in drug relapse. PMID- 26055196 TI - Effect of pH on the Structure and DNA Binding of the FOXP2 Forkhead Domain. AB - Forkhead box P2 (FOXP2) is a transcription factor expressed in cardiovascular, intestinal, and neural tissues during embryonic development and is implicated in language development. FOXP2 like other FOX proteins contains a DNA binding domain known as the forkhead domain (FHD). The FHD interacts with DNA by inserting helix 3 into the major groove. One of these DNA-protein interactions is a direct hydrogen bond that is formed with His554. FOXP2 is localized in the nuclear compartment that has a pH of 7.5. Histidine contains an imidazole side chain in which the amino group typically has a pKa of ~6.5. It seems possible that pH fluctuations around 6.5 may result in changes in the protonation state of His554 and thus the ability of the FOXP2 FHD to bind DNA. To investigate the effect of pH on the FHD, both the structure and the binding affinity were studied in the pH range of 5-9. This was done in the presence and absence of DNA. The structure was assessed using size exclusion chromatography, far-UV circular dichroism, and intrinsic and extrinsic fluorescence. The results indicated that while pH did not affect the secondary structure in the presence or absence of DNA, the tertiary structure was pH sensitive and the protein was less compact at low pH. Furthermore, the presence of DNA caused the protein to become more compact at low pH and also had the potential to increase the dimerization propensity. Fluorescence anisotropy was used to investigate the effect of pH on the FOXP2 FHD DNA binding affinity. It was found that pH had a direct effect on binding affinity. This was attributed to the altered hydrogen bonding patterns upon protonation or deprotonation of His554. These results could implicate pH as a means of regulating transcription by the FOXP2 FHD, which may also have repercussions for the behavior of this protein in cancer cells. PMID- 26055197 TI - Self-administered hearing loss screening using an interactive, tablet play audiometer with ear bud headphones. AB - BACKGROUND AND OBJECTIVE: The timely diagnosis and treatment of acquired hearing loss in the pediatric population has significant implications for a child's development. Audiological assessment in children, however, carries both technological and logistical challenges. Typically, specialized methods (such as play audiometry) are required to maintain the child's attention and can be resource intensive. These challenges were previously addressed by a novel, calibrated, interactive play audiometer for Apple((r)) iOS((r)) called "ShoeBOX Audiometry". This device has potential applications for deployment in environments where traditional clinical audiometry is either unavailable or impractical. The objective of this study was to assess the screening capability of the tablet audiometer in an uncontrolled environment using consumer ear-bud headphones. METHODS: Consecutive patients presenting to the Audiology Clinic at the Children's Hospital of Eastern Ontario (ages 4 and older) were recruited. Participants' hearing was evaluted using the tablet audiometer calibrated to Apple((r)) In-Ear headphones. The warble tone thresholds obtained were compared to gold standard measurements taken with a traditional clinical audiometer inside a soundbooth. RESULTS: 80 patients were enrolled. The majority of participants were capable of completing an audiologic assessment using the tablet computer. Due to ambient noise levels outside a soundbooth, thresholds obtained at 500Hz were not consistent with traditional audiometry. Excluding 500Hz threholds, the tablet audiometer demonstrated strong negative predictive value (89.7%) as well as strong sensitivity (91.2%) for hearing loss. CONCLUSION: Thresholds obtained in an uncontrolled setting are not reflective of diagnostic thresholds due to the uncalibrated nature of the headphones and variability of the setting without a booth. Nevertheless, the tablet audiometer proved to be both a valid and sensitive instrument for unsupervised screening of warble-tone thresholds in children. PMID- 26055198 TI - Audiological findings in Infantile Refsum disease. AB - Audiological manifestations in a four-year-old child with Infantile Refsum disease are reported. He was born to non-consanguineous parents and had normal birth history and mildly delayed milestones prior to presentation. Clinical features were characterized by neuroregression, retinitis pigmentosa, hearing loss, peripheral neuropathy and white matter signal changes on magnetic resonance imaging. Biochemical evaluation showed elevated serum levels of long chain fatty acid and phytanic acid confirming the diagnosis. The audiological profile was characterized by absent auditory brainstem responses with robust otocoustic emissions, which indicated auditory neuropathy as the possible cause of hearing loss. PMID- 26055199 TI - The effect of tonsillectomy on the immune system: A systematic review and meta analysis. AB - IMPORTANCE: The immunological sequelae of tonsillectomy in children have been a source of debate among physicians and a continuous concern for parents. Contradictory pertinent results exist in the literature. OBJECTIVE: To understand the real effect of tonsillectomy on the immune system. DATA SOURCES: MEDLINE, EMBASE and COCHRANE. STUDY SELECTION: Articles addressing the effect of tonsillectomy on the immune system, up to Dec 2014. Related keywords and medical subject headings were used during the search. The abstracts were reviewed to determine suitability for inclusion based on a set of criteria. Manual crosscheck of references was performed. DATA EXTRACTION: We checked the tests results and the conclusion of each study to classify it as supporting or refuting the hypothesis of a negative effect of tonsillectomy on the immune system. RESULTS: We reviewed 35 articles, published between 1971 and 2014, including 1997 patients. Only Four studies (11.4%), including 406 patients (20.3%) found that tonsillectomy negatively affects the immune system. We performed a separate meta analysis on various reviewed humoral and cellular immunological parameters (e.g. total and specific serum Ig's, SecIgA, cellular immunity, and Ag specific Ig). There is more evidence to suggest that tonsillectomy has no negative clinical or immunological sequalae on the immune system. Study limitations included heterogeneity in the diagnostic tools, timing of testing, indication for tonsillectomy and patients' age. CONCLUSION: It is reasonable to say that there is enough evidence to conclude that tonsillectomy has no clinically significant negative effect on the immune system. It will be important for future studies to uniformly use both preoperative and control laboratory tests' levels to compare the postoperative levels with, to have short and long term follow-up levels, and to include both humoral and cellular immunity in their measurements. RELEVANCE: The results should reassure both surgeons and parents that tonsillectomy has no proven clinical sequalae. If more research is to be done in the future, it should be performed in a standardized way to avoid the heterogeneity seen in the literature. PMID- 26055200 TI - Corrigendum: Crowdsourcing Natural Products Discovery to Access Uncharted Dimensions of Fungal Metabolite Diversity. PMID- 26055201 TI - Transcranial direct current stimulation of SMA modulates anticipatory postural adjustments without affecting the primary movement. AB - Recent works provide evidences that anticipatory postural adjustments (APAs) are programmed with the prime mover recruitment as a shared posturo-focal command. However the ability of the CNS to adjust APAs to changes in the postural context implies that the postural and voluntary components should take different pathways before reaching the representation of single muscles in the primary motor cortex. Here we test if such bifurcation takes place at the level of the supplementary motor area (SMA). TDCS was applied over the SMA in 14 subjects, who produced a brisk index-finger flexion. This activity is preceded by inhibitory APAs, carved in the tonic activity of Biceps Brachii and Anterior Deltoid, and by an excitatory APA in Triceps Brachii. Subjects performed a series of 30 flexions before, during and after 20 min of tDCS in CATHODAL, ANODAL or SHAM configuration. The inhibitory APA in Biceps and the excitatory APA in Triceps were both greater in ANODAL than in SHAM and CATHODAL configurations, while no difference was found among the latter two (ANODAL vs. SHAM: biceps +26.5%, triceps +66%; ANODAL vs. CATHODAL: biceps +20.5%, triceps: +63.4%; for both muscles, ANOVA p<0.02, Tukey p<0.05). Instead, the APA in anterior deltoid was unchanged in all configurations. No changes were observed in prime mover recruitment and index-finger kinematics. Results show that the SMA is involved in modulating APAs amplitude. Moreover, the differential effect of tDCS observed on postural and voluntary commands suggests that these two components of the motor program are already separated before entering SMA. PMID- 26055202 TI - Association analysis for corticotropin releasing hormone polymorphisms with the risk of major depressive disorder and the response to antidepressants. AB - Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent neuroendocrine abnormalities observed in patients with major depressive disorder (MDD). The peptide corticotropin-releasing hormone (CRH) is a key mediator for HPA axis function during stress. This study evaluated the associations of CRH polymorphisms with susceptibility to MDD and response to antidepressant treatment, and the gene-environment interaction with stressful life events (SLEs). After screening 31 polymorphisms in the gene encoding CRH, we evaluated the association of polymorphisms with MDD susceptibility in 149 patients with MDD and 193 control subjects; in patients, we also evaluated the response to treatment with antidepressants. Although genotypes and haplotypes were not significantly associated with the risk of MDD, non-remitters were more likely to carry haplotype 1 (ht1) than were remitters (P = 0.019-0.038), when only patients without SLE were included; however, the association was not significant after correction for multiple comparisons. Additionally, after 4 and 8 weeks of treatment in patients who experienced no SLEs, significantly higher 21 item Hamilton Depression Rating scores were found in MDD subjects who were CRH ht1 homozygotes compared to patients carrying one or no ht1 alleles (P = 0.007 and 0.027 at 4 and 8 weeks, respectively). Although these preliminary observations require further confirmation in future studies, these results on the interaction between CRH haplotypes and SLEs, suggest that CRH ht1 which is moderated by SLEs, may be associated with antidepressant treatment outcomes in patients with MDD. PMID- 26055203 TI - Alterations in the hippocampal phosphorylated CREB expression in drug state dependent learning. AB - The present study investigated the possible alterations of hippocampal CREB phosphorylation in drug state-dependent memory retrieval. One-trial step-down passive avoidance task was used to assess memory retrieval in adult male NMRI mice. Pre-training administration of ethanol (1g/kg, i.p.) induced amnesia. Pre test administration of ethanol (1g/kg, i.p) or nicotine (0.7 mg/kg, s.c.) reversed ethanol-induced amnesia, indicating ethanol- or ethanol-nicotine induced state-dependent learning (STD). Using Western blot analysis, it was found that the p-CREB/CREB ratio in the hippocampus increased in the mice that showed successful memory retrieval as compared with untrained mice. In contrast, pre training administration of ethanol (1g/kg, i.p.) decreased the hippocampal p CREB/CREB ratio in comparison with the control group. The hippocampal p-CREB/CREB ratio enhanced in ethanol- and ethanol-nicotine induced STD. Moreover, memory impairment induced by pre-training administration of WIN (1 mg/kg, i.p.) improved in the animals that received pre-test administration of WIN (1 mg/kg, i.p.), ethanol (0.5 g/kg, i.p.) or nicotine (0.7 mg/kg, s.c.), suggesting a cross STD between the drugs. The p-CREB/CREB ratio in the hippocampus decreased in the of WIN-induced amnesia and STD groups in comparison with the control group. In addition, cross state-dependent learning between WIN and ethanol or nicotine was associated with the increase of the hippocampal p-CREB/CREB ratio. It can be concluded that phosphorylation of CREB in the hippocampus is a critical event underlying the interaction of co-administration of drugs on memory retrieval in passive avoidance learning. PMID- 26055204 TI - New surgical staging system for patients with recurrent nasopharyngeal carcinoma based on the AJCC/UICC rTNM classification system. AB - BACKGROUND: Recurrent tumour, node and metastasis (rTNM) stage system does not have an outstanding prognostic value for survival outcome of patients with recurrent nasopharyngeal carcinoma (rNPC) and it cannot aid the clinicians to choose the most suitable treatment for these patients. METHODS: In total, 894 rNPC patients were consecutively enroled. All recurrent (r) tumour (T) stages (rT) and node (N) stages (rN) were stratified as resectable and unresectable based on the imaging data of the head and neck. These stages were re-subdivided into surgical T stages (sT) and surgical N stages (sN) with similar clinical characteristics and death risks and were re-integrated into a new 'surgical' stage using a Cox proportional hazards model. RESULTS: The 5-year overall survival (OS) was 72.0%, 55.1%, 21.1% and 10.1% in 'surgical' stages I, II, III and IV, respectively (P<0.001). The 'surgical' stage was a significant independent prognostic factor for OS (hazard ratio [HR] 1.78, P<0.001) and exhibited enhanced prognostic value compared with the rTNM staging system (area under receiver operating characteristics 0.68 versus 0.63, P<0.001). Endoscopic nasopharyngectomy and intensity-modulated radiation therapy were significant independent positive prognostic factors for the OS of patients with primary lesions in 'surgical' stage I/II and 'surgical' stage III, respectively (P<0.05). A combination of aggressive treatments for loco-regional lesions exhibited a beneficial trend for OS of patients with 'surgical' stage IV (P>0.05). CONCLUSIONS: Compared with the rTNM stage system, the 'surgical' staging system exhibited enhanced prognostic value for rNPC patient survival and could aid clinicians in choosing the most suitable treatment for rNPC patients. PMID- 26055205 TI - Note of clarification of data on the association between CYP2E1 RsaI polymorphism and lung cancer risk. PMID- 26055206 TI - Draft genome of Elstera litoralis, a freshwater epilithic biofilm associated bacterium from littoral zone of Lake Constance. AB - Elstera litoralis, is a Rhodospirillaceae member which was isolated from the littoral zone of Lake Constance from a stone biofilm using diatom extracellular polymeric substances (EPS) as C source. We present here the draft genome of E. litoralis which has a genome size of 3.83 Mb and 61.2% G+C content. Genome analysis indicated utilization of multiple C substrates explaining its heterotrophic lifestyle as a bacterium present in natural biofilms. Further comparative genome analysis of Elstera with other members of Rhodospirillaceae would be helpful to understand the evolutionary relationships and divergence of hydrobacteria from terrabacteria. PMID- 26055207 TI - The diatom molecular toolkit to handle nitrogen uptake. AB - Nutrient concentrations in the oceans display significant temporal and spatial variability, which strongly affects growth, distribution and survival of phytoplankton. Nitrogen (N) in particular is often considered a limiting resource for prominent marine microalgae, such as diatoms. Diatoms possess a suite of N related transporters and enzymes and utilize a variety of inorganic (e.g., nitrate, NO3(-); ammonium, NH4(+)) and organic (e.g., urea; amino acids) N sources for growth. However, the molecular mechanisms allowing diatoms to cope efficiently with N oscillations by controlling uptake capacities and signaling pathways involved in the perception of external and internal clues remain largely unknown. Data reported in the literature suggest that the regulation and the characteristic of the genes, and their products, involved in N metabolism are often diatom-specific, which correlates with the peculiar physiology of these organisms for what N utilization concerns. Our study reveals that diatoms host a larger suite of N transporters than one would expected for a unicellular organism, which may warrant flexible responses to variable conditions, possibly also correlated to the phases of life cycle of the cells. All this makes N transporters a crucial key to reveal the balance between proximate and ultimate factors in diatom life. PMID- 26055208 TI - Diaminodiphenyl sulfone-induced eosinophilic pneumonia in a patient with pemphigus foliaceus. PMID- 26055209 TI - The amniotic band syndrome in the rat is associated with the activation of transforming growth factor-beta. AB - Amniocentesis in rats is associated with different malformations, such as cleft palate and limb deformation, resembling the human congenital amniotic band syndrome (ABS). Despite many human cases reported in the literature, little is known about the mechanisms involved in ABS. This study addressed if the activation of the transforming growth factor-beta1 (TGF-beta1) pathway is, in part, associated with amniotic band formation and growth restriction induced in rats by amniocentesis, as by a previously published model. For this purpose, quantification of TGF-beta1, alpha-smooth muscle actin, and collagen type I mRNA and protein levels were determined by quantitative PCR and Western blot analysis, respectively, in the fetus, its amniotic membrane, and the uterus of experimental and control rats. We found that TGF-beta1 mRNA levels are increased in the fetus and the amniotic membrane at 6 hours, whereas alpha-smooth muscle actin, phosphorylated Smad3, and collagen type I increased at 48 hours, suggesting that a fibrotic response is induced after the amniotic sac puncture. Furthermore, fetuses had hemorrhages, syndactyly, and amputation of limbs, similar to human ABS. PMID- 26055210 TI - Twist contributes to proliferation and epithelial-to-mesenchymal transition induced fibrosis by regulating YB-1 in human peritoneal mesothelial cells. AB - Twist is overexpressed in high glucose (HG) damage of human peritoneal mesothelial cells (HPMCs) in vitro. Herein, we further identified its precise function related to fibrosis of peritoneal membranes (PMs). The overexpression and activation of Twist and YB-1 (official name, YBX1) and a transformed fibroblastic phenotype of HPMCs were found to be positively related to epithelial mesenchymal transition progress and PM fibrosis ex vivo in 93 patients who underwent continuous ambulatory peritoneal dialysis (PD), and also in HG-induced immortal HPMCs and an animal model of PD. Evidence from chromatin immunoprecipitation and luciferase reporter assays supported that YBX1 is transcriptionally regulated by the direct binding of Twist to E-box. Overexpression of Twist and YB-1 led to an increase in epithelial-mesenchymal transition, proliferation, and cell cycle progress of HPMCs, which might contribute to PM fibrosis. In contrast, the silencing of Twist or YB-1 inhibited HG-induced growth and cell cycle progression of HPMCs; this led to a down regulation in the expression of cyclin Ds and cyclin-dependent kinases, finally inhibiting PM fibrosis. Twist contributes to PM fibrosis during PD treatment, mainly through regulation of YB-1. PMID- 26055211 TI - Rationale and Design of the Reduce Elevated Left Atrial Pressure in Patients With Heart Failure (Reduce LAP-HF) Trial. AB - OBJECTIVE: Heart failure with preserved ejection fraction (HFpEF) is characterized by elevated left atrial pressure during rest and/or exercise. The Reduce LAP-HF (Reduce Elevated Left Atrial Pressure in Patients With Heart Failure) trial will evaluate the safety and performance of the Interatrial Shunt Device (IASD) System II, designed to directly reduce elevated left atrial pressure, in patients with HFpEF. METHODS: The Reduce LAP-HF Trial is a prospective, nonrandomized, open-label trial to evaluate a novel device that creates a small permanent shunt at the level of the atria. A minimum of 60 patients with ejection fraction >=40% and New York Heart Association functional class III or IV heart failure with a pulmonary capillary wedge pressure (PCWP) >=15 mm Hg at rest or >=25 mm Hg during supine bike exercise will be implanted with an IASD System II, and followed for 6 months to assess the primary and secondary end points. Safety and standard clinical follow-up will continue through 3 years after implantation. Primary outcome measures for safety are periprocedural and 6-month major adverse cardiac and cerebrovascular events (MACCE) and systemic embolic events (excluding pulmonary thromboembolism). MACCE include death, stroke, myocardial infarction, or requirement of implant removal. Primary outcome measures for device performance include success of device implantation, reduction of PCWP at rest and during exercise, and demonstration of left-to-right flow through the device. Key secondary end points include exercise tolerance, quality of life, and the incidence of heart failure hospitalization. CONCLUSION: Reduce LAP-HF is the first trial intended to lower left atrial pressure in HFpEF by means of creating a permanent shunt through the atrial septum with the use of a device. Although the trial is primarily designed to study safety and device performance, we also test the pathophysiologic hypothesis that reduction of left atrial pressure will improve symptoms and quality of life in patients with HFpEF. PMID- 26055212 TI - Oxidized regenerated cellulose in breast surgery: experimental model. AB - BACKGROUND: Breast-conserving surgery (BCS) combined with postoperative radiotherapy has become the gold standard of locoregional treatment in patients with early-stage breast cancer. When large tumor resections are needed in small medium size breasts, oncoplastic procedures (OPP) have been introduced to improve the cosmetic result; but in several cases, OPP may be not sufficient to accomplish this purpose. Oxidized regenerated cellulose (ORC, Tabotamp fibrillar; Johnson & Johnson; Ethicon) has been reported to be useful in OPP to optimize the cosmetic results after OPP. However, no ultrastructural study is available on the use of ORC as a filler in BCS. MATERIALS AND METHODS: A BCS cavity was simulated in both groin regions in 24 consecutive Wistar rats. The right groin underwent soft tissue displacement and ORC implantation, whereas the left groin was treated only by soft tissue displacement (control side). Rats were sacrificed at 10, 20, and 30 wk to evaluate volume retainment and microscopic features (vascularization, fibrosis, cell population, inflammation, liponecrosis, and capsule formation). RESULTS: The use of ORC was characterized by diffuse fibrosis and homogeneous neovascularization within the construct, with no capsule formation and no inflammation. Volume retainment was similar in the 20- and 30-wk specimens (mean 80.4%, standard deviation, 6.65 and mean 79.9%, standard deviation, 6.51). CONCLUSIONS: Implanted ORC was well integrated within the soft tissue with diffuse fibrosis, angiogenesis, and absence of capsule formation. Preliminary results confirmed that this biomaterial could further contribute to optimize cosmetic results in the oncoplastic surgical spectrum of breast conservation therapy. PMID- 26055213 TI - Neonatal esophageal perforation: nonoperative management. AB - BACKGROUND: Esophageal perforation is a rare complication of enteric instrumentation in neonates. Enteric tube placement in micro-preemies poses a particular hazard to the narrow lumen and thin wall of the developing esophagus. The complication may be difficult to recognize or misdiagnosed as esophageal atresia, and is associated with considerable mortality. Historically, management of this life-threatening iatrogenic disease was operative, but trends have shifted toward nonoperative treatment. Here, we review neonatal esophageal perforation at our own institution for management techniques, risk factors, and outcomes. MATERIALS AND METHODS: Seven neonatal patients with esophageal perforation were identified and charts reviewed for demographics, comorbidities, etiology of perforation, diagnostic modalities, management decisions, complications, and outcomes. RESULTS: Mean gestational age was 27.2 +/- 4.0 wk, and weight at diagnosis was 892 +/- 674 g. All seven patients had esophageal perforation resulting from endotracheal or enterogastric intubation and were managed nonoperatively. Treatment included removal of the offending tube, nil per os, and antibiotics. Five patients required additional interventions: four tube thoracostomies for pneumothoraces and one peritoneal drain for pneumoperitoneum. Three patients died because of sequelae of prematurity (intraventricular hemorrhage, necrotizing enterocolitis, and sepsis). One patient was diagnosed as having esophageal atresia; esophagoscopy before surgical repair established the correct diagnosis. CONCLUSIONS: Neonates, particularly those under 1500 g, are at substantial risk for iatrogenic esophageal perforation during enterogastric intubation. Nonoperative management may be a safe initial strategy in the neonatal setting, but more aggressive interventions may ultimately be required. Despite recent improvement in early recognition of this injury, misdiagnosis still occurs. PMID- 26055214 TI - Global opportunities on 239 general surgery residency Web sites. AB - BACKGROUND: Many general surgical residency programs lack a formal international component. We hypothesized that most surgery programs do not have international training or do not provide the information to prospective applicants regarding electives or programs in an easily accessible manner via Web-based resources. MATERIALS AND METHODS: Individual general surgery program Web sites and the American College of Surgeons residency tool were used to identify 239 residencies. The homepages were examined for specific mention of international or global health programs. Ease of access was also considered. Global surgery specific pages or centers were noted. Programs were assessed for length of rotation, presence of research component, and mention of benefits to residents and respective institution. RESULTS: Of 239 programs, 24 (10%) mentioned international experiences on their home page and 42 (18%) contained information about global surgery. Of those with information available, 69% were easily accessible. Academic programs were more likely than independent programs to have information about international opportunities on their home page (13.7% versus 4.0%, P = 0.006) and more likely to have a dedicated program or pathway Web site (18.8% versus 2.0%, P < 0.0001). Half of the residencies with global surgery information did not have length of rotation available. Research was only mentioned by 29% of the Web sites. Benefits to high-income country residents were discussed more than benefits to low- and middle-income country residents (57% versus 17%). CONCLUSIONS: General surgery residency programs do not effectively communicate international opportunities for prospective residents through Web based resources and should seriously consider integrating international options into their curriculum and better present them on department Web sites. PMID- 26055215 TI - 3D-QSAR and docking studies on adenosine A2A receptor antagonists by the CoMFA method. AB - Parkinson's disease affects millions of people around the world. Recently, adenosine A2A receptor antagonists have been identified as a drug target for the treatment of Parkinson's disease. Consequently, there is an immediate need to develop new classes of A2A receptor antagonists. In the present analysis, three dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed on a series of pyrimidines, using comparative molecular field analysis (CoMFA). The best prediction was obtained with a CoMFA standard model (q(2) = 0.475, r(2) = 0.977) and a CoMFA region focusing model (q(2) = 0.637, r(2) = 0.976) combined with steric and electrostatic fields. The structural insights derived from the contour maps helped to better interpret the structure-activity relationships. Also, to understand the structure-activity correlation of A2A receptor antagonists, we have carried out molecular docking analysis. Based on the results obtained from the present 3D-QSAR and docking studies, we have identified some key features for increasing the activity of compounds, which have been used to design new A2A receptor antagonists. The newly designed molecules showed high activity with the obtained models. PMID- 26055216 TI - Clinical Effects of Liraglutide in a Real-World Setting in Spain: eDiabetes Monitor SEEN Diabetes Mellitus Working Group Study. AB - INTRODUCTION: A limitation with randomized controlled trials is that, while they provide unbiased evidence of the efficacy of interventions, they do so under unreal conditions and in a very limited and highly selected patient population. Our aim was to provide data about the effectiveness of liraglutide treatment in a real-world and clinical practice setting. METHODS: In a retrospective and observational study, data from 753 patients with type 2 diabetes were recorded through an online tool (eDiabetes-Monitor). RESULTS: Mean baseline glycated hemoglobin (HbA1c) was 8.4 +/- 1.4% and mean body mass index (BMI) was 38.6 +/- 5.4 kg/m(2). After 3-6 months of treatment with liraglutide, we observed a change in HbA1c of -1.1 +/- 1.2%, -4.6 +/- 5.3 kg in weight and -1.7 +/- 2.0 kg/m(2) in BMI (p < 0.001 for all). Compared to baseline, there was a significant reduction in systolic blood pressure (-5.9 mmHg, p < 0.001), diastolic blood pressure (-3.2 mmHg, p < 0.001), LDL cholesterol (-0.189 mmol/l, p < 0.001) and triglycerides ( 0.09 mmol/l, p = 0.021). In patients switched from DPP-4 inhibitors, liraglutide induced a decrease of -1.0% in HbA1c (p < 0.001) and a reduction in weight (-4.5 kg, p < 0.001). In patients treated with liraglutide as an add-on therapy to insulin a decrease of -1.08% in HbA1c (p < 0.001) and a weight reduction of -4.15 kg (p < 0.001) were observed. CONCLUSION: Our study confirms the effectiveness of liraglutide in a real-life and clinical practice setting. FUNDING: Spanish Society of Endocrinology and Nutrition. PMID- 26055217 TI - Effects of Miglitol, Acarbose, and Sitagliptin on Plasma Insulin and Gut Peptides in Type 2 Diabetes Mellitus: A Crossover Study. AB - INTRODUCTION: Both dipeptidyl peptidase-4 inhibitors and alpha-glucosidase inhibitors (alpha-GI) have been reported to change the incretin and insulin secretion. To examine the effects of acarbose, miglitol, and sitagliptin on glucose metabolism and secretion of gut peptides, we conducted a crossover study in patients with type 2 diabetes mellitus (T2DM). METHODS: Eleven Japanese patients with T2DM underwent four meal tolerance tests with single administration of acarbose, miglitol, sitagliptin, or nothing. Fasting and postprandial plasma levels of glucose, insulin, glucagon, active glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), ghrelin, and des-acyl ghrelin were measured. RESULTS: Early-phase insulin secretion was reduced following acarbose and miglitol, and the areas under the curve (AUC) of insulin at 180 min following acarbose and miglitol were significantly lower than sitagliptin. AUC of plasma glucose at 180 min after acarbose, miglitol, and sitagliptin tended to be lower than in controls, and plasma glucose levels at 30-60 min following miglitol were significantly lower than in controls. Plasma glucagon, ghrelin, and des-acyl ghrelin levels did not differ among the four conditions. Postprandial plasma active GLP-1 levels and AUC of GLP-1 increased significantly in both the sitagliptin and miglitol groups compared to control. Postprandial plasma total GIP levels increased following sitagliptin but decreased after acarbose and miglitol. Changes in incretin levels tended to be greater with miglitol than acarbose. CONCLUSION: These results showed that sitagliptin and alpha-GIs, miglitol more so than acarbose, improved hyperglycemia in patients with T2DM after single administration, and had different effects on insulin and incretin secretion. TRIAL REGISTRATION: UMIN-CTR number, UMIN000009981. PMID- 26055218 TI - Continuous Glucose Monitoring During Basal-Bolus Therapy Using Insulin Glargine 300 U mL(-1) and Glargine 100 U mL (-1) in Japanese People with Type 1 Diabetes Mellitus: A Crossover Pilot Study. AB - INTRODUCTION: New insulin glargine 300 U mL(-1) (Gla-300) is a basal insulin that shows more stable and prolonged pharmacokinetic and pharmacodynamic profiles than insulin glargine 100 U mL(-1) (Gla-100). This study used continuous glucose monitoring (CGM) to compare 24-h glucose profiles in a Japanese population using Gla-300 versus Gla-100. METHODS: This was an exploratory 8.4-week, single-center, 2-sequence, 2-period, open-label crossover study. Japanese adults with type 1 diabetes mellitus (T1DM) treated with basal-bolus insulin, with glycated hemoglobin (HbA1c) 6.5-10.0% and median fasting self-monitored plasma glucose concentration <=13 mmol L(-1), were randomized to Gla-300 followed by Gla-100 (subgroup 1) or vice versa (subgroup 2), with no washout period. CGM was performed on the last 3 days of the screening period and each treatment period. Primary endpoint was comparison of 24-h glucose variability (area under the curve [AUC]mean_24 h) on the second day of each CGM measurement with Gla-300 versus Gla 100. Baseline and end of treatment period values for HbA1c, fasting plasma glucose (FPG) and daily basal/mealtime insulin doses were recorded. Hypoglycemia and adverse events (AEs) were recorded. RESULTS: Twenty participants were randomized (10 to subgroup 1 and 10 to subgroup 2). Participants showed comparable glucose variability over 24 h (AUCmean_24 h during treatment with Gla 300 or Gla-100 (treatment ratio 0.96; 90% confidence interval 0.79, 1.16). HbA1c and FPG were generally stable across both treatment periods. There was a trend towards fewer participants experiencing >=1 hypoglycemia event at any time (24 h) and at night (00:00-05:59 h) with Gla-300 versus Gla-100. Treatment-emergent AEs, reported by 9/20 (45%) and 4/20 (20%) participants during Gla-300 and Gla-100 treatment, respectively, were unrelated to study medication. CONCLUSIONS: In this cohort of Japanese people with T1DM, no between-treatment difference was observed in glucose variability with Gla-300 versus Gla-100, as measured by CGM. There was a trend for less hypoglycemia with Gla-300, particularly at night, versus Gla 100. Both treatments were well tolerated. FUNDING: Sanofi, Tokyo, Japan. CLINICAL TRIAL REGISTRATION: NCT01676233, ClinicalTrials.gov. PMID- 26055219 TI - Efficacy of treatment with a GnRH antagonist in prostate cancer patients previously treated with a GnRH agonist. AB - PURPOSE: The efficacy of switching from a GnRH agonist to a GnRH antagonist for prostate cancer patients resistant to treatment with the GnRH agonist has not been fully characterized yet. We aimed to evaluate the efficacy of the switch to a GnRH antagonist in patients with PSA failure after hormonal therapy with a GnRH agonist. METHODS: We retrospectively examined 18 patients with prostate cancer who received androgen-deprivation therapy and who were treated with a GnRH antagonist (degarelix) after they showed an elevated PSA while on GnRH agonist therapy. We evaluated the characteristics of the patients and analyzed some clinical factors for their potential association with the patient response to the switch. RESULTS: The median PSA at the switch was 7.9 (0.37-1709) ng/ml, and the median testosterone level was 0.17 (<0.08-0.81) ng/ml. Three months after the switch, the median PSA level was 11.3 (0.22-2636) ng/ml, and the median testosterone level was 0.14 (<0.08-0.23) ng/ml. The PSA decreased in six patients (33.3 %) 1 month after the switch, and in three of them it decreased by more than 50 % by 3 months after the switch. Univariate analyses revealed that the lower number of prior treatment lines for prostate cancer before the switch was associated with a favorable decrease in PSA. CONCLUSIONS: Switching from GnRH agonist to GnRH antagonist therapy was effective for some prostate cancer patients with PSA failure. The small number of prior treatment lines for prostate cancer before the switch was significantly associated with a good PSA response. PMID- 26055220 TI - Identification of the first neuropeptides from the enigmatic hexapod order Protura. AB - The Hexapoda consists of two classes, the Entognatha and the Insecta, with the former group considered basal to the latter. The Protura is a basal order within the Entognatha, the members of which are minute soil dwellers first identified in the early 20th century. Recently, a transcriptome shotgun assembly (TSA) was generated for the proturan Acerentomon sp., providing the first significant molecular resource for this enigmatic hexapod order. As part of an ongoing effort to predict peptidomes for little studied members of the Arthropoda, we have mined this TSA dataset for transcripts encoding putative neuropeptide precursors and predicted the structures of mature peptides from the deduced proteins. Forty seven peptide-encoding transcripts were mined from the Acerentomon TSA dataset, with 202 distinct peptides predicted from them. The peptides identified included isoforms of adipokinetic hormone, adipokinetic hormone-corazonin-like peptide, allatostatin A, allatostatin B, allatostatin C, allatotropin, bursicon alpha, bursicon beta, CCHamide, corazonin, crustacean cardioactive peptide, crustacean hyperglycemic hormone/ion transport peptide, diuretic hormone 31, diuretic hormone 44, ecdysis-triggering hormone, eclosion hormone, FMRFamide-like peptide, GSEFLamide, insulin-like peptide, intocin, leucokinin, myosuppressin, neuropeptide F, orcokinin, proctolin, pyrokinin, RYamide, short neuropeptide F, SIFamide, sulfakinin and tachykinin-related peptide; these are the first neuropeptides described from any proturan. Comparison of the Acerentomon precursors and mature peptides with those from other arthropods revealed features characteristic of both the insects and the crustaceans, which is consistent with the hypothesized phylogenetic position of the Protura within the Pancrustacea, i.e. at or near the point of divergence of the hexapods from the crustaceans. PMID- 26055222 TI - Identifying phenomenological differences and recovery of cognitive and non cognitive symptomatology among delirium superimposed upon dementia patients (DsD) versus those without dementia (DaD) in an acute geriatric care setting. AB - BACKGROUND: Phenomenological differences between delirium superimposed on dementia (DsD) versus delirium in the absence of dementia (DaD) remain poorly understood. We aimed to identify phenomenological differences in delirium symptoms (cognitive and non-cognitive) and compare delirium recovery trajectories between DsD and DaD. METHODS: We conducted a prospective observational study on individuals admitted to the Geriatric Monitoring Unit (GMU), a five-bed unit specializing in managing older adults with delirium, between December 2010 and August 2012 (n = 234; mean age 84.1 +/- 7.4). We collected data on demographics, comorbidities, severity of illness, cognitive and functional scores, and number of precipitants. Cognitive status was assessed using locally validated Chinese Mini-Mental State Examination (CMMSE) and delirium severity assessed using Delirium Rating Scale-Revised-98 (DRS-R98). Delirium disease trajectory was plotted over five days. RESULTS: DsD patients had a longer duration of delirium with slower recovery in terms of cognition and delirium severity scores compared with DaD patients (0.33 (0.0-1.00) vs. 1.0 (0.36-2.00) increase in CMMSE per day, p < 0.001, and 1.49 +/- 1.62 vs. 2.63 +/- 2.28 decrease in DRS-R98 severity per day, p < 0.001). When cognitive and non-cognitive sub-scores of DRS-R98 were examined separately, we observed steeper recovery in both sub-scores in DaD patients. These findings remained significant after adjusting for significant baseline differences. CONCLUSIONS: Our findings of slower cognitive symptom recovery in DsD patients suggest cognitive reserve play a role in delirium syndrome development and recovery. This merits further studies to potentially aid in appropriate discharge planning and to identify potential pharmacological and non-pharmacological cognitive interventions for hospitalized older persons with delirium. PMID- 26055221 TI - Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do? AB - Defects in DNA cross-link repair 1C (DCLRE1C), protein kinase DNA activated catalytic polypeptide (PRKDC), ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive severe combined immunodeficiency (SCID). Results of hematopoietic cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with alkylating agents is associated with a greater likelihood of full T- and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using fludarabine and low-dose cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to alkylators, such as single-agent low-dose targeted busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and graft-versus host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population. PMID- 26055223 TI - Carbendazim has the potential to induce oxidative stress, apoptosis, immunotoxicity and endocrine disruption during zebrafish larvae development. AB - Increasing evidence have suggested deleterious effects of carbendazim on reproduction, apoptosis, immunotoxicity and endocrine disruption in mice and rats, however, the developmental toxicity of carbendazim to aquatic organisms remains obscure. In the present study, we utilized zebrafish as an environmental monitoring model to characterize the effects of carbendazim on expression of genes related to oxidative stress, apoptosis, immunotoxicity and endocrine disruption during larval development. Different trends in gene expression were observed upon exposing the larvae to 4, 20, 100, and 500 MUg/L carbendazim for 4 and 8d. The mRNA levels of catalase, glutathione peroxidase and manganese superoxide dismutase (CAT, GPX, and Mn/SOD) were up-regulated after exposure to different concentrations of carbendazim for 4 or 8d. The up-regulation of p53, Apaf1, Cas8 and the down-regulation of Bcl2, Mdm2, Cas3 in the apoptosis pathway, as well as the increased expression of cytokines and chemokines, including CXCL C1C, CCL1, IL-1b, IFN, IL-8, and TNFalpha, suggested carbendazim might trigger apoptosis and immune response during zebrafish larval development. In addition, the alteration of mRNA expression of VTG, ERalpha, ERbeta1, ERbeta2, TRalpha, TRbeta, Dio1, and Dio2 indicated the potential of carbendazim to induce endocrine disruption in zebrafish larvae. These data suggested that carbendazim could simultaneously induce multiple responses during zebrafish larval development, and bidirectional interactions among oxidative stress, apoptosis pathway, immune and endocrine systems might be present. PMID- 26055225 TI - Erratum to: A Randomized Clinical Trial of Alcohol Care Management Delivered in Department of Veterans Affairs Primary Care Clinics Versus Specialty Addiction Treatment. PMID- 26055224 TI - Overdose Education and Naloxone for Patients Prescribed Opioids in Primary Care: A Qualitative Study of Primary Care Staff. AB - BACKGROUND: The rate of fatal unintentional pharmaceutical opioid poisonings has increased substantially since the late 1990s. Naloxone is an effective opioid antidote that can be prescribed to patients for bystander use in the event of an overdose. Primary care clinics represent settings in which large populations of patients prescribed opioids could be reached for overdose education and naloxone prescription. OBJECTIVE: Our aim was to investigate the knowledge, attitudes and beliefs about overdose education and naloxone prescription among clinical staff in primary care. DESIGN: This was a qualitative study using focus groups to elucidate both clinic-level and provider-level barriers and facilitators. SETTING: Ten primary care internal medicine, family medicine and infectious disease/HIV practices in three large Colorado health systems. METHODS: A focus group guide was developed based on behavioral theory. Focus group transcripts were coded for manifest and latent meaning, and analyzed for themes using a recursive approach that included inductive and deductive analysis. RESULTS: Themes emerged in four content areas related to overdose education and naloxone prescription: knowledge, barriers, benefits and facilitators. Clinical staff (N = 56) demonstrated substantial knowledge gaps about naloxone and its use in outpatient settings. They expressed uncertainty about who to prescribe naloxone to, and identified a range of logistical barriers to its use in practice. Staff also described fears about offending patients and concerns about increased risk behaviors in patients prescribed naloxone. When considering naloxone, some providers reflected critically and with discomfort on their own opioid prescribing. These barriers were balanced by beliefs that prescribing naloxone could prevent death and result in safer opioid use behaviors. LIMITATIONS: Findings from these qualitative focus groups may not be generalizable to other settings. CONCLUSION: In addition to evidence gaps, logistical and attitudinal barriers will need to be addressed to enhance uptake of overdose education and naloxone prescription for patients prescribed opioids for pain. PMID- 26055226 TI - Feasibility of custom-made hydrogel contact lenses in keratoconus with previous implantation of intracorneal ring segments. AB - PURPOSE: To analyze the feasibility of a custom-made hydrogel silicone contact lens (CL) in keratoconus with intracorneal ring segments (ICRS) and to compare outcomes taking in consideration the geometry of the fitted lens-full periphery (FP) vs. sector management control (SMC). METHOD: A retrospective review of cases with previous KeraRings ICRS implantation and subsequently fitted with Kerasoft IC CL was performed. The main outcome measurements were corrected spectacle distance visual acuity (CDVA), differences between flat and steep simulated keratometries (K-diff) and between steep and flat P values (CPV-diff), CL visual acuity (CLVA), wearing time (WT) and complications associated with wear. RESULTS: Thirty eyes of 22 patients and a follow-up time of 10.3+/-2.3 months were reviewed. Statistically significant improvement was observed between LogMAR CDVA and CLVA (0.25+/-0.19 vs. 0.04+/-0.05; P<0.0001). WT was 11.2h+/-1.2. Two eyes with mild corneal staining and another two with mild injection were noted. Twenty SMC designs were recorded and associated with lower levels of CDVA (0.36+/-0.22 vs. 0.18+/-0.10; P=0.006), CLVA (0.06+/-0.05 vs. 0.01+/-0.03; P=0.03), and larger amounts of CPV-diff (2.31+/-1.86 vs. 1.03+/-1.11; P=0.02) than those eyes fitted with FP designs. No statistical differences were found in the amount of K-diff and WT between both sub-groups. CONCLUSIONS: Fitting custom-made hydrogel silicone CL in keratoconus with ICRS is a feasible treatment with low rate of complications and adequate visual acuity and WT. PMID- 26055227 TI - Paliperidone Protects SH-SY5Y Cells Against MK-801-Induced Neuronal Damage Through Inhibition of Ca(2+) Influx and Regulation of SIRT1/miR-134 Signal Pathway. AB - Schizophrenia is a serious psychotic disease. Recently, increasing evidences support that neurodegeneration occurs in the brain of schizophrenia patients with progressive morphological changes. Paliperidone, an atypical antipsychotic drug, could attenuate psychotic symptom and protect neurons from different stressors. However, the underlying mechanisms are largely unknown. In this study, we used SH SY5Y cells to evaluate the neuroprotective capability of paliperidone against the neurotoxicity induced by N-methyl-D-aspartate receptor antagonist, MK-801. And, we also explored the possible molecular mechanism. Neurotoxicity of 100 MUM MK 801, which reduced the cell viability, was diminished by 100 MUM paliperidone using MTT and LDH assays (both p < 0.05). Analysis with Hoechst 33342/PI double staining demonstrated that exposure to MK-801 (100 MUM) for 24 h led to the death of 30 % of cultured cells (p < 0.05). Moreover, the patch clamp technique was employed to detect voltage calcium channel changes; the results showed that paliperidone effectively blocked the Ca(2+) influx through inhibiting the voltage gated calcium channels (p < 0.05). Furthermore, paliperidone significantly reversed MK-801 induced increase of SIRT1 and decrease of miR-134 expression (both p < 0.05). Finally, SIRT1 inhibitor nicotinamide blocked MK-801 injury effects and suppressed miR-134 expression. Taken together, our results demonstrated that paliperidone could protect SH-SY5Y cells against MK-801 induced neurotoxicity via inhibition of Ca(2+) influx and regulation of SIRT1/miR-134 pathway, providing a promising and potential therapeutic target for schizophrenia. PMID- 26055228 TI - Increased Plasma Levels of Xanthurenic and Kynurenic Acids in Type 2 Diabetes. AB - About 350 million people worldwide have type 2 diabetes (T2D). The major risk factor of T2D is impaired glucose tolerance (pre-diabetes) with 10 % of pre diabetes subjects develop T2D every year. Understanding of mechanisms of development of T2D from pre-diabetes is important for prevention and treatment of T2D. Chronic stress and chronic low-grade inflammation are prominent risk factors for T2D development in pre-diabetic subjects. However, molecular mechanisms mediating effect of stress and inflammation on development of T2D from pre diabetes remain unknown. One of such mechanisms might involve kynurenine (KYN) pathway (KP) of tryptophan (TRP) metabolism. We suggested that chronic stress- or chronic low-grade inflammation-induced upregulation of formation of upstream KTP metabolites, KYN and 3-hydroxyKYN, combined with chronic stress- or chronic low grade inflammation-induced deficiency of pyridoxal 5'-phosphate, a co-factor of downstream enzymes of KTP, triggers overproduction of diabetogenic downstream KYN metabolites, kynurenic acid (KYNA) and 3-hydroxyKYNA (also known as xanthurenic acid (XA)). As the initial assessment of our working hypothesis, we evaluated plasma levels of up- and downstream KP metabolites in the same samples of T2D patients. KYN, XA, and KYNA levels in plasma samples of T2D patients were higher than in samples of non-diabetic subjects. Our results provide further support of "kynurenine hypothesis of insulin resistance and its progression to T2D" that suggested that overproduction of diabetogenic KP metabolites, induced by chronic stress or chronic low-grade inflammation, is one of the mechanisms promoting development of T2D from pre-diabetes. Downstream metabolites of KP might serve as biomarkers of T2D and targets for clinical intervention. PMID- 26055229 TI - Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model. AB - Dodecafluoropentane emulsion (DDFPe) nanodroplets are exceptional oxygen transporters and can protect ischemic brain in stroke models 24 h without reperfusion. Current stroke therapy usually fails to reach patients because of delays following stroke onset. We tested using DDFPe to extend the time window for tissue plasminogen activator (tPA). Longer treatment windows will allow more patients more complete stroke recovery. We test DDFPe to safely extend the time window for tPA thrombolysis to 9 h after stroke. With IACUC approval, randomized New Zealand white rabbits (3.4-4.7 kg, n = 30) received angiography and 4-mm blood clot in the internal carotid artery for flow-directed middle cerebral artery occlusion. Seven failed and were discarded. Groups were IV tPA (n = 11), DDFPe + tPA (n = 7), and no therapy controls (n = 5). DDFPe (0.3 ml/kg, 2 % emulsion) IV dosing began at 1 h and continued at 90 min intervals for 6 doses in one test group; the other received saline injections. Both got standard IV tPA (0.9 mg/kg) therapy starting 9 h post stroke. At 24 h, neurological assessment scores (NAS, 0-18) were determined. Following brain removal percent stroke volume (%SV) was measured. Outcomes were compared with Kruskal-Wallis analysis. For NAS, DDFPe + tPA was improved overall, p = 0.0015, and vs. tPA alone, p = 0.0052. For %SV, DDFPe + tPA was improved overall, p = 0.0003 and vs. tPA alone, p = 0.0018. NAS controls and tPA alone were not different but %SV was, p = 0.0078. With delayed reperfusion, DDFPe + tPA was more effective than tPA alone in preserving functioning brain after stroke. DDFPe significantly extends the time window for tPA therapy. PMID- 26055230 TI - Ketamine-Induced Toxicity in Neurons Differentiated from Neural Stem Cells. AB - Ketamine is used as a general anesthetic, and recent data suggest that anesthetics can cause neuronal damage when exposure occurs during development. The precise mechanisms are not completely understood. To evaluate the degree of ketamine-induced neuronal toxicity, neural stem cells were isolated from gestational day 16 rat fetuses. On the eighth day in culture, proliferating neural stem cells were exposed for 24 h to ketamine at 1, 10, 100, and 500 MUM. To determine the effect of ketamine on differentiated stem cells, separate cultures of neural stem cells were maintained in transition medium (DIV 6) for 1 day and kept in differentiation medium for another 3 days. Differentiated neural cells were exposed for 24 h to 10 MUM ketamine. Markers of cellular proliferation and differentiation, mitochondrial health, cell death/damage, and oxidative damage were monitored to determine: (1) the effects of ketamine on neural stem cell proliferation and neural stem cell differentiation; (2) the nature and degree of ketamine-induced toxicity in proliferating neural stem cells and differentiated neural cells; and (3) to provide information regarding receptor expression and possible mechanisms underlying ketamine toxicity. After ketamine exposure at a clinically relevant concentration (10 MUM), neural stem cell proliferation was not significantly affected and oxidative DNA damage was not induced. No significant effect on mitochondrial viability (3-(4,5 dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay) in neural stem cell cultures (growth medium) was observed at ketamine concentrations up to 500 MUM. However, quantitative analysis shows that the number of differentiated neurons was substantially reduced in 10 MUM ketamine-exposed cultures in differentiation medium, compared with the controls. No significant changes in the number of GFAP-positive astrocytes and O4-positive oligodendrocytes (in differentiation medium) were detected from ketamine-exposed cultures. The discussion focuses on: (1) the doses and time-course over which ketamine is associated with damage of neural cells; (2) how ketamine directs or signals neural stem cells/neural cells to undergo apoptosis or necrosis; (3) how functional neuronal transmitter receptors affect neurotoxicity induced by ketamine; and (4) advantages of using neural stem cell models to study critical issues related to ketamine anesthesia. PMID- 26055232 TI - Scouts, forests, and ticks: Impact of landscapes on human-tick contacts. AB - Just as with forest workers or people practicing outdoor recreational activities, scouts are at high risk for tick bites and tick-borne infections. The risk of a tick bite is shaped not only by environmental and climatic factors but also by land management. The aim of this study was to assess which environmental conditions favour scout-tick contacts, and thus to better understand how these factors and their interactions influence the two components of risk: hazard (related to vector and host ecology) and exposure of humans to disease vectors. A survey was conducted in the summer of 2009 on the incidence of tick bites in scout camps taking place in southern Belgium. Joint effects of landscape composition and configuration, weather, climate, forest and wildlife management were examined using a multiple gamma regression with a log link. The landscape was characterized by buffers of varying sizes around the camps using a detailed land use map, and accounting for climate and weather variables. Landscape composition and configuration had a significant influence on scout-tick contacts: the risk was high when the camp was surrounded by a low proportion of arable land and situated in a complex and fragmented landscape. The distance to the nearest forest patch, the composition of the forest ecotone as well as weather and climatic factors were all significantly associated with scout-tick contacts. Both hazard- and exposure-related variables significantly contributed to the frequency of scout-tick contact. Our results show that environmental conditions favour scout-tick contacts. For example, we emphasize the impact of accessibility of environments suitable for ticks on the risk of contact. We also highlight the significant effect of both hazard and exposure. Our results are consistent with current knowledge, but further investigations on the effect of forest management, e.g. through its impact on forest structure, on the tick-host-pathogen system, and on humans exposure, is required. PMID- 26055231 TI - N-Palmitoylethanolamine and Neuroinflammation: a Novel Therapeutic Strategy of Resolution. AB - Inflammation is fundamentally a protective cellular response aimed at removing injurious stimuli and initiating the healing process. However, when prolonged, it can override the bounds of physiological control and becomes destructive. Inflammation is a key element in the pathobiology of chronic pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders. Glia, key players in such nervous system disorders, are not only capable of expressing a pro-inflammatory phenotype but respond also to inflammatory signals released from cells of immune origin such as mast cells. Chronic inflammatory processes may be counteracted by a program of resolution that includes the production of lipid mediators endowed with the capacity to switch off inflammation. These naturally occurring lipid signaling molecules include the N-acylethanolamines, N-arachidonoylethanolamine (an endocannabinoid), and its congener N-palmitoylethanolamine (palmitoylethanolamide or PEA). PEA may play a role in maintaining cellular homeostasis when faced with external stressors provoking, for example, inflammation. PEA is efficacious in mast cell mediated models of neurogenic inflammation and neuropathic pain and is neuroprotective in models of stroke, spinal cord injury, traumatic brain injury, and Parkinson disease. PEA in micronized/ultramicronized form shows superior oral efficacy in inflammatory pain models when compared to naive PEA. Intriguingly, while PEA has no antioxidant effects per se, its co-ultramicronization with the flavonoid luteolin is more efficacious than either molecule alone. Inhibiting or modulating the enzymatic breakdown of PEA represents a complementary therapeutic approach to treat neuroinflammation. This review is intended to discuss the role of mast cells and glia in neuroinflammation and strategies to modulate their activation based on leveraging natural mechanisms with the capacity for self defense against inflammation. PMID- 26055233 TI - Tularaemia in southwest Germany: Three cases of tick-borne transmission. AB - Tularaemia, caused by Francisella tularensis, is an endemic zoonosis frequently occurring in southwest Germany. Since 2005 there is an increase in the number of reported cases of tularaemia in Germany. We report on two cases of ulceroglandular tularaemia and one case of glandular tularaemia that occurred in the summer of 2012 and 2013 in two counties in the Federal State of Baden Wuerttemberg. Bacteria were transmitted through tick bites, which to date has only rarely been reported in Germany. Inadequate treatment of the patients and an aggravation of clinical symptoms were caused by a delay between disease onset and the detection of the pathogen. Although contact to or consumption of infected hares are the most often reported transmission routes of tularaemia in Germany, tick-bites should also be taken into account. Health professionals should include Francisella tularensis in the differential diagnosis of patients with fever and/or ulcerative lymphadenopathy following a tick bite. PMID- 26055234 TI - Antibiotic treatment of the hard tick Ixodes ricinus: Influence on Midichloria mitochondrii load following blood meal. AB - Midichloria mitochondrii is the most prevalent symbiont of the hard tick Ixodes ricinus, present in 100% of eggs and adult females of wild ticks. This bacterium is intracellular, and is the only known symbiont able to invade the mitochondria of the host cells. However, the role that M. mitochondrii plays in the host metabolism has yet to be elucidated. Multiple lines of evidence indicate the possibility of transmission of this bacterium to the vertebrate host during the tick blood meal. In order to investigate the role of M. mitochondrii in the biology of the tick host, we performed an antibiotic treatment on Ixodes ricinus individuals, with the aim of reducing/eliminating the symbiont, and to potentially observe the dynamic of bacterial infection in the tick host. We microinjected engorged adult females of I. ricinus with tetracycline, and we allowed the resulting larvae to feed on gerbils treated with the same antibiotic. The amount of M. mitochondrii was evaluated at different stages of the experiment using molecular techniques. In addition we evaluated the presence/absence of the symbiont DNA in the blood of gerbils used for the larval feeding. The performed treatments did not allow to eliminate the symbiont population from the host tick, however it allowed to reduce the multiplication that occurs after the larval blood meal. These results open the way for future experiments, using different antibiotic molecules, different administration methods and antibiotic administration on subsequent tick stages, to fulfill the goal of eliminating M. mitochondrii from the host I. ricinus, a major step in our understanding of the impact of this bacterium on ticks. PMID- 26055236 TI - Further analysis of the emotional consequences of head and neck cancer as reflected by the Patients' Concerns Inventory. AB - Patients with cancer of the head and neck can experience high levels of distress. The emotional burden of the disease must be recognised and important negative emotions assessed so that appropriate interventions can be provided. We obtained data from 1482 head and neck cancer Patients' Concerns Inventories (HNC-PCI) completed by 813 patients between 1 August 2007 and 9 January 2013, and particularly concentrated on the psychological, emotional, and spiritual well being domain, which comprises 14 items. We also assessed health-related quality of life (HRQoL) using the University of Washington quality of life questionnaire version 4 (UWQoL). A total of 538 patients were male and the mean age of all patients on first completing the PCI was 64 years (range 20-94). Primary tumours were oral (n=392, 48%), oropharyngeal (n=196, 24%), laryngeal (n=142, 17%), other (n=74, 9%), or unknown (n=9, 1%). Fifty-one percent of patients (n=753) chose no items in the emotions category, 16% (n=236) identified fear of recurrence only, 16% (n=236) selected items other than fear of recurrence, and 17% (n=257) selected fear of recurrence and others. Patients who identified fear of recurrence with other issues had significantly worse scores for anxiety, mood, and overall quality of life (QoL). Fear of recurrence is common but patients with multiple emotional concerns need additional support, and further research is required to specify the practical details of the interventions needed at various points during and after treatment. PMID- 26055235 TI - ENaC activity in collecting ducts modulates NCC in cirrhotic mice. AB - Cirrhosis is a frequent and severe disease, complicated by renal sodium retention leading to ascites and oedema. A better understanding of the complex mechanisms responsible for renal sodium handling could improve clinical management of sodium retention. Our aim was to determine the importance of the amiloride-sensitive epithelial sodium channel (ENaC) in collecting ducts in compensate and decompensate cirrhosis. Bile duct ligation was performed in control mice (CTL) and collecting duct-specific alphaENaC knockout (KO) mice, and ascites development, aldosterone plasma concentration, urinary sodium/potassium ratio and sodium transporter expression were compared. Disruption of ENaC in collecting ducts (CDs) did not alter ascites development, urinary sodium/potassium ratio, plasma aldosterone concentrations or Na,K-ATPase abundance in CCDs. Total alphaENaC abundance in whole kidney increased in cirrhotic mice of both genotypes and cleaved forms of alpha and gamma ENaC increased only in ascitic mice of both genotypes. The sodium chloride cotransporter (NCC) abundance was lower in non ascitic KO, compared to non-ascitic CTL, and increased when ascites appeared. In ascitic mice, the lack of alphaENaC in CDs induced an upregulation of total ENaC and NCC and correlated with the cleavage of ENaC subunits. This revealed compensatory mechanisms which could also take place when treating the patients with diuretics. These compensatory mechanisms should be considered for future development of therapeutic strategies. PMID- 26055237 TI - Tracheostomy in head and neck oncology. Results of the 2014 Tracheostomy Survey of the BAOMS Oncology Specialist Interest Group. PMID- 26055238 TI - Down-Regulated NRSN2 Promotes Cell Proliferation and Survival Through PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma. AB - BACKGROUND AND AIMS: Neurensin-2 (NRSN2) is a neuronal membrane protein; previous reports indicated that it might function as a tumor suppressor in hepatocellular carcinoma (HCC). However, its biological functions and associated mechanisms remain unknown. In the current study, we aimed to investigate the biological functions and possible mechanisms of neurensin-2. METHODS: The mRNA and protein level of NRSN2 in HCC has tissues and cell lines were detected by quantitative real-time PCR, immunohistochemistry staning and western blot. Overexpressing and silencing the level of NRSN2 in HCC cell lines were used to investigate the role of NRSN2 in HCC. CCK-8 assays, SA-beta gel staining, Annexin V/PI staining, quantitative real-time PCR and western blot were employed to explore the role and mechanisms of HCC. RESULTS: NRSN2 was more commonly down-regulated HCC tissues compared with adjacent tissues, and the expression pattern of NRSN2 was not only closely correlated with tumor size and TNM stage but also negatively correlated with patient prognosis. Both loss and gain function assays revealed that NRSN2 inhibits cancer cell proliferation and promotes cancer cell senescence and apoptosis. We further found that NRSN2 might regulate PI3K/AKT signaling and p53/p21 pathway to exert its role in HCC cell proliferation, senescence and apoptosis. CONCLUSION: Our study validates the suppressive role of NRSN2 in both clinicopathologic and biological aspects in HCC tumorigenesis. PMID- 26055239 TI - Microgravity Simulated by the 6 degrees Head-Down Tilt Bed Rest Test Increases Intestinal Motility but Fails to Induce Gastrointestinal Symptoms of Space Motion Sickness. AB - BACKGROUND: Space motion sickness (SMS) is the most relevant medical problem during the first days in microgravity. Studies addressing pathophysiology in space face severe technical challenges and microgravity is frequently simulated using the 6 degrees head-down tilt bed rest test (HDT). AIM: We were aiming to test whether SMS could be simulated by HDT, identify related changes in gastrointestinal physiology and test for beneficial effects of exercise interventions. METHODS: HDT was performed in ten healthy individuals. Each individual was tested in three study campaigns varying by a 30-min daily exercise intervention of either standing, an upright exercise regimen, or no intervention. Gastrointestinal symptoms, stool characteristics, gastric emptying time, and small intestinal transit were assessed using standardized questionnaires, (13)C octanoate breath test, and H2 lactulose breath test, respectively, before and at day 2 and 5 of HDT. RESULTS: Individuals described no or minimal gastrointestinal symptoms during HDT. Gastric emptying remained unchanged relative to baseline data collection (BDC). At day 2 of HDT the H2 peak of the lactulose test appeared earlier (mean +/- standard error for BDC-1, HDT2, HDT5: 198 +/- 7, 139 +/- 18, 183 +/- 10 min; p: 0.040), indicating accelerated small intestinal transit. Furthermore, during HDT, stool was softer and stool mass increased (BDC: 47 +/- 6, HDT: 91 +/- 12, recovery: 53 +/- 8 g/day; p: 0.014), indicating accelerated colonic transit. Exercise interventions had no effect. CONCLUSION: HDT did not induce symptoms of SMS. During HDT, gastric emptying remained unchanged, but small and large intestinal transit was accelerated. PMID- 26055240 TI - Women would like their partners to be more synchronized with them in their sleep wake rhythm. AB - Men sleep shorter and go to bed and get up later than women, thus they are later chronotypes. This difference between the sexes is most pronounced between puberty and menopause indicating the possibility that morningness is subject to sexual dimorphism related to reproductive aspects. The objective of the study was to compare the sleep-wake behavior of women with their actual partners and with their preferred partners. As a hypothesis, we expect some assortment in mating concerning chronotype (with the actual partner), but we also expect a higher synchronization with a preferred ideal partner. 167 women were analyzed in this study (mean age: 23.0 +/- 2.57 (SD) years). Mated women were earlier chronotypes than their partners (t = -2.051, p = .042, d = .34) but the difference was small (11:02 min +/- 1:04 min). The results of the present study showed women preferring a partner synchronized to their own sleep-wake-rhythm more than their actual partners were. The above result was true either for single facets of the sleep-wake rhythm (e.g. bed time, sleep onset) or for midpoint of sleep on free days - an indicator of actual chronotype: women's and their partners' correlation of midpoint of sleep was lower (r = .513) than women's and their ideal partners' correlation (r = .855). Amongst various sleep-wake measures, women particularly preferred a partner going to bed at the same time. Assortative mating according to sleep-wake rhythm exists, but women for long-term pair-bonds would like their partners far more synchronized. PMID- 26055241 TI - Migraine and tension type headache in adolescents at grammar school in Germany - burden of disease and health care utilization. AB - BACKGROUND: Tension-type headache and migraine are among the most prevalent chronic disorders in children/adolescents. Data on health care utilization for headache in this age group, however, are sparse. METHODS: In 1399 grammar school students (aged 12-19 years) with headache in the last six months in Germany a) the burden of disease for headache (mean intensity, mean frequency in the last three months and PedMIDAS means), b) medical care utilization defined by proportion of students consulting a physician in the last 12 months and/or taking analgetic drugs in the last three months by headache types (migraine and tension type headache) and by burden of disease were assessed. RESULTS: Primary headache substantially impaired daily living activities in adolescents which was mainly related to migraine. Medical care utilization and drug use, however, was low (consulting a physician: 12.0 %, 95 %-CI = [10.3-13.8]; taking analgetic drugs: 29.9 %, 95 %-CI = [27.5-32.4]) - even among students with severe headache (physician consultation: <35 %; taking analgetic drugs: <63 %). Two thirds of students with any headache and 40 % of those with migraine had neither seen a physician nor used analgetic drugs because of their headache in the preceding 12 months. CONCLUSIONS: Adolescents with headache might too rarely seek professional help for treatment of headache. Health promotion in adolescents should increase awareness for evidence-based treatment options for headache. PMID- 26055242 TI - Single-pulse transcranial magnetic stimulation (sTMS) for the acute treatment of migraine: evaluation of outcome data for the UK post market pilot program. AB - BACKGROUND: Single pulse transcranial magnetic stimulation (sTMS) is a novel treatment for acute migraine. Previous randomised controlled data demonstrated that sTMS is effective and well tolerated in the treatment of migraine with aura. The aim of the programme reported here was to evaluate patient responses in the setting of routine clinical practice. METHODS: Migraine patients with and without aura treating with sTMS had an initial review (n = 426) and training call, and then participated in telephone surveys at week six (n = 331) and week 12 during a 3-month treatment period (n = 190). RESULTS: Of patients surveyed with 3 month data (n = 190; episodic, n = 59; chronic, n = 131), 62 % reported pain relief, finding the device effective at reducing or alleviating migraine pain; in addition there was relief reported of associated features: nausea- 52 %; photophobia- 55 %; and phonophobia- 53 %. At 3 months there was a reduction in monthly headache days for episodic migraine, from 12 (median, 8-13 IQ range) to 9 (4-12) and for chronic migraine, a reduction from 24 (median, 16-30 IQ range) to 16 (10-30). There were no serious or unanticipated adverse events. CONCLUSION: sTMS may be a valuable addition to options for the treatment of both episodic and chronic migraine. PMID- 26055250 TI - Like-charge ion pairs of hydronium and hydroxide in aqueous solution? AB - The like-charge ion pairings of hydronium and hydroxide were investigated using both ab initio cluster calculations and QM/MM-MD aqueous simulations. While only a two-water-bridged H3O(+)(H2O)2H3O(+) is found in hydronium cluster calculations, three clusters of HO(-)(H2O)2HO(-), HO(-)(H2O)3HO(-) and HO( )(H2O)4HO(-) are stable dihydroxide aggregates. In addition, an interesting yet very stable parallelogram structure of [O-H...H-O](2-) without any bridging water was also discovered using QM/MM-MD simulations. According to our analysis, its unique structure reduces the electrostatic repulsion and allows stable coordination with solvents at the same time. In conclusion, hydroxide can form stronger like-ion pairs than hydronium in aqueous solution mostly due to its versatile coordination ability with solvents. PMID- 26055251 TI - The effect of the emotive decisions in prospect theory. AB - The main purpose of this paper was to show that the certainty and reflection effects of prospect theory do not occur when stimuli have an affective value. To this end, 160 participants were asked to reply to a series of problems originally designed by Kahneman and Tversky (1979), but modified according to the contributions of Rottenstreich and Hsee (2001). The sample was divided into four experimental conditions, two in a gain situation and two in a loss situation. In both cases, affect-rich and affect-poor stimuli were applied in sure and probable alternatives. The findings showed that, in agreement with our hypotheses, the affective value of the stimuli altered the outcome predicted by prospect theory, showing response patterns contrary to certainty and reflection effects (p <= .01 and p <= .05 respectively). Therefore, this research supports the influence of the emotions in the decision-making process, and should be extended to other aspects of prospect theory. PMID- 26055247 TI - Novel players in coeliac disease pathogenesis: role of the gut microbiota. AB - Several studies point towards alteration in gut microbiota composition and function in coeliac disease, some of which can precede the onset of disease and/or persist when patients are on a gluten-free diet. Evidence also exists that the gut microbiota might promote or reduce coeliac-disease-associated immunopathology. However, additional studies are required in humans and in mice (using gnotobiotic technology) to determine cause-effect relationships and to identify agents for modulating the gut microbiota as a therapeutic or preventative approach for coeliac disease. In this Review, we summarize the current evidence for altered gut microbiota composition in coeliac disease and discuss how the interplay between host genetics, environmental factors and the intestinal microbiota might contribute to its pathogenesis. Moreover, we highlight the importance of utilizing animal models and long-term clinical studies to gain insight into the mechanisms through which host-microbial interactions can influence host responses to gluten. PMID- 26055252 TI - The gait and energy efficiency of stance control knee-ankle-foot orthoses: A literature review. AB - BACKGROUND: The use of knee-ankle-foot orthoses with drop locked knee joints produces some limitations for walking in subjects with quadriceps muscle weakness. The development of stance control orthoses can potentially improve their functionality. OBJECTIVES: The aim of this review was to compare the evidence of the effect of stance control orthoses to knee-ankle-foot orthoses with drop locked knee joints in improving kinematic variables and energy efficiency of walking by subjects with quadriceps muscle weakness caused by different pathologies. STUDY DESIGN: Literature review. METHODS: Based on selected keywords and their composition, a search was performed in Google Scholar, PubMed, ScienceDirect, and ISI Web of Knowledge databases. In total, 18 articles were finally chosen for review. RESULTS: The results of this study demonstrated that this type of orthosis can improve the walking parameters of subjects with quadriceps muscle weakness and spinal cord injury patients when compared to a locked knee-ankle-foot orthosis. CONCLUSION: There is evidence to show that stance control orthosis designs improve the gait kinematics but not energetic of knee-ankle-foot orthosis users. Development of new designs of stance control orthoses to provide a more normal pattern of walking is still required. CLINICAL RELEVANCE: Stance control orthoses are a new generation of orthotic intervention that could potentially be significant in assisting to improve the gait kinematics by knee-ankle-foot orthosis users. PMID- 26055245 TI - Inflammasome activation and function in liver disease. AB - Inflammation contributes to the pathogenesis of most acute and chronic liver diseases. Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1beta and IL-18. In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold. IL 1beta, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation. Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced liver injury. The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease. PMID- 26055253 TI - Patient-specific positioning guides for total knee arthroplasty: no significant difference between final component alignment and pre-operative digital plan except for tibial rotation. AB - PURPOSE: To assess whether there is a significant difference between the alignment of the individual femoral and tibial components (in the frontal, sagittal and horizontal planes) as calculated pre-operatively (digital plan) and the actually achieved alignment in vivo obtained with the use of patient-specific positioning guides (PSPGs) for TKA. It was hypothesised that there would be no difference between post-op implant position and pre-op digital plan. METHODS: Twenty-six patients were included in this non-inferiority trial. Software permitted matching of the pre-operative MRI scan (and therefore calculated prosthesis position) to a pre-operative CT scan and then to a post-operative full leg CT scan to determine deviations from pre-op planning in all three anatomical planes. RESULTS: For the femoral component, mean absolute deviations from planning were 1.8 degrees (SD 1.3), 2.5 degrees (SD 1.6) and 1.6 degrees (SD 1.4) in the frontal, sagittal and transverse planes, respectively. For the tibial component, mean absolute deviations from planning were 1.7 degrees (SD 1.2), 1.7 degrees (SD 1.5) and 3.2 degrees (SD 3.6) in the frontal, sagittal and transverse planes, respectively. Absolute mean deviation from planned mechanical axis was 1.9 degrees . The a priori specified null hypothesis for equivalence testing: the difference from planning is >3 or <-3 was rejected for all comparisons except for the tibial transverse plane. CONCLUSION: PSPG was able to adequately reproduce the pre-op plan in all planes, except for the tibial rotation in the transverse plane. Possible explanations for outliers are discussed and highlight the importance for adequate training surgeons before they start using PSPG in their day-by-day practise. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 26055254 TI - Nonoperative treatment and return to play after complete proximal adductor avulsion in high-performance athletes. AB - PURPOSE: To assess the outcome of nonoperative treatment after complete avulsion of the proximal adductor longus tendon in high-performance athletes. METHODS: Six consecutive athletes were included. Treatment was conservative following a strict rehabilitation plan. Following parameters were analysed: basic data, mechanism of injury, classification, tendon retraction, size of defect in MRI and return to play (RTP). RESULTS: Mean age at injury was 28 +/- 5 (range 20-32) years. Overstretch (83 %) and kicking (50 %) were the most frequent injury mechanisms, and the dominant leg was involved in 83 %. Average retraction of the avulsed tendon amounted 21 +/- 5 mm. Follow-up MRIs demonstrated a gradual reattachment of the tendon in all cases. All athletes returned to full sportive activity on preinjury level within 88.7 +/- 12.8 (range 75-110) days with no functional deficiencies. Manual muscle strength was equal to the contralateral side. CONCLUSION: Nonoperative treatment with a healing phase and a strict rehabilitation plan results in a functional, efficient reattachment of the tendon and allows unrestricted RTP. Since these injuries are rare, present study may help sports physicians when dealing with this type of injuries in professional athletes. Return to sports can be expected at approximately 13 weeks after injury, but can take even longer. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 26055255 TI - A genetically amenable platensimycin- and platencin-overproducer as a platform for biosynthetic explorations: a showcase of PtmO4, a long-chain acyl-CoA dehydrogenase. AB - Platensimycin (PTM) and platencin (PTN) are members of a new class of promising drug leads that target bacterial and mammalian fatty acid synthases. We previously cloned and sequenced the PTM and PTN gene clusters, discovered six additional PTM-PTN dual producing strains, and demonstrated the dramatic overproduction of PTM and PTN by inactivating the pathway-specific regulators ptmR1 or ptnR1 in five different strains. Our ability to utilize these PTM-PTN dual overproducing strains was limited by their lack of genetic amenability. Here we report the construction of Streptomyces platensis SB12029, a genetically amenable, in-frame DeltaptmR1 dual PTM-PTN overproducing strain. To highlight the potential of this strain for future PTM and PTN biosynthetic studies, we created the DeltaptmR1 DeltaptmO4 double mutant S. platensis SB12030. Fourteen PTM and PTN congeners, ten of which were new, were isolated from SB12030, shedding new insights into PTM and PTN biosynthesis. PtmO4, a long-chain acyl-CoA dehydrogenase, is strongly implicated to catalyze beta-oxidation of the diterpenoid intermediates into the PTM and PTN scaffolds. SB12029 sets the stage for future biosynthetic and bioengineering studies of the PTM and PTN family of natural products. PMID- 26055256 TI - Regulation of feeding behavior and plasma testosterone in response to central neuropeptide Y administration in a songbird. AB - In mammalian and avian model species, neuropeptide Y (NPY) simultaneously promotes feeding behavior and suppresses the secretion of reproductive hormones, thereby modulating the resource allocation trade-off between investing in essential somatic processes or in the reproductive system. Investigations into this dual role of NPY in birds have focused on domesticated species and, to our knowledge, no study has examined this role in songbirds. We determined whether NPY treatment acutely regulates feeding behavior and activity of the reproductive system in a male songbird, the Abert's Towhee, Melozone aberti. Intracerebroventricular (ICV) administration of NPY promoted behaviors associated with feeding (decreased latency to initiate pecking in the food bowl, increased number of feeding bouts following treatment, and increased number of pecks into the food bowl during each feeding bout), and it stimulated hopping and drinking behavior. By contrast, we found no effect of NPY treatment on plasma testosterone secretion 60 min after treatment. These results suggest that in male Abert's Towhees NPY stimulates feeding behavior, but provide no evidence that this peptide concurrently influences testosterone secretion. PMID- 26055257 TI - Identification of the replication region in pBCNF5603, a bacteriocin-encoding plasmid, in the enterotoxigenic Clostridium perfringens strain F5603. AB - BACKGROUND: Most recent studies of Clostridium perfringens plasmids have focused on toxin-encoding or antibiotic resistance plasmids. To cause intestinal disease, a toxigenic strain must grow in the intestines to levels allowing for sufficient toxin production and this in vivo growth often involves overcoming the normal intestinal microbial population. For this purpose, bacteriocin production might be important. RESULTS: In this study, as the first step in the genetic analysis of a co-existing plasmid with an enterotoxin gene (cpe)-encoding plasmid, the bacteriocin gene-encoding plasmid, pBCNF5603, was completely sequenced. This plasmid has some homology with two previously sequenced C. perfringens plasmids, namely, pCP13 carrying a cpb2 gene and pIP404 carrying a bcn gene. Using recombinant plasmids, the rep gene homologous to the PCP63 gene on pCP13 appeared to be functional. Comparative genomics indicated that the identified rep gene homologs were found on two additional toxin plasmids, pCP-OS1 and pCP-TS1. While functional analysis using recombinant plasmids indicated that pBCNF5603 and pCP13 are likely to be incompatible, the plasmid replication and partitioning region of pBCNF5603 alone was insufficient for stable maintenance of this plasmid. CONCLUSIONS: These findings suggest that pBCNF5603 evolved from recombination events between C. perfringens plasmids and inter-species mobile genetic element(s). In addition, the bcn-encoding plasmid, pBCNF5603, is likely to be included in the Inc family, which includes pCP13 and two variant iota-encoding plasmids. Furthermore, the bcn gene on pBCNF5603 could contribute to gastrointestinal disease induced by enterotoxigenic C. perfringens. PMID- 26055258 TI - Are all health gains equally important? An exploration of acceptable health as a reference point in health care priority setting. AB - BACKGROUND: Accumulating evidence suggests that members of society prefer some QALY gains over others. In this paper, we explore the notion of acceptable health as a reference point in assessing the value of health gains. The value of health benefits may be assessed in terms of their position relative to this reference level, benefits above the level of acceptable health being valued differently from benefits below this level. In this paper we focus on assessing the level of acceptable health at different ages and associations with background variables. METHODS: We recruited a sample of the adult population from the Netherlands (n = 1067) to investigate which level of health problems they consider to be acceptable for people aged 40 to 90, using 10-year intervals. We constructed acceptable health curves and associated acceptable health with background characteristics using linear regressions. RESULTS: The results of this study indicate that the level of health problems considered acceptable increases with age. This level was associated with respondents' age, age of death of next of kin, health and health behaviour. CONCLUSIONS: Our results suggest that people are capable of indicating acceptable levels of health at different ages, implying that a reference point of acceptable health may exist. While more investigation into the measurement of acceptable health remains necessary, future studies may also focus on how health gains may be valued relative to this reference level. Gains below the reference point may receive higher weight than those above this level since the former improve unacceptable health states while the latter improve acceptable health states. PMID- 26055259 TI - Clinical Outcomes and Complications of Percutaneous Achilles Repair System Versus Open Technique for Acute Achilles Tendon Ruptures. AB - BACKGROUND: Limited incision techniques for acute Achilles tendon ruptures have been developed in recent years to improve recovery and reduce postoperative complications compared with traditional open repair. The purpose of this retrospective cohort study was to analyze the clinical outcomes and postoperative complications between acute Achilles tendon ruptures treated using a percutaneous Achilles repair system (PARS [Arthrex, Inc, Naples, FL]) versus open repair and evaluate the overall outcomes for operatively treated Achilles ruptures. METHODS: Between 2005 and 2014, 270 consecutive cases of operatively treated acute Achilles tendon ruptures were reviewed (101 PARS, 169 open). Patients with Achilles tendinopathy, insertional ruptures, chronic tears, or less than 3-month follow-up were excluded. Operative treatment consisted of a percutaneous technique (PARS) using a 2-cm transverse incision with FiberWire (Arthrex, Inc, Naples, FL) sutures or open repair using a 5- to 8-cm posteromedial incision with FiberWire in a Krackow fashion reinforced with absorbable sutures. Patient demographics were recorded along with medical comorbidities, activity at injury, time from injury to surgery, length of follow-up, return to baseline activities by 5 months, and postoperative complications. RESULTS: The most common activity during injury for both groups was basketball (PARS: 39%, open: 47%). A greater number of patients treated with PARS were able to return to baseline physical activities by 5 months compared with the open group (PARS: 98%, open: 82%; P = .0001). There were no significant differences (P > .05) between groups in rates of rerupture (P = 1.0), sural neuritis (P = .16), wound dehiscence (P = .74), superficial (P = .29) and/or deep infection (P = .29), or reoperation (P = .13). There were no deep vein thromboses (DVTs) or reruptures in either group. In the PARS group, there were no cases of sural neuritis, 3 cases (3%) of superficial wound dehiscence, and 2 reoperations (2%) for superficial foreign-body reaction to FiberWire. In the open group, there were 5 cases (3%) of sural neuritis, 7 cases (4%) of superficial wound dehiscence, 3 cases (2%) of superficial infection, and 3 reoperations (2%) for deep infection. CONCLUSION: The present study reports the largest single-center series of acute Achilles tendon ruptures in the literature with lower complication rates for operatively treated Achilles ruptures compared with previous reports. The overall complication rate for all operatively treated Achilles ruptures was 8.5% with no reruptures, and most patients (88%) were able to return to baseline activities by 5 months after surgery. There were no significant differences in rates of postoperative complications between PARS and open repair for acute Achilles tendon ruptures. LEVEL OF EVIDENCE: Level III, retrospective cohort study. PMID- 26055260 TI - The effects of grip width on sticking region in bench press. AB - The aim of this study was to examine the occurrence of the sticking region by examining how three different grip widths affect the sticking region in powerlifters' bench press performance. It was hypothesised that the sticking region would occur at the same joint angle of the elbow and shoulder independent of grip width, indicating a poor mechanical region for vertical force production at these joint angles. Twelve male experienced powerlifters (age 27.7 +/- 8.8 years, mass 91.9 +/- 15.4 kg) were tested in one repetition maximum (1-RM) bench press with a narrow, medium and wide grip. Joint kinematics, timing, bar position and velocity were measured with a 3D motion capture system. All participants showed a clear sticking region with all three grip widths, but this sticking region was not found to occur at the same joint angles in all three grip widths, thereby rejecting the hypothesis that the sticking region would occur at the same joint angle of the elbow and shoulder independent of grip width. It is suggested that, due to the differences in moment arm of the barbell about the elbow joint in the sticking region, there still might be a poor mechanical region for total force production that is joint angle-specific. PMID- 26055261 TI - Pharmacological evidence for the folk use of Nefang: antipyretic, anti inflammatory and antinociceptive activities of its constituent plants. AB - BACKGROUND: Nefang is a polyherbal anti-malarial composed of Mangifera indica ( MiB and MiL; bark and leaf), Psidium guajava ( Pg ), Carica papaya ( Cp ), Cymbopogon citratus ( Cc ), Citrus sinensis ( Cs ) and Ocimum gratissimum ( Og ) (leaves). Previous studies have demonstrated its in vitro and in vivo antiplasmodial activities, antioxidant properties and safety profile. This study aimed at evaluating the antipyretic, anti-inflammatory and antinociceptive activities of the constituent plants of Nefang which are relevant to the symptomatic treatment of malaria fever. METHODS: Antipyretic activities were determined by the D-Amphetamine induced pyrexia and Brewer's Yeast induced hyperpyrexia methods. Anti-inflammatory activities were investigated using the carrageenan-induced rat paw edema method. Antinociceptive activities were determined by mechanical nociception in the tail pressure and thermal nociception in the radiant heat tail flick and hot plate methods. Data was analysed using the one way ANOVA followed by Neuman-Keuls multiple comparison test. RESULTS: Best percentage inhibition of induced pyrexia (amphetamine/brewer's yeast; p < 0.05) was exhibited by Cc (95/97) followed by Og (85/94), MiL (90/89), MiB (88/84) and Cs (82/89). Cc and Og exhibited comparable activities to paracetamol (100/95). Anti-inflammatory studies revealed paw edema inhibition (%) as follows (p < 0.05): Indomethacin (47), MiL (40), Cp (30), MiB (28) and Og (22), suggesting best activity by MiL. Antinociceptive studies revealed significant (p < 0.01) pain inhibition (%) as follows: Paracetamol (97), Og (113), MiL (108), Pg (84) and MiB (88). Og and MiL exhibited the best activities. CONCLUSION: The results obtained suggest that the constituent plants possess biologically active compounds with antipyretic, anti-inflammatory and antinociceptive activities. These activities are essential in the symptomatic treatment of malaria fever, thereby justifying the folk use of Nefang. This would be useful in its subsequent development for clinical application. PMID- 26055262 TI - Fractional Flow Reserve in Acute Myocardial Infarction: A Guide for Non-Culprit Lesions? AB - In patients presenting with ST-segment elevation myocardial infarction (STEMI) and multi-vessel disease (MVD), the optimal therapy for non-culprit lesions is still a matter of debate. While guidelines discourage a concomitant treatment of infarct- and non-infarct-related arteries, recent studies document advantages of a complete (preventive) revascularization during primary percutaneous coronary intervention. Such an approach, however, may result in overtreatment, because angiography does not provide robust information about the functional severity of MVD. Fractional flow reserve (FFR) measurements can be a valuable guide for non culprit lesions in acute myocardial infarction, but so far, only the reliability and safety of FFR measurements have been established in this setting. The clinical implications of an FFR-guided treatment strategy in STEMI patients with MVD are currently being tested in a large randomized trial. PMID- 26055263 TI - Exploring the Relationship between Family Functioning and Psycho-Pathology in a Sample in the Pediatric Age. AB - The purpose of this study was to investigate differences in family functioning between families with clinical subjects in paediatric age and families taken from the Italian population. To this aim we used the Family Adaptability and Cohesion Evaluation Scale (FACES). Participants were children diagnosed with a psychopathology, recruited into the psychiatry department in a Paediatric Hospital of Rome. A total of 106 families participated in the study. The non pathological sample is composed by 2,543 parents in different age periods of the life-cycle. Results showed significant differences in family functioning between pathological and non-pathological samples. Specifically, families from the pathological sample (particularly the ones who experienced eating disorders) were more frequently located in extreme or mid-range regions of Olson's circumplex model (p < .001). These findings suggest some considerations that can be useful in therapeutic works with families in a clinical setting. Critical aspects and clinical applications are discussed. PMID- 26055264 TI - Male and female pathological gamblers: bet in a different way and show different mental disorders. AB - Although in the last years several studies comparing male and female pathological gamblers have been published, most of them have been carried out using only samples of males. The aim of this study was to investigate gender differences in a sample of subjects diagnosed with pathological gambling (PG) attending three specialized outpatient units. Retrospective study was carried out of 96 patients (49% female and 51% male), comparing the main socio-demographic, clinical, and behavioral data. Most subjects (94%) met the criteria for pathological gambling. No significant differences between sexes were found in the severity of gambling behavior or the socio-demographic variables studied. Whereas slot machines were the main type of game for most subjects, a higher percentage of women were addicted to bingo (chi2 (1, 4) = 5.19, p = .029 Cohen's d = 0.48) and had more than one type of game as a secondary addiction chi2 (1, 4) = 7.63, p = .006; Cohen's d = 0.59) . Women started gambling at a later age than men (t (94) = 2.95, p = .004; Cohen's d = 0.60), but developed a pattern of addiction faster ( t (94) = 2.95, p = .004; Cohen's d = -0.61) . Women also had higher comorbidity with other psychiatric disorders (chi2 (1) = 7.28, p = .007; Cohen's d = 0.57), specifically with affective (chi2 (1) = 11.31, p = .001; Cohen's d = 0.73) and personality disorders (chi2 (1) = 4.71, p = .030; Cohen's d = 0.45). Our results indicate the existence of differences between women and men in the pattern of gambling behavior and in psychiatric comorbidity. These aspects should be considered in the design of treatment programs for pathological gamblers. PMID- 26055265 TI - Linking dosage compensation and X chromosome nuclear organization in C. elegans. AB - Animal sex is determined by the number of X chromosomes in many species, creating unequal gene dosage (aneuploidy) between sexes. Dosage Compensation mechanisms equalize this dosage difference by regulating X-linked gene expression. In the nematode C. elegans the current model suggests that DC is achieved by a 2-fold transcriptional downregulation in hermaphrodites mediated by the Dosage Compensation Complex (DCC), which restricts access to RNA Polymerase II by an unknown mechanism. Taking a nuclear organization point of view, we showed that the male X chromosome resides in the pore proximal subnuclear compartment whereas the DCC bound to the X, inhibits this spatial organization in the hermaphrodites. Here we discuss our results and propose a model that reassigns the role of DCC from repression of genes to inhibition of activation. PMID- 26055266 TI - Short Course Radiation in the Treatment of Localized Rectal Cancer: A Systematic Review and Meta-Analysis. AB - This meta-analysis sets out to systematically assess the efficacy of short course radiation (SRT) for rectal cancer patients based on randomized, controlled trials. Eight randomized controlled trials involving 6894 patients were ultimately included in this meta-analysis. Three trials (n = 2574) compared SRT with surgery alone. Local recurrence was improved (HR = 0.48, 95% CI 0.40 to 0.58). Overall survival was marginally improved with an HR of 0.90 (95% CI 0.81 to 1.00), but the magnitude of benefit was heterogeneous across trials. An additional three trials (n = 3682) compared SRT with selective postoperative radiation +/- chemotherapy. A significant reduction of local recurrence (HR = 0.44, 95% CI 0.35 to 0.56) was also found after SRT. However, no benefit in overall survival was observed. Moreover, two trials (n = 638) compared SRT with long course chemoradiation. There was no statistically significant local recurrence or overall survival difference observed between the two strategies. Patients receiving SRT had lower grade 3 or 4 acute treatment related toxicity (RR 0.11, 95% CI 0.05 to 0.22) whereas no difference in late toxicity was observed. Overall, SRT is a reasonable alternative for resectable rectal cancer patients and should be part of an informed discussion of treatment options for this group of patients. PMID- 26055267 TI - Smokers' and ex-smokers' understanding of electronic cigarettes: a qualitative study. AB - OBJECTIVE: To explore among a diverse range of smokers and recent ex-smokers, particularly those from disadvantaged groups, how nicotine-containing products, particularly electronic cigarettes (e-cigarettes), are understood and experienced. METHODS: Qualitative study of 64 smokers and ex-smokers in Central Scotland. Twelve focus groups and 11 individual interviews were carried out with a range of purposively selected groups. RESULTS: Nicotine replacement therapies and e-cigarettes were regarded as being very different products. Nicotine replacement therapies were viewed as medical products for smokers who want to quit, while e-cigarettes emerged as an ambiguous product whose meanings are still being negotiated. Participants' attitudes and intentions about smoking and quitting were especially important in shaping their understanding of these products. Four main interpretations of e-cigarettes were identified: a more satisfying replacement for smoking, an ambiguous but potentially useful device, a less desirable cigarette and a threat to smoking cessation. The acceptability of continued nicotine addiction and the similarity of e-cigarettes to conventional cigarettes were central themes on which participants held conflicting views. There was considerable uncertainty among participants around the constituents and safety of e-cigarettes. CONCLUSIONS: Different groups of smokers bring diverse expectations, requirements and concerns to their evaluations and therefore to the potential use of nicotine-containing products. The ambiguity around e-cigarettes in public health debates and medical practice is reflected in the positions and concerns of smokers. There is a need for both clear, up-to-date trustworthy information about their benefits and risks, and stronger regulation. PMID- 26055268 TI - Unpacking commercial sector opposition to European smoke-free policy: lack of unity, 'fear of association' and harm reduction debates. AB - OBJECTIVE: Tobacco companies have made extensive efforts to build alliances against comprehensive smoke-free legislation. This article analyses the interaction between actors who opposed the development of the European Council Recommendation on smoke-free environments. METHODS: Drawing on data from 200 policy documents and 32 semistructured interviews and using qualitative textual analysis and organisational network analysis, opponents' positions on, and responses to, the policy initiative, strategies to oppose the policy, and efforts to build alliances were investigated. RESULTS: The non-binding nature of the policy, scientific evidence and clear political will to adopt EU-wide measures combined to limit the intensity of commercial sector opposition to the comprehensive EU smoke-free policy. Most tobacco companies, led by the Confederation of European Community Cigarette Manufacturers (CECCM), voiced reservations against the proposal, criticised the policy process and fought flanking measures on product regulation. However, some companies focused on instigating harm reduction debates. These divergent approaches and the reluctance of other commercial actors to demonstrate solidarity with the tobacco sector prevented the establishment of a cohesive commercial sector alliance. CONCLUSIONS: The comparatively limited opposition to EU smoke-free policy contrasts with previous accounts of tobacco industry resistance to tobacco control. While context-specific factors can partially explain these differences, the paper indicates that the sector's diminished credibility and lack of unity hampered political engagement and alliance building. Industry efforts to emphasise the benefits of smokeless tobacco during smoke-free policy debates highlight the potential of harm reduction as a gateway for tobacco companies to re-enter the political arena. PMID- 26055269 TI - End stage renal disease as a modifier of the periodontal microbiome. AB - BACKGROUND: Evidence supports high prevalence of periodontitis in patients with chronic kidney disease. Several renal factors have been proposed as possible modifiers of periodontitis pathogenesis in this population. In this cross sectional study, we investigated whether distinct microbial profiles in renal patients could explain high periodontitis prevalence. METHODS: We characterized the subgingival microbiome in 14 End Stage Renal Disease (ESRD) and 13 control individuals with chronic periodontitis with similar demographic and clinical parameters. Medical, demographic and periodontal parameters were recorded. Subgingival biofilm samples were collected from the deepest pocket in two different quadrants and characterized via 454-pyrosequencing of the 16S rRNA gene. RESULTS: We found 874 species-level operational taxonomic units (OTU) across samples. Renal and control groups did not differ in the individual proportions of periodontitis-associated taxa. However, in principal coordinate plots of distance among samples based on OTU prevalence, some renal patients clustered apart from controls, with the microbial communities of these outlier subjects showing less diversity. Univariate correlation analysis showed a significant negative correlation between dialysis vintage and community diversity. CONCLUSIONS: Within the study limitations, dialysis vintage was associated with a less diverse periodontal microbial community in ESRD suggesting the need for further research. PMID- 26055270 TI - A review of the public-funded primary health care facilities for children in the pluralistic health care settings of Barbados, a Caribbean island. AB - Aim The major objectives of this study were to evaluate the existing pediatrics health care service provisions and utilizations of the public polyclinics in Barbados. Furthermore, the aim was to assess if the existing manpower resources were adequate. BACKGROUND: Barbados has a mixed health care system consisting of both a socialized and a private health care system. The Ministry of Health commissioned a needs assessment survey of the pediatrics primary health care at the public polyclinics. METHODS: Primary data were collected through interviews with the public primary health care providers. Secondary data were collected from the Barbados Census Data and Ministry of Health statistics. Data were analyzed to assess the pediatrics primary health care service utilization and adequacy of existing resources at the polyclinics. Findings In 2012, there were 62 934 visits from children <16 years of age to the public polyclinics in Barbados and this accounted for 39.1% of all visits (both adults and children) to the polyclinics. An overall 16.7% of the visits were from children less than five years old to the Well Child Clinic for immunization and for growth and development monitoring; 32% of all physician consultations at the polyclinics were for children <16 years. Utilization of health services by children at the polyclinics was 5245 visits/month. Given an expected monthly demand for 10 822 visits from children, the polyclinics serve 48.5% of the primary health care demand for children in Barbados. CONCLUSIONS: The public polyclinics play a pivotal role in the pluralistic primary health care system in Barbados. They fulfill nearly half of all the primary care demand and more importantly provides for almost the entire immunization demand, and thereby ensuring high coverage. The existing resources, if used optimally, would reduce the long consultation time observed in this setting, and thereby increase the capacity considerably. PMID- 26055271 TI - Stage, age, and EBV status impact outcomes of plasmablastic lymphoma patients: a clinicopathologic analysis of 61 patients. AB - BACKGROUND: Plasmablastic lymphoma (PBL) is a rare aggressive neoplasm with lymphoid and plasmacytic differentiation that is commonly associated with immunodeficiency and an unfavorable prognosis. Clinicopathologic features have been largely derived from cases reports and small series with limited outcome analyses. PATIENTS AND METHODS: The demographic, clinicopathologic features, and clinical outcomes of a cohort of 61 patients with PBL were reviewed and analyzed. RESULTS: Patients had a median age of 49 years (range 21-83 years) and most (49/61; 80%) were men. Human immunodeficiency virus (HIV) status was available for 50 patients: 20 were HIV-positive and 30 HIV-negative. Twenty-three patients were immunocompetent. Abdominal/gastrointestinal complaints were the most common presenting symptoms, reported in 14 of 47 (30%) of patients. At presentation, 24 of 43 (56%) patients had stage III or IV disease. Epstein-Barr virus (EBV) was detected in 40 of 57 (70%) cases. MYC rearrangement was identified in 10/15 (67%) cases assessed, and MYC overexpression was seen in all cases assessed regardless of MYC rearrangement status. HIV-positive patients were significantly younger than those who were HIV-negative (median 42 vs. 58 years; p = 0.006). HIV positive patients were also significantly more likely to have EBV-positive disease compared with HIV-negative patients (19/19, 100% vs. 15/29, 52%; p = 0.002). Patients who received CHOP chemotherapy tended to have better overall survival (OS) compared with those who received hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) (p = 0.078). HIV status had no impact on OS. Patients with EBV-positive PBL had a better event-free survival (EFS) (p = 0.047) but not OS (p = 0.306). Notably, OS was adversely impacted by age >= 50 years (p = 0.013), stage III or IV disease (p = <0.001), and lymph node involvement (p = 0.008). CONCLUSIONS: The most significant prognostic parameters in patients with PBL are age, stage, and, to a lesser extent, EBV status. In this study, two-thirds of PBL cases assessed were associated with MYC rearrangement and all showed MYC overexpression. PMID- 26055274 TI - Scientific publication in orthopedics journals from Chinese authors: a survey of 10-year survey of the literature. AB - PURPOSE: In the scientific community, a scientist's productivity is usually measured by his scientific output. The productivity of a group, an institution or, on a larger scale, a country can be assessed in similar manner. This study aims to show the contribution of Chinese authors to orthopedics research, from three major regions, namely Mainland China, Taiwan, and Hong Kong. METHODS: Articles published in 63 orthopedics journals originating from Mainland China, Taiwan, and Hong Kong from 2003 to 2012 were retrieved from the PubMed database and Journal Citation Report. Quantitative and qualitative analyses were conducted for the total number of articles, clinical trials, randomized controlled trails, case reports, impact factors (IF), citations, and articles published in high impact journals. RESULTS: There were totally 3473 articles from Mainland China (1859), Taiwan (1111), and Hong Kong (503) from 2003 to 2012, showing gradual increase from 2003 to 2012. From 2006 onward, the number of published articles from Mainland China exceeded that from Hong Kong and exceeded that from Taiwan in 2008. The accumulated IF of articles from Mainland China (3746.21) was higher than that from Taiwan (2466.74) and that from Hong Kong (1089.35). However, Taiwan witnessed the highest mean IF (2.22), followed by Hong Kong (2.17), and Mainland China (2.02). Hong Kong displayed the highest mean citations of each article (9.35), followed by Taiwan (9.12), and Mainland China (5.71). By contract, Spine was the most popular journal to choose in these three regions. CONCLUSIONS: The total number of orthopedics articles in China increased markedly from 2003 to 2012. Of the three regions, Mainland China published the most articles, clinical trials, randomized controlled trails, and case reports. In general, Spine was the most popular journal to choose in the three regions. PMID- 26055272 TI - Anatomy of gold catalysts: facts and myths. AB - This review article covers the main types of gold(i) complexes used as precatalysts under homogeneous conditions in organic synthesis and discusses the different ways of catalyst activation as well as ligand, silver, and anion effects. PMID- 26055273 TI - Do in vivo kinematic studies provide insight into adjacent segment degeneration? A qualitative systematic literature review. AB - PURPOSE: While much evidence suggests that adjacent segment degeneration is merely a manifestation of the natural degenerative process unrelated to any spine fusion, a significant body of literature supports the notion that it is a process due in part to the altered biomechanics adjacent to fused spine segments. The purpose of this study was to review and critically analyze the published literature that investigated the in vivo kinematics of the adjacent segments and entire lumbar spine in patients receiving spinal fusion or motion-preserving devices. METHODS: A systematic review of the PubMed database was conducted, initially identifying 697 studies of which 39 addressed the in vivo kinematics of the segments adjacent to spinal implants or non-instrumented fusion of the lumbar spine. RESULTS: Twenty-nine articles studied fusion, of which three reported a decrease in range of motion of the caudal adjacent segment post-fusion. Examining the rostral adjacent segment, twelve studies observed no change, nine studies found a significant increase, and three studies reported a significant decrease in sagittal plane range of motion. Of the six studies that analyzed motion for the entire lumbar spine as a unit, five studies showed a significant decrease and one study reported no change in global lumbar spine motion. Kinematics of the segment rostral to a total disc replacement was investigated in six studies: four found no change and the results for the other two showed dependence on treatment level. Fifteen studies of non-fusion posterior implants analyzed the motion of the adjacent segment with two studies noting an increase in motion at the rostral level. CONCLUSIONS: There appears to be no overall kinematic changes at the rostral or caudal levels adjacent to a fusion, but some patients (~20-30%) develop excessive kinematic changes (i.e., instability) at the rostral adjacent level. The overall lumbar ROM after fusion appears to decrease after a spinal fusion. PMID- 26055275 TI - Study investigating the role of skeletal muscle mass estimation in metastatic spinal cord compression. AB - BACKGROUND: Age-related loss of functional muscle mass is associated with reduced functional ability and life expectancy. In disseminated cancer, age-related muscle loss may be exacerbated by cachexia and poor nutritional intake, increasing functional decline, morbidity and accelerate death. Patients with spinal metastases frequently present for decompressive surgery with decision to operate based upon functional assessment. A subjective assessment of physical performance has, however, been shown to be a poor indicator of life expectancy in these patients. We aimed to develop an objective measure based upon lean muscle mass to aid decision making, in these individuals, by investigating the association between muscle mass and 1-year survival. METHODS: Muscle mass was calculated as total psoas area (TPA)/ vertebral body area (VBA), by two independent blinded doctors from CT images, acquired within 7 days of spinal metastases surgery, at the mid L3 vertebral level. Outcome at 1 year following surgery was recorded from a prospectively updated metastatic spinal cord compression database. RESULTS: 86 patients were followed for 1 year, with an overall mortality of 39.5%. Mortality rates at 1 year were significantly high among patients in the lowest quartile of muscle mass, compared with those in the highest quartile (57.1 vs 23.8%, p=0.02). CONCLUSION: Death within 1 year in individuals with spinal metastases is related to lean muscle mass at presentation. Assessment of lean muscle mass may inform decision to operate in patients with spinal metastases. PMID- 26055276 TI - The Role of Dietary Cholesterol in Lipoprotein Metabolism and Related Metabolic Abnormalities: A Mini-review. AB - Cholesterol plays a vital role in cell biology. Dietary cholesterol or "exogenous" cholesterol accounts for approximately one-third of the pooled body cholesterol, and the remaining 70% is synthesized in the body (endogenous cholesterol). Increased dietary cholesterol intake may result in increased serum cholesterol in some individuals, while other subjects may not respond to dietary cholesterol. However, diet-increased serum cholesterol levels do not increase the low-density lipoprotein/high-density lipoprotein (LDL/HDL) cholesterol ratio, nor do they decrease the size of LDL particles or HDL cholesterol levels. Elevated levels of LDL cholesterol, reduced HDL cholesterol levels, and small, dense LDL particles are independent risk factors for coronary artery disease. Dietary cholesterol is the primary approach for treatment of conditions such as the Smith Lemli-Opitz syndrome. Recent studies have highlighted mechanisms for absorption of dietary cholesterol. These studies have help understand how dietary and/or pharmaceutical agents inhibit cholesterol absorption and thereby reduce LDL cholesterol concentrations. In this article, various aspects of cholesterol metabolism, including dietary sources, absorption, and abnormalities in cholesterol metabolism, have been summarized and discussed. PMID- 26055277 TI - Open access to economic outcome data will help to bridge the gap between clinical trials and clinical guidelines. PMID- 26055278 TI - [Metastatic collision tumour. A case report]. AB - BACKGROUND: Collision tumours are extremely rare. They are defined by the presence of two tumours of different histological origin in the same organ. CLINICAL CASE: A 71 year old female with history of a carcinoid tumour removed 20 years ago without any recurrence. The patient was admitted with intestinal occlusion symptoms secondary to a right flank abdominal tumour. An exploratory laparotomy was performed, removing the tumor and applying optimal debulking. The histopathological study reported bilateral ovary adenocarcinoma, as well as metastatic collision tumour of two histological types: well differentiated adenocarcinoma and a mixed malignant mesodermic Mullerian tumor. The patient was treated with adjuvant chemotherapy with poor results (death in 24 months). CONCLUSIONS: The presence of collision tumours is extremely rare. There are no statistics or specific treatment reported. Diagnosis is made with histopathology. At the moment, no similiar cases have been reported. PMID- 26055279 TI - [Intra-abdominal desmoplastic small round cell tumour]. AB - BACKGROUND: The desmoplastic small round cell tumour is a rare and aggressive intra-abdominal neoplasia, with only 200 cases reported, and a higher incidence in men and predilection for the second decade of life. Histologically characterized by the presence of small nests of undifferentiated tumour cells, wrapped in fibrous desmoplastic stroma. CLINICAL CASE: A 24 year old male started with abdominal pain of 4 weeks onset in the right upper quadrant, colic type, sporadic, self-limiting and accompanied by early satiety, decreased appetite, and involuntary weight loss of 10 kg in 3 months. At the time of admission the abdomen was globular, with decreased peristalsis, soft, depressible. Computed tomography of the abdomen showed multiple enlarged lymph nodes in the abdominal pelvic cavity. A laparotomy was performed, with a subsequent omentum resection due to the presence of multiple tumours, which microscopically were characterised by groups of small, round, blue cells, separated by a desmoplastic stroma. The immunohistochemistry was positive for desmin (> 75%), epithelial membrane antigen (> 75%), CD99 (> 50%), and S100 (25%), concluding with an abdominal tumour of small, round, blue cells as a diagnosis. Chemotherapy treatment was initiated based on IMAP plus GM-CSF. CONCLUSIONS: The desmoplastic small round cell tumour is a rare neoplasia, with diagnostic complexity and a lethal course. Its clinical presentation is unspecific. Histologically, it is classified as an aggressive soft tissue sarcoma that shares similar characteristics with the family of the small and blue cells tumours. PMID- 26055280 TI - [Allogeneic parathyroid: 2-year follow-up]. AB - BACKGROUND: Hypoparathyroidism is one of the most frequent complications of neck surgery. The treatment is currently medical; however this involves several complications secondary to high doses of calcium and vitamin D, thus making parathyroid allotransplantation a good management option. MATERIAL AND METHODS: Patients with hypoparathyroidism were selected in the April-December period of 2011 in the general surgical clinic. They were between 16 and 65 years, and ingested high doses of calcium. The donors were patients with primary and secondary hyperparathyroidism, and the transplants were performed in relation to blood group and human leucocyte antigen. RESULTS: Five parathyroid allografts were performed. All the patients had iatrogenic hypoparathyroidism, all women with a mean age of 49.8 years. The graft was implanted under local anaesthesia in the non-dominant forearm. Four of the patients are so far considered functional due to the increase in paratohormone, and demonstrating its function by scintigraphy with sestamibi. One of the patients showed no increase in paratohormone or imaging studies that demonstrate its functionality. After a two year follow up the graft remains functional but with with oral calcium intake at a lower dose than before transplantation. None of the patients had immunosuppression side effects. CONCLUSIONS: In this study, allogeneic unrelated living parathyroid transplant with an immunosuppressive regimen of six months has proven to be a safe alternative treatment to improve quality of life by decreasing the excessive calcium intake and improving physical activity with adequate graft survival at 24 months follow up. PMID- 26055281 TI - [Prevalence of breast cancer sub-types by immunohistochemistry in patients in the Regional General Hospital 72, Instituto Mexicano del Seguro Social]. AB - BACKGROUND: Breast cancer mortality has increased in women 25 years and over, and since 2006 it has surpassed cervical cancer. Breast cancer is a heterogeneous disease, with several clinical and histological presentations that require a thorough study of all clinical and pathological parameters, including immunohistochemistry to classify it into subtypes, have a better prognosis, provide individualised treatment, increase survival, and reduce mortality. OBJECTIVE: To evaluate the prevalence of sub-types of breast cancer and the association with the clinical and histopathological features of the tumour. MATERIAL AND METHODS: An observational, retrospective, cross-sectional and analytical study conducted on 1380 patients with a diagnosis of breast cancer have been classified by immunohistochemistry into four subtypes: luminal A, triple negative, luminal B and HER2. An analysis was performed on the association with age, risk factors, and the clinical and histopathological features of the tumour. RESULTS: The mean age of the patients was 53.3 +/- 11.4. The frequency was luminal A (65%), triple negative (14%), luminal B (12%), and HER2 (9%). The most frequent characteristics were the 50 to 59 age range, late menopause, the right side, upper external quadrant, stage II, metastatic lymph nodes, and mastectomy. CONCLUSION: The most frequent sub-type was luminal A, and together with the luminal B are those which have better prognosis compared with the triple negative and HER2. PMID- 26055282 TI - [Gastric perforation by MALT lymphoma. Case report]. AB - BACKGROUND: Gastric non-Hodgkin lymphoma is a rare tumour that represents approximately 7% of all stomach cancers and 2% of all lymphomas. The most frequent location of gastric MALT (mucosa associated lymphoid tissue) lymphomas is in the antrum in 41% of the cases, and 33% can be multifocal. The risk of spontaneous perforation of a gastric MALT lymphoma is 4-10%. CLINICAL CASE: 24 year old male patient carrying the Human Immunodeficiency Virus, who began with signs and symptoms of acute abdomen and fever 72 hours before arriving in the emergency room. A computed tomography was performed that showed free fluid in the cavity, and gastric wall thickening. The patient underwent a laparotomy, finding absence of the anterior wall of the stomach, sealed with the left lobe of the liver, colon and omentum. Total gastrectomy, with oesophagosty and jejunostomy tube, was performed. CONCLUSIONS: Gastric perforation secondary to a MALT lymphoma is rare, with high mortality. There is limited information reported of this complication and should be highly suspected in order to provide appropriate treatment for a complication of this type. PMID- 26055283 TI - [Evidence based surgery. A necessary tool]. AB - BACKGROUND: Evidence-based surgery is a tool that has been adopted worldwide by surgeons. As all decisions must be current and have a scientific basis, the approach for performing it must be standardised. Five important steps are required to perform surgery based on evidence. Convert the need for information into a question that can be answered, finding the best information to answer that question, critical evaluation of the evidence, and its validity, impact and applicability, integrating the evidence with your own experience, and with the evaluation of the patients. This should take into account their biology, values and specific circumstances, as well as to evaluate the effectiveness and efficiency of the execution of steps 1-4 and propose how to improve them. CONCLUSION: This article presents the main tools to perform surgery properly based on evidence. PMID- 26055284 TI - [Pedicled gastric lipoma. Case report]. AB - BACKGROUND: The gastrointestinal tract lipomas are a rare, benign, slow-growth condition and can be a diagnostic challenge, they are more frequent in the colon. The gastric lipoma occurs in fewer than 5% of cases, and represents less than 1% of all gastric tumors, usually their finding is incidental and the initial presentation may be obstruction, bleeding and intussusception. The purpose of presenting this case for its rarity, the few symptoms that the patient present and collect the most current information about the diagnosis and treatment. CLINICAL CASE: We report the case of a 59 years-old male patient who after having suffered acute pancreatitis a tomography control was made looking for complications it found a pylorus-duodenal intussusception, an endoscopy was performed and a tumor about 6 cm was found and biopsies without confirm diagnosis, so it was decided to perform a partial gastrectomy, histopathology study confirmed the diagnosis of gastric lipoma as well as disease free margins. Was maintained with adequate postoperative evolution currently asymptomatic. CONCLUSIONS: The gastric lipoma is a rare benign entity that can mimic a malignancy, in our case an incidental finding which was managed by partial gastrectomy with satisfactory postoperative results. PMID- 26055285 TI - [Primary adenocarcinoma of the terminal ileum, synchronous]. AB - BACKGROUND: Among the rarest types of cancer found are the small intestine malignancies, representing only 2% of all gastrointestinal cancer and 0.1-0.3% of all malignancies. The most common subtype of this tumour is the adenocarcinoma, which is located mainly in the duodenum, jejunum and, rarely, in ileum. CLINICAL CASE: A 75 year-old male, with no any surgical history, who in the previous three months, referred to two clinical episodes of partial bowel obstruction and unquantified weight loss. When admitted into the surgical service, the patient referred to a partial bowel obstruction of more than one week onset. A laparotomy was performed, finding 3 stenosis rings at the ileum end portion, carrying out an intestinal resection and enteral-enteral anastomosis. On the seventh day there was dehiscence of the anastomosis and abdominal sepsis. New surgery was performed with the resection of the intestinal anastomosis and an ileostomy. The pathologist report indicated a small bowel adenocarcinoma moderately differentiated, ulcerated, and multifocal. It was classified as stage III or T3N1M0. The patient progress was satisfactorily, managed as outpatient with postoperative chemotherapy with 5 fluorouracil and cisplatin. The patient died a year later due to liver metastases. CONCLUSIONS: Due to the extreme rarity of the case, is very likely that general surgeons may find one or two cases of adenocarcinoma of the ileum in their professional career. Thus, they must suspect this pathology when faced with an episode of intestinal obstruction in the adult. PMID- 26055286 TI - [Non-traumatic spontaneous retroperitoneal bleeding: the effect of an early and accurate diagnosis]. AB - BACKGROUND: Spontaneous sub-capsular or peri-renal haemorrhage (Wunderlich syndrome) is a rare condition that involves a diagnostic challenge. In many cases, bleeding leads to haemodynamic instability that may be life threatening. Therefore, it is important to have a high clinical suspicion for timely action. OBJECTIVE: This paper highlights the experience of the Urology Department of the Western National Medical Center of the Mexican Institute of Social Security. METHODS: Retrospective study of consecutive non-randomized sampling. The Emergency Service Registry was reviewed for all admissions from 1 January 2010 to 31 December 2013 to identify patients with non-traumatic spontaneous retroperitoneal haemorrhage. Patient charts were reviewed to determine sex, age, vital signs, laboratory and imaging results, associated diseases, management, and outcomes. RESULTS: A total of 11 patients met the inclusion criteria for the study. All patients were received in the Emergency Department referred from secondary care hospitals. None of them were referred with a diagnosis of spontaneous retroperitoneal haemorrhage. The diagnosis was made in 100% of patients with abdominal CT scan. All patients received urgent surgical management on the day of admission due to haemodynamic instability. Ten patients underwent nephrectomy. Histopathological findings included, among others, angiomyolipoma, renal carcinoma, and metastatic hepatocellular injury. CONCLUSIONS: Spontaneous retroperitoneal haemorrhage is a lethal condition if not detected on time. The abdominal CT scan is the most accurate diagnostic method for detection. Surgical management is necessary in patients with haemodynamic instability. PMID- 26055287 TI - [Feasibility and cosmetic outcome of oncoplastic surgery in breast cancer treatment]. AB - BACKGROUND: Breast cancer is the leading oncological cause of death in Mexican women over 25 years old. Given the need to improve postoperative cosmetic results in patients with breast cancer, oncoplastic surgery has been developed, which allows larger tumour resections and minor cosmetic alterations. OBJECTIVE: To determine the oncological feasibility and cosmetic outcome of oncoplastic surgery at the Instituto de Enfermedades de la Mama, FUCAM, AC. MATERIAL AND METHODS: A review was conducted from January 2010 to July 2013, which included patients with breast cancer diagnosis treated with conventional breast-conserving surgery or with oncoplastic surgery in the Institute of Diseases of the Breast, FUCAM AC. Clinical and histopathological parameters were compared between the two groups, and a questionnaire of cosmetic satisfaction and quality of life was applied. RESULTS: Of the 171 patients included, 95 of them were treated with conventional breast-conserving surgery and 76 with oncoplastic surgery. Pathological tumour size was significantly larger in patients treated with oncoplastic surgery (p = 0.002). There were no differences found between the groups as regards the number of patients with positive surgical margin, the rate of complications, and cosmetic satisfaction. CONCLUSION: This study demonstrates the oncological feasibility and high cosmetic satisfaction of oncoplastic surgery with minimal psycho-social impact on patients. PMID- 26055288 TI - [Costs of serious adverse events in a community teaching hospital, in Mexico]. AB - BACKGROUND: Serious adverse events during hospital care are a worldwide reality and threaten the safety of the hospitalised patient. OBJECTIVE: To identify serious adverse events related to healthcare and direct hospital costs in a Teaching Hospital in Mexico. MATERIAL AND METHODS: A study was conducted in a 250 bed Teaching Hospital in San Luis Potosi, Mexico. Data were obtained from the Quality and Patient Safety Department based on 2012 incidents report. Every event was reviewed and analysed by an expert team using the "fish bone" tool. The costs were calculated since the event took place until discharge or death of the patient. RESULTS: A total of 34 serious adverse events were identified. The average cost was $117,440.89 Mexican pesos (approx. ?7,000). The great majority (82.35%) were largely preventable and related to the process of care. Undergraduate medical staff were involved in 58.82%, and 14.7% of patients had suffered adverse events in other hospitals. CONCLUSIONS: Serious adverse events in a Teaching Hospital setting need to be analysed to learn and deploy interventions to prevent and improve patient safety. The direct costs of these events are similar to those reported in developed countries. PMID- 26055289 TI - [Treatment of adamantinoma of femur with limb preservation. A case report and review of the literature]. AB - BACKGROUND: Adamantinoma is a rare lesion of low-grade malignancy, and represents 1% of malignant bone tumours of bones, and is mainly located in two regions of the body, jaw (ameloblastoma), and lower extremities. The treatment of choice is surgery due to it being a radio- and chemotherapy-resistant neoplasia. CLINICAL CASE: A 39 year old male with a history of neonatal hydrocephalus with moderate psychomotor retardation. He began with pain in the posterior region of the left thigh for one year before admission, which was managed as posterior radicular syndrome. He had sudden intense pain on walking, that led him to fall over. In the examination, left pelvic limb with deformity in the distal third with increase in volume in the thigh, with pain to palpation, and presence of crackles in the distal third of the femur. A biopsy of the thigh was performed, with subsequent local wide excision + replacement of bone with cadaver bone and a central medullary nail. The final diagnosis was adamantinoma of femur. CONCLUSION: The adamantinomas are rare tumours. It is important to recognise this type of tumor from the beginning, since its prognosis is excellent in initial stages. It is important to have free margins as survival is very high. PMID- 26055290 TI - [Von Willebrand disease. Molecular biology and diagnosis]. AB - BACKGROUND: Von Willebrand disease is the most common inherited disorder of the coagulation proteins in humans. There are three types: 1, 2A, 2B, 2N, 2M and 3. It is associated with mutations on chromosome 12 in the region p13.2, encoding the von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes. DISCUSSION: The VWF gene has been characterised using molecular biology techniques, which have acquired an important role in diagnosis von Willebrand disease, as well as in the investigation of alterations in other genes, which may be involved in regulating the synthesis, processing, and secretion of VWF. However, there are still no strategies to integrate the molecular biology diagnostic tests available. Analysis of VWF multimers is a methodology that meets the characteristics for diagnosis, but it is not easy to standardise. Considering that even in tertiary centres in our country, von Willebrand patients do not have a definitive diagnosis, it is necessary to implement these methodologies to study and improve diagnosis. CONCLUSIONS: Von Willebrand disease is highly heterogeneous due to the molecular mechanisms that produce the various clinical and laboratory phenotypes. In Mexico there are few studies related to this disease; therefore it is essential to conduct a comprehensive study including clinical, basic, and special testing laboratory tests, in order to establish a correct diagnosis, develop new therapeutic approaches, and offer the appropriate medical care and genetic counselling. PMID- 26055291 TI - Complete regression of melanoma skin metastases after electrochemotherapy plus ipilimumab treatment: an unusual clinical presentation. PMID- 26055292 TI - Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression. AB - Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by haematopoietic depletion, mediated by ingestion of alloantibodies in colostrum. It has been linked epidemiologically to vaccination of the dams of affected calves with a particular vaccine (Pregsure) containing a novel adjuvant. Evidence suggests that BNP-alloantibodies are directed against MHC I molecules, induced by contaminant bovine cellular material from Madin-Darby Bovine Kidney (MDBK) cells used in the vaccine's production. We aimed to investigate the specificity of BNP alloantibody for bovine MHC I alleles, particularly those expressed by MDBK cells, and whether depletion of particular cell types is due to differential MHC I expression levels. A complement-mediated cytotoxicity assay was used to assess functional serum alloantibody titres in BNP-dams, Pregsure-vaccinated dams with healthy calves, cows vaccinated with an alternative product and unvaccinated controls. Alloantibody specificity was investigated using transfected mouse lines expressing the individual MHC I alleles identified from MDBK cells and MHC I defined bovine leukocyte lines. All BNP-dams and 50% of Pregsure-vaccinated cows were shown to have MDBK-MHC I specific alloantibodies, which cross-reacted to varying degrees with other MHC I genotypes. MHC I expression levels on different blood cell types, assessed by flow cytometry, were found to correlate with levels of alloantibody-mediated damage in vitro and in vivo. Alloantibody-killed bone marrow cells were shown to express higher levels of MHC I than undamaged cells. The results provide evidence that MHC I-specific alloantibodies play a dominant role in the pathogenesis of BNP. Haematopoietic depletion was shown to be dependent on the titre and specificity of alloantibody produced by individual cows and the density of surface MHC I expression by different cell types. Collectively, the results support the hypothesis that MHC I molecules originating from MDBK cells used in vaccine production, coupled with a powerful adjuvant, are responsible for the generation of pathogenic alloantibodies. PMID- 26055293 TI - Vaccination against serogroup B Neisseria meningitidis: Perceptions and attitudes of parents. AB - BACKGROUND: A vaccine against serogroup B Neisseria meningitidis, major cause of bacterial meningitis in children and adults, has recently been developed. In a context of an increasing parental mistrust against vaccinations, understanding the reason for their choices is crucial in order to improve immunization coverage. Our study aimed at evaluating parental attitudes and perceptions towards serogroup B meningococcal invasive disease vaccination. METHODS: A prospective observational study was conducted in different French independent practice medical offices (general practitioners and paediatricians) and nurseries between May 1 and December 31, 2013, using a questionnaire distributed in electronic and paper forms to parents having at least one child between the ages of 2 months and 16 years old. RESULTS: 1270 parents were included, of whom 671 (52.8%) spontaneously stated to be in favour of this vaccination. Their choice was mainly justified by the severity of the disease (63.8%) and the desire to protect their child (51.7%). In multivariate analysis, the young age of parents (OR 0.949 per additional year; p<10(-3)), the history of vaccination against serogroup C meningococcal invasive diseases (OR 6.755; p<10(-3)), and the prior knowledge of the vaccine (OR 2.081; p=0.001) were associated with vaccination acceptance. The main reasons for refusal were the lack of hindsight on this new vaccine (50.6%) and the fear of side effects (45.5%). After objective information on the disease and the vaccine, only 6.3% of the entire responding population would refuse to consider vaccination. CONCLUSIONS: The spontaneous acceptance rate of vaccination against serogroup B meningococcal invasive disease is insufficient. However, after objective information by their physician or public health authorities, only a few parents would in the end be completely resistant. PMID- 26055294 TI - Transient global T cell activation after vaccination of rhesus macaques with a DNA-poxvirus vaccine regimen for HIV. AB - Persistent T cell activation following immunization with HIV vaccines may increase HIV acquisition risk. We investigated the magnitude and kinetics of T cell activation following vaccination of rhesus macaques with a candidate HIV vaccine consisting of a recombinant DNA and MVA vaccination regimen. We show that global CD4+ and CD8+ T cell activation, as measured by the expression of Ki67 and Bcl-2, peaked one week after boosting with MVA, but then waned rapidly to pre vaccination levels. Furthermore, increased frequencies of CD4+ CCR5+ T cells, which represent potential HIV target cells, were short-lived and decreased to baseline levels within two months. Activated CD4+ T cells were predominantly of a central memory phenotype, and activated CD8+ T cells were distributed between central and effector memory phenotypes. Thus, only transient changes in T cell activation occurred following poxvirus vaccination, indicating a lack of persistent immune activation. PMID- 26055295 TI - Mutual enhancement of IL-2 and IL-7 on DNA vaccine immunogenicity mainly involves regulations on their receptor expression and receptor-expressing lymphocyte generation. AB - Our previous study showed that IL-2 and IL-7 could mutually enhance the immunogenicity of canine parvovirus VP2 DNA vaccine, although the underlying mechanism remained unknown. Here, we used the OVA gene as a DNA vaccine in a mouse model to test their enhancement on DNA vaccine immunogenicity and to explore the molecular mechanism. Results showed that both IL-2 and IL-7 genes significantly increased the immunogenicity of OVA DNA vaccine in mice. Co administration of IL-2 and IL-7 genes with OVA DNA significantly increased OVA specific antibody titers, T cell proliferation and IFN-gamma production compared with IL-2 or IL-7 alone, confirming that IL-2 and IL-7 mutually enhanced DNA vaccine immunogenicity. Mechanistically, we have shown that IL-2 significantly stimulated generation of IL-7 receptor-expressing lymphocytes, and that IL-7 significantly induced IL-2 receptor expression. These results contribute to an explanation of the mechanism of the mutual effects of IL-2 and IL-7 on enhancing DNA vaccine immunogenicity and provided a basis for further investigation on their mutual effects on adjuvant activity and immune regulation. PMID- 26055296 TI - Impact of Adverse Events Following Immunization in Viet Nam in 2013 on chronic hepatitis B infection. AB - Adverse Events Following Immunization in Viet Nam in 2013 led to substantial reductions in hepatitis B vaccination coverage (both the birth dose and the three dose series). In order to estimate the impact of the reduction in vaccination coverage on hepatitis B transmission and future mortality, a widely-used mathematical model was applied to the data from Viet Nam. Using the model, we estimated the number of chronic infections and deaths that are expected to occur in the birth cohort in 2013 and the number of excessive infections and deaths attributable to the drop in immunization coverage in 2013. An excess of 90,137 chronic infections and 17,456 future deaths were estimated to occur in the 2013 birth cohort due to the drop in vaccination coverage. This analysis highlights the importance of maintaining high vaccination coverage and swiftly responding to reported Adverse Events Following Immunization in order to regain consumer confidence in the hepatitis B vaccine. PMID- 26055297 TI - Evaluating the value proposition for improving vaccine thermostability to increase vaccine impact in low and middle-income countries. AB - The need to keep vaccines cold in the face of high ambient temperatures and unreliable access to electricity is a challenge that limits vaccine coverage in low and middle-income countries (LMICs). Greater vaccine thermostability is generally touted as the obvious solution. Despite conventional wisdom, comprehensive analysis of the value proposition for increasing vaccine thermostability has been lacking. Further, while significant investments have been made in increasing vaccine thermostability in recent years, no vaccine products have been commercialized as a result. We analyzed the value proposition for increasing vaccine thermostability, grounding the analysis in specific vaccine use cases (e.g., use in routine immunization [RI] programs, or in campaigns) and in the broader context of cold chain technology and country level supply chain system design. The results were often surprising. For example, cold chain costs actually represent a relatively small fraction of total vaccine delivery system costs. Further, there are critical, vaccine use case-specific temporal thresholds that need to be overcome for significant benefits to be reaped from increasing vaccine thermostability. We present a number of recommendations deriving from this analysis that suggest a rational path toward unlocking the value (maximizing coverage, minimizing total system costs) of increased vaccine thermostability, including: (1) the full range of thermostability of existing vaccines should be defined and included in their labels; (2) for new vaccines, thermostability goals should be addressed up-front at the level of the target product profile; (3) improving cold chain infrastructure and supply chain system design is likely to have the largest impact on total system costs and coverage in the short term-and will influence the degree of thermostability required in the future; (4) in the long term, there remains value in monitoring the emergence of disruptive technologies that could remove the entire RI portfolio out of the cold chain. PMID- 26055298 TI - A Bortezomib-Based Regimen Offers Promising Survival and Graft-versus-Host Disease Prophylaxis in Myeloablative HLA-Mismatched and Unrelated Donor Transplantation: A Phase II Trial. AB - Hematopoietic stem cell transplantation (HSCT) recipients lacking HLA-matched related donors have increased graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). Bortezomib added to reduced-intensity conditioning can offer benefit in T cell-replete HLA-mismatched HSCT and may also benefit myeloablative conditioning (MAC) transplants. We conducted a phase II trial of short-course bortezomib plus standard tacrolimus/methotrexate after busulfan/fludarabine MAC in 34 patients with predominantly myeloid malignancies. Fourteen (41%) received 8/8 HLA-matched unrelated donor (MUD) and 20 (59%) received 7/8 HLA-mismatched related/unrelated donor peripheral blood stem cell grafts. Median age was 49 years (range, 21 to 60), and median follow-up was 25 months (range, 11 to 36). The regimen was well tolerated. No dose modifications were required. Neutrophil and platelet engraftment occurred at a median of 14 (range, 10 to 33) and 17 (range, 10 to 54) days, respectively. Median 30-day donor chimerism was 99% (range, 90 to 100), and 100-day grades II to IV and III to IV acute GVHD incidence was 32% and 12% respectively. One-year chronic GVHD incidence was 50%. Two-year cumulative incidence of both NRM and relapse was 16%. Two-year progression-free and overall survival rates were 70% and 71%, respectively. Outcomes were comparable to an 8/8 MUD MAC cohort (n = 45). Immune reconstitution was robust. Bortezomib-based MAC HSCT is well tolerated, with HLA-mismatched outcomes comparable with 8/8 MUD MAC HSCT, and is suitable for randomized evaluation. (clinicaltrials.gov: NCT01323920.). PMID- 26055299 TI - Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome. AB - Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day * 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which <= 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m(2), where most hematological toxicities occurred. PMID- 26055300 TI - HLA Mismatch Is Associated with Worse Outcomes after Unrelated Donor Reduced Intensity Conditioning Hematopoietic Cell Transplantation: An Analysis from the Center for International Blood and Marrow Transplant Research. AB - Over the past 2 decades, reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC HCT) has increased substantially. Many patients do not have fully HLA-matched donors, and the impact of HLA mismatch on RIC HCT has not been examined in large cohorts. We analyzed 2588 recipients of 8/8 HLA-high resolution matched (n = 2025) or single-locus mismatched (n = 563) unrelated donor (URD) RIC HCT from 1999 to 2011. Overall survival (OS) was the primary outcome. Secondary endpoints included treatment-related mortality (TRM), relapse, disease-free survival (DFS), and acute/chronic graft-versus-host disease (GVHD). Adjusted 1- and 3-year OS was better in 8/8- versus 7/8-matched recipients (54.7% versus 48.8%, P = .01, and 37.4% versus 30.9%, P = .005, respectively). In multivariate models 7/8 URD RIC HCT recipients had more grades II to IV acute GVHD (RR = 1.29, P = .0034), higher TRM (RR = 1.52, P < .0001), and lower DFS (RR = 1.12, P = .0015) and OS (RR = 1.25, P = .0001), with no difference in relapse or chronic GVHD. In subgroup analysis, inferior transplant outcomes were noted regardless of the HLA allele mismatched. Previously reported permissive mismatches at HLA-C (C*03:03/C*03:04) and HLA-DP1 (based on T cell-epitope matching) were not associated with better outcomes. Although feasible, single locus mismatch in RIC URD HCT is associated with inferior outcomes. PMID- 26055301 TI - Adaptive Natural Killer Cell and Killer Cell Immunoglobulin-Like Receptor Expressing T Cell Responses are Induced by Cytomegalovirus and Are Associated with Protection against Cytomegalovirus Reactivation after Allogeneic Donor Hematopoietic Cell Transplantation. AB - Cytomegalovirus (CMV) reactivates in >30% of CMV-seropositive patients after allogeneic hematopoietic cell transplantation (HCT). Previously, we reported an increase of natural killer (NK) cells expressing NKG2C, CD57, and inhibitory killer cell immunoglobulin-like receptors (KIRs) in response to CMV reactivation after HCT. These NK cells persist after the resolution of infection and display "adaptive" or memory properties. Despite these findings, the differential impact of persistent/inactive versus reactivated CMV on NK versus T cell maturation after HCT from different graft sources has not been defined. We compared the phenotype of NK and T cells from 292 recipients of allogeneic sibling (n = 118) or umbilical cord blood (UCB; n = 174) grafts based on recipient pretransplantation CMV serostatus and post-HCT CMV reactivation. This cohort was utilized to evaluate CMV-dependent increases in KIR-expressing NK cells exhibiting an adaptive phenotype (NKG2C(+)CD57(+)). Compared with CMV seronegative recipients, those who reactivated CMV had the highest adaptive cell frequencies, whereas intermediate frequencies were observed in CMV-seropositive recipients harboring persistent/nonreplicating CMV. The same effect was observed in T cells and CD56(+) T cells. These adaptive lymphocyte subsets were increased in CMV-seropositive recipients of sibling but not UCB grafts and were correlated with lower rates of CMV reactivation (sibling 33% versus UCB 51%; P < .01). These data suggest that persistent/nonreplicating recipient CMV induces rapid production of adaptive NK and T cells from mature cells from sibling but not UCB grafts. These adaptive lymphocytes are associated with protection from CMV reactivation. PMID- 26055302 TI - Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia. AB - Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to 'stemness' and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (?60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, that is, miR 126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients. PMID- 26055305 TI - Corrigendum: Antitumor Drug Delivery Modulated by A Polymeric Micelle Having Upper Critical Solution Temperature. PMID- 26055304 TI - Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. PMID- 26055303 TI - Identification of bromodomain-containing protein-4 as a novel marker and epigenetic target in mast cell leukemia. AB - Advanced systemic mastocytosis (SM) is a life-threatening neoplasm characterized by uncontrolled growth and accumulation of neoplastic mast cells (MCs) in various organs and a poor survival. So far, no curative treatment concept has been developed for these patients. We identified the epigenetic reader bromodomain containing protein-4 (BRD4) as novel drug target in aggressive SM (ASM) and MC leukemia (MCL). As assessed by immunohistochemistry and PCR, neoplastic MCs expressed substantial amounts of BRD4 in ASM and MCL. The human MCL lines HMC-1 and ROSA also expressed BRD4, and their proliferation was blocked by a BRD4 specific short hairpin RNA. Correspondingly, the BRD4-targeting drug JQ1 induced dose-dependent growth inhibition and apoptosis in HMC-1 and ROSA cells, regardless of the presence or absence of KIT D816V. In addition, JQ1 suppressed the proliferation of primary neoplastic MCs obtained from patients with ASM or MCL (IC50: 100-500 nm). In drug combination experiments, midostaurin (PKC412) and all-trans retinoic acid were found to cooperate with JQ1 in producing synergistic effects on survival in HMC-1 and ROSA cells. Taken together, we have identified BRD4 as a promising drug target in advanced SM. Whether JQ1 or other BET bromodomain inhibitors are effective in vivo in patients with advanced SM remains to be elucidated. PMID- 26055306 TI - Impaired capsaicin-induced relaxation in diabetic mesenteric arteries. AB - AIMS: To investigate capsaicin-induced vasodilation in the diabetic mesenteric arteries. METHODS: A diabetic rat model was established by intraperitoneal injection of streptozotocin after a 12-h fast. At 12 weeks post-injection, the third branch of the mesenteric artery was dissected out and prepared for vascular reactivity assessment. Capsaicin, capsazepine, N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME), sodium nitroprusside (SNP), calcitonin gene-related peptide 8-37 (CGRP8-37), calcitonin gene-related peptide (CGRP), and substance P (SP) were added to investigate subsequent alterations in vascular activity. Plasma and physiological salt solution (PSS) levels of CGRP and SP were measured using radioimmunoassay. The expression of transient receptor potential vanilloid 1 (TRPV1) and phospho-eNOS were determined using Western blot analysis, and nitric oxide (NO) production was measured using a fluorescence probe. RESULTS: The dilation effect of capsaicin was weaker under the diabetic than control conditions. Capsazepine, L-NAME, and CGRP8-37 attenuated capsaicin-induced vasorelaxation significantly in the diabetic vascular rings. Exogenous CGRP elicited dose-dependent vasodilation in the control arteries, whereas the dilation effect was reduced under diabetic conditions. Plasma and PSS CGRP levels were attenuated and mesenteric artery TRPV1 expression was decreased in the diabetic rats. Phospho-eNOS levels were augmented, and NO production increased following the administration of capsaicin. CONCLUSIONS: Decreased expression of TRPV1 and associated neuropeptide release contributed to the impaired capsaicin induced vasodilation in diabetic mesenteric arteries. Furthermore, an endothelium dependent NO-related pathway was involved in capsaicin-induced vasodilation. PMID- 26055307 TI - Fingerprint on trigger: A real case. AB - The results obtained by employing a usual technique for latent prints development on firearms are presented. A fingermark on a trigger was enhanced and this print was used to identify the person who handled the firearm. Indeed, it is not usual to find a useful fingermark in that position and, more in general, on firearms because of many different factors described in the following sections. The uniqueness of the results reported in this paper allow to consider the present casework as very interesting for the forensic community. PMID- 26055308 TI - A case of sudden death after ultrasound-guided percutaneous alcohol injection of a paraganglioma mis-diagnosed as a peri-renal cyst. AB - Paragangliomas are cromaffin tumors arising from the neural crest cells of parasympathetic or sympathetic ganglia. They are known to be rare causes of sudden death. Here we present the autopsy findings, as well as microscopical and immunohistochemistry study, of a 48-years-old woman who died suddenly after a percutaneous alcohol injection of a peri-renal cyst previously diagnosed as a common complex cyst. She manifested a multiorgan failure, with acute heart failure, systemic and pulmonary vasoconstriction with hypoxia, metabolic acidosis (pH 6.974). It was therefore enacted resuscitation that was ineffective. The autopsy pointed out, close to the upper right renal pole, a cyst characterized by very friable walls and septa, with a thickness of approximately 0.5cm and containing about 75cm(3) of hemoserous fluid. Microscopically, through immunohistochemical examinations, the cyst showed the presence of chromaffin cells, containing enzymes involved in the synthesis of catecholamines, in particular noradrenalin. So, the cause of the death was ascertained in an multi organ failure caused by a massive release of catecholamines (noradrenaline) from the cyst, identified post-mortem (on the basis of histologic and immunohistochemical examinations) in a noradrenalin-secreting paraganglioma, that remained silent until the cyst ablation. PMID- 26055309 TI - Exogenous glutathione supplementation in culture medium improves the bovine embryo development after in vitro fertilization. AB - To determine the beneficial effects and mechanisms of exogenous glutathione (GSH) during IVC on the embryonic development, bovine IVF zygotes were cultured in medium containing different concentrations of GSH, and the rate of cleavage and blastocyst development, total cell number of blastocysts, the inner cell mass:total cell number ratio, and intracellular GSH and reactive oxygen species concentrations were investigated. Gene expressions associated with embryonic development and GSH metabolism were measured using quantitative real-time polymerase chain reaction. At the concentrations of 1, 3, and 5 mM, GSH significantly increased the blastocyst rate and embryo quality. The highest blastocyst rate (51%) and the best embryo quality appeared in the 3-mM GSH treatment. Intracellular content of GSH of embryos at the two- to four-cell stage significantly increased, and the reactive oxygen species level decreased accordingly with 3-mM GSH treatment, but no significant differences were found in the four- to eight-cell stage and blastocysts. Gene expression analysis of the embryo regulator genes (OCT4, SOX2, and KLF4), GSH synthesis genes (GCLM, GCLC, and GSS), and GSH utilization genes (GSTP, GSTM, and GPX) showed that the GSH had no significant impact on these genes. In conclusion, exogenous GSH during IVC improved developmental potential and quality of bovine IVF embryos, which was probably caused by the ability of GSH to maintain the redox balance. PMID- 26055310 TI - A case of hypertensive brainstem encephalopathy presenting with severe headache and unilateral hearing loss. PMID- 26055311 TI - Neuroprotective effect of microRNA-99a against focal cerebral ischemia reperfusion injury in mice. AB - MicroRNA-99a (miR-99a) has been reported to function as a tumor suppressor through regulating cell cycle and apoptosis. But its clinical significance in ischemic stroke and its function in cerebral ischemia-reperfusion (I/R) injury remained unknown. Herein transient middle cerebral artery occlusion was built on C57BL/6 mice, followed by intracerebroventricular injection of miR-99a agomir or antagomir before reperfusion for 24h. Our clinical analysis indicates that plasma miR-99a level was significantly decreased in ischemic stroke patients as compared to healthy subjects, and a significant correlation was observed between miR-99a and clinical parameters. And miR-99a overexpression mitigated I/R injury in mice, as evidenced by reduced brain infarct volume and neural apoptosis, whereas miR 99a downregulation aggravates brain injury. In vitro, miR-99a protected neuro-2a cells against hydrogen peroxide-induced oxidative stress injury, by improving cell viability, suppressing LDH release and cell apoptosis. In addition, miR-99a overexpression inhibited H2O2 induced G1/S phase transition in neuro-2a cells, accompanied by a significant decrease in cyclin D1 level and a tendency of down regulation of CDK6. It was further proved in mice that miR-99a inhibited cyclin D1 and CDK6 expressions following cerebral I/R injury. These findings indicate that miR-99a reduces neuronal damage following cerebral I/R through regulating cell cycle progression and preventing apoptosis, suggesting that miR-99a could be used as a new therapeutic agent targeting neuronal cell cycle re-entry following stroke. PMID- 26055312 TI - Granulocyte colony-stimulating factor attenuates spinal cord injury-induced mechanical allodynia in adult rats. AB - Spinal cord injury (SCI) can cause neuropathic pain (NeP), often reducing a patient's quality of life. We recently reported that granulocyte colony stimulating factor (G-CSF) could attenuate NeP in several SCI patients. However, the mechanism of action underlying G-CSF-mediated attenuation of SCI-NeP remains to be elucidated. The purpose of the present study was to elucidate the therapeutic effect and mechanism of action of granulocyte colony-stimulating factor for SCI-induced NeP. T9 level contusive SCI was introduced to adult male Sprague Dawley rats. Three weeks after injury, rats received intraperitoneal recombinant human G-CSF (15.0 MUg/kg) for 5 days. Mechanical allodynia was assessed using von Frey filaments. Immunohistochemistry and western blot analysis were performed in spinal cord lumbar enlargement samples. Testing with von Frey filaments showed significant increase in the paw withdrawal threshold in the G CSF group compared with the vehicle group 4 weeks, 5 weeks, 6 weeks and 7 weeks after injury. Immunohistochemistry for CD11b (clone OX-42) revealed that the number of OX-42-positive activated microglia was significantly smaller in the G CSF group than that in the vehicle rats. Western blot analysis indicated that phosphorylated-p38 mitogen-activated protein kinase (p38MAPK) and interleukin 1beta expression in spinal cord lumbar enlargement were attenuated in the G-CSF treated rats compared with that in the vehicle-treated rats. The present results demonstrate a therapeutic effect of G-CSF treatment for SCI-induced NeP, possibly through the inhibition of microglial activation and the suppression of p38MAPK phosphorylation and the upregulation of interleukin-1beta. PMID- 26055313 TI - Decreased metabotropic glutamate receptor type 1 availability in a patient with spinocerebellar ataxia type 6: A (11)C-ITMM PET study. AB - OBJECTIVE: Imaging of metabotropic glutamate receptor type 1 (mGluR1), localized exclusively in the cerebellar Purkinje cells and related to cerebellar function, has recently become possible using positron emission tomography (PET). We report the initial mGluR1 imaging in a 74-year-old woman with spinocerebellar ataxia type 6 (SCA6). METHODS: The patient and 9 age-matched healthy controls underwent PET scanning with a mGluR1 radiotracer, N-[4-[6-(isopropylamino)pyrimidin-4-yl] 1,3-thiazol-2-yl] -4-(11)C-methoxy-N-methylbenzamide. Volumes-of-interest were placed on the anterior and posterior lobes, vermis, and flocculus. Binding potential (BPND) was calculated to estimate mGluR1 availability using the simplified reference tissue model. A partial volume correction was applied to the BPND values. Additionally, the volume of the whole cerebellum was measured using MRI. RESULTS: The corrected BPND values of the cerebellar subregions and the volume of the whole cerebellum in the patient were 51.0% to 68.3% and 72.6%, respectively, of the controls. Thus, the magnitude of reduced BPND values was relatively larger than the magnitude of cerebellar atrophy in the patient. CONCLUSION: These findings suggest that the measurement of mGluR1 availability is more sensitive than morphological measurements by MRI to detect reduced cerebellar function. Thus, imaging of mGluR1, probably reflecting the number and distribution of Purkinje cells, can be a specific and sensitive marker for estimation of cerebellar function. PMID- 26055314 TI - Trigeminal root entry zone involvement in neuromyelitis optica and multiple sclerosis. AB - Trigeminal root entry zone abnormality on brain magnetic resonance imaging has been frequently reported in multiple sclerosis patients, but it has not been investigated in neuromyelitis optica patients. Brain magnetic resonance imaging of 128 consecutive multiple sclerosis patients and 46 neuromyelitis optica patients was evaluated. Trigeminal root entry zone abnormality was present in 11 (8.6%) of the multiple sclerosis patients and two (4.3%) of the neuromyelitis optica patients. The pontine trigeminal root entry zone may be involved in both multiple sclerosis and neuromyelitis optica. PMID- 26055315 TI - Microbial rRNA:rDNA gene ratios may be unexpectedly low due to extracellular DNA preservation in soils. AB - We tested a method of estimating the activity of detectable individual bacterial and archaeal OTUs within a community by calculating ratios of absolute 16S rRNA to rDNA copy numbers. We investigated phylogenetically coherent patterns of activity among soil prokaryotes in non-growing soil communities. 'Activity ratios' were calculated for bacteria and archaea in soil sampled from a tropical rainforest and temperate agricultural field and incubated for one year at two levels of moisture availability and with and without carbon additions. Prior to calculating activity ratios, we corrected the relative abundances of OTUs to account for multiple copies of the 16S gene per genome. Although necessary to ensure accurate activity ratios, this correction did not change our interpretation of differences in microbial community composition across treatments. Activity ratios in this study were lower than those previously published (0.0003-210, logarithmic mean=0.24), suggesting significant extracellular DNA preservation. After controlling for the influence of individual incubation jars, significant differences in activity ratios between all members of each phylum were observed. Planctomycetes and Firmicutes had the highest activity ratios and Crenarchaeota had the lowest activity overall. Our results suggest that greater caution should be taken in interpreting soil microbial community data derived from extracted DNA. Indirect extraction methods may be useful in ensuring that microbes identified from extracellular DNA are not erroneously interpreted as components of an active microbial community. PMID- 26055316 TI - Ratio and log odds of positive lymph nodes in breast cancer patients with mastectomy. AB - PURPOSE: This study aimed to investigate the predictive role of lymph nodes (LNs) and assess the prognostic significance of the ratio of positive LNs (LNR) and log odds of positive LNs (LODDS) in breast cancer patients who have undergone a mastectomy. PATIENTS AND METHODS: All of the breast cancer patients in the Taiwan Cancer Database during 2002-2006 were considered. We excluded patients who had inflammatory breast cancer, stage 0 and IV disease, breast conservative surgery or survival <1 month. The primary end point was overall survival (OS). A Cox hazards model was constructed and compared via Nagelkerke R(2) (R(2)N) and receiver operating characteristics (ROC). RESULTS: A total of 11,349 (6042 node negative, 5307 node-positive) patients were enrolled, and 10.5% patients had a limited number of LNs harvested. In a multivariate Cox model, LNR and LODDS demonstrated prognostic significance (<0.001). For node-positive patients, a model with LNR showed the best fit (P < 0.001; R(2)N = 18.2%) when sufficient LNs were examined. However, a model with LODDS showed the best fit in patients with a limited number of LNs harvested (P < 0.001; R(2)N = 21.1%), even in node-negative patients (P = 0.004; R(2)N = 13.5%). The area under the ROC curve (AUC) was highest for LODDS (AUC: 0.761), followed by LNR (AUC: 0.757). A limited LN harvest induced an AUC value for an approximate 3.6% loss (LNR) or 3.1% loss (LODDS). CONCLUSION: The prognostic superiority of LNR is confounded by a limited LN harvest, thus making LODDS the most powerful and unified prognostic classifier in breast cancer patients who have had a mastectomy. PMID- 26055317 TI - Health Disparities Research in Geriatric Mental Health: Commentary from the National Institute of Mental Health. PMID- 26055319 TI - Comment on AAALAC international and compliance with animal welfare laws. PMID- 26055320 TI - The Association for Assessment and Accreditation of Laboratory Animal Care International fails to meaningfully address concerns regarding its accreditation program. PMID- 26055321 TI - Novel Protein Kinase C-Mediated Control of Orai1 Function in Invasive Melanoma. AB - The incidence of malignant melanoma, a cancer of the melanocyte cell lineage, has nearly doubled in the past 20 years. Wnt5A, akey driver of melanoma invasiveness, induces Ca2 signals. To understand how store-operated calcium entry (SOCE) contributes to Wnt5A-induced malignancy in melanoma models, we examined the expression and function of STIM1 and Orai1 in patient-derived malignant melanoma cells, previously characterized as either highly invasive (metastatic) or noninvasive. Using both fluorescence microscopy and electrophysiological approaches, we show that SOCE is greatly diminished in invasive melanoma compared to its level in noninvasive cell types. However, no loss of expression of any members of the STIM and Orai families was observed in invasive melanoma cells. Moreover, overexpressed wild-type STIM1 and Orai1 failed to restore SOCE in invasive melanoma cells, and we observed no defects in their localization before or after store depletion in any of the invasive celllines. Importantly, however, we determined that SOCE was restored by inhibition of protein kinase C, a known downstream target of Wnt5A. Furthermore, coexpression of STIM1 with an Orai1 mutant insensitive to protein kinase C-mediated phosphorylation fully restored SOCE in invasive melanoma. These findings reveal a level of control for STIM/Orai function in invasive melanoma not previously reported. PMID- 26055322 TI - Glucocorticoid Receptor Transcriptional Activation via the BRG1-Dependent Recruitment of TOP2beta and Ku70/86. AB - BRG1, the central ATPase of the human SWI/SNF complex, is critical for biological functions, including nuclear receptor (NR)-regulated transcription. Analysis of BRG1 mutants demonstrated that functional motifs outside the ATPase domain are important for transcriptional activity. In the course of experiments examining protein interactions mediated through these domains, Ku70 (XRCC6) was found to associate with a BRG1 fragment encompassing the conserved helicase-SANT associated (HSA) and BRK domains of BRG1. Subsequent transcriptional activation assays and chromatin immunoprecipitation studies showed that Ku70/86 and components of the topoisomerase IIbeta (TOP2beta)/poly(ADP ribose) polymerase 1 (PARP1) complex are necessary for NR-mediated SWI/SNF-dependent transcriptional activation from endogenous promoters. In addition to establishing Ku-BRG1 binding and TOP2beta/PARP1 recruitment by nuclear receptor transactivation, we demonstrate that the transient appearance of glucocorticoid receptor (GR)/BRG1 dependent, TOP2beta-mediated double-strand DNA breaks is required for efficient GR-stimulated transcription. Taken together, these results suggest that a direct interaction between Ku70/86 and BRG1 brings together SWI/SNF remodeling capabilities and TOP2beta activity to enhance the transcriptional response to hormone stimulation. PMID- 26055323 TI - Probing the Biology of Giardia intestinalis Mitosomes Using In Vivo Enzymatic Tagging. AB - Giardia intestinalis parasites contain mitosomes, one of the simplest mitochondrion-related organelles. Strategies to identify the functions of mitosomes have been limited mainly to homology detection, which is not suitable for identifying species-specific proteins and their functions. An in vivo enzymatic tagging technique based on the Escherichia coli biotin ligase (BirA) has been introduced to G. intestinalis; this method allows for the compartment specific biotinylation of a protein of interest. Known proteins involved in the mitosomal protein import were in vivo tagged, cross-linked, and used to copurify complexes from the outer and inner mitosomal membranes in a single step. New proteins were then identified by mass spectrometry. This approach enabled the identification of highly diverged mitosomal Tim44 (GiTim44), the first known component of the mitosomal inner membrane translocase (TIM). In addition, our subsequent bioinformatics searches returned novel diverged Tim44 paralogs, which mediate the translation and mitosomal insertion of mitochondrially encoded proteins in other eukaryotes. However, most of the identified proteins are specific to G. intestinalis and even absent from the related diplomonad parasite Spironucleus salmonicida, thus reflecting the unique character of the mitosomal metabolism. The in vivo enzymatic tagging also showed that proteins enter the mitosome posttranslationally in an unfolded state and without vesicular transport. PMID- 26055324 TI - A Pitx2-MicroRNA Pathway Modulates Cell Proliferation in Myoblasts and Skeletal Muscle Satellite Cells and Promotes Their Commitment to a Myogenic Cell Fate. AB - The acquisition of a proliferating-cell status from a quiescent state as well as the shift between proliferation and differentiation are key developmental steps in skeletal-muscle stem cells (satellite cells) to provide proper muscle regeneration. However, how satellite cell proliferation is regulated is not fully understood. Here, we report that the c-isoform of the transcription factor Pitx2 increases cell proliferation in myoblasts by downregulating microRNA 15b (miR 15b), miR-23b, miR-106b, and miR-503. This Pitx2c-microRNA (miRNA) pathway also regulates cell proliferation in early-activated satellite cells, enhancing Myf5(+) satellite cells and thereby promoting their commitment to a myogenic cell fate. This study reveals unknown functions of several miRNAs in myoblast and satellite cell behavior and thus may have future applications in regenerative medicine. PMID- 26055325 TI - Genetic Inactivation of ATRX Leads to a Decrease in the Amount of Telomeric Cohesin and Level of Telomere Transcription in Human Glioma Cells. AB - Mutations in ATRX (alpha thalassemia/mental retardation syndrome X-linked), a chromatin-remodeling protein, are associated with the telomerase-independent ALT (alternative lengthening of telomeres) pathway of telomere maintenance in several types of cancer, including human gliomas. In telomerase-positive glioma cells, we found by immunofluorescence that ATRX localized not far from the chromosome ends but not exactly at the telomere termini. Chromatin immunoprecipitation (ChIP) experiments confirmed a subtelomeric localization for ATRX, yet short hairpin RNA (shRNA)-mediated genetic inactivation of ATRX failed to trigger the ALT pathway. Cohesin has been recently shown to be part of telomeric chromatin. Here, using ChIP, we showed that genetic inactivation of ATRX provoked diminution in the amount of cohesin in subtelomeric regions of telomerase-positive glioma cells. Inactivation of ATRX also led to diminution in the amount of TERRAs, noncoding RNAs resulting from transcription of telomeric DNA, as well as to a decrease in RNA polymerase II (RNAP II) levels at the telomeres. Our data suggest that ATRX might establish functional interactions with cohesin on telomeric chromatin in order to control TERRA levels and that one or the other or both of these events might be relevant to the triggering of the ALT pathway in cancer cells that exhibit genetic inactivation of ATRX. PMID- 26055326 TI - Smad7 Modulates Epidermal Growth Factor Receptor Turnover through Sequestration of c-Cbl. AB - Epidermal growth factor (EGF) regulates various cellular events, including proliferation, differentiation, migration, and tumorigenesis. For the maintenance of homeostasis, EGF signaling should be tightly regulated to prevent the aberrant activation. Smad7 has been known as inhibitory Smad that blocks the signal transduction of transforming growth factor beta. In the process of cell proliferation or transformation, Smad7 has been shown the opposite activities as a promoter or suppressor depending on cell types or microenvironments. We found that the overexpression of Smad7 in human HaCaT keratinocyte cells and mouse skin tissues elevated EGF receptor (EGFR) activity by impairing ligand-induced ubiquitination and degradation of activated receptor, which is induced by the E3 ubiquitin ligase c-Cbl. The C-terminal MH2 region but not MH1 region of Smad7 is critical for interaction with c-Cbl to inhibit the ubiquitination of EGFR. Interestingly, wild-type Smad7, but not Smad6 or mutant Smad7, destabilized the EGF-induced complex formation of c-Cbl and EGFR. These data suggest a novel role for Smad7 as a promoter for prolonging the EGFR signal in keratinocyte and skin tissue by reducing its ligand-induced ubiquitination and degradation. PMID- 26055328 TI - A Region of Bdp1 Necessary for Transcription Initiation That Is Located within the RNA Polymerase III Active Site Cleft. AB - The RNA polymerase III (Pol III)-specific transcription factor Bdp1 is crucial to Pol III recruitment and promoter opening in transcription initiation, yet structural information is sparse. To examine its protein-binding targets within the preinitiation complex at the residue level, photoreactive amino acids were introduced into Saccharomyces cerevisiae Bdp1. Mutations within the highly conserved SANT domain cross-linked to the transcription factor IIB (TFIIB) related transcription factor Brf1, consistent with the findings of previous studies. In addition, we identified an essential N-terminal region that cross linked with the Pol III catalytic subunit C128 as well as Brf1. Closer examination revealed that this region interacted with the C128 N-terminal region, the N-terminal half of Brf1, and the C-terminal domain of the C37 subunit, together positioning this region within the active site cleft of the preinitiation complex. With our functional data, our analyses identified an essential region of Bdp1 that is positioned within the active site cleft of Pol III and necessary for transcription initiation. PMID- 26055327 TI - Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism. AB - Serum retinol-binding protein 4 (RBP4) is the sole specific transport protein for retinol in the blood, but it is also an adipokine with retinol-independent, proinflammatory activity associated with obesity, insulin resistance, type 2 diabetes, and cardiovascular disease. Moreover, two separate studies reported that patients with proliferative diabetic retinopathy have increased serum RBP4 levels compared to patients with mild or no retinopathy, yet the effect of increased levels of RBP4 on the retina has not been studied. Here we show that transgenic mice overexpressing RBP4 (RBP4-Tg mice) develop progressive retinal degeneration, characterized by photoreceptor ribbon synapse deficiency and subsequent bipolar cell loss. Ocular retinoid and bisretinoid levels are normal in RBP4-Tg mice, demonstrating that a retinoid-independent mechanism underlies retinal degeneration. Increased expression of pro-interleukin-18 (pro-IL-18) mRNA and activated IL-18 protein and early-onset microglia activation in the retina suggest that retinal degeneration is driven by a proinflammatory mechanism. Neither chronic systemic metabolic disease nor other retinal insults are required for RBP4 elevation to promote retinal neurodegeneration, since RBP4-Tg mice do not have coincident retinal vascular pathology, obesity, dyslipidemia, or hyperglycemia. These findings suggest that elevation of serum RBP4 levels could be a risk factor for retinal damage and vision loss in nondiabetic as well as diabetic patients. PMID- 26055329 TI - TRIM28 Is an E3 Ligase for ARF-Mediated NPM1/B23 SUMOylation That Represses Centrosome Amplification. AB - The tumor suppressor ARF enhances the SUMOylation of target proteins; however, the physiological function of ARF-mediated SUMOylation has been unclear due to the lack of a known, associated E3 SUMO ligase. Here we uncover TRIM28/KAP1 as a novel ARF-binding protein and SUMO E3 ligase for NPM1/B23. ARF and TRIM28 cooperate to SUMOylate NPM1, a nucleolar protein that regulates centrosome duplication and genomic stability. ARF-mediated SUMOylation of NPM1 was attenuated by TRIM28 depletion and enhanced by TRIM28 overexpression. Coexpression of ARF and TRIM28 promoted NPM1 centrosomal localization by enhancing its SUMOylation and suppressed centrosome amplification; these functions required the E3 ligase activity of TRIM28. Conversely, depletion of ARF or TRIM28 increased centrosome amplification. ARF also counteracted oncogenic Ras induced centrosome amplification. Centrosome amplification is often induced by oncogenic insults, leading to genomic instability. However, the mechanisms employed by tumor suppressors to protect the genome are poorly understood. Our findings suggest a novel role for ARF in maintaining genome integrity by facilitating TRIM28-mediated SUMOylation of NPM1, thus preventing centrosome amplification. PMID- 26055331 TI - [Malignant fibrous histiocytoma of the penis]. AB - According to the most recent World Health Organization (WHO) guidelines a diagnosis of malignant fibrous histiocytoma (MFH) should be made only for lesions composed of tumor cells without evidence of a specific line of differentiation. This is therefore a diagnosis by exclusion which is why the name of undifferentiated high-grade pleomorphic sarcoma (UPS) should be preferred. Soft tissue sarcomas currently have an incidence in all body regions of approximately 20 cases per 1 million inhabitants per year. Soft tissue tumors of the penis represent approximately 5 % of all penile tumors and the incidence of penile sarcomas is estimated to be approximately 0.6-1 case per 100,000 patients. Only seven cases have so far been reported in the literature. This article describes the case of a 61-year-old Caucasian male who presented with a painless mass sited in the upper part of the corpus cavernosa. An incisional biopsy with a subsequent investigation using an extensive immunohistochemical panel were performed and a high-grade undifferentiated pleomorphic sarcoma or pleomorphic storiform MFH was diagnosed. In addition to the case report a literature review is presented to elaborate the discussion on the differential diagnoses of these kinds of lesions. PMID- 26055330 TI - MicroRNA 224 Regulates Ion Transporter Expression in Ameloblasts To Coordinate Enamel Mineralization. AB - Enamel mineralization is accompanied by the release of protons into the extracellular matrix, which is buffered to regulate the pH value in the local microenvironment. The present study aimed to investigate the role of microRNA 224 (miR-224) as a regulator of SLC4A4 and CFTR, encoding the key buffering ion transporters, in modulating enamel mineralization. miR-224 was significantly downregulated as ameloblasts differentiated, in parallel with upregulation of SLC4A4 and CFTR. Overexpression of miR-224 downregulated SLC4A4 and CFTR expression in cultured human epithelial cells. A microRNA luciferase assay confirmed the specific binding of miR-224 to the 3' untranslated regions (UTRs) of SLC4A4 and CFTR mRNAs, thereby inhibiting protein translation. miR-224 agomir injection in mouse neonatal incisors resulted in normal enamel length and thickness, but with disturbed organization of the prism structure and deficient crystal growth. Moreover, the enamel Ca/P ratio and microhardness were markedly reduced after miR-224 agomir administration. These results demonstrate that miR 224 plays a pivotal role in fine tuning enamel mineralization by modulating SLC4A4 and CFTR to maintain pH homeostasis and support enamel mineralization. PMID- 26055332 TI - [Intraoperative frozen sections of the thyroid gland]. AB - The goal of evaluation of intraoperative frozen sections of the thyroid gland is to achieve a definitive diagnosis which determines the subsequent surgical management as fast as possible; however, due to the specific methodological situation of thyroid frozen sections evaluation a conclusive diagnosis can be made in only some of the cases. If no conclusive histological diagnosis is possible during the operation, subsequent privileged processing of the specimen allows a final diagnosis at the latest within 48 h in almost all remaining cases. Applying this strategy, both pathologists and surgeons require a high level of communication and knowledge regarding the specific diagnostic and therapeutic peculiarities of thyroid malignancies because different surgical strategies must be employed depending on the histological tumor subtype. PMID- 26055334 TI - Seek and ye shall find... crossed pulmonary arteries. Comment on Crossed pulmonary arteries with hypoplasia of the transverse aortic arch. PMID- 26055333 TI - Transgenic alfalfa (Medicago sativa) with increased sucrose phosphate synthase activity shows enhanced growth when grown under N2-fixing conditions. AB - MAIN CONCLUSION: Overexpression of SPS in alfalfa is accompanied by early flowering, increased plant growth and an increase in elemental N and protein content when grown under N2-fixing conditions. Sucrose phosphate synthase (SPS; EC 2.3.1.14) is the key enzyme in the synthesis of sucrose in plants. The outcome of overexpression of SPS in different plants using transgenic approaches has been quite varied, but the general consensus is that increased SPS activity is associated with the production of new sinks and increased sink strength. In legumes, the root nodule is a strong C sink and in this study our objective was to see how increasing SPS activity in a legume would affect nodule number and function. Here we have transformed alfalfa (Medicago sativa, cv. Regen SY), with a maize SPS gene driven by the constitutive CaMV35S promoter. Our results showed that overexpression of SPS in alfalfa, is accompanied by an increase in nodule number and mass and an overall increase in nitrogenase activity at the whole plant level. The nodules exhibited an increase in the level of key enzymes contributing to N assimilation including glutamine synthetase and asparagine synthetase. Moreover, the stems of the transformants showed higher level of the transport amino acids, Asx, indicating increased export of N from the nodules. The transformants exhibited a dramatic increase in growth both of the shoots and roots, and earlier flowering time, leading to increased yields. Moreover, the transformants showed an increase in elemental N and protein content. The overall conclusion is that increased SPS activity improves the N status and plant performance, suggesting that the availability of more C in the form of sucrose enhances N acquisition and assimilation in the nodules. PMID- 26055335 TI - Atopic donor status does not influence the uptake of the major grass pollen allergen, Phl p 5, by dendritic cells. AB - Dendritic cells (DCs) are sentinels of the immune system for antigen recognition and uptake, as well as presentation to naive T cells for stimulation or priming. Internalization and endocytic degradation of allergens by DCs are important steps required for T cell priming. In the current study we investigated binding and internalization of purified recombinant non-glycosylated grass pollen allergen, Phl p 5, and natural non-specific lipid transfer protein from sunflower, SF-nsLTP to human monocyte derived dendritic cells (MoDCs). Colocalization of Phl p 5 with low affinity (CD23) or high affinity receptor (FcepsilonRI) was investigated by immunofluorescence staining. Likewise, localization of the allergens in early (EE) and late endosomes (LE) was detected by co-staining for early endosome antigen (EEA1) and lysosomal-associated membrane protein 1 (LAMP1). In our experimental setting we could demonstrate that Phl p 5 as well as SF-nsLTP bound to MoDCs from both, grass pollen allergic and non-allergic individuals. Competitive allergen uptake experiments demonstrated non-preferential and simultaneous uptake of Phl p 5 and SF-nsLTP by MoDCs. No overlap of signals from Phl p 5 and CD23 or FcepsilonRI was detectable, excluding IgE-mediated uptake for this allergen. Both allergens, Phl p 5 and SF-nsLTP, were localized in early and late endosomes. The present study applied a set of methods to assess the allergen uptake by MoDCs in an in vitro model. No qualitative and quantitative differences in the allergen uptake of both, Phl p 5 and SF-nsLTP were detected in single and competitive assays. PMID- 26055336 TI - Validation of an automated seizure detection algorithm for term neonates. AB - OBJECTIVE: The objective of this study was to validate the performance of a seizure detection algorithm (SDA) developed by our group, on previously unseen, prolonged, unedited EEG recordings from 70 babies from 2 centres. METHODS: EEGs of 70 babies (35 seizure, 35 non-seizure) were annotated for seizures by experts as the gold standard. The SDA was tested on the EEGs at a range of sensitivity settings. Annotations from the expert and SDA were compared using event and epoch based metrics. The effect of seizure duration on SDA performance was also analysed. RESULTS: Between sensitivity settings of 0.5 and 0.3, the algorithm achieved seizure detection rates of 52.6-75.0%, with false detection (FD) rates of 0.04-0.36FD/h for event based analysis, which was deemed to be acceptable in a clinical environment. Time based comparison of expert and SDA annotations using Cohen's Kappa Index revealed a best performing SDA threshold of 0.4 (Kappa 0.630). The SDA showed improved detection performance with longer seizures. CONCLUSION: The SDA achieved promising performance and warrants further testing in a live clinical evaluation. SIGNIFICANCE: The SDA has the potential to improve seizure detection and provide a robust tool for comparing treatment regimens. PMID- 26055337 TI - Look back to leap forward: The emerging new role of magnetoencephalography (MEG) in nonlesional epilepsy. AB - This review considers accumulating evidence for a new role of MEG/MSI in increasing the diagnostic yield of supposedly negative MRIs, and suggests changes in the use of MEG/MSI in presurgical epilepsy evaluations. Specific alterations in practice protocols for both the MEG practitioner (i.e. physician magnetoencephalographer) and MEG user (i.e. referring physician) are proposed that should further enhance the overall value of MEG/MSI. Although advances in MEG analysis methods will likely become increasingly assisted by computers, interpretive competency and prudent clinical judgment remain irreplaceable. PMID- 26055338 TI - Why Levy Foraging does not need to be 'unshackled' from Optimal Foraging Theory: Comment on "Liberating Levy walk research from the shackles of optimal foraging" by A.M. Reynolds. PMID- 26055339 TI - Gastrointestinal stromal tumors during pregnancy: a systematic review of an uncommon but treatable malignancy. AB - Although modern social structure and medical advances have led to the increasing number of women childbearing in older age, cancer remains a rare diagnosis during pregnancy. There is little given information throughout the literature concerning gestation associated with the coexistence of gastrointestinal stromal tumor (GIST). In this review, we present 12 reported cases of GIST during pregnancy and we discuss the maternal and fetal outcome, as well as the therapeutic plan that was followed in each situation. From the collected data, 8 out of 12 cases had an uneventful outcome of their fetus. In 11 out of 12 cases surgical excision of the tumor was the treatment of choice, while seven women were treated with imatinib. Two of them were already on imatinib therapy during conception due to preexisting GIST diagnosis. Surgery remains the gold standard for the treatment of local or resectable GIST, while published data concerning the use of imatinib during pregnancy indicate that teratogenicity or fetal loss might be induced, especially if given during the first trimester of pregnancy. GIST during gestational period is a rare tumor in which a multidisciplinary approach should be designed, taking always into consideration that it has a favorable outcome on targeted treatment. PMID- 26055340 TI - Hepatic arterial infusion plus systemic chemotherapy as third-line or later treatment in colorectal liver metastases. AB - BACKGROUNDS: The present study aimed to evaluate benefit of hepatic arterial infusion chemotherapy (HAI) combined with systemic chemotherapy (SCT) for patients with colorectal liver metastases (CLMs) in a palliative setting. METHODS: This was a retrospective single-center study including 43 consecutive patients with CLM after failure of standard SCT. Among them, 20 (47 %) patients underwent HAI combined with SCT (Group A) and 23 historical control patients who had received SCT with or without targeted agent treatment (Group B). RESULTS: The two groups had similar characteristics. Compared with SCT alone, HAI combined with SCT prolonged survival (median 19.8 vs. 9.0 months; P = 0.045). Median hepatic progression-free survival was significantly longer for HAI combined with SCT vs. SCT alone (median 8.1 vs. 4.7 months; P = 0.027), as were response rates (25 and 0 %; P = 0.038) and progression-free survival (median 5.7 vs. 3.0 months; P = 0.02). Three patients (15 %) achieved conversion to potentially curative surgery. Grade 3/4 toxicities for Group A and Group B were neutropenia (5 and 8.7 %, respectively), anemia (5 and 0 %, respectively), and hyperbilirubinemia (0 and 4.3 %, respectively). Other complications were mostly grade 1 or 2. CONCLUSIONS: HAI combined with SCT treatment can improve overall survival compared with SCT alone in highly advanced CLM refractory to intravenous chemotherapy. PMID- 26055341 TI - MicroRNA-197 influences 5-fluorouracil resistance via thymidylate synthase in colorectal cancer. AB - PURPOSE: The response rate of first-line fluoropyrimidine-based regimens for metastatic colorectal cancer (mCRC) is generally less than 50 %. The down regulation of miR-197 in colorectal cancer cells after exposure to 5-fluorouracil might be related to the mechanism of resistance to fluoropyrimidine-based chemotherapy. So we investigated the regulatory mechanism of miR-197 on 5-FU sensitivity. METHODS: Dual luciferase reporter gene construct and dual luciferase reporter assay were used to identify the target of miR-197. TYMS expression was evaluated by immunohistochemistry staining. 5-Fu resistance of colorectal cancer cell lines was detected by MTS assay. The expression of miR-197 was detected by real time PCR. RESULTS: A luciferase assay and western blot analysis confirmed that miR-197 directly binds to and negatively regulates TYMS expression. Overexpressing miR-197 could increase the sensitivity of colorectal cancer cells to 5-fluorouracil (5-FU). The expression of miR-197 negatively correlated with TYMS expression in cancerous tissues from patients with stage IV colorectal cancer. CONCLUSION: miR-197 mediates the response of colorectal cancer cells to 5 FU by regulating TYMS expression. PMID- 26055342 TI - Pharmacokinetics and metabolism study of isoboldine, a major bioactive component from Radix Linderae in male rats by UPLC-MS/MS. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Isoboldine is one of the major bioactive constituents in the total alkaloids from Radix Linderae (TARL) which could effectively alleviate inflammation and joints destruction in mouse collagen induced arthritis. To better understand its pharmacological activities, we need to determine its pharmacokinetic and metabolic profiles. MATERIALS AND METHODS: In this study, a sensitive and simple UPLC-MS/MS method was developed and validated for determination of isoboldine in rat plasma. Isoboldine in plasma was recovered by liquid-liquid extraction using 1 mL of methyl tert-butyl ether. Chromatographic separation was performed on a C18 column at 45 degrees C, with a gradient elution consisting of acetonitrile and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. The detection was performed on an electrospray triple-quadrupole MS/MS by positive ion multiple-reaction monitoring mode. This newly developed method was successfully applied to a pharmacokinetic study after oral and intravenous dosing in rats. For metabolites identification, isoboldine was orally administered to rats and the metabolite in plasma, bile, urine and feces were characterized by the established UPLC-MS/MS method. RESULTS: Good linearity (r(2)>0.9956) was achieved in a concentration range of 4.8-2400 ng/mL with a lower limit of quantification of 4.8 ng/mL for isoboldine. The intra and inter-day precisions of the assay were 1.7-5.1% and 2.2-4.4% relative standard deviation with an accuracy of 91.3-102.3%. A total of five phase II metabolites in rat plasma, bile, urine and feces were characterized by comparing retention time in UPLC, and by molecular mass and fragmentation pattern of the metabolites by mass spectrometry with those of isoboldine. CONCLUSION: isoboldine has extremely low oral bioavailability due to the strong first-pass effect by the rats, and glucuronidation and sulfonation were involved in metabolic pathways of isoboldine in rats. These results have paved the way for further clarifying therapeutic ingredients and provided new knowledge regarding pharmacokinetic features of this category of isoquinoline alkaloids. PMID- 26055343 TI - Ethno veterinary uses of medicinal plants of district Karak, Pakistan. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In the study area, the traditional knowledge regarding the uses of local wild medicinal plants for treating diseases of domestic animals and birds is totally in the custody of elders of the existing community. The young ones are not much aware about such important practices. AIM OF THE STUDY: The main aim of the study was to document and to release this knowledge from the custody of elders and share with the community. MATERIALS AND METHODS: Total 115 people between 20 and 80 years of age were interviewed and information was collected through semi-structured questionnaires. The data obtained were quantitatively analyzed using the use value (UV) formula. The collected specimens were pressed, dried, preserved, mounted on Herbarium sheets, identified properly and were submitted in the Herbarium, Department of Botany, Hazara University, Mansehra, Pakistan. RESULTS: With the co-ordination and cooperation of the local people, 46 plant species of 42 genera belonging to 31 families were collected, 3 were monocotyledons while 43 plant species belonged to dicotyledonae class. Considering taxonomic characteristics, it was confirmed that 12 trees, 10 shrubs and 22 herbs were commonly used by the local people in ethno veterinary practices. Two plants like Cistanche tubulosa and Cuscuta reflexa from family Orobanchaceae and family Cuscutaceae respectively lack chlorophyll and are parasites on host plants like Doedonia, Ziziphus, Calligonum and Calotropis. The powder of both plants showed great ethno veterinary value. The parts of 46 plant species commonly used for ethno veterinary practices were whole plants (32.60%), leaves (26.08%), fruits (17.39%), stems (13.04%) and roots (10.86%). Medicinal plants were administered through various routes i.e. oral (78.26%), skin (17.21%) and smoke (4.34%). CONCLUSION: The traditional knowledge of local plants of ethno veterinary values is mainly possessed by elders and transmitted from generation to generation with chances of elimination of such traditional knowledge due to less awareness. The present study was designed to document this ethno veterinary related knowledge and to share it with community members for use in future. PMID- 26055344 TI - Anti-inflammatory activity studies on the stems and roots of Jasminum lanceolarium Roxb. AB - Jasminum lanceolarium Roxb is an important traditional Chinese medicine. Its stems and roots have been used for the treatment of rheumatism and fever while the leaves are used as an anti-inflammatory agent to relieve pain. In order to support its traditional Chinese medicinal uses, five animal models were designed and the anti-inflammatory and analgesic properties of the 70% EtOH-H2O extracts of J. lanceolarium (EJL) were investigated. Meanwhile, biochemical parameters such as cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) in blood serum of rats exposed to acute (carrageenan) inflammation model were evaluated. At doses of 400 mg/kg, EJL exhibited higher anti-inflammation effect than that of indomethacin and better analgesic activity than that of aspirin (P<0.001). Furthermore, eleven isolated compounds including six lignanoids (1, 2, 6, 7, 8, and 11) and five iridoids (3, 4, 5, 9, and 10) were isolated from the active extracts and showed significant anti-inflammatory activities with the IC50 values of 1.76-5.22 mg/mL, respectively, when testing their inhibitory effects on phospholipase A2 in vitro. The results demonstrated that the possible anti-inflammatory mechanisms might be attributed to inhibit the hydrolysis of membrane phospholipids, production on both COX-2 and 5-LOX, and then finally inhibit the release of prostaglandins (PGs), which suggested that EJL had a non-selective inhibitory effect on the release or actions of these mediators, and might be a dual LOX-COX inhibitor for the treatment of inflammation from the natural resource. The studies on the animals and the inflammatory mediators, along with the bioactive compounds presumed that the existences of iridoids and lignanoids could be response for their bioactivities of the whole plants. PMID- 26055345 TI - Leading people positively: cross-cultural validation of the Servant Leadership Survey (SLS). AB - Servant Leadership emphasizes employee's development and growth within a context of moral and social concern. Nowadays, this management change towards workers' wellbeing is highlighted as an important issue. The aims of this paper are to adapt to Spanish speakers the Servant Leadership Survey (SLS) by van Dierendonck and Nuijten (2011), and to analyze its factorial validity through confirmatory factor analysis and measurement invariance in three countries. A sample of 638 working people from three Spanish-speaking countries (Spain, Argentina and Mexico) participated in the study. In all three countries, confirmatory factor analyses corroborate the eight factor structure (empowerment, accountability, standing back, humility, authenticity, courage, forgiveness and stewardship) with one second order factor (servant leadership) (in all three samples, CFI, IFI > .92, TLI > .91, RMSEA < .70). Also, factor loadings, reliability and convergent validity were acceptable across samples. Furthermore, through measurement invariance analysis, we detected model equivalence in all three countries including structural residual invariance (DeltaCFI = .001). Finally, cultural differences in some dimensions were found and discussed, opening the way for future cross-cultural studies. PMID- 26055346 TI - Electrochemical growth of CoNi and Pt-CoNi soft magnetic composites on an alkanethiol monolayer-modified ITO substrate. AB - CoNi and Pt-CoNi magnetic layers on indium-tin oxide (ITO) substrates modified by an alkanethiol self-assembled monolayer (SAM) have been electrochemically obtained as an initial stage to prepare semiconducting layer-SAM-magnetic layer hybrid structures. The best conditions to obtain the maximum compactness of adsorbed layers of dodecanethiol (C12-SH) on ITO substrate have been studied using contact angle, AFM, XPS and electrochemical tests. The electrochemical characterization (electrochemical probe or voltammetric response in blank solutions) is fundamental to ensure the maximum blocking of the substrate. Although the electrodeposition process on the SAM-modified ITO substrate is very slow if the blocking of the surface is significant, non-cracked metallic layers of CoNi, with or without a previously electrodeposited seed-layer of platinum, have been obtained by optimizing the deposition potentials. Initial nucleation is expected to take place at the pinhole defects of the C12-SH SAM, followed by a mushroom-like growth regime through the SAM interface that allows the formation of a continuous metallic layer electrically connected to the ITO surface. Due to the potential of the methodology, the preparation of patterned metallic deposits on ITO substrate using SAMs with different coverage as templates is feasible. PMID- 26055347 TI - A triphasic constrained mixture model of engineered tissue formation under in vitro dynamic mechanical conditioning. AB - While it has become axiomatic that mechanical signals promote in vitro engineered tissue formation, the underlying mechanisms remain largely unknown. Moreover, efforts to date to determine parameters for optimal extracellular matrix (ECM) development have been largely empirical. In the present work, we propose a two pronged approach involving novel theoretical developments coupled with key experimental data to develop better mechanistic understanding of growth and development of dense connective tissue under mechanical stimuli. To describe cellular proliferation and ECM synthesis that occur at rates of days to weeks, we employ mixture theory to model the construct constituents as a nutrient-cell-ECM triphasic system, their transport, and their biochemical reactions. Dynamic conditioning protocols with frequencies around 1 Hz are described with multi scale methods to couple the dissimilar time scales. Enhancement of nutrient transport due to pore fluid advection is upscaled into the growth model, and the spatially dependent ECM distribution describes the evolving poroelastic characteristics of the scaffold-engineered tissue construct. Simulation results compared favorably to the existing experimental data, and most importantly, distinguish between static and dynamic conditioning regimes. The theoretical framework for mechanically conditioned tissue engineering (TE) permits not only the formulation of novel and better-informed mechanistic hypothesis describing the phenomena underlying TE growth and development, but also the exploration/optimization of conditioning protocols in a rational manner. PMID- 26055348 TI - Resveratrol prevents hepatic steatosis and endoplasmic reticulum stress and regulates the expression of genes involved in lipid metabolism, insulin resistance, and inflammation in rats. AB - Previous research demonstrated that resveratrol possesses promising properties for preventing obesity. Endoplasmic reticulum (ER) stress was proposed to be involved in the pathophysiology of both obesity and hepatic steatosis. In the current study, we hypothesized that resveratrol could protect against high-fat diet (HFD)-induced hepatic steatosis and ER stress and regulate the expression of genes related to hepatic steatosis. Rats were fed either a control diet or a HFD for 12 weeks. After 4 weeks, HFD-fed rats were treated with either resveratrol or vehicle for 8 weeks. Body weight, serum metabolic parameters, hepatic histopathology, and hepatic ER stress markers were evaluated. Moreover, an RT2 Profiler Fatty Liver PCR Array was performed to investigate the mRNA expressions of 84 genes related to hepatic steatosis. Our work showed that resveratrol prevented dyslipidemia and hepatic steatosis induced by HFD. Resveratrol significantly decreased activating transcription factor 4, C/EBP-homologous protein and immunoglobulin binding protein levels, which were elevated by the HFD. Resveratrol also decreased PKR-like ER kinase phosphorylation, although it was not affected by the HFD. Furthermore, resveratrol increased the expression of peroxisome proliferator-activated receptor delta, while decreasing the expression of ATP citrate lyase, suppressor of cytokine signaling-3, and interleukin-1beta. Our data suggest that resveratrol can prevent hepatic ER stress and regulate the expression of peroxisome proliferator-activated receptor delta, ATP citrate lyase, suppressor of cytokine signaling-3, tumor necrosis factor alpha, and interleukin-1beta in diet-induced obese rats, and these effects likely contribute to resveratrol's protective function against excessive accumulation of fat in the liver. PMID- 26055352 TI - Wnt/beta-catenin signalling and podocyte dysfunction in proteinuric kidney disease. AB - Podocytes are unique, highly specialized, terminally differentiated cells that are integral components of the kidney glomerular filtration barrier. Podocytes are vulnerable to a variety of injuries and in response they undergo a series of changes ranging from hypertrophy, autophagy, dedifferentiation, mesenchymal transition and detachment to apoptosis, depending on the nature and extent of the insult. Emerging evidence indicates that Wnt/beta-catenin signalling has a central role in mediating podocyte dysfunction and proteinuria. Wnts are induced and beta-catenin is activated in podocytes in various proteinuric kidney diseases. Genetic or pharmacologic activation of beta-catenin is sufficient to impair podocyte integrity and causes proteinuria in healthy mice, whereas podocyte-specific ablation of beta-catenin protects against proteinuria after kidney injury. Mechanistically, Wnt/beta-catenin controls the expression of several key mediators implicated in podocytopathies, including Snail1, the renin angiotensin system and matrix metalloproteinase 7. Wnt/beta-catenin also negatively regulates Wilms tumour protein, a crucial transcription factor that safeguards podocyte integrity. Targeted inhibition of Wnt/beta-catenin signalling preserves podocyte integrity and ameliorates proteinuria in animal models. This Review highlights advances in our understanding of the pathomechanisms of Wnt/beta-catenin signalling in mediating podocyte injury, and describes the therapeutic potential of targeting this pathway for the treatment of proteinuric kidney disease. PMID- 26055354 TI - Early chronic kidney disease: diagnosis, management and models of care. AB - Chronic kidney disease (CKD) is prevalent in many countries, and the costs associated with the care of patients with end-stage renal disease (ESRD) are estimated to exceed US$1 trillion globally. The clinical and economic rationale for the design of timely and appropriate health system responses to limit the progression of CKD to ESRD is clear. Clinical care might improve if early-stage CKD with risk of progression to ESRD is differentiated from early-stage CKD that is unlikely to advance. The diagnostic tests that are currently used for CKD exhibit key limitations; therefore, additional research is required to increase awareness of the risk factors for CKD progression. Systems modelling can be used to evaluate the impact of different care models on CKD outcomes and costs. The US Indian Health Service has demonstrated that an integrated, system-wide approach can produce notable benefits on cardiovascular and renal health outcomes. Economic and clinical improvements might, therefore, be possible if CKD is reconceptualized as a part of primary care. This Review discusses which early CKD interventions are appropriate, the optimum time to provide clinical care, and the most suitable model of care to adopt. PMID- 26055356 TI - The influence of traffic signal solutions on self-reported road-crossing behavior. AB - Injury to pedestrians is a major safety hazard in many countries. Since the beginning of the last century, modern cities have been designed around the use of motor vehicles despite the unfavourable interactions between the vehicles and pedestrians. This push towards urbanization resulted in a substantial number of crashes and fatalities involving pedestrians every day, all over the world. Thus, improving the design of urban cities and townships is a pressing issue for modern society. The study presented here provides a characterization of pedestrian safety problems, with the emphasis on signalized crosswalks (i.e. traffic signal) design solutions. We tested the impact of seven different traffic light configurations (steady [green, yellow, and red], flashing [green, yellow, and red], and light off) on pedestrian self-reported road-crossing behavior, using a 11-point scale -ranging from 0 ("I never cross in this situation") to 10 ("I always cross in this situation"). Results showed that mandatory solutions (steady green vs. steady red) are the best solutions to avoid unsafe pedestrian behaviors while crossing controlled intersections (frequency of crossing: Mgreen = 9.4 +/- 1 vs. Mred = 2.6 +/- 2). These findings offer important guidelines for the design of future traffic signals for encouraging a pedestrian/transit-friendly environment. PMID- 26055357 TI - Evaluation of common variants in CNR2 gene for bone mineral density and osteoporosis susceptibility in postmenopausal women of Han Chinese. AB - Postmenopausal osteoporosis is a major health problem with important genetic factors in postmenopausal women. We thoroughly evaluated the relationship of CNR2 polymorphisms with osteoporosis in a cohort of 1032 osteoporosis patients and 2089 healthy controls from Han Chinese postmenopausal women. Statistically significant differences, depending on different genotypes, were presented. INTRODUCTION: Osteoporosis is a major health problem in postmenopausal women, which is a multifactorial disease in which genetic determinants are modulated by hormonal, environmental, and nutritional factors. An important clinical risk factor in the pathogenesis of osteoporosis is the presence of genetic polymorphism in susceptibility genes. The aim of our study was to investigate whether CNR2 gene, which attributes to osteoporosis susceptibility in some populations, is associated with bone mineral density (BMD) or osteoporosis in Han Chinese postmenopausal women. METHODS: We examine 39 SNPs covering the region of CNR2 gene in 3121 Han Chinese postmenopausal women, consisting of 1032 osteoporosis patients and 2089 healthy controls, to evaluate the association with BMD and osteoporosis. RESULTS: We found that rs4237 and rs2501431 were significantly associated with BMD and osteoporosis (corrected p = 0.020085 and 0.017199) in our sample, and the TT genotype of rs2501431 and the AA genotype of rs4237 had lower lumbar spine BMD and femoral neck BMD compared with the other genotypes. Additionally, analyses by haplotypes indicated that two haplotype blocks, containing rs4237 and rs2501431 respectively, in the CNR2 gene significantly associated with BMD and osteoporosis (both global permutation p < 0.001), and a risk haplotype (ATTT) in the block of rs3003336-rs2501431-rs2502992 rs2501432 had almost 4-fold increase in the cases. CONCLUSIONS: Our results provide further supportive evidence for an important role of CNR2 gene in the etiology of osteoporosis and suggest that it may be a genetic risk factor for BMD and osteoporosis in Han Chinese postmenopausal women. PMID- 26055358 TI - Cardiac adaptations of bullfrog tadpoles in response to chytrid infection. AB - The chytrid fungus Batrachochytrium dendrobatidis (Bd) can result in heart failure in Bd-susceptible species. Since Bd infection generally does not cause mortality in North American bullfrogs, the aim of this work was to verify whether this species presents any cardiac adaptation that could improve the tolerance to the fungus. Thus, we analyzed tadpoles' activity level, relative ventricular mass, ventricle morphology, in loco heart frequency, and in vitro cardiac function. The results indicate that infected animals present an increase in both ventricular relative mass and in myofibrils' incidence, which accompanied the increase in myocytes' diameter. Such morphological alterations enabled an increase in the in vitro twitch force that, in vivo, would result in elevation of the cardiac stroke volume. This response requires much less energy expenditure than an elevation in heart frequency, but still enables the heart to pump a higher volume of blood per minute (i.e., an increase in cardiac output). As a consequence, the energy saved in the regulation of the cardiac function of Bd infected tadpoles can be employed in other homeostatic adjustments to avoid the lethal effect of the fungus. Whether other species present this ability, and to what extent, remains uncertain, but such possible interspecific variability might explain different mortality rates among different species of Bd-infected amphibians. PMID- 26055355 TI - Anaemia in kidney disease: harnessing hypoxia responses for therapy. AB - Improved understanding of the oxygen-dependent regulation of erythropoiesis has provided new insights into the pathogenesis of anaemia associated with renal failure and has led to the development of novel therapeutic agents for its treatment. Hypoxia-inducible factor (HIF)-2 is a key regulator of erythropoiesis and iron metabolism. HIF-2 is activated by hypoxic conditions and controls the production of erythropoietin by renal peritubular interstitial fibroblast-like cells and hepatocytes. In anaemia associated with renal disease, erythropoiesis is suppressed due to inadequate erythropoietin production in the kidney, inflammation and iron deficiency; however, pharmacologic agents that activate the HIF axis could provide a physiologic approach to the treatment of renal anaemia by mimicking hypoxia responses that coordinate erythropoiesis with iron metabolism. This Review discusses the functional inter-relationships between erythropoietin, iron and inflammatory mediators under physiologic conditions and in relation to the pathogenesis of renal anaemia, as well as recent insights into the molecular and cellular basis of erythropoietin production in the kidney. It furthermore provides a detailed overview of current clinical experience with pharmacologic activators of HIF signalling as a novel comprehensive and physiologic approach to the treatment of anaemia. PMID- 26055359 TI - Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis. AB - Rifampin, together with isoniazid, has been the backbone of the current first line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of efficacy. The objective of this study was to develop an optimal sampling procedure based on population pharmacokinetics to predict AUC0-24 values. Patients received rifampin orally once daily as part of their anti-TB treatment. A one-compartmental pharmacokinetic population model with first-order absorption and lag time was developed using observed rifampin plasma concentrations from 55 patients. The population pharmacokinetic model was developed using an iterative two-stage Bayesian procedure and was cross-validated. Optimal sampling strategies were calculated using Monte Carlo simulation (n = 1,000). The geometric mean AUC0 24 value was 41.5 (range, 13.5 to 117) mg . h/liter. The median time to maximum concentration of drug in serum (Tmax) was 2.2 h, ranging from 0.4 to 5.7 h. This wide range indicates that obtaining a concentration level at 2 h (C2) would not capture the peak concentration in a large proportion of the population. Optimal sampling using concentrations at 1, 3, and 8 h postdosing was considered clinically suitable with an r(2) value of 0.96, a root mean squared error value of 13.2%, and a prediction bias value of -0.4%. This study showed that the rifampin AUC0-24 in TB patients can be predicted with acceptable accuracy and precision using the developed population pharmacokinetic model with optimal sampling at time points 1, 3, and 8 h. PMID- 26055360 TI - Phase 1 Randomized, Double-Blind, Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy, in Healthy Adults. AB - Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n = 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n = 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n = 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.). PMID- 26055361 TI - Conformational Change Observed in the Active Site of Class C beta-Lactamase MOX-1 upon Binding to Aztreonam. AB - We solved the crystal structure of the class C beta-lactamase MOX-1 complexed with the inhibitor aztreonam at 1.9A resolution. The main-chain oxygen of Ser315 interacts with the amide nitrogen of aztreonam. Surprisingly, compared to that in the structure of free MOX-1, this main-chain carboxyl changes its position significantly upon binding to aztreonam. This result indicates that the interaction between MOX-1 and beta-lactams can be accompanied by conformational changes in the B3 beta-strand main chain. PMID- 26055362 TI - Salinomycin and other ionophores as a new class of antimalarial drugs with transmission-blocking activity. AB - The drug target profile proposed by the Medicines for Malaria Venture for a malaria elimination/eradication policy focuses on molecules active on both asexual and sexual stages of Plasmodium, thus with both curative and transmission blocking activities. The aim of the present work was to investigate whether the class of monovalent ionophores, which includes drugs used in veterinary medicine and that were recently proposed as human anticancer agents, meets these requirements. The activity of salinomycin, monensin, and nigericin on Plasmodium falciparum asexual and sexual erythrocytic stages and on the development of the Plasmodium berghei and P. falciparum mosquito stages is reported here. Gametocytogenesis of the P. falciparum strain 3D7 was induced in vitro, and gametocytes at stage II and III or stage IV and V of development were treated for different lengths of time with the ionophores and their viability measured with the parasite lactate dehydrogenase (pLDH) assay. The monovalent ionophores efficiently killed both asexual parasites and gametocytes with a nanomolar 50% inhibitory concentration (IC50). Salinomycin showed a fast speed of kill compared to that of standard drugs, and the potency was higher on stage IV and V than on stage II and III gametocytes. The ionophores inhibited ookinete development and subsequent oocyst formation in the mosquito midgut, confirming their transmission blocking activity. Potential toxicity due to hemolysis was excluded, since only infected and not normal erythrocytes were damaged by ionophores. Our data strongly support the downstream exploration of monovalent ionophores for repositioning as new antimalarial and transmission-blocking leads. PMID- 26055363 TI - Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage. AB - Incomplete APOBEC3G/F neutralization by a defective HIV-1Vif protein can promote genetic diversification by inducing G-to-A mutations in the HIV-1 genome. The HIV 1 Env V3 loop, critical for coreceptor usage, contains several putative APOBEC3G/F target sites. Here, we determined if APOBEC3G/F, in the presence of Vif-defective HIV-1 virus, can induce G-to-A mutations at V3 positions critical to modulation of CXCR4 usage. Peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from 2 HIV-1-negative donors were infected with CCR5-using 81.A-VifWT virus (i.e., with wild-type [WT] Vif protein), 81.A VifE45G, or 81.A-VifK22E (known to incompletely/partially neutralize APOBEC3G/F). The rate of G-toA mutations was zero or extremely low in 81.A-VifWT- and 81.A VifE45G-infected PBMC from both donors. Conversely, G-to-A enrichment was detected in 81.A-VifK22E-infected PBMC (prevalence ranging from 2.18% at 7 days postinfection [dpi] to 3.07% at 21 dpi in donor 1 and from 10.49% at 7 dpi to 8.69% at 21 dpi in donor 2). A similar scenario was found in MDM. G-to-A mutations occurred at 8 V3 positions, resulting in nonsynonymous amino acid substitutions. Of them, G24E and E25K strongly correlated with phenotypically/genotypically defined CXCR4-using viruses (P = 0.04 and 5.5e-7, respectively) and increased the CXCR4 N-terminal binding affinity for V3 (WT, 40.1 kcal/mol; G24E, -510 kcal/mol; E25K, -522 kcal/mol). The analysis of paired V3 and Vif DNA sequences from 84 HIV-1-infected patients showed that the presence of a Vif-defective virus correlated with CXCR4 usage in proviral DNA (P = 0.04). In conclusion, incomplete APOBEC3G/F neutralization by a single Vif amino acid substitution seeds a CXCR4-using proviral reservoir. This can have implications for the success of CCR5 antagonist-based therapy, as well as for the risk of disease progression. PMID- 26055364 TI - Antiviral Efficacy of a Respiratory Syncytial Virus (RSV) Fusion Inhibitor in a Bovine Model of RSV Infection. AB - Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants. Effective treatment for RSV infection is a significant unmet medical need. While new RSV therapeutics are now in development, there are very few animal models that mimic the pathogenesis of human RSV, making it difficult to evaluate new disease interventions. Experimental infection of Holstein calves with bovine RSV (bRSV) causes a severe respiratory infection that is similar to human RSV infection, providing a relevant model for testing novel therapeutic agents. In this model, viral load is readily detected in nasal secretions by quantitative real-time PCR (qRT-PCR), and cumulative symptom scoring together with histopathology evaluations of infected tissue allow for the assessment of disease severity. The bovine RSV model was used to evaluate the antiviral activity of an RSV fusion inhibitor, GS1, which blocks virus entry by inhibiting the fusion of the viral envelope with the host cell membrane. The efficacy of GS1, a close structural analog of GS-5806 that is being developed to treat RSV infection in humans was evaluated in two randomized, blind, placebo controlled studies in bRSV-infected calves. Intravenous administration of GS1 at 4 mg/kg of body weight/day for 7 days starting 24 h or 72 h postinoculation provided clear therapeutic benefit by reducing the viral load, disease symptom score, respiration rate, and lung pathology associated with bRSV infection. These data support the use of the bovine RSV model for evaluation of experimental therapeutics for treatment of RSV. PMID- 26055365 TI - The HEPT Analogue WPR-6 Is Active against a Broad Spectrum of Nonnucleoside Reverse Transcriptase Drug-Resistant HIV-1 Strains of Different Serotypes. AB - Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important components of the highly active antiretroviral therapy (HAART) used to treat human immunodeficiency type 1 virus (HIV-1). However, because of the emergence of drug resistance and the adverse effects of current anti-HIV drugs, it is essential to develop novel NNRTIs with an excellent safety profile, improved activity against NNRTI-resistant viruses, and enhanced activity against clinical isolates of different subtypes. Here, we have identified 1-[(benzyloxy)methyl]-6-(3,5 dimethylbenzyl)-5-iodopyrimidine-2,4(1H,3H)-dione (WPR-6), a novel NNRTI with a 50% effective concentration (EC50) of 2 to 4 nM against laboratory-adapted HIV-1 strain SF33 and an EC50 of 7 to 14 nM against nucleoside reverse transcriptase inhibitor-resistant HIV-1 strain 7391 with a therapeutic index of >1 * 10(4). A panel of five representative clinical virus isolates of different subtypes circulating predominantly in China was highly sensitive to WPR-6, with EC50s ranging from 1 to 6 nM. In addition, WPR-6 showed excellent antiviral potency against the most prevalent NNRTI-resistant viruses containing the K103N and Y181C mutations. To determine whether WPR-6 selects for novel resistant mutants, in vitro resistance selection was conducted with laboratory-adapted HIV-1 strain SF33 on MT-4 cells. The results demonstrated that V106I and Y188L were the two dominant NNRTI-associated resistance mutations detected in the breakthrough viruses. Taken together, these in vitro data indicate that WPR-6 has greater efficacy than the reference HEPT analogue TNK651 and the marketed drug nevirapine against HIV-1. However, to develop it as a new NNRTI, further improvement of its pharmacological properties is warranted. PMID- 26055366 TI - Hitting the caspofungin salvage pathway of human-pathogenic fungi with the novel lasso peptide humidimycin (MDN-0010). AB - Fungal infections have increased dramatically in the last 2 decades, and fighting infectious diseases requires innovative approaches such as the combination of two drugs acting on different targets or even targeting a salvage pathway of one of the drugs. The fungal cell wall biosynthesis is inhibited by the clinically used antifungal drug caspofungin. This antifungal activity has been found to be potentiated by humidimycin, a new natural product identified from the screening of a collection of 20,000 microbial extracts, which has no major effect when used alone. An analysis of transcriptomes and selected Aspergillus fumigatus mutants indicated that humidimycin affects the high osmolarity glycerol response pathway. By combining humidimycin and caspofungin, a strong increase in caspofungin efficacy was achieved, demonstrating that targeting different signaling pathways provides an excellent basis to develop novel anti-infective strategies. PMID- 26055367 TI - Effect of Qnr on Plasmid Gyrase Toxins CcdB and ParE. AB - Plasmid toxins CcdB and ParE are part of addiction systems promoting plasmid maintenance. Both target host DNA gyrase, as do quinolones and plasmid-determined Qnr proteins that protect gyrase from quinolone inhibition. We cloned qnrB4, qnrS1, ccdB, parE, and the antitoxin-encoding genes ccdA and parD on compatible plasmids and tested them in combination. CcdB and ParE had no specific effect on quinolone susceptibility or Qnr protection, and Qnr did not act as a CcdB or ParE antitoxin. PMID- 26055368 TI - Emergence of H7N9 Influenza A Virus Resistant to Neuraminidase Inhibitors in Nonhuman Primates. AB - The number of patients infected with H7N9 influenza virus has been increasing since 2013. We examined the efficacy of neuraminidase (NA) inhibitors and the efficacy of a vaccine against an H7N9 influenza virus, A/Anhui/1/2013 (H7N9), isolated from a patient in a cynomolgus macaque model. NA inhibitors (oseltamivir and peramivir) barely reduced the total virus amount because of the emergence of resistant variants with R289K or I219T in NA [residues 289 and 219 in N9 of A/Anhui/1/2013 (H7N9) correspond to 292 and 222 in N2, respectively] in three of the six treated macaques, whereas subcutaneous immunization of an inactivated vaccine derived from A/duck/Mongolia/119/2008 (H7N9) prevented propagation of A/Anhui/1/2013 (H7N9) in all vaccinated macaques. The percentage of macaques in which variant H7N9 viruses with low sensitivity to the NA inhibitors were detected was much higher than that of macaques in which variant H5N1 highly pathogenic influenza virus was detected after treatment with one of the NA inhibitors in our previous study. The virus with R289K in NA was reported in samples from human patients, whereas that with I219T in NA was identified for the first time in this study using macaques, though no variant H7N9 virus was reported in previous studies using mice. Therefore, the macaque model enables prediction of the frequency of emerging H7N9 virus resistant to NA inhibitors in vivo. Since H7N9 strains resistant to NA inhibitors might easily emerge compared to other influenza viruses, monitoring of the emergence of variants is required during treatment of H7N9 influenza virus infection with NA inhibitors. PMID- 26055369 TI - ADS-J1 inhibits semen-derived amyloid fibril formation and blocks fibril-mediated enhancement of HIV-1 infection. AB - Semen-derived enhancer of viral infection (SEVI) is composed of amyloid fibrils that can greatly enhance HIV-1 infectivity. By its cationic property, SEVI promotes viral sexual transmission by facilitating the attachment and internalization of HIV-1 to target cells. Therefore, semen-derived amyloid fibrils are potential targets for microbicide design. ADS-J1 is an anionic HIV-1 entry inhibitor. In this study, we explored an additional function of ADS-J1: inhibition of SEVI fibril formation and blockage of SEVI-mediated enhancement of viral infection. We found that ADS-J1 bound to an amyloidogenic peptide fragment (PAP248-286, comprising amino acids 248 to 286 of the enzyme prostatic acid phosphatase), thereby inhibiting peptide assembly into amyloid fibrils. In addition, ADS-J1 binds to mature amyloid fibrils and antagonizes fibril-mediated enhancement of viral infection. Unlike cellulose sulfate, a polyanion that failed in clinical trial to prevent HIV-1 sexual transmission, ADS-J1 shows no ability to facilitate fibril formation. More importantly, the combination of ADS-J1 with several antiretroviral drugs exhibited synergistic effects against HIV-1 infection in semen, with little cytotoxicity to vaginal epithelial cells. Our results suggest that ADS-J1 or a derivative may be incorporated into a combination microbicide for prevention of the sexual transmission of HIV-1. PMID- 26055370 TI - Frequency and Distribution of Single-Nucleotide Polymorphisms within mprF in Methicillin-Resistant Staphylococcus aureus Clinical Isolates and Their Role in Cross-Resistance to Daptomycin and Host Defense Antimicrobial Peptides. AB - MprF is responsible for the lysinylation of phosphatidylglycerol (PG) to synthesize the positively charged phospholipid (PL) species, lysyl-PG (L-PG). It has been proposed that the single-nucleotide polymorphisms (SNPs) within the mprF open reading frame (ORF) are associated with a gain-in-function phenotype in terms of daptomycin resistance in Staphylococcus aureus. (Note that although the official term is daptomycin nonsusceptibility, we use the term daptomycin resistance in this paper for ease of presentation.) Using 22 daptomycin susceptible (DAP(s))/daptomycin-resistant (DAP(r)) clinical methicillin-resistant S. aureus (MRSA) strain pairs, we assessed (i) the frequencies and distribution of putative mprF gain-in-function SNPs, (ii) the relationships of the SNPs to both daptomycin resistance and cross-resistance to the prototypical endovascular host defense peptide (HDP) thrombin-induced platelet microbicidal protein (tPMP), and (iii) the impact of mprF SNPs on positive surface charge phenotype and modifications of membrane PL profiles. Most of the mprF SNPs identified in our DAP(r) strains were clustered within the two MprF loci, (i) the central bifunctional domain and (ii) the C-terminal synthase domain. Moreover, we were able to correlate the presence and location of mprF SNPs in DAP(r) strains with HDP cross-resistance, positive surface charge, and L-PG profiles. Although DAP(r) strains with mprF SNPs in the bifunctional domain showed higher resistance to tPMPs than DAP(r) strains with SNPs in the synthase domain, this relationship was not observed in positive surface charge assays. These results demonstrated that both charge-mediated and -unrelated mechanisms are involved in DAP resistance and HDP cross-resistance in S. aureus. PMID- 26055371 TI - Sequential chemoimmunotherapy of experimental visceral leishmaniasis using a single low dose of liposomal amphotericin B and a novel DNA vaccine candidate. AB - Combination therapies for leishmaniasis, including drugs and immunomodulators, are one approach to shorten treatment courses and to improve the treatment of complex manifestations of the disease. We evaluated a novel T-cell-epitope enriched DNA vaccine candidate (LEISHDNAVAX) as host-directed immunotherapy in combination with a standard antileishmanial drug in experimental visceral leishmaniasis. Here we show that the DNA vaccine candidate can boost the efficacy of a single suboptimal dose of liposomal amphotericin B in C57BL/6 mice. PMID- 26055373 TI - Endothelial Cell Toxicity of Vancomycin Infusion Combined with Other Antibiotics. AB - French guidelines recommend central intravenous (i.v.) infusion for high concentrations of vancomycin, but peripheral intravenous (p.i.v.) infusion is often preferred in intensive care units. Vancomycin infusion has been implicated in cases of phlebitis, with endothelial toxicity depending on the drug concentration and the duration of the infusion. Vancomycin is frequently infused in combination with other i.v. antibiotics through the same administrative Y site, but the local toxicity of such combinations has been poorly evaluated. Such an assessment could improve vancomycin infusion procedures in hospitals. Human umbilical vein endothelial cells (HUVEC) were challenged with clinical doses of vancomycin over 24 h with or without other i.v. antibiotics. Cell death was measured with the alamarBlue test. We observed an excess cellular death rate without any synergistic effect but dependent on the numbers of combined infusions when vancomycin and erythromycin or gentamicin were infused through the same Y site. Incompatibility between vancomycin and piperacillin-tazobactam was not observed in our study, and rinsing the cells between the two antibiotic infusions did not reduce endothelial toxicity. No endothelial toxicity of imipenem cilastatin was observed when combined with vancomycin. p.i.v. vancomycin infusion in combination with other medications requires new recommendations to prevent phlebitis, including limiting coinfusion on the same line, reducing the infusion rate, and choosing an intermittent infusion method. Further studies need to be carried out to explore other drug combinations in long-term vancomycin p.i.v. therapy so as to gain insight into the mechanisms of drug incompatibility under multidrug infusion conditions. PMID- 26055372 TI - In Vivo Efficacy of Antimicrobials against Biofilm-Producing Pseudomonas aeruginosa. AB - Patients suffering from cystic fibrosis (CF) are commonly affected by chronic Pseudomonas aeruginosa biofilm infections. This is the main cause for the high disease severity. In this study, we demonstrate that P. aeruginosa is able to efficiently colonize murine solid tumors after intravenous injection and to form biofilms in this tissue. Biofilm formation was evident by electron microscopy. Such structures could not be observed with transposon mutants, which were defective in biofilm formation. Comparative transcriptional profiling of P. aeruginosa indicated physiological similarity of the bacteria in the murine tumor model and the CF lung. The efficacy of currently available antibiotics for treatment of P. aeruginosa-infected CF lungs, such as ciprofloxacin, colistin, and tobramycin, could be tested in the tumor model. We found that clinically recommended doses of these antibiotics were unable to eliminate wild-type P. aeruginosa PA14 while being effective against biofilm-defective mutants. However, colistin-tobramycin combination therapy significantly reduced the number of P. aeruginosa PA14 cells in tumors at lower concentrations. Hence, we present a versatile experimental system that is providing a platform to test approved and newly developed antibiofilm compounds. PMID- 26055374 TI - NDM-1-Producing Citrobacter freundii, Escherichia coli, and Acinetobacter baumannii Identified from a Single Patient in China. AB - We identified New Delhi metallo-beta-lactamase (NDM-1)-producing Citrobacter freundii GB032, Escherichia coli GB102, and Acinetobacter baumannii GB661 in urine and stool samples from a single patient in China. Plasmid profiling and Southern blotting indicated that blaNDM-1 from GB032 and that from GB102 were likely located on the same plasmid, while blaNDM-1 from GB661 was located on a very large (>400-kb) plasmid. This case underscores the broad host range of blaNDM-1 and its potential to spread between members of the family Enterobacteriaceae and A. baumannii. PMID- 26055375 TI - Sequence Analysis of Herpes Simplex Virus 1 Thymidine Kinase and DNA Polymerase Genes from over 300 Clinical Isolates from 1973 to 2014 Finds Novel Mutations That May Be Relevant for Development of Antiviral Resistance. AB - A total of 302 clinical herpes simplex virus 1 (HSV-1) strains, collected over 4 decades from 1973 to 2014, were characterized retrospectively for drug resistance. All HSV-1 isolates were analyzed genotypically for nonsynonymous mutations in the thymidine kinase (TK) and DNA polymerase (Pol) genes. The resistance phenotype against acyclovir (ACV) and/or foscarnet (FOS) was examined in the case of novel, unclear, or resistance-related mutations. Twenty-six novel natural polymorphisms could be detected in the TK gene and 69 in the DNA Pol gene. Furthermore, three novel resistance-associated mutations (two in the TK gene and one in the DNA Pol gene) were analyzed, and eight known but hitherto unclear amino acid substitutions (two encoded in TK and six in the DNA Pol gene) could be clarified. Between 1973 and 2014, the distribution of amino acid changes related to the natural gene polymorphisms of TK and DNA Pol remained largely stable. Resistance to ACV was confirmed phenotypically for 16 isolates, and resistance to ACV plus FOS was confirmed for 1 isolate. Acyclovir-resistant strains were observed from the year 1995 onwards, predominantly in immunosuppressed patients, especially those with stem cell transplantation, and the number of ACV-resistant strains increased during the last 2 decades. The data confirm the strong genetic variability among HIV-1 isolates, which is more pronounced in the DNA Pol gene than in the TK gene, and will facilitate considerably the rapid genotypic diagnosis of HSV-1 resistance. PMID- 26055376 TI - Pharmacodynamic Profile of GSK2140944 against Methicillin-Resistant Staphylococcus aureus in a Murine Lung Infection Model. AB - GSK2140944 is a novel bacterial type II topoisomerase inhibitor with in vitro activity against key causative respiratory pathogens, including methicillin resistant Staphylococcus aureus (MRSA). We described the pharmacodynamics of GSK2140944 against MRSA in the neutropenic murine lung infection model. MICs of GSK2140944 were determined by broth microdilution. Plasma and epithelial lining fluid (ELF) pharmacokinetics were evaluated to allow determination of pulmonary distribution. Six MRSA isolates were tested. GSK2140944 doses of 1.56 to 400 mg/kg of body weight every 6 h (q6h) were utilized. Efficacy as the change in log10 CFU at 24 h compared with 0 h controls and the area under the concentration time curve for the free, unbound fraction of a drug (fAUC)/MIC required for various efficacy endpoints were determined. GSK2140944 MICs were 0.125 to 0.5 mg/liter against the six MRSA isolates. ELF penetration ratios ranged from 1.1 to 1.4. Observed maximal decreases were 1.1 to 3.1 log10 CFU in neutropenic mice. The mean fAUC/MIC ratios required for stasis and 1-log-unit decreases were 59.3 +/- 34.6 and 148.4 +/- 83.3, respectively. GSK2140944 displayed in vitro and in vivo activity against MRSA. The pharmacodynamic profile of GSK2140944, as determined, supports its further development as a potential treatment option for pulmonary infections, including those caused by MRSA. PMID- 26055377 TI - The enterovirus 3C protease inhibitor SG85 efficiently blocks rhinovirus replication and is not cross-resistant with rupintrivir. AB - The novel enterovirus protease inhibitor (PI) SG85 effectively inhibits the in vitro replication of 14 rhinoviruses representative of species A and B (median 50% effective concentration, 0.04 MUM). A low-level SG85-resistant variant was selected that carried amino acid substitutions S127G and T143A in the 3C protease. Both substitutions are required for low-level resistance to SG85, as demonstrated by reverse genetics. Interestingly, there is no cross-resistance to SG85 and rupintrivir (another PI); a structural explanation is provided for this observation. PMID- 26055378 TI - Retrospective Comparison of Posaconazole Levels in Patients Taking the Delayed Release Tablet versus the Oral Suspension. AB - While posaconazole prophylaxis decreases the risk of invasive fungal infection compared to fluconazole, low bioavailability of the oral-suspension formulation limits its efficacy. A new delayed-release tablet formulation demonstrated an improved pharmacokinetic profile in healthy volunteers. However, serum levels for the two formulations have not been compared in clinical practice. This study compared achievement of therapeutic posaconazole levels in patients taking the delayed-release tablet to those taking the oral suspension. This retrospective cohort study included 93 patients initiated on posaconazole between 2012 and 2014 and had at least one serum posaconazole level measured. The primary measure was the proportion of patients achieving an initial therapeutic level (>700 ng/ml). An initial therapeutic posaconazole level was seen in 29 of 32 (91%) patients receiving tablets and 37 of 61 (61%) patients receiving suspension (P = 0.003). Among patients with a steady-state level measured 5 to 14 days after initiation, a therapeutic level was observed in 18 of 20 (90%) patients receiving tablets and 25 of 43 (58%) patients receiving suspension (P = 0.01). In these patients, the median posaconazole level of the tablet cohort (1655 ng/ml) was twice that of the suspension cohort (798 ng/ml) (P = 0.004). In this cohort study, the improved bioavailability of delayed-release posaconazole tablets translates into a significantly higher proportion of patients achieving therapeutic serum levels than in the cohort receiving the oral suspension. The results of this study strongly support the use of delayed-release tablets over suspension in patients at risk for invasive fungal infection. PMID- 26055379 TI - Calcium-Mediated Induction of Paradoxical Growth following Caspofungin Treatment Is Associated with Calcineurin Activation and Phosphorylation in Aspergillus fumigatus. AB - The echinocandin antifungal drug caspofungin at high concentrations reverses the growth inhibition of Aspergillus fumigatus, a phenomenon known as the "paradoxical effect," which is not consistently observed with other echinocandins (micafungin and anidulafungin). Previous studies of A. fumigatus revealed the loss of the paradoxical effect following pharmacological or genetic inhibition of calcineurin, yet the underlying mechanism is poorly understood. Here, we utilized a codon-optimized bioluminescent Ca(2+) reporter aequorin expression system in A. fumigatus and showed that caspofungin elicits a transient increase in cytosolic free Ca(2+) ([Ca(2+)]c) in the fungus that acts as the initial trigger of the paradoxical effect by activating calmodulin-calcineurin signaling. While the increase in [Ca(2+)]c was also observed upon treatment with micafungin, another echinocandin without the paradoxical effect, a higher [Ca(2+)]c increase was noted with the paradoxical-growth concentration of caspofungin. Treatments with a Ca(2+)-selective chelator, BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N',N' tetraacetic acid], or the L-type Ca(2+) channel blocker verapamil abolished caspofungin-mediated paradoxical growth in both the wild-type and the echinocandin-resistant (EMFR-S678P) strains. Concomitant with increased [Ca(2+)]c levels at higher concentrations of caspofungin, calmodulin and calcineurin gene expression was enhanced. Phosphoproteomic analysis revealed that calcineurin is activated through phosphorylation at its serine-proline-rich region (SPRR), a domain previously shown to be essential for regulation of hyphal growth, only at a paradoxical-growth concentration of caspofungin. Our results indicate that as opposed to micafungin, the increased [Ca(2+)]c at high concentrations of caspofungin activates calmodulin-calcineurin signaling at both a transcriptional and a posttranslational level and ultimately leads to paradoxical fungal growth. PMID- 26055380 TI - Molecular Markers and In Vitro Susceptibility to Doxycycline in Plasmodium falciparum Isolates from Thailand. AB - Determinations of doxycycline 50% inhibitory concentrations (IC50) for 620 isolates from northwest Thailand were performed via the isotopic method, and the data were analyzed by the Bayesian method and distributed into two populations (mean IC50s of 13.15 MUM and 31.60 MUM). There was no significant difference between the group with low IC50s versus the group with high IC50s with regard to copy numbers of the Plasmodium falciparum tetQ (pftetQ) gene (P = 0.11) or pfmdt gene (P = 0.87) or the number of PfTetQ KYNNNN repeats (P = 0.72). PMID- 26055381 TI - Mode of action and bactericidal properties of surotomycin against growing and nongrowing Clostridium difficile. AB - Surotomycin (CB-183,315), a cyclic lipopeptide, is in phase 3 clinical development for the treatment of Clostridium difficile infection. We report here the further characterization of the in vitro mode of action of surotomycin, including its activity against growing and nongrowing C. difficile. This was assessed through time-kill kinetics, allowing a determination of the effects on the membrane potential and permeability and macromolecular synthesis in C. difficile. Against representative strains of C. difficile, surotomycin displayed concentration-dependent killing of both logarithmic-phase and stationary-phase cultures at a concentration that was <=16* the MIC. Exposure resulted in the inhibition of macromolecular synthesis (in DNA, RNA, proteins, and cell wall). At bactericidal concentrations, surotomycin dissipated the membrane potential of C. difficile without changes to the permeability of propidium iodide. These observations are consistent with surotomycin acting as a membrane-active antibiotic, exhibiting rapid bactericidal activities against growing and nongrowing C. difficile. PMID- 26055382 TI - Structural Insights into Binding of the Antifungal Drug Fluconazole to Saccharomyces cerevisiae Lanosterol 14alpha-Demethylase. AB - Infections by fungal pathogens such as Candida albicans and Aspergillus fumigatus and their resistance to triazole drugs are major concerns. Fungal lanosterol 14alpha-demethylase belongs to the CYP51 class in the cytochrome P450 superfamily of enzymes. This monospanning bitopic membrane protein is involved in ergosterol biosynthesis and is the primary target of azole antifungal drugs, including fluconazole. The lack of high-resolution structural information for this drug target from fungal pathogens has been a limiting factor for the design of modified triazole drugs that will overcome resistance. Here we report the X-ray structure of full-length Saccharomyces cerevisiae lanosterol 14alpha-demethylase in complex with fluconazole at a resolution of 2.05 A. This structure shows the key interactions involved in fluconazole binding and provides insight into resistance mechanisms by revealing a water-mediated hydrogen bonding network between the drug and tyrosine 140, a residue frequently found mutated to histidine or phenylalanine in resistant clinical isolates. PMID- 26055383 TI - In Vitro Antimalarial Activity of Different Inhibitors of the Plasmodial Isoprenoid Synthesis Pathway. AB - Previous studies have shown that fosmidomycin, risedronate, and nerolidol exert antimalarial activity in vitro. We included squalestatin, an inhibitor of the isoprenoid metabolism in Erwinia uredovora, and found that combinations of compounds which act on different targets of the plasmodial isoprenoid pathway possess important supra-additivity effects. PMID- 26055384 TI - Characterization of BKC-1 class A carbapenemase from Klebsiella pneumoniae clinical isolates in Brazil. AB - Three Klebsiella pneumoniae clinical isolates demonstrating carbapenem resistance were recovered from different patients hospitalized at two medical centers in Sao Paulo, Brazil. Resistance to all beta-lactams, quinolones, and some aminoglycosides was observed for these isolates that were susceptible to polymyxin B. Carbapenem hydrolysis, which was inhibited by clavulanic acid, was observed for all K. pneumoniae isolates that belonged to the same pulsed-field gel electrophoresis (PFGE) type and a novel sequence type (ST), ST1781 (clonal complex 442 [CC442]). A 10-kb nonconjugative incompatibility group Q (IncQ) plasmid, denominated p60136, was transferred to Escherichia coli strain TOP10 cells by electroporation. The full sequencing of p60136 showed that it was composed of a mobilization system, ISKpn23, the phosphotransferase aph3A-VI, and a 941-bp open reading frame (ORF) that codified a 313-amino acid protein. This ORF was named bla BKC-1. Brazilian Klebsiella carbapenemase-1 (BKC-1) showed a pI of 6.0 and possessed the highest identity (63%) with a beta-lactamase of Sinorhizobium meliloti, an environmental bacterium. Hydrolysis studies demonstrated that purified BKC-1 not only hydrolyzed carbapenems but also penicillins, cephalosporins, and monobactams. However, the carbapenems were less efficiently hydrolyzed due to their very low kcat values (0.0016 to 0.031 s(-1)). In fact, oxacillin was the best substrate for BKC-1 (kcat /Km , 53,522.6 mM(-1) s(-1)). Here, we report a new class A carbapenemase, confirming the diversity and rapid evolution of beta-lactamases in K. pneumoniae clinical isolates. PMID- 26055385 TI - Relative Strengths of Promoters Provided by Common Mobile Genetic Elements Associated with Resistance Gene Expression in Gram-Negative Bacteria. AB - Comparison of green fluorescent protein expression from outward-facing promoters (POUT) of ISAba1, ISEcp1, and ISAba125 revealed approximate equivalence in strength, intermediate between PCS (strong) and PCWTGN-10 (weak) class 1 integron promoter variants, >30-fold stronger than POUT of ISCR1, and >5 times stronger than Ptac. Consistent with its usual role, PCWTGN-10 produces more mRNA from a "downstream" gfp gene transcriptionally linked to a "usual" PCWTGN-10-associated gene cassette than does POUT of ISAba1. PMID- 26055386 TI - In vitro antifungal activity of ME1111, a new topical agent for onychomycosis, against clinical isolates of dermatophytes. AB - The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interactions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight enhances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC (n = 400) and the minimum fungicidal concentration (MFC) (n = 300). Additionally, we examined the potential for resistance development in dermatophytes (n = 4) following repeated exposure to ME1111. Our data show that the MIC90 of ME1111 against dermatophyte strains was 0.25 MUg/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 MUg/ml, respectively). ME1111 was fungicidal at clinically achievable concentrations against dermatophytes, and its MFC90s against Trichophyton rubrum and Trichophyton mentagrophytes were 8 MUg/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes. PMID- 26055387 TI - The effect of limb dominance on lower limb functional performance--a systematic review. AB - Lower limb dominance (or lateral preference) could potentially effect functional performance. Clinicians are often asked to make judgements as to when a patient has sufficiently "recovered" from an injury, typically using strength and dynamic performance outcome measures. The primary purpose of this study was to systematically review the literature in relation to limb dominance within active adult populations and discuss some limitations to current methods and relate this to current clinical practice. A search of MEDLINE and CINAHL and EMBASE databases and reference lists of those articles identified was performed. Eleven articles were selected for meta-analysis. There was no statistical effect of limb dominance for any of the functional tests: isokinetic quadriceps and hamstring tests, hamstring:quadriceps ratios, single-leg hop for distance, single-leg vertical jump and vertical ground reaction force following a single-leg vertical jump. Pooled symmetry values varied from 94.6% to 99.6% across the tests, above the clinically accepted benchmark of 90% used in clinical practice. Although the results of this study must be used with discretion, asymmetries in the tasks described in this analysis should be viewed as undesirable and remedied accordingly. Further research is needed to quantify asymmetries, particularly in relation to sport-specific contexts. PMID- 26055388 TI - Bifunctional ligands in combination with phosphines and Lewis acidic phosphonium [corrected] for the carbonylative Sonogashira reaction. AB - The combination of phosphine-ligated Pd catalysis and phosphonium(V) [corrected] Lewis acid catalysis has been developed for the carbonylative Sonogashira reaction using phosphino-phosphonium [corrected] salts (L1-L4) as bifunctional ligands, in which the Lewis acidic phosphonium(V) [corrected] cations can form secondary bonds with O atoms (in C=O) to cooperatively stabilize Pd-acyl intermediates. PMID- 26055389 TI - The Role of Overconfidence in Romantic Desirability and Competition. AB - Four studies and a computer simulation tested the hypothesis that people who are overconfident in their self-assessments may be more successful in attracting mates. In Study 1, overconfident people were perceived as more confident in their dating profiles, and this perceived confidence predicted increased romantic desirability. Study 2 revealed that overconfident people also tend to be perceived as arrogant, which counteracts the positive effects of perceived confidence. However, Study 3 revealed that overconfidence might confer an advantage in intrasexual competition, as people were less likely to compete with overconfident individuals by virtue of their perceived confidence and arrogance. Study 4 showed that overconfident raters were also more likely to choose to compete for romantic partners. In Study 5, agent-based modeling incorporating the coefficients from these studies suggested that overconfidence facilitates mate acquisition in the presence of intrasexual competition. PMID- 26055390 TI - Seedling development traits in Brassica napus examined by gene expression analysis and association mapping. AB - BACKGROUND: An optimal seedling development of Brassica napus plants leads to a higher yield stability even under suboptimal growing conditions and has therefore a high importance for plant breeders. The objectives of our study were to (i) examine the expression levels of candidate genes in seedling leaves of B. napus and correlate these with seedling development as well as (ii) detect genome regions associated with gene expression levels and seedling development traits in B. napus by genome-wide association mapping. RESULTS: The expression levels of the 15 candidate genes examined in the 509 B. napus inbreds showed an averaged standard deviation of 5.6 across all inbreds and ranged from 3.2 to 8.8. The gene expression differences between the 509 B. napus inbreds were more than adequate for the correlation with phenotypic variation of seedling development. The average of the absolute value correlations of the correlation coefficients of 0.11 were observed with a range from 0.00 to 0.39. The candidate genes GER1, AILP1, PECT, and FBP were strongly correlated with the seedling development traits. In a genome-wide association study, we detected a total of 63 associations between single nucleotide polymorphisms (SNPs) and the seedling development traits and 31 SNP-gene associations for the candidate genes with a P value < 0.0001. For the projected leaf area traits we identified five different association hot spots on the chromosomes A2, A7, C3, C6, and C7. CONCLUSION: A total of 99.4% of the adjacent SNPs on the A genome and 93.0% of the adjacent SNPs on the C genome had a distance smaller than the average range of linkage disequilibrium. Therefore, this genome-wide association study is expected to result on average in 14.7% of the possible power. Compared to previous studies in B. napus, the SNP marker density of our study is expected to provide a higher power to detect SNP-trait/-gene associations in the B. napus diversity set. The large number of associations detected for the examined 14 seedling development traits indicated that these are genetically complex inherited. The results of our analyses suggested that the studied genes ribulose 1,5-bisphosphate carboxylase/oxygenase small subunit (RBC) on the chromosomes A4 and C4 and fructose-1,6-bisphosphatase precursor (FBP) on the chromosomes A9 and C8 are cis regulated. PMID- 26055391 TI - Treatment satisfaction and quality-of-life between type 2 diabetes patients initiating long- vs. intermediate-acting basal insulin therapy in combination with oral hypoglycemic agents--a randomized, prospective, crossover, open clinical trial. AB - BACKGROUND: Pharmacological and clinical differences between insulin glargine and NPH insulin may translate into differences in patient reported outcomes, but existing data are equivocal. METHODS: In this 48-week, open-label, randomized, multi-center, crossover phase IV trial, insulin naive type 2 diabetes patients with blood glucose not at target on oral hypoglycemic agents had basal insulin added to their treatment regimen. A total of 343 patients were randomized to either receive insulin glargine (n = 176; sequence A) or neutral protamine Hagedorn (NPH) insulin (n = 167; sequence B) in period 1 (weeks 1-24) and vice versa in period 2 (weeks 25-48). The primary objective was to assess patient reported outcomes using a composite Diabetes Related Quality of Life (DRQoL) score based on an unweighted Insulin Treatment Experience Questionnaire (ITEQ) score, a Problem Areas in Diabetes (PAID) questionnaire score, and the mental health score in the Short Form (SF)-12(r) Health Survey, analyzed by analysis of covariance (ANCOVA). RESULTS: Patients (mean age 62.3 +/- 9.0; 39.5 % female) had a mean diabetes duration of 9.6 +/- 5.9 years, a mean baseline HbA1c of 8.15 +/- 0.72 %, and a mean fasting blood glucose (FBG) level of 9.37 +/- 2.19 mmol/L. A total of 229 patients were available for primary endpoint evaluation (modified intention to treat population). Combining all data from both periods for each insulin treatment, on a 0-100 scale, the mean DRQoL score was 69.6 (+/-9.04) with insulin glargine and 70.0 (+/-9.40) with NPH insulin. Neither an effect of treatment with insulin glargine vs NPH insulin (p = 0.31) nor a period effect (p = 0.96), nor a sequence effect (p = 0.76) was observed using ANCOVA. CONCLUSIONS: The results show that in a patient population with sub-optimal glycemic control at baseline, and a low target achievement rate together with a low rate of hypoglycemia, differences in the patient reported outcomes evaluated in this study were negligible between insulin glargine and NPH insulin. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00941369. PMID- 26055392 TI - Acute Bacterial Skin and Skin Structure Infections Treated with Intravenous Antibiotics in the Emergency Department or Observational Unit: Experience at the Detroit Medical Center. AB - INTRODUCTION: Acute bacterial skin and skin structure infections (ABSSSIs) are frequently treated in emergency departments (EDs) or observation units (OUs) initially with intravenous (IV) antibiotics before discharge on oral therapy. This study aims to describe ABSSSI patients discharged directly from EDs/OUs. METHODS: This is a retrospective cohort study of patients with ABSSSIs treated in EDs/OUs of the Detroit Medical Center from 2012 to 2014. Adults with less than 24 h of IV antibiotics without hospital admission were included. Demographics, clinical characteristics, and severity were compared between ED and OU patients. Resource utilization, including tissue and blood cultures, and use of radiographic analysis was also collected. The primary outcome was 96-h ED revisit/hospitalization. RESULTS: Analysis included 308 patients; 219 ED and 89 OU. OU patients were significantly more likely to be obese, have COPD/asthma, be diagnosed with cellulitis, and meet at least one systemic inflammatory response syndrome (SIRS) criterion. Tissue cultures were obtained in 21.7% of abscesses in the ED; 67.9% were in uncomplicated abscesses. In the OU tissue cultures were obtained in 48.8% of abscesses and 37.5% were uncomplicated cases. Blood cultures were drawn in 18.3% of ED patients and 56.2% of OU patients, not significantly associated with the presence of SIRS criteria. Radiology was used in the diagnosis of ABSSSIs in 33.5% of ED versus 69.5% OU patients (p < 0.001), Plain film radiograph being the most common. Thirty patients revisited the ED or required hospitalization within 96 h, 23 from the ED (p = 0.479). Prior history of ABSSSI (adjusted odds ratio [aOR] = 2.382, 95% confidence interval [CI] 1.264 6.346) and location on torso/buttocks (aOR = 2.355, 95% CI 1.067-5.197) were independent predictors. CONCLUSIONS: The low rate of ED revisit/hospitalization supports the use of OUs for low acuity ABSSSIs requiring initial IV therapy. Resource utilization within EDs/OUs for the management of ABSSSIs needs to be evaluated for unnecessary testing/procures. PMID- 26055393 TI - Effectiveness of teleassistance at improving quality of life in people with neuromuscular diseases. AB - Rare neuromuscular diseases (NDs) are a group of inherited or acquired neurological pathologies affecting the muscles and the nervous system. Their low prevalence and high geographical dispersion can cause isolation and difficulties in social interaction between affected equals. New technologies, such as videoconferencing, offer a complementary option for improving the health of this population. The purpose of this study was to assess the effectiveness of a teleassistance program at improving health-related quality of life (HRQoL) through social interaction in adults with NDs. The sample consisted of 45 participants affected by rare NDs. Twenty-four participants were assigned to the experimental group (EG), which participated in the videoconferencing sessions, and 21 to the control group. Three questionnaires were administered: WHO-DAS II, Sickness Impact Profile, and SF-36 Health Survey. Effectiveness was assessed by a pre-post design. An online psychosocial program was applied over three-month period. Data revealed an improvement of the EG in psychosocial variables, e.g. "Getting along with people" (z = -2.289, r = -.47, p <= .05) or "Psychosocial Domain" (z = -2.404, r = -.49, p <= .05), and in physical variables, e.g. "Life activities" (z = -2.844, r = -.58, p <= .05). Social interaction appeared as a relevant factor at improving HRQoL levels. High levels of satisfaction about the teleassistance program were reported. PMID- 26055394 TI - A computational study of diffusion in a glass-forming metallic liquid. AB - Liquid phase diffusion plays a critical role in phase transformations (e.g. glass transformation and devitrification) observed in marginal glass forming systems such as Al-Sm. Controlling transformation pathways in such cases requires a comprehensive description of diffusivity, including the associated composition and temperature dependencies. In the computational study reported here, we examine atomic diffusion in Al-Sm liquids using ab initio molecular dynamics (AIMD) and determine the diffusivities of Al and Sm for selected alloy compositions. Non-Arrhenius diffusion behavior is observed in the undercooled liquids with an enhanced local structural ordering. Through assessment of our AIMD result, we construct a general formulation for Al-Sm liquid, involving a diffusion mobility database that includes composition and temperature dependence. A Volmer-Fulcher-Tammann (VFT) equation is adopted for describing the non Arrhenius behavior observed in the undercooled liquid. The composition dependence of diffusivity is found quite strong, even for the Al-rich region contrary to the sole previous report on this binary system. The model is used in combination with the available thermodynamic database to predict specific diffusivities and compares well with reported experimental data for 0.6 at.% and 5.6 at.% Sm in Al Sm alloys. PMID- 26055395 TI - Perceived Experience of Fatigue in Clinical and General Population: Descriptors and Associated Reactivities. AB - The aim of this study is the analysis of different descriptors and reactions related to the experience of fatigue. Two groups were compared: a clinical sample (n = 92, 31 males, mean age = 38.87) and a non-clinical (n = 225, 135 males, mean age = 32.45) sample. The total sample was composed of 317 participants (52% males), ranging in age from 18 to 76 years. Findings show the experience of fatigue was mainly related to somatic terms (76% of the total sample). Specific results were found only for the clinical group: (a) significant relationships between fatigue and anxiety, chi2(1) = 34.71, p < .01; tension, chi2(1) = 16.80, p < .01; and sadness, chi2(1) = 24.59, p < .01; (b) higher intensity of fatigue (F = 84.15, p = .001), and predominance of the cognitive components of fatigue. Results showed that fatigue in subjects with a clinical disorder (versus those without) was associated both, to negative emotional states, and to a higher intensity of fatigue, especially in its cognitive elements. Important clinical implications for its assessment and intervention are discussed. PMID- 26055396 TI - Teaching old drugs new tricks: Addressing resistance in Francisella. PMID- 26055397 TI - Tanzawaic acids isolated from a marine-derived fungus of the genus Penicillium with cytotoxic activities. AB - Tanzawaic acids M (1), N (2), O (3) and P (4) and the known tanzawaic acids B (5) and E (6), have been isolated from an extract of a cultured marine-derived fungus (strain CF07370) identified as a member of the genus Penicillium. The structures of 1-4 were determined based on spectroscopic evidence. The antimicrobial and cytotoxic activities of compounds 1-6 were evaluated. PMID- 26055398 TI - Cardiac metabolomics and autopsy in a patient with early diffuse systemic sclerosis presenting with dyspnea: a case report. AB - INTRODUCTION: Diffuse systemic sclerosis is associated with high mortality; however, the pathogenesis of cardiac death in these patients is not clear. CASE PRESENTATION: A 56-year-old Caucasian female patient presented with dyspnea and requested to donate her body to science in order to improve understanding of diffuse systemic sclerosis pathogenesis. She had extensive testing for dyspnea including pulmonary function tests, an echocardiogram, cardiac magnetic resonance imaging, and right heart catheterization to characterize her condition. Her case highlights the morbidity seen in this disease, including the presence of extensive skin thickening, digital ulcerations, and scleroderma renal crisis. CONCLUSION: In this case report, we present the finding of cardiac tissue metabolomics, which may indicate a problem with vasodilation as a contributor to cardiac death in diffuse systemic sclerosis. The use of autopsy and tissue metabolomics in rare disease may help clarify disease pathogenesis. PMID- 26055399 TI - Antibiotic-laden PMMA bead chains for the prevention of infection in compound fractures: current state of the art. AB - Antibiotic-laden PMMA bead chains are a valuable method of local antibiotic treatment in the prevention of infection in open fractures. When used in this setting, they provide high concentrations of broad-spectrum antibiotics to the area of the highest risk which may not be well perfused or reached by systemic antibiotics, while also eliminating dead space. In this article, the historical and current state of antibiotic-laden bead chains is discussed. The literature provides evidence that antibiotic-laden bead chains are a useful adjuvant with systemic antibiotics in the prevention of infection in open fractures. These bead chains can be sterilely prepared in the operating room or manufactured, and they maintain their elution and antimicrobial properties for a considerable time period. The bead chains also allow a high local concentration of antibiotics without risk of systemic toxicity or fear of clinically significant growth or persistence of bacteria on the beads. Bead chains are a practical method of local antibiotic therapy when the wounds can be closed. PMID- 26055401 TI - Determining what should be included in a publicly funded health care system: reflecting on 'Individual responsibility for what? A conceptual framework for exploring the suitability of private financing in a publicly funded health-care system'. PMID- 26055400 TI - Efficacy and safety of acupuncture for dizziness and vertigo in emergency department: a pilot cohort study. AB - BACKGROUND: Dizziness and vertigo account for roughly 4% of chief symptoms in the emergency department (ED). Pharmacological therapy is often applied for these symptoms, such as vestibular suppressants, anti-emetics and benzodiazepines. However, every medication is accompanied with unavoidable side-effects. There are several research articles providing evidence of acupuncture treating dizziness and vertigo but few studies of acupuncture as an emergent intervention in ED. We performed a pilot cohort study to evaluate the efficacy and safety of acupuncture in treating patients with dizziness and vertigo in ED. METHODS: A total of 60 participants, recruited in ED, were divided into acupuncture and control group. Life-threatening conditions or central nervous system disorders were excluded to ensure participants' safety. The clinical effect of treating dizziness and vertigo was evaluated by performing statistical analyses on data collected from questionnaires of Dizziness Handicap Inventory (DHI), Visual Analog Scale (VAS) of dizziness and vertigo, and heart rate variability (HRV). RESULTS: The variation of VAS demonstrated a significant decrease (p-value: 0.001 and p-value: 0.037) between two groups after two different durations: 30 mins and 7 days. The variation of DHI showed no significant difference after 7 days. HRV revealed a significant increase in high frequency (HF) in the acupuncture group. No adverse event was reported in this study. CONCLUSION: Acupuncture demonstrates a significant immediate effect in reducing discomforts and VAS of both dizziness and vertigo. This study provides clinical evidence on the efficacy and safety of acupuncture to treat dizziness and vertigo in the emergency department. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02358239 . Registered 5 February 2015. PMID- 26055402 TI - A New Vision for the Eye: Unmet Ocular Drug Delivery Needs. PMID- 26055403 TI - Physico-Mechanical Properties of Coprocessed Excipient MicroceLac(r) 100 by DM(3) Approach. AB - PURPOSE: To determine the effect of relative humidity (RH) and hydroxypropyl methylcellulose (HPMC) on the physico-mechanical properties of coprocessed MacroceLac((r)) 100 using 'DM(3)' approach. METHODS: Effects of RH and 5% w/w HPMC on MacroceLac((r)) 100 Compressibility Index (CI) and tablet mechanical strength (TMS) were evaluated by 'DM(3)'. The 'DM(3)' approach evaluates material properties by combining 'design of experiments', material's 'macroscopic' properties, 'molecular' properties, and 'multivariate analysis' tools. A 4X4 full factorial experimental design was used to study the relationship of MacroceLac((r)) 100 molecular properties (moisture content, dehydration, crystallization, fusion enthalpy, and moisture uptake) and macroscopic particle size and shape on CI and TMS. A physical binary mixture (PBM) of similar composition to MacroceLac((r)) 100 was also evaluated. Multivariate analysis of variance (MANOVA), principle component analysis, and partial least squares (PLS) were used to analyze the data. RESULTS: MANOVA CI ranking was: PBM-HPMC > PBM > MicroceLac((r))100 > MicroceLac((r))100-HPMC (p < 0.0001). MANOVA showed PBM's and PBM-HPMC's TMS values were lower than MicroceLac((r))100 and MicroceLac((r))100-HPMC (p < 0.0001). PLS showed that % RH, HPMC, and several molecular properties significantly affected CI and TMS. CONCLUSIONS: Significant MicroceLac((r))100 changes occurred with % RH exposure affecting performance attributes. HPMC physical addition did not prevent molecular or macroscopic matrix changes. PMID- 26055404 TI - Erratum to: Curdlan-conjugated PLGA Nanoparticles possess macrophage stimulant activity and drug delivery capabilities. PMID- 26055405 TI - Molecular Oxygen and Reactive Oxygen Species in Bread-making Processes: Scarce, but Nevertheless Important. AB - In bread making, O2 is consumed by flour constituents, yeast, and, optionally, some additives optimizing dough processing and/or product quality. It plays a major role especially in the oxidation/reduction phenomena in dough, impacting gluten network structure. The O2 level is about 7.2 mmol/kg dough, of which a significant part stems from wheat flour. We speculate that O2 is quickly lost to the atmosphere during flour hydration. Later, when the gluten network structure develops, some O2 is incorporated in dough through mixing-in of air. O2 is consumed by yeast respiration and in a number of reactions catalyzed by a wide range of enzymes present or added. About 60% of the O2 consumption in yeastless dough is ascribed to oxidation of fatty acids by wheat lipoxygenase activity. In yeasted dough, about 70% of the O2 in dough is consumed by yeast and wheat lipoxygenase. This would leave only about 30% for other reactions. The severe competition between endogenous (and added) O2-consuming systems impacts the gluten network. Moreover, the scarce literature data available suggest that exogenous oxidative enzymes but not those in flour may promote crosslinking of arabinoxylan in yeastless dough. In any case, dough turns anaerobic during the first minutes of fermentation. PMID- 26055406 TI - The visual amplification of goal-oriented movements counteracts acquired non-use in hemiparetic stroke patients. AB - BACKGROUND: Stroke-induced impairments result from both primary and secondary causes, i.e. damage to the brain and the acquired non-use of the impaired limbs. Indeed, stroke patients often under-utilize their paretic limb despite sufficient residual motor function. We hypothesize that acquired non-use can be overcome by reinforcement-based training strategies. METHODS: Hemiparetic stroke patients (n = 20, 11 males, 9 right-sided hemiparesis) were asked to reach targets appearing in either the real world or in a virtual environment. Sessions were divided into 3 phases: baseline, intervention and washout. During the intervention the movement of the virtual representation of the patients' paretic limb was amplified towards the target. RESULTS: We found that the probability of using the paretic limb during washout was significantly higher in comparison to baseline. Patients showed generalization of these results by displaying a more substantial workspace in real world task. These gains correlated with changes in effector selection patterns. CONCLUSIONS: The amplification of the movement of the paretic limb in a virtual environment promotes the use of the paretic limb in stroke patients. Our findings indicate that reinforcement-based therapies may be an effective approach for counteracting learned non-use and may modulate motor performance in the real world. PMID- 26055407 TI - Associations of chemo- and radio-resistant phenotypes with the gap junction, adhesion and extracellular matrix in a three-dimensional culture model of soft sarcoma. AB - BACKGROUND: Three-dimensional (3D) culture models are considered to recapitulate the cell microenvironment in solid tumors, including the extracellular matrix (ECM), cell-cell interactions, and signal transduction. These functions are highly correlated with cellular behaviors and contribute to resistances against chemo- and radio-therapies. However, the biochemical effects and mechanisms remain unknown in soft sarcoma. Therefore, we developed an in vitro 3D model of sarcoma to analyze the reasons of the chemo- and radio-resistance in therapies. METHODS: Four soft sarcoma cell lines, HT1080, RD, SW872, and human osteosarcoma cell line 1 (HOSS1), a cell line established from a patient-derived xenograft, were applied to 3D culture and treated with growth factors in methylcellulose containing medium. Spheroids were examined morphologically and by western blotting, RT-qPCR, and immunofluorescence staining to analyze cell adhesion, gap junctions, ECM genes, and related factors. Proliferation and colony formation assays were performed to assess chemo- and radio-resistances between 3D and two dimensional (2D) cell cultures. Annexin V and Propidium Iodide staining was used to detect early apoptotic sarcoma cells treated with Doxorubicin, Gemcitabine, and Docetaxel in the 3D model. RESULTS: The four soft sarcoma cell lines formed spheres in vitro by culture in modified condition medium. Compared with 2D cell culture, expression of ECM genes and proteins, including COL1A1, LOX, SED1, FN1, and LAMA4, was significantly increased in 3D culture. Analysis of cadherin and gap junction molecules showed significant changes in the gene and protein expression profiles under 3D conditions. These changes affected cell-cell communication and were mainly associated with biological processes such as cell proliferation and apoptosis related to chemo- and radio-resistances. CONCLUSIONS: Our findings revealed significant differences between 3D and 2D cell culture systems, and indicated that cellular responsiveness to external stress such as radiation and chemotherapeutics is influenced by differential expression of genes and proteins involved in regulation of the ECM, cell adhesion, and gap junction signaling. PMID- 26055408 TI - Should bone scintigraphy be used as a routine adjunct to skeletal survey in the imaging of non-accidental injury? A 10 year review of reports in a single centre. AB - AIM: To retrospectively analyse the bone scintigraphy (BS) and skeletal survey (SS) data to evaluate the role and limitations of BS in the diagnosis of non accidental injury (NAI). MATERIALS AND METHODS: All SS and BS performed over a 10 year period, for possible NAI, in children under 2 years old were retrospectively reviewed. Reports were compared in cases where both studies were performed and findings classified into one of three groups: (1) congruent: both reports agreed; (2) BS added confidence to the SS findings; (3) BS demonstrated a new finding. False-positive and false-negative rates for BS were calculated. RESULTS: One hundred and sixty-six patients had both SS and BS. The findings were congruent in 74% of cases. BS added confidence to the SS findings in 8% and revealed a new abnormality in 4% of patients. BS demonstrated false-positive and -negative rates of 2% and 13%, respectively. Occult bony injury was detected in 12% of the 237 patients imaged. DISCUSSION: When used as an adjunct to SS in the investigation of NAI, BS can aid the confidence of diagnosis or identify new findings in 12% of cases. In centres where nuclear medicine is readily available and there is appropriate expertise in paediatric BS, this modality provides a time-effective alternative to follow-up SS at 10-14 days. PMID- 26055409 TI - Comparison of plain radiography and CT in postoperative evaluation of ankle fractures. AB - AIM: To compare postoperative plain radiographs with computed tomography (CT) post-processing images in evaluating the quality of anatomical reduction and internal fixation of ankle fractures. MATERIALS AND METHODS: A total of 168 patients who sustained closed ankle fracture and were treated with open reduction and internal fixation in East Hospital were reviewed. Postoperative plain radiographs and CT post-processing images were evaluated. The observation was performed under volume-rendering mode and multiplanar reconstruction mode. The assessment was performed by two independent orthopaedic surgeons. The inter- and intra-observer variations were analysed by kappa statistics. The differences between plain radiographs and CT post-processing images were compared using chi(2) test (McNemar's test). RESULTS: Inter- and intra-observer agreement was almost perfect (0.813-1.000) using CT post-processing images, which was higher than that using plain radiographs (0.323-0.848). More non-anatomical reduction could be recognised in the supination-external rotation (SER), supination adduction (SAD), pronation-external rotation (PER), and overall groups (p<0.05) and more poor internal fixation could be recognised in the SER, SAD, and overall groups (p<0.05) using CT post-processing images than using radiographs. CONCLUSION: More residual articular step, fracture fragment displacement, and poor internal fixation could be detected by CT post-processing images than plain radiographs. PMID- 26055410 TI - Cultural activity participation and associations with self-perceived health, life satisfaction and mental health: the Young HUNT Study, Norway. AB - BACKGROUND: Leisure time activities and culture participation may have health effects and be important in pulic health promotion. More knowledge on how cultural activity participation may influence self-perceived health, life satisfaction, self-esteem and mental health is needed. METHODS: This article use data from the general population-based Norwegian HUNT Study, using the cross sectional Young-HUNT3 (2006-08) Survey including 8200 adolescents. Data on cultural activity participation, self-perceived health, life-satisfaction, self esteem, anxiety and depression were collected by self-reported questionnaires. RESULTS: Both attending meetings or training in an organisation or club, and attending sports events were positively associated with each of the health parameters good self-percieved health, good life-satisfaction, good self-esteem, and low anxiety and depression symptoms. We found differences according to gender and age (13-15 years versus 16-19 years old) for several culture activities, where girls aged 16-19 years seemed to benefit most from being culturally active. The extent of participation seemed to matter. Those who had frequent participation in cultural activities reported better health outcomes compared to inactive adolecents. CONCLUSIONS: The results from this study indicate that participation in cultural activities may be positively associated with health, life-satisfaction and self-esteem in adolescents and thus important in public health promotion. Possible sex and age differences should be taken into account. PMID- 26055411 TI - Munchausen syndrome mimicking baboon syndrome. PMID- 26055412 TI - Supplementing Dental Student Education. PMID- 26055413 TI - What is hot in infectious diseases? PMID- 26055414 TI - Group B streptococcus neonatal invasive infections, France 2007-2012. AB - Streptococcus agalactiae (group B streptococcus (GBS)) is the leading cause of invasive infections among newborns in industrialized countries, with two described syndromes: early-onset disease (EOD) and late-onset disease (LOD). Since the introduction in many countries of intrapartum antibioprophylaxis (IAP), the incidence of EOD has dramatically decreased, whereas that of LOD remains unchanged. We describe the clinical and bacteriological characteristics of 438 GBS neonatal invasive infections notified to the French National Reference Centre for Streptococci in France from 2007 to 2012. Clinical data were retrieved from hospitalization reports or questionnaires. Capsular type, assignment to the hypervirulent clonal complex (CC)17 and antibiotic susceptibility profiles were determined. One hundred and seventy-four (39.7%) and 264 (60.3%) isolates were responsible for EOD, including death in utero, and LOD, respectively. EOD was associated with bacteraemia (n = 103, 61%) and LOD with meningitis (n = 145, 55%). EOD was mainly due to capsular polysaccharide (CPS) III isolates (n = 99, 57%) and CPS Ia isolates (n = 40, 23%), and CPS III isolates were responsible for 80% (n = 211) of LOD cases. CC17 accounted for 80% (n = 121) of CPS III isolates responsible for meningitis (n = 151; total cases of meningitis, 188). Bad outcome risk factors were low gestational age and low birthweight. LOD represents almost 60% of cases of neonatal GBS disease in France and other countries in which IAP has been implemented. This observation reinforces the need to develop new prevention strategies targeting CC17, which is predominant in GBS neonatal infections. PMID- 26055415 TI - How to best measure the effectiveness of male human papillomavirus vaccine programmes? AB - In many countries now, vaccination of young adolescent girls with prophylactic human papillomavirus (HPV) vaccines has been rolled out as a public health programme. In countries where coverage has been high, this has led to dramatic reductions in cervical high-grade precancerous lesions, as well as genital warts. A reduction in circulating vaccine-related HPV types has also been demonstrated. With the introduction of gender-neutral approaches incorporating universal vaccination of pre-adolescent boys in some countries, implementation of post vaccine monitoring will be critical to evaluate the incremental impact of male vaccination. In contrast to cervical screening programmes, population-wide screening for HPV infection or related disease in males is not recommended; hence real-time monitoring of HPV vaccine effectiveness in males will require dedicated surveillance strategies. Monitoring the prevalence of circulating genital HPV types using a sentinel surveillance model could offer a good surrogate marker of early vaccine effectiveness in males. However, such an approach requires careful consideration of the most appropriate anatomical sites from which to collect specimens, the best sampling methods and the most sensitive assays to use. Additionally, in assessing an accurate measure of the impact of HPV vaccination in the male population, the effect of herd protection will need to be assessed, as most male programmes will commence in the setting of established female programmes. This poses an interesting epidemiological challenge. PMID- 26055416 TI - Accurate genotyping of hepatitis C virus through nucleotide sequencing and identification of new HCV subtypes in China population. AB - Nucleotide sequencing of the phylogenetically informative region of NS5B remains the gold standard for hepatitis C virus (HCV) genotyping. Here we developed a new methodology for sequencing new NS5B regions to increase the accuracy and sensitivity of HCV genotyping and subtyping. The eight new primers were identified by scanning the full-length NS5B regions from 1127 HCV genomic sequences found in HCV databases. The ability of each pair of primers to amplify HCV subtypes was scored, and the new primers were able to amplify the NS5B region better than the previously used primers, therefore more accurately subtyping HCV strains. Sequencing the DNA amplified by the new primer pairs can specifically and correctly detect the five standard HCV subtypes (1a, 2a, 3b, 6a and 1b). We further examined patient samples and found that the new primers were able to identify HCV subtypes in clinical samples with high sensitivity. This method was able to detect all subtypes of HCV in 567 clinical samples. Importantly, three novel HCV subtypes (1b-2a, 1b-2k and 6d-6k) were identified in the samples, which have not been previous reported in China. In conclusion, sequencing the NS5B region amplified by the new NS5B primers is a more reliable method of HCV genotyping and a more sensitive diagnostic tool than sequencing using the previously described primers, and could identify new HCV subtypes. Our research is useful for clinical diagnosis, guidance of clinical treatment, management of clinical patients, and studies on the epidemiology of HCV. PMID- 26055417 TI - Close genetic relationship between Salmonella enterica serovar Enteritidis isolated from patients with diarrhoea and poultry in the Republic of Korea. PMID- 26055418 TI - Immunosuppression and Chagas disease; experience from a non-endemic country. AB - Reactivation of Chagas disease in the chronic phase may occur when immunosuppression is established, sometimes resulting in high parasitaemia and severe clinical manifestations such as meningitis and meningoencephalitis. Although this situation is being increasingly described, there is still scarce information. This retrospective observational study was performed in three Tropical Medicine Units of Barcelona (Spain) included in the International Health Programme of the Catalan Health Institute (PROSICS). The objective of the study was to describe epidemiological, clinical, microbiological, prognostic and therapeutic data from patients with Chagas disease and any kind of immunosuppressive condition attended in these three institutions from January 2007 to October 2014. From 1823 patients with Chagas disease attending these three centres during the study period, 38 (2%) had some kind of immunosuppressive condition: 12 patients had human immunodeficiency virus infection, 8 patients had neoplasia, 4 patients underwent organ transplantation and 14 patients had an autoimmune disease. Eight (21.1%) patients had cardiac involvement, and six (15.8%) patients had gastrointestinal involvement. Acute Trypanosoma cruzi infection was detected in two Spanish patients. Thirty-one (81.6%) patients received treatment with benznidazole, of whom 17 (54.8%) had some kind of adverse event. No patient had a severe manifestation or reactivation of Chagas disease. Patients with Chagas disease under immunosuppressive conditions are being increasingly described, especially in non-endemic countries. More information about this topic is required and international consensus in the diagnosis, treatment and follow up of these patients must be established to reduce the morbidity and mortality. PMID- 26055419 TI - Comparison of renal safety and efficacy of telbivudine, entecavir and tenofovir treatment in chronic hepatitis B patients: real world experience. AB - This study aims to assess the nephrotoxicity and efficacy of tenofovir disoproxil fumarate (tenofovir), telbivudine and entecavir. A retrospective study of 587 patients with chronic hepatitis B treated with tenofovir (n = 170), telbivudine (n = 184) and entecavir (n = 233) for at least 1 year. Renal function and efficacy were assessed. The estimated glomerular filtration rate (eGFR) decreased significantly in the tenofovir group after a mean of 17 months treatment (from 92.2 to 85.6 mL/min/1.73 m(2), p < 0.001), but increased in the telbivudine group after a mean of 32 months of treatment (from 86.1 to 95 mL/min/1.73 m(2), p < 0.001). There was no significant change in eGFR in the entecavir group after a mean of 44 months. By multivariate analysis, pre-existing renal insufficiency (p = 0.003), tenofovir (p = 0.007) and diuretic treatment (p = 0.001) were independent predictors for renal function deterioration. Cumulative virological breakthrough was 0% in tenofovir after 2 years, 3.4% in entecavir after 7 years and 22.9% in telbivudine after 5 years. Liver cirrhosis (p = 0.008) and virological breakthrough (p = 0.040) were independently associated with increased risk of hepatocellular carcinoma development. Tenofovir may lead to deterioration in renal function as assessed by serial eGFR measurements. Although telbivudine appeared to be associated with an improvement in eGFR, it was associated with high rates of virological breakthrough, which was an independent risk factor for HCC development. With low rates of virological breakthrough and preservation of renal function, entecavir could be the best choice among these three agents. PMID- 26055420 TI - Real-Time Visualization of Perylene Nanoclusters in Water and Their Partitioning to Graphene Surface and Macrophage Cells. AB - Hydrophobic organic chemicals (HOCs) are of special ecotoxicological concern because they can be directly incorporated and bioconcentrated in living organisms. However, the effects of self-clustering of HOCs on their environmental behavior and toxicology have not yet received enough attention. With the use of a recently developed technique, single-molecule fluorescence microscopy, the motion and distribution of perylene nanoclusters (PNCs) formed in water at very low concentration (1 MUM) were visualized with high temporal and spatial resolution. The liquid-solid interface process of PNCs adsorbing onto graphene was also recorded. Instead of the traditional view of HOC adsorption as a single molecule, our study revealed the characteristic of irreversible adsorption of perylene onto the carbonaceous surface in the form of nanoclusters, exhibiting random sequential "car-parking" events. More interestingly, the transport of PNCs across the cell membrane was also captured in real time, demonstrating that they entered macrophage cells by endocytosis. Supplementing the well-recognized routine of passive diffusion through a membrane lipid bilayer, the uptake of HOCs in the form of nanoclusters by endocytosis is proposed to be an additional but important mechanism for their uptake into living cells. The distribution of HOCs in environmental systems in the form of nanoclusters, exemplified by PNCs in this study, may have significant implications for understanding their environmental fate and potential toxicological effects. PMID- 26055421 TI - Epidemiological surveys might underestimate waterpipe smoking. PMID- 26055422 TI - Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene-environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition. PMID- 26055423 TI - Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade. AB - A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment. PMID- 26055425 TI - The 3q29 deletion confers >40-fold increase in risk for schizophrenia. PMID- 26055424 TI - GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability. AB - Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding. PMID- 26055426 TI - Autism risk associated with parental age and with increasing difference in age between the parents. AB - Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent's age (mothers 40-49 years vs 20 29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers?50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents. PMID- 26055428 TI - Carbonic anhydrase II is found in the placenta of a viviparous, matrotrophic lizard and likely facilitates embryo-maternal CO2 transport. AB - The evolution of viviparity requires the development of mechanisms that facilitate transport of respiratory gases between mother and developing embryo. Of particular importance is maternal excretion of embryonic carbon dioxide (CO2 ), which increases as the embryo grows in size during development. The carbonic anhydrases are a family of enzymes that convert CO2 to bicarbonate for transport throughout the cardiovascular system and which may also be important for CO2 transport from embryo to mother. We used immunohistochemistry to localize carbonic anhydrase II in the placental tissues of a viviparous and highly placentotrophic lizard, Pseudemoia entrecasteauxii. Carbonic anhydrase II is localized in the uterine component of the paraplacentome, presumably to facilitate transport of embryonic CO2 to the mother. Carbonic anhydrase II is also localized in both the uterine and embryonic components of the placentome, a region heavily involved in placental nutrient transport rather than respiratory gas exchange. In contrast, carbonic anhydrase II is not present in the uterine or embryonic components of the omphaloplacenta, another region responsible for nutrient transport. While carbonic anhydrase II in the paraplacentomal uterus is likely to be responsible for embryo-maternal CO2 transport, the distribution of carbonic anhydrase II throughout the placentome indicates a different function. Instead of transporting embryonic CO2 , placentomal carbonic anhydrase II appears to be responsible for transporting CO2 produced by energetically expensive nutrient transport mechanisms in both the uterus and the embryo, which implies that the mechanisms of nutrient transport in the omphaloplacenta may not be as energetically expensive. PMID- 26055427 TI - Amyloid-PET predicts inhibition of de novo plaque formation upon chronic gamma secretase modulator treatment. AB - In a positron-emission tomography (PET) study with the beta-amyloid (Abeta) tracer [(18)F]-florbetaben, we previously showed that Abeta deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. gamma-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone Abeta42 species without blocking general gamma-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[1-(3-methyl [1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal Abeta microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n=12) and treatment groups (TG-GSM, n=12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 Abeta-PET recordings were acquired at baseline (12 months), follow up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of Abeta were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Delta%-SUVR, indicating individual response prediction. Insoluble Abeta42 was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first Abeta-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations. PMID- 26055429 TI - Polymorphisms in Toll-like receptors 2 and 4 genes and their expression in chronic suppurative otitis media. AB - OBJECTIVE: Toll-like receptors (TLRs) have a prominent role in inducing innate immune response. It has been suggested that regulation of TLRs is involved in the pathogenesis of chronic otitis media. TLR 2 and TLR 4 polymorphisms were connected with susceptibility to acute otitis and chronic otitis with effusion. The objective of this study was to establish expression of TLR 2 and 4 on middle ear mucosa in different types of chronic suppurative otitis media (CSOM), and the influence of gene polymorphisms TLR 2 Arg753Gln and TLR 4 Thr399Ile and Asp299Gly to susceptibility to CSOM. MATERIAL AND METHODS: Middle ear mucosa and full blood samples were obtained from 85 patients with chronic suppurative otitis media with and without cholesteatoma. Control group for mucosal TLR expression consisted of 71 samples of middle ear mucosa taken from patients with otosclerosis, and control group for DNA polymorphism consisted of 100 full blood samples in healthy subjects. DNA polymorphism detection was done with restriction fragment length polymorphism in RT PCR. Expression of TLR 2 and 4 was determined with immunohistochemical staining. RESULTS: TLR 2 and TLR 4 expression on the middle ear mucosa was not influenced by age of the patients with chronic otitis media. Incidence of TLR 2 Arg753Gln polymorphism was significantly higher in patients with chronic otitis media, compared to control group. Significant association between TLR 2 Arg753Gln polymorphism and different types of mucosal changes in patients with chronic otitis media was established. TLR 2 and 4 expression on experimental group mucosa was significantly different compared to control group, where there was no expression (p=0.000). Strong dependence of TLR 2 and TLR 4 expression on middle ear mucosa with different mucosal changes and immunohistochemical activity after staining was detected. CONCLUSION: Certain polymorphisms in TLR genes could be indicative for susceptibility to chronic otitis media. Expression of TLR 2 and 4 on middle ear mucosa was more dependable on different types of mucosal changes and type of CSOM than on bacteria found in the specimens. This can indicate that the type of mucosal changes are closely correlated with TLRs activity in middle ear. PMID- 26055430 TI - Preoperative prostate health index is an independent predictor of early biochemical recurrence after radical prostatectomy: Results from a prospective single-center study. AB - BACKGROUND: The aim of this study was to test the hypothesis that preoperative prostate health index (PHI) levels could help to predict early biochemical recurrence (BCR) in a contemporary population of patients with prostate cancer treated with robot-assisted radical prostatectomy (RARP). METHODS: The study population consisted of 313 patients treated with RARP for clinically localized prostate cancer at a single institution between 2010 and 2011. Patients subjected to neoadjuvant or adjuvant therapies and patients with a follow-up of<2 years were excluded. BCR was defined as a postoperative level of total prostate specific antigen >=0.2 ng/ml and elevating after RARP. The minimum P-value method was used to determine the most significant PHI cutoff value to discriminate between patients with and without BCR. The Kaplan-Meier method was used to determine BCR-free survival rates. Finally, Cox regression models were fitted to determine the predictors of BCR, and the predictive accuracy (area under the curve) of each predictor was determined with the Harrell concordance index. RESULTS: Mean total prostate-specific antigen and mean PHI levels were 5.76 ng/ml (interquartile range: 4.2-8.7) and 46.0 (35-62), respectively. Biopsy Gleason score was 6 in 173 (55.3%), 7 in 121 (38.7%), and >=8 in 19 (6.1%) patients. At final pathology, extracapsular extension was observed in 59 (18.8%), seminal vesicle invasion in 24 (7.7%), and lymph node invasion in 11 (3.5%) patients, whereas 228 (72.8%) patients had organ-confined disease. The 2-year BCR-free survival rate was 92.5% in the overall population and was 96.7% in patients with organ-confined disease. The most significant PHI cutoff value to discriminate between patients with and without BCR was 82. Specifically, the 2-year BCR-free survival rate was 97.7% in patients with a preoperative PHI level<82 relative to 69.7% in patients with a PHI level >=82 (log-rank test: P<0.001). Finally, in multivariable Cox regression analyses, PHI level emerged as an independent predictor of BCR in both the preoperative and the postoperative settings and was more accurate than several established BCR predictors were. CONCLUSIONS: Preoperative PHI levels may discriminate between patients who are at a high risk vs. low risk of BCR after RARP. External validation of our findings within a larger population with a longer follow-up time is needed. PMID- 26055431 TI - Genetic variation of the porcine NR5A1 is associated with meat color. AB - Because of the central role of Steroidogenic factor 1 in the regulation of the development and function of steroidogenic tissues, including the adrenal gland, we chose the encoding gene NR5A1 as a candidate for stress response, meat quality and carcass composition in the domestic pig. To identify polymorphisms of the porcine NR5A1 we comparatively sequenced the coding, untranslated and regulatory regions in four commercial pig lines. Single nucleotide polymorphisms could be found in the 3' UTR and in an intronic enhancer, whereas no polymorphisms were detected in the proximal promoter and coding region. A subset of the detected polymorphisms was genotyped in Pietrain x (German Large White x German Landrace) and German Landrace pigs. For the same animals, carcass composition traits, meat quality characteristics and parameters of adrenal function were recorded. Associations with meat color were found for two of the discovered SNPs in Pietrain x (German Large White x German Landrace) and German Landrace pigs but no connections to parameters of adrenal function could be established. We conclude that NR5A1 variations influence meat color in a hypothalamus-pituitary-adrenal axis independent manner and that further regulatory regions need to be analyzed for genetic variations to understand the discovered effects. PMID- 26055432 TI - Review of alignment and SNP calling algorithms for next-generation sequencing data. AB - Application of the massive parallel sequencing technology has become one of the most important issues in life sciences. Therefore, it was crucial to develop bioinformatics tools for next-generation sequencing (NGS) data processing. Currently, two of the most significant tasks include alignment to a reference genome and detection of single nucleotide polymorphisms (SNPs). In many types of genomic analyses, great numbers of reads need to be mapped to the reference genome; therefore, selection of the aligner is an essential step in NGS pipelines. Two main algorithms-suffix tries and hash tables-have been introduced for this purpose. Suffix array-based aligners are memory-efficient and work faster than hash-based aligners, but they are less accurate. In contrast, hash table algorithms tend to be slower, but more sensitive. SNP and genotype callers may also be divided into two main different approaches: heuristic and probabilistic methods. A variety of software has been subsequently developed over the past several years. In this paper, we briefly review the current development of NGS data processing algorithms and present the available software. PMID- 26055433 TI - Expression of Interleukin-1beta and Matrix Metalloproteinase-8 in Cytolytic and Noncytolytic Enterococcus faecalis-induced Persistent Apical Periodontitis: A Comparative Study in the Rat. AB - INTRODUCTION: Cytolytic Enterococcus faecalis possesses a highly toxic and proinflammatory capacity. Cytokines and proteases play important roles in the host inflammatory response. The aim of this study was to compare the local expression of interleukin (IL)-1beta and matrix metalloproteinase-8 (MMP-8) between persistent apical periodontitis (AP) infected by cytolytic and noncytolytic E. faecalis. METHODS: Eighty-four left upper first rat molars were divided into 4 groups: chronic AP group (n = 6), disinfection group (n = 6), cytolytic E. faecalis-infected persistent AP group (n = 36), and noncytolytic E. faecalis-infected persistent AP group (n = 36). Periradicular lesions were established after pulp exposure. After 3 weeks, root canals were prepared, and disinfected. E. faecalis strains ATCC 29212 or ATCC 700802 suspensions were inoculated into root canals 2 weeks later. Six samples were collected at different time points (1, 2, 3, 4, 5, and 6 weeks). The expression levels of IL 1beta and MMP-8 were detected by immunohistochemical staining. RESULTS: IL-1beta and MMP-8 expression trends in the cytolytic groups were similar to those of the noncytolytic group although at different time points the expression levels in the cytolytic group were significantly higher than those in the noncytolytic group (P < .01). IL-1beta expression enhancement occurred during the early phase of infection, whereas increased MMP-8 expression lasted for a prolonged period. CONCLUSIONS: Both E. faecalis strains could induce local IL-1beta and MMP-8 expression in persistent AP. Compared with noncytolytic E. faecalis, cytolytic E. faecalis may cause more severe local inflammation and tissue destruction in persistent AP. PMID- 26055434 TI - Tissue-specific sparse deconvolution for brain CT perfusion. AB - Enhancing perfusion maps in low-dose computed tomography perfusion (CTP) for cerebrovascular disease diagnosis is a challenging task, especially for low contrast tissue categories where infarct core and ischemic penumbra usually occur. Sparse perfusion deconvolution has been recently proposed to effectively improve the image quality and diagnostic accuracy of low-dose perfusion CT by extracting the complementary information from the high-dose perfusion maps to restore the low-dose using a joint spatio-temporal model. However the low contrast tissue classes where infarct core and ischemic penumbra are likely to occur in cerebral perfusion CT tend to be over-smoothed, leading to loss of essential biomarkers. In this paper, we propose a tissue-specific sparse deconvolution approach to preserve the subtle perfusion information in the low contrast tissue classes. We first build tissue-specific dictionaries from segmentations of high-dose perfusion maps using online dictionary learning, and then perform deconvolution-based hemodynamic parameters estimation for block-wise tissue segments on the low-dose CTP data. Extensive validation on clinical datasets of patients with cerebrovascular disease demonstrates the superior performance of our proposed method compared to state-of-art, and potentially improve diagnostic accuracy by increasing the differentiation between normal and ischemic tissues in the brain. PMID- 26055435 TI - Classification of multiple sclerosis lesions using adaptive dictionary learning. AB - This paper presents a sparse representation and an adaptive dictionary learning based method for automated classification of multiple sclerosis (MS) lesions in magnetic resonance (MR) images. Manual delineation of MS lesions is a time consuming task, requiring neuroradiology experts to analyze huge volume of MR data. This, in addition to the high intra- and inter-observer variability necessitates the requirement of automated MS lesion classification methods. Among many image representation models and classification methods that can be used for such purpose, we investigate the use of sparse modeling. In the recent years, sparse representation has evolved as a tool in modeling data using a few basis elements of an over-complete dictionary and has found applications in many image processing tasks including classification. We propose a supervised classification approach by learning dictionaries specific to the lesions and individual healthy brain tissues, which include white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF). The size of the dictionaries learned for each class plays a major role in data representation but it is an even more crucial element in the case of competitive classification. Our approach adapts the size of the dictionary for each class, depending on the complexity of the underlying data. The algorithm is validated using 52 multi-sequence MR images acquired from 13 MS patients. The results demonstrate the effectiveness of our approach in MS lesion classification. PMID- 26055436 TI - Resurgence of extracorporeal support for the primary management of cardiogenic shock. PMID- 26055437 TI - Who cares about stem cells? We should! PMID- 26055438 TI - Rivaroxaban for treatment of heparin-induced thrombocytopenia after cardiac surgery: A case report. PMID- 26055439 TI - The impact of a second arterial graft on 5-year outcomes after coronary artery bypass grafting in the Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery Trial and Registry. AB - OBJECTIVE: Despite various evidence supporting the advantages of multiple arterial grafting, inconsistencies in use of the procedure have resulted in high variability in the acceptance and practice of arterial grafting. The purpose of this study was to assess the effects of an arterial versus venous second grafts on outcomes at 5-year follow-up in the coronary artery bypass grafting population from the Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery (SYNTAX) trial. METHODS: Patients (n = 1419) with an arterial graft to the left anterior descending artery and >=1 other graft were included and divided according to the second graft's type: 2nd-graft-arterial group (n = 456) and 2nd-graft-venous group (n = 963). Five-year outcomes were compared between subgroups. Event rates were estimated with Kaplan-Meier analyses. Propensity-score matching was used, to control for selection bias due to nonrandom group assignment in a 1:1 manner, resulting in 432 pairs with balanced baseline characteristics. RESULTS: In unmatched groups, the 2nd-graft-arterial group had significantly lower rates of death (8.9% vs 13.1%; P = .02), and composite safety endpoint of death/stroke/myocardial infarction (13.3% vs 18.7%; P = .02), compared with the 2nd-graft-venous group. The rate of major adverse cardiac or cerebrovascular events was similar between groups (22.9% vs 25.5%; P = .30), because it includes the rate of repeat revascularization (12.6% in the 2nd graft-arterial group vs 9.6% in the 2nd-graft-venous group; P = .10). After propensity-score matching, no statistically significant differences were found between groups. CONCLUSIONS: This study reveals comparable 5-year outcomes with arterial and venous conduits as second grafts after an arterial graft anastomosed to the left anterior descending artery. This study demonstrates the multi institutional variation in patient selection and operator technique with regard to arterial revascularization, although extended follow-up beyond 5 years is required to estimate its impact on long-term outcomes. CLINICAL TRIAL NUMBER: NCT00114972. PMID- 26055440 TI - Second stage after initial hybrid palliation for hypoplastic left heart syndrome: Arterial or venous shunt? AB - OBJECTIVE: Hybrid palliation for hypoplastic left heart syndrome has been developed as an alternative to neonatal Norwood surgery. At the second stage, a source of pulmonary blood flow has to be established. Options include an arterial modified Blalock-Taussig or a venous superior cavopulmonary shunt. METHODS: We retrospectively reviewed patients who received second-stage palliation after the initial hybrid. Patients were stratified according to the source of pulmonary blood supply into the arterial shunt (n = 17 patients) or venous shunt (n = 26 patients). RESULTS: Age and weight at second stage were lower in the arterial group (85 [45-268] days vs 152.5 [61-496] days, P = .001 and 3.6 [2.7-9.4] kg vs 5.1 [2.97-9.4] kg, P = .001, respectively). All recorded surgical times were shorter in the arterial group. Mechanical ventilation and intensive care stay were shorter in the venous group (5.82 [2.01-14.9] days vs 2.42 [0.56-13.67] days, P = .005 and 8.5 [3.6-23.7] vs 5.75 [0.8-17.6] days, P = .036, respectively) There was no difference in mortality (2/17 vs 5/26; P = .685) or incidence of complications between the 2 groups. There was a tendency toward a higher need for intervention in the immediate postoperative period in the venous group, but this did not reach significance (6/17 vs 13/26, P = .342). The arterial group has shown better development of the branch pulmonary arteries with a higher lower lobe index (158.38 +/- 39.43 mm(2)/m(2) vs 113.33 +/- 43.96 mm(2)/m(2), respectively, P = .037). CONCLUSIONS: Both arterial and venous shunts are viable options with mortality and morbidity results comparable to those in the literature. The arterial shunt pathway (2-stage Norwood I) may offer better pulmonary arterial growth than the venous shunt (comprehensive/combined Norwood I and II). PMID- 26055441 TI - Spider monkeys (Ateles geoffroyi) are less sensitive to the odor of aliphatic ketones than to the odor of other classes of aliphatic compounds. AB - Aliphatic ketones are widely present in body-borne and food odors of primates. Therefore, we used an operant conditioning paradigm and determined olfactory detection thresholds in four spider monkeys for a homologous series of aliphatic 2-ketones (2-butanone to 2-nonanone) and two of their isomers (3- and 4 heptanone). We found that, with the exception of the two shortest-chained ketones, all animals detected concentrations <1 ppm (parts per million), and with five odorants individual animals even reached threshold values <0.1 ppm. Further, we found a significant correlation between olfactory sensitivity of the spider monkeys and carbon chain length of the 2-ketones which can best be described as a U-shaped function. In contrast, no significant correlation was found between olfactory sensitivity and position of the functional carbonyl group. Across odorant and across-species comparisons revealed the following: spider monkeys are significantly less sensitive to the odors of aliphatic ketones than to the odor of other classes of aliphatic compounds (1-alcohols, n-aldehydes, n-acetic esters, and n-carboxylic acids) sharing the same carbon length. Spider monkeys do not differ significantly in their olfactory sensitivity for aliphatic ketones from squirrel monkeys and pigtail macaques, but are significantly less sensitive to these odorants compared to human subjects and mice. These findings support the notion that neuroanatomical and genetic properties do not allow for reliable predictions with regard to a species' olfactory sensitivity. Further, we conclude that the frequency of occurrence of a class of odorants in a species' chemical environment does not allow for reliable predictions of the species' olfactory sensitivity. PMID- 26055442 TI - Using endophenotypes to examine molecules related to candidate genes as novel therapeutics: The "endophenotype-associated surrogate endpoint (EASE)" concept. AB - In this article, a new concept of an "endophenotype-associated surrogate endpoint (EASE)" is proposed. To examine effect of a novel therapeutic molecule on a target phenotype of a genotype associated with the molecule, state-dependent aspect of an endophenotype can be used as a surrogate endpoint. Desired characteristics for EASE are (1) a close relationship to the endophenotype associated with therapeutics, (2) longitudinal changes in illness severity, while the original "endophenotype" is primarily state independent, (3) a physical sign or laboratory measurement that occurs in association with a pathological process and has putative diagnostic and/or prognostic utility, and (4) serves as a substitute for a clinically meaningful endpoint. Advantages are expected for both surrogate endpoints in drug development and endophenotypes in uncovering pathogenesis. EASE are closer to molecules than clinically meaningful endpoints and can respond to administration of the molecule in a more direct manner. Therefore, a statistically significant effect is likely to be observed in clinical trials with smaller sample sizes and shorter durations. As with endophenotypes, reduced heterogeneity might be expected especially in heterogeneous syndromes such as psychiatric disorders. Potential interactions (e.g., elucidating biological mechanisms underlying novel treatments) can be further expected. PMID- 26055443 TI - One-pot synthesis of levulinic acid from cellulose in ionic liquids. AB - A simple and effective route for the production of levulinic acid (LA) from cellulose has been developed in SO3H-functionalized ionic liquids. The effects of ionic liquid structures, reaction conditions and combination of metal chlorides with ILs on the yield of LA were investigated, where the highest yield of 39.4% was obtained for 120 min in the presence of 1-(4-sulfonic acid) butyl-3 methylimidazolium hydrogen sulphate ([BSMim]HSO4) with addition of H2O. The catalytic activities of ionic liquids depended on the anions and decreased in the order: CF3SO3(-)>HSO4(-) > OAc(-), which was in good agreement with their acidity order. The ILs play a dual solvent-acid role for the cellulose conversion into LA and exhibited favorable catalytic activity over four repeated runs. PMID- 26055445 TI - Development and validity of the Emotion and Motivation Self-regulation Questionnaire (EMSR-Q). AB - This study has two objectives, first, to develop and validate the "Emotion and Motivation Self-regulation Questionnaire" (EMSR-Q), and second, to analyze (in the context of the questionnaire validation process) the relationships between self-regulation styles (SRS) rooted in goal orientations, and classroom motivational climate (CMC). A total of 664 Secondary Education students from Madrid (Spain) formed the sample of the study. It was divided randomly in two groups to perform confirmatory factor analysis and to cross-validate the results. Both analyses supported a five first-order factor structure, organized around two second-order factors, "Learning self-regulation style" (LSR) and "Avoidance self regulation style" (ASR): (chi 2 /df = 2.71; GFI = .89; IFI = .84; CFI = .84; RMSEA = .07). Hypotheses concerning the relationships between SRS, goal orientations and expectancies are supported by additional correlation and factor analyses. Moreover, several regression analyses supported for the most part of the remaining hypotheses concerning the role of self-regulation styles as predictors of classroom motivational climate (CMC) perception, of change in self regulation attributed to teacher work, and of students' satisfaction with this same work. Theoretical and practical implications are discussed. PMID- 26055444 TI - Concomitant osmotic and chaotropicity-induced stresses in Aspergillus wentii: compatible solutes determine the biotic window. AB - Whereas osmotic stress response induced by solutes has been well-characterized in fungi, less is known about the other activities of environmentally ubiquitous substances. The latest methodologies to define, identify and quantify chaotropicity, i.e. substance-induced destabilization of macromolecular systems, now enable new insights into microbial stress biology (Cray et al. in Curr Opin Biotechnol 33:228-259, 2015a, doi: 10.1016/j.copbio.2015.02.010 ; Ball and Hallsworth in Phys Chem Chem Phys 17:8297-8305, 2015, doi: 10.1039/C4CP04564E ; Cray et al. in Environ Microbiol 15:287-296, 2013a, doi: 10.1111/1462-2920.12018 ). We used Aspergillus wentii, a paradigm for extreme solute-tolerant fungal xerophiles, alongside yeast cell and enzyme models (Saccharomyces cerevisiae and glucose-6-phosphate dehydrogenase) and an agar-gelation assay, to determine growth-rate inhibition, intracellular compatible solutes, cell turgor, inhibition of enzyme activity, substrate water activity, and stressor chaotropicity for 12 chemically diverse solutes. These stressors were found to be: (i) osmotically active (and typically macromolecule-stabilizing kosmotropes), including NaCl and sorbitol; (ii) weakly to moderately chaotropic and non-osmotic, these were ethanol, urea, ethylene glycol; (iii) highly chaotropic and osmotically active, i.e. NH4NO3, MgCl2, guanidine hydrochloride, and CaCl2; or (iv) inhibitory due primarily to low water activity, i.e. glycerol. At <=0.974 water activity, Aspergillus cultured on osmotically active stressors accumulated low-M r polyols to >=100 mg g dry weight(-1). Lower-M r polyols (i.e. glycerol, erythritol and arabitol) were shown to be more effective for osmotic adjustment; for higher-M r polyols such as mannitol, and the disaccharide trehalose, water-activity values for saturated solutions are too high to be effective; i.e. 0.978 and 0.970 (25 oC). The highly chaotropic, osmotically active substances exhibited a stressful level of chaotropicity at physiologically relevant concentrations (20.0-85.7 kJ kg(-1)). We hypothesized that the kosmotropicity of compatible solutes can neutralize chaotropicity, and tested this via in-vitro agar-gelation assays for the model chaotropes urea, NH4NO3, phenol and MgCl2. Of the kosmotropic compatible solutes, the most-effective protectants were trimethylamine oxide and betaine; but proline, dimethyl sulfoxide, sorbitol, and trehalose were also effective, depending on the chaotrope. Glycerol, by contrast (a chaotropic compatible solute used as a negative control) was relatively ineffective. The kosmotropic activity of compatible solutes is discussed as one mechanism by which these substances can mitigate the activities of chaotropic stressors in vivo. Collectively, these data demonstrate that some substances concomitantly induce chaotropicity-mediated and osmotic stresses, and that compatible solutes ultimately define the biotic window for fungal growth and metabolism. The findings have implications for the validity of ecophysiological classifications such as 'halophile' and 'polyextremophile'; potential contamination of life support systems used for space exploration; and control of mycotoxigenic fungi in the food-supply chain. PMID- 26055446 TI - Genetic engineering and metabolite profiling for overproduction of polyhydroxybutyrate in cyanobacteria. AB - Genetic engineering and metabolite profiling for the overproduction of polyhydroxybutyrate (PHB), which is a carbon material in biodegradable plastics, were examined in the unicellular cyanobacterium Synechocystis sp. PCC 6803. Transconjugants harboring cyanobacterial expression vectors that carried the pha genes for PHB biosynthesis were constructed. The overproduction of PHB by the engineering cells was confirmed through microscopic observations using Nile red, transmission electron microscopy (TEM), or nuclear magnetic resonance (NMR). We successfully recovered PHB from transconjugants prepared from nitrogen-depleted medium without sugar supplementation in which PHB reached approximately 7% (w/w) of the dry cell weight, showing a value of 12-fold higher productivity in the transconjugant than that in the control strain. We also measured the intracellular levels of acetyl-CoA, acetoacetyl-CoA, and 3-hydroxybutyryl-CoA (3HB-CoA), which are intermediate products for PHB. The results obtained indicated that these products were absent or at markedly low levels when cells were subjected to the steady-state growth phase of cultivation under nitrogen depletion for the overproduction of bioplastics. Based on these results, efficient factors were discussed for the overproduction of PHB in recombinant cyanobacteria. PMID- 26055447 TI - p53-Induced inflammation exacerbates cardiac dysfunction during pressure overload. AB - The rates of death and disability caused by severe heart failure are still unacceptably high. There is evidence that the sterile inflammatory response has a critical role in the progression of cardiac remodeling in the failing heart. The p53 signaling pathway has been implicated in heart failure, but the pathological link between p53 and inflammation in the failing heart is largely unknown. Here we demonstrate a critical role of p53-induced inflammation in heart failure. Expression of p53 was increased in cardiac endothelial cells and bone marrow cells in response to pressure overload, leading to up-regulation of intercellular adhesion molecule-1 (ICAM1) expression by endothelial cells and integrin expression by bone marrow cells. Deletion of p53 from endothelial cells or bone marrow cells significantly reduced ICAM1 or integrin expression, respectively, as well as decreasing cardiac inflammation and ameliorating systolic dysfunction during pressure overload. Conversely, overexpression of p53 in bone marrow cells led to an increase of integrin expression and cardiac inflammation that reduced systolic function. Norepinephrine markedly increased p53 expression in endothelial cells and macrophages. Reducing beta2-adrenergic receptor expression in endothelial cells or bone marrow cells attenuated cardiac inflammation and improved systolic dysfunction during pressure overload. These results suggest that activation of the sympathetic nervous system promotes cardiac inflammation by up-regulating ICAM1 and integrin expression via p53 signaling to exacerbate cardiac dysfunction. Inhibition of p53-induced inflammation may be a novel therapeutic strategy for heart failure. PMID- 26055448 TI - Activation of AMPK restricts coxsackievirus B3 replication by inhibiting lipid accumulation. AB - Coxsackievirus B3 (CVB3) is the major pathogen of human viral myocarditis. CVB3 has been found to manipulate and modify the cellular lipid metabolism for viral replication. The cellular AMP-activated protein kinase (AMPK) is a key regulator of multiple metabolic pathways, including lipid metabolism. Here we explore the potential roles AMPK plays in CVB3 infection. We found that AMPK is activated by the viral replication during CVB3 infection in Hela cells and primary myocardial cells. RNA interference mediated inhibition of AMPK could increase the CVB3 replication in cells, indicating that AMPK contributed to restricting the viral replication. Next, we showed that CVB3 replication could be inhibited by several different pharmacological AMPK activators including metformin, A769662 and AICAR. And the constitutively active AMPK mutant (CA-AMPK) could also inhibit the CVB3 replication. Furthermore, we found that CVB3 infection increased the cellular lipid levels and showed that the AMPK agonist AICAR both restricted CVB3 replication and reduced lipid accumulation through inhibiting the lipid synthesis associated gene expression. We further found that CVB3 infection would also induce AMPK activated in vivo. The AMPK agonist metformin, which has been widely used in diabetes therapy, could decrease the viral replication and further protect the mice from myocardial histological and functional changes in CVB3 induced myocarditis, and improve the survival rate of infected mice. Lastly, it was demonstrated that the AICAR-mediated restriction of viral replication could be rescued partially by exogenous palmitate, the first product of fatty acid biosynthesis, demonstrating that AMPK activation restricted CVB3 infection through its inhibition of lipid synthesis. Taken together, these data in the present study suggest a model in which AMPK is activated by CVB3 infection and restricts viral replication by inhibiting the cellular lipid accumulation, and inform a potential novel therapeutic strategy for CVB3-associated diseases. PMID- 26055449 TI - Influence of age and posture on spinal and corticospinal excitability. AB - This study investigated the modulation of the excitability of spinal and corticospinal pathways from seated to upright standing across adult lifespan. The input-output relations for the Hoffmann (H) reflex and motor-evoked potential (MEP) were recorded in soleus muscle during seated and upright posture in 40 subjects assigned to either young (range: 19-39yrs, n=16), middle-aged (40-59yrs, n=12), and elderly group (60-76yrs, n=12). In seated posture, H reflex and MEP were recorded during voluntary contractions of the ankle plantar flexors inducing similar soleus electromyographic activity that during upright standing. Maximal H reflex and MEP amplitude (Hmax, MEPmax), and the change in response amplitude from seated to standing were analyzed. The Hmax decreased with age (p=0.001) and from seated to standing (p<0.001). The change in Hmax from seated to standing was greater in elderly (-40.1%; p<0.05) compared with young (-20.7%) and middle-aged groups (-23.7%). MEPmax increased with age and from seated to standing (p<0.001). The change in MEPmax from seated to standing did not differ (p>0.05) between young (+53.6%), middle-aged (+43.2%) and elderly groups (+77.3%). These results indicate a posture-related modulation of the excitability of spinal and corticospinal pathways regardless of age, with a more pronounced modulation of spinal pathway in elderly adults. This study further documents the time course of decrease and increase in spinal and corticospinal excitability, respectively, across adult lifespan. PMID- 26055450 TI - Lifelong wheel running exercise and mild caloric restriction attenuate nuclear EndoG in the aging plantaris muscle. AB - Apoptosis plays an important role in atrophy and sarcopenia in skeletal muscle. Recent evidence suggests that insufficient heat shock proteins (HSPs) may contribute to apoptosis and muscle wasting. In addition, long-term caloric restriction (CR) and lifelong wheel running exercise (WR) with CR provide significant protection against caspase-dependent apoptosis and sarcopenia. Caspase-independent mediators (endonuclease G: EndoG; apoptosis-inducing factor: AIF) of apoptosis are also linked to muscles wasting with disuse and aging. However, the efficacy of CR and WR with CR to attenuate caspase-independent apoptosis and preserve HSPs in aging skeletal muscle are unknown. Therefore, we tested the hypothesis that CR and WR with CR would ameliorate age-induced elevation of EndoG and AIF while protecting HSP27 and HSP70 levels in the plantaris. Male Fischer-344 rats were divided into 4 groups at 11weeks: ad libitum feeding until 6months (YAL); fed ad libitum until 24months old (OAL); 8%CR to 24months (OCR); WR+8%CR to 24months (OExCR). Nuclear EndoG levels were significantly higher in OAL (+153%) than in YAL, while CR (-38%) and WR with CR ( 46%) significantly attenuated age-induced increment in nuclear EndoG. HSP27 ( 63%) protein content and phosphorylation at Ser82 (-49%) were significantly lower in OAL than in YAL, while HSP27 protein content was significantly higher in OCR (+136%) and OExCR (+155%) and p-HSP27 (+254%) was significantly higher in OExCR compared with OAL, respectively. In contrast, AIF and HSP70 were unaltered by CR or WR with CR in aging muscle. These data indicate that CR and WR with CR attenuate age-associated upregulation of EndoG translocation in the nucleus, potentially involved with HSP27 signaling. PMID- 26055451 TI - Sinonasal tumour. PMID- 26055453 TI - Interpretation and estimation for dynamic mobility of chlorpyrifos in soils containing different organic matters. AB - The adsorption and removal behaviors of the organophosphate insecticide chlorpyrifos in two soils (AS and GW soils) with different organic matter contents were investigated to predict the dynamic residues in the soil environment. The adsorption test showed that the chlorpyrifos adsorptive power for the AS soil containing high organic matter content was greater than that for the GW soil. The extent of the time-dependent removal of chlorpyrifos in the tested soils was not significantly different except at 90 days after the treatment. The availability of a chemical-specific residue model developed in this study was statistically assessed to estimate the chlorpyrifos residue in soil solutions that could be absorbed into plants. The values modeled using the soil experimental data were satisfactory, having a mean deviation of 32% from the measured data. The correlation between the modeled and measured data was acceptable, with mean coefficients of correlation (R(2)) of 0.89. Furthermore, the average of the residual error was low at 0.43, which corresponded to a mean factor of -1.9. The developed model could be used as a critical tool to predict the subsequent plant uptake of chlorpyrifos. PMID- 26055452 TI - Global Phosphoproteomic Mapping of Early Mitotic Exit in Human Cells Identifies Novel Substrate Dephosphorylation Motifs. AB - Entry into mitosis is driven by the coordinated phosphorylation of thousands of proteins. For the cell to complete mitosis and divide into two identical daughter cells it must regulate dephosphorylation of these proteins in a highly ordered, temporal manner. There is currently a lack of a complete understanding of the phosphorylation changes that occur during the initial stages of mitotic exit in human cells. Therefore, we performed a large unbiased, global analysis to map the very first dephosphorylation events that occur as cells exit mitosis. We identified and quantified the modification of >16,000 phosphosites on >3300 unique proteins during early mitotic exit, providing up to eightfold greater resolution than previous studies. The data have been deposited to the ProteomeXchange with identifier PXD001559. Only a small fraction (~ 10%) of phosphorylation sites were dephosphorylated during early mitotic exit and these occurred on proteins involved in critical early exit events, including organization of the mitotic spindle, the spindle assembly checkpoint, and reformation of the nuclear envelope. Surprisingly this enrichment was observed across all kinase consensus motifs, indicating that it is independent of the upstream phosphorylating kinase. Therefore, dephosphorylation of these sites is likely determined by the specificity of phosphatase/s rather than the activity of kinase/s. Dephosphorylation was significantly affected by the amino acids at and surrounding the phosphorylation site, with several unique evolutionarily conserved amino acids correlating strongly with phosphorylation status. These data provide a potential mechanism for the specificity of phosphatases, and how they co-ordinate the ordered events of mitotic exit. In summary, our results provide a global overview of the phosphorylation changes that occur during the very first stages of mitotic exit, providing novel mechanistic insight into how phosphatase/s specifically regulate this critical transition. PMID- 26055454 TI - Unraveling the antibacterial mode of action of a clay from the Colombian Amazon. AB - Natural antibacterial clays can inhibit growth of human pathogens; therefore, understanding the antibacterial mode of action may lead to new applications for health. The antibacterial modes of action have shown differences based on mineralogical constraints. Here we investigate a natural clay from the Colombian Amazon (AMZ) known to the Uitoto natives as a healing clay. The physical and chemical properties of the AMZ clay were compared to standard reference materials: smectite (SWy-1) and kaolinite (API #5) that represent the major minerals in AMZ. We tested model Gram-negative (Escherichia coli ATCC #25922) and Gram-positive (Bacillus subtilis ATCC #6633) bacteria to assess the clay's antibacterial effectiveness against different bacterial types. The chemical and physical changes in the microbes were examined using bioimaging and mass spectrometry of clay digests and aqueous leachates. Results indicate that a single dose of AMZ clay (250 mg/mL) induced a 4-6 order of magnitude reduction in cell viability, unlike the reference clays that did not impact bacterial survival. AMZ clay possesses a relatively high specific surface area (51.23 m(2)/g) and much higher total surface area (278.82 m(2)/g) than the reference clays. In aqueous suspensions (50 mg clay/mL water), soluble metals are released and the minerals buffer fluid pH between 4.1 and 4.5. We propose that the clay facilitates chemical interactions detrimental to bacteria by absorbing nutrients (e.g., Mg, P) and potentially supplying metals (e.g., Al) toxic to bacteria. This study demonstrates that native traditional knowledge can direct scientific studies. PMID- 26055455 TI - Investigating relationships between biomarkers of exposure and environmental copper and manganese levels in house dusts from a Portuguese industrial city. AB - This study reports on data obtained from a pilot survey focusing on house dust and toenail metal(loids) concentrations in residents living in the industrial city of Estarreja. The study design hereby described aims at investigating relationships between human toenails and both copper and manganese levels in settled house dusts. A total of 21 households and 30 individuals were recruited for the pilot study: 19 households corresponding to 27 residents living near the industrial complex, forming the exposed group, plus 2 households and 3 residents from residential areas with no anticipated environmental contaminants that were used for comparison. Factorial analysis was used for source identification purposes. Investigation on the potential influence of environmental factors over copper and manganese levels in the toenails was carried out via questionnaire data and multiple correspondence analysis. The results show that copper concentrations are more elevated in the indoor dusts, while manganese concentrations are more elevated in the outdoor dust samples. The geometrical relationships in the datasets suggest that the backyard soil is a probable source of manganese to the indoor dust. Copper and manganese contents in the toenail clippings are more elevated in children than in adults, but the difference between the two age groups is not statistically significant (p > 0.05). Investigation of environmental factors influencing the exposure-biomarker association indicates a probable relationship between manganese contents in indoor dust and manganese levels in toenail clippings, a result that is partially supported by the bioaccessibility estimates. However, for copper, no relationship was found between indoor dusts and the biomarkers of exposure. PMID- 26055456 TI - The spatial relationship between human activities and C, N, P, S in soil based on landscape geochemical interpretation. AB - The development and formation of chemical elements in soil are affected not only by parent material, climate, biology, and topology factors, but also by human activities. As the main elements supporting life on earth system, the C, N, P, S cycles in soil have been altered by human activity through land-use change, agricultural intensification, and use of fossil fuels. The present study attempts to analyze whether and how a connection can be made between macroscopical control and microcosmic analysis, to estimate the impacts of human activities on C, N, P, S elements in soil, and to determine a way to describe the spatial relationship between C, N, P, S in soil and human activities, by means of landscape geochemical theories and methods. In addition, the disturbances of human activities on C, N, P, S are explored through the analysis of the spatial relationship between human disturbed landscapes and element anomalies, thereby determining the diversified rules of the effects. The study results show that the rules of different landscapes influencing C, N, P, S elements are diversified, and that the C element is closely related to city landscapes; furthermore, the elements N, P, and S are shown to be closely related to river landscapes; the relationships between mine landscapes and the elements C, N, P, S are apparent; the relationships between the elements C, N, P, S and road landscapes are quite close, which shows that road landscapes have significant effects on these elements. Therefore, the conclusion is drawn that the response mechanism analysis of human disturbance and soil chemical element aggregation is feasible, based on the landscape geochemical theories and methods. The spatial information techniques, such as remote sensing and geographic information systems, are effective for research on soil element migration. PMID- 26055457 TI - Validation of Brief Young Adult Alcohol Consequences Questionnaire (B-YAACQ): Portuguese version. AB - Extant literature suggests that Portuguese college students frequently drinking alcohol and experience a variety of alcohol-related negative consequences. However, to our knowledge, there is no validated measure to assess negative consequences of drinking alcohol for college students in Portugal. This article describes a validation of the Portuguese version of the Brief Young Adult Alcohol Consequences Questionnaire. Originally developed by Kahler, Strong, and Read (2005), this 24-item questionnaire is a widely used self-report measure with strong psychometric properties and validity for the evaluation of the negative consequences of drinking in college students. We collected data from 620 students at the University of Coimbra (Portugal). Participants completed (a) a background questionnaire, (b) the Alcohol Use Disorders Identification Test (AUDIT), (c) the Daily Drinking Questionnaire - Revised (DDQ-R), and (d) the Brief Young Adult Alcohol Consequences Questionnaire (B-YAACQ) translated into Portuguese as part of this study. Analyses showed that items fit a unidimensional Rasch model well with items infit statistics raging from .82 to 1.27, supporting using all items to create a total sum score of the Portuguese version of the B-YAACQ. The Portuguese version of the B-YAACQ showed adequate internal reliability (alpha = .87) and concurrent validity. Results support its use and integration in research on interventions targeted to reduce adverse effects associated with excessive drinking among Portuguese college students. PMID- 26055458 TI - An accurate benchmark description of the interactions between carbon dioxide and polyheterocyclic aromatic compounds containing nitrogen. AB - We assessed the performance of a large variety of modern density functional theory approaches for the adsorption of carbon dioxide on molecular models of pyridinic N-doped graphene. Specifically, we selected eight polyheterocyclic aromatic compounds ranging from pyridine and pyrazine to 1,6-diazacoronene and investigated their complexes with CO2 for a large range of intermolecular distances and including both in-plane and stacked orientations. The benchmark interaction energies were computed at the complete-basis-set limit MP2 level plus a CCSD(T) coupled-cluster correction in a moderate but carefully selected basis set. Using a set of 96 benchmark CCSD(T)-level interaction energies as a reference, we investigated the accuracy of DFT-based approaches as a function of the density functional, the dispersion correction, the basis set, and the counterpoise correction or lack thereof. While virtually all DFT variants exhibit some deterioration of accuracy for distances slightly shorter than the van der Waals minima, we were able to identify several schemes such as B2PLYP-D3 and M05 2X-D3 whose average errors on the entire benchmark data set are in the 5-10% range. The top DFT performers were subsequently used to investigate the energy profile for a carbon dioxide transition through model N-doped graphene pores. All investigated methods confirmed that the largest, N4H4 pore allows for a barrierless CO2 transition to the other side of a graphene sheet. PMID- 26055459 TI - Clinical and pathological analysis of renal damage in elderly patients with type 2 diabetes mellitus. AB - The aim of this study was to investigate the causes and influential factors of renal damage in elderly patients with type 2 diabetes mellitus (T2DM). Clinical data and pathological findings at autopsy of 161 elderly T2DM patients died between October 1994 and August 2011 were retrospectively reviewed. The mean age of these patients was 80.8 +/- 8.3 years (range 60-105 years). The incidences of diabetic nephropathy (DN), non-diabetic renal diseases (NDRD), and DN complicated with NDRD were 31.1, 62.7, and 16.2 %, respectively. In patients with NDRD, the incidence of hypertensive renal damage (HRD) was 54.7 %. In the factors causing renal damage, DN and NDRD accounted for 1/3 and 2/3, respectively. HRD accounted for the largest proportion of NDRD. Blood pressure control may provide additional benefits for elderly T2DM patients by preventing and delaying the occurrence and development of renal disease. PMID- 26055460 TI - Addressing the Health of Formerly Imprisoned Persons in a Distressed Neighborhood Through a Community Collaborative Board. AB - This article provides a case study evaluating the structure and dynamic process of a Community Collaborative Board that had the goal of creating an evidence based substance abuse/health intervention for previously incarcerated individuals. Meeting agendas, attendance, minutes, video recording of meetings, and in-depth interviews with 13 Community Collaborative Board members were used to conduct an independent process evaluation. Open coding identified quotes exemplifying specific themes and/or patterns across answers related to the desired domain. Several themes were identified regarding membership engagement, retention, and power distribution. Results showed member retention was due to strong personal commitment to the targeted problem. Analysis also revealed an unequal power distribution based on participants' background. Nevertheless, the development of an innovative, community-based health intervention manual was accomplished. Aspects of the process, such as incentives, subcommittees, and trainings, enhanced the Board's ability to integrate the community and scientific knowledge to accomplish its research agenda. Community-based participatory research was a useful framework in enhancing quality and efficiency in the development of an innovative, substance abuse/health intervention manual for distressed communities. Overall, this article sheds light on a process that illustrates the integration of community-based and scientific knowledge to address the health, economic, and societal marginalization of low-income, minority communities. PMID- 26055462 TI - Strategies to Increase After-School Program Staff Skills to Promote Healthy Eating and Physical Activity. AB - Standards targeting children's healthy eating and physical activity (HEPA) in after-school programs call for staff to display or refrain from HEPA-promoting or -discouraging behaviors that are linked to children's HEPA. This study evaluated strategies to align staff behaviors with HEPA Standards. Staff at four after school programs serving approximately 500 children participated in professional development training from January 2012 to May 2013. Site leaders also attended workshops and received technical support during the same time frame. Changes in staff behaviors were evaluated using the System for Observing Staff Promotion of Activity and Nutrition in a pre- (fall 2011) multiple-post (spring 2012, fall 2012, and spring 2013), no-control group study design. A total of 8,949 scans were completed across the four measurement periods. Of the 19 behaviors measured, 14 changed in the appropriate direction. For example, staff engaging in physical activity with children increased from 27% to 40% of scans and staff eating unhealthy foods decreased from 56% to 14% of days. Ongoing training and technical assistance can have a measureable impact on staff behaviors linked to child-level HEPA outcomes. Future research should explore the feasibility of disseminating ongoing trainings to after-school program staff on a large scale. PMID- 26055463 TI - Influence of the Home Food Environment on Children's Fruit and Vegetable Consumption: A Study of Rural Low-Income Families. AB - BACKGROUND: This investigation sought to identify micro-level built and sociocultural characteristics of a home food environment that have been theoretically linked with fruit and vegetable (F&V) consumption. METHOD: We examined rural families (n = 298) from the southeastern United States. Hierarchical multiple regression analyses determined the association between the outcome variable (F&V consumption) and micro-level built and sociocultural characteristics of a home food environment. RESULTS: Demographic characteristics were entered at Step 1, explaining 14% of variance in vegetable consumption and 9% in fruit consumption. After entry of sociocultural factors in the home food environment, such as parenting styles and so on, in Block 2, the total variance explained increased by 25% for vegetable consumption and 12% for fruit consumption. Micro-level built environmental factors such as the availability of F&V in the home was entered at Block 3, total variance explained by the model for vegetable consumption was 67%, F(17, 111) = 13.5, p < .001, and for fruit consumption was 57%, F(17, 160) = 12.5, p < .001. CONCLUSION: F&V availability was the most important variable influencing a child's consumption of F&V. There are modifiable factors within the rural low-income home that could serve as priorities for intervention to improve F&V consumption. PMID- 26055464 TI - The origins of translational radiation oncology - In memoriam H. Rodney Withers (21 September 1932-25 February 2015). PMID- 26055465 TI - Heat Shock Proteins, L-Arginine, and Asymmetric Dimethylarginine Levels in Patients With Obstructive Sleep Apnea Syndrome. AB - OBJECTIVE: Vascular endothelial inflammation and enhanced oxidative stress are important factors in the pathogenesis of obstructive sleep apnea syndrome (OSAS). The aim of this study was to determine the levels of heat shock protein (HSP) 27, HSP70, HSP90, L-arginine, and asymmetric dimethylarginine (ADMA) in patients with OSAS and determine their relationship with cardiovascular (CV) risk factors. MATERIAL AND METHODS: Forty patients with OSAS, comprising 26 with and 14 without traditional CV risk factors (obesity, hypercholesterolemia, diabetes, hypertension, and smoking), and 20 control subjects without OSAS were included. All patients underwent a full polysomnographic evaluation, and blood samples were obtained in the morning after the night the diagnostic study was performed. RESULTS: No significant differences were found in serum HSP27 and HSP70 levels between the groups. HSP90 and ADMA levels increased significantly, whereas L arginine levels decreased significantly in patients with OSAS, both with and without CV risk factors, compared with controls, but were not different among the subgroups. In all patients with OSAS, serum HSP70 levels were positively correlated with a percent time with saturation<90% (r=.349, P=.027). Serum L arginine levels were negatively correlated with desaturation number (r=-.360, P=.022) and apnea-hypopnea index (r=-.354, P=.025) and positively correlated with mean oxygen saturation (r=.328, P=.039). CONCLUSION: Serum levels of HSP90 and ADMA increased, whereas those of L-arginine decreased in patients with OSAS regardless of CV risk factors. These findings indicate the presence of oxidative stress and endothelial dysfunction in patients with OSAS. PMID- 26055466 TI - Alzheimer disease: Iron--the missing link between ApoE and Alzheimer disease? PMID- 26055467 TI - Cerebrovascular disease: Subclinical cerebrovascular disease can impede learning. PMID- 26055468 TI - Sleep: Amyloid-beta accumulation impairs memory by disrupting deep sleep--but could the vicious cycle be stopped? PMID- 26055469 TI - Alzheimer disease: Penalized regression can predict conversion to AD. PMID- 26055471 TI - Morphology and magnetic properties of Fe3O 4 nanodot arrays using template assisted epitaxial growth. AB - Arrays of epitaxial Fe3O4 nanodots were prepared using laser molecular beam epitaxy (LMBE), with the aid of ultrathin porous anodized aluminum templates. An Fe3O4 film was also prepared using LMBE. Atomic force microscopy and scanning electron microscopy images showed that the Fe3O4 nanodots existed over large areas of well-ordered hexagonal arrays with dot diameters (D) of 40, 70, and 140 nm; height of approximately 20 nm; and inter-dot distances (D int) of 67, 110, and 160 nm. The calculated nanodot density was as high as 0.18 Tb in.(-2) when D = 40 nm. X-ray diffraction patterns indicated that the as-grown Fe3O4 nanodots and the film had good textures of (004) orientation. Both the film and the nanodot arrays exhibited magnetic anisotropy; the anisotropy of the nanoarray weakened with decreasing dot size. The Verwey transition temperature of the film and nanodot arrays with D >= 70 nm was observed at around 120 K, similar to that of the Fe3O4 bulk; however, no clear transition was observed from the small nanodot array with D = 40 nm. Results showed that magnetic properties could be tailored through the morphology of nanodots. Therefore, Fe3O4 nanodot arrays may be applied in high-density magnetic storage and spintronic devices. PMID- 26055472 TI - Magnetic In x Ga 1 - x N nanowires at room temperature using Cu dopant and annealing. AB - Single-crystal, Cu-doped In x Ga1 - x N nanowires were grown on GaN/Al2O3 substrates via a vapor-liquid-solid (VLS) mechanism using Ni/Au bi-catalysts. The typical diameter of the Cu:In x Ga1 - x N nanowires was 80 to 150 nm, with a typical length of hundreds of micrometers. The as-grown nanowires exhibited diamagnetism. After annealing, the nanowires exhibited ferromagnetism with saturation magnetic moments higher than 0.8 MUB (1 MUB * 10(-24) Am(2)) per Cu atom at room temperature by the measurements using a superconducting quantum interference device (SQUID) magnetometer. X-ray absorption and X-ray magnetic circular dichroism spectra at Cu L 2,3-edges indicated that the doped Cu had a local magnetic moment and that its electronic configuration was mainly 3d (9). It possessed a small trivalent component, and thus, the n-type behavior of electrical property is measured at room temperature. PMID- 26055473 TI - Solvothermal-assisted liquid-phase exfoliation of graphite in a mixed solvent of toluene and oleylamine. AB - We report an effective method for producing graphene sheets using solvothermal assisted exfoliation of graphite in a mixed solvent of toluene and oleylamine. The mixed solvent of toluene and oleylamine produces higher yield of graphene than its constituents, oleylamine and toluene. The oleylamine molecules with its long chain enwrap the graphene sheets efficiently, while toluene helps the oleylamine molecules become more flexible and easily intercalate into the edge of graphite. The prepared graphene sheets have a high quality, and the concentration of graphene in the dispersion is as high as 0.128 mg mL(-1). The high-quality graphene sheets obtained in this work make them suitable for application in many fields such as energy-storage materials and polymer composites. PMID- 26055474 TI - Magnetic Properties of Cluster Glassy Ni/NiO Core-Shell Nanoparticles: an Investigation of Their Static and Dynamic Magnetization. AB - We review the phenomenology of the exchange bias and its related effects in core shell nanocrystals. The static and dynamic properties of the magnetization for ferromagnetic Ni-core and antiferromagnetic NiO-shell cluster glassy nanoparticles are examined, along with the pinning-depinning process, through the measurement of the conventional exchange bias, and associated with different cooling fields and particle sizes. Two significant indexes for the dipolar interaction n and multi-anisotropic barrier beta derived from the dynamic magnetization are proposed, which provide a unified picture of the exchange bias mechanism and insight into the influence of the cooling field. PMID- 26055475 TI - SERS Detection of Dopamine Using Label-Free Acridine Red as Molecular Probe in Reduced Graphene Oxide/Silver Nanotriangle Sol Substrate. AB - The reduced graphene oxide/silver nanotriangle (rGO/AgNT) composite sol was prepared by the reduction of silver ions with sodium borohydride in the presence of H2O2 and sodium citrate. In the nanosol substrate, the molecular probe of acridine red (AR) exhibited a weak surface-enhanced Raman scattering (SERS) peak at 1506 cm(-1) due to its interaction with the rGO of rGO/AgNT. Upon addition of dopamine (DA), the competitive adsorption between DA and AR with the rGO took place, and the AR molecules were adsorbed on the AgNT aggregates with a strong SERS peak at 1506 cm(-1) that caused the SERS peak increase. The increased SERS intensity is linear to the DA concentration in the range of 2.5-500 MUmol/L. This new analytical system was investigated by SERS, fluorescence, absorption, transmission electron microscope (TEM), and scanning electron microscope (SEM) techniques, and a SERS quantitative analysis method for DA was established, using AR as a label-free molecular probe. PMID- 26055476 TI - Characterization of Conventional One-Step Sodium Thiosulfate Facilitated Gold Nanoparticle Synthesis. AB - Gold-gold sulfide nanoparticles are of interest for drug delivery, biomedical imaging, and photothermal therapy applications due to a facile synthesis method resulting in small particles with high near-infrared (NIR) absorption efficiency. Previous studies suggest that the NIR sensitivity of these nanoparticles was due to hexagonally shaped metal-coated dielectric nanoparticles that consist of a gold sulfide core and gold shell. Here, we illustrate that the conventional synthesis procedure results in the formation of polydisperse samples of icosahedral gold particles, gold nanoplates, and small gold spheres. Importantly, through compositional analysis, via UV/vis absorption spectrophotometry, transmission electron microscopy (TEM), and energy dispersive x-ray spectroscopy (EDS), we show that all of the nanoparticles exhibit identical face center cubic (FCC) gold crystalline structures, thus suggesting that sulfide is not present in the final fabricated nanoparticles. We show that icosahedrally shaped nanoparticles result in a blue-shifted absorbance, with a peak in the visible range. Alternatively, the nanoplate nanoparticles result in the characteristic NIR absorbance peak. Thus, we report that the NIR-contributing species in conventional gold-gold sulfide formulations are nanoplates that are comprised entirely of gold. Furthermore, polydisperse gold nanoparticle samples produced by the traditional one-step reduction of HAuCl4 by sodium thiosulfate show increased in vitro toxicity, compared to isolated and more homogeneous constituent samples. This result exemplifies the importance of developing monodisperse nanoparticle formulations that are well characterized in order to expedite the development of clinically beneficial nanomaterials. PMID- 26055477 TI - Modeling Nanoparticle Targeting to a Vascular Surface in Shear Flow Through Diffusive Particle Dynamics. AB - Nanoparticles are regarded as promising carriers for targeted drug delivery and imaging probes. A fundamental understanding of the dynamics of polymeric nanoparticle targeting to receptor-coated vascular surfaces is therefore of great importance to enhance the design of nanoparticles toward improving binding ability. Although the effects of particle size and shear flow on the binding of nanoparticles to a vessel wall have been studied at the particulate level, a computational model to investigate the details of the binding process at the molecular level has not been developed. In this research, dissipative particle dynamics simulations are used to study nanoparticles with diameters of several nanometers binding to receptors on vascular surfaces under shear flow. Interestingly, shear flow velocities ranging from 0 to 2000 s(-1) had no effect on the attachment process of nanoparticles very close to the capillary wall. Increased binding energy between the ligands and wall caused a corresponding linear increase in bonding ability. Our simulations also indicated that larger nanoparticles and those of rod shape with a higher aspect ratio have better binding ability than those of smaller size or rounder shape. PMID- 26055478 TI - Seed/Catalyst-Free Growth of Gallium-Based Compound Materials on Graphene on Insulator by Electrochemical Deposition at Room Temperature. AB - We report the growth of gallium-based compounds, i.e., gallium oxynitride (GaON) and gallium oxide (Ga2O3) on multilayer graphene (MLG) on insulator using a mixture of ammonium nitrate (NH4NO3) and gallium nitrate (Ga(NO3)3) by electrochemical deposition (ECD) method at room temperature (RT) for the first time. The controlling parameters of current density and electrolyte molarity were found to greatly influence the properties of the grown structures. The thicknesses of the deposited structures increase with the current density since it increases the chemical reaction rates. The layers grown at low molarities of both solutions basically show grain-like layer with cracking structures and dominated by both Ga2O3 and GaON. Such cracking structures seem to diminish with the increases of molarities of one of the solutions. It is speculated that the increase of current density and ions in the solutions helps to promote the growth at the area with uneven thicknesses of graphene. When the molarity of Ga(NO3)3 is increased while keeping the molarity of NH4NO3 at the lowest value of 2.5 M, the grown structures are basically dominated by the Ga2O3 structure. On the other hand, when the molarity of NH4NO3 is increased while keeping the molarity of Ga(NO3)3 at the lowest value of 0.8 M, the GaON structure seems to dominate where their cubic and hexagonal arrangements are coexisting. It was found that when the molarities of Ga(NO3)3 are at the high level of 7.5 M, the grown structures tend to be dominated by Ga2O3 even though the molarity of NH4NO3 is made equal or higher than the molarity of Ga(NO3)3. When the grown structure is dominated by the Ga2O3 structure, the deposition process became slow or unstable, resulting to the formation of thin layer. When the molarity of Ga(NO3)3 is increased to 15 M, the nanocluster-like structures were formed instead of continuous thin film structure. This study seems to successfully provide the conditions in growing either GaON-dominated or Ga2O3-dominated structure by a simple and low-cost ECD. The next possible routes to convert the grown GaON-dominated structure to either single-crystalline GaN or Ga2O3 as well as Ga2O3-dominated structure to single crystalline Ga2O3 structure have been discussed. PMID- 26055479 TI - Optical Properties of Pyrolytic Carbon Films Versus Graphite and Graphene. AB - We report a comparative study of optical properties of 5-20 nm thick pyrolytic carbon (PyC) films, graphite, and graphene. The complex dielectric permittivity of PyC is obtained by measuring polarization-sensitive reflectance and transmittance spectra of the PyC films deposited on silica substrate. The Lorentz Drude model describes well the general features of the optical properties of PyC from 360 to 1100 nm. By comparing the obtained results with literature data for graphene and highly ordered pyrolytic graphite, we found that in the visible spectral range, the effective dielectric permittivity of the ultrathin PyC films are comparable with those of graphite and graphene. PMID- 26055480 TI - Synthesis of CaCO3 Nanobelts for Drug Delivery in Cancer Therapy. AB - Nanobelt carriers have demonstrated some advantages such as good biocompatibility, biodegradability, and strain-accommodating properties. We prepared an optimized nanobelt carrier formulation for drug (etoposide) as an oral delivery system and estimated the potential of calcium carbonate (CaCO3) nanobelts. The nanobelts were prepared by the method of binary solvent approach and were characterized by transmission electron microscope (TEM), scanning electron microscopy (SEM), and ultraviolet-visible (UV-vis) spectra. MTT (3-(4,5 dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide) assay test exhibited that etoposide-loaded calcium carbonate nanobelts (ECCNBs) showed a higher cell kill ratio against SGC-7901 cells compared with free drug. The apoptosis test and cell cycle test analysis revealed that etoposide entrapped in calcium carbonate nanobelts (CCNBs) could enhance the delivery efficiencies of drug and improved inhibition effect. The present findings demonstrated that ECCNBs might induce cell cycle arrest at G2/M phase and cell apoptosis in a p53-related manner. It can be foreseen that CCNBs are a promising drug carrier to store the anti-cancer drug for cancer therapy and drug delivery. PMID- 26055481 TI - Electrospinning of Grooved Polystyrene Fibers: Effect of Solvent Systems. AB - Secondary surface texture is of great significance to morphological variety and further expands the application areas of electrospun nanofibers. This paper presents the possibility of directly electrospinning grooved polystyrene (PS) fibers using both single and binary solvent systems. Solvents were classified as low boiling point solvent (LBPS): dichloromethane (DCM), acetone (ACE), and tetrahydrofuran (THF); high boiling point solvent (HBPS): N,N-dimethylformamide (DMF) and cyclohexanone (CYCo); and non-solvent (NS): 1-butanol (BuOH). By the systematic selection and combination of these solvents at given parameters, we found that single solvent systems produced non-grooved fibers. LBPS/DMF solvent systems resulted in fibers with different grooved textures, while LBPS/CYCo led to fibers with double grooved texture. Grooved fibers can also be fabricated from LBPS/LBPS, NS/LBPS, and NS/HBPS systems under specific conditions. The results indicated that the difference of evaporation rate (DER) between the two solvents played a key role in the formation of grooved texture. The formation of this unique texture should be attributed to three separate mechanisms, namely void based elongation, wrinkle-based elongation, and collapsed jet-based elongation. Our findings can serve as guidelines for the preparation of ultrafine fibers with grooved secondary texture. PMID- 26055482 TI - Observation of Shape, Configuration, and Density of Au Nanoparticles on Various GaAs Surfaces via Deposition Amount, Annealing Temperature, and Dwelling Time. AB - Metallic nanoparticles have been widely witnessed in many applications: serving as the catalysts for various nanowire systems, as the active mediums of various device applications, and also for the nanoscale templates for hybrid quantum structures. In the performance of devices and configurations of the resulting nanostructures, the size and density of nanoparticles play critical roles. In this paper, the control of self-assembled Au droplets on GaAs (100), (110), and (111) is systematically investigated through the variation of deposition amount (DA), annealing temperature (AT), and dwelling time (DT). Based on the Volmer Weber growth model, the formation of Au droplets and dramatic evolution of Au nanostructures on various GaAs surfaces is observed from the Au clusters to the round-dome shapes with the AT variation between 250 and 550 degrees C. With the systematic DA control, a radical size and density evolution of Au droplets shows the size expansion of over 400 % in average height and 800 % in average lateral diameter, while the density shows over two orders of decrease. With the DT variation, the self-assembled Au droplets tend to grow larger due to the Ostwald ripening while a clear distinction among the surface indexes is observed. PMID- 26055483 TI - Enhanced non-volatile memory characteristics with quattro-layer graphene nanoplatelets vs. 2.85-nm Si nanoparticles with asymmetric Al2O 3/HfO 2 tunnel oxide. AB - In this work, we demonstrate a non-volatile metal-oxide semiconductor (MOS) memory with Quattro-layer graphene nanoplatelets as charge storage layer with asymmetric Al2O3/HfO2 tunnel oxide and we compare it to the same memory structure with 2.85-nm Si nanoparticles charge trapping layer. The results show that graphene nanoplatelets with Al2O3/HfO2 tunnel oxide allow for larger memory windows at the same operating voltages, enhanced retention, and endurance characteristics. The measurements are further confirmed by plotting the energy band diagram of the structures, calculating the quantum tunneling probabilities, and analyzing the charge transport mechanism. Also, the required program time of the memory with ultra-thin asymmetric Al2O3/HfO2 tunnel oxide with graphene nanoplatelets storage layer is calculated under Fowler-Nordheim tunneling regime and found to be 4.1 ns making it the fastest fully programmed MOS memory due to the observed pure electrons storage in the graphene nanoplatelets. With Si nanoparticles, however, the program time is larger due to the mixed charge storage. The results confirm that band-engineering of both tunnel oxide and charge trapping layer is required to enhance the current non-volatile memory characteristics. PMID- 26055484 TI - Novel 14-nm Scallop-Shaped FinFETs (S-FinFETs) on Bulk-Si Substrate. AB - In this study, novel p-type scallop-shaped fin field-effect transistors (S FinFETs) are fabricated using an all-last high-k/metal gate (HKMG) process on bulk-silicon (Si) substrates for the first time. In combination with the structure advantage of conventional Si nanowires, the proposed S-FinFETs provide better electrostatic integrity in the channels than normal bulk-Si FinFETs or tri gate devices with rectangular or trapezoidal fins. It is due to formation of quasi-surrounding gate electrodes on scalloping fins by a special Si etch process. The entire integration flow of the S-FinFETs is fully compatible with the mainstream all-last HKMG FinFET process, except for a modified fin etch process. The drain-induced barrier lowering and subthreshold swing of the fabricated p-type S-FinFETs with a 14-nm physical gate length are 62 mV/V and 75 mV/dec, respectively, which are much better than those of normal FinFETs with a similar process. With an improved short-channel-effect immunity in the channels due to structure modification, the novel structure provides one of possibilities to extend the FinFET scalability to sub-10-nm nodes with little additional process cost. PMID- 26055485 TI - Emotional reactivity during anticipation and perception of affective pictures. AB - The focus of the present study was on further exploring anticipatory responses to emotional stimuli by measuring the eyeblink startle reflex in a variation of the picture-picture affective learning procedure. Participants (113 undergraduate women) were not explicitly instructed before the experiment began. Instead, they had to learn the specific relations between cues (geometrical shapes) and emotional pictures based on pairings during the first part of the task. Plausible contingency learning effects were tested afterwards, in a parallel sequence of trials including auditory probes during cues and pictures processing during the second part of the task. Results did show the typical affective startle modulation pattern during perception, linear F(1, 200) = 52.67, p < .0001, but unexpected inhibition for both pleasant and unpleasant, compared to neutral cues, during anticipation, quadratic F(1, 200) = 7.07, p < .009. All patterns of startle modulation were independent of cue-picture contingency awareness (all interactions Fs < 1). Skin conductance changes showed the predictable quadratic trend either during picture perception or anticipatory periods (greater activity for emotional vs. neutral; overall quadratic F(1, 224) = 7.04, p < .01), only for participants fully aware of the cue-picture contingency, quadratic F(1, 158) = 5.86, p < .02. Overall, our results during anticipation (cues processing) seem to suggest that more resources were allocated to highly arousing pictures that engage attention. Differences between the present results and prior research may be attributed to procedural variations in the sample, cues, or instructions. Future studies should also explore in more detail the role of the contingency awareness during anticipation. PMID- 26055486 TI - Hydrous RuO2 nanoparticles as an efficient NIR-light induced photothermal agent for ablation of cancer cells in vitro and in vivo. AB - Metal oxides are receiving an incremental attention in recent years for their potential applications in ablation of cancer cells due to their efficient photothermal conversion and good biocompatibility, but the large sizes and poor photo-stability will seriously limit their practical application. Herein, hydrous RuO2 nanoparticles were synthesized by a facile hydrothermal treatment and surface-modified with polyvinylpyrrolidone (PVP) coating. PVP-coated RuO2 nanoparticles exhibit a well dispertion in saline solution, strong characteristic plasmonic absorption in NIR region, enhanced photothermal conversion efficiency of 54.8% and remarkable photo-stability under the irridation of an 808 nm laser. The nanoparticles were further employed as a new photothermal ablation agent for cancer cells which led rapidly to cellular deaths both in vitro and in vivo. PMID- 26055487 TI - Bacterial diversity of Drass, cold desert in Western Himalaya, and its comparison with Antarctic and Arctic. AB - Drass is the coldest inhabited place in India and the second coldest, inhabited place in the world, after Siberia. Using the 16SrDNA amplicon pyrosequencing, bacterial diversity patterns were cataloged across the Drass cold desert. In order to identify the ecotype abundance across cold desert environment, bacterial diversity patterns of Drass were further compared with the bacterial diversity of two other cold deserts, i.e., Antarctic and Arctic. Acidobacteria, Proteobacteria, Actinobacteria, Bacteroidetes, Cyanobacteria and Gemmatimonadetes were among the highly abundant taxonomic groups present across all the three cold deserts and were designated as the core phyla. However, Firmicutes, Nitrospirae, Armatimonadetes (former candidate division OP10), Planctomycetes, TM7, Chloroflexi, Deinococcus-Thermus, Tenericutes and candidate phyla WS3 were identified as rare phyla in Drass, Antarctic and Arctic samples. Differential abundance patterns were also computed across all the three samples, i.e., Acidobacteria (32.1 %) were dominant in Drass and Firmicutes (52.9 +/- 17.6 %) and Proteobacteria (42 +/- 1.3 %) were dominant in Antarctic and Arctic reference samples, respectively. Alpha diversity values Shannon's (H) and Simpson's (1-D) diversity indices were highest for Antarctic samples, whereas richness estimators (ACE and Chao1) were maximum for Drass soil suggesting greater species richness in bacterial communities in Drass than the Antarctic and Arctic samples. PMID- 26055488 TI - Spontaneous Intestinal Perforation and Infantile Hypertrophic Pyloric Stenosis in a Preterm Neonate: A Linked Etiopathogenesis? PMID- 26055489 TI - An urgent referral strategy for symptomatic patients with suspected colorectal cancer based on a quantitative immunochemical faecal occult blood test. AB - BACKGROUND: European health systems have developed referral guidelines for the selection of patients for the urgent investigation of suspected colorectal cancer. AIM: To evaluate whether quantitative faecal immunochemical testing performs better than commonly used high-risk symptoms based strategies for fast tracking cancer referrals. METHODS: We prospectively studied 1054 symptomatic patients referred for a colonoscopy who provided a sample for faecal immunochemical testing. The usefulness of faecal immunochemical testing and two current guidelines for urgent referral were compared for their efficacy in the detection of colorectal cancer and advanced neoplasia. RESULTS: The guidelines detected 46.7% and 43.3% of cases of colorectal cancer while faecal haemoglobin concentration >=15MUg Hb/g detected 96.7% of cases. The diagnostic accuracy of both the guidelines and faecal haemoglobin concentration >=15MUg Hb/g for the detection of advanced neoplasia was: sensitivity 38.3%, 36.1%, 57.1% and specificity 71.8%, 69.5%, 86.6%, respectively. Male gender (OR 2.35; p<0.001), age (1.34; p=0.002), and faecal haemoglobin concentration >=10MUg Hb/g (7.81; p<0.001) were independent predictive factors of advanced neoplasia. CONCLUSIONS: A faecal immunochemical test based-strategy performs better than current high risk symptoms based strategies for fast-tracking cancer referrals. A score that combines gender, age and a faecal immunochemical test could accurately estimate the risk of advanced neoplasia. PMID- 26055490 TI - Recipient female gender is a risk factor for graft loss after liver transplantation for chronic hepatitis C: Evidence from the prospective Liver Match cohort. AB - BACKGROUND: Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. AIMS: To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. METHODS: We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. RESULTS: Five-year graft survival was significantly reduced in HCV positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03-2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03-1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20-4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05-1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. CONCLUSIONS: This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts. PMID- 26055492 TI - Erratum to: The hippo signaling pathway: implications for heart regeneration and disease. PMID- 26055494 TI - Real Time Tracking of Magmatic Intrusions by means of Ground Deformation Modeling during Volcanic Crises. AB - Volcano observatories provide near real-time information and, ultimately, forecasts about volcano activity. For this reason, multiple physical and chemical parameters are continuously monitored. Here, we present a new method to efficiently estimate the location and evolution of magmatic sources based on a stream of real-time surface deformation data, such as High-Rate GPS, and a free geometry magmatic source model. The tool allows tracking inflation and deflation sources in time, providing estimates of where a volcano might erupt, which is important in understanding an on-going crisis. We show a successful simulated application to the pre-eruptive period of May 2008, at Mount Etna (Italy). The proposed methodology is able to track the fast dynamics of the magma migration by inverting the real-time data within seconds. This general method is suitable for integration in any volcano observatory. The method provides first order unsupervised and realistic estimates of the locations of magmatic sources and of potential eruption sites, information that is especially important for civil protection purposes. PMID- 26055493 TI - Study of phosphorylation events for cancer diagnoses and treatment. AB - The activation of signaling cascades in response to extracellular and intracellular stimuli to control cell growth, proliferation and survival, is orchestrated by protein kinases via phosphorylation. A critical issue is the study of the mechanisms of cancer cells for the development of more effective drugs. With the application of the new proteomic technologies, together with the advancement in the sequencing of the human proteome, patients will therefore be benefited by the discovery of novel therapeutic and/or diagnostic protein targets. Furthermore, the advances in proteomic approaches and the Human Proteome Organization (HUPO) have opened a new door which is helpful in the identification of patients at risk and towards improving current therapies. Modification of the signaling-networks via mutations or abnormal protein expression underlies the cause or consequence of many diseases including cancer. Resulting data is used to reveal connections between genes proteins and compounds and the related molecular pathways for underlining disease states. As a delegate of HUPO, for human proteome on children assays and studies, we, at Hospital Universitario Nino Jesus, are seeking to support the human proteome in this context. Clinical goals have to be clearly established and proteomics experts have to set up the appropriate proteomic strategy, which coupled to bioinformatics will make it possible to achieve new therapies for patients with poor prognosis. We envision to combine our up-coming data to the HUPO organization in order to support international efforts to advance the cure of cancer disease. PMID- 26055495 TI - Clinical Spanish norms of the Stroop test for traumatic brain injury and schizophrenia. AB - The Stroop Color-Word Test is a useful tool to evaluate executive attention and speed of processing. Recent studies have provided norms for different populations of healthy individuals to avoid misinterpretation of scores due to demographic and cultural differences. In addition, clinical norms may improve the assessment of cognitive dysfunction severity and its clinical course. Spanish normative data are provided for 158 closed traumatic brain injury (TBI) and 149 first-episode schizophrenia spectrum disorder (SCH) patients. A group of 285 Spanish healthy individuals (HC) was also considered for comparison purposes. Differences between groups were found in all Stroop scores with HC outperforming both clinical groups (p .3 in all cases). TBI patients scored lower than SCH patients in word-reading (p < .001 and d = .6), and color-naming conditions (p < .001 and d = .4), but not in the color-word condition (p = .34 and d = .03). However, SCH patients exhibited a higher interference effect as compared to TBI (p < .002 and d = .5). Three sets of norms stratified by age and education (HC), and by education (TBI and SCH) are presented for clinical use. PMID- 26055496 TI - Dispositional Differences of Collegiate Athletes' Flow State: A Cross-Cultural Comparison. AB - Csikszentmihalyi (1990) suggested that certain types of people might be better psychologically equipped to experience flow. The purpose of this study was to determine if differences exist in one's ability to experience flow based upon factors such as cultural background, gender, years of specialized training, skill level, and sport event type. The English and Chinese versions of the Dispositional Flow Scale-2 were used to assess trait flow in American (N = 160) and Chinese collegiate athletes (N = 341). Using a one-way ANOVA analysis, the flow scores of American participants were found to be higher than those of Chinese participants, eta2 = 0.175, 95% CI: 3.536-3.622, p < .005. The flow scores of male athletes were higher than those of female athletes within the Chinese sample, eta2 = 0.032, 95% CI: 3.390-3.486, p < .005. The flow scores of university athletes were higher than those of national team level athletes within the Chinese sample, eta2 = 0.044, 95% CI: 3.279-3.501, p < .005. Flow scores for athletes in skill-showing events were higher than those of athletes participating in physical ability-showing events for the American participants, eta2 = 0.074, 95% CI: 3.812-3.948, p < .005. This study suggests that individual differences exist in the psychological characteristics of athletes' trait flow. PMID- 26055498 TI - Selective photoregulation of the activity of glycogen synthase and glycogen phosphorylase, two key enzymes in glycogen metabolism. AB - Glycogen is a polymer of alpha-1,4- and alpha-1,6-linked glucose units that provides a readily available source of energy in living organisms. Glycogen synthase (GS) and glycogen phosphorylase (GP) are the two enzymes that control, respectively, the synthesis and degradation of this polysaccharide and constitute adequate pharmacological targets to modulate cellular glycogen levels, by means of inhibition of their catalytic activity. Here we report on the synthesis and biological evaluation of a selective inhibitor that consists of an azobenzene moiety glycosidically linked to the anomeric carbon of a glucose molecule. In the ground state, the more stable (E)-isomer of the azobenzene glucoside had a slight inhibitory effect on rat muscle GP (RMGP, IC50 = 4.9 mM) and Escherichia coli GS (EcGS, IC50 = 1.6 mM). After irradiation and subsequent conversion to the (Z) form, the inhibitory potency of the azobenzene glucoside did not significantly change for RMGP (IC50 = 2.4 mM), while its effect on EcGS increased 50-fold (IC50 = 32 MUM). Sucrose synthase 4 from potatoes, a glycosyltransferase that does not operate on glycogen, was only slightly inhibited by the (E)-isomer (IC50 = 0.73 mM). These findings could be rationalized on the basis of kinetic and computer aided docking analysis, which indicated that both isomers of the azobenzene glucoside mimic the EcGS acceptor substrate and exert their inhibitory effect by binding to the glycogen subsite in the active center of the enzyme. The ability to selectively photoregulate the catalytic activity of key enzymes of glycogen metabolism may represent a new approach for the treatment of glycogen metabolism disorders. PMID- 26055497 TI - In vitro Paracoccidioides brasiliensis biofilm and gene expression of adhesins and hydrolytic enzymes. AB - Paracoccidioides species are dimorphic fungi that initially infect the lungs but can also spread throughout the body. The spreading infection is most likely due to the formation of a biofilm that makes it difficult for the host to eliminate the infection. Biofilm formation is crucial for the development of infections and confines the pathogen to an extracellular matrix. Its presence is associated with antimicrobial resistance and avoidance of host defenses. This current study provides the first description of biofilm formation by Paracoccidioides brasiliensis (Pb18) and an analysis of gene expression, using real-time PCR, associated with 3 adhesins and 2 hydrolytic enzymes that could be associated with the virulence profile. Biofilm formation was analyzed using fluorescence microscopy, scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM). Metabolic activity was determined using the XTT reduction assay. P. brasiliensis was able to form mature biofilm in 144 h with a thickness of 100 MUm. The presence of a biofilm was found to be associated with an increase in the expression of adhesins and enzymes. GP43, enolase, GAPDH and aspartyl proteinase genes were over-expressed, whereas phospholipase was down-regulated in biofilm. The characterization of biofilm formed by P. brasiliensis may contribute to a better understanding of the pathogenesis of paracoccidioidomycosis as well as the search for new therapeutic alternatives; while improving the effectiveness of treatment. PMID- 26055499 TI - The Mediating Role of Visuospatial Planning Skills on Adaptive Function Among Young-Adult Survivors of Childhood Brain Tumor. AB - The Boston Qualitative Scoring System (BQSS) was used as a method to examine executive skills on the Rey-Osterrieth complex figure (ROCF). Young-adult survivors of childhood brain tumor (N = 31) and a demographically-matched comparison group (N = 33) completed the ROCF copy version and Grooved Pegboard, and informants were administered the Scales of Independent Behavior-Revised (SIB R) and Behavior Rating Inventory of Executive Function (BRIEF). Survivors had significantly lower BQSS planning and SIB-R community living skills and greater perseveration. Mediation analyses found that BQSS planning skills mediate the relationship between group and community living skills. Convergent findings of the BRIEF Planning, and discriminant findings with the BQSS Fragmentation, BRIEF Emotional Control, and Grooved Pegboard support the planning construct as the specific mediator in this model. Together, these findings highlight the role of planning skills in adaptive functions of young-adult survivors of childhood brain tumor. PMID- 26055500 TI - Transanal total mesorectal excision for rectal cancer. AB - Although laparoscopic surgery for rectal cancer has been gaining acceptance with the gradual accumulation of evidence, it remains a technically demanding procedure in patients with a narrow pelvis, bulky tumors, or obesity. To overcome the technical difficulties associated with laparoscopic rectal dissection and transection, transanal endoscopic rectal dissection, which is also referred to as transanal (reverse, bottom-up) total mesorectal excision (TME), has recently been introduced. Its potential advantages include the facilitation of the dissection of the anorectum, regardless of the patient body habitus, and a clearly defined safe distal margin and transanal extraction of the specimen. This literature review shows that this approach seems to be feasible with regard to the operative and short-term postoperative outcomes. In experienced hands, transanal TME is a promising method for the resection of mid- and low-rectal cancers. Further investigations are required to clarify the long-term oncological and functional outcomes. PMID- 26055501 TI - Why healthcare providers merge. AB - In many OECD countries, healthcare sectors have become increasingly concentrated as a result of mergers. However, detailed empirical insight into why healthcare providers merge is lacking. Also, we know little about the influence of national healthcare policies on mergers. We fill this gap in the literature by conducting a survey study on mergers among 848 Dutch healthcare executives, of which 35% responded (resulting in a study sample of 239 executives). A total of 65% of the respondents was involved in at least one merger between 2005 and 2012. During this period, Dutch healthcare providers faced a number of policy changes, including increasing competition, more pressure from purchasers, growing financial risks, de-institutionalisation of long-term care and decentralisation of healthcare services to municipalities. Our empirical study shows that healthcare providers predominantly merge to improve the provision of healthcare services and to strengthen their market position. Also efficiency and financial reasons are important drivers of merger activity in healthcare. We find that motives for merger are related to changes in health policies, in particular to the increasing pressure from competitors, insurers and municipalities. PMID- 26055502 TI - Erratum to: Medical Rapid Response in Psychiatry: Reasons for Activation and Immediate Outcome. PMID- 26055503 TI - The Assaultive Staff Action Program (ASAP): 25 Year Program Analysis. AB - The Assaulted Staff Action Program (ASAP) is a voluntary, system-wide, peer-help, crisis intervention program to address the psychological sequelae in staff victims of patient assaults. It has been associated with cost-effective, quality support services to staff victims of patient assaults and declines in assaults facility-wide in several facilities, after an ASAP was fielded. ASAP's functions and service provisions have been reported in previous 5-year intervals. The present paper reports on its most recent 5-year interval as ASAP complete its 25th year of service. The 5-year summary and the basic strengths and limitations of the program over this 25 year period are examined. PMID- 26055504 TI - High-pitch spiral CT with 3D reformation: an alternative choice for imaging vascular anomalies with affluent blood flow in the head and neck of infants and children. AB - OBJECTIVE: To evaluate the feasibility of high-pitch spiral CT in imaging vascular anomalies (VAs) with affluent blood flow in the head and neck of infants and children. METHODS: For patients with suspected VAs and affluent blood flow pre-detected by ultrasound, CT was performed with high-pitch mode, individualized low-dose scan protocol and three-dimensional (3D) reformation. A five-point scale was used for image quality evaluation. Diagnostic accuracy was calculated with clinical diagnosis with/without pathological results as the reference standard. Radiation exposure and single-phase scan time were recorded. Treatment strategies were formulated based on CT images and results and were monitored through follow up results. RESULTS: 20 lesions were identified in 15 patients (median age of 11 months). The mean score of image quality was 4.13 +/- 0.74. 7 patients (7/15, 46.67%) were diagnosed with haemangiomas, 6 patients (6/15, 40%) were diagnosed with venous malformations and 2 patients (2/15, 13.33%) were diagnosed with arteriovenous malformations. The average effective radiation doses of a single phase and of the total procedure were 0.27 +/- 0.08 and 0.86 +/- 0.21 mSv. The average scanning time of a single phase was 0.46 +/- 0.09 s. After treatment, 13 patients (13/15, 86.67%) achieved excellent results, and 2 patients (2/15, 13.33%) showed good results in follow-up visits. CONCLUSION: High-pitch spiral CT with an individualized low-dose scan protocol and 3D reformation is an effective modality for imaging VAs with affluent blood flow in the head and neck of infants and children when vascular details are needed and ultrasound and MRI could not provide the complete information. ADVANCES IN KNOWLEDGE: This study proposes an alternative modality for imaging VAs with affluent blood flow. PMID- 26055505 TI - Tumour volume changes assessed with high-quality KVCT in lung cancer patients undergoing concurrent chemoradiotherapy. AB - OBJECTIVE: We evaluated tumour volume changes in patients with lung cancer undergoing concurrent chemoradiotherapy using image-guided radiotherapy (RT). METHODS: The kilovoltage image was obtained using CT on rail at every five fractions. The gross tumour volumes (GTVs), including the primary tumour and lymph nodes (LNs), were contoured to analyse the time and degree of tumour regression. RESULTS: 46 patients [32, non-small-cell lung cancer (NSCLC), and 14, small-cell lung cancer (SCLC)] were included in this study. In total, 281 CT scans and 82 sites of GTVs were evaluated. Significant volume changes occurred in both the NSCLC and SCLC groups (p < 0.001 and 0.002), and the average GTV change compared with baseline was 49.85 +/- 3.65 [standard error (SE)]% and 65.95 +/- 4.60 (SE)% for the NSCLC and SCLC groups, respectively. A significant difference in the degree of volume reduction between the primary tumour and LNs was observed in only the NSCLC group (p < 0.0001) but not in the SCLC group (p = 0.735). The greatest volume regression compared with the volume before the five fractions occurred between the 15 and 20 fractions in the NSCLC group and between the 5 and 10 fractions in the SCLC group. CONCLUSION: Both primary tumour and LNs were well defined using CT on rail. Significant volume changes occurred during RT, and there was a difference in volume reduction between the NSCLC and SCLC groups, regarding the degree and timing of the tumour reduction in the primary tumour and LNs. ADVANCES IN KNOWLEDGE: NSCLC and SCLC groups showed differences in the degree and timing of volume reduction. The primary tumour and LNs in NSCLC regressed differently. PMID- 26055506 TI - Salvage image-guided intensity modulated or stereotactic body reirradiation of local recurrence of prostate cancer. AB - OBJECTIVE: To retrospectively evaluate external beam reirradiation (re-EBRT) delivered to the prostate/prostatic bed for local recurrence, after radical or adjuvant/salvage radiotherapy (RT). METHODS: 32 patients received re-EBRT between February 2008 and October 2013. All patients had clinical/radiological local relapse in the prostate or prostatic bed and no distant metastasis. re-EBRT was delivered with selective RT technologies [stereotactic RT including CyberKnife(TM) (Accuray, Sunnyvale, CA); image-guidance and intensity-modulated RT etc.]. Toxicity was evaluated using the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. Biochemical control was assessed according to the Phoenix definition (NADIR + 2 ng ml(-1)). RESULTS: Acute urinary toxicity: G0, 24 patients; G1, 6 patients; G2, 2 patients. Acute rectal toxicity: G0, 28 patients; G1, 2 patients; and G2, 1 patient. Late urinary toxicity (evaluated in 30 cases): G0, 23 patients; G1, 6 patients; G2, 1 patient. Late renal toxicity: G0, 25 patients; G1, 5 patients. A mean follow-up of 21.3 months after re-EBRT showed that 13 patients were free of cancer, 3 were alive with biochemical relapse and 12 patients were alive with clinically evident disease. Four patients had died: two of disease progression and two of other causes. CONCLUSION: re-EBRT using modern technology is a feasible approach for local prostate cancer recurrence offering 2-year tumour control in about half of the patients. Toxicity of re-EBRT is low. Future studies are needed to identify the patients who would benefit most from this treatment. ADVANCES IN KNOWLEDGE: Our series, based on experience in one hospital alone, shows that re-EBRT for local relapse of prostate cancer is feasible and offers a 2-year cure in about half of the patients. PMID- 26055507 TI - Protective role of oleic acid against cardiovascular insulin resistance and in the early and late cellular atherosclerotic process. AB - BACKGROUND: Several translational studies have identified the differential role between saturated and unsaturated fatty acids at cardiovascular level. However, the molecular mechanisms that support the protective role of oleate in cardiovascular cells are poorly known. For these reasons, we studied the protective role of oleate in the insulin resistance and in the atherosclerotic process at cellular level such as in cardiomyocytes (CMs), vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). METHODS: The effect of oleate in the cardiovascular insulin resistance, vascular dysfunction, inflammation, proliferation and apoptosis of VSMCs were analyzed by Western blot, qRT-PCR, BrdU incorporation and cell cycle analysis. RESULTS: Palmitate induced insulin resistance. However, oleate not only did not induce cardiovascular insulin resistance but also had a protective effect against insulin resistance induced by palmitate or TNFalpha. One mechanism involved might be the prevention by oleate of JNK-1/2 or NF-kappaB activation in response to TNF-alpha or palmitate. Oleate reduced MCP-1 and ICAM-1 and increased eNOS expression induced by proinflammatory cytokines in ECs. Furthermore, oleate impaired the proliferation induced by TNF alpha, angiotensin II or palmitate and the apoptosis induced by TNF-alpha or thapsigargin in VSMCs. CONCLUSIONS: Our data suggest a differential role between oleate and palmitate and support the concept of the cardioprotector role of oleate as the main lipid component of virgin olive oil. Thus, oleate protects against cardiovascular insulin resistance, improves endothelial dysfunction in response to proinflammatory signals and finally, reduces proliferation and apoptosis in VSMCs that may contribute to an ameliorated atherosclerotic process and plaque stability. PMID- 26055508 TI - Localization and expression of EDS5H a homologue of the SA transporter EDS5. AB - BACKGROUND: An important signal transduction pathway in plant defence depends on the accumulation of salicylic acid (SA). SA is produced in chloroplasts and the multidrug and toxin extrusion transporter ENHANCED DISEASE SUSCEPTIBILITY5 (EDS5; At4g39030) is necessary for the accumulation of SA after pathogen and abiotic stress. EDS5 is localized at the chloroplast and functions in transporting SA from the chloroplast to the cytoplasm. EDS5 has a homologue called EDS5H (EDS5 HOMOLOGUE; At2g21340) but its relationship to EDS5 has not been described and its function is not known. RESULTS: EDS5H exhibits about 72% similarity and 59% identity to EDS5. In contrast to EDS5 that is induced after pathogen inoculation, EDS5H was constitutively expressed in all green tissues, independently of pathogen infection. Both transporters are located at the envelope of the chloroplast, the compartment of SA biosynthesis. EDS5H is not involved with the accumulation of SA after inoculation with a pathogen or exposure to UV stress. A phylogenetic analysis supports the hypothesis that EDS5H may be an H(+)/organic acid antiporter like EDS5. CONCLUSIONS: The data based on genetic and molecular studies indicate that EDS5H despite its homology to EDS5 does not contribute to pathogen-induced SA accumulation like EDS5. EDS5H most likely transports related substances such as for example phenolic acids, but unlikely SA. PMID- 26055509 TI - Methotrexate myelopathy after intrathecal chemotherapy: a case report. AB - INTRODUCTION: Methotrexate is often administered intrathecally or into the cerebral ventricles, particularly in patients with central nervous system tumors. However, in addition to chemical arachnoiditis, methotrexate can induce severe myelopathy. CASE PRESENTATION: A 59-year-old Japanese man with diffuse B-cell lymphoma who underwent systemic chemotherapy including methotrexate and 20 Gy of radiotherapy received intrathecal methotrexate for recurrence. Flaccid paresis of his lower limbs and fecal and urinary incontinence appeared 1 month later. All sensations were impaired below the Th10 dermatome level. Although the clinical symptoms were compatible with transverse myelitis, T2-weighted imaging of his thoracic spinal cord demonstrated signal hyperintensity localized to the posterior and lateral funiculi, which resembled subacute combined degeneration. His serum vitamin B12, folic acid, and total homocysteine levels were within normal limits, but total homocysteine levels in his cerebrospinal fluid were elevated, suggesting spinal cord demyelination. CONCLUSIONS: Little is known of the pathogenesis of methotrexate myelopathy. A possible mechanism of methotrexate myelopathy with demyelination was suggested by the increased homocysteine levels in the cerebrospinal fluid. PMID- 26055510 TI - Structure Identification of Two-Dimensional Colloidal Semiconductor Nanocrystals with Atomic Flat Basal Planes. AB - Discrete nature of thickness and flat basal planes of two-dimensional (2D) nanostructures display unique diffraction features. Their origin was uncovered by a new analysis method of powder X-ray diffraction, which reveals thickness and lattice orientation of the 2D nanostructures. Results indicate necessity of adoption of a different unit cell from the corresponding bulk crystal with the same internal atomic packing. For CdSe 2D nanostructures with zinc blende atomic packing, pseudotetragonal lattices are adequate, instead of face-centered cubic. PMID- 26055511 TI - Touraine's polyfibromatosis: a forgotten disease. PMID- 26055512 TI - Chromium Reaction Mechanisms for Speciation using Synchrotron in-Situ High Temperature X-ray Diffraction. AB - We use in situ high-temperature X-ray diffraction (HT-XRD), ex-situ XRD and synchrotron X-ray absorption near edge structure spectroscopy (XANES) to derive fundamental insights into mechanisms of chromium oxidation during combustion of solid fuels. To mimic the real combustion environment, mixtures of pure eskolaite (Cr(3+)2O3), lime (CaO) and/or kaolinite [Al2Si2O5(OH)4] have been annealed at 600-1200 degrees C in air versus 1% O2 diluted by N2. Our results confirm for the first time that (1) the optimum temperature for Cr(6+) formation is 800 degrees C for the coexistence of lime and eskolaite; (2) upon addition of kaolinite into oxide mixture, the temperature required to produce chromatite shifts to 1000 degrees C with a remarkable reduction in the fraction of Cr(6+). Beyond 1000 degrees C, transient phases are formed that bear Cr in intermediate valence states, which convert to different species other than Cr(6+) in the cooling stage; (3) of significance to Cr mobility from the waste products generated by combustion, chromatite formed at >1000 degrees C has a glassy disposition that prevents its water-based leaching; and (4) Increasing temperature facilitates the migration of eskolaite particles into bulk lime and enhances the extent to which Cr(3+) is oxidized, thereby completing the oxidation of Cr(3+) to Cr(6+) within 10 min. PMID- 26055513 TI - Intradialytic Laughter Yoga therapy for haemodialysis patients: a pre-post intervention feasibility study. AB - BACKGROUND: Laughter Yoga consists of physical exercise, relaxation techniques and simulated vigorous laughter. It has been associated with physical and psychological benefits for people in diverse clinical and non-clinical settings, but has not yet been tested in a haemodialysis setting. The study had three aims: 1) to examine the feasibility of conducting Laughter Yoga for patients with end stage kidney disease in a dialysis setting; 2) to explore the psychological and physiological impact of Laughter Yoga for these patients; and 3) to estimate the sample size required for future research. METHODS: Pre/post intervention feasibility study. Eighteen participants were recruited into the study and Laughter Yoga therapists provided a four week intradialytic program (30-min intervention three times per week). Primary outcomes were psychological items measured at the first and last Laughter Yoga session, including: quality of life; subjective wellbeing; mood; optimism; control; self-esteem; depression, anxiety and stress. Secondary outcomes were: blood pressure, intradialytic hypotensive episodes and lung function (forced expiratory volume). Dialysis nurses exposed to the intervention completed a Laughter Yoga attitudes and perceptions survey (n = 11). Data were analysed using IBM SPSS Statistics v22, including descriptive and inferential statistics, and sample size estimates were calculated using G*Power. RESULTS: One participant withdrew from the study for medical reasons that were unrelated to the study during the first week (94 % retention rate). There were non-significant increases in happiness, mood, and optimism and a decrease in stress. Episodes of intradialytic hypotension decreased from 19 pre and 19 during Laughter Yoga to 4 post Laughter Yoga. There was no change in lung function or blood pressure. All nurses agreed or strongly agreed that Laughter Yoga had a positive impact on patients' mood, it was a feasible intervention and they would recommend Laughter Yoga to their patients. Sample size calculations for future research indicated that a minimum of 207 participants would be required to provide sufficient power to detect change in key psychological variables. CONCLUSIONS: This study provides evidence that Laughter Yoga is a safe, low intensity form of intradialytic physical activity that can be successfully implemented for patients in dialysis settings. Larger studies are required, however, to determine the effect of Laughter Yoga on key psychological variables. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12614001130651 . Registered 23 October 2014. PMID- 26055514 TI - MicroRNA-101 protects cardiac fibroblasts from hypoxia-induced apoptosis via inhibition of the TGF-beta signaling pathway. AB - Cardiac fibroblasts (CFs) are the most numerous cells in the heart and are recognized primarily for their ability to maintain both the structural integrity and the physiological functions of the heart. The transforming growth factor beta (TGF-beta) signaling pathway is reportedly involved in the modulation of CF functions, including apoptosis. Recent studies have indicated that microRNA-101 (miR-101) attenuates the TGF-beta signaling pathway, either by inhibiting the expression of TGFbeta1 or by targeting transforming growth factor-beta receptor type I (TGFbetaRI). The present study aimed to determine whether miR-101 protects CFs from hypoxia-induced apoptosis and to investigate the mechanisms underlying its protective effects. The CCK-8 test, electron microscopy and TUNEL assay results demonstrated that miR-101a/b significantly inhibited hypoxia-induced CF apoptosis. The results of Western blotting, quantitative RT-PCR and immunofluorescence assays indicated that miR-101a dramatically inhibited the hypoxia-induced up-regulation of both TGFbetaRI and p-Smad 3 but not TGFbeta1 in CFs. Additionally, miR-101a significantly reversed the hypoxia-induced up regulation of Bax and Caspase-3, the down-regulation of Bcl-2 and the activation of Caspase-3 in CFs. Moreover, miR-101a markedly inhibited the intracellular Ca(2+) ([Ca(2+)]i) overload caused by hypoxia. Taken together, our results suggest that miR-101a protects CFs against hypoxia-induced apoptosis by inhibiting the TGF-beta signaling pathway, which may be a potential therapeutic target for heart injury. PMID- 26055515 TI - Death-associated protein kinase 2: Regulator of apoptosis, autophagy and inflammation. AB - Death-associated protein kinase 2 (DAPK2/DRP-1) belongs to a family of five related serine/threonine kinases that mediate a range of cellular processes, including membrane blebbing, apoptosis, and autophagy, and possess tumour suppressive functions. The three most conserved family members DAPK1/DAPK, DAPK2 and DAPK3/ZIPK share a high degree of homology in their catalytic domain, but differ significantly in their extra-catalytic structures and tissue-expression profiles. Hence, each orthologue binds to various unique interaction partners, localizes to different subcellular regions and controls some dissimilar cellular functions. In recent years, mechanistic studies have broadened our knowledge of the molecular mechanisms that activate DAPK2 and that execute DAPK2-mediated apoptosis, autophagy and inflammation. In this "molecules in focus" review on DAPK2, the structure, modes of regulation and various cellular functions of DAPK2 will be summarized and discussed. PMID- 26055516 TI - Epigenetic suppression of Fli1, a potential predisposing factor in the pathogenesis of systemic sclerosis. AB - Systemic sclerosis (SSc) is a multisystem connective tissue disease featured by immune abnormalities, vasculopathy and tissue fibrosis with unknown etiology. A series of studies on disease-susceptibility genes and twins have demonstrated the association of genetic factors with autoimmunity and disease severity and the contribution of environmental factors to the induction of clinical features in this disease. Friend leukemia virus integration 1 (Fli1), a member of Ets transcription factor family, is epigenetically suppressed in the lesional skin of SSc patients, suggesting that Fli1 is a potential predisposing factor of SSc reflecting the influence of environmental factors. Consistent with this idea, Fli1 deficiency induces SSc-like phenotypes in dermal fibroblasts and dermal microvascular endothelial cells in vivo and in vitro at molecular levels. Furthermore, Fli1 haploinsufficiency recapitulates tissue fibrosis, vascular activation and inflammation characteristic of SSc to a greater extent in bleomycin-treated mice. Importantly, bosentan, a dual endothelin receptor antagonist with a potential disease-modifying effect on SSc vasculopathy, reverses the expression of Fli1 protein by increasing its protein stability. Therefore, Fli1 may serve as a predisposing factor of SSc and can be a promising therapeutic target of this incurable and devastating disease. This article is part of a Directed Issue entitled: Epigenetics dynamics in development and disease. PMID- 26055517 TI - A perspective on the current treatment strategies for locally advanced rectal cancer. AB - The introduction of total mesorectal excision (TME) and preoperative multimodality treatment have substantially improved the management of rectal cancer reducing local recurrence and increasing sphincter-saving surgery; distant metastases however remain a clinical challenge. Besides, although surgery remains the mainstay for cure of rectal cancer with the multimodality approach (chemotherapy, radiotherapy and surgery) being the standard of care for the majority of rectal cancer patients, there is a need of individualized risk adapted treatment schemes based on clinico-pathological features because of treatment-induced morbidity and quality of life deterioration. This short viewpoint describes the emerging strategies addressing all these issues. PMID- 26055518 TI - Tenascin-C: Its functions as an integrin ligand. AB - This review summarizes the experimental evidence of tenascin-C/integrin interactions, emphasizing the identification of integrin binding sites and the effects of specific interactions on cell behavior. At least four integrins appear to bind to the third fibronectin-type 3 domain of tenascin-C: alpha9beta1, alphaVbeta3, alpha8beta1 and alphaVbeta6. The alpha9beta1 integrin recognizes a highly conserved IDG motif in this domain, while the others recognize an RGD motif. There is also significant evidence that the collagen receptor alpha2beta1 can bind to tenascin-C, but the interacting site is unknown. Tenascin-C interactions with alpha9beta1 and alphaVbeta3 can promote cell proliferation and interactions with alphaVbeta3 can also inhibit apoptosis. Interactions with alpha7beta1 integrin, which may bind to the alternatively spliced domain of tenascin-C, and alpha9beta1 integrin are able to influence the differentiation of mesenchymal stem cells into the neuronal lineage. This illustrates the potential for using our knowledge of tenascins and their integrin receptors in stem cell based therapies. PMID- 26055519 TI - The interferon-related developmental regulator 1 is used by human papillomavirus to suppress NFkappaB activation. AB - High-risk human papillomaviruses (hrHPVs) infect keratinocytes and successfully evade host immunity despite the fact that keratinocytes are well equipped to respond to innate and adaptive immune signals. Using non-infected and freshly established or persistent hrHPV-infected keratinocytes we show that hrHPV impairs the acetylation of NFkappaB/RelA K310 in keratinocytes. As a consequence, keratinocytes display a decreased pro-inflammatory cytokine production and immune cell attraction in response to stimuli of the innate or adaptive immune pathways. HPV accomplishes this by augmenting the expression of interferon-related developmental regulator 1 (IFRD1) in an EGFR-dependent manner. Restoration of NFkappaB/RelA acetylation by IFRD1 shRNA, cetuximab treatment or the HDAC1/3 inhibitor entinostat increases basal and induced cytokine expression. Similar observations are made in IFRD1-overexpressing HPV-induced cancer cells. Thus, our study reveals an EGFR-IFRD1-mediated viral immune evasion mechanism, which can also be exploited by cancer cells. PMID- 26055520 TI - [Propionibacterium granulosum bare-metal stent infection after drug-eluting balloon]. AB - INTRODUCTION: Bare-metal stents are used to treat arterial stenotic lesions. Morbidity and mortality are less important compared with other techniques. Drug eluting balloons are often used to treat stent stenosis. We reported the case of a bare-metal stent infection after drug-eluting balloon and a review on the subject. MATERIAL AND METHOD: Two weeks after percutaneous transluminal angioplasty with paclitaxel-eluting balloon and a bare-metal stent, our patient presented an infection of the stent. Diagnosis was based on the clinical presentation, positron emission tomography findings and isolation of Propionibacterium granulosum in repeated blood cultures. Adapted antibiotic therapy was given for three months with removal of the surgical bare-stent. Antibiotic therapy was interrupted after a second positron emission tomography. A literature search (PubMed and Cochrane) was performed on the subject. RESULTS: We found 49 cases of peripheral bare-metal stent infection including our patient. This is a rare but serious complication with a high morbidity (25% amputation rate) and mortality (30%). It seems to be underestimated. Treatment is based on surgical ablation of the bare-metal stent and intravenous antibiotics. The role of the paclitaxel-eluting balloon is not clearly established but some authors believe that it can produce a local immunosuppression. CONCLUSION: We report the first case of bare-metal stent infection after paclitaxel-eluting balloon. This complication is rare and difficult to diagnose. Manifestations are often limited to skin signs. Functional and vital prognosis is poor. PMID- 26055521 TI - The extramacrochaetae gene is required for blastokinesis in silkworm, Bombyx mori. AB - In silkworm, Bombyx mori Linnaeus (Lepidoptera: Bombycidae), blastokinesis results in embryo reversal from ventrally to dorsally convex flexion. In this study, we showed that the extramacrochaetae (emc) gene is required for blastokinesis in silkworm. Depletion of Bmemc expression via RNA interference led to severe phenotypic defects in blastokinesis. The defective embryos failed to invert their body sides during blastokinesis. This caused the posterior half of the abdomen to abnormally fold back toward the dorsal side, forming a U-shaped morphology. Dorsal closure was also disrupted. Our results suggest that Bmemc is involved in blastokinesis of silkworm embryos. J. Exp. Zool. (Mol. Dev. Evol.) 324B: 405-409, 2015. (c) 2015 Wiley Periodicals, Inc. PMID- 26055523 TI - On the Effects on Cortical Spontaneous Activity of the Symmetries of the Network of Pinwheels in Visual Area V1. AB - This paper challenges and extends earlier seminal work. We consider the problem of describing mathematically the spontaneous activity of V1 by combining several important experimental observations including (1) the organization of the visual cortex into a spatially periodic network of hypercolumns structured around pinwheels, (2) the difference between short-range and long-range intracortical connections, the first ones being rather isotropic and producing naturally doubly periodic patterns by Turing mechanisms, the second one being patchy, and (3) the fact that the Turing patterns spontaneously produced by the short-range connections and the network of pinwheels have similar periods. By analyzing the PO maps, we are able to classify all possible singular points (the pinwheels) as having symmetries described by a small subset of the wallpaper groups. We then propose a description of the spontaneous activity of V1 using a classical voltage based neural field model that features isotropic short-range connectivities modulated by non-isotropic long-range connectivities. A key observation is that, with only short-range connections and because the problem has full translational invariance in this case, a spontaneous doubly periodic pattern generates a 2 torus in a suitable functional space which persists as a flow-invariant manifold under small perturbations, for example when turning on the long-range connections. Through a complete analysis of the symmetries of the resulting neural field equation and motivated by a numerical investigation of the bifurcations of their solutions, we conclude that the branches of solutions which are stable over an extended range of parameters are those that correspond to patterns with an hexagonal (or nearly hexagonal) symmetry. The question of which patterns persist when turning on the long-range connections is answered by (1) analyzing the remaining symmetries on the perturbed torus and (2) combining this information with the Poincare-Hopf theorem. We have developed a numerical implementation of the theory that has allowed us to produce the predicted patterns of activities, the planforms. In particular we generalize the contoured and non-contoured planforms predicted by previous authors. PMID- 26055524 TI - Squamous cell carcinoma of the oral tongue: histopathological parameters associated with outcome. AB - The purpose of this study was to investigate the applicability of the histological risk assessment model proposed by Brandwein-Gensler et al. in a cohort of oral tongue squamous cell carcinoma (OTSCC) patients treated with definitive surgery. We also examined the impact of additional histopathological features on disease acceleration. The cases of 49 OTSCC patients attending our institution between 1995 and 2009, who underwent definitive surgical resection followed by adjunct chemoradiotherapy when indicated, were reviewed retrospectively. Surgical resection specimens and complete clinical and demographic data were available for these patients; follow-up was at least 6 months. In this cohort we only identified a correlation between gender and the histopathological risk model score (P<0.001). With regard to clinical and demographic data, histopathological parameters, and disease status at last follow up, we identified significant correlations between disease status and (1) grade of differentiation (P=0.0086), and (2) keratin score (P=0.026). We found no significant correlations between the histopathological risk assessment model and disease progression or outcomes, with the exception of gender (P<0.0001). Grade of differentiation, keratin score, and the lymphocytic host response significantly impacted disease acceleration. For OTSCC, it appears that clinical characteristics of the tumour as well as histopathological markers play an important role in the outcome. Efforts towards identifying predictive markers should be continued, especially by sub-site of the oral cavity. PMID- 26055522 TI - Effectiveness of non-pharmaceutical measures in preventing pediatric influenza: a case-control study. AB - BACKGROUND: Hygiene behavior plays a relevant role in infectious disease transmission. The aim of this study was to evaluate non-pharmaceutical interventions (NPI) in preventing pediatric influenza infections. METHODS: Laboratory confirmed influenza cases occurred during 2009-10 and 2010-11 seasons matched by age and date of consultation. NPI (frequency of hand washing, alcohol based hand sanitizer use and hand washing after touching contaminated surfaces) during seven days prior to onset of symptoms were obtained from parents of cases and controls. RESULTS: Cases presented higher prevalence of underlying conditions such as pneumonia [OR = 3.23; 95% CI: 1.38-7.58 p = 0.007], asthma [OR = 2.45; 95% CI: 1.17-5.14 p = 0.02] and having more than 1 risk factor [OR = 1.67; 95% CI: 0.99-2.82 p = 0.05]. Hand washing more than 5 times per day [aOR = 0.62; 95% CI: 0.39-0.99 p = 0.04] was the only statistically significant protective factor. When considering two age groups (pre-school age 0-4 yrs and school age 5-17) yrs , only the school age group showed a negative association for influenza infection for both washing more than 5 times per day [aOR = 0.47; 95% CI: 0.22-0.99 p = 0.04] and hand washing after touching contaminated surfaces [aOR = 0.19; 95% CI: 0.04-0.86 p = 0.03]. CONCLUSION: Frequent hand washing should be recommended to prevent influenza infection in the community setting and in special in the school age group. PMID- 26055525 TI - Significance of myofibroblast appearance in squamous cell carcinoma of the oral cavity on the occurrence of occult regional metastases, distant metastases, and survival. AB - The aim of the present study was to assess the frequency of appearance of stromal myofibroblasts in patients with oral squamous cell carcinoma (OSCC) and to further clarify whether myofibroblasts influence tumour suppression or progression. Surgical resection specimens from 152 patients with cT1-T3N0 OSCC were analysed. The frequency of myofibroblasts within the tumour stroma was assessed immunohistochemically and compared with other clinical and histopathological factors. The immunohistochemical reaction for alpha-smooth muscle actin showed positive cells in the stroma of 84.2% of OSCC (n=128). An increased presence of myofibroblasts in the tumour stroma was significantly correlated with T stage (P=0.019), the presence of occult neck metastasis (P<0.001), regional recurrence (P=0.037), and distant metastasis (P=0.008). There was also an association between the presence of myofibroblasts and patient survival (P=0.009). The presence of myofibroblasts was not associated with local recurrence, tumour cell differentiation, mode of invasion, or bone invasion. The results of this study suggest that myofibroblast proliferation facilitates tumour invasion, the occurrence of occult neck disease, and distant metastasis. The survival rate was poorer in patients with abundant myofibroblasts. Further investigations on tumour-associated stroma at the invasive front are needed in order to establish new diagnostic markers and therapeutic strategies. PMID- 26055526 TI - Influence of the Source of Social Support and Size of Social Network on All-Cause Mortality. AB - OBJECTIVE: To examine associations between relative, friend, and partner support, as well as size and source of weekly social network, and mortality risk in the Aerobics Center Longitudinal Study. PATIENTS AND METHODS: In a mail-back survey completed between January 1, 1990, and December 31, 1990, adult participants in the Aerobics Center Longitudinal Study (N=12,709) answered questions on whether they received social support from relatives, friends, and spouse/partner (yes or no for each) and on the number of friends and relatives they had contact with at least once per week. Participants were followed until December 31, 2003, or until the date of death. Cox proportional hazards regression analyses evaluated the strength of the associations, controlling for covariates. RESULTS: Participants (3220 [25%] women) averaged 53.0 +/- 11.3 years of age at baseline. During a median follow-up of 13.5 years, 1139 deaths occurred. Receiving social support from relatives reduced mortality risk by 19% (hazard ratio [HR], 0.81; 95% CI, 0.68-0.95). Receiving spousal/partner support also reduced mortality risk by 19% (HR, 0.81; 95% CI, 0.66-0.99). Receiving social support from friends was not associated with mortality risk (HR, 0.90; 95% CI, 0.75-1.09); however, participants reporting social contact with 6 or 7 friends on a weekly basis had a 24% lower mortality risk than did those in contact with 0 or 1 friend (HR, 0.76; 95% CI, 0.58-0.98). Contact with 2 to 5 or 8 or more friends was not associated with mortality risk, nor was the number of weekly contacts with relatives. CONCLUSION: Receiving social support from one's spouse/partner and relatives and maintaining weekly social interaction with 6 to 7 friends reduced mortality risk. Such data may inform interventions to improve long-term survival. PMID- 26055527 TI - Veno-venous anastomoses in twin-twin transfusion syndrome: A multicenter study. AB - INTRODUCTION: The aim of this study is to evaluate the prevalence of veno-venous (VV) anastomoses in a large cohort of monochorionic (MC) twin placentas with twin twin transfusion syndrome (TTTS) compared to a control group of MC placentas without TTTS. METHODS: All TTTS placentas not treated with fetoscopic laser surgery (TTTS group) and examined at five international fetal therapy centers were included in this study and compared with a control group of MC placentas without TTTS (non-TTTS group). MC placentas were routinely injected with colored dye. We recorded the presence of VV and arterio-arterial (AA) anastomoses. RESULTS: A total of 414 MC placentas were included in this study (TTTS group, n = 106; non-TTTS group, n = 308). The prevalence of VV anastomoses was significantly higher in the TTTS group than in the non-TTTS group, 36% (38/106) and 25% (78/308), respectively (p = .04; odds ratio (OR) 1.65; 95% confidence interval (CI): 1.03-2.64). In the subgroup of MC placentas without AA anastomoses, the prevalence of VV anastomoses in the TTTS group and non-TTTS group was 32% (18/57) and 8% (2/25), respectively (p = .03; OR: 5.31; 95% CI: 1.13-24.98). DISCUSSION: VV anastomoses are detected more frequently in TTTS placentas than in MC placentas without TTTS and may thus play a role in the development of TTTS. PMID- 26055528 TI - Cross-sectional and longitudinal lipid determination studies in pregnant women reveal an association between increased maternal LDL cholesterol concentrations and reduced human umbilical vein relaxation. AB - INTRODUCTION: Maternal hypercholesterolemia and hypertriglyceridemia during pregnancy is correlated with fetoplacental endothelial dysfunction and atherosclerotic lesions in fetal arteries. Few studies have reported the distribution of the concentrations of maternal total cholesterol (TCh), lipoprotein cholesterol and triglycerides during pregnancy. Therefore, we determined maternal lipid concentration during pregnancy and established the percentiles over which fetoplacental endothelial dysfunction is observed. METHODS: A lipoprotein profile was determined for 249 pregnant Chilean women in each trimester of pregnancy in cross-sectional and longitudinal lipid determination studies. Distribution percentiles for TCh, high-, low- and very-low density lipoprotein (HDL, LDL, and vLDL, respectively) cholesterol and triglycerides were estimated. The reactivity of human umbilical vein rings to the calcitonin gene-related peptide (0.1-1000 nmol/L, 5 min) and sodium nitroprusside (10 MUmol/L, 5 min) was measured (wire myography) in KCl-preconstricted vessels. RESULTS: Maternal lipoproteins and triglyceride concentrations increased over time from preconception to the 3rd trimester of pregnancy. Newborn umbilical blood lipoprotein and triglyceride concentrations were lower than those in maternal circulation. Changes in maternal HDL correlated with newborn HDL concentration; however, no correlation between maternal lipoprotein concentrations and newborn weight was found. Maternal TCh and LDL concentrations were inversely correlated with the maximal dilation, but the >75th percentile of maternal TCh and LDL concentrations (>291 and >169 mg/dL, respectively) correlated with reduced calcitonin gene-related peptide sensitivity of the vein rings. DISCUSSION AND CONCLUSION: We identified percentiles for maternal TCh and LDL concentrations over which abnormal endothelium-dependent human fetoplacental vascular response is observed. PMID- 26055529 TI - Sugar chain-binding specificity and native folding state of lectins preserved in hydrated ionic liquids. AB - Lectins, dissolved and stored in hydrated cholinium dihydrogen phosphate, maintained recognition and binding affinity to specific sugar chains even after thermal treatment or long-term storage. Additionally, the dissolved lectin recovered its native folding state after thermal treatment. PMID- 26055530 TI - Synthesis and evaluation of novel prenylated chalcone derivatives as anti leishmanial and anti-trypanosomal compounds. AB - Chalcones form a class of compounds that belong to the flavonoid family and are widely distributed in plants. Their simple structure and the ease of preparation make chalcones attractive scaffolds for the synthesis of a large number of derivatives enabling the evaluation of the effects of different functional groups on biological activities. In this Letter, we report the successful synthesis of a series of novel prenylated chalcones via Claisen-Schmidt condensation and the evaluation of their effect on the viability of the Trypanosomatidae parasites Leishmania amazonensis, Leishmania infantum and Trypanosoma cruzi. PMID- 26055531 TI - The Brief Aggression Questionnaire: Structure, Validity, Reliability, and Generalizability. AB - In contexts that increasingly demand brief self-report measures (e.g., experience sampling, longitudinal and field studies), researchers seek succinct surveys that maintain reliability and validity. One such measure is the 12-item Brief Aggression Questionnaire (BAQ; Webster et al., 2014), which uses 4 3-item subscales: Physical Aggression, Verbal Aggression, Anger, and Hostility. Although prior work suggests the BAQ's scores are reliable and valid, we addressed some lingering concerns. Across 3 studies (N = 1,279), we found that the BAQ had a 4 factor structure, possessed long-term test-retest reliability across 12 weeks, predicted differences in behavioral aggression over time in a laboratory experiment, generalized to a diverse nonstudent sample, and showed convergent validity with a displaced aggression measure. In addition, the BAQ's 3-item Anger subscale showed convergent validity with a trait anger measure. We discuss the BAQ's potential reliability, validity, limitations, and uses as an efficient measure of aggressive traits. PMID- 26055532 TI - Coexistence of TERT promoter and BRAF mutations in cutaneous melanoma is associated with more clinicopathological features of aggressiveness. AB - The recently described telomerase reverse transcriptase (TERT) promoter mutations are recurrent in cutaneous melanoma. Several authors have described an association between these molecular alterations, some histological parameters, and patient survival. BRAF mutations are very frequent in melanoma, but their actual role in the evolution of the disease is still unclear. Here, we investigated the relationship of TERT promoter mutations and BRAF mutations with the most relevant clinicopathological parameters, individually and coexisting, in order to evaluate their role as independent prognostic markers and to determine the effect of their coexistence. A TERT promoter alteration was found in 20 of 53 cases (38 %), significantly associated with histological type, increasing tumor thickness and mitotic rate, more advanced pathologic tumor (pT) stage, and absence of regression. A BRAF mutation was found in 21 of 53 cases (40 %), significantly associated with tumor thickness and presence of metastases in the sentinel lymph node. Coexistence of a TERT promoter and BRAF mutation was detected in 11 of 53 cases (21 %). This was associated with increasing thickness, high mitotic rate, lymph node metastasis, presence of ulceration, and absence of regression. Coexistence of a mutation in the TERT promoter and in the BRAF gene correlated with more prognostically relevant factors than either mutation alone. Our data lead us to hypothesize that TERT promoter and BRAF mutations cooperate in cutaneous melanoma. Further studies in larger cohorts of patients are needed to investigate how this synergistic effect is involved in the evolution of the disease. PMID- 26055533 TI - The early stages of tumor angiogenesis in human osteosarcoma: a nude mice xenotransplant model. AB - Osteosarcoma (Os) is the most common malignant bone tumor in childhood and not rare in adults. In recent years, much research has focused on the role of angiogenesis in tumor development, growth, invasion, and metastasis. The aims of this study were to characterize neovascularization established between the xenotransplanted Os and the host at histological, immunohistochemical, ultrastructural, and molecular level, and to evaluate if this model could be used in testing new anti-angiogenic drugs. Three xenotransplanted human Os were evaluated. Tumor pieces 3-4 mm in size were implanted subcutaneously on the back of athymic Balb-c nude mice (n = 14). The animals were killed at 24, 48, and 72 h and 7, 14, 21, and 28 days after implantation. Tumor samples were either fixed in 10 % formaldehyde and embedded in paraffin for histological analysis, or fixed with glutaraldehyde (2 %) for electron microscopy or retained non-fixed for molecular analysis (ELISA and qRT-PCR). Morphologically, intense neo vasculogenesis within tumor parenchyma was present between the first and third week after transplantation. Immunohistochemistry demonstrated overexpression of VEGF and their receptors together with PDFGFRA 24-48 h after tumor implantation. Additionally, neoplastic cells co-expressed chemokines (CXCL9, CXCL10, and GRO) and their receptors. Molecular studies showed two expression profiles, distinguishing an early and a late phase in the angiogenic process. In Os, our model showed two stages of induced angiogenesis, with close association between histological and molecular events. This approximation could be of use for testing the effect of different anti-angiogenic agents. PMID- 26055534 TI - Evaluation of functional capacity in individuals with signs and symptoms of musculoskeletal disease: results of the BRAZCO population study (Brazilian COPCORD Study). AB - The disability caused by the musculoskeletal signs and symptoms affects the quality of life of a population, especially that related to health. The objective of this study is to evaluate the functional capacity of individuals of the Brazilian population who presented musculoskeletal signs and symptoms (MSK-S). The prevalence of MSK-S was evaluated in 5000 individuals (>15 years) in 16 capitals from the five regions of Brazil using the COPCORD Core Questionnaire. Those individuals (n = 2494) that experienced MSK-S and referred some level of disability at the time of the interview were invited to complete the Health Assessment Questionnaire-Disability Index (HAQ-DI). The HAQ-DI scores were compared among regions, and subgroups according to gender, age and type of activity. Three hundred ninety-four (7.9 %) participants reported disability at the time of the interview. The average score of HAQ-DI was 1.09 (SD = 0.71), and the Brazilian region with the highest level of disability was the North region. Among individuals without history of trauma, the disability was higher when the duration of MSK-S was longer. Disability was shown to worsen with increasing age, and the group with 25-34 years showed the lowest scores. Females showed worse functional capacity scores compared to males (p = 0.002). Individuals showed higher degrees of difficulty or were incapable of performing the activities walking, reaching, usual activities and dressing. MSK-S reduce the functional capacity of individuals of the Brazilian general population. The reduction in functional capacity was mainly observed in individuals with chronic musculoskeletal complaints not due to trauma, as well as in female gender and in advancing age. PMID- 26055536 TI - Managing multiple roles: development of the Work-Family Conciliation Strategies Scale. AB - Juggling the demands of work and family is becoming increasingly difficult in today's world. As dual-earners are now a majority and men and women's roles in both the workplace and at home have changed, questions have been raised regarding how individuals and couples can balance family and work. Nevertheless, research addressing work-family conciliation strategies is limited to a conflict-driven approach and context-specific instruments are scarce. This study develops an instrument for assessing how dual-earners manage their multiple roles detaching from a conflict point of view highlighting the work-family conciliation strategies put forward by these couples. Through qualitative and quantitative procedures the Work-Family Conciliation Strategies Scales was developed and is composed by 5 factors: Couple Coping; Positive Attitude Towards Multiple Roles, Planning and Management Skills, Professional Adjustments and Institutional Support; with good adjustment [chi2/df = 1.22; CFI = .90, RMSEA = .04, SRMR = .08.] and good reliability coefficients [from .67 to .87]. The developed scale contributes to research because of its specificity to the work-family framework and its focus on the proactive nature of balancing work and family roles. The results support further use of this instrument. PMID- 26055535 TI - Left ventricular intracardiac thrombus in a patient with Behcet disease successfully treated with immunosuppressive agents without anticoagulation: a case report and review of the literature. AB - Behcet disease (BD) is a chronic multisystem disorder with vasculitis underlying its systemic manifestations. Cardiac involvement and particularly left ventricular intracardiac thrombus are rarely diagnosed in the course of BD and are often associated with poor prognosis. The causes of intracardiac thrombi are unknown. It is plausible that specific proinflammatory pathways resulting in the endothelial cell injury and hypercoagulation contribute to the formation of thrombotic masses in the heart. Known thrombophilic factors such as methylenetetrahydrofolate reductase gene mutations, factor V Leiden mutation, proteins S and C, antithrombin III, activated protein C resistance, and antiphospholipid antibodies may contribute to the formation of intracardiac thrombi in BD. We report a case of a 24-year-old male patient with BD presented with left ventricular thrombus. Transthoracic echocardiography allowed to describe and monitor such a rare cardiac manifestation of the disease. A combination of high-dose corticosteroid and azathioprine successfully dissolved intracardiac thrombus within ten days without anticoagulation. PMID- 26055537 TI - Frey procedure for chronic pancreatitis: Evidence-based assessment of short- and long-term results in comparison to pancreatoduodenectomy and Beger procedure: A meta-analysis. AB - BACKGROUND AND OBJECTIVE: Patients with chronic pancreatitis often require surgical treatment. The aim of this study was to evaluate the published evidence for Frey procedure in patients with chronic pancreatitis. METHODS: Literature search was undertaken to identify eligible studies until February 2015. Using meta-analytical techniques, Frey procedure was compared with pancreatoduodenectomy or Beger procedure, and the short- and long-term outcomes were analysed. RESULTS: Twenty-three studies comprising a total of 800 patients were reviewed. The postoperative morbidity and mortality were 23.2% and 0.4% respectively. The percentage of postoperative pain-relief patients was 89.4%. New onset of diabetes and exocrine insufficiency was present in 17.3% and 30.7% of patients, respectively. Compared with pancreatoduodenectomy, Frey procedure had favorable outcomes in terms of operation time, blood transfusion, overall morbidity, length of hospital and intensive care unit stay, pancreatic function and quality of life. Compared with Beger procedure, Frey procedure had shorter operation time and lower morbidity. CONCLUSIONS: Frey procedure is a safe and effective surgical procedure for chronic pancreatitis with dilated duct in the absence of neoplasia. PMID- 26055539 TI - ICOSA: A Distance-Dependent, Orientation-Specific Coarse-Grained Contact Potential for Protein Structure Modeling. AB - The relative distance and orientation in contacting residue pairs plays a significant role in protein folding and stabilization. We hereby devise a new knowledge-based, coarse-grained contact potential, so-called ICOSA, by correlating inter-residue contact distance and orientation in evaluating pair wise inter-residue interactions. The rationale of our approach is to establish icosahedral local coordinates to estimate the statistical residue contact distributions in all spherical triangular shells within a sphere. We extend the theory of finite ideal gas reference state to icosahedral local coordinates. ICOSA incorporates long-range contact interactions, which is critical to ICOSA sensitivity and is justified in statistical rigor. With only backbone atoms information, ICOSA is at least comparable to all-atom, fine-grained potentials such as Rosetta, DFIRE, I-TASSER, and OPUS in discriminating near-natives from misfold protein conformations in the Rosetta and I-TASSER protein decoy sets. ICOSA also outperforms a set of widely used coarse-grained potentials and is comparable to all-atom, fine-grained potentials in identifying CASP10 models. PMID- 26055538 TI - E. coli RNA Polymerase Determinants of Open Complex Lifetime and Structure. AB - In transcription initiation by Escherichia coli RNA polymerase (RNAP), initial binding to promoter DNA triggers large conformational changes, bending downstream duplex DNA into the RNAP cleft and opening 13bp to form a short-lived open intermediate (I2). Subsequent conformational changes increase lifetimes of lambdaPR and T7A1 open complexes (OCs) by >10(5)-fold and >10(2)-fold, respectively. OC lifetime is a target for regulation. To characterize late conformational changes, we determine effects on OC dissociation kinetics of deletions in RNAP mobile elements sigma(70) region 1.1 (sigma1.1), beta' jaw and beta' sequence insertion 3 (SI3). In very stable OC formed by the wild type WT RNAP with lambdaPR (RPO) and by Deltasigma1.1 RNAP with lambdaPR or T7A1, we conclude that downstream duplex DNA is bound to the jaw in an assembly with SI3, and bases -4 to +2 of the nontemplate strand discriminator region are stably bound in a positively charged track in the cleft. We deduce that polyanionic sigma1.1 destabilizes OC by competing for binding sites in the cleft and on the jaw with the polyanionic discriminator strand and downstream duplex, respectively. Examples of sigma1.1-destabilized OC are the final T7A1 OC and the lambdaPR I3 intermediate OC. Deleting sigma1.1 and either beta' jaw or SI3 equalizes OC lifetimes for lambdaPR and T7A1. DNA closing rates are similar for both promoters and all RNAP variants. We conclude that late conformational changes that stabilize OC, like early ones that bend the duplex into the cleft, are primary targets of regulation, while the intrinsic DNA opening/closing step is not. PMID- 26055540 TI - Assessment of adhesion, invasion and cytotoxicity potential of oral Staphylococcus aureus strains. AB - The oral cavity is regarded as a relevant site for Staphylococcus aureus colonization. However, characterization of virulence mechanisms of oral S. aureus remains to be uncovered. In this study, twenty one S. aureus strains isolated from the oral cavity of Tunisian patients were screened for adherence, invasion and cytotoxicity against HeLa cells. In addition, the presence of adhesins (icaA, icaD, can, fnbA and fnbB) and alpha-hemolysin (hla) genes in each strain was achieved by polymerase chain reaction (PCR). Our finding revealed that oral S. aureus strains were able to adhere and invade epithelial cells, with variable degrees (P < 0.05). Moreover they exhibited either low (23.8%) or moderate (76.2%) cytotoxic effects. In addition 76.2% of strains were icaA and icaD positive and 90.5% harbor both the fnbA and the fnbB gene. While the cna gene was detected in 12 strains (57.2%). Furthermore, the hla gene encoding the alpha toxin was found in 52.4% of the isolates. All these virulence factors give to S. aureus the right qualities to become a redoubtable pathogen associated to oral infections. PMID- 26055541 TI - Measuring teachers' knowledge of attention deficit hyperactivity disorder: the MAE-TDAH Questionnaire. AB - The lack of methodological rigor is frequent in most of instruments developed to assess the knowledge of teachers regarding Attention Deficit Hyperactivity Disorder (ADHD). The aim of this study was to develop a questionnaire, namely Questionnaire for the evaluation of teachers' knowledge of ADHD (MAE-TDAH), for measuring the level of knowledge about ADHD of infant and primary school teachers. A random sample of 526 teachers from 57 schools in the Autonomous Community of the Basque Country and Navarre was used for the analysis of the psychometric properties of the instrument. The participant teachers age range was between 22 and 65 (M = 42.59; SD = 10.89), and there were both generalist and specialized teachers. The measure showed a 4 factor structure (Etiology of ADHD, Symptoms/Diagnosis of ADHD, General information about ADHD and Treatment of ADHD) with adequate internal consistency (Omega values ranged between .83 and .91) and temporal stability indices (Spearman's Rho correlation values ranged between .62 and .79). Furthermore, evidence of convergent and external validity was obtained. Results suggest that the MAE-TDAH is a valid and reliable measure when it comes to evaluating teachers' level of knowledge of ADHD. PMID- 26055543 TI - Non-Newtonian rheological properties of shearing nematic liquid crystal model systems based on the Gay-Berne potential. AB - The viscosities and normal stress differences of various liquid crystal model systems based on the Gay-Berne potential have been obtained as functions of the shear rate in the non-Newtonian regime. Various molecular shapes such as regular convex calamitic and discotic ellipsoids and non-convex shapes such as bent core molecules and soft ellipsoid strings have been examined. The isotropic phases were found to be shear thinning with the shear rate dependence of the viscosity following a power law in the same way as alkanes and other non-spherical molecules. The nematic phases turned out to be shear thinning but the logarithm of the viscosity proved to be an approximately linear function of the square root of the shear rate. The normal stress differences were found to display a more or less parabolic dependence on the shear rate in the isotropic phase whereas this dependence was linear at low to intermediate shear rates in the nematic phase. PMID- 26055542 TI - Molecular insights into a tetraspanin in the hydatid tapeworm Echinococcus granulosus. AB - BACKGROUND: Cystic echinococcosis (hydatid disease), caused by the tapeworm Echinococcus granulosus (class Cestoda; family Taeniidae), is a neglected tropical disease that results in morbidity and mortality in millions of humans, as well as in huge economic losses in the livestock industry globally. Proteins from the tetraspanin family in parasites have recently become regarded as crucial molecules in interaction with hosts in parasitism and are therefore suitable for the development of vaccines and diagnostic agents. However, no information is available to date on E. granulosus tetraspanin. METHODS: In this study, a uroplakin-I-like tetraspanin (Eg-TSP1) of E. granulosus was cloned and expressed in E. coli. The immunolocalization of Eg-TSP1 in different life stages of E. granulosus was determined using specific polyclonal antibody. The antibody and cytokine profiles of mice that immunized with recombinant Eg-TSP1 (rEg-TSP1) were measured for the immunogenicity analysis of this protein. Additionally, we use RNA interference method to explore the biological function of Eg-TSP1 in larva of E. granulosus. RESULTS: Immunofluorescence analysis showed that endogenous Eg TSP1 mainly localized in the tegument of larvae and adults. Significantly elevated levels of antibodies IgG1 and IgG2a and of cytokines IFN-gamma and IL-12 were observed in the sera of mice after immunization with rEg-TSP1, suggesting a typical T helper (Th)1-mediated immune response elicited by rEg-TSP1. On further probing the role of Eg-TSP1 in E. granulosus by RNA interference, we found that a thinner tegmental distal cytoplasm was induced in protoscoleces treated with siRNA-132 compared to controls. CONCLUSIONS: This is the first report characterizing a tetraspanin from the tapeworm E. granulosus. Our results suggest that Eg-TSP1 is associated with biogenesis of the tegument and maintenance of structural integrity of E. granulosus and could therefore be a candidate intervention target for control of hydatid disease. PMID- 26055544 TI - A Segmentation Framework of Pulmonary Nodules in Lung CT Images. AB - Accurate segmentation of pulmonary nodules is a prerequisite for acceptable performance of computer-aided detection (CAD) system designed for diagnosis of lung cancer from lung CT images. Accurate segmentation helps to improve the quality of machine level features which could improve the performance of the CAD system. The well-circumscribed solid nodules can be segmented using thresholding, but segmentation becomes difficult for part-solid, non-solid, and solid nodules attached with pleura or vessels. We proposed a segmentation framework for all types of pulmonary nodules based on internal texture (solid/part-solid and non solid) and external attachment (juxta-pleural and juxta-vascular). In the proposed framework, first pulmonary nodules are categorized into solid/part-solid and non-solid category by analyzing intensity distribution in the core of the nodule. Two separate segmentation methods are developed for solid/part-solid and non-solid nodules, respectively. After determining the category of nodule, the particular algorithm is set to remove attached pleural surface and vessels from the nodule body. The result of segmentation is evaluated in terms of four contour based metrics and six region-based metrics for 891 pulmonary nodules from Lung Image Database Consortium and Image Database Resource Initiative (LIDC/IDRI) public database. The experimental result shows that the proposed segmentation framework is reliable for segmentation of various types of pulmonary nodules with improved accuracy compared to existing segmentation methods. PMID- 26055545 TI - Connective tissue diseases: Large intergenic noncoding RNA linked to disease activity and organ damage in SLE. PMID- 26055546 TI - Spondyloarthropathies: EULAR recommendations reflect advances in imaging. PMID- 26055547 TI - Rheumatoid arthritis: Manipulating the FLS 'proteoglycan switch' could offer a new approach to RA therapy. PMID- 26055548 TI - Bigger Foot: Kaposi's Sarcoma. PMID- 26055549 TI - Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells. AB - Cullin4A (CUL4A) is implicated in many cellular events including cell survival and growth. However, the specific function and underlying mechanisms of CUL4A in cancer invasion have not yet been elucidated. In this work, we were focused on investigating the role of CUL4A in human osteosarcoma (OS). The expression level of CUL4A was evaluated by immunohistochemical (IHC) assay in human OS tissues. Lentivirus-mediated CUL4A shRNA (Lv-shCUL4A) constructed by us was transfected into OS cells for assessing its effects on cell proliferation and invasive potential, respectively detected by MTT and Transwell assays. It was demonstrated that the expression of CUL4A protein was markedly increased in OS tissues compared with the adjacent non-cancerous tissues (ANCT) (57.8% vs. 25.6%, P = 0.019), and was associated with the distant metastases in OS patients (P = 0.016). In vitro, silencing of CUL4A gene inhibited OS cell proliferation and invasion, and induced cell apoptosis, followed by increased expression of p27 and p53 and decreased expression of MMP-2. Therefore, these findings indicate that elevated expression of CUL4A is positively correlated with distant metastases in OS patients, and knockdown of CUL4A suppresses invasion and induces apoptosis in OS cells, suggesting that CUL4A may serve as a potential target for the treatment of OS. PMID- 26055550 TI - Relationship Between Diet and Body Composition After Biliopancreatic Diversion. AB - BACKGROUND: Biliopancreatic diversion (BPD) has been shown to be one of the most effective techniques for losing weight, although the relationship between body composition and diet after the procedure is not well known. Our aim was to assess dietary changes and their effects on body composition. METHODOLOGY: This longitudinal study included all patients eligible for BPD who had undergone body composition analysis. Two assessments were performed: 6 weeks before and 1 year after surgery. Nutritional education was given after surgery by a registered dietitian, and dual energy X-ray absorptiometry was performed and a 3-day food record was collected for further analysis at both of the visits. RESULTS: Forty six patients were included. The percentage of excess of weight loss was 61.03 % (SD 14.01 %), which was statistically different by gender (p = 0.045). The percentage of subjects reporting a low daily protein consumption of less than 60 g and 1.2 g/kg of ideal body weight (IBW)/day was 15.2 % before surgery and 19.6 % at 12 months (p = 0.006). The weight loss was mainly of fat mass (FM). There were differences of body composition by gender before and after surgery. A simple correlation analysis showed a significant association between daily energy intake and FM (g) only before surgery (p = 0.030), and also between daily protein intake (expressed as total g) and lean body mass (LBM) 12 months after surgery (p = 0.018), but no association was found with achieved protein goal. CONCLUSION: BPD enhanced by nutritional education seems to improve its results by achieving an adequate weight loss, preserving LBM, decreasing FM, and guaranteeing an appropriate protein intake. PMID- 26055551 TI - The Time to Weight-Loss Steady State After Gastric Bypass Predicts Weight-Loss Success. AB - BACKGROUND: There is marked variability in weight loss achieved after laparoscopic Roux-en-Y gastric bypass (LRYGB) with little ability to predict pre operatively poor weight-loss outcomes. In this study, we categorize the patterns of post-operative weight loss after LRYGB by using a novel method of measurement based on the time to weight-loss steady state (SS). METHODS: A bariatric database was retrospectively reviewed for patients who underwent a LRYGB from 01/2001 12/2010. SS was defined as the month when the patient had <=3% excess weight loss (%EWL) or weight gain from the prior visit. Percent total weight loss (%TWL) and %EWL were compared based on time to SS. RESULTS: The average time to SS was 15.5 months (n = 178). A percentage of 7.3 of patients lost >5%EWL after achieving their SS weight. Patients with SS <12 months (n = 47) had a significantly lower %TWL and %EWL at SS and a 3-4-year follow-up compared to SS >=12 months (n = 131, p < 0.05 for all). Initial weight loss velocity (IWLV) and body mass index (BMI) were not significantly associated with the time to SS. Patients with a SS <12 months were significantly older than patients with SS >=months (42.7 +/- 10.5 versus 46.5 +/- 11.8 years, p = 0.05). CONCLUSIONS: Few patients achieve meaningful weight loss after SS. The time to SS varies significantly among LRYGB patients and is not predicted by the IWLV or BMI. Achievement of SS within the first year after surgery is more common with increasing age and may represent rapid physiologic adaptation with significantly lower %TWL and %EWL. PMID- 26055552 TI - Parental communication and life satisfaction in adolescence. AB - This study aims to analyze the influence of communication with the mother and father on adolescents' life satisfaction, as well as possible indirect effects through self-esteem, feelings of loneliness, and perceived classroom environment. These relationships, and possible gender differences, were analyzed in a sample of 1,795 adolescents (52% male, 48% female) aged 11 to 18 years-old (M = 14.2, SD = 1.68), using structural equation modeling. Results indicate a direct effect of communication-mother (girls: beta = .19, p < .001; boys: beta = .16, p < .05) and communication-father (girls: beta = .22, p < .001; boys: beta = .17, p < .05) on adolescent life satisfaction; and also indirect effects through self-esteem (communication-mother: girls, beta = .18, p < .01; boys: beta = .19, p < .05; communication-father: girls: beta = .28, p < .001; boys: beta = .27, p < .01) and feelings of loneliness (communication-mother: girls: beta = -.19, p < .01; boys: beta = -.21, p < .05; communication-father: girls: beta = -.31, p < .001; boys: beta = -.20, p < .01). The results and implications of this study are discussed. PMID- 26055553 TI - CCR5 deficiency increased susceptibility to lipopolysaccharide-induced acute renal injury. AB - C-C chemokine receptor 5 (CCR5) regulates leukocyte chemotaxis and activation, and its deficiency exacerbates development of nephritis. Therefore, we investigated the role of CCR5 during lipopolysaccharide (LPS)-induced acute kidney injury. CCR5-deficient (CCR5-/-) and wild-type (CCR5+/+) mice, both aged about 10 months, had acute renal injury induced by intraperitoneal injection of LPS (10 mg/kg). Compared with CCR5+/+ mice, CCR5-/- mice showed increased mortality and renal injury, including elevated creatinine and blood urea nitrogen levels, following LPS challenge. Compared to CCR5+/+ mice, CCR5-/- mice also exhibited greater increases in the serum concentrations of pro-inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta following LPS challenge. Furthermore, infiltration of macrophages and neutrophils, expression of intracellular adhesion molecule (ICAM)-1, and the number of apoptotic cells were more greatly increased by LPS treatment in CCR5-/- mice than in CCR5+/+ mice. The concentrations of pro-inflammatory cytokines such as TNF-alpha, IL-6, and IL-1beta were also significantly increased in the kidney of CCR5-/- mice after LPS challenge. Moreover, primary kidney cells from CCR5-/- mice showed greater increases in TNF-alpha production and p38 MAP kinase activation following treatment with LPS compared with that observed in the cells from CCR5+/+ mice. LPS-induced TNF-alpha production and apoptosis in the primary kidney cells from CCR5-/- mice were inhibited by treatment with p38 MAP kinase inhibitor. These results suggest that CCR5 deficiency increased the production of TNF-alpha following LPS treatment through increased activation of the p38 pathway in the kidney, resulting in renal apoptosis and leukocyte infiltration and led to exacerbation of LPS-induced acute kidney injury. PMID- 26055555 TI - Dominant luminescence is not due to quantum confinement in molecular-sized silicon carbide nanocrystals. AB - Molecular-sized colloid silicon carbide (SiC) nanoparticles are very promising candidates to realize bioinert non-perturbative fluorescent nanoparticles for in vivo bioimaging. Furthermore, SiC nanoparticles with engineered vacancy-related emission centres may realize magneto-optical probes operating at nanoscale resolution. Understanding the nature of molecular-sized SiC nanoparticle emission is essential for further applications. Here we report an efficient and simple method to produce a relatively narrow size distribution of water soluble molecular-sized SiC nanoparticles. The tight control of their size distribution makes it possible to demonstrate a switching mechanism in the luminescence correlated with particle size. We show that molecular-sized SiC nanoparticles of 1-3 nm show a relatively strong and broad surface related luminescence whilst the larger ones exhibit a relatively weak band edge and structural defect luminescence with no evidence of quantum confinement effect. PMID- 26055554 TI - Zebrafish Oatp-mediated transport of microcystin congeners. AB - Microcystins (MC), representing >100 congeners being produced by cyanobacteria, are a hazard for aquatic species. As MC congeners vary in their toxicity, the congener composition of a bloom primarily dictates the severity of adverse effects and appears primarily to be governed by toxicokinetics, i.e., whether transport of MCs occurs via organic anion-transporting polypeptides (Oatps). Differences in observed MC toxicity in various fish species suggest differential expression of Oatp subtypes leading to varying tissue distribution of the very same MC congener within different species. The objectives of this study were the functional characterization and analysis of the tissue distribution of Oatp subtypes in zebrafish (Danio rerio) as a surrogate model for cyprinid fish. Zebrafish Oatps (zfOatps) were cloned, and the organ distribution was determined at the mRNA level. zfOatps were transiently expressed in HEK293 cells for functional characterization using the Oatp substrates estrone-3-sulfate, taurocholate and methotrexate and specific MC congeners (MC-LR, MC-RR, MC-LF and MC-LW). Novel zfOatp isoforms were isolated. Among these isoforms, the organ specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily was identified. At the functional level, zfOatp1d1, zfOatp1f2, zfOatp1f3 and zfOatp1f4 transported at least one of the Oatp substrates, and zfOatp1d1, zfOatp1f2 and zfOatp1f4 were shown to transport MC congeners. MC-LF and MC-LW were generally transported faster than MC-LR and MC-RR. The subtype-specific expression of zfOatp1d1 and of members of the zfOatp1f subfamily as well as differences in the transport of MC congeners could explain the MC congener dependent differences in toxicity in cyprinids. PMID- 26055556 TI - The differential effects of Autism and Down's syndrome on sexual behavior. AB - Although sexuality plays a major role in the socialization of people, few studies have examined the sexual behaviors of individuals with developmental disabilities. Because of this, we decided to investigate sexuality in adolescents with autism spectrum disorder (ASD) and Down's syndrome (Ds) and to compare them with typically developing adolescents, by surveying their parents. Specifically, it was hypothesized that young people with ASD would display lower levels over five domains: social behavior, privacy, sex education, sexual behavior, and parental concerns, than peers with Ds and typically developing young people. In addition, we sought to verify developmental trends in five domains with age for each group. Overall, 269 parents participated; 94 parents of typically developing adolescents, 93 parents of adolescents diagnosed with Ds, and 82 parents of adolescents diagnosed with ASD. Participants were surveyed with a Sexual Behavior Scale developed by Stokes and Kaur [] that assesses parents' reports of their child's: social behavior, privacy awareness, sex education, sexual behavior and parental concerns about the child's behaviors. It was found that three groups were significantly different on all five domains, adolescents with ASD reportedly displaying lower levels than other groups. Moreover, there was a significant improvement in knowledge of privacy and parental concerns with age for adolescents with ASD and a decline in sex education for adolescents with Ds. The results obtained emphasize the need to train adolescents with developmental disability, and especially for adolescents with ASD through sex education programs. PMID- 26055557 TI - Rapid diagnostics for melioidosis: a comparative study of a novel lateral flow antigen detection assay. AB - The rapid diagnosis of septicaemic melioidosis will have an impact on reduction of mortality. Currently, this relies almost exclusively upon culture of the causative agent Burkholderia pseudomallei from clinical samples. In acute sepsis, blood is the preferred specimen for culture and therefore should be the target for a rapid diagnostic tool. A lateral flow immunoassay (LFI) for the detection of B. pseudomallei antigen has been developed. This was compared with molecular detection using the targets T3SS1 and IpxO. Forty-five clinical samples of EDTA blood, which were culture-positive, were tested using both modalities. The LFI had a sensitivity of 40 %, whilst molecular detection had a sensitivity of 20 %. The poor performance of molecular detection has been described previously and is largely related to the use of whole-blood specimens collected into blood tubes containing EDTA. Whilst suboptimal, the LFI would be an adjunct in the rapid diagnosis of melioidosis. PMID- 26055558 TI - Activation of PrfA results in overexpression of virulence factors but does not rescue the pathogenicity of Listeria monocytogenes M7. AB - Listeria monocytogenes encodes a transcriptional activator, PrfA, to positively regulate the expression of virulence factors. Several mutations in PrfA (PrfA*) have been found to contribute to increased regulatory activity. Here, we describe a strain, M7, containing a PrfA*(G145S) that activates expression of virulence factors but with low pathogenicity. To study this contradictory relationship, we exchanged the prfA genes between strains EGDe and M7 (designated EGDe-prfA(M7) and M7-prfA(EGDe)). The phospholipase B (PlcB) and listeriolysin O (LLO) activities were significantly upregulated in the strain EGDe-prfA(M7) (PrfA*). Constitutive activation of PrfA potentiated virulence of the pathogenic strain EGDe, shown as increased adhesion and invasion as well as enhanced cell-to-cell spread in cultured cell lines. However, the strain M7, though PrfA-activated, had significant defects in these virulence-related phenotypes and low pathogenicity in the murine infection model, as compared with EGDe or EGDe-PrfA(M7). To further uncover the possible mechanisms, we analysed abundance and distributions of InlA, InlB, LLO and ActA proteins, all regulated by PrfA, in EGDe, M7 and their prfA mutants. Western blotting showed that the PrfA-regulated genes of constitutively activated PrfA strains were overexpressed in vitro, while different distributions were observed. In contrast to the virulent strain EGDe-prfA(M7), the majority of InlB in M7 was detected in the culture supernatant and not on the bacterial surface. We suppose that the low virulence of strain M7 is due to its defects in infecting host cells, possibly as a result of failed anchorage on the bacterial cells of surface proteins like InlB, a major protein involved in adhesion and invasion of pathogenic L. monocytogenes strains. Further research is warranted to address why InlB detaches from the bacterial cells of this particular strain. PMID- 26055559 TI - The Impacts of Mosquito Density and Meteorological Factors on Dengue Fever Epidemics in Guangzhou, China, 2006-2014: a Time-series Analysis. AB - OBJECTIVE: To explore the associations between the monthly number of dengue fever(DF) cases and possible risk factors in Guangzhou, a subtropical city of China. METHODS: The monthly number of DF cases, Breteau Index (BI), and meteorological measures during 2006-2014 recorded in Guangzhou, China, were assessed. A negative binomial regression model was used to evaluate the relationships between BI, meteorological factors, and the monthly number of DF cases. RESULTS: A total of 39,697 DF cases were detected in Guangzhou during the study period. DF incidence presented an obvious seasonal pattern, with most cases occurring from June to November. The current month's BI, average temperature (Tave), previous month's minimum temperature (Tmin), and Tave were positively associated with DF incidence. A threshold of 18.25 degrees C was found in the relationship between the current month's Tmin and DF incidence. CONCLUSION: Mosquito density, Tave, and Tmin play a critical role in DF transmission in Guangzhou. These findings could be useful in the development of a DF early warning system and assist in effective control and prevention strategies in the DF epidemic. PMID- 26055560 TI - Hypertension Screening and Follow-up Management by Primary Health Care System among Chinese Population Aged 35 Years and Above. AB - OBJECTIVE: To describe hypertension screening and follow-up management among Chinese population aged 35 years and above within the primary health care system. METHODS: Data from 2010 China Chronic Disease and Risk Factor Surveillance System were used. We investigated previous hypertension diagnosis, screening, and follow up assessments within the primary health care system. The prevalence of self reported and criterion-based hypertension, screening rates, demographic and socioeconomic characteristics associated with screening, and patterns of follow up assessments were recorded. The SAS software system was used for statistical analyses. RESULTS: About 17.1% reported a previous hypertension diagnosis. The rate difference between the two measures of prevalence was 27.2%. Among those without self-reported hypertension, 27.7% reported never visiting a clinic during the past 1 year and 60.4% of those attending a clinic reported ever being screened. Younger age group was associated with lower screening proportion; odds ratios of 35-, 45-, 55-, and ?65 years were 1.7 (95% CI: 1.5-1.9), 1.5 (95% CI: 1.3-1.7), 1.3 (95% CI: 1.2-1.4), and 1.0, respectively. About 35.1% of the patients had undergone follow-up assessments four or more times during the past 1 year. CONCLUSION: Majority of the Chinese population aged 35 years and above, particularly the less educated, elderly population, and rural residents were unaware of that they were suffering from hypertension. Most patients did not receive enough management services by the primary health care system. Thus, strengthening both the screening and follow-up management is needed. PMID- 26055561 TI - Toxicity of Graphene Quantum Dots in Zebrafish Embryo. AB - OBJECTIVE: To evaluate the bio-safety of graphene quantum dots (GQDs), we studied its effects on the embryonic development of zebrafish. METHODS: In vivo, biodistribution and the developmental toxicity of GQDs were investigated in embryonic zebrafish at exposure concentrations ranging from 12.5-200 MUg/mL for 4 96 h post-fertilization (hpf). The mortality, hatch rate, malformation, heart rate, GQDs uptake, spontaneous movement, and larval behavior were examined. RESULTS: The fluorescence of GQDs was mainly localized in the intestines and heart. As the exposure concentration increased, the hatch and heart rate decreased, accompanied by an increase in mortality. Exposure to a high level of GQDs (200 MUg/mL) resulted in various embryonic malformations including pericardial edema, vitelline cyst, bent spine, and bent tail. The spontaneous movement significantly decreased after exposure to GQDs at concentrations of 50, 100, and 200 MUg/mL. The larval behavior testing (visible light test) showed that the total swimming distance and speed decreased dose-dependently. Embryos exposed to 12.5 MUg/mL showed hyperactivity while exposure to higher concentrations (25, 50, 100, and 200 MUg/mL) caused remarkable hypoactivity in the light-dark test. CONCLUSION: Low concentrations of GQDs were relatively non-toxic. However, GQDs disrupt the progression of embryonic development at concentrations exceeding 50 MUg/mL. PMID- 26055562 TI - Association between Ambient Air Pollution and Hospital Emergency Admissions for Respiratory and Cardiovascular Diseases in Beijing: a Time Series Study. AB - OBJECTIVE: To investigate the association between ambient air pollution and hospital emergency admissions in Beijing. METHODS: In this study, a semi parametric generalized additive model (GAM) was used to evaluate the specific influences of air pollutants (PM10, SO2, and NO2) on hospital emergency admissions with different lag structures from 2009 to 2011, the sex and age specific influences of air pollution and the modifying effect of seasons on air pollution to analyze the possible interaction. RESULTS: It was found that a 10 MUg/m3 increase in concentration of PM10 at lag 03 day, SO2 and NO2 at lag 0 day were associated with an increase of 0.88%, 0.76%, and 1.82% respectively in overall emergency admissions. A 10 MUg/m3 increase in concentration of PM10, SO2 and NO2 at lag 5 day were associated with an increase of 1.39%, 1.56%, and 1.18% respectively in cardiovascular disease emergency admissions. For lag 02, a 10 MUg/m3 increase in concentration of PM10, SO2 and NO2 were associated with 1.72%, 1.34%, and 2.57% increases respectively in respiratory disease emergency admissions. CONCLUSION: This study further confirmed that short-term exposure to ambient air pollution was associated with increased risk of hospital emergency admissions in Beijing. PMID- 26055563 TI - Trend Analysis of Cancer Mortality in the Jinchang Cohort, China, 2001-2010. AB - OBJECTIVE: To describe the baseline data of cancers in the Jinchang Cohort, this paper examined trends in cancer mortality among adults investigated in Jinchang, Gansu province from 2001 to 2010. METHODS: Mortality data were collected from company departments through administrative documents, death certificates, etc. Trend analyses of cancer mortality were performed on the basis of 925 cancer deaths between 2001 and 2010. RESULTS: The crude mortality rate of cancer continuously increased from 161.86 per 100,000 in 2001 to 315.32 per 100,000 in 2010, with an average increase of 7.69% per year in the Jinchang Cohort (16.41% in females compared to 6.04% in males), but the age-standardized mortality rate increased only in females. Thirteen leading cancers accounted for 92.10% of all cancer deaths. The five leading causes of cancer mortality in males were lung, gastric, liver, esophageal, and colorectal cancer, whereas those in females were lung, liver, gastric, breast, and esophageal cancer. CONCLUSION: The overall cancer mortality rate increased from 2001 to 2010 in the Jinchang Cohort, with greater rate of increase in females than in males. Lung, breast, and gastric cancer, in that order, were the leading causes of increased cancer mortality in females. PMID- 26055564 TI - Dietary Patterns Associated Metabolic Syndrome in Chinese Adults. AB - Dietary pattern has been revealed to be associated with metabolic syndrome. However, the association was not well documented in Chinese due to the complexity of Chinese foods. We mainly assessed the dietary patterns and examined their effects on metabolic syndrome among Chinese adults. Four dietary patterns including 'Refined Grains & Vegetables' Pattern, 'Dairy & Eggs' Pattern, 'Organ Meat & Poultry' Pattern, and 'Coarse Grains & Beans' Pattern were extracted. 'Dairy & Eggs' Pattern was associated with a decreased odds of metabolic syndrome in women, and 'Coarse Grains & Beans' Pattern was associated with a decreased odds of hypertension in men. These results provided a scientific basis for future research and dietary guideline perfection. PMID- 26055565 TI - Real-time RT-PCR Assay for the detection of Tahyna Virus. AB - A real-time RT-PCR (RT-qPCR) assay for the detection of Tahyna virus was developed to monitor Tahyna virus infection in field-collected vector mosquito samples. The targets selected for the assay were S segment sequences encoding the nucleocapsid protein from the Tahyna virus. Primers and probes were selected in conserved regions by aligning genetic sequences from various Tahyna virus strains available from GenBank. The sensitivity of the RT-qPCR approach was compared to that of a standard plaque assay in BHK cells. RT-qPCR assay can detect 4.8 PFU of titrated Tahyna virus. Assay specificities were determined by testing a battery of arboviruses, including representative strains of Tahyna virus and other arthropod-borne viruses from China. Seven strains of Tahyna virus were confirmed as positive; the other seven species of arboviruses could not be detected by RT qPCR. Additionally, the assay was used to detect Tahyna viral RNA in pooled mosquito samples. The RT-qPCR assay detected Tahyna virus in a sensitive, specific, and rapid manner; these findings support the use of the assay in viral surveillance. PMID- 26055566 TI - Inhibiting Smooth Muscle Cell Proliferation via Immobilization of Heparin/Fibronectin Complexes on Titanium Surfaces. AB - The aim of this study was to investigate the inhibitory effect of heparin/fibronectin (Hep/Fn) complexes on neointimal hyperplasia following endovascular intervention. Hep/Fn complexes were immobilized onto titanium (Ti) surfaces, with subsequent X-ray photoelectron spectroscopy (XPS), Toluidine Blue O (TBO) and immunohistochemistry methods were used to characterize surface properties. Smooth muscle cell (SMC) cultures were used to evaluate the effect of Hep/Fn complexes on SMC proliferation. Results showed that Hep/Fn complexes successfully immobilized onto Ti surfaces and resulted in an inhibition of SMC proliferation. This study suggests that Hep/Fn surface-immobilized biomaterials develop as a new generation of biomaterials to prevent neointimal hyperplasia, particularly for use in cardiovascular implants. PMID- 26055567 TI - Benchmark Dose Estimation for Cadmium-Induced Renal Effects Based on a Large Sample Population from Five Chinese Provinces. AB - A survey involving 6103 participants from five Chinese provinces was conducted to evaluate the threshold value of urinary cadmium (UCd) for renal dysfunction as benchmark dose low (BMDL). The urinary N-acetyl-beta-D-glucosaminidase (UNAG) was chosen as an effect biomarker. The UCd BMDLs for UNAG ranged from 2.18 MUg/g creatinine (cr) to 4.26 MUg/g cr in the populations of different provinces. The selection of the sample population and area affect the evaluation of the BMDL. The reference level of UCd for renal effects was further evaluated based on the data of all 6103 subjects. With benchmark responses (BMR) of 10%/5%, the overall UCd BMDLs for males in the total population were 3.73/2.08 MUg/g cr. The BMD was slightly lower in females, thereby indicating that females may be relatively more sensitive to Cd exposure than are males. PMID- 26055568 TI - Frequency, Duration and Intensity of Dengue Fever Epidemic Risk in Townships in Pearl River Delta and Yunnan in China, 2013. PMID- 26055569 TI - Intervention Strategies for the National Project of Workplace Health Promotion in China. PMID- 26055571 TI - Absolute reliability of adipose tissue volume measurement by computed tomography: application of low-dose scan and minimal detectable change--a phantom study. AB - Metabolic syndrome increases the risk of developing diabetes and cardiovascular disease, particularly heart failure. Abdominal obesity is commonly assessed by measurement of the waist circumference, which exhibits a positive correlation with the visceral fat area measured on computed tomography (CT). CT is an excellent technique for measurement of cross-sectional areas of adipose tissue, but the exposure to ionizing radiation limits broad and repeated application in healthy subjects. Our purpose in this study was to determine the reliability of low-dose CT for abdominal fat quantification as compared with a standard CT protocol. A phantom was scanned by use of changes in the volume of vegetable oil, simulating visceral and subcutaneous adipose tissue, and by changes in the tube current-time products (25-300 mAs). We measured the volume of vegetable oil for each mAs value, and we calculated the minimal detectable change (MDC) in the volume by making repeated measurements. The measured volume of vegetable oil at 50 mAs and higher was not significantly different (p > 0.05), but that at 25 mAs was significantly different (p < 0.001), from that at 300 mAs. The MDC was less than 0.4 ml regardless of the mAs value at all mAs values assessed. We suggest that the adipose tissue volume is determined accurately by CT at 50 mAs (75 % reduction of radiation exposure compared with the standard dose). PMID- 26055573 TI - The physical demands of Super League rugby: Experiences of a newly promoted franchise. AB - The physical match demands for a newly promoted European Super League (ESL) squad were analysed over a full season using global positioning systems. Players were classified into four positional groups: outside backs (OB), pivots (PIV), middle unit forwards (MUF) and wide running forwards (WRF). MUF covered less total distance (4318 +/- 570 m) than WRF (6408 +/- 629 m), PIV (6549 +/- 853) and OB (7246 +/- 333 m) (P < 0.05) and less sprint distance (185 +/- 58 m) than WRF (296 +/- 82 m), PIV (306 +/- 108) and OB (421 +/- 89 m; P < 0.05), likely attributable to less playing time by MUF (47.8 +/- 6.6 min) compared with WRF (77.0 +/- 9.0 min), PIV (72.8 +/- 10.6 min) and OB (86.7 +/- 3.4 min; P < 0.05). Metres per minute were greater for MUF (90.8 +/- 2.2 m.min(-1)) compared with OB (83.6 +/- 2.8 m.min(-1)) and WRF (83.4 +/- 2.4 m.min(-1); P = 0.001) although not different from PIV (90.2 +/- 3.3 m.min(-1); P > 0.05). WRF (36 +/- 5) and MUF (35 +/- 6) were involved in more collisions than OB (20 +/- 3) and PIV (23 +/- 3; P < 0.05). The high-speed running and collision demands observed here were greater than that previously reported in the ESL, which may reflect increased demands placed on the lower ranked teams. The present data may be used to inform coaches if training provides the physical stimulus to adequately prepare their players for competition which may be especially pertinent for newly promoted franchises. PMID- 26055574 TI - Universal Conductance Fluctuation in Two-Dimensional Topological Insulators. AB - Despite considerable interest in two-dimensional (2D) topological insulators (TIs), a fundamental question still remains open how mesoscopic conductance fluctuations in 2D TIs are affected by spin-orbit interaction (SOI). Here, we investigate the effect of SOI on the universal conductance fluctuation (UCF) in disordered 2D TIs. Although 2D TI exhibits UCF like any metallic systems, the amplitude of these fluctuations is distinguished from that of conventional spin orbit coupled 2D materials. Especially, in 2D systems with mirror symmetry, spin flip scattering is forbidden even in the presence of strong intrinsic SOI, hence increasing the amplitude of the UCF by a factor of ?2 compared with extrinsic SOI that breaks mirror symmetry. We propose an easy way to experimentally observe the existence of such spin-flip scattering in 2D materials. Our findings provide a key to understanding the emergence of a new universal behavior in 2D TIs. PMID- 26055575 TI - The Scree Test and the Number of Factors: a Dynamic Graphics Approach. AB - Exploratory Factor Analysis and Principal Component Analysis are two data analysis methods that are commonly used in psychological research. When applying these techniques, it is important to determine how many factors to retain. This decision is sometimes based on a visual inspection of the Scree plot. However, the Scree plot may at times be ambiguous and open to interpretation. This paper aims to explore a number of graphical and computational improvements to the Scree plot in order to make it more valid and informative. These enhancements are based on dynamic and interactive data visualization tools, and range from adding Parallel Analysis results to "linking" the Scree plot with other graphics, such as factor-loadings plots. To illustrate our proposed improvements, we introduce and describe an example based on real data on which a principal component analysis is appropriate. We hope to provide better graphical tools to help researchers determine the number of factors to retain. PMID- 26055576 TI - Aeromonas hydrophila virulence. PMID- 26055578 TI - Treatment outcomes of unruptured intracranial aneurysm; experience of 1,231 consecutive aneurysms. AB - BACKGROUND: The aim of this study was to review our experience with surgical clipping and endovascular treatment (EVT) of unruptured intracranial aneurysms (UIAs), with a special focus on complications. METHODS: We retrospectively analyzed clinical and radiological data from patients who underwent surgery or EVT. Surgery was performed by one neurosurgeon, and EVT was performed by two neurointerventionists according to one hybrid neurosurgeon's decision. Adverse events included the following: (1) decline of the modified Rankin Scale (mRS) score from 1 to 2 and (2) any unexpected neurological deficit or imaging finding affecting the prognosis and/or requiring additional procedures, medication, or prolonged hospital stay. RESULTS: Of the 1231 UIAs in 1124 patients, 625 (50.7 %) aneurysms were treated with surgery, and 606 (49.3 %) aneurysms were treated with EVT. The overall complication rate of UIA treatment was 3.2 %. The rate of adverse events was 2.4 %, and the rates of morbidity and mortality were 0.6 and 0.2 %, respectively. The rates of adverse events, morbidity, and mortality were not significantly different between surgery and EVT. The rate of hospital use for EVT was stationary over the years of the study. Posterior circulation in surgery, large aneurysms (>15 mm) in EVT, and stent- or balloon-assisted procedures in EVT were associated with the occurrence of complications. Poor clinical outcome (mRS of 3-6) was 0.8 % at hospital discharge. CONCLUSIONS: Both UIA treatment modalities decided by one hybrid neurosurgeon showed low complication rates and good clinical outcomes in this study. These results may serve as a point of reference for clinical decision-making for patients with UIA. PMID- 26055577 TI - Animal board invited review: genetic possibilities to reduce enteric methane emissions from ruminants. AB - Measuring and mitigating methane (CH4) emissions from livestock is of increasing importance for the environment and for policy making. Potentially, the most sustainable way of reducing enteric CH4 emission from ruminants is through the estimation of genomic breeding values to facilitate genetic selection. There is potential for adopting genetic selection and in the future genomic selection, for reduced CH4 emissions from ruminants. From this review it has been observed that both CH4 emissions and production (g/day) are a heritable and repeatable trait. CH4 emissions are strongly related to feed intake both in the short term (minutes to several hours) and over the medium term (days). When measured over the medium term, CH4 yield (MY, g CH4/kg dry matter intake) is a heritable and repeatable trait albeit with less genetic variation than for CH4 emissions. CH4 emissions of individual animals are moderately repeatable across diets, and across feeding levels, when measured in respiration chambers. Repeatability is lower when short term measurements are used, possibly due to variation in time and amount of feed ingested prior to the measurement. However, while repeated measurements add value; it is preferable the measures be separated by at least 3 to 14 days. This temporal separation of measurements needs to be investigated further. Given the above issue can be resolved, short term (over minutes to hours) measurements of CH4 emissions show promise, especially on systems where animals are fed ad libitum and frequency of meals is high. However, we believe that for short-term measurements to be useful for genetic evaluation, a number (between 3 and 20) of measurements will be required over an extended period of time (weeks to months). There are opportunities for using short-term measurements in standardised feeding situations such as breath 'sniffers' attached to milking parlours or total mixed ration feeding bins, to measure CH4. Genomic selection has the potential to reduce both CH4 emissions and MY, but measurements on thousands of individuals will be required. This includes the need for combined resources across countries in an international effort, emphasising the need to acknowledge the impact of animal and production systems on measurement of the CH4 trait during design of experiments. PMID- 26055579 TI - Understanding thrombocytopenia: physiological role of microRNA in survival of neonatal megakaryocytes. AB - Neonates are predisposed to developing thrombocytopenia and neonates are affected by megakaryocytic disorders such as thrombocytopenia with absent radius syndrome and transient myeloproliferative disorder. Small double stranded non-coding microRNAs (miRNAs) have been shown to crucially involve in the regulation of stem cell differentiation in normal as well as malignant haematopoiesis. The regulatory mechanism in developmental megakaryocytopoiesis and role of miRNAs in biological differences between adult and neonatal megakaryopoiesis is unknown. Here in we compared miR-99a levels in megakaryocytes (MKs) derived from cord blood (CB) and peripheral blood using qRT-PCR. CTDSPL is predicted as potential target of miR-99a and was confirmed by western blot. CTDSPL is shown to involve in regulation of cell growth and differentiation and exhibits tumor suppressor activity. We believe that miR-99a regulates CTDSPL, which induces the G1/S transition by increasing Cyclin expression and play a significant role in proliferation of CB-MKs. PMID- 26055580 TI - Ileal duplication: an unusual cause of intestinal obstruction in adult life. AB - Gastrointestinal duplications are rare congenital malformations seldom diagnosed in adulthood. They may vary greatly in size and location, with the small intestine being their major focus. Their clinical presentation is widely variable and unspecific, mimicking more common pathologies, thus making preoperative diagnosis very difficult. The intraoperative surgeon's experience and knowledge are crucial in recognising these lesions so that they can be correctly managed. In this report, the authors present a case of a 36-year-old man with an acute intestinal obstruction as the first presentation of ileal duplication. PMID- 26055581 TI - The devastating effects a fire burn in a child. AB - Burn injuries are a serious global public health concern with significant worldwide mortality and morbidity rates. Burns are among the most devastating of all injuries, with outcomes ranging from physical impairment and disability to emotional and mental consequences. Paediatric burns requiring treatment often incur significant health and opportunity costs, and frequently result in death or long-term disability. A recent systemic review showed that almost 50% of patients hospitalised with severe burns in Europe were younger than 16 years of age, and nearly 60% were male. This report discusses the case of a 2-year-old boy with second and third-degree skin burns over almost 45% of his body, including his head and arms, who presented to the eye clinic at the State Hospital in Hakkari 1 month after a fire burn accident. Both eyes had been burnt and the bilateral anterior chambers had been injured so badly that the patient was left blind. PMID- 26055582 TI - Urinary incontinence following transurethral prostatectomy presenting as self inflicted penile gangrene. AB - An elderly diabetic man with a 67 g prostate developed a moderate degree of stress urinary incontinence along with urge urinary incontinence after transurethral resection of the prostate. Initially, he did not perform the recommended pelvic floor exercise and wrapped a rubber band around his penis to control the problem. He presented with late development of penile gangrene requiring partial amputation of his penis. The stress urinary incontinence subsided on subsequent follow-up. The patient is now doing well. PMID- 26055584 TI - Spontaneous rupture of unscarred uterus in a primigravida with preterm prelabour rupture of membranes. AB - Intrapartum uterine rupture is a true obstetrical emergency. Uterine rupture is associated with severe maternal and fetal morbidity and mortality. It is rare in the unscarred uterus of a primigravida. A 23-year-old primigravida with an unscarred uterus was admitted with preterm prelabour rupture of membranes at 36(+4) weeks of gestation. Abnormal fetal heart monitoring, associated with acute onset of severe abdominopelvic pain, developed on admission. Rupture occurred prior to onset of regular uterine contractions and in the absence of any interventional oxytocin. The neonate had evidence of severe acidosis despite emergency caesarean delivery. This case highlights the importance of maintaining a high index of suspicion for uterine rupture, even in the unlikely setting of a primigravida with an unscarred uterus. PMID- 26055583 TI - Ascites and other incidental findings revealing undiagnosed systemic rheumatoid arthritis. AB - We describe a case of a 43-year-old man presenting to the gastroenterology outpatient department with exudative ascites. Mediastinal lymphadenopathy, pericardial effusion and pleural effusion were detected on further imaging. Further clinical examination revealed subcutaneous nodules on the left arm, which were confirmed to be rheumatoid nodules on histology. Inflammatory markers were elevated with positive serology for rheumatoid factor and anticyclic citrullinated protein antibody. Our investigations excluded tuberculosis, pancreatitis and malignancy in the patient. Following review by a rheumatologist, a diagnosis of systemic rheumatoid arthritis (RA) was made. Pleuritis and pericarditis are well recognised as extra-articular manifestation of RA. Ascites, however, is rarely recognised as a manifestation of RA. Our literature search revealed two other cases of ascites due to RA disease activity, and both patients had long-standing known RA. This case adds to the discussion on whether ascites and peritonitis should be classified as extra-articular manifestations of RA. PMID- 26055585 TI - When is pneumonia not pneumonia? AB - A 34-year-old man was admitted to hospital via the accident and emergency department with severe right-sided abdominal pain and raised inflammatory markers. His pain settled with analgaesia and he was discharged with a course of oral co-amoxiclav. He was readmitted to the hospital 7 days later reporting cough and shortness of breath. His chest X-ray showed a raised right hemi-diaphragm, presumed consolidation and a right-sided effusion. As a result, he was treated for pneumonia. Despite antibiotic therapy his C reactive protein remained elevated, prompting an attempt at ultrasound-guided drainage of his effusion. Finding only a small amount of fluid, a CT of the chest was performed, and this showed a subphrenic abscess and free air under the diaphragm. A CT of the abdomen was then carried out, showing a perforated appendix. An emergency laparotomy was performed, the patient's appendix was removed and the abscess drained. PMID- 26055586 TI - Soft tissue releases, bone preservation and patient outcome following revision of the oldest total knee replacement. AB - The patient had a total knee replacement for arthritis secondary to Stills disease performed 35 years earlier, with 20 years of good function followed by 15 years of progressively worsening knee pain. A revision was completed, which improved the patient's quality of life and objective knee scores, with an increase in Oxford Knee Score from 22 to 42 and American Knee Society Score from 76 to 170. We discuss the technical aspects in revising this knee replacement, which is the oldest that we are aware of. The result has been a good recovery, which is the first available in the literature for future comparison. PMID- 26055587 TI - Delayed postpartum abdominal bleeding caused by a spontaneous ruptured branch of the internal iliac artery and successfully treated by arterial embolisation. AB - A 34-year-old gravida 2 para 1 had an uneventful second pregnancy and successful vaginal birth after caesarean section. She was readmitted on the third day postpartum with severe abdominal pain coinciding with lactation. On admission, her vital signs were stable and was expectantly managed. After an unexpected drop in haemoglobin level, a CT scan was ordered, showing a haemoperitoneum. Laparoscopy was performed and 2.5L of blood was evacuated from the peritoneal cavity, no source of the bleeding could be identified. At the intensive care unit the patient's vital signs deteriorated and her haemoglobin level dropped to 2.2 mmol/L. The patient was stabilised and instead of a laparotomy to locate the bleeding, an arterial CT and angiography were performed. This revealed the presence of a blush from a pseudoaneurysm rising from a branch of the internal iliac artery. The artery was successfully occluded by embolisation. PMID- 26055588 TI - Ancillary role of vitamin C in pink aesthetics. AB - A smile expresses feelings of joy, affection and self-confidence in an individual. Melanin hyperpigmentation of the gingiva jeopardises the aesthetics of an individual significantly. In the present case, gingival depigmentation was performed with a surgical scalpel along with local applications of ascorbic acid, yielding satisfactory aesthetic results with low subjective pain levels, and no recurrence has been observed after 9 months of follow-up. PMID- 26055589 TI - Characteristics of 22q 11.2 deletion syndrome undiagnosed until adulthood: an example suggesting the importance of psychiatric manifestations. AB - Patients with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit various combinations of signs and symptoms including facial dysmorphism, thymus absence, hypoparathyroidism, cellular immunodeficiency and cardiac abnormalities caused by microdeletion of chromosome 22q11.2. Most cases are diagnosed during post-natal cardiac evaluation, though some are diagnosed at later stages. We report the case of a 39-year-old man with 22q11.2DS presenting with seizure due to tardily manifested hypocalcaemia and anxiety disorder. Our experience suggests that 22q11.2DS patients lacking fatal or well-recognised manifestations such as cardiac defects, immunodeficiency and facial dysmorphism tend to survive without medical attention, and are therefore overlooked. Recognition of the age-related variance of the manifestations, and specifically of tardily manifested hypocalcaemia and psychiatric or developmental disorders as manifestations of 22q11.2DS in adulthood, is important for diagnosis and can also help us provide appropriate medical and psychosocial support for newly diagnosed 22q11.2DS patients in adolescence or adulthood and their families. PMID- 26055590 TI - Recurrent osteomyelitis of the mandible in osteopetrosis: a common complication of an uncommon disease. PMID- 26055591 TI - Basaloid squamous cell carcinoma of the maxilla. AB - Basaloid squamous cell carcinoma (BSCC) is a distinctive aggressive variant of squamous cell carcinoma. We present a case of a 60-year-old man with tender swelling in the right cheek region for 6 months and continuous unilateral nasal discharge for 2 months. Extraoral examination revealed an ovoid, well-defined swelling from the right infraorbital rim to the angle of the mouth superoinferiorly and the right lateral wall of the nose to preauricular region anteroposteriorly. Intraorally, an ulceroproliferative growth from right upper gingivobuccal sulcus to mid palatine raphe with bicortical expansion was evident. CT revealed a hypodense mass obliterating the right maxillary sinus. Histopathology showed closely packed basaloid cells, with hyperchromatic palisading nuclei, arranged in a solid pattern with a lobular configuration. Prominent areas of comedo necrosis and keratin pearl formation were seen. These features suggested BSCC. The patient underwent surgical excision with adjuvant radiation but was lost to follow-up after 6 months of radiation therapy. PMID- 26055592 TI - Frosted branch angiitis in one eye and impending CRVO in the other: a diagnostic dilemma. AB - We present a unique case of frosted branch angiitis in one eye and impending central retinal vein occlusion in other eye of a pregnant woman, which could be an initial manifestation of Behcet's disease. A 28-year-old, 33 weeks pregnant woman presented with sudden diminution of vision in her right eye. Her best corrected visual acuity was light perception in the right eye and 20/20 in her left eye. The fundus examination revealed frosted branch angiitis in the right eye and impending central retinal vein occlusion in the left eye. After a thorough initial examination, she was administered intravenous methyl prednisolone 1 g once a day for 3 days followed by oral steroids. All extensive work up to find the cause of frosted branch angiitis was negative except for positive human leukocyte antigen B51. Systemic work up was normal. On last follow up at 6 months, the patient had visual acuity of 20/60 in the right eye and 20/20 in the left eye. Her systemic work up was normal up to follow-up. She still remains a diagnostic dilemma, with Behcet's disease as the closest diagnosis. PMID- 26055593 TI - Branch portal vein pyaemia secondary to amoebic liver abscess. AB - We describe a case of a young returning traveller who contracted amoebic dysentery while visiting India. She presented to a major London Hospital several months later with features suggestive of amoebic liver abscesses, a known sequelae of amoebiasis. MRI with intravenous contrast demonstrated an area of likely occlusion of the portal vein. The patient was treated with intravenous metronidazole for 10 days followed by diloxanide furoate, an intraluminal agent. The largest abscess was drained acutely under ultrasound guidance. The portal vein occlusion was treated medically without the use of anticoagulation. A repeat ultrasound at 6 weeks post-treatment confirmed patency of the portal vein indicating spontaneous recanalisation with antimicrobial therapy alone. PMID- 26055594 TI - Lamotrigine-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). PMID- 26055595 TI - A 22-year-old male patient with ascites. AB - A 22-year-old male patient presented with a 3-day history of abdominal pain, diarrhoea, nausea and vomiting. He reported abdominal distention of a couple of weeks' duration. He had been hospitalised 7 months earlier, owing to the same symptoms, however, the cause was never clarified. Initial examination showed abdominal distention and blood tests indicated eosinophilia. An abdominal CT scan showed mild ascites and a diffuse thickening of the small intestinal loops, and a cystic formation 3 cm in diameter on the liver. The differential diagnosis included parasite infection and eosinophilic gastroenteritis. Liver MRI revealed a simple biliary cyst. Microbiological tests, stool and blood cultures as well as stool examination for parasites were negative. The diagnostic paracentesis revealed eosinophilic ascites. An endoscopy was performed and histopathology revealed presence of moderate to marked lymphoplasmacytic infiltrate containing eosinophils, compatible with eosinophilic gastroenteritis. The patient responded well to the initiation of corticosteroids. PMID- 26055596 TI - Intracardiac extension of uterine leiomyomatosis. PMID- 26055597 TI - A novel route of revascularization in basilar artery occlusion and review of the literature. AB - Ischemia of the basilar artery is one of the most devastating types of arterial occlusive disease. Despite treatment of basilar artery occlusions (BAO) with intravenous tissue plasminogen activator, antiplatelet agents, intra-arterial therapy or a combination, fatality rates remain high. Aggressive recanalization with mechanical thrombectomy is therefore often necessary to preserve life. When direct access to the basilar trunk is not possible, exploration of chronically occluded vessels through collaterals with angioplasty and stenting creates access for manual aspiration. We describe the first report of retrograde vertebral artery (VA) revascularization using thyrocervical collaterals for anterograde mechanical aspiration of a BAO followed by stenting of the chronically occluded VA origin. Our novel retrograde-anterograde approach resulted in resolution of the patient's clinical stroke syndrome. PMID- 26055598 TI - Subchondral insufficiency fracture of the knee: a non-traumatic injury with prolonged recovery time. AB - Subchondral insufficiency fractures are non-traumatic fractures that occur immediately below the cartilage of a joint. Although low bone density may be present concurrently, it is not the underlying cause of subchondral insufficiency fractures in the majority of patients. Patients with subchondral insufficiency fracture characteristically have unremarkable plain radiographs, while MRI examination may reveal extensive bone marrow oedema and subchondral bone collapse. This article presents a 51-year-old postmenopausal woman, a physician, who had subchondral insufficiency fractures of the knee associated with prolonged standing during clinical work. She was treated with partial weight bearing on crutches until 14 months after the injury, viscosupplementation at 4 months to treat osteoarthritis and teriparatide treatment to improve bone healing at 7 months. By 26 months after the injury, she tolerated independent walking with a fabric knee support but still experienced mild posterolateral knee pain and numbness on prolonged standing. PMID- 26055599 TI - Isolated acute sphenoid sinusitis presenting with hemicranial headache and ipsilateral abducens nerve palsy. AB - Isolated sphenoid sinusitis is a rare disorder and may present with complications due to its anatomical location and proximity to the intracranial and orbital contents. It is frequently misdiagnosed, because the sphenoid sinus is not visualised adequately with routine sinus radiographs and is not accessible to direct clinical examination. We report a case who presented with hemicranial headache and ipsilateral abducens nerve palsy as the presenting feature of sphenoid sinusitis. The symptoms disappeared within a week of conservative treatment. Sphenoid sinusitis should be kept in the differential diagnosis of isolated sixth cranial nerve palsy, especially in the presence of headache, and all patients should be investigated with CT/MRI brain. Prompt diagnosis and management before intracranial extension can prevent devastating complications. PMID- 26055600 TI - Circle of Willis: as seen during endoscopic fenestration of a suprasellar arachnoid cyst. PMID- 26055601 TI - Significance of an isolated new right bundle branch block in a patient with chest pain. AB - Chest pain is a common presenting symptom in emergency departments, and a typical manifestation of acute myocardial infarction (AMI). Recognition of ECG changes in AMI is essential for timely diagnosis and treatment. Right bundle branch block (RBBB) may be an isolated sign of AMI, and was previously considered as a criterion for fibrinolytic therapy. Since the most recent European Society of Cardiology and American Heart Association guidelines in 2013, RBBB alone is no longer considered a diagnostic criterion of AMI, even if it occurs in the context of acute chest pain, as RBBB does not usually interfere with the interpretation of ST-segment alteration. Our case illustrates an acute septal myocardial infarction with an isolated RBBB, and thus the importance of recognising this pattern in order to permit timely diagnosis and treatment. PMID- 26055602 TI - Clinical and molecular characterisation of two siblings with fibrodysplasia ossificans progressiva, from the Colombian Pacific coast (South America). AB - Fibrodysplasia ossificans progressiva (FOP, MIM 135 100) is an uncommon genetic disease with a dominant autosomal germline transmission pattern; however, most cases are products of spontaneous individual mutations. It is a disabling condition that affects connective tissue, and it is distinguished by progressive heterotopic ossifications and congenital malformations of the great toes. The case of 2 brothers with progressive osseous deformation, along with ankylosis of the jaw, scoliosis and mental retardation, is presented. Blood samples were taken from each patient identifying in both of them a heterozygote mutation in exon 6 of the gene ACVR1 (c.617G>A p.Arg206His), which diagnoses the 'classic' form of FOP. The current medical treatment of this disease is early detection to avoid trauma and aggravating factors, prophylactic measures against infections and respiratory decline, symptomatic relief and physical therapy. There is currently no cure for the disease. PMID- 26055603 TI - Management of necrotising appendicitis associated with widespread necrotising enterocolitis of the small and large bowel and perforated duodenal ulcer. AB - A 7-year-old boy presented in septic shock secondary to appendicitis with generalised peritonitis. Following crystalloid resuscitation, he underwent surgery. Faecopurulent contamination and free air were found. This was secondary to a perforated and gangrenous appendix, multiple large and small bowel segments with perforations, patches of necrosis, interspersed with healthy bowel and segments of questionable viability. There was also a perforated duodenal ulcer. Necrotic segments were resected using a 'clip-and-drop' technique to shorten operative duration and guide resection to preserve bowel length. After six laparotomies and multiple bowel resections, the child was discharged home with an ileostomy that was subsequently reversed. He is currently on a normal diet and pursuing all activities appropriate for his age. Perforated appendicitis can be associated with widespread bowel necrosis and multiple perforations. A conservative damage limitation approach using the 'clip-and-drop' technique and relook laparotomies is useful in the management of extensive bowel necrosis in children. PMID- 26055604 TI - A hairy situation. AB - A 2-day-old neonate was transferred to a specialist paediatric otolaryngology centre with stridor at rest, feeding difficulties and an apparent mass in the oropharynx. The newborn displayed evidence of respiratory distress, however, she remained self-ventilating. MRI highlighted a fat-containing lesion in the postnasal space with no intracranial extension. A CT scan under general anaesthesia showed no underlying bony abnormality, and hence an examination of the nasopharynx, oropharynx and microlaryngoscopy and bronchoscopy were performed. The macroscopically hairy lesion arising from the superior aspect of the soft palate was resected. Histology displayed a benign growth measuring 28*17*12 mm in keeping with a hairy polyp. This is one of very few cases, to the best of our knowledge, in which a hairy polyp (bigerminal choristomas) has resulted in stridor in the first few days of life. Nasal masses in neonates, although a rare phenomenon, remain clinically important as they are obligate nasal breathers. PMID- 26055605 TI - Successful application of venoarterial-venous extracorporeal membrane oxygenation in the reversal of severe cardiorespiratory failure. AB - Typical configurations of extracorporeal membrane oxygenation (ECMO) include venovenous (VV) and venoarterial (VA) configurations; however, other configurations of ECMO may be necessary in certain situations. We performed VA ECMO for a 71-year-old man who experienced refractory hypoxaemia associated with a brief cardiac arrest after resection of the small intestine showing necrosis. As the cardiac function improved, the patient showed a complication of poor oxygenation in the upper body due to insufficient respiratory function. Therefore, we performed VA-venous ECMO, which further improved his cardiac function and allowed him to be converted to VV ECMO. It is very important to consider different configuration strategies of ECMO by adjusting the patient's cardiopulmonary conditions appropriately. PMID- 26055606 TI - Inflammation of actinic keratoses during paclitaxel chemotherapy. PMID- 26055607 TI - Necrotising pyomyositis complicating intramuscular antipsychotic administration. AB - A 26-year-old woman with paranoid schizophrenia was admitted to the medical intensive care unit with septic shock requiring intubation and mechanical ventilation. The source of septic shock was not identified despite obtaining CT of the chest/abdomen/pelvis, bronchoalveolar lavage and microbiological results for tracheal secretions, blood, urine and cervix. An indium-111 tagged white cell count scan was subsequently performed, revealing increased right anterior deltoid uptake. Owing to serial increases (up to 1310 U/L) in serum creatine kinase and a history of local intramuscular paliperidone injections for management of schizophrenia, surgical exploration was performed and identified necrotising skeletal muscle inflammation and extensive fat necrosis with an organising abscess, consistent with pyomyositis. A gram stain of purulent fluid revealed gram-positive cocci, but no organisms grew in culture. The patient recovered after 10 days of daptomycin and 7 weeks of wound care. Paliperidone injections were discontinued and oral risperidone was initiated. PMID- 26055608 TI - Concomitant occurrence of fusion and eagle's talon in a single patient. PMID- 26055609 TI - Lifestyle changes of a family caring for a 25-year-old quadriplegic man after delayed spinal cord infarction. AB - Worldwide, 110-190 million people over the age of 15 years are estimated to live with severe disability-a physical state of being defined by the WHO as "the equivalent of disability inferred for conditions such as quadriplegia, severe depression, or blindness." Modes and qualities of disability care undoubtedly vary globally, dependent on income, health infrastructure and culture. Quadriplegia has a unique set of emotional and physical challenges that demand a great deal from care regimens and health systems. This case study examines a specific-and successful-configuration of quadriplegic care in a Druze village in the Golan and looks to the economic, geographic and sociocultural aspects of care. PMID- 26055610 TI - Left-sided inferior vena cava. PMID- 26055611 TI - Pelvic local recurrence in a patient with muscle-invasive bladder cancer treated with interstitial thermal therapy and interstitial brachytherapy. PMID- 26055612 TI - Stereotactic ablative radiation therapy with volumetric modulated arc therapy in flattening filter-free mode for low-, intermediate-, and high-risk prostate cancer patients: Are 2 arcs better than 1? AB - PURPOSE: In preparation for a phase 2 clinical trial of prostate cancer treatment with stereotactic ablative radiation therapy (SABR), the quality of volumetric modulated arc therapy (VMAT) plans was investigated to determine the preferred delivery technique. METHODS AND MATERIALS: VMAT treatment plans were generated with version 11 of the Eclipse treatment planning system for a Varian TrueBeam linear accelerator operating with 10-MV x-rays in flattening filter-free mode (FFFM). Plans were designed with pelvic computed tomography scans from 10 patients with prostate cancer with an assumption of low-, intermediate-, and high risk target volumes. The prescription dose was set to 36.25 Gy to be delivered in 5 fractions of 7.25 Gy each. Dose-volume constraints imposed during optimization to protect organs at risk (OARs) were based on data from published studies and current SABR clinical trials. One-arc and 2-arc plans were compared in terms of dose homogeneity and conformity to the target volumes, dose to the OAR and to the surrounding normal tissue, the total number of monitor units required, and overall treatment time. RESULTS: Clinically acceptable VMAT-FFFM-based SABR regimens were produced for all low-, intermediate-, and high-risk target volumes using both 1-arc and 2-arc deliveries. No significant dosimetric differences in terms of homogeneity, conformity, or dose to the OAR were observed between 1-arc and 2-arc deliveries, but treatment times were twice as long for 2-arc deliveries and consistently required more monitor units. CONCLUSIONS: Given the similar dosimetry between 1- and 2-arc plans, single-arc delivery of VMAT-FFFM may be preferable to minimize the risk of intrafraction motion and reduce leakage and scatter radiation to the patient. PMID- 26055613 TI - Comparison of endorectal ultrasound versus pelvic magnetic resonance imaging for radiation treatment planning in locally advanced rectal cancer. AB - PURPOSE: Current National Comprehensive Cancer Network guidelines for rectal cancer recommend tumor and nodal staging using endorectal ultrasound (EUS) or pelvic magnetic resonance imaging (MRI). EUS and MRI have similar accuracy for staging rectal cancers. The relative benefits of each modality for radiation therapy (RT) treatment planning are unknown. METHODS AND MATERIALS: EUS, MRI, and treatment planning computed tomography scans were reviewed for 6 patients with locally advanced rectal cancer treated with neoadjuvant chemotherapy followed by neoadjuvant chemoradiation therapy. Thirty rectal gross tumor volumes (GTVs) were contoured: 2 GTVEUS (contoured independently by 2 radiation oncologists), 2 GTVMRI, and one GTV treatment (contoured by the treating physician for the original treatment plan) per patient from the original treatment plan. GTVEUS was based on colonoscopy and EUS. GTVMRI was based on T2 postgadolinium MRI sequences fused with treatment planning computed tomography. GTVEUS and GTVMRI volume, craniocaudal length, and number of suspicious lymph nodes (LN) were compared between EUS vs MRI and compared to GTV treatment. Agreement between contours was calculated as the percentage of overlapping slices over total slices for MRI and EUS-based contours. Paired t test was used to assess relationships between imaging modality and treatment volume, craniocaudal length, and LN number. RESULTS: For volume and craniocaudal length, mean GTVEUS was significantly smaller than mean GTVMRI (P = .02 and P = .04, respectively). The mean number of suspicious LN identified by MRI was significantly greater than by EUS (4.8 vs 3.0; P = .03). Agreement between radiation oncologist GTV contours was greater for GTVMRI than for GTVEUS (71% vs 44%), although not statistically significantly so (P = .11). CONCLUSIONS: Pelvic MRI for RT treatment planning in locally advanced rectal cancer generates more comprehensive and reproducible GTV contours than does the use of EUS. Pelvic MRI can be recommended to aid in RT treatment planning for all eligible patients undergoing RT for locally advanced rectal cancer. PMID- 26055614 TI - Acquisition and Utilization of Information About Alcohol Use in Pregnancy Among Australian Pregnant Women and Service Providers. AB - INTRODUCTION: Because of an unknown safe level of alcohol consumption during pregnancy and inconsistent alcohol guidelines for pregnant women, it is unclear what information is being circulated with regard to alcohol use and pregnancy. This study aimed to explore how pregnant women and service providers acquire and utilize information about alcohol use during pregnancy. METHODS: This qualitative study involved 10-minute semistructured interviews with 74 mothers of young children and focus groups with 14 service providers in urban and rural areas of New South Wales in 2008 and 2009. Mothers were asked about their use of pregnancy related services, social support, and their perceptions about advice they received about alcohol use during pregnancy. Service providers were asked about what they knew about recommended alcohol use during pregnancy, how they knew it, and how they communicated this information to pregnant clients. RESULTS: Women and service providers expressed uncertainty about what the alcohol recommendations were for pregnant women. Health care providers were inclined to discuss alcohol use with women they perceived to be high risk but not otherwise. Women felt pressure to both drink and not drink during their pregnancies. Those who drank discounted abstinence messages and reported a process of internal bargaining on issues such as the stage of their pregnancy and the type of beverages they consumed. Those who abstained did so mainly because they were afraid of being held responsible for any problems with their pregnancies or infants that might have occurred from drinking. DISCUSSION: Confusion surrounding the recommendations regarding alcohol use during pregnancy, inconsistency in addressing alcohol use with pregnant women, information overload, and a perceived culture of drinking appear to contribute to the high proportion of Australian women drinking during pregnancy. PMID- 26055616 TI - Long-Term Anti-Hypertensive Therapy and Stroke Prevention: A Meta-Analysis. AB - BACKGROUND: Stroke causes approximately 6.7 million deaths worldwide per year and is the second leading cause of death. Pharmacotherapy for hypertension, an independent risk factor for stroke, significantly reduces the incidence of stroke. Although prior meta-analyses demonstrate various antihypertensive classes are superior to placebo in reducing stroke risk, which class is most effective is unclear. METHODS: We conducted a systematic MEDLINE search including only randomized controlled trials (RCT) of antihypertensive medications published between 1999 and 2014 in adults with stroke as a primary or secondary outcome. Five classes compared against all others were angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), beta-adrenoceptor antagonists (beta-blockers), calcium channel blockers (CCBs), and thiazide or thiazide-like diuretics (T-TLDs). Among 17 RCTs with 31 comparative arms, risk ratio was used to assess effect size, and a fixed- and random-effect model was used to calculate summary effect size, utilizing comprehensive meta-analysis statistical software version 2.0. RESULTS: The 251,853 subjects (46 +/- 11.4 % female; mean age 67.2 +/- 6.8 years), were grouped as follows: ACEI 52,887; ARB 7278; ACEI/ARB 60,165; beta-blocker 24,099; CCB 98,950; and T-TLD 68,639. The mean follow-up was 42.9 +/- 15 months. A random-effect model was used to assess for summary effect size in ACEI, ACEI/ARB, ARB, and T-TLD groups. The summary risk ratio for stroke occurrence in the different antihypertensive drug classes were as follows: ACEIs 1.01 (95 % confidence interval [CI] 0.81-1.27; p = 0.92); ACEIs/ARBs 0.94 (95 % CI 0.78-1.13; p = 0.51); T-TLDs 0.90 (95 % CI 0.75-1.08; p = 0.25); ARBs 0.83 (95 % CI 0.59-1.18; p = 0.30); beta-blockers 1.42 (95 % CI 1.26-1.61; p < 0.01); and CCBs 0.83 (95 % CI 0.79-0.89; p < 0.01). CONCLUSION: Among the antihypertensive classes, CCBs were most effective in reducing the long term incidence of stroke, whereas beta-blockers were associated with significantly increased risk. PMID- 26055617 TI - Examining visual field in clinical setting in neglect patients. PMID- 26055615 TI - Non-vitamin K antagonist oral anticoagulants: new choices for patient management in atrial fibrillation. AB - Atrial fibrillation (AF) is a significant problem for the aging population and remains a major factor underlying stroke risk. Warfarin anticoagulation has been proven effective for stroke prevention in AF, but can be difficult to manage and requires frequent monitoring. The non-vitamin K antagonist oral anticoagulants (NOACs) have been shown to be as effective as warfarin for stroke prevention in nonvalvular AF (NVAF) and are associated with a reduced risk of bleeding compared with warfarin. Dabigatran, rivaroxaban, apixaban, and edoxaban have been approved in the USA for reducing the risk of stroke in patients with NVAF. In this article, AF risk assessment is discussed and NOAC phase III clinical trials for the prevention of stroke and systemic embolic events are reviewed. Further, differences in stroke and bleeding outcomes between NOACs are highlighted, the use of NOACs for cardioversion and special patient populations is discussed, and management considerations for patients with AF are reviewed. PMID- 26055618 TI - Solution-Processable n-Type Organic Semiconductors Based on Angular-Shaped 2-(12H Dibenzofluoren-12-ylidene)malononitrilediimide. AB - The angular-shaped n-type semiconductors 2-(12H-dibenzofluoren-12 ylidene)malononitrilediimide 2a and 2b were successfully designed, synthesized, and fully characterized by optical absorption and fluorescence, cyclic voltammetry, X-ray crystal structure analysis, XRD, and OFET device performance. The varying alkyl chain lengths of 2a and 2b caused different molecular orientations with respect to the substrate. Thus, 2a presents an electron mobility of 0.01 cm(2) V(-1) s(-1), whereas 2b resulted in poor device performance with a much lower electron mobility of 5 * 10(-4) cm(2) V(-1) s(-1). PMID- 26055619 TI - Serum salusin-alpha and salusin-beta levels in patients with psoriasis. PMID- 26055620 TI - Pharmacokinetics and Metabolism of Delamanid, a Novel Anti-Tuberculosis Drug, in Animals and Humans: Importance of Albumin Metabolism In Vivo. AB - Delamanid, a new anti-tuberculosis drug, is metabolized to M1, a unique metabolite formed by cleavage of the 6-nitro-2,3-dihydroimidazo[2,1-b] oxazole moiety, in plasma albumin in vitro. The metabolic activities in dogs and humans are higher than those in rodents. In this study, we characterized the pharmacokinetics and metabolism of delamanid in animals and humans. Eight metabolites (M1-M8) produced by cleavage of the imidazooxazole moiety of delamanid were identified in the plasma after repeated oral administration by liquid chromatography-mass spectrometry analysis. Delamanid was initially catalyzed to M1 and subsequently metabolized by three separate pathways, which suggested that M1 is a crucial starting point. The major pathway in humans was hydroxylation of the oxazole moiety of M1 to form M2 and then successive oxidation to the ketone form (M3) mainly by CYP3A4. M1 had the highest exposure among the eight metabolites after repeated oral dosing in humans, which indicated that M1 was the major metabolite. The overall metabolism of delamanid was qualitatively similar across nonclinical species and humans but was quantitatively different among the species. After repeated administration, the metabolites had much higher concentrations in dogs and humans than in rodents. The in vitro metabolic activity of albumin on delamanid probably caused the species differences observed. We determined that albumin metabolism is a key component of the pharmacokinetics and metabolism of delamanid. Nonhepatic formation of M1 and multiple separate pathways for metabolism of M1 suggest that clinically significant drug-drug interactions with delamanid and M1 are limited. PMID- 26055621 TI - Metabolic Mechanism of Delamanid, a New Anti-Tuberculosis Drug, in Human Plasma. AB - The metabolism of delamanid (OPC-67683, Deltyba), a novel treatment of multidrug resistant tuberculosis, was investigated in vitro using plasma and purified protein preparations from humans and animals. Delamanid was rapidly degraded by incubation in the plasma of all species tested at 37 degrees C, with half-life values (hours) of 0.64 (human), 0.84 (dog), 0.87 (rabbit), 1.90 (mouse), and 3.54 (rat). A major metabolite, (R)-2-amino-4,5-dihydrooxazole derivative (M1), was formed in the plasma by cleavage of the 6-nitro-2,3-dihydroimidazo(2,1-b)oxazole moiety of delamanid. The rate of M1 formation increased with temperature (0-37 degrees C) and pH (6.0-8.0). Delamanid was not converted to M1 in plasma filtrate, with a molecular mass cutoff of 30 kDa, suggesting that bioconversion is mediated by plasma proteins of higher molecular weight. When delamanid was incubated in plasma protein fractions separated by gel filtration chromatography, M1 was observed in the fraction consisting of albumin, gamma-globulin, and alpha1 acid glycoprotein. In pure preparations of these proteins, only human serum albumin (HSA) metabolized delamanid to M1. The formation of M1 followed Michaelis Menten kinetics in both human plasma and the HSA solution, with similar Km values: 67.8 uM in plasma and 51.5 uM in HSA. The maximum velocity and intrinsic clearance values for M1 were also comparable in plasma and HSA. These results strongly suggest that albumin is predominantly responsible for metabolizing delamanid to M1. We propose that delamanid degradation by albumin begins with a nucleophilic attack of amino acid residues on the electron-poor carbon at the 5 position of nitro-dihydro-imidazooxazole, followed by cleavage of the imidazooxazole moiety to form M1. PMID- 26055623 TI - Mechanism of Arsenic Adsorption on Magnetite Nanoparticles from Water: Thermodynamic and Spectroscopic Studies. AB - Removal of arsenic (As) from water supplies is needed to reduce As exposure through drinking water and food consumption in many regions of the world. Magnetite nanoparticles (MNPs) are promising and novel adsorbents for As removal because of their great adsorption capacity for As and easy separation. This study aimed to investigate the adsorption mechanism of arsenate, As(V), and arsenite, As(III), on MNPs by macroscopic adsorption experiments in combination with thermodynamic calculation and microspectroscopic characterization using synchrotron-radiation-based X-ray absorption spectroscopy (XAS) and X-ray photoelectron spectroscopy (XPS). Adsorption reactions are favorable endothermic processes as evidenced by increased adsorption with increasing temperatures, and high positive enthalpy change. EXAFS spectra suggested predominant formation of bidentate binuclear corner-sharing complexes ((2)C) for As(V), and tridentate hexanuclear corner-sharing ((3)C) complexes for As(III) on MNP surfaces. The macroscopic and microscopic data conclusively identified the formation of inner sphere complexes between As and MNP surfaces. More intriguingly, XANES and XPS results revealed complex redox transformation of the adsorbed As on MNPs exposed to air: Concomitant with the oxidation of MNPs, the oxidation of As(III) and MNPs was expected, but the observed As(V) reduction was surprising because of the role played by the reactive Fe(II). PMID- 26055622 TI - Chronic NF-kappaB blockade improves renal angiotensin II type 1 receptor functions and reduces blood pressure in Zucker diabetic rats. AB - BACKGROUND: Both angiotensin II type 1 receptor (AT1R) and nuclear factor-kappa B (NF-kappaB) play significant roles in the pathogenesis of hypertension and type 2 diabetes. However, the role of NF-kappaB in perpetuating renal AT1 receptors dysfunction remains unclear. The aim of the present study to determine whether blockade of NF-kappaB, could reverse the exaggerated renal AT1R function, reduce inflammatory state and oxidative stress, lower blood pressure in Zucker diabetic fatty (ZDF) rats. METHODS: Pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor (150 mg/kg in drinking water)or vehicle was administered orally to 12 weeks-old ZDF rats and their respective control lean Zucker (LZ) rats for 4 weeks. Blood pressure was measured weekly by tail-cuff method. AT1R functions were determined by measuring diuretic and natriuretic responses to AT1R antagonist (candesartan; 10 MUg/kg/min iv). The mRNA and protein levels of NF kappaB, oxidative stress maker and AT1R were determined using quantitative real time PCR and Western blotting, respectively. The NF-kappaB-DNA binding activity in renal cortex was measured by Electrophoretic mobility shift assay (EMSA). RESULTS: As compared with LZ rats, ZDF rats had higher blood pressure, impaired natriuresis and diuresis, accompanied with higher levels of oxidative stress and inflammation. Furthermore, AT1R expression was higher in renal cortex from ZDF rats; candesartan induced natriresis and diuresis, which was augmented in ZDF rats. Treatment with PDTC lowered blood pressure and improved diuretic and natriuretic effects in ZDF rats; meanwhile, the increased oxidative stress and inflammation were reduced; the increased AT1R expression and augmented candesartan-mediated natriuresis and diuresis were recoverd in ZDF rats. Our further study investigated the mechanisms of PDTC on AT1R receptor expression. It resulted that PDTC inhibited NF-kappaB translocation from cytosol to nucleus, inhibited binding of NF-kappaB with AT1R promoter, therefore, reduced AT1R expression and function. CONCLUSIONS: Our present study indicates blockade of NF kappaB, via inhibition of binding of NF-kappaB with AT1R promoter, reduces renal AT1R expression and function, improves oxidative stress and inflammatory/anti inflammatory balance, therefore, lowers blood pressure and recovers renal function in ZDF rats. PMID- 26055624 TI - Nomogram predicted survival of patients with adenocarcinoma of esophagogastric junction. AB - BACKGROUND: The aim of this study is to develop a prognostic nomogram for patients with adenocarcinoma of esophagogastric junction and compare its predictive accuracy with the traditional tumor-node-metastasis (TNM) malignant staging system. METHODS: Patients from the Surveillance, Epidemiology, and End Results Program (from 1988 to 2011) and the First Affiliated Hospital of Xi'an Jiaotong University (from 2005 to 2010) were collected retrospectively. Preselected multiple potential interactions were tested irrespective of significance as nomogram parameters. And the Harrell's C-index was used to estimate the accuracy of the nomogram system. Model validation was performed using bootstrap to quantify our modeling strategy. RESULTS: In our study, six clinical associated factors (age, sex, depth of invasion, metastasized lymph nodes, examined lymph nodes, histological grade) were evaluated in the nomogram. In the training set, the nomogram exhibited superior discrimination power compared with the American Joint Committee on Cancer (AJCC) TNM classification (Harrell's C-index, 0.69 and 0.63, respectively). Calibration of the nomogram predicted survival was similar to the actual overall survival. In the validation set, the discrimination of nomogram was also better than the AJCC TNM staging system (C-index, 0.75 and 0.65, respectively), and the calibration of nomogram predicted survival was within a 10 % margin of actual overall survival. CONCLUSIONS: Based on the patients with adenocarcinoma of esophagogastric junction from a Western and an Eastern database, the nomogram provided significantly improved discrimination than the traditional AJCC TNM classification and also provided an accurate individualized prediction of the survival. PMID- 26055625 TI - RNA-Seq analysis identifies genes associated with differential reproductive success under drought-stress in accessions of wild barley Hordeum spontaneum. AB - BACKGROUND: The evolutionary basis of reproductive success in different environments is of major interest in the study of plant adaptation. Since the reproductive stage is particularly sensitive to drought, genes affecting reproductive success during this stage are key players in the evolution of adaptive mechanisms. We used an ecological genomics approach to investigate the reproductive response of drought-tolerant and sensitive wild barley accessions originating from different habitats in the Levant. RESULTS: We sequenced mRNA extracted from spikelets at the flowering stage in drought-treated and control plants. The barley genome was used for a reference-guided assembly and differential expression analysis. Our approach enabled to detect biological processes affecting grain production under drought stress. We detected novel candidate genes and differentially expressed alleles associated with drought tolerance. Drought associated genes were shown to be more conserved than non associated genes, and drought-tolerance genes were found to evolve more rapidly than other drought associated genes. CONCLUSIONS: We show that reproductive success under drought stress is not a habitat-specific trait but a shared physiological adaptation that appeared to evolve recently in the evolutionary history of wild barley. Exploring the genomic basis of reproductive success under stress in crop wild progenitors is expected to have considerable ecological and economical applications. PMID- 26055626 TI - Disruption of the mevalonate pathway induces dNTP depletion and DNA damage. AB - The mevalonate pathway is tightly linked to cell division. Mevalonate derived non sterol isoprenoids and cholesterol are essential for cell cycle progression and mitosis completion respectively. In the present work, we studied the effects of fluoromevalonate, a competitive inhibitor of mevalonate diphosphate decarboxylase, on cell proliferation and cell cycle progression in both HL-60 and MOLT-4 cells. This enzyme catalyzes the synthesis of isopentenyl diphosphate, the first isoprenoid in the cholesterol biosynthesis pathway, consuming ATP at the same time. Inhibition of mevalonate diphosphate decarboxylase was followed by a rapid accumulation of mevalonate diphosphate and the reduction of ATP concentrations, while the cell content of cholesterol was barely affected. Strikingly, mevalonate diphosphate decarboxylase inhibition also resulted in the depletion of dNTP pools, which has never been reported before. These effects were accompanied by inhibition of cell proliferation and cell cycle arrest at S phase, together with the appearance of gamma-H2AX foci and Chk1 activation. Inhibition of Chk1 in cells treated with fluoromevalonate resulted in premature entry into mitosis and massive cell death, indicating that the inhibition of mevalonate diphosphate decarboxylase triggered a DNA damage response. Notably, the supply of exogenously deoxyribonucleosides abolished gamma-H2AX formation and prevented the effects of mevalonate diphosphate decarboxylase inhibition on DNA replication and cell growth. The results indicate that dNTP pool depletion caused by mevalonate diphosphate decarboxylase inhibition hampered DNA replication with subsequent DNA damage, which may have important consequences for replication stress and genomic instability. PMID- 26055627 TI - Pharmacogenomic and clinical data link non-pharmacokinetic metabolic dysregulation to drug side effect pathogenesis. AB - Drug side effects cause a significant clinical and economic burden. However, mechanisms of drug action underlying side effect pathogenesis remain largely unknown. Here, we integrate pharmacogenomic and clinical data with a human metabolic network and find that non-pharmacokinetic metabolic pathways dysregulated by drugs are linked to the development of side effects. We show such dysregulated metabolic pathways contain genes with sequence variants affecting side effect incidence, play established roles in pathophysiology, have significantly altered activity in corresponding diseases, are susceptible to metabolic inhibitors and are effective targets for therapeutic nutrient supplementation. Our results indicate that metabolic dysregulation represents a common mechanism underlying side effect pathogenesis that is distinct from the role of metabolism in drug clearance. We suggest that elucidating the relationships between the cellular response to drugs, genetic variation of patients and cell metabolism may help managing side effects by personalizing drug prescriptions and nutritional intervention strategies. PMID- 26055628 TI - In vitro activity of josamycin against Streptococcus pyogenes isolated from patients with upper respiratory tract infections in France. AB - OBJECTIVES: The primary objective of our study was to obtain susceptibility data for josamycin against Streptococcus pyogenes isolated from patients presenting with upper respiratory tract infections in France. The secondary objective was to characterize the molecular mechanism of resistance in macrolide-resistant isolates. PATIENTS AND METHODS: MICs of erythromycin, clarithromycin, azithromycin, josamycin, and clindamycin were determined by the broth microdilution method. Resistance genes erm(B), erm(TR), and mef(A) were screened by PCR. RESULTS: The MIC50 and MIC90 of josamycin against 193 isolates of S. pyogenes were 0.12 and 0.25mg/L, respectively, with a resistance rate estimated at 4.7%. Resistance was due to the erm(B) gene whereas strains harboring erm(TR) or mef(A) remained susceptible. CONCLUSIONS: Josamycin was active against >95% of S. pyogenes isolated from patients with upper respiratory tract infections, and can be used as an alternative for the treatment of pharyngitis. PMID- 26055629 TI - Antifungal agents use in a French administrative region. AB - BACKGROUND: The increased use of new costly antifungal agents has led to a considerable increase in pharmaceutical expenditure. In December 2011, the Lorraine Regional Health Agency commissioned the Antibiolor network to evaluate costly antifungal agent stewardship using as reference regional, French, and international recommendations. METHODS: We performed a regional retrospective multicenter study. The criteria for evaluation were the appropriateness of the indication for treatment, the choice of the agent or of a combination, compliance with dose and treatment duration, and the absence of any alternative. RESULTS: One hundred and fourteen prescriptions were analyzed, in 7 intensive care units, 4 hematology units, and 1 infectious diseases unit. The indication for costly antifungal treatment was appropriate in 110 cases (96.5%), the choice of the antifungal agent in 102 cases (93%), the dose in 98 cases (89%), treatment duration in 102 cases (93%), and an alternative antifungal treatment was possible in 10 cases (9%). Eighty-two prescriptions (74.5%) complied with the marketing authorization, 19 (17%) were related to a protocol for temporary use, and 9 (8%) were considered as inappropriate. CONCLUSION: Our results show a high rate of appropriate prescriptions. The easily accessible and regularly updated local recommendations probably resulted in the standardization and optimization of costly antifungal agent prescriptions. PMID- 26055630 TI - Developmental stages for the divergence of relative limb length between a twig and a trunk-ground Anolis lizard species. AB - The divergent evolution of niche-related traits can facilitate adaptive radiation, yet identification of the genetic or molecular mechanisms underlying such trait changes remains a major challenge in evolutionary biology. Conducting a detailed morphological comparison along growth trajectories is a powerful method for observing the formation of differences in niche-related traits. Here, we focused on hindlimb length of Anolis lizards, differences in which are related to adaptation for use of different microhabitats. We measured the length of hindlimb skeletons in different ecomorphs of anole lizards (A. sagrei, a trunk ground ecomorph with long hindlimbs, and A. angusticeps, a twig ecomorph with short hindlimbs) from early embryonic stages to adulthood, to determine which hindlimb elements mainly differentiate the species and the timing of the formation of these differences. With respect to the digit, differences between the species mainly occurred during the embryonic stages of interdigit reduction, when the cartilage of the distal phalanges was simultaneously forming. In addition, we compared the relative length of developing autopods in early embryonic stages using whole-mount in situ hybridization before the formation of the cartilaginous bones, and the results showed that the relative growth rate of the Hoxa11-negative distal region in A. sagrei was greater than that in A. angusticeps. Our results show that there are several important developmental stages for hindlimb length differentiation between A. angusticeps and A. sagrei, depending on which hindlimb element is considered. In particular, the species differences were largely due to variations in digit length, which arose at early embryonic stages. PMID- 26055631 TI - Effects of imidazolium-based ionic surfactants on the size and dynamics of phosphatidylcholine bilayers with saturated and unsaturated chains. AB - Imidazolium-based ionic surfactants of different sizes were simulated with 1,2 dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphocholine (POPC), and 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayers. Regardless of the phospholipid type, larger surfactants at higher concentrations more significantly insert into the bilayer and increase the bilayer-surface size, in agreement with experiments and previous simulations. Insertion of surfactants only slightly decreases the bilayer thickness, as also observed in experiments. Although the surfactant insertion and its effect on the bilayer size and thickness are similar in different types of bilayers, the volume fractions of surfactants in the bilayer are higher for DMPC bilayers than for POPC and DOPC bilayers. In particular, ionic surfactants with four hydrocarbons yield their volume fractions of 4.6% and 8.7%, respectively, in POPC and DMPC bilayers, in quantitative agreement with experimental values of ~5% and ~10%. Also, the inserted surfactants increase the lateral diffusivity of the bilayer, which depends on the bilayer type. These findings indicate that although the surfactant insertion does not depend on the bilayer type, the effects of surfactants on the volume fraction and bilayer dynamics occur more significantly in the DMPC bilayer because of the smaller area per lipid and shorter saturated tails, which helps explain the experimental observations regarding different volume fractions of surfactants in POPC and DMPC bilayers. PMID- 26055632 TI - Contributions of the hippocampus to feedback learning. AB - Humans learn about the world in a variety of manners, including by observation, by associating cues in the environment, and via feedback. Across species, two brain structures have been predominantly involved in these learning processes: the hippocampus--supporting learning via observation and paired association--and the striatum--critical for feedback learning. This simple dichotomy, however, has recently been challenged by reports of hippocampal engagement in feedback learning, although the role of the hippocampus is not fully understood. The purpose of this experiment was to characterize the hippocampal response during feedback learning by manipulating varying levels of memory interference. Consistent with prior reports, feedback learning recruited the striatum and midbrain. Notably, feedback learning also engaged the hippocampus. The level of activity in these regions was modulated by the degree of memory interference, such that the greatest activation occurred during the highest level of memory interference. Importantly, the accuracy of information learned via feedback correlated with hippocampal activation and was reduced by the presence of high memory interference. Taken together, these findings provide evidence of hippocampal involvement in feedback learning by demonstrating both its relevance for the accuracy of information learned via feedback and its susceptibility to interference. PMID- 26055633 TI - Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course. AB - A growing body of evidence sheds light on the neurodevelopmental nature of schizophrenia with symptoms typically emerging during late adolescence or young adulthood. We compared the pre-symptomatic adolescence period with the full symptomatic period of adulthood at the behavioral and neurobiological level in the poly I:C maternal immune stimulation (MIS) rat model of schizophrenia. We found that in MIS-rats impaired sensorimotor gating, as reflected in disrupted prepusle inhibition (PPI), emerged post-pubertally, with behavioral deficits being only recorded in adulthood but not during adolescence. Using post mortem HPLC we found that MIS-rats show distinct dopamine and serotonin changes in the medial prefrontal cortex (mPFC), nucleus accumbens (Nacc), caudate putamen, globus pallidus, and hippocampus. Further, FDG-PET has shown that these animals had lower glucose uptake in the ventral hippocampus and PFC and a higher metabolism in the amygdala and Nacc when compared to controls. Changes in neurotransmission and metabolic activity varied across brain structures with respect to first appearance and further development. In the mPFC and Hipp, MIS rats showed abnormal neurochemical and metabolic activity prior to and with the development of behavioral deficits in both adolescent and adult states, reflecting an early impairment of these regions. In contrast, biochemical alteration in the Nacc and globus pallidus developed as a matter of age. Our findings suggest that MIS-induced neurochemical and metabolic changes are neurodevelopmental in nature and either progressive or non-progressive and that the behavioral deficits manifest as these abnormalities increase. PMID- 26055634 TI - [Spanish validation of the International Spinal Cord Injury Pulmonary Function Basic Data Set questionnaire for the study of the repercussion of spinal cord injury in the respiratory system]. AB - INTRODUCTION AND OBJECTIVE: The dysfunction of the respiratory system and the breathing complications in persons with injured spinal cord has an effect on the morbidity and the mortality of the disease. The objectives were: 1) to translate to Spanish and validate the questionnaire of international consensus: International Spinal Cord Injury Pulmonary Function Basic Data Set, and 2) to determine the influence of chronic spinal cord injury in the respiratory system in terms of respiratory functionalism. MATERIALS AND METHOD: Translation to Spanish and validation of the questionnaire of international consensus intended for the study of the pulmonary function in spinal cord injury disease. We tested the reliability of that questionnaire. We conducted a descriptive transversal study to determine the degree of involvement of the respiratory system in spinal cord injury. RESULTS: A percentage of 91.9 did not have any respiratory pathology before spinal cord injury and 54.8% of patients smoked. A percentage of 27.4 of patients presented breathing complications one year after the injury. Results of the respiratory function tests were: FVC 67%, FEV1 72% and PEF 70%. Concordance and reliability were 98%. CONCLUSION: The Spanish version of the questionnaire of international consensus about the pulmonary function is a useful tool for the study of the respiratory involvement in spinal cord injury. PMID- 26055635 TI - Effectiveness of a structured circuit class therapy model in stroke rehabilitation: a protocol for a randomised controlled trial. AB - BACKGROUND: Currently, the key advocacy in neuroscientific studies for stroke rehabilitation is that therapy should be directed towards task specificity performed with multiple repetitions. Circuit Class Therapy (CCT) is well suited to accomplish multiple task-specific activities. However, while repetitive task practice is achievable with circuit class therapy, in stroke survivors repetitive activities may be affected by poor neurologic inputs to motor units, resulting in decreases in discharging rates which consequently may reduce the efficiency of muscular contraction. To accomplish multiple repetitions, stroke survivors may require augmented duration of practice. To date, no study has examined the effect of augmented duration of CCT in stroke rehabilitation, and specifically what duration of CCT is more effective in influencing functional capacity among stroke survivors. METHODS/DESIGN: Using a randomised controlled trial with blinded outcome assessment, this study is aimed at determining the effectiveness of structured augmented CCT in stroke rehabilitation. Sixty-eight stroke survivors (to be recruited from a tertiary health institution in Kano, Northwest, Nigeria) will be randomised into one of four groups: three intervention groups of differing CCT durations namely: 60 min, 90 min, and 120 minuntes respectively, and a control group. Participants will take part in an 8-week structured intensive CCT intervention. Participants will be assessed at baseline, post intervention, and six-month follow-up for the effectiveness of the varied durations of therapy, using standardised tools. Based on the WHO-ICF model, the outcomes are body structure/function, activity limitation, and participation restriction measures. DISCUSSION: It is expected that the outcome of this study will clarify whether increasing CCT duration leads to better recovery of motor function in stroke survivors. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR201311000701191. PMID- 26055636 TI - Ca(2+) homeostasis in the budding yeast Saccharomyces cerevisiae: Impact of ER/Golgi Ca(2+) storage. AB - Yeast has proven to be a powerful tool to elucidate the molecular aspects of several biological processes in higher eukaryotes. As in mammalian cells, yeast intracellular Ca(2+) signalling is crucial for a myriad of biological processes. Yeast cells also bear homologs of the major components of the Ca(2+) signalling toolkit in mammalian cells, including channels, co-transporters and pumps. Using yeast single- and multiple-gene deletion strains of various plasma membrane and organellar Ca(2+) transporters, combined with manipulations to estimate intracellular Ca(2+) storage, we evaluated the contribution of individual transport systems to intracellular Ca(2+) homeostasis. Yeast strains lacking Pmr1 and/or Cod1, two ion pumps implicated in ER/Golgi Ca(2+) homeostasis, displayed a fragmented vacuolar phenotype and showed increased vacuolar Ca(2+) uptake and Ca(2+) influx across the plasma membrane. In the pmr1Delta strain, these effects were insensitive to calcineurin activity, independent of Cch1/Mid1 Ca(2+) channels and Pmc1 but required Vcx1. By contrast, in the cod1Delta strain increased vacuolar Ca(2+) uptake was not affected by Vcx1 deletion but was largely dependent on Pmc1 activity. Our analysis further corroborates the distinct roles of Vcx1 and Pmc1 in vacuolar Ca(2+) uptake and point to the existence of not-yet identified Ca(2+) influx pathways. PMID- 26055637 TI - A sporadic case of late-onset familial amyloid polyneuropathy with a monoclonal gammopathy. AB - A 77-year-old Portuguese woman reported gradual worsening of burning and numbness in the feet and hands, fatigue, anorexia, weight loss, diarrhoea and decreased visual acuity. She had a medical history of atrial fibrillation and recent episodes of dizziness and blood pressure fluctuations. There was no relevant family history. The diagnostic workup documented a severe axonal sensorimotor peripheral neuropathy, a monoclonal IgG kappa protein on serum, a severe left ventricular hypertrophy on the echocardiogram and probable vitreous deposits of amyloid on ophthalmologic examination. Pain and dysautonomia with an axonal neuropathy and multisystemic involvement raised the possibility of amyloidosis. The presence of a detectable monoclonal protein, older age at disease onset and absence of family history of disease usually suggest immunoglobulin light-chain amyloidosis. However, in this case, both the genetic testing and the biopsy of the salivary glands confirmed transthyretin amyloidosis. In those patients with a monoclonal protein, particularly in sporadic and late-onset cases, the diagnosis of transthyretin amyloidosis can be challenging, mimicking immunoglobulin light chain amyloidosis. PMID- 26055639 TI - Clinical efficacy and safety of anti-IL-17 agents for the treatment of patients with psoriasis. AB - To evaluate the therapeutic efficacy and safety of anti-IL-17 agents in the treatment of psoriasis, we performed a systemic review and meta-analysis of the relevant published clinical trials, collectively referred to as secukinumab, ixekizumab and brodalumab. 2668 patients in eight eligible trials with psoriasis were selected for the present meta-analysis. The estimated pooled PASI75, PSAI90, physician's global assessment (PGA; clear) showed significant improvements for psoriasis patients who received biotherapy compared with placebo. The results of headache, upper respiratory tract infection and infections demonstrated that there was no significant difference between the biotherapy and placebo groups. But the results of nasopharyngitis demonstrated that there was a significant difference for biotherapy group. The results showed that anti-IL-17 agents were effective and safe for psoriasis patients. PMID- 26055638 TI - The effect of the DcpS inhibitor D156844 on the protective action of follistatin in mice with spinal muscular atrophy. AB - Spinal muscular atrophy (SMA), a leading genetic cause of pediatric death in the world, is an early-onset disease affecting the motor neurons in the anterior horn of the spinal cord. This degeneration of motor neurons leads to loss of muscle function. At the molecular level, SMA results from the loss of or mutation in the survival motor neuron 1 (SMN1) gene. The number of copies of the nearly duplicated gene SMN2 modulates the disease severity in humans as well as in transgenic mouse models for SMA. Most preclinical therapeutic trials focus on identifying ways to increase SMN2 expression and to alter its splicing. Other therapeutic strategies have investigated compounds which protect affected motor neurons and their target muscles in an SMN-independent manner. In the present study, the effect of a combination regimen of the SMN2 inducer D156844 and the protectant follistatin on the disease progression and survival was measured in the SMNDelta7 SMA mouse model. The D156844/follistatin combination treatment improved the survival of, delayed the end stage of disease in and ameliorated the growth rate of SMNDelta7 SMA mice better than follistatin treatment alone. The D156844/follistatin combination treatment, however, did not provide additional benefit over D156844 alone with respect to survival and disease end stage even though it provided some additional therapeutic benefit over D156844 alone with respect to motor phenotype. PMID- 26055640 TI - Mycolic acids, a promising mycobacterial ligand for targeting of nanoencapsulated drugs in tuberculosis. AB - The appearance of drug-resistant strains of Mycobacterium tuberculosis (Mtb) poses a great challenge to the development of novel treatment programmes to combat tuberculosis. Since innovative nanotechnologies might alleviate the limitations of current therapies, we have designed a new nanoformulation for use as an anti-TB drug delivery system. It consists of incorporating mycobacterial cell wall mycolic acids (MA) as targeting ligands into a drug-encapsulating Poly dl-lactic-co-glycolic acid polymer (PLGA), via a double emulsion solvent evaporation technique. Bone marrow-derived mouse macrophages, either uninfected or infected with different mycobacterial strains (Mycobacterium avium, Mycobacterium bovis BCG or Mtb), were exposed to encapsulated isoniazid-PLGA nanoparticles (NPs) using MA as a targeting ligand. The fate of the NPs was monitored by electron microscopy. Our study showed that i) the inclusion of MA in the nanoformulations resulted in their expression on the outer surface and a significant increase in phagocytic uptake of the NPs; ii) nanoparticle-containing phagosomes were rapidly processed into phagolysosomes, whether MA had been included or not; and iii) nanoparticle-containing phagolysosomes did not fuse with non-matured mycobacterium-containing phagosomes, but fusion events with mycobacterium-containing phagolysosomes were clearly observed. PMID- 26055641 TI - The role of albumin receptors in regulation of albumin homeostasis: Implications for drug delivery. AB - Albumin is the most abundant protein in blood and acts as a molecular taxi for a plethora of small insoluble substances such as nutrients, hormones, metals and toxins. In addition, it binds a range of medical drugs. It has an unusually long serum half-life of almost 3weeks, and although the structure and function of albumin has been studied for decades, a biological explanation for the long half life has been lacking. Now, recent research has unravelled that albumin-binding cellular receptors play key roles in the homeostatic regulation of albumin. Here, we review our current understanding of albumin homeostasis with a particular focus on the impact of the cellular receptors, namely the neonatal Fc receptor (FcRn) and the cubilin-megalin complex, and we discuss their importance on uses of albumin in drug delivery. PMID- 26055643 TI - Lexical and phonological processing in visual word recognition by stuttering children: evidence from Spanish. AB - A number of studies have pointed out that stuttering-like disfluencies could be the result of failures in central and linguistic processing. The goal of the present paper is to analyze if stuttering implies deficits in the lexical and phonological processing in visual word recognition. This study compares the performance of 28 children with and without stuttering in a standard lexical decision task in a transparent orthography: Spanish. Word frequency and syllable frequency were manipulated in the experimental words. Stutterers were found to be considerably slower (in their correct responses) and produced more errors than the non- stutterers (chi(1) = 36.63, p < .001, eta2 = .60). There was also a facilitation effect of syllable frequency, restricted to low frequency words and only in the stutterers group (t1(10) = 3.67, p < .005; t2(36) = 3.10, p < .001). These outcomes appear to suggest that the decoding process of stutterers exhibits a deficit in the interface between the phonological-syllabic level and the word level. PMID- 26055644 TI - Autonomic dysreflexia and repeatability of cardiovascular changes during same session repeat urodynamic investigation in women with spinal cord injury. AB - PURPOSE: To investigate autonomic dysreflexia (AD) and repeatability of cardiovascular changes during same session repeat urodynamic investigation (UDI) in women with spinal cord injury (SCI). METHODS: Prospective investigation of 33 consecutive women with suprasacral SCI suffering from neurogenic lower urinary tract dysfunction (NLUTD) undergoing same session repeat UDI and synchronous continuous cardiovascular monitoring [systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR)]. UDIs were performed according to the International Continence Society guidelines. AD was defined according to the International Standards to document remaining Autonomic Function after SCI. Neurological level of SCI was determined using the American Spinal Injury Association impairment scale. RESULTS: Mean age and duration since SCI of the 33 women were 58 +/- 19 and 6 +/- 11 years, respectively. Overall AD incidence was 73 % (24/33), and 19 of the 33 women (58 %) showed AD in both UDIs. The repeatability of detecting AD between the two same session UDIs was good (kappa = 0.67, 95 % CI 0.4-0.94). When applying the Bland and Altman method, wide 95 % limits of agreement for differences in same session SBP, DBP and HR indicated poor repeatability. There was a significant increase in SBP (p < 0.001) and DBP (p < 0.001) and a significant decrease in HR (p = 0.007) in patients with compared to those without AD. CONCLUSIONS: In all women with NLUTD due to suprasacral SCI, we strongly recommend continuous cardiovascular monitoring during UDI and repeat measurements considering the high incidence of AD, the relevant risks involved with sudden hypertension and the poor repeatability of cardiovascular monitoring. PMID- 26055645 TI - Comparison of patient comfort between MR-guided in-bore and MRI/ultrasound fusion guided prostate biopsies within a prospective randomized trial. AB - PURPOSE: The objective of this study was to compare patient comfort between MR guided in-bore prostate biopsy (IB-GB) and MRI/ultrasound fusion-guided prostate biopsy (FUS-GB) with additional systematic 12-core transrectal ultrasound (TRUS) guided biopsy within a prospective randomized trial. METHODS: Two hundred and ten consecutive patients were randomly assigned in a 1:1 ratio to receive either IB GB and prior intrarectal instillation of a 2% lidocaine gel (n = 106) or FUS-GB plus additional systematic 12-core TRUS-guided biopsy and prior application of a periprostatic nerve block (PPNB) with 2% mepivacaine (n = 104). The maximal procedural pain (MPP) on a 0-10 visual analog scale and the operating room time were recorded for each biopsy session. RESULTS: Baseline characteristics and mean number of targeted biopsy cores (5.6 +/- 0.8 vs 5.4 +/- 1.2 for IB-GB and FUS-GB, respectively; p = 0.278) were similar in both study arms. In relation to the IB GB arm, the total number of biopsy cores in the FUS-GB arm, including the systematic 12-core TRUS-guided biopsy, was significantly higher (17.4 +/- 1.2; p < 0.001). Patients with IB-GB had significantly higher MPP scores (2.95 +/- 2.15) compared with subjects with FUS-GB (1.95 +/- 1.56; p < 0.001). FUS-GB required significantly less time (28.22 +/- 11.61 min) in comparison with IB-GB (42.09 +/- 11.37 min; p < 0.001). CONCLUSIONS: The PPNB can easily be administered just prior to performing FUS-GB. Thus, patients have significantly lower pain levels in comparison with IB-GB, which is usually done with intrarectal anesthetic gels. Although the addition of a systematic 12-core TRUS-guided biopsy significantly increases the number of biopsy cores, FUS-GB still requires significantly less time in comparison with IB-GB. PMID- 26055646 TI - The prognostic effect of tumour-infiltrating lymphocytic subpopulations in bladder cancer. AB - BACKGROUND: Intratumoural lymphocytic infiltration is strongly associated with the outcome of many human epithelial cancers. The current paper investigated whether subpopulations of tumour-infiltrating T lymphocytes are associated with certain clinicopathological parameters and the prognosis of patients with invasive bladder cancer (BCa). PATIENTS AND METHODS: The infiltration densities of the adaptive immune markers CD3 (the whole T cell population), FOXP3 (regulatory T cells; Tregs), CD8 (T effector cells) and CD45R0 (T effector memory cells) were analysed by immunohistochemistry and image analysis with tissue microarrays of tumour tissues from 149 patients with invasive BCa treated with radical cystectomy. The findings were correlated with certain clinicopathological parameters. RESULTS: Higher FOXP3/CD3 [OS: p = 0.016, HR 1.29, 95% confidence intervals (95% CIs 1.05-1.59)] and FOXP3/CD8 (OS: p = 0.013, HR 1.32, 95% CIs 1.06-1.65) ratios were significantly associated with briefer overall survival and time to cancer-specific death; the latter ratio represented an independent prognostic factor according to a multivariate analysis adjusted for pathological T and N stages (HR 1.32, 95% CIs 1.05-1.67, p = 0.018). The infiltration densities of individual markers (CD3, CD8, FOXP3 and CD45R0) were not significantly associated with clinicopathological parameters or survival; however, a trend towards a better outcome was observed for higher log-transformed CD8 (p = 0.070, HR 0.80, 95% CIs 0.63-1.02) and CD3 (p = 0.113, HR 0.84, 95% CIs 0.68-1.04) infiltration values. CONCLUSIONS: A high fraction of Tregs amongst CD3 and CD8-positive lymphocytes indicated a poor prognosis, thereby emphasising the important role that Tregs play in the suppression of the anti-tumour immune response. No single lymphocytic marker was significantly correlated with clinical outcomes, but high CD3 and CD8 infiltration showed trends towards better prognosis. PMID- 26055647 TI - Grip strength measured by high precision dynamometry in healthy subjects from 5 to 80 years. AB - BACKGROUND: Grip strength is a variable which may be important to measure and follow in various populations. A new dynamometer with high accuracy and sensitivity has recently been developed to assess grip strength. The objectives of this work were to provide norms of maximal isometric grip strength measured with this new dynamometer (the MyoGrip device), to assess the reliability of measurements, to compare the measurements obtained with MyoGrip and Jamar dynamometers and finally to establish predictive equations from a population of healthy subjects (children and adults). METHODS: Measurements of maximal isometric grip strength using the MyoGrip and the Jamar (which is considered as the gold-standard) were performed on 346 healthy subjects aged from 5 to 80 years. Test-retest reliability for both devices was assessed on 77 subjects. Predictive equations were computed on subjects younger than 60 years of age in order to avoid the effects of aging on strength. RESULTS: This study provides norms for isometric grip strength for health subjects from 5 to 80 years. Reliability of the MyoGrip device was excellent (intraclass correlation coefficient: 0.967). Despite good correlation between devices, the Jamar tended to overestimate maximal grip strength by about 14 %. A single predictive equation for men and women, adults and children incorporating hand circumference only can be used to compute the predicted theoretical maximal grip strength. CONCLUSIONS: The MyoGrip device is a reliable tool for measuring isometric grip strength. Owing to its unique metrological features, it can be used in very weak patients or in any situation where high precision and accuracy are required. PMID- 26055648 TI - Survey of community-associated-methicillin-Resistant Staphylococcus aureus in Slovenia: identification of community-associated and livestock-associated clones. AB - The epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in Slovenia is poorly documented. The aim of this study was to investigate susceptibility patterns, virulence gene profile and clonality among MRSA isolates with positive screened resistance phenotype for CA-MRSA collected from patients in Slovenia, from January 2010 to December 2010. We included only MRSA isolates that were resistant to cefoxitin and oxacillin, and susceptible to at least two of the following four antibiotics: ciprofloxacin, erythromycin, clindamycin or gentamicin (presumptive CA-MRSA). Altogether 151 isolates fulfilled our screening phenotypic definition, 126 MRSA isolates were classified as CA-MRSA and 25 as HA MRSA. Thirty-six per cent of them were resistant to ciprofloxacin, 24% to clindamycin, 33% to erythromycin and 13% to gentamicin. The mecA gene was detected in 150 isolates, while the mecC gene only in 1 isolate. The MRSA isolates were classified to 19 different clones. The most prevalent sequence types were ST5 (26.4%), ST45 (25.2%), ST22 (10.6%), ST398 (9.9%), ST8 (5.9%), ST7 (4.6%), ST1 (3.9%), ST152/377 (3.3%), ST228 (2.6%) and ST2883 (1.3%). The ST6, ST9, ST30, ST72, ST88, ST111, ST130, ST225 and ST772 were identified sporadically. The Panton-Valentine leukocidin (PVL) gene was detected in 13 (8.6%) isolates that belonged to ST5, ST7, ST8, ST22, ST72, ST88, ST 152/377 and ST772. Our results show high variability of CA-MRSA circulating in Slovenia and also the presence of LA-MRSA clones. PMID- 26055649 TI - Modeling evolutionary games in populations with demographic structure. AB - Classic life history models are often based on optimization algorithms, focusing on the adaptation of survival and reproduction to the environment, while neglecting frequency dependent interactions in the population. Evolutionary game theory, on the other hand, studies frequency dependent strategy interactions, but usually omits life history and the demographic structure of the population. Here we show how an integration of both aspects can substantially alter the underlying evolutionary dynamics. We study the replicator dynamics of strategy interactions in life stage structured populations. Individuals have two basic strategic behaviours, interacting in pairwise games. A player may condition behaviour on the life stage of its own, or that of the opponent, or the matching of life stages between both players. A strategy is thus defined as the set of rules that determines a player's life stage dependent behaviours. We show that the diversity of life stage structures and life stage dependent strategies can promote each other, and the stable frequency of basic strategic behaviours can deviate from game equilibrium in populations with life stage structures. PMID- 26055650 TI - Basal efflux of bile acids contributes to drug-induced bile acid-dependent hepatocyte toxicity in rat sandwich-cultured hepatocytes. AB - The bile salt export pump (BSEP or Bsep) functions as an apical transporter to eliminate bile acids (BAs) from hepatocytes into the bile. BSEP or Bsep inhibitors engender BA retention, suggested as an underlying mechanism of cholestatic drug-induced liver injury. We previously reported a method to evaluate BSEP-mediated BA-dependent hepatocyte toxicity by using sandwich cultured hepatocytes (SCHs). However, basal efflux transporters, including multidrug resistance-associated proteins (MRP or Mrp) 3 and 4, also participate in BA efflux. This study examined the contribution of basal efflux transporters to BA-dependent hepatocyte toxicity in rat SCHs. The apical efflux of [(3)H]taurocholic acid (TC) was potently inhibited by 10 MUM cyclosporine A (CsA), with later inhibition of basal [(3)H]TC efflux, while MK571 simultaneously inhibited both apical and basal [(3)H]TC efflux. CsA-induced BA-dependent hepatocyte toxicity was 30% at most at 10 MUM CsA and ~60% at 50 MUM, while MK571 exacerbated hepatocyte toxicity at concentrations of >=50 MUM. Quinidine inhibited only basal [(3)H]TC efflux and showed BA-dependent hepatocyte toxicity in rat SCHs. Hence, inhibition of basal efflux transporters as well as Bsep may precipitate BA-dependent hepatocyte toxicity in rat SCHs. PMID- 26055651 TI - Criteria and challenges of the human placental perfusion - Data from a large series of perfusions. AB - Perfusion of human placental cotyledon has been used extensively to study transplacental transfer of endogenous and exogenous compounds. However, many challenges in the use of the method exist, including availability of placentas and complexity of the method itself. In Kuopio, Finland we have carried out human placental perfusions since 2005 using the same method with data now from over one hundred perfusions. This has allowed us to study whether the way of delivery, placental weight, and/or the length of pregnancy affect the two major criteria of a successful perfusion: volume loss (leak) from fetal to maternal circulation, and transplacental transfer of the reference compound antipyrine. The only statistically significant result was the reduction of the fetomaternal ratio of antipyrine by the placental age over 40 weeks (p=0.0004). The success criteria were not affected by the weight of the placenta or the way of delivery. There was no effect by the antipyrine concentration on antipyrine transfer. In vitro incubation with different concentrations of study compounds and different tubing materials could offer an easy way to study potentially reduced recovery due to binding to perfusion system. PMID- 26055652 TI - Interaction of Eu(III) with mammalian cells: Cytotoxicity, uptake, and speciation as a function of Eu(III) concentration and nutrient composition. AB - In case of the release of lanthanides and actinides into the environment, knowledge about their behavior in biological systems is necessary to assess and prevent adverse health effects for humans. We investigated the interaction of europium with FaDu cells (human squamous cell carcinoma cell line) combining analytical methods, spectroscopy, and thermodynamic modeling with in-vitro cell experiments under defined conditions. Both the cytotoxicity of Eu(III) onto FaDu cells and its cellular uptake are mainly concentration-dependent. Moreover, they are governed by its chemical speciation in the nutrient medium. In complete cell culture medium, i.e., in the presence of fetal bovine serum, Eu(III) is stabilized in solution in a wide concentration range by complexation with serum proteins resulting in low cytotoxicity and cellular Eu(III) uptake. In serum-free medium, Eu(III) precipitates as hardly soluble phosphate species, exhibiting a significantly higher cytotoxicity and slightly higher cellular uptake. The presence of a tenfold excess of citrate in serum-free medium causes the formation of Eu(HCit)2(3-) complexes in addition to the dominating Eu(III) phosphate species, resulting in a decreased Eu(III) cytotoxicity and cellular uptake. The results of this study underline the crucial role of a metal ion's speciation for its toxicity and bioavailability. PMID- 26055653 TI - Beck Anxiety Inventory: psychometric characteristics in a sample from the clinical Spanish population. AB - Even though the Beck Anxiety Inventory (BAI) is one of the most popular instruments to assess anxiety today, only limited data is available about its psychometric characteristics and normative values in clinical Spanish populations. A study was conducted to test the psychometric characteristics of a Spanish adaptation of the Beck Anxiety Inventory (BAI) in a sample of 918 outpatients being treated at a community mental health center in Spain. Results confirmed the adaptation's high internal consistency (? = .91), substantial test retest reliability at 8-10 weeks (r = .84, p < .01), and satisfactory convergent validity with the Anxiety (r = .86, p < .01), Somatization (r = .81, p < .01), Obsessive-compulsive (r = .60, p < .01), and Phobic Anxiety (r = .63, p < .01) dimensions of the SCL-90-R, and with the Anxious Thoughts Inventory (r = .57, p < .01). Gender differences in BAI scores did occur, so normative values appear separately for each gender. PMID- 26055654 TI - Effect of cassava mill effluent on biological activity of soil microbial community. AB - This study assessed the effect of cassava effluent on soil microbiological characteristics and enzymatic activities were investigated in soil samples. Soil properties and heavy metal concentrations were evaluated using standard soil analytical and spectroscopic methods, respectively. The microbiological parameters measured include microbial biomass carbon, basal soil respiration, catalase, urease, dehydrogenase activities and number of culturable aerobic bacteria, fungi and actinomycetes. The pH and temperature regime vary significantly (p < 0.05) throughout the study period. All other physicochemical parameters studied were significantly different (p < 0.05) higher than the control site. Soil organic carbon content gave significant positive correlations with microbial biomass carbon, basal soil respiration, catalase activity and dehydrogenase activity (r = 0.450, 0.461, 0.574 and 0.591 at p < 0.01), respectively. The quantitative analysis of soil microbial density demonstrates a marked decrease in total culturable numbers of the different microbial groups of the polluted soil samples. Soil contamination decreased catalase, urease and dehydrogenase activities. The findings revealed that soil enzymes can be used as indices of soil contamination and bio-indicator of soil quality. PMID- 26055655 TI - Predicting aqueous copper and zinc accumulation in the upside-down jellyfish Cassiopea maremetens through the use of biokinetic models. AB - Jellyfish have a demonstrated capability to accumulate metals within their tissues, but to date, there have been no quantitative assessments of accumulation and retention rates and patterns. Bioconcentration patterns of copper and zinc in the upside-down jellyfish Cassiopea maremetens were modelled over a 28-day study (14 days exposure followed by 14 days clearance). C. maremetens accumulated copper over 14 days with the maximum calculated copper concentrations at 33.78 MUg g(-1) dry weight and bioconcentrated to 99 times water concentrations. Zinc was also accumulated during the exposure period and retained for longer. The maximum theoretical zinc concentration was 125.1 MUg g(-1) dry weight with a kinetic bioconcentration factor of 104. The patterns of uptake and retention were different between the elements. The use of kinetic models provided adequate predictions of aqueous metal uptake and retention in C. maremetens. This species has the capacity to very rapidly absorb measurable metals from short-term water metal exposure. PMID- 26055656 TI - Using remote sensing data to predict road fill areas and areas affected by fill erosion with planned forest road construction: a case study in Kastamonu Regional Forest Directorate (Turkey). AB - Forest roads are essential for transport in managed forests, yet road construction causes environmental disturbance, both in the surface area the road covers and in erosion and downslope deposition of road fill material. The factors affecting the deposition distance of eroded road fill are the slope gradient and the density of plant cover. Thus, it is important to take these factors into consideration during road planning to minimize their disturbance. The aim of this study was to use remote sensing and field surveying to predict the locations that would be affected by downslope deposition of eroding road fill and to compile the data into a geographic information system (GIS) database. The construction of 99,500 m of forest roads is proposed for the Kastamonu Regional Forest Directorate in Turkey. Using GeoEye satellite images and a digital elevation model (DEM) for the region, the location and extent of downslope deposition of road fill were determined for the roads as planned. It was found that if the proposed roads were constructed by excavators, the fill material would cover 910,621 m(2) and the affected surface area would be 1,302,740 m(2). Application of the method used here can minimize the adverse effects of forest roads. PMID- 26055657 TI - Word association norms in Mexican Spanish. AB - The aim of this research is to present a Spanish Word Association Norms (WAN) database of concrete nouns. The database includes 234 stimulus words (SWs) and 67,622 response words (RWs) provided by 478 young Mexican adults. Eight different measures were calculated to quantitatively analyze word-word relationships: 1) Associative strength of the first associate, 2) Associative strength of the second associate, 3) Sum of associative strength of first two associates, 4) Difference in associative strength between first two associates, 5) Number of different associates, 6) Blank responses, 7) Idiosyncratic responses, and 8) Cue validity of the first associate. The resulting database is an important contribution given that there are no published word association norms for Mexican Spanish. The results of this study are an important resource for future research regarding lexical networks, priming effects, semantic memory, among others. PMID- 26055658 TI - Locked nucleic acid (LNA) induced effect on the hybridization and fluorescence properties of oligodeoxyribonucleotides modified with nucleobase-functionalized DNA monomers. AB - LNA and nucleobase-modified DNA monomers are two types of building blocks that are used extensively in oligonucleotide chemistry. However, there are only very few reports in which these two monomer families are used alongside each other. In the present study we set out to characterize the biophysical properties of oligodeoxyribonucleotides in which C5-modified 2'-deoxyuridine or C8-modified 2' deoxyadenosine monomers are flanked by LNA nucleotides. We hypothesized that the LNA monomers would alter the sugar rings of the modified DNA monomers toward more RNA-like North-type conformations for maximal DNA/RNA affinity and specificity. Indeed, the incorporation of LNA monomers almost invariably results in increased target affinity and specificity relative to the corresponding LNA-free ONs, but the magnitude of the stabilization varies greatly. Introduction of LNA nucleotides as direct neighbors into C5-pyrene-functionalized pyrimidine DNA monomers yields oligonucleotide probes with more desirable photophysical properties as compared to the corresponding LNA-free probes, including more intense fluorescence emission upon target binding and improved discrimination of single nucleotide polymorphisms (SNPs). These hybrid oligonucleotides are therefore promising probes for diagnostic applications. PMID- 26055659 TI - Enzymatic conversion of carbon dioxide. AB - With the continuous increase in fossil fuels consumption and the rapid growth of atmospheric CO2 concentration, the harmonious state between human and nature faces severe challenges. Exploring green and sustainable energy resources and devising efficient methods for CO2 capture, sequestration and utilization are urgently required. Converting CO2 into fuels/chemicals/materials as an indispensable element for CO2 capture, sequestration and utilization may offer a win-win strategy to both decrease the CO2 concentration and achieve the efficient exploitation of carbon resources. Among the current major methods (including chemical, photochemical, electrochemical and enzymatic methods), the enzymatic method, which is inspired by the CO2 metabolic process in cells, offers a green and potent alternative for efficient CO2 conversion due to its superior stereo specificity and region/chemo-selectivity. Thus, in this tutorial review, we firstly provide a brief background about enzymatic conversion for CO2 capture, sequestration and utilization. Next, we depict six major routes of the CO2 metabolic process in cells, which are taken as the inspiration source for the construction of enzymatic systems in vitro. Next, we focus on the state-of-the art routes for the catalytic conversion of CO2 by a single enzyme system and by a multienzyme system. Some emerging approaches and materials utilized for constructing single-enzyme/multienzyme systems to enhance the catalytic activity/stability will be highlighted. Finally, a summary about the current advances and the future perspectives of the enzymatic conversion of CO2 will be presented. PMID- 26055660 TI - The politics of attention contextualized: gaze but not arrow cuing of attention is moderated by political temperament. AB - It is known that an averted gaze can trigger shifts of attention in an observer, a phenomenon known as gaze-cuing effect. Recently, Dodd et al. (Atten Percept Psychophys 73:24-29, 2011) have reported a reliable gaze-cuing effect for liberals but not for conservatives. The present study tested whether this result is gaze-specific or extends over nonsocial spatial signals. Conservatives and liberals took part in a spatial-cuing task in which centrally placed gaze and arrow cues, pointing rightward or leftward, were followed by a peripheral onset target requiring a simple detection response. Whereas a reliable cuing effect was present for both gaze and arrow cues in the case of liberals, conservatives showed a reduced cuing response only for gaze cues. These results provide further support for the pattern reported by Dodd et al. (2011) and are consistent with the view that conservatives are less susceptible to the influence of spatial cues provided by other individuals. PMID- 26055661 TI - Anaplasma infection of Bactrian camels (Camelus bactrianus) and ticks in Xinjiang, China. AB - BACKGROUND: To date, anaplasmosis has been reported to be a subclinical disease in Indian and Arabian one-humped camels (Camelus dromedarius) and llamas (Lama glama). However, no information on Anaplasma infection in two-humped Bactrian camels (Camelus bactrianus) in China has been published to date. The aim of this study was to investigate the prevalence of Anaplasma spp. in domestic Bactrian camels and ticks in Xinjiang, China. FINDINGS: A total of 382 ticks were collected from the Bactrian camels and from environmental sources. Of these, 84 were morphologically identified as belonging to the Rhipicephalus sanguineus group and genetically identified (12S rDNA, 16S rDNA and the cytochrome c oxidase 1 genes) as R. sanguineus group ticks (temporally designated as Rhipicephalus sp. Xinjiang). PCR testing showed that 7.2% (20/279) of the camels harbored Anaplasma platys DNA. However, microscopic examination revealed no A. platys inclusions in blood smears from the camels. The PCR prevalence of A. platys DNA was 9.5% (6/63) in Rhipicephalus sp. Xinjiang from the Bactrian camels and 14.3% (3/21) in Rhipicephalus sp. Xinjiang from the vegetation. A. platys DNA was not detected by PCR in other tick species (Hyalomma asiaticum, Dermacentor niveus and Hyalomma dromedarii), and no other Anaplasma species were detected in these samples. CONCLUSIONS: This is the first report of A. platys in Bactrian camels in Xinjiang, China. The moderate positivity observed indicates that these animals might be a natural host for this pathogen in China. PMID- 26055662 TI - Effects of the protonophore carbonyl-cyanide m-chlorophenylhydrazone on intracytoplasmic membrane assembly in Rhodobacter sphaeroides. AB - The effect of carbonyl-cyanide m-chlorophenyl-hydrazone (CCCP) on intracytoplasmic membrane (ICM) assembly was examined in the purple bacterium Rhodobacter sphaeroides. CCCP blocks generation of the electrochemical proton gradient required for integral membrane protein insertion. ICM formation was induced for 8h, followed by a 4-h exposure to CCCP. Measurements of fluorescence induction/relaxation kinetics showed that CCCP caused a diminished quantum yield, a cessation in expansion of the functional absorption cross-section and a 4- to 10-fold slowing in the electron transfer turnover rate. ICM vesicles (chromatophores) and an upper-pigmented band (UPB) containing ICM growth initiation sites, were isolated and subjected to clear-native electrophoresis. Proteomic analysis of the chromatophore gel bands indicated that CCCP produced a 2.7-fold reduction in spectral counts in the preferentially assembled light harvesting 2 (LH2) antenna, while the RC-LH1 complex, F1FO-ATPase and pyridine nucleotide transhydrogenase decreased by 1.7-1.9-fold. For 35 soluble enzymes, the ratio of 0.99 for treated/control proteins demonstrated that protein synthesis was unaffected by CCCP, suggesting that the membrane complex decline arose from the turnover of unassembled apoproteins. In the UPB fraction, an ~2 fold accumulation was observed for the preprotein translocase SecY, the SecA translocation ATPase, SecD and SecF insertion components, and chaperonins DnaJ and DnaK, consistent with the possibility that these factors, which act early in the assembly process, have accumulated in association with nascent polypeptides as stabilized assembly intermediates. PMID- 26055665 TI - Spanish version of the Pain Vigilance and Awareness Questionnaire: psychometric properties in a sample of women with fibromyalgia. AB - Excessive attention to pain is a common psychological characteristic among people who suffer from chronic pain. The Pain Vigilance and Awareness Questionnaire (PVAQ) is an internationally accepted tool to assess this feature, although there is no validated version of this measure for Spanish people with fibromyalgia. Since this pain syndrome mainly affects women, the aim of this study was to determine the psychometric properties of the PVAQ in Spanish women with fibromyalgia. A group of 242 women diagnosed with fibromyalgia aged between 20 and 66 years participated in the study. The goodness of fit of several structures of the PVAQ reported in previous studies was compared via confirmatory factor analysis. A two-factor solution (active vigilance and passive awareness) of the 9 item shortened version (PVAQ-9) was identified as the most appropriate (RMSEA = .08, NNFI = .96, CFI = .97, GFI = .87). It showed good reliability (internal consistency alpha = .82), convergent validity and divergent validity (p < .01). The optimal cutoff point for identifying fibromyalgia women with worse daily functioning was a score of 24.5, with a sensitivity of .71 and a specificity of .75. The relevance of vigilance to pain for clinical research in fibromyalgia is discussed. PMID- 26055663 TI - The biopsy Gleason score 3+4 in a single core does not necessarily reflect an unfavourable pathological disease after radical prostatectomy in comparison with biopsy Gleason score 3+3: looking for larger selection criteria for active surveillance candidates. AB - BACKGROUND: To assess whether the addition of clinical Gleason score (Gs) 3+4 to the Prostate Cancer Research International: Active Surveillance (PRIAS) criteria affects pathologic results in patients who are potentially suitable for active surveillance (AS) and to identify possible clinical predictors of unfavourable outcome. METHODS: Three hundred and twenty-nine men who underwent radical prostatectomy with complete clinical and follow-up data and who would have fulfilled the inclusion criteria of the PRIAS protocol at the time of biopsy except for the addition of biopsy Gs=3+4 and with at least 10 cores taken have been evaluated. One experienced genitourinary pathologist selected those with real Gs=3+3 and 3+4 in only one core according to the 2005 International Society of Urological Pathology criteria. The primary end point was the proportion of unfavourable outcome (nonorgan confined disease or Gs?4+3). Logistic regressions explored the association between preoperative characteristics and the primary end point. RESULTS: Two hundred and four patients were evaluated and 46 (22.5%) patients harboured unfavourable disease at final pathology. After a median follow up of 73.5 months, there was no cancer-specific death, and 4 (2.0%) patients had biochemical relapse. There were no significant differences in terms of high Gs, locally advanced disease, unfavourable disease and biochemical relapse-free survival among patients with clinical Gs=3+3 vs Gs=3+4. At multivariable analysis, the presence of atypical small acinar proliferation (ASAP) and lower number of core taken were independently associated with a higher risk of unfavourable disease. CONCLUSION: The inclusion of Gs=3+4 in patients suitable to AS does not enhance the risk of unfavourable disease after radical prostatectomy. Additional factors such as number of cores taken and the presence of ASAP should be considered in patients suitable for AS. PMID- 26055666 TI - Functionalized ZnO@TiO2 nanorod array film loaded with ZnIn(0.25)Cu(0.02)S(1.395) solid-solution: synthesis, characterization and enhanced visible light driven water splitting. AB - We have designed a novel semiconductor core/layer nanostructure of a uniform ZnO@TiO2 nanorod array modified with a ZnIn0.25Cu0.02S1.395 solid-solution on the surface via a facile hydrothermal synthesis. This novel nanostructure combines the merits of all components and meets the requirements of photovoltaic system application. An intimate PN heterojunction is formed from the ZnO@TiO2 nanorod and polymetallic sulphide solid-solution, which is remarkably beneficial for the effective visible light absorption and rapid charge carrier separation. The nanostructures exhibit higher photocurrent and incident photon to electron conversion efficiency (IPCE) under no bias potential versus the Ag/AgCl electrode. We also analyzed the interface and photoelectrochemical characteristics of the nanostructure and revealed the kinetic process of the electron and hole transmission. In addition, the photoanode test shows the hydrogen production capability of the nanostructures from solar water splitting. These results verified that the ZnO and TiO2 can be sensitized by the polymetallic sulfide for UV-Vis light driven energy conversion. Importantly, the approach we used to design the photoanode enables the development of micro-nano electronic devices with enhanced performance. PMID- 26055667 TI - Inherited metabolic disorders in Turkish patients with autism spectrum disorders. AB - Autism spectrum disorders (ASDs) are a major health problem because of their high prevalence in the general population. The pathophysiology of ASD remains unclear, although genetic defects may be detected in 10-20% of affected patients. Among these cases, the prevalence of inherited metabolic disorders (IMD) has not been extensively evaluated. IMDs responsible for ASDs are usually identified via clinical manifestations such as microcephaly, dysmorphic features, convulsions, and hepatosplenomegaly. Infrequently, patients with no additional clinical symptoms suggestive of an IMD may be diagnosed as having an idiopathic ASD. High consanguinity rates have resulted in an increased prevalence of IMDs in the Turkish population. The aim of this study was to explore the benefits of systematic screening for IMD among Turkish patients with ASDs. In our study, data were retrospectively collected for 778 children with ASDs. In all cases, the metabolic investigations included an arterial blood gas analysis, serum ammonia and lactate levels, a quantitative plasma amino acid analysis, a whole blood acylcarnitine profile via tandem mass spectrometry and a urine organic acid profile. Urinary glycosaminoglycan levels and homocysteine levels were screened in selected cases; 300 of the 778 patients with ASDs whose physical and metabolic investigations were complete and met this study's criteria were enrolled. Among the 300 children with autism, IMD were diagnosed in nine patients as follows: two patients were diagnosed with phenylketonuria, and one patient was diagnosed with partial biotinidase deficiency; one patient was diagnosed with mucopolysaccharidosis type III, and one patient was diagnosed with classical homocystinuria; one patient was diagnosed with glutaric acidemia type 1, and one patient was diagnosed with short chain acyl-CoA dehydrogenase deficiency; one patient was diagnosed with argininemia, and one patient was diagnosed with L-2 hydroxyglutaric aciduria. PMID- 26055668 TI - Sleep Deprivation and Circadian Disruption: Stress, Allostasis, and Allostatic Load. AB - Sleep has important homeostatic functions, and circadian rhythms organize physiology and behavior on a daily basis to insure optimal function. Sleep deprivation and circadian disruption can be stressors, enhancers of other stressors that have consequences for the brain and many body systems. Whether the origins of circadian disruption and sleep disruption and deprivation are from anxiety, depression, shift work, long-distance air travel, or a hectic lifestyle, there are consequences that impair brain functions and contribute to the cumulative wear and tear on body systems caused by too much stress and/or inefficient management of the systems that promote adaptation. PMID- 26055669 TI - Sleep Disturbances in Depression. AB - Major depressive disorder is frequently accompanied by sleep disturbances such as insomnia or hypersomnia and polysomnographic sleep findings of increased rapid eye-movement sleep and decreased slow wave sleep. For many patients, insomnia persists even after mood symptoms have been adequately treated. These patients have poorer outcomes than patients without sleep problems. These outcomes suggest that overlapping neural mechanisms regulate sleep and mood. Treatment of these patients can incorporate sedating antidepressants, nonbenzodiazepine gamma aminobutyric acid agonists, and cognitive behavioral therapy. Sleep restriction has been found to improve mood in depressed patients; however, the benefits typically disappear after recovery sleep. PMID- 26055670 TI - Sleep and Mood During Pregnancy and the Postpartum Period. AB - During the perinatal period, compromises in sleep duration and quality are commonly reported by women and confirmed by objective measurements of sleep. Self reported poor sleep has been associated with concurrent mood disturbance and with increased risk for future mood problems during pregnancy and the postpartum period. Findings on the relationship between objectively measured sleep and mood in perinatal women have been mixed. This article reviews the literature on the nature of and contributing factors to perinatal sleep disturbance, the relationship between sleep and mood, and intervention studies that aim to improve maternal sleep. PMID- 26055671 TI - Sleep Disturbances and Suicide Risk. AB - Suicide occurs in the presence of psychiatric illness, and is associated with biological, psychological, and social risk factors. Insomnia symptoms and nightmares appear to present elevated risk for suicidal ideation, attempts, and death by suicide. Failure to account for the presence of psychopathology and frequent use of single item assessments of sleep and suicidal ideation are common methodological problems in this literature. Preliminary research, addressing these issues, suggests that subjective sleep complaints may confer independent risk for suicidal behaviors. PMID- 26055672 TI - Posttraumatic Stress Disorder and Sleep. AB - The purpose of this article is to provide a brief overview of sleep in the context of posttraumatic stress disorder (PTSD) and focus on the treatment of the most common sleep disorders encountered by patients with PTSD: insomnia and nightmares. The effects of the standard treatments for PTSD are discussed along with a review of available treatments for insomnia and nightmares. Particular emphasis is placed on nonpharmacologic treatments for these sleep disorders and how they may be adapted for delivery to patients with PTSD. PMID- 26055673 TI - Sleep in Schizophrenia: Pathology and Treatment. AB - Both subjective and objective assessments of sleep patterns in schizophrenia include a wide range of dyssomnias, with insomnia being the most frequently cited. Early and middle insomnia can range from mild disruption to total sleeplessness. Severe insomnia is a prodromal sign of clinical exacerbation or relapse. In general, most antipsychotic agents (APs) ameliorate this insomnia. However, in some schizophrenics APs can be associated with residual insomnia or with significant daytime somnolence. Furthermore, in some schizophrenics APs can induce or exacerbate comorbid sleep disorders such as restless legs syndrome, sleep-disordered breathing, and parasomnias such as sleepwalking. PMID- 26055674 TI - Non-Benzodiazepine Receptor Agonists for Insomnia. AB - Because of proven efficacy, reduced side effects, and less concern about addiction, non-benzodiazepine receptor agonists (non-BzRA) have become the most commonly prescribed hypnotic agents to treat onset and maintenance insomnia. First-line treatment is cognitive-behavioral therapy. When pharmacologic treatment is indicated, non-BzRA are first-line agents for the short-term and long-term management of transient and chronic insomnia related to adjustment, psychophysiologic, primary, and secondary causation. In this article, the benefits and risks of non-BzRA are reviewed, and the selection of a hypnotic agent is defined, based on efficacy, pharmacologic profile, and adverse events. PMID- 26055675 TI - Application of Cognitive Behavioral Therapies for Comorbid Insomnia and Depression. AB - This article provides an overview of cognitive behavioral therapy (CBT) for insomnia and depression. Included is a discussion of how CBT for insomnia affects depression symptoms and how CBT for depression affects insomnia symptoms. The extant literature is reviewed on ways that depression/insomnia comorbidity moderates CBT response. The article concludes with an introduction to cognitive behavioral social rhythm therapy, a group therapy that integrates tenets of CBT for both disorders. PMID- 26055676 TI - Hypnosis in the Management of Sleep Disorders. AB - Hypnosis has been used to manage insomnia and disorders of arousal. The alteration in the state of consciousness produced during hypnotic trance is more similar to relaxed reverie than sleep. Hypnosis typically occurs in a state of repose and the accomplished subject may have no recollection of the experience during a trance, 2 commonalities with sleep. Because hypnosis allows for relaxation, increased suggestibility, posthypnotic suggestion, imagery rehearsal, access to preconscious cognitions and emotions, and cognitive restructuring, disorders of sleep such as the insomnias, parasomnias, and related mood or anxiety disorders can be amenable to this therapeutic intervention. PMID- 26055677 TI - Insomnia and Anxiety: Diagnostic and Management Implications of Complex Interactions. AB - Concurrent clinical presentation of insomnia and anxiety is frequent in clinical practice. The onset and course of anxiety and insomnia are intimately related; traditional conceptualizations of insomnia as secondary to anxiety are no longer clinically viable. Evolving evidence suggests a relationship between these 2 conditions that is complex and reciprocal and that evolves over time. In terms of diagnosis and management, unless initial assessment and intervention are initiated in the earliest stages of illness, emerging opinion supports recognition of cooccurring anxiety and insomnia as independent comorbid conditions with each condition likely requiring targeted therapeutic attention to achieve optimal therapeutic outcomes. PMID- 26055683 TI - Sleep and Psychiatry in Adults. PMID- 26055684 TI - Glutamatergic markers, age, intellectual functioning and psychosis in 22q11 deletion syndrome. AB - RATIONALE: Patients with 22q11 deletion syndrome (22q11DS) have a high prevalence of intellectual disabilities and psychiatric disorders, including psychosis. Haplo-insufficiency of genes in the deleted region may offer a partial explanation for the increased vulnerability for psychosis and intellectual disability. One gene of particular interest is the gene coding for proline dehydrogenase (PRODH), an enzyme responsible for the conversion of proline into glutamate. OBJECTIVES: Because abnormalities in glutamatergic signaling are thought to be responsible for cognition and psychosis in the general population, we hypothesized that PRODH haplo-insufficiency may underlie some of the cognitive and psychotic features seen in 22q11DS. METHODS: In this explorative study, we investigated the relation between plasma proline, glutamate, and glutamine and age, intelligence, and psychosis in 64 adults with 22q11DS. RESULTS: Hyperprolinemia was found in 31.3% of subjects with 22q11DS. A relation between glutamine, glutamate, proline, and presence of psychosis was not observed. Regression analysis revealed a positive relation between plasma glutamate and age, a positive relation of glutamate with antipsychotic drugs, a relation of glutamine and gender, and a positive relation of glutamine and mood stabilizing drugs, and a negative relation of the ratio glutamine/glutamate and age. The group with relatively lower IQ had higher glutamate levels compared to the group with relatively higher IQ. CONCLUSIONS: Our results suggest that 22q11DS is accompanied by abnormalities in glutamatergic metabolism. Future longitudinal studies are needed to further investigate the glutamatergic system in 22q11DS and how this affects the development of cognitive problems and psychopathology. PMID- 26055685 TI - Endovascular treatment of cerebral venous thrombosis: Contemporary multicenter experience. AB - Endovascular therapy of cerebral venous thrombosis using modern approaches to intracranial recanalization, such as stent retrievers and aspiration thrombectomy, is not well described. We performed a retrospective review of data for consecutive patients with venous sinus thrombosis who underwent endovascular treatment between 1 January 2010 and 31 December 2013 at participating institutions. We identified a total of 13 patients with a diagnosis of cerebral venous thrombosis. The most frequently utilized type of endovascular intervention was the Penumbra aspiration system (Penumbra Inc., Alameda, California, USA) (nine cases), followed by local infusion of tissue plasminogen activator (bolus and/or drip in six cases) and stent retrievers (Solitaire FR (Covidien, Irvine, California, USA) in three cases and Trevo (Stryker, Kalamazoo, Michigan, USA) in one case). Overall, multimodality treatment (two or more different types of devices or approaches) was performed in 62% of cases. Follow-up data were available for 11 patients; of those, five had a favorable clinical outcome (defined as modified Rankin Scale score of 0-2) and three patients died. Various endovascular approaches are utilized in current clinical practice. A multimodal approach to endovascular therapy for the treatment of cerebral venous thrombosis resulted in partial or complete restoration of flow in all cases, yet the mortality rate of 27% indicates the need for improvement in recanalization strategies for this disorder. PMID- 26055687 TI - Risk factors for sepsis-related death in children and adolescents with hematologic and malignant diseases. AB - BACKGROUND: The aim of this study was to elucidate risk factors for mortality after developing sepsis in pediatric patients with hematologic and malignant disorders. METHODS: A total of 90 patients (43 boys, 47 girls) with various hematologic and malignant diseases who experienced sepsis between June 2006 and March 2014 were enrolled. Clinical and laboratory features of 134 episodes of sepsis observed in the 90 patients were compared between those with and without sepsis-related death which was defined as death within 14 days after sepsis. RESULTS: Age at hospitalization, sex, and type of underlying disease did not differ between patients with and without sepsis-related death. Sepsis episode based univariate analysis identified patients with a history of relapse or in a refractory state of underlying disease (p<0.01), those with high C-reactive protein concentrations (>=50 mg/L) at the beginning of fever (p<0.01), those who had undergone hematopoietic stem cell transplantation (p<0.01), and those who were forced to change initial antibiotics (p = 0.02) because of being at high risk of sepsis-related death. The former two factors were further confirmed by multivariate analysis. More than half (52.9%) the isolates from sepsis-related death were Gram-positive cocci resistant to beta-lactam antibiotics, but susceptible to vancomycin. CONCLUSION: It was found that a history of relapse, a refractory state of underlying disease, and high C-reactive protein concentrations at the beginning of fever were significant risk factors for mortality after developing sepsis. Survival rate of patients with risk factors raised in this study might be improved by early introduction of vancomycin. PMID- 26055688 TI - Distribution of different efflux pump genes in clinical isolates of multidrug resistant Acinetobacter baumannii and their correlation with antimicrobial resistance. AB - BACKGROUND/PURPOSE: Efflux pumps are one of the major mechanisms of antimicrobial resistance in Acinetobacter baumannii. This study aimed to understand the distribution of different types of pump genes in clinical isolates of multidrug resistant A. baumannii (MDRAB) and to reveal the relationship between their presence and expression with antimicrobial resistance. METHODS: MDRAB isolates were collected from five hospitals in Taiwan. Different categories of pump genes, including adeB, adeJ, macB, abeM, abeS, emrA-like, emrB-like, and craA, were chosen, and their presence in the collected isolates was determined. Three induced resistant strains of A. baumannii ATCC 17978 to tigecycline, imipenem, and amikacin were also included. The expressions of the selected pump genes were determined using quantitative reverse transcription-polymerase chain reaction. RESULTS: Twenty-one MDRAB clinical isolates were obtained from five hospitals. All of the studied pump genes were present in the collected MDRAB isolates except one isolate that lacked the emrA-like gene. The gene expression of these efflux pumps was variable among the strains. The upregulation of the adeB, adeJ, and macB genes was responsible for tigecycline resistance, and the increased abeS expression was strongly related to amikacin resistance. Of all the antibiotics studied, tigecycline was the strongest inducer of gene expression for many efflux pumps in A. baumannii. CONCLUSION: Efflux pump genes are universally present in the collected clinical MDRAB isolates. The upregulation of the adeB, adeJ, macB and abeS genes is more related with antibiotic resistance. PMID- 26055689 TI - Immunomodulation and signaling mechanism of Lactobacillus rhamnosus GG and its components on porcine intestinal epithelial cells stimulated by lipopolysaccharide. AB - BACKGROUND/PURPOSE: This study aimed to evaluate the immunomodulatory effects and signaling mechanisms of Lactobacillus rhamnosus GG (LGG) and its components [surface-layer protein (SLP), DNA, exopolysaccharides, and CpG oligodeoxynucleotides] on lipopolysaccharide (LPS)-stimulated porcine intestinal epithelial cell (IEC) IPEC-J2. METHODS: The mRNA expressions of inflammatory cytokines and Toll-like receptors (TLRs) were measured by quantitative real-time polymerase chain reaction. Activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB) signaling was detected by western blot and immunofluorescence. RESULTS: Pretreatment of IPEC-J2 cells with LGG, SLP, or exopolysaccharides significantly alleviated LPS-induced inflammatory cytokines and TLR activation at mRNA level. LGG, SLP, and exopolysaccharides also attenuated LPS-induced MAPK and NF-kappaB signaling activations. CpG oligodeoxynucleotides significantly increased the interleukin 12, tumor necrosis factor alpha, and TLR9 mRNA levels and enhanced NF-kappaB signaling activation in LPS-stimulated cells. CONCLUSION: LGG had immunomodulatory effects on LPS-induced porcine IECs by modulating TLR expressions and inhibiting MAPK and NF-kappaB signaling to decrease inflammatory cytokine expressions. Components of LGG exerted immunomodulatory effects on porcine IECs, especially immunostimulatory CpG oligodeoxynucleotides. PMID- 26055690 TI - Molecular characterization of antimicrobial susceptibility of Salmonella isolates: First identification of a plasmid carrying qnrD or oqxAB in Taiwan. AB - BACKGROUND/PURPOSE: The aim of this study is to characterize antibiotic nonsusceptible Salmonella isolates in Taiwan. METHODS: A total of 76 Salmonella isolates showing lower susceptibility to cephalosporins or quinolones were identified from 1416 clinical isolates from 1999 to 2008. Minimal inhibitory concentrations for selected antimicrobial agents were tested by the agar dilution method. Antibiotic resistance-related genes were determined by polymerase chain reaction (PCR) combined with sequencing. Southern blotting, conjugation tests, and transformation tests were used to characterize plasmid-mediated quinolone resistance (PMQR) determinants. RESULTS: The observed nonsusceptible phenotypes of 76 isolates were against cefoxitin (57.9%), cefotaxime (43.4%), ceftazidime (40.8%), ceftriaxone (42.1%), cefepime (5.3%), ciprofloxacin (80.3%), and levofloxacin (81.6%). Among 44 cephalosporin-resistant isolates, TEM-1, CMY-2, CMY-14, CTX-M-3-like and CTX-M-15-like determinants were present in 31 (70.5%), 32 (72.7%), 1 (2.3%), 1 (2.3%), and 1 (2.3%) of isolates, respectively. PCR screening for PMQR genes of 62 quinolone-nonsusceptible isolates revealed the presence of qnrS, qnrD, aac(6')-Ib-cr, and oqxAB in 3 (4.8%), 2 (3.2%), 1 (1.6%), and 10 (16.1%) isolates, respectively. Among 36 isolates showing high resistance to quinolones, S83F/D87N and S83F/D87G amino acid substitutions of GyrA were found in 29 (80.6%) and 6 (16.7%) isolates, respectively. Moreover, among quinolone highly resistant isolates, eight (22.2%) of isolates showed over expression of the PAbetaN-sensitive efflux pump. Transformants and transconjugants harboring qnrD- or oqxAB-plasmids showed decreased susceptibility to quinolones. CONCLUSION: GyrA mutations are the major mechanisms associated with quinolone-resistant Salmonella isolates in Taiwan. Overproduction of efflux pump genes and the presence of qnr and oqxAB play additional roles in reduced susceptibility to quinolones. PMID- 26055691 TI - Emergence in Taiwan of novel imipenem-resistant Acinetobacter baumannii ST455 causing bloodstream infection in critical patients. AB - BACKGROUND: Acinetobacter baumannii is one of the most important noscomial pathogens worldwide. The study aimed to use multilocus sequence typing (MLST) for epidemiological surveillance of A. baumannii isolates in Taiwan and analyze the clinical presentations and patients' outcomes. METHODS: MLST according to both Bartual's PubMLST and Pasteur's MLST schemes was applied to characterize bloodstream imipenem-resistant A. baumannii (IRAB) infection in intensive care units in a medical center. A total of 39 clinical IRAB bloodstream isolates in 2010 were enrolled. We also collected 13 imipenem-susceptible A. baumannii bloodstream isolates and 30 clinical sputum isolates (24 IRAB and 6 imipenem susceptible A. baumannii) for comparison. Clinical presentations and outcome of the patients were analyzed. RESULTS: We found that infection by ST455B/ST2P and inappropriate initial therapy were statistically significant risk factors for mortality. More than one third of the IRAB isolates belonged to ST455B/ST2P. Most ST455B/ST2P (80%) carried ISAba1-blaOXA-23, including 10 (66.7%) with Tn2006 (ISAba1-blaOXA-23-ISAba1) in an AbaR4-type resistance island. ST455B/ST2P appears to evolve from ST208B/ST2P of clonal complex (CC) 92B/CC2P. In this hospital based study, A. baumannii ST455 accounted for 38.5% of IRAB bacteremia, with a high mortality of 86.7%. Approximately 85% of ST455B/ST2P bacteremia had a primary source of ventilation-associated pneumonia. CONCLUSION: We report the emergence in Taiwan of IRAB ST455B/ST2P, which is the current predominant clone of IRAB in our hospital and has been causing bacteremia with high mortality in critical patients. PMID- 26055692 TI - Emergence in Taiwan of novel imipenem-resistant Acinetobacter baumannii ST455 causing bloodstream infection in critical patients. AB - BACKGROUND: Acinetobacter baumannii is one of the most important nosocomial pathogens worldwide. This study aimed to use multilocus sequence typing (MLST) for the epidemiological surveillance of A. baumannii isolates in Taiwan and analyze the clinical presentations and patients' outcome. METHODS: MLST according to both Bartual's PubMLST and Pasteur's MLST schemes was applied to characterize bloodstream imipenem-resistant A. baumannii (IRAB) infection in intensive care units in a medical center. A total of 39 clinical IRAB bloodstream isolates in 2010 were enrolled. We also collected 13 imipenem-susceptible A. baumannii (ISAB) bloodstream isolates and 30 clinical sputum isolates (24 IRAB and 6 ISAB) for comparison. Clinical presentations and outcome of the patients were analyzed. RESULTS: We found that infection by ST455(B)/ST2(P) and inappropriate initial therapy were statistically significant risk factors for mortality. More than one third of the IRAB isolates belonged to ST455(B)/ST2(P). Most ST455(B)/ST2(P) (80%) carried ISAba1-blaOXA-23, including 10 (66.7%) with Tn2006 (ISAba1-blaOXA 23-ISAba1) in an AbaR4-type resistance island. ST455(B)/ST2(P) appears to evolve from ST208(B)/ST2(P) of clonal complex (CC) 92(B)/CC2(P). In this hospital-based study, A. baumannii ST455 accounted for 38.5% of IRAB bacteremia, with a high mortality of 86.7%. Approximately 85% of ST455(B)/ST2(P)bacteremia had a primary source of ventilation-associated pneumonia. CONCLUSION: We report the emergence in Taiwan of IRAB ST455(B)/ST2(P), which is the current predominant clone of IRAB in our hospital and has been causing bacteremia with high mortality in critical patients. PMID- 26055694 TI - Mg(2+)-assisted low temperature reduction of alloyed AuPd/C: an efficient catalyst for hydrogen generation from formic acid at room temperature. AB - The Mg(2+)-assisted low temperature reduction approach was applied for the preparation of an alloyed AuPd/C nanocatalyst, which exhibited high activity in hydrogen generation from formic acid. At room temperature the initial turnover frequency (TOF) could reach as high as 1120 h(-1). PMID- 26055693 TI - Immunogenicity and safety of the new reduced-dose tetanus-diphtheria vaccine in healthy Korean adolescents: A comparative active control, double-blind, randomized, multicenter phase III study. AB - BACKGROUND/PURPOSE: A new reduced-dose tetanus-diphtheria (Td) vaccine was developed in Korea, and phase I and II clinical trials were successfully undertaken. We conducted this double-blind, randomized, multicenter phase III clinical trial to assess the immunogenicity and safety of the new Td vaccine. METHODS: Healthy adolescents 11-12 years of age were enrolled and randomized to receive the new Td vaccine (study group) or a commercially available Td vaccine (control group). Blood samples were collected prior to and 4 weeks after the vaccination. Between the study and control groups, seroprotection rate, booster response, and geometric mean titer of antibodies against diphtheria and tetanus toxoids were compared after the vaccination. All solicited and unsolicited adverse events and serious adverse events during the 6-week study period were monitored. RESULTS: A total of 164 adolescents received vaccination, and 156 of them were evaluated to assess immunogenicity. The seroprotection rate and geometric mean titer for antibodies against diphtheria were significantly higher in the study group, whereas those against tetanus were significantly higher in the control group. However, all seroprotection rates against diphtheria and tetanus in the study and control groups were high: 100% against diphtheria and tetanus in the study group, and 98.7% against diphtheria and 100% against tetanus in the control group. No significant differences in the frequency of solicited and unsolicited adverse events were observed between the two vaccine groups. CONCLUSION: The new Td vaccine is highly immunogenic and safe, and this new Td vaccine can be effectively used for preventing diphtheria and tetanus. PMID- 26055695 TI - Energy intake and expenditure assessed 'in-season' in an elite European rugby union squad. AB - Rugby union (RU) is a complex high-intensity intermittent collision sport with emphasis placed on players possessing high lean body mass and low body fat. After an 8 to 12-week pre-season focused on physiological adaptations, emphasis shifts towards competitive performance. However, there are no objective data on the physiological demands or energy intake (EI) and energy expenditure (EE) for elite players during this period. Accordingly, in-season training load using global positioning system and session rating of perceived exertion (sRPE), alongside six day assessments of EE and EI were measured in 44 elite RU players. Mean weekly distance covered was 7827 +/- 954 m and 9572 +/- 1233 m with a total mean weekly sRPE of 1776 +/- 355 and 1523 +/- 434 AU for forwards and backs, respectively. Mean weekly EI was 16.6 +/- 1.5 and 14.2 +/- 1.2 megajoules (MJ) and EE was 15.9 +/- 0.5 and 14 +/- 0.5 MJ. Mean carbohydrate (CHO) intake was 3.5 +/- 0.8 and 3.4 +/- 0.7 g.kg(-1) body mass, protein intake was 2.7 +/- 0.3 and 2.7 +/- 0.5 g.kg( 1) body mass, and fat intake was 1.4 +/- 0.2 and 1.4 +/- 0.3 g.kg(-1) body mass. All players who completed the food diary self-selected a 'low' CHO 'high' protein diet during the early part of the week, with CHO intake increasing in the days leading up to a match, resulting in the mean EI matching EE. Based on EE and training load data, the EI and composition seems appropriate, although further research is required to evaluate if this diet is optimal for match day performance. PMID- 26055696 TI - Development and Validation of the Escala de Actitudes Emprendedoras para Estudiantes (EAEE). AB - During the last few years, entrepreneurship has gained an important role in many economic and social policies, with the consequent growth of entrepreneurial research in many social areas. However, in the Spanish psychometric context, there is not an updated scale including recent contributions to entrepreneurship attitudes literature. The aim of this study is to present and validate a new scale named Escala de Actitudes Emprendedoras para Estudiantes-EAEE, (Entrepreneurial Attitudes Scale for Students, EASS), in two samples of high school and university Spanish students. Data comes from a cross-sectional survey of 524 high school and undergraduate students, from Valencia (Spain). Two confirmatory factor analyses (CFAs) were estimated, together with reliability and validity evidence of the scale. Results offered evidence of the adequate psychometric properties of the EASS. The CFAs showed overall and analytical adequate fit indexes (chi 2 (120) = 163.19 (p < .01), GFI = .906, CFI = .959, SRMR = .044, RMSEA = .040 [CI .022-.054]); reliability indices of the entrepreneurial attitudes were appropriate for most of the entrepreneurial attitudes (alpha were between .63 and .87 for the different dimensions); and external evidence relating entrepreneurial dimensions to personality traits was similar to in previous studies. The scale could be a useful instrument both for previous diagnosis and effectiveness assessment of programs on entrepreneurship promotion. PMID- 26055697 TI - Pfizer steps up battle to defend control of pregabalin. PMID- 26055699 TI - Virulence profile: Joshua D Nosanchuk. PMID- 26055698 TI - Non-contact method for directing electrotaxis. AB - We present a method to induce electric fields and drive electrotaxis (galvanotaxis) without the need for electrodes to be in contact with the media containing the cell cultures. We report experimental results using a modification of the transmembrane assay, demonstrating the hindrance of migration of breast cancer cells (SCP2) when an induced a.c. electric field is present in the appropriate direction (i.e. in the direction of migration). Of significance is that migration of these cells is hindered at electric field strengths many orders of magnitude (5 to 6) below those previously reported for d.c. electrotaxis, and even in the presence of a chemokine (SDF-1alpha) or a growth factor (EGF). Induced a.c. electric fields applied in the direction of migration are also shown to hinder motility of non-transformed human mammary epithelial cells (MCF10A) in the presence of the growth factor EGF. In addition, we also show how our method can be applied to other cell migration assays (scratch assay), and by changing the coil design and holder, that it is also compatible with commercially available multi-well culture plates. PMID- 26055700 TI - The Impact of Pelvic Floor Disorders and Pelvic Surgery on Women's Sexual Satisfaction and Function. AB - Pelvic floor disorders have a significant impact on women's daily lives. Sexual health, which includes sexual satisfaction and function, can be altered by pelvic floor disorders and pelvic surgery. This article reviews common pelvic floor disorders (pelvic organ prolapse, urinary and fecal incontinence) and the effect they have on sexual satisfaction and function. Associations between sexual function and pelvic floor disorders are described, as are the relationships between sexual function and pelvic surgery. Women of all ages need to know their options and understand the impact pelvic surgery can have on sexual satisfaction, function, and activity. PMID- 26055701 TI - Molecular Anatomy of ParA-ParA and ParA-ParB Interactions during Plasmid Partitioning. AB - Firmicutes multidrug resistance inc18 plasmids encode parS sites and two small homodimeric ParA-like (delta2) and ParB-like (omega2) proteins to ensure faithful segregation. Protein omega2 binds to parS DNA, forming a short left-handed helix wrapped around the full parS, and interacts with delta2. Protein delta2 interacts with omega2 and, in the ATP-bound form, binds to nonspecific DNA (nsDNA), forming small clusters. Here, we have mapped the omega2.delta2 and delta2.delta2 interacting domains in the delta2 that are adjacent to but distinct from each other. The delta2 nsDNA binding domain is essential for stimulation of omega2.parS-mediated ATP hydrolysis. From the data presented here, we propose that delta2 interacts with ATP, nsDNA, and with omega2 bound to parS at near equimolar concentrations, facilitating a delta2 structural transition. This delta2 "activated" state overcomes its impediment in ATP hydrolysis, with the subsequent release of both of the proteins from nsDNA (plasmid unpairing). PMID- 26055702 TI - CO-releasing Metal Carbonyl Compounds as Antimicrobial Agents in the Post antibiotic Era. AB - The possibility of a "post-antibiotic era" in the 21st century, in which common infections may kill, has prompted research into radically new antimicrobials. CO releasing molecules (CORMs), mostly metal carbonyl compounds, originally developed for therapeutic CO delivery in animals, are potent antimicrobial agents. Certain CORMs inhibit growth and respiration, reduce viability, and release CO to intracellular hemes, as predicted, but their actions are more complex, as revealed by transcriptomic datasets and modeling. Progress is hindered by difficulties in detecting CO release intracellularly, limited understanding of the biological chemistry of CO reactions with non-heme targets, and the cytotoxicity of some CORMs to mammalian cells. PMID- 26055703 TI - In Vivo and in Vitro Evidence for Biochemical Coupling of Reactions Catalyzed by Lysophosphatidylcholine Acyltransferase and Diacylglycerol Acyltransferase. AB - Seed oils of flax (Linum usitatissimum L.) and many other plant species contain substantial amounts of polyunsaturated fatty acids (PUFAs). Phosphatidylcholine (PC) is the major site for PUFA synthesis. The exact mechanisms of how these PUFAs are channeled from PC into triacylglycerol (TAG) needs to be further explored. By using in vivo and in vitro approaches, we demonstrated that the PC deacylation reaction catalyzed by the reverse action of acyl CoA:lysophosphatidylcholine acyltransferase (LPCAT) can transfer PUFAs on PC directly into the acyl-CoA pool, making these PUFAs available for the diacylglycerol acyltransferase (DGAT)-catalyzed reaction for TAG production. Two types of yeast mutants were generated for in vivo and in vitro experiments, respectively. Both mutants provide a null background with no endogenous TAG forming capacity and an extremely low LPCAT activity. In vivo experiments showed that co-expressing flax DGAT1-1 and LPCAT1 in the yeast quintuple mutant significantly increased 18-carbon PUFAs in TAG with a concomitant decrease of 18 carbon PUFAs in phospholipid. We further showed that after incubation of sn-2 [(14)C]acyl-PC, formation of [(14)C]TAG was only possible with yeast microsomes containing both LPCAT1 and DGAT1-1. Moreover, the specific activity of overall LPCAT1 and DGAT1-1 coupling process exhibited a preference for transferring (14)C labeled linoleoyl or linolenoyl than oleoyl moieties from the sn-2 position of PC to TAG. Together, our data support the hypothesis of biochemical coupling of the LPCAT1-catalyzed reverse reaction with the DGAT1-1-catalyzed reaction for incorporating PUFAs into TAG. This process represents a potential route for enriching TAG in PUFA content during seed development in flax. PMID- 26055704 TI - hMSH5 Facilitates the Repair of Camptothecin-induced Double-strand Breaks through an Interaction with FANCJ. AB - Replication stress from stalled or collapsed replication forks is a major challenge to genomic integrity. The anticancer agent camptothecin (CPT) is a DNA topoisomerase I inhibitor that causes fork collapse and double-strand breaks amid DNA replication. Here we report that hMSH5 promotes cell survival in response to CPT-induced DNA damage. Cells deficient in hMSH5 show elevated CPT-induced gamma H2AX and RPA2 foci with concomitant reduction of Rad51 foci, indicative of impaired homologous recombination. In addition, CPT-treated hMSH5-deficient cells exhibit aberrant activation of Chk1 and Chk2 kinases and therefore abnormal cell cycle progression. Furthermore, the hMSH5-FANCJ chromatin recruitment underlies the effects of hMSH5 on homologous recombination and Chk1 activation. Intriguingly, FANCJ depletion desensitizes hMSH5-deficient cells to CPT-elicited cell killing. Collectively, our data point to the existence of a functional interplay between hMSH5 and FANCJ in double-strand break repair induced by replication stress. PMID- 26055705 TI - Insights into the Recruitment of Class IIa Histone Deacetylases (HDACs) to the SMRT/NCoR Transcriptional Repression Complex. AB - Class IIa histone deacetylases repress transcription of target genes. However, their mechanism of action is poorly understood because they exhibit very low levels of deacetylase activity. The class IIa HDACs are associated with the SMRT/NCoR repression complexes and this may, at least in part, account for their repressive activity. However, the molecular mechanism of recruitment to co repressor proteins has yet to be established. Here we show that a repeated peptide motif present in both SMRT and NCoR is sufficient to mediate specific interaction, with micromolar affinity, with all the class IIa HDACs (HDACs 4, 5, 7, and 9). Mutations in the consensus motif abrogate binding. Mutational analysis of HDAC4 suggests that the peptide interacts in the vicinity of the active site of the enzyme and requires the "closed" conformation of the zinc-binding loop on the surface of the enzyme. Together these findings represent the first insights into the molecular mechanism of recruitment of class IIa HDACs to the SMRT/NCoR repression complexes. PMID- 26055706 TI - The Role of Copper and Zinc Toxicity in Innate Immune Defense against Bacterial Pathogens. AB - Zinc (Zn) and copper (Cu) are essential for optimal innate immune function, and nutritional deficiency in either metal leads to increased susceptibility to bacterial infection. Recently, the decreased survival of bacterial pathogens with impaired Cu and/or Zn detoxification systems in phagocytes and animal models of infection has been reported. Consequently, a model has emerged in which the host utilizes Cu and/or Zn intoxication to reduce the intracellular survival of pathogens. This review describes and assesses the potential role for Cu and Zn intoxication in innate immune function and their direct bactericidal function. PMID- 26055707 TI - Topoisomerase II from Human Malaria Parasites: EXPRESSION, PURIFICATION, AND SELECTIVE INHIBITION. AB - Historically, type II topoisomerases have yielded clinically useful drugs for the treatment of bacterial infections and cancer, but the corresponding enzymes from malaria parasites remain understudied. This is due to the general challenges of producing malaria proteins in functional forms in heterologous expression systems. Here, we express full-length Plasmodium falciparum topoisomerase II (PfTopoII) in a wheat germ cell-free transcription-translation system. Functional activity of soluble PfTopoII from the translation lysates was confirmed through both a plasmid relaxation and a DNA decatenation activity that was dependent on magnesium and ATP. To facilitate future drug discovery, a convenient and sensitive fluorescence assay was established to follow DNA decatenation, and a stable, truncated PfTopoII was engineered for high level enzyme production. PfTopoII was purified using a DNA affinity column. Existing TopoII inhibitors previously developed for other non-malaria indications inhibited PfTopoII, as well as malaria parasites in culture at submicromolar concentrations. Even before optimization, inhibitors of bacterial gyrase, GSK299423, ciprofloxacin, and etoposide exhibited 15-, 57-, and 3-fold selectivity for the malarial enzyme over human TopoII. Finally, it was possible to use the purified PfTopoII to dissect the different modes by which these varying classes of TopoII inhibitors could trap partially processed DNA. The present biochemical advancements will allow high throughput chemical screening of compound libraries and lead optimization to develop new lines of antimalarials. PMID- 26055708 TI - alpha-Synuclein Shows High Affinity Interaction with Voltage-dependent Anion Channel, Suggesting Mechanisms of Mitochondrial Regulation and Toxicity in Parkinson Disease. AB - Participation of the small, intrinsically disordered protein alpha-synuclein (alpha-syn) in Parkinson disease (PD) pathogenesis has been well documented. Although recent research demonstrates the involvement of alpha-syn in mitochondrial dysfunction in neurodegeneration and suggests direct interaction of alpha-syn with mitochondria, the molecular mechanism(s) of alpha-syn toxicity and its effect on neuronal mitochondria remain vague. Here we report that at nanomolar concentrations, alpha-syn reversibly blocks the voltage-dependent anion channel (VDAC), the major channel of the mitochondrial outer membrane that controls most of the metabolite fluxes in and out of the mitochondria. Detailed analysis of the blockage kinetics of VDAC reconstituted into planar lipid membranes suggests that alpha-syn is able to translocate through the channel and thus target complexes of the mitochondrial respiratory chain in the inner mitochondrial membrane. Supporting our in vitro experiments, a yeast model of PD shows that alpha-syn toxicity in yeast depends on VDAC. The functional interactions between VDAC and alpha-syn, revealed by the present study, point toward the long sought after physiological and pathophysiological roles for monomeric alpha-syn in PD and in other alpha-synucleinopathies. PMID- 26055710 TI - High Yield Non-detergent Isolation of Photosystem I-Light-harvesting Chlorophyll II Membranes from Spinach Thylakoids: IMPLICATIONS FOR THE ORGANIZATION OF THE PS I ANTENNAE IN HIGHER PLANTS. AB - Styrene-maleic acid copolymer was used to effect a non-detergent partial solubilization of thylakoids from spinach. A high density membrane fraction, which was not solubilized by the copolymer, was isolated and was highly enriched in the Photosystem (PS) I-light-harvesting chlorophyll (LHC) II supercomplex and depleted of PS II, the cytochrome b6/f complex, and ATP synthase. The LHC II associated with the supercomplex appeared to be energetically coupled to PS I based on 77 K fluorescence, P700 photooxidation, and PS I electron transport light saturation experiments. The chlorophyll (Chl) a/b ratio of the PS I-LHC II membranes was 3.2 +/- 0.9, indicating that on average, three LHC II trimers may associate with each PS I. The implication of these findings within the context of higher plant PS I antenna organization is discussed. PMID- 26055709 TI - The Role of Phosphodiesterase 12 (PDE12) as a Negative Regulator of the Innate Immune Response and the Discovery of Antiviral Inhibitors. AB - 2',5'-Oligoadenylate synthetase (OAS) enzymes and RNase-L constitute a major effector arm of interferon (IFN)-mediated antiviral defense. OAS produces a unique oligonucleotide second messenger, 2',5'-oligoadenylate (2-5A), that binds and activates RNase-L. This pathway is down-regulated by virus- and host-encoded enzymes that degrade 2-5A. Phosphodiesterase 12 (PDE12) was the first cellular 2 5A- degrading enzyme to be purified and described at a molecular level. Inhibition of PDE12 may up-regulate the OAS/RNase-L pathway in response to viral infection resulting in increased resistance to a variety of viral pathogens. We generated a PDE12-null cell line, HeLaDeltaPDE12, using transcription activator like effector nuclease-mediated gene inactivation. This cell line has increased 2 5A levels in response to IFN and poly(I-C), a double-stranded RNA mimic compared with the parental cell line. Moreover, HeLaDeltaPDE12 cells were resistant to viral pathogens, including encephalomyocarditis virus, human rhinovirus, and respiratory syncytial virus. Based on these results, we used DNA-encoded chemical library screening to identify starting points for inhibitor lead optimization. Compounds derived from this effort raise 2-5A levels and exhibit antiviral activity comparable with the effects observed with PDE12 gene inactivation. The crystal structure of PDE12 complexed with an inhibitor was solved providing insights into the structure-activity relationships of inhibitor potency and selectivity. PMID- 26055711 TI - Mycobacterium tuberculosis and Copper: A Newly Appreciated Defense against an Old Foe? AB - Several independent studies have recently converged upon the conclusion that the human bacterial pathogen Mycobacterium tuberculosis encounters copper during infections. At least three independently regulated pathways respond to excess copper and are required for the full virulence of M. tuberculosis in animals. In this review, I will discuss the functions of the best-characterized copper responsive proteins in M. tuberculosis, the potential sources of copper during an infection, and remaining questions about the interface between copper and tuberculosis. PMID- 26055712 TI - Phosphorylation-dependent Regulation of Connecdenn/DENND1 Guanine Nucleotide Exchange Factors. AB - Connecdenn 1/2 are DENN (differentially expressed in normal and neoplastic cells) domain-bearing proteins that function as GEFs (guanine nucleotide exchange factors) for the small GTPase Rab35. Disruption of connecdenn/Rab35 function leads to defects in the recycling of multiple cargo proteins from endosomes with altered cell function, yet the regulation of connecdenn GEF activity is unexplored. We now demonstrate that connecdenn 1/2 are autoinhibited such that the purified, full-length proteins have significantly less Rab35 binding and GEF activity than the isolated DENN domain. Both proteins are phosphorylated with prominent phosphorylation sites between residues 500 and 600 of connecdenn 1. A large scale proteomics screen revealed that connecdenn 1 is phosphorylated at residues Ser-536 and Ser-538 in an Akt-dependent manner in response to insulin stimulation of adipocytes. Interestingly, we find that an Akt inhibitor reduces connecdenn 1 interaction with Rab35 after insulin treatment of adipocytes. Remarkably, a peptide flanking Ser-536/Ser-538 binds the DENN domain of connecdenn 1, whereas a phosphomimetic peptide does not. Moreover, connecdenn 1 interacts with 14-3-3 proteins, and this interaction is also disrupted by Akt inhibition and by mutation of Ser-536/Ser-538. We propose that Akt phosphorylation of connecdenn 1 downstream of insulin activation regulates connecdenn 1 function through an intramolecular interaction. PMID- 26055713 TI - Nutritional Immunity: S100 Proteins at the Host-Pathogen Interface. AB - The S100 family of EF-hand calcium (Ca(2+))-binding proteins is essential for a wide range of cellular functions. During infection, certain S100 proteins act as damage-associated molecular patterns (DAMPs) and interact with pattern recognition receptors to modulate inflammatory responses. In addition, these inflammatory S100 proteins have potent antimicrobial properties and are essential components of the immune response to invading pathogens. In this review, we focus on S100 proteins that exhibit antimicrobial properties through the process of metal limitation, termed nutritional immunity, and discuss several recent advances in our understanding of S100 protein-mediated metal sequestration at the site of infection. PMID- 26055714 TI - Tid1, the Mammalian Homologue of Drosophila Tumor Suppressor Tid56, Mediates Macroautophagy by Interacting with Beclin1-containing Autophagy Protein Complex. AB - One of the fundamental functions of molecular chaperone proteins is to selectively conjugate cellular proteins, targeting them directly to lysosome. Some of chaperones, such as the stress-induced Hsp70, also play important roles in autophagosome-forming macroautophagy under various stress conditions. However, the role of their co-chaperones in autophagy regulation has not been well defined. We here show that Tid1, a DnaJ co-chaperone for Hsp70 and the mammalian homologue of the Drosophila tumor suppressor Tid56, is a key mediator of macroautophagy pathway. Ectopic expression of Tid1 induces autophagy by forming LC3+ autophagosome foci, whereas silencing Tid1 leads to drastic impairment of autophagy as induced by nutrient deprivation or rapamycin. In contrast, Hsp70 is dispensable for a role in nutrient deprivation-induced autophagy. The murine Tid1 can be replaced with human Tid1 in murine fibroblast cells for induction of autophagy. We further show that Tid1 increases autophagy flux by interacting with the Beclin1-PI3 kinase class III protein complex in response to autophagy inducing signal and that Tid1 is an essential mediator that connects IkappaB kinases to the Beclin1-containing autophagy protein complex. Together, these results reveal a crucial role of Tid1 as an evolutionarily conserved and essential mediator of canonical macroautophagy. PMID- 26055715 TI - Ligand-induced Dimerization of Middle East Respiratory Syndrome (MERS) Coronavirus nsp5 Protease (3CLpro): IMPLICATIONS FOR nsp5 REGULATION AND THE DEVELOPMENT OF ANTIVIRALS. AB - All coronaviruses, including the recently emerged Middle East respiratory syndrome coronavirus (MERS-CoV) from the beta-CoV subgroup, require the proteolytic activity of the nsp5 protease (also known as 3C-like protease, 3CL(pro)) during virus replication, making it a high value target for the development of anti-coronavirus therapeutics. Kinetic studies indicate that in contrast to 3CL(pro) from other beta-CoV 2c members, including HKU4 and HKU5, MERS-CoV 3CL(pro) is less efficient at processing a peptide substrate due to MERS CoV 3CL(pro) being a weakly associated dimer. Conversely, HKU4, HKU5, and SARS CoV 3CL(pro) enzymes are tightly associated dimers. Analytical ultracentrifugation studies support that MERS-CoV 3CL(pro) is a weakly associated dimer (Kd ~52 MUm) with a slow off-rate. Peptidomimetic inhibitors of MERS-CoV 3CL(pro) were synthesized and utilized in analytical ultracentrifugation experiments and demonstrate that MERS-CoV 3CL(pro) undergoes significant ligand induced dimerization. Kinetic studies also revealed that designed reversible inhibitors act as activators at a low compound concentration as a result of induced dimerization. Primary sequence comparisons and x-ray structural analyses of two MERS-CoV 3CLpro and inhibitor complexes, determined to 1.6 A, reveal remarkable structural similarity of the dimer interface with 3CL(pro) from HKU4 CoV and HKU5-CoV. Despite this structural similarity, substantial differences in the dimerization ability suggest that long range interactions by the nonconserved amino acids distant from the dimer interface may control MERS-CoV 3CL(pro) dimerization. Activation of MERS-CoV 3CL(pro) through ligand-induced dimerization appears to be unique within the genogroup 2c and may potentially increase the complexity in the development of MERS-CoV 3CL(pro) inhibitors as antiviral agents. PMID- 26055716 TI - Rkr1/Ltn1 Ubiquitin Ligase-mediated Degradation of Translationally Stalled Endoplasmic Reticulum Proteins. AB - Aberrant nonstop proteins arise from translation of mRNA molecules beyond the coding sequence into the 3'-untranslated region. If a stop codon is not encountered, translation continues into the poly(A) tail, resulting in C-terminal appendage of a polylysine tract and a terminally stalled ribosome. In Saccharomyces cerevisiae, the ubiquitin ligase Rkr1/Ltn1 has been implicated in the proteasomal degradation of soluble cytosolic nonstop and translationally stalled proteins. Rkr1 is essential for cellular fitness under conditions associated with increased prevalence of nonstop proteins. Mutation of the mammalian homolog causes significant neurological pathology, suggesting broad physiological significance of ribosome-associated quality control. It is not known whether and how soluble or transmembrane nonstop and translationally stalled proteins targeted to the endoplasmic reticulum (ER) are detected and degraded. We generated and characterized model soluble and transmembrane ER targeted nonstop and translationally stalled proteins. We found that these proteins are indeed subject to proteasomal degradation. We tested three candidate ubiquitin ligases (Rkr1 and ER-associated Doa10 and Hrd1) for roles in regulating abundance of these proteins. Our results indicate that Rkr1 plays the primary role in targeting the tested model ER-targeted nonstop and translationally stalled proteins for degradation. These data expand the catalog of Rkr1 substrates and highlight a previously unappreciated role for this ubiquitin ligase at the ER membrane. PMID- 26055717 TI - Yeast Fex1p Is a Constitutively Expressed Fluoride Channel with Functional Asymmetry of Its Two Homologous Domains. AB - Fluoride is a ubiquitous environmental toxin with which all biological species must cope. A recently discovered family of fluoride export (FEX) proteins protects organisms from fluoride toxicity by removing it from the cell. We show here that FEX proteins in Saccharomyces cerevisiae function as ion channels that are selective for fluoride over chloride and that these proteins are constitutively expressed at the yeast plasma membrane. Continuous expression is in contrast to many other toxin exporters in yeast, and this, along with the fact that two nearly duplicate proteins are encoded in the yeast genome, suggests that the threat posed by fluoride ions is frequent and detrimental. Structurally, eukaryotic FEX proteins consist of two homologous four-transmembrane helix domains folded into an antiparallel dimer, where the orientation of the two domains is fixed by a single transmembrane linker helix. Using phylogenetic sequence conservation as a guide, we have identified several functionally important residues. There is substantial functional asymmetry in the effect of mutation at corresponding sites in the two domains. Specifically, mutations to residues in the C-terminal domain proved significantly more detrimental to function than did similar mutations in the N-terminal domain. Our data suggest particular residues that may be important to anion specificity, most notably the necessity of a positive charge near the end of TMH1 in the C-terminal domain. It is possible that a cationic charge at this location may create an electrostatic well for fluoride ions entering the channel from the cytoplasm. PMID- 26055718 TI - New Insights into the Coupling between Microtubule Depolymerization and ATP Hydrolysis by Kinesin-13 Protein Kif2C. AB - Kinesin-13 proteins depolymerize microtubules in an ATP hydrolysis-dependent manner. The coupling between these two activities remains unclear. Here, we first studied the role of the kinesin-13 subfamily-specific loop 2 and of the KVD motif at the tip of this loop. Shortening the loop, the lysine/glutamate interchange and the additional Val to Ser substitution all led to Kif2C mutants with decreased microtubule-stimulated ATPase and impaired depolymerization capability. We rationalized these results based on a structural model of the Kif2C-ATP tubulin complex derived from the recently determined structures of kinesin-1 bound to tubulin. In this model, upon microtubule binding Kif2C undergoes a conformational change governed in part by the interaction of the KVD motif with the tubulin interdimer interface. Second, we mutated to an alanine the conserved glutamate residue of the switch 2 nucleotide binding motif. This mutation blocks motile kinesins in a post-conformational change state and inhibits ATP hydrolysis. This Kif2C mutant still depolymerized microtubules and yielded complexes of one Kif2C with two tubulin heterodimers. These results demonstrate that the structural change of Kif2C-ATP upon binding to microtubule ends is sufficient for tubulin release, whereas ATP hydrolysis is not required. Overall, our data suggest that the conformation reached by kinesin-13s upon tubulin binding is similar to that of tubulin-bound, ATP-bound, motile kinesins but that this conformation is adapted to microtubule depolymerization. PMID- 26055719 TI - Nephron Toxicity Profiling via Untargeted Metabolome Analysis Employing a High Performance Liquid Chromatography-Mass Spectrometry-based Experimental and Computational Pipeline. AB - Untargeted metabolomics has the potential to improve the predictivity of in vitro toxicity models and therefore may aid the replacement of expensive and laborious animal models. Here we describe a long term repeat dose nephrotoxicity study conducted on the human renal proximal tubular epithelial cell line, RPTEC/TERT1, treated with 10 and 35 MUmol.liter(-1) of chloroacetaldehyde, a metabolite of the anti-cancer drug ifosfamide. Our study outlines the establishment of an automated and easy to use untargeted metabolomics workflow for HPLC-high resolution mass spectrometry data. Automated data analysis workflows based on open source software (OpenMS, KNIME) enabled a comprehensive and reproducible analysis of the complex and voluminous metabolomics data produced by the profiling approach. Time and concentration-dependent responses were clearly evident in the metabolomic profiles. To obtain a more comprehensive picture of the mode of action, transcriptomics and proteomics data were also integrated. For toxicity profiling of chloroacetaldehyde, 428 and 317 metabolite features were detectable in positive and negative modes, respectively, after stringent removal of chemical noise and unstable signals. Changes upon treatment were explored using principal component analysis, and statistically significant differences were identified using linear models for microarray assays. The analysis revealed toxic effects only for the treatment with 35 MUmol.liter(-1) for 3 and 14 days. The most regulated metabolites were glutathione and metabolites related to the oxidative stress response of the cells. These findings are corroborated by proteomics and transcriptomics data, which show, among other things, an activation of the Nrf2 and ATF4 pathways. PMID- 26055720 TI - Microbial Copper-binding Siderophores at the Host-Pathogen Interface. AB - Numerous pathogenic microorganisms secrete small molecule chelators called siderophores defined by their ability to bind extracellular ferric iron, making it bioavailable to microbes. Recently, a siderophore produced by uropathogenic Escherichia coli, yersiniabactin, was found to also bind copper ions during human infections. The ability of yersiniabactin to protect E. coli from copper toxicity and redox-based phagocyte defenses distinguishes it from other E. coli siderophores. Here we compare yersiniabactin to other extracellular copper binding molecules and review how copper-binding siderophores may confer virulence associated gains of function during infection pathogenesis. PMID- 26055721 TI - Identification of the Molecular and Genetic Basis of PX2, a Glycosphingolipid Blood Group Antigen Lacking on Globoside-deficient Erythrocytes. AB - The x2 glycosphingolipid is expressed on erythrocytes from individuals of all common blood group phenotypes and elevated on cells of the rare P/P1/P(k) negative p blood group phenotype. Globoside or P antigen is synthesized by UDP-N acetylgalactosamine:globotriaosyl-ceramide 3-beta-N acetylgalactosaminyltransferase encoded by B3GALNT1. It is the most abundant non acid glycosphingolipid on erythrocytes and displays the same terminal disaccharide, GalNAcbeta3Gal, as x2. We encountered a patient with mutations in B3GALNT1 causing the rare P-deficient P1 (k) phenotype and whose pretransfusion plasma was unexpectedly incompatible with p erythrocytes. The same phenomenon was also noted in seven other unrelated P-deficient individuals. Thin-layer chromatography, mass spectrometry, and flow cytometry were used to show that the naturally occurring antibodies made by p individuals recognize x2 and sialylated forms of x2, whereas x2 is lacking on P-deficient erythrocytes. Overexpression of B3GALNT1 resulted in synthesis of both P and x2. Knockdown experiments with siRNA against B3GALNT1 diminished x2 levels. We conclude that x2 fulfills blood group criteria and is synthesized by UDP-N-acetylgalactosamine: globotriaosylceramide 3 beta-N-acetylgalactosaminyltransferase. Based on this linkage, we proposed that x2 joins P in the GLOB blood group system (ISBT 028) and is renamed PX2 (GLOB2). Thus, in the absence of a functional P synthase, neither P nor PX2 are formed. As a consequence, naturally occurring anti-P and anti-PX2 can be made. Until the clinical significance of anti-PX2 is known, we also recommend that rare P1 (k) or P2 (k) erythrocyte units are preferentially selected for transfusion to P(k) patients because p erythrocytes may pose a risk for hemolytic transfusion reactions due to their elevated PX2 levels. PMID- 26055722 TI - Nramp1 and Other Transporters Involved in Metal Withholding during Infection. AB - During the course of infection, many natural defenses are set up along the boundaries of the host-pathogen interface. Key among these is the host response to withhold metals to restrict the growth of invading microbes. This simple act of nutritional warfare, starving the invader of an essential element, is an effective means of limiting infection. The physiology of metal withholding is often referred to as "nutritional immunity," and the mechanisms of metal transport that contribute to this host response are the focus of this review. PMID- 26055723 TI - Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation. AB - Iron is a redox-active metal required as a cofactor in multiple metalloproteins essential for a host of life processes. The metal is highly toxic when present in excess and must be strictly regulated to prevent tissue and organ damage. Hepcidin, a molecule first characterized as an antimicrobial peptide, plays a critical role in the regulation of iron homeostasis. Multiple stimuli positively influence the expression of hepcidin, including iron, inflammation, and infection by pathogens. In this Minireview, I will discuss how inflammation regulates hepcidin transcription, allowing for sufficient concentrations of iron for organismal needs while sequestering the metal from infectious pathogens. PMID- 26055725 TI - Introduction: Metals in Biology: METALS AT THE HOST-PATHOGEN INTERFACE. AB - This seventh Metals in Biology Thematic Series deals with the metal-based interactions of mammalian hosts with pathogens. Both pathogens and hosts have complex regulatory systems for metal homeostasis. Understanding these provides strategies for fighting pathogens, either by excluding essential metals from the microbes, by delivery of excess metals to cause toxicity, or by complexing metals in microorganisms. Intervention is possible by delivery of complexing reagents or by targeting the microbial regulatory apparatus. PMID- 26055724 TI - Copper at the Fungal Pathogen-Host Axis. AB - Fungal infections are responsible for millions of human deaths annually. Copper, an essential but toxic trace element, plays an important role at the host pathogen axis during infection. In this review, we describe how the host uses either Cu compartmentalization within innate immune cells or Cu sequestration in other infected host niches such as in the brain to combat fungal infections. We explore Cu toxicity mechanisms and the Cu homeostasis machinery that fungal pathogens bring into play to succeed in establishing an infection. Finally, we address recent approaches that manipulate Cu-dependent processes at the host pathogen axis for antifungal drug development. PMID- 26055726 TI - Short STAI-Y anxiety scales: validation and normative data for elderly subjects. AB - OBJECTIVES: The aim of this study was to develop short forms of the STAI-Y trait and state scales and associated norms suitable for the screening of anxiety in elderly populations. METHOD: This study was based on population-based cohorts of older persons from two epidemiological French studies that each included one subscale of the STAI-Y, i.e. state and trait anxiety scales. For both scales, the most discriminative items were retained and their factorial structure was examined using principal components analysis. Internal consistency (Cronbach's alpha) was estimated and cut-offs and norms were computed. RESULTS: A 10-item STAI-Y version produced scores similar to those obtained with the full form of the STAI-Y. The factorial structure of the shortened form is comparable to that of the full scales. Results showed good internal consistency (alpha coefficients were 0.92 and 0.85 for short STAI-Y state and trait scales, respectively). Moreover, both short STAI-Y state and trait scales correctly classified 88% of the participants using a cut-off point of 23. Norms for both short trait and state anxiety scales are provided according to age, gender, educational level and depressive symptoms. CONCLUSION: Both shortened scales have similar factorial structure and internal consistency to the longer scales and classify anxious/non anxious elderly with acceptable accuracy. The shorter form is likely to be more acceptable to elderly persons through reduction of fatigue effects. PMID- 26055727 TI - Reproductive and Birth Outcomes in Haiti Before and After the 2010 Earthquake. AB - OBJECTIVE: We aimed to examine the relationship between exposure to the 2010 Haiti earthquake and pregnancy wantedness, interpregnancy interval, and birth weight. METHODS: From the nationally representative Haiti 2012 Demographic and Health Survey, information on "size of child at birth" (too small or not) was available for 7280 singleton births in the previous 5 years, whereas information on birth weight was available for 1607 births. Pregnancy wantedness, short (<1 year) interpregnancy interval, and maternal-reported birth weight were compared before and after the earthquake and by level of damage. Multiple logistic regression and linear regression analyses were conducted. RESULTS: Post earthquake births were less likely to be wanted and more likely to be born after a short interpregnancy interval. Earthquake exposure was associated with increased likelihood of a child being born too small: timing of birth (after earthquake vs. before earthquake, adjusted odds ratio [aOR]: 1.27, 95% confidence interval [CI]: 1.12-1.45), region (hardest-hit vs. rest of country; aOR: 1.43, 95% CI: 1.14- 1.80), and house damage (aOR: 1.27 95% CI: 1.02-1.58). Mean birth weight was 150 to 300 g lower in those exposed to the earthquake. CONCLUSIONS: Experience with the earthquake was associated with worse reproductive and birth outcomes, which underscores the need to provide reproductive health services as part of relief efforts. PMID- 26055728 TI - Resource use and costs in an insured population of patients with chronic idiopathic/spontaneous urticaria. AB - BACKGROUND: Chronic idiopathic or spontaneous urticaria (CIU/CSU) impairs patients' quality of life, and updated information on disease prevalence, treatment patterns, and disease burden is lacking. OBJECTIVES: We aimed to estimate these figures in a large US real-world claims database via a validated algorithm. METHODS: In this retrospective cross-sectional cohort study, we identified patients with CIU/CSU, estimated disease prevalence, comorbidities, and healthcare use (medications, office visits, emergency department visits, and hospitalizations) and costs (urticaria related and all cause). RESULTS: We identified 6350 CIU/CSU patients in a population of just over 5.8 million: 0.11 % prevalence. Women accounted for the majority of sufferers (68.3 %) and had a greater burden of illness than men. Patients had relatively few comorbidities (mean 3.3, standard deviation 2.2). Primary care physicians and allergists were the most common providers of CIU/CSU-related care. Oral corticosteroids were the most commonly prescribed medication, used in 54.7 % of patients. Patients accumulated a mean of 15.1 office visits per year (standard deviation 12.6). The mean all-cause healthcare cost totaled over US$9000 per year. CONCLUSIONS: Although the disease affects a relatively young population, CIU/CSU carries a substantial cost. Frequent oral corticosteroid use in CIU/CSU patients is a concern because of adverse events associated with the drug. PMID- 26055729 TI - Treatment of Primary Craniofacial Hyperhidrosis: A Systematic Review. AB - BACKGROUND: Primary craniofacial hyperhidrosis (CH) can have a profoundly negative impact on quality of life. No comprehensive review of its management exists. OBJECTIVE: The objective of this review is to present the best clinical evidence to guide CH management. METHODS: A systematic review was performed using PRISMA guidelines. MEDLINE and EMBASE were searched from 1966 to 2014 for articles using the MeSH terms "Hyperhidrosis", "Head", "Neck" and synonymous text words. Inclusion criteria were experimental and observational studies addressing CH treatment. Two reviewers independently assessed study quality and analysed data. RESULTS: Of 833 references yielded, 27 met inclusion criteria and were analysed. Twenty-two studies evaluated T2 sympathetic ablation (Level III evidence). Outcome measures were subjective and mean follow-up was 29 months. Reported efficacy was high (70-100%), recurrence rates were generally low (0-8%) and complications largely transient (e.g. pneumothorax 0-1%). However, 8-95.4% experienced troubling compensatory sweating. One randomised controlled trial and one observational study evaluated botulinum toxin A (Level Ib and III, respectively). Both employed objective outcome measures and demonstrated similar findings. Efficacy was 100%, lasted a median of 5-6 months and frontalis muscle inhibition was the main adverse effect (50-100%). Three studies evaluated anticholinergic therapy: topical glycopyrrolate demonstrated high efficacy (96%) with minimal adverse effects (Level Ib) and oral oxybutynin demonstrated relatively high efficacy (80-100%) but with noticeable adverse effects (76.6 83.6%) (Level III). CONCLUSION: There are few quality studies evaluating CH treatment. Based on available evidence, we recommend topical glycopyrrolate, oral oxybutynin and intradermal botulinum toxin A as first-line therapies due to their efficacy and safety. T2 sympathectomy should be considered for patients refractory to first-line therapy. PMID- 26055730 TI - Mouse embryonic stem cells with a multi-integrase mouse artificial chromosome for transchromosomic mouse generation. AB - The mouse artificial chromosome (MAC) has several advantages as a gene delivery vector, including stable episomal maintenance of the exogenous genetic material and the ability to carry large and/or multiple gene inserts including their regulatory elements. Previously, a MAC containing multi-integration site (MI-MAC) was generated to facilitate transfer of multiple genes into desired cells. To generate transchromosomic (Tc) mice containing a MI-MAC with genes of interest, the desired genes were inserted into MI-MAC in CHO cells, and then the MI-MAC was transferred to mouse embryonic stem (mES) cells via microcell-mediated chromosome transfer (MMCT). However, the efficiency of MMCT from CHO to mES cells is very low (<10(-6)). In this study, we constructed mES cell lines containing a MI-MAC vector to directly insert a gene of interest into the MI-MAC in mES cells via a simple transfection method for Tc mouse generation. The recombination rate of the GFP gene at each attachment site (FRT, PhiC31attP, R4attP, TP901-1attP and Bxb1attP) on MI-MAC was greater than 50% in MI-MAC mES cells. Chimeric mice with high coat colour chimerism were generated from the MI-MAC mES cell lines and germline transmission from the chimera was observed. As an example for the generation of Tc mice with a desired gene by the MI-MAC mES approach, a Tc mouse strain ubiquitously expressing Emerald luciferase was efficiently established. Thus, the findings suggest that this new Tc strategy employing mES cells and a MI MAC vector is efficient and useful for animal transgenesis. PMID- 26055731 TI - Ultrastructural study of spermatogenesis in KSR2 deficient mice. AB - The aim of this study was to investigate the spermatogenesis in ksr2(-/-) mice. Spermatogenesis in 12-15 week-old C57BL/6 wt and ksr2(-/-) mice was observed in testicular tissue and epididymal sperm by light and transmission electron microscopy. The reproductive capacity of male ksr2(-/-) mice was strongly impaired. Concentration, morphology and motility of epididymal spermatozoa were altered in ksr2(-/-) mice. In seminiferous tubules from ksr2(-/-) mice, all stages of spermatogenetic process were represented; spermatids displayed defects concerning nuclear and acrosomal shape and periaxonemal structures of the tail; detached head and spermatozoa with an altered head-tail connection were observed; the interstitial tissue was severely disorganized, the Leydig cells have lost their connections. TEM analysis of epididymal spermatozoa confirmed the presence of such kind of alterations. We reported, for the first time, an ultrastructural study of ksr2(-/-) mice spermatogenesis. Remarkable findings regard the altered spermiogenetic process concomitant with a severe disorganization of interstitial tissue. Further studies are needed to assess the ksr2(-/-) mice hormonal status, focussing on testosterone levels since the interstitial tissue, where the Leydig cells reside, was compromised. PMID- 26055733 TI - Generalized morphea with preceding severe pain and coexistent early primary biliary cirrhosis. PMID- 26055735 TI - Mefloquine Versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment in Pregnancy: A Joint Analysis on Efficacy and Tolerability. AB - Since there is no ideal candidate to replace sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment (IPTp), alternatives need to be evaluated on basis of their benefit-risk ratio. We reanalyzed the first Beninese trial on mefloquine (MQ) versus SP for IPTp using a multiple outcome approach, which allowed the joint assessment of efficacy and tolerability. Overall superiority of MQ to SP was defined as superiority on at least one efficacy outcome (low birth weight [LBW], placental malaria, or maternal anemia), non-inferiority on all of them as well as on tolerability defined as cutaneous or neuropsychiatric adverse events (AEs) or low compliance with the treatment. The analysis included 1,601 women. MQ was found to be overall superior to SP (P = 0.004). Performing several sensitivity analyses to handle both missing data and stillbirths provided similar results. Using MQ for IPTp as an example, we show that a multiple outcome analysis is a pragmatic way to assess the benefits/disadvantages of one drug compared with another. In the current context of a lack of antimalarials that could be used for IPTp, such a statistical approach could be widely used by institutional policy makers for future recommendations regarding the prevention of malaria in pregnancy (MiP). PMID- 26055734 TI - Fecal Markers of Environmental Enteropathy are Associated with Animal Exposure and Caregiver Hygiene in Bangladesh. AB - Undernutrition is estimated to be an underlying cause of over half of all deaths in young children globally. There is a growing body of literature suggesting that increased exposure to enteric pathogens is responsible for environmental enteropathy (EE), a disorder associated with impaired growth in children. To determine if household unsanitary environmental conditions were significantly associated with EE and stunting in children, we conducted a cohort of 216 children (<= 30 months) in rural Bangladesh. Stool was analyzed for four fecal markers of EE: alpha-1-antitrypsin, myeloperoxidase, and neopterin combined to form an EE disease activity score, and calprotectin. We observed a significant association between having an animal corral in a child's sleeping room and elevated EE scores (1.0 point difference, 95% confidence interval [CI]: 0.13, 1.88) and a two times higher odds of stunting (height-for-age z-score < -2) (odds ratio [OR]: 2.53, 95% CI: 1.08, 5.43) after adjusting for potential confounders. In addition, children of caregivers with visibly soiled hands had significantly elevated fecal calprotectin (MUg/g) (384.1, 95% CI: 152.37, 615.83). These findings suggest that close contact with animals and caregiver hygiene may be important risk factors for EE in young children. These findings are consistent with the hypothesis that unsanitary environmental conditions can lead to EE in susceptible pediatric populations. PMID- 26055736 TI - Bacteremia Among Febrile Ugandan Children Treated with Antimalarials Despite a Negative Malaria Test. AB - Bacteremia may be inappropriately treated as malaria in children admitted with a febrile illness in Africa. We determined the prevalence, clinical features, and spectrum of bacteremia among febrile children younger than 5 years of age admitted with a negative malaria test, but prescribed antimalarials at a referral hospital in Jinja, Uganda. After initial evaluation, a blood sample was drawn from 250 children for a complete blood count and bacterial culture. Of 250 samples cultured, 15 grew organisms presumed to be skin contaminants, and of the remaining 235 samples, 45 (19.1%) had bacteremia. Staphylococcus aureus (42%), non-typhoidal Salmonella (24%), Pseudomonas aeruginosa (11%), and Streptococcus pneumoniae (9%) were the most common bacterial isolates. On multivariate analysis, history of weight loss (odds ratio [OR] = 2.75; 95% confidence interval [CI] = 1.27-5.95), presence of pulmonary crackles (OR = 3.63; 95% CI = 1.40 9.45), and leukocytosis (OR = 2.21; 95% CI = 1.09-4.47) were independent predictors of bacteremia. At a referral hospital in Uganda, bacteremia was a remarkably common finding in children with febrile illness who were treated for malaria despite negative malaria test results. PMID- 26055737 TI - Strategies for Coordination of a Serosurvey in Parallel with an Immunization Coverage Survey. AB - A community-based immunization coverage survey is the standard way to estimate effective vaccination delivery to a target population in a region. Accompanying serosurveys can provide objective measures of protective immunity against vaccine preventable diseases but pose considerable challenges with respect to specimen collection and preservation and community compliance. We performed serosurveys coupled to immunization coverage surveys in three administrative districts (woredas) in rural Ethiopia. Critical to the success of this effort were serosurvey equipment and supplies, team composition, and tight coordination with the coverage survey. Application of these techniques to future studies may foster more widespread use of serosurveys to derive more objective assessments of vaccine-derived seroprotection and monitor and compare the performance of immunization services in different districts of a country. PMID- 26055738 TI - Diabetes: A Contributor to Tuberculosis in Tropical Australia. AB - In countries with a high-burden of tuberculosis (TB), it has been well established that there is an increased incidence of TB among patients with diabetes. However, in countries with a low burden of TB there are conflicting reports. This study aimed to determine if diabetes was associated with TB in patients admitted to a teaching hospital in tropical Australia. A 20-year retrospective study found patients with comorbid diabetes were seven times overrepresented in the TB patient population when compared with the general population. This study demonstrates a strong association between TB and diabetes regardless of TB endemicity. PMID- 26055739 TI - Thirty-Seven Human Cases of Sparganosis from Ethiopia and South Sudan Caused by Spirometra Spp. AB - Thirty-seven unusual specimens, three from Ethiopia and 34 from South Sudan, were submitted since 2012 for further identification by the Ethiopian Dracunculiasis Eradication Program (EDEP) and the South Sudan Guinea Worm Eradication Program (SSGWEP), respectively. Although the majority of specimens emerged from sores or breaks in the skin, there was concern that they did not represent bona fide cases of Dracunculus medinensis and that they needed detailed examination and identification as provided by the World Health Organization Collaborating Center (WHO CC) at Centers for Disease Control and Prevention (CDC). All 37 specimens were identified on microscopic study as larval tapeworms of the spargana type, and DNA sequence analysis of seven confirmed the identification of Spirometra sp. Age of cases ranged between 7 and 70 years (mean 25 years); 21 (57%) patients were male and 16 were female. The presence of spargana in open skin lesions is somewhat atypical, but does confirm the fact that populations living in these remote areas are either ingesting infected copepods in unsafe drinking water or, more likely, eating poorly cooked paratenic hosts harboring the parasite. PMID- 26055740 TI - Plasma Leptin Levels in Children Hospitalized with Cholera in Bangladesh. AB - Vibrio cholerae, the cause of cholera, induces both innate and adaptive immune responses in infected humans. Leptin is a hormone that plays a role in both metabolism and mediating immune responses. We characterized leptin levels in 11 children with cholera in Bangladesh, assessing leptin levels on days 2, 7, 30, and 180 following cholera. We found that patients at the acute stage of cholera had significantly lower plasma leptin levels than matched controls, and compared with levels in late convalescence. We then assessed immune responses to V. cholerae antigens in 74 children with cholera, correlating these responses to plasma leptin levels on day 2 of illness. In multivariate analysis, we found an association between day 2 leptin levels and development of later anti-cholera toxin B subunit (CtxB) responses. This finding appeared to be limited to children with better nutritional status. Interestingly, we found no association between leptin levels and antibody responses to V. cholerae lipopolysaccharide, a T cell independent antigen. Our results suggest that leptin levels may be associated with cholera, including the development of immune responses to T cell-dependent antigens. PMID- 26055741 TI - Blood-Brain Barrier Function and Biomarkers of Central Nervous System Injury in Rickettsial Versus Other Neurological Infections in Laos. AB - Blood-brain barrier (BBB) function and cerebrospinal fluid (CSF) biomarkers were measured in patients admitted to hospital with severe neurological infections in the Lao People's Democratic Republic (N = 66), including bacterial meningitis (BM; N = 9) or tuberculosis meningitis (TBM; N = 11), Japanese encephalitis virus (JEV; N = 25), and rickettsial infections (N = 21) including murine and scrub typhus patients. The albumin index (AI) and glial fibrillary acidic protein (GFAP) levels were significantly higher in BM and TBM than other diseases but were also raised in individual rickettsial patients. Total tau protein was significantly raised in the CSF of JEV patients. No differences were found between clinical or neurological symptoms, AI, or biomarker levels that allowed distinction between severe neurological involvement by Orientia tsutsugamushi compared with Rickettsia species. PMID- 26055742 TI - Outbreak of Human Brucellosis from Consumption of Raw Goats' Milk in Penang, Malaysia. AB - We report the largest outbreak of brucellosis in Penang, Malaysia. Brucellosis is not endemic in this region. The index case was a 45-year-old goat farm owner presented with 3 weeks of fever, headache, severe lethargy, poor appetite, and excessive sweating. He claimed to have consumed unpasteurized goat's milk that he had also sold to the public. Tests were negative for tropical diseases (i.e., dengue fever, malaria, leptospirosis and scrub typhus) and blood culture showed no growth. Based on epidemiological clues, Brucella serology was ordered and returned positive. Over a period of 1 year, 79 patients who had consumed milk bought from the same farm were diagnosed with brucellosis. Two of these patients were workers on the farm. Four laboratory staff had also contracted the disease presumably through handling of the blood samples. The mean duration from onset of symptoms to diagnosis was 53 days with a maximum duration of 210 days. A combination treatment of rifampin and doxycycline for 6 weeks was the first line of treatment in 90.5% of patients. One-third of the patients had sequelae after recovering and 21% had a relapse. We highlight the importance of Brucellosis as a differential diagnosis when a patient has unexplained chronic fever. PMID- 26055743 TI - Three Human Gnathostomiasis Cases in Thailand with Molecular Identification of Causative Parasite Species. AB - Human gnathostomiasis is one of the important food-borne parasitic zoonoses. The disease is caused by a spirurid roundworm of the genus Gnathostoma. Here, we describe three parasitological confirmed cases of human gnathostomiasis, caused by Gnathostoma spinigerum, in a hospital in Thailand during 2004-2012. Clinical characteristics, treatment, and outcome of cases were revealed. Parasites were accidentally recovered from patients and morphologically identified as Gnathostoma species. Confirmed diagnosis and identification of causative parasite species was made by DNA extraction of the recovered worms, followed by a polymerase chain reaction (PCR) of the second internal transcribed spacer region (ITS2) of DNA and the partial cytochrome c oxidase subunit 1 (cox-1) gene. Sequences corresponding to ITS2 and cox-1 were similar to G. spinigerum. To our knowledge, this study represents the first molecular confirmation that recovered G. spinigerum is a causative agent of human infection in Thailand. PMID- 26055744 TI - Visceral Leishmaniasis Caused by Leishmania infantum in Salta, Argentina: Possible Reservoirs and Vectors. AB - Cases of human visceral leishmaniasis (HVL) were not recorded until recently in the Chaco region of northwestern Argentina. Dogs were surveyed at the sites of infection of two HVL index cases in the Chaco region of Salta province. Canine cases (CanL) were diagnosed by two parasitological methods, two molecular methods targeting mini- and maxicircle DNA, and immunochromatographic dipstick. Among 77 dogs studied, 10 (13%) were found infected with Leishmania spp. In seven dogs and two humans, the infecting species was typed as Leishmania (Leishmania) infantum. The same genotype was detected in the human and two of the CanL. Although several diagnostic methods displayed weak or moderate agreement, the concordance values for serology versus maxicircle PCR were very good (Kappa index = 0.84). Sandflies captured in the area were identified as Lutzomyia migonei and Lu. cortelezzii/Lu. sallesi (cortelezzii complex). The focal appearance of leishmaniasis in dogs and humans in a sylvatic region and its relatively low prevalence of infection suggests that L. (L.) infantum transmission to dogs and humans may, in this region, stem from sylvatic reservoirs. PMID- 26055745 TI - Challenges Associated with Management of Buruli Ulcer/Human Immunodeficiency Virus Coinfection in a Treatment Center in Ghana: A Case Series Study. AB - The synergy between Mycobacterium tuberculosis infection and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome is well established but not so in Buruli ulcer (BU). We screened confirmed BU cases for HIV infection and followed seven BU/HIV-coinfected patients. Management of BU/HIV was based on the World Health Organization guidelines and patient condition. The HIV positivity among BU patients (8.2%; 11/134) was higher compared with that of general patients attending the facility (4.8%; 718/14,863; P = 0.07) and that of pregnant women alone (2.5%; 279/11,125; P = 0.001). All seven BU/HIV-coinfected cases enrolled in the study presented with very large (category III) lesions with four having multiple lesions compared with 54.5% of category III lesions among HIV-negative BU patients. During the recommended BU treatment with streptomycin and rifampicin (SR) all patients developed immune infiltrates including CD4 T cells in their lesions. However, one patient who received antiretroviral therapy (ART) 1 week after beginning SR treatment developed four additional lesions during antibiotic treatment, while two out of the four who did not receive ART died. Further evidence is required to ascertain the most appropriate time to commence ART in relation to SR treatment to minimize paradoxical reactions. PMID- 26055746 TI - Patterns and Risk Factors of Soil-Transmitted Helminthiasis Among Orang Asli Subgroups in Peninsular Malaysia. AB - A cross-sectional study was conducted to provide comprehensive data on the patterns and associated risk factors of soil-transmitted helminth (STH) infections among five Orang Asli subgroups in Peninsular Malaysia. The overall prevalence of STH infections was 59.9% (95% confidence interval [CI] = 56.1 63.7%). Trichuris trichiura (54.3%; 95% CI = 50.4-58.2%) was the predominant species followed by Ascaris lumbricoides (26.7%; 95% CI = 23.3-30.1%) and hookworm (9.1%; 95% CI = 6.9-11.3%). This study showed diversity for STH infections by subgroup with poverty and personal sanitary behavior as important risk factors for infection. Risk profile analyses indicating that Orang Kuala subgroup who has a generally well-developed infrastructure and better quality of life had a low rate of infection. There is a need for poverty reduction and promotion of deworming programs along with mass scale campaigns to create awareness about health and hygiene to reduce STH infections. PMID- 26055747 TI - Influenza A and Parvovirus B19 Seropositivity Rates in Gabonese Infants. AB - Clinical and epidemiological data from Central Africa on influenza A and parvovirus B19 infections are limited. We analyzed 162 blood samples of infants 3, 9, 15, and 30 months of age for IgG antibodies against both pathogens. Antibody responses were 0, 3.7%, 12.3%, and 20.4% against influenza A; and 1.2%, 2.5%, 3.1%, and 9.3% against parvovirus B19, respectively. Seropositivity rates were 89.5 (95% confidence interval [CI]: 59-120.1) and 38.2 (95% CI: 18.9 57.6)/1,000 person-years at risk for influenza A and parvovirus B19, respectively. Our data add to the understanding of the epidemiology of both conditions. PMID- 26055748 TI - Prevalence and Factors Associated with Anemia Among Children Under 5 Years of Age -Uganda, 2009. AB - Anemia in children under 5 years of age, defined by the World Health Organization as a hemoglobin concentration < 11 g/dL, is a global public health problem. According to the 2006 Demographic Health Survey, the prevalence of anemia among children under five in Uganda was 72% in 2006. The 2009 Uganda Malaria Indicator Survey was conducted in late 2009 and revealed that over 60% of children less than 5 years of age were anemic and that over half of children tested positive for malaria via a rapid diagnostic test. Children with concomitant malaria infection, and in households without any type of mosquito net were more likely to be anemic, confirming that children under 5 years, are vulnerable to both the threat of malaria and anemia and the beneficial effect of malaria prevention tools. However, prevention and treatment of other factors associated with the etiology of anemia (e.g., iron deficiency) are likely necessary to combat the toll of anemia in Uganda. PMID- 26055749 TI - West Nile Virus Encephalitis: The First Human Case Recorded in Brazil. AB - A Brazilian ranch worker with encephalitis and flaccid paralysis was evaluated in the regional Acute Encephalitis Syndromic Surveillance Program. This was the first Brazilian patient who met the Centers for Disease Control and Prevention (CDC) confirmation criteria for West Nile virus disease. Owing to the overlapping of neurological manifestations attributable to several viral infections of the central nervous system, this report exemplifies the importance of human acute encephalitis surveillance. The syndromic approach to human encephalitis cases may enable early detection of the introduction of unusual virus or endemic occurrence of potentially alarming diseases within a region. PMID- 26055750 TI - Antimicrobial Disk Susceptibility Testing of Leptospira spp. Using Leptospira Vanaporn Wuthiekanun (LVW) Agar. AB - Leptospira Vanaporn Wuthiekanun (LVW) agar was used to develop a disk diffusion assay for Leptospira spp. Ten pathogenic Leptospira isolates were tested, all of which were susceptible to 17 antimicrobial agents (amoxicillin/clavulanic acid, amoxicillin, azithromycin, cefoxitin, ceftazidime, ceftriaxone, chloramphenicol, ciprofloxacin, clindamycin, doripenem, doxycycline, gentamicin, linezolid, nitrofurantoin, penicillin, piperacillin/tazobactam, and tetracycline). All 10 isolates had no zone of growth inhibition for four antimicrobials (fosfomycin, nalidixic acid, rifampicin, and trimethoprim/sulfamethoxazole). Of the ten Leptospira, seven had a growth inhibition zone of <= 21 mm for aztreonam, the zone diameter susceptibility break point for Enterobacteriaceae. This assay could find utility as a simple screening method during the epidemiological surveillance of antimicrobial resistance in Leptospira spp. PMID- 26055751 TI - Bisphenol A in Solid Waste Materials, Leachate Water, and Air Particles from Norwegian Waste-Handling Facilities: Presence and Partitioning Behavior. AB - The plastic additive bisphenol A (BPA) is commonly found in landfill leachate at levels exceeding acute toxicity benchmarks. To gain insight into the mechanisms controlling BPA emissions from waste and waste-handling facilities, a comprehensive field and laboratory campaign was conducted to quantify BPA in solid waste materials (glass, combustibles, vehicle fluff, waste electric and electronic equipment (WEEE), plastics, fly ash, bottom ash, and digestate), leachate water, and atmospheric dust from Norwegian sorting, incineration, and landfill facilities. Solid waste concentrations varied from below 0.002 mg/kg (fly ash) to 188 +/- 125 mg/kg (plastics). A novel passive sampling method was developed to, for the first time, establish a set of waste-water partition coefficients, KD,waste, for BPA, and to quantify differences between total and freely dissolved concentrations in waste-facility leachate. Log-normalized KD,waste (L/kg) values were similar for all solid waste materials (from 2.4 to 3.1), excluding glass and metals, indicating BPA is readily leachable. Leachate concentrations were similar for landfills and WEEE/vehicle sorting facilities (from 0.7 to 200 MUg/L) and dominated by the freely dissolved fraction, not bound to (plastic) colloids (agreeing with measured KD,waste values). Dust concentrations ranged from 2.3 to 50.7 mg/kgdust. Incineration appears to be an effective way to reduce BPA concentrations in solid waste, dust, and leachate. PMID- 26055752 TI - Intrathecal BCR transcriptome in multiple sclerosis versus other neuroinflammation: Equally diverse and compartmentalized, but more mutated, biased and overlapping with the proteome. AB - The mechanisms driving the intrathecal synthesis of IgG in multiple sclerosis (MS) are unknown. We combined high-throughput sequencing of transcribed immunoglobulin heavy-chain variable (IGHV) genes and mass spectrometry to chart the diversity and compartmentalization of IgG-producing B cells in the cerebrospinal fluid (CSF) of MS patients and controls with other neuroinflammatory diseases. In both groups, a few clones dominated the intrathecal IGHV transcriptome. In most MS patients and some controls, dominant transcripts matched the CSF IgG. The IGHV transcripts in CSF of MS patients frequently carried IGHV4 genes and had more replacement mutations compared to controls. In both groups, dominant IGHV transcripts were identified within clusters of clonally related B cells that had identical or related IGHV transcripts in the blood. These findings suggest more pronounced affinity maturation, but an equal degree of diversity and compartmentalization of the intrathecal B-cell response in MS compared to other neuroinflammatory diseases. PMID- 26055753 TI - Pseudomonas pseudoalcaligenes CECT5344, a cyanide-degrading bacterium with by product (polyhydroxyalkanoates) formation capacity. AB - BACKGROUND: Cyanide is one of the most toxic chemicals produced by anthropogenic activities like mining and jewelry industries, which generate wastewater residues with high concentrations of this compound. Pseudomonas pseudoalcaligenes CECT5344 is a model microorganism to be used in detoxification of industrial wastewaters containing not only free cyanide (CN(-)) but also cyano-derivatives, such as cyanate, nitriles and metal-cyanide complexes. Previous in silico analyses suggested the existence of genes putatively involved in metabolism of short chain length (scl-) and medium chain length (mcl-) polyhydroxyalkanoates (PHAs) located in three different clusters in the genome of this bacterium. PHAs are polyesters considered as an alternative of petroleum-based plastics. Strategies to optimize the bioremediation process in terms of reducing the cost of the production medium are required. RESULTS: In this work, a biological treatment of the jewelry industry cyanide-rich wastewater coupled to PHAs production as by-product has been considered. The functionality of the pha genes from P. pseudoalcaligenes CECT5344 has been demonstrated. Mutant strains defective in each proposed PHA synthases coding genes (Mpha(-), deleted in putative mcl-PHA synthases; Spha(-), deleted in the putative scl-PHA synthase) were generated. The accumulation and monomer composition of scl- or mcl-PHAs in wild type and mutant strains were confirmed by gas chromatography-mass spectrometry (GC-MS). The production of PHAs as by-product while degrading cyanide from the jewelry industry wastewater was analyzed in batch reactor in each strain. The wild type and the mutant strains grew at similar rates when using octanoate as the carbon source and cyanide as the sole nitrogen source. When cyanide was depleted from the medium, both scl PHAs and mcl-PHAs were detected in the wild-type strain, whereas scl-PHAs or mcl PHAs were accumulated in Mpha(-) and Spha(-), respectively. The scl-PHAs were identified as homopolymers of 3-hydroxybutyrate and the mcl-PHAs were composed of 3-hydroxyoctanoate and 3-hydroxyhexanoate monomers. CONCLUSIONS: These results demonstrated, as proof of concept, that talented strains such as P. pseudoalcaligenes might be applied in bioremediation of industrial residues containing cyanide, while concomitantly generate by-products like polyhydroxyalkanoates. A customized optimization of the target bioremediation process is required to gain benefits of this type of approaches. PMID- 26055754 TI - Macro- and microscopic findings of ICG fluorescence in liver tumors. AB - BACKGROUND: Reports detailing microscopic observations of indocyanine green (ICG) fluorescence imaging (IFI) in hepatocellular carcinoma (HCC) and metastatic liver cancer are rare. We were able to perform macro- and microscopic IFI results in postoperative paraffin-embedded tissue samples and formalin-fixed specimens from liver tumors. METHODS: Between April 2010 and March 2014, 19 patients with HCC or liver metastases of colorectal tumors underwent liver resection. ICG solution was injected into the peripheral vein from 14 to 2 days prior to operation. We observed liver tumor IFI during the laparotomy and IFI in resected liver sections using a photo dynamic emission (PDE) camera. The IFI of paraffin-embedded tissue samples was observed using a charge-coupled device (CCD) camera. Moreover, we microscopically performed tissue section IFI using a fluorescence microscope with an ICG-B-NQF. RESULTS: We performed that IFI characteristics depended on tumor type macroscopically and microscopically. In normal liver tissue, fluorescence consistent with the bile canaliculus was observed. HCC had heterogeneous IFI, forming a total or partial tumor and rim pattern. In metastatic carcinoma, we performed that non-tumor cells in the marginal region showed fluorescence and tumor cells in the central region did not fluoresce. CONCLUSIONS: We confirmed that the variations of ICG fluorescence imaging patterns reflect different tumor characteristics in not only macroscopic imaging as previous reports but also microscopic imaging. Moreover, the ICG fluorescence method is useful for postoperative pathological detection of microscopic lesions in histopathological specimens. ICG fluorescence in paraffin-embedded tissue samples and formalin fixed specimens is preserved in the long term. PMID- 26055755 TI - Searching while loaded: Visual working memory does not interfere with hybrid search efficiency but hybrid search uses working memory capacity. AB - In "hybrid search" tasks, such as finding items on a grocery list, one must search the scene for targets while also searching the list in memory. How is the representation of a visual item compared with the representations of items in the memory set? Predominant theories would propose a role for visual working memory (VWM) either as the site of the comparison or as a conduit between visual and memory systems. In seven experiments, we loaded VWM in different ways and found little or no effect on hybrid search performance. However, the presence of a hybrid search task did reduce the measured capacity of VWM by a constant amount regardless of the size of the memory or visual sets. These data are broadly consistent with an account in which VWM must dedicate a fixed amount of its capacity to passing visual representations to long-term memory for comparison to the items in the memory set. The data cast doubt on models in which the search template resides in VWM or where memory set item representations are moved from LTM through VWM to earlier areas for comparison to visual items. PMID- 26055756 TI - Influence of exercise mode on pregnancy outcomes: ENHANCED by Mom project. AB - BACKGROUND: The extent of the benefits of exercise training during pregnancy on maternal, fetal, and neonatal health outcomes has not been sufficiently addressed. While aerobic exercise training has been determined as safe and efficacious throughout pregnancy, the effects of other training modes on fetal health and development as well as any continued benefits for the neonate, especially with regards to cardiovascular development and function, is largely unknown. In the ENHANCED by Mom study we aim to determine the effects of different modes of exercise training (aerobic, circuit, and resistance) throughout pregnancy on childhood health by controlling individual exercise programs and assessing the effects of each on fetal and neonatal health adaptations. METHODS/DESIGN: ENHANCED by mom is a cross sectional comparison study utilizing 3 intervention groups in comparison to a control group. Participants will complete three 5 min warmup + 45 min sessions weekly from 16 weeks to 36 weeks gestation of aerobic, resistance, or circuit training, in comparison to non-exercising controls. Maternal physical measurements will occur every 4 weeks throughout the intervention period. Fetal morphometric and heart measurements will occur at 34 weeks gestation. Neonatal measurements will be acquired at birth and at 1 month, 6 months, and 12 months. DISCUSSION: A better understanding on the effects of exercise training during pregnancy on fetal and neonatal health could have a profound impact on the prevention and development of chronic diseases such as obesity, hypertension, and diabetes. PMID- 26055757 TI - Residential distance from major urban areas, diabetes and cardiovascular mortality in Australia. AB - BACKGROUND: Living outside major urban centres is associated with increased mortality in the general population but whether having diabetes further impacts on the effects of living outside major urban centres is not known. This study explores the impact of residential location and diabetes on all-cause, ischemic heart disease (IHD) and stroke mortality in Australia. METHODS: We included 1,101,053 individuals (all ages) with diabetes on the national diabetes register, between 2000 and 2010. Vital statistics were collected by linkage to the death registry. The Accessibility/Remoteness Index of Australia (ARIA+) was used to categorize residences into major urban, inner regional, outer regional and remote areas, according to distance from major service centres. Standardised mortality ratios (SMRs) by ARIA+ are reported. RESULTS: During follow-up (median 6.7 years), there were 187,761 deaths (46,244 and 12,786 IHD and stroke deaths, respectively). Age-standardized all-cause, stroke and IHD mortality rates increased across ARIA+ categories in diabetes and in the general population. For all outcomes, similar patterns were observed in both sexes and diabetes type, although the rates were higher in males. For all-cause (both sexes, type 1 diabetes (T1DM) and type 2 diabetes (T2DM)), IHD mortality (T2DM only) and stroke mortality (T2DM only), SMRs varied across ARIA+ categories, showing a shallow U shaped relationship, in which the lowest SMR was in the inner regional or outer regional areas, and the highest SMR in the major urban or remote areas. CONCLUSION: The effect of diabetes on mortality varied only modestly by location, and the impact of diabetes was greatest in the major urban and remote areas, and least in the inner and outer regional areas. PMID- 26055758 TI - Physician's attitudes towards diagnosing and treating glucocorticoid induced hyperglycaemia: Sliding scale regimen is still widely used despite guidelines. AB - AIMS: Treatment with glucocorticoids for neoplasms and inflammatory disorders is frequently complicated by glucocorticoid induced hyperglycaemia (GCIH). GCIH is associated with adverse outcomes and its treatment has short term and long term benefits. Currently, treatment targets and modalities depend on local protocols and habits of individual clinicians. We explored current practice of screening and treatment of GCIH in patients receiving glucocorticoid pulse therapy. METHODS: A factorial survey with written case vignettes. All vignette patients received glucocorticoid pulse therapy. Other characteristics (e.g., indication for glucocorticoid therapy, pre-existent diabetes) varied. The survey was held between November 2013 and May 2014 on 2 nationwide conferences and in hospitals across The Netherlands. Pulmonologists and internists expressed their level of agreement with statements on ordering capillary glucose testing and treatment initiation. RESULTS: Respondents ordered screening for GCIH in 85% of vignette patients and initiated treatment in 56%. When initiating treatment, respondents opt for sliding scale insulin in 62% of patients. Sliding scale insulin was more frequently prescribed in patients with pre-existent insulin dependent diabetes (OR 2.4, CI 1.3-4.2) and by residents (vs. specialists, OR 2.1, CI 1.2-3.5). Sixty-nine percent of clinicians experienced a lack of guidelines for GCIH. CONCLUSIONS: Clinicians have a strong tendency to screen for GCIH but subsequent initiation of treatment was low. Sliding scale insulin is still widely used in episodic GCIH despite evidence against its effectiveness. This may be due to lacking evidence on feasible treatment options for GCIH. PMID- 26055759 TI - Phasing of single DNA molecules by massively parallel barcoding. AB - High-throughput sequencing platforms mainly produce short-read data, resulting in a loss of phasing information for many of the genetic variants analysed. For certain applications, it is vital to know which variant alleles are connected to each individual DNA molecule. Here we demonstrate a method for massively parallel barcoding and phasing of single DNA molecules. First, a primer library with millions of uniquely barcoded beads is generated. When compartmentalized with single DNA molecules, the beads can be used to amplify and tag any target sequences of interest, enabling coupling of the biological information from multiple loci. We apply the assay to bacterial 16S sequencing and up to 94% of the hypothesized phasing events are shown to originate from single molecules. The method enables use of widely available short-read-sequencing platforms to study long single molecules within a complex sample, without losing phase information. PMID- 26055760 TI - Bilateral atherosclerotic internal carotid artery occlusion and recurrent ischaemic stroke. AB - Bilateral internal carotid artery occlusion (BICAO) is a rare disease that carries a gloomy prognosis. We report a case of a 52-year-old man who developed ischaemic infarction at the region of the right middle cerebral artery; he was found to have atherosclerotic occlusion of both internal carotid arteries on Doppler-duplex examination. He received medical treatment only. After 1 year, he developed a new infarction at the region of the left middle cerebral artery. Conventional angiography revealed bilateral occlusion of internal carotid arteries at their origin, approximately 50% stenosis of the common carotid bulbs and mild stenosis of the origin of external carotid arteries. The patient did not undergo any form of surgical revascularisation procedures and died of severe aspiration pneumonia approximately 2 months after the second stroke. BICAO portends a poor outcome and carries a risk of recurrent ischaemic events. The best management strategy for this vascular occlusion remains unclear. PMID- 26055761 TI - Drug-resistant vasospastic angina pectoris with plaque erosion in the focal spastic lesion confirmed with coronary angioscopy. PMID- 26055762 TI - Pericardial mass in a patient with rheumatoid arthritis. AB - A 65-year-old man presented with long-standing rheumatoid arthritis (RA), severe fatigue and mild arthritis of metacarpophalaneal joints. Physical examination revealed S3, II/IV decrescendo diastolic murmur and 2+ LL oedema. Anticyclic citrullinated peptide antibodies were >250 units. Echocardiogram showed an 8 cm pericardial mass with no atrial or ventricular collapse and mild to moderate aortic regurgitation. Cardiac MRI defined the mass as a heterogeneous entity attached to the right, anterior and inferior heart borders, with compression on right cardiac structures and the left ventricle. CT-guided biopsy demonstrated fibrinous material without granulomas or infection. Fatigue did not improve on immunosuppression with low-dose prednisone and leflunamide. Cardiac tamponade was confirmed by heart catheterisation and the mass was surgically excised with partial pericardiectomy. The patient had a dramatic improvement and, 4 years later, he remains asymptomatic cardiac wise. This case highlights the clinical significance of pericardial disease in RA and its response to therapy. PMID- 26055763 TI - Primary flap reconstruction of tissue defects after sarcoma surgery enables curative treatment with acceptable functional results: a 7-year review. AB - BACKGROUND: Sarcomas, a heterogeneous group of tumors, are challenging to treat and require multidisciplinary cooperation and planning. We analyzed the efficacy of flap reconstruction in patients with bone and soft tissue sarcoma. METHODS: Patient charts and operative records were retrospectively reviewed from January 2006 through October 2013 to identify sarcoma patient characteristics, postoperative complications, revisions, recurrences, and survival. Pedicled and/or free flap reconstruction was performed in 109 patients. Flap selection was based on defect size, and exposure of anatomically critical structures or major orthopedic implants. RESULTS: Of 109 patients, 71 (65.1 %) were men, and mean age was 56.4 years. Tumors most frequently located in a lower extremity (38.7 %). Primary sarcomas comprised 79.2 % and recurrences occurred in 18.9 %. Wide resection was performed for 65.7 %, and there were 10 planned amputations combined with flap reconstruction. A total of 111 tumors received 128 flaps: 76 pedicled flaps, 42 free flaps, and 5 combined (10 total) pedicled + free-flaps. The success rate was 94 % for the pedicled flap group, 97 % for the free-flap group, and 100 % for the pedicle + free-flap group. Of 35 patients, 5 developed deep prosthetic infections. Only one amputation due to disease progression was performed. Satisfactory functional outcome was achieved in 69 %. Survival rate during a mean (standard deviation) 3(2) year follow-up was 83.5 %. CONCLUSIONS: Primary flap reconstruction after sarcoma surgery satisfies oncologic goals. Large tumors in difficult areas can be removed and complete tumor resection achieved. Our findings indicate a high survival rate after sarcoma surgery utilizing flap reconstruction and a low recurrence rate. PMID- 26055770 TI - The National Hartford Center of Gerontological Nursing Excellence: An Evolution of a Nursing Initiative to Improve Care of Older Adults. AB - The mission of the John A. Hartford Foundation is to improve the health of older Americans. This mission has been realized throughout the evolution of the National Hartford Center of Gerontological Nursing Excellence-an international collaboration between Schools of Nursing and Sigma Theta Tau International Honor Society of Nursing-whose goal is to support research, education, and practice to provide better nursing care for our aging society. The National Hartford Center is the focus of this supplement and an example of the Foundation's grant-making to prepare the nursing workforce to be competent to care for our aging society. This article traces the innovative origin and inception of the National Hartford Center, first as the Building Academic Geriatric Nursing Capacity (BAGNC) Initiative in 2000 under the leadership of two groundbreaking scholars in nursing and aging sciences: Claire M. Fagin, PhD, RN, and Patricia G. Archbold, DNSc. We continue through to today's leadership and culminate by describing the Center's influence on the gerontological nursing workforce and clinical practice; the paper also includes a brief introduction to the articles, highlighting advances in gerontological nursing science. With funding from the John A. Hartford Foundation, The Atlantic Philanthropies, The Mayday Fund, and a number of creative public and nonprofit partnerships, the National Hartford Center celebrates two decades and its greatest asset-the nearly 300 gerontological nursing leaders, including Archbold nursing pre-docs, Fagin nursing post-docs, and expert faculty, along with its Hartford Centers of Gerontological Nursing Excellence across the country. We trace the transition of BAGNC to the membership based National Hartford Center and its move to The Gerontological Society of America to become a self-sustaining, autonomous unit. Current needs, challenges, lessons learned, and strategies of the National Hartford Center are examined within the context of sustainability, which has become paramount as Hartford Foundation funding ends in 2016. Despite the auspicious beginnings of the National Hartford Center, system change has been slow. There remains a strong need to continue to grow the field of gerontological nursing and aging sciences. We are working diligently to drive health system reform, and develop and support gerontological nursing leaders and members of the National Hartford Center as exemplars for innovation in care of older adults. The contributing authors of this supplement are from member schools of the National Hartford Center or are current or past program Scholars or Fellows. Herein these authors showcase innovation for older adults through their research that addresses an array of diseases and conditions affecting human systems, embedded in a variety of environments, including in-home care, subsidized housing communities, nursing homes, assisted living facilities, memory care units, and rural community environs. PMID- 26055771 TI - Vision Impairment Among Older Adults Residing in Subsidized Housing Communities. AB - PURPOSE OF THE STUDY: To examine the rate of vision impairment and the relationship between vision impairment, cognitive impairment, and chronic comorbid conditions in residents of federally subsidized senior housing facilities. DESIGN: Cross-sectional, observational study. METHODS: Vision screening events were held at 14 subsidized senior housing facilities in Jefferson County, Alabama for residents aged 60 years and older. Visual function (distance vision, near vision, and contrast sensitivity) measured with habitual correction if worn, cognitive status, and chronic comorbid conditions (hypertension, heart problems, circulation problems, and diabetes) were assessed. RESULTS: A total of 238 residents participated in the vision screenings. Most residents (75%) were African American. Vision impairment was common, with 40% of participants failing the distance acuity screening and 58% failing the near acuity screening; failure was defined as vision worse than 20/40 in either eye. Additionally, 65% failed the contrast sensitivity screening. A total of 30.6% of seniors had cognitive impairment. Regarding comorbid chronic conditions, 31% had circulation problems, 39% had diabetes, 41% had heart problems, and 76% had hypertension (59% had 2 or more of these). Visual acuity differed significantly between cognitive status groups and with the presence of heart and circulation problems. IMPLICATIONS: This study is among the first to provide information about vision impairment in this socioeconomically disadvantaged group of older adults. Vision impairment was common. Cognitive impairment and comorbid chronic conditions accounted for a small to moderate percentage of the variance in distance vision, near vision, and contrast sensitivity. Future studies should focus on strategies to facilitate access to eye care in this vulnerable population. PMID- 26055772 TI - Search Strategies Used by Older Adults in a Virtual Reality Place Learning Task. AB - PURPOSE OF THE STUDY: Older adults often have problems finding their way in novel environments such as senior living residences and hospitals. The purpose of this study was to examine the types of self-reported search strategies and cues that older adults use to find their way in a virtual maze. DESIGN AND METHODS: Healthy, independently living older adults (n = 129) aged 55-96 were tested in a virtual maze task over a period of 3 days in which they had to repeatedly find their way to a specified goal. They were interviewed about their strategies on days 1 and 3. Content analysis was used to identify the strategies and cues described by the participants in order to find their way. Strategies and cues used were compared among groups. RESULTS: The participants reported the use of multiple spatial and non-spatial strategies, and some of the strategies differed among age groups and over time. The oldest age group was less likely to use strategies such as triangulation and distance strategies. All participants used visual landmarks to find their way, but the use of geometric cues (corners) was used less by the older participants. IMPLICATIONS: These findings add to the theoretical understanding of how older adults find their way in complex environments. The understanding of how wayfinding changes with age is essential in order to design more supportive environments. PMID- 26055773 TI - Electronic Health Record Tools to Care for At-Risk Older Drivers: A Quality Improvement Project. AB - PURPOSE OF THE STUDY: Evaluating driving safety of older adults is an important health topic, but primary care providers (PCP) face multiple barriers in addressing this issue. The study's objectives were to develop an electronic health record (EHR)-based Driving Clinical Support Tool, train PCPs to perform driving assessments utilizing the tool, and systematize documentation of assessment and management of driving safety issues via the tool. DESIGN AND METHODS: The intervention included development of an evidence-based Driving Clinical Support Tool within the EHR, followed by training of internal medicine providers in the tool's content and use. Pre- and postintervention provider surveys and chart review of driving-related patient visits were conducted. Surveys included self-report of preparedness and knowledge to evaluate at-risk older drivers and were analyzed using paired t-test. A chart review of driving related office visits compared documentation pre- and postintervention including: completeness of appropriate focused history and exam, identification of deficits, patient education, and reporting to appropriate authorities when indicated. RESULTS: Data from 86 providers were analyzed. Pre- and postintervention surveys showed significantly increased self-assessed preparedness (p < .001) and increased driving-related knowledge (p < .001). Postintervention charts showed improved documentation of correct cognitive testing, more referrals/consults, increased patient education about community resources, and appropriate regulatory reporting when deficits were identified. IMPLICATIONS: Focused training and an EHR-based clinical support tool improved provider self-reported preparedness and knowledge of how to evaluate at-risk older drivers. The tool improved documentation of driving-related issues and led to improved access to interdisciplinary care coordination. PMID- 26055774 TI - Function Focused Care for Assisted Living Residents With Dementia. AB - PURPOSE OF THE STUDY: Assisted living (AL) residents with dementia require assistance with activities of daily living, encounter limited opportunities to engage in physical activity, and often exhibit challenging behavioral symptoms. The Function Focused Care Intervention for the Cognitively Impaired (FFC-CI) teaches and motivates direct care workers (DCWs) to engage residents with dementia in activities that optimize function and activity while minimizing behavioral symptoms. The purpose of this study was to test the impact of FFC-CI on function, physical activity, behavior, and falls. DESIGN AND METHODS: A cluster-randomized trial included 96 residents with dementia and 76 DCWs from 4 ALs. Generalized estimating equations were used to evaluate outcomes at 3 and 6 months. RESULTS: There were no treatment by time differences with regard to resident behavior, mood, counts of physical activity based on actigraphy, falls, and function. There were significant increases in physical activity based on kilocalories burned (p = .001), time spent in physical activity based on survey results (p = .001), and time spent in repetitive behaviors, such as wandering (p = .01) among the control group over time. There were no treatment by time differences with regard to DCW beliefs, knowledge, or performance of FFC, except for less decline in job satisfaction among the treatment group (p = .002). Treatment fidelity with regard to delivery and receipt were poor due to high staff attrition in the treatment group (46% vs. 16%) and limited site support. IMPLICATIONS: The findings from this study can be used to adapt future FFC intervention studies to improve treatment fidelity and optimize intervention efficacy. PMID- 26055775 TI - Hair Cortisol Analysis: A Promising Biomarker of HPA Activation in Older Adults. AB - Prolonged stress is a potentially harmful and often undetected risk factor for chronic illness in older adults. Cortisol, one indicator of the body's hormonal responses to stress, is regulated by the hypothalamic-pituitary-adrenal (HPA) axis and is commonly measured in saliva, urine, or blood samples. Cortisol possesses a diurnal pattern and thus collection timing is critical. Hair cortisol is a proxy measure to the total retrospective activity of the HPA axis over the preceding months, much like hemoglobin A1c is a proxy measure of glucose control over the past 3 months. The aim of this review is to examine a novel biomarker, hair cortisol, as a practical measure of long-term retrospective cortisol activity associated with chronic stress in older adults. Hair cortisol analysis advances the science of aging by better characterizing chronic stress as a risk factor for chronic illness progression and as a biomarker of the effectiveness of stress reduction interventions. PMID- 26055776 TI - Implementation of an Integrative Holistic Healthcare Model for People Living with Parkinson's Disease. AB - PURPOSE: Research demonstrates that people with Parkinson's disease (PD) benefit greatly from multidisciplinary medical care. Delaware does not have a Movement Disorder Center or a movement disorder specialist. To address this issue, the University of Delaware Nurse Managed Health Center (NMHC) developed a novel PD Telehealth Clinic serving individuals with PD and their caregivers throughout Delaware. DESIGN AND METHODS: The PD clinic is based on a collaborative framework that uses synchronous videoconferencing telehealth technology to bring together out-of-state clinicians and scientists with expertise in PD to help deliver specialized care to PD patients and their caregivers. The team includes a movement disorder specialist, psychologists, nurse practitioners, researchers, physical and speech therapists, exercise physiologists, nutritionists, and graduate students. The PD Clinic delivery model seamlessly blends telehealth provider and onsite provider interactions, enabling the diagnosis, treatment, and ongoing management of PD. RESULTS: In the first 6 months of the Parkinson's clinic opening, the nurse practitioners along with the movement disorder specialist evaluated 36 PD patients. Several patients have received recommendations to change their medication regimen by the movement disorder specialist. About 20 patients were referred to physical therapy, 7 to speech therapy, 9 to mental health services, 1 to occupational therapy, and 12 to local support groups. The location of the NMHC-PD clinic has reduced travel time and distance by as much as 1.5 hr or 80 miles, each way, and wait time for a new patient appointment is less than 3 months. IMPLICATIONS: The NMHC - PD Telehealth Clinic provides access to specialized multidisciplinary and advanced care and was successfully implemented. This model can be replicated in other nurse managed health centers across the United States. PMID- 26055777 TI - Facilitated Learning to Advance Geriatrics: Increasing the Capacity of Nurse Faculty to Teach Students About Caring for Older Adults. AB - PURPOSE: The Facilitated Learning to Advance Geriatrics program (FLAG) was designed to increase the numbers of nurse faculty in prelicensure programs with basic knowledge about aging and teaching effectiveness to prepare students to provide safe, high quality care for older adults. METHODS: Using a framework to improve transfer of learning, FLAG was designed to include: (a) a workshop to increase basic knowledge of aging and common geriatric syndromes, and effective use of evidence-based teaching/learning strategies; (b) a year-long mentoring program to support application of workshop learning and leading change in participants' schools to ensure that geriatrics is a priority. Both formative and summative evaluation methods were used, and included self-assessment of objectives, program satisfaction, and teaching self-efficacy. RESULTS: FLAG achieved its overall purpose by enrolling 152 participants from 19 states including 23 faculty from associate degree programs and 102 from baccalaureate programs. Self-rated teaching effectiveness improved significantly from pre- to post-workshop each year. Achievement of learning objectives was rated highly as was satisfaction. Transfer of learning was evidenced by implementation of educational projects in home schools supported by mentoring. IMPLICATIONS: The FLAG program provided opportunities for nurse educators to learn to teach geriatrics more effectively and to transfer learning to their work environment. Future FLAG programs will be offered in a shortened format, incorporating online content and strategies, adding other health professionals to the audience with the same goal of increasing the knowledge and abilities of educators to prepare learners to provide competent care for older adults. PMID- 26055778 TI - Evaluation of the Nurses Caring for Older Adults Young Scholars Program. AB - There is a "perfect storm" brewing in nursing. We are faced with a growing number of older patients, while at the same time nurses with expertise in gerontological nursing are aging and retiring. This critical shortage is most evident for nurses with research-intensive preparation needed to replenish actual and anticipated nurse faculty vacancies across the United States, especially those in underrepresented minority groups. We describe one solution to this problem; the Nurses Caring for Older Adults Young Scholars Program (YSP) that selects promising, ethnically diverse students and offers them a 1- to 3-year mentorship experience with the focus on students continuing to PhD studies on completion of their basic nursing studies. The YSP has mentored 15 prelicensure students with an identified interest in gerontological nursing research, with 8 young scholars (53%) going on to pursue doctoral studies. Program elements are described as well as philosophical and practical challenges of program implementation. Formative evaluations including student and faculty perceptions of the program as well as summative evaluation including admission success rate, student products, and progression in the doctoral program are discussed. Students indicate that establishing a strong mentor relationship with opportunities to participate in their mentor's research activities leading to the generation of a commitment to a research topic is the strongest factor in young scholars following through with enrollment into a doctoral program. A synergistic outcome of the YSP was the development of a critical mass of students interested in pursuing PhD studies that further extended the impact of the program. PMID- 26055779 TI - The Association Between Characteristics of Care Environments and Apathy in Residents With Dementia in Long-term Care Facilities. AB - PURPOSE: Apathy is highly prevalent in dementia but often overlooked. Environment based interventions have demonstrated positive impact on apathy, yet, influential environmental components are largely understudied. This study examined the relationship between care environments and apathy in long-term care residents with dementia. DESIGN AND METHODS: This study was exploratory and employed a descriptive and repeated observation design. A sample of 40 was selected from a parent study with 185 participants from 28 facilities. Three videos from each participant were coded to measure apathy and environmental stimulation. Data on ambiance, crowding, staff familiarity, light, and sounds were extracted from the parent study. Generalized linear mixed models were used for analysis. RESULTS: The clarity and strength of environmental stimulation were significantly associated with a lower apathy level. An increase of 1 point on stimulation clarity and strength corresponded to a decrease of 1.3 and 1.9 points on apathy score, respectively (p < .0001). Other environmental factors did not show significant effect on apathy. IMPLICATIONS: This study explored influential environmental features on apathy in dementia. Findings suggest that care environments that contain clear and sufficient environmental stimulation are significantly associated with lower resident apathy levels. Findings will guide environmental design and interventions for dementia care. PMID- 26055780 TI - Computer Activities for Persons With Dementia. AB - PURPOSE OF THE STUDY: The study examined participant's experience and individual characteristics during a 7-week computer activity program for persons with dementia. DESIGN AND METHODS: The descriptive study with mixed methods design collected 612 observational logs of computer sessions from 27 study participants, including individual interviews before and after the program. Quantitative data analysis included descriptive statistics, correlational coefficients, t-test, and chi-square. Content analysis was used to analyze qualitative data. RESULTS: Each participant averaged 23 sessions and 591min for 7 weeks. Computer activities included slide shows with music, games, internet use, and emailing. On average, they had a high score of intensity in engagement per session. Women attended significantly more sessions than men. Higher education level was associated with a higher number of different activities used per session and more time spent on online games. Older participants felt more tired. Feeling tired was significantly correlated with a higher number of weeks with only one session attendance per week. More anticholinergic medications taken by participants were significantly associated with a higher percentage of sessions with disengagement. The findings were significant at p < .05. Qualitative content analysis indicated tailoring computer activities appropriate to individual's needs and functioning is critical. All participants needed technical assistance. IMPLICATIONS: A framework for tailoring computer activities may provide guidance on developing and maintaining treatment fidelity of tailored computer activity interventions among persons with dementia. Practice guidelines and education protocols may assist caregivers and service providers to integrate computer activities into homes and aging services settings. PMID- 26055781 TI - "Wish we would have known that!" Communication Breakdown Impedes Person-Centered Care. AB - PURPOSE: To understand how nursing home staff obtain information needed for implementing person-centered care (PCC) to residents with dementia who exhibit behavioral and psychological symptoms of dementia (BPSD), and how they communicate this information to other staff. Barriers to PCC and information exchange were also explored. DESIGN AND METHODS: Participants were 59 staff from two nursing homes. Focus group methodology captured discussions in eight 1-hr sessions. Sessions were audiotaped and transcribed. Data were analyzed using qualitative content analysis to provide a comprehensive summary of real world context of implementing PCC. RESULTS: To deliver PCC staff identified a need for access to psychosocial/medical history of the resident and knowledge of strategies families used for managing BPSD in the past. However, resident information is not routinely shared with all staff and written documentation systems for communicating resident-specific information do not support the time pressured work pattern of certified nursing assistants (CNAs). Word-of-mouth was considered more reliable and expedient than educational sessions. CNAs described themselves as visual learners who prefer educational programs addressing individual resident emergent behaviors and programs that are scheduled at dedicated times. IMPLICATIONS: To improve PCC the flow of information exchange requires: inclusion of all staff, particularly CNAs; systems of communication that consider the time and resource constraints of nursing homes; development of educational programs for BPSD that are responsive to staff learning styles; administrative investment in nursing leadership to effect these changes; and reimbursement approaches to encourage culture change investments. PMID- 26055782 TI - Caregiver Person-Centeredness and Behavioral Symptoms in Nursing Home Residents With Dementia: A Timed-Event Sequential Analysis. AB - PURPOSE: Evidence suggests that person-centered caregiving approaches may reduce dementia-related behavioral symptoms; however, little is known about the sequential and temporal associations between specific caregiver actions and behavioral symptoms. The aim of this study was to identify sequential associations between caregiver person-centered actions, task-centered actions, and resident behavioral symptoms and the temporal variation within these associations. DESIGN AND METHODS: Videorecorded observations of naturally occurring interactions (N = 33; 724min) between 12 nursing home (NH) residents with dementia and eight certified nursing assistants were coded for caregiver person-centered actions, task-centered actions, and resident behavioral symptoms and analyzed using timed-event sequential analysis. RESULTS: Although caregiver actions were predominantly person-centered, we found that resident behavioral symptoms were significantly more likely to occur following task-centered caregiver actions than person-centered actions. IMPLICATIONS: Findings suggest that the person-centeredness of caregivers is sequentially and temporally related to behavioral symptoms in individuals with dementia. Additional research examining the temporal structure of these relationships may offer valuable insights into the utility of caregiver person-centeredness as a low-cost strategy for improving behavioral symptom management in the NH setting. PMID- 26055783 TI - The Interplay of Genetics, Behavior, and Pain with Depressive Symptoms in the Elderly. AB - PURPOSE OF STUDY: About 25% of older adults suffer from depressive symptoms. Commonly studied candidate genes associated with depression include those that influence serotonin (SLC6A4), dopamine (COMT), or neuroplasticity (BDNF, NTRK3). However, the majority of candidate gene studies do not consider the interplay of genetics, demographic, clinical, and behavioral factors and how they jointly contribute to depressive symptoms among older adults. The purpose of this study was to gain a more comprehensive understanding of depressive symptoms among older adults. DESIGN AND METHODS: In this descriptive study, demographic, behavioral, and clinical characteristics (age, gender, comorbidities, volunteering, physical activity, pain, and fear of falling) were obtained via interview of 114 residents in a continuing care retirement community. Peripheral whole blood was collected for DNA extraction. We examined common single nucleotide polymorphisms (SNPs) in the aforementioned genes using path analyses. RESULTS: SNPs in the NTRK3 gene, pain, physical activity, and fear of falling were directly associated with depressive symptoms in older adults. Those who had polymorphisms in the NTRK3 gene, pain, fear of falling, and were less physically active were more likely to exhibit depressive symptoms. None of the SNPs in SLC6A4, COMT, or BDNF genes were significantly associated with depressive symptoms. IMPLICATIONS: Our use of a path analysis to examine a biopsychosocial model of depressive symptoms provided the opportunity to describe a comprehensive clinical picture of older adults at risk for depressive symptoms. Thus, interventions could be implemented to identify older adults at risk for depressive symptoms. PMID- 26055784 TI - Automated In-Home Fall Risk Assessment and Detection Sensor System for Elders. AB - PURPOSE OF THE STUDY: Falls are a major problem for the elderly people leading to injury, disability, and even death. An unobtrusive, in-home sensor system that continuously monitors older adults for fall risk and detects falls could revolutionize fall prevention and care. DESIGN AND METHODS: A fall risk and detection system was developed and installed in the apartments of 19 older adults at a senior living facility. The system includes pulse-Doppler radar, a Microsoft Kinect, and 2 web cameras. To collect data for comparison with sensor data and for algorithm development, stunt actors performed falls in participants' apartments each month for 2 years and participants completed fall risk assessments (FRAs) using clinically valid, standardized instruments. The FRAs were scored by clinicians and recorded by the sensing modalities. Participants' gait parameters were measured as they walked on a GAITRite mat. These data were used as ground truth, objective data to use in algorithm development and to compare with radar and Kinect generated variables. RESULTS: All FRAs are highly correlated (p < .01) with the Kinect gait velocity and Kinect stride length. Radar velocity is correlated (p < .05) to all the FRAs and highly correlated (p < .01) to most. Real-time alerts of actual falls are being sent to clinicians providing faster responses to urgent situations. IMPLICATIONS: The in-home FRA and detection system has the potential to help older adults remain independent, maintain functional ability, and live at home longer. PMID- 26055785 TI - Restorative Care's Effect on Activities of Daily Living Dependency in Long-stay Nursing Home Residents. AB - PURPOSE OF THE STUDY: (a) Identify the prevalence of nursing homes providing Medicare supported restorative care programs and of long stay participants, (b) compare characteristics between restorative care participants and nonparticipants, and (c) assess restorative care's effect on change in activities of daily living (ADL) dependency. DESIGN AND METHODS: Longitudinal analysis of Minimum Data Set assessments linked to the 2004 National Nursing Home Survey using a sample of 7,735 residents, age >= 65 years living in 1,097 nursing homes for at least 6 months. Receipt of any restorative care was used as a time varying predictor to estimate change in ADL dependency over 18 months using linear mixed models. RESULTS: The sample was 75% female, 89% non-Hispanic White, with a mean age of 85+/-8, and average length of stay of 3.2+/-3.4 years. Most nursing homes had restorative care programs (67%), but less than one-third of long-stay residents participated. After controlling for resident and nursing home characteristics, the predicted mean ADL dependency score (range 0-28) at baseline was 18 for restorative care participants and 14 for nonparticipants. Over 18 months, ADL dependency increased 1 point for both participants and nonparticipants (p = .12). IMPLICATIONS: A minority of long-stay residents participated in Medicare supported restorative care programs despite their availability and potential benefits. Even though participants had greater vulnerability for deterioration in physical, mental, and functional health than nonparticipants, both groups had similar rates of ADL decline. Future research is needed to determine if providing restorative care to less dependent long-stay residents is effective. PMID- 26055786 TI - Putting Residents First: Strategies Developed by CNAs to Prevent and Manage Resident-to-Resident Violence in Nursing Homes. AB - PURPOSE OF THE STUDY: Resident-to-resident violence (RRV) in nursing homes (NHs) is common and threatens the safety and quality of life of both residents and caregivers. The purpose of this portion of a larger qualitative study was to explore strategies developed by certified nurses' assistants (CNAs) to prevent and manage RRV in NHs. DESIGN AND METHODS: Semistructured interviews were used to collect data. Data were analyzed utilizing content analysis and constant comparison. RESULTS: Analysis revealed one overriding theme, "Putting Residents First" which the CNAs described as a conscious effort to put themselves or a beloved family member in the place of the resident while administering care. Within this theme, there were three related subthemes: (a) Knowing the Residents, (b) Keeping Residents Safe, and (c) Spending Quality Time. IMPLICATIONS: Together, these themes suggest that the formulation of strategies for decreasing and managing RRV was influenced significantly by the ability of the CNAs to empathize with the residents for whom they were caring. The results indicate that in the absence of evidence-based interventions, CNAs have developed their own strategies for the management and prevention of RRV. These strategies may provide a foundation for the development and testing of interventions aimed at preventing and managing RRV in NHs. PMID- 26055787 TI - Reading skills, creativity, and insight: exploring the connections. AB - Studies of the relationship between creativity and specific reading disabilities have produced inconclusive results. We explored their relationship in a sample of 259 college students (age range: 17 to 38 years-old) from three Chilean universities. The students were tested on their verbal ability, creativity, and insight. A simple linear regression was performed on the complete sample, and on high- and low-achievement groups that were formed based on reading test scores. We observed a significant correlation in the total sample between outcomes on the verbal ability tasks, and on the creativity and insight tasks (range r =. 152 to r =. 356, ps <.001). Scores on the reading comprehension and phonological awareness tasks were the best predictors of performance on creativity and insight tasks (range beta = .315 to beta = .155, ps <.05). A comparison of the low- and high-scoring groups on verbal ability tasks yielded results to the same effect. These findings do not support the hypothesis that specific reading disability is associated with better performance on creative tasks. Instead, higher verbal ability was found to be associated with higher creativity and insight. PMID- 26055788 TI - Attenuation of the unfolded protein response and endoplasmic reticulum stress after mechanical unloading in dilated cardiomyopathy. AB - Abnormal intracellular calcium (Ca(2+)) handling can trigger endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR) in an attempt to prevent cell death. Mechanical unloading with a left ventricular assist device (LVAD) relieves pressure-volume overload and promotes reverse remodeling of the failing myocardium. We hypothesized that mechanical unloading would alter the UPR in patients with advanced heart failure (HF). UPR was analyzed in paired myocardial tissue from 10 patients with dilated cardiomyopathy obtained during LVAD implantation and explantation. Samples from healthy hearts served as controls. Markers of UPR [binding immunoglobulin protein (BiP), phosphorylated (P-) eukaryotic initiation factor (eIF2alpha), and X-box binding protein (XBP1)] were significantly increased in HF, whereas LVAD support significantly decreased BiP, P-eIF2alpha, and XBP1s levels. Apoptosis as reflected by C/EBP homologous protein and DNA damage were also significantly reduced after LVAD support. Improvement in left ventricular dimensions positively correlated with P-eIF2alpha/eIF2alpha and apoptosis level recovery. Furthermore, significant dysregulation of calcium-handling proteins [P-ryanodine receptor, Ca(2+) storing protein calsequestrin, Na(+)-Ca(2+) exchanger, sarcoendoplasmic reticulum Ca(2+)-ATPase (SERCA2a), ER chaperone protein calreticulin] was normalized after LVAD support. Reduced ER Ca(2+) content as a causative mechanism for UPR was confirmed using AC16 cells treated with a calcium ionophore (A23187) and SERCA2a inhibitor (thapsigargin). UPR activation and apoptosis are reduced after mechanical unloading, which may be mediated by the improvement of Ca(2+) handling in patients with advanced HF. These changes may impact the potential for myocardial recovery. PMID- 26055789 TI - Chronic endurance exercise affects paracrine action of CD31+ and CD34+ cells on endothelial tube formation. AB - We aimed to determine if chronic endurance-exercise habits affected redox status and paracrine function of CD34(+) and CD34(-)/CD31(+) circulating angiogenic cells (CACs). Subjects were healthy, nonsmoking men and women aged 18-35 yr and categorized by chronic physical activity habits. Blood was drawn from each subject for isolation and culture of CD34(+) and CD34(-)/CD31(+) CACs. No differences in redox status were found in any group across either cell type. Conditioned media (CM) was generated from the cultured CACs and used in an in vitro human umbilical vein endothelial cell-based tube assay. CM from CD34(+) cells from inactive individuals resulted in tube structures that were 29% shorter in length (P < 0.05) and 45% less complex (P < 0.05) than the endurance-trained group. CD34(-)/CD31(+) CM from inactive subjects resulted in tube structures that were 26% shorter in length (P < 0.05) and 42% less complex (P < 0.05) than endurance-trained individuals. Proteomics analyses identified S100A8 and S100A9 in the CM. S100A9 levels were 103% higher (P < 0.05) and S100A8 was 97% higher in the CD34(-)/CD31(+) CM of inactive subjects compared with their endurance-trained counterparts with no significant differences in either protein in the CM of CD34(+) CACs as a function of training status. Recombinant S100A8/A9 treatment at concentrations detected in inactive subjects' CD34(-)/CD31(+) CAC CM also reduced tube formation (P < 0.05). These findings are the first, to our knowledge, to demonstrate a differential paracrine role in CD34(+) and CD34(-)/CD31(+) CACs on tube formation as a function of chronic physical activity habits and identifies a differential secretion of S100A9 by CD34(-)/CD31(+) CACs due to habitual exercise. PMID- 26055790 TI - Pirfenidone exhibits cardioprotective effects by regulating myocardial fibrosis and vascular permeability in pressure-overloaded hearts. AB - Although cardiac fibrosis causes heart failure, its molecular mechanisms remain elusive. In this study, we investigated the mechanisms of cardiac fibrosis and examined the effects of the antifibrotic drug pirfenidone (PFD) on chronic heart failure. To understand the responsible mechanisms, we generated an in vivo pressure-overloaded heart failure model via transverse aortic constriction (TAC) and examined the effects of PFD on chronic-phase cardiac fibrosis and function. In the vehicle group, contractile dysfunction and left ventricle fibrosis progressed further from 4 to 8 wk after TAC but were prevented by PFD treatment beginning 4 wk after TAC. We isolated cardiac fibroblasts and vascular endothelial cells from the left ventricles of adult male mice and investigated the cell-type-specific effects of PFD. Transforming growth factor-beta induced upregulated collagen 1 expression via p38 phosphorylation and downregulated claudin 5 (Cldn5) expression in cardiac fibroblasts and endothelial cells, respectively; both processes were inhibited by PFD. Moreover, PFD inhibited changes in the collagen 1 and Cldn5 expression levels, resulting in reduced fibrosis and serum albumin leakage into the interstitial space during the chronic phase in TAC hearts. In conclusion, PFD inhibited cardiac fibrosis by suppressing both collagen expression and the increased vascular permeability induced by pressure overload. PMID- 26055791 TI - Preservation of cardiac function by prolonged action potentials in mice deficient of KChIP2. AB - Inherited ion channelopathies and electrical remodeling in heart disease alter the cardiac action potential with important consequences for excitation contraction coupling. Potassium channel-interacting protein 2 (KChIP2) is reduced in heart failure and interacts under physiological conditions with both Kv4 to conduct the fast-recovering transient outward K(+) current (Ito,f) and with CaV1.2 to mediate the inward L-type Ca(2+) current (ICa,L). Anesthetized KChIP2( /-) mice have normal cardiac contraction despite the lower ICa,L, and we hypothesized that the delayed repolarization could contribute to the preservation of contractile function. Detailed analysis of current kinetics shows that only ICa,L density is reduced, and immunoblots demonstrate unaltered CaV1.2 and CaVbeta2 protein levels. Computer modeling suggests that delayed repolarization would prolong the period of Ca(2+) entry into the cell, thereby augmenting Ca(2+) induced Ca(2+) release. Ca(2+) transients in disaggregated KChIP2(-/-) cardiomyocytes are indeed comparable to wild-type transients, corroborating the preserved contractile function and suggesting that the compensatory mechanism lies in the Ca(2+)-induced Ca(2+) release event. We next functionally probed dyad structure, ryanodine receptor Ca(2+) sensitivity, and sarcoplasmic reticulum Ca(2+) load and found that increased temporal synchronicity of the Ca(2+) release in KChIP2(-/-) cardiomyocytes may reflect improved dyad structure aiding the compensatory mechanisms in preserving cardiac contractile force. Thus the bimodal effect of KChIP2 on Ito,f and ICa,L constitutes an important regulatory effect of KChIP2 on cardiac contractility, and we conclude that delayed repolarization and improved dyad structure function together to preserve cardiac contraction in KChIP2(-/-) mice. PMID- 26055793 TI - Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure. AB - Cardiac mitochondrial dysfunction has been implicated in heart failure of diverse etiologies. Generalized mitochondrial disease also leads to cardiomyopathy with various clinical manifestations. Impaired mitochondrial homeostasis may over time, such as in the aging heart, lead to cardiac dysfunction. Mitochondrial DNA (mtDNA), close to the electron transport chain and unprotected by histones, may be a primary pathogenetic site, but this is not known. Here, we test the hypothesis that cumulative damage of cardiomyocyte mtDNA leads to cardiomyopathy and heart failure. Transgenic mice with Tet-on inducible, cardiomyocyte-specific expression of a mutant uracil-DNA glycosylase 1 (mutUNG1) were generated. The mutUNG1 is known to remove thymine in addition to uracil from the mitochondrial genome, generating apyrimidinic sites, which obstruct mtDNA function. Following induction of mutUNG1 in cardiac myocytes by administering doxycycline, the mice developed hypertrophic cardiomyopathy, leading to congestive heart failure and premature death after ~2 mo. The heart showed reduced mtDNA replication, severely diminished mtDNA transcription, and suppressed mitochondrial respiration with increased Pgc-1alpha, mitochondrial mass, and antioxidative defense enzymes, and finally failing mitochondrial fission/fusion dynamics and deteriorating myocardial contractility as the mechanism of heart failure. The approach provides a model with induced cardiac-restricted mtDNA damage for investigation of mtDNA based heart disease. PMID- 26055792 TI - A database of virtual healthy subjects to assess the accuracy of foot-to-foot pulse wave velocities for estimation of aortic stiffness. AB - While central (carotid-femoral) foot-to-foot pulse wave velocity (PWV) is considered to be the gold standard for the estimation of aortic arterial stiffness, peripheral foot-to-foot PWV (brachial-ankle, femoral-ankle, and carotid-radial) are being studied as substitutes of this central measurement. We present a novel methodology to assess theoretically these computed indexes and the hemodynamics mechanisms relating them. We created a database of 3,325 virtual healthy adult subjects using a validated one-dimensional model of the arterial hemodynamics, with cardiac and arterial parameters varied within physiological healthy ranges. For each virtual subject, foot-to-foot PWV was computed from numerical pressure waveforms at the same locations where clinical measurements are commonly taken. Our numerical results confirm clinical observations: 1) carotid-femoral PWV is a good indicator of aortic stiffness and correlates well with aortic PWV; 2) brachial-ankle PWV overestimates aortic PWV and is related to the stiffness and geometry of both elastic and muscular arteries; and 3) muscular PWV (carotid-radial, femoral-ankle) does not capture the stiffening of the aorta and should therefore not be used as a surrogate for aortic stiffness. In addition, our analysis highlights that the foot-to-foot PWV algorithm is sensitive to the presence of reflected waves in late diastole, which introduce errors in the PWV estimates. In this study, we have created a database of virtual healthy subjects, which can be used to assess theoretically the efficiency of physiological indexes based on pulse wave analysis. PMID- 26055794 TI - Inhibition of cyclooxygenase attenuates the blood pressure response to plantar flexion exercise in peripheral arterial disease. AB - Prostanoids are produced during skeletal muscle contraction and subsequently stimulate muscle afferent nerves, thereby contributing to the exercise pressor reflex. Humans with peripheral arterial disease (PAD) have an augmented exercise pressor reflex, but the metabolite(s) responsible for this augmented response is not known. We tested the hypothesis that intravenous injection of ketorolac, which blocks the activity of cyclooxygenase, would attenuate the rise in mean arterial blood pressure (MAP) and heart rate (HR) evoked by plantar flexion exercise. Seven PAD patients underwent 4 min of single-leg dynamic plantar flexion (30 contractions/min) in the supine posture (workload: 0.5-2.0 kg). MAP and HR were measured on a beat-by-beat basis; changes from baseline in response to exercise were determined. Ketorolac did not affect MAP or HR at rest. During the first 20 s of exercise with the most symptomatic leg, DeltaMAP was significantly attenuated by ketorolac (2 +/- 2 mmHg) compared with control (8 +/- 2 mmHg, P = 0.005), but DeltaHR was similar (6 +/- 2 vs. 5 +/- 1 beats/min). Importantly, patients rated the exercise bout as "very light" to "fairly light," and average pain ratings were 1 of 10. Ketorolac had no effect on perceived exertion or pain ratings. Ketorolac also had no effect on MAP or HR in seven age- and sex-matched healthy subjects who performed a similar but longer plantar flexion protocol (workload: 0.5-7.0 kg). These data suggest that prostanoids contribute to the augmented exercise pressor reflex in patients with PAD. PMID- 26055795 TI - Cardiac-specific ablation of the STAT3 gene in the subacute phase of myocardial infarction exacerbated cardiac remodeling. AB - STAT3 is a cardioprotective molecule against acute myocardial injury; however, recent studies have suggested that chronic STAT3 activation in genetically modified mice was detrimental after myocardial infarction (MI). In the present study, we assessed the biological significance of STAT3 activity in subacute MI using tamoxifen (TM)-inducible cardiac-specific STAT3 knockout (STAT3 iCKO) mice. After coronary ligation, STAT3 was rapidly activated in hearts, and its activation was sustained to the subacute phase. To make clear the pathophysiological roles of STAT3 activation specifically in subacute MI, MI was generated in STAT3 iCKO mice followed by TM treatment for 14 consecutive days beginning from day 11 after MI, which ablated the STAT3 gene in the subacute phase. Intriguingly, mortality was increased by TM treatment in STAT3 iCKO mice, accompanied by an increased heart weight-to-body weight ratio. Masson's trichrome staining demonstrated that cardiac fibrosis was dramatically exacerbated in STAT3 iCKO mice 24 days after MI (fibrotic circumference: 58.3 +/- 6.7% in iCKO mice and 40.8 +/- 9.3% in control mice), concomitant with increased expressions of fibrosis-related gene transcripts, including matrix metalloproteinase 9, procollagen 1, and procollagen 3. Echocardiography clarified that cardiac function was deteriorated in STAT3 iCKO mice (fractional shortening: 20.6 +/- 4.1% in iCKO mice and 29.1 +/- 6.0% in control mice). Dihydroethidium fluorescence analysis revealed that superoxide production was increased in STAT3 iCKO mice. Moreover, immunohistochemical analyses revealed that capillary density was decreased in STAT3 iCKO mice. Finally, STAT3 deletion in subacute MI evoked severe cardiac hypertrophy in the border zone. In conclusion, the intrinsic activity of STAT3 in the myocardium confers the resistance to cardiac remodeling in subacute MI. PMID- 26055797 TI - Epidemiological evidence that indoor air pollution from cooking with solid fuels accelerates skin aging in Chinese women. AB - BACKGROUND: Recently, we showed that outdoor air pollution exposure from traffic and industry is associated with an increased risk of skin aging in Caucasian women. In China, indoor air pollution exposure caused by the use of solid fuels like coal is a major health problem and might also increase the risk of skin aging in Chinese women. OBJECTIVE: As cooking with solid fuels is a major source of indoor air pollution exposure in China, we aimed to test if cooking with solid fuels is associated with more pronounced skin aging in Chinese women. METHODS: We conducted two cross-sectional studies in China to assess the association between cooking with solid fuels and signs of skin aging. In Pingding (in northern China) we assessed N=405 and in Taizhou (in southern China) N=857 women between 30 and 90 years of age. Skin aging was evaluated by the SCINEXA score. Indoor air pollution exposure, sun exposure, smoking and other confounders were assessed by questionnaires. Associations were then tested by linear and logistic regression analyses adjusted for further confounders. RESULTS: The analysis showed that cooking with solid fuels was significantly associated with a 5-8% more severe wrinkle appearance on face and an 74% increased risk of having fine wrinkles on back of hands in both studies combined, independent of age and other influences on skin aging. CONCLUSION: The present studies thus corroborate our previous finding that air pollution is associated with skin aging and extend it by showing that indoor air pollution might be another risk factor for skin aging. PMID- 26055796 TI - Analysis of erectile responses to bradykinin in the anesthetized rat. AB - The kallikrein-kinin system is expressed in the corpus cavernosa, and bradykinin (BK) relaxes isolated corpora cavernosal strips. However, erectile responses to BK in the rat have not been investigated in vivo. In the present study, responses to intracorporal (ic) injections of BK were investigated in the anesthetized rat. BK, in doses of 1-100 MUg/kg ic, produced dose-related increases in intracavernosal pressure (ICP) and dose-related deceases in mean arterial pressure (MAP). When decreases in MAP were prevented by intravenous injections of angiotensin II (Ang II), increases in ICP, in response to BK, were enhanced. Increases in ICP, ICP/MAP ratio, and area under the curve and decreases in MAP in response to BK were inhibited by the kinin B2 receptor antagonist HOE-140 and enhanced by the angiotensin-converting enzyme (ACE) inhibitor captopril and by Ang-(1-7). Increases in ICP, in response to BK, were not attenuated by the nitric oxide (NO) synthase inhibitor (N(omega)-nitro-L-arginine methyl ester) or the soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) but were attenuated by the cyclooxygenase inhibitor, sodium meclofenamate. Decreases in MAP were not attenuated by either inhibitor. These data suggest that erectile responses are mediated by kinin B2 receptors and modulated by decreases in MAP. These data indicate that ACE is important in the inactivation of BK and that erectile and hypotensive responses are independent of NO in the penis or the systemic vascular bed. Erectile responses to cavernosal nerve stimulation are not altered by BK or HOE-140, suggesting that BK and B2 receptors do not modulate nerve-mediated erectile responses under physiologic conditions. These data suggest that erectile responses to BK are mediated, in part, by the release of cyclooxygenase products. PMID- 26055798 TI - Leukocyte-derived koebnerisin (S100A15) and psoriasin (S100A7) are systemic mediators of inflammation in psoriasis. AB - BACKGROUND: Psoriasis is a systemic immune-mediated chronic inflammatory disease. In the skin, the antimicrobial proteins koebnerisin (S100A15) and psoriasin (S100A7) are overexpressed in the epidermis of psoriatic lesions and mediate inflammation as chemoattractants for immune cells. Their role for systemic inflammation in circulating leukocytes is unknown. OBJECTIVE: The aim of the study was to identify circulating leukocyte populations as a source of koebnerisin and psoriasin. Further, immune-stimulatory effects of these S100A proteins on circulating leukocytes were evaluated and their role as therapeutic response markers in patients with psoriasis was analyzed upon UVB treatment. METHODS: The expression and production of koebnerisin and psoriasin by leukocytes were assessed by quantitative real-time PCR (qRT-PCR) and immunoblotting. The S100A protein mediated regulation of proinflammatory cytokines by peripheral blood mononuclear cells (PBMCs) was measured with qRT-PCR and cytometric bead assay. RESULTS: We identified circulating leukocytes as novel sources of koebnerisin (S100A15) and psoriasin (S100A7). Circulating leukocytes (PBMCs) of patients with psoriasis produced increased levels of koebnerisin and psoriasin compared to healthy individuals. Both S100A proteins further acted as 'alarmins' on PBMC to induce proinflammatory cytokines implicated in the pathogenesis of psoriasis, such as IL-1beta, TNF-alpha, IL-6 and IL-8. Koebnerisin levels were suppressed in PBMC of psoriatic patients when effectively treated with narrow band UVB. CONCLUSIONS: Data suggest that koebnerisin and psoriasin are systemic pro-inflammatory mediators and koebnerisin acts as a therapeutic response marker in psoriasis. PMID- 26055799 TI - Simultaneous kissing stent technique with stent grafts for subclavian artery aneurysm: a case report. AB - Treatment of subclavian artery aneurysm is typically performed as an open procedure. In recent years, the use of an endovascular approach has been reported. We experienced a case of subclavian artery aneurysm treated by simultaneous kissing stent technique. With fewer complications, this is a promising technique. PMID- 26055800 TI - Understanding liver immunology using intravital microscopy. AB - The liver has come a long way since it was considered only a metabolic organ attached to the gastrointestinal tract. The simultaneous ascension of immunology and intravital microscopy evidenced the liver as a central axis in the immune system, controlling immune responses to local and systemic agents as well as disease tolerance. The multiple hepatic cell populations are organized in a vascular environment that promotes intimate cellular interactions, including initiation of innate and adaptive immune responses, rapid leukocyte recruitment, pathogen clearance and production of a variety of immune mediators. In this review, we focus on the advances in liver immunology supported by intravital microscopy in diseases such as isquemia/reperfusion, acute liver injury and infections. PMID- 26055801 TI - Is skin mottling a predictor of high mortality in non-selected patients with cirrhosis admitted to intensive care unit? PMID- 26055802 TI - John Wooley and JBCB. PMID- 26055803 TI - Resolving the multiple sequence alignment problem using biogeography-based optimization with multiple populations. AB - The multiple sequence alignment (MSA) is one of the most challenging problems in bioinformatics, it involves discovering similarity between a set of protein or DNA sequences. This paper introduces a new method for the MSA problem called biogeography-based optimization with multiple populations (BBOMP). It is based on a recent metaheuristic inspired from the mathematics of biogeography named biogeography-based optimization (BBO). To improve the exploration ability of BBO, we have introduced a new concept allowing better exploration of the search space. It consists of manipulating multiple populations having each one its own parameters. These parameters are used to build up progressive alignments allowing more diversity. At each iteration, the best found solution is injected in each population. Moreover, to improve solution quality, six operators are defined. These operators are selected with a dynamic probability which changes according to the operators efficiency. In order to test proposed approach performance, we have considered a set of datasets from Balibase 2.0 and compared it with many recent algorithms such as GAPAM, MSA-GA, QEAMSA and RBT-GA. The results show that the proposed approach achieves better average score than the previously cited methods. PMID- 26055804 TI - Beneficial effect of levodopa therapy on stooped posture in Parkinson's disease. AB - OBJECTIVE: This study was designated to quantitatively evaluate the effect of levodopa on spinal posture in patients with PD using a computer-assisted handheld SpinalMouse device. METHODS: Prospective case-study involving 48 patients with definite PD. All patients were recruited between September 2011 and September 2013 and included 22 dopa-naive, evaluated before and 3 months after initiation of treatment, and 26 patients with response fluctuations studied during the "off" and "on" states. The SpinalMouse instrument, a computer-assisted mechanical hand held device, designed to noninvasively assess the curvature of the spine was guided along the midline of the vertebral column in upright, full flexion, and full extension positions to objectively assess spinal posture. RESULTS: In the dopa-naive patients, spinal incline in the upright position was 12.4+/-1.2 degrees before and 7.6+/-1.3 degrees after treatment; p=0.002. Corresponding area-under-the-curve (AUC) values were 131.7+/-8.0 cm(2) and 87.1+/-7.3 cm(2); p<0.0001. In the response fluctuations patients, spinal incline was 13.3+/-1.3 degrees in the "off" and 9.3+/-1.2 degrees in the "on" period; p=0.015. Corresponding AUC values were 144.6+/-9.2 cm(2) and 103.1+/-8.2 cm(2); p<0.0001. CONCLUSIONS: This is the first study that objectively measured and quantified abnormalities of spinal posture in patients with PD. Findings suggest that levodopa does have a beneficial effect on anterior flexion of the thoracolumbar spine, and thus indicate that the disorder of stooped posture in PD is mediated, at least in part, by dopamine deficiency. PMID- 26055807 TI - Developmental stages of the climbing gecko Tarentola annularis with special reference to the claws, pad lamellae, and subdigital setae. AB - Studying the in ovo mode of development of squamates has the advantage of allowing easy access to embryos without surgically compromising gravid females. Despite the non-ophidian squamates being a very diverse lineage of reptiles, embryonic tables for individuals of this group are very few. Here, I present the first in ovo embryonic table for a basal multi-scansored, pad-bearing gecko, Tarentola annularis. In this gecko, only the III and IV digits bear claws. Eleven embryonic stages are described based on chronological development of morphological characteristics. In contrast to other previously studied geckos, this species exhibits a longer incubation period. Comparison with other squamates, embryonic development of T. annularis is an indicative of a conserved developmental strategy. Interestingly, the clawless digits of this gecko do exhibit claws during the first half of embryonic development. Thus, regression of claws in these digits could be an advantage of studying this particular taxon, as it raises the question, to be answered in future study, of which mechanisms could be responsible for such claw regression. Before hatching, the outer periderm layer sloughs revealing the functional setae. The present study provides not only a model for pentadactyl limbs and digit development, but also an example of a unique developmental phenomenon, as represented by claw regression. PMID- 26055805 TI - Reverse chemomodulatory effects of the SIRT1 activators resveratrol and SRT1720 in Ewing's sarcoma cells: resveratrol suppresses and SRT1720 enhances etoposide- and vincristine-induced anticancer activity. AB - PURPOSE: SIRT1-activating compounds (STACs) may have potential in the management of cancer. However, the best-studied STAC, the naturally occurring compound resveratrol, is reported to have contradictory effects in combination chemotherapy regimens: It has been shown both to increase and to decrease the action of anticancer agents. To shed more light on this issue, we comparatively investigated the impact of resveratrol and the synthetic STAC SRT1720 on the responsiveness of Ewing's sarcoma (ES) cells to the chemotherapeutic drugs etoposide and vincristine. METHODS: Because the effects of STACs can depend on the functionality of the tumor suppressor protein p53, we used three ES cell lines differing in their p53 status, i.e., wild-type p53 WE-68 cells, mutant p53 SK-ES-1 cells and p53 null SK-N-MC cells. Single agent and combination therapy effects were assessed by flow cytometric analyses of propidium iodide uptake and mitochondrial depolarization, by measuring caspase 3/7 activity and by gene expression profiling. RESULTS: When applied as single agents, both STACs were effective in ES cells irrespective of their p53 status. Strikingly, however, when applied in conjunction with cytostatic agents, the STACs displayed reverse effects: SRT1720 largely enhanced etoposide- and vincristine-induced cell death, while resveratrol inhibited it. Combination index analyses validated the antipodal impact of the STACs on the effectiveness of the chemotherapeutics. CONCLUSION: These findings suggest that the synthetic STAC SRT1720 may be useful to enhance the efficacy of anticancer therapy in ES. But they also suggest that the dietary intake of the natural STAC resveratrol may be detrimental during chemotherapy of ES. PMID- 26055806 TI - Overexpression of microRNA-155 increases IL-21 mediated STAT3 signaling and IL-21 production in systemic lupus erythematosus. AB - INTRODUCTION: Interleukin (IL)-21 is a key cytokine in autoimmune diseases such as systemic lupus erythematosus (SLE) by its regulation of autoantibody production and inflammatory responses. The objective of this study is to investigate the signaling capacity of IL-21 in T and B cells and assess its possible regulation by microRNA (miR)-155 and its target gene suppressor of cytokine signaling 1 (SOCS1) in SLE. METHODS: The signaling capacity of IL-21 was quantified by stimulating peripheral blood mononuclear cells (PBMCs) with IL-21 and measuring phosphorylation of STAT3 (pSTAT3) in CD4+ T cells, B cells, and natural killer cells. Induction of miR-155 by IL-21 was investigated by stimulating purified CD4+ T cells with IL-21 and measuring miR-155 expression levels. The functional role of miR-155 was assessed by overexpressing miR-155 in PBMCs from SLE patients and healthy controls (HCs) and measuring its effects on STAT3 and IL-21 production in CD4+ and CD8+ T cells. RESULTS: Induction of pSTAT3 in CD4+ T cells in response to IL-21 was significantly decreased in SLE patients compared to HCs (p < 0.0001). Further, expression levels of miR-155 were significantly decreased and SOCS1 correspondingly increased in CD4+ T cells from SLE patients. Finally, overexpression of miR-155 in CD4+ T cells increased STAT3 phosphorylation in response to IL-21 treatment (p < 0.01) and differentially increased IL-21 production in SLE patients compared to HCs (p < 0.01). CONCLUSION: We demonstrate that SLE patients have reduced IL-21 signaling capacity, decreased miR-155 levels, and increased SOCS1 levels compared to HCs. The reduced IL-21 signaling in SLE could be rescued by overexpression of miR-155, suggesting an important role for miR-155 in the reduced IL-21 signaling observed in SLE. PMID- 26055808 TI - Therapeutic effects of human urocortin-1, -2 and -3 in intracerebral hemorrhage of rats. AB - Urocortin exerts neuroprotective effects in intracerebral hemorrhage (ICH) of rats. For pre-clinical trial, we intended to study the neuroprotective efficacy of human UCN (hUCN)-1, -2 and -3 in treating ICH rats. ICH was induced by infusing bacterial collagenase VII (0.23 U in sterile saline) to the striatum. The hUCN-1, -2, and -3 were administrated (2.5MUg/kg, i.p.) at 1h after ICH insult, respectively. Neurological deficits were evaluated by modified Neurological Severity Scores. Brain edema and hematoma expansion was evaluated by coronal T2-WI and DWI magnetic resonance imaging on 1, 3, 6, 24, and 56h after ICH insult. Blood-brain barrier permeability was evaluated by Evans blue assay on day 3 after ICH. Brain lesion volume was evaluated by morphormetric measurement on day 7 after ICH. Our results demonstrated that the hUCN-1 significantly reduced hematoma, blood-brain barrier disruption and neurological deficits on day 3, and brain lesion volume on day 7 after ICH insult. The prediction of secondary structure of the hUCNs clarifies that the percentage of alpha-helix, random coil and extended strand between rat-UCN (rUCN)-1 and hUCN-1 are the same. The structure similarity between human- and rat-UCN-1 may be one of the reasons that both can exert similar therapeutic potential in ICH rats. PMID- 26055809 TI - How is time perspective related to perceptions of self and of interpersonal relationships? AB - Previous research has revealed a positive association between balanced time perspective (BTP) and subjective well-being (Boniwell & Zimbardo, 2004), however mechanisms underlying BTP are yet to be determined. The goal of the present study was to examine the contributions of personality and quality of interpersonal relationships in the development of BTP. Additionally, the correlations between these measures and time perspective dimensions were evaluated as an attempt to provide further psychometric properties of the Zimbardo Time Perspective Inventory (ZTPI) in a Turkish sample. 178 undergraduates filled out a survey that included the ZTPI and measures that assessed personality characteristics, and quality of parent, peer, and adult relationships. Results showed that deviation from BTP was positively associated with romantic anxiety (r = .41, p < .001), romantic avoidance (r = .33, p < .001), and neuroticism (r = .49, p < .001) but negatively associated with self-esteem (r = -.50, p < .001) and security of the mother (r = -.38, p < .001), father (r = -.37, p < .001) and peer (r = -.27, p < .001) attachment. When personality and attachment measures were employed in a regression analysis, father attachment, romantic anxiety, self-esteem, and neuroticism were found to be significant predictors of the deviation from BTP scores (adjusted R 2 = .39, f 2 = .75). Finally, the inter-correlations of the ZTPI dimensions and their correlations with the personality and attachment measures provided additional support for the validity and reliability of the Turkish version of the ZTPI. These findings imply that positive perceptions of self and of interpersonal relationships are crucial in the development of BTP. PMID- 26055810 TI - New and efficient approach for synthesis of novel bioactive [1,3,4]thiadiazoles incorporated with 1,3-thiazole moiety. AB - A series of novel 1,3,4-thiadiazoles incorporated with thiazole moiety was synthesized by reaction of 5-acetyl-2-benzoylimino-3-phenyl-1,3,4-thiadiazole thiosemicarbazone 2 with each of N-phenyl 2-oxo-propanehydrazonoyl chloride 3 and ethyl (N-aryl-hydrazono) chloroacetate 5 in dioxane in basic medium. Also, another series of 1,3,4-thiadiazole incorporated with thiazole moiety was prepared by reaction of 5-acetyl-2-benzoylimino-3-phenyl-1,3,4-thiadiazole thiocarbohydrazone with each of hydrazonoyl chlorides 3, 5 and 18 under the same reaction conditions. The mechanisms of the studied reactions were discussed and the assigned structure for each of the new products was identified via elemental and spectral data and by alternative method whenever possible. Moreover, the antimicrobial activity for some selected products was screened, and the results obtained exploring the high potency of some of the tested compounds compared with the employed standard bactericides and fungicide. PMID- 26055811 TI - Osteogenesis imperfecta: pathophysiology and treatment. AB - Osteogenesis imperfecta is a rare hereditary disease mostly caused by mutations impairing collagen synthesis and modification. Recently recessive forms have been described influencing differentiation and activity of osteoblasts and osteoclasts. Most prominent signs are fractures due to low traumata and deformities of long bones and vertebrae. Additional patients can be affected by dwarfism, scoliosis Dentinogenesis imperfecta, deafness and a blueish discoloration of the sclera. During childhood state of the art medical treatment are i.v. bisphosphonates to increase bone mass and to reduce fracture rate. Surgical interventions are needed to treat fractures, to correct deformities and should always be accompanied by physiotherapeutic and rehabilitative interventions. PMID- 26055812 TI - [Tick-borne encephalitis (TBE) and TBE-vaccination in Austria: Update 2014]. AB - TBE is a public health problem well under control in Austria because of a mass vaccination programme. There have been 50-100 registered cases per year for many years, the vaccination rate of the population is currently 85 %. Special attention has to be given to the "older" generation 40 plus as this is the segment of the population where the majority of cases are observed annually. In comparison of the counties, Tyrol and Upper Austria finished first and second after a long time when Styria and Carynthia had observed most of the cases. For TBE applies the same as for Tetanus, namely the principle of disease control or disease elimination: The virus cannot be eliminated and vaccination provides individual protection. The both available TBE vaccines have proven to be very effective with an effectivity of 96-99 %, also when given irregular vaccinations the protection rate is still very high (>90 %). More than 4000 prevented cases between 2000 and 2011 prove this impressively. PMID- 26055813 TI - Novel reversible selective inhibitor of CRM1 for targeted therapy in ovarian cancer. AB - BACKGROUND: Ovarian cancer represents the most fatal type of gynecological malignancies. Unfortunately, there are still no effective targeted treatment strategies for ovarian cancer. Overexpression of CRM1 has been correlated with poor prognosis of patients with ovarian cancer. AIM: In this study, we investigated the antitumor effects of a novel reversible inhibitor of CRM1 in ovarian cancer cells. METHODS: The effects of S109 on proliferation was detected by CCK-8, EdU, clonogenic assay. The protein expression were determined by Western blot. The subcellular localization of RanBP1 was analyzed by immunofluorescence microscopy assay. RESULTS: We demonstrated that S109 could induce nuclear accumulation of RanBP1, a canonical biomarker for CRM1 inhibition. This effect was clearly reversible in the majority of the cells, whereas the inhibitory effect of LMB could not be reversed. Our data reveal that treatment with S109 results in decrease in proliferation and colonogenic capacity of ovarian cancer cells by arresting cell cycle. Mechanistically, S109 treatment increase the expression of the cyclin-dependent kinase inhibitor p21, while it reduced the expression of cell cycle promoting proteins, Cyclin D1 and Cyclin B. CRM1 level itself was also down-regulated following S109 treatment. Furthermore, the nuclei of cells incubated with S109 accumulated tumor suppressor proteins (Foxo1, p27 and IkappaB-alpha). More importantly, Cys528 mutation of CRM1 abolished the ability of S109 to block proliferation of ovarian cancer cells. CONCLUSIONS: Together, our study identifies CRM1 as a valid target in ovarian cancer and provides a basis for the development of S109 in ovarian cancer. PMID- 26055814 TI - Development of a time-resolved fluoroimmunoassay of CFP-10 for rapid diagnosis of tuberculous pleural effusion. AB - Tuberculous pleural effusion is the second most common form of extrapulmonary tuberculosis, which is very difficult to rapidly distinguish from malignant pleural effusion in the clinical setting. A time-resolved fluoroimmunoassay (TRF) of CFP-10, a low molecular weight protein secreted by pathogenic Mycobacterium tuberculosis, was developed to differentiate tuberculous pleural effusion from malignant one. The measuring range was 0.3-187.5 ng/ml with the dose-response coefficient of 0.9998 and detection limit of 0.036 ng/ml. The intra-assay and inter-assay coefficients of variation were 3.6-9.2% and 10.0-12.4%, respectively. The concentration of CFP-10 in malignant pleural effusion was less than 0.8 ng/ml. The negative predictive value was 93.1% in malignant pleural effusion (n = 247) while the positive predictive value was 83.0% in tuberculous pleural effusion (n = 235). Moreover, there was a statistically significant difference in the CFP-10 concentration of pleural effusion between the groups before and after clinical therapy of tuberculosis (P < 0.001, n = 81). In addition, the stability of the diagnostic reagents lasted at least 1 year at 4 degrees C. Therefore, the TRF of CFP-10 may be used for the rapid diagnosis of tuberculous pleural effusion and further monitoring the clinical therapeutic efficacy of tuberculosis. PMID- 26055815 TI - Evaluation of a domestic interferon-gamma release assay for detecting Mycobacterium tuberculosis infection in China. AB - Interferon-gamma release assays (IGRAs) have been demonstrated to be useful in the diagnosis of Mycobacterium tuberculosis (MTB) infection. However, IGRAs have not been recommended for clinical usage in most low-income countries due to the shortage of clinical data available resulting from their high test cost. Recently, a cheaper domestic TB-IGRA was approved in China. In this study, we compared TB-IGRA with QuantiFERON-TB Gold In-Tube (QFT-GIT) for MTB infection diagnosis in 253 active TB patients, 48 non-TB lung disease patients, 115 healthcare workers and 216 healthy individuals. The proportion of positive TB IGRA results in active TB patients, patients with non-TB lung disease, healthcare workers and healthy individuals was 88.3%, 27.1%, 40.9% and 17.6%, respectively, which was similar to the results of QFT-GIT, with an overall agreement of 95% (kappa = 0.89) and a high correlation between their responses (r = 0.85, p < 0.001) being observed. In conclusion, the TB-IGRA has comparable clinical performance with QFT-GIT. PMID- 26055816 TI - Aqueous synthesis of PEGylated copper sulfide nanoparticles for photoacoustic imaging of tumors. AB - By integrating high imaging sensitivity and high resolution in a single modality, photoacoustic (PA) imaging emerges as a promising diagnostic tool for clinical applications. Benefiting from the absorption in the near-infrared region (NIR), copper sulfide nanoparticles (NPs) as a contrast agent are potentially useful for increasing the sensitivity of PA imaging. However, the aqueous synthesis of size tunable, biocompatible and colloidally stable copper sulfide NPs remains challenging due to the intrinsic dipole-dipole interactions among particles. In this work, aqueous synthesis of PEGylated copper sulfide NPs with controllable size between 3 and 7 nm was developed. The particle size-dependent contrast enhancement effect of the copper sulfide NPs for PA imaging was carefully studied both in vitro and in vivo. Although the contrast enhancement effect of the copper sulfide NPs is proportional to particle size, the in vivo studies revealed that copper sulfide NPs smaller than 5 nm presented higher tumor imaging performance, especially at the tumor boundary site, which was further discussed in combination with the pharmacokinetic behaviors of differently sized particles. PMID- 26055817 TI - International spinal cord injury upper extremity basic data set version 1.1. PMID- 26055818 TI - Impact of psychological characteristics in self-management in individuals with traumatic spinal cord injury. AB - STUDY DESIGN: Cross-sectional survey. OBJECTIVE: To examine the association between psychological characteristics in self-management and probable depression status in individuals with a traumatic spinal cord injury (SCI). SETTING: Community-dwelling individuals with traumatic SCI living across Canada. METHODS: Individuals with SCI were recruited by email via the Rick Hansen Institute as well as an outpatient hospital spinal clinic. Data were collected by self-report using an online survey. Standardized questionnaires were embedded within a larger survey and included the Hospital Anxiety and Depression Scale (HADS), the short version of the Patient Activation Measure (PAM), the Moorong Self-Efficacy Scale (MSES) and the Pearlin-Schooler Mastery Scale (PMS). RESULTS: Individuals with probable depression (n=25) had lower self-efficacy (67.9 vs 94.2, P<0.0001), mastery (18.9 vs 22.9, P<0.0001) and patient activation (60.4 vs 71.6, P<0.0001) as well as higher anxiety (9.0 vs 5.5, P<0.0001), compared with their non depressed counterparts (n=75). A logistic regression determined that lower self efficacy and mastery scores as well as less time since injury were associated with depression status (P=0.002; P=0.02 and P=0.02, respectively). Individuals with higher anxiety scores were almost 1.5 times more likely to be depressed, while older age was positively associated with depression status (P=0.016 and P=0.024, respectively). CONCLUSION: Interventions for depression in SCI, including a self-management program, should target factors such as self-efficacy and mastery, which could improve secondary medical complications and overall quality of life. PMID- 26055819 TI - Src-family-tyrosine kinase Lyn is critical for TLR2-mediated NF-kappaB activation through the PI 3-kinase signaling pathway. AB - TLR2 has a prominent role in host defense against a wide variety of pathogens. Stimulation of TLR2 triggers MyD88-dependent signaling to induce NF-kappaB translocation, and activates a Rac1-PI 3-kinase dependent pathway that leads to transactivation of NF-kappaB through phosphorylation of the P65 NF-kappaB subunit. This transactivation pathway involves tyrosine phosphorylations. The role of the tyrosine kinases in TLR signaling is controversial, with discrepancies between studies using only chemical inhibitors and knockout mice. Here, we show the involvement of the tyrosine-kinase Lyn in TLR2-dependent activation of NF-kappaB in human cellular models, by using complementary inhibition strategies. Stimulation of TLR2 induces the formation of an activation cluster involving TLR2, CD14, PI 3-kinase and Lyn, and leads to the activation of AKT. Lyn-dependent phosphorylation of the p110 catalytic subunit of PI 3-kinase is essential to the control of PI 3-kinase biological activity upstream of AKT and thereby to the transactivation of NF-kappaB. Thus, Lyn kinase activity is crucial in TLR2-mediated activation of the innate immune response in human mononuclear cells. PMID- 26055820 TI - Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis. AB - Pro-inflammatory cytokine release (IL-8, IL-6, TNF-alpha, IL-1beta) by peripheral blood neutrophils, isolated from periodontitis patients (before/after therapy) and matched controls, was determined after 18 h culture in the presence/absence of Escherichia coli LPS, opsonised Staphylococcus aureus, heat-killed Fusobacterium nucleatum and Porphyromonas gingivalis. All cultures demonstrated differences in the amounts of each cytokine detected (P < 0.0001), with a clear release pattern (IL-8 > IL-6 > TNF-alpha = IL-1beta). Median cytokine release from unstimulated patient neutrophils was consistently, but non-significantly, higher than from control cells. Stimulated cytokine release from untreated patient neutrophils was also consistently higher than from control cells. This hyper-reactivity was significant for all tested cytokines when data for all stimuli were combined (P < 0.016). In terms of individual stimuli, significant hyper-reactivity was detected with LPS (IL-8), F. nucleatum (IL-8, TNF-alpha), opsonised S. aureus (IL-8, TNF-alpha, IL-1beta) and P. gingivalis (IL-8, IL 1beta). Cytokine production by patient neutrophils did not reduce following successful non-surgical periodontal therapy and, except for responses to F. nucleatum, the cytokine hyper-reactivity detected pre-therapy was retained. These data demonstrate that chronic periodontitis is characterised by neutrophils that constitutively exhibit cytokine hyper-reactivity, the effects of which could modulate local and systemic inflammatory-immune responses and influence the risk and severity of periodontitis-associated systemic inflammatory diseases. PMID- 26055821 TI - Response Properties of Urethral Distension Evoked Unifiber Afferent Potentials in the Lower Urinary Tract. AB - PURPOSE: It is well known that afferent input from the urethra can modulate bladder function. Nevertheless, little is known about the functional properties of urethral afferents. In the current study we investigated the effect of urethral distension on single fiber afferent activities of the lower urinary tract in the female rat. MATERIALS AND METHODS: Female Sprague Dawley(r) rats were anesthetized. Single fiber afferent activities were recorded from the left L6 dorsal root and classified by conduction velocity. The response of pelvic and pudendal units on urethral distension (60 seconds) was measured. Two distension diameters were measured in the proximal and the distal urethra. RESULTS: A total of 93 pelvic and 72 pudendal units were isolated in 15 rats. Of the units 20 (8 pelvic and 12 pudendal) were responsive to urethral distension. Three patterns of response could be distinguished, including a fast adapting and 2 groups of slow adapting afferents. The largest grade of distension resulted in the greatest response in both nerves. Five pelvic and 3 pudendal units responded exclusively to proximal distension, 2 pelvic and 5 pudendal units responded to distal distension, and 1 pelvic and 4 pudendal units responded to both types of distension. The responses were reproducible. No association was found between the type of nerve and the location of the response to distension. CONCLUSIONS: This electrophysiological study demonstrates the presence of urethral distension evoked afferents in the pelvic and pudendal nerves, and describes their response to distension. Differences in sensory signaling in type and in location were demonstrated. The current technique can be used for further investigation of urethral afferents. PMID- 26055822 TI - Radiation Exposure during the Evaluation and Management of Nephrolithiasis. AB - PURPOSE: There is rising concern over the increasing amount of patient radiation exposure from diagnostic imaging and medical procedures. Patients with nephrolithiasis are at potentially significant risk for radiation exposure due to the need for imaging to manage recurrent stone disease. We reviewed the literature in an attempt to better characterize actual risks and discussed methods to reduce radiation exposure for adult patients with nephrolithiasis. MATERIALS AND METHODS: A PubMed search was performed using the key words nephrolithiasis, stones, radiation, fluoroscopy, ureteroscopy, percutaneous nephrolithotomy, computerized tomography and shock wave lithotripsy. Additional citations were identified by reviewing reference lists of pertinent articles. RESULTS: A total of 50 relevant articles were included in this review. Patients with a first time acute stone event are exposed to a significant amount of radiation. Most radiation is from computerized tomography. Patients undergoing percutaneous nephrolithotomy are exposed to an equal or greater amount of radiation than they received from computerized tomography. Risk factors for increased exposure during percutaneous nephrolithotomy include obesity, multiple tracts and a larger stone burden. Ureteroscopy exposes patients to approximately the same amount of radiation as plain x-ray of the kidneys, ureters and bladder. Risk factors for increased exposure during ureteroscopy include obesity and ureteral dilation. During shock wave lithotripsy the amount of radiation exposure is not well characterized. Interventions to reduce exposure to patients include using ultrasound when possible and implementing low dose computerized tomography protocols. The as low as reasonably achievable principle of radiation exposure should always be followed when fluoroscopy is performed. The use of an air retrograde pyelogram may also reduce exposure during percutaneous nephrolithotomy. Fluoroscopy time during ureteroscopy may be decreased by a laser guided C-arm, a dedicated C-arm technician, stent placement under direct vision and tactile feedback to help guide wire placement. CONCLUSIONS: Patients with nephrolithiasis are at significant risk for increased radiation exposure from the imaging and fluoroscopy used during treatment. The true risks of low radiation exposure remain uncertain. It is important to be aware of these risks to provide better counseling for patients. Urologists must also be familiar with techniques to decrease radiation exposure for patients with nephrolithiasis. PMID- 26055823 TI - Implications of Definitive Prostate Cancer Therapy on Soft Tissue Margins and Survival in Patients Undergoing Radical Cystectomy for Bladder Urothelial Cancer. AB - PURPOSE: We evaluated the possibility of an existing link between definitive prostate cancer treatment and its effect on positive soft tissue surgical margins at radical cystectomy. A secondary objective was to determine whether definitive prostate cancer treatment was associated with bladder cancer survival end points. MATERIALS AND METHODS: There were 749 patients who underwent radical cystectomy between 2000 and 2013. After excluding females and patients with nonurothelial histologies 561 men were identified, of whom 69 (12.3%) received single or multimodal definitive prostate cancer treatment. Univariate and multivariable logistic regression was used to determine an association between clinical and pathological features such as definitive prostate cancer treatment and positive soft tissue surgical margins. Cox regression models and competing risk regression were used to investigate the impact of definitive prostate cancer treatment and positive surgical margins on survival. RESULTS: The median age of the male population was 70.0 years. There were 57 cases of positive soft tissue surgical margins in our cohort of 561 men (10.2%). Of men who underwent previous definitive prostate cancer treatment 20 of 69 (29.0%) had positive surgical margins compared to 37 of 492 (7.5%) who never received definitive prostate cancer treatment (p <0.0001). Brachytherapy, radiotherapy, hormonal therapy and radical prostatectomy significantly increased the rate of positive margins. Brachytherapy (OR 5.8), radiotherapy (OR 2.7) and hormonal therapy (OR 5.1) remained independent predictors of positive margins on multivariate analysis. Positive margins were associated with negative effects on recurrence-free (HR 3.1), cancer specific (HR 4.1) and overall survival (HR 2.8). CONCLUSIONS: Patients with a history of definitive prostate cancer treatment are at increased risk for positive soft tissue surgical margins. Positive margins significantly impact bladder cancer recurrence-free, cancer specific and overall survival following radical cystectomy. Careful patient counseling and surgical planning are crucial when treating patients undergoing radical cystectomy who have a history of definitive prostate cancer treatment. PMID- 26055824 TI - Systematic Review of Decision Aids for Newly Diagnosed Patients with Prostate Cancer Making Treatment Decisions. AB - PURPOSE: Despite established evidence for using patient decision aids, use with newly diagnosed patients with prostate cancer remains limited partly due to variability in aid characteristics. We systematically reviewed decision aids for newly diagnosed patients with prostate cancer. MATERIALS AND METHODS: Published peer reviewed journal articles, unpublished literature on the Internet and the Ottawa decision aids web repository were searched to identify decision aids designed for patients with prostate cancer facing treatment decisions. A total of 14 aids were included in study. Supplementary materials on aid development and published studies evaluating the aids were also included. We studied aids designed to help patients make specific choices among options and outcomes relevant to health status that were specific to prostate cancer treatment and in English only. Aids were reviewed for IPDAS (International Patient Decision Aid Standards) and additional standards deemed relevant to prostate cancer treatment decisions. They were also reviewed for novel criteria on the potential for implementation. Acceptable interrater reliability was achieved at Krippendorff alpha = 0.82. RESULTS: Eight of the 14 decision aids (57.1%) were developed in the United States, 6 (42.8%) were print based, 5 (35.7%) were web or print based and only 4 (28.5%) had been updated since 2013. Ten aids (71.4%) were targeted to prostate cancer stage. All discussed radiation and surgery, 10 (71.4%) discussed active surveillance and/or watchful waiting and 8 (57.1%) discussed hormonal therapy. Of the aids 64.2% presented balanced perspectives on treatment benefits and risks, and/or outcome probabilities associated with each option. Ten aids (71.4%) presented value clarification prompts for patients and steps to make treatment decisions. No aid was tested with physicians and only 4 (28.6%) were tested with patients. Nine aids (64.2%) provided details on data appraisal and 4 (28.6%) commented on the quality of evidence used. Seven of the 8 web or computer based aids (87.5%) provided patients with the opportunity to interact with the aid. All except 1 aid scored above the 9th grade reading level. No evidence on aid implementation in routine practice was available. CONCLUSIONS: As physicians look to adopt decision aids in practice, they may base the choice of aid on characteristics that correlate with patient socioeconomic and educational status, personal practice style and practice setting. PMID- 26055825 TI - Renal Autotransplantation: 27-Year Experience at 2 Institutions. AB - PURPOSE: Renal autotransplantation is an infrequently performed procedure. It has been used to manage complex ureteral disease, vascular anomalies and chronic kidney pain. We reviewed our 27-year experience with this procedure. MATERIALS AND METHODS: This is a retrospective, observational study of 51 consecutive patients who underwent renal autotransplantation, including 29 at Oregon Health and Science University between 1986 and 2013, and 22 at Virginia Mason Medical Center between 2007 and 2012. Demographics, indications, operative details and followup data were collected. Early (30 days or less) and late (greater than 30 days) complications were graded according to the Clavien-Dindo system. Factors associated with complications and pain recurrence were evaluated using a logistic regression model. RESULTS: The 51 patients underwent a total of 54 renal autotransplants. Median followup was 21.5 months. The most common indications were loin pain hematuria syndrome/chronic kidney pain in 31.5% of cases, ureteral stricture in 20.4% and vascular anomalies in 18.5%. Autotransplantation of a solitary kidney was performed in 5 patients. Laparoscopic nephrectomy was performed in 23.5% of cases. Median operative time was 402 minutes and median length of stay was 6 days. No significant difference was found between preoperative and postoperative plasma creatinine (p = 0.74). Early, high grade complications (grade IIIa or greater) developed in 14.8% of patients and 12.9% experienced late complications of any grade. Two graft losses occurred. Longer cold ischemia time was associated with complications (p = 0.049). Of patients who underwent autotransplantation for chronic kidney pain 35% experienced recurrence and 2 underwent transplant nephrectomy. No predictors of pain recurrence were identified. CONCLUSIONS: The most common indications for renal autotransplantation were loin pain hematuria syndrome/chronic kidney pain, ureteral stricture and vascular anomalies in descending order. Kidney function was preserved postoperatively and 2 graft losses occurred. At a median followup of 13 months pain resolved in 65% of patients who underwent the procedure. Complication rates compared favorably with those of other major urological operations and cold ischemia time was the only predictor of postoperative complications. PMID- 26055826 TI - Long-Term Outcome of the Pippi Salle Procedure for Intractable Urinary Incontinence in Patients with Severe Intrinsic Urethral Sphincter Deficiency. AB - PURPOSE: We evaluated the long-term outcome of the Pippi Salle procedure in patients with severe intrinsic urethral sphincter deficiency. MATERIALS AND METHODS: We performed the Pippi Salle procedure in 6 males and 6 females with severe intrinsic sphincter deficiency between March 2003 and August 2013. Median patient age was 15 years (range 6 to 45). Mean followup was 75 months (range 17 to 142). Six males and 3 females had neurogenic intrinsic sphincter deficiency (spina bifida in 8 and spinal cord injury in 1). Three females had anatomical intrinsic sphincter deficiency (idiopathic bladder hypoplasia in 2 and pseudo ureterocele in 1). Four patients had previously undergone bladder neck surgery, 3 had been treated with endoscopic injection of collagen, 2 had undergone fascial sling and 1 had been treated with tension-free vaginal tape surgery. The Pippi Salle procedure was performed alone (2 patients), or in combination with bladder augmentation (4) or catheterizable abdominal stoma (1), or both (5). RESULTS: Complete dryness was achieved in 7 patients (58%). Of 9 patients with neurogenic intrinsic sphincter deficiency 7 (78%) achieved complete dryness. Eight patients experienced complications, including continued urinary incontinence (5), difficulty catheterizing per urethra (3) and urinary calculi (1). These 8 patients were successfully treated with additional endoscopic interventions, including injection of collagen in 4, injection of dextranomer-hyaluronic acid in 1, transurethral incision of urethral kink in 3 and vesicolithotripsy in 1. After these simple interventions complete dryness was achieved in all 12 patients. CONCLUSIONS: Although we experienced some minor complications in the short term, most patients were simply and successfully treated with endoscopic surgery. The long-term results of the Pippi Salle procedure are promising. PMID- 26055827 TI - Platelet Derived Growth Factor Has a Role in Pressure Induced Bladder Smooth Muscle Cell Hyperplasia and Acts in a Paracrine Way. AB - PURPOSE: Bladder outlet obstruction is a finding in many urological disorders, leading to bladder wall hyperplasia. We investigated platelet derived growth factor and its receptor in human bladder smooth muscle cells and urothelial cells exposed to hydrostatic pressure or PDGF in vitro. MATERIALS AND METHODS: Bladder smooth muscle cells and urothelial cells were exposed to elevated hydrostatic pressure for 1 hour. The expression of PDGF and PDGFR was evaluated using reverse transcriptase-polymerase chain reaction and Western blot analysis. Pressure or PDGF induced proliferation of bladder smooth muscle cells with or without pretreatment with lovastatin or imatinib was measured by enzyme-linked immunosorbent assay. PDGFRalpha was knocked down with siRNA. RESULTS: After hydrostatic pressure bladder smooth muscle cells showed increased PDGFRalpha and beta expression. PDGF was not expressed in bladder smooth muscle cells. Urothelial cells showed no expression of PDGFR but PDGF expression was noted. Western blot analysis of bladder smooth muscle cells revealed a pressure induced increase in PDGFR in the membrane fraction. Phosphorylation of PDGFR occurred with pressure induction. Bladder smooth muscle cell proliferation was increased in pressure and PDGF mediated fashion. Pretreatment with lovastatin or imatinib prevented proliferation. There was no cell proliferation after PDGFRalpha knockdown. CONCLUSIONS: Increased expression and phosphorylation of PDGFR in bladder smooth muscle cells after hydrostatic pressure suggests a pivotal role of the PDGF pathway in pressure induced hyperplasia of bladder smooth muscle cells. PDGF expressed in urothelial cells may act in a paracrine way. Cholesterol depletion, inhibition of receptor tyrosine kinase activity and knockdown of PDGFRalpha in bladder smooth muscle cells prevent pressure and PDGF mediated cell proliferation. Targeting PDGFR seems a promising way to influence pressure induced bladder wall hyperplasia. PMID- 26055828 TI - Cluster randomised trials with repeated cross sections: alternatives to parallel group designs. PMID- 26055829 TI - N-B dative bond-induced [3.3.0] bicyclic boronate-tethered exo-selective intramolecular Diels-Alder reaction. AB - We report herein a highly exo-selective intramolecular Diels-Alder reaction of alkenyl boronates which employs an N-B dative bond-involved bicyclic rigid tether. Complex C(sp(3))-rich polycyclic molecules containing up to 8 stereocenters can be readily formed via an operationally simple two-step procedure. PMID- 26055830 TI - Normal and abnormal gas patterns: which is which? PMID- 26055831 TI - Giardiasis: a malignant mimicker? PMID- 26055833 TI - Evoked Potentials: They're Not Just for Diagnostics Anymore. PMID- 26055832 TI - Hand-assisted laparoscopic surgery compared with open resection for mid and low rectal cancer: a case-matched study with long-term follow-up. AB - BACKGROUND: This study was designed to compare the long-term surgical outcomes of patients with mid and low rectal cancer after open or hand-assisted laparoscopic surgery (HALS). METHODS: A case-matched controlled prospective analysis of 116 patients who underwent hand-assisted laparoscopic surgery (HALS) for stage I to III mid and low rectal cancer from 2005 to 2010 was performed. Contemporary patients who underwent open rectal surgery were matched to the HALS group at the ratio of 1:1. The perioperative clinical outcomes, postoperative pathology, and survival outcomes were compared between the groups. RESULTS: The patient characteristics between the two groups were comparable. Ninety patients in the open group and 85 in the HALS group received sphincter-preserving surgery. HALS resulted in less blood loss and wound infection, faster return to oral diet, shorter postoperative hospital stay, and longer operating time. The two groups had similar complication rates. Lymph node retrieval and involvement of circumferential and distal margins were similar for both procedures. Cumulative incidences of locoregional recurrence, disease-free, or overall survival rates were statistically similar. CONCLUSIONS: This study suggests that HALS for mid and low rectal cancer is acceptable in terms of short-term clinical outcomes and long-term survival results. PMID- 26055834 TI - Speech Recognition at the Acceptable Noise Level. AB - BACKGROUND: The acceptable noise level (ANL) has been proposed as a prehearing aid fitting measure that could be used for hearing aid selection and counseling purposes. Previous work has demonstrated that a listener's ANL is unrelated to their speech recognition in noise abilities. It is unknown what criteria a listener uses when they select their ANL. To date, no research has explored the amount of speech recognized at the listener's ANL. PURPOSE: To examine the amount of speech recognized at the listener's ANL to determine whether speech recognition in noise is utilized as a factor for setting ANL. RESEARCH DESIGN: A descriptive quasi-experimental study was completed. For all listeners, ANL was measured and speech recognition in noise was tested at ANL and at two additional signal-to-noise ratio (SNR) conditions based on the listener's ANL (ANL + 5 and ANL - 5). STUDY SAMPLE: Forty-four older adults served as participants. Twenty seven participants had normal hearing and seventeen participants had mild to moderately-severe, symmetrical, sensorineural hearing loss. DATA COLLECTION AND ANALYSIS: Acceptance of noise was calculated from the measures of most comfortable listening level and background noise level. Additionally, speech recognition in noise was assessed at three SNRs using the quick speech-in-noise test materials. RESULTS: A significant interaction effect of SNR condition and ANL group occurred for speech recognition. At ANL, a significant difference in speech recognition in noise was found across groups. Those in the mid and high ANL groups had excellent speech recognition at their ANL. Speech recognition in noise at ANL decreased with ANL category. CONCLUSIONS: For listeners with mid and high ANLs, speech recognition appears to play a primary role in setting their ANL. For those with low ANLs, speech recognition may contribute to setting their ANL; however, it does not appear to be the primary determiner of ANL. For those with very low ANLs, speech recognition does not appear to be significant variable for setting their ANL. PMID- 26055835 TI - The Effects of Audiovisual Stimulation on the Acceptance of Background Noise. AB - BACKGROUND: Previous examinations of noise acceptance have been conducted using an auditory stimulus only; however, the effect of visual speech supplementation of the auditory stimulus on acceptance of noise remains limited. PURPOSE: The purpose of the present study was to determine the effect of audiovisual stimulation on the acceptance of noise in listeners with normal and impaired hearing. RESEARCH DESIGN: A repeated measures design was utilized. STUDY SAMPLE: A total of 92 adult participants were recruited for this experiment. Of these participants, 54 were listeners with normal hearing and 38 were listeners with sensorineural hearing impairment. DATA COLLECTION AND ANALYSIS: Most comfortable levels and acceptable noise levels (ANL) were obtained using auditory and auditory-visual stimulation modes for the unaided listening condition for each participant and for the aided listening condition for 35 of the participants with impaired hearing that owned hearing aids. Speech reading ability was assessed using the Utley test for each participant. RESULTS: The addition of visual input did not impact the most comfortable level values for listeners in either group; however, visual input improved unaided ANL values for listeners with normal hearing and aided ANL values in listeners with impaired hearing. ANL benefit received from visual speech input was related to the auditory ANL in listeners in each group; however, it was not related to speech reading ability for either listener group in any experimental condition. CONCLUSIONS: Visual speech input can significantly impact measures of noise acceptance. The current ANL measure may not accurately reflect acceptance of noise values when in more realistic environments, where the signal of interest is both audible and visible to the listener. PMID- 26055836 TI - Age-Related Effects of Dichotic Attentional Mode on Interaural Asymmetry: An AERP Study with Independent Component Analysis. AB - BACKGROUND: The degree of interaural asymmetry (IA) obtained on a dichotic listening task is affected by attentional demands attributable to the mode of test administration. Previous research has shown that IA in the elderly is more influenced by increased attentional demands than young adults (YAs), but the effect of attentional mode on IA in middle-aged adults (MAs) has not been established. Auditory event-related potentials (AERPs), such as the N400, allow the evaluation of subtle differences in linguistic and cognitive processing between YAs and MAs that are imperceptible by behavioral means. PURPOSE: To determine the effect of dichotic attentional mode on IA in the N400 in YA and MA listeners. RESEARCH DESIGN: Participants listened to groups of words that consisted of a reference word followed by dichotic probe words. Participants judged whether probe words were semantically related or unrelated to the reference word. This semantic judgment task was elicited in both divided attention (DIV) and directed-attention (DIR) modes. STUDY SAMPLE: Twenty-three YA (19-25 yr) and twenty-three MA (47-59 yr) females participated in the study. DATA COLLECTION AND ANALYSIS: Individual, as well as grand-averaged, AERP waveforms, scalp topographies, and event-related potential-image plots were analyzed. A mixed design analysis of variance was used to compare the N400 amplitude and latency response between ears in both attentional modes. Independent component analysis was used to isolate temporally overlapping neural sources that contributed to the negativity in the latency range of the N400 component. RESULTS: N400 amplitude was significantly more negative in the DIV mode than DIR in both age groups. IA differences between age groups were evident only in DIV, as indicated by an age-related shift in the direction of IA in the N400 from greater asymmetry on the right in YAs to greater asymmetry on the left in MAs. ICA revealed that the age-related difference in IA in the AERP waveform reflected differences between YAs and MAs primarily in an electroencephalographic source process consistent with attentional processing. CONCLUSIONS: IA differences between YAs and MAs were revealed in the N400 only in DIV, which was the result of an increased information-processing load. ICA successfully separated temporally overlapping EEG sources that contributed to the N400 component, allowing a refined interpretation of differences in the AERP waveform among groups. PMID- 26055837 TI - Effects of Training on the Use of a Manual Microphone Shutoff on a BiCROS Device. AB - BACKGROUND: Bilateral contralateral routing of signals (BiCROS) hearing aids function to restore audibility of sounds originating from the side of the unaidable ear. However, when speech is presented to the side of the aidable ear and noise to the side of the unaidable ear, a BiCROS arrangement may reduce intelligibility of the speech signal. This negative effect may be circumvented if an on/off switch is available on the contralateral routing of signals (CROS) transmitter. PURPOSE: This study evaluated if the proper use of the on/off switch on a CROS transmitter could enhance speech recognition in noise and sound localization abilities. The participants' subjective reactions to the use of the BiCROS, including the use of the on/off switch in real-life were also evaluated. RESEARCH DESIGN: A between-subjects, repeated-measures design was used to assess differences in speech recognition (in quiet and in noise) and localization abilities under four hearing aid conditions (unaided, unilaterally aided, fixed BiCROS setting, and adjusted BiCROS setting) with speech and noise stimuli presented from different azimuths. Participants were trained on the use of the on/off switch on the BiCROS transmitter before testing in the adjusted BiCROS settings. Subjective ratings were obtained with the Speech, Spatial, and Sound Quality (SSQ) questionnaire and a custom questionnaire. STUDY SAMPLE: Nine adult BiCROS candidates participated in this study. DATA COLLECTION AND ANALYSIS: Participants wore the Widex Dream-m-CB hearing aid on the aidable ear for 1 week. They then wore the BiCROS for the remainder of the study. Speech recognition and localization testing were completed in four hearing aid conditions (unaided, unilateral aided, fixed BiCROS, and adjusted BiCROS). Speech recognition was evaluated during the first three visits, whereas localization was evaluated over the course of the study. Participants completed the SSQ questionnaire before each visit. The CROS questionnaire was completed at the final visit. A repeated measures analysis of variance with Bonferroni post hoc analysis was used to evaluate the significance of the results on speech recognition, localization, and the SSQ. RESULTS: The results revealed that the adjusted BiCROS condition improved speech recognition scores by 20 rau (rationalized arcsine unit) when speech was presented to the aidable ear and localization by 37% when sounds are presented from the side of the unaidable ear over the fixed BiCROS condition. Statistically significant benefit on the SSQ was also noted with the adjusted BiCROS condition compared to the unilateral fitting. CONCLUSIONS: These findings supported the value of an on/off switch on a CROS transmitter because it allows convenient selective transmission of sounds. It also highlighted the importance of instructions and practice in using the BiCROS hearing aid successfully. PMID- 26055838 TI - Differences in Perception of Musical Stimuli among Acoustic, Electric, and Combined Modality Listeners. AB - BACKGROUND: Cochlear implants have shown vast improvements in speech understanding for those with severe to profound hearing loss; however, music perception remains a challenge for electric hearing. It is unclear whether the difficulties arise from limitations of sound processing, the nature of a damaged auditory system, or a combination of both. PURPOSE: To examine music perception performance with different acoustic and electric hearing configurations. RESEARCH DESIGN: Chord discrimination and timbre perception were tested in subjects representing four daily-use listening configurations: unilateral cochlear implant (CI), contralateral bimodal (CIHA), bilateral hearing aid (HAHA) and normal hearing (NH) listeners. A same-different task was used for discrimination of two chords played on piano. Timbre perception was assessed using a 10-instrument forced-choice identification task. STUDY SAMPLE: Fourteen adults were included in each group, none of whom were professional musicians. DATA COLLECTION AND ANALYSIS: The number of correct responses was divided by the total number of presentations to calculate scores in percent correct. Data analyses were performed with Kruskal-Wallis one-way analysis of variance and linear regression. RESULTS: Chord discrimination showed a narrow range of performance across groups, with mean scores ranging between 72.5% (CI) and 88.9% (NH). Significant differences were seen between the NH and all hearing-impaired groups. Both the HAHA and CIHA groups performed significantly better than the CI groups, and no significant differences were observed between the HAHA and CIHA groups. Timbre perception was significantly poorer for the hearing-impaired groups (mean scores ranged from 50.3-73.9%) compared to NH (95.2%). Significantly better performance was observed in the HAHA group as compared to both groups with electric hearing (CI and CIHA). There was no significant difference in performance between the CIHA and CI groups. Timbre perception was a significantly more difficult task than chord discrimination for both the CI and CIHA groups, yet the easier task for the NH group. A significant difference between the two tasks was not seen in the HAHA group. CONCLUSIONS: Having impaired hearing decreases performance compared to NH across both chord discrimination and timbre perception tasks. For chord discrimination, having acoustic hearing improved performance compared to electric hearing only. Timbre perception distinguished those with acoustic hearing from those with electric hearing. Those with bilateral acoustic hearing, even if damaged, performed significantly better on this task than those requiring electrical stimulation, which may indicate that CI sound processing fails to capture and deliver the necessary acoustic cues for timbre perception. Further analysis of timbre characteristics in electric hearing may contribute to advancements in programming strategies to obtain optimal hearing outcomes. PMID- 26055839 TI - Evaluation of Speech Recognition of Cochlear Implant Recipients Using Adaptive, Digital Remote Microphone Technology and a Speech Enhancement Sound Processing Algorithm. AB - BACKGROUND: Cochlear implant recipients often experience difficulty with understanding speech in the presence of noise. Cochlear implant manufacturers have developed sound processing algorithms designed to improve speech recognition in noise, and research has shown these technologies to be effective. Remote microphone technology utilizing adaptive, digital wireless radio transmission has also been shown to provide significant improvement in speech recognition in noise. There are no studies examining the potential improvement in speech recognition in noise when these two technologies are used simultaneously. PURPOSE: The goal of this study was to evaluate the potential benefits and limitations associated with the simultaneous use of a sound processing algorithm designed to improve performance in noise (Advanced Bionics ClearVoice) and a remote microphone system that incorporates adaptive, digital wireless radio transmission (Phonak Roger). RESEARCH DESIGN: A two-by-two way repeated measures design was used to examine performance differences obtained without these technologies compared to the use of each technology separately as well as the simultaneous use of both technologies. STUDY SAMPLE: Eleven Advanced Bionics (AB) cochlear implant recipients, ages 11 to 68 yr. DATA COLLECTION AND ANALYSIS: AzBio sentence recognition was measured in quiet and in the presence of classroom noise ranging in level from 50 to 80 dBA in 5-dB steps. Performance was evaluated in four conditions: (1) No ClearVoice and no Roger, (2) ClearVoice enabled without the use of Roger, (3) ClearVoice disabled with Roger enabled, and (4) simultaneous use of ClearVoice and Roger. RESULTS: Speech recognition in quiet was better than speech recognition in noise for all conditions. Use of ClearVoice and Roger each provided significant improvement in speech recognition in noise. The best performance in noise was obtained with the simultaneous use of ClearVoice and Roger. CONCLUSIONS: ClearVoice and Roger technology each improves speech recognition in noise, particularly when used at the same time. Because ClearVoice does not degrade performance in quiet settings, clinicians should consider recommending ClearVoice for routine, full-time use for AB implant recipients. Roger should be used in all instances in which remote microphone technology may assist the user in understanding speech in the presence of noise. PMID- 26055840 TI - Speech Perception Ability in Noise is Correlated with Auditory Brainstem Response Wave I Amplitude. AB - BACKGROUND: Difficulty understanding speech in background noise is a common complaint of individuals with sensorineural hearing loss. Recent animal studies suggest this difficulty may be due, in part, to spiral ganglion cell degeneration related to aging or noise exposure. Although auditory brainstem response (ABR) thresholds and standard clinical audiometric tests are minimally affected by neuronal degeneration, the amplitude of wave I of the ABR is correlated to spiral ganglion cell density. PURPOSE: This study hypothesized that wave I amplitude was correlated to speech-in-noise performance. To test this, the relationships between wave I amplitude, age, and speech perception ability were analyzed in human participants. RESEARCH DESIGN: This is a correlational study. STUDY SAMPLE: A total of 101 ears from 57 adults ranging in age from 19 to 90 yr with a pure tone average of 45 dB HL or better were examined in this study. Only individuals with no history of neurological disease and ears without any evidence of conductive involvement were included. DATA COLLECTION AND ANALYSIS: Speech perception was measured in quiet using NU-6 word lists and in background noise using the QuickSIN. Ear canal electrodes were used to obtain ABR waveforms from each ear and the amplitude of wave I was measured as the absolute difference in voltage between the peak of the wave and the following trough. Speech perception performance in quiet and in background noise were both modeled using a linear mixed model with the covariates age, four-frequency pure-tone average (4fPTA), wave I amplitude, and the interaction between 4fPTA and wave I amplitude. ABR wave I amplitudes were modeled using a linear mixed model with age and 4fPTA as the covariates. The correlation between the right and left ears of the same participant were modeled using random effects. RESULTS: The results indicate that reduced ABR wave I amplitudes are (1) related to increased age, (2) associated with decreased speech-in-noise performance, with the greatest effects in individuals with poorer pure-tone thresholds, and (3) not correlated to speech perception in quiet. CONCLUSIONS: Reduced ABR wave I amplitude, an indicator of cochlear neuronal degeneration, is associated with decreased speech perception ability in noise, with a more pronounced effect in ears with poorer pure-tone thresholds, but does not appear to contribute to decreased speech perception in quiet. PMID- 26055841 TI - Video Head Impulse Testing (vHIT) and the Assessment of Horizontal Semicircular Canal Function. AB - BACKGROUND: Vestibular function (specifically, horizontal semicircular canal function) can be assessed across a broad frequency range using several different techniques. The head impulse test is a qualitative test of horizontal semicircular canal function that can be completed at bedside. Recently, a new instrument (video head impulse test [vHIT]) has been developed to provide an objective assessment to the clinical test. Questions persist regarding how this test may be used in the overall vestibular test battery. PURPOSE: The purpose of this case report is to describe vestibular test results (vHIT, rotational testing, vestibular evoked myogenic potentials, and balance and gait performance) in an individual with a 100% unilateral caloric weakness who was asymptomatic for dizziness, vertigo or imbalance. DATA COLLECTION AND/OR ANALYSIS: Comprehensive assessment was completed to evaluate vestibular function. Caloric irrigations, rotary chair testing, vHIT, and vestibular evoked myogenic potentials were completed. RESULTS: A 100% left-sided unilateral caloric weakness was observed in an asymptomatic individual. vHIT produced normal gain with covert saccades. CONCLUSIONS: This case demonstrates the clinical usefulness of vHIT as a diagnostic tool and indicator of vestibular compensation and functional status. PMID- 26055842 TI - Hearing Loss Terminology Should Be Evidence Based: A Reply to Clark and Martin (2014). PMID- 26055843 TI - Making Sense of "Red Birth Marks". PMID- 26055845 TI - Asymmetric Hearing During Development: The Aural Preference Syndrome and Treatment Options. AB - Deafness affects ~2 in 1000 children and is one of the most common congenital impairments. Permanent hearing loss can be treated by fitting hearing aids. More severe to profound deafness is an indication for cochlear implantation. Although newborn hearing screening programs have increased the identification of asymmetric hearing loss, parents and caregivers of children with single-sided deafness are often hesitant to pursue therapy for the deaf ear. Delayed intervention has consequences for recovery of hearing. It has long been reported that asymmetric hearing loss/single-sided deafness compromises speech and language development and educational outcomes in children. Recent studies in animal models of deafness and in children consistently show evidence of an "aural preference syndrome" in which single-sided deafness in early childhood reorganizes the developing auditory pathways toward the hearing ear, with weaker central representation of the deaf ear. Delayed therapy consequently compromises benefit for the deaf ear, with slow rates of improvement measured over time. Therefore, asymmetric hearing needs early identification and intervention. Providing early effective stimulation in both ears through appropriate fitting of auditory prostheses, including hearing aids and cochlear implants, within a sensitive period in development has a cardinal role for securing the function of the impaired ear and for restoring binaural/spatial hearing. The impacts of asymmetric hearing loss on the developing auditory system and on spoken language development have often been underestimated. Thus, the traditional minimalist approach to clinical management aimed at 1 functional ear should be modified on the basis of current evidence. PMID- 26055844 TI - Cognition and Brain Structure Following Early Childhood Surgery With Anesthesia. AB - BACKGROUND: Anesthetics induce widespread cell death, permanent neuronal deletion, and neurocognitive impairment in immature animals, raising substantial concerns about similar effects occurring in young children. Epidemiologic studies have been unable to sufficiently address this concern, in part due to reliance on group-administered achievement tests, inability to assess brain structure, and limited control for confounders. METHODS: We compared healthy participants of a language development study at age 5 to 18 years who had undergone surgery with anesthesia before 4 years of age (n = 53) with unexposed peers (n = 53) who were matched for age, gender, handedness, and socioeconomic status. Neurocognitive assessments included the Oral and Written Language Scales and the Wechsler Intelligence Scales (WAIS) or WISC, as appropriate for age. Brain structural comparisons were conducted by using T1-weighted MRI scans. RESULTS: Average test scores were within population norms, regardless of surgical history. However, compared with control subjects, previously exposed children scored significantly lower in listening comprehension and performance IQ. Exposure did not lead to gross elimination of gray matter in regions previously identified as vulnerable in animals. Decreased performance IQ and language comprehension, however, were associated with lower gray matter density in the occipital cortex and cerebellum. CONCLUSIONS: The present findings suggest that general anesthesia for a surgical procedure in early childhood may be associated with long-term diminution of language abilities and cognition, as well as regional volumetric alterations in brain structure. Although causation remains unresolved, these findings nonetheless warrant additional research into the phenomenon's mechanism and mitigating strategies. PMID- 26055846 TI - Weapon Involvement in the Victimization of Children. AB - OBJECTIVE: To report the prevalence of weapons involved in the victimization of youth with particular emphasis on weapons with a "high lethality risk" and how such exposure fits into the broader victimization and life experiences of children and adolescents. METHODS: Data were collected as part of the Second National Survey of Children's Exposure to Violence, a nationally representative telephone survey of youth ages 2 to 17 years and caregivers (N = 4114) conducted in 2011. RESULTS: Estimates from the Second National Survey of Children's Exposure to Violence indicate that almost 14 million youth, ages 2-17, in the United States have been exposed to violence involving a weapon in their lifetimes as witnesses or victims,or .1 in 5 children in this age group [corrected]. More than 2 million youth in the United States (1 in 33) have been directly assaulted in incidents where the high lethality risk weapons of guns and knives were used. Differences were noted between victimizations involving higher and lower lethality risk weapons as well as between any weapon involvement versus none. Poly-victims, youth with 7 or more victimization types, were particularly likely to experience victimization with any weapon, as well as victimization with a highly lethal weapon compared with nonpoly-victims. CONCLUSIONS: Findings add to the field's broadening conceptualization of youth victimization highlighting the potentially highly consequential risk factor of weapon exposure as a component of victimization experiences on the mental health of youth. Further work on improving gun safety practices and taking steps to reduce children's exposure to weapon-involved violence is warranted to reduce this problem. PMID- 26055847 TI - Prenatal Hemoglobin Levels and Early Cognitive and Motor Functions of One-Year Old Children. AB - OBJECTIVE: To explore the relationship between prenatal hemoglobin (Hb) concentration and infant cognitive and motor functions. METHODS: Our prospective cohort study included 1-year-old children born to women enrolled at their first antenatal care (ANC) visit in Allada, Benin, before 29 weeks of pregnancy, within a trial comparing the efficacy of sulfadoxine-pyrimethamine and mefloquine. Hb concentrations of pregnant women were determined from venous blood samples collected at first and second ANC visits of at least 1-month interval and at delivery. Women were prescribed oral iron, folic acid, and anthelminthics after the first ANC visit. A total of 636 children (76.8% of eligible children) were assessed by trained research nurses for cognitive and motor functions by using the Mullen Scales of Early Learning. RESULTS: Prevalence of anemia (Hb < 110 g/L) decreased from 67.0% at first ANC visit (mean gestational age [SD], 22.1 [4.0] weeks) to 38.4% at delivery. Mean (SD) Hb concentrations increased from 103.7 (12.3) at first ANC visit to 112.4 (14.1) at delivery. We observed a significant negative quadratic relationship between infant gross motor (GM) function and Hb concentration at first and second ANC visits. Thus, infant GM scores increased sharply with increasing maternal Hb concentration until 90 g/L where increasing GM was mild, and began to decline after 110 g/L. CONCLUSIONS: There appears to be an Hb concentration range that may be optimal for GM function of 1-year-old children. This may reflect the importance of physiologic hemodilution, which occurs after the second trimester until 34 weeks of gestation. PMID- 26055848 TI - An Early Feeding Practices Intervention for Obesity Prevention. AB - OBJECTIVE: Report long-term outcomes of the NOURISH randomized controlled trial (RCT), which evaluated a universal intervention commencing in infancy to provide anticipatory guidance to first-time mothers on "protective" complementary feeding practices that were hypothesized to reduce childhood obesity risk. METHODS: The NOURISH RCT enrolled 698 mothers (mean age 30.1 years, SD = 5.3) with healthy term infants (51% female). Mothers were randomly allocated to usual care or to attend two 6-session, 12-week group education modules. Outcomes were assessed 5 times: baseline (infants 4.3 months); 6 months after module 1 (infants 14 months); 6 months after module 2 (infants 2 years) and at 3.5 and 5 years of age. Maternal feeding practices were self-reported using validated questionnaires. BMI Z-score was calculated from measured child height and weight. Linear mixed models evaluated intervention (group) effect across time. RESULTS: Retention at age 5 years was 61%. Across ages 2 to 5 years, intervention mothers reported less frequent use of nonresponsive feeding practices on 6 of 9 scales. At 5 years, they also reported more appropriate responses to food refusal on 7 of 12 items (Ps <= .05). No statistically significant group effect was noted for anthropometric outcomes (BMI Z-score: P = .06) or the prevalence of overweight/obesity (control 13.3% vs intervention 11.4%, P = .66). CONCLUSIONS: Anticipatory guidance on complementary feeding resulted in first-time mothers reporting increased use of protective feeding practices. These intervention effects were sustained up to 5 years of age and were paralleled by a nonsignificant trend for lower child BMI Z-scores at all postintervention assessment points. PMID- 26055849 TI - A Case of Necrotizing Epiglottitis Due to Nontoxigenic Corynebacterium diphtheriae. AB - Diphtheria is a rare cause of infection in highly vaccinated populations and may not be recognized by modern clinicians. Infections by nontoxigenic Corynebacterium diphtheriae are emerging. We report the first case of necrotizing epiglottitis secondary to nontoxigenic C diphtheriae. A fully vaccinated child developed fever, poor oral intake, and sore throat and was found to have necrotizing epiglottitis. Necrotizing epiglottitis predominantly occurs in the immunocompromised host. Laboratory evaluation revealed pancytopenia, and bone marrow biopsy was diagnostic for acute lymphoblastic leukemia. Clinicians should be aware of aggressive infections that identify immunocompromised patients. This case highlights the features of a reemerging pathogen, C diphtheriae. PMID- 26055850 TI - Simulation in Pediatric Emergency Medicine Fellowships. AB - BACKGROUND AND OBJECTIVES: Graduate medical education faces challenges as programs transition to the next accreditation system. Evidence supports the effectiveness of simulation for training and assessment. This study aims to describe the current use of simulation and barriers to its implementation in pediatric emergency medicine (PEM) fellowship programs. METHODS: A survey was developed by consensus methods and distributed to PEM program directors via an anonymous online survey. RESULTS: Sixty-nine (95%) fellowship programs responded. Simulation-based training is provided by 97% of PEM fellowship programs; the remainder plan to within 2 years. Thirty-seven percent incorporate >20 simulation hours per year. Barriers include the following: lack of faculty time (49%) and faculty simulation experience (39%); limited support for learner attendance (35%); and lack of established curricula (32%). Of those with written simulation curricula, most focus on resuscitation (71%), procedures (63%), and teamwork/communication (38%). Thirty-seven percent use simulation to evaluate procedural competency and resuscitation management. PEM fellows use simulation to teach (77%) and have conducted simulation-based research (33%). Thirty percent participate in a fellows' "boot camp"; however, finances (27%) and availability (15%) limit attendance. Programs receive simulation funding from hospitals (47%), academic institutions (22%), and PEM revenue (17%), with 22% reporting no direct simulation funding. CONCLUSIONS: PEM fellowships have rapidly integrated simulation into their curricula over the past 5 years. Current limitations primarily involve faculty and funding, with equipment and dedicated space less significant than previously reported. Shared curricula and assessment tools, increased faculty and financial support, and regionalization could ameliorate barriers to incorporating simulation into PEM fellowships. PMID- 26055851 TI - Improvement in Perinatal HIV Status Documentation in a Massachusetts Birth Hospital, 2009-2013. AB - BACKGROUND AND OBJECTIVES: Despite recommendations for universal HIV testing during routine prenatal care, maternal HIV status is not always available at the time of delivery, which may lead to missed opportunities for antiretroviral prophylaxis. We completed a quality improvement project focused on increasing the availability of maternal HIV status documentation at our perinatal facility. Our primary aim was to improve documentation rates from 50% to 100% between 2009 and 2013. Our secondary aim was to identify predictors of documentation. METHODS: After an initial needs assessment, we performed a multidisciplinary quality improvement effort to address lack of HIV documentation in perinatal charts. The interventions included a switch to a verbal-only consent process, a rapid HIV testing protocol, and a simplified newborn admission document. To assess the impact of our intervention, we audited 100 charts per month and formally analyzed a second random sample of 200 charts in the postimplementation phase. RESULTS: Rates of HIV status documentation improved between 2009 and 2013, from 55.5% to 96.5%. Multivariable models revealed that before our interventions, mothers receiving care at freestanding offices (versus community-based outreach clinics) and those privately insured (versus publicly) were less likely to have HIV status documented. In 2013, neither ambulatory site nor insurance type predicted documentation. CONCLUSIONS: We demonstrated improvement in maternal HIV status documentation on admission to labor and delivery after implementation of a 3 pronged intervention. Next steps include investigating persistent barriers to achieving universal screening and documentation. PMID- 26055852 TI - Unusually Prolonged Presentation of Designer Drug Encephalopathy Responsive to Steroids. AB - The availability and use of novel psychoactive substances has risen dramatically over the last decade. The unpredictability of their toxicity constitutes a real challenge. We report a case of an adolescent who developed prolonged encephalopathy after ingesting "Hot Molly," which was found to contain the novel psychoactive substance, methylenedioxybenzylpiperazine when analyzed by high resolution mass spectrometry assay. This is the first case of human toxicity from methylenedioxybenzylpiperazine ingestion in the medical literature confirmed by body fluid analysis presenting with significant and prolonged encephalopathy. The prolonged course may be due to CYP2D6 inhibition from a combination of the methylenedioxyphenyl moiety and the patient's ultrarapid metabolizer pharmacokinetics. The response to high dose corticosteroids suggests a possible inflammatory effect that warrants further investigation. PMID- 26055853 TI - Vascular Anomalies Classification: Recommendations From the International Society for the Study of Vascular Anomalies. AB - Vascular anomalies represent a spectrum of disorders from a simple "birthmark" to life- threatening entities. Incorrect nomenclature and misdiagnoses are commonly experienced by patients with these anomalies. Accurate diagnosis is crucial for appropriate evaluation and management, often requiring multidisciplinary specialists. Classification schemes provide a consistent terminology and serve as a guide for pathologists, clinicians, and researchers. One of the goals of the International Society for the Study of Vascular Anomalies (ISSVA) is to achieve a uniform classification. The last classification (1997) stratified vascular lesions into vascular malformations and proliferative vascular lesions (tumors). However, additional disease entities have since been identified that are complex and less easily classified by generic headings, such as capillary malformation, venous malformation, lymphatic malformation, etc. We hereby present the updated official ISSVA classification of vascular anomalies. The general biological scheme of the classification is retained. The section on tumors has been expanded and lists the main recognized vascular tumors, classified as benign, locally aggressive or borderline, and malignant. A list of well-defined diseases is included under each generic heading in the "Simple Vascular Malformations" section. A short definition is added for eponyms. Two new sections were created: one dealing with the malformations of individually named vessels (previously referred to as "truncular" malformations); the second groups lesions of uncertain or debated nature (tumor versus malformation). The known genetic defects underlying vascular anomalies are included in an appendix. This classification is meant to be a framework, acknowledging that it will require modification as new scientific information becomes available. PMID- 26055854 TI - Trainee Perspectives on Manikin Death During Mock Codes. AB - BACKGROUND: The acceptability of simulated death has been debated by experts, but there is scarce information regarding trainees' perspective. METHODS: Trainees in a large pediatric program were invited to perform mock codes, including pre and post questionnaires. Participants were exposed to 2 mock codes of neonates born pulseless. In the RESUSC scenario, the manikin responded to adequate resuscitation; in the DEATH scenario, the manikin remained pulseless. Mock codes were videotaped and evaluated by using the Neonatal Resuscitation Program score sheet. Debriefing was analyzed by using qualitative methodology. RESULTS: Fifty nine of 62 trainees answered the questionnaire, and 42 performed a total of 84 mock codes. All trainees found mock codes beneficial and would appreciate being exposed to more. Most found them realistic and 78% agreed with the following statement: "During mock codes the manikin improves when adequate resuscitation steps are provided." The scenario or order of scenario did not affect performance (RESUSC versus DEATH). Only 1 trainee stopped resuscitation after 10 minutes of asystole; 31% had not ceased resuscitation efforts by 20 minutes. During debriefing and post questionnaire, trainees found the DEATH scenario more stressful than RESUSC. Trainees all answered the following question during debriefing: "How did this go for you?" Two themes were identified in their answers: (1) the manikin does not die; and (2) death equals inadequate resuscitation. CONCLUSIONS: The death of the manikin was stressful, but trainees thought this was acceptable and prepared them for their future. Trainees did not state that "death disclosures" were necessary before a simulated death. PMID- 26055856 TI - The Dimensional Assessment of Personality Psychopathology Basic Questionnaire: shortened versions item analysis. AB - This study has been designed to evaluate and replicate the psychometric properties of the Dimensional Assessment of Personality Psychopathology-Basic Questionnaire (DAPP-BQ) and the DAPP-BQ short form (DAPP-SF) in a large Spanish general population sample. Additionally, we have generated a reduced form called DAPP-90, using a strategy based on a structural equation modeling (SEM) methodology in two independent samples, a calibration and a validation sample. The DAPP-90 scales obtained a more satisfactory fit on SEM adjustment values (average: TLI > .97 and RMSEA < .04) respect to full DAPP-BQ and the 136-item version. According to the factorial congruency coefficients, the DAPP-90 obtains a similar structure to the DAPP-BQ and the DAPP-SF. The DAPP-90 internal consistency is acceptable, with a Cronbach's alpha mean of .75. We did not find any differences in the pattern of relations between the two DAPP-BQ shortened versions and the SCL-90-R factors. The new 90-items version is especially useful when it is difficult to use the long version for diverse reasons, such as the assessment of patients in hospital consultation or in brief psychological assessments. PMID- 26055857 TI - Nurses experience feelings of disempowerment when caring for patients in severe pain. PMID- 26055855 TI - Risk Factors for Recurrent Urinary Tract Infection and Renal Scarring. AB - OBJECTIVES: To identify risk factors for recurrent urinary tract infection (UTI) and renal scarring in children who have had 1 or 2 febrile or symptomatic UTIs and received no antimicrobial prophylaxis. METHODS: This 2-year, multisite prospective cohort study included 305 children aged 2 to 71 months with vesicoureteral reflux (VUR) receiving placebo in the RIVUR (Randomized Intervention for Vesicoureteral Reflux) study and 195 children with no VUR observed in the CUTIE (Careful Urinary Tract Infection Evaluation) study. Primary exposure was presence of VUR; secondary exposures included bladder and bowel dysfunction (BBD), age, and race. Outcomes were recurrent febrile or symptomatic urinary tract infection (F/SUTI) and renal scarring. RESULTS: Children with VUR had higher 2-year rates of recurrent F/SUTI (Kaplan-Meier estimate 25.4% compared with 17.3% for VUR and no VUR, respectively). Other factors associated with recurrent F/SUTI included presence of BBD at baseline (adjusted hazard ratio: 2.07 [95% confidence interval (CI): 1.09-3.93]) and presence of renal scarring on the baseline (99m)Tc-labeled dimercaptosuccinic acid scan (adjusted hazard ratio: 2.88 [95% CI: 1.22-6.80]). Children with BBD and any degree of VUR had the highest risk of recurrent F/SUTI (56%). At the end of the 2-year follow-up period, 8 (5.6%) children in the no VUR group and 24 (10.2%) in the VUR group had renal scars, but the difference was not statistically significant (adjusted odds ratio: 2.05 [95% CI: 0.86-4.87]). CONCLUSIONS: VUR and BBD are risk factors for recurrent UTI, especially when they appear in combination. Strategies for preventing recurrent UTI include antimicrobial prophylaxis and treatment of BBD. PMID- 26055858 TI - Emotional and Cognitive Impact of Sleep Restriction in Children. AB - Several observational, cross-sectional, and longitudinal studies as well as a few well-controlled experimental studies have examined the impact of sleep loss on children's daytime functioning. The emerging results indicate that sleep plays a critical role in various aspects of daytime functioning in children, including cognitive and emotional functioning. Furthermore, studies indicate that daytime functioning may be impaired by even small amounts of sleep restriction in children. PMID- 26055859 TI - The Relations Between Sleep, Personality, Behavioral Problems, and School Performance in Adolescents. AB - According to recent meta-analyses, adolescents across different countries and cultures do not get the recommended amount of sleep. Extracurricular activities, part-time jobs, and use of electronic devices in the evening delay bedtime in adolescents. Early school start times also shorten the time for sleep. Insufficient sleep in adolescents has been associated with weakened emotional behavioral regulation and poor academic achievement. Multicomponent intervention programs have been developed on the basis of cognitive-behavioral therapy for insomnia to improve sleep in youth. PMID- 26055860 TI - Anxiety Disorders and Sleep in Children and Adolescents. AB - Sleep problems are common in children and adolescents. A growing body of research has explored the relationship between sleep problems and anxiety in youth. When reviewing the literature, methodologic inconsistencies need to be considered, such as variation in conceptualization of sleep problems, measurement of sleep, and the classification of anxiety. Despite this, there seems to be good evidence of concurrent and longitudinal associations between sleep difficulties and anxiety in community and clinical samples of young people. Potential mechanisms are proposed. There is a need for further exploration of these relationships, with the hope of aiding preventive capability and developing useful treatments. PMID- 26055861 TI - Sleep in Children and Adolescents with Obsessive-Compulsive Disorder. AB - Sleep problems are not a core feature of obsessive-compulsive disorder (OCD), but emerging empirical data indicate some form of sleep disruption to be highly common. Available research in both adult and child patients is limited in several important ways, including the use of subjective reports (particularly in children), high rates of comorbid depression, and concurrent use of psychotropic medication. The presence of sleep disruption in OCD patients may compound severity and impairment of the disorder. More research is needed to fully understand the nature and consequences of sleep-wake disruption in children with OCD. PMID- 26055862 TI - Attention Deficit/Hyperactivity Disorder and Sleep in Children. AB - Basic assumptions about ADHD in children and sleep are not supported by research. It is unclear that children with hyperactivity or inattention have disrupted sleep. Parents of children with ADHD consistently report more bedtime resistance, but there is no objective evidence that sleep is subsequently disrupted. Treatment of ADHD with stimulants may disrupt sleep. Studies of comorbid sleep or psychiatric disorders consistently show that they disrupt sleep. Melatonin is an effective treatment of sleep problems in children with ADHD. Before any child is placed on stimulants, the pediatrician or other health care professional should insure that the child is obtaining adequate sleep. PMID- 26055863 TI - Kleine-Levin Syndrome. AB - Kleine-Levin syndrome is a rare recurrent encephalopathy primarily affecting teenagers, characterized by relapsing-remitting episodes of hypersomnia along with cognitive, psychiatric and behavioral disturbances. During episodes, patients suddenly present hypersomnia (with sleep lasting 15-21 h/d), cognitive impairment (major apathy, confusion, slowness, amnesia), and a specific feeling of derealization (dreamy state, altered perception). Less frequently, they may also experience hyperphagia (66%), hypersexuality (53%, principally men), depressed mood (53%, principally women), anxiety, hallucinations, and acute brief psychosis (33%). Brain functional imaging is often abnormal. Stimulants are poorly beneficial during episodes, whereas lithium and valproate help reducing the episodes frequency and duration. PMID- 26055864 TI - Rapid Eye Movement Sleep Behavior Disorder During Childhood. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is a type of parasomnia that arises out of REM sleep and is characterized by aggressive or violent motor dream enactment in conjunction with preservation of tonic electromyographic activity (ie, REM sleep without atonia). RBD occurs at all ages and in both sexes, although it remains relatively infrequent during childhood. The literature pertaining to RBD in childhood is scant, and composed only of single case reports or small case series. RBD etiologies include Parkinson disease, multisystem atrophy, and dementia with Lewy body disease. This article presents an updated review of childhood RBD. PMID- 26055865 TI - Sleep-Related Breathing Disorder, Cognitive Functioning, and Behavioral Psychiatric Syndromes in Children. AB - Childhood sleep disordered breathing (SDB) is strongly associated with a range of cognitive and behavioral disturbances, including some psychiatric diagnoses. Despite this, the majority of children with symptoms of SDB go unrecognized, even though simple screening could identify children in need of further evaluation. Definitive evidence showing that SDB causes cognitive and behavioral impairment has yet to emerge, although a randomized controlled trial evaluating neuropsychological and health outcomes of treatment for SDB in children is currently underway. PMID- 26055872 TI - Sleep Medicine and Psychiatric Disorders in Children. PMID- 26055866 TI - Melatonin Treatment in Children with Developmental Disabilities. AB - Melatonin is commonly recommended to treat sleep problems in children with developmental disabilities. However, few studies document the efficacy and safety of melatonin in these populations. This article reviews recent studies of melatonin efficacy in developmental disabilities. Overall, short treatment trials were associated with a significant decrease in sleep onset latency time for each of the disorders reviewed, with 1 notable exception-tuberous sclerosis. Reported side effects were uncommon and mild. Across disorders, additional research is needed to draw disability-specific conclusions. However, studies to date provide positive support for future trials that include larger groups of children with specific disabilities/syndromes. PMID- 26055873 TI - Effects of hypertonic saline and mannitol on cortical cerebral microcirculation in a rabbit craniotomy model. AB - BACKGROUND: Hyperosmolar solutions have been used in neurosurgery to modify brain bulk and prevent neurological deterioration. The aim of this animal study was to compare the short-term effects of equivolemic, equiosmolar solutions of mannitol and hypertonic saline (HTS) on cerebral cortical microcirculation in a rabbit craniotomy model. METHODS: Rabbits (weight, 2.0-3.0 kg) were anesthetized, ventilated mechanically, and subjected to a craniotomy. The animals were allocated randomly to receive a 3.75 ml/kg intravenous infusion of either 3.2% HTS (group HTS, n = 8) or 20% mannitol (group MTL, n = 8). Microcirculation in the cerebral cortex was evaluated using sidestream dark-field (SDF) imaging before and 20 min after the end of the 15-min HTS infusion. Global hemodynamic data were recorded, and blood samples for laboratory analysis were obtained at the time of SDF image recording. RESULTS: No differences in the microcirculatory parameters were observed between the groups before the use of osmotherapy. After osmotherapy, lower proportions of perfused small vessel density (P = 0.0474), perfused vessel density (P = 0.0457), and microvascular flow index (P = 0.0207) were observed in the MTL group compared with those in the HTS group. CONCLUSIONS: Our findings suggest that an equivolemic, equiosmolar HTS solution better preserves perfusion of cortical brain microcirculation compared to MTL in a rabbit craniotomy model. PMID- 26055875 TI - The influence of science popularizers on the public's view of religion and science: An experimental assessment. AB - Research suggests that public figures can play an influential role in forming public opinion; yet, little research has experimentally tested the efficacy of public figures on the cognitive formation of boundaries. Using an experiment embedded within a nationally representative survey, we examine how two science popularizers, Francis Collins and Richard Dawkins, influence perceptions regarding the boundaries between religion and science. We find that learning of Dawkins does not influence people's perceptions of the religion-science relationship, while learning of Collins shifts respondents toward a collaborative view of religion and science. Findings suggest that figures with unexpected views might be more effective in changing conceptual boundaries. PMID- 26055874 TI - MiR-223 targeting MAFB suppresses proliferation and migration of nasopharyngeal carcinoma cells. AB - BACKGROUND: Mounting evidence suggests that miRNAs have major functions in tumor pathogenesis, and this study aimed to identify the candidate miRNA and investigate its role in nasopharyngeal carcinoma (NPC). METHODS: MiRNA and mRNA expressions were screened by microarray assays. The cell proliferation, colony formation and migration ability were measured by MTT, soft agar and wound healing assays, respectively. The tumor growth suppression was evaluated by xenografting in nude mice. The plasma miR-223 levels in NPC patients were detected by TaqMan analysis. Real-time quantitative PCR and Western blotting were used to confirm miR-223 and MAFB expression levels. The targeting relationship between miR-223 and MAFB was verified using dual luciferase reporter assay. RESULTS: The miR-223 expression was decreased in CNE-1, CNE-2 cells as compared with NP69 cells, an immortalized human nasopharyngeal epithelial cell line, and its level also reduced in NPC patients' plasma as compared with healthy controls. Exogenous expression of miR-223 in CNE-2 cells could inhibit cell proliferation both in vitro and in vivo. Extrogenous miR-223 in CNE-2 cells would decrease the ability of colony formation and migration. MAFB, a transcription factor of Maf family members, was identified as a target gene of miR-223. We found that migration and invasion abilities were inhibited by MAFB silencing. CONCLUSIONS: MiR-223 negatively regulates the growth and migration of NPC cells via reducing MAFB expression, and this finding provides a novel insight into understanding miR-223 regulation mechanism in nasopharyngeal carcinoma tumorigenesis. PMID- 26055876 TI - The nature and dimensions of achievement goals: mastery, evaluation, competition, and self-presentation goals. AB - The present study aimed to clarify the nature and dimensions of achievement goals and to examine structural differences in students' goals across school levels. Participants were 134 students from 5th and 6th grades, and 423 students from 7th to 9th grades. A variety of achievement goals were assessed, including mastery goals and several performance-related goals representing three main dimensions: competition, self-presentation, and valence. Two alternative models were tested, using confirmatory factor analysis. For middle-school students a three factor model with presentation, competition, and simple evaluation/mastery goals, was found chi2(132, N = 134) = 160.9, p < .001; CFI = .94; RMSEA = .04, 95%CI [.02 - .06]. In the junior-high sample, one avoidance factor, one competition factor, and a simple evaluation/mastery factor, best fitted the data chi2(114, N = 423) = 269.8638 p < .001; CFI = .93; RMSEA = .06, 95%CI [.05 - .07] thus suggesting that distinct dimensions organize younger and older students' motivation. However, common to both grade levels was the existence of (a) separate but low incidence competition goals, and (b) simple evaluation goals, which encompass neither self presentation nor competition, and are closely linked to mastery goals. Moreover, significant differences were found in the relative importance attached by students to the different types of goals (p < .001 for all comparisons), both at middle-school F(2, 266) = 220.98; p < .001; eta2 = .624) and at junior-high school F(2, 820) = 464.4; p < .001; eta2 = .531. PMID- 26055878 TI - Transplant Ethics: Let's Begin the Conversation Anew : A Critical Look at One Institute's Experience with Transplant Related Ethical Issues. AB - Standardizing consultation processes is increasingly important as clinical ethics consultation (CEC) becomes more utilized in and vital to medical practice. Solid organ transplant represents a relatively nascent field replete with complex ethical issues that, while explored, have not been systematically classified. In this paper, we offer a proposed taxonomy that divides issues of resource allocation from viable solutions to the issue of organ shortage in transplant and then further distinguishes between policy and bedside level issues. We then identify all transplant related ethics consults performed at the Cleveland Clinic (CC) between 2008 and 2013 in order to identify how consultants conceptually framed their consultations by the domains they ascribe to the case. We code the CC domains to those in the Core Competencies for Healthcare Consultation Ethics in order to initiate a broader conversation regarding best practices in these highly complex cases. A discussion of the ethical issues underlying living donor and recipient related consults ensues. Finally, we suggest that the ethical domains prescribed in the Core Competencies provide a strong starting ground for a common intra-disciplinary language in the realm of formal CEC. PMID- 26055877 TI - Study on expression of lncRNA RGMB-AS1 and repulsive guidance molecule b in non small cell lung cancer. AB - BACKGROUND: The relationships between lncRNAs and tumors have currently become one of the focuses on cancer studies. However, there are a few studies about lncRNAs in non-small cell lung cancer (NSCLC) at present. METHODS: Microarray analysis was designed to study the expression patterns of lncRNAs in three pairs of NSCLC tissues. The expression of lncRNA RGMB-AS1 and repulsive guidance molecule b (RGMB) were detected in 72 paired NSCLC tissues and adjacent normal tissues by qRT-PCR assay. The relations of lncRNA RGMB-AS1 and RGMB expression with clinicopathological factors of NSCLC patients were explored. A549 and SPC-A 1 cells were transfected with siRNA of lncRNA RGMB-AS1 and negative control. RGMB expression level was detected by qRT-PCR assay and western blot analysis. RESULTS: The results of microarray found that 571 lncRNAs were differentially expressed in NSCLC tissues (Fold change cut-off: 5.0, P < 0.05), including 304 upregulated and 267 downregulated lncRNAs. The results of qRT-PCR showed that lncRNA RGMB-AS1 expression was significantly higher in NSCLC tissues than in adjacent normal tissues (P < 0.05), while RGMB mRNA showed an opposite trend (P < 0.05). Correlation analysis indicated that the expression of lncRNA RGMB-AS1and RGMB mRNA were inversely correlated (R(2) = 0.590, P < 0.05). While lncRNA RGMB AS1 and RGMB expression levels in NSCLC tissues were associated with the occurrence of differentiation status, lymph node metastases and TNM stage (P < 0.05). Transfection with siRNA of lncRNA RGMB-AS1, subsequent results showed that RGMB mRNA and protein expression were upregulated (P < 0.05) in A549 and SPC-A-1 cells compared to the control groups. CONCLUSION: We identified lncRNA RGMB-AS1 was upregulated and RGMB was downregulated in NSCLC patients. Both were related to differentiation status, lymph node metastases and TNM stage. Studies also indicated that lncRNA RGMB-AS1and RGMB were inversely correlated. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7911587521528276. PMID- 26055879 TI - Networking Ethics: A Survey of Bioethics Networks Across the U.S. AB - Ethics networks have emerged over the last few decades as a mechanism for individuals and institutions over various regions, cities and states to converge on healthcare-related ethical issues. However, little is known about the development and nature of such networks. In an effort to fill the gap in the knowledge about such networks, a survey was conducted that evaluated the organizational structure, missions and functions, as well as the outcomes/products of ethics networks across the country. Eighteen established bioethics networks were identified via consensus of three search processes and were approached for participation. The participants completed a survey developed for the purposes of this study and distributed via SurveyMonkey. Responses were obtained from 10 of the 18 identified and approached networks regarding topic areas of: Network Composition and Catchment Areas; Network Funding and Expenses; Personnel; Services; and Missions and Accomplishments. Bioethics networks are designed primarily to bring ethics education and support to professionals and hospitals. They do so over specifically defined areas-states, regions, or communities-and each is concerned about how to stay financially healthy. At the same time, the networks work off different organizational models, either as stand alone organizations or as entities within existing organizational structures. PMID- 26055880 TI - The application of alkaline lysis and pressure cycling technology in the differential extraction of DNA from sperm and epithelial cells recovered from cotton swabs. AB - This study reports the development of a two-step protocol using pressure cycling technology (PCT) and alkaline lysis for differential extraction of DNA from mixtures of sperm and vaginal epithelial cells recovered from cotton swabs. In controlled experiments, in which equal quantities of sperm and female epithelial cells were added to cotton swabs, 5 min of pressure pulsing in the presence of 0.4 M NaOH resulted in 104 +/- 6% recovery of female epithelial DNA present on the swab. Following the pressure treatment, exposing the swabs to a second 5-min alkaline treatment at 95 degrees C without pressure resulted in the selective recovery of 69 +/- 6% of the sperm DNA. The recovery of the vaginal epithelia and sperm DNA was optimized by examining the effect of sodium hydroxide concentration, incubation temperature, and time. Following the alkaline lysis steps, the samples were neutralized with 2 M Tris (pH 7.5) and purified with phenol-chloroform-isoamyl alcohol to permit downstream analysis. The total processing time to remove both fractions from the swab was less than 20 min. Short tandem repeat (STR) analysis of these fractions obtained from PCT treatment and alkaline lysis generated clean profiles of female epithelial DNA and male sperm DNA for 1:1 mixtures of female and male cells and predominant male profiles for mixtures up to 5:1 female to male cells. By reducing the time and increasing the recovery of DNA from cotton swabs, this new method presents a novel and potentially useful procedure for forensic differential extractions. PMID- 26055881 TI - An integrated strategy for the systematic characterization and discovery of new indole alkaloids from Uncaria rhynchophylla by UHPLC/DAD/LTQ-Orbitrap-MS. AB - The exploration of new chemical entities from herbal medicines may provide candidates for the in silico screening of drug leads. However, this significant work is hindered by the presence of multiple classes of plant metabolites and many re-discovered structures. This study presents an integrated strategy that uses ultrahigh-performance liquid chromatography/linear ion-trap quadrupole/Orbitrap mass spectrometry (UHPLC/LTQ-Orbitrap-MS) coupled with in house library data for the systematic characterization and discovery of new potentially bioactive molecules. Exploration of the indole alkaloids from Uncaria rhynchophylla (UR) is presented as a model study. Initially, the primary characterization of alkaloids was achieved using mass defect filtering and neutral loss filtering. Subsequently, phytochemical isolation obtained 14 alkaloid compounds as reference standards, including a new one identified as 16,17-dihydro-O-demethylhirsuteine by NMR analyses. The direct-infusion fragmentation behaviors of these isolated alkaloids were studied to provide diagnostic structural information facilitating the rapid differentiation and characterization of four different alkaloid subtypes. Ultimately, after combining the experimental results with a survey of an in-house library containing 129 alkaloids isolated from the Uncaria genus, a total of 92 alkaloids (60 free alkaloids and 32 alkaloid O-glycosides) were identified or tentatively characterized, 56 of which are potential new alkaloids for the Uncaria genus. Hydroxylation on ring A, broad variations in the C-15 side chain, new N-oxides, and numerous O-glycosides, represent the novel features of the newly discovered indole alkaloid structures. These results greatly expand our knowledge of UR chemistry and are useful for the computational screening of potentially bioactive molecules from indole alkaloids. Graphical Abstract A four-step integrated strategy for the systematic characterization and efficient discovery of new indole alkaloids from Uncaria rhynchophylla. PMID- 26055882 TI - ABC Spotlight on emerging microRNA analysis methods. PMID- 26055883 TI - On the multimodality of preparative TREF fractionation as detected by advanced analytical methods. AB - Preparative temperature rising elution fractionation (prepTREF) is the standard technique for the preparative fractionation of polyolefins according to crystallisability. For olefin copolymers such as linear low-density polyethylene (LLDPE), it was believed that the TREF elution temperature correlates directly with the copolymer composition. For copolymers having different bulk comonomer contents, the prepTREF fractions of different samples collected at a given temperature were assumed to have the same chemical composition. It was acknowledged quite early that co-crystallisation effects may disturb TREF fractionation and fractions are obtained that are not completely homogeneous. This, however, has not been investigated quantitatively so far. The fundamental statement of prepTREF is challenged for the first time quantitatively using advanced analytical techniques including high-temperature high-performance liquid chromatography (HPLC). Ethylene-1-octene copolymers having bulk comonomer contents ranging from 0.3 to 6.4 mol% were fractionated by prepTREF, and the fractions were analysed by high-temperature size exclusion chromatography, crystallisation analysis fractionation, differential scanning calorimetry and high-temperature HPLC. All analytical results prove that the TREF fractions collected from different samples at the same elution temperature have different chemical compositions. The chemical compositions of the fractions correlate with the compositions of the bulk samples in that the comonomer contents of similar TREF fractions increase with an increase of the comonomer content of the bulk samples. These results are in clear contrast to the previous assumption that the TREF fraction composition is independent of the bulk copolymer composition for a given copolymer type. Graphical abstract Advanced analysis of LLDPE by combination of HT-HPLC, DSC and CRYSTAF. PMID- 26055884 TI - Enhanced magnetic refrigeration properties in Mn-rich Ni-Mn-Sn ribbons by optimal annealing. AB - The influence of annealing time on temperature range of martensitic phase transition (DeltaT(A-M)), thermal hysteresis (DeltaThys), magnetic hysteresis loss (DeltaMhys), magnetic entropy change (DeltaS(M)) and relative refrigeration capacity (RC) of the Mn-rich Ni43Mn46Sn11 melt spun ribbons have been systematically studied. By optimal annealing, an extremely large DeltaS(M) of 43.2 J.kg(-1)K(-1) and a maximum RC of 221.0 J.kg(-1) could be obtained respectively in a field change of 5 T. Both DeltaT(A-M) and DeltaThys decreases after annealing, while DeltaMhys and DeltaS(M) first dramatically increase to a maximum then degenerates as increase of annealing time. A large effective cooling capacity (RC(eff)) of 115.4 J.kg(-1) was achieved in 60 min annealed ribbons, which increased 75% compared with that unannealed ribbons. The evolution of magnetic properties and magnetocaloric effect has been discussed and proved by atomic ordering degree, microstructure and composition analysis. PMID- 26055885 TI - Evaluation of the learning curve for thulium laser enucleation of the prostate with the aid of a simulator tool but without tutoring: comparison of two surgeons with different levels of endoscopic experience. AB - BACKGROUND: The aim of this study was to determine the learning curve for thulium laser enucleation of the prostate (ThuLEP) for two surgeons with different levels of urological endoscopic experience. METHODS: From June 2012 to August 2013, ThuLEP was performed on 100 patients in our institution. We present the results of a prospective evaluation during which we analyzed data related to the learning curves for two surgeons of different levels of experience. RESULTS: The prostatic adenoma volumes ranged from 30 to 130 mL (average 61.2 mL). Surgeons A and B performed 48 and 52 operations, respectively. Six months after surgery, all patients were evaluated with the International Prostate Symptom Score questionnaire, uroflowmetry, and prostate-specific antigen test. Introduced in 2010, ThuLEP consists of blunt enucleation of the prostatic apex and lobes using the sheath of the resectoscope. This maneuver allows clearer visualization of the enucleation plane and precise identification of the prostatic capsule. These conditions permit total resection of the prostatic adenoma and coagulation of small penetrating vessels, thereby reducing the laser emission time. Most of the complications in this series were encountered during morcellation, which in some cases was performed under poor vision because of venous bleeding due to surgical perforation of the capsule during enucleation. CONCLUSIONS: Based on this analysis, we concluded that it is feasible for laser-naive urologists with endoscopic experience to learn to perform ThuLEP without tutoring. Those statements still require further validation in larger multicentric study cohort by several surgeon. The main novelty during the learning process was the use of a simulator that faithfully reproduced all of the surgical steps in prostates of various shapes and volumes. PMID- 26055886 TI - [Clinical research in ophthalmology: Medical prerequisites]. AB - BACKGROUND: The shortage of principal investigators is increasingly constricting the rising demand for clinical trials in Germany. This is partly because clinical trials training is outside the field of ophthalmology but another issue is that clinical trials research often has to be performed on top of the regular workload. OBJECTIVE: Medical personnel in university ophthalmology departments can be motivated for clinical trials research by means of only a few structural improvements. Long-term commitment could be improved through new career tracks in the field of clinical trials. CONCLUSION: The broad adoption of these proposals could convey sustainable growth of clinical ophthalmological research in German. PMID- 26055887 TI - [Bilateral central retinal detachment with whitish chorioretinal foci]. PMID- 26055888 TI - [Not Available]. PMID- 26055889 TI - Molecular characterization of H9N2 avian influenza viruses isolated from vaccinated broiler chickens in northeast Iran. AB - Avian influenza is a highly contagious respiratory disease of poultry caused by influenza A viruses, family Orthomyxoviridae. H9N2 avian influenza outbreaks are a major problem of the poultry industry in Iran. To determine the genetic differences between field viruses and the vaccine strain, the genomes of four strains isolated in 2011 from vaccinated broiler flocks with a history of respiratory illness were sequenced. Genetic and serological comparisons were made. Sequence analysis of the hemagglutinin (HA) and neuraminidase (NA) genes indicated that the isolated strains shared nucleotide homologies of 91.6-93.9 and 90.2-91.7% with the vaccine strain, respectively. Phylogenetic analyses of HA and NA genes showed that all strains isolated in this study fell into the same group and belonged to the influenza A virus (A)/quail/Hong Kong/G1/97 H9N2 sublineage. Several amino acids have changed at the antigenic sites in HA in the field viruses. Extra potential glycosylation sites were observed in the HA and NA proteins expressed by the current isolates relative to those in the vaccine strain. The deduced amino acid sequence at the cleavage site of HA in recent isolates is the KSSR/GLF motif, whereas it is RSSR/GLF in the vaccine strain. A serological analysis revealed that the currently circulating strains are antigenically distinct from the vaccine strain. These results suggest that the commercial vaccine is insufficiently genetically and antigenically similar to the viruses currently circulating in the region. These findings confirm that it is important to monitor the genetic and antigenic variations in H9N2 influenza viruses when selecting a vaccine strain. PMID- 26055890 TI - Effects of genotype and sex on the growth performance and carcass characteristics of broiler chickens. AB - Six hundred and eight day-old chicks of Ross 308 and Cobb Avian 48 broiler strains were used in a 49-day experiment to examine the effects of genotype and sex on the growth performance and carcass characteristics. Body weight, body weight gain, feed intake, feed conversion ratio, and mortality rate were recorded. Over all, genotype had a significant effect only on feed conversion ratio, Cobb being a better efficient in converting feed than Ross. Males consumed more feed, utilized the feed more efficiently, gained more body weight, and were heavier at 49 days of age than females but had a higher mortality rate. There were significant genotype * sex interaction effects on 49-day body weight, body weight gain, feed intake, and mortality rate. As regards carcass characteristics, genotype affected only liver weight with a heavier liver in Cobb than Ross. Sex significantly affected carcass, back, wing, leg, liver, gizzard, and abdominal fat weights with higher means for males than females for all the traits except abdominal fat weight where females had higher means than males. Genotype * sex interaction effects significantly influenced carcass, breast, back, wing, leg, and liver weights. PMID- 26055891 TI - Survey of smallholder beef cattle production systems in different agro-ecological zones of Cambodia. AB - A survey was conducted to better understand the contribution of farm productivity to rural household income and identify differences in production systems, feeding practices and development constraints to smallholder beef cattle producers in the four agro-ecological zones (AEZs) of Cambodia. A semi-structured questionnaire was used to interview 360 households in the four AEZs: I, the Great Lake Floodplain; II, the Mekong Floodplain; III, the Coastal and IV, the Plateau/Mountainous. In addition, samples of common nutritional resources used for cattle feed were collected for nutrient composition analysis, plus cattle were scored for body condition. Rice farming and cattle production were the most common sources of income in all AEZs. The average cattle herd size was 3.7 (SD = 2.4), but the majority of households raised 1-3 animals. The most common cattle management system was grazing with supplementation, mainly with rice straw and 'cut-and-carry' natural grasses fed during the wet season in all AEZs. The body condition score of all cattle types was 3.2 (SD = 0.8), except for cows in lactation that were 1.8. Major constraints to cattle production in AEZs I, II and III were lack of quality feed resources, capital for cattle production and concerns on breed quality, whereas in AEZ IV, diseases were identified as the main constraint. This survey confirms the importance of cattle to smallholders in the four AEZs. Interventions including farmer education to improve husbandry skills, increase the utilisation of forages and crop residues and address disease issues are necessary to enhance cattle production and rural livelihoods in Cambodia. PMID- 26055892 TI - Artificial de novo biosynthesis of hydroxystyrene derivatives in a tyrosine overproducing Escherichia coli strain. AB - BACKGROUND: Styrene and its derivatives as monomers and petroleum-based feedstocks are valuable as raw materials in industrial processes. The chemical reaction for styrene production uses harsh reaction conditions such as high temperatures or pressures, or requires base catalysis with microwave heating. On the other hand, production of styrene and its derivatives in Escherichia coli is an environmental friendly process to produce conventional petroleum-based feedstocks. RESULTS: An artificial biosynthetic pathway was developed in E. coli that yields 4-hydroxystyrene, 3,4-dihydroxystyrene and 4-hydroxy-3-methoxystyrene from simple carbon sources. This artificial biosynthetic pathway has a codon optimized phenolic acid decarboxylase (pad) gene from Bacillus and some of the phenolic acid biosynthetic genes. E. coli strains with the tal and pad genes, the tal, sam5, and pad genes, and the tal, sam5, com, and pad genes produced 4 hydroxystyrene, 3,4-dihydroxystyrene and 4-hydorxy-3-methoxystyrene, respectively. Furthermore, these pathways were expressed in a tyrosine overproducing E. coli. The yields for 4-hydroxystyrene, 3,4-dihydroxystyrene and 4-hydorxy-3-methoxystyrene reached 355, 63, and 64 mg/L, respectively, in shaking flasks after 36 h of cultivation. CONCLUSIONS: Our system is the first to use E. coli with artificial biosynthetic pathways for the de novo synthesis of 3,4 dihydroxystyrene and 4-hydroxy-3-methoxystyrene in a simple glucose medium. Similar approaches using microbial synthesis from simple sugar could be useful in the synthesis of plant-based aromatic chemicals. PMID- 26055893 TI - Selectivity of commonly used inhibitors of clathrin-mediated and caveolae dependent endocytosis of G protein-coupled receptors. AB - Among the multiple G protein-coupled receptor (GPCR) endocytic pathways, clathrin mediated endocytosis (CME) and caveolar endocytosis are more extensively characterized than other endocytic pathways. A number of endocytic inhibitors have been used to block CME; however, systemic studies to determine the selectivity of these inhibitors are needed. Clathrin heavy chain or caveolin1 knockdown cells have been employed to determine the specificity of various chemical and molecular biological tools for CME and caveolar endocytosis. Sucrose, concanavalin A, and dominant negative mutants of dynamin blocked other endocytic pathways, in addition to CME. In particular, concanavalin A nonspecifically interfered with the signaling of several GPCRs tested in the study. Decreased pH, monodansylcadaverine, and dominant negative mutants of epsin were more specific for CME than other treatments were. A recently introduced CME inhibitor, Pitstop2TM, showed only marginal selectivity for CME and interfered with receptor expression on the cell surface. Blockade of receptor endocytosis by epsin mutants and knockdown of the clathrin heavy chain enhanced the beta2AR mediated ERK activation. Overall, our studies show that previous experimental results should be interpreted with discretion if they included the use of endocytic inhibitors that were previously thought to be CME-selective. In addition, our study shows that endocytosis of beta2 adrenoceptor through clathrin mediated pathway has negative effects on ERK activation. PMID- 26055894 TI - Effective protection of biological membranes against photo-oxidative damage: Polymeric antioxidant forming a protecting shield over the membrane. AB - We have prepared a chitosan polymer modified with gallic acid in order to develop an efficient protection strategy biological membranes against photodamage. Lipid bilayers were challenged with photoinduced damage by photosensitization with methylene blue, which usually causes formation of hydroperoxides, increasing area per lipid, and afterwards allowing leakage of internal materials. The damage was delayed by a solution of gallic acid in a concentration dependent manner, but further suppressed by the polymer at very low concentrations. The membrane of giant unilamellar vesicles was covered with this modified macromolecule leading to a powerful shield against singlet oxygen and thus effectively protecting the lipid membrane from oxidative stress. The results have proven the discovery of a promising strategy for photo protection of biological membranes. PMID- 26055895 TI - Impact of two different saponins on the organization of model lipid membranes. AB - Saponins, naturally occurring plant compounds are known for their biological and pharmacological activity. This activity is strongly related to the amphiphilic character of saponins that allows them to aggregate in aqueous solution and interact with membrane components. In this work, Langmuir monolayer techniques combined with polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS) and Brewster angle microscopy were used to study the interaction of selected saponins with lipid model membranes. Two structurally different saponins were used: digitonin and a commercial Merck Saponin. Membranes of different composition, namely, cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine or 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) were formed at the air/water and air/saponin solution interfaces. The saponin-lipid interaction was characterized by changes in surface pressure, surface potential, surface morphology and PM-IRRAS signal. Both saponins interact with model membranes and change the physical state of membranes by perturbing the lipid acyl chain orientation. The changes in membrane fluidity were more significant upon the interaction with Merck Saponin. A higher affinity of saponins for cholesterol than phosphatidylglycerols was observed. Moreover, our results indicate that digitonin interacts strongly with cholesterol and solubilize the cholesterol monolayer at higher surface pressures. It was shown, that digitonin easily penetrate to the cholesterol monolayer and forms a hydrogen bond with the hydroxyl groups. These findings might be useful in further understanding of the saponin action at the membrane interface and of the mechanism of membrane lysis. PMID- 26055896 TI - Lipid polyunsaturation determines the extent of membrane structural changes induced by Amphotericin B in Pichia pastoris yeast. AB - The activity of the potent but highly toxic antifungal drug Amphotericin B (AmB), used intravenously to treat systemic fungal and parasitic infections, is widely accepted to result from its specific interaction with the fungal sterol ergosterol. While the effect of sterols on AmB activity has been intensely investigated, the role of membrane phospholipid composition has largely been ignored, and structural studies of native membranes have been hampered by their complex and disordered nature. We show for the first time that the structure of fungal membranes derived from Pichia pastoris yeast depends on the degree of lipid polyunsaturation, which has an impact on the structural consequences of AmB activity. AmB inserts in yeast membranes even in the absence of ergosterol, and forms an extra-membraneous layer whose thickness is resolved to be 4-5 nm. In ergosterol-containing membranes, AmB insertion is accompanied by ergosterol extraction into this layer. The AmB-sponge mediated depletion of ergosterol from P. pastoris membranes gives rise to a significant membrane thinning effect that depends on the degree of lipid polyunsaturation. The resulting hydrophobic mismatch is likely to interfere with a much broader range of membrane protein functions than those directly involving ergosterol, and suggests that polyunsaturated lipids could boost the efficiency of AmB. Furthermore, a low degree of lipid polyunsaturation leads to least AmB insertion and may protect host cells against the toxic effects of AmB. These results provide a new framework based on lipid composition and membrane structure through which we can understand its antifungal action and develop better treatments. PMID- 26055897 TI - Bone Metastases and the EGFR and KRAS Mutation Status in Lung Adenocarcinoma--The Results of Three Year Retrospective Analysis. AB - Lung cancer is a heterogeneous group of disease and mutational profiling of lung adenocarcinomas is a routine practice in thoracic oncology. Kirsten-RAS (KRAS) and EGFR mutations play an important role in the carcinogenesis of a subset of lung adenocarcinomas. Our aim was to investigate the correlation between bone metastases and EGFR and KRAS mutation status in lung adenocarcinoma patients. Retrospectively we analysed 224 patients with recurrent or metastatic lung adenocarcinomas. Patients were treated with standard chemotherapy as first line therapy and with EGFR-TK inhibitors as a second or third line therapy. 72 of 224 patients (32 %) had verified bone metastases. Bone metastases and Skeletal Related Events (SRE) were more frequent in men, heavy smokers and without treatment of EGFR TK inhibitors. We have found that EGFR and KRAS mutation status are both predictive factors for the treatment efficacy and prognostic factors for the disease progression. However there were no significant correlation between mutation status and the presence of bone metastases (P = 0, 59). In our study the presence of bone metastases proved to be an independent prognostic factor related to poor performance status and worse Quality of Life (QL). PMID- 26055898 TI - Analysis of adolescent profiles by gender: strengths, attitudes toward violence and sexism. AB - The present study analyzes the profiles of boys and girls, considering gender, in the early stages of adolescence in the variables of character strengths, attitudes toward diversity and violence, and sexism. The aim is to explore the gender differences, whether the variables in each set differ from one another and whether these differences are maintained in profiles for boys and girls. The participants were 527 students (mean age = 12.21 and SD = 0.53) from the city of Malaga (Spain). Profile analysis was used to analyze data. The results, using an alpha of 0.0021 for each contrast, indicate that boys and girls differ in their character strengths, particularly in the case of girls, whose prominent strengths relate to pro-social behavior and peer relationships, where Cohen's d are higher than .30. Moreover, boys justify attitudes of violence to a greater extent (Cohen's d from .44 to .81) and show greater agreement with sexist beliefs (d = .63). The research suggests that it would be of interest to encourage advancement in character strengths at this age. PMID- 26055899 TI - Screening enterprising personality in youth: an empirical model. AB - Entrepreneurial attitudes of individuals are determined by different variables, some of them related to the cognitive and personality characteristics of the person, and others focused on contextual aspects. The aim of this study is to review the essential dimensions of enterprising personality and develop a test that will permit their thorough assessment. Nine dimensions were identified: achievement motivation, risk taking, innovativeness, autonomy, internal locus of control, external locus of control, stress tolerance, self-efficacy and optimism. For the assessment of these dimensions, 161 items were developed which were applied to a sample of 416 students, 54% male and 46% female (M = 17.89 years old, SD = 3.26). After conducting several qualitative and quantitative analyses, the final test was composed of 127 items with acceptable psychometric properties. Alpha coefficients for the subscales ranged from .81 to .98. The validity evidence relative to the content was provided by experts (V = .71, 95% CI = .56 - .85). Construct validity was assessed using different factorial analyses, obtaining a dimensional structure in accordance with the proposed model of nine interdependent dimensions as well as a global factor that groups these nine dimensions (explained variance = 49.07%; chi2/df = 1.78; GFI= .97; SRMR = .07). Nine out of the 127 items showed Differential Item Functioning as a function of gender (p < .01, R 2 >.035). The results obtained are discussed and future lines of research analyzed. PMID- 26055900 TI - Assessing the stability of psychopathic traits: adolescent outcomes in a six-year follow-up. AB - Previous research has shown the relevance of psychopathic traits as predictors of severe and persistent antisocial behavior. Given that personality traits refer to developmental constructs, the main purposes of this study were to analyze the stability of psychopathic traits from childhood to adolescence, and to examine differential outcomes derived from distinctive pathways of stability and change. Data was collected in a Spanish sample of 138 children aged 6-11 at the onset of the study (T1), and 12-17 in the subsequent follow-up conducted 6 years later (T2). The stability of psychopathic traits was assessed in terms of differential continuity (rank-order), absolute stability (mean-level) and individual-level change (Reliable Change Index). Results confirmed that psychopathic traits remained moderately to highly stable from childhood to adolescence (p < .001). There were, however, some differences depending on the informant (parents vs. teachers) and the particular assessment method used (rank order vs. mean-level and RCI). A stable high and an increasing developmental pattern of psychopathic traits were related with severe adolescent behavioral and psychosocial problems (n2 = .10-.36). These results support the usefulness of youth psychopathic personality as a developmental construct, and highlight its relevance as a predictor of long-lasting maladjustment, with relevant implications in terms of prevention and treatment. PMID- 26055902 TI - [Abdominal mass in an adolescent]. PMID- 26055903 TI - Molecular nutrition: basic understanding of the digestion, absorption, and metabolism of nutrients. PMID- 26055905 TI - Cross-talk between bile acids and intestinal microbiota in host metabolism and health. AB - Bile acid (BA) is de novo synthesized exclusively in the liver and has direct or indirect antimicrobial effects. On the other hand, the composition and size of the BA pool can be altered by intestinal microbiota via the biotransformation of primary BAs to secondary BAs, and subsequently regulate the nuclear farnesoid X receptor (FXR; NR1H4). The BA-activated FXR plays important roles in BA synthesis and metabolism, glucose and lipid metabolism, and even hepatic autophagy. BAs can also play a role in the interplays among intestinal microbes. In this review, we mainly discuss the interactions between BAs and intestinal microbiota and their roles in regulating host metabolism, and probably the autophagic signaling pathway. PMID- 26055906 TI - Tissue lipid metabolism and hepatic metabolomic profiling in response to supplementation of fermented cottonseed meal in the diets of broiler chickens. AB - This study investigated the effects of fermented cottonseed meal (FCSM) on lipid metabolites, lipid metabolism-related gene expression in liver tissues and abdominal adipose tissues, and hepatic metabolomic profiling in broiler chickens. One hundred and eighty 21-d-old broiler chickens were randomly divided into three diet groups with six replicates of 10 birds in each group. The three diets consisted of a control diet supplemented with unfermented cottonseed meal, an experimental diet of cottonseed meal fermented by Candida tropicalis, and a second experimental diet of cottonseed meal fermented by C. tropicalis plus Saccharomyces cerevisae. The results showed that FCSM intake significantly decreased the levels of abdominal fat and hepatic triglycerides (P<0.05 for both). Dietary FCSM supplementation down-regulated the mRNA expression of fatty acid synthase and acetyl CoA carboxylase in liver tissues and the lipoprotein lipase expression in abdominal fat tissues (P<0.05 for both). FCSM intake resulted in significant metabolic changes of multiple pathways in the liver involving the tricarboxylic acid cycle, synthesis of fatty acids, and the metabolism of glycerolipid and amino acids. These findings indicated that FCSM regulated lipid metabolism by increasing or decreasing the expression of the lipid-related gene and by altering multiple endogenous metabolites. Lipid metabolism regulation is a complex process, this discovery provided new essential information about the effects of FCSM diets in broiler chickens and demonstrated the great potential of nutrimetabolomics in researching complex nutrients added to animal diets. PMID- 26055907 TI - Influence of dietary taurine and housing density on oviduct function in laying hens. AB - Experiments were conducted to study the effects of dietary taurine and housing density on oviduct function in laying hens. Green-shell laying hens were randomly assigned to a free range group and two caged groups, one with low-density and the other with high-density housing. Each group was further divided into control (C) and taurine treatment (T) groups. All hens were fed the same basic diet except that the T groups' diet was supplemented with 0.1% taurine. The experiment lasted 15 d. Survival rates, laying rates, daily feed consumption, and daily weight gain were recorded. Histological changes, inflammatory mediator levels, and oxidation and anti-oxidation levels were determined. The results show that dietary taurine supplementation and reduced housing density significantly attenuated pathophysiological changes in the oviduct. Nuclear factor-kappaB (NF-kappaB) DNA binding activity increased significantly in the high-density housing group compared with the two other housing groups and was reduced by taurine supplementation. Tumor necrosis factor-alpha (TNF-alpha) mRNA expression in the high-density and low-density C and T groups increased significantly. In the free range and low-density groups, dietary taurine significantly reduced the expression of TNF-alpha mRNA. Supplementation with taurine decreased interferon gamma (IFN-gamma) mRNA expression significantly in the low-density groups. Interleukin 4 (IL-4) mRNA expression was significantly higher in caged hens. IL 10 mRNA expression was higher in the high-density C group than in the free range and low-density C groups. Supplementation with taurine decreased IL-10 mRNA expression significantly in the high-density group and increased superoxide dismutase (SOD) activity in the free range hens. We conclude that taurine has important protective effects against oviduct damage. Reducing housing density also results in less oxidative stress, less inflammatory cell infiltration, and lower levels of inflammatory mediators in the oviduct. Therefore, both dietary taurine and reduced housing density can ameliorate oviduct injury, enhance oviduct health, and promote egg production in laying hens. PMID- 26055904 TI - Within-litter variation in birth weight: impact of nutritional status in the sow. AB - Accompanying the beneficial improvement in litter size from genetic selection for high-prolificacy sows, within-litter variation in birth weight has increased with detrimental effects on post-natal growth and survival due to an increase in the proportion of piglets with low birth-weight. Causes of within-litter variation in birth weight include breed characteristics that affect uterine space, ovulation rate, degree of maturation of oocytes, duration of time required for ovulation, interval between ovulation and fertilization, uterine capacity for implantation and placentation, size and efficiency of placental transport of nutrients, communication between conceptus/fetus and maternal systems, as well as nutritional status and environmental influences during gestation. Because these factors contribute to within-litter variation in birth weight, nutritional status of the sow to improve fetal-placental development must focus on the following three important stages in the reproductive cycle: pre-mating or weaning to estrus, early gestation and late gestation. The goal is to increase the homogeneity of development of oocytes and conceptuses, decrease variations in conceptus development during implantation and placentation, and improve birth weights of newborn piglets. Though some progress has been made in nutritional regulation of within-litter variation in the birth weight of piglets, additional studies, with a focus on and insights into molecular mechanisms of reproductive physiology from the aspects of maternal growth and offspring development, as well as their regulation by nutrients provided to the sow, are urgently needed. PMID- 26055908 TI - iTRAQ-based quantitative proteomic analysis of longissimus muscle from growing pigs with dietary supplementation of non-starch polysaccharide enzymes. AB - Non-starch polysaccharide enzymes (NSPEs) have long been used in the feed production of monogastric animals to degrade non-starch polysaccharide to oligosaccharides and promote growth performance. However, few studies have been conducted on the effect of such enzymes on skeletal muscle in monogastric animals. To elucidate the mechanism of the effect of NSPEs on skeletal muscle, an isobaric tag for relative and absolute quantification (iTRAQ) for differential proteomic quantitation was applied to investigate alterations in the proteome in the longissimus muscle (LM) of growing pigs after a 50-d period of supplementation with 0.6% NSPEs in the diet. A total of 51 proteins were found to be differentially expressed in the LM between a control group and the NSPE group. Functional analysis of the differentially expressed protein species showed an increased abundance of proteins related to energy production, protein synthesis, muscular differentiation, immunity, oxidation resistance and detoxification, and a decreased abundance of proteins related to inflammation in the LM of the pigs fed NSPEs. These findings have important implications for understanding the mechanisms whereby dietary supplementation with NSPEs enzymes can promote growth performance and improve muscular metabolism in growing pigs. PMID- 26055909 TI - Effects of alfalfa saponin extract on mRNA expression of Ldlr, LXRalpha, and FXR in BRL cells. AB - We studied the effects of alfalfa saponin extract (ASE) on low density lipoprotein receptor (Ldlr), liver X receptor alpha (LXRalpha), and farnesoid X receptor (FXR) in normal and hyperlipidemic Buffalo rat liver (BRL) cells. Normal and hyperlipidemic BRL cells were divided into eight groups: normal, or normal cells treated with 50, 100, and 150 mg/L ASE, hyperlipidemic, or hyperlipidemic cells treated with 50, 100, and 150 mg/L ASE. After treatment for 24 h, Ldlr, LXRalpha, and FXR mRNA expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Data showed that mRNA expression of Ldlr in normal BRL cells was significantly up-regulated by ASE treatment and mRNA expressions of LXRalpha and FXR were significantly down-regulated both in normal and hyperlipidemic BRL cells after ASE treatment. Thus, ASE might ameliorate hepatic steatosis by regulating genes involved in cholesterol metabolism, including up-regulation of Ldlr as well as down-regulation of LXRalpha and FXR. PMID- 26055910 TI - Effect of dietary supplementation of Bacillus subtilis B10 on biochemical and molecular parameters in the serum and liver of high-fat diet-induced obese mice. AB - While a high-fat diet (HFD) is assumed to be related to fat-mediated oxidative stress decreasing antioxidant enzyme activity, probiotics are believed to have positive effects on the regulation of HFD-induced obesity as well as lipid metabolism, energy homeostasis, and anti-oxidation. Because Bacillus subtilis B10 has beneficial effects on the abnormal lipid metabolism and the oxidative stress in HFD-induced obese mice, ICR mice were randomly assigned into an HFD group and the HFD was supplemented with 0.1% (w/w) Bacillus subtilis B10 (HFD+B10 group). Thereafter, 30-d treatments were run, and then hepatic lipid level and antioxidant status were measured. The expression of genes related to lipid metabolism and oxidative stress in the liver was determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). We found that HFD induced obese mice treated with B10 showed a decrease in weight gain, serum glucose activity as well as hepatic triglyceride (TG), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) activities. In addition, the gene expressions of antioxidant genes, glutathione reductase (GR), xanthine oxidase (XO), heat-shock protein 90 (Hsp90), and lipid synthesis gene 3beta-hydroxysteroid-?24 reductase (DHCR24) in the HFD+B10 group were down regulated, suggesting alleviation of oxidative stress, while the lipolysis gene 3 hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), energy metabolism gene peroxisome proliferator-activated receptor alpha (PPARalpha) and the gene encoding tumor-suppressor protein p53 were up-regulated. The regulatory and positive effect of dietary supplementation of probiotic B10 suggests that it has a beneficial effect on the homeostasis of the lipid metabolism and on alleviating oxidative stress in HFD-induced obese mice. PMID- 26055911 TI - Effects of reducing dietary protein on the expression of nutrition sensing genes (amino acid transporters) in weaned piglets. AB - The effects of crude protein (CP) levels in the diet on the mRNA expression of amino acid (AA) transporters were studied in a 45-d trial. Eighteen piglets with an initial body weight (BW) of 9.57 kg were assigned to three groups (14%, 17%, and 20% CP in the diet) in a completely randomized design (six replicates per treatment). Diets were supplemented with crystalline AA to achieve equal standardized ileal digestible contents of Lys, Met plus Cys, Thr, and Trp, and were provided ad libitum. After 45 d, all piglets were slaughtered to collect small intestine samples. Compared with the values in the 14% CP group, the expressions of ASCT2, 4F2hc, and ATB(0) mRNA in the jejunum were increased by 23.00%, 12.00%, 6.00% and 48.00%, 47.00%, 56.00% in the 17% and 20% CP groups, respectively. These results indicate that a 14% CP diet supplemented with crystalline AA may not transport enough AA into the body and maintain growth performance of piglets. However, a reduction of dietary 17% CP may reduce the excretion of nitrogen into the environment while supporting the development of piglets. Therefore, the 17% CP level is more suitable than 14% CP level. PMID- 26055912 TI - Duodenum has the greatest potential to absorb soluble non-ammonia nitrogen in the nonmesenteric gastrointestinal tissues of dairy cows. AB - In cattle, dietary protein is gradually degraded into peptide-bound amino acids (PBAAs), free amino acids (FAAs), and ultimately into ammonia by the rumen microbes. Both PBAA and FAA are milk protein precursors, and the rumen and small intestines are the main sites where such precursors are produced and absorbed. This work was designed to investigate the expression of the peptide transporter PepT1 and the AA transporters ASCT2, y(+)LAT1, and ATB(0,+), and the concentrations of PBAA, FAA, and soluble protein in the rumen, omasum, and duodenum of dairy cows. Tissues and digesta were collected from six healthy Chinese Holstein dairy cows immediately after the animals were slaughtered. The expression of transporters was analyzed by real-time quantitative polymerase chain reaction (PCR). The FAA concentration was assessed using an amino acid (AA) analyzer, PBAA concentration by quantification of AA before and after acid hydrolysis by 6 mol/L HCl, and soluble protein concentration by quantification of the bicinchoninic acid content. The results showed that the relative abundance of mRNA of the transporters and the soluble non-ammonia nitrogen (SNAN) concentration of each fraction were greater in the duodenum than in the rumen or omasum. These results indicate that the duodenum is the predominant location within the nonmesenteric digestive tract for producing milk protein precursors. In addition, PBAA was the largest component of SNAN in the digesta from the rumen, omasum, and duodenum. In conclusion, the duodenum has the greatest concentrations of SNAN and PBAA, and the greatest potential for absorption of SNAN in the form of PBAA in the nonmesenteric gastrointestinal tissues of dairy cows. PMID- 26055913 TI - Growth of embryo and gene expression of nutrient transporters in the small intestine of the domestic pigeon (Columba livia). AB - The objective of this study was to investigate the relationship between gene expression of nutrient (amino acid, peptide, sodium and proton) transporters in the small intestine and embryonic growth in domestic pigeons (Columba livia). One hundred and twenty-five fertilized eggs were randomly assigned into five groups and were incubated under optimal conditions (temperature of 38.1 degrees C and relative humidity of 55%). Twenty embryos/birds from each group were sacrificed by cervical dislocation on embryonic day (E) 9, 11, 13, 15 and day of hatch (DOH). The eggs, embryos (without yolk sac), and organs (head, brain, heart, liver, lungs, kidney, gizzard, small intestine, legs, and thorax) were dissected, cleaned, and weighed. Small intestine samples were collected for RNA isolation. The mRNA abundance of intestinal nutrient transporters was evaluated by real-time reverse transcription-polymerase chain reaction (RT-PCR). We classified these ten organs into four types according to the changes in relative weight during embryonic development. In addition, the gene expression of nutrient transporters was differentially regulated by embryonic day. The mRNA abundances of b(0,+)AT, EAAT3, y(+)LAT2, PepT1, LAT4, NHE2, and NHE3 increased linearly with age, whereas mRNA abundances of CAT1, CAT2, LAT1, EAAT2, SNAT1, and SNAT2 were increased to higher levels on E9 or E11 and then decreased to lower levels until DOH. The results of correlation analysis showed that the gene expressions of b(0,+)AT, EAAT3, PepT1, LAT4, NHE2, NHE3, and y(+)LAT2 had positive correlations with body weight (0.710.05) from those of the control group. The phosphorylation ratio of the mammalian target of rapamycin (mTOR) (Ser(2448)) increased (P<0.05) within 48 h, and apparent differences were abrogated at 72 h (P>0.05). Moreover, cleaved caspase-3 expression was increased at 72 h (P<0.05). These findings indicate that HS induces apoptosis and disrupts cell cycle distribution to decrease the number of cells. Additionally, HS can promote SC growth via an activated Akt/mTOR/S6K signaling pathway. PMID- 26055918 TI - Leucine and histidine independently regulate milk protein synthesis in bovine mammary epithelial cells via mTOR signaling pathway. AB - The aim of this study is to investigate the effects of leucine (Leu) and histidine (His) on the expression of both the mammalian target of rapamycin (mTOR) signaling pathway-related proteins and caseins in immortalized bovine mammary epithelial cells (CMEC-H), using a single supplement through Western blotting. The Earle's balanced salt solution (EBSS) was set as the control group and other treatment groups, based on the EBSS, were added with different concentrations of Leu or His, respectively. The results showed that, compared with the control group, the expression of caseins and the phosphorylation of mTOR (Ser(2481)), Raptor (Ser(792)), eIF4E (Ser(209)), and eEF2 (Thr(56)) increased with the Leu concentrations ranging from 0.45 to 10.80 mmol/L (P<0.01). The P 4EBP1 (Thr(37)) at 10.80 mmol/L Leu, and P-RPS6 (Ser(235/236)) at 5.40 to 10.80 mmol/L Leu all decreased. Similarly, the His supplementation from 0.15 to 9.60 mmol/L increased the expression of alphas2-casein, beta-casein, kappa-casein, P mTOR (Ser(2481)), P-Raptor (Ser(792)), P-S6K1 (Thr(389)), P-4EBP1 (Thr(37)), P eIF4E (Ser(209)), and P-eEF2 (Thr(56)) (P<0.01) in CMEC-H, whereas the alphas1 casein expression was only reduced at 9.60 mmol/L His, G protein beta subunit like protein (GbetaL) at 0.15 and 9.60 mmol/L His, and P-RPS6 at 4.80 to 9.60 mmol/L His. Our linear regression model assay suggested that the alphas1-casein expression was positively correlated with P-mTOR (P<0.01), P-S6K1 (P<0.01), and P eEF2 (P<0.01) for the addition of Leu, while the expressions of beta-casein (P<0.01) and kappa-casein (P<0.01) were positively correlated with P-eEF2 for the addition of His. In conclusion, the milk protein synthesis was up-regulated through activation of the mTOR pathway with the addition of Leu and His in CMEC H. PMID- 26055919 TI - Clinical Outcomes of Modified Mason-Allen Single-Row Repair for Bursal-Sided Partial-Thickness Rotator Cuff Tears: Comparison With the Double-Row Suture Bridge Technique. AB - BACKGROUND: Various repair techniques have been reported for the operative treatment of bursal-sided partial-thickness rotator cuff tears. Recently, arthroscopic single-row repair using a modified Mason-Allen technique has been introduced. HYPOTHESIS: The arthroscopic, modified Mason-Allen single-row technique with preservation of the articular-sided tendon provides satisfactory clinical outcomes and similar results to the double-row suture-bridge technique after conversion of a partial-thickness tear to a full-thickness tear. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A retrospective study was conducted on 84 consecutive patients with symptomatic, bursal-sided partial thickness rotator cuff tears involving more than 50% thickness of the tendon. A total of 47 patients were treated by the modified Mason-Allen single-row repair technique, preserving the articular-sided tendon, and 37 patients were treated by the double-row suture-bridge repair technique after conversion to a full thickness tear. The clinical and functional outcomes were evaluated using the American Shoulder and Elbow Surgeons (ASES) and Constant scores and a visual analog scale (VAS) for pain and satisfaction of patients. Magnetic resonance imaging (MRI) was used to analyze the integrity of tendons at 6-month follow-up. Patients were followed up for a mean of 32.5 months. RESULTS: In the 47 patients treated with the modified Mason-Allen suture technique, the VAS score decreased from a preoperative mean of 5.3 +/- 0.3 to 0.9 +/- 0.5 at the time of final follow-up. There was a statistically significant increase in the mean ASES score (from 45.4 +/- 2.9 to 88.6 +/- 4.5) and mean Constant score (from 66.9 +/- 2.6 to 88.1 +/- 2.4) (P < .001). Four of 47 patients (8.5%) demonstrated retears at 6 month postoperative MRI. There was no statistical difference in terms of functional outcomes and the retear rate compared with those of patients with the suture-bridge repair technique (3 patients, 8.1%). However, the mean number of suture anchors used in the patients with modified Mason-Allen suture repair (1.2 +/- 0.4) was significantly fewer than that in the patients with suture-bridge repair (3.2 +/- 0.4) (P < .01). CONCLUSION: The modified Mason-Allen single-row repair technique that preserved the articular-sided tendon provided satisfactory clinical outcomes in patients with symptomatic, bursal-sided partial-thickness rotator cuff tears. Despite a fewer number of suture anchors, the shoulder functional outcomes and retear rate in patients after modified Mason-Allen repair were comparable with those of patients who underwent double-row suture-bridge repair. Therefore, the modified Mason-Allen single-row repair technique using a triple-loaded suture anchor can be considered as an effective treatment in patients with bursal-sided partial-thickness rotator cuff tears. PMID- 26055920 TI - A Comparative Assessment of Observational Medical Outcomes Partnership and Mini Sentinel Common Data Models and Analytics: Implications for Active Drug Safety Surveillance. AB - INTRODUCTION: An often key component to coordinating surveillance activities across distributed networks is the design and implementation of a common data model (CDM). The purpose of this study was to evaluate two drug safety surveillance CDMs from an ecosystem perspective to better understand how differences in CDMs and analytic tools affect usability and interpretation of results. METHODS: Humana claims data from 2007 to 2012 were mapped to Observational Medical Outcomes Partnership (OMOP) and Mini-Sentinel CDMs. Data were described and compared at the patient level by source code and mapped concepts. Study cohort construction and effect estimates were also compared using two different analytical methods--one based on a new user design implementing a high-dimensional propensity score (HDPS) algorithm and the other based on univariate self-controlled case series (SCCS) design--across six established positive drug-outcome pairs to learn how differences in CDMs and analytics influence steps in the database analytic process and results. RESULTS: Claims data for approximately 7.7 million Humana health plan members were transformed into the two CDMs. Three health outcome cohorts and two drug cohorts showed differences in cohort size and constituency between Mini-Sentinel and OMOP CDMs, which was a result of multiple factors. Overall, the implementation of the HDPS procedure on Mini-Sentinel CDM detected more known positive associations than that on OMOP CDM. The SCCS method results were comparable on both CDMs. Differences in the implementation of the HDPS procedure between the two CDMs were identified; analytic model and risk period specification had a significant impact on the performance of the HDPS procedure on OMOP CDM. CONCLUSIONS: Differences were observed between OMOP and Mini-Sentinel CDMs. The analysis of both CDMs at the data model level indicated that such conceptual differences had only a slight but not significant impact on identifying known safety associations. Our results show that differences at the ecosystem level of analyses across the CDMs can lead to strikingly different risk estimations, but this can be primarily attributed to the choices of analytic approach and their implementation in the community developed analytic tools. The opportunities of using CDMs are clear, but our study shows the need for judicious comparison of analyses across the CDMs. Our work emphasizes the need for ongoing efforts to ensure sustainable transparent platforms to maintain and develop CDMs and associated tools for effective safety surveillance. PMID- 26055921 TI - Folate and B12 serum levels in association with depression in the aged: a systematic review and meta-analysis. AB - OBJECTIVES: To systematically review and meta-analyse existing evidence on the association between folate/B12, and depression among the aged people. METHODS: Following PRISMA/STROBE guidelines, the Medline abstracts were retrieved using an algorithm comprising relevant MeSH terms. Publications on the association of folate/B12 serum measurements with depression were abstracted independently by two reviewers and included in both gender and gender-specific meta-analyses, following recarculations of published data as appropriate. The Newcastle-Ottawa scale was used to evaluate the quality of included studies. RESULTS: Both gender data were contributed by 11 folate-related (7949 individuals) and 9 B12-related studies (6308 individuals), whereas gender-specific data by 4 folate-related (3409 individuals) and 3 B12-related studies (1934 individuals). A statistically significant overall association between both exposures of interest (low folate and B12 levels) and depression was observed (ORfolate:1.23, 95%CI:1.07-1.43, ORB12:1.20, 95%CI:1.02-1.42). Gender-specific estimates pointed to a statistically significant positive association between low B12 levels and depression only among women (OR:1.33, 95%CI:1.02-1.74); the gender specific associations of low folate levels with depression were, however, non-significant and of counter-direction (ORfemales:1.37, 95%CI:0.90-2.07; ORmales:0.84, 95%CI:0.57-1.25). CONCLUSION: Low folate and B12 serum levels seem to be associated with depression in the aged. The gender-specific analyses are confined to a positive association of low B12 with depression among older women and call for further research in this direction. PMID- 26055922 TI - Serum and cerebrospinal fluid concentrations of homoarginine, arginine, asymmetric and symmetric dimethylarginine, nitrite and nitrate in patients with multiple sclerosis and neuromyelitis optica. AB - The pathogenic hallmarks of multiple sclerosis (MS) and neuromyelitis optica (NMO) are cellular and humoral inflammatory infiltrates and subsequent demyelination, or astrocytic cell death in NMO, respectively. These processes are accompanied by disruption of the blood-brain barrier as regularly observed by gadolinium enhancement on magnetic resonance imaging. The role of the L arginine/nitric oxide (NO) pathway in the pathophysiology of neuroinflammatory diseases, such as MS and NMO, remains unclear. In the present study, we measured the concentrations of the nitric oxide (NO) metabolites nitrate and nitrite, the endogenous substrates of NO synthase (NOS) L-arginine (Arg) and L-homoarginine (hArg), and asymmetric dimethylarginine (ADMA), the endogenous inhibitor of NOS activity, in the serum and cerebrospinal fluid (CSF) of patients with MS, NMO or other neurologic diseases (OND). MS (551 +/- 23 nM, P = 0.004) and NMO (608 +/- 51 nM, P = 0.006) patients have higher ADMA concentrations in serum than healthy controls (HC; 430 +/- 24 nM). For MS, this finding was confirmed in CSF (685 +/- 100 nM in relapsing-remitting multiple sclerosis, RRMS; 597 +/- 51 nM in secondary progressive multiple sclerosis, SPMS) compared with OND (514 +/- 37 nM; P = 0.003). Serum concentrations of Arg (61.1 +/- 9.7 vs. 63.6 +/- 4.9 uM, P = 0.760), hArg (2.62 +/- 0.26 vs. 2.52 +/- 0.23 uM, P = 0.891), nitrate (38.1 +/- 2.2 vs. 38.1 +/- 3.0 uM) and nitrite (1.37 +/- 0.09 vs. 1.55 +/- 0.03 uM) did not differ between MS and OND. Also, CSF concentrations of hArg (0.685 +/- 0.100 uM in RRMS, 0.597 +/- 0.051 uM in SPMS, 0.514 +/- 0.037 uM in OND), nitrate (11.3 +/ 0.6 vs. 10.5 +/- 0.3 uM) and nitrite (2.84 +/- 0.32 vs. 2.41 +/- 0.11 uM) did not differ between the groups. In NMO patients, however, serum Arg (117 +/- 11 vs. 64 +/- 4.9 MUM, P = 0.004), nitrate (29 +/- 2.1 vs. 38 +/- 3 MUM, P = 0.03), and nitrite (1.09 +/- 0.02 vs. 1.55 +/- 0.033 uM, P < 0.0001) were significantly different as compared to OND. Symmetric dimethylarginine (SDMA) concentration did not differ in serum between MS and HC (779 +/- 43 vs. 755 +/- 58 nM, P = 0.681) or in CSF between MS and OND patients (237 +/- 11 vs. 230 +/- 17 nM, P = 0.217). Our study suggests a potential role for ADMA and Arg in neuroinflammatory diseases with diverse functions in MS and NMO. Higher ADMA synthesis may explain reduced NO availability in NMO. hArg and SDMA seem not to play an important role in MS and NMO. PMID- 26055923 TI - Virulence profile: Bernhard Hube. PMID- 26055924 TI - Recent Trends in Out-of-Hospital Births in the United States. AB - INTRODUCTION: Although out-of-hospital births are still relatively rare in the United States, it is important to monitor trends in these births, as they can affect patterns of facility usage, clinician training, and resource allocation, as well as health care costs. Trends and characteristics of home and birth center births are analyzed to more completely profile contemporary out-of-hospital births in the United States. METHODS: National birth certificate data were used to examine a recent increase in out-of-hospital births. RESULTS: After a gradual decline from 1990 to 2004, the number of out-of-hospital births increased from 35,578 in 2004 to 47,028 in 2010. In 2010, 1 in 85 US infants (1.18%) was born outside a hospital; about two-thirds of these were born at home, and most of the rest were born in birth centers. The proportion of home births increased by 41%, from 0.56% in 2004 to 0.79% in 2010, with 10% of that increase occurring in the last year. The proportion of birth center births increased by 43%, from 0.23% in 2004 to 0.33% in 2010, with 14% of the increase in the last year. About 90% of the total increase in out-of hospital births from 2004 to 2010 was a result of increases among non-Hispanic white women, and 1 in 57 births to non-Hispanic white women (1.75%) in 2010 was an out-of-hospital birth. Most home and birth center births were attended by midwives. DISCUSSION: Home and birth center births in the United States are increasing, and the rate of out-of-hospital births is now at the highest level since 1978. There has been a decline in the risk profile of out-of-hospital births, with a smaller proportion of out-of-hospital births in 2010 than in 2004 occurring to adolescents and unmarried women and fewer preterm, low-birth-weight, and multiple births. PMID- 26055925 TI - Toll-like receptor 2 (TLR2) induces migration and invasive mechanisms in rheumatoid arthritis. AB - INTRODUCTION: This study investigates the role of Toll-like receptor 2 (TLR2) in the regulation of migratory and invasive mechanisms in rheumatoid arthritis (RA). METHODS: Invasion, migration, matrix metalloproteinase (MMP)-1, -3 and tissue inhibitor of matrix metalloproteinase-3 (TIMP-3) expression, beta-integrin binding, cytoskeletal rearrangement and Ras-related C3 botulinum toxin substrate 1 (Rac1) activation in response to a TLR2-ligand, Pam3CSK4 (1 MUg/ml), in ex vivo RA synovial tissue explants, primary RA synovial fibroblasts (RASFC) and microvascular endothelial cells (HMVEC) were assessed by Transwell MatrigelTM invasion chambers, enzyme-linked immunosorbent assay (ELISA), multiplex adhesion binding assay, reverse transcription polymerase chain reaction (RT-PCR), F-actin immunofluorescent staining, matrigel synovial outgrowths, Rac1 pull-down assays/Western blot and zymography. beta1-integrin expression in RA/control synovial tissue was assessed by immunohistology. The effect of Pam3CSK4 on cell migration, invasion, MMP-3 and Rac1 activation was examined in the presence or absence of anti-beta1-integrin (10 MUg/ml) or anti-IgG control (10 MUg/ml). The effect of an anti-TLR-2 mAb (OPN301)(1 MUg/ml) or immunoglobulin G (IgG) control (1 MUg/ml) on RASFC migration and RA synovial tissue MMP activity was assessed by wound assays, ELISA and zymography. RESULTS: Pam3CSK4 significantly induced cell migration, invasion, MMP-1, MMP-3, MMP-2 and MMP-9 expression and induced the MMP 1/TIMP-3 and MMP-3/TIMP-3 ratio in RASFC and explants (p <0.05). beta1-integrin expression was significantly higher in RA synovial tissue compared to controls (p <0.05). Pam3CSK4 specifically induced beta1-integrin binding in RASFC (p <0.05), with no effect observed for beta2-4, beta6, alphavbeta5 or alpha5beta1. Pam3CSK4 increased beta1-integrin mRNA expression, Rac1 activation, RASFC outgrowths and altered cytoskeletal dynamic through induction of filopodia formation. Pam3CSK4 regulated cell migration and invasion processes, but not MMP-3, were inhibited in the presence of anti-beta1-integrin (p <0.05), with no effect observed for anti IgG control. Furthermore, anti-beta1-integrin inhibited Pam3CSK4-induced Rac1 activation. Finally, blockade of TLR2 with OPN301 significantly decreased spontaneous release of MMP-3, MMP-2 and MMP-9 and increased TIMP-3 secretion from RA synovial explant cultures (p <0.05). Incubation of RASFC with OPN301 RA ex vivo conditioned media inhibited migration and invasion compared to IgG control. CONCLUSIONS: TLR2 activation induces migrational and invasive mechanisms, which are critically involved in the pathogenesis of RA, suggesting TLR2 as a potential therapeutic target for the treatment of RA. PMID- 26055927 TI - Impact of vancomycin faecal concentrations on clinical and microbiological outcomes in Clostridium difficile infection. AB - To assess the impact of faecal vancomycin concentrations on clinical and microbiological outcomes in patients with Clostridium difficile infection (CDI) and whether these concentrations vary with stool consistency and frequency, faecal concentrations of vancomycin were measured in stools collected at various times from patients initiated on 125mg every 6h (q6h) for 10 days. Stool consistency and frequency were determined over the course of therapy. Clinical and microbiological outcomes were assessed during therapy, at the end of therapy (EOT) and during a 19-38-day follow-up visit. Faecal vancomycin concentrations in 55 stool samples from 15 patients ranged from 175-6299MUg/g at Days 3-5 of therapy (midpoint), 17-5277MUg/g at EOT and 0-70MUg/g at follow-up. Clinical cure or failure at EOT and at follow-up was not dependent on vancomycin concentrations measured at the midpoint (P=0.72) or at EOT (P=0.76). Likewise, concentrations at EOT and at follow-up did not predict colonisation at follow-up (P=0.85 and 0.71, respectively). Faecal vancomycin concentrations during the course of therapy (Days 3-5) did not differ with either stool consistency or frequency (P=0.94 and 0.16, respectively). However, after completion of therapy, patients with more frequent stools showed higher concentrations than patients with less frequent stools (P=0.04). Oral vancomycin 125mg q6h led to faecal concentrations that did not predict clinical outcomes of CDI in terms of cure or gut colonisation and did not vary with stool consistency and frequency. PMID- 26055926 TI - Therapeutic Opportunities in Damage-Associated Molecular Pattern-Driven Metabolic Diseases. AB - SIGNIFICANCE: Sterile inflammation is a common finding present in various metabolic disorders. This type of inflammation is mediated by damage-associated molecular patterns (DAMPs) that are released upon cellular injury to activate pattern recognition receptors on innate immune cells and amplify organ damage. RECENT ADVANCES: In the last decade, DAMPs, such as high-mobility group protein B1, nucleic acids (DNA, RNA), adenosine triphosphate, and other metabolites, were found to contribute to the inflammatory response in diabetes, gout, obesity, steatohepatitis, and atherosclerosis. Varied receptors, including Toll-like receptors (TLRs), the purinergic P2X(7) receptors, and nucleotide-binding domain, and leucine-rich repeat protein 3 (NLRP3)-inflammasome sense DAMPs and DAMP-like molecules and release the proinflammatory cytokines, interleukin (IL)-1beta and IL-18. CRITICAL ISSUES: Available therapeutic approaches that interfered with the signaling of TLRs, P2X(7), NLRP3-inflammasome, and IL-1beta showed encouraging results in metabolic diseases, which will be also highlighted in this review. FUTURE DIRECTIONS: It is important to understand the origination of DAMPs and how they contribute to the inflammatory response in metabolic disorders to develop selective and efficient therapeutics for intervention. PMID- 26055929 TI - Fault detection for discrete-time switched systems with sensor stuck faults and servo inputs. AB - This paper addresses the fault detection problem of switched systems with servo inputs and sensor stuck faults. The attention is focused on designing a switching law and its associated fault detection filters (FDFs). The proposed switching law uses only the current states of FDFs, which guarantees the residuals are sensitive to the servo inputs with known frequency ranges in faulty cases and robust against them in fault-free case. Thus, the arbitrarily small sensor stuck faults, including outage faults can be detected in finite-frequency domain. The levels of sensitivity and robustness are measured in terms of the finite frequency H- index and l2-gain. Finally, the switching law and FDFs are obtained by the solution of a convex optimization problem. PMID- 26055928 TI - Sensorless sliding mode observer for a five-phase permanent magnet synchronous motor drive. AB - This paper deals with the sensorless vector controlled five-phase permanent magnet synchronous motor (PMSM) drive based on a sliding mode observer (SMO). The observer is designed considering the back electromotive force (EMF) of five-phase permanent magnet synchronous motor. The SMO structure and design are illustrated. Stability of the proposed observer is demonstrated using Lyapunov stability criteria. The proposed strategy is asymptotically stable in the context of Lyapunov theory. Simulated results on a five-phase PMSM drive are displayed to validate the feasibility and the effectiveness of the proposed control strategy. PMID- 26055930 TI - Physical and Biological Release of Poly- and Perfluoroalkyl Substances (PFASs) from Municipal Solid Waste in Anaerobic Model Landfill Reactors. AB - A wide variety of consumer products that are treated with poly- and perfluoroalkyl substances (PFASs) and related formulations are disposed of in landfills. Landfill leachate has significant concentrations of PFASs and acts as secondary point sources to surface water. This study models how PFASs enter leachate using four laboratory-scale anaerobic bioreactors filled with municipal solid waste (MSW) and operated over 273 days. Duplicate reactors were monitored under live and abiotic conditions to evaluate influences attributable to biological activity. The biologically active reactors simulated the methanogenic conditions that develop in all landfills, producing ~140 mL CH4/dry g refuse. The average total PFAS leaching measured in live reactors (16.7 nmol/kg dry refuse) was greater than the average for abiotic reactors (2.83 nmol/kg dry refuse), indicating biological processes were primarily responsible for leaching. The low level leaching in the abiotic reactors was primarily due to PFCAs <=C8 (2.48 nmol/kg dry refuse). Concentrations of known biodegradation intermediates, including methylperfluorobutane sulfonamide acetic acid and the n:2 and n:3 fluorotelomer carboxylates, increased steadily after the onset of methanogenesis, with the 5:3 fluorotelomer carboxylate becoming the single most concentrated PFAS observed in live reactors (9.53 nmol/kg dry refuse). PMID- 26055931 TI - Incremental Validity of Personality Measures in Predicting Underwater Performance and Adaptation. AB - Intelligence and personality traits are currently considered effective predictors of human behavior and job performance. However, there are few studies about their relevance in the underwater environment. Data from a sample of military personnel performing scuba diving courses were analyzed with regression techniques, testing the contribution of individual differences and ascertaining the incremental validity of the personality in an environment with extreme psychophysical demands. The results confirmed the incremental validity of personality traits (DeltaR 2 = .20, f 2 = .25) over the predictive contribution of general mental ability (DeltaR 2 = .07, f 2 = .08) in divers' performance. Moreover, personality (R(L)2 = .34) also showed a higher validity to predict underwater adaptation than general mental ability ( R(L)2 = .09). The ROC curve indicated 86% of the maximum possible discrimination power for the prediction of underwater adaptation, AUC = .86, p < .001, 95% CI (.82-.90). These findings confirm the shift and reversal of incremental validity of dispositional traits in the underwater environment and the relevance of personality traits as predictors of an effective response to the changing circumstances of military scuba diving. They also may improve the understanding of the behavioral effects and psychophysiological complications of diving and can also provide guidance for psychological intervention and prevention of risk in this extreme environment. PMID- 26055932 TI - Psychomedical care in gender identity dysphoria during adolescence. AB - INTRODUCTION: In the clinical literature, the term gender dysphoria is used to define the perception of rejection that a person has to the fact of being male or female. In children and adolescents, gender identity dysphoria is a complex clinical entity. The result of entity is variable and uncertain, but in the end only a few will be transsexuals in adulthood. OBJECTIVES: METHODOLOGY: RESULTS AND CONCLUSIONS. PMID- 26055933 TI - Screening the risk of bipolar spectrum disorders: Validity evidence of the Mood Disorder Questionnaire in adolescents and young adults. AB - The aim of this study was to gather sources of validity evidence of the Mood Disorder Questionnaire (MDQ) in young adults for its use as a screening tool for bipolar spectrum disorders. The sample was composed of 1,002 participants, 268 men (26.7%). The mean age of participants was 21.1 years (SD=3.9). The results showed that between 3 and 59% of the sample reported some hypomanic experience. Gender differences were found in the total score of the MDQ. The analysis of the internal structure by exploratory factor analysis yielded 2 factors, called Energy-Activity and Disinhibition-Attention. This dimensional structure was replicated in the exploratory structural equation modeling (ESEM), and also had factorial equivalence by gender. Participants who met the cut-off points of the MDQ reported a worse perceived mental health status and more consummatory and anticipatory pleasure, compared to the low scores group. These findings indicate that the MDQ has adequate psychometric properties in non-clinical samples, and could be useful as a screening tool in psychopathology, with the possibility of optimizing strategies for early identification and prevention in individuals at high risk for bipolar disorders. Future studies should further explore the role of subclinical bipolar phenotype and conduct longitudinal studies in samples of the general population. PMID- 26055934 TI - Utility of (18) F-FDG and (11)C-PBR28 microPET for the assessment of rat aortic aneurysm inflammation. AB - BACKGROUND: The utility of (18) F-FDG and (11)C-PBR28 to identify aortic wall inflammation associated with abdominal aortic aneurysm (AAA) development was assessed. METHODS: Utilizing the porcine pancreatic elastase (PPE) perfusion model, abdominal aortas of male Sprague-Dawley rats were infused with active PPE (APPE, AAA; N = 24) or heat-inactivated PPE (IPPE, controls; N = 16). Aortic diameter increases were monitored by ultrasound (US). Three, 7, and 14 days after induction, APPE and IPPE rats were imaged using (18) F-FDG microPET (approximately 37 MBq IV) and compared with (18) F-FDG autoradiography (approximately 185 MBq IV) performed at day 14. A subset of APPE (N = 5) and IPPE (N = 6) animals were imaged with both (11)C-PBR28 (approximately 19 MBq IV) and subsequent (18) F-FDG (approximately 37 MBq IV) microPET on the same day 14 days post PPE exposure. In addition, autoradiography of the retroperitoneal torso was performed after (11)C-PBR28 (approximately 1,480 MBq IV) or (18) F-FDG (approximately 185 MBq IV) administration at 14 days post PPE exposure. Aortic wall-to-muscle ratios (AMRs) were determined for microPET and autoradiography. CD68 and translocator protein (TSPO) immunohistochemistry (IHC), as well as TSPO gene expression assays, were performed for validation. RESULTS: Mean 3 (p = 0.009), 7 (p < 0.0001) and 14 (p < 0.0001) days aortic diameter increases were significantly greater for APPE AAAs compared to IPPE controls. No significant differences in (18) F-FDG AMR were determined at days 3 and 7 post PPE exposure; however, at day 14, the mean (18) F-FDG AMR was significantly elevated in APPE AAAs compared to IPPE controls on both microPET (p = 0.0002) and autoradiography (p = 0.02). Similarly, mean (11)C-PBR28 AMR was significantly increased at day 14 in APPE AAAs compared to IPPE controls on both microPET (p = 0.04) and autoradiography (p = 0.02). For APPE AAAs, inhomogeneously increased (18) F-FDG and (11)C-PBR28 uptake was noted preferentially at the anterolateral aspect of the AAA. Compared to controls, APPE AAAs demonstrated significantly increased macrophage cell counts by CD68 IHC (p = 0.001) as well as increased TSPO staining (p = 0.004). Mean TSPO gene expression for APPE AAAs was also significantly elevated compared to IPPE controls (p = 0.0002). CONCLUSION: Rat AAA wall inflammation can be visualized using (18) F-FDG and (11)C-PBR28 microPET revealing regional differences of radiotracer uptake on microPET and autoradiography. These results support further investigation of (18) F-FDG and (11)C-PBR28 in the noninvasive assessment of human AAA development. PMID- 26055935 TI - Preliminary clinical assessment of the relationship between tumor alphavbeta3 integrin and perfusion in patients studied with [(18)F]fluciclatide kinetics and [ (15)O]H 2O PET. AB - BACKGROUND: [(18)F]fluciclatide, a peptide ligand with high affinity for alphavbeta3/alphavbeta5 integrins, is a proposed biomarker of tumor angiogenesis. The study rationale was to perform a preliminary evaluation of the relationship between tumor [(18)F]fluciclatide uptake and perfusion by [(15)O]H2O PET. METHODS: Patients with non-small cell lung cancer and melanoma underwent dynamic imaging with arterial sampling following injection of [(15)O]H2O and [(18)F]fluciclatide. Quantification was performed using a one-tissue compartmental model for [(15)O]H2O and a two-tissue model for [(18)F]fluciclatide at volume-of-interest level, and SUV at voxel level. RESULTS: Tumor binding potential (k 3/k 4 ratio) of [(18)F]fluciclatide tumor was 5.39 +/- 1.46, consistent with previous studies in breast cancer metastases. Voxel-by-voxel maps of [(18)F]fluciclatide delivery strongly correlated with [(15)O]H2O-based perfusion (p < 10(-4) tumor, 1,794 +/- 1,331 voxels). Interestingly, this correlation was lost when retention of [(18)F]fluciclatide at late time-points was compared with perfusion (p > 0.15). CONCLUSIONS: Our study suggests tumor [(18)F]fluciclatide retention is unrelated to tumor perfusion, supporting use of late (60-min) imaging protocols in patients. PMID- 26055936 TI - Pilot study of (89)Zr-bevacizumab positron emission tomography in patients with advanced non-small cell lung cancer. AB - BACKGROUND: The aim of this pilot study was to evaluate whether the uptake of (89)Zr-bevacizumab in non-small cell lung cancer (NSCLC) tumors could be visualized and quantified. The correlation between tumor (89)Zr-bevacizumab uptake and tumor response to antitumor therapy with a bevacizumab-based regimen was explored. METHODS: Seven NSCLC patients underwent static PET scans at days 4 and 7 after injection of 36.4 +/- 0.9 MBq (mean +/- SD) (89)Zr-bevacizumab, prior to commencing carboplatin-paclitaxel-bevacizumab chemotherapy (CPB). Overall survival (OS) and progression-free survival (PFS) to CPB followed by bevacizumab maintenance therapy was correlated to tumor tracer uptake, quantified using peak standardized uptake values (SUVpeak). RESULTS: Zr-bevacizumab uptake (SUVpeak) was approximately four times higher in tumor tissues (primary tumor and metastases) than in non-tumor tissues (healthy muscle, lung, and fat) on days 4 and 7. A positive trend but no significant correlation could be found between SUVpeak and OS or PFS. CONCLUSIONS: This pilot study shows that (89)Zr bevacizumab PET imaging in NSCLC is feasible. Further investigation to validate this technique as a predictive biomarker for selecting patients for bevacizumab treatment is warranted. PMID- 26055937 TI - Characterization of SnO2-based (68)Ge/ (68)Ga generators and (68)Ga-DOTATATE preparations: radionuclide purity, radiochemical yield and long-term constancy. AB - BACKGROUND: With the increasing utilization of (68)Ge-(68)Ga radionuclide generators, (68)Ga labelled peptides like DOTATATE are receiving more attention in nuclear medicine. On the one hand, the long half-life of the parent nuclide (68)Ge is an enormous advantage for routine applications, but the question of the long-term stability of the (68)Ge breakthrough arises, which up to now has scarcely been investigated. METHOD: A sum of 123 eluates from four different (68)Ge-(68)Ga generators (iThemba Labs, Faure, South Africa) and 115 samples of the prepared radiopharmaceutical (68)Ga-DOTATATE were measured first with a dose calibrator and again after decay of the eluted (68)Ga via gamma-ray spectrometry. A complete decay curve was recorded for one sample eluate. A further three eluates were eluted in ten fractions of 0.5 ml in order to obtain detailed information concerning the distribution of the two nuclides within the eluates. The influences of factors such as the amount of DOTATATE, addition of Fe(3+) salts and replacement of HEPES buffer with sodium acetate on the radiochemical synthesis were also tested. RESULTS: The content of long-lived (68)Ge breakthrough increases over the entire period of use to more than 100 ppm. The labelling process with the chelator DOTA removes (68)Ge efficiently. The maximum activity found in the residues of the radiopharmaceuticals investigated in this study was below 10 Bq in nearly all cases. In many cases (12% of the labelled substance), the long-lived parent nuclide could not be identified at all. The labelling process is still viable for reduced amounts of the chelator and with acetate buffer. CONCLUSION: Effective doses received by the patient from (68)Ge in the injected radiopharmaceutical (68)Ga-DOTATATE are lower than 0.1 MUSv and are therefore practically negligible, especially when compared with the contribution of the PET radiopharmaceutical itself. Gamma-ray spectrometry as recommended by the European Pharmacopeia is suitable for quantification of radionuclidic impurities. PMID- 26055938 TI - Does quantitative lung SPECT detect lung abnormalities earlier than lung function tests? Results of a pilot study. AB - BACKGROUND: Heterogeneous ventilation in lungs of individuals with allergies, cigarette smokers, asthmatics and chronic obstructive pulmonary disease (COPD) patients has been demonstrated using imaging modalities such as positron emission tomography (PET), magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT). These individuals suffer from narrow and/or closed airways to various extents. By calculating regional heterogeneity in lung ventilation SPECT images as the coefficient of variation (CV) in small elements of the lung, heterogeneity maps and CV-density curves can be generated and used to quantitatively measure heterogeneity. This work explores the potential to use such measurements to detect mild ventilation heterogeneities in lung-healthy subjects. METHOD: Fourteen healthy subjects without documented lung disease or respiratory symptoms, and two patients with documented airway disease, inhaled on average approximately 90 MBq (99m)Tc-Technegas immediately prior to the 20-min SPECT acquisition. Variation in activity uptake between subjects was compensated for in resulting CV values. The area under the compensated CV density curve (AUC), for CV values greater than a threshold value CVT, AUC(CV > CVT), was used as the measure of ventilation heterogeneity. RESULTS: Patients with lung function abnormalities, according to lung function tests, generated higher AUC(CV > 20%) values compared to healthy subjects (p = 0.006). Strong linear correlations with the AUC(CV > 20%) values were found for age (p = 0.006) and height (p = 0.001). These demonstrated that ventilation heterogeneities increased with age and that they depend on lung size. Strong linear correlations were found for the lung function value related to indices of airway closure/air trapping, residual volume/total lung capacity (RV/TLC; p = 0.009), and diffusion capacity of the lung for carbon monoxide adjusted for haemoglobin concentration in the blood (DLCOc; p = 0.009), a value partly related to supposed ventilation/perfusion mismatch. These findings support the association between conventional lung function tests and the AUC(CV > 20%) value. CONCLUSIONS: Among the healthy subjects, there is a group with increased AUC(CV > 20%) values, but with normal lung function tests, which implies that it might be possible to differentiate ventilation heterogeneities earlier in a disease process than by lung function tests. PMID- 26055939 TI - Modification of intracellular glutathione status does not change the cardiac trapping of (64)Cu(ATSM). AB - BACKGROUND: The trapping mechanisms of the PET hypoxia imaging agent copper(II) diacetyl-bis(N (4)-methylthiosemicarbazone) ((64)Cu(ATSM)) remain unresolved, although its reduction prior to dissociation may be mediated by intracellular thiols. Glutathione (GSH) is the most abundant intracellular thiol, and its redox status changes in cancer cells and ischaemic myocardium (two prime applications for (64)Cu(ATSM) PET). We therefore investigated whether modification of intracellular GSH content affects the hypoxia selectivity of (64)Cu(ATSM). METHODS: Isolated rat hearts (n = five per group) were perfused with aerobic buffer (equilibrated with 95%O2/5%CO2) for 15 min, then hypoxic buffer (95%N2/5%CO2) for 20 min. Cardiac glutathione was depleted by buthionine sulphoximine (BSO, 4 mmol/kg/ 48 h intraperitoneal), or augmented by N-acetyl cysteine (NAC, 4 mmol/L) in the perfusion buffer. Cardiac (64)Cu retention from three 2-MBq bolus injections of (64)Cu(ATSM) before and during hypoxia was then monitored by NaI detectors. RESULTS: Cardiac GSH content was elevated by NAC and depleted by BSO (from 7.9 +/- 2.0 to 59.3 +/- 8.3 nmol/mg and 3.7 +/- 1.0 nmol/mg protein, respectively; p < 0.05). Hypoxia did not affect cardiac GSH content in any group. During normoxia, tracer washed out bi-exponentially, with 13.1% +/- 1.7% injected dose being retained; this was not affected by GSH augmentation or depletion. Hypoxia significantly increased tracer retention (to 59.1% +/- 6.3%, p < 0.05); this effect was not modified by GSH augmentation or depletion. CONCLUSION: Modification of GSH levels had no impact upon the pharmacokinetics or hypoxia selectivity of (64)Cu(ATSM). While thiols may yet prove essential for the intracellular trapping of (64)Cu(ATSM), they are not the determinants of its hypoxia selectivity. PMID- 26055940 TI - Imaging VEGF receptor expression to identify accelerated atherosclerosis. AB - BACKGROUND: The biology of the vulnerable plaque includes increased inflammation and rapid growth of vasa vasorum, processes that are associated with enhanced vascular endothelial growth factor (VEGF)/ imaging receptors for VEGF (VEGFR) signaling and are accelerated in diabetes. This study was designed to test the hypothesis that VEGFRs in atherosclerotic plaques with a SPECT tracer scVEGF-PEG DOTA/(99m)Tc (scV/Tc) can identify accelerated atherosclerosis in diabetes. METHODS: Male apolipoprotein E null (ApoE(-/-)) mice (6 weeks of age) were made diabetic (n = 10) or left as non-diabetic (n = 13). At 26 to 28 weeks of age, 5 non-diabetic mice were injected with functionally inactivated scV/Tc (in-scV/Tc) that does not bind to VEGF receptors, while 8 non-diabetic and 10 diabetic mice were injected with scV/Tc. After blood pool clearance, at 3 to 4 h post injection, mice were injected with CT contrast agent and underwent SPECT/CT imaging. From the scans, regions of interest (ROI) were drawn on serial transverse sections comprising the proximal aorta and the percentage of injected dose (%ID) in ROIs was calculated. At the completion of imaging, mice were euthanized, proximal aorta explanted for gamma well counting to determine the percentage of injected dose per gram (%ID/g) uptake and immunohistochemical characterization. RESULTS: The uptake of scV/Tc in the proximal aorta, calculated from SPECT/CT co-registered scans as %ID, was significantly higher in the diabetic mice (0.036 +/- 0.017%ID) compared to non-diabetic mice (0.017 +/- 0.005%ID; P < 0.01), as was uptake measured as %ID/g in harvested aorta, 1.81 +/- 0.50%ID/g in the diabetic group vs. 0.98 +/- 0.25%ID/g in the non-diabetic group (P < 0.01). The nonspecific uptake of in-scV/Tc in proximal aorta was significantly lower than the uptake of functionally active scV/Tc. Immunostaining of the atherosclerotic lesions showed higher expression of VEGFR-1 and VEGFR-2 in the diabetic mice. CONCLUSION: These initial results suggest that imaging VEGFR with scV/Tc shows promise as a non-invasive approach to identify accelerated atherosclerosis. PMID- 26055941 TI - Extramammary Paget's disease associated with underlying syringoma. PMID- 26055943 TI - Ochratoxin A at low concentrations inhibits in vitro growth of canine umbilical cord matrix mesenchymal stem cells through oxidative chromatin and DNA damage. AB - Ochratoxin A (OTA) exposure during pregnancy in laboratory animals induces delayed/abnormal embryo development. Foetal adnexa-derived mesenchymal stem cells (MSCs) could help evaluate the developmental risk of exposure to chemicals in advanced gestational age. We tested the effects of OTA at concentrations ranging from 2.5*10(-4) to 25nM on growth parameters of canine umbilical cord matrix (UCM)-derived MSCs. The hypothesis that oxidative chromatin and DNA damage could underlie OTA-mediated cell toxicity was also investigated. After in vitro exposure, OTA significantly decreased cell density and increased doubling time in a passage- and concentration-dependent manner and no exposed cells survived beyond passage 5. Significantly higher rates of cells showed condensed and fragmented chromatin and oxidized DNA, as assessed by OxyDNA assay. These findings showed that in vitro exposure to OTA, at picomolar levels, perturbs UCM MSC growth parameters through oxidative chromatin and DNA damage, suggesting possible consequences on canine foetal development. PMID- 26055942 TI - Spatial modulation of light transmission through a single microcavity by coupling of photosynthetic complex excitations to surface plasmons. AB - Molecule-plasmon interactions have been shown to have a definite role in light propagation through optical microcavities due to strong coupling between molecular excitations and surface plasmons. This coupling can lead to macroscopic extended coherent states exhibiting increment in temporal and spatial coherency and a large Rabi splitting. Here, we demonstrate spatial modulation of light transmission through a single microcavity patterned on a free-standing Au film, strongly coupled to one of the most efficient energy transfer photosynthetic proteins in nature, photosystem I. Here we observe a clear correlation between the appearance of spatial modulation of light and molecular photon absorption, accompanied by a 13-fold enhancement in light transmission and the emergence of a distinct electromagnetic standing wave pattern in the cavity. This study provides the path for engineering various types of bio-photonic devices based on the vast diversity of biological molecules in nature. PMID- 26055944 TI - Inflammatory-mediated pathway in association with organochlorine pesticides levels in the etiology of idiopathic preterm birth. AB - Elevated inflammation is a known risk factor in the pathogenesis of PTB. Despite intensive research, the etiology of idiopathic PTB is still unknown. The present study was designed to explore associations of blood concentrations of organochlorine pesticides (OCPs) with inflammatory/antioxidant gene expression, and cytokines and prostaglandin levels in PTB cases. Significantly high levels of alpha, beta-hexachlorocyclohexane (alpha, beta-HCH), dichlorodiphenyldichloroethane (o'p'-DDD), dichlorodiphenyldichloroethylene (p'p' DDE), increased expression of cyclooxygenase-2 (COX-2), and decreased expression of manganese superoxide dismutase (Mn-SOD) and catalase (CAT) genes were seen in PTB cases. Also, increased protein levels of interleukin-6 (IL-6) and decreased protein levels of interleukin-4 (IL-4) and prostaglandin F2alpha (PGF2alpha) were found in maternal blood of PTB cases as compared to term controls. Elevated levels of beta-HCH along with high expression of COX-2 gene or low expression of Mn-SOD or CAT genes were associated with the decrease in the period of gestation (POG). PMID- 26055945 TI - Development of hematological and immunological characteristics in neonatal rats. AB - As major immunological and hematological parameters evolve during the early period of life, laboratory data must be interpreted in relation to developmental changes. Wistar (WU) rats were sacrificed on PND2, 4, 7, 10, 14, 17 and 21. Peripheral blood, bone marrow, thymus samples and spleen cells were collected and a bronchoalveolar lavage (BAL) performed. Parameters of blood counts changed considerably between time points. IgM and IgG levels steadily increased. Spontaneous spleen cell proliferation was low before PND21, although mitogens had stimulatory effects above baseline. In the spleen, T-lymphocyte counts tripled by PND17 (mainly attributed to CD8(+) cytotoxic T-cells and CD4(+) T-helper cells). In peripheral blood an increase in B-lymphocytes to about 60% of the cell number was observed. In BAL fluid, macrophages represented 95-98% of the cells. In thymus architecture, lymphoblast migration was seen and epithelial structures appeared. The data presented will help to distinguish between maturational changes and treatment-related effects. PMID- 26055946 TI - Steroidogenic differential effects in neonatal porcine Leydig cells exposed to persistent organic pollutants derived from cod liver oil. AB - Seafood products, including fish and fish oils, are major sources of persistent organic pollutants (POPs) which may cause endocrine disruption related to reproductive dysfunction in males. Primary porcine neonatal Leydig cells were exposed to three extracts of POPs obtained from different stages in production of cod liver oil dietary supplement, in the absence and presence of luteinizing hormone (LH). No reduced viability was observed and all POP extracts showed increased testosterone and estradiol levels in unstimulated cells and decreased testosterone and estradiol secretion in LH-stimulated cells. A decrease in central steriodogenic genes including STAR, CYP11A1, HSD3B and CYP17A1 was obtained in both culture conditions with all POP extracts. We implicate both small differences in composition and concentration of compounds as well as "old" POPs to be important for the observed steroidogenic effects. PMID- 26055947 TI - 2-Year Outcomes in Patients Undergoing Surgical or Self-Expanding Transcatheter Aortic Valve Replacement. AB - BACKGROUND: The U.S. pivotal trial for the self-expanding valve found that among patients with severe aortic stenosis at increased risk for surgery, the 1-year survival rate was 4.9 percentage points higher in patients treated with a self expanding transcatheter aortic valve bioprosthesis than in those treated with a surgical bioprosthesis. OBJECTIVES: Longer-term clinical outcomes were examined to confirm if this mortality benefit is sustained. METHODS: Patients with severe aortic stenosis who were at increased surgical risk were recruited. Eligible patients were randomly assigned in a 1:1 ratio to transcatheter aortic valve replacement with the self-expanding transcatheter valve (transcatheter aortic valve replacement [TAVR] group) or to aortic valve replacement with a surgical bioprosthesis (surgical group). The 2-year clinical and echocardiographic outcomes were evaluated in these patients. RESULTS: A total of 797 patients underwent randomization at 45 centers in the United States. The rate of 2-year all-cause mortality was significantly lower in the TAVR group (22.2%) than in the surgical group (28.6%; log-rank test p < 0.05) in the as-treated cohort, with an absolute reduction in risk of 6.5 percentage points. Similar results were found in the intention-to-treat cohort (log-rank test p < 0.05). The rate of 2-year death or major stroke was significantly lower in the TAVR group (24.2%) than in the surgical group (32.5%; log-rank test p = 0.01). CONCLUSIONS: In patients with severe aortic stenosis who are at increased surgical risk, the higher rate of survival with a self-expanding TAVR compared with surgery was sustained at 2 years. (Safety and Efficacy Study of the Medtronic CoreValve System in the Treatment of Symptomatic Severe Aortic Stenosis in High Risk and Very High Risk Subjects Who Need Aortic Valve Replacement; NCT01240902). PMID- 26055948 TI - Will TAVR Become the Default Treatment for Patients With Severe Aortic Stenosis? PMID- 26055950 TI - Flexible scope for ISO 15189 accreditation: a guidance prepared by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Working Group Accreditation and ISO/CEN standards (WG-A/ISO). AB - The recent revision of ISO15189 has further strengthened its position as the standard for accreditation for medical laboratories. Both for laboratories and their customers it is important that the scope of such accreditation is clear. Therefore the European co-operation for accreditation (EA) demands that the national bodies responsible for accreditation describe the scope of every laboratory accreditation in a way that leaves no room for doubt about the range of competence of the particular laboratories. According to EA recommendations scopes may be fixed, mentioning every single test that is part of the accreditation, or flexible, mentioning all combinations of medical field, examination type and materials for which the laboratory is competent. Up to now national accreditation bodies perpetuate use of fixed scopes, partly by inertia, partly out of fear that a too flexible scope may lead to over-valuation of the competence of laboratories, most countries only use fixed scopes. The EA however promotes use of flexible scopes, since this allows for more readily innovation, which contributes to quality in laboratory medicine. In this position paper, the Working Group Accreditation and ISO/CEN Standards belonging to the Quality and Regulation Committee of the EFLM recommends using an approach that has led to successful introduction of the flexible scope for ISO15189 accreditation as intended in EA-4/17 in The Netherlands. The approach is risk-based, discipline and competence-based, and focuses on defining a uniform terminology transferable across the borders of scientific disciplines, laboratories and countries. PMID- 26055949 TI - Sugar-sweetened beverage, diet soda, and fatty liver disease in the Framingham Heart Study cohorts. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease affects ~30% of US adults, yet the role of sugar-sweetened beverages and diet soda on these diseases remains unknown. We examined the cross-sectional association between intake of sugar sweetened beverages or diet soda and fatty liver disease in participants of the Framingham Offspring and Third Generation cohorts. METHODS: Fatty liver disease was defined using liver attenuation measurements generated from computed tomography in 2634 participants. Alanine transaminase concentration, a crude marker of fatty liver disease, was measured in 5908 participants. Sugar-sweetened beverage and diet soda intake were estimated using a food frequency questionnaire. Participants were categorized as either non-consumers or consumers (3 categories: 1 serving/month to <1 serving/week, 1 serving/week to <1 serving/day, and ?1 serving/day) of sugar-sweetened beverages or diet soda. RESULTS: After adjustment for age, sex, smoking status, Framingham cohort, energy intake, alcohol, dietary fiber, fat (% energy), protein (% energy), diet soda intake, and body mass index, the odds ratios of fatty liver disease were 1, 1.16 (0.88, 1.54), 1.32 (0.93, 1.86), and 1.61 (1.04, 2.49) across sugar-sweetened beverage consumption categories (p trend=0.04). Sugar-sweetened beverage consumption was also positively associated with alanine transaminase levels (p trend=0.007). We observed no significant association between diet soda intake and measures of fatty liver disease. CONCLUSION: In conclusion, we observed that regular sugar-sweetened beverage consumption was associated with greater risk of fatty liver disease, particularly in overweight and obese individuals, whereas diet soda intake was not associated with measures of fatty liver disease. PMID- 26055951 TI - A retrospective dosimetric comparison of TG43 and a commercially available MBDCA for an APBI brachytherapy patient cohort. AB - PURPOSE: To compare dosimetry using a contemporary model based dose calculation algorithm (MBDCA) following TG186 recommendations, and the conventional TG43 method in an (192)Ir high dose rate (HDR) accelerated partial breast irradiation (APBI) patient cohort. METHODS: Data of 38 APBI patients were studied. Dosimetry for the treatment plans was performed using both the TG43 and TG186 dose calculation methods of the Oncentra Brachy v4.4 treatment planning system (TPS). Analysis included indices of clinical interest for the planning target volume (PTV coverage, dose homogeneity, conformity) as well as dose volume histograms (DVH) for the breast, lung, heart, rib and skin. Significance testing of observed differences between TG43 and TG186 results was carried out and the effect of target location to these differences was studied. RESULTS: Statistically significant differences were observed in the values of clinically relevant DVH parameters for the PTV and the organs at risk (OAR), except for the heart. Differences for the PTV are relatively small (<1% for coverage, on the order of 2% for homogeneity and conformity) with a slight TG43 overestimation except for the dose homogeneity. Percentage differences are larger for the rib and lung (on the order of 4% for Dmax and 5% for V10Gy, respectively) and maximum for the skin (on the order of 6% for D10cc), with a correlation of the observed differences with target location. CONCLUSION: While the MBDCA option of the TPS appears to improve dosimetric accuracy, differences from TG43 do not appear to warrant dose prescription changes or treatment protocol amendment.. PMID- 26055952 TI - Cost-utility of fingolimod compared with dimethyl fumarate in highly active relapsing-remitting multiple sclerosis (RRMS) in England. AB - OBJECTIVE: The cost-effectiveness of new oral disease-modifying therapies (DMTs) has not been modeled in highly active (HA) relapsing-remitting multiple sclerosis (RRMS) requiring escalation therapy. This study sought to model the cost effectiveness of fingolimod compared to dimethyl fumarate (DMF), for which relevant HA RRMS sub-group data were available, from the perspective of the National Health Service (NHS) in England. METHODS: A cohort Markov model based on Expanded Disability Status Scale scores, similar to previous model designs, was constructed. Published post hoc clinical data in the HA RRMS sub-groups were taken from the pivotal trials for fingolimod and DMF vs placebo. Utility data for each health state and for relapses were used in line with previous similar models. Published costs were inflated to NHS cost year 2013-2014 and UK list prices used for both drugs. Possible Patient Access Scheme (PAS) discount scenarios were investigated. RESULTS: In the base case, using list prices for each DMT, the average probabilistic incremental cost-effectiveness ratio (ICER) for fingolimod vs DMF was found to be L 14,076, with a 73% chance of fingolimod being cost-effective at a willingness-to-pay threshold of L 30,000. Scenario and sensitivity analyses showed that uncertainty in disability progression efficacy was a key model driver. The model was robust to other changes and the majority of PAS permutations do not contradict the base case finding of cost-effectiveness of fingolimod. CONCLUSIONS: In conclusion, fingolimod remains cost-effective in HA RRMS following the introduction of DMF to the UK market, and this paper supports the evidence that has led fingolimod to be the only oral DMT reimbursed for HA RRMS in England. This model supports the restriction imposed by National Institute for Health and Care Excellence (NICE) on DMF in HA RRMS and highlights the importance of considering different sub-groups of multiple sclerosis when performing health economic analyses. PMID- 26055953 TI - Placental specializations in lecithotrophic viviparous squamate reptiles. AB - Squamate reptiles have been thought to be predisposed to evolution of viviparity because embryos of most oviparous species undergo considerable development in the uterus prior to oviposition. A related hypothesis proposes that prolonged intrauterine gestation, an intermediate condition leading to viviparity, requires little or no physiological adjustment, other than reduction in thickness of the eggshell. This logical framework is often accompanied by an assumption that mode of parity (oviparity, viviparity) and pattern of embryonic nutrition (lecithotrophy, placentotrophy) are independent traits that evolve in sequence. Thus, specializations for viviparity should be absent in some lecithotrophic viviparous species. Studies of species of lizards with geographic variation in mode of parity challenge this scenario by demonstrating that placental specializations are correlated with viviparity. Uterine specializations for placental transport of calcium to viviparous embryos alter uterine physiology compared to oviparous females. In addition, comparative studies of oviparous and viviparous species, i.e., in which gene flow is disrupted, reveal that both uterine and embryonic structural modifications are commonly associated with viviparity, suggesting relatively rapid evolution of placental specializations. Studies of squamate reproductive biology support two hypotheses: 1) evolution of viviparity requires physiological adjustments of the uterine environment, and 2) evolution of viviparity promotes relatively rapid adaptations for placentation. Models for the evolution of viviparity from oviparity, or for reversals from viviparity to oviparity, should reflect current understanding of squamate reproductive biology and future studies should be designed to challenge these models. PMID- 26055954 TI - Use of preoperative FLAIR MRI and ependymal proximity of tumor enhancement as surrogate markers of brain tumor origin. AB - Neural stem cells proliferate in the subventricular zone and give rise to progeny that differentiate and migrate throughout the brain. We aimed to test the hypothesis that glioma behavior and grade may correlate with the identity of the tumor cell of origin. We evaluated three preoperative radiographic features (fluid attenuated inversion recovery [FLAIR] MRI characteristics, tumor proximity to ventricular ependyma, and subependymal representation) as surrogate markers of tumor origin using a retrospective cohort design. The medical records of 228 patients who underwent surgical resection of a glioma from January 2004 to August 2008 were reviewed. Average patient age was 54.5 years (standard deviation [SD] 15.3) with a male predominance (62.9%). World Health Organization glioma grades amongst the cohort were Grade IV (71.6%), Grade III (21.3%) and Grade II (7.1%). Mean survival was 11.2 months (SD 10.5) with a mean follow up of 12.8 months (SD 11.3). Glioma tumor grade was significantly correlated to FLAIR signal proximity to the ependymal surface (p<0.01) and inversely with proximity of tumor mass to the ependyma (p<0.01). The mean distance of tumor-associated FLAIR signal from the ependymal surface for glioblastoma multiforme (GBM) was 1.2mm (SD 3.3) compared to 4.8 (SD 6.5) for anaplastic astrocytomas and 6.6mm (SD 6.7; p<0.01) for low grade gliomas. Conversely, the mean distance of the enhancing tumor mass from the ependyma for GBM was 7.3mm (SD 9.4), Grade III glioma 2.3mm (SD 4.9), and Grade II glioma 3.8mm (SD 6.8; p<0.05). These findings suggest that higher grade gliomas might arise from less differentiated neuroepithelial cells in the subventricular zone that possess greater migratory potential. PMID- 26055955 TI - Association between serum uric acid and motor subtypes of Parkinson's disease. AB - The aim of this study was to evaluate serum uric acid (UA) levels and serum uric acid/creatinine ratios (UA/Cr) in patients with non-tremor dominant (NTD) Parkinson's disease (PD) compared to tremor dominant (TD) PD and healthy controls (HC). UA is believed to have a protective effect on the central nervous system against oxidative damage and neuronal cell death which could impact on progression and motor subtypes of PD. Serum UA levels and UA/Cr were determined in 100 PD patients and 100 age and sex matched HC. Subtypes of PD were classified into TD and NTD. Patients with PD showed statistically significantly lower serum UA (p=0.007) and serum UA/Cr ratios (p<0.001) than HC. Patients with NTD PD had statistically significantly lower serum UA (p<0.001) and serum UA/Cr (p=0.001) than in patients with TD PD. Patients with mild PD severity also had significantly higher serum UA (p=0.015) and serum UA/Cr (p=0.004) than patients with moderate to severe disease. Our study suggests that UA has a pathogenic role in the clinical subtype of PD. Serum UA levels together with serum UA/Cr are potentially useful biomarkers to indicate risk, severity and motor subtype of PD. PMID- 26055956 TI - Neurosyphilis presenting as a new onset lateralized movement disorder. AB - We report a unique and illustrative case of a 52-year-old man with neurosyphilis presenting as subacute hemichorea, and discuss a vascular, metabolic or inflammatory origin. A broad range of neurological findings may be linked to neurosyphilis, potentially complicating its diagnosis. We propose that new onset lateralized movement disorders may constitute the initial clinical presentations of neurosyphilis, and provide evidence for striatal hypermetabolism pointing to direct inflammatory, syphilitic changes as the underlying pathophysiological mechanism. Neurosyphilis is no longer a common disorder, but the prevalence of syphilis is rising again in Western countries and its past reputation as the great imitator should not be forgotten. PMID- 26055957 TI - Hypertonic saline infusion in traumatic brain injury increases the incidence of pulmonary infection. AB - We aimed to investigate the incidence of electrolyte abnormalities, acute kidney injury (AKI), deep venous thrombosis (DVT) and infections in patients with traumatic brain injury (TBI) treated with hypertonic saline (HTS) as osmolar therapy. We retrospectively studied 205 TBI patients, 96 with HTS and 109 without, admitted to the surgical/trauma intensive care unit between 2006 and 2012. Hemodynamics, electrolytes, length of stay (LOS), acute physiological assessment and chronic health evaluation II (APACHE II), injury severity scores (ISS) and mortality were tabulated. Infection, mechanical ventilation, DVT and AKI incidence were reviewed. HTS was associated with increased LOS and all infections (p=0.0001). After correction for the Glasgow coma scale (GCS) and ventilator need, pulmonary infections (p=0.001) and LOS remained higher with HTS (p=0.0048). HTS did not result in increased blood pressure, DVT, AKI or neurological benefits. HTS significantly increased the odds for all infections, most specifically pulmonary infections, in patients with GCS<8. Due to these findings, HTS in TBI should be administered with caution regardless of acuity. PMID- 26055958 TI - Evaluation of weekend admission on the prevalence of hospital acquired conditions in patients receiving thoracolumbar fusions. AB - We evaluated the Nationwide Inpatient Sample (NIS) database for increased hospital acquired condition (HAC) rate as a function of weekend admission in patients receiving thoracolumbar fusions. In 2008, the Centers for Medicare and Medicaid Services (CMS) compiled a list of HAC for a new payment policy for preventable adverse events without reimbursement of resulting hospital costs. In this, the thoracolumbar patients represented a population with significant increased rates of HAC and, to our knowledge, no prior studies have evaluated the effect of weekend admission on HAC rate. We collated data for patients who underwent thoracolumbar fusions from the 2002-2010 NIS database. Using CMS definitions, HAC were abstracted using the Ninth Edition of International Classification of Diseases Clinical Modification (ICD-9CM). Multivariate analysis assessed the impact of a weekend admission on HAC occurrence and prolonged length of stay (LOS) adjusting for patient, admission severity, and hospital covariates. There were 1,842,231 total admissions between 2002 and 2010 associated with thoracolumbar procedures. HAC occurred at a frequency of 5.2% overall. Surgical site infections (n=10,656) and falls/trauma (n=83,999) were the most common. After adjusting for disease severity and urgency of admission, patients admitted on the weekend were more than two times more likely to incur a HAC compared to those admitted on weekdays (odds ratio 2.41; 95% confidence interval 2.19-2.65; p<0.05). HAC occurrence and weekend admission were also associated with prolonged LOS (p<0.05). We found that weekend admission is associated with increased HAC rate. Though our conclusions must be tempered by limitations of the coded national database, further study is warranted to confirm this disparity and evaluate potential for improvement. PMID- 26055959 TI - Increased plasma levels of phospholipid in Parkinson's disease with mild cognitive impairment. AB - This study aimed to observe the clinical characteristics and changes in plasma phospholipid (PL) concentrations in Parkinson's disease patients with mild cognitive impairment (PD-MCI), and to investigate the association between these changes and cognitive function to provide a basis for early diagnosis and intervention for PD-MCI patients. Oxidative stress plays an important role in the development and progression of Parkinson's disease (PD). PL, important components in cellular membranes, are critical for the maintenance of cell integrity and function. Lipid peroxidation products are significantly increased in the brains of PD patients. In the present study, plasma PL levels were significantly increased in PD-MCI patients or in PD patients with no cognitive impairment (PD NCI) compared with controls (p<0.01 and p<0.05, respectively). PL levels were significantly increased in the PD-MCI group compared with PD-NCI patients (p<0.01). There was a negative correlation between plasma PL levels and Montreal cognitive assessment scores (r=-0.542; p<0.001). These findings support the relationship between mild cognitive impairment and membrane injury. The measurement of PL reflects membrane injury in vivo and may be a new useful biomarker for the prognosis of cognitive states in patients with PD. PMID- 26055961 TI - Optimization of sequence alignments according to the number of sequences vs. number of sites trade-off. AB - BACKGROUND: Comparative analysis of homologous sequences enables the understanding of evolutionary patterns at the molecular level, unraveling the functional constraints that shaped the underlying genes. Bioinformatic pipelines for comparative sequence analysis typically include procedures for (i) alignment quality assessment and (ii) control of sequence redundancy. An additional, underassessed step is the control of the amount and distribution of missing data in sequence alignments. While the number of sequences available for a given gene typically increases with time, the site-specific coverage of each alignment position remains highly variable because of differences in sequencing and annotation quality, or simply because of biological variation. For any given alignment-based analysis, the selection of sequences thus defines a trade-off between the species representation and the quantity of sites with sufficient coverage to be included in the subsequent analyses. RESULTS: We introduce an algorithm for the optimization of sequence alignments according to the number of sequences vs. number of sites trade-off. The algorithm uses a guide tree to compute scores for each bipartition of the alignment, allowing the recursive selection of sequence subsets with optimal combinations of sequence and site numbers. By applying our methods to two large data sets of several thousands of gene families, we show that significant site-specific coverage increases can be achieved while controlling for the species representation. CONCLUSIONS: The algorithm introduced in this work allows the control of the distribution of missing data in any sequence alignment by removing sequences to increase the number of sites with a defined minimum coverage. We advocate that our missing data optimization procedure in an important step which should be considered in comparative analysis pipelines, together with alignment quality assessment and control of sampled diversity. An open source C++ implementation is available at http://bioweb.me/physamp. PMID- 26055962 TI - Synthesis of bio-based thermoplastic polyurethane elastomers containing isosorbide and polycarbonate diol and their biocompatible properties. AB - A new family of highly elastic polyurethanes (PUs) partially based on renewable isosorbide were prepared by reacting hexamethylene diisocyanate with a various ratios of isosorbide and polycarbonate diol 2000 (PCD) via a one-step bulk condensation polymerization without catalyst. The influence of the isorsorbide/PCD ratio on the properties of the PU was evaluated. The successful synthesis of the PUs was confirmed by Fourier transform-infrared spectroscopy and (1)H nuclear magnetic resonance. The resulting PUs showed high number-average molecular weights ranging from 56,320 to 126,000 g mol(-1) and tunable Tg values from -34 to -38C. The thermal properties were determined by differential scanning calorimetry and thermogravimetric analysis. The PU films were flexible with breaking strains from 955% to 1795% at from 13.5 to 54.2 MPa tensile stress. All the PUs had 0.9-2.8% weight lost over 4 weeks and continual slow weight loss of 1.1-3.6% was observed within 8 weeks. Although the cells showed a slight lower rate of proliferation than that of the tissue culture polystyrene as a control, the PU films were considered to be cytocompatible and nontoxic. These thermoplastic PUs were soft, flexible and biocompatible polymers, which open up a range of opportunities for soft tissue augmentation and regeneration. PMID- 26055960 TI - miR-155 regulative network in FLT3 mutated acute myeloid leukemia. AB - BACKGROUND: Acute myeloid leukemia (AML) represents a heterogeneous disorder with recurrent chromosomal alterations and molecular abnormalities. Among AML with normal karyotype (NK-AML) FLT3 activating mutation, internal tandem duplication (FLT3-ITD), is present in about 30% of patients, conferring unfavorable outcome. Our previous data demonstrated specific up-regulation of miR-155 in FLT3-ITD+ AML. miR-155 is known to be directly implicated in normal hematopoiesis and in some pathologies such as myeloid hyperplasia and acute lymphoblastic leukemia. METHODS AND RESULTS: To investigate about the potential influence of miR-155 de regulation in FLT3-mutated AML we generated a transcription factors regulatory network and combined this with data from multiple sources that predict miR-155 interactions. From these analyses, we derived a sub-network, called "miR-155 module" that describes functional relationship among miR-155 and transcription factors in FLT3-mutated AML. We found that "miR-155 module" is characterized by the presence of six transcription factors as central hubs: four miR-155 regulators (JUN, RUNX1, FOSb, JUNB) and two targets of miR-155 (SPI1, CEBPB) all known to be "master" genes of myelopoiesis. We found, in FLT3-mutated AML, a significant down-regulation of miR-155 target genes CEBPB and SPI1 and up regulation of miR-155 regulator genes JUN and RUNX1. We also showed that PKC412 related FLT3 inhibition, in MV4-11 cell line, causes down-regulation of miR-155 and increased level of mRNA and protein of miR-155 target SPI1. We showed in experiments of miR-155 mimic in K562 cell line, a high increase of miR-155 and an inverse correlation with the mRNA levels of its targets SPI1 and CEBPB. Moreover silencing of miR-155 in primary AMLs causes mRNA up-regulation of its target SPI1 and CEBPB. CONCLUSION: Our results suggest that activating mutation of FLT3 in AML can lead, through the induction of JUN, to an increased expression of miR 155, which then causes down-regulation of SPI1 and CEBPB and consequently may causes block of myeloid differentiation. PMID- 26055963 TI - The Value of Cardiovascular Magnetic Resonance in Heart Transplant Patients. AB - Heart transplant patients present a unique set of anatomical and pathophysiological considerations. Patients often present non-specifically, requiring a low index for further investigation. Accurate assessment with standard imaging modalities can be difficult, and cardiovascular magnetic resonance (CMR) is becoming an increasingly useful modality in the assessment of heart transplant patients. This review describes the anatomy of the transplanted heart and typical CMR appearances and discusses the role of CMR in heart transplant disease. PMID- 26055964 TI - Gradual loss of vision in adults. PMID- 26055965 TI - Co-assembly of photosystem II/reduced graphene oxide multilayered biohybrid films for enhanced photocurrent. AB - A new type of biohybrid photo-electrochemical cell was fabricated by layer-by layer assembly of photosystem II and reduced graphene oxide. We demonstrate that the photocurrent in the direct electron transfer is enhanced about two fold with improved stability. The assembly strategy without any cross-linker or additional electron mediators makes the cell fabrication and operation much simpler as compared to previous approaches. This work may open new routes for the construction of solar energy conversion systems based on photoactive proteins and graphene materials. PMID- 26055966 TI - Impact factors and the optimal parameter of acoustic structure quantification in the assessment of liver fibrosis. AB - The aims of the present study are to assess the impact factors on acoustic structure quantification (ASQ) ultrasound and find the optimal parameter for the assessment of liver fibrosis. Twenty healthy volunteers underwent ASQ examinations to evaluate impact factors in ASQ image acquisition and analysis. An additional 113 patients with liver diseases underwent standardized ASQ examinations, and the results were compared with histologic staging of liver fibrosis. We found that the right liver displayed lower values of ASQ parameters than the left (p = 0.000-0.021). Receive gain experienced no significant impact except gain 70 (p = 0.193-1.000). With regard to different diameter of involved vessels in regions of interest, the group <=2.0 mm differed significantly with the group 2.1-5.0 mm (p = 0.000-0.033) and the group >5.0 mm (p = 0.000-0.062). However, the region of interest size (p = 0.438-1.000) and depth (p = 0.072 0.764) had no statistical impact. Good intra- and inter-operator reproducibilities were found in both image acquisitions and offline image analyses. In the liver fibrosis study, the focal disturbance ratio had the highest correlation with histologic fibrosis stage (r = 0.67, p < 0.001). In conclusion, the testing position, receive gain and involved vessels were the main factors in ASQ examinations and focal disturbance ratio was the optimal parameter in the assessment of liver fibrosis. PMID- 26055967 TI - Correlation between quantitative shear wave elastography and pathologic structures of thyroid lesions. AB - The aim of this study was to determine the correlation between shear wave velocity (SWV) generated by acoustic radiation force impulse and the pathologic structure of thyroid lesions. A total of 599 thyroid tissue samples were divided into four groups based on pathologic structure: 254 normal thyroid tissue samples as a control, 128 with chronic autoimmune thyroiditis (CAT) that demonstrated diffuse fibrosis, 165 with benign nodules that had high cell density and 52 with papillary thyroid carcinoma (PTC) that showed high cell density and fibrosis. The mean SWVs in each group were as follows: 1.60 +/- 0.18 m/s in normal thyroid, 2.55 +/- 0.28 m/s in CAT, 1.72 +/- 0.31 m/s in benign nodules and 2.66 +/- 0.95 m/s in PTC. The SWVs of CAT and PTC were significantly higher than those of normal thyroid, (p < 0.001). SWV was significantly affected by fibrosis. PMID- 26055968 TI - Radiofrequency ablation for hepatocellular carcinoma: utility of conventional ultrasound and contrast-enhanced ultrasound in guiding and assessing early therapeutic response and short-term follow-up results. AB - The purpose of this study was to assess the efficacy of conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) in guiding and assessing early therapeutic response to radiofrequency (RF) ablation for hepatocellular carcinomas (HCCs; up to 3 lesions, each <=3 cm in diameter) and to report the short-term follow-up results. Between September 2011 and January 2013, 63 patients with 78 HCCs (<=3 cm) underwent conventional US- and CEUS-guided percutaneous RF ablation. CEUS was repeated after 20-30 min to assess therapeutic response, and local efficacy was further confirmed by contrast-enhanced magnetic resonance imaging (MRI) 1 mo after tumor ablation. Patients were followed periodically to look for local tumor or disease progression. Survival probability was estimated with the Kaplan-Meier method. Complete ablation was achieved for 76 (97.4%) of 78 HCCs in one (n = 73) or two (n = 3) sessions. No major complications were observed in any patient. The overall concordance in assessment of therapeutic efficacy of RF ablation between CEUS and MRI was 97.4% (76/78 tumors). The concordance test gave a value of kappa = 0.74 (p < 0.001), indicating that CEUS had a high diagnostic agreement with MRI. During a mean follow-up of 20 mo, the local tumor progression rate was 5.3% (4/76 tumors). The 1-, 1.5- and 2-y cumulative survival rates were 98.4%, 96.1% and 92.6%, respectively. Although CEUS has some intrinsic limitations, the combined use of conventional US and CEUS provides a safe and efficient tool to guide RF ablation for HCCs 3 cm or smaller, with encouraging results in terms of survival rate and minimal complications. Moreover, the immediate post-procedural CEUS can be a reliable alternative to contrast-enhanced MRI for assessing the early therapeutic response to RF ablation. PMID- 26055969 TI - Marker-Free Tracking of Facet Capsule Motion Using Polarization-Sensitive Optical Coherence Tomography. AB - We proposed and tested a method by which surface strains of biological tissues can be captured without the use of fiducial markers by instead, utilizing the inherent structure of the tissue. We used polarization-sensitive optical coherence tomography (PS OCT) to obtain volumetric data through the thickness and across a partial surface of the lumbar facet capsular ligament during three cases of static bending. Reflectivity and phase retardance were calculated from two polarization channels, and a power spectrum analysis was performed on each a-line to extract the dominant banding frequency (a measure of degree of fiber alignment) through the maximum value of the power spectrum (maximum power). Maximum powers of all a-lines for each case were used to create 2D visualizations, which were subsequently tracked via digital image correlation. In plane strains were calculated from measured 2D deformations and converted to 3D surface strains by including out-of-plane motion obtained from the PS OCT image. In-plane strains correlated with 3D strains (R(2) >= 0.95). Using PS OCT for marker-free motion tracking of biological tissues is a promising new technique because it relies on the structural characteristics of the tissue to monitor displacement instead of external fiducial markers. PMID- 26055970 TI - Characterization of the lipopolysaccharide induced model of Parkinson's disease: Role of oxidative stress and neuroinflammation. AB - INTRODUCTION: Primary pathology underlying Parkinson's disease (PD) is the loss of dopaminergic neurons in the substantia nigra (SN). A variety of genetic and environmental factors underlie this loss of dopaminergic neurons. However, recent studies have highlighted the role of elevated oxidative stress and the pro inflammatory responses contributing to or exacerbating the nigrostriatal degeneration. METHODS: With the establishment of neuroinflammation as an important process involved in the PD pathogenesis, in the present study this pathogenic feature was replicated in animals using lipopolysaccharide (LPS) (5 ug/5 ul PBS) infused stereotaxically into the SN of rats. RESULTS: LPS injected into the SN successfully replicated the pathogenic features of PD in rats as it elicited an inflammatory response via action of microglia. LPS infusion resulted in glial cell activation as depicted from immunohistochemistry (IHC) analysis of GFAP and Iba-1. Also, a significant increase in the mRNA expression of proinflammatory cytokines, i.e. TNF-alpha and IL-1beta, was observed after 7 days of LPS infusion whereas the alterations in the oxidative stress markers, i.e ROS, lipid peroxidation, NO formation, NADPH oxidase activity, glutathione system, SOD and catalase, became highly significant after 14 days of infusion. As a consequence, after 21 days of LPS infusion we observed activation of apoptotic pathway indicated by increased expression of caspases 3 and caspase 9. This was followed by a significant decline in the expression of tyrosine hyroxylase (TH) as revealed by IHC. Further, there was a marked decrease in the level of dopamine and its metabolites enough for the production of behavioral abnormality in rats. CONCLUSION: Hence, the present study provides extensive characterization of LPS induced model of PD. Study also confirms the co-existence and complex interplay between inflammation and oxidative stress contributing equally to the dopaminergic neuronal degeneration process in PD. PMID- 26055971 TI - Administration of somatostatin analog octreotide in the ventrolateral orbital cortex produces sex-related antinociceptive effects on acute and formalin-induced nociceptive behavior in rats. AB - The present study was designed to examine whether somatostatin analog octreotide (OCT) was involved in antinociception in the ventrolateral orbital cortex (VLO) and determine whether this effect had a sex difference between male and female rats. The radiant heat-evoked tail flick (TF) reflex was used as an index of acute nociceptive response in lightly anesthetized rats. The number of flinches evoked by formalin injection into the hindpaw was used to evaluate inflammatory persistent pain in conscious rats. Administration of OCT (2.0, 5.0 10.0 ng in 0.5 ul) into the VLO depressed the TF reflex in a dose-dependent manner only in female rats, but not male rats. Pretreatment with a nonselective somatostatin receptor antagonist cyclo-somatostatin (c-SOM) (25.0 ug in 0.5 ul) into the VLO antagonized 10.0 ng OCT-induced inhibition of the TF reflex in female rats. Similarly, application of high dose of OCT (10.0 ng in 0.5 ul) into the VLO depressed formalin-induced flinching response in the early and late phases only in female rats, and had no any effects in male rats. Pretreatment with c-SOM (25.0 ug in 0.5 ul) into the VLO totally antagonized the 10 ng OCT-induced inhibition of the flinches in both phases in female rats. Additionally, single administration of c-SOM into the VLO failed to alter tail reflex latencies and formalin-induced nociceptive behaviors in female rats. The results provide the first valuable evidence that somatostatin and its receptors are involved in antinociception in acute heat-evoked nociception and inflammatory persistent pain only in female rats, not male rats, in the VLO. PMID- 26055972 TI - Alpha lipoic acid inhibits neural apoptosis via a mitochondrial pathway in rats following traumatic brain injury. AB - Alpha lipoic acid (ALA) is a powerful antioxidant that has proven protective effects against brain damage following a traumatic brain injury (TBI) in rats. However, the molecular mechanisms underlying these effects are not well understood. This study investigated the effect of ALA on neural apoptosis and the potential mechanism of these effects in the weight-drop model of TBI in male Sprague-Dawley rats that were treated with ALA (20 or 100 mg/kg) or vehicle via intragastric administration 30 min after TBI. Brain samples were collected 48 h later for analysis. ALA treatment resulted in a downregulation of caspase-3 expression, reduced the number of positive cells in the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay and improved neuronal survival. Furthermore, the level of malondialdehyde and glutathione peroxidase activity were restored, while Bcl-2-associated X protein translocation to mitochondria and cytochrome c release into the cytosol were reduced by ALA treatment. These results demonstrate that ALA improves neurological outcome in rats by protecting neural cell against apoptosis via a mechanism that involves the mitochondria following TBI. PMID- 26055973 TI - Improved Overall Quality of Diets Reported by Expanded Food and Nutrition Education Program Participants in the Mountain Region. AB - OBJECTIVE: To evaluate the Expanded Food and Nutrition Education Program, a large US Department of Agriculture nutrition education program for low-income people, by comparing the overall quality and cost of diets when entering and exiting the program. METHODS: Secondary analysis of data collected in 2011 from female participants in the Mountain region. Dietary recalls were collected by paraprofessionals. Outcome measures were the differences between Healthy Eating Index-2005 scores and costs of diets at entry and exit. Significance was determined using the Wilcoxon signed-rank test. RESULTS: At entry the mean total Healthy Eating Index-2005 score was 49.1 (out of a possible 100) and at exit, 55.2 (P < .001) (n = 3,338). Eight of 12 component scores also improved significantly whereas the sodium score worsened. The estimated median cost of diets was 13% higher at exit compared with entry. CONCLUSIONS: Participants' overall diet quality improved and was accompanied by an increase in food cost. PMID- 26055974 TI - Approaches and impact of non-academic research capacity strengthening training models in sub-Saharan Africa: a systematic review. AB - BACKGROUND: Research is essential to identify and prioritize health needs and to develop appropriate strategies to improve health outcomes. In the last decade, non-academic research capacity strengthening trainings in sub-Saharan Africa, coupled with developing research infrastructure and the provision of individual mentorship support, has been used to build health worker skills. The objectives of this review are to describe different training approaches to research capacity strengthening in sub-Saharan Africa outside academic programs, assess methods used to evaluate research capacity strengthening activities, and learn about the challenges facing research capacity strengthening and the strategies/innovations required to overcome them. METHODOLOGY: The PubMed database was searched using nine search terms and articles were included if 1) they explicitly described research capacity strengthening training activities, including information on program duration, target audience, immediate program outputs and outcomes; 2) all or part of the training program took place in sub-Saharan African countries; 3) the training activities were not a formal academic program; 4) papers were published between 2000 and 2013; and 5) both abstract and full paper were available in English. RESULTS: The search resulted in 495 articles, of which 450 were retained; 14 papers met all inclusion criteria and were included and analysed. In total, 4136 people were trained, of which 2939 were from Africa. Of the 14 included papers, six fell in the category of short-term evaluation period and eight in the long-term evaluation period. Conduct of evaluations and use of evaluation frameworks varied between short and long term models and some trainings were not evaluated. Evaluation methods included tests, surveys, interviews, and systems approach matrix. CONCLUSIONS: Research capacity strengthening activities in sub-Saharan Africa outside of academic settings provide important contributions to developing in-country capacity to participate in and lead research. Institutional support, increased funds, and dedicated time for research activities are critical factors that lead to the development of successful programs. Further, knowledge sharing through scientific articles with sufficient detail is needed to enable replication of successful models in other settings. PMID- 26055975 TI - Clinical Response to Ingenol Mebutate in Patients With Actinic Keratoses. AB - Cryotherapy is the most common treatment for actinic keratosis, but its effect is limited to individual lesions. Several topical drugs, however, are available that, in addition to treating individual actinic keratoses, target field cancerization and thereby act on subclinical lesions. Examples are 5 fluorouracil, imiquimod, diclofenac, and ingenol mebutate. We report on 17 patients with actinic keratoses treated with ingenol mebutate and describe our findings on treatment effectiveness, adherence, and tolerance. Complete and partial response rates were 35% and 53%, respectively. Ninety-four percent of patients fully adhered to treatment and 18% developed severe local reactions. Ingenol mebutate is an effective treatment for actinic keratosis. Although it has a similar rate of local reactions to other treatments available for actinic keratosis, its short treatment regimen favors better adherence. PMID- 26055977 TI - Intratumor cholesteryl ester accumulation is associated with human breast cancer proliferation and aggressive potential: a molecular and clinicopathological study. AB - BACKGROUND: The metabolic effect of intratumor cholesteryl ester (CE) in breast cancer remains poorly understood. The objective was to analyze the relationship between intratumor CE content and clinicopathological variables in human breast carcinomas. METHODS: We classified 30 breast carcinoma samples into three subgroups: 10 luminal-A tumors (ER+/PR+/Her2-), 10 Her-2 tumors (ER-/PR-/Her2+), and 10 triple negative (TN) tumors (ER-/PR-/Her2-). We analyzed intratumor neutral CE, free cholesterol (FC) and triglyceride (TG) content by thin layer chromatography after lipid extraction. RNA and protein levels of lipid metabolism and invasion mediators were analyzed by real time PCR and Western blot analysis. RESULTS: Group-wise comparisons, linear regression and logistic regression models showed a close association between CE-rich tumors and higher histologic grade, Ki 67 and tumor necrosis. CE-rich tumors displayed higher mRNA and protein levels of low-density lipoprotein receptor (LDLR) and scavenger receptor class B member 1 (SCARB1). An increased expression of acetyl-Coenzyme A acetyltransferase 1 (ACAT1) in CE-rich tumors was also reported. CONCLUSIONS: Intratumor CE accumulation is intimately linked to proliferation and aggressive potential of breast cancer tumors. Our data support the link between intratumor CE content and poor clinical outcome and open the door to new antitumor interventions. PMID- 26055976 TI - Treatment Steps, Surgery, and Hospitalization Rates During the First Year of Follow-up in Patients with Inflammatory Bowel Diseases from the 2011 ECCO-Epicom Inception Cohort. AB - BACKGROUND AND AIMS: The ECCO-EpiCom study investigates the differences in the incidence and therapeutic management of inflammatory bowel diseases [IBD] between Eastern and Western Europe. The aim of this study was to analyse the differences in the disease phenotype, medical therapy, surgery, and hospitalization rates in the ECCO-EpiCom 2011 inception cohort during the first year after diagnosis. METHODS: Nine Western, five Eastern European centres and one Australian centre with 258 Crohn's disease [CD], 380 ulcerative colitis [UC] and 71 IBD unclassified [IBDU] patients [female/male: 326/383; mean age at diagnosis: 40.9 years, SD: 17.3 years] participated. Patients' data were registered and entered in the web-based ECCO-EpiCom database [www.epicom-ecco.eu]. RESULTS: In CD, 36 [19%] Western Europe/Australian and 6 [9%] Eastern European patients received biological therapy [p = 0.04], but the immunosuppressive [IS] use was equal and high in these regions [Eastern Europe vs Western Europe/Australia: 53% vs 45%; p = 0.27]. Surgery was performed in 17 [24%] CD patients in Eastern Europe and 13 [7%] in Western Europe/Australia [p < 0.001, pLogRank = 0.001]. Of CD patients from Eastern Europe, 24 [34%] were hospitalized, and 39 [21%] from Western Europe/Australia, [p = 0.02, pLogRank = 0.01]. In UC, exposure to biologicals and colectomy rates were low and hospitalization rates did not differ between these regions during the 1-year follow-up period [16% vs 16%; p = 0.93]. CONCLUSIONS: During the first year after diagnosis, surgery and hospitalization rates were significantly higher in CD patients in Eastern Europe compared with Western Europe/Australia, whereas significantly more CD patients were treated with biologicals in the Western Europe/Australian centres. PMID- 26055978 TI - Nefopam for the prevention of perioperative shivering: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Shivering is a frequent complication following surgery and anaesthesia. A large variety of studies have been reported that nefopam may be efficacious for the prevention and treatment of perioperative shivering. Regrettably, there is still no conclusion of the efficacy and safety of nefopam for the prevention of perioperative shivering. The aim of this analysis is to evaluate the efficacy of nefopam for the prevention of perioperative shivering in patients undergoing different types of anaesthesia compared with placebo group and other active interventions. METHODS: PubMed, EMBASE, Cochrane Central Register of Control Trials were systematically searched for potentially relevant trials. Trial quality and extracted data were evaluated by two authors independently. Dichotomous data on the absence of shivering was extracted and analysed by using relative risk (RR) with 95% confidence interval (CI). Continuous outcome was abstracted and analysed by using weighted mean difference (WMD) with 95% confidence interval (CI). Outcome data was analysed by using random effect model or fixed effect model in accordance with heterogeneity. RESULTS: Compared with placebo, prophylactic administration of nefopam significantly reduced the risk of perioperative shivering not only in the patients under general anaesthesia but also neuraxial anaesthesia (RR 0.08; 95% CI 0.05-0.13). As compared with clonidine, nefopam was more efficacious in the prevention of perioperative shivering (RR 0.34; 95% CI 0.17-0.70). Nefopam has no influence on the extubation time (WMD 0.92; 95% CI -0.15-1.99). CONCLUSION: Our analysis has demonstrated that nefopam is associated with the decrease of risk of perioperative shivering following anaesthesia without influencing the extubation time. PMID- 26055979 TI - Abscisic acid induces biosynthesis of bisbibenzyls and tolerance to UV-C in the liverwort Marchantia polymorpha. AB - Environmental stresses are effective triggers for the biosynthesis of various secondary metabolites in plants, and phytohormones such as jasmonic acid and abscisic acid are known to mediate such responses in flowering plants. However, the detailed mechanism underlying the regulation of secondary metabolism in bryophytes remains unclear. In this study, the induction mechanism of secondary metabolites in the model liverwort Marchantia polymorpha was investigated. Abscisic acid (ABA) and ultraviolet irradiation (UV-C) were found to induce the biosynthesis of isoriccardin C, marchantin C, and riccardin F, which are categorized as bisbibenzyls, characteristic metabolites of liverworts. UV-C led to the significant accumulation of ABA. Overexpression of MpABI1, which encodes protein phosphatase 2C (PP2C) as a negative regulator of ABA signaling, suppressed accumulation of bisbibenzyls in response to ABA and UV-C irradiation and conferred susceptibility to UV-C irradiation. These data show that ABA plays a significant role in the induction of bisbibenzyl biosynthesis, which might confer tolerance against UV-C irradiation in M. polymorpha. PMID- 26055981 TI - [Quality and accreditation in pathology: It all starts with the pre-analytical phase!]. PMID- 26055980 TI - Unusual apocrine carcinoma with neuroendocrine differentiation: a cutaneous neoplasm may be analogous to neuroendocrine carcinoma with apocrine differentiation of breast. AB - Cutaneous apocrine carcinoma (AC) is a rare adnexal neoplasm that histologically can mimic breast carcinoma metastatic to the skin or apocrine carcinoma arising in ectopic breast tissue. As extremely rare condition, neuroendocrine differentiation may be observed in AC although its etiology and pathogenesis is still unclear. We report here a case of unusual AC with neuroendocrine differentiation in right labium majus pudenda. A 43-year-old woman presented with a 6-month history of an asymptomatic pea-sized brownish nodule in right labium majus pudenda without enlargement of inguinal lymph nodes and bilateral breast nodules. The mass was totally resected. Microscopically, the tumor was solitary and located in the deep dermis without epidermal connection. Tumor cells were arranged in a micronodular or formed massive solid nests separated by densely fibroblastic stroma. Scattered glandular or rosette-like structures were identified within the tumor nodules. Immunohistochemically, the tumor cells were diffusely positive to CK7, CEA, GCDFP-15, synaptophysin, estrogen and progesterone receptors. Part of tumor cells expressed androgen receptor, but they were negative to CK20, CK5/6, p63 and S-100. Because of its rarity and histogenesis complexity, there exist diagnostic challenges for pathologists to differentiate cutaneous AC with neuroendocrine differentiation from other carcinomas with apocrine or neuroendocrine features. Our case demonstrates that the tumor shares some features with mammary carcinoma and might originate from mammary-like sweat gland in anogenital region. The results suggest that, for the first time, primary cutaneous AC with neuroendocrine differentiation may be analogous to the mammary neuroendocrine carcinoma with apocrine differentiation in histological feature and biological behavior. Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7732276716685708. PMID- 26055982 TI - Preclinical assessment of potential interactions between botulinum toxin and neuromodulation for bladder micturition reflex. AB - BACKGROUND: While botulinum toxin A (BoNT-A) has become a more commonly used second-line treatment for patients with detrusor overactivity, it remains unknown whether the impacts of this therapy may persist to influence other therapies such as sacral neuromodulation. In this preclinical study we have evaluated urodynamic functions to intradetrusor injection of BoNT-A and the bladder inhibitory effects of spinal nerve stimulation (SNS) following BoNT-A treatment. METHODS: Female rats were anesthetized with 3 % isoflurane. BoNT-A (2 units, 0.2 ml) or saline were injected into the detrusor. Rats then were housed for 2 days to 1 month before neuromodulation study. Monopolar electrodes were placed under each of the L6 spinal nerve bilaterally under urethane anesthesia. A bladder cannula was inserted via the urethra for saline infusion and intravesical pressure recording. RESULTS: Intradetrusor injection of BoNT-A for 1-2 weeks or 1 month significantly increased bladder capacity compared with saline injection (p < 0.05, two-way ANOVA). Following BoNT-A, SNS attenuated the frequency of bladder contractions, either eliminating bladder contractions or reducing the contraction frequency during electrical stimulation. Inhibition of the contraction frequency by SNS following BoNT-A treated rats was not different from that measured following saline injection. CONCLUSIONS: BoNT-A increased the bladder capacity, but compensating for additional saline infusion to the enlarged urinary bladder in BoNT-A pretreated rats, the bladder contractions induced by bladder filling were attenuated by SNS. BoNT-A did not alter the ability of SNS to inhibit bladder contraction following intradetrusor injection of BoNT-A for 2 days, 1-2 weeks or 1 month. These results support further pre-clinical and clinical studies to evaluate potential interactions or combination therapy with neuromodulation and intradetrusor BoNT-A therapeutic approaches. PMID- 26055983 TI - Access to a Car and the Self-Reported Health and Mental Health of People Aged 65 and Older in Northern Ireland. AB - This article examines relationships between access to a car and the self-reported health and mental health of older people. The analysis is based on a sample of N = 65,601 individuals aged 65 years and older from the Northern Ireland Longitudinal Study linked to 2001 and 2011 census returns. The findings from hierarchical linear and binary logistic multilevel path models indicate that having no access to a car is related to a considerable health and mental health disadvantage particularly for older people who live alone. Rural-urban health and mental health differences are mediated by access to a car. The findings support approaches that emphasize the importance of autonomy and independence for the well-being of older people and indicate that not having access to a car can be a problem for older people not only in rural but also in intermediate and urban areas, if no sufficient alternative forms of mobility are provided. PMID- 26055984 TI - Benzyllithiums bearing aldehyde carbonyl groups. A flash chemistry approach. AB - Reductive lithiation of benzyl halides bearing aldehyde carbonyl groups followed by reaction with subsequently added electrophiles was successfully accomplished without affecting the carbonyl groups by taking advantage of short residence times in flow microreactors. PMID- 26055985 TI - African American families on autism diagnosis and treatment: the influence of culture. AB - Cultural factors such as health care access and autism spectrum disorder (ASD) symptom interpretations have been proposed as impacting delayed diagnosis and treatment for African American children with ASD. A qualitative study of urban African American families caring for their child with autism was conducted with 24 family members and 28 ASD professionals. Cultural caring meant families protected their child from harm including potential or actual distrustful encounters, and took action for their child and community to optimize their child's health and address the knowledge deficits of ASD within their community. Families and professionals believed cultural influences delayed families' receiving and seeking appropriate health care for the African American child with ASD affecting timely autism diagnosis and treatment. PMID- 26055986 TI - The evidence for improving housing to reduce malaria: a systematic review and meta-analysis. AB - BACKGROUND: The global malaria burden has fallen since 2000, sometimes before large-scale vector control programmes were initiated. While long-lasting insecticide-treated nets and indoor residual spraying are highly effective interventions, this study tests the hypothesis that improved housing can reduce malaria by decreasing house entry by malaria mosquitoes. METHODS: A systematic review and meta-analysis was conducted to assess whether modern housing is associated with a lower risk of malaria than traditional housing, across all age groups and malaria-endemic settings. Six electronic databases were searched to identify intervention and observational studies published from 1 January, 1900 to 13 December, 2013, measuring the association between house design and malaria. The primary outcome measures were parasite prevalence and incidence of clinical malaria. Crude and adjusted effects were combined in fixed- and random-effects meta-analyses, with sub-group analyses for: overall house type (traditional versus modern housing); screening; main wall, roof and floor materials; eave type; ceilings and elevation. RESULTS: Of 15,526 studies screened, 90 were included in a qualitative synthesis and 53 reported epidemiological outcomes, included in a meta-analysis. Of these, 39 (74%) showed trends towards a lower risk of epidemiological outcomes associated with improved house features. Of studies assessing the relationship between modern housing and malaria infection (n=11) and clinical malaria (n=5), all were observational, with very low to low quality evidence. Residents of modern houses had 47% lower odds of malaria infection compared to traditional houses (adjusted odds ratio (OR) 0 degrees 53, 95% confidence intervals (CI) 0 degrees 42-0 degrees 67, p< 0 degrees 001, five studies) and a 45-65% lower odds of clinical malaria (case-control studies: adjusted OR 0 degrees 35, 95 % CI 0 degrees 20-0 degrees 62, p<0 degrees 001, one study; cohort studies: adjusted rate ratio 0 degrees 55, 95% CI 0 degrees 36-0 degrees 84, p=0 degrees 005, three studies). Evidence of a high risk of bias was found within studies. CONCLUSIONS: Despite low quality evidence, the direction and consistency of effects indicate that housing is an important risk factor for malaria. Future research should evaluate the protective effect of specific house features and incremental housing improvements associated with socio-economic development. PMID- 26055987 TI - A new Toxoplasma gondii chimeric antigen containing fragments of SAG2, GRA1, and ROP1 proteins-impact of immunodominant sequences size on its diagnostic usefulness. AB - This study presents the first evaluation of new Toxoplasma gondii recombinant chimeric antigens containing three immunodominant regions of SAG2, GRA1, and one of two ROP1 fragments differing in length for the serodiagnosis of human toxoplasmosis. The recombinant chimeric antigens SAG2-GRA1-ROP1L (with large fragment of ROP1, 85-396 amino acid residues) and SAG2-GRA1-ROP1S (with a small fragment of ROP1, 85-250 amino acid residues) were obtained as fusion proteins containing His6-tags at both ends using an Escherichia coli expression system. The diagnostic utility of these chimeric antigens was determined using the enzyme linked immunosorbent assay (ELISA) for the detection of specific anti-T. gondii immunoglobulin G (IgG). The IgG ELISA results obtained for the chimeric antigens were compared to those obtained for the use of Toxoplasma lysate antigen (TLA) and for a mixture of recombinant antigens containing rSAG2, rGRA1, and rROP1. The sensitivity of the IgG ELISA was similar for the SAG2-GRA1-ROP1L chimeric antigen (100 %), the mixture of three proteins (99.4 %) and the TLA (97.1 %), whereas the sensitivity of IgG ELISA with the SAG2-GRA1-ROP1S chimeric antigen was definitely lower, reaching 88.4 %. In conclusion, this study shows that SAG2-GRA1-ROP1L chimeric antigen can be useful for serodiagnosis of human toxoplasmosis with the use of the IgG ELISA assay. Therefore, the importance of proper selection of protein fragments for the construction of chimeric antigen with the highest reactivity in ELISA test is demonstrated. PMID- 26055988 TI - Hazard levels of warning signal words modulate the inhibition of return effect: evidence from the event-related potential P300. AB - Warning signal words are often used to convey valuable information about potential dangers in everyday life. In this study, we explored whether and how the hazard level of warning signal words modulated participants' attention to subsequent targets. Event-related potentials with high temporal resolution were employed in a cue-target paradigm. In this task, warning signal words with different hazard levels were used as cues. Participants were required to judge whether targets were presented on the screen horizontally or vertically. We found an inhibition of return (IOR) effect, i.e., participants had longer reaction times to validly cued targets than to invalidly cued targets. Accordingly, the IOR effect was reflected by a smaller P300 amplitude for invalidly cued targets compared to validly cued targets. Furthermore, the IOR effect was eliminated when the cues were high-hazard words. The dampening effect on the P300 was eliminated when the cues were high-hazard warning signal words. The lack of an IOR was attributed to participants' attentional bias to high-hazard stimuli, which are difficult for participants to disengage their attention from. The current study suggests that warning signal words are a particular type of stimulus that can override the IOR effect. Warning signal words with a high hazard level are more effective in successfully alerting people to risk in a hazardous environment. PMID- 26055989 TI - The limb-specific embodiment of a tool following experience. AB - The present study was designed to investigate the incorporation of tools into the human body schema. Previous research on tool use suggests that through physical interaction with a tool, the representation of the body is adjusted to incorporate or "embody" the tool. The present experiment was conducted to test the limb-specific nature of tool embodiment. Participants were presented with images of a person holding a rake and executed hand- and foot-press responses to colored targets superimposed on the hand, foot, and rake of the image. This task was completed before and after moving a ball around a course with a hand-held rake. Consistent with previous research, a body-part compatibility effect emerged response times (RTs) were shorter when the responding limb and target location were compatible (e.g., hand responses to targets on the hand) than when they were incompatible (e.g., hand responses to targets on the foot). Of greater theoretical relevance, hand RTs to targets presented on the hand were shorter than those to targets on the rake prior to experience, but were not different after completing the rake task. The post-experience similarity in hand RTs emerged because there was a significant reduction in RTs to targets on the rake following use. There was no significant pre-/post-experience change in hand RTs to targets on the hand or, importantly, for any response executed by the foot. These results provide new evidence that a tool is embodied in a limb-specific manner and is represented within the body schema as if it was an extension of the limb. PMID- 26055991 TI - Dual catalysis with magnetic chitosan: direct synthesis of cyclic carbonates from olefins with carbon dioxide using isobutyraldehyde as the sacrificial reductant. AB - Chitosan coated magnetic nanoparticles were synthesized and used as a support for the immobilization of the cobalt(II) acetylacetonate complex [Co(acac)2] and quaternary triphenylphosphonium bromide [P(+)Ph3Br(-)] targeting -NH2 and -OH moieties located on the surface of chitosan. The synthesized material was used as a catalyst for one pot direct synthesis of cyclic carbonates from olefins via an oxidative carboxylation approach with carbon dioxide using isobutyraldehyde as the sacrificial reductant and molecular oxygen as the oxidant. After the reaction, the catalyst was recovered by applying an external magnet and reused for several runs without significant loss in catalytic activity and no leaching was observed during this course. PMID- 26055990 TI - Impact of Parkinson's disease on proprioceptively based on-line movement control. AB - Evidence suggests that Parkinson's disease (PD) patients produce large spatial errors when reaching to proprioceptively defined targets. Here, we examined whether these movement inaccuracies result mainly from impaired use of proprioceptive inputs for movement planning mechanisms or from on-line movement guidance. Medicated and non-medicated PD patients and healthy controls performed three-dimensional reaching movements in four sensorimotor conditions that increase proprioceptive processing requirements. We assessed the influence of these sensorimotor conditions on the final accuracy and initial kinematics of the movements. If the patterns of final errors are primarily determined by planning processes before the initiation of the movement, the initial kinematics of reaching movements should show similar trends and predict the pattern of final errors. Medicated and non-medicated PD patients showed a greater mean level of final 3D errors than healthy controls when proprioception was the sole source of information guiding the movement, but this difference reached significance only for medicated PD patients. However, the pattern of initial kinematics and final spatial errors were markedly different both between sensorimotor conditions and between groups. Furthermore, medicated and non-medicated PD patients were less efficient than healthy controls in compensating for their initial spatial errors (hand distance from target location at peak velocity) when aiming at proprioceptively defined compared to visually defined targets. Considered together, the results are consistent with a selective deficit in proprioceptively based movement guidance in PD. Furthermore, dopaminergic medication did not improve proprioceptively guided movements in PD patients, indicating that dopaminergic dysfunction within the basal ganglia is not solely responsible for these deficits. PMID- 26055992 TI - Analysis of segregation distortion and its relationship to hybrid barriers in rice. AB - BACKGROUND: Segregation distortion (SD) is a frequently observed occurrence in mapping populations generated from crosses involving divergent genotypes. In the present study, ten genetic linkage maps constructed from reciprocal F2 and BC1F1 mapping populations derived from the parents Dasanbyeo (indica) and Ilpumbyeo (japonica) were used to identify the distribution, effect, and magnitude of the genetic factors underlying the mechanisms of SD between the two subspecies. RESULTS: SD loci detected in the present study were affected by male function, female function, and zygotic selection. The most pronounced SD loci were mapped to chromosome 3 (transmitted through male gametes), chromosome 5 (transmitted through male gametes), and chromosome 6 (transmitted through female gametes). The level of SD in BC1F1 populations which defined by chi-square value independence multiple tests was relatively low in comparison to F2 populations. Dasanbyeo alleles were transmitted at a higher frequency in both F2 and BC1F1 populations, suggesting that indica alleles are strongly favored in inter-subspecific crosses in rice. SD loci in the present study corresponded to previously reported loci for reproductive barriers. In addition, new SD loci were detected on chromosomes 2 and 12. CONCLUSION: The identification of the distribution of SD and the effect of genetic factors causing SD in genetic mapping populations provides an opportunity to survey the whole genome for new SD loci and their relationships to reproductive barriers. This provides a basis for future research on the elucidation of the genetic mechanisms underlying SD in rice, and will be useful in molecular breeding programs. PMID- 26055993 TI - Response of an aspartic protease gene OsAP77 to fungal, bacterial and viral infections in rice. AB - BACKGROUND: Aspartic protease (APs) plays important roles in plant growth, development and biotic and abiotic stresses. We previously reported that the expression of a rice AP gene (OsAP77, Os10g0537800) was induced by probenazole (PBZ), a chemical inducer of disease resistance. In this study we examined some characteristics of this gene in response to fungal, bacterial and viral pathogens. RESULTS: To elucidate the spatial and temporal expression of OsAP77, the chimeric gene was constructed carrying the structural gene encoding beta glucuronidase (GUS) driven by the OsAP77 promoter. This construct was introduced into rice and the transgenic lines were tested to analyze gene expression by fungal, bacterial and viral infections. Inoculation with Magnaporthe oryzae or Xanthomonas oryzae pv. oryzae revealed the enhanced GUS activities in vascular tissues surrounding the symptom sites by each pathogen. Moreover, GUS activity also increased after inoculation with Cucumber mosaic virus (CMV). Transgenic plants immersed in a solution containing salicylic acid (SA), isonicotinic acid (INA), hydrogen peroxide (H2O2) or abscisic acid (ABA) showed an increased level of GUS activity exclusively in vascular tissues. RT-PCR analysis showed that OsAP77 was induced not only by infection with these pathogens, but also after treatment with SA, INA, H2O2 or ABA. A knockout mutant line of OsAP77 by the insertion of Tos17 after inoculation with M. oryzae, X. oryzae pv. oryzae or CMV showed an enhanced susceptibility compared to wild type. CONCLUSION: These results suggest that the expression of OsAP77 is induced by pathogen infection and defense related signaling molecules in a vascular tissue specific manner and that this gene has a positive role of defense response against fungal, bacterial and viral infections. PMID- 26055994 TI - Update on Bacterial Blight of Rice: Fourth International Conference on Bacterial Blight. AB - [Symbol: see text][Symbol: see text][Symbol: see text]. PMID- 26055995 TI - Workable male sterility systems for hybrid rice: Genetics, biochemistry, molecular biology, and utilization. AB - The exploitation of male sterility systems has enabled the commercialization of heterosis in rice, with greatly increased yield and total production of this major staple food crop. Hybrid rice, which was adopted in the 1970s, now covers nearly 13.6 million hectares each year in China alone. Various types of cytoplasmic male sterility (CMS) and environment-conditioned genic male sterility (EGMS) systems have been applied in hybrid rice production. In this paper, recent advances in genetics, biochemistry, and molecular biology are reviewed with an emphasis on major male sterility systems in rice: five CMS systems, i.e., BT-, HL , WA-, LD- and CW- CMS, and two EGMS systems, i.e., photoperiod- and temperature sensitive genic male sterility (P/TGMS). The interaction of chimeric mitochondrial genes with nuclear genes causes CMS, which may be restored by restorer of fertility (Rf) genes. The PGMS, on the other hand, is conditioned by a non-coding RNA gene. A survey of the various CMS and EGMS lines used in hybrid rice production over the past three decades shows that the two-line system utilizing EGMS lines is playing a steadily larger role and TGMS lines predominate the current two-line system for hybrid rice production. The findings and experience gained during development and application of, and research on male sterility in rice not only advanced our understanding but also shed light on applications to other crops. PMID- 26055996 TI - High-density mapping of quantitative trait loci for grain-weight and spikelet number in rice. AB - BACKGROUND: High grain yield is one of the most important traits requiring improvement in rice breeding programs. Consequently, the genetic basis of spikelets per panicle (SPP) and grain weight (TGW) have received much research focus because of their importance in rice yield. RESULTS: In this study, IL28, which is a near isogenic line (NIL) developed by introgressing chromosomal segments of the cultivar 'Moroberekan' into the cultivar 'Ilpumbyeo', showed a significant increase in the number of spikelets per panicle (SPP) and 1,000-grain weight (TGW) compared to the recurrent parent, Ilpumbyeo. Quantitative trait locus (QTL) analysis in 243 F2 plants derived from a cross between IL28 and Ilpumbyeo indicated that both qSPP6 and qTGW6 are located in the interval RM3430 RM20580. Following substitution mapping with 50 F3:4:5 lines, qSPP6 was mapped to a 429-kb interval between RM20521 and InDel-1, while qTGW6 was mapped to a 37.85 kb interval between InDel-1 and SNP--3 based on the japonica genome sequence. This result indicates that qSPP6 and qTGW6 are different genes. Yield trials with substitution lines indicated that lines harboring the homozygous Moroberekan segment at both the qSPP6 and qTGW6 region showed significantly higher grain yield than Ilpumbyeo. CONCLUSION: Because the Moroberekan alleles for SPP and TGW have been shown to be beneficial in the genetic background of Ilpumbyeo, both the qSPP6 and qTGW6 alleles might prove valuable in improving rice yields. Closely linked SSR markers are expected to facilitate the cloning of genes that underlie these QTLs, as well as with marker-assisted selection for variation in SPP and TGW in rice breeding programs. PMID- 26055997 TI - Image-based phenotyping for non-destructive screening of different salinity tolerance traits in rice. AB - BACKGROUND: Soil salinity is an abiotic stress wide spread in rice producing areas, limiting both plant growth and yield. The development of salt-tolerant rice requires efficient and high-throughput screening techniques to identify promising lines for salt affected areas. Advances made in image-based phenotyping techniques provide an opportunity to use non-destructive imaging to screen for salinity tolerance traits in a wide range of germplasm in a reliable, quantitative and efficient way. However, the application of image-based phenotyping in the development of salt-tolerant rice remains limited. RESULTS: A non-destructive image-based phenotyping protocol to assess salinity tolerance traits of two rice cultivars (IR64 and Fatmawati) has been established in this study. The response of rice to different levels of salt stress was quantified over time based on total shoot area and senescent shoot area, calculated from visible red-green-blue (RGB) and fluorescence images. The response of rice to salt stress (50, 75 and 100 mM NaCl) could be clearly distinguished from the control as indicated by the reduced increase of shoot area. The salt concentrations used had only a small effect on the growth of rice during the initial phase of stress, the shoot Na(+) accumulation independent phase termed the 'osmotic stress' phase. However, after 20 d of treatment, the shoot area of salt stressed plants was reduced compared with non-stressed plants. This was accompanied by a significant increase in the concentration of Na(+) in the shoot. Variation in the senescent area of the cultivars IR64 and Fatmawati in response to a high concentration of Na(+) in the shoot indicates variation in tissue tolerance mechanisms between the cultivars. CONCLUSIONS: Image analysis has the potential to be used for high-throughput screening procedures in the development of salt-tolerant rice. The ability of image analysis to discriminate between the different aspects of salt stress (shoot ion-independent stress and shoot ion dependent stress) makes it a useful tool for genetic and physiological studies to elucidate processes that contribute to salinity tolerance in rice. The technique has the potential for identifying the genetic basis of these mechanisms and assisting in pyramiding different tolerance mechanisms into breeding lines. PMID- 26055998 TI - Generation of transgenic rice with reduced content of major and novel high molecular weight allergens. AB - BACKGROUND: Rice seed proteins contain antigens that provoke allergic responses in some individuals with food allergy, particularly in those with cereal allergy, and these antigens can elicit clinical symptoms such as eczema and dermatitis. We previously generated transgenic rice with reduced accumulation of the three major allergens, which dramatically reduced the level of IgE binding from patients' sera. However, the transgenic rice still possesses allergenic reactivity. Recently, two globulin-like proteins were identified as candidates of novel high molecular weight (HMW) IgE-binding proteins that cause rice allergy. RESULTS: We identified a glucosidase family encoded by four genes as novel HMW rice allergens based on IgE antibody reactivity from individuals with allergy to rice. To further reduce allergenicity, we generated transgenic rice with reduced accumulation of these HMW allergens. We crossed the rice with reduced HMW allergens and with reduced major allergens, and all major and HMW allergens were substantially reduced in the progeny of the crossed rice. Allergen suppression did not significantly alter accumulation patterns of seed storage proteins and protein folding enzymes. The sera of a portion of patients showed low IgE-binding to the crossed line, suggesting that the crossed line is effective for a portion of patients who are allergic to proteins other than major allergens. CONCLUSIONS: The transgenic rice with reduced levels of all major and HMW allergens is thought to be an option for a portion of allergy patients with hypersensitive responses to various kinds of rice allergens. PMID- 26055999 TI - PCSK5 mutation in a patient with the VACTERL association. AB - BACKGROUND: The VACTERL association is a typically sporadic, non-random collection of congenital anomalies that includes vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with esophageal atresia, renal anomalies, and limb abnormalities. Although several chromosomal aberrations and gene mutations have been reported as disease-causative, these findings have been sparsely replicated to date. CASE PRESENTATION: In the present study, whole exome sequencing of a case with the VACTERL association uncovered a novel frameshift mutation in the PCSK5 gene, which has been reported as one of the causative genes for the VACTERL association. Although this mutation appears potentially pathogenic in its functional aspects, it was also carried by the healthy father. Furthermore, a database survey revealed several other deleterious variants in the PCSK5 gene in the general population. CONCLUSIONS: Further studies are necessary to clarify the etiological role of the PCSK5 mutation in the VACTERL association. PMID- 26056001 TI - Characterization of novel mechanisms for steatosis from global protein hyperacetylation in ethanol-induced mouse hepatocytes. AB - Steatosis is the earliest and most common disease of the liver due to chronic ethanol consumption, and stems from alterations in the function of transcription factors related to lipid metabolism. Protein acetylation at the lysine residue (Kac) is known to have diverse functions in cell metabolism. Recent studies showed that ethanol exposure induces global protein hyperacetylation by reducing the deacetylase activities of SIRT1 and SIRT3. Although global acetylome analyses have revealed the involvement of a variety of lysine acetylation sites, the exact sites directly regulated by ethanol exposure are unknown. In this study, to elucidate the exact hyperacetylation sites that contribute to SIRT1 and SIRT3 downregulation, we identified and quantified a total of 1285 Kac sites and 686 Kac proteins in AML-12 cells after ethanol treatment (100 mM) for 3 days. All quantified Kac sites were divided into four quantiles: Q1 (0-15%), Q2 (15-50%), Q3 (50-85%), and Q4 (85-100%). Q4 had 192 Kac sites indicating ethanol-induced hyperacetylation. Using the Motif-x program, the [LXKL], [KH], and [KW] motifs were included in the Q4 category, where [KW] was a specific residue for SIRT3. We also performed gene ontology term and KEGG pathway enrichment analyses. Hyperacetylation sites were significantly enriched in biosynthetic processes and ATPase activities within the biological process and molecular function categories, respectively. In conclusion, ethanol regulates the acetylation of proteins in a variety of metabolic pathways mediated by SIRT1 and SIRT3. As a result, ethanol stimulates increased de novo fatty acid synthesis in hepatocytes. PMID- 26056000 TI - Deep sequencing reveals cell-type-specific patterns of single-cell transcriptome variation. AB - BACKGROUND: Differentiation of metazoan cells requires execution of different gene expression programs but recent single-cell transcriptome profiling has revealed considerable variation within cells of seeming identical phenotype. This brings into question the relationship between transcriptome states and cell phenotypes. Additionally, single-cell transcriptomics presents unique analysis challenges that need to be addressed to answer this question. RESULTS: We present high quality deep read-depth single-cell RNA sequencing for 91 cells from five mouse tissues and 18 cells from two rat tissues, along with 30 control samples of bulk RNA diluted to single-cell levels. We find that transcriptomes differ globally across tissues with regard to the number of genes expressed, the average expression patterns, and within-cell-type variation patterns. We develop methods to filter genes for reliable quantification and to calibrate biological variation. All cell types include genes with high variability in expression, in a tissue-specific manner. We also find evidence that single-cell variability of neuronal genes in mice is correlated with that in rats consistent with the hypothesis that levels of variation may be conserved. CONCLUSIONS: Single-cell RNA-sequencing data provide a unique view of transcriptome function; however, careful analysis is required in order to use single-cell RNA-sequencing measurements for this purpose. Technical variation must be considered in single cell RNA-sequencing studies of expression variation. For a subset of genes, biological variability within each cell type appears to be regulated in order to perform dynamic functions, rather than solely molecular noise. PMID- 26056002 TI - Involvement of trefoil factor family 2 in the enlargement of intestinal tumors in Apc(Min/+) mice. AB - It is assumed that tumor size may be associated with malignant tumor conversion. However, the molecules responsible for determination of tumor size are not well understood. We counted the number of intestinal tumors in 8, 12 and 30-week-old Apc(Min/+) mice and measured tumor sizes, respectively. Genes involved in determining tumor size were examined using microarray analysis. Cultured cells were then, transfected with a mammalian expression vector containing a candidate gene to examine the functional role of the gene. The effect of forced expression of candidate gene on cell growth was evaluated by measuring the doubling time of the cultured cells and the growth of grafted cells in nude mice. Unexpectedly, microarray analysis identified trefoil factor family 2 (Tff2) rather than growth related genes and/or oncogenes as a most variable gene. Overexpressing Tff2 in cultured cells reduced doubling time in vitro and rapidly increased xenograft tumor size in vivo. We found Tff2 as a novel important factor that to be able to enlarge an intestinal tumor size. PMID- 26056003 TI - PKCalpha promotes generation of reactive oxygen species via DUOX2 in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) remains the second leading cause of cancer-related death worldwide, and elevated rates of reactive oxygen species (ROS) have long been considered as a hallmark of almost all types of cancer including HCC. Protein kinase C alpha (PKCalpha), a serine/threonine kinase among conventional PKC family, is recognized as a major player in signal transduction and tumor progression. Overexpression of PKCalpha is commonly observed in human HCC and associated with its poor prognosis. However, how PKCalpha is involved in hepatocellular carcinogenesis remains not fully understood. In this study, we found that among the members of conventional PKC family, PKCalpha, but not PKCbetaI or betaII, promoted ROS production in HCC cells. PKCalpha stimulated generation of ROS by up-regulating DUOX2 at post-transcriptional level. Depletion of DUOX2 abrogated PKCalpha-induced activation of AKT/MAPK pathways as well as cell proliferation, migration and invasion in HCC cells. Moreover, the expression of DUOX2 and PKCalpha was well positively correlated in both HCC cell lines and patient samples. Collectively, our findings demonstrate that PKCalpha plays a critical role in HCC development by inducing DUOX2 expression and ROS generation, and propose a strategy to target PKCalpha/DUOX2 as a potential adjuvant therapy for HCC treatment. PMID- 26056004 TI - TRIF promotes angiotensin II-induced cross-talk between fibroblasts and macrophages in atrial fibrosis. AB - AIMS: Atrial fibroblasts and macrophages have long been thought to participate in atrial fibrillation (AF). However, which specific mediator may regulate the interaction between them remains unclear. METHODS AND RESULTS: We provided the evidence for the involvement of Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF), an important inflammation-related molecule, in the pathophysiology of AF. Patients with AF showed higher levels of angiotensin II (AngII) and TRIF expression and larger number of macrophages infiltration in left atria appendage than individuals with sinus rhythm (SR). In the cell study, AngII induced chemokines expressions in mouse atrial fibroblasts and AngII-stimulated atrial fibroblasts induced the chemotaxis of macrophages, which were reduced by losartan and TRIF siRNA. Meanwhile, AngII-stimulated atrial fibroblasts proliferation was enhanced by macrophages. CONCLUSIONS: Our data demonstrated that TRIF may be a crucial factor promoting the interaction between atrial fibroblasts and macrophages, leading to atrial fibrosis. PMID- 26056005 TI - Selection and characterization of human PCSK9 antibody from phage displayed antibody library. AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9), which involves in low density lipoprotein cholesterol (LDL-C) metabolism by interacting with the LDL receptor, is considered as a potent therapeutic target for treating hypercholesterolemia. Here, a fab antibody phage display library was constructed and employed for bio-panning against recombinant PCSK9. A Fab fragment (designated PA4) bound with high affinity to PCSK9 was isolated after four rounds of panning. The fully human antibody IgG1-PA4 bound specifically to PCSK9 with nanomolar affinity. In vitro, IgG1-PA4 inhibited PCSK9 binding to LDLR and attenuated PCSK9-mediated degradation of LDLR on the HepG2 cell surface. In C57BL/6 mice, administration of IgG1-PA4 at 30 mg/kg increased hepatic LDLR protein levels by as much as 3 fold when compared with control. Taken together, these results suggested that the IgG1-PA4 can be served as a potential candidate for the treatment of hypercholesterolemia by inhibiting PCSK9-mediated degradation of cell surface LDLRs. PMID- 26056006 TI - Characterization of spermidine synthase and spermine synthase--The polyamine synthetic enzymes that induce early flowering in Gentiana triflora. AB - Polyamines are essential for several living processes in plants. However, regulatory mechanisms of polyamines in herbaceous perennial are almost unknown. Here, we identified homologs of two Arabidopsis polyamine-synthetic enzymes, spermidine synthase (SPDS) and spermine synthase (SPMS) denoted as GtSPDS and GtSPMS, from the gentian plant, Gentiana triflora. Our results showed that recombinant proteins of GtSPDS and GtSPMS possessed SPDS and SPMS activities, respectively. The expression levels of GtSPDS and GtSPMS increased transiently during vegetative to reproductive growth phase and overexpression of the genes hastened flowering, suggesting that these genes are involved in flowering induction in gentian plants. PMID- 26056007 TI - Effects of Wnt-10b on proliferation and differentiation of murine melanoma cells. AB - In spite of the strong expression of Wnt-10b in melanomas, its role in melanoma cells has not been elucidated. In the present study, the biological effects of Wnt-10b on murine B16F10 (B16) melanoma cells were investigated using conditioned medium from Wnt-10b-producing COS cells (Wnt-CM). After 2 days of culture in the presence of Wnt-CM, proliferation of B16 melanoma cells was inhibited, whereas tyrosinase activity was increased. An in vitro wound healing assay demonstrated that migration of melanoma cells to the wound area was inhibited with the addition of Wnt-CM. Furthermore, evaluation of cellular senescence revealed prominent induction of SA-beta-gal-positive senescent cells in cultures with Wnt CM. Finally, the growth of B16 melanoma cell aggregates in collagen 3D-gel cultures was markedly suppressed in the presence of Wnt-CM. These results suggest that Wnt-10b represses tumor cell properties, such as proliferation and migration of B16 melanoma cells, driving them toward a more differentiated state along a melanocyte lineage. PMID- 26056008 TI - Identification of ponatinib and other known kinase inhibitors with potent MEKK2 inhibitory activity. AB - The kinase MEKK2 (MAP3K2) may play an important role in tumor growth and metastasis for several cancer types. Thus, targeting MEKK2 may represent a novel strategy for developing more effective therapies for cancer. In order to identify small molecules with MEKK2 inhibitory activity, we screened a collection of known kinase inhibitors using a high throughput MEKK2 intrinsic ATPase enzyme assay and confirmed activity of the most potent hits with this primary assay. We also confirmed activities of these known kinase inhibitors with an MEKK2 transphosphorylation slot blot assay using MKK6 as a substrate. We observed a good correlation in potencies between the two orthogonal MEKK2 kinase activity assay formats for this set of inhibitors. We report that ponatinib, AT9283, AZD7762, JNJ-7706621, PP121 and hesperadin had potent MEKK2 enzyme inhibitory activities ranging from 4.7 to 60 nM IC50. Ponatinib is an FDA-approved drug that potently inhibited MEKK2 enzyme activity with IC50 values of 10-16 nM. AT9283 is currently in clinical trials and produced MEKK2 IC50 values of 4.7-18 nM. This set of known kinase inhibitors represents some of the most potent in vitro MEKK2 inhibitors reported to date and may be useful as research tools. Although these compounds are not selective for MEKK2, the structures of these compounds give insight into pharmacophores that potently inhibit MEKK2 and could be used as initial leads to design highly selective inhibitors of MEKK2. PMID- 26056009 TI - miR-29a promotes scavenger receptor A expression by targeting QKI (quaking) during monocyte-macrophage differentiation. AB - Monocyte differentiation into macrophages results in upregulation of miR-29a and scavenger receptor A (SRA) expression, while the expression of RNA binding protein, QKI is suppressed. Since SRA is a functionally important protein in atherosclerosis, it is imperative to understand the various mechanisms involved in its regulation specially the mechanism involving miR-29a. There are individual studies linking miR-29a to SRA or QKI to monocyte differentiation but there is no evidence of any linkage among them. Therefore, we intend to investigate the association among these three, if any, in terms of regulation of SRA expression. Hence, in this study, the differentiated macrophages were initially transfected with miR-29a or its inhibitor and it was shown that QKI is a direct target of mir 29a. In addition, it was also observed by bioinformatics analysis that 3'UTR in SRA mRNA has QKI binding site. So, we attempted to further understand the role of QKI in SRA regulation. The macrophages were manipulated either with overexpression of QKI or by its ablation and it was observed that QKI suppressed SRA at the transcriptional level. Moreover, with the help of luciferase reporter vector, it was shown that QKI inhibited SRA transcription by binding to QRE region in its 3'UTR mRNA. Furthermore, to link the QKI mediated regulation of SRA expression with its functional activity; we analyzed lipid uptake capacity of macrophages transfected with either ectopic OKI plasmid or ablated for QKI. It was observed that, indeed, QKI upregulation inhibits lipid uptake by repressing SRA expression. Overall, our study demonstrates that miR-29a inhibits QKI, which in turn results in upregulation of SRA and lipid uptake. PMID- 26056010 TI - Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation. AB - Tumor cell extravasation into the brain requires passage through the blood-brain barrier, which is a highly protected microvascular environment fortified with tight junction (TJ) proteins. TJ integrity can be regulated under physiological and pathophysiological conditions. There is evidence that exercise can modulate oxidation status within the brain microvasculature and protect against tumor cell extravasation and metastasis formation. In order to study these events, mature male mice were given access to voluntary exercise on a running wheel (exercise) or access to a locked wheel (sedentary) for five weeks. The average running distance was 9.0 +/- 0.2 km/day. Highly metastatic tumor cells (murine Lewis lung carcinoma) were then infused into the brain microvasculature through the internal carotid artery. Analyses were performed at early stage (48 h) and late stage (3 weeks) post tumor cell infusion. Immunohistochemical analysis revealed fewer isolated tumor cells extravasating into the brain at both 48 h and 3 weeks post surgery in exercised mice. Occludin protein levels were reduced in the sedentary tumor group, but maintained in the exercised tumor group at 48 h post tumor cell infusion. These results indicate that voluntary exercise may participate in modulating blood-brain barrier integrity thereby protecting the brain during metastatic progression. PMID- 26056011 TI - A more pessimistic life orientation is associated with experimental inducibility of a neuropathy-like pain pattern in healthy individuals. AB - The clinical pattern of neuropathic pain, diagnosed using the quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain), could be partly mimicked in healthy volunteers after topical capsaicin application. However, similar to clinical neuropathic pain that develops in only a subgroup of patients who have a neurologic lesion, this attempt to mimick a neuropathic pain pattern succeeded only in a small fraction (18%) of healthy individuals. In the present assessment, we pursued the hypothesis that the inducible subgroup differed from the other healthy participants with respect to their psychological phenotype. Therefore, in an observational study, participants were assessed using a comprehensive set of psychological variables comprising general psychological and pain-related cognitive-emotional mechanisms. The sum scores of the questionnaires were significantly linearly correlated with each other. Principal component analysis indicated that a major source of variance (46%) could be attributed to dispositional optimism examined via the Life Orientation Test (LOT). The LOT score significantly differed between the groups of participants, either those in whom a neuropathy-like pattern of pain assessed via QST could be partly (50-60% of the 11 QST parameters) induced (n = 20) or not (n = 90; P = .0375). It emerged again as the main selection criterion in a classification and regression tree predicting a participant's group assignment (inducible neuropathy-like QST pattern versus noninducible neuropathy-like QST pattern) at a cross-validated accuracy of 95.5 +/- 2.1%. Thus, the few participants in a random sample of healthy volunteers who, after topical capsaicin application, partly resemble (to a degree of about 60%) the clinical pattern of neuropathic pain in the QST test battery, are preselectable on the basis of psychological factors, with a particular emphasis on pessimistic life attitudes. PERSPECTIVE: In a small fraction of 18% of healthy volunteers, topical capsaicin application resulted in a neuropathy-like pattern in 50 to 60% of the components of a clinical test battery. These individuals displayed a more pessimistic life attitude as assessed by means of the LOT. PMID- 26056012 TI - Effects of environmental and biotic factors on carbon isotopic fractionation during decomposition of soil organic matter. AB - Decomposition of soil organic matter (SOM) plays an important role in the global carbon cycle because the CO2 emitted from soil respiration is an important source of atmospheric CO2. Carbon isotopic fractionation occurs during SOM decomposition, which leads to (12)C to enrich in the released CO2 while (13)C to enrich in the residual SOM. Understanding the isotope fractionation has been demonstrated to be helpful for studying the global carbon cycle. Soil and litter samples were collected from soil profiles at 27 different sites located along a vertical transect from 1200 to 4500 m above sea level (a.s.l.) in the south eastern side of the Tibetan Plateau. Their carbon isotope ratios, C and N concentrations were measured. In addition, fiber and lignin in litter samples were also analyzed. Carbon isotope fractionation factor (alpha) during SOM decomposition was estimated indirectly as the slope of the relationship between carbon isotope ratios of SOM and soil C concentrations. This study shows that litter quality and soil water play a significant role in isotope fractionation during SOM decomposition, and the carbon isotope fractionation factor, alpha, increases with litter quality and soil water content. However, we found that temperature had no significant impact on the alpha variance. PMID- 26056013 TI - Duck tembusu virus and its envelope protein induce programmed cell death. AB - The cytopathic effect produced in cells infected with duck tembusu virus (DTMUV) suggests that this emerging virus may induce apoptosis in primary cultures of duck embryo fibroblasts (DEF). Here, we present evidence that DTMUV infection of cultured cells activates apoptosis and that the ability of DTMUV to induce apoptosis is not restricted to cell type because DTMUV-induced apoptosis in duck and mammalian host cells. We further investigated which viral components induce apoptosis in DTMUV-infected host cells. The major envelope glycoprotein (E) was investigated for its apoptotic activities in expressed cells. Transient expression of the E protein alone triggered apoptosis in DEF, Vero, and BHK cells. Expression of the E protein resulted in activation of caspase-3-like proteases in cultured cells. These results indicate that infection of cells with DTMUV or expression of DTMUV E protein alone induces apoptosis, providing the basis for future to define the molecules that play key roles in the fate of DTMUV infected cells. PMID- 26056014 TI - Haemophagocytic syndrome in a rheumatic polymyalgia patient. PMID- 26056015 TI - Gender effect on pre-attentive change detection in major depressive disorder patients revealed by auditory MMN. AB - Gender differences in rates of major depressive disorder (MDD) are well established, but gender differences in cognitive function have been little studied. Auditory mismatch negativity (MMN) was used to investigate gender differences in pre-attentive information processing in first episode MDD. In the deviant-standard reverse oddball paradigm, duration auditory MMN was obtained in 30 patients (15 males) and 30 age-/education-matched controls. Over frontal central areas, mean amplitude of increment MMN (to a 150-ms deviant tone) was smaller in female than male patients; there was no sex difference in decrement MMN (to a 50-ms deviant tone). Neither increment nor decrement MMN differed between female and male patients over temporal areas. Frontal-central MMN and temporal MMN did not differ between male and female controls in any condition. Over frontal-central areas, mean amplitude of increment MMN was smaller in female patients than female controls; there was no difference in decrement MMN. Neither increment nor decrement MMN differed between female patients and female controls over temporal areas. Frontal-central MMN and temporal MMN did not differ between male patients and male controls. Mean amplitude of increment MMN in female patients did not correlate with symptoms, suggesting this sex-specific deficit is a trait- not a state-dependent phenomenon. PMID- 26056016 TI - Normocalcemic hyperparathyroidism is associated with complications similar to those of hypercalcemic hyperparathyroidism. AB - Normocalcemic primary hyperparathyroidism (NC-PHPT) is a variant of hyperparathyroidism, characterized by normal serum calcium levels, high parathyroid hormone (PTH) and normal 25-OH vitamin D status. The present study aimed to compare complications related to hyperparathyroidism in patients with NC PHPT and hypercalcemic PHPT (HC-PHPT). We retrospectively evaluated the records of 307 PHPT patients between January 2010 and March 2013. We excluded patients with impaired renal function and liver failure. All patients underwent a biochemical and hormonal examination including serum glucose, albumin, total calcium, phosphorus, creatinine, lipoproteins, PTH and 25-OH vitamin D. Nephrolithiasis and bone mineral density were documented based on a review of the medical records. The study population consisted of 36 (12 %) males and 271 (88 %) females with a mean age of 53.3 +/- 9.5 years (29-70 years). Twenty-three of the patients were diagnosed with NC-PHPT (group 1) and 284 were diagnosed with HC PHPT (group 2). There were no significant differences in terms of age, gender, prevalence of hypertension, low bone mineral density and kidney stones between the groups. The mean thyroid-stimulating hormone (TSH) and low-density lipoprotein (LDL) levels were significantly higher in group 1 than in group 2. Our study found that patients with NC-PHPT have similar several complications as patients with HC-PHPT. NC-PHPT patients have higher TSH levels despite being within the normal range, and higher LDL-C levels than patients with HC-PHPT. However, this relationship needs to be clarified in future studies with larger cohorts. PMID- 26056017 TI - Gender- and age-group-specific associations between physical performance and bone mineral density, falls, and osteoporotic fractures in Koreans: the Chungju Metabolic Disease Cohort study. AB - Several factors increase the risk of fragility fracture, including low bone mineral density, falls, and poor physical performance. The associations among these factors have been investigated; however, most of the subjects of previous studies were either elderly men or elderly women, and the associations were controversial. The aim of this study was to evaluate the associations between physical performance and bone mineral density, and the history of falls and fractures, stratified by gender and age group. We analyzed 5368 subjects who were aged 50 years or older, including 1288 younger men (younger than 70 years), 1615 younger women (younger than 70 years), 1087 older men (70 years or older), and 1378 older women (70 years or older). We used the one-leg standing time (OLST) for assessing static balance and the timed up-and-go test (TUGT) for assessing dynamic balance. The subjects in the worst performance quartile for the OLST were more likely to have osteoporosis than those in the best performance quartile. Additionally, women who had experienced a fracture during the past 2 years were 1.68 times more likely to be in the worst performance quartile for the OLST than women without a previous fracture. Although the TUGT time was not associated with either the incidence of osteoporosis or the fracture history, the odds ratios for falling were 1.51 and 1.28 as the TUGT time increased by one standard deviation in younger men and younger women, respectively. The findings of the present study show that the OLST was associated with the incidence of osteoporosis and previous fracture and that the TUGT time was associated with the incidence of falling. PMID- 26056018 TI - Severe hypercalcemia following denosumab treatment in a juvenile patient. AB - A 10-year-old boy diagnosed with unresectable giant cell tumor of bone in the sacrum was treated with a bone modifying agent denosumab. Administration of denosumab showed excellent clinical response without any major complications, and the tumor was surgically removed afterwards. However, 4 months after discontinuing denosumab, the patient developed severe hypercalcemia (15.2 mg/dl). There was a sharp surge in the levels of bone resorption markers, indicating that disregulated overt bone resorption after the discontinuation of denosumab led to hypercalcemia. The patient was treated with bisphosphonate and barely recovered from the life-threatening conditions. This case shows that a robust rebound of bone resorption may occur following cessation of denosumab and suggests that hypercalcemia is an underappreciated side effect of denosumab therapy in children. PMID- 26056019 TI - Combination chemotherapy with cyclophosphamide, epirubicin and 5-fluorouracil causes trabecular bone loss, bone marrow cell depletion and marrow adiposity in female rats. AB - The introduction of anthracyclines to adjuvant chemotherapy has increased survival rates among breast cancer patients. Cyclophosphamide, epirubicin and 5 fluorouracil (CEF) combination therapy is now one of the preferred regimens for treating node-positive breast cancer due to better survival with less toxicity involved. Despite the increasing use of CEF, its potential in causing adverse skeletal effects remains unclear. Using a mature female rat model mimicking the clinical setting, this study examined the effects of CEF treatment on bone and bone marrow in long bones. Following six cycles of CEF treatment (weekly intravenous injections of cyclophosphamide at 10 mg/kg, epirubicin at 2.5 mg/kg and 5-flurouracil at 10 mg/kg), a significant reduction in trabecular bone volume was observed at the metaphysis, which was associated with a reduced serum level of bone formation marker alkaline phosphatase (ALP), increased trends of osteoclast density and osteoclast area at the metaphysis, as well as an increased size of osteoclasts being formed from the bone marrow cells ex vivo. Moreover, a severe reduction of bone marrow cellularity was observed following CEF treatment, which was accompanied by an increase in marrow adipose tissue volume. This increase in marrow adiposity was associated with an expansion in adipocyte size but not in marrow adipocyte density. Overall, this study indicates that six cycles of CEF chemotherapy may induce some bone loss and severe bone marrow damage. Mechanisms for CEF-induced bone/bone marrow pathologies and potential preventive strategies warrant further investigation. PMID- 26056020 TI - Bone mineral density and bone microarchitecture after long-term suppressive levothyroxine treatment of differentiated thyroid carcinoma in young adult patients. AB - Bone mineral density (BMD) seems not to be decreased in young patients given long term suppressive doses of levothyroxine (LT4), but information regarding the bone microstructure in these patients is lacking. The aim of this study was to determine whether supraphysiologic doses of LT4, initiated during childhood or adolescence for treatment of differentiated thyroid carcinoma (DTC), have any detrimental effects on bone microarchitecture as evaluated by high-resolution peripheral quantitative computed tomography (HR-pQCT). Seventeen patients (27.3 +/- 7.1 years old) with DTC with subclinical hyperthyroidism since adolescence and 34 healthy volunteers matched for age, sex, and body mass index were studied by dual-energy X-ray absorptiometry (DXA) to determine the areal BMD at the lumbar spine, hip, and proximal third of the radius. Volumetric BMD and structural parameters of the trabecular and cortical bone were assessed by HR pQCT of the distal radius and distal tibia. DTC patients were given suppressive doses of LT4 starting at a mean age of 12.6 years, and the mean duration of treatment was 14.2 years. In DTC patients, clinical parameters did not correlate with DXA or HR-pQCT parameters. No differences were found between the patients and controls with respect to BMD and Z scores at any site evaluated by DXA, and no differences were found in the bone microstructure parameters evaluated by HR pQCT. This cross-sectional study suggests that long-standing suppressive therapy with LT4 during the attainment of peak bone mass may have no significant adverse effects on bone density or microarchitecture. PMID- 26056021 TI - Serum sclerostin and DKK1 in relation to exercise against bone loss in experimental bed rest. AB - The impact of effective exercise against bone loss during experimental bed rest appears to be associated with increases in bone formation rather than reductions of bone resorption. Sclerostin and dickkopf-1 are important inhibitors of osteoblast activity. We hypothesized that exercise in bed rest would prevent increases in sclerostin and dickkopf-1. Twenty-four male subjects performed resistive vibration exercise (RVE; n = 7), resistive exercise only (RE; n = 8), or no exercise (control n = 9) during 60 days of bed rest (2nd Berlin BedRest Study). We measured serum levels of BAP, CTX-I, iPTH, calcium, sclerostin, and dickkopf-1 at 16 time-points during and up to 1 year after bed rest. In inactive control, after an initial increase in both BAP and CTX-I, sclerostin increased. BAP then returned to baseline levels, and CTX-I continued to increase. In RVE and RE, BAP increased more than control in bed rest (p <= 0.029). Increases of CTX-I in RE and RVE did not differ significantly to inactive control. RE may have attenuated increases in sclerostin and dickkopf-1, but this was not statistically significant. In RVE there was no evidence for any impact on sclerostin and dickkopf-1 changes. Long-term recovery of bone was also measured and 6-24 months after bed rest, and proximal femur bone mineral content was still greater in RVE than control (p = 0.01). The results, while showing that exercise against bone loss in experimental bed rest results in greater bone formation, could not provide evidence that exercise impeded the rise in serum sclerostin and dickkopf 1 levels. PMID- 26056022 TI - Two novel mutations of CLCN7 gene in Chinese families with autosomal dominant osteopetrosis (type II). AB - Autosomal dominant osteopetrosis type II (ADO-II) is a heritable bone disorder characterized by osteosclerosis, predominantly involving the spine (vertebral end plate thickening, or rugger-jersey spine), the pelvis ("bone-within-bone" structures) and the skull base. Chloride channel 7 (CLCN7) has been reported to be the causative gene. In this study, we aimed to identify the pathogenic mutation in four Chinese families with ADO-II. All 25 exons of the CLCN7 gene, including the exon-intron boundaries, were amplified and sequenced directly in four probands from the Chinese families with ADO-II. The mutation site was then identified in other family members and 250 healthy controls. In family 1, a known missense mutation c.296A>G in exon 4 of CLCN7 was identified in the proband, resulting in a tyrosine (UAU) to cysteine (UGU) substitution at p.99 (Y99C); the mutation was also identified in his affected father. In family 2, a novel missense mutation c.865G>C in exon 10 was identified in the proband, resulting in a valine (GUC) to leucine (CUC) substitution at p.289 (V289L); the mutation was also identified in her healthy mother and sister. In family 3, a novel missense mutation c.1625C>T in exon 17 of CLCN7 was identified in the proband, resulting in an alanine (GCG) to valine (GUG) substitution at p.542 (A542V); the mutation was also identified in her father. In family 4, a hot spot, R767W (c.2299C>T, CGG>TGG), in exon 24 was found in the proband which once again proved the susceptibility of the site or the similar genetic background in different races. Moreover, two novel mutations, V289L and A542V, occurred at a highly conserved position, found by a comparison of the protein sequences from eight vertebrates, and were predicted to have a pathogenic effect by PolyPhen-2 software, which showed "probably damaging" with a score of approximately 1. These mutation sites were not identified in 250 healthy controls. Our present findings suggest that the novel missense mutations V289L and A542V in the CLCN7 gene were responsible for ADO-II in the two Chinese families. PMID- 26056023 TI - Assessment of osteoporosis using pelvic diagnostic computed tomography. AB - The purpose of the present study is to determine if a correlation exists between bone mineral density (BMD) obtained from dual energy X-ray absorptiometry (DXA) and Hounsfield unit (HU) from pelvic diagnostic computed tomography (dCT), and to evaluate whether HU could be used to identify osteoporosis. Seventy-nine patients were included in this study. HU values were measured in three different sections: the head-neck junction of the femur, the middle portion of the femoral neck, and the intertrochanter of the femur (IT). In each sectional image, HU values were measured at two regions of interest: cortical and cancellous bone (HU_t) and cancellous bone. The correlation between BMD and HU_t of IT was significant (r = 0.839, p < 0.01). In IT, the area under the curve value of HU_t was 0.875 (0.796 0.955). We found that a HU_t of IT <170 can be regarded as indicating osteoporosis: its positive predictive value is 96.9 %. A HU_t of IT >210 can be regarded as indicating an absence of osteoporosis: its negative predictive value is 84.6 %. In conclusion, we found that a significant correlation between HU of pelvic dCT and BMD of DXA, and HU potentially provided an alternative method for determining regional BMD. Therefore, pelvic dCT could possibly be a supplementary method for initial diagnosis of osteoporosis and for initiation of treatment. PMID- 26056024 TI - Body composition and bone density reference data for Korean children, adolescents, and young adults according to age and sex: results of the 2009-2010 Korean National Health and Nutrition Examination Survey (KNHANES). AB - We established the timing of peak bone mass acquisition and body composition maturation and provide an age- and sex-specific body composition and bone density reference database using dual-energy X-ray absorptiometry in Korean subjects 10 25 years of age. Reference percentiles and curves were developed for bone mineral content (BMC), bone mineral density (BMD) of the whole body, the lumbar spine, and the femoral neck, and for fat mass (FM) and lean mass (LM) of 1969 healthy participants (982 males) who participated in the 2009-2010 Korean National Health and Nutrition Examination Survey. Additionally, bone mineral apparent density (BMAD), FM index, and LM index were calculated to adjust for body size. BMC and BMD at all skeletal sites as well as LM increased with age, reaching plateaus at 17-20 years of age in females and 20-23 years of age in males. The femoral neck was the first to reach a bone mass plateau, followed by the lumbar spine and then the whole body. Spine BMAD increased with age in both sexes, but femoral and whole-body BMAD remained the same over time. Females displayed a dramatic increase in FM during puberty, but the FM of males decreased until mid-puberty. These findings indicate that bone health and body composition should be monitored using a normal reference database until the late second to early third decade of life, when statural growth and somatic maturation are completed. PMID- 26056025 TI - Circulating sclerostin and Dickkopf-1 levels in patients with nonalcoholic fatty liver disease. AB - There is increasing evidence for bone-liver interplay. The main aim of this study was to determine serum sclerostin and Dickkopf (DKK)-1 levels in patients with nonalcoholic fatty liver disease (NAFLD) and their association with the disease severity. Patients with biopsy-proven NAFLD, 13 with nonalcoholic simple steatosis (SS) and 14 with steatohepatitis (NASH), and 20 gender-, age-, body mass index- and waist circumference-matched controls were enrolled. Serum sclerostin, DKK-1, bone turnover markers, vitamin D, insulin and standard biochemical and hematologic parameters were measured; lumbar spinal dual-energy X ray absorptiometry was performed. We observed that there was a progressive decline in serum sclerostin levels from the controls (76.1 +/- 6.8) to SS (53.5 +/- 6.4) and NASH (46.0 +/- 8.1 pmol/l) patients (p = 0.009); in adjusted pairwise comparisons, sclerostin was significantly higher in the controls than in NASH patients (p = 0.012). Although serum DKK-1 did not differ between groups (p = 0.135), there was a trend toward U-shaped distribution (controls 35.8 +/- 2.8; SS 27.3 +/- 2.9; NASH 36.8 +/- 4.4 pmol/l). Higher DKK-1 levels were independently associated with NASH. Regarding specific histological lesions, DKK 1 levels were marginally lower in NAFLD patients with lower (<=33 %) than higher (>33 %) steatosis grade (27.7 +/- 3.1 and 38.8 +/- 4.7 pmol/l, respectively; p = 0.049). No other significant difference was observed within histological lesions. In conclusion, serum sclerostin levels were lower in NASH patients than in controls. DKK-1 levels were independently associated with NASH in NAFLD patients. The potential importance of these findings indicates a possible bone-liver interaction and warrants further investigation. PMID- 26056026 TI - Chlamydia pneumoniae and Helicobacter pylori IgG seropositivities are not predictors of osteoporosis-associated bone loss: a prospective cohort study. AB - The potential link between infection with Chlamydia pneumoniae or Helicobacter pylori and osteoporosis has not been investigated in population-based longitudinal studies. A total of 250 healthy postmenopausal women who participated in a prospective cohort study were evaluated for IgG antibodies directed against C. pneumoniae and H. p ylori, osteoprotegerin (OPG), the receptor activator of nuclear factor kappa B ligand (RANKL), CrossLaps, and osteocalcin. Bone mineral density (BMD) was measured at the femoral neck and lumbar spine at baseline and at follow-up 5.8 years later. There were no significant differences in age-adjusted bone turnover markers, OPG, RANKL, the RANKL/OPG ratio, and BMD between the C. p neumoniae and H. p ylori IgG seropositive and seronegative subjects (P > 0.05). Neither C. p neumoniae nor H. p ylori IgG seropositivity was associated with age-and body mass index-adjusted BMD at the femoral neck and lumbar spine or bone loss at the 5.8-year follow-up. In logistic regression analysis, neither C. p neumoniae nor H. p ylori IgG seropositivities predicted incident lumbar or spine osteoporosis 5.8 years later. In conclusion, neither C. p neumoniae nor H. p ylori IgG seropositivity was associated with bone turnover markers, the RANKL/OPG ratio, BMD, or bone loss in postmenopausal women. In addition, chronic infection with C. p neumoniae or H. p ylori did not predict incident osteoporosis among this group of women. PMID- 26056027 TI - Predictors of persistent pulmonary hypertension after mitral valve replacement. AB - Persistent pulmonary hypertension (P-PH) after mitral valve replacement (MVR) leads to an increased risk of morbidity and mortality. We sought to determine which factors were involved in its occurrence. Patients undergoing MVR for a 3 year period were collected in a retrospective way. We excluded those with an available follow-up shorter than 3 months. Sample size was 111 patients. PH was diagnosed if systolic pulmonary artery pressure (sPAP) estimated by Doppler echocardiography was >40 mmHg. Clinical, echocardiographic, and surgical factors were analyzed. P-PH was present in 42.3 % of patients after 12.6 months of mean follow-up. P-PH was more frequently observed in elderly and female patients, in those with severe degrees of PH before surgery, and significant tricuspid regurgitation (TR). On multivariable analysis, significant TR (OR 1.739; p = 0.01) and more severe degrees of PH before surgery (OR 1.761; p = 0.03) were significantly associated with the presence of P-PH after MVR. Surgical factors related to P-PH were prosthesis size and tricuspid annuloplasty: no need for the performing of tricuspid annuloplasty (OR 0.345; p = 0.025) and the implantation of a smaller prosthesis (OR 0.656; p = 0.004) were related to higher rates of P PH after MVR. MVR was associated with high prevalence of P-PH after mid-term follow-up. Both PH and significant TR before surgery were associated with P-PH. Our data point out that MVR should be planned before the development of PH and greater TR. Smaller prosthetic size is also a risk factor for P-PH and bigger prostheses are desirable when possible. PMID- 26056028 TI - Management Strategies for Clopidogrel Hypersensitivity. AB - Clopidogrel is a cornerstone of dual antiplatelet therapy. Hypersensitivity reactions potentially limit the use of this treatment and present a significant clinical challenge. The authors have developed recommendations for the management of clopidogrel hypersensitivity with consideration for the etiology, pathophysiology, and critical evaluation of potential management strategies. The clopidogrel hypersensitivity reaction is complex in mechanism and presents generally around day 5 of treatment. Generalized reactions are most common, but the reaction may also be localized or systemic. Screening patients for hypersensitivity is not always possible because the type IV delayed reaction is not detected reliably by conventional skin prick, intradermal challenge, or patch testing. Proposed strategies for management of clopidogrel hypersensitivity include treatment of the reaction with corticosteroids, clopidogrel desensitization, substituting an alternative P2Y12 inhibitor, or clopidogrel avoidance. The safety, efficacy, and cost of each potential strategy must be considered when managing a patient with clopidogrel hypersensitivity. PMID- 26056029 TI - Modulating Bone Resorption and Bone Formation in Opposite Directions in the Treatment of Postmenopausal Osteoporosis. AB - Bone remodeling, the fundamental process for bone renewal, is targeted by treatments of osteoporosis to correct the imbalance between bone resorption and bone formation and reduce the risk of fractures and associated clinical consequences. Currently available therapeutics affect bone resorption and bone formation in the same direction and either decrease (inhibitors of bone resorption) or increase (parathyroid hormone [PTH] peptides) bone remodeling. Studies of patients with rare bone diseases and genetically modified animal models demonstrated that bone resorption and bone formation may not necessarily be coupled, leading to identification of molecular targets in bone cells for the development of novel agents for the treatment of osteoporosis. Application of such agents to the treatment of women with low bone mass confirmed that bone resorption and bone formation can be modulated in different directions and so far two new classes of therapeutics for osteoporosis have been defined with distinct mechanisms of action. Such treatments, if combined with a favorable safety profile, will offer new therapeutic options and will improve the management of patients with osteoporosis. PMID- 26056030 TI - Aflibercept: A Review of Its Use in Diabetic Macular Oedema. AB - Aflibercept (Eylea((r))) is an anti-vascular endothelial growth factor agent indicated for intravitreal use in the treatment of diabetic macular oedema. In patients with diabetic macular oedema, significantly greater improvements from baseline to week 52 in visual acuity were seen with intravitreal aflibercept versus macular laser photocoagulation in the phase III VISTA-DME and VIVID-DME trials, and versus intravitreal bevacizumab or ranibizumab in those with worse visual acuity at baseline (i.e. Early Treatment Diabetic Retinopathy Study letter score of <69) in the phase III PROTOCOL-T trial. Intravitreal aflibercept was generally well tolerated in patients with diabetic macular oedema. In conclusion, intravitreal aflibercept is an important new treatment for diabetic macular oedema. PMID- 26056031 TI - Dynorphin activation of kappa opioid receptor reduces neuronal excitability in the paraventricular nucleus of mouse thalamus. AB - It has been reported that kappa opioid receptor (KOR) is expressed in the paraventricular nucleus of thalamus (PVT), a brain region associated with arousal, drug reward and stress. Although intra-PVT infusion of KOR agonist was found to inhibit drug-seeking behavior, it is still unclear whether endogenous KOR agonists directly regulate PVT neuron activity. Here, we investigated the effect of the endogenous KOR agonist dynorphin-A (Dyn-A) on the excitability of mouse PVT neurons at different developmental ages. We found Dyn-A strongly inhibited PVT neurons through a direct postsynaptic hyperpolarization. Under voltage-clamp configuration, Dyn-A evoked an obvious outward current in majority of neurons tested in anterior PVT (aPVT) but only in minority of neurons in posterior PVT (pPVT). The Dyn-A current was abolished by KOR antagonist nor-BNI, Ba(2+) and non-hydrolyzable GDP analogue GDP-beta-s, indicating that Dyn-A activates KOR and opens G-protein-coupled inwardly rectifying potassium channels in PVT neurons. More interestingly, by comparing Dyn-A currents in aPVT neurons of mice at various ages, we found Dyn-A evoked significant larger current in aPVT neurons from mice around prepuberty and early puberty stage. In addition, KOR activation by Dyn-A didn't produce obvious desensitization, while mu opioid receptor (MOR) activation induced obvious desensitization of mu receptor itself and also heterologous desensitization of KOR in PVT neurons. Together, our findings indicate that Dyn-A activates KOR and inhibits aPVT neurons in mice at various ages especially around puberty, suggesting a possible role of KOR in regulating aPVT-related brain function including stress response and drug-seeking behavior during adolescence. PMID- 26056033 TI - An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration. AB - Purinergic signalling appears to play important roles in neurodegeneration, neuroprotection and neuroregeneration. Initially there is a brief summary of the background of purinergic signalling, including release of purines and pyrimidines from neural and non-neural cells and their ectoenzymatic degradation, and the current characterisation of P1 (adenosine), and P2X (ion channel) and P2Y (G protein-coupled) nucleotide receptor subtypes. There is also coverage of the localization and roles of purinoceptors in the healthy central nervous system. The focus is then on the roles of purinergic signalling in trauma, ischaemia, stroke and in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases, as well as multiple sclerosis and amyotrophic lateral sclerosis. Neuroprotective mechanisms involving purinergic signalling are considered and its involvement in neuroregeneration, including the role of adult neural stem/progenitor cells. This article is part of the Special Issue entitled 'Purines in Neurodegeneration and Neuroregeneration'. PMID- 26056032 TI - Increased dopamine transporter function as a mechanism for dopamine hypoactivity in the adult infralimbic medial prefrontal cortex following adolescent social stress. AB - Being bullied during adolescence is associated with later mental illnesses characterized by deficits in cognitive tasks mediated by prefrontal cortex (PFC) dopamine (DA). Social defeat of adolescent male rats, as a model of teenage bullying victimization, results in medial PFC (mPFC) dopamine (DA) hypofunction in adulthood that is associated with increased drug seeking and working memory deficits. Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC following adolescent defeat. We propose the functional consequence of this increased DAT expression is enhanced DA clearance and subsequently decreased infralimbic mPFC DA availability. To test this, in vivo chronoamperometry was used to measure changes in accumulation of the DA signal following DAT blockade, with increased DAT-mediated clearance being reflected by lower DA signal accumulation. Previously defeated rats and controls were pre treated with the norepinephrine transporter (NET) inhibitor desipramine (20 mg/kg, ip.) to isolate infralimbic mPFC DA clearance to DAT, then administered the selective DAT inhibitor GBR-12909 (20 or 40 mg/kg, sc.). Sole NET inhibition with desipramine produced no differences in DA signal accumulation between defeated rats and controls. However, rats exposed to adolescent social defeat demonstrated decreased DA signal accumulation compared to controls in response to both doses of GBR-12909, indicating greater DAT-mediated clearance of infralimbic mPFC DA. These results suggest that protracted increases in infralimbic mPFC DAT function represent a mechanism by which adolescent social defeat stress produces deficits in adult mPFC DA activity and corresponding behavioral and cognitive dysfunction. PMID- 26056035 TI - Changes in the care of patients with cervical spine fractures following health reform in Massachusetts. AB - INTRODUCTION: There is a substantial concern among spine surgeons that healthcare reform efforts will alter the processes through which spinal care is delivered and decrease overall quality. We used the Statewide Inpatient Dataset for Massachusetts to evaluate changes in hospital processes and quality of care for patients with cervical fractures following the implementation of health reform. METHODS: This was a pre-post retrospective analysis of patients (n=9,387) treated for cervical fractures in Massachusetts between 2003-2006 and 2008-2010. Changes in hospital processes (surgical intervention, length of stay (LOS) and environment of care) and quality of care (mortality, complications, reoperation and failure to rescue (FTR)) were the outcomes of interest. FTR is a quality measure that evaluates a hospital's capacity to avoid mortality following the occurrence of a sentinel complication. Patients treated between 2003 and 2006 were considered the pre-reform group. The post-reform cohort consisted of those treated from 2008 to 2010. Baseline differences between cohorts were evaluated using chi-square or Mann-Whitney U tests. Unadjusted comparisons between the dependent variables and the onset of healthcare reform were performed, followed by regression techniques that adjusted for differences in case-mix and whether a surgical intervention was performed. Multivariable logistic regression was used for categorical variables and negative binomial regression was employed for continuous variables. RESULTS: The rates of surgical intervention remained unchanged pre- and post-reform (p=0.25). Hospital length of stay (RC: -0.18, 95% CI: -0.22, -0.14) and the FTR rate following surveillance insensitive complications (OR: 0.49, 95% CI: 0.25, 0.94) were significantly reduced following health reform. Post-reform, academic centers experienced a 22% reduction in mortality (95% CI: 0.61, 0.99) a 40% decrease in FTR (95% CI: 0.40, 0.89), a 30% decrease in surveillance insensitive complications (95% CI: 0.51, 0.96) and a 67% reduction in FTR after surveillance insensitive morbidity (95% CI: 0.11, 0.94). CONCLUSIONS: In the period following Massachusetts healthcare reform, significant improvements were noted in hospital process and quality measures around the care of patients with cervical spine fractures. Such findings were particularly robust among academic centers. These results may forecast changes in the delivery of spine surgical care following other health reform initiatives. Level of Evidence III. PMID- 26056036 TI - Being a Midwife. PMID- 26056037 TI - Solving the woolly mammoth conundrum: amino acid 15N-enrichment suggests a distinct forage or habitat. AB - Understanding woolly mammoth ecology is key to understanding Pleistocene community dynamics and evaluating the roles of human hunting and climate change in late Quaternary megafaunal extinctions. Previous isotopic studies of mammoths' diet and physiology have been hampered by the 'mammoth conundrum': woolly mammoths have anomalously high collagen delta(15)N values, which are more similar to coeval carnivores than herbivores, and which could imply a distinct diet and (or) habitat, or a physiological adaptation. We analyzed individual amino acids from collagen of adult woolly mammoths and coeval species, and discovered greater (15)N enrichment in source amino acids of woolly mammoths than in most other herbivores or carnivores. Woolly mammoths consumed an isotopically distinct food source, reflective of extreme aridity, dung fertilization, and (or) plant selection. This dietary signal suggests that woolly mammoths occupied a distinct habitat or forage niche relative to other Pleistocene herbivores. PMID- 26056039 TI - The revision of the European blood directives: A major challenge for transfusion medicine. AB - AIM: Using both patient-focused and donor-focused perspectives, to review the current EU blood directives, in order to derive proposals, in principle, for what should evolve during the revision process of these directives. METHODS: Review of the EU blood directives in the light of scientific literature, related reports from the Directorate General Health and Consumers (DG SANTE), and from the Council of Europe (CoE). RESULTS: The analyses led us to present the main following proposals: developing voluntary unpaid donations: the directives should consider taking into consideration ethically acceptable forms of compensation consistent with altruistic donation (including plasma donations for fractionation); current expertise: more extensive utilization of the expertise of blood establishments and their consultants should be considered; donor selection: an evidence-based approach for basing donor deferral criteria on sound scientific evidence should be promoted; donor reactions: measures to prevent donor reactions and to make donations safer for the donors should also be included; quality control: The quality control requirements should relate to the Council of Europe Blood Guide specifications: these should become minimum standards (as is the case with monographs of the European Pharmacopeia), facilitating regular update of blood component lists and related specifications and compliance with the specifications; haemovigilance: because of reporting difficulties (e.g. lack of number of blood products transfused), the effectiveness of haemovigilance has so far been limited. This should lead appropriate bodies to investigate alternative or complementary ways to help improve patient safety, taking into consideration, in principle, patient blood management and the appropriate use of blood products. Furthermore, donor vigilance, which is still absent from the current directive should be included in a revised directive. CONCLUSIONS: These proposals for revising the current EU blood directives (if taken into account and given appropriate regulatory formulation) should help to optimize patient safety and donor care, progress the compliance with the ethical principles for donors and improve the efficiency of the healthcare systems dedicated to transfusion medicine. PMID- 26056038 TI - Mechanisms of sickle cell alloimmunization. AB - Red blood cell (RBC) alloimmunization can be a life-threatening complication for patients with sickle cell disease (SCD) receiving therapeutic transfusions. Despite provision of extended antigen-matched donor RBCs, patients continue to develop antibodies due to high degree of polymorphisms in the immunogenic antigens in individuals of African ancestry. Identification of biomarkers of alloimmunization in this patient population is therefore of great interest and will help to identify in advance patients most likely to make antibodies in response to transfusion. We have recently identified altered T cell responses and innate immune abnormalities in alloimmunized SCD patients. In this paper, we summarize this work and propose our working model of how innate immune abnormalities can contribute to pathogenic T cell responses in alloimmunized SCD patients. We believe that unravelling the basis of such altered interactions at the cellular and molecular level will help future identification of biomarkers of alloimmunization with the goal that this information will ultimately help guide therapy in these patients. PMID- 26056040 TI - Drug-induced Depression: a Case/Non Case Study in the French Pharmacovigilance Database. AB - Depression is a complex disorder with heterogeneous clinical anomalies whose neurobiological understanding still remains unclear. Medications have been implicated as potential causes of depression but for many of them, data are controversial. The present study aims to investigate association bet ween drugs and reports of depression. We used the case/non case method in the French pharmacovigilance database (FPVD) to identify drugs associated with depression. Cases were reports of depression in the FPVD between January 2007 and December 2011. Non cases were all other reports during the same period. Data were expressed as reporting odds ratio (ROR) with their 95% confidence interval. Of the 114,692 reports recorded in the FPVD during the studied period, we identified 474 cases of depression. For the majority of the patients, they were considered as "non serious" (56%) and evolution was favorable (64%). Significant RORs were found for antiepileptics (topiramate, levetiracetam), anti-infective and especially anti-retroviral drugs (efavirenz, emtricitabine, tenofovir, etravirine, raltegravir), interferons and other agents including isotretinoin, methylphenidate, sodium oxybate, varenicline, montelukast, flunarizine, adalimumab, anastrozole. Taking into account the limits of the methodology, the present study described associations with mainly expected drugs belonging to various therapeutic classes but it also found a signal with some anti retrovirals. On the contrary, we did not find some assumed associations like cardiovascular medications, antimalarial. For most of the drugs, one or more mechanisms were found to explain these depressogenic effects on the basis of animal and human literature. Even if such associations need to be confirmed by further prospective studies, cautions are necessary for many drugs to early detect depressive symptoms. PMID- 26056041 TI - ANGPTL2/LILRB2 signaling promotes the propagation of lung cancer cells. AB - Immune inhibitory receptors expressed on various types of immune cells deliver inhibitory signals that maintain the homeostasis of the immune system. Recently we demonstrated that leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) and its murine homolog, paired immunoglobulin-like receptor B (PIRB), are expressed on hematopoietic stem cells and acute myeloid leukemia stem cells and function in maintenance of stemness. Herein, we determined that both LILRB2 and its soluble ligand ANGPTL2 are highly expressed in non-small cell lung cancer (NSCLC) samples, and levels are adversely related to patient prognosis. Inhibition of LILRB2 expression in NSCLC cell lines, such as A549 cells, resulted in a dramatic decrease in proliferation, colony formation, and migration. Mechanistic analyses indicated that ANGPTL2 binds LILRB2 to support the growth of lung cancer cells and that the SHP2/CaMK1/CREB axis controls the proliferation of lung cancer cell lines. Our results suggest that signaling involving ANGPTL2 and LILRB2 is important for lung cancer development and represents a novel target for treatment of this type of cancer. PMID- 26056042 TI - Functional intronic ERCC1 polymorphism from regulomeDB can predict survival in lung cancer after surgery. AB - We searched for potential regulatory single nucleotide polymorphisms (SNPs) in excision repair cross-complementing group 1 (ERCC1) using RegulomeDB, a database integrating information from the Encyclopedia of DNA Elements (ENCODE) project, and investigated their association with survival after surgery in non-small cell lung cancer (NSCLC). Among 364 SNPs found within ERCC1 region using RegulomeDB, four top priority SNPs (rs2298881C>A, rs1049739A>G, rs10415949A>G and rs6509214G>T) were selected for this study. The four SNPs were investigated in 316 patients. A replication study was performed (n = 579). Of the four SNPs analyzed in the discovery set, rs2298881C>A and rs6509214G>T were significantly associated with survival outcomes. The association was consistently observed only for rs2298881C>A in the validation cohort. In combined analysis, rs2298881C>A was significantly associated with worse overall survival and disease-free survival (P = 0.0002 and 0.02, respectively). A decreased reporter gene expression for rs2298881 A allele was observed compared with C allele by luciferase assay (P = 0.02). ERCC1 rs2298881C>A, an intronic SNP, is the first genetic polymorphism with functional evidence of regulating its expression, and the SNP is associated with prognosis of NSCLC. Our result supports the role of RegulomeDB as a comprehensive source of prioritized candidate SNPs for genetic association studies. PMID- 26056043 TI - Metformin combined with aspirin significantly inhibit pancreatic cancer cell growth in vitro and in vivo by suppressing anti-apoptotic proteins Mcl-1 and Bcl 2. AB - Metformin and aspirin have been studied extensively as cancer preventive or therapeutic agents. However, the effects of their combination on pancreatic cancer cells have not been investigated. Herein, we evaluated the effects of metformin and aspirin, alone or in combination, on cell viability, migration, and apoptosis as well as the molecular changes in mTOR, STAT3 and apoptotic signaling pathways in PANC-1 and BxPC3 cells. Metformin and aspirin, at relatively low concentrations, demonstrated synergistically inhibitory effects on cell viability. Compared to the untreated control or individual drug, the combination of metformin and aspirin significantly inhibited cell migration and colony formation of both PANC-1 and BxPC-3 cells. Metformin combined with aspirin significantly inhibited the phosphorylation of mTOR and STAT3, and induced apoptosis as measured by caspase-3 and PARP cleavage. Remarkably, metformin combined with aspirin significantly downregulated the anti-apoptotic proteins Mcl 1 and Bcl-2, and upregulated the pro-apoptotic proteins Bim and Puma, as well as interrupted their interactions. The downregulation of Mcl-1 and Bcl-2 was independent of AMPK or STAT3 pathway but partially through mTOR signaling and proteasome degradation. In a PANC-1 xenograft mouse model, we demonstrated that the combination of metformin and aspirin significantly inhibited tumor growth and downregulated the protein expression of Mcl-1 and Bcl-2 in tumors. Taken together, the combination of metformin and aspirin significantly inhibited pancreatic cancer cell growth in vitro and in vivo by regulating the pro- and anti-apoptotic Bcl-2 family members, supporting the continued investigation of this two drug combination as chemopreventive or chemotherapeutic agents for pancreatic cancer. PMID- 26056044 TI - Combined estrogenic and anti-estrogenic properties of estetrol on breast cancer may provide a safe therapeutic window for the treatment of menopausal symptoms. AB - Increased risk of breast cancer is a critical side effect associated with the use of a menopausal hormone therapy (MHT). Estetrol (E4) is a natural estrogen produced by the human fetal liver and is a promising compound for clinical use in MHT. However, its impact on breast cancer is controversial and poorly defined. In this preclinical study, we show that E4 acts as a weak estrogen by stimulating the growth of hormone-dependent breast cancer only at concentrations exceeding menopausal therapeutic needs. E4 presents also an antitumor activity by decreasing the strong proliferative effect of estradiol (E2). While estrogen receptor alpha (ERalpha) is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathway are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. Altogether, our results highlight that E4 has a limited impact on breast cancer and may offer a safe therapeutic window for the treatment of menopausal symptoms. PMID- 26056045 TI - TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is a potential prognostic biomarker in lung cancer. AB - Epigenetic silencing of tumour suppressors contributes to the development and progression of lung cancer. We recently found that TMEM196 was hypermethylated in lung cancer. This study aimed to clarify its epigenetic regulation, possible roles and clinical significance. TMEM196 methylation correlated with loss of protein expression in chemical-induced rat lung pathologic lesions and human lung cancer tissues and cell lines. 5-aza-2'-deoxycytidine restored TMEM196 expression. Moreover, TMEM196 hypermethylation was detected in 61.2% of primary lung tumours and found to be associated with poor differentiation and pathological stage of lung cancer. Functional studies showed that ectopic re expression of TMEM196 in lung cancer cells inhibited cell proliferation, clonogenicity, cell motility and tumour formation. However, TMEM196 knockdown increased cell proliferation and inhibited apoptosis and cell-cycle arrest. These effects were associated with upregulation of p21 and Bax, and downregulation of cyclin D1, c-myc, CD44 and beta-catenin. Kaplan-Meier survival curves showed that TMEM196 downregulation was significantly associated with shortened survival in lung cancer patients. Multivariate analysis showed that patients with TMEM196 expression had a better overall survival. Our results revealed for the first time that TMEM196 acts as a novel functional tumour suppressor inactivated by DNA methylation and is an independent prognostic factor of lung cancer. PMID- 26056047 TI - Clotho: addressing the scalability of forward time population genetic simulation. AB - BACKGROUND: Forward Time Population Genetic Simulations offer a flexible framework for modeling the various evolutionary processes occurring in nature. Often this model expressibility is countered by an increased memory usage or computational overhead. With the complexity of simulation scenarios continuing to increase, addressing the scalability of the underlying simulation framework is a growing consideration. RESULTS: We propose a general method for representing in silico genetic sequences using implicit data structures. We provide a generalized implementation as a C++ template library called Clotho. We compare the performance and scalability of our approach with those taken in other simulation frameworks, namely: FWDPP and simuPOP. CONCLUSIONS: We show that this technique offers a 4x reduction in memory utilization. Additionally, with larger scale simulation scenarios we are able to offer a speedup of 6x-46x. PMID- 26056046 TI - The clinical effectiveness of self-care interventions with an exercise component to manage knee conditions: A systematic review. AB - OBJECTIVE: Treatment of knee conditions should include approaches to support self care and exercise based interventions. The most effective way to combine self care and exercise has however not been determined sufficiently. Therefore the aim was to evaluate the clinical effectiveness of self-care programmes with an exercise component for individuals with any type of knee conditions. METHODS: A keyword search of Medline, CINAHL, Amed, PsycInfo, Web of Science, and Cochrane databases was conducted up until January 2015. Two reviewers independently assessed manuscript eligibility against inclusion/exclusion criteria. Study quality was assessed using the Downs and Black quality assessment tool and the Cochrane Risk of Bias Tool. Data were extracted about self-care and exercise intervention type, control intervention, participants, length of follow-up, outcome measures, and main findings. RESULTS: From the 7392 studies identified through the keyword search the title and abstract of 5498 were screened. The full text manuscripts of 106 studies were retrieved to evaluate their eligibility. Twenty-one manuscripts met the inclusion/exclusion criteria. CONCLUSION: The treatment potential of combined self-care and exercise interventions has not been maximised because of limitations in study design and failure to adequately define intervention content. Potentially the most beneficial self-care treatment components are training self-management skills, information delivery, and goal setting. Exercise treatment components could be strengthened by better attention to dose and progression. Modern technology to streamline delivery and support self-care should be considered. More emphasis is required on using self-care and exercise programmes for chronic condition prevention in addition to chronic condition management. PMID- 26056048 TI - Predictors of postpericardiotomy syndrome. PMID- 26056049 TI - Laryngoscopic options for pediatric intubation during CPR-the authors respond. PMID- 26056050 TI - Learning curve and intra/interobserver agreement of transient elastography in chronic hepatitis C patients with or without HIV co-infection. AB - BACKGROUND AND OBJECTIVES: Liver stiffness measurement (LSM) by transient elastography has been validated as a noninvasive method to stage liver fibrosis. Few studies have evaluated the learning curve of this method and its reproducibility has led to controversy results. We aimed to evaluate the intra- and interobserver agreement of transient elastography as well as its learning curve for definition of an experimented operator. METHODS: We retrospectively analyzed 922 examinations performed in 544 patients during a training program of transient elastography. Patients with chronic hepatitis C with or without HIV co infection that had two examinations by the training operator (intraobserver analysis; n=125) or examination by both training and experimented operators (interobserver analysis; n=151) in the same day were included. LSM was converted to METAVIR score: <7.1 as F0F1, 7.1-9.4 as F2, 9.5-12.4, as F3 and >12.4 kPa as F4. RESULTS: The overall intra- and interobserver intraclass correlation coefficient [ICC 95% CI] were 0.926 (0.901-0.951) and 0.912 (0.885-0.939), respectively. Measurements were correlated [Spearman's] in intra- [0.906, P<0.0001] and interobserver [0.907, P<0.0001] analysis. Reliability values [kappa (SE)] were k=0.74 (0.09) and k=0.85 (0.08) for fibrosis stages F >= 2 and k=0.77 (0.09) and k=0.75 (0.08) for cirrhosis in intra- and interobserver analysis, respectively. Agreement was improved when operator's experience was higher than 100 exams. However, it was observed discordance for fibrosis staging between examinations in a quarter of patients. CONCLUSION: Although there was a considerable discrepancy on fibrosis staging between examinations and a small power, transient elastography had an acceptable reproducibility in our population. Performance of at least 100 examinations should be used to define an experimented operator. PMID- 26056052 TI - Approach to a child with excessive daytime sleepiness. PMID- 26056051 TI - Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms. AB - G protein-coupled receptor desensitization is typically mediated by receptor phosphorylation by G protein-coupled receptor kinase (GRK) and subsequent arrestin binding; morphine, however, was previously found to activate a c-Jun N terminal kinase (JNK)-dependent, GRK/arrestin-independent pathway to produce mu opioid receptor (MOR) inactivation in spinally-mediated, acute anti-nociceptive responses [Melief et al.] [1]. In the current study, we determined that JNK2 was also required for centrally-mediated analgesic tolerance to morphine using the hotplate assay. We compared JNK activation by morphine and fentanyl in JNK1(-/-), JNK2(-/-), JNK3(-/-), and GRK3(-/-) mice and found that both compounds specifically activate JNK2 in vivo; however, fentanyl activation of JNK2 was GRK3 dependent, whereas morphine activation of JNK2 was GRK3-independent. In MOR-GFP expressing HEK293 cells, treatment with either arrestin siRNA, the Src family kinase inhibitor PP2, or the protein kinase C (PKC) inhibitor Go6976 indicated that morphine activated JNK2 through an arrestin-independent Src- and PKC dependent mechanism, whereas fentanyl activated JNK2 through a Src-GRK3/arrestin 2-dependent and PKC-independent mechanism. This study resolves distinct ligand directed mechanisms of JNK activation by mu opioid agonists and understanding ligand-directed signaling at MOR may improve opioid therapeutics. PMID- 26056053 TI - Lesion-negative anterior cingulate epilepsy. AB - MRI-negative anterior cingulate epilepsy is a rare entity. Herein, we describe a case of MRI and functional imaging-negative intractable frontal lobe epilepsy in which, initially, secondary bilateral synchrony of surface and intracranial EEG and non-lateralizing semiology rendered identification of the epileptogenic zone difficult. A staged bilateral stereotactic EEG exploration revealed a very focal, putative ictal onset zone in the right anterior cingulate gyrus, as evidenced by interictal and ictal high-frequency oscillations (at 250Hz) and induction of seizures from the same electrode contacts by 50-Hz low-intensity cortical stimulation. This was subsequently confirmed by ILAE class 1 outcome following resection of the ictal onset and irritative zones. Histopathological examination revealed focal cortical dysplasia type 1b (ILAE Commission, 2011) as the cause of epilepsy. The importance of anatomo-electro-clinical correlation is illustrated in this case in which semiological and electrophysiological features pointed to the anatomical localization of a challenging, MRI-negative epilepsy. PMID- 26056054 TI - Erratum. PMID- 26056055 TI - Removal of Dental Biofilms with an Ultrasonically Activated Water Stream. AB - Acidogenic bacteria within dental plaque biofilms are the causative agents of caries. Consequently, maintenance of a healthy oral environment with efficient biofilm removal strategies is important to limit caries, as well as halt progression to gingivitis and periodontitis. Recently, a novel cleaning device has been described using an ultrasonically activated stream (UAS) to generate a cavitation cloud of bubbles in a freely flowing water stream that has demonstrated the capacity to be effective at biofilm removal. In this study, UAS was evaluated for its ability to remove biofilms of the cariogenic pathogen Streptococcus mutans UA159, as well as Actinomyces naeslundii ATCC 12104 and Streptococcus oralis ATCC 9811, grown on machine-etched glass slides to generate a reproducible complex surface and artificial teeth from a typodont training model. Biofilm removal was assessed both visually and microscopically using high speed videography, confocal scanning laser microscopy (CSLM), and scanning electron microscopy (SEM). Analysis by CSLM demonstrated a statistically significant 99.9% removal of S. mutans biofilms exposed to the UAS for 10 s, relative to both untreated control biofilms and biofilms exposed to the water stream alone without ultrasonic activation (P < 0.05). The water stream alone showed no statistically significant difference in removal compared with the untreated control (P = 0.24). High-speed videography demonstrated a rapid rate (151 mm(2) in 1 s) of biofilm removal. The UAS was also highly effective at S. mutans, A. naeslundii, and S. oralis biofilm removal from machine-etched glass and S. mutans from typodont surfaces with complex topography. Consequently, UAS technology represents a potentially effective method for biofilm removal and improved oral hygiene. PMID- 26056056 TI - The Impact of the Crown-Root Ratio on Survival of Abutment Teeth for Dentures. AB - Crown-root ratio (CRR) is commonly recorded when planning prosthodontic procedures. However, there is a lack of longitudinal clinical data evaluating the association between CRR and tooth survival. The aim of this longitudinal practice based study was to assess the impact of CRR on the survival of abutment teeth for removable partial dentures (RPDs). Data were collected from 147 patients provided with RPDs at a dental hospital in Japan. In total, 236 clasp-retained RPDs and 856 abutment teeth were analyzed. Survival of abutment teeth was assessed using Kaplan-Meier methods and Cox's proportional hazard (PH) regression. The Cox PH regression was used to assess the prognostic significance of initial CRR value with adjustments for clinically relevant factors, including age, sex, frequency of periodontal maintenance programs, occlusal support area, type of abutment tooth, status of endodontic treatment, and probing pocket depth. Abutment teeth were divided into 1 of 5 risk groups according to CRR: A (<=0.75), B (0.76-1.00), C (1.01-1.25), D (1.26-1.50) and E (>=1.51). The 7-year survival rate was 89.1% for group A, 85.9% for group B, 86.5% for group C, 76.9% for group D, and 46.7% for group E. The survival curves of groups A, B, and C were illustrated to be quite similar and favorable. The multivariable analysis treating CRR as a continuous variable allowed estimation of the hazard ratio at any specific CRR value. When CRR = 0.80 was set as a reference, the estimated hazard ratio was 0.58 for CRR = 0.50 (95% confidence interval [CI], 0.36-0.91), 1.13 for CRR = 1.00 (95% CI, 0.93-1.37), 1.35 for CRR = 1.25 (95% CI, 1.02-1.80), 1.53 for CRR = 1.50 (95% CI, 1.15-2.08), or 1.95 for CRR = 2.00 (95% CI, 1.44-2.65). These practice-based longitudinal data provide information to improve the evidence based prognosis of teeth in providing prosthodontic procedures. PMID- 26056057 TI - Severity of maltreatment and personality pathology in adolescents of Jammu, India: A latent class approach. AB - The aims of the present study were to identify discrete classes of adolescents based on their reporting of emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect of several levels of severity using a person-centered analytic approach (i.e., latent class analysis), and to compare the latent classes on 17 dimensions of personality pathology. It was hypothesized that based on types of maltreatment and severity levels within each type there would be discrete latent classes, and that classes of adolescents exposed to a larger number of maltreatment types with higher severity (i.e., moderate-severe) would report higher levels of personality pathology than adolescents in classes exposed to less types with less severity, after controlling for age and gender. Participants were 702 adolescents from Jammu, India (13-17 years, 41.5% females). The latent classes were based on three levels of severity for each type of maltreatment assessed via the Childhood Trauma Questionnaire (Bernstein et al., 2003). Four distinct classes of adolescents, namely, Moderate-severe abuse and physical neglect (Class 1), Low to moderate-severe abuse (Class 2), Moderate severe neglect (Class 3), and Minimal abuse or neglect (Class 4) were found. Classes with higher percentages of adolescents reporting abuse and neglect with higher severity (Classes 1 and 2) reported higher levels of personality pathology than the other classes. There are distinct classes of adolescents' identifiable based on levels of severity and types of abuse and neglect, which are differentially associated with specific dimensions of personality pathology. Implications for research and practice are discussed. PMID- 26056058 TI - Burden attributable to child maltreatment in Australia. AB - Child maltreatment is a complex phenomenon, with four main types (childhood sexual abuse, physical abuse, emotional abuse, and neglect) highly interrelated. All types of maltreatment have been linked to adverse health consequences and exposure to multiple forms of maltreatment increases risk. In Australia to date, only burden attributable to childhood sexual abuse has been estimated. This study synthesized the national evidence and quantified the burden attributable to the four main types of child maltreatment. Meta-analyses, based on quality-effects models, generated pooled prevalence estimates for each maltreatment type. Exposure to child maltreatment was examined as a risk factor for depressive disorders, anxiety disorders and intentional self-harm using counterfactual estimation and comparative risk assessment methods. Adjustments were made for co occurrence of multiple forms of child maltreatment. Overall, an estimated 23.5% of self-harm, 20.9% of anxiety disorders and 15.7% of depressive disorders burden in males; and 33.0% of self-harm, 30.6% of anxiety disorders and 22.8% of depressive disorders burden in females was attributable to child maltreatment. Child maltreatment was estimated to cause 1.4% (95% uncertainty interval 0.4 2.3%) of all disability-adjusted life years (DALYs) in males, and 2.4% (0.7-4.1%) of all DALYs in females in Australia in 2010. Child maltreatment contributes to a substantial proportion of burden from depressive and anxiety disorders and intentional self-harm in Australia. This study demonstrates the importance of including all forms of child maltreatment as risk factors in future burden of disease studies. PMID- 26056059 TI - A multistate additive relative survival semi-Markov model. AB - Medical researchers are often interested to investigate the relationship between explicative variables and times-to-events such as disease progression or death. Such multiple times-to-events can be studied using multistate models. For chronic diseases, it may be relevant to consider semi-Markov multistate models because the transition intensities between two clinical states more likely depend on the time already spent in the current state than on the chronological time. When the cause of death for a patient is unavailable or not totally attributable to the disease, it is not possible to specifically study the associations with the excess mortality related to the disease. Relative survival analysis allows an estimate of the net survival in the hypothetical situation where the disease would be the only possible cause of death. In this paper, we propose a semi Markov additive relative survival (SMRS) model that combines the multistate and the relative survival approaches. The usefulness of the SMRS model is illustrated by two applications with data from a French cohort of kidney transplant recipients. Using simulated data, we also highlight the effectiveness of the SMRS model: the results tend to those obtained if the different causes of death are known. PMID- 26056060 TI - Sodium-pump gene-expression, protein abundance and enzyme activity in isolated nephron segments of the aging rat kidney. AB - Aging is associated with alteration in renal tubular functions, including sodium handling and concentrating ability. Na-K-ATPase plays a key role in driving tubular transport, and we hypothesized that decreased concentrating ability of the aging kidney is due in part to downregulation of Na-K-ATPase. In this study, we evaluated Na and K balance, aldosterone levels, and Na-K-ATPase gene expression, protein abundance, and activity in aging rat kidney. Na-K-ATPase activity (assayed microfluorometrically), mRNA (RT-PCR), and protein abundance (immunoblotting) were quantitated in the following isolated nephron segments: PCT, PST, MTAL, DCT, and CCD from 2, 8, 15, and 24 month-old-rats. In the course of aging, creatinine clearance decreased from 0.48 +/- 0.02 mL/min/100 g BW to 0.28 +/- 0.06 (P < 0.001) and aldosterone decreased from 23.6 +/- 0.8 ng/dL to 13.2 +/- 0.6 (P < 0.001). Serum Na(+) and K(+) increased by 4.0% and 22.5%, respectively. Na-K-ATPase activity, mRNA, and protein abundance of the alpha1 subunit displayed similar trends in all assayed segments; increasing in PCT and PST; decreasing in MTAL and DCT; increasing in CCD: in PCT they increased by 40%, 75%, and 250%, respectively; while in PST they increased by 80%, 50%, and 100%, respectively (P < 0.001). In MTAL they declined by 36%, 24%, and 34%, respectively, and in DCT by 38%, 59%, and 60%, respectively (P < 0.001). They were higher in CCD by 110%, 115%, and 246%, respectively (P < 0.001). Rats maintained Na/K balance; however with a steady state elevated serum K(+). These results reveal quantitative changes in axial distribution of Na-K-ATPase at the level of gene expression, protein abundance, and activity in the nephrons of aging animals and may explain, in part, the pathophysiology of the senescent kidney. PMID- 26056061 TI - Quantitative tissue-specific dynamics of in vivo GILZ mRNA expression and regulation by endogenous and exogenous glucocorticoids. AB - Glucocorticoids (GC) are steroid hormones, which regulate metabolism and immune function. Synthetic GCs, or corticosteroids (CS), have appreciable clinical utility via their ability to suppress inflammation in immune-mediated diseases like asthma and rheumatoid arthritis. Recent work has provided insight to novel GC-induced genes that mediate their anti-inflammatory effects, including glucocorticoid-induced leucine zipper (GILZ). Since GILZ comprises an important part of GC action, its regulation by both drug and hormone will influence CS therapy. In addition, GILZ expression is often employed as a biomarker of GC action, which requires judicious selection of sampling time. Understanding the in vivo regulation of GILZ mRNA expression over time will provide insight into both the physiological regulation of GILZ by endogenous GC and the dynamics of its enhancement by CS. A highly quantitative qRT-PCR assay was developed for measuring GILZ mRNA expression in tissues obtained from normal and CS-treated rats. This assay was applied to measure GILZ mRNA expression in eight tissues; to determine its endogenous regulation over time; and to characterize its dynamics in adipose tissue, muscle, and liver following treatment with CS. We demonstrate that GILZ mRNA is expressed in several tissues. GILZ mRNA expression in adipose tissue displayed a robust circadian rhythm that was entrained with the circadian oscillation of endogenous corticosterone; and is strongly enhanced by acute and chronic dosing. Single dosing also enhanced GILZ mRNA in muscle and liver, but the dynamics varied. In conclusion, GILZ is widely expressed in the rat and highly regulated by endogenous and exogenous GCs. PMID- 26056062 TI - Regulation of p53 in NIH3T3 mouse fibroblasts following hyperosmotic stress. AB - The aim of this project was to analyze the regulation of p53 expression in NIH3T3 fibroblasts under the influence of increasing hyperosmotic stress. Expression of p53 showed a biphasic response pattern in NIH3T3 cells under increasing osmotic stress (337 mOsm to 737 mOsm) with a maximum at 587 mOsm. Under isotonic conditions p53 expression increased after addition of the proteasome inhibitor MG132 indicating that cellular p53 levels in unperturbed cells is kept low by proteasomal degradation. However, under hypertonic conditions p53 synthesis as well as p53 degradation were significantly reduced and it is demonstrated that the increase in p53 expression observed when tonicity is increased from 337 to 587 mOsm reflects that degradation is more inhibited than synthesis, whereas the decrease in p53 expression at higher tonicities reflects that synthesis is more inhibited than degradation. The activity of the p53 regulating proteins p38 MAP kinase and the ubiquitin ligase MDM2 were studied as a function of increasing osmolarity. MDM2 protein expression was unchanged at all osmolarities, whereas MDM2 phosphorylation (Ser(166)) increased at osmolarities up to 537 mOsm and remained constant at higher osmolarities. Phosphorylation of p38 increased at osmolarities up to 687 mOsm which correlated with an increased phosphorylation of p53 (Ser(15)) and the decreased p53 degradation. Caspase-3 activity increased gradually with hypertonicity and at 737 mOsm both Caspase-3 activity and annexin V binding are high even though p53 expression and activity are low, indicating that initiation of apoptosis under severe hypertonic conditions is not strictly controlled by p53. PMID- 26056063 TI - Evaluation of the safety, immunogenicity and efficacy of three capripoxvirus vaccine strains against lumpy skin disease virus. AB - The safety, immunogenicity and efficacy of three commercially available vaccines against lumpy skin disease (LSD) in cattle have been evaluated using a combination of vaccine challenge experiments and the monitoring of immune responses in vaccinated animals in the field. The three vaccines evaluated in the study included two locally produced (Ethiopian) vaccines (lumpy skin disease virus (LSDV) Neethling and Kenyan sheep and goat pox (KSGP) O-180 strain vaccines) and a Gorgan goat pox (GTP) vaccine manufactured by Jordan Bio Industries Centre (JOVAC). The latter vaccine was evaluated for the first time in cattle against LSDV. The Ethiopian Neethling and KSGPO-180 vaccines failed to provide protection in cattle against LSDV, whereas the Gorgan GTP vaccine protected all the vaccinated calves from clinical signs of LSD. There was no significant difference in protective efficacy detected between two dosage levels (P=0.2, P=0.25, and P=0.1 for KSGP, Neethling and Gorgan vaccines, respectively). Additionally, the Gorgan GTP vaccinated cattle showed stronger levels of cellular immune responses measured using Delayed-Type Hypersensitivity (DTH) reactions at the vaccination site indicating higher levels of immunogenicity produced by the GTPV vaccine in cattle, as opposed to the other two vaccines. This study indicated, for the first time, that the Gorgan GTP vaccine can effectively protect cattle against LSDV and that the Neethling and KSGP O-180 vaccine were not protective. The results emphasise the need for molecular characterization of the Neethling and KSGP O-180 vaccine seed viruses used for vaccine production in Ethiopia. In addition, the potency and efficacy testing process of the Ethiopian LSD Neethling and KSGP O-180 vaccines should be re-evaluated. PMID- 26056064 TI - The science of foaming. AB - The generation of liquid foams is at the heart of numerous natural, technical or scientific processes. Even though the subject of foam generation has a long standing history, many recent progresses have been made in an attempt to elucidate the fundamental processes at play. We review the subject by providing an overview of the relevant key mechanisms of bubble generation within a coherent hydrodynamic context; and we discuss different foaming techniques which exploit these mechanisms. PMID- 26056065 TI - Enhanced sunlight photocatalytic activity of Ag3PO4 decorated novel combustion synthesis derived TiO2 nanobelts for dye and bacterial degradation. AB - This study demonstrates the synthesis of TiO2 nanobelts using solution combustion derived TiO2 with enhanced photocatalytic activity for dye degradation and bacterial inactivation. Hydrothermal treatment of combustion synthesized TiO2 resulted in unique partially etched TiO2 nanobelts and Ag3PO4 was decorated using the co-precipitation method. The catalyst particles were characterized using X ray diffraction analysis, BET surface area analysis, diffuse reflectance and electron microscopy. The photocatalytic properties of the composites of Ag3PO4 with pristine combustion synthesized TiO2 and commercial TiO2 under sunlight were compared. Therefore the studies conducted proved that the novel Ag3PO4/unique combustion synthesis derived TiO2 nanobelt composites exhibited extended light absorption, better charge transfer mechanism and higher generation of hydroxyl and hole radicals. These properties resulted in enhanced photodegradation of dyes and bacteria when compared to the commercial TiO2 nanocomposite. These findings have important implications in designing new photocatalysts for water purification. PMID- 26056066 TI - Adverse drug reactions for medicine newly approved in Japan from 1999 to 2013: Syncope/loss of consciousness and seizures/convulsions. AB - Many approved medicines are used with their adverse drug reactions (ADRs) appropriately managed in the clinical setting based on their risks and benefits. In this survey, the correlation between human ADR (specifically syncope/loss of consciousness and seizures/convulsions) and safety signals reported in animal studies has been investigated for 393 Japanese medicines which were approved between September 1999 and March 2013. Clinically important drug-induced ADR, syncope/loss of consciousness and seizures/convulsions are reported in this paper. Of 393 medicines, 101 (25.7%) showed syncope/loss of consciousness and 105 (26.7%) showed seizures/convulsions. Syncope/loss of consciousness and seizures/convulsions were reported for many medicines affecting the central nervous system. The animal toxicity concordance ratio with syncope/loss of consciousness and seizures/convulsions was 4.0% (4/101) and 23.8% (25/105), respectively. The underlying cases of syncope/loss of consciousness attributed to hypotension, arrhythmia, hypoglycemia or acute toxic reaction was 16.8%, 5.0%, 4.0% or 4.0%, respectively. Mechanism of seizures/convulsions for the remaining 101 medicines was not identified except for four local anesthetics. This survey suggested that the careful attention to and understanding of medicine profiles is necessary for the appropriate use of recently approved medicines in Japan. PMID- 26056067 TI - [Posterior reversible encephalopathy syndrome and cerebrovascular constriction syndrome in the differential diagnosis of post-partum headaches]. AB - Postpartum headache can be due to many causes. In a patient with previous epidural analgesia, the headache can be attributed to post-dural puncture headache, even if the symptoms are not typical of this clinical entity. We report a case of a post-partum with accidental dural tap during the insertion of an epidural catheter for labour analgesia, and who referred to headaches in the third post-partum day. Initially, a post-dural puncture headache was suspected, but the subsequent onset of seizures and visual impairment meant that the diagnosis had to be reconsidered. In this case report, the clinical and pathophysiological features of posterior reversible encephalopathy syndrome and reversible cerebral vasoconstriction syndrome, as well as the differential diagnosis of post-partum headaches are described. PMID- 26056068 TI - Assessing the Contemporary Role of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma: Another Step in the Right Direction. PMID- 26056069 TI - Clinical Experience with Urethral Reconstruction Using Tissue-engineered Oral Mucosa: A Quiet Revolution. AB - Finalising the use of tissue-engineered materials for urethral reconstruction still represents a difficult challenge. We must not deceive patients into thinking that this "quiet revolution" in urethral reconstruction will be available soon for all urethral conditions (congenital or acquired, simple vs complex) requiring surgery. This research and its clinical application require a prospective, multicentre, randomised, double-blind, and placebo controlled/comparative phase 3 study for a large series of patients, and we are still far from this step. PMID- 26056070 TI - Prostate Cancer Registries: Current Status and Future Directions. AB - CONTEXT: Disease-specific registries that enroll a considerable number of patients play a major role in prostate cancer (PCa) research. OBJECTIVE: To evaluate available registries, describe their strengths and limitations, and discuss the potential future role of PCa registries in outcomes research. EVIDENCE ACQUISITION: We performed a literature review of the Medline, Embase, and Web of Science databases. The search strategy included the terms prostate cancer, outcomes, statistical approaches, population-based cohorts, registries of outcomes, and epidemiological studies, alone or in combination. We limited our search to studies published between January 2005 and January 2015. EVIDENCE SYNTHESIS: Several population-based and prospective disease-specific registries are currently available for prostate cancer. Studies performed using these data sources provide important information on incidence and mortality, disease characteristics at presentation, risk factors, trends in utilization of health care services, disparities in access to treatment, quality of care, long-term oncologic and health-related quality of life outcomes, and costs associated with management of the disease. Although data from these registries have some limitations, statistical methods are available that can address certain biases and increase the internal and external validity of such analyses. In the future, improvements in data quality, collection of tissue samples, and the availability of data feedback to health care providers will increase the relevance of studies built on population-based and disease-specific registries. CONCLUSIONS: The strengths and limitations of PCa registries should be carefully considered when planning studies using these databases. Although randomized controlled trials still provide the highest level of evidence, large registries play an important and growing role in advancing PCa research and care. PATIENT SUMMARY: Several population-based and prospective disease-specific registries for prostate cancer are currently available. Analyses of data from these registries yield information that is clinically relevant for the management of patients with prostate cancer. PMID- 26056071 TI - Osteocyte specific responses to soluble and mechanical stimuli in a stem cell derived culture model. AB - Studying osteocyte behavior in culture has proven difficult because these embedded cells require spatially coordinated interactions with the matrix and surrounding cells to achieve the osteocyte phenotype. Using an easily attainable source of bone marrow mesenchymal stem cells, we generated cells with the osteocyte phenotype within two weeks. These "stem cell derived-osteocytes" (SCD O) displayed stellate morphology and lacunocanalicular ultrastructure. Osteocytic genes Sost, Dmp1, E11, and Fgf23 were maximally expressed at 15 days and responded to PTH and 1,25(OH)2D3. Production of sclerostin mRNA and protein, within 15 days of culture makes the SCD-O model ideal for elucidating regulatory mechanisms. We found sclerostin to be regulated by mechanical factors, where low intensity vibration significantly reduced Sost expression. Additionally, this model recapitulates sclerostin production in response to osteoactive hormones, as PTH or LIV repressed secretion of sclerostin, significantly impacting Wnt mediated Axin2 expression, via beta-catenin signaling. In summary, SCD-O cells produce abundant matrix, rapidly attain the osteocyte phenotype, and secrete functional factors including sclerostin under non-immortalized conditions. This culture model enables ex vivo observations of osteocyte behavior while preserving an organ-like environment. Furthermore, as marrow-derived mesenchymal stem cells can be obtained from transgenic animals; our model enables study of genetic control of osteocyte behaviors. PMID- 26056072 TI - Understanding safety-critical interactions with a home medical device through Distributed Cognition. AB - As healthcare shifts from the hospital to the home, it is becoming increasingly important to understand how patients interact with home medical devices, to inform the safe and patient-friendly design of these devices. Distributed Cognition (DCog) has been a useful theoretical framework for understanding situated interactions in the healthcare domain. However, it has not previously been applied to study interactions with home medical devices. In this study, DCog was applied to understand renal patients' interactions with Home Hemodialysis Technology (HHT), as an example of a home medical device. Data was gathered through ethnographic observations and interviews with 19 renal patients and interviews with seven professionals. Data was analyzed through the principles summarized in the Distributed Cognition for Teamwork methodology. In this paper we focus on the analysis of system activities, information flows, social structures, physical layouts, and artefacts. By explicitly considering different ways in which cognitive processes are distributed, the DCog approach helped to understand patients' interaction strategies, and pointed to design opportunities that could improve patients' experiences of using HHT. The findings highlight the need to design HHT taking into consideration likely scenarios of use in the home and of the broader home context. A setting such as home hemodialysis has the characteristics of a complex and safety-critical socio-technical system, and a DCog approach effectively helps to understand how safety is achieved or compromised in such a system. PMID- 26056073 TI - Designing optimal mortality risk prediction scores that preserve clinical knowledge. AB - Many in-hospital mortality risk prediction scores dichotomize predictive variables to simplify the score calculation. However, hard thresholding in these additive stepwise scores of the form "add x points if variable v is above/below threshold t" may lead to critical failures. In this paper, we seek to develop risk prediction scores that preserve clinical knowledge embedded in features and structure of the existing additive stepwise scores while addressing limitations caused by variable dichotomization. To this end, we propose a novel score structure that relies on a transformation of predictive variables by means of nonlinear logistic functions facilitating smooth differentiation between critical and normal values of the variables. We develop an optimization framework for inferring parameters of the logistic functions for a given patient population via cyclic block coordinate descent. The parameters may readily be updated as the patient population and standards of care evolve. We tested the proposed methodology on two populations: (1) brain trauma patients admitted to the intensive care unit of the Dell Children's Medical Center of Central Texas between 2007 and 2012, and (2) adult ICU patient data from the MIMIC II database. The results are compared with those obtained by the widely used PRISM III and SOFA scores. The prediction power of a score is evaluated using area under ROC curve, Youden's index, and precision-recall balance in a cross-validation study. The results demonstrate that the new framework enables significant performance improvements over PRISM III and SOFA in terms of all three criteria. PMID- 26056074 TI - Privacy preserving processing of genomic data: A survey. AB - Recently, the rapid advance in genome sequencing technology has led to production of huge amount of sensitive genomic data. However, a serious privacy challenge is confronted with increasing number of genetic tests as genomic data is the ultimate source of identity for humans. Lately, privacy threats and possible solutions regarding the undesired access to genomic data are discussed, however it is challenging to apply proposed solutions to real life problems due to the complex nature of security definitions. In this review, we have categorized pre existing problems and corresponding solutions in more understandable and convenient way. Additionally, we have also included open privacy problems coming with each genomic data processing procedure. We believe our classification of genome associated privacy problems will pave the way for linking of real-life problems with previously proposed methods. PMID- 26056075 TI - Aflibercept, bevacizumab and ranibizumab prevent glucose-induced damage in human retinal pericytes in vitro, through a PLA2/COX-2/VEGF-A pathway. AB - Diabetic retinopathy, a major cause of vision loss, is currently treated with anti-VEGF agents. Here we tested two hypotheses: (i) high glucose damages retinal pericytes, the cell layer surrounding endothelial cells, via VEGF induction, which may be counteracted by anti-VEGFs and (ii) activation of PLA2/COX-2 pathway by high glucose might be upstream and/or downstream of VEGF in perycites, as previously observed in endothelial cells. Human retinal pericytes were treated with high glucose (25mM) for 48h and/or anti-VEGFs (40MUg/ml aflibercept, 25MUg/ml bevacizumab, 10MUg/ml ranibizumab). All anti-VEGFs significantly prevented high glucose-induced cell damage (assessed by LDH release) and improved cell viability (assessed by MTT and Evans blue). High glucose-induced VEGF-A expression, as detected both at mRNA (qPCR) and protein (ELISA) level, while receptor (VEGFR1 and VEGFR2) expression, detected in control condition, was unaffected by treatments. High glucose induced also activation of PLA2/COX-2 pathway, as revealed by increased phosphorylation of cPLA2, COX-2 expression and PGE2 release. Treatment with cPLA2 (50MUM AACOCF3) and COX-2 (5MUM NS-392) inhibitors prevented both cell damage and VEGF-A induced by high glucose. Finally, challenge with exogenous VEGF-A (10ng/ml) induced VEGF-A expression, while anti-VEGFs reduced VEGF-A expression induced by either high glucose or exogenous VEGF-A. These data indicate that high glucose directly damages pericytes through activation of PLA2/COX-2/VEGF-A pathway. Furthermore, a kind of feed-forward loop between cPLA2/COX-2/PG axis and VEGF appears to operate in this system. Thus, anti-VEGFs afford protection of pericytes from high glucose by inhibiting this loop. PMID- 26056076 TI - Interaction of prenatal stress and morphine alters prolactin and seizure in rat pups. AB - Prenatal exposure to stress and morphine has complicated effects on epileptic seizure. In the present study, effect of prenatal forced-swim stress and morphine co-administration on pentylenetetrazol (PTZ) induced epileptic behaviors and prolactin blood level (PBL) was investigated in rat offspring. Pregnant Wistar rats were divided to four groups of control-saline, control-morphine, stressed saline and stressed-morphine. In the stressed group, pregnant rats were placed in 25 degrees C water on gestation days 17, 18 and 19 (GD17, GD18 and GD19) for 30 min. In the morphine/saline group, pregnant rats received morphine (10, 12 and 15 mg/kg, IP, on GD17, GD18 and GD19, respectively) or saline (1 ml, IP). In the morphine/saline-stressed group, the rats received morphine or saline and then exposed to stress. On postnatal days 6 and 15 (P6 and P15), blood samples were obtained and PBL was determined. At P15 and P25, the rest of the pups was injected with PTZ to induce seizure. Then, epileptic behaviors of each rat were observed individually. Latency of first convulsion decreased in control-morphine and stressed-saline groups while increased in stressed-morphine rats compared to control-saline group on P15 (P=0.04). Number of tonic-clonic seizures significantly increased in control-morphine and stressed-saline rats compared to control-saline group at P15 (P=0.02). PBL increased in stressed-saline, control morphine and stress-morphine groups compared to control-saline rats. It can be concluded that prenatal exposure of rats to forced-swim stress and morphine changed their susceptibility to PTZ-induced seizure and PBL during infancy and prepubertal period. Co-administration of morphine attenuated effect of stress on epileptic behaviors. PMID- 26056077 TI - Weight-activity associations with cardiometabolic risk factors among U.S. youth. AB - Research among adult populations suggests that underweight is associated with worse cardiometabolic health and that adequate engagement in moderate-to-vigorous physical activity (MVPA) may help to counteract the cardiometabolic consequences of overweight/obesity. Whether these findings are also true in children and adolescents (hereafter 'youth') is unknown. Therefore, the purpose of this study was to determine whether underweight and overweight/obese youth who engage in relatively more MVPA have better or similar cardiometabolic risk factors than normal weight youth who engage in relatively less MVPA. Data were extracted from the 2003-2006 National Health and Nutrition Examination Survey (N=2268). Four cardiometabolic risk factors assessed included C-reactive protein, mean arterial pressure, total cholesterol, and high-density lipoprotein (HDL) cholesterol. Weight status was assessed via dual energy X-ray absorptiometry. MVPA was assessed via accelerometry. Six weight-activity groups were created: 1) Underweight and Inactive; 2) Normal Weight and Inactive; 3) Overweight/Obese and Inactive; 4) Underweight and Active; 5) Normal Weight and Active; and, 6) Overweight/Obese and Active. An overall cardiometabolic risk score was calculated by summing the frequency with which each individual participant scored in the worst quartile for each of the 4 cardiometabolic parameters. Compared to those who were Normal Weight and Inactive, youth who were Underweight and Active (beta= 0.05, p=0.78) had a similar overall cardiometabolic risk score. In contrast, Overweight/Obese and Active youth (beta=1.1, p<0.001) had a higher overall cardiometabolic risk score when compared to Normal Weight and Inactive youth. These cross-sectional findings suggest that MVPA may not fully counteract the cardiometabolic consequences of overweight/obesity in youth. Rather, maintaining a normal weight may be of a more important factor related to cardiometabolic risk in youth. PMID- 26056078 TI - Acute pentobarbital treatment impairs spatial learning and memory and hippocampal long-term potentiation in rats. AB - Reports of the effects of pentobarbital on learning and memory are contradictory. Some studies have not shown any interference with learning and memory, whereas others have shown that pentobarbital impairs memory and that these impairments can last for long periods. However, it is unclear whether acute local microinjections of pentobarbital affect learning and memory, and if so, the potential mechanisms are also unclear. Here, we reported that the intra hippocampal infusion of pentobarbital (8.0mM, 1MUl per side) significantly impaired hippocampus-dependent spatial learning and memory retrieval. Moreover, in vitro electrophysiological recordings revealed that these behavioral changes were accompanied by impaired hippocampal CA1 long-term potentiation (LTP) and suppressed neuronal excitability as reflected by a decrease in the number of action potentials (APs). These results suggest that acute pentobarbital application causes spatial learning and memory deficits that might be attributable to the suppression of synaptic plasticity and neuronal excitability. PMID- 26056079 TI - Screening for ALK in non-small cell lung carcinomas: 5A4 and D5F3 antibodies perform equally well, but combined use with FISH is recommended. AB - OBJECTIVES: Immunohistochemistry (IHC) has become a promising method for pre screening ALK-rearrangements in non-small cell lung carcinomas (NSCLC). Various ALK antibodies, detection systems and automated immunostainers are available. We therefore aimed to compare the performance of the monoclonal 5A4 (Novocastra, Leica) and D5F3 (Cell Signaling, Ventana) antibodies using two different immunostainers. Additionally we analyzed the accuracy of prospective ALK IHC testing in routine diagnostics. MATERIALS AND METHODS: Seventy-two NSCLC with available ALK FISH results and enriched for FISH-positive carcinomas were retrospectively analyzed. IHC was performed on BenchMarkXT (Ventana) using 5A4 and D5F3, respectively, and additionally with 5A4 on Bond-MAX (Leica). Data from our routine diagnostics on prospective ALK-testing with parallel IHC, using 5A4, and FISH were available from 303 NSCLC. RESULTS: All three IHC protocols showed congruent results. Only 1/25 FISH-positive NSCLC (4%) was false negative by IHC. For all three IHC protocols the sensitivity, specificity, positive (PPV) and negative predictive values (NPV) compared to FISH were 96%, 100%, 100% and 97.8%, respectively. In the prospective cohort 3/32 FISH-positive (9.4%) and 2/271 FISH negative (0.7%) NSCLC were false negative and false positive by IHC, respectively. In routine diagnostics the sensitivity, specificity, PPV and NPV of IHC compared to FISH were 90.6%, 99.3%, 93.5% and 98.9%, respectively. CONCLUSIONS: 5A4 and D5F3 are equally well suited for detecting ALK-rearranged NSCLC. BenchMark and BOND-MAX immunostainers can be used for IHC with 5A4. True discrepancies between IHC and FISH results do exist and need to be addressed when implementing IHC in an ALK-testing algorithm. PMID- 26056080 TI - Flux of granular particles through a shaken sieve plate. AB - We experimentally investigate a discharging flux of granular particles through a sieve plate subject to vertical vibrations. The mean mass flux shows a non monotonic relation with the vibration strength. High-speed photography reveals that two stages, the free flight of the particles' bulk over the plate and the adhesion of the particles' bulk with the plate, alternately appear, where only the adhesion stage contributes to the flow. With two independent methods, we then measure the adhesion time under different vibration conditions, and define an adhesion flux. The adhesion flux monotonically increases with increasing vibration strength. By rescaling the adhesion flux, we find that the adhesion flux is approximately determined by the peak vibration velocity of the shaker. The conclusion is examined with other sieve geometries. PMID- 26056081 TI - Nuclear translocation of fibroblast growth factor-2 (FGF2) is regulated by Karyopherin-beta2 and Ran GTPase in human glioblastoma cells. AB - Human glioblastoma multiforme (GBM) is the most malignant tumor of the central nervous system (CNS). Fibroblast growth factor-2 (FGF2) belongs to the FGF superfamily and functions as a potential oncoprotein in GBM. FGF2 has low molecular weight (18K) and high molecular weight (HMW) isoforms. Nuclear accumulation of HMW-FGF2 strongly promotes glioblastoma cell proliferation, yet mechanism governing such cellular distribution remains unexplored. We investigated the mechanisms regulating FGF2 cellular localization in T98G human brain glioblastoma cells. We found HMW-FGF2, but not 18K-FGF2, is primarily located in the nucleus and interacts with nuclear transport protein Karyopherin beta2/Transportin (Kapbeta2). SiRNA-directed Kapbeta2 knockdown significantly reduced HMW-FGF2's nuclear translocation. Moreover, inhibiting Ran GTPase activity also resulted in decreased HMW-FGF2 nuclear accumulation. Proliferation of T98G cells is greatly enhanced with transfections HMW-FGF2. Decreased PTEN expression and activated Akt signaling were observed upon HMW-FGF2 overexpression and might mediate pro-survival effect of FGF2. Interestingly, addition of nuclear localization signal (NLS) to 18K-FGF2 forced its nuclear import and dramatically increased cell proliferation and Akt activation. These findings demonstrated for the first time the molecular mechanisms for FGF2's nuclear import, which promotes GBM cell proliferation and survival, providing novel insights to the development of GBM treatments. PMID- 26056082 TI - Classification and clinical behavior of blastic plasmacytoid dendritic cell neoplasms according to their maturation-associated immunophenotypic profile. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of leukemia/lymphoma, whose diagnosis can be difficult to achieve due to its clinical and biological heterogeneity, as well as its overlapping features with other hematologic malignancies. In this study we investigated whether the association between the maturational stage of tumor cells and the clinico biological and prognostic features of the disease, based on the analysis of 46 BPDCN cases classified into three maturation-associated subgroups on immunophenotypic grounds. Our results show that blasts from cases with an immature plasmacytoid dendritic cell (pDC) phenotype exhibit an uncommon CD56- phenotype, coexisting with CD34+ non-pDC tumor cells, typically in the absence of extramedullary (e.g. skin) disease at presentation. Conversely, patients with a more mature blast cell phenotype more frequently displayed skin/extramedullary involvement and spread into secondary lymphoid tissues. Despite the dismal outcome, acute lymphoblastic leukemia-type therapy (with central nervous system prophylaxis) and/or allogeneic stem cell transplantation appeared to be the only effective therapies. Overall, our findings indicate that the maturational profile of pDC blasts in BPDCN is highly heterogeneous and translates into a wide clinical spectrum -from acute leukemia to mature lymphoma-like behavior-, which may also lead to variable diagnosis and treatment. PMID- 26056083 TI - Integrated analysis of microRNAs, transcription factors and target genes expression discloses a specific molecular architecture of hyperdiploid multiple myeloma. AB - Multiple Myeloma (MM) is a malignancy characterized by the hyperdiploid (HD-MM) and the non-hyperdiploid (nHD-MM) subtypes. To shed light within the molecular architecture of these subtypes, we used a novel integromics approach. By annotated MM patient mRNA/microRNA (miRNA) datasets, we investigated mRNAs and miRNAs profiles with relation to changes in transcriptional regulators expression. We found that HD-MM displays specific gene and miRNA expression profiles, involving the Signal Transducer and Activator of Transcription (STAT)3 pathway as well as the Transforming Growth Factor-beta (TGFbeta) and the transcription regulator Nuclear Protein-1 (NUPR1). Our data define specific molecular features of HD-MM that may translate in the identification of novel relevant druggable targets. PMID- 26056086 TI - Erratum. PMID- 26056084 TI - The PARP inhibitor olaparib enhances the sensitivity of Ewing sarcoma to trabectedin. AB - Recent preclinical evidence has suggested that Ewing Sarcoma (ES) bearing EWSR1 ETS fusions could be particularly sensitive to PARP inhibitors (PARPinh) in combination with DNA damage repair (DDR) agents. Trabectedin is an antitumoral agent that modulates EWSR1-FLI1 transcriptional functions, causing DNA damage. Interestingly, PARP1 is also a transcriptional regulator of EWSR1-FLI1, and PARPinh disrupts the DDR machinery. Thus, given the impact and apparent specificity of both agents with regard to the DNA damage/DDR system and EWSR1 FLI1 activity in ES, we decided to explore the activity of combining PARPinh and Trabectedin in in vitro and in vivo experiments. The combination of Olaparib and Trabectedin was found to be highly synergistic, inhibiting cell proliferation, inducing apoptosis, and the accumulation of G2/M. The drug combination also enhanced gammaH2AX intranuclear accumulation as a result of DNA damage induction, DNA fragmentation and global DDR deregulation, while EWSR1-FLI1 target expression remained unaffected. The effect of the drug combination was corroborated in a mouse xenograft model of ES and, more importantly, in two ES patient-derived xenograft (PDX) models in which the tumors showed complete regression. In conclusion, the combination of the two agents leads to a biologically significant deregulation of the DDR machinery that elicits relevant antitumor activity in preclinical models and might represent a promising therapeutic tool that should be further explored for translation to the clinical setting. PMID- 26056085 TI - Underexpression of LKB1 tumor suppressor is associated with enhanced Wnt signaling and malignant characteristics of human intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is a rare and highly aggressive malignancy. In this study, we identified the presence of gene deletion and missense mutation leading to inactivation or underexpression of liver kinase B1 (LKB1) tumor suppressor and excluded the involvement of LKB1 gene hypermethylation in ICC tissues. Immunohistochemical analysis showed that LKB1 was underexpressed in a portion of 326 ICC tissues compared to their adjacent normal tissues. By statistical analysis underexpression of LKB1 in ICC tissues significantly correlated with poor survival and malignant disease characteristics in ICC patients. Moreover, we showed that knockdown of LKB1 significantly enhanced growth, migration, and invasion of three LKB1-competent ICC cell lines. Global transcriptional profiling analysis identified multiple malignancy-promoting genes, such as HIF-1alpha, CD24, Talin1, Vinculin, Wnt5, and signaling pathways including Hedgehog, Wnt/beta-catenin, and cell adhesion as novel targets of LKB1 underexpression in ICC cells. Furthermore, knockdown of LKB1 gene expression dramatically enhanced Wnt/beta-catenin signaling in ICC cells, while an inverse correlation between LKB1 and nuclear beta-catenin was observed in ICC tissues. Our findings suggest a novel mechanism for ICC carcinogenesis in which LKB1 underexpression enhances multiple signaling pathways including Wnt/beta-catenin to promote disease progression. PMID- 26056087 TI - Somatic c.34G>T KRAS mutation: a new prescreening test for MUTYH-associated polyposis? AB - We investigated the somatic c.34G>T KRAS transversion as a marker suggestive of MUTYH-associated polyposis (MAP). We compared 86 adenomas and 19 colorectal cancers (CRCs) of 30 MAP patients to 135 adenomas and five CRCs of 47 familial adenomatous polyposis (FAP) patients. The c.34G>T mutation was investigated by DNA sequencing. Secondly, the germline MUTYH gene sequence was analyzed in patients carrying c.34G>T in CRCs diagnosed between 2008 and 2012. The c.34G>T was present in 39.7% of MAP adenomas versus 1.6% of FAP adenomas (P < 0.01). Sensitivity and specificity for detecting MAP were 39.7% and 98%, respectively. Sensitivity increased with the number of adenomas tested (P = 0.039). KRAS exon 2 analysis was performed on 2239 CRC and 2.2% harbored the c.34G>T transversion. Among 28 carriers of the c.34G>T mutation, biallelic MUTYH mutations were detected in seven patients (25%). One patient did not have any polyp or family history and did not fulfill criteria for MUTYH testing. With high specificity, the c.34G>T mutation seems to be a useful and promising test for MAP. For polyposis, it may guide genetic testing toward APC or MUTYH. If routinely performed in CRC patients, it could help to diagnose MUTYH-mutation carriers, even when they don't fulfill genetic testing criteria. PMID- 26056089 TI - From the Editors. PMID- 26056090 TI - Meta-analysis of a binary outcome using individual participant data and aggregate data. AB - In this paper, we develop meta-analysis models that synthesize a binary outcome from health-care studies while accounting for participant-level covariates. In particular, we show how to synthesize the observed event-risk across studies while accounting for the within-study association between participant-level covariates and individual event probability. The models are adapted for situations where studies provide individual participant data (IPD), or a mixture of IPD and aggregate data. We show that the availability of IPD is crucial in at least some studies; this allows one to model potentially complex within-study associations and separate them from across-study associations, so as to account for potential ecological bias and study-level confounding. The models can produce pertinent population-level and individual-level results, such as the pooled event risk and the covariate-specific event probability for an individual. Application is made to 14 studies of traumatic brain injury, where IPD are available for four studies and the six-month mortality risk is synthesized in relation to individual age. The results show that as individual age increases the probability of six month mortality also increases; further, the models reveal clear evidence of ecological bias, with the mean age in each study additionally influencing an individual's mortality probability. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26056091 TI - A method for evaluating research syntheses: The quality, conclusions, and consensus of 12 syntheses of the effects of after-school programs. AB - Like all forms of empirical inquiry, research syntheses can be carried out in ways that lead to more or less valid inferences about the phenomenon under study. This synthesis of syntheses (a) examined the methods employed in the syntheses of the effects of after-school programs (ASPs) and determined how closely they conformed to what is defined as best practice for research synthesis, (b) compared the inferences drawn from the ASP research literature by each synthesis with the inferences that plausibly could be made from the data they covered, and (c) determined the points of consistency across the syntheses with regard to both potentially valid and potentially invalid conclusions. It was found that the 12 syntheses used highly divergent methods, varying in problem definitions, search strategies, inclusion criteria for individual studies, and techniques for drawing conclusions about the cumulative evidence. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26056088 TI - A Comprehensive Analysis of Chromoplast Differentiation Reveals Complex Protein Changes Associated with Plastoglobule Biogenesis and Remodeling of Protein Systems in Sweet Orange Flesh. AB - Globular and crystalloid chromoplasts were observed to be region specifically formed in sweet orange (Citrus sinensis) flesh and converted from amyloplasts during fruit maturation, which was associated with the composition of specific carotenoids and the expression of carotenogenic genes. Subsequent isobaric tag for relative and absolute quantitation (iTRAQ)-based quantitative proteomic analyses of purified plastids from the flesh during chromoplast differentiation and senescence identified 1,386 putative plastid-localized proteins, 1,016 of which were quantified by spectral counting. The iTRAQ values reflecting the expression abundance of three identified proteins were validated by immunoblotting. Based on iTRAQ data, chromoplastogenesis appeared to be associated with three major protein expression patterns: (1) marked decrease in abundance of the proteins participating in the translation machinery through ribosome assembly; (2) increase in abundance of the proteins involved in terpenoid biosynthesis (including carotenoids), stress responses (redox, ascorbate, and glutathione), and development; and (3) maintenance of the proteins for signaling and DNA and RNA. Interestingly, a strong increase in abundance of several plastoglobule-localized proteins coincided with the formation of plastoglobules in the chromoplast. The proteomic data also showed that stable functioning of protein import, suppression of ribosome assembly, and accumulation of chromoplast proteases are correlated with the amyloplast-to-chromoplast transition; thus, these processes may play a collective role in chromoplast biogenesis and differentiation. By contrast, the chromoplast senescence process was inferred to be associated with significant increases in stress response and energy supply. In conclusion, this comprehensive proteomic study identified many potentially new plastid-localized proteins and provides insights into the potential developmental and molecular mechanisms underlying chromoplast biogenesis, differentiation, and senescence in sweet orange flesh. PMID- 26056092 TI - Robust variance estimation in meta-regression with dependent effect size estimates. AB - Conventional meta-analytic techniques rely on the assumption that effect size estimates from different studies are independent and have sampling distributions with known conditional variances. The independence assumption is violated when studies produce several estimates based on the same individuals or there are clusters of studies that are not independent (such as those carried out by the same investigator or laboratory). This paper provides an estimator of the covariance matrix of meta-regression coefficients that are applicable when there are clusters of internally correlated estimates. It makes no assumptions about the specific form of the sampling distributions of the effect sizes, nor does it require knowledge of the covariance structure of the dependent estimates. Moreover, this paper demonstrates that the meta-regression coefficients are consistent and asymptotically normally distributed and that the robust variance estimator is valid even when the covariates are random. The theory is asymptotic in the number of studies, but simulations suggest that the theory may yield accurate results with as few as 20-40 studies. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26056093 TI - Graphical displays for meta-analysis: An overview with suggestions for practice. AB - Meta-analyses are fundamental tools for collating and synthesizing large amounts of information, and graphical displays have become the principal tool for presenting the results of multiple studies of the same research question. We review standard and proposed graphical displays for presentation of meta-analytic data, and offer our recommendations on how they might be presented to provide the most useful and user-friendly illustrations. We concentrate on graphs that specifically aim to present similar sorts of univariate results from multiple studies. We start with forest plots and funnel plots, and proceed to Galbraith (or radial) plots, L'Abbe (and related) plots, further plots useful for investigating heterogeneity, plots useful for model diagnostics and plots for illustrating likelihoods and Bayesian meta-analyses. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26056094 TI - Article alerts: Introduction and items from 2009, part I. AB - This 'Article Alerts' feature is intended to apprise readers of recent methodological work in research synthesis and compile previous such contributions from various outlets. In this first installment we introduce the feature by commenting on its main aims and distinguishing between the print and archive versions. The feature's content and process are also described, including encouragement of interactive contributions from readers. The current installment's 100 items, a subset of relevant work published in 2009, are categorized by type of contribution and supplemented with suggested keywords. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26056095 TI - Effectiveness of Minimally Invasive Hybrid Surgery for Ileal Interposition (MIHSII) for the Resolution of Type 2 Diabetes. AB - AIM: To evaluate the effectiveness of minimally invasive hybrid surgery for ileal interposition (MIHSII), a novel procedure for type 2 diabetes (T2DM) in patients with a body mass index (BMI) <30 kg/m(2). MATERIALS AND METHODS: MIHSII is an innovative technique in which sleeve gastrectomy is performed laparoscopically, followed by extracorporeal ileal interposition performed through a 5-cm midline incision. The procedure was performed on 31 T2DM patients, 17 males and 14 females. Their BMI values ranged from 21.8 kg/m(2) to 29.8 kg/m(2), with a mean BMI of 26.61 +/- 2.61 kg/m(2). The average duration of diabetes 8.14 +/- 4.89 (range = 1-20) years. Most of the patients exhibited poorly controlled diabetes despite the use of oral hypoglycemic agents (OHAs) and/or insulin. RESULTS: The mean preoperative glycosylated hemoglobin (HbA1c) for the population was 8.86%. The mean HbA1c 1 year after surgery was 6.80%. The difference between the mean preoperative and 1-year postoperative HbA1c values was significant, at P < .05 (group 1: BMI = 18.5-24.99 kg/m(2), t = 2.83, and P = .022; group 2: BMI = 25 29.99 kg/m(2), t = 4.23, and P = .001). The resolution rate of diabetes was 80.48%; 48.57% experienced complete resolution, and 31.91% experienced partial resolution. The remaining 19.52% of patients exhibited a significant reduction in HbA1c, although the HbA1c levels did not fall below 6.5%, even with medications. CONCLUSION: MIHSII is an innovative technique of metabolic surgery and is a cost effective and minimal procedure for the resolution of T2DM in patients with BMI <30 kg/m(2). PMID- 26056096 TI - When communicable and non-communicable diseases collide. PMID- 26056097 TI - Screening and smoking cessation support for TB contacts: cost-effective good clinical practice. PMID- 26056098 TI - Quality of tuberculosis care in India: a systematic review. AB - BACKGROUND: While Indian studies have assessed care providers' knowledge and practices, there is no systematic review on the quality of tuberculosis (TB) care. METHODS: We searched multiple sources to identify studies (2000-2014) on providers' knowledge and practices. We used the International Standards for TB Care to benchmark quality of care. RESULTS: Of the 47 studies included, 35 were questionnaire surveys and 12 used chart abstraction. None assessed actual practice using standardised patients. Heterogeneity in the findings precluded meta-analysis. Of 22 studies evaluating provider knowledge about using sputum smears for diagnosis, 10 found that less than half of providers had correct knowledge; 3 of 4 studies assessing self-reported practices by providers found that less than a quarter reported ordering smears for patients with chest symptoms. In 11 of 14 studies that assessed treatment, less than one third of providers knew the standard regimen for drug-susceptible TB. Adherence to standards in practice was generally lower than correct knowledge of those standards. Eleven studies with both public and private providers found higher levels of appropriate knowledge/practice in the public sector. CONCLUSIONS: Available evidence suggests suboptimal quality of TB care, particularly in the private sector. Improvement of quality of care should be a priority for India. PMID- 26056099 TI - Tuberculosis in Malaysia: predictors of treatment outcomes in a national registry. AB - OBJECTIVES: To determine treatment outcomes and associated predictors of all patients registered in 2012 with the Malaysian National Tuberculosis (TB) Surveillance Registry. METHODS: Sociodemographic and clinical data were analysed. Unfavourable outcomes included treatment failure, transferred out and lost to follow-up, treatment defaulters, those not evaluated and all-cause mortality. RESULTS: In total, 21 582 patients were registered. The mean age was 42.36 +/- 17.77 years, and 14.2% were non-Malaysians. The majority were new cases (93.6%). One fifth (21.5%) had unfavourable outcomes; of these, 46% died, 49% transferred out or defaulted and 1% failed treatment. Predictors of unfavourable outcomes were older age, male sex, foreign citizenship, lower education, no bacille Calmette-Guerin (BCG) vaccination scar, treatment in tertiary settings, smoking, previous anti-tuberculosis treatment, human immunodeficiency virus infection, not receiving directly observed treatment, advanced chest radiography findings, multidrug-resistant TB (MDR-TB) and extra-pulmonary TB. For all-cause mortality, predictors were similar except for rural dwelling and nationality (higher mortality among locals). Absence of BCG scar, previous treatment for TB and MDR TB were not found to be predictors of all-cause mortality. Indigenous populations in East Malaysia had lower rates of unfavourable treatment outcomes. CONCLUSIONS: One fifth of TB patients had unfavourable outcomes. Intervention strategies should target those at increased risk of unfavourable outcomes and all-cause mortality. PMID- 26056100 TI - A population-based study of tuberculosis case fatality in Canada: do Aboriginal peoples fare less well? AB - SETTING: The Province of Alberta, Canada. OBJECTIVES: To explore trends in tuberculosis (TB) case fatality, compare TB case-fatality rates by population group and determine prognostic factors associated with TB-related death in Alberta from 1996 to 2012. DESIGN: Retrospective cohort analysis. RESULTS: During the study years, all-cause TB case fatality fell from 10.7% to 6.3%; the fall was attributable to a change in population structure, as there were more foreign-born and fewer older cases with time. A stable 2% of TB cases died without treatment. Compared to other population groups, Canadian-born Aboriginal case patients were more likely to die without treatment and to die younger. Of TB deaths that were TB-related, 68.9% occurred before or during the initial phase of treatment; of these, TB was a contributory cause of death in 77.5%, i.e., another medical condition was the primary cause of death. In multivariate analysis, age >64 years, aboriginality and miliary/disseminated or central nervous system disease were independent predictors for TB-related death. CONCLUSION: Preventive therapy for those with latent tuberculous infection and a high-risk medical condition, early diagnosis of disease, and special support of older, Aboriginal or comorbid cases, once diagnosed, are necessary to further minimise TB case fatality in Alberta, Canada. PMID- 26056101 TI - Two-stage activity-safety study of daily rifapentine during intensive phase treatment of pulmonary tuberculosis. AB - BACKGROUND: Rifapentine (RPT) has potent activity against Mycobacterium tuberculosis; however, the optimal dose for anti-tuberculosis treatment is unknown. OBJECTIVE: To determine the antimicrobial activity, safety and tolerability of RPT 450 mg or 600 mg administered daily during the first 8 weeks of treatment for pulmonary tuberculosis (TB). DESIGN: In a two-stage, randomised open-label study, adults with sputum smear-positive TB were randomised to receive RPT 450 mg, RPT 600 mg or rifampicin (RMP) 600 mg daily for 8 weeks with isoniazid, pyrazinamide and ethambutol. The primary endpoint was sputum culture status on Lowenstein-Jensen (LJ) medium at completion of 8 weeks of treatment. RESULTS: A total of 153 participants were enrolled. Both RPT regimens met pre specified criteria to advance to stage 2. At completion of 8 weeks of treatment, LJ culture conversion occurred in 85% (35/41), 96% (43/45) and 94% (34/36) of participants in the RPT 450 mg, RPT 600 mg and RMP groups, respectively. The proportions of participants discontinuing treatment were similar (respectively 1/54 [2.0%], 1/51 [2.0%] and 4/48 [8.3%] in the RPT 450 mg, RPT 600 mg and RMP groups), as were ?grade 3 adverse events (0/54 [0%], 1/51 [2.0%] and 4/48 [8.3%]). CONCLUSIONS: There was a trend towards greater efficacy with RPT 600 mg than with RPT 450 mg. Daily RPT was safe and well-tolerated. PMID- 26056102 TI - Integrating tuberculosis screening into annual health examinations for the rural elderly improves case detection. AB - OBJECTIVE: To assess the feasibility and effects of identifying tuberculosis (TB) cases by integrating TB screening into routine health examinations for the elderly in rural China. METHODS: Three counties in Shandong Province were randomly selected for TB screening among three groups of elderly individuals (aged ?60 years) at high risk for TB: 1) those with symptoms of TB, 2) patients with type 2 diabetes mellitus (DM), and 3) close contacts of TB cases. Individuals with X-rays suggestive of TB were referred to the county TB dispensary for further investigation. RESULTS: Among the 93 094 elderly residents who underwent health examinations, 9044 (9.7%) were identified as high risk for TB. TB detection rates were 0.87 per 1000 among those who showed TB symptoms only and 3.36/1000 among those with DM only; however, the rate was significantly higher (115/1000) among those who had both DM and TB symptoms. No TB cases were identified from the close contacts group. CONCLUSION: Integrating TB screening into annual health examinations for the elderly in rural areas was effective in identifying new cases, especially among elderly DM patients with TB symptoms. PMID- 26056103 TI - Incidence and correlates of tuberculosis IGRA conversion among HIV-infected postpartum women. AB - SETTING: Prevention of maternal-to-child transmission program at a tertiary care hospital in Nairobi, Kenya. The risk of acquiring Mycobacterium tuberculosis infection among peripartum human immunodeficiency virus (HIV) infected women is poorly defined. OBJECTIVE: To determine the incidence of and co-factors for interferon-gamma release assay (IGRA) conversion among postpartum HIV-infected women using T-SPOT.TB. DESIGN: We used data and cryopreserved peripheral blood mononuclear cells from a historical cohort of HIV-infected women enrolled at 32 weeks' gestation and followed for 1 year postpartum between 1999 and 2005. RESULTS: Of 89 women initially IGRA-negative during pregnancy, 11 (12.4%) became positive, 53 (59.5%) remained negative and 25 (28.1%) were indeterminate at 1 year postpartum. Mean interferon-gamma (IFN-gamma) response among converters increased from ~1 to >50 spot-forming cells/well (P = 0.015). IGRA conversion was significantly associated with partner HIV infection, flush toilets, maternal illness and cough during follow-up, but not maternal CD4 count or HIV viral load. CONCLUSION: The high rates of IGRA conversion seen among HIV-infected postpartum women in our study are similar to those of other groups at high risk for M. tuberculosis infection. This has important implications for M. tuberculosis infection screening strategies and provision of preventive therapy for the health of women and their infants. PMID- 26056104 TI - Cost of nurse-managed latent tuberculous infection treatment among hard-to-reach immigrants in Israel. AB - BACKGROUND: Adherence to treatment of latent tuberculous infection (LTBI), an essential component of tuberculosis (TB) elimination, is generally unsatisfactory. OBJECTIVES: To examine the adherence and costs of nurse-managed, semi-directly observed preventive treatment (semi-DOPT) with twice-weekly isoniazid among hard-to-reach Ethiopian immigrants, and to compare the treatment outcomes of onsite vs. regional TB clinic-based physician's follow-up. METHODS: This was a quasi-experimental retrospective cohort analysis of LTBI treatment among Ethiopian immigrants in reception centres in the Zefat subdistrict of Northern Israel, screened and treated for LTBI during 2005-2011. Two physician follow-up appointments were scheduled for each patient. RESULTS: Of 663 eligible Ethiopian immigrants included in the study, 628 (94.7%) completed treatment. Treatment outcomes were similar among onsite vs. regional TB clinic-based physician follow-up. Non-completion was significantly associated with side effects (P < 0.001). The total costs of treatment were relatively low, but were significantly higher for the TB clinic-based physician follow-up group. CONCLUSION: Nurse-managed semi-DOPT for LTBI treatment with reduced physician follow-up among hard-to-reach Ethiopian immigrants was efficient and safe. Providing on-site physician follow-up proved to be cheaper than standard follow up at the regional TB clinic. Starting LTBI treatment at an early stage after immigration, and providing treatment and convenient transportation free of charge probably also contributed to the high treatment completion rates. PMID- 26056105 TI - RMP exposure is lower in HIV-infected TB patients receiving intermittent than daily anti-tuberculosis treatment. AB - We compared the pharmacokinetics of rifampicin (RMP) during daily and intermittent (thrice weekly) anti-tuberculosis treatment in human immunodeficiency virus infected tuberculosis patients. Patients treated with a thrice-weekly regimen had significantly lower plasma peak concentration, area under the time concentration curve from 0 to 24 h and higher oral clearance of RMP than those treated with the daily regimen. The median values were respectively 3.7 and 6.4 MUg/ml (P < 0.001), 20.7 and 29.4 MUg/ml.h (P = 0.03) and 21.7 and 15.3 ml/min (P = 0.03). PMID- 26056106 TI - Chronic airway obstruction after successful treatment of tuberculosis and its impact on quality of life. AB - SETTING: Tuberculosis (TB) clinic in Tijuana, Mexico. BACKGROUND: Chronic airway obstruction (CAO) can be a sequella of pulmonary tuberculosis (PTB), independently of smoking history. OBJECTIVE: To determine the prevalence of CAO in subjects recently recorded as cured after treatment of PTB, and its impact on quality of life. DESIGN: Cross-sectional study. RESULTS: Overall, 34.3% of patients with a history of PTB had non-reversible CAO, defined as FEV1 <70% post bronchodilator. Subjects with CAO had significantly more radiographic fibrocavitary sequellae on chest X-rays, more extensive changes (1.8 +/- 0.8 affected quadrants vs. 1.3 +/- 0.6, P = 0.04), more residual lung cavities (1.4 +/- 0.8 vs. 0.5 +/- 0.7, P = 0.002), and greater mediastinal retraction (42.4% vs. 16.7%, P = 0.026). The mean COPD Assessment Test score for subjects with CAO was 15.1 +/- 10.4. The prevalence of irreversible CAO using the lower limit of normal criteria was higher (40%) than that calculated with fixed ratio criteria (34.3%). CONCLUSION: Functional abnormalities are frequently already present at the end of treatment for PTB; patients with CAO are often symptomatic and experience a significant impact on quality of life. PMID- 26056107 TI - The patient impact of point-of-care vs. laboratory placement of Xpert((r)) MTB/RIF. AB - BACKGROUND: The Xpert((r)) MTB/RIF assay can diagnose tuberculosis (TB) rapidly and with great accuracy. The effect of Xpert placement at point of care (POC) vs. at an off-site laboratory on patient management remains unknown. DESIGN: At a primary care clinic in Johannesburg, South Africa, we compared TB diagnosis and treatment initiation among 1861 individuals evaluated for pulmonary TB using Xpert performed either at POC or offsite. RESULTS: When Xpert was performed at POC, a higher proportion of Xpert-positive individuals started treatment (95% vs. 87%, P = 0.047) and time to treatment initiation was shorter (median 0 vs. 5 days, P < 0.001). In contrast, among Xpert-negative TB cases, a higher proportion (87% vs. 72%, P = 0.001) started treatment when the sample was sent to the laboratory, with a shorter time to treatment (median 9 vs. 13 days, P = 0.056). While the overall proportion of presumed TB patients starting treatment was independent of Xpert placement, the proportion started based on a bacteriologically confirmed diagnosis was higher when Xpert was performed at POC (73% vs. 58%, P = 0.006). CONCLUSIONS: Placement of Xpert at POC resulted in more Xpert-positive patients receiving treatment, but did not increase the total number of presumed TB patients starting treatment. When samples were sent to a laboratory for Xpert testing, empiric decision making increased. PMID- 26056108 TI - Evaluation of a novel line-probe assay for genotyping-based diagnosis of Mycobacterium tuberculosis in Thailand. AB - SETTING: The Supranational Tuberculosis Reference Laboratory (NTRL), Bangkok, and Chiangrai Prachanukroh Hospital, Chiangrai, Thailand OBJECTIVE: To evaluate the diagnostic performance of newly developed line-probe assay (LiPA) kits in tuberculosis (TB) endemic settings. DESIGN: LiPA kits were used to evaluate 404 clinical isolates of Mycobacterium species and 163 sputum samples in Thailand. RESULTS: LiPA kits were able to identify M. tuberculosis, M. avium, M. intracellulare and M. kansasii with 100% sensitivity and specificity when compared with the commercially available AccuProbe assay. Testing of the LiPA kits for their ability to detect mutations in clinical isolates resistant to anti tuberculosis drugs such as rifampicin, isoniazid, pyrazinamide and fluoroquinolones showed that the assay had very high sensitivity (65.9-100%) and specificity (98.2-100%) compared with drug susceptibility testing and DNA sequencing. LiPA had a sensitivity of 75.0-85.7% and a specificity of 96.4-100% in testing clinical sputum samples. CONCLUSION: The novel LiPA kits have high sensitivity and specificity, and may enhance the rapid detection of first- and second-line anti-tuberculosis drug resistance, improving the selection of suitable chemotherapy agents to treat multidrug-resistant and extensively drug resistant TB. PMID- 26056109 TI - Mycobacterium tuberculosis resistance in pulmonary TB patients in Cameroon: a phenotypic susceptibility assay. AB - OBJECTIVE: To determine the resistance of Mycobacterium tuberculosis to first- and second-line agents in adult pulmonary tuberculosis (TB) patients in Cameroon using a novel phenotypic assay. SETTING: Samples were collected from TB patients at Bamenda Hospital in Bamenda, Cameroon. DESIGN: Samples were collected consecutively from adult pulmonary TB patients over a 2-month period. TREK Sensititre(TM) MYCOTB panels were used to perform phenotypic drug susceptibility testing (DST). Susceptibility/resistance was determined by comparing minimum inhibitory concentrations to standard critical concentrations established for first- and second-line anti-tuberculosis drugs. RESULTS: Of 103 sputum samples processed, growth on Lowenstein-Jensen media was confirmed in 78 samples, 65 of which were suitable for DST. Thirty-nine strains (60%) were susceptible to all first- and second-line drugs. Five strains (8%) were categorized as multidrug resistant TB. Two strains (3%) were classified as pre-extensively drug-resistant TB. Of those isolates susceptible to first-line drugs, 20% were resistant to at least one second-line drug. CONCLUSION: Antimicrobial resistance may be higher than assumed in TB strains in Cameroon, especially with regard to second-line drugs. There remains a need for rapid, comprehensive DST. PMID- 26056110 TI - Molecular drug susceptibility testing in the Netherlands: performance of the MTBDRplus and MTBDRsl assays. AB - BACKGROUND: The performance of molecular drug susceptibility testing in countries with a low prevalence of drug resistance, such as the Netherlands, has not been adequately studied. OBJECTIVE: To evaluate the diagnostic accuracy of the GenoType((r)) MTBDRplus and MTBDRsl assays to detect resistance to first- and second-line anti-tuberculosis drugs in the context of a nationwide screening programme in the Netherlands. RESULTS: The MTBDRplus assay had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100%, 99%, 80% and 100% for detecting rifampicin resistance. The sensitivity, specificity, PPV and NPV of either a katG or inhA mutation for detecting isoniazid resistance were 88%, 100%, 100% and 99%. The MTBDRsl assay had a sensitivity, specificity, PPV and NPV of 100%, 99%, 83%, and 100% for detecting moxifloxacin resistance; 62%, 71%, 58% and 74%, respectively, for detecting ethambutol resistance; 86%, 99%, 86% and 99% for detecting amikacin resistance; and 50%, 96%, 71% and 91% for detecting capreomycin resistance. CONCLUSION: The MTBDRplus and MTBDRsl assays may aid in decision making in tuberculosis treatment in low-level drug resistance settings and should preferably be used to exclude resistance. PMID- 26056111 TI - Molecular typing of drug-susceptible and -resistant Mycobacterium tuberculosis in Johannesburg, South Africa. AB - SETTING: Knowledge about spoligotyping families of drug-susceptible and drug resistant Mycobacterium tuberculosis circulating in the Johannesburg area, South Africa, is lacking. OBJECTIVE: To determine the genetic diversity of M. tuberculosis isolates circulating in the Johannesburg area and to compare the results with both national and international databanks. DESIGN: Five hundred cultured M. tuberculosis isolates from within the greater Johannesburg metropolitan area collected from January 2009 to December 2010 were obtained from the National Health Laboratory Services (NHLS) Mycobacteriology Referral Laboratory, Johannesburg, in MGIT vials. The isolates were specimens from individuals with tuberculosis (TB) symptoms and known TB patients submitted to the NHLS for routine mycobacterial culture and drug susceptibility testing. The isolates were genotyped using spoligotyping. RESULTS: Spoligotyping generated 62 shared types, with 92% (458/500) of the sample size matching pre-existing shared types. Of the 62 shared types, eight families were predominant (clustering from 16 to 132), representing 64% (340/500) of the sample. The Beijing family (135/500) predominated (P < 0.001). CONCLUSION: TB incidence in Johannesburg does not appear to be due to clonality, but is rather due to diverse circulating strains, namely the Beijing family, followed by the S, Latin American Mediterranean and T families. PMID- 26056112 TI - Relationship of HLA-DRB1 gene polymorphism with susceptibility to pulmonary tuberculosis: updated meta-analysis. AB - BACKGROUND: Studies indicate that human leukocyte antigen (HLA) gene polymorphisms are implicated in the risk of pulmonary tuberculosis (PTB). However, research findings are contradictory. OBJECTIVE: To examine the association between HLA-DRB1 alleles and PTB risk using a meta-analysis on case control studies. METHODS: We searched for relevant studies in the PubMed and EMBASE databases. We used fixed-effects or random-effects models and reported combined odds ratios (ORs) and 95% confidence intervals (CI). The Newcastle Ottawa Scale (NOS) was used to estimate the quality of each case-control study. RESULTS: A total of 21 individual case-control studies were identified, including studies of 14 family alleles and 28 specific alleles. Compared with controls, DRB1*15 and DRB1*08:03 were found to have significantly higher frequencies in PTB patients; however, DRB1*03, DRB1*11, DRB1*11:03 and DRB1*12:02 had significantly lower frequencies in the total population. The association between other HLA-DRB1 family alleles and specific alleles and predisposition to PTB was not statistically significant. Among Asian populations, DRB1*03 and DRB1*07:01 were associated with a reduced incidence of PTB, while DRB1*15 and DRB1*08:03 were associated with an increased incidence of PTB. CONCLUSION: We conclude that HLA DRB1 may be a valuable marker to predict the risk for PTB, especially in Asian populations. PMID- 26056113 TI - Multidrug-resistant tuberculosis in New South Wales, Australia, 1999-2010: a case series report. AB - SETTING: The emergence of multidrug-resistant tuberculosis (MDR-TB) threatens the ongoing control of tuberculosis (TB). The Australian state of New South Wales (NSW) has low TB and MDR-TB incidence. OBJECTIVE: To examine the epidemiology and the clinical and public health management of MDR-TB in NSW. DESIGN: A retrospective case-series analysis of MDR-TB diagnosed in NSW between 1999 and 2010 was undertaken. A standardised questionnaire was used to collect information from the public health surveillance system, medical records and the State Mycobacterium Reference Laboratory about clinical features, drug susceptibility, treatment regimens, hospitalisation, risk factors for tuberculous infection, contact tracing and patient outcomes. RESULTS: Fifty-five cases of culture confirmed MDR-TB, including two cases of extensively drug-resistant TB, were diagnosed. All cases were reviewed by an expert management panel. Fifty cases (91%) were foreign-born, and 50 cases (91%) had fully supervised treatment. Of the 55 cases, 46 (84%) successfully completed treatment, 3 (5%) died of TB and 3 (5%) required surgery. No MDR-TB cases were reported among contacts. CONCLUSION: Using a multidisciplinary, expert guided, case-management approach, the NSW TB Control Program achieved excellent MDR-TB outcomes. The impact of global increases in MDR-TB requires sustained commitment to TB in all settings. PMID- 26056114 TI - Cost-effectiveness of tobacco cessation support combined with tuberculosis screening among contacts who smoke. AB - SETTING: Tobacco smoking is associated with significantly increased risks of latent tuberculous infection, active tuberculosis (TB), TB recurrence and mortality. Tobacco cessation interventions not only increase health benefits, they also reduce the risk of TB. OBJECTIVE: To assess the cost-effectiveness of nicotine replacement therapy (NRT) combined with TB screening strategies using interferon-gamma release assays (IGRAs; QuantiFERON((r))-TB Gold In-Tube [QFT] and T-SPOT((r)).TB [T-SPOT]) and comparing these with the tuberculin skin test (TST) among TB contacts who smoke. DESIGN: Decision trees and Markov models were constructed from a public health perspective. The target population was a hypothetical cohort of 20-year-old contacts who smoke until the age of 70 years, with or without NRT. The main outcome measure of effectiveness was quality adjusted life-years (QALYs). The incremental cost-effectiveness ratio was compared. RESULTS: QFT alone led to lower costs but fewer QALYs. TST alone and TST+NRT were absolutely dominated. IGRAs+NRT yielded greater benefits than IGRAs alone, and T-SPOT+NRT yielded the greatest benefits. Cost-effectiveness was sensitive to NRT effectiveness and rate of mortality reduction using NRT. CONCLUSION: TB screening using an IGRA combined with NRT is more cost-effective among contacts who smoke. Positive smoking cessation interventions are recommended for their cost-effectiveness in low-incidence countries. PMID- 26056115 TI - Asthma and COPD overlap syndrome is associated with increased risk of hospitalisation. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with poor prognosis and a high health care burden. The incidence of asthma and COPD overlap syndrome is increasing, and contributes to a high financial burden and poor prognosis. OBJECTIVE: To investigate clinical features of the overlap syndrome among Asian patients and to analyse its impact on hospitalisation due to respiratory problems or death compared to COPD alone. DESIGN: We performed a retrospective cohort analysis of 2933 COPD patients presenting at the Asan Medical Center from 1 January 2000 to 31 December 2009. Kaplan-Meier and Cox proportional hazard models were used to analyse the significance of clinical parameters, including age, sex, smoking history, body mass index (BMI), severity of airflow limitation, airway obstruction reversibility and overlap syndrome with hospitalisation due to respiratory problems or death. RESULTS: Overlap syndrome patients were older, included smaller proportions of males and of smokers and had lower forced expiratory volume in 1 s (FEV1) (% predicted). Shorter hospitalisation-free and survival periods were noted among overlap syndrome patients. Overlap syndrome was significantly associated with risk of hospitalisation due to respiratory problems after adjusting for age, smoking history, BMI, FEV1 (% predicted) and changes in FEV1 (P < 0.001). CONCLUSION: Asthma and COPD overlap syndrome is associated with a higher risk of hospitalisation due to respiratory problems than COPD alone. PMID- 26056116 TI - Fixed-dose combination drugs for the treatment of tuberculosis under India's RNTCP. PMID- 26056117 TI - Xpert((r)) MTB/RIF and very low positive detection in bronchoalveolar lavage: diagnostic concerns. PMID- 26056118 TI - Immune reconstitution inflammatory syndrome after BCG infection mimicking miliary tuberculosis. PMID- 26056119 TI - Efficacy and safety of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at week 97 (SUMMACTA). AB - OBJECTIVES: To evaluate the long-term efficacy and safety of subcutaneous (SC) tocilizumab (TCZ) versus intravenous (IV) TCZ, including switching formulations, in patients with rheumatoid arthritis (RA) and inadequate response to disease modifying antirheumatic drugs (DMARDs). METHODS: Patients (n=1262) were randomised 1:1 to receive TCZ-SC 162 mg weekly (qw)+placebo-IV every four weeks (q4w) or TCZ-IV 8 mg/kg q4w+placebo-SC qw in combination with DMARD(s). After a 24-week double-blind period, patients receiving TCZ-SC were re-randomised 11:1 to TCZ-SC (n=521) or TCZ-IV (TCZ-SC-IV, n=48), and patients receiving TCZ-IV were re randomised 2:1 to TCZ-IV (n=372) or TCZ-SC (TCZ-IV-SC; n=186). Maintenance of clinical responses and safety through week 97 were assessed. RESULTS: The proportions of patients who achieved American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score in 28 joints remission and improvement from baseline in Health Assessment Questionnaire Disability Index >=0.3 were sustained through week 97 and comparable across arms. TCZ-SC had a comparable safety profile to TCZ-IV through week 97, except that injection site reactions (ISRs) were more common with TCZ-SC. Safety profiles in patients who switched were similar to those in patients who received continuous TCZ-SC or TCZ IV treatment. The proportion of patients who developed anti-TCZ antibodies remained low across treatment arms. No association between anti-TCZ antibody development and clinical response or adverse events was observed. CONCLUSIONS: The long-term efficacy and safety of TCZ-SC was maintained and comparable to that of TCZ-IV, except for ISRs. Profiles in patients who switched formulations were comparable to those in patients who received TCZ-IV or TCZ-SC. TCZ-SC provides additional treatment options for patients with RA. TRIAL REGISTRATION NUMBER: NCT01194414. PMID- 26056120 TI - The utility of Google Trends data to examine interest in cancer screening. AB - OBJECTIVES: We examined the utility of January 2004 to April 2014 Google Trends data from information searches for cancer screenings and preparations as a complement to population screening data, which are traditionally estimated through costly population-level surveys. SETTING: State-level data across the USA. PARTICIPANTS: Persons who searched for terms related to cancer screening using Google, and persons who participated in the Behavioral Risk Factor Surveillance System (BRFSS). PRIMARY AND SECONDARY OUTCOME MEASURES: (1) State level Google Trends data, providing relative search volume (RSV) data scaled to the highest search proportion per week (RSV100) for search terms over time since 2004 and across different geographical locations. (2) RSV of new screening tests, free/low-cost screening for breast and colorectal cancer, and new preparations for colonoscopy (Prepopik). (3) State-level breast, cervical, colorectal and prostate cancer screening rates. RESULTS: Correlations between Google Trends and BRFSS data ranged from 0.55 for ever having had a colonoscopy to 0.14 for having a Pap smear within the past 3 years. Free/low-cost mammography and colonoscopy showed higher RSV during their respective cancer awareness months. RSV for Miralax remained stable, while interest in Prepopik increased over time. RSV for lung cancer screening, virtual colonoscopy and three-dimensional mammography was low. CONCLUSIONS: Google Trends data provides enormous scientific possibilities, but are not a suitable substitute for, but may complement, traditional data collection and analysis about cancer screening and related interests. PMID- 26056121 TI - Cost-effectiveness of nurse practitioners in primary and specialised ambulatory care: systematic review. AB - OBJECTIVE: To determine the cost-effectiveness of nurse practitioners delivering primary and specialised ambulatory care. DESIGN: A systematic review of randomised controlled trials reported since 1980. DATA SOURCES: 10 electronic bibliographic databases, handsearches, contact with authors, bibliographies and websites. INCLUDED STUDIES: Randomised controlled trials that evaluated nurse practitioners in alternative and complementary ambulatory care roles and reported health system outcomes. RESULTS: 11 trials were included. In four trials of alternative provider ambulatory primary care roles, nurse practitioners were equivalent to physicians in all but seven patient outcomes favouring nurse practitioner care and in all but four health system outcomes, one favouring nurse practitioner care and three favouring physician care. In a meta-analysis of two studies (2689 patients) with minimal heterogeneity and high-quality evidence, nurse practitioner care resulted in lower mean health services costs per consultation (mean difference: -?6.41; 95% CI -?9.28 to -?3.55; p<0.0001) (2006 euros). In two trials of alternative provider specialised ambulatory care roles, nurse practitioners were equivalent to physicians in all but three patient outcomes and one health system outcome favouring nurse practitioner care. In five trials of complementary provider specialised ambulatory care roles, 16 patient/provider outcomes favouring nurse practitioner plus usual care, and 16 were equivalent. Two health system outcomes favoured nurse practitioner plus usual care, four favoured usual care and 14 were equivalent. Four studies of complementary specialised ambulatory care compared costs, but only one assessed costs and outcomes jointly. CONCLUSIONS: Nurse practitioners in alternative provider ambulatory primary care roles have equivalent or better patient outcomes than comparators and are potentially cost-saving. Evidence for their cost effectiveness in alternative provider specialised ambulatory care roles is promising, but limited by the few studies. While some evidence indicates nurse practitioners in complementary specialised ambulatory care roles improve patient outcomes, their cost-effectiveness requires further study. PMID- 26056122 TI - Are family, neighbourhood and school social capital associated with higher self rated health among Croatian high school students? A population-based study. AB - OBJECTIVES: We investigated the associations between self-rated health and social capital among Croatian high school students. DESIGN: A cross-sectional survey among high school students was carried out in the 2013-2014 school year. SETTING: High schools in Croatia. PARTICIPANTS: Subjects were 3427 high school students (1688 males and 1739 females), aged 17-18 years. MAIN OUTCOME MEASURE: Self-rated health was assessed by the single item: "How do you perceive your health?". Possible responses were arranged along a five-item Likert-type scale: 1 very poor, 2 poor, 3 fair, 4 good, 5 excellent. The outcome was binarised as 'good health' (excellent, good or fair) versus 'poor health' (poor or very poor). METHODS: We calculated ORs and 95% CIs for good self-rated health associated with family, neighbourhood and school social capital, while adjusting for gender, self perceived socioeconomic status, psychological distress, physical activity and body mass index. We used generalised estimating equations using an exchangeable correlation matrix with robust SEs. RESULTS: Good self-rated health was significantly associated with higher family social capital (OR 2.43; 95% CI 1.55 to 3.80), higher neighbourhood trust (OR 2.02; 95% CI 1.48 to 2.76) and higher norms of reciprocity at school (OR 1.79; 95% CI 1.13 to 2.84). When all of the social capital variables were entered simultaneously, good self-rated health remained significantly associated with higher family social capital (OR 1.98; 95% CI 1.19 to 3.30), neighbourhood trust (OR 1.77; 95% CI 1.25 to 2.51) and reciprocity at school (OR 1.71; 95% CI 1.08 to 2.73). CONCLUSIONS: Higher levels of social capital were independently associated with higher self-rated health among youth. Intervention and policies that leverage community social capital might serve as an avenue for health promotion in youth. PMID- 26056123 TI - Scoping review of physical rehabilitation interventions in long-term care: protocol for tools, models of delivery, outcomes and quality indicators. AB - INTRODUCTION: A growing number of medically complex older adults reside in long term care (LTC) and often require physical rehabilitation (PR). While PR is effective at maintaining or improving a patient's physical function, the breadth of PR interventions evaluated in LTC, which outcomes or quality indicators (QI) can be used to evaluate PR, and what tools or models can be used to determine eligibility for PR services remain unknown. METHODS AND ANALYSIS: A scoping review will be conducted to address the following research questions: (1) What types of PR have been evaluated for efficacy or effectiveness in LTC? (2) Which outcomes or QIs have been used when evaluating PR interventions in LTC, and how can this inform evaluation of PR using existing QIs in the Canadian context? (3) What tools or models exist or have been validated for decision-making in the allocation of PR resources in LTC? We will conduct a comprehensive literature search in MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, Physiotherapy Evidence Database (PEDro) and Occupational Therapy Systematic Evaluation of Evidence database (OTseeker) and a structured grey literature search. Two team members will screen articles and abstract the data. The results will be displayed according to the research question they address. Data abstracted regarding outcomes and QIs will be mapped onto existing, publicly reported QIs used in Ontario, Canada. ETHICS AND DISSEMINATION: The scoping review will synthesise the characteristics of PR interventions described in the literature, the outcomes used to evaluate them and tools to determine eligibility for services. The review will be the first step in formally identifying what outcomes and QIs have been used to evaluate PR in LTC, and will be used to inform a stakeholder consensus process exploring the same question. The scoping review may also identify knowledge gaps. The results will be disseminated via publication and presentation at conferences, in addition to a 1-day stakeholder meeting. PMID- 26056124 TI - UNderstanding uptake of Immunisations in TravellIng aNd Gypsy communities (UNITING): protocol for an exploratory, qualitative study. AB - INTRODUCTION: Gypsies, Travellers and Roma (referred to here as Travellers) experience significantly poorer health and have shorter life expectancy than the general population. They are also less likely to access health services including immunisation. To improve immunisation rates, we need to understand what helps and hinders individuals in these communities in taking up immunisations. This study has two aims: (1) Investigate the barriers and facilitators to acceptability and uptake of immunisations among six Traveller communities in the UK; (2) Identify potential interventions to increase uptake in these Traveller communities. METHODS AND ANALYSIS: A three-phase qualitative study with six Traveller communities. PHASE 1: In each community, we will explore up to 45 Travellers' views about the influences on their immunisation behaviours and ideas for improving uptake in their community. PHASE 2: In each community, we will investigate 6-8 service providers' perspectives on barriers and facilitators to childhood and adult immunisations for Traveller communities with whom they work, and ideas to improve uptake. Interview data will be analysed using the Framework approach. PHASE 3: The findings will be discussed and interventions prioritised in six workshops, each with 10-12 phase 1 and 3-4 phase 2 participants. ETHICS AND DISSEMINATION: This research received approval from NRES Committee Yorkshire and The Humber-Leeds East (Ref. 13/YH/02). It will produce (1) findings on the barriers and facilitators to uptake of immunisations in six Traveller communities; (2) a prioritised list of potentially feasible and acceptable interventions for increasing uptake in these communities; and (3) methodological development in undertaking research with diverse Traveller communities. The study has the potential to inform new ways of delivering services to ensure high immunisation uptake. Findings will be disseminated to participants, relevant UK organisations with responsibility for the implementation of immunisation policy and Traveller health/welfare; and submitted for publication in academic journals. TRIAL REGISTRATION NUMBER: ISRCTN20019630. PMID- 26056126 TI - Multi-modal imaging support in a staging percutaneous pulmonary valve implantation. PMID- 26056127 TI - Established methodological issues in electronic nose research: how far are we from using these instruments in clinical settings of breath analysis? AB - Electronic noses (e-noses) represent an easy and cheap method for exhaled volatile compound analysis. Various electronic noses are available which differ in material and thus analytical performance. In this review, we describe a wide range of electronic noses and summarize data on the methodological issues in electronic nose research. We also review studies which show the ability of electronic noses to distinguish pulmonary and extrapulmonary disorders from health. PMID- 26056125 TI - Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: the STOP-HF randomized Phase II trial. AB - BACKGROUND: Stromal cell-derived factor-1 (SDF-1) promotes tissue repair through mechanisms of cell survival, endogenous stem cell recruitment, and vasculogenesis. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure (STOP-HF) is a Phase II, double-blind, randomized, placebo controlled trial to evaluate safety and efficacy of a single treatment of plasmid stromal cell-derived factor-1 (pSDF-1) delivered via endomyocardial injection to patients with ischaemic heart failure (IHF). METHODS: Ninety-three subjects with IHF on stable guideline-based medical therapy and left ventricular ejection fraction (LVEF) <=40%, completed Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and 6-min walk distance (6 MWD), were randomized 1 : 1 : 1 to receive a single treatment of either a 15 or 30 mg dose of pSDF-1 or placebo via endomyocardial injections. Safety and efficacy parameters were assessed at 4 and 12 months after injection. Left ventricular functional and structural measures were assessed by contrast echocardiography and quantified by a blinded independent core laboratory. Stromal Cell-Derived Factor-1 Plasmid Treatment for Patients with Heart Failure was powered based on change in 6 MWD and MLWHFQ at 4 months. RESULTS: Subject profiles at baseline were (mean +/- SD): age 65 +/- 9 years, LVEF 28 +/- 7%, left ventricular end-systolic volume (LVESV) 167 +/- 66 mL, N-terminal pro brain natriuretic peptide (BNP) (NTproBNP) 1120 +/- 1084 pg/mL, MLWHFQ 50 +/- 20 points, and 6 MWD 289 +/- 99 m. Patients were 11 +/- 9 years post most recent myocardial infarction. Study injections were delivered without serious adverse events in all subjects. Sixty-two patients received drug with no unanticipated serious product-related adverse events. The primary endpoint was a composite of change in 6 MWD and MLWHFQ from baseline to 4 months follow-up. The primary endpoint was not met (P = 0.89). For the patients treated with pSDF-1, there was a trend toward an improvement in LVEF at 12 months (placebo vs. 15 mg vs. 30 mg DeltaLVEF: -2 vs. -0.5 vs. 1.5%, P = 0.20). A pre specified analysis of the effects of pSDF-1 based on tertiles of LVEF at entry revealed improvements in EF and LVESV from lowest-to-highest LVEF. Patients in the first tertile of EF (<26%) that received 30 mg of pSDF-1 demonstrated a 7% increase in EF compared with a 4% decrease in placebo (DeltaLVEF = 11%, P = 0.01) at 12 months. There was also a trend towards improvement in LVESV, with treated patients demonstrating an 18.5 mL decrease compared with a 15 mL increase for placebo at 12 months (DeltaLVESV = 33.5 mL, P = 0.12). The change in end diastolic and end-systolic volume equated to a 14 mL increase in stroke volume in the patients treated with 30 mg of pSDF-1 compared with a decrease of -11 mL in the placebo group (DeltaSV = 25 mL, P = 0.09). In addition, the 30 mg-treated cohort exhibited a trend towards improvement in NTproBNP compared with placebo at 12 months (-784 pg/mL, P = 0.23). CONCLUSIONS: The blinded placebo-controlled STOP-HF trial demonstrated the safety of a single endocardial administration of pSDF-1 but failed to demonstrate its primary endpoint of improved composite score at 4 months after treatment. Through a pre-specified analysis the STOP-HF trial demonstrates the potential for attenuating LV remodelling and improving EF in high-risk ischaemic cardiomyopathy. The safety profile supports repeat dosing with pSDF-1 and the degree of left ventricular remodelling suggests the potential for improved outcomes in larger future trials. PMID- 26056128 TI - Outcomes and complications after percutaneous release for trigger digits in diabetic and non-diabetic patients. AB - We compared the short-term (3 months) and long-term (2 years) outcomes and complications of percutaneous release of 187 trigger digits of 154 patients treated between 2009 and 2012, all treated by a single surgeon. The 154 patients included 48 patients with diabetes mellitus and 106 non-diabetic patients. The only short-term complication was pain, occurring in three digits (5%) in the diabetic patients and six digits (5%) in the non-diabetic patients. The long-term complications were pain in 15 digits (25%) in the diabetic patients and 18 digits (14%) in the non-diabetic patients. This was not significant (p = 0.058). Recurrent triggering occurred in nine digits (15%) in the diabetic patients, which was significantly greater than the six digits (5%) in the non-diabetic patients (p = 0.013). The non-diabetic patients were significantly more satisfied. LEVEL OF EVIDENCE: level III. PMID- 26056129 TI - Treatment of fracture subluxations of the proximal interphalangeal joint using a ligamentotaxis device: a multidisciplinary approach. AB - Complex fracture subluxations of the proximal interphalangeal joint are often difficult to treat and their outcome variable. A number of methods for treatment of these injuries have been described. We have used a ligamentotaxis device (Ligamentotaxor, Arex, Palaiseau Cedex, France) since 2008. We performed 28 operations in 28 patients with complex proximal interphalangeal joint injuries over a 3-year period. Patients followed a standardized postoperative rehabilitation regime, including fixator adjustment as necessary. The mean age was 33 years (range 18-67). The mean time to surgery was 7 days. At final follow up (mean 22 months, range 6-52) the mean proximal interphalangeal joint range of motion was 85 degrees (range 60 degrees -110 degrees ). The mean QuickDASH functional outcome score was 4.8 (range 0-36.4). Our results compare favourably with other devices reported in the literature. PMID- 26056130 TI - Decreased eIF3e Expression Can Mediate Epithelial-to-Mesenchymal Transition through Activation of the TGFbeta Signaling Pathway. AB - The eIF3e protein is a component of the multisubunit eIF3 complex, which is essential for cap-dependent translation initiation. Decreased eIF3e expression is often observed in breast and lung cancer and has been shown to induce epithelial to-mesenchymal transition (EMT) in breast epithelial cells by an unknown mechanism. Here, we study the effect of decreased eIF3e expression in lung epithelial cells by creating stable clones of lung epithelial cells (A549) that express an eIF3e-targeting shRNA. Our data indicate that decreased eIF3e expression in lung epithelial cells leads to EMT, as it does in breast epithelial cells. Importantly, we show that decreased eIF3e expression in both lung and breast epithelial cells leads to the overproduction of the TGFbeta cytokine and that inhibition of TGFbeta signaling can reverse eIF3e-regulated EMT in lung epithelial cells. In addition, we discovered that several mRNAs that encode important EMT regulators are translated by a cap-independent mechanism when eIF3e levels are reduced. These findings indicate that EMT mediated by a decrease in eIF3e expression may be a general phenomenon in epithelial cells and that it requires activation and maintenance of the TGFbeta signaling pathway. IMPLICATIONS: These results indicate that inhibition of TGFbeta signaling could be an efficient way to prevent metastasis in patients with NSCLC that display reduced eIF3e expression. PMID- 26056132 TI - Understanding Resistance to Cancer Immunotherapy. PMID- 26056131 TI - Polychlorinated biphenyls: New evidence from the last decade. AB - Millions of pounds of polychlorinated biphenyl (PCB) compounds have been produced in multiple countries for industrial applications over the last several decades. PCB exposure induces various adverse health effects in animals and humans. Environmental and occupational exposures to PCBs have been associated with liver, kidney, endocrine, and neurodevelopmental adverse effects. We have collected and reviewed animal and human data cited in the US National Library of Medicine from 2000 to 2010. In brief, our review shows new evidence, that is, in animal studies, exposure to one of the PCBs, A1221, induces a significant alteration of serum luteinizing hormone. The effects were more profound in the F2 generation, particularly with respect to fluctuations in hormones and reproductive tract tissues across the estrous cycle. Morphological analyses of brain tissue from rats exposed to A1254 confirmed the results of an earlier work which showed that the relative size of the intra- and infrapyramidal (II-P) mossy fibers was smaller than that in the controls and also reduction in growth was selective for the II-P mossy fibers. PCB exposure increased anogenital distance and prostate size but decreased epididymal weight, epididymal sperm count, and motile epididymal sperm count. No effects were observed on testicular weight or size. The epidemiological data showed an association between diabetes mellitus prevalence and elevated concentrations of PCB 153. Additionally, prenatal PCB exposure studies were associated with a smaller thymic index at birth and could adversely affect immune responses to childhood vaccinations and resistance to respiratory infections. PCB exposure was also reported to adversely affect enamel development in children in a dose-dependent manner. Because PCBs and their metabolites are potential health hazards, understanding the risk factors associated with individual PCBs, PCB mixtures, and PCB metabolites is important. PCB exposures of vulnerable populations (pregnant women, fetuses, infants, and children) are of particular concern because of heightened sensitivity during this period of brain development. PMID- 26056133 TI - Leaf economics of evergreen and deciduous tree species along an elevational gradient in a subtropical mountain. AB - The ecophysiological mechanisms underlying the pattern of bimodal elevational distribution of evergreen tree species remain incompletely understood. Here we used leaf economics spectrum (LES) theory to explain such patterns. We measured leaf economic traits and constructed an LES for the co-existing 19 evergreen and 15 deciduous species growing in evergreen broad-leaved forest at low elevation, beech-mixed forest at middle elevation and hemlock-mixed forest at high elevation in Mao'er Mountain, Guangxi, Southern China (25 degrees 50'N, 110 degrees 49'E). Leaf economic traits presented low but significant phylogenetic signal, suggesting trait similarity between closely related species. After considering the effects of phylogenetic history, deciduous species in general showed a more acquisitive leaf strategy with a higher ratio of leaf water to dry mass, higher leaf nitrogen and phosphorous contents, higher photosynthetic and respiratory rates and greater photosynthetic nitrogen-use efficiency. In contrast, evergreen species exhibited a more conservative leaf strategy with higher leaf mass per area, greater construction costs and longer leaf life span. With the elevation induced decreases of temperature and soil fertility, both evergreen and deciduous species showed greater resource conservation, suggesting the increasing importance of environmental filtering to community assembly with increasing elevation. We found close inter-specific correlations between leaf economic traits, suggesting that there are strong genetic constraints limiting the independent evolution of LES traits. Phylogenetic signal increased with decreasing evolutionary rate across leaf economic traits, suggesting that genetic constraints are important for the process of trait evolution. We found a significantly positive relationship between primary axis species score (PASS) distance and phylogenetic distance across species pairs and an increasing average PASS distance between evergreen and deciduous species with increasing elevation, implying that the frequency of distantly related evergreen and deciduous pairs with wide spreading of leaf economic values increases with increasing elevation. Our findings thus suggest that elevation acts as an environmental filter to both select the locally adapted evergreen and deciduous species with sufficient phylogenetic variation and regulate their distribution along the elevational gradient based on their coordinated spreading of phylogenetic divergence and leaf economic variation. PMID- 26056135 TI - Junjie Hu: Shape-shifting in the endoplasmic reticulum. PMID- 26056134 TI - Prognostic value of left ventricular global function index in patients after ST segment elevation myocardial infarction. AB - AIMS: The left ventricular global function index (LVGFI) is a novel indicator of left ventricular performance. Its prognostic value in patients after ST-segment elevation myocardial infarction (STEMI) is unknown. We sought to evaluate the prognostic significance of LVGFI measured by cardiovascular magnetic resonance (CMR) imaging after STEMI. METHODS AND RESULTS: Two hundred eligible STEMI patients (56 +/- 11 years, 16% female) revascularized by primary percutaneous coronary intervention were followed-up for 3.1 [2-4.1] years for major adverse cardiac events (MACE). MACE was defined as a composite of death, non-fatal myocardial re-infarction, and new congestive heart failure. All patients underwent CMR imaging within 2 [2-4] days after STEMI. Late enhancement and cine images were acquired to assess myocardial injury as well as myocardial function, including LVGFI. Patients suffering a MACE event (n = 20, 10%) had a significantly lower LVGFI (P = 0.001). In Kaplan-Meier analysis, a decreased LVGFI was associated with a reduced MACE-free survival (P < 0.001). Multivariate Cox regression analysis revealed a decreased LVGFI as a predictor for MACE [hazard ratio = 4.79, 95% confidence interval (CI) 1.46-15.67, P = 0.010] after adjusting for microvascular obstruction, left ventricular mass, and multivessel disease. In receiver operating characteristic analysis, LVGFI was a strong predictor for MACE (area under the curve = 0.73, CI 0.61-0.85). However, c statistics revealed that LVGFI does not provide incremental prognostic information over left ventricular ejection fraction (LVEF) (P = 0.38). CONCLUSION: LVGFI assessed by CMR is a strong predictor of MACE within 3 years after first STEMI. A superior predictive value as compared with LVEF was not found in this study. PMID- 26056136 TI - Cell biology: More than skin deep. AB - In studying how stem cells make and maintain tissues, nearly every chapter of a cell biology textbook is of interest. The field even allows us to venture where no chapters have yet been written. In studying this basic problem, we are continually bombarded by nature's surprises and challenges. PMID- 26056137 TI - Nanobodies and recombinant binders in cell biology. AB - Antibodies are key reagents to investigate cellular processes. The development of recombinant antibodies and binders derived from natural protein scaffolds has expanded traditional applications, such as immunofluorescence, binding arrays, and immunoprecipitation. In addition, their small size and high stability in ectopic environments have enabled their use in all areas of cell research, including structural biology, advanced microscopy, and intracellular expression. Understanding these novel reagents as genetic modules that can be integrated into cellular pathways opens up a broad experimental spectrum to monitor and manipulate cellular processes. PMID- 26056138 TI - KCC2 regulates actin dynamics in dendritic spines via interaction with beta-PIX. AB - Chloride extrusion in mature neurons is largely mediated by the neuron-specific potassium-chloride cotransporter KCC2. In addition, independently of its chloride transport function, KCC2 regulates the development and morphology of dendritic spines through structural interactions with the actin cytoskeleton. The mechanism of this effect remains largely unknown. In this paper, we show a novel pathway for KCC2-mediated regulation of the actin cytoskeleton in neurons. We found that KCC2, through interaction with the b isoform of Rac/Cdc42 guanine nucleotide exchange factor beta-PIX, regulates the activity of Rac1 GTPase and the phosphorylation of one of the major actin-regulating proteins, cofilin-1. KCC2 deficient neurons had abnormally high levels of phosphorylated cofilin-1. Consistently, dendritic spines of these neurons exhibited a large pool of stable actin, resulting in reduced spine motility and diminished density of functional synapses. In conclusion, we describe a novel signaling pathway that couples KCC2 to the cytoskeleton and regulates the formation of glutamatergic synapses. PMID- 26056139 TI - Diffusion and retention are major determinants of protein targeting to the inner nuclear membrane. AB - Newly synthesized membrane proteins are constantly sorted from the endoplasmic reticulum (ER) to various membranous compartments. How proteins specifically enrich at the inner nuclear membrane (INM) is not well understood. We have established a visual in vitro assay to measure kinetics and investigate requirements of protein targeting to the INM. Using human LBR, SUN2, and LAP2beta as model substrates, we show that INM targeting is energy-dependent but distinct from import of soluble cargo. Accumulation of proteins at the INM relies on both a highly interconnected ER network, which is affected by energy depletion, and an efficient immobilization step at the INM. Nucleoporin depletions suggest that translocation through nuclear pore complexes (NPCs) is rate-limiting and restricted by the central NPC scaffold. Our experimental data combined with mathematical modeling support a diffusion-retention-based mechanism of INM targeting. We experimentally confirmed the sufficiency of diffusion and retention using an artificial reporter lacking natural sorting signals that recapitulates the energy dependence of the process in vivo. PMID- 26056140 TI - Live imaging and modeling of inner nuclear membrane targeting reveals its molecular requirements in mammalian cells. AB - Targeting of inner nuclear membrane (INM) proteins is essential for nuclear architecture and function, yet its mechanism remains poorly understood. Here, we established a new reporter that allows real-time imaging of membrane protein transport from the ER to the INM using Lamin B receptor and Lap2beta as model INM proteins. These reporters allowed us to characterize the kinetics of INM targeting and establish a mathematical model of this process and enabled us to probe its molecular requirements in an RNA interference screen of 96 candidate genes. Modeling of the phenotypes of genes involved in transport of these INM proteins predicted that it critically depended on the number and permeability of nuclear pores and the availability of nuclear binding sites, but was unaffected by depletion of most transport receptors. These predictions were confirmed with targeted validation experiments on the functional requirements of nucleoporins and nuclear lamins. Collectively, our data support a diffusion retention model of INM protein transport in mammalian cells. PMID- 26056141 TI - Erbin is a novel substrate of the Sag-betaTrCP E3 ligase that regulates KrasG12D induced skin tumorigenesis. AB - SAG/RBX2 is the RING (really interesting new gene) component of Cullin-RING ligase, which is required for its activity. An organ-specific role of SAG in tumorigenesis is unknown. We recently showed that Sag/Rbx2, upon lung-targeted deletion, suppressed Kras(G12D)-induced tumorigenesis via inactivating NF-kappaB and mammalian target of rapamycin pathways. In contrast, we report here that, upon skin-targeted deletion, Sag significantly accelerated Kras(G12D)-induced papillomagenesis. In Kras(G12D)-expressing primary keratinocytes, Sag deletion promotes proliferation by inhibiting autophagy and senescence, by inactivating the Ras-Erk pathway, and by blocking reactive oxygen species (ROS) generation. This is achieved by accumulation of Erbin to block Ras activation of Raf and Nrf2 to scavenge ROS and can be rescued by knockdown of Nrf2 or Erbin. Simultaneous one-allele deletion of the Erbin-encoding gene Erbb2ip partially rescued the phenotypes. Finally, we characterized Erbin as a novel substrate of SAG-betaTrCP E3 ligase. By degrading Erbin and Nrf2, Sag activates the Ras-Raf pathway and causes ROS accumulation to trigger autophagy and senescence, eventually delaying Kras(G12D)-induced papillomagenesis and thus acting as a skin-specific tumor suppressor. PMID- 26056142 TI - Secreted HHIP1 interacts with heparan sulfate and regulates Hedgehog ligand localization and function. AB - Vertebrate Hedgehog (HH) signaling is controlled by several ligand-binding antagonists including Patched-1 (PTCH1), PTCH2, and HH-interacting protein 1 (HHIP1), whose collective action is essential for proper HH pathway activity. However, the molecular mechanisms used by these inhibitors remain poorly understood. In this paper, we investigated the mechanisms underlying HHIP1 antagonism of HH signaling. Strikingly, we found evidence that HHIP1 non-cell autonomously inhibits HH-dependent neural progenitor patterning and proliferation. Furthermore, this non-cell-autonomous antagonism of HH signaling results from the secretion of HHIP1 that is modulated by cell type-specific interactions with heparan sulfate (HS). These interactions are mediated by an HS binding motif in the cysteine-rich domain of HHIP1 that is required for its localization to the neuroepithelial basement membrane (BM) to effectively antagonize HH pathway function. Our data also suggest that endogenous, secreted HHIP1 localization to HS-containing BMs regulates HH ligand distribution. Overall, the secreted activity of HHIP1 represents a novel mechanism to regulate HH ligand localization and function during embryogenesis. PMID- 26056144 TI - Asbestosis in a Japanese Macaque (Macaca fuscata). AB - Asbestosis is a chronic lung disease caused by inhalation of asbestos, a fibrous mineral. It is one of the most severe diseases resulting from environmental contamination. We found asbestosis in a female Japanese macaque over 25 years of age that died from senility. Clear needle-like crystals were deposited throughout the lung lobes, particularly in the perivascular areas. Asbestos bodies were observed in some of these crystals. Fibrosis without inflammation was observed in the periarterial and peribronchiolar regions. The crystals were identified as tremolite, and a total of 16,633,968 asbestos bodies and 465,334,411 tremolite fibers were observed in 1 g of dry lung tissue. No tumors or pleural adhesions were seen. This is the first report of spontaneous asbestosis in a nonhuman animal. PMID- 26056143 TI - Spatiotemporal dynamics of traction forces show three contraction centers in migratory neurons. AB - Traction force against the substrate is required for neuronal migration, but how it is generated and regulated remains controversial. Using traction force microscopy, we showed in cultured granule cells the coexistence of three distinct contraction centers (CCs) that are located at the distal and proximal regions of the leading process as well as at the trailing process, regions exhibiting high level myosin-II activities. The CC activities depended on myosin-II, actin filaments, and microtubules, as well as substrate adhesion, and exhibited apparently independent fluctuation. The difference of strain energies associated with CC activities between leading versus trailing processes tightly correlated with the displacement of the soma at any given time. Application of brain-derived neurotrophic factor (BDNF) and Slit2, factors known to guide neuronal migration, at the leading process altered CC activities by regulating the small GTPases Cdc42 and RhoA, respectively, leading to forward and rearward soma translocation. These results delineate the multiple origins and spatiotemporal dynamics of the traction force underlying neuronal migration. PMID- 26056145 TI - Decitabine Enhances Lymphocyte Migration and Function and Synergizes with CTLA-4 Blockade in a Murine Ovarian Cancer Model. AB - The lack of second-line treatment for relapsed ovarian cancer necessitates the development of improved combination therapies. Targeted therapy and immunotherapy each confer clinical benefit, albeit limited as monotherapies. Ovarian cancer is not particularly responsive to immune checkpoint blockade, so combination with a complementary therapy may be beneficial. Recent studies have revealed that a DNA methyl transferase inhibitor, azacytidine, alters expression of immunoregulatory genes in ovarian cancer. In this study, the antitumor effects of a related DNA methyl transferase inhibitor, decitabine (DAC), were demonstrated in a syngeneic murine ovarian cancer model. Low-dose DAC treatment increases the expression of chemokines that recruit NK cells and CD8(+) T cells, promotes their production of IFNgamma and TNFalpha, and extends the survival of mice bearing subcutaneous or orthotopic tumors. While neither DAC nor immune checkpoint blockade confers durable responses as a monotherapy in this model, the efficacy of anti-CTLA-4 was potentiated by combination with DAC. This combination promotes differentiation of naive T cells into effector T cells and prolongs cytotoxic lymphocyte responses as well as mouse survival. These results suggest that this combination therapy may be worthy of further consideration for improved treatment of drug-resistant ovarian cancer. PMID- 26056146 TI - Cumulative risks and cessation of exclusive breast feeding: Australian cross sectional survey. AB - OBJECTIVES: To estimate the prevalence of cessation of exclusive breast feeding at each month up to 6 months and document key factors and cumulative risks associated with exclusive breastfeeding cessation for children aged from 0 to 6 months. METHODS: Secondary analysis using a national representative sample of 22 202 mother and infant pairs derived from the 2010 Australian Institute of Health and Welfare cross-sectional survey, the Australian Infant Feeding Survey. RESULTS: Among breastfed infants, 49% had ceased exclusive breast feeding before they had reached 2 months of age. In the final Cox proportional hazards model, cessation of exclusive breast feeding was most strongly associated with partners preferring bottle feeding (HR 1.86, 95% CI 1.69 to 20.6) or having no preference (HR 1.37, 95% CI 1.33 to 1.42), regular dummy use (HR 1.35, 95% CI 1.31 to 1.39) and maternal obesity (HR 1.29, 95% CI 1.24 to 1.35). Living within the most disadvantaged areas of Australia (quintile 1) was not strongly associated with cessation (HR 1.08, 95% CI 1.02 to 1.14) compared with least disadvantaged areas. Having three risk factors significantly increased the risk of cessation by 31% (HR 1.31, 95% CI 1.07 to 1.6). CONCLUSIONS: The prevalence of early cessation of exclusive breast feeding is alarmingly high with 50% of infants no longer exclusively breast fed by age 2 months. Given that not one factor is associated with cessation of exclusive breast feeding, the greatest public health impact is likely to be achieved when multiple risk factors are modified or prevented. PMID- 26056147 TI - Fibrosis Progression in Paired Liver Biopsies from HIV/HCV-Coinfected Patients without Prior Treatment of Hepatitis C. AB - Several studies have demonstrated that HIV/hepatitis C virus (HCV)-coinfected patients experience more rapid fibrosis progression. In this study, to estimate the annual rate of direct liver fibrosis progression, we used analyses of paired biopsy samples from HIV/HCV-coinfected patients without prior treatment of hepatitis and assessed the possible association of fibrosis progression with certain clinical variables. We evaluated 30 HIV/HCV-coinfected patients, with no history of prior treatment of hepatitis C, who underwent paired liver biopsies. All patients were under antiretroviral therapy at first and second biopsies. The average annual progression rate was 0.13 fibrosis unit/year, with 36.7% of patients defined as progressors. Liver fibrosis progression was associated with alanine aminotransferase (ALT; P < .001) and aspartate aminotransferase (AST; P < .0340) levels over 3 times the upper limit of normal present at first biopsy. Elevated ALT and AST levels appear to be associated with more accelerated liver fibrosis progression among HIV/HCV-coinfected patients. PMID- 26056148 TI - Motivational Interviewing among HIV Health Care Providers: Challenges and Opportunities to Enhance Engagement and Retention in Care in Buenos Aires, Argentina. AB - In Argentina, providers' response to motivational interviewing (MI) to improve engagement and retention in care among challenging patients with HIV was evaluated. Twelve HIV care physicians participated, and their video recordings pre- and post-MI training were also obtained. One week post-training, 11 of the 12 participants were committed to using MI strategies during consult session. Of the 12 participants, 9 demonstrated appropriate utilization of MI techniques and change in HIV education provided during consultation (Z = -2.375, P = .018). Motivational interviewing appears to be a viable strategy to enhance engagement and retention in challenging HIV-positive patients. PMID- 26056149 TI - Peloruside A Inhibits Growth of Human Lung and Breast Tumor Xenografts in an Athymic nu/nu Mouse Model. AB - Peloruside A is a microtubule-stabilizing agent isolated from a New Zealand marine sponge. Peloruside prevents growth of a panel of cancer cell lines at low nanomolar concentrations, including cell lines that are resistant to paclitaxel. Three xenograft studies in athymic nu/nu mice were performed to assess the efficacy of peloruside compared with standard anticancer agents such as paclitaxel, docetaxel, and doxorubicin. The first study examined the effect of 5 and 10 mg/kg peloruside (QD*5) on the growth of H460 non-small cell lung cancer xenografts. Peloruside caused tumor growth inhibition (%TGI) of 84% and 95%, respectively, whereas standard treatments with paclitaxel (8 mg/kg, QD*5) and docetaxel (6.3 mg/kg, Q2D*3) were much less effective (%TGI of 50% and 18%, respectively). In a second xenograft study using A549 lung cancer cells and varied schedules of dosing, activity of peloruside was again superior compared with the taxanes with inhibitions ranging from 51% to 74%, compared with 44% and 50% for the two taxanes. A third xenograft study in a P-glycoprotein overexpressing NCI/ADR-RES breast tumor model showed that peloruside was better tolerated than either doxorubicin or paclitaxel. We conclude that peloruside is highly effective in preventing the growth of lung and P-glycoprotein overexpressing breast tumors in vivo and that further therapeutic development is warranted. Mol Cancer Ther; 14(8); 1816-23. (c)2015 AACR. PMID- 26056151 TI - Systematic review and meta-analysis of migration after endovascular abdominal aortic aneurysm repair. AB - AIM: To identify patients who are under higher threat for migration because of an old generation stent graft application. METHODS: A systematic review and meta analysis of the literature was undertaken to identify all studies which included older generation endografts and data reporting on graft migration after EVAR. Outcome data were pooled and combined, and were calculated using fixed or random effects models. RESULTS: From 2000 to 2014, 22 retrospective studies were identified reporting on stent- graft migration after EVAR (8.6%). From those patients, 39% received re-intervention with the mean time of identification ranging from 12 to 36 months. Six of these retrospective nonrandomized studies were eligible for meta-analysis. AAA diameter (AAA diameter: 0.719 mm; 95% confidence interval [CI]: 0.00065-1.4384 mm; p = 0.00497) and neck length (neck length: 4.36 mm; 95% CI: 1.3277-7.394; p = 0.0048) were the only significant factors associated with stent- graft migration. Neck diameter and neck angulation did not have any important influence on stent-graft migration. CONCLUSIONS: Patients with large AAA and short necks who were treated with older generation stent grafts such as AneurX and Talent are in higher risk for endograft migration than others. Stent- graft migration consists of an insidious and underestimated threat. PMID- 26056152 TI - Dora the Brave. PMID- 26056150 TI - NF-kappaB2/p52:c-Myc:hnRNPA1 Pathway Regulates Expression of Androgen Receptor Splice Variants and Enzalutamide Sensitivity in Prostate Cancer. AB - Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one of the principal mechanisms that promote the development of resistance to next-generation antiandrogens such as enzalutamide. Here, we demonstrate that the splicing factor heterogeneous nuclear RNA-binding protein A1 (hnRNPA1) plays a pivotal role in the generation of AR splice variants such as AR-V7. hnRNPA1 is overexpressed in prostate tumors compared with benign prostates, and its expression is regulated by NF-kappaB2/p52 and c-Myc. CRPC cells resistant to enzalutamide exhibit higher levels of NF-kappaB2/p52, c-Myc, hnRNPA1, and AR-V7. Levels of hnRNPA1 and AR-V7 are positively correlated with each other in prostate cancer. The regulatory circuit involving NF-kappaB2/p52, c-Myc, and hnRNPA1 plays a central role in the generation of AR splice variants. Downregulation of hnRNPA1 and consequently of AR-V7 resensitizes enzalutamide-resistant cells to enzalutamide, indicating that enhanced expression of hnRNPA1 may confer resistance to AR-targeted therapies by promoting the generation of splice variants. These findings may provide a rationale for cotargeting these pathways to achieve better efficacy through AR blockade. PMID- 26056154 TI - Correspondence Between Self-Report Measures and Clinician Assessments of Psychopathology in Female Intimate Partner Violence Survivors. AB - Intimate partner violence (IPV) has potentially severe and long-lasting mental health consequences for survivors, including elevated symptoms and diagnoses of posttraumatic stress disorder (PTSD), depression, and generalized anxiety disorder (GAD). The current study examined the relationship between three self report measures of psychological distress and ratings obtained from the corresponding clinician-administered measures in women seeking assessment for mental health problems following IPV ( N = 185). PTSD symptoms were assessed using the self-report Impact of Event Scale-Revised (IES-R) and the interview based Clinician-Administered PTSD Scale (CAPS). Depression symptoms were assessed using the self-report Beck Depression Inventory-II (BDI-II) and the depressive disorders sections from the clinician-administered Anxiety Disorders Interview Schedule-IV (ADIS-IV). Anxiety symptoms were assessed using the self-report Beck Anxiety Inventory (BAI) and the clinician-administered GAD section from the ADIS IV. Results indicated that psychological distress was prevalent in the sample, with 27% receiving a PTSD diagnosis, 40% diagnosed with a depressive disorder, and 55% meeting criteria for GAD. Although each self-report measure was significantly and positively correlated with its corresponding clinician administered measure, rates of diagnostic concordance were mixed. The BDI-II showed a high degree of agreement with the ADIS-IV depression section, but the IES-R and the CAPS were discordant at classifying PTSD. The BAI had acceptable sensitivity but poor specificity in relation to the ADIS-IV GAD section. These findings suggest that multiple assessment modalities should be considered when rating symptoms and estimating the prevalence of diagnoses among survivors of IPV. PMID- 26056153 TI - Structural basis for processivity and antiviral drug toxicity in human mitochondrial DNA replicase. AB - The human DNA polymerase gamma (Pol gamma) is responsible for DNA replication in mitochondria. Pol gamma is particularly susceptible to inhibition by dideoxynucleoside-based inhibitors designed to fight viral infection. Here, we report crystal structures of the replicating Pol gamma-DNA complex bound to either substrate or zalcitabine, an inhibitor used for HIV reverse transcriptase. The structures reveal that zalcitabine binds to the Pol gamma active site almost identically to the substrate dCTP, providing a structural basis for Pol gamma mediated drug toxicity. When compared to the apo form, Pol gamma undergoes intra- and inter-subunit conformational changes upon formation of the ternary complex with primer/template DNA and substrate. We also find that the accessory subunit Pol gammaB, which lacks intrinsic enzymatic activity and does not contact the primer/template DNA directly, serves as an allosteric regulator of holoenzyme activities. The structures presented here suggest a mechanism for processivity of the holoenzyme and provide a model for understanding the deleterious effects of Pol gamma mutations in human disease. Crystal structures of the mitochondrial DNA polymerase, Pol gamma, in complex with substrate or antiviral inhibitor zalcitabine provide a basis for understanding Pol gamma-mediated drug toxicity. PMID- 26056155 TI - Gastric Langerhans Cell Histiocytosis: Case Report and Review of the Literature. PMID- 26056156 TI - Are plasma cell-rich inflammatory conditions of the oral mucosa manifestations of IgG4-related disease? AB - AIM: The aim of this study was to characterise plasma cell infiltrates, in terms of IgG4 positivity, in specific and non-specific plasma cell-rich chronic inflammatory conditions of the oral mucosa. Exploring the possibility that specific plasma cell-rich oral inflammatory conditions have association with or represent an oral manifestation of immunoglobulin G4-related disease (IgG4-RD). METHODS: Ten patients with plasma cell-rich chronic inflammatory conditions of the oral mucosa were identified (seven--plasma cell mucositis and three--non specific diffuse oral mucosal inflammation with ulceration). For each patient, the clinical record and H&E-stained sections were reviewed. Immunohistochemistry for IgG and IgG4 antibodies was performed on sections from the corresponding paraffin block, permitting calculation of the mean number of IgG4+ plasma cells per high-power field (HPF) and the IgG4+/IgG+ plasma cell ratio. RESULTS: In all the cases, only one histological hallmark of IgG4-RD--a dense lymphoplasmacytic infiltrate--was seen. Review of the medical histories did not reveal any features representing other manifestations of IgG4-RD. The number of IgG4+ plasma cells exceeded 100 per HPF in half of the cases. Only two cases had an IgG4+/IgG+ plasma cell ratio of >40%; both of which were in the non-specific oral inflammatory group. CONCLUSIONS: Our study suggests that plasma cell mucositis does not meet microscopic criteria for IgG4-RD. It importantly reinforces the opinion that IgG4+ plasma cells are major components of chronic inflammation in the oral cavity and the pertinence of correct contextual interpretation of histopathological features with clinical findings. PMID- 26056157 TI - The use of whole-genome sequencing for molecular epidemiology and antimicrobial surveillance: identifying the role of IncX3 plasmids and the spread of blaNDM-4 like genes in the Enterobacteriaceae. AB - AIMS: To characterise the resistome of a multi-drug resistant Klebsiella pneumoniae (Kp0003) isolated from an Australian traveller who was repatriated to a Sydney Metropolitan Hospital from Myanmar with possible prosthetic aortic valve infective endocarditis. METHODS: Kp0003 was recovered from a blood culture of the patient and whole genome sequencing was performed. Read mapping and de novo assembly of reads facilitated in silico multi-locus sequence and plasmid replicon typing as well as the characterisation of antibiotic resistance genes and their genetic context. Conjugation experiments were also performed to assess the plasmid (and resistance gene) transferability and the effect on the antibiotic resistance phenotype. RESULTS: Importantly, and of particular concern, the carbapenem-hydrolysing beta-lactamase gene blaNDM-4 was identified on a conjugative IncX3 plasmid (pJEG027). In this respect, the blaNDM-4 genetic context is similar (at least to some extent) to what has previously been identified for blaNDM-1 and blaNDM-4-like variants. CONCLUSIONS: This study highlights the potential role that IncX3 plasmids have played in the emergence and dissemination of blaNDM-4-like variants worldwide and emphasises the importance of resistance gene surveillance. PMID- 26056158 TI - Associations of epithelial c-kit expression in phyllodes tumours of the breast. AB - BACKGROUND: Mammary phyllodes tumours (PT) are rare biphasic neoplasms but have important clinical significance. Both epithelial and stromal components participate in PT development. Despite a number of studies on stromal c-kit in PT, little is known about the role of its epithelial expression. OBJECTIVE: To further evaluate the stromal and epithelial expression of c-kit in a cohort of patients with PT. METHOD AND RESULTS: Expression of c-kit in both epithelial and stromal components was examined and correlated with histological features in PT. Stromal c-kit expression was associated positively with stromal cellularity (median expression=10.0, 30.0 and 50.0 from mild to severe cellularity; p=0.019). Conversely, a significant negative trend between epithelial c-kit expression with stromal pleomorphism (median expression=55.0, 30.0 and 2.5 from mild to severe pleomorphism; p=0.043) and mitosis (median expression=70.0 and 20.0 for low and high mitosis respectively; p=0.003); and a trend of negative correlation with increased PT grade was found. Despite these reverse associations, epithelial and stromal c-kit expressions were positively correlated with each other. Notably, the correlation of stromal c-kit expression with malignant histological features appeared to be stronger in cases with low epithelial c-kit expression but not in those with high epithelial c-kit expression. CONCLUSIONS: This study demonstrated the association of epithelial c-kit expression with stromal histological features and stromal c-kit. Interestingly, epithelial c-kit expression affected the strength of the correlation of stromal c-kit with these histological features. These findings provide further evidence of the interaction between the epithelial and stromal components in PT. PMID- 26056159 TI - Liver Autotransplantation in Pigs without Venovenous Bypass: A Simplified Model using a Supraceliac Aorta Cross-Clamping Maneuver. AB - BACKGROUND: The pig is an essential model for liver transplantation research and training. However, it develops hemodynamic instability during the anhepatic phase, requiring a short anhepatic phase or an extracorporeal circulation not appropriate for training purposes because it increases the risk of intraoperative complications. In this article we describe an economical and reproductive experimental model for training surgeon fellows in liver transplantation, without veno-venous bypass, using a supraceliac aortic cross-clamping maneuver. MATERIAL AND METHODS: After liver liberation, we cross-clamped the supraceliac aorta and cross-clamped and divided the infrahepatic inferior vena cava (IVC), bile duct (BD), hepatic artery (HA), portal vein (PV), and suprahepatic IVC. We rapidly removed and flushed the liver ex situ, repositioned it orthotopically, and performed anastomosis in suprahepatic IVC, infrahepatic IVC and PV, reperfusing the liver. Lastly, we anastomosed the HA and BD. We also performed pulmonary artery catheter exams and recovery blood samples serially before and after graft reperfusion (beginning of anesthesia = basal; 5 min after reperfusion and 120 min after reperfusion = end-point) for hemodynamic and metabolic assessment. RESULTS: Transplantation fellows were able to perform the operations assisted by a senior surgeon. The median procedure time was 211 min (188-233 min). One pig died due to hemorrhage and 5 remained alive for up to 2 h after liver reperfusion, achieving at this time normal hemodynamic and metabolic parameters. CONCLUSIONS: This model is suitable for training and experimentation, avoids venovenous bypass, is low cost, avoids immunological reaction, and prevents hemodynamic and metabolic complications. PMID- 26056161 TI - The case of the gene: Postgenomics between modernity and postmodernity. PMID- 26056160 TI - A Multifaceted GABAA Receptor Modulator: Functional Properties and Mechanism of Action of the Sedative-Hypnotic and Recreational Drug Methaqualone (Quaalude). AB - In the present study, we have elucidated the functional characteristics and mechanism of action of methaqualone (2-methyl-3-o-tolyl-4(3H)-quinazolinone, Quaalude), an infamous sedative-hypnotic and recreational drug from the 1960s 1970s. Methaqualone was demonstrated to be a positive allosteric modulator at human alpha1,2,3,5beta2,3gamma2S GABAA receptors (GABAARs) expressed in Xenopus oocytes, whereas it displayed highly diverse functionalities at the alpha4,6beta1,2,3delta GABAAR subtypes, ranging from inactivity (alpha4beta1delta), through negative (alpha6beta1delta) or positive allosteric modulation (alpha4beta2delta, alpha6beta2,3delta), to superagonism (alpha4beta3delta). Methaqualone did not interact with the benzodiazepine, barbiturate, or neurosteroid binding sites in the GABAAR. Instead, the compound is proposed to act through the transmembrane beta((+))/alpha((-)) subunit interface of the receptor, possibly targeting a site overlapping with that of the general anesthetic etomidate. The negligible activities displayed by methaqualone at numerous neurotransmitter receptors and transporters in an elaborate screening for additional putative central nervous system (CNS) targets suggest that it is a selective GABAAR modulator. The mode of action of methaqualone was further investigated in multichannel recordings from primary frontal cortex networks, where the overall activity changes induced by the compound at 1-100 MUM concentrations were quite similar to those mediated by other CNS depressants. Finally, the free methaqualone concentrations in the mouse brain arising from doses producing significant in vivo effects in assays for locomotion and anticonvulsant activity correlated fairly well with its potencies as a modulator at the recombinant GABAARs. Hence, we propose that the multifaceted functional properties exhibited by methaqualone at GABAARs give rise to its effects as a therapeutic and recreational drug. PMID- 26056162 TI - Sexual Assault Perpetrators' Justifications for Their Actions: Relationships to Rape Supportive Attitudes, Incident Characteristics, and Future Perpetration. AB - Perpetrators use rape supportive attitudes and sexual assault incident characteristics to justify forcing sex on their victims. Perpetrators who can justify their behaviors are at increased risk for future perpetration. This study examined the relationships between rape supportive attitudes, sexual assault incident characteristics, and the post-assault justifications of 183 men sampled from the community who self-reported committing at least one act of sexual aggression. Hierarchical multiple regression analyses indicated that rape supportive attitudes, expectations for having sex, misperceptions of sexual intent, victims' alcohol consumption, attempts to be alone with her, and the number of consensual sexual activities prior to the unwanted sex were significant predictors of perpetrators' post-assault use of justifications. Greater use of justifications was a significant predictor of sexual aggression over a 1-year follow-up interval. These findings demonstrate the need for further research exploring when and why perpetrators use post-assault justifications and whether they are amenable to change. PMID- 26056163 TI - Domestic Violence Courts: A Multisite Test of Whether and How They Change Offender Outcomes. AB - Findings are from an investigation of 24 criminal domestic violence courts (DVCs) across New York, testing their effect on recidivism, case processing, and case resolutions. Overall, we found a small positive impact on recidivism among convicted offenders. We further found that the sex of defendants moderated the court impact on case resolutions; that is, among male defendants only, DVCs increased conviction rates and sentences involving jail or prison. In addition, multi-level, multivariate analyses found that court policies specifically designed to increase victim safety, hold offenders accountable, and reduce offender recidivism (through deterrence or rehabilitation) were instrumental in reducing recidivism. PMID- 26056164 TI - Prenatal Training Improves New Mothers' Understanding of Jaundice. AB - BACKGROUND: Mothers' knowledge of neonatal jaundice (NNJ) is grossly deficient or inaccurate, which may adversely affect the actions of mothers in the recognition of NNJ and cause a delay in seeking medical attention. MATERIAL AND METHODS: A total of 1036 primiparas were separated randomly into the intervention group and the control group, with 518 primiparas in each group. RESULTS: All (100%) mothers in the intervention group understood that NNJ is a yellow discoloration of the skin and sclera; 94.19% of them considered that NNJ is a common problem in newborns; 82.80% and 95.27% replied that jaundice appearing within the first 36 hours and lasting more than 2 weeks usually indicates pathological NNJ; 96.34%, 80.86%, and 90.32% realized that premature newborns, low birth weight, and perinatal asphyxia, respectively, are more likely to be accompanied by NNJ; 97.41%, 78.71%, and 64.95% knew that maternal-fetal blood group incompatibility, infection, and glucose-6-phosphate dehydrogenase deficiency, respectively, are the common inducements to NNJ; 94.84% could associate NNJ with brain damage; 92.26%, 93.12%, and 74.62% agreed that phototherapy, strengthen feeding, and exchange blood transfusion, respectively, can greatly relieve NNJ. However, some respondents in the control group responded in other ways, such as stopping breastfeeding (9.19%), placing newborns in sunlight (10.24%) and traditional Chinese medicine (10.24%), which was significantly higher than that of the intervention group. There was also a significant delay for respondents in the control group in consulting a pediatrician, and 6.30% of them did not seek medical help until after the interview. CONCLUSIONS: Prenatal training could significantly improve new mothers' understanding of NNJ. PMID- 26056166 TI - Interaction of kindlin-3 and beta2-integrins differentially regulates neutrophil recruitment and NET release in mice. AB - Kindlin-3 essentially supports integrin activation in blood cells. Absence of kindlin-3 in humans causes leukocyte adhesion deficiency-III characterized with severe bleeding disorder and recurrent infections. Previously, we generated kindlin-3 knock-in (K3KI) mice carrying an integrin-interaction disrupting mutation in kindlin-3 and verified the functional significance of the binding of kindlin-3 to integrin alphaIIbbeta3 in platelets. Here, using K3KI mice, we functionally evaluate the crosstalk between kindlin-3 and beta2-integrins in neutrophils. Although the kindlin-3 mutant in K3KI neutrophils is normally expressed, its binding ability to beta2-integrins in neutrophils is disabled. In vitro and in vivo analyses disclose that beta2-integrin-mediated K3KI neutrophil adhesion and recruitment are significantly suppressed. Interestingly, the ability of releasing neutrophil extracellular traps (NETs) from K3KI neutrophils is also compromised. Substantially, a peptide derived from the integrin beta2 cytoplasmic tail that can inhibit the interaction between kindlin-3 and beta2-inegrins significantly jeopardizes NET release without affecting neutrophil adhesion and recruitment under the experimental conditions. These findings suggest that crosstalk between kindlin-3 and beta2-integrins in neutrophils is required for supporting both neutrophil recruitment and NET release, but the involved regulatory mechanisms in these two cellular events might be differential, thus providing a novel therapeutic concept to treat innate immune-related diseases. PMID- 26056165 TI - A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. AB - Options for targeted therapy of T-cell malignancies remain scarce. Recent clinical trials demonstrated that chimeric antigen receptors (CARs) can effectively redirect T lymphocytes to eradicate lymphoid malignancies of B-cell origin. However, T-lineage neoplasms remain a more challenging task for CAR T cells due to shared expression of most targetable surface antigens between normal and malignant T cells, potentially leading to fratricide of CAR T cells or profound immunodeficiency. Here, we report that T cells transduced with a CAR targeting CD5, a common surface marker of normal and neoplastic T cells, undergo only limited fratricide and can be expanded long-term ex vivo. These CD5 CAR T cells effectively eliminate malignant T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma lines in vitro and significantly inhibit disease progression in xenograft mouse models of T-ALL. These data support the therapeutic potential of CD5 CAR in patients with T-cell neoplasms. PMID- 26056167 TI - Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation. AB - Liver regeneration is stimulated by blood platelets, but the molecular mechanisms involved are largely unexplored. Although platelets are anucleate, they do contain coding or regulatory RNAs that can be functional within the platelet or, after transfer, in other cell types. Here, we show that platelets and platelet like particles (PLPs) derived from the megakaryoblastic cell line MEG-01 stimulate proliferation of HepG2 cells. Platelets or PLPs were internalized within 1 hour by HepG2 cells and accumulated in the perinuclear region of the hepatocyte. Platelet internalization also occurred following a partial hepatectomy in mice. Annexin A5 blocked platelet internalization and HepG2 proliferation. We labeled total RNA of MEG-01 cells by incorporation of 5 ethynyluridine (EU) and added EU-labeled PLPs to HepG2 cells. PLP-derived RNA was detected in the cytoplasm of the HepG2 cell. We next generated PLPs containing green fluorescent protein (GFP)-tagged actin messenger RNA. PLPs did not synthesize GFP, but in coculture with HepG2 cells, significant GFP protein synthesis was demonstrated. RNA-degrading enzymes partly blocked the stimulating effect of platelets on hepatocyte proliferation. Thus, platelets stimulate hepatocyte proliferation via a mechanism that is dependent on platelet internalization by hepatocytes followed by functional transfer of RNA stored in the anucleate platelet. This mechanism may contribute to platelet-mediated liver regeneration. PMID- 26056168 TI - Facial and Cochlear Nerve Complications following Microsurgical Resection of Vestibular Schwannomas in a Series of 221 Cases. AB - BACKGROUND: Despite improvements in microsurgical technique and the use of intraoperative electrophysiological monitoring, the potential for facial and cochlear nerve injury remains a possibility in the resection of vestibular schwannomas (VS). We reviewed a series of 221 cases of VS resected via a retrosigmoid approach at our institution from October 2008 to April 2014 and determined the incidence of postoperative facial and cochlear deficits. MATERIAL AND METHODS: A total of 221 patients - 105 (47.5%) male and 116 (52.5%) female - with a mean age of 46.1 years (range 29-73 years), with VS >=3 cm (n=183, 82.8%) and <3 cm (n=38, 17.2%) underwent surgical resection via a retrosigmoid approach and were evaluated for postoperative facial and cochlear nerve deficits. RESULTS: Near-total resection (>95% removal) was achieved in 199 cases (90%) and subtotal resection (>90% removal) in 22 cases (10%). At 6 month follow-up, House-Brackmann grades I-III were observed in 183 cases (82.8%), grade IV in 16 cases (7.2%), and grade V in 22 cases (10%). Of the 10 patients that had preoperative functional hearing, 3 (33%) retained hearing postoperatively. Cerebrospinal fluid leakage occurred in 6 patients (2.7%), lower cranial nerve palsies in 9 patients (4.1%), and intracranial hematomas 3 cases (1.4%). CONCLUSIONS: The observed incidence of persistent postoperative nerve deficits is very low. Meticulous microsurgical dissection of and around the facial and cochlear nerves with the aid of intraoperative electrophysiological nerve monitoring in the retrosigmoid approach allows for near-total resection of medium and large VS with the possibility of preservation of facial and cochlear nerve function. PMID- 26056169 TI - Is there still a role for lesioning in functional neurosurgery? Preliminary Italian (and world-first) experience with a trans-cranial MRI-guided focused ultrasound surgery system operating at 1.5 Tesla. PMID- 26056170 TI - Stroke care after discharge varies widely across UK, audit finds. PMID- 26056171 TI - Controlling tetramer formation, subunit rotation and DNA ligation during Hin catalyzed DNA inversion. AB - Two critical steps controlling serine recombinase activity are the remodeling of dimers into the chemically active synaptic tetramer and the regulation of subunit rotation during DNA exchange. We identify a set of hydrophobic residues within the oligomerization helix that controls these steps by the Hin DNA invertase. Phe105 and Met109 insert into hydrophobic pockets within the catalytic domain of the same subunit to stabilize the inactive dimer conformation. These rotate out of the catalytic domain in the dimer and into the subunit rotation interface of the tetramer. About half of residue 105 and 109 substitutions gain the ability to generate stable synaptic tetramers and/or promote DNA chemistry without activation by the Fis/enhancer element. Phe106 replaces Phe105 in the catalytic domain pocket to stabilize the tetramer conformation. Significantly, many of the residue 105 and 109 substitutions support subunit rotation but impair ligation, implying a defect in rotational pausing at the tetrameric conformer poised for ligation. We propose that a ratchet-like surface involving Phe105, Met109 and Leu112 within the rotation interface functions to gate the subunit rotation reaction. Hydrophobic residues are present in analogous positions in other serine recombinases and likely perform similar functions. PMID- 26056173 TI - Clinical commissioning groups' performance will be formally assessed. PMID- 26056172 TI - DNA hairpins destabilize duplexes primarily by promoting melting rather than by inhibiting hybridization. AB - The effect of secondary structure on DNA duplex formation is poorly understood. Using oxDNA, a nucleotide level coarse-grained model of DNA, we study how hairpins influence the rate and reaction pathways of DNA hybridzation. We compare to experimental systems studied by Gao et al. (1) and find that 3-base pair hairpins reduce the hybridization rate by a factor of 2, and 4-base pair hairpins by a factor of 10, compared to DNA with limited secondary structure, which is in good agreement with experiments. By contrast, melting rates are accelerated by factors of ~100 and ~2000. This surprisingly large speed-up occurs because hairpins form during the melting process, and significantly lower the free energy barrier for dissociation. These results should assist experimentalists in designing sequences to be used in DNA nanotechnology, by putting limits on the suppression of hybridization reaction rates through the use of hairpins and offering the possibility of deliberately increasing dissociation rates by incorporating hairpins into single strands. PMID- 26056174 TI - Motivations and barriers to exercise in chronic kidney disease: a qualitative study. AB - BACKGROUND: Exercise has the potential to modulate a number of complications associated with chronic kidney disease (CKD). However, typically, CKD patients lead very sedentary lifestyles, the reasons for which are not fully known. The aim of this qualitative study was to gain an understanding of the motivators, barriers and beliefs held by CKD patients regarding exercise. METHODS: We conducted 3 focus groups and 22 semi-structured interviews. Data were collected from nephrology outpatient clinics in the United Kingdom. A total of 36 individuals with CKD stages 1-5 not requiring renal replacement therapy, aged 26 83 years participated in this study. This manuscript outlines the findings from patients with CKD stages 3-5. Focus groups and interviews were transcribed verbatim and analysed thematically. RESULTS: Positive attitudes to exercise reflected autonomous motivations including: exercising for health; enjoyment and social interaction. Family support and goal setting were seen as motivators for exercise and the accessibility of local facilities influenced activity levels. Barriers to exercise were poor health, fear of injury or aggravating their condition, a lack of guidance from healthcare professionals and a lack of facilities. CONCLUSIONS: These findings are an important first stage in the development of a CKD-specific exercise behaviour change intervention. Interventions should operate at multiple levels, with a focus on improving patient autonomy and exercise self-efficacy, support networks and the physical environment (e.g. the accessibility of local facilities). In addition, strategies are required to ensure that the healthcare system is actively promoting and routinely supporting exercise for all patients with CKD. PMID- 26056175 TI - Bacteraemia in haemodialysis patients--not always Staphylococcus aureus. PMID- 26056176 TI - Thrombin may modulate dendritic cell activation in kidney transplant recipients with delayed graft function. AB - BACKGROUND: Coagulation and complement activation represent key events in ischaemia-reperfusion-induced renal injury leading to delayed graft function (DGF). It is still unclear whether the coagulation cascade may also influence the acquired immunity. The aim of the present study was to investigate the expression of protease-activated receptor 1 (PAR-1), the main thrombin receptor, by graft infiltrating dendritic cells (DCs), and to evaluate whether thrombin may influence DCs complement production and T-cell response. METHODS: PAR-1, BDCA1, CD11c, BDCA4, fibrin, C3c and C3d protein expression were evaluated by confocal microscopy. Cultured DCs were obtained incubating monocytes (Ms) with IL-4 and GM CSF. DC maturation was obtained with IFN-g+sCD40L or with a cytokine cocktail (IL 1b, TNF-a, PGE2, IL-6). PAR1 protein expression on cultured DC was evaluated by flow-cytometry. Complement receptors, C3, IL12/IL17p40 and IL10 gene expression was evaluated by qPCR. T cell phenotype was evaluated by ELISPOT. IFN-g protein presence was evaluated by ELISA. RESULTS: PAR-1 was expressed by infiltrating myeloid DCs in pre-transplant and in DGF biopsies. In DGF grafts, myeloid DCs localized within fibrin and C3d deposits and expressed C3c. In vitro, PAR-1 protein expression was increased in monocyte-derived immature DCs and in cytokine induced mature DCs compared to monocytes. PAR-1 activation caused a time dependent increase in C3 and complement receptors expression. Moreover, thrombin stimulation, while reducing interleukin-10 mRNA abundance, induced interleukin 12/IL-17 p40 gene expression, and promoted C3a ability to increase interleukin 12/IL17 mRNA abundance. These changes in the DCs' cytokine pattern influenced their ability to induce interferon-g production by T cells, suggesting the activation of a T helper-1 bias. CONCLUSION: Our data suggest that PAR-1 is expressed by DCs in DGF grafts and its activation may induce complement production and a Th1 bias. This observation suggests a potential pathogenic link between DGF and acquired allo-response leading to graft damage. PMID- 26056177 TI - Community-Based Phase IIIB Trial of Three UPFRONT Bortezomib-Based Myeloma Regimens. AB - PURPOSE: The US community-based, phase IIIB UPFRONT trial was designed to compare three frontline bortezomib-based regimens in transplantation-ineligible patients with myeloma. PATIENTS AND METHODS: Patients (N = 502) were randomly assigned 1:1:1 to 24 weeks (eight 21-day cycles) of induction with bortezomib dexamethasone (VD; n = 168; intravenous bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11 plus oral dexamethasone 20 mg, days 1, 2, 4, 5, 8, 9, 11, and 12 [cycles 1 to 4], or 1, 2, 4, and 5 [cycles 5 to 8]), bortezomib-thalidomide-dexamethasone (VTD; n = 167; bortezomib and dexamethasone as before plus oral thalidomide 100 mg, days 1 to 21), or bortezomib-melphalan-prednisone (VMP; n = 167; bortezomib as before plus oral melphalan 9 mg/m(2) and oral prednisone 60 mg/m(2), days 1 to 4, every other cycle), followed by 25 weeks (five 35-day cycles) of bortezomib maintenance (1.6 mg/m(2), days 1, 8, 15, and 22). The primary end point was progression-free survival. RESULTS: After 42.7 months' median follow-up, median progression-free survival with VD, VTD, and VMP was 14.7, 15.4, and 17.3 months, respectively; median overall survival was 49.8, 51.5, and 53.1 months, with no significant differences among treatments for either end point (global P = .46 and P = .79, respectively, Wald test). Overall response rates were 73% (VD), 80% (VTD), and 70% (VMP). Adverse events were more common with VTD than VD or VMP. Bortezomib maintenance was feasible without producing cumulative toxicity. CONCLUSION: Although all bortezomib-containing regimens produced good outcomes, VTD and VMP did not appear to offer an advantage over VD in transplantation ineligible patients with myeloma treated in US community practice. PMID- 26056178 TI - Prospective Cohort Study of Hospital Palliative Care Teams for Inpatients With Advanced Cancer: Earlier Consultation Is Associated With Larger Cost-Saving Effect. AB - PURPOSE: Previous studies report that early palliative care is associated with clinical benefits, but there is limited evidence on economic impact. This article addresses the research question: Does timing of palliative care have an impact on its effect on cost? PATIENTS AND METHODS: Using a prospective, observational design, clinical and cost data were collected for adult patients with an advanced cancer diagnosis admitted to five US hospitals from 2007 to 2011. The sample for economic evaluation was 969 patients; 256 were seen by a palliative care consultation team, and 713 received usual care only. Subsamples were created according to time to consult after admission. Propensity score weights were calculated, matching the treatment and comparison arms specific to each subsample on observed confounders. Generalized linear models with a gamma distribution and a log link were applied to estimate the mean treatment effect on cost within subsamples. RESULTS: Earlier consultation is associated with a larger effect on total direct cost. Intervention within 6 days is estimated to reduce costs by $1,312 (95% CI, -$2,568 to -$56; P = .04) compared with no intervention and intervention within 2 days by -$2,280 (95% CI, -$3,438 to -$1,122; P < .001); these reductions are equivalent to a 14% and a 24% reduction, respectively, in cost of hospital stay. CONCLUSION: Earlier palliative care consultation during hospital admission is associated with lower cost of hospital stay for patients admitted with an advanced cancer diagnosis. These findings are consistent with a growing body of research on quality and survival suggesting that early palliative care should be more widely implemented. PMID- 26056179 TI - High Graft CD8 Cell Dose Predicts Improved Survival and Enables Better Donor Selection in Allogeneic Stem-Cell Transplantation With Reduced-Intensity Conditioning. AB - PURPOSE: To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic malignancies. PATIENTS AND METHODS: We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content. RESULTS: Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio [aHR], 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 * 10(8) CD8 cells per kilogram optimally segregated patients receiving CD8(hi) and CD8(lo) grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8(hi) graft, whereas approximately half of younger donors provided CD8(hi) grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8(lo) doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8(hi) doses (P = .03), but not for recipients of younger unrelated donor CD8(lo) grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors. CONCLUSION: Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT. PMID- 26056180 TI - YAPing Hippo Forecasts a New Target for Lung Cancer Prevention and Treatment. PMID- 26056181 TI - National Prostate Cancer Screening Rates After the 2012 US Preventive Services Task Force Recommendation Discouraging Prostate-Specific Antigen-Based Screening. AB - PURPOSE: In 2012, the US Preventive Services Task Force (USPSTF) discouraged prostate-specific antigen (PSA) -based prostate cancer screening. Previous USPSTF recommendations did not appreciably alter prostate cancer screening. Therefore, we designed a trend analysis to determine the population-based impact of the 2012 recommendation. METHODS: The nationally representative National Health Interview Survey was used to estimate the proportion of men age 40 years and older who saw a physician and were screened for prostate cancer in 2013. An externally validated 9-year mortality index was used to analyze screening rates based on remaining life expectancy. Screening rates from 2005, 2010, and 2013 were compared using logistic regression. RESULTS: PSA-based screening did not significantly change from 2010 to 2013 among 40- to 49-year-old men (from 12.5% to 11.2%; P = .4). Screening rates significantly declined in men age 50 to 59 years (from 33.2% to 24.8%; P < .01), age 60 to 74 years (from 51.2% to 43.6%; P < .01), and age 75 years or older (from 43.9% to 37.1%; P = .03). A large percentage of men were screened for prostate cancer despite a high risk (> 52%) of 9-year mortality, including approximately one third of men older than age 75 years. Approximately 1.4 million men age 65 years or older with a high risk (> 52%) of 9-year mortality were screened in 2013. CONCLUSION: Prostate cancer screening significantly declined among men older than age 50 years after the 2012 USPSTF guideline discouraging PSA-based screening. A significant proportion of men continue to be screened despite a high risk of 9-year mortality, including one third of men age 75 years and older. PMID- 26056182 TI - R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability. AB - PURPOSE: Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS: Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS: YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION: These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management. PMID- 26056184 TI - Quantitative assessment of cardiac mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy in patients with non-ischaemic dilated cardiomyopathy using equilibrium radionuclide angiography. AB - AIMS: The aim of this study was to evaluate equilibrium radionuclide angiography (ERNA) in prediction of response to cardiac resynchronization therapy (CRT) in non-ischaemic dilated cardiomyopathy (DCM) patients. METHODS AND RESULTS: Thirty two patients (23 males, 57.5 +/- 12.1 years) were prospectively included. Equilibrium radionuclide angiography and clinical evaluation were performed before and 3 months after CRT implantation. Standard deviation of left ventricle mean phase angle (SD LVmPA) and difference between LV and right ventricle mPA (LV RVmPA) expressed in degrees ( degrees ) were used to quantify left intraventricular synchrony and interventricular synchrony, respectively. Left ventricular ejection fraction (LVEF) was also evaluated. At the baseline, mean NYHA class was 3.3 +/- 0.5, LVEF 22.5 +/- 5.6%, mean QRS duration 150.3 +/- 18.2 ms, SD LVmPA 43.5 +/- 18 degrees , and LV-RVmPA 30.4 +/- 15.6 degrees . At 3 month follow-up, 22 patients responded to CRT with improvement in NYHA class >=1 and EF >5%. Responders had significantly larger SD LVmPA (51.2 +/- 13.9 vs. 26.5 +/- 14 degrees ) and LV-RVmPA (35.8 +/- 13.7 vs. 18.4 +/- 13 degrees ) than non responders. Receiver-operating characteristic curve analysis demonstrated 95% sensitivity and 80% specificity at a cut-off value of 30 degrees for SD LVmPA, and 81% sensitivity and 80% specificity at a cut-off value of 23 degrees for LV RVmPA in prediction of response to CRT. CONCLUSION: Baseline SD LVmPA and LV RVmPA derived from ERNA are useful for prediction of response to CRT in non ischaemic DCM patients. PMID- 26056183 TI - Randomized Phase III Trial of Paclitaxel Once Per Week Compared With Nanoparticle Albumin-Bound Nab-Paclitaxel Once Per Week or Ixabepilone With Bevacizumab As First-Line Chemotherapy for Locally Recurrent or Metastatic Breast Cancer: CALGB 40502/NCCTG N063H (Alliance). AB - PURPOSE: We compared nab-paclitaxel or ixabepilone once per week to paclitaxel with bevacizumab as first-line therapy for patients with advanced breast cancer (BC) to evaluate progression-free survival (PFS) for nab-paclitaxel or ixabepilone versus paclitaxel. PATIENTS AND METHODS: Eligible patients were age >= 18 years with chemotherapy-naive advanced BC. Patients were randomly assigned to bevacizumab with paclitaxel 90 mg/m(2) (arm A), nab-paclitaxel 150 mg/m(2) (arm B), or ixabepilone 16 mg/m(2) (arm C), once per week for 3 of 4 weeks. Planned enrollment was 900 patients, which would give 88% power to detect a hazard ratio of 0.73. RESULTS: In all, 799 patients were enrolled, and 783 received treatment (97% received bevacizumab). Arm C was closed for futility at the first interim analysis (n = 241), and arm A (n = 267) and arm B (n = 275) were closed for futility at the second interim analysis. Median PFS for paclitaxel was 11 months, ixabepilone was inferior to paclitaxel (PFS, 7.4 months; hazard ratio, 1.59; 95% CI, 1.31 to 1.93; P < .001), and nab-paclitaxel was not superior to paclitaxel (PFS, 9.3 months; hazard ratio, 1.20; 95% CI, 1.00 to 1.45; P = .054). Results were concordant with overall survival; time to treatment failure was significantly shorter in both experimental arms v paclitaxel. Hematologic and nonhematologic toxicity, including peripheral neuropathy, was increased with nab-paclitaxel, with more frequent and earlier dose reductions. CONCLUSION: In patients with chemotherapy-naive advanced BC, ixabepilone once per week was inferior to paclitaxel, and nab-paclitaxel was not superior with a trend toward inferiority. Toxicity was increased in the experimental arms, particularly for nab-paclitaxel. Paclitaxel once per week remains the preferred palliative chemotherapy in this setting. PMID- 26056186 TI - Author's reply: To PMID 24585884. PMID- 26056185 TI - Bundled preparation of skin antisepsis decreases the risk of cardiac implantable electronic device-related infection. AB - AIMS: To evaluate the efficacy of bundled skin antiseptic preparation to prevent cardiac implantable electronic device (CIED) infections. METHODS AND RESULTS: From January 2010 to November 2013, 665 consecutive patients were divided into two groups according to the strategy of skin preparation. In Period 1 (January 2010 to June 2012), 395 patients received the standard skin antiseptic preparation. In Period 2 (July 2012 to November 2013), 270 patients received a triple-step skin antiseptic preparation, 'bundled skin antiseptic preparation', consisting of applying 75% alcohol over anterior chest on the night before the index day, povidone-iodine 10 min before operation, and the standard skin antiseptic preparation before incision. During follow-up, the occurrence of CIED infection was recorded. Multiple logistic regression analysis was used to determinate the risk factors of CIED infection. During a mean follow-up of 26.9 +/- 16.2 months, 20 episodes of CIED infection developed in 19 patients (2.9%), and the incidence of minor and major infection episodes was 2.2% and 0.8%, respectively. Patients with the bundled skin antiseptic preparation had a significantly lower incidence of CIED infection, compared with patients with the standard preparation (0.7 vs. 4.3%, P = 0.007). In multivariate analysis, pocket haematoma (P = 0.020), atrial fibrillation (P = 0.033), and complex procedures (P = 0.047) were independent predictors for CIED infection. In contrast, the bundled skin antiseptic preparation was a significant predictor against CIED infection (P = 0.014). CONCLUSION: Pocket haematoma was the most important risk factor for CIED infection. The bundled skin antiseptic preparation strategy significantly reduced the risk of minor CIED infection. PMID- 26056187 TI - A note on the prevalence of cardiac ion channelopathies in the sudden infant death syndrome. PMID- 26056188 TI - Atrial fibrillation: prevalence in a large database of primary care patients in Brazil. AB - AIMS: Although an increasing prevalence of atrial fibrillation (AF) has been reported worldwide, there are few studies from low- and middle-income countries. Our objective is to assess the prevalence of AF and the associated medical conditions in Brazilian primary care patients. METHODS AND RESULTS: This is an observational retrospective study. Patients >=5 years of age from primary care centres of 658 municipalities in Minas Gerais, Brazil, who performed digital electrocardiograms (ECGs) by a public telehealth service in 2011 were assessed. Clinical data were self-reported, and ECGs were interpreted by a team of trained cardiologists using standardized criteria. To assess the relation between clinical characteristics and AF, odds ratios were estimated by logistic regression. A total of 262 685 primary care patients were included, mean (SD) age of 50.3 (19.3) years, 59.6% female. Hypertension was reported in 32.0%, family history of coronary heart disease in 15.0%, diabetes in 5.4%, hyperlipidaemia in 2.8%, Chagas disease in 2.9%, and 7.1% reported current smoking. The prevalence of AF was 1.8% overall: 2.4% in men (ranging from 0.001% from 5-19 years old to 14.6% in nonagenarians) and 1.3% in women (ranging from 0.001% from 5-19 years old to 8.7% in nonagenarians) (P < 0.001). The prevalence of AF increased with advancing age. The comorbidities associated with AF were Chagas disease, previous myocardial infarction, hypertension, and chronic obstructive pulmonary disease. Vitamin K antagonist use was reported by 1.5% of patients. CONCLUSION: The prevalence and age distribution of AF were similar to studies in high-income countries. The proportion of patients who reported the use of anticoagulants was alarmingly low. Our findings point out the necessity to formulate effective treatment strategies for AF in Brazilian primary care settings. PMID- 26056189 TI - Vernakalant-facilitated electrical cardioversion: comparison of intravenous vernakalant and amiodarone for drug-enhanced electrical cardioversion of atrial fibrillation after failed electrical cardioversion. AB - AIMS: Electrical cardioversion is one cornerstone for the rhythm control strategy of atrial fibrillation (AF), which is, however, hampered by immediate AF recurrence (IRAF) or failed electrical cardioversion (FECV). We aimed to investigate the potential role of vernakalant for facilitated electrical cardioversion in cardioversion-resistant AF. METHODS AND RESULTS: The subjects of this study were 63 patients referred to the Heart Centre Leipzig between November 2011 and May 2014 for transthoracic electrical cardioversion of AF. All patients experienced after antiarrhythmic-naive electrical cardioversion either IRAF (n = 44; 70%) or FECV (n = 19; 30%). After drug infusion, electrical cardioversion was successful in 66.7% of vernakalant-treated as opposed to 46.7% of amiodarone treated patients (P = 0.109). Multivariate analysis revealed treatment with vernakalant (OR 0.057, 95% CI 0.006-0.540, P = 0.013), treatment with ACEI or ARB (OR 0.101, 95% CI 0.015-0.691 P = 0.019), and IRAF after initial CV (OR 0.047, 95% CI 0.004-0.498, P = 0.011) as predictors for successful, drug-facilitated electrical cardioversion. Subgroup analysis of 18 patients with previous AF ablation revealed a significantly higher success rate of electrical cardioversion after infusion of vernakalant than after infusion of amiodarone (66.7 vs. 11.1%, P = 0.016). CONCLUSION: Vernakalant may therefore be considered as a useful agent for facilitated electrical cardioversion in cardioversion-resistant AF. PMID- 26056190 TI - Differences in predictors of implantable cardioverter-defibrillator therapies in patients with ischaemic and non-ischaemic cardiomyopathies. AB - AIMS: Implantable cardioverter-defibrillators (ICDs) have been shown to reduce mortality in patients with both ischaemic and non-ischaemic cardiomyopathy by terminating life-threatening arrhythmias. However, such arrhythmic events are unequally distributed among different patient subgroups. We aimed to evaluate predictors of appropriate ICD therapies as a step towards risk stratification in a real-world cohort. METHODS AND RESULTS: The prevalence and predictors of appropriate ICD therapies were analysed in 330 consecutive patients (mean age 65 +/- 11, 81% male) with implanted ICDs due to ischaemic (n = 204) or dilated (n = 126) cardiomyopathy. During a mean follow-up of 19 +/- 9 months, 1545 appropriate ICD therapies (antitachycardia pacing and shocks) were detected in 94 patients (29%). In multivariate analysis applied on the whole cohort, the presence of atrial fibrillation [AF: odds ratio (OR) = 1.906, confidence interval (CI) = 1.143-3.177, P = 0.013] and secondary prevention indication (OR = 1.963, CI = 1.123-3.432, P = 0.018) was associated with ICD therapy. The presence of cardiac resynchronization therapy (CRT) had a protective value (OR = 0.563, CI = 0.327 0.968, P = 0.038). Moreover, the predictors were different depending on the aetiology of the cardiomyopathy: in the ischaemic group, only secondary prevention indication (OR = 2.0, CI = 1.029-3.891, P = 0.041) and the presence of a biventricular system (OR = 0.359, CI = 0.163-0.794, P = 0.011) remained significant, while in the non-ischaemic group, an association with AF was observed (OR = 4.281, CI = 1.632-11.231, P = 0.003). CONCLUSION: The aetiology of cardiomyopathy should be taken into consideration for the therapy of ICD patients. The protective role of CRT devices should be pointed out in ischaemic cardiomyopathy (ICM) and a more rigorous antiarrhythmic treatment should be considered for ICM patients with secondary prevention or for dilated cardiomyopathy patients with AF. PMID- 26056192 TI - Markets, Prices, And Incentives. PMID- 26056191 TI - Propafenone shows class Ic and class II antiarrhythmic effects. AB - AIMS: Propafenone is a well-known Class Ic antiarrhythmic agent. It has the typical chemical structure of a beta-blocker, but human studies on its beta blocking effects revealed conflicting results. METHODS AND RESULTS: Twelve healthy males received single oral doses of 600 mg propafenone and placebo according to a randomized, double-blind, placebo-controlled, cross-over protocol. Four hours following drug intake, heart rate and blood pressure were measured, and plasma concentrations of propafenone were determined at rest, during exercise and after recovery. At exercise, propafenone significantly decreased heart rate ( 6%, P < 0.05), systolic blood pressure (-6%, P < 0.05), and the rate-pressure product (-11%, P < 0.05). Plasma concentrations of propafenone increased during exercise (+23%, P < 0.05) and decreased during recovery (-33%, P < 0.05). CONCLUSION: Both effects on heart rate and blood pressure as well as the changes of plasma concentrations of propafenone during exercise represent two particular features of beta-blockers. Therefore, we conclude that propafenone is both a Class Ic and a Class II antiarrhythmic agent, and 600 mg propafenone, i.e. the dose recommended in current guidelines for cardioversion of paroxysmal atrial fibrillation, cause clinically significant beta-blockade. Thus, single oral doses of 600 mg propafenone appear also suitable for cardioversion of paroxysmal atrial fibrillation in patients with structural heart disease since beta-blockers are explicitly indicated in the treatment of both coronary artery disease and heart failure. PMID- 26056193 TI - As Fracking Booms, Dearth Of Health Risk Data Remains. PMID- 26056194 TI - Medicare Payment Policy Creates Incentives For Long-Term Care Hospitals To Time Discharges For Maximum Reimbursement. AB - Long-term care hospitals are postacute care facilities for patients requiring extended hospital-level care. These facilities are reimbursed by Medicare under a prospective payment system with a short-stay outlier policy, which results in substantially lower payments for patients discharged before a diagnosis-related group-specific short-stay threshold. Using Medicare data, we examined the impact of the short-stay policy on lengths-of-stay and Medicare reimbursement among patients in long-term care hospitals who require prolonged mechanical ventilation. After accounting for case-mix and facility-level differences, we found that discharges for reasons other than death in the period 2005-10 were most likely to occur on the day of or immediately after the short-stay threshold; this held true regardless of facility ownership. In contrast, live discharges in 2002-the year before the prospective payment system started phasing out cost based payment-were evenly distributed around the day that later became the short stay threshold. Our findings confirm that the short-stay outlier payment policy created a strong financial incentive for long-term care hospitals to time patient discharges to maximize Medicare reimbursement. The results suggest that the new very-short-stay policy implemented in December 2012 could have a similar effect. PMID- 26056195 TI - Concentration In Orthopedic Markets Was Associated With A 7 Percent Increase In Physician Fees For Total Knee Replacements. AB - Physician groups are growing larger in size and fewer in number. Although this consolidation could result in improved patient care, the resulting increase in market concentration also could allow larger groups to negotiate higher physician fees from private insurers. We examined the association between market concentration and physician fees in the case of total knee arthroplasty by calculating market concentration for orthopedic groups practicing in a given market and by analyzing administrative claims data from Marketscan. In the period 2001-10 the average professional fee for total knee arthroplasty was $2,537. During this time, in markets that moved from the bottom quartile of concentration to the top quartile, physician fees paid by private payers increased by $168 per procedure. The increase nearly offset the $261 decline in fees that we observed, absent changes in market concentration. These findings suggest that caution should be used in implementing policies designed to encourage further group concentration, which could produce similar effects. PMID- 26056196 TI - Extreme Markup: The Fifty US Hospitals With The Highest Charge-To-Cost Ratios. AB - Using Medicare cost reports, we examined the fifty US hospitals with the highest charge-to-cost ratios in 2012. These hospitals have markups (ratios of charges over Medicare-allowable costs) approximately ten times their Medicare-allowable costs compared to a national average of 3.4 and a mode of 2.4. Analysis of the fifty hospitals showed that forty-nine are for profit (98 percent), forty-six are owned by for-profit hospital systems (92 percent), and twenty (40 percent) operate in Florida. One for-profit hospital system owns half of these fifty hospitals. While most public and private health insurers do not use hospital charges to set their payment rates, uninsured patients are commonly asked to pay the full charges, and out-of-network patients and casualty and workers' compensation insurers are often expected to pay a large portion of the full charges. Because it is difficult for patients to compare prices, market forces fail to constrain hospital charges. Federal and state governments may want to consider limitations on the charge-to-cost ratio, some form of all-payer rate setting, or mandated price disclosure to regulate hospital markups. PMID- 26056197 TI - Understanding Pay Differentials Among Health Professionals, Nonprofessionals, And Their Counterparts In Other Sectors. AB - About half of the $2.1 trillion of US health services spending constitutes compensation to employees. We examined how the wages paid to health-sector employees compared to those paid to workers with similar qualifications in other sectors. Overall, we found that health care workers are paid only slightly more than workers elsewhere in the US economy, but the patterns are starkly different for nonprofessional and professional employees. Nonprofessional health care workers earn slightly less than their counterparts elsewhere in the economy. By contrast, the average nurse earns about 40 percent more than the median comparable worker in a different sector. The average physician earns about 50 percent more than a comparable worker in another sector of the economy, and this differential has increased sharply since 1993. Cost containment is likely to lead to reductions in the earnings of health care professionals, but it will also require using fewer or less skilled employees to produce a given service. PMID- 26056198 TI - Future Demand For Long-Term Care Workers Will Be Influenced By Demographic And Utilization Changes. AB - A looming question for policy makers is how growing diversity of the US elderly population and greater use of home and community-based services will affect demand for long-term care workers. We used national surveys to analyze current use and staffing of long-term care, project demand for long-term care services and workers through 2030, and assess how projections varied if we changed assumptions about utilization patterns. If current trends continue, the occupations anticipated to grow the most over the period are counselors and social workers (94 percent), community and social services workers (93 percent), and home health and personal care aides (88 percent). Alternative projections were computed for scenarios that assumed changing racial and ethnic patterns of long-term care use or shifts toward noninstitutional care. For instance, if Hispanics used services at the same rate as non-Hispanic blacks, the projected demand for long-term care workers would be 5 percent higher than if current trends continued. If 20 percent of nursing home care were shifted to home health services, total employment growth would be about 12 percent lower. Demographic and utilization changes would have little effect on projections of robust long term care employment growth between now and 2030. Policy makers and educators should redouble efforts to create and sustainably fund programs to recruit, train, and retain long-term care workers. PMID- 26056199 TI - PEPFAR Funding Associated With An Increase In Employment Among Males in Ten Sub Saharan African Countries. AB - The President's Emergency Plan for AIDS Relief (PEPFAR) has provided billions of US tax dollars to expand HIV treatment, care, and prevention programs in sub Saharan Africa. This investment has generated significant health gains, but much less is known about PEPFAR's population-level economic effects. We used a difference-in-differences approach to compare employment trends between ten countries that received a large amount of PEPFAR funding (focus countries) and eleven countries that received little or no funding (control countries). We found that PEPFAR was associated with a 13 percent differential increase in employment among males in focus countries, compared to control countries. However, we observed no change in employment among females. In addition, we found that increasing PEPFAR per capita funding by $100 was associated with a 9.1-percentage point increase in employment among males. This rise in employment generates economic benefits equal to half of PEPFAR's cost. These findings suggest that PEPFAR's economic impact should be taken into account when making aid allocation decisions. PMID- 26056200 TI - A Public-Private Partnership Improves Clinical Performance In A Hospital Network In Lesotho. AB - Health care public-private partnerships (PPPs) between a government and the private sector are based on a business model that aims to leverage private-sector expertise to improve clinical performance in hospitals and other health facilities. Although the financial implications of such partnerships have been analyzed, few studies have examined the partnerships' impact on clinical performance outcomes. Using quantitative measures that reflected capacity, utilization, clinical quality, and patient outcomes, we compared a government managed hospital network in Lesotho, Africa, and the new PPP-managed hospital network that replaced it. In addition, we used key informant interviews to help explain differences in performance. We found that the PPP-managed network delivered more and higher-quality services and achieved significant gains in clinical outcomes, compared to the government-managed network. We conclude that health care public-private partnerships may improve hospital performance in developing countries and that changes in management and leadership practices might account for differences in clinical outcomes. PMID- 26056201 TI - Teen Crashes Declined After Massachusetts Raised Penalties For Graduated Licensing Law Restricting Night Driving. AB - In 2007, as part of the Massachusetts graduated driver-licensing program designed to allow junior operators (ages 161/2-17 years) to gain experience before receiving full licensure, stringent penalties were introduced for violating a law prohibiting unsupervised driving at night; driver education, including drowsy driving education, became mandatory; and other new restrictions and penalties began. We evaluated the impact of these changes on police-reported vehicle crash records for one year before and five years after the law's implementation in drivers ages 16-17, inclusive, and two comparison groups. We found that crash rates for the youngest drivers fell 18.6 percent, from 16.24 to 13.22 per 100 licensed drivers. For drivers ages 18-19 the rates fell by 6.7 percent (from 9.59 to 8.95 per 100 drivers), and for those ages 20 and older, the rate remained relatively constant. The incidence rate ratio for drivers ages 16-17 relative to those ages 20 and older decreased 19.1 percent for all crashes, 39.8 percent for crashes causing a fatal or incapacitating injury, and 28.8 percent for night crashes. Other states should consider implementing strict penalties for violating graduated driver-licensing laws, including restrictions on unsupervised night driving, to reduce the risk of sleep-related crashes in young people. PMID- 26056202 TI - Prevention Program Lowered The Risk Of Falls And Decreased Claims For Long-Term Services Among Elder Participants. AB - The LIFT (Living Independently and Falls-free Together) Wellness Program is a multifactorial fall-prevention intervention developed for community-dwelling elders. Its effectiveness was tested in a randomized controlled trial of consenting people who were ages seventy-five and older and who held long-term care insurance policies with one of three major insurers. The study was conducted during 2008-12. In the first year following the intervention, participants in the intervention group had an 11 percent reduction in risk of falling and an 18 percent reduction in risk of injurious falls, compared to participants in the active control group. In the three years after the intervention, participants in the intervention group had a significantly (33 percent) lower incidence of claims for long-term services and supports than those in the administrative control group, for an estimated return of $1.68 on every dollar invested in program delivery. The results of this evaluation are unique in demonstrating that a multifactorial fall prevention program can do more than reduce falls in this population; they suggest that the broader availability of LIFT could benefit long term care insurers and policyholders alike. PMID- 26056203 TI - Readmissions To New York Hospitals Fell For Three Target Conditions From 2008 To 2012, Consistent With Medicare Goals. AB - The Medicare Hospital Readmissions Reduction Program (HRRP), an initiative of the Affordable Care Act, imposes considerable financial penalties on hospitals with excess thirty-day readmissions for patients with selected high-volume conditions. We investigated the intended impact of the program by examining changes in thirty day readmissions among Medicare patients admitted for three conditions targeted by the program in New York State, compared to Medicare patients with other conditions and with privately insured patients, before and after the program's introduction. We also examined potential unintended strategic responses by hospitals that might allow them to continue to treat target-condition patients while avoiding the readmission penalty. We found that thirty-day readmissions fell for the three conditions targeted by the HRRP, consistent with the goals of the program. Second, there also was a substantial fall in readmissions for a comparison group although not as large as for the target group, which suggests modest spillover effects in Medicare for other conditions. We did not find strong evidence of unintended effects associated with the program. These early findings suggest that the HRRP is affecting hospitals in the direction intended by the Affordable Care Act. PMID- 26056204 TI - Hospitals In 'Magnet' Program Show Better Patient Outcomes On Mortality Measures Compared To Non-'Magnet' Hospitals. AB - Hospital executives pursue external recognition to improve market share and demonstrate institutional commitment to quality of care. The Magnet Recognition Program of the American Nurses Credentialing Center identifies hospitals that epitomize nursing excellence, but it is not clear that receiving Magnet recognition improves patient outcomes. Using Medicare data on patients hospitalized for coronary artery bypass graft surgery, colectomy, or lower extremity bypass in 1998-2010, we compared rates of risk-adjusted thirty-day mortality and failure to rescue (death after a postoperative complication) between Magnet and non-Magnet hospitals matched on hospital characteristics. Surgical patients treated in Magnet hospitals, compared to those treated in non Magnet hospitals, were 7.7 percent less likely to die within thirty days and 8.6 percent less likely to die after a postoperative complication. Across the thirteen-year study period, patient outcomes were significantly better in Magnet hospitals than in non-Magnet hospitals. However, outcomes did not improve for hospitals after they received Magnet recognition, which suggests that the Magnet program recognizes existing excellence and does not lead to additional improvements in surgical outcomes. PMID- 26056206 TI - Primary Care Providers Ordered Fewer Preventive Services For Women With Medicaid Than For Women With Private Coverage. AB - As the number of beneficiaries in the Medicaid program grows under the Affordable Care Act, with over half of the states opting to expand Medicaid eligibility, it is important to understand more about the care provided to Medicaid patients. Using visit-level data for 2006-10 from the National Ambulatory Medical Care Survey, we examined the provision of recommended preventive services to women with Medicaid and those with private insurance at visits to primary care providers in private office-based practices. We found that after patient and provider characteristics were controlled for, Medicaid-insured visits were less likely than privately insured visits to include several preventive services, including clinical breast exams and Pap tests. The differences in provision of services by payer were generally driven by the differences in care at visits classified as preventive and at visits to obstetrician-gynecologists. Further investigation is required to determine what may be driving the differences in content of care across payers and their implications for quality of care. PMID- 26056205 TI - Physician Characteristics Strongly Predict Patient Enrollment In Hospice. AB - Individual physicians are widely believed to play a large role in patients' decisions about end-of-life care, but little empirical evidence supports this view. We developed a novel method for measuring the relationship between physician characteristics and hospice enrollment, in a nationally representative sample of Medicare patients. We focused on patients who died with a diagnosis of poor-prognosis cancer in the period 2006-11, for whom palliative treatment and hospice would be considered the standard of care. We found that the proportion of a physician's patients who were enrolled in hospice was a strong predictor of whether or not that physician's other patients would enroll in hospice. The magnitude of this association was larger than that of other known predictors of hospice enrollment that we examined, including patients' medical comorbidity, age, race, and sex. Patients cared for by medical oncologists and those cared for in not-for-profit hospitals were significantly more likely than other patients to enroll in hospice. These findings suggest that physician characteristics are among the strongest predictors of whether a patient receives hospice care-which mounting evidence indicates can improve care quality and reduce costs. Interventions geared toward physicians, both by specialty and by previous history of patients' hospice enrollment, may help optimize appropriate hospice use. PMID- 26056207 TI - The Impact Of State Policies On ACA Applications And Enrollment Among Low-Income Adults In Arkansas, Kentucky, And Texas. AB - States are taking variable approaches to the Affordable Care Act (ACA) Medicaid expansion, Marketplace design, enrollment outreach, and application assistance. We surveyed nearly 3,000 low-income adults in late 2014 to compare experiences in three states with markedly different policies: Kentucky, which expanded Medicaid, created a successful state Marketplace, and supported outreach efforts; Arkansas, which enacted the private option and a federal-state partnership Marketplace, but with legislative limitations on outreach; and Texas, which did not expand Medicaid and passed restrictions on navigators. We found that application rates, successful enrollment, and positive experiences with the ACA were highest in Kentucky, followed by Arkansas, with Texas performing worst. Limited awareness remains a critical barrier: Fewer than half of adults had heard some or a lot about the coverage expansions. Application assistance from navigators and others was the strongest predictor of enrollment, while Latino applicants were less likely than others to successfully enroll. Twice as many respondents felt that the ACA had helped them as hurt them (although the majority reported no direct impact), and advertising was strongly associated with perceptions of the law. State policy choices appeared to have had major impacts on enrollment experiences among low-income adults and their perceptions of the ACA. PMID- 26056208 TI - Medicare Advantage Members' Expected Out-Of-Pocket Spending For Inpatient And Skilled Nursing Facility Services. AB - Inpatient and skilled nursing facility (SNF) cost sharing in Medicare Advantage (MA) plans may reduce unnecessary use of these services. However, large out-of pocket expenses potentially limit access to care and encourage beneficiaries at high risk of needing inpatient and postacute care to avoid or leave MA plans. In 2011 new federal regulations restricted inpatient and skilled nursing facility cost sharing and mandated limits on out-of-pocket spending in MA plans. After these regulations, MA members in plans with low premiums averaged $1,758 in expected out-of-pocket spending for an episode of seven hospital days and twenty skilled nursing facility days. Among members with the same low-premium plan in 2010 and 2011, 36 percent of members belonged to plans that added an out-of pocket spending limit in 2011. However, these members also had a $293 increase in average cost sharing for an inpatient and skilled nursing facility episode, possibly to offset plans' expenses in financing out-of-pocket limits. Some MA beneficiaries may still have difficulty affording acute and postacute care despite greater regulation of cost sharing. PMID- 26056209 TI - Growth In Buprenorphine Waivers For Physicians Increased Potential Access To Opioid Agonist Treatment, 2002-11. AB - Opioid use disorders are a significant public health problem, affecting two million people in the United States. Treatment with buprenorphine, methadone, or both is predominantly offered in methadone clinics, yet many people do not receive the treatment they need. In 2002 the Food and Drug Administration approved buprenorphine for prescription by physicians who completed a course and received a waiver from the Drug Enforcement Administration, exempting them from requirements in the Controlled Substances Act. To determine the waiver program's impact on the availability of opioid agonist treatment, we analyzed data for the period 2002-11 to identify counties with opioid treatment shortages. We found that the percentage of counties with a shortage of waivered physicians fell sharply, from 98.9 percent in 2002 to 46.8 percent in 2011. As a result, the percentage of the US population residing in what we classified as opioid treatment shortage counties declined from 48.6 percent in 2002 to 10.4 percent in 2011. These findings suggest that the increase in waivered physicians has dramatically increased potential access to opioid agonist treatment. Policy makers should focus their efforts on further increasing the number and geographical distribution of physicians, particularly in more rural counties, where prescription opioid misuse is rapidly growing. PMID- 26056211 TI - Amid Fears And Controversy, A Doctor Chooses A Home Birth. PMID- 26056210 TI - Growth Of New York Physician Participation In Meaningful Use Of Electronic Health Records Was Variable, 2011-12. AB - The federal government has invested $30 billion to promote the adoption and use of electronic health records (EHRs) through the Medicare and Medicaid EHR Incentive Programs. However, the associations between the characteristics of physicians, practices, and markets and the patterns of provider participation in ongoing federal meaningful-use incentive programs over time have been largely unexplored. In this article we describe the participation of New York physicians during the first two years of the meaningful-use initiative. We examined longitudinal patterns to identify characteristics associated with nonparticipation, late adoption of EHRs, noncontinuous participation, and switching programs. We found that 8.1 percent of 26,368 New York physicians participated in the Medicare incentive program in 2011, and 6.1 percent participated in the Medicaid program. Physician participation in the programs grew to 23.9 percent and 8.5 percent, respectively, in 2012. Many physicians in the Medicaid incentive program in 2011 did not participate in either program in 2012. Prior EHR use, access to financial resources, and organizational capacity were physician characteristics associated with early and consistent participation in the meaningful-use initiative. Annual participation requirements, coupled with different options to meet meaningful-use criteria under the incentive programs, create disparate groups of physicians, which illustrates the need to monitor participants for continued participation. PMID- 26056212 TI - Foundation Grants To Prevent Substance Use Disorders. PMID- 26056214 TI - Evidence And Medicare's Coverage Of Interventions. PMID- 26056215 TI - Medicare's Interventions Coverage: The Authors Reply. PMID- 26056216 TI - National Health Insurance In Taiwan. PMID- 26056217 TI - The Single-Payer System In Taiwan. PMID- 26056218 TI - Health Insurance In Taiwan: The Author Replies. PMID- 26056219 TI - Compulsory Licenses For Medicines. PMID- 26056220 TI - Compulsory Licenses: The Authors Reply. PMID- 26056221 TI - Assessing Hospital Productivity. PMID- 26056222 TI - Hospital Productivity: The Authors Reply. PMID- 26056223 TI - Health Information Exchange And Jails. PMID- 26056224 TI - Health Information Exchange: The Authors Reply. PMID- 26056225 TI - Medicare's Hospital Value-Based Purchasing Program. PMID- 26056226 TI - Higher fine particulate matter and temperature levels impair exercise capacity in cardiac patients. AB - OBJECTIVE: Fine particulate matter (PM2.5) air pollution and variations in ambient temperature have been linked to increased cardiovascular morbidity and mortality. However, no large-scale study has assessed their effects on directly measured aerobic functional capacity among high-risk patients. METHODS: Using a cross-sectional observational design, we evaluated the effects of ambient PM2.5 and temperature levels over 7 days on cardiopulmonary exercise test results performed among 2078 patients enrolling into a cardiac rehabilitation programme at the University of Michigan (from January 2003 to August 2011) using multiple linear regression analyses (controlling for age, sex, body mass index). RESULTS: Peak exercise oxygen consumption was significantly decreased by approximately 14.9% per 10 MUg/m(3) increase in ambient PM2.5 levels (median 10.7 MUg/m(3), IQR 10.1 MUg/m(3)) (lag days 6-7). Elevations in PM2.5 were also related to decreases in ventilatory threshold (lag days 5-7) and peak heart rate (lag days 2-3) and increases in peak systolic blood pressure (lag days 4-5). A 10 degrees C increase in temperature (median 10.5 degrees C, IQR 17.5 degrees C) was associated with reductions in peak exercise oxygen consumption (20.6-27.3%) and ventilatory threshold (22.9-29.2%) during all 7 lag days. In models including both factors, the outcome associations with PM2.5 were attenuated whereas the effects of temperature remained significant. CONCLUSIONS: Short-term elevations in ambient PM2.5, even at low concentrations within current air quality standards, and/or higher temperatures were associated with detrimental changes in aerobic exercise capacity, which can be linked to a worse quality of life and cardiovascular prognosis among cardiac rehabilitation patients. PMID- 26056227 TI - ZC4H2, an XLID gene, is required for the generation of a specific subset of CNS interneurons. AB - Miles-Carpenter syndrome (MCS) was described in 1991 as an XLID syndrome with fingertip arches and contractures and mapped to proximal Xq. Patients had microcephaly, short stature, mild spasticity, thoracic scoliosis, hyperextendable MCP joints, rocker-bottom feet, hyperextended elbows and knees. A mutation, p.L66H, in ZC4H2, was identified in a XLID re-sequencing project. Additional screening of linked families and next generation sequencing of XLID families identified three ZC4H2 mutations: p.R18K, p.R213W and p.V75in15aa. The families shared some relevant clinical features. In silico modeling of the mutant proteins indicated all alterations would destabilize the protein. Knockout mutations in zc4h2 were created in zebrafish and homozygous mutant larvae exhibited abnormal swimming, increased twitching, defective eye movement and pectoral fin contractures. Because several of the behavioral defects were consistent with hyperactivity, we examined the underlying neuronal defects and found that sensory neurons and motoneurons appeared normal. However, we observed a striking reduction in GABAergic interneurons. Analysis of cell-type-specific markers showed a specific loss of V2 interneurons in the brain and spinal cord, likely arising from mis-specification of neural progenitors. Injected human wt ZC4H2 rescued the mutant phenotype. Mutant zebrafish injected with human p.L66H or p.R213W mRNA failed to be rescued, while the p.R18K mRNA was able to rescue the interneuron defect. Our findings clearly support ZC4H2 as a novel XLID gene with a required function in interneuron development. Loss of function of ZC4H2 thus likely results in altered connectivity of many brain and spinal circuits. PMID- 26056229 TI - ERRATA. "Minimal Disseminated Disease in High-Risk Burkitt's Lymphoma Identifies Patients With Different Prognosis". PMID- 26056228 TI - I2020T mutant LRRK2 iPSC-derived neurons in the Sagamihara family exhibit increased Tau phosphorylation through the AKT/GSK-3beta signaling pathway. AB - Leucine-rich repeat kinase 2 (LRRK2) is the causative molecule of the autosomal dominant hereditary form of Parkinson's disease (PD), PARK8, which was originally defined in a study of a Japanese family (the Sagamihara family) harboring the I2020T mutation in the kinase domain. Although a number of reported studies have focused on cell death mediated by mutant LRRK2, details of the pathogenetic effect of LRRK2 still remain to be elucidated. In the present study, to elucidate the mechanism of neurodegeneration in PD caused by LRRK2, we generated induced pluripotent stem cells (iPSC) derived from fibroblasts of PD patients with I2020T LRRK2 in the Sagamihara family. We found that I2020T mutant LRRK2 iPSC-derived neurons released less dopamine than control-iPSC-derived neurons. Furthermore, we demonstrated that patient iPSC-derived neurons had a lower phospho-AKT level than control-iPSC-derived neurons, and that the former showed an increased incidence of apoptosis relative to the controls. Interestingly, patient iPSC-derived neurons exhibited activation of glycogen synthase kinase-3beta (GSK-3beta) and high Tau phosphorylation. In addition, the postmortem brain of the patient from whom the iPSC had been established exhibited deposition of neurofibrillary tangles as well as increased Tau phosphorylation in neurons. These results suggest that I2020T LRRK2-iPSC could be a promising new tool for reproducing the pathology of PD in the brain caused by the I2020T mutation, and applicable as a model in studies of targeted therapeutics. PMID- 26056231 TI - Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors. AB - To investigate how transcription factor levels impact B-lymphocyte development, we generated mice carrying transheterozygous mutations in the Pax5 and Ebf1 genes. Whereas combined reduction of Pax5 and Ebf1 had minimal impact on the development of the earliest CD19(+) progenitors, these cells displayed an increased T cell potential in vivo and in vitro. The alteration in lineage fate depended on a Notch1-mediated conversion process, whereas no signs of de differentiation could be detected. The differences in functional response to Notch signaling in Wt and Pax5(+/-)Ebf1(+/-) pro-B cells were reflected in the transcriptional response. Both genotypes responded by the generation of intracellular Notch1 and activation of a set of target genes, but only the Pax5(+/-)Ebf1(+/-) pro-B cells down-regulated genes central for the preservation of stable B cell identity. This report stresses the importance of the levels of transcription factor expression during lymphocyte development, and suggests that Pax5 and Ebf1 collaborate to modulate the transcriptional response to Notch signaling. This provides an insight on how transcription factors like Ebf1 and Pax5 preserve cellular identity during differentiation. PMID- 26056232 TI - CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. AB - Pulmonary metastasis of breast cancer cells is promoted by a distinct population of macrophages, metastasis-associated macrophages (MAMs), which originate from inflammatory monocytes (IMs) recruited by the CC-chemokine ligand 2 (CCL2). We demonstrate here that, through activation of the CCL2 receptor CCR2, the recruited MAMs secrete another chemokine ligand CCL3. Genetic deletion of CCL3 or its receptor CCR1 in macrophages reduces the number of lung metastasis foci, as well as the number of MAMs accumulated in tumor-challenged lung in mice. Adoptive transfer of WT IMs increases the reduced number of lung metastasis foci in Ccl3 deficient mice. Mechanistically, Ccr1 deficiency prevents MAM retention in the lung by reducing MAM-cancer cell interactions. These findings collectively indicate that the CCL2-triggered chemokine cascade in macrophages promotes metastatic seeding of breast cancer cells thereby amplifying the pathology already extant in the system. These data suggest that inhibition of CCR1, the distal part of this signaling relay, may have a therapeutic impact in metastatic disease with lower toxicity than blocking upstream targets. PMID- 26056238 TI - Targeted Electrolyte Replacement in Patients With Ebola Virus Disease. PMID- 26056233 TI - The Dishevelled-binding protein CXXC5 negatively regulates cutaneous wound healing. AB - Wnt/beta-catenin signaling plays important roles in cutaneous wound healing and dermal fibrosis. However, its regulatory mechanism has not been fully elucidated, and a commercially available wound-healing agent targeting this pathway is desirable but currently unavailable. We found that CXXC-type zinc finger protein 5 (CXXC5) serves as a negative feedback regulator of the Wnt/beta-catenin pathway by interacting with the Dishevelled (Dvl) protein. In humans, CXXC5 protein levels were reduced in epidermal keratinocytes and dermal fibroblasts of acute wounds. A differential regulation of beta-catenin, alpha-smooth muscle actin (alpha-SMA), and collagen I by overexpression and silencing of CXXC5 in vitro indicated a critical role for this factor in myofibroblast differentiation and collagen production. In addition, CXXC5(-/-) mice exhibited accelerated cutaneous wound healing, as well as enhanced keratin 14 and collagen synthesis. Protein transduction domain (PTD)-Dvl-binding motif (DBM), a competitor peptide blocking CXXC5-Dvl interactions, disrupted this negative feedback loop and activated beta catenin and collagen production in vitro. Co-treatment of skin wounds with PTD DBM and valproic acid (VPA), a glycogen synthase kinase 3beta (GSK3beta) inhibitor which activates the Wnt/beta-catenin pathway, synergistically accelerated cutaneous wound healing in mice. Together, these data suggest that CXXC5 would represent a potential target for future therapies aimed at improving wound healing. PMID- 26056239 TI - Endo-epicardial versus only-endocardial ablation as a first line strategy for the treatment of ventricular tachycardia in patients with ischemic heart disease. AB - BACKGROUND: Epicardial ablation has shown improvement in clinical outcomes of patients with ischemic heart disease (IHD) after ventricular tachycardia (VT) ablation. However, usually epicardial access is only performed when endocardial ablation has failed. Our aim was to compare the efficacy of endocardial+epicardial ablation versus only endocardial ablation in the first procedure in patients with IHD. METHODS AND RESULTS: Fifty-three patients with IHD, referred for a first VT ablation to our institution, from 2012 to 2014, were included. They were divided in 2 groups according to enrollment time: from May 2013, we started to systematically perform endo-epicardial access (Epi-Group) as first-line approach in consecutive patients with IHD (n=15). Patients who underwent only an endocardial VT ablation in their first procedure (Endo-Group) included patients with previous cardiac surgery and the historical (before May 2013; n=35). All late-potentials in the scar zone were eliminated, and if VT was tolerated, critical isthmuses were also approached. The end point was the noninducibility of any VT. During a median follow-up of 15+/-10 months, the combined end point (hospital or emergency admission because of a ventricular tachycardia or reablation) occurred in 14 patients of the Endo-group and in one patient in the Epi-group (event-free survival curves by Grey-test, P=0.03). Ventricular arrhythmia recurrences occurred in 16 and in 3 patients in the Endo and Epi-Group, respectively (Grey-test, P=0.2). CONCLUSIONS: A combined endocardial-epicardial ablation approach for initial VT ablation was associated with fewer readmissions for VT and repeat ablations. Further studies are warranted. PMID- 26056240 TI - Modulation of work and power by the human lower-limb joints with increasing steady-state locomotion speed. AB - We investigated how the human lower-limb joints modulate work and power during walking and running on level ground. Experimental data were recorded from seven participants for a broad range of steady-state locomotion speeds (walking at 1.59+/-0.09 m s(-1) to sprinting at 8.95+/-0.70 m s(-1)). We calculated hip, knee and ankle work and average power (i.e. over time), along with the relative contribution from each joint towards the total (sum of hip, knee and ankle) amount of work and average power produced by the lower limb. Irrespective of locomotion speed, ankle positive work was greatest during stance, whereas hip positive work was greatest during swing. Ankle positive work increased with faster locomotion until a running speed of 5.01+/-0.11 m s(-1), where it plateaued at ~1.3 J kg(-1). In contrast, hip positive work during stance and swing, as well as knee negative work during swing, all increased when running speed progressed beyond 5.01+/-0.11 m s(-1). When switching from walking to running at the same speed (~2.0 m s(-1)), the ankle's contribution to the average power generated (and positive work done) by the lower limb during stance significantly increased from 52.7+/-10.4% to 65.3+/-7.5% (P=0.001), whereas the hip's contribution significantly decreased from 23.0+/-9.7% to 5.5+/-4.6% (P=0.004). With faster running, the hip's contribution to the average power generated (and positive work done) by the lower limb significantly increased during stance (P<0.001) and swing (P=0.003). Our results suggest that changing locomotion mode and faster steady-state running speeds are not simply achieved via proportional increases in work and average power at the lower-limb joints. PMID- 26056241 TI - Elevated temperature causes metabolic trade-offs at the whole-organism level in the Antarctic fish Trematomus bernacchii. AB - As a response to ocean warming, shifts in fish species distribution and changes in production have been reported that have been partly attributed to temperature effects on the physiology of animals. The Southern Ocean hosts some of the most rapidly warming regions on earth and Antarctic organisms are reported to be especially temperature sensitive. While cellular and molecular organismic levels appear, at least partially, to compensate for elevated temperatures, the consequences of acclimation to elevated temperature for the whole organism are often less clear. Growth and reproduction are the driving factors for population structure and abundance. The aim of this study was to assess the effect of long term acclimation to elevated temperature on energy budget parameters in the high Antarctic fish Trematomus bernacchii. Our results show a complete temperature compensation for routine metabolic costs after 9 weeks of acclimation to 4 degrees C. However, an up to 84% reduction in mass growth was measured at 2 and 4 degrees C compared with the control group at 0 degrees C, which is best explained by reduced food assimilation rates at warmer temperatures. With regard to a predicted temperature increase of up to 1.4 degrees C in the Ross Sea by 2200, such a significant reduction in growth is likely to affect population structures in nature, for example by delaying sexual maturity and reducing production, with severe impacts on Antarctic fish communities and ecosystems. PMID- 26056242 TI - Stress in Atlantic salmon: response to unpredictable chronic stress. AB - Combinations of stressors occur regularly throughout an animal's life, especially in agriculture and aquaculture settings. If an animal fails to acclimate to these stressors, stress becomes chronic, and a condition of allostatic overload arises with negative results for animal welfare. In the current study, we describe effects of exposing Atlantic salmon parr to an unpredictable chronic stressor (UCS) paradigm for 3 weeks. The paradigm involves exposure of fish to seven unpredictable stressors three times a day. At the end of the trial, experimental and control fish were challenged with yet another novel stressor and sampled before and 1 h after that challenge. Plasma cortisol decreased steadily over time in stressed fish, indicative of exhaustion of the endocrine stress axis. This was confirmed by a lower cortisol response to the novel stressor at the end of the stress period in chronically stressed fish compared with the control group. In the preoptic area (POA) and pituitary gland, chronic stress resulted in decreased gene expression of 11betahsd2, gr1 and gr2 in the POA and increased expression of those genes in the pituitary gland. POA crf expression and pituitary expression of pomcs and mr increased, whereas interrenal gene expression was unaffected. Exposure to the novel stressor had no effect on POA and interrenal gene expression. In the pituitary, crfr1, pomcs, 11betahsd2, grs and mr were down regulated. In summary, our results provide a novel overview of the dynamic changes that occur at every level of the hypothalamic-pituitary gland-interrenal gland (HPI) axis as a result of chronic stress in Atlantic salmon. PMID- 26056243 TI - Vibrissal sensitivity in a harbor seal (Phoca vitulina). AB - Prior efforts to characterize the capabilities of the vibrissal system in seals have yielded conflicting results. Here, we measured the sensitivity of the vibrissal system of a harbor seal (Phoca vitulina) to directly coupled sinusoidal stimuli delivered by a vibrating plate. A trained seal was tested in a psychophysical paradigm to determine the smallest velocity that was detectable at nine frequencies ranging from 10 to 1000 Hz. The stimulus plate was driven by a vibration shaker and the velocity of the plate at each frequency-amplitude combination was calibrated with a laser vibrometer. To prevent cueing from other sensory stimuli, the seal was fitted with a blindfold and headphones playing broadband masking noise. The seal was sensitive to vibrations across the range of frequencies tested, with best sensitivity of 0.09 mm s(-1) at 80 Hz. Velocity thresholds as a function of frequency showed a characteristic U-shaped curve with decreasing sensitivity below 20 Hz and above 250 Hz. To ground-truth the experimental setup, four human subjects were tested in the same paradigm using their thumb to contact the vibrating plate. Threshold measurements for the humans were similar to those of the seal, demonstrating comparable tactile sensitivity for their structurally different mechanoreceptive systems. The thresholds measured for the harbor seal in this study were about 100 times more sensitive than previous in-air measures of vibrissal sensitivity for this species. The results were similar to those reported by others for the detection of waterborne vibrations, but show an extended range of frequency sensitivity. PMID- 26056244 TI - Morphology and burrowing energetics of semi-fossorial skinks (Liopholis spp.). AB - Burrowing is an important form of locomotion in reptiles, but no study has examined the energetic cost of burrowing for reptiles. This is significant because burrowing is the most energetically expensive mode of locomotion undertaken by animals and many burrowing species therefore show specialisations for their subterranean lifestyle. We examined the effect of temperature and substrate characteristics (coarse sand or fine sand) on the net energetic cost of burrowing (NCOB) and burrowing rate in two species of the Egernia group of skinks (Liopholis striata and Liopholis inornata) compared with other burrowing animals. We further tested for morphological specialisations among burrowing species by comparing the relationship between body shape and retreat preference in Egernia group skinks. For L. striata and L. inornata, NCOB is 350 times more expensive than the predicted cost of pedestrian terrestrial locomotion. Temperature had a positive effect on burrowing rate for both species, and a negative effect on NCOB for L. striata but not L. inornata. Both NCOB and burrowing rate were independent of substrate type. Burrows constructed by skinks had a smaller cross-sectional area than those constructed by mammals of comparable mass, and NCOB of skinks was lower than that of mammals of similar mass. After accounting for body size, retreat preference was significantly correlated with body shape in Egernia group skinks. Species of Egernia group skinks that use burrows for retreats have narrower bodies and shorter front limbs than other species. We conclude that the morphological specialisations of burrowing skinks allow them to construct relatively narrow burrows, thereby reducing NCOB and the total cost of constructing their burrow retreats. PMID- 26056245 TI - 3D tracking of animals in the field using rotational stereo videography. AB - We describe a method for tracking the path of animals in the field, based on stereo videography and aiming-angle measurements, combined in a single, rotational device. In open environments, this technique has the potential to extract multiple 3D positions per second, with a spatial uncertainty of <1 m (rms) within 300 m of the observer, and <0.1 m (rms) within 100 m of the observer, in all directions. The tracking device is transportable and operated by a single observer, and does not involve any animal tagging. As a video of the moving animal is recorded, track data can easily be completed with behavioural data. We present a prototype device based on accessible components that achieves about 70% of the theoretical maximal range. We show examples of bird ground and flight tracks, and discuss the strengths and limits of the method, compared with existing fine-scale (e.g. fixed-camera stereo videography) and large-scale tracking methods (e.g. GPS tracking). PMID- 26056246 TI - Functional development of carbon dioxide detection in the maxillary palp of Anopheles gambiae. AB - Olfactory information drives several behaviours critical for the survival and persistence of insect pests and vectors. Insect behaviour is variable, linked to their biological needs, and regulated by physiological dynamics. For mosquitoes, CO2 is an important cue that signifies the presence of a host, and which elicits activation and attraction. To investigate the genetic basis of olfactory modulation in mosquitoes, we assayed changes in CO2 detection from receptor gene expression through physiological function to behaviour, associated with the onset of host seeking in the malaria vector, Anopheles gambiae. The gene encoding a subunit of the CO2 receptor, AgGr22, was found to be significantly up-regulated in host-seeking females, consistent with a significant increase in sensitivity of CO2-responsive neurons (cpA) housed in capitate peg sensilla of the maxillary palp. In addition, the odorant receptor AgOr28, which is expressed in cpC neurons, was significantly up-regulated. In contrast, AgOr8, which is expressed in cpB neurons, was not affected by this change in physiological state, in agreement with results for the obligate co-receptor Orco. Moreover, the sensitivity of the cpB neuron to (R)-1-octen-3-ol, a well-known mammalian kairomone, did not change in response to the onset of host seeking. The concentration of CO2 flux influenced both the propensity of A. gambiae to take off into the wind and the speed with which this activation occurred. Female A. gambiae mosquitoes responded to CO2 whether mature for host seeking or not, but onset of host seeking enhanced sensitivity and speed of activation at relevant doses of CO2. PMID- 26056247 TI - Support for the beam focusing hypothesis in the false killer whale. AB - The odontocete sound production system is complex and composed of tissues, air sacs and a fatty melon. Previous studies suggested that the emitted sonar beam might be actively focused, narrowing depending on target distance. In this study, we further tested this beam focusing hypothesis in a false killer whale. Using three linear arrays of hydrophones, we recorded the same emitted click at 2, 4 and 7 m distance and calculated the beamwidth, intensity, center frequency and bandwidth as recorded on each array at every distance. If the whale did not focus her beam, acoustics predicts the intensity would decay with range as a function of spherical spreading and the angular beamwidth would remain constant. On the contrary, our results show that as the distance from the whale to the array increases, the beamwidth is narrower and the received click intensity is higher than that predicted by a spherical spreading function. Each of these measurements is consistent with the animal focusing her beam on a target at a given range. These results support the hypothesis that the false killer whale is 'focusing' its sonar beam, producing a narrower and more intense signal than that predicted by spherical spreading. PMID- 26056248 TI - Prevalence and impact of high platelet reactivity in chronic kidney disease: results from the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents registry. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with increased rates of adverse events after percutaneous coronary intervention. We sought to determine the impact of CKD on platelet reactivity in clopidogrel-treated patients and whether high platelet reactivity (HPR) confers a similar or differential risk for adverse events among patients with CKD and non-CKD. METHODS AND RESULTS: We performed a post hoc analysis of the Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents (ADAPT-DES) registry, which included 8582 patients undergoing percutaneous coronary intervention with drug-eluting stents and platelet function testing using the VerifyNow assay. We compared HPR and its impact on ischemic and bleeding events >2 years among patients with CKD and non-CKD. Patients with CKD (n=1367) were older, more often female, diabetic, and had lower ejection fraction compared with their non-CKD counterparts (n=7043). Although HPR prevalence increased with worsening renal function in unadjusted analyses, these associations were no longer present after adjustment. Major adverse cardiac event rates at 2 years among those without CKD or HPR, HPR alone, CKD alone, and both CKD and HPR were 9.0%, 11.2%, 13.3%, and 17.5%, respectively (P<0.001). Associations between HPR and adverse events were uniform across CKD strata without evidence of interaction. CONCLUSIONS: HPR is more common among those with versus without CKD, an association that is attributable to confounding risk factors that are more prevalent in CKD. The impact of HPR on ischemic and bleeding events is similar irrespective of CKD status. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794. PMID- 26056250 TI - Is it time to join the cult? Radial access and percutaneous coronary intervention. PMID- 26056249 TI - Impact of arterial access site on outcomes after primary percutaneous coronary intervention: prespecified subgroup analysis from the EUROMAX trial. AB - BACKGROUND: In European Ambulance Acute Coronary Syndrome Angiography (EUROMAX), bivalirudin improved 30-day clinical outcomes with reduced major bleeding compared with heparins plus optional glycoprotein IIb/IIIa inhibitors. We assessed whether choice of access site (radial or femoral) had an impact on 30 day outcomes and whether it interacted with the benefit of bivalirudin. METHODS AND RESULTS: In EUROMAX, choice of arterial access was left to operator discretion. Overall, 47% of patients underwent radial and 53% femoral access. Baseline risk was higher in the femoral access group. Unadjusted proportions for the primary outcome (death or noncoronary artery bypass graft protocol major bleeding at 30 days) were lower with radial access, however, without differences in major or major plus minor bleeding proportions. After multivariable adjustment, ischemic outcomes were no longer different between access site groups, except for a lower risk of stroke in radial patients. Bivalirudin was associated with lower proportions of the primary outcome in both the radial (odds ratio, 0.58; 95% CI, 0.33-1.03; P=0.058) and the femoral groups (odds ratio, 0.59; 95% CI, 0.37-0.93; P=0.022; interaction P=0.97). Bleeding was significantly lower in the bivalirudin group both in the radial- and femoral-treated patients but no significant difference was observed in ischemic outcomes. In multivariable analysis, bivalirudin emerged as the only independent predictor of reduced major bleeding (odds ratio, 0.45; 95% CI, 0.27-0.74; P=0.002). CONCLUSIONS: In this prespecified analysis from EUROMAX, radial access was preferred in lower risk patients and did not improve clinical outcomes. Bivalirudin was associated with less bleeding irrespective of access site. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01087723. PMID- 26056251 TI - Defining the link between chronic kidney disease, high platelet reactivity, and clinical outcomes in clopidogrel-treated patients undergoing percutaneous coronary intervention. PMID- 26056252 TI - Determinants and Outcomes of Accelerated Arteriosclerosis: Major Impact of Circulating Antibodies. AB - RATIONALE: The role of circulating antibodies in addition to traditional cardiovascular risk factors in the development of accelerated arteriosclerosis and their long-term clinical consequences have not been demonstrated. OBJECTIVE: We investigated the role of circulating antibodies in accelerated arteriosclerosis and the role of immune-associated arteriosclerosis in graft and patient survival and the occurrence of major adverse cardiovascular events. METHODS AND RESULTS: This was an observational prospective cohort study that included 1065 kidney transplant patients (principal cohort, n=744; validation cohort, n=321) between 2004 and 2010. Participants were assessed for traditional cardiovascular risk factors and circulating anti-human leukocyte antigen (HLA) antibodies. All patients underwent allograft biopsies to assess arteriosclerotic lesions and endothelial activation, endarteritis, and complement deposition. In the principal cohort, 250 (33.6%) patients had severe arteriosclerosis (luminal narrowing >25% via fibrointimal arterial thickening). Circulating donor-specific anti-HLA antibodies were significantly associated with severe allograft arteriosclerosis (hazard ratio, 2.9; P<0.0001), independently of traditional risk factors. Patients with severe arteriosclerosis and anti-HLA antibodies (n=91, 12.2%) demonstrated allograft endothelial activation, endarteritis, and complement deposition. High levels of anti-HLA antibodies and their complement binding capacity were associated with increased severity of arteriosclerosis. Patients with antibody-associated severe arteriosclerosis had decreased allograft survival and increased mortality (P<0.0001); they exhibited a 2.5- and 4.1-fold increased risk of major adverse cardiovascular events compared with patients who had severe arteriosclerosis without antibodies and patients with minimal arteriosclerosis, respectively (P<0.0005). Circulating donor-specific anti-HLA antibodies were significantly associated with occurrence of major adverse cardiovascular events (hazard ratio, 2.4; P=0.0004), independently of traditional risk factors. CONCLUSIONS: Circulating antibodies are major determinants of severe arteriosclerosis and major adverse cardiovascular events, independent of traditional cardiovascular risk factors. PMID- 26056253 TI - Early Development in the Peritoneal Cavity of CD49dhigh Th1 Memory Phenotype CD4+ T Cells with Enhanced B Cell Helper Activity. AB - The Th cells that regulate peritoneal B-1 cell functions have not yet been well characterized. To address this question, we investigated peritoneal CD4(+) T cells, observed a high frequency of the conjugates of B-CD4(+) T cells in the peritoneal cavity, and identified a population of CD49d(high)CD4(+) T cells that constituted about half of all CD4(+) T cells in the peritoneal cavity, but were rarely found in other compartments. Peritoneal CD49d(high)CD4(+) T cells were CD44(high)CD62L(low); expressed integrin alpha4beta1 and CXCR3; and rapidly secreted IFN-gamma, TNF-alpha, and IL-2, showing features of proinflammatory Th1 cells. Peritoneal CD49d(high)CD4(+) T cells developed spontaneously, were detected at the age of 12 d, and showed stem cell-like properties. Their development was observed in mice deficient for signaling lymphocytic activation molecule-associated protein, but not in athymic nude mice and mice lacking in expression of MHC class II on thymic epithelial cells. Peritoneal CD49d(high)CD4(+) T cells were more resistant to irradiation and more sensitive to NAD-induced cell death than CD49d(low)CD4(+) T cells. Notably, peritoneal CD49d(high)CD4(+) T cells also showed some characteristics of follicular Th cells, such as the expression of programmed cell death 1, ICOS, IL-21, and CXCR5. Moreover, peritoneal CD49d(high)CD4(+) T cells enhanced the secretion of IgM Abs by B-1a cells and IgG Abs by splenic B cells. These data suggest that peritoneal CD49d(high)CD4(+) T cells may be innate-like CD4(+) T cells, which develop early and have a dual capacity to support both humoral and cellular immunity. PMID- 26056254 TI - Cutting Edge: Drebrin-Regulated Actin Dynamics Regulate IgE-Dependent Mast Cell Activation and Allergic Responses. AB - Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5 bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcepsilonRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcepsilonRI, and agents that relieve actin reorganization rescue mast cell FcepsilonRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo. PMID- 26056255 TI - Tr1 Cells, but Not Foxp3+ Regulatory T Cells, Suppress NLRP3 Inflammasome Activation via an IL-10-Dependent Mechanism. AB - The two best-characterized types of CD4(+) regulatory T cells (Tregs) are Foxp3(+) Tregs and Foxp3(-) type 1 regulatory (Tr1) cells. The ability of Foxp3(+) Tregs and Tr1 cells to suppress adaptive immune responses is well known, but how these cells regulate innate immunity is less defined. We discovered that CD44(hi)Foxp3(-) T cells from unmanipulated mice are enriched in Tr1 cell precursors, enabling differentiation of cells that express IL-10, as well as Tr1 associated cell surface markers, CD49b and LAG-3, and transcription factors, cMaf, Blimp-1, and AhR. We compared the ability of Tr1 cells versus Foxp3(+) Tregs to suppress IL-1beta production from macrophages following LPS and ATP stimulation. Surprisingly, Tr1 cells, but not Foxp3(+) Tregs, inhibited the transcription of pro-IL-1beta mRNA, inflammasome-mediated activation of caspase 1, and secretion of mature IL-1beta. Consistent with the role for IL-10 in Tr1 cell-mediated suppression, inhibition of inflammasome activation and IL-1beta secretion was abrogated in IL-10R-deficient macrophages. Moreover, IL-1beta production from macrophages derived from Nlrp3(A350V) knockin mice, which carry a mutation found in cryopyrin-associated periodic syndrome patients, was suppressed by Tr1 cells but not Foxp3(+) Tregs. Using an adoptive transfer model, we found a direct correlation between Tr1 cell engraftment and protection from weight loss in mice expressing a gain-of-function NLRP3. Collectively, these data provide the first evidence for a differential role of Tr1 cells and Foxp3(+) Tregs in regulating innate immune responses. Through their capacity to produce high amounts of IL-10, Tr1 cells may have unique therapeutic effects in disease associated inflammasome activation. PMID- 26056256 TI - Transmission potential of Rickettsia felis infection by Anopheles gambiae mosquitoes. AB - A growing number of recent reports have implicated Rickettsia felis as a human pathogen, paralleling the increasing detection of R. felis in arthropod hosts across the globe, primarily in fleas. Here Anopheles gambiae mosquitoes, the primary malarial vectors in sub-Saharan Africa, were fed with either blood meal infected with R. felis or infected cellular media administered in membrane feeding systems. In addition, a group of mosquitoes was fed on R. felis-infected BALB/c mice. The acquisition and persistence of R. felis in mosquitoes was demonstrated by quantitative PCR detection of the bacteria up to day 15 postinfection. R. felis was detected in mosquito feces up to day 14. Furthermore, R. felis was visualized by immunofluorescence in salivary glands, in and around the gut, and in the ovaries, although no vertical transmission was observed. R. felis was also found in the cotton used for sucrose feeding after the mosquitoes were fed infected blood. Natural bites from R. felis-infected An. gambiae were able to cause transient rickettsemias in mice, indicating that this mosquito species has the potential to be a vector of R. felis infection. This is particularly important given the recent report of high prevalence of R. felis infection in patients with "fever of unknown origin" in malaria-endemic areas. PMID- 26056258 TI - Unconscious and conscious mediation of analgesia and hyperalgesia. PMID- 26056257 TI - Conformational processing of oncogenic v-Src kinase by the molecular chaperone Hsp90. AB - Hsp90 is a molecular chaperone involved in the activation of numerous client proteins, including many kinases. The most stringent kinase client is the oncogenic kinase v-Src. To elucidate how Hsp90 chaperones kinases, we reconstituted v-Src kinase chaperoning in vitro and show that its activation is ATP-dependent, with the cochaperone Cdc37 increasing the efficiency. Consistent with in vivo results, we find that Hsp90 does not influence the almost identical c-Src kinase. To explain these findings, we designed Src kinase chimeras that gradually transform c-Src into v-Src and show that their Hsp90 dependence correlates with compactness and folding cooperativity. Molecular dynamics simulations and hydrogen/deuterium exchange of Hsp90-dependent Src kinase variants further reveal increased transitions between inactive and active states and exposure of specific kinase regions. Thus, Hsp90 shifts an ensemble of conformations of v-Src toward high activity states that would otherwise be metastable and poorly populated. PMID- 26056259 TI - TOE1 is an inhibitor of HIV-1 replication with cell-penetrating capability. AB - Target of Egr1 (TOE1) is a nuclear protein localized primarily in nucleoli and Cajal bodies that was identified as a downstream target of the immediate early gene Egr1. TOE1 displays a functional deadenylation domain and has been shown to participate in spliceosome assembly. We report here that TOE1 can function as an inhibitor of HIV-1 replication and show evidence that supports a direct interaction of TOE1 with the viral specific transactivator response element as part of the inhibitory mechanism. In addition, we show that TOE1 can be secreted by activated CD8(+) T lymphocytes and can be cleaved by the serine protease granzyme B, one of the main components of cytotoxic granules. Both full-length and cleaved TOE1 can spontaneously cross the plasma membrane and penetrate cells in culture, retaining HIV-1 inhibitory activity. Antiviral potency of TOE1 and its cell-penetrating capability have been identified to lie within a 35-amino acid region containing the nuclear localization sequence. PMID- 26056260 TI - GABAB receptor deficiency causes failure of neuronal homeostasis in hippocampal networks. AB - Stabilization of neuronal activity by homeostatic control systems is fundamental for proper functioning of neural circuits. Failure in neuronal homeostasis has been hypothesized to underlie common pathophysiological mechanisms in a variety of brain disorders. However, the key molecules regulating homeostasis in central mammalian neural circuits remain obscure. Here, we show that selective inactivation of GABAB, but not GABA(A), receptors impairs firing rate homeostasis by disrupting synaptic homeostatic plasticity in hippocampal networks. Pharmacological GABA(B) receptor (GABA(B)R) blockade or genetic deletion of the GB(1a) receptor subunit disrupts homeostatic regulation of synaptic vesicle release. GABA(B)Rs mediate adaptive presynaptic enhancement to neuronal inactivity by two principle mechanisms: First, neuronal silencing promotes syntaxin-1 switch from a closed to an open conformation to accelerate soluble N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly, and second, it boosts spike-evoked presynaptic calcium flux. In both cases, neuronal inactivity removes tonic block imposed by the presynaptic, GB(1a) containing receptors on syntaxin-1 opening and calcium entry to enhance probability of vesicle fusion. We identified the GB(1a) intracellular domain essential for the presynaptic homeostatic response by tuning intermolecular interactions among the receptor, syntaxin-1, and the Ca(V)2.2 channel. The presynaptic adaptations were accompanied by scaling of excitatory quantal amplitude via the postsynaptic, GB(1b)-containing receptors. Thus, GABA(B)Rs sense chronic perturbations in GABA levels and transduce it to homeostatic changes in synaptic strength. Our results reveal a novel role for GABA(B)R as a key regulator of population firing stability and propose that disruption of homeostatic synaptic plasticity may underlie seizure's persistence in the absence of functional GABA(B)Rs. PMID- 26056261 TI - Tenebrionid secretions and a fungal benzoquinone oxidoreductase form competing components of an arms race between a host and pathogen. AB - Entomopathogenic fungi and their insect hosts represent a model system for examining invertebrate-pathogen coevolutionary selection processes. Here we report the characterization of competing components of an arms race consisting of insect protective antimicrobial compounds and evolving fungal mechanisms of detoxification. The insect pathogenic fungus Beauveria bassiana has a remarkably wide host range; however, some insects are resistant to fungal infection. Among resistant insects is the tenebrionid beetle Tribolium castaneum that produces benzoquinone-containing defensive secretions. Reduced fungal germination and growth was seen in media containing T. castaneum dichloromethane extracts or synthetic benzoquinone. In response to benzoquinone exposure, the fungus expresses a 1,4-benzoquinone oxidoreductase, BbbqrA, induced >40-fold. Gene knockout mutants (DeltaBbbqrA) showed increased growth inhibition, whereas B. bassiana overexpressing BbbqrA (Bb::BbbqrA(O)) displayed increased resistance to benzoquinone compared with wild type. Increased benzoquinone reductase activity was detected in wild-type cells exposed to benzoquinone and in the overexpression strain. Heterologous expression and purification of BbBqrA in Escherichia coli confirmed NAD(P)H-dependent benzoquinone reductase activity. The DeltaBbbqrA strain showed decreased virulence toward T. castaneum, whereas overexpression of BbbqrA increased mortality versus T. castaneum. No change in virulence was seen for the DeltaBbbqrA or Bb::BbbqrA(O) strains when tested against the greater wax moth Galleria mellonella or the beetle Sitophilus oryzae, neither of which produce significant amounts of cuticular quinones. The observation that artificial overexpression of BbbqrA results in increased virulence only toward quinone-secreting insects implies the lack of strong selection or current failure of B. bassiana to counteradapt to this particular host defense throughout evolution. PMID- 26056262 TI - Cytochrome cbb3 of Thioalkalivibrio is a Na+-pumping cytochrome oxidase. AB - Cytochrome c oxidases (Coxs) are the basic energy transducers in the respiratory chain of the majority of aerobic organisms. Coxs studied to date are redox-driven proton-pumping enzymes belonging to one of three subfamilies: A-, B-, and C-type oxidases. The C-type oxidases (cbb3 cytochromes), which are widespread among pathogenic bacteria, are the least understood. In particular, the proton-pumping machinery of these Coxs has not yet been elucidated despite the availability of X ray structure information. Here, we report the discovery of the first (to our knowledge) sodium-pumping Cox (Scox), a cbb3 cytochrome from the extremely alkaliphilic bacterium Thioalkalivibrio versutus. This finding offers clues to the previously unknown structure of the ion-pumping channel in the C-type Coxs and provides insight into the functional properties of this enzyme. PMID- 26056263 TI - Regulation by a chaperone improves substrate selectivity during cotranslational protein targeting. AB - The ribosome exit site is a crowded environment where numerous factors contact nascent polypeptides to influence their folding, localization, and quality control. Timely and accurate selection of nascent polypeptides into the correct pathway is essential for proper protein biogenesis. To understand how this is accomplished, we probe the mechanism by which nascent polypeptides are accurately sorted between the major cotranslational chaperone trigger factor (TF) and the essential cotranslational targeting machinery, signal recognition particle (SRP). We show that TF regulates SRP function at three distinct stages, including binding of the translating ribosome, membrane targeting via recruitment of the SRP receptor, and rejection of ribosome-bound nascent polypeptides beyond a critical length. Together, these mechanisms enhance the specificity of substrate selection into both pathways. Our results reveal a multilayered mechanism of molecular interplay at the ribosome exit site, and provide a conceptual framework to understand how proteins are selected among distinct biogenesis machineries in this crowded environment. PMID- 26056264 TI - Fundamental limits on the accuracy of demographic inference based on the sample frequency spectrum. AB - The sample frequency spectrum (SFS) of DNA sequences from a collection of individuals is a summary statistic that is commonly used for parametric inference in population genetics. Despite the popularity of SFS-based inference methods, little is currently known about the information theoretic limit on the estimation accuracy as a function of sample size. Here, we show that using the SFS to estimate the size history of a population has a minimax error of at least O(1/log s), where s is the number of independent segregating sites used in the analysis. This rate is exponentially worse than known convergence rates for many classical estimation problems in statistics. Another surprising aspect of our theoretical bound is that it does not depend on the dimension of the SFS, which is related to the number of sampled individuals. This means that, for a fixed number s of segregating sites considered, using more individuals does not help to reduce the minimax error bound. Our result pertains to populations that have experienced a bottleneck, and we argue that it can be expected to apply to many populations in nature. PMID- 26056265 TI - Amelioration of toxicity in neuronal models of amyotrophic lateral sclerosis by hUPF1. AB - Over 30% of patients with amyotrophic lateral sclerosis (ALS) exhibit cognitive deficits indicative of frontotemporal dementia (FTD), suggesting a common pathogenesis for both diseases. Consistent with this hypothesis, neuronal and glial inclusions rich in TDP43, an essential RNA-binding protein, are found in the majority of those with ALS and FTD, and mutations in TDP43 and a related RNA binding protein, FUS, cause familial ALS and FTD. TDP43 and FUS affect the splicing of thousands of transcripts, in some cases triggering nonsense-mediated mRNA decay (NMD), a highly conserved RNA degradation pathway. Here, we take advantage of a faithful primary neuronal model of ALS and FTD to investigate and characterize the role of human up-frameshift protein 1 (hUPF1), an RNA helicase and master regulator of NMD, in these disorders. We show that hUPF1 significantly protects mammalian neurons from both TDP43- and FUS-related toxicity. Expression of hUPF2, another essential component of NMD, also improves survival, whereas inhibiting NMD prevents rescue by hUPF1, suggesting that hUPF1 acts through NMD to enhance survival. These studies emphasize the importance of RNA metabolism in ALS and FTD, and identify a uniquely effective therapeutic strategy for these disorders. PMID- 26056267 TI - Relationship of the quaternary structure of human secretory IgA to neutralization of influenza virus. AB - Secretory IgA (S-IgA) antibodies, the major contributors to humoral mucosal immunity to influenza virus infection, are polymeric Igs present in many external secretions. In the present study, the quaternary structures of human S-IgA induced in nasal mucosa after administration of intranasal inactivated influenza vaccines were characterized in relation to neutralization potency against influenza A viruses. Human nasal IgA antibodies have been shown to contain at least five quaternary structures. Direct and real-time visualization of S-IgA using high-speed atomic force microscopy (AFM) demonstrated that trimeric and tetrameric S-IgA had six and eight antigen-binding sites, respectively, and that these structures exhibited large-scale asynchronous conformational changes while capturing influenza HA antigens in solution. Furthermore, trimeric, tetrameric, and larger polymeric structures, which are minor fractions in human nasal IgA, displayed increased neutralizing potency against influenza A viruses compared with dimeric S-IgA, suggesting that the larger polymeric than dimeric forms of S IgA play some important roles in protection against influenza A virus infection in the human upper respiratory tract. PMID- 26056266 TI - Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis. AB - Recent genetic evidence suggests that aberrant glycosphingolipid metabolism plays an important role in several neuromuscular diseases including hereditary spastic paraplegia, hereditary sensory neuropathy type 1, and non-5q spinal muscular atrophy. Here, we investigated whether altered glycosphingolipid metabolism is a modulator of disease course in amyotrophic lateral sclerosis (ALS). Levels of ceramide, glucosylceramide, galactocerebroside, lactosylceramide, globotriaosylceramide, and the gangliosides GM3 and GM1 were significantly elevated in spinal cords of ALS patients. Moreover, enzyme activities (glucocerebrosidase-1, glucocerebrosidase-2, hexosaminidase, galactosylceramidase, alpha-galactosidase, and beta-galactosidase) mediating glycosphingolipid hydrolysis were also elevated up to threefold. Increased ceramide, glucosylceramide, GM3, and hexosaminidase activity were also found in SOD1(G93A) mice, a familial model of ALS. Inhibition of glucosylceramide synthesis accelerated disease course in SOD1(G93A) mice, whereas infusion of exogenous GM3 significantly slowed the onset of paralysis and increased survival. Our results suggest that glycosphingolipids are likely important participants in pathogenesis of ALS and merit further analysis as potential drug targets. PMID- 26056268 TI - Essential role of the cytochrome P450 CYP4F22 in the production of acylceramide, the key lipid for skin permeability barrier formation. AB - A skin permeability barrier is essential for terrestrial animals, and its impairment causes several cutaneous disorders such as ichthyosis and atopic dermatitis. Although acylceramide is an important lipid for the skin permeability barrier, details of its production have yet to be determined, leaving the molecular mechanism of skin permeability barrier formation unclear. Here we identified the cytochrome P450 gene CYP4F22 (cytochrome P450, family 4, subfamily F, polypeptide 22) as the long-sought fatty acid omega-hydroxylase gene required for acylceramide production. CYP4F22 has been identified as one of the autosomal recessive congenital ichthyosis-causative genes. Ichthyosis-mutant proteins exhibited reduced enzyme activity, indicating correlation between activity and pathology. Furthermore, lipid analysis of a patient with ichthyosis showed a drastic decrease in acylceramide production. We determined that CYP4F22 was a type I membrane protein that locates in the endoplasmic reticulum (ER), suggesting that the omega-hydroxylation occurs on the cytoplasmic side of the ER. The preferred substrate of the CYP4F22 was fatty acids with a carbon chain length of 28 or more (>=C28). In conclusion, our findings demonstrate that CYP4F22 is an ultra-long-chain fatty acid omega-hydroxylase responsible for acylceramide production and provide important insights into the molecular mechanisms of skin permeability barrier formation. Furthermore, based on the results obtained here, we proposed a detailed reaction series for acylceramide production. PMID- 26056269 TI - Structural basis of a Ni acquisition cycle for [NiFe] hydrogenase by Ni metallochaperone HypA and its enhancer. AB - The Ni atom at the catalytic center of [NiFe] hydrogenases is incorporated by a Ni-metallochaperone, HypA, and a GTPase/ATPase, HypB. We report the crystal structures of the transient complex formed between HypA and ATPase-type HypB (HypBAT) with Ni ions. Transient association between HypA and HypBAT is controlled by the ATP hydrolysis cycle of HypBAT, which is accelerated by HypA. Only the ATP-bound form of HypBAT can interact with HypA and induces drastic conformational changes of HypA. Consequently, upon complex formation, a conserved His residue of HypA comes close to the N-terminal conserved motif of HypA and forms a Ni-binding site, to which a Ni ion is bound with a nearly square-planar geometry. The Ni binding site in the HypABAT complex has a nanomolar affinity (Kd = 7 nM), which is in contrast to the micromolar affinity (Kd = 4 uM) observed with the isolated HypA. The ATP hydrolysis and Ni binding cause conformational changes of HypBAT, affecting its association with HypA. These findings indicate that HypA and HypBAT constitute an ATP-dependent Ni acquisition cycle for [NiFe] hydrogenase maturation, wherein HypBAT functions as a metallochaperone enhancer and considerably increases the Ni-binding affinity of HypA. PMID- 26056270 TI - BMP9 and BMP10 are necessary for proper closure of the ductus arteriosus. AB - The transition to pulmonary respiration after birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. Two members of the TGFbeta family, bone morphogenetic protein 9 (BMP9) and BMP10, have been recently involved in postnatal angiogenesis, both being necessary for remodeling of newly formed microvascular beds. The aim of the present work was to study whether BMP9 and BMP10 could be involved in closure of the DA. We found that Bmp9 knockout in mice led to an imperfect closure of the DA. Further, addition of a neutralizing anti-BMP10 antibody at postnatal day 1 (P1) and P3 in these pups exacerbated the remodeling defect and led to a reopening of the DA at P4. Transmission electron microscopy images and immunofluorescence stainings suggested that this effect could be due to a defect in intimal cell differentiation from endothelial to mesenchymal cells, associated with a lack of extracellular matrix deposition within the center of the DA. This result was supported by the identification of the regulation by BMP9 and BMP10 of several genes known to be involved in this process. The involvement of these BMPs was further supported by human genomic data because we could define a critical region in chromosome 2 encoding eight genes including BMP10 that correlated with the presence of a patent DA. Together, these data establish roles for BMP9 and BMP10 in DA closure. PMID- 26056271 TI - Bioimage analysis of Shigella infection reveals targeting of colonic crypts. AB - Few studies within the pathogenic field have used advanced imaging and analytical tools to quantitatively measure pathogenicity in vivo. In this work, we present a novel approach for the investigation of host-pathogen processes based on medium throughput 3D fluorescence imaging. The guinea pig model for Shigella flexneri invasion of the colonic mucosa was used to monitor the infectious process over time with GFP-expressing S. flexneri. A precise quantitative imaging protocol was devised to follow individual S. flexneri in a large tissue volume. An extensive dataset of confocal images was obtained and processed to extract specific quantitative information regarding the progression of S. flexneri infection in an unbiased and exhaustive manner. Specific parameters included the analysis of S. flexneri positions relative to the epithelial surface, S. flexneri density within the tissue, and volume of tissue destruction. In particular, at early time points, there was a clear association of S. flexneri with crypts, key morphological features of the colonic mucosa. Numerical simulations based on random bacterial entry confirmed the bias of experimentally measured S. flexneri for early crypt targeting. The application of a correlative light and electron microscopy technique adapted for thick tissue samples further confirmed the location of S. flexneri within colonocytes at the mouth of crypts. This quantitative imaging approach is a novel means to examine host-pathogen systems in a tailored and robust manner, inclusive of the infectious agent. PMID- 26056272 TI - Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly. AB - Membrane contact sites (MCS) between organelles are proposed as nexuses for the exchange of lipids, small molecules, and other signals crucial to cellular function and homeostasis. Various protein complexes, such as the endoplasmic reticulum-mitochondrial encounter structure (ERMES), function as dynamic molecular tethers between organelles. Here, we report the reconstitution and characterization of subcomplexes formed by the cytoplasm-exposed synaptotagmin like mitochondrial lipid-binding protein (SMP) domains present in three of the five ERMES subunits--the soluble protein Mdm12, the endoplasmic reticulum (ER) resident membrane protein Mmm1, and the mitochondrial membrane protein Mdm34. SMP domains are conserved lipid-binding domains found exclusively in proteins at MCS. We show that the SMP domains of Mdm12 and Mmm1 associate into a tight heterotetramer with equimolecular stoichiometry. Our 17-A-resolution EM structure of the complex reveals an elongated crescent-shaped particle in which two Mdm12 subunits occupy symmetric but distal positions at the opposite ends of a central ER-anchored Mmm1 homodimer. Rigid body fitting of homology models of these SMP domains in the density maps reveals a distinctive extended tubular structure likely traversed by a hydrophobic tunnel. Furthermore, these two SMP domains bind phospholipids and display a strong preference for phosphatidylcholines, a class of phospholipids whose exchange between the ER and mitochondria is essential. Last, we show that the three SMP-containing ERMES subunits form a ternary complex in which Mdm12 bridges Mmm1 to Mdm34. Our findings highlight roles for SMP domains in ERMES assembly and phospholipid binding and suggest a structure-based mechanism for the facilitated transport of phospholipids between organelles. PMID- 26056273 TI - Cooperative folding of a polytopic alpha-helical membrane protein involves a compact N-terminal nucleus and nonnative loops. AB - Despite the ubiquity of helical membrane proteins in nature and their pharmacological importance, the mechanisms guiding their folding remain unclear. We performed kinetic folding and unfolding experiments on 69 mutants (engineered every 2-3 residues throughout the 178-residue transmembrane domain) of GlpG, a membrane-embedded rhomboid protease from Escherichia coli. The only clustering of significantly positive phi-values occurs at the cytosolic termini of transmembrane helices 1 and 2, which we identify as a compact nucleus. The three loops flanking these helices show a preponderance of negative phi-values, which are sometimes taken to be indicative of nonnative interactions in the transition state. Mutations in transmembrane helices 3-6 yielded predominantly phi-values near zero, indicating that this part of the protein has denatured-state-level structure in the transition state. We propose that loops 1-3 undergo conformational rearrangements to position the folding nucleus correctly, which then drives folding of the rest of the domain. A compact N-terminal nucleus is consistent with the vectorial nature of cotranslational membrane insertion found in vivo. The origin of the interactions in the transition state that lead to a large number of negative phi-values remains to be elucidated. PMID- 26056274 TI - Host lysozyme-mediated lysis of Lactococcus lactis facilitates delivery of colitis-attenuating superoxide dismutase to inflamed colons. AB - Beneficial microbes that target molecules and pathways, such as oxidative stress, which can negatively affect both host and microbiota, may hold promise as an inflammatory bowel disease therapy. Prior work showed that a five-strain fermented milk product (FMP) improved colitis in T-bet(-/-) Rag2(-/-) mice. By varying the number of strains used in the FMP, we found that Lactococcus lactis I 1631 was sufficient to ameliorate colitis. Using comparative genomic analyses, we identified genes unique to L. lactis I-1631 involved in oxygen respiration. Respiration of oxygen results in reactive oxygen species (ROS) generation. Also, ROS are produced at high levels during intestinal inflammation and cause tissue damage. L. lactis I-1631 possesses genes encoding enzymes that detoxify ROS, such as superoxide dismutase (SodA). Thus, we hypothesized that lactococcal SodA played a role in attenuating colitis. Inactivation of the sodA gene abolished L. lactis I-1631's beneficial effect in the T-bet(-/-) Rag2(-/-) model. Similar effects were obtained in two additional colonic inflammation models, Il10(-/-) mice and dextran sulfate sodium-treated mice. Efforts to understand how a lipophobic superoxide anion (O2 (-)) can be detoxified by cytoplasmic lactoccocal SodA led to the finding that host antimicrobial-mediated lysis is a prerequisite for SodA release and SodA's extracytoplasmic O2 (-) scavenging. L. lactis I-1631 may represent a promising vehicle to deliver antioxidant, colitis-attenuating SodA to the inflamed intestinal mucosa, and host antimicrobials may play a critical role in mediating SodA's bioaccessibility. PMID- 26056275 TI - Inference of transcriptional regulation in cancers. AB - Despite the rapid accumulation of tumor-profiling data and transcription factor (TF) ChIP-seq profiles, efforts integrating TF binding with the tumor-profiling data to understand how TFs regulate tumor gene expression are still limited. To systematically search for cancer-associated TFs, we comprehensively integrated 686 ENCODE ChIP-seq profiles representing 150 TFs with 7484 TCGA tumor data in 18 cancer types. For efficient and accurate inference on gene regulatory rules across a large number and variety of datasets, we developed an algorithm, RABIT (regression analysis with background integration). In each tumor sample, RABIT tests whether the TF target genes from ChIP-seq show strong differential regulation after controlling for background effect from copy number alteration and DNA methylation. When multiple ChIP-seq profiles are available for a TF, RABIT prioritizes the most relevant ChIP-seq profile in each tumor. In each cancer type, RABIT further tests whether the TF expression and somatic mutation variations are correlated with differential expression patterns of its target genes across tumors. Our predicted TF impact on tumor gene expression is highly consistent with the knowledge from cancer-related gene databases and reveals many previously unidentified aspects of transcriptional regulation in tumor progression. We also applied RABIT on RNA-binding protein motifs and found that some alternative splicing factors could affect tumor-specific gene expression by binding to target gene 3'UTR regions. Thus, RABIT (rabit.dfci.harvard.edu) is a general platform for predicting the oncogenic role of gene expression regulators. PMID- 26056276 TI - High-resolution helix orientation in actin-bound myosin determined with a bifunctional spin label. AB - Using electron paramagnetic resonance (EPR) of a bifunctional spin label (BSL) bound stereospecifically to Dictyostelium myosin II, we determined with high resolution the orientation of individual structural elements in the catalytic domain while myosin is in complex with actin. BSL was attached to a pair of engineered cysteine side chains four residues apart on known alpha-helical segments, within a construct of the myosin catalytic domain that lacks other reactive cysteines. EPR spectra of BSL-myosin bound to actin in oriented muscle fibers showed sharp three-line spectra, indicating a well-defined orientation relative to the actin filament axis. Spectral analysis indicated that orientation of the spin label can be determined within <2.1 degrees accuracy, and comparison with existing structural data in the absence of nucleotide indicates that helix orientation can also be determined with <4.2 degrees accuracy. We used this approach to examine the crucial ADP release step in myosin's catalytic cycle and detected reversible rotations of two helices in actin-bound myosin in response to ADP binding and dissociation. One of these rotations has not been observed in myosin-only crystal structures. PMID- 26056277 TI - Predicting visual acuity from the structure of visual cortex. AB - Three decades ago, Rockel et al. proposed that neuronal surface densities (number of neurons under a square millimeter of surface) of primary visual cortices (V1s) in primates is 2.5 times higher than the neuronal density of V1s in nonprimates or many other cortical regions in primates and nonprimates. This claim has remained controversial and much debated. We replicated the study of Rockel et al. with attention to modern stereological precepts and show that indeed primate V1 is 2.5 times denser (number of neurons per square millimeter) than many other cortical regions and nonprimate V1s; we also show that V2 is 1.7 times as dense. As primate V1s are denser, they have more neurons and thus more pinwheels than similar-sized nonprimate V1s, which explains why primates have better visual acuity. PMID- 26056278 TI - Neurons selective to the number of visual items in the corvid songbird endbrain. AB - It is unknown whether anatomical specializations in the endbrains of different vertebrates determine the neuronal code to represent numerical quantity. Therefore, we recorded single-neuron activity from the endbrain of crows trained to judge the number of items in displays. Many neurons were tuned for numerosities irrespective of the physical appearance of the items, and their activity correlated with performance outcome. Comparison of both behavioral and neuronal representations of numerosity revealed that the data are best described by a logarithmically compressed scaling of numerical information, as postulated by the Weber-Fechner law. The behavioral and neuronal numerosity representations in the crow reflect surprisingly well those found in the primate association cortex. This finding suggests that distantly related vertebrates with independently developed endbrains adopted similar neuronal solutions to process quantity. PMID- 26056279 TI - Pathways for abiotic organic synthesis at submarine hydrothermal fields. AB - Arguments for an abiotic origin of low-molecular weight organic compounds in deep sea hot springs are compelling owing to implications for the sustenance of deep biosphere microbial communities and their potential role in the origin of life. Theory predicts that warm H2-rich fluids, like those emanating from serpentinizing hydrothermal systems, create a favorable thermodynamic drive for the abiotic generation of organic compounds from inorganic precursors. Here, we constrain two distinct reaction pathways for abiotic organic synthesis in the natural environment at the Von Damm hydrothermal field and delineate spatially where inorganic carbon is converted into bioavailable reduced carbon. We reveal that carbon transformation reactions in a single system can progress over hours, days, and up to thousands of years. Previous studies have suggested that CH4 and higher hydrocarbons in ultramafic hydrothermal systems were dependent on H2 generation during active serpentinization. Rather, our results indicate that CH4 found in vent fluids is formed in H2-rich fluid inclusions, and higher n-alkanes may likely be derived from the same source. This finding implies that, in contrast with current paradigms, these compounds may form independently of actively circulating serpentinizing fluids in ultramafic-influenced systems. Conversely, widespread production of formate by SigmaCO2 reduction at Von Damm occurs rapidly during shallow subsurface mixing of the same fluids, which may support anaerobic methanogenesis. Our finding of abiogenic formate in deep-sea hot springs has significant implications for microbial life strategies in the present-day deep biosphere as well as early life on Earth and beyond. PMID- 26056280 TI - Spatial gradient in value representation along the medial prefrontal cortex reflects individual differences in prosociality. AB - Despite the importance of valuing another person's welfare for prosocial behavior, currently we have only a limited understanding of how these values are represented in the brain and, more importantly, how they give rise to individual variability in prosociality. In the present study, participants underwent functional magnetic resonance imaging while performing a prosocial learning task in which they could choose to benefit themselves and/or another person. Choice behavior indicated that participants valued the welfare of another person, although less so than they valued their own welfare. Neural data revealed a spatial gradient in activity within the medial prefrontal cortex (MPFC), such that ventral parts predominantly represented self-regarding values and dorsal parts predominantly represented other-regarding values. Importantly, compared with selfish individuals, prosocial individuals showed a more gradual transition from self-regarding to other-regarding value signals in the MPFC and stronger MPFC-striatum coupling when they made choices for another person rather than for themselves. The present study provides evidence of neural markers reflecting individual differences in human prosociality. PMID- 26056281 TI - Late Oligocene-early Miocene birth of the Taklimakan Desert. AB - As the world's second largest sand sea and one of the most important dust sources to the global aerosol system, the formation of the Taklimakan Desert marks a major environmental event in central Asia during the Cenozoic. Determining when and how the desert formed holds the key to better understanding the tectonic climatic linkage in this critical region. However, the age of the Taklimakan remains controversial, with the dominant view being from ~ 3.4 Ma to ~ 7 Ma based on magnetostratigraphy of sedimentary sequences within and along the margins of the desert. In this study, we applied radioisotopic methods to precisely date a volcanic tuff preserved in the stratigraphy. We constrained the initial desertification to be late Oligocene to early Miocene, between ~ 26.7 Ma and 22.6 Ma. We suggest that the Taklimakan Desert was formed as a response to a combination of widespread regional aridification and increased erosion in the surrounding mountain fronts, both of which are closely linked to the tectonic uplift of the Tibetan-Pamir Plateau and Tian Shan, which had reached a climatically sensitive threshold at this time. PMID- 26056282 TI - RNASEK is required for internalization of diverse acid-dependent viruses. AB - Viruses must gain entry into cells to establish infection. In general, viruses enter either at the plasma membrane or from intracellular endosomal compartments. Viruses that use endosomal pathways are dependent on the cellular factors that control this process; however, these genes have proven to be essential for endogenous cargo uptake, and thus are of limited value for therapeutic intervention. The identification of genes that are selectively required for viral uptake would make appealing drug targets, as their inhibition would block an early step in the life cycle of diverse viruses. At this time, we lack pan antiviral therapeutics, in part because of our lack of knowledge of such cellular factors. RNAi screening has begun to reveal previously unknown genes that play roles in viral infection. We identified dRNASEK in two genome-wide RNAi screens performed in Drosophila cells against West Nile and Rift Valley Fever viruses. Here we found that ribonuclease kappa (RNASEK) is essential for the infection of human cells by divergent and unrelated positive- and negative-strand-enveloped viruses from the Flaviviridae, Togaviridae, Bunyaviridae, and Orthomyxoviridae families that all enter cells from endosomal compartments. In contrast, RNASEK was dispensable for viruses, including parainfluenza virus 5 and Coxsackie B virus, that enter at the plasma membrane. RNASEK is dispensable for attachment but is required for uptake of these acid-dependent viruses. Furthermore, this requirement appears specific, as general endocytic uptake of transferrin is unaffected in RNASEK-depleted cells. Therefore, RNASEK is a potential host cell Achilles' heel for viral infection. PMID- 26056283 TI - Molecular diffusion in the human nail measured by stimulated Raman scattering microscopy. AB - The effective treatment of diseases of the nail remains an important unmet medical need, primarily because of poor drug delivery. To address this challenge, the diffusion, in real time, of topically applied chemicals into the human nail has been visualized and characterized using stimulated Raman scattering (SRS) microscopy. Deuterated water (D2O), propylene glycol (PG-d8), and dimethyl sulphoxide (DMSO-d6) were separately applied to the dorsal surface of human nail samples. SRS microscopy was used to image D2O, PG-d8/DMSO-d6, and the nail through the O-D, -CD2, and -CH2 bond stretching Raman signals, respectively. Signal intensities obtained were measured as functions of time and of depth into the nail. It was observed that the diffusion of D2O was more than an order of magnitude faster than that of PG-d8 and DMSO-d6. Normalization of the Raman signals, to correct in part for scattering and absorption, permitted semiquantitative analysis of the permeation profiles and strongly suggested that solvent diffusion diverged from classical behavior and that derived diffusivities may be concentration dependent. It appeared that the uptake of solvent progressively undermined the integrity of the nail. This previously unreported application of SRS has permitted, therefore, direct visualization and semiquantitation of solvent penetration into the human nail. The kinetics of uptake of the three chemicals studied demonstrated that each altered its own diffusion in the nail in an apparently concentration-dependent fashion. The scale of the unexpected behavior observed may prove beneficial in the design and optimization of drug formulations to treat recalcitrant nail disease. PMID- 26056284 TI - Altered thalamocortical rhythmicity and connectivity in mice lacking CaV3.1 T type Ca2+ channels in unconsciousness. AB - In unconscious status (e.g., deep sleep and anesthetic unconsciousness) where cognitive functions are not generated there is still a significant level of brain activity present. Indeed, the electrophysiology of the unconscious brain is characterized by well-defined thalamocortical rhythmicity. Here we address the ionic basis for such thalamocortical rhythms during unconsciousness. In particular, we address the role of CaV3.1 T-type Ca(2+) channels, which are richly expressed in thalamic neurons. Toward this aim, we examined the electrophysiological and behavioral phenotypes of mice lacking CaV3.1 channels (CaV3.1 knockout) during unconsciousness induced by ketamine or ethanol administration. Our findings indicate that CaV3.1 KO mice displayed attenuated low-frequency oscillations in thalamocortical loops, especially in the 1- to 4-Hz delta band, compared with control mice (CaV3.1 WT). Intriguingly, we also found that CaV3.1 KO mice exhibited augmented high-frequency oscillations during unconsciousness. In a behavioral measure of unconsciousness dynamics, CaV3.1 KO mice took longer to fall into the unconscious state than controls. In addition, such unconscious events had a shorter duration than those of control mice. The thalamocortical interaction level between mediodorsal thalamus and frontal cortex in CaV3.1 KO mice was significantly lower, especially for delta band oscillations, compared with that of CaV3.1 WT mice, during unconsciousness. These results suggest that the CaV3.1 channel is required for the generation of a given set of thalamocortical rhythms during unconsciousness. Further, that thalamocortical resonant neuronal activity supported by this channel is important for the control of vigilance states. PMID- 26056285 TI - MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma. AB - Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37 C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37 C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism. PMID- 26056286 TI - Optogenetic stimulation of infralimbic PFC reproduces ketamine's rapid and sustained antidepressant actions. AB - Ketamine produces rapid and sustained antidepressant actions in depressed patients, but the precise cellular mechanisms underlying these effects have not been identified. Here we determined if modulation of neuronal activity in the infralimbic prefrontal cortex (IL-PFC) underlies the antidepressant and anxiolytic actions of ketamine. We found that neuronal inactivation of the IL-PFC completely blocked the antidepressant and anxiolytic effects of systemic ketamine in rodent models and that ketamine microinfusion into IL-PFC reproduced these behavioral actions of systemic ketamine. We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects and that these effects are associated with increased number and function of spine synapses of layer V pyramidal neurons. The results demonstrate that ketamine infusions or optogenetic stimulation of IL-PFC are sufficient to produce long-lasting antidepressant behavioral and synaptic responses similar to the effects of systemic ketamine administration. PMID- 26056288 TI - High-capacity electrode materials for rechargeable lithium batteries: Li3NbO4 based system with cation-disordered rocksalt structure. AB - Rechargeable lithium batteries have rapidly risen to prominence as fundamental devices for green and sustainable energy development. Lithium batteries are now used as power sources for electric vehicles. However, materials innovations are still needed to satisfy the growing demand for increasing energy density of lithium batteries. In the past decade, lithium-excess compounds, Li2MeO3 (Me = Mn(4+), Ru(4+), etc.), have been extensively studied as high-capacity positive electrode materials. Although the origin as the high reversible capacity has been a debatable subject for a long time, recently it has been confirmed that charge compensation is partly achieved by solid-state redox of nonmetal anions (i.e., oxide ions), coupled with solid-state redox of transition metals, which is the basic theory used for classic lithium insertion materials, such as LiMeO2 (Me = Co(3+), Ni(3+), etc.). Herein, as a compound with further excess lithium contents, a cation-ordered rocksalt phase with lithium and pentavalent niobium ions, Li3NbO4, is first examined as the host structure of a new series of high capacity positive electrode materials for rechargeable lithium batteries. Approximately 300 mAh ? g(-1) of high-reversible capacity at 50 degrees C is experimentally observed, which partly originates from charge compensation by solid-state redox of oxide ions. It is proposed that such a charge compensation process by oxide ions is effectively stabilized by the presence of electrochemically inactive niobium ions. These results will contribute to the development of a new class of high-capacity electrode materials, potentially with further lithium enrichment (and fewer transition metals) in the close-packed framework structure with oxide ions. PMID- 26056287 TI - Mechanochemical tuning of myosin-I by the N-terminal region. AB - Myosins are molecular motors that generate force to power a wide array of motile cellular functions. Myosins have the inherent ability to change their ATPase kinetics and force-generating properties when they encounter mechanical loads; however, little is known about the structural elements in myosin responsible for force sensing. Recent structural and biophysical studies have shown that myosin-I isoforms, Myosin-Ib (Myo1b) and Myosin-Ic (Myo1c), have similar unloaded kinetics and sequences but substantially different responses to forces that resist their working strokes. Myo1b has the properties of a tension-sensing anchor, slowing its actin-detachment kinetics by two orders of magnitude with just 1 pN of resisting force, whereas Myo1c has the properties of a slow transporter, generating power without slowing under 1-pN loads that would stall Myo1b. To examine the structural elements that lead to differences in force sensing, we used single-molecule and ensemble kinetic techniques to show that the myosin-I N terminal region (NTR) plays a critical role in tuning myosin-I mechanochemistry. We found that replacing the Myo1c NTR with the Myo1b NTR changes the identity of the primary force-sensitive transition of Myo1c, resulting in sensitivity to forces of <2 pN. Additionally, we found that the NTR plays an important role in stabilizing the post-power-stroke conformation. These results identify the NTR as an important structural element in myosin force sensing and suggest a mechanism for generating diversity of function among myosin isoforms. PMID- 26056289 TI - Pre-TCR ligand binding impacts thymocyte development before alphabetaTCR expression. AB - Adaptive cellular immunity requires accurate self- vs. nonself-discrimination to protect against infections and tumorous transformations while at the same time excluding autoimmunity. This vital capability is programmed in the thymus through selection of alphabetaT-cell receptors (alphabetaTCRs) recognizing peptides bound to MHC molecules (pMHC). Here, we show that the pre-TCR (preTCR), a pTalpha-beta heterodimer appearing before alphabetaTCR expression, directs a previously unappreciated initial phase of repertoire selection. Contrasting with the ligand independent model of preTCR function, we reveal through NMR and bioforce-probe analyses that the beta-subunit binds pMHC using Vbeta complementarity-determining regions as well as an exposed hydrophobic Vbeta patch characteristic of the preTCR. Force-regulated single bonds akin to those of alphabetaTCRs but with more promiscuous ligand specificity trigger calcium flux. Thus, thymic development involves sequential beta- and then, alphabeta-repertoire tuning, whereby preTCR interactions with self pMHC modulate early thymocyte expansion, with implications for beta-selection, immunodominant peptide recognition, and germ line-encoded MHC interaction. PMID- 26056291 TI - Retro-translocation of mitochondrial intermembrane space proteins. AB - The content of mitochondrial proteome is maintained through two highly dynamic processes, the influx of newly synthesized proteins from the cytosol and the protein degradation. Mitochondrial proteins are targeted to the intermembrane space by the mitochondrial intermembrane space assembly pathway that couples their import and oxidative folding. The folding trap was proposed to be a driving mechanism for the mitochondrial accumulation of these proteins. Whether the reverse movement of unfolded proteins to the cytosol occurs across the intact outer membrane is unknown. We found that reduced, conformationally destabilized proteins are released from mitochondria in a size-limited manner. We identified the general import pore protein Tom40 as an escape gate. We propose that the mitochondrial proteome is not only regulated by the import and degradation of proteins but also by their retro-translocation to the external cytosolic location. Thus, protein release is a mechanism that contributes to the mitochondrial proteome surveillance. PMID- 26056290 TI - Molecular transitions from papillomavirus infection to cervical precancer and cancer: Role of stromal estrogen receptor signaling. AB - To study the multistep process of cervical cancer development, we analyzed 128 frozen cervical samples spanning normalcy, increasingly severe cervical intraepithelial neoplasia (CIN1- CIN3), and cervical cancer (CxCa) from multiple perspectives, revealing a cascade of progressive changes. Compared with normal tissue, expression of many DNA replication/repair and cell proliferation genes was increased in CIN1/CIN2 lesions and further sustained in CIN3, consistent with high-risk human papillomavirus (HPV)-induced tumor suppressor inactivation. The CIN3-to-CxCa transition showed metabolic shifts, including decreased expression of mitochondrial electron transport complex components and ribosomal protein genes. Significantly, despite clinical, epidemiological, and animal model results linking estrogen and estrogen receptor alpha (ERalpha) to CxCa, ERalpha expression declined >15-fold from normalcy to cancer, showing the strongest inverse correlation of any gene with the increasing expression of p16, a marker for HPV-linked cancers. This drop in ERalpha in CIN and tumor cells was confirmed at the protein level. However, ERalpha expression in stromal cells continued throughout CxCa development. Our further studies localized stromal ERalpha to FSP1+, CD34+, SMA- precursor fibrocytes adjacent to normal and precancerous CIN epithelium, and FSP1-, CD34-, SMA+ activated fibroblasts in CxCas. Moreover, rank correlations with ERalpha mRNA identified IL-8, CXCL12, CXCL14, their receptors, and other angiogenesis and immune cell infiltration and inflammatory factors as candidates for ERalpha-induced stroma-tumor signaling pathways. The results indicate that estrogen signaling in cervical cancer has dramatic differences from ERalpha+ breast cancers, and imply that estrogen signaling increasingly proceeds indirectly through ERalpha in tumor-associated stromal fibroblasts. PMID- 26056292 TI - SAR11 lipid renovation in response to phosphate starvation. AB - Phytoplankton inhabiting oligotrophic ocean gyres actively reduce their phosphorus demand by replacing polar membrane phospholipids with those lacking phosphorus. Although the synthesis of nonphosphorus lipids is well documented in some heterotrophic bacterial lineages, phosphorus-free lipid synthesis in oligotrophic marine chemoheterotrophs has not been directly demonstrated, implying they are disadvantaged in phosphate-deplete ecosystems, relative to phytoplankton. Here, we show the SAR11 clade chemoheterotroph Pelagibacter sp. str. HTCC7211 renovates membrane lipids when phosphate starved by replacing a portion of its phospholipids with monoglucosyl- and glucuronosyl-diacylglycerols and by synthesizing new ornithine lipids. Lipid profiles of cells grown with excess phosphate consisted entirely of phospholipids. Conversely, up to 40% of the total lipids were converted to nonphosphorus lipids when cells were starved for phosphate, or when growing on methylphosphonate. Cells sequentially limited by phosphate and methylphosphonate transformed >75% of their lipids to phosphorus free analogs. During phosphate starvation, a four-gene cluster was significantly up-regulated that likely encodes the enzymes responsible for lipid renovation. These genes were found in Pelagibacterales strains isolated from a phosphate deficient ocean gyre, but not in other strains from coastal environments, suggesting alternate lipid synthesis is a specific adaptation to phosphate scarcity. Similar gene clusters are found in the genomes of other marine alpha proteobacteria, implying lipid renovation is a common strategy used by heterotrophic cells to reduce their requirement for phosphorus in oligotrophic habitats. PMID- 26056293 TI - Climate mediates hypoxic stress on fish diversity and nursery function at the land-sea interface. AB - Coastal ecosystems provide numerous important ecological services, including maintenance of biodiversity and nursery grounds for many fish species of ecological and economic importance. However, human population growth has led to increased pollution, ocean warming, hypoxia, and habitat alteration that threaten ecosystem services. In this study, we used long-term datasets of fish abundance, water quality, and climatic factors to assess the threat of hypoxia and the regulating effects of climate on fish diversity and nursery conditions in Elkhorn Slough, a highly eutrophic estuary in central California (United States), which also serves as a biodiversity hot spot and critical nursery grounds for offshore fisheries in a broader region. We found that hypoxic conditions had strong negative effects on extent of suitable fish habitat, fish species richness, and abundance of the two most common flatfish species, English sole (Parophrys vetulus) and speckled sanddab (Citharichthys stigmaeus). The estuary serves as an important nursery ground for English sole, making this species vulnerable to anthropogenic threats. We determined that estuarine hypoxia was associated with significant declines in English sole nursery habitat, with cascading effects on recruitment to the offshore adult population and fishery, indicating that human land use activities can indirectly affect offshore fisheries. Estuarine hypoxic conditions varied spatially and temporally and were alleviated by strengthening of El Nino conditions through indirect pathways, a consistent result in most estuaries across the northeast Pacific. These results demonstrate that changes to coastal land use and climate can fundamentally alter the diversity and functioning of coastal nurseries and their adjacent ocean ecosystems. PMID- 26056294 TI - Children with autism spectrum disorder show reduced adaptation to number. AB - Autism is known to be associated with major perceptual atypicalities. We have recently proposed a general model to account for these atypicalities in Bayesian terms, suggesting that autistic individuals underuse predictive information or priors. We tested this idea by measuring adaptation to numerosity stimuli in children diagnosed with autism spectrum disorder (ASD). After exposure to large numbers of items, stimuli with fewer items appear to be less numerous (and vice versa). We found that children with ASD adapted much less to numerosity than typically developing children, although their precision for numerosity discrimination was similar to that of the typical group. This result reinforces recent findings showing reduced adaptation to facial identity in ASD and goes on to show that reduced adaptation is not unique to faces (social stimuli with special significance in autism), but occurs more generally, for both parietal and temporal functions, probably reflecting inefficiencies in the adaptive interpretation of sensory signals. These results provide strong support for the Bayesian theories of autism. PMID- 26056295 TI - Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species. AB - Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140, featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. Upon reductive activation in the presence of cellular thiols, LNM exerts its antitumor activity by an episulfonium ion-mediated DNA alkylation. Previously, we have cloned the lnm gene cluster from S. atroolivaceus S-140 and characterized the biosynthetic machinery responsible for the 18-membered lactam backbone and the alkyl branch at C3 of LNM. We now report the isolation and characterization of leinamycin E1 (LNM E1) from S. atroolivacues SB3033, a DeltalnmE mutant strain of S. atroolivaceus S 140. Complementary to the reductive activation of LNM by cellular thiols, LNM E1 can be oxidatively activated by cellular reactive oxygen species (ROS) to generate a similar episulfonium ion intermediate, thereby alkylating DNA and leading to eventual cell death. The feasibility of exploiting LNM E1 as an anticancer prodrug activated by ROS was demonstrated in two prostate cancer cell lines, LNCaP and DU-145. Because many cancer cells are under higher cellular oxidative stress with increased levels of ROS than normal cells, these findings support the idea of exploiting ROS as a means to target cancer cells and highlight LNM E1 as a novel lead for the development of anticancer prodrugs activated by ROS. The structure of LNM E1 also reveals critical new insights into LNM biosynthesis, setting the stage to investigate sulfur incorporation, as well as the tailoring steps that convert the nascent hybrid peptide-polyketide biosynthetic intermediate into LNM. PMID- 26056296 TI - A simple nutrient-dependence mechanism for predicting the stoichiometry of marine ecosystems. AB - It is widely recognized that the stoichiometry of nutrient elements in phytoplankton varies within the ocean. However, there are many conflicting mechanistic explanations for this variability, and it is often ignored in global biogeochemical models and carbon cycle simulations. Here we show that globally distributed particulate P:C varies as a linear function of ambient phosphate concentrations, whereas the N:C varies with ambient nitrate concentrations, but only when nitrate is most scarce. This observation is consistent with the adjustment of the phytoplankton community to local nutrient availability, with greater flexibility of phytoplankton P:C because P is a less abundant cellular component than N. This simple relationship is shown to predict the large-scale, long-term average composition of surface particles throughout large parts of the ocean remarkably well. The relationship implies that most of the observed variation in N:P actually arises from a greater plasticity in the cellular P:C content, relative to N:C, such that as overall macronutrient concentrations decrease, N:P rises. Although other mechanisms are certainly also relevant, this simple relationship can be applied as a first-order basis for predicting organic matter stoichiometry in large-scale biogeochemical models, as illustrated using a simple box model. The results show that including variable P:C makes atmospheric CO2 more sensitive to changes in low latitude export and ocean circulation than a fixed-stoichiometry model. In addition, variable P:C weakens the relationship between preformed phosphate and atmospheric CO2 while implying a more important role for the nitrogen cycle. PMID- 26056297 TI - Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. AB - The correlations between intramyocellular lipid (IMCL), decreased fatty acid oxidation (FAO), and insulin resistance have led to the hypothesis that impaired FAO causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 KO model, we show that prolonged and severe mitochondrial FAO inhibition results in increased carbohydrate utilization, along with reduced physical activity; increased circulating nonesterified fatty acids; and increased IMCLs, diacylglycerols, and ceramides. Perhaps more importantly, inhibition of mitochondrial FAO also initiates a local, adaptive response in muscle that invokes mitochondrial biogenesis, compensatory peroxisomal fat oxidation, and amino acid catabolism. Loss of its major fuel source (lipid) induces an energy deprivation response in muscle coordinated by signaling through AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1alpha) to maintain energy supply for locomotion and survival. At the whole-body level, these adaptations result in resistance to obesity. PMID- 26056298 TI - Single-molecule analysis reveals widespread structural variation in multiple myeloma. AB - Multiple myeloma (MM), a malignancy of plasma cells, is characterized by widespread genomic heterogeneity and, consequently, differences in disease progression and drug response. Although recent large-scale sequencing studies have greatly improved our understanding of MM genomes, our knowledge about genomic structural variation in MM is attenuated due to the limitations of commonly used sequencing approaches. In this study, we present the application of optical mapping, a single-molecule, whole-genome analysis system, to discover new structural variants in a primary MM genome. Through our analysis, we have identified and characterized widespread structural variation in this tumor genome. Additionally, we describe our efforts toward comprehensive characterization of genome structure and variation by integrating our findings from optical mapping with those from DNA sequencing-based genomic analysis. Finally, by studying this MM genome at two time points during tumor progression, we have demonstrated an increase in mutational burden with tumor progression at all length scales of variation. PMID- 26056299 TI - Broadband surface-wave transformation cloak. AB - Guiding surface electromagnetic waves around disorder without disturbing the wave amplitude or phase is in great demand for modern photonic and plasmonic devices, but is fundamentally difficult to realize because light momentum must be conserved in a scattering event. A partial realization has been achieved by exploiting topological electromagnetic surface states, but this approach is limited to narrow-band light transmission and subject to phase disturbances in the presence of disorder. Recent advances in transformation optics apply principles of general relativity to curve the space for light, allowing one to match the momentum and phase of light around any disorder as if that disorder were not there. This feature has been exploited in the development of invisibility cloaks. An ideal invisibility cloak, however, would require the phase velocity of light being guided around the cloaked object to exceed the vacuum speed of light--a feat potentially achievable only over an extremely narrow band. In this work, we theoretically and experimentally show that the bottlenecks encountered in previous studies can be overcome. We introduce a class of cloaks capable of remarkable broadband surface electromagnetic waves guidance around ultrasharp corners and bumps with no perceptible changes in amplitude and phase. These cloaks consist of specifically designed nonmagnetic metamaterials and achieve nearly ideal transmission efficiency over a broadband frequency range from 0(+) to 6 GHz. This work provides strong support for the application of transformation optics to plasmonic circuits and could pave the way toward high performance, large-scale integrated photonic circuits. PMID- 26056300 TI - Structural basis for mutation-induced destabilization of profilin 1 in ALS. AB - Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the destabilized M114T variant. In contrast, the E117G mutation only modestly perturbs the structure and stability of PFN1, an observation that reconciles the occurrence of this mutation in the control population. These findings suggest that a destabilized form of PFN1 underlies PFN1-mediated ALS pathogenesis. PMID- 26056301 TI - Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells. AB - The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes. PMID- 26056303 TI - Selective buckling via states of self-stress in topological metamaterials. AB - States of self-stress--tensions and compressions of structural elements that result in zero net forces--play an important role in determining the load-bearing ability of structures ranging from bridges to metamaterials with tunable mechanical properties. We exploit a class of recently introduced states of self stress analogous to topological quantum states to sculpt localized buckling regions in the interior of periodic cellular metamaterials. Although the topological states of self-stress arise in the linear response of an idealized mechanical frame of harmonic springs connected by freely hinged joints, they leave a distinct signature in the nonlinear buckling behavior of a cellular material built out of elastic beams with rigid joints. The salient feature of these localized buckling regions is that they are indistinguishable from their surroundings as far as material parameters or connectivity of their constituent elements are concerned. Furthermore, they are robust against a wide range of structural perturbations. We demonstrate the effectiveness of this topological design through analytical and numerical calculations as well as buckling experiments performed on two- and three-dimensional metamaterials built out of stacked kagome lattices. PMID- 26056302 TI - Disregulated expression of the transcription factor ThPOK during T-cell development leads to high incidence of T-cell lymphomas. AB - The transcription factor T-helper-inducing POZ/Krueppel-like factor (ThPOK, encoded by the Zbtb7b gene) plays widespread and critical roles in T-cell development, particularly as the master regulator of CD4 commitment. Here we show that mice expressing a constitutive T-cell-specific ThPOK transgene (ThPOK(const) mice) develop thymic lymphomas. These tumors resemble human T-cell acute lymphoblastic leukemia (T-ALL), in that they predominantly exhibit activating Notch1 mutations. Lymphomagenesis is prevented if thymocyte development is arrested at the DN3 stage by recombination-activating gene (RAG) deficiency, but restored by introduction of a T-cell receptor (TCR) transgene or by a single injection of anti-alphabetaTCR antibody into ThPOK(const) RAG-deficient mice, which promotes development to the CD4(+)8(+) (DP) stage. Hence, TCR signals and/or traversal of the DN (double negative) > DP (double positive) checkpoint are required for ThPOK-mediated lymphomagenesis. These results demonstrate a novel link between ThPOK, TCR signaling, and lymphomagenesis. Finally, we present evidence that ectopic ThPOK expression gives rise to a preleukemic and self perpetuating DN4 lymphoma precursor population. Our results collectively define a novel role for ThPOK as an oncogene and precisely map the stage in thymopoiesis susceptible to ThPOK-dependent tumor initiation. PMID- 26056305 TI - Estimating the global number of tropical tree species, and Fisher's paradox. PMID- 26056304 TI - Establishing task- and modality-dependent dissociations between the semantic and default mode networks. AB - The default mode network (DMN) and semantic network (SN) are two of the most extensively studied systems, and both are increasingly used as clinical biomarkers in neurological studies. There are strong theoretical reasons to assume a relationship between the networks, as well as anatomical evidence that they might rely on overlapping cortical regions, such as the anterior temporal lobe (ATL) or angular gyrus (AG). Despite these strong motivations, the relationship between the two systems has received minimal attention. We directly compared the SN and DMN using a large (n = 69) distortion-corrected functional MRI (fMRI) dataset, spanning a range of semantic and nonsemantic tasks that varied input modality. The results showed that both networks fractionate depending on the semantic nature of the task, stimulus type, modality, and task difficulty. Furthermore, despite recent claims that both AG and ATL are semantic hubs, the two areas responded very differently, with results supporting the role of ATL, but not AG, in semantic representation. Specifically, the left ATL was positively activated for all semantic tasks, but deactivated during nonsemantic task performance. In contrast, the left AG was deactivated for all tasks, with the level of deactivation related to task difficulty. Thus, ATL and AG do not share a common interest in semantic tasks, but, rather, a common "disinterest" in nonsemantic tasks. The implications for the variability in the DMN, its cognitive coherence, and interpretation of resting-state fMRI data are discussed. PMID- 26056306 TI - Synthesis of lithium polyhydrides above 130 GPa at 300 K. AB - The prediction of novel lithium hydrides with nontraditional stoichiometries at high pressure has been seminal for highlighting a promising line of research on hydrogen-dense materials. Here, we report the evidences of the disproportionation of LiH above 130 GPa to form lithium hydrides containing H2 units. Measurements have been performed using the nonperturbing technique of synchrotron infrared absorption. The observed vibron frequencies match the predictions for LiH2 and LiH6. These polyhydrides remain insulating up to 215 GPa. A disproportionation mechanism based on the diffusion of lithium into the diamond anvil and a stratification of the sample into LiH6/LiH2/LiH layers is proposed. Polyhydrides containing an H2 sublattice do exist and could be ubiquitously stable at high pressure. PMID- 26056307 TI - Novel pathways for fuels and lubricants from biomass optimized using life-cycle greenhouse gas assessment. AB - Decarbonizing the transportation sector is critical to achieving global climate change mitigation. Although biofuels will play an important role in conventional gasoline and diesel applications, bioderived solutions are particularly important in jet fuels and lubricants, for which no other viable renewable alternatives exist. Producing compounds for jet fuel and lubricant base oil applications often requires upgrading fermentation products, such as alcohols and ketones, to reach the appropriate molecular-weight range. Ketones possess both electrophilic and nucleophilic functionality, which allows them to be used as building blocks similar to alkenes and aromatics in a petroleum refining complex. Here, we develop a method for selectively upgrading biomass-derived alkyl methyl ketones with >95% yields into trimer condensates, which can then be hydrodeoxygenated in near-quantitative yields to give a new class of cycloalkane compounds. The basic chemistry developed here can be tailored for aviation fuels as well as lubricants by changing the production strategy. We also demonstrate that a sugarcane biorefinery could use natural synergies between various routes to produce a mixture of lubricant base oils and jet fuels that achieve net life-cycle greenhouse gas savings of up to 80%. PMID- 26056308 TI - Mass extinction in poorly known taxa. AB - Since the 1980s, many have suggested we are in the midst of a massive extinction crisis, yet only 799 (0.04%) of the 1.9 million known recent species are recorded as extinct, questioning the reality of the crisis. This low figure is due to the fact that the status of very few invertebrates, which represent the bulk of biodiversity, have been evaluated. Here we show, based on extrapolation from a random sample of land snail species via two independent approaches, that we may already have lost 7% (130,000 extinctions) of the species on Earth. However, this loss is masked by the emphasis on terrestrial vertebrates, the target of most conservation actions. Projections of species extinction rates are controversial because invertebrates are essentially excluded from these scenarios. Invertebrates can and must be assessed if we are to obtain a more realistic picture of the sixth extinction crisis. PMID- 26056309 TI - Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum. AB - Most secretory cargo proteins in eukaryotes are synthesized in the endoplasmic reticulum and actively exported in membrane-bound vesicles that are formed by the cytosolic coat protein complex II (COPII). COPII proteins are assisted by a variety of cargo-specific adaptor proteins required for the concentration and export of secretory proteins from the endoplasmic reticulum (ER). Adaptor proteins are key regulators of cargo export, and defects in their function may result in disease phenotypes in mammals. Here we report the role of 14-3-3 proteins as a cytosolic adaptor in mediating SAC1 transport in COPII-coated vesicles. Sac1 is a phosphatidyl inositol-4 phosphate (PI4P) lipid phosphatase that undergoes serum dependent translocation between the endoplasmic reticulum and Golgi complex and controls cellular PI4P lipid levels. We developed a cell free COPII vesicle budding reaction to examine SAC1 exit from the ER that requires COPII and at least one additional cytosolic factor, the 14-3-3 protein. Recombinant 14-3-3 protein stimulates the packaging of SAC1 into COPII vesicles and the sorting subunit of COPII, Sec24, interacts with 14-3-3. We identified a minimal sorting motif of SAC1 that is important for 14-3-3 binding and which controls SAC1 export from the ER. This LS motif is part of a 7-aa stretch, RLSNTSP, which is similar to the consensus 14-3-3 binding sequence. Homology models, based on the SAC1 structure from yeast, predict this region to be in the exposed exterior of the protein. Our data suggest a model in which the 14-3-3 protein mediates SAC1 traffic from the ER through direct interaction with a sorting signal and COPII. PMID- 26056310 TI - Calcium activates the light-dependent conductance in melanopsin-expressing photoreceptors of amphioxus. AB - Melanopsin, the photopigment of the "circadian" receptors that regulate the biological clock and the pupillary reflex in mammals, is homologous to invertebrate rhodopsins. Evidence supporting the involvement of phosphoinositides in light-signaling has been garnered, but the downstream effectors that control the light-dependent conductance remain unknown. Microvillar photoreceptors of the primitive chordate amphioxus also express melanopsin and transduce light via phospholipase-C, apparently not acting through diacylglycerol. We therefore examined the role of calcium in activating the photoconductance, using simultaneous, high time-resolution measurements of membrane current and Ca(2+) fluorescence. The light-induced calcium rise precedes the onset of the photocurrent, making it a candidate in the activation chain. Moreover, photolysis of caged Ca elicits an inward current of similar size, time course and pharmacology as the physiological photoresponse, but with a much shorter latency. Internally released calcium thus emerges as a key messenger to trigger the opening of light-dependent channels in melanopsin-expressing microvillar photoreceptors of early chordates. PMID- 26056311 TI - Protein synthesis during cellular quiescence is inhibited by phosphorylation of a translational elongation factor. AB - In nature, most organisms experience conditions that are suboptimal for growth. To survive, cells must fine-tune energy-demanding metabolic processes in response to nutrient availability. Here, we describe a novel mechanism by which protein synthesis in starved cells is down-regulated by phosphorylation of the universally conserved elongation factor Tu (EF-Tu). Phosphorylation impairs the essential GTPase activity of EF-Tu, thereby preventing its release from the ribosome. As a consequence, phosphorylated EF-Tu has a dominant-negative effect in elongation, resulting in the overall inhibition of protein synthesis. Importantly, this mechanism allows a quick and robust regulation of one of the most abundant cellular proteins. Given that the threonine that serves as the primary site of phosphorylation is conserved in all translational GTPases from bacteria to humans, this mechanism may have important implications for growth rate control in phylogenetically diverse organisms. PMID- 26056312 TI - Contingency and entrenchment in protein evolution under purifying selection. AB - The phenotypic effect of an allele at one genetic site may depend on alleles at other sites, a phenomenon known as epistasis. Epistasis can profoundly influence the process of evolution in populations and shape the patterns of protein divergence across species. Whereas epistasis between adaptive substitutions has been studied extensively, relatively little is known about epistasis under purifying selection. Here we use computational models of thermodynamic stability in a ligand-binding protein to explore the structure of epistasis in simulations of protein sequence evolution. Even though the predicted effects on stability of random mutations are almost completely additive, the mutations that fix under purifying selection are enriched for epistasis. In particular, the mutations that fix are contingent on previous substitutions: Although nearly neutral at their time of fixation, these mutations would be deleterious in the absence of preceding substitutions. Conversely, substitutions under purifying selection are subsequently entrenched by epistasis with later substitutions: They become increasingly deleterious to revert over time. Our results imply that, even under purifying selection, protein sequence evolution is often contingent on history and so it cannot be predicted by the phenotypic effects of mutations assayed in the ancestral background. PMID- 26056313 TI - Gate-controlled proton diffusion and protonation-induced ratchet motion in the stator of the bacterial flagellar motor. AB - The proton permeation process of the stator complex MotA/B in the flagellar motor of Escherichia coli was investigated. The atomic model structure of the transmembrane part of MotA/B was constructed based on the previously published disulfide cross-linking and tryptophan scanning mutations. The dynamic permeation of hydronium/sodium ions and water molecule through the channel formed in MotA/B was observed using a steered molecular dynamics simulation. During the simulation, Leu46 of MotB acts as the gate for hydronium ion permeation, which induced the formation of water wire that may mediate the proton transfer to Asp32 on MotB. Free energy profiles for permeation were calculated by umbrella sampling. The free energy barrier for H3O(+) permeation was consistent with the proton transfer rate deduced from the flagellar rotational speed and number of protons per rotation, which suggests that the gating is the rate-limiting step. Structure and dynamics of the MotA/B with nonprotonated and protonated Asp32, Val43Met, and Val43Leu mutants in MotB were investigated using molecular dynamics simulation. A narrowing of the channel was observed in the mutants, which is consistent with the size-dependent ion selectivity. In MotA/B with the nonprotonated Asp32, the A3 segment in MotA maintained a kink whereas the protonation induced a straighter shape. Assuming that the cytoplasmic domain not included in the atomic model moves as a rigid body, the protonation/deprotonation of Asp32 is inferred to induce a ratchet motion of the cytoplasmic domain, which may be correlated to the motion of the flagellar rotor. PMID- 26056314 TI - Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. AB - The consumption of caffeine (an adenosine receptor antagonist) correlates inversely with depression and memory deterioration, and adenosine A2A receptor (A2AR) antagonists emerge as candidate therapeutic targets because they control aberrant synaptic plasticity and afford neuroprotection. Therefore we tested the ability of A2AR to control the behavioral, electrophysiological, and neurochemical modifications caused by chronic unpredictable stress (CUS), which alters hippocampal circuits, dampens mood and memory performance, and enhances susceptibility to depression. CUS for 3 wk in adult mice induced anxiogenic and helpless-like behavior and decreased memory performance. These behavioral changes were accompanied by synaptic alterations, typified by a decrease in synaptic plasticity and a reduced density of synaptic proteins (synaptosomal-associated protein 25, syntaxin, and vesicular glutamate transporter type 1), together with an increased density of A2AR in glutamatergic terminals in the hippocampus. Except for anxiety, for which results were mixed, CUS-induced behavioral and synaptic alterations were prevented by (i) caffeine (1 g/L in the drinking water, starting 3 wk before and continued throughout CUS); (ii) the selective A2AR antagonist KW6002 (3 mg/kg, p.o.); (iii) global A2AR deletion; and (iv) selective A2AR deletion in forebrain neurons. Notably, A2AR blockade was not only prophylactic but also therapeutically efficacious, because a 3-wk treatment with the A2AR antagonist SCH58261 (0.1 mg/kg, i.p.) reversed the mood and synaptic dysfunction caused by CUS. These results herald a key role for synaptic A2AR in the control of chronic stress-induced modifications and suggest A2AR as candidate targets to alleviate the consequences of chronic stress on brain function. PMID- 26056315 TI - Scrambled and not-so-tiny genomes of fungal endosymbionts. PMID- 26056316 TI - Long-circulating siRNA nanoparticles for validating Prohibitin1-targeted non small cell lung cancer treatment. AB - RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid-polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (t1/2 ~ 8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies. PMID- 26056318 TI - Relative Abundance of Carsonella ruddii (Gamma Proteobacterium) in Females and Males of Cacopsylla pyricola (Hemiptera: Psyllidae) and Bactericera cockerelli (Hemiptera: Triozidae). AB - Carsonella ruddii (Gamma Proteobacterium) is an obligate bacterial endosymbiont of psyllids that produces essential amino acids that are lacking in the insect's diet. Accurate estimations of Carsonella populations are important to studies of Carsonella-psyllid interactions and to developing ways to target Carsonella for control of psyllid pests including pear psylla, Cacopsylla pyricola (Forster) (Hemiptera: Psyllidae) and potato psyllid, Bactericera cockerelli (Sulc) (Hemiptera: Triozidae). We used two methods, namely fluorescence in situ hybridization and quantitative polymerase chain reaction (qPCR), to estimate relative abundance of Carsonella in bacteriocytes and whole bodies of psyllids, respectively. Using these two methods, we compared Carsonella populations between female and male insects. Estimations using fluorescence in situ hybridization indicated that Carsonella was more abundant in bacteriocytes of female C. pyricola than in those of males, but Carsonella abundance in bacteriocytes did not differ between sexes of B. cockerelli. Analyses by qPCR using whole-body specimens indicated Carsonella was more abundant in females than in males of both psyllids. Neither fluorescence in situ hybridization nor qPCR indicated that Carsonella populations differed in abundance among adults of different ages (0-3 wk after adult eclosion). Using fluorescence in situ hybridization, Carsonella was observed in ovarioles of newly emerged females and formed an aggregation in the posterior end of mature oocytes. Results of our study indicate that female psyllids harbor greater populations of Carsonella than do males and that sex should be controlled for in studies which require estimations of Carsonella populations. PMID- 26056317 TI - Extracellular ATP induces the rapid release of HIV-1 from virus containing compartments of human macrophages. AB - HIV type 1 (HIV-1) infects CD4(+) T lymphocytes and tissue macrophages. Infected macrophages differ from T cells in terms of decreased to absent cytopathicity and for active accumulation of new progeny HIV-1 virions in virus-containing compartments (VCC). For these reasons, infected macrophages are believed to act as "Trojan horses" carrying infectious particles to be released on cell necrosis or functional stimulation. Here we explored the hypothesis that extracellular ATP (eATP) could represent a microenvironmental signal potentially affecting virion release from VCC of infected macrophages. Indeed, eATP triggered the rapid release of infectious HIV-1 from primary human monocyte-derived macrophages (MDM) acutely infected with the CCR5-dependent HIV-1 strain. A similar phenomenon was observed in chronically infected promonocytic U1 cells differentiated to macrophage-like cells (D-U1) by costimulation with phorbol esters and urokinase type plasminogen activator. Worthy of note, eATP did not cause necrotic, apoptotic, or pyroptotic cell death, and its effect on HIV-1 release was suppressed by Imipramine (an antidepressant agent known to inhibit microvesicle formation by interfering with membrane-associated acid sphingomyelinase). Virion release was not triggered by oxidized ATP, whereas the effect of eATP was inhibited by a specific inhibitor of the P2X7 receptor (P2X7R). Thus, eATP triggered the discharge of virions actively accumulating in VCC of infected macrophages via interaction with the P2X7R in the absence of significant cytopathicity. These findings suggest that the microvesicle pathway and P2X7R could represent exploitable targets for interfering with the VCC-associated reservoir of infectious HIV-1 virions in tissue macrophages. PMID- 26056319 TI - Identification and Function Analysis of enolase Gene NlEno1 from Nilaparvata lugens (Stal) (Hemiptera:Delphacidae). AB - The enolase [EC 4.2.1.11] is an essential enzyme in the glycolytic pathway catalyzing the conversion of 2-phosphoglycerate (2-PGE) to phosphoenolpyruvate (PEP). In this study, a full-length cDNA encoding alpha-enolase was cloned from rice brown planthopper (Nilaparvata lugens) and is provisionally designated as NlEno1. The cDNA sequence of NlEno1 was 1,851 bp with an open reading frame (ORF) of 1,305 bp and encoding 434 amino acids. The deduced protein shares high identity of 80-87% with ENO1-like protein from Hemiptera, Diptera, and Lepidoptera speices. The NlEno1 showed the highest mRNA expression level in hemolymph, followed by fat body, salivary gland, ovaries and egg, and showed trace mRNA levels in testis. The mRNA of NlEno1 showed up-regulated level in virulent N. lugens population Mudgo, IR56 and IR42 when compared with TN1 population. Injection of double-stranded RNA (dsRNA) of NlEno1 into the adults significantly down-regulated the NlEno1 mRNA level along with decreased eggs and offspring. Moreover, injection of NlEno1-dsRNA decreased mRNA level of Vitellogenin (Vg) gene. These results showed that the NlEno1, as a key glycolytic enzyme, may play roles in regulation of fecundity and adaptation of N. lugens to resistant rice varieties. PMID- 26056320 TI - Expanding the scope of Critical Care Rapid Response Teams: a feasible approach to identify adverse events. A prospective observational cohort. AB - INTRODUCTION: Adverse events (AEs) affect 3-12% of hospitalised patients. These are estimates from a labour-intensive chart review process,which is not feasible outside research. Clinical deterioration on the wards triggers a rapid response teams (RRTs) consult and can be used to identify an AE prospectively. OBJECTIVES: To demonstrate the feasibility of using RRT to detect AEs and compare this methodology to the rates reported using an electronic safety reporting system. METHODS: Prospective observational cohort of RRT consults. Three independent physicians reviewed all cases for the occurrence of an AE and its preventability. We summarise AEs as rates per 1000 patient-days, and compared the rates between RRT and the safety reporting system using a Poisson model. RESULTS: There were 8713 hospital admissions, with 531 RRT consults and 247 (2.8%) cases included. Forty-four (17.8%) and 35 cases (14.2%) were judged as AEs and preventable AEs, respectively. RRT identified 0.52 AE/1000 patient-days, compared with 0.21 AE/1000 patient-days detected through the electronic safety reporting system (rate ratio 2.4, 95% CI 1.4 to 4.2, p=0.0014). Patients in surgical wards had more AEs (0.83/1000 vs 0.36/1000, p<0.01) and preventable AEs (0.70 vs 0.21, p<0.01) than patients in medical wards. Agreement for AE (kappa 0.46, 95% CI 0.39 to 0.53) and preventable AE (kappa 0.47, 95% CI 0.40 to 0.53) was moderate among reviewers. CONCLUSIONS: Reviewing RRT consults identified a high proportion of AEs and preventable AEs. This methodology detected twice as many AEs as the hospital's safety reporting system. RRT clinicians provide a complementary and more sensitive mechanism than traditional safety reporting systems to identify possible AEs in hospitals. PMID- 26056321 TI - Reliable implementation of evidence: a qualitative study of antenatal corticosteroid administration in Ohio hospitals. AB - BACKGROUND: Antenatal corticosteroids (ANCS) reduce complications of preterm birth; however, not all eligible women receive them. Many hospitals and providers do not have the right processes and conditions to enable ANCS administration with high reliability. The objective of this study was to understand conditions that enable delivery of ANCS with high reliability among hospitals participating in an Ohio Perinatal Quality Collaborative (OPQC) ANCS project. METHODS: We conducted focus groups and semistructured interviews with members of the OPQC project team (n=27) and other care providers (n=70) using a purposeful sample of 6 sites involved in the OPQC ANCS project. Participants including nurses (n=57), attending obstetricians (n=17), physician trainees (n=21) and certified nurse midwives (n=2) were asked to reflect on their experiences and to identify factors contributing to optimal use of ANCS. Focus groups and interviews were transcribed verbatim and were analysed by a multidisciplinary team using an iterative approach that combined inductive and deductive methods to identify and categorise themes. RESULTS: Six major themes supporting reliable implementation of ANCS at these hospitals emerged including: (1) presence of a high reliability culture, (2) processes that emphasise high reliability, (3) timely and efficient administration process, (4) multiple disciplines are involved, (5) evidence of benefit supports ANCS use and (6) benefit is recognised at all levels of the care team. CONCLUSIONS: Our findings identify the key processes and supports needed to ensure delivery of ASCS with high reliability and are reinforced by implementation and reliability science. They are useful for foundation of the successful implementation of other evidence-based practices at high levels of reliability. PMID- 26056322 TI - Availability of tissue rinse liquid-based cytology for the rapid diagnosis of sentinel lymph node metastasis and improved bilateral detection by photodynamic eye camera. AB - OBJECTIVE: On sentinel lymph node navigation surgery for early invasive cervical cancers, to gain high sensitivity and specificity, the sentinel nodes should be detected bilaterally and pathological diagnosis should be sensitive to detect micrometastasis. To improve these problems, we tried tissue rinse liquid-based cytology and the photodynamic eye. METHODS: From 2005 to 2013, 102 patients with Stage Ib1 uterine cervical cancer were subjected to sentinel lymph node navigation surgery with Technetium-99 m colloid and blue dye. For the recent 11 patients with whom bilateral sentinel node detection was not available, the photodynamic eye was selectively examined. The detected sentinel node was cut along the minor axis into 2 mm slices, soaked in 10 ml CytoRich red and then subjected to tissue rinse liquid-based cytology at the time of surgery. RESULTS: With the accumulation of 102 Ib1 patients subjected to sentinel lymph node navigation surgery, the bilateral sentinel node detection rate was 67.7%. The photodynamic eye was examined for the recent 11 patients who did not have bilateral signals. Out of the 11, 10 patients obtained bilateral signals successfully. During the period of examining the photodynamic eye, a total of 34 patients were subjected to sentinel lymph node navigation surgery. Thus, the overall bilateral detection rate increased to 97% in this subset. Two hundred and five lymph nodes were available as sentinel nodes. The sensitivity of tissue rinse liquid-based cytology was 91.7%, and the specificity was 100%. False positivity was 0% and false negativity was 8.3%. Detection failure was observed only with one micrometastasis and one case of isolated tumor cells. CONCLUSION: Combination of photodynamic eye detection and tissue rinse liquid-based cytology pathology can be a promising method for more rewarding sentinel node detection. PMID- 26056324 TI - Radiologic findings to predict low-grade malignant tumour among clinical T1bN0 lung adenocarcinomas: lessons from histological subtypes. AB - OBJECTIVE: Some clinical T1bN0 (cT1bN0) lung adenocarcinomas (2-3 cm) are thought to have less-aggressive and less-malignant behaviour although most cT1aN0 tumours (<=2 cm) are indolent. The present study aimed to identify pre-operative radiographic findings that can predict cT1bN0 lung adenocarcinoma with low malignant aggressiveness in consideration of histological subtypes. METHODS: The clinicopathological features and prognoses of 224 consecutive patients (histological subtype set, n = 122; prognosis set, n = 224) with cT1bN0 lung adenocarcinoma were retrospectively examined. Adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic, node-negative papillary and node-negative acinar predominant invasive adenocarcinomas were defined as low-grade malignant, whereas solid, micropapillary, node-positive acinar and node-positive papillary predominant invasive adenocarcinoma were defined as high-grade malignant. RESULTS: Receiver operating characteristics analysis revealed that the criteria of solid tumour size <=1.8 cm on high-resolution computed tomography and the maximum standardized uptake value <=3.2 on positron emission tomography/computed tomography could predict low-grade malignant tumour in the histological subtype set. Among 95 (42.4%) of 224 patients who met the criteria for the prognosis set, 94 (98.9%) had no lymph node metastasis and 93 (97.9%) had no recurrence (median follow-up, 43.6 months). The 3 year recurrence-free survival rates were 94.9 and 79.0% in patients whose pre-operative findings met and did not meet the criteria, respectively. CONCLUSIONS: Pre-operative radiographic findings of solid tumour size and the maximum standardized uptake value could identify low-grade malignant tumour among cT1bN0 lung adenocarcinomas, which account for about half of all cT1bN0 tumours. Patients with pre-operative lung tumour findings that fulfill the criteria could be candidates for sublobar resection. PMID- 26056323 TI - Gemcitabine plus cisplatin for patients with recurrent or metastatic nasopharyngeal carcinoma in Taiwan: a multicenter prospective Phase II trial. AB - OBJECTIVE: This multicenter Phase II trial evaluated the toxicity/efficacy of gemcitabine plus cisplatin as first-line chemotherapy in patients with recurrent/metastatic nasopharyngeal carcinoma. METHODS: Gemcitabine 1250 mg/m(2) on Days 1 and 8 and cisplatin 75 mg/m(2) on Day 1 were administered at a 3-week interval. The primary endpoint was the response rate. Secondary endpoints included progression-free survival, overall survival, response duration and safety. RESULTS: Fifty-two patients were recruited between 2004 and 2008. The response rate was 51.9% (complete remission rate, 9.6%) in the intent-to-treat group. The median progression-free and overall survivals were 9.8 and 14.6 months, respectively. The major Grade III/IV adverse event was leucopenia (61.6%). The mean number of cycles was 6.63 +/- 0.40. The regimen was well tolerated, although one treatment-related death occurred after severe sepsis from aspiration pneumonia. CONCLUSIONS: Gemcitabine plus cisplatin is an effective, well-tolerated regimen as a first-line treatment for recurrent/metastatic nasopharyngeal carcinoma. PMID- 26056325 TI - Successful desensitization protocol for hypersensitivity reaction probably caused by dabrafenib in a patient with metastatic melanoma. AB - Vemurafenib and dabrafenib are both orally bioavailable small molecule agents that block mitogen activated protein kinase signalling in patients with melanoma and BRAF(V600E) mutation. Generalized hypersensitivity reactions to vemurafenib or dabrafenib have not been described. Continuing vemurafenib or dabrafenib therapy despite hypersensitivity reaction is especially important in patients with melanoma and BRAF(V600E) mutation, in whom this mutation plays a critical role in tumour growth. Desensitization protocols to overcome hypersensitivity reactions by gradual reintroduction of small amounts of the offending drug up to full therapeutic doses are available for many anti-cancer agents, including vemurafenib but, to the best of our knowledge, have not been reported for dabrafenib. We describe a patient with metastatic melanoma who developed Type I hypersensitivity reaction to vemurafenib and to subsequent treatment with dabrafenib, and who was successfully treated by drug desensitization which allowed safe prolonged continuation of dabrafenib. The development of hypersensitivity reactions for both dabrafenib and vemurafinib in the current case could be because these drugs have a similar chemical structure and cause a cross-reactivity. However, hypersensitivity reaction to a non-medicinal ingredient shared by the two drugs is also possible. Oral desensitization appears to be an option for patients with hypersensitivity Type I to dabrafenib. This approach may permit clinicians to safely administer dabrafenib to patients who experience hypersensitivity reactions to this life-prolonging medication. PMID- 26056326 TI - Prognostic value of p16 expression irrespective of human papillomavirus status in patients with oropharyngeal carcinoma. AB - OBJECTIVE: In a previous study, we reported the value of p16 expression and alcohol consumption in oropharyngeal carcinoma in Japan. We now report the clinical significance of human papillomavirus status and p16 expression in oropharyngeal carcinoma in Japan. METHODS: Over a 9-year period, a retrospective case comparison study of the pathology database was conducted at the University of Tokyo to identify tumor samples of oropharyngeal carcinoma. We performed immunohistochemistry for the p16 protein, in situ hybridization for human papillomavirus-deoxyribonucleic acid and polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 in oropharyngeal carcinoma in Japanese patients. We evaluated the human papillomavirus status in patients with oropharyngeal carcinoma to determine its prevalence and association with prognosis. We defined human papillomavirus(+) and human papillomavirus(-) oropharyngeal carcinoma cohorts as those with and without polymerase chain reaction for the human papillomavirus-deoxyribonucleic acid oncogene E6 or in situ hybridization-human papillomavirus. RESULTS: In oropharyngeal carcinoma, the prevalences of p16(+)human papillomavirus(+), p16(+)human papillomavirus(-), p16( )human papillomavirus(+) and p16(-)human papillomavirus(-) were 32% (48/150), 7% (10/150), 2% (3/150) and 59% (89/150), respectively. Low tobacco and alcohol consumption, tonsil or base of tongue localization, but not age, were associated with p16(+)human papillomavirus(+). Low alcohol consumption was associated with p16(+)human papillomavirus(-). There was a significant difference in overall survival between p16(+)human papillomavirus(-) and p16(-)human papillomavirus(-) (P = 0.03). In multivariate Cox regression models, p16 was the independent prognostic factor, regardless of human papillomavirus status. CONCLUSION: p16 expression was a reliable prognostic biomarker regardless of human papillomavirus status. PMID- 26056327 TI - Platinum hypersensitivity and desensitization. AB - Platinum agents are drugs used for various types of cancer. With increased frequency of administration of platinum agents, hypersensitivity reactions appear more frequently, occurring in over 25% of cases from the seventh cycle or second line onward. It then becomes difficult to conduct treatment using these agents. Various approaches have been investigated to address hypersensitivity reactions to platinum agents. Desensitization, which gradually increases the concentration of the anticancer drug considered to be the antigen until the target dosage, has been reported as being particularly effective, with a success rate of 80-100%. The aims of this paper are to present the current findings regarding hypersensitivity reactions to platinum agents and to discuss attempts of using desensitization against hypersensitivity reactions worldwide. PMID- 26056328 TI - Impact of renal function of patients with advanced urothelial cancer on eligibility for first-line chemotherapy and treatment outcomes. AB - OBJECTIVE: The aim of the study is to clarify the clinical effects of first-line chemotherapy regimens for advanced urothelial cancer on clinical responses and survival of patients grouped by renal function. METHODS: In this multicenter retrospective cohort study, 345 urothelial cancer patients received systemic chemotherapy for metastatic or unresectable disease in 17 centers (2004-10). RESULTS: Two hundred and forty-one patients were treated with methotrexate, vinblastine, doxorubicin and cisplatin/methotrexate, epirubicin and cisplatin (n = 136) or gemcitabine and cisplatin (n = 105) followed by carboplatin-based treatments, non-platinum treatments or other regimens. After 2008, gemcitabine and cisplatin was the most frequently used regimen in patients with an estimated glomerular filtration rate < 60 ml/min/1.73 m(2) and in those with estimated glomerular filtration rate >= 60 ml/min/1.73 m(2). The gemcitabine and cisplatin patients' complete response rate was 10.5% and their response rate was 52.4%, which was highest among all regimens. Gemcitabine and cisplatin demonstrated a better 3-year overall survival when the estimated glomerular filtration rate was >= 60 ml/min/1.73 m(2) (31.4%), but it tended to be worse when the estimated glomerular filtration rate was < 60 ml/min/1.73 m(2) (14.1%). In the latter cases, the dose reduction rate of gemcitabine and cisplatin was high (43.9%). Among the patients with estimated glomerular filtration rate < 60 ml/min/1.73 m(2), the 1-year overall survival of the patients treated with a reduced dose of gemcitabine and cisplatin was significantly lower than that of those treated with standard-dose gemcitabine and cisplatin (26.2 vs. 60.3%, respectively, P = 0.0108). CONCLUSIONS: Gemcitabine and cisplatin provided favorable responses and survival in patients with estimated glomerular filtration rate >= 60 ml/min/1.73 m(2) but unsatisfactory oncological outcomes in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m(2), especially when treated with a reduced dose. Alternative regimens might be optimal rather than reduced-dose gemcitabine and cisplatin in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m(2). PMID- 26056329 TI - Prognostic significance of beta1,6-N-acetylglucosaminyltransferase V expression in patients with hepatocellular carcinoma. AB - OBJECTIVE: Alterations to the N-glycans in glycoproteins have been suggested to play important roles in the proliferation, differentiation, invasion and metastasis of hepatocellular carcinoma (HCC). This study aims to evaluate the potential prognostic value of beta1,6-N-acetylglucosaminyltransferase V (Mgat5) in hepatocellular carcinoma patients after surgical resection. METHODS: We retrospectively enrolled 300 patients (156 in the training cohort and 144 in the validation cohort) with hepatocellular carcinoma undergoing hepatectomy at a single institution. Mgat5 intensities were assessed by immunohistochemistry in the specimens of patients. The Kaplan-Meier method was applied to compare survival curves. Cox regression models were used to analyze the impact of prognostic factors on overall survival and recurrence-free survival. The concordance index was calculated to assess predictive accuracy. RESULTS: Intratumoral Mgat5 expression was significantly higher than non-tumoral tissues (P < 0.001). In both cohorts, elevated Mgat5 expression in tumor tissues positively correlated with vascular invasion and advanced tumor-node-metastasis stage. High Mgat5 expression indicated poor survival (P < 0.001 in the training cohort and P < 0.001 in the validation cohort) and recurrence (P < 0.001 in both cohorts, respectively) in patients with hepatocellular carcinoma, particularly with early-stage disease. Mgat5 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of tumor-node-metastasis and Barcelona Clinic Liver Cancer prognostic models was improved when Mgat5 expression was added. CONCLUSION: Mgat5 expression is a potential independent adverse prognostic biomarker for recurrence and survival of patients with hepatocellular carcinoma after hepatectomy. PMID- 26056330 TI - Vitamin D supplementation is associated with stabilization of cardiac autonomic tone in IgA nephropathy. PMID- 26056331 TI - Adiposity and vascular aging: indication for weight loss? PMID- 26056333 TI - Is microglia the new target for the treatment of resistant hypertension? PMID- 26056332 TI - Circulating vascular cell adhesion molecule-1 is associated with cerebral blood flow dysregulation, mobility impairment, and falls in older adults. AB - Soluble vascular cell adhesion molecule-1 (sVCAM-1) is associated with hypertension, vascular inflammation, and systemic endothelial dysfunction. We evaluated whether elevated plasma sVCAM-1 is associated with impaired cerebrovascular function and mobility impairments in elderly people. We studied the cross-sectional relationships between plasma sVCAM-1 level, gait speed, and cerebrovascular hemodynamics, and its longitudinal relationship with falls in 680 community-dwelling participants aged >=65 years in the Maintenance of Balance, Independent Living, Intellect, and Zest in the Elderly (MOBILIZE) Boston Study. Falls were recorded prospectively for 1 year on daily calendars. sVCAM-1 was measured by ELISA assay and beat-to-beat blood flow velocity in the middle cerebral artery during rest and in response to changes in end-tidal CO2 was measured by transcranial Doppler ultrasound. sVCAM-1 concentration was 1094+/-340 ng/mL in normotensives, 1195+/-438 ng/mL in controlled hypertensives, and 1250+/ 445 ng/mL in uncontrolled hypertensives (P=0.008). The mean resting blood flow velocity and cerebral vasomotor range were, respectively, 41.0+/-10.3 cm/s and 1.3+/-0.4 cm/s per millimeter of mercury. Elevated sVCAM-1 levels indicative of endothelial dysfunction were associated with reduced resting blood flow velocity (P=0.017) and cerebral vasomotor range (P=0.0048). Elevated sVCAM-1 levels were associated with slower gait speed (<0.8 m/s; odds ratio, 3.01; 95% confidence interval, 1.56-5.83; P=0.0011) and an increased odds of injurious falls (odds ratio, 2.4; 95% confidence interval, 1.4-4.2; P=0.0028). An elevated sVCAM-1 level may be a marker of cerebral blood flow dysregulation because of endothelial damage from hypertension. It may also signal the presence of cerebral microvascular disease and its clinical consequences, including slow gait speed and falls. PMID- 26056334 TI - Genetic and potential autoimmune triggers of primary aldosteronism. PMID- 26056336 TI - Effect of lower on-treatment systolic blood pressure on the risk of atrial fibrillation in hypertensive patients. AB - There is a well-established association between hypertension and atrial fibrillation (AF); indeed, even upper normal systolic blood pressures (SBP) are long-term predictors of incident AF. These findings suggest that more aggressive BP control may reduce the risk of new AF. However, whether lower achieved SBP is associated with a lower incidence of AF remains unclear. The risk of new-onset AF was examined in relation to last in-treatment SBP before AF diagnosis or last in study measurement in the absence of new AF in 8831 hypertensive patients with ECG left ventricular hypertrophy with no history of AF, in sinus rhythm on their baseline ECG, randomly assigned to losartan- or atenolol-based treatment. Patients with in-treatment SBP <=130 mm Hg (lowest quintile at last measurement) and SBP between 131 and 141 mm Hg were compared with patients with in-treatment SBP >=142 mm Hg (median SBP at last measurement). During follow-up of 4.6+/-1.1 years, new-onset AF was diagnosed in 701 patients (7.9%). In multivariate Cox analyses, compared with in-treatment SBP >=142 mm Hg, in-treatment SBP <=130 mm Hg entered as a time-varying covariate was associated with a 40% lower risk (95% confidence interval, 18%-55%) and in-treatment SBP of 131 to 141 mm Hg with a 24% lower risk (95% confidence interval, 7%-38%) of new AF. Thus, achieved SBP <=130 mm Hg is associated with a lower risk of new-onset AF in hypertensive patients with ECG left ventricular hypertrophy. Further study is needed to determine whether targeting hypertensive patients without AF to lower SBP goals can reduce the burden of new AF in this high-risk population. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00338260. PMID- 26056335 TI - Adiposity, obesity, and arterial aging: longitudinal study of aortic stiffness in the Whitehall II cohort. AB - We sought to determine whether adiposity in later midlife is an independent predictor of accelerated stiffening of the aorta. Whitehall II study participants (3789 men; 1383 women) underwent carotid-femoral applanation tonometry at the mean age of 66 and again 4 years later. General adiposity by body mass index, central adiposity by waist circumference and waist:hip ratio, and fat mass percent by body impedance were assessed 5 years before and at baseline. In linear mixed models adjusted for age, sex, ethnicity, and mean arterial pressure, all adiposity measures were associated with aortic stiffening measured as increase in pulse wave velocity (PWV) between baseline and follow-up. The associations were similar in the metabolically healthy and unhealthy, according to Adult Treatment Panel-III criteria excluding waist circumference. C-reactive protein and interleukin-6 levels accounted for part of the longitudinal association between adiposity and PWV change. Adjusting for chronic disease, antihypertensive medication and risk factors, standardized effects of general and central adiposity and fat mass percent on PWV increase (m/s) were similar (0.14, 95% confidence interval: 0.05-0.24, P=0.003; 0.17, 0.08-0.27, P<0.001; 0.14, 0.05 0.22, P=0.002, respectively). Previous adiposity was associated with aortic stiffening independent of change in adiposity, glycaemia, and lipid levels across PWV assessments. We estimated that the body mass index-linked PWV increase will account for 12% of the projected increase in cardiovascular risk because of high body mass index. General and central adiposity in later midlife were strong independent predictors of aortic stiffening. Our findings suggest that adiposity is an important and potentially modifiable determinant of arterial aging. PMID- 26056338 TI - Gait decline: the role of cerebral small vessel disease and biomarkers. PMID- 26056337 TI - Hypertension-related alterations in white matter microstructure detectable in middle age. AB - Most studies examining associations between hypertension and brain white matter microstructure have focused on older adults or on cohorts with a large age range. Because hypertension effects on the brain may vary with age, it is important to focus on middle age, when hypertension becomes more prevalent. We used linear mixed-effect models to examine differences in white matter diffusion metrics as a function of hypertension in a well-characterized cohort of middle-aged men (n=316; mean, 61.8 years; range, 56.7-65.6). Diffusion metrics were examined in 9 tracts reported to be sensitive to hypertension in older adults. Relative to normotensive individuals, individuals with long-standing hypertension (>5.6 years) showed reduced fractional anisotropy or increased diffusivity in most tracts. Effects were stronger among carriers than among noncarriers of the apolipoprotein E epsilon4 allele for 2 tracts connecting frontal regions with other brain areas. Significant differences were observed even after adjustment for potentially related lifestyle and cardiovascular risk factors. Shorter duration of hypertension or better blood pressure control among hypertensive individuals did not lessen the adverse effects. These findings suggest that microstructural white matter alterations appear early in the course of hypertension and may persist despite adequate treatment. Although longitudinal studies are needed to confirm these findings, the results suggest that prevention rather than management-of hypertension may be vital to preserving brain health in aging. PMID- 26056339 TI - Microglia participate in neurogenic regulation of hypertension. AB - Hypertension is associated with neuroinflammation and increased sympathetic tone. Interference with neuroinflammation by an anti-inflammatory reagent or overexpression of interleukin-10 in the brain was found to attenuate hypertension. However, the cellular mechanism of neuroinflammation, as well as its impact on neurogenic regulation of blood pressure, is unclear. Here, we found that hypertension, induced by either angiotensin II or l-N(G)-nitro-l-arginine methyl ester, is accompanied by microglial activation as manifested by microgliosis and proinflammatory cytokine upregulation. Targeted depletion of microglia significantly attenuated neuroinflammation, glutamate receptor expression in the paraventricular nucleus, plasma vasopressin level, kidney norepinephrine concentration, and blood pressure. Furthermore, when microglia were preactivated and transferred into the brains of normotensive mice, there was a significantly prolonged pressor response to intracerebroventricular injection of angiotensin II, and inactivation of microglia eliminated these effects. These data demonstrate that microglia, the resident immune cells in the brain, are the major cellular factors in mediating neuroinflammation and modulating neuronal excitation, which contributes to the elevated blood pressure. PMID- 26056340 TI - Blood pressure targets and absolute cardiovascular risk. AB - In the Eighth Joint National Committee guideline on hypertension, the threshold for the initiation of blood pressure-lowering treatment for elderly adults (>=60 years) without chronic kidney disease or diabetes mellitus was raised from 140/90 mm Hg to 150/90 mm Hg. However, the committee was not unanimous in this decision, particularly because a large proportion of adults >=60 years may be at high cardiovascular risk. On the basis of Eighth Joint National Committee guideline, we sought to determine the absolute 10-year risk of cardiovascular disease among these adults through analyzing the National Health and Nutrition Examination Survey (2005-2012). The primary outcome measure was the proportion of adults who were at >=20% predicted absolute cardiovascular risk and above goals for the Seventh Joint National Committee guideline but reclassified as at target under the Eighth Joint National Committee guideline (reclassified). The Framingham General Cardiovascular Disease Risk Score was used. From 2005 to 2012, the surveys included 12 963 adults aged 30 to 74 years with blood pressure measurements, of which 914 were reclassified based on the guideline. Among individuals reclassified as not in need of additional treatment, the proportion of adults 60 to 74 years without chronic kidney disease or diabetes mellitus at >=20% absolute risk was 44.8%. This corresponds to 0.8 million adults. The proportion at high cardiovascular risk remained sizable among adults who were not receiving blood pressure-lowering treatment. Taken together, a sizable proportion of reclassified adults 60 to 74 years without chronic kidney disease or diabetes mellitus was at >=20% absolute cardiovascular risk. PMID- 26056341 TI - Angiotensin type 2 receptor: hidden partner. PMID- 26056342 TI - Adverse prognostic value of persistent office blood pressure elevation in white coat hypertension. AB - Stratification of cardiovascular risk is of fundamental importance in white coat hypertension (WCH) to identify individuals in need of closer follow-up and perhaps antihypertensive drug treatment. In subjects representative of the general population of Monza (Italy), the risk of cardiovascular and all-cause mortality was assessed >16 years in stable and unstable WCH individuals, that is, those in whom ambulatory blood pressure (BP) normality was associated with a persistent or nonpersistent office BP elevation at 2 consecutive visits, respectively. Data were compared with those from an entirely normotensive group, that is, ambulatory and persistent office BP normality. Compared with the normotensive group, the risk of cardiovascular and all-cause death was not significantly different in unstable WCH, whereas in stable WCH the risk was increased also when data were adjusted for baseline confounders, including ambulatory BP (hazard ratio, 16; P=0.001 for cardiovascular death and 1.92; P=0.02 for all-cause death). At a multivariable analysis, office BP was among the factors independently predicting death, and results were superimposable with use of Monza population-derived and guidelines-derived cutoff values for ambulatory BP normality (125/79 and 130/80 mm Hg, respectively). Thus, only when office BP is persistently elevated does WCH reflect the existence of an abnormal long-term mortality risk. This means that in WCH office BP is prognostically relevant and that repeated collection of its values is clinically important to better define patient risk. PMID- 26056343 TI - Angiotensin II type 2 receptor- and acetylcholine-mediated relaxation: essential contribution of female sex hormones and chromosomes. AB - Angiotensin-induced vasodilation, involving type 2 receptor (AT2R)-induced generation of nitric oxide (NO; by endothelial NO synthase) and endothelium derived hyperpolarizing factors, may be limited to women. To distinguish the contribution of female sex hormones and chromosomes to AT2R function and endothelium-derived hyperpolarizing factor-mediated vasodilation, we made use of the four-core genotype model, where the testis-determining Sry gene has been deleted (Y(-)) from the Y chromosome, allowing XY(-) mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY(-)Sry and XXSry transgenic mice develop into gonadal male mice. Four core genotype mice underwent a sham or gonadectomy (GDX) operation, and after 8 weeks, iliac arteries were collected to assess vascular function. XY(-)Sry male mice responded more strongly to angiotensin than XX female mice, and the AT2R antagonist PD123319 revealed that this was because of a dilator AT2R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY(-) female mice nor in XX female mice after GDX, suggesting that it depends on both sex hormones and chromosomes. Indeed, treating C57bl/6 GDX male mice with estrogen could not restore angiotensin-mediated, AT2R dependent relaxation. To block acetylcholine-induced relaxation of iliac arteries obtained from four-core genotype XX mice, both endothelial NO synthase and endothelium-derived hyperpolarizing factor inhibition were required, whereas in four-core genotype XY animals, endothelial NO synthase inhibition alone was sufficient. These findings were independent of gonadal sex and unaltered after GDX. In conclusion, AT2R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium derived hyperpolarizing factors. PMID- 26056344 TI - Pressure changes within the sac of human cerebral aneurysms in response to artificially induced transient increases in systemic blood pressure. AB - Formation and rupture of cerebral aneurysms have been associated with chronic hypertension. The effect of transient increase in blood pressure and its effect on intra-aneurysmal hemodynamics have not been studied. We examined the effects of controlled increases in blood pressure on different pressure parameters inside the sac of human cerebral aneurysms and corresponding parent arteries using invasive technology. Twelve patients (10 female, 2 male, age 54+/-15 years) with unruptured cerebral aneurysms undergoing endovascular coiling were recruited. Dual-sensor microwires with the capacity to simultaneously measure flow velocity and pressure were used to measure systolic, diastolic, and mean pressure inside the aneurysm sac and to measure both pressures and flow velocities in the feeder vessel just outside the aneurysm. These pressures were recorded simultaneously with pressures from a radial arterial catheter. Measurements were taken at baseline and then during a gradual increase in systemic systolic blood pressure to a target value of ~25 mm Hg above baseline, using a phenylephrine infusion. The dose needed to achieve the required increase in radial arterial systolic blood pressure was 0.8+/-0.2 MUg/kg/min. There was a clear linear relationship between changes in radial and aneurysmal pressures with substantial patient-by patient variation in the slopes of those relationships. The overall increases in systolic and mean pressures in both radial artery and in the aneurysms were similar. Pressures in the aneurysm and in the parent vessels were similar. Peak and mean flow velocities in the parent arteries did not change significantly with phenylephrine infusion, nor did vessel diameters as measured angiographically. PMID- 26056347 TI - Stroke Caused by a Pulmonary Vein Thrombosis Revealing a Metastatic Choriocarcinoma. PMID- 26056348 TI - Dengue Myopericarditis Mimicking Acute Myocardial Infarction. PMID- 26056345 TI - Emerging Concepts in the Molecular Basis of Pulmonary Arterial Hypertension: Part II: Neurohormonal Signaling Contributes to the Pulmonary Vascular and Right Ventricular Pathophenotype of Pulmonary Arterial Hypertension. PMID- 26056349 TI - Letter by Scott and Haykowsky Regarding Articles, "Can Intensive Exercise Harm the Heart? The Benefits of Competitive Endurance Training for Cardiovascular Structure and Function" and "Can Intensive Exercise Harm the Heart? You Can Get Too Much of a Good Thing". PMID- 26056350 TI - Letter by Mohlenkamp et al Regarding Articles, "Can Intensive Exercise Harm the Heart? The Benefits of Competitive Endurance Training for Cardiovascular Structure and Function" and "Can Intensive Exercise Harm the Heart? You Can Get Too Much of a Good Thing". PMID- 26056351 TI - Response to the Letters Regarding Article, "Can Intensive Exercise Harm the Heart? The Benefits of Competitive Endurance Training for Cardiovascular Structure and Function". PMID- 26056352 TI - Response to Letters Regarding Article, "Can Intensive Exercise Harm the Heart? You Can Get Too Much of a Good Thing". PMID- 26056353 TI - Phase I Clinical Trial to Determine the Feasibility and Maximum Tolerated Dose of Panitumumab to Standard Gemcitabine-Based Chemoradiation in Locally Advanced Pancreatic Cancer. AB - PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors may improve both the therapeutic efficacy of radiotherapy and the radiosensitizing activity of gemcitabine. Based on this rationale and the nonoverlapping toxicity profiles of gemcitabine and the monoclonal EGFR antibody panitumumab, we designed a phase I trial to investigate the maximum-tolerated dose (MTD), safety, and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC). EXPERIMENTAL DESIGN: Patients with LAPC and WHO performance status 0 to 1 were treated with weekly panitumumab at four dose levels (1-2.5 mg/kg), combined with weekly gemcitabine 300 mg/m(2) and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m(2) weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity. Each cohort was monitored during the combination therapy to establish dose limiting toxicity. Tumor evaluation was performed after CRT and during gemcitabine monotherapy. RESULTS: Fourteen patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg. Three of the 6 patients, treated at MTD, experienced grade 3 adverse events during the combination therapy; neutropenia (n = 2; 33%), fatigue (n = 1; 17%), nausea (n = 1; 17%), and vomiting (n = 1; 17%). Partial response was achieved by 3 patients (23%), 1 in each dose cohort. Median progression free survival of the three cohorts together was 8.9 months. CONCLUSIONS: The addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC has manageable toxicity and potential clinical efficacy. PMID- 26056354 TI - Influence of glycosylation on diagnostic and prognostic accuracy of N-terminal pro-B-type natriuretic peptide in acute dyspnea: data from the Akershus Cardiac Examination 2 Study. AB - BACKGROUND: The N-terminal part of pro-B-type natriuretic peptide (NT-proBNP) is glycosylated, but whether glycosylation influences the diagnostic and prognostic accuracy of NT-proBNP measurements is not known. METHODS: We measured NT-proBNP concentrations of 309 patients with acute dyspnea by use of standard EDTA tubes and EDTA tubes pretreated with deglycosylation enzymes. The primary cause of dyspnea was classified as heart failure (HF) or non-HF, and the diagnosis was adjudicated by 2 independent physicians. We collected information on all-cause mortality during follow-up. RESULTS: In all, 142 patients (46%) were diagnosed with HF. NT-proBNP concentrations in nondeglycosylated samples distinguished HF patients from patients with non-HF related dyspnea [median 3588 (quartiles 1-3 1578-8404) vs 360 (126-1139) ng/L, P < 0.001], but concentrations were markedly higher in samples pretreated with deglycosylation enzymes (total NT-proBNP) [7497 (3374-14 915) vs 798 (332-2296) ng/L, P < 0.001]. The AUC to separate HF patients from patients with non-HF related dyspnea was 0.871 (95% CI 0.829-0.907) for total NT-proBNP compared with 0.852 (0.807-0.890) for NT-proBNP measurements in standard EDTA plasma. During a median follow-up of 816 days, 112 patients (36%) died. Both NT-proBNP and total NT-proBNP concentrations were associated with mortality in separate multivariate models, but only total NT-proBNP concentrations provided added value to the basic risk model of our dataset as assessed by the net reclassification index: 0.24 (95% CI 0.003-0.384). There was a graded increase in risk across total NT-proBNP quartiles, in contrast with the results for NT-proBNP measurements. CONCLUSIONS: NT-proBNP concentrations were higher, and diagnostic and prognostic accuracy was improved, by pretreating tubes with deglycosylation enzymes. PMID- 26056355 TI - Tumor microRNA expression profiling identifies circulating microRNAs for early breast cancer detection. AB - BACKGROUND: The identification of novel biomarkers for early breast cancer detection would be a great advance. Because of their role in tumorigenesis and stability in body fluids, microRNAs (miRNAs) are emerging as a promising diagnostic tool. Our aim was to identify miRNAs deregulated in breast tumors and evaluate the potential of circulating miRNAs in breast cancer detection. METHODS: We conducted miRNA expression profiling of 1919 human miRNAs in paraffin-embedded tissue from 122 breast tumors and 11 healthy breast tissue samples. Differential expression analysis was performed, and a microarray classifier was generated. The most relevant miRNAs were analyzed in plasma from 26 healthy individuals and 83 patients with breast cancer (36 before and 47 after treatment) and validated in 116 healthy individuals and 114 patients before treatment. RESULTS: We identified a large number of miRNAs deregulated in breast cancer and generated a 25-miRNA microarray classifier that discriminated breast tumors with high diagnostic sensitivity and specificity. Ten miRNAs were selected for further investigation, of which 4 (miR-505-5p, miR-125b-5p, miR-21-5p, and miR-96-5p) were significantly overexpressed in pretreated patients with breast cancer compared with healthy individuals in 2 different series of plasma. MiR-505-5p and miR-96-5p were the most valuable biomarkers (area under the curve 0.72). Moreover, the expression levels of miR-3656, miR-505-5p, and miR-21-5p were decreased in a group of treated patients. CONCLUSIONS: Circulating miRNAs reflect the presence of breast tumors. The identification of deregulated miRNAs in plasma of patients with breast cancer supports the use of circulating miRNAs as a method for early breast cancer detection. PMID- 26056356 TI - Towards cancer-aware life-history modelling. AB - Studies of body size evolution, and life-history theory in general, are conducted without taking into account cancer as a factor that can end an organism's reproductive lifespan. This reflects a tacit assumption that predation, parasitism and starvation are of overriding importance in the wild. We argue here that even if deaths directly attributable to cancer are a rarity in studies of natural populations, it remains incorrect to infer that cancer has not been of importance in shaping observed life histories. We present first steps towards a cancer-aware life-history theory, by quantifying the decrease in the length of the expected reproductively active lifespan that follows from an attempt to grow larger than conspecific competitors. If all else is equal, a larger organism is more likely to develop cancer, but, importantly, many factors are unlikely to be equal. Variations in extrinsic mortality as well as in the pace of life--larger organisms are often near the slow end of the fast-slow life-history continuum- can make realized cancer incidences more equal across species than what would be observed in the absence of adaptive responses to cancer risk (alleviating the so called Peto's paradox). We also discuss reasons why patterns across species can differ from within-species predictions. Even if natural selection diminishes cancer susceptibility differences between species, within-species differences can remain. In many sexually dimorphic cases, we predict males to be more cancer prone than females, forming an understudied component of sexual conflict. PMID- 26056357 TI - Peto's paradox and human cancers. AB - Peto's paradox is the lack of the expected trend in cancer incidence as a function of body size and lifespan across species. The leading hypothesis to explain this pattern is natural selection for differential cancer prevention in larger, longer lived species. We evaluate whether a similar effect exists within species, specifically humans. We begin by reanalysing a recently published dataset to separate the effects of stem cell number and replication rate, and show that each has an independent effect on cancer risk. When considering the lifetime number of stem cell divisions in an extended dataset, and removing cases associated with other diseases or carcinogens, we find that lifetime cancer risk per tissue saturates at approximately 0.3-1.3% for the types considered. We further demonstrate that grouping by anatomical site explains most of the remaining variation. Our results indicate that cancer risk depends not only on the number of stem cell divisions but varies enormously (approx. 10 000 times) depending on anatomical site. We conclude that variation in risk of human cancer types is analogous to the paradoxical lack of variation in cancer incidence among animal species and may likewise be understood as a result of evolution by natural selection. PMID- 26056358 TI - Inclusive fitness effects can select for cancer suppression into old age. AB - Natural selection can favour health at youth or middle age (high reproductive value) over health at old age (low reproductive value). This means, all else being equal, selection for cancer suppression should dramatically drop after reproductive age. However, in species with significant parental investment, the capacity to enhance inclusive fitness may increase the reproductive value of older individuals or even those past reproductive age. Variation in parental investment levels could therefore contribute to variation in cancer susceptibility across species. In this article, we describe a simple model and framework for the evolution of cancer suppression with varying levels of parental investment and use this model to make testable predictions about variation in cancer suppression across species. This model can be extended to show that selection for cancer suppression is stronger in species with cooperative breeding systems and intergenerational transfers. We consider three cases that can select for cancer suppression into old age: (i) extended parental care that increases the survivorship of their offspring, (ii) grandparents contributing to higher fecundity of their children and (iii) cooperative breeding where helpers forgo reproduction or even survivorship to assist parents in having higher fecundity. PMID- 26056359 TI - Peto's paradox and the hallmarks of cancer: constructing an evolutionary framework for understanding the incidence of cancer. AB - An evolutionary perspective can help unify disparate observations and make testable predictions. We consider an evolutionary model in relation to two mechanistic frameworks of cancer biology: multistage carcinogenesis and the hallmarks of cancer. The multistage model predicts that cancer risk increases with body size and longevity; however, this is not observed across species (Peto's paradox), but the paradox is resolved by invoking the evolution of additional genetic mechanisms to suppress cancer in large, long-lived species. It is when cancer cells overcome these defence mechanisms that they exhibit the hallmarks of cancer, driving the ongoing evolution of these defences, which in turn is expected to create the differences observed in the genetics of cancer across species and tissues. To illustrate the utility of an evolutionary model we examined some recently published data linking stem-cell divisions and cancer incidence across a range of tissues and show why the original analysis was faulty, and demonstrate that the data are consistent with a multistage model varying from three to seven mutational hits across different tissues. Finally, we demonstrate how an evolutionary model can both define patterns of inherited (familial) cancer and explain the prevalence of cancer in post-reproductive years, including the dominance of epithelial cancers. PMID- 26056360 TI - Quantitative implications of the approximate irrelevance of mammalian body size and lifespan to lifelong cancer risk. PMID- 26056361 TI - Peto's paradox and the promise of comparative oncology. AB - The past several decades have seen a paradigm shift with the integration of evolutionary thinking into studying cancer. The evolutionary lens is most commonly employed in understanding cancer emergence, tumour growth and metastasis, but there is an increasing realization that cancer defences both between tissues within the individual and between species have been influenced by natural selection. This special issue focuses on discoveries of these deeper evolutionary phenomena in the emerging area of 'comparative oncology'. Comparing cancer dynamics in different tissues or species can lead to insights into how biology and ecology have led to differences in carcinogenesis, and the diversity, incidence and lethality of cancers. In this introduction to the special issue, we review the history of the field and outline how the contributions use empirical, comparative and theoretical approaches to address the processes and patterns associated with 'Peto's paradox', the lack of a statistical relationship of cancer incidence with body size and longevity. This burgeoning area of research can help us understand that cancer is not only a disease but is also a driving force in biological systems and species life histories. Comparative oncology will be key to understanding globally important health issues, including cancer epidemiology, prevention and improved therapies. PMID- 26056362 TI - Maternal-fetal conflict, genomic imprinting and mammalian vulnerabilities to cancer. AB - Antagonistic coevolution between maternal and fetal genes, and between maternally and paternally derived genes may have increased mammalian vulnerability to cancer. Placental trophoblast has evolved to invade maternal tissues and evade structural and immunological constraints on its invasion. These adaptations can be co-opted by cancer in intrasomatic selection. Imprinted genes of maternal and paternal origin favour different degrees of proliferation of particular cell types in which they reside. As a result, the set of genes favouring greater proliferation will be selected to evade controls on cell-cycle progression imposed by the set of genes favouring lesser proliferation. The dynamics of stem cell populations will be a particular focus of this intragenomic conflict. Gene networks that are battlegrounds of intragenomic conflict are expected to be less robust than networks that evolve in the absence of conflict. By these processes, maternal-fetal and intragenomic conflicts may undermine evolved defences against cancer. PMID- 26056365 TI - The multiple facets of Peto's paradox: a life-history model for the evolution of cancer suppression. AB - Large animals should have higher lifetime probabilities of cancer than small animals because each cell division carries an attendant risk of mutating towards a tumour lineage. However, this is not observed--a (Peto's) paradox that suggests large and/or long-lived species have evolved effective cancer suppression mechanisms. Using the Euler-Lotka population model, we demonstrate the evolutionary value of cancer suppression as determined by the 'cost' (decreased fecundity) of suppression verses the 'cost' of cancer (reduced survivorship). Body size per se will not select for sufficient cancer suppression to explain the paradox. Rather, cancer suppression should be most extreme when the probability of non-cancer death decreases with age (e.g. alligators), maturation is delayed, fecundity rates are low and fecundity increases with age. Thus, the value of cancer suppression is predicted to be lowest in the vole (short lifespan, high fecundity) and highest in the naked mole rat (long lived with late female sexual maturity). The life history of pre-industrial humans likely selected for quite low levels of cancer suppression. In modern humans that live much longer, this level results in unusually high lifetime cancer risks. The model predicts a lifetime risk of 49% compared with the current empirical value of 43%. PMID- 26056363 TI - Cancer across the tree of life: cooperation and cheating in multicellularity. AB - Multicellularity is characterized by cooperation among cells for the development, maintenance and reproduction of the multicellular organism. Cancer can be viewed as cheating within this cooperative multicellular system. Complex multicellularity, and the cooperation underlying it, has evolved independently multiple times. We review the existing literature on cancer and cancer-like phenomena across life, not only focusing on complex multicellularity but also reviewing cancer-like phenomena across the tree of life more broadly. We find that cancer is characterized by a breakdown of the central features of cooperation that characterize multicellularity, including cheating in proliferation inhibition, cell death, division of labour, resource allocation and extracellular environment maintenance (which we term the five foundations of multicellularity). Cheating on division of labour, exhibited by a lack of differentiation and disorganized cell masses, has been observed in all forms of multicellularity. This suggests that deregulation of differentiation is a fundamental and universal aspect of carcinogenesis that may be underappreciated in cancer biology. Understanding cancer as a breakdown of multicellular cooperation provides novel insights into cancer hallmarks and suggests a set of assays and biomarkers that can be applied across species and characterize the fundamental requirements for generating a cancer. PMID- 26056364 TI - Cancer susceptibility and reproductive trade-offs: a model of the evolution of cancer defences. AB - The factors influencing cancer susceptibility and why it varies across species are major open questions in the field of cancer biology. One underexplored source of variation in cancer susceptibility may arise from trade-offs between reproductive competitiveness (e.g. sexually selected traits, earlier reproduction and higher fertility) and cancer defence. We build a model that contrasts the probabilistic onset of cancer with other, extrinsic causes of mortality and use it to predict that intense reproductive competition will lower cancer defences and increase cancer incidence. We explore the trade-off between cancer defences and intraspecific competition across different extrinsic mortality conditions and different levels of trade-off intensity, and find the largest effect of competition on cancer in species where low extrinsic mortality combines with strong trade-offs. In such species, selection to delay cancer and selection to outcompete conspecifics are both strong, and the latter conflicts with the former. We discuss evidence for the assumed trade-off between reproductive competitiveness and cancer susceptibility. Sexually selected traits such as ornaments or large body size require high levels of cell proliferation and appear to be associated with greater cancer susceptibility. Similar associations exist for female traits such as continuous egg-laying in domestic hens and earlier reproductive maturity. Trade-offs between reproduction and cancer defences may be instantiated by a variety of mechanisms, including higher levels of growth factors and hormones, less efficient cell-cycle control and less DNA repair, or simply a larger number of cell divisions (relevant when reproductive success requires large body size or rapid reproductive cycles). These mechanisms can affect intra- and interspecific variation in cancer susceptibility arising from rapid cell proliferation during reproductive maturation, intrasexual competition and reproduction. PMID- 26056366 TI - Solutions to Peto's paradox revealed by mathematical modelling and cross-species cancer gene analysis. AB - Whales have 1000-fold more cells than humans and mice have 1000-fold fewer; however, cancer risk across species does not increase with the number of somatic cells and the lifespan of the organism. This observation is known as Peto's paradox. How much would evolution have to change the parameters of somatic evolution in order to equalize the cancer risk between species that differ by orders of magnitude in size? Analysis of previously published models of colorectal cancer suggests that a two- to three-fold decrease in the mutation rate or stem cell division rate is enough to reduce a whale's cancer risk to that of a human. Similarly, the addition of one to two required tumour-suppressor gene mutations would also be sufficient. We surveyed mammalian genomes and did not find a positive correlation of tumour-suppressor genes with increasing body mass and longevity. However, we found evidence of the amplification of TP53 in elephants, MAL in horses and FBXO31 in microbats, which might explain Peto's paradox in those species. Exploring parameters that evolution may have fine-tuned in large, long-lived organisms will help guide future experiments to reveal the underlying biology responsible for Peto's paradox and guide cancer prevention in humans. PMID- 26056367 TI - A metabolic perspective of Peto's paradox and cancer. AB - The frequency of cancer is postulated to be proportional to the number of cells an animal possesses, as each cell is similarly exposed to mutagens with every cell division. Larger animals result from more cell divisions with more mutagenic exposure, and hence are expected to have higher frequencies of cancer. Yet, as stipulated by Peto's paradox, larger animals do not have the higher rates of cancers seen in smaller animals despite the significant differences in cell numbers and a longer lifetime that would expose larger animals to more mutagens. The rates of cancer appear to be inversely proportional to animal body size, which scales inversely with specific metabolic rates of mammals. Studies over the past 20 years have linked oncogenes and tumour suppressors to alterations in cancer metabolism, and conversely, mutations in metabolic genes have been documented to trigger tumorigenesis. The by-products and intermediates of metabolism, such as reactive oxygen species, oxoglutarate, citrate and acetate, all have the potential to mutate and alter the genome or epigenome. On the basis of these general observations, it is proposed that metabolic rates correlate with mutagenic rates, which are higher in small animals and give the mechanistic basis for Peto's paradox. The observations discussed in this overview collectively indicate that specific metabolic rate varies inversely with body size, which seems to support the hypothesis that metabolism drives tumorigenesis and accounts for Peto's paradox. PMID- 26056368 TI - Infection and cancer in multicellular organisms. AB - Evolutionary considerations suggest that oncogenic infections should be pervasive among animal species. Infection-associated cancers are well documented in humans and domestic animals, less commonly reported in undomesticated captive animals, and rarely documented in nature. In this paper, we review the literature associating infectious agents with cancer to evaluate the reasons for this pattern. Non-malignant infectious neoplasms occur pervasively in multicellular life, but oncogenic progression to malignancy is often uncertain. Evidence from humans and domestic animals shows that non-malignant infectious neoplasms can develop into cancer, although generally with low frequency. Malignant neoplasms could be difficult to find in nature because of a low frequency of oncogenic transformation, short survival after malignancy and reduced survival prior to malignancy. Moreover, the evaluation of malignancy can be ambiguous in nature, because criteria for malignancy may be difficult to apply consistently across species. The information available in the literature therefore does not allow for a definitive assessment of the pervasiveness of infectious cancers in nature, but the presence of infectious neoplasias and knowledge about the progression of benign neoplasias to cancer is consistent with a widespread but largely undetected occurrence. PMID- 26056369 TI - On the apparent rarity of epithelial cancers in captive chimpanzees. AB - Malignant neoplasms arising from epithelial cells are called carcinomas. Such cancers are diagnosed in about one in three humans in 'developed' countries, with the most common sites affected being lung, breast, prostate, colon, ovary and pancreas. By contrast, carcinomas are said to be rare in captive chimpanzees, which share more than 99% protein sequence homology with humans (and possibly in other related 'great apes'-bonobos, gorillas and orangutans). Simple ascertainment bias is an unlikely explanation, as these nonhuman hominids are recipients of excellent veterinary care in research facilities and zoos, and are typically subjected to necropsies when they die. In keeping with this notion, benign tumours and cancers that are less common in humans are well documented in this population. In this brief overview, we discuss other possible explanations for the reported rarity of carcinomas in our closest evolutionary cousins, including inadequacy of numbers surveyed, differences in life expectancy, diet, genetic susceptibility, immune responses or their microbiomes, and other potential environmental factors. We conclude that while relative carcinoma risk is a likely difference between humans and chimpanzees (and possibly other 'great apes'), a more systematic survey of available data is required for validation of this claim. PMID- 26056370 TI - Common cancer in a wild animal: the California sea lion (Zalophus californianus) as an emerging model for carcinogenesis. AB - Naturally occurring cancers in non-laboratory species have great potential in helping to decipher the often complex causes of neoplasia. Wild animal models could add substantially to our understanding of carcinogenesis, particularly of genetic and environmental interactions, but they are currently underutilized. Studying neoplasia in wild animals is difficult and especially challenging in marine mammals owing to their inaccessibility, lack of exposure history, and ethical, logistical and legal limits on experimentation. Despite this, California sea lions (Zalophus californianus) offer an opportunity to investigate risk factors for neoplasia development that have implications for terrestrial mammals and humans who share much of their environment and diet. A relatively accessible California sea lion population on the west coast of the USA has a high prevalence of urogenital carcinoma and is regularly sampled during veterinary care in wildlife rehabilitation centres. Collaborative studies have revealed that genotype, persistent organic pollutants and a herpesvirus are all associated with this cancer. This paper reviews research to date on the epidemiology and pathogenesis of urogenital carcinoma in this species, and presents the California sea lion as an important and currently underexploited wild animal model of carcinogenesis. PMID- 26056371 TI - The Golden Retriever Lifetime Study: establishing an observational cohort study with translational relevance for human health. AB - The Golden Retriever Lifetime Study (GRLS) is the first prospective longitudinal study attempted in veterinary medicine to identify the major dietary, genetic and environmental risk factors for cancer and other important diseases in dogs. The GRLS is an observational study that will follow a cohort of 3000 purebred Golden Retrievers throughout their lives via annual online questionnaires from the dog owner and annual physical examinations and collection of biological samples by the primary care veterinarian. The field of comparative medicine investigating naturally occurring disorders in pets is specifically relevant to the many diseases that have a genetic basis for disease in both animals and humans, including cancer, blindness, metabolic and behavioural disorders and some neurodegenerative disorders. The opportunity for the GRLS to provide high-quality data for translational comparative medical initiatives in several disease categories is great. In particular, the opportunity to develop a lifetime dataset of lifestyle and activity, environmental exposure and diet history combined with simultaneous annual biological sample sets and detailed health outcomes will provide disease incidence data for this cohort of geographically dispersed dogs and associations with a wide variety of potential risk factors. The GRLS will provide a lifetime historical context, repeated biological sample sets and outcomes necessary to interrogate complex associations between genes and environmental influences and cancer. PMID- 26056374 TI - Intermittent Versus Daily Pulmonary Tuberculosis Treatment Regimens: A Meta Analysis. AB - BACKGROUND: Several systematic reviews suggest that intermittent pulmonary tuberculosis (TB) chemotherapy is effective, but intensity (daily versus intermittent) and duration of rifampicin use (intensive phase only versus both phases) have not been distinguished. In addition, the various outcomes (success, failure, relapse, and default) have only selectively been evaluated. METHODS: We conducted a meta-analysis of proportions using all four outcomes as multi category proportions to examine the effectiveness of WHO category 1 TB treatment regimens. Database searches of studies reporting treatment outcomes of HIV negative subjects were included and stratified by intensity of therapy and duration of rifampicin therapy. Using a bias-adjusted statistical model, we pooled proportions of the four treatment outcome categories using a method that handles multi-category proportions. RESULTS: A total of 27 studies comprising of 48 data sets with 10,624 participants were studied. Overall, treatment success was similar among patients treated with intermittent (I/I) (88%) (95% CI, 81-92) and daily (D/D) (90%) (95% CI, 84-95) regimens. Default was significantly less with I/I (0%) (95% CI, 0-2) compared to D/D regimens (5%) (95% CI, 1-9). Nevertheless, I/I relapse rates (7%) (95% CI, 3-11) were higher than D/D relapse rates (1%) (95% CI, 0-3). CONCLUSION: Treatment regimens that are offered completely intermittently versus completely daily are associated with a trade-off between treatment relapse and treatment default. There is a possibility that I/I regimens can be improved by increasing treatment duration, and this needs to be urgently addressed by future studies. PMID- 26056372 TI - Comparative oncology: what dogs and other species can teach us about humans with cancer. AB - Over 1.66 million humans (approx. 500/100,000 population rate) and over 4.2 million dogs (approx. 5300/100,000 population rate) are diagnosed with cancer annually in the USA. The interdisciplinary field of comparative oncology offers a unique and strong opportunity to learn more about universal cancer risk and development through epidemiology, genetic and genomic investigations. Working across species, researchers from human and veterinary medicine can combine scientific findings to understand more quickly the origins of cancer and translate these findings to novel therapies to benefit both human and animals. This review begins with the genetic origins of canines and their advantage in cancer research. We next focus on recent findings in comparative oncology related to inherited, or genetic, risk for tumour development. We then detail the somatic, or genomic, changes within tumours and the similarities between species. The shared cancers between humans and dogs that we discuss include sarcoma (osteosarcoma, soft tissue sarcoma, histiocytic sarcoma, hemangiosarcoma), haematological malignancies (lymphoma, leukaemia), bladder cancer, intracranial neoplasms (meningioma, glioma) and melanoma. Tumour risk in other animal species is also briefly discussed. As the field of genomics advances, we predict that comparative oncology will continue to benefit both humans and the animals that live among us. PMID- 26056375 TI - Unilateral Nodular Scleritis Secondary to Latent Syphilis. PMID- 26056373 TI - Species differences in tumour responses to cancer chemotherapy. AB - Despite advances in chemotherapy, radiotherapy and targeted drug development, cancer remains a disease of high morbidity and mortality. The treatment of human cancer patients with chemotherapy has become commonplace and accepted over the past 100 years. In recent years, and with a similar incidence of cancer to people, the use of cancer chemotherapy drugs in veterinary patients such as the dog has also become accepted clinical practice. The poor predictability of tumour responses to cancer chemotherapy drugs in rodent models means that the standard drug development pathway is costly, both in terms of money and time, leading to many drugs failing in Phase I and II clinical trials. This has led to the suggestion that naturally occurring cancers in pet dogs may offer an alternative model system to inform rational drug development in human oncology. In this review, we will explore the species variation in tumour responses to conventional chemotherapy and highlight our understanding of the differences in pharmacodynamics, pharmacokinetics and pharmacogenomics between humans and dogs. Finally, we explore the potential hurdles that need to be overcome to gain the greatest value from comparative oncology studies. PMID- 26056376 TI - Navigating the Needs of Rural Women with Breast Cancer: A Breast Care Program. AB - We describe the development and establishment of a breast care program (BCP) with service for rural breast cancer patients. Our program is a comprehensive program serving rural communities in Wisconsin. Our BCP is committed to breast health throughout the continuum from breast cancer risk assessment and prevention, advanced diagnostics, and screening tools to genetic testing and state-of-the-art surgical techniques. To provide the highest level of care, we coordinate a breast care team involving collaboration of multidisciplinary healthcare professionals. Experts from various departments, including radiologists, pathologists, breast surgeons, medical and radiation oncologists, genetic counselors, clinical trial specialists, and our breast care navigator, all work together to provide cutting edge cancer treatment and management. Our distinctive BCP allows patients to see multiple providers without having to make multiple appointments and promotes discussion of treatment recommendations and creation of a personalized treatment plan for each patient by a team of specialists. PMID- 26056377 TI - Dose measurements in pulsed radiation fields with commercially available measuring components. AB - Dose measurements in pulsed radiation fields with dosemeters using the counting technique are known to be inappropriate. Therefore, there is a demand for a portable device able to measure the dose in pulsed radiation fields. As a detector, ionisation chambers seem to be a good alternative. In particular, using a secondary standard ionisation chamber in combination with a reliable charge measuring system would be a good solution. The Physikalisch-Technische Bundesanstalt (PTB) uses secondary standard ionisation chambers in combination with PTB-made measuring electronics for dose measurements at its reference fields. However, for general use, this equipment is too complex. For measurements on-site, a mobile special electronic system [Hupe, O. and Ankerhold, U. Determination of ambient and personal dose equivalent for personnel and cargo security screening. Radiat. Prot. Dosim. 121: (4), 429-437 (2006)] has been used successfully. Still, for general use, there is a need for a much simpler but a just as good solution. A measuring instrument with very good energy dependence for H*(10) is the secondary standard ionisation chamber HS01. An easy-to-use and commercially available electrometer for measuring the generated charges is the UNIDOS by PTW Freiburg. Depending on the expected dose values, the ionisation chamber used can be selected. In addition, measurements have been performed by using commercially available area dosemeters, e.g. the Mini SmartION 2120S by Thermo Scientific, using an ionisation chamber and the Szintomat 6134 A/H by Automess, using a scintillation detector. PMID- 26056378 TI - Correspondence of DNA Methylation Between Blood and Brain Tissue and Its Application to Schizophrenia Research. AB - Given the difficulty of procuring human brain tissue, a key question in molecular psychiatry concerns the extent to which epigenetic signatures measured in more accessible tissues such as blood can serve as a surrogate marker for the brain. Here, we aimed (1) to investigate the blood-brain correspondence of DNA methylation using a within-subject design and (2) to identify changes in DNA methylation of brain-related biological pathways in schizophrenia.We obtained paired blood and temporal lobe biopsy samples simultaneously from 12 epilepsy patients during neurosurgical treatment. Using the Infinium 450K methylation array we calculated similarity of blood and brain DNA methylation for each individual separately. We applied our findings by performing gene set enrichment analyses (GSEA) of peripheral blood DNA methylation data (Infinium 27K) of 111 schizophrenia patients and 122 healthy controls and included only Cytosine phosphate-Guanine (CpG) sites that were significantly correlated across tissues.Only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue, a proportion that although small was significantly greater than predicted by chance. GSEA analysis of schizophrenia data revealed altered methylation profiles in pathways related to precursor metabolites and signaling peptides.Our findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status. However, a subset of peripheral data may proxy methylation status of brain tissue. Restricting the analysis to these markers can identify meaningful epigenetic differences in schizophrenia and potentially other brain disorders. PMID- 26056379 TI - Aerobactin, but not yersiniabactin, salmochelin, or enterobactin, enables the growth/survival of hypervirulent (hypermucoviscous) Klebsiella pneumoniae ex vivo and in vivo. AB - The siderophore aerobactin is the dominant siderophore produced by hypervirulent Klebsiella pneumoniae (hvKP) and was previously shown to be a major virulence factor in systemic infection. However, strains of hvKP commonly produce the additional siderophores yersiniabactin, salmochelin, and enterobactin. The roles of these siderophores in hvKP infection have not been optimally defined. To that end, site-specific gene disruptions were created in hvKP1 (wild type), resulting in the generation of hvKP1DeltaiucA (aerobactin deficient), hvKP1DeltairoB (salmochelin deficient), hvKP1DeltaentB (enterobactin and salmochelin deficient), hvKP1Deltairp2 (yersiniabactin deficient), and hvKP1DeltaentBDeltairp2 (enterobactin, salmochelin, and yersiniabactin deficient). The growth/survival of these constructs was compared to that of their wild-type parent hvKP1 ex vivo in human ascites fluid, human serum, and human urine and in vivo in mouse systemic infection and pulmonary challenge models. Interestingly, in contrast to aerobactin, the inability to produce enterobactin, salmochelin, or yersiniabactin individually or in combination did not decrease the ex vivo growth/survival in human ascites or serum or decrease virulence in the in vivo infection models. Surprisingly, none of the siderophores increased growth in human urine. In human ascites fluid supplemented with exogenous siderophores, siderophores increased the growth of hvKP1DeltaiucA, with the relative activity being enterobactin > aerobactin > yersiniabactin > salmochelin, suggesting that the contribution of aerobactin to virulence is dependent on both innate biologic activity and quantity produced. Taken together, these data confirm and extend a role for aerobactin as a critical virulence factor for hvKP. Since it appears that aerobactin production is a defining trait of hvKP strains, this factor is a potential antivirulence target. PMID- 26056380 TI - TREM-1 signaling promotes host defense during the early stage of infection with highly pathogenic Streptococcus suis. AB - Infection with highly pathogenic Streptococcus suis can cause septic shock, which is characterized by high levels of inflammatory cytokines and a high mortality rate. Our previous study indicated that TREM-1 (triggering receptor expressed on myeloid cells 1) was upregulated in swine spleen cells in response to S. suis infection. The role of TREM-1 signaling in enhancement of the proinflammatory response promoted us to examine its effect on the outcome of S. suis infection. In the present study, the recombinant extracellular domain of TREM-1 (rTREM-1) and an agonistic TREM-1 antibody were used to inhibit and activate TREM-1 signaling to evaluate its role in neutrophil activation, pathogen clearance, proinflammatory cytokine response, and the outcome of highly pathogenic S. suis infection in a mouse model. Blockage of TREM-1 signaling caused a more severe proinflammatory response to S. suis infection and increased the mortality rate, while its activation had the opposite effect. Blockage or activation of TREM-1 signaling lowered or raised the number of neutrophils in the blood, which correlated well with host clearance of S. suis. In conclusion, the TREM-1 mediated innate immune response played an essential role in the activation of neutrophils and S. suis clearance, which further reduced severe inflammation and finally benefited the outcome of the infection. PMID- 26056381 TI - DksA and (p)ppGpp have unique and overlapping contributions to Haemophilus ducreyi pathogenesis in humans. AB - The (p)ppGpp-mediated stringent response is important for bacterial survival in nutrient limiting conditions. For maximal effect, (p)ppGpp interacts with the cofactor DksA, which stabilizes (p)ppGpp's interaction with RNA polymerase. We previously demonstrated that (p)ppGpp was required for the virulence of Haemophilus ducreyi in humans. Here, we constructed an H. ducreyi dksA mutant and showed it was also partially attenuated for pustule formation in human volunteers. To understand the roles of (p)ppGpp and DksA in gene regulation in H. ducreyi, we defined genes potentially altered by (p)ppGpp and DksA deficiency using transcriptome sequencing (RNA-seq). In bacteria collected at stationary phase, lack of (p)ppGpp and DksA altered expression of 28% and 17% of H. ducreyi open reading frames, respectively, including genes involved in transcription, translation, and metabolism. There was significant overlap in genes differentially expressed in the (p)ppGpp mutant relative to the dksA mutant. Loss of (p)ppGpp or DksA resulted in the dysregulation of several known virulence determinants. Deletion of dksA downregulated lspB and rendered the organism less resistant to phagocytosis and increased its sensitivity to oxidative stress. Both mutants had reduced ability to attach to human foreskin fibroblasts; the defect correlated with reduced expression of the Flp adhesin proteins in the (p)ppGpp mutant but not in the dksA mutant, suggesting that DksA regulates the expression of an unknown cofactor(s) required for Flp-mediated adherence. We conclude that both (p)ppGpp and DksA serve as major regulators of H. ducreyi gene expression in stationary phase and have both overlapping and unique contributions to pathogenesis. PMID- 26056382 TI - Distinct Contributions of Neutrophils and CCR2+ Monocytes to Pulmonary Clearance of Different Klebsiella pneumoniae Strains. AB - Klebsiella pneumoniae is a common respiratory pathogen, with some strains having developed broad resistance to clinically available antibiotics. Humans can become infected with many different K. pneumoniae strains that vary in genetic background, antibiotic susceptibility, capsule composition, and mucoid phenotype. Genome comparisons have revealed differences between K. pneumoniae strains, but the impact of genomic variability on immune-mediated clearance of pneumonia remains unclear. Experimental studies of pneumonia in mice have used the rodent adapted 43816 strain of K. pneumoniae and demonstrated that neutrophils are essential for optimal host defense. It remains unclear, however, whether CCR2(+) monocytes contribute to K. pneumoniae clearance from the lung. We selectively depleted neutrophils, CCR2(+) monocytes, or both from immunocompetent mice and determined susceptibility to infection by the 43816 strain and 4 newly isolated clinical K. pneumoniae strains. The clinical K. pneumoniae strains, including one carbapenem-resistant ST258 strain, are less virulent than 43816. Optimal clearance of each of the 5 strains required either neutrophils or CCR2(+) monocytes. Selective neutrophil depletion markedly worsened infection with K. pneumoniae strain 43816 and three clinical isolates but did not increase susceptibility of mice to infection with the carbapenem-resistant K. pneumoniae ST258 strain. Depletion of CCR2(+) monocytes delayed recovery from infection with each of the 5 K. pneumoniae strains, revealing a contribution of these cells to bacterial clearance from the lung. Our findings demonstrate strain-dependent variation in the contributions of neutrophils and CCR2(+) monocytes to clearance of K. pneumoniae pulmonary infection. PMID- 26056383 TI - Flagellin Is Required for Host Cell Invasion and Normal Salmonella Pathogenicity Island 1 Expression by Salmonella enterica Serovar Paratyphi A. AB - Salmonella enterica serovar Paratyphi A is a human-specific serovar that, together with Salmonella enterica serovar Typhi and Salmonella enterica serovar Sendai, causes enteric fever. Unlike the nontyphoidal Salmonella enterica serovar Typhimurium, the genomes of S. Typhi and S. Paratyphi A are characterized by inactivation of multiple genes, including in the flagellum-chemotaxis pathway. Here, we explored the motility phenotype of S. Paratyphi A and the role of flagellin in key virulence-associated phenotypes. Motility studies established that the human-adapted typhoidal S. Typhi, S. Paratyphi A, and S. Sendai are all noticeably less motile than S. Typhimurium, and comparative transcriptome sequencing (RNA-Seq) showed that in S. Paratyphi A, the entire motility chemotaxis regulon is expressed at significantly lowers levels than in S. Typhimurium. Nevertheless, S. Paratyphi A, like S. Typhimurium, requires a functional flagellum for epithelial cell invasion and macrophage uptake, probably in a motility-independent mechanism. In contrast, flagella were found to be dispensable for host cell adhesion. Moreover, we demonstrate that in S. Paratyphi A, but not in S. Typhimurium, the lack of flagellin results in increased transcription of the flagellar and the Salmonella pathogenicity island 1 (SPI-1) regulons in a FliZ-dependent manner and in oversecretion of SPI-1 effectors via type three secretion system 1. Collectively, these results suggest a novel regulatory linkage between flagellin and SPI-1 in S. Paratyphi A that does not occur in S. Typhimurium and demonstrate curious distinctions in motility and the expression of the flagellum-chemotaxis regulon between these clinically relevant pathogens. PMID- 26056384 TI - A Genome-Wide Screen Reveals that the Vibrio cholerae Phosphoenolpyruvate Phosphotransferase System Modulates Virulence Gene Expression. AB - Diverse environmental stimuli and a complex network of regulatory factors are known to modulate expression of Vibrio cholerae's principal virulence factors. However, there is relatively little known about how metabolic factors impinge upon the pathogen's well-characterized cascade of transcription factors that induce expression of cholera toxin and the toxin-coregulated pilus (TCP). Here, we used a transposon insertion site (TIS) sequencing-based strategy to identify new factors required for expression of tcpA, which encodes the major subunit of TCP, the organism's chief intestinal colonization factor. Besides identifying most of the genes known to modulate tcpA expression, the screen yielded ptsI and ptsH, which encode the enzyme I (EI) and Hpr components of the V. cholerae phosphoenolpyruvate phosphotransferase system (PTS). In addition to reduced expression of TcpA, strains lacking EI, Hpr, or the associated EIIA(Glc) protein produced less cholera toxin (CT) and had a diminished capacity to colonize the infant mouse intestine. The PTS modulates virulence gene expression by regulating expression of tcpPH and aphAB, which themselves control expression of toxT, the central activator of virulence gene expression. One mechanism by which PTS promotes virulence gene expression appears to be by modulating the amounts of intracellular cyclic AMP (cAMP). Our findings reveal that the V. cholerae PTS is an additional modulator of the ToxT regulon and demonstrate the potency of loss of-function TIS sequencing screens for defining regulatory networks. PMID- 26056385 TI - Novel Paraoxonase 2-Dependent Mechanism Mediating the Biological Effects of the Pseudomonas aeruginosa Quorum-Sensing Molecule N-(3-Oxo-Dodecanoyl)-L-Homoserine Lactone. AB - Pseudomonas aeruginosa produces N-(3-oxo-dodecanoyl)-L-homoserine lactone (3OC12), a crucial signaling molecule that elicits diverse biological responses in host cells thought to subvert immune defenses. The mechanism mediating many of these responses remains unknown. The intracellular lactonase paraoxonase 2 (PON2) hydrolyzes and inactivates 3OC12 and is therefore considered a component of host cells that attenuates 3OC12-mediated responses. Here, we demonstrate in cell lines and in primary human bronchial epithelial cells that 3OC12 is rapidly hydrolyzed intracellularly by PON2 to 3OC12 acid, which becomes trapped and accumulates within the cells. Subcellularly, 3OC12 acid accumulated within the mitochondria, a compartment where PON2 is localized. Treatment with 3OC12 caused a rapid PON2-dependent cytosolic and mitochondrial pH decrease, calcium release, and phosphorylation of stress signaling kinases. The results indicate a novel, PON2-dependent intracellular acidification mechanism by which 3OC12 can mediate its biological effects. Thus, PON2 is a central regulator of host cell responses to 3OC12, acting to decrease the availability of 3OC12 for receptor-mediated effects and acting to promote effects, such as calcium release and stress signaling, via intracellular acidification. PMID- 26056386 TI - In contrast to Chlamydia trachomatis, Waddlia chondrophila grows in human cells without inhibiting apoptosis, fragmenting the Golgi apparatus, or diverting post Golgi sphingomyelin transport. AB - The Chlamydiales are an order of obligate intracellular bacteria sharing a developmental cycle inside a cytosolic vacuole, with very diverse natural hosts, from amoebae to mammals. The clinically most important species is Chlamydia trachomatis. Many uncertainties remain as to how Chlamydia organizes its intracellular development and replication. The discovery of new Chlamydiales species from other families permits the comparative analysis of cell-biological events and may indicate events that are common to all or peculiar to some species and more or less tightly linked to "chlamydial" development. We used this approach in the infection of human cells with Waddlia chondrophila, a species from the family Waddliaceae whose natural host is uncertain. Compared to C. trachomatis, W. chondrophila had slightly different growth characteristics, including faster cytotoxicity. The embedding in cytoskeletal structures was not as pronounced as for the C. trachomatis inclusion. C. trachomatis infection generates proteolytic activity by the protease Chlamydia protease-like activity factor (CPAF), which degrades host substrates upon extraction; these substrates were not cleaved in the case of W. chondrophila. Unlike Chlamydia, W. chondrophila did not protect against staurosporine-induced apoptosis. C. trachomatis infection causes Golgi apparatus fragmentation and redirects post Golgi sphingomyelin transport to the inclusion; both were absent from W. chondrophila-infected cells. When host cells were infected with both species, growth of both species was reduced. This study highlights differences between bacterial species that both depend on obligate intracellular replication inside an inclusion. Some features seem principally dispensable for intracellular development of Chlamydiales in vitro but may be linked to host adaptation of Chlamydia and the higher virulence of C. trachomatis. PMID- 26056387 TI - The Staphylococcus aureus protein-coding gene gdpS modulates sarS expression via mRNA-mRNA interaction. AB - Staphylococcus aureus is an important Gram-positive pathogen responsible for numerous diseases ranging from localized skin infections to life-threatening systemic infections. The virulence of S. aureus is essentially determined by a wide spectrum of factors, including cell wall-associated proteins and secreted toxins that are precisely controlled in response to environmental changes. GGDEF domain protein from Staphylococcus (GdpS) is the only conserved staphylococcal GGDEF domain protein that is involved not in c-di-GMP synthesis but in the virulence regulation of S. aureus NCTC8325. Our previous study showed that the inactivation of gdpS generates an extensive change of virulence factors together with, in particular, a major Spa (protein A) surface protein. As reported, sarS is a direct positive regulator of spa. The decreased transcript levels of sarS in the gdpS mutant compared with the parental NCTC8325 strain suggest that gdpS affects spa through interaction with sarS. In this study, site mutation and complementary experiments showed that the translation product of gdpS was not involved in the regulation of transcript levels of sarS. We found that gdpS functioned through direct RNA-RNA base pairing with the 5' untranslated region (5'UTR) of sarS mRNA and that a putative 18-nucleotide region played a significant role in the regulatory process. Furthermore, the mRNA half-life analysis of sarS in the gdpS mutant showed that gdpS positively regulates the mRNA levels of sarS by contributing to the stabilization of sarS mRNA, suggesting that gdpS mRNA may regulate spa expression in an RNA-dependent pathway. PMID- 26056388 TI - Persistent Staphylococcus aureus isolates from two independent cases of bacteremia display increased bacterial fitness and novel immune evasion phenotypes. AB - Staphylococcus aureus bacteremia cases are complicated by bacterial persistence and treatment failure despite the confirmed in vitro susceptibility of the infecting strain to administered antibiotics. A high incidence of methicillin resistant S. aureus (MRSA) bacteremia cases are classified as persistent and are associated with poorer patient outcomes. It is still unclear how S. aureus evades the host immune system and resists antibiotic treatment for the prolonged duration of a persistent infection. In this study, the genetic changes and associated phenotypic traits specific to S. aureus persistent bacteremia were identified by comparing temporally dispersed isolates from persistent infections (persistent isolates) originating from two independent persistent S. aureus bacteremia cases with the initial infection isolates and with three resolved S. aureus bacteremia isolates from the same genetic background. Several novel traits were associated specifically with both independent sets of persistent S. aureus isolates compared to both the initial isolates and the isolates from resolved infections (resolved isolates). These traits included (i) increased growth under nutrient-poor conditions; (ii) increased tolerance of iron toxicity; (iii) higher expression of cell surface proteins involved in immune evasion and stress responses; and (iv) attenuated virulence in a Galleria mellonella larva infection model that was not associated with small-colony variation or metabolic dormancy such as had been seen previously. Whole-genome sequence analysis identified different single nucleotide mutations within the mprF genes of all the isolates with the adaptive persistence traits from both independent cases. Overall, our data indicate a novel role for MprF function during development of S. aureus persistence by increasing bacterial fitness and immune evasion. PMID- 26056389 TI - Estimating the impact of the US President's Emergency Plan for AIDS Relief on HIV treatment and prevention programmes in Africa. AB - BACKGROUND: Since 2004, the US President's Emergency Plan for AIDS Relief (PEPFAR) has supported the tremendous scale-up of HIV prevention, care and treatment services, primarily in sub-Saharan Africa. We evaluate the impact of antiretroviral treatment (ART), prevention of mother-to-child transmission (PMTCT) and voluntary medical male circumcision (VMMC) programmes on survival, mortality, new infections and the number of orphans from 2004 to 2013 in 16 PEPFAR countries in Africa. METHODS: PEPFAR indicators tracking the number of persons receiving ART for their own health, ART regimens for PMTCT and biomedical prevention of HIV through VMMC were collected across 16 PEPFAR countries. To estimate the impact of PEPFAR programmes for ART, PMTCT and VMMC, we compared the current scenario of PEPFAR-supported interventions to a counterfactual scenario without PEPFAR, and assessed the number of life years gained (LYG), number of orphans averted and HIV infections averted. Mathematical modelling was conducted using the SPECTRUM modelling suite V.5.03. RESULTS: From 2004 to 2013, PEPFAR programmes provided support for a cumulative number of 24 565 127 adults and children on ART, 4 154 878 medical male circumcisions, and ART for PMTCT among 4 154 478 pregnant women in 16 PEPFAR countries. Based on findings from the model, these efforts have helped avert 2.9 million HIV infections in the same period. During 2004-2013, PEPFAR ART programmes alone helped avert almost 9 million orphans in 16 PEPFAR countries and resulted in 11.6 million LYG. CONCLUSIONS: Modelling results suggest that the rapid scale-up of PEPFAR-funded ART, PMTCT and VMMC programmes in Africa during 2004-2013 led to substantially fewer new HIV infections and orphaned children during that time and longer lives among people living with HIV. Our estimates do not account for the impact of the PEPFAR-funded non-biomedical interventions such as behavioural and structural interventions included in the comprehensive HIV prevention, care and treatment strategy used by PEPFAR countries. Therefore, the number of HIV infections and orphans averted and LYG may be underestimated by these models. PMID- 26056390 TI - Chlamydia infection in individuals reporting contact with sexual partners with chlamydia: a cross-sectional study of sexual health clinic attendees. AB - OBJECTIVES: We aimed to ascertain the proportion of positive, and predictive factors of chlamydia infection among females, heterosexual males and men who have sex with men (MSM) presenting to a sexual health service reporting contact with a chlamydia infected sexual partner. METHODS: A cross-sectional analysis of patients attending the Melbourne Sexual Health Centre from October 2010 to September 2013. Behavioural data obtained using computer assisted self-interview were analysed to determine factors predictive of chlamydia. RESULTS: Of the 491 female, 808 heterosexual male, and 268 MSM chlamydia contacts, the proportion diagnosed with chlamydia were 39.9% (95% CI 35.7% to 44.3%), 36.1% (95% CI 32.9% to 39.9%) and 23.5% (95% CI 18.8% to 29.0%), respectively. Female chlamydia contacts were more likely to have chlamydia if age <25 (adjusted OR (AOR) 1.86, 95% CI 1.12 to 3.10) or if they reported inconsistent condom use during vaginal sex with a regular male partner (AOR 2.5, 95% CI 1.12 to 6.14). Heterosexual male contacts were more likely to have chlamydia if age <25 (AOR 1.69, 95% CI 1.25 to 2.28) or if they had a regular female sexual partner (AOR 1.38, 95% CI 1.03 to 1.85). In MSM urethral chlamydia was diagnosed in 8.8%, rectal chlamydia in 20.2%, and 3.9% at both sites. MSM were more likely to have chlamydia if they had a regular male sexual partner (OR 2.12, 95% CI 1.18 to 3.81). CONCLUSIONS: This study of female, heterosexual male, and MSM presentations with self-reported chlamydia contact provides insight into the likelihood and predictive factors of infection. The data may inform policy and individual clinical decision making regarding presumptive treatment of chlamydia contacts. PMID- 26056391 TI - Rapid and sensitive analysis of reduced and oxidized coenzyme Q10 in human plasma by ultra performance liquid chromatography-tandem mass spectrometry and application to studies in healthy human subjects. AB - BACKGROUND: Coenzyme Q10 is an endogenous antioxidant as well as a popular dietary supplement. In blood circulation, coenzyme Q10 exists predominantly as its reduced ubiquinol-10 form, which readily oxidizes to ubiquinone-10 ex vivo. Plasma concentrations of coenzyme Q10 reflect net overall metabolic demand, and the ratio of ubiquinol-10:ubiquinone-10 has been established as an important biomarker for oxidative stress. However, the lability of ubiquinol-10 makes accurate determination of both forms of coenzyme Q10 difficult. Ex vivo oxidation of ubiquinol-10 to ubiquinone-10 during sample collection, processing and analysis may obfuscate the in vivo ratio. METHODS: We developed a rapid and sensitive method for the determination of ubiquinol-10 and ubiquinone-10 in human plasma, using coenzyme Q9 analogues as internal standards. Single-step protein precipitation in 1-propanol, a lipophilic and water-soluble alcohol, allowed for rapid extraction. RESULTS: Analysis by ultra performance liquid chromatography tandem mass spectrometry provided rapid run-time and high sensitivity, with lower limits of quantitation for ubiquinol-10 and ubiquinone-10 of 5 MUg/L and 10 MUg/L, respectively. CONCLUSIONS: This method is suitable for clinical studies with coenzyme Q10 supplementation in various disease states where this lipid antioxidant may be beneficial. We have applied this method to >300 plasma samples from coenzyme Q10 research studies in chronic haemodialysis patients and postsurgical patients. PMID- 26056392 TI - Troponin T elevation in acute aortic syndromes: Frequency and impact on diagnostic delay and misdiagnosis. AB - AIMS: Despite troponin assay being a part of the diagnostic work up in many conditions with acute chest pain, little is known about its frequency and clinical implications in acute aortic syndromes (AASs). In our study we assessed frequency, impact on diagnostic delay, inappropriate treatments, and prognosis of troponin elevation in AAS. METHODS AND RESULTS: Data were collected from a prospective metropolitan AAS registry (398 patients diagnosed between 2000 and 2013). Cardiac troponin test, using either standard or high sensitivity assay, was performed according to standard protocol used in chest pain units. Troponin T values were available in 248 patients (60%) of the registry population; the overall frequency of troponin positivity was 28% (ranging from 16% to 54%, using standard or high sensitivity assay respectively, p = 0.001). Troponin positivity was frequently associated with acute coronary syndromes (ACS)-like electrocardiogram findings, and with a twofold increased risk of long in-hospital diagnostic time (odds ratio (OR) 1.92, 95% confidence interval (CI) 1.05-3.52, p = 0.03). The combination of positive troponin and ACS-like electrocardiogram abnormalities resulted in a significantly increased risk of in-hospital delay/coronary angiography/antithrombotic therapy due to a misdiagnosis of ACS (OR 2.48, 95% CI 1.12-5.54, p = 0.02). However, troponin positivity was not associated with in-hospital mortality (OR 1.63, 95% CI 0.86-3.10, p = 0.131). CONCLUSIONS: Troponin positivity was a frequent finding in AAS patients, particularly when a high sensitivity assay was employed. Abnormal troponin values were strongly associated with ACS-like electrocardiogram findings and with in hospital diagnostic delay but apparently they did not influence in-hospital mortality. PMID- 26056393 TI - Screening for Peripheral Arterial Disease and Carotid Artery Disease in Patients With Abdominal Aortic Aneurysm. AB - Screening for concomitant atherosclerotic disease is important in cardiovascular risk reduction. This study assessed the prevalence of carotid artery disease (CAD) and peripheral arterial disease (PAD) in patients with known abdominal aortic aneurysms (AAAs). All patients with AAA attending the vascular laboratory between the January 1, 2007, and December 31, 2009, were eligible for a carotid ultrasound and measurement of ankle brachial indices. A total of 389 (305 males) patients were identified on the AAA surveillance program with a mean (+/-standard deviation) age of 76 (+/-8) years. The mean age of the males was 75.4 (+/-7.8) years, and the mean age of the females was 77 (+/-11) years. A total of 332 patients were assessed for CAD, and 101 (30.4%) of those were found to have significant disease. A total of 289 patients were assessed for PAD of which 131 (45.3%) were found to have PAD at rest, and 289 patients were assessed for both and 59 (20.4%) patients had significant CAD + PAD. Patients with AAAs are at high risk of other atherosclerotic disorders, and, therefore, they should receive intensive medical optimization. PMID- 26056394 TI - Dangerous views require scientific evidence. PMID- 26056395 TI - Narrow Band Imaging: A Tool for Endoscopic Examination of Patients With Laryngeal Papillomatosis. AB - OBJECTIVES: Narrow band imaging (NBI) is supposed to be a technique for a better visualization of vessel structures in superficial tissue as it selects the wavelengths of hemoglobin. It was hypothesized that, in the regular follow-up examination of patients with recurrent laryngeal papillomatosis, NBI enables a better detection of laryngeal papillomatosis in contrast to normal white light endoscopy. METHODS: Eleven patients, 10 with a known recurrent papillomatosis (8 with a relapse, 2 without) and 1 with a primary diagnosis of papillomatosis, were examined with normal white light and NBI endoscopy. Twenty-six video sequences (11 white, 11 NBI, 4 doubled for validity) were generated and randomly presented to 20 otolaryngologists who rated the videos in terms of lesions seen and number of lesions identified. Results were compared with the histopathologic findings of microlaryngoscopy. RESULTS: Detection of papillomatosis and the correct number of lesions identified were more accurate with NBI than with normal white light endoscopy. There was a significantly higher probability of detecting laryngeal papillomata with NBI. CONCLUSIONS: NBI endoscopy enables a more accurate detection of laryngeal papillomatosis than white light endoscopy. PMID- 26056397 TI - Which Comes First--Credentialing and Privileging in Pharmacy or Pharmacist Provider Status? PMID- 26056398 TI - Knowledge, Skills--and Accountability? PMID- 26056396 TI - Ionizing Radiation Perturbs Cell Cycle Progression of Neural Precursors in the Subventricular Zone Without Affecting Their Long-Term Self-Renewal. AB - Damage to normal human brain cells from exposure to ionizing radiation may occur during the course of radiotherapy or from accidental exposure. Delayed effects may complicate the immediate effects resulting in neurodegeneration and cognitive decline. We examined cellular and molecular changes associated with exposure of neural stem/progenitor cells (NSPs) to (137)Cs gamma-ray doses in the range of 0 to 8 Gy. Subventricular zone NSPs isolated from newborn mouse pups were analyzed for proliferation, self-renewal, and differentiation, shortly after irradiation. Strikingly, there was no apparent increase in the fraction of dying cells after irradiation, and the number of single cells that formed neurospheres showed no significant change from control. Upon differentiation, irradiated neural precursors did not differ in their ability to generate neurons, astrocytes, and oligodendrocytes. By contrast, progression of NSPs through the cell cycle decreased dramatically after exposure to 8 Gy (p < .001). Mice at postnatal day 10 were exposed to 8 Gy of gamma rays delivered to the whole body and NSPs of the subventricular zone were analyzed using a four-color flow cytometry panel combined with ethynyl deoxyuridine incorporation. Similar flow cytometric analyses were performed on NSPs cultured as neurospheres. These studies revealed that neither the percentage of neural stem cells nor their proliferation was affected. By contrast, gamma-irradiation decreased the proliferation of two classes of multipotent cells and increased the proliferation of a specific glial restricted precursor. Altogether, these results support the conclusion that primitive neural precursors are radioresistant, but their proliferation is slowed down as a consequence of gamma-ray exposure. PMID- 26056399 TI - A Faculty Toolkit for Formative Assessment in Pharmacy Education. AB - This paper aims to increase understanding and appreciation of formative assessment and its role in improving student outcomes and the instructional process, while educating faculty on formative techniques readily adaptable to various educational settings. Included are a definition of formative assessment and the distinction between formative and summative assessment. Various formative assessment strategies to evaluate student learning in classroom, laboratory, experiential, and interprofessional education settings are discussed. The role of reflective writing and portfolios, as well as the role of technology in formative assessment, are described. The paper also offers advice for formative assessment of faculty teaching. In conclusion, the authors emphasize the importance of creating a culture of assessment that embraces the concept of 360-degree assessment in both the development of a student's ability to demonstrate achievement of educational outcomes and a faculty member's ability to become an effective educator. PMID- 26056400 TI - A Survey of Pharmacy Education in Thailand. AB - OBJECTIVE: To explore the current status of pharmacy education in Thailand. METHODS: The International Pharmaceutical Federation of the World Health Organization's (FIP-WHO) Global Survey of Pharmacy Schools was used for this study. The survey instrument was distributed to the deans of the 19 faculties (colleges) of pharmacy in Thailand. RESULTS: More than half the colleges have been in existence less than 20 years, and the government owns 80% of them. There were 2 paths of admission to study pharmacy: direct admission and central admission system. The doctor of pharmacy (PharmD) programs can be divided into 4 types. Approximately 60% of all teaching staff holds a doctoral degree. Regarding the work balance among teaching staff, around 60% focus on teaching activities, 20% focus on research, and less than 20% focus on patient care services concurrent with real practice teaching. The proportion of student time dedicated to theory, practice, and research in PharmD programs is 51.5%, 46.7%, and 1.8%, respectively. Sites owned by the colleges or by others were used for student training. Colleges followed the Office of the National Education Standards' Internal Quality Assurance (IQA) and External Quality Assurance (EQA), and the Pharmacy Council's Quality Assessment (ONESQA). CONCLUSION: This study provides a picture of the current status of curriculum, teaching staff, and students in pharmacy education in Thailand. The curriculum was adapted from the US PharmD program with the aim of meeting the country's needs and includes industrial pharmacy and public health tracks as well as clinical tracks. However, this transition in pharmacy education in Thailand needs to be monitored and evaluated. PMID- 26056401 TI - Comparison of Introductory Pharmacy Practice Experiences Among US Pharmacy Programs. AB - OBJECTIVE: To identify the various IPPE designs utilized by US pharmacy programs. METHODS: A 20-question survey was developed and distributed to experiential affairs professionals at 129 pharmacy institutions nationwide addressing school demographics and IPPE design. Results were analyzed in aggregate. RESULTS: Ninety three schools responded (72%). Eighty-nine percent of those reported beginning IPPE experiences in the first professional year, although there was a great variation regarding whether the IPPE was held while didactic classes were in session or during school breaks. The number of required practice experiences varied. Institutions prohibited students from completing rotations in the same pharmacy chain (72%) or hospital (70%) where employed, and from completing 2 rotations at the same site (62%). Fifty-seven percent utilized faculty members as preceptors. 51% allowed a maximum of 2 students per preceptor per practice experience. CONCLUSION: While clear trends existed in IPPE curricula, institutions incorporated aspects that addressed unique needs. Further research can determine the benefits and drawbacks of different IPPE designs. PMID- 26056402 TI - Long-term Results of an Analytical Assessment of Student Compounded Preparations. AB - OBJECTIVE: To investigate the long-term (ie, 6-year) impact of a required remake vs an optional remake on student performance in a compounding laboratory course in which students' compounded preparations were analyzed. METHODS: The analysis data for several preparations made by students were compared for differences in the analyzed content of the active pharmaceutical ingredient (API) and the number of students who successfully compounded the preparation on the first attempt. RESULTS: There was a consistent statistical difference in the API amount or concentration in 4 of the preparations (diphenhydramine, ketoprofen, metoprolol, and progesterone) in each optional remake year compared to the required remake year. As the analysis requirement was continued, the outcome for each preparation approached and/or attained the expected API result. Two preparations required more than 1 year to demonstrate a statistical difference. CONCLUSION: The analytical assessment resulted in a consistent, long-term improvement in student performance during the 5-year period after the optional remake policy was instituted. Our assumption is that investment in such an assessment would result in a similar benefits at other colleges and schools of pharmacy. PMID- 26056403 TI - A Subgroup Analysis of the Impact of Self-testing Frequency on Examination Scores in a Pathophysiology Course. AB - OBJECTIVE: To determine if the frequency of self-testing of course material prior to actual examination improves examination scores, regardless of the actual scores on the self-testing. METHODS: Practice quizzes were randomly generated from a total of 1342 multiple-choice questions in pathophysiology and made available online for student self-testing. Intercorrelations, 2-way repeated measures ANOVA with post hoc tests, and 2-group comparisons following rank ordering, were conducted. RESULTS: During each of 4 testing blocks, more than 85% of students took advantage of the self-testing process for a total of 7042 attempts. A consistent significant correlation (p<=0.05) existed between the number of practice quiz attempts and the subsequent examination scores. No difference in the number of quiz attempts was demonstrated compared to the first testing block. Exam scores for the first and second testing blocks were both higher than those for third and fourth blocks. CONCLUSION: Although self-testing strategies increase retrieval and retention, they are uncommon in pharmacy education. The results suggested that the number of self-testing attempts alone improved subsequent examination scores, regardless of the score for self-tests. PMID- 26056404 TI - Outcomes of Individualized Formative Assessments in a Pharmacy Skills Laboratory. AB - OBJECTIVE: To determine the effectiveness of an individualized teaching method in a pharmacy skills laboratory. DESIGN: All third-year students enrolled in an Accreditation Council for Pharmacy Education (ACPE) accredited doctor of pharmacy program (n=150) received an individual formative assessment from clinical pharmacists on communication skills and clinical competency after the students counseled standardized mock glaucoma patients during a laboratory focused on alternative dosing formulations. Objective structured clinical examination (OSCE) scores for this station from the 2012 and 2013 classes were compared before and after the intervention. ASSESSMENT: Ophthalmic OSCE station scores were higher after the individual formative feedback intervention. Students in 2013 had a mean score of 83.2 +/- 8.3% compared to a mean of 74.3 +/- 12.9% in 2012 for this OSCE station. The percentage of students receiving an "A" on the OSCE station increased from 8.1% to 31.3% after the intervention. CONCLUSION: Individualized formative teaching methods benefited students in both their communication skills and clinical assessment. Future research should focus on wider implementation and overcoming obstacles, such as increased facilitator needs. PMID- 26056405 TI - An Educational Program for Underserved Middle School Students to Encourage Pursuit of Pharmacy and Other Health Science Careers. AB - OBJECTIVE: To develop and implement an active, hands-on program for underrepresented minority (URM) seventh grade students and to determine if participation in the program increased interest in health care careers and understanding of pharmacy and physician assistant (PA) professions. DESIGN: A hands-on educational program was developed in conjunction with local middle school administrators and staff for URM 7th grade students. The program was designed to be hands-on and focus on pharmacy and PA laboratory skills. A discussion component was included, allowing participants to interact personally with pharmacy and PA students and faculty members. ASSESSMENT: Students' responses to survey questions about interest in health care careers and knowledge about health professions were compared before and after 2 separate offerings of the program. After the program, significant increases were seen in participants' understanding of the pharmacy and PA professions. An increased percentage of participants reported interest in health care careers after the program than before the program. CONCLUSION: Introducing middle school-aged URM students to the pharmacy and PA professions through a hands-on educational program increased interest in, and knowledge of, these professions. PMID- 26056406 TI - A Computer Simulation of Community Pharmacy Practice for Educational Use. AB - OBJECTIVE: To provide a computer-based learning method for pharmacy practice that is as effective as paper-based scenarios, but more engaging and less labor intensive. DESIGN: We developed a flexible and customizable computer simulation of community pharmacy. Using it, the students would be able to work through scenarios which encapsulate the entirety of a patient presentation. We compared the traditional paper-based teaching method to our computer-based approach using equivalent scenarios. The paper-based group had 2 tutors while the computer group had none. Both groups were given a prescenario and postscenario clinical knowledge quiz and survey. ASSESSMENT: Students in the computer-based group had generally greater improvements in their clinical knowledge score, and third-year students using the computer-based method also showed more improvements in history taking and counseling competencies. Third-year students also found the simulation fun and engaging. CONCLUSION: Our simulation of community pharmacy provided an educational experience as effective as the paper-based alternative, despite the lack of a human tutor. PMID- 26056407 TI - Evaluating the Potential Impact of Pharmacist Counseling on Medication Adherence Using a Simulation Activity. AB - OBJECTIVE: To evaluate the impact of counseling in a simulated medication adherence activity. DESIGN: Students were randomized into 2 groups: patient medication monograph only (PMMO) and patient medication monograph with counseling (PMMC). Both groups received a fictitious medication and monograph. Additionally, the PMMC group received brief counseling. A multiple-choice, paper-based survey instrument was used to evaluate simulated food-drug interactions, adherence, and perceptions regarding the activity's value and impact on understanding adherence challenges. ASSESSMENT: Ninety-two students participated (PMMC, n=45; and PMMO, n=47). Overall, a significantly higher incidence of simulated food-drug interactions occurred in the PMMO group (30%) vs the PMMC group (22%) (p=0.02). Doses taken without simulated food-drug interactions were comparable: 46.2% (PMCC) vs 41.9% (PMMO) (p=0.19). The average number of missed doses were 3.2 (PMMC) vs 2.8 (PMMO) (p=0.55). Approximately 70% of the students found the activity to be valuable and 89% believed it helped them better understand adherence challenges. CONCLUSION: This activity demonstrated the challenges and important role of counseling in medication adherence. PMID- 26056408 TI - The Utility of Concept Maps to Facilitate Higher-Level Learning in a Large Classroom Setting. AB - OBJECTIVE: To describe the utility of concept mapping in a cardiovascular therapeutics course within a large classroom setting. DESIGN: Students enrolled in a cardiovascular care therapeutics course completed concept maps for each major chronic cardiovascular condition. A grading rubric was used to facilitate peer-assessment of the concept map. ASSESSMENT: Students were administered a survey at the end of the course assessing their perceptions on the usefulness of the concept maps during the course and also during APPEs to assess utility beyond the course. Question item analyses were conducted on cumulative final examinations comparing student performance on concept-mapped topics compared to nonconcept-mapped topics. CONCLUSION: Concept maps help to facilitate meaningful learning within the course and the majority of students utilized them beyond the course. PMID- 26056409 TI - A Novel Structured Format for Engaging Pharmacy Students in Bioethics Discussions. AB - OBJECTIVE: To describe an active, structured ethics/professionalism discussion format developed for an elective course titled Ethics and Professionalism in Pharmacy. DESIGN: The format uses the acronym ETHICS (Evaluate, Teach, Hear, Interview, Concede, Self-reflect). Before class, students evaluated (Evaluate) literature pertaining to ethics/professionalism topics. Class consisted of faculty-led ethics/professionalism lecture (Teach), student-driven, case discussion, and online self-reflection. Guided by Hear, Interview, and Concede, groups addressed cases from stakeholder perspectives (patient, pharmacist, etc.) considering ethical rules and principles. At the end of class, students answered self-reflection questions. Precourse and postcourse surveys evaluated the impact on students' perceptions of ethical and professional tenets. ASSESSMENT: The format allowed students to actively engage in ethics/professionalism discussions, transforming class into an interactive, structured, student-centered session with self-reflection. CONCLUSION: The format allowed application of concepts to controversial situations. Although the format was created for a pharmacy elective, it is adaptable to any teaching situation. PMID- 26056410 TI - The Sustained, Positive Impact of a Native American Cultures and Health Course on Students' Education and Practice-Related Choices. AB - OBJECTIVE: To encourage pharmacy students to elect education and practice opportunities in Native American communities, including careers with the Indian Health Service (IHS). METHODS: Students in 2 elective courses were educated on various aspects of contemporary Native American life in urban and reservation environments, including cultural traditions, social and health-related challenges, health access disparities, and cultural approaches to health and wellness. The teachers were Native American leaders and healers primarily from Plains tribes, as well as non-Native American practitioners affiliated with IHS hospitals and tribal health facilities. Students kept reflective journals, and a subset spent 5 days immersed in a rural Navajo community where they lived and worked alongside IHS practitioners and Community Health Representatives. RESULTS: Student engagement with IHS opportunities was tracked for 11 years. Of the 69 pharmacy students who completed the electives, 11 applied for a Junior Commissioned Officer Student Training and Externship Program (Jr. COSTEP) (8 accepted, 6 completed), 43 requested one or more IHS APPEs (43 accepted, 32 completed, 8 in progress), 17 applied for an IHS residency (1 pending, 8 accepted, 5 completed), and 5 became IHS Commissioned Corps officers. Five additional students accepted an IHS or tribal position, with 3 pursuing a USPHS commission. CONCLUSION: Since the first report on the impact of this elective experience was published, the course continues to meet its primary objective of promoting interest in IHS/tribal education experiences and pharmacy practice careers. PMID- 26056411 TI - Integrating Internships with Professional Study in Pharmacy Education in Finland. AB - Pharmacy internships are an important part of undergraduate pharmacy education worldwide. Internships in Finland are integrated into professional study during the second and third year, which has several pedagogic advantages, such as better understanding of the association between academic studies and pharmaceutical work life during the studies, and enhanced self-reflection through the feedback from preceptors and peers during the internships. The objective of this paper is to describe the Finnish integrated internship using the pharmacy curriculum at the University of Helsinki as an example. PMID- 26056421 TI - Oxygen Sensing Difluoroboron Dinaphthoylmethane Polylactide. AB - Dual emissive luminescence properties of solid-state difluoroboron beta diketonate-poly(lactic acid) (BF2bdk-PLA) materials have been utilized as biological oxygen sensors. Dyes with red-shifted absorption and emission are important for multiplexing and in vivo imaging, thus hydroxyl-functionalized dinaphthoylmethane initiators and dye-PLA conjugates BF2dnm(X)PLA (X = H, Br, I) with extended conjugation were synthesized. The luminescent materials show red shifted absorbance (~435 nm) and fluorescence tunability by molecular weight. Fluorescence colors range from yellow (~530 nm) in 10 - 12 kDa polymers to green (~490 nm) in 20 - 30 kDa polymers. Room-temperature phosphorescence (RTP) and thermally activated delayed fluorescence (TADF) are present under a nitrogen atmosphere. For the iodine-substituted derivative, BF2dnm(I)PLA, clearly distinguishable fluorescence (green) and phosphorescence (orange) peaks are present, making it ideal for ratiometric oxygen-sensing and imaging. Bromide and hydrogen analogues with weaker relative phosphorescence intensities and longer phosphorescence lifetimes can be used as highly sensitive, concentration independent, lifetime-based oxygen sensors or for gated emission detection. BF2dnm(I)PLA nanoparticles were taken up by T41 mouse mammary cells and successfully demonstrated differences in vitro ratiometric measurement of oxygen. PMID- 26056422 TI - Computing Systemic Risk Using Multiple Behavioral and Keystone Networks: The Emergence of a Crisis in Primate Societies and Banks. AB - What do the behavior of monkeys in captivity and the financial system have in common? The nodes in such social systems relate to each other through multiple and keystone networks, not just one network. Each network in the system has its own topology, and the interactions among the system's networks change over time. In such systems, the lead into a crisis appears to be characterized by a decoupling of the networks from the keystone network. This decoupling can also be seen in the crumbling of the keystone's power structure toward a more horizontal hierarchy. This paper develops nonparametric methods for describing the joint model of the latent architecture of interconnected networks in order to describe this process of decoupling, and hence provide an early warning system of an impending crisis. PMID- 26056423 TI - Reactions of a heme-superoxo complex toward a cuprous chelate and *NO(g): CcO and NOD chemistry. AB - Following up on the characterization of a new (heme)FeIII-superoxide species formed from the cryogenic oxygenation of a ferrous-heme (PPy)FeII (1) (PPy = a tetraarylporphyrinate with a covalently tethered pyridine group as a potential axial base), giving (PPy)FeIII-O2*- (2) (Li Y et al., Polyhedron 2013; 58: 60 64), we report here on (i) its use in forming a cytochrome c oxidase (CcO) model compound, or (ii) in a reaction with nitrogen monoxide (*NO; nitric oxide) to mimic nitric oxide dioxygenase (NOD) chemistry. Reaction of (2) with the cuprous chelate [CuI(AN)][B(C6F5)4] (AN = bis[3-(dimethylamino) propyl]amine) gives a meta-stable product [(PPy)FeIII-([Formula: see text])-CuII(AN)][B(C6F5)4] (3a), possessing a high-spin iron(III) and Cu(II) side-on bridged peroxo moiety with a MU-eta2:eta2-binding motif. This complex thermally decays to a corresponding MU oxo complex [(PPy)FeIII-(O2-)-CuII(AN)][B(C6F5)4] (3). Both (3) and (3a) have been characterized by UV-vis, 2H NMR and EPR spectroscopies. When (2) is exposed to *NO(g), a ferric heme nitrato compound forms; if 2,4-di-tert-butylphenol is added prior to *NO(g) exposure, phenol ortho-nitration occurs with the iron product being the ferric hydroxide complex (PPy) FeIII(OH) (5). The latter reactions mimic the action of NOD's. PMID- 26056424 TI - TRUFA: A User-Friendly Web Server for de novo RNA-seq Analysis Using Cluster Computing. AB - Application of next-generation sequencing (NGS) methods for transcriptome analysis (RNA-seq) has become increasingly accessible in recent years and are of great interest to many biological disciplines including, eg, evolutionary biology, ecology, biomedicine, and computational biology. Although virtually any research group can now obtain RNA-seq data, only a few have the bioinformatics knowledge and computation facilities required for transcriptome analysis. Here, we present TRUFA (TRanscriptome User-Friendly Analysis), an open informatics platform offering a web-based interface that generates the outputs commonly used in de novo RNA-seq analysis and comparative transcriptomics. TRUFA provides a comprehensive service that allows performing dynamically raw read cleaning, transcript assembly, annotation, and expression quantification. Due to the computationally intensive nature of such analyses, TRUFA is highly parallelized and benefits from accessing high-performance computing resources. The complete TRUFA pipeline was validated using four previously published transcriptomic data sets. TRUFA's results for the example datasets showed globally similar results when comparing with the original studies, and performed particularly better when analyzing the green tea dataset. The platform permits analyzing RNA-seq data in a fast, robust, and user-friendly manner. Accounts on TRUFA are provided freely upon request at https://trufa.ifca.es. PMID- 26056425 TI - Molecular Evolutionary Analysis of beta-Defensin Peptides in Vertebrates. AB - Vertebrate beta-defensins comprise an important family of antimicrobial peptides that protect organisms from a diverse spectrum of bacteria, viruses, fungi, and protozoan parasites. Previous studies have shown a marked variation in the number of beta-defensins among species, but the underlying reason is unclear. To address this question, we performed comprehensive computational searches to study the intact beta-defensin genes from 29 vertebrates. Phylogenetic analysis of the beta defensin genes in vertebrates identified frequent changes in the number of beta defensin genes and multiple species-specific gene gains and losses that have been occurring throughout the evolution of vertebrates. The number of intact beta defensin genes varied from 1 in the western clawed frog to 20 in cattle, with numerous expansions and contractions of the gene family throughout vertebrates, especially among tetrapods. The beta-defensin gene number in a species is relevant to the ever-changing microbial challenges from the environment that they inhabit. Selection pressure analysis shows there exist three amino acid sites under significant positive selection. Protein structural characteristics analysis suggests that structural diversity determines the diverse functions of beta defensins. Our study provides a new perspective on the relationships among vertebrate beta-defensin gene repertoires and different survival circumstances, which helps explain how beta-defensins have evolved. PMID- 26056426 TI - Thymosin beta 4 ophthalmic solution for dry eye: a randomized, placebo controlled, Phase II clinical trial conducted using the controlled adverse environment (CAETM) model. AB - BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of thymosin beta 4 ophthalmic solution (RGN-259; Tbeta4) in subjects with moderate to severe dry eye using the CAETM model. METHODS: This single-center, prospective, double-masked, placebo-controlled Phase II study randomized 72 qualifying subjects 1:1 to receive either 0.1% Tbeta4 or placebo treatment for a total of 28 days. The study consisted of six visits over a 32-day period, including a screening visit (day -1), controlled adverse environment challenge (CAE) visits (day 1, day 28), and follow-up visits (days 14, 29, and 30). The primary efficacy endpoints were ocular discomfort scores and inferior corneal staining measured at visit 5 on day 29. Secondary endpoints included central and superior corneal staining, conjunctival staining, conjunctival redness, tear-film break-up time, and daily symptom scores recorded over the course of the study. Safety measures included visual acuity, slit-lamp evaluation, conjunctival redness, tear film break-up time, intraocular pressure, dilated funduscopy, and corneal sensitivity. RESULTS: Neither of the primary endpoints, ie, ocular discomfort or inferior corneal staining, showed a significant difference between treatment and control groups at visit 5. Despite this, significant differences between treatment groups were observed for a number of secondary endpoints. The discomfort scores in the CAE on day 28 were reduced by 27% in 0.1% Tbeta4-treated subjects compared with the placebo group (P=0.0244). Subjects in the 0.1% Tbeta4 treatment group also showed statistically significant improvements in central and superior corneal staining compared with staining scores in the control group (P=0.0075 and P=0.0210). No adverse events were observed. CONCLUSION: This study confirms the efficacy of 0.1% Tbeta4 as a topical treatment for relief of signs and symptoms of dry eye. Significant improvements in both signs and symptoms of dry eye were observed, and the treatment exhibited a large safety window, with no adverse events reported by any subjects enrolled in the study. PMID- 26056427 TI - Central retinal vein occlusion resulting from anomalous retinal vascular anatomy in a 24-year-old man. AB - An otherwise healthy 24-year-old man presented with a painless decrease of vision in the left eye for 2 days. Best-corrected visual acuity was 20/20 in the right eye and 20/80 in the left eye. Anterior exam was unremarkable and funduscopic exam in the left eye revealed retinal hemorrhages in all four quadrants with venous dilation and tortuosity consistent with central retinal vein occlusion. Fluorescein angiography revealed delayed venous filling with neither leakage nor vasculitis. A comprehensive work-up that included infectious, inflammatory, and hypercoagulability studies was unremarkable, and magnetic resonance imaging of the orbits was unrevealing. After 2 months, best-corrected visual acuity returned to 20/20-2 in the left eye. Upon closer review of the vascular anatomy in the left eye, a bifurcation of the central retinal artery at the level of the optic disc was tightly intertwined with an undilated nasal retinal vein in a manner that appeared to compress the underlying central retinal vein, resulting in dilation and tortuosity of the remaining venous branches. The vessel wall damage, turbulent venous flow, and compressive mass effect resulting from the anomalous retinal vasculature relationship is the proposed mechanism of the central retinal vein occlusion. Careful attention to the retinal vascular anatomy is suggested to aid in assessing the risk of retinal vein occlusion in any age group. PMID- 26056428 TI - Epidemiology of uveitis in the mid-Atlantic United States. AB - PURPOSE: To demonstrate the demographic, anatomic, and diagnostic classification of patients with uveitis seen in a tertiary care center in central Virginia. METHODS: Retrospective chart review of patient demographics, disease characteristics, and disease severity-related outcomes (therapies, visual outcomes, and complications) from 1984 to 2014. RESULTS: There were 491 patients (644 eyes) with mean age of 46 years (+/-21.4 years) and mean duration of follow up of 4.8 years (+/-6.8 years). Of these, 278 patients were female (56.6%). Further, 60.5% were Caucasian, and 27.3% were African American. The anatomic types seen were anterior uveitis (67.3%), panuveitis (14.5%), posterior uveitis (12.6%), and intermediate uveitis (5.3%). The most common etiology was post traumatic (12.2%), followed by post-procedural (10.0%), herpetic (7.9%), human leukocyte antigen (HLA)-B27-associated (6.7%), and sarcoidosis (6.7%). Herpetic uveitis was more common among Caucasians than African Americans (sex-adjusted odds ratio [OR]: 7.69, 95% confidence interval [CI] [2.12, 50.00]), and sarcoidosis was more common among African Americans than Caucasians (sex-adjusted OR: 6.54, 95% CI [2.98, 15.29]). Herpetic anterior uveitis was more common among females than males (race-adjusted OR: 3.03, 95% CI [1.32, 7.71]). Multifocal choroiditis was more common among males than females (race-adjusted OR: 9.09, 95% CI [1.47, 100.00]). Mean logMAR visual acuity was 0.18 at initial and final visit. A total 388 (79%) and 133 (27.3%) patients received local and systemic steroids, respectively. A total 52 patients (10.6%) received an antimetabolite. A total 116 patients (23.7%) were managed with topical glaucoma medication. A total 43 (8.8%), 129 (26.4%), and 46 patients (9.4%) underwent glaucoma surgery, cataract surgery, and vitrectomy, respectively. CONCLUSION: Over the period of this study, Caucasian patients were more frequently seen than non-Caucasians, although African Americans constituted a considerable size of study population. The most common diagnoses were undifferentiated anterior uveitis, traumatic uveitis, post-procedural uveitis, herpetic disease, HLA-B27 associated uveitis, and sarcoidosis. Unlike previous reports, traumatic and post-procedural uveitis were frequently reported. Mean visual acuity remained stable from initial to final visit. PMID- 26056429 TI - Aqueous misdirection following pars plana vitrectomy and silicone oil injection. AB - PURPOSE: To report a retrospective series of seven phakic eyes of seven patients suffering from a malignant glaucoma-like syndrome following pars plana vitrectomy and silicone oil (SO) injection. MATERIALS AND METHODS: Seven eyes with retinal detachment treated with pars plana vitrectomy with or without scleral buckling with SO tamponade. This was followed by cataract extraction to manage the elevated intraocular pressure (IOP). RESULTS: This was a retrospective review of seven cases that received pars plana vitrectomy and SO with or without scleral buckling for different causes of retinal detachment (three were rhegmatogenous and four were tractional). After a period ranging from 1 week to 1 month, they presented with malignant glaucoma-like manifestations; high IOP, shallow axial anterior chamber, and remarkable decrease of visual acuity. Atropine eye drops and anti-glaucoma medical treatment (topical and systemic) had been tried but failed to improve the condition. Dramatic decrease of IOP and deepening of the axial anterior chamber was observed in all cases in the first postoperative day after phacoemulsification and posterior chamber foldable intraocular lens implantation with posterior capsulotomy. CONCLUSION: Aqueous misdirection syndrome may be observed following pars plana vitrectomy and SO tamponade. This must be differentiated from other causes of post vitrectomy glaucoma. Cataract extraction with posterior capsulotomy controls the condition. PMID- 26056430 TI - p53 Contributes to Differentiating Gene Expression Following Exposure to Acetaminophen and Its Less Hepatotoxic Regioisomer Both In Vitro and In Vivo. AB - The goal of the present study was to compare hepatic toxicogenomic signatures across in vitro and in vivo mouse models following exposure to acetaminophen (APAP) or its relatively nontoxic regioisomer 3'-hydroxyacetanilide (AMAP). Two different Affymetrix microarray platforms and one Agilent Oligonucleotide microarray were utilized. APAP and AMAP treatments resulted in significant and large changes in gene expression that were quite disparate, and likely related to their different toxicologic profiles. Ten transcripts, all of which have been implicated in p53 signaling, were identified as differentially regulated at all time-points following APAP and AMAP treatments across multiple microarray platforms. Protein-level quantification of p53 activity aligned with results from the transcriptomic analysis, thus supporting the implicated mechanism of APAP induced toxicity. Therefore, the results of this study provide good evidence that APAP-induced p53 phosphorylation and an altered p53-driven transcriptional response are fundamental steps in APAP-induced toxicity. PMID- 26056431 TI - Anti-Warburg effect of rosmarinic acid via miR-155 in gastric cancer cells. AB - BACKGROUND: The Warburg effect refers to glycolytic production of adenosine triphosphate under aerobic conditions, and is a universal property of most cancer cells. Chronic inflammation is a key factor promoting the Warburg effect. This study aimed to determine whether rosmarinic acid (RA) has an anti-Warburg effect in gastric carcinoma in vitro and in vivo. The mechanism for the anti-Warburg effect was also investigated. METHODS: An MTT assay was used to examine MKN45 cell growth in vitro. An enzyme-linked immunosorbent assay was used to detect proinflammatory cytokines. Real-time polymerase chain reaction was used to evaluate levels of microRNA expression in cells. Protein expression was determined by Western blotting assay. Mouse xenograft models were established using MKN45 cells to assess the anti-Warburg effect in gastric carcinoma in vivo. RESULTS: RA suppressed glucose uptake and lactate production. It also inhibited expression of transcription factor hypoxia-inducible factor-1alpha, which affects the glycolytic pathway. Inflammation promoted the Warburg effect in cancer cells. As expected, RA inhibited proinflammatory cytokines and microRNAs related to inflammation, suggesting that RA may suppress the Warburg effect via an inflammatory pathway, such as that involving interleukin (IL)-6/signal transducer and activator of transcription-3 (STAT3). miR-155 was found to be an important mediator in the relationship between inflammation and tumorigenesis. We further showed that miR-155 was the target gene regulating the Warburg effect via inactivation of the IL-6/STAT3 pathway. Moreover, we found that RA suppressed the Warburg effect in vivo. CONCLUSION: RA might potentially be a therapeutic agent for suppressing the Warburg effect in gastric carcinoma. PMID- 26056432 TI - Comments on a systematic review and meta-analysis of steroids for epidural injections in spinal stenosis. PMID- 26056433 TI - Effects of strontium ranelate on bone formation in the mid-palatal suture after rapid maxillary expansion. AB - BACKGROUND: The aim of this experimental study was to investigate the effects of strontium ranelate on bone regeneration in the mid-palatal suture in response to rapid maxillary expansion (RME). METHODS: Thirty-six male 6-week-old Wistar rats were randomly divided into three groups, ie, an expansion only (EO) group, an expansion plus strontium ranelate (SE) group, and a control group. An orthodontic appliance was set between the right and left upper molars of rats with an initial expansive force of 0.98 N. Rats in the SE group were administered strontium ranelate (600 mg/kg body weight) and then euthanized in batches on days 4, 7, and 10. Morphological changes in the mid-palatal suture were investigated using micro computed tomography and hematoxylin and eosin staining after RME. Bone morphogenetic protein-2 expression in the suture was also examined to evaluate bone formation in the mid-palatal suture. Image-Pro Plus software was then used to determine the mean optical density of the immunohistochemical images. Analysis of variance was used for statistical evaluation at the P<0.05 level. RESULTS: With expansive force, the mid-palatal suture was expanded, but there was no statistically significant difference (P>0.05) between the SE and EO groups. The bone volume of the suture decreased after RME, but was higher in the SE group than in the EO group on days 7 and 10. Further, expression of bone morphogenetic protein-2 in the SE group was higher than in the other two groups (P<0.05). CONCLUSION: Strontium ranelate may hasten new bone formation in the expanded mid palatal suture, which may be therapeutically beneficial in prevention of relapse and shortening the retention period after RME. PMID- 26056434 TI - Antitumor effects of traditional Chinese medicine targeting the cellular apoptotic pathway. AB - Defects in apoptosis are common phenomena in many types of cancer and are also a critical step in tumorigenesis. Targeting the apoptotic pathway has been considered an intriguing strategy for cancer therapy. Traditional Chinese medicine (TCM) has been used in the People's Republic of China for thousands of years, and many of the medicines have been confirmed to be effective in the treatment of a number of tumors. With increasing cancer rates worldwide, the antitumor effects of TCMs have attracted more and more attention globally. Many of the TCMs have been shown to have antitumor activity through multiple targets, and apoptosis pathway-related targets have been extensively studied and defined to be promising. This review focuses on several antitumor TCMs, especially those with clinical efficacy, based on their effects on the apoptotic signaling pathway. The problems with and prospects of development of TCMs as anticancer agents are also presented. PMID- 26056435 TI - An update on the use of natalizumab in the treatment of multiple sclerosis: appropriate patient selection and special considerations. AB - In the context of an increasing repertoire of multiple sclerosis (MS) therapeutics, choosing the appropriate treatment for an individual patient is becoming increasingly challenging. Natalizumab, a humanized monoclonal antibody directed against alpha4beta1 integrin, has proven short-term and long-term efficacies in terms of relapse rate reduction, prevention of disability progression, and reduction of magnetic resonance imaging-detectable activity. It is well tolerated and has further been shown to improve patients' quality of life. Its use is limited by the risk of progressive multifocal leukoencephalopathy (PML), which occurs at an overall incidence of 3.78 cases per 1,000 patients. Three major risk factors for the occurrence of natalizumab associated PML have been identified: John Cunningham virus (JCV) seropositivity, prior use of immunosuppressants, and treatment duration >=2 years. Therefore, in patients considered for natalizumab therapy, as well as in patients receiving natalizumab, effective control of MS activity has to be balanced against the risk of an opportunistic central nervous system infection associated with a high risk of significant morbidity or death. Discontinuation of natalizumab is an issue in daily clinical practice, since it is an option to reduce the PML risk. However, after cessation of natalizumab therapy, currently, there is no approved strategy for avoiding postnatalizumab disease reactivation available. In this paper, short term and long-term safety and efficacy data are reviewed. Issues in daily clinical practice, such as selection of patients, monitoring of patients, and natalizumab discontinuation, are discussed. PMID- 26056436 TI - Patient experience and practice trends in multiple sclerosis - clinical utility of fingolimod. AB - Targeting sphingosine-1-phosphate pathway with orally available immune-modulatory fingolimod (GilenyaTM) therapy ameliorates relapsing-remitting multiple sclerosis (RRMS) by decreasing relapse rate as shown in FREEDOMS and TRANSFORMS. Fingolimod has also been shown to be superior to interferon-beta therapy as evidenced by TRANSFORMS. Albeit multiple benefits in treatment of multiple sclerosis including high efficacy and ease of administration, potential untoward effects such as cardiotoxicity, risk of infection, and cancer exist, thus mandating careful screening and frequent monitoring of patients undergoing treatment with fingolimod. This review outlines mechanism of action, observations, side effects, and practice guidelines on use of fingolimod in treatment of RRMS. PMID- 26056437 TI - Central retinal vein occlusion and pseudoexfoliation syndrome. AB - PURPOSE: The purpose of this study was to investigate the existence of pseudoexfoliation syndrome (PXF) as a risk factor for the development of central retinal vein occlusion (CRVO). METHODS: This was a retrospective, comparative study of the prevalence of pseudoexfoliation in three groups of patients: 48 patients with CRVO, 164 patients with branch retinal vein occlusion (BRVO), and 70 control patients (70 eyes). All patients were phakic and had no previous diagnosis of glaucoma. Patients were matched in terms of age and systemic hypertension. All patients had normal intraocular pressure (IOP) at presentation (defined as less than or equal to 21 mmHg). RESULTS: In the CRVO group, 14 out of 48 patients were diagnosed as having PXF (29.17%). In the BRVO group, 14 out of 164 patients had PXF (8.5%), and in the control group, six out of 70 patients had PXF (8.6%). Differences of percentage between groups were statistically significant (P<0.001, chi(2) test). When comparing patient subgroup with ischemic CRVO with subgroup with non-ischemic CRVO, we found that in the ischemic CRVO group, 13 out of 27 patients were diagnosed as having PXF (48.15%), and in the non-ischemic CRVO group, one out of 21 patients was diagnosed as having PXF (4.7%; P<0.001, chi(2) test). The relative odds of having CRVO in patients with PXF versus patients without PXF were 4.406 (confidence interval [CI], 2.03-9.54). CONCLUSION: PXF and CRVO, especially ischemic, are strongly associated in our study. Our results indicate that PXF might be an independent factor for CRVO, as it is related with CRVO independently from glaucoma. PMID- 26056438 TI - Effectiveness of a low-threshold physical activity intervention in residential aged care--results of a randomized controlled trial. AB - PURPOSE: Research on effectiveness of low-threshold mobility interventions that are viable for users of residential aged care is scarce. Low-threshold is defined as keeping demands on organizations (staff skills, costs) and participants (health status, discipline) rather low. The study explored the effectiveness of a multi-faceted, low-threshold physical activity program in three residential aged care facilities in Austria. Main goals were enhancement of mobility by conducting a multi-faceted training program to foster occupational performance and thus improve different aspects of health-related quality of life (QoL). PARTICIPANTS AND METHODS: The program consisted of a weekly session of 60 minutes over a period of 20 weeks. A standardized assessment of mobility status and health related QoL was applied before and after the intervention. A total of 222 of 276 participants completed the randomized controlled trial study (intervention group n=104, control group n=118; average age 84 years, 88% female). RESULTS: Subjective health status (EuroQoL-5 dimensions: P=0.001, d=0.36) improved significantly in the intervention group, and there were also positive trends in occupational performance (Canadian Occupational Performance Measure). No clear effects were found concerning the functional and cognitive measures applied. CONCLUSION: Thus, the low-threshold approach turned out to be effective primarily on subjective health-related QoL. This outcome could be a useful asset for organizations offering low-threshold physical activity interventions. PMID- 26056439 TI - Seasonality, ambient temperatures and hospitalizations for acute exacerbation of COPD: a population-based study in a metropolitan area. AB - BACKGROUND: Excluding the tropics, exacerbations of chronic obstructive pulmonary disease (COPD) are more frequent in winter. However, studies that directly relate hospitalizations for exacerbation of COPD to ambient temperature are lacking. The aim of this study was to assess the influence of temperature on the number of hospitalizations for COPD. METHODS: This was a population-based study in a metropolitan area. All hospital discharges for acute exacerbation of COPD during 2009 in Barcelona and its metropolitan area were analyzed. The relationship between the number of hospitalizations for COPD and the mean, minimum, and maximum temperatures alongside comorbidity, humidity, influenza rate, and environmental pollution were studied. RESULTS: A total of 9,804 hospitalization discharges coded with COPD exacerbation as a primary diagnosis were included; 75.4% of cases were male with a mean age of 74.9+/-10.5 years and an average length of stay of 6.5+/-6.1 days. The highest number of admissions (3,644 [37.2%]) occurred during winter, followed by autumn with 2,367 (24.1%), spring with 2,347 (23.9%), and summer with 1,446 (14.7%; P<0.001). The maximum, minimum, and mean temperatures were associated similarly with the number of hospitalizations. On average, we found that for each degree Celsius decrease in mean weekly temperature, hospital admissions increased by 5.04% (r(2)=0.591; P<0.001). After adjustment for humidity, comorbidity, air pollution, and influenza-like illness, only mean temperatures retained statistical significance, with a mean increase of 4.7% in weekly admissions for each degree Celsius of temperature (r(2)=0.599, P<0.001). CONCLUSION: Mean temperatures are closely and independently related to the number of hospitalizations for COPD. PMID- 26056440 TI - Reduction-responsive cross-linked stearyl peptide for effective delivery of plasmid DNA. AB - Low efficiency and significant toxicity are the main obstacles to successful gene delivery. We have developed a cationic reduction-responsive vector based on a disulfide cross-linked stearylated polyarginine peptide modified with histidine (C-SHR) for DNA delivery. The structure of the C-SHR was characterized, and the in vitro and in vivo transfection efficiency and cytotoxicity of C-SHR/plasmid DNA complexes were examined. Compared with non-cross-linked stearylated polyarginine peptide (SHR), C-SHR increased the intracellular uptake and dissociation behavior of the complexes. In addition, the gene transfection efficiency of C-SHR/plasmid DNA complexes in HEK293 and HeLa cells was improved and was comparable with that of bPEI-25K/plasmid DNA complexes, and the cytotoxicity of C-SHR was significantly less than that of bPEI-25K. Importantly, the in vivo gene transfection efficiency of C-SHR/plasmid DNA complexes was five fold higher than that of SHR/plasmid DNA complexes, suggesting that C-SHR is an efficient non-viral vector for DNA delivery. PMID- 26056441 TI - Novel stable cytokine delivery system in physiological pH solution: chitosan oligosaccharide/heparin nanoparticles. AB - BACKGROUND: Cell therapy is a promising strategy for tissue regeneration. Key to this strategy is mobilization and recruitment of exogenous or autologous stem/progenitor cells by cytokines. However, there is no effective cytokine delivery system available for clinic application, in particular for myocardial regeneration. The aim of this study was to develop a novel cytokine delivery system that is stable in solution at physiological pH. METHODS: Four groups of self-assembled chitosan oligosaccharide/heparin (CSO/H) nanoparticles were prepared with various volume ratios of chitosan oligosaccharide to heparin (5:2, 5:4, 4:15, 1:5) and characterized by laser diffraction, particle size analysis, and transmission electron microscopy. The encapsulation efficiency and loading content of two cytokines, ie, stromal cell-derived factor (SDF)-1alpha and vascular endothelial growth factor (VEGF) were quantified using an enzyme-linked immunosorbent assay. The biological activity of the loaded SDF-1alpha and VEGF was evaluated using the transwell migration assay and MTT assay. The dispersion profiles for the cytokine-loaded nanoparticles were quantified using fluorescence molecular tomography. RESULTS: CSO/H nanoparticles were prepared successfully in solution with physiological pH. The particle sizes in the four treatment groups were in the range of 96.2-210.5 nm and the zeta potential ranged from -29.4 mV to 24.2 mV. The loading efficiency in the CSO/H nanoparticle groups with the first three ratios was more than 90%. SDF-1alpha loaded into CSO/H nanoparticles retained its migration activity and VEGF loaded into CSO/H nanoparticles continued to show proliferation activity. The in vivo dispersion test showed that the CSO/H nanoparticles enabled to VEGF to accumulate locally for a longer period of time. CONCLUSION: CSO/H nanoparticles have a high cytokine loading capacity and allow cytokines to maintain their bioactivity for longer, are stable in an environment with physiological pH, and may be a promising cytokine delivery system for tissue regeneration. PMID- 26056442 TI - Effects of PVA coated nanoparticles on human immune cells. AB - Nanotechnology provides new opportunities in human medicine, mainly for diagnostic and therapeutic purposes. The autoimmune disease rheumatoid arthritis (RA) is often diagnosed after irreversible joint structural damage has occurred. There is an urgent need for a very early diagnosis of RA, which can be achieved by more sensitive imaging methods. Superparamagnetic iron oxide nanoparticles (SPION) are already used in medicine and therefore represent a promising tool for early diagnosis of RA. The focus of our work was to investigate any potentially negative effects resulting from the interactions of newly developed amino functionalized amino-polyvinyl alcohol coated (a-PVA) SPION (a-PVA-SPION), that are used for imaging, with human immune cells. We analyzed the influence of a-PVA SPION with regard to cell survival and cell activation in human whole blood in general, and in human monocytes and macrophages representative of professional phagocytes, using flow cytometry, multiplex suspension array, and transmission electron microscopy. We found no effect of a-PVA-SPION on the viability of human immune cells, but cytokine secretion was affected. We further demonstrated that the percentage of viable macrophages increased on exposure to a-PVA-SPION. This effect was even stronger when a-PVA-SPION were added very early in the differentiation process. Additionally, transmission electron microscopy analysis revealed that both monocytes and macrophages are able to endocytose a-PVA-SPION. Our findings demonstrate an interaction between human immune cells and a-PVA SPION which needs to be taken into account when considering the use of a-PVA SPION in human medicine. PMID- 26056443 TI - Amino-functionalized poly(L-lactide) lamellar single crystals as a valuable substrate for delivery of HPV16-E7 tumor antigen in vaccine development. AB - BACKGROUND: Poly(L-lactide) (PLLA) is a biodegradable polymer currently used in many biomedical applications, including the production of resorbable surgical devices, porous scaffolds for tissue engineering, nanoparticles and microparticles for the controlled release of drugs or antigens. The surfaces of lamellar PLLA single crystals (PLLAsc) were provided with amino groups by reaction with a multifunctional amine and used to adsorb an Escherichia coli produced human papillomavirus (HPV)16-E7 protein to evaluate its possible use in antigen delivery for vaccine development. METHODS: PLLA single crystals were made to react with tetraethylenepentamine to obtain amino-functionalized PLLA single crystals (APLLAsc). Pristine and amino-functionalized PLLAsc showed a two dimensional microsized and one-dimensional nanosized lamellar morphology, with a lateral dimension of about 15-20 MUm, a thickness of about 12 nm, and a surface specific area of about 130 m(2)/g. Both particles were characterized and loaded with HPV16-E7 before being administered to C57BL/6 mice for immunogenicity studies. The E7-specific humoral-mediated and cell-mediated immune response as well as tumor protective immunity were analyzed in mice challenged with TC-1 cancer cells. RESULTS: Pristine and amino-functionalized PLLAsc adsorbed similar amounts of E7 protein, but in protein-release experiments E7-PLLAsc released a higher amount of protein than E7-APLLAsc. When the complexes were dried for observation by scanning electron microscopy, both samples showed a compact layer, but E7-APLLAsc showed greater roughness than E7-PLLAsc. Immunization experiments in mice showed that E7-APLLAsc induced a stronger E7-specific immune response when compared with E7-PLLAsc. Immunoglobulin G isotyping and interferon gamma analysis suggested a mixed Th1/Th2 immune response in both E7-PLLAsc-immunized and E7-APLLAsc-immunized mice. However, only the mice receiving E7-APLLAsc were fully protected from TC-1 tumor growth after three doses of vaccine. CONCLUSION: Our results show that APLLA single crystals improve the immunogenicity of HPV16 E7 and indicate that E7-APLLAsc could be used for development of an HPV16 therapeutic vaccine against HPV16-related tumors. PMID- 26056444 TI - Doxorubicin-loaded aromatic imine-contained amphiphilic branched star polymer micelles: synthesis, self-assembly, and drug delivery. AB - Redox-and pH-sensitive branched star polymers (BSPs), BP(DMAEMA-co-MAEBA-co DTDMA)(PMAIGP)(n)s, have been successively prepared by two steps of reversible addition-fragmentation chain transfer (RAFT) polymerization. The first step is RAFT polymerization of 2-(N,N-dimethylaminoethyl)methacrylate (DMAEMA) and p (methacryloxyethoxy) benzaldehyde (MAEBA) in the presence of divinyl monomer, 2,2'-dithiodiethoxyl dimethacrylate (DTDMA). The resultant branched polymers were used as a macro-RAFT agent in the subsequent RAFT polymerization. After hydrolysis of the BSPs to form BP(DMAEMA-co-MAEBA-co-DTDMA)(PMAGP)(n)s (BSP-H), the anticancer drug doxorubicin (DOX) was covalently linked to branched polymer chains by reaction of primary amine of DOX and aldehyde groups in the polymer chains. Their compositions, structures, molecular weights, and molecular weight distributions were respectively characterized by nuclear magnetic resonance spectra and gel permeation chromatography measurements. The DOX-loaded micelles were fabricated by self-assembly of DOX-containing BSPs in water, which were characterized by transmission electron microscopy and dynamic light scattering. Aromatic imine linkage is stable in neutral water, but is acid-labile; controlled release of DOX from the BSP-H-DOX micelles was realized at pH values of 5 and 6, and at higher acidic solution, fast release of DOX was observed. In vitro cytotoxicity experiment results revealed low cytotoxicity of the BSPs and release of DOX from micelles in HepG2 and HeLa cells. Confocal laser fluorescence microscopy observations showed that DOX-loaded micelles have specific interaction with HepG2 cells. Thus, this type of BSP micelle is an efficient drug delivery system. PMID- 26056445 TI - External beam radiotherapy synergizes 188Re-liposome against human esophageal cancer xenograft and modulates 188Re-liposome pharmacokinetics. AB - External beam radiotherapy (EBRT) treats gross tumors and local microscopic diseases. Radionuclide therapy by radioisotopes can eradicate tumors systemically. Rhenium 188 ((188)Re)-liposome, a nanoparticle undergoing clinical trials, emits gamma rays for imaging validation and beta rays for therapy, with biodistribution profiles preferential to tumors. We designed a combinatory treatment and examined its effects on human esophageal cancer xenografts, a malignancy with potential treatment resistance and poor prognosis. Human esophageal cancer cell lines BE-3 (adenocarcinoma) and CE81T/VGH (squamous cell carcinoma) were implanted and compared. The radiochemical purity of (188)Re liposome exceeded 95%. Molecular imaging by NanoSPECT/CT showed that BE-3, but not CE81T/VGH, xenografts could uptake the (188)Re-liposome. The combination of EBRT and (188)Re-liposome inhibited tumor regrowth greater than each treatment alone, as the tumor growth inhibition rate was 30% with EBRT, 25% with (188)Re liposome, and 53% with the combination treatment at 21 days postinjection. Combinatory treatment had no additive adverse effects and significant biological toxicities on white blood cell counts, body weight, or liver and renal functions. EBRT significantly enhanced the excretion of (188)Re-liposome into feces and urine. In conclusion, the combination of EBRT with (188)Re-liposome might be a potential treatment modality for esophageal cancer. PMID- 26056446 TI - Dual-color immunofluorescent labeling with quantum dots of the diabetes associated proteins aldose reductase and Toll-like receptor 4 in the kidneys of diabetic rats. AB - Diabetes is one of the major chronic diseases diagnosed worldwide with a common complication of diabetic nephropathy (DN). There are multiple possible mechanisms associated with DN. Aldose reductase (AR) and Toll-like receptor 4 (TLR4) may be involved in the occurrence and development of DN. Here, we describe the distribution of AR and TLR4 in cells and renal tissues of diabetic rats through a quantum dot (QD)-based immunofluorescence technique and conventional immunohistochemistry. As a new type of nanosized fluorophore, QDs have been recognized in imaging applications and have broad prospects in biomedical research. The results of the reported study demonstrate that both the AR and the TLR4 proteins were upregulated in the renal tissues of diabetic rats. Further, to explore the relationship between AR and TLR4 in the pathogenesis of DN, a dual color immunofluorescent labeling technique based on QDs was applied, where the expressions of AR and TLR4 in the renal tissues of diabetic rats were simultaneously observed - for the first time, as far as we are aware. The optimized QD-based immunofluorescence technique has not only shown a satisfying sensitivity and specificity for the detection of biomarkers in cells and tissues, but also is a valuable supplement of immunohistochemistry. The QD-based multiplexed imaging technology provides a new insight into the mechanistic study of the correlation among biological factors as well as having potential applications in the diagnosis and treatment of diseases. PMID- 26056447 TI - Cetuximab-conjugated iron oxide nanoparticles for cancer imaging and therapy. AB - We have developed a theranostic nanoparticle, ie, cet-PEG-dexSPIONs, by conjugation of the anti-epidermal growth factor receptor (EGFR) monoclonal antibody, cetuximab, to dextran-coated superparamagnetic iron oxide nanoparticles (SPIONs) via periodate oxidation. Approximately 31 antibody molecules were conjugated to each nanoparticle. Cet-PEG-dexSPIONs specifically bind to EGFR expressing tumor cells and enhance image contrast on magnetic resonance imaging. Cet-PEG-dexSPION-treated A431 cells showed significant inhibition of epidermal growth factor-induced EGFR phosphorylation and enhancement of EGFR internalization and degradation. In addition, a significant increase in apoptosis was detected in EGFR-overexpressing cell lines, A431 and 32D/EGFR, after 24 hours of incubation at 37 degrees C with cet-PEG-dexSPIONs compared with cetuximab alone. The antibody-dependent cell-mediated cytotoxicity of cetuximab was observed in cet-PEG-dexSPIONs. The results demonstrated that cet-PEG-dexSPIONs retained the therapeutic effect of cetuximab in addition to having the ability to target and image EGFR-expressing tumors. Cet-PEG-dexSPIONs represent a promising targeted magnetic probe for early detection and treatment of EGFR-expressing tumor cells. PMID- 26056448 TI - Effects of carbon nanofiber on physiology of Drosophila. AB - As nanomaterials are now widely utilized in a wide range of fields for both medical and industrial applications, concerns over their potential toxicity to human health and the environment have increased. To evaluate the toxicity of long term exposure to carbon nanofibers (CNFs) in an in vivo system, we selected Drosophila melanogaster as a model organism. Oral administration of CNFs at a concentration of 1,000 MUg/mL had adverse effects on fly physiology. Long-term administration of a high dose of CNFs (1,000 MUg/mL) reduced larval viability based on the pupa:egg ratio, adult fly lifespan, reproductive activity, climbing activity, and survival rate in response to starvation stress. However, CNFs at a low concentration (100 MUg/mL) did not show any significant deleterious effect on developmental rate or fecundity. Furthermore, long-term administration of a low dose of CNFs (100 MUg/mL) increased lifespan and climbing ability, coincident with mild reactive oxygen species generation and stimulation of the antioxidant system. Taken together, our data suggest that a high dose of CNFs has obvious physiological toxicity, whereas low-dose chronic exposure to CNFs can actually have beneficial effects via stimulation of the antioxidant defense system. PMID- 26056449 TI - Efficacy and mechanism of tanshinone IIA liquid nanoparticles in preventing experimental postoperative peritoneal adhesions in vivo and in vitro. AB - Up to 90% of patients develop adhesion following laparotomy. Upregulating fibrinolysis within the peritoneum reduces adhesions. Tanshinone IIA (Tan IIA) promotes fibrinolysis in hepatic fibrosis and the cardiovascular system and may play a role in preventing adhesions. We report preparation and characterization of liquid nanoparticles of Tan IIA for intravenous administration and investigate its feasibility in clinical practice. Tan IIA liquid nanoparticles (Tan IIA-NPs) were prepared using the emulsion/solvent evaporation method. Adhesions were induced in Sprague-Dawley rats by injuring the parietal peritoneum and cecum, followed by intravenous administration of various Tan IIA-NP dosages. The adhesion scores for each group were collected 7 days after the initial laparotomy. The activity of tissue-type plasminogen activator (tPA) was measured from the peritoneal lavage fluid. The messenger RNA and protein expression levels of plasminogen activator inhibitor-1 (PAI-1) were measured by quantitative real time polymerase chain reaction and enzyme-linked immunosorbent assay. TGF-beta1 and collagen I expressions were measured immunohistochemically in the ischemic tissues. The effects of Tan IIA-NPs and free-Tan IIA on tPA and PAI-1 were measured in vitro in TGF-beta1-induced HMrSV5 cells. Tan IIA-NPs exhibited small particle size, high encapsulation efficiency, good stability for storage, and safety for intravenous administration. Tan IIA-NPs were effective in preventing adhesion. Tan IIA-NPs increased tPA activity in peritoneal lavage fluid, and tPA mRNA and protein expression, and decreased PAI-1 mRNA and protein expression in the ischemic tissues. Moreover, Tan IIA-NPs decreased TGF-beta1 and collagen I expressions in the ischemic tissues. Tan IIA-NPs administered via tail veins upregulated fibrinolysis in the peritoneum. In vitro studies showed that these effects may be mediated by the TGF-beta signal pathway. PMID- 26056450 TI - High relapse rate and poor medication adherence in the Chinese population with schizophrenia: results from an observational survey in the People's Republic of China. AB - BACKGROUND: Relapse is common in schizophrenia, and seriously impacts patients' quality of life and social functioning. Many factors have been identified that may potentially increase the risk of relapse. This study was designed to investigate the relapse rate in the year following hospital discharge among Chinese patients with schizophrenia in the naturalistic condition, and to explore possible risk factors related to relapse. METHODS: We conducted a large, multicenter, retrospective, observational study in ten psychiatric hospitals throughout the People's Republic of China. Nine hundred and ninety-two schizophrenic outpatients aged 18-65 years discharged from these hospitals between September 2011 and February 2012 with recovery/improvement of their condition were included in the study. Information about relapse and correlative factors during the year after discharge was collected by telephone interview using a questionnaire. RESULTS: Eight hundred and seventy-six of 992 eligible patients completed the telephone survey. Of these patients, 293 (33.4%) had at least one relapse within 1 year after discharge, and 165 (18.8%) were rehospitalized. In respondents' view, the most important factor contributing to relapse was poor medication adherence (50.7%). Approximately 30% of the respondents had a negative attitude toward medication, with the impression that there was no need to take drugs at all or for a long time. Nonadherent patients (37.9%) had a relapse rate that was 2.5-fold higher than adherent patients (54.5% versus 20.7%, P<0.001). The top five risk factors associated with relapse were nonadherence to medication (odds ratio [OR] 4.602, 95% confidence interval [CI] 3.410-6.211), being without work (OR 3.275, 95% CI 2.291-4.681), poor self-care ability (OR 2.996, 95% CI 2.129-4.214), poor interpersonal skills (OR 2.635, 95% CI 1.951-3.558), and hospitalization on more than three occasions (OR 2.299, 95% CI 1.691-3.126). CONCLUSION: The 1-year relapse rate after discharge in patients with schizophrenia was 33.5% in our study. The most important risk factor related to relapse was poor medication adherence, which was mainly due to patients having a negative attitude toward their medication. Lack of psychosocial support and a complicated disease history also increased the risk of relapse. PMID- 26056451 TI - Evaluation of acute cardiovascular effects of immediate-release methylphenidate in children and adolescents with attention-deficit hyperactivity disorder. AB - Attention-deficit hyperactivity disorder is a frequent condition in children and often extends into adulthood. Use of immediate-release methylphenidate (MPH) has raised concerns about potential cardiovascular adverse effects within a few hours after administration. This study was carried out to investigate acute effects of MPH on electrocardiogram (ECG) in a pediatric population. A total of 54 consecutive patients with attention-deficit hyperactivity disorder (51 males and 3 females; mean age =12.14+/-2.6 years, range 6-19 years), receiving a new prescription of MPH, underwent a standard ECG 2 hours before and after the administration of MPH 10 mg per os. Basal and posttreatment ECG parameters, including mean QT (QT interval when corrected for heart rate [QTc]), QTc dispersion (QTd) interval duration, T-peak to T-end (TpTe) intervals, and TpTe/QT ratio were compared. Significant modifications of both QTc and QTd values were not found after drug administration. QTd fluctuated slightly from 25.7+/-9.3 milliseconds to 25.1+/-8.4 milliseconds; QTc varied from 407.6+/-12.4 milliseconds to 409.8+/-12.7 milliseconds. A significant variation in blood pressure (systolic blood pressure 105.4+/-10.3 vs 109.6+/-11.5; P<0.05; diastolic blood pressure 59.2+/-7.1 vs 63.1+/-7.9; P<0.05) was observed, but all the data were within normal range. Heart rate moved from 80.5+/-15.5 bpm to 87.7+/-18.8 bpm. No change in TpTe values was found, but a statistically significant increase in TpTe/QTc intervals was found with respect to basal values (0.207+/-0.02 milliseconds vs 0.214+/-0.02 milliseconds; P<0.01). The findings of this study show no significant changes in ECG parameters. TpTe values can be an additional parameter to evaluate borderline cases. PMID- 26056452 TI - Differences in gray matter volume corresponding to delusion and hallucination in patients with schizophrenia compared with patients who have bipolar disorder. AB - BACKGROUND: Although schizophrenia and bipolar disorder (BD) are classified as different disease entities, they share critical pathognomonic symptoms in terms of hallucination and delusion. Because the characteristics of clinical symptoms are not sufficient to differentiate schizophrenia from BD, several studies have applied brain imaging methods to provide biological evidence of differences. We compared gray matter (GM) volume differences in schizophrenia and BD patients and examined volumetric differences associated with hallucination and delusion in these two groups. METHODS: Ninety-three schizophrenia patients and 75 BD patients who were followed for at least 3 years in an outpatient department were recruited for this study. Magnetic resonance data from 71 schizophrenia patients and 44 BD patients were obtained using a 3.0 T scanner. Volumetric differences were analyzed using Matlab 8.0.0 and SPM8 software. RESULTS: The results showed that delusion symptoms were negatively correlated with GM volume within both frontal and both temporal cortices in the schizophrenia group and were negatively correlated with GM volume within the bilateral frontal cortices in the BD group. Hallucination symptoms were negatively correlated with GM volume within the bilateral frontal, bilateral temporal, and left parietal cortices in the schizophrenia group and were negatively correlated with GM volume within the bilateral frontal, right parietal, occipital, and insular cortices in the BD group. CONCLUSION: Delusions in schizophrenia were correlated with GM volume in multiple brain regions, including the frontal, temporal, and parietal cortices, compared to those in patients with BD. Hallucination was associated with temporal lobe GM volume in patients with schizophrenia and with insular cortex GM volume in patients with BD. PMID- 26056453 TI - Comparative efficacy of alemtuzumab and established treatment in the management of multiple sclerosis. AB - Alemtuzumab is the newest disease-modifying therapy approved for the treatment of relapsing multiple sclerosis. Alemtuzumab is an anti-CD52 targeted antibody that causes lysis of T and B lymphocytes, monocytes, natural killer cells, macrophages, and dendritic cells. Following its administration, a prolonged T cell lymphopenia results with emergence of a reconstituted immune system that differs in its composition from that pretreatment. In clinical trials, alemtuzumab has shown impressive efficacy with regard to clinical and radiological outcomes in relapsing multiple sclerosis, along with sustained long term beneficial effects, and it is attractive for its once-yearly administration. Despite this, the occurrence of serious secondary autoimmune disorders, infections, and a potential risk of malignancy necessitates a careful evaluation of risks versus benefits for an individual patient prior to its use. The requirement of patient commitment to the intense mandatory monitoring program is also a factor to be considered when incorporating alemtuzumab into the treatment regimen. PMID- 26056454 TI - Efficacy and safety of intravenous nimodipine administration for treatment of hypertension in patients with intracerebral hemorrhage. AB - BACKGROUND: Nicardipine (NC) is the most commonly used antihypertensive drug in neurological patients with hypertension. Although nimodipine (NM) is widely used to treat cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage, trials exploring its antihypertensive effect after intravenous administration in subjects with intracerebral hemorrhage (ICH) are scarce. METHODS: A retrospective study was carried out to compare the safety and efficacy of NC and NM administered intravenously in patients with ICH. Therapeutic responses were assessed by achievement of goal blood pressure (BP); use of additional medications for BP control; proportion of time spent within goal; variability in BP; time to goal BP; number of dose adjustments; variability in ICH volume, Glasgow Coma Scale score, and intracranial pressure; and drug-related complications. RESULTS: A total of 87 patients were eligible for analysis (n=46 [NC]; n=41 [NM]), and baseline characteristics between groups were similar. Both agents were effective in achieving goal BP during infusion, with 93.5% and 87.8% patients in the NC and NM groups achieving goal, respectively. Fewer additional medications were needed to control BP in the NC group. BP variability was similar and no differences were observed in the mean time to goal BP and mean numbers of dose adjustments between both groups. Interestingly, intracranial pressure declined (P=0.048) during NC administration but increased (P=0.066) after NM treatment. Finally, the incidences of hematoma expansion, neurological deterioration, and adverse drug events were similar in both groups. CONCLUSION: NM is effective and safe for BP control in patients with ICH. PMID- 26056455 TI - Assessment of knowledge, attitude, and practice related to epilepsy: a community based study. AB - Religious and sociocultural beliefs influence the nature of treatment and care received by people with epilepsy. Many communities in Africa and other developing nations believe that epilepsy results from evil spirits, and thus, treatment should be through the use of herbaceous plants from traditional doctors and religious leadership. Community-based cross-sectional study designs were used to assess the knowledge, attitude, and practice related to epilepsy and its associated factors by using a pretested, semi-structured questionnaire among 660 respondents living in Sululta Woreda, Oromia, Ethiopia. According to the results of this study, 59.8% of the respondents possessed knowledge about epilepsy, 35.6% had a favorable attitude, and 33.5% of them adopted safe practices related to epilepsy. The following factors had significant association to knowledge, attitude, and practice related to epilepsy: being rural dwellers, living alone, those with more years of formal education, heard information about epilepsy, distance of health facility from the community, had witnessed an epileptic seizure, age range from 46 years to 55 years, had heard about epilepsy, prior knowledge of epilepsy, occupational history of being self-employed or a laborer, history of epilepsy, and history of epilepsy in family member. The findings indicated that the Sululta community is familiar with epilepsy, has an unfavorable attitude toward epilepsy, and unsafe practices related to epilepsy, but has a relatively promising knowledge of epilepsy. PMID- 26056456 TI - Comprehensive family therapy: an effective approach for cognitive rehabilitation in schizophrenia. AB - BACKGROUND: Antipsychotic medication has limited abilities to improve the cognitive impairments that accompany schizophrenia. Adding psychosocial treatment may result in marked improvements in cognitive function, as compared to antipsychotic treatment alone. We hypothesized that a combination of individual and family interventions may be a useful cognitive rehabilitation paradigm for schizophrenia. MATERIALS AND METHODS: An 18-month follow-up clinical trial of 256 stabilized patients with schizophrenia at six communities in Shanghai, People's Republic of China were randomly assigned to into either a comprehensive family therapy (CFT) group or a usual daily care (UDC) group. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Positive and Negative Syndrome Scale (PANSS) were the primary outcome instruments for this study. RESULTS: There was no significant difference between the CFT and UDC for all demographic characteristics at the baseline assessment. During the 18-month follow-up observation, changes in RBANS total score indicated that patients undergoing CFT showed greater improvement from baseline to the follow-up assessments in cognitive function than those in the UDC group (F=9.77, P=0.002). Post hoc analysis showed that the CFT group presented with significant differences in the RBANS total score, immediate memory, visuospatial skill, language, attention, and delayed memory sections compared with the UDC after 18 months of follow-up (all P<0.01). CONCLUSION: Our findings suggest that CFT can be easily adapted and may prove to be an effective approach for improving cognitive function in patients with schizophrenia. Our program provides a potential paradigm for cognitive rehabilitation for schizophrenia patients in the community. PMID- 26056457 TI - Refractory cachexia is associated with increased plasma concentrations of fentanyl in cancer patients. AB - BACKGROUND: An appropriate plasma concentration of fentanyl is the key to achieving good pain control in cancer patients. Cachexia, a multifactorial syndrome, is known to affect drug-metabolizing enzymes. However, the fentanyl concentrations in the blood of patients with cachexia have not been analyzed. The aim of this study was to evaluate the influence of cancer cachexia on dose adjusted plasma fentanyl concentrations in cancer patients. METHODS: Blood was collected from 21 Japanese cancer patients treated with a 24-hour trans-dermal fentanyl patch during the steady state of fentanyl plasma concentration. Plasma fentanyl concentrations were analyzed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), and the levels were adjusted with the dose of fentanyl. Laboratory data were collected, and the cachexia stage was determined, based on study by Fearon et al. Multiple regression analysis was performed to identify the factors that affected fentanyl plasma concentrations. RESULTS: Eight patients were classified as precachexia, nine as cachexia, and four as refractory cachexia, and the median dose-adjusted fentanyl concentrations (ng/mL per mg/kg/day) were 27.5, 34.4, and 44.5, respectively. The dose-adjusted fentanyl concentration in patients with refractory cachexia was higher than that in patients with precachexia (Kruskal-Wallis test and post hoc Mann-Whitney U-test, P<0.01). The factors that were found to possibly affect the dose-adjusted concentration of fentanyl included aspartate aminotransferase, C-reactive protein, and estimated glomerular filtration rate, when analyzed as six independent variables (multiple regression analysis, P<0.05). CONCLUSION: The dose-adjusted plasma concentrations of fentanyl increased with progression of cancer cachexia. Such an increase is associated with a multifactorial and systemic syndrome in cancer cachexia patients, including lower albumin, higher C reactive protein, and impaired kidney function. In patients with cancer cachexia, we suggest that evaluation of cancer cachexia might help pain management when using a transdermal fentanyl patch in palliative care. PMID- 26056458 TI - Profile of PEGylated interferon beta in the treatment of relapsing-remitting multiple sclerosis. AB - Several treatments are currently available for relapsing-remitting multiple sclerosis. Among them, interferon (IFN) beta remains a valid treatment approach because of its good benefit/risk profile. Due to the need for frequent administration (weekly, at a minimum), the use of IFN beta is limited by uncomfortable side effects that could reduce adherence to and persistence with the treatment. The use of subcutaneous polyethylene glycol (PEG)ylated interferon beta-1a (PEG-IFN) has been proposed to offer a better combination of pharmacokinetic and pharmacodynamic profiles and therapy-related side effects. A 125 MUg dose of PEG-IFN given every 2 or 4 weeks was tested in two Phase I studies and shown to be as safe and efficient as IFN beta-1a but with a longer half-life. A Phase III trial (ADVANCE) comparing 125 MUg of PEG-IFN given every 2 or 4 weeks with placebo in 1,512 patients with relapsing-remitting multiple sclerosis showed significant reductions in both the annualized relapse rate (ARR) and the occurrence of new or newly enlarged T2 brain lesions in both experimental groups versus placebo after the first year. Moreover, 38% fewer patients showed progression of disability (P=0.04) in the PEG-IFN groups. During the second year, the ARR was further reduced in the PEG-IFN 2-week treatment group (0.230 at 1 year versus 0.178 at 2 years) and was maintained in the 4-week treatment group. Patients who received immediate PEG-IFN treatment showed improved clinical efficacy (ARR, risk of relapse, 12-week disability progression) and magnetic resonance imaging parameters (new T2 and newly enlarging lesions, gadolinium positive lesions) compared with those with delayed treatment. The effects were more evident with the 2-week dose for all endpoints considered. Furthermore, PEG IFN was well tolerated, and no new safety concerns arose. In conclusion, PEG-IFN has good efficacy and a good safety profile. The available data support the use of PEG-IFN as a suitable therapeutic option in patients with relapsing-remitting multiple sclerosis. PMID- 26056459 TI - To what extent is clinical and laboratory information used to perform medication reviews in the nursing home setting? the CLEAR study. AB - BACKGROUND: The aim of this study was to evaluate to what extent laboratory data, actual medication, medical history, and/or drug indication influence the quality of medication reviews for nursing home patients. METHODS: Forty-six health care professionals from different fields were requested to perform medication reviews for three different cases. Per case, the amount of information provided varied in three subsequent stages: stage 1, medication list only; stage 2, adding laboratory data and reason for hospital admission; and stage 3, adding medical history/drug indication. Following a slightly modified Delphi method, a multidisciplinary team performed the medication review for each case and stage. The results of these medication reviews were used as reference reviews (gold standard). The remarks from the participants were scored, according to their potential clinical impact, from relevant to harmful on a scale of 3 to -1. A total score per case and stage was calculated and expressed as a percentage of the total score from the expert panel for the same case and stage. RESULTS: The overall mean percentage over all cases, stages, and groups was 37.0% when compared with the reference reviews. For one of the cases, the average score decreased significantly from 40.0% in stage 1, to 30.9% in stage 2, and 27.9% in stage 3; no significant differences between stages was found for the other cases. CONCLUSION: The low performance, against the gold standard, of medication reviews found in the present study highlights that information is incorrectly used or wrongly interpreted, irrespective of the available information. Performing medication reviews without using the available information in an optimal way can have potential implications for patient safety. PMID- 26056461 TI - Association of low potassium diet and folic acid deficiency in patients with CKD. AB - BACKGROUND: Most of the folic acid sources are rich also in potassium. Patients with chronic kidney disease (CKD) usually receive a low potassium diet. We investigated the possibility of an association between low potassium diet and folic acid deficiency. METHODS: In total, 128 CKD patients participated in this cross-sectional study. Sixty-four patients with CKD grades 1 and 2 were on an unrestricted potassium diet when enrolled in the study, and 64 patients with CKD grades 3 and 4 had received instructions to restrict their intake of potassium at least 6 months before enrollment in the study. Subjects were evaluated for daily intake of folic acid (DIFA), daily intake of potassium (DIK), and serum folic acid levels (SFA). RESULTS: DIFA correlated with the estimated glomerular filtration rate, the DIK, and the SFA (P<0.001). SFA correlated with the estimated glomerular filtration rate (P<0.001). Mean DIFA and mean SFA were lower among patients with CKD grades 3 and 4 than among those with CKD grades 1 and 2 (P<0.001). The mean DIFA in patients with folic acid deficiency was lower than that in those with SFA >=7.1 nmol/L (P<0.001). There was lower SFA and threefold greater frequency of folic acid deficiency among patients with CKD grades 3 and 4 who had received instructions to restrict their intake of potassium than among patients with CKD grades 1 and 2 who were on an unrestricted potassium diet. CONCLUSION: A potassium-restricted diet offered to patients with CKD grades 3 and 4 may be associated with folic acid deficiency. Serum levels of folic acid should be investigated before starting potassium restriction in patients with CKD grades 3 and 4, in order to identify individuals with folic acid deficiency or with marginal serum levels who should receive folic acid replacement therapy. PMID- 26056462 TI - Functional and histological improvement after everolimus rescue of chronic allograft dysfunction in renal transplant recipients. AB - BACKGROUND: We tested the strategy of mTOR inhibitors with calcineurin inhibitor minimization in renal transplant recipients with known chronic allograft dysfunction. METHODS: In this open-label, single-arm study, renal transplant patients were recruited after biopsy-confirmed chronic allograft dysfunction in the absence of acute rejection episode within 2 months, with proteinuria <0.8 g/day, and serum creatinine <220 MUmol/L or estimated glomerular filtration rate >40 mL/min/1.73 m(2). They were converted to everolimus (aiming for trough everolimus level 3-8 ng/mL) with cyclosporine minimization, to assess the effect on renal function, rate of glomerular filtration rate decline, and longitudinal transplant biopsy at 12 months. RESULTS: Seventeen Chinese patients (median transplant duration, 4.2 years) were recruited; no patients discontinued study medication. The mean slope of the glomerular filtration rate over time was 4.31+/-6.65 mL/min/1.73 m(2) per year in the year before everolimus, as compared with 1.29+/-5.84 mL/min/1.73 m(2) per year in the 12 months of everolimus therapy, a difference of 5.61 mL/min/1.73 m(2) per year (95% confidence interval [CI], 0.40-10.8) favoring everolimus therapy (P=0.036). Serial renal biopsy histology showed significant decrease of tubular atrophy (15.7%+/-11.3% versus 7.1%+/-7.3%, P=0.005) and interstitial fibrosis (14.8%+/-11.5% versus 7.2%+/ 8.2%, P=0.013). Intrarenal expression of TGF-beta1 mRNA showed a nonsignificant decrease after everolimus treatment. CONCLUSION: In renal transplant recipients with biopsy-confirmed chronic allograft dysfunction, we found a significant beneficial effect of everolimus rescue therapy and calcineurin inhibitor minimization strategy on the improvement of glomerular filtration rate decline rate. In secondary analysis, everolimus was shown to slow down the disease progression by reducing the tubular atrophy and interstitial fibrosis scoring. PMID- 26056463 TI - Residual disease and risk factors in patients with high-grade cervical intraepithelial neoplasia and positive margins after initial conization. AB - BACKGROUND: The purpose of this study was to determine the clinicopathologic predictors of residual disease in patients with high-grade cervical intraepithelial neoplasia (CIN) and margin involvement after initial conization. METHODS: Data from 145 patients who underwent subsequent surgery for high-grade CIN with positive margins were retrospectively analyzed. RESULTS: After subsequent surgery, residual disease was diagnosed in 47 (34.2%) patients, of whom five had invasive cervical carcinoma, 31 had CIN 3, nine had CIN 2, and two had CIN 1. Multivariate analysis revealed that only age >=35 years (P=0.033), major abnormal cytology (P=0.002), and pre-cone high-risk human papillomavirus load >=300 relative light units (P=0.011) were significant factors associated with residual disease. CONCLUSION: Age >=35 years, major abnormal cytology, and pre-cone high-risk human papillomavirus load >=300 relative light units were the only significant factors predicting post-cone residual disease. Appropriate application of these predictive factors may avoid delayed treatment and overtreatment. PMID- 26056460 TI - Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists' arsenal. AB - Experimental data indicate that several pharmacological agents that have long been used for the management of various diseases unrelated to cancer exhibit profound in vitro and in vivo anticancer activity. This is of major clinical importance, since it would possibly aid in reassessing the therapeutic use of currently used agents for which clinicians already have experience. Further, this would obviate the time-consuming process required for the development and the approval of novel antineoplastic drugs. Herein, both pre-clinical and clinical data concerning the antineoplastic function of distinct commercially available pharmacological agents that are not currently used in the field of oncology, ie, nonsteroidal anti-inflammatory drugs, antihypertensive agents, and anti-human immunodeficiency virus agents inhibiting viral protease, are reviewed. The aim is to provide integrated information regarding not only the molecular basis of the antitumor function of these agents but also the applicability of the reevaluation of their therapeutic range in the clinical setting. PMID- 26056464 TI - Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of the Evidence. AB - Drug addiction is a chronically relapsing disorder characterized by the compulsive desire to use drugs and a loss of control over consumption. Cannabidiol (CBD), the second most abundant component of cannabis, is thought to modulate various neuronal circuits involved in drug addiction. The goal of this systematic review is to summarize the available preclinical and clinical data on the impact of CBD on addictive behaviors. MEDLINE and PubMed were searched for English and French language articles published before 2015. In all, 14 studies were found, 9 of which were conducted on animals and the remaining 5 on humans. A limited number of preclinical studies suggest that CBD may have therapeutic properties on opioid, cocaine, and psychostimulant addiction, and some preliminary data suggest that it may be beneficial in cannabis and tobacco addiction in humans. Further studies are clearly necessary to fully evaluate the potential of CBD as an intervention for addictive disorders. PMID- 26056465 TI - Emergency Department Visits Involving Misuse and Abuse of the Antipsychotic Quetiapine: Results from the Drug Abuse Warning Network (DAWN). AB - Case reports in medical literature suggest that the atypical antipsychotic quetiapine, a medication not previously considered to have abuse potential, is now being subject to misuse and abuse (MUA; ie, taken when not prescribed for them or used in a way other than instructed by their health professional). Here we present systematic, nationally representative data from the 2005 to 2011 Drug Abuse Warning Network (DAWN) for prevalence of emergency department (ED) visits among the U.S. general population involving quetiapine and related to MUA, suicide attempts, and adverse reactions. Nationally, quetiapine-related ED visits increased 90% between 2005 and 2011, from 35,581 ED visits to 67,497. DAWN data indicate that when used without medical supervision for recreational/self medication purposes, quetiapine poses health risks for its users, especially among polydrug users and women. These findings suggest that the medical and public health communities should increase vigilance concerning this drug and its potential for MUA. PMID- 26056466 TI - Impact Evaluation of an Addiction Intervention Program in a Quebec Prison. AB - OBJECTIVES: This study evaluates the effects of a prison-based addiction intervention program. The evaluation is based on a multidimensional data collection that draws a portrait of the respondents' substance use, and of their psychological/emotional, social, and judicial spheres. It measures the changes, or lack thereof, in substance use; the psychological/emotional, social, and judicial spheres; as well as the post-treatment services used. METHOD: A quasi experimental repeated measures design (0, 6 weeks, and 6 months) was used. Effects of the program were identified by comparing the results obtained by a group of inmates who had participated in the program (n = 80; experimental group) with those of another group who had received no intervention (n = 70; control group). RESULTS: The preliminary results suggested a certain treatment effect related to impulsivity and psychological distress. CONCLUSION: Although the preliminary results were promising, the experimental and control groups did not differ significantly when more robust analyses were used. PMID- 26056467 TI - Use of oral anticoagulants in African-American and Caucasian patients with atrial fibrillation: is there a treatment disparity? AB - Atrial fibrillation (AF) is a very common cardiac arrhythmia, and its prevalence is increasing along with aging in the developed world. This review discusses racial differences in the epidemiology and treatment of AF between African American and Caucasian patients. Additionally, the effect of race on warfarin and novel oral anticoagulant use is discussed, as well as the role that physicians and patients play in achieving optimal treatment outcomes. Despite having a lower prevalence of AF compared with Caucasians, African-Americans suffer disproportionately from stroke and its sequelae. The possible reasons for this paradox include poorer access to health care, lower health literacy, and a higher prevalence of other stroke-risk factors among African-Americans. Consequently, it is important for providers to evaluate the effects of race, health literacy, access to health care, and cultural barriers on the use of anticoagulation in the management of AF. Warfarin-dose requirements vary across racial groups, with African-American patients requiring a higher dose than Caucasians to maintain a therapeutic international normalized ratio; the novel oral anticoagulants (dabigatran, rivaroxaban, and apixaban) seem to differ in this regard, although data are currently limited. Minority racial groups are not proportionally represented in either real-world studies or clinical trials, but as more information becomes available and other social issues are addressed, the treatment disparities between African-American and Caucasian patients should decrease. PMID- 26056468 TI - Nonpharmacological therapies and provision of aids in outpatient dementia networks in Germany: utilization rates and associated factors. AB - BACKGROUND: Nonpharmacological therapies and the provision of aids are described to be supportive in the treatment of persons with dementia (PWDs). These aim to maintain individuals' participation in daily activities as long as possible, to slow the progression of their disease, and to support their independent living at home. However, there is a lack of knowledge about the utilization of therapies and aids among community-dwelling PWDs. OBJECTIVE: The aims of the study were a) to describe the utilization of nonpharmacological therapies and aids among community-dwelling PWDs and b) to analyze the factors associated with utilization. METHOD: As part of a cross-sectional study of n=560 caregivers of PWDs in dementia networks throughout Germany, we assessed sociodemographics, clinical variables, and the utilization of nonpharmacological therapies (physiotherapy [PT], occupational therapy [OT]), and aids (sensory, mobility, and others), using face-to-face interviews and questionnaires. RESULTS: Approximately every fourth PWD received PT and every seventh PWD received OT. Sensory aids were utilized by 91.1%, personal hygiene aids by 77.2%, mobility aids by 58.6%, and medical aids by 57.7% of the sample. Regression analysis revealed that the utilization of PT and medical aids was associated with comorbidities (odds ratio [OR] 1.17 and OR 1.27, respectively) and that the utilization of OT and sensory aids was associated with age (OR 1.06 and OR 0.95, respectively). CONCLUSION: The utilization of nonpharmacological therapies and aids among community-dwelling people served by dementia networks is more frequent than that reported for people in other settings. This result indicates that PWDs in integrated care models such as dementia networks receive better health care. PMID- 26056469 TI - Correlation of Carotid Intraplaque Hemorrhage and Stroke Using 1.5 T and 3 T MRI. AB - Carotid therosclerotic disease causes approximately 25% of the nearly 690,000 ischemic strokes each year in the United States. Current risk stratification based on percent stenosis does not provide specific information on the actual risk of stroke for most individuals. Prospective randomized studies have found only 10 to 12% of asymptomatic patients will have a symptomatic stroke within 5 years. Measurements of percent stenosis do not determine plaque stability or composition. Reports have concluded that cerebral ischemic events associated with carotid plaque are intimately associated with plaque instability. Analysis of retrospective studies has found that plaque composition is important in risk stratification. Only MRI has the ability to identify and measure the detailed components and morphology of carotid plaque and provides more detailed information than other currently available techniques. MRI can accurately detect carotid hemorrhage, and MRI identified carotid hemorrhage correlates with acute stroke. PMID- 26056470 TI - Fungal Presence in Selected Tree Nuts and Dried Fruits. AB - Sixty-four tree nut samples (almonds, pecans, pine nuts, and walnuts) and 50 dried fruit samples (apricots, cranberries, papaya, pineapple, and raisins) were purchased from local supermarkets and analyzed for fungal contamination using conventional culture as well as molecular methods. The results of our study showed that the highest yeast and mold (YM) counts (5.34 log10 CFU g(-1)) were found in walnuts and the lowest in pecans. The most common mold in nuts was Aspergillus niger, relatively low numbers of A. flavus were found across the board, while Penicillium spp. were very common in pine nuts and walnuts. Low levels (2.00-2.84 log10 CFU g(-1)) of yeasts were recovered from only two pine nut samples. Fungal contamination in dried fruits was minimal (ranging from <2.00 to 3.86 log10 CFU g(-1)). The highest fungal levels were present in raisins. All papaya samples and the majority of cranberry, pineapple, and apricot samples were free of live fungi. The most common mold in dried fruits was A. niger followed by Penicillium spp. One apricot sample also contained low levels (2.00 log10 CFU g( 1)) of yeasts. PMID- 26056471 TI - Hemoglobin and Ferritin Concentrations in Subjects with Metabolic Syndrome. AB - BACKGROUND: Metabolic syndrome (MetS), a clinical condition characterized by insulin resistance, glucose intolerance, dyslipidemia, hypertension, and obesity, has been linked with raised levels of serum ferritin (Sfr) concentrations. OBJECTIVES: This study was carried out to compare hemoglobin (Hb) and Sfr concentrations in patients with MetS, regular donors and first-time donors. MATERIALS AND METHODS: A total of 102 subjects who were between 18 and 60 years were enrolled for the study. They were divided into three groups. The first group (n = 20) was made up of 5 males and 15 females, all who met the criteria that define MetS. The second group (n = 52; M = 34, F = 18) were regular donors, while the last group (n = 30; M = 16, F = 14) were first-time donors or those who had not donated before. Following an overnight fast, 20 mL of venous blood was drawn from each subject. About 5 mL of this was put into sodium ethylenediaminetetraacetate (EDTA) specimen bottles for the full blood count parameters with Sysmex KX-21N hematology analyzer (made in Japan). The remaining 15 mL had serum separated for Sfr assay using enzyme-linked immunosorbent assay (ELISA) with a commercial assay kit manufactured by Teco Diagnostics. RESULTS: Significant difference was found in the mean Sfr concentration of subjects with MetS (163 +/- 136.92 ng/mL) and regular donors (41.46 +/- 40.33 ng/mL), P = 0.001. The mean Sfr concentrations of subjects with MetS (163 +/- 136.92 ng/mL) were also higher than that of first-time donors (102.46 +/- 80.26 ng/mL), but it was not statistically significant, P = 0.053. The Hb concentrations of the three groups were not significantly different. CONCLUSION: Sfr concentrations of regular donors were lower than that of subjects with MetS and first-time donors. The difference between regular donors and subjects with MetS was statistically significant. However, there is no significant difference in the Hb concentrations in the three groups. MetS is not associated with anemia or hyperferritinemia. PMID- 26056472 TI - Comparison of tumor markers using different detection devices. AB - BACKGROUND: With the development of proteomics, tumor markers have attracted increasing attention for the early diagnosis and treatment of lung cancer. As biochip technology and nanotechnology continues to grow, rapid and highly sensitive joint detection of multi-tumor markers has become possible. METHODS: Eighty-six patients with lung cancer and 42 healthy controls were recruited for this study. Based on analysis of the detection results, we plotted four standard tumor marker graphs, and compared the results of the highly sensitive nanogold probe and protein chip detection with the results of electrochemiluminescence immunoassay and Dickkopf-1 (DKK1) detection used in the clinic. We then analyzed the relationship between the detection results and our clinical data. RESULTS: Four plotted standard protein graphs all had stages with sound linear relationships. It was found in a correlation analysis of the detection results that overall the two methods showed consistency. CONCLUSION: We developed a detection method for ultra-trace protein that can detect four tumor markers, namely carcinoembryonic antigen, cytokeratin-19 fragments, neuron-specific enolase, and DKK1 in a highly sensitive way within 1.5 hours by magnifying the signal of nanogold deposition based on protein chips and nanogold probes. By comparing the results from the different detection devices, we have developed an experimental basis for detection of tumor markers in the clinic. PMID- 26056473 TI - Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm associated myelofibrosis. AB - The recent approval of molecular-targeted therapies for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF) has dramatically changed its therapeutic landscape. Ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor, is now widely used for first- and second-line therapy in persons with MPN-MF, especially those with disease-related splenomegaly, intermediate- or high-risk disease, and constitutional symptoms. The goal of this work is to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). We systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II) on which FDA and EMA approval was based. Our strategy was to apply the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach by evaluating five dimensions of evidence: (1) overall risk of bias, (2) imprecision, (3) inconsistency, (4) indirectness, and (5) publication bias. Based on these criteria, we downgraded the evidence from the COMFORT I and COMFORT II trials for performance, attrition, and publication bias. In the disease-associated splenomegaly sphere, we upgraded the quality of evidence because of large effect size but downgraded it because of comparator choice and outcome indirectness (quality of evidence, low). In the sphere of treating persons with intermediate- or high-risk disease, we downgraded the evidence because of imprecision in effect size measurement and population indirectness. In the sphere of disease-associated symptoms, we upgraded the evidence because of the large effect size, but downgraded it because of comparator indirectness (quality of evidence, moderate). In conclusion, using the GRADE technique, we identified factors affecting the quality of evidence that were otherwise unstated. Identifying and evaluating these factors should influence the confidence with which physicians use ruxolitinib in persons with MPN-MF. PMID- 26056474 TI - Radium-223 for the treatment of castration-resistant prostate cancer. AB - The vast majority of patients with metastatic castration-resistant prostate cancer (mCRPC) develop bone metastases. Bone metastases are a source of significant morbidity and affect quality of life in these patients. Several bone targeting agents are approved for the treatment of bone metastases in prostate cancer, including bisphosphonates, denosumab, and radiopharmaceuticals. Radium 223 is a novel first-in-class alpha-emitting radiopharmaceutical that has been approved for treatment of patients with mCRPC with bone metastases. Radium-223 delivers cytotoxic radiation to the sites of bone metastases and offers the advantage of minimal myelosuppression. The landmark Phase III ALSYMPCA trial demonstrated that, in addition to providing bone-related palliation, radium-223 can also prolong overall survival in patients with mCRPC with bone metastases in the absence of visceral metastases and in the absence of lymphadenopathy greater than 3 cm. Ongoing trials will further elucidate its use in sequence or combination with other available therapies for mCRPC. PMID- 26056475 TI - Perioperative FOLFOX4 plus bevacizumab for initially unresectable advanced colorectal cancer (NAVIGATE-CRC-01). AB - BACKGROUND: Perioperative chemotherapy combined with surgery for liver metastases is considered an active strategy in metastatic colorectal cancer (CRC). However, its impact on initially unresectable, previously untreated advanced CRC, regardless of concurrent metastases, remains to be clarified. METHODS: A Phase II study was conducted to evaluate the safety and efficacy of perioperative FOLFOX4 plus bevacizumab for initially unresectable advanced CRC. Patients with previously untreated advanced colon or rectal cancer initially diagnosed as unresectable advanced CRC (TNM stage IIIb, IIIc, or IV) but potentially resectable after neoadjuvant chemotherapy (NAC) were studied. Preoperatively, patients received six cycles of NAC (five cycles of neoadjuvant FOLFOX4 plus bevacizumab followed by one cycle of FOLFOX4 alone). The interval between the last dose of bevacizumab and surgery was at least 5 weeks. Six cycles of adjuvant FOLFOX4 plus bevacizumab were given after surgery. The completion rate of NAC and feasibility of curative surgery were the primary endpoints. RESULTS: An interim analysis was performed at the end of NAC in the 12th patient to assess the completion rate of NAC. The median follow-up time was 56 months. The characteristics of the patients were as follows: sex, eight males and four females; tumor location, sigmoid colon in three, ascending colon in one, and rectum (above the peritoneal reflection) in eight; stage, III in eight and IV in four (liver or lymph nodes). All patients completed six cycles of NAC. There were no treatment-related severe adverse events or deaths. An objective response to NAC was achieved in nine patients (75%), and no disease progression was observed. Eleven patients underwent curative tumor resection, including metastatic lesions. In December 2012, this Phase II study was terminated because of slow registration. CONCLUSION: Perioperative FOLFOX4 plus bevacizumab is well tolerated and has a promising response rate leading to curative surgery, which offers a survival benefit in initially unresectable advanced CRC with concurrent metastatic lesions. PMID- 26056476 TI - Knockdown of immature colon carcinoma transcript-1 inhibits proliferation of glioblastoma multiforme cells through Gap 2/mitotic phase arrest. AB - "Glioblastoma multiforme" (GBM) is the frequent form of malignant glioma. Immature colon carcinoma transcript-1 (ICT1) is essential for cell vitality and mitochondrial function and has been recognized in several human cancers. In the study reported here, we attempted to evaluate the functional role of ICT1 in GBM cells. Lentivirus-mediated RNA interference (RNAi) was applied to silence ICT1 expression in human GBM cell lines U251 and U87. Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays. Cell-cycle progression was determined by flow cytometry with propidium iodide staining. The results revealed that lentivirus-mediated short hairpin RNA (shRNA) can specifically suppress the expression of ICT1 in U251 and U87 cells. Functional investigations proved for the first time, as far as we are aware, that ICT1 knockdown significantly inhibited the proliferation of both cell lines. Moreover, the cell cycle of U251 cells was arrested at Gap 2 (G2)/mitotic (M) phase after ICT1 knockdown, with a concomitant accumulation of cells in the Sub-Gap 1 (G1) phase. This study highlights the crucial role of ICT1 in promoting GBM cell proliferation, and provides a foundation for further study into the clinical potential of lentivirus-mediated silencing of ICT1 for GBM therapy. PMID- 26056477 TI - Transforming growth factor-beta-1 is a serum biomarker of radiation-induced pneumonitis in esophageal cancer patients treated with thoracic radiotherapy: preliminary results of a prospective study. AB - OBJECTIVE: To examine the relationship between cytokine levels of transforming growth factor-beta-1 (TGF-beta1), interleukin-1 beta (IL-1beta), and angiotensin converting enzyme (ACE) in the plasma of esophageal carcinoma patients and radiation-induced pneumonitis (RP). MATERIALS AND METHODS: Sixty-three patients with esophageal carcinoma were treated with three-dimensional conformal radiotherapy (RT) using the Elekta Precise treatment planning system with a prescribed dose of 50-70 Gy. Dose-volume histograms were collected from three dimensional conformal RT to determine the volume percentage of the lung received V5, V10, V20, and the normal tissue complication probability. RP was diagnosed based on computed tomography imaging, respiratory symptoms, and signs. The severity of radiation-induced lung toxicity was determined using the Lent-Soma scale defined by the Radiation Therapy Oncology Group. Plasma samples obtained before RT, during RT (at 40 Gy), and at 1 day, 1 month, and 3 months after RT were assayed for TGF-beta1, IL-1beta, and ACE levels by enzyme-linked immunosorbent assay. RESULTS: From the 63 patients, 17 (27%) developed RP, and 13 (21%) had RP of grade I and four (6%) had grade II or higher. We found plasma TGF beta1 levels were elevated in the patients that had RP when compared with the other 46 patients who did not have RP. The plasma IL-1beta levels were not changed. The ACE levels were significantly lower in the 17 patients with RP compared to the 46 patients without RP throughout the RT. As expected, RP is associated with a higher dose of irradiation (>60 Gy); no other factors, including dose-volume histogram, age, sex, smoking status, location of tumor, and methods of treatment, are associated with RP. CONCLUSION: Elevated plasma TGF beta1 levels can be used as a marker for RP. PMID- 26056478 TI - Combination of afatinib with cetuximab in patients with EGFR-mutant non-small cell lung cancer resistant to EGFR inhibitors. AB - Tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR) have shown effectiveness for advanced non-small-cell lung cancer (NSCLC) with activating mutations in the EGFR gene. However, resistance to the EGFR TKIs develops mostly secondary to T790M mutation in exon 20. The use of afatinib associated with cetuximab represents a new possibility of therapy following progression on gefitinib or erlotinib. We present two patients who acquired resistance to first-generation TKI and who underwent combination treatment with afatinib plus cetuximab as third-line therapy. Both patients presented partial response, and the time duration of disease control was 8 months and 10 months. The combined use of afatinib plus cetuximab emerges as a new possibility for the treatment of patients with advanced NSCLC harboring mutated EGFR after progression on first-generation EGFR TKIs with consequently acquired resistance to TKIs. Further studies are necessary to consolidate the data. PMID- 26056479 TI - Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma with involvement of the urinary bladder: a case report and review of literature. AB - We report a unique case of anaplastic large-cell lymphoma (ALCL) involving the urinary bladder in a 22-year-old man. The patient presented with left lower back pain for 4 weeks. The computed tomography (CT) scan demonstrated an exophytic nodule on the left bladder wall and abdominopelvic lymphadenopathy. Histologically, a population of large pleomorphic cells extensively infiltrated the lamina propria of the bladder. These cells were diffusely and strongly immunoreactive for CD30, ALK, EMA, and vimentin, but were negative for AE1/AE3, CK20, CK7, CK5/6, P63, SMA, HMB-45, pan-Melan, S-100, Myo D1, synaptophysin, CD56, desmin, CD15, CD20, Pax-5, and CD3. Few cells exhibited positive immunohistochemical staining of CD45. The patient underwent cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regime of chemotherapy and achieved a complete remission after four cycles. This case is the tenth documented case of systemic ALCL involving urinary bladder. Due to its rarity, it is important to be aware of the features of ALCL in bladder, and make prompt and accurate diagnosis. PMID- 26056480 TI - DDMC-p53 gene therapy with or without cisplatin and microwave ablation. AB - Lung cancer remains the leading cause of death in cancer patients. Severe treatment side effects and late stage of disease at diagnosis continue to be an issue. We investigated whether local treatment using 2-diethylaminoethyl-dextran methyl methacrylate copolymer with p53 (DDMC-p53) with or without cisplatin and/or microwave ablation enhances disease control in BALBC mice. We used a Lewis lung carcinoma cell line to inoculate 140 BALBC mice, which were divided into the following seven groups; control, cisplatin, microwave ablation, DDMC-p53, DDMC p53 plus cisplatin, DDMC-p53 plus microwave, and DDMC-p53 plus cisplatin plus microwave. Microwave ablation energy was administered at 20 W for 10 minutes. Cisplatin was administered as 1 mL/mg and the DDMC-p53 complex delivered was 0.5 mL. Increased toxicity was observed in the group receiving DDMC-p53 plus cisplatin plus microwave followed by the group receiving DDMC-p53 plus cisplatin. Infection after repeated treatment administration was a major issue. We conclude that a combination of gene therapy using DDMC-p53 with or without cisplatin and microwave is an alternative method for local disease control. However, more experiments are required in a larger model to identify the appropriate dosage profile. PMID- 26056481 TI - Corynebacterium urealyticum: a comprehensive review of an understated organism. AB - Corynebacterium urealyticum is a Gram positive, slow-growing, lipophilic, multi drug resistant, urease positive micro-organism with diphtheroid morphology. It has been reported as an opportunistic nosocomial pathogen and as the cause of a variety of diseases including but not limited to cystitis, pyelonephritis, and bacteremia among others. This review serves to describe C. urealyticum with respect to its history, identification, laboratory investigation, relationship to disease and treatment in order to allow increased familiarity with this organism in clinical disease. PMID- 26056482 TI - Safety and tolerability of exenatide once weekly in patients with type 2 diabetes: an integrated analysis of 4,328 patients. AB - BACKGROUND: Exenatide once weekly (QW) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes. Safety and tolerability are key considerations in treatment selection. This analysis examines the safety and tolerability profile of exenatide QW, other approved GLP-1RAs (exenatide twice daily and liraglutide once daily), and a pooled population of commonly used non-GLP-1RA treatments. METHODS: Intent-to-treat populations from eight randomized Phase III trials with 24-week and 30-week comparator-controlled periods were analyzed. Data were pooled for exenatide QW, exenatide twice daily, and non-GLP-1RA comparator groups; comparisons between exenatide QW and liraglutide were analyzed separately to better match study groups. The incidence of treatment-emergent adverse events with 95% confidence intervals and exposure adjusted incidence were calculated. Duration and recurrence were analyzed for gastrointestinal adverse events and adverse events of special interest. RESULTS: Incidences of serious adverse events did not differ between treatments. Discontinuations due to adverse events occurred numerically less frequently with exenatide QW than with other GLP-1RAs but numerically more frequently than with non-GLP-1RA comparators. The most frequent adverse events in the GLP-1RA groups were gastrointestinal and generally mild, with decreasing incidence over time. Gastrointestinal adverse event incidences appeared lower with exenatide QW versus other GLP-1RAs and greater than with non-GLP-1RA comparators. Injection site related adverse events seemed highest with exenatide QW, but generally did not lead to withdrawal and abated over time. Hypoglycemia was infrequent overall, but occurred numerically more frequently in the non-GLP-1RA comparator group and increased with concomitant sulfonylurea use. Pancreatitis, thyroid cancer, renal failure, and gallbladder disease were rarely reported. CONCLUSION: The overall safety and tolerability profile of exenatide QW was similar to that of other GLP 1RAs, with improved gastrointestinal tolerability. The safety and tolerability profile of exenatide QW compared with non-GLP-1RA comparators was similar overall, with the exception of a lower incidence of hypoglycemia and anticipated differences in gastrointestinal and injection site-related adverse events. PMID- 26056483 TI - Body vectoring technique with Radiesse((r)) for tightening of the abdomen, thighs, and brachial zone. AB - BACKGROUND: The objective of this study was to investigate the efficacy, safety, and subject satisfaction of the calcium hydroxylapatite-based dermal filler Radiesse((r)) in a novel body vectoring technique to correct skin flaccidity in the thighs, abdomen, and brachial zones. METHODS: Female subjects with self evaluated flaccidity scores >=3 on a 6-point scale (0, no flaccidity; 5, very severe flaccidity) in the zones of interest were included. Radiesse was injected according to predesigned vector maps (3 mL per thigh, 1.5 mL per hemiabdomen or brachial zone). Clinical assessments (skin density and thickness) were made by an independent reviewer at an exact position before and 5 weeks after treatment using a cutometer and an ultrascan. Subjects rated skin flaccidity before and 5 weeks after treatment on the 6-point scale and performed a pinch test to self assess changes in skin thickness. All adverse events were recorded. RESULTS: Twenty females (aged 28-67 years) were enrolled, contributing 36 treatment zones. Across all zones, 78% of flaccidity measurements improved after treatment. Improvements in skin flaccidity were most common in the thighs (82% of cases). An improvement in skin density versus baseline was observed in the majority across all zones, most frequently in the abdomen (88% of cases). Skin thickness in each zone also improved versus baseline for the majority, most frequently in the thighs (88% of cases). Mean self-assessed flaccidity scores at baseline were 3.6 (thighs), 3.7 (abdomen), and 3.8 (brachial zone), and 2.6, 2.7, and 3.0, respectively, posttreatment. All subjects reported a positive pinch test. In total, 47.0% of subjects had bruising after treatment, which resolved within a week. No serious adverse events were reported. CONCLUSION: Using this novel technique, Radiesse had notable results on skin flaccidity, density and thickness in the thighs, abdomen, and brachial zones, and was well tolerated. PMID- 26056484 TI - Regulation of indoleamine 2,3-dioxygenase in primary human saphenous vein endothelial cells. AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is an enzyme associated with the regulation of immune responses. Cytokines such as IFNgamma induce its expression in endothelial cells originating from immune-privileged sites. In this study, we investigate regulators of IDO in primary endothelial cells from a non-immune privileged site and determine whether IDO expression affects immune cell behavior. METHODS: IDO expression was determined using real-time quantitative polymerase chain reaction and immunoblotting. IDO activity was estimated using an IDO enzyme assay. Primary cells were transfected using microporation, and T-cell migration was determined using a cell transmigration assay. RESULTS: IDO is expressed in human saphenous vein endothelial cells after stimulation with IFNgamma but not after treatment with TNFalpha, IL-1beta, IL-2, IL-4, IL-6, or IL 10. VEGFbeta and heparin negatively regulate IFNgamma-driven increases in IDO. Overexpression of IDO in endothelial cells does not affect transmigration of T cells. CONCLUSION: IDO is expressed in human saphenous vein endothelial cells after stimulation with IFNgamma. Heparin and angiogenesis stimulators such as VEGFbeta negatively regulate its expression. PMID- 26056485 TI - Association of inflammatory markers and poor outcome in diabetic patients presenting with ST segment elevation myocardial infarction. AB - OBJECTIVE: Carbohydrate metabolism disorders (CMD) significantly impact the development and progression of all forms of ischemic heart disease, and inflammation is regarded as a general pathogenetic link between CMD and ischemic heart disease. METHODS: A total of 601 patients with ST segment elevation myocardial infarction (MI) (STEMI), admitted within 24 hours from the onset of symptoms during 1 year, were included in this registry study. The blood levels of inflammation markers were measured at days 10-14 with further follow up at 1 year. RESULTS: The analysis of acute-phase percutaneous coronary intervention impact on the 1-year outcomes showed that endovascular revascularization significantly improved the 1-year prognosis of STEMI patients both with and without CMD. The analysis of inflammation markers showed significantly higher levels of interleukin (IL)-6 and sCD40L in MI patients with diabetes mellitus, and impaired glucose tolerance. Additionally, the patients with impaired glucose tolerance had significantly higher IL-12 levels. In the diabetic MI patients, the odds ratio of a poor 1-year outcome was high for patients with a high Killip classification of acute heart failure upon admission. CONCLUSION: Persistent inflammation in STEMI patients with CMD undergoing percutaneous coronary intervention might be responsible for vascular complications within 1 year after MI. Comorbid diabetes mellitus or impaired glucose tolerance can amplify the significance of the inflammatory response for the development of adverse 1-year outcomes. PMID- 26056486 TI - 22q11 deletion syndrome: current perspective. AB - Chromosome 22q11 is characterized by the presence of chromosome-specific low-copy repeats or segmental duplications. This region of the chromosome is very unstable and susceptible to mutations. The misalignment of low-copy repeats during nonallelic homologous recombination leads to the deletion of the 22q11.2 region, which results in 22q11 deletion syndrome (22q11DS). The 22q11.2 deletion is associated with a wide variety of phenotypes. The term 22q11DS is an umbrella term that is used to encompass all 22q11.2 deletion-associated phenotypes. The haploinsufficiency of genes located at 22q11.2 affects the early morphogenesis of the pharyngeal arches, heart, skeleton, and brain. TBX1 is the most important gene for 22q11DS. This syndrome can ultimately affect many organs or systems; therefore, it has a very wide phenotypic spectrum. An increasing amount of information is available related to the pathogenesis, clinical phenotypes, and management of this syndrome in recent years. This review summarizes the current clinical and genetic status related to 22q11DS. PMID- 26056487 TI - A combined continuous and interval aerobic training improves metabolic syndrome risk factors in men. AB - Individuals with metabolic syndrome have significantly higher risk of cardiovascular disease and type 2 diabetes leading to premature death mortality. Metabolic syndrome has a complex etiology; thus, it may require a combined and multi-targeted aerobic exercise regimen to improve risk factors associated with it. Therefore, the aim of this study was to evaluate the effect of combined continuous and interval aerobic training on patients with metabolic syndrome. Thirty adult male with metabolic syndrome (54+/-8 years) were randomly divided into two groups: test training group (TTG; n=15) and control group (CG; n=15). Subjects in TTG performed combined continuous and interval aerobic training using a motorized treadmill three times per week for 16 weeks. Subjects in CG were advised to continue with their normal activities of life. Twenty-two men completed the study (eleven men in each group). At the end of the study, in TTG, there were significant (for all, P<0.05) reductions in total body weight (-3.2%), waist circumference (-3.43 cm), blood pressure (up to -12.7 mmHg), and plasma insulin, glucose, and triacylglyceride levels. Moreover, there were significant (for all, P<0.05) increases VO2max (-15.3%) and isometric strength of thigh muscle (28.1%) and high-density lipoprotein in TTG. None of the above indices were changed in CG at the end of 16-week study period. Our study suggests that adoption of a 16-week combined continuous and interval aerobic training regimen in men with metabolic syndrome could significantly reduce cardiovascular risk factors in these patients. PMID- 26056488 TI - A New Technique for Collection of Cerebrospinal Fluid in Rat Pups. AB - BACKGROUND: Neuroprotective strategies to prevent or decrease brain injury in hypoxic ischemic newborns are one of the main research lines in neonatology. Animal models have been used to assess the efficiency of new therapeutic strategies. Brain damage biomarkers in cerebrospinal fluid (CSF) are frequently used to evaluate the outcome at the bedside. Despite the importance of this approach in clinical practice, there are many difficulties in using it in small animals. The aim of this paper was to describe a new technique for collecting CSF in rat pups. Furthermore the reference values of S100beta protein levels, commonly used in common clinical practice, were analyzed in animals between 7 to 12 days. METHODS: 42 Wistar rat pups aged 7 to 12 days were used. CSF was obtained by direct puncture of the cisterna magna with a 24-gauge needle. S100beta protein levels were determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: CSF was successfully obtained in 96% of the cases, with an average amount of 21.28 MUl (5-40 MUl). Normal values for S100beta were described. HI animals presented higher S100beta values than controls. CONCLUSIONS: A simple, reproducible technique for CSF collection in rat pups has been described. This new method will allow study of brain injury biomarkers in newborn hypoxic ischemic animal models. PMID- 26056489 TI - The expanding role of pertuzumab in the treatment of HER2-positive breast cancer. AB - Breast cancer tumors that demonstrate gene amplification or overexpression of human epidermal growth factor receptor 2 (HER2) are classified as HER2-positive. They account for approximately 15% of all breast cancers and represent an adverse prognostic factor. Over the past years, many new therapies have become available for the treatment of breast cancer. Particularly, the treatment of patients with HER2-positive breast cancer has developed with the arrival of anti-HER2 targeted therapies that have been proven to increase survival in both the metastatic and early-stage settings of the disease. Trastuzumab, a monoclonal antibody targeting HER2, significantly improves survival in HER2-positive breast cancer. Nevertheless, it is still a challenge to evolve anti-HER2 therapies, as the disease may progress. Pertuzumab inhibits HER2 by binding to a different HER2 epitope than trastuzumab and represents a complementary mechanism of action to trastuzumab. The efficacy and safety of pertuzumab in combination with trastuzumab with or without chemotherapy have been demonstrated in both advanced and early stages of HER2-positive breast cancer. Herein, we review the available data on the use of pertuzumab for the treatment of patients with HER2-positive breast cancer. PMID- 26056490 TI - The Danish National Prescription Registry in studies of a biological pharmaceutical: palivizumab - validation against two external data sources. AB - BACKGROUND: National prescription databases are important tools in pharmacoepidemiological studies investigating potential long-term adverse events after drug use. Palivizumab is a biological pharmaceutical used as passive prophylaxis against severe infection with respiratory syncytial virus in high risk children. OBJECTIVE: To assess the registration of palivizumab in the Danish National Prescription Registry (DNPR) and to examine if palivizumab reimbursement data obtained from the Danish Health and Medicines Authority could serve as a supplement to data from the DNPR. METHODS: Registration of palivizumab exposure in the DNPR between 1999 and 2010 was compared to two external data sources: registration of palivizumab exposure in medical records, and palivizumab reimbursement data. RESULTS: During the study period, 182 children with palivizumab exposure were registered in the DNPR. A total of 207 children were registered for palivizumab reimbursement. The sensitivity of palivizumab registration in the DNPR was 26% (20%-34%), and the specificity of no palivizumab registration in the DNPR was 97% (94%-99%), with data from the medical record as the reference. Palivizumab registration sensitivity in reimbursement data was 29% (22%-36%), and the specificity of no palivizumab registration in the DNPR was 97% (94%-99%), with data from the medical record as the reference. CONCLUSION: Exposure to palivizumab was underestimated in the DNPR. Reimbursement data are a readily accessible data supplement, which only slightly increased the sensitivity of palivizumab registration in the DNPR. Our findings underline the need to improve DNPR information concerning drugs administered in hospitals. PMID- 26056491 TI - Hormone withdrawal-associated symptoms with ethinylestradiol 20 MUg/drospirenone 3 mg (24/4 regimen) versus ethinylestradiol 20 MUg/desogestrel 150 MUg (21/7 regimen). AB - OBJECTIVE: To assess whether the combined oral contraceptive (COC) ethinylestradiol (EE) 20 MUg/drospirenone 3 mg taken in a 24/4-day regimen (ie, 4 day hormone-free interval) is more effective than an EE 20 MUg/desogestrel (DSG) 150 MUg COC taken in a 21/7-day regimen (ie, 7-day hormone-free interval) in reducing hormone withdrawal-associated symptoms (HWAS). METHODS: This double blind, randomized study (NLM identifier: NCT01076582) was conducted at 34 centers in 12 countries. Otherwise healthy women who experienced >=2 HWAS of headache, pelvic pain, and/or bloating when using their current COCs in a 21/7-day regimen were recruited. Subjects rated the severity of their HWAS daily on a seven-point Likert scale during a baseline cycle and during four 28-day cycles with EE/drospirenone 24/4 (n=290) or EE/DSG 21/7 (n=304). The primary variable was the mean change from baseline to cycle 4 in the composite HWAS score (sum of scores for all three symptoms) during cycle days 22-28. RESULTS: In the EE/drospirenone 24/4 group, the mean (standard deviation) composite HWAS score during cycle days 22-28 was reduced from 42.2 (24.8) at baseline to 12.8 (13.4) at cycle 4 (change from baseline: -30.3 [22.9]). In the EE/DSG 21/7 group, the corresponding value was reduced from 41.9 (25.8) to 14.3 (13.2) (change from baseline: -27.7 [24.8]), not significantly different versus EE/drospirenone 24/4. Bleeding pattern, treatment response, rescue medication use, compliance, quality of life, and tolerability were similar between treatments. CONCLUSION: Both EE/drospirenone 24/4 and EE/DSG 21/7 reduced the composite HWAS score from baseline to cycle 4 in otherwise healthy women. The differences between treatments were too small to be statistically significant. PMID- 26056492 TI - Lichen sclerosus: a potpourri of misdiagnosed cases based on atypical clinical presentations. AB - OBJECTIVE: Lichen sclerosus (LS) is a chronic progressive inflammatory autoimmune induced disease that primarily affects the epidermis and dermis of the external genital-anal region. Intense and recalcitrant pruritus is the hallmark of LS. Physical exam reveals thinning, hyperkeratosis, and parchment-like appearance. However, the classic symptom and signs of LS may not always be present and patients may be asymptomatic for pruritus. Hence, we describe 15 misdiagnosed cases with atypical clinical presentations. We believe that the absence of pruritus contributed to their initial misdiagnosis. The purpose of this paper is to increase awareness of atypical presentations of LS. METHODS: Data base review of de-identified clinical case pictures was performed. All patients had histopathology-confirmed diagnoses of LS. The data base file contains 800 cases of vulvovaginal disorders. The Institutional Review Board (IRB) considered that searching a de-identified data base of pictures did not require IRB approval. RESULTS: We identified 15 different atypical clinical cases. Patient ages were 18 75 years old. These patients were asymptomatic for pruritus and were misdiagnosed before they presented to the vulvovaginal specialized clinic. CONCLUSION: Fifteen patients asymptomatic for pruritus with histopathology-confirmed diagnosis of LS were identified. They illustrate atypical clinical presentations that LS may have. PMID- 26056494 TI - Unilateral corneal leukoplakia without limbal involvement. AB - PURPOSE: Leukoplakia is the term given to a white patch or plaque that is found mainly on the oral mucus membrane. It can occasionally be seen on the corneal surface. We report our clinical and histopathological findings in a case of unilateral corneal leukoplakia. METHODS: A 26-year-old woman was referred to our hospital because of a white patch on her right cornea that continued to expand. She first noticed the white patch when she was 20 years old, and the white patch had expanded to cover the pupillary area affecting her vision. After plastic surgery on both eyelids for bilateral entropion to alleviate the pain caused by the eyelashes rubbing the cornea, the white corneal patch decreased in size. Because of this reduction, we performed surgery to remove the patch with microforceps under topical anesthesia. The plaque was removed easily and completely, and submitted for histopathological examination. RESULTS: Histopathological examination showed that the specimen had characteristics of epidermis with a basal cell layer, spinous cell layer, granular cell layer, and horny layer with hyperkeratosis. She was diagnosed with leukoplakia of the corneal surface. The basic structure of the squamous cell layer was preserved, and there were no signs of metaplasia. Six months after the removal of the leukoplakia, no recurrence was seen and her corrected decimal visual acuity recovered to 1.0. CONCLUSION: Our case of unilateral corneal leukoplakia without limbal involvement was most likely caused by chronic irritation of the cornea by the eyelashes. Although it was totally removed with good recovery of vision, we continue to follow the patient because of the potential of malignant transformation. PMID- 26056493 TI - Updated guidelines on screening for gestational diabetes. AB - Gestational diabetes mellitus (GDM) is associated with an increased risk of complications for both mother and baby during pregnancy as well as in the postpartum period. Screening and identifying these high-risk women is important to improve short- and long-term maternal and fetal outcomes. However, there is a lack of international uniformity in the approach to the screening and diagnosis of GDM. The main purpose of this review is to provide an update on screening for GDM and overt diabetes during pregnancy, and discuss the controversies in this field. We take on debatable issues such as adoption of the new International association of diabetes and pregnancy study groups criteria instead of the Carpenter and Coustan criteria, one-step versus two-step screening, universal screening versus high-risk screening before 24 weeks of gestation for overt diabetes, and, finally, the role of HbA1c as a screening test of GDM. This discussion is followed by a review of recommendations by professional bodies. Certain clinical situations, in which a pragmatic approach is needed, are highlighted to provide a comprehensive overview of the subject. PMID- 26056495 TI - Toxocara polymerase chain reaction on ocular fluids in bilateral granulomatous chorioretinitis. AB - To report a rare case of bilateral granulomatous chorioretinitis complicated by bilateral peripapillary choroidal neovascular membranes. This is the first reported case in Australia where intravitreal injections of anti-vascular endothelial growth factor ranibizumab were used to successfully treat choroidal neovascular membrane caused by granulomatous chorioretinitis. This is also the first reported case in Australia of Toxocara polymerase chain reaction being performed on intraocular fluids. PMID- 26056496 TI - Pharmacokinetics and skin-tissue penetration of daptomycin in rats. AB - BACKGROUND: Daptomycin is recommended for complicated skin and skin-structure infections. However, information on the penetration of daptomycin into skin is limited. Therefore, the aim of this in vivo investigation was to determine the pharmacokinetics and skin penetration of daptomycin in rats. MATERIALS AND METHODS: Concentrations of daptomycin were determined by high-performance liquid chromatography. A noncompartmental pharmacokinetic analysis was conducted to estimate the rate and extent of daptomycin penetration from the systemic circulation into skin tissue. Since protein binding of daptomycin in rat serum was 89.3%, the free maximum concentration (Cmax) and free area under the curve from time 0 to infinity (AUC0-infinity) for plasma were calculated as follows: fCmax, plasma = (1 - 0.893) * Cmax, plasma, fAUC0-infinity, plasma = (1 - 0.893) * AUC0-infinity, plasma. RESULTS: The following values (mean +/- standard deviation) were obtained: 0.06+/-0 L/h/kg for total clearance (CLtotal), 0.44+/ 0.06 hours for elimination-rate constant, 1.58+/-0.23 hours for half-life, 0.14+/ 0.02 L/kg for steady-state volume distribution, and 2.28+/-0.33 hours for mean residence time. Time to Cmax was 3.0 hours for plasma and skin tissue. Cmax and AUC0-infinity for plasma were 175.8+/-5.1 MUg/mL and 811.8+/-31.9 MUg * h/mL, respectively. Cmax and AUC0-infinity for skin tissue were 19.1+/-1.7 MUg/mL and 113.9+/-21.8 MUg * h/mL, respectively. Furthermore, fCmax and fAUC0-infinity for plasma were 18.8 MUg/mL and 86.9 MUg * h/mL, respectively. The degrees of skin tissue penetration, defined as the Cmax, skin tissue/fCmax, plasma ratio and AUC0 infinity, skin tissue/fAUC0-infinity, plasma ratio, were 1.0 and 1.3, respectively. CONCLUSION: Daptomycin exhibited good penetration into skin tissue, supporting its use for the treatment of complicated skin and skin-structure infections. However, further studies are needed in infected patients in order to investigate the relationship between the antimicrobial efficacy of daptomycin and its drug concentrations in skin tissues. PMID- 26056497 TI - Percutaneous hepatic radiofrequency for hepatocellular carcinoma: results and outcome of 46 patients. AB - Radiofrequency ablation (RFA) is a curative option for hepatocellular carcinoma (HCC), the most common primary malignancy of the liver. This bicentric retrospective study includes 46 patients admitted for their first percutaneous RFA for HCC. Sixty-three nodules were treated, with an average size of 32.5 mm. Our study confirms the efficiency of this technique for attaining necrosis of HCC nodules, with few complications. Subgroup studies according to RFA mode (mono- or multipolar), etiology of cirrhosis (alcoholic or viral), and HCC size showed better efficiency for multipolar RFA when applied to small tumors and better survival when the cirrhosis was due to viral infection. However, we noted a high rate of local recurrence in our and other recent works compared to previous studies, probably due to improved imaging techniques. The main problem is still de novo intrahepatic recurrence in diseased livers. PMID- 26056499 TI - The connection between typological complexes of properties of the nervous system, temperaments, and personality types in the professions and sports. AB - Based on experimental studies in education, professions and sports, an attempt was made to combine the following two historically disconnected research directions in the study of the natural human traits into a single coordinate system: Pavlov's theory on the properties of the nervous system, as well as the types of higher nervous activity, and Jung's theory on psychological types. It is noted that Pavlov's school of thought was developed by his followers in Russia within the scientific school of differential psychophysiology, while Yung's theory was developed through the works of well-known American researchers Myers and Keirsey. The spatial model that is presented here rests on the knowledge of the properties of the human nervous system and enables the prediction of psychological characteristics, temperament, and psychological types of individuals belonging to a wide age range. PMID- 26056498 TI - What predicts performance in ultra-triathlon races? - a comparison between Ironman distance triathlon and ultra-triathlon. AB - OBJECTIVE: This narrative review summarizes recent intentions to find potential predictor variables for ultra-triathlon race performance (ie, triathlon races longer than the Ironman distance covering 3.8 km swimming, 180 km cycling, and 42.195 km running). Results from studies on ultra-triathletes were compared to results on studies on Ironman triathletes. METHODS: A literature search was performed in PubMed using the terms "ultra", "triathlon", and "performance" for the aspects of "ultra-triathlon", and "Ironman", "triathlon", and "performance" for the aspects of "Ironman triathlon". All resulting papers were searched for related citations. Results for ultra-triathlons were compared to results for Ironman-distance triathlons to find potential differences. RESULTS: Athletes competing in Ironman and ultra-triathlon differed in anthropometric and training characteristics, where both Ironmen and ultra-triathletes profited from low body fat, but ultra-triathletes relied more on training volume, whereas speed during training was related to Ironman race time. The most important predictive variables for a fast race time in an ultra-triathlon from Double Iron (ie, 7.6 km swimming, 360 km cycling, and 84.4 km running) and longer were male sex, low body fat, age of 35-40 years, extensive previous experience, a fast time in cycling and running but not in swimming, and origins in Central Europe. CONCLUSION: Any athlete intending to compete in an ultra-triathlon should be aware that low body fat and high training volumes are highly predictive for overall race time. Little is known about the physiological characteristics of these athletes and about female ultra-triathletes. Future studies need to investigate anthropometric and training characteristics of female ultra-triathletes and what motivates women to compete in these races. Future studies need to correlate physiological characteristics such as maximum oxygen uptake (VO2max) with ultra-triathlon race performance in order to investigate whether these characteristics are also predictive for ultra-triathlon race performance. PMID- 26056500 TI - The impact of age and severity of comorbid illness on outcomes after isolated aortic valve replacement for aortic stenosis. AB - OBJECTIVES: This study examines outcomes in a national sample of patients undergoing isolated aortic valve replacement (AVR) for aortic stenosis, with particular focus on advanced-age patients and those with extreme severity of comorbid illness (SOI). METHODS: Data were obtained from the Nationwide Inpatient Sample and included all patients undergoing AVRs performed from January 1, 2006 to December 31, 2008. Patients with major concomitant cardiac procedures, as well as those aged, 20 years, and those with infective endocarditis or aortic insufficiency without aortic stenosis, were excluded from analysis. The analysis included 13,497 patients. Patients were stratified by age and further stratified by All Patient Refined Diagnosis Related Group SOI into mild/moderate, major, and extreme subgroups. RESULTS: Overall in-hospital mortality was 2.96% (n=399); in hospital mortality for the >=80-year-old group (n=139, 4.78%) was significantly higher than the 20- to 49-year-old (n=9, 0.84%, P<0.001) or 50- to 79-year-old (n=251, 2.64%, P<0.001) groups. In-hospital mortality was significantly higher in the extreme SOI group (n=296, 15.33%) than in the minor/moderate (n=22, 0.35%, P<0.001) and major SOI groups (n=81, 1.51%, P<0.001). Median in-hospital costs in the mild/moderate, major, and extreme SOI strata were $29,202.08, $36,035.13, and $57,572.92, respectively. CONCLUSION: In the minor, moderate, and major SOI groups, in-hospital mortality and costs are low regardless of age; these groups represent >85% of patients undergoing isolated AVR for aortic stenosis. Conversely, in patients classified as having extreme SOI, surgical therapy is associated with exceedingly high inpatient mortality, low home discharge rates, and high resource utilization, particularly in the advanced age group. PMID- 26056502 TI - User preference for a portable syringe pump for iloprost infusion. AB - PURPOSE: Administration of intravenous iloprost - a first-line European League Against Rheumatism (EULAR)-recommended choice for the treatment of scleroderma (SSc)-related digital vasculopathy - requires repeated treatment cycles of 6 hours per day in a hospital setting. During the infusion, patient mobility is considerably restricted due to the size and fixity of traditional syringe pumps. The aim of this study was to evaluate the satisfaction level of patients and nurses, after the introduction of a new portable syringe pump (Infonde((r)), Italfarmaco S.p.A., Milan, Italy) at the Department of Rheumatology, Magenta Hospital, Milan, Italy. PATIENTS AND METHODS: Thirty-four consecutive SSc patients receiving stable therapy with iloprost, previously administered with a fixed pump, were treated using the portable Infonde((r)) pump. Patients (n=34) and nurses (n=4) were asked to answer a nine- and six-item questionnaire, respectively, to assess the satisfaction of the administration comparing the new device versus the previous one. The health care staff of the ward developed the questionnaire, and the response scores ranged from 0 (fixed device better) to 10 (portable device better); thus a score >5 indicates a preference for Infonde((r)). RESULTS: Patients' answers indicated a preference towards the new portable syringe pump, versus the previous fixed pump. Questionnaires administered to patients generated a total of 306 responses, with over 95% of the responses in the range 8-10, of which 89% had a score equal to 10. The responses of nurses showed a score equal to 10 in 100% cases. No significant adverse events were recorded, indicating no change in the tolerability profile of the drug. CONCLUSION: Iloprost administration with Infonde((r)) pump was preferred by both patients and health care professionals, and was well tolerated. The possibility to perform daily activities and the freedom of movement suggest a positive impact of Infonde((r)) on the treatment, with a potential favorable effect on the quality of life of patients during the many hours spent receiving the infusion. PMID- 26056501 TI - Optimal delivery of colorectal cancer follow-up care: improving patient outcomes. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. With population aging and increases in survival, the number of CRC survivors is projected to rise dramatically. The time following initial treatment is often described as a period of transition from intensive hospital-based care back into "regular life." This review provides an overview of recommended follow-up care for people with CRC who have been treated with curative intent, as well as exploring the current state of the research that underpins these guidelines. For patients, key concerns following treatment include the development of recurrent and new cancers, late and long-term effects of cancer and treatment, and the interplay of these factors with daily function and general health. For physicians, survivorship care plans can be a tool for coordinating the surveillance, intervention, and prevention of these key patient concerns. Though much of the research in cancer survivorship to date has focused on surveillance for recurrent disease, many national guidelines differ in their conclusions about the frequency and timing of follow-up tests. Most CRC guidelines refer only briefly to the management of side effects, despite reports that many patients have a range of ongoing physiological, psychosocial, and functional needs. Guidance for surveillance and intervention is often limited by a small number of heterogeneous trials conducted in this patient group. However, recently released survivorship guidelines emphasize the potential for the effectiveness of secondary prevention strategies, such as physical activity, to improve patient outcomes. There is also emerging evidence for the role of primary care providers and nurse coordinated care to support the transition and increase the cost effectiveness of follow-up. The shift in focus from recurrence alone to the assessment and management of a range of survivorship issues will be important for ensuring that this growing group of patients achieves optimal outcomes. PMID- 26056503 TI - Development of the Oxford Participation and Activities Questionnaire: constructing an item pool. AB - PURPOSE: The Oxford Participation and Activities Questionnaire is a patient reported outcome measure in development that is grounded on the World Health Organization International Classification of Functioning, Disability, and Health (ICF). The study reported here aimed to inform and generate an item pool for the new measure, which is specifically designed for the assessment of participation and activity in patients experiencing a range of health conditions. METHODS: Items were informed through in-depth interviews conducted with 37 participants spanning a range of conditions. Interviews aimed to identify how their condition impacted their ability to participate in meaningful activities. Conditions included arthritis, cancer, chronic back pain, diabetes, motor neuron disease, multiple sclerosis, Parkinson's disease, and spinal cord injury. Transcripts were analyzed using the framework method. Statements relating to ICF themes were recast as questionnaire items and shown for review to an expert panel. Cognitive debrief interviews (n=13) were used to assess items for face and content validity. RESULTS: ICF themes relevant to activities and participation in everyday life were explored, and a total of 222 items formed the initial item pool. This item pool was refined by the research team and 28 generic items were mapped onto all nine chapters of the ICF construct, detailing activity and participation. Cognitive interviewing confirmed the questionnaire instructions, items, and response options were acceptable to participants. CONCLUSION: Using a clear conceptual basis to inform item generation, 28 items have been identified as suitable to undergo further psychometric testing. A large-scale postal survey will follow in order to refine the instrument further and to assess its psychometric properties. The final instrument is intended for use in clinical trials and interventions targeted at maintaining or improving activity and participation. PMID- 26056504 TI - Acquired hemophilia A: emerging treatment options. AB - Acquired hemophilia A is a rare autoimmune disorder caused by an autoantibody (inhibitor) to factor VIII (FVIII) that interferes with its coagulant function and predisposes to severe, potentially life-threatening hemorrhage. Disease management focuses on controlling bleeding, primarily with the use of bypassing therapy and recombinant porcine FVIII, and permanently eradicating the autoantibody using various immunosuppressants. Treatment challenges include delayed diagnosis, difficulty achieving hemostasis and durable remissions, and complications associated with the use of hemostatic and immunosuppressive therapy in a primarily older patient population. PMID- 26056505 TI - Gastrointestinal Stromal Tumors (GIST): A Prospective Analysis and an Update on Biomarkers and Current Treatment Concepts. AB - Gastrointestinal stromal tumors (GIST) are the most common sarcomas of the gastrointestinal tract, with transformation typically driven by activating mutations of cKIT and less commonly platelet-derived growth factor receptor alpha (PDGFRA). Successful targeting of tyrosine-protein kinase Kit with imatinib, a tyrosine kinase inhibitor, has had a major impact in the survival of patients with GIST in both the adjuvant and metastatic setting. A recent modification of treatment guidelines for patients with localized, high-risk GIST extended the adjuvant treatment duration from 1 year to 3 years. In this paper, we review the clinical data of patients with GIST treated in the Oncology Outpatient Unit of "Attikon" University Hospital and aim to assess which patients are eligible for prolongation of adjuvant imatinib therapy as currently suggested by treatment recommendations. PMID- 26056506 TI - Intra-Adenoid Cyst: A Case Report with an Immunohistochemical Study and Review of Literature. AB - A woman in her 50s was referred to our department with the chief complaint of nasal congestion and pharyngeal discomfort. The patient had been diagnosed with sleep apnea at the Department of Internal Medicine, and had undergone nasal continuous positive airway pressure (nCPAP) therapy, but her response to the treatment was poor. A cystic lesion occupying the nasopharynx, which was detected by nasopharyngeal fiberscopy, computed tomography, and magnetic resonance imaging, was thought to be the cause of the nasal congestion, pharyngeal discomfort, and obstructive sleep apnea syndrome (OSAS). Consequently, the patient underwent extirpation of the lesion under general anesthesia for the purpose of obtaining a definitive diagnosis as well as for treatment of the nasopharyngeal tumor. The diagnosis of intra-adenoid cyst was eventually made based on the pathological findings, which revealed lymphoid tissue accompanied by expansion of the crypt, as well as inflammatory cell infiltration with follicular hyperplasia. After the operation, the patient reported subjective improvement of her symptoms, and began to respond to the nCPAP therapy for her sleep apnea syndrome. Nasopharyngeal cysts, in particular adult intra-adenoid cyst, are relatively rare. The outcomes of the current case indicated that the presence of a nasopharyngeal cystic disease was hampering the nCPAP treatment of refractory OSAS. PMID- 26056508 TI - Prevalence and Predictors of Malnutrition in Nasopharyngeal Carcinoma. AB - We assessed the prevalence and predictors of malnutrition in patients with nasopharyngeal carcinoma. Sixty cases and 123 controls matched for age and gender were included. Bio-data, dietary history, height, weight, body mass index (BMI), ideal body weight, and serum albumin levels were recorded. Pretreatment weight loss of >5% was present in 35% of subjects (P < 0.0001). A BMI of < 18.5 kg/m(2) was present in 13.3% (P < 0.001), percent ideal body weight of <90% was present in 30% (P < 0.001), and serum albumin levels <30 g/dL was present in 23.3% (P < 0.001) of cases. Nasopharyngeal carcinoma increased the likelihood of having a BMI < 18.5 kg/m(2) (odds ratio, 9.3 (3.4-25.3) P <= 0.001). Logistic regression shows that stage IV disease was associated with a decrease in all parameters except protein-calorie intake. Stage IV nasopharyngeal carcinoma is a predictive marker for weight loss and low serum albumin levels. Nutritional management is important for ensuring the patients' ability to withstand chemoradiation and thus improve survival and quality of life. PMID- 26056507 TI - Genetics of Interstitial Lung Disease: Vol de Nuit (Night Flight). AB - Interstitial lung disease (ILD) is a chronic, progressive fibrotic lung disease with a dismal prognosis. ILD of unknown etiology is referred to as idiopathic interstitial pneumonia (IIP), which is sporadic in the majority of cases. ILD is frequently accompanied by rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), and other autoimmune diseases, and is referred to as collagen vascular disease-associated ILD (CVD-ILD). Susceptibility to ILD is influenced by genetic and environmental factors. Recent advances in radiographic imaging techniques such as high-resolution computed tomography (CT) scanning as well as high-throughput genomic analyses have provided insights into the genetics of ILD. These studies have repeatedly revealed an association between IIP (sporadic and familial) and a single nucleotide polymorphism (SNP) in the promoter region of the mucin 5B (MUC5B). HLA-DRB1*11 alleles have been reported to correlate with ILD in European patients with SSc, whereas in Japanese patients with RA, the HLA-DR2 serological group was identified. The aim of this review is to describe the genetic background of sporadic IIP, CVD-ILD, drug induced-ILD (DI-ILD), pneumoconiosis, and hypersensitivity pneumonitis. The genetics of ILD is still in progress. However, this information will enhance the understanding of the pathogenesis of ILD and aid the identification of novel therapeutic targets for personalized medicine in future. PMID- 26056509 TI - Transcriptome Analysis of Minimal Residual Disease in Subtypes of Pediatric B Cell Acute Lymphoblastic Leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and the leading cause of cancer-related death in children and adolescents. Minimal residual disease (MRD) is a strong, independent prognostic factor. The objective of this study was to identify molecular signatures distinguishing patients with positive MRD from those with negative MRD in different subtypes of ALL, and to identify molecular networks and biological pathways deregulated in response to positive MRD at day 46. We compared gene expression levels between patients with positive MRD and negative MRD in each subtype to identify differentially expressed genes. Hierarchical clustering was applied to determine their functional relationships. We identified subtype-specific gene signatures distinguishing patients with positive MRD from those with negative MRD. We identified the genes involved in cell cycle, apoptosis, transport, and DNA repair. We also identified molecular networks and biological pathways dysregulated in response to positive MRD, including Granzyme B, B-cell receptor, and PI3K signaling pathways. PMID- 26056510 TI - Competency-structured case discussion in the morning meeting: enhancing CanMEDS integration in daily practice. AB - Outcome-focused, competency-based educational curricula have become the norm in residency training programs. The Canadian Medical Education Directives for Specialists (CanMEDS) framework is one example of such a curriculum. However, models for incorporating all the competencies in everyday clinical practice have been difficult to accomplish. In this manuscript, a CanMEDS, competency structured, acute case discussion in a regular morning meeting was undertaken. All the diagnostic and therapeutic interventions were explicitly organized and discussed under their respective CanMEDS competency headings. Post exercise, the majority of residents felt that they were more competent in all the competencies and indicated their willingness to continue having similarly structured acute case discussions in the future. PMID- 26056512 TI - Should an iBSc in Management be compulsory for all UK medical students? PMID- 26056511 TI - Feedback and assessment for clinical placements: achieving the right balance. AB - During clinical placements, the provision of feedback forms an integral part of the learning process and enriches students' learning experiences. The purpose of feedback is to improve the learner's knowledge, skills, or behavior. Receipt of accurate feedback can help to narrow the gap between actual and desired performance. Effective and regular feedback has the potential to reinforce good practice and motivate the learner toward the desired outcome. Despite the obvious role of feedback in effective teaching and learning, a common complaint from students is that they do not receive adequate feedback. Unfortunately, skills in giving and receiving feedback are rarely taught to students or clinicians. This study aims to provide an understanding of the role of feedback within the learning process, consider consequences of inadequate or poorly given feedback, consider the barriers to the feedback process, provide practical guidelines for providing feedback, and consider the need for student and faculty development in feedback skills. PMID- 26056513 TI - Impact of clerkship attachments on students' attitude toward pharmaceutical care in Ethiopia. AB - OBJECTIVE: The study objective is to investigate the impact of mandatory clinical clerkship courses on 5th-year pharmacy students' attitudes and perceived barriers toward providing pharmaceutical care (PC). METHODS: A cross-sectional survey was conducted among 5th-year pharmacy students undertaking mandatory clinical clerkship in the University of Gondar, Ethiopia. A pharmaceutical care attitudes survey (PCAS) questionnaire was used to assess the attitude (14 items), commonly identified drug-related problem/s (1 item) during clerkships, and perceived barriers (12 items) toward the provision of PC. Statistical analysis was conducted on the retrieved data. RESULTS: Out of the total of 69 clerkship students, 65 participated and completed the survey (94.2% response rate). Overall, 74.45% of participants opinioned a positive attitude toward PC provision. Almost all respondents agreed that the primary responsibility of pharmacists in the healthcare setting was to prevent and solve medication-related problems (98.5%), practice of PC was valuable (89.3%), and the PC movement will improve patient health (95.4%), respectively. Unnecessary drug therapy (43%), drug-drug interactions (33%), and non-adherence to medications (33%) were the most common drug-related problems identified in wards. Highly perceived barriers for PC provision included lack of a workplace for counseling in the pharmacy (75.4%), a poor image of pharmacist's role in wards (67.7%), and inadequate technology in the pharmacy (64.6%). Lack of access to a patient's medical record in the pharmacy had significant association (P<0.05) with PC practice, performance of PC during clerkship, provision of PC as clinical pharmacists, and Ethiopian pharmacists benefiting by PC. CONCLUSION: Ethiopian clinical pharmacy students have a good attitude toward PC. Efforts should be targeted toward reducing these drug therapy issues, and aiding the integration of PC provision with pharmacy practice. PMID- 26056514 TI - Assessing drug and metabolite detection in liver tissue by UV-MALDI and IR MALDESI mass spectrometry imaging coupled to FT-ICR MS. AB - Determining the distribution of a drug and its metabolites within tissue is a key facet of evaluating drug candidates. Drug distribution can have a significant implication in appraising drug efficacy and potential toxicity. The specificity and sensitivity of mass spectrometry imaging (MSI) make it a perfect complement to the analysis of drug distributions in tissue. The detection of lapatinib as well as several of its metabolites in liver tissue was determined by MSI using infrared matrix-assisted laser desorption electrospray ionization (IR-MALDESI) coupled to high resolving power Fourier transform ion cyclotron resonance (FT ICR) mass spectrometers. IR-MALDESI required minimal sample preparation while maintaining high sensitivity. The effect of the electrospray solvent composition on IR-MALDESI MSI signal from tissue analysis was investigated and an empirical comparison of IR-MALDESI and UV-MALDI for MSI analysis is also presented. PMID- 26056515 TI - Effects of a moderate intake of beer on markers of hydration after exercise in the heat: a crossover study. AB - BACKGROUND: Exercise in the heat causes important water and electrolytes losses through perspiration. Optimal rehydration is crucial to facilitate the recuperation process after exercise. The aim of our study was to examine whether a moderate beer intake as part of the rehydration has any negative effect protocol after a short but dehydrating bout of exercise in the heat. METHODS: Sixteen active male (VO2max, 56 +/- 4 mL/kg/min), were included in a crossover study and performed a dehydrating exercise (<=1 h running, 60 %VO2max) twice and 3 weeks apart, in a hot laboratory setting (35 +/- 1 degrees C, humidity 60 +/- 2 %). During the two hours following the exercise bouts participants consumed either mineral water ad-libitum (W) or up to 660 ml regular beer followed by water ad-libitum (BW). Body composition, hematological and serum parameters, fluid balance and urine excretion were assessed before, after exercise and after rehydration. RESULTS: Body mass (BM) decreased (both ~ 2.4%) after exercise in both trials. After rehydration, BM and fat free mass significantly increased although BM did not return to baseline levels (BM, 72.6 +/- 6.7 to 73.6 +/- 6.9; fat free mass, 56.9 +/- 4.7 to 57.5 +/- 4.5, no differences BW vs W). Beer intake did not adversely affect any measured parameter. Fluid balance and urine excretion values did not differ between the rehydration strategies. CONCLUSIONS: After exercise and subsequent water losses, a moderate beer (regular) intake has no deleterious effects on markers of hydration in active individuals. PMID- 26056517 TI - Effect of Diode Laser Irradiation Combined with Topical Fluoride on Enamel Microhardness of Primary Teeth. AB - OBJECTIVES: Laser irradiation has been suggested as an adjunct to traditional caries prevention methods. But little is known about the cariostatic effect of diode laser and most studies available are on permanent teeth.The purpose of the present study was to investigate the effect of diode laser irradiation combined with topical fluoride on enamel surface microhardness. MATERIALS AND METHODS: Forty-five primary teeth were used in this in vitro study. The teeth were sectioned to produce 90 slabs. The baseline Vickers microhardness number of each enamel surface was determined. The samples were randomly divided into 3 groups. Group 1: 5% NaF varnish, group 2: NaF varnish+ diode laser at 5 W power and group 3: NaF varnish+ diode laser at 7 W power. Then, the final microhardness number of each surface was again determined. The data were statistically analyzed by repeated measures ANOVA at 0.05 level of significance. RESULTS: In all 3 groups, microhardness number increased significantly after surface treatment (P<0.05). However, Microhardness change after treatment was not significantly different among groups (P >0.05). CONCLUSION: The combined application of diode laser and topical fluoride varnish on enamel surface did not show any significant additional effect on enamel resistance to caries. PMID- 26056518 TI - Bond Strength of 5(th), 6(th) and 7(th) Generation Bonding Agents to Intracanal Dentin of Primary Teeth. AB - OBJECTIVES: This in-vitro study sought to assess the push-out bond strength of a total etch and 2 self-etch bonding systems to intracanal dentin of primary anterior teeth (PAT). MATERIALS AND METHODS: Thirty-six primary anterior teeth were randomly divided into 3 groups of 5(th) generation (Single Bond 2), 6(th) generation (Clearfil SE) and 7(th) generation (Single Bond Universal) bonding agents. The canal orifice was restored with composite resin and the push-out test was carried out to assess the bond strength. After applying the push-out load, specimens were evaluated under a light microscope at 40X magnification. One-way ANOVA and log-rank test on Kaplan-Meier curves were applied for the comparison of bond strength among the 3 groups. RESULTS: The mean+/- standard deviation (SD) bond strength was 13.6+/-5.33 MPa for Single Bond 2, 13.85+/-5.86 MPa for Clearfil SE and 12.28+/-5.24 MPa for Single Bond Universal. The differences in bond strength among the 3 groups were not statistically significant (P>0.05). CONCLUSION: All three bonding agents are recommended for use with composite posts in PAT. However, due to high technical sensitivity of the Total Etch system, single or two-step self etch systems may be preferred for uncooperative children. PMID- 26056519 TI - Comparison of Obturation Quality in Modified Continuous Wave Compaction, Continuous Wave Compaction, Lateral Compaction and Warm Vertical Compaction Techniques. AB - OBJECTIVES: The aim of this study was to introduce modified continuous wave compaction (MCWC) technique and compare its obturation quality with that of lateral compaction (LC), warm vertical compaction (WVC) and continuous wave compaction techniques (CWC). The obturation time was also compared among the four techniques. MATERIALS AND METHODS: Sixty-four single-rooted teeth with 0-5 degrees root canal curve and 64 artificially created root canals with 15 degrees curves in acrylic blocks were evaluated. The teeth and acrylic specimens were each divided into four subgroups of 16 for testing the obturation quality of four techniques namely LC, WVC, CWC and MCWC. Canals were prepared using the Mtwo rotary system and filled with respect to their group allocation. Obturation time was recorded. On digital radiographs, the ratio of area of voids to the total area of filled canals was calculated using the Image J software. Adaptation of the filling materials to the canal walls was assessed at three cross-sections under a stereomicroscope (X30). Data were statistically analyzed using ANOVA, Tukey's post hoc HSD test, the Kruskal Wallis test and t-test. RESULTS: No significant difference existed in adaptation of filling materials to canal walls among the four subgroups in teeth samples (P >= 0.139); but, in artificially created canals in acrylic blocks, the frequency of areas not adapted to the canal walls was significantly higher in LC technique compared to MCWC (P <= 0.02). The void areas were significantly more in the LC technique than in other techniques in teeth (P < 0.001). The longest obturation time belonged to WVC technique followed by LC, CW and MCWC techniques (P<0.05). The difference between the artificially created canals in blocks and teeth regarding the obturation time was not significant (P = 0.41). CONCLUSION: Within the limitations of this in vitro study, MCWC technique resulted in better adaptation of gutta-percha to canal walls than LC at all cross-sections with fewer voids and faster obturation time compared to other techniques. PMID- 26056516 TI - The Case for Addressing Operator Fatigue. AB - Sleep deficiency, which can be caused by acute sleep deprivation, chronic insufficient sleep, untreated sleep disorders, disruption of circadian timing, and other factors, is endemic in the U.S., including among professional and non professional drivers and operators. Vigilance and attention are critical for safe transportation operations, but fatigue and sleepiness compromise vigilance and attention by slowing reaction times and impairing judgment and decision-making abilities. Research studies, polls, and accident investigations indicate that many Americans drive a motor vehicle or operate an aircraft, train or marine vessel while drowsy, putting themselves and others at risk for error and accident. In this chapter, we will outline some of the factors that contribute to sleepiness, present evidence from laboratory and field studies demonstrating how sleepiness impacts transportation safety, review how sleepiness is measured in laboratory and field settings, describe what is known about interventions for sleepiness in transportation settings, and summarize what we believe are important gaps in our knowledge of sleepiness and transportation safety. PMID- 26056520 TI - Comparison of Antifungal Activity of 2% Chlorhexidine, Calcium Hydroxide, and Nanosilver gels against Candida Albicans. AB - OBJECTIVES: Residual microorganisms in the root canal system (RCS) after endodontic therapy such as Candida albicans are a major cause of endodontic failure. Calcium hydroxide (CH) and chlorhexidine (CHX) have suitable antimicrobial activity against bacteria and can be used as intracanal medicaments. Nanosilver has also shown antimicrobial activity against microorganisms. This study aimed to compare the antifungal effect of calcium hydroxide, 2% chlorhexidine and nanosilver gels on Candida albicans. MATERIALS AND METHODS: Eighty-one single-rooted teeth were selected. After root canal preparation, the teeth were contaminated. After culture, the teeth were randomly divided into 4 groups. In experimental groups, 24 teeth were selected and completely filled with CH, 2% CHX and nanosilver gels in each group. Nine teeth were selected in the control group and filled with saline solution. After 1, 3, and 7 days, samples were obtained by #30 sterile paper points, and #2 and #4 Gates Glidden drills and cultured on solid Sabouraud agar. RESULTS: The results demonstrated that CH and 2% CHX had equal antifungal effects on samples taken by paper point and #2 Gates Glidden drill at all time points. Both CH and 2% CHX were more effective than nanosilver at all time periods. There was no statistically significant difference between medicaments in samples taken by #4 Gates Glidden drill. CONCLUSION: CH and 2% CHX gels have significantly higher antifungal activity than nanosilver gel. Also, CH and 2% CHX gels are equally effective against Candida albicans. PMID- 26056521 TI - Comparison of Microleakage under Rebonded Stainless Steel Orthodontic Brackets Using Two Methods of Adhesive Removal: Sandblast and Laser. AB - OBJECTIVES: Debonding is a common occurrence in orthodontic treatment and a considerable number of orthodontists prefer to rebond the detached brackets because of economic issues. The aim of this study was to compare the microleakage beneath rebonded stainless steel brackets using two methods of adhesive removal namely sandblast and laser. MATERIALS AND METHODS: Sixty human premolar teeth were randomly divided into three groups. Following bonding the brackets, group 1 served as the control group. Brackets in groups 2 and 3 were debonded, and adhesive removal from the bracket bases was done by means of sandblasting and Er YAG laser, respectively. After rebonding, teeth in each group were stained with 2% methylene blue for 24 hours, sectioned and examined under a stereomicroscope. Marginal microleakage at the adhesive-enamel and bracket-adhesive interfaces in the occlusal and gingival margins was determined. Statistical analysis was done using the Kruskal-Wallis test. RESULTS: Comparison of the microleakage scores among the three groups revealed no statistically significant difference (P > 0.05). At the enamel-adhesive interface, the gingival margins in all groups showed higher microleakage while in the adhesive-bracket interface, the occlusal margin exhibited greater microleakage. CONCLUSION: Er-YAG laser irradiation and sandblasting for adhesive removal from the debonded brackets yielded clinically acceptable microleakage scores. PMID- 26056522 TI - Fracture Resistance of Simulated Immature Teeth Obturated with Gutta-Percha or Resilon and Reinforced by Composite or Post. AB - OBJECTIVES: The purpose of this ex- vivo study was to evaluate the fracture resistance of simulated immature teeth, obturated with Gutta-percha or Resilon and reinforced by either composite resin or fiber post. MATERIALS AND METHODS: Eighty-four human maxillary incisors were divided into seven groups (n=12). Teeth in all groups were prepared until Peeso #5 (1.5mm) could be passed through the apex. Root ends received 4mm of MTA plug as an apical barrier. Groups received the followings: 1.Gutta-percha, 2.Resilon, 3.Gutta-percha + composite resin, 4.Resilon + composite resin, 5.Gutta-percha + fiber post, 6.Resilon + fiber post and 7.No obturation (control group). Access openings were filled with composite resin. Specimens were then subjected to oblique load using Instron Testing Machine. The mean peak load at fracture was recorded and analyzed using ANOVA. RESULTS: Experimental groups had a significantly more fracture resistance than the control group (P< 0.05). No significant difference was seen between experimental groups. Teeth reinforced by fiber post showed favorable fracture resistance. CONCLUSION: Treatment plans used in this study increase the fracture resistance of immature teeth. Use of fiber posts in immature teeth, may be the most favorable clinically applicable technique. PMID- 26056523 TI - Effect of Bacterial Lipopolysaccharide Contamination on Gutta Percha- versus Resilon-Induced Human Monocyte Cell Line Toxicity. AB - OBJECTIVES: Cytotoxic effects of obturation materials were tested in presence and absence of endotoxin on human monocytes in vitro. MATERIALS AND METHODS: Human monocytes from THP-1 cell line were cultured. Three millimeters from the tip of each Resilon and gutta percha points were cut and directly placed at the bottom of the culture wells. Cultured cells were exposed to gutta percha (groups G1 and G2) and Resilon (R1 and R2). Ten MUg/ml bacterial lipopolysaccharide (LPS) was added to the culture wells in groups G1 and R1. Positive control included the bacterial LPS without the root canal filling material and the negative control contained the cells in culture medium only. Viability of cells was tested in all groups after 24, 48, and 72 hours using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay for at least 3 times to obtain reproducible results. Optical density values were read and the data were analyzed using three-way ANOVA and post hoc statistical test. RESULTS: The results showed that cells in G2 had the lowest rate of viability at 24 hours, but the lowest rate of viable cells was recorded in G1 at 48 and 72 hours. The effect of LPS treatment was not statistically significant. Resilon groups showed cell viability values higher than those of gutta percha groups, although statistically non-significant (P=0.105). Cell viability values were lower in gutta percha than Resilon groups when LPS-treated and LPS-untreated groups were compared independently at each time point. CONCLUSION: It could be concluded that none of the tested root canal filling materials had toxic effects on cultured human monocyte cells whether in presence or absence of LPS contamination. PMID- 26056524 TI - Effect of Extension and Type of Composite-Restored Class II Cavities on Biomechanical Properties of Teeth: A Three Dimensional Finite Element Analysis. AB - OBJECTIVES: Controversy exists regarding cavity preparation for restoration of interproximal caries in posterior teeth in terms of preserving the tooth structure and suitable stress distribution. This study aimed to assess the effect of extension and type of class II cavities and the remaining tooth structure in maxillary premolars restored with composite resin on the biomechanical properties of teeth using finite element method (FEM). MATERIALS AND METHODS: Using FEM, eight three-dimensional (3D) models of class II cavities in maxillary premolars with variable mesiodistal (MD) dimensions, variable thickness of the residual wall in-between the mesial and distal cavities and different locations of the wall were designed. Other dimensions were the same in all models. Cavities were restored with composite resin. A load equal to the masticatory force (200N) was applied to the teeth. Finite element analysis (FEA) was used to calculate the von Mises stress. RESULTS: Stress in the enamel margin increased by increasing the MD dimensions of the cavities. Deviation of the residual wall between the mesial and distal cavities from the tooth center was found to be an important factor in increasing stress concentration in the enamel. Increasing the MD dimensions of the cavity did not cause any increase in stress concentration in dentin. CONCLUSION: Increasing the MD dimensions of the cavities, decreasing the thickness of the residual wall between the mesial and distal cavities and its deviation from the tooth center can increase stress concentration in the enamel but not in dentin. PMID- 26056525 TI - Effect of Periodontal Dressing on Wound Healing and Patient Satisfaction Following Periodontal Flap Surgery. AB - OBJECTIVES: It has been claimed that periodontal dressing reduces the risk of wound infection, bleeding and granulation tissue formation and improves tissue healing. This study sought to assess the effect of periodontal dressing on wound healing and patient satisfaction following periodontal flap surgery. MATERIALS AND METHODS: This clinical trial was conducted on 33 patients presenting to Hamadan University, School of Dentistry in 2012 whose treatment plan included two periodontal surgical procedures on both quadrants of the maxilla or mandible. The variables evaluated were severity of pain, bleeding, facial swelling and ease of nutrition experienced by patient during the first 3 days after surgery and inflammation, granulation tissue formation and gingival color at 7 and 14 days. Obtained data were analyzed using SPSS version 16.0 and R software and chi-square and t-tests. RESULTS: The mean (+/-SD) pain score was 1.73+/-1.153 and 2.79+/ 1.933 in surgical sites with and without periodontal dressing, respectively and this difference was statistically significant (P=0.005). No significant difference was noted between sites with and without periodontal dressing in terms of swelling, bleeding, gingival consistency, granulation tissue formation, gingival color and ease of nutrition (P>0.05). CONCLUSION: According to the results of the present study, patients did not experience more bleeding, facial swelling or nutritional problems without periodontal dressing; however, the level of pain experienced was lower after surgeries with the use of periodontal dressing. PMID- 26056526 TI - Nonsyndromic Synchronous Multifocal Central Giant Cell Granulomas of the Maxillofacial Region: Report of a Case. AB - Central giant cell granuloma (CGCG) is a benign proliferation of fibroblasts and multinucleated giant cells that almost exclusively occurs in the jaws. It commonly occurs in young adults showing a female predilection in the anterior mandible. Multifocal CGCGs in maxillofacial region are very rare and suggestive of systemic diseases such as hyperparathyroidism, an inherited syndrome such as Noonan-like multiple giant cell lesion syndrome or other disorders. Only 10 cases of multifocal CGCGs in the maxillofacial region without any concomitant systemic disease have been reported in the English literature. Here, we report an unusual case of 36 year-old female presented with non-syndromic synchronous, multifocal CGCGs in the left posterior mandible and left posterior maxilla without any concomitant systemic disease. Relevant literature is reviewed and the incidence, clinical features, radiological features, differential diagnosis and management of CGCGs are discussed. PMID- 26056527 TI - Scoliosis Research Society members attitudes towards physical therapy and physiotherapeutic scoliosis specific exercises for adolescent idiopathic scoliosis. AB - BACKGROUND: Attitudes regarding non-operative treatment for adolescent idiopathic scoliosis (AIS) may be changing with the publication of BRAiST. Physiotherapeutic Scoliosis Specific Exercises (PSSE) are used to treat AIS, but high-quality evidence is limited. The purpose of this study is to assess the attitudes of members of the Scoliosis Research Society towards PSSE. METHODS: A survey was sent to all SRS members with questions on use of Physical Therapy (PT) and PSSE for AIS. RESULTS: The majority of the 263 respondents were from North America (175, 67 %), followed by Asia (37, 14 %) and Europe (36, 14 %). The majority of respondents (166, 63 %) prescribed neither PT nor PSSE, 28 (11 %) prescribed both PT and PSSE, 39 (15 %) prescribe PT only and 30 (11 %) prescribe PSSE only. PT was prescribed by 67 respondents, as an adjunct to bracing (39) and in small curves (32); with goals to improve aesthetics (27) and post-operative outcomes (25). Of the 196 who do not prescribe PT, the main reasons were lack of evidence (149) and the perception that PT had no value (112). PSSE was prescribed by 58 respondents. The most common indication was as an adjunct to bracing (49) or small curves (41); with goals to improve aesthetics (36), prevent curve progression (35) and improve quality of life (31). Of the respondents who do not prescribe PSSE, the main reasons were lack of supporting research (149), a perception that PSSE had no value (108), and lack of access (63). Most respondents state that evidence of efficacy may increase the role of PSSE, with 85 % (223 of 263) favoring funding PSSE studies by the SRS. CONCLUSION: The results show that 22 % of the respondents use PSSE for AIS, skepticism remains regarding the benefit of PSSE for AIS. Support for SRS funded research suggests belief that there is potential benefit from PSSE and the best way to assess that potential is through evidence development. PMID- 26056528 TI - Adolescent idiopathic scoliosis and spinal fusion do not substantially impact on postural balance. AB - BACKGROUND: The spinal curvature in patients with Adolescent Idiopathic Scoliosis (AIS) causes an asymmetry of upper body postural alignment, which might affect postural balance. However, the currently available studies on balance in AIS patients are not consistent. Furthermore, it is not known whether potential deficits are similar between patients with single and double curves. Finally, the effects of a corrective posterior spinal fusion on postural balance have not yet been well established. METHODS: Postural balance was tested on a force plate, in 26 female subjects with AIS (12-18 years old; preoperative Cobb-angle: 42-71 degrees ; single curve n = 18, double curve n = 6) preoperatively, at 3 months and 1 year postoperatively. We also conducted a balance assessment in 18 healthy age-matched female subjects. Subjects were tested during quiet double-leg standing in four conditions (eyes open/closed; foam/solid surface), while standing on one leg, while performing a dynamic balance (weight shifting) task and while performing a reaching task in four directions. RESULTS: AIS subjects did not demonstrate greater COP velocities than controls during the double-leg standing tasks. In the reaching task, however, they achieved smaller COP displacements than healthy controls, except in the anterior direction. AIS patients with double curves had significantly greater COP velocities in all test conditions compared to those with a single curve (p < 0.05). For the AIS group, a slight increase in COP velocities was observed in the foam eyes closed and right leg standing condition at 3 months post surgery. At 1-year post surgery, however, there were no significant differences in any of the outcome measures compared to the pre-surgery assessment, irrespective of the curve type. CONCLUSIONS: Postural balance in AIS patients scheduled for surgery was similar to healthy age matched controls, except for a poorer reaching capacity. The latter finding may be related to their reduced range of motion of the spine. Patients with double curves demonstrated poorer balance than those with a single curve, despite the fact that they have a more symmetrical trunk posture. Postural balance one year after surgery did not improve as a result of the better spinal alignment, neither did the reduced range of trunk motion inherent to fusion negatively affect postural balance. PMID- 26056529 TI - Laparoscopic surgery in abdominal trauma: a single center review of a 7-year experience. AB - INTRODUCTION: Laparoscopic surgery has greatly improved surgical outcome in many areas of abdominal surgery. But many concerns of safety have limited its application in abdominal trauma. We hypothesized that laparoscopy could be safe and efficacious in treatment of patients with abdominal trauma, and reduce the laparotomy related complications (i.e. wound infection, pain, or long hospital stay) as avoiding unnecessary laparotomy. METHODS: From January 2006 to August 2012, a total of 111 patients underwent emergent surgical exploration (laparoscopic, 41; open laparotomy, 70) in Andong General Hospital. Of the 41 patients subjected to laparoscopy, 30 patients had suffered blunt trauma, the remaining 11 patients had sustained penetrating trauma. 31 patients were treated exclusively by laparoscopy and 10 patients underwent laparoscopy-assisted surgery. RESULTS: The conversion rate was 18%. Major complication was none without postoperative mortality. Comparing laparoscopic surgery with open laparotomy, lesser wound infection, early gas passage, and shorter hospital stay. Otherwise operative times were similar, and neither approach was complicated by missed injury or postoperative intra-abdominal abscess. CONCLUSIONS: Laparoscopic surgery can be performed safely whether injuries are blunt or penetrating, given hemodynamic stability and proper technique. Patients may thus benefit from the shorter hospital stays, greater postoperative comfort (less pain), quicker recoveries, and low morbidity/mortality rates that laparoscopy affords. PMID- 26056530 TI - The duration of intra-abdominal hypertension strongly predicts outcomes for the critically ill surgical patients: a prospective observational study. AB - INTRODUCTION: Intra-abdominal hypertension (IAH) is associated with morbidity and mortality in critically ill patients. The present study analyzed the clinical significance of IAH in surgical patients with severe sepsis. METHODS: This was a prospective study carried out in the surgical intensive care unit (SICU). Intra abdominal pressure (IAP) was measured three times a day via a urinary catheter filled with 25 mL of saline. IAH was defined as an IAP >= 12 mmHg, and the peak IAP was recorded as the IAP for the day. Data were analyzed in terms of IAH development and the IAH duration. RESULTS: Of the 46 patients enrolled in the study, 42 developed IAH while in the SICU. The development of IAH aggravated the clinical outcomes; such as longer SICU stay, requirement of ventilator support, and delayed initiation of enteral feeding (EF). The IAH duration showed a significant correlation with pulmonary, renal, and cardiovascular function, and enteral feeding. The IAH duration was an independent predictor of 60-day mortality (odds ratio: 1.196; p = 0.014). CONCLUSIONS: The duration of IAH is a more important prognostic factor than the development of IAH; thus every effort should be made to reduce the IAH duration in critically ill patients. TRIAL REGISTRATION: NCT01784458. PMID- 26056531 TI - Health status and health needs of older refugees from Syria in Lebanon. AB - BACKGROUND: The flight of Syrian and Palestinian families into Lebanon from Syria included a number of older refugees. This study sought to characterize the physical and emotional conditions, dietary habits, coping practices, and living conditions of this elderly population arriving in Lebanon between March 2011 and March 2013. METHODS: A systematic selection of 210 older refugees from Syria was drawn from a listing of 1800 refugees over age 60 receiving assistance from the Caritas Lebanon Migrant Center (CLMC) or the Palestinian Women's Humanitarian Organization (PALWHO). CLMC and PALWHO social workers collected qualitative and quantitative information during 2013. RESULTS: Two-thirds of older refugees described their health status as poor or very poor. Most reported at least one non-communicable disease, with 60% having hypertension, 47% reporting diabetes, and 30% indicating some form of heart disease. Difficulties in affording medicines were reported by 87%. Physicial limitations were common: 47% reported difficulty walking and 24% reported vision loss. About 10% were physically unable to leave their homes and 4% were bedridden. Most required medical aids such as walking canes and eyeglasses. Diet was inadequate with older refugees reporting regularly reducing portion sizes, skipping meals, and limiting intake of fruits, vegetables, and meats. Often this was done to provide more food to younger family members. Some 61% of refugees reported feeling anxious, and significant proportions of older persons reported feelings of depression, loneliness, and believing they were a burden to their families. 74% of older refugees indicated varying degrees of dependency on humanitarian assistance. CONCLUSION: The study concluded older refugees from Syria are a highly vulnerable population needing health surveillance and targeted assistance. Programs assisting vulnerable populations may concentrate services on women and children leaving the elderly overlooked. PMID- 26056532 TI - Analyzing Katana referral hospital as a complex adaptive system: agents, interactions and adaptation to a changing environment. AB - This study deals with the adaptation of Katana referral hospital in Eastern Democratic Republic of Congo in a changing environment that is affected for more than a decade by intermittent armed conflicts. His objective is to generate theoretical proposals for addressing differently the analysis of hospitals governance in the aims to assess their performance and how to improve that performance. The methodology applied approach uses a case study using mixed methods ( qualitative and quantitative) for data collection. It uses (1) hospital data to measure the output of hospitals, (2) literature review to identify among others, events and interventions recorded in the history of hospital during the study period and (3) information from individual interviews to validate the interpretation of the results of the previous two sources of data and understand the responsiveness of management team referral hospital during times of change. The study brings four theoretical propositions: (1) Interaction between key agents is a positive force driving adaptation if the actors share a same vision, (2) The strength of the interaction between agents is largely based on the nature of institutional arrangements, which in turn are shaped by the actors themselves, (3) The owner and the management team play a decisive role in the implementation of effective institutional arrangements and establishment of positive interactions between agents, (4) The analysis of recipient population's perception of health services provided allow to better tailor and adapt the health services offer to the population's needs and expectations. Research shows that it isn't enough just to provide support (financial and technical), to manage a hospital for operate and adapt to a changing environment but must still animate, considering that it is a complex adaptive system and that this animation is nothing other than the induction of a positive interaction between agents. PMID- 26056533 TI - Development of Agave as a dedicated biomass source: production of biofuels from whole plants. AB - BACKGROUND: Agave species can grow well in semi-arid marginal agricultural lands around the world. Selected Agave species are used largely for alcoholic beverage production in Mexico. There are expanding research efforts to use the plentiful residues (bagasse) for ethanol production as the beverage manufacturing process only uses the juice from the central core of mature plants. Here, we investigate the potential of over a dozen Agave species, including three from cold semi-arid regions of the United States, to produce biofuels using the whole plant. RESULTS: Ethanol was readily produced by Saccharomyces cerevisiae from hydrolysate of ten whole Agaves with the use of a proper blend of biomass degrading enzymes including inulinase that overcomes inhibition of most of the species tested. As an example, US grown Agave neomexicana produced 119 +/- 11 mg ethanol/g biomass. Unlike yeast fermentations, Clostridium beijerinckii produced n-butanol plus acetone from all species tested. Butyric acid, a precursor of n-butanol, was also present due to incomplete conversion during the screening process. Since Agave contains high levels of free and polyfructose which are readily destroyed by acidic pretreatment, a two-step procedure was developed to depolymerize polyfructose while maintaining its fermentability. The hydrolysate from before and after dilute acid processing was used in C. beijerinckii fermentations with selected Agave species with A. neomexicana producing 144 +/- 4 mg fermentation products/g biomass. CONCLUSIONS: Results showed Agave's potential to be a source of fermentable sugars beyond the existing beverage species to now include many species previously unfermentable by yeast, including cold-tolerant lines. This development should stimulate development of Agave as a dedicated feedstock for biofuels in semi-arid regions throughout the globe. PMID- 26056534 TI - Enhancement of photosynthetic capacity in Euglena gracilis by expression of cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphosphatase leads to increases in biomass and wax ester production. AB - BACKGROUND: Microalgae have recently been attracting attention as a potential platform for the production of biofuels. Euglena gracilis, a unicellular phytoflagellate, has been proposed as an attractive feedstock to produce biodiesel because it can produce large amounts of wax esters, consisting of medium-chain fatty acids and alcohols with 14:0 carbon chains. E. gracilis cells highly accumulate a storage polysaccharide, a beta-1,3-glucan known as paramylon, under aerobic conditions. When grown aerobically and then transferred into anaerobic conditions, E. gracilis cells degrade paramylon to actively synthesize and accumulate wax esters. Thus, the enhanced accumulation of paramylon through the genetic engineering of photosynthesis should increase the capacity for wax ester production. RESULTS: We herein generated transgenic Euglena (EpFS) cells expressing the cyanobacterial fructose-1,6-/sedoheptulose-1,7-bisphosphatase (FBP/SBPase), which is involved in the Calvin cycle, to enhance its photosynthetic activity. FBP/SBPase was successfully expressed within Euglena chloroplasts. The cell volume of the EpFS4 cell line was significantly larger than that of wild-type cells under normal growth conditions. The photosynthetic activity of EpFS4 cells was significantly higher than that of wild type under high light and high CO2, resulting in enhanced biomass production, and the accumulation of paramylon was increased in transgenic cell lines than in wild type cells. Furthermore, when EpFS cell lines grown under high light and high CO2 were placed on anaerobiosis, the productivity of wax esters was approximately 13- to 100-fold higher in EpFS cell lines than in wild-type cells. CONCLUSION: Our results obtained here indicate that the efficiency of biomass production in E. gracilis can be improved by genetically modulating photosynthetic capacity, resulting in the enhanced production of wax esters. This is the first step toward the utilization of E. gracilis as a sustainable source for biofuel production under photoautotrophic cultivation. PMID- 26056535 TI - Microvascular reactivity in women with gestational diabetes mellitus studied during pregnancy. AB - AIM: To compare microvascular reactivity assessed in the skin using laser Doppler fluximetry (LDF) in women with gestational diabetes mellitus (GDM) and gestational age-matched control during pregnancy. METHODS: 110 pregnant women at ~33 weeks gestation participated in the study. Skin microvascular reactivity was evaluated by LDF, at rest, during the response to brief arterial occlusion (post occlusive hyperaemic response) and during sympathetically mediated vasoconstrictor response to deep inspiratory breath hold. RESULTS: No statistically significant differences were found in the microvascular variables studied (resting and maximum rate flux, post-ischaemic reactive hyperaemia and deep inspiratory breath holds) between +GDM and -GDM groups women. In women with GDM there was a negative correlation between resting flux and the response to the oral glucose tolerance test (OGTT), r = -0.282 (p = 0.037). There was also a negative correlation between the response to the OGTT and the sympathetically mediated constrictor response to inspiratory breath holds (r = -.298, p = .030) but not in women with GDM (r = .102, r = .468). CONCLUSION: Attenuated microvascular reactivity as an early marker of endothelial dysfunction is not present in women with GDM when assessed during pregnancy. PMID- 26056536 TI - Association of HSD11B1 polymorphic variants and adipose tissue gene expression with metabolic syndrome, obesity and type 2 diabetes mellitus: a systematic review. AB - The HSD11B1 gene is highly expressed in abdominal adipose tissue, and the enzyme it encodes catalyzes the interconversion of inactive cortisone to hormonally active cortisol. Genetic abnormalities of HSD11B1 have been associated with the development of abnormal glucose metabolism and body fat distribution. To systematically review studies evaluating the association of HSD11B1 gene expression in abdominal adipose tissue and HSD11B1 polymorphisms with obesity, the metabolic syndrome (MetS), and type 2 diabetes (T2DM), we conducted a search in MEDLINE, SCOPUS, and Cochrane Library databases in April 2015. The inclusion criteria were observational studies (cross-sectional, cohort, or case-control), conducted in adults, which analyzed the relationship of HSD11B1 polymorphisms and/or HSD11B1 expression in abdominal adipose tissue with obesity, MetS, or T2DM. Of 802 studies retrieved, 32 met the inclusion criteria (23 gene expression and 9 polymorphism studies). Twenty one studies analyzed the relationship between abdominal subcutaneous and/or visceral HSD11B1 expression with central and/or generalized obesity. Most studies reported that abdominal adipose HSD11B1 expression increased with increasing body mass index (15 studies) and abnormalities of glucose metabolism (7 studies), and varied with the presence of MetS (3 studies). Nine studies analyzed the association of 26 different HSD11B1 polymorphic variants with obesity, MetS, and T2DM. Only an Indian study found an association between a polymorphic variant at the HSD11B1 gene with MetS whereas in Pima Indians another polymorphic variant was found to be associated with T2DM. While the literature suggests that HSD11B1 is hyperexpressed in abdominal adipose tissue in subjects with obesity and abnormal glucose metabolism, this seems to be not true for HSD11B1 gene expression and MetS. Although an association of polymorphic variants of HSD11B1 with MetS in Indians and in the T2DM population of Pima Indians were found, most studies did not find a relationship between genetic polymorphic variants of HSD11B1 and obesity, MetS, and T2DM. Their reported conflicting and inconclusive results, suggesting that polymorphic variants of HSD11B1 may have only a small role in the development of metabolic abnormalities of susceptible populations in the development of MetS and T2DM. PMID- 26056537 TI - Advances in clinical studies of cardiopulmonary resuscitation. AB - BACKGROUND: The survival rate of patients after cardiac arrest (CA) remains lower since 2010 International Consensus on Cardiopulmonary Resuscitation (CPR) and Emergency Cardiovascular Care (ECC) was published. In clinical trials, the methods and techniques for CPR have been overly described. This article gives an overview of the progress in methods and techniques for CPR in the past years. DATA SOURCES: Original articles about cardiac arrest and CPR from MEDLINE (PubMed) and relevant journals were searched, and most of them were clinical randomized controlled trials (RCTs). RESULTS: Forty-two articles on methods and techniques of CPR were reviewed, including chest compression and conventional CPR, chest compression depth and speed, defibrillation strategies and priority, mechanical and manual chest compression, advanced airway management, impedance threshold device (ITD) and active compression-decompression (ACD) CPR, epinephrine use, and therapeutic hypothermia. The results of studies and related issues described in the international guidelines had been testified. CONCLUSIONS: Although large multicenter studies on CPR are still difficult to carry out, progress has been made in the past 4 years in the methods and techniques of CPR. The results of this review provide evidences for updating the 2015 international guidelines. PMID- 26056538 TI - The reliability of the Australasian Triage Scale: a meta-analysis. AB - BACKGROUND: Although the Australasian Triage Scale (ATS) has been developed two decades ago, its reliability has not been defined; therefore, we present a meta analyis of the reliability of the ATS in order to reveal to what extent the ATS is reliable. DATA SOURCES: Electronic databases were searched to March 2014. The included studies were those that reported samples size, reliability coefficients, and adequate description of the ATS reliability assessment. The guidelines for reporting reliability and agreement studies (GRRAS) were used. Two reviewers independently examined abstracts and extracted data. The effect size was obtained by the z-transformation of reliability coefficients. Data were pooled with random effects models, and meta-regression was done based on the method of moment's estimator. RESULTS: Six studies were included in this study at last. Pooled coefficient for the ATS was substantial 0.428 (95%CI 0.340-0.509). The rate of mis-triage was less than fifty percent. The agreement upon the adult version is higher than the pediatric version. CONCLUSION: The ATS has shown an acceptable level of overall reliability in the emergency department, but it needs more development to reach an almost perfect agreement. PMID- 26056539 TI - Progress in research into the genes associated with venous thromboembolism. AB - BACKGROUND: Venous thromboembolism (VTE), including both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, lethal disorder that affects hospitalized and non-hospitalized patients. This study aimed to review the progress in the research into VTE. DATA SOURCES: We reviewed the studies about VTE and verified different genetic polymoriphisms of VTE. RESULTS: The pathogenesis of VTE involves hereditary and acquired factors. Many studies indicated that the disorder of coagulation and fibirnolytic system is of utmost importance to this disease. Genetic polymoriphism-related VTE demonstrated significant differences among geographies and ethnicities. CONCLUSION: VTE has many risk factors, but genetic factors play an important role. PMID- 26056540 TI - Association of low non-invasive near-infrared spectroscopic measurements during initial trauma resuscitation with future development of multiple organ dysfunction. AB - BACKGROUND: Near-infrared spectroscopy (NIRS) non-invasively monitors muscle tissue oxygen saturation (StO2). It may provide a continuous noninvasive measurement to identify occult hypoperfusion, guide resuscitation, and predict the development of multiple organ dysfunction (MOD) after severe trauma. We evaluated the correlation between initial StO2 and the development of MOD in multi-trauma patients. METHODS: Patients presenting to our urban, academic, Level I Trauma Center/Emergency Department and meeting standardized trauma-team activation criteria were enrolled in this prospective trial. NIRS monitoring was initiated immediately on arrival with collection of StO2 at the thenar eminence and continued up to 24 hours for those admitted to the Trauma Intensive Care Unit (TICU). Standardized resuscitation laboratory measures and clinical evaluation tools were collected. The primary outcome was the association between initial StO2 and the development of MOD within the first 24 hours based on a MOD score of 6 or greater. Descriptive statistical analyses were performed; numeric means, multivariate regression and rank sum comparisons were utilized. Clinicians were blinded from the StO2 values. RESULTS: Over a 14 month period, 78 patients were enrolled. Mean age was 40.9 years (SD 18.2), 84.4% were male, 76.9% had a blunt trauma mechanism and mean injury severity score (ISS) was 18.5 (SD 12.9). Of the 78 patients, 26 (33.3%) developed MOD within the first 24 hours. The MOD patients had mean initial StO2 values of 53.3 (SD 10.3), significantly lower than those of non-MOD patients 61.1 (SD 10.0); P=0.002. The mean ISS among MOD patients was 29.9 (SD 11.5), significantly higher than that of non-MODS patients, 12.1 (SD 9.1) (P<0.0001). The mean shock index (SI) among MOD patients was 0.92 (SD 0.28), also significantly higher than that of non-MODS patients, 0.73 (SD 0.19) (P=0.0007). Lactate values were not significantly different between groups. CONCLUSION: Non-invasive, continuous StO2 near-infrared spectroscopy values during initial trauma resuscitation correlate with the later development of multiple organ dysfunction in this patient population. PMID- 26056541 TI - Emergency physician's perception of cultural and linguistic barriers in immigrant care: results of a multiple-choice questionnaire in a large Italian urban emergency department. AB - BACKGROUND: A poor communication with immigrants can lead to inappropriate use of healthcare services, greater risk of misdiagnosis, and lower compliance with treatment. As precise information about communication between emergency physicians (EPs) and immigrants is lacking, we analyzed difficulties in communicating with immigrants in the emergency department (ED) and their possible associations with demographic data, geographical origin and clinical characteristics. METHODS: In an ED with approximately 85 000 visits per year, a multiple-choice questionnaire was given to the EPs 4 months after discharge of each immigrant in 2011. RESULTS: Linguistic comprehension was optimal or partial in the majority of patients. Significant barriers were noted in nearly one fourth of patients, for only half of them compatriots who were able to translate. Linguistic barriers were mainly found in older and sicker patients; they were also frequently seen in patients coming from western Africa and southern Europe. Non-linguistic barriers were perceived by EPs in a minority of patients, more frequently in the elderly and frequent attenders. Factors independently associated with a poor final comprehension led to linguistic barriers, non linguistic obstacles, the absence of intermediaries, and the presence of patient's fear and hostility. The latter probably is a consequence, not the cause, of a poor comprehension. CONCLUSION: Linguistic and non-linguistic barriers, although quite infrequent, are the main factors that compromise communication with immigrants in the ED, with negative effects especially on elderly and more seriously ill patients as well as on physician satisfaction and appropriateness in using services. PMID- 26056542 TI - Assessment of knowledge and attitude about basic life support among dental interns and postgraduate students in Bangalore city, India. AB - BACKGROUND: Life-threatening emergencies can occur at anytime, at anywhere and in anyone. Effective management of an emergency situation in the dental office is ultimately the dentist's responsibility. The lack of training and inability to cope with medical emergencies can lead to tragic consequences and sometimes legal complications. Therefore, health professionals including dentists must be well prepared to deal with medical emergencies. This study was undertaken to assess the knowledge about and attitude towards basic life support (BLS) among dental interns and postgraduate students in Bangalore city, India. METHODS: A cross sectional survey was conducted among dental interns and postgraduate students from May 2014 to June 2014 since few studies have been conducted in Bangalore city. A questionnaire with 17 questions regarding the knowledge about and attitude towards BLS was distributed to 202 study participants. RESULTS: The data analyzed using the Chi-square test showed that dental interns and postgraduate students had average knowledge about BLS. In the 201 participants, 121 (59.9%) had a positive attitude and 81 (40.1%) had a negative attitude towards BLS. CONCLUSIONS: Cardiopulmonary resuscitation should be considered as part of the dental curriculum. Workshops on a regular basis should be focused on skills of cardiopulmonary resuscitation for dental students. PMID- 26056543 TI - Relationships between genetic polymorphisms of triggering receptor expressed on myeloid cells-1 and septic shock in a Chinese Han population. AB - BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a cell surface receptor expressed on neutrophils and monocytes. TREM-1 acts to amplify inflammation and serves as a critical mediator of inflammatory response in the context of sepsis. To date, the predisposition of TREM-1 gene polymorphisms to septic shock has not been reported. This study was designed to investigate whether TREM-1 genomic variations are associated with the development of septic shock. METHODS: We genotyped two TREM-1 single nucleotide polymorphisms (SNPs, rs2234237 and rs2234246) and evaluated the relationships between these SNPs and septic shock on susceptibility and prognosis. RESULTS: TREM-1 rs2234246 A allele in the promoter region was significantly associated with the susceptibility of septic shock in recessive model (AA, OR=3.10, 95%CI 1.15 to 8.32, P=0.02), and in codominant model (AG, OR=0.72, 95%CI 0.43-1.19, P=0.02; AA, OR=2.71, 95%CI 1.00 7.42; P=0.03). However, in three inherited models (dominant model, recessive model, and codominant model), none of the assayed loci was significantly associated with the prognosis of septic shock. The non-survivor group demonstrated higher plasma IL-6 levels (99.7+/-34.7 pg/mL vs. 61.2+/-26.5 pg/mL, P<0.01) than the survivor group. Plasma concentrations of IL-6 among the three genotypes of rs2234246 were AA 99.4+/-48.9 pg/mL, AG 85.4+/-43 pg/mL, and GG 65.3+/-30.7 pg/mL (P<0.01). The plasma concentrations of IL-6 in patients with AA genotypes were significantly higher than those in patients with GG genotypes (P<0.01). CONCLUSION: TREM-1 genetic polymorphisms rs2234246 may be significantly correlated only with susceptibility to septic shock in the Chinese Han population. PMID- 26056544 TI - B-type natriuretic peptide in predicting the severity of community-acquired pneumonia. AB - BACKGROUND: Although pneumonia severity index (PSI) is widely used to evaluate the severity of community-acquired pneumonia (CAP), the calculation of PSI is very complicated. The present study aimed to evaluate the role of B-type natriuretic peptide (BNP) in predicting the severity of CAP. METHODS: For 202 patients with CAP admitted to the emergency department, BNP levels, cardiac load indexes, inflammatory indexes including C-reactive protein (CRP), white blood cell count (WBC), and PSI were detected. The correlation between the indexes and PSI was investigated. BNP levels for survivor and non-survivor groups were compared, and a receiver operating characteristic (ROC) curve analysis was performed on the BNP levels versus PSI. RESULTS: The BNP levels increased with CAP severity (r=0.782, P<0.001). The BNP levels of the high-risk group (PSI classes IV and V) were significantly higher than those of the low-risk group (PSI classes I-III) (P<0.001). The BNP levels were significantly higher in the non survivor group than in the survivor group (P<0.001). In addition, there were positive correlations between BNP levels and PSI scores (r=0.782, P<0.001). The BNP level was highly accurate in predicting the severity of CAP (AUC=0.952). The optimal cut-off point of BNP level for distinguishing high-risk patients from low risk ones was 125.0 pg/mL, with a sensitivity of 0.891 and a specificity of 0.946. Moreover, BNP level was accurate in predicting mortality (AUC=0.823). Its optimal cut-off point for predicting death was 299.0 pg/mL, with a sensitivity of 0.675 and a specificity of 0.816. Its negative predictive cut-off value was 0.926, and the positive predictive cut-off value was 0.426. CONCLUSION: BNP level is positively correlated with the severity of CAP, and may be used as a biomarker for evaluating the severity of CAP. PMID- 26056545 TI - Noninvasive monitoring of intra-abdominal pressure by measuring abdominal wall tension. AB - BACKGROUND: Noninvasive monitoring of intra-abdominal pressure (IAP) by measuring abdominal wall tension (AWT) was effective and feasible in previous postmortem and animal studies. This study aimed to investigate the feasibility of the AWT method for noninvasively monitoring IAP in the intensive care unit (ICU). METHODS: In this prospective study, we observed patients with detained urethral catheters in the ICU of Shanghai Tenth People's Hospital between April 2011 and March 2013. The correlation between AWT and urinary bladder pressure (UBP) was analyzed by linear regression analysis. The effects of respiratory and body position on AWT were evaluated using the paired samples t test, whereas the effects of gender and body mass index (BMI) on baseline AWT (IAP<12 mmHg) were assessed using one-way analysis of variance. RESULTS: A total of 51 patients were studied. A significant linear correlation was observed between AWT and UBP (R=0.986, P<0.01); the regression equation was Y=-1.369+9.57X (P<0.01). There were significant differences among the different respiratory phases and body positions (P<0.01). However, gender and BMI had no significant effects on baseline AWT (P=0.457 and 0.313, respectively). CONCLUSIONS: There was a significant linear correlation between AWT and UBP and respiratory phase, whereas body position had significant effects on AWT but gender and BMI did not. Therefore, AWT could serve as a simple, rapid, accurate, and important method to monitor IAP in critically ill patients. PMID- 26056546 TI - Efficacy of fascia iliaca compartment nerve block as part of multimodal analgesia after surgery for femoral bone fracture. AB - BACKGROUND: Fascia iliaca compartment nerve block (FICNB) has been an established technique for postoperative analgesia after surgery for femoral bone fracture. FICNB is technically easy, effective for postoperative pain control after operation for femoral bone fracture and decreases the complications induced by systemic analgesic drugs. The severity of postoperative pain is affected by genetics, cultural and social factors across the world. In this study we assessed the efficacy of fascia iliaca compartment nerve block when it is used as part of multimodal analgesia after surgery for femoral bone fracture. METHODS: An institution-based case control study was conducted from September, 2013 to May, 2014. All patients who had been operated on under spinal anesthesia for femoral bone fracture were included. The patients divided into a FICNB group (n=20) and a control group (n=20). The FICNB group was given 30 mL of 0.25% bupivacaine at the end of the operation. Postoperative pain was assessed within the first 24 hours, i.e. at 15 minutes, 2 hours, 6 hours, 12 hours and 24 hours using 100 mm visual analogue scale (VAS), total analgesic consumption, and the time for the first analgesic request. RESULTS: VAS pain scores were reduced within the first 24 hours after operation in the FICNB group compared wtih the control group. VAS scores at 2 hours were taken as median values (IQR) 0.00 (0.00) vs.18.00 (30.00), P=0.001; at 6 hours 0.00 (0.00) vs. 34.00 (20.75), P=0.000; at 24 hours 12.50 (10.00) vs. 31.50 (20.75), P=0.004; and at 12 hours (17.80+/-12.45) vs. (29.95+/ 12.40), P=0.004, respectively. The total analgesic consumption of diclofenac at 12 and 24 hours was reduced in the FICNB group, and the time for the first analgesic request was significantly prolonged (417.50 vs. 139.25 minutes, P=0.000). CONCLUSIONS: A single injection for FICNB could lead to postoperative pain relief, reduction of total analgesic consumption and prolonged time for the first analgesic request in the FICNB group after surgery for femoral bone fracture. We recommend FICNB for analgesia after surgery for femoral bone fracture and for patients with femoral bone fracture at the emergency department. PMID- 26056547 TI - Effect of sedation on short-term and long-term outcomes of critically ill patients with acute respiratory insufficiency. AB - BACKGROUND: The present study aimed to determine the short-term and long-term outcomes of critically ill patients with acute respiratory insufficiency who had received sedation or no sedation. METHODS: The data of 91 patients who had received mechanical ventilation in the first 24 hours between November 2008 and October 2009 were retrospectively analyzed. These patients were divided into two groups: a sedation group (n=28) and a non-sedation group (n=63). The patients were also grouped in two groups: deep sedation group and daily interruption and /or light sedation group. RESULTS: Overall, the 91 patients who had received ventilation >=48 hours were analyzed. Multivariate analysis demonstrated two independent risk factors for in-hospital death: sequential organ failure assessment score (P=0.019, RR 1.355, 95%CI 1.051-1.747, B=0.304, SE=0.130, Wald=50483) and sedation (P=0.041, RR 5.015, 95%CI 1.072-23.459, B=1.612, SE=0.787, Wald=4.195). Compared with the patients who had received no sedation, those who had received sedation had a longer duration of ventilation, a longer stay in intensive care unit and hospital, and an increased in-hospital mortality rate. The Kaplan-Meier method showed that patients who had received sedation had a lower 60-month survival rate than those who had received no sedation (76.7% vs. 88.9%, Log-rank test=3.630, P=0.057). Compared with the patients who had received deep sedation, those who had received daily interruption or light sedation showed a decreased in-hospital mortality rate (57.1% vs. 9.5%, P=0.008). The 60-month survival of the patients who had received deep sedation was significantly lower than that of those who had daily interruption or light sedation (38.1% vs. 90.5%, Log-rank test=6.783, P=0.009). CONCLUSIONS: Sedation was associated with in hospital death. The patients who had received sedation had a longer duration of ventilation, a longer stay in intensive care unit and in hospital, and an increased in-hospital mortality rate compared with the patients who did not receive sedation. Compared with daily interruption or light sedation, deep sedation increased the in-hospital mortality and decreased the 60-month survival for patients who had received sedation. PMID- 26056548 TI - Thrombolysis during extended cardiopulmonary resuscitation for autoimmune-related pulmonary embolism. AB - BACKGROUND: Massive pulmonary embolism (MPE) and acute myocardial infarction are the two most common causes of cardiac arrest (CA). At present, lethal hemorrhage makes thrombolytic therapy underused during cardiopulmonary resuscitation, despite the potential benefits for these underlying conditions. Hypercoagulability of the blood in autoimmune disorders (such as autoimmune hemolytic anemia) carries a risk of MPE. It is critical to find out the etiology of CA for timely thrombolytic intervention. METHODS: A 23-year-old woman with a 10-year medical history of autoimmune hemolytic anemia suffered from CA in our emergency intensive care unit. ECG and echocardiogram indicated the possibility of MPE, so fibrinolytic therapy (alteplase) was successful during prolonged resuscitation. RESULTS: Neurological recovery of the patient was generally good, and no fatal bleeding developed. MPE was documented by CT pulmonary angiography. CONCLUSIONS: A medical history of autoimmune disease poses a risk of PE, and the causes of CA (such as this) should be investigated etiologically. A therapy with alteplase may be used early during cardiopulmonary resuscitation once there is presumptive evidence of PE. Clinical trials are needed in this setting to study patients with hypercoagulable states. PMID- 26056549 TI - Effects of hydroalcoholic extract of Coriandrum sativum on oxidative damage in pentylenetetrazole-induced seizures in rats. AB - BACKGROUND: An important role for oxidative stress, as a consequence of epileptic seizures, has been suggested. Coriandrum sativum has been shown that have antioxidant effects. Central nervous system depressant effects of C. sativum have also been reported. In this study, the effects of hydroalcoholic extract of aerial parts of the plants on brain tissues oxidative damages following seizures induced by pentylenetetrazole (PTZ) was investigated in rats. METHODS: The rats were divided into five groups and treated: (1) Control (saline), (2) PTZ (90 mg/kg, i.p.), (3-5) three doses (100, 500 and 1000 mg/kg of C. sativum extract (CSE) before PTZ. Latencies to the first minimal clonic seizures (MCS) and the first generalized tonic-clonic seizures (GTCS) were recorded. The cortical and hippocampal tissues were then removed for biochemical measurements. RESULTS: The extract significantly increased the MCS and GTCS latencies (P < 0.01, P < 0.001) following PTZ-induced seizures. The malondialdehyde (MDA) levels in both cortical and hippocampal tissues of PTZ group were significantly higher than those of the control animals (P < 0.001). Pretreatment with the extract prevented elevation of the MDA levels (P < 0.010-P < 0.001). Following PTZ administration, a significant reduction in total thiol groups was observed in both cortical and hippocampal tissues (P < 0.050). Pre-treatment with the 500 mg/kg of the extract caused a significant prevention of decreased in total thiol concentration in the cortical tissues (P < 0.010). CONCLUSION: The present study showed that the hydroalcoholic extract of the aerial parts of C. sativum possess significant antioxidant and anticonvulsant activities. PMID- 26056550 TI - Efficacy of high-dose vitamin D3 supplementation in vitamin D deficient pregnant women with multiple sclerosis: Preliminary findings of a randomized-controlled trial. AB - BACKGROUND: The aim of this preliminary study was to assess the safety and efficacy of high-dose oral vitamin D3 supplementation during pregnancy in women with multiple sclerosis (MS) in Isfahan, Iran. METHODS: In a single center open label randomized, controlled clinical Phase I/II pilot study, 15 pregnant women with confirmed MS with low serum 25-hydroxyvitamin D (25(OH)D) levels were randomly allocated to receive either 50,000 IU/week vitamin D3 or routine care from 12 to 16 weeks of gestation till delivery. The main outcome measures were mean change in serum 25(OH)D levels, expanded disability status scale (EDSS) score, and number of relapse events during pregnancy and within 6 months after delivery. RESULTS: Average serum 25(OH)D level at the end of trial in vitamin D3 supplemented group was higher than routine care group (33.7 ng/mL vs. 14.6 ng/ml, P < 0.050). In vitamin D3 group, the mean EDSS did not changed 6 months after delivery (P > 0.050), whereas in routine care group, the mean EDSS increased from 1.3 (0.4) to 1.7 (0.6) (P < 0.070). Women in vitamin D3 group appeared to have fewer relapse events during pregnancy and within 6 months after delivery. No significant adverse events occurred. CONCLUSION: Adding high dose vitamin D3 supplementation during pregnancy to routine care of women with MS had significant effect on the serum 25(OH)D levels, EDSS and number of relapse events during pregnancy and within 6 months after delivery. PMID- 26056551 TI - Effects of pyridoxine supplementation on severity, frequency and duration of migraine attacks in migraine patients with aura: A double-blind randomized clinical trial study in Iran. AB - BACKGROUND: Migraine is a chronic disease that affects nearly 6% of men and 18% of women worldwide. There are various drugs, which can successfully decrease migraine symptoms and frequency of migraine attacks, but these drugs usually are expensive. Hence, this study aimed to assess the effects of pyridoxine supplementation on severity, frequency and duration of migraine attacks as well as headache diary results (HDR). METHODS: This double-blind randomized clinical trial study was conducted on 66 patients with migraine with aura (MA) in Khorshid and Emam Mosa Sadr clinics of Isfahan University of Medical Sciences, Iran, in 2013. Patients were randomly allocated to receive either pyridoxine supplements (80 mg pyridoxine per day) or placebo. Severity, frequency and duration of migraine attacks and HDR were measured at baseline and at the end of the study. RESULTS: Mean age of patients was 34.24 +/- 9.44 years old. Pyridoxine supplementation led to a significant decrease in headache severity (-2.20 +/- 1.70 compared with -1 +/- 1.50; P = 0.007), attacks duration (-8.30 +/- 12.60 compared with -1.70 +/- 9.60; P = 0.030) and HDR (-89.70 +/- 134.60 compared with -6.10 +/- 155.50; P = 0.040) compared with placebo, but was not effective on the frequency of migraine attacks (-2.30 +/- 4 compared with -1.20 +/- 7.80; P = 0.510). CONCLUSION: Pyridoxine supplementation in patients with MA was effective on headache severity, attacks duration and HDR, but did not affect the frequency of migraine attacks. PMID- 26056552 TI - Comparison of serum vitamin D level in multiple sclerosis patients, their siblings, and healthy controls. AB - BACKGROUND: Multiple sclerosis (MS) is an autoimmune, neuro-inflammatory disease of central nervous system affecting physical, emotional, and cognitive aspects of patients. Association of vitamin D deficiency and MS has been shown in previous studies. The aim of this study was to evaluate serum vitamin D level in MS cases and their sex-matched healthy siblings (who are genetically near similar) and non relative sex-matched healthy controls. METHODS: A total of 135 subjects enrolled in this case-control study. Group one (n = 45) consisted of patients with established MS. Group two (n = 45) included sex-matched healthy siblings of the group one and group three participants (n = 45) were non-relative sex-matched healthy controls. Demographic data (age, sex), level of education, daily sun exposure duration, and month of birth gathered for all. Serum sample of all participants was collected for 25-hydroxy vitamin D measurement. RESULTS: There was no significant difference between vitamin D level, sun exposure duration, education level, and season of birth in three evaluated groups. Mean vitamin D level was 8.2 +/- 10.1 (nmol/l) in women and 13.3 +/- 7 (nmol/l) in men (P = 0.001). There was a significant positive correlation between daily sun exposure duration and vitamin D level in whole participants (r = 0.28, P < 0.001) as well as in MS patients (r = 0.32, P = 0.030). Mean vitamin D level was significantly lower in participants who have born in spring and summer. CONCLUSION: Vitamin D deficiency is high among Iranian population as well as MS patients. PMID- 26056553 TI - Comparison of frequencies of non motor symptoms in Indian Parkinson's disease patients on medical management versus deep brain stimulation: A case-control study. AB - BACKGROUND: Non motor symptoms (NMS) of idiopathic Parkinson's disease (PD) are a major cause of disability and recognition of these symptoms and treatment is important for comprehensive health care. Deep brain stimulation of bilateral subthalamic nucleus deep brain stimulation (STN DBS) has been shown to improve motor symptoms in PD and effects on NMS are unknown. To investigate the NMS among PD patients who underwent STN DBS. METHODS: We recruited prospectively 56 patients with PD, who had undergone bilateral STN DBS and 53 age and duration of illness matched PD patients on dopaminergic therapy (controls). NMS were assessed using 30 item questionnaire NMS Quest. These questions evaluated 9 domains, gastrointestinal, urinary, cardiovascular, sexual, cognition (apathy/attention/memory), anxiety/depression, hallucinations/delusions, sleep and miscellaneous. Comparison was done on individual symptoms as well as in various domains. This study was carried at Nizam's Institution of Medical Sciences and study period was from January 2011 to December 2012. RESULTS: Patients who underwent STN DBS had a significantly lower mean total score on NMS quest (6.7 +/- 3.8) compared to controls (8.4 +/- 3.7) (P < 0.00100). Symptoms in the domains of cardiovascular, gastrointestinal, sleep were significantly less frequent while sexual disturbances were significantly more frequent among patients compared to controls. On individual symptom analysis, nocturia (P < 0.00010), unexplained pains (P < 0.00010), nausea and vomiting, constipation, lightheadedness, depression, and insomnia were less prevalent, while sexual disturbances were significantly more common in STN DBS group compared to controls. CONCLUSION: Bilateral STN DBS not only improves the motor symptoms but also improves many NMS in PD patients. PMID- 26056555 TI - Development, cross-cultural adaptation, and validation of the Persian Mississippi Aphasia Screening Test in patients with post-stroke aphasia. AB - BACKGROUND: The Mississippi Aphasia Screening Test (MAST) is a brief screening test for assessing the expressive and receptive language abilities in patients with aphasia. The objective of the study was to develop and validate the Persian version of the MAST (MASTp) as a screening test for language disorders in patients with post-stroke aphasia. METHODS: This study used a cross-sectional design to cross-culturally adapt the MASTp following the guidelines for the process of cross-cultural adaptation of measures. A total of 40 subjects (20 patients with post-stroke aphasia and 20 healthy subjects) were included. The MASTp was tested for floor or ceiling effects, internal consistency reliability, intra-rater reliability, discriminative validity, and factor structure. RESULTS: There were no floor or ceiling effects for MASTp total score. The MASTp yielded values for internal consistency reliability that were not adequate (Cronbach's alpha 0.64 and 0.66 for test and retest, respectively. The intra-rater reliability of the MASTp within a 7 day-interval was excellent for total score (ICC agreement = 0.96) and both expressive index (ICC = 0.95) and receptive index (ICC agreement = 0.98). here were statistically significant differences in MASTp total scores and both indexes between patients and healthy subjects suggesting the discriminative validity of the MASTp (P < 0.001). Factor analysis revealed a 3-factor solution, which jointly accounted for 72.06% of the total variance. Additional factor analysis suggested 6-item MASTp as a unidimensional measure. CONCLUSION: The MASTp is useful as a valid and reliable screening tool for evaluation of language abilities in Persian speaking patients with aphasia after stroke. PMID- 26056554 TI - Stroke specific quality of life questionnaire: Test of reliability and validity of the Persian version. AB - BACKGROUND: The aim was to assess the reliability and the validity of the translated version of the stroke specific quality of life (SS-QOL) questionnaire in Iranian post-stroke patients. METHODS: This project was performed at the Shiraz University of Medical Sciences, Shiraz, Iran, between 12 April 2010 and 24 February 2011. The English version of the SS-QOL was translated into Persian by "forward-backward" translation, cognitive inquiring and cultural adaptation process. The reliability and internal consistency were measured by Cronbach's alpha coefficient. Validity was assessed using convergent and divergent validity through Spearman's correlation coefficient. RESULTS: Our study included 117 post stroke patients, consisting of 57 (48.7%) men and 60 (51.3%) women. The mean age of the patients was 81.60 +/- 7.52 (range 60-88) years. The Persian version of the SS-QOL proved reliable (Cronbach's alpha = 0.96). Internal consistency was excellent for both demographic and patients' clinical characteristics (Cronbach's alpha >= 0.70). The scaling success rates were 100% for convergent validity of each scale. Divergent validity for all 12 scales was considered acceptable, whereas each scale had a 100% scaling success rate for convergent validity. CONCLUSION: The Persian version of SS-QOL should be mentioned as a noteworthy instrument to specify different aspects of health related QOL of patients suffering stroke and hence that clinicians, researchers and epidemiologist can exploit it trustfully. PMID- 26056556 TI - Unilateral cortical hyperintensity in diffusion-weighted MRI; New criteria for early sporadic Creutzfeldt-Jakob disease. PMID- 26056557 TI - Cyclic headaches in beta-thalassemia intermedia case presenting as moyamoya syndrome. PMID- 26056558 TI - Intracranial hypertension and cerebellar symptoms due to Lhermitte-Duclos disease. PMID- 26056559 TI - Coexistence of Ehlers-Danlos syndrome and multiple sclerosis. PMID- 26056560 TI - Do women with eating disorders who have social and flexibility difficulties really have autism? A case series. AB - BACKGROUND: Many women with eating disorders (EDs) have social impairments and difficulties with flexibility. It is unclear to what extent these are manifestations of an underlying autism spectrum disorder (ASD); or whether they are instead the consequence of starvation, anxiety, low mood or obsessive compulsive disorder, all of which are highly prevalent in EDs. The resolution of this clinically and theoretically important uncertainty will require the use of gold-standard ASD assessment measures. To date these have not been employed in ED research. This case series is the first report of a well-validated, direct observational measure of ASD, the Autism Diagnostic Observation Schedule (ADOS), being administered to women with EDs. We aimed to learn about the feasibility of the ADOS in this population, and to contribute to debates about whether a sub group with EDs really have ASD. METHODS: Ten women (mean age = 26.4 years, range = 19 to 38 years) who had a suspected ASD due to social and flexibility difficulties and were receiving treatment for ED (seven anorexia, two ED not otherwise specified, one bulimia) at a specialist service (four inpatient, six outpatient) received an ADOS Module 4 assessment. RESULTS: All 10 participants completed all activities of the ADOS Module 4. Five scored in the ASD range on the ADOS diagnostic algorithm. An additional two were judged likely to have ASD, even though they scored below the ADOS's diagnostic threshold. This was on the basis of clinical observation, participant self-report and parent report. The seven women who we estimated to have ASD all reported autistic difficulties prior to the onset of their ED. They commonly described longstanding non-autistic neurodevelopmental problems, including dyslexia, dyspraxia and epilepsy. Only one had a childhood diagnosis of ASD. CONCLUSIONS: A substantial proportion of women with EDs who present with social and flexibility difficulties may have an unrecognised ASD, indicated by a constellation of autistic difficulties that appears to predate the onset of their eating problems. The ADOS is a useful component of an ASD assessment for adult women with ED. PMID- 26056561 TI - Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism. AB - BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by significant impairment in reciprocal social interactions and communication coupled with stereotyped, repetitive behaviors and restricted interests. Although genomic and functional studies are beginning to reveal some of the genetic complexity and underlying pathobiology of ASD, the consistently reported male bias of ASD remains an enigma. We have recently proposed that retinoic acid-related orphan receptor alpha (RORA), which is reduced in the brain and lymphoblastoid cell lines of multiple cohorts of individuals with ASD and oppositely regulated by male and female hormones, might contribute to the sex bias in autism by differentially regulating target genes, including CYP19A1 (aromatase), in a sex-dependent manner that can also lead to elevated testosterone levels, a proposed risk factor for autism. METHODS: In this study, we examine sex differences in RORA and aromatase protein levels in cortical tissues of unaffected and affected males and females by re-analyzing pre-existing confocal immunofluorescence data from our laboratory. We further investigated the expression of RORA and its correlation with several of its validated transcriptional targets in the orbital frontal cortex and cerebellum as a function of development using RNAseq data from the BrainSpan Atlas of the Developing Human Brain. In a pilot study, we also analyzed the expression of Rora and the same transcriptional targets in the cortex and cerebellum of adult wild type male and female C57BL/6 mice. RESULTS: Our findings suggest that Rora/RORA and several of its transcriptional targets may exhibit sexually dimorphic expression in certain regions of the brain of both mice and humans. Interestingly, the correlation coefficients between Rora expression and that of its targets are much higher in the cortex of male mice relative to that of female mice. A strong positive correlation between the levels of RORA and aromatase proteins is also seen in the cortex of control human males and females as well as ASD males, but not ASD females. CONCLUSIONS: Based on these studies, we suggest that disruption of Rora/RORA expression may have a greater impact on males, since sex differences in the correlation of RORA and target gene expression indicate that RORA-deficient males may experience greater dysregulation of genes relevant to ASD in certain brain regions during development. PMID- 26056562 TI - Quantitative proteomic analysis of single or fractionated radiation-induced proteins in human breast cancer MDA-MB-231 cells. AB - BACKGROUND: Radiotherapy is widely used to treat cancer alone or in combination with surgery, chemotherapy, and immunotherapy. However, damage to normal tissues and radioresistance of tumor cells are major obstacles to successful radiotherapy. Furthermore, the immune network around tumors appears to be connected to tumor progression and recurrence. METHODS: We investigated the cytosolic proteins produced by irradiated tumor cells by using a quantitative proteomic approach based on stable isotope labeling by amino acids in cell culture. MDA-MB-231 breast cancer cells were treated with a single or fractionated 10 Gray dose of (137)Cs gamma-radiation, which was selected based on cell viability. RESULTS: Radiation-induced proteins were differentially expressed based on the fractionated times of radiation and were involved in multiple biological functions, including energy metabolism and cytoskeleton organization. We identified 46 proteins increased by at least 1.3-fold, and high ranks were determined for cathepsin D, gelsolin, arginino-succinate synthase 1, peroxiredoxin 5, and C-type mannose receptor 2. CONCLUSION: These results suggest that a number of tumor-derived factors upregulated by gamma-radiation are promising targets for modulation of the immune response during radiation treatment. PMID- 26056563 TI - Preparedness of institutions around the world for managing patients with Ebola virus disease: an infection control readiness checklist. AB - BACKGROUND: In response to global concerns about the largest Ebola virus disease (EVD), outbreak to-date in West Africa documented healthcare associated transmission and the risk of global spread, the International Society of Chemotherapy (ISC) Infection Control Working Group created an Ebola Infection Control Readiness Checklist to assess the preparedness of institutions around the globe. We report data from the electronic checklist that was disseminated to medical professionals from October to December 2014 and identify action needed towards better preparedness levels. FINDINGS: Data from 192 medical professionals (one third from Africa) representing 125 hospitals in 45 countries around the globe were obtained through a specifically developed electronic survey. The survey contained 76 specific questions in 7 major sections: Administrative/operational support; Communications; Education and audit; Human resources, Supplies, Infection Prevention and Control practices and Clinical management of patients. The majority of respondents were infectious disease specialists/infection control consultants/clinical microbiologists (75; 39 %), followed by infection control professionals (59; 31 %) and medical doctors of other specialties (17; 9 %). Nearly all (149; 92 %) were directly involved in Ebola preparedness activities. Whilst, 54 % indicated that their hospital would need to handle suspected and proven Ebola cases, the others would subsequently transfer suspected cases to a specialized centre. CONCLUSION: The results from our survey reveal that the general preparedness levels for management of potentially suspected cases of Ebola virus disease is only partially adequate in hospitals. Hospitals designated for admitting EVD suspected and proven patients had more frequently implemented Infection Control preparedness activities than hospitals that would subsequently transfer potential EVD cases to other centres. Results from this first international survey provide a framework for future efforts to improve hospital preparedness worldwide. PMID- 26056565 TI - Strong spurious transcription likely contributes to DNA insert bias in typical metagenomic clone libraries. AB - BACKGROUND: Clone libraries provide researchers with a powerful resource to study nucleic acid from diverse sources. Metagenomic clone libraries in particular have aided in studies of microbial biodiversity and function, and allowed the mining of novel enzymes. Libraries are often constructed by cloning large inserts into cosmid or fosmid vectors. Recently, there have been reports of GC bias in fosmid metagenomic libraries, and it was speculated to be a result of fragmentation and loss of AT-rich sequences during cloning. However, evidence in the literature suggests that transcriptional activity or gene product toxicity may play a role. RESULTS: To explore possible mechanisms responsible for sequence bias in clone libraries, we constructed a cosmid library from a human microbiome sample and sequenced DNA from different steps during library construction: crude extract DNA, size-selected DNA, and cosmid library DNA. We confirmed a GC bias in the final cosmid library, and we provide evidence that the bias is not due to fragmentation and loss of AT-rich sequences but is likely occurring after DNA is introduced into Escherichia coli. To investigate the influence of strong constitutive transcription, we searched the sequence data for promoters and found that rpoD/sigma(70) promoter sequences were underrepresented in the cosmid library. Furthermore, when we examined the genomes of taxa that were differentially abundant in the cosmid library relative to the original sample, we found the bias to be more correlated with the number of rpoD/sigma(70) consensus sequences in the genome than with simple GC content. CONCLUSIONS: The GC bias of metagenomic libraries does not appear to be due to DNA fragmentation. Rather, analysis of promoter sequences provides support for the hypothesis that strong constitutive transcription from sequences recognized as rpoD/sigma(70) consensus like in E. coli may lead to instability, causing loss of the plasmid or loss of the insert DNA that gives rise to the transcription. Despite widespread use of E. coli to propagate foreign DNA in metagenomic libraries, the effects of in vivo transcriptional activity on clone stability are not well understood. Further work is required to tease apart the effects of transcription from those of gene product toxicity. PMID- 26056566 TI - The association of comorbid diabetes mellitus and symptoms of depression with all cause mortality and cardiac rehospitalization in patients with heart failure. AB - BACKGROUND: More than 22% of individuals with diabetes mellitus have concomitant heart failure (HF), and the prevalence of diabetes in those with HF is nearly triple that of individuals without HF. Comorbid depressive symptoms are common in diabetes and HF. Depressive symptoms are an independent predictor of mortality in individuals with diabetes alone, as well as those with HF alone and are a predictor of rehospitalization in those with HF. However, the association of comorbid HF, diabetes and depressive symptoms with all-cause mortality and rehospitalization for cardiac causes has not been determined. OBJECTIVE: The purpose of this study was to evaluate the association of comorbid HF, diabetes and depression with all-cause mortality and rehospitalization for cardiac cause. METHOD: Patients provided data at baseline about demographic and clinical variables and depressive symptoms; patients were followed for at least 2 years. Participants were divided into four groups based on the presence and absence of diabetes and depressive symptoms. Cox regression analysis was used to determine whether comorbid diabetes and depressive symptoms independently predicted all cause mortality and cardiac rehospitalization in these patients with HF. RESULTS: Patients (n=663) were primarily male (69%), white (76%), and aged 61+/-13 years. All-cause mortality was independently predicted by the presence of concomitant diabetes and depressive symptoms (HR 3.71; 95% CI 1.49 to 9.25; p=0.005), and depressive symptoms alone (HR 2.29; 95% CI 0.94 to 5.40; p=0.05). The presence of comorbid diabetes and depressive symptoms was also an independent predictor of cardiac rehospitalization (HR 2.36; 95% CI 1.27 to 4.39; p=0.007). CONCLUSIONS: Comorbid diabetes and depressive symptoms are associated with poorer survival and rehospitalization in patients with HF; effective strategies to regularly evaluate and effectively manage these comorbid conditions are necessary to improve survival and reduce rehospitalization rates. PMID- 26056567 TI - Molecular and Cellular Therapies: New challenges and opportunities. AB - Gene therapy is suggested to be one of the most specific and efficient modulations for gene deficient diseases and extended to other diseases like cancer and inflammation, even though there are still challenges to be faced, such as specific and selective delivery, minimal to no toxicity, efficient metabolism, simplicity, and measurable efficiency. It is important to identify and validate drug-able disease-specific targets for molecular and cellular therapies, while it is equally important to have disease biomarkers to trace and define the biological effects of molecular and cellular therapies. The importance and significance of allostery in molecular and cellular therapies and "allosteric disease", "allosteric effect", and "allosteric drug" should be more carefully examined and validated. Cell therapy has been attracting an increasing amount of consideration in the development of new treatments for diseases. Molecular and Cellular Therapies (MCT) is a new, open-access journal, devoted to molecular mechanisms, preclinical and clinical research and development of gene-, peptide-, protein-, and cell-based therapies. PMID- 26056569 TI - Flowing through the CRISPR-CAScade: Will genome editing boost cell therapies? AB - Recent years have seen great advancements in genome editing technologies, allowing for efficient and specific targeting of DNA sequences into the genome. In parallel, advancements in stem cell research, and especially the ability to induce pluripotency in somatic cells, have brought stem cell-derived therapies closer to the clinic. In this commentary, I envision how groundbreaking genome editing technologies will influence stem cell biology research, paving the way to regenerative medicine with genetically engineered cells. PMID- 26056568 TI - Properties and prospects of adjuvants in influenza vaccination - messy precipitates or blessed opportunities? AB - Influenza is a major challenge to healthcare systems world-wide. While prophylactic vaccination is largely efficient, long-lasting immunity has not been achieved in immunized populations, at least in part due to the challenges arising from the antigen variation between strains of influenza A virus as a consequence of genetic drift and shift. From progress in our understanding of the immune system, the mode-of-action of vaccines can be divided into the stimulation of the adaptive system through inclusion of appropriate vaccine antigens and of the innate immune system by the addition of adjuvant to the vaccine formulation. A shared property of many vaccine adjuvants is found in their nature of water insoluble precipitates, for instance the particulate material made from aluminum salts. Previously, it was thought that embedding of vaccine antigens in these materials provided a "depot" of antigens enabling a long exposure of the immune system to the antigen. However, more recent work points to a role of particulate adjuvants in stimulating cellular parts of the innate immune system. Here, we briefly outline the infectious medicine and immune biology of influenza virus infection and procedures to provide sufficient and stably available amounts of vaccine antigen. This is followed by presentation of the many roles of adjuvants, which involve humoral factors of innate immunity, notably complement. In a perspective of the ultrastructural properties of these humoral factors, it becomes possible to rationalize why these insoluble precipitates or emulsions are such a provocation of the immune system. We propose that the biophysics of particulate material may hold opportunities that could aid the development of more efficient influenza vaccines. PMID- 26056570 TI - Current status of miRNA-targeting therapeutics and preclinical studies against gastroenterological carcinoma. AB - Expanding knowledge about the crucial roles of microRNAs (miRNAs) in human diseases has led to the idea that miRNAs may be novel, promising therapeutic targets against various pathological conditions. The recent success of a human clinical trial using anti-miR-122 oligonucleotides against chronic hepatitis C virus has paved the way for this approach. In this review, we summarize briefly the current status of clinical trials of miRNA-targeting therapy and several representative preclinical trials against hepato-gastrointestinal carcinoma. In addition, we describe the currently available technologies for modification and delivery of oligonucleotides, which are essential in providing efficient, specific and safe approaches to targeting miRNAs. PMID- 26056571 TI - A brief perspective on neural cell therapy. AB - For a range of nervous system disorders current treatment options remain limited. Focusing on Parkinson's disease as a neurodegenerative entity that affects an increasing quantity of people in our aging societies, we briefly discuss remaining challenges and opportunities that neural stem cell therapy might be able to offer. Providing a snapshot of neural transplantation paradigms, we contemplate possible imminent translational scenarios and discuss critical requirements to be considered before clinical implementation. PMID- 26056572 TI - Human lung telocytes could promote the proliferation and angiogenesis of human pulmonary microvascular endothelial cells in vitro. AB - BACKGROUND: In the previous studies, telocytes were found near the capillaries in many tissues, especially on the extracellular matrix of blood vessels and positive to CD34 and c-kit. Therefore, the present study aimed to explore if telocytes could produce angiogenesis associated cytokines, promote the proliferation and the angiogenesis of vascular endothelial cells in vitro. METHODS: Human lung telocytes were isolated and cultured, and were identified by immunofluorescence cytochemistry with CD34, c-kit and vimentin. Telocytes conditional media (TCM) was prepared, and the expressions of angiogenesis associated cytokines in TCM were detected by ELISA. Human pulmonary microvascular endothelial cells (HPMECs) were cultured with DMEM media or TCM for 72 hours. The proliferation of HPMECs was continuously detected with CCK-8 kit at an interval of 12 hours. HPMECs were also injured by lipopolysaccharide, and cultured with TCM and DMEM respectively, and the tube formation capacity was detected. RESULTS: Telocytes were positive for CD34, c-kit and vimentin. The expressions of VEGF and EGF in TCM were significantly higher, the proliferation of HPMECs cultured with TCM significantly increased, and the tube formation of HPMECs injured by endotoxin was improved with the culture of TCM, as compared with the culture of DMEM. CONCLUSION: The present study provides the evidence that human lung telocytes could produce the growth factors, such as VEGF and EGF. Telocytes conditional media induced the proliferation of pulmonary endothelial cells and prevented from endotoxin-induced compromise of pulmonary endothelial angiogenesis. PMID- 26056573 TI - Apixaban for oral antithrombotic therapy: is a new era coming? AB - Apixaban, a new oral inhibitor of activated factor Xa, may simplify antithrombotic therapy with fixed doses and no necessity for coagulation monitoring. Apixaban is non-inferior to conventional therapy (enxoaparin, followed by warfarin) with lower risk of major bleeding in the treatment of acute venous thromboembolism. Compared with placebo, extended treatment with apixaban may reduce the recurrence rate in patients with venous thromboembolism. Thromboprophylaxis therapy with apixaban in surgery (hip or knee replacement) and atrial fibrillation has been proved to be superior to warfarin or enxoaparin. Apixaban offers a convenient and more effective alternative choice in anticoagulant therapy. PMID- 26056574 TI - Harnessing RNAi nanomedicine for precision therapy. AB - Utilizing RNA interference as an innovative therapeutic strategy has an immense likelihood to generate novel concepts in precision medicine. Several clinical trials are on the way with some positive initial results. Yet, targeting of RNAi payloads such as small interfering RNAs (siRNAs), microRNA (miR) mimetic or anti miR (antagomirs) into specific cell types remains a challenge. Major attempts are done for developing nano-sized carriers that could overcome systemic, local and cellular barriers. This progress report will focus on the recent advances in the RNAi world, detailing strategies of systemic passive tissue targeting and active cellular targeting, which is often considered as the holy grail of drug delivery. PMID- 26056575 TI - Low pH of interstitial fluid around hippocampus of the brain in diabetic OLETF rats. AB - BACKGROUND: We have reported that pH values of ascites and interstitial fluids around the liver in Otsuka Long-Evans Tokushima Fatty (OLETF) rats are significantly lower than normal pH, 7.40, of mammalian body fluids (Biochem Biophys Res Commun 2013, 432:650), and that this lowered pH of interstitial fluid causes the insulin resistance in diabetic patients by decreasing insulin-binding to its receptors (J Physiol Sci 2013, 63:S199). In the preset study, we tried to measure the interstitial fluid pH in diabetic OLETF rats, since the interstitial fluid pH plays key factors in the brain function from a viewpoint of the binding affinity of neurotransmitters to their receptors. FINDINGS: We found that the pH value of interstitial fluids around hippocampus, the most important area for memory, in diabetic OLETF rats was lower than that in normal rats by measuring pH with antimony pH electrodes. CONCLUSIONS: The lowered pH of interstitial fluid around hippocampus of the brain in diabetic rats observed in the present study suggests that the function of hippocampus of the brain would be diminished due to low affinity of various types of neurotransmitters, playing key roles in the hippocampus function, to their receptors. Therefore, we indicate that maintenance of the interstitial fluid pH at the normal level would be one of the most important key factors for molecular and cellular therapies in various types of diseases including diabetes mellitus. PMID- 26056577 TI - Application of circulating tumor cells scope technique on circulating tumor cell research. AB - Circulating tumor cells (CTCs) are becoming promising biomarkers in several cancers, such as colon, prostate, and breast carcinomas. Independent research groups have reported a correlation between CTC numbers and patient prognosis. Even more, the development of personalized medicine gives physicians impetus to utilize the advancement of molecular characterization of CTCs. This review introduces a new technique, CTCscope, and compares it with the current methods of CTCs detection, with particular emphasis on cancer research, and discusses the future application of this new method from bench to bed-side. PMID- 26056576 TI - microRNA therapies in cancer. AB - MicroRNAs (miRNAs or miRs) are a family of small non-coding RNA species that have been implicated in the control of many fundamental cellular and physiological processes such as cellular differentiation, proliferation, apoptosis and stem cell maintenance. miRNAs regulate gene expression by the sequence-selective targeting of mRNAs, leading to translational repression or mRNA degradation. Some microRNAs have been categorized as "oncomiRs" as opposed to "tumor suppressor miRs" Modulating the miRNA activities may provide exciting opportunities for cancer therapy. This review highlights the latest discovery of miRNAs involved in carcinogenesis as well as the potential applications of miRNA regulations in cancer treatment. Several studies have demonstrated the feasibility of restoring tumor suppressive miRNAs and targeting oncogenic miRNAs for cancer therapy using in vivo model systems. PMID- 26056578 TI - "Much ado to achieve nothing: prospects for curing HIV infection". AB - Currently there is significant scientific effort being directed at developing ways to create either a sterilizing cure, or functional cure for HIV infection. Multiple approaches are being evaluated under the broad headings of gene therapy, immune based interventions, and treatments which depend upon HIV reactivation from latency to cause the death of cells which harbor the virus. Molecular and Cellular Therapies (MCT) welcomes all manuscripts devoted to increasing our understanding of determinants of affecting a cure for HIV and mechanistic studies determine the cellular and viral interventions necessary for achieving HIV cure. PMID- 26056580 TI - Genome-wide analysis of primary peripheral blood mononuclear cells from HIV + patients-pre-and post- HAART show immune activation and inflammation the main drivers of host gene expression. AB - BACKGROUND: Although the host gene expression in the context of HIV has been explored by several studies, it remains unclear how HIV is able to manipulate and subvert host gene machinery before and after highly active antiretroviral therapy (HAART) in the same individual. In order to define the underlying pharmaco genomic basis of HIV control during HAART and genomic basis of immune deterioration prior to HAART initiation, we performed a genome-wide expression analysis using primary peripheral blood mononuclear cells (PBMC) derived from 14 HIV + subjects pre-highly active antiretroviral therapy (HAART) (time point-1 or TP1) with detectable plasma viremia and post-HAART (time point-2 or TP2) with effective control of plasma viremia (<40 HIV RNA copies/mL of plasma). METHODS: Genomic RNA extracted from the PBMCs was used in microarray analysis using HT 12V3 Illumina chips. Illumina(r)BeadStudio Software was used to obtain differentially expressed (DE) genes. Only the genes with p value <0.01 and FDR of <5% were considered for analysis. Pathway analysis was performed in MetaCoreTM to derive functional annotations. Functionally significant genes were validated by qRT-PCR. RESULTS: Between TP1 and TP2, 234 genes were differentially expressed (DE). During viremic phase (TP1), there was an orchestrated and coordinated up regulation of immune, inflammation and antiviral genes, consistent with HIV infection and immune activation, which comprised of genes mainly involved in antiviral action of interferons and their signalling. In contrast, the therapy mediated control phase (TP2) showed systematic down-regulation of these pathways, suggesting that the reduction in plasma viremia with HAART has a considerable influence on reducing the immune activation, thereby implying a definitive role of HIV in subverting the human gene machinery. CONCLUSIONS: This is the first study to show the evidence for the differential regulation of gene expression between the untreated and treated time points, suggesting that gene expression is a consequence of cellular activation during plasma viremia. Affirmation to these observations comes from down-modulation of genes involved in cellular activation and inflammation upon initiation of HAART coinciding with below detectable levels of plasma viremia. PMID- 26056579 TI - The macrophage: a therapeutic target in HIV-1 infection. AB - Human immunodeficiency virus (HIV) is still a serious global health concern responsible for more than 25 million deaths in last three decades. More than 34 million people are living with HIV infection. Macrophages and CD4+ T cells are the principal targets of HIV-1. The pathogenesis of HIV-1 takes different routes in macrophages and CD4+ T cells. Macrophages are resistant to the cytopathic effect of HIV-1 and produce virus for longer periods of time. In addition, macrophages being present in every organ system thus can disseminate virus to the different anatomical sites leading to the formation of viral sanctuaries. Complete cure of HIV-1 needs better understanding of viral pathogenesis in these reservoirs and implementation of knowledge into robust therapeutic products. In this review we will focus on the unique relationship between HIV-1 and macrophages. Furthermore, we will describe how successful antiretroviral therapy (ART) is in suppressing HIV and novel molecular and cellular strategies against HIV-1 in macrophages. PMID- 26056581 TI - Advances toward regenerative medicine in the central nervous system: challenges in making stem cell therapy a viable clinical strategy. AB - Over recent years, there has been a great deal of interest in the prospects of stem cell-based therapies for the treatment of nervous system disorders. The eagerness of scientists, clinicians, and spin-out companies to develop new therapies led to premature clinical trials in human patients, and now the initial excitement has largely turned to skepticism. Rather than embracing a defeatist attitude or pressing blindly ahead, I argue it is time to evaluate the challenges encountered by regenerative medicine in the central nervous system and the progress that is being made to solve these problems. In the twenty years since the adult brain was discovered to have an endogenous regenerative capacity, much basic research has been done to elucidate mechanisms controlling proliferation and cellular identity; how stem cells may be directed into neuronal lineages; genetic, pharmacological, and behavioral interventions that modulate neurogenic activity; and the exact nature of limitations to regeneration in the adult, aged, diseased and injured CNS. These findings should prove valuable in designing realistic clinical strategies to improve the prospects of stem cell-based therapies. In this review, I discuss how basic research continues to play a critical role in identifying both barriers and potential routes to regenerative therapy in the CNS. PMID- 26056582 TI - Extracellular matrix macromolecules: potential tools and targets in cancer gene therapy. AB - Tumour cells create their own microenvironment where they closely interact with a variety of soluble and non-soluble molecules, different cells and numerous other components within the extracellular matrix (ECM). Interaction between tumour cells and the ECM is bidirectional leading to either progression or inhibition of tumourigenesis. Therefore, development of novel therapies targeted primarily to tumour microenvironment (TME) is highly rational. Here, we give a short overview of different macromolecules of the ECM and introduce mechanisms whereby they contribute to tumourigenesis within the TME. Furthermore, we present examples of individual ECM macromolecules as regulators of cell behaviour during tumourigenesis. Finally, we focus on novel strategies of using ECM macromolecules as tools or targets in cancer gene therapy in the future. PMID- 26056583 TI - Role of solute carriers in response to anticancer drugs. AB - Membrane transporters play critical roles in moving a variety of anticancer drugs across cancer cell membrane, thereby determining chemotherapy efficacy and/or toxicity. The retention of anticancer drugs in cancer cells is the result of net function of efflux and influx transporters. The ATP-binding cassette (ABC) transporters are mainly the efflux transporters expressing at cancer cells, conferring the chemo-resistance in various malignant tumors, which has been well documented over the past decades. However, the function of influx transporters, in particular the solute carriers (SLC) in cancer cells, has only been recently well recognized to have significant impact on cancer therapy. The SLC transporters not only directly bring anticancer agents into cancer cells but also serve as the uptake mediators of essential nutrients for tumor growth and survival. In this review, we concentrate on the interaction of SLC transporters with anticancer drugs and nutrients, and their impact on chemo-sensitivity or resistance of cancer cells. The differential expression patterns of SLC transporters between normal and tumor tissues may be well utilized to achieve specific delivery of chemotherapeutic agents. PMID- 26056584 TI - MicroRNAs: short non-coding players in cancer chemoresistance. AB - Chemoresistance is one of the main problems in the therapy of cancer. There are a number of different molecular mechanisms through which a cancer cell acquires resistance to a specific treatment, such as alterations in drug uptake, drug metabolism and drug targets. There are several lines of evidence showing that miRNAs are involved in drug sensitivity of cancer cells in different tumor types and by different treatments. In this review, we provide an overview of the more recent and significant findings on the role of miRNAs in cancer cell drug resistance. In particular, we focus on specific miRNA mechanisms of action that in various steps lead from drug cell sensitivity to drug cell resistance. We also provide evidence on how miRNA profiling may unveil relevant predictive biomarkers for therapy outcomes. PMID- 26056585 TI - Molecular mechanisms of tissue inhibitor of metalloproteinase 2 in the tumor microenvironment. AB - There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease. Their endogenous inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs), primarily function to prevent degradation of the ECM via inhibition of MMPs. However, recent studies demonstrate that TIMP family members also possess MMP-independent functions. One TIMP member in particular, TIMP-2, has many distinct properties and functions, that occur independent of MMP inhibition, including the inhibition of tumor growth and reduction of angiogenesis through decreased endothelial cell proliferation and migration. The MMP-independent molecular mechanisms and signaling pathways elicited by TIMP-2 in the TME are described in this review. PMID- 26056587 TI - Making sense of how HIV kills infected CD4 T cells: implications for HIV cure. AB - Defining how HIV does, and does not, kill the host CD4 T cell that it infects is of paramount importance in an era when research is approaching a cure for infection. Three mutually exclusive pathways can lead to the death of HIV infected cells during the HIV life cycle, before, coincident and after HIV integration and consequently may affect viral replication. We discuss the molecular mechanism underlying these pathways, the evidence supporting their roles in vivo, and contemplate how understanding these pathways might inform novel approaches to promote viral cure of HIV. PMID- 26056586 TI - Improvements in biomaterial matrices for neural precursor cell transplantation. AB - Progress is being made in developing neuroprotective strategies for traumatic brain injuries; however, there will never be a therapy that will fully preserve neurons that are injured from moderate to severe head injuries. Therefore, to restore neurological function, regenerative strategies will be required. Given the limited regenerative capacity of the resident neural precursors of the CNS, many investigators have evaluated the regenerative potential of transplanted precursors. Unfortunately, these precursors do not thrive when engrafted without a biomaterial scaffold. In this article we review the types of natural and synthetic materials that are being used in brain tissue engineering applications for traumatic brain injury and stroke. We also analyze modifications of the scaffolds including immobilizing drugs, growth factors and extracellular matrix molecules to improve CNS regeneration and functional recovery. We conclude with a discussion of some of the challenges that remain to be solved towards repairing and regenerating the brain. PMID- 26056589 TI - Relevance of Wnt signaling for osteoanabolic therapy. AB - The Wnt signaling pathway is long known to play fundamental roles in various aspects of embryonic development, but also in several homeostatic processes controlling tissue functions in adults. The complexity of this system is best underscored by the fact that the mammalian genome encodes for 19 different Wnt ligands, most but not all of them acting through an intracellular stabilization of beta-catenin, representing the key molecule within the so-called canonical Wnt signaling pathway. Wnt ligands primarily bind to 10 different serpentine receptors of the Fzd family, and this binding can be positively or negatively regulated by additional molecules present at the surface of the respective target cells. One of these molecules is the transmembrane protein Lrp5, which has been shown to act as a Wnt co-receptor. In 2001, Lrp5, and thereby Wnt signaling, entered center stage in the research area of bone remodeling, a homeostatic process controlling bone mass, whose disturbance causes osteoporosis, one of the most prevalent disorders worldwide. More specifically, it was found that inactivating mutations of the human LRP5 gene cause osteoporosis-pseudoglioma syndrome, a rare genetic disorder characterized by impaired bone formation and persistence of hyaloid vessels in the eyeballs. In addition, activating LRP5 mutations were identified in individuals with osteosclerosis, a high bone mass condition characterized by excessive bone formation. Especially explained by the lack of cost-effective osteoanabolic treatment options, these findings had an immediate impact on the research regarding the bone-forming cell type, i.e. the osteoblast, whose differentiation and function is apparently controlled by Wnt signaling. This review summarizes the most important results obtained in a large number of studies, involving tissue culture experiments, mouse models and human patients. While there are still many open questions regarding the precise molecular interactions controlling Wnt signaling in osteoblasts, it is obvious that understanding this pathway is a key to optimize the therapeutic strategies for treating various skeletal disorders, including osteoporosis. PMID- 26056590 TI - Magnetic nanoparticles for oligodendrocyte precursor cell transplantation therapies: progress and challenges. AB - Oligodendrocyte precursor cells (OPCs) have shown high promise as a transplant population to promote regeneration in the central nervous system, specifically, for the production of myelin - the protective sheath around nerve fibers. While clinical trials for these cells have commenced in some areas, there are currently key barriers to the translation of neural cell therapies. These include the ability to (a) image transplant populations in vivo; (b) genetically engineer transplant cells to augment their repair potential; and (c) safely target cells to sites of pathology. Here, we review the evidence that magnetic nanoparticles (MNPs) are a 'multifunctional nanoplatform' that can aid in safely addressing these translational challenges in neural cell/OPC therapy: by facilitating real time and post-mortem assessment of transplant cell biodistribution, and biomolecule delivery to transplant cells, as well as non-invasive 'magnetic cell targeting' to injury sites by application of high gradient fields. We identify key issues relating to the standardization and reporting of physicochemical and biological data in the field; we consider that it will be essential to systematically address these issues in order to fully evaluate the utility of the MNP platform for neural cell transplantation, and to develop efficacious neurocompatible particles for translational applications. PMID- 26056588 TI - Gene therapy for malignant glioma. AB - Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each. PMID- 26056591 TI - Stem cell in alternative treatments for brain tumors: potential for gene delivery. AB - Despite ongoing research efforts and attempts to bring new drugs into trial, the prognosis for brain tumors remains poor. Patients with the most common and lethal intracranial neoplasia, glioblastoma multiforme (GBM), have an average survival of one year with combination of surgical resection, radiotherapy and temozolomide. One of the main problems in the treatment of GBM is getting drugs across the blood brain barrier (BBB) efficiently. In an attempt to solve this problem, there are ongoing experimental and clinical trials to deliver drugs within stem cells. The purpose for this method is the ease by which stem cells home to the brain. This review discusses the experimental and clinical applications of stem cells for GBM. We also discuss the different properties of stem cells. This information is important to understand why one stem cell would be advantageous over another in cell therapy. We provide an overview of the different drug delivery methods, gene-based treatments and cancer vaccines for GBM, including the stem cell subset. PMID- 26056592 TI - Adoptive T-cell therapy for Leukemia. AB - Allogeneic stem cell transplantation (alloSCT) is the most robust form of adoptive cellular therapy (ACT) and has been tremendously effective in the treatment of leukemia. It is one of the original forms of cancer immunotherapy and illustrates that lymphocytes can specifically recognize and eliminate aberrant, malignant cells. However, because of the high morbidity and mortality that is associated with alloSCT including graft-versus-host disease (GvHD), refining the anti-leukemia immunity of alloSCT to target distinct antigens that mediate the graft-versus-leukemia (GvL) effect could transform our approach to treating leukemia, and possibly other hematologic malignancies. Over the past few decades, many leukemia antigens have been discovered that can separate malignant cells from normal host cells and render them vulnerable targets. In concert, the field of T-cell engineering has matured to enable transfer of ectopic high affinity antigen receptors into host or donor cells with greater efficiency and potency. Many preclinical studies have demonstrated that engineered and conventional T-cells can mediate lysis and eradication of leukemia via one or more leukemia antigen targets. This evidence now serves as a foundation for clinical trials that aim to cure leukemia using T-cells. The recent clinical success of anti-CD19 chimeric antigen receptor (CAR) cells for treating patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia displays the potential of this new therapeutic modality. In this review, we discuss some of the most promising leukemia antigens and the novel strategies that have been implemented for adoptive cellular immunotherapy of lymphoid and myeloid leukemias. It is important to summarize the data for ACT of leukemia for physicians in-training and in practice and for investigators who work in this and related fields as there are recent discoveries already being translated to the patient setting and numerous accruing clinical trials. We primarily focus on ACT that has been used in the clinical setting or that is currently undergoing preclinical testing with a foreseeable clinical endpoint. PMID- 26056593 TI - Selective vulnerability of motoneuron and perturbed mitochondrial calcium homeostasis in amyotrophic lateral sclerosis: implications for motoneurons specific calcium dysregulation. AB - Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder characterized by the selective degeneration of defined subgroups of motoneuron in the brainstem, spinal cord and motor cortex with signature hallmarks of mitochondrial Ca(2+) overload, free radical damage, excitotoxicity and impaired axonal transport. Although intracellular disruptions of cytosolic and mitochondrial calcium, and in particular low cytosolic calcium ([Ca(2+)]c) buffering and a strong interaction between metabolic mechanisms and [Ca(2+)]i have been identified predominantly in motoneuron impairment, the causes of these disruptions are unknown. The existing evidence suggests that the mutant superoxide dismutase1 (mtSOD1)-mediated toxicity in ALS acts through mitochondria, and that alteration in cytosolic and mitochondria-ER microdomain calcium accumulation are critical to the neurodegenerative process. Furthermore, chronic excitotoxcity mediated by Ca(2+)-permeable AMPA and NMDA receptors seems to initiate vicious cycle of intracellular calcium dysregulation which leads to toxic Ca(2+) overload and thereby selective neurodegeneration. Recent advancement in the experimental analysis of calcium signals with high spatiotemporal precision has allowed investigations of calcium regulation in-vivo and in-vitro in different cell types, in particular selectively vulnerable/resistant cell types in different animal models of this motoneuron disease. This review provides an overview of latest advances in this field, and focuses on details of what has been learned about disrupted Ca(2+) homeostasis and mitochondrial degeneration. It further emphasizes the critical role of mitochondria in preventing apoptosis by acting as a Ca(2+) buffers, especially in motoneurons, in pathophysiological conditions such as ALS. PMID- 26056594 TI - Gene therapy for cancer: present status and future perspective. AB - Advancements in human genomics over the last two decades have shown that cancer is mediated by somatic aberration in the host genome. This discovery has incited enthusiasm among cancer researchers; many now use therapeutic approaches in genetic manipulation to improve cancer regression and find a potential cure for the disease. Such gene therapy includes transferring genetic material into a host cell through viral (or bacterial) and non-viral vectors, immunomodulation of tumor cells or the host immune system, and manipulation of the tumor microenvironment, to reduce tumor vasculature or to increase tumor antigenicity for better recognition by the host immune system. Overall, modest success has been achieved with relatively minimal side effects. Previous approaches to cancer treatment, such as retrovirus integration into the host genome with the risk of mutagenesis and second malignancies, immunogenicity against the virus and/or tumor, and resistance to treatment with disease relapse, have markedly decreased with the new generation of viral and non-viral vectors. Several tumor-specific antibodies and genetically modified immune cells and vaccines have been developed, yet few are presently commercially available, while many others are still ongoing in clinical trials. It is anticipated that gene therapy will play an important role in future cancer therapy as part of a multimodality treatment, in combination with, or following other forms of cancer therapy, such as surgery, radiation and chemotherapy. The type and mode of gene therapy will be determined based on an individual's genomic constituents, as well as his or her tumor specifics, genetics, and host immune status, to design a multimodality treatment that is unique to each individual's specific needs. PMID- 26056596 TI - Extended blood circulation and joint accumulation of a p(HPMA-co-AzMA)-based nanoconjugate in a murine model of rheumatoid arthritis. AB - BACKGROUND: We recently synthesized a hydrophilic polymer, poly(N-(2 hydroxypropyl)methacrylamide-co-N-(3-azidopropyl)methacrylamide), p(HPMA-co AzMA), by RAFT polymerization using a novel azide-containing methacrylamide monomer that through a post modification strategy using click chemistry enabled facile preparation of a panel of versatile and well-defined bioconjugates. In this work we screen a panel of different molecular weight (Mw) fluorescently tagged p(HPMA-co-AzMA) in healthy mice, by live bioimaging, to select an extended circulatory half-life material for investigating joint accumulation in a murine collagen antibody-induced arthritis model. FINDINGS: Fluorescence image analysis revealed half-lifes of <20 min, 2.8 h and 6.4 h for p(HPMA-co-AzMA) of 15, 36 and 54 kDa, respectively, with ~10% polymer retained in the blood after 24 h for the highest Mw. p(HPMA-co-AzMA) of 54 kDa showed enhanced accumulation in the joints of the arthritic mouse model with a bioavailability (AUC = 1783% . h) ~12 times higher (P = 0.01) than healthy control (AUC = 148% . h). CONCLUSIONS: p(HPMA-co AzMA) of 54 kDa exhibited extended circulatory half-life and preferential accumulation in inflamed joints of a murine model of rheumatoid arthritis (RA). This combined with well-defined polymer size and versatility for conjugation of a range of biomolecules promotes p(HPMA-co-AzMA) for potential applications in the delivery of drugs for treatment of RA. PMID- 26056595 TI - Targeting the Wnt pathways for therapies. AB - The Wnt/beta-catenin signaling pathway is crucial in animal development from sponges to humans. Its activity in the adulthood is less general, with exceptions having huge medical importance. Namely, improper activation of this pathway is carcinogenic in many tissues, most notably in the colon, liver and the breast. On the other hand, the Wnt/beta-catenin signaling must be re-activated in cases of tissue damage, and insufficient activation results in regeneration failure and degeneration. These both medically important implications are unified by the emerging importance of this signaling pathway in the control of proliferation of various types of stem cells, crucial for tissue regeneration and, in case of cancer stem cells - cancer progression and relapse. This article aims at briefly reviewing the current state of knowledge in the field of Wnt signaling, followed by a detailed discussion of current medical developments targeting distinct branches of the Wnt pathway for anti-cancer and pro-regeneration therapies. PMID- 26056597 TI - Neural stem cells: ready for therapeutic applications? AB - Neural stem cells (NSCs) offer a unique and powerful tool for basic research and regenerative medicine. However, the challenges that scientists face in the comprehension of the biology and physiological function of these cells are still many. Deciphering NSCs fundamental biological aspects represents indeed a crucial step to control NSCs fate and functional integration following transplantation, and is essential for a safe and appropriate use of NSCs in injury/disease conditions. In this review, we focus on the biological properties of NSCs and discuss how these cells may be exploited to provide effective therapies for neurological disorders. We also review and discuss ongoing NSC-based clinical trials for these diseases. PMID- 26056598 TI - A critical evaluation of PI3K inhibition in Glioblastoma and Neuroblastoma therapy. AB - Members of the PI3K/Akt/mTor signaling cascade are among the most frequently altered proteins in cancer, yet the therapeutic application of pharmacological inhibitors of this signaling network, either as monotherapy or in combination therapy (CT) has so far not been particularly successful. In this review we will focus on the role of PI3K/Akt/mTOR in two distinct tumors, Glioblastoma multiforme (GBM), an adult brain tumor which frequently exhibits PTEN inactivation, and Neuroblastoma (NB), a childhood malignancy that affects the central nervous system and does not harbor any classic alterations in PI3K/Akt signaling. We will argue that inhibitors of PI3K/Akt signaling can be components for potentially promising new CTs in both tumor entities, but further understanding of the signal cascade's complexity is essential for successful implementation of these CTs. Importantly, failure to do this might lead to severe adverse effects, such as treatment failure and enhanced therapy resistance. PMID- 26056600 TI - Targeting the Wnt/beta-catenin pathway in endometriosis: a potentially effective approach for treatment and prevention. AB - Endometriosis is a chronic, estrogen-dependent disease associated with infertility and pelvic pain. Endometriosis is defined by the presence of extra uterine endometrial tissue. It affects approximately 10% of reproductive-aged women. However, the underlying etiology, pathogenesis and pathophysiology remain to be fully elucidated. Knowledge of these factors is indispensable for the development of targeted therapies for prevention and treatment of endometriosis. Several studies, including those from our laboratory, have suggested that aberrant activation of the Wnt/beta-catenin pathway may be involved in the pathophysiology of endometriosis. This is a review of the literature focused on the aberrant activation of the Wnt/beta-catenin pathway in patients with endometriosis, and on how targeting the Wnt/targeting pathway may be a potentially effective approach for treating and/or preventing endometriosis. PMID- 26056599 TI - Aptamer technology for tracking cells' status & function. AB - In fields such as cancer biology and regenerative medicine, obtaining information regarding cell bio-distribution, tropism, status, and other cellular functions are highly desired. Understanding cancer behaviors including metastasis is important for developing effective cancer treatments, while assessing the fate of therapeutic cells following implantation is critical to validate the efficacy and efficiency of the therapy. For visualization purposes with medical imaging modalities (e.g. magnetic resonance imaging), cells can be labeled with contrast agents (e.g. iron-oxide nanoparticles), which allows their identification from the surrounding environment. Despite the success of revealing cell biodistribution in vivo, most of the existing agents do not provide information about the status and functions of cells following transplantation. The emergence of aptamers, single-stranded RNA or DNA oligonucleotides of 15 to 60 bases in length, is a promising solution to address this need. When aptamers bind specifically to their cognate molecules, they undergo conformational changes which can be transduced into a change of imaging contrast (e.g. optical, magnetic resonance). Thus by monitoring this signal change, researchers can obtain information about the expression of the target molecules (e.g. mRNA, surface markers, cell metabolites), which offer clues regarding cell status/function in a non-invasive manner. In this review, we summarize recent efforts to utilize aptamers as biosensors for monitoring the status and function of transplanted cells. We focus on cancer cell tracking for cancer study, stem cell tracking for regenerative medicine, and immune cell (e.g. dendritic cells) tracking for immune therapy. PMID- 26056601 TI - Platelet dysfunction in injured patients. AB - A renewed understanding of Trauma Induced Coagulopathy (TIC) has implicated platelets as a crucial mediator and potential therapeutic target in hemostasis. While the importance of abnormal coagulation tests is well described in trauma, there is a paucity of data regarding the role of platelets in coagulopathy. New coagulation models, namely the cell-based-model of hemostasis, have refocused attention toward the platelet and endothelium as key regulators of clot formation. Although platelet dysfunction has been associated with worse outcomes in trauma, the mechanisms which platelet dysfunction contributes to coagulopathy are poorly understood. The goal of this review article is to outline recent advances in understanding hemostasis and the ensuing cellular dysfunction that contributes to the exsanguination of a critically injured patient. PMID- 26056602 TI - The Wnt/beta-catenin pathway in human fibrotic-like diseases and its eligibility as a therapeutic target. AB - The canonical Wnt signaling pathway is involved in a variety of biological processes like cell proliferation, cell polarity, and cell fate determination. This pathway has been extensively investigated as its deregulation is linked to different diseases, including various types of cancer, skeletal defects, birth defect disorders (including neural tube defects), metabolic diseases, neurodegenerative disorders and several fibrotic diseases like desmoid tumors. In the "on state", beta-catenin, the key effector of Wnt signaling, enters the nucleus where it binds to the members of the TCF-LEF family of transcription factors and exerts its effect on gene transcription. Disease development can be caused by direct or indirect alterations of the Wnt/beta-catenin signaling. In the first case germline or somatic mutations of the Wnt components are associated to several diseases such as the familial adenomatous polyposis (FAP) - caused by germline mutations of the tumor suppressor adenomatous polyposis coli gene (APC) and the desmoid-like fibromatosis, a sporadic tumor associated with somatic mutations of the beta-catenin gene (CTNNB1). In the second case, epigenetic modifications and microenvironmental factors have been demonstrated to play a key role in Wnt pathway activation. The natural autocrine Wnt signaling acts through agonists and antagonists competing for the Wnt receptors. Anomalies in this regulation, whichever is their etiology, are an important part in the pathogenesis of Wnt pathway linked diseases. An example is promoter hypermethylation of Wnt antagonists, such as SFRPs, that causes gene silencing preventing their function and consequently leading to the activation of the Wnt pathway. Microenvironmental factors, such as the extracellular matrix, growth factors and inflammatory mediators, represent another type of indirect mechanism that influence Wnt pathway activation. A favorable microenvironment can lead to aberrant fibroblasts activation and accumulation of ECM proteins with subsequent tissue fibrosis that can evolve in fibrotic disease or tumor. Since the development and progression of several diseases is the outcome of the Wnt pathway cross-talk with other signaling pathways and inflammatory factors, it is important to consider not only direct inhibitors of the Wnt signaling pathway but also inhibitors of microenvironmental factors as promising therapeutic approaches for several tumors of fibrotic origin. PMID- 26056603 TI - Outlook on PI3K/AKT/mTOR inhibition in acute leukemia. AB - Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy. PMID- 26056604 TI - Polymeric nanocarriers for the treatment of systemic iron overload. AB - Desferrioxamine (DFO), deferiprone (L1) and desferasirox (ICL-670) are clinically approved iron chelators used to treat secondary iron overload. Although iron chelators have been utilized since the 1960s and there has been much improvement in available therapy, there is still the need for new drug candidates due to limited long-term efficacy and drug toxicity. Moreover, all currently approved iron chelators are of low molecular weight (MW) (<600 Da) and the objectives reported for the "ideal" chelator of low MW, including possessing the ability to promote iron excretion without causing toxic side effects, has proven difficult to realize in practice. With prolonged iron chelator use, patients may develop toxicities or become insensitive. In contrast, the limited research that has been geared towards developing higher MW, polymeric, long circulating iron chelators has shown promise. The inherent potential of polymeric iron chelators toward longer plasma half-lives and reduction in toxicity provides optimism and may be a significant addition to the currently available low MW iron chelators. This article reviews knowledge pertaining to this theme, highlights some unique advantages that these nanomedicines have in treating systemic iron overload as well as their potential utility in the treatment of other disease states. PMID- 26056605 TI - Cross talk of the first-line defense TLRs with PI3K/Akt pathway, in preconditioning therapeutic approach. AB - Toll-like receptor family (TLRs), pattern recognition receptors, is expressed not only on immune cells but also on non-immune cells, including cardiomyocytes, fibroblasts, and vascular endothelial cells. One main function of TLRs in the non immune system is to regulate apoptosis. TLRs are the central mediators in hepatic, pulmonary, brain, and renal ischemic/reperfusion (I/R) injury. Up regulation of TLRs and their ligation by either exogenous or endogenous danger signals plays critical roles in ischemia/reperfusion-induced tissue damage. Conventional TLR-NF-kappaB pathways are markedly activated in failing and ischemic myocardium. Recent studies have identified a cross talk between TLR activation and the PI3K/Akt pathway. The activation of TLRs is proposed to be the most potent preconditioning method after ischemia, to improve the cell survival via the mechanism involved the PI3K/Akt signaling pathway and to attenuate the subsequent TLR-NF-kappaB pathway stimulation. Thus, TLRs could be a great target in the new treatment approaches for myocardial I/R injury. PMID- 26056606 TI - Influence of renal complications on the efficacy and adverse events of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase: a single-centre, prospective study. AB - OBJECTIVES: The study investigated whether renal complications affected the efficacy and safety of tacrolimus combination therapy in patients with systemic lupus erythematosus (SLE) during a maintenance phase. METHODS: Fifty-seven patients with SLE (A: 30 cases with renal complication, B: 27 cases without renal complications) were included. The presence of renal complications was defined as proteinuria >=0.5 g/day and lupus nephritis on renal biopsy. Major outcome measures included SLE disease activity index (SLEDAI), steroid dose, serum anti dsDNA Ab, C3 and creatinine (Cr) levels and estimated glomerular filtration rate (eGFR). The patient's background factors included age, gender, disease duration and ACE-I/angiotensin II receptor blocker and statin therapies. We compared these outcome measures pre treatment and after 1 year of treatment. RESULTS: The SLEDAI and serum C3 levels improved in both groups from pretreatment period to post treatment period: from 7.2+/-5.0 to 2.8+/-2.3 in A and 6.4+/-3.8 to 2.4+/-2.2 in B, p<0.001, and from 65.9+/-24.6 to 77.7+/-18.2 mg/dL in A and 81.8+/-23.0 to 90.6+/-19.4 mg/dL in B, p=0.002, respectively. The anti-dsDNA antibody level was reduced, and the serum Cr and eGFR levels were slightly elevated. No patients developed end-stage renal failure that required artificial dialysis. CONCLUSIONS: Tacrolimus combination therapy had additive beneficial effects on reduced proteinuria and increased serum C3 levels in patients with SLE with renal complications during a maintenance phase. PMID- 26056607 TI - Dialogue: Early predictors of long-term lupus nephritis outcomes: looking into the future. PMID- 26056608 TI - Non-invasive EEG-based brain-computer interfaces in patients with disorders of consciousness. AB - Disorders of consciousness (DoCs) are chronic conditions resulting usually from severe neurological deficits. The limitations of the existing diagnosis systems and methodologies cause a need for additional tools for relevant patients with DoCs assessment, including brain-computer interfaces (BCIs). Recent progress in BCIs' clinical applications may offer important breakthroughs in the diagnosis and therapy of patients with DoCs. Thus the clinical significance of BCI applications in the diagnosis of patients with DoCs is hard to overestimate. One of them may be brain-computer interfaces. The aim of this study is to evaluate possibility of non-invasive EEG-based brain-computer interfaces in diagnosis of patients with DOCs in post-acute and long-term care institutions. PMID- 26056609 TI - Chorea: A Journey through History. AB - The original descriptions of chorea date from the Middle Ages, when an epidemic of "dancing mania" swept throughout Europe. The condition was initially considered a curse sent by a saint, but was named "Saint Vitus's dance" because afflicted individuals were cured if they touched churches storing Saint Vitus's relics. Paracelsus coined the term chorea Sancti Viti and recognized different forms of chorea (imaginativa, lasciva, and naturalis). In the 17th century, Thomas Sydenham provided an accurate description of what he termed chorea minor. He also described rheumatic fever but did not associate it with chorea. It was only in 1850 that See established a relationship between chorea and rheumatic disease. A connection with cardiac involvement was soon recognized and in 1866 Roger postulated that chorea, arthritis, and heart disease had a common cause. The last quarter of the 19th century is marked by the works of Jean-Martin Charcot, Silas Weir Mitchell, William Osler, and William Richard Gowers, all of paramount importance in the refinement of the definition of chorea, its causes, and differential diagnosis. In 1841, Charles Oscar Waters gave a concise account of a syndrome, likely to be Huntington's disease (HD), later described further by George Huntington and named after him. In 1955, the Venezuelan physician Americo Negrette published a book describing communities in the State of Zulia in Venezuela, with unusual numbers of individuals with chorea. Negrette's works culminated in the creation of the Venezuela project and the subsequent discovery of seminal findings in HD. We review the historical facts and outstanding physicians that mark both HD and Sydenham's chorea's history in various sections. PMID- 26056610 TI - White Matter Microstructure in Idiopathic Craniocervical Dystonia. AB - BACKGROUND: Dystonias are hyperkinetic movement disorders characterized by involuntary muscle contractions resulting in abnormal torsional movements and postures. Recent neuroimaging studies in idiopathic craniocervical dystonia (CCD) have uncovered the involvement of multiple areas, including cortical ones. Our goal was to evaluate white matter (WM) microstructure in subjects with CCD using diffusion tensor imaging (DTI) analysis. METHODS: We compared 40 patients with 40 healthy controls. Patients were then divided into subgroups: cervical dystonia, blepharospasm, blepharospasm + oromandibular dystonia, blepharospasm + oromandibular dystonia + cervical dystonia, using tract-based spatial statistics. We performed a region of interest-based analysis and tractography as confirmatory tests. RESULTS: There was no significant difference in the mean fractional anisotropy (FA) and mean diffusivity (MD) between the groups in any analysis. DISCUSSION: The lack of DTI changes in CCD suggests that the WM tracts are not primarily affected. PMID- 26056611 TI - Functional Aspects of Gait in Essential Tremor: A Comparison with Age-Matched Parkinson's Disease Cases, Dystonia Cases, and Controls. AB - BACKGROUND: An understanding of the functional aspects of gait and balance has wide ramifications. Individuals with balance disorders often restrict physical activity, travel, and social commitments to avoid falling, and loss of balance confidence, itself, is a source of disability. We studied the functional aspects of gait in patients with essential tremor (ET), placing their findings within the context of two other neurological disorders (Parkinson's disease [PD] and dystonia) and comparing them with age-matched controls. METHODS: We administered the six-item Activities of Balance Confidence (ABC-6) Scale and collected data on number of falls and near-falls, and use of walking aids in 422 participants (126 ET, 77 PD, 46 dystonia, 173 controls). RESULTS: Balance confidence was lowest in PD, intermediate in ET, and relatively preserved in dystonia compared with controls. This ordering reoccurred for each of the six ABC-6 items. The number of near-falls and falls followed a similar ordering. Use of canes, walkers, and wheelchairs was elevated in ET and even greater in PD. Several measures of balance confidence (ABC-6 items 1, 4, 5, and 6) were lower in torticollis cases than in those with blepharospasm, although the two groups did not differ with respect to falls or use of walking aids. DISCUSSION: Lower balance confidence, increased falls, and greater need for walking aids are variably features of a range of movement disorder patients compared to age-matched controls. While most marked among PD patients, these issues affected ET patients as well and, to a small degree, some patients with dystonia. PMID- 26056612 TI - Cryopreservation of lumpfish Cyclopterus lumpus (Linnaeus, 1758) milt. AB - This study has established a successful protocol to cryopreserve lumpfish Cyclopterus lumpus (Linnaeus, 1758) milt. Three cryosolutions were tested based on Mounib's medium; the original medium including reduced l-glutathione (GSH), the basic sucrose and potassium bicarbonate medium without GSH, or with hen's egg yolk (EY). Dimethyl sulphoxide (DMSO) was used as the cryoprotectant along with all three diluents in a 1-2 dilution. Cryopreservation was performed with the mentioned cryosolutions at two freezing rates. Motility percentages of spermatozoa were evaluated using ImageJ with a computer assisted sperm analyzer (CASA) plug-in. Findings revealed that spermatozoa cryopreserved in Mounib's medium without GSH had a post-thaw motility score of 6.4 percentage points (pp) higher than those in the original Mounib's medium, and an addition of EY to the modified Mounib's medium lowered the post-thaw motility score by 19.3 pp. The difference in motility between both freezing rates was 13.0 pp, and samples cryopreserved on a 4.8 cm high tray resulted in a better post-thaw motility score. On average, cryopreserved milt had a 24.1 pp lower post-thaw motility score than fresh milt. There was no significant difference in fertilisation success between cryopreserved and fresh milt. Cryopreservation of lumpfish milt has, to our knowledge, never been successfully carried out before. The established protocol will be a main contributing factor in a stable production of lumpfish juveniles in future. PMID- 26056613 TI - Seven new microendemic species of Brachycephalus (Anura: Brachycephalidae) from southern Brazil. AB - Brachycephalus (Anura: Brachycephalidae) is a remarkable genus of miniaturized frogs of the Brazilian Atlantic Rainforest. Many of its species are highly endemic to cloud forests, being found only on one or a few mountaintops. Such level of microendemism might be caused by their climatic tolerance to a narrow set of environmental conditions found only in montane regions. This restriction severely limits the chance of discovery of new species, given the difficulty of exploring these inaccessible habitats. Following extensive fieldwork in montane areas of the southern portion of the Atlantic Rainforest, in this study we describe seven new species of Brachycephalus from the states of Parana and Santa Catarina, southern Brazil. These species can be distinguished from one another based on coloration and the level of rugosity of the skin in different parts of their body. These discoveries increase considerably the number of described species of Brachycephalus in southern Brazil. PMID- 26056614 TI - Assessment of water pollution in the Brazilian Pampa biome by means of stress biomarkers in tadpoles of the leaf frog Phyllomedusa iheringii (Anura: Hylidae). AB - The Brazilian Pampa biome is currently under constant threat due to increase of agriculture and improper management of urban effluents. Studies with a focus on the assessment of impacts caused by human activities in this biome are scarce. In the present study, we measured stress-related biomarkers in tadpoles of the leaf frog Phyllomedusa iheringii, an endemic species to the Pampa biome, and tested its suitability as a bioindicator for the assessment of potential aquatic contamination in selected ponds (S1 and S2) nearby agricultural areas in comparison to a reference site. A significant decrease in acetylcholinesterase activity was observed in S2 when compared to S1 and reference. The levels of total-hydroperoxides were increased in S2 site. In parallel, increased activity of the antioxidant enzymes catalase, superoxide dismutase and glutathione S transferase were observed in S2 when compared to S1 and reference. Further studies are necessary in order to correlate the changes observed here with different chemical stressors in water, as well as to elucidate mechanisms of toxicity induced by pesticides in amphibian species endemic to the Pampa biome. Nevertheless, our study validates Phyllomedusa iheringii as a valuable bioindicator in environmental studies. PMID- 26056615 TI - The role of multiple negative social relationships in inflammatory cytokine responses to a laboratory stressor. AB - The present study examined the unique impact of perceived negativity in multiple social relationships on endocrine and inflammatory responses to a laboratory stressor. Via hierarchical cluster analysis, those who reported negative social exchanges across relationships with a romantic partner, family, and their closest friend had higher mean IL-6 across time and a greater increase in TNF-alpha from 15 min to 75 min post stress. Those who reported negative social exchanges across relationships with roommates, family, and their closest friend showed greater IL 6 responses to stress. Differences in mean IL-6 were accounted for by either depressed mood or hostility, whereas differences in the cytokine stress responses remained significant after controlling for those factors. Overall, this research provides preliminary evidence to suggest that having multiple negative relationships may exacerbate acute inflammatory responses to a laboratory stressor independent of hostility and depressed mood. PMID- 26056616 TI - Prior CT imaging history for patients who undergo PAN CT for acute traumatic injury. AB - Objective. A single PAN scan may provide more radiation to a patient than is felt to be safe within a one-year period. Our objective was to determine how many patients admitted to the trauma service following a PAN scan had prior CT imaging within our six-hospital system. Methods. We performed a secondary analysis of a prospectively collected trauma registry. The study was based at a level-two trauma center and five affiliated hospitals, which comprise 70.6% of all Emergency Department visits within a twelve county region of southern Texas. Electronic medical records were reviewed dating from the point of trauma evaluation back to December 5, 2005 to determine evidence of prior CT imaging. Results. There were 867 patients were admitted to the trauma service between January 1, 2012 and December 31, 2012. 460 (53%) received a PAN scan and were included in the study group. The mean age of the study group was 37.7 +/- 1.54 years old, 24.8% were female, and the mean ISS score was 13.4 +/- 1.07. The most common mechanism of injury was motor vehicle collision (47%). 65 (14%; 95% CI [11 18]%) of the patients had at least one prior CT. The most common prior studies performed were: CT head (29%; 19-42%), CT Face (29%; 19-42%) and CT Abdomen and Pelvis (18%; 11-30%). Conclusion. Within our trauma registry, 14% of patients had prior CT imaging within our hospital system before their traumatic event and PAN scan. PMID- 26056617 TI - Elevational gradient of Hemiptera (Heteroptera, Auchenorrhyncha) on a tropical mountain in Papua New Guinea. AB - Malaise trap sampling of Hemiptera (Heteroptera; Auchenorrhyncha) was conducted at 500 m intervals along an elevational gradient from 200 m to 3,700 m on the east slope of Mount Wilhelm, Madang Province, Papua New Guinea. Hemiptera had a decrease in morphospecies richness and overall abundance with increasing elevation, however, the Heteroptera did not exhibit either pattern. A few species were relatively abundant at each elevation, whereas the majority of species were represented by <=5 specimens. Morphospecies richness of Auchenorrhyncha, Cicadomorpha, Fulgoromorpha, Cicadellidae, Cixiidae, and Derbidae also decreased with increasing elevation but abundance decline was not significant due to the large number of specimens captured at 200 m relative to those captured at higher elevations. The percentage of Cicadomorpha specimens decreased with increasing elevation relative to that of the Fulgoromorpha which increased with increasing elevation. Environmental factors that may influence patterns of species richness along the elevational gradient are discussed. PMID- 26056618 TI - A four-year cardiovascular risk score for type 2 diabetic inpatients. AB - As cardiovascular risk tables currently in use were constructed using data from the general population, the cardiovascular risk of patients admitted via the hospital emergency department may be underestimated. Accordingly, we constructed a predictive model for the appearance of cardiovascular diseases in patients with type 2 diabetes admitted via the emergency department. We undertook a four-year follow-up of a cohort of 112 adult patients with type 2 diabetes admitted via the emergency department for any cause except patients admitted with acute myocardial infarction, stroke, cancer, or a palliative status. The sample was selected randomly between 2010 and 2012. The primary outcome was time to cardiovascular disease. Other variables (at baseline) were gender, age, heart failure, renal failure, depression, asthma/chronic obstructive pulmonary disease, hypertension, dyslipidaemia, insulin, smoking, admission for cardiovascular causes, pills per day, walking habit, fasting blood glucose and creatinine. A cardiovascular risk table was constructed based on the score to estimate the likelihood of cardiovascular disease. Risk groups were established and the c-statistic was calculated. Over a mean follow-up of 2.31 years, 39 patients had cardiovascular disease (34.8%, 95% CI [26.0-43.6%]). Predictive factors were gender, age, hypertension, renal failure, insulin, admission due to cardiovascular reasons and walking habit. The c-statistic was 0.734 (standard error: 0.049). After validation, this study will provide a tool for the primary health care services to enable the short-term prediction of cardiovascular disease after hospital discharge in patients with type 2 diabetes admitted via the emergency department. PMID- 26056619 TI - The metabolic cost of walking on an incline in the Peacock (Pavo cristatus). AB - Altering speed and moving on a gradient can affect an animal's posture and gait, which in turn can change the energetic requirements of terrestrial locomotion. Here, the energetic and kinematic effects of locomoting on an incline were investigated in the Indian peacock, Pavo cristatus. The mass-specific metabolic rate of the Indian peacock was elevated on an incline, but this change was not dependent on the angle ascended and the cost of lifting remained similar between the two inclines (+5 and +7 degrees ). Interestingly, the Indian peacock had the highest efficiency when compared to any other previously studied avian biped, despite the presence of a large train. Duty factors were higher for birds moving on an incline, but there was no difference between +5 and +7 degrees . Our results highlight the importance of investigating kinematic responses during energetic studies, as these may enable explanation of what is driving the underlying metabolic differences when moving on inclines. Further investigations are required to elucidate the underlying mechanical processes occurring during incline movement. PMID- 26056620 TI - The sensitivity of biological finite element models to the resolution of surface geometry: a case study of crocodilian crania. AB - The reliability of finite element analysis (FEA) in biomechanical investigations depends upon understanding the influence of model assumptions. In producing finite element models, surface mesh resolution is influenced by the resolution of input geometry, and influences the resolution of the ensuing solid mesh used for numerical analysis. Despite a large number of studies incorporating sensitivity studies of the effects of solid mesh resolution there has not yet been any investigation into the effect of surface mesh resolution upon results in a comparative context. Here we use a dataset of crocodile crania to examine the effects of surface resolution on FEA results in a comparative context. Seven high resolution surface meshes were each down-sampled to varying degrees while keeping the resulting number of solid elements constant. These models were then subjected to bite and shake load cases using finite element analysis. The results show that incremental decreases in surface resolution can result in fluctuations in strain magnitudes, but that it is possible to obtain stable results using lower resolution surface in a comparative FEA study. As surface mesh resolution links input geometry with the resulting solid mesh, the implication of these results is that low resolution input geometry and solid meshes may provide valid results in a comparative context. PMID- 26056621 TI - Profiling and initial validation of urinary microRNAs as biomarkers in IgA nephropathy. AB - Background. MicroRNAs (miRNAs) have been found in virtually all body fluids and used successfully as biomarkers for various diseases. Evidence indicates that miRNAs have important roles in IgA nephropathy (IgAN), a major cause of renal failure. In this study, we looked for differentially expressed miRNAs in IgAN and further evaluated the correlations between candidate miRNAs and the severity of IgAN. Methods. Microarray and RT-qRCR (real-time quantitative polymerase chain reaction) were sequentially used to screen and further verify miRNA expression profiles in urinary sediments of IgAN patients in two independent cohorts. The screening cohort consisted of 32 urine samples from 18 patients with IgAN, 4 patients with MN (membranous nephropathy), 4 patients with MCD (minimal changes disease) and 6 healthy subjects; the validation cohort consisted of 102 IgAN patients, 41 MN patients, 27 MCD patients and 34 healthy subjects. The renal pathological lesions of patients with IgAN were evaluated according to Lee's grading system and Oxford classification. Results. At the screening phase, significance analysis of microarrays analysis showed that no miRNA was differentially expressed in the IgAN group compared to all control groups. But IgAN grade I-II and III subgroups (according to Lee's grading system) shared dysregulation of two miRNAs (miR-3613-3p and miR-4668-5p). At the validation phase, RT-qPCR results showed that urinary level of miR-3613-3p was significantly lower in IgAN than that in MN, MCD and healthy controls (0.47, 0.44 and 0.24 folds, respectively, all P < 0.01 by Mann-Whitney U test); urinary level of miR 4668-5p was also significantly lower in IgAN than that in healthy controls (0.49 fold, P < 0.01). Significant correlations were found between urinary levels of miR-3613-3p with 24-hour urinary protein excretion (Spearman r = 0.50, P = 0.034), eGFR (estimated glomerular filtration rate) (r = - 0.48, P = 0.043) and Lee's grades (r = 0.57, P = 0.014). Similarly, miR-4668-5p was significantly correlated with eGFR (r = - 0.50, P = 0.034) and Lee's grades (r = 0.57, P = 0.013). For segmental glomerulosclerosis according to Oxford classification, patients scored as S0 had significantly lower levels of urinary miR-3613-3p and miR-4668-5p than those scored as S1 (0.41 and 0.43 folds, respectively, all P < 0.05). Conclusions. The expression profile of miRNAs was significantly altered in urinary sediments from patients with IgAN. Urinary expression of miR-3613-3p was down-regulated in patients with IgAN. Moreover, urinary levels of both miR-3613 3p and miR-4668-5p were correlated with disease severity. Further studies are needed to explore the roles of miR-3613-3p and miR-4668-5p in the pathogenesis and progression of IgA nephropathy. PMID- 26056622 TI - Population structure of three Psammodromus species in the Iberian Peninsula. AB - The knowledge of a species' population structure is essential for the development of adequate conservation actions as well as for the understanding of its evolution. The population structure is unknown in all species of the Genus Psammodromus, including the Western Sand Racer (Psammodromus occidentalis; a recently described species), the Edward's Sand Racer (P. edwardsianus) and the Spanish Sand Racer (P. hispanicus). In this article, the genetic variability and population structure of Psammodromus edwardsianus, P. hispanicus, and P. occidentalis were studied in the Iberian Peninsula covering their natural geographic distribution. Mitochondrial DNA showed genetically different units in all species with higher genetic variability in their southern populations (latitudinal variation). Genetic differentiation was different among species and contrasted to those of species with similar characteristics. Our results therefore highlight the importance of species-specific studies analysing population structure. PMID- 26056623 TI - NxRepair: error correction in de novo sequence assembly using Nextera mate pairs. AB - Scaffolding errors and incorrect repeat disambiguation during de novo assembly can result in large scale misassemblies in draft genomes. Nextera mate pair sequencing data provide additional information to resolve assembly ambiguities during scaffolding. Here, we introduce NxRepair, an open source toolkit for error correction in de novo assemblies that uses Nextera mate pair libraries to identify and correct large-scale errors. We show that NxRepair can identify and correct large scaffolding errors, without use of a reference sequence, resulting in quantitative improvements in the assembly quality. NxRepair can be downloaded from GitHub or PyPI, the Python Package Index; a tutorial and user documentation are also available. PMID- 26056624 TI - Soundscape manipulation enhances larval recruitment of a reef-building mollusk. AB - Marine seafloor ecosystems, and efforts to restore them, depend critically on the influx and settlement of larvae following their pelagic dispersal period. Larval dispersal and settlement patterns are driven by a combination of physical oceanography and behavioral responses of larvae to a suite of sensory cues both in the water column and at settlement sites. There is growing evidence that the biological and physical sounds associated with adult habitats (i.e., the "soundscape") influence larval settlement and habitat selection; however, the significance of acoustic cues is rarely tested. Here we show in a field experiment that the free-swimming larvae of an estuarine invertebrate, the eastern oyster, respond to the addition of replayed habitat-related sounds. Oyster larval recruitment was significantly higher on larval collectors exposed to oyster reef sounds compared to no-sound controls. These results provide the first field evidence that soundscape cues may attract the larval settlers of a reef-building estuarine invertebrate. PMID- 26056625 TI - The Association between Family Structure and Adolescent Smoking among Multicultural Students in Hawaii. AB - OBJECTIVE: The purpose of this study was to examine whether the prevalence of smoking was associated with family structure among multicultural adolescents and whether there was gender disparity on the association. METHODS: Data were collected from a sample of 7th graders in Hawaii who completed in-class questionnaires in 2004. The final sample included 821 multicultural students from different family structures. Descriptive analyses, Chi-square tests and logistic regression were performed to examine the prevalence of smoking and the association between family structure and smoking prevalence. RESULTS: This sample contained students who lived in intact (61.7%), single-parent (16.5%), step parent (15.6%), and no-parent (6.2%) families. The overall prevalence of ever/lifetime smoking was 24.0%, and was not significantly different between genders in each family structure (p>0.05). Compared with living in intact families, living in single-parent, step-parent, or no-parent families was significantly associated with higher odds of ever/lifetime smoking among all students (p<0.05) and living in single-parent and stepparent families was significantly associated with higher odds of ever/lifetime smoking among females (p<0.05) and among males (p<0.05) respectively, after adjusting for covariates. CONCLUSIONS: These findings suggest that family structure is a risk factor for smoking among multicultural students. Anti-smoking programs should consider this factor. PMID- 26056626 TI - The short term effects of preoperative neuroscience education for lumbar radiculopathy: A case series. AB - BACKGROUND: Recently a preoperative pain neuroscience education (NE) program was developed for lumbar surgery (LS) for radiculopathy as a means to decrease postoperative pain and disability. This study attempts to determine the short term effects, if any, of providing NE before surgery on patient outcomes. METHODS: A case series of 10 patients (female = 7) received preoperative one-on one educational session by a physical therapist on the neuroscience of pain, accompanied by an evidence-based booklet, prior to LS for radiculopathy. Post intervention data was gathered immediately after NE, as well as 1, 3 and 6 months following LS. Primary outcome measures were Pain Catastrophization Scale (PCS), forward flexion, straight leg raise (SLR) and beliefs regarding LS. RESULTS: Immediately following NE for LS for radiculopathy, all patients had lower PCS scores, with 5 patients exceeding the MDC score of 9.1 and 8 of the patients had PCS change scores exceeding the MDC by the 1, 3 and 6 month follow ups. Physical changes showed that fingertip-to-floor test in 6 patients had changes in beyond the MDC of 4.5 cm and 6 patients had changes in SLR beyond the MDC of 5.7 degrees . The main finding, however, indicated a positive and more realistic shift in expectations regarding pain after the impending LS by all patients. CONCLUSIONS: The results of the case series suggest that immediately after NE, patients scheduled for LS for radiculopathy had meaningful detectable changes in pain catastrophizing, fingertip-to-floor test, passive SLR and positive shifts in their beliefs about LS. PMID- 26056627 TI - The Incidence of Lumbar Discectomy after Epidural Steroid Injections or Selective Nerve Root Blocks. AB - BACKGROUND: The purpose of this study was to determine the use of Central Epidural Steroid Injections (ESI) and Selective Nerve Root Blocks (SNRB) along with the crossover rate to lumbar discectomy in patients with a lumbar disc herniation using retrospective records database search. Butterman et al found a crossover rate for patients with symptomatic disc herniations treated with ESI of 54% (27/50), while Riew similarly found a 53% (29/55) crossover patients receiving SNRB. METHODS: The database was searched in a sequential Boolean style for patients with the diagnosis of a lumbar disc herniation (Displaced Lumbar Disc - 722.1) and a SNRB (64483) or ESI (62311) who subsequently underwent a Lumbar Discectomy (63030) over a three year time period from January 2004 through December 2006. Statistical analysis was preformed examining the impact of injection type, age, location, gender, and year. RESULTS: Of 482,893 patients with the diagnosis of a disc herniation, 27,799(5.76%) underwent a lumbar discectomy. The 29,941 patients who received at least one SNRB for a disc herniation, 10.80% later underwent a lumbar discectomy. The 41,420 patients who received at least one ESI for a disc herniation 9.34% later underwent a lumbar discectomy. There was a noted increase in injection procedures, particularly SNRB during the study with a greater than 50% increase. CONCLUSIONS: Our examination found a much smaller, but similar crossover rate to surgery between both injection methods, which argues against one method being more effective than another in avoiding surgery. It is likely that patients are receiving these procedures more frequently during the course of conservative treatment for a disc herniation. LEVEL OF EVIDENCE: This was a Level III study. PMID- 26056628 TI - Role of posterior elements in the disc bulging of a degenerated cervical spine. AB - BACKGROUND: Many studies have been developed to characterize the mechanical behavior of the intervertebral disc specifically for the lumbar spine and there have been limited studies done on the cervical spine with the goal to evaluate the strength of the cervical spine under compression without any information on the bulging of the intervertebral discs. The goal of the current study is to examine the deformation response of the cervical intervertebral disc classified with grade III or greater degeneration and analyze the relationship between axial deformation and anterior and posterior bulge under compression up to 550 N. METHODS: Each specimen was compressed for 3 cycles to a maximum load of 550N in steps of 50 N. The bulge was measured using Linear Variable Differential Transformers (LVDTs on an intact spinal segment, spinal segment with post laminectomy, and spinal segment post facetectomy. RESULTS: The anterior budge for an intact spinal segment shows a change of slope at loads of 262N+/-66N. For a physiological load of 250N the vertical displacement or spine segment height was reduced by 10.1% for an intact segment and 8.78% for the laminectomy and facetectomy configurations with F = 0.159 (Fcrit = 3.89) with no statistical difference observed. For the post laminectomy there was a decrease of 35% in anterior bulge compared to the intact specimen. CONCLUSIONS: Our results show that for grade III disc degeneration the cervical segments bulging for both the laminectomy and facetectomy procedures are not significantly different. In post laminectomy the average anterior and posterior bulges are similar to the average anterior and posterior bulge post facetectomy. PMID- 26056629 TI - Comparison of Single-Level and Multiple-Level Outcomes of Total Disc Arthroplasty: 24-Month Results. AB - BACKGROUND: Low back pain is one of the most prevalent problems in industrialized countries, affecting as many as 80% of all adults at some time in their lives. Among the significant contributors to low back pain is degenerative disc disease (DDD). Although fusion has been well accepted for treatment of DDD, high rates of complications and stress to adjacent segments remain a concern. Lumbar total disc replacement (TDR) was developed with a goal of preserving motion and avoiding various fusion-related complications, but the relative merits of single vs. multiple level arthroplasty remain unclear. METHODS: This is a multi-center, single arm, prospective post-market registry of the M6-L, consisting of consecutive patients presenting with lumbar DDD who agreed to participate. This paper reports on those patients who have completed at least 24 months of followup to date. Clinical outcome measures include the Oswestry Disability Index (ODI) and back and leg Visual Analogue Scales (VAS). Radiographic analysis of disc angle and range of motion (ROM) was also performed. RESULTS: Results for 83 patients comprising 121 implants in two cohorts (49 single level (SL), 34 multiple levels (ML)) are reported. Both cohorts experienced significant improvement at 24 months including significant decreases in ODI and VAS. Relative to SL procedures, ML procedures demonstrated either comparable results, or results that trended favorably towards the ML procedures. Index and global ROM at 24 months were not significantly different between the two cohorts, while the disc angles were larger in the SL cohort regardless of index level. CONCLUSIONS: This is the first study to report clinical and radiographic outcomes of TDR with the M6-L in SL vs ML procedures with two years of followup. The results suggest initial device safety and effectiveness when used for the treatment of lumbar degenerative disc disease at one or more levels. PMID- 26056630 TI - Therapeutic sustainability and durability of coflex interlaminar stabilization after decompression for lumbar spinal stenosis: a four year assessment. AB - BACKGROUND: Approved treatment modalities for the surgical management of lumbar spinal stenosis encompass a variety of direct and indirect methods of decompression, though all have varying degrees of limitations and morbidity which potentially limit the efficacy and durability of the treatment. The coflex((r)) interlaminar stabilization implant (Paradigm Spine, New York, NY), examined under a United States Food and Drug Administration (US FDA) Investigational Device Exemption (IDE) clinical trial, is shown to have durable outcomes when compared to posterolateral fusion in the setting of post-decompression stabilization for stenotic patients. Other clinical and radiographic parameters, more indicative of durability, were also evaluated. The data collected from these parameters were used to expand the FDA composite clinical success (CCS) endpoint; thus, creating a more stringent Therapeutic Sustainability Endpoint (TSE). The TSE allows more precise calculation of the durability of interlaminar stabilization (ILS) when compared to the fusion control group. METHODS: A retrospective analysis of data generated from a prospective, randomized, level-1 trial that was conducted at 21 US sites was carried out. Three hundred forty-four per-protocol subjects were enrolled and randomized to ILS or fusion after decompression for lumbar stenosis with up to grade 1 degenerative spondylolisthesis. Clinical, safety, and radiographic data were collected and analyzed in both groups. Four-year outcomes were assessed, and the TSE was calculated for both cohorts. The clinical and radiographic factors thought to be associated with therapeutic sustainability were added to the CCS endpoints which were used for premarket approval (PMA). RESULTS: Success rate, comprised of no second intervention and an ODI improvement of >= 15 points, was 57.6% of ILS and 46.7% of fusion patients (p = 0.095). Adding lack of fusion in the ILS cohort and successful fusion in the fusion cohort showed a CCS of 42.7% and 33.3%, respectively. Finally, adding adjacent level success to both cohorts and maintenance of foraminal height in the coflex cohort showed a CCS of 36.6% and 25.6%, respectively. With additional follow-up to five years in the U.S. PMA study, these trends are expected to continue to show the superior therapeutic sustainability of ILS compared to posterolateral fusion after decompression for spinal stenosis. CONCLUSION: There are clear differences in both therapeutic sustainability and intended clinical effect of ILS compared to posterolateral fusion with pedicle screw fixation after decompression for spinal stenosis. There are CCS differences between coflex and fusion cohorts noted at four years post-op similar to the trends revealed in the two year data used for PMA approval. When therapeutic sustainability outcomes are added to the CCS, ILS is proven to be a sustainable treatment for stabilization of the vertebral motion segment after decompression for lumbar spinal stenosis. PMID- 26056631 TI - Gene expression profiling reveals a possible role for somatostatin in the innate immune response of the liver. AB - Somatostatin is a neuropeptide hormone that inhibits pituitary growth hormone (GH) release. Using microarray analysis of gene expression in the livers of wildtype control and somatostatin knockout mice, we have previously identified a panel of genes whose GH-dependent and sexually dimorphic expression patterns are significantly altered by the absence of somatostatin (1). Here, we provide methodological and analytical details of that study, the raw data of which is deposited in the Gene Expression Omnibus as data set GSE56520. In addition, we performed further gene ontology analysis of the data and found that the differential expression of a second subset of genes in the livers of somatostatin knockout mice versus wildtype controls is likely independent of GH signaling and involved in the innate immune response. PMID- 26056632 TI - Medical Tourism in Malaysia: Prospect and Challenges. AB - BACKGROUND: Tourism, combined with the phrase medical, seems to be a new form of tourism which has gained huge popularity in recent decades. Though, a number of literatures available with regard to the tourism industry and the competitiveness of the destination, however, the major aspects which determine the satisfaction of medical tourists are hardly focused specifically on Malaysia. There is a lack of empirical evidence in this area of study which needs to be bridged. Hence, this study aimed at investigating the various factors contributing towards the development of medical tourism in Malaysia. METHODS: As the purpose of the research was to find out various factors contributing towards the development of medical tourism in Malaysia, so this study used Structural Equation modeling (SEM) for data analysis. The target population for this study consisted of the medical tourists coming to Malaysia with the primary intension of seeking medical procedures other than sightseeing. A total sample size of 266 was collected through non-probability judgment sampling during the period between December 2012 and February 2013. RESULTS: The result confirms that destination competitiveness and service quality play an important role in the medical tourist's mind towards medical tourism aspect in Malaysia. Thus, Malaysia need to promote various medical success stories together with the services they offer to attract more foreign patients. CONCLUSION: This study contributes to the theoretical development in the tourism industry by offering the structured relationship among various aspects contributing towards the development of medical tourism in Malaysia. PMID- 26056633 TI - Influence of Social Support on Health-Related Quality of Life in New-Generation Migrant Workers in Eastern China. AB - BACKGROUND: The World Health Organization Quality of Life-BREF (WHOQOL-BREF) has generally been used for patients, few studies in migrants who move from rural to urban within one country. Many studies asserted that social isolation presents a risk to individual health. Poor social networks are associated with worse QOL. This study examined health-related quality of life (HRQOL) and social support in new-generation migrant workers and compared it with urban workers. METHODS: Nine hundred thirty new-generation migrant workers and 939 urban controls completed the WHOQOL-BREF questionnaire and Social Support Rating Scale (SSRS) by stratified sampling in 2011. Spearman's correlation was performed to clarify the relationship between social support and HRQOL in migrants. Multiple linear regression analyses were used to identify the variables that were associated with HRQOL. RESULTS: The general health, psychological health, and environmental scores of QOL in new-generation migrant workers were lower than in urban workers. New-generation migrants had poorer social support compared with urban controls with regard to general support, objective support, and support utilization. A positive correlation was found between social support and HRQOL. Workers with a higher level of education achieved better psychological, environmental, and general scores than workers with a primary education. Physical, social, environmental, and general health was also closely connected with the age factor. Physical health scores were higher in males than in females. CONCLUSION: These data suggest that new-generation migrant workers have significant impairment in HRQOL and receive less social support. HRQOL may be affected by social support, education, age, and gender. PMID- 26056634 TI - Comparative Assessment of Intelligence Quotient among Children Living in High and Low Fluoride Areas of Kutch, India-a Pilot Study. AB - BACKGROUND: Long-term ingestion of large amounts of fluoride can lead to potentially severe skeletal problems and neurological consequences. The study was conducted to assess and compare intelligence quotient of children living in high and low fluoride areas in Kutch, Gujarat, India. METHODS: A cross-sectional descriptive survey was conducted among 100 school children aged 8 to 10 years, living in Kutch District, Gujarat, India during July 2012. Mundra (2.4 to 3.5 mg/L) and Bhuj (0.5mg/L) were the two villages randomly selected to represent the high and low water fluoride areas respectively. Seguin Form Board Test was used to assess the intelligence quotient (IQ) level of children. Descriptive statistics and independent sample t-test was used for analysis. RESULTS: Mean scores for average, shortest and total timing category were found to be significantly higher (P<0.05) among children living in Mundra (30.45+/-4.97) than those living in Bhuj (23.20+/-6.21). Mean differences at 95% confidence interval for these timings were found to be 7.24, 7.28 and 21.78 respectively. In both the villages, females had lower mean timing scores than males but the difference was not statistically significant (P>0.05). CONCLUSION: Chronic exposure to high levels of fluoride in water was observed to be associated with lower intelligence quotient. PMID- 26056635 TI - Back Pain - Are Health Care Undergraduates At Risk? AB - BACKGROUND: To study the prevalence of low back pain in medical and nursing undergraduate students in our institutes and its association with physical activity, smoking, depression, use of computer and other variables. METHODS: It was a comparative cross sectional study carried out at two institutes of Dow University of Health Sciences, Karachi, Pakistan during October to December 2011. Two hundred and fifteen undergraduate students representing different semesters were asked to fill out the structured questionnaire. Back pain was assessed in terms of lifetime, one year and point prevalence. Bivariate analysis was done to study the relationship between back pain and different variables; including gender, study program, smoking, computer use, depression and level of physical activity. Both the groups were compared for duration/intensity of pain, seeking medical advice and duration of computer use. RESULTS: There were 183 undergraduate students who completed the questionnaire for back pain. Mean age was 22.84 (SD +/- 5.85) years. Gender distribution was nearly equal (females = 51.4%). Life time prevalence was 57.9% (72% in medical students; 41% in nursing students). Medical students were 0.47 times more at risk of having back pain (95% CI 0.15-1.48; P=0.198). Smoking (OD=0.39; 95% CI 0.04-3.6; P=0.001) and use of laptop (OD=4.9; 95% CI 1.2-19.2; P=0.031) were found to be associated with increased prevalence of back pain. Nursing students sought medical opinion more as compared to medical students but it was not significant. However duration of computer use was more in medical students which was significant (P=0.03). CONCLUSION: High lifetime prevalence of back pain was observed in undergraduate students. Medical students appeared to be more at risk. Preventive measures are required to improve the quality of life in future health care professionals. PMID- 26056636 TI - Application of Western Blotting for the Post-Treatment Monitoring of Human Cystic Echinococcosis. AB - BACKGROUND: Cystic echinococcosis (CE) is one of the most important parasitic zoonosis worldwide. Due to the high recurrence rate of the disease after surgery, follow up of the patient is necessary. The aim of current research was to assess the performance of Western blotting (WB), using sheep hydatid fluid, for serological diagnosis and post-treatment monitoring of human CE. METHODS: Serum samples obtained from 50 clinically/radiologically proven cases of CE along with serum samples from non-CE patients and healthy persons were tested by WB, using sheep hydatid fluid as antigen. RESULTS: The WB test enabled the detection of antibodies in the pre-operative samples for proteins of 18-239 kDa in molecular weight. From 50 sera of CE patients, 31 cases (72.09%) detected 52 kDa subunit, 27 cases (62.79%) detected 24 kDa band, 26 cases (60.46%) recognised 39 kDa band and 21 cases (48.83%) identified 46 kDa component of sheep hydatid antigen. Sera from patients with other parasitic infections and malignancy showed cross reactivity with the cluster of 54-59 kDa bands. The healthy control sera were not reactive to any antigenic fraction. The antigenic bands with molecular weight of 52, 24, 39 and 46 kDa were specific for CE, and may serve as useful diagnostic markers. The antibodies specific to proteins 24 and 39 kDa significantly decreased in the patients cured after surgery, while in patients with recurrent parasitism the bands present before surgery persisted. CONCLUSION: The WB with sheep hydatid antigen might be useful in the diagnosis and post-surgical monitoring of CE patients. PMID- 26056637 TI - Gender Differences in Mental Health among Adult Population in Vojvodina, Serbia. AB - BACKGROUND: Mental health and mental disorders are determined by multiple and interacting social, psychological and biological factors which determine the prevalence, onset and course of mental and behavioral disorders. The aim of the study was to evaluate differences in mental health status regarding gender of the adult population in the Province of Vojvodina. METHODS: Research was carried out as a retrospective cross-sectional study. Data was obtained from the "National Health Survey in Serbia, 2006" database that refers to the representative adult population of Vojvodina, aged 20 and over. A specially designed questionnaire was applied as a research instrument. RESULTS: This study included 3627 examinees, average age 49.9 years. In the month prior to the study, a half of the adult population in Vojvodina (48.4%) was exposed to stress and one third had emotional problems (32.9%), while both stress and emotional problems were more prevalent in females. The average score value on the psychological distress scale (presence of negative conditions and feelings) of all examinees was 64.1 (from 0 to 100) and it was statistically significantly lower in women (62.0), compared to men (66.6) (P<0.001). Statisticaly significant differences were also observed between average score values on the role-emotional and vitality scales (P<0.001). CONCLUSION: When mental health is considered, this research showed that female population is more vulnerable compared to males. Women are more often exposed to stressful situations and emotional problems and more often faced with negative conditions and feelings. PMID- 26056638 TI - Barrier and Facilitators of HIV Related Risky Sexual Behavior. AB - BACKGROUND: This study was conducted to identify the determinants of protective behavior in relation to HIV transmission. Since the risk of transmission is higher among those who have extramarital intercourse, the study sample constituted of such people. METHODS: We started this study in 2010 and finished it in 2011. Participants were divided into low-risk and high-risk groups. High risk people included sex workers and those who presented at drop-in centers. Interviewees were 18 men and women in the low-risk group and 12 men and women in the high-risk group. Data were collected through in-depth interviews and were analyzed using the thematic framework method. RESULTS: In both groups, protective behavior was influenced by willingness to protect, intention or decision to protect, and personal, social, and environmental barriers and facilitators. In terms of willingness, behavior was influenced to preserve sexual pleasure by avoiding condoms. In terms of barriers and facilitators, trust in partner, misperceptions, condom inaccessibility, unplanned sex, fear of contracting the disease, partner's wish, ethical commitments were mentioned by both groups, stigma of condom possession by the low-risk group, and partner's force was mentioned by the high-risk group. CONCLUSION: Educational programs need to focus on changing the concept that "condoms reduce sexual pleasure". In addition, interventional programs to strengthen factors such as self-efficacy, ethical commitments, faithfulness, and correct beliefs such as undue trust in partner, misconception of being safe, unplanned sex, and the stigma of possessing condoms can be very effective in changing high-risk sexual behavior. PMID- 26056639 TI - Predictors of Unintended Pregnancy among Married Women in Hamadan, Western Iran: A Case-Control Study. AB - BACKGROUND: Literatures that focus on the risk factors of unintended pregnancy among married women are limited especially in developing countries. The aim of this study was to determine the predictors of unintended pregnancy in a west region of Iran. METHODS: This case-control study was conducted from September to November 2011 in Hamadan City, western Iran. A stratified cluster random sampling method was used for data collection. All participants were enrolled voluntarily into the study including 181 cases and 391 controls. Cases were married women with unintended pregnancy. Controls were married women with planned pregnancy. RESULTS: Of 572 participants, 31 (5.4%) women had not used any methods of contraception prior to the recent pregnancy. The proportion of using ineffective contraceptive methods such as withdrawal was higher in cases than in controls. The most effective predictor of unintended pregnancy was the number of previous alive children so that the risk of unplanned pregnancy increased 3.68 per one child (P<0.001). CONCLUSION: This study introduced several effective predictors for unintended pregnancy among married women which may be useful for family planning programs. The high-risk population should be strongly advised to use highly effective contraceptive methods such as tubal ligation, vasectomy or OCP provided that being used correctly. PMID- 26056640 TI - Investigation of Anaerobic Fluidized Bed Reactor/ Aerobic Moving Bed Bio Reactor (AFBR/MMBR) System for Treatment of Currant Wastewater. AB - BACKGROUND: Anaerobic treatment methods are more suitable for the treatment of concentrated wastewater streams, offer lower operating costs, the production of usable biogas product. The aim of this study was to investigate the performance of an Anaerobic Fluidized Bed Reactor (AFBR)-Aerobic Moving Bed Bio Reactor (MBBR) in series arrangement to treat Currant wastewater. METHODS: The bed materials of AFBR were cylindrical particles made of PVC with a diameter of 2-2.3 mm, particle density of 1250 kg/m(3). The volume of all bed materials was 1.7 liter which expanded to 2.46 liters in fluidized situation. In MBBR, support media was composed of 1.5 liters Bee-Cell 2000 having porosity of 87% and specific surface area of 650m(2)/m(3). RESULTS: When system operated at 35 oC, chemical oxygen demand (COD) removal efficiencies were achieved to 98% and 81.6% for organic loading rates (OLR) of 9.4 and 24.2 g COD/l.d, and hydraulic retention times (HRT) of 48 and 18 h, in average COD concentration feeding of 18.4 g/l, respectively. CONCLUSION: The contribution of AFBR in total COD removal efficiency at an organic loading rate (OLR) of 9.4 g COD/l.d was 95%, and gradually decreased to 76.5% in OLR of 24.2 g COD/l.d. Also with increasing in organic loading rate the contribution of aerobic reactor in removing COD gradually decreased. In this system, the anaerobic reactor played the most important role in the removal of COD, and the aerobic MBBR was actually needed to polish the anaerobic treated wastewater. PMID- 26056641 TI - Evaluation of Occupational Exposure of Glazers of a Ceramic Industry to Cobalt Blue Dye. AB - BACKGROUND: Cobalt is one of the most important constituent present in ceramic industries. Glazers are the relevant workers when they are producing blue colored ceramic, causing occupational exposure to such metal. Through this study, urinary cobalt was determined in glazers in a ceramic industry when they were producing blue-colored ceramic glazes. METHODS: In this case-control study, spot urine samples were collected from 49 glazers at the start and end of work shifts (totally 98 samples) in 2011. Control group were well matched for age, height, and weight. A solid phase extraction system was used for separation and preconcentration of samples followed by analysis by inductively coupled plasma atomic emission spectroscopy (ICP-AES). All participants filled out a self administered questionnaire comprises questions about duration of exposure, work shift, use of mask, skin dermatitis, kind of job, ventilation system, overtime work, age, weight, and height. The lung function tests were performed on each control and cobalt exposed subjects. Analysis of covariance (ANCOVA) was used to evaluate the obtained results. RESULTS: Urinary levels of cobalt were significantly higher in the glazers compared to the control group. There were significant differences at urinary concentration of cobalt at the start and end of the work shift in glazers. Spirometric parameters were significantly lower in the glazers compared to the control group. Among the variables used in questionnaire the significant variables were dermatitis skin, mask, ventilation, and overtime work. CONCLUSION: This study verified existence of cobalt in the urine glazers, showing lower amount than the ACGIH standard. PMID- 26056642 TI - Performance Ratio Analysis: A National Study on Iranian Hospitals Affiliated to Ministry of Health and Medical Education. AB - BACKGROUND: This study was designed to present and compare Iranian hospitals' performance applying ratio analysis technique. METHODS: This cross-sectional survey was conducted to present an instant image of 139 Iranian hospitals' performance status applying ratio analysis as one of the non parametric technical efficiency assessment methods in 2008. Data was collected using nine dimensional questionnaires supported by world wide web to achieve main hospital ratios. Final analysis was performed applying classic statistics and relevant statistical tests on significant level of 0.05. RESULTS: Four hospital performance indicators were estimated in the studied hospitals as follows: Bed turnover rate (BTR) was fluctuated from 64.5 to 114.8 times for hospitals located in rich and poor areas respectively. Moreover Bed Interval Rate (BIT) was calculated 1.36 versus 2.4 in the poor and rich areas. Average length of stay (ALS) was computed 1.82 for the poor regions but 3.27 for the rich ones furthermore, a positive statistical significant correlation was seen between ALS and the hospital size (P=0.001, r=0.28). Average bed occupancy rate (BOR) was 57.8% and its variation was from 31.4% to 64.5% depending on the hospital size so that there was a positive statistical significant relationship between the hospital size and BOR (P=0.006, r=0.32). CONCLUSION: Regarding that BOR, ALS, BTR and BIT along with mortality rates are mentioned as the most considerable performance indicators, applying analytic frameworks more than considering single and raw indicators are severely recommended. PMID- 26056643 TI - Evaluation of Effectiveness of Ethanolic Extract of Artemisia aucheri, Individually and in Combination with Chloroquine, on Chloroquine - Sensitive Strain of Plasmodium berghei in Sourian Mice. AB - BACKGROUND: Drug resistance in malaria parasites is extending in the world particularly in chemical synthesized drugs such as 4- aminoquinolines and aminoalcoholes. Employing herbal extracts is encouraged by WHO in the malarious areas. In this study, the effectiveness of ethanolic extract of Artemisia aucheri individually and in combination with chloroquine, has been considered against chloroquine - sensitive strain of Plasmodium berghei. METHODS: At the first stage, ED50 of A. aucheri and chloroquine on P. berghei was calculated using in vivo test. Then based on the ED50s combination of A. aucheri and chloroquine with ratios of 0/100,10/90,20/80,30/70,40/60,50/50,60/40,70/30,80/20,90/10 and100/0 were tested against the parasite. For evaluating the adverse effect of A. aucheri on the mice, for two weeks 1000mg/kg of the extract was daily employed and the mice were followed up for fifty days. RESULTS: ED50s for chloroquine and A. aucheri were 1.6mg/kg and 1000mg/kg respectively. The outcome of two drugs combination on the mice showed antagonistic effects on the chloroquine - sensitive strain of parasite. Two weeks daily administration of A. aucheri had no toxic effect on the mice. CONCLUSION: A. aucheri individually can be effective in reducing the parasite while in combination with chloroquine loses its property. PMID- 26056644 TI - Effect of Family Structure and Behavioral and Eyesight Problems on Caries Severity in Pupils by Using an Ordinal Logistic Model. AB - BACKGROUND: Dental caries is one of the most preventable yet prevalent chronic diseases worldwide. Our objective was to evaluate the effect of family structure and behavioral and eyesight problems as they relate to caries severity in schoolchildren. METHODS: This research was carried out on 845 primary schoolchildren aged 9 yr in Kerman, Iran, in 2012. Ten variables, including health records, family structure information and a dmft/DMFT index, were collected. Children were categorized into three groups based on the WHO caries severity classification. Low caries level was defined as dmft/DMFT<2.6, moderate as dmft/DMFT of 2.7-4.4 and high as dmft/DMFT>4.4. The Cochran-Armitage test and ordinal logistic regression were employed for data analysis. RESULTS: Almost half of pupils had moderate or high caries severity. The odds of being in a higher caries severity category in pupils with behavioral problems (OR=2.37, 95% CI: 1.29-4.38) and girls (OR=1.6, 95% CI: 1.22-2.06) were higher than in other categories. In addition, pupils with eyesight problems (OR=0.58, 95% CI: 0.37 0.90) and overweight pupils (OR=0.46, 95% CI: 0.31-0.71) had lower caries severity than others. The effects of parents' education, birth rank, living with parents and consanguineous relationship between parents were not significant on caries severity (P>0.05). CONCLUSIONS: Female pupils with behavioral problems were at a higher risk of caries severity than other pupils. These pupils need to be educated and coached on proper dental care. In addition, overweight pupils and those with eyesight problems had less caries severity than others. Family structure in this study did not have an effect on the severity of dental caries. PMID- 26056645 TI - Effectiveness of Relapse Prevention Cognitive-Behavioral Model in Opioid Dependent Patients Participating in the Methadone Maintenance Treatment in Iran. AB - BACKGROUND: To evaluate the effectiveness of a relapse prevention cognitive behavioral model, based on Marlatt treatment approach, in Opioid-dependent patients participating in the Methadone Maintenance Treatment (MMT) in Iran. METHODS: The study consisted of 92 individuals treated with methadone in Iranian National Center of Addiction Studies (INCAS). Participants were randomized into two groups: educational intervention group (N=46) and control group (N=46). The intervention was comprised of 10 weekly 90 minute sessions, done during a period of 2.5 months based on the most high risk situations determined using Inventory Drug Taking Situation instrument. Relapse was defined as not showing up for MMT, drug use for at least 5 continuous days, and a positive urinary morphine test. RESULTS: While, only 36.4% of the intervention group relapsed into drug use, 63.6% of the control group relapsed. The result of the logistic regressions showed that the odd ratio of the variable of intervention program for the entire follow up period was 0.43 (P<0.01). Further, the odd ratio of this variable in one month, three months, and 195 days after the therapy were 0.48 (P<.03), 0.31 (P<.02), and 0.13 (P<.02) respectively that revealed that on average, the probability of relapse among individuals in the intervention group was lower than patients in control group. CONCLUSION: Relapse prevention model based on Marlatt treatment approach has an effective role in decreasing relapse rate. This model can be introduced as a complementary therapy in patients treated with methadone maintenance. PMID- 26056646 TI - Measurement of (226) Ra, (232) Th, (137) Cs and (40) K activities of Wheat and Corn Products in Ilam Province - Iran and Resultant Annual Ingestion Radiation Dose. AB - BACKGROUND: BACKGROUND: Natural background radiation is the main source of human exposure to radioactive material. Soils naturally have radioactive mineral contents. The aim of this study is to determine natural ((238) U, (232) Th, (40) K) and artificial ((137) Cs) radioactivity levels in wheat and corn fields of Eilam province. METHODS: HPGe detector was used to measure the concentration activity of (238) U and (232) Th series, (40) K and (137) Cs in wheat and corn samples taken from different regions of Eilam province, in Iran. RESULTS: In wheat and corn samples, the average activity concentrations of (226) Ra, (232) Th, (40) K and (137) Cs were found to be 1, 67, 0.5, 91.73, 0.01 and 0.81, 0.85, 101.52, 0.07 Bq/kg (dry weight), respectively. H ex and H in in the present work are lower than 1. The average value of H ex was found to be 0.02 and 0.025 and average value of H in to be found 0.025 and 0.027 in wheat fields samples and corn samples in Eilam provinces, respectively. The obtained values of AGDE are 30.49 mSv/yr for wheat filed samples and 37.89 mSv/yr for corn samples; the AEDE rate values are 5.28 mSv/yr in wheat filed samples and this average value was found to be 6.13 mSv/yr in corn samples in Eilam. Transfer factors (TFs) of long lived radionuclide such as (137) Cs, (226) Ra, (232) Th and (40) K from soils to corn and wheat plants have been studied by radiotracer experiments. CONCLUSION: The natural radioactivity levels in Eilam province are not at the range of high risk of morbidity and are under international standards. PMID- 26056647 TI - Simultaneous Determination of Sodium Benzoate, Potassium Sorbate and Natamycin Content in Iranian Yoghurt Drink (Doogh) and the Associated Risk of Their Intake through Doogh Consumption. AB - BACKGROUND: Regarding the public health concerns over the use of food preservatives in yoghurt drink "Doogh", the aim of this study was the determination of sodium benzoate, potassium sorbate and natamycin in Doogh. Based on Iranian national standard, none of these preservatives are permitted to be used in Doogh. METHODS: A total of 39 Doogh samples were analyzed through RP-HPLC in order to quantify sodium benzoate, potassium sorbate and natamaycin simultaneously. Exposure to each preservative is estimated by mean and maximum concentrations as the residue levels. The per capita Doogh consumption was calculated by the published data from official reports for Doogh annual production in Iran. RESULTS: All samples were shown to contain sodium benzoate while natamaycin was detected in 10.25% of the samples and potassium sorbate was not detected in any of them. Sodium benzoate concentration extremely varied among the investigated samples ranged from 0.94 to 9.77 mg/l. Due to the result of the exposure estimation, no serious public health concern would exist regarding the mentioned preservatives. CONCLUSIONS: The detection of sodium benzoate in all Doogh samples could indicate the natural production of benzoic acid in yoghurt. Sodium benzoate may be formed through the interaction of the added food grade salt to the Doogh formula which contains benzoic acid. The results of exposure estimation show the lack of health risk within the usage of preservatives in spite of the national regulatory agencies does not permit the preservative use. PMID- 26056648 TI - "Science Citation Index Worship" in China. PMID- 26056649 TI - Fall Injury Prevention-a Neglected Public Health Issue: Challenges and Way Forward in the Indian Scenario. PMID- 26056650 TI - Prevalence of Hypertension among Working Adults in Rwanda. PMID- 26056651 TI - Etiology of the Vaginal, Cervical, and Uterine Laceration on Avicenna Viewpoints. PMID- 26056652 TI - Euthanasia: Murder or Not: A Comparative Approach. AB - Background Euthanasia is one of the most intriguing ethical, medical and law issues that marked whole XX century and beginning of the XXI century, sharply dividing scientific and unscientific public to its supporters and opponents. It also appears as one of the points where all three major religions (Catholic, Orthodox, and Islamic) have the same view. They are strongly against legalizing mercy killing, emphasizing the holiness of life as a primary criterion by which the countries should start in their considerations. Studying criminal justice systems in the world, the authors concluded that the issue of deprivation of life from compassion is solved on three ways. On the first place, we have countries where euthanasia is murder like any other murder from the criminal codes. Second, the most numerous are states where euthanasia is murder committed under privilege circumstances. On the third place, in the Western Europe we have countries where euthanasia is a legal medical procedure, under requirements prescribed by the law. In this paper, authors have made a brief comparison of the solutions that exist in some Islamic countries, where euthanasia is a murder, with Western countries, where it represents completely decriminalized medical procedure. PMID- 26056653 TI - Rhazes Contribution to the Role of Nutrition in Preventive Medicine and Public Health. PMID- 26056654 TI - The Effect of Shoe Outsole Containing Nanoilica Particles on Knee Valgus Angle in Athlete Females with Anterior Cruciate Ligament Injury during Drop Jump and Single Leg Landing. PMID- 26056655 TI - Alcohol-Related Violence among the Australian Aboriginal and Torres Strait Islanders of the Northern Territory: Prioritizing an Agenda for Prevention Narrative Review Article. AB - Alcohol - related violence among Australian Aboriginal and Torres Strait Islanders (also called as "Indigenous") is a major public health concern in Northern Territory of Australia. There is dearth of epidemiological data that link three contributing epidemics: alcohol misuse, violence, and trauma in the Northern Territory. In this review, we aimed to concentrate on how these epidemics intersect among the Indigenous people in the Northern Territory. In our descriptive review, we have searched published papers, publicly available government and health department reports web sites reporting relevant data on these three risk factors in the Northern Territory. The high rate of family and domestic violence and assaults in the Australian Territory indicates an increased correlation with high risk alcohol use compared to unintentional injuries. Heavy drinking pattern and harmful use of alcohol among Indigenous people are more likely to be associated with the incidence of violent assaults and physical injuries in the Northern Territory. We are trying to emphasize our understanding of co-occurring risk factors on the alcohol - violence relationship and urging a need for interventional approaches to reduce the public health issues in the Northern Territory. PMID- 26056656 TI - Collaboration between Government and Non-Governmental Organizations (NGOs) in Delivering Curative Health Services in North Darfur State, Sudan- a National Report. AB - BACKGROUND: North Darfur State has been affected by conflict since 2003 and the government has not been able to provide adequate curative health services to the people. The government has come to rely on Non-Governmental Organizations (NGOs) to provide curative health services. This study was conducted to examine the existing collaboration between government and NGOs in curative health service delivery in North Darfur State, and to identify the challenges that affect their collaboration. METHODS: Documentary data were collected from government offices and medical organizations. Primary data were obtained through interviews with government and NGOs representatives. The interviews were conducted with (1) expatriates working for international NGOs (N=15) and (2), health professionals and administrators working in the health sector (N= 45). RESULTS: The collaboration between the government and NGOs has been very weak because of security issues and lack of trust. The NGOs collaborate by providing human and financial resources, material and equipment, and communication facilities. The NGOs supply 70% of curative health services, and contribute 52.9% of the health budget in North Darfur State. The NGOs have employed 1 390 health personnel, established 44 health centres and manage and support 83 health facilities across the State. CONCLUSION: The NGOs have played a positive role in collaborating with the government in North Darfur State in delivering curative health services, while government's role has been negative. The problem that faces the government in future is how health facilities will be run should a peaceful settlement be reached and NGOs leave the region. PMID- 26056657 TI - Identification of Malassezia Species Isolated from Patients with Pityriasis Versicolor Using PCR-RFLP Method in Markazi Province, Central Iran. AB - BACKGROUND: The lipophilic yeasts of Malassezia species are members of the normal skin microbial that are cause of pityriasis versicolor. Pityriasis versicolor is a common superficial fungal infection with world-wide distribution. The phenotypic methods for identification of Malassezia species usually are time consuming and unreliable to differentiate newly identified species. But DNA-based techniques rapidly and accurately identified Malassezia species. The purpose of this study was isolation and identification of Malassezia Species from patients with pityriasis versicolor by molecular methods in Markazi Province, Central Iran in 2012. METHODS: Mycologic examinations including direct microscopy and culture were performed on clinical samples. DNA extraction was performed from colonies. The ITS1 region of rDNA from isolates of Malassezia species were amplified by PCR reaction. The PCR were digested by Cfo I enzyme. RESULTS: From 70 skin samples, were microscopically positive for Malassezia elements, 60 samples were grown on culture medium (85.7%). Using PCR-RFLP method, that was performed on 60 isolates, 37(61.6%) M. globosa, 14(23.3%) M. furfur, 5(8.4%) M. sympodialis and 4(6.7%) M. restrictawere identified. In one case was isolated M. globosa along with M. restricta. CONCLUSION: The PCR-RFLP method is a useful and reliable technique for identification of differentiation of Malas-sezia species. PMID- 26056658 TI - Analysis of Job Stress, Psychosocial Stress and Fatigue among Korean Police Officers. PMID- 26056659 TI - Employment Discrimination against Obese Women in Poland: A Focus Study Involving Patients of an Obesity Management Clinic. PMID- 26056660 TI - Clinical Evaluation of 38 Patients with Juvenile Myoclonic Epilepsy. PMID- 26056661 TI - Making the Public Health and Industrial Objectives Balanced; the Big Challenge of Iran's Food and Drug Organization. PMID- 26056662 TI - Risk Factors of Cardiovascular Disease and Their Related Socio-Economical, Environmental and Health Behavioral Factors: Focused on Low-Middle Income Countries- A Narrative Review Article. AB - BACKGROUND: In order to decrease the burden of cardiovascular disease (CVD), social determinants for CVD risk factors have been extensively studied in developed countries. However, few studies about them have been performed in low middle-income countries. This study describes factors related to CVD risk factors in low-middle-income countries at a national level. METHODS: Data were assembled from international databases for 47 low-middle-income countries and were collected from various sources including WHO, World Bank, and previous studies. Coefficient estimates between male and female CVD risk factor prevalence and each independent variable were calculated via linear regression. RESULTS: Statistically significant inverse associations were observed between adult literacy rate and systolic blood pressure, blood glucose. Pump price for gasoline was negatively associated with blood glucose also. Associations for female unemployment, adult literacy rate, paved roads and urban population, alcohol and western diet were positively associated with CVD risk factors. Unemployment, urban population and alcohol were positively associated with CVD risk factors in males. CONCLUSION: The effectiveness of intervention program for the prevention of cardiovascular disease in populations in developing countries should be explored, and more attention should be given to women. PMID- 26056663 TI - Equality of Medical Health Resource Allocation in China Based on the Gini Coefficient Method. AB - BACKGROUND: The Chinese government is trying to achieve the goal of "universal access to basic health care services". However, the inequality of the distribution of health care resources across the country is the biggest obstacle. This paper aims to explore these inequalities and the extent to which the method of analysis influences the perception. METHODS: The indicators of health care resource distribution studied consisted of the number of health care institutions, the number of beds in health care institutions and the number of medical personnel. Data were obtained from the China Statistical Yearbook 2014. The extent of equality was assessed using the Lorenz Curve and Gini Coefficient Method. RESULTS: Health care resource distribution in China demonstrates inequalities. The demographic Gini Coefficients based on the Lorenz Curves for the distribution of health care institutions, beds in health care institutions and medical personnel are 0.190, 0.070 and 0.070 respectively, while the corresponding Coefficients based on geographical areas are 0.616, 0.639 and 0.650. CONCLUSION: The equality of China's demographically assessed distribution of health care resources is greater than that of its geographically measured distribution. Coefficients expressed by population imply there is ready access to healthcare in all regions, whilst the Coefficients by geographical area apparently indicate inequality. This is the result of the sparsity of population. PMID- 26056664 TI - Translated Versions of Voice Handicap Index (VHI)-30 across Languages: A Systematic Review. AB - BACKGROUND: In this systematic review, the aim is to investigate different VHI-30 versions between languages regarding their validity, reliability and their translation process. METHODS: Articles were extracted systematically from some of the prime databases including Cochrane, googlescholar, MEDLINE (via PubMed gate), Sciencedirect, Web of science, and their reference lists by Voice Handicap Index keyword with only title limitation and time of publication (from 1997 to 2014). However the other limitations (e.g. excluding non-English, other versions of VHI ones, and so on) applied manually after studying the papers. In order to appraise the methodology of the papers, three authors did it by 12-item diagnostic test checklist in "Critical Appraisal Skills Programme" or (CASP) site. After applying all of the screenings, the papers that had the study eligibility criteria such as; translation, validity, and reliability processes, included in this review. RESULTS: The remained non-repeated articles were 12 from different languages. All of them reported validity, reliability and translation method, which presented in details in this review. CONCLUSION: Mainly the preferred method for translation in the gathered papers was "Brislin's classic back-translation model (1970), although the procedure was not performed completely but it was more prominent than other translation procedures. High test-retest reliability, internal consistency and moderate construct validity between different languages in regards to all 3 VHI-30 domains confirm the applicability of translated VHI-30 version across languages. PMID- 26056665 TI - Seatbelt Use and Traumatic Brain Injury in Taiwan: A 16-Year Study. AB - BACKGROUND: A motor vehicle seat belt use law for the driver and front-seat passenger was implemented in Taiwan on June 1, 2001. The purpose of this study was to determine the effect of motor vehicle seat belt use on the severity of traumatic brain injuries because of motor vehicle accidents. METHODS: Data were collected from 27 major teaching hospitals four years before June 1, 2001 and until May 31, 2013. A total of 822 brain-injured patients with a mean age of 37.4 (+/- 13.4) years were included; 251 were injured prior to implementation of the law and 571 after. The Glasgow coma scale was adapted to rate the severity of traumatic brain injury on admission. The Glasgow outcome scale was used to categorize the outcome on discharge. RESULTS: After the seat belt law was implemented, traumatic brain injuries were less severe (P<0.001) and the rates of loss of consciousness, neurologic deficit, intracranial hematoma, craniotomy, and poor physical condition at discharge were all significantly lower (all P< 0.05). Male gender, longer hospital stays, not wearing a seat belt, and injury before the law was enacted were all associated with poorer physical condition at the time of discharge (all P <0.01). CONCLUSION: Among occupants who survived a motor vehicle accident but had traumatic brain injuries, those who had worn seat belts had a better prognosis. Seat belts remain one of the best methods to reduce both the severity of injuries and the number of fatalities. PMID- 26056666 TI - Factors Influencing the Quality of Life (Qol) Among Thai Older People in a Rural Area of Thailand. AB - BACKGROUND: The population prevalence of older people has been growing worldwide. Quality of Life (QoL) among older people is a significant public health concern. Hence, this study aimed to assess level of QoL and factors influencing QoL among rural Thai older people. METHODS: The study was undertaken in Phayao Province where is one of the top ten provinces with the highest index of Thai aging. A district in this province was purposively selected to be the study area and the quota-sampling technique was used for sample collection, totally 400 older people participated according to Taro Yamane. The WHO QoL-Old was employed to interview elderly QoL. Multivariate linear regression was performed to determine the factors influencing QoL among the older people. RESULTS: Over two-thirds of older people (68.5%) had QoL at fair level. The vast majority (96%) had high scores for Activity Daily Living (ADL). Approximately one-fifth (20.5%) reported current smoking and 31.7% reported ever drinking during previous year. Following univariate analysis, nine factors - gender, age, education, working, income, present illness, drinking, ADL, and participating in elderly club were identified as being significantly associated with QoL (P <0.05). Multivariate analysis revealed four factors predictive of QoL among elderly: ADL, income, alcohol drinking, and present illness (P < 0.01). CONCLUSION: Physical function, health status and financial were the predictor of QoL among elderly. Noticeably, drinking was one predictive factor of QoL but only among moderate drinkers. Hence, healthy life style should be considered as key areas in attempts to promote QoL among elderly people. PMID- 26056667 TI - Comparative Study of Lifestyle: Eating Habits, Sedentary Lifestyle and Anthropometric Development in Spanish 5- To 15-yr-Olds. AB - BACKGROUND: The infant-juvenile period is one of high vulnerability during the lifestyles chosen become determining factors for future health status. This study aimed to evaluate lifestyle, specifically eating habits and physical activity, in 5-15-year-olds in Spain and their health status (anthropometry). METHODS: This cross-sectional population study with two time points (2006 and 2013) was conducted by compiling data from the Spanish National Health Survey. We used the minor survey, specifically the data from the Health Determinants module, which included 5-15-year-olds. Compiled information was obtained from parents or guardians. RESULTS: The overall overweight and obesity prevalence in Spain (2013) in 5- to 15-year-olds is 24.3%. A drop of 8.2% in meat consumption was found, while overall intake was high. Daily intake of plant-based food (fruit, vegetables, pulses) was low, especially vegetables (32.9%). Increased sedentary lifestyle was observed, probably because the use of communication technologies has increased in recent years (P<0.001). Moreover, watching TV rose to 19.3% for 1 hour/day watching TV on weekdays and to 23.5% at weekends. CONCLUSION: When comparing the two time points (2006 and 2013), we observed that lifestyle, eating habits and physical activity strongly associated with the Spanish infant-juvenile population's anthropometry. Mediterranean diet patterns seem to be abandoned and physical activity is practiced less, which will have a negative impact on future quality of life. PMID- 26056668 TI - The Relationship between Nicotine Dependence and Age among Current Smokers. AB - BACKGROUND: A recent study indicates that the incidence of smoking cessation varies with age. Although nicotine dependence (ND) has been regarded as one of the most significant barriers of successful smoking cessation, few researches have focused on the relationship between nicotine dependence and age. METHODS: A cross-sectional study (conducted in 2013) with 596 Chinese rural male current smokers was performed to study the relationship between ND and age. The ND level was assessed using the Fagerstrom Test for Nicotine Dependence (FTND) scale. The univariate two-degree fractional polynomials (FPs) regression was used to explore the relation of ND to age. RESULTS: The mean of FTND scores in the middle-aged group (45-64 yr old) was higher than that in the younger (<45 yr old) and older groups (>=65 yr old). The FPs regression showed an inverse U-shaped relationship between ND and age. CONCLUSION: The middle-aged current smokers had higher degree of ND than the younger and the older groups, which showed an inverse U-shaped relationship between ND and age. This finding needs to be confirmed by further researches. PMID- 26056669 TI - The Endemicity of Human Fascioliasis in Guilan Province, Northern Iran: the Baseline for Implementation of Control Strategies. AB - BACKGROUND: The largest global outbreaks of liver fluke disease (Fascioliasis) in humans, caused by species of the genus Fasciola, have occurred in Guilan Province of Iran, affecting more than 15000 people. Although, different aspects of fascioliasis have been the subject of various researches during last two decades, nevertheless no community-based study has been performed in endemic regions of Guilan. The aim of present study was to obtain the basic information needed to develop future control strategies. METHODS: Fecal and blood samples were collected from 1,984 volunteers in the Bandar-Anzali district, the region where previous epidemics occurred. Fecal samples were examined by Kato-Katz and formalin-ether methods for the presence of Fasciola eggs. Sera samples were analyzed by ELISA to detect anti-cathepsin L antibodies. RESULTS: Twenty-seven (1.36%) individuals were seropositive, 9 (0.45%) individuals were egg positive (mean egg count 50.7 (+/-30.36) eggs per gram of faeces) and 30 individuals (1.51%) were positive using both methods. No statistical association was observed between infection and age, gender, location, occupation, educational status and dietary habits. The prevalence of intestinal parasites is also included. CONCLUSION: Human fascioliasis is hypoendemic in this region and recommends a passive case-finding approach, effective primary prevention measures, health education through mass media and effective veterinary public health measures for control of human disease. PMID- 26056670 TI - The Economic Burden of Liver Cirrhosis in Iran: a Cost of Illness Study. AB - BACKGROUND: According to importance of cirrhosis of the liver and the lack of information about the economic burden of the disease, we performed this study to estimate the economic burden of liver Cirrhosis in Iran in 2011. METHODS: The cost-of-illness method, based on the human capital theory, has been used. Both direct and indirect costs have been estimated using a prevalence approach and bottom-up method. The inpatient and outpatient records were investigated for obtaining the medical costs. Also, a questionnaire was used for collection the other data such as transportation costs, out of pocket payment and times of inpatients, etc. Costs consisted of expenditures which happened during March 2011 to February 2012 and the perspective of the study was Iranian society. RESULTS: The total cost of the disease was 2014.5 billion Rials (USD164.32 million). Direct and indirect costs were 1384.16 and 630.4 billion Rials (86.7% and 11.3% of the total cost), respectively. Cost due to premature death was USD 38.66 million, included 23.52% of the total cost and 75% of indirect cost. CONCLUSION: Liver Cirrhosis impose enormous economic burden on Iranian society. Policymakers should therefore take this into consideration and according to available health resources provide services and facilities for the prevention and treatment of the disease. PMID- 26056671 TI - Developing a Shortened Quality of Life Scale from Persian Version of the WHOQOL 100 Using the Rasch Analysis. AB - BACKGROUND: Few studies use modern approaches to develop a quality of life (QOL) questionnaire with acceptable construct validity, especially in Iran. Our main objective was to construct a new validated and uni-dimensional questionnaire, based on WHOQOL-100, using the Rasch analysis. METHODS: In a population-based, cross-sectional study in 2007, 500 Tehran residents aged>=18 were randomly sampled. The Persian version of WHOQOL-100 was used to measure the participants' QOL. After using targeting and person fit analysis, we performed category/threshold ordering, item fit, and differential item functioning analyses, in succession. We used outfit or infit statistics>1.5 and <0.5 for detecting under-fit and overfit items/persons, respectively. We also deleted items with disordered category and/or threshold. Person Separation Index and test reliability were also calculated in the datasets. RESULTS: Male to female ratio was 0.98 and the mean age (SD) of participants was 35.1 (12.8) years. Initial analyses showed significant differences in quality of life between age groups (P=0.002), educational levels (P=0.001), and current health status groups (P<0.001). We eliminated 67 persons for under-fitting, 38 items for category and/or threshold disordering, 6 items for under-fitting, and 26 items for item bias. Test reliability for the final 30-item scale was 0.89. CONCLUSION: We prepared a shortened version of the WHOQOL-100 that is single construct, uni dimensional and free of item bias or any disordering, according to the Rasch model. PMID- 26056672 TI - Content Validity of National Post Marriage Educational Program Using Mixed Methods. AB - BACKGROUND: Although the validity of content of program is mostly conducted with qualitative methods, this study used both qualitative and quantitative methods for the validation of content of post marriage training program provided for newly married couples. Content validity is a preliminary step of obtaining authorization required to install the program in country's health care system. METHODS: This mixed methodological content validation study carried out in four steps with forming three expert panels. Altogether 24 expert panelists were involved in 3 qualitative and quantitative panels; 6 in the first item development one; 12 in the reduction kind, 4 of them were common with the first panel, and 10 executive experts in the last one organized to evaluate psychometric properties of CVR and CVI and Face validity of 57 educational objectives. RESULTS: The raw data of post marriage program had been written by professional experts of Ministry of Health, using qualitative expert panel, the content was more developed by generating 3 topics and refining one topic and its respective content. In the second panel, totally six other objectives were deleted, three for being out of agreement cut of point and three on experts' consensus. The validity of all items was above 0.8 and their content validity indices (0.8-1) were completely appropriate in quantitative assessment. CONCLUSION: This study provided a good evidence for validation and accreditation of national post marriage program planned for newly married couples in health centers of the country in the near future. PMID- 26056673 TI - Application of the Multiplicative-Additive Model in the Bone Marrow Transplantation Survival Data Including Competing Risks. AB - BACKGROUND: Cox proportional hazard model is a popular choice in modeling the survival data, but sometimes proportionality assumption is not satisfied. One of the tools for handling the non-proportional effects is the multiplicative additive model named "Cox-Aalen model". Recently these flexible regression models developed for competing risks setting. The aim of this paper is showing the application of the multiplicative-additive model in competing risks setting on real bone marrow transplantation (BMT) data when the proportionality assumption is violated. METHODS: The data was from a retrospective study on class III thalassemia patients who undergo hematopoietic stem cell transplantation (HSCT) in BMT ward of Shariatei Hospital, Tehran, Iran. The neutrophil engraftment time as the early outcome of HSCT on37 patients who received mesenchymal stem cell infusion (MSC group) compared with 50 patients who did not. We fit the standard proportional models and flexible Cox-Aalen model in the sub distribution hazards. RESULTS: By day 30 after transplantation, the cumulative incidence of neutrophil recovery was 97% (95%CI: 89%-100%) and 76%(95%CI: 64%-88%) in MSC and control group, respectively. Based on the Cox-Aalen model for cumulative incidence function, the MSC infusion had a significant delay effect on neutrophil engraftment (P=.044). In patients who did not neutrophil recovery immediately after HSCT, those who received MSC had faster recovery. CONCLUSION: Cox-Aalen model provides more accurate statistical description for time-varying covariate effects. There is a positive effect of MSCs on the neutrophil recovery, however further study on the advantages and disadvantages of MSCs are needed. PMID- 26056674 TI - Personality Traits and Their Relationship to Demographic Features in Addicts Referring to a Drug Rehabilitation Center in the City of Isfahan, Iran. AB - BACKGROUND: Addiction is one of the most serious social damages and due to its progressive nature in all aspects, adversely affects people's physical and psychological health. Hence, this paper investigates the characteristics of drug addicts in a drug rehabilitation center in the city of Isfahan. METHODS: In this cross-sectional study conducted in 2012, the population consisted of all addicts that referred to Shefa Drug Rehabilitation Center. A sample of 201 individuals was selected randomly. Two questionnaires were drawn up to collect data; the first questionnaire examined demographic characteristics and the second was the 71-item Minnesota Multiphase Personality Inventory short form. Chi-square test, Fisher's exact test and Kruskal-Wallis test were used in SPSS20 to analyze the data. RESULTS: Overall, 98% of participants were men, 65.7% were married, and 13.3% were unemployed. Depression and hypomania were respectively the most and the least prevalent disorders among individuals with high-risk psychological profiles of clinical scales respectively. Psychopathic deviation and schizophrenia were seen among the unemployed more than the employed ones. CONCLUSION: Considering the fact that depression was the most common personality disorder among the addicts participating, it is recommended that this disorder be given priority in investigations in the treatment programs of these patients. In addition, the scales of disorder, schizophrenia, mental infirmity, mental deviation, and paranoia had a significant relationship to aggression, delirium and hallucination, which must be taken into consideration in the treatment of such patients. PMID- 26056675 TI - The Role of Positive Personality Traits in Emotion Regulation of Patients with Irritable Bowel Syndrome (IBS). AB - BACKGROUND: Personality traits and emotion regulation processes play an important role in human health. The purpose of this study was to investigate the role of positive personality traits (psychological hardiness and interpersonal forgiveness) in emotion regulation of patients with Irritable Bowel Syndrome. METHODS: The research was a cross-sectional study. Statistical population included all of IBS patients referred to the Subspecialty Center of Psychiatry in Isfahan in 2013. Overall, 123 subjects (100 women, 83.3%, and 30 men, 16.7%) were selected by census method, according to criteria of research and during a particularperiod. To collect data, the Difficulties in Emotion Regulation Scale (DERS), Lang and Goulet Hardiness Scale (LGHS) and Interpersonal forgiveness Inventory (IFI) were used. Data was analyzed using Pearson's correlation coefficient and Multivariate and Binary Logistic regression analyses. RESULTS: Mean age of patients was 33.82+/-10.45 years and 83.3% (100) of them were female. Regression analyses showed that both personality traits of hardiness and forgiveness were as protective factors for emotional dysregulation with OR, 95% CI: 0.93 and 0.96 sequentially, with adjusting demographic variables (age, gender, and education level and disease duration). CONCLUSION: Patients who are more hardy and forgiving toward others, are likely more successful at adaptive emotion regulation. It emphasizes the positive and beneficial role of the personality traits in regulating of emotional problems of IBS patients. Hence, these variables should be considered as effective factors in the treatment process of the patients. PMID- 26056676 TI - Effects of Targeted Subsidies Policy on Health Behavior in Iranian Households: A Qualitative Study. AB - BACKGROUND: This study aimed to explore the effects of national targeted subsidies policy on health behavior of Iranian households. METHODS: In this qualitative study, data were collected between January 2012 and December 2013 through face-to-face interviews (23 experts in national and provincial levels of health system and 18 household heads) and through a comprehensive and purposive document analysis. The data was analyzed using a thematic analysis method (inductive-deductive) and assisted by Atlas-ti software. RESULTS: Rising health care costs, removing some food subsidies and the increase in price of most goods and services due to the implementation of economic policy of targeted subsidies have led to significant changes in the demand for health services, changes in the consumption trends of goods and services affecting health as well as changes in the health habits of households. CONCLUSION: Targeted subsidies and the cash subsidy policy have some negative effects on population health behavior especially among poor people. Hence, maintaining or increasing the cash subsidy is not an efficient allocation of resources toward health care system. So, it is necessary to identify appropriate strategies and policies and apply interventions in order to moderate negative effects and enhance positive effects resulted from implementing this economic reform on population health behavior. PMID- 26056677 TI - Perception of the Elderly by Youth and Seniors in Poland. PMID- 26056678 TI - Fluoride Burden of Aluminum Plant Workers. PMID- 26056679 TI - Breast Cancer among Pakistani Women. PMID- 26056680 TI - The Anxiety and Influence Factor of the Nurse Students in Different Levels before the NCLEX-RN. PMID- 26056681 TI - Medical Malpractice: Sight of the Physicians at the Gulhane Military Medical Academy. PMID- 26056682 TI - Overuse of Anticoagulation in Treatment of Atrial Fibrillation Patients in University Hospitals of Tehran. PMID- 26056683 TI - Social Media and Health Care: Necessity of Facing Their Challenges. PMID- 26056684 TI - Ethics and Sentences in Midwifery. PMID- 26056685 TI - Passive Smoking: Oral and Dental Effects. PMID- 26056686 TI - A pilot study of acotiamide hydrochloride hydrate in patients with detrusor underactivity. AB - AIM: To investigate the clinical efficacy of acotiamide hydrochloride hydrate in patients with detrusor underactivity. METHODS: We measured the post-void residual urinary volume in 19 patients with underactive bladders. All these patients had been under treatment with distigmine bromide and were prescribed acotiamide hydrochloride hydrate at a dose of 100 mg three times daily for 2 weeks. RESULTS: Compared with the post-void residual urinary volume value at baseline (161.4+/ 90.0 mL) a statistically significant reduction was observed at the end of treatment (116.3+/-63.1 mL) (P=0.006). The drug was generally well tolerated by the majority of patients. CONCLUSION: Maybe, acotiamide hydrochloride hydrate showed clinical efficacy in patients with underactive bladders and may, therefore, be used alternatively in patients who do not respond sufficiently to distigmine bromide. PMID- 26056687 TI - Nanoparticle colloidal stability in cell culture media and impact on cellular interactions. AB - Nanomaterials are finding increasing use for biomedical applications such as imaging, diagnostics, and drug delivery. While it is well understood that nanoparticle (NP) physico-chemical properties can dictate biological responses and interactions, it has been difficult to outline a unifying framework to directly link NP properties to expected in vitro and in vivo outcomes. When introduced to complex biological media containing electrolytes, proteins, lipids, etc., nanoparticles (NPs) are subjected to a range of forces which determine their behavior in this environment. One aspect of NP behavior in biological systems that is often understated or overlooked is aggregation. NP aggregation will significantly alter in vitro behavior (dosimetry, NP uptake, cytotoxicity), as well as in vivo fate (pharmacokinetics, toxicity, biodistribution). Thus, understanding the factors driving NP colloidal stability and aggregation is paramount. Furthermore, studying biological interactions with NPs at the nanoscale level requires an interdisciplinary effort with a robust understanding of multiple characterization techniques. This review examines the factors that determine NP colloidal stability, the various efforts to stabilize NP in biological media, the methods to characterize NP colloidal stability in situ, and provides a discussion regarding NP interactions with cells. PMID- 26056689 TI - Abstracts of the Melanoma Bridge Meeting 2014, December 3-6, 2014, Naples, Italy. PMID- 26056690 TI - Abstracts of the 84th Annual Meeting of the American Association of Physical Anthropologists, March 25-28, 2015, St. Louis, Missouri. PMID- 26056691 TI - Focusing on staff development. PMID- 26056693 TI - Abstracts of the 12th Asian Congress of Urology of the Urological Association of Asia, December 5-9, 2014, Kish Island, Iran. PMID- 26056692 TI - Abstracts of the 10th Congress of ECCO, February 18-21, 2015, Barcelona, Spain. PMID- 26056694 TI - [Abstracts of the 15th National Infectious Disease Meeting, Bordeaux Lac, France]. PMID- 26056695 TI - Abstracts of the Challenges for Occupational Epidemiology in the 21st Century EPICOH 2014, June 24-27, 2014, Chicago, USA. PMID- 26056688 TI - Development of individualized anti-metastasis strategies by engineering nanomedicines. AB - Metastasis is deadly and also tough to treat as it is much more complicated than the primary tumour. Anti-metastasis approaches available so far are far from being optimal. A variety of nanomedicine formulae provide a plethora of opportunities for developing new strategies and means for tackling metastasis. It should be noted that individualized anti-metastatic nanomedicines are different from common anti-cancer nanomedicines as they specifically target different populations of malignant cells. This review briefly introduces the features of the metastatic cascade, and proposes a series of nanomedicine-based anti metastasis strategies aiming to block each metastatic step. Moreover, we also concisely introduce the advantages of several promising nanoparticle platforms and their potential for constructing state-of-the-art individualized anti metastatic nanomedicines. PMID- 26056698 TI - [Not Available]. PMID- 26056696 TI - Abstracts of the 2014 World Transplantation Congress, July 26-31, 2014, San Francisco, CA. PMID- 26056699 TI - Letter from our president, Cheryl Dennison Himmelfarb, PhD, RN, ANP, FAHA, FPCNA, FAAN, associate professor, Johns Hopkins University. PMID- 26056700 TI - Rocky Mountain Chapter Initiative: a unique approach to sharing knowledge among chapter members. PMID- 26056701 TI - What can we do to improve care beyond National Minority Health Month. PMID- 26056702 TI - Preventive Cardiovascular Nurses Association's leadership on hypertension continues. PMID- 26056703 TI - [Total knee replacement - High benefit in terms of quality of life]. PMID- 26056704 TI - [Hip fractures - Geriatric complex therapy helps patients]. PMID- 26056705 TI - [The distal radius fracture of the elderly man - a missed opportunity?]. PMID- 26056706 TI - [Hip arthroscopy -Hip osteoarthritis as an acceptable indication for surgery]. PMID- 26056707 TI - [How I explore ... the cheetah-look of the skin under selected light wavelengths]. AB - The melanotic facial pigmentation of each individual is frequently heterogeneous, even when this condition remains imperceptible under natural ambient light. However, with aging, this aspect may appear to everybody. The melanin heterochromia has various origins including ethnicity, the hormonal impact, the influence of various inflammatory, toxic and drug-induced disorders, as well as the impact of photoaging. The cheetah-look aspect is thus established and well identified under ultraviolet light or using an ingenious trick selecting some wavelengths of visible light. PMID- 26056709 TI - MagRET Nanoparticles: An Iron Oxide Nanocomposite Platform for Gene Silencing from MicroRNAs to Long Noncoding RNAs. AB - Silencing of RNA to knock down genes is currently one of the top priorities in gene therapies for cancer. However, to become practical the obstacle of RNA delivery needs to be solved. In this study, we used innovative maghemite (gamma Fe2O3) nanoparticles, termed magnetic reagent for efficient transfection (MagRET), which are composed of a maghemite core that is surface-doped by lanthanide Ce(3/4+) cations using sonochemistry. Thereafter, a polycationic polyethylenimine (PEI) polymer phase is bound to the maghemite core via coordinative chemistry enabled by the [CeL(n)](3/4+)cations/complex. PEI oxidation was used to mitigate the in vivo toxicity. Using this approach, silencing of 80-100% was observed for mRNAs, microRNAs, and lncRNA in a variety of cancer cells. MagRET NPs are advantageous in hard to transfect leukemias. This versatile nanoscale carrier can silence all known types of RNAs and these MagRET NPs with oxidized PEI are not lethal upon injection, thus holding promise for therapeutic applications, as a theranostic tool. PMID- 26056710 TI - Retraction: Editorial Removal. AB - This article was withdrawn by the authors before final publication on October 1, 2009. PMID- 26056711 TI - Dynamic changes in phrenic motor output following high cervical hemisection in the decerebrate rat. AB - Hemisection of the spinal cord at C2 eliminates ipsilateral descending drive to the phrenic nucleus and causes hemidiaphragmatic paralysis in rats. Phrenic nerve (PhN) or diaphragmatic activity ipsilateral to hemisection can occasionally be induced acutely following hemisection by respiratory stressors (i.e., hypercapnia, asphyxia, contralateral phrenicotomy) and becomes spontaneously active days-to-weeks later. These investigations, however, are potentially confounded by the use of anesthesia, which may suppress spontaneously-active crossed phrenic pathways. Experiments were performed on vecuronium-paralyzed, unanesthetized, decerebrate adult male rats and whole PhN activity recorded continuously before, during, and after high cervical hemisection at the C1 spinal level. Crossed phrenic activity recovered spontaneously over minutes-to-hours with maximal recovery of 11.8 +/- 3.1% (m +/- SE) in the PhN ipsilateral to hemisection. Additionally, there was a significant increase in PhN activity contralateral to hemisection of 221.0 +/- 4 0.4% (m +/- SE); since animals were artificially-ventilated, these changes likely represent an increase in central respiratory drive. These results underscore the state-dependence of crossed bulbophrenic projections and suggest that unanesthetized models may be more sensitive in detecting acute recovery of respiratory output following spinal cord injury (SCI). Additionally, our results may suggest an important role for a group of C1-C2 neurons exhibiting respiratory-related activity, spared by the higher level of hemisection. These units may function as relays of polysynaptic bulbophrenic pathways and/or provide excitatory drive to phrenic motoneurons. Our findings provide a new model for investigating acute respiratory recovery following cervical SCI, the high C1-hemisected unanesthetized decerebrate rat and suggest a centrally-mediated increase in central respiratory drive in response to high cervical SCI. PMID- 26056712 TI - Determining drug efficacy parameters for mathematical models of influenza. AB - Antivirals are the first line of defence against influenza, so drug efficacy should be re-evaluated for each new strain. However, due to the time and expense involved in assessing the efficacy of drug treatments both in vitro and in vivo, treatment regimens are largely not re-evaluated even when strains are found to be resistant to antivirals. Mathematical models of the infection process can help in this assessment, but for accurate model predictions, we need to measure model parameters characterizing the efficacy of antivirals. We use computer simulations to explore whether in vitro experiments can be used to extract drug efficacy parameters for use in viral kinetics models. We find that the efficacy of neuraminidase inhibitors can be determined by measuring viral load during a single cycle assay, while the efficacy of adamantanes can be determined by measuring infected cells during the preparation stage for the single cycle assay. PMID- 26056713 TI - Characterization of skn-1/wdr-23 phenotypes in Caenorhabditis elegans; pleiotrophy, aging, glutathione, and interactions with other longevity pathways. AB - The SKN-1/Nrf transcription factors are master regulators of oxidative stress responses and are emerging as important determinants of longevity. We previously identified a protein named WDR-23 as a direct repressor of SKN-1 in C. elegans. Loss of wdr-23 influences stress resistance, longevity, development, and reproduction, but it is unknown if WDR-23 influences development and reproduction solely through SKN-1 and the mechanisms by which SKN-1 promotes stress resistance and longevity are poorly defined. Here, we characterize phenotypes of wdr-23 and skn-1 manipulation and explore the role of glutathione. We provide evidence that diverse wdr-23 phenotypes are dependent on SKN-1, that beneficial and detrimental phenotypes of wdr-23 and skn-1 can be partially decoupled, and that SKN-1 activation delays degenerative tissue changes during aging. We also show that total glutathione levels are substantially elevated when the wdr-23/skn-1 pathway is activated and that skn-1 is required for preserving this cellular antioxidant during stress and aging. Alternatively, total glutathione was not elevated in worms with reduced insulin/IGF-1-like signaling or dietary restriction suggesting that SKN-1 ensures longevity via different mechanisms under these conditions. Lastly, genetic interaction data revise our understanding of which skn-1 variants are required for longevity during dietary restriction. PMID- 26056714 TI - Novel ageing-biomarker discovery using data-intensive technologies. AB - Ageing is accompanied by many visible characteristics. Other biological and physiological markers are also well-described e.g. loss of circulating sex hormones and increased inflammatory cytokines. Biomarkers for healthy ageing studies are presently predicated on existing knowledge of ageing traits. The increasing availability of data-intensive methods enables deep-analysis of biological samples for novel biomarkers. We have adopted two discrete approaches in MARK-AGE Work Package 7 for biomarker discovery; (1) microarray analyses and/or proteomics in cell systems e.g. endothelial progenitor cells or T cell ageing including a stress model; and (2) investigation of cellular material and plasma directly from tightly-defined proband subsets of different ages using proteomic, transcriptomic and miR array. The first approach provided longitudinal insight into endothelial progenitor and T cell ageing. This review describes the strategy and use of hypothesis-free, data-intensive approaches to explore cellular proteins, miR, mRNA and plasma proteins as healthy ageing biomarkers, using ageing models and directly within samples from adults of different ages. It considers the challenges associated with integrating multiple models and pilot studies as rational biomarkers for a large cohort study. From this approach, a number of high-throughput methods were developed to evaluate novel, putative biomarkers of ageing in the MARK-AGE cohort. PMID- 26056715 TI - Crystallization Kinetics of Indomethacin/Polyethylene Glycol Dispersions Containing High Drug Loadings. AB - The reproducibility and consistency of physicochemical properties and pharmaceutical performance are major concerns during preparation of solid dispersions. The crystallization kinetics of drug/polyethylene glycol solid dispersions, an important factor that is governed by the properties of both drug and polymer has not been adequately explored, especially in systems containing high drug loadings. In this paper, by using standard and modulated differential scanning calorimetry and X-ray powder diffraction, we describe the influence of drug loading on crystallization behavior of dispersions made up of indomethacin and polyethylene glycol 6000. Higher drug loading increases the amorphicity of the polymer and inhibits the crystallization of PEG. At 52% drug loading, polyethylene glycol was completely transformed to the amorphous state. To the best of our knowledge, this is the first detailed investigation of the solubilization effect of a low molecular weight drug on a semicrystalline polymer in their dispersions. In mixtures containing up to 55% indomethacin, the dispersions exhibited distinct glass transition events resulting from amorphous amorphous phase separation which generates polymer-rich and drug-rich domains upon the solidification of supercooled polyethylene glycol, whereas samples containing at least 60% drug showed a single amorphous phase during the period in which crystallization normally occurs. The current study demonstrates a wide range in physicochemical properties of drug/polyethylene glycol solid dispersions as a result of the complex nature in crystallization of this system, which should be taken into account during preparation and storage. PMID- 26056716 TI - Vascularization strategies of engineered tissues and their application in cardiac regeneration. AB - The primary function of vascular networks is to transport blood and deliver oxygen and nutrients to tissues, which occurs at the interface of the microvasculature. Therefore, the formation of the vessels at the microcirculatory level, or angiogenesis, is critical for tissue regeneration and repair. Current strategies for vascularization of engineered tissues have incorporated multi disciplinary approaches including engineered biomaterials, cells and angiogenic factors. Pre-vascularization of scaffolds composed of native matrix, synthetic polymers, or other biological materials can be achieved through the use of single cells in mono or co-culture, in combination or not with angiogenic factors or by the use of isolated vessels. The advance of these methods, together with a growing understanding of the biology behind vascularization, has facilitated the development of vascularization strategies for engineered tissues with therapeutic potential for tissue regeneration and repair. Here, we review the different cell based strategies utilized to pre-vascularize engineered tissues and in making more complex vascularized cardiac tissues for regenerative medicine applications. PMID- 26056717 TI - Decellularized myocardial matrix hydrogels: In basic research and preclinical studies. AB - A variety of decellularized materials have been developed that have demonstrated potential for treating cardiovascular diseases and improving our understanding of cardiac development. Of these biomaterials, decellularized myocardial matrix hydrogels have shown great promise for creating cellular microenvironments representative of the native cardiac tissue and treating the heart after a myocardial infarction. Decellularized myocardial matrix hydrogels derived from porcine cardiac tissue form a nanofibrous hydrogel once thermally induced at physiological temperatures. Use of isolated cardiac extracellular matrix in 2D and 3D in vitro platforms has demonstrated the capability to provide tissue specific cues for cardiac cell growth and differentiation. Testing of the myocardial matrix hydrogel as a therapy after myocardial infarction in both small and large animal models has demonstrated improved left ventricular function, increased cardiac muscle, and cellular recruitment into the treated infarct. Based on these results, steps are currently being taken to translate these hydrogels into a clinically used injectable biomaterial therapy. In this review, we will focus on the basic science and preclinical studies that have accelerated the development of decellularized myocardial matrix hydrogels into an emerging novel therapy for treating the heart after a myocardial infarction. PMID- 26056719 TI - Albumin corona on nanoparticles - a strategic approach in drug delivery. AB - Nanomaterials have been used widely for delivery of therapeutic agents. Protein nanoparticle (NP) complexes have gained importance as vehicles for targeted drug delivery due to increased ease of administration, stability and half-life of drug, and reduced toxic side effects. Designing of phospholipid-bovine serum albumin (BSA) complexes and stealth NPs with BSA has paved the way for drug delivery carriers with prolonged blood circulation times. Preformed albumin corona has shown to decrease non-specific association and thereby reduce the clearance rate. Albumin corona has enabled the localization of drug carriers in specific tissues such as liver and heart, thus regulating biodistribution. Tailored albumin-NP conjugates have also enabled controlled degradation of NP and drug release. However, the binding of albumin with NP is associated with conformational and functional modulations in protein as observed with silver, gold and superparamagnetic iron oxide NPs. In this review, we highlight the various potential albumin-NP hybrids as nano drug carriers. PMID- 26056718 TI - Rational Polypharmacology: Systematically Identifying and Engaging Multiple Drug Targets To Promote Axon Growth. AB - Mammalian central nervous system (CNS) neurons regrow their axons poorly following injury, resulting in irreversible functional losses. Identifying therapeutics that encourage CNS axon repair has been difficult, in part because multiple etiologies underlie this regenerative failure. This suggests a particular need for drugs that engage multiple molecular targets. Although multitarget drugs are generally more effective than highly selective alternatives, we lack systematic methods for discovering such drugs. Target-based screening is an efficient technique for identifying potent modulators of individual targets. In contrast, phenotypic screening can identify drugs with multiple targets; however, these targets remain unknown. To address this gap, we combined the two drug discovery approaches using machine learning and information theory. We screened compounds in a phenotypic assay with primary CNS neurons and also in a panel of kinase enzyme assays. We used learning algorithms to relate the compounds' kinase inhibition profiles to their influence on neurite outgrowth. This allowed us to identify kinases that may serve as targets for promoting neurite outgrowth as well as others whose targeting should be avoided. We found that compounds that inhibit multiple targets (polypharmacology) promote robust neurite outgrowth in vitro. One compound with exemplary polypharmacology was found to promote axon growth in a rodent spinal cord injury model. A more general applicability of our approach is suggested by its ability to deconvolve known targets for a breast cancer cell line as well as targets recently shown to mediate drug resistance. PMID- 26056720 TI - Prodrug-based nano-drug delivery system for co-encapsulate paclitaxel and carboplatin for lung cancer treatment. AB - CONTEXT: Paclitaxel (PTX) and carboplatin (CBP) are widely used for the combined chemotherapy of non-small cell lung cancer (NSCLC). However, the development of multidrug resistance of cancer cells, as well as systemic toxic side effects resulting from nonspecific localization of anticancer drugs to non-tumor areas are major obstacles to the success of chemotherapy in treating cancers. OBJECTIVE: This study aimed to engineer a prodrug-based nano-drug delivery system for co-encapsulate hydrophilic (CBP) and hydrophobic anti-tumor drugs (PTX). This system was expected to resolve the multidrug resistance cause by single drug, and the dual-drug-loaded liposome was also planned to specifically target the cancer cells without obvious influence on normal cells and tissues. METHODS: In this paper, PLGA-PEG-CBP was synthesized by the conjugation between the carboxylic group of PLGA-PEG-COOH and the amino group of CBP. Then, self-assembled nanoparticles for combination delivery of PTX and PLGA-PEG-CBP (PTX/CBP NPs) were prepared by solvent displacement technique. The in vitro and in vivo anti-tumor efficacy was assessed in NCL-H460 human non-small cell lung carcinoma cell line. RESULTS: PTX/CBP NPs achieved the highest cytotoxic effect among all formulations in vitro, as compared with single drug delivery NPs. In vivo investigation on NSCLC animal models showed that co-delivery of PTX and CBP possessed high tumor targeting capacity and strong anti-tumor activity. CONCLUSIONS: The PTX/CBP NPs constructed in this research offers an effective strategy for targeted combinational lung cancer therapy. PMID- 26056721 TI - Low molecular weight heparins for current and future uses: approaches for micro- and nano-particulate delivery. AB - Low molecular weight heparins (LMWHs), the anticoagulant drug of choice in many indications, had been suggested as novel drug treatment for a range of diseases. Their superior pharmacokinetic properties compared to unfractionated heparin (UFH), motivated scientists to explore new delivery systems for improved therapeutic outcomes. Micro- and nano-carriers, with the versatile nature and characteristics of materials used for their fabrication, are able to surmount the challenges opposed by their native structures. The present review discusses the recent perspectives on the development of micro- and nano-particulate vectors for the delivery of LMWHs through various routes. Special focus on the application of the suggested systems, their characterization and the achieved improved bioavailability will be given throughout the review. PMID- 26056722 TI - "Social Media has Opened a World of 'Open communication:'" experiences of Adults with Cerebral Palsy who use Augmentative and Alternative Communication and Social Media. AB - An online focus group was used to investigate the experiences of nine individuals with cerebral palsy who use augmentative and alternative communication (AAC) and social media. Information was gathered related to (a) advantages of social media, (b) disadvantages of social media, (c) barriers to successful use, (d) supports to successful use, and (e) recommendations for other individuals using AAC, support personnel, policy makers, and technology developers. Participants primarily chose to focus on social media as a beneficial tool and viewed it as an important form of communication. The participants did describe barriers to social media use (e.g., technology). Despite barriers, all the participants in this study took an active role in learning to use social media. The results are discussed as they relate to themes and with reference to published literature. PMID- 26056723 TI - Sr36- and Sr5-Mediated Resistance Response to Puccinia graminis f. sp. tritici Is Associated with Callose Deposition in Wheat Guard Cells. AB - Race-specific resistance of wheat to Puccinia graminis f. sp. tritici is primarily posthaustorial and often involves the induction of a hypersensitive response (HR). The aim of this study was to investigate host defense responses induced in interactions between P. graminis f. sp. tritici races and wheat lines carrying different race-specific stem rust resistance (Sr) genes. In incompatible interactions between wheat lines carrying Sr36 in three genetic backgrounds (LMPG, Prelude, or W2691) and avirulent P. graminis f. sp. tritici races MCCFC or RCCDM, callose accumulated within 24 h in wheat guard cells contacted by a P. graminis f. sp. tritici appressorium, and P. graminis f. sp. tritici ingress was inhibited following appressorium formation. Accordingly, the expression of transcripts encoding a callose synthase increased in the incompatible interaction between LMPG-Sr36 and avirulent P. graminis f. sp. tritici race MCCFC. Furthermore, the inhibition of callose synthesis through the infiltration of 2 deoxy-D-glucose (DDG) increased the ability of P. graminis f. sp. tritici race MCCFC to infect LMPG-Sr36. A similar induction of callose deposition in wheat guard cells was also observed within 24 h after inoculation (hai) with avirulent P. graminis f. sp. tritici race HKCJC on LMPG-Sr5 plants. In contrast, this defense response was not induced in incompatible interactions involving Sr6, Sr24, or Sr30. Instead, the induction of an HR and cellular lignification were noted. The manifestation of the HR and cellular lignification was induced earlier (24 hai) and was more extensive in the resistance response mediated by Sr6 compared with those mediated by Sr24 or Sr30. These results indicate that the resistance mediated by Sr36 is similar to that mediated by Sr5 but different from those triggered by Sr6, Sr24, or Sr30. Resistance responses mediated by Sr5 and Sr36 are prehaustorial, and are a result of very rapid recognition of molecules derived from avirulent isolates of P. graminis f. sp. tritici, in contrast to the responses triggered in lines with Sr6, Sr24, and Sr30. PMID- 26056724 TI - Collateral consequences: implications of male incarceration rates, imbalanced sex ratios and partner availability for heterosexual Black women. AB - While studies have found correlations between rates of incarceration and sexually transmitted infections (STIs), few studies have explored the mechanisms linking these phenomena. This qualitative study examines how male incarceration rates and sex ratios influence perceived partner availability and sexual partnerships for heterosexual Black women. Semi-structured interviews were conducted with 33 Black women living in two US neighbourhoods, one with a high male incarceration rate and an imbalanced sex ratio (referred to as 'Allentown') and one with a low male incarceration rate and an equitable sex ratio (referred to as 'Blackrock'). Data were analysed using grounded theory. In Allentown, male incarceration reduced the number of available men, and participants largely viewed men available for partnerships as being of an undesirable quality. The number and desirability of men impacted on the nature of partnerships such that they were shorter, focused on sexual activity and may be with higher-risk sexual partners (e.g. transactional sex partners). In Blackrock, marriage rates contributed to the shortage of desirable male partners. By highlighting the role that the quantity and quality of male partners has on shaping sexual partnerships, this study advances current understandings of how incarceration and sex ratios shape HIV- and STI-related risk. PMID- 26056725 TI - Shifts in oxidation states of cerium oxide nanoparticles detected inside intact hydrated cells and organelles. AB - Cerium oxide nanoparticles (CNPs) have been shown to induce diverse biological effects, ranging from toxic to beneficial. The beneficial effects have been attributed to the potential antioxidant activity of CNPs via certain redox reactions, depending on their oxidation state or Ce(3+)/Ce(4+) ratio. However, this ratio is strongly dependent on the environment and age of the nanoparticles and it is unclear whether and how the complex intracellular environment impacts this ratio and the possible redox reactions of CNPs. To identify any changes in the oxidation state of CNPs in the intracellular environment and better understand their intracellular reactions, we directly quantified the oxidation states of CNPs outside and inside intact hydrated cells and organelles using correlated scanning transmission x-ray and super resolution fluorescence microscopies. By analyzing hundreds of small CNP aggregates, we detected a shift to a higher Ce(3+)/Ce(4+) ratio in CNPs inside versus outside the cells, indicating a net reduction of CNPs in the intracellular environment. We further found a similar ratio in the cytoplasm and in the lysosomes, indicating that the net reduction occurs earlier in the internalization pathway. Together with oxidative stress and toxicity measurements, our observations identify a net reduction of CNPs in the intracellular environment, which is consistent with their involvement in potentially beneficial oxidation reactions, but also point to interactions that can negatively impact the health of the cells. PMID- 26056726 TI - Biomimetic DNA nanoballs for oligonucleotide delivery. AB - Here, we designed biomimetic DNA nanoballs for delivery of multiple antisense oligonucleotides (ASOs). DNA templates with ASOs-complementary sequences were amplified by rolling circle amplification (RCA). RCA products were loaded with two types of ASOs by hybridization, condensed using adenovirus-derived Mu peptide, and coated with hyaluronic acid (HA) for delivery into CD44 overexpressing tumor cells. HA-coated, Mu peptide-condensed, dual ASO-loaded DNA nanoballs (HMA nanoballs) showed considerable cellular entry of Cy5-incorporated RCA product DNA and fluorescent ASOs, whereas Mu peptide-condensed, dual ASO loaded DNA nanoballs (MA nanoballs) revealed limited uptake. Dual ASOs, Dz13 and OGX-427, delivered by HMA nanoballs could reduce the levels of protein targets and exert anticancer effects. Enhanced tumor distribution was observed for fluorescent HMA nanoballs than the corresponding MA nanoballs. Upon intravenous co-administration with doxorubicin, HMA nanoballs exerted the greatest anti-tumor effects among the groups. These results suggest HMA nanoballs as a nanoplatform for sequence-specific delivery of multiple ASOs and other functional oligonucleotides. PMID- 26056727 TI - Biomimetic 3D tissue printing for soft tissue regeneration. AB - Engineered adipose tissue constructs that are capable of reconstructing soft tissue with adequate volume would be worthwhile in plastic and reconstructive surgery. Tissue printing offers the possibility of fabricating anatomically relevant tissue constructs by delivering suitable matrix materials and living cells. Here, we devise a biomimetic approach for printing adipose tissue constructs employing decellularized adipose tissue (DAT) matrix bioink encapsulating human adipose tissue-derived mesenchymal stem cells (hASCs). We designed and printed precisely-defined and flexible dome-shaped structures with engineered porosity using DAT bioink that facilitated high cell viability over 2 weeks and induced expression of standard adipogenic genes without any supplemented adipogenic factors. The printed DAT constructs expressed adipogenic genes more intensely than did non-printed DAT gel. To evaluate the efficacy of our printed tissue constructs for adipose tissue regeneration, we implanted them subcutaneously in mice. The constructs did not induce chronic inflammation or cytotoxicity postimplantation, but supported positive tissue infiltration, constructive tissue remodeling, and adipose tissue formation. This study demonstrates that direct printing of spatially on-demand customized tissue analogs is a promising approach to soft tissue regeneration. PMID- 26056728 TI - Degradation of the Common Aqueous Antibiotic Tetracycline using a Carbon Nanotube Electrochemical Filter. AB - In this work, a carbon nanotube (CNT) electrochemical filter was investigated for treatment of aqueous antibiotics using tetracycline (TC) as a model compound. Electrochemical filtration of 0.2 mM TC at a total cell potential of 2.5 V and a flow rate of 1.5 mL min(-1) (hydraulic residence time <2 s) resulted in an oxidative flux of 0.025 +/- 0.001 mol h(-1) m(-2). Replacement of the perforated Ti cathode with a CNT cathode increased the TC oxidative flux by 2.3-fold to 0.020 +/- 0.001 mol h(-1) m(-2) at a total cell potential of 1.0 V. Effluent analysis by liquid chromatography-mass spectrometry and disk agar biocidal diffusion tests indicate that the electrochemical filtration process can degrade the TC molecular structure and significantly decrease its antimicrobial activity, respectively. Addition of dissolved natural organic matter (NOM) negatively affected the TC electrooxidation because of competition for CNT sorption and electrooxidation sites. At 2.0 V total cell potential, TC spiked (0.2 mM) into drinking water reservoir and wastewater treatment plant effluent samples had an oxidative flux of 0.015 +/- 0.001 and 0.022 +/- 0.001 mol h(-1) m(-2), respectively, and an energy requirement of 0.7 kWh kgCOD(-1) or 0.084 kWh m(-3). These results indicate a CNT electrochemical filter may have potential to effectively and efficiently treat antibiotics in water and wastewater effluent. PMID- 26056729 TI - The role of base excision repair in the development of primary open angle glaucoma in the Polish population. AB - Glaucoma is a leading cause of irreversible blindness in developing countries. Previous data have shown that progressive loss of human TM cells may be connected with chronic exposure to oxidative stress. This hypothesis may suggest a role of the base excision repair (BER) pathway of oxidative DNA damage in primary open angle glaucoma (POAG) patients. The aim of our study was to evaluate an association of BER gene polymorphism with a risk of POAG. Moreover, an association of clinical parameters was examined including cup disk ratio (c/d), rim area (RA) and retinal nerve fiber layer (RNFL) with glaucoma progression according to BER gene polymorphisms. Our research included 412 patients with POAG and 454 healthy controls. Gene polymorphisms were analyzed by PCR-RFLP. Heidelberg Retinal Tomography (HRT) clinical parameters were also analyzed. The 399 Arg/Gln genotype of the XRCC1 gene (OR 1.38; 95% CI 1.02-1.89 p = 0.03) was associated with an increased risk of POAG occurrence. It was indicated that the 399 Gln/Gln XRCC1 genotype might increase the risk of POAG progression according to the c/d ratio (OR 1.67; 95% CI 1.07-2.61 P = 0.02) clinical parameter. Moreover, the association of VF factor with 148 Asp/Glu of APE1 genotype distribution and POAG progression (OR 2.25; 95% CI 1.30-3.89) was also found. Additionally, the analysis of the 324 Gln/His MUTYH polymorphism gene distribution in the patient group according to RNFL factor showed that it might decrease the progression of POAG (OR 0.47; 95% CI 0.30-0.82 P = 0.005). We suggest that the 399 Arg/Gln polymorphism of the XRCC1 gene may serve as a predictive risk factor of POAG. PMID- 26056730 TI - GABAA overactivation potentiates the effects of NMDA blockade during the brain growth spurt in eliciting locomotor hyperactivity in juvenile mice. AB - Both NMDA receptor blockade and GABAA receptor overactivation during the brain growth spurt may contribute to the hyperactivity phenotype reminiscent of attention-deficit/hyperactivity disorder. Here, we evaluated the effects of exposure to MK801 (a NMDA antagonist) and/or to muscimol (a GABAA agonist) during the brain growth spurt on locomotor activity of juvenile Swiss mice. This study was carried out in two separate experiments. In the first experiment, pups received a single i.p. injection of either saline solution (SAL), MK801 (MK, 0.1, 0.3 or 0.5 mg/kg) or muscimol (MU, 0.02, 0.1 or 0.5 mg/kg) at the second postnatal day (PND2), and PNDs 4, 6 and 8. In the second experiment, we investigated the effects of a combined injection of MK (0.1 mg/kg) and MU (doses: 0.02, 0.1 or 0.5 mg/kg) following the same injection schedule of the first experiment. In both experiments, locomotor activity was assessed for 15 min at PND25. While MK promoted a dose-dependent increase in locomotor activity, exposure to MU failed to elicit significant effects. The combined exposure to the highest dose of MU and the lowest dose of MK induced marked hyperactivity. Moreover, the combination of the low dose of MK and the high dose of MU resulted in a reduced activity in the center of the open field, suggesting an increased anxiety-like behavior. These findings suggest that, during the brain growth spurt, the blockade of NMDA receptors induces juvenile locomotor hyperactivity whereas hyperactivation of GABAA receptors does not. However, GABAA overactivation during this period potentiates the effects of NMDA blockade in inducing locomotor hyperactivity. PMID- 26056731 TI - 2-Bromopalmitate impairs neural stem/progenitor cell proliferation, promotes cell apoptosis and induces malformation in zebrafish embryonic brain. AB - 2-Bromopalmitate (2BP) is a widely used palmitoylation inhibitor. Besides, it has been reported that 2BP can inhibit T-cell activation, making it a potential immunosuppressor for the treatment of autoimmune diseases. Although the important roles of palmitoylation in a neural system have been noted during the past decades, the effect of 2BP on neural development is still not very clear. In this study, we demonstrated that 25 MUM-100 MUM 2BP exposure caused apparent neural malformation in the presumptive brains of zebrafish embryos at 14 hpf. Further studies implied that the mRNA quantities and distributions of neural stem/progenitor cell (NSPC) markers (neurog1, sox2, and sox3) in the affected regions of 50 MUM 2BP treated embryos significantly decreased. In addition, we found that 2BP impaired the NSPC proliferation at 10 hpf and 14 hpf as well as promoted cell apoptosis at 14 hpf, consistent with which the interference with FGF/ERK signaling pathway was also detected. For the first time, this study provided information about the toxicity and teratogenicity of 2BP for neural development in vivo. PMID- 26056732 TI - Novel role of microRNAs in renal ischemia reperfusion injury. AB - Renal ischemia reperfusion injury (IRI) contributes to the development of acute kidney injury (AKI). Several processes are involved in the development of renal IRI with the generation of reactive oxygen species, inflammation and apoptosis. MicroRNAs (miRNAs) are endogenous, small and noncoding RNAs that repress gene expression of target mRNA in animals post-transcriptionally. miRNA-mediated gene repression is a major modulatory mechanism to regulate fundamental cellular processes such as the cell cycle, proliferation, growth, and apoptosis, which in turn have pivotal influences on pathophysiological outcomes. Recent studies have revealed the pathogenic roles played by miRNAs in many renal diseases, such as IRI, AKI and renal carcinoma. In addition, the majority of miRNAs identified appear to be differentially expressed, probably to quell the injury response by modulating inflammation, apoptosis and proliferation and may point us toward new pathways that can be targeted to regulate or prevent renal IRI. They may represent novel diagnostic biomarkers of renal IR injury. PMID- 26056733 TI - Acute renal failure after high-dose antibiotic bone cement: case report and review of the literature. AB - High-dose antibiotic-loaded bone cement (ALBC) spacers are commonly used to treat prosthetic joint infections following total hip and knee arthroplasties. This methodology can provide high local antibiotic concentrations while minimizing systemic exposure and toxicity. The occurrence of acute kidney injury (AKI) is rarely reported. Available literature suggests that the rate may be higher than previously thought. We report a case of significant systemic tobramycin absorption with concomitant acute renal failure in a 69-year-old female following the implantation of a high-dose ALBC spacer containing both tobramycin and vancomycin. The tobramycin level 24 h post-surgery was 5.8 mcg/mL. Due to concomitant renal failure, antibiotic clearance was poor and resulted in prolonged exposure to elevated aminoglycoside levels. Recovery of renal function occurred, but clinicians should be vigilant in considering the potential impact ALBC spacers can have on post-operative renal function if antibiotic elution is higher than expected. PMID- 26056734 TI - The association of serum-free light-chain levels with markers of renal function. AB - BACKGROUND: The kidney is often affected in plasma cell dyscrasias, usually due to the effects of nephrotoxic monoclonal-free light chains. Renal failure due to a monoclonal gammopathy may be detected by the highly sensitive serum-free light chain (sFLC) ratio yet missed by electrophoretic assays. The aim of this study was to assess sFLC levels in relation to markers of renal function. METHODS: Five hundred thirteen patients were included in this study. sFLC levels were measured by Freelite(r) (The Binding Site Group Ltd, Birmingham, UK) assay using the BNII nephelometer (Siemens Diagnostics, Germany). Kappa/lambda (kappa/lambda) sFLC ratio was calculated. Serum creatinine levels were analyzed by modified Jaffe method in Cobas 8000 analyser. GFR was estimated by the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Patients were assigned to two groups depending on their eGFR values: <= 60 mL/min/1.73 m(2) (Group 1, n = 103) and > 60 mL/min/1.73 m(2) (Group 2, n = 410). Data were expressed as median and min-max. All the statistical analyses were done with SPSS version 20.0 and a significance level of 0.05 was considered. RESULTS: Serum kappa-FLC median value was 36.4 (5.62-16,000) mg/L, serum lambda-FLC was 21.7 (4.91-8770) mg/L, kappa/lambda sFLC ratio was 1.33 (0.01-3258) and serum creatinine was 1.56 (0.63 7.21) mg/dL in Group 1. Both lambda sFLC and kappa/lambda sFLC ratios were correlated with eGFR (r = -0.318, r = 0.198, p < 0.05, respectively). We did not find any significant correlation between kappa/lambda sFLC ratio and eGFR in Group 2. CONCLUSIONS: We examined the association between sFLC concentrations and renal function. Our preliminary findings suggest that serum lambda-FLC might be considered as a useful marker for predicting renal function. Prospective studies are needed to clarify the usefulness of these parameters for identifying renal failure due to a monoclonal gammopathy. PMID- 26056735 TI - Direct Observation of a Carbon Filament in Water-Resistant Organic Memory. AB - The memory for the Internet of Things (IoT) requires versatile characteristics such as flexibility, wearability, and stability in outdoor environments. Resistive random access memory (RRAM) to harness a simple structure and organic material with good flexibility can be an attractive candidate for IoT memory. However, its solution-oriented process and unclear switching mechanism are critical problems. Here we demonstrate iCVD polymer-intercalated RRAM (i-RRAM). i RRAM exhibits robust flexibility and versatile wearability on any substrate. Stable operation of i-RRAM, even in water, is demonstrated, which is the first experimental presentation of water-resistant organic memory without any waterproof protection package. Moreover, the direct observation of a carbon filament is also reported for the first time using transmission electron microscopy, which puts an end to the controversy surrounding the switching mechanism. Therefore, reproducibility is feasible through comprehensive modeling. Furthermore, a carbon filament is superior to a metal filament in terms of the design window and selection of the electrode material. These results suggest an alternative to solve the critical issues of organic RRAM and an optimized memory type suitable for the IoT era. PMID- 26056736 TI - Host preference of an introduced 'generalist' parasite for a non-native host. AB - Parasites can invade new ecosystems if they are introduced with their native hosts or if they successfully infect and colonise new hosts upon arrival. Here, we ask to what extent an introduced parasite demonstrates specialisation among novel host species. Infection surveys across three field sites in Gatun Lake, Panama, revealed that the invasive peacock bass, Cichla monoculus, was more commonly infected by the introduced trematode parasite Centrocestus formosanus than were three other common cichlid fishes. Laboratory infection experiments were conducted to determine whether parasitism might be driven by differential encounter/exposure to parasites or by differential infection susceptibility/preference across different host species. These experiments were performed by controlling for parasite exposure in single host (compatibility) experiments and in mixed host (preference) experiments. In all cases, the peacock bass exhibited higher infection rates with viable metacercariae relative to the other potential fish hosts. Our experiments thus support that an introduced generalist parasite shows apparent specialisation on a specific novel host. Further studies are needed to determine whether these patterns of specialisation are the result of local adaptation following invasion by the parasite. PMID- 26056737 TI - The Strait of Gibraltar poses an effective barrier to host-specialised but not to host-generalised lineages of avian Haemosporidia. AB - One of the major concerns with ongoing environmental global change is the ability of parasites to shift their distribution (both geographically and across hosts) and to increase in virulence. To understand the structure, diversity and connectivity of parasite communities across the Mediterranean Sea, we used avian haemosporidian communities associated with forest birds of northwestern Africa and northwestern Iberia as a model system. We characterised host specificity of lineages and tested whether host generalists are more likely to cross the biogeographic barrier imposed by the Strait of Gibraltar than host specialists. We sampled 321 birds of 43 species in northwestern Africa and 735 birds of 49 species in northwestern Iberia. Using a PCR-based approach to amplify Plasmodium, Haemoproteus and Leucocytozoon parasites, we retrieved 969 sequences representing 200 unique cytochrome-b lineages. Haemosporidians infected a significantly higher proportion of birds in northwestern Africa (78.5%) than in northwestern Iberia (50.5%). Relative diversity of different haemosporidian genera did not differ between our study areas, but Plasmodium was overrepresented among individual infections in northwestern Iberia. Haemoproteus and Leucocytozoon lineages were predominantly host-specialised and Plasmodium lineages were host-generalised. The number of regions occupied by lineages was significantly associated with their host specificity and abundance. These data are consistent with the positive abundance-occupancy relationship and patterns of host specificity among different haemosporidian genera observed in other studies. PMID- 26056738 TI - One Versus Two Photon Control of Dynamical Tunneling: Influence of the Irregular Floquet States. AB - A useful approach to control quantum processes involves driving systems with two colored laser fields and varying the relative phase between the fields to control the quantum interferences. A particularly interesting class of bichromatic control schemes involves the so-called M versus N-photon control that results in laser-induced symmetry breaking and leads to directed transport; however, recent studies have shown that the mechanism of laser-induced symmetry breaking has a common classical and quantum origin. In this context, a relevant question is the extent to which such a detailed classical-quantum correspondence holds if the process to be controlled involves quantum tunneling. In this work, we address this issue in terms of controlling dynamical tunneling between field-induced islands of stability in the classical phase space of a model system, a periodically driven pendulum. This is also a paradigmatic model for Hamiltonian ratchets wherein the islands of stability, that is, nonlinear resonances, play a crucial role in the observed directed transport. We compute an appropriate control landscape for the process and show that despite breaking the relevant symmetries, there exist regions in the control landscape where the control fails. The lack of control can be understood in terms of the phase-space nature of the quantum Floquet states that participate in the dynamics of the initial wavepacket. We argue that robust regions of no control arise due to the phenomenon of chaos-assisted tunneling and comment on the possible influence of such regions on the directed transport in the model system. PMID- 26056739 TI - Human African trypanosomiasis prevention, treatment and control costs: a systematic review. AB - The control and eventual elimination of human African trypanosomiasis (HAT) requires the expansion of current control and surveillance activities. A systematic review of the published literature on the costs of HAT prevention, treatment, and control, in addition to the economic burden, was conducted. All studies that contained primary or secondary data on costs of prevention, treatment and control were considered, resulting in the inclusion of 42 papers. The geographically focal nature of the disease and a lack of standardization in the cost data limit the usefulness of the available information for making generalizations across diverse settings. More recent information on the costs of treatment and control interventions for HAT is needed to provide accurate information for analyses and planning. The cost information contained herein can be used to inform rational decision making in control and elimination programs, and to assess potential synergies with existing vector-borne disease control programs, but programs would benefit significantly from new cost data collection. PMID- 26056740 TI - Life cycle and vectorial competence of Triatoma williami (Galvao, Souza e Lima, 1965) under the influence of different blood meal sources. AB - Triatoma williami is naturally infected by Trypanosoma cruzi, the ethiological agent of Chagas disease, the most significant cause of morbidity and mortality in South and Central America.The possibility of domiciliation of T. williami increases the risk of human T. cruzi vetorial transmission. Despite this, there is a lack of data demonstrating the bionomic aspects, the vectorial competence or the natural ecotope and the wild hosts of T. williami. This study describes for the first time the life cycle of T. williami under the influence of two blood meal sources and also evaluates the vectorial potential of the species. The development of two groups of hundred triatomines was followed over the nymphal stages and adulthood. Each group was exposed to a sole blood meal source, mammalian or bird. The average egg-to-adult development time in both groups was similar, except by shorter stages of N3 and N4 in triatomines fed on mammals. The group fed on birds needed more blood feedings to suffer the ecdysis and had higher cumulative mortality in the nymphal stages. Although the observed delay at defecation of adults after feeding, our results suggest that T. williami in the third and fifth nymphal stages may be good vectors. PMID- 26056741 TI - Dark dyes-bright complexes: fluorogenic protein labeling. AB - Complexes formed between organic dyes and genetically encoded proteins combine the advantages of stable and tunable fluorescent molecules and targetable, biologically integrated labels. To overcome the challenges imposed by labeling with bright fluorescent dyes, a number of approaches now exploit chemical or environmental changes to control the properties of a bound dye, converting dyes from a weakly fluorescent state to a bright, easily detectable complex. Optimized, such approaches avoid the need for removal of unbound dyes, facilitate rapid and simple assays in cultured cells and enable hybrid labeling to function more robustly in living model organisms. PMID- 26056742 TI - New approaches to HIV vaccine development. AB - Development of a safe and effective vaccine for HIV is a major global priority. However, to date, efforts to design an HIV vaccine with methods used for development of other successful viral vaccines have not succeeded due to HIV diversity, HIV integration into the host genome, and ability of HIV to consistently evade anti-viral immune responses. Recent success in isolation of potent broadly neutralizing antibodies (bnAbs), in discovery of mechanisms of bnAb induction, and in discovery of atypical mechanisms of CD8T cell killing of HIV-infected cells, have opened new avenues for strategies for HIV vaccine design. PMID- 26056743 TI - Maternal distress associates with placental genes regulating fetal glucocorticoid exposure and IGF2: Role of obesity and sex. AB - Maternal emotional distress symptoms, including life satisfaction, anxiety and depressed mood, are worse in Severely Obese (SO) than lean pregnancy and may alter placental genes regulating fetal glucocorticoid exposure and placental growth. We hypothesised that the associations between increased maternal distress symptoms and changes in placental gene expression including IGF2 and genes regulating fetal glucocorticoid exposure are more pronounced in SO pregnancy. We also considered whether there were sex-specific effects. Placental mRNA levels of 11beta-HSDs, NR3C1-alpha, NR3C2, ABC transporters, mTOR and the IGF2 family were measured in term placental samples from 43 lean (BMI<=25kg/m(2)) and 50 SO (BMI>=40kg/m(2)) women, in whom distress symptoms were prospectively evaluated during pregnancy. The mRNA levels of genes with a similar role in regulating fetal glucocorticoid exposure were strongly inter-correlated. Increased maternal distress symptoms associated with increased NR3C2 and IGF2 isoform 1(IGF2-1) in both lean and SO group (p<=0.05). Increased distress was associated with higher ABCB1 and ABCG2 mRNA levels in SO but lower ABCB1 and higher 11beta-HSD1 mRNA levels in lean (p<=0.05) suggesting a protective adaptive response in SO placentas. Increased maternal distress associated with reduced mRNA levels of ABCB1, ABCG2, 11beta-HSD2, NR3C1-alpha and IGF2-1 in placentas of female but not male offspring. The observed sex differences in placental responses suggest greater vulnerability of female fetuses to maternal distress with potentially greater fetal glucocorticoid exposure and excess IGF2. Further studies are needed to replicate these findings and to test whether this translates to potentially greater negative outcomes of maternal distress in female offspring in early childhood. PMID- 26056744 TI - MoS2 actuators: reversible mechanical responses of MoS2-polymer nanocomposites to photons. AB - New molybdenum disulfide (MoS2)-based polymer composites and their reversible mechanical responses to light are presented, suggesting MoS2 as an excellent candidate for energy conversion. Homogeneous mixtures of MoS2/polydimethylsiloxane (PDMS) nanocomposites (0.1-5 wt.%) were prepared and their near infrared (NIR) mechanical responses studied with increasing pre strains. NIR triggering resulted in an extraordinary change in stress levels of the actuators by ~490 times. Actuation responses of MoS2 polymer composites depended on applied pre-strains. At lower levels of pre-strains (3-9%) the actuators showed reversible expansion while at high levels (15-50%), the actuators exhibited reversible contraction. An opto-mechanical conversion (eta)~0.5-3 MPa W(-1) was calculated. The ratio of maximum stress due to photo actuation (sigmamax) at 50% strain to the minimum stress due to photo-actuation (sigmamin) at 3% strain was found to be ~315-322% for MoS2 actuators (for 0.1 to 5 wt.% additive), greater than single layer graphene (~188%) and multi-wall nanotube (~172%) photo-mechanical actuators. Unlike other photomechanical actuators, the MoS2 actuators exhibited strong light-matter interactions and an unambiguous increase in amplitude of photomechanical response with increasing strains. A power law dependence of sigmamax/sigmamin on strains with a scaling exponent of beta = 0.87-1.32 was observed, suggesting that the origin of photomechanical response is intertwined dynamically with the molecular mechanisms at play in MoS2 actuators. PMID- 26056745 TI - The diversification of developmental biology. AB - In the 1960s, "developmental biology" became the dominant term to describe some of the research that had previously been included under the rubrics of embryology, growth, morphology, and physiology. As scientific societies formed under this new label, a new discipline took shape. Historians, however, have a number of different perspectives on what changes led to this new field of developmental biology and how the field itself was constituted during this period. Using the General Embryological Information Service, a global index of post-World War II development-related research, we have documented and visualized significant changes in the kinds of research that occurred as this new field formed. In particular, our analysis supports the claim that the transition toward developmental biology was marked by a growth in new topics and forms of research. Although many historians privilege the role of molecular biology and/or the molecularization of biology in general during this formative period, we have found that the influence of molecular biology is not sufficient to account for the wide range of new research that constituted developmental biology at the time. Overall, our work creates a robust characterization of the changes that occurred with regard to research on growth and development in the decades following World War II and provides a context for future work on the specific drivers of those changes. PMID- 26056746 TI - Intuitive anatomy: Distortions of conceptual knowledge of hand structure. AB - Knowledge of the spatial layout of bodies is mediated by a representation called the body structural description, damage to which results in the condition of autotopagnosia in which patients are impaired in judgments about the location and configuration of body parts. While a large literature has investigated disruption of the body structural description, little research has examined its accuracy in healthy individuals. I show that people have systematically distorted knowledge of the configuration of hands. Participants judged the location of their knuckles (i.e., the metacarpophalangeal joint) by pointing with a baton on their palm. Participants showed clear distal biases, judging their knuckles as farther forward in the hand than they actually are for all fingers except the thumb. This effect appeared both when participants localized the knuckles of their own hand and another person's hand. These results suggest that intuitive beliefs about body form are systematically distorted. PMID- 26056747 TI - Modeling the approximate number system to quantify the contribution of visual stimulus features. AB - The approximate number system (ANS) subserves estimation of the number of items in a set. Typically, ANS function is assessed by requiring participants to compare the number of dots in two arrays. Accuracy is determined by the numerical ratio of the sets being compared, and each participant's Weber fraction (w) provides a quantitative index of ANS acuity. When making numerical comparisons, however, performance is also influenced by non-numerical features of the stimuli, such as the size and spacing of dots. Current models of numerosity comparison do not account for these effects and consequently lead to different estimates of w depending on the methods used to control for non-numerical features. Here we proffer a new model that teases apart the effects of ANS acuity from the effects of non-numerical stimulus features. The result is an estimate of w that is a more theoretically valid representation of numerical acuity and novel terms that denote the degree to which a participant's perception of number is affected by non-numerical features. We tested this model in a sample of 20 adults and found that, by correctly attributing errors due to non-numerical stimulus features, the w obtained was more reliable across different stimulus conditions. We found that although non-numerical features biased numerosity discriminations in all participants, number was the primary feature driving discriminations in most of them. Our findings support the idea that, while numerosity is a distinct visual quantity, the internal representation of number is tightly bound to the representation of other magnitudes. This tool for identifying the different effects of the numerical and non-numerical features of a stimulus has important implications not only for the behavioral investigation of the ANS, but also for the collection and analyses of neural data sets associated with ANS function. PMID- 26056748 TI - Antimalarial Isocyano and Isothiocyanato Sesquiterpenes with Tri- and Bicyclic Skeletons from the Nudibranch Phyllidia ocellata. AB - Five new isocyano/isothiocyanato sesquiterpenes (1-5) with tri- or bicyclic carbon skeletons have been characterized from Australian specimens of the nudibranch Phyllidia ocellata. Spectroscopic analyses at 900 MHz were informed by DFT calculations. The 1S, 5S, 8R configuration of 2-isocyanoclovene (1) was determined by X-ray crystallographic analysis of formamide 6. A biosynthetic pathway to clovanes 1 and 2 from epicaryolane precursors is proposed. Isocyanides 1, 2, and 4 showed activity against Plasmodium falciparum (IC50 0.26-0.30 MUM), while isothiocyanate 3 and formamide 6 had IC50 values of >10 MUM. PMID- 26056750 TI - Current world literature: current opinion in organ transplantation. PMID- 26056749 TI - Effectiveness trial of a selective dissonance-based eating disorder prevention program with female college students: Effects at 2- and 3-year follow-up. AB - OBJECTIVE: An efficacy trial found that a dissonance-based prevention program reduced risk factors, eating disorder symptoms, and future eating disorder onset, but smaller effects emerged when high school clinicians recruited students and delivered the program under real-world conditions in an effectiveness trial. The current report describes results at 2- and 3-year follow-up from an effectiveness trial that tested whether a new enhanced dissonance version of this program produced larger effects when college clinicians recruit students and deliver the intervention using improved train and supervision procedures. METHOD: Young women from eight universities (N = 408, M age = 21.6, SD = 5.64) were randomized to the prevention program or an educational brochure control condition. RESULTS: Dissonance participants showed greater decreases in risk factors, eating disorder symptoms, and psychosocial impairment by 3-year follow-up than controls, but not healthcare utilization, BMI, or eating disorder onset. CONCLUSIONS: This novel multisite effectiveness trial found that the enhanced dissonance intervention and improved training and supervision procedures produced an average effect size at 3 year follow-up that was 290% and 160% larger than effects observed in the high school effectiveness trial and efficacy trial respectively. Yet, the lack of eating disorder onset effects may imply that factors beyond pursuit of the thin ideal now contribute to eating disorder onset. PMID- 26056752 TI - Robotic radical hysterectomy in early stage cervical cancer: A systematic review and meta-analysis. AB - OBJECTIVE: To compare intraoperative and short-term postoperative outcomes of robotic radical hysterectomy (RRH) to laparoscopic and open approaches in the treatment of early stage cervical cancer. METHODS: A search of MEDLINE, EMBASE (using Ovid interface) and SCOPUS databases was conducted from database inception through February 15, 2014. We included studies comparing surgical approaches to radical hysterectomy (robotic vs. laparoscopic or abdominal, or both) in women with stages IA1-IIA cervical cancer. Intraoperative outcomes included estimated blood loss (EBL), operative time, number of pelvic lymph nodes harvested and intraoperative complications. Postoperative outcomes were hospital stay and surgical morbidity. The random effects model was used to pool weighted mean differences (WMDs) and odds ratios (OR). RESULTS: Twenty six nonrandomized studies were included (10 RRH vs abdominal radical hysterectomy [ARH], 9 RRH vs laparoscopic radical hysterectomy [LRH] and 7 compared all 3 approaches) enrolling 4013 women (1013 RRH, 710 LRH and 2290 ARH). RRH was associated with less EBL (WMD=384.3, 95% CI=233.7, 534.8) and shorter hospital stay (WMD=3.55, 95% CI=2.10, 5.00) than ARH. RRH was also associated with lower odds of febrile morbidity (OR=0.43, 95% CI=0.20-0.89), blood transfusion (OR=0.12, 95% CI 0.06, 0.25) and wound-related complications (OR=0.31, 95% CI=0.13, 0.73) vs. ARH. RRH was comparable to LRH in all intra- and postoperative outcomes. CONCLUSION: Current evidence suggests that RRH may be superior to ARH with lower EBL, shorter hospital stay, less febrile morbidity and wound-related complications. RRH and LRH appear equivalent in intraoperative and short-term postoperative outcomes and thus the choice of approach can be tailored to the choice of patient and surgeon. PMID- 26056753 TI - Ultrasound guided subcostal transversus abdominis plane (TAP) infiltration with liposomal bupivacaine for patients undergoing robotic assisted hysterectomy: A prospective randomized controlled study. AB - INTRODUCTION: Optimal pain control after major surgery contributes to a patient's recovery and satisfaction. The use of liposomal bupivacaine in subcostal transversus abdominis plane (TAP) blocks for postoperative pain control after robot assisted abdominal surgery has yet to be studied. METHODS: We conducted a prospective randomized controlled observer-blinded study comparing bilateral subcostal TAP blocks with bupivacaine to bilateral subcostal TAP blocks with liposomal bupivacaine. These were performed prior to the patient undergoing robot assisted hysterectomy. The patients' pain scores, opioid use, side effects, and satisfaction were followed for 72h after injection. RESULTS: Total opioid use in the first 72h after injection was significantly decreased in the group that received liposomal bupivacaine compared to bupivacaine. Patients in the liposomal bupivacaine group had significantly lower maximal pain scores at all time periods studied as well as decreased incidence of nausea/vomiting. There was a trend toward decreased length of stay in the liposomal bupivacaine group. CONCLUSION: Subcostal TAP blocks with liposomal bupivacaine decreased the total opioid requirement for the first 72h after robot assisted hysterectomy when compared to subcostal TAP blocks with bupivacaine. PMID- 26056754 TI - Trace Element Supplementation Following Severe Burn Injury: A Systematic Review and Meta-Analysis. AB - Trace elements have an important physiological role after severe burn injury with patients routinely receiving supplementation. Although commonly prescribed after burn injury, variation exists among supplement composition, frequency, and the dosage administered. This review aims to assess the effectiveness of trace element supplementation on clinically meaningful outcomes in patients who have sustained a severe burn injury. Supplementation of selenium, copper and zinc, either alone or combined, compared with placebo or standard treatment were eligible for inclusion. Predetermined primary outcome measures were mortality, length of stay, rate of wound healing, and complications. A comprehensive search strategy was undertaken. Methodological quality of eligible studies was appraised and relevant data extracted for meta-analysis. Eight studies met eligibility criteria for the review; four randomized controlled trials and four nonrandomized experimental trials, including a total of 398 participants with an age range of 6 to 67 years. Parenteral supplementation of combined trace elements was associated with a significant decrease in infectious episodes (weighted mean difference: 1.25 episodes, 95% confidence intervals: -1.70, -0.80; P < .00001). The results of this review indicate that the use of parentally administered combined trace elements after burn injury confer positive effects in decreasing infectious complications. Combined parenteral trace element supplementation and combined oral and parenteral zinc supplementation have potentially clinically significant findings on reducing length of stay. Oral zinc supplementation shows possible beneficial effects on mortality. Definitive studies are required to accurately define optimal trace element supplementation regimens, dosages, and routes after burn injury. PMID- 26056755 TI - Multidrug-Resistant Bacterial Outbreaks in Burn Units: A Synthesis of the Literature According to the ORION Statement. AB - The objective of this study is to review the literature on multidrug-resistant bacteria (MDRB) outbreaks in burn units according to the outbreak reports and intervention studies of nosocomial infection statement. A PubMed search engine was enlisted to identify reports, in English and French, on MDRB outbreaks in burn units, with no date restrictions, using the following key words: ("burn" OR "burns" OR "severe burn") AND ("unit" OR "critical care" OR "acute care" OR "intensive care" OR "center" OR "centre" OR "department") AND ("outbreak" OR "epidemic") AND ("resistant" OR "multidrug-resistant" OR "resistance" OR "MDR" OR "MDRO"). Twenty-nine articles on such outbreaks in burn units were analyzed. A wide variety of these outbreaks were studied in terms of the microbial agents involved, length of outbreak, and attack rate (1.9-66.7%). The most frequent bacteria were methicillin-resistant Staphylococcus aureus and Acinetobacter baumannii. Screening of staff revealed carrier rates of 0 to 20% in 16 studies. Environmental samples were taken in 21 studies and were positive in 14 of them. The mortality rate among infected patients varied from 0 to 33%. Implementation of isolation precautions did not always suffice, with unit closure being necessary in five outbreaks. The lack of consensus on how to manage such outbreak was highlighted. MDRB infections or colonizations are responsible for increased morbidity and mortality in vulnerable burn patients. Their management is problematic because of multifactorial transmission and limited therapeutic possibilities. PMID- 26056756 TI - Using "The Burns Suite" as a Novel High Fidelity Simulation Tool for Interprofessional and Teamwork Training. AB - Educational theory highlights the importance of contextualized simulation for effective learning. The authors recently published the concept of "The Burns Suite" (TBS) as a novel tool to advance the delivery of burns education for residents/clinicians. Effectively, TBS represents a low-cost, high-fidelity, portable, immersive simulation environment. Recently, simulation-based team training (SBTT) has been advocated as a means to improve interprofessional practice. The authors aimed to explore the role of TBS in SBTT. A realistic pediatric burn resuscitation scenario was designed based on "advanced trauma and life support" and "emergency management of severe burns" principles, refined utilizing expert opinion through cognitive task analysis. The focus of this analysis was on nontechnical and interpersonal skills of clinicians and nurses within the scenario, mirroring what happens in real life. Five-point Likert-type questionnaires were developed for face and content validity. Cronbach's alpha was calculated for scale reliability. Semistructured interviews captured responses for qualitative thematic analysis allowing for data triangulation. Twenty-two participants completed TBS resuscitation scenario. Mean face and content validity ratings were high (4.4 and 4.7 respectively; range 4-5). The internal consistency of questions was high. Qualitative data analysis revealed two new themes. Participants reported that the experience felt particularly authentic because the simulation had high psychological and social fidelity, and there was a demand for such a facility to be made available to improve nontechnical skills and interprofessional relations. TBS provides a realistic, novel tool for SBTT, addressing both nontechnical and interprofessional team skills. Recreating clinical challenge is crucial to optimize SBTT. With a better understanding of the theories underpinning simulation and interprofessional education, future simulation scenarios can be designed to provide unique educational experiences whereby team members will learn with and from other specialties and professions in a safe, controlled environment. PMID- 26056757 TI - Bacterial Contamination of Burn Unit Employee Identity Cards. AB - The purpose of this study was to identify the presence or absence of pathogenic bacteria on burn intensive care unit employees' common access cards (CACs) and identity badges (IDs) and to identify possible variables that may increase risk for the presence of those bacteria. A prospective, cross-sectional study was conducted in our regional Burn Center in which bacterial swab specimens were collected from both the CAC and ID of 10 burn intensive care unit employees in each of five cohorts (nurses, respiratory therapists, physical therapists, physicians, and ancillary staff). Ten additional paired samples, collected from direct care staff in the outpatient burn clinic, served as control. Additional information described how the cards were worn and if/how they had been cleaned in the previous week. Fifty-eight CACs and 60 IDs were swabbed from participants. The overall contamination rate was 75%, with no trends identified based on how cards were worn. Bacteria were recovered from 86% (50/58) of CACs and 65% (39/60) of IDs, with CACs being significantly more contaminated overall than IDs (P < .01). In terms of potentially pathogenic bacteria, the overall rate was 3%, with 100% of those isolates coming from the outpatient clinic staff cohort (P < .001). When cleaned in the last week (n = 16), the contamination rate dropped to 50% overall (P = .003), indicating that even periodic cleaning appears to have a positive effect on bacterial contamination rates. The simple practice of routine identity card decontamination may reduce potential threats to patient safety as a result of nosocomial bacterial transmission. PMID- 26056758 TI - Explanatory Model of Resilience in Pediatric Burn Survivors. AB - Identifying factors of adjustment in pediatric burn patients may facilitate appropriate mental health interventions postinjury. The aim of this is study was to explore the roles of both the patient's and caregivers' resilience and posttraumatic stress in pediatric burn survivor adjustment. For the purposes of the study, "51 patient-parent/guardian" dyads participated. Patients answered the Resilience Questionnaire for Children and Adolescents, and caregivers answered the Mexican Resilience Scale and the Davidson Trauma Scale. The roles of patient age, time since the burn, and size of burn injury were also considered. Statistical analyses included Spearman's rho for correlations and structural equation modeling. P less than .05 was considered significant. Patients and caregivers reported high levels of resilience, and the majority of caregivers reported low severity of posttraumatic stress disorder symptoms. Pediatric burn survivors' resilience was associated with being younger at the time of the burn and less severity of intrusive and avoidance symptoms in caregivers; it was also associated with a higher resilience in caregivers. It can be concluded that psychological responses of caregivers of pediatric burn survivors affect the well being and positive adjustment of patients; thus psychological services for caregivers would likely have a double benefit for both caregivers and patients. PMID- 26056759 TI - Functioning, Disability, and Social Adaptation Six Months After Burn Injury. AB - Major injuries commonly cause long-standing functional impairment. The authors investigated the levels of and predictors for functioning, disability, and social adaptation 6 months after a burn injury. The overall level of functioning at 6 months postburn was assessed among 87 (81%) of the 107 consecutive acute adult burn patients (mean TBSA 9.7%) admitted to the Helsinki Burn Centre during an 18 month period. Social and Occupational Functioning Assessment Scale (SOFAS) was used to evaluate functioning overall, and Sheehan Disability Scale (SDS) to assess the domains of working capacity, social life, and family life. Social Adaptation Self-Evaluation Scale (SASS) was used to measure social adaptation. Structured clinical interview was used to assess mental disorders at baseline and 6 months after injury. The mean SOFAS score was 69.7 (SD = 20.8), indicating some impairment in social and occupational functioning. The strongest independent predictors of SOFAS were mental disorders during follow-up (P < .001), particularly major depressive disorder (P < .001) and delirium (P = .016), but also length of stay (P = .004) and hand burn (P = .012). Concerning disability (SDS), the authors found mild impairment in all three domains, the most in SDS work (mean 3.59, SD = 3.46). The strongest predictor of SDS was major depressive disorder during follow-up (P < .001) and of SASS personality disorders (P = .007). Six months after a burn injury, some difficulties in social and occupational functioning remained. Level of functioning was predicted strongly and consistently by mental disorders, particularly depression. Length of stay and hand burns also predicted functioning, more in a clinician's evaluation (SOFAS) than in self-reported measures (SDS and SASS). PMID- 26056760 TI - Development of a Best Evidence Statement for the Use of Pressure Therapy for Management of Hypertrophic Scarring. AB - Pressure therapy has been considered standard, first-line intervention for the treatment of hypertrophic scars since its introduction in the 1960s. Although widely used, this scar management technique has historically been based on a wide array of anecdotal evidence as opposed to strong scientific support. Evidence has become more prevalent in recent years, necessitating a synthesis to develop an evidence-based clinical guideline. The clinical question was asked, "Among individuals with or at risk to develop active hypertrophic scars, does treatment with pressure therapy improve aesthetic and functional outcomes?" An evidence based practice project was completed with aims to synthesize relevant literature to determine recommendations for the use of pressure therapy in individuals at risk for hypertrophic scars. A systematic search of the literature was conducted for the dates January 1950 to February 2014 of the following databases: MEDLINE, CINAHL, Cochrane Database for Systematic Reviews, Burntherapist.com, Cochrane Libraries, Ebsco, Google Scholar, OT Seeker, Ovid, MedLine, PEDro.org, Pubmed.gov, Pubmed Clinical Queries, and hand search of relevant articles through use of reference lists. Search terms included scar, hypertroph*, pressure therapy, compression therapy, pressure garment, burn, scald, trauma as well as MeSH terms cicatrix and hypertrophic. Articles were reviewed in terms of ability to answer the clinical question as well as strength of conclusions. A total of 45 articles were found and critiqued, 28 of which were relevant to the clinical question. Evidence strength ranged from level 1 to level 5. Results from the studies were synthesized to create clinical recommendations to guide treatment. Based on best available evidence, it is recommended that pressure therapy is utilized to decrease scar height and erythema that it is used for grafts and wounds requiring 14 to 21 days to heal, for 23 hours/day for 12 months, fit to achieve 20 to 30 mm Hg of pressure, fit by a skilled technician, and replaced every 2-3 months. In addition, it is not recommended that pressure therapy is used to treat abnormal pigmentation, nor used to hasten scar maturation. This literature search revealed insufficient evidence addressing the impact of pressure therapy on scar pliability. Among individuals with or at risk to develop active hypertrophic scars, treatment with pressure therapy does improve outcomes, particularly for aesthetic concerns including scar thickness and erythema. Applicability of research to practice: The practical treatment recommendations presented may improve consistency and efficacy of pressure therapy utilization at the point of care. PMID- 26056761 TI - Long-Term Outcomes in Patients Surviving Large Burns: The Musculoskeletal System. AB - The authors have previously described long-term outcomes related to the skin in patients surviving large burns. The objective of this study was to describe the long-term musculoskeletal complications following major burn injury. This is a cross-sectional descriptive study that includes a one-time evaluation of 98 burn survivors (mean age = 47 years; mean TBSA = 57%; and mean time from injury = 17 years), who consented to participate in the study. A comprehensive history and physical examination was conducted by a senior and experienced Physical Medicine and Rehabilitation physician. In addition to completing a Medical Problem Checklist, subjects also completed the Burn-Specific Health Scale (Abbreviated 80 item), a self-report measure used to review the level of functional adaptation. Joint pain, joint stiffness, problems walking or running, fatigue, and weak arms and hands are conditions that continue to be reported at an average of 17 years from the time of burn injury. Seventy-three percent (68 of 93) of the study sample were found to have a limitation of motion and areas most affected were the neck (47%), hands (45%), and axilla (38%). The global (Burn-Specific Health Scale total) score for the overall sample was 0.78. Subjects with limitation of motion had significant difficulty in areas of mobility, self-care, hand function, and role activities. This study underscores the importance of long-term follow-up care and therapeutic interventions for survivors of major burn injury, as they continue to have significant and persistent burn-related impairments even several years following injury. PMID- 26056762 TI - Fostering Disaster Preparedness through the "Grass Roots Efforts" of an American Burn Association Special Interest Group. PMID- 26056763 TI - Cytomegalovirus Colitis in a Burn Patient. AB - The prevalence of cytomegalovirus in the burn population is high. However, its role in the clinical management of burn patients is still being defined. This report documents a 41-year-old man who developed cytomegalovirus (CMV) colitis after being admitted with a 72% burn. Before the administration of ganciclovir, the authors had difficulty controlling his quantitative wound cultures with serial debridements, topical agents, and systemic antibiotics for known pathogens, which led to graft loss. After the ganciclovir was given, his quantitative wound cultures improved without changing the authors' topical agents or systemic antibiotics and had improved graft take. Whether CMV infection alone contributed to an increased morbidity in this patient or the combination of bacteria/fungal infection with CMV led to a synergistic effect is still not clearly understood. CMV may have contributed to a dysfunction in his cell mediated immunity, which, in turn, lowered the bacterial and fungal load necessary to cause graft loss. Patients who continue to do poorly despite adequate treatment for known pathogens may need to be screened for CMV and treated. PMID- 26056764 TI - Fibres and cellular structures preserved in 75-million-year-old dinosaur specimens. AB - Exceptionally preserved organic remains are known throughout the vertebrate fossil record, and recently, evidence has emerged that such soft tissue might contain original components. We examined samples from eight Cretaceous dinosaur bones using nano-analytical techniques; the bones are not exceptionally preserved and show no external indication of soft tissue. In one sample, we observe structures consistent with endogenous collagen fibre remains displaying ~ 67 nm banding, indicating the possible preservation of the original quaternary structure. Using ToF-SIMS, we identify amino-acid fragments typical of collagen fibrils. Furthermore, we observe structures consistent with putative erythrocyte remains that exhibit mass spectra similar to emu whole blood. Using advanced material characterization approaches, we find that these putative biological structures can be well preserved over geological timescales, and their preservation is more common than previously thought. The preservation of protein over geological timescales offers the opportunity to investigate relationships, physiology and behaviour of long extinct animals. PMID- 26056765 TI - Biotransformation of trace organic chemicals during groundwater recharge: How useful are first-order rate constants? AB - This study developed relationships between the attenuation of emerging trace organic chemicals (TOrC) during managed aquifer recharge (MAR) as a function of retention time, system characteristics, and operating conditions using controlled laboratory-scale soil column experiments simulating MAR. The results revealed that MAR performance in terms of TOrC attenuation is primarily determined by key environmental parameters (i.e., redox, primary substrate). Soil columns with suboxic and anoxic conditions performed poorly (i.e., less than 30% attenuation of moderately degradable TOrC) in comparison to oxic conditions (on average between 70-100% attenuation for the same compounds) within a residence time of three days. Given this dependency on redox conditions, it was investigated if key parameter-dependent rate constants are more suitable for contaminant transport modeling to properly capture the dynamic TOrC attenuation under field-scale conditions. Laboratory-derived first-order removal kinetics were determined for 19 TOrC under three different redox conditions and rate constants were applied to MAR field data. Our findings suggest that simplified first-order rate constants will most likely not provide any meaningful results if the target compounds exhibit redox dependent biotransformation behavior or if the intention is to exactly capture the decline in concentration over time and distance at field scale MAR. However, if the intention is to calculate the percent removal after an extended time period and subsurface travel distance, simplified first-order rate constants seem to be sufficient to provide a first estimate on TOrC attenuation during MAR. PMID- 26056767 TI - The Americans With Disabilities Act and HIV/AIDS Discrimination: Unfinished Business. PMID- 26056766 TI - Breathing new life into nitric oxide signaling: A brief overview of the interplay between oxygen and nitric oxide. AB - Nitric oxide ((*)NO, nitrogen monoxide) is one of the most unique biological signaling molecules associated with a multitude of physiologic and pathological conditions. In order to fully appreciate its numerous roles, it is essential to understand its basic biochemical properties. Most signaling effector molecules such as steroids or proteins have a significant life-span and function through classical receptor-ligand interactions. (*)NO, however, is a short-lived free radical gas that only reacts with two types of molecules under biological conditions; metals and other free radicals. These simple interactions can lead to a myriad of complex intermediates which in turn have their own phenotypic effects. For these reasons, responses to (*)NO often appear to be random or contradictory when outcomes are compared across various experimental settings. This article will serve as a brief overview of the chemical, biological, and microenvironmental factors that dictate (*)NO signaling with an emphasis on (*)NO metabolism. The prominent role that oxygen (dioxygen, O2) plays in (*)NO metabolism and how it influences the biological effects of (*)NO will be highlighted. This information and these concepts are intended to help students and investigators think about the interpretation of data from experiments where biological effects of (*)NO are being elucidated. PMID- 26056768 TI - Paraphenylenediamine Containing Hair Dye: An Emerging Household Poisoning. AB - Paraphenylenediamine poisoning is among one of the emerging causes of poisoning in Asian countries, because it is a constituent of hair dye formulations and is easily available in market at low cost. Hair dyes are rampantly used in Asian households compared with the western world. Locally, hair dye constituents may have allergic adverse effects, and acute systemic poisoning presents with characteristic angioedema, upper airway obstruction, rhabdomyolysis, methemoglobinemia, myoglobinuria, and acute renal failure. This study reports about the death of a 24-year-old Indian housewife who committed suicide by taking hair dye emulsion. She had an argument with her husband, and because of fit of rage, took a bowlful (80 mL) of hair dye emulsion kept prepared for the use by husband. She developed angioedema, cervical swelling, and rhabdomyolysis and died of acute renal failure within 24 hours. Toxicological analysis of viscera and blood revealed varying levels of paraphenylenediamine. Histopathological samples of kidney showed features of acute tubular necrosis and myoglobin casts in renal tubules. The aim of the study is to create awareness about the adverse effects of the hair dye, its poisoning outcome, and possible preventive measures. PMID- 26056769 TI - Use of somatostatin analogues to treat chylothorax in a child with Generalised Lymphatic Dysplasia. AB - Generalised Lymphatic Dysplasia is a rare condition that may be associated with significant chylothoraces. The management of such effusions is often challenging. We present the case of a 15-year-old girl with bilateral chylothoraces and lymphoedema of her limbs. A clinical diagnosis of Generalised Lymphatic Dysplasia was made and long-term treatment with somatostatin analogues (somatostatin initially followed by monthly octreotide) was initiated. Over 12 months there was symptomatic benefit with some objective improvement in lung function and no adverse effects. After a year of treatment there was some reaccumulation of fluid, however this did not require any intervention. This is the first paediatric report of the use of somatostatin analogues to manage chylothorax in Generalised Lymphatic Dysplasia and we conclude that they represent a potentially useful treatment modality. Experience is only anecdotal however and further studies are required to establish an evidence base with regard to efficacy and safety. PMID- 26056770 TI - Microbial diversity of hypersaline environments: a metagenomic approach. AB - Recent studies based on metagenomics and other molecular techniques have permitted a detailed knowledge of the microbial diversity and metabolic activities of microorganisms in hypersaline environments. The current accepted model of community structure in hypersaline environments is that the square archaeon Haloquadratum waslbyi, the bacteroidete Salinibacter ruber and nanohaloarchaea are predominant members at higher salt concentrations, while more diverse archaeal and bacterial taxa are observed in habitats with intermediate salinities. Additionally, metagenomic studies may provide insight into the isolation and characterization of the principal microbes in these habitats, such as the recently described gammaproteobacterium Spiribacter salinus. PMID- 26056771 TI - DNA repair in hyperthermophilic and hyperradioresistant microorganisms. AB - The genome of a living cell is continuously under attack by exogenous and endogenous genotoxins. Especially, life at high temperature inflicts additional stress on genomic DNA, and very high rates of potentially mutagenic DNA lesions, including deamination, depurination, and oxidation, are expected. However, the spontaneous mutation rates in hyperthermophiles are similar to that in Escherichia coli, and it is interesting to determine how the hyperthermophiles preserve their genomes under such grueling environmental conditions. In addition, organisms with extremely radioresistant phenotypes are targets for investigating special DNA repair mechanisms in extreme environments. Multiple DNA repair mechanisms have evolved in all organisms to ensure genomic stability, by preventing impediments that result in genome destabilizing lesions. PMID- 26056772 TI - The relationship between the clinical course and cytokine in a patient with cigarette smoking-induced acute eosinophilic pneumonia - A case report. AB - A 19-year-old female was admitted to our hospital because of a sudden onset fever and cough, and she was diagnosed to have acute eosinophilic pneumonia (AEP). The cause was thought to be cigarette smoking, because she had started smoking just before the development of AEP and her condition improved after cigarette smoking cessation, without corticosteroid treatment. The cytokines which are thought to be involved in eosinophilic accumulation in the lungs were analyzed using bronchoalveolar lavage fluid (BALF) and serum. Of the analyzed cytokines, only regulated on activation, normal T cell expressed and secreted (RANTES) increased in the serum after the improvement. RANTES is a unique chemokine which attracts not only eosinophils, but also T cells. Interestingly, in this case, the eosinophil count in the blood increased in parallel with the lymphocyte count after the improvement. These findings are interesting because it may help to understand the pathogenesis of AEP and the role of RANTES. PMID- 26056773 TI - Hydrodynamic cavitation as a novel pretreatment approach for bioethanol production from reed. AB - In this study, hydrodynamic cavitation (HC) was employed as a physical means to improve alkaline pretreatment of reed. The HC-assisted alkaline pretreatment was undertaken to evaluate the influence of NaOH concentration (1-5%), solid-to liquid ratio (5-15%), and reaction time (20-60 min) on glucose yield. The optimal condition was found to be 3.0% NaOH at solid-to-liquid (S/L) ratio of 11.8% for 41.1 min, which resulted in the maximum glucose yield of 326.5 g/kg biomass. Furthermore, simultaneous saccharification and fermentation (SSF) was conducted to assess the ethanol production. An ethanol concentration of 25.9 g/L and ethanol yield of 90% were achieved using batch SSF. These results clearly demonstrated HC system can be indeed a promising pretreatment tool for lignocellulosic bioethanol production. PMID- 26056774 TI - Removal of acetic acid from simulated hemicellulosic hydrolysates by emulsion liquid membrane with organophosphorus extractants. AB - Selective removal of acetic acid from simulated hemicellulosic hydrolysates containing xylose and sulfuric acid was attempted in a batch emulsion liquid membrane (ELM) system with organophosphorus extractants. Various experimental variables were used to develop a more energy-efficient ELM process. Total operation time of an ELM run with a very small quantity of trioctylphosphine oxide as the extractant was reduced to about a third of those required to attain almost the same extraction efficiency as obtained in previous ELM works without any extractant. Under specific conditions, acetic acid was selectively separated with a high degree of extraction and insignificant loss of xylose, and its purity and enrichment ratio in the stripping phase were higher than 92% and 6, respectively. Also, reused organic membrane solutions exhibited the extraction efficiency as high as fresh organic solutions did. These results showed that the current ELM process would be quite practical. PMID- 26056775 TI - Enhancement of dalesconols A and B production via upregulation of laccase activity by medium optimization and inducer supplementation in submerged fermentation of Daldinia eschscholzii. AB - Dalesconols (dalesconols A and B) are novel polyketides with strong immunosuppressive activity produced by Daldinia eschscholzii. In this work, the effects of different media (M1, M2, and M3) on fungus growth and dalesconols biosynthesis were firstly tested and compared. Intermediates and enzyme analysis indicated that laccase had the major contribution to dalesconols biosynthesis. The key role of laccase on dalesconols biosynthesis was further experimentally confirmed, which suggested that the modified M2 was more favored for laccase and dalesconols production. Thereafter, the medium composition was optimized by RSM with a fermentation titer of 36.66 mg/L obtained. Furthermore, Ca(2+) induction was employed to up-regulate of laccase activity and further enhanced dalesconols production (76.90 mg/L), which was 308% higher than that in M2. In addition, dalesconols production reached 63.42 mg/L in scale-up experiments. This work indicated great potential of laccase as a key enzyme on regulation of dalesconols production. PMID- 26056776 TI - Advanced nitrogen removal via nitrite using stored polymers in a modified sequencing batch reactor treating landfill leachate. AB - A modified sequencing batch reactor (SBR) operated at the anaerobic-aerobic anoxic mode was developed in this study to fully utilize the organics in landfill leachate (ammonia concentration of 1000 +/- 50 mg N/L and COD/total nitrogen (TN) ratio of 1-4). The unique feature of modified SBR process was the addition of an anaerobic stage after feeding stage, so that microorganisms could store the organics during anaerobic stage and supply the carbon source for endogenous denitritation after aeration stage. The 70-day operational tests showed the effluent TN was below 10 mg N/L at C/N ratio of 4. The intracellular stored polymers were analyzed and the microorganisms were capable of storing the carbon source as polyhydroxybutyrate (PHB) and glycogen in anaerobic stage, which were the electron donors for endogenous denitritation. Fluorescence in situ hybridization (FISH) analysis showed that glycogen accumulating organisms (GAOs) account for 39.8% of microorganisms in SBR, and carried out advanced nitrogen removal. PMID- 26056777 TI - Stratification structure of polysaccharides and proteins in activated sludge with different aeration in membrane bioreactor. AB - The effect of distribution pattern of polysaccharides (PS) and proteins (PN) in activated sludge (AS) stratification with different aeration rates on membrane fouling and rejection efficiency were investigated. During high aeration, PN and PS concentrations increased in supernatant, the dominant fraction (84% of PN and 73% of PS) was small molecules (<1 kDa). Less slime and loose bound extracellular polymeric substances (LB-EPS), more tight bound EPS (TB-EPS) were observed compared with low aeration. The decrease in PN/PS ratio and Ca(2+) concentration within EPS deteriorated AS flocculation ability. At slow trans-membrane pressure (TMP) rise stage, fouling rate under high aeration was 41% lower than low aeration due to lower PN within EPS outer. Low PS rejection rate (about 23%) leaded to higher PS in effluent at this stage. High PS rejection rate (about 94%) at rapid TMP rise stage resulted in about 2.2-time higher fouling rate than that low aeration. PMID- 26056778 TI - Effects of glycerol on enzymatic hydrolysis and ethanol production using sugarcane bagasse pretreated by acidified glycerol solution. AB - In this study, for the first time the effects of glycerol on enzymatic hydrolysis and ethanol fermentation were investigated. Enzymatic hydrolysis was inhibited slightly with 2.0 wt% glycerol, leading to reduction in glucan digestibility from 84.9% without glycerol to 82.9% (72 h). With 5.0 wt% and 10.0 wt% glycerol, glucan digestibility was reduced by 4.5% and 11.0%, respectively. However, glycerol did not irreversibly inhibit cellulase enzymes. Ethanol fermentation was not affected by glycerol up to 5.0 wt%, but was inhibited slightly at 10.0 wt% glycerol, resulting in reduction in ethanol yield from 86.0% in the absence of glycerol to 83.7% (20 h). Based on the results of laboratory and pilot-scale experiments, it was estimated that 0.142 kg ethanol can be produced from 1.0 kg dry bagasse (a glucan content of 38.0%) after pretreatment with acidified glycerol solution. PMID- 26056779 TI - Microalgal growth with intracellular phosphorus for achieving high biomass growth rate and high lipid/triacylglycerol content simultaneously. AB - Nutrient deprivation is a commonly-used trigger for microalgal lipid accumulation, but its adverse impact on microalgal growth seems to be inevitable. In this study, Scenedesmus sp. LX1 was found to show similar physiological and biochemical variation under oligotrophic and eutrophic conditions during growth with intracellular phosphorus. Under both conditions microalgal chlorophyll content and photosynthesis activity was stable during this growth process, leading to significant increase of single cell weight and size. Therefore, while algal density growth rate dropped significantly to below 1.0 * 10(5)cells mL(-1) d(-1) under oligotrophic condition, the biomass dry weight growth rate still maintained about 40 mg L(-1) d(-1). Meanwhile, the lipid content in biomass and triacylglycerols (TAGs) content in lipids increased significantly to about 35% and 65%, respectively. Thus, high biomass growth rate and high lipid/TAG content were achieved simultaneously at the late growth phase with intracellular phosphorus. Besides, microalgal biomass produced was rich in carbohydrate with low protein content. PMID- 26056780 TI - Cultivation of Chlorella sp. using raw dairy wastewater for nutrient removal and biodiesel production: Characteristics comparison of indoor bench-scale and outdoor pilot-scale cultures. AB - The biomass productivity and nutrient removal capacity of simultaneous Chlorella sp. cultivation for biodiesel production and nutrient removal in raw dairy wastewater (RDW) in indoor bench-scale and outdoor pilot-scale photobioreactors were compared. Results from the current work show that maximum biomass productivity in indoor bench-scale cultures can reach 260 mg L(-1) day(-1), compared to that of 110 mg L(-1) day(-1) in outdoor pilot-scale cultures. Maximum chemical oxygen demand (COD), total nitrogen (TN), and total phosphorous (TP) removal rate obtained in indoor conditions was 88.38, 38.34, and 2.03 mg L(-1) day(-1), respectively, this compared to 41.31, 6.58, and 2.74 mg L(-1) day(-1), respectively, for outdoor conditions. Finally, dominant fatty acids determined to be C16/C18 in outdoor pilot-scale cultures indicated great potential for scale up of Chlorella sp. cultivation in RDW for high quality biodiesel production coupling with RDW treatment. PMID- 26056781 TI - Supercritical carbon dioxide combined with 1-butyl-3-methylimidazolium acetate and ethanol for the pretreatment and enzymatic hydrolysis of sugarcane bagasse. AB - The use of green solvents for the partial delignification of milled sugarcane bagasse (1mm particle size) and for the enhancement of its susceptibility to enzymatic hydrolysis was demonstrated. The experiments were carried out for 2h using 40 g of supercritical carbon dioxide combined with 1-butyl-3 methylimidazolium acetate and 15.8 g of ethanol. The effects of temperature (110 180 degrees C), pressure (195-250 bar) and IL-to-bagasse mass ratio (0:1-1:1) were investigated through a factorial design in which the response variables were the extent of delignification and both anhydroglucose and anhydroxylose contents in the pretreated materials. The highest delignification degree (41%) led to the best substrate for hydrolysis, giving a 70.7 wt% glucose yield after 12h using 5 wt% and Cellic CTec2(r) (Novozymes) at 10 mg g(-1) total solids. Hence, excellent substrates for hydrolysis were produced with a minimal IL requirement, which could be recovered by ethanol washing for its downstream processing and reuse. PMID- 26056782 TI - Performance of biofuel processes utilising separate lignin and carbohydrate processing. AB - Novel biofuel pathways with increased product yields are evaluated against conventional lignocellulosic biofuel production processes: methanol or methane production via gasification and ethanol production via steam-explosion pre treatment. The novel processes studied are ethanol production combined with methanol production by gasification, hydrocarbon fuel production with additional hydrogen produced from lignin residue gasification, methanol or methane synthesis using synthesis gas from lignin residue gasification and additional hydrogen obtained by aqueous phase reforming in synthesis gas production. The material and energy balances of the processes were calculated by Aspen flow sheet models and add on excel calculations applicable at the conceptual design stage to evaluate the pre-feasibility of the alternatives. The processes were compared using the following criteria: energy efficiency from biomass to products, primary energy efficiency, GHG reduction potential and economy (expressed as net present value: NPV). Several novel biorefinery concepts gave higher energy yields, GHG reduction potential and NPV. PMID- 26056783 TI - Tailoring resistive switching in Pt/SrTiO3 junctions by stoichiometry control. AB - Resistive switching effects in transition metal oxide-based devices offer new opportunities for information storage and computing technologies. Although it is known that resistive switching is a defect-driven phenomenon, the precise mechanisms are still poorly understood owing to the difficulty of systematically controlling specific point defects. As a result, obtaining reliable and reproducible devices remains a major challenge for this technology. Here, we demonstrate control of resistive switching based on intentional manipulation of native point defects. Oxide molecular beam epitaxy is used to systematically investigate the effect of Ti/Sr stoichiometry on resistive switching in high quality Pt/SrTiO3 junctions. We demonstrate resistive switching with improved state retention through the introduction of Ti- and Sr-excess into the near interface region. More broadly, the results demonstrate the utility of high quality metal/oxide interfaces and explicit control over structural defects to improve control, uniformity, and reproducibility of resistive switching processes. Unintentional interfacial contamination layers, which are present if Schottky contacts are processed at low temperature, can easily dominate the resistive switching characteristics and complicate the interpretation if nonstoichiometry is also present. PMID- 26056785 TI - Conservative Management of Downhill Esophageal Varices Secondary to Central Line related Thrombosis After Hematopoietic Stem Cell Transplant. AB - Occlusive central line-related complications are not infrequent in children undergoing cancer therapy, but are generally not associated with life-threatening complications. Thrombosis of the superior vena cava (SVC) is rarely described in such patients, and downhill esophageal varices have been described in children and adults as a complication of altered SVC blood flow. The management of patients with SVC thrombosis and associated varices is complicated by the need to treat the thrombus weighed against bleeding risk. We present a 14-year-old adolescent with a history of acute leukemia and central line-related complications, including SVC thrombosis with subsequent formation of downhill esophageal varices. Conservative management consisting of anticoagulation alone resulted in resolution of the varices with no bleeding complications. PMID- 26056784 TI - The radish genome and comprehensive gene expression profile of tuberous root formation and development. AB - Understanding the processes that regulate plant sink formation and development at the molecular level will contribute to the areas of crop breeding, food production and plant evolutionary studies. We report the annotation and analysis of the draft genome sequence of the radish Raphanus sativus var. hortensis (long and thick root radish) and transcriptome analysis during root development. Based on the hybrid assembly approach of next-generation sequencing, a total of 383 Mb (N50 scaffold: 138.17 kb) of sequences of the radish genome was constructed containing 54,357 genes. Syntenic and phylogenetic analyses indicated that divergence between Raphanus and Brassica coincide with the time of whole genome triplication (WGT), suggesting that WGT triggered diversification of Brassiceae crop plants. Further transcriptome analysis showed that the gene functions and pathways related to carbohydrate metabolism were prominently activated in thickening roots, particularly in cell proliferating tissues. Notably, the expression levels of sucrose synthase 1 (SUS1) were correlated with root thickening rates. We also identified the genes involved in pungency synthesis and their transcription factors. PMID- 26056786 TI - Peripherally Inserted Central Venous Catheters in Pediatric Hematology/Oncology Patients in Tertiary Care Setting: A Developing Country Experience. AB - PURPOSE: Peripherally inserted central venous catheters (PICC) have been successfully used to provide central access for chemotherapy and frequent transfusions. The purpose of this study was to assess the feasibility of PICCs and determine PICC-related complications in pediatric hematology/oncology patients in a resource-poor setting. METHODS: All pediatric patients (age below 16 y) with hematologic and malignant disorders who underwent PICC line insertion at Aga Khan University Hospital from January 2008 to June 2010 were enrolled in the study. Demographic features, primary diagnosis, catheter days, complications, and reasons for removal of device were recorded. RESULTS: Total of 36 PICC lines were inserted in 32 pediatric patients. Complication rate of 5.29/1000 catheter days was recorded. Our study showed comparable complication profile such as infection rate, occlusion, breakage, and dislodgement. The median catheter life was found to be 69 days. CONCLUSIONS: We conclude that PICC lines are feasible in a resource-poor setting and recommend its use for chemotherapy administration and prolonged venous access. PMID- 26056787 TI - Atypical Clinical Course in Pediatric Hodgkin Lymphoma: Association With Germline Mutations in Interleukin-2-inducible T-Cell Kinase. AB - BACKGROUND: Inherited or acquired immune dysregulation is associated with increased risk of lymphoproliferative disorders (LPDs), including classic Hodgkin lymphoma (cHL). A germline mutation in interleukin-2-inducible T-cell kinase (ITK) is described in individuals manifesting B-cell LPDs, cHL, and hemophagocytic syndromes following Epstein-Barr virus (EBV) infection. OBSERVATIONS: We report a novel ITK mutation in a child with EBV-associated cHL and multiple-site reactive polyclonal B-cell hyperplasia followed by relapsed cHL at another site. Following relapse, the child was successfully treated with allogeneic hematopoietic stem cell transplantation and EBV cytotoxic T cells. CONCLUSIONS: ITK-mutated T cells cause a defective antiviral immune response and the resulting immune dysregulation can lead to EBV-associated polyclonal hyperplasia with subsequent outgrowth of neoplastic B-cell clones, which in some instances may progress to LPDs, including cHL. PMID- 26056788 TI - Zoledronic Acid for the Treatment of Children With Refractory Central Giant Cell Granuloma. AB - There are no approved medical therapies for the treatment of pediatric central giant cell granuloma (CGCG), a benign but potentially aggressive tumor of the jaw. Zoledronic acid (ZA), a third-generation bisphosphonate, has been used in CGCG occurring in adults. We describe 4 patients with CGCG treated with ZA, 3 of whom achieved resolution of disease up to 4 years of follow-up. Our experience suggests that ZA may be considered as treatment for pediatric CGCG. PMID- 26056789 TI - The Relationship Between Parent Trait Anxiety and Parent-reported Pain, Solicitous Behaviors, and Quality of Life Impairment in Children With Cancer. AB - Pain-related disability in youth has been shown to be associated with parental psychological distress and solicitous behaviors. This study sought to investigate how parental anxiety may impact children's functioning with respect to pain and health-related quality of life in a sample of children with cancer. A total of 353 parents of children treated for cancer completed measures of anxiety, behavioral responses to children's pain, and of their child's quality of life and pain. Children ages 8 to 18 completed measures of their own quality of life and pain. Parent anxiety was significantly associated with parent ratings of children's pain severity (P=0.004) and frequency (P=0.008), as well as parent solicitous responses (P=0.041) and child quality of life. Regression analysis revealed that parent anxiety significantly predicted solicitous behaviors (P=0.006), pain frequency (P=0.043), and child quality of life (P <= 0.004). These findings suggest parent anxiety plays a significant role in parent perception of children's pain and quality of life in pediatric cancer patients. Future research is needed to further clarify the nature of these relationships, which will help identify how parent anxiety may be an important target for pain management in children with cancer. PMID- 26056790 TI - Outcome of B-Cell Acute Lymphoblastic Leukemia in Brazilian Children: Immunophenotypical, Hematological, and Clinical Evaluation. AB - The aim of this study is to investigate the clinical, hematological, and immunophenotypic characteristics of Brazilian children with B-cell acute lymphoblastic leukemia (B-ALL) to identify prognostic biomarkers of the disease. Thirty-three children newly diagnosed with B-ALL were followed between March 2004 and December 2009. Information about the demographic profile, diagnosis, immunophenotype, clinical manifestations, and disease outcome were gathered from the patients' medical records. Of the 33 patients with B-ALL, 18 were male and 15 female. Eighteen patients were classified as high risk; 13 as low risk, and 2 as true low risk. The frequencies of cluster of differentiation (CD)10, CD19, and CD20 antigens were 69.7%, 81.8%, and 18.2%, respectively. Six patients (18.2%) had aberrant expression of myeloid antigens. At diagnosis, patients immunopositive for CD20 had elevated white blood cell counts (P = 0.018) and lower platelet counts (P = 0.017). The 6-year overall survival was 67.5%+/- 3.47%. Our results demonstrate the distinct immunophenotypic and prognostic characteristics of patients with B-ALL, which can be related to the Brazilian racial admixture. Consequently, these results will most likely aid in the selection of additional prognostic markers and their use in monitoring the clinical manifestations and treatment response among B-ALL patients. PMID- 26056791 TI - Cytotoxic Molecule-positive Epstein-Barr Virus-associated Peripheral T-cell Lymphoma in a 20-Month-old Child: A Case Report and Review of the Literature. AB - Peripheral T-cell lymphoma (PTCL) is rare in children. Expression of cytotoxic molecules (CM) in nodal PTCL has unique clinicopathologic features, including an Epstein-Barr virus (EBV) association. However, CM+, EBV-associated PTCL is extremely rare in the childhood, with only 1 study having been reported to date, including both pediatric and adult patients. We report a case of CM+ PTCL in a 20 month-old boy with left neck lymphadenopathy as well as multiple visceral lesions. A biopsied lymph node was diffusely infiltrated by atypical lymphoid cells with a CD4/CD8, granzyme B+, perforin+, and TIA-1+ phenotype, and EBV positivity by in situ hybridization. Rearrangements of the TCR gamma-chain and beta-chain genes were demonstrated by polymerase chain reaction. Ancillary genetic studies detected trisomy 2, trisomy 10, a structurally abnormal 6p, and additional copies of the IRF4 gene. Multiple bone marrow biopsies failed to show any evidence of tumor, histiocytic hyperplasia, or hemophagocytosis. This lesion was therefore diagnosed as "CM+, EBV-associated high-grade peripheral T-cell lymphoma." After 5 cycles of chemotherapy, the patient was in remission 8 months following initial diagnosis. To our knowledge, this represents the youngest child with this rare tumor in the published literature, and showing an unusually favorable initial response to therapy. PMID- 26056792 TI - Respiratory Failure in Children With Hemato-oncological Diseases Admitted to the PICU: A Single-center Experience. AB - Respiratory failure (RF) is a main cause of pediatric intensive care unit (PICU) admission in children with hemato-oncological diseases. We present a retrospective chart review of children admitted to our PICU because of RF (January 2006 to December 2010). The aims of this study are the following: (1) to describe the demographical and clinical characteristics and respiratory management of these children; and (2) to identify the factors associated with mechanical ventilation (MV) and mortality. A total of 69 patients, encompassing 88 episodes, were included (55/88 cases were hypoxemic RF). The first respiratory support at PICU admission was, in decreasing order of frequency, high-flow oxygen nasal cannula (HFNC; 50/88), noninvasive ventilation (NIV; 13/88), and oxygen nasal cannula (16/88). MV was necessary in 47/88 episodes, 38/47 after another respiratory support. In 18/28 children with initial NIV, MV was required later. MV was associated with O-PRISM score, NIV requirement, suspected respiratory infection, and days of PICU treatment. Patients without MV showed an increased survival rate (P=0.001). In summary, the hypoxemic RF was the main cause of PICU admission, and HFNC or NIV was almost always the first respiratory support. The use of MV was associated with a higher mortality rate. The utility of precocious HFNC or NIV should be investigated in larger clinical studies. PMID- 26056793 TI - A Case Report: Jacobsen Syndrome Complicated by Paris-Trousseau Syndrome and Shone's Complex. AB - A preterm infant presenting with a congenital cardiac malformation and thrombocytopenia was found to have a karyotype showing a terminal deletion of the long arm of chromosome 11 of the segment 11q24.1-11qter consistent with Jacobsen syndrome. The infant was later diagnosed with Paris-Trousseau syndrome, commonly associated with Jacobsen syndrome. Because children with cardiac malformations often require high-risk surgical procedures in the early neonatal period, those with platelet dysfunction require prompt identification at birth. PMID- 26056794 TI - Response of Relapsed Pancreatoblastoma to a Combination of Vinorelbine and Oral Cyclophosphamide. AB - Pancreatoblastoma is a rare tumor of the pancreas in children, with favorable prognosis if completely resected. If unresectable, neoadjuvant chemotherapy with cisplatin-based regimens are commonly used with good response that allows for resection. For locally aggressive or metastatic disease, neoadjuvant chemotherapy has been reported. Treatment for relapsed or refractory cases is based on anecdotal experiences. We report 2 cases of relapsing pancreatoblastoma with clinical and radiologic response to vinorelbine and cyclophosphamide. Although cure was not achieved, this combination can be offered as an easily tolerated alternative to aggressive chemotherapy for relapsed cases in a palliative setting. PMID- 26056795 TI - Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma. AB - BACKGROUND: Management of low-grade gliomas (LGG) can be a challenge, particularly when not resectable and refractory or recurrent following standard treatments. We undertook a retrospective analysis of 2 institutions' experiences treating children for refractory or progressive LGG with bevacizumab-based therapy (BBT). PROCEDURE: Inclusion criteria were patients younger than 18 years of age who had previously failed one or more lines of therapy. Treatment was intravenous bevacizumab 10 mg/kg and intravenous irinotecan 125 to 150 mg/m2 every 2 weeks. RESULTS: Sixteen children (median age of 8.6 y), 5 with neurofibromatosis type 1 and 8 with disseminated disease were treated between 2009 and 2013. Median duration of treatment was 12 months (range, 3 to 45 mo). Seven patients (44%) showed clinical improvement (3 patients within a month) and 8 patients (50%) remained clinically stable during BBT. Imaging studies showed 3 (19%) had a partial response, 11 (69%) stable disease, and 2 (12%) had progressive disease. Four patients had progressive disease after stopping BBT (median duration of 5 mo). Three of these 4 were able to be retreated with BBT and all achieved an objective response. Treatment was well tolerated with no grade 3 or 4 toxicities related to bevacizumab. Irinotecan was discontinued in 4 patients because of grade 2-3 toxicities. CONCLUSIONS: We conclude that BBT is well tolerated and led to disease control in patients with refractory or recurrent cases of LGG. Retreatment with BBT led to disease control in most of these cases. Larger, prospective studies are warranted to confirm these results. PMID- 26056796 TI - Hypersegmented Neutrophils in an Adolescent Male With Heatstroke. PMID- 26056797 TI - Genotype-phenotype Correlation of the p.R1165C Mutation in the MYH9 Disorder: Report of a Japanese Pedigree. AB - MYH9 disorder is a rare autosomal dominant disease characterized by congenital thrombocytopenia with giant platelets and leukocyte inclusion bodies and is often associated with Alport-like symptoms, such as glomerulonephritis, sensorineural hearing loss, and cataracts. We report a Japanese pedigree wherein the MYH9 p.R1165C mutation was present in over 4 generations. Three individuals were misdiagnosed as Bernard-Soulier syndrome carriers. Among the 12 patients with abnormal hematological features, the proband's mother, aunt, and grandaunt presented with sensorineural hearing impairment, and the mother presented with presenile cataract, and nephritis. This case report confirms the previously established genotype-phenotype correlations of the MYH9 disorder that p.R1165C is associated with variable expression of nonhematological manifestations. Careful detection of leukocyte inclusion bodies in peripheral blood smears is necessary to prevent misdiagnosis. PMID- 26056798 TI - Predicting, Monitoring, and Managing Hypercalcemia Secondary to 13-Cis-Retinoic Acid Therapy in Children With High-risk Neuroblastoma. AB - 13-cis-retinoic acid is an established component of treatment for children with high-risk neuroblastoma. However, significant hypercalcemia is increasingly recognized as a potentially life-threatening dosage-related side effect. We present 2 patients with significant hypercalcemia secondary to 13-cis-retinoic acid and their management, and identified the predictive factors for susceptibility to hypercalcemia. Assessing glomerular filtration rate and concomitant medication help predict individual susceptibility to hypercalcemia. Calcium levels should be monitored at days 1, 7, and 14 of each course of retinoic acid. An algorithm for the management of hypercalcemia during the affected and subsequent cycles of retinoid therapy is proposed. PMID- 26056799 TI - Chronic Complications After Femoral Central Venous Catheter-related Thrombosis in Critically Ill Children. AB - Prescription of thromboprophylaxis is not a common practice in pediatric intensive care units. Most thrombi are catheter-related and asymptomatic, without causing acute complications. However, chronic complications of these (a)symptomatic catheter-related thrombi, that is, postthrombotic syndrome (PTS) and residual thrombosis have not been studied. To investigate these complications, critically ill children of 1 tertiary center with percutaneous inserted femoral central venous catheters (FCVCs) were prospectively followed. Symptomatic FCVC-thrombosis occurred in 10 of the 134 children (7.5%; 95% confidence interval [CI], 2.4-9.5). Only FCVC-infection appeared to be independently associated (P=0.001) with FCVC-thrombosis. At follow-up 2 of the 5 survivors diagnosed with symptomatic thrombosis developed mild PTS; one of them had an occluded vein on ultrasonography. A survivor without PTS had a partial occluded vein at follow-up. Asymptomatic FCVC-thrombosis occurred in 3 of the 42 children (7.1%; 95% CI, 0.0-16.7) screened by ultrasonography within 72 hours after catheter removal. At follow-up, mild PTS was present in 6 of the 33 (18.2%; 95% CI, 6.1-30.3) screened children. Partial and total vein occlusion was present in 1 (3%) and 4 (12%) children, respectively. In conclusion, children on pediatric intensive care units are at risk for (a)symptomatic FCVC-thrombosis, especially children with FCVC-infection. Chronic complications of FCVC-thrombosis are common. Therefore, thromboprophylaxis guidelines are warranted in pediatric intensive care units to minimize morbidity as a result of FCVC-thrombosis. PMID- 26056800 TI - Insulin-like Growth Factor 2 Gene Expression Molecularly Differentiates Pleuropulmonary Blastoma and Embryonal Rhabdomyosarcoma. AB - The sarcomatous element in pleuropulmonary blastoma (PPB) is often histologically indistinguishable from embryonal rhabdomyosarcoma (ERMS). A diagnosis of PPB is often made after definitive surgical resection based on pathologic features, most notably the presence of hamartomatous pulmonary elements. Samples from seven PPB patients were obtained from the rhabdomyosarcomatous portion of the tumor by macrodissection. Representative ERMS tumor tissue was selected from 21 ERMS patient samples. Formalin-fixed paraffin-embedded tissue scrolls from each sample were analyzed using the Affymetrix Human Exon arrays. All PPB patients and 7 of 21 ERMS patients were 3 years old and younger. Twenty transcripts (10 annotated, 10 noncoding RNAs) were significantly differentially expressed in ERMS when compared with PPB samples. Insulin-like growth factor 2 (IGF2) was uniformly overexpressed in ERMS (19/21>400) but was expressed at low levels in PPB (P<0.001). Two ERMS cases that had low level IGF2 expression were 3 years and younger of age. No other differences between the 2 approached this degree of significance, despite a common rhabdomyogenic phenotype in the sarcomatous areas of PPB. PPB, unlike most ERMS, appears not to be driven by autocrine IGF2 signaling. PMID- 26056801 TI - Utilizing knowledge from prior plans in the evaluation of quality assurance. AB - Increased interest regarding sensitivity of pre-treatment intensity modulated radiotherapy and volumetric modulated arc radiotherapy (VMAT) quality assurance (QA) to delivery errors has led to the development of dose-volume histogram (DVH) based analysis. This paradigm shift necessitates a change in the acceptance criteria and action tolerance for QA. Here we present a knowledge based technique to objectively quantify degradations in DVH for prostate radiotherapy. Using machine learning, organ-at-risk (OAR) DVHs from a population of 198 prior patients' plans were adapted to a test patient's anatomy to establish patient specific DVH ranges. This technique was applied to single arc prostate VMAT plans to evaluate various simulated delivery errors: systematic single leaf offsets, systematic leaf bank offsets, random normally distributed leaf fluctuations, systematic lag in gantry angle of the mutli-leaf collimators (MLCs), fluctuations in dose rate, and delivery of each VMAT arc with a constant rather than variable dose rate.Quantitative Analyses of Normal Tissue Effects in the Clinic suggests V75Gy dose limits of 15% for the rectum and 25% for the bladder, however the knowledge based constraints were more stringent: 8.48 +/- 2.65% for the rectum and 4.90 +/- 1.98% for the bladder. 19 +/- 10 mm single leaf and 1.9 +/- 0.7 mm single bank offsets resulted in rectum DVHs worse than 97.7% (2sigma) of clinically accepted plans. PTV degradations fell outside of the acceptable range for 0.6 +/- 0.3 mm leaf offsets, 0.11 +/- 0.06 mm bank offsets, 0.6 +/- 1.3 mm of random noise, and 1.0 +/- 0.7 degrees of gantry-MLC lag.Utilizing a training set comprised of prior treatment plans, machine learning is used to predict a range of achievable DVHs for the test patient's anatomy. Consequently, degradations leading to statistical outliers may be identified. A knowledge based QA evaluation enables customized QA criteria per treatment site, institution and/or physician and can often be more sensitive to errors than criteria based on organ complication rates. PMID- 26056802 TI - Folic acid inhibits COLO-205 colon cancer cell proliferation through activating the FRalpha/c-SRC/ERK1/2/NFkappaB/TP53 pathway: in vitro and in vivo studies. AB - To investigate the molecular mechanism underlying folic acid (FA)-induced anti colon caner activity, we showed that FA caused G0/G1 arrest in COLO-205. FA activated the proto-oncogene tyrosine-protein kinase Src (c-SRC)-mediated signaling pathway to enhance nuclear factor of kappa light polypeptide gene enhancer in B-cells (NFkappaB) nuclear translocation and binding onto the tumor protein p53 (TP53) gene promoter, and up-regulated expressions of TP53, cyclin dependent kinase inhibitor 1A (CDKN1A) and cyclin-dependent kinase inhibitor 1B (CDKN1B). Knock-down of TP53 abolished FA-induced increases in the levels of CDKN1A and CDKN1B protein and G0/G1 arrest in COLO-205. Knock-down of folate receptor alpha (FRalpha) abolished FA-induced activations in the c-SRC-mediated pathway and increases in the levels of CDKN1A, CDKN1B and TP53 protein. These data suggest that FA inhibited COLO-205 proliferation through activating the FRalpha/c-SRC/mitogen-activated protein kinase 3/1 (ERK1/2)/NFkappaB/TP53 pathway mediated up-regulations of CDKN1A and CDKN1B protein. In vivo studies demonstrated that daily i.p. injections of FA led to profound regression of the COLO-205 tumors and prolong the lifespan. In these tumors, the levels of CDKN1A, CDKN1B and TP53 protein were increased and von willebrand factor (VWF) protein levels were decreased. These findings suggest that FA inhibits COLO-205 colon cancer growth through anti-cancer cell proliferation and anti-angiogenesis. PMID- 26056803 TI - Assessment of quantitative corticospinal tract diffusion changes in patients affected by subcortical gliomas using common available navigation software. AB - OBJECTIVE: The aim of this study is to analyze the quantitative DTI parameters of the CST in patients suffering from subcortical gliomas affecting the CST using generally available navigation software. METHODS: A retrospective study was conducted on 22 subjects with diagnosis of primary cerebral glioma and preoperative motor deficits. Exclusion criteria were: involvement of motor cortex, lesion involving both hemispheres, previous surgical treatment. All patients were studied using magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) sequences. Volume, fractional anisotropy (FA) and mean diffusivity value (MD) of the entire CSTs were estimated. Moreover, distance from midline, diameters, FA and MD were calculated on axial images at the point of minimal distance between tumor and CST. Statistical analysis was performed. RESULTS: There was a statistically significant difference of CST volume between affected and non-affected hemispheres (p<0.01). Mean overall/local FA, overall/local MD and sagittal diameter of CST were also significantly different between the two sides (p<0.05). Correlation tests resulted positive between the shift of CST and overall/local MD. Moreover there is significance between CST volume of tumor hemisphere and preoperative duration of motor deficits (p<0.05). CONCLUSION: The present study has demonstrated for the first time a significant difference of DTI based quantitative parameters of the CST between a tumor affected and a non-affected hemisphere in patients with a corresponding motor deficit. This preliminary data suggests a correlation between DTI based integrity of CST and its function. PMID- 26056804 TI - Management of idiopathic intracranial hypertension with a programmable lumboperitoneal shunt: Early experience. AB - OBJECTIVE: To evaluate the clinical outcomes and complications rate among idiopathic intracranial hypertension (IIH) patients who underwent lumboperitoneal (LP) shunt insertion with a programmable Strata valve. METHODS: We retrospectively evaluated patients who underwent LP shunt with a programmable Strata valve insertion at the University of Ottawa Civic Hospital from November 2012 to June 2013. The demographic data, clinical symptoms, opening pressure, pre operative and post-operative visual fields, neuroimaging, visual acuity, disc status, and complications were recorded and analyzed. RESULTS: Seven female patients with IIH underwent insertion of an LP shunt with a programmable Strata valve. The mean opening pressure was 35.8 cm H2O. The initial valve setting was 1.5, and four patients required post-operative valve pressure adjustment. All patients showed significant improvement in objective visual testing at follow-up as well as less frequent headaches. None of the patients developed intra- or post operative complications. CONCLUSION: LP shunts with programmable Strata valve systems are a potential alternative to conventional LP and programmable ventriculoperitoneal shunt systems as well as optic nerve sheath fenestration, due to their potential in avoiding brain injury, lower failure and complication rates, lower intracranial hypotension incidence, and flexibility in adjusting valve pressure settings post-operatively evading under- and overdrainage complications. They should be considered for the management of IIH instead of early design LP systems and VP shunts. A randomized multi-center trial should be conducted to compare the efficacy of these surgical techniques. PMID- 26056805 TI - Radiation-associated grade 2 meningiomas: A nine patient-series and review of the literature. AB - INTRODUCTION: Radiation-associated meningiomas (RAM) remain rare but recognized to harbor a high potential of aggressiveness. Only few studies focused on grade 2 histological variants. OBJECTIVE: Our study aims to report the natural history of patients with radiation-associated grade 2 meningiomas followed in a single institution. MATERIALS AND METHODS: This retrospective study included all patients with grade 2 RAM operated in our institution between 1994 and 2011. We used the WHO 2007 classification for histological grading. The degree of resection was evaluated using Simpson Classification. The tumor was considered radiation-associated, if the patient had a medical history of cranial irradiation for another medical condition (1 year before at least). Patients benefited from a post-operative close clinical and radiological (cranial MRI) follow-up every 4 months during 2 years and annually thereafter, to detect any tumor progression. Adjuvant therapy and/or monitoring were systematically decided during a multidisciplinary team meeting. RESULTS: Nine patients (6 men and 3 women) were included in the study. The mean age at diagnosis was 34 years old (range 20-55 years). The mean follow-up was 77 months (range 31-180 months). The mean delay between initial cranial radiation therapy and the diagnosis of grade 2 RAM was 23 years (range 16-33 years). Among all patients, 4 harbored a meningiomatosis, while 5 patients harbored a single tumor. Post-operative local tumor progression was noted in 4 patients. Progression free survival (PFS) after the first surgery in these 4 patients was 15, 23, 35, and 47 months. In these 4 progressive patients, 7 surgical resections, 3 GKS and 1 fractionated radiation therapy have been performed. Post-operative tumor progression was noted at distance from the operated meningioma in 1 patient with meningiomatosis. At final control, 2 patients had severe oculomotor palsy and 1 patient needed palliative cares related to progressive meningiomatosis with anorexia and swallowing disturbance. CONCLUSION: Grade 2 RAM is a severe radiation-associated disease occurring preferentially in younger male patients. Although, surgery remains the mainstay treatment, the high potential of tumor progression often requires adjuvant therapeutic tools. Thus, new radiation therapy should be discussed in some cases and the role of radio surgery is still to be better defined. PMID- 26056806 TI - Risk factors for predicting complications associated with growing rod surgery for early-onset scoliosis. AB - OBJECTIVE: To identify risk factors for postoperative complications associated with growing rod surgery for early-onset scoliosis (EOS). METHODS: A total of 55 consecutive patients underwent growing rod surgery for EOS were examined from database. Data included age at initial surgeries, sex, diagnosis, body mass index (BMI), duration of follow-up, initial and final measure of major curve, T2-5, T5 12, T10-L2, and T12-S1 kyphosis angles, levels and type of instrumentation, total number of surgeries, number of rods inserted, number of lengthenings, lengthening intervals and rod location were studied. Risk factors for postoperative complications were analyzed using binomial multiple logistic regression analysis. RESULTS: Postoperative complications were associated with 37 of 272 procedures (14%) and affected 23 patients (42%). Complications included 25 implant-related failures (66%), 4 alignment complications (11%), 4 infections (11%), 1 neurological impairment (3%), 3 respiratory problems, 2 gastrointestinal problems, 1 urinary problem, and 1 dural tear. The most frequent implant-related failure was dislodged implant (76%) and 92% of the dislodgements occurred at the proximal foundation. Binomial multiple logistic regression analysis demonstrated that curve magnitude in last follow-up (OR: 1.042; P=0.036), duration between growing-rod lengthening procedures (OR: 1.121; P=0.003) and duration of follow-up (OR: 1.079; P=0.001) maintained its significance in predicting likelihood of postoperative complications. CONCLUSION: The occurrence of postoperative complications in growing rod surgery for EOS is most likely multifactorial and is related to curve magnitude in last follow-up and duration between growing-rod lengthening procedures. PMID- 26056807 TI - Association of pituitary stalk management with endocrine outcomes and recurrence in microsurgery of craniopharyngiomas: A meta-analysis. AB - OBJECTIVE: A craniopharyngioma (CP) is a benign tumor commonly considered to originate from the pituitary stalk. However, it is still controversial as to whether the pituitary stalk should be maintained after microsurgery to resect the tumor despite its own physiological function of the pituitary stalk. In this study, meta-analysis was conducted to evaluate the influence of the pituitary stalk resection on endocrine function and tumor recurrence rate. METHODS: The relevant publications were identified by searching databases including Pubmed, Embase, Medline, and Web of Science. The extracted data were used as the basis for the meta-analysis by the RevMan 5.2 software program. RESULTS: Seven articles were selected, including 420 clinical cases. The meta-analysis showed that retaining the pituitary stalk might reduce the occurrence rate of diabetes insipidus (OR=0.21, 95%CI=0.10, 0.46, P=0.0001) and the risk of potential impairment of anterior pituitary function (OR=0.04, 95%CI=0.01, 0.13, P<0.0001). However, there was no significant relationship between craniopharyngioma recurrence and pituitary stalk treatment (i.e., preservation or resection) (OR=1.40, 95%CI=0.59, 3.34, P=0.45). CONCLUSION: The maintenance of the pituitary stalk may reduce the alterations in endocrine function and the occurrence of diabetes insipidus. However, it is not likely to enhance the recurrence rate of craniopharyngiomas. PMID- 26056808 TI - nTMS-based DTI fiber tracking for language pathways correlates with language function and aphasia - A case report. PMID- 26056809 TI - Incomplete resection of lumbar synovial cysts - Evaluating the risk of recurrence. AB - OBJECT: Synovial cysts are generally located in the lumbar spine adjacent to facet joints. Most studies recommend surgical resection. Adhesions of the lumbar synovial cyst to the dura are common and can result in dural tears with subsequent CSF fistula or nerve injury. The recurrence rate after incomplete resection of lumbar synovial cysts is unclear. For this purpose, we report on our experience of 148 patients who underwent synovial cyst resection from 2000 to 2011. METHODS: We reviewed records of patients who underwent microsurgical resection of symptomatic lumbar synovial cysts between 2000 and 2011 with a minimum one-year follow-up to identify cases with incomplete synovial cyst resection. Patient and surgical reports were retrospectively evaluated regarding extent of cyst resection, dural tears and surgery-related complications. Patients were asked to complete questionnaires regarding their clinical outcome and to report on further lumbar operations. RESULTS: We identified 148 patients with lumbar synovial cysts who were surgically treated in our department. In 8 patients (5.4%), the synovial cysts were not resected completely due to dural adhesions and high risk for dural tears. Sufficient decompression was achieved in all patients. Seven of these patients were pleased with the results of the operation and would undergo surgery again. The remaining patient suffered from a facet joint syndrome, which was successfully treated conservatively, without evidence of a recurrent synovial cyst in the MRI. CONCLUSIONS: Only in case of severe adhesions to the dura complete resection was not enforced to avoid dural tears. In none of the 8 patients symptomatic recurrence of synovial cysts occurred. Aware of the limited numbers, we suggest rather leaving remnants of an attached synovial cyst behind after a sufficient decompression than risking dural tears and surgery-related complications. This trial is registered with DRKS00006133. PMID- 26056810 TI - Early cranioplasty vs. late cranioplasty for the treatment of cranial defect: A systematic review. AB - BACKGROUND: Cranioplasty is considered as a routine procedure in everyday neurosurgical practice for the patient with cranial defect, however, there is no established consensus on optimal surgical timing. OBJECTIVE: To compare the effect of early cranioplasty (1-3 months after DC) and late cranioplasty (3-6 months after DC) on the complications and recovery of neurological function in the management of patients who received decompressive craniotomy. METHODS: In this paper, the authors report a systematic review and meta-analysis of operative time, complications and neurological function outcomes on different timing of cranioplasty. Randomized or non-randomized controlled trials of early cranioplasty and late cranioplasty surgery were considered for inclusion. RESULTS: Nine published reports of eligible studies involving 1209 participants meet the inclusion criteria. Compared with late cranioplasty, early cranioplasty had no significant difference in overall complications [RR=1.14, 95%CI (0.83, 1.55), p>0.05], infection rates [RR=0.87, 95%CI (0.47, 1.61), p>0.05], intracranial hematoma [RR=1.09, 95%CI (0.53, 2.25), p>0.05]; subdural fluid collection [RR=0.47, 95%CI (0.15, 1.41), p>0.05]. However, early CP significantly reduced the duration of cranioplasty [mean difference=-13.46, 95%CI (-21.26, 5.67), p<0.05]. The postoperative hydrocephalus rates were significant higher in the early cranioplasty group [RR=2.67, 95%CI (1.24, 5.73), p<0.05]. CONCLUSION: Early CP can only reduce the duration of operation, but cannot reduce the complications of patients and even increase the risk of hydrocephalus. More evidence from advanced multi-center studies is needed to provide illumination for the timing selection of CP surgery. PMID- 26056811 TI - Experiences in surgery of primary malignant brain tumours in the primary sensori motor cortex practical recommendations and results of a single institution. AB - OBJECTIVE: Tumour resection in the Rolandic region is a challenge. Aim of this study is to review a series of patients malignant glioma surgery in the Rolandic region which was performed by combinations of neuronavigation, sonography, 5 aminolevulinic acid fluorescence guided (5-ALA) surgery and intraoperative electrophysiological monitoring (IOM). METHODS: 29 patients suffering malignant gliomas in the motor cortex (17) and sensory cortex (12) were analyzed with respect to functional outcome and grade of resections. RESULTS: Improvement of motor function was seen in 41.5% one week after surgery, 41.5% were stable, only 17% deteriorated. After three months patients had an improvement of motor function in 56%, of Karnofsky Score (KPS) 27% and sensory function was improved in 8%. Deterioration of motor function was seen in 16%, in sensory function 4% and in KPS 28% after three months. 25% showed no residual tumour in early post surgical contrast enhanced MRI. 10% had less than 2% residual tumour and 15% had 2-5% residual tumour. CONCLUSIONS: Preoperative functional neuroimaging, neuronavigation for planning the surgical approach and resection margins, intraoperative sonography and 5-ALA guided surgery in combination with the application of IOM shows that functional outcome and total to subtotal resection of malignant glioma in the Rolandic region is feasible. PMID- 26056812 TI - A retrospective controlled study of three different operative approaches for the treatment of thoracic and lumbar spinal tuberculosis. PMID- 26056813 TI - Glutathione Levels and Susceptibility to Chemically Induced Injury in Two Human Prostate Cancer Cell Lines. AB - More aggressive prostate cancer cells (PCCs) are often resistant to chemotherapy. Differences exist in redox status and mitochondrial metabolism that may help explain this phenomenon. Two human PCC lines, PC-3 cells (more aggressive) and LNCaP cells (less aggressive), were compared with regard to cellular glutathione (GSH) levels, susceptibility to either oxidants or GSH depletors, and expression of several proteins involved in apoptosis and stress response to test the hypothesis that more aggressive PCCs exhibit higher GSH concentrations and are relatively resistant to cytotoxicity. PC-3 cells exhibited 4.2-fold higher GSH concentration than LNCaP cells but only modest differences in acute cytotoxicity were observed at certain time points. However, only LNCaP cells underwent diamide induced apoptosis. PC-3 cells exhibited higher levels of Bax and caspase-8 cleavage product but lower levels of Bcl-2 than LNCaP cells. However, LNCaP cells exhibited higher expression of Fas receptor (FasR) but also higher levels of several stress response and antioxidant proteins than PC-3 cells. LNCaP cells also exhibited higher levels of several mitochondrial antioxidant systems, suggesting a compensatory response. Thus, significant differences in redox status and expression of proteins involved in apoptosis and stress response may contribute to PCC aggressiveness. PMID- 26056814 TI - Molecular Characterisation of the Haemagglutinin Glycan-Binding Specificity of Egg-Adapted Vaccine Strains of the Pandemic 2009 H1N1 Swine Influenza A Virus. AB - The haemagglutinin (HA) glycan binding selectivity of H1N1 influenza viruses is an important determinant for the host range of the virus and egg-adaption during vaccine production. This study integrates glycan binding data with structure recognition models to examine the impact of the K123N, D225G and Q226R mutations (as seen in the HA of vaccine strains of the pandemic 2009 H1N1 swine influenza A virus). The glycan-binding selectivity of three A/California/07/09 vaccine production strains, and purified recombinant A/California/07/09 HAs harboring these mutations was examined via a solid-phase ELISA assay. Wild-type A/California/07/09 recombinant HA bound specifically to alpha2,6-linked sialyl glycans, with no affinity for the alpha2,3-linked sialyl-glycans in the array. In contrast, the vaccine virus strains and recombinant HA harboring the Q226R HA mutation displayed a comparable pattern of highly specific binding to alpha2,3 linked sialyl-glycans, with a negligible affinity for alpha2,6-linked sialyl glycans. The D225G A/California/07/09 recombinant HA displayed an enhanced binding affinity for both alpha2,6- and alpha2,3-linked sialyl-glycans in the array. Notably its alpha2,6-glycan affinity was generally higher compared to its alpha2,3-glycan affinity, which may explain why the double mutant was not naturally selected during egg-adaption of the virus. The K123N mutation which introduces a glycosylation site proximal to the receptor binding site, did not impact the alpha2,3/alpha2,6 glycan selectivity, however, it lowered the overall glycan binding affinity of the HA; suggesting glycosylation may interfere with receptor binding. Docking models and 'per residues' scoring were employed to provide a structure-recognition rational for the experimental glycan binding data. Collectively, the glycan binding data inform future vaccine design strategies to introduce the D225G or Q226R amino acid substitutions into recombinant H1N1 viruses. PMID- 26056815 TI - KMUP-1 Attenuates Endothelin-1-Induced Cardiomyocyte Hypertrophy through Activation of Heme Oxygenase-1 and Suppression of the Akt/GSK-3beta, Calcineurin/NFATc4 and RhoA/ROCK Pathways. AB - The signaling cascades of the mitogen activated protein kinase (MAPK) family, calcineurin/NFATc4, and PI3K/Akt/GSK3, are believed to participate in endothelin 1 (ET-1)-induced cardiac hypertrophy. The aim of this study was to investigate whether KMUP-1, a synthetic xanthine-based derivative, prevents cardiomyocyte hypertrophy induced by ET-1 and to elucidate the underlying mechanisms. We found that in H9c2 cardiomyocytes, stimulation with ET-1 (100 nM) for 4 days induced cell hypertrophy and enhanced expressions of hypertrophic markers, including atrial natriuretic peptide and brain natriuretic peptide, which were all inhibited by KMUP-1 in a dose-dependent manner. In addition, KMUP-1 prevented ET 1-induced intracellular reactive oxygen species generation determined by the DCFH DA assay in cardiomyocytes. KMUP-1 also attenuated phosphorylation of ERK1/2 and Akt/GSK-3beta, and activation of calcineurin/NFATc4 and RhoA/ROCK pathways induced by ET-1. Furthermore, we found that the expression of heme oxygenase-1 (HO-1), a stress-response enzyme implicated in cardio-protection, was up regulated by KMUP-1. Finally, KMUP-1 attenuated ET-1-stimulated activator protein 1 DNA binding activity. In conclusion, KMUP-1 attenuates cardiomyocyte hypertrophy induced by ET-1 through inhibiting ERK1/2, calcineurin/NFATc4 and RhoA/ROCK pathways, with associated cardioprotective effects via HO-1 activation. Therefore, KMUP-1 may have a role in pharmacological therapy of cardiac hypertrophy. PMID- 26056816 TI - Optimization of Purification, Identification and Evaluation of the in Vitro Antitumor Activity of Polyphenols from Pinus Koraiensis Pinecones. AB - In this study, an efficient purification method for the polyphenols of Pinus koraiensis pinecone (PPP) has been developed. AB-8 resin was verified to offer good adsorption and desorption ratio for PPP. Response surface methodology (RSM) indicated that the optimized purification parameters for PPP were 1.70 mg GAE/mL phenolic sample concentration, 22.00 mL sample volume, and 63.00% ethanol concentration. Under these conditions, the experimental purity of PPP was 27.93 +/- 0.14% (n = 3), which matched well with the predicted purity of 28.17%. Next, the antiproliferative effects of PPP on seven cancer cell lines, including A375 (human skin melanoma cancer cell line), A549 (human lung cancer cell line), SH SY5Y (human neuroblastoma cell line), LOVO (human colon cancer stem cell line), MCF-7 (human breast cancer cell line), HeLa (human cervical cancer line), and HT29 (human colon cancer line), were examined by MTT assays. The results indicated that PPP had the highest capacity for inhibiting LOVO cells growth with an EC50 value of 0.317 +/- 0.0476 mg/mL. Finally, Ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS) was used to tentatively identify twenty-four peaks in the purified PPP, of which five representative peaks were identified as catechin, methyl quercetin, o-vanillin, luteolin and coronaric acid. Our results demonstrate that Pinus koraiensis pinecone is a readily available source of polyphenols, and the purified PPP could be a promising natural antitumor agent for applications in functional foods. PMID- 26056817 TI - Amino Acid Flux from Metabolic Network Benefits Protein Translation: the Role of Resource Availability. AB - Protein translation is a central step in gene expression and affected by many factors such as codon usage bias, mRNA folding energy and tRNA abundance. Despite intensive previous studies, how metabolic amino acid supply correlates with protein translation efficiency remains unknown. In this work, we estimated the amino acid flux from metabolic network for each protein in Escherichia coli and Saccharomyces cerevisiae by using Flux Balance Analysis. Integrated with the mRNA expression level, protein abundance and ribosome profiling data, we provided a detailed description of the role of amino acid supply in protein translation. Our results showed that amino acid supply positively correlates with translation efficiency and ribosome density. Moreover, with the rank-based regression model, we found that metabolic amino acid supply facilitates ribosome utilization. Based on the fact that the ribosome density change of well-amino-acid-supplied genes is smaller than poorly-amino-acid-supply genes under amino acid starvation, we reached the conclusion that amino acid supply may buffer ribosome density change against amino acid starvation and benefit maintaining a relatively stable translation environment. Our work provided new insights into the connection between metabolic amino acid supply and protein translation process by revealing a new regulation strategy that is dependent on resource availability. PMID- 26056818 TI - Early expansion and expression of the lipopolysaccharide (LPS)-induced TNF-alpha factor (LITAF) gene family in the LPS-exposed monogonont rotifer Brachionus koreanus. AB - To date, a single lipopolysaccharide-induced TNF-alpha factor (LITAF) homologue, mediating the expression of inflammatory cytokines including TNF-alpha in terms of host defense was identified in vertebrates and most invertebrates such as insects, mollusks, and crustaceans. However, LITAF gene family members have recently been characterized in only two mollusks, Crassostrea gigas and Mytilus galloprovincialis. Although a large gene family expansion of LITAF homologues was observed in the nematode Caenorhabditis elegans, the amino acid sequences encoded by the C. elegans LITAF homologue have low similarities to other LITAF gene family members. In this study, three LITAF genes were identified in the monogonont rotifer Brachionus koreanus. In silico analyses of B. koreanus LITAF genes of conserved domains and phylogenetic relationships supported gene annotations that indicated that LITAF is involved in innate immunity in primitive rotifers. To examine transcriptional sensitivity of B. koreanus LITAF genes, the rotifers were exposed to different concentrations of lipopolysaccharide (LPS). Transcriptional levels of LITAF1 and LITAF2 gene were significantly upregulated dose- and time-dependently in response to LPS exposure for 24 h. LPS exposure induced glutathione (GSH) depletion and antioxidant enzyme activity levels for 24 h in B. koreanus. These results suggested that the B. koreanus LITAF gene family has potential sensitivities directly and/or indirectly to immune stimulator triggered oxidative stress. PMID- 26056819 TI - Molecular Characterization of NF1 and Neurofibromatosis Type 1 Genotype-Phenotype Correlations in a Chinese Population. AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary disease that is primarily characterized by multiple cafe au-lait spots (CALs) and skin neurofibromas, which are attributed to defects in the tumor suppressor NF1. Because of the age-dependent presentation of NF1, it is often difficult to make an early clinical diagnosis. Moreover, identifying genetic alterations in NF1 patients represents a complex challenge. Currently, there are no effective detective methods, and no comprehensive NF1 mutation data are available for mainland China. We screened 109 Chinese patients from 100 families with NF1-like phenotypes (e.g., CALs, neurofibromas, etc.) using Sanger sequencing, multiplex ligation-dependent probe amplification and cDNA sequencing. NF1 mutations were identified in 97 individuals, among which 34 intragenic mutations have not previously been reported. Our exhaustive mutational analysis detected mutations in 89% (89/100) of the NF1-like probands and 93% (70/75) of subjects fulfilling the National Institutes of Health (NIH) criteria. Our findings indicate that individuals who exclusively present with multiple CALs exhibit a high possibility (76%) of having NF1 and show a significantly lower mutation rate (p = 0.042) compared with subjects who fulfill the NIH criteria, providing clinicians with the information that subjects only with multiple CALs harbor a considerable possibility (24%) of being attributed to other comparable diseases. PMID- 26056822 TI - Neurophysiological Differences between Flail Arm Syndrome and Amyotrophic Lateral Sclerosis. AB - There are many clinical features of flail arm syndrome (FAS) that are different from amyotrophic lateral sclerosis (ALS), suggesting they are probably different entities. Studies on electrophysiological differences between them are limited at present, and still inconclusive. Therefore, we aimed to find clinical and neurophysiological differences between FAS and ALS. Eighteen healthy control subjects, six FAS patients and forty-one ALS patients were recruited. The upper motor neuron signs (UMNS), split-hand index (SI), resting motor threshold (RMT), central motor conduction time (CMCT) were evaluated and compared. There was no obvious upper motor neuron signs in FAS. The SI and RMT level in FAS was similar to control subjects, but significantly lower than that of in ALS. Compared with control group, the RMT and SI in ALS group were both significantly increased to higher level. However, no significant difference of CMCT was found between any two of these three groups. The differences in clinical and neurophysiological findings between FAS and ALS, argue against they are the same disease entity. Since there was no obvious UMNS, no split-hand phenomenon, and no obvious changes of RMT and CMCT in FAS patients, the development of FAS might be probably not originated from motor cortex. PMID- 26056823 TI - Monitoring the Progress towards the Elimination of Gambiense Human African Trypanosomiasis. AB - BACKGROUND: Over the last few years, momentum has gathered around the feasibility and opportunity of eliminating gambiense human African trypanosomiasis (g-HAT). Under the leadership of the World Health Organization (WHO), a large coalition of stakeholders is now committed to achieving this goal. A roadmap has been laid out, and indicators and milestones have been defined to monitor the progress of the elimination of g-HAT as a public health problem by 2020. Subsequently, a more ambitious objective was set for 2030: to stop disease transmission. This paper provides a situational update to 2012 for a number of indicators of elimination: number of cases annually reported, geographic distribution of the disease and areas and populations at different levels of risk. RESULTS: Comparing the 5-year periods 2003-2007 and 2008-2012, the area at high or very high risk of g-HAT shrank by 60%, while the area at moderate risk decreased by 22%. These are the areas where g-HAT is still to be considered a public health problem (i.e. > 1 HAT reported case per 10,000 people per annum). This contraction of at-risk areas corresponds to a reduction of 57% for the population at high or very high risk (from 4.1 to 1.8 million), and 20% for moderate risk (from 14.0 to 11.3 million). DISCUSSION: Improved data completeness and accuracy of the Atlas of HAT enhanced our capacity to monitor the progress towards the elimination of g-HAT. The trends in the selected indicators suggest that, in recent years, progress has been steady and in line with the elimination goal laid out in the WHO roadmap on neglected tropical diseases. PMID- 26056824 TI - Correction: Potential 'Ecological Traps' of Restored Landscapes: Koalas Phascolarctos cinereus Re-Occupy a Rehabilitated Mine Site. PMID- 26056827 TI - Brain Treatments and Creativity. PMID- 26056825 TI - Intranasal Immunization with Pressure Inactivated Avian Influenza Elicits Cellular and Humoral Responses in Mice. AB - Influenza viruses pose a serious global health threat, particularly in light of newly emerging strains, such as the avian influenza H5N1 and H7N9 viruses. Vaccination remains the primary method for preventing acquiring influenza or for avoiding developing serious complications related to the disease. Vaccinations based on inactivated split virus vaccines or on chemically inactivated whole virus have some important drawbacks, including changes in the immunogenic properties of the virus. To induce a greater mucosal immune response, intranasally administered vaccines are highly desired as they not only prevent disease but can also block the infection at its primary site. To avoid these drawbacks, hydrostatic pressure has been used as a potential method for viral inactivation and vaccine production. In this study, we show that hydrostatic pressure inactivates the avian influenza A H3N8 virus, while still maintaining hemagglutinin and neuraminidase functionalities. Challenged vaccinated animals showed no disease signs (ruffled fur, lethargy, weight loss, and huddling). Similarly, these animals showed less Evans Blue dye leakage and lower cell counts in their bronchoalveolar lavage fluid compared with the challenged non-vaccinated group. We found that the whole inactivated particles were capable of generating a neutralizing antibody response in serum, and IgA was also found in nasal mucosa and feces. After the vaccination and challenge we observed Th1/Th2 cytokine secretion with a prevalence of IFN-gamma. Our data indicate that the animals present a satisfactory immune response after vaccination and are protected against infection. Our results may pave the way for the development of a novel pressure-based vaccine against influenza virus. PMID- 26056826 TI - A Novel Europium Chelate Coated Nanosphere for Time-Resolved Fluorescence Immunoassay. AB - A novel europium ligand 2,2',2'',2'''-(4,7-diphenyl-1,10-phenanthroline-2,9-diyl) bis (methylene) bis (azanetriyl) tetra acetic acid (BC-EDTA) was synthesized and characterized. It shows an emission spectrum peak at 610 nm when it is excited at 360 nm, with a large Stock shift (250 nm). It is covalently coated on the surface of a bare silica nanosphere containi free amino groups, using 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide hydrochloride and N-Hydroxysuccinimide. We also observed an interesting phenomenon that when BC-EDTA is labeled with a silica nanosphere, the chelate shows different excitation spectrum peaks of about 295 nm. We speculate that the carboxyl has a significant influence on its excitation spectrum. The BC-EDTA/Eu3+coated nanosphere could be used as a fluorescent probe for time-resolved fluorescence immunoassay. We labeled the antibody with the fluorescent nanosphere to develop a nanosphere based hepatitis B surface antigen as a time-resolved fluorescence immunoassay reagent, which is very easy to operate and eliminates potential contamination of Eu3+ contained in the environment. The analytical and functional sensitivities are 0.0037 MUg/L and 0.08 MUg/L (S/N>=2.0) respectively. The detection range is 0.08-166.67 MUg/L, which is much wider than that of ELISA (0.2-5 MUg/L). It is comparable to the commercial dissociation-enhanced lanthanide fluoro-immunoassay system (DELFIA) reagents (0.2-145 MUg/L). We propose that it can fulfill clinical applications. PMID- 26056828 TI - The Changing World of Long-term Care in RI. PMID- 26056829 TI - The Nuts and Bolts of Long-term Care In Rhode Island: Demographics, Services and Costs. AB - Nearly 8,000 people reside in Rhode Island's (RI's) 84 nursing homes at any single point in time. Many of these people are highly vulnerable because of illness or frailty. In this article, we describe the reasons that RI residents seek care from nursing homes, the associated costs (with a focus on Medicare and Medicaid payment), and different ways to assess nursing home quality. We also describe the home- and community-based services that can help people remain in the community. A resource list provides additional information for those seeking to better understand RI nursing homes and long-term care supports and services. PMID- 26056830 TI - The Roles and Functions of Medical Directors in Nursing Homes. AB - The medical director is an important member of the healthcare team in a nursing home, and is responsible for overall coordination of care and for implementation of policies related to care of the residents in a nursing home. The residents in nursing homes are frail, medically complex, and have multiple disabilities. The medical director has an important leadership role in assisting nursing home administration in providing quality care that is consistent with current standards of care. This article provides an overview of roles and functions of the medical director, and suggests ways the medical director can be instrumental in achieving excellent care in today's nursing facilities. PMID- 26056831 TI - A Nursing Home Administrator's Perspective on Culture Change: Tockwotton's Commitment to Resident-Centered Care. AB - Tockwotton Home, a 150+-year-old long-term care organization reinvented itself by adopting the household model of management ("culture change") to enable residents to play an integral role in self-directing their care. Staff was cross-trained and cross- certified to be nimble in meeting resident needs. In addition to philosophical changes, the organization made a $53.2M investment in a new building with architectural features that reflected the new focus. The process of change, the resources facilitating this change and our responses to challenges are described. Early indicators (and long-term studies at other institutions) have suggested that the new model of care is leading to fewer medications, falls and pressure ulcers and higher resident satisfaction. PMID- 26056832 TI - The Changing World of Long-term Care in RI: One Nurse's Journey. AB - This paper presents a personal look at the changing world of long-term nursing care in one facility over the course of a 38-year nursing career. The paper reviews the ways the role of "nurse" has evolved and expanded due to changes in patient populations, industry standards, and technology advancement. Though the job has changed dramatically over the decades, the most integral parts of successful nursing remain the same: Connection to patients and their families, and a commitment to quality care and patient well-being. PMID- 26056833 TI - Prescription Opioid Use and Misuse Among Older Adult Rhode Island Hospital Emergency Department Patients. AB - Because of the multitude of financial, health, and social problems associated with prescription opioid misuse, effective methods of identifying older adults who are misusing these medications are needed. We conducted a pilot investigation to determine the prevalence of previous and current prescription opioid use among older adults visiting the Rhode Island Hospital Emergency Department and their need for opioid misuse interventions. Among 88 randomly selected older adults (>= 65 years of age) presenting to the ED with sub-critical illness or injury, 19% (95% CI: 11-27%) were current opioid users and 6% (95% CI: 4-8%) would require an intervention for prescription opioid misuse. We identified problems of improper acquisition, diversion, provider refusal to prescribe opioids, hoarding, and inappropriate use of opioids among this population. Emergency medicine clinicians should query their older adult patients about prescription opioid misuse and associated problematic behaviors. PMID- 26056834 TI - Hypokalemic Quadriparesis Secondary to Abuse of Cocaine and Heroin. AB - Low plasma potassium level can cause muscle weakness, lassitude, constipation as well as rhabdomyolysis and arrhythmias, when severe. In muscle, low plasma potassium increases resting membrane potential (hyperpolarization) of myocytes that tend to make muscle more refractory to excitation, leading to muscle weakness. Hypokalemia can be associated with a myriad of causes including drugs of abuse. We present a case of hypokalemia and muscle weakness following use of cocaine and heroin. PMID- 26056835 TI - Unilateral Greater Occipital Nerve Compression Causing Scalp Numbness. PMID- 26056836 TI - Lactescent Serum and Abdominal Pain. PMID- 26056837 TI - Prepregnancy Obesity and Adverse Health Conditions in Rhode Island. PMID- 26056838 TI - Paravertebral Catheter for Three-Level Injection in Radical Mastectomy: A Randomised Controlled Study. AB - INTRODUCTION: Paravertebral block (PVB) is an alternative to general anaesthesia (GA) for breast surgery. However, for extensive surgery multiple punctures are needed increasing the immanent risk of the method. The purpose of this study was to evaluate PVB via catheter and injections at three different levels. Primary outcome was the quality of postoperative analgesia, in particular, the number of patients requiring additional morphine. METHODS: In a randomised single blinded clinical study patients scheduled for breast surgery including axillary approach, were randomly allocated to different anaesthetic techniques, n = 35 each. Patients received either GA with sevoflurane or PVB with catheter at level Th 4. In PVB-patients a 1:2 mixture of bupivacaine 0.5% and lidocaine 2% with adrenaline was injected sequentially 10 ml each at three different levels. RESULTS: Complication-free catheter insertion was possible in all 35 scheduled patients. The need for postoperative analgesics was higher after GA compared to PVB (22 vs.14 patients); p = 0.056. Postoperative morphine consumption was 1.55 (GA) and 0.26 mg (PVB) respectively (p < 0.001). Visual rating score (VRS) for pain at rest and at movement was higher in GA patients on post anaesthesia care unit (PACU) as well as on the ward at 1-6 h and 6-12 h. Readiness for discharge was earlier after PVB (4.96 and 6.52 hours respectively). After GA the incidence and severity of postoperative nausea and vomiting (PONV) was higher, though not significantly. Patients' satisfaction was comparable in both groups. CONCLUSIONS: Three-level injection PVB via catheter for extensive mastectomy was efficient and well accepted. Using a catheter may enhance safety by avoiding multiple paravertebral punctures when extended spread of analgesia is required. TRIAL REGISTRATION: www.ClinicalTrial.gov NCT02065947. PMID- 26056839 TI - Preterm delivery and intimacy during pregnancy: interaction between oral, vaginal and intestinal microbiomes. AB - During pregnancy, the microbiomes of the mouth, vagina and intestine undergo changes to adapt to the demands of the body, increasing the relationship and similarity between them. Therefore, it is pertinent to consider a literature review to determine the existence of influencing factors for a specific microbiome, which could also modify others. An example is the case of the mouth microbiome that is dependent on the intimate activities of the female, and therefore could be a factor that relates to preterm labor. PMID- 26056840 TI - Caregiver Burden in Patients Receiving Ranibizumab Therapy for Neovascular Age Related Macular Degeneration. AB - PURPOSE: To assess the caregiver burden and factors determining the burden in patients receiving ranibizumab therapy for neovascular AMD (nAMD). METHODS: This is a cross-sectional questionnaire survey of 250 matched patient caregiver dyads across three large ophthalmic treatment centres in United Kingdom. The primary outcome was the subjective caregiver burden measured using caregiver reaction assessment scale (CRA). Objective caregiver burden was determined by the caregiver tasks and level of care provided. The factors that may predict the caregiver burden such as the patient's visual acuity of the better eye and vision related quality of life, demographics, satisfaction and support provided by the healthcare and the health status of the dyads were also collected and assessed in a hierarchical regression model. RESULTS: The mean CRA score was 3.2+/-0.5, similar to the score reported by caregivers for atrial fibrillation who require regular hospital appointments for monitoring their thromboprophylaxis. Caregiver tasks including accompanying for hospital appointments for eye treatment and patient's visual acuity in the better eye were the biggest contributors to the caregiver burden hierarchical model explaining 18% and 11% of the variance respectively. CONCLUSION: Ranibizumab therapy for nAMD is associated with significant caregiver burden. Both disease impact and treatment frequency contributed to the overall burden. PMID- 26056841 TI - Identification of Breast Cancer Using Integrated Information from MRI and Mammography. AB - OBJECTIVES: Integration of information from corresponding regions between the breast MRI and an X-ray mammogram could benefit the detection of breast cancer in clinical diagnosis. We aimed to provide a framework of registration from breast MRI to mammography and to evaluate the diagnosis using the combined information. MATERIALS AND METHODS: 43 patients with 46 lesions underwent both MRI and mammography scans, and the interval between the two examinations was around one month. The distribution of malignant to benign lesions was 31/46 based on histological results. Maximum intensity projection and thin-plate spline methods were applied for image registration for MRI to mammography. The diagnosis using integrated information was evaluated using results of histology as the reference. The assessment of annotations and statistical analysis were performed by the two radiologists. RESULTS: For the cranio-caudal view, the mean post-registration error between MRI and mammography was 2.2+/-1.9 mm. For the medio-lateral oblique view, the proposed approach performed even better with a mean error of 3.0+/-2.4 mm. In the diagnosis using MRI assessment with information of mammography, the sensitivity was 91.9+/-2.3% (29/31, 28/31), specificity 70.0+/-4.7% (11/15, 10/15), accuracy 84.8+/-3.1% (40/46, 38/46), positive predictive value 86.4+/ 2.1% (29/33, 28/33) and negative predictive value 80.8+/-5.4% (11/13, 10/13). CONCLUSION: MRI with the aid of mammography shows potential improvements of sensitivity, specificity, accuracy, PPV and NPV in clinical breast cancer diagnosis compared to the use of MRI alone. PMID- 26056843 TI - Corrigendum. PMID- 26056842 TI - Preparing for the Rollout of Pre-Exposure Prophylaxis (PrEP): A Vignette Survey to Identify Intended Sexual Behaviors among Women in Kenya and South Africa if Using PrEP. AB - INTRODUCTION: Several clinical trials have demonstrated the efficacy of pre exposure prophylaxis (PrEP) in reducing HIV risk. One concern with introducing PrEP is whether users will engage in riskier sexual behaviors. METHODS: We assessed the effect that PrEP may have on sexual risk behaviors by administering a survey to 799 women in Bondo, Kenya, and Pretoria, South Africa. Participants were asked about their sexual behavior intentions twice--once as if they were taking PrEP and once as if they were not taking PrEP--within four risk situations (vignettes). They responded using a 5-point ordinal scale. We used a series of linear mixed effects models with an unstructured residual covariance matrix to estimate the between- and within-subject differences in the mean likelihood of engaging in risky sexual behavior across the PrEP and non-PrEP contexts. We also calculated the total percentage of participants who reported a greater likelihood of engaging in risky sexual behavior if taking PrEP than if not taking PrEP, by vignette. RESULTS: We found statistically significant differences in the mean likelihood of engaging in risky sexual behavior with the between-subject comparison (-0.17, p < 0.01) and with the within-subject comparison (-0.31, p < 0.001). Depending on the vignette, 27% to 40% of participants reported a greater likelihood of engaging in risky sexual behavior if taking PrEP than if not taking PrEP. CONCLUSIONS: Our findings indicate that modest increases in risky sexual behavior could occur with PrEP. Although responses from the majority of participants suggest they would not be more likely to engage in risky sexual behavior if they took PrEP, a substantial proportion might. Programs rolling out PrEP should be prepared to assist similar women in making informed choices about reducing their risk of HIV and about their sexual health beyond HIV prevention. PMID- 26056844 TI - Interactions of Cu(B) with Carbon Monoxide in Cytochrome c Oxidase: Origin of the Anomalous Correlation between the Fe-CO and C-O Stretching Frequencies. AB - In heme-copper oxidases, the correlation curve between the iron-CO and C-O stretching vibrational modes (nu(Fe-CO) and nu(C-O), respectively) is anomalous as compared to the correlation in other heme proteins. To extend the correlation curve, the resonance Raman (RR) and infrared (IR) spectra of the CO adducts of cytochrome ba3 (ba3) from Thermus thermophilus were measured. The RR spectrum has two strong nu(Fe-CO) lines (508 and 515 cm(-1)) and a very weak line at 526 cm( 1), and the IR spectrum has three nu(C-O) lines (1966, 1973, and 1981 cm(-1)), indicating the presence of multiple conformers. Employing photodissociation methods, the nu(Fe-CO) RR and nu(C-O) IR lines were assigned to each conformer, enabling the establishment of a reliable inverse correlation curve for the nu(Fe CO) versus the nu(C-O) stretching frequencies. To determine the molecular basis of the correlation, a series of DFT calculations on 6-coordinate porphyrin-CO compounds and a model of the binuclear center of the heme-copper oxidases were carried out. The calculations demonstrated that the copper unit model caused significant mixing among porphyrin-CO molecular orbitals (MOs) that contribute to the Fe-C and C-O bonding interactions, and also indicated the presence of mixing between the d(z)(2) orbital of the copper and MOs that are responsible for the nu(Fe-CO) vs nu(C-O) inverse correlation. Together, the spectroscopic and DFT results clarify the origin of the anomaly of nu(Fe-CO) and nu(C-O) frequencies in the heme-copper oxidases, a long-standing issue. PMID- 26056845 TI - Solution Processable Holey Graphene Oxide and Its Derived Macrostructures for High-Performance Supercapacitors. AB - Scalable preparation of solution processable graphene and its bulk materials with high specific surface areas and designed porosities is essential for many practical applications. Herein, we report a scalable approach to produce aqueous dispersions of holey graphene oxide with abundant in-plane nanopores via a convenient mild defect-etching reaction and demonstrate that the holey graphene oxide can function as a versatile building block for the assembly of macrostructures including holey graphene hydrogels with a three-dimensional hierarchical porosity and holey graphene papers with a compact but porous layered structure. These holey graphene macrostructures exhibit significantly improved specific surface area and ion diffusion rate compared to the nonholey counterparts and can be directly used as binder-free supercapacitor electrodes with ultrahigh specific capacitances of 283 F/g and 234 F/cm(3), excellent rate capabilities, and superior cycling stabilities. Our study defines a scalable pathway to solution processable holey graphene materials and will greatly impact the applications of graphene in diverse technological areas. PMID- 26056846 TI - The oxidation of As(III) in groundwater using biological manganese removal filtration columns. AB - Arsenic is known as a toxic element to humans, and has been reported to co-exist with iron and manganese in groundwater worldwide. The typical method for arsenic removal from groundwater is to oxidize trivalent (As(III)) to pentavalent (As(V)) followed by the As(V) removal. This study aims to evaluate the oxidization efficiency of As(III) in a mature biological manganese (Mn(2+)) removal filtration system with different elevated influent As(III) concentrations. The effects of influent Mn(2+) concentrations, influent As(III) concentrations, filtration rates and dissolved oxygen (DO) levels on the efficiency of As(III) oxidation were assessed. The results showed that As(III) oxidation can be simultaneously achieved with removing Mn(2+) in the filtration system. The oxidation efficiency was not impacted by increasing the influent As(III) concentration up to nearly 2500 ug L(-1), but the filtration rate was limited at 11 m h(-1) for maintaining the effluent As(III) concentration below 10 ug L(-1). The oxidation process followed first-order kinetics with the constant reaching 0.56-0.61 min(-1). The As(III) oxidation process was most likely to be mediated by the bacterial community initially developed for Mn(2+) removal in the filtration system, which performed the catalytic oxidation for As(III). PMID- 26056847 TI - Plant Virus Metagenomics: Advances in Virus Discovery. AB - In recent years plant viruses have been detected from many environments, including domestic and wild plants and interfaces between these systems-aquatic sources, feces of various animals, and insects. A variety of methods have been employed to study plant virus biodiversity, including enrichment for virus-like particles or virus-specific RNA or DNA, or the extraction of total nucleic acids, followed by next-generation deep sequencing and bioinformatic analyses. All of the methods have some shortcomings, but taken together these studies reveal our surprising lack of knowledge about plant viruses and point to the need for more comprehensive studies. In addition, many new viruses have been discovered, with most virus infections in wild plants appearing asymptomatic, suggesting that virus disease may be a byproduct of domestication. For plant pathologists these studies are providing useful tools to detect viruses, and perhaps to predict future problems that could threaten cultivated plants. PMID- 26056848 TI - Accelerating Strain-Promoted Azide-Alkyne Cycloaddition Using Micellar Catalysis. AB - Bioorthogonal conjugation reactions such as strain-promoted azide-alkyne cycloaddition (SPAAC) have become increasingly popular in recent years, as they enable site-specific labeling of complex biomolecules. However, despite a number of improvements to cyclooctyne design, reaction rates for SPAAC remain significantly lower than those of the related copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Here we explore micellar catalysis as a means to increase reaction rate between a cyclooctyne and hydrophobic azide. We find that anionic and cationic surfactants provide the most efficient catalysis, with rate enhancements of up to 179-fold for reaction of benzyl azide with DIBAC cyclooctyne. Additionally, we find that the presence of surfactant can provide up to 51-fold selectivity for reaction with a hydrophobic over hydrophilic azide. A more modest, but still substantial, 11-fold rate enhancement is observed for micellar catalysis of the reaction between benzyl azide and a DIBAC functionalized DNA sequence, demonstrating that micellar catalysis can be successfully applied to hydrophilic biomolecules. Together, these results demonstrate that micellar catalysis can provide higher conjugation yields in reduced time when using hydrophobic SPAAC reagents. PMID- 26056849 TI - Visualization of RNA-Quadruplexes in Live Cells. AB - Visualization of DNA and RNA quadruplex formation in human cells was demonstrated recently with different quadruplex-specific antibodies. Despite the significant interest in these immunodetection approaches, dynamic detection of quadruplex in live cells remains elusive. Here, we report on NaphthoTASQ (N-TASQ), a next generation quadruplex ligand that acts as a multiphoton turn-on fluorescent probe. Single-step incubation of human and mouse cells with N-TASQ enables the direct detection of RNA-quadruplexes in untreated cells (no fixation, permeabilization or mounting steps), thus offering a unique, unbiased visualization of quadruplexes in live cells. PMID- 26056850 TI - The molecular mechanisms of liver and islets of Langerhans toxicity by benzene and its metabolite hydroquinone in vivo and in vitro. AB - Benzene (C6H6) is one of the most commonly used industrial chemicals causing environmental pollution. This study aimed to examine the effect of benzene and its metabolite hydroquinone on glucose regulating organs, liver and pancreas, and to reveal the involved toxic mechanisms, in rats. In the in vivo part, benzene was dissolved in corn oil and administered through intragastric route at doses of 200, 400 and 800 mg/kg/day, for 4 weeks. And, in the in vitro part, toxic mechanisms responsible for weakening the antioxidant system in islets of Langerhans by hydroquinone at different concentrations (0.25, 0.5 and 1 mM), were revealed. Benzene exposure raised the activity of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6Pase) enzymes and increased fasting blood sugar (FBS) in comparison to control animals. Also, the activity of hepatic glucokinase (GK) was decreased significantly. Along with, a significant increase was observed in hepatic tumor necrosis factor (TNF-alpha) and plasma insulin in benzene treated rats. Moreover, benzene caused a significant rise in hepatic lipid peroxidation, DNA damage and oxidation of proteins. In islets of Langerhans, hydroquinone was found to decrease the capability of antioxidant system to fight free radicals. Also, the level of death proteases (caspase 3 and caspase 9) was found higher in hydroquinone exposed islets. The current study demonstrated that benzene and hydroquinone causes toxic effects on liver and pancreatic islets by causing oxidative impairment. PMID- 26056851 TI - Effects of methylmercury on dopamine release in MN9D neuronal cells. AB - Epidemiological evidence has shown associations between prevalence of Parkinson's disease (PD) and exposure to environmental pollutants, but the mechanisms of pathogensis are still unclear. The objective of this study is to investigate effects of methylmercury (MeHg) on a dopaminergic neuronal cell line, MN9D and compare that to 1-methyl-4-phenylpyridinium (MPP+), a well-established agent associated with pathogenesis of PD. MN9D cells were exposed to MeHg (1-10 uM) and MPP+ (10-400 uM) for 24 or 48 h. Our results showed that MeHg induced cell death dose-dependently. MeHg also decreased the release of dopamine (DA), 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) similar to the effects of MPP+. There was an increase in DOPAC + HVA/DA ratio. At the same time, both MeHg and MPP+ decreased the synthesis of tyrosine hydroxylase and dopamine transporter at the mRNA and protein levels. Expression of the alpha-Synuclein (alpha-Syn), a hallmark neuropathological indicator of PD, was also up-regulated at the mRNA level but not at the protein level after both MeHg and MPP+ dosing. Monoamine oxidase-B activity was suppressed in all MeHg treatments and MPP+ (1 uM)-treated cells. These findings suggest that MeHg can disrupt the synthesis, the uptake of DA and the metabolism as well as alter the biology of alpha-Syn similar to MPP+. Exposure to MeHg may potentially be a risk factor for the development of PD. PMID- 26056852 TI - Preventive effects of oleuropein against cardiac remodeling after myocardial infarction in Wistar rat through inhibiting angiotensin-converting enzyme activity. AB - OBJECTIVE: Myocardial infarction remains the major cause of global death due to cardiovascular diseases. This study aimed to assess the protective role of oleuropein in attenuating the cardiac remodeling in isoproterenol-induced myocardial infarction in rats. METHODS AND RESULTS: Male Wistar rats were randomly divided into four groups, control, isoproterenol (Isop) and pretreated animals with oleuropein at two different doses (20 and 40 mg/kg) orally for 7 days and intoxicated with isoproterenol (Isop+Oleu20) and (Isop+Oleu40) groups. The subcutaneous injection of isoproterenol (100 mg/kg body weight) to untreated rats for two consecutive days showed significant increases in ST-segment elevation, heart weight index and alteration in the ECG pattern and hemodynamic function. Else, serum levels of cardiac troponin-T, creatine kinase isoenzyme (CK MB), lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) underwent a notable rise in serum of Isop group by (345, 82, 73 and 106%, respectively) as compared to normal rats. Isoproterenol-induced myocardial injury was evidenced by alteration in serum lipids profile and increased activities of pancreatic lipase by 94% and angiotensin-converting enzyme (ACE) by 78% which reflects the occurrence of cardiac remodeling process. The histopathological findings of the infarcted group showed myocardium necrosis and cells inflammatory infiltration. However, the treatment with oleuropein gave a good protection of the myocardium by decreasing cardiac injury markers specially troponin-T, restoring hemodynamic parameters and attenuating cardiac remodeling process through inhibition of ACE activity. CONCLUSION: Oleuropein offers high preventive effects from cardiac remodeling process in rats with acute myocardial infarction. PMID- 26056853 TI - Perfluorononanoic acid disturbed the metabolism of lipid in the liver of streptozotocin-induced diabetic rats. AB - Most studies on the liver toxicity of perfluorinated compounds (PFCs) are focused on healthy individuals, whereas the effects of PFCs on individuals with diabetes mellitus have not been fully characterized. This study aimed to investigate the acute exposure of perfluorononanoic acid (PFNA) on the metabolism of lipid in the liver of streptozotocin-induced diabetic rats. Male diabetic rats were orally dosed by gavage for 7 days with 0, 0.2, 1 and 5 mg/kg/day PFNA. The contents of lipid, the activities of enzyme, the expressions of protein in the liver and the serum parameters were detected. The results indicate that dose-dependent accumulation of triglyceride and total cholesterol occurred in the livers of diabetic rats after PFNA treatment. PFNA increased the activities of lipid synthetase, fatty acid synthease, glucose-6-phosphate dehydrogenase and decreased the activity of lipolytic enzyme, hepatic lipase, in the liver of diabetic rats. The changes of the isocitrate dehydrogenase, malicenzyme and lipoprotein lipase were not obvious. The expressions of protein related to lipid homeostasis, liver X receptor alpha and apolipoprotein E, were decreased after PFNA administration. Exposure to PFNA also increased the activity of serum alanine aminotransferase in diabetic rats. In conclusion, this study discloses that exposure to PFNA impacts on enzymes and proteins related to liver lipid metabolism and lead to obvious accumulation of lipid in the liver of diabetic rats, which may be responsible for hepatotoxicity of this compound in individuals with diabetes mellitus. PMID- 26056854 TI - Mechanisms of Acute Alcohol Intoxication-Induced Modulation of Cyclic Mobilization of [Ca2+] in Rat Mesenteric Lymphatic Vessels. AB - BACKGROUND: We have demonstrated that acute alcohol intoxication (AAI) increases the magnitude of Ca(2+) transients in pumping lymphatic vessels. We tested the contribution of extracellular Ca(2+) via L-type Ca(2+) channels and intracellular Ca(2+) release from the sarcoplasmic reticulum (SR) to the AAI-induced increase in Ca(2+) transients. METHODS AND RESULTS: AAI was produced by intragastric administration of 30% alcohol to conscious, unrestrained rats; isovolumic administration of water served as the control. Mesenteric lymphatic vessels were isolated, cannulated, and loaded with Fura-2 AM to measure changes in intracellular Ca(2+). Measurements were made at intraluminal pressures of 2, 6, and 10 cm H2O. L-type Ca(2+) channels were blocked with nifedipine; IP-3 receptors were inhibited with xestospongin C; and SR Ca(2+) release and Ca(2+) pool (Ca(2+) free APSS) were achieved using caffeine. Nifedipine reduced lymphatic Ca(2+) transient magnitude in both AAI and control groups at all pressures tested, but reduced lymphatic contraction frequency only in the control group. Xestospongin C did not significantly change any of the Ca(2+) parameters in either group; however, fractional shortening increased in the controls at low transmural pressure. RyR (ryanodine receptor) activation with caffeine resulted in a single contraction with a greater Ca(2+) transient in lymphatics from AAI than those from controls. SR Ca(2+) pool was also greater in lymphatics isolated from AAI- than from control animals. CONCLUSIONS: These data suggest that 1) L type Ca(2+) channels contribute to the AAI-induced increase in lymphatic Ca(2+) transient, 2) blockage of IP-3 receptors could increase calcium sensitivity, and 3) AAI increases Ca(2+) storage in the SR in lymphatic vessels. PMID- 26056855 TI - Photodegradable Gelatin-Based Hydrogels Prepared by Bioorthogonal Click Chemistry for Cell Encapsulation and Release. AB - In this study, we present a method for the fabrication of in situ forming gelatin and poly(ethylene glycol)-based hydrogels utilizing bioorthogonal, strain promoted alkyne-azide cycloaddition as the cross-linking reaction. By incorporating nitrobenzyl moieties within the network structure, these hydrogels can be designed to be degradable upon irradiation with low intensity UV light, allowing precise photopatterning. Fibroblast cells encapsulated within these hydrogels were viable at 14 days and could be readily harvested using a light trigger. Potential applications of this new class of injectable hydrogel include its use as a 3D culturing platform that allows the capture and release of cells, as well as light-triggered cell delivery in regenerative medicine. PMID- 26056856 TI - The effects of progressive resistance training on daily physical activity in young people with cerebral palsy: a randomised controlled trial. AB - PURPOSE: To examine if individualised resistance training increases the daily physical activity of adolescents and young adults with bilateral spastic cerebral palsy (CP). METHOD: Young people with bilateral spastic CP were randomly assigned to intervention or to usual care. The intervention group completed an individualised lower limb progressive resistance training programme twice a week for 12 weeks in community gymnasiums. The primary outcome was daily physical activity (number of steps, and time sitting and lying). Secondary outcomes included muscle strength measured with a one-repetition maximum (1RM) leg press and reverse leg press. Outcomes were measured at baseline, 12 weeks and 24 weeks. RESULTS: From the 36 participants with complete data at 12 weeks, there were no between-group differences for any measure of daily physical activity. There was a likely increase in leg press strength in favour of the intervention group (mean difference 11.8 kg; 95% CI -1.4 to 25.0). No significant adverse events occurred during training. CONCLUSIONS: A short-term resistance training programme that may increase leg muscle strength was not effective in increasing daily physical activity. Other strategies are needed to address the low-daily physical activity levels of young people with bilateral spastic CP. IMPLICATIONS FOR REHABILITATION: Progressive resistance training may increase muscle strength but does not lead to increases in daily physical activity of young people with bilateral spastic cerebral palsy (CP) and mild to moderate walking disabilities. Other strategies apart from or in addition to resistance training are needed to address the low daily physical activity levels of young people with bilateral spastic CP and mild to moderate walking disabilities. PMID- 26056857 TI - Foot and ankle impairments affect balance and mobility in stroke (FAiMiS): the views and experiences of people with stroke. AB - PURPOSE: To explore the nature and impact of foot and ankle impairments on mobility and balance in community-dwelling, chronic stroke survivors. METHODS: A qualitative research design using face to face semi-structured, audio recorded interviews. Thirteen community-dwelling stroke survivors, all of whom had self reported foot and ankle impairments, were interviewed (female n = 6, mean age = 67 years, SD = 12 years, mean time since stroke = 4 years, SD = 6 years, right stroke n = 7, left stroke n = 6). A framework analysis approach was used to analyse and interpret transcribed interviews. RESULTS: Three themes emerged: (1) Impact. The influence of foot and ankle impairments on mobility and balance. (2) Standing out. How participants felt they "stood out" because of their impairments and wanted to be normal. (3) Help. The specific help and advice participants received in managing their problems. CONCLUSIONS: Foot and ankle impairments such as pain, altered somatosensory input and weakness significantly contribute to problems with community ambulation, balance and fear of falling in people with chronic stroke. Specific foot and ankle impairments may also negatively contribute to perceptions of physical appearance and self-esteem. Therapeutic management approaches within clinical practice appear to focus mostly on the gross performance of the lower limb with little emphasis on the specific assessment or treatment of the foot or ankle. IMPLICATIONS FOR REHABILITATION: Foot pain, sensory impairments and muscle weakness in the foot and ankle can impact on community ambulation, balance and fear of falling following stroke. Foot and ankle function post-stroke should be routinely assessed and monitored. Clinicians should be aware of the potentially distressing negative perceptions associated with altered gait patterns, footwear and orthotic use. PMID- 26056858 TI - Enhancing caregivers' understanding of dementia and tailoring activities in frontotemporal dementia: two case studies. AB - PURPOSE: The purpose of this study is to describe the intervention process and results of the Tailored Activities Program (TAP) in two people diagnosed with Frontotemporal Dementia (FTD). METHOD: TAP is an occupational therapy (OT) community-based intervention program that prescribes personalised activities to reduce difficult behaviours of dementia. The OT works with carers over a 4-month period (assessment, activity prescription and generalisation of strategies). Study measures were collected (blind researcher) pre- and post-intervention: cognition, functional disability, behavioural symptoms and Caregiver Confidence and Vigilance. RESULTS: A 51-year-old woman with behavioural-variant FTD could consistently engage in more activities post-intervention, with scores indicating improvements to behaviour, function and caregiver confidence. A 63-year-old man with semantic variant FTD engaged well in the prescribed activities, with scores reflecting reduced carer distress regarding challenging behaviours and improved caregiver vigilance. CONCLUSIONS: TAP is efficacious in FTD, allowing for differences in approach for FTD subtype, where behavioural symptoms are very severe and pervasive. IMPLICATIONS FOR REHABILITATION: The Tailored Activities Program is an intervention which can be tailored to account for unique behavioural and language profiles inherent across frontotemporal dementia (FTD) subtypes. Maintaining a flexible approach when applying an intervention in FTD allows for tailoring to individual case variability within FTD subtypes. PMID- 26056859 TI - Postoperative infections following colorectal surgery in an English teaching hospital. AB - A retrospective case note review of postoperative infections within 30 days of colorectal surgery was completed. Surgical site infections (SSIs) were identified in 22% of patients (84/378), with other infections, e.g. urinary tract infections, identified in 18.3% of patients. SSIs, urinary and respiratory tract infections were all associated with increased durations of hospital admission compared with non-infected patients. Consideration should be given to postoperative surveillance for all infections, using antibiotic consumption as an objective outcome measure. Nine percent of patients developed an organ space SSI. Organ space SSIs were associated with the longest additional duration of hospital admission (15.5 days) and were the only infection associated with an increase in mortality at 1 year; 37% (13/35) mortality with an organ space SSI vs 4% (8/225) without an infection (odds ratio = 16, 95% confidence interval = 6, 43). Further research to prevent and treat organ space SSIs should be prioritized. PMID- 26056860 TI - Relapsing nitrofurantoin-induced pneumonitis. AB - Nitrofurantoin has well-described associations with a range of adverse pulmonary effects. We report the case of a 72-year old woman with relapsing pneumonitis secondary to the intermittent use of nitrofurantoin, a pattern of disease not well-represented in the literature. The case is also noteworthy as the diagnosis was initially overlooked due to the circumstances of the patient's medication use. Lung biopsy was avoided by detailed history taking. PMID- 26056861 TI - Lighting up the Raman signal of molecules in the vicinity of graphene related materials. AB - Surface enhanced Raman scattering (SERS) is a popular technique to detect the molecules with high selectivity and sensitivity. It has been developed for 40 years, and many reviews have been published to summarize the progress in SERS. Nevertheless, how to make the SERS signals repeatable and quantitative and how to have deeper understanding of the chemical enhancement mechanism are two big challenges. A strategy to target these issues is to develop a Raman enhancement substrate that is flat and nonmetal to replace the conventional rough and metal SERS substrate. At the same time, the newly developed substrate should have a strong interaction with the adsorbate molecules to guarantee strong chemical enhancement. The flatness of the surface allows better control of the molecular distribution and configuration, while the nonmetal surface avoids disturbance of the electromagnetic mechanism. Recently, graphene and other two-dimensional (2D) materials, which have an ideal flat surface and strong chemical interaction with plenty of organic molecules, were developed to be used as Raman enhancement substrates, which can light up the Raman signals of the molecules, and these substrates were demonstrated to be a promising for microspecies or trace species detection. This effect was named "graphene enhanced Raman scattering (GERS)". The GERS technique offers significant advantages for studying molecular vibrations due to the ultraflat and chemically inert 2D surfaces, which are newly available, especially in developing a quantitative and repeatable signal enhancement technique, complementary to SERS. Moreover, GERS is a chemical mechanism dominated effect, which offers a valuable model to study the details of the chemical mechanism. In this Account, we summarize the systematic studies exploring the character of GERS. In addition, as a practical technique, the combination of GERS with a metal substrate incorporates the advantages from both conventional SERS and GERS. The introduction of graphene to the Raman enhancement substrate extended SERS applications in a more controllable and quantitative way. Looking to the future, we expect the combination of the SERS concept with the GERS technology to lead to the solution of some important issues in chemical dynamics and in biological processes monitoring. PMID- 26056862 TI - The Effect of Oriental Medicine Music Therapy on Idiopathic Chronic Fatigue. AB - OBJECTIVE: Idiopathic chronic fatigue (ICF), defined as medically unexplained chronic fatigue, is common these days. To date, there is no definite cure for ICF, and alternative therapies are being investigated. Oriental medicine music therapy (OMMT), a novel music therapy that occurs through an active behavioral process, has been applied to various chronic diseases, including ICF. In the present study, we aimed to evaluate the effect of OMMT on ICF. DESIGN: Randomized controlled trial of OMMT compared with the waitlist control (6 sessions each) during a 2-week period. PARTICIPANTS: Thirty participants who had had ICF for at least 6 months before the experiments were recruited. OUTCOME MEASURES: We evaluated fatigue severity scale (FSS), visual analog scale (VAS) for overall fatigue, revised Chalder fatigue scale (RCFS), World Health Organization quality of life scale abbreviated version (WHOQOL-BREF), Buzhongyiqi-Tang questionnaire (BZTQ), and salivary cortisol level at baseline (week 0) and at the end of the study (week 2) in the two groups. RESULTS: FSS, VAS, and RCFS scores were significantly lower, and WHOQOL-BREF scores were significantly higher in the OMMT group than in the waitlist group (p=0.006, p=0.004, p=0.002, and p=0.002, respectively). In contrast, salivary cortisol level and BZTQ scores were not significantly different between the OMMT group and the waitlist group. CONCLUSIONS: The present study suggests that OMMT may be an alternative treatment for ICF. Based on this result, further studies including possible mechanisms are needed. PMID- 26056863 TI - Copper-Catalyzed Domino Three-Component Approach for the Assembly of 2-Aminated Benzimidazoles and Quinazolines. AB - A copper-promoted three-component synthesis of 2-aminobenzimidazoles (1) or of 2 aminoquinazolines (2) involving cyanamides, arylboronic acids, and amines has been developed. The operationally simple oxidative process, performed in the presence of K2CO3, a catalytic amount of CuCl2.2H2O, 2,2'-bipyridine, and an O2 atmosphere (1 atm), allows the rapid assembly of either benzimidazoles or quinazolines starting from aryl- or benzyl-substituted cyanamides, respectively. In this process, the copper promotes the formation of three bonds, two C-N bonds, and an additional bond resulting from C-H functionalization event. PMID- 26056864 TI - Rapid synthesis of ultra-long silver nanowires for tailor-made transparent conductive electrodes: proof of concept in organic solar cells. AB - Rapid synthesis of ultralong silver nanowires (AgNWs) has been obtained using a one-pot polyol-mediated synthetic procedure. The AgNWs have been prepared from the base materials in less than one hour with nanowire lengths reaching 195 MUm, which represents the quickest synthesis and one of the highest reported aspect ratios to date. These results have been achieved through a joint analysis of all reaction parameters, which represents a clear progress beyond the state of the art. Dispersions of the AgNWs have been used to prepare thin, flexible, transparent and conducting films using spray coating. Due to the higher aspect ratio, an improved electrical percolation network is observed. This allows a low sheet resistance (RS = 20.2 Omega/sq), whilst maintaining high optical film transparency (T = 94.7%), driving to the highest reported figure-of-merit (FoM = 338). Owing to the light-scattering influence of the AgNWs, the density of the AgNW network can also be varied to enable controllability of the optical haze through the sample. Based on the identification of the optimal haze value, organic photovoltaics (OPVs) have been fabricated using the AgNWs as the transparent electrode and have been benchmarked against indium tin oxide (ITO) electrodes. Overall, the performance of OPVs made using AgNWs sees a small decrease in power conversion efficiency (PCE), primarily due to a fall in open circuit voltage (50 mV). This work indicates that AgNWs can provide a low cost, rapid and roll-to-roll compatible alternative to ITO in OPVs, with only a small compromise in PCE needed. PMID- 26056865 TI - Myelomatous pleural effusion-A case report. AB - Multiple myeloma is a malignant proliferation of plasma cells, predominantly involving the bone marrow and skeletal system. Pleural effusions are rarely associated with multiple myeloma and most often signify a concurrent disease process, e.g. amyloidosis.(1,2) Malignant myelomatous pleural effusions are even more unusual, occurring in less than 1% of cases of multiple myeloma.(1) Here we report the case of a patient with multiple myeloma presenting with a myelomatous pleural effusion at disease recurrence. PMID- 26056866 TI - Topology polymorphism graph for lung tumor segmentation in PET-CT images. AB - Accurate lung tumor segmentation is problematic when the tumor boundary or edge, which reflects the advancing edge of the tumor, is difficult to discern on chest CT or PET. We propose a 'topo-poly' graph model to improve identification of the tumor extent. Our model incorporates an intensity graph and a topology graph. The intensity graph provides the joint PET-CT foreground similarity to differentiate the tumor from surrounding tissues. The topology graph is defined on the basis of contour tree to reflect the inclusion and exclusion relationship of regions. By taking into account different topology relations, the edges in our model exhibit topological polymorphism. These polymorphic edges in turn affect the energy cost when crossing different topology regions under a random walk framework, and hence contribute to appropriate tumor delineation. We validated our method on 40 patients with non-small cell lung cancer where the tumors were manually delineated by a clinical expert. The studies were separated into an 'isolated' group (n = 20) where the lung tumor was located in the lung parenchyma and away from associated structures / tissues in the thorax and a 'complex' group (n = 20) where the tumor abutted / involved a variety of adjacent structures and had heterogeneous FDG uptake. The methods were validated using Dice's similarity coefficient (DSC) to measure the spatial volume overlap and Hausdorff distance (HD) to compare shape similarity calculated as the maximum surface distance between the segmentation results and the manual delineations. Our method achieved an average DSC of 0.881 +/- 0.046 and HD of 5.311 +/- 3.022 mm for the isolated cases and DSC of 0.870 +/- 0.038 and HD of 9.370 +/- 3.169 mm for the complex cases. Student's t-test showed that our model outperformed the other methods (p values <0.05). PMID- 26056867 TI - COMPARISON OF FRESH AND FROZEN FECAL SAMPLES FOR DETECTION OF ENTERIC SALMONELLA FROM CAPTIVE INDIAN STAR TORTOISES (GEOCHELONE ELEGANS). AB - The use of frozen fecal samples in enrichment media to detect Salmonella spp. strains was evaluated in Indian star tortoises (Geochelone elegans) to determine the utility of this test method for field collection. Fresh fecal samples were collected from 10 captive adult Indian star tortoises. Each sample was split, with one portion in enrichment media at room temperature for 1 or 2 days before submission to a reference laboratory for standard enteric culture. The other was placed in the same enrichment media and frozen at -20 degrees C for 2 wk. Afterwards, it was transferred to a -80 degrees C freezer for 1 mo before submission to the same reference laboratory. These freezer temperatures and holding times were selected to replicate typical field collection procedures. Salmonella enterica was isolated from all 10 fresh samples but from only six frozen samples. Statistically, results showed no significant difference between the two methods; however, this may be due to the limited sample size, and if so, utilization of frozen fecal samples to determine Salmonella spp. prevalence may underestimate the actual prevalence. PMID- 26056868 TI - CLINICAL AND EPIDEMIOLOGIC CONSIDERATIONS OF CLOSTRIDIUM DIFFICILE IN HARBOR SEALS (PHOCA VITULINA) AT A MARINE MAMMAL REHABILITATION CENTER. AB - Between 1998 and 2008, 15 cases of segmental to diffuse hemorrhagic to necrohemorrhagic enterocolitis were diagnosed in neonatal and weaned juvenile harbor seals (Phoca vitulina) presented from the Vancouver Aquarium Marine Mammal Rescue Centre for rehabilitation. Based on a combination of gross pathology, histopathology, bacterial isolation, and toxin testing, Clostridium difficile enterocolitis was diagnosed. Most pups were anorexic or inappetant and died acutely with few other premonitory signs. Due to ongoing clinical concerns and possible emergence of this pathogen at the facility, efforts to better characterize the disease and understand the epidemiology of C. difficile was initiated in 95 harbor seal pups presented for rehabilitation in a single stranding season. Fecal samples were collected on admission, following completion of antibiotic treatment, and also prerelease or postmortem. All samples were collected fresh and submitted either directly or stored frozen. Fecal samples were inoculated into selective media for culture and screened by enzyme-linked immunosorbant assay (ELISA) for C. difficile toxins A, B, or both. Results of the 95 seals in the study were as follows: on hospital admit 72 seals were sampled, 10 were culture positive, 12 were ELISA positive; following antibiotic therapy 46 seals were sampled noting three culture positive and nine ELISA positive; prior to release 58 seals were sampled noting zero culture positive and one ELISA positive; and on postmortem exam seven seals were sampled noting zero culture positive and two ELISA positive. Clostridium difficile was not deemed to be the cause of death in any of the animals. Although the exact mechanism of disease is unknown, this study suggests that C. difficile infection is not a significant cause of mortality and may be part of the normal flora in harbor seals undergoing rehabilitation. Morbidity and mortality from this bacterium can likely be minimized by judicious use of antibiotics, effective biosecurity-biocontainment protocols, and clean husbandry practices. PMID- 26056869 TI - THE NUTRIENT COMPOSITION OF THE DIET OF BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS) IS BETTER ASSESSED RELATIVE TO METABOLIZABLE ENERGY THAN DRY MATTER. AB - Nutrient concentrations in a diet can be expressed either "as fed," relative to dry matter (DM), or relative to metabolizable energy (ME). Most published literature evaluates the diet of dolphins by comparing nutrient content relative to DM. Nevertheless, ME requirements, not DM, determine how much food dolphins need to maintain their body condition. The purpose of this paper is to illustrate why it is important to calculate the ME content of fish fed to dolphins and compare nutrient concentrations in dolphin diets relative to ME, not DM. Two studies that compared the nutrient composition of fish species on a DM basis were reevaluated. The ME content of each fish species was calculated and found to vary widely among species, from 0.94 to 1.58 Mcal/kg as fed. Water, mineral, and fat concentrations relative to ME also varied markedly among fish species. To demonstrate the magnitude of nutrient content differences between fish, the percent change in nutrient concentration for each species was calculated relative to herring. The percent changes for DM and ME analyses were then compared. Percent change in nutrient concentration was either over- or underestimated on a DM basis when compared with the percent change on an ME basis. Notable discrepancies were evident among important nutrients, such as crude protein, water, and sodium. Caretakers of managed dolphins must account for differences in energy density when deciding how much to feed and assessing the nutrient composition of the diet. PMID- 26056870 TI - ESTABLISHMENT OF ECHOCARDIOGRAPHIC PARAMETERS OF CLINICALLY HEALTHY FLORIDA MANATEES (TRICHECHUS MANATUS LATIROSTRIS). AB - A standardized echocardiographic technique was recently established for the Florida manatee (Trichechus manatus latirostris). There are no available published data on normal echocardiographic parameters in any Sirenian species. The purpose of this study was to report reference parameters for various echocardiographic measurements. These parameters are intended to serve as a comparison for future research into the prevalence of cardiac diseases in the manatee and to aid in diagnosing animals with suspected cardiac disease in rehabilitation facilities. Annual health assessments of free-ranging manatees in Crystal River National Wildlife Refuge, Florida, and pre-release health assessments of rehabilitated manatees at Tampa's Lowry Park Zoo permitted comparison of echocardiographic measurements in adult (n=14), subadult (n=7), and calf (n=8) animals under manual restraint. PMID- 26056871 TI - IMMOBILIZING THE VULNERABLE APENNINE CHAMOIS (RUPICAPRA PYRENAICA ORNATA) WITH A LOW-DOSE XYLAZINE-KETAMINE COMBINATION, REVERSED WITH IDAZOXAN OR ATIPAMEZOLE. AB - Little information is available on chemical capture of the vulnerable subspecies within the genus Rupicapra. Low-dosage combinations of xylazine and ketamine were tested for immobilization of captive and free-ranging Apennine chamois, Rupicapra pyrenaica ornata (85 and 66 immobilizations, respectively) in a retrospective analysis. Of the six dosage groups, all of them providing an acceptable level of immobilization, the optimal trade-off between safety and efficacy was found following administration of a mean dosage of 0.24+/-0.03 mg/kg xylazine and 1.07+/-0.15 mg/kg ketamine, resulting in 7.50+/-3.31 min induction time, deep sedation with no or limited reaction to handling in 96% of the chamois, minimal deviation of physiologic parameters from previously reported physiologic values for anesthetized or physically restrained chamois, and no mortality. Intravenous injection of idazoxan (0.05+/-0.01 mg/kg) or atipamezole (0.38+/-0.37 mg/kg) resulted in faster reversal than intravenous injection of tolazoline (1.05+/-0.15 mg/kg) in 1.3 vs. 4.1 min. When free-ranging chamois were darted with similar xylazine and ketamine dosages, induction time was 8.49+/-5.48 min, 88% of the animals were deeply sedated, and a single animal died from respiratory arrest (1.5% mortality). Intramuscular atipamezole provided smoother reversal than intravenous idazoxan. The results of this study suggest that xylazine/ketamine combinations, at remarkably lower dosage than previously published in Caprinae, may be safely and effectively used in chemical capture protocols of Apennine chamois, to facilitate conservation-oriented relocation and research. PMID- 26056872 TI - EVALUATION OF CARDIORESPIRATORY, BLOOD GAS, AND LACTATE VALUES DURING EXTENDED IMMOBILIZATION OF WHITE RHINOCEROS (CERATOTHERIUM SIMUM). AB - Ten white rhinoceros (Ceratotherium simum) were immobilized for a total of 13 procedures in holding facilities in Kruger National Park using etorphine, azaperone, and hyaluronidase to assess the effect of extended immobilization on serial cardiorespiratory, blood gas, and lactate values. Butorphanol was administered intravenously following initial blood collection and physiologic assessment (t=0). Respiratory and cardiovascular parameters, body temperature, and arterial blood gases were monitored at 10-min intervals for a total of 100 min. Initial parameters at the time of recumbency revealed severe hypoxemia, hypercapnia, tachycardia, an increased alveolar-arterial (A-a) gradient, and mildly elevated lactate levels. At 10 min and 20 min, there were significant (P<0.05) changes in the following physiologic parameters: heart rate decreased [96 and 80 beats/min, respectively, vs. 120 beats/min], arterial partial pressure of oxygen (PaO2) increased [48 and 45 mm Hg, respectively vs. 30 mm Hg], arterial hemoglobin oxygen saturation increased [79% and 74%, respectively, vs. 47%], A-a gradient decreased [29.13 and 30.00 mm Hg, respectively, vs. 49.19 mm Hg], and respiratory rate decreased [5 and 5 breaths/min vs. 7 breaths/min]. Blood lactate levels also decreased from 2.54 mM/L to 1.50 and 0.89 mM/L, respectively. Despite initial improvements in blood oxygen levels at t=10 and 20 min, the rhinoceros remained severely hypoxemic for the remainder of the procedure (median PaO2=50.5 mm Hg, 95% confidence interval, 43.8-58.1). Median values for respiratory rate (5 breaths/min) and arterial partial pressure of carbon dioxide (PaCO2; 68.5 mm Hg) did not change significantly for the remaining 80 min. Median lactate, base excess, bicarbonate, and pH values improved between 20 and 100 min despite the persistent hypercapnia, indicating that the animals adequately compensated for respiratory and lactic acidosis. White rhinoceros were immobilized for 100 min with no negative effects, a desirable outcome if procedures require extended chemical immobilization without oxygen supplementation. PMID- 26056873 TI - PREVALENCE OF SALMONELLA IN CAPTIVE REPTILES FROM CROATIA. AB - Salmonellosis transmitted by pet reptiles is an increasing public health issue worldwide. The aim of this study was to investigate the prevalence of Salmonella strains from captive reptiles in Croatia. From November 2009 to November 2011 a total of 292 skin, pharyngeal, cloacal, and fecal samples from 200 apparently healthy reptiles were tested for Salmonella excretions by bacteriologic culture and serotyping. These 200 individual reptiles included 31 lizards, 79 chelonians, and 90 snakes belonging to private owners or housed at the Zagreb Zoo, Croatia. Salmonella was detected in a total of 13% of the animals, among them 48.4% lizards, 8.9% snakes, and 3.8% turtles. Representatives of five of the six Salmonella enterica subspecies were identified with the following proportions in the total number of isolates: Salmonella enterica enterica 34.6%, Salmonella enterica houtenae 23.1%, Salmonella enterica arizonae 23.1%, Salmonella enterica diarizonae 15.4%, and Salmonella enterica salamae 3.8%. The 14 different serovars isolated included several rarely occurring serovars such as Salmonella Apapa, Salmonella Halle, Salmonella Kisarawe, and Salmonella Potengi. These findings confirm that the prevalence of Salmonella is considerable in captive reptiles in Croatia, indicating that these animals may harbor serovars not commonly seen in veterinary or human microbiologic practice. This should be addressed in the prevention and diagnostics of human reptile-transmitted infections. PMID- 26056874 TI - OCCURRENCE OF PASTEURELLACEAE BACTERIA IN THE ORAL CAVITY OF THE TASMANIAN DEVIL (SARCOPHILUS HARRISII). AB - The occurrence of bacteria belonging to the family Pasteurellaceae in the oral cavity of captive Tasmanian devils (Sarcophilus harrisii) was investigated using phenotypic and subsequent genotypic characterization and phylogenetic analyses. A total of 62 bacterial isolates obtained from Tasmanian devils, tentatively classified with the family Pasteurellaceae, were further characterized by phylogenetic analysis of rpoB gene sequence similarity, which showed that the isolates investigated formed five distinct groups. A total of 15 strains formed a novel genus-like group within Pasteurellaceae. Thirty-six strains grouped with the type strain of Frederiksenia canicola. Five strains clustered with the type strain of Pasteurella multocida . Interestingly, four of the P. multocida-like strains were beta-hemolytic when incubated on blood agar, which is atypical for this genus. Five strains grouped with a 100% rpoB similarity with Pasteurella dagmatis. Finally, a single strain showed 97.1% resemblance to Haemophilus haemoglobinophilus. The results demonstrate that Tasmanian devils are hosting a variety of bacterial taxa affiliated with the family of Pasteurellaceae as part of their oral microflora. PMID- 26056875 TI - SURVEY FOR INFECTIOUS DISEASE IN THE SOUTH AMERICAN FUR SEAL (ARCTOCEPHALUS AUSTRALIS) POPULATION AT PUNTA SAN JUAN, PERU. AB - The Peruvian population of the South American fur seal ( Arctocephalus australis ) is a distinct evolutionarily significant unit that is endangered. One of the largest rookeries for this species in Peru is located within the Punta San Juan marine protected area (15 degrees 22'S, 75 degrees 12'W). To better understand the current health status of this population, exposure to 10 pinniped pathogens was evaluated in adult female fur seals (n=29) via serology and polymerase chain reaction (PCR) techniques in November 2010. The results suggest this population is naive to canine and phocine distemper viruses (serum neutralization test), five Leptospira interrogans serovars (microscopic agglutination test), and Brucella canis (card test). Indirect fluorescent antibody testing for Toxoplasma gondii , Neospora caninum , and Sarcocystis neurona was also uniformly negative. PCR testing of nasal swabs using previously described Mycoplasma spp. primers was positive in 37.9% (11/29) of samples. One animal was positive via card test for Brucella abortus , whereas 53.7% (15/28) were positive or suspect using a marine Brucella competitive enzyme-linked immunosorbent assay. Antibody to phocine herpesvirus-1 (PHV-1) was identified in 85.7% (24/28) of the sampled population by serum neutralization testing. Overall, exposure to Mycoplasma spp., Brucella spp., and PHV-1 was observed, but results demonstrated low to no exposure to many key pinniped pathogens. The expansion of human populations, agriculture, and industry along the Peruvian coast may lead to increased pathogen exposure from human, domestic, and wild animal sources. The naive nature of this key population of South American fur seals raises concerns about potential risk for disease outbreaks. PMID- 26056876 TI - DISPOSITION OF CEFTIOFUR AND ITS ACTIVE METABOLITES IN FALLOW DEER (DAMA DAMA) FOLLOWING SINGLE-DOSE INTRAVENOUS AND INTRAMUSCULAR ADMINISTRATION. AB - Septicemia and foot infections associated with Fusobacterium necrophorum , Pasturella multocida, and Streptococcus suis in captive fallow deer (Dama dama) are reasonably treated with ceftiofur hydrochloride. This study describes the disposition of ceftiofur after single-dose intravenous and intramuscular administration of 3.65+/-0.1678 mg/kg in six female adult fallow deer using a nonrandomized crossover design and a 7-day washout period. Serial blood samples were collected for 12 hr postdrug administration. Ceftiofur bioactivity, including its active metabolite desfuroylceftiofur, was quantitated in serum using a microbiologic assay. After i.v. administration, the extrapolated serum drug concentration reported as median (range) was 52.83 (43.32-57.49) MUg/ml and elimination half-life was 178.36 (19.75-217.22) min. The volume of distribution at steady-state was 0.171 (0.101-0.229) L/kg and serum clearance was 0.97 (0.48 4.3) ml/min per kg. After i.m. administration, median peak plasma concentration (Cmax) was 14.37 (9.00-32.00) MUg/ml at 54.5 (11.00-95.00) min. The median elimination half-life and mean residence time were 128.32 (38.03-242.40) and 203.65 (62.48-347.15) min, respectively. The median absorption time after i.m. administration was 14.77 (-57.74 to 94.79) min. Bioavailability of ceftiofur following i.m. administration was 78.00 (58.00-137.00) percent. Based on this study, a mean i.m. dose of ceftiofur of 3.65+/-0.1678 mg/kg every 12 hr is recommended for maintaining serum concentrations above MIC90 levels for infections associated with F. necrophorum, P. multocida, and S. suis, in addition to other susceptible infectious bacteria. PMID- 26056877 TI - PHARMACOKINETICS OF TRAMADOL AND O-DESMETHYLTRAMADOL IN LOGGERHEAD SEA TURTLES (CARETTA CARETTA). AB - The objective of this study was to determine the pharmacokinetics of two orally administered doses of tramadol (5 and 10 mg/kg) and its major metabolite (O desmethyltramadol) (M1) in loggerhead sea turtles (Caretta caretta). After oral administration, the half-life of tramadol administered at 5 and 10 mg/kg was 20.35 and 22.67 hr, whereas the half-life of M1 was 10.23 and 11.26 hr, respectively. The maximum concentration (Cmax) for tramadol after oral administration at 5 mg/kg and 10 mg/kg was 373 and 719 ng/ml, whereas that of M1 was 655 and 1,376 ng/ml, respectively. Tramadol administered orally to loggerhead sea turtles at both dosages provided measurable plasma concentrations of tramadol and O-desmethyltramadol for several days with no adverse effects. Plasma concentrations of tramadol and O-desmethyltramadol remained >=100 ng/ml for at least 48 and 72 hr when tramadol was administered at 10 mg/kg. PMID- 26056878 TI - PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS). AB - Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 MUg hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 MUg/ml was observed at 1.01 hr, with an elimination half life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions. PMID- 26056879 TI - RETROSPECTIVE REVIEW OF THE PREVALENCE OF MYELOLIPOMA IN GOELDI'S MONKEYS (CALLIMICO GOELDII). AB - Myelolipomas are mesenchymal tumors composed of adipose and hematopoietic tissue. They have been reported in many species, including domestic dogs and cats, birds, mustelids, wild felids, and nonhuman primates. Myelolipomas in Callitrichidae have been reported at postmortem examination and rarely antemortem. Multiple cases of hepatic myelolipomas associated with morbidity in Chicago Zoological Society's collection of Goeldi's monkeys (Callimico goeldii) prompted a global retrospective study to determine the prevalence and investigate factors associated with this condition. A total of 842 postmortem examination reports (1965-2013) collected from 133 captive collections were reviewed. Myelolipomas were reported in 17.2% (n=145) of animals, with significantly more female cases than male (P=0.023). There was a significantly older mean age at death in affected animals (134 months) compared to unaffected animals (79 months) (P<0.0001). Myelolipomas were diagnosed in the liver in all affected animals, and rarely in the adrenal or spleen. One in five (22.1%) affected Callimico had notable morbidity associated with this disease, which is markedly different from the primarily benign reports in other species. To identify disease, prevent morbidity from hepatic myelolipoma, and improve care of Callimico species in zoological collections, new Species Survival Plan (SSP) medical management recommendations include incorporating abdominal ultrasonographic examination during routine physical examinations in addition to previously recommended hematological and serum biochemical evaluations. Future studies are merited to examine the prevalence, risk factors, health effects, and treatment options of myelolipoma in living collections. PMID- 26056880 TI - EFFECT OF ACTIVE COOLING AND alpha-2 ADRENOCEPTOR ANTAGONISM ON CORE TEMPERATURE IN ANESTHETIZED BROWN BEARS (URSUS ARCTOS). AB - Hyperthermia is a common complication during anesthesia of bears, and it can be life threatening. The objective of this study was to evaluate the effectiveness of active cooling on core body temperature for treatment of hyperthermia in anesthetized brown bears (Ursus arctos). In addition, body temperature after reversal with atipamezole was also evaluated. Twenty-five adult and subadult brown bears were captured with a combination of zolazepam-tiletamine and xylazine or medetomidine. A core temperature capsule was inserted into the bears' stomach or 15 cm into their rectum or a combination of both. In six bears with gastric temperatures>=40.0 degrees C, an active cooling protocol was performed, and the temperature change over 30 min was analyzed. The cooling protocol consisted of enemas with 2 L of water at approximately 5 degrees C/100 kg of body weight every 10 min, 1 L of intravenous fluids at ambient temperature, water or snow on the paws or the inguinal area, intranasal oxygen supplementation, and removing the bear from direct sunlight or providing shade. Nine bears with body temperature>39.0 degrees C that were not cooled served as control for the treated animals. Their body temperatures were recorded for 30 min, prior to administration of reversal. At the end of the anesthetic procedure, all bears received an intramuscular dose of atipamezole. In 10 bears, deep rectal temperature change over 30 min after administration of atipamezole was evaluated. The active cooling protocol used in hyperthermic bears significantly decreased their body temperatures within 10 min, and it produced a significantly greater decrease in their temperature than that recorded in the control group. PMID- 26056881 TI - GAIT ANALYSIS IN GIANT ANTEATER (MYRMECOPHAGA TRIDACTYLA) WITH THE USE OF A PRESSURE-SENSITIVE WALKWAY. AB - The aim of this study was to evaluate the kinetic and temporospatial parameters of clinically healthy juvenile giant anteaters (Myrmecophaga tridactyla) by using a pressure-sensing walkway. Three free-ranging clinically healthy giant anteaters (M. tridactyla), two males and one female, aged 5-7 mo, were used. There was no statistically significant difference between the right and left sides for the kinetic and temporospatial parameters for both forelimbs and hind limbs. Although the gait velocity was similar for all giant anteaters, the stride frequency was higher in the smaller anteaters. The difference in stride frequency is associated with body size, which also influenced other temporospatial parameters. The percentage of body distribution was higher on the forelimbs than the hind limbs. The contact surface and trajectory of the force of the forepaws differed from the hind paws. In conclusion, the anteaters have gait peculiarities associated with the anatomical differences between forelimbs and hind limbs. PMID- 26056882 TI - IMMOBILIZATION OF CAPTIVE NUBIAN IBEX (CAPRA NUBIANA) WITH BUTORPHANOL-MIDAZOLAM MEDETOMIDINE OR BUTORPHANOL-AZAPERONE-MEDETOMIDINE AND ATIPAMEZOLE REVERSAL. AB - Seventeen captive Nubian ibex (Capra nubiana) were immobilized for transportation and/or hoof trimming, deworming, and vaccinations. Of these, 11 were immobilized with a combination of butorphanol (0.13+/-0.03 mg/kg), midazolam (0.13+/-0.03 mg/kg), and medetomidine (0.13+/-0.03 mg/kg) (BMM), and 6 were immobilized with a combination of butorphanol (0.11+/-0.03 mg/kg), azaperone (0.22+/-0.06 mg/kg), and medetomidine (0.11+/-0.03 mg/kg) (BAM) by intramuscular injection. Induction and recovery times were recorded. Heart rate, respiratory rate, rectal temperature, blood pressure, and oxygen saturation were measured. The quality of induction, immobilization, and recovery were scored (scale 1-5; 1=poor, 5=excellent). Mean induction time was significantly shorter in the BMM group versus the BAM group (8.8+/-2.7 and 20.1+/-7.8 min, respectively). Median induction score and median immobilization score were significantly higher (i.e., better) in the BMM group than the BAM group (5 versus 2.5 and 4 versus 3, respectively). The mean and diastolic blood pressures were significantly higher in the BMM group at the 25-min time point. Atipamezole was administered at the end of procedures, and all ibex recovered smoothly. Mean recovery time was significantly longer in the BMM group versus the BAM group (9.5+/-4.3 and 3.3+/ 2.2, respectively). In conclusion, at the doses used, the combination of BMM was superior to BAM for short-term immobilization in captive Nubian ibex. PMID- 26056883 TI - PREVALENCE, BIOCHEMICAL CHARACTERISTICS, AND ANTIBIOTIC SUSCEPTIBILITY OF AEROMONADS, VIBRIOS, AND PLESIOMONADS ISOLATED FROM DIFFERENT SOURCES AT A ZOO. AB - Aeromonas spp., Vibrio parahaemolyticus , and Plesiomonas shigelloides are commonly implicated in foodborne and waterborne diarrheal illnesses of humans and other animals. The present study assessed the prevalence, biochemical characteristics, and antibiotic susceptibility of Aeromonas spp., V. parahaemolyticus , and P. shigelloides by analyzing samples from 729 sources at a zoo, including animal feces (n=607), watering facilities (n=104), and pond water samples (n=18). Of the 729 samples collected, 40 (5.5%) contained one of these four species of bacteria: A. hydrophila (n=16; 2.2%), A. sobria (n=12; 1.6%), V. parahaemolyticus (n=10; 1.4%), and P. shigelloides (n=2; 0.3%). The 16 isolates of A. hydrophila came from three fecal samples, eight watering facilities, and five pond water samples. The 12 isolates of A. sobria came from four fecal samples, three watering facilities, and five pond water samples. The 10 isolates of V. parahaemolyticus came from one fecal sample and nine watering facilities. The two isolates of P. shigelloides came from one watering facility and one pond water sample. Of the 40 isolates, 16 (40.0%), 21 (52.5%), and three (7.5%) originated from mammals, birds, and reptiles, respectively. All isolates tested positive for NO3, tryptophan, p-nitrophenyl-beta-D-galactopyranoside, glucose assimilation, N-acetyl-glucosamine, maltose, gluconate, malate, and oxidase. Aeromonas spp. and V. parahaemolyticus exhibited similar biochemical characteristics, whereas P. shigelloides exhibited distinct fermentation characteristics. All the isolated strains exhibited hemolytic activity; variable results of DNase, protease, and Congo red uptake tests; and resistance to ampicillin, bacitracin, novobiocin, penicillin, and vancomycin. All the strains were sensitive to amikacin, chloramphenicol, colistin, gentamicin, kanamycin, norfloxacin, and trimethoprim-sulfadimethoxazole. Because of the high proportion of asymptomatic carriers of these potentially pathogenic bacteria and their wide distribution, consistent monitoring of food and water sources is necessary to prevent disease outbreaks. PMID- 26056884 TI - INDUCTION OF CYTOKINE PRODUCTION IN CHEETAH (ACINONYX JUBATUS) PERIPHERAL BLOOD MONONUCLEAR CELLS AND VALIDATION OF FELINE-SPECIFIC CYTOKINE ASSAYS FOR ANALYSIS OF CHEETAH SERUM. AB - Peripheral blood mononuclear cells (PBMCs) were isolated from the whole blood of cheetahs (Acinonyx jubatus ; n=3) and stimulated with lipopolysaccharides (LPS) to induce the production of proinflammatory cytokines TNF-alpha, IL-1beta, and IL 6 for establishment of cross-reactivity between these cheetah cytokines and feline-specific cytokine antibodies provided in commercially available Feline DuoSet(r) ELISA kits (R&D Systems, Inc., Minneapolis, Minnesota 55413, USA). This study found that feline-specific cytokine antibodies bind specifically to cheetah proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6 from cell culture supernatants. The assays also revealed that cheetah PBMCs produce a measurable, cell concentration-dependent increase in proinflammatory cytokine production after LPS stimulation. To enable the use of these kits, which are designed for cell culture supernatants for analyzing cytokine concentrations in cheetah serum, percent recovery and parallelism of feline cytokine standards in cheetah serum were also evaluated. Cytokine concentrations in cheetah serum were approximated based on the use of domestic cat standards in the absence of cheetah standard material. In all cases (for cytokines TNF-alpha, IL-1beta, and IL-6), percent recovery increased as the serum sample dilution increased, though percent recovery varied between cytokines at a given dilution factor. A 1:2 dilution of serum resulted in approximately 45, 82, and 7% recovery of TNF-alpha, IL-1beta, and IL-6 standards, respectively. Adequate parallelism was observed across a large range of cytokine concentrations for TNF-alpha and IL-1beta; however, a significant departure from parallelism was observed between the IL-6 standard and the serum samples (P=0.004). Therefore, based on our results, the Feline DuoSet ELISA (R&D Systems, Inc.) kits are valid assays for the measurement of TNF-alpha and IL-1beta in cheetah serum but should not be used for accurate measurement of IL-6. PMID- 26056885 TI - CARDIOTHORACIC RATIO AND VERTEBRAL HEART SCALE IN CLINICALLY NORMAL BLACK-RUMPED AGOUTIS (DASYPROCTA PRYMNOLOPHA, WAGLER 1831). AB - Wild rodents, such as the lowland paca (Cuniculus paca), capybara (Hydrochoerus hydrochaeris), rock cavy (Kerodon rupestris), guinea pig (Cavia aperea), and black-rumped agouti (Dasyprocta prymnolopha) are intensely hunted throughout Amazonia and at the semiarid regions of northeastern Brazil. To contribute to the preservation of these species, more information about their anatomy, physiology and pathophysiology is needed. The aim of this study was to standardize the vertebral heart scale (VHS) and cardiothoracic ratio (CTR) in clinically normal black-rumped agouti, as well as to compare the results of these two methods, which are commonly used to evaluate the cardiac silhouette in domestic animals. Twelve healthy black-rumped agoutis, divided into two groups (six males and six females), obtained from the Nucleus for Wild Animal Studies and Conservation at the Federal University of Piaui, were radiographed in right and left lateral and dorsoventral projections. The values of the VHS were 8.00+/-0.31v (the number of thoracic vertebral length spanned by each dimension, starting at T4) for males and 8.11+/-0.41v for females, and there was no statistical difference between the decubitus (right and left) or between males and females (P>0.05). The CTR mean values obtained were 0.51+/-0.03 for males, and 0.52+/-0.02 for females, and there was no statistical difference between the genders (P>0.05). However, there was positive correlation between VHS and CTR (r=0.77 right decubitus and r=0.82 left decubitus). The thoracic and heart diameter had mean values of 6.72+/-0.61 and 3.48+/-0.30 cm (males), and for the females, it was 6.61+/-0.51 and 3.5+/ 0.30 cm, respectively, and there was statistical difference between the genders. The results demonstrated high correlation between the VHS and CTR producing similar results, indicating similar clinical precision for assessing the size of the cardiac silhouette in the black-rumped agoutis. PMID- 26056886 TI - USE OF COMPUTED TOMOGRAPHY FOR INVESTIGATION OF HEPATIC LIPIDOSIS IN CAPTIVE CHELONOIDIS CARBONARIA (SPIX, 1824). AB - Computed tomography is a sensitive and highly applicable technique for determining the degree of radiographic attenuation of the hepatic parenchyma. Radiodensity measurements of the liver can help in the diagnosis of hepatic lipidosis in humans and animals. The objective was to investigate the presence of hepatic lipidosis in captive red-footed tortoises (Chelonoidis carbonaria) using computed tomography. Computed tomography was performed in 10 male red-footed tortoises. Mean radiographic attenuation values for the hepatic parenchyma were 11.2+/-3.0 Hounsfield units (HU). Seven red-footed tortoises had values lower than 20 HU, which is compatible with C. carbonaria hepatic lipidosis. These results allowed an early diagnosis of the hepatic changes and suggested corrective measures regarding feeding and management protocols. PMID- 26056887 TI - RETROSPECTIVE EVALUATION OF CASES OF NEOPLASIA IN A CAPTIVE POPULATION OF EGYPTIAN FRUIT BATS (ROUSETTUS AEGYPTIACUS). AB - Reports of neoplasia in Chiroptera species are rare. (6, 10) This retrospective study describes five types of neoplasia identified within a captive population of male Egyptian fruit bats (Rousettus aegyptiacus) housed in a zoo from 2004 through November of 2014. Tumor types identified include fibrosarcoma, cutaneous lymphoma, benign focal bronchioloalveolar neoplasm, anaplastic sarcoma, and sebaceous epithelioma. To the author's knowledge, aside from a recent report of focal brochioloalveolar adenoma, (8) these tumor types have not previously been described in the Rousettus species, nor in chiropterans in general. Based upon these findings and other recent publications regarding R. aegyptiacus, neoplasia does appear to be a significant cause of morbidity and mortality in captive members of this megachiropterid species. PMID- 26056888 TI - SQUAMOUS CELL CARCINOMA IN A NINE-BANDED ARMADILLO (DASYPUS NOVEMCINCTUS). AB - Squamous cell carcinomas (SCCs) are tumors that occur in most animals and show strong invasiveness into surrounding tissues and nearby osseous tissues. This report describes a case of SCC in a 5-yr-old female nine-banded armadillo (Dasypus novemcinctus) with a hemorrhagic mass on the left mandibular region. The tumor originated in skin tissues and showed invasion of the oral cavity, adjacent to the submandibular salivary gland histologically. To our knowledge, this is the first report of a SCC in a nine-banded armadillo. PMID- 26056889 TI - CHARACTERIZATION OF NATURAL EJACULATES AND SPERM CRYOPRESERVATION IN A GOLDEN EAGLE (AQUILA CHRYSAETUS). AB - This paper describes the sperm characteristics and response to cooling and freezing of naturally ejaculated semen from a captive, adult golden eagle (Aquila chrysaetus) trained to allow sperm recovery via cooperative copulation. A basic spermiogram was prepared, and sperm motility and morphometric variables recorded using a computer-aided system. For sperm storage, the effects of a polyvinylpyrrolidone-based extender were evaluated at 5 degrees C. The same extender was also used in freezing procedures in which glycerol (11%) and dimethylacetamide (6%) were compared as cryoprotectants. The extender preserved sperm viability over storage periods of up to 6 days. Although sperm motility and percentage live sperm values were poorer for frozen-thawed (5.8-14.6% and 44-42%, respectively) than for fresh samples (46.7 and 74.6%, respectively), no differences were seen between the effects of the two cryoprotectants. These results could be of use when attempting to store the sperm of golden eagles and other raptors. PMID- 26056890 TI - IDENTIFICATION OF MYCOBACTERIUM GENAVENSE IN A DIANA MONKEY (CERCOPITHECUS DIANA) BY POLYMERASE CHAIN REACTION AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY. AB - A 25-yr-old Diana monkey (Cercopithecus diana) with a 1.5-yr history of chronic colitis and diarrhea was found to have disseminated granulomatous disease with intralesional acid fast bacilli. Bacilli were identified as Mycobacterium genavense by polymerase chain reaction, sequencing of the 16S-23S ribosomal RNA intergenic spacer (ITS) gene, and mycolic acid analysis by high-performance liquid chromatography. Mycobacterium genavense is a common cause of mycobacteriosis in free-ranging and captive birds. In addition, recognition of opportunistic infection in human immunodeficiency virus-positive patients is increasing. Disease manifestations of M. genavense are similar to Mycobacterium avium complex (MAC) and include fever, wasting, and diarrhea with disseminated disease. Similar clinical signs and lesions were observed in this monkey. Mycobacterium genavense should be considered as a differential for disseminated mycobacterial disease in nonhuman primates as this agent can mimic MAC and related mycobacteria. PMID- 26056891 TI - EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY AND ENDOSCOPIC URETERAL STENT PLACEMENT IN AN ASIAN SMALL-CLAWED OTTER (AONYX CINEREA) WITH NEPHROLITHIASIS. AB - Urolithiasis is a significant disease concern in Asian small-clawed otters (Aonyx cinerea), with over 60% of captive animals affected. Bilateral ureteral stent placement, using endoscopic and fluoroscopic guidance, and extracorporeal shock wave lithotripsy (ESWL) were performed as salvage procedures in a 13-yr-old intact female Asian small-clawed otter following a 7-yr history of nephrolithiasis and progressive renal insufficiency. Following the procedure, radiographs revealed a slight shifting of urolith position, although a decrease in urolith mass was not observed. As a result of declining quality of life related to severe osteoarthritis, the otter was euthanized 5 wk after the procedure. While this treatment approach was unsuccessful in this case, the technique was clinically feasible, so ESWL and ureteral stent placement may remain a consideration for other individuals of this species presented earlier in the course of this disease. PMID- 26056892 TI - FILAMENTOUS FUNGI ISOLATED FROM THE FUR MICROBIOTA OF CALLITRICHIDS KEPT IN CAPTIVITY IN BRAZIL. AB - This study aimed to isolate filamentous fungi from the fur of primates of the genus Callithrix kept in the Centre for Rehabilitation of Wild Animals (CRWA) at the Tiete Ecological Park, Sao Paulo, SP, Brazil. Samples of the fur of 19 specimens of black-tufted marmosets (Callithrix penicillata) and 6 specimens of white-tufted-ear marmosets (Callithrix jacchus) were obtained by the square carpet technique. The samples were plated on MycoselTM agar medium (DifcoTM) and incubated at 25 degrees C for 21 days. The identification of each isolated mold was based on its macroscopic and microscopic features and followed classical recommendations. The following filamentous fungi were isolated: Penicillium spp. (76%), Cladosporium spp. (60%), Acremonium spp. (44%), Scopulariopsis spp. (24%), Aspergillus spp. (16%), Chrysosporium spp. (16%), and Fusarium spp. (8%). Dermatophyte fungi were not detected. We conclude that C. penicillata and C. jacchus kept in captivity are sources of potentially pathogenic filamentous fungi that may represent a risk factor for immunocompromised individuals who may eventually establish contact with them. PMID- 26056893 TI - APPLICATION OF NONINVASIVE PREGNANCY DIAGNOSIS IN BACTRIAN CAMELS (CAMELUS BACTRIANUS) USING CUBONI REACTION AND BARIUM CHLORIDE TEST. AB - Pregnancy diagnoses in half-tamed animals are often very complicated. This study aimed to examine the alternative noninvasive and cheap methods of pregnancy diagnosis from urine in domestic Bactrian camels (Camelus bactrianus). Urine from 14 female camels kept in four European zoologic gardens was collected and tested by two chemical tests--Cuboni reaction and barium chloride test. The Cuboni reaction was significantly (P<0.01) affected by the pregnancy status of female camels. The total accuracy of the Cuboni reaction was 70.5% but it increased significantly (P<0.05) in the time leading up to parturition. The accuracy was 100% in the 3rd third of pregnancy. Urine of nonpregnant females did not react with a solution of barium chloride while, contrary to other studies, white precipitates formed mostly (80 to 100%) in urine of pregnant females. This study concluded that the Cuboni reaction is applicable for pregnancy diagnosis in camels. PMID- 26056894 TI - SURGICAL CORRECTION OF BILATERAL PATELLAR LUXATION IN AN AMERICAN BLACK BEAR CUB (URSUS AMERICANUS). AB - A wild orphaned male American black bear cub ( Ursus americanus ) presented with hind limb gait abnormalities and was found to have bilateral grade 3 laterally luxating patellas. There were no other significant abnormalities detected on neurologic, radiographic, or hematologic examinations. The trochlear grooves were deepened with a chondroplasty, and the redundant soft tissues imbricated. There was a marked improvement in the bear's gait postoperatively, with an apparent full return to function. To the authors' knowledge, patellar luxation has not been reported in the Ursidae family, and the success in this case suggests that this technique may be used in large wild or captive carnivore cubs. PMID- 26056895 TI - DENTAL LESIONS IN THE LOWLAND TAPIR (TAPIRUS TERRESTRIS). AB - Dental ailments, mandibular swelling, and dentoalveolar abscesses are common in tapirs, but knowledge about prevalence or etiology of these lesions in the Tapiridae family in general, and in lowland tapirs (Tapirus terrestris) in particular, is scarce. A recent study identified resorptive lesions of unknown etiology as a common problem in the Malayan tapir (Tapirus indicus). In order to investigate the type and prevalence of dental lesions occurring in lowland tapirs, and to compare these with findings with the Malayan tapir, skulls and teeth from 46 deceased lowland tapirs were visually and radiographically examined. The specimens were divided into subpopulations according to age (juveniles, young adults, adults) and origin (free-range or captive). Dental lesions were identified in 24% (11/46) of the study population. The most common pathologic findings were complicated dental fractures with associated periapical reaction (15%) and periapical reactions of various degrees without associated detectable dental pathology (13%). All these lesions likely originated from dental trauma. As in Malayan tapirs, juveniles had significantly fewer lesions than adults. This study shows that dental lesions present frequent problems for lowland tapirs, occurring both in captive and in free-ranging individuals, and indicates that increasing age should be considered a risk factor for the development of these lesions. Notably, the predominant dental problems in lowland tapirs and Malayan tapirs are not the same. PMID- 26056896 TI - DIAGNOSIS AND SUCCESSFUL TREATMENT OF EIMERIA INFECTION IN A GROUP OF ZOO-KEPT BLACK-TAILED PRAIRIE DOGS (CYNOMYS LUDOVICIANUS). AB - A group of seven, zoo-kept, male black-tailed prairie dogs (Cynomys ludovicianus) were examined as part of their quarantine health evaluation. Microscopic fecal examination demonstrated that all animals were passing oocysts of Eimeria spp. All prairie dogs were treated individually with ponazuril (30 mg/kg p.o.) administered in two treatments 48 hr apart. Three weekly pooled fecal samples following treatment were negative, suggesting clearing of the infection. No adverse clinical signs were noted. Most of the reported anti-coccidian treatments in rodents describe prolonged treatment protocols or administration of treatment in the water, which can result in unnecessary stress and handling or ineffective and uncontrolled level of drug administration, respectively. This is the first report of this treatment protocol in a rodent species, suggesting it is efficacious, easy to administer, and safe when treating similar infections in prairie dogs. PMID- 26056897 TI - FATAL CASE OF STREPTOCOCCUS SUIS INFECTION IN A YOUNG WILD BOAR (SUS SCROFA) FROM SOUTHWESTERN SPAIN. AB - Streptococcus suis is a recognized pathogen that may cause important diseases in pigs and humans. This microorganism has been repeatedly isolated from wild boar (Sus scrofa). However, its health implications for this wild species are still unknown. This article reports a detailed description of a fatal case of septicemia by S. suis affecting a young wild boar. The affected animal, about 15 days old, was found near death and exhibiting neurologic signs at a wild boar estate in southwestern Spain. Postmortem examination showed generalized congestion, brain hemorrhages and lobular pneumonia. Histopathological evaluation demonstrated the presence of meningitis and encephalitis with marked congestion and suppurative bronchopneumonia. Streptococcus suis serotype 2 isolates exhibiting important virulence factors (extracellular factor, muramidase-released protein, and suylisin) were isolated from the affected animal. This study confirms the presence of potentially virulent and zoonotic strains of S. suis in wild boar from Spain. PMID- 26056898 TI - OVARIECTOMY IN A COMMON HIPPOPOTAMUS (HIPPOPOTAMUS AMPHIBIUS). AB - Common hippopotami (Hippopotamus amphibius) introduced to Colombia in the 80s have since spread into livestock areas. Measures such as breeding control are needed to prevent further uncontrolled population growth. A young female hippopotamus was moved to a university veterinary hospital and anesthetized. Laparoscopic ovariectomy was attempted, but because of the difficulty of inserting the trocars in an apparently lax peritoneum, lateral laparotomy was performed. Both ovaries were transected with the use of an ultrasonic hemostatic device and clamping. Patient recovery was completely successful and the wound healed with few complications. To the authors' knowledge, this is the first report describing a successful ovariectomy in a hippopotamus. PMID- 26056899 TI - INFECTION OF A GOELDI'S MONKEY (CALLIMICO GOELDII) WITH A EUROPEAN STRAIN OF ECHINOCOCCUS MULTILOCULARIS IN A CANADIAN INSTITUTION. AB - A 12-yr-old female Goeldi's monkey (Callimico goeldii) in British Columbia, Canada was diagnosed with alveolar echinococcosis (AE) on postmortem examination. Echinococcus multilocularis has been identified in several species of nonhuman primates, most frequently Old World primates, in zoos and research facilities in Europe and Asia. The strain affecting this monkey was identified as a European haplotype, indistinguishable from E. multilocularis recently identified in several canids in British Columbia. The animal is suspected to have been exposed while living in a zoological institution in Alberta, where E. multilocularis has also been reported in urban coyotes. Alveolar echinococcosis is a zoonotic disease of increasing concern in the United States and Canada, and this disease should be considered on the differential list of any nonhuman primate exhibiting signs of abdominal pain or distension, along with diagnostic imaging consistent with cystic structures of the liver or other organs. PMID- 26056900 TI - PRESUMPTIVE DYSGERMINOMA IN AN ORANGE-SPOT FRESHWATER STINGRAY (POTAMOTRYGON MOTORO). AB - A captive-born, 13-yr-old female orange-spot freshwater stingray, (Potamotrygon motoro), presented with an acute caudodorsal swelling. Ultrasonography revealed an intracoelomic mass of mixed echogenicity containing fluid pockets. The ray was euthanatized and gross postmortem examination confirmed the presence of a fluid filled coelomic mass in the region of the reproductive tract. The mass was identified histologically as a malignant round cell tumor of the ovary. Although immunohistochemistry for protein gene product 9.5 (PGP9.5), octamer-3/4 (OCT 3/4), and inhibin was attempted, antibodies that had been validated in mammalian species did not cross-react with stingray control tissues and did not label neoplastic cells. The final diagnosis was a presumptive dysgerminoma. PMID- 26056901 TI - DIAGNOSIS AND PALLIATIVE MANAGEMENT OF ATOPIC DERMATITIS IN A MALAYAN FLYING FOX (PTEROPUS VAMPYRUS). AB - A 7-yr-old male Malayan flying fox (Pteropus vampyrus) presented with chronic, recurrent bilateral conjunctivitis and palpebral chemosis. Variable, temporary response to topical ocular antibiotic-corticosteroid therapy occurred. Histopathology of a conjunctival biopsy was consistent with allergic conjunctivitis. The bat was treated systemically with antihistamines and topically with an ocular antibiotic-corticosteroid combination for acute episodes of conjunctivitis. Pruritus, severe alopecia of the head and neck, and moist dermatitis later developed in conjunction with bilateral conjunctivitis. Cytology and histopathology of affected skin supported a diagnosis of atopic dermatitis. Although the assay was not validated for P. vampyrus, serum immunoglobulin E levels against multiple possible antigens were measured. Acceptable resolution of clinical signs was achieved for 20 mo following systemic cyclosporine administration. Cyclosporine levels were measured in whole blood for additional therapeutic monitoring. This is the first reported case of histopathologic support for atopic dermatitis, novel diagnostics, and palliative management of atopy using cyclosporine in a flying fox. PMID- 26056902 TI - FATAL ENCEPHALOMYOCARDITIS VIRUS INFECTION IN AN AFRICAN SAVANNA ELEPHANT (LOXODONTA AFRICANA) IN A FRENCH ZOO. AB - A fatal case of encephalomyocarditis virus (EMCV) involving an African elephant ( Loxodonta africana ) occurred in November 2013 at the Reserve Africaine de Sigean, France. An adult female was found dead without any preliminary symptoms. Gross pathologic changes consisted of petechiae and hemorrhages on mucosae and internal organs, abundant transudate in the abdominal and pericardial cavities, and myocarditis. Histopathologic examination showed extensive degeneration and necrosis of ventricular cardiomyocytes with concurrent lymphoplasmocytic and eosinophilic infiltrate. An EMCV was isolated from several organs and considered the causative agent of the myocarditis. The same strain of virus was also isolated in rodents captured on zoo premises and considered to be the reservoir of the virus. To the authors' knowledge, this is the first EMCV case in a captive African elephant in Europe. PMID- 26056903 TI - SURGICAL TREATMENT OF PULMONARY MELANOPHOROMA IN A BEADED LIZARD (HELODERMA HORRIDUM EXASPERATUM). AB - An adult male Rio Fuerte beaded lizard (Heloderma horridum exasperatum) was examined because of a history of anorexia and lethargy of one week duration. Diagnostic tests included a physical exam, complete blood cell count, plasma biochemistries, whole-body radiographs, and ultrasonography. The physical exam revealed the presence of a large mass in the midcoelomic cavity. Radiographs confirmed the presence of the midcoelomic mass and showed a smaller mass in the right cranial lung field. The ultrasonogram showed a homogeneous mass with soft tissue echogenicity. A fine-needle aspirate was collected, and the cytology results were suggestive of a melanophoroma. Exploratory surgery revealed a large mass (10*6 cm) within the right lung, with extensive adhesions to the caudolateral margin of the right liver lobe. The smaller mass (2*3 cm) was within the cranial aspect of the right lung. A right pulmonectomy and partial hepatectomy were performed to remove the tumors. The animal died 3.5-yr postsurgery, and histopathologic evaluation did not show evidence of melanophoroma in any of the tissues evaluated. PMID- 26056904 TI - SOLITARY T-CELL HEPATIC LYMPHOMA WITH LARGE GRANULAR LYMPHOCYTE MORPHOLOGY IN A CAPTIVE CHEETAH (ACINONYX JUBATUS). AB - A 13-yr-old male cheetah (Acinonyx jubatus) presented for an acute history of lateral recumbency and anorexia. Upon physical examination under general anesthesia, severe icterus was noted. A serum biochemical profile confirmed markedly elevated total bilirubin and alanine transaminase. Based on ultrasound guided liver aspirates and cytology, a presumptive diagnosis of large granular lymphocyte hepatic lymphoma was reached. Abdominal and thoracic radiographs did not assist in reaching an antemortem diagnosis. Postmortem examination and histopathology provided a definitive diagnosis of hepatic lymphoma with acute massive hepatocelluar necrosis and hemorrhage, as well as concurrent lesions of gastric ulcers, ulcerative and sclerosing enteritis, myocardial hypertrophy, and splenic myelolipomas. Immunohistochemistry of the liver yielded CD-3 positive and CD-20 negative results, confirming lymphocytes of a T-cell lineage. Due to concern for possible retrovirus-associated disease, enzyme-linked immunosorbent assays for feline leukemia virus and feline immunodeficiency virus were performed retrospectively on a banked serum sample and yielded negative results, thus diminishing concern for the male conspecific housed in the same exhibit. PMID- 26056905 TI - ABDOMINAL PREGNANCY IN A SERVAL (LEPTAILURUS SERVAL) SECONDARY TO UTERINE RUPTURE. AB - A 14-yr-old female serval (Leptailurus serval) died unexpectedly after 2 wk of inappetence and lethargy. Necropsy revealed a pyoabdomen with a full-term, well developed fetus in the caudal abdomen covered by a mesenteric sac. The mesenteric sac communicated with a tear in the wall of the right uterine horn, supporting a diagnosis of secondary abdominal pregnancy. The uterine wall had evidence of adenomyosis at the rupture site with no evidence of pyometra. The fetus, supporting mesentery, and peritoneum were coated with mixed bacteria, which may have ascended through an open cervix to the site of uterine rupture. This is the first case of abdominal pregnancy related to uterine rupture reported in a large felid species. PMID- 26056906 TI - CUTANEOUS EPITHELIOTROPIC T-CELL LYMPHOMA WITH METASTASES IN A VIRGINIA OPOSSUM (DIDELPHIS VIRGINIANA). AB - A 2-yr-old, captive, intact female Virginia opossum ( Didelphis virginiana ) with a 7-mo history of ulcerative dermatitis and weight loss was euthanatized for progressive worsening of clinical signs. Initially the opossum was treated with several courses of antibiotics, both topically and systemically; systemic nonsteroidal anti-inflammatory medication; and, later, systemic glucocorticoids, with no improvement in clinical signs. Histopathologic samples of skin lesions taken 3 mo into the course of disease revealed no evidence of neoplasia; however, cytologic samples of a skin lesion taken 5 mo into the course of disease revealed mature lymphocytes, and were suggestive of cutaneous lymphoma. Postmortem histopathology revealed neoplastic cells consistent with lymphoma; these were found in the haired skin of the forearm, axilla, hind limb, face, and lateral body wall, as well as the liver, kidney, axillary lymph node, heart, and spleen. Multifocal neutrophilic and eosinophilic ulcerative and necrotizing dermatitis and folliculitis of the haired skin were also present. To the authors' knowledge, this is the first documented case of cutaneous lymphoma in a Virginia opossum and the first documented case with visceral metastases in a marsupial. PMID- 26056907 TI - LAPAROSCOPIC GASTROPEXY FOR CORRECTION OF A HIATAL HERNIA IN A NORTHERN ELEPHANT SEAL (MIROUNGA ANGUSTIROSTRIS). AB - A female northern elephant seal (Mirounga angustirostris) weaned pup presented with malnutrition. During rehabilitation, the seal developed regurgitation and reduced lung sounds on auscultation. Radiographs and endoscopy performed under sedation suggested a diaphragmatic hernia. A Type I (or sliding) hiatal hernia was confirmed with a positive contrast upper gastrointestinal study, revealing varying degrees of herniation of the gastric fundus through the diaphragm into the caudal thorax as well as esophageal reflux. The animal was treated preoperatively with an H2 antagonist and antinausea medication. A laparoscopic gastropexy was performed under general anesthesia. The animal recovered well postoperatively and resolution of clinical signs was achieved. The animal was released back into the wild 21 kg above admit weight. To our knowledge, we report here the first surgical correction of a hiatal hernia in a marine mammal. PMID- 26056908 TI - COMPARISON OF TWO alpha2-ADRENERGIC AGONISTS ON URINE CONTAMINATION OF SEMEN COLLECTED BY ELECTROEJACULATION IN CAPTIVE AND SEMI-FREE-RANGING CHEETAH (ACINONYX JUBATUS). AB - Alpha2-adrenergic agonists are used to immobilize many veterinary species, but use has been infrequently linked to urine contamination of semen collected via electroejaculation. The objective of the study was to compare the alpha2-agonists medetomidine and dexmedetomidine on urine contamination of semen in anesthetized cheetahs (Acinonyx jubatus) during electroejaculation procedures. From 2009-2012, a retrospective medical record review revealed 21 anesthesia events in 12 adult male cheetahs. Animals were immobilized with combinations of Telazol(r) (2.33+/ 0.43 mg/kg) and ketamine (2.38+/-1 mg/kg); Telazol (1.17+/-0.14 mg/kg), ketamine (1.17+/-0.14 mg/kg), and medetomidine (0.012+/-0.0017 mg/kg); or Telazol (1.59+/ 0.1 mg/kg), ketamine (1.59+/-0.1 mg/kg) and dexmedetomidine (0.01+/-0.001 mg/kg). Semen was successfully collected in all animals; four animals anesthetized with medetomidine had urine contamination (P=0.037). Medetomidine may contribute to urine contamination; however, further investigation is needed to determine significance in cheetahs. PMID- 26056909 TI - MEASUREMENT OF INTRAOCULAR PRESSURE USING TONOVET(r) IN EUROPEAN POND TURTLE (EMYS ORBICULARIS). AB - Twenty-two captive adult European pond turtles (12 males and 10 females) were unrestrained without sedation while intraocular pressure (IOP) was measured by means of a Tonovet(r). Mean+/-SD IOP values between 8 and 10 am for all turtles were 5.42+/-0.96 mm Hg (range, 3-9 mm Hg). IOP between the right and left eye and between males and females was not significantly different. There was no correlation between IOP and body weight or body length of animals. PMID- 26056910 TI - SUSPECTED LYME BORRELIOSIS IN A CAPTIVE ADULT CHIMPANZEE (PAN TROGLODYTES). AB - An 18-yr-old female captive-born chimpanzee (Pan troglodytes) presented with an intermittent history of inappetence, lethargy, and lower limb stiffness. No notable abnormalities were found on exam or complete blood cell count and serum biochemistry analysis. Serologic testing was strongly positive via indirect fluorescent antibody testing and Western blot for Borrelia burgdorferi. Treatment with doxycycline was initiated, and a clinical response was seen within 1 wk. Convalescent serum exhibited an eightfold increase in titer. Serologic testing was performed on several conspecifics with banked serum; while some low positive titers were present and presumed indicative of past exposure, no titer was elevated to the extent of the affected chimpanzee during its course of disease. To the authors' knowledge, this is the first report of suspected Lyme borreliosis in a great ape species, and the case originates from an area of the United States with a high incidence of human borreliosis. PMID- 26056911 TI - DIAGNOSIS AND MEDICAL AND SURGICAL MANAGEMENT OF CHRONIC INFECTIOUS FIBRINOUS PLEURITIS IN AN OKAPI (OKAPIA JOHNSTONI). AB - A 10-yr-old female okapi (Okapia johnstoni) at the San Diego Zoo Safari Park was evaluated for intermittent malaise, inappetence, occasional cough, abdominal splinting, and licking at both flanks. Physical examination revealed tachypnea, tachycardia, and fluid sounds on thoracic auscultation. Transthoracic ultrasound showed multiple uniform, anechoic filled structures in the right and left pleural space. Surgical exploration of the thoracic cavity revealed bilateral, mature, fibrous, compartmentalizing adhesions between the visceral and parietal pleura, confirming a diagnosis of chronic, infectious, fibrinous pleuritis. The suspected etiology was occult aspiration pneumonia secondary to historical episodes of regurgitation associated with general anesthesia. Culture of the pleural fluid and fibrous adhesions grew Trueperella (Arcanobacterium) pyogenes, Arcanobacterium haemolyticum, and few Fusobacterium species. Treatment consisted of chest-tube placement to establish drainage, thoracic lavage, unilateral surgical debridement, and long-term antibiotics. The animal made a complete clinical recovery over 7 mo. PMID- 26056912 TI - CHARACTERIZATION OF A FOLLICULAR CELL CARCINOMA OF THE THYROID IN A YELLOWBAR ANGELFISH (POMACANTHUS MACULOSUS). AB - Histopathologic diagnosis of thyroid neoplasia in teleosts is complicated, because thyroid tissue is unencapsulated, and normal tissue can have wide ectopic extensions. Assessment of thyroid hormone concentrations in conjunction with histologic evaluation of thyroid carcinoma has not been reported in teleosts, even though routinely performed in other species. A yellowbar angelfish (Pomacanthus maculosus) presented with a mass that extended beyond the gill arches. Partial surgical resection was performed, and a histologic diagnosis of thyroid carcinoma was made. Plasma from the affected fish and two control Pomacanthus were used to assess thyroid hormone concentrations using a domestic mammalian assay. Thyroid-stimulating hormone and throxine were undetectable in two of three fish. Triiodothyronine was lower in the affected fish than in controls. The tumor did not appear to be actively secreting hormone. This is the first characterization of thyroid tumors and corresponding thyroid hormones in teleosts, which may assist in diagnosis of this disease. PMID- 26056913 TI - THADEUA GREENI-ASSOCIATED DERMATITIS IN AN EASTERN BETTONG (BETTONGIA GAIMARDI). AB - An adult female bettong (Bettongia gaimardi) presented with extensive alopecia and dermatitis affecting the ventral and lateral aspects of the neck and thorax. Microscopic examination of skin scrapings collected from the affected area revealed large numbers of the dermanyssid mite Thadeua greeni. A histopathologic diagnosis of chronic proliferative and hyperkeratotic perivascular dermatitis with intralesional mites was returned. Treatment with a combination of topical fipronil and parenteral ivermectin weekly for 3 wk resulted in the resolution of clinical signs and apparent elimination of the mite. PMID- 26056914 TI - CHRONICALLY EMBEDDED LEAD PROJECTILES IN WILDLIFE: A CASE SERIES INVESTIGATING THE POTENTIAL FOR LEAD TOXICOSIS. AB - Research has demonstrated that intramuscularly embedded lead in humans and rats may cause direct plumbism, albeit rarely, and has identified risk factors to this end. To the authors' knowledge, this has not been investigated in wildlife, despite a high incidence of embedded lead in these animals secondary to cynegetic activities. Fourteen wildlife cases submitted to the National Fish and Wildlife Forensics Laboratory for cause-of-death determination had chronically embedded lead projectiles that were unrelated to the cause of death. Tissue lead levels were measured in all cases and revealed clinically significant hepatic lead levels in two cases. The results corroborate comparative literature and suggest that embedded lead fragments carry a low risk for direct plumbism, even in the face of risk factors such as fractures, inflammation, and projectile fragmentation. Wildlife morbidity and mortality from embedded lead is more commonly realized secondary to incidental ingestion and ballistic trauma rather than by direct toxicity. PMID- 26056918 TI - Zinc Status of Vegetarians during Pregnancy: A Systematic Review of Observational Studies and Meta-Analysis of Zinc Intake. AB - Pregnant women are vulnerable to a low zinc status due to the additional zinc demands associated with pregnancy and foetal development. The present systematic review explores the relationship between habitual vegetarian diets and dietary zinc intake/status during pregnancy. The association between vegetarian diets and functional pregnancy outcome also is considered. A literature search was conducted of MEDLINE; PubMed; Embase; the Cochrane Library; Web of Science; and Scopus electronic databases up to September 2014. Six English-language observational studies qualified for inclusion in the systematic review. A meta analysis was conducted that compared the dietary zinc intake of pregnant vegetarian and non-vegetarian (NV) groups; the zinc intake of vegetarians was found to be lower than that of NV (-1.38 +/- 0.35 mg/day; p < 0.001); and the exclusion of low meat eaters from the analysis revealed a greater difference ( 1.53 +/- 0.44 mg/day; p = 0.001). Neither vegetarian nor NV groups met the recommended dietary allowance (RDA) for zinc. In a qualitative synthesis; no differences were found between groups in serum/plasma zinc or in functional outcomes associated with pregnancy. In conclusion; pregnant vegetarian women have lower zinc intakes than NV control populations and both groups consume lower than recommended amounts. Further information is needed to determine whether physiologic adaptations in zinc metabolism are sufficient to meet maternal and foetal requirements during pregnancy on a low zinc diet. PMID- 26056919 TI - Long-Term Supplementation with Beta Serum Concentrate (BSC), a Complex of Milk Lipids, during Post-Natal Brain Development Improves Memory in Rats. AB - We have previously reported that the supplementation of ganglioside-enriched complex-milk-lipids improves cognitive function and that a phospholipid-enriched complex-milk-lipid prevents age-related cognitive decline in rats. This current study evaluated the effects of post-natal supplementation of ganglioside- and phospholipid-enriched complex-milk-lipids beta serum concentrate (BSC) on cognitive function in young rats. The diet of male rats was supplemented with either gels formulated BSC (n = 16) or blank gels (n = 16) from post-natal day 10 to day 70. Memory and anxiety-like behaviors were evaluated using the Morris water maze, dark-light boxes, and elevated plus maze tests. Neuroplasticity and white matter were measured using immunohistochemical staining. The overall performance in seven-day acquisition trials was similar between the groups. Compared with the control group, BSC supplementation reduced the latency to the platform during day one of the acquisition tests. Supplementation improved memory by showing reduced latency and improved path efficiency to the platform quadrant, and smaller initial heading error from the platform zone. Supplemented rats showed an increase in striatal dopamine terminals and hippocampal glutamate receptors. Thus BSC supplementation during post-natal brain development improved learning and memory, independent from anxiety. The moderately enhanced neuroplasticity in dopamine and glutamate may be biological changes underlying the improved cognitive function. PMID- 26056921 TI - Synthesis, structural and theoretical studies of dithiodiglycolamide compounds of palladium(II). AB - The reaction of palladium(ii) halide with dithiodiglycolamide ligands yielded compounds of the type [PdX2L] (where X = Cl, L = (CH2SCH2CON(i)Pr2)2 (1); L = (CH2SCH2CON(i)Bu2)2 (2); L = (CH2SCH2CONBu2)2 (3); L = C7H6(SCH2CON(i)Bu2)2 (4); X = Br, L = (CH2SCH2CON(i)Bu2)2 (5); X = I, L = (CH2SCH2CON(i)Bu2)2 (6)), whereas palladium(ii) nitrate yielded compounds of the type [PdL2](NO3)2 (where L = (CH2SCH2CON(i)Pr2)2 (7); L = (CH2SCH2CON(i)Bu2)2 (8)). All compounds were characterized by using IR, (1)H NMR spectral techniques and CHN analyses. The structures of compounds 4, 5 and 7 have been determined by using X-ray diffraction methods. The structures show that the ligands bond through the thioether group to the metal centre in all compounds. They show further that the palladium(ii) ion is surrounded by four atoms (two halogens and two thio groups in 4 and 5 and four thio groups in 7) in a square planar arrangement. The dithiodiglycolamide ligand acts as a bidentate chelating ligand and bonds through both the thioether groups to the metal centre, leaving the carbamoyl groups uncoordinated. Theoretical studies reveal that the 1 : 2 compound is energetically more stable and nicely correlates with the IR carbamoyl stretching frequencies as compared to the 1 : 1 compound in which the ligand acts as a tetradentate ligand. PMID- 26056920 TI - Non-Celiac Gluten Sensitivity Has Narrowed the Spectrum of Irritable Bowel Syndrome: A Double-Blind Randomized Placebo-Controlled Trial. AB - Several studies have shown that a large number of patients who are fulfilling the criteria for irritable bowel syndrome (IBS) are sensitive to gluten. The aim of this study was to evaluate the effect of a gluten-free diet on gastrointestinal symptoms in patients with IBS. In this double-blind randomized, placebo controlled trial, 148 IBS patients fulfilling the Rome III criteria were enrolled between 2011 and 2013. However, only 72 out of the 148 commenced on a gluten-free diet for up to six weeks and completed the study; clinical symptoms were recorded biweekly using a standard visual analogue scale (VAS). In the second stage after six weeks, patients whose symptoms improved to an acceptable level were randomly divided into two groups; patients either received packages containing powdered gluten (35 cases) or patients received placebo (gluten free powder) (37 cases). Overall, the symptomatic improvement was statistically different in the gluten containing group compared with placebo group in 9 (25.7%), and 31 (83.8%) patients respectively (p < 0.001). A large number of patients labelled as irritable bowel syndrome are sensitive to gluten. Using the term of IBS can therefore be misleading and may deviate and postpone the application of an effective and well-targeted treatment strategy in gluten sensitive patients. PMID- 26056922 TI - [des-Arg(1)]-Proctolin: A novel NEP-like enzyme inhibitor identified in Tityus serrulatus venom. AB - The scorpion Tityus serrulatus venom comprises a complex mixture of molecules that paralyzes and kills preys, especially insects. However, venom components also interact with molecules in humans, causing clinic envenomation. This cross interaction may result from homologous molecular targets in mammalians and insects, such as (NEP)-like enzymes. In face of these similarities, we searched for peptides in Tityus serrulatus venom using human NEP as a screening tool. We found a NEP-inhibiting peptide with the primary sequence YLPT, which is very similar to that of the insect neuropeptide proctolin (RYLPT). Thus, we named the new peptide [des-Arg(1)]-proctolin. Comparative NEP activity assays using natural substrates demonstrated that [des-Arg(1)]-proctolin has high specificity for NEP and better inhibitory activity than proctolin. To test the initial hypothesis that molecular homologies allow Tityus serrulatus venom to act on both mammal and insect targets, we investigated the presence of a NEP-like in cockroaches, the main scorpion prey, that could be likewise inhibited by [des-Arg(1)]-proctolin. Indeed, we detected a possible NEP-like in a homogenate of cockroach heads whose activity was blocked by thiorphan and also by [des-Arg(1)]-proctolin. Western blot analysis using a human NEP monoclonal antibody suggested a NEP-like enzyme in the homogenate of cockroach heads. Our study describes for the first time a proctolin-like peptide, named [des-Arg(1)]-proctolin, isolated from Tityus serrulatus venom. The tetrapeptide inhibits human NEP activity and a NEP-like activity in a cockroach head homogenate, thus it may play a role in human envenomation as well as in the paralysis and death of scorpion preys. PMID- 26056923 TI - Laparoscopic endometrioma resection increases peri-implantation endometrial HOXA 10 and HOXA-11 mRNA expression. AB - OBJECTIVE: To determine whether laparoscopic endometrioma resection alters peri implantation endometrial HOXA-10, HOXA-11, LIF, ITGB3 and ITGAV mRNA expression. DESIGN: Case-control study. SETTING: Medical school. PATIENT(S): Twenty infertile patients with uni- or bilateral endometrioma, five infertile patients having nonendometriotic benign ovarian cyst, and five fertile control subjects. INTERVENTION(S): Mid-luteal-phase endometrial sampling was performed at the time of surgery. Second endometrial biopsies were obtained 3 months after laparoscopic endometrioma resection during the mid-luteal phase of the cycle. MAIN OUTCOME MEASURE(S): Endometrial HOXA-10, HOXA-11, LIF, ITGAV, and ITGB3 mRNA expressions were evaluated with the use of reverse-transcription polymerase chain reaction. RESULT(S): Significantly decreased endometrial ITGAV mRNA expression was noted in biopsies obtained from endometrioma and nonendometriotic cyst groups before surgery. Trends toward decreased endometrial HOXA-10, HOXA-11, LIF, and ITGB3 mRNA expressions were noted in the endometrioma and nonendometriotic cyst groups before surgery compared with the fertile subjects. However, the differences failed to show statistical significance. Compared with preoperative values, significantly increased HOXA-10 (12.1-fold change) and HOXA-11 (17.2-fold change) mRNA expressions were noted in endometrial biopsies obtained from subjects who were undergoing endometrioma surgery. Fold change in endometrial ITGAV mRNA after endometrioma surgery was found to be 30.1 and indicated a positive regulation. However, this fold increase was statistically insignificant. Expressions of these endometrial receptivity markers did not change significantly after surgical removal of nonendometriotic benign ovarian cysts. CONCLUSION(S): Laparoscopic endometrioma resection increases peri-implantation endometrial HOXA-10 and HOXA 11 mRNA expression, suggesting an improvement in endometrial receptivity. PMID- 26056924 TI - Comparison of enzymatic digestion and mechanical dissociation of human testicular tissues. AB - OBJECTIVE: To compare mechanical dissociation, employing the Medimachine system, and enzymatic digestion of human testicular tissues with respect to the proportion of spermatogonia and somatic cells, with the long-term objective of establishing human spermatogonial cultures. DESIGN: Experimental basic science study. SETTING: Reproductive biology laboratory. PATIENT(S): Testicular tissues were obtained from patients with gender dysphoria on the day of sex reassignment surgery. On the basis of the histological evaluation, tissue samples with complete spermatogenesis (fresh, n = 6; cryopreserved, n = 7) and with meiotic arrest (cryopreserved, n = 4) were selected. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The composition of testicular cell suspensions was assessed performing quantitative real-time polymerase chain reaction (qPCR) analyses for germ cell-specific (FGFR3, SALL4, UTF1, MAGE-A4) and somatic marker genes (ACTA2 and VIM). Additionally, flow-cytometric analyses were used to evaluate the percentage of SALL4-and vimentin-positive cells. RESULT(S): While Medimachine dissociation yielded higher cell numbers in all patient groups, viability of cells was highly variable and correlated with the histological status of the tissue. Interestingly, qPCR analysis revealed a significantly decreased expression of the somatic marker genes ACTA2 and VIM and an increased expression of the spermatogonial marker genes FGFR3 and SALL4 after Medimachine dissociation. These findings were corroborated by flow-cytometric analyses that demonstrated that the proportion of SALL4-positive cells was up to 4 times higher after mechanical dissociation. CONCLUSION(S): Medimachine dissociation of human testicular tissues is comparably fast and leads to an enrichment of SALL4 positive spermatogonia. The use of this method may therefore constitute an advantage for the establishment of human spermatogonial cell cultures. PMID- 26056925 TI - Creating a collaborative model of mental health counseling for the future. AB - Infertility patients report high levels of anxiety and depressive symptoms, leading to a variety of challenges for the health care team. These include the impact of patient distress on nurses and physicians, patient treatment termination, and potentially lower pregnancy rates. Integrating a mental health professional into the infertility treatment team has the potential to lower distress for patients, support staff, and clinicians, leading to increased patient retention and an easier working environment. PMID- 26056926 TI - Role of the mental health professional in education and support of the medical staff. AB - This review argues that mental health professionals are underutilized in the reproductive health care system. Counselors in the field of reproductive medicine could broaden their care from a strictly one-on-one patient care perspective to a more integrated and collaborative approach that also involves education, training, and support of the fertility clinic staff. The literature has shed light on reasons for patient discontinuation, but little is known about staff burnout in reproductive health care, and even less has been done to address work related stress, job dissatisfaction, and poor emotional and physical health among fertility clinic staff. Specific educational strategies and training techniques are addressed to help reduce staff stress, prevent burnout, and improve overall patient care. PMID- 26056927 TI - Dysregulation of apoptotic pathway candidate genes and proteins in infertile azoospermia patients. AB - OBJECTIVE: To dissect the role of the apoptotic pathway and its regulation in the pathogenesis of male infertility in nonobstructive azoospermia. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): Sixty-three infertile azoospermic patients with different histologic phenotypes were recruited (obstructive azoospermia, n = 16; hypospermatogenesis, n = 11; maturation arrest, n = 15; Sertoli cell only, n = 21). INTERVENTION(S): Testicular biopsies for histopathologic and expression analysis. MAIN OUTCOME MEASURE(S): Expression analysis by quantitative reverse transcription-polymerase chain reaction, protein localization by immunohistochemistry and apoptotic proteome array. RESULT(S): Results showed significantly increased expression of proapoptotic proteins like BAX, BAD, and BAK and comparatively lowered expression of antiapoptotic BCL2 and BCLW. Immunostaining revealed increased active caspase 3 activity and more TUNEL-positive cells in different impaired phenotypes as compared with normal. In addition, significantly increased m-RNA expression of TGFB1, P53, and FASLG along with significant down-regulation of VEGFA were observed. Expression of phosphorylated P53 at the S15 position and phosphorylated RAD17 at S635 was observed in cases with spermatogenic impairment at the translational level. CONCLUSION(S): The results clearly indicate increased levels of apoptosis along with its other regulatory factors. The balance between pro- (BAX and BAK) and antiapoptotic (BCL2 and BCLW) genes was disturbed, which may lead to altered apoptosis. Therefore, altered regulation of apoptosis might be associated with impaired spermatogenesis, eventually leading to male infertility. PMID- 26056928 TI - Innovative approach in Pompe disease therapy: Induction of immune tolerance by antigen-encapsulated red blood cells. AB - Pompe disease is a glycogen storage disease caused by acid alpha-glucosidase enzyme deficiency. Currently, the unique treatment is lifelong enzyme replacement therapy ERT with frequent intravenous administration of the recombinant analog alglucosidase-alpha (AGA), which ultimately generates a sustained humoral response resulting in treatment discontinuation. Our aim is to use the tolerogenic properties of antigen-encapsulated red blood cells (RBCs) to abolish the humoral response against AGA and to restore tolerance to replacement therapy. To demonstrate that our approach could prevent the AGA-induced immune response, mice were intravenously injected three times with AGA encapsulated into RBCs before being sensitized to AGA with several adjuvant molecules. Control animals received injections of free AGA instead of the encapsulated molecule. One-week after treatment with AGA-loaded RBCs, a strong decrease in specific humoral response was observed despite three stimulations with AGA and adjuvant molecules. Furthermore, this specific immunomodulation was maintained for at least two months without affecting the overall immune response. AGA-loaded RBCs represent a promising strategy to induce or restore tolerance in Pompe disease patients who develop hypersensitivity reactions following repeated AGA administrations. PMID- 26056929 TI - Formulation and pharmacokinetics of colon-specific double-compression coated mini tablets: Chronopharmaceutical delivery of ketorolac tromethamine. AB - The present study is designed and significantly planned to study the effect of double-compression coating on core mini-tablets to attain the chronopharmaceutical delivery of ketorolac tromethamine to colon. Double compression coated tablets were prepared based on time-controlled hydroxypropyl methylcellulose K100M inner compression coat and pH-sensitive Eudragit S100 outer compression coat. From the in vitro drug release studies, F6 tablets was considered as the optimized formulation, which retarded the drug release in stomach and small intestine (3.51 +/- 0.15% in 5h) and progressively released to colon (99.82 +/- 0.69% in 24h). The release process followed supercase-II transport with zero order release kinetics. Similarity factor calculated from stability studies was found to be 84.73. From the pharmacokinetic evaluation, the immediate release core mini-tablets reached peak plasma concentration (Cmax of 4532.68 +/- 28.14 ng/ml) at 2h Tmax and colon targeted tablets showed Cmax=3782.29 +/- 17.83 ng/ml at 12h Tmax. The area under the curve and mean resident time of core mini-tablets were found to be 11,278.26 +/- 132.67 ng-h/ml and 3.68 h respectively while 17,324.48 +/- 56.32 ng-h/ml and 10.39 h for compression coated tablets. Hence the development of double-compression coated tablets is a promising way to gain the chronopharmaceutical delivery of ketorolac tromethamine to colon. PMID- 26056930 TI - Enzymatic action of phospholipase A2 on liposomal drug delivery systems. AB - The overexpression of secretory phospholipase A2 (sPLA2) in tumors has opened new avenues for enzyme-triggered active unloading of liposomal antitumor drug carriers selectively at the target tumor. However, the effects of the liposome composition, drug encapsulation, and tumor microenvironment on the activity of sPLA2 are still not well understood. We carried out a physico-chemical study to characterize the sPLA2-assisted breakdown of liposomes using dye-release assays in the context of drug delivery and under physiologically relevant conditions. The influence of temperature, lipid concentration, enzyme concentration, and drug loading on the hydrolysis of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC, Tm=42 degrees C) liposomes with snake venom sPLA2 was investigated. The sensitivity of human sPLA2 to the liposome composition was checked using binary lipid mixtures of phosphatidylcholine (PC) and phosphatidylglycerol (PG) phospholipids with C14 and C16 acyl chains. Increasing temperature (36-41 degrees C) was found to mainly shorten the enzyme lag-time, whereas the effect on lipid hydrolysis rate was modest. The enzyme lag-time was also found to be inversely dependent on the lipid-to-enzyme ratio. Drug encapsulation can alter the hydrolysis profile of the carrier liposomes. The activity of human sPLA2 was highly sensitive to the phospholipid acyl-chain length and negative surface charge density of the liposomes. We believe our work will prove useful for the optimization of sPLA2-susceptible liposomal formulations as well as will provide a solid ground for predicting the hydrolysis profile of the liposomes in vivo at the target site. PMID- 26056931 TI - Regeneration through reprogramming adult cell identity in vivo. AB - The discovery and in vivo application of cell fate reprogramming concepts have jumpstarted new technologies aimed at the functional regeneration of damaged tissues. As most adult organ systems retain only a limited potential for self regeneration after trauma, the production of fate-specific cells by in vivo transdifferentiation offers a targeted method for tissue bioengineering. Proof-of principle studies have demonstrated the induction of neural precursor cells, neurons, cardiomyocytes, and insulin-producing beta islet cells. Each of these induced cell types survive, mature, and integrate into the local environment in a functionally meaningful manner. Here, we briefly highlight recent advances in the in vivo reprogramming of cell identity and the current challenges that face the clinical relevance of these methods. PMID- 26056932 TI - Human polyomavirus receptor distribution in brain parenchyma contrasts with receptor distribution in kidney and choroid plexus. AB - The human polyomavirus, JCPyV, is the causative agent of progressive multifocal leukoencephalopathy, a rare demyelinating disease that occurs in the setting of prolonged immunosuppression. After initial asymptomatic infection, the virus establishes lifelong persistence in the kidney and possibly other extraneural sites. In rare instances, the virus traffics to the central nervous system, where oligodendrocytes, astrocytes, and glial precursors are susceptible to lytic infection, resulting in progressive multifocal leukoencephalopathy. The mechanisms by which the virus traffics to the central nervous system from peripheral sites remain unknown. Lactoseries tetrasaccharide c (LSTc), a pentasaccharide containing a terminal alpha2,6-linked sialic acid, is the major attachment receptor for polyomavirus. In addition to LSTc, type 2 serotonin receptors are required for facilitating virus entry into susceptible cells. We studied the distribution of virus receptors in kidney and brain using lectins, antibodies, and labeled virus. The distribution of LSTc, serotonin receptors, and virus binding sites overlapped in kidney and in the choroid plexus. In brain parenchyma, serotonin receptors were expressed on oligodendrocytes and astrocytes, but these cells were negative for LSTc and did not bind virus. LSTc was instead found on microglia and vascular endothelium, to which virus bound abundantly. Receptor distribution was not changed in the brains of patients with progressive multifocal leukoencephalopathy. Virus infection of oligodendrocytes and astrocytes during disease progression is LSTc independent. PMID- 26056934 TI - Family legal status and health: Measurement dilemmas in studies of Mexican-origin children. AB - Family legal status is a potentially important source of variation in the health of Mexican-origin children. However, a comprehensive understanding of its role has been elusive due to data limitations and inconsistent measurement procedures. Using restricted data from the 2011-2012 California Health Interview Survey, we investigate the implications of measurement strategies for estimating the share of children in undocumented families and inferences about how legal status affects children's health. The results show that inferences are sensitive to how this "fundamental cause" is operationalized under various combinatorial approaches used in previous studies. We recommend alternative procedures with greater capacity to reveal how the statuses of both parents affect children's well-being. The results suggest that the legal statuses of both parents matter, but the status of mothers is especially important for assessments of child health. The investigation concludes with a discussion of possible explanations for these findings. PMID- 26056935 TI - Does rising crime lead to increasing distress? Longitudinal analysis of a natural experiment with dynamic objective neighbourhood measures. AB - Identifying 'neighbourhood effects' to support widespread beliefs that where we live matters for our health remains a major challenge due to the reliance upon observational data. In this study we reassess the issue of local crime rates and psychological distress by applying unobserved ('fixed') effects models to a sample of participants who remain in the same neighbourhoods throughout the study. Baseline data was extracted from the 45 and Up Study between 2006 and 2008 and followed up as part of the Social Economic and Environmental Factors (SEEF) Study between 2009 and 2010. Kessler 10 scores were recorded for 25,545 men and 29,299 women reported valid outcomes. Annual crime rates per 1000 (including non domestic violence, malicious damage, break and enter, and stealing, theft and robbery) from 2006 to 2010 inclusive were linked to the person-level data. Change in exposure to crime among participants in this study, therefore, occurs as a result of a change in the local crime rate, rather than a process of neighbourhood selection. Gender stratified unobserved effects logistic regression adjusting for sources of time-varying confounding (age, income, employment, couple status and physical functioning) indicated that an increase in the risk of experiencing psychological distress was generally associated with an increase in the level of neighbourhood crime. Effect sizes were particularly high for women, especially for an increase in malicious damage (Odds Ratio Tertile 3 vs Tertile 1 2.40, 95% Confidence Interval 1.88, 3.05), which may indicate that damage to local built environment is an important pathway linking neighbourhood crime with psychological distress. No statistically significant association was detected for an increase in non-domestic violence, although the effect was in the hypothesised direction. In summary, the application of unobserved effects models to analyse data that takes into account the temporally dynamic characteristics of where people live warrants further investigation. PMID- 26056933 TI - miRNA control of tissue repair and regeneration. AB - Tissue repair and regeneration rely on the function of miRNA, molecular silencers that enact post-transcriptional gene silencing of coding genes. Disruption of miRNA homeostasis is developmentally lethal, indicating that fetal tissue development is tightly controlled by miRNAs. Multiple critical facets of adult tissue repair are subject to control by miRNAs, as well. Sources of cell pool for tissue repair and regeneration are diverse and provided by processes including cellular dedifferentiation, transdifferentiation, and reprogramming. Each of these processes is regulated by miRNAs. Furthermore, induced pluripotency may be achieved by miRNA-based strategies independent of transcription factor manipulation. The observation that miRNA does not integrate into the genome makes miRNA-based therapeutic strategies translationally valuable. Tools to manipulate cellular and tissue miRNA levels include mimics and inhibitors that may be specifically targeted to cells of interest at the injury site. Here, we discuss the extraordinary importance of miRNAs in tissue repair and regeneration based on emergent reports and rapid advances in miRNA-based therapeutics. PMID- 26056936 TI - Depressive symptoms and self-reported adherence to medical recommendations to prevent cardiovascular disease: NHANES 2005-2010. AB - This study's aim was to examine the relationships between depressive symptom severity and adherence to medication and lifestyle recommendations intended to prevent cardiovascular disease (CVD) in a large, diverse sample of men and women representative of the U.S. POPULATION: Participants were adults from the National Health and Nutrition Examination Survey (NHANES) 2005-2010 with a self-reported history of hypertension and/or hypercholesterolemia, but no CVD. The Patient Health Questionnaire-9 (PHQ-9) was used to assess depressive symptoms, and the Blood Pressure and Cholesterol interview was used to assess self-reported adherence to five medical recommendations: take antihypertensive medication (n = 3313), eat fewer high fat/cholesterol foods (n = 2924), control/lose weight (n = 2177), increase physical activity (n = 2540), and take cholesterol medication (n = 2266). Logistic regression models (adjusted for demographics, diabetes, body mass index, smoking, and alcohol intake) revealed that a 1-SD increase in PHQ-9 score was associated with a 14% lower odds of adherence to the control/lose weight recommendation (OR = 0.86, 95% CI: 0.75-0.98, p = .02) and a 25% lower odds of adherence to the increase physical activity recommendation (OR = 0.75, 95% CI: 0.65-0.86, p < .001). PHQ-9 score, however, was not related to the odds of adherence to the take antihypertensive medication (p = .21), eat fewer high fat/cholesterol foods (p = .40), or take cholesterol medication (p = .90) recommendations. Our findings suggest that poor adherence to provider recommendations to control/lose weight and to increase physical activity may partially explain the excess risk of CVD among depressed persons. PMID- 26056937 TI - [Prevalence of clinically important species of the genus Vibrio in catered seafood of city and port of Progreso de Castro, Yucatan, Mexico]. AB - INTRODUCTION: Species of the genus Vibrio are invariably gram-negative bacilli, between 2 and 3 um long and curved in shape, sometimes equipped with a single polar flagellum that allows high mobility. They tolerate well alkaline media and high-salt concentrations in their environment. They do not form spores, are oxidase-positive and facultative anaerobes. The aim of this study was to determine the prevalence of clinically-important species of the genus Vibrio in raw, marinated without heat, partially cooked with heat and completely cooked with heat seafood. METHODS: This is a study with a quantitative approach. We obtained a list of 38 caterers that specialized in the sale of marine foods of animal origin for human consumption. The number of marine animal foods in those caterers was 790. For homogenization and enrichment of samples and for the isolation and identification of species, we proceeded according to the methodology described in the Bacteriological Analytical Manual. Intervals to estimate a confidence level of 95% were applied. RESULTS: The prevalence obtained in raw, marinated without heat, partially cooked with heat and completely cooked with heat seafood were 44.30% (276/623), 32.00% (8/25), 30.53% (29/95) and 17.02% (8/47), respectively. CONCLUSIONS: These results should be taken into consideration when planning to avoid healthcare problems and food-borne diseases in the population that consumes this type of food in the city and port of Progreso de Castro, in Yucatan, Mexico. PMID- 26056938 TI - Poor correlation between T-cell activation assays and HLA-DR binding prediction algorithms in an immunogenic fragment of Pseudomonas exotoxin A. AB - The ability to identify immunogenic determinants that activate T-cells is important for the development of new vaccines, allergy therapy and protein therapeutics. In silico MHC-II binding prediction algorithms are often used for T cell epitope identification. To understand how well those programs predict immunogenicity, we computed HLA binding to peptides spanning the sequence of PE38, a fragment of an anti-cancer immunotoxin, and compared the predicted and experimentally identified T-cell epitopes. We found that the prediction for individual donors did not correlate well with the experimental data. Furthermore, prediction of T-cell epitopes in an HLA heterogenic population revealed that the two strongest epitopes were predicted at multiple cutoffs but the third epitope was predicted negative at all cutoffs and overall 4/9 epitopes were missed at several cutoffs. We conclude that MHC class-II binding predictions are not sufficient to predict the T-cell epitopes in PE38 and should be supplemented by experimental work. PMID- 26056940 TI - Derivatives of Dictyostelium differentiation-inducing factors inhibit lysophosphatidic acid-stimulated migration of murine osteosarcoma LM8 cells. AB - Osteosarcoma is a common metastatic bone cancer that predominantly develops in children and adolescents. Metastatic osteosarcoma remains associated with a poor prognosis; therefore, more effective anti-metastatic drugs are needed. Differentiation-inducing factor-1 (DIF-1), -2, and -3 are novel lead anti-tumor agents that were originally isolated from the cellular slime mold Dictyostelium discoideum. Here we investigated the effects of a panel of DIF derivatives on lysophosphatidic acid (LPA)-induced migration of mouse osteosarcoma LM8 cells by using a Boyden chamber assay. Some DIF derivatives such as Br-DIF-1, DIF-3(+2), and Bu-DIF-3 (5-20 MUM) dose-dependently suppressed LPA-induced cell migration with associated IC50 values of 5.5, 4.6, and 4.2 MUM, respectively. On the other hand, the IC50 values of Br-DIF-1, DIF-3(+2), and Bu-DIF-3 versus cell proliferation were 18.5, 7.2, and 2.0 MUM, respectively, in LM8 cells, and >20, 14.8, and 4.3 MUM, respectively, in mouse 3T3-L1 fibroblasts (non-transformed). Together, our results demonstrate that Br-DIF-1 in particular may be a valuable tool for the analysis of cancer cell migration, and that DIF derivatives such as DIF-3(+2) and Bu-DIF-3 are promising lead anti-tumor agents for the development of therapies that suppress osteosarcoma cell proliferation, migration, and metastasis. PMID- 26056939 TI - Clonal analysis of human dendritic cell progenitor using a stromal cell culture. AB - Different dendritic cell (DC) subsets co-exist in humans and coordinate the immune response. Having a short life, DCs must be constantly replenished from their progenitors in the bone marrow through hematopoiesis. Identification of a DC-restricted progenitor in mouse has improved our understanding of how DC lineage diverges from myeloid and lymphoid lineages. However, identification of the DC-restricted progenitor in humans has not been possible because a system that simultaneously nurtures differentiation of human DCs, myeloid and lymphoid cells, is lacking. Here we report a cytokine and stromal cell culture that allows evaluation of CD34(+) progenitor potential to all three DC subsets as well as other myeloid and lymphoid cells, at a single cell level. Using this system, we show that human granulocyte-macrophage progenitors are heterogeneous and contain restricted progenitors to DCs. PMID- 26056941 TI - A highly sensitive assay of IRE1 activity using the small luciferase NanoLuc: Evaluation of ALS-related genetic and pathological factors. AB - Activation of inositol-requiring enzyme 1 (IRE1) due to abnormal conditions of the endoplasmic reticulum (ER) is responsible for the cleavage of an unspliced form of X-box binding protein 1 (uXBP1), producing its spliced form (sXBP1). To estimate IRE1 activation, several analytical procedures using green fluorescence protein and firefly luciferase have been developed and applied to clarify the roles of IRE1-XBP1 signaling pathways during development and disease progression. In this study, we established a highly sensitive assay of IRE1 activity using a small luciferase, NanoLuc, which has approximately 100-fold higher activity than firefly luciferase. The NanoLuc reporter, which contained a portion of the spliced region of XBP1 upstream of NanoLuc, was highly sensitive and compatible with several types of cell lines. We found that NanoLuc was secreted into the extracellular space independent of the ER-Golgi pathway. The NanoLuc activity of an aliquot of culture medium from the neuroblastoma-spinal neuron hybrid cell line NSC-34 reflected the toxic stimuli-induced elevation of intracellular activity well. Using this technique, we evaluated the effects of several genetic and pathological factors associated with the onset and progression of amyotrophic lateral sclerosis (ALS) on NanoLuc reporter activity. Under our experimental conditions, inhibition of ER-Golgi transport by the overexpression of mutant Sar1 activated luciferase activity, whereas the co-expression of mutant SOD1 or the C terminal fragment of TDP-43 (TDP-25) did not. The addition of homocysteine elevated the reporter activity; however, we did not observe any synergistic effect due to the overexpression of the mutant genes described above. Taken together, these data show that our analytical procedure is highly sensitive and convenient for screening useful compounds that modulate IRE1-XBP1 signaling pathways as well as for estimating IRE1 activation in several pathophysiological diseases. PMID- 26056942 TI - Hispolon inhibits the growth of estrogen receptor positive human breast cancer cells through modulation of estrogen receptor alpha. AB - Human estrogen receptor alpha (ERalpha) is a nuclear transcription factor that is a major therapeutic target in breast cancer. The transcriptional activity of ERalpha is regulated by certain estrogen-receptor modulators. Hispolon, isolated from Phellinus linteus, a traditional medicinal mushroom called Sanghwang in Korea, has been used to treat various pathologies, such as inflammation, gastroenteric disorders, lymphatic diseases, and cancers. In this latter context, Hispolon has been reported to exhibit therapeutic efficacy against various cancer cells, including melanoma, leukemia, hepatocarcinoma, bladder cancer, and gastric cancer cells. However, ERalpha regulation by Hispolon has not been reported. In this study, we investigated the effects of Hispolon on the growth of breast cancer cells. We found that Hispolon decreased expression of ERalpha at both mRNA and the protein levels in MCF7 and T47D human breast cancer cells. Luciferase reporter assays showed that Hispolon decreased the transcriptional activity of ERalpha. Hispolon treatment also inhibited expression of the ERalpha target gene pS2. We propose that Hispolon, an anticancer drug extracted from natural sources, inhibits cell growth through modulation of ERalpha in estrogen-positive breast cancer cells and is a candidate for use in human breast cancer chemotherapy. PMID- 26056943 TI - Hypermethylation of MST1 in IgG4-related autoimmune pancreatitis and rheumatoid arthritis. AB - The serine/threonine kinase Mst1 plays important roles in the control of immune cell trafficking, proliferation, and differentiation. Previously, we reported that Mst1 was required for thymocyte selection and regulatory T-cell functions, thereby the prevention of autoimmunity in mice. In humans, MST1 null mutations cause T-cell immunodeficiency and hypergammaglobulinemia with autoantibody production. RASSF5C(RAPL) is an activator of MST1 and it is frequently methylated in some tumors. Herein, we investigated methylation of the promoter regions of MST1 and RASSF5C(RAPL) in leukocytes from patients with IgG4-related autoimmune pancreatitis (AIP) and rheumatoid arthritis (RA). Increased number of CpG methylation in the 5' region of MST1 was detected in AIP patients with extrapancreatic lesions, whereas AIP patients without extrapancreatic lesions were similar to controls. In RA patients, we detected a slight increased CpG methylation in MST1, although the overall number of methylation sites was lower than that of AIP patients with extrapancreatic lesions. There were no significant changes of the methylation levels of the CpG islands in the 5' region of RASSF5C(RAPL) in leukocytes from AIP and RA patients. Consistently, we found a significantly down-regulated expression of MST1 in regulatory T cells of AIP patients. Our results suggest that the decreased expression of MST1 in regulatory T cells due to hypermethylation of the promoter contributes to the pathogenesis of IgG4-related AIP. PMID- 26056944 TI - Cylindromatosis (CYLD) inhibits Streptococcus pneumonia-induced plasminogen activator inhibitor-1 expression via interacting with TRAF-6. AB - Streptococcus pneumoniae (S. p) remains one of the foremost causes of community acquired pneumonia. Recent studies have shown that S. p lung infection is associated with plasminogen activator inhibitor-1 (PAI-1) expression, which inhibits acute lung injury. Such effects by S. p were negatively regulated by cylindromatosis (CYLD). The current study explored the underlying mechanisms. We showed that S. p-induced PAI-1 expression requires tumor necrosis factor receptor associated factor 6 (TRAF-6) signaling. Si-RNA-mediated knockdown of TRAF-6 remarkably inhibited S. p-induced PAI-1 expression. Reversely, over-expression of wild type (wt-) TRAF-6 further potentiated PAI-1 expression in S. p-treated cells. We provided evidences to support that CYLD-mediated anti-PAI-1 activity might be through direct regulation of TRAF-6. Our results from co immunoprecipitation (co-IP) and confocal microscopy assays confirmed a direct association between the CYLD and TRAF-6 in A549 cells. Over-expression of wt-CYLD remarkably inhibited TRAF-6 ubiquitination and subsequent PAI-1 expression. Introducing a mutated CYLD, on the other hand, enhanced TRAF-6 ubiquitination and PAI-1 expression. Together, these results indicate that TRAF-6 mediates S. p induced PAI-1 expression, and CYLD inhibits PAI-1 expression probably through deubiquitinating TRAF-6. The current study provided molecular insights of CYLD mediated activities in S. p-induced PAI-1 expression and possible acute lung injury. PMID- 26056945 TI - Piwil1 causes epigenetic alteration of PTEN gene via upregulation of DNA methyltransferase in type I endometrial cancer. AB - Piwil1, a member of the Piwi family, has been well demonstrated to mediate tumorigenesis associated with DNA hypermethylation. It has been reported that Piwil1 is overexpressed in various types of cancer, including endometrial cancer. However, the underlying mechanism of Piwil1 in endometrial cancer remains largely unclear. PTEN exerts an important tumor suppressor role in endometrial carcinogenesis. The present study aimed to investigate whether Piwil1 could regulate the expression of PTEN. Herein, we found that Piwil1 could promote the loss of PTEN expression and increase aberrant hypermethylation of PTEN gene promoter in Ishikawa cells. We also found that Piwil1 could regulate the expression of DNA methyltransferase 1 (DNMT1). Silencing DNMT1 gene could upregulate the PTEN gene expression and change the methylation status of PTEN gene promoter in Ishikawa cells. These results suggested that Piwil1 caused the loss of PTEN expression through DNMT1-mediated PTEN hypermethylation. Taken together, these data provide a novel regulatory mechanism of Piwil1 in endometrial cancer. PMID- 26056946 TI - Bridging NCL research gaps. AB - The neuronal ceroid lipofuscinoses, collectively called NCLs, are rare and fatal lysosomal storage diseases that mainly affect children. Due to the fact that NCLs are both rare and heterogeneous (mutations in thirteen different genes) significant gaps exist in both preclinical and clinical research. Altogether, these gaps are major hurdles to bring therapies to patients while the need for new therapies is urgent to help them and their families. To define gaps and discuss solutions, a round table discussion involving teams and different stake holders took place during the 14th International Conference on Neuronal Ceroid Lipofuscinoses (Batten Disease) in Cordoba, Argentina. Topics covered by the teams and their leaders (in parentheses) included basic and translational research gaps with regard to large animal models (I. Tammen, D.N. Palmer), human NCL pathology and access to human tissue (J.D. Cooper, H.H. Goebel), rare NCLs (S. Hofman, I. Noher), links of NCLs to other diseases (F.M. Platt), gaps between clinic and clinical trials (H. Adams, A. Schulz), international collaborative efforts working towards a cure (S.E. Mole, H. Band) perspectives on palliative care from patient organizations (M. Frazier, A. West), and issues NCL researchers face when progressing to independent career in academia (M. Bond). Thoughts presented by the team leaders include previously unpublished opinions and information on the lack of understanding of disease pathomechanisms, gene function, assays for drug discovery and target validation, natural history of disease, and biomarkers for monitoring disease progression and treatment effects. This article is not intended to review the NCL literature. It includes personal opinions of the authors and it provides the reader with a summary of gaps discussed and solutions proposed by the teams. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease). PMID- 26056948 TI - Development of biosensors and their application in metabolic engineering. AB - In a sustainable bioeconomy, many commodities and high value chemicals, including pharmaceuticals, will be manufactured using microbial cell factories from renewable feedstocks. These cell factories can be efficiently generated by constructing libraries of diversified genomes followed by screening for the desired phenotypes. However, methods available for microbial genome diversification far exceed our ability to screen and select for those variants with optimal performance. Genetically encoded biosensors have shown the potential to address this gap, given their ability to respond to small molecule binding and ease of implementation with high-throughput analysis. Here we describe recent progress in biosensor development and their applications in a metabolic engineering context. We also highlight examples of how biosensors can be integrated with synthetic circuits to exert feedback regulation on the metabolism for improved performance of cell factories. PMID- 26056949 TI - DNA nanotechnology: new adventures for an old warhorse. AB - As the blueprint of life, the natural exploits of DNA are admirable. However, DNA should not only be viewed within a biological context. It is an elegantly simple yet functionally complex chemical polymer with properties that make it an ideal platform for engineering new nanotechnologies. Rapidly advancing synthesis and sequencing technologies are enabling novel unnatural applications for DNA beyond the realm of genetics. Here we explore the chemical biology of DNA nanotechnology for emerging applications in communication and digital data storage. Early studies of DNA as an alternative to magnetic and optical storage mediums have not only been promising, but have demonstrated the potential of DNA to revolutionize the way we interact with digital data in the future. PMID- 26056950 TI - Getting pumped: membrane efflux transporters for enhanced biomolecule production. AB - Small molecule production in microbial hosts is limited by the accumulation of the product inside the cell. Efflux transporters show promise as a solution to removal of the often-toxic products. Recent advances in transporter identification through expression profiling, heterologous expression, and knockout studies have identified transporters capable of secreting compounds of biotechnological interest. In addition, engineering of well-studied transporters has shown that substrate specificity in these transporters is malleable. Future work in identification, engineering, and expression of small molecule exporters can be instrumental in expanding the biocatalysis portfolio. PMID- 26056952 TI - Novel theranostic agents for next-generation personalized medicine: small molecules, nanoparticles, and engineered mammalian cells. AB - Modern medicine is currently undergoing a paradigm shift from conventional disease treatments based on the diagnosis of a generalized disease state to a more personalized, customized treatment model based on molecular-level diagnosis. This uses novel biosensors that can precisely extract disease-related information from complex biological systems. Moreover, with the recent progress in chemical biology, materials science, and synthetic biology, it has become possible to simultaneously conduct diagnosis and targeted therapy (theranostics/theragnosis) by directly connecting the readout of a biosensor to a therapeutic output. These advances pave the way for more advanced and better personalized treatment for intractable diseases with fewer side effects. In this review, we describe recent advances in the development of cutting-edge theranostic agents that contain both diagnostic and therapeutic functions in a single integrated system. By comparing the advantages and disadvantages of each modality, we discuss the future challenges and prospects of developing ideal theranostic agents for the next generation of personalized medicine. PMID- 26056951 TI - Synthetic biology expands chemical control of microorganisms. AB - The tools of synthetic biology allow researchers to change the ways engineered organisms respond to chemical stimuli. Decades of basic biology research and new efforts in computational protein and RNA design have led to the development of small molecule sensors that can be used to alter organism function. These new functions leap beyond the natural propensities of the engineered organisms. They can range from simple fluorescence or growth reporting to pathogen killing, and can involve metabolic coordination among multiple cells or organisms. Herein, we discuss how synthetic biology alters microorganisms' responses to chemical stimuli resulting in the development of microbes as toxicity sensors, disease treatments, and chemical factories. PMID- 26056953 TI - Studies on an on/off-switchable immunosensor for troponin T. AB - Regeneration is a key goal in the design of immunosensors. In this study, we report the temperature-regulated interaction of N-isopropylacrylamide (PNIPAAm) functionalised cardiac troponin T (cTnT) with anti-cTnT. Covalently bonded PNIPAAm on an anti-cTnT bioelectrode showed on/off-switchability, regeneration capacity and temperature triggered sensitivity for cTnT. Above the lower critical solution temperature (LCST), PNIPAAm provides a liphophilic microenvironment with specific volume reduction at the bioelectrode surface, making available binding space for cTnT, and facilitating analyte recognition. Computational studies provide details about the structural changes occurring at the electrode above and below the LCST. Furthermore, free energies associated with the binding of cTnT with PNIPAAm at 25 (DeltaGcoil=-6.0 Kcal/mole) and 37 degrees C (DeltaGglobular= 41.0 kcal/mole) were calculated to elucidate the interaction and stability of the antigen-antibody complex. The responsiveness of such assemblies opens the way for miniaturised, smart immuno-technologies with 'built-in' programmable interactions of antigen-antibody upon receiving stimuli. PMID- 26056954 TI - Label free colorimetric and fluorimetric direct detection of methylated DNA based on silver nanoclusters for cancer early diagnosis. AB - Epigenetic changes such as DNA methylation of CpG islands located in the promoter region of some tumor suppressor genes are very common in human diseases such as cancer. Detection of aberrant methylation pattern could serve as an excellent diagnostic approach. Recently, the direct detection of methylated DNA sequences without using chemical and enzymatic treatments or antibodies has received great deal of attentions. In this study, we report a colorimetric and fluorimetric technique for direct detection of DNA methylation. Here, the DNA is being used as an effective template for fluorescent silver nanoclusters formation without any chemical modification or DNA labeling. The sensitivity test showed that upon the addition of target methylated DNA, the fluorescence intensity is decreased in a linear range when the concentration of methylated DNA has increased from 2.0*10( 9) to 6.3 *10(-7) M with the detection limit of 9.4*10(-10) M. The optical and fluorescence spectral behaviors were highly reproducible and clearly discriminated between unmethylated, methylated and even partially methylated DNA in CpG rich sequences. The results were also reproducible when the human plasma was present in our assay system. PMID- 26056955 TI - Microelectrospotting as a new method for electrosynthesis of surface-imprinted polymer microarrays for protein recognition. AB - Here we introduce microelectrospotting as a new approach for preparation of protein-selective molecularly imprinted polymer microarrays on bare gold SPR imaging chips. During electrospotting both the gold chip and the spotting tip are electrically connected to a potentiostat as working and counter electrodes, respectively. The spotting pin encloses the monomer-template protein cocktail that upon contacting the gold surface is in-situ electropolymerized resulting in surface confined polymer spots of ca. 500 um diameter. By repeating this procedure at preprogrammed locations for various composition monomer-template mixtures microarrays of nanometer-thin surface-imprinted films are generated in a controlled manner. We show that the removal and rebinding kinetics of the template and various potential interferents to such microarrays can be monitored in real-time and multiplexed manner by SPR imaging. The proof of principle for microelectrospotting of electrically insulating surface-imprinted films is made by using scopoletin as monomer and ferritin as protein template. It is shown that microelectrospotting in combination with SPR imaging can offer a versatile platform for label-free and enhanced throughput optimization of the molecularly imprinted polymers for protein recognition and for their analytical application. PMID- 26056956 TI - Real-time and label-free ring-resonator monitoring of solid-phase recombinase polymerase amplification. AB - In this work we present the use of a silicon-on-insulator (SOI) chip featuring an array of 64 optical ring resonators used as refractive index sensors for real time and label-free DNA detection. Single ring functionalisation was achieved using a click reaction after precise nanolitre spotting of specific hexynyl terminated DNA capture probes to link to an azido-silanised chip surface. To demonstrate detectability using the ring resonators and to optimise conditions for solid-phase amplification, hybridisation between short 25-mer single stranded DNA (ssDNA) fragments and a complementary capture probe immobilised on the surface of the ring resonators was carried out and detected through the shift in the resonant wavelength. Using the optimised conditions demonstrated via the solid-phase hybridisation, a 144-bp double stranded DNA (dsDNA) was then detected directly using recombinase and polymerase proteins through on-chip target amplification and solid-phase elongation of immobilised forward primers on specific rings, at a constant temperature of 37 degrees C and in less than 60min, achieving a limit of detection of 7.8.10(-13)M (6.10(5) copies in 50uL). The use of an automatic liquid handler injection instrument connected to an integrated resealable chip interface (RCI) allowed programmable multiple injection protocols. Air plugs between different solutions were introduced to prevent intermixing and a proportional-integral-derivative (PID) temperature controller minimised temperature based drifts. PMID- 26056957 TI - Increment of pentraxin3 expression in abdominal aortic aneurysm. PMID- 26056958 TI - Pulsed levosimendan therapy in the management of chronic end stage cardiac failure in 'adult congenital heart disease'. PMID- 26056959 TI - Novel potential therapeutic strategies of senile cardiac amyloidosis: Heat shock factor 1 blocks senile cardiac amyloidosis via HSPA1A in mouse model. PMID- 26056960 TI - Revisiting annulus paradoxus in constrictive pericarditis. PMID- 26056961 TI - A deletion mutation in myosin heavy chain 11 causing familial thoracic aortic dissection in two Japanese pedigrees. PMID- 26056962 TI - Recurrent stroke in patients with patent foramen ovale: An observational prospective study of percutaneous closure of PFO versus non-closure. AB - AIMS: Observational studies favor percutaneous closure of patent foramen ovale (PFO) over medical therapy to reduce the risk of recurrent stroke, whereas randomized clinical trials have not shown significant differences. This study aims to compare long-term outcomes of PFO closure versus non-closure. METHODS AND RESULTS: Patients with PFO and stroke considered for PFO closure were invited to a long-term clinical follow-up. Of the 314 patients, 151 (48%) were accepted for closure and 163 (52%) were not accepted (mean age 50 vs. 58 years). The cumulative incidence of all-cause mortality, stroke or transient ischemic attacks (TIAs) for closure vs. non-closure under a mean follow-up time of five years was 10.6% (16 events) vs. 12.9% (21 events), p=0.53. Six patients, 3.7% vs. 3.6%, died in each group, but no deaths were associated with PFO closure, recurrent stroke or TIA. The incidence of recurrent stroke or TIA for closure vs. non closure was 6.6% (10 events) vs. 9.2% (15 events), p=0.63. The respective event rates for stroke were 3.9% (6 events) vs. 5.5% (9 events), p=0.50 and for TIA, 2.6% (4 events) vs. 3.7% (6 events), p=0.59. CONCLUSION: PFO closure was associated with a low risk of recurrent events; however, compared to the non closure group, no significant differences could be demonstrated. Careful patient selection can avoid under- as well as over-treatment of PFO patients. PMID- 26056963 TI - Diallyl trisulfide protects against high glucose-induced cardiac apoptosis by stimulating the production of cystathionine gamma-lyase-derived hydrogen sulfide. AB - BACKGROUND: Cystathionine-gamma-lyase (CSE)-derived hydrogen sulfide (H2S) is a potent cardioprotective agent. We investigated the effects of diallyl trisulfide (DATS) on CSE expression and H2S generation in myocardium and examined whether DATS-mediated H2S generation effectively protects rat heart from diabetes-induced cardiac damage. METHODS: The correlations between the effects of hyperglycemia and diabetes on CSE expression and the effects of DATS and H2S on hyperglycemia and diabetes were examined in vitro in the cardiomyocyte cell line H9c2 and in vivo in hearts from rats with streptozotocin-induced diabetes mellitus (DM). RESULTS: Expression of CSE, a catalyst of H2S production, was suppressed in H9c2 cells treated with high glucose (33 mM) and in DM rat hearts. CSE suppression also correlated with a decrease in the activation of the pro-survival protein kinase Akt. Treatment of H9c2 cells with DATS resulted in increased CSE expression and a reduction in apoptosis via a mechanism involving IGF1R/pAkt signaling and by modulating the expression of reactive oxygen species-related enzymes. The role CSE plays in the cardioprotective effects of DATS was further confirmed by CSE inhibition assays including inhibitors and siRNA. CONCLUSION: DATS produces H2S as efficiently as NaSH and DATS-derived H2S provides effective cardioprotection. Further, our data indicate that H2S plays a major role in the protective effect of DATS against apoptosis of cardiomyocytes. PMID- 26056964 TI - Targeted delivery of interleukin-10 to chronic cardiac allograft rejection using a human antibody specific to the extra domain A of fibronectin. AB - BACKGROUND AND AIMS: Management of chronic rejection is challenging since there are not sufficient preventive or therapeutic strategies. The rejection process leads to overexpression of ED-A(+) fibronectin (ED-A(+) Fn). The human antibody F8, specific to ED-A(+) Fn, may serve as a vehicle for targeted delivery of bioactive payloads, e.g. interleukin 10 (IL-10). The aim of this study was to investigate the therapeutic effects of the fusion protein F8-interleukin-10 (F8 IL10) in the process of chronic rejection development. METHODS: A heterotopic rat heart transplantation model was used to induce chronic rejection. For therapeutic interventions, the immunocytokines F8-humanIL10 (DEKAVIL), F8-ratIL10 as well as KSF-humanIL10 (irrelevant antigen-specificity) were used. Treatment was performed weekly for 10 weeks starting at day 7 after transplantation (1mg/animal). RESULTS: In the cardiac allografts, treatment with F8-huIL10 or F8-ratIL10 was associated with increased heart weights, a higher grade of chronic rejection, increased CIF, higher protein expression levels of alpha-smooth muscle actin (alpha-SMA), an augmented infiltration with inflammatory cells (CD4+, CD8+ and CD68+ cells) and higher serum levels of brain natriuretic peptide (BNP) compared to the control groups. CONCLUSIONS: All observed treatment effects are transplantation-specific since the F8 antibody is specific to ED-A(+) Fn that is not expressed in healthy hearts. A clear targeting effect of F8-huIL10 as well as F8-ratIL10 could be proven. Against that background, a further study is needed to address the question, if F8-IL10 treatment is capable to reduce CAV and CIF starting at a time point when chronic rejection has fully developed (therapeutic approach). PMID- 26056965 TI - Application of the United States acute heart failure risk prediction model in Japanese patients; analysis from a contemporary multicenter registry. PMID- 26056966 TI - The care of adults with congenital heart disease across the globe: Current assessment and future perspective: A position statement from the International Society for Adult Congenital Heart Disease (ISACHD). AB - The number of adults with congenital heart disease (CHD) has increased markedly over the past few decades as a result of astounding successes in pediatric cardiac care. Nevertheless, it is now well understood that CHD is not cured but palliated, such that life-long expert care is required to optimize outcomes. All countries in the world that experience improved survival in CHD must face new challenges inherent to the emergence of a growing and aging CHD population with changing needs and medical and psychosocial issues. Founded in 1992, the International Society for Adult Congenital Heart Disease (ISACHD) is the leading global organization of professionals dedicated to pursuing excellence in the care of adults with CHD worldwide. Recognizing the unique and varied issues involved in caring for adults with CHD, ISACHD established a task force to assess the current status of care for adults with CHD across the globe, highlight major challenges and priorities, and provide future direction. The writing committee consisted of experts from North America, South America, Europe, South Asia, East Asia, and Oceania. The committee was divided into subgroups to review key aspects of adult CHD (ACHD) care. Regional representatives were tasked with investigating and reporting on relevant local issues as accurately as possible, within the constraints of available data. The resulting ISACHD position statement addresses changing patterns of worldwide epidemiology, models of care and organization of care, education and training, and the global research landscape in ACHD. PMID- 26056967 TI - Real-time three-dimensional transesophageal echocardiographic evaluation of the association of bicuspid aortic valve and mitral posterior leaflet hypoplasia. PMID- 26056968 TI - Rescues conducted by surfers on Australian beaches. AB - This study describes the demographics, occurrence, location, primary hazards and outcomes involved in rescues performed by surfers on Australian beaches. Conservative estimates suggest that the number of rescues conducted by Australian surfers each year is on par with the number conducted by volunteer surf lifesavers. Surfers perform a considerable number of serious rescues in both lifesaver/lifeguard patrolled (45%) and unpatrolled (53%) beach locations. Rip currents represent the major physical hazard leading to rescue (75%) and the dominant emotional response of people rescued is one of panic (85%). Most surfer rescue events occur during conditions of moderate waves and sunny, fine weather with the highest proportion of rescues occurring on quiet beaches with few people around (26%). Swimming is the activity associated with most rescue events (63%), followed by board riding (25%). Males aged 18-29 represent the largest demographic of people rescued. Surfers with prior water-safety training are more likely to perform a higher number of rescues, however ability to perform rescues is not associated with formal training, but rather number of years' experience surfing. Seventy-eight percent of surfers were happy to help, while 28% expressed feelings of annoyance or inconvenience, generally towards unwary swimmers. Results of this research suggest that 63% of surfers feel they have saved a life. This value may be enhanced through improved training of surfers in basic water safety rescue techniques. PMID- 26056969 TI - Seemingly irrational driving behavior model: The effect of habit strength and anticipated affective reactions. AB - An increasing amount of evidence suggests that aberrant driving behaviors are not entirely rational. On the basis of the dual-process theory, this study postulates that drivers may learn to perform irrational aberrant driving behaviors, and these behaviors could be derived either from a deliberate or an intuitive decision-making approach. Accordingly, a seemingly irrational driving behavior model is proposed; in this model, the theory of planned behavior (TPB) was adopted to represent the deliberate decision-making mechanism, and habit strength was incorporated to reflect the intuitive decision process. A multiple trivariate mediation structure was designed to reflect the process through which driving behaviors are learned. Anticipated affective reactions (AARs) were further included to examine the effect of affect on aberrant driving behaviors. Considering the example of speeding behaviors, this study developed scales and conducted a two-wave survey of students in two departments at a university in Northern Taiwan. The analysis results show that habit strength consists of multiple aspects, and frequency of past behavior cannot be a complete repository for accumulating habit strength. Habit strength appeared to be a crucial mediator between intention antecedents (e.g., attitude) and the intention itself. Including habit strength in the TPB model enhanced the explained variance of speeding intention by 26.7%. In addition, AARs were different from attitudes; particularly, young drivers tended to perform speeding behaviors to reduce negative feelings such as regret. The proposed model provides an effective alternative approach for investigating aberrant driving behaviors; corresponding countermeasures are discussed. PMID- 26056970 TI - Metro passenger behaviors and their relations to metro incident involvement. AB - The frequent incidents caused by metro passengers in China suggest that it is necessary to explore the classification and effects of passenger behaviors and their relations to incident involvement. A metro passenger behavior questionnaire (MPBQ) and a metro station staff questionnaire (MSSQ), both comprising 32 behavior items, were developed and surveyed on a sample of metro passengers (N=579) and metro staff (N=99). Using the MPBQ, the self-reported frequency of each aberrant behavior was measured and subjected to explanatory factor analysis, which revealed a three-factor solution on the 28 retained behavior items: transgressions, self-willed inattentions and abrupt violations. ANOVA was used to examine the effects of demographic and riding profile variables on different types of behaviors. The MSSQ was used to collect metro staff opinions on behavior frequency, severity and entities that might be affected, given that a specific behavior occurred. An importance hierarchy was established over the 32 identified behaviors to determine the most important riding behaviors. Finally, logistic regression showed that riding time, number of stops experienced by a passenger and, more importantly, transgressions and abrupt violations, were significant predictors of incident involvement. The possible explanations and implications of the findings might help in understanding passenger behaviors and targeting metro safety interventions in ways that promote safer operations. PMID- 26056971 TI - Effect of tocopherol and acetylsalicylic acid on the biochemical indices of blood in dioxin-exposed rats. AB - New sources of dioxins and increased dioxin concentrations in the environment, coupled with their increased bioavailability along the food chain and accumulation in adipose tissues, contribute to various adverse long-term biological effects. The purpose of the study was to determine whether tocopherol protects the CNS by decreasing the pro-inflammatory influence of free radicals generated by TCDD; whether acetylsalicylic acid inhibits the production of inflammatory mediators; and whether the combined administration of tocopherol and acetylsalicylic acid to TCDD-exposed rats has a potential CNS-protective effect. The study included 117 rats divided into 8 groups: 75 female and 12 male Buffalo rats aged 8-10 weeks, weighing 140-160 g; as well as 30 female rats aged 6 weeks and weighing 120 g, which were the offspring of females from each study group. In the experiment, the following substances were used: 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD), dosed at 5 MUg/kg BW and 12.5 MUg/kg BW, diluted in a 1% DMSO solution at the concentration of 1 MUg/ml; alpha-tocopherol acetate, dosed at 30 mg/kg BW, in 0.2 ml of oil solution; and acetylsalicylic acid, 50mg/kg BW, suspended in 0.5 ml of starch solution, administered orally using a feeding tube. Pleurisy was induced by an injection of 0.15 ml of 1% carrageenin solution. The use of tocopherol reduces the adverse effects of the inflammatory reaction induced by TCDD. Administering tocopherol improves protein metabolism by reducing protein catabolism, and raises gamma-globulin fraction levels. Combined acetylsalicylic acid and tocopherol suppress catabolic processes accompanying inflammation. PMID- 26056972 TI - Expression of the Mre11-Rad50-Nbs1 complex in cisplatin nephrotoxicity. AB - The aim of this study was to explore whether the Mre11, Rad50, and Nbs1 (MRN) complex is associated with DNA repair mechanisms in cisplatin-induced acute renal failure. Rats were randomly allocated into three groups: control, sacrificed 5 days (5D), and 10 days (10D) after 5mg/kg of cisplatin injection. The 5D group showed disrupted renal function together with enhanced MRN complex- and DNA repair-related protein expression. Meanwhile, in the 10D group, recovery from cisplatin-induced damage was accompanied by the reduced MRN expression, although the expression was still distinctive in proximal tubular cells and higher than the control group. Moreover, pretreatment with mirin, an MRN complex inhibitor, decreased cell viability and inhibited proliferating cell nuclear antigen expression in cisplatin-treated human embryonic kidney 293 cells. Taken together, cisplatin treatment could trigger the MRN complex expression in the kidney and inhibition of the complex might aggravate damage recovery processes. PMID- 26056973 TI - Reference values of hair toxic trace elements content in occupationally non exposed Russian population. AB - A total of 5908 occupationally non-exposed adults (4384 women and 1524 men) living in Moscow and Moscow region were involved in the current investigation. Hair Al, As, Be, Bi, Cd, Hg, Li, Ni, Pb, Sn, and Sr content was estimated by inductively-coupled plasma mass spectrometry using NexION 300D. Men are characterized by significantly higher hair Al, As, Cd, Hg, Li, and Pb content. At the same time, hair levels of Bi, Ni, Sn, and Sr were significantly higher in women. Consequently, the reference ranges were estimated for male, female, and general cohort as coverage intervals in accordance with IUPAC recommendations. PMID- 26056947 TI - Sigma receptors [sigmaRs]: biology in normal and diseased states. AB - This review compares the biological and physiological function of Sigma receptors [sigmaRs] and their potential therapeutic roles. Sigma receptors are widespread in the central nervous system and across multiple peripheral tissues. sigmaRs consist of sigma receptor one (sigma1R) and sigma receptor two (sigma2R) and are expressed in numerous regions of the brain. The sigma receptor was originally proposed as a subtype of opioid receptors and was suggested to contribute to the delusions and psychoses induced by benzomorphans such as SKF-10047 and pentazocine. Later studies confirmed that sigmaRs are non-opioid receptors (not an u opioid receptor) and play a more diverse role in intracellular signaling, apoptosis and metabolic regulation. sigma1Rs are intracellular receptors acting as chaperone proteins that modulate Ca2+ signaling through the IP3 receptor. They dynamically translocate inside cells, hence are transmembrane proteins. The sigma1R receptor, at the mitochondrial-associated endoplasmic reticulum membrane, is responsible for mitochondrial metabolic regulation and promotes mitochondrial energy depletion and apoptosis. Studies have demonstrated that they play a role as a modulator of ion channels (K+ channels; N-methyl-d-aspartate receptors [NMDAR]; inositol 1,3,5 triphosphate receptors) and regulate lipid transport and metabolism, neuritogenesis, cellular differentiation and myelination in the brain. sigma1R modulation of Ca2+ release, modulation of cardiac myocyte contractility and may have links to G-proteins. It has been proposed that sigma1Rs are intracellular signal transduction amplifiers. This review of the literature examines the mechanism of action of the sigmaRs, their interaction with neurotransmitters, pharmacology, location and adverse effects mediated through them. PMID- 26056974 TI - Effects of N-butylphthalide on the activation of Keap1/Nrf-2 signal pathway in rats after carbon monoxide poisoning. AB - Carbon monoxide (CO) is the leading cause of death by poisoning all over the world and may result in neuropathologic changes and cognitive and neurologic sequelae, yet little is known regarding its outcomes. The present study aimed to evaluate the neuroprotective effects of N-butylphthalide (NBP) against brain damage after acute CO poisoning. The animal model of CO poisoning was established by exposed to 1000 ppm CO in air for 40 min and then to 3000 ppm for another 20 min. RT-PCR was used to assess the expressions of apoptosis-associated genes Bcl 2 mRNA and Bax mRNA. Mitochondrial membrane potential (MMP) was detected by fluorescent probe JC-1. Immunohistochemistry stain and Western blot assay were used to evaluate the expression levels of Kelch-like ECH-associated protein 1 (Keapl), nuclear factor erythroid 2-related factor 2 (Nrf-2) and NAD(P)H: quinone oxidoreductase 1(NQO-1). CO poisoning could increase the levels of Bcl-2 mRNA and Bax mRNA expressions, and obviously decrease the MMP of cells. NBP treatment could maintain the high MMP, significantly up-regulate Bcl-2 mRNA and down regulate Bax mRNA expression, and the ratio of Bcl-2 mRNA/Bax mRNA expressions was higher than that in the CO poisoning group (P<0.05). CO poisoning could start oxidative stress response. The expressions of Keap1, Nrf-2 and NQO-1 proteins significantly increased at 1, 3 and 7 day after NBP administration as compared with the CO poisoning group (P<0.01). These findings suggest that N butylphthalide may protect mitochondrial function, balance the expressions of anti-apoptosis genes and pro-apoptosis genes, be in part associated with activation of Keap1-Nrf-2/antioxidant response element (ARE) signaling pathway, and play a neuroprotective role in brain damage after acute CO poisoning. PMID- 26056975 TI - Anti-metastatic effects of Rheum Palmatum L. extract in human MDA-MB-231 breast cancer cells. AB - Rheum palmatum L. (RP) has been widely used in traditional medicine for the treatment of various diseases in Asian countries. The molecular mechanism of its anti-metastasis effect remains elusive. The present study assessed the effect of RP ethanol extract (RPE) on the highly metastatic human MDA-MB-231 breast cancer cells in vitro. At a non-toxic concentration, RPE inhibited migration, motility and invasion in a concentration-dependent manner. To investigate the mechanisms involved, real-time PCR and Western blot analyses were performed. Results showed that RPE down-regulated the levels of extracellular matrix degradation-associated proteins, including MMP-2/-9, uPA and uPAR, and up-regulated PAI-1. In addition, RPE affected NF-kappaB by degrading IkBalpha, and affected the mitogen-activated protein kinase signal transduction pathway by depressing the activation of p38, ERK and Akt. These results suggest that RPE has potential anti-metastatic activity and warrants further investigation. PMID- 26056976 TI - Comparative high pressure Raman studies on perfluorohexane and perfluoroheptane. AB - High pressure Raman spectroscopic studies on perfluorohexane and perfluoroheptane have performed up to 12 GPa. Perfluorohexane under goes two pressure induced transitions: (1) liquid-solid transition at 1.6 GPa and (2) solid-solid transition at 8.2 GPa. On the contrary, perfluoroheptane under goes three phase transitions, they are as follows: (1) liquid-solid transition at 1.3 GPa, (2) intermediate solid I transition at 3 GPa, (3) solid II transition at 7 GPa. The change in slope (domega/dP) shows that the solid I transition at 3.0 GPa could be the conversion of mid-gauche defect into trans conformers for perfluoroheptane. The pressure induced Raman spectra and the behavior of individual band with pressure shows that the solid phase comprises more than one conformer beyond crystallization. The intensity ratio for both the compounds shows that the high pressure phase beyond 8.2 and 7.0 GPa tends to have close packing with distorted all-trans conformers. PMID- 26056977 TI - Structural characterization of new Schiff bases of sulfamethoxazole and sulfathiazole, their antibacterial activity and docking computation with DHPS protein structure. AB - New Schiff bases (1, 2) of substituted salicylaldehydes and sulfamethoxazole (SMX)/sulfathiazole (STZ) are synthesized and characterized by elemental analysis and spectroscopic data. Single crystal X-ray structure of one of the compounds (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(5-methylisoxazol-3 yl)benzenesulfonamide (1c) has been determined. Antimicrobial activities of the Schiff bases and parent sulfonamides (SMX, STZ) have been examined against several Gram-positive and Gram-negative bacteria and sulfonamide resistant pathogens; the lowest MIC is observed for (E)-4-((3,5-dichloro-2 hydroxybenzylidene)amino)-N-(thiazol-2-yl)benzene sulfonamide (2c) (8.0 MUg mL( 1)) and (E)-4-((3,5-dichloro-2-hydroxybenzylidene)amino)-N-(5-methylisoxazol-3 yl)benzene sulfonamide (1c) (16.0 MUg mL(-1)) against sulfonamide resistant pathogens. DFT optimized structures of the Schiff bases have been used to carry out molecular docking studies with DHPS (dihydropteroate synthase) protein structure (downloaded from Protein Data Bank) using Discovery Studio 3.5 to find the most preferred binding mode of the ligand inside the protein cavity. The theoretical data have been well correlated with the experimental results. Cell viability assay and ADMET studies predict that 1c and 2c have good drug like characters. PMID- 26056978 TI - Spectral, morphological, linear and nonlinear optical properties of nanostructured benzimidazole metal complex thin films. AB - Metal organic materials are widely investigated to find their suitability for nonlinear optical applications due to the advantage of combined organic and inorganic properties. In this work benzimidazole based metal organic thin films of dichlorobis (1H-Benzimidazole) Co(II) and dichlorobis (1H-Benzimidazole) Cu(II) were deposited by chemical bath deposition method. The deposited films were annealed at 100, 150 and 200 degrees C to investigate the effect of annealing on the properties of thin films. Surface homogeneity of the films was increased with the annealing temperature due to the surface diffusion of the films and the same was evidently shown by Raman spectroscopy and Atomic Force Microscopy studies. But annealing the films at 200 degrees C yielded bulk patches on the surface due to the distortion of molecules. Linear and nonlinear optical properties of the films annealed at 150 degrees C showed relatively higher transmittance and improved nonlinear optical properties than the other as prepared and annealed samples. PMID- 26056979 TI - Synthesis, structure, protein binding of Cu(II) complexes with a tridentate NNO Schiff-base ligand. AB - Four new Cu(II) complexes (1, 2, 3 and 4) in the presence of different anions (Cl(-), Br(-), I(-) and ClO4(-)) have been prepared by tridentate NNN Schiff-base ligand (N,N-dimethyl-N'-[phenyl(2-pyridyl)methylene]ethane-1,2-diamine) and well characterized by single-crystal X-ray diffraction, elemental analysis, IR and UV Vis spectroscopy. The interactions of complexes 1-4 with human serum albumin (HSA) have been investigated in Tris-HCl buffer solution at pH 7.4 by spectroscopic methods and a molecular docking technique. Experimental results proved that the four complexes quench the fluorescence of HSA through a static quenching mechanism. Thermodynamic parameters were calculated from Van't Hoff equation. The distance r between the donor (HSA) and acceptor (complexes 1-4) has been obtained by means of Forester resonance energy transfer (FRET). Molecular docking results indicated that the main active binding sites for complexes 1, 2 and 4 are site III in subdomain IB and for complex 3 is site II in subdomain III A. The combination of molecular docking results and fluorescence experimental results indicate that the interaction between 1-4 and HSA are dominated by hydrophobic forces as well as hydrogen bonds. PMID- 26056980 TI - Far infrared spectra of solid state L-serine, L-threonine, L-cysteine, and L methionine in different protonation states. AB - In this study, experimental far infrared measurements of L-serine, L-threonine, L cysteine, and L-methionine are presented showing the spectra for the 1.0-13.0 pH range. In parallel, solid state DFT calculations were performed on the amino acid zwitterions in the crystalline form. We focused on the lowest frequency far infrared normal modes, which required the most precision and convergence of the calculations. Analysis of the computational results, which included the potential energy distribution of the vibrational modes, permitted a detailed and almost complete assignment of the experimental spectrum. In addition to characteristic signals of the two main acid-base couples, CO2H/CO2(-) and NH3(+)/NH2, specific side chain contributions for these amino acids, including CCO and CCS vibrational modes were analyzed. This study is in line with the growing application of FIR measurements to biomolecules. PMID- 26056981 TI - Synthesis, crystal structure, photoluminescence property of a series of 3d-4f coordination supramolecular complexes. AB - A series of 3d-4f heterobinuclear complexes were constructed by employing the 2,2'-bipy (2,2'-bipy=2,2'-bipyridine) ligand and corresponding metal ions (M(II)/Ln(III), M=Co(II), Cu(II) and Zn(II); Ln(III)=Nd(III), Sm(III), Eu(III) and Tb(III)). Elemental analyses, IR, UV-vis-NIR spectra, PXRD and single crystal X-ray diffraction analysis reveal that complexes 1-4, 5-8, and 9-12 are isomorphous, respectively. The zero-dimensional structures are further connected to 2D or 3D supramolecular network structures via extensive intermolecular hydrogen bonds. Luminescence studies for the heterobinuclear complexes containing Sm(III), Eu(III) and Tb(III) reveal that the chromophoric composed of Zn(II)/L may efficiently sensitize the luminescence of the rare earth cations which acts as an antenna, whereas the existence of Cu(II) leads to the quenching of the luminescence of Ln(III) ions. PMID- 26056982 TI - Synthesis, crystal structures and photoluminescence of anthracen- and pyrene based coumarin derivatives. AB - Two new anthracen- and pyrene-based coumarin derivatives, 3-(4-(anthracen-10 yl)phenyl)coumarin (4) and 3-(4-(pyrene-1-yl)phenyl)coumarin (5), were synthesized and characterized by FT-IR, (1)H NMR, element analysis and single crystal X-ray crystallography. The UV-vis absorption and photoluminescence spectra of these coumarin derivatives were investigated. The results show that compound 4 and 5 exhibit blue and blue-green emissions, respectively, under ultraviolet light excitation. Compared with the compound 4, the emission peak of compound 5 was bathochromically shifted by about 80 nm due to the more planar structure and larger pi-conjugation. PMID- 26056983 TI - Albumin-induced circular dichroism in Congo red: Applications for studies of amyloid-like fibril aggregates and binding sites. AB - Congo red (CR), one of the most commonly used dyes for the identification of amyloid fibril aggregates, is also a ligand of native bovine serum albumin (BSA). Induced circular dichroism (ICD) is a phenomenon observed when a chiral compound induces chirality in an achiral one. Here, we study the spectral properties and analytical applications of ICD in Congo red provoked by its interaction with BSA. The complex BSA:CR displays a strong ICD spectrum with a positive band at 412 nm and two negative bands at 356 and 490 nm. The use of site I and site II albumin ligands as warfarin and ibuprofen, respectively, provoked different alterations in the Congo red ICD spectrum. The BSA binding sites were modified by oxidation and the ICD signal was sensitive to this alteration. The thermal treatment of the BSA:CR complex (30-90 degrees C) was monitored by ICD at 490 nm and showed a sigmoidal pattern typical of phase transition in proteins. The altered ICD spectrum is consistent with the formation of amyloid-like fibril aggregates in BSA, which was confirmed by thioflavin T and Rayleigh scattering assays. In conclusion, the ICD provoked by the binding of Congo red to albumin may represent a new spectroscopic technique for studying alterations in the structure of albumin regarding its binding sites and the formation of amyloid aggregates. PMID- 26056984 TI - Inhibiting plasmon catalyzed conversion of para-nitrothiophenol on monolayer film of Au nanoparticles probed by surface enhanced Raman spectroscopy. AB - The plasmon catalyzed surface reaction has been attracted considerable attention due to its promising application in heterogeneous catalysis. This kind of plasmon catalysis played bilateral roles in driving the unconventional reactions or destructing the surface molecule layer. The acceleration or inhibition on this catalysis is still remained significant challenge. In this paper, monolayer film of Au nanoparticles was fabricated at air/water interface as substrates both for surface enhanced Raman spectroscopy (SERS) and plasmon catalyzed surface reaction. The influence from several issues, involving surfactants, coadsorption species, the solvent and water, were systemically investigated to probe the acceleration and inhibition on the plasmon catalysis reaction. The concentration and molecular weight of surfactant polyvinylpyrrolidone (PVP) exhibited significant influence in the reactive activity for the plasmon catalyzed dimerization of para-nitrothiophenol (PNTP) to p,p'-dimercaptoazobenzene (DMAB). A suitable molecular weight of 10,000 and concentration of 10mg/mL were beneficial for improving the conversion efficiency of PNTP to DMAB. The higher molar ratio of coadsorbed 1-octanethiol and the aprotic solvents resulted in the inhibition of dimerization because 1-octanethiol occupied the surface sites to isolate the adsorbed PNTP molecules with a larger distance and lack of proton source. The plasmon catalysis occurred in ionic liquids suggested that water was essential for the dimerization of PNTP, in which it was used to accelerate the reaction rate and severed as the hydrogen source. PMID- 26056985 TI - Raman, infrared and NMR spectral analysis, normal coordinate analysis and theoretical calculations of 5-(methylthio)-1,3,4-thiadiazole-2(3H)-thione and its thiol tautomer. AB - Raman (3400-100 cm(-1)) and infrared (4000-200 cm(-1)) spectra of 5-(methylthio) 1,3,4-thiadiazole-2(3H)-thione (C3H4N2S3; MTT) were measured in the solid state, and the (1)H/(13)C NMR spectra were obtained in DMSO-d6. Initially, twelve structures were proposed as a result of thiol-thione tautomerism and the internal rotation about the C-S bonds. The energies and vibrational frequencies of the optimized structures were calculated using the 6-31G(d) basis set with the methods of MP2 and DFT/B3LYP with Gaussian 98 quantum calculations. Additionally, (1)H/(13)C NMR chemical shifts were predicted for the thiol (structure 5) and thione (structure 9) tautomers by means of B3LYP/6-311+G(d,p) calculations utilizing the GIAO approximation and the PCM solvation model. After complete relaxation of twelve candidate isomers, the thione tautomer (structure 9) was favored owing to its low energy and its predicted real spectral frequencies. These results agree with the recorded infrared and Raman results, in addition to the observed/calculated (1)H and (13)C NMR spectra. Aided by normal coordinate analysis and potential energy distributions (PEDs), complete vibrational assignments have been proposed for all observed fundamentals for the thione tautomer. With the aid of MP2/6-31G(d) potential surface scans, CH3, CH3S, and SH barriers to internal rotations were estimated with the optimized structural parameters from the MP2 method with the 6-31G(d) basis set. The results are discussed herein and compared with similar model compounds whenever appropriate. PMID- 26056986 TI - Investigation of role of silver nanoparticles on spectroscopic properties of biologically active coumarin dyes 4PTMBC and 1IPMBC. AB - The role of silver nanoparticles on spectroscopic properties of biologically active coumarin dyes 4-p-tolyloxymethyl-benzo[h]coumarin (4PTMBC) and 1-(4 iodophenoxymethyl)-benzo[f]coumarin (1IPMBC) has been investigated using absorption and fluorescence spectroscopy. Silver nanoparticles are synthesized by chemical reduction method and the estimated size by Mie theory is 12 nm. The absorption spectral changes of dyes in the presence of silver nanoparticles suggest their possible interaction with silver nanoparticles. The apparent association constants of the interaction are estimated using Benesi-Hildebrand model. Fluorescence quenching has been observed in both the dyes with the addition of silver nanoparticles. The Stern-Volmer plots of fluorescence quenching are found to be nonlinear showing positive deviation. The magnitudes of quenching rate parameter and fluorescence lifetime measurements indicate the presence of both collisional and static quenching mechanisms. The binding constants and the number of binding sites for the static type of quenching have been estimated from the fluorescence data. The role of diffusion, energy transfer and electron transfer processes in fluorescence quenching mechanism has been discussed. PMID- 26056987 TI - Breath-holding in a marijuana smoker. AB - It is vital to ask about illicit drug smoking in the respiratory history as marijuana smoking augments the detrimental effects of tobacco. We describe the case of a 28 year old marijuana smoker who developed a pneumothorax during a breath-holding competition. Pneumothorax is a common clinical entity that every physician should be aware of how to manage and lifetime risk is considerably increased by smoking and in exposure to barotrauma. PMID- 26056988 TI - pH-Responsive guar gum hydrogels for controlled delivery of dexamethasone to the intestine. AB - pH-Responsive hydrogel systems based on guar gum (GG), poly(acrylic acid) (PAA) and beta-cyclodextrin (CD) using a non-toxic crosslinker, tetraethyl orthosilicate for intestinal delivery of dexamethasone (DX) has been reported. Hydrogels of different compositions were synthesized and evaluated for the controlled delivery of DX. The hydrogels exhibited pH-responsive swelling behavior with a maximum swelling around neutral pH. The CD-containing hydrogels deliver the drug at much slower rate in contrast to the ones without CD. Moreover, the drug release rate is found to show a strong dependence on the GG content and the effect of GG is more pronounced in case of the CD containing hydrogels. As the GG content increases, the rate of drug release decreases considerably and the drug release is prolonged. The release studies in the simulated conditions reveal that these hydrogels can be used as delivery vehicles for oral administration of DX targeting the intestine. Cell viability studies reveal the hydrogels to be biocompatible in nature thus validating them as good drug delivery systems. PMID- 26056989 TI - Fabrication of biodendrimeric beta-cyclodextrin via click reaction with potency of anticancer drug delivery agent. AB - The aim of this work was the synthesis of biodendrimeric beta-cyclodextrin (beta CD) on the secondary face with encapsulation efficacy, with beta-CDs moiety to preserve the biocompatibility properties, also particularly growth their loading capacity for drugs with certain size. The new dendrimer, having 14 beta-CD residues attached to the core beta-CD in secondary face (11), was prepared through click reaction. The encapsulation property of the prepared compound was evaluated by methotrexate (MTX) drug molecule. Characterization of compound 11 was performed with (1)H NMR, (13)C NMR and FTIR and its supramolecular inclusion complex structure was determined using FTIR, DLS, DSC and SEM techniques. In vitro cytotoxicity test results showed that compound 11 has very low or no cytotoxic effect on T47D cancer cells. In vitro drug release study at pHs 3, 5 and 7.4 showed that the release process was noticeably pH dependent and the dendrimer could be used as an appropriate controlled drug delivery system (DDS) for cancer treatment. PMID- 26056990 TI - Structural features and immunostimulating effects of three acidic polysaccharides isolated from Panax quinquefolius. AB - Three acidic polysaccharides (PPQA2, PPQA4 and PPQA5) were successfully purified from the water-extracted crude polysaccharides of Panax quinquefolius by combination of DEAE Sepharose and Sephacryl S-300 chromatography. The average molecular weights (Mws) of PPQA2, PPQA4 and PPQA5 were 2.3*10(4) Da, 1.2*10(5) Da, and 5.3*10(3) Da, respectively. Monosaccharides components analysis indicated that PPQA2 and PPQA5 were composed of arabinose, rhammose, mannose, galactose, glucose, galacturonic acid and glucuronic acid in a molar percent of 8.0:4.0:2.9:7.2:12.5:26.6:38.8 and 8.5:3.2:5.3:10.8:32.4:15.5:24.4. PPQA4 was composed of arabinose, rhammose, mannose, galactose, glucose and glucuronic acid in a molar percent of 19.7:5.1:8.1:23.9:41.3:2.0. The (13)C NMR spectra indicated the existence of O-acetyl groups in PPQA2 and PPQA5, while absence in PPQA4. The in vitro study showed that PPQA2, PPQA4 and PPQA5 were all able to stimulate the production of secretory molecules (NO, TNF-alpha, and IL-6) of RAW264.7 murine macrophages in a dose-dependent manner. These findings suggest that the three acidic polysaccharides isolated in our study have immunopotentiating effects on macrophages and should be used as a beneficial health food. PMID- 26056991 TI - A novel detergent-stable solvent-tolerant serine thiol alkaline protease from Streptomyces koyangensis TN650. AB - An alkaline proteinase (STAP) was produced from strain TN650 isolated from a Tunisian off-shore oil field and assigned as Streptomyces koyangensis strain TN650 based on physiological and biochemical properties and 16S rRNA gene sequencing. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) analysis revealed that the purified enzyme was a monomer with a molecular mass of 45125.17-Da. The enzyme had an NH2-terminal sequence of TQSNPPSWGLDRIDQTTAFTKACSIKY, thus sharing high homology with those of Streptomyces proteases. The results showed that this protease was completely inhibited by phenylmethanesulfonyl fluoride (PMSF), diiodopropyl fluorophosphates (DFP), and partially inhibited by 5,5-dithio-bis-(2-nitro benzoic acid) (DTNB), which strongly suggested its belonging to the serine thiol protease family. Using casein as a substrate, the optimum pH and temperature values for protease activity were pH 10 and 70 degrees C, respectively. The protease was stable at pH 7-10 and 30-60 degrees C for 24 h. STAP exhibited high catalytic efficiency, significant detergent stability, and elevated organic solvent resistance compared to the SG-XIV proteases from S. griseus and KERAB from Streptomyces sp. AB1. The stap gene encoding STAP was isolated, and its DNA sequence was determined. These properties make STAP a potential candidate for future application in detergent formulations and non-aqueous peptide biocatalysis. PMID- 26056992 TI - Influence factors and gene expression patterns during MeJa-induced gummosis in peach. AB - Jasmonates (JAs) play important roles in gummosis in peach. Mechanical damage, methyl jasmonate (MeJa), and ethylene can induce gummosis on peach shoots in the field. In this study, we used MeJa (2%, w/w) to induce gummosis on current-year shoots in peach on high temperature (35 degrees C). Based on the experimental model, we studied the influence of factors on the development of peach gummosis. Our experimental results showed that high temperature could promote gummosis development induced by MeJa. Exogenous CaCl2 treatment reduced the degree of gummosis by increasing the calcium content in shoots, which is conducive to the synthesis and maintenance of the cell wall. Using digital gene expression (DGE), 3831 differentially expressed genes were identified in the MeJa treatment versus the control. By analyzing changes in gene expression associated with cell wall degradation, genes encoding pectin methylesterase (PME) and endo polygalacturonase (PG) were found to be significantly induced, suggesting that they are key enzymes in cell wall degradation that occurs during MeJa-induced gummosis. Genes for glycosyltransferase (GT) and cellulose synthase (CS) were also significantly upregulated by MeJa. This result suggests that MeJa treatment not only promotes the degradation of polysaccharides to destroy the cell wall, but also promotes the synthesis of new polysaccharides. We also analyzed changes in gene expression associated with sugar metabolism, senescence, and defense. MeJa treatment affected the expression of genes related to sugar metabolism and promoted plant senescence. Among the defense genes, the expression pattern of phenylalanine ammonium lyase (PAL) suggested that PAL may play an important role in protecting against the effects of MeJa treatment. Our experimental results showed that MeJa treatment can promote the biosynthesis and signal transduction of ethylene in peach shoots; they can induce gummosis on peach shoots respectively, and there are overlaps between the molecular mechanisms of gummosis induced by them, the intersection point between them remains unclear. PMID- 26056993 TI - Plant development regulation: Overview and perspectives. AB - Plant development, as occur in other eukaryotes, is conducted through a complex network of hormones, transcription factors, enzymes and micro RNAs, among other cellular components. They control developmental processes such as embryo, apical root and shoot meristem, leaf, flower, or seed formation, among others. The research in these topics has been very active in last decades. Recently, an explosion of new data concerning regulation mechanisms as well as the response of these processes to environmental changes has emerged. Initially, most of investigations were carried out in the model eudicot Arabidopsis but currently data from other plant species are available in the literature, although they are still limited. The aim of this review is focused on summarize the main molecular actors involved in plant development regulation in diverse plant species. A special attention will be given to the major families of genes and proteins participating in these regulatory mechanisms. The information on the regulatory pathways where they participate will be briefly cited. Additionally, the importance of certain structural features of such proteins that confer ductility and flexibility to these mechanisms will also be reported and discussed. PMID- 26056994 TI - Organophosphorus flame retardants in the European eel in Flanders, Belgium: Occurrence, fate and human health risk. AB - The present study investigated the levels, profiles and human health risk of organophosphorus flame retardants and plasticizers (PFRs) in wild European eels (Anguilla anguilla) from freshwater bodies in the highly populated and industrial Flanders region (Belgium). Yellow eels (n=170) were collected at 26 locations between 2000 and 2009 and for each site, muscle samples of 3-10 eels were pooled and analyzed (n=26). Muscle lipid percentages varied widely between 2.4% and 21%, with a median value of 10%. PFRs were detected in all pooled samples in the order of tris-2-chloroisopropyl phosphate (TCIPP)>triphenyl phosphate (TPHP)>2 ethylhexyl diphenyl phosphate (EHDPHP)>tris-2-butoxyethyl phosphate (TBOEP)>tris 2-chloroethyl phosphate (TCEP)>tris-1,3-dichloro-2-propyl phosphate (TDCIPP). The median sum PFR concentration for all 26 sites was 44 ng/g lw (8.4 ng/g ww), and levels ranged between 7.0 and 330 ng/g lw (3.5 and 45 ng/g ww). Levels and profiles of PFRs in eels showed that sampling locations and river basin catchments are possible drivers of spatial variation in the aquatic environment. Median PFR concentrations were lower than those of polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs). No correlation was observed between the PFR concentrations and lipid contents, suggesting that the accumulation of PFRs is not primarily associated with lipids. Human exposure to PFRs, due to consumption of wild eels, seems to be of minor importance compared to other potential sources, such as inhalation and ingestion of indoor dust. Nevertheless, considering the very limited data available on PFRs in human dietary items and their expected increasing use after the phase out of PBDEs and HBCDs, further investigations on PFRs in biota and human food items are warranted. PMID- 26056995 TI - Fetal growth and maternal exposure to particulate air pollution--More marked effects at lower exposure and modification by gestational duration. AB - While there is growing evidence that air pollution reduces fetal growth, results are inconclusive with respect to the gestational window of effect. We investigated maternal exposure to particulate matter (PM10) in association with birth weight and fetus growth with a focus on the shape of the association and gestational age at birth as a potential effect modifier. The study population consisted of 525,635 singleton live births in Flanders (Belgium) between 1999 and 2009. PM10 exposure at maternal residence was averaged over various time windows. We used robust linear and logistic regression to estimate the effect of PM10 on birth weight and small for gestational age (SGA). Segmented regression models were applied for non-linear associations. Among moderately preterm (32-36 weeks) and term (>36 weeks) births, we found significant lower birth weight for all studied time windows. The estimated reduction in birth weight for a 10 ug/m(3) increase in average PM10 during pregnancy was 39.0 g (95% confidence interval [CI]: 26.4, 51.5 g) for moderately preterm births and 24.0 g (95% CI: 20.9, 27.2g) for term births. The corresponding odds ratios for SGA were 1.19 (95% CI: 1.07, 1.32) and 1.09 (95% CI: 1.06, 1.12) respectively. Segmented regression models showed stronger effects of PM10 on fetal growth at lower concentrations. Maternal PM10 exposure was significantly associated with a reduction in fetal growth among term and moderately preterm births, with a tendency of stronger effects for the latter and a flattening out of the slope at higher PM10 concentrations. PMID- 26056996 TI - The effect of C content on the mechanical properties of Ti-Zr coatings. AB - In this study, Ti-Zr and Ti-Zr-C coatings were deposited at room temperature via pulsed-DC magnetron sputtering. A 70Ti-30Zr at% target and a 99.99% graphite plate were used to deposit samples. In order to modify C content, coatings were deposited at different target powers such as 50, 75 and 100 W. Changes on the structure, microstructure and mechanical properties due to C addition were studied. Results indicate that the as-deposited coatings were partly crystalline and that an increment on C content stabilized alpha' phase and inhibited the appearance of omega precipitates. Therefore, Ti-Zr-C alloys with C>1.9 at% showed only alpha' phase whereas the others alloys exhibited alpha'+omega structures. Hardness values from 12.94 to 34.31 GPa were obtained, whereas the elastic modulus was found between 181.84 and 298 GPa. Finally, a high elastic recovery ratio (0.69-0.87) was observed as a function of composition. The overall properties of these coatings were improved due to C content increment, martensitic alpha' phase and nanocrystalline grain size (10-16 nm). PMID- 26056997 TI - Modeling of damage driven fracture failure of fiber post-restored teeth. AB - Mechanical failure of biomaterials, which can be initiated by either violent force, or progressive stress fatigue, is a serious issue. Great efforts have been made to improve the mechanical performances of dental restorations. Virtual simulation is a promising approach for biomechanical investigations, which presents significant advantages in improving efficiency than traditional in vivo/in vitro studies. Over the past few decades, a number of virtual studies have been conducted to investigate the biomechanical issues concerning dental biomaterials, but only with limited incorporation of brittle failure phenomena. Motivated by the contradictory findings between several finite element analyses and common clinical observations on the fracture resistance of post-restored teeth, this study aimed to provide an approach using numerical simulations for investigating the fracture failure process through a non-linear fracture mechanics model. The ability of this approach to predict fracture initiation and propagation in a complex biomechanical status based on the intrinsic material properties was investigated. Results of the virtual simulations matched the findings of experimental tests, in terms of the ultimate fracture failure strengths and predictive areas under risk of clinical failure. This study revealed that the failure of dental post-restored restorations is a typical damage-driven continuum-to-discrete process. This approach is anticipated to have ramifications not only for modeling fracture events, but also for the design and optimization of the mechanical properties of biomaterials for specific clinically determined requirements. PMID- 26056998 TI - On the mechanical integrity of retrieved dental implants. AB - The objective of this work is to investigate the potential state of mechanical damage in used, albeit mechanically intact, dental implants, after their retrieval from the oral cavity because of progressive bone loss (peri implantitis). 100 retrieved dental implants were characterized with no medical record made available prior to the analysis. The implants' composition, dimensions, and surface treatments were characterized using energy dispersive X ray analysis and scanning electron microscopy (SEM-EDX). Each implant was thoroughly examined for signs of mechanical defects and damage. The implants represent a random combination of two materials, titanium alloy (Ti-6Al-4V) and commercially pure titanium (CP-Ti), surface treatments and geometries. Two kinds of surface defects were identified: crack-like defects and full cracks that were arbitrarily divided according to their length and appearance. We found that over 60% of the implants contained both crack-like defects and full cracks. In the retrieved sample, we observed that the CP-Ti implants contained more defects and cracks than the Ti-6Al-4V ones. For the various surface roughening treatments, a general correlation with the presence of defects was observed, but without a clear differentiation between the treatments. The high incidence of embedded particles among the observed defect further strengthens the role played by the particles upon defects generation, some of which later evolve into full cracks. It was also found that the dimensions of the implant (width and length) were not correlated with the observed defects, for this specific sample. Our observations indicate that early retrieval of biologically failed implants, many of which contain early signs of mechanical failure as shown here, does actually hinder the later occurrence of implant fracture. It seems that once biological complications will be successfully overcome, such defects might grow later into full cracks as a result of cyclic mastication loads (fatigue). In such a case, the occurrence of implants' fracture is likely to markedly increase. PMID- 26056999 TI - Polymerization kinetics and polymerization stress in resin composites after accelerated aging as a function of the expiration date. AB - OBJECTIVES: To determine the effect of material condition (new, aged, and expired) on the polymerization kinetics and polymerization stress of different classifications of dental composites. MATERIALS AND METHODS: Specimens were obtained according to the following factors: Composites: (3M ESPE) Filtek P60, Filtek Z250, Filtek Z350XT, and Filtek Silorane; and Material conditions: new, aged, and expired. The syringe composites underwent an accelerated aging protocol (Arrhenius model) representing approximately 9 months of aging. Infrared (IR) spectra were obtained kinetically and were analyzed for: maximum conversion rate (%/s), time into exposure when maximum rate occurred (s), conversion at maximum rate (%), and total conversion (%) at 90 s by comparison of absorption IR peak ratios before and after polymerization. Polymerization was evaluated at the bottom surface of 2.0 mm-thick specimens. Polymerization stress was determined in a tensilometer, inserting the composite between acrylic rods fixed to clamps in a universal test machine and dividing the maximum load recorded by the rods cross sectional area. Polymerization stress (MPa) was calculated at 300 s. Data were statistically analyzed by two-way ANOVA and Tukey's post hoc test (alpha=0.05). RESULTS: The majority of the polymerization kinetic parameters were not influenced by the material condition. Silorane composite presented significantly lower conversion rate and lower conversion at the maximum rate when expired (p<0.05). The nanofilled composite (Filtek Z350XT) presented a significantly higher total conversion when aged and expired compared to the new one (p>0.05). In all conditions, Filtek Z350XT and Filtek Silorane presented significantly lower conversion rates (p < 0.05). Filtek Silorane also exhibited the lowest stress, irrespective of the material condition (p<0.05). The polymerization stress was not influenced by the material condition (p>0.05). CONCLUSIONS: Most of the kinetic parameters are not influenced by the material condition. Filtek P60 and Filtek Z250 are more stable as both composites present similar polymerization kinetic results, irrespective of the material condition. Silorane composite presents lower stress values among the tested materials in all conditions. Aging does not affect stress development in restorative composites. PMID- 26057000 TI - Silica coated upconversion nanoparticles: a versatile platform for the development of efficient theranostics. AB - Next generation theranostic devices will rely on the smart integration of different functional moieties into one system. These individual chemical elements will have a variety of desired chemical and physical properties and will need to behave in a multifunctional manner. Researchers have used upconversion nanoparticles (UCNPs) as a basis for superior imaging probes to locate cancerous lesions. The features of these nanoparticles, such as large anti-Stokes shifts, sharp emission bands, long-lived luminescence, and high resistance to photobleaching, have produced versatile probes. One way to improve these probes is to add a layer of dense or mesoporous silica to the outer surface of UCNPs (UCNP@SiO2). These modified UCNPs are chemically stable and much less cytotoxic than the original UCNPs. In addition, their surface can be easily modified to introduce various functional groups (e.g., -NH2, -COOH, -SH) via silanization, which facilitates conjugations with various biological molecules for multimodal imaging or synergetic therapeutics. This versatility makes UCNP@SiO2 particles excellent platforms for the construction of efficient theranostics. In this Account, we provide a comprehensive summary of recent progress in the development of UCNP@SiO2 nanocomposites for theranostics in the hope of speeding their translation into the clinic. We first discuss the major design principles and protocols for engineering various nanocomposites based on UCNP@SiO2 structures including those coated with dense silica, mesoporous silica, or hollow mesoporous silica. Next we summarize several representative efforts that probe the relaxivity mechanisms of these nanostructures as a way to optimize magnetic resonance sensitivity, multimode cancer imaging, near-infrared light-triggered chemotherapy, photodynamic therapy, and synergetic therapy (the combination of radiotherapy with chemotherapy, thermotherapy, or photodynamic therapy) using UCNP@SiO2-based theranostics. By rational integration of a wide range of features that convey multiple functions (such as imaging and therapy) into the structure or onto the surfaces of UCNP@SiO2, the constructed theranostics show promise for multimodal cancer imaging, biosensing, and effective cancer therapy. Finally, we discuss the limitations of UCNP@SiO2 nanostructures, the difficulties in the design of smart theranostics, and their potential role in clinical cancer research. PMID- 26057001 TI - Unilateral pulmonary agenesis presenting in adulthood. AB - Agenesis of lung,a rare congenital anomaly,may present in adult life with features of recurrent chest infections and radiologically may mimic many common conditions presenting as opaque hemithorax with ipsilateral shifting of mediastinum.Here, a case of a young man presenting with frequent attacks of cough expectoration and progressive dyspnoea since childhood,proved to be a case of left pulmonary agenesis on CT scan and bronchoscopy, is to be discussed. PMID- 26057003 TI - Metabolic engineering of Escherichia coli for the production of 3-aminopropionic acid. AB - A novel metabolic pathway was designed for the production of 3-aminopropionic acid (3-AP), an important platform chemical for manufacturing acrylamide and acrylonitrile. Using a fumaric acid producing Escherichia coli strain as a host, the Corynebacterium glutamicum panD gene (encoding L-aspartate-alpha decarboxylase) was overexpressed and the native promoter of the aspA gene was replaced with the strong trc promoter, which allowed aspartic acid production through the aspartase-catalyzed reaction. Additional overexpression of aspA and ppc genes, and supplementation of ammonium sulfate in the medium allowed production of 3.49 g/L 3-AP. The 3-AP titer was further increased to 3.94 g/L by optimizing the expression level of PPC using synthetic promoters and RBS sequences. Finally, native promoter of the acs gene was replaced with strong trc promoter to reduce acetic acid accumulation. Fed-batch culture of the final strain allowed production of 32.3 g/L 3-AP in 39 h. PMID- 26057002 TI - WEE1 kinase polymorphism as a predictive biomarker for efficacy of platinum gemcitabine doublet chemotherapy in advanced non-small cell lung cancer patients. AB - DNA-damaging agents are commonly used for first-line chemotherapy of advanced non small cell lung cancer (NSCLC). As a G2/M checkpoint kinase, Wee1 can phosphorylate CDC2-tyr15 and induce G2/M cell cycle arrest in response to DNA damage. The correlation of WEE1 polymorphisms to the efficacy of chemotherapy was tested in 663 advanced NSCLC patients. WEE1 rs3910384 genotype correlated to overall survival (OS) and progress-free survival (PFS) of NSCLC patients treated with platinum-based chemotherapy. Sub-group analysis revealed that rs3910384 was particularly associated with the efficacy of doublet chemotherapy combining two DNA-damaging agents, i.e. platinum and gemcitabine. NSCLC patients with the WEE1 rs3910384 G/G homozygote genotype showed 13.5 months extended OS, 3.2 months extended PFS, and a 274% relative increase in their 3-year survival rate (from 7.4% to 27.7%) compared to the A/A+A/G genotype after treatment with platinum gemcitabine regimen. This finding was reproduced in the validation cohort. We utilized a luciferase reporter assay and Electrophoretic Mobility Shift Assay (EMSA) to demonstrate that rs3910384-linked WEE1 promoter haplotype can mediate allele-specific transcriptional binding and WEE1 expression in DNA damage response. In conclusion, the WEE1 rs3910384 G/G homozygote genotype can be used as a selective biomarker for NSCLC patients to indicate treatment with platinum and gemcitabine regimen. PMID- 26057004 TI - Carbohydrate-Specific Uptake of Fucosylated Polymeric Micelles by Different Cancer Cell Lines. AB - Inspired by upregulated levels of fucosylated proteins on the surfaces of multiple types of cancer cells, micelles carrying beta-l-fucose and beta-d glucose were prepared. A range of block copolymers were synthesized by reacting a mixture of 2-azidoethyl beta-l-fucopyranoside (FucEtN3) and 2-azideoethyl beta-d glucopyranoside (GlcEtN3) with poly(propargyl methacrylate)-block-poly(n-butyl acrylate) (PPMA-b-PBA) using copper-catalyzed azide-alkyne cycloaddition (CuAAC). Five block copolymers were obtained ranging from 100 mol % fucose to 100% glucose functionalization. The resulting micelles had hydrodynamic diameters of around 30 nm. In this work, we show that fucosylated micelles reveal an increased uptake by pancreatic, lung, and ovarian carcinoma cell lines, whereas the uptake by the healthy cell lines (CHO) is negligible. This finding suggests that these micelles can be used for targeted drug delivery toward cancer cells. PMID- 26057005 TI - Microscopic Barrier Mechanism of Ion Transport through Liquid-Liquid Interface. AB - Microscopic mechanism of ion transport through water-oil interface was investigated with molecular dynamics simulation. The formation/breaking of a water finger during the ion passage was explicitly formulated in the free energy surface. The calculated 2D free energy surface clearly revealed a hidden barrier of ion passage accompanied by the water finger. This barrier elucidates the retarded rate of interfacial ion transfer. PMID- 26057006 TI - Phylogenetic studies of four Anser cygnoides (Anserini: Anserinae) in Hunan province of China based on complete mitochondrial DNA sequences. AB - In this study, we cloned and sequenced the complete mitochondrial DNAs of Chinese goose, Anser cygnoides populations from three different areas of Hunan province in China. The Anser cygnoides breed Wugangtong white goose (WGTW) sample and Wugangtong grey goose sample (WGTG) were taken from the Wugang county of Shaoyang city, the Anser cygnoides breed Xupu goose (XP) sample was taken from the Xupu county of Huaihua city, and the Anser cygnoides breed Yanling white goose (YLW) sample was taken from the Yanling county of Zhuzhou city. The organization of the four Anser cygnoides breeds mitochondrial genomes was similar. Phylogenetic analyses using N-J computational algorithms showed that the analyzed species are divided into four major clades: Anatinae, Anserinae, Dendrocygninae and Anseranatidae. It was noted that Wugangtong white goose, Yanling white goose and Xupu goose have highly similar phylogenetic relationship. PMID- 26057007 TI - The complete mitochondrial genome of Conus tulipa (Neogastropoda: Conidae). AB - The complete mitogenome sequence of the cone snail Conus tulipa (Linnaeus, 1758) has been sequenced by next-generation sequencing method. The assembled mitogenome is 16,599 bp in length, including 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. The overall base composition of C. tulipa is 28.7% A, 15.2% C, 18.4% G and 37.7% T. It shows 81.1% identity to the cone snail C. consors, 78.5% to C. borgesi and 77.5% to C. textile. Using the 13 protein-coding genes and 2 ribosomal RNA genes of C. tulipa in this study, together with 18 other closely species, we constructed the species phylogenetic tree to verify the accuracy and utility of new determined mitogenome sequence. The complete mitogenome of the C. tulipa provides an essential and important DNA molecular data for further phylogeography and evolutionary analysis for cone snail phylogeny. PMID- 26057008 TI - Phylogenetic studies of two Anas platyrhynchos (Anatini: Anatinae) in Hunan province of China based on complete mitochondrial DNA sequences. AB - In this study, we cloned and sequenced the complete mitochondrial DNAs of Chinese duck, Anas platyrhynchos, population from two different areas of Hunan province in China. The Anas platyrhynchos breed Linwu duck (LW) sample was taken from the Linwu county of Chenzhou city, and the Anas platyrhynchos breed Youxian duck (YX) sample was taken from the Youxian county of Zhuzhou city. The lengths of their complete mitochondrial genome were 16,604 bp (LW) and 16,606 bp (YX), respectively. The organization of the two Anas platyrhynchos breed mitochondrial genomes was similar to those reported from other duck mitochondrial genomes. Phylogenetic analyses using N-J computational algorithms showed that the analyzed species are divided into four major clades: Anatinae, Anserinae, Dendrocygninae and Anseranatidae. Also, the Linwu duck and Youxian duck have highly similar phylogenetic relationship. PMID- 26057009 TI - The complete mitochondrial genome of Myotis lucifugus (Chiroptera: Vespertilionidae). AB - The mitochondrial genome of the little brown bat, Myotis lucifugus (Chiroptera: Vespertilionidae), is a circular molecule of 17,038 bp in length, containing 22 transfer RNAs genes, 13 protein-coding genes, two ribosomal RNAs, and one D-loop region. The A + T content of the overall base composition of the H-strand is 63.2% with individual nucleotides comprising T 29.8%, C 23.4%, A 33.3%, and G 13.5%. In BI and ML trees, we found M. lucifugus is a sister clade to M. brandtii, Myotis is a sister clade to Murina, and Pipistrellus is a sister clade to (Chalinolobus + (Eptesicus + Vespertilio)) (1.00 in BI, >100% in ML). The monophyly of Myotis, Murina, and Plecotus is well supported (1.00 in BI, 100% in ML). PMID- 26057010 TI - Characterization of the complete mitochondrial genome of the Rhinolophus sinicus sinicus (Chiroptera: Rhinolophidae) from Central China. AB - We present a complete mitochondrial genome sequence of Rhinolophus sinicus sinicus from Central China and provide its annotation, as well as showed the phylogenetic relationship and mitogenomic variation with other published mitochondrial genomes of congeneric bat species. Our results revealed a relatively high mitogenomic variation between two R. s. sinucus from Central and East China, which is similar to interspecific divergence level. PMID- 26057011 TI - DNA barcoding to fishes: current status and future directions. AB - DNA barcoding appears to be a promising approach for taxonomic identification, characterization, and discovery of newer species, facilitating biodiversity studies. It helps researchers to appreciate genetic and evolutionary associations by collection of molecular, morphological, and distributional data. Fish DNA barcoding, based on the sequencing of a uniform area of Cytochrome C Oxidase type I (COI) gene, has received significant interest as an accurate tool for species identification, authentication, and phylogenetic analysis. The aim of this review article was to investigate recent global status, approaches, and future direction of DNA barcoding in fisheries sectors. We have tried to highlight its possible impacts, complications, and validation issues at species levels for biodiversity analysis. Moreover, an effort has been put forward to understand issues related to various marker genes associated with barcode process as primer sequences and have concluded barcode promotion as an indispensable tool of molecular biology for the development of taxonomic support systems. PMID- 26057012 TI - Complete mitochondrial genome of the blind vent crab Gandalfus puia (Crustacea: Bythograeidae) from the Tonga Arc. AB - The brachyuran crab Gandalfus puia is a species endemic to the hydrothermal vent fields in the Tonga-Kermadec Arc. In order to understand G. puia at the genomic level, we sequenced its mitochondrial genome (mitogenome) and then compared to other bythograeids. The mitogenome is 15,548 bp in length and exhibits brachyuran typical gene arrangement. Its protein-coding genes were very similar to other bythograeid species with respect to length, AT content and start and stop codons. Additionally, we compared the mitogenomes of Gandalfus and the closely related Austinograea. The inter-specific nucleotide divergence was 13.4% in Gandalfus and 13.7-14.0% in Austinograea. The inter-generic nucleotide divergence between Gandalfus and Austinograea was 16.3-19.7%. Based on the phylogenetic tree constructed with maximum likelihood and Bayesian inference, bythograeid crabs were recognized as the monophyletic taxon with the high supporting values (100% bootstrap proportions and 1.00 posterior probabilities). These results are useful for understanding the phylogenetic relationships and evolution of bythograeid crabs. PMID- 26057013 TI - DNA barcoding of Nilssonia congeners corroborates existence of wild N. nigricans in northeast India. AB - DNA barcode data of soft-shell turtles is limited in global DNA database while it is completely lacking for the highly debated species Nilssonia nigricans. We employed DNA barcoding technique to discriminate the species cluster for Nilssonia congeners, especially for the highly debated N. nigricans from different localities of northeast India. Sampling across the region included a few live specimens from wild, market sold carcass specimens, and a few dry carapaces meant for home decoration purpose. The generated sequences (621 bp of mtCOI) of dry carapaces showed 99-100% homology with the generated sequences of morphologically identified N. nigricans. The COI barcode sequences of N. nigricans (n = 12) showed 3.8% mean genetic divergence with N. hurum (n = 3), 10% with N. gangetica (n = 4), and 9.2% with N. formosa (GenBank sequences). Similarly, the mtCytb sequences of the dry carapace and live specimens of N. nigricans were 99-100% homologous with the conspecific database sequences and formed specific clusters. The inferred Neighbor-Joining (NJ), Maximum Likelihood (ML), and Bayesian (BA) phylogeny based on partial mtCOI gene efficiently discriminated all the congeners of Nilssonia into specific clusters and, therefore, it was helpful to detect the existence of N. nigricans. PMID- 26057014 TI - Sequencing and analysis of the complete mitochondrial genome of Elaphe anomala (Squamata Colubridae). AB - In this study, the complete mitogenome sequence of Elaphe anomala (Squamata: Colubridae) is first determined using long PCR. It is a circular molecule of 17,164 bp in length and contains 13 protein-coding genes (PCGs), 22 transfer RNA (tRNA) genes, 2 ribosomal RNA (rRNA) genes and 2 control regions (CRI and CRII). The gene order and nucleotide composition of E. anomala are very similar with E. schrenckii. Mitochondrial genomes analyses based on the NJ method yield phylogenetic tree of 17 species snakes of Colubridae. Species E. anomala, E. schrenckii, E. bimaculata and E. davidi seemed to have formed a monophyletic group with the high bootstrap value (100%) except E. poryphyracea. Oligodon ningshaanensis and Thermophis zhaoermii are special species. The molecular data presented here provide a useful tool for setting the stage for further studies. PMID- 26057015 TI - The mitochondrial genome of the multicolored Asian lady beetle Harmonia axyridis (Pallas) and a phylogenetic analysis of the Polyphaga (Insecta: Coleoptera). AB - Here, we report the mitochondrial genome sequence of the multicolored Asian lady beetle Harmonia axyridis (Pallas, 1773) (Coleoptera: Coccinellidae) (GenBank accession No. KR108208). This is the first species with sequenced mitochondrial genome from the genus Harmonia. The current length with partitial A + T-rich region of this mitochondrial genome is 16,387 bp. All the typical genes were sequenced except the trnI and trnQ. As in most other sequenced mitochondrial genomes of Coleoptera, there is no re-arrangement in the sequenced region compared with the pupative ancestral arrangement of insects. All protein-coding genes start with ATN codons. Five, five and three protein-coding genes stop with termination codon TAA, TA and T, respectively. Phylogenetic analysis using Bayesian method based on the first and second codon positions of the protein coding genes supported that the Scirtidae is a basal lineage of Polyphaga. The Harmonia and the Coccinella form a sister lineage. The monophyly of Staphyliniformia, Scarabaeiformia and Cucujiformia was supported. The Buprestidae was found to be a sister group to the Bostrichiformia. PMID- 26057016 TI - The complete chloroplast genome of the Taiwan red pine Pinus taiwanensis (Pinaceae). AB - The complete nucleotide sequence of the Taiwan red pine Pinus taiwanensis Hayata chloroplast genome (cpDNA) is determined in this study. The genome is composed of 119,741 bp in length, containing a pair of very short inverted repeat (IRa and IRb) regions of 495 bp, which was divided by a large single-copy (LSC) region of 65,670 bp and a small single-copy (SSC) region of 53,080 bp in length. The cpDNA contained 115 genes, including 74 protein-coding genes (73 PCG species), 4 ribosomal RNA genes (four rRNA species) and 37 tRNA genes (22 tRNA species). Out of these genes, 12 harbored a single intron, and one (rps12) contained a couple of introns. The overall AT content of the Taiwan red pine cpDNA is 61.5%, while the corresponding values of the LSC, SSC and IR regions are 62.2%, 60.6% and 63.6%, respectively. A maximum parsimony phylogenetic analysis suggested that the genus Pinus, Picea, Abies and Larix were strongly supported as monophyletic, and the cpDNA of P. taiwanensis is closely related to that of P. thunbergii. PMID- 26057017 TI - Sulfonated Polyethylenimine for Photosensitizer Conjugation and Targeting. AB - Polysulfonated macromolecules are known to bind selectins, adhesion membrane proteins which are broadly implicated in inflammation. Commercially available branched polyethylenimine (PEI) was reacted with chlorosulfonic acid to generate sulfonated PEI with varying degrees of sulfonation. Remaining unreacted amine groups were then used for straightforward conjugation with pyropheophoribide-a, a near-infrared photosensitizer. Photosensitizer-labeled sulfonated PEI conjugates inhibited blood coagulation and were demonstrated to specifically bind to cells genetically programmed to overexpress L-selectin (CD62L) or P-selectin (CD62P). In vitro, following targeting, selectin-expressing cells could be destroyed via photodynamic therapy. PMID- 26057018 TI - Lantana camara leaf extract mediated silver nanoparticles: Antibacterial, green catalyst. AB - Silver nanoparticles (AgNPs) have been synthesized by Lantana camara leaf extract through simple green route and evaluated their antibacterial and catalytic activities. The leaf extract (LE) itself acts as both reducing and stabilizing agent at once for desired nanoparticle synthesis. The colorless reaction mixture turns to yellowish brown attesting the AgNPs formation and displayed UV-Vis absorption spectra. Structural analysis confirms the crystalline nature and formation of fcc structured metallic silver with majority (111) facets. Morphological studies elicit the formation of almost spherical shaped nanoparticles and as AgNO3 concentration is increased, there is an increment in the particle size. The FTIR analysis evidences the presence of various functional groups of biomolecules of LE is responsible for stabilization of AgNPs. Zeta potential measurement attests the higher stability of synthesized AgNPs. The synthesized AgNPs exhibited good antibacterial activity when tested against Escherichia coli, Pseudomonas spp., Bacillus spp. and Staphylococcus spp. using standard Kirby-Bauer disc diffusion assay. Furthermore, they showed good catalytic activity on the reduction of methylene blue by L. camara extract which is monitored and confirmed by the UV-Vis spectrophotometer. PMID- 26057019 TI - Bio-relevant complexes of novel N2O2 type heterocyclic ligand: Synthesis, structural elucidation, biological evaluation and docking studies. AB - Organic and inorganic entities [Cu(II), Co(II), Ni(II) and Zn(II)] have been bridged by N2O2 type heterocyclic imine (CN) ligand for the synthesis of novel organic-inorganic bridged complexes of the type [M(H2L)]. The synthesized complexes were characterized by spectral techniques such as FT-IR, UV-visible, (1)H NMR, (13)C NMR, EPR, ESI-Mass, elemental analysis, magnetic susceptibility and molar conductivity measurements. The metal complexes adopt square planar geometrical arrangement around the metal ions. DNA binding ability of these complexes has been explored by different techniques viz. electronic absorption, fluorescence, cyclic voltammetry, differential pulse voltammetry and viscosity measurements. These studies prove that CT DNA interaction of the complexes follows intercalation mode. The oxidative cleavage of the complexes with pUC19 DNA has been investigated by gel electrophoresis. Molecular docking calculations have been performed to understand the nature of binding of the complexes with DNA. Moreover, the anti-pathogenic actions of the complexes were tested in vitro against few bacteria and fungi by disk diffusion method. The data reveal that the complexes have higher anti-pathogenic activity than the ligand. PMID- 26057020 TI - In-situ sonosynthesis of nano N-doped ZnO on wool producing fabric with photo and bio activities, cell viability and enhanced mechanical properties. AB - Here, a simple processing route is introduced for preparation of N-doped nano structure ZnO at 75-80 degrees C using in-situ sonosynthesis method through hydrolysis of zinc acetate at pH~9-10 adjusting with ammonia. Synthesis and fabrication of nano N-doped ZnO were carried out on the wool fabric through impregnation of the fabric in ultrasound bath using different concentrations of zinc acetate followed by curing. The antibacterial and antifungal activities of the treated fabrics were assessed against two common pathogenic bacteria including Escherichia coli, Staphylococcus aureus and the diploid fungus namely Candida albicans. The photo-catalytic activity of nano N-doped ZnO particles on the wool fabric was determined by degradation of Methylene Blue under daylight irradiation. Increasing zinc acetate and prolonged sonication time led to higher photo-catalytic activity as more dye stain degraded from the stained treated fabric under daylight. Higher photo-catalytic activity was observed on the nano N doped ZnO sonotreated wool fabric having more hydrophilicity. Finally, the treatment indicated no negative effect on the fabric safety while reduced alkaline solubility and yellowness even enhanced the fabric tensile strength. The response surface methodology was also utilized to optimize the wool fabric treatment conditions. PMID- 26057021 TI - Doxorubicin loaded polymeric gold nanoparticles targeted to human folate receptor upon laser photothermal therapy potentiates chemotherapy in breast cancer cell lines. AB - The current research focuses on the application of folate conjugated and doxorubicin loaded polymeric gold nanoparticles (GNPs) for the targeted treatment of folate receptor overexpressing breast cancers, augmented by adjunctive laser photothermal therapy. Herein, GNPs surface modified with folate, drug doxorubicin and polyethylene glycol were engineered and were used as vehicles for folate receptor targeted delivery of doxorubicin into cancer cells. Subsequently, the GNPs were photo-excited using laser light for mediating hyperthermia in the cancer cells. In vitro studies were performed to validate the efficacy of the combined modality of folate conjugated and doxorubicin loaded polymeric GNP mediated chemotherapy followed by photothermal therapy in comparison to treatment with free drug; and the combination modality showed better therapeutic efficacy than that of plain doxorubicin treatment in MDA-MB-231 breast cancer cells that express increased levels of surface folate receptors when compared to MCF-7 breast cancer cells that express low levels of folate receptor. The mechanism of cell death was investigated using fluorescent microscopy. Immunoassays showed the up-regulation of the pro-apoptotic protein p53 and down-regulation of the anti apoptotic protein Bcl-2. Collectively, these results suggest that the folate tagged doxorubicin loaded GNPs are an attractive platform for targeted delivery of doxorubicin and are agents suitable for photothermal cancer therapy. PMID- 26057022 TI - Synthesis and crystal structure of new dicopper(II) complexes having asymmetric N,N'-bis(substituted)oxamides with DNA/protein binding ability: In vitro anticancer activity and molecular docking studies. AB - Two new dicopper(II) complexes bridged by asymmetric N,N'-bis(substituted)oxamide ligands: N-(5-chloro-2-hydroxyphenyl)-N'-[2-(dimethylamino)ethyl]oxamide (H3chdoxd) and N-hydroxypropyl-N'-(2-carboxylatophenyl)oxamide (H3oxbpa), and end capped with 2,2'-bipyridine (bpy), namely [Cu2(ClO4)(chdoxd)(CH3OH)(bpy)].H2O (1) and [Cu2(pic)(oxbpa)(CH3OH)(bpy)].0.5CH3OH (2) (pic denotes picrate anion), have been synthesized and characterized by elemental analysis, molar conductivity measurement, IR and electronic spectral studies, and single-crystal X-ray diffraction. The X-ray diffraction analysis revealed that both the copper(II) ions bridged by the cis-oxamido ligands in dicopper(II) complexes 1 and 2 are all in square-pyramidal environments with the corresponding Cu?Cu separations of 5.194(3) and 5.1714(8)A, respectively. In the crystals of the two complexes, there are abundant hydrogen bonds and pi-pi stacking interactions contributing to the supramolecular structure. The reactivities toward herring sperm DNA (HS-DNA) and bovine serum albumin (BSA) of the two complexes are studied both theoretically and experimentally, indicating that both the two complexes can interact with the DNA in the mode of intercalation, and effectively bind to BSA via the favored binding sites Trp134 for the complex 1 and Trp213 for the complex 2. Interestingly, the in vitro anticancer activities of the two complexes against the selected tumor cell lines are consistent with their DNA/BSA-binding affinities following the order of 1>2. The effects of coordinated counterions in the two complexes on DNA/BSA-binding ability and in vitro anticancer activity are preliminarily discussed. PMID- 26057023 TI - TUGs into VUGs and Friendly BUGs: Transforming the Gracilis Territory into the Best Secondary Breast Reconstructive Option. AB - BACKGROUND: The best secondary option for autologous breast reconstruction remains controversial. Limitations of the gracilis myocutaneous flap, including volume, skin paddle reliability, and donor morbidity, have been addressed by several modifications, hereby expanding its role in the decision tree for autologous breast reconstruction. This report documents the authors' experience with gracilis flap breast reconstruction. METHODS: This is a retrospective case series of a prospectively maintained database of patients undergoing breast reconstruction with the free gracilis myocutaneous flap, including the transverse upper gracilis, vertical upper gracilis, and bilateral stacked vertical upper gracilis. RESULTS: Twenty-two patients received gracilis myocutaneous flaps. Fourteen (63.6 percent) had previous attempted breast reconstructions. Indications for gracilis donor site were previous abdominoplasty/abdominal flap (n = 15, 68 percent), insufficient abdominal tissue (n = 6, 27 percent), and patient preference (n = 1, 5 percent). Six patients underwent bilateral reconstruction, and five underwent unilateral reconstruction with bilateral stacked gracilis flaps. The skin paddle was transverse in four flaps (12 percent) and vertical in 29 (88 percent). There was one flap loss (3 percent); there were two occurrences of fat necrosis (6 percent). There were two minor donor site dehiscences (6 percent), one infection (3 percent), and one seroma (3 percent). CONCLUSIONS: The free gracilis flap is a versatile option for patients undergoing breast reconstruction, particularly when the abdominal donor site is unavailable. The vertical pattern is the authors' preferred technique, as it avoids some of the problems associated with transverse patterns. Stacked flaps further expand the utility of this technique, which the authors regard as the best secondary option for autologous breast reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 26057024 TI - Reply: Face Lifting in the Massive Weight Loss Patient: Modifications of Our Technique for This Population. PMID- 26057026 TI - Response to the Letter to the Editor on "Review of Secondary Health Conditions in Postpolio Syndrome". PMID- 26057025 TI - Negeviruses found in multiple species of mosquitoes from southern Portugal: Isolation, genetic diversity, and replication in insect cell culture. AB - In this report, an RT-PCR approach based on the use of degenerate primers allowed the identification of negeviruses in four different species of mosquitoes (Ochlerotatus caspius, Culex pipiens, Cx. theileri and Cx. univittatus) collected in southern Portugal. The genomes of two of these viruses, sequenced to full completion, were shown to encode all the proteins encoded by previously described negeviruses. One of these viruses induces exuberant cytopathic effect in insect cell culture, with no obvious signs of apoptosis induction, replicating very rapidly and allowing for the detection of viral genomes in the infected culture supernatant as soon as 4h post-infection. This virus was also shown to use a dsRNA intermediate, which was found to be fully formed and active 3h after infection. Phylogenetic analysis of two products encoded by the viral ORF1 placed both viruses among Negev virus cluster, in the recently proposed Nelorpivirus taxon. PMID- 26057027 TI - Risk of alcohol abuse in urban versus rural DUI offenders. AB - BACKGROUND: Research concerning driving under the influence (DUI) offenses in rural populations is scarce and has often been carried out in the context of substance abuse and illicit drug use. Although previous studies have suggested that rural individuals are more likely to abstain from alcohol use, recent trends suggest that alcohol and substance abuse problems in rural areas are occurring at rates similar to urban areas. It is possible that urban and rural DUI offenders may differ on psychological and behavioral characteristics associated with heavy alcohol consumption. OBJECTIVE: The aim of this study was to examine alcohol use differences between urban and rural DUI offenders. METHODS: Data from 11 066 DUI offenders in a Midwestern state were used for this study. The Alcohol subscale of the Driver Risk Inventory II was used to assess the risk of problem alcohol use. RESULTS: Higher levels of alcohol risk were associated with rural DUI offenders after adjusting for several demographic variables and blood-alcohol content level at time of arrest [Medium Risk OR = 1.43, 95% CI: (1.20, 1.71); Problem Risk OR = 1.43, 95% CI: (1.19, 1.72); Severe Risk OR = 1.38, 95% CI: (1.14, 1.67)]. CONCLUSIONS: The results of this study indicate that rural DUI offenders have a significantly greater risk of heavy alcohol use when compared to urban DUI offenders. Practical implications of these results suggest that evaluators and assessors should be aware of an increased likelihood of alcohol problems in rural DUI individuals relative to those in urban areas. PMID- 26057028 TI - Core-Shell Structural CdS@SnO2 Nanorods with Excellent Visible-Light Photocatalytic Activity for the Selective Oxidation of Benzyl Alcohol to Benzaldehyde. AB - Core-shell structural CdS@SnO2 nanorods (NRs) were fabricated by synthesizing SnO2 nanoparticles with a solvent-assisted interfacial reaction and further anchoring them on the surface of CdS NRs under ultrasonic stirring. The morphology, composition, and microstructures of the obtained samples were characterized by field-emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and nitrogen adsorption-desorption. It was found that SnO2 nanoparticles can be tightly anchored on the surface of CdS NRs, and the thickness of SnO2 shells can be conveniently adjusted by simply changing the addition amount of SnO2 quantum dots. UV-vis diffuse reflectance spectrum indicated that SnO2 shell layer also can enhance the visible light absorption of CdS NRs to a certain extent. The results of transient photocurrents and photoluminescence spectra revealed that the core-shell structure can effectively promote the separation rate of electron hole pairs and prolong the lifetime of electrons. Compared with the single CdS NRs, the core-shell structural CdS@SnO2 exhibited a remarkably enhanced photocatalytic activity for selective oxidation of benzyl alcohol (BA) to benzaldehyde (BAD) under visible light irradiation, attributed to the more efficient separation of electrons and holes, improved surface area, and enhanced visible light absorption of core-shell structure. The radical scavenging experiments proved that in acetonitrile solution, .O2- and holes are the main reactive species responsible for BA to BAD transformation, and the lack of .OH radicals is favorable to obtaining high reaction selectivity. PMID- 26057029 TI - Discrimination of healthy and osteoarthritic articular cartilages by Fourier transform infrared imaging and partial least squares-discriminant analysis. AB - Fourier transform infrared imaging (FTIRI) combined with chemometrics algorithm has strong potential to obtain complex chemical information from biology tissues. FTIRI and partial least squares-discriminant analysis (PLS-DA) were used to differentiate healthy and osteoarthritic (OA) cartilages for the first time. A PLS model was built on the calibration matrix of spectra that was randomly selected from the FTIRI spectral datasets of healthy and lesioned cartilage. Leave-one-out cross-validation was performed in the PLS model, and the fitting coefficient between actual and predicted categorical values of the calibration matrix reached 0.95. In the calibration and prediction matrices, the successful identifying percentages of healthy and lesioned cartilage spectra were 100% and 90.24%, respectively. These results demonstrated that FTIRI combined with PLS-DA could provide a promising approach for the categorical identification of healthy and OA cartilage specimens. PMID- 26057030 TI - Light for Life: International Year of Light 2015. PMID- 26057031 TI - Glasses-free randot stereotest. AB - We proposed a glasses-free randot stereotest using a multiview display system. We designed a four-view parallax barrier system and proposed the use of a random-dot multigram as a set of view images for the glasses-free randot stereotest. The glasses-free randot stereotest can be used to verify the effect of glasses in a stereopsis experience. Furthermore, the proposed system is convertible between two-view and four-view structures so that the motion parallax effect could be verified within the system. We discussed the design principles and the method used to generate images in detail and implemented a glasses-free randot stereotest system with a liquid crystal display panel and a customized parallax barrier. We also developed graphical user interfaces and a method for their calibration for practical usage. We performed experiments with five adult subjects with normal vision. The experimental results show that the proposed system provides a stereopsis experience to the subjects and is consistent with the glasses-type randot stereotest and the Frisby-Davis test. The implemented system is free from monocular cues and provides binocular disparity only. The crosstalk of the system is about 6.42% for four-view and 4.17% for two-view, the time required for one measurement is less than 20 s, and the minimum angular disparity that the system can provide is about 23 arc sec. PMID- 26057032 TI - Development and validation of a custom made indocyanine green fluorescence lymphatic vessel imager. AB - Lymphoedema is a chronic progressive condition often producing significant morbidity. An in-depth understanding of an individual's lymphatic architecture is valuable both in the understanding of underlying pathology and for targeting and tailoring treatment. Severe lower limb injuries resulting in extensive loss of soft tissue require transposition of a flap consisting of muscle and/or soft tissue to close the defect. These patients are at risk of lymphoedema and little is known about lymphatic regeneration within the flap. Indocyanine green (ICG), a water-soluble dye, has proven useful for the imaging of lymphatic vessels. When injected into superficial tissues it binds to plasma proteins in lymph. By exposing the dye to specific wavelengths of light, ICG fluoresces with near infrared light. Skin is relatively transparent to ICG fluorescence, enabling the visualization and characterization of superficial lymphatic vessels. An ICG fluorescence lymphatic vessel imager was manufactured to excite ICG and visualize real-time fluorescence as it travels through the lymphatic vessels. Animal studies showed successful ICG excitation and detection using this imager. Clinically, the imager has assisted researchers to visualize otherwise hidden superficial lymphatic pathways in patients postflap surgery. Preliminary results suggest superficial lymphatic vessels do not redevelop in muscle flaps. PMID- 26057033 TI - Incubator proof miniaturized Holomonitor to in situ monitor cancer cells exposed to green tea polyphenol and preosteoblast cells adhering on nanostructured titanate surfaces: validity of the measured parameters and their corrections. AB - The in situ observation of cell movements and morphological parameters over longer periods of time under physiological conditions is critical in basic cell research and biomedical applications. The quantitative phase-contrast microscope applied in this study has a remarkably small size, therefore it can be placed directly into a humidified incubator. Here, we report on the successful application of this M4 Holomonitor to observe cancer cell motility, motility speed, and migration in the presence of the green tea polyphenol, epigallocatechin gallate, as well as to monitor the adhesion of preosteoblast cells on nanostructured titanate coatings, relevant for biomedical applications. A special mechanical stage was developed to position the sample into that range of the optical arrangement where digital autofocusing works with high reproducibility and precision. By in-depth analyzing the obtained single cell morphological parameters, we show that the limited vertical resolution of the optical setup results in underestimated single cell contact area and volume and overestimated single cell averaged thickness. We propose a simple model to correct the recorded data to obtain more precise single cell parameters. We compare the results with the kinetic data recorded by a surface sensitive optical biosensor, optical waveguide lightmode spectroscopy. PMID- 26057035 TI - CPM Signals for Satellite Navigation in the S and C Bands. AB - Frequency allocations in the L band suitable for global navigation satellite system (GNSS) services are getting crowded and system providers face an ever tougher job when they try to bring in new signals and services while maintaining radio frequency compatibility. With the successive opening of the S and C bands to GNSS service, the multi-band combined navigation is predicted to become a key technology for future high-precision positioning navigation systems, and a single modulation scheme satisfying the requirements in each band is a promising solution for reducing user terminal complexity. A universal modulation scheme based on the continuous phase modulation (CPM) family suitable for the above bands' demands is proposed. Moreover, this paper has put forward two specific CPM signals for the S and C bands, respectively. Then the proposed modulation schemes, together with existing candidates, are comprehensively evaluated. Simulation results show that the proposed CPM signals can not only satisfy the constraint condition of compatibility in different bands well and reduce user terminal complexity, but also provide superior performance in terms of tracking accuracy, multi-path mitigation and anti-jamming compared to other candidate modulation schemes. PMID- 26057034 TI - mDurance: A Novel Mobile Health System to Support Trunk Endurance Assessment. AB - Low back pain is the most prevalent musculoskeletal condition. This disorder constitutes one of the most common causes of disability worldwide, and as a result, it has a severe socioeconomic impact. Endurance tests are normally considered in low back pain rehabilitation practice to assess the muscle status. However, traditional procedures to evaluate these tests suffer from practical limitations, which potentially lead to inaccurate diagnoses. The use of digital technologies is considered here to facilitate the task of the expert and to increase the reliability and interpretability of the endurance tests. This work presents mDurance, a novel mobile health system aimed at supporting specialists in the functional assessment of trunk endurance by using wearable and mobile devices. The system employs a wearable inertial sensor to track the patient trunk posture, while portable electromyography sensors are used to seamlessly measure the electrical activity produced by the trunk muscles. The information registered by the sensors is processed and managed by a mobile application that facilitates the expert's normal routine, while reducing the impact of human errors and expediting the analysis of the test results. In order to show the potential of the mDurance system, a case study has been conducted. The results of this study prove the reliability of mDurance and further demonstrate that practitioners are certainly interested in the regular use of a system of this nature. PMID- 26057036 TI - Highly Sensitive Multi-Channel IDC Sensor Array for Low Concentration Taste Detection. AB - In this study, we designed and developed an interdigitated capacitor (IDC)-based taste sensor array to detect different taste substances. The designed taste sensing array has four IDC sensing elements. The four IDC taste sensing elements of the array are fabricated by incorporating four different types of lipids into the polymer, dioctyl phenylphosphonate (DOPP) and tetrahydrofuran (THF) to make the respective dielectric materials that are individually placed onto an interdigitated electrode (IDE) via spin coating. When the dielectric material of an IDC sensing element comes into contact with a taste substance, its dielectric properties change with the capacitance of the IDC sensing element; this, in turn, changes the voltage across the IDC, as well as the output voltage of each channel of the system. In order to assess the effectiveness of the sensing system, four taste substances, namely sourness (HCl), saltiness (NaCl), sweetness (glucose) and bitterness (quinine-HCl), were tested. The IDC taste sensor array had rapid response and recovery times of about 12.9 s and 13.39 s, respectively, with highly stable response properties. The response property of the proposed IDC taste sensor array was linear, and its correlation coefficient R2 was about 0.9958 over the dynamic range of the taste sensor array as the taste substance concentration was varied from 1 MUM to 1 M. The proposed IDC taste sensor array has several other advantages, such as real-time monitoring capabilities, high sensitivity 45.78 mV/decade, good reproducibility with a standard deviation of about 0.029 and compactness, and the circuitry is based on readily available and inexpensive electronic components. The proposed IDC taste sensor array was compared with the potentiometric taste sensor with respect to sensitivity, dynamic range width, linearity and response time. We found that the proposed IDC sensor array has better performance. Finally, principal component analysis (PCA) was applied to discriminate different types of taste of the mixed taste substances. PMID- 26057037 TI - Region-Based Collision Avoidance Beaconless Geographic Routing Protocol in Wireless Sensor Networks. AB - Due to the lack of dependency on beacon messages for location exchange, the beaconless geographic routing protocol has attracted considerable attention from the research community. However, existing beaconless geographic routing protocols are likely to generate duplicated data packets when multiple winners in the greedy area are selected. Furthermore, these protocols are designed for a uniform sensor field, so they cannot be directly applied to practical irregular sensor fields with partial voids. To prevent the failure of finding a forwarding node and to remove unnecessary duplication, in this paper, we propose a region-based collision avoidance beaconless geographic routing protocol to increase forwarding opportunities for randomly-deployed sensor networks. By employing different contention priorities into the mutually-communicable nodes and the rest of the nodes in the greedy area, every neighbor node in the greedy area can be used for data forwarding without any packet duplication. Moreover, simulation results are given to demonstrate the increased packet delivery ratio and shorten end-to-end delay, rather than well-referred comparative protocols. PMID- 26057038 TI - Sensor Prototype to Evaluate the Contact Force in Measuring with Coordinate Measuring Arms. AB - This paper describes the design, development and evaluation tests of an integrated force sensor prototype for portable Coordinate Measuring Arms (CMAs or AACMMs). The development is based on the use of strain gauges located on the surface of the CMAs' hard probe. The strain gauges as well as their cables and connectors have been protected with a custom case, made by Additive Manufacturing techniques (Polyjet 3D). The same method has been selected to manufacture an ergonomic handle that includes trigger mechanics and the electronic components required for synchronizing the trigger signal when probing occurs. The paper also describes the monitoring software that reads the signals in real time, the calibration procedure of the prototype and the validation tests oriented towards increasing knowledge of the forces employed in manual probing. Several experiments read and record the force in real time comparing different ways of probing (discontinuous and continuous contact) and measuring different types of geometric features, from single planes to exterior cylinders, cones, or spheres, through interior features. The probing force is separated into two components allowing the influence of these strategies in probe deformation to be known. The final goal of this research is to improve the probing technique, for example by using an operator training programme, allowing extra-force peaks and bad contacts to be minimized or just to avoid bad measurements. PMID- 26057039 TI - A Flight Test of the Strapdown Airborne Gravimeter SGA-WZ in Greenland. AB - An airborne gravimeter is one of the most important tools for gravity data collection over large areas with mGal accuracy and a spatial resolution of several kilometers. In August 2012, a flight test was carried out to determine the feasibility and to assess the accuracy of the new Chinese SGA-WZ strapdown airborne gravimeter in Greenland, in an area with good gravity coverage from earlier marine and airborne surveys. An overview of this new system SGA-WZ is given, including system design, sensor performance and data processing. The processing of the SGA-WZ includes a 160 s length finite impulse response filter, corresponding to a spatial resolution of 6 km. For the primary repeated line, a mean r.m.s. deviation of the differences was less than 1.5 mGal, with the error estimate confirmed from ground truth data. This implies that the SGA-WZ could meet standard geophysical survey requirements at the 1 mGal level. PMID- 26057040 TI - Monocular-Vision-Based Autonomous Hovering for a Miniature Flying Ball. AB - This paper presents a method for detecting and controlling the autonomous hovering of a miniature flying ball (MFB) based on monocular vision. A camera is employed to estimate the three-dimensional position of the vehicle relative to the ground without auxiliary sensors, such as inertial measurement units (IMUs). An image of the ground captured by the camera mounted directly under the miniature flying ball is set as a reference. The position variations between the subsequent frames and the reference image are calculated by comparing their correspondence points. The Kalman filter is used to predict the position of the miniature flying ball to handle situations, such as a lost or wrong frame. Finally, a PID controller is designed, and the performance of the entire system is tested experimentally. The results show that the proposed method can keep the aircraft in a stable hover. PMID- 26057042 TI - Passive Acoustic Source Localization at a Low Sampling Rate Based on a Five Element Cross Microphone Array. AB - Accurate acoustic source localization at a low sampling rate (less than 10 kHz) is still a challenging problem for small portable systems, especially for a multitasking micro-embedded system. A modification of the generalized cross correlation (GCC) method with the up-sampling (US) theory is proposed and defined as the US-GCC method, which can improve the accuracy of the time delay of arrival (TDOA) and source location at a low sampling rate. In this work, through the US operation, an input signal with a certain sampling rate can be converted into another signal with a higher frequency. Furthermore, the optimal interpolation factor for the US operation is derived according to localization computation time and the standard deviation (SD) of target location estimations. On the one hand, simulation results show that absolute errors of the source locations based on the US-GCC method with an interpolation factor of 15 are approximately from 1/15- to 1/12-times those based on the GCC method, when the initial same sampling rates of both methods are 8 kHz. On the other hand, a simple and small portable passive acoustic source localization platform composed of a five-element cross microphone array has been designed and set up in this paper. The experiments on the established platform, which accurately locates a three-dimensional (3D) near field target at a low sampling rate demonstrate that the proposed method is workable. PMID- 26057041 TI - Forster Resonance Energy Transfer between Quantum Dot Donors and Quantum Dot Acceptors. AB - Forster (or fluorescence) resonance energy transfer amongst semiconductor quantum dots (QDs) is reviewed, with particular interest in biosensing applications. The unique optical properties of QDs provide certain advantages and also specific challenges with regards to sensor design, compared to other FRET systems. The brightness and photostability of QDs make them attractive for highly sensitive sensing and long-term, repetitive imaging applications, respectively, but the overlapping donor and acceptor excitation signals that arise when QDs serve as both the donor and acceptor lead to high background signals from direct excitation of the acceptor. The fundamentals of FRET within a nominally homogeneous QD population as well as energy transfer between two distinct colors of QDs are discussed. Examples of successful sensors are highlighted, as is cascading FRET, which can be used for solar harvesting. PMID- 26057043 TI - The Survey on Near Field Communication. AB - Near Field Communication (NFC) is an emerging short-range wireless communication technology that offers great and varied promise in services such as payment, ticketing, gaming, crowd sourcing, voting, navigation, and many others. NFC technology enables the integration of services from a wide range of applications into one single smartphone. NFC technology has emerged recently, and consequently not much academic data are available yet, although the number of academic research studies carried out in the past two years has already surpassed the total number of the prior works combined. This paper presents the concept of NFC technology in a holistic approach from different perspectives, including hardware improvement and optimization, communication essentials and standards, applications, secure elements, privacy and security, usability analysis, and ecosystem and business issues. Further research opportunities in terms of the academic and business points of view are also explored and discussed at the end of each section. This comprehensive survey will be a valuable guide for researchers and academicians, as well as for business in the NFC technology and ecosystem. PMID- 26057045 TI - Current world literature: current opinion in pediatrics. PMID- 26057044 TI - Pd loaded amphiphilic COF as catalyst for multi-fold Heck reactions, C-C couplings and CO oxidation. AB - COFs represent a class of polymers with designable crystalline structures capable of interacting with active metal nanoparticles to form excellent heterogeneous catalysts. Many valuable ligands/monomers employed in making coordination/organic polymers are prepared via Heck and C-C couplings. Here, we report an amphiphilic triazine COF and the facile single-step loading of Pd(0) nanoparticles into it. An 18-20% nano-Pd loading gives highly active composite working in open air at low concentrations (Conc. Pd(0) <0.05 mol%, average TON 1500) catalyzing simultaneous multiple site Heck couplings and C-C couplings using 'non-boronic acid' substrates, and exhibits good recyclability with no sign of catalyst leaching. As an oxidation catalyst, it shows 100% conversion of CO to CO2 at 150 degrees C with no loss of activity with time and between cycles. Both vapor sorptions and contact angle measurements confirm the amphiphilic character of the COF. DFT-TB studies showed the presence of Pd-triazine and Pd-Schiff bond interactions as being favorable. PMID- 26057047 TI - Deletion of Rapgef6, a candidate schizophrenia susceptibility gene, disrupts amygdala function in mice. AB - In human genetic studies of schizophrenia, we uncovered copy-number variants in RAPGEF6 and RAPGEF2 genes. To discern the effects of RAPGEF6 deletion in humans, we investigated the behavior and neural functions of a mouse lacking Rapgef6. Rapgef6 deletion resulted in impaired amygdala function measured as reduced fear conditioning and anxiolysis. Hippocampal-dependent spatial memory and prefrontal cortex-dependent working memory tasks were intact. Neural activation measured by cFOS phosphorylation demonstrated a reduction in hippocampal and amygdala activation after fear conditioning, while neural morphology assessment uncovered reduced spine density and primary dendrite number in pyramidal neurons of the CA3 hippocampal region of knockout mice. Electrophysiological analysis showed enhanced long-term potentiation at cortico-amygdala synapses. Rapgef6 deletion mice were most impaired in hippocampal and amygdalar function, brain regions implicated in schizophrenia pathophysiology. The results provide a deeper understanding of the role of the amygdala in schizophrenia and suggest that RAPGEF6 may be a novel therapeutic target in schizophrenia. PMID- 26057050 TI - Multiplexing and scaling-down of nanostructured photon-triggered silicon field emitter arrays for maximum total electron yield. AB - Femtosecond ultrabright cathodes with spatially structured emission are a critical technology for applications such as free-electron lasers, tabletop coherent x-ray sources, and ultrafast imaging. In this work, the optimization of the total electron yield of ultrafast photon-triggered field emission cathodes composed of arrays of nanosharp, high-aspect-ratio, single-crystal silicon pillars is explored through the variation of the emitter pitch and height. Arrays of 6 nm tip radius silicon emitters with emitter densities between 1.2 and 73.9 million tips cm(-2) (hexagonally packed arrays with emitter pitch between 1.25 and 10 MUm) and emitter height between 2.0 and 8.5 MUm were characterized using 35 fs 800 nm laser pulses. Three-photon electron emission for low-energy (<0.3 MUJ) light pulses and strong-field emission for high-energy (>1 MUJ) light pulses was observed, in agreement with the literature. Of the devices tested, the arrays with emitter pitch equal to 2.5 MUm produced the highest total electron yield; arrays with larger emitter pitch suffer area sub-utilization, and in devices with smaller emitter pitch the larger emitter density does not compensate the smaller per-emitter current due to the electric field shadowing that results from the proximity of the adjacent tips. Experimental data and simulations suggest that 2 MUm tall emitters achieve practical optimal performance as shorter emitters have visibly smaller field factors due to the proximity of the emitter tip to the substrate, and taller emitters show marginal improvement in the electron yield at the expense of greater fabrication difficulty. PMID- 26057048 TI - Acute and chronic stress differentially regulate cyclin-dependent kinase 5 in mouse brain: implications to glucocorticoid actions and major depression. AB - Stress activates the hypothalamic-pituitary-adrenal axis, which in turn increases circulating glucocorticoid concentrations and stimulates the glucocorticoid receptor (GR). Chronically elevated glucocorticoids by repetitive exposure to stress are implicated in major depression and anxiety disorders. Cyclin-dependent kinase 5 (CDK5), a molecule essential for nervous system development, function and pathogenesis of neurodegenerative disorders, can modulate GR activity through phosphorylation. We examined potential contribution of CDK5 to stress response and pathophysiology of major depression. In mice, acute immobilized stress (AS) caused a biphasic effect on CDK5 activity, initially reducing but increasing afterwards in prefrontal cortex (PFC) and hippocampus (HIPPO), whereas chronic unpredictable stress (CS) strongly increased it in these brain areas, indicating that AS and CS differentially regulate this kinase activity in a brain region specific fashion. GR phosphorylation contemporaneously followed the observed changes of CDK5 activity after AS, thus CDK5 may in part alter GR phosphorylation upon this stress. In the postmortem brains of subjects with major depression, CDK5 activity was elevated in Brodmann's area 25, but not in entire PFC and HIPPO. Messenger RNA expression of glucocorticoid-regulated/stress-related genes showed distinct expression profiles in several brain areas of these stressed mice or depressive subjects in which CDK5-mediated changes in GR phosphorylation may have some regulatory roles. Taken together, these results indicate that CDK5 is an integral component of stress response and major depression with regulatory means specific to different stressors, brain areas and diseases in part through changing phosphorylation of GR. PMID- 26057049 TI - Glutamate transporter splice variant expression in an enriched pyramidal cell population in schizophrenia. AB - Dysregulation of the glutamate transporters EAAT1 and EAAT2 and their isoforms have been implicated in schizophrenia. EAAT1 and EAAT2 expression has been studied in different brain regions but the prevalence of astrocytic glutamate transporter expression masks the more subtle changes in excitatory amino acid transporters (EAATs) isoforms in neurons in the cortex. Using laser capture microdissection, pyramidal neurons were cut from the anterior cingulate cortex of postmortem schizophrenia (n = 20) and control (n = 20) subjects. The messenger RNA (mRNA) levels of EAAT1, EAAT2 and the splice variants EAAT1 exon9skipping, EAAT2 exon9skipping and EAAT2b were analyzed by real time PCR (RT-PCR) in an enriched population of neurons. Region-level expression of these transcripts was measured in postmortem schizophrenia (n = 25) and controls (n = 25). The relationship between selected EAAT polymorphisms and EAAT splice variant expression was also explored. Anterior cingulate cortex pyramidal cell expression of EAAT2b mRNA was increased (P < 0.001; 67%) in schizophrenia subjects compared with controls. There was no significant change in other EAAT variants. EAAT2 exon9skipping mRNA was increased (P < 0.05; 38%) at region level in the anterior cingulate cortex with no significant change in other EAAT variants at region level. EAAT2 single-nucleotide polymorphisms were significantly associated with changes in EAAT2 isoform expression. Haloperidol decanoate-treated animals, acting as controls for possible antipsychotic effects, did not have significantly altered neuronal EAAT2b mRNA levels. The novel finding that EAAT2b levels are increased in populations of anterior cingulate cortex pyramidal cells further demonstrates a role for neuronal glutamate transporter splice variant expression in schizophrenia. PMID- 26057052 TI - Risk stratification: an important stroke risk reduction strategy in elderly patients with nonvalvular atrial fibrillation. PMID- 26057053 TI - Analytical computation of prompt gamma ray emission and detection for proton range verification. AB - A prompt gamma (PG) slit camera prototype recently demonstrated that Bragg Peak position in a clinical proton scanned beam could be measured with 1-2 mm accuracy by comparing an expected PG detection profile to a measured one. The computation of the expected PG detection profile in the context of a clinical framework is challenging but must be solved before clinical implementation. Obviously, Monte Carlo methods (MC) can simulate the expected PG profile but at prohibitively long calculation times. We implemented a much faster method that is based on analytical processing of precomputed MC data that would allow practical evaluation of this range monitoring approach in clinical conditions. Reference PG emission profiles were generated with MC simulations (PENH) in targets consisting of either (12)C, (14)N, (16)O, (31)P or (40)Ca, with 10% of (1)H. In a given geometry, the local PG emission can then be derived by adding the contribution of each element, according to the local energy of the proton obtained by continuous slowing down approximation and the local composition. The actual incident spot size is taken into account using an optical model fitted to measurements and by super sampling the spot with several rays (up to 113). PG transport in the patient/camera geometries and the detector response are modelled by convolving the PG production profile with a transfer function. The latter is interpolated from a database of transfer functions fitted to MC data (PENELOPE) generated for a photon source in a cylindrical phantom with various radiuses and a camera placed at various positions. As a benchmark, the analytical model was compared to MC and experiments in homogeneous and heterogeneous phantoms. Comparisons with MC were also performed in a thoracic CT. For all cases, the analytical model reproduced the prediction of the position of the Bragg peak computed with MC within 1 mm for the camera in nominal configuration. When compared to measurements, the shape of the profiles was well reproduced and agreement for the estimation of the position of the Bragg peak was within 2.7 mm on average (1.4 mm standard deviation). On a non-optimized MATLAB code, computation time with the analytical model is between 0.3 to 10 s depending on the number of rays simulated per spot. The analytical model can be further used to determine which spots are the best candidates to evaluate the range in clinical conditions and eventually correct for over- and under-shoots depending on the acquired PG profiles. PMID- 26057054 TI - [Urethroplasty with buccal mucosa graft or penile skin graft for anterior urethral stricture?]. AB - Currently the treatment for urethral stricture considers various techniques, including augmentation urethroplasty using tissue from different parts of the body. The more used are the buccal mucosa and penile skin, but are there any differences in success between both tissues? Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified one systematic review including 18 primary studies addressing this question, six of them prospective. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded there is uncertainty about the superiority of one technique over another because the certainty of the evidence is very low. A new systematic review is urgently needed on this topic as randomized studies have been published after the most recent review, which could provide greater certainty. PMID- 26057055 TI - Imaging: CNS changes in interstitial cystitis/painful bladder syndrome. PMID- 26057060 TI - Prostate cancer: TGF-beta signalling regulator PMEPA1 halts metastases to bone. PMID- 26057061 TI - Nuclear imaging of renal tumours: a step towards improved risk stratification. AB - Patients presenting with a clinically localized renal mass should ideally be managed with a risk-adapted approach that incorporates data regarding the metastatic potential of a given tumour. Unfortunately, currently available anatomical imaging techniques are unable to reliably distinguish between the various types of renal tumours, which include both benign and malignant histologies. Nuclear imaging offers a potential noninvasive means to characterize clinically localized renal tumours. A number of nuclear imaging tests are currently under investigation for this purpose and might one day be incorporated into patient care. PMID- 26057062 TI - Prostate cancer: Antiandrogens reverse docetaxel resistance via ABCB1 inhibition. PMID- 26057064 TI - BPH: P2Y6 blockade might help control bladder storage symptoms. PMID- 26057063 TI - Effects of psychological stress on male fertility. AB - Psychological stress can be defined as any uncomfortable 'emotional experience' accompanied by predictable biochemical, physiological and behavioural changes or responses. Many clinical studies looking at the effects of psychological stress on male fertility have shown that stress is associated with reduced paternity and abnormal semen parameters. Enough scientific evidence exists to suggest that psychological stress could severely affect spermatogenesis, mainly as a result of varying testosterone secretion. The hypothalamic-pituitary-adrenal axis has a direct inhibitory action on the hypothalamic-pituitary-gonadal (HPG) axis and Leydig cells in the testes. The newly discovered hormone, gonadotropin-inhibitory hormone (GnIH), also has an inhibitory effect on the HPG axis. Inhibition of the HPG axis results in a fall in testosterone levels, which causes changes in Sertoli cells and the blood-testis barrier, leading to the arrest of spermatogenesis. Germ cells also become vulnerable to gonadotoxins and oxidation. However, the extent and severity of the effects of psychological stress on human testes is difficult to study and data mostly come from animal models. Despite this limitation, stress as a causative factor in male infertility cannot be ignored and patients should be made aware of its effects on testicular function and fertility and helped to manage them. PMID- 26057065 TI - Ability of PROMIS Pediatric Measures to Detect Change in Children With Cerebral Palsy Undergoing Musculoskeletal Surgery. AB - BACKGROUND: The Patient Reported Outcomes Measurement Information System (PROMIS) was developed to provide patient-reported outcome measures that are designed as being universally relevant across health conditions, low burden, and precise. A major problem for research and clinical practice in cerebral palsy (CP) is the void of outcomes instruments that are capable of evaluating the wide range of abilities and broad age spectrum inherent in this clinical population. Given the tremendous potential of PROMIS, the research questions for this study were "How do PROMIS pediatric computer adaptive tests and short forms detect change in children with CP following elective musculoskeletal surgery?" and "How do PROMIS instruments compare to the Pediatric Quality of Life Inventory Cerebral Palsy Module Version 3.0 (PedsQL CP), Pediatric Outcomes Data Collection Instrument (PODCI), the Timed Up and Go (TUG), and the Gross Motor Functional Measure (GMFM)." METHODS: PROMIS Pediatric computer adaptive tests and short forms and the PedsQL, PODCI, TUG, and GMFM were administered before and after surgery. Effect size (ES) and standardized response mean (SRM) were calculated. Floor and ceiling effects were evaluated and, exposure rates for the PROMIS item banks were examined. RESULTS: ES and SRM for all PROMIS Pediatric Measures were nonsignificant. PedsQL CP detected significant, positive change in mobility at 6 (ES=0.26; SRM=0.31) and 12 (ES=0.36; SRM=0.36) months; pain at 12 months (ES=0.29; SRM=0.34); and fatigue at 6 (ES=0.24; SRM=0.22) and 12 (ES=0.36; SRM=0.41) months. Significant negative changes were detected by the PODCI (ES= 0.20; SRM=-0.26), GMFM (ES=-0.13; SRM=-0.24), and TUG (ES=-0.29; SRM=-0.25). Ceiling effects were high. Exposure to an appropriate range of the PROMIS Mobility item bank was limited. CONCLUSIONS: PROMIS measures were less able to detect change than other measures. PROMIS measures may be improved by tailoring start/stop rules or by adding items to include content appropriate for children with mobility impairments. LEVEL OF EVIDENCE: Level III-diagnostic study. PMID- 26057066 TI - A Reliable and Valid Objective Structured Assessment of Technical Skill for the Application of a Pavlik Harness Based on International Expert Consensus. AB - BACKGROUND: The use of competency-based training is increasing in medical education as it offers individualized learning opportunities to master required skills. Inherent to this method of teaching is the need for standardized and objective assessments of skill mastery. In orthopaedic surgery, educational programs have focused on surgical skills with lesser emphasis on nonoperative techniques. Accordingly, formal evaluation tools specific to Pavlik Harness application do not exist, despite its widespread use and potential complications from inappropriate application. This study sought to develop a reliable and valid evaluation tool based on international expert consensus to standardize and evaluate Pavlik Harness application for developmental dysplasia of the hip. METHODS: Consensus was sought from 10 content experts using Delphi methodology. Resulting items formed the Objective Structured Assessment of Technical Skill (OSATS). Thirty-five participants were selected into 3 a priori groups (expert, intermediate and novice) based on Pavlik Harness experience. On 2 occasions, 3 content experts assessed randomized and deidentified videotapes of each participant applying a Pavlik Harness to an infant model using the OSATS and global rating scales (GRS). The reliability and validity of the OSATS was determined with intraclass (ICC) and Pearson correlations and analysis of variance (ANOVA). RESULTS: Consensus was obtained after 2 rounds of structured surveying and resulted in a 25-item OSATS. The reliability of the OSATS was excellent with an ICC of 0.96 for interrater and 0.98 for test-retest reliability. Construct validity was excellent with high correlations between OSATS and GRS (>0.90). In addition, the OSATS discriminated between expert, intermediate, and novice users. CONCLUSIONS: We have developed a competency-based evaluation tool for Pavlik Harness application based on consensus from international experts. The OSATS has been shown to be a reliable and valid method for assessing Pavlik Harness application that can discriminate between expert, intermediate, and novice users. LEVEL OF EVIDENCE: Level II. PMID- 26057067 TI - Developmental Morphology in Childhood Patellar Instability: Age-dependent Differences on Magnetic Resonance Imaging. AB - BACKGROUND: Magnetic resonance imaging (MRI) has been used to define pathologic morphology of patellar instability primarily in adults, but few studies have evaluated skeletally immature patients. The purpose of this study was to delineate differences in morphologic parameters between normal children and children with patellar instability. METHODS: A retrospective review of knee MRIs, ages 8 to 18 years, using a "normal" cohort without evidence of patella instability (normal group, NG) and a cohort with unstable patella (unstable group, UG). Thirty-four measurements were made on patellar characteristics, trochlear morphology, limb alignment, and the medial patellofemoral ligament (MPFL). Spearman's rho correlations were calculated between age and MRI measures. RESULTS: There were 132 NG and 66 UG children that met criteria. The majority of parameters considered diagnostically relevant in adults, also seem to be statistically relevant for children. A new measure, MPFL insertion site to the physis distance, was also significantly different (NG: -1.8+/-3.5 vs. UG: 0+/-3.4 mm). More importantly, some measurements demonstrated both a difference between the 2 groups and an age correlation: osseous sulcus angle (NG: 133.4+/-12.4 vs. UG: 145.2+/-11.2 degrees, age correlation P=0.01) and cartilaginous sulcus angle (NG: 138.2+/-9.5 vs. UG: 152.5+/-11.7 degrees, age correlation P=0.03). CONCLUSIONS: Several end-stage adult parameters are significant as good predictors of patellar instability when seen on a child's MRI; but, some parameters, such as sulcus angle, are dependent on the age of the child. The most significant variation in regards to age is seen with sulcus angles. Moreover, there is a significant change in the location of the MPFL attachment on the femur as it relates to the physis with age, as well as stability. LEVEL OF EVIDENCE: Level III-prognostic study, case-control study. PMID- 26057068 TI - Reducing Cost and Radiation Exposure During the Treatment of Pediatric Greenstick Fractures of the Forearm. AB - BACKGROUND: We hypothesize that after successful closed reduction of pediatric greenstick fractures of the forearm, there is a low rate of lost reduction requiring intervention. By reducing the frequency of clinical and radiographic follow-up, we can reduce costs and radiation exposure. METHODS: A retrospective analysis was performed on patients aged 2 to 16 years treated with closed reduction and cast immobilization for greenstick fractures of the forearm at our institution between 2003 and 2013. The primary endpoint was a healed fracture with acceptable alignment at the final radiographic evaluation. Time-derived activity-based costing was used for cost analysis. We estimated radiation exposure in consultation with our hospital's radiation safety office. RESULTS: One hundred and nine patients with an average age of 6.9 years (range, 2 to 15 y) met the inclusion criteria. The initial maximal fracture angulation of the affected radius and/or ulna averaged 19.3 (SD=+/-8.7) degrees (range, 2 to 55 degrees). Patients were followed for an average of 60 days (range, 19 to 635 d). On average, patients received 3.6 follow-up clinical visits and 3.5 sets of radiographs following immediate emergency department care. Ninety-four percent of patients met criteria for acceptable radiographic alignment. Only 1 patient (0.9%; 95% confidence interval, 0.2%-5.0%) underwent rereduction, as determined by the treating physician. If clinical follow-up were limited to 2 visits and 3 sets of radiographs total, there would be a 14.3% reduction in total cost of fracture care and a 41% reduction in radiation exposure. CONCLUSIONS: This retrospective study suggests that pediatric greenstick fractures of the forearm rarely require intervention after initial closed reduction. We propose that 2 clinical follow-up visits and 3 sets of radiographs would reduce overall care costs and radiation exposure without compromising clinical results. LEVEL OF EVIDENCE: Level IV-economic and decision analyses. PMID- 26057069 TI - Hip Reconstruction in Children With Unilateral Cerebral Palsy and Hip Dysplasia. AB - BACKGROUND: Highly functioning children with unilateral cerebral palsy (CP) who have hip involvement (type IV hemiplegia) may present with hip dysplasia during their adolescence. The aim of this report is to assess the outcomes of combined femoral and acetabular reconstruction in this population. METHODS: This study is a retrospective review of all patients with unilateral CP, Gross Motor Function Classification System types I and II, who had hip reconstruction for unilateral dysplasia between 1989 and 2013. Clinical variables (pain and hip passive range of motion) were reviewed. Hip morphology was assessed radiographically according to Melbourne Cerebral Palsy Hip Classification System. Three-dimensional gait analyses were also reviewed to evaluate the effect of surgery on these patients' gaits. RESULTS: Twelve patients were included with a mean age at surgery of 14 years (range, 7 to 19 y) and follow-up mean of 4 years (range, 1 to 8 y). Nine hips were improved according to Melbourne Cerebral Palsy Hip Classification System. Migration percentage decreased significantly (P<0.001) from 45% (30% to 86%) to 15% (0% to 28%). Neck shaft angle decreased (P<0.001) from 144 degrees (range, 129 to 156 degrees) to 125 degrees (range, 114 to 139 degrees). Tonnis angle and Sharp angle also decreased significantly. All patients were pain free at the last visit. Overall level of gait function as measured by Gait Deviation Index and Gait Profile Score [78 (61 to 89) and 12 (8 to 16), respectively] for all patients was maintained without significant changes. CONCLUSIONS: In hemiplegic type IV CP, with high functional level (Gross Motor Function Classification System I and II), hip dysplasia is a rare occurrence during adolescent years. Combined hip reconstruction improves hip morphology, relieves pain, and maintains a high level of function. LEVEL OF EVIDENCE: Level IV therapeutic study. PMID- 26057070 TI - Diagnosis in Infants and Children With Osteogenesis Imperfecta. PMID- 26057071 TI - Can Subclinical Rickets Cause SCFE? A Prospective, Pilot Study. AB - BACKGROUND: Slipped capital femoral epiphysis (SCFE) is a common disorder of the growing hip; however, its etiology remains unknown. Vitamin D (25-OH) is a major regulator of bone homeostasis and calcium metabolism. Vitamin D deficiency is one of the major causes of rickets, and rickets has been associated with SCFE. Increased body mass index (BMI) has been linked to SCFE and obese children are known to have lower vitamin D levels. Therefore, we hypothesize that children who develop SCFE may have subclinical rickets predisposing them to the development of physeal disease. METHODS: This was a pilot, prospective study designed to determine the relationship between vitamin D, bone, muscle, and fat in patients with SCFE. We enrolled 20 consecutive patients with idiopathic SCFE aged 9 to 14 years. Upon diagnosis, vitamin D, PTH, T4, and thyroid-stimulating hormone blood levels were obtained. A single-slice computed tomography was used to measure cortical bone density (CBD) of the femur. Demographics, BMI, and the results obtained were compared to generate a relationship between vitamin D levels and SCFE. RESULTS: Twenty patients were enrolled, 13 males and 7 females, at an average age of 12 years (range, 9 to 14 y), and mean BMI% was 93.9 (range, 81.3 to 99.5). There were 15 stable and 5 unstable SCFE. Overall, mean and SD values for vitamin D, 25-OH were within the normal range (43.9 +/- 13.5). We found no difference in values in vitamin D between nonobese (BMI < 95%) and obese (BMI >= 95%) subjects (34.8 +/- 16.8 vs. 51.6 +/- 22.4, P = 0.144). Moreover, we found no difference in CBD between these 2 groups (1126 +/- 33.1 vs. 1147 +/- 41.2, P = 0.333). There was no relation between blood values of vitamin D and measures of CBD. CONCLUSIONS: Although obese children are known to have lower levels of vitamin D and a higher prevalence of SCFE, we found no correlation between low vitamin D and the development of SCFE in this subset of patients. PMID- 26057072 TI - Combined Medial Cuneiform Osteotomy and Multiple Metatarsal Osteotomies For Correction of Persistent Metatarsus Adductus in Children. AB - BACKGROUND: Metatarsus adductus may occur in children after otherwise successful clubfoot treatment or may be an isolated deformity. There are various bony procedures currently in use for treatment of this problem. The purpose of this study was to review our experience with medial cuneiform opening-wedge osteotomy along with transmetatarsal osteotomy through the base of the second to fifth for treatment of the forefoot adductus in children. METHODS: From 1992 to 2008, we found 16 patients, 25 feet who underwent the procedure by a single surgeon (MDS) at the Shriners Hospitals for Children in Portland. All preoperative and postoperative radiographs were measured and analyzed and all clinic notes were reviewed. RESULTS: Major improvements were seen in the configuration of the foot. Significant differences were found between preoperative and postoperative anteroposterior standing radiographs by measuring the talo-first metatarsal angle, the talo-calcaneal angle, the calcaneal-second metatarsal angle, and the calcaneal-fifth metatarsal angle (P<0.005). On the lateral view the talo-first metatarsal, the talo-calcaneal, the tibio-talar, the tibio-calcaneal, and the pitch angle did not show any change. An unexpected finding was that after the surgery, the lateral subluxation of talo-navicular joint was partially corrected. CONCLUSIONS: This retrospective study suggests that combined medial cuneiform opening-wedge osteotomy with transmetatarsal osteotomy through the base of second to fifth can effectively correct this deformity regardless of the underlying cause. In our cases, we achieved good clinical and radiographic results. We have used this procedure for patients 6 years and older who have moderate to severe forefoot adductus. LEVEL OF EVIDENCE: Level IV-therapeutic studies. PMID- 26057073 TI - Controlling the degradation kinetics of porous iron by poly(lactic-co-glycolic acid) infiltration for use as temporary medical implants. AB - Iron and its alloy have been proposed as biodegradable metals for temporary medical implants. However, the formation of iron oxide and iron phosphate on their surface slows down their degradation kinetics in both in vitro and in vivo scenarios. This work presents new approach to tailor degradation behavior of iron by incorporating biodegradable polymers into the metal. Porous pure iron (PPI) was vacuum infiltrated by poly(lactic-co-glycolic acid) (PLGA) to form fully dense PLGA-infiltrated porous iron (PIPI) and dip coated into the PLGA to form partially dense PLGA-coated porous iron (PCPI). Results showed that compressive strength and toughness of the PIPI and PCPI were higher compared to PPI. A strong interfacial interaction was developed between the PLGA layer and the iron surface. Degradation rate of PIPI and PCPI was higher than that of PPI due to the effect of PLGA hydrolysis. The fast degradation of PIPI did not affect the viability of human fibroblast cells. Finally, this work discusses a degradation mechanism for PIPI and the effect of PLGA incorporation in accelerating the degradation of iron. PMID- 26057074 TI - Assessment of cardiac function in mice lacking the mitochondrial calcium uniporter. AB - Mitochondrial calcium is thought to play an important role in the regulation of cardiac bioenergetics and function. The entry of calcium into the mitochondrial matrix requires that the divalent cation pass through the inner mitochondrial membrane via a specialized pore known as the mitochondrial calcium uniporter (MCU). Here, we use mice deficient of MCU expression to rigorously assess the role of mitochondrial calcium in cardiac function. Mitochondria isolated from MCU(-/-) mice have reduced matrix calcium levels, impaired calcium uptake and a defect in calcium-stimulated respiration. Nonetheless, we find that the absence of MCU expression does not affect basal cardiac function at either 12 or 20months of age. Moreover, the physiological response of MCU(-/-) mice to isoproterenol challenge or transverse aortic constriction appears similar to control mice. Thus, while mitochondria derived from MCU(-/-) mice have markedly impaired mitochondrial calcium handling, the hearts of these animals surprisingly appear to function relatively normally under basal conditions and during stress. PMID- 26057075 TI - Phosphorylation of myosin regulatory light chain controls myosin head conformation in cardiac muscle. AB - The effect of phosphorylation on the conformation of the regulatory light chain (cRLC) region of myosin in ventricular trabeculae from rat heart was determined by polarized fluorescence from thiophosphorylated cRLCs labelled with bifunctional sulforhodamine (BSR). Less than 5% of cRLCs were endogenously phosphorylated in this preparation, and similarly low values of basal cRLC phosphorylation were measured in fresh intact ventricle from both rat and mouse hearts. BSR-labelled cRLCs were thiophosphorylated by a recombinant fragment of human cardiac myosin light chain kinase, which was shown to phosphorylate cRLCs specifically at serine 15 in a calcium- and calmodulin-dependent manner, both in vitro and in situ. The BSR-cRLCs were exchanged into demembranated trabeculae, and polarized fluorescence intensities measured for each BSR-cRLC in relaxation, active isometric contraction and rigor were combined with RLC crystal structures to calculate the orientation distribution of the C-lobe of the cRLC in each state. Only two of the four C-lobe orientation populations seen during relaxation and active isometric contraction in the unphosphorylated state were present after cRLC phosphorylation. Thus cRLC phosphorylation alters the equilibrium between defined conformations of the cRLC regions of the myosin heads, rather than simply disordering the heads as assumed previously. cRLC phosphorylation also changes the orientation of the cRLC C-lobe in rigor conditions, showing that the orientation of this part of the myosin head is determined by its interaction with the thick filament even when the head is strongly bound to actin. These results suggest that cRLC phosphorylation controls the contractility of the heart by modulating the interaction of the cRLC region of the myosin heads with the thick filament backbone. PMID- 26057076 TI - Exogenous salicylic acid protects phospholipids against cadmium stress in flax (Linum usitatissimum L.). AB - Salicylic acid (SA) promotes plant defense responses against toxic metal stresses. The present study addressed the hypothesis that 8-h SA pretreatment, would alter membrane lipids in a way that would protect against Cd toxicity. Flax seeds were pre-soaked for 8h in SA (0, 250 and 1000uM) and then subjected, at seedling stage, to cadmium (Cd) stress. At 100uM CdCl2, significant decreases in the percentages of phosphatidylcholine (PC), phosphatidylglycerol (PG), phosphatidylethanolamine (PE) and monogalactosyldiacylglycerol (MGDG) and changes in their relative fatty acid composition were observed in Cd-treated roots in comparison with controls. However, in roots of 8-h SA pretreated plantlets, results showed that the amounts of PC and PE were significantly higher as compared to non-pretreated plantlets. Additionally, in both lipid classes, the proportion of linolenic acid (18:3) increased upon the pretreatment with SA. This resulted in a significant increase in the fatty acid unsaturation ratio of the root PC and PE classes. As the exogenous application of SA was found to be protective of flax lipid metabolism, the possible mechanisms of protection against Cd stress in flax roots were discussed. PMID- 26057077 TI - Physiological changes of the lichen Parmotrema tinctorum as result of carbon nanotubes exposition. AB - Carbon nanotubes (CNT) is one of the more abundant nanomaterial produced in the world. Therefore, it is desirable to access its effects in all environment compartments, in order to mitigate environmental distress. This study aims to verify the potential use of lichens - classical atmospheric pollution indicators as biomonitors of carbon nanotubes aerosols. To examine cause-effect relationships, preserving environmental microclimatic parameters, the lichen Parmotrema tinctorum (Nyl.) Hale was transplanted to open top chambers where aerosols of CNT were daily added. Physiological parameters such as cell viability, photosynthetic efficiency, cell permeability as well as nanoparticle internalization were assessed. Carbon nanotubes exposure led to reduction on the cell viability of P. tinctorum. The treatment with 100ug/mL of MWCNT-COOH resulted in intracellular ion leakage, probably due to changes in membrane permeability. No alterations on photosynthetic efficiency were detected. Carbon nanotubes entrapment and internalization into the lichen thallus were observed. Short term exposition of CNT produced measurable physiological changes in P. tinctorum lichen. This suggests the possibility of use of lichens as models to assess the environmental impact (air related) of engineered nanomaterials. PMID- 26057078 TI - Hormesis depends upon the life-stage and duration of exposure: Examples for a pesticide and a nanomaterial. AB - Tests to assess toxic effects on the reproduction of adult C. elegans after 72h exposure for two chemicals, (3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU)), also known as diuron, and silver nanoparticles (Ag NPs) indicated potential, although not significant hormesis. Follow up toxicity tests comparing the potential hormesis concentrations with controls at high replication confirmed that the stimulatory effect was repeatable and also statistically significant within the test. To understand the relevance of the hormesis effects for overall population fitness, full life-cycle toxicity tests were conducted for each chemical. When nematodes were exposed to DCMU over the full life-span, the hormesis effect for reproduction seen in short-term tests was no longer evident. Further at the putative hormesis concentrations, a negative effect of DCMU on time to maturation was also seen. For the Ag NPs, the EC50 for effects on reproduction in the life-cycle exposure was substantially lower than in the short term test, the EC50s estimated by a three parameter log logistic model being 2.9mg/L and 0.75mg/L, respectively. This suggests that the level of toxicity for Ag NPs for C. elegans reproduction is dependant on the life stage exposed and possibly the duration of the exposure. Further, in the longer duration exposures, hormesis effects on reproduction seen in the short-term exposures were no longer apparent. Instead, all concentrations reduced both overall brood size and life span. These results for both chemicals suggest that the hormesis observed for a single endpoint in short-term exposure may be the result of a temporary reallocation of resources between traits that are not sustained over the full life-time. Such reallocation is consistent with energy budget theories for organisms subject to toxic stress. PMID- 26057079 TI - Targeting key metabolic points for an enhanced phytoremediation of wastewaters pre-treated by the photo-Fenton process using Solanum nigrum L. AB - Several physiological, biochemical and molecular biology responses were analysed in Solanum nigrum L. plants exposed for 28 days to an effluent that resulted from the photo-Fenton treatment of a highly concentrated pesticide and systemic fungicide aqueous solution, containing metalaxyl as active compound (150mgL(-1)), in order to pinpoint metabolic steps for a future increase of these plants' capacity to deal with the chemical process by-products. Although plants suffered oxidative stress, as indicated by increased membrane damage and a negative effect on plant biomass, they absorbed the excess iron and acted on the resulting by products present in the effluent after the photo-Fenton process. Nitrogen assimilation and metallothionein gene expression were down regulated, while glutathione biosynthesis increased. These results suggest an enhanced nitrogen assimilation and/or metallothionein accumulation as relevant key points for further plant improvement in order to increase the efficiency of this innovative strategy that considers integration of the photo-Fenton process (as chemical primary treatment) with S. nigrum L. plants (as biological remediation post treatment) for heavily polluted wastewaters. PMID- 26057080 TI - Correlation Equation for Predicting the Single-Collector Contact Efficiency of Colloids in a Horizontal Flow. AB - The single-collector contact efficiency (eta0) for physicochemical colloid filtration under horizontal flow in saturated porous media was calculated using trajectory analysis in three dimensions. Past studies have developed correlation equations for colloids with densities close to that of water, such as bacteria and latex particles. A new correlation equation was developed for predicting eta0 based on a large number of trajectory simulations to account for higher-density particles representative of metal colloids. The correlation equation was developed by assuming Brownian diffusion, interception, and gravitational sedimentation contributed to eta0 in an additive manner. Numerical simulations for colloid trajectory analysis used for calculating eta0 were based on horizontal flow around a collector under the action of van der Waals attractive forces, gravity, and hydrodynamic forces as well as Brownian motion. The derived correlation equation shows excellent agreement with existing correlation equations for particles with density close to that of water. However, the correlation equation presented in this study shows that eta0 of high-density colloids, such as metal particles, transported under horizontal flow deviates from that predicted by existing correlations for colloids larger than 4 MUm and under low approach velocities. Simulations of trajectory paths show that a significantly reduced contact of high-density colloids larger than 4 MUm in size with a collector is due to gravity forces causing trajectory paths to deviate away from the underside of collectors. The new correlation equation is suitable for predicting the single collector efficiency of large particles (several hundred nanometers to several micrometers) and with a large amount of density transport in the horizontal flow mode but is unsuitable for particles with a quite small size (several to tens of nanometers) and for the particle with a large amount of density flow in the vertical flow mode. The trajectory analysis was conducted for particles under favorable deposition conditions. PMID- 26057081 TI - Performance monitoring in obsessive-compulsive undergraduates: Effects of task difficulty. AB - Both obsessive-compulsive disorder and subclinical obsessive-compulsive (OC) symptoms seem to be associated with hyperactive error-related brain activity. The current study examined performance monitoring in subjects with subclinical OC symptoms using a new task with different levels of difficulty. Nineteen subjects with high and 18 subjects with low OC characteristics performed a random dot cinematogram (RDC) task with three levels of difficulty. The high and low OC groups did not differ in error-related negativity (ERN), correct-related negativity (CRN) and performance irrespective of task difficulty. The amplitude of the ERN decreased with increasing difficulty whereas the magnitude of CRN did not vary. ERN and CRN approached in size and topography with increasing difficulty, which suggests that errors and correct responses are processed more similarly. These results add to a growing number of studies that fail to replicate hyperactive performance monitoring in individuals with OC symptoms in task with higher difficulty or requiring learning. Together with these findings our results suggest that the relationship between OC symptoms and performance monitoring may be sensitive to type of task and task characteristics and cannot be observed in a RDC that differs from typically used tasks in difficulty and the amount of response-conflict. PMID- 26057083 TI - Plant growth improvement mediated by nitrate capture in co-composted biochar. AB - Soil amendment with pyrogenic carbon (biochar) is discussed as strategy to improve soil fertility to enable economic plus environmental benefits. In temperate soils, however, the use of pure biochar mostly has moderately-negative to -positive yield effects. Here we demonstrate that co-composting considerably promoted biochars' positive effects, largely by nitrate (nutrient) capture and delivery. In a full-factorial growth study with Chenopodium quinoa, biomass yield increased up to 305% in a sandy-poor soil amended with 2% (w/w) co-composted biochar (BC(comp)). Conversely, addition of 2% (w/w) untreated biochar (BC(pure)) decreased the biomass to 60% of the control. Growth-promoting (BC(comp)) as well as growth-reducing (BC(pure)) effects were more pronounced at lower nutrient supply levels. Electro-ultra filtration and sequential biochar-particle washing revealed that co-composted biochar was nutrient-enriched, particularly with the anions nitrate and phosphate. The captured nitrate in BC(comp) was (1) only partly detectable with standard methods, (2) largely protected against leaching, (3) partly plant-available, and (4) did not stimulate N2O emissions. We hypothesize that surface ageing plus non-conventional ion-water bonding in micro- and nano-pores promoted nitrate capture in biochar particles. Amending (N-rich) bio-waste with biochar may enhance its agronomic value and reduce nutrient losses from bio-wastes and agricultural soils. PMID- 26057085 TI - Effectiveness of 6% hydrogen peroxide concentration for tooth bleaching-A double blind, randomized clinical trial. AB - OBJECTIVE: The aim of this clinical randomized double-blind split-mouth study was to assess the effectiveness of a 6% hydrogen peroxide with nitrogen-doped titanium dioxide light activated bleaching agent. METHOD: 31 patients were treated with: one upper hemiarcade with a 35% hydrogen peroxide bleaching agent and the other hemiarcade with a 6% hydrogen peroxide. Two applications were completed each treatment session and three sessions were appointed, with one week interval between them. Tooth colour was registered each session and 1 week and 1 months after completing the treatment by spectrophotometer, registering parameters L*, a* and b*, and subjectively using VITA Classic guide. Tooth sensitivity was registered by VAS and patient satisfaction and self-perception result was determined using OHIP-14. Tooth colour variation and sensitivity were compared between both bleaching agents. RESULTS: Both treatment showed a change between baseline colour and all check-points with a DeltaE=5.57 for 6% and of DeltaE=7.98 for the 35% one month after completing the (p<0.05). No statistical differences were seen when subjective evaluations were compared. Also, no differences were seen in tooth sensitivity between bleaching agents. OHIP-14 questionnaire demonstrated a significant change for all patients after bleaching. CONCLUSIONS: A 6% hydrogen peroxide with nitrogen-doped titanium dioxide light activated agent is effective for tooth bleaching, reaching a DeltaE of 5.57 one month after completing the treatment, with no clinical differences to a 35% agent neither in colour change or in tooth sensitivity. CLINICAL SIGNIFICANCE: A low concentration hydrogen peroxide bleaching agent may reach good clinical results with less adverse effects. PMID- 26057084 TI - Merlin status regulates p75(NTR) expression and apoptotic signaling in Schwann cells following nerve injury. AB - After nerve injury, Schwann cells (SCs) dedifferentiate, proliferate, and support axon regrowth. If axons fail to regenerate, denervated SCs eventually undergo apoptosis due, in part, to increased expression of the low-affinity neurotrophin receptor, p75(NTR). Merlin is the protein product of the NF2 tumor suppressor gene implicated in SC tumorigenesis. Here we explore the contribution of merlin to SC responses to nerve injury. We find that merlin becomes phosphorylated (growth permissive) in SCs following acute axotomy and following gradual neural degeneration in a deafness model, temporally correlated with increased p75(NTR) expression. p75(NTR) levels are elevated in P0SchDelta39-121 transgenic mice that harbor an Nf2 mutation in SCs relative to wild-type mice before axotomy and remain elevated for a longer period of time following injury. Replacement of wild type, but not phospho-mimetic (S518D), merlin isoforms suppresses p75(NTR) expression in primary human schwannoma cultures which otherwise lack functional merlin. Despite elevated levels of p75(NTR), SC apoptosis following axotomy is blunted in P0SchDelta39-121 mice relative to wild-type mice suggesting that loss of functional merlin contributes to SC resistance to apoptosis. Further, cultured SCs from mice with a tamoxifen-inducible knock-out of Nf2 confirm that SCs lacking functional merlin are less sensitive to p75(NTR)-mediated cell death. Taken together these results point to a model whereby loss of axonal contact following nerve injury results in merlin phosphorylation leading to increased p75(NTR) expression. Further, they demonstrate that merlin facilitates p75(NTR) mediated apoptosis in SCs helping to explain how neoplastic SCs that lack functional merlin survive long-term in the absence of axonal contact. PMID- 26057086 TI - Diet influenced tooth erosion prevalence in children and adolescents: Results of a meta-analysis and meta-regression. AB - OBJECTIVE: The aim of the present study was to assess the influence of diet in tooth erosion presence in children and adolescents by meta-analysis and meta regression. DATA: Two reviewers independently performed the selection process and the quality of studies was assessed. SOURCES: Studies published until May 2014 were identified in electronic databases: Pubmed, EBSHost, Scopus, Science direct, Web of Science and Scielo, using keywords. STUDY SELECTION: Criteria used included: observational studies, tooth erosion and diet, subject age range 8-19 years old, permanent dentition and index. Meta-analysis was performed and in case of heterogeneity a random-effects model was used. Thirteen studies that fulfilled the inclusion criteria were selected. Higher consumption of carbonated drinks (p=0.001) or acid snacks/sweets (p=0.01 and for acid fruit juices (p=0.03)) increased the odds for tooth erosion, while higher intake of milk (p=0.028) and yogurt (p=0.002) reduced the erosion occurrence. Heterogeneity was observed in soft drinks, confectionary and snacks and acidic fruit juices models. Methodological issues regarding the questionnaires administration and the inclusion of other variables, such as food groups and tooth brushing, explained partially the heterogeneity observed. CONCLUSIONS: Some dietary components (carbonated drinks, acid snacks/sweets and natural acidic fruits juice) increased erosion occurrence while milk and yogurt had a protective effect. Methods to assess diet could influence the homogeneity of the studies and should be considered during the study design. CLINICAL SIGNIFICANCE: The method to assess diet should be carefully considered and well conducted as part of the clinical assessment of tooth erosion, since diet could influence the occurrence of tooth erosion. PMID- 26057087 TI - Exercise for Mood and Anxiety Disorders: The State-of-the Science. PMID- 26057088 TI - Response to Cheluvappa and Eri: Conjugate products of pyocyanin-glutathione reactions. PMID- 26057090 TI - Synthesis of a DNA-targeting nickel (II) complex with testosterone thiosemicarbazone which exhibits selective cytotoxicity towards human prostate cancer cells (LNCaP). AB - Testosterone thiosemicarbazone, L and its nickel (II) complex 1 were synthesized and characterized by using FTIR, CHN, (1)H NMR, and X-ray crystallography. X-ray diffraction study confirmed the formation of L from condensation of testosterone and thiosemicarbazide. Mononuclear complex 1 is coordinated to two Schiff base ligands via two imine nitrogens and two tautomeric thiol sulfurs. The cytotoxicity of both compounds was investigated via MTT assay with cisplatin as positive reference standard. L is more potent towards androgen-dependent LNCaP (prostate) and HCT 116 (colon). On the other hand, complex 1, which is in a distorted square planar environment with L acting as a bidentate NS-donor ligand, is capable of inhibiting the growth of all the cancer cell lines tested, including PC-3 (prostate). It is noteworthy that both compounds are less toxic towards human colon cell CCD-18Co. The intrinsic DNA binding constant (Kb) of both compounds were evaluated via UV-Vis spectrophotometry. Both compounds showed Kb values which are comparable to the reported Kb value of typical classical intercalator such as ethidium bromide. The binding constant of the complex is almost double compared with ligand L. Both compounds were unable to inhibit the action topoisomerase I, which is the common target in cancer treatment (especially colon cancer). This suggest a topoisomerase I independent-cell death mechanism. PMID- 26057089 TI - Plant expansins: diversity and interactions with plant cell walls. AB - Expansins were discovered two decades ago as cell wall proteins that mediate acid induced growth by catalyzing loosening of plant cell walls without lysis of wall polymers. In the interim our understanding of expansins has gotten more complex through bioinformatic analysis of expansin distribution and evolution, as well as through expression analysis, dissection of the upstream transcription factors regulating expression, and identification of additional classes of expansin by sequence and structural similarities. Molecular analyses of expansins from bacteria have identified residues essential for wall loosening activity and clarified the bifunctional nature of expansin binding to complex cell walls. Transgenic modulation of expansin expression modifies growth and stress physiology of plants, but not always in predictable or even understandable ways. PMID- 26057091 TI - Study of carotenoids in cyanobacteria by Raman spectroscopy. AB - Cyanobacteria have established dominant aquatic populations around the world, generally in aggressive environments and under severe stress conditions, e.g., intense solar radiation. Several marine strains make use of compounds such as the polyenic molecules for their damage protection justifying the range of colours observed for these species. The peridinin/chlorophyll-a/protein complex is an excellent example of essential structures used for self-prevention; their systems allow to them surviving under aggressive environments. In our simulations, few protective dyes are required to the initial specimen defense; this is an important data concern the synthetic priority in order to supply adequate damage protection. Raman measurements obtained with 1064 and 514.5 nm excitations for Cylindrospermopsis raciborskii and Microcystis aeruginosa strains shows bands assignable to the carotenoid peridinin. It was characterized by bands at 1940, 1650, 1515, 1449, 1185, 1155 and 1000 cm(-1) assigned to nu(C=C=C) (allenic vibration), nu(C=C/CO), nu(C=C), delta(C-H, C-18/19), delta(C-H), nu(C-C), and rho(C-CH3), respectively. Recognition by Raman spectroscopy proved to be an important tool for preliminaries detections and characterization of polyene molecules in several algae, besides initiate an interesting discussion about their synthetic priority. PMID- 26057092 TI - Vibrational and structural study of onopordopicrin based on the FTIR spectrum and DFT calculations. AB - In the present work, the structural and vibrational properties of the sesquiterpene lactone onopordopicrin (OP) were studied by using infrared spectroscopy and density functional theory (DFT) calculations together with the 6 31G(*) basis set. The harmonic vibrational wavenumbers for the optimized geometry were calculated at the same level of theory. The complete assignment of the observed bands in the infrared spectrum was performed by combining the DFT calculations with Pulay's scaled quantum mechanical force field (SQMFF) methodology. The comparison between the theoretical and experimental infrared spectrum demonstrated good agreement. Then, the results were used to predict the Raman spectrum. Additionally, the structural properties of OP, such as atomic charges, bond orders, molecular electrostatic potentials, characteristics of electronic delocalization and topological properties of the electronic charge density were evaluated by natural bond orbital (NBO), atoms in molecules (AIM) and frontier orbitals studies. The calculated energy band gap and the chemical potential (MU), electronegativity (chi), global hardness (eta), global softness (S) and global electrophilicity index (omega) descriptors predicted for OP low reactivity, higher stability and lower electrophilicity index as compared with the sesquiterpene lactone cnicin containing similar rings. PMID- 26057093 TI - In vitro DNA and BSA-binding, cell imaging and anticancer activity against human carcinoma cell lines of mixed ligand copper(II) complexes. AB - Binding studies of two water soluble copper(II) complexes of the type [Cu(phen dion)(diimine)Cl]Cl, where phen-dione is 1,10-phenanthroline-5,6-dione and diimine is 1,10-phenanthroline (1) and 2,2'-bipyridine (2), with fish sperm DNA (FS-DNA) and bovine serum albumin (BSA) have been examined under physiological conditions by a series of experimental methods (UV-Vis absorption, fluorescence, viscosity, cyclic voltammetry (CV) and circular dichroism (CD) spectroscopic techniques). The experimental results indicate that the complexes interact with FS-DNA by electrostatic and partial insertion of pyridyl rings between the base stacks of double-stranded DNA. The complexes could quench the intrinsic fluorescence of BSA with the binding constants (Kbin) of 32*10(5) M(-1) (1) and 1.7*10(5) M(-1) (2) at 290 K. The quenching mechanism, thermodynamic parameters, the number of binding sites and the effect of the Cu(II) complexes on the secondary structure of BSA have been explored. The in vitro anticancer chemotherapeutic potential of two copper(II) complexes against the three human carcinoma cell lines (MCF-7, A-549, and HT-29) and one normal cell line (DPSC) were evaluated by MTT assay. The results of in vitro cytotoxicity indicate that the complex (1) has greater cytotoxicity activity against all of the cell lines, especially HT-29 with IC50 values of 1.8 MUM. Based on the IC50 values, these complexes did not display an apparent cyto-selective profile, because it would appear that two complexes are toxic to all four model cell lines. The microscopic analyses of the cancer cells confirm results of cytotoxicity. PMID- 26057094 TI - A chemometric-assisted method for the simultaneous determination of malachite green and crystal violet in water based on absorbance-pH data generated by a homemade pH gradient apparatus. AB - An attractive method of generating second-order data was developed by a dropping technique to generate pH gradient simultaneously coupled with diode-array spectrophotometer scanning. A homemade apparatus designed for the pH gradient. The method and the homemade apparatus were used to simultaneously determine malachite green (MG) and crystal violet (CV) in water samples. The absorbance-pH second-order data of MG or CV were obtained from the spectra of MG or CV in a series of pH values of HCl-KCl solution. The second-order data of mixtures containing MG and CV that coexisted with interferents were analyzed using multidimensional partial least-squares with residual bilinearization. The method and homemade apparatus were used to simultaneously determine MG and CV in fish farming water samples and in river ones with satisfactory results. The presented method and the homemade apparatus could serve as an alternative tool to handle some analysis problems. PMID- 26057095 TI - Synthesis, X-ray crystal structure, thermal behavior and spectroscopic analysis of 1-(1-naphthoyl)-3-(halo-phenyl)-thioureas complemented with quantum chemical calculations. AB - Two novel 1-(1-naphthoyl)-3-(halo-phenyl) substituted thioureas, namely 1-(1 naphthoyl)-3-(2,4-di-fluoro-phenyl)-thiourea (1) and 1-(1-naphthoyl)-3-(3-chloro 4-fluoro-phenyl)-thiourea (2), were synthesized and fully characterized. The X ray crystal and molecular structures have been determined resulting in a planar acylthiourea group, with the C=O and C=S adopting a pseudo-antiperiplanar conformation. An intramolecular N-H?O=C hydrogen bond occurs between the thioamide and carbonyl groups. The crystal packing of both compounds is characterized by extended intermolecular N-H?S=C and N-H?O=C hydrogen-bonding interactions involving the acylthiourea moiety. Compound 2 is further stabilized by pi-stacking between adjacent naphthalene and phenyl rings. The thermal behavior, as well as the vibrational properties, studied by infrared and Raman spectroscopy data complemented by quantum chemical calculations at the B3PW91/6 311++G(d,p) support the formation of these intra- and intermolecular hydrogen bonds. Furthermore, the UV-Vis spectrum is interpreted in terms of TD-DFT quantum chemical calculations with the shapes of the simulated absorption spectra in good accordance with the experimental data. PMID- 26057096 TI - Synthesis and luminescence characterization of Sr(0.5)Ca(0.5)TiO3:Sm(3+) phosphor. AB - The spectroscopic properties of trivalent samarium doped Sr0.5Ca0.5TiO3 perovskite phosphor material (Sr0.5Ca0.5TiO3:xSm(3+), x=0.05, 0.1, 0.5, 1, 1.5) synthesized by the solid state method have been studied. The X-Ray Diffraction profile confirms the orthorhombic perovskite Sr0.5Ca0.5TiO3 structure of the prepared samples. The SEM study reveals the surface morphology. The Judd-Ofelt intensity parameters were calculated for 0.5 wt% Sm(3+) doped Sr0.5Ca0.5TiO3. Transition probabilities, branching ratios and radiative lifetime were evaluated by using Judd-Ofelt analysis. The emission spectra under 405 nm excitation shows five emission peaks at 564 nm, 599 nm, 645 nm, 707 nm and 776 nm corresponding to the transitions (4)G5/2->(6)Hj (j=5/2, 7/2, 9/2, 11/2 and 13/2) respectively. The higher values of branching ratio and stimulated emission cross-section for (4)G5/2->(6)H7/2 transition of Sr0.5Ca0.5TiO3:0.5 wt% Sm(3+) shows its suitability in the field of visible lasers and optical fiber amplifiers. The experimental lifetimes of Sm(3+) doped samples were estimated using the decay curves corresponding to (4)G5/2->(6)H7/2 transition upon 405 nm excitation. Concentration dependence on emission intensity and experimental lifetime were also studied. From the CIE diagram we can see that as the concentration of Sm(3+) ions increases from 0.05 wt% to 1.5 wt% the CIE color co-ordinates changes from greenish yellow to yellowish orange. PMID- 26057097 TI - Sensitive spectrofluorimetric methods for determination of ethopabate and amprolium hydrochloride in chicken plasma and their residues in food samples. AB - Two sensitive and selective spectrofluorimetric methods are proposed to determine ethopabate (ETH) and amprolium hydrochloride (AMP). First derivative synchronous spectrofluorimetry determines the natively fluorescent ethopabate at 288 nm in presence of amprolium hydrochloride which is a non fluorescent quaternary compound with average recovery 100.54+/-0.721 over a concentration range of 0.01 0.8 MUg/mL. Limits of detection (LOD) and quantification (LOQ) are 0.002 and 0.007 MUg/mL, respectively. The second method is direct synchronous spectrofluorimetry for determining amprolium hydrochloride at 362 nm after a reaction with 5% NaOH and 0.08% potassium ferricyanide that is optimized by a two level factorial design. This method is linear over a concentration range of 0.01 0.65 MUg/mL with average recovery 99.4+/-1.28. Limits of detection (LOD) and quantification (LOQ) are 0.002 and 0.006 MUg/mL, respectively. The proposed methods are found to be valid and applicable for the analysis of ETH and AMP in their veterinary formulation. They are successfully applied to determine the studied drugs in chicken plasma and their residues in chicken muscle, liver, egg and chicken-based baby food product with recoveries in the ranges of 95.71 108.73% and 97.36-111.89% and for ETH and AMP, respectively. PMID- 26057098 TI - Conformational alterations induced by novel green 16-E2-16 gemini surfactant in xanthine oxidase: Biophysical insights from tensiometry, spectroscopy, microscopy and molecular modeling. AB - Herein we report the interaction of a biodegradable gemini surfactant, ethane-1,2 diyl bis(N,N-dimethyl-N-hexadecylammoniumacetoxy) dichloride (16-E2-16) with bovine milk xanthine oxidase (XO), employing tensiometry, fluorescence spectroscopy, UV spectroscopy, far-UV circular dichroism spectroscopy (CD), Fourier transform infrared (FT-IR) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and computational molecular modeling. Surface tension results depict substantial changes in the micellar as well as interfacial parameters (CMC, PiCMC, gammaCMC, Gammamax, Amin, DeltaGmic degrees and DeltaGads degrees ) of 16-E2-16 gemini surfactant upon XO combination, deciphering the interaction of XO with the gemini surfactant. Fluorescence measurements reveal that 16-E2-16 gemini surfactant causes quenching in the xanthine oxidase (XO) fluorescence spectra via static procedure and the values of various evaluated binding parameters (KSV, Kb, kq, DeltaGb degrees and n) describe that 16-E2-16 effectively binds to XO. Three dimensional fluorescence, 8-anilino-1-naphthalene sulfonic acid (ANS) binding, F1F3 ratio, UV, CD, FTIR, SEM and TEM results delineate changes in the secondary structure of xanthine oxidase. Molecular docking results provide complement to the steady state fluorescence findings and support the view that quenching occurs due to non polar environment experienced by aromatic residues of the enzyme. The results of this study can help scientists to tune the conformation of an enzyme (XO) with biocompatible amphiphilic microstructures, which will help to unfold further understanding in the treatment modes of various diseases like gout, hyperuricemia, liver and brain necrosis. PMID- 26057100 TI - Network-Based Analysis on Orthogonal Separation of Human Plasma Uncovers Distinct High Density Lipoprotein Complexes. AB - High density lipoprotein (HDL) particles are blood-borne complexes whose plasma levels have been associated with protection from cardiovascular disease (CVD). Recent studies have demonstrated the existence of distinct HDL subspecies; however, these have been difficult to isolate and characterize biochemically. Here, we present the first report that employs a network-based approach to systematically infer HDL subspecies. Healthy human plasma was separated into 58 fractions using our previously published three orthogonal chromatography techniques. Similar local migration patterns among HDL proteins were captured with a novel similarity score, and individual comigration networks were constructed for each fraction. By employing a graph mining algorithm, we identified 183 overlapped cliques, among which 38 were further selected as candidate HDL subparticles. Each of these 38 subparticles had at least two literature supports. In addition, GO function enrichment analysis showed that they were enriched with fundamental biological and CVD protective functions. Furthermore, gene knockout experiments in mouse model supported the validity of these subparticles related to three apolipoproteins. Finally, analysis of an apoA I deficient human patient's plasma provided additional support for apoA-I related complexes. Further biochemical characterization of these putative subspecies may facilitate the mechanistic research of CVD and guide targeted therapeutics aimed at its mitigation. PMID- 26057099 TI - The chromatin fiber: multiscale problems and approaches. AB - The structure of chromatin, affected by many factors from DNA linker lengths to posttranslational modifications, is crucial to the regulation of eukaryotic cells. Combined experimental and computational methods have led to new insights into its structural and dynamical features, from interactions due to the flexible core histone tails or linker histones to the physical mechanism driving the formation of chromosomal domains. Here we present a perspective of recent advances in chromatin modeling techniques at the atomic, mesoscopic, and chromosomal scales with a view toward developing multiscale computational strategies to integrate such findings. Innovative modeling methods that connect molecular to chromosomal scales are crucial for interpreting experiments and eventually deciphering the complex dynamic organization and function of chromatin in the cell. PMID- 26057101 TI - Endometriosis: the effects of dienogest. AB - INTRODUCTION: Ectopic endometrial tissue is found in 2% to 6% of women of reproductive age, in up to 60% of those with dysmenorrhoea, and in up to 30% of women with subfertility, with a peak incidence at around 40 years of age. However, symptoms may not correlate with laparoscopic findings. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of dienogest for the treatment of endometriosis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2014 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: Five studies were included. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review we present information relating to the effectiveness and safety of the following interventions: dienogest versus placebo or no treatment; dienogest versus gonadorelin analogues; dienogest versus combined oral contraceptives; dienogest versus other progestogens. PMID- 26057102 TI - The decline in BMI among Japanese women after World War II. AB - The body mass index (BMI) of the Japanese is significantly lower than is found in other high-income countries. Moreover, the average BMI of Japanese women is lower than that of Japanese men, and the age-specific BMI of Japanese women has decreased over time. The average BMI of Japanese women at age 25 decreased from 21.8 in 1948 to 20.4 in 2010 whereas that of men increased from 21.4 to 22.3 over the same period. We examine the long-term BMI trend in Japan by combining several historical data sources spanning eleven decades, from 1901 to 2012, to determine not only when but also how the BMI decline among women began: whether its inception was period-specific or cohort-specific. Our nonparametric regression analysis generated five findings. First, the BMI of Japanese women peaked with the 1930s birth cohort. This means that the trend is cohort-specific. Second, the BMI of men outpaced that of women in the next cohort. Third, the BMI of Japanese children, boys and girls alike, increased steadily throughout the 20th century. Fourth, the gender difference in the BMI trend is due to a gender difference in the weight trend, not the height trend. Fifth, these BMI trends are observed in urban and rural populations alike. We conclude that the BMI decline among Japanese women began with those who were in their late teens shortly after World War II. PMID- 26057103 TI - Surface complexation modeling of Cr(VI) adsorption at the goethite-water interface. AB - In this study, a charge distribution multisite surface complexation model (CD MUSIC) for adsorption of chromate onto goethite was carefully developed. The adsorption of Cr(VI) on goethite was firstly investigated as a function of pH, ionic strength and Cr(VI) concentration. Results showed that an inner-sphere complexation mechanism was involved because the retention of Cr(VI) was little influenced by ionic strength. Then two surface species: a bidentate complex (=Fe2O2CrOOH) and a monodentate complex (=FeOCrO3(-3/2)), which is constrained by prior spectroscopic evidence were proposed to fit the macroscopic adsorption data. Modeling results showed that the bidentate complex was found to be the dominant species at low pH, whereas, with increasing pH, monodentate species became more pronounced. The model was then verified by prediction of competitive adsorption of chromate and phosphate at various ratios and ionic strengths. The model successfully predicted the inhibition of chromate with the presence of phosphate, suggesting phosphate has higher affinity to goethite surface than Cr(VI). Results showed that the model developed in this study for Cr(VI) onto goethite was applicable for various conditions. It is a useful supplement for the surface complexation model database for oxyanions onto goethite surfaces. PMID- 26057104 TI - Functionalization of graphene with self-doped conducting polypyrrole by click coupling. AB - The synthesis of self-doped conducting polypyrrole-grafted graphene sheets (GS PPy) for non-volatile memory applications is reported. First, the alkyne-modified graphene sheets (GS-alkyne) were covalently functionalized with a water-soluble polymer containing numerous anionic SO3(-) dopants by a copper-catalyzed click reaction. Then, polypyrrole was covalently grafted onto the functionalized graphene sheets by chemical oxidative polymerization to produce GS-PPy hybrids. The GS-PPy hybrids showed a uniform coating of PPy on the GS sheets, good dispersion in aqueous solutions, high electrical conductivity, and red-shifted absorption peak in the UV/Visible spectra. The non-volatile memory device composed of a Al/(GS-PPy/poly(vinyl alcohol))/Al structure, produced by spin coating of the aqueous GS-PPy/poly(vinyl alcohol) solution, showed a good write once read-many times memory behavior, which was due to good electrical and optical absorption properties of the GS-PPy hybrids. The findings of this study provide a potential solution for the fabrication of water-soluble graphene-based hybrids for non-volatile resistive-memory-based applications. PMID- 26057105 TI - Phosphate alteration of chloride behavior at the boehmite-water interface: New insights from ion-probe flow adsorption microcalorimetry. AB - Surface complexation of phosphate to aluminum oxyhydroxides can alter surface reactivity depending on the time-scale and mode of attachment. The effects of phosphate adsorption on reactivity of boehmite (gamma-AlOOH) particles were investigated using ion-probe flow adsorption microcalorimetry (ipFAMC). Consistent with previous studies on adsorption energetics, probing the surface of pristine gamma-AlOOH with chloride ions yielded endothermically unimodal temperature signals with a measured molar heat of exchange (DeltaH(exc)) of -3.1 kJ/mol. However, when the surface of gamma-AlOOH was probed with chloride following phosphate complexation, significant changes in surface reactivity resulted. Irrespective of phosphate loading, the typical endothermic response of the chloride-surface hydroxyl interaction was replaced with a multi-modal energy signature consisting of exothermic and endothermic features. These features indicate that in the presence of phosphate, the overall nature of the interaction of chloride with specific surface hydroxyls located on different exposed planes and their subsequent reactivity was transformed to a more complex environment accompanied by two or more short-lived secondary reactions. It was also shown that phosphate-promoted surface alteration of gamma-AlOOH was highly selective to probing with chloride since no changes in reactivity were observed when nitrate was employed as the primary ion probe under identical experimental conditions. PMID- 26057106 TI - Highly sensitive and simple SERS substrate based on photochemically generated carbon nanotubes-gold nanorods hybrids. AB - We report a simple and easy formation of hybrids between multi-wall carbon nanotubes and gold nanorods by one-pot in situ photochemical synthesis. Measurements of surface-enhanced Raman scattering (SERS) through the effect "coffee ring" in visible and near infrared (NIR) show high sensitivity with detection of nanomolar concentrations of aromatic dyes. The formation of nanocomposites between carbon nanotubes and gold nanorods without chemical binders simplifies the preparation. Photochemical synthesis is an advance over the techniques previously published. PMID- 26057107 TI - Di- and triethanolamine grafted kaolinites of different structural order as adsorbents of heavy metals. AB - Efficient sorbents based on widely available clay minerals are of particular value in the field of pollution control. The research shows mineral-based sorbents formed through organic modification of two kaolinites differing in structural order. Their structure and texture was characterized by XRD, FTIR, DTA/TG, CHN, XPS and N2 adsorption/desorption methods. The obtained materials were tested as adsorbents of Cd(II), Zn(II), Pb(II) and Cu(II) in equilibrium and kinetic experiments. Moreover, the sorption mechanisms were subjected to investigation. The synthesis procedure involved interlayer grafting of kaolinites with diethanolamine (DEA) and triethanolamine (TEA). The organo-kaolinites showed resistance to hydrolysis and temperature up to ~300 degrees C. The adsorption improvement was observed for the modified materials, particular the DEA derivatives and materials based on the poorly ordered kaolinite. The XPS analyses of elements local environment coupled with binding strength tests enabled to confirm the immobilization mechanisms. The pure kaolinites removed metal ions through either the ion-exchange or the surface complexation, exclusively on the external surfaces. In turn, the grafted materials additionally immobilized ions in the interlayer space which was expanded. The ions were attracted by the grafted DEA or TEA, which are N and O-donors and readily form complexes with metals, particularly with the Cu(II). PMID- 26057108 TI - Recurrent inflight chest pain due to a solitary bulla. AB - Ms L is a 47-year-old lady who was referred with severe, left-sided pleuritic chest pain and painful left arm weakness that occurred predictably during consecutive commercial flights. Subsequent investigations diagnosed a large left sided, isolated bulla. A VATS bullectomy was performed with no complications, and a symptomless flight followed. We discuss here the physiological explanation for her symptoms and the treatment of bulla in this unusual case. PMID- 26057109 TI - Functional csdA is needed for effective adaptation and initiation of growth of Clostridium botulinum ATCC 3502 at suboptimal temperature. AB - The activity of RNA helicase csdA (cbo2802) after temperature downshift was compared to its activity at optimal growth temperature, and the effect of sense and antisense oriented insertional inactivation of cbo2802 on the growth of ATCC 3502 at suboptimal temperature was evaluated. The relative cbo2802 transcript level was significantly induced for 30min to 5h after cold shock. In contrast, a significant decrease in the relative transcript level of cbo2802 was observed within the same time frame at 37 degrees C. Inactivation of cbo2802 led to an extensive delay in initiation of exponential growth at 20 degrees C but not at 37 degrees C. In addition, the mean minimum growth temperatures of the mutant strains were higher than those of the wild-type strain. During a 24-hour incubation at 37 degrees C, all strains were motile, whereas at 20 degrees C the mutant strains showed severely impaired motility compared to the wild-type strain. This study shows that a functional csdA is needed for effective adaptation and initiation of growth and motility of Clostridium botulinum ATCC 3502 at suboptimal temperature. PMID- 26057110 TI - Antimicrobial property and microstructure of micro-emulsion edible composite films against Listeria. AB - Edible antimicrobial composite films from micro-emulsions containing all natural compounds were developed and their antimicrobial properties and microstructures were investigated. Chitosan, allyl isothiocyanate (AIT), barley straw arabinoxylan (BSAX), and organic acids (acetic, lactic and levulinic acids) were used as film-forming agent, antimicrobial agent, emulsifier, and solvent, respectively. Micro-emulsions were obtained using high pressure homogenization (HPH) processing at 138MPa for 3cycles. The composite films made from the micro emulsions significantly (p<0.05) inactivated Listeria innocua in tryptic soy broth (TSB) and on the surface of ready-to-eat (RTE) meat samples, achieving microbial reductions of over 4logCFU/ml in TSB after 2days at 22 degrees C and on meat samples after 35days at 10 degrees C. AIT was a major contributor to the antimicrobial property of the films and HPH processing further enhanced its antimicrobial efficacy, while the increase of chitosan from 1.5% to 3%, or addition of acetic acid to the formulations didn't result in additional antimicrobial effects. This study demonstrated an effective approach to developing new edible antimicrobial films and coatings used for food applications. PMID- 26057111 TI - Effect of cell immobilization on the growth dynamics of Salmonella Typhimurium and Escherichia coli at suboptimal temperatures. AB - Predictive microbiology has recently acknowledged the impact of the solid(like) food structure on microbial behavior. The presence of this solid(like) structure causes microorganisms to grow as colonies and no longer planktonically as in liquid. In this paper, the growth dynamics of Salmonella Typhimurium and Escherichia coli were studied as a function of temperature, considering different growth morphologies, i.e., (i) planktonic cells, (ii) immersed colonies and (iii) surface colonies. For all three growth morphologies, both microorganisms were grown in petri dishes. While E. coli was grown under optimal pH and water activity (aw), for S. Typhimurium pH and aw were adapted to 5.5 and 0.990. In order to mimic a solid(like) environment, 5% (w/v) gelatin was added. All petri dishes were incubated under static conditions at temperatures in the range [8.0 degrees C-22.0 degrees C]. Cell density was determined via viable plate counting. This work demonstrates that the growth morphology (planktonic vs. colony) has a negligible effect on the growth dynamics as a function of temperature. The observation of almost equal growth rates for planktonic cultures and colonies is in contrast to literature where, mostly, a difference is observed, i.e., MUplanktonic cells>=MUimmersed colonies>=MUsurface colonies. This difference might be due to shaking of the liquid culture in these studies, which results in a nutrient and oxygen rich environment, in contrast to the diffusion-limited gel system. Experiments also indicate that lag phases for solid(like) systems are similar to those for the planktonic cultures, as can be found in literature for similar growth conditions. Considering the maximum cell density, no clear trend was deducted for either of the microorganisms. This study indicates that the growth parameters in the suboptimal temperature range do not depend on the growth morphology. For the considered experimental conditions, models previously developed for liquid environments can be used for solid(like) systems. PMID- 26057112 TI - Identification and mycotoxigenic capacity of fungi associated with pre- and postharvest fruit rots of pomegranates in Greece and Cyprus. AB - Pre- and postharvest fruit rots of fungal origin are an important burden for the pomegranate industry worldwide, affecting the produce both quantitatively and qualitatively. During 2013, local orchards were surveyed and 280 fungal isolates from Greece (GR) and Cyprus (CY) were collected from pomegranates exhibiting preharvest rot symptoms, and additional 153 isolates were collected postharvest from cold-stored fruit in GR. Molecular identification revealed that preharvest pomegranate fruit rots were caused predominately by species of the genera Aspergillus (Aspergillus niger and Aspergillus tubingensis) and Alternaria (Alternaria alternata, Alternaria tenuissima, and Alternaria arborescens). By contrast, postharvest fruit rots were caused mainly by Botrytis spp. and to a lesser extent by isolates of Pilidiella granati and Alternaria spp. Considering that a significant quota of the fungal species found in association with pomegranate fruit rots are known for their mycotoxigenic capacity in other crop systems, their mycotoxin potential was examined. Alternariol (AOH), alternariol monomethyl-ether (AME) and tentoxin (TEN) production was estimated among Alternaria isolates, whereas ochratoxin A (OTA) and fumonisin B2 (FB2) production was assessed within the black aspergilli identified. Overall in both countries, 89% of the Alternaria isolates produced AOH and AME in vitro, while TEN was produced only by 43.9%. In vivo production of AOH and AME was restricted to 54.2% and 31.6% of the GR and CY isolates, respectively, while none of the isolates produced TEN in vivo. Among black aspergilli 21.7% of the GR and 17.8% of the CY isolates produced OTA in vitro, while in vivo OTA was detected in 8.8% of the isolates from both countries. FB2 was present in vitro in 42.0% of the GR and 22.2% of the CY isolates, while in vivo the production was limited to 27.5% and 4.5% of the GR and the CY isolates, respectively. Our data imply that mycotoxigenic Alternaria and Aspergillus species not only constitute a significant subset of the fungal population associated with pomegranate fruit rots responsible for fruit deterioration, but also pose a potential health risk factor for consumers of pomegranate-based products. PMID- 26057113 TI - A novel approach to identify time-frequency oscillatory features in electrocortical signals. AB - BACKGROUND: Sensory, motor, and cognitive events could not only evoke phase locked event-related potentials in ongoing electrocortical signals, but also induce non-phase-locked changes of oscillatory activities. These oscillatory activities, whose functional significances differ greatly according to their temporal, spectral, and spatial characteristics, are commonly detected when single-trial signals are transformed into time-frequency distributions (TFDs). Parameters characterizing oscillatory activities are normally measured from multi channel TFDs within a time-frequency region-of-interest (TF-ROI), pre-defined using a hypothesis-driven or data-driven approach. However, both approaches could ignore the possibility that the pre-defined TF-ROI contains several spatially/functionally distinct oscillatory activities. NEW METHOD: We proposed a novel approach based on topographic segmentation analysis to optimally and automatically identify detailed time-frequency features. This approach, which could effectively exploit the spatial information of oscillatory activities, has been validated in both simulation and real electrocortical studies. RESULTS: Simulation study showed that the proposed approach could successfully identify noise-contaminated time-frequency features if their signal-to-noise ratio was relatively high. Real electrocortical study demonstrated that several time frequency features with distinct scalp distributions and evident neurophysiological functions were identified when the same analysis was applied on stimulus-elicited TFDs. COMPARISON WITH EXISTING METHODS: Unlike traditional approaches, the proposed approach could provide an optimal identification of detailed time-frequency features by making use of their distinct spatial distributions. CONCLUSIONS: Our findings illustrated the validity and usefulness of the presented approach in isolating detailed time-frequency features, thus having wide applications in cognitive neuroscience to provide a precise assessment of the functional significance of oscillatory activities. PMID- 26057114 TI - Amygdalar and hippocampal volume: A comparison between manual segmentation, Freesurfer and VBM. AB - Automated segmentation of the amygdala and the hippocampus is of interest for research looking at large datasets where manual segmentation of T1-weighted magnetic resonance tomography images is less feasible for morphometric analysis. Manual segmentation still remains the gold standard for subcortical structures like the hippocampus and the amygdala. A direct comparison of VBM8 and Freesurfer is rarely done, because VBM8 results are most often used for voxel-based analysis. We used the same region-of-interest (ROI) for Freesurfer and VBM8 to relate automated and manually derived volumes of the amygdala and the hippocampus. We processed a large manually segmented dataset of n=92 independent samples with an automated segmentation strategy (VBM8 vs. Freesurfer Version 5.0). For statistical analysis, we only calculated Pearsons's correlation coefficients, but used methods developed for comparison such as Lin's concordance coefficient. The correlation between automatic and manual segmentation was high for the hippocampus [0.58-0.76] and lower for the amygdala [0.45-0.59]. However, concordance coefficients point to higher concordance for the amygdala [0.46-0.62] instead of the hippocampus [0.06-0.12]. VBM8 and Freesurfer segmentation performed on a comparable level in comparison to manual segmentation. We conclude (1) that correlation alone does not capture systematic differences (e.g. of hippocampal volumes), (2) calculation of ROI volumes with VBM8 gives measurements comparable to Freesurfer V5.0 when using the same ROI and (3) systematic and proportional differences are caused mainly by different definitions of anatomic boundaries and only to a lesser part by different segmentation strategies. This work underscores the importance of using method comparison techniques and demonstrates that even with high correlation coefficients, there can be still large differences in absolute volume. PMID- 26057115 TI - Measuring the face-sensitive N170 with a gaming EEG system: A validation study. AB - BACKGROUND: The N170 is a "face-sensitive" event-related potential (ERP) that occurs at around 170ms over occipito-temporal brain regions. The N170's potential to provide insight into the neural processing of faces in certain populations (e.g., children and adults with cognitive impairments) is limited by its measurement in scientific laboratories that can appear threatening to some people. NEW METHOD: The advent of cheap, easy-to-use portable gaming EEG systems provides an opportunity to record EEG in new contexts and populations. This study tested the validity of the face-sensitive N170 ERP measured with an adapted commercial EEG system (the Emotiv EPOC) that is used at home by gamers. RESULTS: The N170 recorded through both the gaming EEG system and the research EEG system exhibited face-sensitivity, with larger mean amplitudes in response to the face stimuli than the non-face stimuli, and a delayed N170 peak in response to face inversion. COMPARISON WITH EXISTING METHOD: The EPOC system produced very similar N170 ERPs to a research-grade Neuroscan system, and was capable of recording face sensitivity in the N170, validating its use as research tool in this arena. CONCLUSIONS: This opens new possibilities for measuring the face-sensitive N170 ERP in people who cannot travel to a traditional ERP laboratory (e.g., elderly people in care), who cannot tolerate laboratory conditions (e.g., people with autism), or who need to be tested in situ for practical or experimental reasons (e.g., children in schools). PMID- 26057116 TI - Erratum to "the spectrum of ZEB2 mutations causing the Mowat-Wilson syndrome in Japanese populations". PMID- 26057117 TI - Unfinished Business in Bereavement. AB - Unfinished business (incomplete, unexpressed or unresolved relationship issues with the deceased) is frequently discussed as a risk factor for chronic and severe grief reactions. However, few empirical studies have examined this construct. The present study aimed to address this gap in the literature by examining the presence and severity of unfinished business as well as common themes of unfinished business reported in open-ended qualitative narratives among a sample of 224 bereaved individuals. In bivariate analyses, self-reported presence of unfinished business and the severity of distress due to unfinished business were both found to be associated with poorer bereavement outcomes. However, after controlling for potential confounds, distress related to unresolved issues with the deceased emerged as a more robust correlate of these outcomes. Qualitative responses were categorized, and the type of reported unfinished business was not significantly related to the degree of unfinished business distress or other bereavement outcomes. These findings provide preliminary justification for bereavement interventions that aim to ameliorate distress related to unresolved relational issues with the deceased. PMID- 26057118 TI - Development of oxidative coupling strategies for site-selective protein modification. AB - As the need to prepare ever more complex but well-defined materials has increased, a similar need for reliable synthetic strategies to access them has arisen. Accordingly, recent years have seen a steep increase in the development of reactions that can proceed under mild conditions, in aqueous environments, and with low concentrations of reactants. To enable the preparation of well-defined biomolecular materials with novel functional properties, our laboratory has a continuing interest in developing new bioconjugation reactions. A particular area of focus has been the development of oxidative reactions to perform rapid site- and chemoselective couplings of electron rich aromatic species with both unnatural and canonical amino acid residues. This Account details the evolution of oxidative coupling reactions in our laboratory, from initial concepts to highly efficient reactions, focusing on the practical aspects of performing and developing reactions of this type. We begin by discussing our rationale for choosing an oxidative coupling approach to bioconjugation, highlighting many of the benefits that such strategies provide. In addition, we discuss the general workflow we have adopted to discover protein modification reactions directly in aqueous media with biologically relevant substrates. We then review our early explorations of periodate-mediated oxidative couplings between primary anilines and p-phenylenediamine substrates, highlighting the most important lessons that were garnered from these studies. Key mechanistic insights allowed us to develop second-generation reactions between anilines and anisidine derivatives. In addition, we summarize the methods we have used for the introduction of aniline groups onto protein substrates for modification. The development of an efficient and chemoselective coupling of anisidine derivatives with tyrosine residues in the presence of ceric ammonium nitrate is next described. Here, our logic and workflow are used to highlight the challenges and opportunities associated with the optimization of site-selective chemistries that target native amino acids. We close by discussing the most recent reports from our laboratory that have capitalized on the unique reactivity of o-iminoquinone derivatives. We discuss the various oxidants and conditions that can be used to generate these reactive intermediates from appropriate precursors, as well as the product distributions that result. We also describe our work to determine the nature of iminoquinone reactivity with proteins and peptides bearing free N-terminal amino groups. Through this discussion, we hope to facilitate the use of oxidative approaches to protein bioconjugation, as well as inspire the discovery of new reactions for the site-selective modification of biomolecular targets. PMID- 26057119 TI - Epigenetic age signatures in the forensically relevant body fluid of semen: a preliminary study. AB - To date, DNA methylation has been regarded as the most promising age-predictive biomarker. In support of this, several researchers have reported age predictive models based on the use of blood or even across a broad spectrum of tissues. However, there have been no publications that report epigenetic age signatures from semen, one of the most forensically relevant body fluids. In genome-wide DNA methylation profiles of 36 body fluids including blood, saliva, and semen, the previous age predictive models showed considerable prediction accuracy in blood and saliva but not in semen. Therefore, we selected CpG sites, whose methylation levels are strongly correlated with age in 12 semen profiles obtained from individuals of different ages, and investigated DNA methylation changes at these CpGs in 68 additional semen samples obtained from individuals aged 20 to 73 years using methylation SNaPshot reaction. Among the selected age-related CpG candidates, outstanding age correlation was obtained at cg06304190 in the TTC7B gene. Interestingly, the region around the TTC7B gene has been reported to show age-related DNA methylation alteration in the sperm methylome of 2 samples collected from individuals at certain time intervals. The age-predictive linear regression model trained with 3 CpGs (cg06304190 in the TTC7B gene, cg06979108 in the NOX4 gene and cg12837463) showed a high correlation between the predicted age and the chronological age, with an average absolute difference of approximately 5 years. These selected epigenetic age signatures are expected to be useful for considerably accurate age estimation in the forensically relevant body fluid of semen. However, because the findings were limited by small sample size, it will be necessary to further evaluate the age correlation of the selected CpGs and to encourage further investigation. PMID- 26057120 TI - Conical Gradient Junctions of Dendritic Viologen Arrays on Electrodes. AB - The three-dimensional construction of arrays of functional molecules on an electrode surface, such as organic semiconductors and redox-active molecules, is a considerable challenge in the fabrication of sophisticated junctions for molecular devices. In particular, well-defined organic layers with precise molecular gradients are anticipated to function as novel metal/organic interfaces with specific electrical properties, such as a space charge layer at the metal/semiconductor interface. Here, we report a strategy for the construction of a three-dimensional molecular array with an electrical connection to a metal electrode by exploiting dendritic molecular architecture. Newly designed dendritic molecules consisting of viologens (1,1'-disubstituted-4,4'-bipyridilium salts) as the framework and mercapto groups as anchor units form unique self assembled monolayers (SAMs) on a gold surface reflecting the molecular design. The dendritic molecules exhibit a conical shape and closely pack to form cone arrays on the substrate, whereas, in solution, they expand into more flexible conformations. Differences in the introduction position of the anchor units in the dendritic structure result in apical- and basal-type cone arrays in which the spatial concentration of the viologen units can be precisely configured in the cones. The concentration in apical-type SAMs increases away from the substrate, whereas the opposite is true in basal-type SAMs. PMID- 26057121 TI - Adsorption in a Fixed-Bed Column and Stability of the Antibiotic Oxytetracycline Supported on Zn(II)-[2-Methylimidazolate] Frameworks in Aqueous Media. AB - A metal-organic framework, Zn-[2-methylimidazolate] frameworks (ZIF-8), was used as adsorbent material to remove different concentrations of oxytetracycline (OTC) antibiotic in a fixed-bed column. The OTC was studied at concentrations of 10, 25 and 40 mg L(-1). At 40 mg L(-1), the breakthrough point was reached after approximately 10 minutes, while at 10 and 25 mg L(-1) this point was reached in about 30 minutes. The highest removal rate of 60% for the 10 mg L(-1) concentration was reached after 200 minutes. The highest adsorption capacity (28.3 mg g(-1)) was attained for 25 mg L(-1) of OTC. After the adsorption process, a band shift was observed in the UV-Vis spectrum of the eluate. Additional studies were carried out to determine the cause of this band shift, involving a mass spectrometry (MS) analysis of the supernatant liquid during the process. This investigation revealed that the main route of adsorption consisted of the coordination of OTC with the metallic zinc centers of ZIF-8. The materials were characterized by thermal analysis (TA), scanning electron microscopy (SEM), powder X-ray diffraction (XRD), and infrared spectroscopy (IR) before and after adsorption, confirming the presence of OTC in the ZIF-8 and the latter's structural stability after the adsorption process. PMID- 26057122 TI - C1 Positive Surface over Positive Scattered Data Sites. AB - The aim of this paper is to develop a local positivity preserving scheme when the data amassed from different sources is positioned at sparse points. The proposed algorithm first triangulates the irregular data using Delauny triangulation method, therewith interpolates each boundary and radial curve of the triangle by C1 rational trigonometric cubic function. Half of the parameters in the description of the interpolant are constrained to keep up the positive shape of data while the remaining half are set free for users' requirement. Orthogonality of trigonometric function assures much smoother surface as compared to polynomial functions. The proposed scheme can be of great use in areas of surface reconstruction and deformation, signal processing, CAD/CAM design, solving differential equations, and image restoration. PMID- 26057123 TI - Multi-Analytical Approach Reveals Potential Microbial Indicators in Soil for Sugarcane Model Systems. AB - This study focused on the effects of organic and inorganic amendments and straw retention on the microbial biomass (MB) and taxonomic groups of bacteria in sugarcane-cultivated soils in a greenhouse mesocosm experiment monitored for gas emissions and chemical factors. The experiment consisted of combinations of synthetic nitrogen (N), vinasse (V; a liquid waste from ethanol production), and sugarcane-straw blankets. Increases in CO2-C and N2O-N emissions were identified shortly after the addition of both N and V to the soils, thus increasing MB nitrogen (MB-N) and decreasing MB carbon (MB-C) in the N+V-amended soils and altering soil chemical factors that were correlated with the MB. Across 57 soil metagenomic datasets, Actinobacteria (31.5%), Planctomycetes (12.3%), Deltaproteobacteria (12.3%), Alphaproteobacteria (12.0%) and Betaproteobacteria (11.1%) were the most dominant bacterial groups during the experiment. Differences in relative abundance of metagenomic sequences were mainly revealed for Acidobacteria, Actinobacteria, Gammaproteobacteria and Verrucomicrobia with regard to N+V fertilization and straw retention. Differential abundances in bacterial groups were confirmed using 16S rRNA gene-targeted phylum-specific primers for real-time PCR analysis in all soil samples, whose results were in accordance with sequence data, except for Gammaproteobacteria. Actinobacteria were more responsive to straw retention with Rubrobacterales, Bifidobacteriales and Actinomycetales related to the chemical factors of N+V-amended soils. Acidobacteria subgroup 7 and Opitutae, a verrucomicrobial class, were related to the chemical factors of soils without straw retention as a surface blanket. Taken together, the results showed that MB-C and MB-N responded to changes in soil chemical factors and CO2-C and N2O-N emissions, especially for N+V-amended soils. The results also indicated that several taxonomic groups of bacteria, such as Acidobacteria, Actinobacteria and Verrucomicrobia, and their subgroups acted as early-warning indicators of N+V amendments and straw retention in sugarcane cultivated soils, which can alter the soil chemical factors. PMID- 26057124 TI - Disruption of the C. elegans Intestinal Brush Border by the Fungal Lectin CCL2 Phenocopies Dietary Lectin Toxicity in Mammals. AB - Lectins are non-immunoglobulin carbohydrate-binding proteins without enzymatic activity towards the bound carbohydrates. Many lectins of e.g. plants or fungi have been suggested to act as toxins to defend the host against predators and parasites. We have previously shown that the Coprinopsis cinerea lectin 2 (CCL2), which binds to alpha1,3-fucosylated N-glycan cores, is toxic to Caenorhabditis elegans and results in developmental delay and premature death. In this study, we investigated the underlying toxicity phenotype at the cellular level by electron and confocal microscopy. We found that CCL2 directly binds to the intestinal apical surface and leads to a highly damaged brush border with loss of microvilli, actin filament depolymerization, and invaginations of the intestinal apical plasma membrane through gaps in the terminal web. We excluded several possible toxicity mechanisms such as internalization and pore-formation, suggesting that CCL2 acts directly on intestinal apical plasma membrane or glycocalyx proteins. A genetic screen for C. elegans mutants resistant to CCL2 generated over a dozen new alleles in bre 1, ger 1, and fut 1, three genes required for the synthesis of the sugar moiety recognized by CCL2. CCL2-induced intestinal brush border defects in C. elegans are similar to the damage observed previously in rats after feeding the dietary lectins wheat germ agglutinin or concanavalin A. The evolutionary conserved reaction of the brush border between mammals and nematodes might allow C. elegans to be exploited as model organism for the study of dietary lectin-induced intestinal pathology in mammals. PMID- 26057125 TI - Mutation Analysis of the RAD51C and RAD51D Genes in High-Risk Ovarian Cancer Patients and Families from the Czech Republic. AB - Recent studies have conferred that the RAD51C and RAD51D genes, which code for the essential proteins involved in homologous recombination, are ovarian cancer (OC) susceptibility genes that may explain genetic risks in high-risk patients. We performed a mutation analysis in 171 high-risk BRCA1 and BRCA2 negative OC patients, to evaluate the frequency of hereditary RAD51C and RAD51D variants in Czech population. The analysis involved direct sequencing, high resolution melting and multiple ligation-dependent probe analysis. We identified two (1.2%) and three (1.8%) inactivating germline mutations in both respective genes, two of which (c.379_380insG, p.P127Rfs*28 in RAD51C and c.879delG, p.C294Vfs*16 in RAD51D) were novel. Interestingly, an indicative family cancer history was not present in four carriers. Moreover, the ages at the OC diagnoses in identified mutation carriers were substantially lower than those reported in previous studies (four carriers were younger than 45 years). Further, we also described rare missense variants, two in RAD51C and one in RAD51D whose clinical significance needs to be verified. Truncating mutations and rare missense variants ascertained in OC patients were not detected in 1226 control samples. Although the cumulative frequency of RAD51C and RAD51D truncating mutations in our patients was lower than that of the BRCA1 and BRCA2 genes, it may explain OC susceptibility in approximately 3% of high-risk OC patients. Therefore, an RAD51C and RAD51D analysis should be implemented into the comprehensive multi-gene testing for high-risk OC patients, including early-onset OC patients without a family cancer history. PMID- 26057126 TI - Enhanced Heavy Metal Tolerance and Accumulation by Transgenic Sugar Beets Expressing Streptococcus thermophilus StGCS-GS in the Presence of Cd, Zn and Cu Alone or in Combination. AB - Phytoremediation is a promising means of ameliorating heavy metal pollution through the use of transgenic plants as artificial hyperaccumulators. A novel Streptococcus thermophilus gamma-glutamylcysteine synthetase-glutathione synthetase (StGCS-GS) that synthesizes glutathione (GSH) with limited feedback inhibition was overexpressed in sugar beet (Beta vulgaris L.), yielding three transgenic lines (s2, s4 and s5) with enhanced tolerance to different concentrations of cadmium, zinc and copper, as indicated by their increased biomass, root length and relative growth compared with wild-type plants. Transgenic sugar beets accumulated more Cd, Zn and Cu ions in shoots than wild type, as well as higher GSH and phytochelatin (PC) levels under different heavy metal stresses. This enhanced heavy metal tolerance and increased accumulation were likely due to the increased expression of StGCS-GS and consequent overproduction of both GSH and PC. Furthermore, when multiple heavy metal ions were present at the same time, transgenic sugar beets overexpressing StGCS-GS resisted two or three of the metal combinations (50 MUM Cd-Zn, Cd-Cu, Zn-Cu and Cd-Zn-Cu), with greater absorption in shoots. Additionally, there was no obvious competition between metals. Overall, the results demonstrate the explicit role of StGCS-GS in enhancing Cd, Zn and Cu tolerance and accumulation in transgenic sugar beet, which may represent a highly promising new tool for phytoremediation. PMID- 26057127 TI - Treatment of a large pulmonary artery pseudoaneurysm secondary to fungal infection using Amplatzer plugs: New embolisation devices for the management of haemoptysis. AB - Pulmonary artery pseudoaneurysms (PAP) may result in life threatening haemoptysis but are fortunately uncommon. Most are caused by trauma, iatrogenic injury or infection. We describe a case of large PAP secondary to fungal infection in an immunocompromised patient, which was successfully treated percutaneously using Amplatzer embolisation plugs. The technical considerations and advantages of these new devices are explained. PMID- 26057128 TI - Epidermal Growth Factor Removal or Tyrphostin AG1478 Treatment Reduces Goblet Cells & Mucus Secretion of Epithelial Cells from Asthmatic Children Using the Air Liquid Interface Model. AB - RATIONALE: Epithelial remodelling in asthma is characterised by goblet cell hyperplasia and mucus hypersecretion for which no therapies exist. Differentiated bronchial air-liquid interface cultures from asthmatic children display high goblet cell numbers. Epidermal growth factor and its receptor have been implicated in goblet cell hyperplasia. OBJECTIVES: We hypothesised that EGF removal or tyrphostin AG1478 treatment of differentiating air-liquid interface cultures from asthmatic children would result in a reduction of epithelial goblet cells and mucus secretion. METHODS: In Aim 1 primary bronchial epithelial cells from non-asthmatic (n = 5) and asthmatic (n = 5) children were differentiated under EGF-positive (10 ng/ml EGF) and EGF-negative culture conditions for 28 days. In Aim 2, cultures from a further group of asthmatic children (n = 5) were grown under tyrphostin AG1478, a tyrosine kinase inhibitor, conditions. All cultures were analysed for epithelial resistance, markers of differentiation using immunocytochemistry, ELISA for MUC5AC mucin secretion and qPCR for MUC5AC mRNA. RESULTS: In cultures from asthmatic children the goblet cell number was reduced in the EGF negative group (p = 0.01). Tyrphostin AG1478 treatment of cultures from asthmatic children had significant reductions in goblet cells at 0.2 MUg/ml (p = 0.03) and 2 MUg/ml (p = 0.003) as well as mucus secretion at 2 MUg/ml (p = 0.04). CONCLUSIONS: We have shown in this preliminary study that through EGF removal and tyrphostin AG1478 treatment the goblet cell number and mucus hypersecretion in differentiating air-liquid interface cultures from asthmatic children is significantly reduced. This further highlights the epidermal growth factor receptor as a potential therapeutic target to inhibit goblet cell hyperplasia and mucus hypersecretion in asthma. PMID- 26057129 TI - Risk Score to Predict 1-Year Mortality after Haemodialysis Initiation in Patients with Stage 5 Chronic Kidney Disease under Predialysis Nephrology Care. AB - BACKGROUND: Few risk scores are available for predicting mortality in chronic kidney disease (CKD) patients undergoing predialysis nephrology care. Here, we developed a risk score using predialysis nephrology practice data to predict 1 year mortality following the initiation of haemodialysis (HD) for CKD patients. METHODS: This was a multicenter cohort study involving CKD patients who started HD between April 2006 and March 2011 at 21 institutions with nephrology care services. Patients who had not received predialysis nephrology care at an estimated glomerular filtration rate (eGFR) of approximately 10 mL/min per 1.73 m2 were excluded. Twenty-nine candidate predictors were selected, and the final model for 1-year mortality was developed via multivariate logistic regression and was internally validated by a bootstrapping technique. RESULTS: A total of 688 patients were enrolled, and 62 (9.0%) patients died within one year of HD initiation. The following variables were retained in the final model: eGFR, serum albumin, calcium, Charlson Comorbidity Index excluding diabetes and renal disease (modified CCI), performance status (PS), and usage of erythropoiesis-stimulating agent (ESA). Their beta-coefficients were transformed into integer scores: three points were assigned to modified CCI>=3 and PS 3-4; two to calcium>8.5 mg/dL, modified CCI 1-2, and no use of ESA; and one to albumin<3.5 g/dL, eGFR>7 mL/min per 1.73 m2, and PS 1-2. Predicted 1-year mortality risk was 2.5% (score 0-4), 5.5% (score 5-6), 15.2% (score 7-8), and 28.9% (score 9-12). The area under the receiver operating characteristic curve was 0.83 (95% confidence interval, 0.79 0.89). CONCLUSIONS: We developed a simple 6-item risk score predicting 1-year mortality after the initiation of HD that might help nephrologists make a shared decision with patients and families regarding the initiation of HD. PMID- 26057130 TI - B cells influence sex specificity of arthritis via myeloid suppressors and chemokines in humanized mice. AB - Rheumatoid arthritis (RA) occurs two times more often in women than men. B cell depletion has been shown to be efficacious in treating RA. Our previous studies suggested that antigen presentation via B cells results in a sex-specific immune response in DR4 and DR4/DQ8 mice. Here we evaluated the mechanism of efficacy of the B cell depletion in treating arthritis-susceptible DQ8 mice. The data show that arthritic DQ8 mice treated with anti-CD20 antibody in therapeutic protocols show milder disease severity in females as compared to males, which is associated with decreased antibodies to citrullinated proteins and reduced levels of IL-23 and CCL5. Treatment led to significantly increased numbers of T regulatory and monocyte-derived suppressor F4/80+Gr1hi cells in females as compared to male DQ8 mice. Our observations suggest that therapeutic strategies that target B cells may benefit females while functions of DCs might be relatively more important for men than women. PMID- 26057132 TI - Nanoporous copper oxide ribbon assembly of free-standing nanoneedles as biosensors for glucose. AB - Inspired by a sequential hydrolysis-precipitation mechanism, morphology controllable hierarchical cupric oxide (CuO) nanostructures are facilely fabricated by a green water/ethanol solution-phase transformation of Cu(x)(OH)(2x 2)(SO4) precursors in the absence of any organic capping agents and without annealing treatment in air. Antlerite Cu3(OH)4(SO4) precursors formed in a low volume ratio between water and ethanol can transform into a two-dimensional (2D) hierarchical nanoporous CuO ribbon assembly of free-standing nanoneedle building blocks and hierarchical nanoneedle-aggregated CuO flowers. Brochantite Cu4(OH)6(SO4) precursors formed in a high volume ratio between water and ethanol can transform into hierarchical nanoplate-aggregated CuO nanoribbons and nanoflowers. Such 2D hierarchical nanoporous CuO ribbons serving as a promising electrode material for nonenzymatic glucose detection show high sensitivity, a low detection limit, fast amperometric response and good selectivity. Significantly, this green water-induced precursor-hydrolysis method might be used to control effectively the growth of other metal oxide micro-/nanostructures. PMID- 26057131 TI - Trypanosoma cruzi Intracellular Amastigotes Isolated by Nitrogen Decompression Are Capable of Endocytosis and Cargo Storage in Reservosomes. AB - Epimastigote forms of Trypanosoma cruzi (the etiologic agent of Chagas disease) internalize and store extracellular macromolecules in lysosome-related organelles (LROs) called reservosomes, which are positive for the cysteine protease cruzipain. Despite the importance of endocytosis for cell proliferation, macromolecule internalization remains poorly understood in the most clinically relevant proliferative form, the intracellular amastigotes found in mammalian hosts. The main obstacle was the lack of a simple method to isolate viable intracellular amastigotes from host cells. In this work we describe the fast and efficient isolation of viable intracellular amastigotes by nitrogen decompression (cavitation), which allowed the analysis of amastigote endocytosis, with direct visualization of internalized cargo inside the cells. The method routinely yielded 5x10(7) amastigotes--with typical shape and positive for the amastigote marker Ssp4--from 5x10(6) infected Vero cells (48 h post-infection). We could visualize the endocytosis of fluorescently-labeled transferrin and albumin by isolated intracellular amastigotes using immunofluorescence microscopy; however, only transferrin endocytosis was detected by flow cytometry (and was also analyzed by western blotting), suggesting that amastigotes internalized relatively low levels of albumin. Transferrin binding to the surface of amastigotes (at 4 degrees C) and its uptake (at 37 degrees C) were confirmed by binding dissociation assays using acetic acid. Importantly, both transferrin and albumin co-localized with cruzipain in amastigote LROs. Our data show that isolated T. cruzi intracellular amastigotes actively ingest macromolecules from the environment and store them in cruzipain-positive LROs functionally related to epimastigote reservosomes. PMID- 26057134 TI - Trends in differences between births and surviving infants reported for immunization program planning and external data sources in Eastern and Southern Africa 2000-2013. AB - To inform our WHO team's support for immunization programs in Member States in Eastern and Southern Africa, we compared annual trends from 2000 to 2013 in target populations reported by Member States through the WHO-UNICEF joint reporting form with United Nations (UN) population projections and modeled infant mortality estimates from the UN Inter-agency Group for Child Mortality Estimation. Our findings indicated a tendency of underestimating births and surviving infants used by Member States as denominators for administrative immunization coverage rates, resulting in or contributing to overestimation of coverage. The difference with UN estimates appeared to be more pronounced for surviving infants than births. Measures of central tendency for individual country differences indicated that those differences decreased over time. Comparing trends of births and surviving infants with external sources can help monitoring progress in efforts to provide accurate and reliable target population estimates and sampling frames. PMID- 26057133 TI - The self-assembling camptothecin-tocopherol prodrug: An effective approach for formulating camptothecin. AB - Camptothecin (CPT) is a potent antitumor agent and functions via inhibiting the activity of topoisomerase I during DNA replication. However, the clinical application of CPT has been greatly hindered by its extremely poor solubility, the instability of its active lactone ring in blood stream, as well as the non specific toxicity to normal tissues. In addition, most of the formulations developed so far are not applicable for formulating CPT. In this study, two novel CPT prodrugs were developed by conjugating CPT to alpha-tocopherol via a carbonate ester bond (CPT-VE) or disulfide linkage (CPT-S-S-VE). Both CPT prodrugs were able to self-assemble into nanofibers with the facilitation of a PEG5K-Fmoc-VE2-based nanomicellar carrier. Both prodrug nanoassemblies exhibited excellent stability. Fluorescence quenching, UV absorbance, and FT-IR studies demonstrated strong interactions between carrier and prodrugs, including hydrophobic interaction, pi-pi stacking, as well as hydrogen bonding. NMR studies suggested that prodrugs were successfully incorporated into PEG5K-Fmoc-VE2 during self-assembly process. In vitro, PEG5K-Fmoc-VE2/CPT-S-S-VE presented significantly higher level of cytotoxicity on tumor cells compared to PEG5K-Fmoc VE2/CPT-VE. Biodistribution study showed that CPT-S-S-VE formulated in PEG5K-Fmoc VE2 micelles was effectively converted to parent CPT following delivery to tumor tissues. Finally, PEG5K-Fmoc-VE2/CPT-S-S-VE nanofibers showed superior tumor growth inhibition in an aggressive murine breast cancer model (4T1.2). PMID- 26057135 TI - Two consecutive randomized controlled pertussis booster trials in children initially vaccinated in infancy with an acellular vaccine: The first with a five component Tdap vaccine to 5-year olds and the second with five- or monocomponent Tdap vaccines at age 14-15 years. AB - Prior study children from a DTaP efficacy trial were recruited at ages 5 and 15 years to randomized booster trials addressing immunogenicity and reactogenicity; 475 preschool children received mixed or separate injections of a reduced antigen vaccine (Tdap5, Sanofi Pasteur MSD) and an inactivated polio vaccine, and 230 adolescents received the same or another booster vaccine (Tdap1, SSI, Denmark). Pre-vaccination antibody concentrations against pertussis antigens were significantly higher at 15 than 5 years of age, probably due to natural boosting between the studies. Tdap5 induced comparable anti-PT concentrations at both ages, but antibody responses were significantly higher to filamentous haemagglutinin, pertactin and fimbriae 2/3 in adolescents. As expected, a higher amount of PT (Tdap1, 20MUg) induced a stronger anti-PT response than a lower amount (Tdap5, 2.5MUg). The frequency of adverse events was low and there were no serious adverse reactions. All local reactions had an early onset and a short duration. A large swelling or redness of more than half of the upper arm circumference was reported in 8/475 5-year-olds and in 6/230 15-year-olds. Children vaccinated with Tdap5 reported more moderate pain in adolescence than at preschool age, whereas itching was only reported in preschool children. Sweden introduced DTaP vaccines in 1996 after a 17-year hiatus with no general pertussis vaccination and pertussis was still endemic at the time of the studies. The frequency of adverse events was nevertheless low in both preschool children and adolescents and antibody responses were adequate. These studies document immunogenicity and reactogenicity in a trial cohort consecutively vaccinated with acellular pertussis vaccines from infancy to adolescence. The adolescent study was registered at ClinicalTrials.gov on 26 March 2009 (NCT00870350). PMID- 26057136 TI - Introduction of a National HPV vaccination program into Bhutan. AB - BACKGROUND: Cervical cancer is the most common cancer in Bhutanese women. To help prevent the disease, the Ministry of Health (MoH) developed a national human papillomavirus (HPV) vaccine program. METHODS: MoH considerations included disease incidence, the limited reach of cervical screening, poor outcomes associated with late diagnosis of the disease, and Bhutan's ability to conduct the program. For national introduction, it was decided to implement routine immunization for 12 year-old girls with the quadrivalent HPV6/11/16/18 (QHPV) vaccine and a one-time catch-up campaign for 13-18 year-old girls in the first year of the program (2010). Health workers would administer the vaccine in schools, with out-of-school girls to receive the vaccine at health facilities. From 2011, HPV vaccination would enter into the routine immunization schedule using health-center delivery. RESULTS: During the initial campaign in 2010, over 130,000 doses of QHPV were administered and QHPV 3-dose vaccination coverage was estimated to be around 99% among 12 year-olds and 89% among 13-18 year-olds. QHPV vaccine was well tolerated and no severe adverse events were reported. In the three following years, QHPV vaccine was administered routinely to 12 year-olds primarily through health centers instead of schools, during which time the population-level 3-dose coverage decreased to 67-69%, an estimate which was confirmed by individual-level survey data in 2012 (73%). In 2014, when HPV delivery was switched back to schools, 3-dose coverage rose again above 90%. DISCUSSION: The rapid implementation and high coverage of the national HPV vaccine program in Bhutan were largely attributable to the strength of political commitment, primary healthcare and support from the education system. School based delivery appeared clearly superior to health centers in achieving high coverage among 12 year-olds. CONCLUSIONS: Bhutan's lessons for other low/middle income countries include the superiority of school-based vaccination and the feasibility of a broad catch-up campaign in the first year. PMID- 26057137 TI - Persistence and avidity maturation of antibodies to A(H1N1)pdm09 in healthcare workers following repeated annual vaccinations. AB - Healthcare workers are at increased risk of influenza infection through direct patient care, particularly during the early stages of a pandemic. Although influenza vaccination is widely recommended in Healthcare workers, data on long term immunogenicity of vaccination in healthcare workers are lacking. The present study was designed to assess the persistence of the humoral response after pandemic vaccination as well as the impact of repeated annual vaccination in healthcare workers (n=24). Pandemic influenza vaccination resulted in a significant increase in haemagglutination inhibition (HI) antibody titers with 93 100% of subjects achieving protective titers 21-days post each of the three annual vaccinations. Seroprotective antibodies measured by HI, microneutralization and single radial hemolysis assays were present in 77-94% of healthcare workers 6 months post-vaccination. Repeated vaccination resulted in an increased duration of seroprotective antibodies with seroprotective titers increasing from 35-62% 12 months after 2009 pandemic vaccination to 50-75% 12 months after 2010 vaccination. Furthermore, repeated annual vaccination augmented the avidity of influenza-specific IgG antibodies. In conclusion, we have shown that A(H1N1)pdm09 vaccination induces high seroprotective titers that persist for at least 6 months. We demonstrate that repeated vaccination is beneficial to healthcare workers and results in further avidity maturation of vaccine-induced antibodies. PMID- 26057138 TI - The doses of 10 MUg should replace the doses of 5 MUg in newborn hepatitis B vaccination in China: A cost-effectiveness analysis. AB - OBJECTIVE: To identify whether Chinese current series of three 5 MUg doses for newborn hepatitis B vaccination should be replaced by the series of three 10 MUg doses. METHODS: A cost-effectiveness analysis was conducted from the societal perspective based on the constructed decision tree-Markov model. Model parameters were estimated from published literatures, government documents and our surveys. The expected cost and effectiveness were compared between the 3-dose 5 MUg series (the 5 MUg strategy) and the 3-dose 10 MUg series (the 10 MUg strategy), and the incremental cost-effectiveness ratio (ICER, additional cost per quality-adjusted life-years gained) was calculated. Threshold values of the efficacy difference of the two series for the ICER=0, 1 and 3 times per capita gross domestic product were analyzed under different scenarios to understand whether the 10 MUg strategy should replace the 5 MUg strategy according to the recommendation of World Health Organization. RESULTS: The 10 MUg strategy would be cost-saving compared with the 5 MUg strategy under the base-case scenario. Under keeping all the other parameters at the base-case values or further adjusting any one of them to the value most unfavorable to the 10 MUg strategy, as long as the efficacy of 3-dose 10 MUg series was slightly higher than that of 3-dose 5 MUg series, the 10 MUg strategy would be cost-effective, highly cost-effective, or even cost-saving. Even under the most pessimistic scenario, i.e. all the other parameters, but the discount rate, at the values most unfavorable to the 10 MUg strategy, the 10 MUg strategy would be cost-effective if the efficacy difference reached higher than 1.23 percentage point. CONCLUSION: For newborn hepatitis B vaccination in China, the 10 MUg strategy should be cost-effective, even more possibly highly cost effective or cost-saving compared with the current 5 MUg strategy. The doses of 10 MUg should be considered to replace the doses of 5 MUg in newborn hepatitis B vaccination in China. PMID- 26057139 TI - Highly Active Nickel Catalysts for C-H Functionalization Identified through Analysis of Off-Cycle Intermediates. AB - An inhibitory role of 1,5-cyclooctadiene (COD) in nickel-catalyzed C-H functionalization processes was identified and studied. The bound COD participates in C-H activation by capturing the hydride, leading to a stable off cycle pi-allyl complex that greatly diminished overall catalytic efficiency. Computational studies elucidated the origin of the effect and enabled identification of a 1,5-hexadiene-derived pre-catalyst that avoids the off-cycle intermediate and provides catalytic efficiencies that are superior to those of catalysts derived from Ni(COD)2. PMID- 26057140 TI - LASIC: Light Activated Site-Specific Conjugation of Native IgGs. AB - Numerous biological applications, from diagnostic assays to immunotherapies, rely on the use of antibody-conjugates. The efficacy of these conjugates can be significantly influenced by the site at which Immunoglobulin G (IgG) is modified. Current methods that provide control over the conjugation site, however, suffer from a number of shortfalls and often require large investments of time and cost. We have developed a novel adapter protein that, when activated by long wavelength UV light, can covalently and site-specifically label the Fc region of nearly any native, full-length IgG, including all human IgG subclasses. Labeling occurs with unprecedented efficiency and speed (>90% after 30 min), with no effect on IgG affinity. The adapter domain can be bacterially expressed and customized to contain a variety of moieties (e.g., biotin, azide, fluorophores), making reliable and efficient conjugation of antibodies widely accessible to researchers at large. PMID- 26057142 TI - Digoxin-Specific Antibody Fragment Dosing: A Case Series. AB - Digoxin-specific antibody fragments (DSFab) are used for the treatment of poisoning by cardiac glycosides, such as pharmaceutical digoxin. Dosing of this therapy for chronic and acute poisonings is based on the steady-state serum concentrations of digoxin, historical data in acute ingestions, or empiric regimens purportedly based on the average requirements. Empiric dosing for adult patients involves utilization of 3-6 vials for chronic poisoning and 10-20 vials for acute poisoning. The aim of this study was to describe the average dosing requirements based on the steady-state serum concentration of digoxin or historical data and compare this with the empiric dosing regimens. We performed a retrospective analysis of cases over an 11-year period presented to the Illinois Poison Center where administration of DSFab was recommended. We identified 140 cases of chronic digoxin poisoning and 26 cases or acute digoxin poisoning for analysis. The average dose of DSFab recommended in the cases of chronic digoxin poisoning was 3.05 vials (SD +/- 1.31). The average dose of DSFab recommended in the cases of acute digoxin poisoning was 6.33 vials (SD +/- 5.26). These values suggest that empiric dosing regimens may overestimate the need for DSFab in cases of both chronic and acute poisonings of pharmaceutical digoxin. PMID- 26057141 TI - Recurrent Drug-Induced Hepatitis in Tuberculosis-Comparison of Two Drug Regimens. AB - Drug-induced hepatitis (DIH) is one of the major complications among the treatment of patients with tuberculosis (TB); it might even be fatal. This study tries to address the recurrence of DIH with 2 anti-TB regimens. In the retrospective study from 2007 to 2010, 135 TB patients with DIH who were older than 16 years were entered to study. The patients with DIH were randomly treated with a regimen, including isoniazid, rifampin, and ethambutol, plus either ofloxacin or pyrazinamide. The patients were reviewed for occurrence of recurrent DIH. Cure and completed treatment were considered as acceptable treatment outcomes, whereas default of treatment, treatment failure, and death were considered to be unacceptable outcomes. Therefore, 135 subjects with DIH were reviewed, and 23 patients (17%) experienced recurrence of hepatitis (19 cases in the ofloxacin group and 4 cases in the pyrazinamide group). There is no significant difference in recurrence of hepatitis between these 2 groups (P = 0.803). An acceptable outcome was observed in 95 patients (70.4%), and an unacceptable outcome was seen in 14 cases (10.3%). There was no significant difference in outcomes between these 2 regimens (P = 0.400, odds ratio = 1.62, 95% confidence interval, 0.524-4.98). The results of our study suggest that ofloxacin-based anti-TB regimen does not decrease the risk of recurrent DIH. Therefore, adding ofloxacin in the case of DIH is not recommended. PMID- 26057148 TI - Amino acid substitution D222N from fatal influenza infection affects receptor binding properties of the influenza A(H1N1)pdm09 virus. AB - We have analyzed the receptor binding profile of A(H1N1)pdm09 recombinant influenza viruses containing the amino acid substitution D222N which has been associated with a fatal case of infection. This mutation was investigated in conjunction with a secondary mutation, S185N. Using human tracheobronchial epithelial cells (HTBE), we found that single mutation D222N affects the binding and replication of the virus during initial stages of infection, with limited but preferred tropism to non-ciliated cells expressing alpha2,6-SA. However, in conjunction with the S185N change, the (D222N, S185N) virus shows a remarkable increase in binding and replication efficiency, with tropism for both ciliated and non-ciliated cells. Glycan microarray analysis demonstrated correlation between the binding profile and the cell tropism observed in the HTBE cells. These findings suggest that viruses with D222N required compensatory mutations such as S185N to maintain viral fitness, and in combination, affect the pathogenicity of the virus and the clinical outcome. PMID- 26057149 TI - Epstein-Barr virus latent membrane protein 2A mediated activation of Sonic Hedgehog pathway induces HLA class Ia downregulation in gastric cancer cells. AB - One of the immune evasion strategies manifested by malignant cells is the downregulation of the Human Leukocyte Antigen (HLA). HLA Class I (HLA- A, -B, -C) present endogenous peptides including viral and tumor antigens to cytotoxic T lymphocytes for immune mediated destruction. We have found the Epstein Barr Virus (EBV) Latent Membrane Protein 2A (LMP2A) to be responsible for this HLA downregulation in gastric cancer cells. Our results further indicate the Sonic Hedgehog pathway; primarily Gli1 to bring about the LMP2A mediated decrease in HLA expression. PMID- 26057147 TI - COX-2 induces lytic reactivation of EBV through PGE2 by modulating the EP receptor signaling pathway. AB - Inflammation is one of the predisposing factors known to be associated with Epstein Barr Virus (EBV) mediated tumorigenesis. However it is not well understood whether inflammation in itself plays a role in regulating the life cycle of this infectious agent. COX-2, a key mediator of the inflammatory processes is frequently over-expressed in EBV positive cancer cells. In various tumors, PGE2 is the principle COX-2 regulated downstream product which exerts its effects on cellular processes through the EP1-4 receptors. In this study, we further elucidated how upregulated COX-2 levels can modulate the events in EBV life cycle related to latency-lytic reactivation. Our data suggest a role for upregulated COX-2 on modulation of EBV latency through its downstream effector PGE2. This study demonstrates a role for increased COX-2 levels in modulation of EBV latency. This is important for understanding the pathogenesis of EBV associated cancers in people with chronic inflammatory conditions. PMID- 26057150 TI - The Epstein-Barr virus BRRF2 gene product is involved in viral progeny production. AB - The Epstein-Barr virus (EBV) predominantly establishes a latent infection in B lymphocytes, and occasionally switches from the latent state to the lytic cycle. In this report, we identified and examined the role of a lytic gene, BRRF2. We first prepared an antibody against BRRF2 and identified the gene product as a viral lytic protein expressed in B95-8 cells with late kinetics. Immunofluorescence revealed that BRRF2 localized in the cytoplasm of cells during the lytic phase. We also found that BRRF2 protein was phosphorylated in lytic cells, but the only viral protein kinase, BGLF4, was not involved in the phosphorylation. Knockout EBV and a repaired strain were then prepared, and we found that BRRF2 disruption did not affect viral gene expression and DNA replication, but decreased virus production. These results demonstrated that BRRF2 is involved in production of infectious progeny, although it is not essential for lytic replication. PMID- 26057151 TI - Differential action of pateamine A on translation of genomic and subgenomic mRNAs from Sindbis virus. AB - Pateamine A (Pat A) is a natural marine product that interacts specifically with the translation initiation factor eIF4A leading to the disruption of the eIF4F complex. In the present study, we have examined the activity of Pat A on the translation of Sindbis virus (SINV) mRNAs. Translation of genomic mRNA is strongly suppressed by Pat A, as shown by the reduction of nsP1 or nsP2 synthesis. Notably, protein synthesis directed by subgenomic mRNA is resistant to Pat A inhibition when the compound is added at late times following infection; however, subgenomic mRNA is sensitive to Pat A in transfected cells or in cell free systems, indicating that this viral mRNA exhibits a dual mechanism of translation. A detailed kinetic analysis of Pat A inhibition in SINV-infected cells demonstrates that a switch occurs approximately 4h after infection, rendering subgenomic mRNA translation more resistant to Pat A inhibition. PMID- 26057152 TI - Comparative Study of Ether-Based Electrolytes for Application in Lithium-Sulfur Battery. AB - Herein, we report the characteristics of electrolytes using various ether solvents with molecular composition CH3O[CH2CH2O]nCH3, differing by chain length, and LiCF3SO3 as the lithium salt. The electrolytes, considered as suitable media for lithium-sulfur batteries, are characterized in terms of thermal properties (TGA, DSC), lithium ion conductivity, lithium interface stability, cyclic voltammetry, self-diffusion properties of the various components, and lithium transference number measured by NMR. Furthermore, the electrolytes are characterized in lithium cells using a sulfur-carbon composite cathode by galvanostatic charge-discharge tests. The results clearly evidence the influence of the solvent chain length on the species mobility within the electrolytes that directly affects the behavior in lithium sulfur cell. The results may effectively contribute to the progress of an efficient, high-energy lithium-sulfur battery. PMID- 26057154 TI - The merry month of-June! PMID- 26057153 TI - Review of hookah tobacco smoking among college students: policy implications and research recommendations. AB - BACKGROUND: About 30% of college students have smoked hookah tobacco. Although most students perceive this product to be innocuous and non-addictive, hookah tobacco increases the risk for disease and nicotine dependence. Currently, the US Food and Drug Administration (FDA) does not regulate the manufacture, distribution, or sale of hookah tobacco. OBJECTIVE: Empirical literature pertaining to hookah tobacco smoking is reviewed with a focus on the implications for regulatory policy. METHODS: PubMed, PsycINFO, and Scopus databases were searched to locate articles published in English. The literature search combined several key words including "hookahs", "college", "advertising", "health effects", and "health policy". RESULTS: Smoking hookah tobacco may play a role in the initiation of smoking among tobacco-naive college students and may portend persistent smoking among those who have smoked cigarettes. College students are typically nondaily, social smokers. They do not perceive that their heightened risk for tobacco diseases and nicotine dependence relates to their smoking behavior. However, few public health messages target college-age adults to counter media messages that endorse hookah tobacco smoking. CONCLUSION: Given that the FDA is not authorized to ban specific tobacco products, policy actions should focus on the development of effective risk communication strategies that target college-age adults and on limiting the accessibility of hookah tobacco products to these adults. Accordingly, a research agenda that would inform these policy actions is proposed. PMID- 26057155 TI - Another level of leadership: nurses on boards. PMID- 26057156 TI - Using gaps to design educational programs. AB - To adequately address the professional development needs of nurses, continuing nursing education programs must focus on identified gaps in knowledge, skill, and practice. However, attention must be paid not only to content areas but also to the types of gaps, as these can provide guidance about the best learning techniques and evaluation methods to use. PMID- 26057157 TI - Enhancing nurse-physician collaboration using pediatric simulation. PMID- 26057158 TI - Use of remote video auditing to validate Ebola level II personal protective equipment competency. AB - Faced with an Ebola-related mandate to regularly train frontline hospital staff with the donning and doffing of personal protective equipment, a community hospital's emergency department implemented remote video auditing (RVA) to assist in the training and remediation of its nursing staff. RVA was found to be useful in assessing performance and facilitating remediation. PMID- 26057159 TI - Defining moments in leadership character development. AB - Critical moments in life define one's character and clarify true values. Reflective leadership is espoused as an important practice for transformational leaders. Professional development educators can help surface and explore defining moments, strengthen leadership behavior with defining moments as a catalyst for change, and create safe spaces for leaders to expand their leadership capacity. PMID- 26057160 TI - Storytelling: a leadership and educational tool. AB - A powerful tool that leaders and educators can use to engage the listeners-both staff and learners-is storytelling. Stories demonstrate important points, valuable lessons, and the behaviors that are preferred by the leader. PMID- 26057161 TI - Professional development needs of nurse managers. AB - BACKGROUND: Nurse managers have a key role in creating positive work environments where safe, high-quality care is consistently provided. This requires a broad range of skills to be successful within today's complex health care environment; however, managers are frequently selected based on their clinical expertise and are offered little formal preparation for this leadership role. METHOD: We conducted three focus groups with 20 nurse managers to understand their professional development needs. Transcripts were analyzed using conventional content analysis. RESULTS: Three themes emerged: Managing Versus Leading, Gaining a Voice, and Garnering Support. Managers focused on daily tasks, such as matching staffing to patient needs. However, the data suggested gaps in foundational management skills, such as understanding organizational behavior, use of data to make decisions, and refined problem-solving skills. CONCLUSION: Professional development activities focusing on higher level leadership competencies could assist managers to be more successful in this challenging, but critical, role. PMID- 26057163 TI - Evaluation of work stress, turnover intention, work experience, and satisfaction with preceptors of new graduate nurses using a 10-minute preceptor model. AB - BACKGROUND: Preparing new graduate nurses (NGNs) to achieve standards of nursing competence is challenging; therefore, this study developed and evaluated the effects of a 10-minute preceptor (10MP) model for assisting NGNs in their professional development and increasing their retention in hospitals. METHOD: A repeated-measures design study, with an intervention and a two-group comparison, was conducted. A total of 107 NGNs participated in the study. At day 7, work stress and work experience were moderately high for the NGNs in both the 10MP and traditional preceptor model (TPM) groups. RESULTS: The preceptorship program showed significant differences between groups (p = 0.001) regarding work stress at months 2 and 3 and work experience at months 1, 2, and 3. The 10MP group reported lower turnover intention and higher satisfaction with the preceptors than the TPM group. CONCLUSION: The 10MP model is effective at improving training outcomes and facilitating the professional development of NGNs. PMID- 26057164 TI - Clinical competencies of emergency nurses toward violence against women: a delphi study. AB - BACKGROUND: An increasing number of survivors of intimate partner violence (IPV) have begun to seek help from hospital emergency departments. This study was conducted to develop a list of requisite clinical competencies for emergency nurses to provide adequate care for women experiencing IPV. METHOD: An e-mail survey using the Delphi technique was administered, involving three rounds of questionnaires from 30 participants. Participants were asked to score the importance of each item on a 4-point Likert scale. RESULTS: The study identified three dimensions, comprising 38 items of competencies related to care for individuals experiencing IPV, including Knowledge (10 items), Attitudes (11 items), and Practice (17 items). CONCLUSION: The emergency department is where direct medical treatment and care is provided for those who have experienced IPV. The study findings can provide a reference for the development of in-service educational programs in hospitals and can guide future policy making. PMID- 26057165 TI - Team-based education in a palliative approach for rural nurses and unlicensed care providers. AB - This article describes the preparation and delivery of an educational intervention designed to improve rural nurses and unlicensed care providers' confidence in a palliative approach to care. A palliative approach takes the principles of supportive palliative care and adapts them for application earlier in nonspecialized palliative contexts for individuals living with life-limiting chronic illness. Curriculum in a palliative approach was constructed for nurses and unlicensed care providers (care aides and home health workers) and was delivered through a workshop and monthly follow-up sessions offered through distance technology. Participants valued the joint interactive education and came away with greater appreciation for one another's contributions to care. Insights were gained into common challenges when attempting to apply a palliative approach in rural areas. Important lessons were learned about educating nurses and unlicensed care providers together, about the use of technology for this group, and about teaching the concept of a palliative approach. PMID- 26057166 TI - Contribution of the Major ND10 Proteins PML, hDaxx and Sp100 to the Regulation of Human Cytomegalovirus Latency and Lytic Replication in the Monocytic Cell Line THP-1. AB - Promyelocytic leukemia nuclear bodies, also termed nuclear domain 10 (ND10), have emerged as nuclear protein accumulations mediating an intrinsic cellular defense against viral infections via chromatin-based mechanisms, however, their contribution to the control of herpesviral latency is still controversial. In this study, we utilized the monocytic cell line THP-1 as an in vitro latency model for human cytomegalovirus infection (HCMV). Characterization of THP-1 cells by immunofluorescence andWestern blot analysis confirmed the expression of all major ND10 components. THP-1 cells with a stable, individual knockdown of PML, hDaxx or Sp100 were generated. Importantly, depletion of the major ND10 proteins did not prevent the terminal cellular differentiation of THP-1 monocytes. After construction of a recombinant, endotheliotropic human cytomegalovirus expressing IE2-EYFP, we investigated whether the depletion of ND10 proteins affects the onset of viral IE gene expression. While after infection of differentiated, THP-1 derived macrophages as well as during differentiation-induced reactivation from latency an increase in the number of IE-expressing cells was readily detectable in the absence of the major ND10 proteins, no effect was observed in non differentiated monocytes. We conclude that PML, hDaxx and Sp100 primarily act as cellular restriction factors during lytic HCMV replication and during the dynamic process of reactivation but do not serve as key determinants for the establishment of HCMV latency. PMID- 26057167 TI - Activation of DNA Damage Response Pathways during Lytic Replication of KSHV. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of several human malignancies. Human tumour viruses such as KSHV are known to interact with the DNA damage response (DDR), the molecular pathways that recognise and repair lesions in cellular DNA. Here it is demonstrated that lytic reactivation of KSHV leads to activation of the ATM and DNA-PK DDR kinases resulting in phosphorylation of multiple downstream substrates. Inhibition of ATM results in the reduction of overall levels of viral replication while inhibition of DNA-PK increases activation of ATM and leads to earlier viral release. There is no activation of the ATR-CHK1 pathway following lytic replication and CHK1 phosphorylation is inhibited at later times during the lytic cycle. Despite evidence of double-strand breaks and phosphorylation of H2AX, 53BP1 foci are not consistently observed in cells containing lytic virus although RPA32 and MRE11 localise to sites of viral DNA synthesis. Activation of the DDR following KSHV lytic reactivation does not result in a G1 cell cycle block and cells are able to proceed to S-phase during the lytic cycle. KSHV appears then to selectively activate DDR pathways, modulate cell cycle progression and recruit DDR proteins to sites of viral replication during the lytic cycle. PMID- 26057168 TI - The Roles of Syncytin-Like Proteins in Ruminant Placentation. AB - Recent developments in genome sequencing techniques have led to the identification of huge numbers of endogenous retroviruses (ERV) in various mammals. ERVs, which occupy 8%-13% of mammalian genomes, are believed to affect mammalian evolution and biological diversity. Although the functional significance of most ERVs remains to be elucidated, several ERVs are thought to have pivotal roles in host physiology. We and other groups recently identified ERV envelope proteins (e.g., Fematrin-1, Syncytin-Rum1, endogenous Jaagsiekte sheep retrovirus Env) that may determine the morphogenesis of the unique fused trophoblast cells, termed trinucleate cells and syncytial plaques, found in ruminant placentas; however, there are still a number of outstanding issues with regard to the role of ERVs that remain to be resolved. Here, we review what is known about how these ERVs have contributed to the development of ruminant specific trophoblast cells. PMID- 26057169 TI - Characterization of two-step deglycosylation via oxidation by glycoside oxidoreductase and defining their subfamily. AB - Herein, we report a two-step deglycosylation mediated by the oxidation of glycoside which is different from traditional glycoside hydrolase (GH) mechanism. Previously, we reported a novel flavin adenine dinucleotide (FAD)-dependent glycoside oxidoreductase (FAD-GO) having deglycosylation activity. Various features of the reaction of FAD-GO such as including mechanism and catalytic residue and substrate specificity were studied. In addition, classification of novel FAD-GO subfamily was attempted. Deglycosylation of glycoside was performed spontaneously via oxidation of 3-OH of glycone moiety by FAD-GO mediated oxidation reaction. His493 residue was identified as a catalytic residue for the oxidation step. Interestingly, this enzyme has broad glycone and aglycon specificities. For the classification of FAD-GO enzyme subfamily, putative FAD GOs were screened based on the FAD-GO from Rhizobium sp. GIN611 (gi 365822256) using BLAST search. The homologs of R. sp. GIN611 included the putative FAD-GOs from Stenotrophomonas strains, Sphingobacterium strains, Agrobacterium tumefaciens str. C58, and etc. All the cloned FAD-GOs from the three strains catalyzed the deglycosylation via enzymatic oxidation. Based on their substrate specificities, deglycosylation and oxidation activities to various ginsenosides, the FAD-GO subfamily members can be utilized as novel biocatalysts for the production of various aglycones. PMID- 26057171 TI - [Two new publications of the World Health Organization's Regional Office for Europe]. PMID- 26057172 TI - [Audit as a tool to assess and promote the quality of medical records and hospital appropriateness: metodology and preliminary results]. AB - In the actual economic context, with increasing health needs, efficiency and efficacy represents fundamental keyword to ensure a successful use of the resources and the best health outcomes. Together, the medical record, completely and correctly compiled, is an essential tool in the patient diagnostic and therapeutic path, but it's becoming more and more essential for the administrative reporting and legal claims. Nevertheless, even if the improvement of medical records quality and of hospital stay appropriateness represent priorities for every health organization, they could be difficult to realize. This study aims to present the methodology and the preliminary results of a training and improvement process: it was carried out from the Hospital Management of a third level Italian teaching hospital through audit cycles to actively involve their health professionals. A self assessment process of medical records quality and hospital stay appropriateness (inpatients admission and Day Hospital) was conducted through a retrospective evaluation of medical records. It started in 2012 and a random sample of 2295 medical records was examined: the quality assessment was performed using a 48-item evaluation grid modified from the Lombardy Region manual of the medical record, while the appropriateness of each days was assessed using the Italian version of Appropriateness Evaluation Protocol (AEP) - 2002ed. The overall assessment was presented through departmental audit: the audit were designed according to the indication given by the Italian and English Ministry of Health to share the methodology and the results with all the involved professionals (doctors and nurses) and to implement improvement strategies that are synthesized in this paper. Results from quality and appropriateness assessment show several deficiencies, due to 40% of minimum level of acceptability not completely satisfied and to 30% of inappropriateness between days of hospitalization. Furthermore, there are great discrepancies among departments and among Care Units: the higher problems are centered in DHs, which are generally lacking on both profiles. Finally, our audit model, that could be considered a good project according the NHS (score of 20/25), has allowed to involve in 34 editions 480 professionals of different care Unit which are satisfied and stimulated to keep going in continuous improvement of the quality and appropriateness with these arrangements. The tools used in the project have proven their value for measuring the minimum quality of healthcare documentation and organizational appropriateness: furthermore, the audit has been shown as an effective methodology for their introduction because it ensures their acceptability among the staff and creates the basis for a rapid and quantifiable improvement that, through the promotion of accountability and transparency, could support the risk management activities and ensure greater efficiency in hospitalization. PMID- 26057173 TI - [Morbidity for congenital malformations. From 2005 to 2009 in Vercelli and neighboring countries]. AB - Special attention is now placed in the diagnosis of congenital malformations, MC, and several recent studies attest to the role of indicators of injury is inherent is extrinsic to the environmental component. In the Vercelli area recognize different sources of environmental pressure can result in damage potential direct and indirect effects on community residents; about, identify plants with high environmental impact on health including a MSW incinerator off in March 2014. The study refers to the morbidity derived from SDO from 2005 to 2009 than the specific rates ASL VC. The main concern the excess female for the area south and central ages 50-69 years old for the rest of the areas considered. Worthy of investigation is the excess of males in the group 5-19 years. Events have been of important insights, but in light of its limitations is certainly worth a discussion in terms expansion is as period of observation that as more data sources for the precise and reliable diagnosis of CD. PMID- 26057174 TI - [Adapting a private health care facility to the new Peruvian Public Health Sistem. Quality rating in a Middle Income Economy country]. AB - The aim of the study is the Assessment of Quality Sevices provided by a no-profit Medical Center in Peruvian Sierra, through an evidence-based decision-making process to identify infrastructure and capacity building interventions, to achieve accreditation and economic sustainability and increase competitiveness in the renewed Peruvian National Health System. The quali-quantitative collection of data shows how is fundamental an Healthcare Management focused on the responsiveness of services to the real needs and the local culture to reach the goals. PMID- 26057175 TI - [Study of diagnostic features, health care quality and surgical treatment among women living in the LHAs of Novara and Verbano Cusio Ossola hospitalized for breast cancer]. AB - This study included 304 women, 128 Screen Detected (SD) e 176 non Screen Detected (NSD), aged 50-69, living in the ex-local health authorities (LHAs) 13 and 14, hospitalized for breast cancer or related chemotherapy or radiation treatments in 2003-2004. Some variables were detected from medical records in order to evaluate the local screening program. The results confirm that a prevention activity allows a rapid identification of cancer and less invasive surgery procedures. PMID- 26057176 TI - [Chronicity practices - The integrated management for chronic conditions in the health district of Campi Salentina (Lecce ASL)]. AB - A program concerning the care management of chronic conditions has been carried out in the primary care setting, starting from previous projects based on delivering integrated care and on promoting patient empowerment. The chronicity practice, which is based on common facilities and time of work, is aimed to improve communication about individual care plan of patients, to improve adherence to the treatment and to the follow-up. The expected outcome are: the increasing adherence to healthy lifestyle and doctor's recommendations, improved clinical outcome, satisfaction of patients and health professionals. PMID- 26057177 TI - [Wastes in nursing practice: findings from a phenomenological study]. AB - BACKGROUND: the International economic crisis has challenged the sustainability of health care systems imposing reforms aimed to reduce costs and increase production efficiency. At the international level, waste reduction is considered to be the basis to ensure the heath care systems sustainability. To reduce waste and increase production efficiency is required to document the types, the extent and the level were they occur. The purpose of this paper is to document the experience of waste in nurses clinical practice. METHODS: a descriptive phenomenological study was conducted. Clinical nursing operating in different care settings of the National Heath Care Service were recruited adopting a maximum variation purposeful sampling. Data saturation was considered as the finish line for the participants recruitment. RESULTS: thirty nurses participated in the study. They were mainly female (n = 28, 93.3%) and with an average age of 41.4 +/- 7.3 years. For nurses waste means inadequate allocation of resources. Wastes are caused by individual and organizational choices determining improper, inefficient or ineffective use of material, human or virtual heath care resources and time as well as the incorrect application of clinical pathways, the inadequate use of electricity, food, and the improper disposal of the hospital waste. Wastes generates negative emotional impact on nurses such as frustration, anger and sense of impotence. Avoidable wastes were identified. They were mainly related to the expiration date, the use and the type of drugs and materials. Also unavoidable wastes were identified and they were related to established practices to ensure patients safety and changes in treatment choices due to the clinical instability of the patients. CONCLUSION: within the limits of the qualitative approach, in this study have been identified different types of waste present in clinical practice as perceived by nurses. National Health Service policies could focus on this evidences to improve production efficiency. To involve health care professionals in the choices and their awareness to the conscious and responsible use of public resources available, would avoid linear cuts and enhancing such operators. PMID- 26057178 TI - [Relationship between pharmaceutical industry and public health in vaccination]. AB - Vaccines play the main role in primary prevention in Public Health as they allow the control of many infectious diseases progression, reducing complications, morbidity and mortality. Pharmaceutical industry has spread worldwide the production and distribution of vaccines; moreover, research and new technological approaches inside industry make possible new formulations and preparations with an increasing safety. In spite of these positive aspects, lack of confidence in the utility of vaccination as well as in the real role of the pharmaceutical industry has grown in importance in recent decades. Aim of the study was to analyze these issues, with regards to cost and timing of vaccine production, and complex vaccine planning, related to efficacy, safety and tolerability assessment. Relationship between pharmaceutical industry and Public Health was finally considered; in particular, the role of Public Health as mediator between the pharmaceutical industry and the general population. PMID- 26057179 TI - Electrochemical capacitance of iron oxide nanotube (Fe-NT): effect of annealing atmospheres. AB - The effect of annealing atmosphere on the supercapacitance behavior of iron oxide nanotube (Fe-NT) electrodes has been explored and reported here. Iron oxide nanotubes were synthesized on a pure iron substrate through an electrochemical anodization process in an ethylene glycol solution containing 3% H2O and 0.5 wt.% NH4F. Subsequently, the annealing of the nanotubes was carried out at 500 degrees C for 2 h in various gas atmospheres such as air, oxygen (O2), nitrogen (N2), and argon (Ar). The morphology and crystal phases evolved after the annealing processes were examined via field emission scanning electron microscopy, x-ray diffraction, Raman spectroscopy, and x-ray photoelectron spectroscopy. The electrochemical capacitance properties of the annealed Fe-NT electrodes were evaluated by conducting cyclic voltammetry (CV), galvanostatic charge-discharge, and electrochemical impedance spectroscopy tests in the Li2SO4 electrolyte. Based on these experiments, it was found that the capacitance of the Fe-NT electrodes annealed in air and O2 atmospheres shows mixed behavior comprising both the electric double layer and pseudocapacitance. However, annealing in N2 and Ar environments resulted in well-defined redox peaks in the CV profiles of the Fe-NT electrodes, which are therefore attributed to the relatively higher pseudonature of the capacitance in these electrodes. Based on the galvanostatic charge-discharge studies, the specific capacitance achieved in the Fe-NT electrode after annealing in Ar was about 300 mF cm(-2), which was about twice the value obtained for N2-annealed Fe-NTs and three times higher than those annealed in air and O2. The experiments also demonstrated excellent cycle stability for the Fe-NT electrodes with 83%-85% capacitance retention, even after many charge-discharge cycles, irrespective of the gas atmospheres used during annealing. The increase in the specific capacitance was discussed in terms of increased oxygen vacancies as a result of the enhanced transformation of the hematite (alpha-Fe2O3) phase to the magnetite (Fe3O4) phase for the electrodes annealed in the N2 and Ar atmospheres. PMID- 26057180 TI - Age- and Sex-Dependent Distribution of OGTT-Related Variables in a Population of Cystic Fibrosis Patients. AB - CONTEXT: Cystic fibrosis (CF) causes an exceptionally high prevalence of diabetes that increases with age, especially in females. The glucose tolerance defect is progressive, but a cystic fibrosis transmembrane conductance regulator-dependent insulin secretory defect cannot be excluded. The age and sex dependence of the secretory defect is unclear. OBJECTIVE: The objective of the study was to analyze the age and sex dependency of insulin secretory and sensitivity parameters in CF. DESIGN: This was a cross-sectional analysis in an observational ongoing cohort (mean follow-up duration 7.5 y). SETTING: The study was conducted at the CF Center of Milan. PATIENTS: The study included 187 patients aged 8-30 years. INTERVENTION: Interventions included 3-hour oral glucose tolerance tests (n = 478) with 30-minute insulin and c-peptide sampling. MAIN OUTCOME MEASURES: Model derived insulin secretory and sensitivity parameters were measured. RESULTS: Age was associated with a progressive decrement in insulinemia (at 30 min) and a subsequent increment in glycemia (at 60-90 min), returning at or below baseline (at 180 min). These changes are explained by a progressive reduction in beta-cell sensitivity to glucose and a progressive increment in insulin clearance. Fasting and postprandial insulin sensitivity do not seem to be involved. Compared with males, females display higher glucose, insulin, and c-peptide responses with greater insulin secretion, beta-cell sensitivity to glucose, insulin clearance, and equal insulin sensitivity. CONCLUSIONS: A defect in beta-cell sensitivity to glucose progressively develops with age, but it is not sex specific and does not explain the worse glucose tolerance reported in females. In contrast, insulin clearance increases with age, especially in females, contributing to the deterioration in glucose tolerance. The effects of age and sex should be considered when evaluating oral glucose tolerance test results in CF patients. PMID- 26057181 TI - Tumor Recurrence or Regrowth in Adults With Nonfunctioning Pituitary Adenomas Using GH Replacement Therapy. AB - CONTEXT: GH replacement therapy (GH-RT) is a widely accepted treatment in GH deficient adults with nonfunctioning pituitary adenoma (NFPAs). However, some concerns have been raised about the safety of GH-RT because of its potentially stimulating effect on tumor growth. OBJECTIVE: The aim of this study was to evaluate tumor progression in NFPA patients using GH-RT. DESIGN, SETTING, AND PATIENTS: From the Dutch National Registry of Growth Hormone Treatment in Adults, a nationwide surveillance study in severely GH-deficient adults (1998-2009), all NFPA patients with >= 30 days of GH-RT were selected (n = 783). Data were retrospectively collected from the start of GH-RT in adulthood (baseline). MAIN OUTCOME MEASURE: Tumor progression, including tumor recurrence after complete remission at baseline and regrowth of residual tumor. RESULTS: Tumor progression developed in 12.1% of the patients after a median (range) time of 2.2 (0.1-14.9) years. Prior radiotherapy decreased tumor progression risk compared to no radiotherapy (hazard ratio = 0.16; 95% confidence interval, 0.09-0.26). Analysis in 577 patients with available baseline imaging data showed that residual tumor at baseline increased tumor progression risk compared to no residual tumor (hazard ratio = 4.5; 95% confidence interval, 2.4-8.2). CONCLUSIONS: The findings in this large study were in line with those reported in literature and provide further evidence that GH-RT does not appear to increase tumor progression risk in NFPA patients. Although only long-term randomized controlled trials will be able to draw firm conclusions, our data support the current view that GH-RT is safe in NFPA patients. PMID- 26057183 TI - Adsorption and Thermal Processing of Glycolaldehyde, Methyl Formate, and Acetic Acid on Graphite at 20 K. AB - We present the first detailed comparative study of the adsorption and thermal processing of the three astrophysically important C2O2H4 isomers glycolaldehyde, methyl formate, and acetic acid adsorbed on a graphitic grain analogue at 20 K. The ability of the individual molecule to form intermolecular hydrogen bonds is extremely important, dictating the growth modes of the ice on the surface and the measured desorption energies. Methyl formate forms only weak intermolecular bonds and hence wets the graphite surface, forming monolayer, bilayer, and multilayer ices, with the multilayer having a desorption energy of 35 kJ mol(-1). In contrast, glycolaldehyde and acetic acid dewet the surface, forming clusters even at the very lowest coverages. The strength of the intermolecular hydrogen bonding for glycolaldehyde and acetic acid is reflected in their desorption energies (46.8 and 55 kJ mol(-1), respectively), which are comparable to those measured for other hydrogen-bonded species such as water. Infrared spectra show that all three isomers undergo structural changes as a result of thermal processing. In the case of acetic acid and glycolaldehyde, this can be assigned to the formation of well-ordered, crystalline, structures where the molecules form chains of hydrogen-bonded moieties. The data reported here are of relevance to astrochemical studies of hot cores and star-forming regions and can be used to model desorption from interstellar ices during the warm up phase with particular importance for complex organic molecules. PMID- 26057184 TI - Infection with multidrug-resistant gram-negative bacteria in a pediatric oncology intensive care unit: risk factors and outcomes. AB - OBJECTIVE: This study aimed at evaluating the predictors and outcomes associated with multidrug-resistant gram-negative bacterial (MDR-GNB) infections in an oncology pediatric intensive care unit (PICU). METHODS: Data were collected relating to all episodes of GNB infection that occurred in a PICU between January of 2009 and December of 2012. GNB infections were divided into two groups for comparison: (1) infections attributed to MDR-GNB and (2) infections attributed to non-MDR-GNB. Variables of interest included age, gender, presence of solid tumor or hematologic disease, cancer status, central venous catheter use, previous Pseudomonas aeruginosa infection, healthcare-associated infection, neutropenia in the preceding 7 days, duration of neutropenia, length of hospital stay before ICU admission, length of ICU stay, and the use of any of the following in the previous 30 days: antimicrobial agents, corticosteroids, chemotherapy, or radiation therapy. Other variables included initial appropriate antimicrobial treatment, definitive inadequate antimicrobial treatment, duration of appropriate antibiotic use, time to initiate adequate antibiotic therapy, and the 7- and 30 day mortality. RESULTS: Multivariate logistic regression analyses showed significant relationships between MDR-GNB and hematologic diseases (odds ratio [OR] 5.262; 95% confidence interval [95% CI] 1.282-21.594; p=0.021) and healthcare-associated infection (OR 18.360; 95% CI 1.778-189.560; p=0.015). There were significant differences between MDR-GNB and non-MDR-GNB patients for the following variables: inadequate initial empirical antibiotic therapy, time to initiate adequate antibiotic treatment, and inappropriate antibiotic therapy. CONCLUSIONS: Hematologic malignancy and healthcare-associated infection were significantly associated with MDR-GNB infection in this sample of pediatric oncology patients. PMID- 26057185 TI - Predictive capacity of anthropometric indicators for dyslipidemia screening in children and adolescents. AB - OBJECTIVE: To analyze the predictive capacity of anthropometric indicators and their cut-off values for dyslipidemia screening in children and adolescents. METHODS: This was a cross-sectional study involving 1139 children and adolescents, of both sexes, aged 6-18 years. Body weight, height, waist circumference, subscapular, and triceps skinfold thickness were measured. The body mass index and waist-to-height ratio were calculated. Children and adolescents exhibiting at least one of the following lipid alterations were defined as having dyslipidemia: elevated total cholesterol, low high-density lipoprotein, elevated low-density lipoprotein, and high triglyceride concentration. A receiver operating characteristic curve was constructed and the area under the curve, sensitivity, and specificity was calculated for the parameters analyzed. RESULTS: The prevalence of dyslipidemia was 62.1%. The waist to-height ratio, waist circumference, subscapular, body mass index, and triceps skinfold thickness, in this order, presented the largest number of significant accuracies, ranging from 0.59 to 0.78. The associations of the anthropometric indicators with dyslipidemia were stronger among adolescents than among children. Significant differences between accuracies of the anthropometric indicators were only observed by the end of adolescence; the accuracy of waist-to-height ratio was higher than that of subscapular (p=0.048) for females, and the accuracy of waist circumference was higher than that of subscapular (p=0.029) and body mass index (p=0.012) for males. In general, the cut-off values of the anthropometric predictors of dyslipidemia increased with age, except for waist-to-height ratio. Sensitivity and specificity varied substantially between anthropometric indicators, ranging from 75.6 to 53.5 and from 75.0 to 50.0, respectively. CONCLUSIONS: The anthropometric indicators studied had little utility as screening tools for dyslipidemia, especially in children. PMID- 26057186 TI - PHITS simulations of absorbed dose out-of-field and neutron energy spectra for ELEKTA SL25 medical linear accelerator. AB - Monte Carlo (MC) based calculation methods for modeling photon and particle transport, have several potential applications in radiotherapy. An essential requirement for successful radiation therapy is that the discrepancies between dose distributions calculated at the treatment planning stage and those delivered to the patient are minimized. It is also essential to minimize the dose to radiosensitive and critical organs. With MC technique, the dose distributions from both the primary and scattered photons can be calculated. The out-of-field radiation doses are of particular concern when high energy photons are used, since then neutrons are produced both in the accelerator head and inside the patients. Using MC technique, the created photons and particles can be followed and the transport and energy deposition in all the tissues of the patient can be estimated. This is of great importance during pediatric treatments when minimizing the risk for normal healthy tissue, e.g. secondary cancer. The purpose of this work was to evaluate 3D general purpose PHITS MC code efficiency as an alternative approach for photon beam specification. In this study, we developed a model of an ELEKTA SL25 accelerator and used the transport code PHITS for calculating the total absorbed dose and the neutron energy spectra infield and outside the treatment field. This model was validated against measurements performed with bubble detector spectrometers and Boner sphere for 18 MV linacs, including both photons and neutrons. The average absolute difference between the calculated and measured absorbed dose for the out-of-field region was around 11%. Taking into account a simplification for simulated geometry, which does not include any potential scattering materials around, the obtained result is very satisfactorily. A good agreement between the simulated and measured neutron energy spectra was observed while comparing to data found in the literature. PMID- 26057187 TI - Fusarium Wilt of Banana. AB - Banana (Musa spp.) is one of the world's most important fruits. In 2011, 145 million metric tons, worth an estimated $44 billion, were produced in over 130 countries. Fusarium wilt (also known as Panama disease) is one of the most destructive diseases of this crop. It devastated the 'Gros Michel'-based export trades before the mid-1900s, and threatens the Cavendish cultivars that were used to replace it; in total, the latter cultivars are now responsible for approximately 45% of all production. An overview of the disease and its causal agent, Fusarium oxysporum f. sp. cubense, is presented below. Despite a substantial positive literature on biological, chemical, or cultural measures, management is largely restricted to excluding F. oxysporum f. sp. cubense from noninfested areas and using resistant cultivars where the pathogen has established. Resistance to Fusarium wilt is poor in several breeding targets, including important dessert and cooking cultivars. Better resistance to this and other diseases is needed. The history and impact of Fusarium wilt is summarized with an emphasis on tropical race 4 (TR4), a 'Cavendish'-killing variant of the pathogen that has spread dramatically in the Eastern Hemisphere. PMID- 26057188 TI - Tunable broadband plasmonic field enhancement on a graphene surface using a normal-incidence plane wave at mid-infrared frequencies. AB - We investigate optical field enhancement for a wide mid-infrared range, originating from the excitation of graphene plasmons, by introducing a graded dielectric grating of varying period underneath a graphene monolayer. Excitation of the plasmonic mode can be achieved by illuminating a normal-incidence plane wave on the gratings due to guided-mode resonance. The gratings of varying period enable the excitation of the plasmonic mode with a very high field enhancement factor (to the order of magnitude of 1000) within a wide spectral band, which leads to the frequency-dependent spatially separated localization of the infrared spectrum modes. We also demonstrate that the excitation position of the plasmonic mode can be freely tuned by varying the thickness of the interlayer as well as the chemical potential of the graphene monolayer. This structure enables the design of two-dimensional plasmonic photonic circuits and metamaterials targeted towards numerous potential applications including optoelectronic detectors, light harvest devices, on-chip optical interconnects, biosensors, and light-matter interactions. PMID- 26057189 TI - Spatial patterns in the tropical forest reveal connections between negative feedback, aggregation and abundance. AB - The spatial arrangement of trees in a tropical forest reflects the interplay between aggregating processes, like dispersal limitation, and negative feedback that induces effective repulsion among individuals. Monitoring the variance-mean ratio for conspecific individuals along length-scales, we show that the effect of negative feedback is dominant at short scales, while aggregation characterizes the large-scale patterns. A comparison of different species indicates, surprisingly, that both aggregation and negative feedback scales are related to the overall abundance of the species. This suggests a bottom-up control mechanism, in which the negative feedback dictates the dispersal kernel and the overall abundance. PMID- 26057190 TI - Player Load, Acceleration, and Deceleration During Forty-Five Competitive Matches of Elite Soccer. AB - The use of time-motion analysis has advanced our understanding of position specific work rate profiles and the physical requirements of soccer players. Still, many of the typical soccer activities can be neglected, as these systems only examine activities measured by distance and speed variables. This study used triaxial accelerometer and time-motion analysis to obtain new knowledge about elite soccer players' match load. Furthermore, we determined acceleration/deceleration profiles of elite soccer players and their contribution to the players' match load. The data set includes every domestic home game (n = 45) covering 3 full seasons (2009, 2010, and 2011) for the participating team (Rosenborg FC), and includes 8 central defenders (n = 68), 9 fullbacks (n = 83), 9 central midfielders (n = 70), 7 wide midfielders (n = 39), and 5 attackers (A, n = 50). A novel finding was that accelerations contributed to 7-10% of the total player load for all player positions, whereas decelerations contributed to 5-7%. Furthermore, the results indicate that other activities besides the high intensity movements contribute significantly to the players' total match workload. Therefore, motion analysis alone may underestimate player load because many high-intensity actions are without a change in location at the pitch or they are classified as low-speed activity according to current standards. This new knowledge may help coaches to better understand the different ways players achieve match load and could be used in developing individualized programs that better meet the "positional physical demands" in elite soccer. PMID- 26057191 TI - Erythroivorensin: A novel anti-inflammatory diterpene from the root-bark of Erythrophleum ivorense (A Chev.). AB - The stem- and root-bark of Erythrophleum ivorense (A Chev., family, Fabaceae) are routinely employed in the West African traditional medicine to treat inflammation and a variety of other disease conditions. Although the chemistry and pharmacology of cassaine-type diterpene alkaloids isolated from the stem-bark of the plant are fairly established, the root-bark has not yet been investigated. In the present study, the crude aqueous-alcohol extract of the root-bark was demonstrated to display a time- and dose (30-300 mg/kg p.o.)-dependent anti inflammatory effect in chicks. Comprehensive chromatographic analysis coupled with spectroscopic and X-ray study further allowed the assignment of one of the major anti-inflammatory constituents as a novel cassaine-type diterpene, erythroivorensin. The other major constituents were known anti-inflammatory compounds: a triterpene, betulinic acid and a flavonoid, eriodictyol. The dose (10-100mg/kg p.o.)-dependent anti-inflammatory effects of the three compounds were either comparable or more significant than the positive control, diclofenac. PMID- 26057192 TI - The role of autoreactive T cell in the pathogenesis of rheumatoid arthritis and implications for T cell targeted vaccine therapy. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease characterised by chronic inflammation of joint synovial tissue and subsequent destruction of associated bone, cartilage and soft tissues. RA is commonly treated with non steroidal anti-inflammatory drugs (NSAIDs), traditional disease-modifying antirheumatic drugs (DMARDs), glucocorticoids and biologic inhibitors of TNF, IL 1, IL-6, T cells and B cells. The use of these drugs especially biological agents has greatly improved the treatment of RA. Although the pathogenesis of RA remains unclear, T-cell mediated immune response is considered as a critical contributor in RA initiation and progression. It has been hypothesized that arthritogenic T cells (autoreactive T cells) escaping negative selection can recognize arthritogenic antigens and lead to autoimmunity and tissue destruction. Due to the important role of autoreactive T cells in the mechanisms of RA, they might be a novel therapeutic target. Many vaccines targeting autoreactive T cells which can establish immunological self tolerance have been developed. The efficacy of these vaccines has been justified in experimental models of RA and clinical trials. Inhibition of autoreactive T cell response by vaccination might provide a new treatment opinion in RA. PMID- 26057193 TI - Why gastrointestinal tolerance would be similar for coxibs and diclofenac? PMID- 26057194 TI - Rho kinase, oxidative stress, ACE2/Ang 1-7 and lung fibrosis. PMID- 26057195 TI - Effects of guanine bases at the central loop on stabilization of the quadruplex DNAs and their interactions with Meso-tetrakis(N-methylpyridium-4-yl)porphyrin. AB - The thermal stability of the G-quadruplex formed from the thrombin-binding aptamer, 5'G2T2G2TGTG2T2G2, in which the guanine (G) base at the central loop was replaced with an adenine (A) or inosine (I) base, was examined to determine the role of the central G base in stabilizing the quadruplex. Replacement of the central G base by the I base resulted in a slight decrease in thermal stability. On the other hand, the stability of the G-quadruplex decreased to a significant extent when it was replaced with the A base. The optimized structure of the G quadruplex, which was obtained by a molecular dynamic simulation, showed that the carbonyl group of the C5 position of the central G base could form hydrogen bonds with the G1 amine group at the C7 position on the upper G-quartet. This formation of a hydrogen bond contributes to the stability of the G-quadruplex. The spectral property of meso-tetrakis(N-methylpyridium-4yl)porphyrin (TMPyP) associated with the G-quadruplex was characterized by a moderate red shift and hypochromism in the absorption spectrum, a positive CD signal, and two emission maxima in the fluorescence emission spectrum, suggesting that TMPyP binds at the exterior of the G-quadruplex. Spectral properties were slightly altered when the G base at the central loop was replaced with A or I, while the fluorescence decay times of TMPyP associated with the G-quadruplex were identical. Observed spectral properties removes the possibility of intercalation binding mode for TMPyP. TMPyP binds at the exterior of the quadruplex. Whether it stacks on the central loop or binds at the side of the quadruplex is unclear at this stage. PMID- 26057196 TI - Performance monitoring and empathy during active and observational learning in patients with major depression. AB - Previous literature established a link between major depressive disorder (MDD) and altered reward processing as well as between empathy and (observational) reward learning. The aim of the present study was to assess the effects of MDD on the electrophysiological correlates - the feedback-related negativity (FRN) and the P300 - of active and observational reward processing and to relate them to trait cognitive and affective empathy. Eighteen patients with MDD and 16 healthy controls performed an active and an observational probabilistic reward-learning task while event- related potentials were recorded. Also, participants were assessed with regard to self-reported cognitive and affective trait empathy. Relative to healthy controls, patients with MDD showed overall impaired learning and attenuated FRN amplitudes, irrespective of feedback valence and learning type (active vs. observational), but comparable P300 amplitudes. In the patient group, but not in controls, higher trait perspective taking scores were significantly correlated with reduced FRN amplitudes. The pattern of results suggests impaired prediction error processing and a negative effect of higher trait empathy on feedback-based learning in patients with MDD. PMID- 26057197 TI - Third and fifth graders' processing of parafoveal information in reading: A study in single-word recognition. AB - We assessed third and fifth graders' processing of parafoveal word information using a lexical decision task. On each trial, a preview word was first briefly presented parafoveally in the left or right visual field before a target word was displayed. Preview and target words could be identical, share the first three letters, or have no letters in common. Experiment 1 showed that developing readers receive the same word recognition benefit from parafoveal previews as expert readers. The impact of a change of case between preview and target in Experiment 2 showed that in all groups of readers, the preview benefit resulted from the identification of letters at an abstract level rather than from facilitation at a purely visual level. Fifth graders identified more letters from the preview than third graders. The results are interpreted within the framework of the interactive activation model. In particular, we suggest that although the processing of parafoveal information led to letter identification in developing readers, the processes involved may differ from those in expert readers. Although expert readers' processing of parafoveal information led to activation at the level of lexical representations, no such activation was observed in developing readers. PMID- 26057198 TI - Deep brain stimulation to reduce sexual drive. AB - To date there are few treatment options to reduce high sexual drive or sexual urges in paraphilic patients with a risk for sexual offending. Pharmacological therapy aims to reduce sexual drive by lowering testosterone at the cost of severe side effects. We hypothesize that high sexual drive could also be reduced with deep brain stimulation (DBS) of circuits that generate sexual drive. This approach would help to avoid systemic side effects of antiandrogenic drug therapies. So far the best investigated target to reduce sexual drive is the ventromedial hypothalamus, which was lesioned unilaterally and bilaterally by stereotaxic interventions in paraphilic patients in the 1970s. Here, we discuss DBS as a treatment strategy in patients with severe paraphilic disorders with a serious risk of sexual offending. There are profound ethical and practical issues associated with DBS treatment of paraphilic patients that must be solved before considering such a treatment approach. PMID- 26057199 TI - Corrigendum: ferrocene and cobaltocene derivatives for non-aqueous redox flow batteries. PMID- 26057200 TI - Circulating chemerin levels elevated in dilated cardiomyopathy patients with overt heart failure. AB - BACKGROUND: Recent evidence demonstrated that the circulating concentrations of adipokine are related to the presence of heart failure secondary to ischemic heart disease and dilated cardiomyopathy (DCM). However, the plasma concentrations of chemerin in patients with DCM have yet to be investigated. METHODS: The present study enrolled 109 DCM patients with typical symptoms of heart failure and 60 healthy controls and measured plasma concentrations of chemerin, IL-6 and TNF-alpha using enzyme-linked immunosorbent assay. Left ventricular end-diastolic diameter (LVEDD) and left ventricular ejection fraction (LVEF) were measured using a GE ViVid E7 ultrasonography machine. RESULTS: Plasma chemerin, IL-6 and TNF-alpha concentrations were significantly higher in DCM patients compared to the control group. A correlation analysis revealed that plasma chemerin concentrations were positively correlated with the concentrations of IL-6 (R=0.270, P=0.004), TNF-alpha (R=0.302, P=0.001), C-reactive protein (CRP) (R=0.256, P=0.004), N-terminal pro-brain natriuretic peptide (NT-proBNP) (R=0.386, P=0.000), and LVEDD (R=0.212, P=0.027) but negatively correlated with LVEF (R=-0.543, P=0.000). Furthermore, chemerin (OR 1.102, 95% CI 1.052 to 1.153; p=0.000) was independently associated with the presence of DCM before NT-proBNP was added in the multivariable regression model. CONCLUSIONS: The results indicate that chemerin is a novel biomarker of DCM. PMID- 26057201 TI - Dysfibrinogenemia in a patient undergoing artificial abortion after misdiagnosis and review of the literature. AB - BACKGROUND: Dysfibrinogenemia is characterized by dysfunction induced by an abnormal fibrinogen molecule structure that results in blood coagulation dysfunction. The clinical manifestations are diverse. Dysfibrinogenemia is misdiagnosed or miss diagnosis in the absence of an appropriate laboratory examination. Treatment during pregnancy or surgery is suggested to be adapted to the individual patient. METHODS: A 26-y-old woman took drugs that may cause fetal malformation during early pregnancy. She required an artificial abortion in a local municipal hospital and was misdiagnosed with hypofibrinogenemia. RESULTS: A preoperative coagulation test revealed a fibrinogen concentration of 0.56g/l, prompting a diagnosis of hypofibrinogenemia at the local municipal hospital. She underwent fresh plasma and cryoprecipitate infusion with a poor outcome. However, the coagulation test results in our hospital showed a prothrombin time of 12.60s, activated partial thromboplastin time of 34.60s, thrombin time of 25.30s, and fibrinogen concentrations of 0.51g/l (Clauss method) and 3.82g/l (immunoturbidimetry). Ultrasound examination showed early intrauterine pregnancy with a fetal heartbeat. The patient was finally diagnosed with dysfibrinogenemia. A detailed inquiry regarding her personal and family histories revealed no abnormal bleeding or thrombotic events. Therefore, other therapies were not conducted and operation was successfully performed. No abnormal bleeding or thrombotic events occurred postoperatively. CONCLUSIONS: Simultaneous determination of fibrinogen concentrations using the Clauss method, prothrombin time-derived method, and immunoturbidimetry as well as measurement of the thrombin time, reptilase time, prothrombin time, activated partial thromboplastin time and so on can effectively distinguish dysfibrinogenemia from other diseases. Special treatment of asymptomatic dysfibrinogenemia is not needed during pregnancy or surgery in the absence of bleeding or thrombotic events in the patient's personal or family history. PMID- 26057203 TI - Membrane-Integrated Glass Capillary Device for Preparing Small-Sized Water-in-Oil in-Water Emulsion Droplets. AB - In this study, a membrane-integrated glass capillary device for preparing small sized water-in-oil-in-water (W/O/W) emulsion droplets is demonstrated. The concept of integrating microfluidics to prepare precise structure-controlled double emulsion droplets with the membrane emulsification technique provides a simple method for preparing small-sized and structure-controlled double emulsion droplets. The most important feature of the integrated device is the ability to decrease droplet size when the emulsion droplets generated at the capillary pass through the membrane. At the same time, most of the oil shell layer is stripped away and the resultant double emulsion droplets have thin shells. It is also demonstrated that the sizes of the resultant double emulsion droplets are greatly affected by both the double emulsion droplet flux through membranes and membrane pore size; when the flux is increased and membrane pore size is decreased, the generated W/O/W emulsion droplets are smaller than the original. In situ observation of the permeation behavior of the W/O/W emulsion droplets through membranes using a high-speed camera demonstrates (1) the stripping of the middle oil phase, (2) the division of the double emulsion droplets to generate two or more droplets with smaller size, and (3) the collapse of the double emulsion droplets. The first phenomenon results in a thinner oil shell, and the second division phenomenon produces double emulsion droplets that are smaller than the original. PMID- 26057202 TI - Ha83, a Chitin Binding Domain Encoding Gene, Is Important to Helicoverpa armigera Nucleopolyhedrovirus Budded Virus Production and Occlusion Body Assembling. AB - Helicoerpa armigera nucleopolyhedrovirus (HearNPV) ha83 is a late expressed gene that encodes a chitin binding protein. Chitin domain truncation studies revealed that the cysteine at the 128 amino acid position probably played an important role in both chitin binding ability and protein transmission of Ha83. In order to study the function of ha83 in the HearNPV infection cycle, an ha83 knockout HearNPV (Ha83KO) was constructed via homologous recombination. Viral growth and viral DNA replication curves showed that fewer budded virions were produced in Ha83KO transfected cells, while viral DNA replication was increased. Electron microscopy revealed that fewer nucleocapsids were transmitted from virogenic stroma in the Ha83KO transfected cell nucleus, and the morphology of occlusion bodies was prominently larger and cube-shaped. Furthermore, DNA quantity in occlusion bodies of Ha83KO was significantly lower than the occlusion bodies of HaWT. The transcription analysis indicated that these changes may be due to the decreased expression level of viral structural associated genes, such as polyhedrin, p10, pif-2, or cg30 in Ha83KO infected cells. Above results demonstrated that the cysteine at the 128 amino acid position in Ha83 might be the key amino acid, and Ha83 plays an important role in BVs production and OBs assembling. PMID- 26057204 TI - Perampanel in the treatment of partial seizures: Time to onset and duration of most common adverse events from pooled Phase III and extension studies. AB - Perampanel (PER) is a novel noncompetitive AMPA-receptor antagonist approved in over 40 countries for treatment of partial seizures. The safety and tolerability of PER have been well-documented in three double-blind, randomized, placebo (PBO) controlled Phase III studies and an open-label extension (OLE). This post hoc analysis evaluated the occurrence and characteristics of the most common treatment-emergent adverse events (TEAEs) associated with PER. Results from the Phase III studies were pooled; post hoc analyses on the double-blind phase and up to 1 year of the OLE were performed on the four most common TEAEs for which incidence was higher for PER than PBO. The four most common TEAEs were dizziness, somnolence, fatigue, and irritability. For most subjects in the Phase III double blind studies, these TEAEs were observed during 6-week titration and were mild or moderate in severity. For severe AEs, no dose-response relationship was observed. Patients in the PBO group during Phase III (who therefore received their first PER treatment during OLE) experienced these TEAEs with incidence and timing similar to that of PER-treated patients in Phase III. The first onset of these TEAEs occurred during the early weeks of PER conversion in the OLE. After 6months and up to 1 year of PER treatment, low to no incidence of the first onset of the four TEAEs was observed. Post hoc analyses of data from pooled Phase III studies provide greater insight into occurrence/duration of TEAEs. Phase III double-blind and OLE data showed that dizziness, somnolence, fatigue, and irritability were the most common TEAEs reported by patients taking PER. Additionally, these results suggest consistency between studies in patient responses to onset of these TEAEs. Although concomitant antiepileptic drugs (AEDs) might be predicted to affect development of TEAEs in patients taking PER, an effect was not observed in this analysis. The low incidence of TEAEs in these studies provides additional support for long-term PER treatment. PMID- 26057205 TI - Auditory verbal memory and psychosocial symptoms are related in children with idiopathic epilepsy. AB - OBJECTIVE: Idiopathic epilepsies are considered to have relatively good prognoses and normal or near normal developmental outcomes. Nevertheless, accumulating studies demonstrate memory and psychosocial deficits in this population, and the prevalence, severity and relationships between these domains are still not well defined. We aimed to assess memory, psychosocial function, and the relationships between these two domains among children with idiopathic epilepsy syndromes using an extended neuropsychological battery and psychosocial questionnaires. METHODS: Cognitive abilities, neuropsychological performance, and socioemotional behavior of 33 early adolescent children, diagnosed with idiopathic epilepsy, ages 9 14years, were assessed and compared with 27 age- and education-matched healthy controls. RESULTS: Compared to controls, patients with stabilized idiopathic epilepsy exhibited higher risks for short-term memory deficits (auditory verbal and visual) (p<0.0001), working memory deficits (p<0.003), auditory verbal long term memory deficits (p<0.0021), and more frequent psychosocial symptoms (p<0.0001). The severity of auditory verbal memory deficits was related to severity of psychosocial symptoms among the children with epilepsy but not in the healthy controls. SIGNIFICANCE: Results suggest that deficient auditory verbal memory may be compromising psychosocial functioning in children with idiopathic epilepsy, possibly underscoring that cognitive variables, such as auditory verbal memory, should be assessed and treated in this population to prevent secondary symptoms. PMID- 26057206 TI - Identification of the Protective Role of DJ-1 in Hypoglycemic Astrocyte Injury Using Proteomics. AB - As a common complication of glycemic control in patients with diabetes, hypoglycemia often leads to brain dysfunction or damage. To identify new mechanisms underlying hypoglycemic brain injury, we determined the difference of protein expression profiles in brains between hypoglycemic rats and sham hypoglycemic controls by isobaric tags for relative and absolute quantitation (iTRAQ) analysis. Among the 89 deregulated proteins, DJ-1 protein (Park7) was verified to be upregulated following hypoglycemia insult in vivo and glucose deprivation in an astrocyte cell line (CTX-TNA2) cultured in vitro. Further studies indicated the pro-survival role of autophagy activation and impaired autophagy flux in CTX-TNA2 cells short of glucose. DJ-1 knockdown hindered the initiation of the autophagy process via the AMPK/mTOR pathway and aggravated cell death induced by glucose deficiency. Taken together, our results show that responsive overexpression of DJ-1 plays a protective role against hypoglycemic astrocyte injury partly mediated by the regulation of autophagy. PMID- 26057207 TI - T-cell lymphoma: Microenvironment-related biomarkers. AB - Mature T-cell lymphomas are a heterogeneous group of lymphoid malignancies that occur in nodal and extranodal sites. The diverse tissues involved and the highly variable clinicopathologic features are related to an interaction between the neoplastic lymphoid cells and the tissues that they infiltrate. When different subpopulations of T-cells undergo transformation, they retain some of their inherent characteristics, including tissue tropisms, gene expression profiles and cytokine secretion patterns; which collaborate to impact on the cellular composition and structure of the lymphoma. Non-neoplastic cellular components of the lymphoma, including normal T and B lymphocytes, macrophages and eosinophils are altered by the neoplastic lymphoid cells, leading to changes in patterns of gene and protein expressions. These changes in turn modify the microenvironment of the lymphoma, inducing blood vessel formation and providing survival and proliferative signals to the neoplastic lymphoid cells. Tumor-infiltrating macrophages undergo M2 polarization as a result of the cytokines produced by the neoplastic T-cells. These macrophages in turn promote angiogenesis and inhibit anti-tumor cellular immunity. The macrophage content has been shown to correlate with treatment outcome in clinical studies. The effects of normal lymphocytes on T-cell lymphoma biology are more conflicting, with both stimulatory and inhibitory effects on the neoplastic cells demonstrated in vitro. Endothelial cells from micro-vessels interact with neoplastic T-cells mainly through the production of vascular endothelial growth factor. The prognostic and therapeutic significance of microvasculature have also been demonstrated in some clinical trials. This complex network of cellular, immunological and molecular interactions underlies the pathologies, clinical manifestations and treatment outcome of T-cell lymphomas. The understanding of the impact of the microenvironment on neoplastic T-cells should be further exploited in translational research to generate biomarkers that may be applicable to disease classification, treatment and prognostication. PMID- 26057208 TI - Facet-Selective Epitaxy of Compound Semiconductors on Faceted Silicon Nanowires. AB - Integration of compound semiconductors with silicon (Si) has been a long-standing goal for the semiconductor industry, as direct band gap compound semiconductors offer, for example, attractive photonic properties not possible with Si devices. However, mismatches in lattice constant, thermal expansion coefficient, and polarity between Si and compound semiconductors render growth of epitaxial heterostructures challenging. Nanowires (NWs) are a promising platform for the integration of Si and compound semiconductors since their limited surface area can alleviate such material mismatch issues. Here, we demonstrate facet-selective growth of cadmium sulfide (CdS) on Si NWs. Aberration-corrected transmission electron microscopy analysis shows that crystalline CdS is grown epitaxially on the {111} and {110} surface facets of the Si NWs but that the Si{113} facets remain bare. Further analysis of CdS on Si NWs grown at higher deposition rates to yield a conformal shell reveals a thin oxide layer on the Si{113} facet. This observation and control experiments suggest that facet-selective growth is enabled by the formation of an oxide, which prevents subsequent shell growth on the Si{113} NW facets. Further studies of facet-selective epitaxial growth of CdS shells on micro-to-mesoscale wires, which allows tuning of the lateral width of the compound semiconductor layer without lithographic patterning, and InP shell growth on Si NWs demonstrate the generality of our growth technique. In addition, photoluminescence imaging and spectroscopy show that the epitaxial shells display strong and clean band edge emission, confirming their high photonic quality, and thus suggesting that facet-selective epitaxy on NW substrates represents a promising route to integration of compound semiconductors on Si. PMID- 26057210 TI - Bacteraemic pneumonia caused by Neisseria meningitidis serogroup Y. AB - In this article, we describe a case of bacteraemic pneumonia caused by Neisseria meningitidis serogroup Y. PMID- 26057209 TI - Co-existence of intact stemness and priming of neural differentiation programs in mES cells lacking Trim71. AB - Regulatory networks for differentiation and pluripotency in embryonic stem (ES) cells have long been suggested to be mutually exclusive. However, with the identification of many new components of these networks ranging from epigenetic, transcriptional, and translational to even post-translational mechanisms, the cellular states of pluripotency and early differentiation might not be strictly bi-modal, but differentiating stem cells appear to go through phases of simultaneous expression of stemness and differentiation genes. Translational regulators such as RNA binding proteins (RBPs) and micro RNAs (miRNAs) might be prime candidates for guiding a cell from pluripotency to differentiation. Using Trim71, one of two members of the Tripartite motif (Trim) protein family with RNA binding activity expressed in murine ES cells, we demonstrate that Trim71 is not involved in regulatory networks of pluripotency but regulates neural differentiation. Loss of Trim71 in mES cells leaves stemness and self-maintenance of these cells intact, but many genes required for neural development are up regulated at the same time. Concordantly, Trim71(-/-) mES show increased neural marker expression following treatment with retinoic acid. Our findings strongly suggest that Trim71 keeps priming steps of differentiation in check, which do not pre-require a loss of the pluripotency network in ES cells. PMID- 26057211 TI - Advances in the development of histone lysine demethylase inhibitors. AB - The covalent modification of histones is closely associated with regulation of gene transcription. Chromatin modifications have been suggested to represent an epigenetic code that is dynamically 'written' and 'erased' by specialized proteins, and 'read', or interpreted, by proteins that translate the code into gene expression changes. Initially thought to be an irreversible process, histone methylation is now known to be reversed by demethylases, FAD dependent amineoxidases and by iron(II)-alpha-ketoglutarate dependent deoxygenases of the Jumonji family. Altered histone demethylase activities have been associated with human disease, including cancer. The first wave of novel investigational drugs directed against KDM1A has recently entered the clinic, and the first specific inhibitor targeting a Jumonji KDM is advancing in preclinical regulatory studies. PMID- 26057212 TI - MEK inhibitors beyond monotherapy: current and future development. AB - The development of MEK inhibitors has led to improved progression-free survival in patients with mutant BRAF(V600) cancers when used in combination with BRAF inhibitors. However, resistance to combination therapy remains an issue. This review summarizes our current understanding of the role of MEK in cancer cell proliferation and the mechanisms which lead to resistance in patients. Specific adverse events, which have been linked to the MEK inhibitor class, have been described. Future combinations of MEK inhibitors with other cancer therapy options, currently under investigation in clinical trials, are also discussed. PMID- 26057213 TI - Volume comparison of radiofrequency ablation at 3- and 5-cm target volumes for four different radiofrequency generators: MR volumetry in an open 1-T MRI system versus macroscopic measurement. AB - INTRODUCTION: In a patient, it is usually not macroscopically possible to estimate the non-viable volume induced by radiofrequency ablation (RFA) after the procedure. The purpose of this study was to use an ex vivo bovine liver model to perform magnetic resonance (MR) volumetry of the visible tissue signal change induced by RFA and to correlate the MR measurement with the actual macroscopic volume measured in the dissected specimens. MATERIALS AND METHODS: Sixty-four liver specimens cut from 16 bovine livers were ablated under constant simulated, close physiological conditions with target volumes set to 14.14 ml (3-cm lesion) and 65.45 ml (5-cm lesion). Four commercially available radiofrequency (RF) systems were tested (n=16 for each system; n=8 for 3 cm and n=8 for 5 cm). A T1 weighted turbo spin echo (TSE) sequence with inversion recovery and a proton density (PD)-weighted TSE sequence were acquired in a 1.0-T open magnetic resonance imaging (MRI) system. After manual dissection, actual macroscopic ablation diameters were measured and volumes calculated. MR volumetry was performed using a semiautomatic software tool. To validate the correctness and feasibility of the volume formula in macroscopic measurements, MR multiplanar reformation diameter measurements with subsequent volume calculation and semiautomatic MR volumes were correlated. RESULTS: Semiautomatic MR volumetry yielded smaller volumes than manual measurement after dissection, irrespective of RF system used, target lesion size, and MR sequence. For the 3-cm lesion, only 43.3% (T1) and 41.5% (PD) of the entire necrosis are detectable. For the 5-cm lesion, only 40.8% (T1) and 37.2% (PD) are visualized in MRI directly after intervention. The correlation between semiautomatic MR volumes and calculated MR volumes was 0.888 for the T1-weighted sequence and 0.875 for the PD sequence. CONCLUSION: After correlation of semiautomatic MR volumes and calculated MR volumes, it seems reasonable to use the respective volume formula for macroscopic volume calculation. Hyperacute MRI after ex vivo intervention may result in the underestimation of the real expansion of the produced necrosis zone. This must be kept in mind when using MRI for validating ablation success directly after RFA. One reason for the discrepancy between macroscopic and MRI appearance immediately after RFA may be that the transitional zone shows no or only partially visible MR signal change. PMID- 26057214 TI - Staphylococcus epidermidis adhesion on surface-treated open-cell Ti6Al4V foams. AB - The effect of alkali and nitric acid surface treatments on the adhesion of Staphylococcus epidermidis to the surface of 60% porous open-cell Ti6Al4V foam was investigated. The resultant surface roughness of foam particles was determined from the ground flat surfaces of thin foam specimens. Alkali treatment formed a porous, rough Na2Ti5O11 surface layer on Ti6Al4V particles, while nitric acid treatment increased the number of undulations on foam flat and particle surfaces, leading to the development of finer surface topographical features. Both surface treatments increased the nanometric-scale surface roughness of particles and the number of bacteria adhering to the surface, while the adhesion was found to be significantly higher in alkali-treated foam sample. The significant increase in the number of bacterial attachment on the alkali-treated sample was attributed to the formation of a highly porous and nanorough Na2Ti5O11 surface layer. PMID- 26057215 TI - Residual stress analysis of fixed retainer wires after in vitro loading: can mastication-induced stresses produce an unfavorable effect? AB - The aim of the present study was to compare four different types of fixed canine to-canine retainer regarding the maximum and residual force system generated on a canine during the intrusive in vitro loading of the rest of the anterior teeth. Retainers constructed from Ortho-FlexTech gold chain 0.038 * 0.016-inch (rectangular, 0.96 * 0.40 mm(2)), Tru-Chrome(r) 7-strand twisted 0.027-inch (round, 0.68 mm diameter) steel wire, and Wildcat 0.0175-inch (round, 0.44 mm) and 0.0215-inch (round, 0.55 mm) 3-strand Twistflex steel wire bonded on the anterior teeth of an acrylic resin model, installed in the Orthodontic Measurement and Simulation System. The force system on the canine was recorded during the loading of the anterior teeth as well as the residual force system at the same tooth after the unloading. During maximum loading, the gold chain exerted the lowest and the 0.0215-inch archwire the highest force and moment magnitude. Residual forces and moments were exerted on the canine after the unloading in all retainer types, i.e., the evaluated fixed retainers were not passive after in vitro vertical loading. The lowest magnitude was measured in gold chain retainers and the highest in cases of the high formable/low yield strength 0.027-inch archwire. This fact may explain the unexpected movements of teeth bonded on fixed retainers detected long-term in vivo. PMID- 26057216 TI - The importance of the negative blood-oxygenation-level-dependent (BOLD) response in the somatosensory cortex. AB - In recent years, multiple studies have shown task-induced negative blood oxygenation-level-dependent responses (NBRs) in multiple brain regions in humans and animals. Converging evidence suggests that task-induced NBRs can be interpreted in terms of decreased neuronal activity. However, the vascular and metabolic dynamics and functional importance of the NBR are highly debated. Here, we review studies investigating the origin and functional importance of the NBR, with special attention to the somatosensory cortex. PMID- 26057217 TI - Automated urine screening devices make urine sediment microscopy in diagnostic laboratories economically viable. AB - Automated urinalysis devices are reproducible, accurate and faster than the standard manual microscopy. Economic analysis has shown that decreases in turn around-time and labour cost savings offered by these devices make them more economic than manual microscopy. PMID- 26057218 TI - Vitamin D3 in cancer prevention and therapy: the nutritional issue. AB - The action of vitamin D3, in its biological form 1alpha,25(OH)2vitD3 or calcitriol, may be summarized as a steroid-like hormone able to modulate basic functions of cell encompassing energy balance, stress response, mitochondria biogenesis, intracellular calcium oscillations, and replication/apoptosis mechanisms leading to cell survival. Moreover, calcitriol exerts a potent role as an innate and adaptive immune cytokine as immunity is closely related to self maintenance through its energetic/metabolic balance and homeostasis of cell turnover. Therefore, vitamin D might be the ancestral form of survival hormones developed with calcified vertebrate bearing skeleton in order to survive far from water. This characteristic may suggest that the role of dietary vitamin D in preventing cancer is simply ancillary to the many factors playing a major role in contrasting impairment in energy balance and cell survival. Most probably, the immune role of calcitriol might be included in the maintenance, mostly by adipose tissue, of an anti-inflammatory, tolerant immune status, depending on the immune tolerance and modulation from the gut. A balance closely modulated by the leptin axis, which when impairments in metabolism occur, such as in insulin resistance or obesity, calcitriol is unable to face at this imbalance, while leptin plays a major role and cancer progression may be promoted. Furthermore, this mechanism promotes epithelial/mesenchymal transition-mediated fibrosis, leading to cancer resistance to immune control and drug action. Interestingly, this pathologic picture is triggered by deficiency in vitamin D from the diet. Therefore, a dietary habit including vitamin D sources, besides flavonoids, may ameliorate lifestyle and health span in most individuals, depending on their genetic background. PMID- 26057219 TI - Adiponectin as a biomarker linking obesity and adiposopathy to hematologic malignancies. AB - Higher body mass index and adiposopathy have been associated with increased risk of hematologic malignancies such as leukemia, multiple myeloma, myeloproliferative disorders, Hodgkin's and non-Hodgkin's lymphoma, and myelodysplastic syndromes. Adiponectin is a multimeric protein of the white adipose tissue presenting anti-inflammatory, insulin-sensitizing, anti atherogenic, cardioprotective, and anti-neoplastic properties. Its anti neoplastic actions are manifested via two mechanisms: (i) direct action on tumor cells by enhancing receptor-mediated signaling pathways and (ii) indirect action by regulating inflammatory responses, influencing cancer angiogenesis, and modulating insulin sensitivity at the target tissue site. In the bone marrow milieu, adiponectin and its main receptors are expressed by the majority of bone marrow stromal cell populations influencing hematopoietic stem cells function. Adiponectin may represent a molecular mediator relating adiposopathy with leukemogenesis and myelomagenesis. Several epidemiological studies conducted to date relate hypoadiponectinemia to the risk of myeloid-derived hematopoietic cancer and multiple myeloma. Adiponectin may be a promising biomarker with potential diagnostic and prognostic utility in determining the likelihood of myeloma and leukemia progression in certain cohorts of monoclonal gammopathy of undetermined significance patients and in myeloid hematologic malignancies, respectively. This review summarizes experimental and epidemiologic data regarding the role of adiponectin in hematologic malignancies in the context of adiposopathy. Enhancement of endogenous adiponectin, adiponectin replacement, or manipulation of adiponectin receptor sensitivity may be an attractive goal for prevention and an effective therapeutic strategy against hematopoietic cancer, specifically in overweight/obese individuals. Further studies are required to elucidate the role of the bone marrow microenvironment adiponectin in complex interactions involved in preleukemic and leukemic states. PMID- 26057220 TI - An efficient and rapid influenza gene cloning strategy for reverse genetics system. AB - Influenza reverse genetics plays vital roles in understanding influenza molecular characteristics and vaccine development. However, current influenza reverse genetics heavily depends on restriction enzyme and ligation for gene cloning. The traditional cloning process of influenza eight fragments for virus rescuing generally requires considerable work. To simplify and increase the pace of gene cloning for influenza reverse genetics system, we developed a rapid restriction enzyme-free ExnaseTM II-based in vitro recombination approach for influenza gene cloning. We used this strategy rapidly and successfully to clone influenza eight genes both from viruses PR8 and H9N2 for virus rescuing. Our data demonstrate that the strategy developed here can accelerate the process of influenza gene cloning into reverse genetics system, and shows high potential for applications in both influenza basic and applied research. PMID- 26057221 TI - Quantification of human papilloma virus (HPV) DNA using the Cobas 4800 system in women with and without pathological alterations attributable to the virus. AB - BACKGROUND AND PURPOSE: Surrogate markers such as viral load are necessary to follow the evolution of disease resulting from infection with Human Papilloma virus (HPV), especially in this era of vaccination. As such, this paper uses the automated system Cobas-4800-HPV to define viral load as number of HPV copies/cell and apply the results to clinical samples. STUDY DESIGN: A curve to determine viral load per cell was constructed from HPV plasmid and cell concentrations using the Cobas-4800-HPV system. According to these curves, HPV viral load was determined in 309 positive endocervical swabs (58 from patients with previous HPV infection, 118 with current lesions and 133 symptom-free patients presenting for screening) from women attending gynaecology consultations from January to June 2013. RESULTS: In curves with r(2)>=0.95 the Cobas-4800-HPV system has a detection limit of 150 (2.18 log) viral copies, and the limit for beta-globin corresponds to that of a single cell. In women reporting for screening, viral load was under 10(4) (4 log) copies/10(3) cells. For women with lesions or previous HPV infection loads were significantly higher particularly in the 30-45 year group (p=0.038). Elevated viral loads were especially noticeable in non-HPV 16/HPV 18. CONCLUSIONS: Automated system Cobas-4800-HPV is suitable for define viral load of HPV. Correlation between viral load and number of cells established. Higher viral load in women with disease, and those between 30 and 45 years. Increased viral load of non-16/18 high-risk HPV genotypes detected in patients with lesions compared to screening patients. A difference not observed for HPV 16/18, or in coinfections. PMID- 26057222 TI - Ferrocene-pyrimidine conjugates: Synthesis, electrochemistry, physicochemical properties and antiplasmodial activities. AB - The promise of hybrid antimalarial agents and the precedence set by the antimalarial drug ferroquine prompted us to design ferrocene-pyrimidine conjugates. Herein, we report the synthesis, electrochemistry and anti-plasmodial evaluation of ferrocenyl-pyrimidine conjugates against chloroquine susceptible NF54 strain of the malaria parasite Plasmodium falciparum. Also their physicochemical properties have been studied. PMID- 26057223 TI - Structure and cytotoxic activity of sesquiterpene glycoside esters from Calendula officinalis L.: Studies on the conformation of viridiflorol. AB - Topic applications of Calendula officinalis L. lipophilic extracts are used in phytotherapy to relieve skin inflammatory conditions whereas infusions are used as a remedy for gastric complaints. Such a different usage might be explained by some cytotoxicity of lipophilic extracts at gastric level but little is known about this. Therefore, we screened the CH2Cl2 extract from the flowers of C. officinalis by MTT and LDH assays in human epithelial gastric cells AGS. This bioassay-oriented approach led to the isolation of several sesquiterpene glycosides which were structurally characterized by spectroscopic measurements, chemical reactions and MM calculations. The conformational preferences of viridiflorol fucoside were established and a previously assigned stereochemistry was revised. The compounds 1a, 2a and 3f showed comparably high cytotoxicity in the MTT assays, whereas the effect on LDH release was lower. Our study provides new insights on the composition of C. officinalis extracts of medium polarity and identifies the main compounds that could be responsible for cytotoxic effects at gastric level. PMID- 26057224 TI - Entonalactams A-C: Isoindolinone derivatives from an Australian rainforest fungus belonging to the genus Entonaema. AB - Bioassay-guided fractionation of an antimalarial DCM/MeOH extract derived from the Australian rainforest fungus Entonaema sp. resulted in the isolation of three new isoindolinone derivatives, entonalactams A-C (1-3), along with the known natural products 3-methoxy-5-methylbenzene-1,2-diol (4), daldinal B (5), and ergosta-4,6,8(14),22-tetraen-3-one (6). The chemical structures of the new secondary metabolites were determined following extensive 1D/2D NMR and MS data analysis. A single crystal X-ray structure for entonalactam A (1) confirmed the NMR-based structure assignment. Entonalactams A-C (1-3) were all determined to be racemic based on chiro-optical data. All secondary metabolites were tested in vitro against Plasmodium falciparum malaria parasites, and ergosta-4,6,8(14),22 tetraen-3-one (6) was identified as the most active compound with 66% inhibition at 50 MUM. PMID- 26057225 TI - Single cell subtractive transcriptomics for identification of cell-specifically expressed candidate genes of pyrrolizidine alkaloid biosynthesis. AB - Progress has recently been made in the elucidation of pathways of secondary metabolism. However, because of its diversity, genetic information concerning biosynthetic details is still missing for many natural products. This is also the case for the biosynthesis of pyrrolizidine alkaloids. To close this gap, we tested strategies using tissues that express this pathway in comparison to tissues in which this pathway is not expressed. As many pathways of secondary metabolism are known to be induced by jasmonates, the pyrrolizidine alkaloid producing species Heliotropium indicum, Symphytum officinale, and Cynoglossum officinale of the Boraginales order were treated with methyl jasmonate. An effect on pyrrolizidine alkaloid levels and on transcript levels of homospermidine synthase, the first specific enzyme of pyrrolizidine alkaloid biosynthesis, was not detectable. Therefore, a method was developed by making use of the often observed cell-specific production of secondary compounds. H. indicum produces pyrrolizidine alkaloids exclusively in the shoot. Homospermidine synthase is expressed only in the cells of the lower leaf epidermis and the epidermis of the stem. Suggesting that the whole pathway of pyrrolizidine alkaloid biosynthesis might be localized in these cells, we have isolated single cells of the upper and lower epidermis by laser-capture microdissection. The resulting cDNA preparations have been used in a subtractive transcriptomic approach. Quantitative real-time polymerase chain reaction has shown that the resulting library is significantly enriched for homospermidine-synthase-coding transcripts providing a valuable source for the identification of further genes involved in pyrrolizidine alkaloid biosynthesis. PMID- 26057226 TI - Indole-3-acetic acid UDP-glucosyltransferase from immature seeds of pea is involved in modification of glycoproteins. AB - The glycosylation of auxin is one of mechanisms contributing to hormonal homeostasis. The enzyme UDPG: indole-3-ylacetyl-beta-D-glucosyltransferase (IAA glucosyltransferase, IAGlc synthase) catalyzes the reversible reaction: IAA+UDPG< >1-O-IA-glucose+UDP, which is the first step in the biosynthesis of IAA-ester conjugates in monocotyledonous plants. In this study, we report IAA glucosyltransferase isolated using a biochemical approach from immature seed of pea (Pisum sativum). The enzyme was purified by PEG fractionation, DEAE-Sephacel anion-exchange chromatography and preparative PAGE. LC-MS/MS analysis of tryptic peptides of the enzyme revealed the high identity with maize IAGlc synthase, but lack of homology with other IAA-glucosyltransferases from dicots. Biochemical characterization showed that of several acyl acceptors tested, the enzyme had the highest activity on IAA as the glucosyl acceptor (Km=0.52 mM, Vmax=161 nmol min( 1), kcat/Km=4.36 mM s(-1)) and lower activity on indole-3-propionic acid and 1 naphthalene acetic acid. Whereas indole-3-butyric acid and indole-3-propionic acid were competitive inhibitors of IAGlc synthase, D-gluconic acid lactone, an inhibitor of beta-glucosidase activity, potentiated the enzyme activity at the optimal concentration of 0.3mM. Moreover, we demonstrated that the 1-O-IA-glucose synthesized by IAGlc synthase is the substrate for IAA labeling of glycoproteins from pea seeds indicating a possible role of this enzyme in the covalent modification of a class of proteins by a plant hormone. PMID- 26057227 TI - Diacylglyceryltrimethylhomoserine content and gene expression changes triggered by phosphate deprivation in the mycelium of the basidiomycete Flammulina velutipes. AB - Diacylglyceryltrimethylhomoserines (DGTS) are betaine-type lipids that are phosphate-free analogs of phosphatidylcholines (PC). DGTS are abundant in some bacteria, algae, primitive vascular plants and fungi. In this study, we report inorganic phosphate (Pi) deficiency-induced DGTS synthesis in the basidial fungus Flammulina velutipes (Curt.: Fr.) Sing. We present results of an expression analysis of the BTA1 gene that codes for betaine lipid synthase and two genes of PC biosynthesis (CHO2 and CPT1) during phosphate starvation of F. velutipes culture. We demonstrate that FvBTA1 gene has increased transcript abundance under phosphate starvation. Despite depletion in PC, both CHO2 and CPT1 were determined to have increased expression. We also describe the deduced amino acid sequence and genomic structure of the BTA1 gene in F. velutipes. Phylogenetic relationships between putative orthologs of BTA1 proteins of basidiomycete fungi are discussed. PMID- 26057228 TI - Biotic elicitors and mechanical damage modulate glucosinolate accumulation by co ordinated interplay of glucosinolate biosynthesis regulators in polyploid Brassica juncea. AB - Glucosinolates are nitrogen and sulfur containing secondary metabolites found mainly in the Brassicaceae. They function as plant defense compounds against a broad spectrum of pathogens and pests. Since these molecules form part of the plant defense mechanism, glucosinolate biosynthesis may be modulated by environmental signals leading to activation of a biological stress response. In the current study, we have mimicked such conditions by exogenously applying biotic elicitors such as methyl jasmonate, salicylic acid, glucose and mechanical injury in Brassica juncea seedling over a time course experiment. We found that total glucosinolates over-accumulated under these stress conditions with maximum accumulation observed 24h post treatment. Indole glucosinolates like 1-methoxy indol-3-ylmethyl and its precursor indol-3-methyl glucosinolates showed a more significant induction compared to aliphatic glucosinolates thereby suggesting a prominent role of indole glucosinolates during plant defense response in B. juncea seedlings. In contrast, the higher amounts of aliphatic glucosinolates were less regulated by the tested biotic elicitors in B. juncea. Expression profiling of multiple homologs of key transcriptional regulators of glucosinolate biosynthesis further showed that a complex interplay of these regulators exists in polyploid B. juncea where they exert co-ordinated and overlapping effects toward altering glucosinolate accumulation. This study has a significant role toward understanding and augmenting plant defense mechanisms in B. juncea, a globally important oilseed crop of genus Brassica. PMID- 26057229 TI - Toxic proteins in plants. AB - Plants have evolved to synthesize a variety of noxious compounds to cope with unfavorable circumstances, among which a large group of toxic proteins that play a critical role in plant defense against predators and microbes. Up to now, a wide range of harmful proteins have been discovered in different plants, including lectins, ribosome-inactivating proteins, protease inhibitors, ureases, arcelins, antimicrobial peptides and pore-forming toxins. To fulfill their role in plant defense, these proteins exhibit various degrees of toxicity towards animals, insects, bacteria or fungi. Numerous studies have been carried out to investigate the toxic effects and mode of action of these plant proteins in order to explore their possible applications. Indeed, because of their biological activities, toxic plant proteins are also considered as potentially useful tools in crop protection and in biomedical applications, such as cancer treatment. Genes encoding toxic plant proteins have been introduced into crop genomes using genetic engineering technology in order to increase the plant's resistance against pathogens and diseases. Despite the availability of ample information on toxic plant proteins, very few publications have attempted to summarize the research progress made during the last decades. This review focuses on the diversity of toxic plant proteins in view of their toxicity as well as their mode of action. Furthermore, an outlook towards the biological role(s) of these proteins and their potential applications is discussed. PMID- 26057230 TI - Purification, sequencing and characterization of phospholipase D from Indian mustard seeds. AB - Phospholipase D (PLD; E.C. 3.1.4.4) is widespread in plants where it fulfills diverse functions in growth and in the response to stresses. The enzyme occurs in multiple forms that differ in their biochemical properties. In the present paper PLD from medicinally relevant Indian mustard seeds was purified by Ca(2+) mediated hydrophobic interaction and anion exchange chromatography to electrophoretic homogeneity. Based on mass-spectrometric sequence analysis of tryptic protein fragments, oligonucleotide primers for cloning genomic DNA fragments that encoded the enzyme were designed and used to derive the complete amino acid sequence of this PLD. The sequence data, as well as the molecular properties (molecular mass of 92.0 kDa, pI 5.39, maximum activity at pH 5.5-6.0 and Ca(2+) ion concentrations ?60 mM), allowed the assignment of this enzyme to the class of alpha-type PLDs. The apparent kinetic parameters Vmax and Km, determined for the hydrolysis of phosphatidylcholine (PC) in an aqueous mixed micellar system were 356+/-15 MUmol min(-1) mg(-1) and 1.84+/-0.17 mM, respectively. Phosphate analogs such as NaAlF4 and Na3VO4 displayed strong inhibition of the enzyme. Phosphatidylinositol 4,5-bisphosphate had a strong activating effect at 2-10 mM CaCl2. PLD was inactivated at temperatures >45 degrees C. The enzyme exhibited the highest activity toward PC followed by phosphatidylethanolamine and phosphatidylglycerol. PCs with short-chain fatty acids were better substrates than PCs with long fatty acid chains. Lyso-PC was not accepted as substrate. PMID- 26057231 TI - The Persistent Complex Bereavement Inventory: A Measure Based on the DSM-5. AB - The Persistent Complex Bereavement Inventory (PCBI) was developed to facilitate research into the construct of persistent complex bereavement disorder (PCBD). Across 2 studies, the PCBI yielded a stable 3-factor structure that corresponded with DSM-5 criteria for PCBD. The PCBI demonstrated solid reliability in the forms of internal consistency and test-retest reliability. Correlation analyses provided evidence of the measure's construct, convergent, and divergent validity. The PCBI predicted outcomes, above and beyond measures of prolonged grief disorder, separation anxiety, depression, and post-traumatic stress. In addition, the Social/Identity Disruption subscale was able to predict future negative religious coping, harmful health behaviors, hallucinations, somatic complaints, medical conditions, and suicidal ideation. This article provides preliminary evidence for a reliable and valid way to measure PCBD symptomatology. PMID- 26057232 TI - Crowd-Sourced Assessment of Technical Skill: A Valid Method for Discriminating Basic Robotic Surgery Skills. AB - BACKGROUND: A surgeon's skill in the operating room has been shown to correlate with a patient's clinical outcome. The prompt accurate assessment of surgical skill remains a challenge, in part, because expert faculty reviewers are often unavailable. By harnessing the power of large readily available crowds through the Internet, rapid, accurate, and low-cost assessments may be achieved. We hypothesized that assessments provided by crowd workers highly correlate with expert surgeons' assessments. MATERIALS AND METHODS: A group of 49 surgeons from two hospitals performed two dry-laboratory robotic surgical skill assessment tasks. The performance of these tasks was video recorded and posted online for evaluation using Amazon Mechanical Turk. The surgical tasks in each video were graded by (n=30) varying crowd workers and (n=3) experts using a modified global evaluative assessment of Robotic Skills (GEARS) grading tool, and the mean scores were compared using Cronbach's alpha statistic. RESULTS: GEARS evaluations from the crowd were obtained for each video and task and compared with the GEARS ratings from the expert surgeons. The crowd-based performance scores agreed with the performance assessments by experts with a Cronbach's alpha of 0.84 and 0.92 for the two tasks, respectively. CONCLUSION: The assessment of surgical skill by crowd workers resulted in a high degree of agreement with the scores provided by expert surgeons in the evaluation of basic robotic surgical dry-laboratory tasks. Crowd responses cost less and were much faster to acquire. This study provides evidence that crowds may provide an adjunctive method for rapidly providing feedback of skills to training and practicing surgeons. PMID- 26057233 TI - From one to many: dynamic assembly and collective behavior of self-propelled colloidal motors. AB - The assembly of complex structures from simpler, individual units is a hallmark of biology. Examples include the pairing of DNA strands, the assembly of protein chains into quaternary structures, the formation of tissues and organs from cells, and the self-organization of bacterial colonies, flocks of birds, and human beings in cities. While the individual behaviors of biomolecules, bacteria, birds, and humans are governed by relatively simple rules, groups assembled from many individuals exhibit complex collective behaviors and functions that do not exist in the absence of the hierarchically organized structure. Self-assembly is a familiar concept to chemists who study the formation and properties of monolayers, crystals, and supramolecular structures. In chemical self-assembly, disorder evolves to order as the system approaches equilibrium. In contrast, living assemblies are typically characterized by two additional features: (1) the system constantly dissipates energy and is not at thermodynamic equilibrium; (2) the structure is dynamic and can transform or disassemble in response to stimuli or changing conditions. To distinguish them from equilibrium self-assembled structures, living (or nonliving) assemblies of objects with these characteristics are referred to as active matter. In this Account, we focus on the powered assembly and collective behavior of self-propelled colloids. These nano- and microparticles, also called nano- and micromotors or microswimmers, autonomously convert energy available in the environment (in the form of chemical, electromagnetic, acoustic, or thermal energy) into mechanical motion. Collections of these colloids are a form of synthetic active matter. Because of the analogy to living swimmers of similar size such as bacteria, the dynamic interactions and collective behavior of self-propelled colloids are interesting in the context of understanding biological active matter and in the development of new applications. The progression from individual particle motion to pairwise interactions, and then to multiparticle behavior, can be studied systematically with colloidal particles. Colloidal particles are also amenable to designs (in terms of materials, shapes, and sizes) that are not readily available in, for example, microbial systems. We review here our efforts and those of other groups in studying these fundamental interactions and the collective behavior that emerges from them. Although this field is still very new, there are already unique and interesting applications in analysis, diagnostics, separations, and materials science that derive from our understanding of how powered colloids interact and assemble. PMID- 26057234 TI - Protomer Roles in Chloroplast Chaperonin Assembly and Function. AB - The individual roles of three chloroplast CPN60 protomers (CPN60alpha, CPN60beta1, and CPN60beta2) and whether and how they are assembled into functional chaperonin complexes are investigated in Chlamydomonas reinhardtii. Protein complexes containing all three potential subunits were identified in Chlamydomonas, and their co-expression in Escherichia coli yielded a homogeneous population of oligomers containing all three subunits (CPN60alphabeta1beta2), with a molecular weight consistent with a tetradecameric structure. While homo oligomers of CPN60beta could form, they were dramatically reduced when CPN60alpha was present and homo-oligomers of CPN60beta2 were readily changed into hetero oligomers in the presence of ATP and other protomers. ATP hydrolysis caused CPN60 oligomers to disassemble and drove the purified protomers to reconstitute oligomers in vitro, suggesting that the dynamic nature of CPN60 oligomers is dependent on ATP. Only hetero-oligomeric CPN60alphabeta1beta2, containing CPN60alpha, CPN60beta1, and CPN60beta2 subunits in a 5:6:3 ratio, cooperated functionally with GroES. The combination of CPN60alpha and CPN60beta subunits, but not the individual subunits alone, complemented GroEL function in E. coli with subunit recognition specificity. Down-regulation of the CPN60alpha subunit in Chlamydomonas resulted in a slow growth defect and an inability to grow autotrophically, indicating the essential role of CPN60alpha in vivo. PMID- 26057235 TI - AGEseq: Analysis of Genome Editing by Sequencing. PMID- 26057236 TI - Choice of antiretroviral therapy differentially impacts survival of HIV-infected CD4 T cells. AB - BACKGROUND: HIV eradication strategies are now being evaluated in vitro and in vivo. A cornerstone of such approaches is maximal suppression of viral replication with combination antiretroviral therapy (ART). Since many antiretroviral agents have off target effects, and different classes target different components of the viral life cycle, we questioned whether different classes of ART might differentially affect the survival and persistence of productively HIV-infected CD4 T cells. METHODS: In vitro infections of primary CD4 T cells using clinical isolates of HIV-1 that were either protease inhibitor susceptible (HIV PI-S), or resistant (HIV PI-R) were treated with nothing, lopinavir, efavirenz or raltegravir. Cell viability, apoptosis, and the proportion of surviving cells that were P24 positive was assessed by flow cytometry. RESULTS: In HIV PI-S infected primary cultures, all three antiretroviral agents decreased viral replication, and reduced the total number of cells that were undergoing apoptosis (P < 0.01) similarly. Similarly, in the HIV PI-R infected cultures, both efavirenz and raltegravir reduced viral replication and reduced apoptosis compared to untreated control (P < 0.01), while lopinavir did not, suggesting that HIV replication drives T cell apoptosis, which was confirmed by association by linear regression (P < 0.0001) . However since HIV protease has been suggested to directly induce apoptosis of infected CD4 T cells, and HIV PI are intrinsically antiapoptotic, we evaluated apoptosis in productively infected (HIV P24+) cells. More HIV p24 positive cells were apoptotic in the Efavirenz or raltegravir treated cultures than the lopinavir treated cultures (P = 0.0008 for HIV PI-R and P = 0.06 for the HIV PI-S), indicating that drug class impacts survival of productively infected CD4 T cells. CONCLUSIONS: Inhibiting HIV replication with a PI, NNRTI or INSTI reduces total HIV-induced T cell apoptosis. However, blocking HIV replication with PI but not with NNRTI or INSTI promotes survival of productively HIV-infected cells. Thus, selection of antiretroviral agents may impact the success of HIV eradication strategies. PMID- 26057237 TI - Prolonged Sitting Time: Barriers, Facilitators and Views on Change among Primary Healthcare Patients Who Are Overweight or Moderately Obese. AB - BACKGROUND AND OBJECTIVES: Prolonged sitting time has negative consequences on health, although the population is not well aware of these harmful effects. We explored opinions expressed by primary care patients diagnosed as overweight or moderately obese concerning their time spent sitting, willingness to change, and barriers, facilitators, goals and expectations related to limiting this behaviour. METHODS: A descriptive-interpretive qualitative study was carried out at three healthcare centres in Barcelona, Spain, and included 23 patients with overweight or moderate obesity, aged 25 to 65 years, who reported sitting for at least 6 hours a day. Exclusion criteria were inability to sit down or stand up from a chair without help and language barriers that precluded interview participation. Ten in-depth, semi-structured interviews (5 group, 5 individual) were audio recorded from January to July 2012 and transcribed. The interview script included questions about time spent sitting, willingness to change, barriers and facilitators, and the prospect of assistance from primary healthcare professionals. An analysis of thematic content was made using ATLAS.Ti and triangulation of analysts. RESULTS: The most frequent sedentary activities were computer use, watching television, and motorized journeys. There was a lack of awareness of the amount of time spent sitting and its negative consequences on health. Barriers to reducing sedentary time included work and family routines, lack of time and willpower, age and sociocultural limitations. Facilitators identified were sociocultural change, free time and active work, and family surroundings. Participants recognized the abilities of health professionals to provide help and advice, and reported a preference for patient-centred or group interventions. CONCLUSIONS: Findings from this study have implications for reducing sedentary behaviour. Patient insights were used to design an intervention to reduce sitting time within the frame of the SEDESTACTIV clinical trial. PMID- 26057238 TI - Exogenous Tryptophan Promotes Cutaneous Wound Healing of Chronically Stressed Mice through Inhibition of TNF-alpha and IDO Activation. AB - Stress prolongs the inflammatory response compromising the dermal reconstruction and wound closure. Acute stress-induced inflammation increases indoleamine 2, 3 dioxygenase-stimulated tryptophan catabolism. To investigate the role of indoleamine 2, 3-dioxygenase expression and tryptophan administration in adverse effects of stress on cutaneous wound healing, mice were submitted to chronic restraint stress and treated with tryptophan daily until euthanasia. Excisional lesions were created on each mouse and 5 or 7 days later, the lesions were analyzed. In addition, murine skin fibroblasts were exposed to elevated epinephrine levels plus tryptophan, and fibroblast activity was evaluated. Tryptophan administration reversed the reduction of the plasma tryptophan levels and the increase in the plasma normetanephrine levels induced by stress 5 and 7 days after wounding. Five days after wounding, stress-induced increase in the protein levels of tumor necrosis factor-alpha and indoleamine 2, 3-dioxygenase, and this was inhibited by tryptophan. Stress-induced increase in the lipid peroxidation and the amount of the neutrophils, macrophages and T cells number was reversed by tryptophan 5 days after wounding. Tryptophan administration inhibited the reduction of myofibroblast density, collagen deposition, re epithelialization and wound contraction induced by stress 5 days after wounding. In dermal fibroblast culture, the tryptophan administration increased the cell migration and AKT phosphorylation in cells treated with high epinephrine levels. In conclusion, tryptophan-induced reduction of inflammatory response and indoleamine 2, 3-dioxygenase expression may have accelerated cutaneous wound healing of chronically stressed mice. PMID- 26057241 TI - Partner Choice Drives the Evolution of Cooperation via Indirect Reciprocity. AB - Indirect reciprocity potentially provides an important means for generating cooperation based on helping those who help others. However, the use of 'image scores' to summarize individuals' past behaviour presents a dilemma: individuals withholding help from those of low image score harm their own reputation, yet giving to defectors erodes cooperation. Explaining how indirect reciprocity could evolve has therefore remained problematic. In all previous treatments of indirect reciprocity, individuals are assigned potential recipients and decide whether to cooperate or defect based on their reputation. A second way of achieving discrimination is through partner choice, which should enable individuals to avoid defectors. Here, I develop a model in which individuals choose to donate to anyone within their group, or to none. Whereas image scoring with random pairing produces cycles of cooperation and defection, with partner choice there is almost maximal cooperation. In contrast to image scoring with random pairing, partner choice results in almost perfect contingency, producing the correlation between giving and receiving required for cooperation. In this way, partner choice facilitates much higher and more stable levels of cooperation through image scoring than previously reported and provides a simple mechanism through which systems of helping those who help others can work. PMID- 26057239 TI - Low Genetic Diversity and Strong Geographical Structure of the Critically Endangered White-Headed Langur (Trachypithecus leucocephalus) Inferred from Mitochondrial DNA Control Region Sequences. AB - Many Asian colobine monkey species are suffering from habitat destruction and population size decline. There is a great need to understand their genetic diversity, population structure and demographic history for effective species conservation. The white-headed langur (Trachypithecus leucocephalus) is a Critically Endangered colobine species endemic to the limestone karst forests in southwestern China. We analyzed the mitochondrial DNA (mtDNA) control region sequences of 390 fecal samples from 40 social groups across the main distribution areas, which represented one-third of the total extant population. Only nine haplotypes and 10 polymorphic sites were identified, indicating remarkably low genetic diversity in the species. Using a subset of 77 samples from different individuals, we evaluated genetic variation, population structure, and population demographic history. We found very low values of haplotype diversity (h = 0.570 +/- 0.056) and nucleotide diversity (pi = 0.00323 +/- 0.00044) in the hypervariable region I (HVRI) of the mtDNA control region. Distribution of haplotypes displayed marked geographical pattern, with one population (Chongzuo, CZ) showing a complete lack of genetic diversity (having only one haplotype), whereas the other population (Fusui, FS) having all nine haplotypes. We detected strong population genetic structure among habit patches (PhiST = 0.375, P < 0.001). In addition, the Mantel test showed a significant correlation between the pairwise genetic distances and geographical distances among social groups in FS (correlation coefficient = 0.267, P = 0.003), indicting isolation-by-distance pattern of genetic divergence in the mtDNA sequences. Analyses of demographic history suggested an overall stable historical population size and modest population expansion in the last 2,000 years. Our results indicate different genetic diversity and possibly distinct population history for different local populations, and suggest that CZ and FS should be considered as one evolutionarily significant unit (ESU) and two management units (MUs) pending further investigation using nuclear markers. PMID- 26057240 TI - Confined chemiluminescence detection of nanomolar levels of H2O2 in a paper plastic disposable microfluidic device using a smartphone. AB - We report the design and characterization of a disposable light shielded paper plastic microfluidic device that can detect nanomolar levels of H2O2 using a smartphone camera and a light sealed accessory. Chemiluminescence reaction of H2O2 with bis(2,4,6-trichlorophenyl)oxalate in the presence of rubrene and imidazole is confined to a paper reaction site where the individual reagents are delivered via plastic microfluidic channels. The net photon emission from the chemiluminescence reactions, detected by using a smartphone, is correlated with H2O2 concentrations. With a total reagent volume of 25 MUL, the sensor system was able to detect H2O2 concentrations as low as 250 nM. The smartphone based chemiluminescence sensing system has great potential as a point of care diagnostic tool for monitoring nanomolar levels of H2O2 in biological samples. PMID- 26057242 TI - Electrical Pacing of Cardiac Tissue Including Potassium Inward Rectification. AB - In this study cardiac tissue is stimulated electrically through a small unipolar electrode. Numerical simulations predict that around an electrode are adjacent regions of depolarization and hyperpolarization. Experiments have shown that during pacing of resting cardiac tissue the hyperpolarization is often inhibited. Our goal is to determine if the inward rectifying potassium current (IK1) causes the inhibition of hyperpolarization. Numerical simulations were carried out using the bidomain model with potassium dynamics specified to be inward rectifying. In the simulations, adjacent regions of depolarization and hyperpolarization were observed surrounding the electrode. For cathodal currents the virtual anode produces a hyperpolarization that decreases over time. For long duration pulses the current-voltage curve is non-linear, with very small hyperpolarization compared to depolarization. For short pulses, the hyperpolarization is more prominent. Without the inward potassium rectification, the current voltage curve is linear and the hyperpolarization is evident for both long and short pulses. In conclusion, the inward rectification of the potassium current explains the inhibition of hyperpolarization for long duration stimulus pulses, but not for short duration pulses. PMID- 26057243 TI - Faceted phospholipid vesicles tailored for the delivery of Santolina insularis essential oil to the skin. AB - The aim of this work was to formulate Santolina insularis essential oil-loaded nanocarriers, namely Penetration Enhancer containing Vesicles (PEVs), evaluate the physico-chemical features and stability, and gain insights into their ability to deliver the oil to the skin. S. insularis essential oil was obtained by steam distillation, and was predominantly composed of terpenes, the most abundant being beta-phellandrene (22.6%), myrcene (11.4%) and curcumenes (12.1%). Vesicles were prepared using phosphatidylcholine, and ethylene or propylene glycol were added to the water phase (10% (v/v)) to improve vesicle performances as delivery systems. Vesicles were deeply characterized by light scattering, cryogenic transmission electron microscopy and small/wide-angle X-ray scattering, the results showing polyhedral, faceted, unilamellar vesicles of ~115 nm in size. The presence of the glycols improved vesicle stability under accelerated ageing conditions, without changes in size or migration phenomena (e.g. sedimentation and creaming). Confocal laser scanning microscopy images of pig skin treated with S. insularis formulations displayed a penetration ability of PEVs greater than that of control liposomes. Moreover, all formulations showed a marked in vitro biocompatibility in human keratinocytes. These findings suggest that the nanoformulation may be of value in enhancing the delivery of S. insularis essential oil to the skin, where it can exert its biological activities. PMID- 26057244 TI - Tunable, antibacterial activity of silicone polyether surfactants. AB - Silicone surfactants are used in a variety of applications, however, limited data is available on the relationship between surfactant structure and biological activity. A series of seven nonionic, silicone polyether surfactants with known structures was tested for in vitro antibacterial activity against Escherichia coli BL21. The compounds varied in their hydrophobic head, comprised of branched silicone structures with 3-10 siloxane linkages and, in two cases, phenyl substitution, and hydrophilic tail of 8-44 poly(ethylene glycol) units. The surfactants were tested at three concentrations: below, at, and above their Critical Micelle Concentrations (CMC) against 5 concentrations of E. coli BL21 in a three-step assay comprised of a 14-24h turbidometric screen, a live-dead stain and viable colony counts. The bacterial concentration had little effect on antibacterial activity. For most of the surfactants, antibacterial activity was higher at concentrations above the CMC. Surfactants with smaller silicone head groups had as much as 4 times the bioactivity of surfactants with larger groups, with the smallest hydrophobe exhibiting potency equivalent to sodium dodecyl sulfate (SDS). Smaller PEG chains were similarly associated with higher potency. These data link lower micelle stability and enhanced permeability of smaller silicone head groups to antibacterial activity. The results demonstrate that simple manipulation of nonionic silicone polyether structure leads to significant changes in antibacterial activity. PMID- 26057245 TI - Effect of energy source, salt concentration and loading force on colloidal interactions between Acidithiobacillus ferrooxidans cells and mineral surfaces. AB - The surface appendages and extracellular polymeric substances of cells play an important role in the bacterial adhesion process. In this work, colloidal forces and nanomechanical properties of Acidithiobacillus ferrooxidans (A. f) interacted with silicon wafer and pyrite (FeS2) surfaces in solutions of varying salt concentrations were quantitatively examined using the bacterial probe technique with atomic force microscopy. A. f cells were cultured with either ferrous sulfate or elemental sulfur as key energy sources. Our results show that A. f cells grown with ferrous ion and elemental sulfur exhibit distinctive retraction force vs separation distance curves with stair-step and saw tooth shapes, respectively. During the approach of bacterial probes to the substrate surfaces, surface appendages and biopolymers of cells are sequentially compressed. The conformations of surface appendages and biopolymers are significantly influenced by the salt concentrations. PMID- 26057246 TI - Study on the antibacterial mechanism of copper ion- and neodymium ion-modified alpha-zirconium phosphate with better antibacterial activity and lower cytotoxicity. AB - To improve the antibacterial activity of Cu(2+), a series of Cu(2+) and/or Nd(3+) modified layered alpha-zirconium phosphate (ZrP) was prepared and characterized, and the antibacterial activities of the prepared Cu(2+) and/or Nd(3+)-modified ZrP on Gram-negative Escherichia coli were investigated. The results showed that the basal spacing of ZrP was not obviously affected by the incorporation of Cu(2+), but the basal spacing of the modified ZrP changed into an amorphous state with increasing additions of Nd(3+). An antibacterial mechanism showed that Cu(2+) and Nd(3+) could enter into E. coli cells, leading to changes in ion concentrations and leakage of DNA, RNA and protein. The Cu(2+)- and Nd(3+) modified ZrP, combining the advantages of Cu(2+) and Nd(3+), displayed excellent additive antibacterial activity and lower cytotoxicity, suggesting the great potential application as an antibacterial powder for microbial control. PMID- 26057247 TI - Rhamnolipids functionalized AgNPs-induced oxidative stress and modulation of toxicity pathway genes in cultured MCF-7 cells. AB - Rhamnolipids extracted from Pseudomonas aeruginosa strain JS-11 were utilized for synthesis of stable silver nanoparticles (Rh-AgNPs). The Rh-AgNPs (23 nm) were characterized by Fourier transform infra-red (FTIR) spectroscopy, atomic force microscopy (AFM) and transmission electron microscopy (TEM). The cytotoxicity assays suggested significant decrease in viability of Rh-AgNPs treated human breast adenocarcinoma (MCF-7) cells, compared with normal human peripheral blood mononuclear (PBMN) cells. Flow cytometry data revealed 1.25-fold (p<0.05) increase in the fluorescence of 2',7'-dichlorofluorescein (DCF) at 0.25 MUg/mL. However, at Rh-AgNPs concentrations of 0.5 and 1.0 MUg/mL, much lesser fluorescence was noticed, which is attributed to cell death. Results with the fluorescent probe Rh123 demonstrated change in inner mitochondrial membrane and dissipation of membrane potential. The cell cycle analysis suggested 19.9% (p<0.05) increase in sub-G1 peak with concomitant reduction in G1 phase at 1 MUg/mL of Rh-AgNPs, compared to 2.7% in untreated control. The real-time RT(2) ProfilerTM PCR array data elucidated the overexpression of seven oxidative stress and DNA damage pathways genes viz. BAX, BCl2, Cyclin D1, DNAJA1, E2F transcription factor 1, GPX1 and HSPA4, associated with apoptosis signaling, proliferation and carcinogenesis, pro inflammatory and heat shock responses in Rh AgNPs treated cells. Thus, the increased ROS production, mitochondrial damage and appearance of sub-G1 (apoptotic) population suggested the anti-proliferative activity, and role of oxidative stress pathway genes in Rh-AgNPs induced death of MCF-7 cancer cells. PMID- 26057248 TI - The effects of anionic electrolytes and human serum albumin on the LCST of poly(N isopropylacrylamide)-based temperature-responsive copolymers. AB - Poly(N-isopropylacrylamide) (PNIPAm) is one of the most widely studied temperature-responsive polymers among those that have been applied to biomaterials science and technology. Here, we investigated the importance of interactions between PNIPAm-based copolymers and biological factors. The effects of a series of major anionic electrolytes in biological environments and of human serum albumin (HSA) on the lower critical solution temperature (LCST) of homo PNIPAm and PNIPAm copolymers were studied, using either a hydrophobic monomer or a cationic monomer. We synthesized P(NIPAm-co-BMA3%) with butyl methacrylate (BMA) as a hydrophobic monomer and P(NIPAm-co-DMAPAm2%) with N,N dimethylaminopropyl acrylamide (DMAPAm) as a cationic monomer. The LCST of PNIPAm and P(NIPAm-co-DMAPAm2%) decreased with increasing salt concentrations, and the effects of anions on each polymer corresponded to the Hofmeister series. The LCST of P(NIPAm-co-DMAPAm2%) was greatly affected by anionic electrolytes compared with those of homo-PNIPAm and P(NIPAm-co-BMA3%). While the LCST of homo-PNIPAm was not affected by HSA, the LCST of P(NIPAm-co-DMAPAm2%) decreased non-linearly with increasing HSA concentrations. These effects were due to the electrostatic interactions between the positively charged polymer chains and the negatively charged HSA, as well as the stabilization of polymer aggregations with HSA. Under physiological buffer conditions, the LCST of P(NIPAm-co-DMAPAm2%) was not significantly affected by the HSA concentration. These results indicated that depending on the types of copolymers used for biological applications, it is necessary to take into account the effect of biological media while designing polymers. PMID- 26057249 TI - Long-Term Grazing Exclusion Improves the Composition and Stability of Soil Organic Matter in Inner Mongolian Grasslands. AB - Alteration of the composition of soil organic matter (SOM) in Inner Mongolian grassland soils associated with the duration of grazing exclusion (GE) has been considered an important index for evaluating the restoring effects of GE practice. By using five plots from a grassland succession series from free grazing to 31-year GE, we measured the content of soil organic carbon (SOC), humic acid carbon (HAC), fulvic acid carbon (FAC), humin carbon (HUC), and humic acid structure to evaluate the changes in SOM composition. The results showed that SOC, HUC, and the ratios of HAC/FAC and HAC/extractable humus carbon (C) increased significantly with prolonged GE duration, and their relationships can be well fitted by positive exponential equations, except for FAC. In contrast, the HAC content increased logarithmically with prolonged GE duration. Long-term GE enhanced the content of SOC and soil humification, which was obvious after more than 10 years of GE. Solid-state 13C nuclear magnetic resonance spectroscopy showed that the ratios of alkyl C/O-alkyl C first decreased, and then remained stable with prolonged GE. Alternately, the ratios of aromaticity and hydrophobicity first increased, and then were maintained at relatively stable levels. Thus, a decade of GE improved the composition and structure of SOM in semiarid grassland soil and made it more stable. These findings provide new evidence to support the positive effects of long-term GE on soil SOC sequestration in the Inner Mongolian grasslands, in view of the improvement of SOM structure and stability. PMID- 26057250 TI - High-Throughput, Amplicon-Based Sequencing of the CREBBP Gene as a Tool to Develop a Universal Platform-Independent Assay. AB - High-throughput sequencing technologies are widely used to analyse genomic variants or rare mutational events in different fields of genomic research, with a fast development of new or adapted platforms and technologies, enabling amplicon-based analysis of single target genes or even whole genome sequencing within a short period of time. Each sequencing platform is characterized by well defined types of errors, resulting from different steps in the sequencing workflow. Here we describe a universal method to prepare amplicon libraries that can be used for sequencing on different high-throughput sequencing platforms. We have sequenced distinct exons of the CREB binding protein (CREBBP) gene and analysed the output resulting from three major deep-sequencing platforms. platform-specific errors were adjusted according to the result of sequence analysis from the remaining platforms. Additionally, bioinformatic methods are described to determine platform dependent errors. Summarizing the results we present a platform-independent cost-efficient and timesaving method that can be used as an alternative to commercially available sample-preparation kits. PMID- 26057251 TI - FabV/Triclosan Is an Antibiotic-Free and Cost-Effective Selection System for Efficient Maintenance of High and Medium-Copy Number Plasmids in Escherichia coli. AB - Antibiotic resistance genes and antibiotics are frequently used to maintain plasmid vectors in bacterial hosts such as Escherichia coli. Due to the risk of spread of antibiotic resistance, the regulatory authorities discourage the use of antibiotic resistance genes/antibiotics for the maintenance of plasmid vectors in certain biotechnology applications. Overexpression of E. coli endogenous fabI gene and subsequent selection on Triclosan has been proposed as a practical alternative to traditional antibiotic selection systems. Unfortunately, overexpression of fabI cannot be used to select medium-copy number plasmids, typically used for the expression of heterologous proteins in E. coli. Here we report that Vibrio cholera FabV, a functional homologue of E. coli FabI, can be used as a suitable marker for the selection and maintenance of both high and medium-copy number plasmid vectors in E. coli. PMID- 26057252 TI - Ligand-Induced Proton Transfer and Low-Barrier Hydrogen Bond Revealed by X-ray Crystallography. AB - Ligand binding can change the pKa of protein residues and influence enzyme catalysis. Herein, we report three ultrahigh resolution X-ray crystal structures of CTX-M beta-lactamase, directly visualizing protonation state changes along the enzymatic pathway: apo protein at 0.79 A, precovalent complex with nonelectrophilic ligand at 0.89 A, and acylation transition state (TS) analogue at 0.84 A. Binding of the noncovalent ligand induces a proton transfer from the catalytic Ser70 to the negatively charged Glu166, and the formation of a low barrier hydrogen bond (LBHB) between Ser70 and Lys73, with a length of 2.53 A and the shared hydrogen equidistant from the heteroatoms. QM/MM reaction path calculations determined the proton transfer barrier to be 1.53 kcal/mol. The LBHB is absent in the other two structures although Glu166 remains neutral in the covalent complex. Our data represents the first X-ray crystallographic example of a hydrogen engaged in an enzymatic LBHB, and demonstrates that desolvation of the active site by ligand binding can provide a protein microenvironment conducive to LBHB formation. It also suggests that LBHBs may contribute to stabilization of the TS in general acid/base catalysis together with other preorganized features of enzyme active sites. These structures reconcile previous experimental results suggesting alternatively Glu166 or Lys73 as the general base for acylation, and underline the importance of considering residue protonation state change when modeling protein-ligand interactions. Additionally, the observation of another LBHB (2.47 A) between two conserved residues, Asp233 and Asp246, suggests that LBHBs may potentially play a special structural role in proteins. PMID- 26057254 TI - Pyrethroid insecticide exposure and cognitive developmental disabilities in children: The PELAGIE mother-child cohort. AB - Pyrethroid insecticides are widely used in agriculture and in homes. Despite the neurotoxicity of these insecticides at high doses, few studies have examined whether lower-level exposures could adversely affect children's neurodevelopment. The PELAGIE cohort included 3421 pregnant women from Brittany, France between 2002 and 2006. When their children reached their sixth birthday, 428 mothers from the cohort were randomly selected, successfully contacted and found eligible. A total of 287 (67%) mothers agreed to participate with their children in the neuropsychological follow-up. Two cognitive domains were assessed by the Wechsler Intelligence Scale for Children: verbal comprehension and working memory. Five pyrethroid and two organophosphate insecticide metabolites were measured in maternal and child first-void urine samples collected between 6 and 19 gestational weeks and at 6years of age, respectively. Linear regression models were used to estimate associations between cognitive scores and urinary pyrethroid metabolite concentrations, adjusting for organophosphate metabolite concentrations and potential confounders. Maternal prenatal pyrethroid metabolite concentrations were not consistently associated with any children's cognitive scores. By contrast, childhood 3-PBA and cis-DBCA concentrations were both negatively associated with verbal comprehension scores (P-trend=0.04 and P trend<0.01, respectively) and with working memory scores (P-trend=0.05 and P trend<0.01, respectively). No associations were observed for the three other childhood pyrethroid metabolite concentrations (4-F-3-PBA, cis-DCCA, and trans DCCA). Low-level childhood exposures to deltamethrin (as cis-DBCA is its principal and selective metabolite), in particular, and to pyrethroid insecticides, in general (as reflected in levels of the 3-PBA metabolite) may negatively affect neurocognitive development by 6years of age. Whatever their etiology, these cognitive deficits may be of importance educationally, because cognitive impairments in children interfere with learning and social development. Potential causes that can be prevented are of paramount public health importance. PMID- 26057253 TI - A Lipid Transfer Protein Increases the Glutathione Content and Enhances Arabidopsis Resistance to a Trichothecene Mycotoxin. AB - Fusarium head blight (FHB) or scab is one of the most important plant diseases worldwide, affecting wheat, barley and other small grains. Trichothecene mycotoxins such as deoxynivalenol (DON) accumulate in the grain, presenting a food safety risk and health hazard to humans and animals. Despite considerable breeding efforts, highly resistant wheat or barley cultivars are not available. We screened an activation tagged Arabidopsis thaliana population for resistance to trichothecin (Tcin), a type B trichothecene in the same class as DON. Here we show that one of the resistant lines identified, trichothecene resistant 1 (trr1) contains a T-DNA insertion upstream of two nonspecific lipid transfer protein (nsLTP) genes, AtLTP4.4 and AtLTP4.5. Expression of both nsLTP genes was induced in trr1 over 10-fold relative to wild type. Overexpression of AtLTP4.4 provided greater resistance to Tcin than AtLTP4.5 in Arabidopsis thaliana and in Saccharomyces cerevisiae relative to wild type or vector transformed lines, suggesting a conserved protection mechanism. Tcin treatment increased reactive oxygen species (ROS) production in Arabidopsis and ROS stain was associated with the chloroplast, the cell wall and the apoplast. ROS levels were attenuated in Arabidopsis and in yeast overexpressing AtLTP4.4 relative to the controls. Exogenous addition of glutathione and other antioxidants enhanced resistance of Arabidopsis to Tcin while the addition of buthionine sulfoximine, an inhibitor of glutathione synthesis, increased sensitivity, suggesting that resistance was mediated by glutathione. Total glutathione content was significantly higher in Arabidopsis and in yeast overexpressing AtLTP4.4 relative to the controls, highlighting the importance of AtLTP4.4 in maintaining the redox state. These results demonstrate that trichothecenes cause ROS accumulation and overexpression of AtLTP4.4 protects against trichothecene-induced oxidative stress by increasing the glutathione-based antioxidant defense. PMID- 26057256 TI - Microparticle entrapment for drug release from porous-surfaced bone implants. AB - Metallic bone implants face interfacial concerns, such as infection and insufficient bone formation. Combination of drug-loaded microparticles with the implant surface is a promising approach to reducing the concerns. The present study reports a simple method for this purpose. Drug-loaded chitosan and alginate microparticles were separately prepared by emulsion methods. Dry microparticles were introduced into porous titanium (Ti) coatings on Ti discs, and induced to agglomerate in pores by wetting with water. Agglomerates were stably entrapped in the pores: 77-82% retained in the coating after immersion in a water bath for 7 d. Discs carrying drug-loaded microparticles showed a rapid release within 6 h and a subsequent slow release up to 1 d. After coculture with Staphylococcus epidermidis for 24 h, the discs formed inhibition zones, confirming antibacterial properties. These suggest that the microparticle entrapment-based method is a promising method for reducing some of the bone-implant interfacial concerns. PMID- 26057255 TI - Long-term effects of elemental composition of particulate matter on inflammatory blood markers in European cohorts. AB - BACKGROUND: Epidemiological studies have associated long-term exposure to ambient particulate matter with increased mortality from cardiovascular and respiratory disorders. Systemic inflammation is a plausible biological mechanism behind this association. However, it is unclear how the chemical composition of PM affects inflammatory responses. OBJECTIVES: To investigate the association between long term exposure to elemental components of PM and the inflammatory blood markers high-sensitivity C-reactive protein (hsCRP) and fibrinogen as part of the European ESCAPE and TRANSPHORM multi-center projects. METHODS: In total, 21,558 hsCRP measurements and 17,428 fibrinogen measurements from cross-sections of five and four cohort studies were available, respectively. Residential long-term concentrations of particulate matter <10MUm (PM10) and <2.5MUm (PM2.5) in diameter and selected elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, zinc) were estimated based on land-use regression models. Associations between components and inflammatory markers were estimated using linear regression models for each cohort separately. Cohort-specific results were combined using random effects meta-analysis. As a sensitivity analysis the models were additionally adjusted for PM mass. RESULTS: A 5ng/m(3) increase in PM2.5 copper and a 500ng/m(3) increase in PM10 iron were associated with a 6.3% [0.7; 12.3%] and 3.6% [0.3; 7.1%] increase in hsCRP, respectively. These associations between components and fibrinogen were slightly weaker. A 10ng/m(3) increase in PM2.5 zinc was associated with a 1.2% [0.1; 2.4%] increase in fibrinogen; confidence intervals widened when additionally adjusting for PM2.5. CONCLUSIONS: Long-term exposure to transition metals within ambient particulate matter, originating from traffic and industry, may be related to chronic systemic inflammation providing a link to long-term health effects of particulate matter. PMID- 26057257 TI - Hybrid palm-oil/styrene-maleimide nanoparticles synthesized in aqueous dispersion under different conditions. AB - Poly(styrene-co-maleic anhydride) was imidized with ammonium hydroxide and palm oil, resulting in an aqueous dispersion of hybrid nanoparticles with diameters 85 180 nm (dispersed) or 20-50 nm (dried). The reaction conditions were optimized for different precursors by evaluating the relative amount ammonium hydroxide and maximizing the incorporated palm oil up to 70 wt.%. The interactions between palm oil and polymer phase have been studied by TEM, IR, Raman spectroscopy and thermal analysis (TGA, [TM] DSC). From Raman spectra, the amount of imide and reacted oil were quantified. Through concurring effects of imidization and coupling of fatty acids, the imidization needs a slight excess of NH3 relatively to maleic anhydride. The oxidative stability highly depends on oxidative crosslinking of free or non-reacted oil. Comparing the imide content from spectroscopic and thermal analysis suggests that a complex rigid imide phase without strong relaxation behavior has formed in combination with oil. PMID- 26057258 TI - EXUDATIVE RETINAL DETACHMENT AS THE PRESENTING FEATURE OF TUBEROUS SCLEROSIS COMPLEX. AB - PURPOSE: To report a case of exudative retinal detachment as the presenting feature of tuberous sclerosis complex. METHODS: A 14-year-old girl presented with loss of vision in the right eye for 1 month. Visual acuity was no perception of light in the right eye and 20/20 in the left eye. Clinical examination, fundus fluorescein angiography, spectral domain optical coherence tomography, and ultrasound B-scan was performed along with complete systemic evaluation. RESULTS: On examination, the right eye had an exudative retinal detachment and the left eye had multiple lesions suggestive of retinal astrocytic hamartomas. Ultrasonography of the right eye revealed a total retinal detachment with subretinal exudates and an acoustically solid mass lesion in the inferonasal quadrant, whereas that of the left eye detected a small mass in inferonasal quadrant. Fundus fluorescein angiography of the left eye revealed staining in the late phase in the lesions. Spectral domain optical coherence tomography taken through the lesion demonstrated an elevated lesion with high reflectivity arising from inner retinal layers and causing backshadowing. On systemic examination, she had multiple skin colored bumps on cheeks and nose and multiple hypomelanotic macules on lower legs. Contrast-enhanced magnetic resonance imaging brain revealed features suggestive of multiple cortical tubers. Contrast-enhanced magnetic resonance imaging orbits showed a T2-hypointense nodule in the right globe medially with intense postcontrast enhancement, and contrast-enhanced magnetic resonance imaging abdomen detected multiple renal cysts suggestive of angiomyolipoma. CONCLUSION: Retinal astrocytic hamartomas in association with tuberous sclerosis complex is considered to be a relatively stationary lesion that has little potential for aggressive behavior. In rare instances, however, a retinal astrocytic hamartomas can show progressive growth and cause exudative retinal detachment. PMID- 26057260 TI - Degradation of pharmaceutical compounds in water by non-thermal plasma treatment. AB - Pharmaceutical compounds became an important class of water pollutants due to their increasing consumption over the last years, as well as due to their persistence in the environment. Since conventional waste water treatment plants are unable to remove certain non-biodegradable pharmaceuticals, advanced oxidation processes was extensively studied for this purpose. Among them, non thermal plasma was also recently investigated and promising results were obtained. This work reviews the recent research on the oxidative degradation of pharmaceuticals using non-thermal plasma in contact with liquid. As target compounds, several drugs belonging to different therapeutic groups were selected: antibiotics, anticonvulsants, anxiolytics, lipid regulators, vasodilatators, contrast media, antihypertensives and analgesics. It was found that these compounds were removed from water relatively fast, partly degraded, and partly even mineralized. In order to ensure the effluent is environmentally safe it is important to identify the degradation intermediates and to follow their evolution during treatment, which requires complex chemical analysis of the solutions. Based on this analysis, degradation pathways of the investigated pharmaceuticals under plasma conditions were suggested. After sufficient plasma treatment the final organic by-products present in the solutions were mainly small molecules in an advanced oxidation state. PMID- 26057259 TI - Resting-state Functional Magnetic Resonance Imaging Correlates of Sevoflurane induced Unconsciousness. AB - BACKGROUND: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been used to study the effects of anesthetic agents on correlated intrinsic neural activity. Previous studies have focused primarily on intravenous agents. The authors studied the effects of sevoflurane, an inhaled anesthetic. METHODS: Resting-state BOLD fMRI was acquired from 10 subjects before sedation and from 9 subjects rendered unresponsive by 1.2% sevoflurane. The fMRI data were analyzed taking particular care to minimize the impact of artifact generated by head motion. RESULTS: BOLD correlations were specifically weaker within the default mode network and ventral attention network during sevoflurane induced unconsciousness, especially between anterior and posterior midline regions. Reduced functional connectivity between these same networks and the thalamus was also spatially localized to the midline frontal regions. The amplitude of BOLD signal fluctuations was substantially reduced across all brain regions. The importance of censoring epochs contaminated by head motion was demonstrated by comparative analyses. CONCLUSIONS: Sevoflurane-induced unconsciousness is associated with both globally reduced BOLD signal amplitudes and selectively reduced functional connectivity within cortical networks associated with consciousness (default mode network) and orienting to salient external stimuli (ventral attention network). Scrupulous attention to minimizing the impact of head motion artifact is critical in fMRI studies using anesthetic agents. PMID- 26057261 TI - Effect-based trigger values for in vitro bioassays: Reading across from existing water quality guideline values. AB - Cell-based bioassays are becoming increasingly popular in water quality assessment. The new generations of reporter-gene assays are very sensitive and effects are often detected in very clean water types such as drinking water and recycled water. For monitoring applications it is therefore imperative to derive trigger values that differentiate between acceptable and unacceptable effect levels. In this proof-of-concept paper, we propose a statistical method to read directly across from chemical guideline values to trigger values without the need to perform in vitro to in vivo extrapolations. The derivation is based on matching effect concentrations with existing chemical guideline values and filtering out appropriate chemicals that are responsive in the given bioassays at concentrations in the range of the guideline values. To account for the mixture effects of many chemicals acting together in a complex water sample, we propose bioanalytical equivalents that integrate the effects of groups of chemicals with the same mode of action that act in a concentration-additive manner. Statistical distribution methods are proposed to derive a specific effect-based trigger bioanalytical equivalent concentration (EBT-BEQ) for each bioassay of environmental interest that targets receptor-mediated toxicity. Even bioassays that are indicative of the same mode of action have slightly different numeric trigger values due to differences in their inherent sensitivity. The algorithm was applied to 18 cell-based bioassays and 11 provisional effect-based trigger bioanalytical equivalents were derived as an illustrative example using the 349 chemical guideline values protective for human health of the Australian Guidelines for Water Recycling. We illustrate the applicability using the example of a diverse set of water samples including recycled water. Most recycled water samples were compliant with the proposed triggers while wastewater effluent would not have been compliant with a few. The approach is readily adaptable to any water type and guideline or regulatory framework and can be expanded from the protection goal of human health to environmental protection targets. While this work constitutes a proof of principle, the applicability remains limited at present due to insufficient experimental bioassay data on individual regulated chemicals and the derived effect-based trigger values are of course only provisional. Once the experimental database is expanded and made more robust, the proposed effect-based trigger values may provide guidance in a regulatory context. PMID- 26057262 TI - Long-term continuous production of H2 in a microbial electrolysis cell (MEC) treating saline wastewater. AB - A biofilm-based 4 L two chamber microbial electrolysis cell (MEC) was continuously fed with acetate under saline conditions (35 g/L NaCl) for more than 100 days. The MEC produced a biogas highly enriched in H2 (>=90%). Both current (10.6 +/- 0.2 A/m(2)Anode or 199.1 +/- 4.0 A/m(3)MEC) and H2 production (201.1 +/ 7.5 LH2/m(2)Cathode.d or 0.9 +/- 0.0 m(3)H2/m(3)MEC.d) rates were highly significant when considering the saline operating conditions. A microbial analysis revealed an important enrichment in the anodic biofilm with five main bacterial groups: 44% Proteobacteria, 32% Bacteroidetes, 18% Firmicutes and 5% Spirochaetes and 1% Actinobacteria. Of special interest is the emergence within the Proteobacteria phylum of the recently described halophilic anode-respiring bacteria Geoalkalibacter (unk. species), with a relative abundance up to 14%. These results provide for the first time a noteworthy alternative for the treatment of saline effluents and continuous production of H2. PMID- 26057263 TI - Kinetics of ethyl paraben degradation by simulated solar radiation in the presence of N-doped TiO2 catalysts. AB - Ethyl paraben (EP), an emerging micro-pollutant representative of the parabens family, has been subject to photocatalytic degradation under simulated solar radiation at a photon flux of 1.3.10(-4) E/(m(2) s). Six nitrogen-doped titania catalysts synthesized by annealing a sol-gel derived TiO2 powder under ammonia flow and their un-doped counterparts, calcined in air at different temperatures in the range 450-800 degrees C, were compared under solar and visible light and the most active one (N-doped TiO2 calcined at 600 degrees C) was used for further tests. Experiments were performed at EP concentrations between 150 and 900 MUg/L, catalyst loadings between 100 and 1000 mg/L, pH between 3 and 9, different matrices (ultrapure water, water spiked with humic acids or bicarbonates, drinking water and secondary treated wastewater) and hydrogen peroxide between 10 and 100 mg/L. For EP concentrations up to 300 MUg/L, the degradation rate can be approached by first order kinetics but then shifts to lower order as the concentration increases. The rate increases linearly with catalyst loading up to 750 mg/L and hydrogen peroxide up to 100 mg/L. Near neutral (pH = 6.5-7.5) and alkaline conditions (pH = 9) do not affect degradation, which is reduced at acidic pH. The presence of humic acids at 10-20 mg/L impedes degradation due to the competition with EP for the oxidizing species and this is more pronounced in actual wastewater matrices. UPLC-ESI-HRMS and HPLC DAD were employed to follow EP concentration changes, as well as identify and quantify transformation by-products during the early stages of the reaction. Five such products were successfully detected and, based on their concentration-time profiles, a reaction network for the degradation of EP is proposed. Hydroxyl radical reactions appear to prevail during the initial steps as evidenced by the rapid formation of hydroxylated and dealkylated intermediates. PMID- 26057264 TI - Direct contact membrane distillation for the concentration of saline dairy effluent. AB - The ability of direct contact membrane distillation to concentrate the waste effluent from salty whey, a by-product from the cheese making industry has been investigated. The effect of trace protein in the feed, cross-flow velocity and feed acidity were the factors examined. Flat Sheet PTFE membranes of nominal pore sizes 0.05, 0.22 and 0.45 MUm were utilised. A decline in feed flux in the presence of trace protein in the feed was observed, but liquid penetration through the membrane could still be prevented by utilization of a membrane of smaller pore size, to achieve a final total solids concentration of +/-30% w/w with water recovery from 37 to 83 %. The pressure-drop across the channel length was also predicted accounting for the feed spacer. To increase the channel length up to 1 m will require operation using the smallest pore size of 0.05 MUm, unless very low cross-flow velocities are used. The fouling of the membrane is primarily governed by precipitation of a calcium phosphate salt. However, operation at low pH does not improve the flux or the final salt concentration significantly. PMID- 26057267 TI - AL 3: Laszlo Moholy-Nagy. PMID- 26057268 TI - Advanced prosthetics provide more functional limbs. PMID- 26057269 TI - The "doc fix" is over, but unresolved concerns linger. PMID- 26057276 TI - The ADA and the Supreme Court: a mixed record. PMID- 26057277 TI - Impaired physicians and the ADA. PMID- 26057278 TI - Innovations of the Americans with Disabilities Act: confronting disability discrimination in employment. PMID- 26057279 TI - The promise of the Americans with Disabilities Act for people with mental illness. PMID- 26057280 TI - Why the Americans with Disabilities Act Matters for genetics. PMID- 26057281 TI - The ADA, disability, and identity. PMID- 26057282 TI - A piece of my mind. Assuming the worst. PMID- 26057283 TI - The Americans with Disabilities Act at 25: the highest expression of American values. PMID- 26057284 TI - Traumatic spinal cord injury in the United States, 1993-2012. AB - IMPORTANCE: Acute traumatic spinal cord injury results in disability and use of health care resources, yet data on contemporary national trends of traumatic spinal cord injury incidence and etiology are limited. OBJECTIVE: To assess trends in acute traumatic spinal cord injury incidence, etiology, mortality, and associated surgical procedures in the United States from 1993 to 2012. DESIGN, SETTING, AND PARTICIPANTS: Analysis of survey data from the US Nationwide Inpatient Sample databases for 1993-2012, including a total of 63,109 patients with acute traumatic spinal cord injury. MAIN OUTCOMES AND MEASURES: Age- and sex stratified incidence of acute traumatic spinal cord injury; trends in etiology and in-hospital mortality of acute traumatic spinal cord injury. RESULTS: In 1993, the estimated incidence of acute spinal cord injury was 53 cases (95% CI, 52-54 cases) per 1 million persons based on 2659 actual cases. In 2012, the estimated incidence was 54 cases (95% CI, 53-55 cases) per 1 million population based on 3393 cases (average annual percentage change, 0.2%; 95% CI, -0.5% to 0.9%). Incidence rates among the younger male population declined from 1993 to 2012: for age 16 to 24 years, from 144 cases/million (2405 cases) to 87 cases/million (1770 cases) (average annual percentage change, -2.5%; 95% CI, 3.3% to -1.8%); for age 25 to 44 years, from 96 cases/million (3959 cases) to 71 cases/million persons (2930 cases), (average annual percentage change, -1.2%; 95% CI, -2.1% to -0.3%). A high rate of increase was observed in men aged 65 to 74 years (from 84 cases/million in 1993 [695 cases] to 131 cases/million [1465 cases]; average annual percentage change, 2.7%; 95% CI, 2.0%-3.5%). The percentage of spinal cord injury associated with falls increased significantly from 28% (95% CI, 26%-30%) in 1997-2000 to 66% (95% CI, 64%-68%) in 2010-2012 in those aged 65 years or older (P < .001). Although overall in-hospital mortality increased from 6.6% (95% CI, 6.1%-7.0%) in 1993-1996 to 7.5% (95% CI, 7.0%-8.0%) in 2010-2012 (P < .001), mortality decreased significantly from 24.2% (95% CI, 19.7%-28.7%) in 1993-1996 to 20.1% (95% CI, 17.0%-23.2%) in 2010-2012 (P = .003) among persons aged 85 years or older. CONCLUSIONS AND RELEVANCE: Between 1993 and 2012, the incidence rate of acute traumatic spinal cord injury remained relatively stable but, reflecting an increasing population, the total number of cases increased. The largest increase in incidence was observed in older patients, largely associated with an increase in falls, and in-hospital mortality remained high, especially among elderly persons. PMID- 26057285 TI - Intuitive control of a powered prosthetic leg during ambulation: a randomized clinical trial. AB - IMPORTANCE: Some patients with lower leg amputations may be candidates for motorized prosthetic limbs. Optimal control of such devices requires accurate classification of the patient's ambulation mode (eg, on level ground or ascending stairs) and natural transitions between different ambulation modes. OBJECTIVE: To determine the effect of including electromyographic (EMG) data and historical information from prior gait strides in a real-time control system for a powered prosthetic leg capable of level-ground walking, stair ascent and descent, ramp ascent and descent, and natural transitions between these ambulation modes. DESIGN, SETTING, AND PARTICIPANTS: Blinded, randomized crossover clinical trial conducted between August 2012 and November 2013 in a research laboratory at the Rehabilitation Institute of Chicago. Participants were 7 patients with unilateral above-knee (n = 6) or knee-disarticulation (n = 1) amputations. All patients were capable of ambulation within their home and community using a passive prosthesis (ie, one that does not provide external power). INTERVENTIONS: Electrodes were placed over 9 residual limb muscles and EMG signals were recorded as patients ambulated and completed 20 circuit trials involving level-ground walking, ramp ascent and descent, and stair ascent and descent. Data were acquired simultaneously from 13 mechanical sensors embedded on the prosthesis. Two real time pattern recognition algorithms, using either (1) mechanical sensor data alone or (2) mechanical sensor data in combination with EMG data and historical information from earlier in the gait cycle, were evaluated. The order in which patients used each configuration was randomized (1:1 blocked randomization) and double-blinded so patients and experimenters did not know which control configuration was being used. MAIN OUTCOMES AND MEASURES: The main outcome of the study was classification error for each real-time control system. Classification error is defined as the percentage of steps incorrectly predicted by the control system. RESULTS: Including EMG signals and historical information in the real time control system resulted in significantly lower classification error (mean, 7.9% [95% CI, 6.1%-9.7%]) across a mean of 683 steps (range, 640-756 steps) compared with using mechanical sensor data only (mean, 14.1% [95% CI, 9.3% 18.9%]) across a mean of 692 steps (range, 631-775 steps), with a mean difference between groups of 6.2% (95% CI, 2.7%-9.7%] (P = .01). CONCLUSIONS AND RELEVANCE: In this study of 7 patients with lower limb amputations, inclusion of EMG signals and temporal gait information reduced classification error across ambulation modes and during transitions between ambulation modes. These preliminary findings, if confirmed, have the potential to improve the control of powered leg prostheses. PMID- 26057286 TI - Association of MCAT scores obtained with standard vs extra administration time with medical school admission, medical student performance, and time to graduation. AB - IMPORTANCE: Individuals with documented disabilities may receive accommodations on the Medical College Admission Test (MCAT). Whether such accommodations are associated with MCAT scores, medical school admission, and medical school performance is unclear. OBJECTIVE: To determine the comparability of MCAT scores obtained with standard vs extra administration time with respect to likelihood of acceptance to medical school and future medical student performance. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of applicants to US medical schools for the 2011-2013 entering classes who reported MCAT scores obtained with standard time (n = 133,962) vs extra time (n = 435), and of students who matriculated in US medical schools from 2000-2004 who reported MCAT scores obtained with standard time (n = 76,262) vs extra time (n = 449). EXPOSURES: Standard or extra administration time during MCAT. MAIN OUTCOMES AND MEASURES: Primary outcome measures were acceptance rates at US medical schools and graduation rates within 4 or 5 years after matriculation. Secondary outcome measures were pass rates on the United States Medical Licensing Examination (USMLE) Step examinations and graduation rates within 6 to 8 years after matriculation. RESULTS: Acceptance rates were not significantly different for applicants who had MCAT scores obtained with standard vs extra time (44.5% [59,585/133,962] vs 43.9% [191/435]; difference, 0.6% [95% CI, -4.1 to 5.3]). Students who tested with extra time passed the Step examinations on first attempt at significantly lower rates (Step 1, 82.1% [344/419] vs 94.0% [70,188/74,668]; difference, 11.9% [95% CI, 9.6% to 14.2%]; Step 2 CK, 85.5% [349/408] vs 95.4% [70,476/73,866]; difference, 9.9% [95% CI, 7.8% to 11.9%]; Step 2 CS, 92.0% [288/313] vs 97.0% [60,039/61,882]; difference, 5.0% [95% CI, 3.1% to 6.9%]). They also graduated from medical school at significantly lower rates at different times (4 years, 67.2% [285/424] vs 86.1% [60,547/70,305]; difference, 18.9% [95% CI, 15.6% to 22.2%]; 5 years, 81.6% [346/424] vs 94.4% [66,369/70,305]; difference, 12.8% [95% CI, 10.6% to 15.0%]; 6 years, 85.4% [362/424] vs 95.8% [67,351/70,305]; difference, 10.4% [95% CI, 8.5% to 12.4%]; 7 years, 88.0% [373/424] vs 96.2% [67,639/70,305]; difference, 8.2% [95% CI, 6.4% to 10.1%]; 8 years, 88.4% [375/424] vs 96.5% [67,847/70,305]; difference, 8.1% [95% CI, 6.3% to 9.8%]). These differences remained after controlling for MCAT scores and undergraduate grade point averages. CONCLUSIONS AND RELEVANCE: Among applicants to US medical schools, those with MCAT scores obtained with extra test administration time, compared with standard administration time, had no significant difference in rate of medical school admission but had lower rates of passing the USMLE Step examinations and of medical school graduation within 4 to 8 years after matriculation. These findings raise questions about the types of learning environments and support systems needed by students who test with extra time on the MCAT to enable them to succeed in medical school. PMID- 26057287 TI - Nonalcoholic fatty liver disease: a systematic review. AB - IMPORTANCE: Nonalcoholic fatty liver disease and its subtype nonalcoholic steatohepatitis affect approximately 30% and 5%, respectively, of the US population. In patients with nonalcoholic steatohepatitis, half of deaths are due to cardiovascular disease and malignancy, yet awareness of this remains low. Cirrhosis, the third leading cause of death in patients with nonalcoholic fatty liver disease, is predicted to become the most common indication for liver transplantation. OBJECTIVES: To illustrate how to identify patients with nonalcoholic fatty liver disease at greatest risk of nonalcoholic steatohepatitis and cirrhosis; to discuss the role and limitations of current diagnostics and liver biopsy to diagnose nonalcoholic steatohepatitis; and to provide an outline for the management of patients across the spectrum of nonalcoholic fatty liver disease. EVIDENCE REVIEW: PubMed was queried for published articles through February 28, 2015, using the search terms NAFLD and cirrhosis, mortality, biomarkers, and treatment. A total of 88 references were selected, including 16 randomized clinical trials, 44 cohort or case-control studies, 6 population-based studies, and 7 meta-analyses. FINDINGS: Sixty-six percent of patients older than 50 years with diabetes or obesity are thought to have nonalcoholic steatohepatitis with advanced fibrosis. Even though the ability to identify the nonalcoholic steatohepatitis subtype within those with nonalcoholic fatty liver disease still requires liver biopsy, biomarkers to detect advanced fibrosis are increasingly reliable. Lifestyle modification is the foundation of treatment for patients with nonalcoholic steatosis. Available treatments with proven benefit include vitamin E, pioglitazone, and obeticholic acid; however, the effect size is modest (<50%) and none is approved by the US Food and Drug Administration. The association between nonalcoholic steatohepatitis and cardiovascular disease is clear, though causality remains to be proven in well-controlled prospective studies. The incidence of nonalcoholic fatty liver disease-related hepatocellular carcinoma is increasing and up to 50% of cases may occur in the absence of cirrhosis. CONCLUSIONS AND RELEVANCE: Between 75 million and 100 million individuals in the United States are estimated to have nonalcoholic fatty liver disease and its potential morbidity extends beyond the liver. It is important that primary care physicians, endocrinologists, and other specialists be aware of the scope and long-term effects of the disease. Early identification of patients with nonalcoholic steatohepatitis may help improve patient outcomes through treatment intervention, including transplantation for those with decompensated cirrhosis. PMID- 26057288 TI - Insulin dosing in pediatric diabetic ketoacidosis: where to start? PMID- 26057289 TI - Nonsteroidal anti-inflammatory drugs for treatment of acute gout. AB - CLINICAL QUESTION: Are nonsteroidal anti-inflammatory drugs (NSAIDs) associated with better outcomes than cyclooxygenase inhibitors, glucocorticoids, IL-1 inhibitors or placebo in the treatment of acute gout? BOTTOM LINE: NSAIDs are not significantly associated with a difference in pain reduction compared with cyclooxygenase inhibitors and glucocorticoids for treating acute gout. However, NSAIDs are associated with higher rates of adverse events and higher rates of withdrawal due to adverse events compared with cyclooxygenase inhibitors. PMID- 26057290 TI - Pulmonary function tests for diagnosing lung disease. PMID- 26057291 TI - Acute gastroenteritis hospitalizations among US children following implementation of the rotavirus vaccine. PMID- 26057292 TI - Varenicline for smoking reduction prior to cessation. PMID- 26057293 TI - Varenicline for smoking reduction prior to cessation. PMID- 26057294 TI - Varenicline for smoking reduction prior to cessation--reply. PMID- 26057295 TI - Chronic care management for Medicare patients. PMID- 26057296 TI - Chronic care management for Medicare patients--reply. PMID- 26057297 TI - Incorrect data for absolute rates of adverse effects. PMID- 26057298 TI - Incorrect outcomes data. PMID- 26057299 TI - Incorrect description for basis of household income. PMID- 26057301 TI - The employment and placement of handicapped persons in industry. PMID- 26057302 TI - JAMA patient page. The Americans with Disabilities Act. PMID- 26057303 TI - Highly Conductive Diamond-Graphite Nanohybrid Films with Enhanced Electron Field Emission and Microplasma Illumination Properties. AB - Bias-enhanced nucleation and growth of diamond-graphite nanohybrid (DGH) films on silicon substrates by microwave plasma enhanced chemical vapor deposition using CH4/N2 gas mixture is reported herein. It is observed that by controlling the growth time, the microstructure of the DGH films and, thus, the electrical conductivity and the electron field emission (EFE) properties of the films can be manipulated. The films grown for 30 min (DGHB30) possess needle-like geometry, which comprised of a diamond core encased in a sheath of sp(2)-bonded graphitic phase. These films achieved high conductivity of sigma = 900 S/cm and superior EFE properties, namely, low turn-on field of 2.9 V/MUm and high EFE current density of 3.8 mA/cm(2) at an applied field of 6.0 V/MUm. On increasing the growth time to 60 min (the DGHB60), the acicular grain growth ceased and formed nanographite clusters or defective diamond clusters (n-diamond). Even though DGHB60 films possess higher electrical conductivity (sigma = 1549 S/cm) than the DGHB30 films, the EFE properties degraded. The implication of this result is that higher conductivity by itself does not guarantee better EFE properties. The nanosized diamond grains with needle-like geometry are the most promising ones for the electron emission, exclusively when they are encased in graphene-like layers. The salient feature of such materials with unique granular structure is that their conductivity and EFE properties can be tuned in a wide range, which makes them especially useful in practical applications. PMID- 26057306 TI - Ethical Overview of Placebo Control in Psychiatric Research - Concepts and Challenges. AB - Permissibility of placebo controls in psychiatric research is raising everlasting controversies. The main ethical issue remains: whether, when, under what conditions, and to what extent is it justifiable to disregard subject's present (best) interest for the presumably "greater" ones. In relation to this main ethical concern, two distinct arguments arose: proponents of placebo controls trials (placebo ortxodoxy) and proponents of active controls trials (active control orthodoxy). More recently, in new ethical guidelines, Declaration of Helsinki and International Ethical Guidelines for Biomedical Research Involving Human Subjects, a "middle way" approach was formulated, acceptable to both sides of the argument, saying placebo controls can be justified under certain conditions: when and only when, they firstly present undisputed methodological reasoning, and secondly, fulfill certain ethical considerations - mainly regarding the permissibility of accompanied risks. These ethical evaluations are inevitably contextual and evoke the need for the principle of proportionality. In scope of recent findings of substantial and progressively increasing placebo response in psychiatric research, contextual factors are identified and both theoretical and practical challenges are discussed. PMID- 26057304 TI - Attitudes Towards PrEP and Anticipated Condom Use Among Concordant HIV-Negative and HIV-Discordant Male Couples. AB - Since the July 2012 approval by the FDA of emtricitabine/ tenofovir disoproxil fumarate (Truvada) for use as pre-exposure prophylaxis (PrEP) against HIV, its feasibility and acceptability has been under study. HIV-discordant couples are likely targets for PrEP but little is known about how this new prevention tool impacts relationships. We examined, among gay male couples, the acceptability of individual and partner use of PrEP and intentions to use condoms with primary and outside partners in the context of PrEP use. Data are from two independent samples of couples recruited in the San Francisco bay area and New York City-a qualitative one (N=48 couples) between March and November, 2011, and a quantitative one (N=171 couples) between June, 2012 and May, 2013. Data were categorized by couple HIV status and general linear models; chi-square tests of independence were used to examine condom-use intentions with primary and outside partners, by sexual risk profile, and race. Almost half of the HIV-negative couples felt PrEP was a good HIV prevention strategy for themselves and their partner. Over half reported that they would not change their current condom use if they or their partner were taking PrEP. However, approximately 30% of HIV negative couples reported that they would stop using condoms or use them less with primary and outside partners if they were on PrEP or if their partner was on PrEP. A large percentage of couples view PrEP positively. However, to ensure safety for both partners, future programing must consider those who intend not to use condoms while on PrEP. PMID- 26057307 TI - Boredom, dopamine, and the thrill of psychosis: psychiatry in a new key. AB - Medication non-adherence is a great challenge in the treatment of psychotic disorders. Several factors leading to medication non-adherence in schizophrenia have been identified: drug side-effects, lack of illness insight, negative attitude of the patient and friends/relatives toward medication, stigma of mental illness and taking medication, poor therapeutic alliance, substance abuse, and role of the illness in maintaining the family system. In this work I propose a new vista on the phenomenon of medication non-adherence in psychosis. Rather rule than exception, non-adherence is to be expected in psychosis, it can be considered as a symptom of psychosis similarly as substance craving and use are symptoms of the substance use disorders. Relying on the last refinements of the concepts of boredom, anticipatory anhedonia, intrinsic motivation, and thrill I assume that there is a lure of psychotic episode. In order to escape an extremely unpleasant and distressing experience of boredom and to experience the thrill of psychosis, the patients are prone to quit antipsychotic therapy. The phenomena of boredom and the thrill of psychosis are evident but unexploited for strengthening the therapeutic adherence. Making the lure of psychosis an explicit reason for medication non-adherence would bring to the awareness a personal choice between short-term pleasure of the psychotic thrill and prevention of long-term losses due to a psychotic episode. Neurobiological and psychobiological underpinning of the psychotic thrill has been suggested. An explanation of the pleasure of psychosis and substance use, which overcomes the circular explanation of reward in which dopamine appears as the cause and consequence of reward, has been proposed. The present synthesis can be regarded as a contribution to the field of theoretical psychiatry. It points to a chance for psychiatry to do more for patients' wellbeing and treatment adherence performing in a new key - dealing with boredom and pleasure in patients' everyday life. PMID- 26057308 TI - Suicide and the conflicted soldier: a view from psychodiagnomics. AB - BACKGROUND: To move beyond the traditional, cross-sectional, ontogenetic, biopsychosocial, diagnostic formulation of suicide. METHOD: Analysis of media reports, principally via Highbeam Research, of a noted case of a sudden and unexpected military suicide: Jacob Kovco. RESULTS: Ontogenetic diagnostic analysis, centering on the person, was successfully amplified by diagnostic analysis of time and place, in the cultural and historical, phylogenetic domain. It revealed an occult, dissociative depression. This method is called psychodiagnomics. CONCLUSION: Ontogenetic analysis of suicide, especially biomedical analysis must be complemented by ontogenetic and phylogenetic analysis in the socio-cultural domains. PMID- 26057309 TI - Pain manifestations in schizophrenia - clinical and experimental aspects in human patients and animal models. AB - Pain is a subjective phenomenon, not fully understood, which is manifesting abnormally in most of the disorders. Also, in the case of schizophrenia, a psychiatric disorder marked by gross distortion from reality, disturbances in thinking, feeling and behavior, pain behaves in an unpredictable manner, just like the evolution of this mental disorder. In this way, findings on this matter are contradictory, some pleading for decreased pain perception in schizophrenia, others for increased pain sensitivity, while there are also reports stating no differences between healthy controls and schizophrenic patients. Still, it is now generally accepted that pain perception is impaired in various ways in schizophrenics. Nevertheless, pain is a very important clinical issue in this population that needs to be clarified. Throughout this paper, we are going to review these contradictory information regarding pain manifestations in the context of schizophrenia in both human patients and animal models, emphasizing the importance of determining pain mechanism, its particularities and evolution in the context of schizophrenic disease, so that this phenomenon could be evaluated, quantified and controlled with the intention of obtaining a superior management for this disorder and to possibly raise hopes of higher life quality and expectancy in patients suffering from schizophrenia. Also, we would like to raise awareness on this matter, making psychiatrists, general practitioners, and other medical specialists more conscious of the importance of this problem, so that medical care could improve for these patients in the future. PMID- 26057310 TI - Pineal gland volume in schizophrenia and mood disorders. AB - BACKGROUND: The majority of patients with schizophrenia and mood disorders have disruptions in sleep and circadian rhythm. Melatonin, which is secreted by the human pineal gland, plays an important role in sleep and circadian rhythm. The aim of the present study was to evaluate and compare pineal gland volumes in patients with schizophrenia and mood disorders. SUBJECTS AND METHODS: We retrospectively evaluated the pineal gland volumes of 80 cases, including 16 cases of unipolar depression, 17 cases of bipolar disorder, 17 cases of schizophrenia, and 30 controls. The total pineal gland volume of all cases was measured via magnetic resonance images, and the total mean pineal volume of each group was compared. RESULTS: The mean pineal volumes of patients with schizophrenia, bipolar disorder, unipolar depression, and the controls were 83.55+/-10.11 mm(3), 93.62+/-11.00 mm(3), 95.19+/-11.61 mm(3) and 99.73+/-12.03 mm(3), respectively. The mean pineal gland volume of the patients with schizophrenia was significantly smaller than those of the other groups. CONCLUSIONS: Our data show that patients with schizophrenia have smaller pineal gland volumes, and this deviation in pineal gland morphology is not seen in those with mood disorders. We hypothesize that volumetric changes in the pineal gland of patients with schizophrenia may be involved in the pathophysiology of this illness. PMID- 26057311 TI - Generalized and specific emotion impairments as potential markers of severity in Obsessive-Compulsive Disorder: a preliminary study using Facial Action Coding System (FACS). AB - BACKGROUND: The role of emotional deficits in the poor outcomes of patients with Obsessive-Compulsive Disorder (OCD) has been emphasized. Generalized and specific emotional abnormalities have been reported, often related to OCD severity and functional disabilities. The objective of the present study was to assess the abilities of experiencing and displaying emotions in OCD patients in response to specific stimuli in relation with the severity of their clinical condition. SUBJECTS AND METHODS: Thirty-six individuals participated in the study: 10 OCD patients with severe symptoms, 11 with mild-moderate symptoms, and 15 healthy controls. All participants watched emotion-eliciting video clips while their facial activity was videotaped. The congruent/incongruent feeling of emotions and the facial expression in reaction to emotions were evaluated. RESULTS: The two subgroups of OCD patients presented similarly incongruent emotive feelings and facial expressions (significantly worse than healthy participants). Moreover, OCD patients with severe symptoms expressed the emotion of happiness and disgust significantly less appropriately than OCD patients with mild-moderate symptoms. CONCLUSIONS: The present data support the hypothesis that impaired emotional processing may: (i) represent a potential contributor to poor outcome in OCD; (ii) constitute a warning sign for clinicians to establish a more comprehensive protocol for more severe cases; (iii) influence therapeutic strategies used to treat this disorder. PMID- 26057312 TI - Depression and serum interleukin-6 levels in patients on dialysis. AB - BACKGROUND: Depression is a common psychiatric problem in patients undergoing dialysis. Several studies have been performed to validate the association between depression and inflammation in haemodialysis patients. The levels of proinflammatory cytokines are increased in chronic renal failure patients, as in depression. The objective of this study was to compare the incidence of depression in the patients on dialysis (on hemodialysis /HD/ and on continuous ambulatory peritoneal dialysis /CAPD/), and a relationship between depression and the presence of inflammation. SUBJECTS AND METHODS: 88 patients (52 on HD and 36 on CAPD) were enrolled in this study. Depressive symptoms were measured with the Beck Depression Inventory (BDI). The BDI is a 21-item self-report instrument, and the elevated symptoms of depression were defined as a BDI score >=16. HD patients were treated with high-flux polysulphone biocompatible dialyzers and CAPD patients were treated with usual dwell time (4-6 hours during the day and 8-10 hours at night). The presence of an inflammatory state was assesded by determinations of plasma interleukin-6 (IL-6) levels. RESULTS: Depression (BDI >=16) was present in 28.4% of dialysis patients, 35% of patients on hemodialysis (HD) and 18.1% of patients on continous ambulatory peritoneal dialysis (CAPD). The BDI score was significantly lower in CAPD patients comparing to HD patients, as well as the levels of albumin, C-reactive protein (CRP) and interleukin-6 (IL 6). IL-6 serum levels were similar in patients with depression and patients without depression in the whole group, as in HD patients. In CAPD patients without depression IL-6 levels were significantly lower. CONCLUSIONS: The prevalence of depression was higher in HD comparing to CAPD patients. Although IL 6 level was higher in HD compared to CAPD patients, the relationship between depression and presence of inflammation parametars were observed in CAPD, but not in HD patients. PMID- 26057313 TI - Effects of Twenty-four Move Shadow Boxing Combined with psychosomatic relaxation on Depression and Anxiety in Patients with Type-2 Diabetes. AB - BACKGROUND: The aim of the current study was to observe the effects of Twenty four Move Shadow Boxing combined with psychosomatic relaxation on depression and anxiety in patients with Type-2 Diabetes. SUBJECTS AND METHODS: One hundred and twenty (120) patients with Type-2 Diabetes and depressive/anxious symptoms were divided into intervention group (60 cases) and control group (60 cases) according to the minimum distribution principle of unbalanced indicators. Twenty-four Move Shadow Boxing group used this intervention combined with psychosomatic relaxation. Control group underwent conventional treatment. All the patients in the two groups completed the Self-rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) before and after treatment. RESULTS: Among the 52 people included in the statistical analysis, the recovery rate was 13.3%. The differences between depression and anxiety scores in the intervention group before and after treatment were statistically significant (P<0.001), whereas these differences were non-significant in the control group (P=0.123). After the treatment, the glycated hemoglobin reduction in the intervention group was greater than that of the control group (t=2.438, P=0.016). CONCLUSION: The combination of Twenty-four Move Shadow Boxing and psychosomatic relaxation has a beneficial auxiliary therapeutic effect on depression and anxiety accompanying Type-2 Diabetes. PMID- 26057314 TI - Increased neutrophil/lymphoctye ratio in patients with bipolar disorder: a preliminary study. AB - BACKGROUND: In this study, it has been aimed to investigate whether neutrophil lymphocyte ratio (NLR) was higher in non-obese patients with bipolar disorder (BD) than in a healthy control group matched for age, sex, and body mass index, and also to determine if there was an interaction between NLR and severity of the bipolar disorder. SUBJECTS AND METHODS: In this retrospective study, 103 non obese patients with BD and 126 healthy control subjects were analyzed for complete blood count. The Young Mania Rating Scale (YMRS) was used to determine the severity of the disorder. RESULTS: The NLR was higher in female patients than in female comparison subjects (3.2+/-2.2; versus 1.7+/-0.4) (p<0.001). Also, compared with the healthy male subjects, the male patients had significantly higher neutrophil/lymphocyte ratio (3.3+/-2.4; versus 2.0+/-0.7) (p<0.001). In the patients with bipolar disorder, NLR did not significantly correlate with severity (as measured with the YMRS) (r=0.052; p=0.204) and duration of the disorder (r=0.045; p=0.301). CONCLUSIONS: Results of this study revealed that patients with bipolar disorder have statistically significant elevated NRL than healthy compares. According to this finding, elevated levels of NLR may be involved in inflammatory pathophysiology of bipolar disorder. Further studies are needed for a better understanding of the mechanism between elevation of NRL in patients with bipolar disorder. PMID- 26057315 TI - Numbers of early career psychiatrists vary markedly among European countries. AB - In the field of psychiatry the decline of recruitment and brain-drain are currently one of the most discussed topics among stakeholders on national and European level. Even though comprehensive data on psychiatric training in Europe have been already reported, no data are available on even the approximate number of early career psychiatrists (ECPs). With this objective in mind, the Early Career Psychiatrists Committee of the European Psychiatric Association (EPAECPC) and the European Federation of Psychiatric Trainees (EFPT) have undertaken a survey. Based on the methodology used, the total number of ECPs in all European countries was 46 144 with the average number of ECPs being 5.5/100 000 country inhabitants. The actual numbers in this respect varied greatly among countries from 0.4 and 0.6 ECPs/100 000 in Azerbaijan resp. Russia; to 20.4 and 28.4 ECPs/100 000 in Norway resp. Switzerland. An obvious East-West gradient with increasing numbers of ECPs when moving from East to West, and from South to North were found, mirroring the economic strength of European countries. This is the first study to specifically explore the number of ECPs across Europe which might have key implications for planning and establishing recruitment activities and for developing strategies for prevention of brain-drain, such as improvement of educational system and enlargement of professional opportunities. PMID- 26057316 TI - Depression and circadian typology. AB - BACKGROUND: The relationship between circadian disruptions and depressive disorders is a topic of great interest in contemporary psychiatry. Circadian rhythms include all physiological processes displaying a period around 24 hours. Sleep/wake cycles, body temperature, hormone secretion and other functions are subjected to person's individual circadian rhythm. Circadian typology includes three chronotypes: morning, neither and evening. The aim of this study was to examine the chronobiological aspects of depression. METHODS: This cross-sectional study aimed to determine circadian rhythmic expression in 60 patients suffering from depression. The patients were in remission and were treated as outpatients at the Department of Psychiatry of the University Hospital Center Zagreb. The data were compared to a control group consisting of 40 medical workers employed at the University Hospital Centre Zagreb. A self-report measure of circadian typology was utilized - the Morningness-Eveningness Questionnaire. RESULTS: According to our findings, among depressed patients 35% were morning, 58.3% neither and 6.7% evening types. In the control group 46% were morning, 48% neither and 6.0% evening types. Depressed patients reported stronger morning fatigue. Further, they tended to go to sleep earlier and felt more tired earlier in the evening, and they were less prone to choosing morning periods for completing complex cognitive tasks. CONCLUSION: This study supports the association between depression and some alterations in circadian rhythms of behavior and sleep. Depression may be considered as the consequence or trigger of circadian disturbances. However, both depression and circadian rhythm disturbances may have a common aetiology: a decreased cellular resilience associated with lower resistance to stressful events. PMID- 26057317 TI - Everlasting fire - persistent mania: a case report. PMID- 26057318 TI - Efficacy of aripiprazole in antidepressants-induced tardive dystonia and tardive dyskinesia: a case report. PMID- 26057319 TI - Low-dose clozapine therapy for a bipolar patient with abnormal levels of thyroid function and anti-thyroid antibodies. PMID- 26057320 TI - [Field studies for the ICD-11 chapter on mental disorders: information for WPA members]. PMID- 26057321 TI - Highly Efficient Photon Upconversion in Self-Assembled Light-Harvesting Molecular Systems. AB - To meet the world's demands on the development of sunlight-powered renewable energy production, triplet-triplet annihilation-based photon upconversion (TTA UC) has raised great expectations. However, an ideal highly efficient, low-power, and in-air TTA-UC has not been achieved. Here, we report a novel self-assembly approach to achieve this, which enabled highly efficient TTA-UC even in the presence of oxygen. A newly developed lipophilic 9,10-diphenylanthracene-based emitter molecule functionalized with multiple hydrogen-bonding moieties spontaneously coassembled with a triplet sensitizer in organic media, showing efficient triplet sensitization and subsequent triplet energy migration among the preorganized chromophores. This supramolecular light-harvesting system shows a high UC quantum yield of 30% optimized at low excitation power in deaerated conditions. Significantly, the UC emission largely remains even in an air saturated solution, and this approach is facilely applicable to organogel and solid-film systems. PMID- 26057322 TI - Lower Dose Infliximab for Ulcerative Colitis: How Low Can We Go and How Much Can be Saved? PMID- 26057323 TI - Cross-sectional scanning thermal microscopy of ErAs/GaAs superlattices grown by molecular beam epitaxy. AB - Scanning thermal microscopy has been implemented in a cross-sectional geometry, and its application for quantitative, nanoscale analysis of thermal conductivity is demonstrated in studies of an ErAs/GaAs nanocomposite superlattice. Spurious measurement effects, attributable to local thermal transport through air, were observed near large step edges, but could be eliminated by thermocompression bonding to an additional structure. Using this approach, bonding of an ErAs/GaAs superlattice grown on GaAs to a silicon-on-insulator wafer enabled thermal signals to be obtained simultaneously from Si, SiO2, GaAs, and ErAs/GaAs superlattice. When combined with numerical modeling, the thermal conductivity of the ErAs/GaAs superlattice measured using this approach was 11 +/- 4 W m(-1) K( 1). PMID- 26057324 TI - Distribution and Repeatability of Corneal Astigmatism Measurements (Magnitude and Axis) Evaluated With Color Light Emitting Diode Reflection Topography. AB - PURPOSE: To evaluate and investigate the distribution and repeatability of anterior corneal surface astigmatism measurements (axis and magnitude) using a novel corneal topographer. METHODS: Anterior corneal surface astigmatism was investigated in a total of 195 eyes using a novel multicolored spot reflection topographer (Cassini; i-Optics). Two patient groups were studied, a younger-age group A and an older-age group B. Three consecutive acquisitions were obtained from each eye. The repeatability of measurement was assessed using Bland-Altman plot analysis and is reported as the coefficient of repeatability. RESULTS: Group A (average age 34.3 years) had on average with-the-rule astigmatism, whereas the older-age group B (average age 72.3 years) had on average against-the-rule astigmatism. Average astigmatism magnitude measurement repeatability in group A was 0.4 diopters (D) and in group B 0.4 D. Average astigmatism axis measurement repeatability in group A was 5.4 degrees and in group B 5.5 degrees. The axis measurement repeatability improved with increasing magnitude of astigmatism: in the subgroups with astigmatism between 3.0 and 6.0 D, the axis repeatability was 1.4 degrees (group A) and 1.2 degrees (group B), whereas in the subgroups with astigmatism larger than 6.0 D, the repeatability was 1.1 and 0.6 degrees, respectively. CONCLUSIONS: This novel corneal topography device seems to offer high precision in reporting corneal astigmatism. This study reaffirms the established trend of a corneal astigmatism shift from an average "with-the-rule" to "against-the-rule" with aging. PMID- 26057325 TI - Evolution of Corneal Transplantation in the Province of Quebec From 2000 to 2011. AB - PURPOSE: The goal of this study was to determine the changes in surgical techniques and leading indications for corneal transplantations performed in the last decade. The impact of administrative changes of corneal banking in Quebec was also evaluated. METHODS: The records of all corneal transplantations performed between January 2000 and December 2011 in the territory subserved by the Quebec Eye Bank and Hema-Quebec (Quebec, Canada) were retrospectively reviewed. RESULTS: A total of 3459 corneal transplantations were performed between 2000 and 2011. The rate of corneal transplantation more than doubled from 234 grafts per year in 2000 to 592 grafts per year in 2011. Imported tissue represented 40% of grafted corneas. Increases in tissue importation were seen in 2003 and 2009 to address local tissue shortage and peaks in wait time. The average wait time decreased from 434 +/- 456 days (2000-2008) to 418 +/- 551 days (2009-2011) (P = 0.01). The leading surgical indications were Fuchs endothelial corneal dystrophy (27%), pseudophakic corneal edema (26%), keratoconus (13%), and viral keratitis (8%). Regrafts represented 25% of procedures. Descemet stripping automated endothelial keratoplasty became the preferred technique for endothelial diseases, surpassing penetrating keratoplasty in 2011. CONCLUSIONS: The surgical indications and techniques used for corneal transplantation in Quebec reflected those of the literature. However, long wait times and corneal tissue shortages mandated significant changes in the organization of the Quebec Eye Bank. Partnering with a larger agency responsible for tissue and blood donation coordination (Hema-Quebec) had a positive impact on yearly transplantation rates and wait times. PMID- 26057326 TI - Outcomes After Descemet Stripping Automated Endothelial Keratoplasty in Patients With Glaucoma Drainage Devices. AB - PURPOSE: To evaluate outcomes after Descemet stripping automated endothelial keratoplasty in eyes with glaucoma drainage devices. METHODS: This is a retrospective review of 24 cases performed by a single surgeon (S.B.H.) on 20 eyes. Data were gathered on demographics, ocular history, surgical details, and postoperative outcomes. Outcome measures included primary graft failure, secondary graft failure, endothelial cell density (ECD), central corneal thickness (CCT), intraocular pressure, and visual acuity. RESULTS: With a mean follow-up of 30.3 +/- 19.6 months, there was no occurrence of primary graft failure, and the rate of secondary graft failure was 29%. Survival rates at 1, 2, and 3 years, respectively, were 87% [95% confidence interval (CI): 65%-96%], 80% (95% CI: 55%-92%), and 70% (95% CI: 39%-88%). Compared with ECD of the donor lenticule, endothelial cell loss was 49 +/- 16% (n = 21) at postoperative month 3, 59 +/- 16% (n = 20) at month 6, 61 +/- 20% (n = 16) at month 12, and stabilized at 75 +/- 17% (n = 9) by month 18. Compared with CCT during the visit before surgery, CCT decreased to 83 +/- 18% (n = 18) at postoperative month 3 and gradually increased to 95 +/- 11% (n = 6) at month 24. There were 4 (17%) cases of intraocular pressure elevation above 25 mm Hg. Improved visual acuity occurred in 71% of patients. CONCLUSIONS: Descemet stripping automated endothelial keratoplasty in eyes with corneal edema secondary to endothelial dysfunction in the presence of a previous glaucoma drainage device is a successful procedure. However, intermediate term endothelial cell loss is significant, as is the graft failure rate. PMID- 26057327 TI - Stratification of Tear Components During Tear Microdesiccation on Vertical Glass Surfaces: A Novel Approach in Tear Fluid Assessment. AB - PURPOSE: Tear desiccation on a horizontal glass surface followed by low resolution light microscopy has been used as an expeditious diagnostic aid to evaluate patients suspected of dry eye. The presence of fern-like crystalloids in the dry specimen is the only feature taken into consideration. We demonstrate that different morphological domains of tear microdesiccates can be separated based on distinctive physicochemical properties. METHODS: Healthy subjects (Ocular Surface Disease Index questionnaire, laboratory tests, and slit-lamp examination) and 74 young adults from a random student population were recruited as volunteer tear donors. Single tear samples were taken from individual eyes (n = 154) using absorbing polyurethane minisponges. From each sample, aliquots were allowed to desiccate simultaneously on microscope slides positioned either horizontally or vertically followed by comparative dark-field microscopy. RESULTS: Vertical desiccation of each tear sample resulted in highly reproducible top-to-bottom stratification. Particular layers in any vertical microdesiccate represented morphological domains of the corresponding horizontal microdesiccate. Major fern-like crystalloids located at the center of Rolando type I horizontal microdesiccates became concentrated in a prominent layer at the bottom of vertical microdesiccates. Often, these fern-like crystalloids were more vigorous than those of the horizontal counterpart. A number of tear samples from the random population showed no ability to form fern-like crystalloids either by vertical or horizontal microdesiccation. Other prominent layers in vertical microdesiccates represented less noticeable circularly distributed morphological domains of the corresponding horizontal specimens. CONCLUSIONS: Microdesiccation of tear fluid on a vertical glass surface causes top-to-bottom stratification of diverse tear components. A more comprehensive expeditious tear assessment is feasible. PMID- 26057329 TI - Pre-Descemet Endothelial Keratoplasty With Infant Donor Corneas: A Prospective Analysis. AB - PURPOSE: To evaluate the outcomes and feasibility of the use of infant donor tissue (<1 year) in pre-Descemet endothelial keratoplasty (PDEK). METHODS: Three eyes of 3 patients with pseudophakic bullous keratopathy underwent the procedure in this single-center, prospective interventional series. Diseased Descemet membrane of the recipient cornea was replaced with the pre-Descemet layer Descemet membrane-endothelium complex stripped from the infant donor cornea (9-12 months old) with the creation of a type 1 bubble. The main outcome measures were best-corrected visual acuity, endothelial cell density, endothelial cell loss, and ease and predictability of the donor lenticule preparation. RESULTS: In the postoperative period, there was improvement in the visual acuity in all the patients. The mean donor endothelial cell density was 3073 +/- 68 cells per square millimeter, and the mean postoperative specular count at 6 months was 2230 +/- 43 cells per square millimeter. The mean percentage loss of endothelial cells at 6 months was 27 +/- 2%. The mean coefficient of variation was 36 +/- 5.2%. The mean central corneal thickness measured at a 6-month postoperative period was 515 +/- 7 MUm. No incidence of tissue loss during graft preparation, graft dislocation, or graft failure was reported. The mean graft thickness as measured with optical coherence tomography on the first postoperative day was 35 +/- 3 MUm. CONCLUSIONS: PDEK using an infant cornea provided an effective means of restoring optical clarity with good visual outcomes. The infant cornea can be a reliable source of donor tissue for the PDEK procedure, and no difficulties were noted in the donor lenticule preparation, insertion of the donor graft, or air bubble management. PMID- 26057328 TI - Effect of the Regenerative Agent Poly(Carboxymethylglucose Sulfate) on Corneal Wound Healing After Corneal Cross-Linking for Keratoconus. AB - PURPOSE: To evaluate the effect of a regenerative agent (RGTA) [Cacicol20 poly(carboxymethyl glucose sulfate); OTR3, Paris, France] on corneal reepithelialization and pain after corneal cross-linking (CXL) for keratoconus. METHODS: In this prospective comparative (contralateral) clinical study, patients with bilateral progressive keratoconus underwent CXL treatment. The corneal epithelium during CXL was removed using transepithelial phototherapeutic keratectomy (Cretan protocol). One eye of each patient was randomly instilled with an RGTA (Cacicol20) once a day (study group), whereas the fellow eye was instilled with artificial tears (control group). Patients were examined daily until complete reepithelialization. Postoperative examinations included slit-lamp biomicroscopy to assess the epithelial defect size and subjective evaluation of pain. RESULTS: The study enrolled 18 patients (36 eyes). The mean epithelial defect size for study and control groups was 19.6 +/- 4.2 mm versus 21.5 +/- 2.8 mm, respectively, at day 1 (P = 0.019) and 6.4 +/- 3.4 mm versus 7.9 +/- 4.3 mm, respectively, at day 2 (P = 0.014). At day 3 postoperatively, 61.1% of study eyes were fully reepithelialized, compared with 11.1% of control eyes (P = 0.002). CONCLUSIONS: RGTA (Cacicol20) instillation seems to result in faster corneal reepithelialization after CXL in this study. However, there was no significant effect in subjective pain/discomfort. PMID- 26057330 TI - Cyclosporine A Downregulates MMP-3 and MMP-13 Expression in Cultured Pterygium Fibroblasts. AB - PURPOSE: To investigate the regulation of matrix metalloproteinase (MMP)-3 and MMP-13 expression over time and in the presence of cyclosporine A (CsA) in primary cultured human pterygium fibroblasts. We also examined the effects of CsA on cultured human pterygium fibroblasts. METHODS: Primary cultured human pterygium fibroblasts subjected to scratch assays were exposed to 1 and 100 ug/mL of CsA for 3 or 10 minutes. Cells were washed with Dulbecco phosphate-buffered saline, and then incubated with serum-depleted Dulbecco modified Eagle medium/F 12 medium for 48 hours. Expression levels of MMP-3 and MMP-13 proteins and the corresponding mRNA transcripts were determined by western blotting and reverse transcription polymerase chain reaction assays, respectively. RESULTS: Migration of cultured pterygium fibroblast cells was suppressed by pretreatment with CsA compared with controls in a time-dependent and dose-dependent manner (3 minutes, 50.6% +/- 1.1 in 1 ug/mL, 60.0% +/- 1.2 in 100 ug/mL; 10 minutes, 59.8% +/- 5.7 in 1 ug/mL, 60.5 +/- 2.4 in 100 ug/mL, respectively, P < 0.01). Pretreatment with CsA also reduced the mRNA (P < 0.05) and protein expression levels (P < 0.05). CONCLUSIONS: CsA was actively involved in the migration of pterygium fibroblasts. Cell migration is inhibited in response to CsA through the inhibition of MMP-3 and MMP-13 expression. These findings reveal the therapeutic potential of CsA on pterygium progression. Further studies will be necessary to elucidate the precise intracellular signal mechanism responsible for CsA-induced downregulation of MMPs in pterygium fibroblasts. PMID- 26057331 TI - Nodular Fasciitis Involving the Cornea: A Case Report and Review of the Literature. AB - PURPOSE: To report a case of nodular fasciitis involving the cornea and to review the literature of all published cases of epibulbar nodular fasciitis. METHODS: A 38-year-old man presented with a progressively enlarging flesh-colored nodule adherent to the central cornea of his right eye. RESULTS: The nodule was surgically excised. Pathologic examination and immunohistochemistry were consistent with nodular fasciitis, a pseudoneoplastic spindle cell tumor. CONCLUSIONS: A review of the literature confirms this is the first reported case of nodular fasciitis involving the cornea since the original series by Zimmerman et al describing nodular fasciitis of the eye. Surgical excision alone is likely the most appropriate treatment option. PMID- 26057332 TI - Regulation of Granulocyte Colony-Stimulating Factor and Its Receptor in Skeletal Muscle is Dependent Upon the Type of Inflammatory Stimulus. AB - The cytokine granulocyte colony-stimulating factor (G-CSF) binds to its receptor (G-CSFR) to stimulate hematopoietic stem cell mobilization, myelopoiesis, and the production and activation of neutrophils. In response to exercise-induced muscle damage, G-CSF is increased in circulation and G-CSFR has recently been identified in skeletal muscle cells. While G-CSF/G-CSFR activation mediates pro- and anti inflammatory responses, our understanding of the role and regulation in the muscle is limited. The aim of this study was to investigate, in vitro and in vivo, the role and regulation of G-CSF and G-CSFR in skeletal muscle under conditions of muscle inflammation and damage. First, C2C12 myotubes were treated with lipopolysaccharide (LPS) with and without G-CSF to determine if G-CSF modulates the inflammatory response. Second, the regulation of G-CSF and its receptor was measured following eccentric exercise-induced muscle damage and the expression levels we investigated for redox sensitivity by administering the antioxidant N-acetylcysteine (NAC). LPS stimulation of C2C12 myotubes resulted in increases in G-CSF, interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP 1), and tumor necrosis factor-alpha (TNFalpha) messenger RNA (mRNA) and an increase in G-CSF, IL-6, and MCP-1 release from C2C12 myotubes. The addition of G CSF following LPS stimulation of C2C12 myotubes increased IL-6 mRNA and cytokine release into the media, however it did not affect MCP-1 or TNFalpha. Following eccentric exercise-induced muscle damage in humans, G-CSF levels were either marginally increased in circulation or remain unaltered in skeletal muscle. Similarly, G-CSFR levels remained unchanged in response to damaging exercise and G-CSF/G-CSFR did not change in response to NAC. Collectively, these findings suggest that G-CSF may cooperate with IL-6 and potentially promote muscle regeneration in vitro, whereas in vivo aseptic inflammation induced by exercise did not change G-CSF and G-CSFR responses. These observations suggest that different models of inflammation produce a different G-CSF response. PMID- 26057334 TI - Flow mediated dilation with photoplethysmography as a substitute for ultrasonic imaging. AB - Flow mediated dilation (FMD) is a non-invasive method for endothelial function assessment providing an index extracted from ultrasonic B-mode images. Although utilized in the research community, the difficulty of its application and high cost of ultrasonic devices prevent it from being widely used in clinical settings. In this study we show that substituting the ultrasonic device with more easily handled and low cost photoplethysmography and electrocardiography is possible. We introduce new indices based on the photoplethysmogram (PPG) and electrocardiogram (ECG) and show that they are correlated with the ultrasound based FMD Index. To this end, a conventional ultrasound FMD test was carried out whereas PPG and ECG were simultaneously recorded from 20 healthy volunteers (13 M, 7 F) in the age range of 23-32 years. Our results show a significant correlation between our proposed index and ultrasound FMD when using the ECG in conjunction with the PPG (R = 0.77, p < 0.000 01). Using the PPG alone produces a lower correlation (R = 0.72, p < 0.0001). Compared to conventional FMD, the proposed method is low cost and does not require any special operator skills. Hence it may be easily utilized as a screening tool in locations deprived of high end ultrasound imaging devices. PMID- 26057336 TI - Ageing-related stereotypes in memory: When the beliefs come true. AB - Age-related stereotype concerns culturally shared beliefs about the inevitable decline of memory with age. In this study, stereotype priming and stereotype threat manipulations were used to explore the impact of age-related stereotype on metamemory beliefs and episodic memory performance. Ninety-two older participants who reported the same perceived memory functioning were divided into two groups: a threatened group and a non-threatened group (control). First, the threatened group was primed with an ageing stereotype questionnaire. Then, both groups were administered memory complaints and memory self-efficacy questionnaires to measure metamemory beliefs. Finally, both groups were administered the Logical Memory task to measure episodic memory, for the threatened group the instructions were manipulated to enhance the stereotype threat. Results indicated that the threatened individuals reported more memory complaints and less memory efficacy, and had lower scores than the control group on the logical memory task. A multiple mediation analysis revealed that the stereotype threat effect on the episodic memory performance was mediated by both memory complaints and memory self-efficacy. This study revealed that stereotype threat impacts belief in one's own memory functioning, which in turn impairs episodic memory performance. PMID- 26057337 TI - Repeated, long-distance migrations by a philopatric predator targeting highly contrasting ecosystems. AB - Long-distance movements of animals are an important driver of population spatial dynamics and determine the extent of overlap with area-focused human activities, such as fishing. Despite global concerns of declining shark populations, a major limitation in assessments of population trends or spatial management options is the lack of information on their long-term migratory behaviour. For a large marine predator, the tiger shark Galeocerdo cuvier, we show from individuals satellite-tracked for multiple years (up to 1101 days) that adult males undertake annually repeated, round-trip migrations of over 7,500 km in the northwest Atlantic. Notably, these migrations occurred between the highly disparate ecosystems of Caribbean coral reef regions in winter and high latitude oceanic areas in summer, with strong, repeated philopatry to specific overwintering insular habitat. Partial migration also occurred, with smaller, immature individuals displaying reduced migration propensity. Foraging may be a putative motivation for these oceanic migrations, with summer behaviour showing higher path tortuosity at the oceanic range extremes. The predictable migratory patterns and use of highly divergent ecosystems shown by male tiger sharks appear broadly similar to migrations seen in birds, reptiles and mammals, and highlight opportunities for dynamic spatial management and conservation measures of highly mobile sharks. PMID- 26057335 TI - The genetics of early-onset bipolar disorder: A systematic review. AB - BACKGROUND: Early-onset bipolar disorder has been associated with a significantly worse prognosis than late-onset BD and has been hypothesized to be a genetically homogenous subset of BD. A sizeable number of studies have investigated early onset BD through linkage-analyses, candidate-gene association studies, genome wide association studies (GWAS), and analyses of copy number variants (CNVs), but this literature has not yet been reviewed. METHODS: A systematic review was conducted using the PubMed database on articles published online before January 15, 2015 and after 1990. Separate searches were made for linkage studies, candidate gene-association studies, GWAS, and studies on CNVs. RESULTS: Seventy three studies were included in our review. There is a lack of robust positive findings on the genetics of early-onset BD in any major molecular genetics method. LIMITATIONS: Early-onset populations were quite small in some studies. Variance in study methods hindered efforts to interpret results or conduct meta analysis. CONCLUSIONS: The field is still at an early phase for research on early onset BD. The largely null findings mirror the results of most genetics research on BD. Although most studies were underpowered, the null findings could mean that early-onset BD may not be as genetically homogenous as has been hypothesized or even that early-onset BD does not differ genetically from adult-onset BD. Nevertheless, clinically the probabilistic developmental risk trajectories associated with early-onset that may not be primarily genetically determined continued to warrant scrutiny. Future research should dramatically expand sample sizes, use atheoretical research methods like GWAS, and standardize methods. PMID- 26057338 TI - Seminoma in Cryptorchid Testis in Prune Belly Syndrome. PMID- 26057340 TI - The Economics of Reproducibility in Preclinical Research. AB - Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total) prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B)/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures. PMID- 26057341 TI - Tryptophan hydroxylase 2 gene is associated with cognition in late-onset depression in a Chinese Han population. AB - Accumulating evidences suggest that Tryptophan hydroxylase 2 (TPH2) gene is associated with major depressive disorder (MDD) and cognitive function. In present study, we aimed to explore the association of cognitive disturbances in patients with late-onset depression (LOD) in the Chinese Han population. One hundred and ninety unrelated LOD patients who met DSM-IV criteria for major depressive disorder were recruited for the study and 155 normal controls were recruited from local community. All subjects completed the demographic assessments. Furthermore, 97 patients and 44 controls completed a series of neuropsychological tests. Patients and normal controls were genotyped for TPH2 (rs4290270 and rs7305115) variants using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results of our analysis indicated no significant differences in the frequencies of the single alleles and genotypes of two polymorphisms in TPH2 gene between LOD patients and normal controls. Haplotype association indicated that no differences were found in the frequencies of haplotype between two groups. A significant main effect of rs4290270 genotype on Verbal Fluency Test (VFT) test performance was found (P<0.05). There was a significant interactive effect of rs7305115 polymorphisms and depression diagnosis on Symbol Digit Modalities Test (SDMT) (P<0.05). After controlling for covariates, the subjects with carriers of GG genotype in rs7305115 had more better SDMT performance compared to AG and AA carriers in LOD groups. The result suggests that there is a major effect of rs4290270 in TPH2 on cognitive function alone. Moreover, an interaction of rs7305115 polymorphisms and depression diagnosis may be associated with the cognitive function. Further studies in a large sample are needed to replicate the genetic role in the LOD patients. PMID- 26057342 TI - Acute aerobic exercise influences the inhibitory process in the go/no-go task in humans. AB - This study evaluated the influence of acute aerobic exercise on the human inhibitory system. For studies on the neural mechanisms of somato-motor inhibitory processing in humans, the go/no-go task is a useful paradigm for recording event-related potentials. Ten subjects performed somatosensory go/no-go tasks in a control condition and exercise condition. In the control condition, the subjects performed the go/no-go task before and after 20 min of rest. In the exercise condition, the subjects performed the go/no-go task before and after 15 min of treadmill running with the exercise intensity set individually for each subject at 50% of peak oxygen intake. We successfully recorded a clear-cut N140 component under all conditions, and found that the peak amplitude of no-go-N140 at Fz and Cz was significantly enhanced during moderate exercise. In contrast, there were no significant changes in Fz and Cz in the control condition. These results suggest that moderate exercise can affect the amplitude of no-go-N140, which could be interpreted as an index of the human inhibition process in the central nervous system. The human inhibitory system is an important cognitive process, and this system may underlie the hypothetical ability of physical exercise to maintain and improve cognitive performance throughout the lifespan. PMID- 26057343 TI - Residence time distribution measurements in a pilot-scale poison tank using radiotracer technique. AB - Various types of systems are used to control the reactivity and shutting down of a nuclear reactor during emergency and routine shutdown operations. Injection of boron solution (borated water) into the core of a reactor is one of the commonly used methods during emergency operation. A pilot-scale poison tank was designed and fabricated to simulate injection of boron poison into the core of a reactor along with coolant water. In order to design a full-scale poison tank, it was desired to characterize flow of liquid from the tank. Residence time distribution (RTD) measurement and analysis was adopted to characterize the flow dynamics. Radiotracer technique was applied to measure RTD of aqueous phase in the tank using Bromine-82 as a radiotracer. RTD measurements were carried out with two different modes of operation of the tank and at different flow rates. In Mode-1, the radiotracer was instantaneously injected at the inlet and monitored at the outlet, whereas in Mode-2, the tank was filled with radiotracer and its concentration was measured at the outlet. From the measured RTD curves, mean residence times (MRTs), dead volume and fraction of liquid pumped in with time were determined. The treated RTD curves were modeled using suitable mathematical models. An axial dispersion model with high degree of backmixing was found suitable to describe flow when operated in Mode-1, whereas a tanks-in-series model with backmixing was found suitable to describe flow of the poison in the tank when operated in Mode-2. The results were utilized to scale-up and design a full-scale poison tank for a nuclear reactor. PMID- 26057344 TI - Differentially expressed gene profiles in the serum before and after the ultrasound-guided ethanol sclerotherapy in patients with ovarian endometriomas. AB - OBJECTIVES: To detect the differentially expressed genes and subsequently identify disease-related signatures and potential biomarkers for patients with ovarian endometriomas in the serum before and after the ultrasound-guided ethanol sclerotherapy in patients with ovarian endometriomas. DESIGN AND METHODS: Venous blood samples were collected from nine patients with ovarian endometriomas before and after ultrasound-guided ethanol sclerotherapy, and the serum were isolated after centrifugation. NimbleGen human gene expression microarrays analysis was conducted to analyse gene ontology categories (GO terms) and signalling pathways of differentially expressed genes. The accuracy of some typical genes from microarray analysis was verified by quantitative PCR (qPCR). RESULTS: Approximately 45,033 genes were analysed by NimbleGen human gene expression microarrays, which identified 447 genes that showed differential expressions before and after therapy. Of these, 225 genes were up-regulated and 222 genes were down-regulated. The GO terms of the down-regulated genes were strongly associated with the pathogenesis of ovarian endometriomas; 15 down-regulated genes showed overlaps in both signalling pathways and GO terms. Among these, six genes showed statistical significance including IL6, CD36, JUNB, B4GALT1, HES1, and NR4A1, which were also validated by qPCR analysis. CONCLUSIONS: There were differentially expressed genes in the serum before and after ultrasound-guided ethanol sclerotherapy in patients with ovarian endometriomas. Notably, the expressions of IL6, CD36, JUNB, B4GALT1, HES1, and NR4A1, which are strongly associated with the pathogenesis of ovarian endometriomas, were significantly down-regulated after ethanol sclerotherapy. This may not only help us understand EMs pathogenesis, but also provide potential biomarkers for verifying the effects of ethanol sclerotherapy. PMID- 26057345 TI - Comprehensive prediction of drug-protein interactions and side effects for the human proteome. AB - Identifying unexpected drug-protein interactions is crucial for drug repurposing. We develop a comprehensive proteome scale approach that predicts human protein targets and side effects of drugs. For drug-protein interaction prediction, FINDSITE(comb), whose average precision is ~30% and recall ~27%, is employed. For side effect prediction, a new method is developed with a precision of ~57% and a recall of ~24%. Our predictions show that drugs are quite promiscuous, with the average (median) number of human targets per drug of 329 (38), while a given protein interacts with 57 drugs. The result implies that drug side effects are inevitable and existing drugs may be useful for repurposing, with only ~1,000 human proteins likely causing serious side effects. A killing index derived from serious side effects has a strong correlation with FDA approved drugs being withdrawn. Therefore, it provides a pre-filter for new drug development. The methodology is free to the academic community on the DR. PRODIS (DRugome, PROteome, and DISeasome) webserver at http://cssb.biology.gatech.edu/dr.prodis/. DR. PRODIS provides protein targets of drugs, drugs for a given protein target, associated diseases and side effects of drugs, as well as an interface for the virtual target screening of new compounds. PMID- 26057346 TI - What Controls the "Off/On Switch" in the Toehold-Mediated Strand Displacement Reaction on DNA Conjugated Gold Nanoparticles? AB - In DNA dynamic nanotechnology, a toehold-mediated DNA strand-displacement reaction has demonstrated its capability in building complex autonomous system. In most cases, the reaction is performed in pure DNA solution that is essentially a one-phase system. In the present work, we systematically investigated the reaction in a heterogeneous media, in which the strand that implements a displacing action is conjugated on gold nanoparticles. By monitoring the kinetics of spherical nucleic acid (SNA) assembly driven by toehold-mediated strand displacement reaction, we observed significant differences, i.e., the abrupt jump in behavior of an "off/on switch", in the reaction rate when the invading toehold was extended to eight bases from seven bases. These phenomena are attributed to the effect of steric hindrance arising from the high density of invading strand conjugated to AuNPs. Based on these studies, an INHIBIT logic gate presenting good selectivity was developed. PMID- 26057347 TI - Label-free microscopy and stress responses reveal the functional organization of Pseudodiaptomus marinus copepod myofibrils. AB - Pseudodiaptomus marinus copepods are small crustaceans living in estuarine areas endowed with exceptional swimming and adaptative performances. Since the external cuticle acts as an impermeable barrier for most dyes and molecular tools for labeling copepod proteins with fluorescent tags are not available, imaging cellular organelles in these organisms requires label free microscopy. Complementary nonlinear microscopy techniques have been used to investigate the structure and the response of their myofibrils to abrupt changes of temperature or/and salinity. In contrast with previous observations in vertebrates and invertebrates, the flavin autofluorescence which is a signature of mitochondria activity and the Coherent Anti-Stokes Raman Scattering (CARS) pattern assigned to T-tubules overlapped along myofibrils with the second harmonic generation (SHG) striated pattern generated by myosin tails in sarcomeric A bands. Temperature jumps from 18 to 4 degrees C or salinity jumps from 30 to 15 psu mostly affected flavin autofluorescence. Severe salinity jumps from 30 to 0 psu dismantled myofibril organization with major changes both in the SHG and CARS patterns. After a double stress (from 18 degrees C/30 psu to 4 degrees C/0 psu) condensed and distended regions appeared within single myofibrils, with flavin autofluorescence bands located between sarcomeric A bands. These results shed light on the interactions between the different functional compartments which provide fast acting excitation-contraction coupling and adequate power supply in copepods muscles. PMID- 26057348 TI - All-Diamond Microelectrodes as Solid State Probes for Localized Electrochemical Sensing. AB - The fabrication of an all-diamond microprobe is demonstrated for the first time. This ME (microelectrode) assembly consists of an inner boron doped diamond (BDD) layer and an outer undoped diamond layer. Both layers were grown on a sharp tungsten tip by chemical vapor deposition (CVD) in a stepwise manner within a single deposition run. BDD is a material with proven potential as an electrochemical sensor. Undoped CVD diamond is an insulating material with superior chemical stability in comparison to conventional insulators. Focused ion beam (FIB) cutting of the apex of the ME was used to expose an electroactive BDD disk. By cyclic voltammetry, the redox reaction of ferrocenemethanol was shown to take place at the BDD microdisk surface. In order to ensure that the outer layer was nonelectrically conductive, a diffusion barrier for boron atoms was established seeking the formation of boron-hydrogen complexes at the interface between the doped and the undoped diamond layers. The applicability of the microelectrodes in localized corrosion was demonstrated by scanning amperometric measurements of oxygen distribution above an Al-Cu-CFRP (Carbon Fiber Reinforced Polymer) galvanic corrosion cell. PMID- 26057349 TI - Heterogeneous Fluorescence Intermittency in Single Layer Reduced Graphene Oxide. AB - We provide, for the first time, direct experimental evidence for heterogeneous blinking in reduced graphene oxide (rGO) during photolysis. The spatially resolved intermittency originates from regions within individual rGO sheets and shows 1/f-like power spectral density. We describe the evolution of rGO blinking using the multiple recombination center (MRC) model that captures common features of nanoscale blinking. Our results illustrate the universal nature of blinking and suggest a common microscopic origin for the effect. PMID- 26057351 TI - The ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies. AB - Hormonal therapy or ketogenic diet often permits overcoming the challenging periods of many epileptic encephalopathies (West and Lennox-Gastaut syndromes and encephalopathy with continuous spike-waves in slow sleep), but relapse affects over 20% of patients. We report here a monocenter pilot series of 42 consecutive patients in whom we combined oral steroids with the ketogenic diet for corticosteroid-resistant or -dependent epileptic encephalopathy. We retrospectively evaluated the effect on seizure frequency, interictal spike activity, neuropsychological course, and steroid treatment course. Twenty-three patients had West syndrome (WS), 13 had encephalopathy with continuous spike waves in slow sleep (CSWS), and six others had miscellaneous epileptic encephalopathies. All patients succeeded to reach 0.8 to 1.6g/l ketone bodies in the urine following the usual KD regimen. For at least 6 months, 14/42 responded to the addition of the ketogenic diet: 4/23 with WS, 8/13 with CSWS, and 2/6 with miscellaneous epileptic encephalopathies. The addition of the KD allowed withdrawing steroids in all responders. Among them, 10/15 had been patients with steroid-dependent epileptic encephalopathy and 4/27 patients with steroid resistant epileptic encephalopathy. Therefore, the ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies. Patients presenting with steroid-dependent CSWS seem to be the best candidates. PMID- 26057350 TI - HIV Subtypes B and C gp120 and Methamphetamine Interaction: Dopaminergic System Implicates Differential Neuronal Toxicity. AB - HIV subtypes or clades differentially induce HIV-associated neurocognitive disorders (HAND) and substance abuse is known to accelerate HIV disease progression. The HIV-1 envelope protein gp120 plays a major role in binding and budding in the central nervous system (CNS) and impacts dopaminergic functions. However, the mechanisms utilized by HIV-1 clades to exert differential effects and the methamphetamine (METH)-associated dopaminergic dysfunction are poorly understood. We hypothesized that clade B and C gp120 structural sequences, modeling based analysis, dopaminergic effect, and METH potentiate neuronal toxicity in astrocytes. We evaluated the effect of clade B and C gp120 and/or METH on the DRD-2, DAT, CaMKs and CREBP transcription. Both the structural sequence and modeling studies demonstrated that clade B gp120 in V1-V4, alpha -2 and N-glycosylated sites are distinct from clade C gp120. The distinct structure and sequence variation of clade B gp120 differentially impact DRD-2, DAT, CaMK II and CaMK IV mRNA, protein and intracellular expression compared to clade C gp120. However, CREB transcription is upregulated by both clade B and C gp120, and METH co-treatment potentiated these effects. In conclusion, distinct structural sequences of HIV-1 clade B and C gp120 differentially regulate the dopaminergic pathway and METH potentiates neurotoxicity. PMID- 26057352 TI - Fibronectin is a potential cerebrospinal fluid and serum epilepsy biomarker. AB - PURPOSE: Previous studies have demonstrated that fibronectin (FN) levels are increased in brain tissues from patients and animals with epilepsy. This study aimed to assess FN levels in cerebrospinal fluid (CSF) and serum samples from patients with epilepsy. METHODS: Fibronectin levels were assessed in CSF and serum samples from 56 patients with epilepsy (27 and 29 individuals with intractable epilepsy and nonintractable epilepsy, respectively) and 25 healthy controls, using sandwich enzyme-linked immunosorbent assays (ELISA). RESULTS: CSF FN levels were higher in patients with epilepsy (8.07 +/- 1.51 mg/l versus 6.20 +/- 1.18 mg/l, p<0.05) than in the control group. In addition, serum-FN levels in the group with epilepsy and in the control group were 236.96 +/- 65.7 mg/l and 181.43 +/- 72.82 mg/l, respectively, indicating a statistically significant difference (p=0.01). Interestingly, serum- and CSF-FN levels in individuals with epilepsy were not affected by antiepileptic drug and duration of epilepsy. Of note, the increase of CSF- and serum-FN levels was more pronounced in subjects with intractable epilepsy than in patients with nonintractable epilepsy. CONCLUSION: Serum- and CSF-FN levels constitute a potential clinical diagnostic biomarker for epilepsy and could also be used for differential diagnosis. PMID- 26057353 TI - Pneumonia presenting with lower right abdominal pain and migratory polyarthritis. AB - The clinical presentation of community acquired pneumonia (CAP) in adults includes mainly symptoms from the respiratory system, whereas CAP is considered as a main cause of abdominal pain in pediatric patients. We present the case of a patient, who was admitted to our hospital due to abdominal pain that deteriorated progressively and radiated to the lumbar region. The clinical examination revealed decreased breath sounds at the right lung base after 72 h, while the chest X-ray showed pneumonia of the right lung base. The blood culture isolated Streptococcus pneumoniae, and the patient received penicillin according to the results of the antibiogram. In addition, the patient developed symptoms of migratory arthritis, which resolved after 48 h. CAP should be included in the differential diagnosis of abdominal pain in adult patients. Furthermore, the hematogenous spread of S. pneumoniae may be associated with the development of migratory arthritis. PMID- 26057354 TI - Signet ring cell carcinoma of the ampulla of vater: Report of a case and a review of the literature. AB - INTRODUCTION: Signet ring cell carcinoma (SRCC) of the ampulla of vater is a very rare tumor that is reported infrequently in the literature. PRESENTATION OF CASE: A 59-year-old woman visited our hospital for evaluation of elevated transaminase levels. On laboratory examination of tumor marker levels, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 levels were normal, and DUPAN-2 was elevated. Computed tomography (CT) confirmed a 2cm, enhanced mass in the periampullary region, with marked common bile duct dilatation. Endoscopic retrograde cholangiopancreatography (ERCP) showed a swollen papilla of vater, with a reddish, erosive mucosa. Histological examination of biopsy samples from the ampulla of vater showed signet ring cell carcinoma (SRCC). The patient underwent radical pancreatoduodenectomy. Pathological examination showed that the SRCC had infiltrated into the duodenal muscularis propria and pancreatic parenchyma, and lymph node metastases were identified around the abdominal aorta and common hepatic artery. Based on the immunohistochemical staining patterns of the positive results for CDX2 and MUC2, the tumor cells in the present case appeared to have an intestinal type origin. The ampullary cancer was diagnosed as T3bN1M1, Stage IV according to the International Union Against Cancer TNM classification (UICC). After undergoing adjuvant chemotherapy with cisplatin gemcitabine chemotherapy for 6 months, the patient has remained disease-free in the 7 months since surgery. DISCUSSION: SRCC of intestinal-type origin is associated with a favorable outcome. CONCLUSION: Investigation to confirm the histological origin of SRCC by immunohistochemical staining might inform the treatment strategy and identify patients with ampullary SRCC who may have a good prognosis. PMID- 26057355 TI - Educational climate perception by preclinical and clinical medical students in five Spanish medical schools. AB - OBJECTIVE: The purpose of this study was to investigate student's perceptions of Educational Climate (EC) in Spanish medical schools, comparing various aspects of EC between the 2nd (preclinical) and the 4th (clinical) years to detect strengths and weaknesses in the on-going curricular reform. METHODS: This study utilized a cross-sectional design and employed the Spanish version of the "Dundee Ready Education Environment Measure" (DREEM). The survey involved 894 2nd year students and 619 4th year students from five Spanish medical schools. RESULTS: The global average score of 2nd year students from the five medical schools was found to be significantly higher (116.2+/-24.9, 58.2% of maximum score) than that observed in 4th year students (104.8+/-29.5, 52.4% of maximum score). When the results in each medical school were analysed separately, the scores obtained in the 2nd year were almost always significantly higher than in the 4th year for all medical schools, in both the global scales and the different subscales. CONCLUSIONS: The perception of the EC by 2nd and 4th year students from five Spanish medical schools is more positive than negative although it is significantly lower in the 4th year. In both years, although more evident in the 4th year, students point out the existence of several important "problematic educational areas" associated with the persistence of traditional curricula and teaching methodologies. Our findings of this study should lead medical schools to make a serious reflection and drive the implementation of the necessary changes required to improve teaching, especially during the clinical period. PMID- 26057356 TI - Betaine prevents homocysteine-induced memory impairment via matrix metalloproteinase-9 in the frontal cortex. AB - Betaine plays important roles that include acting as a methyl donor and converting homocysteine (Hcy) to methionine. Elevated plasma Hcy levels are known as hyperhomocysteinemia (HHcy) and contribute to impairments of learning and memory. Although it is commonly known that betaine plays an important role in Hcy metabolism, the effects of betaine on Hcy-induced memory impairment have not been investigated. Previously, we demonstrated the beneficial effects of betaine on acute stress and lipopolysaccharide-induced memory impairment. In the present study, we investigated whether betaine ameliorates Hcy-induced memory impairment and the underlying mechanisms of this putative effect. Mice were treated with Hcy (0.162mg/kg, s.c.) twice a day for nine days, and betaine (25mg/kg, s.c.) was administered 30min before the Hcy injections. The memory functions were evaluated using a spontaneous alternation performance test (Y-maze) at seven days and a step-down type passive avoidance test (SD) at nine and ten days after Hcy injection. We found that betaine suppressed the memory impairment induced by repeated Hcy injections. However, the blood concentrations of Hcy were significantly increased in the Hcy-treated mice immediately after the passive avoidance test, and betaine did not prevent this increase. Furthermore, Hcy induces redox stress in part by activating matrix metalloproteinase-9 (MMP-9), which leads to BBB dysfunction. Therefore, we tested whether betaine affected MMP 9 activity. Interestingly, treatment with betaine significantly inhibited Hcy induced MMP-9 activity in the frontal cortex but not in the hippocampus after acute Hcy injection. These results suggest that the changes in MMP-9 activity after betaine treatment might have been partially responsible for the amelioration of the memory deficits and that MMP-9 might be a candidate therapeutic target for HHcy. PMID- 26057357 TI - Psychophysical inference of frequency-following fidelity in the neural substrate for brain stimulation reward. AB - The rewarding effect of electrical brain stimulation has been studied extensively for 60 years, yet the identity of the underlying neural circuitry remains unknown. Previous experiments have characterized the directly stimulated ("first stage") neurons implicated in self-stimulation of the medial forebrain bundle. Their properties are consistent with those of fine, myelinated axons, at least some of which project rostro-caudally. These properties do not match those of dopaminergic neurons. The present psychophysical experiment estimates an additional first-stage characteristic: maximum firing frequency. We test a frequency-following model that maps the experimenter-set pulse frequency into the frequency of firing induced in the directly stimulated neurons. As pulse frequency is increased, firing frequency initially increases at the same rate, then becomes probabilistic, and finally levels off. The frequency-following function is based on the counter model which holds that the rewarding effect of a pulse train is determined by the aggregate spike rate triggered in first-stage neurons during a given interval. In 7 self-stimulating rats, we measured current- vs. pulse-frequency trade-off functions. The trade-off data were well described by the frequency-following model, and its upper asymptote was approached at a median value of 360 Hz (IQR = 46 Hz). This value implies a highly excitable, non dopaminergic population of first-stage neurons. Incorporating the frequency following function and parameters in Shizgal's 3-dimensional reward-mountain model improves its accuracy and predictive power. PMID- 26057358 TI - Central relaxin-3 receptor (RXFP3) activation reduces elevated, but not basal, anxiety-like behaviour in C57BL/6J mice. AB - Anxiety disorders are among the most prevalent neuropsychiatric conditions, but their precise aetiology and underlying pathophysiological processes remain poorly understood. In light of putative anatomical and functional interactions of the relaxin-3/RXFP3 system with anxiety-related neural circuits, we assessed the ability of central administration of the RXFP3 agonist, RXFP3-A2, to alter anxiety-like behaviours in adult C57BL/6J mice. We assessed how RXFP3-A2 altered performance in tests measuring rodent anxiety-like behaviour (large open field (LOF), elevated plus maze (EPM), light/dark (L/D) box, social interaction). We examined effects of RXFP3-A2 on low 'basal' anxiety, and on elevated anxiety induced by the anxiogenic benzodiazepine, FG-7142; and explored endogenous relaxin-3/RXFP3 signalling modulation by testing effects of an RXFP3 antagonist, R3(B1-22)R, on these behaviours. Intracerebroventricular (icv) injection of RXFP3 A2 (1 nmol, 15 min pre-test) did not alter anxiety-like behaviour under 'basal' conditions in the LOF, EPM or L/D box, but reduced elevated indices of FG-7142 induced (30 mg/kg, ip) anxiety-like behaviour in the L/D box and a single-chamber social interaction test. Furthermore, R3(B1-22)R (4 nmol, icv, 15 min pre-test) increased anxiety-like behaviour in the EPM (reflected by reduced entries into the open arms), but not consistently in the LOF, L/D box or social interaction tests, suggesting endogenous signaling only weakly participates in regulating 'basal' anxiety-like behaviour, in line with previous studies of relaxin-3 and RXFP3 gene knockout mice. Overall, these data suggest exogenous RXFP3 agonists can reduce elevated (FG-7142-induced) levels of anxiety in mice; data important for gauging how conserved such effects are, with a view to modelling human pathophysiology and the likely therapeutic potential of RXFP3-targeted drugs. PMID- 26057359 TI - Neural correlates of valence generalization in an affective conditioning paradigm. AB - In case of uncertainty, predictions that are based on prior, similar experiences guide our decision by processes of generalization. Over-generalization of negative information has been identified as an important feature of several psychopathologies, including anxiety disorders and depression, and might underlie biased interpretation of ambiguous information. Here, we investigated the neural correlates of valence generalization to ambiguous stimuli using a translational affective conditioning task during fMRI. Twenty-five healthy individuals participated in a conditioning procedure with (1) an initial acquisition phase, where participants learned the positive and negative valence of two different tones (reference tones) through their responses and subsequent feedback and (2) a test phase, where participants were presented with the previously learned reference tones and three additional tones with intermediate frequency to the learned reference tones. By recording the responses to these intermediate stimuli we were able to assess the participantsi interpretation of ambiguous tones as either positive or negative. Behavioral results revealed a graded response pattern to the three intermediate tones, which was mirrored on the neural level. More specifically, parametric analyses OF BOLD responses to all five tones revealed a linear effect in bilateral anterior insula and SMA with lowest activation to the negative reference tone and highest activation to the positive negative tone. In addition, a cluster in the SMA showed a reverse-quadratic response, i.e., the strongest response for the most ambiguous tone. These findings suggest overlapping regions in the salience network that mediate valence generalization and decision-making under ambiguity, potentially underlying biased ambiguous cue interpretation. PMID- 26057360 TI - Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: Possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. AB - Many patients who have received chemotherapy to treat cancer experience depressive- and anxiety-like symptoms or cognitive impairment. However, despite the evidence for this, the underlying mechanisms are still not understood. This study investigated behavioral and biochemical changes upon treatment with doxorubicin and cyclophosphamide, focusing on mental and cognitive systems, as well as neurogenesis in male rats. Doxorubicin (2 mg/kg), cyclophosphamide (50 mg/kg), and the combination of doxorubicin and cyclophosphamide were injected intraperitoneally once per week for 4 weeks. In particular, the co-administration of doxorubicin and cyclophosphamide produced anhedonia-like, anxiety-like, and spatial cognitive impairments in rats. It also reduced both the number of proliferating cells in the subgranular zone of the hippocampal dentate gyrus and their survival. Serum brain-derived neurotrophic factor (BDNF) levels were decreased along with chemotherapy-induced decreases in platelet levels. However, hippocampal BDNF levels and Bdnf mRNA levels were not decreased by this treatment. On the other hand, hippocampal cyclin D1 levels were significantly decreased by chemotherapy. These results suggest that the co-administration of doxorubicin and cyclophosphamide induces psychological and cognitive impairment, in addition to negatively affecting hippocampal neurogenesis, which may be related to hippocampal cyclin D1 levels, but not hippocampal BDNF levels. PMID- 26057361 TI - Effect of humic acid (HA) on sulfonamide sorption by biochars. AB - Effect of quantity and fractionation of loaded humic acid (HA) on biochar sorption for sulfonamides was investigated. The HA was applied in two different modes, i.e. pre-coating and co-introduction with sorbate. In pre-coating mode, the polar fractions of HA tended to interact with low-temperature biochars via H bonding, while the hydrophobic fractions were likely to be adsorbed by high temperature biochars through hydrophobic and pi-pi interactions, leading to different composition and structure of the HA adlayers. The influences of HA fractionation on biochar sorption for sulfonamides varied significantly, depending on the nature of interaction between HA fraction and sorbate. Meanwhile, co-introduction of HA with sulfonamides revealed that the effect of HA on sulfonamide sorption was also dependent on HA concentration. These findings suggest that the amount and fractionation of adsorbed HA are tailored by the surface properties of underlying biochars, which differently affect the sorption for organic contaminants. PMID- 26057362 TI - Agglomeration of Ag and TiO2 nanoparticles in surface and wastewater: Role of calcium ions and of organic carbon fractions. AB - This study aims to investigate factors leading to agglomeration of citrate coated silver (AgNP-Cit), polyvinylpyrrolidone coated AgNPPVP and titanium dioxide (TiO2) nanoparticles in surface waters and wastewater. ENPs (1 mg/L) were spiked to unfiltered, filtered, ultrafiltered (<10 kDa and <1 kDa) samples. Z-average particle sizes were measured after 1 h, 1 day and 1 week. AgNP-PVP was stable in all fractions of the samples and kept their original size around 60 nm over 1 week. Agglomeration of AgNP-Cit and TiO2 was positively correlated with Ca(2+) concentration, but dissolved organic carbon concentrations > 2 mg/L contributed to stabilizing these NP. Moreover, agglomeration of AgNP-Cit in the various organic matter fractions showed that high molecular weight organic compounds such as biopolymers provide stabilization in natural water. A generalized scheme for the agglomeration behavior of AgNP-Cit, AgNP-PVP and TiO2 in natural waters was proposed based on their relation with Ca(2+), Mg(2+) and DOC concentration. PMID- 26057363 TI - Leaf reflectance variation along a vertical crown gradient of two deciduous tree species in a Belgian industrial habitat. AB - The reflectometry of leaf asymmetry is a novel approach in the bio-monitoring of tree health in urban or industrial habitats. Leaf asymmetry responds to the degree of environmental pollution and reflects structural changes in a leaf due to environmental pollution. This paper describes the boundary conditions to scale up from leaf to canopy level reflectance, by describing the variability of adaxial and abaxial leaf reflectance, hence leaf asymmetry, along the crown height gradients of two tree species. Our findings open a research pathway towards bio-monitoring based on the airborne remote sensing of tree canopies and their leaf asymmetric properties. PMID- 26057364 TI - Quantification of in vitro wear of a synthetic meniscus implant using gravimetric and micro-CT measurements. AB - A synthetic meniscus implant was recently developed for the treatment of patients with mild to moderate osteoarthritis with knee pain associated with medial joint overload. The implant is distinctively different from most orthopedic implants in its pliable construction, and non-anchored design, which enables implantation through a mini-arthrotomy without disruption to the bone, cartilage, and ligaments. Due to these features, it is important to show that the material and design can withstand knee joint conditions. This study evaluated the long-term performance of this device by simulating loading for a total of 5 million gait cycles (Mc), corresponding to approximately five years of service in-vivo. All five implants remained in good condition and did not dislodge from the joint space during the simulation. Mild abrasion was detected by electron microscopy, but u-CT scans of the implants confirmed that the damage was confined to the superficial surfaces. The average gravimetric wear rate was 14.5 mg/Mc, whereas volumetric changes in reconstructed u-CT scans point to an average wear rate of 15.76 mm(3)/Mc (18.8 mg/Mc). Particles isolated from the lubricant had average diameter of 15 um. The wear performance of this polycarbonate-urethane meniscus implant concept under ISO-14243 loading conditions is encouraging. PMID- 26057365 TI - Electronic Cigarette Use Among College Students: Links to Gender, Race/Ethnicity, Smoking, and Heavy Drinking. AB - OBJECTIVE: Electronic cigarette (e-cigarette) use continues to rise, and current data regarding use of e-cigarettes among college students are needed. The purpose of this study was to examine e-cigarette use and the relation of such use with gender, race/ethnicity, traditional tobacco use, and heavy drinking. PARTICIPANTS AND METHODS: A sample of 599 college students enrolled in General Psychology at a state university completed a self-report questionnaire. RESULTS: Twenty-nine percent of students reported prior use of e-cigarettes, with 14% reporting use in the past 30 days. E-cigarette use was linked to male gender but not to race/ethnicity. Dual use (ie, concurrent use of both traditional and e cigarettes) was related to heavier use of traditional and e-cigarettes, and nicotine use was linked to pronounced rates of heavy drinking. CONCLUSIONS: E cigarette use among college students is exponentially on the rise, and its co-use with alcohol may contribute to negative outcomes in this population. PMID- 26057366 TI - RELEVANT AND NEW DATA GRACE THE CLINICAL RESEARCH OFFICE OF THE ENDOUROLOGICAL SOCIETY URETEROSCOPY URS STUDY GROUP COLLABORATION. PMID- 26057367 TI - The active role of osteoporosis in the interaction between osteoblasts and bone metastases. AB - INTRODUCTION: To minimize the severity of bone metastases and to delay their onset, it is important to analyze the underlying biological mechanisms. The present study focused on the link between OP and metastatic cells, with particular attention to osteoblast behavior. METHODS: Osteoblasts (OB) were isolated from the trabecular bone of iliac crest of healthy (SHAM) and ovariectomized (OVX) adult female rats and co-cultured with MRMT-1 rat breast carcinoma cells as conditioned medium (CM) or alone (CTR) for 24h, 7 and 14 days and tested for cell viability, morphology and synthetic activity, i.e. C-terminal procollagen type I, alkaline phosphatase, osteoprotegerin, receptor activator for nuclear factor KB ligand and interleukin-8. RESULTS: Osteoblast morphology showed a reduced organization in the OVX group, in particular in the CM condition. Conversely, the analysis of cell viability revealed significantly higher values in the OVXCM group with respect to the SHAMCM group at all experimental times, whereas the OVXCTR group had significantly lower values at 7 and 14 days in comparison to those of the SHAM group. ALP release was significantly lower in the CM condition than that of CTR at all timepoints, and so was procollagen type I at 7 and 14 days. The RANKL/OPG ratio showed significantly higher values in OVX osteoblasts in comparison with those of the SHAM group, both in CTR and in CM conditions at each experimental time. Finally, OVXCM showed significantly higher values of IL-8 than those of SHAMCM at 7 and 14 days. CONCLUSIONS: The results clearly indicate an influence of the metastatic cells on the osteoblastic physiology at different levels: morphology, viability, release of typical proteins, and also IL-8 as a proinflammatory cytokine, especially marked by osteoporosis. Further investigations might highlight the relationship between osteoblasts and breast cancer cells, which might be useful to improve common drugs used against osteoporosis and bone metastases, by enhancing the bone deposition/tumor progression ratio. PMID- 26057368 TI - The selectivity of water-based pyrophosphate recognition is tuned by metal substitution in dimetallic receptors. AB - The three dimetallic compounds [Ga2(bpbp)(OH)2(H2O)2](ClO4)3, [In2(bpbp)(CH3CO2)2](ClO4)3 and [Zn2(bpbp)(HCO2)2](ClO4) (bpbp(-) = 2,6-bis((N,N' bis(2-picolyl)amino)methyl)-4-tertbutylphenolate) were evaluated as stable solid state precursors for reactive solution state receptors to use for the recognition of the biologically important anion pyrophosphate in water at neutral pH. Indicator displacement assays using in situ generated complex-pyrocatechol violet adducts, {M2(bpbp)(HxPV)}(n+) M = Ga(3+), In(3+), Zn(2+), were tested for selectivity in their reactions with a series of common anions: pyrophosphate, phosphate, ATP, arsenate, nitrate, perchlorate, chloride, sulfate, formate, carbonate and acetate. The receptor employing Ga(3+) showed a slow but visually detectable response (blue to yellow) in the presence of one equivalent of pyrophosphate but no response to any other anion, even when they were present in much higher concentrations. The systems based on In(3+) or Zn(2+) show less selectivity in accord with visibly discernible responses to several of the anions. These results demonstrate a facile method for increasing anion selectivity without modification of an organic dinucleating ligand scaffold. The comfortable supramolecular recognition of pyrophosphate by the dimetallic complexes is demonstrated by the single crystal X-ray structure of [Ga2(bpbp)(HP2O7)](ClO4)2 in which the pyrophosphate is coordinated to the two gallium ions via four of its oxygen atoms. PMID- 26057369 TI - High-sensitivity NMR beyond 200,000 atmospheres of pressure. AB - Pressure-induced changes in the chemical or electronic structure of solids require pressures well into the Giga-Pascal (GPa) range due to the strong bonding. Anvil cell designs can reach such pressures, but their small and mostly inaccessible sample chamber has severely hampered NMR experiments in the past. With a new cell design that has a radio frequency (RF) micro-coil in the high pressure chamber, NMR experiments beyond 20 Giga-Pascal are reported for the first time. (1)H NMR of water shows sensitivity and resolution obtained with the cells, and (63)Cu NMR on a cuprate superconductor (YBa2Cu3O7-delta) demonstrates that single-crystals can be investigated, as well. (115)In NMR of the ternary chalcogenide AgInTe2 discovers an insulator-metal transition with shift and relaxation measurements. The pressure cells can be mounted easily on standard NMR probes that fit commercial wide-bore magnets with regular cryostats for field- and temperature-dependent measurements ready for many applications in physics and chemistry. PMID- 26057370 TI - Determining an optimal management strategy for upper airway obstruction in Pierre Robin sequence. PMID- 26057371 TI - Not your 'garden variety' atelectasis. PMID- 26057372 TI - A 47-year-old stem cell transplant recipient with fever, cough and chest pain. AB - Infections and malignancies are among the most serious complications that follow organ or stem cell transplantation. They may have a mild course, and nonspecific and overlapping manifestations. The present article describes a case of symptomatic nodular pulmonary disease that complicated hematopoietic stem cell transplantation. It was diagnosed to be post-transplant lymphoproliferative disorder, a potential sequela of immunosuppression and a very difficult entity to treat in profoundly immunosuppressed patients. PMID- 26057373 TI - New-onset atrial fibrillation in critically ill patients. AB - New-onset atrial fibrillation is a common problem in critically ill patients, with reported incidence ranging from 5% to 46%. It is associated with significant morbidity and mortality. The present review summarizes studies investigating new onset atrial fibrillation conducted in the critical care setting, focusing on the etiology, management of the hemodynamically unstable patient, rate versus rhythm control, ischemic stroke risk and anticoagulation. Recommendations for an approach to management in the intensive care unit are drawn from the results of these studies. PMID- 26057374 TI - Investigation on cellular interactions of astrocytes with zinc oxide nanoparticles using rat C6 cell lines. AB - Zinc oxide nanoparticles (ZnO NPs) are widely used in cosmetic industries and have also found important applications in electrical and chemical industries. It is well documented that inhaled ZnO NPs can reach the brain through the olfactory neuronal pathway and can interfere with the brain zinc homeostasis. Most of the studies focus on the toxicity of ZnO NPs on neuronal cells and microglia. Not much work is available on the bio interaction of ZnO NPs with astrocytes, the major cells involved in brain homeostasis. Therefore, this study focuses on the interaction of ZnO NPs with rat C6 glial cells. The results of this study reveal that the nanoparticles are taken up by the astrocytes and induce a time and dose dependent toxicological response which is indicated by the nanoparticle uptake studies and cell viability assays. Also the results of DCFH-DA (2',7' dichlorofluorescein diacetate) assay show that the ZnO NPs induce strong oxidative stress in cells at 3 and 6h. However, at 24h the reactive oxygen species (ROS) detected in the nanoparticles treated groups were same as that of control. The mode of cell death induced by ZnO NPs was apoptosis as revealed by the nuclear condensation studies, live dead assay using acridine orange/ethidium bromide and apoptosis detection kit. This study, which explores the interaction of ZnO NPs with astrocytes, concludes that the persistence of particle can continue to have a damaging effect on the astrocytes. And hence the time of exposure and particle clearance by the system should be evaluated more thoroughly to prevent the health hazards due to these particles. PMID- 26057375 TI - Stereoisomerism effect on sugar-lectin binding of self-assembled glyco nanoparticles of linear and brush copolymers. AB - Binding behavior of carbohydrate and protein is known to be crucial to the biological roles of sugars. Recently, we notice that, even to the same lectin, some reported binding results based on glycopolymers and/or self-assembled glyco nanoparticles are different from those obtained on small molecular level. Some of such discrepancy could be associated with the different detection methods used. In this paper, by using self-assembled nanoparticles based on brush and linear glycopolymers, this stereoisomerism effect was evaluated systematically, both in solution and on solution-solid interface by different methods. All measurements led to the same conclusion that the stereoisomer of sugars determined the binding ability of glyco-nanoparticles with different lectins. The investigation also provided evidence on the different binding modes of nanoparticles of linear polymers and brush polymers. PMID- 26057376 TI - Enhanced biocompatibility and adhesive properties of modified allyl 2 cyanoacrylate-based elastic bio-glues. AB - Despite cyanoacrylate's numerous advantages such as good cosmetic results and fast application for first aid, drawbacks such as brittleness and local tissue toxicity have limited their applicability. In this study, to improve both the biocompatibility and mechanical properties of cyanoacrylate, allyl 2 cyanoacrylate (AC) was pre-polymerized and mixed with poly(L-lactide-co-E caprolactone) (PLCL, 50:50) as biodegradable elastomer. For various properties of pre-polymerized AC (PAC)/PLCL mixtures, bond strength, elasticity of flexure test as bending recovery, cell viability, and in vivo test using rat were conducted and enhanced mechanical properties and biocompatibility were confirmed. Especially, optimal condition for pre-polymerization of AC was determined to 150 degrees C for 40min through cytotoxicity test. Bond strength of PAC/PLCL mixture was decreased (over 10 times) with increasing of PLCL. On the other hand, biocompatibility and flexibility were improved than commercial bio-glue. Optimal PAC/PLCL composition (4g/20mg) was determined through these tests. Furthermore, harmful side effects and infection were not observed by in vivo wound healing test. These results indicate that PAC/PLCL materials can be used widely as advanced bio-glues in various fields. PMID- 26057377 TI - Impact of the Processes of Total Testicular Regression and Recrudescence on the Epididymal Physiology of the Bat Myotis nigricans (Chiroptera: Vespertilionidae). AB - Myotis nigricans is a species of vespertilionid bat, whose males show two periods of total testicular regression within the same annual reproductive cycle in the northwest Sao Paulo State, Brazil. Studies have demonstrated that its epididymis has an elongation of the caudal portion, which stores spermatozoa during the period of testicular regression in July, but that they had no sperm during the regression in November. Thus, the aim of this study was to analyze the impact of the total testicular regression in the epididymal morphophysiology and patterns of its hormonal regulation. The results demonstrate a continuous activity of the epididymis from the Active to the Regressing periods; a morphofunctional regression of the epididymis in the Regressed period; and a slow recrudescence process. Thus, we concluded that the processes of total testicular regression and posterior recrudescence suffered by M. nigricans also impact the physiology of the epididymis, but with a delay in epididymal response. Epididymal physiology is regulated by testosterone and estrogen, through the production and secretion of testosterone by the testes, its conduction to the epididymis (mainly through luminal fluid), conversion of testosterone to dihydrotestosterone by the 5alpha reductase enzyme (mainly in epithelial cells) and to estrogen by aromatase; and through the activation/deactivation of the androgen receptor and estrogen receptor alpha in epithelial cells, which regulate the epithelial cell morphophysiology, prevents cell death and regulates their protein expression and secretion, which ensures the maturation and storage of the spermatozoa. PMID- 26057379 TI - Experimental Support for a Single Electron-Transfer Oxidation Mechanism in Firefly Bioluminescence. AB - Firefly luciferase produces light by converting substrate beetle luciferin into the corresponding adenylate that it subsequently oxidizes to oxyluciferin, the emitter of bioluminescence. We have confirmed the generally held notions that the oxidation step is initiated by formation of a carbanion intermediate and that a hydroperoxide (anion) is involved. Additionally, structural evidence is presented that accounts for the delivery of oxygen to the substrate reaction site. Herein, we report key convincing spectroscopic evidence of the participation of superoxide anion in a related chemical model reaction that supports a single electron-transfer pathway for the critical oxidative process. This mechanism may be a common feature of bioluminescence processes in which light is produced by an enzyme in the absence of cofactors. PMID- 26057380 TI - Evaluating the Effect of Three Water Management Techniques on Tomato Crop. AB - The effects of three water management techniques were evaluated on subsurface drip irrigated tomatoes. The three techniques were the intermittent flow (3 pulses), the dual-lateral drip system (two lateral lines per row, at 15 and 25 cm below soil surface), and the physical barrier (buried at 30 cm below soil surface). Field experiments were established for two successive seasons. Water movement in soil was monitored using continuously logging capacitance probes up to 60 cm depth. The results showed that the dual lateral technique positively increased the yield up to 50%, water use efficiency up to 54%, while the intermittent application improved some of the quality measures (fruit size, TSS, and Vitamin C), not the quantity of the yield that decreased in one season, and not affected in the other. The physical barrier has no significant effect on any of the important growth measures. The soil water patterns showed that the dual lateral method lead to uniform wetting pattern with depth up to 45 cm, the physical barrier appeared to increase lateral and upward water movement, while the intermittent application kept the wetting pattern at higher moisture level for longer time. The cost analysis showed also that the economic treatments were the dual lateral followed by the intermittent technique, while the physical barrier is not economical. The study recommends researching the effect of the dual lateral method on the root growth and performance. The intermittent application may be recommended to improve tomato quality but not quantity. The physical barrier is not recommended unless in high permeable soils. PMID- 26057378 TI - Mechanisms of Hypoxic Up-Regulation of Versican Gene Expression in Macrophages. AB - Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte derived macrophages (HMDM), and, intriguingly, show that versican mRNA is up regulated much more highly (>600 fold) by long term hypoxia (5 days) than by 1 day of hypoxia (48 fold). We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K), LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression. PMID- 26057381 TI - Methylated Host Cell Gene Promoters and Human Papillomavirus Type 16 and 18 Predicting Cervical Lesions and Cancer. AB - Change in the host and/or human papillomavirus (HPV) DNA methylation profile is probably one of the main factors responsible for the malignant progression of cervical lesions to cancer. To investigate those changes we studied 173 cervical samples with different grades of cervical lesion, from normal to cervical cancer. The methylation status of nine cellular gene promoters, CCNA1, CDH1, C13ORF18, DAPK1, HIC1, RARbeta2, hTERT1, hTERT2 and TWIST1, was investigated by Methylation Specific Polymerase Chain Reaction (MSP). The methylation of HPV18 L1-gene was also investigated by MSP, while the methylated cytosines within four regions, L1, 5'LCR, enhancer, and promoter of the HPV16 genome covering 19 CpG sites were evaluated by bisulfite sequencing. Statistically significant methylation biomarkers distinguishing between cervical precursor lesions from normal cervix were primarily C13ORF18 and secondly CCNA1, and those distinguishing cervical cancer from normal or cervical precursor lesions were CCNA1, C13ORF18, hTERT1, hTERT2 and TWIST1. In addition, the methylation analysis of individual CpG sites of the HPV16 genome in different sample groups, notably the 7455 and 7694 sites, proved to be more important than the overall methylation frequency. The majority of HPV18 positive samples contained both methylated and unmethylated L1 gene, and samples with L1-gene methylated forms alone had better prognosis when correlated with the host cell gene promoters' methylation profiles. In conclusion, both cellular and viral methylation biomarkers should be used for monitoring cervical lesion progression to prevent invasive cervical cancer. PMID- 26057382 TI - Multilocus Bayesian Estimates of Intra-Oceanic Genetic Differentiation, Connectivity, and Admixture in Atlantic Swordfish (Xiphias gladius L.). AB - Previous genetic studies of Atlantic swordfish (Xiphias gladius L.) revealed significant differentiation among Mediterranean, North Atlantic and South Atlantic populations using both mitochondrial and nuclear DNA data. However, limitations in geographic sampling coverage, and the use of single loci, precluded an accurate placement of boundaries and of estimates of admixture. In this study, we present multilocus analyses of 26 single nucleotide polymorphisms (SNPs) within 10 nuclear genes to estimate population differentiation and admixture based on the characterization of 774 individuals representing North Atlantic, South Atlantic, and Mediterranean swordfish populations. Pairwise FST values, AMOVA, PCoA, and Bayesian individual assignments support the differentiation of swordfish inhabiting these three basins, but not the current placement of the boundaries that separate them. Specifically, the range of the South Atlantic population extends beyond 5 degrees N management boundary to 20 degrees N-25 degrees N from 45 degrees W. Likewise the Mediterranean population extends beyond the current management boundary at the Strait of Gibraltar to approximately 10 degrees W. Further, admixture zones, characterized by asymmetric contributions of adjacent populations within samples, are confined to the Northeast Atlantic. While South Atlantic and Mediterranean migrants were identified within these Northeast Atlantic admixture zones no North Atlantic migrants were identified respectively in these two neighboring basins. Owing to both, the characterization of larger number of loci and a more ample spatial sampling coverage, it was possible to provide a finer resolution of the boundaries separating Atlantic swordfish populations than previous studies. Finally, the patterns of population structure and admixture are discussed in the light of the reproductive biology, the known patterns of dispersal, and oceanographic features that may act as barriers to gene flow to Atlantic swordfish. PMID- 26057384 TI - Comparative Analysis of Codon Usage Bias Patterns in Microsporidian Genomes. AB - The sub-3 Mbp genomes from microsporidian species of the Encephalitozoon genus are the smallest known among eukaryotes and paragons of genomic reduction and compaction in parasites. However, their diminutive stature is not characteristic of all Microsporidia, whose genome sizes vary by an order of magnitude. This large variability suggests that different evolutionary forces are applied on the group as a whole. In this study, we have compared the codon usage bias (CUB) between eight taxonomically distinct microsporidian genomes: Encephalitozoon intestinalis, Encephalitozoon cuniculi, Spraguea lophii, Trachipleistophora hominis, Enterocytozoon bieneusi, Nematocida parisii, Nosema bombycis and Nosema ceranae. While the CUB was found to be weak in all eight Microsporidia, nearly all (98%) of the optimal codons in S. lophii, T. hominis, E. bieneusi, N. parisii, N. bombycis and N. ceranae are fond of A/U in third position whereas most (64.6%) optimal codons in the Encephalitozoon species E. intestinalis and E. cuniculi are biased towards G/C. Although nucleotide composition biases are likely the main factor driving the CUB in Microsporidia according to correlation analyses, directed mutational pressure also likely affects the CUB as suggested by ENc-plots, correspondence and neutrality analyses. Overall, the Encephalitozoon genomes were found to be markedly different from the other microsporidians and, despite being the first sequenced representatives of this lineage, are uncharacteristic of the group as a whole. The disparities observed cannot be attributed solely to differences in host specificity and we hypothesize that other forces are at play in the lineage leading to Encephalitozoon species. PMID- 26057385 TI - Comparison of High-Level Microarray Analysis Methods in the Context of Result Consistency. AB - MOTIVATION: When we were asked for help with high-level microarray data analysis (on Affymetrix HGU-133A microarray), we faced the problem of selecting an appropriate method. We wanted to select a method that would yield "the best result" (detected as many "really" differentially expressed genes (DEGs) as possible, without false positives and false negatives). However, life scientists could not help us--they use their "favorite" method without special argumentation. We also did not find any norm or recommendation. Therefore, we decided to examine it for our own purpose. We considered whether the results obtained using different methods of high-level microarray data analyses- Significant Analysis of Microarrays, Rank Products, Bland-Altman, Mann-Whitney test, T test and the Linear Models for Microarray Data--would be in agreement. Initially, we conducted a comparative analysis of the results on eight real data sets from microarray experiments (from the Array Express database). The results were surprising. On the same array set, the set of DEGs by different methods were significantly different. We also applied the methods to artificial data sets and determined some measures that allow the preparation of the overall scoring of tested methods for future recommendation. RESULTS: We found a very low level concordance of results from tested methods on real array sets. The number of common DEGs (detected by all six methods on fixed array sets, checked on eight array sets) ranged from 6 to 433 (22,283 total array readings). Results on artificial data sets were better than those on the real data. However, they were not fully satisfying. We scored tested methods on accuracy, recall, precision, f measure and Matthews correlation coefficient. Based on the overall scoring, the best methods were SAM and LIMMA. We also found TT to be acceptable. The worst scoring was MW. Based on our study, we recommend: 1. Carefully taking into account the need for study when choosing a method, 2. Making high-level analysis with more than one method and then only taking the genes that are common to all methods (which seems to be reasonable) and 3. Being very careful (while summarizing facts) about sets of differentially expressed genes: different methods discover different sets of DEGs. PMID- 26057383 TI - Dialyzer Reuse and Outcomes of High Flux Dialysis. AB - BACKGROUND: The bulk of randomized trial evidence for the expanding use of High Flux (HF) hemodialysis worldwide comes from two randomized controlled trials, one of which (HEMODIALYSIS, HEMO) allowed, while the other (Membrane Outcomes Permeability, MPO) excluded, the reuse of membranes. It is not known whether dialyzer reuse has a differential impact on outcomes with HF vs low flyx (LF) dialyzers. METHODS: Proportional Hazards Models and Joint Models for longitudinal measures and survival outcomes were used in HEMO to analyze the relationship between beta2-microglobulin (beta2M) concentration, flux, and reuse. Meta analysis and regression techniques were used to synthesize the evidence for HF dialysis from HEMO and MPO. FINDINGS: In HEMO, minimally reused (< 6 times) HF dialyzers were associated with a hazard ratio (HR) of 0.67 (95% confidence interval, 95%CI: 0.48-0.92, p = 0.015), 0.64 (95%CI: 0.44 - 0.95, p = 0.03), 0.61 (95%CI: 0.41 - 0.90, p = 0.012), 0.53 (95%CI: 0.28 - 1.02, p = 0.057) relative to minimally reused LF ones for all cause, cardiovascular, cardiac and infectious mortality respectively. These relationships reversed for extensively reused membranes (p for interaction between reuse and flux < 0.001, p = 0.005) for death from all cause and cardiovascular causes, while similar trends were noted for cardiac and infectious mortality (p of interaction between reuse and flux of 0.10 and 0.08 respectively). Reduction of beta2M explained only 1/3 of the effect of minimally reused HF dialyzers on all cause mortality, while non-beta2M related factors explained the apparent attenuation of the benefit with more extensively reused dialyzers. Meta-regression of HEMO and MPO estimated an adjusted HR of 0.63 (95% CI: 0.51-0.78) for non-reused HF dialyzers compared with non-reused LF membranes. CONCLUSIONS: This secondary analysis and synthesis of two large hemodialysis trials supports the widespread use of HF dialyzers in clinical hemodialysis over the last decade. A mechanistic understanding of the effects of HF dialysis and the reuse process on dialyzers may suggest novel biomarkers for uremic toxicity and may accelerate membrane technology innovations that will improve patient outcomes. PMID- 26057386 TI - Interference between Redroot Pigweed (Amaranthus retroflexus L.) and Cotton (Gossypium hirsutum L.): Growth Analysis. AB - Redroot pigweed is one of the injurious agricultural weeds on a worldwide basis. Understanding of its interference impact in crop field will provide useful information for weed control programs. The effects of redroot pigweed on cotton at densities of 0, 0.125, 0.25, 0.5, 1, 2, 4, and 8 plants m(-1) of row were evaluated in field experiments conducted in 2013 and 2014 at Institute of Cotton Research, CAAS in China. Redroot pigweed remained taller and thicker than cotton and heavily shaded cotton throughout the growing season. Both cotton height and stem diameter reduced with increasing redroot pigweed density. Moreover, the interference of redroot pigweed resulted in a delay in cotton maturity especially at the densities of 1 to 8 weed plants m(-1) of row, and cotton boll weight and seed numbers per boll were reduced. The relationship between redroot pigweed density and seed cotton yield was described by the hyperbolic decay regression model, which estimated that a density of 0.20-0.33 weed plant m(-1) of row would result in a 50% seed cotton yield loss from the maximum yield. Redroot pigweed seed production per plant or per square meter was indicated by logarithmic response. At a density of 1 plant m(-1) of cotton row, redroot pigweed produced about 626,000 seeds m(-2). Intraspecific competition resulted in density dependent effects on weed biomass per plant, a range of 430-2,250 g dry weight by harvest. Redroot pigweed biomass ha(-1) tended to increase with increasing weed density as indicated by a logarithmic response. Fiber quality was not significantly influenced by weed density when analyzed over two years; however, the fiber length uniformity and micronaire were adversely affected at density of 1 weed plant m(-1) of row in 2014. The adverse impact of redroot pigweed on cotton growth and development identified in this study has indicated the need of effective redroot pigweed management. PMID- 26057387 TI - Zinc Modulates Self-Assembly of Bacillus thermocatenulatus Lipase. AB - Thermoalkalophilic lipases are prone to aggregation from their dimer interface to which structural zinc is very closely located. Structural zinc sites have been shown to induce protein aggregation, but the interaction between zinc and aggregation tendency in thermoalkalophilic lipases remains elusive. Here we delineate the interplay between zinc and aggregation of the lipase from Bacillus thermocatenulatus (BTL2), which is taken to be a representative of thermoalkalophilic lipase. Results showed that zinc removal disrupted the BTL2 dimer, leading to monomer formation and reduced thermostability manifesting as a link between zinc and dimerization that leads to thermostability, while zinc addition induced aggregation. Biochemical and kinetic characterizations of zinc induced aggregates showed that the aggregates obtained from the early and late stages of aggregation had differential characteristics. In the early stages, the aggregates were soluble and possessed native-like structures, while in the late stages, the aggregates became insoluble and showed fibrillar characteristics with binding affinities for Congo red and thioflavin T. The impact of temperature on zinc-induced aggregation was further investigated, and it was found that the native-like early aggregates could completely dissociate into functional lipase forms at high temperatures while dissociation of the late aggregates was limited. To this end, we report that the zinc-induced aggregation of BTL2 can be reversed by temperature switches and initiated by ordered aggregates in the early stages that gain fibrillar-like features over time. Insights revealed by this work contributes to the knowledge of aggregation mechanisms that exist in thermophilic proteins, reflecting the potential use of metal addition and/or removal to fine tune aggregation tendency. PMID- 26057388 TI - Activation of Mst11 and Feedback Inhibition of Germ Tube Growth in Magnaporthe oryzae. AB - Appressorium formation and invasive growth are two important steps in the infection cycle of Magnaporthe oryzae that are regulated by the Mst11-Mst7-Pmk1 mitogen-activated protein kinase (MAPK) pathway. However, the molecular mechanism involved in the activation of Mst11 MAPK kinase kinase is not clear in the rice blast fungus. In this study, we functionally characterized the regulatory region of Mst11 and its self-inhibitory binding. Deletion of the middle region of Mst11, which contains the Ras-association (RA) domain and two conserved phosphorylation sites (S453 and S458), blocked Pmk1 activation and appressorium formation. However, the MST11(DeltaRA) transformant MRD-2 still formed appressoria, although it was reduced in virulence. Interestingly, over 50% of its germ tubes branched and formed two appressoria by 48 h, which was suppressed by treatments with exogenous cAMP. The G18V dominant active mutation enhanced the interaction of Ras2 with Mst11, suggesting that Mst11 has stronger interactions with the activated Ras2. Furthermore, deletion and site-directed mutagenesis analyses indicated that phosphorylation at S453 and S458 of Mst11 is important for appressorium formation and required for the activation of Pmk1. We also showed that the N-terminal region of Mst11 directly interacted with its kinase domain, and the S789G mutation reduced their interactions. Expression of the MST11(S789G) allele rescued the defect of the mst11 mutant in plant infection and resulted in the formation of appressoria on hydrophilic surfaces, suggesting the gain-of function effect of the S789G mutation. Overall, our results indicate that the interaction of Mst11 with activated Ras2 and phosphorylation of S453 and S458 play regulatory roles in Mst11 activation and infection-related morphogenesis, possibly by relieving its self-inhibitory interaction between its N-terminal region and the C-terminal kinase domain. In addition, binding of Mst11 to Ras2 may be involved in the feedback inhibition of cAMP signaling and further differentiation of germ tubes after appressorium formation. PMID- 26057389 TI - Persistence of the Host-Selective Toxin Ptr ToxB in the Apoplast. AB - The necrotrophic fungus Pyrenophora tritici-repentis is responsible for the disease tan spot of wheat. Ptr ToxB (ToxB), a proteinaceous host-selective toxin, is one of the effectors secreted by P. tritici-repentis. ToxB induces chlorosis in toxin-sensitive wheat cultivars and displays characteristics common to apoplastic effectors. We addressed the hypothesis that ToxB exerts its activity extracellularly. Our data indicate that hydraulic pressure applied in the apoplast following ToxB infiltration can displace ToxB-induced symptoms. In addition, treatment with a proteolytic cocktail following toxin infiltration results in reduction of symptom development and indicates that ToxB requires at least 8 h in planta to induce maximum symptom development. In vitro assays demonstrate that apoplastic fluids extracted from toxin-sensitive and insensitive wheat cultivars cannot degrade ToxB. Additionally, ToxB can be reisolated from apoplastic fluid after toxin infiltration. Furthermore, localization studies of fluorescently labeled ToxB indicate that the toxin remains in the apoplast in toxin-sensitive and -insensitive wheat cultivars. Our findings support the hypothesis that ToxB acts as an extracellular effector. PMID- 26057390 TI - Prediction of the fate of Hg and other contaminants in soil around a former chlor alkali plant using Fuzzy Hierarchical Cross-Clustering approach. AB - An associative simultaneous fuzzy divisive hierarchical algorithm was used to predict the fate of Hg and other contaminants in soil around a former chlor alkali plant. The algorithm was applied on several natural and anthropogenic characteristics of soil including water leachable, mobile, semi-mobile, non mobile fractions and total Hg, Al, Ba, Ca, Cr, Cu, Fe, K, Li, Mg, Mn, Na, Sr, Zn, water leachable fraction of Cl(-), NO3(-) and SO4(2)(-), pH and total organic carbon. The cross-classification algorithm provided a divisive fuzzy partition of the soil samples and associated characteristics. Soils outside the perimeter of the former chlor-alkali plant were clustered based on the natural characteristics and total Hg. In contaminated zones Hg speciation becomes relevant and the assessment of species distribution is necessary. The descending order of concentration of Hg species in the test site was semi-mobile>mobile>non mobile>water-leachable. Physico-chemical features responsible for similarities or differences between uncontaminated soil samples or contaminated with Hg, Cu, Zn, Ba and NO3(-) were also highlighted. Other characteristics of the contaminated soil were found to be Ca, sulfate, Na and chloride, some of which with influence on Hg fate. The presence of Ca and sulfate in soil induced a higher water leachability of Hg, while Cu had an opposite effect by forming amalgam. The used algorithm provided an in-deep understanding of processes involving Hg species and allowed to make prediction of the fate of Hg and contaminants linked to chlor alkali-industry. PMID- 26057391 TI - Adsorption and desorption of ammonium by maple wood biochar as a function of oxidation and pH. AB - The objective of this work was to investigate the retention mechanisms of ammonium in aqueous solution by using progressively oxidized maple wood biochar at different pH values. Hydrogen peroxide was used to oxidize the biochar to pH values ranging from 8.1 to 3.7, with one set being adjusted to a pH of 7 afterwards. Oxidizing the biochars at their lowered pH did not increase their ability to adsorb ammonium. However, neutralizing the oxygen-containing surface functional groups on oxidized biochar to pH 7 increased ammonia adsorption two to three-fold for biochars originally at pH 3.7-6, but did not change adsorption of biochars oxidized to pH 7 and above. The adsorption characteristics of ammonium are well described by the Freundlich equation. Adsorption was not fully reversible in water, and less than 27% ammonium was desorbed in water in two consecutive steps than previously adsorbed, for biochars with a pH below 7, irrespective of oxidation. Recovery using an extraction with 2M KCl increased from 34% to 99% of ammonium undesorbed by both preceding water extractions with increasing oxidation, largely irrespective of pH adjustment. Unrecovered ammonium in all extractions and residual biochar was negligible at high oxidation, but increased to 39% of initially adsorbed amounts at high pH, likely due to low amounts adsorbed and possible ammonia volatilization losses. PMID- 26057392 TI - Re: Pachychoroid neovasculopathy. PMID- 26057393 TI - Re: Choroidal thickness in clinically significant pseudophakic cystoid macular edema. PMID- 26057394 TI - Re: Scleral imbrication combined with vitrectomy and gas tamponade for refractory macular hole retinal detachment associated with high myopia. PMID- 26057395 TI - Re: Visual outcomes from pars plana vitrectomy versus combined pars plana vitrectomy, phacoemulsification, and intraocular lens implantation in patients with diabetes. PMID- 26057396 TI - Reply: To PMID 25158945. PMID- 26057397 TI - Reply: To PMID 25170855. PMID- 26057398 TI - Reply: To PMID 24830822. PMID- 26057399 TI - Reply: To PMID 25062437. PMID- 26057400 TI - Size and Aging Effects on Antimicrobial Efficiency of Silver Nanoparticles Coated on Polyamide Fabrics Activated by Atmospheric DBD Plasma. AB - This work studies the surface characteristics, antimicrobial activity, and aging effect of plasma-pretreated polyamide 6,6 (PA66) fabrics coated with silver nanoparticles (AgNPs), aiming to identify the optimum size of nanosilver exhibiting antibacterial properties suitable for the manufacture of hospital textiles. The release of bactericidal Ag(+) ions from a 10, 20, 40, 60, and 100 nm AgNPs-coated PA66 surface was a function of the particles' size, number, and aging. Plasma pretreatment promoted both ionic and covalent interactions between AgNPs and the formed oxygen species on the fibers, favoring the deposition of smaller-diameter AgNPs that consequently showed better immediate and durable antimicrobial effects against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus bacteria. Surprisingly, after 30 days of aging, a comparable bacterial growth inhibition was achieved for all of the fibers treated with AgNPs <100 nm in size. The Ag(+) in the coatings also favored the electrostatic stabilization of the plasma-induced functional groups on the PA66 surface, thereby retarding the aging process. At the same time, the size-related ratio (Ag(+)/Ag(0)) of the AgNPs between 40 and 60 nm allowed for the controlled release of Ag(+) rather than bulk silver. Overall, the results suggest that instead of reducing the size of the AgNPs, which is associated with higher toxicity, similar long-term effects can be achieved with larger NPs (40-60 nm), even in lower concentrations. Because the antimicrobial efficiency of AgNPs larger than 30 nm is mainly ruled by the release of Ag(+) over time and not by the size and number of the AgNPs, this parameter is crucial for the development of efficient antimicrobial coatings on plasma-treated surfaces and contributes to the safety and durability of clothing used in clinical settings. PMID- 26057401 TI - Interferons and systemic sclerosis: correlation between interferon gamma and interferon-lambda 1 (IL-29). AB - BACKGROUND: Interferon (IFN)-lambda1 is a newly described cytokine, member of type III interferons family, which is known for its antiviral, anti-proliferative and antitumor activity. Recent studies indicated that this cytokine has also immune-regulatory function, but its role in the pathogenesis of autoimmune diseases is not established yet. We evaluated serum levels of IFN-lambda1 in systemic sclerosis (SSc) patients and healthy controls and its association with IFN-gamma and clinical manifestations. METHODS: IFN-lambda1 and IFN-gamma serum levels were measured by ELISA from 52 patients with SSc and 53 healthy controls. Association of cytokines serum levels was sought with clinical parameters. RESULTS: IFN-lambda1 and IFN-gamma levels in SSc patients were significantly higher than those in healthy individuals (24.82 +/- 8.78 and 11.04 +/- 3.04 pg/ml, p < 0.0001; 34.11 +/- 8.11 and 10.73 +/- 2.77 pg/ml, p < 0.0001, respectively). We found a positive correlation between IFN-lambda1 and IFN-gamma levels in SSc patients (p = 0.0103, r = 0.3526). IFN-gamma levels were associated with muscle involvement (p = 0.0483). CONCLUSION: We first showed raised IFN lambda1 levels in SSc patients. Furthermore, we found a correlation between IFN lambda1 and IFN-gamma levels and an association between IFN-gamma and myositis. Additional in vitro and in vivo studies are needed to understand IFN-lambda1 role in SSc. PMID- 26057402 TI - Does level of processing affect the transition from unconscious to conscious perception? AB - Recently, Windey, Gevers, and Cleeremans (2013) proposed a level of processing (LoP) hypothesis claiming that the transition from unconscious to conscious perception is influenced by the level of processing imposed by task requirements. Here, we carried out two experiments to test the LoP hypothesis. In both, participants were asked to classify briefly presented pairs of letters as same or different, based either on the letters' physical features (a low-level task), or on a semantic rule (a high-level task). Stimulus awareness was measured by means of the four-point Perceptual Awareness Scale (PAS). The results showed that low or moderate stimulus visibility was reported more frequently in the low-level task than in the high-level task, suggesting that the transition from unconscious to conscious perception is more gradual in the former than in the latter. Therefore, although alternative interpretations remain possible, the results of the present study fully support the LoP hypothesis. PMID- 26057403 TI - What is French for deja vu? Descriptions of deja vu in native French and English speakers. AB - Little is known about how people characterise and classify the experience of deja vu. The term deja vu might capture a range of different phenomena and people may use it differently. We examined the description of deja vu in two languages: French and English, hypothesising that the use of deja vu would vary between the two languages. In French, the phrase deja vu can be used to indicate a veridical experience of recognition - as in "I have already seen this face before". However, the same is not true in English. In an online questionnaire, we found equal rates of deja vu amongst French and English speakers, and key differences in how the experience was described. As expected, the French group described the experience as being more frequent, but there was the unexpected finding that they found it to be more troubling. PMID- 26057404 TI - Neuroticism and vigilance revisited: A transcranial doppler investigation. AB - Selecting for vigilance assignments remains an important factor in human performance research. The current study revisits the potential relationship between vigilance performance and trait neuroticism, in light of two possible theories. The first theory suggests that neuroticism impairs vigilance performance by competing for available resources. The second theory, attentional control theory, posits that high neuroticism can result in similar or superior performance levels due to the allocation of compensatory effort. In the present study, Transcranial Doppler Sonography was used to investigate the neurophysiological underpinnings of neuroticism during a 12-min abbreviated vigilance task. Performance results were not modified by level of neuroticism, but high neuroticism was associated with higher initial CBFV levels and a greater CBFV decrement over time. These findings indicate that participants higher in neuroticism recruited additional cognitive resources in order to achieve similar performance, suggesting that there is more of an effect on processing efficiency than effectiveness. PMID- 26057405 TI - Hypnosis and belief: A review of hypnotic delusions. AB - Hypnosis can create temporary, but highly compelling alterations in belief. As such, it can be used to model many aspects of clinical delusions in the laboratory. This approach allows researchers to recreate features of delusions on demand and examine underlying processes with a high level of experimental control. This paper reviews studies that have used hypnosis to model delusions in this way. First, the paper reviews studies that have focused on reproducing the surface features of delusions, such as their high levels of subjective conviction and strong resistance to counter-evidence. Second, the paper reviews studies that have focused on modelling underlying processes of delusions, including anomalous experiences or cognitive deficits that underpin specific delusional beliefs. Finally, the paper evaluates this body of research as a whole. The paper discusses advantages and limitations of using hypnotic models to study delusions and suggests some directions for future research. PMID- 26057406 TI - Motivating meta-awareness of mind wandering: A way to catch the mind in flight? AB - Given the negative effects of mind wandering on performance, it may be profitable to be aware of task-unrelated thoughts (TUTs) as they occur. The present study investigated whether motivating people to catch TUTs increases meta-awareness. We offered incentives for increased self-catching during reading. To enhance the veracity of these self-reports, we used a "bogus-pipeline" procedure; we convinced participants that their mental states were being covertly monitored using physiological measures. In reality, mind wandering was assessed covertly by a secondary task ("gibberish detection"), and overtly by experience sampling. The results showed that incentives increased the number of self-catches without increasing overall mind wandering. Moreover, both the bogus pipeline and the opportunity for incentives increased the validity of self-reports, evidenced by significantly increased correlations between self-caught and behaviorally assessed mind wandering. We discuss the relevance of this methodological approach for research on mind wandering and research building on introspective reports more generally. PMID- 26057407 TI - A fast 3D reconstruction system with a low-cost camera accessory. AB - Photometric stereo is a three dimensional (3D) imaging technique that uses multiple 2D images, obtained from a fixed camera perspective, with different illumination directions. Compared to other 3D imaging methods such as geometry modeling and 3D-scanning, it comes with a number of advantages, such as having a simple and efficient reconstruction routine. In this work, we describe a low-cost accessory to a commercial digital single-lens reflex (DSLR) camera system allowing fast reconstruction of 3D objects using photometric stereo. The accessory consists of four white LED lights fixed to the lens of a commercial DSLR camera and a USB programmable controller board to sequentially control the illumination. 3D images are derived for different objects with varying geometric complexity and results are presented, showing a typical height error of <3 mm for a 50 mm sized object. PMID- 26057408 TI - Could EEG Monitoring in Critically Ill Children Be a Cost-effective Neuroprotective Strategy? AB - PURPOSE: Electrographic status epilepticus (ESE) in critically ill children is associated with unfavorable functional outcomes, but identifying candidates for ESE management requires resource-intense EEG monitoring. A cost-effectiveness analysis was performed to estimate how much ESE identification and management would need to improve patient outcomes to make EEG monitoring strategies a good value. METHODS: A decision tree was created to examine the relationships among variables important to deciding whether to perform EEG monitoring. Variable costs were estimated from their component parts, outcomes were estimated in quality adjusted life-years, and incremental cost-effectiveness ratios were calculated to compare the relative values using four alternative EEG monitoring strategies that varied by monitoring duration. RESULTS: Forty-eight hours of EEG monitoring would be worth its cost if ESE identification and management improved patient outcomes by >=7%. If ESE identification and management improved patient outcomes by 3% to 6%, then 24 or 48 hours of EEG monitoring would be worth the cost depending on how much decision makers were willing to pay per quality-adjusted life-year gained. If ESE identification and management improved outcomes by as little as 3%, then 24 hours of EEG monitoring would be worth the cost. CONCLUSIONS: EEG monitoring has the potential to be cost-effective if ESE identification and management improves patient outcomes by as little as 3%. PMID- 26057409 TI - Persistence of Upper Blepharoptosis After Cosmetic Botulinum Toxin Type A. AB - BACKGROUND: Upper eyelid ptosis after cosmetic botulinum toxin is generally considered short-lived and responsive to apraclonidine ophthalmic drops. The authors present a series with persistent ptosis. OBJECTIVE: To report a series of patients with persistent upper eyelid ptosis after cosmetic botulinum toxin. MATERIALS AND METHODS: A retrospective case review series of 7 patients referred for management after developing visually significant upper eyelid ptosis after cosmetic botulinum toxin type A treatment. RESULTS: Patients in this series experienced persistent visually significant ptosis after cosmetic botulinum toxin lasting from 6 weeks to 13 months. Six of the 7 patients were treated with apraclonidine ophthalmic solution. Apraclonidine drops appeared to be clinically effective within 4 to 6 weeks of the resolution of ptosis. CONCLUSION: Upper eyelid ptosis after cosmetic botulinum toxin can persist for many months after treatment. Based on this series, the authors propose that apraclonidine drops can be used at the time of initial assessment to predict the relative longevity of ptosis after cosmetic botulinum toxin treatment (Level 4 evidence recommendation). After a 1-week trial, responders can be advised that ptosis is likely to resolve in 4 to 6 weeks. Nonresponders should be counseled that resolution may take longer than 6 weeks. PMID- 26057410 TI - Complications With New Oral Anticoagulants Dabigatran and Rivaroxaban in Cutaneous Surgery. AB - BACKGROUND: Anticoagulant medications to date are not associated with increased risk of severe life-threatening complications during cutaneous surgery. Dabigatran and rivaroxaban are new orally administered anticoagulants that do not require laboratory monitoring and have no available specific antidotes, making perioperative management more complex. To the authors' knowledge, published data on the use of dabigatran or rivaroxaban in patients undergoing cutaneous surgery are limited. OBJECTIVE: The authors sought to study perioperative complications associated with dabigatran and rivaroxaban during cutaneous surgery. MATERIALS AND METHODS: Retrospective chart analysis was performed for all patients who underwent Mohs micrographic surgery or basic excision while taking dabigatran or rivaroxaban between January 1, 2010, and September 1, 2013, at Mayo Clinic, Rochester, MN. RESULTS: Twenty-seven patients taking dabigatran underwent 41 cutaneous surgeries, with only 1 mild bleeding complication observed that was remedied with a pressure dressing. Four patients on rivaroxaban underwent 5 cutaneous surgeries without complication. CONCLUSION: Because no patients on dabigatran or rivaroxaban experienced severe hemorrhagic complications during cutaneous surgery, a strategy of continuing these medically necessary medications during cutaneous surgery seems reasonable. PMID- 26057411 TI - A Survey Comparing Delegation of Cosmetic Procedures Between Dermatologists and Nondermatologists. AB - BACKGROUND: How delegation of procedures varies among cosmetic specialties in the United States is not well described. OBJECTIVE: To better describe current practices in delegation of procedures to nonphysicians among physicians of different cosmetic specialties in the United States. METHODS: An Internet-based survey was administered to physician members of the American Society for Dermatologic Surgery (ASDS), the American Society for Aesthetic Plastic Surgery (ASAPS), and the American Society for Laser Medicine and Surgery (ASLMS). RESULTS: A total of 823 responses were collected. Two hundred ninety-one of the 521 dermatologists (55.9%) reported delegating cosmetic procedures compared with 223 of the 302 nondermatologists (73.8%) (p < .05). When delegation occurred, dermatologists were more likely than nondermatologists to delegate the following procedures to higher level non-physician providers (NPP): chemical peels, neuromodulator and filler injections, laser hair removal, pulsed dye laser, tattoo removal, intense pulsed light, nonablative fractional laser, and sclerotherapy. No difference in delegation rate was noted between dermatologists and non-dermatologist physicians with respect to microdermabrasion, ablative fractional laser, cryolipolysis, radiofrequency skin tightening, focused ultrasound skin tightening, and focused ultrasound fat reduction. CONCLUSION: Dermatologists delegate procedures to NPP less frequently than non-dermatologist physicians, and when they do, it is typically to higher level NPP. PMID- 26057412 TI - Atomic-layer-deposited silver and dielectric nanostructures for plasmonic enhancement of Raman scattering from nanoscale ultrathin films. AB - Plasmonic silver nanostructures and a precise ZnO cover layer prepared by capacitively coupled plasma atomic layer deposition (ALD) were exploited to enhance the Raman scattering from nanoscale ultrathin films on a Si substrate. The plasmonic activity was supported by a nanostructured Ag (nano-Ag) layer, and a ZnO cover layer was introduced upon the nano-Ag layer to spectrally tailor the localized surface plasmon resonance to coincide with the laser excitation wavelength. Because of the optimized dielectric environment provided by the precise growth of ZnO cover layer using ALD, the intensity of Raman scattering from nanoscale ultrathin films was significantly enhanced by an additional order of magnitude, leading to the observation of the monoclinic and tetragonal phases in the nanoscale ZrO2 high-K gate dielectric as thin as ~6 nm on Si substrate. The excellent agreement between the finite-difference time-domain simulation and experimental measurement further confirms the so-called [absolute value]E( >)[absolute value](4) dependence of the surface-enhanced Raman scattering. This technique of plasmonic enhancement of Raman spectroscopy, assisted by the nano-Ag layer and optimized dielectric environment prepared by ALD, can be applied to characterize the structures of ultrathin films in a variety of nanoscale materials and devices, even on a Si substrate with overwhelming Raman background. PMID- 26057415 TI - In vivo epicardial force and strain characterisation in normal and MLP-knockout murine hearts. AB - The study's objective is to quantify in vivo epicardial force and strain in the normal and transgenic myocardium using microsensors.Male mice (n = 39), including C57BL/6 (n = 26), 129/Sv (n = 5), wild-type (WT) C57 * 129Sv (n = 5), and muscle LIM protein (MLP) knock-out (n = 3), were studied under 1.5% isoflurane anaesthesia. Microsurgery allowed the placement of two piezoelectric crystals at longitudinal epicardial loci at the basal, middle, and apical LV regions, and the independent (and/or concurrent) placement of a cantilever force sensor. The findings demonstrate longitudinal contractile and relaxation strains that ranged between 4.8-9.3% in the basal, middle, and apical regions of C57BL/6 mice, and in the mid-ventricular regions of 129/Sv, WT, and MLP mice. Measured forces ranged between 3.1-8.9 mN. The technique's feasibility is also demonstrated in normal mice following afterload, occlusion-reperfusion challenges.Furthermore, the total mid-ventricular forces developed in MLP mice were significantly reduced compared to the WT controls (5.9 +/- 0.4 versus 8.9 +/- 0.2 mN, p < 0.0001), possibly owing to the fibrotic and stiffer myocardium. No significant strain differences were noted between WT and MLP mice.The possibility of quantifying in vivo force and strain from the normal murine heart is demonstrated with a potential usefulness in the characterisation of transgenic and diseased mice, where regional myocardial function may be significantly altered. PMID- 26057416 TI - SILENCING SHARAPOVA'S GRUNT IMPROVES THE PERCEPTION OF HER SERVE SPEED. AB - In recent years, grunting has become a familiar although generally unwelcome element of tennis. The behavior is considered to deny opponents the benefit of receiving optimal multi-sensory information in order to plan their own shots. The ability to make accurate serve-speed judgments of identical tennis serves presented on a computer screen, and accompanied by a grunt or not, was assessed among 38 participants (19 men). Accuracy and response time were measured. Analysis compared performance for below versus above average speed serves and for the grunt versus the no grunt condition. Grunting had a disruptive effect on serve-speed perception for below average serves, with most judged incorrectly to be above average. Response times for below average serves were also slower in the grunt condition. Grunting provides a complex perceptual challenge, and greater effort may be attributed to tennis serves with an accompanying grunt. PMID- 26057417 TI - THE EFFECTS OF SEX, TOPOLOGICAL STRUCTURE, AND TASK TYPE ON HYPERTEXT NAVIGATIONAL PERFORMANCE. AB - Currently, almost all online materials use hyperlinks to provide users access to background, supplemental, or alternative information presented in context, greatly increasing the potential integration of information. However, a major problem is that people do not navigate hyperlinks effectively when the links become more topologically complex. Thus, identification of the variables that lead to navigational errors is necessary for the effective design of hyperlinks. Ninety-one participants (45 women, 46 men) were recruited for this experiment. All were college students and ranged in age from 19 to 23 yr. (M = 20.87, SD = 1.02). Navigational performance was examined in relation to sex, topological structure, and task type. A network topology with single-node task was superior to one with a linear topology under a single-node task condition, but equal to one with a linear topology under a multi-node task condition. Men navigated the linear topology with multi-node task and a network topology with a single-node task significantly faster than women, whereas no significant differences were observed under the other conditions. Sex interacted with topological structure and task type. This study extended the research in this domain by demonstrating an interactive effect among sex, topological structure, and task type on the navigational performance of users and can contribute to research regarding web page design. PMID- 26057418 TI - PSYCHOSOCIAL PREDICTORS OF FEMALE COLLEGE STUDENTS' MOTIVATIONAL RESPONSES: A PROSPECTIVE ANALYSIS. AB - According to social cognitive theory, group cohesion and self-efficacy have been identified as important environmental and individual elements in students' physical activity. This study examined the correlations among group cohesion, exercise self-efficacy, perceived interest, and physical activity among 143 female college students (M age = 21.2 yr., SD = 4.2) enrolled in aerobics dance classes. Participants were recruited by researchers at the beginning of the semester. In the 6th wk., students completed a questionnaire measuring group cohesion construct. At the end of the 13th wk., a survey on self-efficacy, perceived interest, and physical activity measures was completed by the students. Multiple regression analyses indicated both exercise self-efficacy and task cohesion explained significant variance in students' physical activity; also, Individual Attraction to the Group-Task (ATG-T) accounted for 9.6% of the variance in exercise self-efficacy. The results suggest that enhancing group cohesiveness may promote competence beliefs, which could motivate students' participation in group activity programs. PMID- 26057419 TI - PERCEIVED AUTONOMY SUPPORT AND BEHAVIORAL ENGAGEMENT IN PHYSICAL EDUCATION: A CONDITIONAL PROCESS MODEL OF POSITIVE EMOTION AND AUTONOMOUS MOTIVATION. AB - A variety of theoretical perspectives describe the crucial behavioral roles of motivation and emotion, but how these interact with perceptions of social contexts and behaviors is less well understood. This study examined whether autonomous motivation mediated the relationship between perceived autonomy support and behavioral engagement in physical education and whether this mediating process was moderated by positive emotion. A sample of 592 Korean middle-school students (304 boys, 288 girls; M age = 14.0 yr., SD = 0.8) completed questionnaires. Autonomous motivation partially mediated the positive association between perceived autonomy support and behavioral engagement. Positive emotion moderated the relationship between autonomous motivation and behavioral engagement. This indirect link was stronger as positive emotion increased. These findings suggest the importance of integrating emotion into motivational processes to understand how and when perceived autonomy support is associated with behavioral engagement in physical education. PMID- 26057420 TI - A WORKLOAD SELECTION PROCEDURE FOR THE ASTRAND-RYHMING TEST FOR WOMEN. AB - The Astrand-Ryhming Submaximal Bicycle Test is an accurate and widely used test to estimate maximal oxygen consumption. This test requires a participant to maintain a workload over a 6-min. PERIOD: The issue facing many employing this protocol is the identification of an appropriate workload for the cycling regimen. The present study is designed to identify a method for determining an appropriate workload for female participants. A prior study designed a workload selection procedure specifically for men; however, the selection procedure designed for women in this study was better able to elicit a final heart rate (average of minutes five and six) between 165-170 bpm compared to the original Astrand-Ryhming procedure. PMID- 26057421 TI - DEVELOPMENT OF A TURKISH VERSION OF THE SENSORY PROFILE: TRANSLATION, CROSS CULTURAL ADAPTATION, AND PSYCHOMETRIC VALIDATION. AB - The purpose of this study was to translate and culturally adapt the Sensory Profile (SP), which is used to measure sensory processing abilities of children ages of 3-10 years, and test its reliability and validity for use with Turkish children with autism. A cross-cultural adaptation process was carried out by bilingual experts, following typical guidelines. The test-retest reliability, internal consistency, and construct validity studies of the Turkish SP were done for 144 children with autism. A comparison was also made between results of children with autism and 101 healthy children to test the validity of the Turkish SP. There were significant differences between results of autistic and healthy children on all subsections of the test. The Cronbach's as ranged from .63 to .97 for all subsections except I, J, and N, which had poor internal consistency reliability. Test-retest reliability over a one-week period was excellent (ICC > .90). PMID- 26057422 TI - MUSIC TEMPO'S EFFECT ON EXERCISE PERFORMANCE: COMMENT ON DYER AND McKUNE. AB - Dyer and McKune (2013) stated that music tempo has no influence on performance, physiological, and psychophysical variables in well-trained cyclists during high intensity endurance tasks. However, there are important limitations in the methodology of the study. The participants' music preferences and tempo change were not well measured. It is not possible to affirm that music tempo does not influence athletes' performance. Potential areas of future research include: (a) use of instruments to assess the qualities of music; (b) standardizing music of tempo according to exercise type (e.g., running, cycling, etc.); PMID- 26057423 TI - Instructional design: more important than ever! PMID- 26057424 TI - Revision and psychometric testing of the Incivility in Nursing Education (INE) survey: introducing the INE-R. AB - BACKGROUND: Academic incivility is a serious challenge for nursing education, which needs to be empirically measured and fully addressed. METHOD: A convenience sample of nursing faculty and students from 20 schools of nursing in the United States participated in a mixed-methods study to test the psychometric properties of the Incivility in Nursing Education-Revised (INE-R) Survey. RESULTS: A factor analysis and other reliability analyses support the use of the INE-R as a valid and reliable measurement of student and faculty perceptions of incivility in nursing education. CONCLUSION: The INE-R is a psychometrically sound instrument to measure faculty and student perceptions of incivility; to examine differences regarding levels of nursing education, program type, gender, age, and ethnicity; to compare perceptions of incivility between and among adjunct, clinical, teaching, and research faculty; and to conduct pre- and postassessments of the perceived levels of faculty and student incivility in nursing programs to inform evidence-based interventions. PMID- 26057426 TI - Mentoring Hispanic undergraduate and graduate research assistants: building research capacity in nursing. AB - BACKGROUND: This article discusses and describes the experiences of five Hispanic bilingual (English and Spanish) research assistants (RAs) who were undergraduate and graduate nursing students and who were part of a research team. METHOD: A capacity-building framework was used, which has six guiding principles: a whole system approach; accommodating diversity; reducing barriers to participation; enabling collaboration; mentoring; and facilitating networking. In addition, mentorship and peer learning were essential components of building research capacity. RESULTS: Reflections of the five RAs highlighting how these principles were applied are described. The experiences of the five Hispanic RAs and the outcomes of the projects are also described. CONCLUSION: These experiences demonstrate the importance of involving undergraduate and graduate nursing students in research, which can build research capacity and increase the number of Hispanic nurses in the workforce. PMID- 26057425 TI - An interprofessional consensus of core competencies for prelicensure education in pain management: curriculum application for nursing. AB - BACKGROUND: Ineffective assessment and management of pain is a significant problem. A gap in prelicensure health science program pain content has been identified for the improvement of pain care in the United States. METHOD: Through consensus processes, an expert panel of nurses, who participated in the interdisciplinary development of core competencies in pain management for prelicensure health professional education, developed recommendations to address the gap in nursing curricula. RESULTS: Challenges and incentives for implementation of pain competencies in nursing education are discussed, and specific recommendations for how to incorporate the competencies into entry-level nursing curricula are provided. CONCLUSION: Embedding pain management core competencies into prelicensure nursing education is crucial to ensure that nurses have the essential knowledge and skills to effectively manage pain and to serve as a foundation on which clinical practice skills can be later honed. [J Nurs Educ. 2015;54(6):317-327.]. PMID- 26057427 TI - Effects of a community-based hospice experience on attitudes and self-perceived competencies of baccalaureate senior nursing students. AB - BACKGROUND: Educational programs preparing nurses have devoted little time in the curricula to the care of the dying patient and the grieving family. METHOD: An experimental design was used to determine the effects of a 2-day hospice experience on the attitudes and competencies of 61 baccalaureate nursing students enrolled in their final semester. Measures included an end-of-life attitudes survey, an end-of-life competency survey, and student reflections. RESULTS: Mean scores changed significantly after the hospice experience, suggesting a positive attitude change as a result of the intervention. Although mean scores in competency changed, these were not statistically significant. Student reflections supported attitude changes about end-of-life care and improved competencies. CONCLUSION: Although the experience seemed to make a difference, larger samples and longer exposure to the care of the dying are needed to more accurately assess the impact of a hospice experience on student attitudes and competencies related to end-of-life care. [J Nurs Educ. 2015;54(6):335-338.]. PMID- 26057428 TI - Comparing professional values and authentic leadership dimensions in baccalaureate nursing students: a longitudinal study. AB - BACKGROUND: A series of three baccalaureate Nursing Leadership and Patient Centered Care (NLPCC) courses were developed to strengthen students' perceptions and preparation as leaders in the delivery of patient-centered care through more effective professional socialization. METHOD: A mixed-methods design was used, administering two surveys to students at the start of the junior year and the end of their senior year, plus two qualitative questions were administered after the second-semester junior and senior years. RESULTS: Qualitative data reflected a growing awareness of the professional nurse's role and responsibilities beyond the bedside. Graduating senior students demonstrated a heightened awareness for the socialization and realities of practice and a growing sense of readiness and empowerment to embrace the professional role of an RN. CONCLUSION: Through role modeling, scripted conversations, and focused dialogue, the infusion of knowledge, skills, and attitudes from the Quality and Safety Education for Nurses competencies allowed students to hone their socialization skills prior to entering the workforce. PMID- 26057429 TI - Faculty to faculty: advice for educators new to teaching in accelerated second baccalaureate degree nursing programs. AB - BACKGROUND: Despite a growing faculty shortage, accelerated second baccalaureate degree nursing programs (ASBSN) proliferate. To prepare faculty for this teaching role, guide their development, and enhance recruitment and retention, ASBSN faculty in this descriptive study offered advice to new ASBSN educators. METHOD: Data were collected online from ASBSN faculty (N = 93) across the midwestern United States. RESULTS: Six themes emerged: (a) Plan for Program Intensity That Stresses Students and Faculty, (b) Be Available, Flexible, Open-Minded, and Patient, (c) Uphold Early-Established Expectations and Rigorous Standards, (d) Be Prepared for Challenging Questions: Know Your Material and Be Organized, (e) Integrate Students' Diversity Into Teaching and Learning, and (f) Adapt Content and Teaching Strategies to Align With Student and Program Characteristics. Consistency with the Suplee and Gardner new faculty orientation model was explored. CONCLUSION: Respondents viewed new ASBSN faculty as active agents who can influence their own effectiveness and success. [J Nurs Educ. 2015;54(6):343 346.]. PMID- 26057430 TI - Focusing on the "T" in LGBT: an online survey of related content in texas nursing programs. AB - BACKGROUND: As nurses, we advocate for the most vulnerable and underserved, who, within the lesbian, gay, bisexual, and transgender (LGBT) community, are transgender individuals. Yet, the existence of LGBT education in nursing schools has not been examined. METHOD: After approval by the university institutional review board, 113 nursing programs in Texas were surveyed between November 2013 and January 2014, with a 12-question, Web-based questionnaire. A Verisign certificate and 128-bit encryption program supported compliance with the Health Insurance Portability and Accountability Act of 1996. RESULTS: Nineteen percent of the surveys were returned. Ten (47.62%) of 21 respondents addressed transgender or transsexual individuals. Fifteen (71.43%) of 21 answered a free text question to estimate the number of hours spent addressing LGBT content, reporting an average of 1.6 hours. CONCLUSION: Our study suggests that, in Texas, nursing students may not be receiving sufficient content, nor do they understand transgender health needs or how to best deliver competent, compassionate care to this population. PMID- 26057431 TI - Using wikis to stimulate collaborative learning in two online health sciences courses. AB - BACKGROUND: The use of wiki technology fits well in courses that encourage constructive knowledge building and social learning by a community of learners. Pedagogically, wikis have attracted interest in higher education environments because they facilitate the collaborative processes required for developing student group assignments. METHOD: This article describes a pilot project to assess the implementation of wikis in two online small- and mid-sized elective courses comprising nursing students in third- or fourth-year undergraduate levels within interdisciplinary health sciences courses. RESULTS: The need exists to further develop the pedagogical use of wiki environments before they can be expected to support collaboration among undergraduate nursing students. CONCLUSION: Adapting wiki implementation to suitable well-matched courses will make adaptation of wikis into nursing curricula more effective and may increase the chances that nursing students will hone the collaborative abilities that are essential in their future professional roles in communities of practice. PMID- 26057432 TI - Essential II: safety in the clinical setting. PMID- 26057433 TI - Generation of mutant mice via the CRISPR/Cas9 system using FokI-dCas9. AB - Genome editing, which introduces mutations in genes of interest using artificial DNA nucleases such as the ZFN, TALEN, and CRISPR/Cas9 systems in living cells, is a useful tool for generating mutant animals. Although CRISPR/Cas9 provides advantages over the two other systems, such as an easier vector construction and high efficiency of genome editing, it raises concerns of off-target effects when single guide RNA (gRNA) is used. Recently, FokI-dCas9 (fCas9), a fusion protein comprised of the inactivated mutant form of Cas9 and the DNA nuclease domain of FokI, has been developed. It enables genome editing with reduced risks of off target effects in mammalian cultured cell lines, as fCas9 requires gRNAs to bind opposite strands with an appropriate distance between them. Here, we demonstrated that fCas9 efficiently generates living mutant mice through microinjection of its mRNA and gRNAs into zygotes. A comparison of the relative efficiencies of genome editing using fCas9 and other modified Cas9s showed that these mutagenesis efficiencies are similar when the targets of two gRNAs are separated by an appropriate distance, suggesting that in addition to the ease of vector construction, fCas9 exhibit high efficiency in producing mutant mice and in reducing risks of off-target effects. PMID- 26057434 TI - Neuroelectromagnetic signatures of the reproduction of supra-second durations. AB - When participants are asked to reproduce an earlier presented duration, EEG recordings typically show a slow potential that develops over the fronto-central regions of the brain and is assumed to be generated in the supplementary motor area (SMA). This contingent negative variation (CNV) has been linked to anticipation, preparation and formation of temporal judgment (Macar, Vidal, and Casini, 1999, Experimental Brain Research, 125(3), 271-80). Although the interpretation of the CNV amplitude is problematic (Kononowicz and Van Rijn, (2011), Frontiers in Integrative Neuroscience, 5(48); Ng, Tobin, and Penney, 2011, Frontiers in Integrative Neuroscience, 5(77)), the observation of this slow potential is extremely robust, and thus one could assume that magnetic recordings of brain activity should show similar activity patterns. However, interval timing studies using durations shorter than one second did not provide unequivocal evidence as to whether CNV has a magnetic counterpart (CMV). As interval timing has been typically associated with durations longer than one second, participants in this study were presented intervals of 2, 3 or 4s that had to be reproduced in setup similar to the seminal work of Elbert et al. (1991, Psychophysiology, 28(6), 648-55) while co-recording EEG and MEG. The EEG data showed a clear CNV during the standard and the reproduction interval. In the reproduction interval the CNV steadily builds up from the onset of interval for both stimulus and response locked data. The MEG data did not show a CNV-resembling ramping of activity, but only showed a pre-movement magnetic field (preMMF) that originated from the SMA, occurring approximately 0.6s before the termination of the timed interval. These findings support the notion that signatures of timing are more straightforwardly measured using EEG, and show that the measured MEG signal from the SMA is constrained to the end of reproduction interval, before the voluntary movement. Moreover, we investigated a link between timing behavior and the early iCNV and late CNV amplitudes to evaluate the hypothesis that these amplitudes reflect the accumulation of temporal pulses. Larger iCNV amplitudes predicted shorter reproduced durations. This effect was more pronounced for the 2s interval reproduction, suggesting that preparatory strategies depend on the length of reproduced interval. Similarly to Elbert et al. (1991, Psychophysiology, 28(6), 648-55), longer reproductions were associated with smaller CNV amplitudes, both between conditions and across participants within the same condition. As the temporal accumulation hypothesis predicts the inverse, these results support the proposal by Van Rijn et al. (2011, Frontiers in Integrative Neuroscience, 5) that the CNV reflects other temporally driven processes such as temporal expectation and preparation rather than temporal accumulation itself. PMID- 26057435 TI - Motion perception deficit in Down Syndrome. AB - It is a well established fact that Down Syndrome (DS) individuals have a tendency to develop Alzheimer's disease (AD) (Lott, I.T., Head, E., 2005. Alzheimer disease and Down syndrome: factors in pathogenesis. Neurobiol. Aging 26, 383 389). They have therefore been proposed as a model to study the pre-dementia stage of Alzheimer's (Mann, D.M., 1988. The pathological association between Down syndrome and Alzheimer disease. Mech. Ageing Dev. 43, 99-136). One of the specific deficits exhibited by AD patients is optic flow motion perception (Tetewsky, S.J., Duffy, C.J., 1999. Visual loss and getting lost in Alzheimer's disease. Neurology 52, 958-965), but there are no corresponding systematic studies in DS individuals. We performed sensitivity measurements to optic flow with Visual Evoked Potentials (VEP) and psychophysical techniques in a group of young DS participants with mild mental retardation and without significant Alzheimer's clinical symptoms. We found a significant reduction in direction discrimination sensitivity to optic flow (random dots moving in radial, rotational and translational trajectories) in DS participants compared to mental age-matched controls, while their sensitivity to direction of control moving stimuli (sinusoidal gratings) was similar to age-matched controls. Measurements of Visual Evoked Potentials (VEP) showed no response to optic flow, although the response to control stimuli (contrast-reversal checkerboard patterns) was significant. Overall, our results show a selective and substantial deficit in the perception of optic flow motion and a corresponding suppression of electroencephalographic activity in DS individuals, thus establishing a further common trait between Down Syndrome and Alzheimer's disease. PMID- 26057436 TI - Expert Opinion: Is there Still a Role for Filtered-back Projection Reconstruction in Cardiothoracic CT? PMID- 26057437 TI - Emotional intensity reduces later generalized anxiety disorder symptoms when fear of anxiety and negative problem-solving appraisal are low. AB - While research based on the emotion dysregulation model indicates a positive relationship between intense emotions and generalized anxiety disorder (GAD) symptoms, emotion-focused intervention involves the use of techniques to enhance emotional experiences, based on the notion that GAD patients are engaging in avoidance strategies. To reveal the conditions under which intense emotions lead to reduced GAD symptoms, we designed a longitudinal study to monitor changes in GAD symptoms among students (N = 129) over 3 months. Our focus was on possible moderators of the effect of emotional intensity. Results indicated that when fear of emotions and negative appraisals about problem solving were low, negative emotional intensity reduced later GAD symptoms. Moreover, under the condition of high responsibility to continue thinking, emotional intensity tended to reduce later GAD symptoms. Results suggest that reduced fear of emotions and reduced negative appraisals about problem solving may enhance the use of emotional processing techniques (e.g., emotional exposure). The interaction between responsibility to continue thinking and emotional intensity requires further examination. PMID- 26057438 TI - Treatment manuals, training and successful provision of stop smoking behavioural support. AB - OBJECTIVE: Translating evidence-based behaviour change interventions into practice is aided by use of treatment manuals specifying the recommended content and format of interventions, and evidence-based training. This study examined whether outcomes of stop smoking behavioural support differed with practitioner's use and evaluation of treatment manuals, or practitioner's training. METHODS: English stop smoking practitioners were invited to complete an online survey including questions on: practitioners' training, availability, use and perceived utility of manuals, and annual biochemically-validated success rates of quit attempts supported (practitioner-reported). Mean success rates were compared between practitioners with/without access to manuals, those using/not using manuals, perceived utility ratings of manuals, and consecutive levels of training completed. RESULTS: Success rates were higher if practitioners had a manual (Mean (SD) = 54.0 (24.0) versus 48.0 (25.3), t(838) = 2.48, p = 0.013; n = 840), used a manual (F(2,8237) = 4.78, p = 0.009, n = 840), perceived manuals as more useful (F(3,834) = 2.90, p = 0.034, n = 840), and had completed training (F(3,709) = 4.81, p = 0.002, n = 713). Differences were diminished when adjusting for professional and demographic characteristics and no longer reached statistical significance using a conventional alpha for perceived utility of manuals and training status (both p = 0.1). CONCLUSIONS: Practitioners' performance in supporting smokers to quit varied with availability and use of treatment manuals. Evidence was weaker for perceived utility of manuals and practitioners' evidence based training. Ensuring practitioners have access to treatment manuals within their service, promoting manual use, and training practitioners to competently apply manuals is likely to contribute to higher success rates in clinical practice. PMID- 26057439 TI - Weight loss maintenance in relation to locus of control: The MedWeight study. AB - Locus of control, i.e. the degree of an individual's belief on the control of his/her life, has been related to many health outcomes, including weight loss in overweight/obese individuals. No information is available on the impact of locus of control in maintaining weight loss. We aimed to investigate the effect of locus of control in weight loss maintenance and explore potential associations with lifestyle factors. Study participants included 239 individuals (41% males) who had lost at least 10% of body weight in the past and either maintained the loss (maintainers: weight maintenance of at least 10% of initial weight) or regained it (regainers). Locus of control was defined by a relevant multi dimensional scale; participants were categorised to internals and externals, based on "internal" and "others" sub-scales. A significant interaction was found between locus of control and weight loss maintenance status (p < 0.001), with internals being more likely to be maintainers. Regainers had a more external orientation, compared to maintainers. Weight loss methods differ between groups, with internals reporting loosing weight by themselves more frequently, while externals reporting loosing weight mainly with the aid of an expert. Weight cycling of 2-3 kg in a typical year was reported more frequently in internals. Total and vigorous physical activity, as well as total hobbies score were associated with an internal profile, while sedentary activities with an external profile. No differences were found in dietary intake between internals and externals. Our results suggest that weight loss maintenance is associated with an internal locus of control. Individualised treatment, according to locus of control, may increase weight loss maintenance rates in former overweight/obese individuals. PMID- 26057440 TI - Room-temperature NH3 gas sensors based on Ag-doped gamma-Fe2O3/SiO2 composite films with sub-ppm detection ability. AB - In this report, NH3 gas sensors based on Ag-doped gamma-Fe2O3/SiO2 composite films are investigated. The composite films were prepared with a sol-gel process, and the films' electrical resistance responded to the change of NH3 concentration in the environment. The SEM and AFM investigations showed that the films had a porous structure, and the XRD investigation indicated that the size of Ag particles changed with the modification of Ag loading content. Through a comparative gas sensing study among the Ag-doped composite films, undoped composite film, gamma-Fe2O3 film, and SiO2 film, the Ag-doped composite films were found to be much more sensitive than the sensors based on the undoped composite film and gamma-Fe2O3 film at room temperature, indicating the significant influences of the SiO2 and Ag on the sensing property. Moreover, the sensor based on Ag-doped (4%) gamma-Fe2O3/SiO2 composite film was able to detect the NH3 gas at ppb level. Conversely, the responses of the sensor to other test gases (C2H5OH, CO, H2, CH4 and H2S) were all markedly low, suggesting excellent selectivity. PMID- 26057441 TI - Metallic ions catalysis for improving bioleaching yield of Zn and Mn from spent Zn-Mn batteries at high pulp density of 10. AB - Bioleaching of spent batteries was often conducted at pulp density of 1.0% or lower. In this work, metallic ions catalytic bioleaching was used for release Zn and Mn from spent ZMBs at 10% of pulp density. The results showed only Cu(2+) improved mobilization of Zn and Mn from the spent batteries among tested four metallic ions. When Cu(2+) content increased from 0 to 0.8 g/L, the maximum release efficiency elevated from 47.7% to 62.5% for Zn and from 30.9% to 62.4% for Mn, respectively. The Cu(2+) catalysis boosted bioleaching of resistant hetaerolite through forming a possible intermediate CuMn2O4 which was subject to be attacked by Fe(3+) based on a cycle of Fe(3+)/Fe(2+). However, poor growth of cells, formation of KFe3(SO4)2(OH)6 and its possible blockage between cells and energy matters destroyed the cycle of Fe(3+)/Fe(2+), stopping bioleaching of hetaerolite. The chemical reaction controlled model fitted best for describing Cu(2+) catalytic bioleaching of spent ZMBs. PMID- 26057442 TI - A novel nanoprobe for the sensitive detection of Francisella tularensis. AB - Francisella tularensis is a human zoonotic pathogen and the causative agent of tularemia, a severe infectious disease. Given the extreme infectivity of F. tularensis and its potential to be used as a biological warfare agent, a fast and sensitive detection method is highly desirable. Herein, we construct a novel detection platform composed of two units: (1) Magnetic beads conjugated with multiple capturing antibodies against F. tularensis for its simple and rapid separation and (2) Genetically-engineered apoferritin protein constructs conjugated with multiple quantum dots and a detection antibody against F. tularensis for the amplification of signal. We demonstrate a 10-fold increase in the sensitivity relative to traditional lateral flow devices that utilize enzyme based detection methods. We ultimately envision the use of our novel nanoprobe detection platform in future applications that require the highly-sensitive on site detection of high-risk pathogens. PMID- 26057443 TI - Ecotoxicological assessment of residues from different biogas production plants used as fertilizer for soil. AB - Residues from biogas production (RBP) are a relatively new materials, which may be an interesting resource for the improvement of soil fertility. Nevertheless, in spite of the potential benefits from the agricultural utilization of RBP, there is a need of comprehensive estimation of their toxicity. This information is needed to exclude potential negative environmental impacts arising from the use of RBP. Samples of RBP obtained from six biogas production plants with varied biogas production methods were analysed. The samples with and without separation on solid and liquid phases were investigated. The physicochemical properties of the RBP, heavy metals content (Cr, Cu, Ni, Cd, Pb i Zn) and toxicity on bacteria (Vibrio fischeri, MARA test - 11 different strains), collembolans (Folsomia candida) and two plant species (Lepidium sativum and Sinapis alba) was investigated. Toxicity of RBP was examined using Phytotoxkit F (root growth inhibition), collembolan test (mortality, inhibition of reproduction), Microtox(r) (inhibition of the luminescence of V. fischeri) and MARA test (growth of microorganisms). An especially negative effect on the tested organisms whereas was noted for the liquid phase after separation. In many cases, RBP without separation also showed unfavourable effects on the tested organisms. Liquid phase after separation and non-separated materials caused inhibition of root growth of L. sativum and S. alba at the level of 17.42-100% and 30.5-100%, respectively, as well as the inhibition of reproduction of F. candida with the range from 68.89 to 100%. In most cases, no ecotoxicological effect was observed for solid phase after separation for tested organisms. The solid phase after separation presented the most favorable properties between all investigated RBP. Therefore, it can be a potential material for the improvement of soil properties and for later use in agriculture. PMID- 26057444 TI - An X-ray absorption study of synthesis- and As adsorption-induced microstructural modifications in Fe oxy-hydroxides. AB - Synthetic adsorbents based on Fe oxy-hydroxides (FeOOH) prepared under a wide range of pH-values via intense oxidation conditions of FeSO4 as well as the As(III) and As(V) adsorption mechanism are investigated using X-ray absorption fine structure (XAFS) spectroscopies at the Fe- and As-K-edges. Synthesis in an alkaline environment promotes the face-connectivity of the Fe(O,OH)6 chains at the expense of edge- and corner-sharing linkage, which is consistent with the lower surface charge density and in turn with the lower arsenic adsorption capacity. Microstructural changes are also detected after As(V) adsorption onto FeOOH synthesized at pH 5.5: the ratio of face-/edge-sharing sites increases from approximately 0.4-0.7 as a function of the As(V)-loading. This modification of the polymeric Fe(O,OH)6 structure at higher As/Fe ratios is attributed to strong As(V) bidentate mononuclear ((2)E) and binuclear ((2)C) adsorption. In contrast, no alterations in the FeOOH microstructure were observed, possibly due to the weaker (2)E linkage of As(III). PMID- 26057445 TI - Concurrent maternal and pup postnatal tobacco smoke exposure in Wistar rats changes food preference and dopaminergic reward system parameters in the adult male offspring. AB - Children from pregnant smokers are more susceptible to become obese adults and to become drug or food addicts. Drugs and food activate the mesolimbic reward pathway, causing a sense of pleasure that induces further consumption. Here, we studied the relationship between tobacco smoke exposure during lactation with feeding, behavior and brain dopaminergic reward system parameters at adulthood. Nursing Wistar rats and their pups were divided into two groups: tobacco smoke exposed (S: 4times/day, from the 3rd to the 21th day of lactation), and ambient air-exposed (C). On PN175, both offspring groups were subdivided for a food challenge: S and C that received standard chow (SC) or that chose between high fat (HFD) and high-sucrose diets (HSDs). Food intake was recorded after 30min and 12h. Offspring were tested in the elevated plus maze and open field on PN178-179; they were euthanized for dopaminergic analysis on PN180. SSD (self-selected diet) animals presented a higher food intake compared to SC ones. S-SSD animals ate more than C-SSD ones at 30min and 12h. Both groups preferred the HFD. However, S SSD animals consumed relatively more HFD than C-SSD at 30min. No behavioral differences were observed between groups. S animals presented lower tyrosine hydroxylase (TH) content in the ventral tegmental area, lower TH, dopaminergic receptor 2, higher dopaminergic receptor 1 contents in the nucleus accumbens and lower OBRb in hypothalamic arcuate nucleus. Tobacco-smoke exposure during lactation increases preference for fat in the adult progeny possibly due to alterations in the dopaminergic system. PMID- 26057446 TI - Prenatal ethanol exposure alters ethanol-induced Fos immunoreactivity and dopaminergic activity in the mesocorticolimbic pathway of the adolescent brain. AB - Prenatal ethanol exposure (PEE) promotes alcohol intake during adolescence, as shown in clinical and pre-clinical animal models. The mechanisms underlying this effect of prenatal ethanol exposure on postnatal ethanol intake remain, however, mostly unknown. Few studies assessed the effects of moderate doses of prenatal ethanol on spontaneous and ethanol-induced brain activity on adolescence. This study measured, in adolescent (female) Wistar rats prenatally exposed to ethanol (0.0 or 2.0g/kg/day, gestational days 17-20) or non-manipulated (NM group) throughout pregnancy, baseline and ethanol-induced cathecolaminergic activity (i.e., colocalization of c-Fos and tyrosine hydroxylase) in ventral tegmental area (VTA), and baseline and ethanol-induced Fos immunoreactivity (ir) in nucleus accumbens shell and core (AcbSh and AcbC, respectively) and prelimbic (PrL) and infralimbic (IL) prefrontal cortex. The rats were challenged with ethanol (dose: 0.0, 1.25, 2.5 or 3.25g/kg, i.p.) at postnatal day 37. Rats exposed to vehicle prenatally (VE group) exhibited reduced baseline dopaminergic tone in VTA; an effect that was inhibited by prenatal ethanol exposure (PEE group). Dopaminergic activity in VTA after the postnatal ethanol challenge was greater in PEE than in VE or NM animals. Ethanol-induced Fos-ir at AcbSh was found after 1.25g/kg and 2.5g/kg ethanol, in VE and PEE rats, respectively. PEE did not alter ethanol induced Fos-ir at IL but reduced ethanol-induced Fos-ir at PrL. These results suggest that prenatal ethanol exposure heightens dopaminergic activity in the VTA and alters the response of the mesocorticolimbic pathway to postnatal ethanol exposure. These effects may underlie the enhanced vulnerability to develop alcohol-use disorders of adolescents with a history of in utero ethanol exposure. PMID- 26057447 TI - Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease. AB - The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAMTOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans. PMID- 26057448 TI - Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence. METHODS: The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression. RESULTS: A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001). CONCLUSIONS: Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention. PMID- 26057449 TI - Association between cytosolic expression of BRCA1 and metastatic risk in breast cancer. AB - BACKGROUND: Although BRCA1 has been extensively studied for its role as a tumour suppressor protein, the role of BRCA1 subcellular localisation in oncogenesis and tumour progression has remained unclear. This study explores the impact of BRCA1 mislocalisation on clinical outcomes in breast cancer. METHODS: Tissue microarrays assembled from a cohort of patients with all stages of breast cancer were analysed for BRCA1 localisation and correlated with patient survival. Tissue microarrays of patients who had breast cancer that had metastasised to the lung were assembled from an independent cohort of patients. These were analysed for BRCA1 subcellular expression. In vitro studies using cultured human breast cancer cells were conducted to examine the effect of cytosolic BRCA1 on cell migration and efficiency of invasion. RESULTS: An inverse association was found between cytosolic BRCA1 expression and metastasis-free survival in patients aged >40 years. Further analysis of BRCA1 subcellular expression in a cohort of breast cancer patients with metastatic disease revealed that the cytosolic BRCA1 content of breast tumours that had metastasised to the lung was 36.0% (95% CI=(31.7%, 40.3%), which was markedly higher than what is reported in the literature (8.2 14.8%). Intriguingly, these lung metastases and their corresponding primary breast tumours demonstrated similarly high cytosolic BRCA1 distributions in both paired and unpaired analyses. Finally, in vitro studies using human breast cancer cells demonstrated that genetically induced BRCA1 cytosolic sequestration (achieved using the cytosol-sequestering BRCA1 5382insC mutation) increased cell invasion efficiency. CONCLUSIONS: Results from this study suggest a model where BRCA1 cytosolic mislocalisation promotes breast cancer metastasis, making it a potential biomarker of metastatic disease. PMID- 26057450 TI - Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-1. AB - BACKGROUND: Tongue squamous cell carcinoma (TSCC) is increasing in incidence, especially among young patients and preferably females. Infection with human papilloma virus (HPV) has been suggested as a cause of SCC in the head and neck, and the proportion of oropharyngeal cancers caused by HPV has steadily increased. METHODS: Samples from 109 patients with primary TSCC were analysed for the presence of HPV16 by in situ hybridisation and for expression of its surrogate marker p16 and the HPV receptor syndecan-1 by immunhistochemistry. RESULTS: No evidence of HPV16 DNA was observed in the tumours, although one-third showed p16 staining. There was no difference in the expression of the primary HPV receptor, syndecan-1, between TSCC and a group of tonsil SCC. CONCLUSION: Whereas p16 is expressed in some TSCCs, HPV16 is undetectable, therefore, p16 cannot be used as a surrogate marker for high-risk HPV-infection in this tumour. Despite presence of the HPV-receptor syndecan-1 in TSCC, HPV prefers the tonsillar environment. Lack of p16 associates with worse prognosis primarily in patients aged ?40 years with tongue SCC. The improved prognosis seen in p16-positive TSCC can be due to induction of a senescent phenotype or an inherent radiosensitivity due to the ability of p16 to inhibit homologous recombination repair. PMID- 26057451 TI - Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. AB - BACKGROUND: Functional microRNAs (miRNAs) in exosomes have been recognised as potential stable biomarkers in cancers. The aim of this study is to identify specific miRNAs in exosome as serum biomarkers for the early detection of recurrence in human colorectal cancer (CRC). METHODS: Serum samples were sequentially obtained from six patients with and without recurrent CRC. The miRNAs were purified from exosomes, and miRNA microarray analysis was performed. The miRNA expression profiles and copy number aberrations were explored using microarray and array CGH analyses in 124 CRC tissues. Then, we validated exosomal miRNAs in 2 serum sample sets (90 and 209 CRC patients) by quantitative real-time RT-PCR. RESULTS: Exosomal miR-17-92a cluster expression level in serum was correlated with the recurrence of CRC. Exosomal miR-19a expression levels in serum were significantly increased in patients with CRC as compared with healthy individuals with gene amplification. The CRC patients with high exosomal miR-19a expression showed poorer prognoses than the low expression group (P<0.001). CONCLUSIONS: Abundant expression of exosomal miR-19a in serum was identified as a prognostic biomarker for recurrence in CRC patients. PMID- 26057452 TI - Circulating microRNAs as prognostic therapy biomarkers in head and neck cancer patients. AB - BACKGROUND: The prediction of therapy response in head and neck squamous cell cancer (HNSCC) requires biomarkers, which are also a prerequisite for personalised therapy concepts. The current study aimed to identify therapy responsive microRNAs (miRNAs) in the circulation that can serve as minimally invasive prognostic markers for HNSCC patients undergoing radiotherapy. METHODS: We screened plasma miRNAs in a discovery cohort of HNSCC patients before therapy and after treatment. We further compared the plasma miRNAs of the patients to age and sex-matched healthy controls. All miRNAs identified as biomarker candidates were then confirmed in an independent validation cohort of HNSCC patients and tested for correlation with the clinical outcome. RESULTS: We identified a signature of eight plasma miRNAs that differentiated significantly (P=0.003) between HNSCC patients and healthy donors. MiR-186-5p demonstrated the highest sensitivity and specificity to classify HNSCC patients and healthy individuals. All therapy-responsive and patient-specific miRNAs in plasma were also detectable in tumour tissues derived from the same patients. High expression of miR-142-3p, miR-186-5p, miR-195-5p, miR-374b-5p and miR-574-3p in the plasma correlated with worse prognosis. CONCLUSIONS: Circulating miR-142-3p, miR-186-5p, miR-195-5p, miR 374b-5p and miR-574-3p represent the most promising markers for prognosis and therapy monitoring in the plasma of HNSCC patients. We found strong evidence that the circulating therapy-responsive miRNAs are tumour related and were able to validate them in an independent cohort of HNSCC patients. PMID- 26057453 TI - Tumour-suppressive microRNA-144-5p directly targets CCNE1/2 as potential prognostic markers in bladder cancer. AB - BACKGROUND: Analysis of a microRNA (miRNA) expression signature of bladder cancer (BC) by deep-sequencing revealed that clustered miRNAs microRNA (miR)-451a, miR 144-3p, and miR-144-5p were significantly downregulated in BC tissues. We hypothesised that these miRNAs function as tumour suppressors in BC. The aim of this study was to investigate the functional roles of these miRNAs and their modulation of cancer networks in BC cells. METHODS: The functional studies of BC cells were performed using transfection of mature miRNAs. Genome-wide gene expression analysis, in silico analysis, and dual-luciferase reporter assays were applied to identify miRNA targets. The association between miR-144-5p levels and expression of the target genes was determined, and overall patient survival as a function of target gene expression was estimated by the Kaplan-Meier method. RESULTS: Gain-of-function studies showed that miR-144-5p significantly inhibited cell proliferation by BC cells. Four cell cycle-related genes (CCNE1, CCNE2, CDC25A, and PKMYT1) were identified as direct targets of miR-144-5p. The patients with high CCNE1 or CCNE2 expression had lower overall survival probabilities than those with low expression (P=0.025 and P=0.032). CONCLUSION: miR-144-5p functions as tumour suppressor in BC cells. CCNE1 and CCNE2 were directly regulated by miR 144-5p and might be good prognostic markers for survival of BC patients. PMID- 26057454 TI - miR-30e* is an independent subtype-specific prognostic marker in breast cancer. AB - BACKGROUND: Breast cancer clinical outcome is affected by tumor molecular features, and the identification of subtype-specific prognostic biomarkers is relevant for breast cancer translational research. Gene expression signatures proved to be able to complement prognostic information provided by classical clinico-pathological features. Recently, microRNAs (miRNAs) have been causally linked to tumorigenesis and cancer progression and have been associated with patient outcome, also in breast cancer. METHODS: MicroRNAs associated with the development of distant metastasis were identified in a cohort of 92 ESR1+/ERBB2- lymph node-negative breast cancers from patients not receiving adjuvant treatment. Results were confirmed and further investigated in a total of 1246 miRNA and gene expression profiles of the Molecular Taxonomy of Breast Cancer International Consortium data set. Moderated t-test, univariable and multivariable Cox regression models were used for statistical analyses. RESULTS: miR-30e* was identified as independent protective prognostic factor in lymph node negative untreated patients with ESR1+/ERBB2- tumours and retained a significant association with a good prognosis in treated patients with the same tumor subtype as well as in the ERBB2+ subtype, but not in ESR1-/ERBB2- tumours. CONCLUSIONS: We highlighted a relevant and subtype-specific role in breast cancer for miR-30e* and demonstrated that adding miRNA markers to gene signatures and clinico pathological features can help for a better prognostication. PMID- 26057456 TI - Surface Functionalization of Oxide-Covered Zinc and Iron with Phosphonated Phenylethynyl Phenothiazine. AB - Phenothiazines are redox-active, fluorescent molecules with potential applications in molecular electronics. Phosphonated phenylethynyl phenothiazine can be easily obtained in a four-step synthesis, yielding a molecule with a headgroup permitting surface linkage. Upon modifying hydroxylated polycrystalline zinc and iron, both covered with their respective native oxides, ultrathin organic layers were formed and investigated by use of infrared (IR) reflection spectroscopy, X-ray photoelectron spectroscopy (XPS), time-of-flight secondary ion mass spectrometry (ToF-SIMS), contact angle measurement, and ellipsometry. While stable monolayers with upright oriented organic molecules were formed on oxide-covered iron, multilayer formation is observed on oxide-covered zinc. ToF SIMS measurements reveal a bridging bidentate bonding state of the organic compound on oxide-covered iron, whereas monodentate complexes were observed on oxide-covered zinc. Both organically modified and unmodified surfaces exhibit reactive wetting, but organic modification makes the surfaces initially more hydrophobic. Cyclic voltammetry (CV) indicates redox activity of the multilayers formed on oxide-covered zinc. On the other hand, the monolayers on oxide-covered iron desorb after electrochemical modifications in the state of the oxide, but are stable at open circuit conditions. Exploiting an electronic coupling of phenothiazines to oxides may thus assist in corrosion protection. PMID- 26057455 TI - High-throughput sequencing of small RNAs and anatomical characteristics associated with leaf development in celery. AB - MicroRNAs (miRNAs) exhibit diverse and important roles in plant growth, development, and stress responses and regulate gene expression at the post transcriptional level. Knowledge about the diversity of miRNAs and their roles in leaf development in celery remains unknown. To elucidate the roles of miRNAs in celery leaf development, we identified leaf development-related miRNAs through high-throughput sequencing. Small RNA libraries were constructed using leaves from three stages (10, 20, and 30 cm) of celery cv.'Ventura' and then subjected to high-throughput sequencing and bioinformatics analysis. At Stage 1, Stage 2, and Stage 3 of 'Ventura', a total of 333, 329, and 344 conserved miRNAs (belonging to 35, 35, and 32 families, respectively) were identified. A total of 131 miRNAs were identified as novel in 'Ventura'. Potential miRNA target genes were predicted and annotated using the eggNOG, GO, and KEGG databases to explore gene functions. The abundance of five conserved miRNAs and their corresponding potential target genes were validated. Expression profiles of novel potential miRNAs were also detected. Anatomical characteristics of the leaf blades and petioles at three leaf stages were further analyzed. This study contributes to our understanding on the functions and molecular regulatory mechanisms of miRNAs in celery leaf development. PMID- 26057457 TI - Continuing pregnancy after mifepristone and "reversal" of first-trimester medical abortion: a systematic review. AB - OBJECTIVE: We conducted a systematic review of the literature on the effectiveness of medical abortion "reversal" treatment. Since the usual care for women seeking to continue pregnancies after ingesting mifepristone is expectant management with fetal surveillance, we also performed a systematic review of continuing pregnancy after mifepristone alone. STUDY DESIGN: We searched PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Scopus and the Cochrane Library for articles published through March 2015 reporting the proportion of pregnancies continuing after treatment with either mifepristone alone or after an additional treatment following mifepristone aimed at reversing its effect. RESULTS: From 1115 articles retrieved, 1 study met inclusion criteria for abortion reversal, and 13 studies met criteria for continuing pregnancy after mifepristone alone. The one report of abortion reversal was a case series of 7 patients receiving varying doses of progesterone in oil intramuscularly or micronized progesterone orally or vaginally; 1 patient was lost to follow-up. The study was of poor quality and lacked clear information on patient selection. Four of six women continued the pregnancy to term [67%, 95% confidence interval (CI) 30-90%]. Assuming the lost patient aborted resulted in a continuing pregnancy proportion of 57% (95% CI 25-84%). The proportion of pregnancies continuing 1-2 weeks after mifepristone alone varied from 8% (95% CI 3-22%) to 46% (95% CI 37 56%). Continuing pregnancy was more common with lower mifepristone doses and advanced gestational age. CONCLUSIONS: In the rare case that a woman changes her mind after starting medical abortion, evidence is insufficient to determine whether treatment with progesterone after mifepristone results in a higher proportion of continuing pregnancies compared to expectant management. IMPLICATIONS: Legislation requiring physicians to inform patients about abortion reversal transforms an unproven therapy into law and represents legislative interference in the patient-physician relationship. PMID- 26057458 TI - Improvement in antiproliferative activity of Angelica gigas Nakai by solid dispersion formation via hot-melt extrusion and induction of cell cycle arrest and apoptosis in HeLa cells. AB - Angelica gigas Nakai (AGN) is one of the most popular herbal medicines and widely used as a functional food product. In this study, AGN was firstly processed by a low-temperature turbo mill and a hot melting extruder to reduce particle size and form solid dispersion (SD). Anticancer activity against HeLa cells was then examined. AGN-SD based on Soluplus was formed via hot-melt extrusion (HME) and showed the strongest cytotoxic effect on HeLa cells. In addition, the possible mechanism of cell death induced by AGN-SD on HeLa cells was also investigated. AGN-SD decreased cell viability, induced apoptosis, increased the production of reactive oxygen species, regulated the expression of Bcl-2 and Bax, and induced G2/M phase arrest in HeLa cells. This study suggested that AGN-SD based on Soluplus and the method to improve antiproliferative effect by SD formation via HME may be suitable for application in the pharmaceutical industry. PMID- 26057459 TI - Induction of apoptosis by UV in the flat oyster, Ostrea edulis. AB - Apoptosis is a fundamental feature in the development of many organisms and tissue systems. It is also a mechanism of host defense against environmental stress factors or pathogens by contributing to the elimination of infected cells. Hemocytes play a key role in defense mechanisms in invertebrates and previous studies have shown that physical or chemical stress can increase apoptosis in hemocytes in mollusks. However this phenomenon has rarely been investigated in bivalves especially in the flat oyster Ostrea edulis. The apoptotic response of hemocytes from flat oysters, O. edulis, was investigated after exposure to UV and dexamethasone, two agents known to induce apoptosis in vertebrates. Flow cytometry and microscopy were combined to demonstrate that apoptosis occurs in flat oyster hemocytes. Investigated parameters like intracytoplasmic calcium activity, mitochondrial membrane potential and phosphatidyl-serine externalization were significantly modulated in cells exposed to UV whereas dexamethasone only induced an increase of DNA fragmentation. Morphological changes were also observed on UV-treated cells using fluorescence microscopy and transmission electron microscopy. Our results confirm the apoptotic effect of UV on hemocytes of O. edulis and suggest that apoptosis is an important mechanism developed by the flat oyster against stress factors. PMID- 26057460 TI - Molecular and functional roles of 6C CC chemokine 19 in defense system of striped murrel Channa striatus. AB - In this study, we have reported the molecular information of chemokine-19 (Chem19) from striped murrel Channa striatus (Cs). CsCC-Chem19 cDNA sequence was 555 base pair (bp) in length which is 68bp 5' untranslated region (UTR), 339bp translated region and 149bp 3' UTR. The translated region is encoded for a polypeptide of 112 amino acids. CsCC-Chem19 peptide contains a signal sequence between 1 and 26 and an interleukin (IL) 8 like domain between 24 and 89. The multiple sequence alignment showed a 'DCCL' motif, an indispensable motif present in all CC chemokines which was conserved throughout the evolution. Phylogenetic tree showed that CsCC-Chem19 formed a cluster with chemokine 19 from fishes. Secondary structure of CsCC-Chem19 revealed that the peptide contains maximum amount of coils (61.6%) compared to alpha-helices (25.9%%) and beta-sheet (12.5%). Further, 3D analysis indicated that the cysteine residues at 33, 34, 59 and 75 making the disulfide bridges as 33 = 59 and 34 = 75. Significantly (P < 0.05) highest CsCC-Chem19 mRNA expression was observed in blood and it was up regulated upon fungus and bacterial infection. Utilizing the coding region of CsCC-Chem19, recombinant CsCC-Chem19 protein was produced. The recombinant CsCC Chem19 protein induced the cellular proliferation and respiratory burst activity of C. striatus peripheral blood leukocytes (PBL) in a concentration dependent manner. Moreover, the chemotactic activity showed that the recombinant CsCC Chem19 significantly (P < 0.05) enhanced the movement of PBL of C. striatus. Conclusively, CsCC-Chem19 is a 6C CC chemokine having an ability to perform both inflammatory and homeostatic functions. However, further research is necessary to understand the potential of 6C CC chemokine 19 of C. striatus, particularly their regulatory ability on different cellular components in the defense system. PMID- 26057461 TI - The tight junction protein transcript abundance changes and oxidative damage by tryptophan deficiency or excess are related to the modulation of the signalling molecules, NF-kappaB p65, TOR, caspase-(3,8,9) and Nrf2 mRNA levels, in the gill of young grass carp (Ctenopharyngodon idellus). AB - This study is for the first time to explore the possible effects of dietary tryptophan (Trp) on structural integrity and the related signalling factor gene expression in the gill of young grass carp (Ctenopharyngodon idella). Fish were fed with six different experimental diets containing graded levels of Trp at 0.7 (control), 1.7, 3.1, 4.0, 5.2 and 6.1 g kg(-1) diet for 8 weeks. The results firstly demonstrated that Trp deficiency or excess caused increases in reactive oxygen species (ROS) contents, and severe oxidative damage (lipid peroxidation and protein oxidation) in the gill of fish, and those negative effects could be reversed by optimal Trp levels. Secondly, compared with the optimal Trp levels, Trp deficiency could cause decreases in the mRNA levels of the barrier functional proteins (occludin, zonula occludens-1, claudin-c, and -3) and increases in the mRNA levels of the pore-formation proteins (claudin-12 and -15) mRNA levels in the gill of fish, and those were reversed by the optimal levels of Trp. The negative effects of Trp deficiency on those tight junction protein gene expression might be partly related to the increases in the mRNA levels of pro inflammatory cytokines and related signalling factors (tumor necrosis factor alpha, interleukin 8, interleukin 1beta and transcription factor-kappaB) and decreases in the mRNA levels of anti-inflammatory cytokines and related signalling factors [interleukin 10, transforming growth factor-beta1, nuclear inhibitor factor kappaBalpha (ikappaBalpha), target of rapamyc and ribosome protein S6 kinase 1 (S6K1)] in the gill of fish. In addition, optimal dietary Trp protected the gill of fish against its deficiency-caused increases in the mRNA levels of the apoptosis signalling (caspase-3, caspase-8, caspase-9) and decreases in anti-superoxide radicals capacity, anti-hydroxyl radical capacity, glutathione contents and the activities of Cu/Zn superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione-S-transferase (GST) in the gill of fish. Additionally, compared with the Trp deficiency, optimal Trp up-regulated the mRNA levels of SOD, CAT, GPx, GR and GST, which might be partly ascribed to the up-regulation of the NF-E2-related factor 2 (Nrf2) mRNA levels and the down-regulation of Kelch-like-ECH-associated protein 1 (Keap1) mRNA levels in the gill of fish. Interestingly, excessive Trp caused similar results with its deficiency. Collectively, Trp deficiency or excess could cause antioxidant system disruption and change tight junction protein transcription abundances, which were partly related to the signalling factors, NF-kappaB p65, TOR, caspase-(3,8,9) and Nrf2, in fish gill, those could be blocked by the optimal Trp levels. PMID- 26057462 TI - Metabolome strategy against Edwardsiella tarda infection through glucose-enhanced metabolic modulation in tilapias. AB - Edwardsiella tarda causes fish disease and great economic loss. However, metabolic strategy against the pathogen remains unexplored. In the present study, GC-MS based metabolomics was used to investigate the metabolic profile from tilapias infected by sublethal dose of E. tarda. The metabolic differences between the dying group and survival group allow the identification of key pathways and crucial metabolites during infections. More importantly, those metabolites may modulate the survival-related metabolome to enhance the anti infective ability. Our data showed that tilapias generated two different strategies, survival-metabolome and death-metabolome, to encounter EIB202 infection, leading to differential outputs of the survival and dying. Glucose was the most crucial biomarker, which was upregulated and downregulated in the survival and dying groups, respectively. Exogenous glucose by injection or oral administration enhanced hosts' ability against EIB202 infection and increased the chances of survival. These findings highlight that host mounts the metabolic strategy to cope with bacterial infection, from which crucial biomarkers may be identified to enhance the metabolic strategy. PMID- 26057464 TI - Deciphering the Origin of Stereoinduction in Cooperative Asymmetric Catalysis Involving Pd(II) and a Chiral Bronsted Acid. AB - The density functional (M06) computations on a cooperative multicatalytic reaction involving palladium acetate and a chiral Bronsted acid in the conversion of an indenyl cyclobutanol to spirocyclic indene bearing a quaternary carbon ring junction are reported. A chiral Pd-bis-phosphate is identified as the active catalyst in the enantioselective ring expansion as compared to alternative possibilities wherein the chiral phosphate/phosphoric acid is in the outer sphere of palladium. The enantiocontrolling transition state exhibited more effective C H...pi interactions, lower distortion of the catalyst, and an orthogonal orientation of the bulky phosphate ligands. PMID- 26057463 TI - Transcriptome analyses of Atlantic salmon (Salmo salar L.) erythrocytes infected with piscine orthoreovirus (PRV). AB - Heart and skeletal muscle inflammation (HSMI) is a widespread disease of farmed Atlantic salmon (Salmo salar L.) and is associated with piscine orthoreovirus (PRV) infection. PRV is detectable in blood long before development of pathology in cardiac- and skeletal muscle appear, and erythrocytes have been identified as important target cells for the virus. The effects of PRV infection on cellular processes of erythrocytes are not known, but haemolytic anemia or systemic lysis of erythrocytes does not seem to occur, even with high virus loads in erythrocytes. In this study, gene expression profiling performed with high density oligonucleotide microarray showed that PRV infection of erythrocytes induced a large panel of virus responsive genes. These involved interferon regulated antiviral genes, as well as genes involved in antigen presentation via MHC class I. PRV infection also stimulated negative immune regulators. In contrast, a large number of immune genes expressed prior to infection were down regulated. Moderate reduction of expression was also found for many genes encoding components of cytoskeleton and myofiber, proteins involved in metabolism, ion exchange, cell-cell interactions as well as growth factors and regulators of differentiation. PRV did not affect expression of genes involved in heme biosynthesis, gas exchange or erythrocyte-specific markers, but some regulators of erythropoiesis showed decreased transcription levels. These results indicate that PRV infection activates innate antiviral immunity in salmon erythrocytes, but suppresses other gene expression programs. Gene expression profiles suggest major phenotypic changes in PRV infected erythrocytes, but the functional consequences remain to be explored. PMID- 26057465 TI - Comparison of Mannose, Ethylene Glycol, and Methoxy-Terminated Diluents on Specificity and Selectivity of Electrochemical Peptide-Based Sensors. AB - We report the synthesis and application of three new antifouling diluents for the fabrication of an E-PB HIV sensor. Among the three thiolated antifouling diluents used in this study, the methoxy-terminated diluent (C6-MEG) is the most effective in alleviating both nonspecific binding and adsorption of matrix contaminants onto the sensor surface, especially when compared to the mannose- (C6-MAN) and ethylene-glycol-terminated (C6-EG) diluents. The sensor fabricated with C6-MEG has a specificity factor (~13.5) substantially higher than the sensor passivated with only 6-mercapto-1-hexanol (~1.5). It is functional even when employed directly in 25% serum, an achievement that has not been observed with this class of E-PB sensors. More importantly, incorporation of these antifouling diluents has negligible impact on other important sensor properties such as sensitivity and binding kinetics. This sensor passivation strategy is versatile and can potentially be used with other E-PB sensors, as well as surface-based sensors that utilize thiol-gold self-assembled monolayer chemistry. PMID- 26057466 TI - On the role of scales in contact mechanics and friction between elastomers and randomly rough self-affine surfaces. AB - The paper is devoted to a qualitative analysis of friction of elastomers from the point of view of scales contributing to the force of friction. We argue that- contrary to widespread opinion--friction between a randomly rough self-affine fractal surface and an elastomer is not a multiscale phenomenon, but is governed mostly by the interplay of only two scales--as a rule the largest and the smallest scales of roughness of the contacting bodies. The hypothesis of two scale character of elastomer friction is illustrated by computer simulations in the framework of the paradigm of Greenwood, Tabor and Grosch using a simplified one-dimensional model. PMID- 26057467 TI - Letter to the Editor: Optical measurements of excitability with FluoVoltTM Membrane Potential Dye. PMID- 26057468 TI - A case of preventable pulmonary tuberculosis in a Greenlandic, heavily immune suppressed patient. AB - Immune modulating therapy, such as tumour necrosis factor (TNF)-alpha inhibitors, is becoming increasingly more widespread in the treatment of many autoimmune diseases. One of the well-documented side effects of TNF-alpha inhibitors is an increased risk of reactivating latent tuberculosis infection (LTBI). Diagnostic tools available for diagnosing LTBI lack sensitivity and specificity. We report the case of a rheumatoid arthritis (RA) patient at high-risk of reactivation of LTBI, who should have been offered prophylactic anti-tuberculous treatment on two separate occasions: firstly, before initiating anti-TNF-alpha treatment and secondly, as part of routine tuberculosis contact tracing. He subsequently developed severe pulmonary tuberculosis and was hospitalised for 6 weeks. PMID- 26057469 TI - Evaluation on efficacy and safety of tyrosine kinase inhibitors plus radiotherapy in NSCLC patients with brain metastases. AB - OBJECTIVE: The study was designed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs) plus radiotherapy in patients with brain metastases (BM) of non-small cell lung cancer. METHODS: Medline PubMed, Google Scholar, Web of Science, Oxford Journals Collection, clinical trials and current controlled trials were searched to identify relevant publications. After screening literature and undertaking quality assessment and data extraction, the meta analysis was performed using RevMan5.3 software. RESULTS: Eight controlled trials (980 participants) were included in the study. Compared with radiotherapy without TKIs (non-TKI-group), TKIs plus radiotherapy (TKI-group) had a significant benefit on objective response rate (ORR) (RR = 1.56, 95%CI [1.25,2.03]; P =0.0008), significantly prolonged the time to central nerves system progression (CNS-TTP) (HR =0.58, 95% CI [0.35, 0.96]; P =0.03) and median overall survival (MOS) (HR =0.68, 95% CI [0.47, 0.98]; P =0.04) of NSCLC patients with BM. There was no significant difference in overall severe adverse events (Grade>=3) (RR = 1.49, 95% CI [0.88,2.54]; P = 0.14) between two groups. CONCLUSION: This meta analysis showed TKI-group produced superior response rate when compared with non TKI-group. TKIs plus radiotherapy significantly prolong the CNS-TTP and MOS of patients without enhancing overall severe adverse events. PMID- 26057470 TI - Elevated preoperative aspartate aminotransferase to lymphocyte ratio index as an independent prognostic factor for patients with hepatocellular carcinoma after hepatic resection. AB - Few studies have elucidated the relationship between preoperative aspartate aminotransferase (AST) to lymphocyte ratio and high incidence of hepatocellular carcinoma (HCC). In search of a simple non-invasive prognostic marker, we investigated the prognostic significance of AST to lymphocyte ratio index (ALRI) in HCC.We reviewed retrospectively clinical parameters of 371 HCC patients who were treated with hepatectomy. Receiver operating characteristic (ROC) curve analysis was performed to determine the cut-off value of preoperative ALRI. The predictive value of preoperative ALRI in HCC was evaluated by univariate and multivariate analyses using Cox proportional hazards regression modeling, and the survival probability of HCC patients was acquired by the Kaplan-Meier plots. In addition, stratified analysis was used to investigate the impact of preoperative ALRI on survival in different HCC subgroups. The results showed that preoperative ALRI was closely correlated with age (p = 0.007), median size (p = 0.004), clinical tumor-node-metastasis (TNM) stage (p < 0.001), and portal vein tumor thrombosis (PVTT) (p < 0.001). Survival analysis indicated that HCC patients with preoperative ALRI > 25.2 have a poorer disease-free survival (DFS) and overall survival (OS) after tumor resection. Multivariate analysis further identified preoperative ALRI > 25.2 (p = 0.002), III-IV of TNM stage (p = 0.011), PVTT (p = 0.035), size of tumor > 5 cm (p < 0.001) as independent risk factors of DFS; and preoperative ALRI > 25.2 (p = 0.001), III-IV of TNM stage (p = 0.005), PVTT (p = 0.012), size of tumor > 5 cm (p < 0.001), recurrence (p < 0.001) as independent prognostic factors for OS in HCC patients. Additionally, preoperative ALRI also showed different prognostic value in various subgroups of HCC. Elevated preoperative ALRI as a noninvasive, simple, and easily assessable parameter is an independent effective predictor of prognosis for patients with HCC. PMID- 26057473 TI - Effect of inorganic nanoparticles on 17beta-estradiol and 17alpha ethynylestradiol adsorption by multi-walled carbon nanotubes. AB - With extensive application of diverse engineered nanoparticles (NPs), multiple NPs would inevitably be released into the environment. However, much emphasis in most previous studies on the interactions of pollutants with NPs has been placed on only one type of NPs at a time. This study investigated the impact of inorganic NPs (I-NPs) on the adsorption of 17beta-estradiol (E2) and 17alpha ethynylestradiol (EE2) by multi-walled carbon nanotubes (CNTs). The presence of I NPs inhibited the adsorption and increased the equilibrium time of E2 and EE2 by CNTs. Moreover, the effect of Al2O3 was stronger than that of SiO2, because electrostatic attraction enhanced the interaction between oppositely charged Al2O3 and CNTs. The addition sequence of I-NPs and pollutant also influences adsorption. This is among the first studies investigating the effect of I-NPs on pollutants adsorption by CNTs, which is useful for understanding the transport and fate of CNTs and contaminants in natural aquatic systems. PMID- 26057472 TI - Revealing the fate of cell surface human P-glycoprotein (ABCB1): The lysosomal degradation pathway. AB - P-glycoprotein (P-gp) transports a variety of chemically dissimilar amphipathic compounds including anticancer drugs. Although mechanisms of P-gp drug transport are widely studied, the pathways involving its internalization are poorly understood. The present study is aimed at elucidating the pathways involved in degradation of cell surface P-gp. The fate of P-gp at the cell surface was determined by biotinylating cell surface proteins followed by flow cytometry and Western blotting. Our data shows that the half-life of endogenously expressed P gp is 26.7+/-1.1 h in human colorectal cancer HCT-15 cells. Treatment of cells with Bafilomycin A1 (BafA1) a vacuolar H+ ATPase inhibitor increased the half life of P-gp at the cell surface to 36.1+/-0.5 h. Interestingly, treatment with the proteasomal inhibitors MG132, MG115 or lactacystin alone did not alter the half-life of the protein. When cells were treated with both lysosomal and proteasomal inhibitors (BafA1 and MG132), the half-life was further prolonged to 39-50 h. Functional assays done with rhodamine 123 or calcein-AM, fluorescent substrates of P-gp, indicated that the transport function of P-gp was not affected by either biotinylation or treatment with BafA1 or proteasomal inhibitors. Immunofluorescence studies done with the antibody against lysosomal marker LAMP1 and the P-gp-specific antibody UIC2 in permeabilized cells indicated that intracellular P-gp is primarily localized in the lysosomal compartment. Our results suggest that the lysosomal degradation system could be targeted to increase the sensitivity of P-gp- expressing cancer cells towards chemotherapeutic drugs. PMID- 26057471 TI - Circulating small non-coding RNA signature in head and neck squamous cell carcinoma. AB - The Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common human cancer, causing 350,000 individuals die worldwide each year. The overall prognosis in HNSCC patients has not significantly changed for the last decade. Complete understanding of the molecular mechanisms in HNSCC carcinogenesis could allow an earlier diagnosis and the use of more specific and effective therapies. In the present study we used deep sequencing to characterize small non-coding RNAs (sncRNAs) in serum from HNSCC patients and healthy donors. We identified, for the first time, a multi-marker signature of 3 major classes of circulating sncRNAs in HNSCC, revealing the presence of circulating novel and known miRNAs, and tRNA- and YRNA-derived small RNAs that were significantly deregulated in the sera of HNSCC patients compared to healthy controls. By implementing a triple filtering approach we identified a subset of highly biologically relevant miRNA mRNA interactions and we demonstrated that the same genes/pathways affected by somatic mutations in cancer are affected by changes in the abundance of miRNAs. Therefore, one important conclusion from our work is that during cancer development, there seems to be a convergence of oncogenic processes driven by somatic mutations and/or miRNA regulation affecting key cellular pathways. PMID- 26057474 TI - Source and risk apportionment of selected VOCs and PM2.5 species using partially constrained receptor models with multiple time resolution data. AB - This study was conducted to identify and quantify the sources of selected volatile organic compounds (VOCs) and fine particulate matter (PM2.5) by using a partially constrained source apportionment model suitable for multiple time resolution data. Hourly VOC, 12-h and 24-h PM2.5 speciation data were collected during three seasons in 2013. Eight factors were retrieved from the Positive Matrix Factorization solutions and adding source profile constraints enhanced the interpretability of source profiles. Results showed that the evaporative emission factor was the largest contributor (25%) to VOC mass concentration, while the largest contributor to PM2.5 mass concentration was soil dust/regional transport related factor (26%). In terms of risk prioritization, traffic/industry related factor was the major cause for benzene, ethylbenzene, Cr, and polycyclic aromatic hydrocarbons (29-69%) while petrochemical related factor contributed most to the Ni risk (36%). This indicated that a larger contributor to mass concentration may not correspond to a higher risk. PMID- 26057475 TI - Carbon black retention in saturated natural soils: Effects of flow conditions, soil surface roughness and soil organic matter. AB - We evaluated factors affecting the transport, retention, and re-entrainment of carbon black nanoparticles (nCBs) in two saturated natural soils under different flow conditions and input concentrations using the two-site transport model and Kelvin probe force microscopy (KPFM). Soil organic matter (SOM) was found to create unfavorable conditions for the retention. Despite an increased flow velocity, the relative stability of the estimated maximum retention capacity in soils may suggest that flow-induced shear stress forces were insufficient to detach nCB. The KPFM observation revealed that nCBs were retained at the grain boundary and on surface roughness, which brought about substantial discrepancy between theoretically-derived attachment efficiency factors and the ones obtained by the experiments using the two-site transport model. Thus, decreasing ionic strength and increasing solution pH caused re-entrainment of only a small fraction of retained nCB in the soil columns. PMID- 26057476 TI - Urban rivers as hotspots of regional nitrogen pollution. AB - Excess nitrogen inputs to terrestrial ecosystems via human activities have deteriorated water qualities on regional scales. Urban areas as settlements of over half global population, however, were usually not considered in the analysis of regional water pollution. Here, we used a 72-month monitoring data of water qualities in Hangzhou, China to test the role of urban rives in regional nitrogen pollution and how they response to the changes of human activities. Concentrations of ammonium nitrogen in urban rivers were 3-5 times higher than that in regional rivers. Urban rivers have become pools of reactive nitrogen and hotspots of regional pollution. Moreover, this river pollution is not being measured by current surface water monitoring networks that are designed to measure broader regional patterns, resulting in an underestimation of regional pollution. This is crucial to urban environment not only in China, but also in other countries, where urban rivers are seriously polluted. PMID- 26057477 TI - Short-term exposure of arsenite disrupted thyroid endocrine system and altered gene transcription in the HPT axis in zebrafish. AB - Arsenic (As) pollution in aquatic environment may adversely impact fish health by disrupting their thyroid hormone homeostasis. In this study, we explored the effect of short-term exposure of arsenite (AsIII) on thyroid endocrine system in zebrafish. We measured As concentrations, As speciation, and thyroid hormone thyroxine levels in whole zebrafish, oxidative stress (H2O2) and damage (MDA) in the liver, and gene transcription in hypothalamic-pituitary-thyroid (HPT) axis in the brain and liver tissues of zebrafish after exposing to different AsIII concentrations for 48 h. Result indicated that exposure to AsIII increased inorganic As in zebrafish to 0.46-0.72 mg kg(-1), induced oxidative stress with H2O2 being increased by 1.4-2.5 times and caused oxidative damage with MDA being augmented by 1.6 times. AsIII exposure increased thyroxine levels by 1.3-1.4 times and modulated gene transcription in HPT axis. Our study showed AsIII caused oxidative damage, affected thyroid endocrine system and altered gene transcription in HPT axis in zebrafish. PMID- 26057478 TI - Can the Air Pollution Index be used to communicate the health risks of air pollution? AB - The validity of using the Air Pollution Index (API) to assess health impacts of air pollution and potential modification by individual characteristics on air pollution effects remain uncertain. We applied distributed lag non-linear models (DLNMs) to assess associations of daily API, specific pollution indices for PM10, SO2, NO2 and the weighted combined API (APIw) with mortality during 2003-2011 in Guangzhou, China. An increase of 10 in API was associated with a 0.88% (95% confidence interval (CI): 0.50, 1.27%) increase of non-accidental mortality at lag 0-2 days. Harvesting effects appeared after 2 days' exposure. The effect estimate of API over lag 0-15 days was statistically significant and similar with those of pollutant-specific indices and APIw. Stronger associations between API and mortality were observed in the elderly, females and residents with low educational attainment. In conclusion, the API can be used to communicate health risks of air pollution. PMID- 26057479 TI - Combination or Differentiation? Two theories of processing order in classification. AB - Does cognition begin with an undifferentiated stimulus whole, which can be divided into distinct attributes if time and cognitive resources allow (Differentiation Theory)? Or does it begin with the attributes, which are combined if time and cognitive resources allow (Combination Theory)? Across psychology, use of the terms analytic and non-analytic imply that Differentiation Theory is correct-if cognition begins with the attributes, then synthesis, rather than analysis, is the more appropriate chemical analogy. We re-examined four classic studies of the effects of time pressure, incidental training, and concurrent load on classification and category learning (Kemler Nelson, 1984; Smith & Kemler Nelson, 1984; Smith & Shapiro, 1989; Ward, 1983). These studies are typically interpreted as supporting Differentiation Theory over Combination Theory, while more recent work in classification (Milton et al., 2008, et seq.) supports the opposite conclusion. Across seven experiments, replication and re analysis of the four classic studies revealed that they do not support Differentiation Theory over Combination Theory-two experiments support Combination Theory over Differentiation Theory, and the remainder are compatible with both accounts. We conclude that Combination Theory provides a parsimonious account of both classic and more recent work in this area. The presented data do not require Differentiation Theory, nor a Combination-Differentiation hybrid account. PMID- 26057480 TI - Assessment of mercury and cadmium via seafood consumption in Italy: estimated dietary intake (EWI) and target hazard quotient (THQ). AB - Mercury (Hg) and cadmium (Cd) were quantified in fish, cephalopods and crustaceans from Italian supermarkets. Sample compliance with European dietary standards as well as human health risks according to provisional tolerable weekly intake (PTWI) and the methodology of target hazard quotient (THQ) were evaluated. Both element levels were under European legal limits, except for some fish having Hg and Cd contents exceeding or equal to critical values. Estimated weekly intakes (Hg: fish = 0.07-1.44 ug kg(-1) bw week(-1); cephalopods = 0.05-0.15 ug kg(-1) bw week(-1); crustaceans = 0.04-0.08 ug kg(-1) bw week(-1); and Cd: fish = 0.04-0.32 ug kg(-1) bw week(-1); cephalopods = 0.07-0.27 ug kg(-1) bw week(-1); crustaceans = 0.05-0.11 ug kg(-1) bw week(-1)) as well as THQ < 1 were within safe limits. Although there seems to be no important risks associated with seafood consumption, Hg exposure was in some cases close to safety margins and thus levels of this metal should be under frequent surveillance. PMID- 26057481 TI - Prophylaxis therapy in paediatric patients with haemophilia: a survey of clinical management trends in Italy. AB - BACKGROUND: Although current treatment guidelines recommend prophylaxis in paediatric patients with haemophilia, specific indications for and barriers to the prescription of prophylaxis in the paediatric haemophiliac population have not been established. The aim of this web-based survey of clinicians at Haemophilia Treatment Centres in Italy was to identify factors for and against the initiation of prophylactic coagulation factor replacement therapy in paediatric patients with haemophilia. MATERIALS AND METHODS: A literature search was conducted to identify factors to include in the survey. Seventeen clinicians from Italian Haemophilia Centres were invited to complete the web-based survey and to rank factors in favour of and those that acted as barriers to prophylaxis in terms of "importance" and "influence" on a numerical scale (0=not important to 100=very important). Any factors for which there was a large discrepancy in results from the survey were further "ranked" by clinicians at an interactive question and answer session at a symposium. RESULTS: A total of 13 web surveys were returned; the most highly scored factors favouring prophylaxis were "bleeding frequency", "bleeding severity" and "presence of target joints", and the most highly scored barriers were "parents' acceptance", "venous access" and "compliance to therapy". Other important factors favouring prophylaxis were "severity of coagulation defect" and "orthopaedic score". DISCUSSION: This survey gives helpful clinician-derived information for people treating haemophiliacs in Italy, to help the treatment-providers orient themselves better regarding the prescription of prophylaxis for paediatric patients. PMID- 26057482 TI - Some reflections on the Code of Ethics of the International Society of Blood Transfusion. PMID- 26057483 TI - The Code of Ethics of the International Society of Blood Transfusion. PMID- 26057484 TI - Prospective randomised evaluation of a collagen/thrombin and autologous platelet haemostatic agent during cementless total hip arthroplasty. AB - BACKGROUND: Total hip arthroplasty (THA) can be associated with substantial peri operative blood loss which can negatively influence a patient's clinical outcome. Few haemostatic agents have been tested in THA. The aim of this study was to determine whether the use of a collagen/thrombin/ autologous platelet haemostatic agent would result in a significant decrease of blood transfusions for patients undergoing primary THA. MATERIALS AND METHODS: THA patients meeting inclusion/exclusion criteria (n=109) were enrolled in this prospective, double blind trial and randomised to a treatment arm (standard haemostatic methods plus haemostatic agent) or control arm (standard haemostatic methods only). The primary outcome was transfusion. Secondary outcome measures included peri operative narcotic usage and post-operative haemoglobin levels, pain scores, function, and general health quality of life. RESULTS: Transfusions were required by 5/60 (8.3%) patients in the treatment group and 7/49 (14.3%) in the control group (p=0.33). The mean number of units transfused was not significantly different between the treatment group (2.2+/-1.3) and the control group (1.6+/ 0.5) (p=0.36). Haemoglobin values on post-operative days 1, 2, and 3 were significantly higher in the treatment group (p=0.002, 0.04, and 0.02, respectively). Hip Disability and Osteoarthritis Outcome Score and Short Form-12 scores were not different between the two groups. DISCUSSION: In relatively healthy patients undergoing primary cementless THA there was no significant difference in number of transfusions or number of units transfused. It is unlikely that we will routinely use the investigated haemostatic agent to reduce blood loss in a healthy patient undergoing THA. The product may have some benefit in patients who refuse blood transfusions, have minimal ability to increase blood volume, are undergoing total joint revision, or have markedly low pre-operative haemoglobin levels, but this needs to be demonstrated. PMID- 26057485 TI - ABO blood group and fertility: a single-centre study. PMID- 26057486 TI - Passenger lymphocyte syndrome in liver transplant recipients: a description of 12 cases. AB - BACKGROUND: Passenger lymphocyte syndrome is an important cause of immune haemolysis after solid organ transplantation. It mainly occurs in minor ABO and Rh mismatched transplants. The haemolysis is usually mild and self-limited. We present our experience in passenger lymphocyte syndrome and liver transplantation and review the literature. MATERIALS AND METHODS: We reviewed liver transplants performed in our centre from January 2002 to September 2013, searching for ABO or Rh incompatibility and serological findings of haemolysis. A direct antiglobulin test was systematically performed in each pre-transfusion assessment. RESULTS: A total of 1,217 liver transplants were performed and 12 passenger lymphocyte syndromes were detected: of the 56 cases with minor ABO incompatibility, ten patients developed passenger lymphocyte syndrome (17.9%) and of 147 cases with minor Rh incompatibility, two patients developed the syndrome (1.40%). All patients with passenger lymphocyte syndrome had haemolysis, a decrease of haemoglobin (median 6.8 g/dL) and an increase of bilirubin (median 5.15 mg/dL). The treatment of passenger lymphocyte syndrome consisted of increasing the dose of corticosteroids that the patients were receiving as post-transplantation immunosuppressive therapy and, in the majority of cases, transfusion of donor compatible red blood cells. DISCUSSION: Passenger lymphocyte syndrome in liver transplantation has significant clinical consequences. It is, therefore, important to make the diagnosis rapidly, performing pre-transfusion direct antiglobulin tests, and manage the problem correctly with donor compatible red blood cell transfusions and/or immunosuppressive treatment. PMID- 26057487 TI - Human neutrophil antigen profiles in Banjar, Bugis, Champa, Jawa and Kelantan Malays in Peninsular Malaysia. AB - BACKGROUND: Human neutrophil antigens (HNA) are polymorphic and immunogenic proteins involved in the pathogenesis of neonatal alloimmune neutropenia, transfusion-related acute lung injury (TRALI) and transfusion-related alloimmune neutropenia. The characterisation of HNA at a population level is important for predicting the risk of alloimmunisation associated with blood transfusion and gestation and for anthropological studies. MATERIALS AND METHODS: Blood samples from 192 healthy, unrelated Malays were collected and genotyped using polymerase chain reaction-sequence specific primers (HNA-1, -3, -4) and polymerase chain reaction-restriction fragment length polymorphisms (HNA-5). The group comprised 30 Banjar, 37 Bugis, 51 Champa, 39 Jawa and 35 Kelantan Malays. RESULTS: The most common HNA alleles in the Malays studied were HNA-1a (0.641-0.765), -3a (0.676 0.867), -4a (0.943-1.000) and -5a (0.529-0.910). According to principal coordinate plots constructed using HNA allele frequencies, the Malay sub-ethnic groups are closely related and grouped together with other Asian populations. The risks of TRALI or neonatal neutropenia were not increased for subjects with HNA 1, -3 and -4 loci even for donor and recipient or pairs from different Malay sub ethnic groups. Nonetheless, our estimates showed significantly higher risks of HNA alloimmunisation during pregnancy and transfusion between Malays and other genetically differentiated populations such as Africans and Europeans. DISCUSSION: This study reports HNA allele and genotype frequencies for the five Malay sub-ethnic groups living in Peninsular Malaysia for the first time. These Malay sub-ethnic groups show closer genetic relationships with other Asian populations than with Europeans and Africans. The distributions of HNA alleles in other lineages of people living in Malaysia (e.g. Chinese, Indian and Orang Asli) would be an interesting subject for future study. PMID- 26057488 TI - Advances in alloimmune thrombocytopenia: perspectives on current concepts of human platelet antigens, antibody detection strategies, and genotyping. AB - Alloimmunisation to platelets leads to the production of antibodies against platelet antigens and consequently to thrombocytopenia. Numerous molecules located on the platelet surface are antigenic and induce immune-mediated platelet destruction with symptoms that can be serious. Human platelet antigens (HPA) cause thrombocytopenias, such as neonatal alloimmune thrombocytopenia, post transfusion purpura, and platelet transfusion refractoriness. Thirty-four HPA are classified into 28 systems. Assays to identify HPA and anti-HPA antibodies are critically important for preventing and treating thrombocytopenia caused by anti HPA antibodies. Significant progress in furthering our understanding of HPA has been made in the last decade: new HPA have been discovered, antibody-detection methods have improved, and new genotyping methods have been developed. We review these advances and discuss issues that remain to be resolved as well as future prospects for preventing and treating immune thrombocytopenia. PMID- 26057489 TI - Impact of sickle cell trait on the thrombotic risk associated with non-O blood groups in northern Nigeria. AB - BACKGROUND: The non-O blood group is an established risk factor for deep vein thrombosis (DVT), while controversy surrounds the role of sickle cell trait (SCT) as a risk factor for DVT. We hypothesised that if SCT is a risk factor for DVT, individuals with non-O blood groups and SCT (Hb AS) would have a higher risk of DVT than their counterparts with non-O blood groups and normal haemoglobin phenotype (Hb AA). MATERIALS AND METHODS: We retrospectively analysed the prevalence of SCT and non-O blood groups among 148 DVT patients with control subjects in order to determine the role of SCT as a risk factor for DVT and its impact on the risk of DVT among patients with non-O blood groups. RESULTS: In comparison with control subjects, DVT patients had significantly higher prevalences of SCT (35.1% vs 27.7%, p=0.04) and non-O blood groups (68.9% vs 45.9%, p=0.02). The odds ratios for DVT due to SCT, non-O blood groups with normal Hb phenotype (Hb AA) and non-O blood groups with SCT (Hb AS) were 1.3, 2.4 and 3.5, respectively. DISCUSSION: These results suggest that SCT by itself is a weak risk factor for DVT but it has the potential of escalating the DVT risk among patients with non-O blood groups. The combined effects of elevated clotting factors (non-O group effect) and increased clotting factor activation (SCT effect) were responsible for the escalated DVT risk among patients with co inheritance of non-O blood groups and SCT. Co-inheritance of SCT and non-O blood group is, therefore, an important mixed risk factor for DVT. This should be taken into account when assessing DVT risk profiles of patients in Africa and other parts of the world where the SCT is prevalent. PMID- 26057490 TI - Specific and global coagulation tests in patients with mild haemophilia A with a double mutation (Glu113Asp, Arg593Cys). AB - BACKGROUND: Heterogeneous bleeding phenotypes are observed in haemophilia A patients with the same mutation in the F8 gene. Specific mutations in the A2 domain of factor VIII are associated with mild haemophilia and a higher risk of inhibitor development. Double mutations in mild haemophilia A are rarely reported. In this study, we investigated the in vitro function of factor VIII, performing different specific and global coagulation assays, observed clinical characteristics and assessed the possible predictive diagnostic value of the differences. MATERIALS AND METHODS: The clinical features of haemophiliacs with a mild phenotype were reviewed. Blood samples were obtained and analysed for mutations and coagulation assays: activated partial thromboplastin time, one stage and chromogenic factor VIII activity, factor VIII antigen and rotational thromboelastometry. RESULTS: We report on a cohort of 22 patients with double Glu113Asp, Arg593Cys mutations. All our patients have a quantitative defect of factor VIII and preserved similar functional activity. Factor VIII activities measured by the one-stage or chromogenic method were not discrepant, although the chromogenic assay resulted in 20% lower factor VIII activities. Waveform analysis showed a lower maximum value of the second derivative curve (Max2) of APTT with curve shape alternation, while thromboelastometry (INTEM) showed low sensitivity in comparison to results in a normal population. DISCUSSION: In genotyping, the coexistence of a second mutation should never be excluded, especially in cases of discordant clinical presentation. Waveform analysis correlates better with factor VIII activity than thromboelastometry and the Max2 parameter could provide additional information in managing haemophilia patients. The utility of specific factor activity and global haemostatic assays in general practice still needs to be investigated. PMID- 26057491 TI - Sample stability for complete blood cell count using the Sysmex XN haematological analyser. AB - BACKGROUND: Sample stability is a crucial aspect for the quality of results of a haematology laboratory. This study was conducted to investigate the reliability of haematological testing using Sysmex XN in samples stored for up to 24 h at different temperatures. MATERIALS AND METHODS: Haematological tests were performed on whole blood samples collected from 16 ostensibly healthy outpatients immediately after collection and 3 h, 6 h or 24 h afterwards, with triple aliquots kept at room temperature, 4 degrees C or 37 degrees C. RESULTS: No meaningful bias was observed after 3 h under different storage conditions, except for red blood cell distribution width (RDW) and platelet count (impedance technique, PLT-I) at 37 degrees C. After 6 h, meaningful bias was observed for mean corpuscular haemoglobin (MCH) and mean corpuscular volume (MCV) at room temperature, red blood cell (RBC) count, mean corpuscular haemoglobin concentration (MCHC), MCH, MCV and PLT-I at 4 degrees C, and RBC, RDW, MCHC, MCH and PLT-I at 37 degrees C. After 24 h, a meaningful bias was observed for MCHC, MCV, platelet count (fluorescent technique, PLT-F) and mean platelet volume (MPV) at room temperature, MCHC, MCV, PLT-I and MPV at 4 degrees C, and all parameters except RBC count and MPV at 37 degrees C. DISCUSSION: Great caution should be observed when analysing results of haematological tests conducted more than 3 h after sample collection. PMID- 26057492 TI - Use of a haemostatic matrix (Floseal(r)) does not reduce blood loss in minimally invasive total knee arthroplasty performed under continued aspirin. AB - BACKGROUND: Aspirin is being used for primary and secondary cardiovascular prevention. It has been proposed that aspirin should be discontinued 5 to 7 days before surgery. However, discontinuation might increase the risk of cardiac and thrombo-embolic co-morbidity. Aspirin also increases the risk of bleeding during and after total knee arthroplasty. This study evaluated if the intra-articular use of a haemostatic matrix (Floseal(r)) might decrease blood loss in total knee arthroplasty performed under continued aspirin use. MATERIALS AND METHODS: We retrospectively compared matched pairs in two groups (80 patients in each group). Patients in both groups were taking aspirin: one group was managed with conventional haemostasis (with bovie electrocoagulation), while the other group was treated with an intra-articular haemostatic matrix as an adjunct to electrocoagulation. The outcomes compared were haemoglobin and haematocrit levels at days 2 and 4 after surgery as surrogates for blood loss, transfusion rate, surgical time, and length of stay in the hospital. RESULTS: No differences were observed between the two groups for haemoglobin and haematocrit levels on days 2 and 4. There were no differences in transfusion rate, surgical time or length of stay in hospital between the two groups. DISCUSSION: The present study shows that the use of Floseal(r) has no effect on reducing either visible or hidden blood loss after total knee arthroplasty with peri-operative continuation of aspirin use, as assessed by a drop in haemoglobin or haematocrit. PMID- 26057494 TI - A possible case of a haemolytic transfusion reaction caused by anti-Le(a) antibody. PMID- 26057493 TI - Tailoring care to haemophilia patients' needs: which specialty and when? PMID- 26057495 TI - Blood donors' positivity for transfusion-transmissible infections: the Serbian Military Medical Academy experience. AB - BACKGROUND: Members of armed forces worldwide are considered to be very susceptible to sexually transmitted infections, thus falling into a high-risk group of blood donors regarding transfusion-transmissible infections. In the Serbian Military Medical Academy a significant number (44% for the period 2005 2013) of blood donations were from members of the Serbian Army. The aim of this study was to determine the significance of military blood donors for the safety of blood transfusion. MATERIAL AND METHODS: Between January 2005 and December 2013, a total of 155,479 blood donations were tested for hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) and syphilis using serological assays (enzyme immunoassays, chemiluminescent microparticle immunoassay and western blot) and molecular testing (polymerase chain reaction analysis). RESULTS: The percentage of blood donations positive for transfusion transmissible infections in the estimated period was 0.38%, and the percentage of HBV, HCV, HIV and syphilis positive blood donations was 0.20%, 0.12%, 0.005% and 0.06%, respectively. During that period, the percentage of all transfusion transmissible infections, and in particular of HBV and HCV, declined significantly. In contrast, the percentage of HIV and syphilis positive blood donations remained unchanged. Higher rates of positivity for transfusion transmissible infections in blood donations from members of the Serbian Army were not found, especially after mandatory military service was abolished in 2009. DISCUSSION: The reported rate of positivity for transfusion-transmissible infections in blood donations from the Military Medical Academy was considered low. This information is of great significance for further implementation of public health measures. PMID- 26057496 TI - The association of rituximab and a thrombopoietin receptor agonist in high-risk refractory immune thrombocytopenic purpura. PMID- 26057497 TI - An unusual case of red blood cell immunisation following liver transplantation. PMID- 26057498 TI - One pot synthesis and anti-biofilm potential of copper nanoparticles (CuNPs) against clinical strains of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa, an opportunistic pathogen frequently associated with nosocomial infections, is emerging as a serious threat due to its resistance to broad spectrum antimicrobials. The biofilm mode of growth confers resistance to antibiotics and novel anti-biofilm agents are urgently needed. Nanoparticle based treatments and therapies have been of recent interest because of their versatile applications. This study investigates the anti-biofilm activity of copper nanoparticles (CuNPs) synthesized by the one pot method against P. aeruginosa. Standard physical techniques including UV-visible and Fourier transform infrared spectroscopy, X-ray diffraction and transmission electron microscopy were used to characterize the synthesized CuNPs. CuNP treatments at 100 ng ml(-1) resulted in a 94, 89 and 92% reduction in biofilm, cell surface hydrophobicity and exopolysaccharides respectively, without bactericidal activity. Evidence of biofilm inhibition was also seen with light and confocal microscope analysis. This study highlights the anti-biofilm potential of CuNPs, which could be utilized as coating agents on surgical devices and medical implants to manage biofilm associated infections. PMID- 26057499 TI - Evaluation of cationic micropeptides derived from the innate immune system as inhibitors of marine biofouling. AB - A series of 13 short synthetic amphiphilic cationic micropeptides, derived from the antimicrobial iron-binding innate defence protein lactoferrin, have been evaluated for their capacity to inhibit the marine fouling process. The whole biofouling process was studied and microfouling organisms such as marine bacteria and microalgae were included as well as the macrofouling barnacle Balanus improvisus. In total 19 different marine fouling organisms (18 microfoulers and one macrofouler) were included and both the adhesion and growth of the microfoulers were investigated. It was shown that the majority of the peptides inhibited barnacle cyprid settlement via a reversible nontoxic mechanism, with IC50 values as low as 0.5 MUg ml(-1). Six peptides inhibited adhesion and growth of microorganisms. Two of these were particularly active against the microfoulers with MIC-values ranging between 0.01 and 1 MUg ml(-1), which is comparable with the commercial reference antifoulant SeaNine. PMID- 26057500 TI - Correction to Aluminum Conducts Better than Copper at the Atomic Scale: A First Principles Study of Metallic Atomic Wires. PMID- 26057501 TI - Control and Alcohol-Problem Recognition Among College Students. AB - OBJECTIVE: This study examined negative control (ie, perceived lack of control over life outcomes) and need for control as predictors of alcohol-problem recognition, evaluations (good/bad), and expectancies (likely/unlikely) among college students. The study also explored the interaction between the need for control and alcohol consumption in alcohol-related outcomes. PARTICIPANTS: Participants were a convenience sample of 500 college students from a rural Midwest university. Data were collected during the 2009-2010 academic year. METHODS: Participants completed a survey assessing control and alcohol-problem recognition, evaluations, and expectancies. RESULTS: Negative control demonstrated a significant positive association with alcohol-problem recognition, evaluations, and expectancies after controlling for gender and alcohol consumption. Need for control did not have a main effect. However, the interaction was significant in that the association between need for control and negative evaluation of alcohol problems was strongest among participants with the highest levels of alcohol consumption. CONCLUSIONS: These results demonstrate that individuals' differences in sense of control are associated with alcohol problem recognition, evaluations, and expectancies in young adults. PMID- 26057502 TI - Influence of PNIPAm on log K(f) of a copolymerized 2,2'-bipyridine: revised bifunctional ligand design for ratiometric metal-ion sensing. AB - Here we describe the synthesis of a model compound (1) based upon a previously reported bifunctional 2,2'-bipyridine (2). Ligand pKa and thermodynamic stability constants were investigated by potentiometric titrations for 1 in order to assess the metal-binding capabilities of 2 following subsequent incorporation within a temperature-responsive polymer that functions as a fluorescent metal-ion indicator. While the log KCu1 measured here was found to be 8.86 +/- 0.05 at 25 degrees C, this value was previously seen to fall 2.8 orders of magnitude following copolymerization of 2 with poly(N-isopropylacrylamide) (PNIPAm). This drop in affinity was attributed to stabilization of the neutral ligand by the polymer environment and elevated temperatures at which metal-binding experiments were performed. DeltaH (-54.4 kJ mol(-1)) and DeltaS (-12.8 J K(-1) mol(-1)) were therefore determined through variable temperature titrations in order to establish the temperature dependence of log KCu1. Doing so enabled elucidation of the overall effect that the polymer environment exerts on thermodynamic stability of copolymerized 2. Specifically, the polymer indicator was found to decrease the thermodynamic stability by 2.2 orders of magnitude, whereas elevated temperatures account for the additional 0.6 order of magnitude drop observed. This finding has implications regarding the design of future bifunctional ligands for ratiometric sensing within our temperature-responsive polymer indicator. PMID- 26057503 TI - Physician advocacy for zoster vaccination. PMID- 26057504 TI - Vitiligo disease triggers: psychological stressors preceding the onset of disease. AB - Vitiligo is the loss of skin pigmentation caused by autoimmune destruction of melanocytes. Little is known about the impact of psychological stressors preceding vitiligo onset on symptoms associated with vitiligo and the extent of disease. We performed a questionnaire-based study of 1541 adults with vitiligo to evaluate the impact of psychological stressors in this patient population. Psychological stressors should be considered as potential disease triggers in vitiligo patients, and screening of vitiligo patients for psychological stressors and associated symptoms should be included in routine assessment. PMID- 26057505 TI - Acne scarring: a review of cosmetic therapies. AB - Acne vulgaris is one of the most commonly encountered skin conditions and frequently is seen in both adolescent and adult populations. Scarring is a common result of acne and may take the form of atrophic or hypertrophic scars. Acne scarring often occurs in highly visible areas such as the face, thus resulting not only in an un-desirable cosmetic appearance but also potential impairment of mental health, social functioning, and overall well-being. There is a wide variety of medical and surgical therapies available for treatment of acne scarring. In this article, we review some of the most commonly used cosmetic therapies for acne scarring, including dermabrasion, laser resurfacing, radiofrequency (RF), subcision, skin needling, punch techniques, chemical peels, soft-tissue augmentation, intralesional therapy, cryotherapy, and silicone dressings, with a focus on cosmetic outcomes. PMID- 26057506 TI - Novel psoriasis therapies and patient outcomes, part 2: biologic treatments. AB - Biologic treatments have revolutionized the management of psoriasis and psoriatic arthritis (PsA). Anti-tumor necrosis factor (TNF) alpha monoclonal antibodies presently are approved by the US Food and Drug Administration (FDA) for treatment of these conditions. In this article, new therapies that target this pathway and other steps in the pathogenesis of psoriasis and PsA are discussed, including IL 12/IL-23, IL-17, T-cell activation in antigen-presenting cells, regulatory T cells, toll-like receptors, and granulocyte-macrophage colony-stimulating factor. This article is the second in a 3-part series on treatments presently in the pipeline for the management of psoriasis and PsA including topical agents, biologic treatments, and systemic therapies in phase 2 through phase 4 clinical trials as well as agents that are recently FDA approved. Pivotal clinical trials, mechanisms of action, patient outcomes, and pertinent safety information will be discussed for each new therapy. As our knowledge of the underlying pathogenesis of psoriasis and PsA deepens, it enables the development of more targeted therapies in the management of these conditions. PMID- 26057507 TI - Individualizing patient education for greater patient satisfaction. AB - The benefits of educational intervention on health outcomes has been widely discussed, but the most educational methods have not been addressed. We sought to assess preferred modes of education during an outpatient dermatology visit (ie, verbal instruction [VI], written instruction [WI], demonstration [DM], Internet resources [IR]). We secondarily looked at patient satisfaction with the educational methods used. The results indicate the most preferred method of education among 157 patients who completed a 12-question survey and areas where physicians may need to improve patient education. PMID- 26057508 TI - Necrobiosis lipoidica diabeticorum. PMID- 26057509 TI - What is your diagnosis? pemphigoid gestationis (herpes gestationis). PMID- 26057510 TI - Primary apocrine adenocarcinoma of the axilla. AB - Primary apocrine adenocarcinoma (AA) is a rare malignant cutaneous neoplasm that typically arises in areas of high apocrine gland density such as the axillae and the anogenital region. Due to the nonspecific clinical manifestation of AA, the differential diagnosis may be broad. The rarity of this neoplasm has led to a relative lack of well-established histologic and immunohistochemical diagnostic criteria, further complicating the diagnosis of AA. We report the case of a 49 year-old man with primary AA of the left axilla and provide a review of the clinical and histologic findings, epidemiology, and treatment modalities of this rare cutaneous neoplasm. PMID- 26057511 TI - Dreadlocks. PMID- 26057512 TI - Shiitake mushroom dermatitis. PMID- 26057513 TI - Mycoplasma pneumoniae infection in adults with acute and chronic urticaria. PMID- 26057514 TI - Onychomycosis treatment in the United States. AB - Onychomycosis is a common progressive infection of the nails that may result in remarkable morbidity. Although there are a variety of treatments available for fungal nail infections with different efficacy and safety profiles, there are limited reports on the ways in which physicians use these treatments or the frequency with which they prescribe them. In this retrospective study, major trends in the prescription and use of antifungal agents for treatment of onychomycosis in the United States were evaluated using data from the National Ambulatory Medical Care Survey. Results showed that current treatment and trends in use of drugs for onychomycosis in the United States are in accordance with recommendations in current guidelines. PMID- 26057515 TI - Papules on the face and body. PMID- 26057516 TI - Lupus-like rash of chronic granulomatous disease effectively treated with hydroxychloroquine. PMID- 26057517 TI - Intralesional vinblastine injections for treatment of classic Kaposi sarcoma in diabetic patients. AB - Classic Kaposi sarcoma (KS) usually is a localized and slowly progressing disease that mainly affects elderly patients; therefore, local treatment generally is recommended. In this study, we evaluated the clinical efficacy of intralesional vinblastine (VNB) for the treatment of classic KS in 6 participants with type 2 diabetes mellitus. Results indicated that intralesional VNB injections may be an effective alternative treatment of classic KS in diabetic patients. PMID- 26057518 TI - Sports purpura from floorball, indoor climbing, and archery. PMID- 26057519 TI - International educational opportunities for dermatology residents. AB - International resident opportunities in dermatology allow residents to become immersed in different systems of medical care and expose physicians to different dermatologic conditions, cultures, and traditions that are prevalent in each country. Due to the prevalence of some dermatologic conditions in only certain regions, international opportunities expose residents to a variety of skin pathology and disease as well as a rich and diverse experience abroad. PMID- 26057520 TI - Reflectance confocal microscopy: an overview of technology and advances in telepathology. AB - The value of in vivo reflectance confocal microscopy (RCM) as a noninvasive adjunctive tool in dermatology has steadily advanced since its inception. With RCM, dermatologists can view horizontal sections of lesions in a resolution comparable to histology, observe dynamic processes in living skin, and monitor lesion evolution longitudinally. This article will compare RCM to dermoscopy and histology, review the general principles of the microscope, describe the findings seen on confocal images, and discuss the clinical applications of this noninvasive tool. Additionally, we describe a telepathology network dedicated to the transfer of confocal images to remote dermatopathologists for interpretation. Finally, we will discuss the adoption of RCM and the telepathology network in clinical practice. PMID- 26057521 TI - Erythematous friable papule under the great toenail. PMID- 26057522 TI - Marjolin ulcer in a surgical scar. PMID- 26057523 TI - Mechanism of Orientation-Dependent Asymmetric Charge Transport in Tunneling Junctions Comprising Photosystem I. AB - Recently, photoactive proteins have gained a lot of attention due to their incorporation into bioinspired (photo)electrochemical and solar cells. This paper describes the measurement of the asymmetry of current transport of self-assembled monolayers (SAMs) of the entire photosystem I (PSI) protein complex (not the isolated reaction center, RCI), on two different "director SAMs" supported by ultraflat Au substrates. The director SAMs induce the preferential orientation of PSI, which manifest as asymmetry in tunneling charge-transport. We measured the oriented SAMs of PSI using eutectic Ga-In (EGaIn), a large-area technique, and conducting probe atomic force microscopy (CP-AFM), a single-complex technique, and determined that the transport properties are comparable. By varying the temperatures at which the measurements were performed, we found that there is no measurable dependence of the current on temperature from +/-0.1 to +/-1.0 V bias, and thus, we suggest tunneling as the mechanism for transport; there are no thermally activated (e.g., hopping) processes. Therefore, it is likely that relaxation in the electron transport chain is not responsible for the asymmetry in the conductance of SAMs of PSI complexes in these junctions, which we ascribe instead to the presence of a large, net dipole moment present in PSI. PMID- 26057524 TI - Computational Study of Subdural Cortical Stimulation: Effects of Simulating Anisotropic Conductivity on Activation of Cortical Neurons. AB - Subdural cortical stimulation (SuCS) is an appealing method in the treatment of neurological disorders, and computational modeling studies of SuCS have been applied to determine the optimal design for electrotherapy. To achieve a better understanding of computational modeling on the stimulation effects of SuCS, the influence of anisotropic white matter conductivity on the activation of cortical neurons was investigated in a realistic head model. In this paper, we constructed pyramidal neuronal models (layers 3 and 5) that showed primary excitation of the corticospinal tract, and an anatomically realistic head model reflecting complex brain geometry. The anisotropic information was acquired from diffusion tensor magnetic resonance imaging (DT-MRI) and then applied to the white matter at various ratios of anisotropic conductivity. First, we compared the isotropic and anisotropic models; compared to the isotropic model, the anisotropic model showed that neurons were activated in the deeper bank during cathodal stimulation and in the wider crown during anodal stimulation. Second, several popular anisotropic principles were adapted to investigate the effects of variations in anisotropic information. We observed that excitation thresholds varied with anisotropic principles, especially with anodal stimulation. Overall, incorporating anisotropic conductivity into the anatomically realistic head model is critical for accurate estimation of neuronal responses; however, caution should be used in the selection of anisotropic information. PMID- 26057525 TI - Cardiac Iodine-123-Meta-Iodo-Benzylguanidine Uptake in Carotid Sinus Hypersensitivity. AB - BACKGROUND: Carotid sinus syndrome is the association of carotid sinus hypersensitivity with syncope, unexplained falls and drop attacks in generally older people. We evaluated cardiac sympathetic innervation in this disorder in individuals with carotid sinus syndrome, asymptomatic carotid sinus hypersensitivity and controls without carotid sinus hypersensitivity. METHODS: Consecutive patients diagnosed with carotid sinus syndrome at a specialist falls and syncope unit were recruited. Asymptomatic carotid sinus hypersensitivity and non-carotid sinus hypersensitivity control participants recruited from a community-dwelling cohort. Cardiac sympathetic innervation was determined using Iodine-123-metaiodobenzylguanidine (123-I-MIBG) scanning. Heart to mediastinal uptake ratio (H:M) were determined for early and late uptake on planar scintigraphy at 20 minutes and 3 hours following intravenous injection of 123-I MIBG. RESULTS: Forty-two subjects: carotid sinus syndrome (n = 21), asymptomatic carotid sinus hypersensitivity (n = 12) and no carotid sinus hypersensitivity (n = 9) were included. Compared to the non- carotid sinus hypersensitivity control group, the carotid sinus syndrome group had significantly higher early H:M (estimated mean difference, B = 0.40; 95% confidence interval, CI = 0.13 to 0.67, p = 0.005) and late H:M (B = 0.32; 95%CI = 0.03 to 0.62, p = 0.032). There was, however, no significant difference in early H:M (p = 0.326) or late H:M (p = 0.351) between the asymptomatic carotid sinus hypersensitivity group and non- carotid sinus hypersensitivity controls. CONCLUSIONS: Cardiac sympathetic neuronal activity is increased relative to age-matched controls in individuals with carotid sinus syndrome but not those with asymptomatic carotid sinus hypersensitivity. Blood pressure and heart rate measurements alone may therefore represent an over simplification in the assessment for carotid sinus syndrome and the relative increase in cardiac sympathetic innervation provides additional clues to understanding the mechanisms behind the symptomatic presentation of carotid sinus hypersensitivity. PMID- 26057526 TI - Characterization of the subsets of human NKT-like cells and the expression of Th1/Th2 cytokines in patients with unexplained recurrent spontaneous abortion. AB - The objective was to investigate the subsets of natural killer T (NKT)-like cells and the expression of Th1/Th2 cytokines in the peripheral blood (PB) and/or decidual tissue of patients with unexplained recurrent spontaneous abortion (URSA). The percentages of NKT-like cells in the PB and deciduas of URSA patients in early pregnancy and in the PB of nonpregnant women were analyzed by flow cytometry. The expression of interferon (IFN)-gamma (Th1 cytokine) and Th2 cytokines, interleukin (IL)-4 and IL-10, in the PB and decidual tissue was measured by quantitative RT-PCR and enzyme-linked immunosorbent assay (ELISA). Most percentages of subsets of NKT-like cells (CD3(+)CD56(+), CD3(+)CD56(+)CD16(+)) in the PB and deciduas were significantly greater in URSA patients than in normal pregnant and nonpregnant women. A cut-off value of 3.75% for the increased percentage of CD3(+)CD56(+)CD16(+) NKT-like cells in the PB appeared to be predictive of pregnancy failure. Moreover, we found that in the decidua, IFN-gamma expression was significantly higher, while IL-4 and IL-10 expression was significantly lower in URSA patients compared with those with a normal pregnancy. The ratio of decidual Th1/Th2 cytokines in URSA patients was significantly increased compared with that in normal pregnant women. Decidual IL 4 expression correlated negatively with the percentages of blood CD3(+)CD56(+)CD16(+) NKT-like cells and the decidual CD3(+)CD56(+) and CD3(+)CD56(+)CD16(+) NKT-like cells. NKT-like cells may play an important role in maintaining normal pregnancy. Measurement of CD3(+)CD56(+)CD16(+) NKT-like cells in the PB may provide a potential tool for assessing patients' risk of spontaneous abortion. PMID- 26057527 TI - Heart Rate Detection During Sleep Using a Flexible RF Resonator and Injection Locked PLL Sensor. AB - Novel nonintrusive technologies for wrist pulse detection have been developed and proposed as systems for sleep monitoring using three types of radio frequency (RF) sensors. The three types of RF sensors for heart rate measurement on wrist are a flexible RF single resonator, array resonators, and an injection-locked PLL resonator sensor. To verify the performance of the new RF systems, we compared heart rates between presleep time and postsleep onset time. Heart rates of ten subjects were measured using the RF systems during sleep. All three RF devices detected heart rates at 0.2 to 1 mm distance from the skin of the wrist over clothes made of cotton fabric. The wrist pulse signals of a flexible RF single resonator were consistent with the signals obtained by a portable piezoelectric transducer as a reference. Then, we confirmed that the heart rate after sleep onset time significantly decreased compared to before sleep. In conclusion, the RF system can be utilized as a noncontact nonintrusive method for measuring heart rates during sleep. PMID- 26057528 TI - Cup Implant Planning Based on 2-D/3-D Radiographic Pelvis Reconstruction-First Clinical Results. AB - GOAL: In the following, we will present a newly developed X-ray calibration phantom and its integration for 2-D/3-D pelvis reconstruction and subsequent automatic cup planning. Two different planning strategies were applied and evaluated with clinical data. METHODS: Two different cup planning methods were investigated: The first planning strategy is based on a combined pelvis and cup statistical atlas. Thereby, the pelvis part of the combined atlas is matched to the reconstructed pelvis model, resulting in an optimized cup planning. The second planning strategy analyzes the morphology of the reconstructed pelvis model to determine the best fitting cup implant. RESULTS: The first planning strategy was compared to 3-D CT-based planning. Digitally reconstructed radiographs of THA patients with differently severe pathologies were used to evaluate the accuracy of predicting the cup size and position. Within a discrepancy of one cup size, the size was correctly identified in 100% of the cases for Crowe type I datasets and in 77.8% of the cases for Crowe type II, III, and IV datasets. The second planning strategy was analyzed with respect to the eventually implanted cup size. In seven patients, the estimated cup diameter was correct within one cup size, while the estimation for the remaining five patients differed by two cup sizes. CONCLUSION: While both planning strategies showed the same prediction rate with a discrepancy of one cup size (87.5%), the prediction of the exact cup size was increased for the statistical atlas-based strategy (56%) in contrast to the anatomically driven approach (37.5%). SIGNIFICANCE: The proposed approach demonstrated the clinical validity of using 2-D/3-D reconstruction technique for cup planning. PMID- 26057529 TI - The Feasibility of a Smart Surgical Probe for Verification of IRE Treatments Using Electrical Impedance Spectroscopy. AB - SIGNIFICANCE: Irreversible electroporation (IRE) is gaining popularity as a focal ablation modality for the treatment of unresectable tumors. One clinical limitation of IRE is the absence of methods for real-time treatment evaluation, namely actively monitoring the dimensions of the induced lesion. This information is critical to ensure a complete treatment and minimize collateral damage to the surrounding healthy tissue. GOAL: In this study, we are taking advantage of the biophysical properties of living tissues to address this critical demand. METHODS: Using advanced microfabrication techniques, we have developed an electrical impedance microsensor to collect impedance data along the length of a bipolar IRE probe for treatment verification. For probe characterization and interpretation of the readings, we used potato tuber, which is a suitable platform for IRE experiments without having the complexities of in vivo or ex vivo models. We used the impedance spectra, along with an electrical model of the tissue, to obtain critical parameters such as the conductivity of the tissue before, during, and after completion of treatment. To validate our results, we used a finite element model to simulate the electric field distribution during treatments in each potato. RESULTS: It is shown that electrical impedance spectroscopy could be used as a technique for treatment verification, and when combined with appropriate FEM modeling can determine the lesion dimensions. CONCLUSIONS: This technique has the potential to be readily translated for use with other ablation modalities already being used in clinical settings for the treatment of malignancies. PMID- 26057531 TI - Extreme Beta-Cell Deficiency in Pancreata of Dogs with Canine Diabetes. AB - The pathophysiology of canine diabetes remains poorly understood, in part due to enigmatic clinical features and the lack of detailed histopathology studies. Canine diabetes, similar to human type 1 diabetes, is frequently associated with diabetic ketoacidosis at onset or after insulin omission. However, notable differences exist. Whereas human type 1 diabetes often occurs in children, canine diabetes is typically described in middle age to elderly dogs. Many competing theories have been proposed regarding the underlying cause of canine diabetes, from pancreatic atrophy to chronic pancreatitis to autoimmune mediated beta-cell destruction. It remains unclear to what extent beta-cell loss contributes to canine diabetes, as precise quantifications of islet morphometry have not been performed. We used high-throughput microscopy and automated image processing to characterize islet histology in a large collection of pancreata of diabetic dogs. Diabetic pancreata displayed a profound reduction in beta-cells and islet endocrine cells. Unlike humans, canine non-diabetic islets are largely comprised of beta-cells. Very few beta-cells remained in islets of diabetic dogs, even in pancreata from new onset cases. Similarly, total islet endocrine cell number was sharply reduced in diabetic dogs. No compensatory proliferation or lymphocyte infiltration was detected. The majority of pancreata had no evidence of pancreatitis. Thus, canine diabetes is associated with extreme beta-cell deficiency in both new and longstanding disease. The beta-cell predominant composition of canine islets and the near-total absence of beta-cells in new onset elderly diabetic dogs strongly implies that similar to human type 1 diabetes, beta-cell loss underlies the pathophysiology of canine diabetes. PMID- 26057530 TI - Toward Ubiquitous Blood Pressure Monitoring via Pulse Transit Time: Theory and Practice. AB - Ubiquitous blood pressure (BP) monitoring is needed to improve hypertension detection and control and is becoming feasible due to recent technological advances such as in wearable sensing. Pulse transit time (PTT) represents a well known potential approach for ubiquitous BP monitoring. The goal of this review is to facilitate the achievement of reliable ubiquitous BP monitoring via PTT. We explain the conventional BP measurement methods and their limitations; present models to summarize the theory of the PTT-BP relationship; outline the approach while pinpointing the key challenges; overview the previous work toward putting the theory to practice; make suggestions for best practice and future research; and discuss realistic expectations for the approach. PMID- 26057532 TI - Activation of Blood Coagulation in Two Prototypic Autoimmune Skin Diseases: A Possible Link with Thrombotic Risk. AB - Coagulation activation has been demonstrated in two prototypic autoimmune skin diseases, chronic autoimmune urticaria and bullous pemphigoid, but only the latter is associated with increased thrombotic risk. Two markers of coagulation activation (prothrombin fragment F1+2 and fibrin fragment D-dimer) were measured by immunoenzymatic methods in plasma samples from 30 patients with active chronic autoimmune urticaria, positive for autologous serum skin test, 30 patients with active bullous pemphigoid and 30 healthy subjects. In skin biopsies, tissue factor expression was evaluated by both immunohistochemistry and in situ hybridization. F1+2 and D-dimer levels were higher in active chronic autoimmune urticaria (276.5+/-89.8 pmol/L and 5.56+/-4.40 nmol/L, respectively) than in controls (145.2+/-38.0 pmol/L and 1.06+/-0.25 nmol/L; P=0.029 and P=0.011) and were much higher in active bullous pemphigoid (691.7+/-318.7 pmol/L and 15.24+/ 9.09 nmol/L, respectively) (P<0.0001). Tissue factor positivity was evident in skin biopsies of both disorders with higher intensity in bullous pemphigoid. F1+2 and D-dimer, during remission, were markedly reduced in both disorders. These findings support the involvement of coagulation activation in the pathophysiology of both diseases. The strong systemic activation of coagulation in bullous pemphigoid may contribute to increase the thrombotic risk and provides the rationale for clinical trials on anticoagulant treatments in this disease. PMID- 26057533 TI - Identification and Expression Analysis of the Barley (Hordeum vulgare L.) Aquaporin Gene Family. AB - Aquaporins (AQPs) are major intrinsic proteins (MIPs) that mediate bidirectional flux of water and other substrates across cell membranes, and play critical roles in plant-water relations, dehydration stress responses and crop productivity. However, limited data are available as yet on the contributions of these proteins to the physiology of the major crop barley (Hordeum vulgare). The present work reports the identification and expression analysis of the barley MIP family. A comprehensive search of publicly available leaf mRNA-seq data, draft barley genome data, GenBank transcripts and sixteen new annotations together revealed that the barley MIP family is comprised of at least forty AQPs. Alternative splicing events were likely in two plasma membrane intrinsic protein (PIP) AQPs. Analyses of the AQP signature sequences and specificity determining positions indicated a potential of several putative AQP isoforms to transport non-aqua substrates including physiological important substrates, and respond to abiotic stresses. Analysis of our publicly available leaf mRNA-seq data identified notable differential expression of HvPIP1;2 and HvTIP4;1 under salt stress. Analyses of other gene expression resources also confirmed isoform-specific responses in different tissues and/or in response to salinity, as well as some potentially inter-cultivar differences. The work reports systematic and comprehensive analysis of most, if not all, barley AQP genes, their sequences, expression patterns in different tissues, potential transport and stress response functions, and a strong framework for selection and/or development of stress tolerant barley varieties. In addition, the barley data would be highly valuable for genetic studies of the evolutionarily closely related wheat (Triticum aestivum L.). PMID- 26057534 TI - Manganese-Catalyzed Aerobic Oxytrifluoromethylation of Styrene Derivatives Using CF3SO2Na as the Trifluoromethyl Source. AB - A mild and practical protocol for manganese-catalyzed aerobic oxytrifluoromethylation of olefinic bonds of styrene derivatives using CF3SO2Na (Langlois' reagent) as the CF3 source is described. A distinguishing feature of this method is the generation of trifluoromethyl radicals from CF3SO2Na using the simple manganese salt/O2 system. The reaction proceeds under ambient conditions, free of added peroxide initiators, and provides moderate to good selectivities for alcohol versus ketone product. PMID- 26057536 TI - Intensity-modulated and 3D-conformal radiotherapy in hypofractionated prostate cancer treatment using Elekta Beam ModulatorTM micro-MLC: A dosimetric analysis. PMID- 26057535 TI - Keratin 34betaE12/keratin7 expression is a prognostic factor of cancer-specific and overall survival in patients with early stage non-small cell lung cancer. AB - BACKGROUND: Carcinomas and their metastases often retain the keratin patterns of their epithelial origin, and are therefore useful as lineage-specific markers in diagnostic pathology. Recently, it has become clear that intermediate filaments composed by keratins play a role in modulation of cell proliferation, migration, and possibly cancer invasion, factors impacting prognosis in early stage non small cell lung cancer (NSCLC). MATERIAL AND METHODS: Tumor tissue from a retrospective Danish cohort of 177 patients with completely resected NSCLC, stage I-IIIA tumors, were analyzed for keratin 7 (K7) and keratin 34betaE12 expression by immunohistochemistry and validated in a comparable independent Norwegian cohort of 276 stage I-IIIA NSCLC patients. RESULTS: Based on keratin 34betaE12/K7 expression, three subgroups with significantly different median cancer-specific survival rates were identified (34betaE12+/K7+, 168 months vs. 34betaE12+/K7+, 73 months vs. 34betaE12-/K7+, 30 months; p = 0.0004). In multivariate analysis, stage II-IIIA (HR 2.9), 34betaE12+/K7+ (HR 1.90) and 34betaE12-/K7+ (HR 3.7), were prognostic factors of poor cancer-specific survival (CSS) (p < 0.001). Validation in the Norwegian cohort confirmed that stage II-IIIA (HR 2.3), 34betaE12+/K7+ (HR 1.6), and 34betaE12-/K7+ (HR 2.0) were prognostic factors of poor CSS (p < 0.05). Multivariate Cox proportional-hazard analysis demonstrated that 34betaE12+/K7 + and 34betaE12+/K7 + status was significantly associated with poor overall survival (p < 0.05). CONCLUSION: Keratin 34betaE12/K7 expression is a prognostic parameter in resected early stage NSCLC that allows identification of high-risk NSCLC patients with poor cancer-specific and overall survival. PMID- 26057537 TI - Mimicking and Understanding the Agglutination Effect of the Antimicrobial Peptide Thanatin Using Model Phospholipid Vesicles. AB - Thanatin is a cationic 21-residue antimicrobial and antifongical peptide found in the spined soldier bug Podisus maculiventris. It is believed that it does not permeabilize membranes but rather induces the agglutination of bacteria and inhibits cellular respiration. To clarify its mode of action, lipid vesicle organization and aggregation propensity as well as peptide secondary structure have been studied using different membrane models. Dynamic light scattering and turbidimetry results show that specific mixtures of negatively charged and zwitterionic phospholipid vesicles are able to mimic the agglutination effect of thanatin observed on Gram-negative and Gram-positive bacterial cells, while monoconstituent ("conventional") models cannot reproduce this phenomenon. The model of eukaryotic cell reveals no particular interaction with thanatin, which is consistent with the literature. Infrared spectroscopy shows that under the conditions under which vesicle agglutination occurs, thanatin exhibits a particular spectral pattern in the amide I' region and in the region associated with Arg side chains. The data suggest that thanatin mainly retains its hairpin structure, Arg residues being involved in strong interactions with anionic groups of phospholipids. In the absence of vesicle agglutination, the peptide conformation and Arg side-chain environment are similar to those observed in solution. The data show that a negatively charged membrane is required for thanatin to be active, but this condition is insufficient. The activity of thanatin seems to be modulated by the charge surface density of membranes and thanatin concentration. PMID- 26057538 TI - Insulin Resistance Is Not Associated with an Impaired Mitochondrial Function in Contracting Gastrocnemius Muscle of Goto-Kakizaki Diabetic Rats In Vivo. AB - Insulin resistance, altered lipid metabolism and mitochondrial dysfunction in skeletal muscle would play a major role in type 2 diabetes mellitus (T2DM) development, but the causal relationships between these events remain conflicting. To clarify this issue, gastrocnemius muscle function and energetics were investigated throughout a multidisciplinary approach combining in vivo and in vitro measurements in Goto-Kakizaki (GK) rats, a non-obese T2DM model developing peripheral insulin resistant without abnormal level of plasma non esterified fatty acids (NEFA). Wistar rats were used as controls. Mechanical performance and energy metabolism were assessed strictly non-invasively using magnetic resonance (MR) imaging and 31-phosphorus MR spectroscopy (31P-MRS). Compared with control group, plasma insulin and glucose were respectively lower and higher in GK rats, but plasma NEFA level was normal. In resting GK muscle, phosphocreatine content was reduced whereas glucose content and intracellular pH were both higher. However, there were not differences between both groups for basal oxidative ATP synthesis rate, citrate synthase activity, and intramyocellular contents for lipids, glycogen, ATP and ADP (an important in vivo mitochondrial regulator). During a standardized fatiguing protocol (6 min of maximal repeated isometric contractions electrically induced at a frequency of 1.7 Hz), mechanical performance and glycolytic ATP production rate were reduced in diabetic animals whereas oxidative ATP production rate, maximal mitochondrial capacity and ATP cost of contraction were not changed. These findings provide in vivo evidence that insulin resistance is not caused by an impairment of mitochondrial function in this diabetic model. PMID- 26057539 TI - Bipolarization of Risk Perception about the Health Effects of Radiation in Residents after the Accident at Fukushima Nuclear Power Plant. AB - The late health effects of low-dose rate radiation exposure are still a serious public concern in the Fukushima area even four years after the accident at Fukushima Daiichi Nuclear Power Plant (FNPP). To clarify the factors associated with residents' risk perception of radiation exposure and consequent health effects, we conducted a survey among residents of Kawauchi village in May and June 2014, which is located within 30 km of FNPP. 85 of 285 residents (29.8%) answered that acute radiation syndrome might develop in residents after the accident, 154 (54.0%) residents responded that they had anxieties about the health effects of radiation on children, and 140 (49.1%) residents indicated that they had anxieties about the health effects of radiation on offspring. Furthermore, 107 (37.5%) residents answered that they had concerns about health effects that would appear in the general population simply by living in an environment with a 0.23 MUSv per hour ambient dose for one year, 149 (52.2%) residents reported that they were reluctant to eat locally produced foods, and 164 (57.5%) residents believed that adverse health effects would occur in the general population by eating 100 Bq per kg of mushrooms every day for one year. The present study shows that a marked bipolarization of the risk perception about the health effects of radiation among residents could have a major impact on social well-being after the accident at FNPP. PMID- 26057540 TI - Tillage impact on herbicide loss by surface runoff and lateral subsurface flow. AB - There is worldwide interest in conservation tillage practices because they can reduce surface runoff, and agrichemical and sediment losses from farm fields. Since these practices typically increase infiltration, their use may increase subsurface transport of water-soluble contaminants. Thus, to assess long-term environmental benefits of conservation tillage data may be needed that quantify both surface and subsurface contaminant fluxes. This study focused on the herbicide fluometuron (N,N-dimethyl-N'-[3-(trifluoromethyl)phenyl]-urea) and its soil degradate DMF (N-methyl-N'-[3-(trifluoromethyl) phenyl]-urea). Both compounds are classed as "leachable". They were measured for 10 years in surface runoff and lateral subsurface flow from paired fields located on a hill slope in the Atlantic Coastal Plain region of the southeastern USA. One group of fields was conventionally tilled incorporating all crop residues into soil prior to planting. The second was strip tilled, a common conservation tillage practice. Seven fluometuron applications were made to cotton (Gossypium hirsutum) produced in rotation with peanut (Arachis hypogea). Combined fluometuron and DMF surface and subsurface losses from the conventionally tilled fields were equivalent to 1.2% and 0.13% of fluometuron applied and 0.31% and 0.32% from the strip tilled fields. Annual surface runoff losses were significantly greater from the conventionally tilled fields while the strip tilled fields had significantly greater annual subsurface losses. Results demonstrated that shifting from conventional to conservation tillage management of farm fields in this landscape will reduce surface runoff losses of herbicides like fluometuron but subsurface losses will likely increase. The same trends can be expected in landscapes with similar soil and hydrologic properties. This should be considered when planning implementation of programs that promote conservation tillage use. PMID- 26057541 TI - Assessment of copper and zinc salts as selectors of antibiotic resistance in Gram negative bacteria. AB - Some metals are nowadays considered environmental pollutants. Although some, like Cu and Zn, are essential for microorganisms, at high concentrations they can be toxic or exert selective pressures on bacteria. This study aimed to assess the potential of Cu or Zn as selectors of specific bacterial populations thriving in wastewater. Populations of Escherichia coli recovered on metal-free and metal supplemented culture medium were compared based on antibiotic resistance phenotype and other traits. In addition, the bacterial groups enriched after successive transfers in metal-supplemented culture medium were identified. At a concentration of 1mM, Zn produced a stronger inhibitory effect than Cu on the culturability of Enterobacteriaceae. It was suggested that Zn selected populations with increased resistance prevalence to sulfamethoxazole or ciprofloxacin. In non-selective culture media, Zn or Cu selected for mono-species populations of ubiquitous Betaproteobacteria and Flavobacteriia, such as Ralstonia pickettii or Elizabethkingia anophelis, yielding multidrug resistance profiles including resistance against carbapenems and third generation cephalosporins, confirming the potential of Cu or Zn as selectors of antibiotic resistant bacteria. PMID- 26057542 TI - Evaluation of chlorophyll-a retrieval algorithms based on MERIS bands for optically varying eutrophic inland lakes. AB - Fourteen field campaigns were conducted in five inland lakes during different seasons between 2006 and 2013, and a total of 398 water samples with varying optical characteristics were collected. The characteristics were analyzed based on remote sensing reflectance, and an automatic cluster two-step method was applied for water classification. The inland waters could be clustered into three types, which we labeled water types I, II and III. From water types I to III, the effect of the phytoplankton on the optical characteristics gradually decreased. Four chlorophyll-a retrieval algorithms for Case II water, a two-band, three band, four-band and SCI (Synthetic Chlorophyll Index) algorithm were evaluated for three water types based on the MERIS bands. Different MERIS bands were used for the three water types in each of the four algorithms. The four algorithms had different levels of retrieval accuracy for each water type, and no single algorithm could be successfully applied to all water types. For water types I and III, the three-band algorithm performed the best, while the four-band algorithm had the highest retrieval accuracy for water type II. However, the three-band algorithm is preferable to the two-band algorithm for turbid eutrophic inland waters. The SCI algorithm is recommended for highly turbid water with a higher concentration of total suspended solids. Our research indicates that the chlorophyll-a concentration retrieval by remote sensing for optically contrasted inland water requires a specific algorithm that is based on the optical characteristics of inland water bodies to obtain higher estimation accuracy. PMID- 26057543 TI - Biodegradation of pharmaceuticals in hospital wastewater by a hybrid biofilm and activated sludge system (Hybas). AB - Hospital wastewater contributes a significant input of pharmaceuticals into municipal wastewater. The combination of suspended activated sludge and biofilm processes, as stand-alone or as hybrid process (hybrid biofilm and activated sludge system (HybasTM)) has been suggested as a possible solution for hospital wastewater treatment. To investigate the potential of such a hybrid system for the removal of pharmaceuticals in hospital wastewater a pilot plant consisting of a series of one activated sludge reactor, two HybasTM reactors and one moving bed biofilm reactor (MBBR) has been established and adapted during 10 months of continuous operation. After this adaption phase batch and continuous experiments were performed for the determination of degradation of pharmaceuticals. Removal of organic matter and nitrification mainly occurred in the first reactor. Most pharmaceuticals were removed significantly. The removal of pharmaceuticals (including X-ray contrast media, beta-blockers, analgesics and antibiotics) was fitted to a single first-order kinetics degradation function, giving degradation rate constants from 0 to 1.49 h(-1), from 0 to 7.78 * 10(-1)h(-1), from 0 to 7.86 * 10(-1)h(-1) and from 0 to 1.07 * 10(-1)h(-1) for first, second, third and fourth reactors respectively. Generally, the highest removal rate constants were found in the first and third reactors while the lowest were found in the second one. When the removal rate constants were normalized to biomass amount, the last reactor (biofilm only) appeared to have the most effective biomass in respect to removing pharmaceuticals. In the batch experiment, out of 26 compounds, 16 were assessed to degrade more than 20% of the respective pharmaceutical within the HybasTM train. In the continuous flow experiments, the measured removals were similar to those estimated from the batch experiments, but the concentrations of a few pharmaceuticals appeared to increase during the first treatment step. Such increase could be attributed to de-conjugation or formation from other metabolites. PMID- 26057544 TI - Speciated OVOC and VOC emission inventories and their implications for reactivity based ozone control strategy in the Pearl River Delta region, China. AB - The increasing ground-ozone (O3) levels, accompanied by decreasing SO2, NO2, PM10 and PM2.5 concentrations benefited from air pollution control measures implemented in recent years, initiated a serious challenge to control Volatile Organic Compound (VOC) emissions in the Pearl River Delta (PRD) region, China. Speciated VOC emission inventory is fundamental for estimating Ozone Formation Potentials (OFPs) to identify key reactive VOC species and sources in order to formulate efficient O3 control strategies. With the use of the latest bulk VOC emission inventory and local source profiles, this study developed the PRD regional speciated Oxygenated Volatile Organic Compound (OVOC) and VOC emission inventories to identify the key emission-based and OFP-based VOC sources and species. Results showed that: (1) Methyl alcohol, acetone and ethyl acetate were the major constituents in the OVOC emissions from industrial solvents, household solvents, architectural paints and biogenic sources; (2) from the emission-based perspective, aromatics, alkanes, OVOCs and alkenes made up 39.2%, 28.2%, 15.9% and 10.9% of anthropogenic VOCs; (3) from the OFP-based perspective, aromatics and alkenes become predominant with contributions of 59.4% and 25.8% respectively; (4) ethene, m/p-xylene, toluene, 1,2,4-trimethyl benzene and other 24 high OFP-contributing species were the key reactive species that contributed to 52% of anthropogenic emissions and up to 80% of OFPs; and (5) industrial solvents, industrial process, gasoline vehicles and motorcycles were major emission sources of these key reactive species. Policy implications for O3 control strategy were discussed. The OFP cap was proposed to regulate VOC control policies in the PRD region due to its flexibility in reducing the overall OFP of VOC emission sources in practice. PMID- 26057545 TI - Organ Transplantation: An Introduction to Game Theory. PMID- 26057547 TI - Effect of material perception on mode of color appearance. AB - The mode of color appearance (mode) is a concept suggesting that variations in a medium that emits, transmits, or reflects light can cause differences in color appearance. For example, the same light beams that appear brown (or gray) when reflected from a given object surface may appear orange (or white) when emitted from a light source. The present study investigated the relationships between material perception and perceived mode, especially in terms of luminosity. In the experiment, a rotating spheroid was presented with surrounds of various luminance levels. The surface texture of the spheroid was either matte gray (three surface reflectance levels) or one of two fabrics. The participants were asked to evaluate the luminosity (mode) and perceived reflectance of the object. The results show that the mode perception is clearly different from the lightness perception. The luminosity was fit with a linear function of the lightness scale in CIE (Commission Internationale de l'Eclairage) L* value of the object surface, unless the material of the surface was identifiable. To conclude, the luminosity (mode) perception can be strongly affected by the material percept, and the luminosity perception of the same object can vary when its surface property is ambiguous. PMID- 26057546 TI - Sensitivity to gaze-contingent contrast increments in naturalistic movies: An exploratory report and model comparison. AB - Sensitivity to luminance contrast is a prerequisite for all but the simplest visual systems. To examine contrast increment detection performance in a way that approximates the natural environmental input of the human visual system, we presented contrast increments gaze-contingently within naturalistic video freely viewed by observers. A band-limited contrast increment was applied to a local region of the video relative to the observer's current gaze point, and the observer made a forced-choice response to the location of the target (~25,000 trials across five observers). We present exploratory analyses showing that performance improved as a function of the magnitude of the increment and depended on the direction of eye movements relative to the target location, the timing of eye movements relative to target presentation, and the spatiotemporal image structure at the target location. Contrast discrimination performance can be modeled by assuming that the underlying contrast response is an accelerating nonlinearity (arising from a nonlinear transducer or gain control). We implemented one such model and examined the posterior over model parameters, estimated using Markov-chain Monte Carlo methods. The parameters were poorly constrained by our data; parameters constrained using strong priors taken from previous research showed poor cross-validated prediction performance. Atheoretical logistic regression models were better constrained and provided similar prediction performance to the nonlinear transducer model. Finally, we explored the properties of an extended logistic regression that incorporates both eye movement and image content features. Models of contrast transduction may be better constrained by incorporating data from both artificial and natural contrast perception settings. PMID- 26057548 TI - How crowding, masking, and contour interactions are related: A developmental approach. AB - Young children are characterized by poor visual performances. Visual crowding, lateral interactions, and contour detection are critical functions for visual perception, context effect, and recognition that develop over the years up to maturity. The age at which the maturation's onset of the functions can be observed and the functions' underlying neural basis remain unclear. Here we used a development approach to investigate the onset of the foveal visual functions in order to learn about their neuronal basis and their relationships. We measured lateral interactions, crowding, and contour integration in participants aged 3-15 years. The results show that very young children do not exhibit collinear facilitation; rather, their vision is dominated by suppression and a high degree of crowding. Our results show sequential changes in the visual functions in parallel with the development of facilitation-that is, a significant reduction in crowding and an improved contour detection threshold. Our data suggest that the correlation between the onset age of maturation of collinear facilitation with crowding reduction and improvement of contour integration has underlying mutual neuronal mechanisms. PMID- 26057549 TI - Acquisition, representation, and transfer of models of visuo-motor error. AB - We examined how human subjects acquire and represent models of visuo-motor error and how they transfer information about visuo-motor error from one task to a closely related one. The experiment consisted of three phases. In the training phase, subjects threw beanbags underhand towards targets displayed on a wall mounted touch screen. The distribution of their endpoints was a vertically elongated bivariate Gaussian. In the subsequent choice phase, subjects repeatedly chose which of two targets varying in shape and size they would prefer to attempt to hit. Their choices allowed us to investigate their internal models of visuo motor error distribution, including the coordinate system in which they represented visuo-motor error. In the transfer phase, subjects repeated the choice phase from a different vantage point, the same distance from the screen but with the throwing direction shifted 45 degrees . From the new vantage point, visuo-motor error was effectively expanded horizontally by ?2. We found that subjects incorrectly assumed an isotropic distribution in the choice phase but that the anisotropy they assumed in the transfer phase agreed with an objectively correct transfer. We also found that the coordinate system used in coding two dimensional visuo-motor error in the choice phase was effectively one dimensional. PMID- 26057550 TI - Electrochemical Insights on the Hydrophobicity of Cellulose Substrates Imparted by Enzymatically Oxidized Gallates with Increasing Alkyl Chain Length. AB - In this work, we studied the influence of the alkyl chain length in enzymatically oxidized gallates on the development of hydrophobicity on paper-based materials, and further correlated the obtained effect to the redox mechanism of the enzymatic treatment. Laccase (Lac) enzyme was used to oxidize various members of the gallate homologous series in the presence or not of lignosulfonates (SL) to produce several functionalization solutions (FS), which were subsequently applied to cellulosic substrates. The hydrophobicity of the substrates was then assessed by means of water drop test (WDT) and contact angle (WCA) measurements. Hydrophobicity peaked reaching WDT and WCA values around 5000 s and 130 degrees , respectively, and then decreased with increasing length of the hydrocarbon chain of gallate. Cyclic voltrammetry (CV) was used to study the effect of SL on the redox reactions of several gallates. The intensity of the anodic peak in their voltammograms decreased increasing the chain length of the gallate. The electrochemical behavior of lauryl gallate (LG) differed from that of other gallates. The fact that the voltammetric curves for SL and LG intersected at a potential of 478 mV indicates an enhancing effect of SL on LG oxidation at high potentials (above 478 mV). PMID- 26057551 TI - The ultimate social network: breastmilk sharing via the internet. PMID- 26057553 TI - Brain-derived neurotrophic factor in sera of breastfed epileptic infants and in breastmilk of their mothers. AB - BACKGROUND: Human milk contains leukocytes expressing brain-derived neurotrophic factor (BDNF), which may facilitate epileptogenesis. Our study aimed to estimate levels of BDNF in the sera of breastfed infants with idiopathic epilepsy and in breastmilk of their mothers and to assess its value as a marker of epilepsy severity. PATIENTS AND METHODS: Thirty breastfed infants <2 years of age with idiopathic epilepsy and 15 control healthy breastfed infants were recruited for the study. Patients were subjected to thorough medical history, clinical examination, and assessment of disease severity. Routine laboratory and radiological investigations, including, liver, renal, and thyroid screen, brain magnetic resonance imaging, and measurement of serum and breastmilk BDNF levels, were performed. RESULTS: Serum BDNF levels of epileptic infants and milk BDNF levels of their mothers were significantly higher than values for controls (p=0.0001). They were positively correlated with age, weight, length, and head circumference of epileptic children. Also, serum and milk BDNF levels were significantly increased with increased duration of illness and frequency of seizures. There was a significant positive correlation between serum and breastmilk levels of BDNF and significantly higher levels in severe cases of epilepsy. CONCLUSIONS: Serum and milk BDNF levels are higher in epileptic infants than in controls and may be used as a marker of disease severity. PMID- 26057552 TI - O-glycosylation of alpha-1-acid glycoprotein of human milk is lactation stage related. AB - BACKGROUND: Human milk provides a multitude of glycoproteins, including highly glycosylated alpha-1-acid glycoprotein (AGP), which elicits anti-inflammatory and immunomodulatory properties. The milk AGP glycoforms may provide the breastfed infant with a wide range of biological benefits. Here, we analyzed the reactivity of O-linked sugar-specific lectins with human milk AGP over the process of lactation and compared the results with those of the lactating mother's plasma. MATERIALS AND METHODS: Relative amounts of human skim milk AGP O-glycans were analyzed in early colostrum, colostrum, and transitional and mature milk samples of 127 healthy mothers by lectin-AGP enzyme-linked immunosorbent assay using sialyl T (sialyl-alpha2,3/alpha2,6 Galbeta1,3GalNAc-), asialyl T (Galbeta1,3GalNAc-), and Tn (GalNAc-) antigen-specific biotinylated Artocarpus integrifolia (Jacalin), Arachis hypogaea (PNA), and Vicia villosa (VVA) lectins, respectively. RESULTS: Milk AGP elicited high expression of Jacalin- and PNA reactive glycotopes and low expression of VVA-reactive glycotopes, which were absent on plasma AGP of lactating mothers and healthy individuals. The expression of sialyl, asialyl T, and Tn glycotopes of human milk AGP was lactation stage related. The relative amount of Jacalin-reactive AGP glycotope was highest in the colostrum samples and then decreased starting from Day 8 of lactation. In contrast, an increase of the relative amount of PNA-reactive glycotope with milk maturation was observed. The relative amount of VVA-reactive glycotope remained almost constant over the development of lactation. CONCLUSIONS: Milk AGP differs from mother's plasma AGP by the presence of O-linked sialylated and asialylated T as well as Tn antigens. The variation of the expression of sialylated and asialylated T and Tn antigens on AGP is associated with milk maturation. PMID- 26057554 TI - Breastfeeding-related vaginal symptoms. PMID- 26057555 TI - Racial disparities in breastfeeding. PMID- 26057556 TI - Correction to: Breastfeed Med 2015;10(3):175-182. PMID- 26057557 TI - A Critical Role for CLSP2 in the Modulation of Antifungal Immune Response in Mosquitoes. AB - Entomopathogenic fungi represent a promising class of bio-insecticides for mosquito control. Thus, detailed knowledge of the molecular mechanisms governing anti-fungal immune response in mosquitoes is essential. In this study, we show that CLSP2 is a modulator of immune responses during anti-fungal infection in the mosquito Aedes aegypti. With a fungal infection, the expression of the CLSP2 gene is elevated. CLSP2 is cleaved upon challenge with Beauveria bassiana conidia, and the liberated CLSP2 CTL-type domain binds to fungal cell components and B. bassiana conidia. Furthermore, CLPS2 RNA interference silencing significantly increases the resistance to the fungal challenge. RNA-sequencing transcriptome analysis showed that the majority of immune genes were highly upregulated in the CLSP2-depleted mosquitoes infected with the fungus. The up-regulated immune gene cohorts belong to melanization and Toll pathways, but not to the IMD or JAK-STAT. A thioester-containing protein (TEP22), a member of alpha2-macroglobulin family, has been implicated in the CLSP2-modulated mosquito antifungal defense. Our study has contributed to a greater understanding of immune-modulating mechanisms in mosquitoes. PMID- 26057558 TI - Fundamental Use of Surgical Energy (FUSE): Closing a Gap in Medical Education. PMID- 26057559 TI - RNAi-Mediated Knock-Down of transformer and transformer 2 to Generate Male-Only Progeny in the Oriental Fruit Fly, Bactrocera dorsalis (Hendel). AB - The transformer (tra) gene appears to act as the genetic switch that promotes female development by interaction with the transformer2 (tra-2) gene in several dipteran species including the Medfly, housefly and Drosophila melanogaster. In this study, we describe the isolation, expression and function of tra and tra-2 in the economically important agricultural pest, the oriental fruit fly, Bactrocera dorsalis (Hendel). Bdtra and Bdtra-2 are similar to their homologs from other tephritid species. Bdtra demonstrated sex-specific transcripts: one transcript in females and two transcripts in males. In contrast, Bdtra-2 only had one transcript that was common to males and females, which was transcribed continuously in different adult tissues and developmental stages. Bdtra-2 and the female form of Bdtra were maternally inherited in eggs, whereas the male form of Bdtra was not detectable until embryos of 1 and 2 h after egg laying. Function analyses of Bdtra and Bdtra-2 indicated that both were indispensable for female development, as nearly 100% males were obtained with embryonic RNAi against either Bdtra or Bdtra-2. The fertility of these RNAi-generated males was subsequently tested. More than 80% of RNAi-generated males could mate and the mated females could lay eggs, but only 40-48.6% males gave rise to progeny. In XX reversed males and intersex individuals, no clear female gonadal morphology was observed after dissection. These results shed light on the development of a genetic sexing system with male-only release for this agricultural pest. PMID- 26057560 TI - Clinical Predictors of Progressive Beta-Cell Failure in Type 2 Diabetes. AB - OBJECTIVES: The aim of the study was to identify factors associated with progressive beta-cell failure in a cohort of nonselected subjects with type 2 diabetes. METHODS: Two hundred twenty-four medical records were evaluated. Progressive beta-cell failure was defined as the following: glycated hemoglobin is higher than 7.5% despite combined drug therapy and appropriate diet (ie, isocaloric or hypocaloric diet depending on body weight) and absence of any illness causing acute hyperglycemia. The following factors were considered as possible predictors: diabetes-related symptoms, fasting plasma glucose at the onset of disease, family history of type 2 diabetes, number of visits per year, and residency. Further potential predictors were disease duration, age, body mass index, estimated glomerular filtration rate, and hypertension and/or hyperlipidemia at the enrollment in the study. RESULTS: The prevalence of beta cell failure was 41%. Independent predictors of failure were longer disease duration (hazard ratio [HR] for each year of diabetes, 1.03; confidence intervals (CIs), 1.01-1.05; P = 0.03), history of hypertension (HR, 1.90; CIs, 1.73-2.89; P = 0.04), hyperlipidemia (HR, 1.65; CIs, 1.06-2.58; P = 0.03), residence in suburb (HR, 1.78; CIs, 1.06-3.01; P = 0.03), and presence of symptoms at the onset of disease (HR, 2.47; CIs, 1.51-4.03; P = 0.0001). CONCLUSIONS: Patients with long disease duration, hypertension, and hyperlipidemia who are residents in suburbs and had diabetes-related symptoms at diagnosis might deserve intensive treatment to obtain adequate and stable glycemic control. PMID- 26057561 TI - Rhinovirus-Induced Airway Disease: A Model to Understand the Antiviral and Th2 Epithelial Immune Dysregulation in Childhood Asthma. AB - Rhinovirus (RV) infections account for most asthma exacerbations among children and adults, yet the fundamental mechanism responsible for why asthmatics are more susceptible to RV than otherwise healthy individuals remains largely unknown. Nonetheless, the use of models to understand the mechanisms of RV-induced airway disease in asthma has dramatically expanded our knowledge about the cellular and molecular pathogenesis of the disease. For instance, ground-breaking studies have recently established that the susceptibility to RV in asthmatic subjects is associated with a dysfunctional airway epithelial inflammatory response generated after innate recognition of viral-related molecules, such as double-stranded RNA. This review summarizes the novel cardinal features of the asthmatic condition identified in the past few years through translational and experimental RV-based approaches. Specifically, we discuss the evidence demonstrating the presence of an abnormal innate antiviral immunity (airway epithelial secretion of types I and III interferons), exaggerated production of the master Th2 molecule thymic stromal lymphopoietin, and altered antimicrobial host defense in the airways of asthmatic individuals with acute RV infection. PMID- 26057562 TI - Unraveling adaptation of Pontibacter korlensis to radiation and infertility in desert through complete genome and comparative transcriptomic analysis. AB - The desert is a harsh habitat for flora and microbial life due to its aridness and strong radiation. In this study, we constructed the first complete and deeply annotated genome of the genus Pontibacter (Pontibacter korlensis X14-1(T) = CCTCC AB 206081(T), X14-1). Reconstruction of the sugar metabolism process indicated that strain X14-1 can utilize diverse sugars, including cellulose, starch and sucrose; this result is consistent with previous experiments. Strain X14-1 is also able to resist desiccation and radiation in the desert through well-armed systems related to DNA repair, radical oxygen species (ROS) detoxification and the OstAB and TreYZ pathways for trehalose synthesis. A comparative transcriptomic analysis under gamma radiation revealed that strain X14-1 presents high-efficacy operating responses to radiation, including the robust expression of catalase and the manganese transport protein. Evaluation of 73 novel genes that are differentially expressed showed that some of these genes may contribute to the strain's adaptation to radiation and desiccation through ferric transport and preservation. PMID- 26057563 TI - Protein function from its emergence to diversity in contemporary proteins. AB - The goal of this work is to learn from nature the rules that govern evolution and the design of protein function. The fundamental laws of physics lie in the foundation of the protein structure and all stages of the protein evolution, determining optimal sizes and shapes at different levels of structural hierarchy. We looked back into the very onset of the protein evolution with a goal to find elementary functions (EFs) that came from the prebiotic world and served as building blocks of the first enzymes. We defined the basic structural and functional units of biochemical reactions-elementary functional loops. The diversity of contemporary enzymes can be described via combinations of a limited number of elementary chemical reactions, many of which are performed by the descendants of primitive prebiotic peptides/proteins. By analyzing protein sequences we were able to identify EFs shared by seemingly unrelated protein superfamilies and folds and to unravel evolutionary relations between them. Binding and metabolic processing of the metal- and nucleotide-containing cofactors and ligands are among the most abundant ancient EFs that became indispensable in many natural enzymes. Highly designable folds provide structural scaffolds for many different biochemical reactions. We show that contemporary proteins are built from a limited number of EFs, making their analysis instrumental for establishing the rules for protein design. Evolutionary studies help us to accumulate the library of essential EFs and to establish intricate relations between different folds and functional superfamilies. Generalized sequence-structure descriptors of the EF will become useful in future design and engineering of desired enzymatic functions. PMID- 26057564 TI - The never ending story or the search for a nondepolarising alternative to succinylcholine. PMID- 26057565 TI - Pro: rocuronium should replace succinylcholine for rapid sequence induction. PMID- 26057566 TI - Con: succinylcholine should not be replaced by rocuronium for rapid sequence induction. PMID- 26057567 TI - Modeling the clinical and economic implications of obesity using microsimulation. AB - OBJECTIVES: The obesity epidemic has raised considerable public health concerns, but there are few validated longitudinal simulation models examining the human and economic cost of obesity. This paper describes a microsimulation model as a comprehensive tool to understand the relationship between body weight, health, and economic outcomes. METHODS: Patient health and economic outcomes were simulated annually over 10 years using a Markov-based microsimulation model. The obese population examined is nationally representative of obese adults in the US from the 2005-2012 National Health and Nutrition Examination Surveys, while a matched normal weight population was constructed to have similar demographics as the obese population during the same period. Prediction equations for onset of obesity-related comorbidities, medical expenditures, economic outcomes, mortality, and quality-of-life came from published trials and studies supplemented with original research. Model validation followed International Society for Pharmacoeconomics and Outcomes Research practice guidelines. RESULTS: Among surviving adults, relative to a matched normal weight population, obese adults averaged $3900 higher medical expenditures in the initial year, growing to $4600 higher expenditures in year 10. Obese adults had higher initial prevalence and higher simulated onset of comorbidities as they aged. Over 10 years, excess medical expenditures attributed to obesity averaged $4280 annually-ranging from $2820 for obese category I to $5100 for obese category II, and $8710 for obese category III. Each excess kilogram of weight contributed to $140 higher annual costs, on average, ranging from $136 (obese I) to $152 (obese III). Poor health associated with obesity increased work absenteeism and mortality, and lowered employment probability, personal income, and quality-of-life. CONCLUSIONS: This validated model helps illustrate why obese adults have higher medical and indirect costs relative to normal weight adults, and shows that medical costs for obese adults rise more rapidly with aging relative to normal weight adults. PMID- 26057569 TI - Differences in age-related fiber atrophy between vastii muscles of active subjects: a multichannel surface EMG study. AB - The aim of the study was to non-invasively determine if vastus lateralis (VL) and vastus medialis obliquus (VM) muscles are equally affected by age-related fiber atrophy. Multichannel surface electromyography was used since it allows to estimate muscle fiber conduction velocity (CV), which has been demonstrated to be related to the size of recruited muscle fibers. Twelve active elderly men (age 69 +/- 4 years) and 12 active young men (age 23 +/- 2 years) performed isometric knee extension at 30%, 50%, and 70% of maximal voluntary contraction. Electromyographic signals were recorded from VL and VM muscles of the dominant limb using arrays with eight electrodes and CVs were estimated for each contraction. CV estimates showed a different behavior in the two muscles: in VL at 50% and 70% of maximum voluntary contraction they were greater in young than in elderly; whereas such a difference was not observed in VM. This finding suggest that in active elderly VM seems to be less affected by the age-related fibers atrophy than VL. Hence, the common choice of studying VL as a muscle representative of the whole quadriceps could generate misleading findings. Indeed, it seemed that the sarcopenic ageing effects might be heterogeneous within quadriceps muscle. PMID- 26057570 TI - Successful Combination Therapy with Rituximab and Glucocorticoids for Autoimmune Optic Neuropathy. AB - BACKGROUND: Autoimmune optic neuropathy is optic neuropathy caused by an autoimmune mechanism. As treatment, steroid is usually used. If steroid is ineffective to improve visual function, other immunosuppressive agents are used as needed. Rituximab is one of molecular target agents and is now used as treatment for several types of autoimmune disorders. CASE REPORT: A 77-year-old woman presented with vision loss in her left eye. Her past medical history included disturbances of multiple organs. Laboratory tests revealed positive myeloperoxidase-anti-neutrophil cytoplasmic antibody. We assumed that her vision loss was caused by autoimmune optic neuropathy and put her on high-dose glucocorticoid therapy. Her visual function quickly re-deteriorated after high dose glucocorticoid therapy discontinuation. To achieve vision improvement, we added rituximab to her treatment regimen. Her visual acuity recovered to almost 20/20 within a week later. She received other 3 rituximab-infusions and her visual acuity remained 20/20 while tapering glucocorticoid. CONCLUSIONS: Autoimmune optic neuropathy may result in blindness if treatment fails. Rituximab may be a therapeutic option for autoimmune optic neuropathy and may produce immediate response. PMID- 26057571 TI - Automated Phone Assessments and Hospital Readmissions. AB - This analysis examined the efficacy of an automated postdischarge phone assessment for reducing hospital readmissions. All patients discharged between April 1, 2013, and January 31, 2014, from a single Level 1 trauma hospital of a large regional health system center utilizing an automated postdischarge phone assessment service were contacted via automated call between 24 and 72 hours post discharge. Patients answered 5 questions assessing perceived well-being, understanding of discharge instructions and medication regimen, satisfaction, and scheduled follow-up appointments. Responses could automatically prompt health personnel to speak directly with the patient. Data analysis examined rates of hospital readmission-any admission occurring within 30 days of a previous admission-for 3 broad categories of respondents: Answering Machine, Live Answer, and Unsuccessful. There were 6867 discharges included in the analysis. Of the Live Answer patients, 3035 answered all assessment questions; 153 (5.0%) of these had a subsequent readmission. Of the 738 Unsuccessful patients, 62 (8.4%) had a subsequent readmission. Unsuccessful patients were almost 2 times more likely to have a readmission than those who answered all 5 assessment questions. Of the latter group, readmission rates were highest for those who perceived a worsening of their condition (7.4%), and lowest for those reporting no follow-up appointment scheduled (3.8%). (Population Health Management 2016;19:120-124). PMID- 26057573 TI - New treatment approaches for severe and enduring eating disorders. AB - OBJECTIVE: The aim of this paper is to map the possibility of new treatment approaches for eating disorders. BACKGROUND: Eating disorders have a protracted trajectory with over 50% of cases developing a severe and enduring stage of illness. Although a good response to family-based interventions occurs in the early phase, once the illness has become severe and enduring there is less of a response to any form of treatment. Neuroprogressive changes brought about by poor nutrition and abnormal eating patterns contribute to this loss of treatment responsivity. METHOD: We have summarised the profile of symptoms at the various stages of illness and considered new treatments that might be applied. RESULTS: In the enduring stage of illness in addition to problems with body image, food and eating, there are additional problems of low mood, high anxiety and compulsivity and problems in social functioning. This suggests that there are dysfunctions in circuits subsuming reward, punishment, decision-making and social processes. New approaches have been developed targeting these areas. CONCLUSION: New interventions targeting both the primary and secondary symptoms seen in the enduring stage of eating disorders may improve the response to treatment. PMID- 26057572 TI - Potent Paracrine Effects of human induced Pluripotent Stem Cell-derived Mesenchymal Stem Cells Attenuate Doxorubicin-induced Cardiomyopathy. AB - Transplantation of bone marrow mesenchymal stem cells (BM-MSCs) can protect cardiomyocytes against anthracycline-induced cardiomyopathy (AIC) through paracrine effects. Nonetheless the paracrine effects of human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) on AIC are poorly understood. In vitro studies reveal that doxorubicin (Dox)-induced reactive oxidative stress (ROS) generation and cell apoptosis in neonatal rat cardiomyocytes (NRCMs) are significantly reduced when treated with conditioned medium harvested from BM-MSCs (BM-MSCs-CdM) or iPSC-MSCs (iPSC-MSCs-CdM). Compared with BM-MSCs-CdM, NRCMs treated with iPSC MSCs-CdM exhibit significantly less ROS and cell apoptosis in a dose-dependent manner. Transplantation of BM-MSCs-CdM or iPSC-MSCs-CdM into mice with AIC remarkably attenuated left ventricular (LV) dysfunction and dilatation. Compared with BM-MSCs-CdM, iPSC-MSCs-CdM treatment showed better alleviation of heart failure, less cardiomyocyte apoptosis and fibrosis. Analysis of common and distinct cytokines revealed that macrophage migration inhibitory factor (MIF) and growth differentiation factor-15 (GDF-15) were uniquely overpresented in iPSC-MSC CdM. Immunodepletion of MIF and GDF-15 in iPSC-MSCs-CdM dramatically decreased cardioprotection. Injection of GDF-15/MIF cytokines could partially reverse Dox induced heart dysfunction. We suggest that the potent paracrine effects of iPSC MSCs provide novel "cell-free" therapeutic cardioprotection against AIC, and that MIF and GDF-15 in iPSC-MSCs-CdM are critical for these enhanced cardioprotective effects. PMID- 26057574 TI - Intra-accumbal CB1 receptor blockade reduced extinction and reinstatement of morphine. AB - The limbic dopaminergic reward system is the main target of morphine-like drugs which begins from the ventral tegmental area (VTA) and sends its dopaminergic projections to the nucleus accumbens (NAc), amygdala, hippocampus and prefrontal cortex. Cannabinoid receptors exist in afferent neurons from these areas to the NAc and can modulate glutamate synaptic transmission in the NAc. Cannabinoids can interact with the opiate system in reward-related behaviors; nevertheless these systems' interaction in extinction duration and reinstatement has not been shown. In the present study, the effects of bilateral intra-accumbal administration of AM251, a CB1 receptor antagonist, on the duration of the extinction phase and reinstatement to morphine were investigated by conditioned place preference (CPP) paradigm. Forty eight adult male albino Wistar rats were used. Bilateral intra accumbal administration of AM251 (15, 45 and 90MUM/0.5MUl DMSO per side) was performed. Subcutaneous administration of morphine (5mg/kg) in three consecutive days was used to induce CPP. The results showed that administration of the maximal dose of AM251 during the extinction period significantly reduces duration of extinction and reinstatement to morphine. Administration of the middle dose during the extinction period significantly attenuated reinstatement to morphine. A single microinjection of the middle dose just before the reinstatement phase significantly attenuated reinstatement to morphine only, while bilateral intra accumbal administration of neither the lowest dose nor the vehicle (DMSO) had any effects. These results for the first time indicated that CB1 receptors within the NAc are involved in the maintenance of morphine rewarding properties, and morphine seeking behaviors in extinguished morphine-induced CPP rats. PMID- 26057576 TI - An On-Demand Optical Quantum Random Number Generator with In-Future Action and Ultra-Fast Response. AB - Random numbers are essential for our modern information based society e.g. in cryptography. Unlike frequently used pseudo-random generators, physical random number generators do not depend on complex algorithms but rather on a physical process to provide true randomness. Quantum random number generators (QRNG) do rely on a process, which can be described by a probabilistic theory only, even in principle. Here we present a conceptually simple implementation, which offers a 100% efficiency of producing a random bit upon a request and simultaneously exhibits an ultra low latency. A careful technical and statistical analysis demonstrates its robustness against imperfections of the actual implemented technology and enables to quickly estimate randomness of very long sequences. Generated random numbers pass standard statistical tests without any post processing. The setup described, as well as the theory presented here, demonstrate the maturity and overall understanding of the technology. PMID- 26057575 TI - Examining Causes of Racial Disparities in General Surgical Mortality: Hospital Quality Versus Patient Risk. AB - BACKGROUND: Racial disparities in general surgical outcomes are known to exist but not well understood. OBJECTIVES: To determine if black-white disparities in general surgery mortality for Medicare patients are attributable to poorer health status among blacks on admission or differences in the quality of care provided by the admitting hospitals. RESEARCH DESIGN: Matched cohort study using Tapered Multivariate Matching. SUBJECTS: All black elderly Medicare general surgical patients (N=18,861) and white-matched controls within the same 6 states or within the same 838 hospitals. MEASURES: Thirty-day mortality (primary); others include in-hospital mortality, failure-to-rescue, complications, length of stay, and readmissions. RESULTS: Matching on age, sex, year, state, and the exact same procedure, blacks had higher 30-day mortality (4.0% vs. 3.5%, P<0.01), in hospital mortality (3.9% vs. 2.9%, P<0.0001), in-hospital complications (64.3% vs. 56.8% P<0.0001), and failure-to-rescue rates (6.1% vs. 5.1%, P<0.001), longer length of stay (7.2 vs. 5.8 d, P<0.0001), and more 30-day readmissions (15.0% vs. 12.5%, P<0.0001). Adding preoperative risk factors to the above match, there was no significant difference in mortality or failure-to-rescue, and all other outcome differences were small. Blacks matched to whites in the same hospital displayed no significant differences in mortality, failure-to-rescue, or readmissions. CONCLUSIONS: Black and white Medicare patients undergoing the same procedures with closely matched risk factors displayed similar mortality, suggesting that racial disparities in general surgical mortality are not because of differences in hospital quality. To reduce the observed disparities in surgical outcomes, the poorer health of blacks on presentation for surgery must be addressed. PMID- 26057577 TI - Salsolinol: a potential modulator of the activity of the hypothalamic-pituitary adrenal axis in nursing and postweaning sheep. AB - The most well-known physiological action of salsolinol (1-methyl-6,7-dihydroxy 1,2,3,4-tetrahydroisoquinoline) is the stimulation of prolactin secretion, especially during lactation. In addition, our recent work demonstrated that salsolinol inhibits the stress-induced activity of the hypothalamic-pituitary adrenal (HPA) axis in lactating sheep. Here, we investigated whether salsolinol regulates the basal activity of the HPA axis in lactating sheep and whether its inhibitory action on the stress-induced activity of the HPA axis is present during the postweaning period. The first experiment was performed during the fifth week of lactation, in which unstressed sheep received an intracerebroventricular infusion of an antagonistic analogue of salsolinol, 1 MeDIQ (1-methyl-3,4-dihydroisoquinoline). Simultaneously, the infundibular nucleus and/or median eminence was perfused using the push-pull method. Sheep that received 1-MeDIQ infusion showed significantly higher concentration of plasma ACTH during the second, third, and fourth hour (P < 0.001, P < 0.01, and P < 0.001, respectively) and cortisol during the third and fourth hour (P < 0.001 and P < 0.01, respectively) than did sheep that received control infusion. There was no significant difference in the mean perfusate corticotropin-releasing hormone concentration between the 1-MeDIQ and control treatments. In the second experiment, sheep received an intracerebroventricular infusion of salsolinol during the ninth week of lactation and 48 h after lamb weaning. A comparison between the control groups in the first and second experiments revealed that sheep after weaning (ninth week of lactation) had significantly higher mean ACTH (P < 0.001) and cortisol (P < 0.001) concentrations during the first 2 h of the experiment than the nursing females (fifth week of lactation) had. Salsolinol significantly reduced the increased concentrations of ACTH and cortisol (P < 0.01) in sheep after lamb weaning. However, there was no difference in the expression of proopiomelanocortin messenger RNA within the anterior pituitary between the control and salsolinol-treated groups. In conclusion, salsolinol regulates the basal activity of the HPA axis in lactating sheep. In addition, the HPA axis of postweaning females is more sensitive to stressors associated with the experimental procedures, and salsolinol attenuates ACTH and cortisol release in this phenomenon. PMID- 26057578 TI - Anisometric Polyelectrolyte/Mixed Surfactant Nanoassemblies Formed by the Association of Poly(diallyldimethylammonium chloride) with Sodium Dodecyl Sulfate and Dodecyl Maltoside. AB - The soluble complexes of oppositely charged macromolecules and amphiphiles, formed in the one-phase concentration range, are usually described on the basis of the beads on a string model assuming spherelike bound surfactant micelles. However, around and above the charge neutralization ionic surfactant to polyion ratio, a variety of ordered structures of the precipitates and large polyion/surfactant aggregates have been reported for the different systems which are difficult to connect to globular-like surfactant self-assembly units. In this article we have demonstrated through SAXS measurements that the structure of precipitates and those of the soluble polyion/mixed surfactant complexes of poly(diallyldimethylammonium chloride) (PDADMAC), sodium dodecyl sulfate (SDS), and dodecyl-maltoside (DDM) are strongly correlated. Specifically, SDS binds to the PDADMAC molecules in the form of small cylindrical surfactant micelles even at very low SDS-to-PDADMAC ratios. In this way, these anisometric surfactant self assemblies formed in excess polyelectrolyte mimic the basic building units of the hexagonal structure of the PDADMAC/SDS precipitate and/or suspensions formed at charge equivalence or at higher SDS-to-PDADMAC ratios. The presence of DDM reduces the cmc and cac for the system but does not alter significantly the structure of the complexes in either the one-phase or two-phase region. The only exception is for samples at SDS-to-PDADMAC ratios close to charge neutralization and a high concentration of DDM where the precipitate forms a multiphasic or distorted hexagonal structure. PMID- 26057579 TI - Control of stomach smooth muscle development and intestinal rotation by transcription factor BARX1. AB - Diverse functions of the homeodomain transcription factor BARX1 include Wnt dependent, non-cell autonomous specification of the stomach epithelium, tracheo bronchial septation, and Wnt-independent expansion of the spleen primordium. Tight spatio-temporal regulation of Barx1 levels in the mesentery and stomach mesenchyme suggests additional roles. To determine these functions, we forced constitutive BARX1 expression in the Bapx1 expression domain, which includes the mesentery and intestinal mesenchyme, and also examined Barx1(-/)(-) embryos in further detail. Transgenic embryos invariably showed intestinal truncation and malrotation, in part reflecting abnormal left-right patterning. Ectopic BARX1 expression did not affect intestinal epithelium, but intestinal smooth muscle developed with features typical of the stomach wall. BARX1, which is normally restricted to the developing stomach, drives robust smooth muscle expansion in this organ by promoting proliferation of myogenic progenitors at the expense of other sub-epithelial cells. Undifferentiated embryonic stomach and intestinal mesenchyme showed modest differences in mRNA expression and BARX1 was sufficient to induce much of the stomach profile in intestinal cells. However, limited binding at cis-regulatory sites implies that BARX1 may act principally through other transcription factors. Genes expressed ectopically in BARX1(+) intestinal mesenchyme and reduced in Barx1(-/-) stomach mesenchyme include Isl1, Pitx1, Six2 and Pitx2, transcription factors known to control left-right patterning and influence smooth muscle development. The sum of evidence suggests that potent BARX1 functions in intestinal rotation and stomach myogenesis occur through this small group of intermediary transcription factors. PMID- 26057580 TI - In Vivo Senescence in the Sbds-Deficient Murine Pancreas: Cell-Type Specific Consequences of Translation Insufficiency. AB - Genetic models of ribosome dysfunction show selective organ failure, highlighting a gap in our understanding of cell-type specific responses to translation insufficiency. Translation defects underlie a growing list of inherited and acquired cancer-predisposition syndromes referred to as ribosomopathies. We sought to identify molecular mechanisms underlying organ failure in a recessive ribosomopathy, with particular emphasis on the pancreas, an organ with a high and reiterative requirement for protein synthesis. Biallelic loss of function mutations in SBDS are associated with the ribosomopathy Shwachman-Diamond syndrome, which is typified by pancreatic dysfunction, bone marrow failure, skeletal abnormalities and neurological phenotypes. Targeted disruption of Sbds in the murine pancreas resulted in p53 stabilization early in the postnatal period, specifically in acinar cells. Decreased Myc expression was observed and atrophy of the adult SDS pancreas could be explained by the senescence of acinar cells, characterized by induction of Tgfbeta, p15(Ink4b) and components of the senescence-associated secretory program. This is the first report of senescence, a tumour suppression mechanism, in association with SDS or in response to a ribosomopathy. Genetic ablation of p53 largely resolved digestive enzyme synthesis and acinar compartment hypoplasia, but resulted in decreased cell size, a hallmark of decreased translation capacity. Moreover, p53 ablation resulted in expression of acinar dedifferentiation markers and extensive apoptosis. Our findings indicate a protective role for p53 and senescence in response to Sbds ablation in the pancreas. In contrast to the pancreas, the Tgfbeta molecular signature was not detected in fetal bone marrow, liver or brain of mouse models with constitutive Sbds ablation. Nevertheless, as observed with the adult pancreas phenotype, disease phenotypes of embryonic tissues, including marked neuronal cell death due to apoptosis, were determined to be p53-dependent. Our findings therefore point to cell/tissue-specific responses to p53-activation that include distinction between apoptosis and senescence pathways, in the context of translation disruption. PMID- 26057581 TI - Potential for direct interspecies electron transfer in an electric-anaerobic system to increase methane production from sludge digestion. AB - Direct interspecies electron transfer (DIET) between Geobacter species and Methanosaeta species is an alternative to interspecies hydrogen transfer (IHT) in anaerobic digester, which however has not been established in anaerobic sludge digestion as well as in bioelectrochemical systems yet. In this study, it was found that over 50% of methane production of an electric-anaerobic sludge digester was resulted from unknown pathway. Pyrosequencing analysis revealed that Geobacter species were significantly enriched with electrodes. Fluorescence in situ hybridization (FISH) further confirmed that the dominant Geobacter species enriched belonged to Geobacter metallireducens. Together with Methanosaeta species prevailing in the microbial communities, the direct electron exchange between Geobacter species and Methanosaeta species might be an important reason for the "unknown" increase of methane production. Conductivity of the sludge in this electric-anaerobic digester was about 30% higher than that of the sludge in a control digester without electrodes. This study not only revealed for the first time that DIET might be the important mechanism on the methanogenesis of bioelectrochemical system, but also provided a new method to enhance DIET by means of bioelectric enrichment of Geobacter species. PMID- 26057582 TI - Tumour antigen expression in hepatocellular carcinoma in a low-endemic western area. AB - BACKGROUND: Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs. METHODS: We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry. RESULTS: A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P=0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL 4 expression (P=0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P=0.018). CONCLUSIONS: We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment. PMID- 26057584 TI - Evaluation of site-specific lateral inclusion zone for vapor intrusion based on an analytical approach. AB - In 2002, U.S. EPA proposed a general buffer zone of approximately 100 feet (30 m) laterally to determine which buildings to include in vapor intrusion (VI) investigations. However, this screening distance can be threatened by factors such as extensive surface pavements. Under such circumstances, EPA recommended investigating soil vapor migration distance on a site-specific basis. To serve this purpose, we present an analytical model (AAMLPH) as an alternative to estimate lateral VI screening distances at chlorinated compound-contaminated sites. Based on a previously introduced model (AAML), AAMLPH is developed by considering the effects of impervious surface cover and soil geology heterogeneities, providing predictions consistent with the three-dimensional (3 D) numerical simulated results. By employing risk-based and contribution-based screening levels of subslab concentrations (50 and 500 MUg/m(3), respectively) and source-to-subslab attenuation factor (0.001 and 0.01, respectively), AAMLPH suggests that buildings greater than 30 m from a plume boundary can still be affected by VI in the presence of any two of the three factors, which are high source vapor concentration, shallow source and significant surface cover. This finding justifies the concern that EPA has expressed about the application of the 30 m lateral separation distance in the presence of physical barriers (e.g., asphalt covers or ice) at the ground surface. PMID- 26057585 TI - MUC5B mucin production is upregulated by fibronectin and laminin in human lung epithelial cells via the integrin and ERK dependent pathway. AB - MUC5B mucin is a principal component of airway mucus and plays a key role in biodefense. We investigated the regulation of MUC5B production using the signals from extracellular matrix (ECM) components in NCI-H292 human lung epithelial cells. We found that MUC5B production in NCI-H292 cells cultured on fibronectin or laminin increased by 4-5-fold, with the increase occurring in a dose- and time dependent manner. In contrast, MUC5B production was unchanged on type-IV collagen. Inhibition of integrin beta1 induced upregulation of MUC5B and MUC5AC; however, inhibition of p38 MAPK did not show any remarkable change in overproduced MUC5B. Inhibition of extracellular signal-regulated kinase (ERK) pathway or the transcription factor NF-kappaB induced the recovery of overproduced MUC5B on fibronectin and laminin. These results suggest that MUC5B production can be regulated by ECM components and that MUC5B is upregulated by fibronectin and laminin via the integrin, ERK, and NF-kappaB dependent pathway. PMID- 26057586 TI - Surface-Enhanced Raman Spectroscopy-Based Approach for Ultrasensitive and Selective Detection of Hydrazine. AB - A probe mediated SERS-based strategy is developed to selectively detect hydrazine with superb sensitivity. Ortho-phthaldialdehyde, a simple probe, reacts specifically with hydrazine to form phthalazine, a molecule that possesses a larger Raman cross section and better affinity toward the SERS substrate. We observed a limit of detection of 8.5 * 10(-11) M. Our method shows both qualitative and quantitative measurement of hydrazine with high sensitivity, low cost, and fast analysis time. PMID- 26057587 TI - A Convergent Radical Based Route to Trifluoromethyl Ketones and to alpha,beta Unsaturated Trifluoromethyl Ketones. AB - A convergent synthesis of trifluoromethyl ketones and alpha,beta-unsaturated trifluoromethyl ketones is described, starting with aliphatic iodides and dithiocarbonates (xanthates) and exploiting both the alpha- and beta fragmentations of a sulfonyl radical. The transformation initially furnishes the ketones in a masked enol carbonate form, from which they can be easily regenerated. PMID- 26057588 TI - Mechanisms Involved in the Formation of Biocompatible Lipid Polymeric Hollow Patchy Particles. AB - Patchy polymeric particles have anisotropic surface domains that can be remarkably useful in diverse medical and industrial fields because of their ability to simultaneously present two different surface chemistries on the same construct. In this article, we report the mechanisms involved in the formation of novel lipid-polymeric hollow patchy particles during their synthesis. By cross sectioning the patchy particles, we found that a phase segregation phenomenon occurs between the core, shell, and patch. Importantly, we found that the shear stress that the polymer blend undergoes during the particle synthesis is the most important parameter for the formation of these patchy particles. In addition, we found that the interplay of solvent-solvent, polymer-solvent, and polymer-polymer solvent interactions generates particles with different surface morphologies. Understanding the mechanisms involved in the formation of patchy particles allows us to have a better control on their physicochemical properties. Therefore, these fundamental studies are critical to achieve batch control and scalability, which are essential aspects that must be addressed in any type of particle synthesis to be safely used in medicine. PMID- 26057590 TI - Hippocampal volume and functional connectivity changes during the female menstrual cycle. AB - Hippocampal volume has been shown to be sensitive to variations in estrogen and progesterone levels across rodents' estrous cycle. However, little is known about the covariation of hormone levels and brain structure in the course of the human menstrual cycle. Here, we examine this covariation with a multi-method approach that includes several brain imaging methods and hormonal assessments. We acquired structural and functional scans from 21 naturally cycling women on four time points during their cycles (early follicular phase, late follicular phase, ovulation and luteal phase). Hormone blood concentrations and cognitive performance in different domains were assessed on each of the measurement occasions. Structural MRI images were processed by means of whole-brain voxel based morphometry and FreeSurfer. With either method, bilateral increases in hippocampal volume were found in the late follicular phase relative to the early follicular phase. The gray matter probability in regions of hippocampal volume increase was associated with lower mean diffusivity in the same region. In addition, we observed higher functional connectivity between the hippocampi and the bilateral superior parietal lobe in the late follicular phase. We did not find any reliable cycle-related performance variations on the cognitive tasks. The present results show that hormonal fluctuations covary with hippocampal structure and function in the course of the human menstrual cycle. PMID- 26057589 TI - Structural and mutational analyses of dipeptidyl peptidase 11 from Porphyromonas gingivalis reveal the molecular basis for strict substrate specificity. AB - The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to the S46 family of serine peptidases and preferentially cleaves substrates with Asp/Glu at the P1 position. The molecular mechanism underlying the substrate specificity of PgDPP11, however, is unknown. Here, we report the crystal structure of PgDPP11. The enzyme contains a catalytic domain with a typical double beta-barrel fold and a recently identified regulatory alpha-helical domain. Crystal structure analyses, docking studies, and biochemical studies revealed that the side chain of Arg673 in the S1 subsite is essential for recognition of the Asp/Glu side chain at the P1 position of the bound substrate. Because S46 peptidases are not found in mammals and the Arg673 is conserved among DPP11s, we anticipate that DPP11s could be utilised as targets for antibiotics. In addition, the present structure analyses could be useful templates for the design of specific inhibitors of DPP11s from pathogenic organisms. PMID- 26057591 TI - Automatic segmentation of MR brain images of preterm infants using supervised classification. AB - Preterm birth is often associated with impaired brain development. The state and expected progression of preterm brain development can be evaluated using quantitative assessment of MR images. Such measurements require accurate segmentation of different tissue types in those images. This paper presents an algorithm for the automatic segmentation of unmyelinated white matter (WM), cortical grey matter (GM), and cerebrospinal fluid in the extracerebral space (CSF). The algorithm uses supervised voxel classification in three subsequent stages. In the first stage, voxels that can easily be assigned to one of the three tissue types are labelled. In the second stage, dedicated analysis of the remaining voxels is performed. The first and the second stages both use two-class classification for each tissue type separately. Possible inconsistencies that could result from these tissue-specific segmentation stages are resolved in the third stage, which performs multi-class classification. A set of T1- and T2 weighted images was analysed, but the optimised system performs automatic segmentation using a T2-weighted image only. We have investigated the performance of the algorithm when using training data randomly selected from completely annotated images as well as when using training data from only partially annotated images. The method was evaluated on images of preterm infants acquired at 30 and 40weeks postmenstrual age (PMA). When the method was trained using random selection from the completely annotated images, the average Dice coefficients were 0.95 for WM, 0.81 for GM, and 0.89 for CSF on an independent set of images acquired at 30weeks PMA. When the method was trained using only the partially annotated images, the average Dice coefficients were 0.95 for WM, 0.78 for GM and 0.87 for CSF for the images acquired at 30weeks PMA, and 0.92 for WM, 0.80 for GM and 0.85 for CSF for the images acquired at 40weeks PMA. Even though the segmentations obtained using training data from the partially annotated images resulted in slightly lower Dice coefficients, the performance in all experiments was close to that of a second human expert (0.93 for WM, 0.79 for GM and 0.86 for CSF for the images acquired at 30weeks, and 0.94 for WM, 0.76 for GM and 0.87 for CSF for the images acquired at 40weeks). These results show that the presented method is robust to age and acquisition protocol and that it performs accurate segmentation of WM, GM, and CSF when the training data is extracted from complete annotations as well as when the training data is extracted from partial annotations only. This extends the applicability of the method by reducing the time and effort necessary to create training data in a population with different characteristics. PMID- 26057592 TI - A two-step super-Gaussian independent component analysis approach for fMRI data. AB - Independent component analysis (ICA) has been widely applied to functional magnetic resonance imaging (fMRI) data analysis. Although ICA assumes that the sources underlying data are statistically independent, it usually ignores sources' additional properties, such as sparsity. In this study, we propose a two step super-GaussianICA (2SGICA) method that incorporates the sparse prior of the sources into the ICA model. 2SGICA uses the super-Gaussian ICA (SGICA) algorithm that is based on a simplified Lewicki-Sejnowski's model to obtain the initial source estimate in the first step. Using a kernel estimator technique, the source density is acquired and fitted to the Laplacian function based on the initial source estimates. The fitted Laplacian prior is used for each source at the second SGICA step. Moreover, the automatic target generation process for initial value generation is used in 2SGICA to guarantee the stability of the algorithm. An adaptive step size selection criterion is also implemented in the proposed algorithm. We performed experimental tests on both simulated data and real fMRI data to investigate the feasibility and robustness of 2SGICA and made a performance comparison between InfomaxICA, FastICA, mean field ICA (MFICA) with Laplacian prior, sparse online dictionary learning (ODL), SGICA and 2SGICA. Both simulated and real fMRI experiments showed that the 2SGICA was most robust to noises, and had the best spatial detection power and the time course estimation among the six methods. PMID- 26057594 TI - Anatomically-adapted graph wavelets for improved group-level fMRI activation mapping. AB - A graph based framework for fMRI brain activation mapping is presented. The approach exploits the spectral graph wavelet transform (SGWT) for the purpose of defining an advanced multi-resolutional spatial transformation for fMRI data. The framework extends wavelet based SPM (WSPM), which is an alternative to the conventional approach of statistical parametric mapping (SPM), and is developed specifically for group-level analysis. We present a novel procedure for constructing brain graphs, with subgraphs that separately encode the structural connectivity of the cerebral and cerebellar gray matter (GM), and address the inter-subject GM variability by the use of template GM representations. Graph wavelets tailored to the convoluted boundaries of GM are then constructed as a means to implement a GM-based spatial transformation on fMRI data. The proposed approach is evaluated using real as well as semi-synthetic multi-subject data. Compared to SPM and WSPM using classical wavelets, the proposed approach shows superior type-I error control. The results on real data suggest a higher detection sensitivity as well as the capability to capture subtle, connected patterns of brain activity. PMID- 26057593 TI - Venous cerebral blood volume increase during voluntary locomotion reflects cardiovascular changes. AB - Understanding how changes in the cardiovascular system contribute to cerebral blood flow (CBF) and volume (CBV) increases is critical for interpreting hemodynamic signals. Here we investigated how systemic cardiovascular changes affect the cortical hemodynamic response during voluntary locomotion. In the mouse, voluntary locomotion drives an increase in cortical CBF and arterial CBV that is localized to the forelimb/hindlimb representation in the somatosensory cortex, as well as a diffuse venous CBV increase. To determine if the heart rate increases that accompany locomotion contribute to locomotion-induced CBV and CBF increases, we occluded heart rate increases with the muscarinic cholinergic receptor antagonist glycopyrrolate, and reduced heart rate with the beta1 adrenergic receptor antagonist atenolol. We quantified the effects of these cardiovascular manipulations on CBV and CBF dynamics by comparing the hemodynamic response functions (HRF) to locomotion across these conditions. Neither the CBF HRF nor the arterial component of the CBV HRF was significantly affected by pharmacological disruption of the heart rate. In contrast, the amplitude and spatial extent of the venous component of the CBV HRF were decreased by atenolol. These results suggest that the increase in venous CBV during locomotion was partially driven by peripheral cardiovascular changes, whereas CBF and arterial CBV increases associated with locomotion reflect central processes. PMID- 26057596 TI - Monitoring of the interaction between U937 cells and electroactive daunomycin with an arginine-rich peptide. AB - Daunomycin penetrates the membrane of a U937 cell, which is a human histiocyte related lymphoma cell. Several arginine-rich peptides have also exhibited a high degree of permeability with these cells. Therefore, we attempted to improve the membrane permeability of daunomycin by coupling it with an arginine-rich peptide. The cell membrane permeability of daunomycin was monitored using voltammetry, because daunomycin is an electroactive compound. First, daunomycin was combined with N-(6-maleimidocaproyloxy)sulfosuccinimide. Second, the cross-linking agent with daunomycin was bound to the cysteine residue of RRRRRRRRGC (peptide-1). The two-step synthesis suppressed the formation of by-products that might have conjugated with the amino groups of peptide-1. After the quinone moieties of daunomycin were reduced using an electrode, an oxidation peak appeared due to the moieties. The peak current of daunomycin with U937 cells had decreased. For the mixture of the daunomycin/peptide-1 probe and cells, the electrode response was smaller than that of daunomycin with the cells. Thus, the membrane penetration of the daunomycin/peptide-1 probe was improved compared with the use of only daunomycin. In addition, the membrane penetration of the probe was measured using fluorescence spectroscopy. The sensitivity of the electrochemical procedure was 100-fold that was obtained by fluorescence spectrometry. PMID- 26057595 TI - Developmental changes in spontaneous electrocortical activity and network organization from early to late childhood. AB - We investigated the development of spontaneous (resting state) cerebral electric fields and their network organization from early to late childhood in a large community sample of children. Critically, we examined electrocortical maturation across one-year windows rather than creating aggregate averages that can miss subtle maturational trends. We implemented several novel methodological approaches including a more fine grained examination of spectral features across multiple electrodes, the use of phase-lagged functional connectivity to control for the confounding effects of volume conduction and applying topological network analyses to weighted cortical adjacency matrices. Overall, there were major decreases in absolute EEG spectral density (particularly in the slow wave range) across cortical lobes as a function of age. Moreover, the peak of the alpha frequency increased with chronological age and there was a redistribution of relative spectral density toward the higher frequency ranges, consistent with much of the previous literature. There were age differences in long range functional brain connectivity, particularly in the alpha frequency band, culminating in the most dense and spatially variable networks in the oldest children. We discovered age-related reductions in characteristic path lengths, modularity and homogeneity of alpha-band cortical networks from early to late childhood. In summary, there is evidence of large scale reorganization in endogenous brain electric fields from early to late childhood, suggesting reduced signal amplitudes in the presence of more functionally integrated and band limited coordination of neuronal activity across the cerebral cortex. PMID- 26057597 TI - Multicentric epithelioid hemangioendothelioma involving the lungs, trachea, liver and skeletal muscles. AB - Epithelioid hemangioendothelioma (EH) is a rare benign vascular tumor, which typically present as multinodular lesions that can involve one organ or more. We report a 12 years old female who presented with one-year history of progressive intolerance to physical activity and 3 months history of dry cough and weight loss. Physical examination was positive for diminished breath sounds and crackles of right hemithorax, and small mass in abdominal wall. CT of chest and abdomen revealed multiple nodular lesions in both lungs, liver, and right abdominal rectal muscle. Bronchoscopy showed multiple small tracheal lesions. Immunhistochemical staining of biopsy specimens obtained from the trachea, liver and muscle was consistent with EH. PMID- 26057598 TI - Motion trajectory information and agency influence motor learning during observational practice. AB - Fundamental to performing actions is the acquisition of motor behaviours. We examined if motor learning, through observational practice, occurs by viewing an agent displaying naturalistic or constant velocity, and whether motion trajectory, as opposed to end-state, information is required. We also investigated if observational practice is sensitive to belief regarding the origin of an agent. Participants had to learn a novel movement sequence timing task, which required upper-limb movements to a series of targets within a pre specified absolute and relative time goal. Experiment 1 showed learning after viewing naturalistic and constant velocity, but not end-state information. For Experiment 2, in addition to learning the movement sequence, participants observed a series of movement stimuli that were either the trained or new sequences and asked to rate their confidence on whether the observed sequence was the same or different to observational practice. The results indicated that agency belief modulates how naturalistic and constant velocity is coded. This indicated that the processes associated with belief are part of an interpretative predictive coding system where the association between belief and observed motion is determined. When motion is constant velocity, or believed to be computer generated, coding occurs through top-down processes. When motion is naturalistic velocity, and believed to be human-generated, it is most likely coded by gaining access to bottom-up sensorimotor processes in the action-observation network. PMID- 26057599 TI - Deciphering interference control in adults with ADHD by using distribution analyses and electromyographic activity. AB - A deficit in "interference control" is commonly found in adults with Attention Deficit Hyperactivity Disorder (ADHD). This has mainly been interpreted as difficulties in inhibiting inappropriate responses. However, interference control involves processes other than simply the ability to inhibit. Consequently, we used sophisticated analysis to decipher the additional processes of interference control in these patients. We compared interference control between 16 adults with ADHD and 15 control adults performing a Simon task. In most studies, performance is generally reported in terms of mean error rates and reaction times (RTs). However, here we used distribution analyses of behavioral data, complemented by analyses of electromyographic (EMG) activity. This allowed us to better quantify the control of interference, specifically the part that remains hidden when pure correct trials are not distinguished from partial errors. Partial errors correspond to sub-threshold EMG bursts induced by incorrect responses that immediately precede a correct response. Moreover, besides "online" control, we also investigated cognitive control effects manifesting across consecutive trials. The main findings were that adults with ADHD were slower and showed a larger interference effect in comparison to controls. However, the data revealed that the larger interference effect was due neither to higher impulse expression, nor to a deficit in inhibition but that these patients presented a larger interference effect than the controls after congruent trials. We propose and discuss the hypothesis that the interference control deficit found in adults with ADHD is secondary to impairments in sustained attention. PMID- 26057601 TI - Highly efficient degradation of dyes by carbon quantum dots/N-doped zinc oxide (CQD/N-ZnO) photocatalyst and its compatibility on three different commercial dyes under daylight. AB - Eco-friendly carbon quantum dots/nitrogen-doped ZnO (CQD/N-ZnO) composites were successfully prepared by a facile one-step method. The various techniques were employed to characterize the phase structure, morphology and optical properties of CQD/N-ZnO composites. The nitrogen doping was confirmed by Raman and X-ray photoelectron spectroscopy. Three commercial dyes, such as malachite green, methylene blue and fluorescein dyes were chosen to investigate the photocatalytic performance of CQD/N-ZnO under daylight irradiation. It was found that the CQD/N ZnO photocatalyst established a high compatibility to degrade all three commercial dyes within 30-45 min, under daylight irradiation. Also, it remains capable of reusing the CQD/N-ZnO photocatalyst for repeated photocatalytic performance due to anti-photocorrosion offered by CQDs. The synergetic effect of N-doping and CQDs is key to design a new class of photocatalyst for environmental remediation under naturally available daylight source. PMID- 26057600 TI - Influence of binary microgel phase behavior on the assembly of multi-functional raspberry-structured microgel heteroaggregates. AB - We investigate the influence of microgel composition on phase behavior of binary microgel dispersions using poly(N-isopropylacrylamide) microgels cross-linked with 5 mol% and 1 mol% N,N'-methylenebis(acrylamide), or poly(N isopropylmethacrylamide) microgels cross-linked with 5 mol% N,N' methylenebis(acrylamide). We then explore the dispersion phase behavior in the context of microgel deposition at a planar interface. These results are then compared to the observed assembly of microgels at curved interfaces, in the form of raspberry-like patchy particles (RLPPs) consisting of a polystyrene core surrounded by a (two-component) microgel shell. Results suggest that microgel composition has a large influence on the ability of binary dispersions to coat planar and curved interfaces. In particular, we demonstrate that binary dispersions of microgels containing higher cross-linker content exhibit decreased packing densities that are very pronounced at a curved interface. To enhance packing density we also explore the use of a two-step coating process to fabricate RLPPs with enhanced control over topography. Development of these complex vehicles is potentially beneficial in the modulation of biological systems where spatial and temporal presentation of molecules can have a large influence on cellular behavior. PMID- 26057602 TI - BHRF1 exerts an antiapoptotic effect and cell cycle arrest via Bcl-2 in murine hybridomas. AB - Apoptosis has been widely studied in order to find methods to increase the life span and production performance in large-scale animal cell cultures. The use of anti-apoptotic genes has emerged as an efficient method to reduce apoptosis in a variety of biotechnological relevant cell lines, including CHO and hybridomas, alternatively to small molecule inhibitors. It is already known that expression of BHRF1, an Epstein-Barr virus-encoded early protein homologous to the anti apoptotic protein Bcl-2, protects hybridoma cells from apoptosis in batch and continuous operation modes resulting in a delay in the cell death process under glutamine starvation conditions. In the present study, the mechanism of action of BHRF1 was investigated in a murine hybridoma cell line. BHRF1 protein was found in the mitochondrial cell fraction both under normal growing conditions and apoptosis-inducing conditions. Remarkably, the expression of the anti-apoptotic gene bcl2 in BHRF1-expressing cells was up-regulated 25-fold compared to mock transfected controls under apoptosis triggering conditions and its expression correlated with survival of transgenic cultures and cell cycle arrest in G1. Bcl 2 activity was revealed to be crucial for the BHRF1-mediated effect since the addition of specific inhibitors of Bcl-2 (namely HA14-1 and YC-137) resulted in a loss of function of BHRF1-expressing cells under glutamine starvation conditions. Moreover, the interaction of BHRF1 with the pro-apoptotic BH3-only Bim conferred mitochondrial stability to BHRF1 expressing cells under apoptosis-triggering conditions. PMID- 26057603 TI - Combining Primary Prevention and Risk Reduction Approaches in Sexual Assault Protection Programming. AB - OBJECTIVE: The object of this study is to extend prior evaluations of Elemental, a sexual assault protection program that combines primary prevention and risk reduction strategies within a single program. PARTICIPANTS AND METHODS: During 2012 and 2013, program group and control group students completed pretest, posttest, and 6-week and 6-month follow-up surveys assessing sexual attitudes and knowledge as well as experiences with assault. RESULTS: The results reinforce previous findings that Elemental is effective in reducing sexual assault risk. Program effects were both direct, in that participation was associated with lower risk of assault, and mediated, in that participation impacted attitudes and beliefs that are empirically linked to risk of later assault. CONCLUSIONS: By combining both primary prevention and risk reduction approaches, Elemental is not only effective at reducing incidences of assault, it is also consistent with a number of recent recommendations for directions in sexual assault prevention programming. PMID- 26057604 TI - Isolation of beta-Cryptoxanthin-epoxides, Precursors of Cryptocapsin and 3' Deoxycapsanthin, from Red Mamey (Pouteria sapota). AB - From an extract of red mamey (Pouteria sapota) beta-cryptoxanthin-5,6-epoxide, beta-cryptoxanthin-5',6'-epoxide, 3'-deoxycapsanthin, and cryptocapsin were isolated and characterized by UV-vis spectroscopy, electronic circular dichroism (ECD), nuclear magnetic resonance (NMR) spectroscopy, and mass spectrometry (MS). Epoxidation of beta-cryptoxanthin delivered the beta-(5'R,6'S)- and (5'S,6'R) cryptoxanthin-5',6'-epoxides, which were identified by HPLC-ECD analysis. These carotenoids among others are quite common in the fruits of Central America, and as they are natural provitamins A, they should play an important role in the diet of the mostly vitamin A deficient population of this region. PMID- 26057605 TI - Migration of Tinuvin P and Irganox 3114 into milk and the corresponding authorised food simulant. AB - Migration of Tinuvin P (UV stabiliser) and Irganox 3114 (antioxidant) from high density polyethylene (HDPE) was studied. HDPE pieces were soaked in either milk (1.5% or 3.5% fat content) or 50% (v/v) ethanol-water mixture - the food simulant for milk as specified in Regulation No. 10/2011/EC. The obtained extracts were analysed by LC-MS/MS. For statistical assessment variography was used. It proved to be a useful tool for making a distinction between the early migration range and the equilibrium, despite the variance of the data. Regulation No. 10/2011/EC specifies 10 days of contact time for milk at 5 degrees C. Our experiments with the food simulant with 24 dm(2) kg(-1) surface/mass ratio showed that both Tinuvin P and Irganox 3114 need less than 1 h to reach equilibrium. Furthermore, 10-day experiments with daily sampling showed that these additives are stable in milk, as well as in the food simulant. The effect of the concentration of the additives in HDPE was studied in the 0.01-5% (m/m) range. For both Tinuvin P and Irganox 3114 and all three extractants the migrated amount became independent of the concentration of the additive in the HDPE approximately at 1% (m/m). For Tinuvin P the food simulant gave a close estimate for the milk samples. However, using the food simulant for modelling the migration of Irganox 3114 into milk gave an overestimation with a factor of minimum 3.5. In the case of Tinuvin P special care must be taken, since the recommended amount in the HDPE can result in additive concentrations near or even over the specific migration limit (SML). However, Irganox 3114 cannot reach the SML either in milk or in the food simulant. PMID- 26057607 TI - A dynamic multibody model of the physiological knee to predict internal loads during movement in gravitational field. AB - Obtaining tibio-femoral (TF) contact forces, ligament deformations and loads during daily life motor tasks would be useful to better understand the aetiopathogenesis of knee joint diseases or the effects of ligament reconstruction and knee arthroplasty. However, methods to obtain this information are either too simplified or too computationally demanding to be used for clinical application. A multibody dynamic model of the lower limb reproducing knee joint contact surfaces and ligaments was developed on the basis of magnetic resonance imaging. Several clinically relevant conditions were simulated, including resistance to hyperextension, varus-valgus stability, anterior posterior drawer, loaded squat movement. Quadriceps force, ligament deformations and loads, and TF contact forces were computed. During anterior drawer test the anterior cruciate ligament (ACL) was maximally loaded when the knee was extended (392 N) while the posterior cruciate ligament (PCL) was much more stressed during posterior drawer when the knee was flexed (319 N). The simulated loaded squat revealed that the anterior fibres of ACL become inactive after 60 degrees of flexion in conjunction with PCL anterior bundle activation, while most components of the collateral ligaments exhibit limited length changes. Maximum quadriceps and TF forces achieved 3.2 and 4.2 body weight, respectively. The possibility to easily manage model parameters and the low computational cost of each simulation represent key points of the present project. The obtained results are consistent with in vivo measurements, suggesting that the model can be used to simulate complex and clinically relevant exercises. PMID- 26057606 TI - Relating structure and function of viral membrane-spanning miniproteins. AB - Many viruses express small hydrophobic membrane proteins. These proteins are often referred to as viroporins because they exhibit ion channel activity. However, the channel activity has not been definitively associated with a biological function in all cases. More generally, protein-protein and protein phospholipid interactions have been associated with specific biological activities of these proteins. As research has progressed there is a decreased emphasis on potential roles of the channel activity, and increased research on multiple other biological functions. This being the case, it may be more appropriate to refer to them as 'viral membrane-spanning miniproteins'. Structural studies are illustrated with Vpu from HIV-1 and p7 from HCV. PMID- 26057608 TI - Inhibitory effects of high stability fucoxanthin on palmitic acid-induced lipid accumulation in human adipose-derived stem cells through modulation of long non coding RNA. AB - Obesity is a serious worldwide disease, which is growing in epidemic proportions. Adipose-derived stem cells (ADSCs) are characterized as a source of mesenchymal stem cells that have acted as a potential application for regeneration. Recently, seaweeds rich in flavonoids and polysaccharides have been supposed to show the ability to modulate risk factors for obesity and related diseases. In the present study, we investigated the anti-obesity properties of high stability fucoxanthin (HS-Fx) derived from brown seaweeds on the adipogenesis of ADSCs upon treatment with palmitic acid (PA). First, we showed the differentiation capability of ADSCs from morbid obesity patients to transform into different cell types. Second, we found that the co-treatment of ADSCs with HS-Fx and PA showed no significant cytotoxicity against ADSCs, but PA induced the elevation of reactive oxygen species (ROS) and lipid droplet accumulation was abolished. Thirdly, the PA mediated down-regulation of lipid metabolism genes was reversed by the treatment of HS-Fx. By long non-coding RNAs (lncRNAs) screening, we found that PA-induced increases in the targeted lncRNAs were also decreased upon treatment with HS-Fx. On Silencing, these lncRNAs corresponded to the decrease in the lipid droplet accumulation of ADSCs induced by PA. ADSCs from obese patients would be direct and meaningful model cells to investigate the development of obesity-related diseases and their treatments, rather than cell lines from other species. HS-Fx showed anti-obesity capability through modulating the elevation of ROS, down regulation of lipid metabolism genes induced by PA, and upstream signaling, which might be critically resulted from the expression of lncRNAs. PMID- 26057610 TI - Compressed Sensing Reconstruction of 3D Ultrasound Data Using Dictionary Learning and Line-Wise Subsampling. AB - In this paper we present a compressed sensing (CS) method adapted to 3D ultrasound imaging (US). In contrast to previous work, we propose a new approach based on the use of learned overcomplete dictionaries that allow for much sparser representations of the signals since they are optimized for a particular class of images such as US images. In this study, the dictionary was learned using the K SVD algorithm and CS reconstruction was performed on the non-log envelope data by removing 20% to 80% of the original data. Using numerically simulated images, we evaluate the influence of the training parameters and of the sampling strategy. The latter is done by comparing the two most common sampling patterns, i.e., point-wise and line-wise random patterns. The results show in particular that line-wise sampling yields an accuracy comparable to the conventional point-wise sampling. This indicates that CS acquisition of 3D data is feasible in a relatively simple setting, and thus offers the perspective of increasing the frame rate by skipping the acquisition of RF lines. Next, we evaluated this approach on US volumes of several ex vivo and in vivo organs. We first show that the learned dictionary approach yields better performances than conventional fixed transforms such as Fourier or discrete cosine. Finally, we investigate the generality of the learned dictionary approach and show that it is possible to build a general dictionary allowing to reliably reconstruct different volumes of different ex vivo or in vivo organs. PMID- 26057609 TI - Patterns of neighborhood environment attributes in relation to children's physical activity. AB - Characterizing neighborhood environments in relation to physical activity is complex. Latent profiles of parents' perceptions of neighborhood characteristics were examined in relation to accelerometer-measured moderate-to-vigorous physical activity (MVPA) among 678 children (ages 6-12) in two US regions. Neighborhood environment profiles derived from walkability, transit access, aesthetics, crime and traffic safety, pedestrian infrastructure, and recreation/park access were created for each region. The San Diego County profile lowest on walkability and recreation/park access was associated with an average of 13 fewer min/day of children's out-of-school MVPA compared to profiles higher on walkability and recreation/park access. Seattle/King County profiles did not differ on children's MVPA. Neighborhood environment profiles were associated with children's MVPA in one region, but results were inconsistent across regions. PMID- 26057611 TI - Automatic SWI Venography Segmentation Using Conditional Random Fields. AB - Susceptibility-weighted imaging (SWI) venography can produce detailed venous contrast and complement arterial dominated MR angiography (MRA) techniques. However, these dense reversed-contrast SWI venograms pose new segmentation challenges. We present an automatic method for whole-brain venous blood segmentation in SWI using Conditional Random Fields (CRF). The CRF model combines different first and second order potentials. First-order association potentials are modeled as the composite of an appearance potential, a Hessian-based shape potential and a non-linear location potential. Second-order interaction potentials are modeled using an auto-logistic (smoothing) potential and a data dependent (edge) potential. Minimal post-processing is used for excluding voxels outside the brain parenchyma and visualizing the surface vessels. The CRF model is trained and validated using 30 SWI venograms acquired within a population of deep brain stimulation (DBS) patients (age range [Formula: see text] years). Results demonstrate robust and consistent segmentation in deep and sub-cortical regions (median kappa = 0.84 and 0.82), as well as in challenging mid-sagittal and surface regions (median kappa = 0.81 and 0.83) regions. Overall, this CRF model produces high-quality segmentation of SWI venous vasculature that finds applications in DBS for minimizing hemorrhagic risks and other surgical and non surgical applications. PMID- 26057612 TI - Convergence analysis of an augmented algorithm for fully complex-valued neural networks. AB - This paper presents an augmented algorithm for fully complex-valued neural network based on Wirtinger calculus, which simplifies the derivation of the algorithm and eliminates the Schwarz symmetry restriction on the activation functions. A unified mean value theorem is first established for general functions of complex variables, covering the analytic functions, non-analytic functions and real-valued functions. Based on so introduced theorem, convergence results of the augmented algorithm are obtained under mild conditions. Simulations are provided to support the analysis. PMID- 26057613 TI - Improving nonlinear modeling capabilities of functional link adaptive filters. AB - The functional link adaptive filter (FLAF) represents an effective solution for online nonlinear modeling problems. In this paper, we take into account a FLAF based architecture, which separates the adaptation of linear and nonlinear elements, and we focus on the nonlinear branch to improve the modeling performance. In particular, we propose a new model that involves an adaptive combination of filters downstream of the nonlinear expansion. Such combination leads to a cooperative behavior of the whole architecture, thus yielding a performance improvement, particularly in the presence of strong nonlinearities. An advanced architecture is also proposed involving the adaptive combination of multiple filters on the nonlinear branch. The proposed models are assessed in different nonlinear modeling problems, in which their effectiveness and capabilities are shown. PMID- 26057614 TI - Effects of endocytosis on receptor-mediated signaling. AB - Cellular mechanisms of membrane traffic and signal transduction are deeply interconnected. The present review discusses how membrane trafficking in the endocytic pathway impacts receptor-mediated signaling. Examples of recent progress are highlighted, focusing on the endocytosis-signaling nexus in mammals. PMID- 26057615 TI - The Albicidin Resistance Factor AlbD Is a Serine Endopeptidase That Hydrolyzes Unusual Oligoaromatic-Type Peptides. AB - The para-aminobenzoic acid-containing peptide albicidin is a pathogenicity factor synthesized by Xanthomonas albilineans in infections of sugar cane. Albicidin is a nanomolar inhibitor of the bacterial DNA gyrase with a strong activity against various Gram-negative bacteria. The bacterium Pantoea dispersa expresses the hydrolase AlbD, conferring natural resistance against albicidin. We show that AlbD is a novel type of endopeptidase that catalyzes the cleavage of albicidin at a peptide backbone amide bond, thus abolishing its antimicrobial activity. Additionally, we determined the minimal cleavage motif of AlbD with substrates derived by chemical synthesis. Our results clearly identify AlbD as a unique endopeptidase that is the first member of a new subfamily of peptidases. Our findings provide the molecular basis for a natural detoxification mechanism, potentially rendering a new tool in biological chemistry approaches. PMID- 26057616 TI - Hepatic Transcriptome Responses in Mice (Mus musculus) Exposed to the Nafion Membrane and Its Combustion Products. AB - Nafion 117 membrane (N117), an important polymer electrolyte membrane (PEM), has been widely used for numerous chemical technologies. Despite its increasing production and use, the toxicity data for N117 and its combustion products remain lacking. Toxicity studies are necessary to avoid problems related to waste disposal in landfills and incineration that may arise. In this study, we investigated the histopathological alterations, oxidative stress biomarker responses, and transcriptome profiles in the liver of male mice exposed to N117 and its combustion products for 24 days. An ion-chromatography system and liquid chromatography system coupled to a hybrid quadrupole time-of-flight mass spectrometry were used to analyze the chemical compositions of these combustion products. The transcriptomics analysis identified several significantly altered molecular pathways, including the metabolism of xenobiotics, carbohydrates and lipids; signal transduction; cellular processes; immune system; and signaling molecules and interaction. These studies provide preliminary data for the potential toxicity of N117 and its combustion products on living organisms and may fill the information gaps in the toxicity databases for the currently used PEMs. PMID- 26057617 TI - Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry. AB - Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within alpha,beta-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible. PMID- 26057618 TI - Molecular Characterization of Babesia bovis M17 Leucine Aminopeptidase and Inhibition of Babesia Growth by Bestatin. AB - The M17 leucine aminopeptidase (M17LAP) enzymes of the other apicomplexan parasites have been characterized and shown to be inhibited by bestatin. Though Babesia bovis also belongs to the apicomplexan group, it is not known whether its M17LAP could display similar biochemical properties as well as inhibition profile. To unravel this uncertainty, a B. bovis M17LAP (BbM17LAP) gene was expressed in Escherichia coli , and activity of the recombinant enzyme as well as its inhibition by bestatin were evaluated. The inhibitory effect of the compound on growths of B. bovis and Babesia gibsoni in vitro was also determined. The expression of the gene fused with glutathione S-transferase (GST) yielded approximately 81-kDa recombinant BbM17LAP (rBbM17LAP). On probing with mouse anti rBbM17LAP serum, a green fluorescence was observed on the parasite cytosol on confocal laser microscopy, and a specific band greater than the predicted molecular mass was seen on Western blotting. The Km and Vmax values of the recombinant enzyme were 139.3 +/- 30.25 and 64.83 +/- 4.6 MUM, respectively, while the Ki was 2210 +/- 358 MUM after the inhibition. Bestatin was a more potent inhibitor of the growth of B. bovis [IC50 (50% inhibition concentration) = 131.7 +/- 51.43 MUM] than B. gibsoni [IC50 = 460.8 +/- 114.45 MUM] in vitro. The modest inhibition of both the rBbM17LAP activity and Babesia parasites' growth in vitro suggests that this inhibition may involve the endogenous enzyme in live parasites. Therefore, BbM17LAP may be a target of bestatin, though more studies with other aminopeptidase inhibitors are required to confirm this. PMID- 26057619 TI - Effect of 10.5 M Aqueous Urea on Helicobacter pylori Urease: A Molecular Dynamics Study. AB - The effects of a 10.5 M solution of aqueous urea on Helicobacter pylori urease were investigated over the course of a 500 ns molecular dynamics (MD) simulation. The enzyme was solvated by 25321 water molecules, and additionally, 4788 urea molecules were added to the solution. Although concentrated urea solutions are known laboratory denaturants, the protein secondary structure is retained throughout the simulation largely because of the short simulation time (urea denaturation occurs on the millisecond time scale). The relatively constant solvent accessible surface area over the last 400 ns of the simulation further confirms the overall lack of denaturation. The wide-open flap state observed previously in Klebsiella areogenes urease [Roberts, B. P., et al. (2012) J. Am. Chem. Soc. 134, 9934] and H. pylori [Minkara, M. S., et al. (2014) J. Chem. Theory Comput. 10, 1852-1862] was also identified in this aqueous urea simulation. Over the course of the trajectory, we were able to observe urea molecules entering the active site in proportions related to the extent of opening of the active site-covering flap. Furthermore, urea molecules were observed to approach the pentacoordinate Ni(2+) ion in position to bind in a manner consistent with the proposed initial coordination step of the hydrolysis mechanism. We also observed a specific and unique pattern in the regions of the protein with a high root-mean-square fluctuation (rmsf). The high-rmsf regions in the beta-chain form a horseshoelike arrangement surrounding the active site covering flap on the surface of the protein. We hypothesize that the function of these regions is to both attract and shuttle urea toward the loop of the active site-covering flap before entry into the cavity. Indeed, urea is observed to interact with these regions for extended periods of simulation time before active site ingress. PMID- 26057620 TI - Effects of Spatial Frequency Similarity and Dissimilarity on Contour Integration. AB - We examined the effects of spatial frequency similarity and dissimilarity on human contour integration under various conditions of uncertainty. Participants performed a temporal 2AFC contour detection task. Spatial frequency jitter up to 3.0 octaves was applied either to background elements, or to contour and background elements, or to none of both. Results converge on four major findings. (1) Contours defined by spatial frequency similarity alone are only scarcely visible, suggesting the absence of specialized cortical routines for shape detection based on spatial frequency similarity. (2) When orientation collinearity and spatial frequency similarity are combined along a contour, performance amplifies far beyond probability summation when compared to the fully heterogenous condition but only to a margin compatible with probability summation when compared to the fully homogenous case. (3) Psychometric functions are steeper but not shifted for homogenous contours in heterogenous backgrounds indicating an advantageous signal-to-noise ratio. The additional similarity cue therefore not so much improves contour detection performance but primarily reduces observer uncertainty about whether a potential candidate is a contour or just a false positive. (4) Contour integration is a broadband mechanism which is only moderately impaired by spatial frequency dissimilarity. PMID- 26057621 TI - Correlations between land covers and honey bee colony losses in a country with industrialized and rural regions. AB - High levels of honey bee colony losses were recently reported from Canada, China, Europe, Israel, Turkey and the United States, raising concerns of a global pollinator decline and questioning current land use practices, in particular intense agricultural cropping systems. Sixty-seven crops (data from the years 2010-2012) and 66 mid-term stable land cover classes (data from 2007) were analysed for statistical relationships with the honey bee colony losses experienced over the winters 2010/11-2012/13 in Luxembourg (Western Europe). The area covered by each land cover class, the shortest distance between each land cover class and the respective apiary, the number of plots covered by each land use class and the size of the biggest plot of each land cover class within radii of 2 km and 5 km around 166 apiaries (2010), 184 apiaries (2011) and 188 apiaries (2012) were tested for correlations with honey bee colony losses (% per apiary) experienced in the winter following the season when the crops were grown. Artificial water bodies, open urban areas, large industrial facilities including heavy industry, railways and associated installations, buildings and installations with socio-cultural purpose, camping-, sports-, playgrounds, golf courts, oilseed crops other than oilseed rape like sunflower or linseed, some spring cereals and former forest clearcuts or windthrows were the land cover classes most frequently associated with high honey bee colony losses. Grain maize, mixed forest and mixed coniferous forest were the land cover classes most frequently associated with low honey bee colony losses. The present data suggest that land covers related to transport, industry and leisure may have made a more substantial contribution to winter honey bee colony losses in developed countries than anticipated so far. Recommendations for the positioning of apiaries are discussed. PMID- 26057622 TI - To what extent can portable fluorescence spectroscopy be used in the real-time assessment of microbial water quality? AB - The intrinsic fluorescence of aquatic organic matter emitted at 350 nm when excited at 280 nm correlates widely with water quality parameters such as biochemical oxygen demand. Hence, in sewage-impacted rivers and groundwater, it might be expected that fluorescence at these wavelengths will also correlate with the microbial water quality. In this paper we use a portable fluorimeter to assess the relationship between fluorescence intensity at this wavelength pair and Escherichia coli enumeration in contrasting river catchments of poor water quality: in KwaZulu-Natal, S. Africa and the West Midlands, UK. Across all catchments we demonstrate a log correlation (r = 0.74) between fluorescence intensity and E. coli over a seven-log range in E. coli enumerations on non perturbed (unfiltered) samples. Within specific catchments, the relationship between fluorescence intensity and E. coli is more variable, demonstrating the importance of catchment-specific interference. Our research demonstrates the potential of using a portable fluorimeter as an initial screening tool for indicative microbial water quality, and one that is ideally suited to simple pollution scenarios such as assessing the impact of faecal contamination in river or groundwater at specific sites. PMID- 26057623 TI - Potential impacts to perennial springs from tar sand mining, processing, and disposal on the Tavaputs Plateau, Utah, USA. AB - Similar to fracking, the development of tar sand mining in the U.S. has moved faster than understanding of potential water quality impacts. Potential water quality impacts of tar sand mining, processing, and disposal to springs in canyons incised approximately 200 m into the Tavaputs Plateau, at the Uinta Basin southern rim, Utah, USA, were evaluated by hydrogeochemical sampling to determine potential sources of recharge, and chemical thermodynamic estimations to determine potential changes in transfer of bitumen compounds to water. Because the ridgetops in an area of the Tavaputs Plateau named PR Spring are starting to be developed for their tar sand resource, there is concern for potential hydrologic connection between these ridgetops and perennial springs in adjacent canyons on which depend ranching families, livestock, wildlife and recreationalists. Samples were collected from perennial springs to examine possible progression with elevation of parameters such as temperature, specific conductance, pH, dissolved oxygen, isotopic tracers of phase change, water-rock interaction, and age since recharge. The groundwater age dates indicate that the springs are recharged locally. The progression of hydrogeochemical parameters with elevation, in combination with the relatively short groundwater residence times, indicate that the recharge zone for these springs includes the surrounding ridges, and thereby suggests a hydrologic connection between the mining, processing, disposal area and the springs. Estimations based on chemical thermodynamic approaches indicate that bitumen compounds will have greatly enhanced solubility in water that comes into contact with the residual bitumen solvent mixture in disposed tailings relative to water that currently comes into contact with natural tar. PMID- 26057624 TI - Speaker Input Variability Does Not Explain Why Larger Populations Have Simpler Languages. AB - A learner's linguistic input is more variable if it comes from a greater number of speakers. Higher speaker input variability has been shown to facilitate the acquisition of phonemic boundaries, since data drawn from multiple speakers provides more information about the distribution of phonemes in a speech community. It has also been proposed that speaker input variability may have a systematic influence on individual-level learning of morphology, which can in turn influence the group-level characteristics of a language. Languages spoken by larger groups of people have less complex morphology than those spoken in smaller communities. While a mechanism by which the number of speakers could have such an effect is yet to be convincingly identified, differences in speaker input variability, which is thought to be larger in larger groups, may provide an explanation. By hindering the acquisition, and hence faithful cross-generational transfer, of complex morphology, higher speaker input variability may result in structural simplification. We assess this claim in two experiments which investigate the effect of such variability on language learning, considering its influence on a learner's ability to segment a continuous speech stream and acquire a morphologically complex miniature language. We ultimately find no evidence to support the proposal that speaker input variability influences language learning and so cannot support the hypothesis that it explains how population size determines the structural properties of language. PMID- 26057625 TI - Hierarchical Conformational Analysis of Native Lysozyme Based on Sub-Millisecond Molecular Dynamics Simulations. AB - Hierarchical organization of free energy landscape (FEL) for native globular proteins has been widely accepted by the biophysics community. However, FEL of native proteins is usually projected onto one or a few dimensions. Here we generated collectively 0.2 milli-second molecular dynamics simulation trajectories in explicit solvent for hen egg white lysozyme (HEWL), and carried out detailed conformational analysis based on backbone torsional degrees of freedom (DOF). Our results demonstrated that at micro-second and coarser temporal resolutions, FEL of HEWL exhibits hub-like topology with crystal structures occupying the dominant structural ensemble that serves as the hub of conformational transitions. However, at 100 ns and finer temporal resolutions, conformational substates of HEWL exhibit network-like topology, crystal structures are associated with kinetic traps that are important but not dominant ensembles. Backbone torsional state transitions on time scales ranging from nanoseconds to beyond microseconds were found to be associated with various types of molecular interactions. Even at nanoseconds temporal resolution, the number of conformational substates that are of statistical significance is quite limited. These observations suggest that detailed analysis of conformational substates at multiple temporal resolutions is both important and feasible. Transition state ensembles among various conformational substates at microsecond temporal resolution were observed to be considerably disordered. Life times of these transition state ensembles are found to be nearly independent of the time scales of the participating torsional DOFs. PMID- 26057627 TI - Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial. AB - Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 MUg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00803309. PMID- 26057626 TI - Interaction between Neuromelanin and Alpha-Synuclein in Parkinson's Disease. AB - Parkinson's disease (PD) is a very common neurodegenerative disorder characterized by the accumulation of alpha-synuclein (alpha-syn) into Lewy body (LB) inclusions and the loss of neuronmelanin (NM) containing dopamine (DA) neurons in the substantia nigra (SN). Pathological alpha-syn and NM are two prominent hallmarks in this selective and progressive neurodegenerative disease. Pathological alpha-syn can induce dopaminergic neuron death by various mechanisms, such as inducing oxidative stress and inhibiting protein degradation systems. Therefore, to explore the factors that trigger alpha-syn to convert from a non-toxic protein to toxic one is a pivotal question to clarify the mechanisms of PD pathogenesis. Many triggers for pathological alpha-syn aggregation have been identified, including missense mutations in the alpha-syn gene, higher concentration, and posttranslational modifications of alpha-Syn. Recently, the role of NM in inducing alpha-syn expression and aggregation has been suggested as a mechanism for this pigment to modulate neuronal vulnerability in PD. NM may be responsible for PD and age-associated increase and aggregation in alpha-syn. Here, we reviewed our previous study and other recent findings in the area of interaction between NM and alpha-syn. PMID- 26057628 TI - TaPP2C1, a Group F2 Protein Phosphatase 2C Gene, Confers Resistance to Salt Stress in Transgenic Tobacco. AB - Group A protein phosphatases 2Cs (PP2Cs) are essential components of abscisic acid (ABA) signaling in Arabidopsis; however, the function of group F2 subfamily PP2Cs is currently less known. In this study, TaPP2C1 which belongs to group F2 was isolated and characterized from wheat. Expression of the TaPP2C1-GFP fusion protein suggested its ubiquitous localization within a cell. TaPP2C1 expression was downregulated by abscisic acid (ABA) and NaCl treatments, but upregulated by H2O2 treatment. Overexpression of TaPP2C1 in tobacco resulted in reduced ABA sensitivity and increased salt resistance of transgenic seedlings. Additionally, physiological analyses showed that improved resistance to salt stress conferred by TaPP2C1 is due to the reduced reactive oxygen species (ROS) accumulation, the improved antioxidant system, and the increased transcription of genes in the ABA independent pathway. Finally, transgenic tobacco showed increased resistance to oxidative stress by maintaining a more effective antioxidant system. Taken together, these results demonstrated that TaPP2C1 negatively regulates ABA signaling, but positively regulates salt resistance. TaPP2C1 confers salt resistance through activating the antioxidant system and ABA-independent gene transcription process. PMID- 26057629 TI - Red Blood Cell Distribution Width as a Pragmatic Marker for Outcome in Pediatric Critical Illness. AB - BACKGROUND: Red cell distribution width (RDW) is a routine laboratory measure associated with poor outcomes in adult critical illness. OBJECTIVE: We determined the utility of RDW as an early pragmatic biomarker for outcome in pediatric critical illness. METHODS: We used multivariable logistic regression to test the association of RDW on the first day of pediatric intensive care unit (PICU) admission with prolonged PICU length of stay (LOS) >48 hours and mortality. The area under the receiver operating characteristic curve (AUROC) for RDW was compared to the Pediatric Index of Mortality (PIM)-2 score. RESULTS: Over a 13 month period, 596 unique patients had RDW measured on the first day of PICU admission. Sepsis was an effect modifier for LOS >48 hours but not mortality. In sepsis, RDW was not associated with LOS >48 hours. For patients without sepsis, each 1% increase in RDW was associated with 1.17 (95% CI 1.06, 1.30) increased odds of LOS >48 hours. In all patients, RDW was independently associated with PICU mortality (OR 1.25, 95% CI 1.09, 1.43). The AUROC for RDW to predict LOS >48 hours and mortality was 0.61 (95% CI 0.56, 0.66) and 0.65 (95% CI 0.55, 0.75), respectively. Although the AUROC for mortality was comparable to PIM-2 (0.75, 95% CI 0.66, 0.83; p = 0.18), RDW did not increase the discriminative utility when added to PIM-2. Despite the moderate AUROC, RDW <13.4% (upper limit of lower quartile) had 53% risk of LOS >48 hours and 3.3% risk of mortality compared to patients with an RDW >15.7% (lower limit of upper quartile) who had 78% risk of LOS >48 hours and 12.9% risk of mortality (p<0.001 for both outcomes). CONCLUSIONS: Elevated RDW was associated with outcome in pediatric critical illness and provided similar prognostic information as the more complex PIM-2 severity of illness score. Distinct RDW thresholds best discriminate low- versus high-risk patients. PMID- 26057630 TI - The Anti-inflammatory Effects of Agmatine on Transient Focal Cerebral Ischemia in Diabetic Rats. AB - BACKGROUND: In the previous study, we observed agmatine (AGM) posttreatment immediately after 30 minutes of suture occlusion of the middle cerebral artery (MCAO) reduced the infarct size and neurological deficit in diabetic rats. The aim of the present study was to investigate the anti-inflammatory effect of AGM to reduce cerebral ischemic damage in diabetic rats. MATERIALS AND METHODS: Normoglycemic (n=20) and streptozotocin-induced diabetic rats (n=40) were subjected to 30 minutes of MCAO followed by reperfusion. Twenty diabetic rats were treated with AGM (100 mg/kg, intraperitoneal) immediately after 30 minutes of MCAO. Modified neurological examinations and rotarod exercises were performed to evaluate motor function. Western blot and immunohistochemical analysis were performed to determine the expression of inflammatory cytokines in ischemic brain tissue. Real-time polymerase chain reaction was performed to measure the mRNA expression of high-mobility group box 1, receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, and TLR4 RESULTS AND CONCLUSIONS:: AGM posttreatment improved the neurobehavioral activity and motor function of diabetic MCAO rats at 24 and 72 hours after reperfusion. Immunohistochemical analysis showed that AGM treatment significantly decreased the expression of inflammatory cytokines in diabetic MCAO rats at 24 and 72 hours after reperfusion (P<0.01). Western blotting and real-time polymerase chain reaction results indicated that AGM treatment significantly decreased the expression of high mobility group box 1, RAGE, TLR2, and TLR4 in diabetic rats at 24 hours after reperfusion (P<0.05). This neuroprotective effect of AGM after MCAO was associated with modulation of the postischemic neuronal inflammation cascade. PMID- 26057631 TI - Mucin1 promotes the migration and invasion of hepatocellular carcinoma cells via JNK-mediated phosphorylation of Smad2 at the C-terminal and linker regions. AB - Mucin1 (MUC1), as an oncogene, plays a key role in the progression and tumorigenesis of many human adenocarcinomas. In this study, wound-healing, transwell migration and matrigel invasion assays showed that MUC1 promotes human hepatocellular carcinoma (HCC) cell migration and invasion by MUC1 gene silencing and overexpressing. Treatment with exogenous transforming growth factor beta (TGF beta)1, TGF-beta type I receptor (TbetaRI) inhibitor, TGF-beta1 siRNAs, or activator protein 1 (AP-1) inhibitor to MUC1-overexpressing HCC cells revealed that MUC1-induced autocrine TGF-beta via JNK/AP-1 pathway promotes the cell migration and invasion. In addition, the migration and invasion of HCC cells were more significantly inhibited by JNK inhibitor compared with that by TbetaRI inhibitor or TGF-beta1 siRNAs. Further studies demonstrated that MUC1-mediated JNK activation not only enhances the phosphorylation of Smad2 C-terminal at Ser 465/467 site (Smad2C) through TGF-beta/TbetaRI, but also directly enhances the phosphorylation of Smad2 linker region at Ser-245/250/255 site (Smad2L), and then both of them collaborate to upregulate matrix metalloproteinase (MMP)-9-mediated cell migration and invasion of HCC. These results indicate that MUC1 is an attractive target in liver cancer therapy. PMID- 26057632 TI - Distinct effects of TRAIL on the mitochondrial network in human cancer cells and normal cells: role of plasma membrane depolarization. AB - Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) is a promising anticancer drug due to its tumor-selective cytotoxicity. Here we report that TRAIL exhibits distinct effects on the mitochondrial networks in malignant cells and normal cells. Live-cell imaging revealed that multiple human cancer cell lines and normal cells exhibited two different modes of mitochondrial responses in response to TRAIL and death receptor agonists. Mitochondria within tumor cells became fragmented into punctate and clustered in response to toxic stimuli. The mitochondrial fragmentation was observed at 4 h, then became more pronounced over time, and associated with apoptotic cell death. In contrast, mitochondria within normal cells such as melanocytes and fibroblasts became only modestly truncated, even when they were treated with toxic stimuli. Although TRAIL activated dynamin-related protein 1 (Drp1)-dependent mitochondrial fission, inhibition of this process by Drp1 knockdown or with the Drp1 inhibitor mdivi-1, potentiated TRAIL-induced apoptosis, mitochondrial fragmentation, and clustering. Moreover, mitochondrial reactive oxygen species (ROS)-mediated depolarization accelerated mitochondrial network abnormalities in tumor cells, but not in normal cells, and TRAIL caused higher levels of mitochondrial ROS accumulation and depolarization in malignant cells than in normal cells. Our findings suggest that tumor cells are more prone than normal cells to oxidative stress and depolarization, thereby being more vulnerable to mitochondrial network abnormalities and that this vulnerability may be relevant to the tumor-targeting killing by TRAIL. PMID- 26057633 TI - siRNAs with decreased off-target effect facilitate the identification of essential genes in cancer cells. AB - Since the essential genes are crucial to the proliferation and survival of cancer cells, the interference of these genes is promising to be an option for cancer therapy to overcome heterogeneity. However, the essential genes are highly overestimated by RNA interference (RNAi) screenings, which is mainly caused by the pervasive off-target effect of small interference RNA (siRNA) and short hairpin RNA (shRNA). In the present study, we designed Match-Mismatch paired siRNAs to discriminate the on-target effect from off-target effect of siRNAs on cell viability. Only one of the 7 potential essential genes was validated as essential to cell viability, which demonstrates the high false positive rate in RNAi screenings. We modified the siRNA by introducing random nucleotides (N) into the guide strand to mitigate the off-target effect, without significantly compromising the on-target effect. The whole transcriptome profile analysis of cells transfected with siRNAs with or without Nindicates that siRNA-dN (with Ns on both the 2nd and the 18th bases of the guide strand) weakens the off-target effect by decreasing the unintended targets. The optimized siRNAs can be applied in the characterization of essential genes in cancer cells. PMID- 26057635 TI - Spontaneous magnetization and anomalous Hall effect in an emergent Dice lattice. AB - Ultracold atoms in optical lattices serve as a tool to model different physical phenomena appearing originally in condensed matter. To study magnetic phenomena one needs to engineer synthetic fields as atoms are neutral. Appropriately shaped optical potentials force atoms to mimic charged particles moving in a given field. We present the realization of artificial gauge fields for the observation of anomalous Hall effect. Two species of attractively interacting ultracold fermions are considered to be trapped in a shaken two dimensional triangular lattice. A combination of interaction induced tunneling and shaking can result in an emergent Dice lattice. In such a lattice the staggered synthetic magnetic flux appears and it can be controlled with external parameters. The obtained synthetic fields are non-Abelian. Depending on the tuning of the staggered flux we can obtain either anomalous Hall effect or its quantized version. Our results are reminiscent of Anomalous Hall conductivity in spin-orbit coupled ferromagnets. PMID- 26057634 TI - Effects of TGF-beta signalling inhibition with galunisertib (LY2157299) in hepatocellular carcinoma models and in ex vivo whole tumor tissue samples from patients. AB - Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-beta receptor (TbetaR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK Suni). Exogenous stimulation of all HCC cell lines with TGF-beta yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 uM and 10 uM galunisertib, 5 uM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-beta signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib. PMID- 26057636 TI - A simple double quantum coherence ESR sequence that minimizes nuclear modulations in Cu(2+)-ion based distance measurements. AB - Double quantum coherence (DQC) ESR is a sensitive method to measure magnetic dipolar interactions between spin labels. However, the DQC experiment on Cu(2+) centers presents a challenge at X-band. The Cu(2+) centers are usually coordinated to histidine residues in proteins. The electron-nuclear interaction between the Cu(2+) ion and the remote nitrogen in the imidazole ring can interfere with the electron-electron dipolar interaction. Herein, we report on a modified DQC experiment that has the advantage of reduced contributions from electron-nuclear interactions, which enhances the resolution of the DQC signal to the electron-electron dipolar modulations. The modified pulse-sequence is verified on Cu(2+)-NO system in a polyalanine-based peptide and on a coupled Cu(2+) system in a polyproline-based peptide. The modified DQC data were compared with the DEER data and good agreement was found. PMID- 26057637 TI - [Safer Swedish healthcare requires coherent and persistent efforts]. AB - Despite a development in Swedish patient safety work in recent years, unambiguous results are missing. Here we propose some activities that will result in improved patient safety. Patients and employees are a strong driving force, and should be given a more important role. The level of education in patient safety must be raised in all levels in the system. Effective systems for learning, sharing and follow-up need to be reinforced. The understanding on how the health-care system adapts to varying circumstances, resilience, needs development. The knowledge basis of what constitutes and creates safety in psychiatry, paediatric care, primary care, and in care of the elderly must be developed. PMID- 26057638 TI - [Anterior cruciate ligament injury--the fall of women's football?]. PMID- 26057639 TI - [Emergency health care is not the place for dietary changes]. PMID- 26057640 TI - [Screening for abdominal aortic aneurysm is still indicated]. PMID- 26057641 TI - [Screening for abdominal aortic aneurysm is not ethically justifiable]. PMID- 26057642 TI - [The care of Sture Bergwall--some historical observations]. PMID- 26057643 TI - [We are not forcing anyone to test a new diet]. PMID- 26057644 TI - [The council for new therapies position on eculizumab is unacceptable]. PMID- 26057646 TI - Implementing change in healthcare: evidence utilization. PMID- 26057647 TI - Reconsidering healthcare evidence as dynamic and distributed: the role of information and cognition. AB - AIM: The basic thrust of evidence-based healthcare is that current best evidence should be used explicitly and judiciously for diagnosis, management, and other activities in healthcare settings. For this to be possible, researchers, practitioners, and other stakeholders must have a clear and accurate conceptualization of what constitutes 'evidence' in healthcare environments, and the manner in which it is used in decision-making and other activities. Currently, the dominant conceptualization of evidence is that of a body of information that can be retrieved by stakeholders for use in healthcare practice. The aim of this article is to critically examine the concept of evidence, particularly in light of recent models of human cognition and information use in decision-making and other cognitive activities. METHODS: In this theoretical article, we employ both analytical and synthetic methods to critically examine the concepts under investigation. Key concepts, such as evidence and information, and the essential relationships between them are analyzed from the vantage point of cognitive science, information science, and other relevant disciplines to explicate a conceptualization of evidence that moves past static and objectivist accounts. RESULTS: We demonstrate that evidence is fundamentally information that takes various forms-i.e., artifacts, mental structures, or communication processes. Specific forms and manifestations of evidence can thus be described in the context of information use in dynamic information environments. Furthermore, evidence-based healthcare activities are shown to be fundamentally cognitive in nature. For any given evidence-based healthcare activity, its quality and outcome can be understood in the context of how different sources of evidence are coordinated within a distributed cognitive system. In this sense, evidence based health care activity becomes more a matter of understanding the movement of information and knowledge within a distributed and dynamic cognitive system than mere access to or translation of a ready-at-hand resource. CONCLUSIONS: The conceptualization of evidence presented in this article has a number of implications for evidence-based healthcare-in terms of where attention is focused, the direction of future research efforts, how evidence generation, use, and practice are conceptualized and discussed, and how healthcare technologies are designed and evaluated. Furthermore, the conceptualization presented in this article has implications for the manner in which evidence 'hierarchies' are developed. Such hierarchies do not provide a complete picture of evidence and the way it is used in healthcare activities. Understanding the dynamic nature of evidence and its role in distributed cognitive activities may lead to more robust and multi-faceted taxonomies, frameworks, and hierarchies related to evidence based healthcare. PMID- 26057645 TI - TRIM32 Senses and Restricts Influenza A Virus by Ubiquitination of PB1 Polymerase. AB - Polymerase basic protein 1 (PB1) is the catalytic core of the influenza A virus (IAV) RNA polymerase complex essential for viral transcription and replication. Understanding the intrinsic mechanisms which block PB1 function could stimulate development of new anti-influenza therapeutics. Affinity purification coupled with mass spectrometry (AP-MS) was used to identify host factors interacting with PB1. Among PB1 interactors, the E3 ubiquitin ligase TRIM32 interacts with PB1 proteins derived from multiple IAV strains. TRIM32 senses IAV infection by interacting with PB1 and translocates with PB1 to the nucleus following influenza infection. Ectopic TRIM32 expression attenuates IAV infection. Conversely, RNAi depletion and knockout of TRIM32 increase susceptibility of tracheal and lung epithelial cells to IAV infection. Reconstitution of trim32-/- mouse embryonic fibroblasts with TRIM32, but not a catalytically inactive mutant, restores viral restriction. Furthermore, TRIM32 directly ubiquitinates PB1, leading to PB1 protein degradation and subsequent reduction of polymerase activity. Thus, TRIM32 is an intrinsic IAV restriction factor which senses and targets the PB1 polymerase for ubiquitination and protein degradation. TRIM32 represents a model of intrinsic immunity, in which a host protein directly senses and counters viral infection in a species specific fashion by directly limiting viral replication. PMID- 26057648 TI - Format guidelines to make them vivid, intuitive, and visual: use simple formatting rules to optimize usability and accessibility of clinical practice guidelines. AB - AIM: We present simple formatting rules derived from an extensive literature review that can improve the format of clinical practice guidelines (CPGs), and potentially increase the likelihood of being used. METHODS: We recently conducted a review of the literature from medicine, psychology, design, and human factors engineering on characteristics of guidelines that are associated with their use in practice, covering both the creation and communication of content. The formatting rules described in this article are derived from that review. RESULTS: The formatting rules are grouped into three categories that can be easily applied to CPGs: first, Vivid: make it stand out; second, Intuitive: match it to the audience's expectations, and third, Visual: use alternatives to text. We highlight rules supported by our broad literature review and provide specific 'how to' recommendations for individuals and groups developing evidence-based materials for clinicians. CONCLUSION: The way text documents are formatted influences their accessibility and usability. Optimizing the formatting of CPGs is a relatively inexpensive intervention and can be used to facilitate the dissemination of evidence in healthcare. Applying simple formatting principles to make documents more vivid, intuitive, and visual is a practical approach that has the potential to influence the usability of guidelines and to influence the extent to which guidelines are read, remembered, and used in practice. PMID- 26057649 TI - Evidence-based management of patients with chest tube drainage system to reduce complications in cardiothoracic vascular surgery wards. AB - AIM: This evidence-based project was to implement the best practice to provide safe and effective care to patients with chest tube drainage system in cardiothoracic wards. METHODS: Best practice recommendations on monitoring and maintenance of chest drains were retrieved from the Joanna Briggs Institute COnNECT+ database. A checklist was developed based on these recommendations. Nurses in the two cardiovascular wards were taught how to use the checklist. Two post-implementation audits on the nurses' compliance to use the checklist were conducted. Data were analysed using the Joanna Briggs Institute Practical Application of Evidence System. RESULTS: Initial post-implementation audit results showed that the compliance rates of monitoring underwater seal, suction pressure and connector were 100%, checking of dressings 90%, and swinging and/or bubbling 70%. The checklist also detected 36 near-miss events. The second post implementation audit results showed that the compliance rate of monitoring insertion site for air infiltration was 100%, checking of dressings 78%, and swinging and/or bubbling 91%. Fifty-seven near-miss events were detected. CONCLUSION: The use of the checklist prevented adverse events during the evidence implementation period. It can thus be concluded that using a systematic guide to observe and monitor patients with chest tubes enhances the effectiveness and safety of nursing care in the hospital. PMID- 26057650 TI - Is the practice of public or private sector doctors more evidence-based? A qualitative study from Vellore, India. AB - AIM: The literature on the use of evidence-based practice is sparse, both in the public and private sectors in middle-and low-income countries, and the present literature shows that physician understanding and use of evidence-based practice is poor. The study aimed to explore the perception of medical practitioners in the private for-profit, private not-for-profit and government sectors in Vellore, India, on evidence-based practice, in order to explain the factors affecting the use of evidence-based practice among the practitioners and to inform local policy and management decisions for improvement in quality of care. METHODS: Qualitative methodology was employed in the study. Sixteen in-depth and two key informant interviews were carried out with medical practitioners selected by purposive sampling in the private for-profit, private not-for-profit and government sectors. The interviews explored participants' knowledge of evidence-based practice, factors affecting its use and possible ways of improving the use of evidence-based practice among physicians in all the health sectors. Data from the in-depth and key informant interviews were analyzed with the NVIVO (version 8) software package using the framework approach. RESULTS: Although most practitioners interviewed have heard of evidence-based practice, knowledge about evidence-based practice seems inadequate. However, doctors in the private not-for profit sector seem to be more familiar with the concept of evidence-based practice. Also, practitioners in the private not-for profit sector appear to use medical evidence more in their practices compared to government practitioners or doctors in the private for-profit sector. Perceived factors affecting physician use of evidence-based practice include lack of personal time for literature appraisal as a result of high case load, weak regulatory system, pressure from patients, caregivers and pharmaceutical companies, as well as financial considerations. Opinions of the respondents are that use of evidence-based practice is mostly found among practitioners in the private not-for-profit health sector. CONCLUSION: Better training in evidence-based practice, improved regulatory system and greater collaboration between the public, private for profit and private not-for-profit sectors with regards to training in evidence based practice - literature search and critical appraisal skills - were suggested as needed to improve the present situation. PMID- 26057651 TI - The evidence-based practice readiness survey: a structural equation modeling approach for a Greek sample. AB - The present study reports on the translation, cultural adaptation and validation of the Evidence-Based Practice Readiness Survey into the Greek language. Back translation strategy for cross-cultural research was used to translate the questionnaire into Greek. The psychometric measurements that were performed included: reliability coefficients and explanatory factor analysis using a Varimax Rotation and Principal Components Method. In a further step, confirmatory analysis of the principal components was conducted. The internal consistency of the Greek Evidence-Based Practice Readiness Survey version, as assessed by the Cronbach's alpha coefficient, showed satisfactory results. The value for alpha was found equal to 0.85. The explanatory and confirmatory factor analysis demonstrated a four-factor structure of the tool. PMID- 26057652 TI - The effect of Cincinnati Prehospital Stroke Scale on telephone triage of stroke patients: evidence-based practice in emergency medical services. AB - BACKGROUND: The emergency medical service is designed to recognize and transfer critically ill patients. Evidence-based practice has rarely been emphasized in the emergency medical service field, especially in the dispatch center. AIMS: To identify the effect of the Cincinnati Prehospital Stroke Scale (CPSS) on telephone triage of stroke patients by telephone triage nurses at the emergency medical dispatch center and to compare CPSS with the National Guidelines for Telephone Triage Tool (NGTT). METHODS: A quasi-empirical study was conducted from June 2013 to June 2014. The setting of the study was the Mashhad dispatch center of the EMS. Two hundred and forty-six patients were randomly allocated to the CPSS intervention group (n = 121) and the NGTT control group (n = 125). True triage, triage error and odds ratio were statistically reported. RESULTS: The mean age of the patients was 70.9 +/- 12.7 years. Of all the cases, 77.7 and 65.6% of patients in the intervention and the control groups, respectively, were accurately triaged. Under-triage cases were 10.7 and 13.6% of the patients in the intervention and the control groups. Odds ratio was 1.14 (95% confidence interval 0.62-2.07) for the CPSS compared with the NGTT. CONCLUSION: CPSS is more efficient for use by telephone triage nurses in identifying stroke. The use of CPSS assists nurses by reducing the triage error and supports the evidence-based care. It needs to be developed to cover signs and symptoms of posterior circulation stroke patients. PMID- 26057653 TI - A mixed-methods research approach to the review of competency standards for orthotist/prosthetists in Australia. AB - AIM: The requirement for an allied health workforce is expanding as the global burden of disease increases internationally. To safely meet the demand for an expanded workforce of orthotist/prosthetists in Australia, competency based standards, which are up-to-date and evidence-based, are required. The aims of this study were to determine the minimum level for entry into the orthotic/prosthetic profession; to develop entry level competency standards for the profession; and to validate the developed entry-level competency standards within the profession nationally, using an evidence-based approach. METHODS: A mixed-methods research design was applied, using a three-step sequential exploratory design, where step 1 involved collecting and analyzing qualitative data from two focus groups; step 2 involved exploratory instrument development and testing, developing the draft competency standards; and step 3 involved quantitative data collection and analysis - a Delphi survey. In stage 1 (steps 1 and 2), the two focus groups - an expert and a recent graduate group of Australian orthotist/prosthetists - were led by an experienced facilitator, to identify gaps in the current competency standards and then to outline a key purpose, and work roles and tasks for the profession. The resulting domains and activities of the first draft of the competency standards were synthesized using thematic analysis. In stage 2 (step 3), the draft-competency standards were circulated to a purposive sample of the membership of the Australian Orthotic Prosthetic Association, using three rounds of Delphi survey. A project reference group of orthotist/prosthetists reviewed the results of both stages. RESULTS: In stage 1, the expert (n = 10) and the new graduate (n = 8) groups separately identified work roles and tasks, which formed the initial draft of the competency standards. Further drafts were refined and performance criteria added by the project reference group, resulting in the final draft-competency standards. In stage 2, the final draft-competency standards were circulated to 56 members (n = 44 final round) of the Association, who agreed on the key purpose, 6 domains, 18 activities, and 68 performance criteria of the final competency standards. CONCLUSION: This study outlines a rigorous and evidence-based mixed-methods approach for developing and endorsing professional competency standards, which is representative of the views of the profession of orthotist/prosthetists. PMID- 26057654 TI - Prevention of in-hospital falls: development of criteria for the conduct of a multi-site audit. AB - BACKGROUND: Patient falls are a significant issue for hospitals due to the high rates of morbidity and mortality associated with these events, as well as the financial costs for the healthcare system. OBJECTIVES: To establish what constitutes best practice in terms of fall prevention in acute care facilities and use this to inform the development of best practice audit criteria. METHODS: Criteria for clinical audit were developed from evidence derived from systematic reviews and guidelines. While these were drawn from the best available evidence, they were also developed in conjunction with clinicians undertaking a fall prevention clinical audit and key stakeholders from the clinical settings to ensure their relevance and applicability to the acute care setting. RESULTS: Current literature recommends a comprehensive and multifactorial approach to fall prevention. Eight audit criteria were derived from the best available evidence including the domains of physical environment, hospital culture and care processes, use of technology and targeted interventions. CONCLUSIONS: Existing research evidence and consultation with stakeholders has allowed the development of applicable, evidence-based audit criteria for fall prevention in acute care settings. This model can promote engagement, impact clinical practice and lead to improved outcomes. PMID- 26057655 TI - Decision aids for people facing health treatment or screening decisions. PMID- 26057657 TI - Corrigendum. PMID- 26057656 TI - Establishment and Validation of SSCLIP Scoring System to Estimate Survival in Hepatocellular Carcinoma Patients Who Received Curative Liver Resection. AB - BACKGROUND AND AIMS: There is no prognostic model that is reliable and practical for patients who have received curative liver resection (CLR) for hepatocellular carcinoma (HCC). This study aimed to establish and validate a Surgery-Specific Cancer of the Liver Italian Program (SSCLIP) scoring system for those patients. METHODS: 668 eligible patients who underwent CLR for HCC from five separate tertiary hospitals were selected. The SSCLIP was constructed from a training cohort by adding independent predictors that were identified by Cox proportional hazards regression analyses to the original Cancer of the Liver Italian Program (CLIP). The prognostic performance of the SSCLIP at 12 and 36-months was compared with data from existing models. The patient survival distributions at different risk levels of the SSCLIP were also assessed. RESULTS: Four independent predictors were added to construct the SSCLIP, including age (HR = 1.075, 95%CI: 1.019-1.135, P = 0.009), albumin (HR = 0.804, 95%CI: 0.681-0.950, P = 0.011), prothrombin time activity (HR = 0.856, 95%CI: 0.751-0.975, P = 0.020) and microvascular invasion (HR = 19.852, 95%CI: 2.203-178.917, P = 0.008). In both training and validation cohorts, 12-month and 36-month prognostic performance of the SSCLIP were significantly better than those of the original CLIP, model of end-stage liver disease-based CLIP, Okuda and Child-Turcotte-Pugh score (all P < 0.05). The stratification of risk levels of the SSCLIP showed an enhanced ability to differentiate patients with different outcomes. CONCLUSIONS: A novel SSCLIP to predict survival of HCC patients who received CLR based on objective parameters may provide a refined, useful prognosis algorithm. PMID- 26057659 TI - Comparison of High-Flexion and Conventional Implants in Total Knee Arthroplasty: A Meta-Analysis. AB - BACKGROUND: The purpose of this study was to evaluate whether high-flexion prostheses are superior to conventional prostheses after total knee arthroplasty (TKA). MATERIAL AND METHODS: We searched the PubMed and Embase databases for randomized trials and cohort studies comparing high-flexion with conventional knee implants. The heterogeneity across studies was examined by I2 and Cochran's Q-tests. Then the overall weighted mean differences of range of motion (ROM) and knee functional scores were evaluated. RESULTS: A total of 16 trials involving 2643 knees met our inclusion criteria. The results revealed that high-flexion implants were superior to conventional implants in the improvement of range of motion (weighted mean difference, 2.92; 95% CI, 1.63-4.22; p<0.0001). The clear advantage of high-flex PS (posterior stabilized) as well as high-flex CR (cruciate retaining) implants was found in ROM when compared to PS implants (2.73; 95% CI, 1.27-4.20; p=0.0003) and CR implants (3.24; 95% CI, 0.28-6.20; p=0.003), respectively. However, there was no difference in Knee Society Scores (0.42; 95% CI, -0.60-1.43; p=0.42), Knee Society function (0.37; 95% CI, -1.48 2.22; p=0.70) and Hospital for Special Surgery scores (0.26; 95% CI, -0.47-1.00; p=0.48) between high-flexion and conventional groups. CONCLUSIONS: The current meta-analysis revealed that high-flexion implants were superior to conventional implants in the improvement of ROM but not in functional outcome scores. PMID- 26057660 TI - Involuntary psychiatric admission: The referring general practitioners' assessment of patients' dangerousness and need for psychiatric hospital treatment. AB - BACKGROUND: In Norway, GPs may decide to refer patients to involuntary psychiatric treatment. Internationally, there has been a discussion regarding criteria for involuntary admission. In Norway and in other countries where the treatment criterion is still used, some have suggested its removal. AIMS: To examine which legal criteria GPs used to refer patients to involuntary admission, whether they had thought about using a different criterion, and on which information they based their decision. METHODS: A total of 74 doctors who had referred patients to involuntary admission at one major Norwegian psychiatric hospital participated in semi-structured interviews. RESULTS: In total, 38% (28) had applied the danger criterion only and 23% (17) had applied the treatment criterion only; 32% (24) had applied both criteria, while 7% (5) did not answer this question; 74% (55) said that they could not have chosen a different criterion; 45% (33) had based their decision on events/behaviour prior to and during the consultation, 43% (32) on events prior to the consultation only, and 8% (6) on information obtained during the consultation only; 4% (3) did not answer this question. None had used tools to aid in the assessment of danger. CLINICAL IMPLICATIONS: The danger criterion was frequently used by the referring GPs. It is unclear how a removal of the treatment criterion from Norwegian legislation might impact clinical practice. CONCLUSIONS: While the danger criterion was applied by a majority, the treatment criterion was also chosen by many and was of importance to the doctors' reasoning regarding referrals to involuntary admission. Most thought they could not have chosen a different criterion. PMID- 26057661 TI - Stacked optical antennas for plasmon propagation in a 5 nm-confined cavity. AB - The sub-wavelength concentration and propagation of electromagnetic energy are two complementary aspects of plasmonics that are not necessarily co-present in a single nanosystem. Here we exploit the strong nanofocusing properties of stacked optical antennas in order to highly concentrate the electromagnetic energy into a 5 nm metal-insulator-metal (MIM) cavity and convert free radiation into guided modes. The proposed nano-architecture combines the concentration properties of optical nanoantennas with the propagation capability of MIM systems, paving the way to highly miniaturized on-chip plasmonic waveguiding. PMID- 26057662 TI - Beyond the C18 frontier: Androgen and glucocorticoid metabolism in breast cancer tissues: The role of non-typical steroid hormones in breast cancer development and progression. AB - Breast cancer's hormonal dependence is well known and has been so for a long time. However in the last two decades great advances have been made in understanding the local metabolism of steroids within tissue. In the form of aromatase inhibition this is already one of the mainstays of breast cancer therapy. This review aims to summarise briefly what is known in terms of the metabolism of C18 steroids but perhaps more importantly to touch on the new developments regarding the importance of the metabolism of androgens and glucocorticoids in breast tissue. It is our hope that this review should provide the reader with a "birds eye view" of the current state of knowledge regarding localised steroid metabolism in the breast. PMID- 26057663 TI - Advances in membrane protein crystallography: in situ and in meso data collection. PMID- 26057664 TI - Structure determination of an integral membrane protein at room temperature from crystals in situ. AB - The structure determination of an integral membrane protein using synchrotron X ray diffraction data collected at room temperature directly in vapour-diffusion crystallization plates (in situ) is demonstrated. Exposing the crystals in situ eliminates manual sample handling and, since it is performed at room temperature, removes the complication of cryoprotection and potential structural anomalies induced by sample cryocooling. Essential to the method is the ability to limit radiation damage by recording a small amount of data per sample from many samples and subsequently assembling the resulting data sets using specialized software. The validity of this procedure is established by the structure determination of Haemophilus influenza TehA at 2.3 A resolution. The method presented offers an effective protocol for the fast and efficient determination of membrane-protein structures at room temperature using third-generation synchrotron beamlines. PMID- 26057666 TI - The structure of the giant haemoglobin from Glossoscolex paulistus. AB - The sequences of all seven polypeptide chains from the giant haemoglobin of the free-living earthworm Glossoscolex paulistus (HbGp) are reported together with the three-dimensional structure of the 3.6 MDa complex which they form. The refinement of the full particle, which has been solved at 3.2 A resolution, the highest resolution reported to date for a hexagonal bilayer haemoglobin composed of 12 protomers, is reported. This has allowed a more detailed description of the contacts between subunits which are essential for particle stability. Interpretation of features in the electron-density maps suggests the presence of metal-binding sites (probably Zn(2+) and Ca(2+)) and glycosylation sites, some of which have not been reported previously. The former appear to be important for the integrity of the particle. The crystal structure of the isolated d chain (d HbGp) at 2.1 A resolution shows different interchain contacts between d monomers compared with those observed in the full particle. Instead of forming trimers, as seen in the complex, the isolated d chains associate to form dimers across a crystallographic twofold axis. These observations eliminate the possibility that trimers form spontaneously in solution as intermediates during the formation of the dodecameric globin cap and contribute to understanding of the possible ways in which the particle self-assembles. PMID- 26057665 TI - In meso in situ serial X-ray crystallography of soluble and membrane proteins. AB - The lipid cubic phase (LCP) continues to grow in popularity as a medium in which to generate crystals of membrane (and soluble) proteins for high-resolution X-ray crystallographic structure determination. To date, the PDB includes 227 records attributed to the LCP or in meso method. Among the listings are some of the highest profile membrane proteins, including the beta2-adrenoreceptor-Gs protein complex that figured in the award of the 2012 Nobel Prize in Chemistry to Lefkowitz and Kobilka. The most successful in meso protocol to date uses glass sandwich crystallization plates. Despite their many advantages, glass plates are challenging to harvest crystals from. However, performing in situ X-ray diffraction measurements with these plates is not practical. Here, an alternative approach is described that provides many of the advantages of glass plates and is compatible with high-throughput in situ measurements. The novel in meso in situ serial crystallography (IMISX) method introduced here has been demonstrated with AlgE and PepT (alginate and peptide transporters, respectively) as model integral membrane proteins and with lysozyme as a test soluble protein. Structures were solved by molecular replacement and by experimental phasing using bromine SAD and native sulfur SAD methods to resolutions ranging from 1.8 to 2.8 A using single digit microgram quantities of protein. That sulfur SAD phasing worked is testament to the exceptional quality of the IMISX diffraction data. The IMISX method is compatible with readily available, inexpensive materials and equipment, is simple to implement and is compatible with high-throughput in situ serial data collection at macromolecular crystallography synchrotron beamlines worldwide. Because of its simplicity and effectiveness, the IMISX approach is likely to supplant existing in meso crystallization protocols. It should prove particularly attractive in the area of ligand screening for drug discovery and development. PMID- 26057667 TI - Bond distances in polypeptide backbones depend on the local conformation. AB - By combining quantum-mechanical analysis of small model peptides and statistical surveys of high-resolution protein structures, a systematic conformational dependence of bond lengths in polypeptide backbones has been unveiled which involves both the peptide bond (C-O and C-N) and those bonds centred on the C(alpha) atom. All of these bond lengths indeed display a systematic variability in the psi angle according to both calculations and surveys of protein structures. The overall agreement between the computed and the statistical data suggests that these trends are essentially driven by local effects. The dependence of C(alpha) distances on psi is governed by interactions between the sigma system of the C(alpha) moiety and the C-O pi system of the peptide bond. Maximum and minimum values for each bond distance are found for conformations with the specific bond perpendicular and parallel to the adjacent CONH peptide plane, respectively. On the other hand, the variability of the C-O and C-N distances is related to the strength of the interactions between the lone pair of the N atom and the C-O pi* system, which is modulated by the psi angle. The C-O and C-N distances are related but their trends are not strictly connected to peptide-bond planarity, although a correlation amongst all of these parameters is expected on the basis of the classical resonance model. PMID- 26057668 TI - Structural analysis of Dis3l2, an exosome-independent exonuclease from Schizosaccharomyces pombe. AB - After deadenylation and decapping, cytoplasmic mRNA can be digested in two opposite directions: in the 5'-3' direction by Xrn1 or in the 3'-5' direction by the exosome complex. Recently, a novel 3'-5' RNA-decay pathway involving Dis3l2 has been described that differs from degradation by Xrn1 and the exosome. The product of the Schizosaccharomyces pombe gene SPAC2C4.07c was identified as a homologue of human Dis3l2. In this work, the 2.8 A resolution X-ray crystal structure of S. pombe Dis3l2 (SpDis3l2) is reported, the conformation of which is obviously different from that in the homologous mouse Dis3l2-RNA complex. Fluorescence polarization assay experiments showed that RNB and S1 are the primary RNA-binding domains and that the CSDs (CSD1 and CSD2) play an indispensable role in the RNA-binding process of SpDis3l2. Taking the structure comparison and mutagenic experiments together, it can be inferred that the RNA recognition pattern of SpDis3l2 resembles that of its mouse homologue rather than that of the Escherichia coli RNase II-RNA complex. Furthermore, a drastic conformation change could occur following the binding of the RNA substrate to SpDis3l2. PMID- 26057669 TI - The structure of haemoglobin bound to the haemoglobin receptor IsdH from Staphylococcus aureus shows disruption of the native alpha-globin haem pocket. AB - Staphylococcus aureus is a common and serious cause of infection in humans. The bacterium expresses a cell-surface receptor that binds to, and strips haem from, human haemoglobin (Hb). The binding interface has previously been identified; however, the structural changes that promote haem release from haemoglobin were unknown. Here, the structure of the receptor-Hb complex is reported at 2.6 A resolution, which reveals a conformational change in the alpha-globin F helix that disrupts the haem-pocket structure and alters the Hb quaternary interactions. These features suggest potential mechanisms by which the S. aureus Hb receptor induces haem release from Hb. PMID- 26057670 TI - The structure of Aquifex aeolicus FtsH in the ADP-bound state reveals a C2 symmetric hexamer. AB - The crystal structure of a truncated, soluble quadruple mutant of FtsH from Aquifex aeolicus comprising the AAA and protease domains has been determined at 2.96 A resolution in space group I222. The protein crystallizes as a hexamer, with the protease domain forming layers in the ab plane. Contacts between these layers are mediated by the AAA domains. These are highly disordered in one crystal form, but are clearly visible in a related form with a shorter c axis. Here, adenosine diphosphate (ADP) is bound to each subunit and the AAA ring exhibits twofold symmetry. The arrangement is different from the ADP-bound state of an analogously truncated, soluble FtsH construct from Thermotoga maritima. The pore is completely closed and the phenylalanine residues in the pore line a contiguous path. The protease hexamer is very similar to those described for other FtsH structures. To resolve certain open issues regarding a conserved glycine in the linker between the AAA and protease domains, as well as the active site switch beta-strand, mutations have been introduced in the full-length membrane-bound protein. Activity analysis of these point mutants reveals the crucial importance of these residues for proteolytic activity and is in accord with previous interpretation of the active-site switch and the importance of the linker glycine residue. PMID- 26057671 TI - Two crystal structures of the FK506-binding domain of Plasmodium falciparum FKBP35 in complex with rapamycin at high resolution. AB - Antimalarial chemotherapy continues to be challenging in view of the emergence of drug resistance, especially artemisinin resistance in Southeast Asia. It is critical that novel antimalarial drugs are identified that inhibit new targets with unexplored mechanisms of action. It has been demonstrated that the immunosuppressive drug rapamycin, which is currently in clinical use to prevent organ-transplant rejection, has antimalarial effects. The Plasmodium falciparum target protein is PfFKBP35, a unique immunophilin FK506-binding protein (FKBP). This protein family binds rapamycin, FK506 and other immunosuppressive and non immunosuppressive macrolactones. Here, two crystallographic structures of rapamycin in complex with the FK506-binding domain of PfFKBP35 at high resolution, in both its oxidized and reduced forms, are reported. In comparison with the human FKBP12-rapamycin complex reported previously, the structures reveal differences in the beta4-beta6 segment that lines the rapamycin binding site. Structural differences between the Plasmodium protein and human hFKBP12 include the replacement of Cys106 and Ser109 by His87 and Ile90, respectively. The proximity of Cys106 to the bound rapamycin molecule (4-5 A) suggests possible routes for the rational design of analogues of rapamycin with specific antiparasitic activity. Comparison of the structures with the PfFKBD-FK506 complex shows that both drugs interact with the same binding-site residues. These two new structures highlight the structural differences and the specific interactions that must be kept in consideration for the rational design of rapamycin analogues with antimalarial activity that specifically bind to PfFKBP35 without immunosuppressive effects. PMID- 26057672 TI - Structure of the bovine COPI delta subunit MU homology domain at 2.15 A resolution. AB - The heptameric COPI coat (coatomer) plays an essential role in vesicular transport in the early secretory system of eukaryotic cells. While the structures of some of the subunits have been determined, that of the delta-COP subunit has not been reported to date. The delta-COP subunit is part of a subcomplex with structural similarity to tetrameric clathrin adaptors (APs), where delta-COP is the structural homologue of the AP MU subunit. Here, the crystal structure of the MU homology domain (MHD) of delta-COP (delta-MHD) obtained by phasing using a combined SAD-MR method is presented at 2.15 A resolution. The crystallographic asymmetric unit contains two monomers that exhibit short sections of disorder, which may allude to flexible regions of the protein. The delta-MHD is composed of two subdomains connected by unstructured linkers. Comparison between this structure and those of known MHD domains from the APs shows significant differences in the positions of specific loops and beta-sheets, as well as a more general change in the relative positions of the protein subdomains. The identified difference may be the major source of cargo-binding specificity. Finally, the crystal structure is used to analyze the potential effect of the I422T mutation in delta-COP previously reported to cause a neurodegenerative phenotype in mice. PMID- 26057674 TI - DATASW, a tool for HPLC-SAXS data analysis. AB - Small-angle X-ray scattering (SAXS) in solution is a common low-resolution method which can efficiently complement the high-resolution information obtained by crystallography or NMR. Sample monodispersity is key to reliable SAXS data interpretation and model building. Beamline setups with inline high-performance liquid chromatography (HPLC) are particularly useful for accurate profiling of heterogeneous samples. The program DATASW performs averaging of individual data frames from HPLC-SAXS experiments using a sliding window of a user-specified size, calculates overall parameters [I(0), Rg, Dmax and molecular weight] and predicts the folding state (folded/unfolded) of the sample. Applications of DATASW are illustrated for several proteins with various oligomerization behaviours recorded on different beamlines. DATASW binaries for major operating systems can be downloaded from http://datasw.sourceforge.net/. PMID- 26057673 TI - Structural bases for N-glycan processing by mannoside phosphorylase. AB - The first crystal structure of Uhgb_MP, a beta-1,4-mannopyranosyl-chitobiose phosphorylase belonging to the GH130 family which is involved in N-glycan degradation by human gut bacteria, was solved at 1.85 A resolution in the apo form and in complex with mannose and N-acetylglucosamine. SAXS and crystal structure analysis revealed a hexameric structure, a specific feature of GH130 enzymes among other glycoside phosphorylases. Mapping of the -1 and +1 subsites in the presence of phosphate confirmed the conserved Asp104 as the general acid/base catalytic residue, which is in agreement with a single-step reaction mechanism involving Man O3 assistance for proton transfer. Analysis of this structure, the first to be solved for a member of the GH130_2 subfamily, revealed Met67, Phe203 and the Gly121-Pro125 loop as the main determinants of the specificity of Uhgb_MP and its homologues towards the N-glycan core oligosaccharides and mannan, and the molecular bases of the key role played by GH130 enzymes in the catabolism of dietary fibre and host glycans. PMID- 26057675 TI - Structural characterization of a novel subfamily of leucine-rich repeat proteins from the human pathogen Leptospira interrogans. AB - Pathogenic Leptospira spp. are the agents of leptospirosis, an emerging zoonotic disease. Analyses of Leptospira genomes have shown that the pathogenic leptospires (but not the saprophytes) possess a large number of genes encoding proteins containing leucine-rich repeat (LRR) domains. In other pathogenic bacteria, proteins with LRR domains have been shown to be involved in mediating host-cell attachment and invasion, but their functions remain unknown in Leptospira. To gain insight into the potential function of leptospiral LRR proteins, the crystal structures of four LRR proteins that represent a novel subfamily with consecutive stretches of a 23-amino-acid LRR repeat motif have been solved. The four proteins analyzed adopt the characteristic alpha/beta solenoid horseshoe fold. The exposed residues of the inner concave surfaces of the solenoid, which constitute a putative functional binding site, are not conserved. The various leptospiral LRR proteins could therefore recognize distinct structural motifs of different host proteins and thus serve separate and complementary functions in the physiology of these bacteria. PMID- 26057676 TI - 3-Sulfinopropionyl-coenzyme A (3SP-CoA) desulfinase from Advenella mimigardefordensis DPN7(T): crystal structure and function of a desulfinase with an acyl-CoA dehydrogenase fold. AB - 3-Sulfinopropionyl-coenzyme A (3SP-CoA) desulfinase (AcdDPN7; EC 3.13.1.4) was identified during investigation of the 3,3'-dithiodipropionic acid (DTDP) catabolic pathway in the betaproteobacterium Advenella mimigardefordensis strain DPN7(T). DTDP is an organic disulfide and a precursor for the synthesis of polythioesters (PTEs) in bacteria, and is of interest for biotechnological PTE production. AcdDPN7 catalyzes sulfur abstraction from 3SP-CoA, a key step during the catabolism of DTDP. Here, the crystal structures of apo AcdDPN7 at 1.89 A resolution and of its complex with the CoA moiety from the substrate analogue succinyl-CoA at 2.30 A resolution are presented. The apo structure shows that AcdDPN7 belongs to the acyl-CoA dehydrogenase superfamily fold and that it is a tetramer, with each subunit containing one flavin adenine dinucleotide (FAD) molecule. The enzyme does not show any dehydrogenase activity. Dehydrogenase activity would require a catalytic base (Glu or Asp residue) at either position 246 or position 366, where a glutamine and a glycine are instead found, respectively, in this desulfinase. The positioning of CoA in the crystal complex enabled the modelling of a substrate complex containing 3SP-CoA. This indicates that Arg84 is a key residue in the desulfination reaction. An Arg84Lys mutant showed a complete loss of enzymatic activity, suggesting that the guanidinium group of the arginine is essential for desulfination. AcdDPN7 is the first desulfinase with an acyl-CoA dehydrogenase fold to be reported, which underlines the versatility of this enzyme scaffold. PMID- 26057677 TI - Full-length structure of the major autolysin LytA. AB - LytA is responsible for the autolysis of many Streptococcus species, including pathogens such as S. pneumoniae, S. pseudopneumoniae and S. mitis. However, how this major autolysin achieves full activity remains unknown. Here, the full length structure of the S. pneumoniae LytA dimer is reported at 2.1 A resolution. Each subunit has an N-terminal amidase domain and a C-terminal choline-binding domain consisting of six choline-binding repeats, which form five canonical and one single-layered choline-binding sites. Site-directed mutageneses combined with enzymatic activity assays indicate that dimerization and binding to choline are two independent requirements for the autolytic activity of LytA in vivo. Altogether, it is suggested that dimerization and full occupancy of all choline binding sites through binding to choline-containing TA chains enable LytA to adopt a fully active conformation which allows the amidase domain to cleave two lactyl-amide bonds located about 103 A apart on the peptidoglycan. PMID- 26057678 TI - Structural analysis of the alpha-glucosidase HaG provides new insights into substrate specificity and catalytic mechanism. AB - alpha-Glucosidases, which catalyze the hydrolysis of the alpha-glucosidic linkage at the nonreducing end of the substrate, are important for the metabolism of alpha-glucosides. Halomonas sp. H11 alpha-glucosidase (HaG), belonging to glycoside hydrolase family 13 (GH13), only has high hydrolytic activity towards the alpha-(1 -> 4)-linked disaccharide maltose among naturally occurring substrates. Although several three-dimensional structures of GH13 members have been solved, the disaccharide specificity and alpha-(1 -> 4) recognition mechanism of alpha-glucosidase are unclear owing to a lack of corresponding substrate-bound structures. In this study, four crystal structures of HaG were solved: the apo form, the glucosyl-enzyme intermediate complex, the E271Q mutant in complex with its natural substrate maltose and a complex of the D202N mutant with D-glucose and glycerol. These structures explicitly provide insights into the substrate specificity and catalytic mechanism of HaG. A peculiar long beta -> alpha loop 4 which exists in alpha-glucosidase is responsible for the strict recognition of disaccharides owing to steric hindrance. Two residues, Thr203 and Phe297, assisted with Gly228, were found to determine the glycosidic linkage specificity of the substrate at subsite +1. Furthermore, an explanation of the alpha-glucosidase reaction mechanism is proposed based on the glucosyl-enzyme intermediate structure. PMID- 26057679 TI - Structure of the RsbX phosphatase involved in the general stress response of Bacillus subtilis. AB - In the general stress response of Bacillus subtilis, which is governed by the sigma factor sigma(B), stress signalling is relayed by a cascade of Rsb proteins that regulate sigma(B) activity. RsbX, a PPM II phosphatase, halts the response by dephosphorylating the stressosome composed of RsbR and RsbS. The crystal structure of RsbX reveals a reorganization of the catalytic centre, with the second Mn(2+) ion uniquely coordinated by Gly47 O from the beta4-alpha1 loop instead of a water molecule as in PPM I phosphatases. An extra helical turn of alpha1 tilts the loop towards the metal-binding site, and the beta2-beta3 loop swings outwards to accommodate this tilting. The residues critical for this defining feature of the PPM II phosphatases are highly conserved. Formation of the catalytic centre is metal-specific, as crystallization with Mg(2+) ions resulted in a shift of the beta4-alpha1 loop that led to loss of the second ion. RsbX also lacks the flap subdomain characteristic of PPM I phosphatases. On the basis of a stressosome model, the activity of RsbX towards RsbR-P and RsbS-P may be influenced by the different accessibilities of their phosphorylation sites. PMID- 26057680 TI - A revised partiality model and post-refinement algorithm for X-ray free-electron laser data. AB - Research towards using X-ray free-electron laser (XFEL) data to solve structures using experimental phasing methods such as sulfur single-wavelength anomalous dispersion (SAD) has been hampered by shortcomings in the diffraction models for X-ray diffraction from FELs. Owing to errors in the orientation matrix and overly simple partiality models, researchers have required large numbers of images to converge to reliable estimates for the structure-factor amplitudes, which may not be feasible for all biological systems. Here, data for cytoplasmic polyhedrosis virus type 17 (CPV17) collected at 1.3 A wavelength at the Linac Coherent Light Source (LCLS) are revisited. A previously published definition of a partiality model for reflections illuminated by self-amplified spontaneous emission (SASE) pulses is built upon, which defines a fraction between 0 and 1 based on the intersection of a reflection with a spread of Ewald spheres modelled by a super Gaussian wavelength distribution in the X-ray beam. A method of post-refinement to refine the parameters of this model is suggested. This has generated a merged data set with an overall discrepancy (by calculating the R(split) value) of 3.15% to 1.46 A resolution from a 7225-image data set. The atomic numbers of C, N and O atoms in the structure are distinguishable in the electron-density map. There are 13 S atoms within the 237 residues of CPV17, excluding the initial disordered methionine. These only possess 0.42 anomalous scattering electrons each at 1.3 A wavelength, but the 12 that have single predominant positions are easily detectable in the anomalous difference Fourier map. It is hoped that these improvements will lead towards XFEL experimental phase determination and structure determination by sulfur SAD and will generally increase the utility of the method for difficult cases. PMID- 26057681 TI - Characteristics of Newly Enrolled Members of an Integrated Delivery System after the Affordable Care Act. AB - Of 89,289 newly enrolled non-Medicare members, 25.3% completed the Brief Health Questionnaire between 1/1/2014, and 8/31/2014. Of these, 3593 respondents were insured through Medicaid, 9434 through the individual health exchange, and 9521 through primarily commercial plans. Of Medicaid, exchange, and commercial members, 19.5%, 7.1%, and 5.3%, respectively, self-reported fair or poor health; 12.9%, 2.0%, and 3.3% of each group self-reported 2 or more Emergency Department visits during the previous year; and 8.1%, 4.3%, and 4.4% self-reported an inpatient admission during the previous year. PMID- 26057682 TI - A Community-Based Hip Fracture Registry: Population, Methods, and Outcomes. AB - Cases of hip fracture recorded from 1/2009 to 12/2011 were ascertained using the Kaiser Permanente Hip Fracture Registry. The registry collects information on patient, procedure, surgeon, facility, and surgical outcomes. The population (N = 12,562) was predominantly white, women, and older (>= 75 years), and 32% had at least 5 comorbidities. The average length of follow-up was 1.1 years. Hemiarthroplasty was the most common procedure (33.1%). Most fractures were treated by medium-volume surgeons at high-volume facilities. The 90-day readmission rate was 22.1%, and the mortality rate was 12.3%. PMID- 26057683 TI - 2014 Hypertension Guideline: Recommendation for a Change in Goal Systolic Blood Pressure. AB - The 2014 Kaiser Permanente Care Management Institute National Hypertension Guideline was developed to assist primary care physicians and other health care professionals in the outpatient treatment of uncomplicated hypertension in adult men and nonpregnant women aged 18 years and older. A major practice change is the recommendation for goal systolic blood pressure less than 150 mmHg in patients aged 60 years and older who are treated for hypertension in the absence of diabetes or chronic kidney disease. This article describes the reasons for, evidence for, and consequences of the change, and includes the guideline. PMID- 26057684 TI - A Metrics Taxonomy and Reporting Strategy for Rule-Based Alerts. AB - An action-oriented alerts taxonomy according to structure, actions, and implicit intended process outcomes using a set of 333 rule-based alerts at Kaiser Permanente Northwest (KPNW) was developed. The authors identified 9 major and 17 overall classes of alerts and developed a specific metric approach for 5 of these classes, including the 3 most numerous ones in KPNW, accounting for 224 (67%) of the alerts. PMID- 26057685 TI - Evidence-Based Referral: Effects of the Revised "Youth Fit 4 Life" Protocol on Physical Activity Outputs. AB - The authors contrasted 2 physical activity/nutrition treatments on the basis of social cognitive and self-efficacy theory, and a comparison condition, on time in moderate-to-vigorous physical activity (MVPA) during the 45-min/day physical activity segment of elementary after-school care. The Revised Youth Fit 4 Life protocol that sought to maximize participants' cardiovascular physical activity appeared to improve upon the Original Youth Fit For Life treatment on time in MVPA. Thus, pediatricians might have confidence in referring their patients to such evidence-based approaches. PMID- 26057686 TI - "Getting off the Bus Closer to Your Destination": Patients' Views about Pharmacogenetic Testing. AB - The authors conducted focus groups with patients prescribed antidepressants (pilot session plus 2 focus groups, n = 27); patients prescribed carbamazepine (2 focus groups, n = 17); and healthy patients (2 focus groups, n = 17). Although participants understood the potential advantages of pharmacogenetic testing, many felt that the risks (discrimination, stigmatization, physician overreliance on genomic results, and denial of certain medications) may outweigh the benefits. These concerns were shared across groups but were more strongly expressed among participants with chronic mental health diagnoses. PMID- 26057688 TI - The ASTRA Toolbox: A platform for advanced algorithm development in electron tomography. AB - We present the ASTRA Toolbox as an open platform for 3D image reconstruction in tomography. Most of the software tools that are currently used in electron tomography offer limited flexibility with respect to the geometrical parameters of the acquisition model and the algorithms used for reconstruction. The ASTRA Toolbox provides an extensive set of fast and flexible building blocks that can be used to develop advanced reconstruction algorithms, effectively removing these limitations. We demonstrate this flexibility, the resulting reconstruction quality, and the computational efficiency of this toolbox by a series of experiments, based on experimental dual-axis tilt series. PMID- 26057687 TI - Regulation of NDR1 activity by PLK1 ensures proper spindle orientation in mitosis. AB - Accurate chromosome segregation during mitosis requires the physical separation of sister chromatids which depends on correct position of mitotic spindle relative to membrane cortex. Although recent work has identified the role of PLK1 in spindle orientation, the mechanisms underlying PLK1 signaling in spindle positioning and orientation have not been fully illustrated. Here, we identified a conserved signaling axis in which NDR1 kinase activity is regulated by PLK1 in mitosis. PLK1 phosphorylates NDR1 at three putative threonine residues (T7, T183 and T407) at mitotic entry, which elicits PLK1-dependent suppression of NDR1 activity and ensures correct spindle orientation in mitosis. Importantly, persistent expression of non-phosphorylatable NDR1 mutant perturbs spindle orientation. Mechanistically, PLK1-mediated phosphorylation protects the binding of Mob1 to NDR1 and subsequent NDR1 activation. These findings define a conserved signaling axis that integrates dynamic kinetochore-microtubule interaction and spindle orientation control to genomic stability maintenance. PMID- 26057689 TI - Mechanisms of acid tolerance in bacteria and prospects in biotechnology and bioremediation. AB - Acidogenic and aciduric bacteria have developed several survival systems in various acidic environments to prevent cell damage due to acid stress such as that on the human gastric surface and in the fermentation medium used for industrial production of acidic products. Common mechanisms for acid resistance in bacteria are proton pumping by F1-F0-ATPase, the glutamate decarboxylase system, formation of a protective cloud of ammonia, high cytoplasmic urease activity, repair or protection of macromolecules, and biofilm formation. The field of synthetic biology has rapidly advanced and generated an ever-increasing assortment of genetic devices and biological modules for applications in biofuel and novel biomaterial productions. Better understanding of aspects such as overproduction of general shock proteins, molecular mechanisms, and responses to cell density adopted by microorganisms for survival in low pH conditions will prove useful in synthetic biology for potential industrial and environmental applications. PMID- 26057690 TI - Hepatoprotective effect of vitamin C on lithocholic acid-induced cholestatic liver injury in Gulo(-/-) mice. AB - Prevention and restoration of hepatic fibrosis from chronic liver injury is essential for the treatment of patients with chronic liver diseases. Vitamin C is known to have hepatoprotective effects, but their underlying mechanisms are unclear, especially those associated with hepatic fibrosis. Here, we analyzed the impact of vitamin C on bile acid induced hepatocyte apoptosis in vitro and lithocholic acid (LCA)-induced liver injury in vitamin C-insufficient Gulo(-/-) mice, which cannot synthesize vitamin C similarly to humans. When Huh-BAT cells were treated with bile acid, apoptosis was induced by endoplasmic reticulum stress-related JNK activation but vitamin C attenuated bile acid-induced hepatocyte apoptosis in vitro. In our in vivo experiments, LCA feeding increased plasma marker of cholestasis and resulted in more extensive liver damage and hepatic fibrosis by more prominent apoptotic cell death and recruiting more intrahepatic inflammatory CD11b(+) cells in the liver of vitamin C-insufficient Gulo(-/-) mice compared to wild type mice which have minimal hepatic fibrosis. However, when vitamin C was supplemented to vitamin C-insufficient Gulo(-/-) mice, hepatic fibrosis was significantly attenuated in the liver of vitamin C sufficient Gulo(-/-) mice like in wild type mice and this hepatoprotective effect of vitamin C was thought to be associated with both decreased hepatic apoptosis and necrosis. These results suggested that vitamin C had hepatoprotective effect against cholestatic liver injury. PMID- 26057691 TI - Caffeic acid exhibits anti-pruritic effects by inhibition of multiple itch transmission pathways in mice. AB - Itch is an unpleasant sensation that evokes a desire to scratch. Although often regarded as a trivial 'alarming' sensation, itch may be debilitating and exhausting, leading to reduction in quality of life. In the current study, the question of whether caffeic acid can be used to alleviate itch sensation induced by various pruritic agents, including histamine, chloroquine, SLIGRL-NH2, and beta-alanine was investigated. It turned out that histamine-induced intracellular calcium increase was significantly blocked by caffeic acid in HEK293T cells that express H1R and TRPV1, molecules required for transmission of histamine-induced itch in sensory neurons. In addition, inhibition of histamine-induced intracellular calcium increase by caffeic acid was demonstrated in primary cultures of mouse dorsal root ganglion (DRG). When chloroquine, an anti-malaria agent known to induce histamine-independent itch - was used, it was also found that caffeic acid inhibits the induced response in both DRG and HEK293T cells that express MRGPRA3 and TRPA1, underlying molecular entities responsible for chloroquine-mediated itch. Likewise, intracellular calcium changes by SLIGRL-NH2 an itch-inducing agent via PAR2 and MRGPRC11 - were decreased by caffeic acid as well. However, it was found that caffeic acid is not capable of inhibiting beta alanine-induced responses via its specific receptor MRGPRD. Finally, in vivo scratching behavior tests showed that caffeic acid indeed has anti-scratching effects against histamine, chloroquine, and SLIGRL-NH2 administration but not by beta-alanine. Overall, the current study demonstrated that caffeic acid has anti itch effects by inhibition of multiple itch mechanisms induced by histamine, chloroquine and SLIGRL-NH2. PMID- 26057693 TI - Effect of telmisartan on the therapeutic efficacy of pitavastatin in high-fat diet induced dyslipidemic guinea pigs. AB - Angiotensin II-receptor blockers (ARBs), similar to HMG-CoA reductase inhibitors (statins), could improve lipid metabolism abnormalities. There might be some cross-talking pathways between statins and ARBs to produce additive beneficial effects on lipid metabolism in dyslipidemia. However, few studies investigate the effects of ARBs on the therapeutic efficacy of statins in dyslipidemia. The present study was designed to systematically evaluate the effects of telmisartan on the therapeutic efficacy of pitavastatin on lowering lipid level and reducing fat deposition by employing a dyslipidemia model, guinea pigs. 48 Male guinea pigs fed with high-fat diet were randomly grouped and treated with vehicle, telmisartan, pitavastatin or telmisartan/pitavastatin combinations. After treatment for eight weeks, telmisartan could significantly enhance the therapeutic efficacy of pitavastatin by extremely reducing body weight gain, weight of adipose tissue and adipocyte size. However, telmisartan/pitavastatin combinations could not further improve lipid levels on the basis of pitavastain, though single telmisartan markedly decreased triglyceride (TG) and slightly increased high density lipoprotein cholesterol (HDL-C). Moreover, telmisartan/pitavastatin combinations significantly upregulated the gene expression level of peroxisome proliferator-activated receptor (PPAR)-delta, but no effects on the expression of PPAR-alpha/gamma, leptin and adiponectin compared to monotherapy. Taken together, our studies provided new evidences that telmisartan has an additive beneficial influence on decreasing fat deposition and weight gain through PPAR-delta pathway but cannot enhance the therapeutic efficacy of pitavastatin on lowering lipid levels. The combinational administration of telmisartan and pitavastatin could be a potential therapeutic strategy for dyslipidemia related obesity and worthy of further investigation in obese animal models. PMID- 26057692 TI - Intrinsic relative activities of kappa opioid agonists in activating Galpha proteins and internalizing receptor: Differences between human and mouse receptors. AB - Several investigators recently identified biased kappa opioid receptor (KOP receptor) agonists. However, no comprehensive study of the functional selectivity of available KOP receptor agonists at the human and mouse KOP receptors (hKOP receptor and mKOP receptor, respectively) has been published. Here we examined the ability of over 20 KOP receptor agonists to activate G proteins and to internalize the receptor. Clonal neuro-2a mouse neuroblastoma (N2a) cells stably transfected with the hKOP receptor or mKOP receptor were used. We employed agonist-induced [(35)S]GTPgammaS binding and KOP receptor internalization as measures of activation of G protein and beta-arrestin pathways, respectively. The method of Ehlert and colleagues was used to quantify intrinsic relative activities at G protein activation (RAi-G) and receptor internalization (RAi-I) and the degree of functional selectivity between the two [Log RAi-G - logRAi-I, RAi-G/RAi-I and bias factor]. The parameter, RAi, represents a relative estimate of agonist affinity for the active receptor state that elicits a given response. The endogenous ligand dynorphin A (1-17) was designated as the balanced ligand with a bias factor of 1. Interestingly, we found that there were species differences in functional selectivity. The most striking differences were for 12 epi-salvinorin A, U69,593, and ICI-199,441. 12-Epi-salvinorin A was highly internalization-biased at the mKOP receptor, but apparently G protein-biased at hKOP receptor. U69,593 was much more internalization-biased at mKOP receptor than hKOP receptor. ICI199,441 showed internalization-biased at the mKOP receptor and G protein-biased at the hKOP receptor. Possible mechanisms for the observed species differences are discussed. PMID- 26057694 TI - Pre-treatment with LCZ696, an orally active angiotensin receptor neprilysin inhibitor, prevents ischemic brain damage. AB - Angiotensin II receptor blockers (ARBs) are known to prevent ischemic brain damage after stroke. Natriuretic peptides, which are increased by a neprilysin inhibitor, are also reported to protect against brain damage. Therefore, we investigated the possible protective effect of valsartan (VAL) compared with LCZ696 (VAL+ neprilysin inhibitor; 1:1) after middle cerebral artery (MCA) occlusion. Eight-week-old male C57BL/6J mice were treated with VAL (3mg/kg per day) or LCZ696 (6mg/kg per day) for 2 weeks before MCA occlusion. Blood pressure and heart rate were measured by telemetry. Cerebral blood flow (CBF) was determined by laser-Doppler flowmetry. Ischemic area was evaluated by triphenytetrasodium chloride staining, and oxidative stress was determined by dihydroethidium staining. Blood pressure and heart rate were not significantly different before and after treatment. Pre-treatment with LCZ696 or VAL reduced the ischemic area, and this effect of LCZ696 was more marked than that of VAL pre treatment. The decrease in CBF in the peripheral region of the ischemic area was significantly attenuated by pre-treatment with LCZ696 or VAL, without any significant effect on CBF in the core region. VAL or LCZ696 pre-treatment significantly decreased the increase of superoxide anion production in the cortex on the ischemic side. However, no significant difference in CBF and superoxide anion production was observed between VAL and LCZ696 pre-treatment. The preventive effect of LCZ696 on ischemic brain damage after stroke was more marked than that of VAL. LCZ696 could be used as a new approach to prevent brain damage after stroke. (246 words). PMID- 26057695 TI - The role of PPAR-gamma receptor in pruritus. AB - Recent studies have clarified the novel mediators and neuronal pathways involved in itch transmission, which might result in introduction of new therapies for management of pruritus in the near future. Involvement of peroxisome proliferator activated receptor (PPAR) signaling in the pathogenesis of skin diseases was suggested in recent experiments. PPAR-gamma agonists, thiazolidinediones, which are used in the treatment of diabetes mellitus, have been recently shown to diminish pruritus not only in animal models, but also in patients suffering from psoriasis; nevertheless, the role of PPAR-gamma receptors in the pruritus is not well understood. In this perspective, a brief overview on the function of PPAR signaling in the pathogenesis of skin disorders as well as the involvement of PPAR-gamma impact on pruritus is argued. Detecting the relationship between PPAR gamma signaling and itching could lead to the emergence of novel therapies for management of pruritus in a wide range of dermatological and systemic disorders. PMID- 26057696 TI - Zwitterion-Coated Iron Oxide Nanoparticles: Surface Chemistry and Intracellular Uptake by Hepatocarcinoma (HepG2) Cells. AB - Nanoparticles (NPs) have received much attention in recent years for their diverse potential biomedical applications. However, the synthesis of NPs with desired biodistribution and pharmacokinetics is still a major challenge, with NP size and surface chemistry being the main factors determining the behavior of NPs in vivo. Here we report on the surface chemistry and in vitro cellular uptake of magnetic iron oxide NPs coated with zwitterionic dopamine sulfonate (ZDS). ZDS coated NPs were compared to similar iron oxide NPs coated with PEG-like 2-[2-(2 methoxyethoxy)ethoxy]acetic acid (MEEA) to investigate how surface chemistry affects their in vitro behavior. ZDS-coated NPs had a very dense coating, guaranteeing high colloidal stability in several aqueous media and negligible interaction with proteins. Treatment of HepG2 cells with increasing doses (2.5 100 MUg Fe/mL) of ZDS-coated iron oxide NPs had no effect on cell viability and resulted in a low, dose-dependent NP uptake, inferior than most reported data for the internalization of iron oxide NPs by HepG2 cells. MEEA-coated NPs were scarcely stable and formed micrometer-sized aggregates in aqueous media. They decreased cell viability for dose >=50 MUg Fe/mL, and were more efficiently internalized than ZDS-coated NPs. In conclusion, our data indicate that the ZDS layer prevented both aggregation and sedimentation of iron oxide NPs and formed a biocompatible coating that did not display any biocorona effect. The very low cellular uptake of ZDS-coated iron NPs can be useful to achieve highly selective targeting upon specific functionalization. PMID- 26057697 TI - Gender Bias in U.S. Pediatric Growth Hormone Treatment. AB - Growth hormone (GH) treatment of idiopathic short stature (ISS), defined as height <-2.25 standard deviations (SD), is approved by U.S. FDA. This study determined the gender-specific prevalence of height <-2.25 SD in a pediatric primary care population, and compared it to demographics of U.S. pediatric GH recipients. Data were extracted from health records of all patients age 0.5-20 years with >= 1 recorded height measurement in 28 regional primary care practices and from the four U.S. GH registries. Height <-2.25 SD was modeled by multivariable logistic regression against gender and other characteristics. Of the 189,280 subjects, 2073 (1.1%) had height <-2.25 SD. No gender differences in prevalence of height <-2.25 SD or distribution of height Z-scores were found. In contrast, males comprised 74% of GH recipients for ISS and 66% for all indications. Short stature was associated (P < 0.0001) with history of prematurity, race/ethnicity, age and Medicaid insurance, and inversely related (P < 0.0001) with BMI Z-score. In conclusion, males outnumbered females almost 3:1 for ISS and 2:1 for all indications in U.S. pediatric GH registries despite no gender difference in height <-2.25 SD in a large primary care population. Treatment and/or referral bias was the likely cause of male predominance among GH recipients. PMID- 26057698 TI - DNA damage and gene transcription: accident or necessity? AB - The extent to which DNA repair machinery facilitates gene activation remains poorly appreciated. A new study published in Cell Research reports a novel function of H2AX, a substrate of ATM and known DNA damage marker, in transcriptional initiation. PMID- 26057699 TI - Systemic regulation of photosynthetic function in field-grown sorghum. AB - The photosynthetic characteristics of developing leaves of plants grown under artificial conditions are, to some extent, regulated systemically by mature leaves; however, whether systemic regulation of photosynthesis occurs in field grown crops is unclear. To explore this question, we investigated the effects of planting density on growth characteristics, gas exchange, leaf nitrogen concentration and chlorophyll a fluorescence in field-grown sorghum (Sorghum bicolor L.). Our results showed that close planting resulted in a marked decline in light intensity in lower canopy. Sorghum plants grown at a high planting density had lower net photosynthetic rate (Pn), stomatal conductance (Gs), and transpiration rate (E) than plants grown at a low planting density. Moreover, in the absence of mineral deficiency, close planting induced a slight increase in leaf nitrogen concentration. The decreased photosynthesis in leaves of the lower canopy at high planting density was caused mainly by the low light. However, newly developed leaves exposed to high light in the upper canopy of plants grown at high planting density also exhibited a distinct decline in photosynthesis relative to plants grown at low planting density. Based on these results, the photosynthetic function of the newly developed leaves in the upper canopy was not determined fully by their own high light environment. Accordingly, we suggest that the photosynthetic function of newly developed leaves in the upper canopy of field-grown sorghum plants is regulated systemically by the lower canopy leaves. The differences in systemic regulation of photosynthesis were also discussed between field conditions and artificial conditions. PMID- 26057700 TI - Exogenously applied selenium reduces oxidative stress and induces heat tolerance in spring wheat. AB - Heat stress (HS) is a worldwide threat to productivity of wheat, especially in arid and semiarid regions of the world. Earlier studies suggested the beneficial effects of selenium (Se) on the growth of some crop species grown under stressful environments. In the present study, we assessed whether Se application could increase antioxidative potential, and thus enhance tolerance to heat in wheat at the sensitive stage i.e., heading stage. At the heading stage, after foliar application of sodium selenate solutions (0, 2 and 4 mg Se L(-1)), the plants of wheat cultivars, namely Chakwal-97 (drought tolerant) and Faisalabad-08 (drought sensitive), were subjected to HS (38 +/- 2 degrees C). The HS significantly altered antioxidative potential, affected growth, photosynthetic pigments and grain yield in both cultivars. Exogenous application of low (2 mg L(-1)) Se increased chlorophyll a and total chlorophyll contents and modulated the growth of wheat plants under HS. However, high concentration (4 mg L(-1)) of Se was much more effective in increasing grains per spike and grain yield in heat stressed plants of both wheat cultivars. Exogenous Se increased both enzymatic (catalase and ascorbate peroxidase activities) and non-enzymatic (carotenoids, anthocyanins and ascorbic acid contents) antioxidants while decreased oxidants (hydrogen peroxide and malondialdehyde contents) under HS in both wheat cultivars. In conclusion, foliar application of Se (4 mg L(-1)) was much more effective in mitigating the deleterious effects of HS on grain yield of wheat plants. The results suggested that Se-mediated up-regulation of antioxidative system (both enzymatic and non-enzymatic) helped the wheat plants to increase fertility, and hence avoid reduction of grain yield under HS. PMID- 26057701 TI - Engineered Nanostructures of Haptens Lead to Unexpected Formation of Membrane Nanotubes Connecting Rat Basophilic Leukemia Cells. AB - A recent finding reports that co-stimulation of the high-affinity immunoglobulin E (IgE) receptor (FcepsilonRI) and the chemokine receptor 1 (CCR1) triggered formation of membrane nanotubes among bone-marrow-derived mast cells. The co stimulation was attained using corresponding ligands: IgE binding antigen and macrophage inflammatory protein 1alpha (MIP1 alpha), respectively. However, this approach failed to trigger formation of nanotubes among rat basophilic leukemia (RBL) cells due to the lack of CCR1 on the cell surface (Int. Immunol. 2010, 22 (2), 113-128). RBL cells are frequently used as a model for mast cells and are best known for antibody-mediated activation via FcepsilonRI. This work reports the successful formation of membrane nanotubes among RBLs using only one stimulus, a hapten of 2,4-dinitrophenyl (DNP) molecules, which are presented as nanostructures with our designed spatial arrangements. This observation underlines the significance of the local presentation of ligands in the context of impacting the cellular signaling cascades. In the case of RBL, certain DNP nanostructures suppress antigen-induced degranulation and facilitate the rearrangement of the cytoskeleton to form nanotubes. These results demonstrate an important scientific concept; engineered nanostructures enable cellular signaling cascades, where current technologies encounter great difficulties. More importantly, nanotechnology offers a new platform to selectively activate and/or inhibit desired cellular signaling cascades. PMID- 26057702 TI - Lactoferrin and ovotransferrin contribute toward antioxidative effects of Edible Bird's Nest against hydrogen peroxide-induced oxidative stress in human SH-SY5Y cells. AB - There are reports of improved redox outcomes due to consumption of Edible Bird's Nest (EBN). Many of the functional effects of EBN can be linked to its high amounts of antioxidants. Interestingly, dietary components with high antioxidants have shown promise in the prevention of aging and its related diseases like Alzheimer's disease. In this study, the antioxidative potentials of EBN and its constituents, lactoferrin (LF) and ovotransferrin (OVF), were determined and protective effects against hydrogen peroxide (H2O2)- induced toxicity on SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and acridine orange and propidium iodide (AO/PI) staining with microscopy were examined. Results showed that EBN and its constituents attenuated H2O2 induced cytotoxicity, and decreased radical oxygen species (ROS) through increased scavenging activity. Furthermore, LF, OVF, and EBN produced transcriptional changes in antioxidant related genes that tended towards neuroprotection as compared to H2O2-treated group. Overall, the results suggest that LF and OVF may produce synergistic or all-or-none antioxidative effects in EBN. PMID- 26057703 TI - Efficacy of Handwashing with Soap and Nail Clipping on Intestinal Parasitic Infections in School-Aged Children: A Factorial Cluster Randomized Controlled Trial. AB - BACKGROUND: Intestinal parasitic infections are highly endemic among school-aged children in resource-limited settings. To lower their impact, preventive measures should be implemented that are sustainable with available resources. The aim of this study was to assess the impact of handwashing with soap and nail clipping on the prevention of intestinal parasite reinfections. METHODS AND FINDINGS: In this trial, 367 parasite-negative school-aged children (aged 6-15 y) were randomly assigned to receive both, one or the other, or neither of the interventions in a 2 * 2 factorial design. Assignment sequence was concealed. After 6 mo of follow up, stool samples were examined using direct, concentration, and Kato-Katz methods. Hemoglobin levels were determined using a HemoCue spectrometer. The primary study outcomes were prevalence of intestinal parasite reinfection and infection intensity. The secondary outcome was anemia prevalence. Analysis was by intention to treat. Main effects were adjusted for sex, age, drinking water source, latrine use, pre-treatment parasites, handwashing with soap and nail clipping at baseline, and the other factor in the additive model. Fourteen percent (95% CI: 9% to 19%) of the children in the handwashing with soap intervention group were reinfected versus 29% (95% CI: 22% to 36%) in the groups with no handwashing with soap (adjusted odds ratio [AOR] 0.32, 95% CI: 0.17 to 0.62). Similarly, 17% (95% CI: 12% to 22%) of the children in the nail clipping intervention group were reinfected versus 26% (95% CI: 20% to 32%) in the groups with no nail clipping (AOR 0.51, 95% CI: 0.27 to 0.95). Likewise, following the intervention, 13% (95% CI: 8% to 18%) of the children in the handwashing group were anemic versus 23% (95% CI: 17% to 29%) in the groups with no handwashing with soap (AOR 0.39, 95% CI: 0.20 to 0.78). The prevalence of anemia did not differ significantly between children in the nail clipping group and those in the groups with no nail clipping (AOR 0.53, 95% CI: 0.27 to 1.04). The intensive follow-up and monitoring during this study made it such that the assessment of the observed intervention benefits was under rather ideal circumstances, and hence the study could possibly overestimate the effects when compared to usual conditions. CONCLUSIONS: Handwashing with soap at key times and weekly nail clipping significantly decreased intestinal parasite reinfection rates. Furthermore, the handwashing intervention significantly reduced anemia prevalence in children. The next essential step should be implementing pragmatic studies and developing more effective approaches to promote and implement handwashing with soap and nail clipping at larger scales. PMID- 26057704 TI - Cavity-Enhanced Near-Infrared Laser Absorption Spectrometer for the Measurement of Acetonitrile in Breath. AB - Elevated concentrations of acetonitrile have been found in the exhaled breath of patients with cystic fibrosis1 and may indicate the severity of their condition or the presence of an accompanying bacterial infection of the airways. There is therefore interest in detecting acetonitrile in exhaled breath. For this purpose, a cavity-enhanced laser absorption spectrometer (lambda = 1.65 MUm) with a preconcentration stage was built and is described here. The spectrometer has a limit of detection of 72 ppbv and 114 ppbv of acetonitrile in nitrogen and breath, respectively, with a measurement duration of just under 5 min. The preconcentration stage, which employs a carbon molecular sieve and an adsorption/thermal desorption cycle, can increase the acetonitrile concentration by up to a factor 93, thus, lowering the overall limit of detection to approximately 1 ppbv. The suitability of the system for acetonitrile measurements in breath is demonstrated with breath samples taken from the authors, which yielded acetonitrile concentrations of 23 +/- 3 ppbv and 29 +/- 3 ppbv, respectively. PMID- 26057705 TI - Synthesis and quantitative structure-activity relationships study for phenylpropenamide derivatives as inhibitors of hepatitis B virus replication. AB - A series of new phenylpropenamide derivatives containing different substituents was synthesized, characterized and evaluated for their anti-hepatitis B virus (HBV) activities. The quantitative structure-activity relationships (QSAR) of phenylpropenamide compound have been studied. The 2D-QSAR models, based on DFT and multiple linear regression analysis methods, revealed that higher values of total energy (TE) and lower entropy (S(?)) enhanced the anti-HBV activities of the phenylpropenamide molecules. Predictive 3D-QSAR models were established using SYBYL multifit molecular alignment rule. The optimum models were all statistically significant with cross-validated and conventional coefficients, indicating that they were reliable enough for activity prediction. PMID- 26057706 TI - Chemistry for oncotheranostic gold nanoparticles. AB - This review presents in a comprehensive ways the chemical methods used to functionalize gold nanoparticles with focus on anti-cancer applications. The review covers the parameters required for the synthesis gold nanoparticles with defined shapes and sizes, method for targeted delivery in tumours, and selected examples of anti-cancers compounds delivered with gold nanoparticles. A short survey of bioassays for oncology based on gold nanoparticles is also presented. PMID- 26057708 TI - Ring Selective Generation of Isobenzofuran for Divergent Access to Polycyclic Aromatic Compounds. AB - Ring selective generation of isobenzofuran, a formal equivalent to bis isobenzofuran, was developed. Importantly, selective introduction of functionalities and/or fused rings in the isobenzofuran core by iterative cycloadditions can achieve the divergent construction of polycyclic compounds. This selective approach enables us to prepare a regioisomeric pair of pentacenes. PMID- 26057707 TI - Inhibition of hypoxia inducible factors combined with all-trans retinoic acid treatment enhances glial transdifferentiation of neuroblastoma cells. AB - Neuroblastoma (NBL) is a heterogeneous tumor characterized by a wide range of clinical manifestations. A high tumor cell differentiation grade correlates to a favorable stage and positive outcome. Expression of the hypoxia inducible factors HIF1-alpha (HIF1A gene) and HIF2-alpha (EPAS1 gene) and/or hypoxia-regulated pathways has been shown to promote the undifferentiated phenotype of NBL cells. Our hypothesis is that HIF1A and EPAS1 expression represent one of the mechanisms responsible for the lack of responsiveness of NBL to differentiation therapy. Clinically, high levels of HIF1A and EPAS1 expression were associated with inferior survival in two NBL microarray datasets, and patient subgroups with lower expression of HIF1A and EPAS1 showed significant enrichment of pathways related to neuronal differentiation. In NBL cell lines, the combination of all trans retinoic acid (ATRA) with HIF1A or EPAS1 silencing led to an acquired glial cell phenotype and enhanced expression of glial-cell differentiation markers. Furthermore, HIF1A or EPAS1 silencing might promote cell senescence independent of ATRA treatment. Taken together, our data suggest that HIF inhibition coupled with ATRA treatment promotes differentiation into a more benign phenotype and cell senescence in vitro. These findings open the way for additional lines of attack in the treatment of NBL minimal residue disease. PMID- 26057709 TI - Fibrinolytic therapy for parapneumonic empyema during pregnancy. AB - Pneumonia and parapneumonic complicated effusion during pregnancy is uncommon but poses potentially serious risks to both mother and fetus. Enzymatic debridement of the pleural cavity with fibrinolytic agents is a noninvasive option that can facilitate drainage and prevent the need for surgery. Herein, we describe the cases of two pregnant women with parapneumonic empyema who were successfully treated with intrapleural fibrinolytic therapy. PMID- 26057710 TI - Host cell targets for African swine fever virus. AB - Viruses are strict intracellular pathogens that require the cellular environment to complete a successful infection. Among them, African swine fever virus (ASFV) is an evolutionary ancient DNA virus, endemic in Africa, which is nowadays causing an emergent disease in Europe with a potential high economic impact in the pig industry. It is well known that host-cell components are critical crossroads mapping the virus path for a productive infection, some of them at the endocytic pathway. Considering that ASFV infectious cycle strongly relies in several factors from the host cell, the study of virus-host interactions remains crucial as they will reveal the obstacles, routes and tracks, hints and the target waypoint in the virus journey to destination. PMID- 26057711 TI - Against the clock towards new Ebola virus therapies. AB - Since the end of 2013, West Africa has been suffering the largest Ebola virus (EBOV) outbreak in recorded history. The lack of health care infrastructure in the affected countries, as well as a concentration of infected cases in the most populated areas allowed the virus to spread with no control during the first months of the outbreak. With no specific treatment available to combat EBOV infection and its associated disease, an extraordinary worldwide effort was made to confront the severity of the situation and to establish new therapeutic strategies that would lead to better and faster control and eradicate the outbreak. In the last two years, several candidate therapies and potential vaccines against EBOV have arisen and human clinical trials are ongoing, in hopes of starting their deployment in the affected countries. This article reviews the current candidate therapies against EBOV, their stage of development and future prospects in battling EBOV outbreaks. PMID- 26057712 TI - Constructing a Nonnegative Low-Rank and Sparse Graph With Data-Adaptive Features. AB - This paper aims at constructing a good graph to discover the intrinsic data structures under a semisupervised learning setting. First, we propose to build a nonnegative low-rank and sparse (referred to as NNLRS) graph for the given data representation. In particular, the weights of edges in the graph are obtained by seeking a nonnegative low-rank and sparse reconstruction coefficients matrix that represents each data sample as a linear combination of others. The so-obtained NNLRS-graph captures both the global mixture of subspaces structure (by the low rankness) and the locally linear structure (by the sparseness) of the data, hence it is both generative and discriminative. Second, as good features are extremely important for constructing a good graph, we propose to learn the data embedding matrix and construct the graph simultaneously within one framework, which is termed as NNLRS with embedded features (referred to as NNLRS-EF). Extensive NNLRS experiments on three publicly available data sets demonstrate that the proposed method outperforms the state-of-the-art graph construction method by a large margin for both semisupervised classification and discriminative analysis, which verifies the effectiveness of our proposed method. PMID- 26057713 TI - Silhouette analysis for human action recognition based on supervised temporal t SNE and incremental learning. AB - This paper develops a human action recognition method for human silhouette sequences based on supervised temporal t-stochastic neighbor embedding (ST-tSNE) and incremental learning. Inspired by the SNE and its variants, ST-tSNE is proposed to learn the underlying relationship between action frames in a manifold, where the class label information and temporal information are introduced to well represent those frames from the same action class. As to the incremental learning, an important step for action recognition, we introduce three methods to perform the low-dimensional embedding of new data. Two of them are motivated by local methods, locally linear embedding and locality preserving projection. Those two techniques are proposed to learn explicit linear representations following the local neighbor relationship, and their effectiveness is investigated for preserving the intrinsic action structure. The rest one is based on manifold-oriented stochastic neighbor projection to find a linear projection from high-dimensional to low-dimensional space capturing the underlying pattern manifold. Extensive experimental results and comparisons with the state-of-the-art methods demonstrate the effectiveness and robustness of the proposed ST-tSNE and incremental learning methods in the human action silhouette analysis. PMID- 26057715 TI - Physical Activity in the Transition to University: The Role of Past Behavior and Concurrent Self-regulatory Efficacy. AB - OBJECTIVE: Two studies were conducted to examine the relationship between past physical activity, concurrent self-regulatory efficacy (CSRE), and current physical activity during the transition to university. PARTICIPANTS: Study 1 included 110 first-year undergraduate students recruited during October/November of 2012. Study 2 involved 86 first-year undergraduate students recruited during October/November of 2013. METHODS: Surveys were completed online, concurrently (Study 1) and prospectively (Study 2). RESULTS: CSRE was found to positively predict current physical activity participation in both studies. However, the relation of CSRE to physical activity was attenuated when past behavior was taken into account. CONCLUSIONS: Physical activity is one goal that university students pursue concurrently with other goals. Not only is current planned activity related to one's past participation in physical activity, it is also related to self-regulatory beliefs about managing that activity in the new context of university life. PMID- 26057714 TI - Prolonged Local Hypothermia Has No Long-Term Adverse Effect on the Spinal Cord. AB - Hypothermia is known to be neuroprotective and is one of the most effective and promising first-line treatments for central nervous system (CNS) trauma. At present, induction of local hypothermia, as opposed to general hypothermia, is more desired because of its ease of application and safety; fewer side effects and an absence of severe complications have been noted. Local hypothermia involves temperature reduction of a small and specific segment of the spinal cord. Our group has previously shown the neuroprotective effect of short-term, acute moderate general hypothermia through improvements in electrophysiological and motor behavioral assessments, as well as histological examination following contusive spinal cord injury (SCI) in rats. We have also shown the benefit of using short-term local hypothermia versus short-term general hypothermia post acute SCI. The overall neuroprotective benefit of hypothermia can be categorized into three main components: (1) induction modality, general versus local, (2) invasive, semi-invasive or noninvasive, and (3) duration of hypothermia induction. In this study, a series of experiments were designed to investigate the feasibility, long-term safety, as well as eventual complications and side effects of prolonged, semi-invasive, moderate local hypothermia (30 degrees C+/ 0.5 degrees C for 5 and 8 hours) in rats with uninjured spinal cord while maintaining their core temperature at 37 degrees C+/-0.5 degrees C. The weekly somatosensory evoked potential and motor behavioral (Basso, Beattie and Bresnahan) assessments of rats that underwent 5 and 8 hours of semi-invasive local hypothermia, which revealed no statistically significant changes in electrical conductivity and behavioral outcomes. In addition, 4 weeks after local hypothermia induction, histological examination showed no anatomical damages or morphological changes in their spinal cord structure and parenchyma. We concluded that this method of prolonged local hypothermia is feasible, safe, and has the potential for clinical translation. PMID- 26057716 TI - VS-APPLE: A Virtual Screening Algorithm Using Promiscuous Protein-Ligand Complexes. AB - As the number of structurally resolved protein-ligand complexes increases, the ligand-binding pockets of many proteins have been found to accommodate multiple different compounds. Effective use of these structural data is important for developing virtual screening (VS) methods that identify bioactive compounds. Here, we introduce a VS method, VS-APPLE (Virtual Screening Algorithm using Promiscuous Protein-Ligand complExes), based on promiscuous protein-ligand binding structures. In VS-APPLE, multiple ligands bound to a pocket are combined into a query template for screening. Both the structural match between a test compound and the multiple-ligand template and the possible collisions between the test compound and the target protein are evaluated by an efficient geometric hashing method. The performance of VS-APPLE was examined on a filtered, clustered version of the Directory of Useful Decoys data set. In Area Under the Curve analyses of this data set, VS-APPLE outperformed several popular screening programs. Judging from the performance of VS-APPLE, the structural data of promiscuous protein-ligand bindings could be further analyzed and exploited for developing VS methods. PMID- 26057717 TI - Treatment of a mixture of food color additives (E122, E124 and E129) in different water matrices by UVA and solar photoelectro-Fenton. AB - The degradation of 130 mL of mixtures of food azo dyes E122, E124 and E129 has been studied by electro-Fenton (EF) and UVA photoelectro-Fenton (PEF) using a stirred tank reactor with either a boron-doped diamond (BDD) or Pt anode and an air-diffusion cathode. The main oxidant was hydroxyl radical formed at the anode from water oxidation and in the bulk from Fenton's reaction between added Fe(2+) and H2O2 generated at the cathode. In sulfate medium, fast decolorization was found for all systems, but the almost total mineralization was more rapidly achieved by PEF with BDD. The performance with a real water matrix was slightly worse, although the removal of total organic load was still as high as 95%. The solar PEF (i.e., SPEF) treatment of dye mixtures using a 2.5 L flow plant with a BDD/air-diffusion cell coupled to a planar solar photoreactor is also reported. Fast decolorization and almost total mineralization was found in the presence of either sulfate, perchlorate, nitrate or a mixture of sulfate + chloride ions. In chloride medium, however, the formation of recalcitrant chloroderivatives decelerated the degradation process. Greater current efficiency and lower specific energy consumption were attained in sulfate medium at lower current density and higher azo dye content. A plausible reaction sequence based on 18 aromatic intermediates identified by GC-MS and 6 short-linear carboxylic acids detected by ion-exclusion HPLC has been proposed. The SPEF process promoted the photodegradation of Fe(III)-oxalate complexes and other undetected products. Sulfate and nitrate ions were always released to the medium. PMID- 26057718 TI - Bioelectrochemical recovery of waste-derived volatile fatty acids and production of hydrogen and alkali. AB - Volatile fatty acids (VFA) are organic compounds of great importance for various industries and environmental processes. Fermentation and anaerobic digestion of organic wastes are promising alternative technologies for VFA production. However, one of the major challenges is development of sustainable downstream technologies for VFA recovery. In this study, an innovative microbial bipolar electrodialysis cell (MBEDC) was developed to meet the challenge of waste-derived VFA recovery, produce hydrogen and alkali, and potentially treat wastewater. The MBEDC was operated in fed-batch mode. At an applied voltage of 1.2 V, a VFA recovery efficiency of 98.3%, H2 of 18.4 mL and alkali production presented as pH of 12.64 were obtained using synthetic fermentation broth. The applied voltage, initial VFA concentrations and composition were affecting the VFA recovery. The energy balance revealed that net energy (5.20-6.86 kWh/kg-VFA recovered) was produced at all the applied voltages (0.8-1.4 V). The coexistence of other anionic species had no negative effect on VFA transportation. The VFA concentration was increased 2.96 times after three consecutive batches. Furthermore, the applicability of MBEDC was successfully verified with digestate. These results demonstrate for the first time the possibility of a new method for waste-derived VFA recovery and valuable products production that uses wastewater as fuel and bacteria as catalyst. PMID- 26057719 TI - Genetic polymorphisms and HPV infection in oral squamous cell carcinomas. AB - Despite declining smoking rates in the United States, the incidence of oral squamous cell carcinomas (OSCC, including oral cavity and oropharynx) is rising in young adults. The reasons have been attributed to changes in sexual behaviors and the increasingly prevalent infection of oncogenic subtypes of human papillomavirus (HPV), principally type16 and occasionally type18. However, only small proportion of individuals who have contracted HPV infection will develop OSCC, suggesting that there is an inter-individual variation in susceptibility to HPV infection and related OSCC. Identification of susceptible biomarkers for HPV status would be useful to identify those individuals who are susceptible to HPV infection, to refine the prognostication of HPV associated OSCC, and ultimately to improve prevention efforts for OSCC and potentially other HPV-associated diseases. Our public health OSCC prevention paradigm will need to expand beyond tobacco and alcohol control. PMID- 26057721 TI - Does Cerebral Water and Ion Imbalance After Intense Exercise of Short Duration Under Hypoxic Conditions Contribute to Occurrence of Acute Mountain Sickness? PMID- 26057720 TI - Beyond cultural factors to understand immigrant mental health: Neighborhood ethnic density and the moderating role of pre-migration and post-migration factors. AB - Pre-migration and post-migration factors may influence the health of immigrants. Using a cross-national framework that considers the effects of the sending and receiving social contexts, we examined the extent to which pre-migration and post migration factors, including individual and neighborhood level factors, influence depressive symptoms at a 2-year follow-up time point. Data come from the Boston Puerto Rican Health Study, a population-based prospective cohort of Puerto Ricans between the ages of 45 and 75 y. The association of neighborhood ethnic density with depressive symptomatology at follow-up was significantly modified by sex and level of language acculturation. Men, but not women, experienced protective effects of ethnic density. The interaction of neighborhood ethnic density with language acculturation had a non-linear effect on depressive symptomatology, with lowest depressive symptomatology in the second highest quartile of language acculturation, relative to the lowest and top two quartiles among residents of high ethnic density neighborhoods. Results from this study highlight the complexity, and interplay, of a number of factors that influence the health of immigrants, and emphasize the significance of moving beyond cultural variables to better understand why the health of some immigrant groups deteriorates at faster rates overtime. PMID- 26057722 TI - Biological fate and effects of propranolol in an experimental aquatic food chain. AB - The aim of this study was to evaluate the trophic transfer of the beta-blocker propranolol (PRP) in an experimental aquatic food chain involving the green algae Scenedesmus obliquus, the water flea Daphnia magna and the crucian carp Carassius auratus, as well as the metabolism and effects of PRP in the liver of crucian carp. After a 48 h PRP aqueous exposure for algae, with a subsequent 48 h dietary exposure for daphnia and an 8d dietary exposure for crucian carp, PRP was observed in each trophic level, despite significant bioaccumulation did not occur in daphnia and crucian carp. A portion of the absorbed PRP was metabolized by the crucian carp to N-desisopropylated propranolol, propranolol glucuronic acid, monohydroxylated propranolol, hydroxypropranolol glucuronide and dihydroxypropranolol glucuronide, which were similar to those in mammals. In addition, multiple biomarkers in the liver of crucian carp (7-ethoxyresorufin O deethylase, EROD; 7-benzyloxyresorufin O-dealkylation, BROD; superoxide dismutase, SOD and malondialdehyde, MDA) were measured. BROD and MDA were not significantly affected by PRP, while EROD and SOD did change significantly during the 8d dietary exposure. This work indicated that the trophic transfer of PRP, resulting in biochemical perturbations of fish biological systems, should be a concern for the assessment of the environmental risks to aquatic food chains. PMID- 26057723 TI - Wading bird guano enrichment of soil nutrients in tree islands of the Florida Everglades. AB - Differential distribution of nutrients within an ecosystem can offer insight of ecological and physical processes that are otherwise unclear. This study was conducted to determine if enrichment of phosphorus (P) in tree island soils of the Florida Everglades can be explained by bird guano deposition. Concentrations of total carbon, nitrogen (N), and P, and N stable isotope ratio (delta(15)N) were determined on soil samples from 46 tree islands. Total elemental concentrations and delta(15)N were determined on wading bird guano. Sequential chemical extraction of P pools was also performed on guano. Guano contained between 53.1 and 123.7 g-N kg(-1) and 20.7 and 56.7 g-P kg(-1). Most of the P present in guano was extractable by HCl, which ranged from 82 to 97% of the total P. Total P of tree islands classified as having low or high P soils averaged 0.71 and 40.6 g kg(-1), respectively. Tree island soil with high total P concentration was found to have a similar delta(15)N signature and total P concentration as bird guano. Phosphorus concentrations and delta(15)N were positively correlated in tree island soils (r = 0.83, p< 0.0001). Potential input of guano with elevated concentrations of N and P, and (15)N enriched N, relative to other sources suggests that guano deposition in tree island soils is a mechanism contributing to this pattern. PMID- 26057724 TI - Alternative future analysis for assessing the potential impact of climate change on urban landscape dynamics. AB - Assessing the impact of climate change on urban landscape dynamics (ULD) is the foundation for adapting to climate change and maintaining urban landscape sustainability. This paper demonstrates an alternative future analysis by coupling a system dynamics (SD) and a cellular automata (CA) model. The potential impact of different climate change scenarios on ULD from 2009 to 2030 was simulated and evaluated in the Beijing-Tianjin-Tangshan megalopolis cluster area (BTT-MCA). The results suggested that the integrated model, which combines the advantages of the SD and CA model, has the strengths of spatial quantification and flexibility. Meanwhile, the results showed that the influence of climate change would become more severe over time. In 2030, the potential urban area affected by climate change will be 343.60-1260.66 km(2) (5.55 -20.37 % of the total urban area, projected by the no-climate-change-effect scenario). Therefore, the effects of climate change should not be neglected when designing and managing urban landscape. PMID- 26057725 TI - An economic evaluation of solar radiation management. AB - Economic evaluations of solar radiation management (SRM) usually assume that the temperature will be stabilized, with no economic impacts of climate change, but with possible side-effects. We know from experiments with climate models, however, that unlike emission control the spatial and temporal distributions of temperature, precipitation and wind conditions will change. Hence, SRM may have economic consequences under a stabilization of global mean temperature even if side-effects other than those related to the climatic responses are disregarded. This paper addresses the economic impacts of implementing two SRM technologies; stratospheric sulfur injection and marine cloud brightening. By the use of a computable general equilibrium model, we estimate the economic impacts of climatic responses based on the results from two earth system models, MPI-ESM and NorESM. We find that under a moderately increasing greenhouse-gas concentration path, RCP4.5, the economic benefits of implementing climate engineering are small, and may become negative. Global GDP increases in three of the four experiments and all experiments include regions where the benefits from climate engineering are negative. PMID- 26057726 TI - Decomposition and carbon storage of selected paper products in laboratory-scale landfills. AB - The objective of this study was to measure the anaerobic biodegradation of different types of paper products in laboratory-scale landfill reactors. The study included (a) measurement of the loss of cellulose, hemicellulose, organic carbon, and (b) measurement of the methane yields for each paper product. The test materials included two samples each of newsprint (NP), copy paper (CP), and magazine paper (MG), and one sample of diaper (DP). The methane yields, carbon storage factors and the extent of cellulose and hemicellulose decomposition all consistently show that papers made from mechanical pulps (e.g., NPs) are less degradable than those made from chemical pulps where essentially all lignin was chemically removed (e.g., CPs). The diaper, which is not only made from chemical pulp but also contains some gel and plastic, exhibited limited biodegradability. The extent of biogenic carbon conversion varied from 21 to 96% among papers, which contrasts with the uniform assumption of 50% by the Intergovernmental Panel on Climate Change (IPCC) for all degradable materials discarded in landfills. Biochemical methane potential tests also showed that the solids to liquid ratio used in the test can influence the results. PMID- 26057727 TI - Stream pollution concentration in riffle geomorphic units (Yzeron basin, France). AB - In urbanized areas, small streams can be greatly damaged by urban inflows and combined sewer overflows. These polluted inputs can be several times higher than the natural stream flow over short time periods. Sound knowledge of the spatial distribution of the discharged pollutants in sediments is therefore crucial for designing monitoring strategies and suitable remediation operations. This field study combines geomorphic characterization, hydraulic conductivity measurement and pollutant assays in sediments of a small suburban river. The study site was divided up into geomorphic units: riffles, pools and runs. The last two were grouped into one class named "pool-runs" owing to their closely similar open channel flow hydraulics. Benthic and hyporheic sediments were sampled at 2m intervals. Conventional particulate pollutants (Cr, Pb, N(org), P(tot) & C(org)) were assayed in samples. The main result was: pollutants were not randomly distributed in the stream sediments, but their location showed clear concentration differences by geomorphic units, with preferential accumulation in the hyporheic zones of riffle units and a lesser one in the hyporheic zones of pools. A decrease in hydraulic conductivity was significantly correlated with an increase in pollutant concentration. This occurred mainly at the transition between riffles and pool units. The down-welling water fluxes in the sediment calculated using Darcy's formula reflect this slowdown. Our findings highlight the need to take into account the geomorphological and hydrological functioning of a stream to accurately locate the biogeochemical hotspots to be treated and thereby develop more relevant monitoring and remediation methodologies. PMID- 26057728 TI - The DIONESUS algorithm provides scalable and accurate reconstruction of dynamic phosphoproteomic networks to reveal new drug targets. AB - Many drug candidates fail in clinical trials due to an incomplete understanding of how small-molecule perturbations affect cell phenotype. Cellular responses can be non-intuitive due to systems-level properties such as redundant pathways caused by co-activation of multiple receptor tyrosine kinases. We therefore created a scalable algorithm, DIONESUS, based on partial least squares regression with variable selection to reconstruct a cellular signaling network in a human carcinoma cell line driven by EGFR overexpression. We perturbed the cells with 26 diverse growth factors and/or small molecules chosen to activate or inhibit specific subsets of receptor tyrosine kinases. We then quantified the abundance of 60 phosphosites at four time points using a modified microwestern array, a high-confidence assay of protein abundance and modification. DIONESUS, after being validated using three in silico networks, was applied to connect perturbations, phosphorylation, and cell phenotype from the high-confidence, microwestern dataset. We identified enhancement of STAT1 activity as a potential strategy to treat EGFR-hyperactive cancers and PTEN as a target of the antioxidant, N-acetylcysteine. Quantification of the relationship between drug dosage and cell viability in a panel of triple-negative breast cancer cell lines validated proposed therapeutic strategies. PMID- 26057729 TI - Quantum Dots in an Amphiphilic Polyethyleneimine Derivative Platform for Cellular Labeling, Targeting, Gene Delivery, and Ratiometric Oxygen Sensing. AB - Amphiphilic polyethyleneimine derivatives (amPEIs) were synthesized and used to encapsulate dozens of quantum dots (QDs). The QD-amPEI composite was ~100 nm in hydrodynamic diameter and had the slightly positive outer surface that suited well for cellular internalization. The QD-amPEI showed very efficient QD cellular labeling with the labeled cell fluorescence intensity more than 10 times higher than conventional techniques such as Lipofectamine-assisted QD delivery. QD-amPEI was optimal for maximal intracellular QD delivery by the large QD payload and the rapid endocytosis kinetics. QD-amPEI platform technology was demonstrated for gene delivery, cell-specific labeling, and ratiometric oxygen sensing. Our QD amPEI platform has two partitions: positive outer surface and hydrophobic inside pocket. The outer positive surface was further exploited for gene delivery and targeting. Co-delivery of QDs and GFP silencing RNAs was successfully demonstrated by assembling siRNAs to the outer surfaces, which showed the transfection efficiency an order of magnitude higher than conventional gene transfections. Hyaluronic acids were tethered onto the QD-amPEI for cell-specific targeted labeling which showed the specific-to-nonspecific signal ratio over 100. The inside hydrophobic compartment was further applied for cohosting oxygen sensing phosphorescence Ru dyes along with QDs. The QD-Ru-amPEI oxygen probe showed accurate and reversible oxygen sensing capability by the ratiometric photoluminescence signals, which was successfully applied to cellular and spheroid models. PMID- 26057730 TI - Doxorubicin-loaded poly(lactic-co-glycolic acid) microspheres prepared using the solid-in-oil-in-water method for the transarterial chemoembolization of a liver tumor. AB - Doxorubicin (DOX)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres (MSs) were fabricated using the solid-in-oil-in-water (S/O/W) emulsification method for transarterial chemoembolization (TACE) of a liver tumor. DOX-loaded PLGA MSs with a mean diameter of 26 MUm and a spherical shape were prepared. The biodegradation of PLGA MSs was observed in serum using a scanning electron microscope (SEM). Drug release from the PLGA MSs was accelerated at an acidic pH (pH 5.5) compared to a normal physiological pH (pH 7.4). According to the results of a pharmacokinetic study in rats, the area under the curve (AUC) value of a drug, which indicates the systemic exposure extent of the drug, of the PLGA MSs group was 29.9% of that of a hepatic arterial injection (HAI) group. The DOX concentration ratio for liver tumors compared to normal livers was significantly higher in the PLGA MSs group than that of the HAI group (p<0.05). After the TACE procedure was performed with DOX-PLGA MSs in a rat hepatoma model, the mean size increment of tumor in DOX-PLGA MSs group was found to be lower than that of the HAI group, and the viable portion of the DOX-PLGA MSs group was less than the other groups (p<0.05). All these findings suggested that the developed DOX-loaded PLGA MSs fabricated with the S/O/W method can be used as a promising drug delivery system in TACE for liver tumors. PMID- 26057731 TI - Thermodynamic insights into drug-surfactant interactions: Study of the interactions of naporxen, diclofenac sodium, neomycin, and lincomycin with hexadecytrimethylammonium bromide by using isothermal titration calorimetry. AB - The success of drug delivery depends on the efficiency of the route of administration, which in turn relies on properties of the drug and its transport vehicle. A quantitative knowledge of association of drugs with transport vehicles is lacking when the latter are in the category of self assembled structures. The work reported in this manuscript addresses the mechanism of partitioning of naproxen, diclofenac sodium, neomycin and lincomycin in the micelles of hexadecytrimethylammonium bromide and that is quantitatively based on the measurement of thermodynamic parameters of interactions by using isothermal titration calorimetry. The addressed mechanism of partitioning is based on the identification of the type of interactions of these drugs with the surfactant micelles and monomers, along with the effect of the former on the micellization properties of the surfactant. The conclusions are based on the interpretation of the values of partitioning constant, standard molar enthalpy change, standard molar entropy change and the stoichiometry of the interaction. The results of this study have implications for deriving guidelines for the target oriented synthesis of new drugs that are to be used for effective delivery via micellar media. PMID- 26057732 TI - Reduced graphene oxide modified smart conducting paper for cancer biosensor. AB - We report results of the studies relating to the fabrication of a paper based sensor comprising of poly (3,4-ethylenedioxythiophene):poly(styrenesulfonate) ( PEDOT: PSS) and reduced graphene oxide (RGO) composite. The effect of various solvents like methanol, ethylene glycol and H2SO4 on the electrical conductivity of PEDOT: PSS coated Whatman paper has been investigated. The conductivity of this solution processed conducting paper significantly increases from ~1.16*10( 4) S cm(-1) up to ~3.57*10(-2) S cm(-1) (~300 times) on treatment with ethylene glycol. The observed significant increase in electrical conductivity is due to conformational rearrangement in the polymer and is due to strong non-covalent cooperative interaction between PEDOT and the cellulose molecules. Further, incorporation of RGO into the conducting paper results in improved electrochemical performance and signal stability. This paper electrode is a promising alternative over the expensive conventional electrodes (ITO, gold and glassy carbon), that are known to have limited application in smart point-of-care (POC) devices. This low cost, flexible and environment friendly conducting paper based biosensor utilized for cancer biomarker (carcinoembryonic antigen, CEA) detection reveals high sensitivity of 25.8 uA ng(-1) mL cm(-2) in the physiological range, 1-10 ng mL(-1). PMID- 26057733 TI - Label-free and sensitive detection of T4 polynucleotide kinase activity via coupling DNA strand displacement reaction with enzymatic-aided amplification. AB - Several fluorescence signal amplification strategies have been developed for sensitive detection of T4 polynucleotide kinase (T4 PNK) activity, but they need fluorescence dye labeled DNA probe. We have addressed the limitation and report here a label-free strategy for sensitive detection of PNK activity by coupling DNA strand displacement reaction with enzymatic-aided amplification. A hairpin oligonucleotide (hpDNA) with blunt ends was used as the substrate for T4 PNK phosphorylation. In the presence of T4 PNK, the stem of hpDNA was phosphorylated and further degraded by lambda exonuclease (lambda exo) from 5' to 3' direction to release a single-stranded DNA as a trigger of DNA strand displacement reaction (SDR). The trigger DNA can continuously displace DNA P2 from P1/P2 hybrid with the help of specific cleavage of nicking endonuclease (Nt.BbvCI). Then, DNA P2 can form G-quadruplex in the presence of potassium ions and quadruplex-selective fluorphore, N-methyl mesoporphyrin IX (NMM), resulting in a significant increase in fluorescence intensity of NMM. Thus, the accumulative release of DNA P2 led to fluorescence signal amplification for determining T4 PNK activity with a detection limit of 6.6*10(-4) U/mL, which is superior or comparative with established approaches. By ingeniously utilizing T4 PNK-triggered DNA SDR, T4 PNK activity can be specifically and facilely studied in homogeneous solution containing complex matrix without any external fluorescence labeling. Moreover, the influence of different inhibitors on the T4 PNK activity revealed that it also can be explored to screen T4 PNK inhibitors. Therefore, this label-free amplification strategy presents a facile and cost-effective approach for nucleic acid phosphorylation related research. PMID- 26057734 TI - Multiplexed magnetic nanoparticle-antibody conjugates (MNPs-ABS) based prognostic detection of ovarian cancer biomarkers, CA-125, beta-2M and ApoA1 using fluorescence spectroscopy with comparison of surface plasmon resonance (SPR) analysis. AB - A multiplexed MNPs-Abs based fluorescence spectroscopic system in analysis of serum biomarkers; CA-125, beta2-M and ApoA1 for the early detection of ovarian cancer was first time proposed. The lowest detection limits measured in multiplexed setup were 0.26 U/mL, 0.55 ng/mL and 7.7 ng/mL respectively for CA 125, beta2-M and ApoA1. A comparative real sample analysis of healthy normal (Control), benign and ovarian cancer patients with SPR has also been done to validate the process. Moreover CA-125 detection only confirms 50-60% of early stage disease. This multiplexed system achieved sensitivity and specificity up to 94% and 98% respectively to distinguish early stage ovarian cancer patients from healthy individuals. PMID- 26057735 TI - The effect of hyperbaric air on the electric activity of neuronal in vitro networks. AB - Breathing hyperbaric air or gas mixtures, for example during diving or when working underwater is known to alter the electrophysiological behavior of neuronal cells, which may lead to restricted cognition. During the last few decades, only very few studies into hyperbaric effects have been published, especially for the most relevant pressure range of up to 10 bar. We designed a pressurized measuring chamber to record pressure effects on the electrical activity of neuronal networks formed by primary cells of the frontal cortex of NMRI mice. Electrical activity was recorded with multi-electrode arrays (MEAs) of glass neuro chips while subjected to a step-by-step pressure increase from atmospheric pressure (1 bar) to 2 and 4 bar, followed by a decompression to 1 bar, in order to record recovery effects. The effects of pressure on the total spike rates (TSRs), which were averaged from at least 45 chips, were detected in two cell culture media with different compositions. In a DMEM medium with 6% horse serum, the TSR was increased by 19% after a pressure increase to 2 bar and remained stable at 4 bar. In NMEM medium with 2% B27, the TSR was not altered by a pressure increase to 2 bar but increased by 9% at 4 bar. After decompression to 1 bar, the activities decreased to 76% and 101% of their respective control levels in the two media. MEA recordings from neuronal networks in miniaturized hyperbaric measuring chambers provide new access for exploring the neuronal effects of hyperbaric breathing gases. PMID- 26057736 TI - One-pot synthesis of mesoporous structured ratiometric fluorescence molecularly imprinted sensor for highly sensitive detection of melamine from milk samples. AB - A facile strategy was developed to prepare mesoporous structured ratiometric fluorescence molecularly imprinted sensor for highly sensitive and selective determination of melamine using CdTe QDs as target sensitive dye and hematoporphyrin as reference dyes. One-pot synthesis method was employed because it could simplify the imprinting process and shorten the experimental period. The as-prepared fluorescence MIPs sensor, which combined ratiometric fluorescence technique with mesoporous silica materials into one system, exhibited excellent selectivity and sensitivity. Under optimum conditions, these mesoporous structured ratiometric fluorescence MIP@QDs sensors showed detection limit as low as 38 nM, which was much lower than those non-mesoporous one. The recycling process was sustainable at least 10 times without obvious efficiency decrease. The feasibility of the developed method in real samples was successfully evaluated through the analysis of melamine in raw milk and milk powder samples with satisfactory recoveries of 92-101%. The developed method proposed in this work proved to be a convenient, rapid, reliable and practical way to prepared high sensitive and selective fluorescence sensors with potentially applicable for trace pollutants analysis in complicated samples. PMID- 26057737 TI - Iron-Catalyzed Intramolecular C(sp(2))-N Cyclization of 1-(N-Arylpyrrol-2 yl)ethanone O-Acetyl Oximes toward Pyrrolo[1,2-a]quinoxaline Derivatives. AB - An efficient and convenient iron-catalyzed protocol has been developed for the synthesis of substituted pyrrolo[1,2-a]quinoxalines from 1-(N-arylpyrrol-2 yl)ethanone O-acetyl oximes through N-O bond cleavage and intramolecular directed C-H arylation reactions in acetic acid. PMID- 26057738 TI - Prophylactic Effect of Lamivudine for Chemotherapy-Induced Hepatitis B Reactivation in Breast Cancer: A Meta-Analysis. AB - BACKGROUND: Three strategies using lamivudine have been proposed to prevent chemotherapy-induced HBV (hepatitis B virus) reactivation in the clinical setting. The purpose of this meta-analysis is to evaluate the efficacy of the early preemptive strategy, deferred preemptive strategy and therapeutic strategy in patients with HBsAg-positive breast cancer during chemotherapy. METHODS: Clinical studies published from database inception until Nov 1, 2014, were included for analysis. The primary outcomes were overall survival, rate of chemotherapy disruption and virological and clinical reactivation. The secondary outcomes were the rates of HBV-related chemotherapy disruption, HBV-related mortality, YMDD mutations and withdrawal hepatitis. RESULTS: Four hundred and thirty patients in four studies that compared the early preemptive strategy with a therapeutic strategy were included. Application of early preemptive lamivudine was superior in reducing HBV recurrence (pooled OR: 0.12, 95% CI, 0.04 to 0.31, P< 0.0001), the incidence of HBV-related hepatitis (pooled OR: 0.13, 95% CI, 0.04 to 0.37, P< 0.0001) and the rate of chemotherapy disruption (pooled OR: 0.37, 95% CI, 0.23 to 0.60, P< 0.0001). In these two groups, no significant difference was found in overall mortality (P = 0.32), YMDD mutant rate (P = 0.13) or incidence of withdrawal hepatitis (P = 0.38). Of the two studies that compared the efficacy of an early and a deferred preemptive strategy, one showed that an early preemptive strategy significantly reduced the incidence of hepatitis (P = 0.046), whereas the other showed no significant difference (P = 0.7). CONCLUSIONS: An early preemptive strategy is superior to a therapeutic strategy in decreasing the incidence of HBV reactivation, incidence of HBV-related hepatitis and rate of chemotherapy disruption in patients with breast cancer. A deferred preemptive strategy might be an alternative approach to controlling viral replication. PMID- 26057739 TI - Effects of Climate Change and Fisheries Bycatch on Shy Albatross (Thalassarche cauta) in Southern Australia. AB - The impacts of climate change on marine species are often compounded by other stressors that make direct attribution and prediction difficult. Shy albatrosses (Thalassarche cauta) breeding on Albatross Island, Tasmania, show an unusually restricted foraging range, allowing easier discrimination between the influence of non-climate stressors (fisheries bycatch) and environmental variation. Local environmental conditions (rainfall, air temperature, and sea-surface height, an indicator of upwelling) during the vulnerable chick-rearing stage, have been correlated with breeding success of shy albatrosses. We use an age-, stage- and sex-structured population model to explore potential relationships between local environmental factors and albatross breeding success while accounting for fisheries bycatch by trawl and longline fisheries. The model uses time-series of observed breeding population counts, breeding success, adult and juvenile survival rates and a bycatch mortality observation for trawl fishing to estimate fisheries catchability, environmental influence, natural mortality rate, density dependence, and productivity. Observed at-sea distributions for adult and juvenile birds were coupled with reported fishing effort to estimate vulnerability to incidental bycatch. The inclusion of rainfall, temperature and sea-surface height as explanatory variables for annual chick mortality rate was statistically significant. Global climate models predict little change in future local average rainfall, however, increases are forecast in both temperatures and upwelling, which are predicted to have detrimental and beneficial effects, respectively, on breeding success. The model shows that mitigation of at least 50% of present bycatch is required to offset losses due to future temperature changes, even if upwelling increases substantially. Our results highlight the benefits of using an integrated modeling approach, which uses available demographic as well as environmental data within a single estimation framework, to provide future predictions. Such predictions inform the development of management options in the face of climate change. PMID- 26057740 TI - A Socio-Demographic Examination of Adults Responding to Governmental Vaccination Recommendations during the Japanese Rubella Outbreak of 2013. AB - BACKGROUND: In 2013 a rubella outbreak occurred among Japanese people of working age which resulted in 14,357 reported cases. The Japanese government subsequently recommended voluntary vaccination or rubella antibody testing for young women (15 49 years of age) who were planning to conceive and for adult men, children, and other persons in potential contact with pregnant women at home. However, the expense and time involved for vaccination, antibody testing and visiting a clinic may represent a major barrier to voluntary compliance among this busy demographic. The aim of the current study was, therefore, to examine potential relationships between the social background of Japanese working-age individuals affected by the 2013 voluntary vaccination campaign. METHODS: A web-based survey of 1,889 Japanese men and women aged 20-49 years was conducted in early 2014. Statistical analyses were used to explore the associations between social background and testing for rubella antibody and / or vaccination uptake during the previous year. RESULTS: Twenty-four percent of respondents who were planning a pregnancy had been tested for rubella antibody or vaccinated in 2013. However, among those without a current desire for pregnancy, 3% of men and 7% of women, respectively, were tested or vaccinated. Regardless of whether they were planning to conceive, testing for rubella antibodies or vaccination was statistically associated with having acquaintances who had been vaccinated, understanding the government recommendations, and being able to confirm their lack of rubella vaccination history using Maternal and Child Health Handbook records in both men and women. CONCLUSION: To help eliminate rubella in Japan, additional initiatives need to target Japanese individuals who cannot envisage a direct benefit from vaccination. The results of this study suggest that disseminating the government recommendation to all potentially affected subpopulations, along with maintaining life-time vaccination records might offer a solution to encourage vaccination uptake among working-age adults in Japan, as elsewhere. PMID- 26057741 TI - Autogenous Metallic Pipe Leak Repair in Potable Water Systems. AB - Copper and iron pipes have a remarkable capability for autogenous repair (self repair) of leaks in potable water systems. Field studies revealed exemplars that metallic pipe leaks caused by nails, rocks, and erosion corrosion autogenously repaired, as confirmed in the laboratory experiments. This work demonstrated that 100% (N = 26) of 150 MUm leaks contacting representative bulk potable water in copper pipes sealed autogenously via formation of corrosion precipitates at 20-40 psi, pH 3.0-11.0, and with upward and downward leak orientations. Similar leaks in carbon steel pipes at 20 psi self-repaired at pH 5.5 and 8.5, but two leaks did not self-repair permanently at pH 11.0 suggesting that water chemistry may control the durability of materials that seal the leaks and therefore the permanence of repair. Larger 400 MUm holes in copper pipes had much lower (0-33%) success of self-repair at pH 3.0-11.0, whereas all 400 MUm holes in carbon steel pipes at 20 psi self-repaired at pH 4.0-11.0. Pressure tests indicated that some of the repairs created at 20-40 psi ambient pressure could withstand more than 100 psi without failure. Autogenous repair has implications for understanding patterns of pipe failures, extending the lifetime of decaying infrastructure, and developing new plumbing materials. PMID- 26057742 TI - A Mutant Library Approach to Identify Improved Meningococcal Factor H Binding Protein Vaccine Antigens. AB - Factor H binding protein (FHbp) is a virulence factor used by meningococci to evade the host complement system. FHbp elicits bactericidal antibodies in humans and is part of two recently licensed vaccines. Using human complement Factor H (FH) transgenic mice, we previously showed that binding of FH decreased the protective antibody responses to FHbp vaccination. Therefore, in the present study we devised a library-based method to identify mutant FHbp antigens with very low binding of FH. Using an FHbp sequence variant in one of the two licensed vaccines, we displayed an error-prone PCR mutant FHbp library on the surface of Escherichia coli. We used fluorescence-activated cell sorting to isolate FHbp mutants with very low binding of human FH and preserved binding of control anti FHbp monoclonal antibodies. We sequenced the gene encoding FHbp from selected clones and introduced the mutations into a soluble FHbp construct. Using this approach, we identified several new mutant FHbp vaccine antigens that had very low binding of FH as measured by ELISA and surface plasmon resonance. The new mutant FHbp antigens elicited protective antibody responses in human FH transgenic mice that were up to 20-fold higher than those elicited by the wild type FHbp antigen. This approach offers the potential to discover mutant antigens that might not be predictable even with protein structural information and potentially can be applied to other microbial vaccine antigens that bind host proteins. PMID- 26057743 TI - Glycerol Monolaurate Microbicide Protection against Repeat High-Dose SIV Vaginal Challenge. AB - Measures to prevent sexual mucosal transmission are critically needed, particularly to prevent transmission to young women at high risk in the microepidemics in South Africa that disproportionally contribute to the continued pandemic. To that end, microbicides containing anti-retroviral (ARV) agents have been shown to prevent transmission, but with efficacy limited both by adherence and pre-existing innate immune and inflammatory conditions in the female reproductive tract (FRT). Glycerol monolaurate (GML) has been proposed as a microbicide component to enhance efficacy by blocking these transmission facilitating innate immune response to vaginal exposure. We show here in an especially rigorous test of protection in the SIV-rhesus macaque model of HIV-1 transmission to women, that GML used daily and before vaginal challenge protects against repeat high doses of SIV by criteria that include virological and immunological assays to detect occult infection. We also provide evidence for indirect mechanisms of action in GML-mediated protection. Developing a sustained formulation for GML delivery could contribute an independent, complementary protective component to an ARV-containing microbicide. PMID- 26057744 TI - Detection of miR-33 Expression and the Verification of Its Target Genes in the Fatty Liver of Geese. AB - BACKGROUND: miRNAs are single-stranded, small RNA molecules with a length of 18 25 nucleotides. They bind to the 3' untranslated regions of mRNA transcripts to reduce the translation of these transcripts or to cause their degradation. The roles of these molecules differ in biological processes, such as cell differentiation, proliferation, apoptosis and tumor genesis. miRNA-33 is encoded by the gene introns of proteins that bind sterol-regulatory elements. This molecule cooperates with these proteins to control cholesterol homeostasis, fatty acid levels and the genes that are related to the expression of fat metabolism. The examination of miR-33 expression and its target genes can promote the in depth study of the miRNA regulation mechanism in the formation process of goose fatty liver and can lay a foundation for research into human fatty liver. METHODOLOGY/PRINCIPAL FINDINGS: (1) Through real-time fluorescent quantitative polymerase chain reaction (TaqMan MicroRNA Assay), we detected the expression of miR-33 during the feeding of Landes geese. The expression level of miR-33 increases significantly in the liver after 19 days in comparison with the control group; (2) By using the bioinformatics software programs TargetScan, miRDB and miRCosm to predict the target genes of miR-33 according to laboratory prophase transcriptome results and references, we screen nine target genes: adenosine triphosphate binding cassette transporters A1, adenosine triphosphate binding cassette transporters G1, Neimann Pick C, carnitine O-octanoyltransferase (CROT), cyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), AMP-activated protein kinase, alpha subunit 1 (AMPKalpha1), insulin receptor substrate 2, glutamic pyruvate transaminase and adipose differentiation related protein. The dual luciferase reporter gene system in the CHO cell line verifies that CROT, HADHB and NPC1 are the target genes of miR-33 in geese. The inhibition rate of CROT is highest and reaches 70%; (3) The seed sequence (5' 2-8 bases) is the acting site of miR-33. The two predicted target sites of CROT are the target sites of miR-33. Moreover, the predicted target site of HADHB and NPC1 is the target site of miR-33. CONCLUSIONS/SIGNIFICANCE: (1) After 19 days of overfeeding, the expression level of miR-33 increases significantly in the livers of geese; (2) CROT, HADHB and NPC1 are the target genes of miR-33 in geese. These genes determine the combined target site. PMID- 26057745 TI - The Effect of Growth Hormone Administration on the Regulation of Mitochondrial Apoptosis in-Vivo. AB - The purpose of this study was to determine whether recombinant human growth hormone (rhGH) would show any significant effects on the expression of apoptosis regulating proteins in peripheral blood mononuclear cells (PBMCs). Additionally, the potential for post-transcriptional regulation of gene expression by miRNA was assessed in two cellular compartments, the cytosol and the mitochondria. Ten male subjects were subcutaneously injected with either rhGH (1 mg) or saline (0.9%) for seven consecutive days in a double-blinded fashion. Blood sampling was undertaken prior to treatment administration and over a period of three weeks following treatment cessation. Bcl-2 and Bak gene and protein expression levels were measured in PBMCs, while attention was also directed to the expression of miR-181a and miR-125b, known translational inhibitors of Bcl-2 and Bak respectively. Results showed that rhGH significantly decreased Bak protein concentrations compared to placebo samples for up to 8 days post treatment. While cytosolic miRNA expression was not found to be significantly affected by rhGH, measurement of the expression of miR-125b in mitochondrial fractions showed a significant down-regulation eight days post-rhGH administration. These findings suggest that rhGH induces short-term anti-apoptotic effects which may be partially mediated through a novel pathway that alters the concentration of mitochondrially-associated miRNAs. PMID- 26057746 TI - Families of microRNAs Expressed in Clusters Regulate Cell Signaling in Cervical Cancer. AB - Tumor cells have developed advantages to acquire hallmarks of cancer like apoptosis resistance, increased proliferation, migration, and invasion through cell signaling pathway misregulation. The sequential activation of genes in a pathway is regulated by miRNAs. Loss or gain of miRNA expression could activate or repress a particular cell axis. It is well known that aberrant miRNA expression is well recognized as an important step in the development of cancer. Individual miRNA expression is reported without considering that miRNAs are grouped in clusters and may have similar functions, such as the case of clusters with anti-oncomiRs (23b~27b~24-1, miR-29a~29b-1, miR-29b-2~29c, miR-99a~125b-2, miR-99b~125a, miR-100~125b-1, miR-199a-2~214, and miR-302s) or oncomiRs activity (miR-1-1~133a-2, miR-1-2~133a-1, miR-133b~206, miR-17~92, miR-106a~363, miR183~96~182, miR-181a-1~181b-1, and miR-181a-2~181b-2), which regulated mitogen activated protein kinases (MAPK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), NOTCH, proteasome-culling rings, and apoptosis cell signaling. In this work we point out the pathways regulated by families of miRNAs grouped in 20 clusters involved in cervical cancer. Reviewing how miRNA families expressed in cluster-regulated cell path signaling will increase the knowledge of cervical cancer progression, providing important information for therapeutic, diagnostic, and prognostic methodology design. PMID- 26057747 TI - Cultivation, Genetic, Ethnopharmacology, Phytochemistry and Pharmacology of Moringa oleifera Leaves: An Overview. AB - Moringa oleifera is an interesting plant for its use in bioactive compounds. In this manuscript, we review studies concerning the cultivation and production of moringa along with genetic diversity among different accessions and populations. Different methods of propagation, establishment and cultivation are discussed. Moringa oleifera shows diversity in many characters and extensive morphological variability, which may provide a resource for its improvement. Great genetic variability is present in the natural and cultivated accessions, but no collection of cultivated and wild accessions currently exists. A germplasm bank encompassing the genetic variability present in Moringa is needed to perform breeding programmes and develop elite varieties adapted to local conditions. Alimentary and medicinal uses of moringa are reviewed, alongside the production of biodiesel. Finally, being that the leaves are the most used part of the plant, their contents in terms of bioactive compounds and their pharmacological properties are discussed. Many studies conducted on cell lines and animals seem concordant in their support for these properties. However, there are still too few studies on humans to recommend Moringa leaves as medication in the prevention or treatment of diseases. Therefore, further studies on humans are recommended. PMID- 26057748 TI - Virulence Factors of Erwinia amylovora: A Review. AB - Erwinia amylovora, a Gram negative bacteria of the Enterobacteriaceae family, is the causal agent of fire blight, a devastating plant disease affecting a wide range of host species within Rosaceae and a major global threat to commercial apple and pear production. Among the limited number of control options currently available, prophylactic application of antibiotics during the bloom period appears the most effective. Pathogen cells enter plants through the nectarthodes of flowers and other natural openings, such as wounds, and are capable of rapid movement within plants and the establishment of systemic infections. Many virulence determinants of E. amylovora have been characterized, including the Type III secretion system (T3SS), the exopolysaccharide (EPS) amylovoran, biofilm formation, and motility. To successfully establish an infection, E. amylovora uses a complex regulatory network to sense the relevant environmental signals and coordinate the expression of early and late stage virulence factors involving two component signal transduction systems, bis-(3'-5')-cyclic di-GMP (c-di-GMP) and quorum sensing. The LPS biosynthetic gene cluster is one of the relatively few genetic differences observed between Rubus- and Spiraeoideae-infecting genotypes of E. amylovora. Other differential factors, such as the presence and composition of an integrative conjugative element associated with the Hrp T3SS (hrp genes encoding the T3SS apparatus), have been recently described. In the present review, we present the recent findings on virulence factors research, focusing on their role in bacterial pathogenesis and indicating other virulence factors that deserve future research to characterize them. PMID- 26057749 TI - De Novo Characterization of Flower Bud Transcriptomes and the Development of EST SSR Markers for the Endangered Tree Tapiscia sinensis. AB - Tapiscia sinensis Oliv (Tapisciaceae) is an endangered species native to China famous for its androdioecious breeding system. However, there is a lack of genomic and transcriptome data on this species. In this study, the Tapiscia sinensis transcriptomes from two types of sex flower buds were sequenced. A total of 97,431,176 clean reads were assembled into 52,169 unigenes with an average length of 1116 bp. Through similarity comparison with known protein databases, 36,662 unigenes (70.27%) were annotated. A total of 10,002 (19.17%) unigenes were assigned to 124 pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. Additionally, 10,371 simple sequence repeats (SSRs) were identified in 8608 unigenes, with 16,317 pairs of primers designed for applications. 150 pairs of primers were chosen for further validation, and the 68 pairs (45.5%) were able to produce clear polymorphic bands. Six polymorphic SSR markers were used to Bayesian clustering analysis of 51 T. sinensis individuals. This is the first report to provide transcriptome information and to develop large-scale SSR molecular markers for T. sinensis. This study provides a valuable resource for conservation genetics and functional genomics research on T. sinensis for future work. PMID- 26057750 TI - Fatty Acids Composition of Vegetable Oils and Its Contribution to Dietary Energy Intake and Dependence of Cardiovascular Mortality on Dietary Intake of Fatty Acids. AB - Characterizations of fatty acids composition in % of total methylester of fatty acids (FAMEs) of fourteen vegetable oils--safflower, grape, silybum marianum, hemp, sunflower, wheat germ, pumpkin seed, sesame, rice bran, almond, rapeseed, peanut, olive, and coconut oil--were obtained by using gas chromatography (GC). Saturated (SFA), monounsaturated (MUFA) and polyunsaturated fatty acids (PUFA), palmitic acid (C16:0; 4.6%-20.0%), oleic acid (C18:1; 6.2%-71.1%) and linoleic acid (C18:2; 1.6%-79%), respectively, were found predominant. The nutritional aspect of analyzed oils was evaluated by determination of the energy contribution of SFAs (19.4%-695.7% E(RDI)), PUFAs (10.6%-786.8% E(RDI)), n-3 FAs (4.4%-117.1% E(RDI)) and n-6 FAs (1.8%-959.2% E(RDI)), expressed in % E(RDI) of 1 g oil to energy recommended dietary intakes (E(RDI)) for total fat (E(RDI)--37.7 kJ/g). The significant relationship between the reported data of total fat, SFAs, MUFAs and PUFAs intakes (% E(RDI)) for adults and mortality caused by coronary heart diseases (CHD) and cardiovascular diseases (CVD) in twelve countries has not been confirmed by Spearman's correlations. PMID- 26057751 TI - HIF-1alpha Promotes Epithelial-Mesenchymal Transition and Metastasis through Direct Regulation of ZEB1 in Colorectal Cancer. AB - It is well recognized that hypoxia-inducible factor 1 alpha (HIF-1alpha) is involved in cancer metastasis, chemotherapy and poor prognosis. We previously found that deferoxamine, a hypoxia-mimetic agent, induces epithelial-mesenchymal transition (EMT) in colorectal cancer. Therefore, here we explored a new molecular mechanism for HIF-1alpha contributing to EMT and cancer metastasis through binding to ZEB1. In this study, we showed that overexpression of HIF 1alpha with adenovirus infection promoted EMT, cell invasion and migration in vitro and in vivo. On a molecular level, HIF-1alpha directly binding to the proximal promoter of ZEB1 via hypoxia response element (HRE) sites thus increasing the transactivity and expression of ZEB1. In addition, inhibition of ZEB1 was able to abrogate the HIF-1alpha-induced EMT and cell invasion. HIF 1alpha expression was highly correlated with the expression of ZEB1 in normal colorectal epithelium, primary and metastatic CRC tissues. Interestingly, both HIF-1alpha and ZEB1 were positively associated with Vimentin, an important mesenchymal marker of EMT, whereas negatively associated with E-cadherin expression. These findings suggest that HIF-1alpha enhances EMT and cancer metastasis by binding to ZEB1 promoter in CRC. HIF-1alpha and ZEB1 are both widely considered as tumor-initiating factors, but our results demonstrate that ZEB1 is a direct downstream of HIF-1alpha, suggesting a novel molecular mechanism for HIF-1alpha-inducing EMT and cancer metastasis. PMID- 26057753 TI - Individualizing the intravitreal anti-VEGF dosing regimen for long-term management of neovascular AMD. PMID- 26057752 TI - Cystatin C Is Not Causally Related to Coronary Artery Disease. AB - BACKGROUND: Strong and independent associations between plasma concentration of cystatin C and risk of cardiovascular disease (CVD) suggests causal involvement of cystatin C. AIM: The aim of our study was to assess whether there is a causal relationship between plasma concentration of cystatin C and risk of coronary artery disease (CAD) using a Mendelian Randomization approach. METHODS: We estimated the strength of association of plasma cystatin C on CAD risk and the strength of association of the strongest GWAS derived cystatin C SNP (rs13038305) on plasma cystatin C in the population-based Malmo Diet and Cancer Study (MDC) and thereafter the association between rs13038305 and CAD in the MDC (3200 cases of CAD and 24418 controls) and CARDIOGRAM (22233 cases of CAD and 64762 controls). RESULTS: Each standard deviation (SD) increment of plasma cystatin C was associated with increased risk of CAD (OR = 1.20, 95% CI 1.07-1.34) after full adjustment. Each copy of the major allele of rs13038305 was associated with 0.34 SD higher plasma concentration of cystatin C (P<1 x 10-35), resulting in a power of >98% to detect a significant relationship between rs13038305 and CAD in MDC and CARDIOGRAM pooled. The odds ratio for CAD (per copy of the major rs13038305 allele) was 1.00 (0.94-1.07); P = 0.92 in MDC, 0.99 (0.96-1.03); P = 0.84 in CARDIOGRAM and 1.00 (0.97-1.03); P = 0.83 in MDC and CARDIOGRAM pooled. CONCLUSION: Genetic elevation of plasma cystatin C is not related to altered risk of CAD, suggesting that there is no causal relationship between plasma cystatin C and CAD. Rather, the association between cystatin C and CAD appears to be due to the association of eGFR and CAD. PMID- 26057754 TI - Association Between Subfoveal Choroidal Thickness, Reticular Pseudodrusen, and Geographic Atrophy in Age-Related Macular Degeneration. AB - BACKGROUND AND OBJECTIVE: To compare subfoveal choroidal thickness (CT) measurements in eyes with nonexudative age-related macular degeneration (AMD) in the presence or absence of reticular pseudodrusen (RPD). PATIENTS AND METHODS: Subfoveal CT measurements obtained from patients with AMD enrolled in the COMPLETE study (30 drusen-only eyes and 30 eyes with geographic atrophy [GA]) were compared with an age-distributed normal control group. Multimodal images were evaluated to detect the presence of RPD. RESULTS: After controlling for age and axial length, the mean CT was significantly thinner in the GA group with RPD (213.7 +/- 53.1 um) than in the GA group without RPD (335.3 +/- 123.2 um; P = .001). The mean CT in the GA group without RPD was not statistically different from the mean CT in the normal control group (P = .076) or the drusen group without RPD (P = .45). In eyes without RPD, there was a correlation between the increasing size of GA and a decrease in CT measurements. CONCLUSION: Subfoveal choroidal thinning in eyes with nonexudative AMD was associated with the presence of RPD. In the absence of RPD, CT only decreased as the size of GA increased. PMID- 26057755 TI - Relationship Between Subretinal Hyperreflective Material Reflectivity and Volume in Patients With Neovascular Age-Related Macular Degeneration Following Anti Vascular Endothelial Growth Factor Treatment. AB - BACKGROUND AND OBJECTIVE: To assess the relationship between subretinal hyperreflective material (SRHM) reflectivity and volume in patients treated with anti-vascular endothelial growth factor (VEGF) therapy for choroidal neovascularization secondary to exudative age-related macular degeneration (AMD). PATIENTS AND METHODS: Data from 17 eyes of 16 patients with neovascular AMD undergoing anti-VEGF therapy were collected retrospectively. Optical coherence tomography (OCT) data were obtained using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) 512 * 128 macular cube protocol. Detailed manual segmentation was performed for each case using customized grading software. RESULTS: The mean macular volume declined from 10.4 mm(3) at baseline to 9.6 mm(3) at 12 months. SRHM volume declined from 0.33 mm(3) to 0.12 mm(3), whereas reflectivity increased from 0.48 to 0.64 units (P = .012). SRHM reflectivity correlated positively with logarithm of the minimum angle of resolution (logMAR) acuity (r = .49, P = .04) but correlated with SRHM volume (r = -0.50, P = .04) only at baseline. CONCLUSION: SRHM reflectivity, which correlated partially with SRHM volume, appears to carry independent information regarding disease activity. SRHM reflectivity may be useful for monitoring disease activity and response to therapy. PMID- 26057756 TI - Combined Nonmydriatic Spectral-Domain Optical Coherence Tomography and Nonmydriatic Fundus Photography for the Detection of Age-Related Macular Degeneration Changes. AB - BACKGROUND AND OBJECTIVE: Nonmydriatic fundus photography (FP) has been a suboptimal tool for detecting age-related macular degeneration (AMD) changes. This study sought to enhance the detection of AMD changes by combining nonmydriatic FP with nonmydriatic spectral-domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS: The study population included 249 patients aged 65 years and older who were assessed for AMD changes using standard mydriatic biomicroscopic fundus examination. Each eye then underwent nonmydriatic FP in one session followed 1 week later with nonmydriatic FP coupled with nonmydriatic SD OCT. Images were interpreted for detection of AMD changes, and findings were compared to the original mydriatic biomicroscopic examination. RESULTS: Nonmydriatic FP had 64% sensitivity, 97% specificity, and a kappa value of 0.67 in detecting AMD changes compared with the traditional mydriatic biomicroscopic examination. Combined nonmydriatic FP and nonmydriatic SD-OCT increased sensitivity to 91.5%, specificity to 98.6%, and kappa to 0.91. CONCLUSION: The addition of nonmydriatic SD-OCT to nonmydriatic FP enhances the detection of AMD changes. PMID- 26057757 TI - Experience With Aflibercept for the Treatment of Neovascular Age-Related Macular Degeneration. AB - BACKGROUND AND OBJECTIVE: Describe visual and anatomic outcomes of eyes with exudative age- related macular degeneration (AMD) after treatment with aflibercept. PATIENTS AND METHODS: Eyes treated with intravitreal injections of aflibercept for exudative AMD were retrospectively reviewed to compare visual acuity and central subfield thickness (CST) on optical coherence tomography. RESULTS: A total of 142 eyes receiving aflibercept were previously treated with bevacizumab or ranibizumab intravitreal injections. Baseline vision was 20/73 +/- 5.18 lines when switched to aflibercept. It improved by 0.2 +/- 1.91 lines (P =.14) after three injections but decreased by 0.45 +/- 2.9 lines (P = .06) after 1 year of follow-up. The reduction in CST was 9.9 +/- 46.5 um (P = .06) after three injections and grew to 19.3 +/- 50.6 um (P = .002), a statistically significant amount, after 1 year. CONCLUSION: Switching to aflibercept resulted in no clinically significant differences in visual acuity after 1 year. There was a significant reduction in CST, but this may not be clinically significant. PMID- 26057758 TI - Widefield En Face Optical Coherence Tomography Imaging of Subretinal Drusenoid Deposits. AB - BACKGROUND AND OBJECTIVE: To determine whether subretinal drusenoid deposits (SDD) can be detected on widefield en face slab images derived from spectral domain (SD) and swept-source (SS) optical coherence tomography (OCT) volume scans. PATIENTS AND METHODS: Retrospective study of patients with dry age-related macular degeneration (AMD) enrolled prospectively in an OCT imaging study using SD-OCT (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) with a central wavelength of 840 nm, and a prototype 100-kHz SS-OCT instrument (Carl Zeiss Meditec) with a central wavelength of 1,050 nm. Seven en face slabs were evaluated with thicknesses from 20 to 55 um and positioned at distances up to 55 um above the retinal pigment epithelium (RPE). A montage of 6 * 6 mm SD-OCT en face images of the posterior pole from each patient was compared with a 9 * 12 mm SS-OCT single en face slab image and with color, autofluorescence, and infrared reflectance images. RESULTS: A total of 160 patients (256 eyes) underwent scanning with both OCT instruments; 57 patients (95 eyes) also underwent multimodal fundus imaging. Of 95 eyes, 32 (34%) were diagnosed with reticular pseudodrusen (RPD) using multimodal imaging. All eyes with RPD demonstrated a pattern of SDD on widefield en face OCT similar to that observed for RPD. The en face slab image that consistently identified SDD was the 20-um thick slab with boundaries from 35 to 55 um above the RPE. CONCLUSION: Widefield en face slab imaging with SD-OCT and SS-OCT can detect SDD and could replace multimodal imaging for the diagnosis of RPD in the future. PMID- 26057759 TI - En Face Optical Coherence Tomography for Visualization of the Choroid. AB - BACKGROUND AND OBJECTIVE: To assess posterior pole choroid patterns in healthy eyes using en face optical coherence tomography (OCT). PATIENTS AND METHODS: This observational study included 154 healthy eyes of 77 patients who underwent en face OCT. The mean age of the patients was 31.2 years (standard deviation: 13 years); 40 patients were women, and 37 patients were men. En face imaging of the choroidal vasculature was assessed using an OCT Optovue RTVue (Optovue, Fremont, CA). To generate an appropriate choroid image, the best detectable vessels in Haller's layer below the retinal pigment epithelium surface parallel plane were selected. RESULTS: Images of diverse choroidal vessel patterns at the posterior pole were observed and recorded with en face OCT. Five different patterns of Haller's layer with different occurrences were assessed. Pattern 1 (temporal herringbone) represented 49.2%, pattern 2 (branched from below) and pattern 3 (laterally diagonal) represented 14.2%, pattern 4 (doubled arcuate) was observed in 11.9%, and pattern 5 (reticular feature) was observed in 10.5% of the reference plane. CONCLUSION: In vivo assessment of human choroid microvasculature in healthy eyes using en face OCT demonstrated five different patterns. The choroid vasculature pattern may play a role in the origin and development of neuroretinal pathologies, with potential importance in chorioretinal diseases and circulatory abnormalities. PMID- 26057760 TI - Contemporary Management of Rhegmatogenous Retinal Detachment Due to Giant Retinal Tears: A Consecutive Case Series. AB - BACKGROUND AND OBJECTIVE: To investigate outcomes of contemporary surgical techniques for repair of rhegmatogenous retinal detachments (RRD) associated with giant retinal tears (GRT). PATIENTS AND METHODS: Retrospective, consecutive case series including 58 eyes of 58 patients. Mean age was 52 years (range: 16 to 83 years). All patients underwent 23-gauge pars plana vitrectomy with use of perfluorocarbon liquid and intravitreal tamponade (28 with silicone oil, 25 with octafluoropropane gas, and five with sulfur hexafluoride gas). Scleral buckle (SB) was placed in 30 eyes (52%). RESULTS: At a mean follow-up of 17 months, mean visual acuity improved from 20/500 preoperatively to 20/88 at final follow-up. Fifty-one patients (88%) had single-surgery anatomic success, and all patients achieved final retinal reattachment. Use of SB (P = 1.0), silicone oil (P = .1), or 360 degrees endophotocoagulation (P = .7) did not correlate with higher rates of successful repair. CONCLUSION: Contemporary vitreoretinal surgery techniques achieve high rates of primary anatomic success in GRT-related RRDs. PMID- 26057762 TI - Unassisted Scleral Depression During Vitrectomy Surgery: Two Simple, Cost Effective Techniques. AB - BACKGROUND AND OBJECTIVE: The ability to visualize and work in the region of the vitreous base during vitrectomy surgery is important. However, this usually requires the use of a surgical assistant for scleral depression or expensive chandelier systems requiring extra incisions. The authors describe two alternative simple, cost-effective techniques to independently and simultaneously view and cut (or apply laser) in this difficult anatomical region. TECHNIQUE: Light-pipe assisted scleral depression using a standard light pipe and ring depressor indentation while maintaining two intraocular instruments are described. CONCLUSION: The described techniques are simple, cost-effective, safe, suitable for phakic and pseudo-phakic patients, and allow the surgeon to operate independently with maximum control. PMID- 26057761 TI - Clinical Course of Vitreomacular Traction Managed Initially by Observation. AB - BACKGROUND AND OBJECTIVE: To investigate the clinical course and outcomes of patients with vitreomacular traction (VMT) managed initially by observation. PATIENTS AND METHODS: This noncomparative case series included patients with a diagnosis of VMT based on clinical symptoms and findings on spectral-domain optical coherence tomography (SD-OCT) between 2005 and 2014. VMT was documented using a standardized grading system based on the degree of distortion of the foveal contour. Data were collected at five retina clinics using standardized collection forms. Visual acuity, changes in SD-OCT findings, and timing of the release of VMT as seen on SD-OCT were recorded. RESULTS: The study included 230 eyes of 185 patients. Mean age was 72.5 years, and mean follow-up was 32 months. At baseline, VMT grading was grade 1 in 92 eyes (40%), grade 2 in 118 eyes (51.3%), and grade 3 in 20 eyes (8.7%). By last follow-up, spontaneous release of VMT occurred in 73 eyes (31.7%). Spontaneous release of VMT occurred at a mean of 18 months (median: 10.9 months) after initial visit. Mean logMAR best corrected visual acuity (BCVA) was 0.28 (20/55) (range: 20/20 to 20/400) at baseline and 0.25 (20/51) (range: 20/20 to 20/400) at last follow-up. Pars plana vitrectomy was performed in 10 eyes (4.1%) for macular hole (six eyes) and increased VMT (four eyes); BCVA was at least 20/40 in eight of the 10 eyes at last follow-up. CONCLUSION: Patients with VMT generally had a favorable clinical course when managed initially by observation. Spontaneous release of VMT occurred in approximately one-third of patients. At last follow-up, pars plana vitrectomy was performed in fewer than 5% of patients. PMID- 26057763 TI - OCT Angiography of Paracentral Acute Middle Maculopathy Associated With Central Retinal Artery Occlusion and Deep Capillary Ischemia. AB - An 82-year-old man presented with acute, painless vision loss in the left eye associated with headaches, jaw claudication, and scalp tenderness. Clinical examination and fluorescein angiography confirmed the diagnosis of a central retinal artery occlusion of the left eye. Spectral-domain optical coherence tomography (OCT) of the left eye showed paracentral acute middle maculopathy (PAMM), and OCT angiography showed severe attenuation of the deep capillary plexus. This is the first case report of OCT angiography of PAMM associated with central retinal artery occlusion confirming the presence of ischemia of the deep retinal capillary plexus. PMID- 26057764 TI - Confirmation of Choroidal Varix Through Divot Sign on Spectral-Domain Optical Coherence Tomography. AB - Enhanced depth imaging spectral-domain optical coherence tomography (EDI SD-OCT) provides a rapid and easily accessible measure to evaluate suspicious choroidal lesions. A 60-year-old woman was referred for evaluation of an inferotemporal slightly pigmented lesion that showed a large hyporeflective elevation in the deep choroid on EDI SD-OCT. After applying pressure to the globe, repeat EDI SD OCT showed flattening of the lesion with a prominent depression or "divot" within the choroid of the center of the lesion. If noted on imaging, this divot sign is an additional reproducible diagnostic finding that can correctly identify a suspicious choroidal lesion as a benign choroidal varix. PMID- 26057765 TI - Spectral-Domain Optical Coherence Tomography of Presumed Solitary Circumscribed Retinal Astrocytic Proliferation Versus Astrocytic Hamartoma. AB - The retinal tumor provisionally referred to as presumed solitary circumscribed retinal astrocytic proliferation (PSCRAP) is a rare, benign lesion of unknown pathogenesis and histopathology. The authors present a case of PSCRAP that was analyzed with spectral-domain optical coherence tomography (OCT), which demonstrated a demarcation between the mass and the retinal nerve fiber layer. This finding stands in contrast to previous descriptions using time-domain OCT, suggesting that this tumor may originate from mid-retinal layers rather than the nerve fiber layer. In addition, the OCT of PSCRAP is distinct from that of astrocytic hamartoma associated with tuberous sclerosis complex. PMID- 26057766 TI - Peripheral Avascular Retina in a Term Male Neonate With Microvillus Inclusion Disease and Pancreatic Insufficiency. AB - The authors present the first case of peripheral avascular retina in a term male neonate with pancreatic exocrine insufficiency, atypical microvillus inclusion disease, flat tympanograms, and recurrent urinary tract infections. Clinical examination showed avascular peripheral retina to posterior zone II temporally, with a flat stage 1-like demarcation line, and no plus disease. Genetic testing results were normal. The patient developed peripheral neovascularization and underwent panretinal photocoagulation. This case likely represents mild Norrie disease, familial exudative vitreoretinopathy, or incontinentia pigmenti due to a Wnt signaling abnormality. While these conditions are usually more severe, a variable spectrum of Wnt abnormalities exists throughout the body. PMID- 26057767 TI - Middle Cerebral Artery, Ophthalmic Artery, and Multibranch Retinal Vessel Occlusion After Cosmetic Autologous Fat Transfer to Forehead. AB - A 65-year-old woman with left hemiparesis and sudden loss of visual acuity in her right eye presented a few hours after cosmetic injection of autologous fat to her forehead. Right eye visual acuity was no light perception. Funduscopy revealed widespread retinal whitening and multibranch retinal vessel occlusion. Fluorescein angiography showed markedly delayed choroidal and retinal filling together with occlusion of multiple branches of retinal arteries and veins. On magnetic resonance imaging of the brain, multiple lesions compatible with recent infarction were detected. The authors diagnosed multibranch retinal artery and vein occlusion in the right ophthalmic and middle cerebral arteries due to fat emboli. This case emphasizes the need to reevaluate the safety of such aesthetic procedures, particularly in the facial zone to prevent devastating complications. PMID- 26057768 TI - Digital Audio Recording of Initial Patient Visits to an Ocular Oncology Clinic: A Pilot Study. AB - It is challenging for patients to receive a new diagnosis of a life-threatening ocular tumor when visiting an ocular oncology clinic for the first time. Audio recording of patient-physician interactions has been shown to be an effective memory aid and stress-reducing technique for patients with various types of nonophthalmic cancer. This study evaluated a protocol for digitally recording the initial conversation between the ocular oncologist and the patient. Twenty patients were enrolled in the study, and 13 patients (65%) returned the survey. All of the patients who returned the survey reported being "very satisfied" with the audio recording, indicating that patients with a newly diagnosed ocular tumor were highly satisfied with the audio recording of their conversations with the ocular oncologist. Although larger studies are needed to confirm this conclusion, the initial results are encouraging. PMID- 26057769 TI - Nanoneurotherapeutics approach intended for direct nose to brain delivery. AB - CONTEXT: Brain disorders remain the world's leading cause of disability, and account for more hospitalizations and prolonged care than almost all other diseases combined. The majority of drugs, proteins and peptides do not readily permeate into brain due to the presence of the blood-brain barrier (BBB), thus impeding treatment of these conditions. OBJECTIVE: Attention has turned to developing novel and effective delivery systems to provide good bioavailability in the brain. METHODS: Intranasal administration is a non-invasive method of drug delivery that may bypass the BBB, allowing therapeutic substances direct access to the brain. However, intranasal administration produces quite low drug concentrations in the brain due limited nasal mucosal permeability and the harsh nasal cavity environment. Pre-clinical studies using encapsulation of drugs in nanoparticulate systems improved the nose to brain targeting and bioavailability in brain. However, the toxic effects of nanoparticles on brain function are unknown. RESULT AND CONCLUSION: This review highlights the understanding of several brain diseases and the important pathophysiological mechanisms involved. The review discusses the role of nanotherapeutics in treating brain disorders via nose to brain delivery, the mechanisms of drug absorption across nasal mucosa to the brain, strategies to overcome the blood brain barrier, nanoformulation strategies for enhanced brain targeting via nasal route and neurotoxicity issues of nanoparticles. PMID- 26057770 TI - The effect of tiagabine on physical development and neurological reflexes and their relationship with the gamma-aminobutyric acid switch in the rat cerebral cortex during developmental stages. AB - In the present study, we focused on gamma-aminobutyric acid (GABA) signaling through the gamma-aminobutyric acid transporter (GAT) in the developing rat cerebral cortex. Tiagabine was used as a GAT inhibitor. The offspring received injections from birth until postnatal day 21 intraperitoneally. Physical development and neurological reflexes were assessed daily. Tiagabine did not influence body weight, the onset and completion of incisor eruption, or the time to appearance of cliff avoidance. However, the onset and completion of eye opening, ear unfolding, and fur growth occurred earlier in treated pups. Further, the slanted board test and righting reflex showed accelerated development (i.e. decreased time to criterion) when compared with the control group. To determine whether the obtained effects are related to the GABA switch, we examined the protein and mRNA expression of the K(+)-Cl(-) cotransporter KCC2 using western blotting and RT-PCR, respectively. Downregulation of KCC2 mRNA and protein levels was observed when GAT was inhibited. The results may indicate a role of GAT in the neurobehavioral changes that accompany the developmental switch in GABA function. PMID- 26057771 TI - FK506 attenuates intracerebroventricular streptozotocin-induced neurotoxicity in rats. AB - Upregulation in calcineurin (CaN) signaling has been implicated in various neurodegenerative disorders. In the present study, we have investigated the effect of FK506--a CaN inhibitor--on streptozotocin (STZ)-induced experimental dementia of the Alzheimer's type in rats. STZ was administered intracerebroventricularly to induce a cognitive deficit and oxidative stress. Nonimmunosuppressive doses (0.5 and 1 mg/kg postoperatively) of FK506 (tacrolimus) were administered for 21 day in STZ-treated rats. Cognitive functions were assessed using the Morris water maze and passive avoidance tasks. Malondialdehyde and nitrite glutathione levels, as well as acetylcholinesterase activity, were determined to evaluate oxidative stress and cholinergic functions. Lactate dehydrogenase levels were estimated and histological analysis of the dentate gyrus and the CA1 region of the hippocampus was carried out to identify degenerative changes. STZ produced significant deterioration of cognitive functions, oxidative stress, and degenerative changes in the cortical and hippocampal brain regions. FK506 dose-dependently attenuated STZ-induced cognitive deficits, oxidative stress, and degenerative changes in the cortex and hippocampus. These results suggest a potential role of CaN signaling in degenerative processes, and that inhibition of CaN may be useful in the treatment of neurodegenerative disorders such as Alzheimer's disease. PMID- 26057772 TI - Binding Temporal Context in Memory: Impact of Emotional Arousal as a Function of State Anxiety and State Dissociation. AB - Encoding of stressful experiences plays an important role in the development of posttraumatic stress disorder. A crucial aspect of memory encoding is binding: the "gluing" of the temporal and spatial elements of an episode into a cohesive unit. This study investigated the effect of emotional arousal on temporal binding and examined whether temporal binding varied as a function of state anxiety and/or state dissociation. Participants saw picture sequences that varied in arousal and valence. After each sequence, participants were presented with all the pictures simultaneously and had to sort the pictures in the original order. Temporal context binding was indexed by sorting accuracy. Binding was generally lower for high than low arousing pictures. Reduced binding of arousing material was specifically pronounced in participants with high state anxiety, whereas it seemed independent of state dissociation. These findings point to the relevance of impaired temporal binding as a component of aberrant memory encoding in stressful situations. PMID- 26057773 TI - Are Suicide Attempters Wired Differently?: A Comparison With Nonsuicidal Depressed Individuals Using Plan Analysis. AB - Limited research exists on internal risk processes in suicide attempters and factors that distinguish them from nonsuicidal depressive individuals. In this qualitative study, we investigated Plans, motives, and underlying self-regulatory processes of the two groups and conducted a comparative analysis. We analyzed narrative interviews of 17 suicide attempters and intake interviews of 17 nonsuicidal depressive patients using Plan Analysis. Then, we developed a prototypical Plan structure for both groups. Suicidal behavior serves various Plans found only in suicide attempters. Plans of this group are especially related to social perfectionism and withdrawal to protect their self-esteem. Depressive patients use several interpersonal control and coping strategies, which might help prevent suicidal behavior. The prototypical Plan structure of suicide attempters may be a valuable tool for clinicians to detect critical Plans and motives in their interaction with patients, which are related to suicide risk. PMID- 26057775 TI - Erratum: Omasa M, Date H, Sozu T, Sato T, Nagai K, Yokoi K, Okamoto T, Ikeda N, Tanaka F, and Maniwa Y, and the Japanese Association for Research on the Thymus. Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: The Japanese Association for Research on the Thymus Database Study. Cancer. doi: 10.1002/cncr.29166. PMID- 26057776 TI - Determining appropriate imaging parameters for kilovoltage intrafraction monitoring: an experimental phantom study. AB - Kilovoltage intrafraction monitoring (KIM) utilises the kV imager during treatment for real-time tracking of prostate fiducial markers. However, its effectiveness relies on sufficient image quality for the fiducial tracking task. To guide the performance characterisation of KIM under different clinically relevant conditions, the effect of different kV parameters and patient size on image quality, and quantification of MV scatter from the patient to the kV detector panel were investigated in this study. Image quality was determined for a range of kV acquisition frame rates, kV exposure, MV dose rates and patient sizes. Two methods were used to determine image quality; the ratio of kV signal through the patient to the MV scatter from the patient incident on the kilovoltage detector, and the signal-to-noise ratio (SNR). The effect of patient size and frame rate on MV scatter was evaluated in a homogeneous CIRS pelvis phantom and marker segmentation was determined utilising the Rando phantom with embedded markers. MV scatter incident on the detector was shown to be dependent on patient thickness and frame rate. The segmentation code was shown to be successful for all frame rates above 3 Hz for the Rando phantom corresponding to a kV to MV ratio of 0.16 and an SNR of 1.67. For a maximum patient dimension less than 36.4 cm the conservative kV parameters of 5 Hz at 1 mAs can be used to reduce dose while retaining image quality, where the current baseline kV parameters of 10 Hz at 1 mAs is shown to be adequate for marker segmentation up to a patient dimension of 40 cm. In conclusion, the MV scatter component of image quality noise for KIM has been quantified. For most prostate patients, use of KIM with 10 Hz imaging at 1 mAs is adequate however image quality can be maintained and imaging dose reduced by altering existing acquisition parameters. PMID- 26057774 TI - DNA methylation at IL32 in juvenile idiopathic arthritis. AB - Juvenile idiopathic arthritis (JIA) is the most common autoimmune rheumatic disease of childhood. We recently showed that DNA methylation at the gene encoding the pro-inflammatory cytokine interleukin-32 (IL32) is reduced in JIA CD4+ T cells. To extend this finding, we measured IL32 methylation in CD4+ T cells from an additional sample of JIA cases and age- and sex-matched controls, and found a reduction in methylation associated with JIA consistent with the prior data (combined case-control dataset: 25.0% vs 37.7%, p = 0.0045). Further, JIA was associated with reduced IL32 methylation in CD8+ T cells (15.2% vs 25.5%, p = 0.034), suggesting disease-associated changes to a T cell precursor. Additionally, we measured regional SNPs, along with CD4+ T cell expression of total IL32, and the gamma and beta isoforms. Several SNPs were associated with methylation. Two SNPs were also associated with JIA, and we found evidence of interaction such that methylation was only associated with JIA in minor allele carriers (e.g. rs10431961 p(interaction) = 0.011). Methylation at one measured CpG was inversely correlated with total IL32 expression (Spearman r = -0.73, p = 0.0009), but this was not a JIA-associated CpG. Overall, our data further confirms that reduced IL32 methylation is associated with JIA, and that SNPs play an interactive role. PMID- 26057777 TI - Accuracy of a Digital Impression System Based on Active Triangulation Technology With Blue Light for Implants: Effect of Clinically Relevant Parameters. AB - PURPOSE: To evaluate the accuracy of a digital impression system considering clinical parameters. MATERIALS AND METHODS: A master model with 6 implants (27, 25, 22, 12, 15, and 17) was fitted with polyether ether ketone scan bodies. Implant no. 25 was placed with 30 degrees mesial angulation and no. 15 with 30 degrees distal angulation in relation to the vertical plane (y axis). Implant no. 22 was placed at 2 mm and no. 12 placed 4 mm below the gingiva. Experienced (n = 2) and inexperienced (n = 2) operators performed the scanning (CEREC system). Measurements involved 5 distances (27-25, 27-22, 27-12, 27-15, 27-17). Measurements with coordinated measuring machine of the master model acted as the true values. RESULTS: The experience of the operator affected the accuracy. Operator 3 (inexperienced) performed better than the rest. Angulation and implant depth did not affect the accuracy results. The position of the camera affected the accuracy of the system. The first scanned quadrant had significantly smaller error, -17 +/- 26.3 MUm, than the second quadrant, -116 +/- 103 MUm. CONCLUSIONS: Digital impressions with CEREC Bluecam system can be a feasible alternative for challenging cases where angulation and depth of the implants are present. The accuracy of the CEREC system for the first scanned quadrant is high, and it decreases when completing a full arch. PMID- 26057778 TI - CT Evaluation of Morphology of Transferred Fibula for Implant Placement in Reconstructed Mandible. AB - BACKGROUND: Dental rehabilitation with osseointegrated implants in reconstructed mandibles remains one of the most challenging procedures for oral and maxillofacial surgeons. Satisfactory outcome requires appropriate assessment of graft morphology. There are few analyses of the morphology of fibulae in reconstructed mandibles, although cadaver studies on fibular shape have been performed. MATERIALS AND METHODS: In this study, we used postoperative computed tomography to retrospectively evaluate the shape, height, and orientation of fibulae transferred after mandibulectomy in 19 patients. RESULTS: The average height of transferred fibulae was 14.3 mm (range, 10.8-20.5 mm). The cross sectional morphology of transferred fibulae could be classified into 2 types: apex and nonapex. The former type included knife-edged and triangular shapes; the latter included square and circular shapes. CONCLUSION: When implant insertion is planned in a reconstructed mandible, the orientation of the apex of transferred fibula should be evaluated preoperatively to allow for adjustments in implant procedure because the ridge at the apex of the fibula is narrow. PMID- 26057779 TI - Angulations of Anterior Teeth With Reference to the Alveolar Bone Measured by CBCT in a Chinese Population. AB - OBJECTIVE: To analyze angulations of anterior teeth with reference to the alveolar bone. METHODS: Cone-beam computed tomographic (CBCT) images of 105 participants were taken with the same machine (ProMax 3D Max CBCT), showing the intact anterior teeth. The angulations formed between the long axis of the anterior teeth and the alveolus were measured using cross-sectional images. The thicknesses of alveolar bone on different area of root surfaces were also measured. RESULTS: Maxillary anterior teeth were found to be close to the buccal alveolar surface in apical level with the angulations referred to alveolar bone in center incisor, lateral incisor, and canine were 17.65 +/- 6.8, 18.79 +/- 7.4, and 23.82 +/- 6.96 degrees, respectively. Means of angulations of mandibular anterior teeth were less than 8 degree. The thicknesses of buccal bone at mid root level in 77% to 90% maxillary anterior teeth were less than 1 mm. The determinations provided high intrarater/interrater reliability. CONCLUSIONS: The application of CBCT is reliable for a complete calculation of angulations and thicknesses in a Chinese Han population. As a result, adequate planning combined with image examination preoperatively would contribute to a favorable outcome. PMID- 26057780 TI - Platelet-Rich Plasma and Deproteinized Bovine Bone Matrix in Maxillary Sinus Lift Surgery: A Split-Mouth Histomorphometric Evaluation. AB - PURPOSE: The purpose of this split-mouth controlled study was to evaluate and compare the amount of vital bone after lateral sinus lift surgery using either a mixture of pure platelet concentrate and deproteinized bovine bone mineral (test group) or solely deproteinized bovine bone as grafting material (control group). MATERIALS AND METHODS: Six patients with edentulous posterior maxilla and a residual ridge height of less than 4 mm were recruited in this study. Six months after grafting procedure, 2 bone biopsies per patient were taken bilaterally from the anterolateral sinus wall. Histological and histomorphometrical analysis was carried out. RESULTS: A total of 10 sinus surgeries in 5 patients were analyzed. The mean percentage of vital bone was 22.72% +/- 9.21% (range, 11.45%-33.30%) in the control group and 30.70% +/- 7.89% (range, 18.30%-39.99%) in the test group. CONCLUSION: The adjunct of pure platelet-rich plasma to deproteinized bovine bone mineral may enhance vital bone formation in the first 6 months after sinus floor augmentation. However, no statistically significant difference was found between groups (P = 0.18). PMID- 26057781 TI - Profound bradycardia associated with NIV removal. AB - A patient with lower-limb onset ALS presented with a one-month history of vasovagal episodes and a one-week history of cough productive of green sputum and lethargy. She was drowsy and in acute on chronic type-two respiratory failure. She responded to non-invasive ventilation, however she suffered recurrent episodes of profound bradycardia on removal of the mask, which gradually resolved over ten days. We have reviewed the literature and offer a potential explanation for these events. PMID- 26057782 TI - Impact of Vitamin D Replacement on Markers of Glucose Metabolism and Cardio Metabolic Risk in Women with Former Gestational Diabetes--A Double-Blind, Randomized Controlled Trial. AB - Gestational Diabetes Mellitus (GDM) and vitamin D deficiency are related to insulin resistance and impaired beta cell function, with heightened risk for future development of diabetes. We evaluated the impact of vitamin D supplementation on markers of glucose metabolism and cardio metabolic risk in Asian women with former GDM and hypovitaminosis D. In this double blind, randomized controlled trial, 26 participants were randomized to receive either daily 4000 IU vitamin D3 or placebo capsules. 75 g Oral Glucose Tolerance Test (OGTT) and biochemistry profiles were performed at baseline and 6 month visits. Mathematical models, using serial glucose, insulin and C peptide measurements from OGTT, were employed to calculate insulin sensitivity and beta cell function. Thirty three (76%) women with former GDM screened had vitamin D level of <50 nmol/L at baseline. Supplementation, when compared with placebo, resulted in increased vitamin D level (+51.1 nmol/L vs 0.2 nmol/L, p<0.001) and increased fasting insulin (+20% vs 18%, p = 0.034). The vitamin D group also demonstrated a 30% improvement in disposition index and an absolute 0.2% (2 mmol/mol) reduction in HbA1c. There was no clear change in insulin sensitivity or markers of cardio metabolic risk. This study highlighted high prevalence of vitamin D deficiency among Asian women with former GDM. Six months supplementation with 4000 IU of vitamin D3 safely restored the vitamin D level, improved basal pancreatic beta cell function and ameliorated the metabolic state. There was no effect on markers of cardio metabolic risk. Further mechanistic studies exploring the role of vitamin D supplementation on glucose homeostasis among different ethnicities may be needed to better inform future recommendations for these women with former GDM at high risk of both hypovitaminosis D and future diabetes. PMID- 26057783 TI - Abortion: taking the debate seriously. AB - Voluntarily induced abortion has been under permanent dispute and legal regulations, because societies invariably condemn extramarital pregnancies. In recent decades, a measure of societal tolerance has led to decriminalize and legalize abortion in accordance with one of two models: a more restricted and conservative model known as therapeutic abortion, and the model that accepts voluntary abortion within the first trimester of pregnancy. Liberalization of abortion aims at ending clandestine abortions and decriminalizes the practice in order to increase reproductive education and accessibility of contraceptive methods, dissuade women from interrupting their pregnancy and, ultimately, make abortion a medically safe procedure within the boundaries of the law, inspired by efforts to reduce the incidence of this practice. The current legal initiative to decriminalize abortion in Chile proposes a notably rigid set of indications which would not resolve the three main objectives that need to be considered: 1) Establish the legal framework of abortion; 2) Contribute to reduce social unrest; 3) Solve the public health issue of clandestine, illegal abortions. Debate must urgently be opened to include alternatives in line with the general tendency to respect women's decision within the first trimester of pregnancy. PMID- 26057784 TI - Intracranial Aneurysms: Recurrences More than 10 Years after Endovascular Treatment-A Prospective Cohort Study, Systematic Review, and Meta-Analysis. AB - PURPOSE: To assess the efficacy of endovascular treatment (EVT) of intracranial aneurysms for recurrence, bleeding, and de novo aneurysm formation at long-term follow-up (> 10 years after treatment) with magnetic resonance (MR) angiography and to identify risk factors for recurrence through a prospective study and a systematic review of the literature. MATERIALS AND METHODS: Clinical examinations and 3-T MR angiography were performed prospectively 10 years after EVT of intracranial aneurysms in a single institution. Ethics committee approval and informed consent were obtained. PubMed, EMBASE, and Cochrane databases were searched to identify studies in which authors reported bleeding and/or aneurysm recurrence rates in patients who received follow-up more than 10 years after EVT. Univariate and multivariate subgroup analyses were performed to identify risk factors (midterm MR angiographic results, aneurysm characteristics, retreatment within 5 years). RESULTS: In the prospective study, sac recanalization occurred between midterm and long-term MR angiography in 16 of 129 (12.4%) aneurysms. Grade 2 classification on the Raymond scale at midterm MR angiography (relative risk [RR], 4.16; 99% confidence interval [CI]: 2.12, 8.14) and retreatment within 5 years (RR, 4.67; 99% CI: 1.55, 14.03) were risk factors for late recurrence. In the systematic review (15 cohorts, 2773 patients, 2902 aneurysms), bleeding, aneurysm recurrence, and de novo lesion formation rates were, respectively, 0.7% (99% CI: 0.2%, 2.7%; I(2), 0%; one of 694 patients), 11.4% (99% CI: 7.0%, 18.0%; I(2), 21.6%), and 4.1% (99% CI: 1.7, 9.4%; I(2), 54.1%). Raymond grade 2 initial result (RR, 7.08; 99% CI: 1.24, 40.37; I(2), 82.6%) and aneurysm size greater than 10 mm (RR, 4.37; 99% CI: 1.83, 10.44; I(2), 0%) were risk factors for late recurrence. CONCLUSION: EVT of intracranial aneurysm is effective for prevention of long-term bleeding, but recurrences occur in a clinically relevant percentage of patients, a finding that may justify follow-up of selected patients for 10 years or more, such as patients with aneurysms larger than 10 mm or classified as Raymond grade 2 at midterm MR angiography. PMID- 26057786 TI - Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study. AB - Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3(+) apoptotic cells. At >=120mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at >=120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at >=120mg/kg decreased phosphorylated TRKB(+) interneurons, although the number of reelin(+) interneurons was unchanged. At 600mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. PMID- 26057787 TI - Practical macromolecular cryocrystallography. AB - Cryocrystallography is an indispensable technique that is routinely used for single-crystal X-ray diffraction data collection at temperatures near 100 K, where radiation damage is mitigated. Modern procedures and tools to cryoprotect and rapidly cool macromolecular crystals with a significant solvent fraction to below the glass-transition phase of water are reviewed. Reagents and methods to help prevent the stresses that damage crystals when flash-cooling are described. A method of using isopentane to assess whether cryogenic temperatures have been preserved when dismounting screened crystals is also presented. PMID- 26057788 TI - The structure of hookworm platelet inhibitor (HPI), a CAP superfamily member from Ancylostoma caninum. AB - Secreted protein components of hookworm species include a number of representatives of the cysteine-rich/antigen 5/pathogenesis-related 1 (CAP) protein family known as Ancylostoma-secreted proteins (ASPs). Some of these have been considered as candidate antigens for the development of vaccines against hookworms. The functions of most CAP superfamily members are poorly understood, but one form, the hookworm platelet inhibitor (HPI), has been isolated as a putative antagonist of the platelet integrins alphaIIbbeta3 and alpha2beta1. Here, the crystal structure of HPI is described and its structural features are examined in relation to its possible function. The HPI structure is similar to those of other ASPs and shows incomplete conservation of the sequence motifs CAP1 and CAP2 that are considered to be diagnostic of CAP superfamily members. The asymmetric unit of the HPI crystal contains a dimer with an extensive interaction interface, but chromatographic measurements indicate that it is primarily monomeric in solution. In the dimeric structure, the putative active-site cleft areas from both monomers are united into a single negatively charged depression. A potential Lys-Gly-Asp disintegrin-like motif was identified in the sequence of HPI, but is not positioned at the apex of a tight turn, making it unlikely that it interacts with the integrin. Recombinant HPI produced in Escherichia coli was found not to inhibit the adhesion of human platelets to collagen or fibrinogen, despite having a native structure as shown by X-ray diffraction. This result corroborates previous analyses of recombinant HPI and suggests that it might require post-translational modification or have a different biological function. PMID- 26057789 TI - Structure of human dual-specificity phosphatase 7, a potential cancer drug target. AB - Human dual-specificity phosphatase 7 (DUSP7/Pyst2) is a 320-residue protein that belongs to the mitogen-activated protein kinase phosphatase (MKP) subfamily of dual-specificity phosphatases. Although its precise biological function is still not fully understood, previous reports have demonstrated that DUSP7 is overexpressed in myeloid leukemia and other malignancies. Therefore, there is interest in developing DUSP7 inhibitors as potential therapeutic agents, especially for cancer. Here, the purification, crystallization and structure determination of the catalytic domain of DUSP7 (Ser141-Ser289/C232S) at 1.67 A resolution are reported. The structure described here provides a starting point for structure-assisted inhibitor-design efforts and adds to the growing knowledge base of three-dimensional structures of the dual-specificity phosphatase family. PMID- 26057790 TI - Multiple crystal forms of N,N'-diacetylchitobiose deacetylase from Pyrococcus furiosus. AB - Native N,N'-diacetylchitobiose deacetylase from Pyrococcus furiosus (Pf-Dac) and its selenomethionine derivative (Se-Pf-Dac) were crystallized and analyzed in the presence and absence of cadmium ion. The four crystal structures fell into three different crystal-packing groups, with the cadmium-free Pf-Dac and Se-Pf-Dac belonging to the same space group, with homologous unit-cell parameters. The crystal structures in the presence of cadmium contained distorted octahedral cadmium complexes coordinated by three chlorides, two O atoms and an S or Se atom from the N-terminal methionine or selenomethionine, respectively. The N-terminal cadmium complex was involved in crystal contacts between symmetry-related molecules through hydrogen bonding to the N-termini. While all six N-termini of Se-Pf-Dac were involved in cadmium-complex formation, only two of the Pf-Dac N termini participated in complex formation in the Cd-containing crystal, resulting in different crystal forms. These differences are discussed in light of the higher stability of the Cd-Se bond than the Cd-S bond. This work provides an example of the contribution of cadmium towards determining protein crystal quality and packing depending on the use of the native protein or the selenomethionine derivative. PMID- 26057791 TI - Cloning, expression, purification, crystallization and X-ray crystallographic analysis of CofB, the minor pilin subunit of CFA/III from human enterotoxigenic Escherichia coli. AB - Colonization factor antigen III (CFA/III) is one of the virulence factors of human enterotoxigenic Escherichia coli (ETEC) that forms the long, thin, proteinaceous fibres of type IV pili through assembly of its major and minor subunits CofA and CofB, respectively. The crystal structure of CofA has recently been reported; however, the lack of structural information for CofB, the largest among the known type IV pilin subunits, hampers a comprehensive understanding of CFA/III pili. In this study, constructs of wild-type CofB with an N-terminal truncation and the corresponding SeMet derivative were cloned, expressed, purified and crystallized. The crystals belonged to the rhombohedral space group R32, with unit-cell parameters a = b = 103.97, c = 364.57 A for the wild-type construct and a = b = 103.47, c = 362.08 A for the SeMet-derivatized form. Although the diffraction quality of these crystals was initially very poor, dehydration of the crystals substantially improved the resolution limit from ~ 4.0 to ~ 2.0 A. The initial phase was solved by the single-wavelength anomalous dispersion (SAD) method using a dehydrated SeMet CofB crystal, which resulted in an interpretable electron-density map. PMID- 26057792 TI - Crystallographic study of a novel DNA-binding domain of human HLTF involved in the template-switching pathway to avoid the replication arrest caused by DNA damage. AB - HLTF is a pivotal protein in the template-switching pathway that allows DNA synthesis to continue even in the presence of DNA damage by utilizing a newly synthesized undamaged strand as a template. HLTF has a novel DNA-binding domain termed HIRAN that has been recently found in various proteins, although its detailed function remains unclear. In this study, the HIRAN domain of human HLTF was successfully crystallized. The crystals belonged to space group P4(1)2(1)2 or P4(3)2(1)2, with unit-cell parameters a = b = 130.0, c = 150.1 A. PMID- 26057793 TI - Overexpression, purification, crystallization and preliminary X-ray diffraction of the nisin resistance protein from Streptococcus agalactiae. AB - Nisin is a 34-amino-acid antimicrobial peptide produced by Lactococcus lactis belonging to the class of lantibiotics. Nisin displays a high bactericidal activity against various Gram-positive bacteria, including some human-pathogenic strains. However, there are some nisin-non-producing strains that are naturally resistant owing to the presence of the nsr gene within their genome. The encoded protein, NSR, cleaves off the last six amino acids of nisin, thereby reducing its bactericidal efficacy. An expression and purification protocol has been established for the NSR protein from Streptococcus agalactiae COH1. The protein was successfully crystallized using the vapour-diffusion method in hanging and sitting drops, resulting in crystals that diffracted X-rays to 2.8 and 2.2 A, respectively. PMID- 26057794 TI - Purification, crystallization and preliminary X-ray diffraction analysis of the Escherichia coli common pilus chaperone EcpB. AB - Pili are key cell-surface components that allow the attachment of bacteria to both biological and abiotic solid surfaces, whilst also mediating interactions between themselves. In Escherichia coli, the common pilus (Ecp) belongs to an alternative chaperone-usher (CU) pathway that plays a major role in both early biofilm formation and host-cell adhesion. The chaperone EcpB is involved in the biogenesis of the filament, which is composed of EcpA and EcpD. Initial attempts at crystallizing EcpB using natively purified protein from the bacterial periplasm were not successful; however, after the isolation of EcpB under denaturing conditions and subsequent refolding, crystals were obtained at pH 8.0 using the sitting-drop method of vapour diffusion. Diffraction data have been processed to 2.4 A resolution. These crystals belonged to the trigonal space group P3(1)21 or P3(2)21, with unit-cell parameters a = b = 62.65, c = 121.14 A and one monomer in the asymmetric unit. Molecular replacement was unsuccessful, but selenomethionine-substituted protein and heavy-atom derivatives are being prepared for phasing. The three-dimensional structure of EcpB will provide invaluable information on the subtle mechanistic differences in biogenesis between the alternative and classical CU pathways. Furthermore, this is the first time that this refolding strategy has been used to purify CU chaperones, and it could be implemented in similar systems where it has not been possible to obtain highly ordered crystals. PMID- 26057795 TI - Expression, purification and crystallization of a family 55 beta-1,3-glucanase from Chaetomium thermophilum. AB - A beta-1,3-glucanase from the thermophilic fungus Chaetomium thermophilum was overexpressed in Pichia pastoris, purified and crystallized in the presence of 1.8 M sodium/potassium phosphate pH 6.8 as a precipitant. Data to 2.0 A resolution were collected in-house at 293 K from a single crystal. The crystal was found to belong to space group P2(1), with unit-cell parameters a = 64.1, b = 85.8, c = 68.5 A, beta = 93.1 degrees and one molecule in the asymmetric unit. PMID- 26057796 TI - High-resolution crystal structure of the leucine-rich repeat domain of the human tumour suppressor PP32A (ANP32A). AB - Acidic leucine-rich nuclear phosphoprotein 32A (PP32A) is a tumour suppressor whose expression is altered in many cancers. It is an apoptotic enhancer that stimulates apoptosome-mediated caspase activation and also forms part of a complex involved in caspase-independent apoptosis (the SET complex). Crystals of a fragment of human PP32A corresponding to the leucine-rich repeat domain, a widespread motif suitable for protein-protein interactions, have been obtained. The structure has been refined to 1.56 A resolution. This domain was previously solved at 2.4 and 2.69 A resolution (PDB entries 2je0 and 2je1, respectively). The new high-resolution structure shows some differences from previous models: there is a small displacement in the turn connecting the first alpha-helix (alpha1) to the first beta-strand (beta1), which slightly changes the position of alpha1 in the structure. The shift in the turn is observed in the context of a new crystal packing unrelated to those of previous structures. PMID- 26057797 TI - Functional characterization of heat-shock protein 90 from Oryza sativa and crystal structure of its N-terminal domain. AB - Heat-shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone that is essential for the normal functioning of eukaryotic cells. It plays crucial roles in cell signalling, cell-cycle control and in maintaining proteome integrity and protein homeostasis. In plants, Hsp90s are required for normal plant growth and development. Hsp90s are observed to be upregulated in response to various abiotic and biotic stresses and are also involved in immune responses in plants. Although there are several studies elucidating the physiological role of Hsp90s in plants, their molecular mechanism of action is still unclear. In this study, biochemical characterization of an Hsp90 protein from rice (Oryza sativa; OsHsp90) has been performed and the crystal structure of its N-terminal domain (OsHsp90-NTD) was determined. The binding of OsHsp90 to its substrate ATP and the inhibitor 17-AAG was studied by fluorescence spectroscopy. The protein also exhibited a weak ATPase activity. The crystal structure of OsHsp90-NTD was solved in complex with the nonhydrolyzable ATP analogue AMPPCP at 3.1 A resolution. The domain was crystallized by cross-seeding with crystals of the N-terminal domain of Hsp90 from Dictyostelium discoideum, which shares 70% sequence identity with OsHsp90 NTD. This is the second reported structure of a domain of Hsp90 from a plant source. PMID- 26057798 TI - Expression, crystallization and X-ray diffraction analysis of a complex between B7-H6, a tumor cell ligand for the natural cytotoxicity receptor NKp30, and an inhibitory antibody. AB - Natural killer (NK) cells are essential components of the innate immune response to tumors and viral infections. In humans, the activating natural cytotoxicity receptor NKp30 plays a major role in NK cell-mediated tumor cell lysis. NKp30 recognizes the cell-surface protein B7-H6, which is expressed on tumor, but not healthy, cells. A mouse monoclonal antibody (17B1.3) against human B7-H6 has been developed (Kd = 0.2 uM) to investigate NKp30-mediated NK cell activation and to target tumors expressing B7-H6. Surprisingly, 17B1.3 blocks NK cell activation without interfering with the binding of B7-H6 to NKp30. Understanding the inhibitory mechanism of this antibody will require knowing the structure of 17B1.3 bound to B7-H6. The antigen-binding fragment (Fab) of 17B1.3 was expressed by in vitro folding from bacterial inclusion bodies. The extracellular domain of B7-H6 was produced by secretion from baculovirus-infected insect cells. Crystals of the Fab 17B1.3-B7-H6 complex grown by macro-seeding diffracted to 2.5 A resolution and belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 89.6, b = 138.0, c = 171.4 A, alpha = beta = gamma = 90 degrees . Comparison of the Fab 17B1.3-B7-H6 structure with the known NKp30-B7-H6 structure will elucidate the inhibitory mechanism of 17B1.3. PMID- 26057799 TI - The structure of a contact-dependent growth-inhibition (CDI) immunity protein from Neisseria meningitidis MC58. AB - Contact-dependent growth inhibition (CDI) is an important mechanism of intercellular competition between neighboring Gram-negative bacteria. CDI systems encode large surface-exposed CdiA effector proteins that carry a variety of C terminal toxin domains (CdiA-CTs). All CDI(+) bacteria also produce CdiI immunity proteins that specifically bind to the cognate CdiA-CT and neutralize its toxin activity to prevent auto-inhibition. Here, the X-ray crystal structure of a CdiI immunity protein from Neisseria meningitidis MC58 is presented at 1.45 A resolution. The CdiI protein has structural homology to the Whirly family of RNA binding proteins, but appears to lack the characteristic nucleic acid-binding motif of this family. Sequence homology suggests that the cognate CdiA-CT is related to the eukaryotic EndoU family of RNA-processing enzymes. A homology model is presented of the CdiA-CT based on the structure of the XendoU nuclease from Xenopus laevis. Molecular-docking simulations predict that the CdiA-CT toxin active site is occluded upon binding to the CdiI immunity protein. Together, these observations suggest that the immunity protein neutralizes toxin activity by preventing access to RNA substrates. PMID- 26057800 TI - Crystallization of interleukin-18 for structure-based inhibitor design. AB - Interleukin-18 (IL-18) is a pleiotropic pro-inflammatory cytokine belonging to the IL-1 superfamily. IL-18 plays an important role in host innate and acquired immune defense, with its activity being modulated in vivo by its naturally occurring antagonist IL-18 binding protein (IL-18BP). Recent crystal structures of human IL-18 (hIL-18) in complex with its antagonist or cognate receptor(s) have revealed a conserved binding interface on hIL-18 representing a promising drug target. An important step in this process is obtaining crystals of apo hIL 18 or hIL-18 in complex with small-molecule inhibitors, preferably under low ionic strength conditions. In this study, surface-entropy reduction (SER) and rational protein design were employed to facilitate the crystallization of hIL 18. The results provide an excellent platform for structure-based drug design. PMID- 26057801 TI - Structure of Chlamydomonas reinhardtii THB1, a group 1 truncated hemoglobin with a rare histidine-lysine heme ligation. AB - THB1 is one of several group 1 truncated hemoglobins (TrHb1s) encoded in the genome of the unicellular green alga Chlamydomonas reinhardtii. THB1 expression is under the control of NIT2, the master regulator of nitrate assimilation, which also controls the expression of the only nitrate reductase in the cell, NIT1. In vitro and physiological evidence suggests that THB1 converts the nitric oxide generated by NIT1 into nitrate. To aid in the elucidation of the function and mechanism of THB1, the structure of the protein was solved in the ferric state. THB1 resembles other TrHb1s, but also exhibits distinct features associated with the coordination of the heme iron by a histidine (proximal) and a lysine (distal). The new structure illustrates the versatility of the TrHb1 fold, suggests factors that stabilize the axial ligation of a lysine, and highlights the difficulty of predicting the identity of the distal ligand, if any, in this group of proteins. PMID- 26057802 TI - X-ray structure of cyanide-bound bovine heart cytochrome c oxidase in the fully oxidized state at 2.0 A resolution. AB - The X-ray structure of cyanide-bound bovine heart cytochrome c oxidase in the fully oxidized state was determined at 2.0 A resolution. The structure reveals that the peroxide that bridges the two metals in the fully oxidized state is replaced by a cyanide ion bound in a nearly symmetric end-on fashion without significantly changing the protein conformation outside the two metal sites. PMID- 26057803 TI - Purification, crystallization and X-ray crystallographic studies of a Bacillus cereus MepR-like transcription factor, BC0657. AB - Transcription factors of the MarR family respond to internal and external changes and regulate a variety of biological functions through ligand association with microorganisms. MepR belongs to the MarR family, and its mutations are associated with the development of multidrug resistance in Staphylococcus aureus, which has caused a growing health problem. In this study, a Bacillus cereus MepR-like transcription regulator, BC0657, was crystallized. The BC0657 crystals diffracted to 2.05 A resolution and belonged to either space group P6(2)22 or P6(4)22, with unit-cell parameters a = 110.57, b = 110.57, c = 67.29 A. There was one molecule per asymmetric unit. Future comparative structural studies on BC0657 would extend knowledge of ligand-induced transcriptional regulatory mechanisms in the MarR family and would make a significant contribution to the design of antibiotic drugs against multidrug-resistant bacteria. PMID- 26057804 TI - Crystallization and preliminary X-ray diffraction analysis of the CRISPR-Cas RNA silencing Cmr complex. AB - Clustered regularly interspaced short palindromic repeat (CRISPR)-derived RNA (crRNA) and CRISPR-associated (Cas) proteins constitute a prokaryotic adaptive immune system (CRISPR-Cas system) that targets and degrades invading genetic elements. The type III-B CRISPR-Cas Cmr complex, composed of the six Cas proteins (Cmr1-Cmr6) and a crRNA, captures and cleaves RNA complementary to the crRNA guide sequence. Here, a Cmr1-deficient functional Cmr (CmrDelta1) complex composed of Pyrococcus furiosus Cmr2-Cmr3, Archaeoglobus fulgidus Cmr4-Cmr5-Cmr6 and the 39-mer P. furiosus 7.01-crRNA was prepared. The CmrDelta1 complex was cocrystallized with single-stranded DNA (ssDNA) complementary to the crRNA guide by the vapour-diffusion method. The crystals diffracted to 2.1 A resolution using synchrotron radiation at the Photon Factory. The crystals belonged to the triclinic space group P1, with unit-cell parameters a = 75.5, b = 76.2, c = 139.2 A, alpha = 90.3, beta = 104.8, gamma = 118.6 degrees . The asymmetric unit of the crystals is expected to contain one CmrDelta1-ssDNA complex, with a Matthews coefficient of 2.03 A(3) Da(-1) and a solvent content of 39.5%. PMID- 26057805 TI - Structure of the MarR family protein Rv0880 from Mycobacterium tuberculosis. AB - Rv0880 from the pathogen Mycobacterium tuberculosis is classified as a MarR family protein in the Pfam database. It consists of 143 amino acids and has an isoelectric point of 10.9. Crystals of Rv0880 belonged to space group P1, with unit-cell parameters a = 54.97, b = 69.60, c = 70.32 A, alpha = 103.71, beta = 111.06, gamma = 105.83 degrees . The structure of the MarR family transcription regulator Rv0880 was solved at a resolution of 2.0 A with an R(cryst) and R(free) of 21.2 and 24.9%, respectively. The dimeric structure resembles that of other MarR proteins, with each subunit comprising a winged helix-turn-helix domain connected to an alpha-helical dimerization domain. PMID- 26057806 TI - Crystallization and preliminary crystallographic analysis of latent, active and recombinantly expressed aurone synthase, a polyphenol oxidase, from Coreopsis grandiflora. AB - Aurone synthase (AUS), a member of a novel group of plant polyphenol oxidases (PPOs), catalyzes the oxidative conversion of chalcones to aurones. Two active cgAUS1 (41.6 kDa) forms that differed in the level of phosphorylation or sulfation as well as the latent precursor form (58.9 kDa) were purified from the petals of Coreopsis grandiflora. The differing active cgAUS1 forms and the latent cgAUS1 as well as recombinantly expressed latent cgAUS1 were crystallized, resulting in six different crystal forms. The active forms crystallized in space groups P2(1)2(1)2(1) and P12(1)1 and diffracted to ~ 1.65 A resolution. Co crystallization of active cgAUS1 with 1,4-resorcinol led to crystals belonging to space group P3(1)21. The crystals of latent cgAUS1 belonged to space group P12(1)1 and diffracted to 2.50 A resolution. Co-crystallization of recombinantly expressed pro-AUS with the hexatungstotellurate(VI) salt Na6[TeW6O24] within the liquid-liquid phase separation zone significantly improved the quality of the crystals compared with crystals obtained without hexatungstotellurate(VI). PMID- 26057807 TI - Structure of the catalytic domain of Mre11 from Chaetomium thermophilum. AB - Together with the Rad50 ATPase, the Mre11 nuclease forms an evolutionarily conserved protein complex that plays a central role in the repair of DNA double strand breaks (DSBs). Mre11-Rad50 detects and processes DNA ends, and has functions in the tethering as well as the signalling of DSBs. The Mre11 dimer can bind one or two DNA ends or hairpins, and processes DNA endonucleolytically as well as exonucleolytically in the 3'-to-5' direction. Here, the crystal structure of the Mre11 catalytic domain dimer from Chaetomium thermophilum (CtMre11(CD)) is reported. CtMre11(CD) crystals diffracted to 2.8 A resolution and revealed previously undefined features within the dimer interface, in particular fully ordered eukaryote-specific insertion loops that considerably expand the dimer interface. Furthermore, comparison with other eukaryotic Mre11 structures reveals differences in the conformations of the dimer and the capping domain. In summary, the results reported here provide new insights into the architecture of the eukaryotic Mre11 dimer. PMID- 26057808 TI - Purification, crystallization and preliminary X-ray diffraction analysis of 3 ketoacyl-CoA thiolase A1887 from Ralstonia eutropha H16. AB - The gene product of A1887 from Ralstonia eutropha (ReH16_A1887) has been annotated as a 3-ketoacyl-CoA thiolase, an enzyme that catalyzes the fourth step of beta-oxidation degradative pathways by converting 3-ketoacyl-CoA to acyl-CoA. ReH16_A1887 was overexpressed and purified to homogeneity by affinity and size exclusion chromatography. The degradative thiolase activity of the purified ReH16_A1887 was measured and enzyme-kinetic parameters for the protein were obtained, with Km, Vmax and kcat values of 158 uM, 32 mM min(-1) and 5 * 10(6) s( 1), respectively. The ReH16_A1887 protein was crystallized in 17% PEG 8K, 0.1 M HEPES pH 7.0 at 293 K and a complete data set was collected to 1.4 A resolution. The crystal belonged to space group P4(3)2(1)2, with unit-cell parameters a = b = 129.52, c = 114.13 A, alpha = beta = gamma = 90 degrees . The asymmetric unit contained two molecules, with a solvent content of 58.9%. PMID- 26057809 TI - Cloning, expression, purification, crystallization and preliminary X-ray diffraction studies of NAD synthetase from methicillin-resistant Staphylococcus aureus. AB - Staphylococcus aureus is an important human and animal pathogen that causes a wide range of infections. The prevalence of multidrug-resistant S. aureus strains in both hospital and community settings makes it imperative to characterize new drug targets to combat S. aureus infections. In this context, enzymes involved in NAD metabolism and synthesis are significant drug targets as NAD is a central player in several cellular processes. NAD synthetase catalyzes the last step in the biosynthesis of nicotinamide adenine dinucleotide, making it a crucial intermediate enzyme linked to the biosynthesis of several amino acids, purine and pyrimidine nucleotides, coenzymes and antibiotics. PMID- 26057810 TI - Crystallization and preliminary X-ray diffraction analysis of the Csu pili CsuC CsuA/B chaperone-major subunit pre-assembly complex from Acinetobacter baumannii. AB - The attachment of many Gram-negative pathogens to biotic and abiotic surfaces is mediated by fimbrial adhesins, which are assembled via the classical, alternative and archaic chaperone-usher (CU) pathways. The archaic CU fimbrial adhesins have the widest phylogenetic distribution, yet very little is known about their structure and mechanism of assembly. To elucidate the biogenesis of archaic CU systems, structural analysis of the Csu fimbriae, which are used by Acinetobacter baumannii to form stable biofilms and cause nosocomial infection, was focused on. The major fimbriae subunit CsuA/B complexed with the CsuC chaperone was purified from the periplasm of Escherichia coli cells co-expressing CsuA/B and CsuC, and the complex was crystallized in PEG 3350 solution using the hanging-drop vapour diffusion method. Selenomethionine-labelled CsuC-CsuA/B complex was purified and crystallized under the same conditions. The crystals diffracted to 2.40 A resolution and belonged to the hexagonal space group P6(4)22, with unit-cell parameters a = b = 94.71, c = 187.05 A, alpha = beta = 90, gamma = 120 degrees . Initial phases were derived from a single anomalous diffraction (SAD) experiment using the selenomethionine derivative. PMID- 26057811 TI - Protein production, crystallization and preliminary crystallographic analysis of the four N-terminal immunoglobulin domains of Down syndrome cell adhesion molecule 1. AB - Down syndrome cell adhesion molecule 1 (Dscam1), a member of the immunoglobulin (Ig) superfamily, plays important roles in both the nervous and the immune systems. Via alternative RNA splicing, Drosophila Dscam1 encodes a vast family of Ig-containing proteins that exhibit isoform-specific homophilic binding. Whether different Dscam1 isoforms adopt the same dimerization mode is under debate, and the detailed mechanism of Dscam1 specificity remains unclear. In this study, eight different isforms of Dscam1 Ig1-4 have been cloned, overexpressed, purified to homogeneity and crystallized. X-ray data were collected to 1.9-4.0 A resolution. These structures will provide the opportunity to perform extensive structural comparisons of different Dscam1 isoforms and provide insight into its specificity. PMID- 26057812 TI - Crystallization and preliminary crystallographic analysis of the major acid phosphatase from Legionella pneumophila. AB - The major acid phosphatase from Legionella pneumophila (LpMAP) belongs to the histidine acid phosphatase superfamily. It contains the characteristic histidine acid phosphatase (HAP) sequence motif RHGXRXP responsible for the hydrolysis of a phosphoryl group from phosphate monoesters under acidic conditions. Here, the crystallization and preliminary X-ray analysis of crystals of LpMAP in the apo form and in complex with L-(+)-tartrate are described. By using the hanging-drop vapour-diffusion method, apo LpMAP and LpMAP-tartrate were crystallized in space group P2(1), with unit-cell parameters a = 91.50, b = 56.48, c = 146.35 A, beta = 110.01 degrees , and in space group P1, with unit-cell parameters a = 55.51, b = 73.51, c = 98.78 A, alpha = 78.82, beta = 77.65, gamma = 67.73 degrees , respectively. Diffraction data were collected at 100 K and the phases were determined using the molecular-replacement method. PMID- 26057813 TI - Expression, purification, crystallization and preliminary X-ray analysis of CttA, a putative cellulose-binding protein from Ruminococcus flavefaciens. AB - A number of anaerobic microorganisms produce multi-modular, multi-enzyme complexes termed cellulosomes. These extracellular macromolecular nanomachines are designed for the efficient degradation of plant cell-wall carbohydrates to smaller sugars that are subsequently used as a source of carbon and energy. Cellulolytic strains from the rumens of mammals, such as Ruminococcus flavefaciens, have been shown to have one of the most complex cellulosomal systems known. Cellulosome assembly requires the binding of dockerin modules located in cellulosomal enzymes to cohesin modules located in a macromolecular scaffolding protein. Over 220 genes encoding dockerin-containing proteins have been identified in the R. flavefaciens genome. The dockerin-containing enzymes can be incorporated into the primary scaffoldin (ScaA), which in turn can bind to adaptor scaffoldins (ScaB or ScaC) and subsequently to anchoring scaffoldin (ScaE), thereby attaching the whole complex to the cell surface. However, unlike other cellulosomes such as that from Clostridium thermocellum, the Ruminococcus species lack a specific carbohydrate-binding module (CBM) on ScaA which recruits the entire complex onto the surface of the substrate. Instead, a cellulose binding protein, CttA, comprising two putative tandem novel carbohydrate-binding modules and a C-terminal X-dockerin module, which can bind to the cohesin of ScaE, may mediate the attachment of bacterial cells to cellulose. Here, the expression, purification and crystallization of the carbohydrate-binding modular part of the CttA from R. flavefaciens are described. X-ray data have been collected to resolutions of 3.23 and to 1.61 A in space groups P3(1)21 or P3(2)21 and P2(1), respectively. The structure was phased using bound iodide from the crystallization buffer by SAD experiments. PMID- 26057814 TI - A preliminary X-ray study of 3-deoxy-D-manno-oct-2-ulosonic acid 8-phosphate phosphatase (YrbI) from Burkholderia pseudomallei. AB - 3-Deoxy-D-manno-oct-2-ulosonic acid 8-phosphate phosphatase (YrbI), the third enzyme in the pathway for the biosynthesis of 3-deoxy-D-manno-oct-2-ulosonic acid (KDO), hydrolyzes KDO 8-phosphate to KDO and inorganic phosphate. YrbI belongs to the haloacid dehalogenase (HAD) superfamily, which is a large family of magnesium dependent phosphatase/phosphotransferase enzymes. In this study, YrbI from Burkholderia pseudomallei, the causative agent of melioidosis, has been cloned, expressed, purified and crystallized. Synchrotron X-ray data were also collected to 2.25 A resolution. The crystal belonged to the primitive orthorhombic space group P2(1)2(1)2(1), with unit-cell parameters a = 63.7, b = 97.5, c = 98.0 A. A full structural determination is in progress to elucidate the structure-function relationship of this protein. PMID- 26057815 TI - Crystallization and preliminary X-ray diffraction analysis of the two distinct types of zebrafish beta2-microglobulin. AB - beta(2)-Microglobulin (beta(2)m) noncovalently associates with the heavy chain of major histocompatibility complex class I (MHC I) molecules, which bind foreign antigen peptides to control the cytotoxic T lymphocyte (CTL) immune response. In contrast to mammals, there are distinct types of beta(2)ms derived from two loci in a number of teleost species. In order to clarify the structures of the beta(2)ms, the zebrafish (Danio rerio) beta(2)ms Dare-beta(2)m-I and Dare beta(2)m-II were expressed in Escherichia coli, purified and crystallized, and diffraction data were collected to 1.6 and 1.9 A resolution, respectively. Both crystals belonged to space group P2(1)2(1)2(1). The unit-cell parameters were determined to be a = 38.2, b = 50.4, c = 50.9 A for Dare-beta(2)m-I and a = 38.9, b = 52.7, c = 65.8 A for Dare-beta(2)m-II. Each asymmetric unit was constituted of one molecule, with Matthews coefficients of 2.22 and 3.01 A(3) Da(-1) and solvent contents of 45 and 59% for Dare-beta(2)m-I and Dare-beta(2)m-II, respectively. These two beta(2)m structures will provide relevant information for further studies of the structures of the MHC I complex. PMID- 26057817 TI - Retraction: Mode of binding of the antithyroid drug propylthiouracil to mammalian haem peroxidases. AB - The results in the article by Singh et al. [(2015), Acta Cryst. F71, 304-310] have been brought into question and the article is retracted. PMID- 26057816 TI - Structure-activity correlations for three pyrido[2,3-d]pyrimidine antifolates binding to human and Pneumocystis carinii dihydrofolate reductase. AB - To further define the interactions that enhance the selectivity of binding and to directly compare the binding of the most potent analogue {N(6)-methyl-N(6)-(3,4,5 trifluorophenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine; compound 26} in the series of bicyclic pyrido[2,3-d]pyrimidine analogues of piritrexim (PTX) with native human (h), Pneumocystis carinii (pc) and Pneumocystis jirovecii (pj) dihydrofolate reductase (DHFR) enzymes, the crystal structures of hDHFR complexed with N(6)-methyl-N(6)-(4-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,6-triamine (compound 22), of hDHFR complexed with compound 26 and of pcDHFR complexed with N(6)-methyl-N(6)-1-naphthylpyrido[2,3-d]pyrimidine-2,4,6-triamine (compound 24) are reported as ternary complexes with NADPH. This series of bicyclic pyrido[2,3 d]pyrimidines were designed in which there was a transposition of the 5-methyl group of PTX to the N9 position of the pyrido[2,3-d]pyrimidine. It was hypothesized that the N9-methyl group would preferentially interact with Ile123 of pcDHFR (and Ile123 of pjDHFR), but not with the shorter Val115 in hDHFR. Structure-activity data for this series of antifolates revealed that a trifluoro derivative (26) was the most selective against pjDHFR compared with mammalian DHFR (h/pj = 35.7). Structural data for the hDHFR-26 complex revealed that 26 binds in a different conformation from that observed in the pcDHFR-26 complex. In the hDHFR-26 complex the trifluorophenyl ring of 26 occupies a position near the cofactor-binding site, with close intermolecular contacts with Asp21, Ser59 and Ile60, whereas this ring in the pcDHFR-26 complex is positioned away from the cofactor site and near Ile65, with weaker contacts with Ile65, Phe69 and Ile123. Comparison of the intermolecular contacts between the N9-methyl group with Val115/Ile123 validates the hypothesis that the N9-methyl substituent preferentially interacts with Ile123 compared with Val115 of hDHFR, as the weaker contact with Val115 in the hDHFR structure is consistent with its weaker binding affinity compared with pcDHFR. The results for the structures of hDHFR-22 and pcDHFR-24 show that their inhibitor-binding orientation is similar to that observed in pcDHFR-26 and the pcDHFR variant (F69N) reported previously. The naphthyl moiety of 24 makes several intermolecular contacts with the active-site residues in pcDHFR that help to stabilize the binding, resulting in a more potent inhibitor. PMID- 26057818 TI - Reactive Liftoff of Crystalline Cellulose Particles. AB - The condition of heat transfer to lignocellulosic biomass particles during thermal processing at high temperature (>400 degrees C) dramatically alters the yield and quality of renewable energy and fuels. In this work, crystalline cellulose particles were discovered to lift off heated surfaces by high speed photography similar to the Leidenfrost effect in hot, volatile liquids. Order of magnitude variation in heat transfer rates and cellulose particle lifetimes was observed as intermediate liquid cellulose droplets transitioned from low temperature wetting (500-600 degrees C) to fully de-wetted, skittering droplets on polished surfaces (>700 degrees C). Introduction of macroporosity to the heated surface was shown to completely inhibit the cellulose Leidenfrost effect, providing a tunable design parameter to control particle heat transfer rates in industrial biomass reactors. PMID- 26057819 TI - Apology and forgiveness evolve to resolve failures in cooperative agreements. AB - Making agreements on how to behave has been shown to be an evolutionarily viable strategy in one-shot social dilemmas. However, in many situations agreements aim to establish long-term mutually beneficial interactions. Our analytical and numerical results reveal for the first time under which conditions revenge, apology and forgiveness can evolve and deal with mistakes within ongoing agreements in the context of the Iterated Prisoners Dilemma. We show that, when the agreement fails, participants prefer to take revenge by defecting in the subsisting encounters. Incorporating costly apology and forgiveness reveals that, even when mistakes are frequent, there exists a sincerity threshold for which mistakes will not lead to the destruction of the agreement, inducing even higher levels of cooperation. In short, even when to err is human, revenge, apology and forgiveness are evolutionarily viable strategies which play an important role in inducing cooperation in repeated dilemmas. PMID- 26057820 TI - Longitudinal analysis of associations between women's consultations with complementary and alternative medicine practitioners/use of self-prescribed complementary and alternative medicine and menopause-related symptoms, 2007-2010. AB - OBJECTIVE: This study aims to determine associations between consultations with complementary and alternative medicine (CAM) practitioners/use of self-prescribed CAM and menopause-related symptoms. METHODS: Data were obtained from the Australian Longitudinal Study on Women's Health. Generalized estimating equations were used to conduct longitudinal data analyses, which were restricted to women born in 1946-1951 who were surveyed in 2007 (survey 5; n = 10,638) and 2010 (survey 6; n = 10,011). RESULTS: Women with menopause-related symptoms were more likely to use self-prescribed CAM but were not more likely to consult a CAM practitioner. Overall, CAM use was lower among women who had undergone hysterectomy or women who had undergone oophorectomy, compared with naturally postmenopausal women, and decreased with increasing age of postmenopausal women. Weak associations between CAM use and hot flashes were observed. Women experiencing hot flashes were more likely to consult a massage therapist (odds ratio, 1.09; 95% CI, 1.00-1.20) and/or use self-prescribed herbal medicines (odds ratio, 1.13; 95% CI, 1.03-1.23) than women not experiencing hot flashes. CONCLUSIONS: Consultations with CAM practitioners and use of self-prescribed CAM among naturally or surgically postmenopausal women are associated with menopause related symptoms. Our study findings should prompt healthcare providers, in particular family medicine practitioners, to be cognizant of clinical evidence for CAM typically used for the management of common menopause-related symptoms in their aim to provide safe, effective, and coordinated care for women. PMID- 26057821 TI - Effects of long-term risedronate treatment on serum ferritin levels in postmenopausal women with osteoporosis: the impact of cardiovascular risk factor load. AB - OBJECTIVE: Although ferritin has been considered as a possible link between accelerated bone loss and atherosclerosis, the long-term impact of therapeutic agents widely used to treat osteoporosis, such as bisphosphonates, on ferritin levels has not been investigated. The present study investigated the effects of risedronate on serum ferritin levels in postmenopausal women with osteoporosis. METHODS: In an open-label, prospective, uncontrolled study, 68 postmenopausal women with osteoporosis were evaluated. Study participants received risedronate orally at a dose of 35 mg/week during a 6-month treatment period. Blood sampling for lipid profile, hemoglobin A1c, insulin, fibrinogen, C-reactive protein, osteoprotegerin, and ferritin was performed at baseline and after 6 months of treatment. Pulse-wave velocity and augmentation index at baseline were determined using SphygmoCor version 7.1 (AtCor Medical, Sydney, Australia). RESULTS: Mean (SD) serum ferritin decreased significantly from 62.1 (44.8) to 46.7 (29.4) MUg/dL (P < 0.0001) during the treatment period. On multiple linear regression analysis, the significant predictors of Deltaferritin were pulse-wave velocity (P = 0.04; effect size, 0.188), C-reactive protein (P = 0.021; effect size, 0.043), insulin (P = 0.011; effect size, 0.100), and high-density lipoprotein cholesterol (P = 0.046; effect size, 0.132) at baseline. CONCLUSIONS: Risedronate treatment is associated with significantly decreased serum ferritin levels in postmenopausal women with osteoporosis and cardiovascular risk factors. PMID- 26057822 TI - Menopausal hot flashes and white matter hyperintensities. AB - OBJECTIVE: Hot flashes are classic symptoms of menopause. Emerging data link hot flashes to cardiovascular disease (CVD) risk, yet whether hot flashes are related to brain health is poorly understood. We examined the relationship between hot flashes (measured via physiologic monitor and self-report) and white matter hyperintensities (WMH) among midlife women. METHODS: Twenty midlife women (aged 40-60 y) without clinical CVD, with an intact uterus and ovaries, and not taking hormone therapy were recruited. Women underwent 24 hours of ambulatory physiologic and diary hot flash monitoring to quantify hot flashes; magnetic resonance imaging to assess WMH burden; 72 hours of actigraphy to quantify sleep; and a blood draw, questionnaires, and physical measures to quantify demographics and CVD risk factors. Tests of a priori hypotheses regarding relationships between physiologically monitored and self-reported wake and sleep hot flashes and WMH were conducted in linear regression models. RESULTS: More physiologically monitored hot flashes during sleep were associated with greater WMH, controlling for age, race, and body mass index (beta [SE] = 0.0002 [0.0001], P = 0.03]. Findings persisted after controlling for sleep characteristics and additional CVD risk factors. No relationships were observed for self-reported hot flashes. CONCLUSIONS: More physiologically monitored hot flashes during sleep are associated with greater WMH burden among midlife women without clinical CVD. Results suggest that the relationship between hot flashes and CVD risk observed in the periphery may extend to the brain. Future work should consider the unique role of sleep hot flashes in brain health. PMID- 26057823 TI - Combined exercise ameliorates ovariectomy-induced cognitive impairment by enhancing cell proliferation and suppressing apoptosis. AB - OBJECTIVE: Estrogen plays an important role in cognitive function, including attention, learning, and memory, and affects the structure and function of brain areas. We investigated the effects of combined exercise on memory deficits induced by ovariectomy (OVX) in relation to cell proliferation and apoptosis in the hippocampus. METHODS: Rats were randomly divided into four groups: sham, sham and exercise, OVX, and OVX and exercise. Rats in combined exercise groups were subjected to 3 days of resistance training and 3 days of running (for a total of 6 d/wk) for eight consecutive weeks. Rats were tested in step-down avoidance task and Morris water maze task to verify the effects of OVX on short-term and spatial working memory. RESULTS: In the present study, the number of BrdU-positive and doublecortin-positive cells and expression of brain-derived neurotrophic factor, TrkB, and Bcl-2 decreased; expression of Bax and the number of caspase-3-positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling positive cells increased; and short-term and spatial working memory decreased in the OVX group compared with the sham group. Conversely, when the combined exercise group was compared with the OVX group, the number of BrdU-positive and doublecortin-positive cells and expression of brain-derived neurotrophic factor, TrkB, and Bcl-2 increased; expression of Bax and the number of caspase-3-positive and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling positive cells decreased; and short-term and spatial working memory increased. CONCLUSIONS: Combined exercise increases cell proliferation and inhibits apoptosis in the hippocampus and improves cognitive function despite estrogen deficiency. PMID- 26057824 TI - Human papillomavirus genotyping as a reliable prognostic marker of recurrence after loop electrosurgical excision procedure for high-grade cervical intraepithelial neoplasia (CIN2-3) especially in postmenopausal women. AB - OBJECTIVE: This study was conducted to determine, using the HPV DNA Chip (HDC) test, whether the human papillomavirus (HPV) genotype is predictive of recurrent high-grade cervical intraepithelial neoplasia (CIN; CIN2-3) after a loop electrosurgical excision procedure (LEEP) in postmenopausal women. METHODS: Between January 2007 and February 2013, 206 postmenopausal women with CIN2-3 were treated with LEEP, followed by cytology, Hybrid Capture II (HC2) assay, and HDC test. Post-LEEP follow-up was performed at 3, 6, 9, 12, 18, and 24 months during the first 2 years and yearly thereafter. RESULTS: Among 206 women, HC2 yielded positive results in 199 women (96.6%) and HDC yielded positive results in 201 women (97.6%) before LEEP. The overall agreement between HDC and HC2 was 99.0%. The area under the receiver operating characteristic curve for high-risk HPV (HR HPV) viral load measured by HC2 predicting recurrent CIN2-3 was 0.567 (P = 0.335). Twenty-six women (12.6%) developed recurrence, and those who developed recurrence tested positive for the same HR-HPV genotype before and after LEEP. The same HR-HPV genotype by HDC during follow-up had a sensitivity and negative predictive value of 100% in detecting recurrent disease. HPV-18 was significantly associated with recurrent CIN2-3 (P < 0.05). CONCLUSIONS: Among postmenopausal women, persistent infection with the same HR-HPV genotype, especially HPV-18, should be considered a risk factor for developing recurrent CIN2-3. After LEEP, such women warrant special attention with intense follow-up. PMID- 26057825 TI - Duration of ovarian hormone exposure and atherosclerotic cardiovascular disease in Korean women: the Korean Heart Study. AB - OBJECTIVE: Although reproductive and hormonal factors, such as menarche and menopause, have been reported as independent risk factors for atherosclerotic cardiovascular disease (ASCVD), few studies have examined these factors in East Asian populations. In the Korean Heart Study, ASCVD risk related to duration of ovarian hormone exposure was examined in a cohort of 66,104 Korean women. METHODS: Study members were recruited from participants of routine health examinations at health promotion centers across South Korea in 1996-2004. Ovarian hormone exposure was defined as duration between menarche and menopause. Incidence rates for ASCVD, stroke, and ischemic heart disease were examined in relation to ovarian hormone exposure. RESULTS: The mean duration of ovarian hormone exposure at study baseline was 33.7 years, and risk for ASCVD was negatively associated with duration. Women with shorter ovarian hormone exposure (<30 y) had a higher risk of developing ASCVD (hazard ratio [HR], 1.30; 95% CI, 1.01-1.68) than women with longer ovarian hormone exposure (35-35 y). In similar comparison groups, women with ovarian hormone exposure shorter than 30 years were at increased risk for developing total stroke (HR, 1.18; 95% CI, 1.00-1.38), thrombotic stroke (HR, 1.30; 95% CI, 1.05-1.61), ischemic heart disease (HR, 1.40; 95% CI, 1.19-1.63), and acute myocardial infarction (HR, 1.73; 95% CI, 1.08 2.47). CONCLUSIONS: Our study provides further confirmation of increased cardiovascular risk with shorter reproductive years. Therefore, women with reduced lifetime ovarian hormone exposure should focus on minimizing ASCVD risk by lifestyle modifications such as smoking avoidance or increased physical activities. PMID- 26057826 TI - Herbal formula menoprogen alters insulin-like growth factor-1 and insulin-like growth factor binding protein-1 levels in the serum and ovaries of an aged female rat model of menopause. AB - OBJECTIVE: Menoprogen (MPG), a traditional Chinese medicine formula for menopause, improves menopausal symptoms; however, its mechanism remains unknown. Previous studies have shown that MPG is not directly estrogenic; thus, the goal of this study was to investigate the effects of MPG on insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein-1 (IGFBP-1) levels in an aged female rat model of menopause. METHODS: In a six-arm study, 14-month-old female Sprague-Dawley rats (n = 8 per arm) were randomly divided into the following groups: untreated aged, 17beta-estradiol-treated aged (estradiol [E2]), and three arms with increasing doses of MPG (162, 324, or 648 mg/kg/d). The sixth arm contained 4-month-old female Sprague-Dawley rats as a normal comparison group. Four weeks after MPG or E2 administration, animals were killed after blood draws, and ovarian tissues were excised. Levels of E2 and progesterone (P4) were determined by radioimmunoassay. Serum and ovarian tissue levels of IGF-1, IGFBP 1, and IGF-1 receptor were determined by enzyme-linked immunosorbent assay. RESULTS: Compared with the normal group, aged rats had significantly reduced serum levels of E2, P4, and IGF-1, and increased serum and ovarian tissue levels of IGFBP-1. MPG restored serum IGF-1 and IGFBP-1 levels and down-regulated ovarian levels of IGFBP-1, which were closely related to increases in E2 and P4 levels in aged rats. No significant differences in either IGF-1 or IGFBP-1 were observed between the three doses of MPG. CONCLUSIONS: MPG exerts a direct in vivo effect on aged female rats by positively regulating serum and ovarian IGF-1 and IGFBP-1 levels. PMID- 26057827 TI - Current perspectivesin pathogenesis and antimicrobial resistance of enteroaggregative Escherichia coli. AB - Enteroaggregative Escherichia coli (EAEC) is an emerging pathogen that causes acute and persistent diarrhea in children and adults. While the pathogenic mechanisms of EAEC intestinal colonization have been uncovered (including bacterial adhesion, enterotoxin and cytotoxin secretion, and stimulation of mucosal inflammation), those of severe extraintestinal infections remain largely unknown. The recent emergence of multidrug resistant EAEC represents an alarming public health threat and clinical challenge, and research on the molecular mechanisms of resistance is urgently needed. PMID- 26057828 TI - Stem cells and fluid flow drive cyst formation in an invertebrate excretory organ. AB - Cystic kidney diseases (CKDs) affect millions of people worldwide. The defining pathological features are fluid-filled cysts developing from nephric tubules due to defective flow sensing, cell proliferation and differentiation. The underlying molecular mechanisms, however, remain poorly understood, and the derived excretory systems of established invertebrate models (Caenorhabditis elegans and Drosophila melanogaster) are unsuitable to model CKDs. Systematic structure/function comparisons revealed that the combination of ultrafiltration and flow-associated filtrate modification that is central to CKD etiology is remarkably conserved between the planarian excretory system and the vertebrate nephron. Consistently, both RNA-mediated genetic interference (RNAi) of planarian orthologues of human CKD genes and inhibition of tubule flow led to tubular cystogenesis that share many features with vertebrate CKDs, suggesting deep mechanistic conservation. Our results demonstrate a common evolutionary origin of animal excretory systems and establish planarians as a novel and experimentally accessible invertebrate model for the study of human kidney pathologies. PMID- 26057830 TI - Circular RNA biogenesis can proceed through an exon-containing lariat precursor. AB - Pervasive expression of circular RNA is a recently discovered feature of eukaryotic gene expression programs, yet its function remains largely unknown. The presumed biogenesis of these RNAs involves a non-canonical 'backsplicing' event. Recent studies in mammalian cell culture posit that backsplicing is facilitated by inverted repeats flanking the circularized exon(s). Although such sequence elements are common in mammals, they are rare in lower eukaryotes, making current models insufficient to describe circularization. Through systematic splice site mutagenesis and the identification of splicing intermediates, we show that circular RNA in Schizosaccharomyces pombe is generated through an exon-containing lariat precursor. Furthermore, we have performed high-throughput and comprehensive mutagenesis of a circle-forming exon, which enabled us to discover a systematic effect of exon length on RNA circularization. Our results uncover a mechanism for circular RNA biogenesis that may account for circularization in genes that lack noticeable flanking intronic secondary structure. PMID- 26057829 TI - Identification of a lipid scrambling domain in ANO6/TMEM16F. AB - Phospholipid scrambling (PLS) is a ubiquitous cellular mechanism involving the regulated bidirectional transport of phospholipids down their concentration gradient between membrane leaflets. ANO6/TMEM16F has been shown to be essential for Ca(2+)-dependent PLS, but controversy surrounds whether ANO6 is a phospholipid scramblase or an ion channel like other ANO/TMEM16 family members. Combining patch clamp recording with measurement of PLS, we show that ANO6 elicits robust Ca(2+)-dependent PLS coinciding with ionic currents that are explained by ionic leak during phospholipid translocation. By analyzing ANO1-ANO6 chimeric proteins, we identify a domain in ANO6 necessary for PLS and sufficient to confer this function on ANO1, which normally does not scramble. Homology modeling shows that the scramblase domain forms an unusual hydrophilic cleft that faces the lipid bilayer and may function to facilitate translocation of phospholipid between membrane leaflets. These findings provide a mechanistic framework for understanding PLS and how ANO6 functions in this process. PMID- 26057831 TI - Go when you know: Chimpanzees' confidence movements reflect their responses in a computerized memory task. AB - Three chimpanzees performed a computerized memory task in which auditory feedback about the accuracy of each response was delayed. The delivery of food rewards for correct responses also was delayed and occurred in a separate location from the response. Crucially, if the chimpanzees did not move to the reward-delivery site before food was dispensed, the reward was lost and could not be recovered. Chimpanzees were significantly more likely to move to the dispenser on trials they had completed correctly than on those they had completed incorrectly, and these movements occurred before any external feedback about the outcome of their responses. Thus, chimpanzees moved (or not) on the basis of their confidence in their responses, and these confidence movements aligned closely with objective task performance. These untrained, spontaneous confidence judgments demonstrated that chimpanzees monitored their own states of knowing and not knowing and adjusted their behavior accordingly. PMID- 26057832 TI - Using instruments to understand argument structure: Evidence for gradient representation. AB - The arguments of a verb are commonly assumed to correspond to the event participants specified by the verb. That is, drink has two arguments because drink specifies two participants: someone who drinks and something that gets drunk. This correspondence does not appear to hold, however, in the case of instrumental participants, e.g. John drank the soda with a straw. Verbs such as slice and write have been argued to specify an instrumental participant, even though instruments do not pattern like arguments given other criteria. In this paper, we investigated how instrumental verbs are represented, testing the hypothesis that verbs such as slice encode three participants in the same way that dative verbs such as lend encode three participants. In two experiments English-speakers reported their judgments about the number of participants specified by a verb, e.g., that drink specifies two participants. These judgments indicate that slice does not encode three distinct arguments. Nonetheless, some verbs were systematically more likely to elicit the judgment that the instrument is specified by the verb, a pattern that held across individual subjects. To account for these findings, we propose that instruments are not independent verbal arguments but are represented in a gradient away: an instrument may be a more or less salient part of the force exerted by an agent. These results inform our understanding of the relationship between argument structure and event representation, raising questions concerning the role of arguments in language processing and learning. PMID- 26057833 TI - Human papillomavirus infection in oral squamous cell carcinomas from Chilean patients. AB - Human papillomavirus (HPV) is the causal agent of cervical, anogenital and a subset of oropharyngeal carcinomas. In addition, the role of HPV in oral carcinogenesis has been suggested, although the findings are inconclusive. In this study, using conventional polymerase chain reaction (PCR) and genotyping by specific PCR and DNA sequencing, we analyzed the HPV presence in 80 oral squamous cell carcinomas (OSCCs) from Chilean subjects. In addition, we determined the expression of p16, p53, pRb and Ki-67 using immunohistochemistry (IHC). The CDKN2A (p16) promoter methylation was evaluated using methylation-specific PCR (MSP). HPV sequences were found in 9/80 (11%) OSCCs. Non-statistically significant association with p53, pRb, Ki-67 and p16 levels were found (p=0.77; 0.29; 0.83; 0.21, respectively). HPV-16 and 18 were the most prevalent HPV genotypes in 8/9 (89%) OSCCs. In addition, CDKN2A (p16) was methylated in 39% of OSCCs. No association with HPV presence (p=0.917) was found. These results suggest that HPV positive OSCCs are entities that do not resemble the molecular alterations of HPV-associated tumors in a Chilean population. More studies are warranted to determine the role of HPV in OSCCs. PMID- 26057834 TI - Combination of high spatial resolution and low minimum detection limit using thinned specimens in cutting-edge electron probe microanalysis. AB - The effect of sample thickness on the spatial resolution and minimum detection limit (MDL) has been investigated for field-emission electron probe microanalysis with wavelength dispersive X-ray spectroscopy (FE-EPMA-WDX). Indium gallium phosphide samples thinned to thicknesses of about 100, 130, 210, 310, and 430 nm provided effective thin-sample FE-EPMA-WDX in the resolution range of 40-350 nm and MDL range of 13,000-600 ppm (mass). A comparison of the FE-EPMA results for thin and bulk samples demonstrated that thin-sample FE-EPMA can achieve both higher sensitivity and better spatial resolution than is possible using bulk samples. Most of the X-rays that determine the MDL are generated in a surface region of the sample with a depth of approximately 300 nm. The spatial resolution and MDL can be tuned by the sample thickness. Furthermore, analysis of small amounts of Cl in SiO2 indicated that thin-sample FE-EPMA can realize a spatial resolution and MDL of 41 nm and 446 ppm at Iprob=50 nA, respectively, whereas bulk-sample FE-EPMA offers a resolution of only 348 nm and MDL of 426 ppm. PMID- 26057835 TI - The ability of adults with an intellectual disability to recognise facial expressions of emotion in comparison with typically developing individuals: A systematic review. AB - This review systematically examined the literature on the ability of adults with an intellectual disability (ID) to recognise facial expressions of emotion. Studies were included that: recruited only adult participants with ID; that did not specifically recruit participants with co-morbid diagnoses of syndrome(s) related to ID; and that directly compared the performance of adults with ID with a group of people without ID. Nine papers met the eligibility criteria for review and were assessed against pre-defined quality rating criteria and the findings synthesised. The majority of included studies were assessed as being of acceptable overall methodological quality. All of the studies reported a relative impairment in emotion recognition for participants with ID on at least some of the tasks administered, with a large effect size being found for most of the significant results. The review suggests that adults with ID are relatively impaired in recognising facial expressions of emotion, when compared with either adults or children without ID. Methodological variation between studies limits the extent to which any interpretations can be made as to the cause of impaired emotion recognition in adults with ID. PMID- 26057836 TI - A review of five tests to identify motor coordination difficulties in young adults. AB - Difficulties with low motor competence in childhood and adolescence, such as that seen in Developmental Coordination Disorder (DCD), often persist into adulthood. Identification of DCD at all ages is particularly challenging and problematic because of the diversity of motor symptoms. Many tests of motor proficiency and impairment have been developed for children up to 12 years of age. Whilst identification of DCD is important during childhood, it is of equal importance to identify and monitor the impact of this impairment as an individual grows and develops. Currently there is no test specifically designed to support diagnosis and monitor change in the age range 16-30 years. In this article we review five tests that have been used to assess motor competence among young adults (Bruininks-Oseretsky Test of Motor Proficiency-2, McCarron Assessment of Neuromuscular Development, Movement Assessment Battery for Children-2, Tufts Assessment of Motor Performance and the Zurich Neuromotor Assessment). Key issues relevant to testing motor skills in older populations, such as the inclusion of age appropriate skills, are explored. While the BOT-2 provided the most evidence for valid and reliable measurement of Criterion A of the diagnostic criteria for DCD among this age group, no test adequately evaluated Criterion B. Further evaluation of motor skill assessment among the young adult population is needed. PMID- 26057837 TI - Foot pressure distribution in children with cerebral palsy while standing. AB - Foot deformity is a major component of impaired functioning in cerebral palsy (CP). While gait and balance issues related to CP have been studied extensively, there is little information to date on foot-ground interaction (i.e. contact area and plantar pressure distribution). This study aimed to characterize quantitatively the foot-ground contact parameters during static upright standing in hemiplegia and diplegia. We studied 64 children with hemiplegia (mean age 8.2 years; SD 2.8 years) and 43 with diplegia (mean age 8.8 years; SD 2.3 years) while standing on both legs statically on a pressure sensitive mat. We calculated pressure data for the whole foot and sub-regions (i.e. rearfoot, midfoot and forefoot) and average contact pressure. The Arch Index (AI) served for classifying the feet as flat, normal or cavus feet. The data were compared with those from a sample of age- and gender-matched participants (control group, 68 children). Most of the feet showed very high AI values, thus indicating a flat foot. This deformity was more common in diplegia (74.4%) than in hemiplegia (54.7%). In both diplegic and hemiplegic children, average plantar pressure was significantly increased in the forefoot and midfoot and decreased in the rearfoot (p<0.001). The present data indicate an increased load on the front parts of the foot, which may be due to plantarflexor overactivity or knee flexion, combined with an increased incidence of low foot arches. As a low foot arch does not necessarily increase forefoot load, this deformity can be regarded as secondary. PMID- 26057838 TI - Numerical and area comparison abilities in Down syndrome. AB - Individuals with Down syndrome (DS) have great difficulty in learning mathematics. In recent years, research has focused on investigating whether precursors of later mathematical competence, such as estimating and comparing numerosities, are preserved in DS. Although studies have suggested a strong relationship between the ability to compare continuous quantities (e.g., area of an object) and that of comparing numerosities, it is still unknown whether this ability is preserved in DS. This study investigated the abilities of individuals with DS to compare area and number and contrasted them with those of two control groups of typically developing individuals. Participants were 16 individuals with DS, 16 typically developing individuals matched by mental age (MA group), and 16 typically developing individuals matched by chronological age (CA group). All participants performed two eye-tracking tasks: an Area Comparison Task (ACT) and a Number Comparison Task (NCT). Stimuli in the two tasks differed in the same ratio to enable comparison of individual performance across both tasks. The results showed that in general, the performance of the three groups was better in the ACT than in the NCT. Critically, performance of individuals with DS in both tasks was consistent with that of individuals with the same MA. The study shows that the abilities to compare area and numerosity are both preserved in DS, and that individuals with this syndrome, like typically developing individuals, show better performance in comparing area than number. PMID- 26057839 TI - Construction of regulatory networks mediated by small RNAs responsive to abiotic stresses in rice (Oryza sativa). AB - Plants have evolved exquisite molecular mechanisms to adapt to diverse abiotic stresses. MicroRNAs play an important role in stress response in plants. However, whether the other small RNAs (sRNAs) possess stress-related roles remains elusive. In this study, thousands of sRNAs responsive to cold, drought and salt stresses were identified in rice seedlings and panicles by using high-throughput sequencing data. These sRNAs were classified into 12 categories, including "Panicle_Cold_Down", "Panicle_Cold_Up", "Panicle_Drought_Down", "Panicle_Drought_Up", "Panicle_Salt_Down", "Panicle_Salt_Up", "Seedling_Cold_Down", "Seedling_Cold_Up", "Seedling_Drought_Down", "Seedling_Drought_Up", "Seedling_Salt_Down" and "Seedling_Salt_Up". The stress responsive sRNAs enriched in Argonaute 1 were extracted for target prediction and degradome sequencing data-based validation, which enabled network construction. Within certain subnetworks, some target genes were further supported by microarray data. Literature mining indicated that certain targets were potentially involved in stress response. These results demonstrate that the established networks are biologically meaningful. We discovered that in some cases, one sRNA sequence could be assigned to two or more categories. Moreover, within certain target-centered subnetworks, one transcript was regulated by several stress-responsive sRNAs assigned to different categories. It implies that these subnetworks are potentially implicated in stress signal crosstalk. Together, our results could advance the current understanding of the biological role of plant sRNAs in stress signaling. PMID- 26057840 TI - Hot Carrier-Induced Tautomerization within a Single Porphycene Molecule on Cu(111). AB - Here, we report the study of tautomerization within a single porphycene molecule adsorbed on a Cu(111) surface using low-temperature scanning tunneling microscopy (STM) at 5 K. While molecules are adsorbed on the surface exclusively in the thermodynamically stable trans tautomer after deposition, a voltage pulse from the STM can induce the unidirectional trans -> cis and reversible cis <-> cis tautomerization. From the voltage and current dependence of the tautomerization yield (rate), it is revealed that the process is induced by vibrational excitation via inelastic electron tunneling. However, the metastable cis molecules are thermally switched back to the trans tautomer by heating the surface up to 30 K. Furthermore, we have found that the unidirectional tautomerization can be remotely controlled at a distance from the STM tip. By analyzing the nonlocal process in dependence on various experimental parameters, a hot carrier-mediated mechanism is identified, in which hot electrons (holes) generated by the STM travel along the surface and induce the tautomerization through inelastic scattering with a molecule. The bias voltage and coverage dependent rate of the nonlocal tautomerization clearly show a significant contribution of the Cu(111) surface state to the hot carrier-induced process. PMID- 26057841 TI - Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. AB - One of the major problems influencing the therapeutic efficacy of stem cell therapy is the poor cell survival following transplantation. This is partly attributed to insufficient resistance of transplanted stem cells to oxidative and inflammatory stresses at the injured sites. In the current study, we demonstrated the pivotal role of antioxidant levels in human umbilical cord mesenchymal stem cells (hUCMSCs) dynamic in vitro anti-stress abilities against lipopolysaccharide (LPS)/H2O2 intoxication and in vivo therapeutic efficacy in a murine acute liver failure model induced by D-galactosamine/LPS (Gal/LPS) by either reducing the antioxidant levels with diethyl maleate (DEM) or increasing antioxidant levels with edaravone. Both the anti- and pro-oxidant treatments dramatically influenced the survival, apoptosis, and reactive oxygen species (ROS) production of hUCMSCs through the MAPK-PKC-Nrf2 pathway in vitro. When compared with untreated and DEM treated cells, edaravone-treated hUCMSCs rescued NOD/SCID mice from Gal/LPS induced death, significantly improved hepatic functions and promoted host liver regeneration. These effects were probably from increased stem cell homing, promoted proliferation, decreased apoptosis and enhanced secretion of hepatocyte growth factor (HGF) under hepatic stress environment. In conclusion, elevating levels of antioxidants in hUCMSCs with edaravone can significantly influence their hepatic tissue repair capacity. PMID- 26057842 TI - Riverbed methanotrophy sustained by high carbon conversion efficiency. AB - Our understanding of the role of freshwaters in the global carbon cycle is being revised, but there is still a lack of data, especially for the cycling of methane, in rivers and streams. Unravelling the role of methanotrophy is key to determining the fate of methane in rivers. Here we focus on the carbon conversion efficiency (CCE) of methanotrophy, that is, how much organic carbon is produced per mole of CH4 oxidised, and how this is influenced by variation in methanotroph communities. First, we show that the CCE of riverbed methanotrophs is consistently high (~50%) across a wide range of methane concentrations (~10-7000 nM) and despite a 10-fold span in the rate of methane oxidation. Then, we show that this high conversion efficiency is largely conserved (50%+/- confidence interval 44-56%) across pronounced variation in the key functional gene (70 operational taxonomic units (OTUs)), particulate methane monooxygenase (pmoA), and marked shifts in the abundance of Type I and Type II methanotrophs in eight replicate chalk streams. These data may suggest a degree of functional redundancy within the variable methanotroph community inhabiting these streams and that some of the variation in pmoA may reflect a suite of enzymes of different methane affinities which enables such a large range of methane concentrations to be oxidised. The latter, coupled to their high CCE, enables the methanotrophs to sustain net production throughout the year, regardless of the marked temporal and spatial changes that occur in methane. PMID- 26057843 TI - ProDeGe: a computational protocol for fully automated decontamination of genomes. AB - Single amplified genomes and genomes assembled from metagenomes have enabled the exploration of uncultured microorganisms at an unprecedented scale. However, both these types of products are plagued by contamination. Since these genomes are now being generated in a high-throughput manner and sequences from them are propagating into public databases to drive novel scientific discoveries, rigorous quality controls and decontamination protocols are urgently needed. Here, we present ProDeGe (Protocol for fully automated Decontamination of Genomes), the first computational protocol for fully automated decontamination of draft genomes. ProDeGe classifies sequences into two classes--clean and contaminant- using a combination of homology and feature-based methodologies. On average, 84% of sequence from the non-target organism is removed from the data set (specificity) and 84% of the sequence from the target organism is retained (sensitivity). The procedure operates successfully at a rate of ~0.30 CPU core hours per megabase of sequence and can be applied to any type of genome sequence. PMID- 26057844 TI - Microbial DNA records historical delivery of anthropogenic mercury. AB - Mercury (Hg) is an anthropogenic pollutant that is toxic to wildlife and humans, but the response of remote ecosystems to globally distributed Hg is elusive. Here, we use DNA extracted from a dated sediment core to infer the response of microbes to historical Hg delivery. We observe a significant association between the mercuric reductase gene (merA) phylogeny and the timing of Hg deposition. Using relaxed molecular clock models, we show a significant increase in the scaled effective population size of the merA gene beginning ~200 years ago, coinciding with the Industrial Revolution and a coincident strong signal for positive selection acting on residues in the terminal region of the mercuric reductase. This rapid evolutionary response of microbes to changes in the delivery of anthropogenic Hg indicates that microbial genomes record ecosystem response to pollutant deposition in remote regions. PMID- 26057845 TI - Microbial and biochemical basis of a Fusarium wilt-suppressive soil. AB - Crops lack genetic resistance to most necrotrophic pathogens. To compensate for this disadvantage, plants recruit antagonistic members of the soil microbiome to defend their roots against pathogens and other pests. The best examples of this microbially based defense of roots are observed in disease-suppressive soils in which suppressiveness is induced by continuously growing crops that are susceptible to a pathogen, but the molecular basis of most is poorly understood. Here we report the microbial characterization of a Korean soil with specific suppressiveness to Fusarium wilt of strawberry. In this soil, an attack on strawberry roots by Fusarium oxysporum results in a response by microbial defenders, of which members of the Actinobacteria appear to have a key role. We also identify Streptomyces genes responsible for the ribosomal synthesis of a novel heat-stable antifungal thiopeptide antibiotic inhibitory to F. oxysporum and the antibiotic's mode of action against fungal cell wall biosynthesis. Both classical- and community-oriented approaches were required to dissect this suppressive soil from the field to the molecular level, and the results highlight the role of natural antibiotics as weapons in the microbial warfare in the rhizosphere that is integral to plant health, vigor and development. PMID- 26057846 TI - Monitoring host responses to the gut microbiota. AB - The gastrointestinal (GI) ecosystem is increasingly understood to be a fundamental component of health, and has been identified as a new focal point for diagnosing, correcting and preventing countless disorders. Shotgun DNA sequencing has emerged as the dominant technology for determining the genetic and microbial composition of the gut microbiota. This technology has linked microbiota dysbioses to numerous GI diseases including inflammatory bowel disease, obesity and allergy, and to non-GI diseases like autism and depression. The importance of establishing causality in the deterioration of the host-microbiota relationship is well appreciated; however, discovery of candidate molecules and pathways that underlie mechanisms remains a major challenge. Targeted approaches, transcriptional assays, cytokine panels and imaging analyses, applied to animals, have yielded important insight into host responses to the microbiota. However, non-invasive, hypothesis-independent means of measuring host responses in humans are necessary to keep pace with similarly unbiased sequencing efforts that monitor microbes. Mass spectrometry-based proteomics has served this purpose in many other fields, but stool proteins exist in such diversity and dynamic range as to overwhelm conventional proteomics technologies. Focused analysis of host protein secretion into the gut lumen and monitoring proteome-level dynamics in stool provides a tractable route toward non-invasively evaluating dietary, microbial, surgical or pharmacological intervention efficacies. This review is intended to guide GI biologists and clinicians through the methods currently used to elucidate host responses in the gut, with a specific focus on mass spectrometry-based shotgun proteomics applied to the study of host protein dynamics within the GI ecosystem. PMID- 26057847 TI - Improving impurities clearance by amino acids addition to buffer solutions for chromatographic purifications of monoclonal antibodies. AB - The performance of amino acids in Protein A affinity chromatography, anion exchange chromatography and cation exchange chromatography for monoclonal antibody purification was investigated. Glycine, threonine, arginine, glutamate, and histidine were used as buffer components in the equilibration, washing, and elution steps of these chromatographies. Improved clearance of impurity, high molecular weight species (HMW) and host cell proteins (HCP) was observed in the purification processes when using the amino acids as base-buffer constituents, additives or eluents compared with that of buffers without these amino acids. In addition, we designed a buffer system in which the mobile phases were composed of only a single amino acid, histidine, and applied it to the above three chromatographies. Effective HMW and HCP clearance was also obtained in this manner. These results suggest that amino acids may enhance impurity clearance during the purification of monoclonal antibodies. PMID- 26057848 TI - Patterns of fertility preferences and contraceptive behaviour over time: change and continuities among the urban poor in Nairobi, Kenya. AB - The main objective of this paper is to investigate the association between fertility preferences and contraceptive use among 15-49-year-old women living in Korogocho and Viwandani, informal settlements in Nairobi, Kenya. We draw on longitudinal data collected under the Maternal and Child Health project conducted between 2006 and 2010 in the two settlements. There is substantial regularity and stability but also unusual instability in reported fertility preferences over time among women living in these settings. Younger women, aged 15-24 years, are likely to change their preferences over time, passing from limiting to wanting additional children. But women aged 35-49 are likely to change their preferences from desiring more children to limiting their childbearing. The desire to limit childbearing is strongly associated with the use of modern and long-acting contraceptive methods. Findings have major implications for the success of family planning programmes in informal settlements where access to and knowledge about contraception may be limited. PMID- 26057849 TI - Estimation of articular cartilage properties using multivariate analysis of optical coherence tomography signal. AB - OBJECTIVE: The aim was to investigate the applicability of multivariate analysis of optical coherence tomography (OCT) information for determining structural integrity, composition and mechanical properties of articular cartilage. DESIGN: Equine osteochondral samples (N = 65) were imaged with OCT, and their total attenuation and backscattering coefficients (MUt and MUb) were measured. Subsequently, the Mankin score, optical density (OD) describing the fixed charge density, light absorbance in amide I region (Aamide), collagen orientation, permeability, fibril network modulus (Ef) and non-fibrillar matrix modulus (Em) of the samples were determined. Partial least squares (PLS) regression model was calculated to predict tissue properties from the OCT signals of the samples. RESULTS: Significant correlations between the measured and predicted mean collagen orientation (R(2) = 0.75, P < 0.0001), permeability (R(2) = 0.74, P < 0.0001), mean OD (R(2) = 0.73, P < 0.0001), Mankin scores (R(2) = 0.70, P < 0.0001), Em (R(2) = 0.50, P < 0.0001), Ef (R(2) = 0.42, P < 0.0001), and Aamide (R(2) = 0.43, P < 0.0001) were obtained. Significant correlation was also found between MUb and Ef (rho = 0.280, P = 0.03), but not between MUt and any of the determined properties of articular cartilage (P > 0.05). CONCLUSION: Multivariate analysis of OCT signal provided good estimates for tissue structure, composition and mechanical properties. This technique may significantly enhance OCT evaluation of articular cartilage integrity, and could be applied, for example, in delineation of degenerated areas around cartilage injuries during arthroscopic repair surgery. PMID- 26057850 TI - Efferent Feedback in a Spinal-Like Controller: Reaching With Perturbations. AB - We use simulations of a controller that adopts a spinal-like network topology for goal-oriented reaching and assess its sensitivity to the dynamics of internal elements that allow context-independent performance. Such internal elements are often referred to as inverse or forward models of the periphery dynamics, depending on the proposed controller theory. Here, the "models" are used in a forward implementation, and we evaluate how the controller's performance would be affected by the nature of the model. For each point-to-point reaching motion experiment, we use forms of internal "efference models" (e.g., full mathematical representations of peripheral dynamics, simple spindle feedback, etc.) driven by motor reafference, then compare hand trajectories and hand path speeds in the presence or absence of external perturbations. It is demonstrated that a simple velocity-based model reduced the effects of dynamic perturbations by as much as 66%. In addition, the 2D hand trajectories varied from a biological reference by only 0.05 cm. Thus, the controller facilitated biological like motions while providing response to dynamic events which are omitted in earlier biomimetic controllers. This research suggests that these spinal-like systems are robust and tunable via gain-fields without the need of context dependent pre-planning. PMID- 26057851 TI - Locomotor Adaptation by Transtibial Amputees Walking With an Experimental Powered Prosthesis Under Continuous Myoelectric Control. AB - Lower limb amputees can use electrical activity from their residual muscles for myoelectric control of a powered prosthesis. The most common approach for myoelectric control is a finite state controller that identifies behavioral states and discrete changes in motor tasks. An alternative approach to state based myoelectric control is continuous proportional myoelectric control where ongoing electrical activity has a proportional relationship to the prosthetic joint torque or power. To test the potential of continuous proportional myoelectric control for powered lower limb prostheses, we recruited five unilateral transtibial amputees to walk on a treadmill with an experimental powered prosthesis. Subjects walked using the powered prosthesis with and without visual feedback of their control signal in real time. Amputee subjects were able to adapt their residual muscle activation patterns to alter prosthetic ankle mechanics when we provided visual feedback of their myoelectric control signal in real time. During walking with visual feedback, subjects significantly increased their peak prosthetic ankle power ( p = 0.02, ANOVA) and positive work ( p = 0.02, ANOVA) during gait above their prescribed prosthesis values. However, without visual feedback, the subjects did not increase their peak ankle power during push off. These results show that amputee users were able to volitionally alter their prosthesis mechanics during walking, but only when given an explicit goal for their residual muscle motor commands. Future studies that examine the motor and learning capabilities of lower limb amputees using their residual muscles for continuous proportional myoelectric control are needed to determine the viability of integrating continuous high-level control with existing finite state prosthetic controllers. PMID- 26057854 TI - Silver-Mediated N-Trifluoromethylation of Sulfoximines. AB - An unprecedented approach to N-trifluoromethylations of electron-rich nucleophilic sites following a radical pathway is reported. Accordingly, various sulfoximines (19 examples) have been N-trifluoromethylated, providing previously unreported products with satisfying functionality tolerance in moderate to good yields. With a C-N bond length at the N-CF3 moiety of 1.341 A the respective linkage is shorter than a traditional C-N single bond and comparable with that of a C-N double bond. PMID- 26057852 TI - Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. AB - Microglia have been shown to contribute to the clearance of brain amyloid beta peptides (Abeta), the major component of amyloid plaques, in Alzheimer's disease (AD). However, it is not known whether microglia play a similar role in the clearance of tau, the major component of neurofibrillary tangles (NFTs). We now report that murine microglia rapidly internalize and degrade hyperphosphorylated pathological tau isolated from AD brain tissue in a time-dependent manner in vitro. We further demonstrate that microglia readily degrade human tau species released from AD brain sections and eliminate NFTs from brain sections of P301S tauopathy mice. The anti-tau monoclonal antibody MC1 enhances microglia-mediated tau degradation in an Fc-dependent manner. Our data identify a potential role for microglia in the degradation and clearance of pathological tau species in brain and provide a mechanism explaining the potential therapeutic actions of passively administered anti-tau monoclonal antibodies. PMID- 26057853 TI - Shifts in the Antibiotic Susceptibility, Serogroups, and Clonal Complexes of Neisseria meningitidis in Shanghai, China: A Time Trend Analysis of the Pre Quinolone and Quinolone Eras. AB - BACKGROUND: Fluoroquinolones have been used broadly since the end of the 1980s and have been recommended for Neisseria meningitidis prophylaxis since 2005 in China. The aim of this study was to determine whether and how N. meningitidis antimicrobial susceptibility, serogroup prevalence, and clonal complex (CC) prevalence shifted in association with the introduction and expanding use of quinolones in Shanghai, a region with a traditionally high incidence of invasive disease due to N. meningitidis. METHODS AND FINDINGS: A total of 374 N. meningitidis isolates collected by the Shanghai Municipal Center for Disease Control and Prevention between 1965 and 2013 were studied. Shifts in the serogroups and CCs were observed, from predominantly serogroup A CC5 (84%) in 1965-1973 to serogroup A CC1 (58%) in 1974-1985, then to serogroup C or B CC4821 (62%) in 2005-2013. The rates of ciprofloxacin nonsusceptibility in N. meningitidis disease isolates increased from 0% in 1965-1985 to 84% (31/37) in 2005-2013 (p < 0.001). Among the ciprofloxacin-nonsusceptible isolates, 87% (27/31) were assigned to either CC4821 (n = 20) or CC5 (n = 7). The two predominant ciprofloxacin-resistant clones were designated ChinaCC4821-R1-C/B and ChinaCC5-R14-A. The ChinaCC4821-R1-C/B clone acquired ciprofloxacin resistance by a point mutation, and was present in 52% (16/31) of the ciprofloxacin nonsusceptible disease isolates. The ChinaCC5-R14-A clone acquired ciprofloxacin resistance by horizontal gene transfer, and was found in 23% (7/31) of the ciprofloxacin-nonsusceptible disease isolates. The ciprofloxacin nonsusceptibility rate was 47% (7/15) among isolates from asymptomatic carriers, and nonsusceptibility was associated with diverse multi-locus sequence typing profiles and pulsed-field gel electrophoresis patterns. As detected after 2005, ciprofloxacin-nonsusceptible strains were shared between some of the patients and their close contacts. A limitation of this study is that isolates from 1986-2004 were not available and that only a small sample of convenience isolates from 1965 1985 were available. CONCLUSIONS: The increasing prevalence of ciprofloxacin resistance since 2005 in Shanghai was associated with the spread of hypervirulent lineages CC4821 and CC5. Two resistant meningococcal clones ChinaCC4821-R1-C/B and ChinaCC5-R14-A have emerged in Shanghai during the quinolone era. Ciprofloxacin should be utilized with caution for the chemoprophylaxis of N. meningitidis in China. PMID- 26057855 TI - Exciting times for the journal. PMID- 26057856 TI - Clinical Q & A: Translating therapeutic temperature management from theory to practice. PMID- 26057857 TI - PLGA nanoparticles prepared by nano-emulsion templating using low-energy methods as efficient nanocarriers for drug delivery across the blood-brain barrier. AB - Neurodegenerative diseases have an increased prevalence and incidence nowadays, mainly due to aging of the population. In addition, current treatments lack efficacy, mostly due to the presence of the blood-brain barrier (BBB) that limits the penetration of the drugs to the central nervous system. Therefore, novel drug delivery systems are required. Polymeric nanoparticles have been reported to be appropriate for this purpose. Specifically, the use of poly-(lactic-co-glycolic acid) (PLGA) seems to be advantageous due to its biocompatibility and biodegradability that ensure safe therapies. In this work, a novel approximation to develop loperamide-loaded nanoparticles is presented: their preparation by nano-emulsion templating using a low-energy method (the phase inversion composition, PIC, method). This nano-emulsification approach is a simple and very versatile technology, which allows a precise size control and it can be performed at mild process conditions. Drug-loaded PLGA nanoparticles were obtained using safe components by solvent evaporation of template nano-emulsions. Characterization of PLGA nanoparticles was performed, together with the study of the BBB crossing. The in vivo results of measuring the analgesic effect using the hot-plate test evidenced that the designed PLGA loperamide-loaded nanoparticles are able to efficiently cross the BBB, with high crossing efficiencies when their surface is functionalized with an active targeting moiety (a monoclonal antibody against the transferrin receptor). These results, together with the nanoparticle characterization performed here are expected to provide sufficient evidences to end up to clinical trials in the near future. PMID- 26057858 TI - Pulmonary alveolar proteinosis and superinfection with pulmonary tuberculosis in a case. AB - Pulmonary alveolar proteinosis (PAP) is a rare and diffuse lung process, characterized by the presence of alveolar spaces filled with amorphous eosinophilic material. Impaired macrophage function and impaired host defence due to abnormalities of surfactant proteins may favor the growth of microorganisms. The association of alveolar proteinosis with mycobacterial infections is rarely reported. The PAP and superinfection with pulmonary tuberculosis is defined by radiologic and histopathologic in a 46 year-old patient. The patients with PAP should be monitored for superinfection. It may cause the disease progression and radiological, clinical symptoms may improve with treatment of superinfection. PMID- 26057859 TI - Potent Apoptotic Response Induced by Chloroacetamidine Anthrathiophenediones in Bladder Cancer Cells. AB - We previously found that two neighboring G-quadruplexes behave as a molecular switch controlling the expression of HRAS (Cogoi, S.; Schekotikhin, A. E.; Xodo, L. E. Nucl. Acids Res. 2014, DOI: 10.1093/nar/gku574). In this study we have designed anthrathiophenediones with two chloroacetamidine-containing side chains (CATDs) as G-quadruplex binders and have examined their anticancer activity in T24 bladder cancer cells bearing mutant HRAS and in T24 xenografts. The designed CATDs (3a-e), bearing alkyl side chains of different length, penetrate T24 cancer cells more than their analogues with guanidine-containing side chains. The lead compounds 3a and 3c inhibit HRAS expression, metabolic activity, and colony formation in T24 cancer cells. They also activate a strong apoptotic response, as indicated by PARP-1, caspases 3/7, and annexin V/propidium iodide assays. Apoptosis occurs under conditions where cyclin D1 is down-regulated and the cell cycle arrested in G2 phase. Finally, compound 3a inhibits the growth of T24 xenografts and increases the median survival time of nude mice. PMID- 26057860 TI - Specific inhibition of fibroblast activation protein (FAP)-alpha prevents tumor progression in vitro. AB - PURPOSE: Solid tumors modulate their environment to keep non-malignant stromal cells in a tumor-promoting state. The main cells in the stroma of epithelial derived tumors are cancer associated fibroblasts (CAF) that are critical to tumorigenesis and angiogenesis. CAFs also supply the tumor cells with growth factors and extracellular matrix (ECM) degrading enzymes. They are thus essential for tumor initiation as well as tumor progression and metastasis, suggesting that they represent an ideal cellular target of an integrative tumor therapy. Fibroblast activation protein (FAP) is a well-defined marker, expressed at high levels on the cell surface of CAFs. FAP, a constitutively active serine peptidase with both dipeptidyl peptidase IV (DPP IV) and collagenase/gelatinase activity, promotes malignant and invasive behavior of epithelial cancers. High stromal expression levels of FAP correlate with poor prognosis. FAP is difficult to detect in non-diseased adult tissue, but it is generally expressed at sites of tissue remodeling. MATERIALS AND METHODS: In our experiments, we aimed for a reduction of the pro-tumorigenic activities of CAFs by depleting FAP from fibroblasts growing in a composite environment with epithelial tumor cells. RESULTS: FAP depletion was achieved by two therapeutically relevant approaches: a novel internalizing anti-FAP IgG1 antibody and FAP gene knock-down by siRNA delivery. The antibody effectively removed FAP from the cell surface and was capable of reversing the FAP mediated migratory and invasive capacity. FAP RNA interference was equally effective when compared to the antibody. CONCLUSIONS: Thus, targeting FAP on CAF suppresses pro-tumorigenic activities and may result in a clinically effective reduction of tumor progression and dissemination. PMID- 26057861 TI - Structure-based design of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3beta inhibitors to activate Wnt/beta-catenin pathway. AB - Deregulation of Wnt/beta-catenin pathway is closely related to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD), and glycogen synthase kinase 3beta (GSK-3beta), the central negative regulator of Wnt pathway, is regarded as an important target for these diseases. Here, we report a series of benzo[e]isoindole-1,3-dione derivatives as selective GSK-3beta inhibitors by rational-design and synthesis, which show high selectivity against GSK-3beta over Cyclin-dependent kinase 2 (CDK2), and significantly activate the cellular Wnt/beta-catenin pathway. The structure-activity relationship of these GSK-3beta inhibitors was also explored by in silico molecular docking. PMID- 26057862 TI - S100A4 and its role in metastasis - simulations of knockout and amplification of epithelial growth factor receptor and matrix metalloproteinases. AB - The calcium-binding signalling protein S100A4 enhances metastasis in a variety of cancers. Despite a wealth of data available, the molecular mechanism by which S100A4 drives metastasis is unknown. Integration of the current knowledge defies straightforward intuitive interpretation and requires computer-aided approaches to represent the complexity emerging from cross-regulating species. Here we carried out a systematic sensitivity analysis of the S100A4 signalling network in order to identify key control parameters for efficient therapeutic intervention. Our approach only requires limited details of the molecular interactions and permits a straightforward integration of the available experimental information. By integrating the available knowledge, we investigated the effects of combined inhibition of signalling pathways. Through selective knockout or inhibition of the network components, we show that the interaction between epidermal growth factor receptor (EGFR) and S100A4 modulates the sensitivity of angiogenesis development to matrix metalloproteinases (MMPs) activity. We also show that, in cells that express high EGFR, MMP inhibitors are not expected to be useful in tumours if high activity of S100A4 is present. PMID- 26057863 TI - Long-lasting humoral immune response induced in HIV-1-infected patients by a synthetic peptide (AT20) derived from the HIV-1 matrix protein p17 functional epitope. AB - OBJECTIVE: A therapeutic vaccination based on a synthetic peptide (AT20) representative of the HIV-1 matrix protein p17 (p17) functional region, coupled to keyhole limpet hemocyanin (KLH) AT20-KLH was capable of inducing the production of high-avidity antibodies (Abs) toward a previous untargeted p17 hotspot of functional activity in highly active antiretroviral therapy (HAART) treated HIV-1-infected patients. Since avidity of Abs after immunization and the retention of antigens are important in sustaining the long-lasting production of specific humoral responses, we asked whether AT20-KLH vaccination would result in development of a long-lived immune response. METHODS: The long-term duration of Ab response to AT20-KLH has been evaluated in 10 patients previously enrolled for the AT20-KLH vaccination trial at day 898 post-immunization. Ab titer and their avidity was assessed using specifically designed ELISA assays, whereas their neutralizing capacity was estimated in vitro using a 'wound sealing assay'. RESULTS: Data obtained show that high titers of specific anti-AT20 Abs were maintained at more than 2 years after the last immunization. Furthermore, these Abs were capable to neutralize exogenous p17, as assessed by ability of sera derived from AT20-KLH-immunized patients to block the ability of p17 to promote cell migration in vitro. CONCLUSION: This finding attests for a successful AT20 KLH vaccine molecule formulation and for an effective HAART-dependent Ab persistence. PMID- 26057864 TI - Automated extraction and labelling of the arterial tree from whole-body MRA data. AB - In this work, we present a fully automated algorithm for extraction of the 3D arterial tree and labelling the tree segments from whole-body magnetic resonance angiography (WB-MRA) sequences. The algorithm developed consists of two core parts (i) 3D volume reconstruction from different stations with simultaneous correction of different types of intensity inhomogeneity, and (ii) Extraction of the arterial tree and subsequent labelling of the pruned extracted tree. Extraction of the arterial tree is performed using the probability map of the "contrast" class, which is obtained as one of the results of the inhomogeneity correction scheme. We demonstrate that such approach is more robust than using the difference between the pre- and post-contrast channels traditionally used for this purpose. Labelling the extracted tree is performed by using a combination of graph-based and atlas-based approaches. Validation of our method with respect to the extracted tree was performed on the arterial tree subdivided into 32 segments, 82.4% of which were completely detected, 11.7% partially detected, and 5.9% were missed on a cohort of 35 subjects. With respect to automated labelling accuracy of the 32 segments, various registration strategies were investigated on a training set consisting of 10 scans. Further analysis on the test set consisting of 25 data sets indicates that 69% of the vessel centerline tree in the head and neck region, 80% in the thorax and abdomen region, and 84% in the legs was accurately labelled to the correct vessel segment. These results indicate clinical potential of our approach in enabling fully automated and accurate analysis of the entire arterial tree. This is the first study that not only automatically extracts the WB-MRA arterial tree, but also labels the vessel tree segments. PMID- 26057865 TI - Geochemical Triggers of Arsenic Mobilization during Managed Aquifer Recharge. AB - Mobilization of arsenic and other trace metal contaminants during managed aquifer recharge (MAR) poses a challenge to maintaining local groundwater quality and to ensuring the viability of aquifer storage and recovery techniques. Arsenic release from sediments into solution has occurred during purified recycled water recharge of shallow aquifers within Orange County, CA. Accordingly, we examine the geochemical processes controlling As desorption and mobilization from shallow, aerated sediments underlying MAR infiltration basins. Further, we conducted a series of batch and column experiments to evaluate recharge water chemistries that minimize the propensity of As desorption from the aquifer sediments. Within the shallow Orange County Groundwater Basin sediments, the divalent cations Ca(2+) and Mg(2+) are critical for limiting arsenic desorption; they promote As (as arsenate) adsorption to the phyllosilicate clay minerals of the aquifer. While native groundwater contains adequate concentrations of dissolved Ca(2+) and Mg(2+), these cations are not present at sufficient concentrations during recharge of highly purified recycled water. Subsequently, the absence of dissolved Ca(2+) and Mg(2+) displaces As from the sediments into solution. Increasing the dosages of common water treatment amendments including quicklime (Ca(OH)2) and dolomitic lime (CaO.MgO) provides recharge water with higher concentrations of Ca(2+) and Mg(2+) ions and subsequently decreases the release of As during infiltration. PMID- 26057866 TI - Technique determinants of knee joint loads during cutting in female soccer players. AB - The aim of this study was to investigate the relationships between technique characteristics and knee abduction moments during 90 degrees cuts. A cross sectional design involving 26 elite and sub-elite female soccer players (mean +/- SD; age: 21 +/- 3.2 years, height: 1.68 +/- 0.07 m, and mass: 59.1 +/- 6.8 kg) was used to explore relationships between pre-determined technical factors on knee abduction moments during cutting. Three dimensional motion analyses of 90 degrees cuts on the right leg were performed using 'Qualisys Pro Reflex' infrared cameras (240 Hz). Ground reaction forces were collected from two AMTI force platforms (1200 Hz) embedded into the running track to examine 2nd last and last footfalls. Pearson's correlation coefficients, co-efficients of determination and hierarchical multiple regression were used to explore relationships between a range of technique parameters and peak knee abduction moments. Significance was set at p < .05. Hierarchical multiple regression revealed that initial knee abduction angle, lateral leg plant distance and initial lateral trunk lean could explain 67% (62% adjusted) of the variation in peak knee abduction moments (F(1,22) = 8.869, p = .007). These findings reveal potential modifiable technical factors to lower peak knee abduction moments during cutting. PMID- 26057867 TI - Influence of observing another person's action on self-generated performance in schizophrenia. AB - INTRODUCTION: Observing another person's action influences the execution of one's own action via the mirror neuron system. However, the ability to control the effect of such action observation on one's voluntary action has not been investigated. The aim of this study was to elucidate the influence of observing another's action on own voluntary movement in patients with schizophrenia. METHODS: Fifteen patients with schizophrenia and 15 healthy age-matched controls participated in this study. Subjects were asked to perform a gripping task at 50% of their maximal voluntary force (MVF), whereas simultaneously watching others performed the same task with a different grip force (0%, 50% and 100% MVF). RESULTS: The healthy controls applied a constant grip force under each condition. In patients with schizophrenia, the grip force was significantly reduced during viewing the gripping of others at 50% MVF compared to during viewing other's gripping at 0% and 100% MVF. The score of the Brief Psychiatric Rating Scale (BPRS) and the Scale for the Assessment of Positive Symptoms were correlated with the fluctuation in grip force among the action observation conditions. CONCLUSION: Patients with schizophrenia might have difficulty controlling the influence of action observation on self-generated performance. PMID- 26057868 TI - Factors influencing self-assessment of cognition and functioning in bipolar disorder: a preliminary study. AB - INTRODUCTION: Self-assessment deficits are common in schizophrenia and span multiple aspects of functioning, including awareness of symptoms, and the ability to assess objective levels of cognitive deficits and everyday functioning. Whereas impaired awareness of illness in bipolar disorder during symptomatic periods is well understood, awareness of disability and cognitive deficits has been less well studied. METHODS: In this pilot study, 30 patients with a lifetime history of bipolar I disorder and current bipolar depression completed performance-based tests of cognition and functional capacity and self-reported their opinions of their cognitive abilities, everyday functioning and symptoms. High contact clinicians also provided impressions of the patients' cognitive performance and everyday functioning. RESULTS: Clinician impressions of cognition and everyday functioning were correlated with the results of the performance based assessments, whereas the patient self-reports of cognition and functioning were uncorrelated both with their own performance and with the clinician impressions. However, severity of depressive symptoms was correlated with self reports of functioning in cognitive and functional domains, but not with either performance-based data or clinician impressions of cognition or functioning. CONCLUSIONS: Depression appears to be a factor affecting self-assessment in bipolar disorder and reports of cognition and functioning were minimally related to objective information and clinician impressions. Symptoms of mania were minimal and not correlated with performance-based assessments or clinician impressions. PMID- 26057869 TI - Triage of Atypical Glandular Cell by SOX1 and POU4F3 Methylation: A Taiwanese Gynecologic Oncology Group (TGOG) Study. AB - INTRODUCTION: Invasive procedures including loop electrosurgical excision, cervical conization, and endometrial sampling are often recommended when atypical glandular cells (AGC) are detected on Pap smear with unsatisfactory colposcopy. These invasive procedures may result in patient anxiety, increased medical expense, and increasing the risk of preterm delivery in subsequent pregnancies. This study was performed to assess methylation biomarkers in the triage of AGC on Pap smear for invasive procedures. METHODS: We conducted a multicenter study in 13 medical centers in Taiwan from May 2012 to May 2014. A total of 55 samples diagnosed "AGC not otherwise specified" (AGC-NOS) were included. All patients with AGC underwent colposcopy, cervical biopsy, endometrial sampling, and conization if indicated. Multiplex quantitative methylation-specific polymerase chain reaction (QMSPCR) was performed. Sensitivity, specificity, and accuracy were calculated for detecting CIN3+ and endometrial complex hyperplasia. RESULTS: In 55 patients with AGC, the sensitivity for methylated (m) SOX1m, PAX1 m, ZNF582m,PTPRRm, AJAP1m, HS3ST2m, and POU4F3m for detecting CIN3+ and endometrial complex hyperplasia lesions was 100, 86, 71, 86, 86, 57, and 100%; specificity was 67, 79, 85, 50, 52, 96, and 52%, respectively. Testing for high risk-HPV had a sensitivity of 57% and specificity of 75% for CIN3+ and endometrial complex hyperplasia lesions. CONCLUSION: Methylated (m) SOX1m and POU4F3m could be new methylation biomarkers for detection of CIN3+ and endometrial complex hyperplasia in AGC. Women with AGC and positive SOX1m / POU4F3m, colposcopy, cervical conization or endometrial sampling should be considered. PMID- 26057870 TI - Regulation of Phagocyte Migration by Signal Regulatory Protein-Alpha Signaling. AB - Signaling through the inhibitory receptor signal regulatory protein-alpha (SIRPalpha) controls effector functions in phagocytes. However, there are also indications that interactions between SIRPalpha and its ligand CD47 are involved in phagocyte transendothelial migration. We have investigated the involvement of SIRPalpha signaling in phagocyte migration in vitro and in vivo using mice that lack the SIRPalpha cytoplasmic tail. During thioglycolate-induced peritonitis in SIRPalpha mutant mice, both neutrophil and macrophage influx were found to occur, but to be significantly delayed. SIRPalpha signaling appeared to be essential for an optimal transendothelial migration and chemotaxis, and for the amoeboid type of phagocyte migration in 3-dimensional environments. These findings demonstrate, for the first time, that SIRPalpha signaling can directly control phagocyte migration, and this may contribute to the impaired inflammatory phenotype that has been observed in the absence of SIRPalpha signaling. PMID- 26057871 TI - The Routes of Emergence of Life from LUCA during the RNA and Viral World: A Conspectus. AB - How did life emerge on Earth? The aim of the Network of Researchers on Horizontal Gene Transfer and the Last Universal Cellular Ancestor (NoR HGT & LUCA) is to understand how the genetics of LUCAs were reorganised prior to the advent of the three domains of life. This paper reports the research of eminent scientists who have come together within the network and are making significant contributions to the wider knowledge base surrounding this, one of science's remaining mysteries. I also report on their relevance in relation to LUCAs and life's origins, as well as ask a question: what next? PMID- 26057872 TI - Correction: Predictive Value of a Profile of Routine Blood Measurements on Mortality in Older Persons in the General Population: The Leiden 85-Plus Study. PMID- 26057874 TI - Impact of adolescent peer aggression on later educational and employment outcomes in an Australian cohort. AB - This study used prospective birth cohort data to analyse the relationship between peer aggression at 14 years of age and educational and employment outcomes at 17 years (N = 1091) and 20 years (N = 1003). Participants from the Western Australian Pregnancy Cohort (Raine) study were divided into mutually exclusive categories of peer aggression. Involvement in peer aggression was reported by 40.2% (10.1% victims; 21.4% perpetrators; 8.7% victim-perpetrators) of participants. Participants involved in any form of peer aggression were less likely to complete secondary school. Perpetrators and victim-perpetrators of peer aggression were more likely to be in the 'No Education, Employment or Training' group at 20 years of age. This association was explained by non-completion of secondary school. These findings demonstrate a robust association between involvement in peer aggression and non-completion of secondary school, which in turn was associated with an increased risk of poor educational and employment outcomes in early adulthood. PMID- 26057873 TI - ApoM Suppresses TNF-alpha-Induced Expression of ICAM-1 and VCAM-1 Through Inhibiting the Activity of NF-kappaB. AB - To explore the anti-inflammatory effect of apolipoprotein M (apoM) on regulation of tumor necrosis factor-alpha (TNF-alpha)-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) and further investigate the molecular mechanism of apoM in this process. We found that TNF-alpha could decrease expression of apoM and inhibitor of NF-kappaB-alpha (IkappaBalpha) in HepG2 cells. Overexpression of apoM caused a significant decrease of ICAM-1 and VCAM-1 expression, while it caused a significant increase of IkappaBalpha expression in HepG2 cells. Furthermore, the treatment with TNF alpha could increase ICAM-1 and VCAM-1 expression, decrease IkappaBalpha protein expression, and increase nuclear factor-kappaB (NF-kappaB) activity, and these effects were markedly enhanced by small interfering RNA (siRNA)-mediated silencing of apoM in HepG2 cells. Our findings demonstrated that apoM suppressed TNF-alpha-induced expression of ICAM-1 and VCAM-1 through inhibiting the activity of NF-kappaB. PMID- 26057875 TI - Adolescents' unconditional acceptance by parents and teachers and educational outcomes: A structural model of gender differences. AB - The purpose of this study was to detect gender specific patterns in the network of relations between unconditionality of parental and teacher acceptance in the form of unconditional positive regard and a range of educational outcomes, as indexed by academic self-perception, academic intrinsic motivation, and academic achievement. To test the role of gender as a moderator, a multi-group analysis was employed within the framework of structural equation modelling with increasing restrictions placed on the structural paths across genders. The results on a sample of 427 adolescents in grades 7-9 showed that conditionality of acceptance undermined level of perceived acceptance for both social agents. Moreover, unconditionality of teacher acceptance exerted stronger influences on students' educational outcomes than unconditionality of parental acceptance, with effect sizes being larger for girls than for boys. PMID- 26057876 TI - Cumulative experiences with life adversity: Identifying critical levels for targeting prevention efforts. AB - This paper aims to assess the role of individual types and cumulative life adversity for understanding depressive symptomatology and aggressive behavior. Data were collected in 2011 as part of the Teen Life Online and in Schools Study from 916 ethnically-diverse students from 12 middle, K-8, 6-12 and high schools in the Midwest United States. Youth reported an average of 4.1 non-victimization adversities and chronic stressors in their lifetimes. There was a linear relationship between number of adversities and depression and aggression scores. Youth reporting the highest number of adversities (7 or more) had significantly higher depression and aggression scores than youth reporting any other number of adversities suggesting exposure at this level is a critical tipping point for mental health concerns. Findings underscore an urgent need to support youth as they attempt to negotiate, manage, and cope with adversity in their social worlds. PMID- 26057877 TI - Tailored Presentation of Carbohydrates on a Coiled Coil-Based Scaffold for Asialoglycoprotein Receptor Targeting. AB - The coiled-coil folding motif represents an ideal scaffold for the defined presentation of ligands due to the possibility of positioning them at specific distances along the axis. We created a coiled-coil glycopeptide library to characterize the distances between the carbohydrate-binding sites of the asialoglycoprotein receptors (ASGPR) on hepatocytes. The components of the glycopeptide library vary for the number of displayed ligands (galactose), their position on the peptide sequence, and the space between peptide backbone and carbohydrate. We determined the binding of the glycopeptides to the hepatocytes, and we established the optimal distance and orientation of the galactose moieties for interaction with the ASGPR using flow cytometry. We confirmed that the binding occurs through endocytosis mediated by ASGPR via inhibition studies with cytochalasin D; fluorescence microscopy studies display the uptake of the carrier peptides inside the cell. Thus, this study demonstrates that the coiled-coil motif can be used as reliable scaffold for the rational presentation of ligands. PMID- 26057878 TI - Effect of Food Regulation on the Spanish Food Processing Industry: A Dynamic Productivity Analysis. AB - This article develops the decomposition of the dynamic Luenberger productivity growth indicator into dynamic technical change, dynamic technical inefficiency change and dynamic scale inefficiency change in the dynamic directional distance function context using Data Envelopment Analysis. These results are used to investigate for the Spanish food processing industry the extent to which dynamic productivity growth and its components are affected by the introduction of the General Food Law in 2002 (Regulation (EC) No 178/2002). The empirical application uses panel data of Spanish meat, dairy, and oils and fats industries over the period 1996-2011. The results suggest that in the oils and fats industry the impact of food regulation on dynamic productivity growth is negative initially and then positive over the long run. In contrast, the opposite pattern is observed for the meat and dairy processing industries. The results further imply that firms in the meat processing and oils and fats industries face similar impacts of food safety regulation on dynamic technical change, dynamic inefficiency change and dynamic scale inefficiency change. PMID- 26057879 TI - Speed spinal anesthesia revisited: new drugs and their clinical effects. AB - PURPOSE OF REVIEW: Spinal anesthesia (SPA) has not been popular for day-case surgery because of prolonged neurologic blockade with long-acting local anesthetics such as bupivacaine, thereby delaying discharge. Although the intermediate duration of action of lidocaine and mepivacaine appears to be more suitable for day-case surgery, their use is not deemed appropriate by many because of a high incidence of transient neurologic symptoms (TNSs). The present review summarizes recent clinical data on the intrathecal use of alternative local anesthetics and adjuvants that may offer valuable alternatives to general anesthesia in day-case surgery. RECENT FINDINGS: Prilocaine has a similar intrathecal pharmacokinetic profile as lidocaine but with a significantly lower risk of TNSs. Onset of spinal after 2-chloroprocaine is comparable with lidocaine or prilocaine, but with a considerably shorter duration of action. Also, TNS is clearly less frequent compared with lidocaine. Although its intrathecal use has recently been approved in Europe, this is still considered to be off-label in the USA. Articaine provides an extraordinary fast onset and a short duration of spinal block, the latter being approximately intermediate between chloroprocaine and prilocaine. However, articaine is associated with a high risk for intraoperative hypotension and a small risk for TNS, albeit but less frequent than after lidocaine. Concerns regarding possible neurotoxicity of articaine remain to be resolved. SUMMARY: SPA for day cases might become a most valuable method for ambulatory surgery when using short acting local anesthetics. This, however, not only depends on drugs being used but also on infrastructure (post anaesthesia care unit) and organizational issues. PMID- 26057880 TI - Current world literature. Neuroanesthesia. PMID- 26057882 TI - Impaired Expression of Prostaglandin E2 (PGE2) Synthesis and Degradation Enzymes during Differentiation of Immortalized Urothelial Cells from Patients with Interstitial Cystitis/Painful Bladder Syndrome. AB - PURPOSE: The differentiated superficial cells of the urothelium restrict urine flow into the bladder wall. We have demonstrated that urothelial cells isolated from bladders of patients with interstitial cystitis/painful bladder syndrome (IC/PBS) fail to release PGE2 in response to tryptase. This study examines the expression of PGE2 synthesis and degradation enzymes in urothelial cells during differentiation. MATERIALS AND METHODS: We measured immunoprotein expression of cyclooxygenase-2 (COX-2), prostaglandin E2 synthase (PGES) and 15 hydroxyprostaglandin dehydrogenase (PGDH) in human urothelial cells and in immortalized urothelial cells isolated from the bladders of IC/PBS patients or normal subjects during stratification and differentiation produced by increased calcium and fetal bovine serum (Ca/FBS) in the culture medium for 1, 3 and 7 days. RESULTS: PGES immunoprotein expression increased during differentiation in normal and IC/PBS urothelial cells. COX-2 expression also increased in cells from normal patients following differentiation. Remarkably, no COX-2 expression was detectable in urothelial cells isolated from 3 out of 4 IC/PBS patients. PGDH immunoprotein expression decreased in normal cells after 1 and 3 days of Ca/FBS addition, but returned to normal after 7 days. PGDH expression was unchanged during differentiation at 1 and 3 days, but was more than 2-fold higher at 7 days compared to day 0 in the IC/PBS cells. Urothelial cells isolated from IC/PBS patients demonstrated no PGE2 release in response to tryptase under any of the experimental conditions studied. CONCLUSIONS: Taken together, our results indicate that PGE2 release is compromised during stratification and differentiation in IC/PBS urothelium and may contribute to impaired barrier function. PMID- 26057883 TI - Invited Commentary. PMID- 26057884 TI - In response. PMID- 26057885 TI - Current Practice in the Management of Open Fractures Among Orthopaedic Trauma Surgeons. Part A: Initial Management. A Survey of Orthopaedic Trauma Surgeons. AB - OBJECTIVES: Open fractures are one of the injuries with the highest rate of infection that orthopaedic trauma surgeons treat. The main purpose of this survey was to determine current practice and practice variation among Orthopaedic Trauma Association (OTA) members and make treatment recommendations based on previously published resources. DESIGN: Survey. SETTING: Web-based survey. PARTICIPANTS: Three hundred seventy-nine orthopaedic trauma surgeons. METHODS: A 15-item questionnaire-based study titled "OTA Open Fracture Survey" was constructed. The survey was delivered to all OTA membership categories. Different components of the data charts were used to analyze numerous aspects of open fracture management, focusing on parameters of initial and definitive treatment. RESULTS: Eighty-six percent of participants responded that a period of time of less than 1 hour is the optimal time to antibiotic administration after identification of open fracture. Despite concerns with nephrotoxicity, 24.0%-76.3% of respondents reported the use of aminoglycosides in management of open fractures. A little over half of survey respondents continue antibiotics until next debridement in wounds that were not definitively closed after initial debridement and stabilization. CONCLUSIONS: Rapid administration of antibiotics in open fracture management is important. Aminoglycoside use is still prevalent despite evidence questioning efficacy and toxicity concerns. Time to debridement of open fractures is controversial among OTA members. Antibiotic administration is commonly continued >48 hours despite concerns raised by Surgical Infection Society and The Eastern Association of the Surgery of Trauma. Regarding study logistics, survey participation reminders should be used when conducting this type of study as it can increase data accrual by 50%. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 26057886 TI - Current Practice in the Management of Open Fractures Among Orthopaedic Trauma Surgeons. Part B: Management of Segmental Long Bone Defects. A Survey of Orthopaedic Trauma Association Members. AB - OBJECTIVES: Treatment of segmental long bone defects is one of the areas of substantial controversy in current orthopaedic trauma. The main purpose of this survey was to determine current practice and practice variation within the Orthopaedic Trauma Association (OTA) membership on this topic. DESIGN: Survey. SETTING: Web-based survey. PARTICIPANTS: Three hundred seventy-nine orthopaedic trauma surgeons. METHODS: A 15-item questionnaire-based study titled "OTA Open Fracture Survey" was constructed. The survey was delivered to all OTA membership categories. Different components of the data charts were used to analyze various aspects of open fracture management, focusing on definitive treatment and materials used for grafting in "critical-sized" segmental bone defects. RESULTS: Between July and August 2012, a total of 379/1545 members responded for a 25% response rate. Overall, 89.5% (339/379) of respondents use some sort of antibiotic cement spacer before bone grafting. It was found that 92% of respondents preferred to use some type of autograft at time of definitive grafting of segmental defects. When using a grafting technique, 88% said they used some type of antibiotic cement. Within that context, 60.1% said graft placement should be done at 6 weeks. CONCLUSIONS: There continues to be substantial variation in the timing of bone graft placement after soft tissue healing and the source and form of graft used. The use of antibiotic cement is common in segmental defects that require delayed bone grafting. Obtaining base line practice characteristics on controversial topics will help provide a foundation for assessing research needs and, therefore, goals. LEVEL OF EVIDENCE: Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence. PMID- 26057887 TI - Scapula Fractures: Interobservor Reliability of Classification and Treatment. PMID- 26057888 TI - In Response. PMID- 26057889 TI - In Response. PMID- 26057890 TI - Membrane-Associated Transporter Protein (MATP) Regulates Melanosomal pH and Influences Tyrosinase Activity. AB - The SLC45A2 gene encodes a Membrane-Associated Transporter Protein (MATP). Mutations of this gene cause oculocutaneous albinism type 4 (OCA4). However, the molecular mechanism of its action in melanogenesis has not been elucidated. Here, we discuss the role of MATP in melanin production. The SLC45A2 gene is highly enriched in human melanocytes and melanoma cell lines, and its protein, MATP, is located in melanosomes. The knockdown of MATP using siRNAs reduced melanin content and tyrosinase activity without any morphological change in melanosomes or the expression of melanogenesis-related proteins. Interestingly, the knockdown of MATP significantly lowered the melanosomal pH, as verified through DAMP analysis, suggesting that MATP regulates melanosomal pH and therefore affects tyrosinase activity. Finally, we found that the reduction of tyrosinase activity associated with the knockdown of MATP was readily recovered by copper treatment in the in vitro L-DOPA oxidase activity assay of tyrosinase. Considering that copper is an important element for tyrosinase activity and that its binding to tyrosinase depends on melanosomal pH, MATP may play an important role in regulating tyrosinase activity via controlling melanosomal pH. PMID- 26057891 TI - Who Are the True Fans? Evidence from an Event-Related Potential Study. AB - Fans of celebrities commonly exist in modern society. Researchers from social science have been concerned with this problem for years. Furthermore, such researchers have attempted to measure people's involvement with celebrities in various ways. However, no study measured the degree of addiction to a specific celebrity at the neurological level. Therefore, the current study employed visually evoked event related potentials (ERPs) to examine people's attitude toward celebrities by comparing different brain activities of fans and non-fans when they were shown a set of photos. These photos include a specific celebrity, a familiar person, a stranger and a butterfly. Furthermore, to examine the validity of the detected neural index, we also investigated the correlation between brain activity and the score of the Celebrity Attitude Scale (CAS), which was a questionnaire used to explore people's attitude toward celebrities at behavioral level. Two groups of subjects were asked to complete an implicit task, i.e., to press a button when a picture of a butterfly appeared. Results revealed that fans showed significant positive N2 and P300 deflection when viewing the photos of their favorite celebrity, whereas in the non-fan group, the subjects only showed larger P300 amplitude as a response to the celebrity's photos. Furthermore, a positive correlation between P300 amplitude elicited by the stimuli of a celebrity face and CAS scores was also observed. These findings indicated fan attitude to a specific celebrity can also be observed at the neurological level and suggested the potential utility of using ERP component as an index of fandom involvement. PMID- 26057893 TI - Geometric stability, electronic structure, and intercalation mechanism of Co adatom anchors on graphene sheets. AB - We perform a systematic study of the adsorption of Co adatom on monolayer and bilayer graphene sheets, and the calculated results are compared through the van der Waals density functional (vdW-DF) and the generalized gradient approximation of Perdew, Burke and Ernzernhof (GGA + PBE) methods. For the single Co adatom, its adsorption energy at vacancy site was found to be larger than at the high symmetry adsorption sites. For the different vdW corrections, the calculated adsorption energies of Co adatom on grapheme substrates are slightly changed to some extent, but they do not affect the most preferable adsorption configurations. NEB calculations prove that the Co adatom has smaller energy barrier within pristine bilayer graphene (PBG) than that on the upper layer, indicating the high mobility of Co atom anchors at overlayer and easily aggregates. For the PBG substrate, the Co adatom intercalates into graphene sheets with a large energy barrier (9.29 eV). On the bilayer graphene with a single-vacancy (SV), the Co adatom can easily be trapped at the SV site and intercalates into graphene sheets with a much lower energy barrier (2.88 eV). These results provide valuable information on the intercalation reaction and the formation mechanism of metal impurity in graphene sheets. PMID- 26057892 TI - Miniaturized GPS Tags Identify Non-breeding Territories of a Small Breeding Migratory Songbird. AB - For the first time, we use a small archival global positioning system (GPS) tag to identify and characterize non-breeding territories, quantify migratory connectivity, and identify population boundaries of Ovenbirds (Seiurus aurocapilla), a small migratory songbird, captured at two widely separated breeding locations. We recovered 15 (31%) GPS tags with data and located the non breeding territories of breeding Ovenbirds from Maryland and New Hampshire, USA (0.50 +/- 0.15 ha, mean +/- SE). All non-breeding territories had similar environmental attributes despite being distributed across parts of Florida, Cuba and Hispaniola. New Hampshire and Maryland breeding populations had non overlapping non-breeding population boundaries that encompassed 114,803 and 169,233 km(2), respectively. Archival GPS tags provided unprecedented pinpoint locations and associated environmental information of tropical non-breeding territories. This technology is an important step forward in understanding seasonal interactions and ultimately population dynamics of populations throughout the annual cycle. PMID- 26057894 TI - Reduced street lighting at night and health: A rapid appraisal of public views in England and Wales. AB - Financial and carbon reduction incentives have prompted many local authorities to reduce street lighting at night. Debate on the public health implications has centred on road accidents, fear of crime and putative health gains from reduced exposure to artificial light. However, little is known about public views of the relationship between reduced street lighting and health. We undertook a rapid appraisal in eight areas of England and Wales using ethnographic data, a household survey and documentary sources. Public concern focused on road safety, fear of crime, mobility and seeing the night sky but, for the majority in areas with interventions, reductions went unnoticed. However, more private concerns tapped into deep-seated anxieties about darkness, modernity 'going backwards', and local governance. Pathways linking lighting reductions and health are mediated by place, expectations of how localities should be lit, and trust in local authorities to act in the best interests of local communities. PMID- 26057895 TI - "Too much moving...there's always a reason": Understanding urban Aboriginal peoples' experiences of mobility and its impact on holistic health. AB - Urban Indigenous peoples face a disproportionate burden of ill health compared to non-Indigenous populations, and experience more frequent geographic mobility. However, most of what is known about Indigenous health is limited to rural, northern, or in the case of Canada, reserve-based populations. Little is known about the complexities of urban Indigenous health, and the differential impacts of residential mobility and urban migration remain poorly understood. Drawing upon interviews with Aboriginal movers and service providers in Winnipeg, Canada, we apply a critical population health lens, informed by holistic health, to examine these impacts. The results demonstrate mobility is an intergenerational phenomenon, influenced by colonial practices. While migration can contribute to positive health experiences, residential mobility, which is largely involuntary, and linked to stressors such as neighborhood safety, results in negative health effects. PMID- 26057896 TI - Corrigendum: cyclooctane metathesis catalyzed by silica-supported tungsten pentamethyl [(?SiO)W(Me)5]: distribution of macrocyclic alkanes. PMID- 26057897 TI - Measurement of prompt gamma profiles in inhomogeneous targets with a knife-edge slit camera during proton irradiation. AB - Proton and ion beam therapies become increasingly relevant in radiation therapy. To fully exploit the potential of this irradiation technique and to achieve maximum target volume conformality, the verification of particle ranges is highly desirable. Many research activities focus on the measurement of the spatial distributions of prompt gamma rays emitted during irradiation. A passively collimating knife-edge slit camera is a promising option to perform such measurements. In former publications, the feasibility of accurate detection of proton range shifts in homogeneous targets could be shown with such a camera. We present slit camera measurements of prompt gamma depth profiles in inhomogeneous targets. From real treatment plans and their underlying CTs, representative beam paths are selected and assembled as one-dimensional inhomogeneous targets built from tissue equivalent materials. These phantoms have been irradiated with monoenergetic proton pencil beams. The accuracy of range deviation estimation as well as the detectability of range shifts is investigated in different scenarios. In most cases, range deviations can be detected within less than 2 mm. In close vicinity to low-density regions, range detection is challenging. In particular, a minimum beam penetration depth of 7 mm beyond a cavity is required for reliable detection of a cavity filling with the present setup. Dedicated data post processing methods may be capable of overcoming this limitation. PMID- 26057898 TI - Is Mindful Practice Our Ethical Responsibility as Anesthesiologists? PMID- 26057899 TI - What a Patient or Parent Wants to Tell a Doctor. PMID- 26057900 TI - Ethics of Physician Strikes in Health Care. PMID- 26057901 TI - Current Issues in Prison Health Care. PMID- 26057902 TI - Challenges in the LGBTQI+ Community. PMID- 26057903 TI - A Matter of Mice and Men: Ethical Issues in Animal Experimentation. PMID- 26057904 TI - The Taxonomy of Calamity: The View From the Operating Room. PMID- 26057905 TI - Ethics of Global Health Care. PMID- 26057906 TI - Health Care Journalism: Help or Hindrance? PMID- 26057907 TI - Distraction Implications for the Practice of Anesthesia. PMID- 26057909 TI - Introduction: Unfamiliar Ethical Issues. PMID- 26057910 TI - Posterior mediastinal goiters: Report of two cases and literature review. AB - Intrathoracic goiters represent substantial enlargement and descent of cervical thyroid tissue into the thoracic cavity, usually in the anterior mediastinum. Rarely, they extend posteriorly, causing obstructive symptoms, sometimes with acute onset. Posterior mediastinal goiters should be differentiated from other mediastinal masses by appropriate work-up, while computed tomography is the most valuable technique. We report two cases of such symptomatic goiters. First reported case was atypically presented with aspiration pneumonia and second was successfully operated. Our overview aims to increase awareness of this rare clinical entity due to possible respiratory compromise. Reasonable surgical management is mandatory. PMID- 26057911 TI - Two male nurses' experiences of caring for female patients after intimate partner violence: a South African perspective. AB - BACKGROUND: South Africa is perceived to be one of the countries with the worst reputation regarding the occurrence of intimate partner violence. The women who suffer from serious physical injuries are admitted to emergency care units and their first contact with health care is through the nurses in these units. Emergency care nurses become secondary victims of violence due to their exposure to the pain of assaulted patients. Female nurses tend to identify with these patients as some nurses are in similar relationships. Not much research has been done on the challenges that male nurses face when they are confronted with abuse of women inflicted by males. METHODOLOGY: In this case study with a phenomenological research methodology two African male emergency care nurses were interviewed. FINDINGS: The participants experienced a dichotomy of being-in nursing and being-in-society and had been confronted with the conflicting roles of being men (the same sex as the perpetrators) and being nurses (the carer of the victim). They tried to manage the situation by using the 'self' to care for the patient and to be a problem solver for the patient and her partner or husband. CONCLUSION: The authors conclude that society expects men not to be in a caring profession and nursing is still a female-dominated caring profession that finds it difficult to move away from its engendered and caring image. The participants experienced role conflict when they took care of female patients who have suffered intimate partner violence. PMID- 26057912 TI - Influence of standard load micro- and nanopatterned in surface roughness of bleached teeth and submitted to different surface treatments. AB - The aim of this study was evaluate the dental enamel after whitening treatment with Opalescence Boost PFTM 38%, correlating the structural alterations in the surface of the enamel with its respective pH and verify if whitened teeth submitted to different finishing and polishing techniques show similar surface texture to healthy teeth (control group). Sixty premolars were divided in 6 groups (n = 10), which had been immersed in artificial saliva during all the experiment. Protocol whitening was performed according to the manufacturer recommendations, and then the specimens were submitted to different polishing technique with Sof-Lex Pop OnTM disks, Flex DiamondTM felt disks using two different micrometric polishing pastes (EnamelizeTM and Diamond PolishTM) and two nanometric polishing pastes (Lummina-E Diamond and Lummina-E Alumina), according to the groups. Representative specimens were analyzed in scanning electronic microscopy (SEM). Whitening gel used in this experiment had modified the morphologic aspect of the enamel surface. It was found that two nanometric polishing pastes (G5 and G6) promoted a less rough surface compared to control group even after the whitening process. PMID- 26057913 TI - Planning oral health and clinical discharge in primary care: the comprehensive dental care protocol outcome. AB - INTRODUCTION: The dental care must be driven by preventive and curative measures that can contribute to the population's oral health promotion. OBJECTIVE: To evaluate the impact of the actions proposed by a comprehensive dental care protocol (CDCP) on the oral health condition of primary care users. MATERIALS AND METHODS: The sample consisted of 32 volunteers, assisted throughout the six phases proposed by the CDCP: diagnosis of dental needs; resolution of urgencies; restorative interventions; application of promotional measures; evaluation of the achieved health level; and periodic controls. Data were collected through clinical exams, which measured the simplified oral hygiene index (OHI-S), gingival bleeding index (GBI) and the decayed, missing and filled teeth (DMFT) Index, before and after the CDCP was implemented. Statistical analysis consisted of the Wilcoxon test, at 5% significance level (alpha = 0.05). RESULTS: The OHI-S and GBI indices showed a significant reduction (p < 0.05) from the initial (1.4 +/- 0.6 and 46.3 +/- 19.9) to final condition (0.9 +/- 0.3 and 21.5 +/- 7.5). The decayed, missing and filled teeth and the missing teeth component were not significantly altered (p > 0.05), showing final values equal to 12.7 +/- 9.6 and 5.6 +/- 7.8, respectively. Decayed elements were fully converted into filled elements, and the final values of the decayed and filled elements were, respectively, 0.0 +/- 0.0 and 7.3 +/- 5.7 (p < 0.05). CONCLUSIONS: The enactment of the CDCP had a beneficial effect on the oral health of the population assisted by the dental services offered in primary care and this protocol seems to ft the public dental service demands. CLINICAL SIGNIFICANCE: The CDCP can be useful to public dental service planning since it showed an efficient clinical outcome to the patients. We consider that this protocol should be employed in primary care oral health services in order to achieve overall upgrade, access enlargement and public oral health promotion. PMID- 26057914 TI - Evaluation of the influence of three different temperatures on microleakage of two self-etch and one total-etch adhesives. AB - AIM: To evaluate the bonding temperature effect on dentin-restoration microleakage. The null hypothesis of the study is that the score of microleakage is identical among different adhesive bondings at different temperatures. MATERIALS AND METHODS: Ninety caries free maxillary premolars were selected. Class V cavities were prepared on the cemento enamel junction (CEJ) of the buccal sides with enamel margins on occlusal sides and cementum margins on gingival sides. The specimens were divided into 3 groups: G1, single bond adhesive + Z250 composite; G2, P90 adhesive + Filtek Silorane composite; and G3, Clearfil SE bond + Clearfil APX. All groups were divided into three subgroups based on the adhesive temperature: A-4 degrees C; B-25 degrees C; and C-40 degrees C. After coating the specimens with nail polish 1 mm beyond the margin of the restorations, they were stored in 0.5% basic Fuchsin dye solution for 24 hours. The teeth then were buccolingually sectioned and observed under a stereomicroscope. RESULTS: There was no significant difference between microleakage of occlusal and gingival margins in each group. Clearfil SE bond and Adper single bond displayed lower microleakage than P90 adhesive at 4 degrees C and 25 degrees C. The most and least microleakage score for Adper single bond was at 40 degrees C and 25 degrees C respectively. Clearfil SE bond showed less microleakage at 25 degrees C than 4 degrees C and 40 degrees C. CONCLUSION: Clearfil SE bond and Adper single bond displayed less microleakage at 25 degrees C while there was no significant difference among for P90 adhesive microleakage at three temperatures. PMID- 26057915 TI - Evaluation of the effect of using electrosurgery in pulpectomy of deciduous teeth on succedaneous teeth: an animal study. AB - OBJECTIVES: The aim of this study was to determine the probable side effects of electrosurgery in pulpectomy of deciduous teeth on succedaneous teeth in dogs. MATERIALS AND METHODS: In this animal study, all maxillary and mandibular teeth at one side of five puppies' mouths were treated employing electrosurgical pulpectomy and were then compared with those of the other side treated using the conventional method. The electrosurgical dental electrode was placed in canals to the point of working length for the experimental group. After pulpectomy, the canals were filled with zinc oxide eugenol paste and the access cavity was restored with amalgam. The dogs remained under care until their successor teeth erupted and clinical examination was performed. RESULTS: The teeth treated employing electrosurgical pulpectomy presented natural appearance with no observable defects including enamel hypoplasia, diffuse opacities of enamel, demarcated opacities, and enamel discoloration. CONCLUSION: Electrosurgical pulpectomy can be considered as an option for pulpectomy of deciduous teeth. PMID- 26057916 TI - Evaluation of different irrigating solutions on smear layer removal of primary root dentin. AB - AIM: To evaluate the efficacy of ethanolic extract of Salvadora persica (S. persica) and BioPure MTAD (a mixture of a tetracycline isomer, an acid, and a detergent) in removing the intracanal smear layer of primary teeth. MATERIALS AND METHODS: The root canal of 40 extracted human primary anterior teeth were cleaned, shaped and grouped into experimental (n = 30) and control (n = 10). The root canals of the positive (n = 5) and the negative control (n = 5) were irrigated for 3 minutes with 5 ml of 17% ethylenediaminetetraacetic acid (EDTA) or saline respectively. The canals in the experimental groups were irrigated for 3 minutes with 5 ml of 1 mg/ml ethanolic extract of S. persica (n = 15) or BioPure MTAD (n = 15) and then flushed with 2 ml of saline. The presence or absence of smear layer at the coronal and middle portion of each canal were examined under a scanning electron microscope (SEM). RESULTS: A significant difference (p = 0.004) in smear layer removal between S. persica and MTAD at the middle third of the canal was observed. MTAD solution was as effective as 17% EDTA in removing the smear layer. CONCLUSION: MTAD was significantly more effective in smear layer removal than S. persica solution at the middle third of the canal wall. CLINICAL SIGNIFICANCE: Both tested irrigant solutions have the ability to remove the intracanal smear from primary root dentin following cleaning and shaping of the root canal and could be an alternative to EDTA. PMID- 26057917 TI - Mandibular tori as bone grafts: an alternative treatment for periodontal osseous defects - clinical, radiographic and histologic morphology evaluation. AB - OBJECTIVES: The present study was designed to evaluate the clinical, radiographic and histochemical significance of using the mandibular tori as autogenous bone graft for treatment of intraosseous defects in patients with chronic periodontitis. MATERIALS AND METHODS: Twenty-eight sites from 14 patients with chronic periodontitis were included in this study. Each patient was treated with split mouth design; one site received torus mandibularis bone graft and the other site received a full-thickness fap alone. Histopathologic assessment was evaluated on removal of torus mandibularis to evaluate its histologic structure and by the end of the study 9 month later. Clinical and radiographic parameters were re-evaluated at 3 months interval for 1 year. RESULTS: The results of the present study revealed significant gain in the clinical attachment level (CAL) (88.4%, 4.53 +/- 0.06 mm) for torus mandibularis sites compared to (39.7%, 2.01 +/- 0.04 mm) for full-thickness fap. Moreover, there was a reduction in the probing pocket depth (PPD) of (75.4%, 5.75 +/- 0.12 mm) for torus mandibularis sites and (49.6%, 3.73 +/- 0.14 mm) for sites treated with a full-thickness fap only; CAL and PPD differences were significant at p-value <=0.01. Concomitantly, significant radiographic increase in the bone height and density were recorded in the test group. CONCLUSION: The use of mandibular tori as autogenous bone graft could provide benefits as a periodontal therapeutic modality and enhance regenerative potential of periodontal intraosseous defects. PMID- 26057918 TI - Patient preferences in selecting a dentist: survey results from the urban population of Riyadh, Saudi Arabia. AB - INTRODUCTION: Awareness of gender- or nationality-driven preconceptions can help dentists to have a better interpretation of the dentist-patient relationship. It is even more noteworthy to understand these predilections in Saudi society, where women and men are usually segregated due to religion- and culture-based considerations. This study is one of the first to explore the preferences of patients when selecting a dentist with respect to gender and nationality in the city of Riyadh, Saudi Arabia. MATERIALS AND METHODS: A total of 445 community residents residing in Riyadh were randomly selected for a cross-sectional study. The participants completed a survey designed to assess which of two factors (gender and/or nationality) were perceived as most relevant in choosing a dentist. Statistical analysis of the data was performed using the SPSS 11.5 software. RESULTS: Female participants did not show any preference for the gender of the dentist, whereas 40% of the male participants preferred a male dentist. Participants also favored male dentists in the felds of oral surgery (78.9%), implants (74.1%), endodontics (67.5%), orthodontics (65.8%) and prosthodontics (64.2%). An exception was noted in pediatric dentistry, for which female dentists were favored by 52.8% of the participants. Additionally, most (66.1%) participants did not have any preference for the nationality of the dentist. CONCLUSION: Riyadh residents showed a general preference for a male dentist but demonstrated no preference for nationality when selecting a dentist. PMID- 26057919 TI - Eradication of gastric Helicobacter pylori ameliorates halitosis and tongue coating. AB - BACKGROUND: The influence of gastric Helicobacter pylori infection on the development of oral pathoses remains unclear. The aim of this study is to examine the influence of gastric H. pylori infection on occurrence of halitosis and coated tongue. MATERIALS AND METHODS: Ninety-eight patients with dyspepsia were included in the study and their salivary samples and gastric biopsies were analyzed for the presence of H. pylori by Nested-PCR. Halitosis and coated tongue were assessed at the initial examination and 3 months after systemic eradication therapy against H. pylori. RESULTS: Gastric biopsies of 66 patients were positive for H. pylori. Only one saliva sample was H. pylori positive. At initial examination, halitosis was observed in 20 patients (30.3%) out of 66 who had gastric H. pylori infection and in only 3 patients (9.4%) out of 32 without H. pylori infection (p = 0.0236). Coated tongue was diagnosed in 18 (27.2%) patients with the infection compared to only 2 (6.25%) patients negative for gastric H. pylori (p = 0.0164). Patients with gastric infection were treated with the triple eradication therapy (Amoxicillin, Clarythromycin, Pantoprazol) and their gastric biopsies and oral status were examined 3 months later. Halitosis was significantly more prevalent in the group of patients with persistent H. pylori infection (42.1%) compared to only 6.4% of patients in the group where infection was successfully eradicated (p = 0.0012). Coated tongue was diagnosed in 47.4% of patients where H. pylori was still present after eradication therapy and in only 6.4% where eradication succeeded (p = 0.0003). CONCLUSION: Our findings suggest that eradication of gastric H. pylori significantly alleviates halitosis and coated tongue, the two oral conditions that may be considered as extragastric manifestations of this common chronic bacterial infection. PMID- 26057920 TI - Sealing ability of root-end filling materials. AB - BACKGROUND: The aim of this research was to compare the apical sealing ability of different root-end filling materials (SuperEBA((r)), ProRoot MTA((r)), thermoplasticized gutta-percha + AH-Plus((r)), thermoplasticized RealSeal((r))), by means of microbial indicators. MATERIALS AND METHODS: Thus, 50 human single rooted teeth were employed, which were shaped until size 5 0, retro - prepared with ultrasonic tips and assigned to 4 groups, retro-filled with each material or controls. A platform was employed, which was split in two halves: upper chamber where the microbial suspension containing the biological indicators was introduced (E. faecalis + S. aureus + P. aeruginosa + B. subtilis + C. albicans); and a lower chamber containing the culture medium brain, heart influsion, where 3 mm of the apical region of teeth were kept immersed. Lectures were made daily for 60 days, using the turbidity of the culture medium as indicative of microbial contamination. Statistical analyses were carried out at 5% level of significance. RESULTS: The results showed microbial leakage at least in some specimens in all of the groups. RealSeal((r)) has more microbial leakage, statistically significant, compared to ProRoot((r)) MTA and SuperEBA((r)). No significant differences were observed when compared ProRoot((r)) MTA and SuperEBA((r)). The gutta-percha + AH Plus results showed no statistically significant differences when compared with the other groups. CONCLUSIONS: All the tested materials showed microbial leakage. Root-end fillings with Super-EBA or MTA had the lowest bacterial filtration and RealSeal shows highest bacterial filtration. PMID- 26057921 TI - Efficacy of oral exfoliative cytology in diabetes mellitus patients: a light microscopic and confocal microscopic study. AB - AIM: Diabetes mellitus (DM) has become a global problem. By monitoring the health status of these individuals, diabetic complications can be prevented. We aimed to analyze alterations in the morphology and cytomorphometry of buccal epithelial cells of type 2 DM patients using oral exfoliative cytology technique and determine its importance in public health screening, diagnosis and monitoring of diabetes mellitus. MATERIALS AND METHODS: The study was carried out in 100 type 2 DM patients and 30 healthy individuals. Smears were taken from the right buccal mucosa and stained by the Papanicolaou technique. Staining with Acridine orange was carried out to view qualitative changes with confocal laser scanning microscope (LSM-510 Meta). The cytomorphometry was evaluated using IMAGE PRO PLUS 5.5 software with Evolution LC camera. All findings were statistically analyzed. RESULTS: The results showed that with increase in fasting plasma glucose levels, there is significant increase in nuclear area, decrease in cytoplasmic area, and increase in nuclear cytoplasmic ratio (p < 0.05) when compared to the control group. Various qualitative changes were noted, such as cell degeneration, micronuclei, binucleation, intracytoplasmic inclusion, candida and keratinization. CONCLUSION: In the present study, we found significant alterations in the cytomorphometry and cytomorphology of buccal epithelial cells of type 2 DM patients. This study supports and extends the view that these cellular changes can alert the clinician to the possibility of diabetes and aid in monitoring of diabetes throughout the lifetime of the patient. PMID- 26057922 TI - Mandibular coronoid fractures, how rare? AB - BACKGROUND: To study the rarity of mandibular coronoid process fractures and treatment strategies based on the displacement of these fractures. MATERIALS AND METHODS: A retrospective study of 11 cases of coronoid process fractures among 307 treated cases from 2008 to 2013 was conducted. Six patients were treated conservatively and 5 underwent ORIF with associated fractures. A statistical analysis of the data obtained after subjective and objective evaluation was done. RESULTS: The incidence of coronoid process fractures was 3.58% of all mandibular fractures analyzed. There was no statistically significant difference found between two treatment modalities, but differences in maximum interincisal opening (MIO) and pain in the postoperative period were significant. CONCLUSION: We recommend that linear coronoid fractures with minimal displacement can be managed with conservative treatment. For patients with significant displacement of coronoid process, limited mouth opening or concomitant mid-face or lower-face fractures, rigid internal fixation is recommended. PMID- 26057923 TI - Occurrence of domestic violence among women and its impact on oral health in Jodhpur City. AB - BACKGROUND: This study had a two objectives to determine the prevalence of domestic violence and to know the impact of the same on the oral health. MATERIALS AND METHODS: An observational cross-sectional study was done in Jodhpur, Rajasthan; among 150 married women of 18 to 60 years of age using a predesigned pretested proforma from 18th January 2014 to 27th February 2014. Pretested semistructured open-ended questionnaire used for collecting the data from the study subjects. Pearson's Chi-square test and p-value were used to calculated the occurrence and impact of domestic violence on oral health among women. RESULTS: The most common form of domestic violence found was physical abuse (54.7%) followed by emotional abuse (20.0%) and financial abuse (14.0%). The most important risk factor was alcoholism followed by literacy status and having a girl child. Study shows that physical abuse is more in graduate than lower level of educational females. Females living in urban area show highest frequency of physical abuse than those living in rural area. Injury to the face were highly reported (38.7%) followed by injury to lip (13.3%) and nose fracture/bleeding nose (9.3%). CONCLUSION: Government has to take stringent action to prevent domestic violence by making women more self-reliant especially by making women more literate and more financially independent. PMID- 26057924 TI - Comparative evaluation and correlation of salivary total antioxidant capacity and salivary pH in caries-free and severe early childhood caries children. AB - BACKGROUND: Dental caries is a major problem in preschool children. The contribution of saliva in providing defense during caries process is of primary importance. pH buffer capacity through bicarbonate, phosphate and protein buffer systems have universal acceptance as a caries defense mechanism. Antioxidant capacity of saliva can constitute a first line of defense against chronic degenerative diseases including dental caries. Till date, no study is presented with salivary antioxidant capacity of younger children affected with severe early childhood caries with its salivary pH correlation. Hence, this study was carried out to compare, evaluate and correlate the salivary total antioxidant capacity (TAC) and salivary pH of children with caries-free and severe early childhood caries. MATERIALS AND METHODS: Fifty children from ages 3 to 5 years divided into two study groups had undergone screening. Group I (n = 25) with severe early childhood caries (S-ECC) and group II (n = 25) who were caries free. Unstimulated whole saliva of subjects were in the collection during the study by draining method. Salivary pH determination of saliva samples was done using pH indicator paper strips. The TAC was done using an antioxidant assay with the help of a spectrophotometer at wavelength 532 nm. The means of salivary pH and TAC were subjected to analysis using unpaired student 't' test and correlation was determined using Pearsons correlation coefficient analysis. RESULTS: Mean salivary pH was higher in group II (7.46 +/- 0.37). Mean TAC was greater in group I (1.82 +/- 0.19). A statistically significant negative correlation as seen between TAC and salivary pH in S-ECC patients. CONCLUSION: The study concludes that salivary TAC increases in patients with S-ECC are by that showing a high indirect relationship with salivary pH. PMID- 26057925 TI - Removal of an instrument fractured by ultrasound and the instrument removal system under visual magnification. AB - AIM: The case of a lower molar with apical periodontitis, which had previous root canal treatment and a fractured instrument in the distal root beyond the foramen, is presented. BACKGROUND: The simultaneous presence of a foreign body (endodontic instrument or material) in periapical tissues and microorganisms in the root canal, are etiological factors in the formation or maintenance of a periapical lesion, and can lead to failure in endodontic treatment. CASE DESCRIPTION: This instrument was removed through the staging platform technique, by using ultrasound and an Instrument removal system (IRS) microtube under microscope visual amplification. All the canals were re-instrumented, irrigated with sodium hypochlorite and passive ultrasonic irrigation, removal of smear layer and intracanal medication with calcium hydroxide for 8 days, after which they were filled. The symptoms disappeared and clinical and radiograph 2-year follow-up shows healing of periapical tissues. CONCLUSION: The combined use of visual magnification microscope, ultrasound and the IRS system by staging platform technique, allowed the removal of an endodontic instrument beyond the foramen, which made it possible to apply a conventional disinfection protocol. CLINICAL SIGNIFICANCE: Endodontic re-treatment by conservative approach of complicated cases it is an option with good clinical prognosis, before apical surgery or extraction. PMID- 26057926 TI - Anterior open bite treated with myofunctional therapy and palatal crib. AB - This case report demonstrates the treatment effects of palatal crib combined with the myofunctional therapy in a child with anterior open bite (AOB) due to thumb sucking and habitual anterior and low tongue position. The patient, an 11-year old boy, had an anterior open bite and flared and spaced upper and lower incisors. Palatal cribs in conjunction with myofunctional therapy were used to discourage sucking habit and to adapt normal tongue position. Successful correction of the AOB with adequate overjet and overbite were achieved with total treatment time of 7 months. The importance of myofunctional therapy in adopting normal tongue position and in maintaining the stability of open bite correction is emphasized. PMID- 26057927 TI - Diaphonization: a recipe to study teeth. AB - AIM: There are various techniques to study root canal morphology and diaphonization is one of them. There are various methods of decalcification and diaphonization, cited in literature and the main aim of this paper was to give a brief account of the various techniques and share our experience of the technique at a teaching institution in Karachi, Pakistan. MATERIALS AND METHODS: Diaphonization is one of the oldest methods and is based on decalcification of teeth followed by clearing and dye penetration. The specimen is later studied under microscope without sectioning. RESULTS: After the process of clearing a three-dimensional (3D) structure of the internal canal anatomy was visible with naked eye. CONCLUSION: This paper entails a detailed historical background as well as the author's technique including percentages of various chemicals used and the timing of immersion of teeth into these agents. CLINICAL SIGNIFICANCE: The read out is simple and can be subjected to interpretation by direct observation under microscope and can be helpful for students undertaking research in not only the discipline of dentistry but also in other fields such as botany and zoology. PMID- 26057928 TI - Potential role of tumor microenvironment in the progression of oral cancer. AB - The stromal cells adjacent to the tumor including the fibroblasts, infammatory cells, lymphatic and vascular endothelial cells constitute the 'tumor microenvironment' (TM).(1) Recent in vivo and invitro studies have emphasized the role of stromal components on the growth, differentiation and invasiveness of the tumor cells. In addition, vascular, lymphatic or perineural invasion have proven to have independent prognostic value.(2) Despite the compelling evidence correlating the TM with the initiation and progression of cancer, our knowledge on the role of the genes mediating the various cellular interactions in the tumour stroma is limited.(2,3). PMID- 26057929 TI - Exogenous features versus prior experiences modulate different subregions of the right IPL during episodic memory retrieval. AB - The fractionation view holds that distinct cognitive operations are mediated by subregions of the inferior parietal lobule (IPL). Within IPL, we hypothesised that retrieval-related activity in different parts of the right supramarginal gyrus (rSMG) may be modulated differentially by information acquired via different combinations of attention signals at encoding. We had two groups of participants watch a 42-min TV episode and, after a 24-hr delay, perform a temporal-order judgment task during fMRI. Each retrieval trial comprised three images presented sequentially, requiring participants to judge the temporal order between the first and last images while ignoring the second image ("distractor"). We manipulated the bottom-up factor by presenting distractors that were extracted from either an event-boundary or a non-boundary of the movie. The top-down factor was manipulated by instructing one group perform a segmentation task reporting the event-boundaries at encoding, while the other group watched the movie passively. Across groups, we found that the stimulus-related factor modulated retrieval activation in the anterior rSMG (areas PFt and PFop), whereas the goal related influence of prior segmentation interacted with this effect in the middle rSMG (area PF), demonstrating IPL segregation during retrieval as a function of prior bottom-up vs. top-down attention signals. PMID- 26057930 TI - Oxytocin in Uniject Disposable Auto-Disable Injection System versus Standard Use for the Prevention of Postpartum Hemorrhage in Latin America and the Caribbean: A Cost-Effectiveness Analysis. AB - Postpartum hemorrhage (PPH) is a leading cause of maternal death. Despite strong evidence showing the efficacy of routine oxytocin in preventing PPH, the proportion of women receiving it after delivery is still below 100%. The Uniject injection system prefilled with oxytocin (Uniject) has the potential advantage, due to its ease of use, to increase oxytocin utilization rates. We aimed to assess its cost-effectiveness in Latin America and the Caribbean (LAC). We used an epidemiological model to estimate: a) the impact of replacing oxytocin in ampoules with Uniject on the incidence of PPH, quality-adjusted life years (QALYs) and costs from a health care system perspective, and b) the minimum increment in oxytocin utilization rates required to make Uniject a cost-effective strategy. A consensus panel of LAC experts was convened to quantify the expected increase in oxytocin rates as a consequence of making Uniject available. Deterministic and probabilistic sensitivity analyses were performed. In the base case, the incremental cost of Uniject with respect to oxytocin in ampoules was estimated to be USD 1.00 (2013 US dollars). In the cost-effectiveness analysis, Uniject ranged from being cost-saving (in 8 out of 30 countries) to having an incremental cost-effectiveness ratio (ICER) of USD 8,990 per QALY gained. In most countries these ICERs were below one GDP per capita. The minimum required increment in oxytocin rates to make Uniject a cost-effective strategy ranged from 1.3% in Suriname to 16.2% in Haiti. Switching to Uniject could prevent more than 40,000 PPH events annually in LAC. Uniject was cost-saving or very cost-effective in almost all countries. Even if countries can achieve only small increases in oxytocin rates by incorporating Uniject, this strategy could be considered a highly efficient use of resources. These results were robust in the sensitivity analysis under a wide range of assumptions. PMID- 26057931 TI - Interactive effects of waterborne metals in binary mixtures on short-term gill metal binding and ion uptake in rainbow trout (Oncorhynchus mykiss). AB - Metal binding to fish gills forms the basis of the biotic ligand model (BLM) approach, which has emerged as a useful tool for conducting site-specific water quality assessments for metals. The current BLMs are designed to assess the toxicity of individual metals, and cannot account for the interactive effects of metal mixtures to aquatic organisms including fish. The present study was designed mainly to examine the interactive effects of waterborne metals (Cd, Zn, Cu, Ag, and Ni) in specific binary combinations on short-term (3h) gill-metal binding and essential ion (Ca(2+) and Na(+)) uptake (a physiological index of toxicity) in fish, using juvenile freshwater rainbow trout (Oncorhynchus mykiss) as the model species. We hypothesized that binary mixtures of metals that share a common mode of uptake and toxicity (e.g., Cd and Zn - Ca(2+) antagonists, Cu and Ag - Na(+) antagonists) would reduce the gill binding of each other via competitive interactions and induce less than additive effects on ion transport. In addition, the mixture of metals that have different modes of uptake and toxicity (e.g., Cd and Cu, or Cd and Ni) would not exhibit any interactive effects either on gill-metal binding or ion transport. We found that both Zn and Cu reduced gill-Cd binding and vice versa, however, Ni did not influence gill-Cd binding in fish. Surprisingly, Ag was found to stimulate gill-Cu binding especially at high exposure concentrations, whereas, Cu had no effect on gill-Ag binding. The inhibitory effect of Cd and Zn in mixture on branchial Ca(2+) uptake was significantly greater than that of Cd or Zn alone. Similarly, the inhibitory effect of Cu and Ag in mixture on branchial Na(+) uptake was significantly greater than that of Cu or Ag alone. The inhibitory effects of Cd and Zn mixture on Ca(2+) uptake as well as Cu and Ag mixture on Na(+) uptake were found to follow the principles of simple additivity. In contrast, no significant additive effect on either Ca(2+) or Na(+) uptake was recorded in fish exposed to the mixture of Cd and Cu. Overall, we found that although the effects of metal mixture interactions on gill-metal binding did not always match with our original assumptions, the effects of metal mixtures on toxicity in fish were generally consistent with our predictions. The findings of the present study have important implications for improving the BLM approach to assess metal mixture toxicity in fish. PMID- 26057932 TI - Toxicity of solid residues resulting from wastewater treatment with nanomaterials. AB - Nanomaterials (NMs) are widely recommended for wastewater treatments due to their unique properties. Several studies report the different advantages of nanotechnology in the remediation of wastewaters, but limited research has been directed toward the fate and potential impacts of the solid residues (SRs) produced after the application of such technologies. The present work aimed at investigating the ecotoxicity of SRs resulting from the treatment of three effluents (OOMW, kraft pulp mill, and mining drainage) with two NMs (TiO2 and Fe2O3). The invertebrate Chironomus riparius was selected as test organism and exposed to the residues. The effect on percentage of survival and growth was assessed. Results showed that the SRs from the treatments nano-TiO2(1.0gL( 1))/H2O2(0.5M) and nano-Fe2O3(1.0gL(-1))/H2O2(1.0M) from OOMW and nano Fe2O3(0.75gL(-1))/H2O2(0.01M) from kraft pulp mill effluent exhibited lethal toxicity to C. riparius. Only the exposure to SRs resulting from the treatment with nano-Fe2O3(0.75gL(-1))/H2O2(0.01M) applied to the kraft pulp mill effluent significantly affected the growth rate based on the head capsule width. In terms of growth rate, based on the body length, it decreased significantly after exposure to the SRs from the treatments nano-TiO2 (1.0gL(-1)) and nano Fe2O3(0.75gL(-1))/H2O2(0.01M) of kraft paper mill effluent and nano-Fe2O3(1.0gL( 1))/H2O2(1.0M) of OOMW. According to our study the SRs can promote negative effects on C. riparius. However, the effects are dependent on the type of effluent treated as well as on the organic and inorganic compounds attached to the NMs. PMID- 26057933 TI - Undergraduate medical research requires change. PMID- 26057934 TI - Molding acoustic, electromagnetic and water waves with a single cloak. AB - We describe two experiments demonstrating that a cylindrical cloak formerly introduced for linear surface liquid waves works equally well for sound and electromagnetic waves. This structured cloak behaves like an acoustic cloak with an effective anisotropic density and an electromagnetic cloak with an effective anisotropic permittivity, respectively. Measured forward scattering for pressure and magnetic fields are in good agreement and provide first evidence of broadband cloaking. Microwave experiments and 3D electromagnetic wave simulations further confirm reduced forward and backscattering when a rectangular metallic obstacle is surrounded by the structured cloak for cloaking frequencies between 2.6 and 7.0 GHz. This suggests, as supported by 2D finite element simulations, sound waves are cloaked between 3 and 8 KHz and linear surface liquid waves between 5 and 16 Hz. Moreover, microwave experiments show the field is reduced by 10 to 30 dB inside the invisibility region, which suggests the multi-wave cloak could be used as a protection against water, sonic or microwaves. PMID- 26057935 TI - Low micromolar concentrations of the superoxide probe MitoSOX uncouple neural mitochondria and inhibit complex IV. AB - MitoSOX Red is a fluorescent probe used for the detection of mitochondrial reactive oxygen species by live cell imaging. The lipophilic, positively charged triphenylphosphonium moiety within MitoSOX concentrates the superoxide-sensitive dihydroethidium conjugate within the mitochondrial matrix. Here we investigated whether common MitoSOX imaging protocols influence mitochondrial bioenergetic function in primary rat cortical neurons and microglial cell lines. MitoSOX dose dependently uncoupled neuronal respiration, whether present continuously in the assay medium or washed following a ten minute loading protocol. Concentrations of 5-10MUM MitoSOX caused severe loss of ATP synthesis-linked respiration. Redistribution of MitoSOX to the cytoplasm and nucleus occurred concomitant to mitochondrial uncoupling. MitoSOX also dose-dependently decreased the maximal respiration rate and this impairment could not be rescued by delivery of a complex IV specific substrate, revealing complex IV inhibition. As in neurons, loading microglial cells with MitoSOX at low micromolar concentrations resulted in uncoupled mitochondria with reduced respiratory capacity whereas submicromolar MitoSOX had no adverse effects. The MitoSOX parent compound dihydroethidium also caused mitochondrial uncoupling and respiratory inhibition at low micromolar concentrations. However, these effects were abrogated by pre-incubating dihydroethidium with cation exchange beads to remove positively charged oxidation products, which would otherwise by sequestered by polarized mitochondria. Collectively, our results suggest that the matrix accumulation of MitoSOX or dihydroethidium oxidation products causes mitochondrial uncoupling and inhibition of complex IV. Because MitoSOX is inherently capable of causing severe mitochondrial dysfunction with the potential to alter superoxide production, its use therefore requires careful optimization in imaging protocols. PMID- 26057937 TI - Metabolism alteration in follicular niche: The nexus among intermediary metabolism, mitochondrial function, and classic polycystic ovary syndrome. AB - Classic polycystic ovary syndrome (PCOS) is a high-risk phenotype accompanied by increased risks of reproductive and metabolic abnormalities; however, the local metabolism characteristics of the ovaries and their effects on germ cell development are unclear. The present study used targeted metabolomics to detect alterations in the intermediate metabolites of follicular fluid from classic PCOS patients, and the results indicated that hyperandrogenism but not obesity induced the changed intermediate metabolites in classic PCOS patients. Regarding the direct contact, we identified mitochondrial function, redox potential, and oxidative stress in cumulus cells which were necessary to support oocyte growth before fertilization, and suggested dysfunction of mitochondria, imbalanced redox potential, and increased oxidative stress in cumulus cells of classic PCOS patients. Follicular fluid intermediary metabolic profiles provide signatures of classic PCOS ovary local metabolism and establish a close link with mitochondria dysfunction of cumulus cells, highlighting the role of metabolic signal and mitochondrial cross talk involved in the pathogenesis of classic PCOS. PMID- 26057936 TI - Structural basis of Keap1 interactions with Nrf2. AB - Keap1 is a highly redox-sensitive member of the BTB-Kelch family that assembles with the Cul3 protein to form a Cullin-RING E3 ligase complex for the degradation of Nrf2. Oxidative stress disables Keap1, allowing Nrf2 protein levels to accumulate for the transactivation of critical stress response genes. Consequently, the Keap1-Nrf2 system is extensively pursued for the development of protein-protein interaction inhibitors that will stabilize Nrf2 for therapeutic effect in conditions of neurodegeneration, inflammation, and cancer. Here we review current progress toward the structure determination of Keap1 and its protein complexes with Cul3, Nrf2 substrate, and small-molecule antagonists. Together the available structures establish a rational three-dimensional model to explain the two-site binding of Nrf2 as well as its efficient ubiquitination. PMID- 26057938 TI - Bilirubin scavenges chloramines and inhibits myeloperoxidase-induced protein/lipid oxidation in physiologically relevant hyperbilirubinemic serum. AB - Hypochlorous acid (HOCl), an oxidant produced by myeloperoxidase (MPO), induces protein and lipid oxidation, which is implicated in the pathogenesis of atherosclerosis. Individuals with mildly elevated bilirubin concentrations (i.e., Gilbert syndrome; GS) are protected from atherosclerosis, cardiovascular disease, and related mortality. We aimed to investigate whether exogenous/endogenous unconjugated bilirubin (UCB), at physiological concentrations, can protect proteins/lipids from oxidation induced by reagent and enzymatically generated HOCl. Serum/plasma samples supplemented with exogenous UCB (<=250uM) were assessed for their susceptibility to HOCl and MPO/H2O2/Cl(-) oxidation, by measuring chloramine, protein carbonyl, and malondialdehyde (MDA) formation. Serum/plasma samples from hyperbilirubinemic Gunn rats and humans with GS were also exposed to MPO/H2O2/Cl(-) to: (1) validate in vitro data and (2) determine the relevance of endogenously elevated UCB in preventing protein and lipid oxidation. Exogenous UCB dose-dependently (P<0.05) inhibited HOCl and MPO/H2O2/Cl(-)-induced chloramine formation. Albumin-bound UCB efficiently and specifically (3.9-125uM; P<0.05) scavenged taurine, glycine, and N-alpha acetyllysine chloramines. These results were translated into Gunn rat and GS serum/plasma, which showed significantly (P<0.01) reduced chloramine formation after MPO-induced oxidation. Protein carbonyl and MDA formation was also reduced after MPO oxidation in plasma supplemented with UCB (P<0.05; 25 and 50uM, respectively). Significant inhibition of protein and lipid oxidation was demonstrated within the physiological range of UCB, providing a hypothetical link to protection from atherosclerosis in hyperbilirubinemic individuals. These data demonstrate a novel and physiologically relevant mechanism whereby UCB could inhibit protein and lipid modification by quenching chloramines induced by MPO induced HOCl. PMID- 26057939 TI - Effect of Aspirin Supplementation on Hemodynamics in Older Firefighters. AB - PURPOSE: Cardiovascular events are the leading cause of line-of-duty fatality for firefighters. Aspirin reduces the risk of cardiovascular events in men and may reduce fatalities in older (>40 yr) firefighters. We hypothesized that both chronic and acute aspirin supplementation would improve vascular function after live firefighting but that chronic supplementation would also improve resting hemodynamics. METHODS: Twenty-four firefighters (40-60 yr) were randomly assigned to acute or chronic aspirin supplementation or placebo in a balanced, crossover design. Arterial stiffness, brachial and central blood pressures, as well as forearm vasodilatory capacity and blood flow were measured at rest and immediately after live firefighting. RESULTS: Total hyperemic blood flow (area under the curve (AUC)) was increased (P < 0.001) after firefighting with no effects for aspirin supplementation or acute versus chronic administration (AUC, from 107 +/- 5 to 223 +/- 9 in aspirin condition and from 97 +/- 5 to 216 +/- 7 mL.min-1 per 100-mL forearm tissue for placebo; P < 0.05 for main, and P > 0.05 for interaction). Arterial stiffness/central blood pressure increased (P < 0.04) with no effect of aspirin (from 0.0811 +/- 0.001 to 0.0844 +/- 0.003 m.s.mm-1 Hg 1 in aspirin condition versus 0.0802 +/- 0.002 to 0.0858 +/- 0.002 m.s-1.mm Hg-1 in placebo condition), whereas peripheral and central systolic and pulse pressures decreased after firefighting across conditions (P < 0.05). CONCLUSIONS: Live firefighting resulted in increased AUC and pressure-controlled arterial stiffness and decreased blood pressure in older firefighters, but aspirin supplementation did not affect macro- or microvascular responsiveness at rest or after firefighting. PMID- 26057940 TI - Role of KATP Channels in Beneficial Effects of Exercise in Ischemic Heart Failure. AB - PURPOSE: Exercise training reduces pathological remodeling and improves cardiac function in ischemic heart failure; however, causal mechanisms underlying the cardiac benefits of exercise are poorly understood. Because opening of adenosine triphosphate (ATP)-sensitive K +(KATP) channels protects the heart during myocardial stress, we hypothesized that such a mechanism is responsible for some of the cardiac benefits induced by exercise in postinfarction chronic heart failure (CHF). METHODS: Left ventricular myocytes were isolated from three groups of rats: Sham, CHF Tr (4 wk after myocardial infarction, rats underwent 8 wk of aerobic interval training 5 d.wk-1) and CHF Sed (rats sedentary for 12 wk after infarction). Cardiomyocyte survival after oxidative stress exposure (200 MUM H2O2) and calcium handling (cells loaded with Fura-2 AM and electrically paced at 1 Hz) were assessed in the presence of KATP channel inhibitor glibenclamide. Expression of KATP subunits (SUR2A and Kir6.2) was evaluated using immunoblotting. RESULTS: Exercise improved cardiac function in CHF Tr animals. Cardiomyocytes from CHF Sed rats were more susceptible to oxidative stress induced cell death than CHF Tr and Sham cardiomyocytes, with glibenclamide completely abolishing the protective effect of exercise. Glibenclamide did not affect cardiomyocyte survival in Sham or CHF Sed rats. In addition, exercise increased the systolic Ca2+ transient amplitude and improved diastolic Ca2+ removal in CHF Tr cardiomyocytes (compared with CHF Sed); both were significantly attenuated by glibenclamide. Exercise resulted in increased expression of KATP channel subunits in CHF Tr hearts, with more pronounced and significant effect on SUR2A. CONCLUSIONS: Our data suggest that KATP channel upregulation induced by chronic exercise likely mediates some of exercise-induced beneficial effects on cardiac function in postischemic heart failure. PMID- 26057941 TI - Acute Lower Extremity Injury Rates Increase after Concussion in College Athletes. AB - Dynamic postural control deficits and disrupted cortical pathways have been reported to persist beyond an athlete's return to activity after concussion, potentially increasing the risk of acute lower extremity musculoskeletal injury. PURPOSE: This study aimed to investigate acute lower extremity musculoskeletal injury rates before and after concussion in athletes with concussion and their matched control. METHODS: College athletes with concussion (n = 44; age, 20.0 +/- 1.2 yr) were physician-diagnosed. Nonconcussed college athletes (n = 58; age, 20.5 +/- 1.3 yr) were matched to individuals with concussion. Acute lower extremity musculoskeletal injury data were collected for 2 yr (+/-1 yr of the diagnosed concussion) using electronic medical records. Control participants' 2 yr window for exposure and musculoskeletal injury data were anchored to their match's concussion injury date. Pre- and postconcussion musculoskeletal injury rates were calculated for 90-, 180-, and 365-d periods for both study cohorts. Risk ratios were calculated to determine differences within and between groups for all periods. RESULTS: Within 1 yr after concussion, the group with concussion was 1.97 (95% confidence interval (CI), 1.19-3.28; P = 0.01) times more likely to have experienced an acute lower extremity musculoskeletal injury after concussion than before concussion and 1.64 times (95% CI, 1.07-2.51; P = 0.02) more likely to have experienced an acute lower extremity musculoskeletal injury after concussion than their matched nonconcussed cohort over the same period. Up to 180 d after concussion, the group with concussion was 2.02 (95% CI, 1.08-3.78; P = 0.02) times more likely to have experienced an acute lower extremity musculoskeletal injury after concussion than before concussion. CONCLUSIONS: Previous literature has identified dynamic postural control deficits along with increased motor evoked potential latency and decreased amplitude after concussion, suggesting that the brain may be unable to effectively coordinate movement. Our findings underscore the need to explore functional movement and dynamic postural control assessments in postconcussion injury assessment protocols. PMID- 26057942 TI - The Acute Effect of Exercise Intensity on Vascular Function in Adolescents. AB - INTRODUCTION: Impairments in vascular function are present in asymptomatic youths with risk factors for cardiovascular disease. Exercise can promote vascular health in youth, but the effects of exercise intensity and the time course in response to acute exercise are unknown. METHODS: Twenty adolescents (10 male, 14.1 +/- 0.3 yr) performed the following on separate days in a counterbalanced order: 1) cycling at 90% of the gas exchange threshold (moderate-intensity exercise (MIE)) and 2) 8 * 1-min cycling at 90% peak power with 75-s recovery (high-intensity interval exercise (HIIE)). The duration of MIE (25.8 +/- 2.1 min) was work-matched to HIIE (23.0 min). Macro- and microvascular functions were assessed before, immediately after, and 1 and 2 h after exercise by flow-mediated dilation (FMD) and laser Doppler imaging (total reactive hyperemia). RESULTS: FMD was attenuated immediately after HIIE (P < 0.001, effect size (ES) = 1.20) but not after MIE (P = 0.28, ES = 0.26). Compared with that before exercise, FMD was elevated 1 and 2 h after HIIE (P < 0.001, ES = 1.33; P < 0.001, ES = 1.36) but unchanged in MIE (P = 0.67, ES = 0.10; P = 0.72, ES = 0.08). Changes in FMD were unrelated to shear or baseline arterial diameter. Compared with that in preexercise, total reactive hyperemia was always greater after MIE (P < 0.02, ES > 0.60 for all) and HIIE (P < 0.001, ES > 1.18 for all). Total reactive hyperemia was greater in HIIE compared with that in MIE immediately after (P = 0.03, ES = 0.67) and 1 h after (P = 0.01, ES = 0.62) exercise, with a trend to be greater 2 h after (P = 0.06, ES = 0.45). CONCLUSIONS: Exercise intensity is positively associated with macro- and microvascular function 1 and 2 h after exercise. Performing HIIE may provide superior vascular benefits than MIE in adolescents. PMID- 26057943 TI - The new aspects of the anticorrosive ZnO@SiO2 core-shell NPs in stabilizing of the electrolytic Ni bath and the Ni coating structure; electrochemical behavior of the resulting nano-composite coatings. AB - The pure phase of the ZnO nanoparticles (NPs) as anticorrosive pigments was synthesized by the sonication method. The surfaces of the sono-synthesized nanoparticles were covered with the protective silica layer. The durability of the coated and uncoated ZnO NPs in the used electrolytic Ni bath was determined by flame atomic absorption spectrometry. In the present research the multicomponent Ni bath as the complex medium was replaced by the simple one. The used nickel-plating bath was just composed of the Ni salts (as the sources of the Ni(2+) ions) to better clarify the influence of the presence of the ZnO@SiO2 core shell NPs on the stability of the medium. The effect of ZnO@SiO2 NPs incorporation on the morphology of the solid electroformed Ni deposit was studied by scanning electron microscopy (SEM). Furthermore, the influence of the co deposited particles in the Ni matrix on the corrosion resistance of the Ni coating was evaluated by the electrochemical methods including linear polarization resistance (LPR) and Tafel extrapolation. PMID- 26057944 TI - Rice husk based porous carbon loaded with silver nanoparticles by a simple and cost-effective approach and their antibacterial activity. AB - In this paper, we chose rice husk as raw material and synthesized successfully porous carbon loaded with silver nanoparticles (RH-Ag) composites by simple and cost-effective method. The as-prepared RH-Ag composites have a BET-specific surface area of 1996 m(2) g(-1) and result in strong capacity of bacteria adsorption. The result of antibacterial study indicated that the RH-Ag system displayed antibacterial activity that was two times better than pure Ag NPs. Our study demonstrates that the antibacterial activity of RH-Ag composites may be attributed to their strong adsorption ability with bacteria and result in the disorganization of the bacterial membrane ultrastructure. In addition, RH-Ag system was found to be durative slow-releasing of silver ions and biocompatible for human skin keratinocytes cells. In terms of these advantages, the RH-Ag composites have potential application in antibacterial infections and therapy. PMID- 26057945 TI - Synthesis of a novel ionic liquid modified copolymer hydrogel and its rapid removal of Cr (VI) from aqueous solution. AB - A novel ionic liquid modified copolymer hydrogel (PAMDA) was successfully synthesized by a simple water solution copolymerization using acrylamide (AM), dimethyldiallylammonium chloride (DADMAC) and ionic liquid (1-allyl-3 methylimidazolium chloride; [Amim]Cl) as copolymerization monomers. The structure and morphology of as-prepared copolymer hydrogel PAMDA were confirmed by Fourier transform infrared (FT-IR), field-emission scanning electron microscope (FE-SEM) and thermogravimetric analysis (TG). The copolymer hydrogel was applied as a novel adsorbent for the rapid removal of Cr (VI) from aqueous solution. The effects of several parameters such as the content of ionic liquid [Amim]Cl, solution pH, contact time, adsorbent dosage and initial Cr (VI) concentration on the adsorption were also investigated. The modification of [Amim]Cl significantly enhanced Cr (VI) adsorption. The adsorption equilibrium data fitted with Langmuir isotherm model better than Freundlich isotherm model. The maximum adsorption capacity for Cr (VI) ions was 74.5 mg L(-1) at 323 K based on Langmuir isotherm model. The removal rate could reach 95.9% within 10 min at 323 K and the adsorption process of Cr (VI) on PAMDA was well described by the pseudo-second order kinetic model. The activation energy of adsorption was further investigated and found to be 1.094 kJ mol(-1), indicating the adsorption of Cr (VI) onto PAMDA was physisorption. PMID- 26057946 TI - Efficient gaseous toluene photoconversion on graphene-titanium dioxide nanocomposites with dominate exposed {001} facets. AB - A series of GnTiO2 {001} nanocomposites (GTN) with dominate exposed {001} facets has been synthesized by various dosage of graphite oxide (GO) and hydrofluoric acid (HF) during a facile solvothermal process successfully. The photocatalytic degradation efficiency (PDE) of the optimal sample reached up to 98.7% for liquids methyl orange and up to 78.6% for gaseous toluene under the UV-light irradiation for 30 min, which is much higher than P25. The effects mechanism of HF and GO on the percentage of {001} facets exposed and the crystal morphology are investigated by XRD, SEM, TEM, UV-Vis, XPS and BET measurement, particularly. Cyclic voltammograms (CV) and electrochemical impedance spectroscopy (EIS) were used to explore the electron transfer mechanisms of GnTiO2 {001} nanocomposites. These results reveal the enhanced photocatalytic properties attribute to the excellent electron transport of Gn and highly reactive {001} facets can facilitate the separation of photo-generated charge carriers. Moreover, Gn can extend the absorption range of light and improve the adsorptivity of pollutant molecules. PMID- 26057947 TI - Systemic pyruvate administration markedly reduces neuronal death and cognitive impairment in a rat model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a major neurodegenerative disease of old age, characterized by progressive cognitive impairment, dementia and atrophy of the central nervous system. Amyloid-beta (Abeta) oligomers are derived from proteolytic cleavage of amyloid precursor protein (APP) and recognized as the primary neurotoxic agents in AD. Pyruvate has a protective effect against Abeta oligomer-induced neuronal cell death and inhibition of long-term potentiation (LTP) in hippocampal slice cultures, leading us to investigate the effect of systemic pyruvate administration in an intracerebroventricular Abeta oligomer infusion model. We found that sodium pyruvate (500 mg/kg, intraperitoneally) improved neuron survival and sustained improvement in cognitive function as assessed by the Morris water maze. Pyuvate prevented the Abeta oligomer-induced inhibition of LTP and protein phosphatase 2A (PP2A) activation. Pyruvate suppressed the Abeta oligomer-induced poly[adenosine diphosphate (ADP) ribose] polymerase-1 (PARP-1) activity and ameliorated Abeta oligomer-induced decrease of NAD(+) level. Moreover, pyuvate, but not lactate, decreased reactive oxygen species (ROS) accumulation in hippocampus of Abeta1-42 oligomer-injection rat model. These results suggest that systemic pyruvate administration could significantly ameliorate Abeta oligomer-induced spatial learning and memory impairment by the improvement of neuron survival and prevention of LTP inhibition, and the beneficial effect of pyruvate could be linked, at least in part, to the elimination of ROS accumulation, prevention of PP2A activation, amelioration of NAD(+) level and suppression of PARP-1 activity. PMID- 26057948 TI - Gender- and anxiety level-dependent effects of perinatal stress exposure on medial prefrontal cortex. AB - Early life stress leads to psychopathological processes correlated with the predisposition of individuals. Prolonged development of the prefrontal cortex (PFC), playing a critical role in the cognition, personality and social behavior, makes it susceptible to adverse conditions. In this study, we evaluated the dendritic morphology of medial PFC neurons in rats subjected to perinatal stress exposure. Unbiased stereological counting methods showed that total number estimation of c-Fos (+) nuclei, indicating the neuronal activation upon stressful challenge, significantly increased in high anxious animals compared with low anxious and control groups, in both gender. Golgi-Cox staining of neurons displayed anxiety level- and sex-dependent reduction in the dendritic complexity and spine density of pyramidal neurons, especially in the stressed males. While the total length of dendrites were not correlational; density of spines, specifically the mushroom subtypes, showed a negative correlation with the anxiety level of stressed animals. These results suggest that medial PFC is a critical site of neural plasticity within the stressor controllability paradigm. Outcomes of early life stress might be predicted by analyzing the density and morphology of spines in the apical dendrites of pyramidal neurons in correlation with the anxiety-like behavior of animals. PMID- 26057949 TI - Therapeutic hypothermia for stroke: Where to go? AB - Ischemic stroke is a major cause of death and long-term disability worldwide. Thrombolysis with recombinant tissue plasminogen activator is the only proven and effective treatment for acute ischemic stroke; however, therapeutic hypothermia is increasingly recognized as having a tissue-protective function and positively influencing neurological outcome, especially in cases of ischemia caused by cardiac arrest or hypoxic-ischemic encephalopathy in newborns. Yet, many aspects of hypothermia as a treatment for ischemic stroke remain unknown. Large-scale studies examining the effects of hypothermia on stroke are currently underway. This review discusses the mechanisms underlying the effect of hypothermia, as well as trends in hypothermia induction methods, methods for achieving optimal protection, side effects, and therapeutic strategies combining hypothermia with other neuroprotective treatments. Finally, outstanding issues that must be addressed before hypothermia treatment is implemented at a clinical level are also presented. PMID- 26057950 TI - Formation Mechanism of Coamorphous Drug-Amino Acid Mixtures. AB - Two coamorphous drug-amino acid systems, indomethacin-tryptophan (Ind-Trp) and furosemide-tryptophan (Fur-Trp), were analyzed toward their ease of amorphization and mechanism of coamorphization during ball milling. The two mixtures were compared to the corresponding amorphization of the pure drug without amino acid. Powder blends at a 1:1 molar ratio were milled for varying times, and their physicochemical properties were investigated using XRPD, (13)C solid state NMR (ssNMR), and DSC. Comilling the drug with the amino acid reduced the milling time required to obtain an amorphous powder from more than 90 min in the case of the pure drugs to 30 min for the coamorphous powders. Amorphization was observed as reductions in XRPD reflections and was additionally quantified based on normalized principal component analysis (PCA) scores of the ssNMR spectra. Furthermore, the evolution in the glass temperature (Tg) of the coamorphous systems over time indicated complete coamorphization after 30 min of milling. Based on the DSC data it was possible to identify the formation mechanism of the two coamorphous systems. The Tg position of the samples suggested that coamorphous Ind-Trp was formed by the amino acid being dissolved in the amorphous drug, whereas coamorphous Fur-Trp was formed by the drug being dissolved in the amorphous amino acid. PMID- 26057952 TI - The coming era of human phenotyping. PMID- 26057951 TI - PC, a Novel Oral Insecticidal Toxin from Bacillus bombysepticus Involved in Host Lethality via APN and BtR-175. AB - Insect pests have developed resistance to chemical insecticides, insecticidal toxins as bioinsecticides or genetic protection built into crops. Consequently, novel, orally active insecticidal toxins would be valuable biological alternatives for pest control. Here, we identified a novel insecticidal toxin, parasporal crystal toxin (PC), from Bacillus bombysepticus (Bb). PC shows oral pathogenic activity and lethality towards silkworms and Cry1Ac-resistant Helicoverpa armigera strains. In vitro assays, PC after activated by trypsin binds to BmAPN4 and BtR-175 by interacting with CR7 and CR12 fragments. Additionally, trypsin-activated PC demonstrates cytotoxicity against Sf9 cells expressing BmAPN4, revealing that BmAPN4 serves as a functional receptor that participates in Bb and PC pathogenicity. In vivo assay, knocking out BtR-175 increased the resistance of silkworms to PC. These data suggest that PC is the first protein with insecticidal activity identified in Bb that is capable of causing silkworm death via receptor interactions, representing an important advance in our understanding of the toxicity of Bb and the contributions of interactions between microbial pathogens and insects to disease pathology. Furthermore, the potency of PC as an insecticidal protein makes it a good candidate for inclusion in integrated agricultural pest management systems. PMID- 26057953 TI - First oncolytic virus edges towards approval in surprise vote. PMID- 26057954 TI - CAR-T field booms as next-generation platforms attract big players. PMID- 26057955 TI - Takeda moves into stem cells. PMID- 26057956 TI - Heart failure gene therapy disappoints but experts keep the faith. PMID- 26057957 TI - Biogen's anti-LINGO promises nerve repair. PMID- 26057958 TI - Industry chases pan-genotypic and shorter HCV treatments. PMID- 26057959 TI - Cold Spring Harbor in translation. PMID- 26057960 TI - Alnylam's RNAi therapy targets amyloid disease. PMID- 26057961 TI - Brazil approves transgenic eucalyptus. PMID- 26057962 TI - Backlog cripples China's drug regulator. PMID- 26057963 TI - EC approves long overdue GM plants. PMID- 26057964 TI - Medtronic deal flurry raises artificial pancreas prospects. PMID- 26057965 TI - Around the world in a month. PMID- 26057966 TI - Drug pipeline: 1Q15. PMID- 26057967 TI - Bridging tech and biotech. PMID- 26057969 TI - Cardiac regeneration validated. PMID- 26057970 TI - Response to cardiac regeneration validated. PMID- 26057971 TI - Biological products and GAIN Act eligibility. PMID- 26057972 TI - Accelerating innovation in rapid diagnostics and targeted antibacterials. PMID- 26057973 TI - The ethics of publishing human germline research. PMID- 26057974 TI - Alexander Rich 1924-2015. PMID- 26057975 TI - Access to new technologies in multipatented vaccines: challenges for Brazil. PMID- 26057977 TI - Beyond the reference genome. PMID- 26057978 TI - Epigenome editing made easy. PMID- 26057979 TI - The heritable immune system. PMID- 26057981 TI - Career coaching for scientists. PMID- 26057983 TI - A Wireless FSCV Monitoring IC With Analog Background Subtraction and UWB Telemetry. AB - A 30-MUW wireless fast-scan cyclic voltammetry monitoring integrated circuit for ultra-wideband (UWB) transmission of dopamine release events in freely-behaving small animals is presented. On-chip integration of analog background subtraction and UWB telemetry yields a 32-fold increase in resolution versus standard Nyquist rate conversion alone, near a four-fold decrease in the volume of uplink data versus single-bit, third-order, delta-sigma modulation, and more than a 20-fold reduction in transmit power versus narrowband transmission for low data rates. The 1.5- mm(2) chip, which was fabricated in 65-nm CMOS technology, consists of a low-noise potentiostat frontend, a two-step analog-to-digital converter (ADC), and an impulse-radio UWB transmitter (TX). The duty-cycled frontend and ADC/UWB TX blocks draw 4 MUA and 15 MUA from 3-V and 1.2-V supplies, respectively. The chip achieves an input-referred current noise of 92 pA(rms) and an input current range of +/-430 nA at a conversion rate of 10 kHz. The packaged device operates from a 3-V coin-cell battery, measures 4.7 * 1.9 cm(2), weighs 4.3 g (including the battery and antenna), and can be carried by small animals. The system was validated by wirelessly recording flow-injection of dopamine with concentrations in the range of 250 nM to 1 MUM with a carbon-fiber microelectrode (CFM) using 300-V/s FSCV. PMID- 26057984 TI - Cross-linguistic validity of the French and Dutch versions of the Very Short form of the Physical Self-Inventory among adolescents. AB - The study tested the cross-linguistic validity of the Very Short form of the Physical Self-Inventory (PSI-VS) among 1115 Flemish (Dutch version) adolescents, and a comparison sample of 1103 French adolescents (French version; from Morin & Maiano, 2011a). Flemish adolescents also completed a positively worded reformulation of the reverse-keyed item of the physical attractiveness (PA) subscale. Confirmatory factor analyses (CFA) supported the factor validity and reliability (except for the Dutch PA subscale) of the PSI-VS, and its partial measurement invariance across samples. CFA conducted on the modified version of the Dutch PSI-VS (11 original items plus the positively worded replacement), presented satisfactory reliability (omega=.67-.89), and was fully invariant across sexes, age groups, and body mass index categories. Additionally, results revealed latent mean differences across sexes and body mass index categories. Therefore, the modified Dutch PSI-VS can be used whenever there is a need for a very short physical self-concept questionnaire. PMID- 26057985 TI - Public exposure due to external gamma background radiation in boundary areas of Iran. AB - A monitoring program in boundary areas of a country is an appropriate way to indicate the level of public exposure. In this research, gamma background radiation was measured using TL dosimeters at 12 boundary areas as well as in the capital city of Iran during the period 2010 to 2011. The measurements were carried out in semi-annual time intervals from January to June and July to December in each year. The maximum average dose equivalent value measured was approximately 70 MUSv/month for Tehran city. Also, the average dose values obtained were less than 40 MUSv/month for all the cities located at the sea level except that of high level natural radiation area of Ramsar, and more than 55 MUSv/month for the higher elevation cities. The public exposure due to ambient gamma dose equivalent in Iran is within the levels reported by UNSCEAR. PMID- 26057986 TI - Equation to predict the (137)Cs leaching dynamic from evergreen canopies after a radio-cesium deposit. AB - The Fukushima Daiishi nuclear power plant (FDNPP) accident led to a massive radionuclide deposition mainly onto Japanese forest canopies. In our previous study, an improved double exponential (IDE) equation including rainfall intensity was proposed to estimate the (137)Cs hydrological transport from evergreen canopies to the ground. This equation used two types of parameters, kinetic (k1 and k2) and leachable stock (A1 and A2). Those parameters have been estimated by adjusting them in the IDE equation in order to accurately describe the measured cumulative leached (137)Cs from canopies (k1 = 4.2E-04-5.0E-04 d(-1), k2 = 1.2E 02-1.7E-02 d(-1), A1 = 62-99 kBq/m(2), A2 = 25-61 kBq/m(2)). In this study, we linked the total leachable stock (Aleachable, a parameter of the IDE equation corresponding to A1 + A2) to a physiological criteria (the canopy closure CC, which can be measured with a simple camera equipped with a fish-eye objective). Furthermore, the kinetic parameters measured for Japanese cedar (k1 = 5.0E-04 d( 1), k2 = 1.2E-02 d(-1), and r12 = 0.22 (r12 = A1/A2) could also be used for two other coniferous species: Japanese cypress and spruce. This suggests that these parameters could be constants for coniferous forests. PMID- 26057987 TI - Iodide uptake by negatively charged clay interlayers? AB - Understanding iodide interactions with clay minerals is critical to quantifying risk associated with nuclear waste disposal. Current thought assumes that iodide does not interact directly with clay minerals due to electrical repulsion between the iodide and the negatively charged clay layers. However, a growing body of work indicates a weak interaction between iodide and clays. The goal of this contribution is to report a conceptual model for iodide interaction with clays by considering clay mineral structures and emergent behaviors of chemical species in confined spaces. To approach the problem, a suite of clay minerals was used with varying degrees of isomorphic substitution, chemical composition, and mineral structure. Iodide uptake experiments were completed with each of these minerals in a range of swamping electrolyte identities (NaCl, NaBr, KCl) and concentrations. Iodide uptake behaviors form distinct trends with cation exchange capacity and mineral structure. These trends change substantially with electrolyte composition and concentration, but do not appear to be affected by solution pH. The experimental results suggest that iodide may directly interact with clays by forming ion-pairs (e.g., NaI(aq)) which may concentrate within the interlayer space as well as the thin areas surrounding the clay particle where water behavior is more structured relative to bulk water. Ion pairing and iodide concentration in these zones is probably driven by the reduced dielectric constant of water in confined space and by the relatively high polarizability of the iodide species. PMID- 26057988 TI - Actinomycosis of eye: Forgotten but not uncommon. AB - Actinomyces species are known to cause a variety of human infections. Ocular actinomycosis is a rare disease. We report an unusual case of bilateral actinomycotic blepharoconjunctivitis in the absence of canaliculitis that presented with forniceal masses in eye. The case report is discussed here along with Indian literature. PMID- 26057989 TI - Hagfish: Champions of CO2 tolerance question the origins of vertebrate gill function. AB - The gill is widely accepted to have played a key role in the adaptive radiation of early vertebrates by supplanting the skin as the dominant site of gas exchange. However, in the most basal extant craniates, the hagfishes, gills play only a minor role in gas exchange. In contrast, we found hagfish gills to be associated with a tremendous capacity for acid-base regulation. Indeed, Pacific hagfish exposed acutely to severe sustained hypercarbia tolerated among the most severe blood acidoses ever reported (1.2 pH unit reduction) and subsequently exhibited the greatest degree of acid-base compensation ever observed in an aquatic chordate. This was accomplished through an unprecedented increase in plasma [HCO3(-)] (>75 mM) in exchange for [Cl(-)]. We thus propose that the first physiological function of the ancestral gill was acid-base regulation, and that the gill was later co-opted for its central role in gas exchange in more derived aquatic vertebrates. PMID- 26057990 TI - Mass spectrometry-based N-linked glycomic profiling as a means for tracking pancreatic cancer metastasis. AB - The aberrant glycosylation profile on the surface of cancer cells has been recognized for its potential diagnostic value towards assessing tumor progression. In this study, we initially investigate N-glycan profiles on the surface of normal (HPDE) and cancerous (Capan-1, Panc-1, and MIA PaCa-2) pancreatic cell lines, which are from different sites of pancreatic tumor. The enzymatically deglycosylated total N-glycans are permethylated via a quantitative solid-phase method and then analyzed by using MALDI-TOF MS and MALDI-QIT-TOF MS. We demonstrate that the level of high-mannose type glycans is higher among Capan 1 cells-pancreatic cancer cells that have metastasized to the liver-than that observed among Panc-1 and MIA PaCa-2 cells-pancreatic cancer cells from the pancreas duct head and tail regions, respectively. Furthermore, the relative abundance of highly-branched sialyted N-glycans is significantly up-regulated on Panc-1 and MIA PaCa-2 pancreatic cancer cells compared to that of normal HPDE pancreas cells. Taken together, these results indicate that specific N glycosylation profile changes in pancreatic cancer cells can be used to not only distinguish between normal and cancerous cells but also provide more information on their location and metastatic potential. PMID- 26057991 TI - Structure of the neutral capsular polysaccharide of Acinetobacter baumannii NIPH146 that carries the KL37 capsule gene cluster. AB - Capsular polysaccharide (CPS) was isolated from Acinetobacter baumannii NIPH146, and the following structure of branched pentasaccharide repeating unit was established by sugar analyses along with 1D and 2D NMR spectroscopy: In comparison to most other known capsular polysaccharides of A. baumannii, the CPS studied is neutral and lacks any specific monosaccharide component. The synthesis, assembly and export of this structure could be attributed to genes in a novel capsule biosynthesis gene cluster, designated KL37, which was found in the NIPH146 genome. The CPS of A. baumannii NIPH146 shares the alpha-d-Galp-(1 >6)-beta-d-Glcp-(1->3)-d-GalpNAc-(1-> trisaccharide fragment with the CPS units of several A. baumannii strains, including ATCC 17978 and LUH 5537 that carry the KL3 and KL22 gene clusters, respectively. KL37 contains two genes for glycosyltransferases that are related to two glycosyltransferase genes present in both KL3 and KL22, and the encoded proteins could be tentatively assigned to linkages between sugars in the CPS repeat. PMID- 26057992 TI - Navigation liver surgery for complex hydatid cyst with biliary tree communication. AB - INTRODUCTION: Today, liver surgery navigation is utilized only in high specialized centers for patients affected by malignant diseases. However, navigated surgery may also be of great interest for benign diseases such as hydatidosis in particular if the hydatid cyst is communicating with the biliary tree. With navigation we know exactly in each moment during the surgery the relationship of the cyst with the vascular/biliary structures around it. PRESENTATION OF CASE: Herein, we report a case of a 20-year-old W/M affected by hepatic hydatid cyst communicating with the right bile duct, causing recurrent cholangitis. The diagnosis was confirmed by endoscopic retrograde cholangiography and magnetic resonance imaging. The liver cystectomy was easily performed using a navigation system incorporating instrument tracking and three-dimensional CT reconstruction, thus permitting a selective suture of the bile duct communicating with the cyst. CONCLUSIONS: The navigated system may guide the surgeon in patients with severe and complicated hydatid cysts. PMID- 26057993 TI - Double concentric craniotomy: Safe and effective technique to achieve an en bloc resection of tumor involving both skull and duraa. AB - INTRODUCTION: Many tumors can involve the skull. Meningiomas are one of the most common intracranial neoplasms and invasion of the bone was described in 49% of cases. Other neoplastic lesions that can arise in bone, or involve it, are metastases, hemangiomas, aggressive cutis carcinomas and sarcomas. Radical excision is the golden standard of treatment but elevating a bone flap when the tumor involves both the skull and the dura could represent a technical challenge. PRESENTATION OF CASE: We report the technical details of our approach to remove a meningioma involving both skull and dura in a man aged 45. Patient underwent gross total excision and cranioplasty with PEEK custom made prothesis (SynthesTM). DISCUSSION: We describe a double concentric craniotomy (DCC) technique where the tumor involving the bone is before left in situ, exposing normal dura, to perform afterwards en-bloc excision with minimal traction of brain surface. CONCLUSION: DCC is a safe and effective technique to remove tumor involving both skull and dural structures under direct vision. PMID- 26057994 TI - The Potential for Reducing the Number of Pneumococcal Conjugate Vaccine Doses While Sustaining Herd Immunity in High-Income Countries. PMID- 26057995 TI - A new formula for calculating standard liver volume for living donor liver transplantation without using body weight. AB - BACKGROUND & AIMS: The standard liver volume (SLV) is widely used in liver surgery, especially for living donor liver transplantation (LDLT). All the reported formulas for SLV use body surface area or body weight, which can be influenced strongly by the general condition of the patient. METHODS: We analyzed the liver volumes of 180 Japanese donor candidates and 160 Swiss patients with normal livers to develop a new formula. The dataset was randomly divided into two subsets, the test and validation sample, stratified by race. The new formula was validated using 50 LDLT recipients. RESULTS: Without using body weight-related variables, age, thoracic width measured using computed tomography, and race independently predicted the total liver volume (TLV). A new formula: 203.3 (3.61*age)+(58.7*thoracic width)-(463.7*race [1=Asian, 0=Caucasian]), most accurately predicted the TLV in the validation dataset as compared with any other formulas. The graft volume for LDLT was correlated with the postoperative prothrombin time, and the graft volume/SLV ratio calculated using the new formula was significantly better correlated with the postoperative prothrombin time than the graft volume/SLV ratio calculated using the other formulas or the graft volume/body weight ratio. CONCLUSIONS: The new formula derived using the age, thoracic width and race predicted both the TLV in the healthy patient group and the SLV in LDLT recipients more accurately than any other previously reported formulas. PMID- 26057996 TI - Reply to: "Is skin mottling a predictor of high mortality in non-selected patients with cirrhosis admitted to intensive care unit?". PMID- 26057997 TI - Does river restoration affect diurnal and seasonal changes to surface water quality? A study along the Thur River, Switzerland. AB - Changes in river water quality were investigated along the lower reach of the Thur River, Switzerland, following river restoration and a summer storm event. River restoration and hydrological storm events can each cause dramatic changes to water quality by affecting various bio-geochemical processes in the river, but have to date not been well documented, especially in combination. Evaluating the success of river restoration is often restricted in large catchments due to a lack of high frequency water quality data, which are needed for process understanding. These challenges were addressed in this study by measuring water quality parameters including dissolved oxygen (DO), temperature, pH, electrical conductivity (EC), nitrate and dissolved organic carbon (DOC) with a high temporal frequency (15 min-1h) over selected time scales. In addition, the stable isotopes of water (deltaD and delta(18)O-H2O) as well as those of nitrate (delta(15)N-NO3(-) and delta(18)O-NO3(-)) were measured to follow changes in water quality in response to the hydrological changes in the river. To compare the spatial distribution of pre- and post-restoration water quality, the sampling stations were chosen upstream and downstream of the restored section. The diurnal and seasonal changes were monitored by conducting 24-hour campaigns in three seasons (winter, summer and autumn) in 2012 and 2013. The amplitude of the diurnal changes of the various observed parameters showed significant seasonal and spatial variability. Biological processes--mainly photosynthesis and respiration--were found to be the major drivers of these diurnal cycles. During low flow in autumn, a reduction of nitrate (attributed to assimilation by autotrophs) in the pre-dawn period and a production of DOC during the daytime (attributed to photosynthesis) were observed downstream of the restored site. Further, a summer storm event was found to override the influence of these biological processes that control the diurnal changes. High frequency daily monitoring of key water quality parameters over different seasons is shown to be essential in evaluating river restoration success. PMID- 26057998 TI - Particle phase distribution of polycyclic aromatic hydrocarbons in stormwater- Using humic acid and iron nano-sized colloids as test particles. AB - The distribution of polycyclic aromatic hydrocarbons (PAHs) in different particulate fractions in stormwater: Total, Particulate, Filtrated, Colloidal and Dissolved fractions, were examined and compared to synthetic suspensions of humic acid colloids and iron nano-sized particles. The distribution of low-molecular weight PAHs (LMW PAHs), middle-molecular weight PAHs (MMW PAHs) and high molecular weight PAHs (HMW PAHs) among the fractions was also evaluated. The results from the synthetic suspensions showed that the highest concentrations of the PAHs were found in the Filtrated fractions and, surprisingly, high loads were found in the Dissolved fractions. The PAHs identified in stormwater in the Particulate fractions and Dissolved fractions follow their hydrophobic properties. In most samples >50% of the HMW PAHs were found in the Particulate fractions, while the LMW and MMW PAHs were found to a higher extent in the Filtrated fractions. The highest concentrations of PAHs were present in the stormwater with the highest total suspended solids (TSS); the relative amount of the HMW PAHs was highest in the Particulate fractions (particles>0.7 MUm). The highest concentration of PAHs in the Colloidal fraction was found in the sample with occurrence of small nano-sized particles (<10nm). The results show the importance of developing technologies that both can manage particulate matter and effectively remove PAHs present in the Colloidal and Dissolved fractions in stormwater. PMID- 26057999 TI - Adsorptive removal of antibiotics from water and wastewater: Progress and challenges. AB - Antibiotics as emerging contaminants are of global concern due to the development of antibiotic resistant genes potentially causing superbugs. Current wastewater treatment technology cannot sufficiently remove antibiotics from sewage, hence new and low-cost technology is needed. Adsorptive materials have been extensively used for the conditioning, remediation and removal of inorganic and organic hazardous materials, although their application for removing antibiotics has been reported for ~30 out of 250 antibiotics so far. The literature on the adsorptive removal of antibiotics using different adsorptive materials is summarized and critically reviewed, by comparing different adsorbents with varying physicochemical characteristics. The efficiency for removing antibiotics from water and wastewater by different adsorbents has been evaluated by examining their adsorption coefficient (Kd) values. For sulfamethoxazole the different adsorbents followed the trend: biochar (BC)> multi-walled carbon nanotubes (MWCNTs)>graphite = clay minerals, and for tetracycline the adsorptive materials followed the trend: SWCNT > graphite > MWCNT = activated carbon (AC) > bentonite = humic substance = clay minerals. The underlying controlling parameters for the adsorption technology have been examined. In addition, the cost of preparing adsorbents has been estimated, which followed the order of BCs < ACs < ion exchange resins < MWCNTs < SWCNTs. The future research challenges on process integration, production and modification of low-cost adsorbents are elaborated. PMID- 26058000 TI - Recommendations for fluoride limits in drinking water based on estimated daily fluoride intake in the Upper East Region, Ghana. AB - Both dental and skeletal fluorosis caused by high fluoride intake are serious public health concerns around the world. Fluorosis is particularly pronounced in developing countries where elevated concentrations of naturally occurring fluoride are present in the drinking water, which is the primary route of exposure. The World Health Organization recommended limit of fluoride in drinking water is 1.5 mg F(-) L(-1), which is also the upper limit for fluoride in drinking water for several other countries such as Canada, China, India, Australia, and the European Union. In the United States the enforceable limit is much higher at 4 mg F(-) L(-1), which is intended to prevent severe skeletal fluorosis but does not protect against dental fluorosis. Many countries, including the United States, also have notably lower unenforced recommended limits to protect against dental fluorosis. One consideration in determining the optimum fluoride concentration in drinking water is daily water intake, which can be high in hot climates such as in northern Ghana. The results of this study show that average water intake is about two times higher in Ghana than in more temperate climates and, as a result, the fluoride intake is higher. The results also indicate that to protect the Ghanaian population against dental fluorosis, the maximum concentration of fluoride in drinking water for children under 6-8 years should be 0.6 mg F(-) L(-1) (and lower in the first two years of life), and the limit for older children and adults should be 1.0 mg F(-) L(-1). However, when considering that water treatment is not cost-free, the most widely recommended limit of 1.5 mg F(-) L(-1) - which is currently the limit in Ghana- may be appropriate for older children and adults since they are not vulnerable to dental fluorosis once the tooth enamel is formed. PMID- 26058001 TI - Differences in the impacts of formal and informal recreational trails on urban forest loss and tree structure. AB - Recreational trails are one of the most common types of infrastructure used for nature-based activities such as hiking and mountain biking worldwide. Depending on their design, location, construction, maintenance and use, these trails differ in their environmental impacts. There are few studies, however, comparing the impacts of different trail types including between formal management-created trails and informal visitor-created trails. Although both types of trails can be found in remote natural areas, dense networks of them often occur in forests close to cities where they experience intense visitor use. To assess the relative impacts of different recreational trails in urban forests, we compared the condition of the trail surface, loss of forest strata and changes in tree structure caused by seven types of trails (total network 46.1 km) traversing 17 remnants of an endangered urban forest in Australia. After mapping and classifying all trails, we assessed their impact on the forest condition at 125 sites (15 sites per trail type, plus 15 control sites within undisturbed forest). On the trail sites, the condition of the trail surface, distance from the trail edge to four forest strata (litter, understory, midstorey and tree cover) and structure of the tree-line were assessed. Informal trails generally had poorer surface conditions and were poorly-designed and located. Per site, formal and informal trails resulted in similar loss of forest strata, with wider trails resulting in greater loss of forest. Because there were more informal trails, however, they accounted for the greatest cumulative forest loss. Structural impacts varied, with the widest informal trails and all formal hardened trails resulting in similar reductions in canopy cover and tree density but an increase in saplings. These structural impacts are likely a function of the unregulated and intense use of large informal trails, and disturbance from the construction and maintenance of formal trails. The results demonstrate that different types of recreational trails vary in the type and range of impacts they cause to forests. They highlight the importance of careful consideration towards management options when dealing with trail networks especially in areas of high conservation value. PMID- 26058002 TI - The influence of zinc(II) on thioredoxin/glutathione disulfide exchange: QM/MM studies to explore how zinc(II) accelerates exchange in higher dielectric environments. AB - QM/MM studies were performed to explore the energetics of exchange reactions of glutathione disulfide (GSSG) and the active site of thioredoxin [Cys32-Gly33 Pro34-Cys35] with and without zinc(II), in vacuum and solvated models. The activation energy for exchange, in the absence of zinc, is 29.7 kcal mol(-1) for the solvated model. This is 3.3 kcal mol(-1) higher than the activation energy for exchange in the gas phase, due to ground state stabilization of the active site Cys-32 thiolate in a polar environment. In the presence of zinc, the activation energy for exchange is 4.9 kcal mol(-1) lower than in the absence of zinc (solvated models). The decrease in activation energy is attributed to stabilization of the charge-separated transition state, which has a 4-centered, cyclic arrangement of Zn-S-S-S with an estimated dipole moment of 4.2 D. A difference of 4.9 kcal mol(-1) in activation energy would translate to an increase in rate by a factor of about 4000 for zinc-assisted thiol-disulfide exchange. The calculations are consistent with previously reported experimental results, which indicate that metal-thiolate, disulfide exchange rates increase as a function of solvent dielectric. This trend is opposite to that observed for the influence of the dielectric environment on the rate of thiol-disulfide exchange in the absence of metal. The results suggest a dynamic role for zinc in thiol disulfide exchange reactions, involving accessible cysteine sites on proteins, which may contribute to redox regulation and mechanistic pathways during oxidative stress. PMID- 26058003 TI - Changes in family cohesion and links to depression during the college transition. AB - Parent relationships remain an important component in the lives of adolescents, with particular respect to their well-being. In the current study, we sought to understand how changes in family cohesion across the high school-college transition may be related to changes in depressive symptoms. Three hundred and thirty-eight college freshman completed self-report measures prior to attending college and again two months into their first semester. Although depressive symptoms significantly increased, adolescents who reported increases in family cohesion reported declines in depressive symptoms during the college transition. Furthermore, this effect was mediated by changes in self-esteem and optimism. Finally, we show unique associations for male and female adolescents, such that changes in family cohesion were only related to changes in depression for girls. Results suggest that parent relationships may buffer against increased depressive symptoms during this important transition period. PMID- 26058004 TI - Microflora in oral ecosystems and salivary secretion rates--A 3-year follow-up after radiation therapy to the head and neck region. AB - OBJECTIVE: Results indicate that late improvements of radiation therapy (RT) in the head and neck region may diminish the long-term effects on salivary glands and oral microflora. The aim was therefore to analyze salivary secretion rates and oral microflora over time in RT subjects. DESIGN: Twelve dentate subjects (28+/-2 teeth) and 12 controls were included. A clinical examination was performed and the salivary secretion rates were determined. Microbial samples, analyzed using cultivation technique, were collected from the soft tissues, supragingival plaque and gingival crevice region. RESULTS: Compared with the controls, the RT group (n=11) had 3 years post RT higher numbers and proportions of lactobacilli (p<0.001 and p<0.01) and Candida albicans (p<0.01 and p<0.05) in the supragingival plaque, higher numbers of enterococci in the vestibulum in the molar region and on the tongue (p<0.05 for both), a lower total count (p<0.001) and lower numbers of streptococci, Streptococcus salivarius and Fusobacterium nucleatum (p<0.01) on the tongue. Although both stimulated and unstimulated salivary secretion rates were increased over time, the proportion of microorganisms associated with oral health decreased, and microorganisms associated with oral disorders increased. Despite a comparable oral hygiene, it was only the 27% who had a stimulated salivary secretion rate >=1.0ml/min and a buffering capacity >=6.0, where a recovery of the flora could be seen. CONCLUSION: The results indicate that regaining a normal, stimulated salivary secretion rate and buffering capacity are prerequisites to regaining an oral flora associated with good oral health. PMID- 26058005 TI - In vitro effect of caffeic acid phenethyl ester on matrix metalloproteinases (MMP 1 and MMP-9) and their inhibitor (TIMP-1) in lipopolysaccharide-activated human monocytes. AB - OBJECTIVE: The role of matrix metalloproteinases (MMPs) in tissue degradation has become evident in many diseases and great interest therefore exists in the pharmacological control of the activity of these enzymes. This study evaluated the effect of caffeic acid phenethyl ester (CAPE) on the production of MMPs and their inhibitor (TIMP) in monocytes activated by lipopolysaccharide (LPS). DESIGN: The human monocytic cell line (THP-1) was treated with non-cytotoxic concentrations of CAPE (10 and 60MUM) combined with 1MUg/mL of LPS. The gene expression of MMP-1, MMP-9 and TIMP-1 was evaluated by quantitative real-time polymerase chain reaction. The protein secretion into the culture medium was assessed via enzyme-linked immunosorbent assay and the gelatinolytic activity of MMP-9 by zymography. RESULTS: CAPE, especially at the highest concentration, down regulated MMP-1 and MMP-9 gene expression but up-regulated the gene expression of TIMP-1. Furthermore, CAPE reduced the secreted protein level of MMP-1 and MMP-9 as well as the gelatinolytic activity of MMP-9. CONCLUSION: CAPE was able to inhibit the gene expression, production and the activity of MMPs induced by LPS and also increased the gene expression of TIMP-1. The present observations suggest that CAPE exerted a positive effect on the regulatory mechanism between MMPs and TIMP, which is important for the control of different diseases. PMID- 26058006 TI - Quality and shelf-life prediction for retail fresh hake (Merluccius merluccius). AB - Fish quality has a direct impact on market price and its accurate assessment and prediction are of main importance to set prices, increase competitiveness, resolve conflicts of interest and prevent food wastage due to conservative product shelf-life estimations. In this work we present a general methodology to derive predictive models of fish freshness under different storage conditions. The approach makes use of the theory of optimal experimental design, to maximize data information and in this way reduce the number of experiments. The resulting growth model for specific spoilage microorganisms in hake (Merluccius merluccius) is sufficiently informative to estimate quality sensory indexes under time varying temperature profiles. In addition it incorporates quantitative information of the uncertainty induced by fish variability. The model has been employed to test the effect of factors such as fishing gear or evisceration, on fish spoilage and therefore fish quality. Results show no significant differences in terms of microbial growth between hake fished by long-line or bottom-set nets, within the implicit uncertainty of the model. Similar conclusions can be drawn for gutted and un-gutted hake along the experiment horizon. In addition, whenever there is the possibility to carry out the necessary experiments, this approach is sufficiently general to be used in other fish species and under different stress variables. PMID- 26058007 TI - Decontamination of Pangasius fish (Pangasius hypophthalmus) with chlorine or peracetic acid in the laboratory and in a Vietnamese processing company. AB - This study evaluated the decontamination of Pangasius fillets in chlorine or peracetic acid treated wash water. First, the decontamination efficacy of the washing step with chlorinated water applied by a Vietnamese processing company during trimming of Pangasius fillets was evaluated and used as the basis for the experiments performed on a laboratory scale. As chlorine was only added at the beginning of the batch and used continuously without renewal for 239min; a rapid increase of the bacterial counts and a fast decrease of chlorine in the wash water were found. This could be explained by the rapid accumulation of organic matter (ca. 400mg O2/L of COD after only 24min). Secondly, for the experiments performed on a laboratory scale, a single batch approach (one batch of wash water for treating a fillet) was used. Chlorine and PAA were evaluated at 10, 20, 50 and 150ppm at contact times of 10, 20 and 240s. Washing with chlorine and PAA wash water resulted in a reduction of Escherichia coli on Pangasius fish which ranged from 0-1.0 and 0.4-1.4logCFU/g, respectively while less to no reduction of total psychrotrophic counts, lactic acid bacteria and coliforms on Pangasius fish was observed. However, in comparison to PAA, chlorine was lost rapidly. As an example, 53-83% of chlorine and 15-17% of PAA were lost after washing for 40s (COD=238.2+/-66.3mg O2/L). Peracetic acid can therefore be an alternative sanitizer. However, its higher cost will have to be taken into consideration. Where (cheaper) chlorine is used, the processors have to pay close attention to the residual chlorine level, pH and COD level during treatment for optimal efficacy. PMID- 26058008 TI - Spray Layer-by-Layer Assembled Clay Composite Thin Films as Selective Layers in Reverse Osmosis Membranes. AB - Spray layer-by-layer assembled thin films containing laponite (LAP) clay exhibit effective salt barrier and water permeability properties when applied as selective layers in reverse osmosis (RO) membranes. Negatively charged LAP platelets were layered with poly(diallyldimethylammonium) (PDAC), poly(allylamine) (PAH), and poly(acrylic acid) (PAA) in bilayer and tetralayer film architectures to generate uniform films on the order of 100 nm thick that bridge a porous poly(ether sulfone) support to form novel RO membranes. Nanostructures were formed of clay layers intercalated in a polymeric matrix that introduced size-exclusion transport mechanisms into the selective layer. Thermal cross-linking of the polymeric matrix was used to increase the mechanical stability of the films and improve salt rejection by constraining swelling during operation. Maximum salt rejection of 89% was observed for the tetralayer film architecture, with an order of magnitude increase in water permeability compared to commercially available TFC-HR membranes. These clay composite thin films could serve as a high-flux alternative to current polymeric RO membranes for wastewater and brackish water treatment as well as potentially for forward osmosis applications. In general, we illustrate that by investigating the composite systems accessed using alternating layer-by-layer assembly in conjunction with complementary covalent cross-linking, it is possible to design thin film membranes with tunable transport properties for water purification applications. PMID- 26058009 TI - 1H NMR Spectroscopy and MVA Analysis of Diplodus sargus Eating the Exotic Pest Caulerpa cylindracea. AB - The green alga Caulerpa cylindracea is a non-autochthonous and invasive species that is severely affecting the native communities in the Mediterranean Sea. Recent researches show that the native edible fish Diplodus sargus actively feeds on this alga and cellular and physiological alterations have been related to the novel alimentary habits. The complex effects of such a trophic exposure to the invasive pest are still poorly understood. Here we report on the metabolic profiles of plasma from D. sargus individuals exposed to C. cylindracea along the southern Italian coast, using 1H NMR spectroscopy and multivariate analysis (Principal Component Analysis, PCA, Orthogonal Partial Least Square, PLS, and Orthogonal Partial Least Square Discriminant Analysis, OPLS-DA). Fish were sampled in two seasonal periods from three different locations, each characterized by a different degree of algal abundance. The levels of the algal bisindole alkaloid caulerpin, which is accumulated in the fish tissues, was used as an indicator of the trophic exposure to the seaweed and related to the plasma metabolic profiles. The profiles appeared clearly influenced by the sampling period beside the content of caulerpin, while the analyses also supported a moderate alteration of lipid and choline metabolism related to the Caulerpa-based diet. PMID- 26058010 TI - Drimane Sesquiterpene-Conjugated Amino Acids from a Marine Isolate of the Fungus Talaromyces minioluteus (Penicillium Minioluteum). AB - Four new sesquiterpene lactones (3, 4, 6 and 7) and three known compounds, purpuride (1), berkedrimane B (2) and purpuride B (5), were isolated from the marine fungus, Talaromyces minioluteus (Penicillium minioluteum). New compounds were drimane sesquiterpenes conjugated with N-acetyl-l-valine, and their structures were elucidated by analysis of spectroscopic data, as well as by single crystal X-ray analysis. The isolated compounds could not inhibit the apoptosis-regulating enzyme, caspase-3, while three of the compounds (2, 3 and 7) exhibited weak cytotoxic activity. PMID- 26058011 TI - Antibiofilm Activity of the Brown Alga Halidrys siliquosa against Clinically Relevant Human Pathogens. AB - The marine brown alga Halidrys siliquosa is known to produce compounds with antifouling activity against several marine bacteria. The aim of this study was to evaluate the antimicrobial and antibiofilm activity of organic extracts obtained from the marine brown alga H. siliquosa against a focused panel of clinically relevant human pathogens commonly associated with biofilm-related infections. The partially fractionated methanolic extract obtained from H. siliquosa collected along the shores of Co. Donegal; Ireland; displayed antimicrobial activity against bacteria of the genus Staphylococcus; Streptococcus; Enterococcus; Pseudomonas; Stenotrophomonas; and Chromobacterium with MIC and MBC values ranging from 0.0391 to 5 mg/mL. Biofilms of S. aureus MRSA were found to be susceptible to the algal methanolic extract with MBEC values ranging from 1.25 mg/mL to 5 mg/mL respectively. Confocal laser scanning microscopy using LIVE/DEAD staining confirmed the antimicrobial nature of the antibiofilm activity observed using the MBEC assay. A bioassay-guided fractionation method was developed yielding 10 active fractions from which to perform purification and structural elucidation of clinically-relevant antibiofilm compounds. PMID- 26058012 TI - White Shrimp Litopenaeus vannamei That Have Received Gracilaria tenuistipitata Extract Show Early Recovery of Immune Parameters after Ammonia Stressing. AB - White shrimp Litopenaeus vannamei immersed in seawater (350/00) containing Gracilaria tenuistipitata extract (GTE) at 0 (control), 400, and 600 mg/L for 3 h were exposed to 5 mg/L ammonia-N (ammonia as nitrogen), and immune parameters including hyaline cells (HCs), granular cells (GCs, including semi-granular cells), total hemocyte count (THC), phenoloxidase (PO) activity, respiratory bursts (RBs), superoxide dismutase (SOD) activity, lysozyme activity, and hemolymph protein level were examined 24~120 h post-stress. The immune parameters of shrimp immersed in 600 mg/L GTE returned to original values earlier, at 96~120 h post-stress, whereas in control shrimp they did not. In another experiment, shrimp were immersed in seawater containing GTE at 0 and 600 mg/L for 3 h and examined for transcript levels of immune-related genes at 24 h post-stress. Transcript levels of lipopolysaccharide and beta-1,3-glucan binding protein (LGBP), peroxinectin (PX), cytMnSOD, mtMnSOD, and HSP70 were up-regulated at 24 h post-stress in GTE receiving shrimp. We concluded that white shrimp immersed in seawater containing GTE exhibited a capability for maintaining homeostasis by regulating cellular and humoral immunity against ammonia stress as evidenced by up-regulated gene expression and earlier recovery of immune parameters. PMID- 26058013 TI - Activation of RAF1 (c-RAF) by the Marine Alkaloid Lasonolide A Induces Rapid Premature Chromosome Condensation. AB - Lasonolide A (LSA), a potent antitumor polyketide from the marine sponge, Forcepia sp., induces rapid and reversible protein hyperphosphorylation and premature chromosome condensation (PCC) at nanomolar concentrations independent of cyclin-dependent kinases. To identify cellular targets of LSA, we screened 2951 shRNAs targeting a pool of human kinases and phosphatases (1140 RefSeqs) to identify genes that modulate PCC in response to LSA. This led to the identification of RAF1 (C-RAF) as a mediator of LSA-induced PCC, as shRNAs against RAF1 conferred resistance to LSA. We found that LSA induced RAF1 phosphorylation on Serine 338 within minutes in human colorectal carcinoma HCT 116, ovarian carcinoma OVCAR-8, and Burkitt's lymphoma CA46 cell lines. RAF1 depletion by siRNAs attenuated LSA-induced PCC in HCT-116 and OVCAR-8 cells. Furthermore, mouse embryonic fibroblasts (MEF) with homozygous deletion in Raf1, but not deletion in the related kinase Braf, were resistant to LSA-induced PCC. Complementation of Raf1-/- MEFs with wild-type human RAF1, but not with kinase dead RAF1 mutant, restored LSA-induced PCC. Finally, the Raf inhibitor sorafenib, but not the MEK inhibitor AZD6244, effectively suppressed LSA-induced PCC. Our findings implicate a previously unknown, MAPK-independent role of RAF1 in chromatin condensation and potent activation of this pathway by LSA. PMID- 26058014 TI - Peniciadametizine A, a Dithiodiketopiperazine with a Unique Spiro[furan-2,7' pyrazino[1,2-b][1,2]oxazine] Skeleton, and a Related Analogue, Peniciadametizine B, from the Marine Sponge-Derived Fungus Penicillium adametzioides. AB - Peniciadametizine A (1); a new dithiodiketopiperazine derivative possessing a unique spiro[furan-2,7'-pyrazino[1,2-b][1,2]oxazine] skeleton, together with a highly oxygenated new analogue, peniciadametizine B (2); as well as two known compounds, brasiliamide A (3); and viridicatumtoxin (4), were isolated and identified from Penicillium adametzioides AS-53, a fungus obtained from an unidentified marine sponge. The unambiguous assignment of the relative and absolute configuration for the spiro center C-2 of compound 1 was solved by the combination of NMR and ECD measurements with Density-Functional Theory (DFT) conformational analysis and Time-Dependent Density-Functional Theory-Electronic Circular Dichroism (TDDFT-ECD) calculations. The spiro[furan-2,7'-pyrazino[1,2 b][1,2]oxazine] skeleton of 1 has not been reported yet among natural products and the biosynthetic pathway for 1 and 2 was discussed. Compounds 1 and 2 showed inhibitory activity against the pathogenic fungus Alternaria brassicae. PMID- 26058015 TI - Effect of Marine Collagen Peptides on Physiological and Neurobehavioral Development of Male Rats with Perinatal Asphyxia. AB - Asphyxia during delivery produces long-term deficits in brain development. We investigated the neuroprotective effects of marine collagen peptides (MCPs), isolated from Chum Salmon skin by enzymatic hydrolysis, on male rats with perinatal asphyxia (PA). PA was performed by immersing rat fetuses with uterine horns removed from ready-to-deliver rats into a water bath for 15 min. Caesarean delivered pups were used as controls. PA rats were intragastrically administered with 0.33 g/kg, 1.0 g/kg and 3.0 g/kg body weight MCPs from postnatal day 0 (PND 0) till the age of 90-days. Behavioral tests were carried out at PND21, PND 28 and PND 90. The results indicated that MCPs facilitated early body weight gain of the PA pups, however had little effects on early physiological development. Behavioral tests revealed that MCPs facilitated long-term learning and memory of the pups with PA through reducing oxidative damage and acetylcholinesterase (AChE) activity in the brain, and increasing hippocampus phosphorylated cAMP response element binding protein (p-CREB) and brain derived neurotrophic factor (BDNF) expression. PMID- 26058016 TI - Discrete Logic Modelling Optimization to Contextualize Prior Knowledge Networks Using PRUNET. AB - High-throughput technologies have led to the generation of an increasing amount of data in different areas of biology. Datasets capturing the cell's response to its intra- and extra-cellular microenvironment allows such data to be incorporated as signed and directed graphs or influence networks. These prior knowledge networks (PKNs) represent our current knowledge of the causality of cellular signal transduction. New signalling data is often examined and interpreted in conjunction with PKNs. However, different biological contexts, such as cell type or disease states, may have distinct variants of signalling pathways, resulting in the misinterpretation of new data. The identification of inconsistencies between measured data and signalling topologies, as well as the training of PKNs using context specific datasets (PKN contextualization), are necessary conditions to construct reliable, predictive models, which are current challenges in the systems biology of cell signalling. Here we present PRUNET, a user-friendly software tool designed to address the contextualization of a PKNs to specific experimental conditions. As the input, the algorithm takes a PKN and the expression profile of two given stable steady states or cellular phenotypes. The PKN is iteratively pruned using an evolutionary algorithm to perform an optimization process. This optimization rests in a match between predicted attractors in a discrete logic model (Boolean) and a Booleanized representation of the phenotypes, within a population of alternative subnetworks that evolves iteratively. We validated the algorithm applying PRUNET to four biological examples and using the resulting contextualized networks to predict missing expression values and to simulate well-characterized perturbations. PRUNET constitutes a tool for the automatic curation of a PKN to make it suitable for describing biological processes under particular experimental conditions. The general applicability of the implemented algorithm makes PRUNET suitable for a variety of biological processes, for instance cellular reprogramming or transitions between healthy and disease states. PMID- 26058017 TI - Cytotoxicity of TSP in 3D Agarose Gel Cultured Cell. AB - PURPOSE: A reference reagent, 3-(trimethylsilyl) propionic-2, 2, 3, 3-d4 acid sodium (TSP), has been used frequently in nuclear magnetic resonance (NMR) and magnetic resonance spectroscopy (MRS) as an internal reference to identify cell and tissue metabolites, and determine chemical and protein structures. This reference material has been exploited for the quantitative and dynamic analyses of metabolite spectra acquired from cells. The aim of this study was to evaluate the cytotoxicity of TSP on three-dimensionally, agarose gel, cultured cells. MATERIALS AND METHODS: A human osteosarcoma cell line (MG-63) was selected, and cells were three dimensionally cultured for two weeks in an agarose gel. The culture system contained a mixture of conventional culture medium and various concentrations (0, 1, 3, 5, 7, 10, 20 30 mM) of TSP. A DNA quantification assay was conducted to assess cell proliferation using Quant-iT PicoGreen dsDNA reagent and kit, and cell viability was determined using a LIVE/DEAD Viability/Cytotoxicity kit. Both examinations were performed simultaneously at 1, 3, 7 and 14 days from cell seeding. RESULTS: In this study, the cytotoxicity of TSP in the 3D culture of MG-63 cells was evaluated by quantifying DNA (cell proliferation) and cell viability. High concentrations of TSP (from 10 to 30 mM) reduced both cell proliferation and viability (to 30% of the control after one week of exposure), but no such effects were found using low concentrations of TSP (0-10 mM). CONCLUSIONS: This study shows that low concentrations of TSP in 3D cell culture medium can be used for quantitative NMR or MRS examinations for up to two weeks post exposure. PMID- 26058018 TI - Macroscopic and microscopic view of refractive surgery today. PMID- 26058019 TI - Advances in scleral lenses for refractive surgery complications. AB - PURPOSE OF REVIEW: The last two decades have brought advances in materials and manufacturing of large diameter rigid gas-permeable contact lenses, and a greater appreciation of the role of scleral lenses for therapeutic indications. The purpose of this review is to provide an update on the use of rigid gas-permeable scleral lenses in the management of patients with complications after refractive surgery. RECENT FINDINGS: There are recent reports on clinical experience with specific scleral lens designs from single institutions in cohorts that include patients who have undergone refractive surgery. Typically, these are patients with 'irregular corneas' after radial keratotomy or LASER assisted in-situ keratomileusis, but patients with keratectasia, dry eye syndrome, and corneal neuralgia are also reported. Visual outcomes and wearing success rates are high in these reports, although outcomes for refractive surgery patients are not reported separately. SUMMARY: Clinicians who encounter patients with complications after corneal refractive surgery should be aware of advances in scleral lenses. Scleral lenses are an alternative to surgical intervention in patients who might otherwise be considered poor contact lens candidates. PMID- 26058020 TI - Macroeconomic landscape of refractive surgery in the United States. AB - PURPOSE OF REVIEW: This review examines the economic history of refractive surgery and the decline of laser-assisted in-situ keratomileusis (LASIK) in the USA, and the emergence of refractive cataract surgery as an area of growth. RECENT FINDINGS: Since it peaked in 2007 at 1.4 million procedures per year, LASIK has declined 50% in the USA, whereas refractive cataract surgery, including presbyopia-correcting intraocular lenses (IOLs), astigmatism-correcting IOLs, and femtosecond laser-assisted cataract surgery, has grown to 350 000 procedures per year, beginning in 2003. SUMMARY: Patients are price-sensitive and responsive to publicity (good or bad) about refractive surgery and refractive cataract surgery. LASIK's decline has been partially offset by the emergence of refractive cataract surgery. About 11% of all cataract surgery in the USA involves presbyopia correcting IOLs, astigmatism-correcting IOLs, or a femtosecond laser. From the surgeon's perspective, there are high barriers to entry into the marketplace for refractive surgery and refractive cataract surgery due to the high capital cost of excimer and femtosecond lasers, the high skill level required to deliver spectacular results to demanding patients who pay out of pocket, and the necessity to perform a high volume of surgeries to satisfy both of these requirements. Probably, less than 7% of US cataract surgeons can readily meet all of these requirements. PMID- 26058021 TI - Current trends in pain management after photorefractive and phototherapeutic keratectomy. AB - PURPOSE OF REVIEW: Since the introduction of photoablative procedures, postoperative pain management has been a major challenge for both the patient and the surgeon. Over the years, significant advances have been made in our ability to overcome this challenge. The purpose of this article is to discuss the most current strategies for pain control after photorefractive keratectomy and phototherapeutic keratectomy. RECENT FINDINGS: Methods for pain control can be targeted locally or systemically and can be pharmacological or nonpharmalogical. Options include anesthetics, NSAIDs, opiates, and anticonvulsants, as well as bandage contact lenses and corneal cooling. SUMMARY: Literature and experience provide insight on the efficacy and safety of the many options for post photorefractive keratectomy pain control. Generally, refractive surgeons are using a combination approach to achieve pain control with excellent results. PMID- 26058022 TI - Femtosecond laser refractive surgery: small-incision lenticule extraction vs. femtosecond laser-assisted LASIK. AB - PURPOSE OF REVIEW: Small-incision lenticule extraction (SMILE) is a novel technique devised to correct refractive errors. SMILE circumvents excimer laser photoablation of cornea, as the stromal lenticule cut by femtosecond laser is removed manually. Smaller incisions and preservation of anterior corneal biomechanical strength have been suggested as some of the advantages of SMILE over femtosecond laser-assisted LASIK (FS-LASIK). In this review, we compared previous published results of SMILE and FS-LASIK. The advantage, efficacy and safety of SMILE are compared with FS-LASIK. RECENT FINDINGS: SMILE achieved similar efficacy, predictability and safety as FS-LASIK. Greater preservations of corneal biomechanical strength and corneal nerves were observed in SMILE when compared with LASIK or PRK. Additionally, the incidence of postoperative dry eye syndrome was found to be less problematic in SMILE than in FS-LASIK. SUMMARY: SMILE is a promising new surgery for refractive error correction. Prospective and retrospective studies of SMILE have shown that results of SMILE are similar to FS LASIK. With advances in femtosecond laser technology, SMILE may gain greater acceptance in the future. PMID- 26058023 TI - PresbyLASIK approach for the correction of presbyopia. AB - PURPOSE OF REVIEW: The aim of this review is to offer a comprehensive overview of the different PresbyLASIK approaches, which have been published in peer-reviewed journals. RECENT FINDINGS: Comprehensive search was conducted in scopus using keywords presbyLASIK, presbyopia, LASIK, corneal multifocality. We reviewed binocular uncorrected and corrected distance and near visual acuity, and loss of lines of best corrected visual acuity, for presbyopic patients among three different basic treatment modalities. SUMMARY: Additional trials and standards for reporting results for presbyopic approaches are necessary. Careful patient selection and counseling is imperative in all PresbyLASIK treatments. PMID- 26058024 TI - Recent advances in the treatment of corneal ectasia with intrastromal corneal ring segments. AB - PURPOSE OF REVIEW: To review the recent advances and reported outcomes in the use of intrastromal corneal ring segments (ICRS) for the treatment of corneal ectasia. RECENT FINDINGS: ICRS are a well-tolerated and effective treatment for patients with corneal ectasia, particularly keratoconus, offering long-term improvement in visual, refractive, and keratometric measures. ICRS do not consistently decrease corneal aberrations. Patients with mild-to-moderate keratoconus, known to have less predictable outcomes with ICRS, may be better selected and treated with the use of customized nomograms, accounting for factors such as internal astigmatism. Corneal collagen cross-linking performed after ICRS implantation is an important complementary treatment in preventing the progression of ectasia, whereas subsequent treatment with either photorefractive keratectomy or toric intraocular lens implantation offers a significantly improved visual and refractive result. SUMMARY: ICRS are an important component to the treatment of corneal ectasia. Knowledge of outcomes among specific groups of patients should improve treatment planning and nomograms. Combined treatments with ICRS allow for notable improvements in corneal stability and refractive error, in addition to the improvement in irregular astigmatism seen with ICRS. PMID- 26058025 TI - Refractive surgery following corneal graft. AB - PURPOSE OF REVIEW: To review the different surgical procedures for management of postkeratoplasty refractive errors after total suture removal. RECENT FINDINGS: There are different surgical options to address residual refractive errors that frequently occur after corneal transplantation. The correction can be done on the corneal surface or intraocular with intraocular lens (IOL) implantation which requires complete tectonic and refractive stability after suture removal. The most commonly used procedures are photorefractive keratectomy, laser in-situ keratomileusis and Phakic IOLs. Keratoplasty has been profited by recent advances in refractive surgery. Custom excimer laser ablation is an alternative way to treat irregular errors. New IOL modalities are good practical options for a wide range of errors. Femtosecond laser, as a new option in the toolbox, can modify corneal grafting refractive results and assist corrective refractive procedures. SUMMARY: Although being the most successful organ transplantation, keratoplasty is usually followed by significant ametropia. Different corrective modalities exist and the choice should fit ocular conditions, patient requirements, surgeon skills and the available technologies. Recent advances in ophthalmic surgery have improved the outcomes. PMID- 26058026 TI - Evaporative dry eye disease: promising new approaches for diagnosis and treatment. PMID- 26058027 TI - Medical management of blepharitis. AB - PURPOSE OF REVIEW: Blepharitis is one of the most common ocular pathologies encountered in the clinical setting. Despite its prevalence, successful treatment is often difficult. The purpose of this review is to provide an update on the medical management of blepharitis. RECENT FINDINGS: The available treatment options for blepharitis have expanded rapidly in recent years. Eyelid hygiene remains the foundation of most treatment regimens, but the addition of topical and oral antibiotics, steroids, and calcineurin inhibitors is showing promising results. Dietary considerations and interventional procedures may also play a role in the future of blepharitis management. SUMMARY: Although a curative therapy for blepharitis is unlikely in the near future, several novel treatment options may result in better control of this chronic condition. PMID- 26058028 TI - Recent advances on ocular Demodex infestation. AB - PURPOSE OF REVIEW: To summarize recent advances on ocular Demodex infestation. RECENT FINDINGS: Demodex infestation is a potential cause of ocular surface inflammation. The pathogenesis of Demodex in eliciting ocular surface inflammation has been further clarified. Cliradex is currently the treatment of choice, it comprises the most active ingredient of tea tree oil, that is terpinen 4-ol, which helps eradicate Demodex mites and reduce ocular surface inflammation. SUMMARY: Ocular demodicosis is a common but overlooked eye disease that manifests a number of morbidities. Demodex folliculorum causes chronic anterior blepharitis whereas Demodex brevis causes posterior blepharitis, meibomian gland dysfunction, recurrent chalazia, and refractory keratoconjunctivitis. The lash sampling and microscopic counting method and in-vivo confocal microscopy are key diagnostic methods. Cliradex shows promising potential to reduce Demodex counts with additional antibacterial, antifungal, and anti-inflammatory actions. PMID- 26058029 TI - Blepharokeratoconjunctivitis in children. AB - PURPOSE OF REVIEW: This article reviews the current literature on pediatric blepharokeratoconjunctivitis (BKC) to enhance the understanding on the incidence, clinical course, and treatment options. RECENT FINDINGS: Pediatric BKC is a disorder with a wide spectrum of clinical manifestations. Therapies target both the infectious and inflammatory components of this disorder. SUMMARY: Pediatric BKC is a disorder with a wide spectrum of clinical manifestations and severity, which is often overlooked or misdiagnosed. PMID- 26058030 TI - Treatment for meibomian gland dysfunction and dry eye symptoms with a single-dose vectored thermal pulsation: a review. AB - PURPOSE OF REVIEW: Meibomian gland dysfunction (MGD) is understood to be a highly prevalent, chronic progressive disease and the leading cause of dry eye. All available published peer-reviewed results of the novel vectored thermal pulsation therapy for patients with MGD are investigated. RECENT FINDINGS: The PubMed and meeting abstract search revealed a total of 31 peer-reviewed reports on vectored thermal pulsation therapy at the time of the search (eight manuscripts and 23 meeting abstracts). All manuscripts evidence a significant increase in meibomian gland function (~3*) and symptom improvement post a single 12-min treatment. Additional reported objective measures such as osmolarity, tear break-up time, or lipid layer thickness also increased as a result of the therapy; however, not all findings were statistically significant. The randomized controlled studies evidence sustained gland function and symptom relief lasting out to 12 months. The uncontrolled case series evidence significantly longer duration of effect. SUMMARY: A single 12 minute vectored thermal pulsation treatment allows for reducing dry eye symptoms, improving meibomian gland function and other correlates of the ocular surface health. PMID- 26058031 TI - Intense pulsed light therapy for the treatment of evaporative dry eye disease. AB - PURPOSE OF REVIEW: Evaporative dry eye disease is one of the most common types of dry eye. It is often the result of chronic meibomian gland dysfunction (MGD) and associated ocular rosacea. Evaporative dry eye and MGD significantly reduce patient's quality of life. Traditional treatments, such as artificial tears, warm compresses, and medications, such as topical cyclosporine, azithromycin, and oral doxycycline, provide some relief; however, many patients still suffer from dry eye symptoms. Intense pulsed light (IPL) therapy, which has been used extensively in dermatology to treat chronic skin conditions, is a relatively new treatment in ophthalmology for patients with evaporative dry eye disease. RECENT FINDINGS: There are very few studies published on the use of IPL in patients with dry eye disease. The present review describes the theoretical mechanisms of IPL treatment of MGD and ocular rosacea. Personal clinical experience and recently presented data are reported as well. SUMMARY: IPL therapy has promising results for evaporative dry eye patients. There are statistically significant improvements in clinical exam findings of dry eye disease. More importantly, patients report subjective improvement in their symptoms. More research is needed in this area to help understand the mechanism of dry eye disease and how it can be effectively treated. PMID- 26058032 TI - Scleral lens use in dry eye syndrome. AB - PURPOSE OF REVIEW: Dry eye syndrome can be difficult to manage in severe or refractory cases. In patients in whom traditional treatments have limited efficacy, alternative treatments may be considered for dry eye syndrome, including scleral lenses. The present review summarizes the evidence regarding scleral lens use in dry eye syndrome. RECENT FINDINGS: Scleral lenses have become a viable option for severe dry eye syndrome, and have been shown to be efficacious and well tolerated, with most reports citing improved visual acuity and relief of symptoms. Currently, there are 18 manufacturers of scleral lenses, although published reports on scleral lenses primarily focus on the BostonSight PROSE and the Jupiter Lens. SUMMARY: Scleral lenses are efficacious and well tolerated for use in severe dry eye syndrome. Further research is needed to compare different sizes and types of lenses, and to standardize outcome measures. PMID- 26058033 TI - Eye platelet-rich plasma in the treatment of ocular surface disorders. AB - PURPOSE OF REVIEW: Blood-derived products [autologous serum, eye platelet-rich plasma (E-PRP), plasma rich in growth factors] are successful therapies for ocular surface disorders, which compromise the integrity of the cornea surface and conjunctiva. RECENT FINDINGS: The most noteworthy and recent research has been directed towards hemoderivatives that include platelets. PRP for ophthalmologic use (E-PRP) has achieved successful outcomes as reported in the peer-review literature in the treatment of dry eye, post-laser in-situ keratomileusis ocular surface syndrome, dormant ulcers, and for ocular surface surgical reconstruction after corneal perforation associated to amniotic membrane transplantation, bovine pericardium membrane transplantation, or autologous fibrin membrane combined with solid PRP clot. SUMMARY: PRP is a portion of the patient's own blood having a platelet concentration above baseline. The main advantage of PRP over other products is the presence of the platelets and associated with this the prolonged release of growth factors that are involved in the wound healing process of the cornea and conjunctival surface. E-PRP seems to be a reliable and effective therapeutic approach to enhance epithelial wound healing and promote ocular surface regeneration in different pathological conditions. PMID- 26058035 TI - Correction: The Role of Hydrodynamic Processes on Anchovy Eggs and Larvae Distribution in the Sicily Channel (Mediterranean Sea): A Case Study for the 2004 Data Set. PMID- 26058036 TI - Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia? AB - A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-alpha and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P < 0.001, condition effects), with more pronounced LPS-induced cytokine increases in women (P < 0.05, interaction effects). Although both rectal and pressure pain thresholds were significantly decreased in the LPS condition (all P < 0.05, condition effect), no sex differences in endotoxin-induced sensitization were observed. In summary, LPS induced systemic immune activation leads to visceral and musculoskeletal hyperalgesia, irrespective of biological sex. These findings support the broad applicability of experimental endotoxin administration as a translational preclinical model of inflammation-induced pain sensitization in both sexes. PMID- 26058037 TI - Touch inhibits subcortical and cortical nociceptive responses. AB - The neural mechanisms of the powerful analgesia induced by touching a painful body part are controversial. A long tradition of neurophysiologic studies in anaesthetized spinal animals indicate that touch can gate nociceptive input at spinal level. In contrast, recent studies in awake humans have suggested that supraspinal mechanisms can be sufficient to drive touch-induced analgesia. To investigate this issue, we evaluated the modulation exerted by touch on established electrophysiologic markers of nociceptive function at both subcortical and cortical levels in humans. Adelta and C skin nociceptors were selectively activated by high-power laser pulses. As markers of subcortical and cortical function, we recorded the laser blink reflex, which is generated by brainstem circuits before the arrival of nociceptive signals at the cortex, and laser-evoked potentials, which reflect neural activity of a wide array of cortical areas. If subcortical nociceptive responses are inhibited by concomitant touch, supraspinal mechanisms alone are unlikely to be sufficient to drive touch induced analgesia. Touch induced a clear analgesic effect, suppressed the laser blink reflex, and inhibited both Adelta-fibre and C-fibre laser-evoked potentials. Thus, we conclude that touch-induced analgesia is likely to be mediated by a subcortical gating of the ascending nociceptive input, which in turn results in a modulation of cortical responses. Hence, supraspinal mechanisms alone are not sufficient to mediate touch-induced analgesia. PMID- 26058038 TI - Is temporal summation of pain and spinal nociception altered during normal aging? AB - This study examines the effect of normal aging on temporal summation (TS) of pain and the nociceptive flexion reflex (RIII). Two groups of healthy volunteers, young and elderly, received transcutaneous electrical stimulation applied to the right sural nerve to assess pain and the nociceptive flexion reflex (RIII reflex). Stimulus intensity was adjusted individually to 120% of RIII-reflex threshold, and shocks were delivered as a single stimulus or as a series of 5 stimuli to assess TS at 5 different frequencies (0.17, 0.33, 0.66, 1, and 2 Hz). This study shows that robust TS of pain and RIII-reflex is observable in individuals aged between 18 and 75 years and indicates that these effects are comparable between young and older individuals. These results contrast with some previous findings and imply that at least some pain regulatory processes, including TS, may not be affected by normal aging, although this may vary depending on the method. PMID- 26058039 TI - The puzzle of attentional bias to pain: beyond attention. PMID- 26058040 TI - Cardioprotective Effect of Licochalcone D against Myocardial Ischemia/Reperfusion Injury in Langendorff-Perfused Rat Hearts. AB - Flavonoids are important components of 'functional foods', with beneficial effects on cardiovascular function. The present study was designed to investigate whether licochalcone D (LD) could be a cardioprotective agent in ischemia/reperfusion (I/R) injury and to shed light on its possible mechanism. Compared with the I/R group, LD treatment enhanced myocardial function (increased LVDP, dp/dtmax, dp/dtmin, HR and CR) and suppressed cardiac injury (decreased LDH, CK and myocardial infarct size). Moreover, LD treatment reversed the I/R induced cleavage of caspase-3 and PARP, resulting in a significant decrease in proinflammatory factors and an increase in antioxidant capacity in I/R myocardial tissue. The mechanisms underlying the antiapoptosis, antiinflammation and antioxidant effects were related to the activation of the AKT pathway and to the blockage of the NF-kappaB/p65 and p38 MAPK pathways in the I/R-injured heart. Additionally, LD treatment markedly activated endothelial nitric oxide synthase (eNOS) and reduced nitric oxide (NO) production. The findings indicated that LD had real cardioprotective potential and provided support for the use of LD in myocardial I/R injury. PMID- 26058041 TI - Identification of New Candidate Genes and Chemicals Related to Esophageal Cancer Using a Hybrid Interaction Network of Chemicals and Proteins. AB - Cancer is a serious disease responsible for many deaths every year in both developed and developing countries. One reason is that the mechanisms underlying most types of cancer are still mysterious, creating a great block for the design of effective treatments. In this study, we attempted to clarify the mechanism underlying esophageal cancer by searching for novel genes and chemicals. To this end, we constructed a hybrid network containing both proteins and chemicals, and generalized an existing computational method previously used to identify disease genes to identify new candidate genes and chemicals simultaneously. Based on jackknife test, our generalized method outperforms or at least performs at the same level as those obtained by a widely used method--the Random Walk with Restart (RWR). The analysis results of the final obtained genes and chemicals demonstrated that they highly shared gene ontology (GO) terms and KEGG pathways with direct and indirect associations with esophageal cancer. In addition, we also discussed the likelihood of selected candidate genes and chemicals being novel genes and chemicals related to esophageal cancer. PMID- 26058044 TI - Superconductivity in the surface states of a Bi2X3 topological insulator: effects of a realistic model. AB - Superconductivity in the topological surface states is essential to both the surface spectrum of bulk superconducting state and the proximity-induced superconductivity of Bi2X3 (X is Se or Te) topological insulators. While previous theories were mostly based on simplified models for the bulk topological insulator and the surface states, the accumulating experiments stimulate us to make an analysis using realistic model for the normal state electronic structures, incorporating terms responsible for particle-hole asymmetry and hexagonal warping. An effective low-energy model for the topological surface states is derived first. Then we identify all the bulk time-reversal-invariant superconducting pairings in the topological insulator that can open a gap in the topological surface states. Many more pairings are found to be able to gap the topological surface states as compared to conclusions based on simplified models. The number of proximity-induced pairing channels in the topological surface states increases by one as a result of the hexagonal warping term, but is not changed by the particle-hole asymmetry term. PMID- 26058043 TI - Levodopa in Mucuna pruriens and its degradation. AB - Mucuna pruriens is the best known natural source of L-dopa, the gold standard for treatment of Parkinsonism. M. pruriens varieties are protein rich supplements, and are used as food and fodder worldwide. Here, we report L-dopa contents in seeds of fifty six accessions of four M. pruriens varieties, M. pruriens var. pruriens, M. pruriens var. hirsuta, M. pruriens var. utilis and M. pruriens var. thekkadiensis, quantified by HPTLC-densitometry. L-dopa contents varied between 0.58 to 6.42 (%, dr. wt.). High and low L-dopa yielding genotypes/chemotypes of M. pruriens could be multiplied for medicinal and nutritional purposes, respectively. HPTLC profiles of M. pruriens seeds on repeated extraction (24 h) in 1:1 formic acid-alcohol followed by development in butanol:acetic acid:water (4:1:1, v/v) showed consistent degradation of L-dopa (Rf 0.34 +/- 0.02) into a second peak (Rf 0.41 +/- 0.02). An average of 52.11% degradation of L-dopa was found in seeds of M. pruriens varieties. Since M. pruriens seeds and/or L-dopa are used for treatment of Parkinson's disease and as an aphrodisiac both in modern and/or traditional systems of medicine, the finding of high level of L dopa degradation (in pure form and in M. pruriens extracts) into damaging quinones and ROS is very significant. PMID- 26058042 TI - Cigarette Smoke-Induced Emphysema and Pulmonary Hypertension Can Be Prevented by Phosphodiesterase 4 and 5 Inhibition in Mice. AB - RATIONALE: Chronic obstructive pulmonary disease (COPD) is a widespread disease, with no curative therapies available. Recent findings suggest a key role of NO and sGC-cGMP signaling for the pathogenesis of the disease. Previous data suggest a downregulation/inactivation of the cGMP producing soluble guanylate cyclase, and sGC stimulation prevented cigarette smoke-induced emphysema and pulmonary hypertension (PH) in mice. We thus aimed to investigate if the inhibition of the cGMP degrading phosphodiesterase (PDE)5 has similar effects. Results were compared to the effects of a PDE 4 inhibitor (cAMP elevating) and a combination of both. METHODS: C57BL6/J mice were chronically exposed to cigarette smoke and in parallel either treated with Tadalafil (PDE5 inhibitor), Piclamilast (PDE4 inhibitor) or both. Functional measurements (lung compliance, hemodynamics) and structural investigations (alveolar and vascular morphometry) as well as the heart ratio were determined after 6 months of tobacco smoke exposure. In addition, the number of alveolar macrophages in the respective lungs was counted. RESULTS: Preventive treatment with Tadalafil, Piclamilast or a combination of both almost completely prevented the development of emphysema, the increase in lung compliance, tidal volume, structural remodeling of the lung vasculature, right ventricular systolic pressure, and right ventricular hypertrophy induced by cigarette smoke exposure. Single, but not combination treatment prevented or reduced smoke-induced increase in alveolar macrophages. CONCLUSION: Cigarette smoke-induced emphysema and PH could be prevented by inhibition of the phosphodiesterases 4 and 5 in mice. PMID- 26058046 TI - Corrigendum: Cycloelimination of Imidazolidin-2-ylidene N-Heterocyclic Carbenes: Mechanism and Insights into the Synthesis of Stable "NHC-CDI" Amidinates. PMID- 26058047 TI - Comparison of Aggregometry with Flow Cytometry for the Assessment of Agonists' Induced Platelet Reactivity in Patients on Dual Antiplatelet Therapy. AB - Data on the agreement between aggregometry and platelet activation by flow cytometry regarding the measurement of on-treatment platelet reactivity to arachidonic acid (AA) and adenosine diphosphate (ADP) are scarce. We therefore sought to compare three platelet aggregation tests with flow cytometry for the assessment of the response to antiplatelet therapy. Platelet aggregation in response to AA and ADP was determined by light transmission aggregometry (LTA), the VerifyNow assays, and multiple electrode aggregometry (MEA) in 316 patients receiving aspirin and clopidogrel therapy after angioplasty with stent implantation. AA- and ADP-induced P-selectin expression and activated glycoprotein (GP) IIb/IIIa were determined by flow cytometry. LTA, the VerifyNow P2Y12 assay and MEA in response to ADP correlated significantly (all p<0.001), and the best correlation was observed between LTA and the VerifyNow P2Y12 assay (r = 0.63). ADP-induced platelet reactivity by all aggregation tests correlated significantly with ADP-induced P-selectin expression and activated GPIIb/IIIa (all p<0.001). The best correlation was seen between the VerifyNow P2Y12 assay and activated GPIIb/IIIa (r = 0.68). The platelet surface expressions of P selectin and activated GPIIb/IIIa in response to ADP were significantly higher in patients with high on-treatment residual platelet reactivity (HRPR) to ADP by all test systems (all p<0.001). A rather poor correlation was observed between AA induced platelet reactivity by LTA and the VerifyNow aspirin assay (r = 0.15, p = 0.007), while both methods did not correlate with MEA. AA-induced platelet reactivity by all aggregation tests correlated significantly, but rather poorly with AA-induced P-selectin expression (all p<0.05), while only AA-induced platelet reactivity by LTA correlated significantly with AA-induced activated GPIIb/IIIa (r = 0.21, p<0.001). The platelet surface expression of P-selectin in response to AA was significantly higher in patients with HRPR by LTA AA and MEA AA (both p<0.02). In contrast, P-selectin expression in response to AA was similar in patients without and with HRPR by the VerifyNow aspirin assay (p = 0.5), and platelet surface activated GPIIb/IIIa in response to AA did not differ significantly between patients without and with HRPR to AA by all test systems (all p>0.1). In conclusion, ADP-induced platelet reactivity by aggregometry translates partly into flow cytometry. In contrast, AA-induced platelet reactivity correlates poorly between different platelet aggregation tests, and between aggregometry and flow cytometry. Overall, both approaches capture different aspects of platelet function and are therefore not interchangeable in the assessment of agonists'-induced platelet reactivity. Clinical outcome data are needed to determine which test systems and settings are associated with different in vivo consequences. PMID- 26058048 TI - Recurrent breast cancer and endobronchial ultrasound-transbronchial needle aspiration. AB - A 67 years old female with previous breast cancer and a 40-pack year smoking history presented with recurrent lower respiratory tract infections on a background of chronic obstructive pulmonary disease. Despite a normal chest X ray, the history of recurrent infections led to a high resolution computed tomography scan to exclude structural lung disease. This showed subcarinal lymphadenopathy, multiple nodules in the right lung and suggestion of lymphangitis. She proceeded to have EBUS-TBNA of the enlarged paratracheal and subcarinal lymph nodes. Cytology was consistent with the diagnosis of recurrent metastatic breast carcinoma. The patient went on to receive Letrozole and radiotherapy. EBUS-TBNA is typically used to both diagnose and stage suspected lung cancer, usually in a solitary procedure. However, it is also useful in patients with undiagnosed mediastinal and hilar lymphadenopathy. This case adds to the paucity of literature whereby EBUS-TBNA was used as a quick and effective tool by which recurrent breast cancer was diagnosed. PMID- 26058045 TI - Chest Low-Dose Computed Tomography for Early Lung Cancer Diagnosis as an Opportunity to Diagnose Vertebral Fractures in HIV-Infected Smokers, an ANRS EP48 HIV CHEST Substudy. AB - BACKGROUND: To estimate the prevalence of vertebral fractures on chest low-dose computed tomography (LDCT) in HIV-infected smokers. METHODS: Cross-sectional study of vertebral fractures visualized on chest LDCT from a multicenter prospective cohort evaluating feasibility of chest LDCT for early lung cancer diagnosis in HIV-infected subjects. Subjects were included if 40 years or older, had been active smokers within the last 3 years of at least 20 pack-years, and had a CD4 T-lymphocyte nadir cell count <350 per microliter and an actual CD4 T cell count >100 cells per microliter. Spinal reconstructed sagittal planes obtained from chest axial native acquisitions were blindly read by a musculoskeletal imaging specialist. Assessment of the fractured vertebra used Genant semiquantitative method. The study end point was the prevalence of at least 1 vertebral fracture. RESULTS: Three hundred ninety-seven subjects were included. Median age was 49.5 years, median smoking history was 30 pack-years, median last CD4 count was 584 cells per microliter, and median CD4 nadir count was 168 cells per microliter; 90% of subjects had a viral load below 50 copies per milliliter. At least 1 fracture was visible in 46 (11.6%) subjects. In multivariate analysis, smoking >=40 packs-years [OR = 2.5; 95% CI: (1.2 to 5.0)] was associated with an increased risk of vertebral fracture, while HIV viral load <200 copies per milliliter [OR = 0.3; 95% CI: (0.1 to 0.9)] was protective. CONCLUSIONS: Prevalence of vertebral fractures on chest LDCT was 11.6% in this high-risk population. Smoking cessation and early introduction of antiretroviral therapy for prevention of vertebral fractures could be beneficial. Chest LDCT is an opportunity to diagnose vertebral fractures. PMID- 26058049 TI - Selective Functional Disconnection of the Dorsal Subregion of the Temporal Pole in Schizophrenia. AB - Although extensive resting-state functional connectivity (rsFC) changes have been reported in schizophrenia, rsFC changes in the temporal pole (TP) remain unknown. The TP contains several subregions with different connection patterns; however, it is not known whether TP subregions are differentially affected in schizophrenia. Sixty-six schizophrenia patients and 76 healthy comparison subjects underwent resting-state fMRI using a sensitivity-encoded spiral-in (SENSE-SPIRAL) imaging sequence to reduce susceptibility-induced signal loss and distortion. The TP was subdivided into the dorsal (TPd) and ventral (TPv) subregions. Mean fMRI time series were extracted for each TP subregion and entered into a seed-based rsFC analysis. Direct between-group comparisons revealed reduced rsFC between the right TPd and brain regions involved in language processing and multisensory integration in schizophrenia, including the left superior temporal gyrus, left mid-cingulate cortex, and right insular cortex. The rsFC changes of the right TPd in schizophrenia were independent of the grey matter reduction of this subregion. Moreover, these rsFC changes were unrelated to illness severity, duration of illness and antipsychotic medication dosage. No significant group differences were observed in the rsFC of the left TPd and bilateral TPv subregions. These findings suggest a selective (the right TPd) functional disconnection of TP subregions in schizophrenia. PMID- 26058050 TI - Bromide (Br)--Based Synthesis of Ag Nanocubes with High-Yield. AB - The geometry of metal nanoparticles greatly affects the properties of the localized surface plasmon resonance and surface-enhanced Raman scattering. The synthesis of metal nanoparticles with controllable geometry has thus attracted extensive attentions. In this work, we report a modified polyol synthesis approach of silver (Ag) nanocubes through tuning the concentration of bromide ions (Br(-) ions). We have systematically investigated the effect of Br(-) ions in the polyol process, and find that higher concentration of Br(-) ions can enhance oxidative etching effect, which is the dominative factor in determining nanostructure geometry. Therefore, one can realize control over nanostructure geometry by manipulating the concentration of Br(-) ions. Our work provides an effective approach to control the shape of metallic nanostructures for potential applications. PMID- 26058051 TI - Planar Pol(o)arity. AB - Asymmetric localization of planar cell polarity (PCP) proteins is essential for tissue integrity, but how asymmetric localization is regulated during cell division is not known. In this issue of Developmental Cell, Shrestha et al. (2015) show that mitotic Polo-like kinase 1 (Plk1) links internalization of PCP proteins to cell-cycle progression. PMID- 26058052 TI - Turn Up the Volume: Uncovering Nucleus Size Control Mechanisms. AB - Reporting in Developmental Cell, Hara and Merten (2015) apply the use of microfabrication and in vitro analysis in cell-free extracts to the old problem of nuclear size control. The authors make insights into the regulation of nuclear growth that potentially explain the widely reported correlation between nucleus size and cell size. PMID- 26058053 TI - A TAD Closer to Understanding Dosage Compensation. AB - Eukaryotic chromosomes are organized into topological domains, but how these are established and maintained is poorly understood. Writing in Nature, Crane et al. (2015) show that a specialized condensin complex enforces the domain boundaries along the C. elegans X chromosome to equalize transcription from the X between males and hermaphrodites. PMID- 26058054 TI - Aurora B/C in Meiosis: Correct Me If I'm Right. AB - In this issue of Developmental Cell, Yoshida et al. (2015) report that during meiosis I in mouse oocytes, the kinase Aurora B/C continuously destabilizes chromosome attachments to spindle microtubules, which potentially provides an explanation for the notably high error rate of chromosome segregation in mammalian oocytes. PMID- 26058055 TI - Menage a Trois to Form the Tricellular Junction. AB - Tricellular junctions tightly seal epithelia at the corners of three cells. In this issue of Developmental Cell, Byri et al. (2015) show that Anakonda, a novel Drosophila transmembrane protein, contains an unusual tripartite extracellular domain organization, which explains the tripartite septum filling the tricellular junction, previously revealed by ultrastructure analysis. PMID- 26058057 TI - A Novel Framework for Learning Geometry-Aware Kernels. AB - The data from real world usually have nonlinear geometric structure, which are often assumed to lie on or close to a low-dimensional manifold in a high dimensional space. How to detect this nonlinear geometric structure of the data is important for the learning algorithms. Recently, there has been a surge of interest in utilizing kernels to exploit the manifold structure of the data. Such kernels are called geometry-aware kernels and are widely used in the machine learning algorithms. The performance of these algorithms critically relies on the choice of the geometry-aware kernels. Intuitively, a good geometry-aware kernel should utilize additional information other than the geometric information. In many applications, it is required to compute the out-of-sample data directly. However, most of the geometry-aware kernel methods are restricted to the available data given beforehand, with no straightforward extension for out-of sample data. In this paper, we propose a framework for more general geometry aware kernel learning. The proposed framework integrates multiple sources of information and enables us to develop flexible and effective kernel matrices. Then, we theoretically show how the learned kernel matrices are extended to the corresponding kernel functions, in which the out-of-sample data can be computed directly. Under our framework, a novel family of geometry-aware kernels is developed. Especially, some existing geometry-aware kernels can be viewed as instances of our framework. The performance of the kernels is evaluated on dimensionality reduction, classification, and clustering tasks. The empirical results show that our kernels significantly improve the performance. PMID- 26058058 TI - Generalization Performance of Regularized Ranking With Multiscale Kernels. AB - The regularized kernel method for the ranking problem has attracted increasing attentions in machine learning. The previous regularized ranking algorithms are usually based on reproducing kernel Hilbert spaces with a single kernel. In this paper, we go beyond this framework by investigating the generalization performance of the regularized ranking with multiscale kernels. A novel ranking algorithm with multiscale kernels is proposed and its representer theorem is proved. We establish the upper bound of the generalization error in terms of the complexity of hypothesis spaces. It shows that the multiscale ranking algorithm can achieve satisfactory learning rates under mild conditions. Experiments demonstrate the effectiveness of the proposed method for drug discovery and recommendation tasks. PMID- 26058056 TI - Physical Activity and Different Concepts of Fall Risk Estimation in Older People- Results of the ActiFE-Ulm Study. AB - OBJECTIVES: To investigate the relationship between physical activity and two measures of fall incidence in an elderly population using person-years as well as hours walked as denominators and to compare these two approaches. DESIGN: Prospective cohort study with one-year follow-up of falls using fall calendars. Physical activity was defined as walking duration and recorded at baseline over one week using a thigh-worn uni-axial accelerometer (activPAL; PAL Technologies, Glasgow, Scotland). Average daily physical activity was extracted from these data and categorized in low (0-59 min), medium (60-119 min) and high (120 min and more) activity. SETTING: The ActiFE Ulm study located in Ulm and adjacent regions in Southern Germany. PARTICIPANTS: 1,214 community-dwelling older people (>=65 years, 56.4% men). MEASUREMENTS: Negative-binomial regression models were used to calculate fall rates and incidence rate ratios for each activity category each with using (1) person-years and (2) hours walked as denominators stratified by gender, age group, fall history, and walking speed. All analyses were adjusted either for gender, age, or both. RESULTS: No statistically significant association was seen between falls per person-year and average daily physical activity. However, when looking at falls per 100 hours walked, those who were low active sustained more falls per hours walked. The highest incidence rates of falls were seen in low-active persons with slow walking speed (0.57 (95% confidence interval (95% CI): 0.33 to 0.98) falls per 100 hours walked) or history of falls (0.60 (95% CI: 0.36 to 0.99) falls per 100 hours walked). CONCLUSION: Falls per hours walked is a relevant and sensitive outcome measure. It complements the concept of incidence per person years, and gives an additional perspective on falls in community-dwelling older people. PMID- 26058059 TI - Taylor O(h3) Discretization of ZNN Models for Dynamic Equality-Constrained Quadratic Programming With Application to Manipulators. AB - In this paper, a new Taylor-type numerical differentiation formula is first presented to discretize the continuous-time Zhang neural network (ZNN), and obtain higher computational accuracy. Based on the Taylor-type formula, two Taylor-type discrete-time ZNN models (termed Taylor-type discrete-time ZNNK and Taylor-type discrete-time ZNNU models) are then proposed and discussed to perform online dynamic equality-constrained quadratic programming. For comparison, Euler type discrete-time ZNN models (called Euler-type discrete-time ZNNK and Euler type discrete-time ZNNU models) and Newton iteration, with interesting links being found, are also presented. It is proved herein that the steady-state residual errors of the proposed Taylor-type discrete-time ZNN models, Euler-type discrete-time ZNN models, and Newton iteration have the patterns of O(h(3)), O(h(2)), and O(h), respectively, with h denoting the sampling gap. Numerical experiments, including the application examples, are carried out, of which the results further substantiate the theoretical findings and the efficacy of Taylor type discrete-time ZNN models. Finally, the comparisons with Taylor-type discrete time derivative model and other Lagrange-type discrete-time ZNN models for dynamic equality-constrained quadratic programming substantiate the superiority of the proposed Taylor-type discrete-time ZNN models once again. PMID- 26058060 TI - Electric tuning of magnetization dynamics and electric field-induced negative magnetic permeability in nanoscale composite multiferroics. AB - Steering magnetism by electric fields upon interfacing ferromagnetic (FM) and ferroelectric (FE) materials to achieve an emergent multiferroic response bears a great potential for nano-scale devices with novel functionalities. FM/FE heterostructures allow, for instance, the electrical manipulation of magnetic anisotropy via interfacial magnetoelectric (ME) couplings. A charge-mediated ME effect is believed to be generally weak and active in only a few angstroms. Here we present an experimental evidence uncovering a new magnon-driven, strong ME effect acting on the nanometer range. For Co92Zr8 (20 nm) film deposited on ferroelectric PMN-PT we show via ferromagnetic resonance (FMR) that this type of linear ME allows for electrical control of simultaneously the magnetization precession and its damping, both of which are key elements for magnetic switching and spintronics. The experiments unravel further an electric-field-induced negative magnetic permeability effect. PMID- 26058061 TI - Correction: Intra-tumor Genetic Heterogeneity and Mortality in Head and Neck Cancer: Analysis of Data from The Cancer Genome Atlas. PMID- 26058062 TI - Damped spin waves in the intermediate ordered phases in Ni3V2O8. AB - Spin dynamics in the intermediate ordered phases (between 4 and 9 K) in Ni3V2O8 have been studied with inelastic neutron scattering. It is found that the spin waves are very diffuse, indicative of short lived correlations and the coexistence of paramagnetic moments with the long-range ordered state. PMID- 26058063 TI - Ambient Fine Particulate Matter Suppresses In Vivo Proliferation of Bone Marrow Stem Cells through Reactive Oxygen Species Formation. AB - AIMS: Some environmental insults, such as fine particulate matter (PM) exposure, significantly impair the function of stem cells. However, it is unknown if PM exposure could affect the population of bone marrow stem cells (BMSCs). The present study was to investigate the effects of PM on BMSCs population and related mechanism(s). MAIN METHEODS: PM was intranasally distilled into male C57BL/6 mice for one month. Flow cytometry with antibodies for BMSCs, Annexin V and BrdU ware used to determine the number of BMSCs and the levels of their apoptosis and proliferation in vivo. Phosphorylated Akt (P-Akt) level was determined in the BM cells with western blotting. Intracellular reactive oxygen species (ROS) formation was quantified using flow cytometry analysis. To determine the role of PM-induced ROS in BMSCs population, proliferation, and apotosis, experiments were repeated using N-acetylcysteine (NAC)-treated wild type mice or a triple transgenic mouse line with overexpression of antioxidant network (AON) composed of superoxide dismutase (SOD)1, SOD3, and glutathione peroxidase-1 with decreased in vivo ROS production. KEY FINDINGS: PM treatment significantly reduced BMSCs population in association with increased ROS formation, decreased P-Akt level, and inhibition of proliferation of BMSCs without induction of apoptosis. NAC treatment or AON overexpression with reduced ROS formation effectively prevented PM-induced reduction of BMSCs population and proliferation with partial recovery of P-Akt level. SIGNIFICANCE: PM exposure significantly decreased the population of BMSCs due to diminished proliferation via ROS-mediated mechanism (could be partially via inhibition of Akt signaling). PMID- 26058064 TI - Quantifying and Reducing Posture-Dependent Distortion in Ballistocardiogram Measurements. AB - Ballistocardiography is a noninvasive measurement of the mechanical movement of the body caused by cardiac ejection of blood. Recent studies have demonstrated that ballistocardiogram (BCG) signals can be measured using a modified home weighing scale and used to track changes in myocardial contractility and cardiac output. With this approach, the BCG can potentially be used both for preventive screening and for chronic disease management applications. However, for achieving high signal quality, subjects are required to stand still on the scale in an upright position for the measurement; the effects of intentional (for user comfort) or unintentional (due to user error) modifications in the position or posture of the subject during the measurement have not been investigated in the existing literature. In this study, we quantified the effects of different standing and seated postures on the measured BCG signals, and on the most salient BCG-derived features compared to reference standard measurements (e.g., impedance cardiography). We determined that the standing upright posture led to the least distorted signals as hypothesized, and that the correlation between BCG-derived timing interval features (R-J interval) and the preejection period, PEP (measured using ICG), decreased significantly with impaired posture or sitting position. We further implemented two novel approaches to improve the PEP estimates from other standing and sitting postures, using system identification and improved J-wave detection methods. These approaches can improve the usability of standing BCG measurements in unsupervised settings (i.e., the home), by improving the robustness to nonideal posture, as well as enabling high-quality seated BCG measurements. PMID- 26058065 TI - Ca2+/Calmodulin and Apo-Calmodulin Both Bind to and Enhance the Tyrosine Kinase Activity of c-Src. AB - Src family non-receptor tyrosine kinases play a prominent role in multiple cellular processes, including: cell proliferation, differentiation, cell survival, stress response, and cell adhesion and migration, among others. And when deregulated by mutations, overexpression, and/or the arrival of faulty incoming signals, its hyperactivity contributes to the development of hematological and solid tumors. c-Src is a prototypical member of this family of kinases, which is highly regulated by a set of phosphorylation events. Other factor contributing to the regulation of Src activity appears to be mediated by the Ca2+ signal generated in cells by different effectors, where the Ca2+ receptor protein calmodulin (CaM) plays a key role. In this report we demonstrate that CaM directly interacts with Src in both Ca2+-dependent and Ca2+-independent manners in vitro and in living cells, and that the CaM antagonist N-(6 aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) inhibits the activation of this kinase induced by the upstream activation of the epidermal growth factor receptor (EGFR), in human carcinoma epidermoide A431 cells, and by hydrogen peroxide-induced oxidative stress, in both A431 cells and human breast adenocarcinoma SK-BR-3 cells. Furthermore, we show that the Ca2+/CaM complex strongly activates the auto-phosphorylation and tyrosine kinase activity of c-Src toward exogenous substrates, but most relevantly and for the first time, we demonstrate that Ca2+-free CaM (apo-CaM) exerts a far higher activatory action on Src auto-phosphorylation and kinase activity toward exogenous substrates than the one exerted by the Ca2+/CaM complex. This suggests that a transient increase in the cytosolic concentration of free Ca2+ is not an absolute requirement for CaM mediated activation of Src in living cells, and that a direct regulation of Src by apo-CaM could be inferred. PMID- 26058066 TI - Reexamining Sample Size Requirements for Multivariate, Abundance-Based Community Research: When Resources are Limited, the Research Does Not Have to Be. AB - Community ecologists commonly perform multivariate techniques (e.g., ordination, cluster analysis) to assess patterns and gradients of taxonomic variation. A critical requirement for a meaningful statistical analysis is accurate information on the taxa found within an ecological sample. However, oversampling (too many individuals counted per sample) also comes at a cost, particularly for ecological systems in which identification and quantification is substantially more resource consuming than the field expedition itself. In such systems, an increasingly larger sample size will eventually result in diminishing returns in improving any pattern or gradient revealed by the data, but will also lead to continually increasing costs. Here, we examine 396 datasets: 44 previously published and 352 created datasets. Using meta-analytic and simulation-based approaches, the research within the present paper seeks (1) to determine minimal sample sizes required to produce robust multivariate statistical results when conducting abundance-based, community ecology research. Furthermore, we seek (2) to determine the dataset parameters (i.e., evenness, number of taxa, number of samples) that require larger sample sizes, regardless of resource availability. We found that in the 44 previously published and the 220 created datasets with randomly chosen abundances, a conservative estimate of a sample size of 58 produced the same multivariate results as all larger sample sizes. However, this minimal number varies as a function of evenness, where increased evenness resulted in increased minimal sample sizes. Sample sizes as small as 58 individuals are sufficient for a broad range of multivariate abundance-based research. In cases when resource availability is the limiting factor for conducting a project (e.g., small university, time to conduct the research project), statistically viable results can still be obtained with less of an investment. PMID- 26058067 TI - Correction: Transcriptome Analysis Comparison of Lipid Biosynthesis in the Leaves and Developing Seeds of Brassica napus. PMID- 26058068 TI - Population Trend of the World's Monitored Seabirds, 1950-2010. AB - Seabird population changes are good indicators of long-term and large-scale change in marine ecosystems, and important because of their many impacts on marine ecosystems. We assessed the population trend of the world's monitored seabirds (1950-2010) by compiling a global database of seabird population size records and applying multivariate autoregressive state-space (MARSS) modeling to estimate the overall population trend of the portion of the population with sufficient data (i.e., at least five records). This monitored population represented approximately 19% of the global seabird population. We found the monitored portion of the global seabird population to have declined overall by 69.7% between 1950 and 2010. This declining trend may reflect the global seabird population trend, given the large and apparently representative sample. Furthermore, the largest declines were observed in families containing wide ranging pelagic species, suggesting that pan-global populations may be more at risk than shorter-ranging coastal populations. PMID- 26058069 TI - Different Modes of Transactivation of Bacteriophage Mu Late Promoters by Transcription Factor C. AB - Transactivator protein C is required for the expression of bacteriophage Mu late genes from lys, I, P and mom promoters during lytic life cycle of the phage. The mechanism of transcription activation of mom gene by C protein is well understood. C activates transcription at Pmom by initial unwinding of the promoter DNA, thereby facilitating RNA polymerase (RNAP) recruitment. Subsequently, C interacts with the beta' subunit of RNAP to enhance promoter clearance. The mechanism by which C activates other late genes of the phage is not known. We carried out promoter-polymerase interaction studies with all the late gene promoters to determine the individual step of C mediated activation. Unlike at Pmom, at the other three promoters, RNAP recruitment and closed complex formation are not C dependent. Instead, the action of C at Plys, PI, and PP is during the isomerization from closed complex to open complex with no apparent effect at other steps of initiation pathway. The mechanism of transcription activation of mom and other late promoters by their common activator is different. This distinction in the mode of activation (promoter recruitment and escape versus isomerization) by the same activator at different promoters appears to be important for optimized expression of each of the late genes. PMID- 26058070 TI - A 20-year-old woman with rapidly progressive dyspnea and diffuse pulmonary infiltrates. AB - Silicone is a liquid polymer previously considered to be immunologically inert and favored in cosmetic procedures. Increasing evidence shows a multisystemic inflammatory reaction to its administration constituting the silicone embolism syndrome (SES). The majority of adverse effects are seen in the pulmonary system resulting in extensive diffuse alveolar damage and ultimately ARDS. Neurologic involvement occurs frequently and is uniformly fatal. Large volume injections, high pressure infiltrations and prior exposure to silicone have been implicated, with an IgG polydimethylsiloxane antibody described. Most patients meet Schonfield criteria for fat embolism syndrome and treatment is largely supportive. As the illicit use of injectable silicone rises worldwide, so does the incidence of related morbidities and fatalities, necessitating a high index of suspicion for SES in patients with neurologic or pulmonary symptoms and recent exposure to liquid silicone. We report an unusual case of multi-organ dysfunction following silicone injection. PMID- 26058071 TI - T-ALL: Home Is where the CXCL12 Is. AB - T cell acute lymphoblastic leukemia (T-ALL) is caused by mutations affecting cell survival, proliferation, and differentiation. In addition to requiring these mutations, Passaro and colleagues and Pitt and colleagues in this issue of Cancer Cell demonstrate that T-ALL initiating cells residing in bone marrow depend on the CXCR4/CXCL12 signaling axis for disease maintenance and progression. PMID- 26058072 TI - Antagonizing ClpP: A New Power Play in Targeted Therapy for AML. AB - In this issue of Cancer Cell, Cole and colleagues report a non-mutant mitochondrial protein (ClpP) that is overexpressed in a wide range of acute myeloid leukemia (AML) cases, but not in normal hematopoietic precursors. This finding suggests a potentially unique therapeutic targeting opportunity for this difficult-to-treat disease. PMID- 26058073 TI - Excluding T Cells: Is beta-Catenin the Full Story? AB - Spranger and colleagues reported recently in Nature an inverse relationship between melanoma intrinsic beta-catenin signaling and intratumoral T cell infiltration, providing an explanation for potential mechanisms of T cell exclusion. Further insights are needed into the mechanisms leading to a lack of T cell infiltration of cancers and primary immune resistance. PMID- 26058074 TI - The Next Wave of EGFR Tyrosine Kinase Inhibitors Enter the Clinic. AB - The T790M mutation in EGFR accounts for approximately half of all lung cancer cases with acquired resistance to the current clinical EGFR tyrosine kinase inhibitors. In tyrosine kinase inhibitor-resistant lung tumors, rociletinib and AZD9291 are highly active when T790M is present and modestly active when T790M is absent. PMID- 26058076 TI - CXCR4 Is Required for Leukemia-Initiating Cell Activity in T Cell Acute Lymphoblastic Leukemia. AB - Impaired cell migration has been demonstrated in T cell acute lymphoblastic leukemia (T-ALL) cells upon calcineurin inactivation, among other phenotypic traits including increased apoptosis, inhibition of cell proliferation, and ultimately inhibition of leukemia-initiating cell (LIC) activity. Herein we demonstrate that the chemokine receptor CXCR4 is essential to the LIC activity of T-ALL leukemic cells both in NOTCH-induced mouse T-ALL and human T-ALL xenograft models. We further demonstrate that calcineurin regulates CXCR4 cell-surface expression in a cortactin-dependent manner, a mechanism essential to the migratory properties of T-ALL cells. Because 20%-25% of pediatric and over 50% of adult patients with T-ALL do not achieve complete remission and relapse, our results call for clinical trials incorporating CXCR4 antagonists in T-ALL treatment. PMID- 26058075 TI - CXCL12-Producing Vascular Endothelial Niches Control Acute T Cell Leukemia Maintenance. AB - The role of the microenvironment in T cell acute lymphoblastic leukemia (T-ALL), or any acute leukemia, is poorly understood. Here we demonstrate that T-ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Cxcl12 deletion from vascular endothelial, but not perivascular, cells impeded tumor growth, suggesting a vascular niche for T-ALL. Moreover, genetic targeting of Cxcr4 in murine T-ALL after disease onset led to rapid, sustained disease remission, and CXCR4 antagonism suppressed human T-ALL in primary xenografts. Loss of CXCR4 targeted key T-ALL regulators, including the MYC pathway, and decreased leukemia initiating cell activity in vivo. Our data identify a T-ALL niche and suggest targeting CXCL12/CXCR4 signaling as a powerful therapeutic approach for T-ALL. PMID- 26058077 TI - A Functional Role for VEGFR1 Expressed in Peripheral Sensory Neurons in Cancer Pain. AB - Cancer pain is a debilitating disorder and a primary determinant of the poor quality of life. Here, we report a non-vascular role for ligands of the Vascular Endothelial Growth Factor (VEGF) family in cancer pain. Tumor-derived VEGF-A, PLGF-2, and VEGF-B augment pain sensitivity through selective activation of VEGF receptor 1 (VEGFR1) expressed in sensory neurons in human cancer and mouse models. Sensory-neuron-specific genetic deletion/silencing or local or systemic blockade of VEGFR1 prevented tumor-induced nerve remodeling and attenuated cancer pain in diverse mouse models in vivo. These findings identify a therapeutic potential for VEGFR1-modifying drugs in cancer pain and suggest a palliative effect for VEGF/VEGFR1-targeting anti-angiogenic tumor therapies. PMID- 26058078 TI - ERG Activates the YAP1 Transcriptional Program and Induces the Development of Age Related Prostate Tumors. AB - The significance of ERG in human prostate cancer is unclear because mouse prostate is resistant to ERG-mediated transformation. We determined that ERG activates the transcriptional program regulated by YAP1 of the Hippo signaling pathway and found that prostate-specific activation of either ERG or YAP1 in mice induces similar transcriptional changes and results in age-related prostate tumors. ERG binds to chromatin regions occupied by TEAD/YAP1 and transactivates Hippo target genes. In addition, in human luminal-type prostate cancer cells, ERG binds to the promoter of YAP1 and is necessary for YAP1 expression. These results provide direct genetic evidence of a causal role for ERG in prostate cancer and reveal a connection between ERG and the Hippo signaling pathway. PMID- 26058079 TI - Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy. AB - Unsustained enzyme inhibition is a barrier to targeted therapy for cancer. Here, resistance to a class I PI3K inhibitor in a model of metastatic breast cancer driven by PI3K and MYC was associated with feedback activation of tyrosine kinase receptors (RTKs), AKT, mTOR, and MYC. Inhibitors of bromodomain and extra terminal domain (BET) proteins also failed to affect tumor growth. Interestingly, BET inhibitors lowered PI3K signaling and dissociated BRD4 from chromatin at regulatory regions of insulin receptor and EGFR family RTKs to reduce their expression. Combined PI3K and BET inhibition induced cell death, tumor regression, and clamped inhibition of PI3K signaling in a broad range of tumor cell lines to provide a strategy to overcome resistance to kinase inhibitor therapy. PMID- 26058080 TI - Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. AB - From an shRNA screen, we identified ClpP as a member of the mitochondrial proteome whose knockdown reduced the viability of K562 leukemic cells. Expression of this mitochondrial protease that has structural similarity to the cytoplasmic proteosome is increased in leukemic cells from approximately half of all patients with AML. Genetic or chemical inhibition of ClpP killed cells from both human AML cell lines and primary samples in which the cells showed elevated ClpP expression but did not affect their normal counterparts. Importantly, Clpp knockout mice were viable with normal hematopoiesis. Mechanistically, we found that ClpP interacts with mitochondrial respiratory chain proteins and metabolic enzymes, and knockdown of ClpP in leukemic cells inhibited oxidative phosphorylation and mitochondrial metabolism. PMID- 26058081 TI - Association of Adiposity Indices with Platelet Distribution Width and Mean Platelet Volume in Chinese Adults. AB - Hypoxia is a prominent characteristic of inflammatory tissue lesions. It can affect platelet function. While mean platelet volume (MPV) and platelet distribution width (PDW) are sample platelet indices, they may reflect subcinical platelet activation. To investigated associations between adiposity indices and platelet indices, 17327 eligible individuals (7677 males and 9650 females) from the Dongfeng-Tongji Cohort Study (DFTJ-Cohort Study, n=27009) were included in this study, except for 9682 individuals with missing data on demographical, lifestyle, physical indicators and diseases relative to PDW and MPV. Associations between adiposity indices including waist circumstance (WC), waist-to-height ratio (WHtR), body mass index (BMI), and MPV or PDW in the participants were analyzed using multiple logistic regressions. There were significantly negative associations between abnormal PDW and WC or WHtR for both sexes (ptrend<0.001 for all), as well as abnormal MPV and WC or WHtR among female participants (ptrend<0.05 for all). In the highest BMI groups, only females with low MPV or PDW were at greater risk for having low MPV (OR=1.33, 95% CI=1.10, 1.62 ptrend<0.001) or PDW (OR=1.34, 95% CI=1.14, 1.58, ptrend<0.001) than those who had low MPV or PDW in the corresponding lowest BMI group. The change of PDW seems more sensitive than MPV to oxidative stress and hypoxia. Associations between reduced PDW and MPV values and WC, WHtR and BMI values in Chinese female adults may help us to further investigate early changes in human body. PMID- 26058082 TI - Association of Perfluoroalkyl Substances, Bone Mineral Density, and Osteoporosis in the U.S. Population in NHANES 2009-2010. AB - BACKGROUND: Perfluoroalkyl substances (PFASs), including perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), are detectable in the serum of 95% of the U.S. OBJECTIVE: Considering the role of PFASs as endocrine disruptors, we examined their relationships with bone health. METHODS: The association between serum PFAS concentration and bone mineral density at total femur (TFBMD), femoral neck (FNBMD), lumbar spine (LSBMD), and physician-diagnosed osteoporosis was assessed in 1,914 participants using data from the National Health and Nutritional Examination Survey 2009-2010. RESULTS: The mean age of the participants was 43 years. Men had higher serum PFAS concentrations than women (p < 0.001) except for PFNA. In both sexes, serum PFOS concentrations were inversely associated with FNBMD (p < 0.05). In women, significant negative associations were observed for natural log (ln)-transformed PFOS exposure with TFBMD and FNBMD, and for ln-transformed PFOA exposure with TFBMD (p < 0.05). In postmenopausal women, serum PFOS was negatively associated with TFBMD and FNBMD, and PFNA was negatively associated with TFBMD, FNBMD, and LSBMD (all p < 0.05). With one log unit increase in serum PFOA, PFHxS, and PFNA, osteoporosis prevalence in women increased as follows: [adjusted odds ratios (aORs)] 1.84 (95% CI: 1.17, 2.905), 1.64 (95% CI: 1.14, 2.38), and 1.45 (95% CI: 1.02, 2.05), respectively. In women, the prevalence of osteoporosis was significantly higher in the highest versus the lowest quartiles of PFOA, PFHxS, and PFNA, with aORs of 2.59 (95% CI: 1.01, 6.67), 13.20 (95% CI: 2.72, 64.15), and 3.23 (95% CI: 1.44, 7.21), respectively, based on 77 cases in the study sample. CONCLUSION: In a representative sample of the U.S. adult population, serum PFAS concentrations were associated with lower bone mineral density, which varied according to the specific PFAS and bone site assessed. Most associations were limited to women. Osteoporosis in women was also associated with PFAS exposure, based on a small number of cases. CITATION: Khalil N, Chen A, Lee M, Czerwinski SA, Ebert JR, DeWitt JC, Kannan K. 2016. Association of perfluoroalkyl substances, bone mineral density, and osteoporosis in the U.S. population in NHANES 2009-2010. Environ Health Perspect 124:81-87; http://dx.doi.org/10.1289/ehp.1307909. PMID- 26058083 TI - Patient Preferences for Treatment of Psoriasis with Biologicals: A Discrete Choice Experiment. AB - Treatment dissatisfaction and non-adherence are common among patients with psoriasis, partly due to discordance between individual preferences and recommended treatments. However, patients are more satisfied with biologicals than with other treatments. The aim of our study was to assess patient preferences for treatment of psoriasis with biologicals by using computer-based conjoint analysis. Biologicals approved for psoriasis in Germany were decomposed into outcome (probability of 50% and 90% improvement, time until response, sustainability of success, probability of mild and severe adverse events (AE), probability of American College of Rheumatology (ACR) 20 response) and process attributes (treatment location, frequency, duration and delivery method). Impact of sociodemographic and socioeconomic characteristics and disease severity on Relative Importance Scores (RIS) of each attribute was assessed with analyses of variance, post hoc tests, and multivariate regression. Averaged across the cohort of 200 participants with moderate-to-severe psoriasis, preferences were highest for avoiding severe AE (RIS = 17.3), followed by 90% improvement (RIS = 14.0) and avoiding mild AE (RIS = 10.5). Process attributes reached intermediate RIS (8.2 8.8). Men were more concerned about efficacy than women (50% improvement: RIS = 6.9 vs. 9.5, p = 0.008; beta = -0.191, p = 0.011 in multivariate models; 90% improvement: RIS = 12.1 vs. 15.4, p = 0.002; beta = -0.197, p = 0.009). Older participants judged the probability of 50% and 90% improvement less relevant than younger ones (50% improvement: Pearson's Correlation (PC) = -0.161, p = 0.022; beta = -0.219, p = 0.017; 90% improvement: PC = -0.155, p = 0.028; beta = -0.264, p = 0.004) but worried more about severe AE (PC = 0.175, p = 0.013; beta = 0.166, p = 0.082). In summary, participants with moderate-to-severe psoriasis were most interested in safety of biologicals, followed by efficacy, but preferences varied with sociodemographic characteristics and working status. Based on this knowledge, physicians should identify preferences of each individual patient during shared decision-making in order to optimize treatment satisfaction, adherence and outcome. PMID- 26058084 TI - Organochlorine Compounds and Ultrasound Measurements of Fetal Growth in the INMA Cohort (Spain). AB - BACKGROUND: Several studies have reported decreases in birth size associated with exposure to organochlorine compounds (OCs), but uncertainties remain regarding the critical windows of prenatal exposure and the effects on fetal body segments. OBJECTIVE: We examined the relationship between prenatal OC concentrations and fetal anthropometry. METHODS: We measured 4,4'-dichlorodiphenyldichloroethylene (4,4'-DDE), hexachlorobenzene (HCB), and polychlorinated biphenyl (PCB) congeners (138, 153, and 180) in 2,369 maternal and 1,140 cord serum samples in four Spanish cohorts (2003-2008). We used linear mixed models to obtain longitudinal growth curves for estimated fetal weight (EFW), abdominal circumference (AC), biparietal diameter (BPD), and femur length (FL) adjusted by parental and fetal characteristics. We calculated standard deviation (SD) scores of growth at 0-12, 12-20, and 20-34 weeks of gestation as well as size at gestational week 34 for the four parameters. We studied the association between OCs and the fetal outcomes by cohort-specific linear models and subsequent meta-analyses. RESULTS: PCBs were associated with a reduction in AC up to mid-pregnancy, and BPD and FL from gestational week 20 onward. An inverse association was also found between HCB and AC growth in early pregnancy. The reduction of these parameters ranged from -4% to -2% for a doubling in the OC concentrations. No association between 4,4'-DDE and fetal growth was observed. CONCLUSIONS: To our knowledge, this is the first study to report an association between prenatal exposure to some PCBs and HCB and fetal growth: AC during the first two trimesters of pregnancy, and BPD and FL later in pregnancy. CITATION: Lopez-Espinosa MJ, Murcia M, Iniguez C, Vizcaino E, Costa O, Fernandez-Somoano A, Basterrechea M, Lertxundi A, Guxens M, Gascon M, Goni-Irigoyen F, Grimalt JO, Tardon A, Ballester F. 2016. Organochlorine compounds and ultrasound measurements of fetal growth in the INMA cohort (Spain). Environ Health Perspect 124:157-163; http://dx.doi.org/10.1289/ehp.1408907. PMID- 26058085 TI - Confusion about Cadmium Risks: The Unrecognized Limitations of an Extrapolated Paradigm. AB - BACKGROUND: Cadmium (Cd) risk assessment presently relies on tubular proteinuria as a critical effect and urinary Cd (U-Cd) as an index of the Cd body burden. Based on this paradigm, regulatory bodies have reached contradictory conclusions regarding the safety of Cd in food. Adding to the confusion, epidemiological studies implicate environmental Cd as a risk factor for bone, cardiovascular, and other degenerative diseases at exposure levels that are much lower than points of departure used for setting food standards. OBJECTIVE: The objective was to examine whether the present confusion over Cd risks is not related to conceptual or methodological problems. DISCUSSION: The cornerstone of Cd risk assessment is the assumption that U-Cd reflects the lifetime accumulation of the metal in the body. The validity of this assumption as applied to the general population has been questioned by recent studies revealing that low-level U-Cd varies widely within and between individuals depending on urinary flow, urine collection protocol, and recent exposure. There is also evidence that low-level U-Cd increases with proteinuria and essential element deficiencies, two potential confounders that might explain the multiple associations of U-Cd with common degenerative diseases. In essence, the present Cd confusion might arise from the fact that this heavy metal follows the same transport pathways as plasma proteins for its urinary excretion and the same transport pathways as essential elements for its intestinal absorption. CONCLUSIONS: The Cd risk assessment paradigm needs to be rethought taking into consideration that low-level U-Cd is strongly influenced by renal physiology, recent exposure, and factors linked to studied outcomes. CITATION: Bernard A. 2016. Confusion about cadmium risks: the unrecognized limitations of an extrapolated paradigm. Environ Health Perspect 124:1-5; http://dx.doi.org/10.1289/ehp.1509691. PMID- 26058086 TI - Graphene-Induced Oriented Interfacial Microstructures in Single Fiber Polymer Composites. AB - Interfacial interactions between the polymer and graphene are pivotal in determining the reinforcement efficiency in the graphene-enhanced polymer nanocomposites. Here, we report on the dynamic process of graphene-induced oriented interfacial crystals of isotactic polypropylene (iPP) in the single fiber polymer composites by means of polarized optical microscopy (POM) and scanning electron microscopy (SEM). The graphene fibers are obtained by chemical reduction of graphene oxide fibers, and the latter is produced from the liquid crystalline dispersion of graphene oxide via a wet coagulation route. The lamellar crystals of iPP grow perpendicular to the fiber axis, forming an oriented transcrystalline (TC) interphase surrounding the graphene fiber. Various factors including the diameter of graphene fibers, crystallization temperature, and time are investigated. The dynamic process of polymer transcrystallization surrounding the graphene fiber is studied in the temperature range 124-132 degrees C. The Lauritzen-Hoffman theory of heterogeneous nucleation is applied to analyze the transcrystallization process, and the fold surface free energy is determined. Study into microstructures demonstrates a cross-hatched lamellar morphology of the TC interphase and the strong interfacial adhesion between the iPP and graphene. Under appropriate conditions, the beta-form transcrystals occur whereas the alpha-form transcrystals are predominant surrounding the graphene fibers. PMID- 26058088 TI - Erratum for Maheux et al., Abilities of the mCP Agar Method and CRENAME Alpha Toxin-Specific Real-Time PCR Assay To Detect Clostridium perfringens Spores in Drinking Water. PMID- 26058090 TI - [Case of systemic lupus erythematosus encephalopathy with binocular retinal and optic neuropathy]. PMID- 26058091 TI - Where residues found in meat, more found in milk. PMID- 26058092 TI - AAVMC continues to move the needle on diversity. PMID- 26058093 TI - Veterinarians' role in public policy. PMID- 26058094 TI - Don't leave "medical" out. PMID- 26058095 TI - More on animal welfare. PMID- 26058096 TI - More on animal welfare. PMID- 26058097 TI - Testosterone therapy may not be as safe as once thought. Screening men for cardiovascular risks before starting testosterone therapy may help avert dangerous blood clots. PMID- 26058098 TI - What happens when heart drug refills look different? PMID- 26058100 TI - High blood pressure in midlife linked to brain decline. PMID- 26058099 TI - FDA approves another device to replace aortic valve without surgery. PMID- 26058101 TI - 4 easy ways to cut your drug spending. Minimizing your prescription drug costs is easier than it may seem. PMID- 26058102 TI - Ask the doctor. Your advise women to eat 46 grams of protein daily, but I don't know what that translates to in ounces. PMID- 26058103 TI - In response: Platelet-rich plasma and myofibroblasts: is the composition the key to success?. PMID- 26058104 TI - Rekindling the immortal debate- telecobalt versus linear accelerator. PMID- 26058105 TI - [Viral hepatitis delta. Is there the delta infection problem in the Russian Federation?]. AB - Hepatitis delta (HD) is characterized by rapid progression to fibrosis, and development of hepatocellular carcinoma, and a high mortality rate. The article presents data on the epidemiology, diagnosis, treatment of HD. The views of the epidemiological, clinical and virological characteristics of HD-infection among population of the Russian Federation (RF) are limited due to absence of official HD registration and detection of antibodies to the HD virus (anti-HDV) in HBsAg positive individuals. However, some areas of the country are characterized by a high HDV circulation (Republic Tyva (RT) - 46,5%, Republic Sakha (Yakutia) - 12,5%) according to our studies conducted in 6 regions of Russia. Clinical epidemiological situation of HDV infection in RT can be considered as a model to create a program of optimize diagnosis, prevention and treatment of HDV-infection in the Russian Federation. PMID- 26058106 TI - [New metabolic index in the diagnosis of insulin resistance in patients with nonalcoholic fatty liver disease]. AB - Early diagnosis of insulin resistance (IR) in patients with non-alcoholic fatty liver disease (NAFLD) is relevant in connection with the possibility of timely correction and the primary prevention of cardiovascular disease. OBJECTIVE: To evaluate the diagnostic significance of the new metabolic index (MI) in the early diagnosis of IR in patients with NAFLD. MATERIALS AND METHODS: In 494 patients with ultrasonographic evidence of NAFLD have been studied lipid and carbohydrate metabolism. Indirect methods of assessment of IR were analyzed and we proposed a new MI. RESULTS AND DISCUSSION: NAFLD is accompanied by a progression of metabolic disorders and atherogenic dyslipidemia, disorders of carbohydrate metabolism, changes in the functional state of the liver. In the early stages of IR for the initial isolate changes of carbohydrates and lipid metabolism MI index is more sensitive to the existing violations, and with the progression of changes in laboratory parameters observed its gradual increase. CONCLUSIONS: MI can be recommended in clinical practice for screening IR in NAFLD patients for further in-depth examination. PMID- 26058107 TI - [Disorders of gut microflora in the pathogenesis of liver cirrhosis and complications of portal hypertension]. AB - A total of 85 patients with alcoholic and viral cirrhosis were included in study to assess the prevalence of dysbiosis and its relationship with the severity of disease, and with development of dyspeptic disorders. Intestinal bacterial over growth was measured by means of a lactulose breath test, fecal flora was cultured under aerobic and anaerobic conditions. Intestinal bacterial overgrowth and colon dysbiosis were determined in 82.4% of patients with equal prevalence in alcoholic and viral cirrhosis. Intestinal dysbiosis was found to be risk factor of increasing cirrhosis severity and liver dysfunction, as well as development of complications of portal hypertension. It was documented, that intestinal dyspepsia syndrome in cirrhotic patients is strongly associated with the presence of gut microflora disorders. PMID- 26058108 TI - [Blood serum cholecystokinin and clinical-functional variability of biliary pathology]. AB - RESULTS: Basal and stimulated serum CCK concentrations were not statistically significant differences (p > 0.05) with the control group in patients studied in the whole and in patients subgroups, formed by the diagnosis of biliary pathology and the character of gallbladder emptying. Increased stimulated CCK concentration was found in patients with symptomatic variants. Reduce of serum-cholecystokinin concentration growth (ACCK) after intake of Sorbitol was revealed in subgroup of patients with low-symptom variant. Reduced sensitivity of the gallbladder to CCK was observed in subgroups of patients with gallbladder hypokinetic dyskinesia and one with symptomatic variant of biliary pathology. CONCLUSION: The sensitivity of the gallbladder neuromuscular apparatus to CCK is associated with clinical and functional variability of the biliary pathology. PMID- 26058110 TI - [Peculiarities of the clinical course of ulcerative colitis, depending on the spectrum of cross-linked autoantibodies from the same family to antigens of neutrophils]. AB - There were found that patients with ulcerative colitis (UC) in the presence of two types of autoantibodies to antigens of neutrophils is observed in less pronounced activity in the course of the disease compared with those patients with a spectrum of autoantibodies one of the wider family. The patients with three or more types of antibodies from the same family, cross-linked, ware accompanied by an increase in clinical and endoscopic disease activity. It is shown that a--greater range of autoantibodies one family determines not only the degree of activity of the YAK, but the nature and intensity of its extraintestinal manifestations. Identify different spectra of autoantibodies one family to antigens of neutrophils, cross-linked, allows us to predict the nature of the disease in each particular patient. PMID- 26058109 TI - [Syndrome of bacterial overgrowth in patients with the reduced stomach acid secretion: some aspects of the diagnosis]. AB - OBJECTIVE: To study the frequency of occurrence of small intestinal bacterial overgrowth (SIBO) in GERD patients with reduced stomach acid secretion receiving long-term PPI treatment, and patients with chronic atrophic gastritis with reduced stomach acid secretion, using the hydrogen breath test (HBT) and studies of short-chain fatty acids (SCFA) in various biological substrates; compare the obtained results. MATERIAL AND METHODS: There were 100 people surveyed: 1 group consisted of 40 patients with chronic atrophic gastritis (HG) with reduced stomach acid secretion; 2 group consisted of 60 patients of GERD in patients receiving PPI different duration (0-6 months, 6-12 months more than 12 months). All the patients were examined by a load of lactulose and research SCFA using gas liquid chromatographic analysis (GC-analysis) in various biological substrates (duodenal secretion and feces). RESULTS: When performing HBT in patients with chronic atrophic gastritis frequency detection SIBO amounted to 57.5 per cent. In GERD patients receiving PPI SIBO was detected in 8.3% of cases (0-6 months of treatment), 21.7% (6-12 months of treatment), 61.6% (over 12 months). 15% of HG patients and 13.3% of GERD patients receiving PPI, with clinical manifestations of SIBO, the data turned out to be negative. The SCFA parameters in the duodenal secretion in patients with GERD during PPI therapy depending on the duration of the admission and in HG patients with reduced stomach acid secretion were studied, as well as in patients with clinical manifestations of SIBO depending on the data of HBT (+/-). We also studied SCFA parameters in patients with positive HBT results depending on time of registration of the increase of hydrogen concentration. It is established that the study of SCFA in the duodenal secretion is an important diagnostic SIBO test, which allows not only to detect increased activity of the microflora, but also to determine its tribal affiliation. In some cases, its information value exceeds the HBT. The study of SCFA in various biological substrates (duodenal secretion, feces) allows you to specify the localization of existing violations. The rapidity of obtaining results allows to consider this method as screening. PMID- 26058111 TI - [Defining groups of patients with atrophic gastritis for endoscopic mucosal resection using mathematical modeling]. AB - The article is devoted to the problem of diagnostics of atrophic gastritis. The main principles of morphological diagnostics are presented. The endoscopic findings are discussed. The authors had used the mathematical regression model to reveal groups of patients with some specific signs of atrophic gastritis, such as endoscopic sings, morphological and clinical signs. This model can be used to put a diagnosis and to look after the patients with metaplasia, dysplasia and early cancer. PMID- 26058112 TI - [Laparoscopy as a method of final diagnosis of acute adhesive small bowel obstruction in a previously unoperated patients]. AB - The article presents the use of laparoscopic interventions in 38 patients with Acute Adhesive Small Bowel Obstruction (AASBO) in patients without previous history of abdominal surgery. Clinical, radiological and ultrasound patterns of disease are analyzed. The use of laparoscopy has proved itself the most effective and relatively safe diagnostic procedure. In 14 (36.8%) patients convertion to laparotomy was made due to contraindications for laparoscopy. In 24 (63.2%) patients laparosopic adhesyolisis was performed and AASBO subsequently treated with complications rate of 4.2%. PMID- 26058114 TI - [Lymphocyte apoptosis enhancement by the synthetic peptide E in experimental ulcer]. AB - The influence of regulatory peptide type of AFP on the course of experimental ulcer was investigated. It has been shown that activation of apoptosis enhances local necrotic inflammatory reaction, on the one hand, and enables the development of adhesions with on the other. PMID- 26058113 TI - [Local level of neoangiogenesis factors in dynamics of experimental metastatic process in liver]. AB - The aim--to study the dynamics content of VEGF-A, VEGF-R1, EGF and EGF-R1 in liver and spleen tissues from rats at different stages of liver metastases. MATERIALS AND METHODS: We have designed a model of liver metastases in male rats. The content of growth factors was examined by ELISA at 1, 2 and 5 weeks of carcinogenesis in tissue of liver and tumors of spleen. RESULTS: The content of growth factors increased in liver tissue at different stages of metastasis. The concentration of VEGF-A increased gradually from the 1st to 5th week carcinogenesis. The concentration of VEGF-R1 increased after 2 weeks and decreased slightly after 5 weeks of carcinogenesis. The level of all components of EGF/EGF-R1 increased after 2 weeks of carcinogenesis. CONCLUSION: The following pathogenetic aspects of liver metastasis were defined: change in levels of VEGF-A/VEGF-R1 indicating the progressive development of the process of neoangiogenesis, and increased levels of EGF/EGF-R1 responsible for metastasis processes. PMID- 26058115 TI - [Metabolic syndrome and intestinal microflora: what overall?]. AB - The article highlights the problem of the relationship of the intestinal microbiome person with metabolic syndrome. Changes in bacterial intestinal proportions in obesity captured the attention of scientists around the world, especially in relation to their effect on the metabolism. Increasing the proportion of Firmicutes and Actinobacteria and decrease of Bacteroidetes associated with increased levels of serum lipopolysaccharides, insulin resistance, weight gain, and other co-morbid manifestations of the metabolic syndrome. The mechanisms, underlying this interdisciplinary problems, actively studied to optimize the prevention and treatment of obesity and type 2 diabetes. PMID- 26058116 TI - [Clinical case. Chronic gastritis associated with Helicobacter pylori and Epstein Barr virus]. AB - The article describes a clinical case of chronic gastritis associated with Helicobacter pylori infection and Epstein-Barr virus. The authors draw attention to the peculiarities of dyspepsia syndrome, on the characteristics of this disease in the endoscopic and morphological study. PMID- 26058117 TI - [On the 40th anniversary of the Central Research Scientific Institute of Gastroenterology]. PMID- 26058118 TI - [European gastroenterology bridging meeting (Berlin, Germany, 13-15 November 2014)]. PMID- 26058119 TI - The future of the maintenance of certification. PMID- 26058120 TI - Delawareans with current asthma who smoke--a snapshot. AB - OBJECTIVE: Because they experience respiratory symptoms, adults with asthma might be expected to avoid cigarette smoking. This study sought to determine whether Delawareans with asthma are less likely to smoke cigarettes than members of the general population. METHODS: The authors used data from a combined sample of 8,560 Delaware adults (ages 18 years or older) who participated in the Behavior Risk Factor Surveillance System (2011 and 2012). Sampling weights were used in all analyses. In this cross-sectional study, 827 participants reported a physician diagnosis of asthma. RESULTS: The prevalence of cigarette smoking is similar in Delawareans with and without asthma (20.91 percent and 20.30 percent respectively). After controlling for gender, race, and education, younger age groups had significantly higher odds of being current smokers. There was evidence that young adults (18-44 years) were six times more likely to be current smokers as compared to the 65 or older reference group. CONCLUSIONS: Delawareans with asthma do not appear to selectively avoid cigarette smoking. Specific smoking prevention and cessation efforts should be targeted to adults with asthma. PMID- 26058121 TI - Accidental methadone intoxication masquerading as asthma exacerbation with respiratory arrest in a six-year-old boy. AB - A 6-year-old boy is brought to the emergency department of a level 1 trauma center by emergency medical services (EMS) for presumed asthma exacerbation with subsequent unresponsiveness and transient bradycardia. The initial physician exam was remarkable for an unresponsive child, with diffusely diminished breath sounds bilaterally, accompanied by diffuse wheezing, as well as pinpoint pupils. This last observation led to the recommendation to attempt a dose of naloxone for a possible overdose prior to proceeding with intubation for the altered mental status. The child had a brisk response to the naloxone, was subsequently placed on a naloxone drip, and admitted to the hospital. Initial provider thoughts were that the naloxone had worked on an accidental overdose of over-the-counter dextromethorphan containing medication. These suspicions were later proven incorrect after mass spectrometry yielded a positive methadone presence in the urine. The child was ultimately discharged home with ongoing input from child protective services, without further medical complications. The increased utilization of methadone for the treatment of both opioid withdrawal, as well as for chronic pain management demands, heightened awareness of the clinicians, as cases such as this will continue to appear. PMID- 26058122 TI - Autopsies at the Christiana Care Health System: a short review of the last 28 years. PMID- 26058123 TI - President signs into law changes to Medicare physician reimbursement formula. PMID- 26058124 TI - Time-dependent appearances of myofibroblasts during the repair of contused skeletal muscle in rat and its application for wound age determination. AB - OBJECTIVE: To research the relation between the time-dependent appearances of myotibroblasts during the repair of contused skeletal muscle in rat and wound age determination. METHODS: A total of 35 SD male rats were divided into the control and six injured groups according to wound age as follows: 12 h, 1 d, 5 d, 7 d, 10 d and 14 d after injury. The appearances of myofibroblasts were detected by HE staining, immunohistochemistry and confocal laser scanning microscopy. Masson's trichrome staining was utilized to examine collagen accumulation in the contused areas. RESULTS: Immunohistochemical staining showed that alpha-SMA+ myofibroblasts were initially observed at 5 d post-injury. The average ratio of myofibroblasts was highest at 14 d post-injury, with all samples, ratios more than 50%. In the other five groups, the average of alpha-SMA positive ratios were less than 50%. The collagen stained areas in the contused zones, concomitant with myofibroblast appearance, were increasingly augmented along with advances of posttraumatic interval. CONCLUSION: The immunohistochemical detection of myofibroblasts can be applied to wound age determination. The myofibroblasts might be involved in collagen deposition during the repair of contused skeletal muscle in rat. PMID- 26058125 TI - [Expression of caspase-3 and HAX-1 after cerebral contusion in rat]. AB - OBJECTIVE: To observe the expression pattern of caspase-3 and HCLS1-associated protein X-1 (HAX-1) at different time after cerebral contusion in rat, and explore the new method for estimating the injury interval. METHODS: The cerebral contusion model was established using adult SD male rats. Then the rats were randomly allocated into 8 groups: 2 h, 6 h, 12 h, 1 d, 3 d, and 7 d after cerebral contusion, sham-operation and normal control. Expression of caspase-3 and HAX-1 protein after cerebral contusion in rat was detected by Western blotting. Laser scanning confocal microscope was used to observe the number of HAX-1 positive cells and TUNEL-stained cells after cerebral contusion. RESULTS: The expression of caspase-3 increased parallelly with the time after cerebral contusion and reached the peak value on 3 d. The expression of caspase-3 decreased gradually and still maintained a high level expression on 7 d (P < 0.05). The expression of HAX-1 positive cell went up after injury, and reached the peak value at 6 h (P < 0.05), then turned down gradually after 12 h and went out of detection after 3 d. The number of TUNEL-stained cells increased obviously at 2 h and reached the peak value on 3 d. The number of TUNEL-stained apoptotic cells decreased gradually and still maintained a high level expression on 7 d (P < 0.05). CONCLUSION: The expression of caspase-3 and HAX-1 after cerebral contusion has time sequential regularity, which may provide new evidence for forensic diagnosis of cerebral contusion interval. PMID- 26058126 TI - [Expression of S100B and GFAP after primary brainstem injury in rat]. AB - OBJECTIVE: To study the expression of S100B and glial tibrillory acidic protein (GFAP) atter primary brainstem injury in rat and discuss the changes with brainstern injury time and their mechanism in the injury. METHODS: The brainstem injury animal model was established using the mechanical impacting method. The HE staining, Gless argentaffin staining and SP immunohistochemical method were applied to observe the changes of S100B and GFAP at different injury time. The immunostaining results were measured statistically with imaging analysis technology. RESULTS: A large number of S100B positive cells could be seen in 30 min. Afterward, expression increased gradually with time and peaked up in 24 h, and reversed back the normal in 72h. The GFAP positive cells showed rise continually in 30 min, and reached the peak in 48 h, then started to decrease, but still higher than that in control. CONCLUSION: The expression of S100B and GFAP is correlated with post traumatic intervals after brainstem injury in rat, and may be useful in estimation post traumatic intervals and nerve regeneration. PMID- 26058127 TI - [Application of MSCT in the identification and analysis of traffic accidents: 2 fatal cases]. AB - OBJECTIVE: To explore the application value of multi-slice spiral computed tomography (MSCT) in traffic accidents through observing and analyzing the injury features of the accidents. METHODS: Two fatal cases caused by traffic accidents were fully examined using MSCT, 3D imaging reconstruction and angiography through cardiac puncture. The features of traffic injury mechanism were analyzed through combination of MSCT and postmortem external examination. RESULTS: In case 1, right cardiac rupture was found by MSCT and angiography through cardiac puncture. The cause of death was cardiac tamponade and right ventricular rupture due to the crush injury of chest in the traffic accident. In case 2, splenic rupture and intra-abdominal hemorrhage was found and caused by injury of left trunk by MSCT. The cause of death was hemorrhage and traumatic shock. CONCLUSION: MSCT could observe skeletal injury, soft tissue injury, and hematologic disorder well. The combination use of MSCT and angiography through cardiac puncture provided assistance to the diagnosis of cardiovascular system injury. PMID- 26058128 TI - [Correlation between contrast vision and sweep visual evoked potential acuity]. AB - OBJECTIVE: To compare the correlation between contrast vision (LV) and sweep visual evoked potential acuity (SVEP-A) among people with emmetropia, mild myopia, and moderate myopia. METHODS: The CV and SVEP-A were tested individually in 96 eyes from healthy young volunteers, including 37 eyes of emmetropia, 27 eyes of mild myopia, and 32 eyes of moderate myopia. The statistic analysis was done by ANOVA analysis and rank sum test. RESULTS: (1) With the decrease of contrast, CV and SVEP-A decreased in every group. (2) At 100% contrast, the difference of CV between emmetropia and mild myopia had statistical significance (P<0.05). At 100%, 25% and 10% contrast, the difference of CV between emmetropia and moderate myopia had statistical significance (P<0.05). (3) In the same group, the difference of 100% and 25% contrast had statistical significance (P < 0.05). So was between 100% and 10% contrast. (4) At 100% and 10% contrast, the difference of CV and SVEP-A had statistical significance (P < 0.05). CONCLUSION: The CV of myopia relates to many factors including ametropia and fundus lesions. The correction of ametropia is important to the values of CV and SVEP-A. PMID- 26058129 TI - [Establishment of a 15 loci multiplex amplification system and the genetic poly- morphism in Xinjiang Uygur population]. AB - OBJECTIVE: To develop a five fluorescence-labeled multiplex amplification system for 15 loci and study genetic polymorphism in Xinjiang Uygur population. METHODS: The STR loci were screened. The alleles were named according to the number of repeats by sequencing. The sensitivity, species specificity, identity and stability of the five fluorescence-labeled multiplex amplification system for the 15 loci were all tested. Then, the genetic polymorphism was analyzed in Xinjiang Uygur population and compared with other ethnic groups including Xizang Tibetan, Xiuyan Manchu, and Guangzhou Han population. RESULTS: The 15 loci multiplex amplification system was established. The sensitivity was 0.3 ng with good species specificity, identity and stability. The distributions of genotype for 13 STR loci in Uygur population were in accordance with Hardy-Weinberg equilibrium with no genetic linkage between these loci. Most loci showed statistically significant among different populations. CONCLUSION: The established system has application value in forensic evidence. The 13 STR loci in Uygur population have PMID- 26058130 TI - Simultaneous screening for 45 poisonous alkaloids in blood by LC-MS/MS. AB - OBJECTIVE: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) screening method for 45 poisonous alkaloids in blood. METHODS: Identification was based on the compound's retention time and two precursor-to-production transitions. The method involved a liquid-liquid extraction (LLE) followed by LC MS/MS with multiple-reaction monitoring (MRM). When 1 mL of blood was extracted with diethyl ether at pH = 9.2 with SKF525A as the internal standard, the target compounds were analyzed with LC-MS/MS in the positive ionization mode. RESULTS: The target alkaloids had good linearity (r>0.995 1), both the intra-day precision and inter-day precision being less than 14.77%. The limits of detection ranged from 0.05 to 25 ng/mL in blood. CONCLUSION: The method is selective and sensitive in detecting poisonous alkaloids with a total running time of 12 minutes; therefore it was successfully applied to some actual cases of suspected alkaloids poisoning. PMID- 26058131 TI - [Relation between partial mechanical injuries and nature of death in high-falling cases: an analysis of 205 cases]. AB - OBJECTIVE: To explore the relation between the behavior psychology analysis of partial mechanical injuries and the nature of death in high-falling cases, and provide reference, for such cases. METHODS: Of 311 death victims of high-falling injuries collected from 2008 to 2013, 205 cases were associated with partial mechanical injuries. The characteristics of injury formation, preliminary crime scene traces, fatal injury of high-falling, and text messages were all retrospectively analyzed. RESULTS: According to the investigation of preliminary crime scene traces, fatal injury of high-falling and text message, there were 86 suicide, 24 accident and 95 uncertainty in the 205 cases. According to the behavior psychology analysis of partial mechanical injuries, there were 80 suicide, 11 accident, and 4 homicide in the 95 uncertainty cases. CONCLUSION: The partial mechanical injuries uncertainly caused by high-falling correlate with the manner of high-falling death. According to the behavior psychology analysis of the partial mechanical injuries in high-falling death cases, the presumption of high-falling death is usually accurate PMID- 26058132 TI - [Fifty-two cases analysis of cliff suicide]. AB - OBJECTIVE: To analyze suicide scene, damage morphology and case investigation of mountain type scenic spot for giving the references to determine the nature of cliff suicide cases. METHODS: The suicide cases collected from 2002 to 2012 in scenic spot of Mount Huangshan. The age, gender, native place, case location, damage inspection and behavior were analyzed. RESULTS: In the 52 suicide cases, the suicide rate of male was higher than that of female. The numbers from other provinces were higher than that of local province. The age was mainly range from 19 to 50. The time of suicide cases mostly happened between 16:00 to 24:00. The major damage was compound injury with varying degrees of traumatic brain injury, organic injury of pleuroperitoneal cavity and surface bruise and scratch. CONCLUSION: In order to determine the nature of cliff suicide cases, it needs to work synthetically in the investigation of crime scene and interview. PMID- 26058133 TI - [Determination of five pesticides in fishpond by SPE-GC/MS]. AB - OBJECTIVE: To establish the solid phase extraction (SPE) with GC/MS technology for fish poisoning cases to determine five pesticides in fishpond. METHODS: By three solid phase extraction column including Oasis HLB cartridge, Bond Elut C18 and SampliQ C18, the recovery rate was compared to extract and purify five pesticides in fishpond. The effects of different kinds and dosages of eluents on extract rate were also reviewed. RESULTS: Using Bond Elut C18 as solid phase extraction column and 3 mL benzene as eluent, the linear range of mass concentration of five pesticides in fishpond was 1-50 MUg/mL, and the correlation coefficient was 0.996 2-0.999 6. The limit of detection was 3.4-26 MUg/L and the recovery was 61.49%-102.48%. The relative standard deviations was less than or equal to 3.01%. CONCLU-SION: With high sensitivity, good accuracy and precision, SPE-GC/MS has simple and quick operation and less solvent. It can be applied to determination of five pesticides in fishpond. PMID- 26058134 TI - [Informed consent right of the appraised individuals in forensic clinical examination]. AB - Informed consent right is not just for basic ethical consideration, but is important for protecting patient's right by law, which is expressed through informed consent contract. The appraised individuals of forensic clinical examination have the similar legal status as the patients in medical system. However, the law does not require informed consent right for the appraised individuals. I recommend giving certain informed consent right to the appraised individuals in the forensic clinical examination. Under the contracted relationship with the institution, the appraised individuals could participate in the examination process, know the necessary information, and make a selected consent on the examination results, which can assure the justice and fairness of judicial examination procedure. PMID- 26058135 TI - [Whiplash injury analysis of cervical vertebra by finite element method]. AB - Finite element method (FEM) is an effective mathematical method for stress analysis, and has been gradually applied in the study of biomechanics of human body structures. This paper reviews the construction, development, materials assignment and verification of FEM model of cervical vertebra, and it also states the research results of injury mechanism of whiplash injury and biomechanical response analysis of the cervical vertebra using FEM by researchers at home and abroad. PMID- 26058137 TI - Metabolism and biological function of natural products in plants preface. PMID- 26058138 TI - Stereocontrolled total synthesis of tetrodotoxin from myo-inositol and D-glucose by three routes: aspects for constructing complex multi-functionalized cyclitols with branched-chain structures. AB - This report describes the stereocontrolled total synthesis of the multi functionalized cyclitol derivative, tetrodotoxin, containing eight asymmetric carbons and different types of branched-chains, from myo-inositol and D-glucose using three different methods. The tetrodotoxin derivatives possess a relatively small molecular weight but unique structural and chemical properties. Selection of the appropriate synthetic method may be useful not only for compounds related to TTX (including related derivatives), but also for other highly complex multi functionalized cyclitols containing branched-chains. PMID- 26058139 TI - Occurrence and de novo biosynthesis of caffeine and theanine in seedlings of tea (Camellia sinensis). AB - Caffeine (1,3,7-trimethyl xanthine) and theanine (gamma-glutamyl-L-ethylamide) are the major nitrogen-containing secondary metabolites in tea leaves. The aim of the present study was to elucidate the relative concentration and amounts of these compounds and the de novo biosynthetic activity in different parts of tea seedlings grown for 27-, 106- and 205 days. The results indicated that caffeine and its biosynthetic activity occur only in leaves and stems, while theanine is distributed in all organs, including roots. The concentration of caffeine and theanine in leaves ranged from 0.3-1.1 mg N/g and 0.1-0.5 mg N/g fresh weight, respectively. A higher concentration of theanine was found in roots (0.5-1.1 mg N). The total amounts of theanine expressed as g N/seedling were 1.1-1.5 times higher than that of caffeine. The high biosynthetic activity of caffeine from NH4+ was found in young leaves during the first 106 days after germination. Theanine biosynthetic activity probably occurs in roots, since higher 15N atom% excess was observed in roots during the first 27 days. Theanine may be synthesized mainly in roots and translocated to leaves. The de novo biosynthesis of caffeine and theanine in tea seedlings and their accumulation and translocation are discussed. PMID- 26058140 TI - Metabolism of purine alkaloids and xanthine in leaves of mate (Ilex paraguariensis). AB - Accumulation and metabolism of purine alkaloids in leaves of mate (Ilex paraguariensis) were investigated. In winter, leaves accumulated caffeine but not theobromine, indicating that caffeine is the end product of purine alkaloid synthesis in mate. To elucidate the purine alkaloid metabolism in mate leaves, the metabolic fate of [8-(14)C]theobromine, [8-(14)C]theophylline, [8 (14)C]caffeine and [8-(14)C] xanthine was investigated in the leaf disks of young and mature leaves. In young mate leaves, significant amounts of theobromine and theophylline were utilized for caffeine biosynthesis, but the conversion was not observed in mature leaves. A small amount of theophylline was converted to theobromine. Practically no caffeine catabolism was detected in mate leaves during a 24 h-incubation. Catabolism of theobromine and theophylline via 3 methylxanthine was observed mainly in mature leaves. Xanthine was catabolised extensively via ureides in both young and mature leaves, but limited amounts are also utilized for the synthesis of theobromine, theophylline and caffeine. Possible pathways for the metabolism of purine alkaloids in mate leaves are discussed. PMID- 26058141 TI - Comparative analysis of two DOPA dioxygenases from Phytolacca Americana. AB - The comparative analysis of two Phytolacca americana DOPA dioxygenases (PaDOD1 and PaDOD2) that may be involved in betalain biosynthesis was carried out. The recombinant protein of PaDOD catalyzed the conversion of DOPA to betalamic acid, whereas DOD activity was not detected in PaDOD2 in vitro. The role of DOD genes is discussed in the evolutionary context using phylogenetic analysis, suggesting that DOD might have been duplicated early in evolution and that accumulation of base substitutions could have led to the different characteristics of DODs within the betalain-producing Caryophyllales. PMID- 26058142 TI - Biochemical analysis of Phytolacca DOPA dioxygenase. AB - The biochemical analysis of Phytolacca americana DOPA dioxygenases (PaDOD1 and PaDOD2) was carried out. The recombinant protein of PaDOD1 catalyzed the conversion of DOPA to betalamic acid, whereas DOD activity was not detected in PaDOD2 in vitro. While the reported motif conserved in DODs from betalain producing plants was found in PaDOD1, a single amino acid residue alteration was detected in PaDOD2. A mutated PaDOD1 protein with a change of 177 Asn to Gly showed reduced specific activity compared with PaDOD1, while DOPA dioxygenase activity was not observed for a mutated PaDOD2 protein which had its conserved motif replaced with that of PaDOD. A three-dimensional (3D) structural model of PaDOD1 and PaDOD2 showed that the conserved motif in DODs was located in the N terminal side of a loop, which was found close to the putative active site. The difference in stability of the loop may affect the enzymatic activity of PaDOD2. PMID- 26058143 TI - Unraveling the biosynthesis of pilocarpine in Pilocarpus microphyllus. AB - Pilocarpine is found exclusively in species of Pilocarpus and the presence of other imidazole alkaloids has been reported in several species of the genus. Pilocarpine has several important pharmaceutical applications. Although several imidazole alkaloids related to pilocarpine have been reported in the previous years, little is still known about its biosynthetic route. At most, histidine has been reported as the precursor of pilocarpine. Based on our own previous reports and in an experiment where pilocarpine and related alkaloids (pilosine, trachyllophiline and anhydropilosine) were supplied to P. microphyllus leaves and the alkaloid profile analyzed by UPLC-MS, we suggest a biosynthesis pathway for pilocarpine. Further experiments using labeled precursors associated with transcriptome data may allow us to understand the whole biosynthesis pathway and its genetic control. PMID- 26058144 TI - Transcriptomic evaluation of plant growth inhibitory activity of goniothalamin from the Malaysian medicinal plant Goniothalamus andersonii. AB - Goniothalamin produced by the Malaysian medicinal plant, Goniothalamus andersonii J. Sinclair, strongly inhibits plant growth. However, its mode of action has not been characterized at the gene expression level. We conducted DNA microarray assay to analyze the changes in early gene responses of Arabidopsis thaliana seedlings. After a 6-h exposure to goniothalamin, we observed an upregulation of genes highly associated with heat response, and 22 heat shock protein (AtHSP) genes were upregulated more than 50 fold. Together with these genes, we observed upregulation of the genes related to oxidative stress and protein folding. Also, the genes related to cell wall modification and cell growth, expansin (AtEXPA) genes, were significantly downregulated. The results suggested that goniothalamin induces oxidative stresses and inhibits the expression of cell wall-associated proteins resulting in growth inhibition of Arabidopsis seedlings. PMID- 26058145 TI - Momilactone sensitive proteins in Arabidopsis thaliana. AB - The labdane-related diterpenoid, momilactone B has potent growth inhibitory activity and was demonstrated to play a particularly critical role in the allelopathy of rice (Oryza sativa L.). However, there is limited information available about the mode of action of momilactone B on the growth inhibition. The present research describes the effects of momilactone B on protein expression in the early development of Arabidopsis thaliana seedling, which was determined by two-dimensional electrophoresis and MALDI-TOFMS. Momilactone B inhibited the accumulation of subtilisin-like serine protease, amyrin synthase LUP2, beta glucosidase and malate synthase at 1 h after the momilactone application. Those proteins are involved in the metabolic turnover and the production of intermediates needed for cell structures resulting in plant growth and development. Momilactone B also inhibited the breakdown of cruciferin 2, which is essential for seed germination and seedling growth to construct cell structures. Momilactone B induced the accumulation of translationally controlled tumor protein, glutathione S-transferase and 1-cysteine peroxiredoxin 1. These proteins are involved in stress responses and increased stress tolerance. In addition, glutathione S-transferase has the activity of herbicide detoxification and 1 cysteine peroxiredoxin 1 has inhibitory activity for seed germination under unfavorable conditions. The present research suggests that momilactone B may inhibit the seedling growth by the inhibition of the metabolic turnover and the production of intermediates for cell structures. In addition, momilactone induced proteins associated with plant defense responses. PMID- 26058146 TI - Effect of caffeine on the expression pattern of water-soluble proteins in rice (Oryza sativa) seedlings. AB - It has been suggested that caffeine acts as an allelochemical which influences the germination and growth of plants. The effect of caffeine on the expression profiles of proteins was investigated in shoot-root axes of rice (Oryza sativa) seedlings. Two-dimensional difference gel electrophoresis combined with Matrix Assisted Laser Desorption/Ionization Time of Flight/Time of Flight Mass Spectrometry was employed for the separation and identification of proteins. The results indicated that amounts of 51 protein spots were reduced and 14 were increased by treatment with 1 mM caffeine. Twelve rice seedling proteins were identified. Down-regulated proteins were beta-tubulin, sucrose synthase, glyceraldehyde-3-phosphate dehydrogenase, reversibly glycosylated polypeptide/alpha-1,4-glucan protein synthase and cytoplasmic malate dehydrogenase. In contrast, up-regulated proteins were alanyl-aminopeptidase, acetyl-CoA carboxylase, adenine phosphoribosyltransferase, NAD-malate dehydrogenase, ornithine carbamoyltransferase, glucose-6-phosphate isomerase and nuclear RNA binding protein. Possible alternation of metabolism caused by caffeine is discussed with the protein expression data. PMID- 26058147 TI - Short-term effect of caffeine on purine, pyrimidine and pyridine metabolism in rice (Oryza sativa) seedlings. AB - As part of our studies on the physiological and ecological function of caffeine, we investigated the effect of exogenously supplied caffeine on purine, pyrimidine and pyridine metabolism in rice seedlings. We examined the effect of 1 mM caffeine on the in situ metabolism of 14C-labelled adenine, guanine, inosine, uridine, uracil, nicotinamide and nicotinic acid. The segments of 4-day-old dark grown seedlings were incubated with these labelled compounds for 6 h. For purines, the incorporation of radioactivity from [8-(14)C]adenine and [8 (14)C]guanine into nucleotides was enhanced by caffeine; in contrast, incorporation into CO2 were reduced. The radioactivity in ureides (allantoin and allantoic acid) from [8-(14)C]guanine and [8-(14)C]inosine was increased by caffeine. For pyrimidines, caffeine enhanced the incorporation of radioactivity from [2-(14)C]uridine into nucleotides, which was accompanied by a decrease in pyrimidine catabolism. Such difference was not found in the metabolism of [2 (14)C]uracil. Caffeine did not influence the pyridine metabolism of [carbonyl 14C]- nicotinamide and [2-(14)C]nicotinic acid. The possible control steps of caffeine on nucleotide metabolism in rice are discussed. PMID- 26058148 TI - Cyanamide phytotoxicity in soybean (Glycine max) seedlings involves aldehyde dehydrogenase inhibition and oxidative stress. AB - The phytotoxic effect of the allelochemical cyanamide has been well-documented yet the underlying mechanism for this phenomenon has not been fully characterized. Cognizant of the putative inhibitory effect of cyanamide on aldehyde dehydrogenases (ALDHs), we hereby show that the capacity of mitochondrial preparations from cyanamide-treated soybean seedlings to oxidize acetaldehyde and succinic-semialdehyde was dose-dependently reduced to at most 55% and 70%, respectively. Cyanamide-treated plants exhibited oxidative stress (i.e. increased lipid peroxidation and H2O2 accumulation) that was exacerbated upon exposure to UV-A--symptoms reminiscent of ALDH and succinic-semialdehyde dehydrogenase (SSADH) knock-out Arabidopsis mutants. We suggest that the inhibition of mitochondrial ALDH and SSADH may be a contributory mechanism to the burst in oxidative stress mediated by cyanamide. PMID- 26058149 TI - Allelopathy in a leguminous mangrove plant, Derris indica: protoplast co-culture bioassay and rotenone effect. AB - To investigate allelopathic activity of a leguminous mangrove plant, Derris indica, the 'Protoplasts Co-culture Method' for bioassay of allelopathy was developed using suspension culture. A suspension culture was induced from immature seed and sub-cultured in Murashige and Skoog's (MS) basal medium containing 10 MUM each of 2,4-dichlorophenoxyacetic acid (2,4-D) and 6 benzyladenine (BA). The protoplasts were isolated using the separate wells method with 2% each of Cellulase RS, Driselase 20 and Macerozyme R10 in 0.4 M mannitol solution. Protoplast cultures of D. indica revealed that high concentrations of cytokinins, BA and thidiazuron, were effective for cell divisions. The co cultures of D. indica protoplasts with recipient lettuce protoplasts using 96 multi-well culture plates were performed in MS basal medium containing 0.4 M mannitol solution and 1 MUM 2,4-D and 0.1 MUM BA. The protoplast density of D. indica used in co-culturing varied from 6 x 10(3) - 10(5) / mL. Very strong inhibitory allelopathic effects of D. indica protoplasts on lettuce protoplast growth were found. A similar strong inhibitory allelopathic activity of dried young leaves on lettuce seedling growth was also observed by using the sandwich method. Rotenone, which is a component of Derris root, dissolved in DMSO, was highly inhibitory on the growth of lettuce protoplasts in culture and this could be one of the causes of the strong allelopathic activity of D. indica. PMID- 26058150 TI - Effect of purine alkaloids on the proliferation of lettuce cells derived from protoplasts. AB - To investigate the ecological role of caffeine, theobromine, theophylline and paraxanthine, which are released from purine alkaloid forming plants, the effects of these purine alkaloids on the division and colony formation of lettuce cells were assessed at concentrations up to 1 mM. Five days after treatment with 500 MUM caffeine, theophylline and paraxanthine, division of isolated protoplasts was significantly inhibited. Thirteen days treatment with > 250 MUM caffeine had a marked inhibitory effect on the colony formation of cells derived from the protoplasts. Other purine alkaloids also acted as inhibitors. The order of the inhibition was caffeine > theophylline > paraxanthine > theobromine. These observations suggest that a relatively low concentration of caffeine is toxic for proliferation of plant cells. In contrast, theobromine is a weak inhibitor of proliferation. Possible allelopathic roles of purine alkaloids in natural ecosystems are discussed. PMID- 26058151 TI - A protocol for axenic liquid cell cultures of a woody leguminous mangrove, Caesalpinia crista, and their amino acids profiling. AB - Callus induction, maintenance and protoplast cultures were achieved from immature seeds of a woody leguminous mangrove, Caesalpinia crista. Axenic cultures were possible during 1.5 months of pod storage in 0.1% benzalkonium chloride solution. Callus induction was achieved using 1 mL liquid medium in a 10 mL flat-bottomed culture tube. Protoplasts were isolated using Cellulase R10, Hemicellulase, and Driselase 20 in 0.6 M mannitol solution and sub-culturable calluses were obtained in 50 MUL liquid medium using a 96-microplate method. The optimal hormonal concentration was 10 MUM each of 2,4-dichlorophenoxyacetic acid and benzyladenine in liquid Murashige and Skoog's basal medium for both callus induction and maintenance, and protoplast cultures. Similarities and differences in amino acid profiles and culture conditions are discussed among woody mangrove species and non-mangrove leguminous species. Caesalpinia crista cultures were unique as they secreted a large amount of amino acids, including proline, into the liquid culture medium. PMID- 26058152 TI - Phytotoxic substance with allelopathic activity in Brachiaria decumbens. AB - The grass Brachiaria decumbens becomes naturalized and quickly dominant in non native areas. It was hypothesized that phytotoxic substances of plants may contribute to the domination and invasion of the plants. However, no potent phytotoxic substance has been reported in B. decumbens. Therefore, we searched for phytotoxic substances with allelopathic activity in this species. An aqueous methanol extract of B. decumbens inhibited the growth of roots and shoots of cress (Lepidium sativum), lettuce (Lactuca sativa), timothy (Phleum pratense) and ryegrass (Lolium multiflorum) seedlings. The extract was then purified using chromatographic methods and a phytotoxic substance with allelopathic activity was isolated and identified by spectral analysis as (6R,9S)-3-oxo-alpha-ionol. These results suggest that this compound may contribute to the allelopathic effect caused by the B. decumbens extract and may be in part responsible for the invasion and domination of B. decumbens. Two other Brachiaria species, B. brizantha and a Brachiaria hybrid were also confirmed to contain (6R,9S)-3-oxo alpha-ionol. Therefore, this compound may play an important role in the phytotoxicity of the Brachiaria species. PMID- 26058153 TI - Isolation and identification of an allelopathic substance from Hibiscus sabdariffa. AB - In this study, an allelopathic substance was isolated from an aqueous methanol extract of Hibiscus sabdariffa L. by column chromatography and reverse phase HPLC. The chemical structure of the substance was determined by 1H NMR spectroscopy and mass spectrometry as trimethyl allo-hydroxycitrate. Trimethyl allo-hydroxycitrate inhibited the growth of cress hypocotyls and roots at concentrations greater than 10 mM. The concentrations required for 50% growth inhibition of the hypocotyls and roots of cress were 20.3 and 14.4 mM, respectively. The inhibitory activity of trimethyl allo-hydroxycitrate suggests that the substance may act as an allelopathic substance of H. sabdariffa. PMID- 26058154 TI - Angelicin as the principal allelochemical in Heracleum sosnowskyi fruit. AB - Distribution patterns of furocoumarins in fruits of the invasive species Heracleum sosnowskyi Manden. (Sosnowskyi's hogweed) during a cold stratification period were investigated. Angelicin, bergapten, methoxalen and imperatorin were mainly localized in the fruit coats and their content varied depending on the fruit source. Cold stratification treatment (90 days, 2-3 degrees C) reduced the content of furocoumarins in the fruit coats by more than two times, compared with those before stratification. The specific activity of the detected furocoumarins and total activity of crude extracts were evaluated using Lactuca sativa, as acceptor plant. Crude extracts obtained from fruit coats and seeds of H. sosnowskyi suppressed 50% of radicle and hypocotyl growth of lettuce seedlings at the concentration range of 1.0-1.7 mg/mL. The inhibitory activity of angelicin was proved to be the highest compared with the other tested furocoumarins, and the inhibitory activity of crude extracts could be explained mainly by the presence of angelicin. Both, monocots (Lolium multiflorum, Phleum pratensis, Festuca pratesis, Lolium perenne) and dicots (Tripholium repens, Trifolium pretense) were found to be sensitive to the exudates of whole H. sosnowskyi fruits. Thus, we assume, that high inhibitory potential of furocoumarins, especially angelicin, at high seed productivity of H. sosnowskyi might have an ecological significance in plant-plant interaction. PMID- 26058155 TI - Identification of octanal as plant growth inhibitory volatile compound released from Heracleum sosnowskyi fruit. AB - Heracleum sosnowskyi Manden of the Apiaceae family is a malignant invasive plant in Eastern Europe, Belarus and Russia. The species is known for its prolific seed production, which has been linked to the plant's invasive success. The fruit also has a strong aroma, but the contribution of the fruit's volatile constituent to out-compete neighboring plants has not been fully established. In this study, fruit volatiles of H. sosnowskyi and conspecifics (i.e. H. asperum, H. lescovii, H. dissectum, H. hirtum) were identified by headspace gas chromatography-mass spectrometry (HS-GC-MS). Octyl acetate, octanol, octanal, hexyl isobutyrate, and hexyl-2-methyl butyrate were found to be the principal volatiles. Using authentic standards, the growth-inhibitory property of the individual compounds was assayed by the novel Cotton swab method. Assay results with lettuce (Lactuca sativa) showed that octanal strongly inhibited seed germination and radicle elongation of seedlings. The results suggest that octanal may be the main contributor to the allelopathic activity of H. sosnowksyi fruits. Furthermore, the mixture of fruit volatiles from the invasive H. sosnowskyi more strongly delayed lettuce seedling elongation than the volatiles from fruits of the non-invasive H. asperum, H. lescovii, H. dissectum and H. hirtum. Thus, the present study is the first to demonstrate the possible involvement of fruit volatiles of Heracleum species in plant-plant interaction. PMID- 26058156 TI - Identification of safranal as the main allelochemical from saffron (Crocus sativus). AB - Dried parts of 75 medicinal plant species collected from different regions in Iran were assayed by the Dish Pack Method for volatile allelopathic activity, using Lactuca sativa (lettuce) as the test plant. The highest (60%) inhibition was observed for saffron (stigma of Crocus sativus), followed by Dracocephalum kotschyi, Solanum nigrum and Artemisia aucheri. Safranal was identified as the main chemical by Headspace Gas Chromatography-Mass Spectrometry (HS- GC-MS) analyses of saffron. Moreover, the EC50 of safranal was evaluated as 1.2 MUg/L (ppb). This is the first report on allelopathic activity of safranal as a bioactive compound identified from saffron. PMID- 26058157 TI - The biosynthetic activities of primary and secondary metabolites in suspension cultures of Aquilaria microcarpa. AB - Two types of suspension-cultured Aquilaria microcarpa cells, friable and aggregated, were selectively generated. The biosynthetic activities of primary and secondary metabolites in target cells were detected using laser scanning microscopy (LSM) imaging with diphenylboric acid 2-amino ethyl ester (DPBA) and 9 diethylamino-5H-benzo[alpha]phenoxazine-5-one (Nile red) staining. Scanned friable cells produced weakly fluorescent images revealing low productivity of metabolites. On the other hand, scanning of aggregated cells produced clear fluorescent images depicting the accumulations of flavonoids and lipids. Furthermore, abundant deposition of an unknown resinous compound in extracellular portion of aggregated cells could be visualized. The resinous compound was white to whitish-gray in color and highly sedimented in the medium. Based on these observations, we focused our investigation of metabolite productivity on aggregated suspension cells. Some prominent extracellular compounds were detected in the used liquid medium, as well as in the resinous residue within the medium. The characteristics of these metabolites were investigated in detail via gas chromatography-mass spectrometry (GC-MS) analysis. PMID- 26058158 TI - A stepwise protocol for induction and selection of prominent coniferous cell cultures for the production of beta-thujaplicin. AB - In order to demonstrate the potential of plant cell culture systems to produce a target natural bioactive compound, we proposed a stepwise protocol for beta thujaplicin production as follows. 1. Induction phase: Characteristics of callus cultures originating from newly flushed shoots of 10 conifer species were evaluated on different basal media such as Murashige and Skoog (MS), Schenk and Hildebrandt (SH), and Lloyd and McCown's Woody Plant medium (WP) containing 10 MUM 2,4-dichlorophenoxyacetic acid (2,4-D) either alone or in combination with 1 MUM of N6-benzyladenine (BA). The conifer species used were as follows: Chamaecyparis (C. obtusa Sieb. et Zucc. and C. pisifera Sieb. et Zucc.), Juniperus (J. chinensis L. 'Kaizuka', J. chinensis L. var. sargentii, and J. conferta Parlatore), Thuja (T. occidentalis L. and T. standishii (Gord.) Carr.), Thujopsis (T. dolabrata Sieb. et Zucc. and T. dolabrata Sieb. et Zucc. var. hondae), and Cryptomeria (C. japonica D. Don). We observed the phenotypes of each callus to determine the optimal conditions for callus induction and to infer biosynthetic activity of the calli over 4-8 weeks. 2. Habituation phase: Each of the cell cultures obtained was transferred to a modified MS medium containing 680 mg L(-1) KH2PO4 and 10 MUM Picloram to select the habituated cells with synchronous growth pattern. The growth of each cell culture was highly improved in the habituation medium, except that of J. chinensis 'Kaizuka'. 3. Metabolite production phase: The concentration of beta-thujaplicin (known as hinokitiol in Japan) in the shoots of donor trees and the habituated cell cultures was analyzed via high-performance liquid chromatography (HPLC). Histochemical characteristics of the cells were also observed using laser scanning microscopy (LSM) imaging. After the third step, we tested the biosynthetic activity of two habituated calli (C. obtusa and J. conferta) on a 0.3%, w/v, yeast extract (YE)-containing medium. We found significant improvement in beta-thujaplicin production in J. conferta callus (4600 MUg g DW-1), which was up to 20-fold higher than in the habituation phase. PMID- 26058159 TI - Low caffeine content in novel grafted tea with Camellia sinensis as scions and Camellia oleifera as stocks. AB - Caffeine, a purine alkaloid, is a major secondary metabolite in tea leaves. The demand for low caffeine tea is increasing in recent years, especially for health reasons. We report a novel grafted tea material with low caffeine content. The grafted tea plant had Camellia sinensis as scions and C. oleifera as stocks. The content of purine alkaloids was determined in the leaves of one-year-old grafted tea plants by HPLC. We also characterized caffeine synthase (CS), a key enzyme involved in caffeine biosynthesis in tea plants, at the expression level. The expression patterns of CS were examined in grafted and control leaves by Western blot, using a self-prepared polyclonal antibody with high specificity and sensitivity. The expression of related genes (TCS1, tea caffeine synthase gene, GenBank accession No. AB031280; sAMS, SAM synthetase gene, AJ277206; TIDH, IMP dehydrogenase gene, EU106658) in the caffeine biosynthetic pathway was investigated by qRT-PCR. HPLC showed that the caffeine content was only 38% as compared with the non-grafted tea leaves. Immunoblotting analysis showed that CS protein decreased by half in the leaves of grafted tea plants. qRT-PCR revealed no significant changes in the expression of two genes in the upstream pathway (sAMS and TIDH), while the expression of TCS1 was greatly decreased (50%). Taken together, these data revealed that the low caffeine content in the grafted tea leaves is due to low TCS1 expression and CS protein accumulation. PMID- 26058160 TI - Revisiting caffeine biosynthesis--speculations about the proximate source of its purine ring. AB - The prevailing hypothesis of caffeine biosynthesis starting from xanthosine was combined with Kremers' speculation on NAD as a biochemical precursor of caffeine and trigonelline in coffee. This bold sketch together with a few free-spirited ideas may channel future caffeine biosynthesis studies into novel directions. PMID- 26058161 TI - Biosynthesis of caffeine underlying the diversity of motif B' methyltransferase. AB - Caffeine (1,3,7-trimethylxanthine) and theobromine (3,7-dimethylxanthine) are well-known purine alkaloids in Camellia, Coffea, Cola, Paullinia, Ilex, and Theobroma spp. The caffeine biosynthetic pathway depends on the substrate specificity of N-methyltransferases, which are members of the motif B' methyl transferase family. The caffeine biosynthetic pathways in purine alkaloid containing plants might have evolved in parallel with one another, consistent with different catalytic properties of the enzymes involved in these pathways. PMID- 26058162 TI - Occurrence, biosynthesis and metabolism of theanine (gamma-glutamyl-L-ethylamide) in plants: a comprehensive review. AB - Theanine (gamma-glutamyl-L-ethylamide) is the most abundant non-protein amino acid in tea leaves. In addition to Camellia sinensis, theanine occurs in several plants belonging to the Ericales. Biosynthesis of theanine from glutamic acid and ethylamine by theanine synthetase is present in all organs of tea seedlings, but roots are the major site of theanine biosynthesis in adult tea trees. Theanine is transported from roots to young leaves via the xylem sap. Theanine is hydrolysed to glutamic acid and ethylamine in leaves. Ethylamine produced from theanine is predominantly used for catechin biosynthesis. Concentration of ammonia and light intensity influence the biosynthesis and degradation of theanine, respectively. Biosynthesis, translocation and degradation of theanine and related enzymes and genes are reviewed. PMID- 26058163 TI - Involvement of allelopathy in the formation of monospecific colonies of ferns. AB - Some fern species often dominate plant communities by forming large monospecific colonies. However, the potential mechanism for this domination of the ferns remains obscure. Many plants secrete a wide range of compounds into the rhizosphere and change the chemical and physical properties of the rhizosphere soil. Through the secretion of compounds, such as allelopathic substances, plants inhibit the germination and growth of neighboring plants to compete more effectively for the resources. Ferns contain a variety of secondary metabolites and some of those compounds are released from the ferns into the rhizosphere soil, either as exudates from living ferns or by decomposition of fern residues in sufficient quantities to affect the germination and growth of neighboring plants as allelopathic substances. Therefore, allelopathic chemical interaction of the ferns with neighboring plants may play an important role in the formation of the monospecific colonies of the ferns. PMID- 26058164 TI - Plant cell, tissue and organ culture: the most flexible foundations for plant metabolic engineering applications. AB - Significant advances in plant cell, tissue and organ culture (PCTOC) have been made in the last five decades. PCTOC is now thought to be the underlying technique for understanding general or specific biological functions of the plant kingdom, and it is one of the most flexible foundations for morphological, physiological and molecular biological applications of plants. Furthermore, the recent advances in the field of information technology (IT) have enabled access to a large amount of information regarding all aspects of plant biology. For example, sequencing information is stored in mega repositories such as the National Center for Biotechnology Information (NCBI), which can be easily accessed by researchers worldwide. To date, the PCTOC and IT combination strategy for regulation of target plant metabolism and the utilization of bioactive plant metabolites for commercial purposes is essential. In this review, the advantages and the limitations of these methodologies, especially regarding the production of bioactive plant secondary metabolites and metabolic engineering in target plants are discussed mainly from the phenotypic view point. PMID- 26058165 TI - [Editorial]. PMID- 26058166 TI - [Socio-economic and psycho-affective factors and their influence on academic performance of residents in Obstetrics and Gynecology]. AB - BACKGROUND: Academic performance is the mean objective of the teaching-learning process, but there are many other variables or factors outside the OB/GYN resident involved in this process, such as those related to the environment in which they operate, teachers, interaction with their peers, family, society, and many other factors contained individually, such as learning styles, motivation, study habits, personality traits, among others. OBJECTIVE: Identify which are the main socio-economic and psycho-affective factors that influence on academic performance of residents in Obstetrics and Gynecology. MATERIAL AND METHODS: Observational, cross-sectional quantitative, correlational and non-experimental study in Obstetrics and Gynecology residents of a public general hospital tertiary care. A type survey to obtain data and deepen personal and socioeconomic status of each resident instrument was designed. RESULTS: Females predominated with 15 cases and only 5 were male. Sixteen of medical residents claimed that having a good habit of sleep helps improve their academic performance and their performance in academic and healthcare activities. Fifteen felt that work much better with peers of the opposite sex. Ten felt that developing a type of self directed learning contributes greatly to improve their performance and 19 felt that having a mentor during residency contributes to improve their academic performance. Fifteen reported being victim of abuse or discrimination from their peers. Sixteen claimed to have been very sad or depressed at some point during residency. Eight consumed alcohol and seven used tobacco to relax. PMID- 26058167 TI - [Vaginal hysterectomy for the enlarged non-prolapse uterus using morcellation techniques and/or Deschamps needle: a retrospective cohort study]. AB - OBJECTIVE: To compare surgical outcomes in women who underwent vaginal hysterectomy with enlarged (> 12 weeks size) and non-prolapsed uterus utilizing different morcellation techniques with or without concomitant Deschamps needle use to vaginal hysterectomy for prolapsed uterus. MATERIAL AND METHODS: Retrospective cohort study in women who underwent vaginal hysterectomy performed between January 2009 and June 2014 in the National Institute of Perinatology. The study group comprised 48 women who had vaginal hysterectomy with enlarged and non prolapsed uterus in which were utilized different morcellation techniques with or without concomitant Deschamps needle use and 50 women who had vaginal hysterectomy for prolapsed uterus served as control. RESULTS: The groups had statistical difference in age, number of cesarean sections, body mass index (BMI), grade of prolapse (Point Cx and D with POPQ quantification system) and surgical prediagnosis (p < 0.001); mean uterus weight was 182.5 g and 106 g, respectively (p < 0.001), as well as for transverse and antero-posterior dimensions and realization of morcellation with or without use of Deschamps needle. Both groups had no statistical difference in preoperative hemoglobin, concomitant surgeries for incontinence and prolapsed, estimated blood loss, operation time, length of stay and complications. CONCLUSION: Vaginal hysterectomy utilizing different morcellation techniques with or without concomitant Deschamps needle use in women with enlarged and non-prolapsed uterus is safe, effective, and with similar complications to vaginal hysterectomies in prolapse uterus. PMID- 26058168 TI - [Assessment of progesterone levels on the day of the hCG administration as a predictor of success of antagonist stimulation protocols for IVF]. AB - BACKGROUND: There are reports of deleterious effect when progesterone concentration is high during the follicular phase in cycles of in vitro fertilization. In our environment has not carried out a study to evaluate the pregnancy rate compared with progesterone concentration on the day of application of hCG. OBJECTIVE: To evaluate the pregnancy rate and outcome of in vitro fertilization cycle according to serum progesterone concentration on the day of application of hCG. MATERIAL AND METHODS: A retrospective, observational, cross sectional study of 486 cycles of in vitro fertilization was done in the Centro Mexicano de Fertilidad of CEPAM (Hospital Angeles de las Lomas) from January 2009 to February 2014. We included all cases where it was used a stimulation protocol GnRH antagonist flexible scheme. RESULTS: When levels of progesterone are high, those of estradiol are also high and the number of retrieved oocytes and oocyte quality are lower. There was no difference in the percentage of fertilization, but at higher concentration of progesterone lower percentage of embryonic segmentation. Difference was recorded in the pregnancy rate only when progesterone concentration on the day of hCG application was > 4 ng/mL. CONCLUSION: Pregnancy rate decreases when the concentration of progesterone on the day of hCG application is >= 4 ng/mL. PMID- 26058169 TI - [The burden of cervical cancer in patients with limited access to health services]. AB - BACKGROUND: Cervical cancer is caused by high-risk HPV, a sexually transmitted virus. In Mexico, this disease represents a public health problem. San Luis Potosi is located within ten states with the highest rates in the country. Indigenous women of Mexico will likely to develop cervical cancer due to inequality in access to health services and their determinants. Epidemiological studies can be supported by investigations of diverse geographical nature to undertake the identification and analysis of spatial patterns of disease. OBJECTIVE: To locate by geographical distribution of Huasteca Potosina women high risk HPV positive to observe the burden of disease in patients with limited access to health services and propose specific primary prevention activities was made with a sample of 605 women. Cervico-vaginal specimens were taken. High-risk HPV infection was determined by hybrid capture. Age and date of the last Papanicolaou were obtained through a structured poll. It was use descriptive statistics and georeference was made in a map using the software ILWIS 3.3. RESULTS: Countyes with the highest and lowest percentages of infection were found. The prevalence of infection with high-risk HPV was 9.9% and age groups with the highest percentages of infection were in 51-60 and 41-50 years. Most women had been made the Papanicolaou at time of the present study. CONCLUSIONS: Georeferenceas like epidemiological tool for generating risk profiles allowed suggest strategies for improve prevention, early detection and control of the cervical cancer. PMID- 26058170 TI - [Burnout syndrome in medical and obstetric perception of violence]. AB - BACKGROUND: Obstetric violence involves a violation of reproductive rights of women during pregnancy, childbirth and postpartum. It has been associated with lack of empathy and emotional discomfort of physicians. OBJECTIVE: To identify the perceptions of obstetric violence and to determine the possible relationship with burnout syndrome. MATERIAL AND METHODS: We evaluated 29 physicians whose scope of work relates to obstetrics and gynecology. The evaluation instruments were: a) questionnaire on professional perception that collects demographic information, situations of perceived obstetric violence, major concerns of physicians in their professional work, and includes an scale about level of job satisfaction, b) the Maslach Burnout inventory, and c) Jefferson Scale of Physician Empathy. RESULTS: The most prevalent obstetric violence situations perceived were: medical malpractice and harmful practices (10/29), discrimination (10/29), rude treatment and verbal attacks (11/29). Seventeen participants reported lack of information on obstetric violence and not have tools to cope with this problem. Regarding the burnout syndrome, it was associated with several items of the scale of empathy and with the scale of job satisfaction. CONCLUSIONS: This study shows the importance of providing knowledge and tools to deal with obstetric violence and stress management to prevent such situations on medical practices. PMID- 26058171 TI - [Vulvar pruritus: determination of the most common causes and their treatments]. AB - Vulvar pruritus can be caused by a wide spectrum of diseases, that depend on age, environmental and genetic factors. The most common causes are candidiasis, contact dermatitis and lichen simplex chronicus. Candidiasis is the most common cause of acute vulvar pruritus and is characterized by burning, itching and vaginal whitish secretion. Contact dermatitis is caused by irritants or allergens that are in contact with the genital area, which causes imbalance in the skin barrier causing irritation, swelling, burning, among other manifestations. Lichen simplex chronicus is characterized by lichenification (thickening of the skin) secondary to the chronic itch-scratch cycle in vulvar area. It is an illnes with a tendency to chronicity, but with topical corticosteroids treatment usually might be controlled. Prompt treatment, multidisciplinary and careful attention to irritants and secondary infections prevent these entities become an important and permanent problem. PMID- 26058172 TI - [Metastatic choriocarcinoma associated with Wunderlich syndrome: case report and literature review]. AB - Choriocarcinoma is a rare condition, with an incidence of 1 in 30 to 40,000 pregnancies in the United States and Europe. In Mexico it is reported in 1 in 10,000 pregnancies. Wunderlich syndrome is a spontaneous perirenal hematoma, a very rare entity. This paper reports the case of a young patient with a history of molar pregnancy one year prior to admission, valuation due to fainting, generalized headache, spontaneous pain in the right flank and data of hypovolemic shock. Computed tomography reported right perirenal hematoma, normal uterus, two annexes with data of tecaluteinic cysts, beta human chorionic gonadotropin greater than 200,000 IU/mL. Patient was stabilized with crystalloid, blood products and right adrenal artery embolization. It was corroborated the brain, mediastinum and abdomen metastases. She was sent to a third level hospital, starting holocraneal radiotherapy, she had retroperitoneal bleeding and died a week later. PMID- 26058173 TI - [Uterine prolapse and pregnancy. A case report]. AB - Uterine prolapse associated with pregnancy is rare today. The case of a 34-year old woman whose pregnancy ended at 39 weeks and analyzed with those reported in the literature is presented. PMID- 26058175 TI - [The happiness of travel]. PMID- 26058174 TI - [Mayer-Rokitansky-Kuster-Hauser syndrome: two cases report]. AB - Agenesia of the Mullerian ducts is a low-frequency congenital disease but with devastating effects on women's reproductive health. In this paper we present two cases of women affected by Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH). First case was a 17-year-old woman with aplasia of the upper vagina and absence of uterus. No other defects were found and was classified as type 1-MRKH. Second case was 18-year-old woman with absence of uterus, escoliosis and polycystic ovary syndrome, classified as type II-MRKH. Patients were seen at the Hospital with primary amenorrhea and fully developed secondary sexual characteristics. A clinical follow-up protocol, including the use of high-resolution image studies was used for diagnosis. Diagnostic procedures and current medical approaches to the treatment of MRKH are discussed, including psychological advisory, surgical procedures and new tissue-engineering techniques. PMID- 26058176 TI - [New oral anticoagulants do not demonstrate equivalent effectiveness]. PMID- 26058177 TI - [Why is nutritional information necessary on food labels?]. PMID- 26058178 TI - [The use of hypnosis in healthcare]. AB - Hypnosis has proved successful in a variety of clinical situations such as alleviation of acute or chronic pain and other chronic debilitating conditions (asthma-eczema). Many psychotherapists utilize imagery to facilitate the process of change, treating depression with hypnosis and integrating patient centered strategic approaches (challenge efficacy of psychotherapy). This article focuses on delivering of hypnotic interventions for pain and will provide a very short overview of core issues in the development of the cognitive neuroscience of hypnosis and conscious state. PMID- 26058179 TI - [Air embolism during an interventional radiography procedure]. PMID- 26058180 TI - [Neuroendocrine well-differentiated pancreatic tumors]. AB - Neuroendocrine pancreatic tumors are rare tumors which require specific diagnosis and management. They are characterized by complex histopathologic criteria, large differences in secretory profile and evolutivity, and be associated to hereditary endocrine disease as NEM1 or VHL. Therapeutic strategy is currently discussed throught the regional or national pluridisciplinary workups organized by the 17 experts centers of the French RENATEN network. Treatment of these tumors requires the optimal control of hormonal secretory features for functioning neuroendocrine tumors while antiproliferative treatments are indicated for metastatic large or/and progressive tumors. Their optimal treatment may include locoregional procedures as chemoembolization, radiopeptide therapy, chemotherapy, targeted therapies and clinical trials. PMID- 26058181 TI - [Genetic ocular diseases]. AB - Genetic ocular diseases are inherited Mendelian conditions (prevalence 1/1000) in which any tissue of the eye could be involved (cornea, lens, iridocomeal angle, vitrous, retina, choroid, sclera). More than 200 genes are responsible for inherited retinal dystrophies and even more genes remain to be identified. These genes belong to many metabolisms essential to the photoreceptor function. Gene therapy and retinal prosthesis are the two most promising therapeutic strategies currently in clinical trials which are expected to provide visual improvement in short term. PMID- 26058182 TI - [Pyogenic granuloma]. PMID- 26058183 TI - [Combination of granulocyte colony-stimulating factor and erythropoietin in decompensated cirrhosis: a positive essay?]. PMID- 26058184 TI - [In choosing an antihypertensive, the body mass index is not too important]. PMID- 26058185 TI - [Adapting the dose to the residual concentration of infliximab in cryptogenic inflammatory diseases of the intestines]. PMID- 26058187 TI - [Drugs that make gain weight or make lose weight]. PMID- 26058188 TI - [Travel medicine: a case-by-case risk and benefit analysis for the traveler]. PMID- 26058189 TI - [Current immunizations for travelers]. AB - The recommendations on travelers' immunizations are regularly evolving in accordance with the data of clinical studies and the epidemiological situation in the world. The recent changes concern the schedule of injections: primovaccination DTCaPolio of children and boosters for adults, accelerated schedule of Japanese encephalitis and hepatitis B immunization, preexposure rabies immunization and vaccination against yellow fever; and the indications of poliomyelitis vaccine, immunization of children against Japanese encephalitis and conjugated vaccines against meningococcal meningitis. PMID- 26058190 TI - [Malaria chemoprophylaxis: towards a European harmonization]. AB - Multi-facetted control efforts against malaria in endemic areas have led in the last decade to a sizeable decrease in its prevalence and incidence in almost all tropical regions. A parallel decline of the number of malaria cases in returning travelers is being observed, even if this trend is not so spectacular after a stay in West or Central Africa. This fast evolution should question the need of systematic chemoprophylaxis for all short-term travelers going to the tropics, in particular to very low risk areas of Southern Asia or Latin America. Surprisingly both North American and European guidelines diverge substantially regarding the indications of chemoprophylaxis according to the geographic risk, with more or less liberal recommendations, often not strongly supported. A neutral comparison between the low risk of contracting a potentially severe (P. falciparum) malaria in most Asian or Latin American regions with the very limited but "uncompressible" risk of severe drug toxicity should lead to a decrease in unnecessary prescriptions based on erroneous feelings rather than robust evidence. An harmonization of the European recommendations is highly desirable for this mobile and informed population. Intermediate or alternative preventive strategies should be also be explored. PMID- 26058191 TI - [Management of febrile illness in the traveler returning from the tropics]. AB - Fever in the traveler returning from the tropics is a common clinical situation in primary care or emergency. The first priority of clinicians should be to eliminate severe infectious diseases whose treatment is urgent, the first of which is still malaria due to P. falciparum. In a second step, after the emergency diagnosis eliminated, geographic updated epidemiological context must be taken into account to consider some other diagnosis. Finally, risk factors and patient's clinical characteristics should be analyzed. The diagnostic approach that we propose should enable any clinician to perform the first steps of the management of fever in the traveler returning from the tropics. PMID- 26058192 TI - [Diagnosing and treating malaria]. PMID- 26058193 TI - [Management of skin lesions in returning travelers]. AB - Dermatoses in returning travellers are common. These dermatoses are mainly infectious, the most common being bacterial infections of cosmopolitan origin (cellulitis, pyoderma and abcess). Others dermatoses are environmental diseases such as sunburns, arthropod-related reactions and superficial injuries. The most common tropical skin disease is hookworm-related cutaneous larva migrans but treating physicians may also face patients with localized cutaneous leishmaniasis, tungiasis, or myiasis. Also some systemic infections can be associated with skin manifestations. The most useful treatments in this setting are oral antihistamines, topical steroids, antibiotics effective against bacterial skin infection, booster for tetanus immunization, and rabies vaccination in case of animal exposure. PMID- 26058194 TI - [Management of traveler's diarrhea]. AB - Traveler's diarrhea is very common, cosmopolitan, and usually benign. However, it can lead to significant complications because of underlying conditions (very young or elderly travelers, immunodeficiency...) or professionnal reasons (politicians, artists...). Prevention is based primarily on hygiene standard, chemoprophylaxis should be reserved for special situations. Although traveler's diarrhea is most often of bacterial origin, rehydration is the mainstay of its management. PMID- 26058195 TI - [Can we prevent traveler's diarrhea?]. PMID- 26058196 TI - [Risks of psychiatric decompensation in travel]. AB - In the general consideration of travel-related illnesses, not much attention is given to mental health, while a significant proportion is due to psychiatric problems. Any trip is a source of stress that may trigger or worsen mental disorders ranging from culture shock to a pathogenic trip via the classic pathological trip: for a tourist seeking exotic adventure, young people in initiatory journey, an expatriate, a political refugee or an immigrant in search of better economic conditions, any traveler may stumble upon the traces of his own family history or of his home culture fantasy, and show symptoms at some stage along his path of psychological disorders. Indeed every culture identify appointed destinations where its members are seemingly more likely to falter: the roads to the east or the search for paradise lost for westerners (the Florence syndrome, the India syndrome or the island syndrome), those of the West (the Japanese in Paris syndrome), or places rich with mystical associations: Mecca for Muslims, Benares for Hindis, Jerusalem for the monotheistic religions. A return to the home country is mostly a necessary requirement for the subject to regain a footing in his culture. PMID- 26058197 TI - [Travel at high altitude]. PMID- 26058198 TI - [Best air travel]. PMID- 26058199 TI - [Travel and accidents]. AB - Traumatic pathologies are the most frequent medical events to be observed among French travellers. Accidents on the public highway by lack of respect of the fundamental rules of road security, particularly abroad, traffic conditions in bad repair in numerous emergent countries, usually the destination of mass tourism and underdeveloped organization of health care and local urgency help. Sports activities are also a source of accidents. A good physical training is essential. Drowning is a real plague, especially among children due to a lack of vigilance. Preventive measures are simple, keep them constantly in mind and apply them carefully so as to have beautiful memories of our trip back home. PMID- 26058200 TI - [What does travel insurance cover in case of accident or illness abroad?]. PMID- 26058201 TI - [Is it necessary to screen migrants?]. PMID- 26058202 TI - [Travelers with underlying medical conditions]. AB - Travelers with pre-existing medical disease are at risk of exacerbation of their underlying disease during their journey but are also more susceptible to various infectious agents, which consequences could be much more severe than in healthy subjects. Prevention and education are primordial in order to optimize the trip. Each new prescription should be checked for potential drug/drug interactions. Malaria chemoprophylaxis should be considered if applicable, as well as mechanical protection against insect-bites. Vaccinations should be recommended after weighting risks and benefits, keeping in mind that live-attenuated vaccines are not recommended in case of cellular immune suppression. Prevention of travel- related diarrhea by general hygiene measures is of particular interest in this population. Thereafter, we are discussing specific preventive measure according to different medical conditions. PMID- 26058203 TI - [Highly transmissible diseases]. PMID- 26058204 TI - [A multi-professional protocol it is ... and it is not]. PMID- 26058205 TI - [Protocols and new methods of payment]. PMID- 26058206 TI - [Diagnostic strategy in the face of a coagulation abnormality]. PMID- 26058207 TI - [Etiologic factors of adolescent behavioral disorders]. PMID- 26058208 TI - [Adolescent behavioral disorders]. PMID- 26058209 TI - [Hemorrhagic syndrome with hematologic origin]. PMID- 26058210 TI - [Superficial lymph nodes of the child]. PMID- 26058211 TI - [Leg ulcer]. PMID- 26058212 TI - [Peripheral neuropathies]. PMID- 26058213 TI - [Hemoptysis]. PMID- 26058215 TI - Closing thoughts and the road forward. PMID- 26058214 TI - [From what did we suffer? What did we complain about in the Middle Ages?]. PMID- 26058216 TI - The effect of follow-up inspections on critical violations identified during restaurant inspections. AB - Follow-up inspections are recommended by the Food and Drug Administration as a tool to verify corrections to violations cited during restaurant inspections. The effectiveness of follow-up inspections as a tool in reducing critical violations is unknown, however. The purpose of the authors' study was to assess whether a serious violation that leads to a follow-up inspection reduces the probability of specific critical violations occurring during the next routine inspection. Outcome measures included poor personal hygiene, improper holding temperatures, substandard equipment cleanliness, potential cross contamination, and improper sanitizer concentration. The risk of having a violation increased for all targeted critical violations during inspections conducted after a follow-up inspection compared to restaurant inspections without a prior follow-up, when adjusting for restaurant type, inspector experience, and season. PMID- 26058217 TI - Change in childhood lead exposure prevalence with new reference level. AB - In 2012, the Centers for Disease Control and Prevention changed the "actionable" reference blood lead level from 10 MUg/dL to 5 MUg/dL, representing the highest 2.5 percentile of lead levels nationwide. In a high-risk urban community, the prevalence of children classified as lead exposed increased ninefold, from 1% to 9.1% (p < .0001) with the new reference level. This dramatic increase in the prevalence of children newly classified as lead exposed will require additional health care and public health resources for tracking, surveillance, and home lead abatement. PMID- 26058218 TI - Food safety knowledge and practices of young adults. AB - The objective of the study described in this article was to ascertain the food safety knowledge and practices of undergraduate students attending a major American university. The study participants were undergraduate college students (mean age 18.9 +/- 1.14 SD) enrolled in a required health course. The students were invited to take a validated food safety knowledge questionnaire as part of a health risk behavior online survey. The 786 respondents indicated their food is most often prepared at on-campus dining facilities and the majority of the students (72%) felt they were "unlikely or "very unlikely" at risk of foodborne disease. The mean food safety knowledge score of the participants was 10.23 (43%) +/- 4.13 SD (25%-60%), indicating the study population overall has poor knowledge of safe food practices. As a result, food safety educational initiatives and awareness campaigns should be developed to better inform young adults about safe food handling practices and habits. PMID- 26058219 TI - An evaluation of southeastern Ontario recreational water quality. AB - Fecal contamination in recreational waters causes adverse health outcomes in humans; yet, surprisingly, a paucity of literature addresses recreational water quality in North America. The authors addressed this gap by evaluating E. coli contamination of southeastern Ontario, Canada, recreational beach waters between the years 2008-2011. They tested water samples for microbial contamination by the membrane filtration method. They used Friedman's and repeated measures analyses of variance and descriptive statistics to assess annual and monthly E. coli levels as well as noncompliance to the Ontario bathing beach standard. Seven waters showed high noncompliance to the Ontario standard, which could negatively affect the health of local recreational beach users. The authors' study provides much needed baseline information on beach water quality. They call for greater recreational water sampling and reporting standardization across North American jurisdictions. PMID- 26058220 TI - Internet of things builds capacity for automatic temperature logging. PMID- 26058221 TI - Are schools safe from indoor radon? PMID- 26058222 TI - Environmental health professionals work the bugs out--school integrated pest management. PMID- 26058223 TI - A top ten for dental research publications. PMID- 26058224 TI - Pain. Part 1: Introduction to pain. AB - This series of papers aims to provide the dental and medical teams with an update in pain, both acute and chronic orofacial conditions, relevant to dentistry and medicine. Pain is the most common symptom for patients presenting to their dentist, and is increasingly commonly presenting to doctors as well, in general practice and A & E departments. Most of the dental team take for granted their knowledge and ability to manage acute dental pain. However, the education and preparation in managing patients with chronic pain conditions remains poor in many medical and dental schools. Conversely, medics are better educated and exposed to chronic pain during their undergraduate education, however, with regards to orofacial pain education, exposure is diminishing due to decreased exposure to dentistry, ENT, otolaryngology, OMFS and oral surgery. Thus many clinical teams remain disadvantaged when diagnosing and managing orofacial pain. Clinical Relevance: Significant advances that have been made in understanding the pain mechanisms are not to be overlooked and have a huge impact on how we manage patients in pain. PMID- 26058225 TI - The value of cone beam CT in assessing and managing a dilated odontome of a maxillary canine. AB - A case of an unusual anomaly in a maxillary canine is described. A deep enamel invagination resulted in pulpal necrosis, longstanding infection and development of an associated radicular cyst. Diagnostic X-ray imaging was invaluable in demonstrating the complex root anatomy of the dilated odontome. In particular, a cone beam CT scan helped in the formulation of an appropriate treatment plan. Clinical Relevance: Three-dimensional imaging using cone beam CT was valuable in this case to demonstrate the complicated anatomy of a rare dental anomaly, and to help plan treatment. PMID- 26058226 TI - Emergencies in orthodontics. Part 1: Management of general orthodontic problems as well as common problems with fixed appliances. AB - Fixed appliance treatment is a popular treatment modality with a burgeoning increase in the numbers of children and adults realizing the benefits that can be gained. Appliance breakage is an unavoidable nuisance which is at best inconvenient, and at worst may result in significant pain or discomfort for the patient. General dental practitioners (GDPs) should have the practical knowledge of how to provide timely and appropriate orthodontic 'emergency treatment'. This will significantly reduce the sometimes considerable inconvenience and discomfort for both the patient and his/her parents, and the inevitable frustration for the clinician providing ongoing care. This first paper will deal with general orthodontic problems that commonly present, as well as some issues specific to fixed appliances. The second paper will deal with the other orthodontic appliances that may be encountered by GDPs in their daily practice. Clinical Relevance: Appropriate handling of an orthodontic 'emergency' by the general practitioner will, on many occasions, provide immediate relief of pain and distress for the patient. This will in turn allow treatment to continue moving in the right direction, thus allowing more efficient and effective use of valuable resources. PMID- 26058227 TI - Case report: transpalatal arch resulting in soft tissue damage of the tongue 3 years post-orthodontic treatment. AB - Whilst transient effects of orthodontic appliances on the oral mucosa are well recognized, chronic lesions, persisting post therapy are unusual. We describe a persistent lingual mucosal defect related to a transpalatal arch (TPA) in a healthy 19-year-old female. The asymptomatic lesion is presently being monitored, however, surgical revision in the future may be requested by the patient if the area fails to remodel. Clinical Relevance: Soft tissue trauma to the tongue by anchorage reinforcing appliances may result in long-term effects that could require surgical management. PMID- 26058228 TI - An update on crown lengthening. Part 1: Gingival tissue excess. AB - This is the first article in a two-part series which aims to provide an overview of the different techniques used to increase clinical crown height. In the first paper, the focus will be on the management of patients who present with gingival tissue excess. The different aetiologies are discussed and illustrated with clinical cases, following which a range of procedures that may be employed in the management of these patients are presented. With an increasingly ageing population, more patients are taking regular medications prescribed from their general medical practitioner, and so having a working knowledge of the specific drugs that may cause gingival enlargement is essential. Clinical Relevance: When patients with gingival tissue excess present in primary or secondary care, a clinician must have a good knowledge of the possible causes of the condition, as well as an idea of how the patient may be managed. PMID- 26058229 TI - Why, what and how: caries control for erupting molars. AB - This article aims to update the practitioner on the various techniques and interventions available to prevent or control caries during this high-risk period. The evidence to support provision of toothbrushing advice, placement of fissure sealants and fluoride varnish application is considered, along with more novel methods. An evidence-based protocol is suggested to help the practitioner determine when further intervention is required and what action to undertake. Clinical Relevance: This article aims to reinforce the need for rigorous caries prevention in an erupting permanent molar and provides an update on the evidence behind a range of clinical techniques used for this purpose. PMID- 26058230 TI - Is oral health a risk factor for sexual health? AB - New evidence suggests that the extent and severity of periodontal disease may be a significant risk factor for erectile dysfunction, sperm motility and time to conception. This paper reviews the evidence and informs members of the dental team when dealing with this sensitive issue. As more research is forthcoming the topic of oral and sexual health is likely to be part of regular routine medical screening. Any issue concerning oral health as a risk factor for sexual health is likely to be a sensitive subject, rarely discussed in the dental setting. However, as new evidence emerges, this topic is likely to get into the public domain. All members of the dental team should be aware of such an association. Clinical Relevance: Furthermore, the information in this paper may provide further incentive for certain patients to improve their oral health. PMID- 26058231 TI - Peri-implant diseases: an overview. AB - The use of dental implants in replacing missing teeth is proven to be a valid treatment with a high success rate. To achieve the best treatment outcome in all implant systems, the implant has to be able to integrate with the surrounding tissue. However, dental implants are affected by peri-implant diseases and may fail as a result. As the number of implants placed continues to increase, the prevalence of peri-implant disease will also increase. This requires preventive measures to inhibit the development of the disease and stop its progression. Clinical Relevance: Understanding how to maintain healthy peri-implant tissue as well as diagnosis and treatment of disease are vital for every dentist and dental student. PMID- 26058232 TI - A review of communication models and frameworks in a healthcare context. AB - This paper reviews six key communication models and frameworks in healthcare contexts. Comparison suggests key inter-relationships between the different stages of the clinical consultations. Implications are identified for future study in healthcare provider-patient communication. Clinical Relevance: To understand the healthcare provider-patient interaction through communication models. PMID- 26058233 TI - Clinical Challenges Q&A. 8. Lumps under tongue. PMID- 26058234 TI - Technique tips--the ABC of the ESIPC jig: the 'elegantly simple incisal platform, customized' (ESIPC) jig for capturing/recording centric relation. PMID- 26058235 TI - Implant stability comparison of immediate and delayed maxillary implant placement by use of resonance frequency analysis--a clinical study. AB - The purpose of this study was to objectively evaluate the stability of dental implants by use of resonance frequency analysis (RFA). In this study, 60 Nobel Replace Tapered Groovy implants were placed in the premolar region of the maxilla in 60 patients. Thirty implants were placed immediately after tooth extraction and 30 implants were placed in healed bone sites. Implant stability quotient (ISQ) was obtained by use of the Osstell Mentor device and was recorded at the time of implant placement (T1) and 20 weeks after placement, at the time of implant loading (T2). All implants were not functionally loaded during the follow up period. Data were analyzed using simple linear regression. No implant failures were reported in the 6-month follow up period. The mean ISQvalue for immediate implant placement was 61.43 at T1 and 66.23 at T2. The implants placed in healed bone showed higher ISQvalues compared to the immediately placed implants (mean ISQvalue was 64.17 at T1 and 68.83 at T2). Differences in the mean ISQ values were statistically significant (p < 0.001). After the completed period of osseointegration, the mean ISQ value was 4.8 for immediately placed implants compared to 4.67 for implants placed in delayed sites. PMID- 26058236 TI - Perinatal epidemiological risk factors for preeclampsia. AB - In the present study, the impact of the potential perinatal epidemiological factors on preeclampsia development was assessed. This clinical study included 55 pregnant women with preeclampsia and control group of 50 healthy pregnant women. Positive family history of cardiovascular disease, diabetes mellitus or thromboembolic disease was recorded in 50% of women with preeclampsia versus 28% of control group women. Positive personal history of this disease was recorded in 15% of women with preeclampsia, whereas all control group women had negative personal history of preeclampsia. Dietary habits, i.e. the intake of meat and meat products, fruit and vegetables, coffee and alcohol drinks were similar in the two groups, without statistically significant differences. The women with preeclampsia and control women reported comparable habits; there was no difference in the consumption of meat, fruit, vegetables, coffee and alcohol, smoking, use of folate and oral hormonal contraception before pregnancy, or in physical activity as the potential risk factors for preeclampsia in current pregnancy. However, personal and family history of vascular disease proved to be significant risk factors for the occurrence of preeclampsia, emphasizing the need of lifestyle and dietary modifications with healthy dietary habits, while avoiding adverse habits in pregnancy. PMID- 26058237 TI - The prevalance of epilepsy among college students in Canakkale, Turkey. AB - The aim of this study was to investigate the frequency of epilepsy among students of the Canakkale Onsekiz Mart University. This cross sectional epidemiological study was performed on 4762 of 19,988 Canakkale Onsekiz Mart University students in the academic year 2007-2008. Participants that answered "epilepsy" to the question "Do you have any disease diagnosed by a doctor?" in a questionnaire including 4 subgroups were identified. Data were transferred to the Epi-Info Version 6.0 statistics program and controlled data were analyzed in the SPSS 15.0 statistics program. There were 53.1% of female and 46.9% of male students, mean age 20.4 +/- 2.1 (range 17-43) years. Twelve (0.25%) students had epilepsy diagnosis, eight (66.7%) female and four (33.3%) male, mean age 20.8 +/- 1.8 years. In our study, epilepsy was detected in 0.25% of students (n = 12). Age specific prevalence studies related to epilepsy epidemiology are extremely rare, especially in university students with average intelligence. Thus, we considered that it would be epidemiologically significant to share the results of our cross sectional study with all those involved in epilepsy epidemiology and management. PMID- 26058238 TI - The epidemiology of forearm nerve injuries--a retrospective study. AB - The aim of this study was to investigate the mechanisms and etiologic factors of forearm nerve injuries. This retrospective survey included all patients treated surgically in Clinical Department of Neurosurgery, Clinical Center of Serbia, from January 1, 2000 to December 31, 2010. All relevant data were collected from medical records. Statistical procedures were done using the PASW 18 statistical package. Our study included 104 patients that underwent surgery after forearm nerve injury. The majority of admitted patients were male (n = 84; 80.8%) and only 20 (19.2%) were female. Ulnar nerve injury predominated with 70 cases, followed by median nerve with 54 (51.9%) cases and radial nerve with only 5 cases. Transection was the dominant mechanism of injury and it occurred in 84.6% of cases. Injury by a sharp object was the most frequent etiologic factor and it occurred in 62 (59.6%) patients, while traffic accident and gunshot injuries were the least common etiologic factor of forearm nerve injury, occurring in 7 (6.7%) and 6 (5.8%) cases, respectively. Associated injuries of muscles and tendons, bones and blood vessels occurred in 20 (19.2%), 16 (15.4%) and 15 (14.4%) patients, respectively. The etiology and mechanism of peripheral nerve injury are of great importance when choosing the right course of treatment in each individual patient because timing and type of treatment are closely related to these factors. PMID- 26058239 TI - Prevalence and risk factors for developing oral allergy syndrome in adult patients with seasonal allergic rhinitis. AB - The aim of this study was to assess the prevalence of oral allergy syndrome (OAS) in patients with seasonal allergic rhinitis (SAR) and the possible risk factors for its development. This cross-sectional study was conducted in primary care offices in the Split-Dalmatia County during the period from March 1 to September 30, 2012. Data sources were medical history with confirmation of SAR (positive skin-prick test to seasonal inhalant allergens: grass, tree and weed pollens), anthropometric patient data (age, sex, weight and height), and a questionnaire in which patients evaluated their nasal and ocular symptoms, comorbidities and lifestyle. The chi2-test, Pearson chi2-test, Spearman's rho correlation coefficient and Kolmogorov-Smirnov test were used on statistical analysis. The prevalence of OAS was 45.7%. The risk factors for OAS development were diabetes (p < 0.001), severity of nasal symptoms (p < 0.05) and severity of ocular symptoms (p < 0.001). In conclusion, the prevalence of OAS in the Split-Dalmatia County is very high. The risks factors for OAS in patients with SAR are diabetes and severity of nasal and ocular symptoms. PMID- 26058240 TI - Thyroid cancer incidence and mortality trends in Croatia 1988-2010. AB - The aim of our study was to describe and interpret national trends in thyroid cancer in Croatian men and women during the 1988-2010 period, to better understand the incidence and mortality trends in comparison with other populations, and to determine the proportion of certain histologic subtypes of thyroid cancer and their impact on these trends. Using information from the Croatian National Cancer Registry and WHO Mortality Database, we estimated trends in the age-standardized incidence and mortality rates by joinpoint regression analysis. Thyroid cancer incidence increased in both women and men during the study period, with the estimated annual percent change (EAPC) of 6.4% and 5.5%, with no joinpoints identified. A significant decrease in mortality (EAPC-2.1%) was observed in women, while in men mortality rates decreased nonsignificantly (EAPC-1.3%). A statistically significant incidence increase was observed only for papillary carcinomas with annual incidence increase by 6.7% for women and 7.9% for men. During the study period, thyroid cancer showed an incidence increase in Croatia with persistent and steady decrease in mortality in women and statistically nonsignificant decrease in mortality in men. The increase in papillary carcinomas led to the thyroid cancer incidence increase and also affected the thyroid cancer mortality decrease in women. The trends observed are similar to those in other European countries and require additional analysis to determine all factors that have an effect on them. PMID- 26058241 TI - Effect of motor limitations on the expression of aggressiveness among adolescents. AB - This study examined how motor limitations in terms of reduced possibilities to move influence aggression, starting from the fact that motor skills and movement have an important place in the expression of aggression, as well as the tendency of adolescents to "body language". Adolescent with motor deficit is hindered in gaining experience of one's own body, which is reflected in the formation of complete experience of himself, or constitution of the self. In many of the functions of motor skills and movement aggression has a significant place that we wanted to determine without deeper analysis of whether the origin of aggression is instinctive or it is always just the result of frustration. The sample on which testing was performed consisted of 100 randomly selected subjects of both genders aged 16-18 years. Fifty subjects had motor limitations due to illness or injury, and another fifty subjects had intact motor functions. The study used three instruments: 1) A-87 questionnaire for aggressiveness examination; 2) structured interview; and 3) protocol for observation under natural conditions. Results of the analysis of data obtained in total score, as well as in all five subscales of the A-87 questionnaire for aggressiveness examination showed that the two groups were not significantly different. The results obtained by structured interview showed the adolescents with motor limitations to demonstrate greater verbal aggressiveness, then latent physical aggressiveness. A statistically significant between-group difference was obtained on the factor of self-destructiveness, which implies that adolescents with motor limitations are somewhat more self-destructive compared to those in control group. From the results obtained by the protocol for systematic observation in natural conditions, it was evident that there were significant differences on most of perceptual conducts between control and experimental group, whereby adolescents with motor limitations were more aggressive than control group subjects, especially in behaviors that apply to all forms of verbal aggressiveness. All examined adolescents in which some apparent forms of aggressive behavior were noticed in the observation protocol showed comparable expression of aggressiveness according to the results obtained on the subscales of the A-87 aggressiveness questionnaire, which connects these two measuring instruments and justifies their use in the study of aggressiveness regardless of the understanding of the origin of aggression. PMID- 26058243 TI - Thyrotropin and thyroid hormone economy in euthyroid Hashimoto's thyroiditis. AB - Little is known about thyrotropin (TSH) and thyroid hormones in euthyroid Hashimoto's thyroiditis (HT), thus the aim was to investigate TSH and thyroid hormone economy in euthyroid HT and its relation to thyroid function. Ninety-five patients with euthyroid HT with normal TSH and thyroid hormones on the last follow up between 2009 and 2011 were investigated. Previous observation period ranged from 1.5 to 4.8 (mean 2.8) years, and they had never been treated with levothyroxine. The results of TSH and thyroid hormones were compared with 210 healthy subjects and expressed as median (25%-75%). According to TSH value, the subjects were divided into quartiles: TSH 0.4-0.99 (1q), 1.0-1.99 (2q), 2.0-2.99 (3q) and 3.0-4.0 mIU/L (4q). Euthyroid HT patients had higher TSH (2.53 [1.79 3.14] vs.1.95 [1.24-2.72], p < 0.001). T4 and T3 were not different. The distribution of TSH in HT patients was significantly shifted to the right; 71% of patients were in the 3q and 4q groups. When HT patients with higher TSH (3q and 4q) were compared with those with lower TSH (1q and 2q), significant differences emerged in TSH (3.01 [2.48-3.48] vs.1.45 [1.07-1.71] mIU/L), T4 (99.0 [88.2 112.0] vs.112.0 [105.0-122.0] nmol/L) and T3 (1.78 [1.48-2.05] vs. 2.10 [1.85 2.21] nmol/L; p < 0.01). TPO values were similar in both groups. A gradually increasing proportion of euthyroid HT patients with at least one supranormal TSH during the observation period were found: 0% in 1q, 10% in 2q, 15% in 3q and 44% in 4q TSH group. Euthyroid HT patients maintain euthyroidism only under strenuous TSH stimulation. The patients with high normal TSH are identified as those with a major risk of hypothyroidism in the near future. PMID- 26058242 TI - Therapeutic efficacy of clindamycin gel as an adjunct to scaling and root planing therapy in chronic periodontal disease. AB - Clindamycin, a lincosamide antibiotic, has been under-recognized as an antimicrobial agent for use in dentistry. The aim of the present work was to evaluate clinical efficacy of 2% clindamycin gel in addition to the basic mechanical periodontal therapy. At baseline, scaling and root planing (SRP) was performed at all 50 subjects (control group and test group). Clindamycin gel was applied after SRP only in the test group. Clinical measurements including periodontal pocket depth (PPD), clinical attachment level (CAL), bleeding on probing (BOP) and plaque index (PI) were done at baseline, and at 3 and 6 months after treatment. Compared to baseline, the PPD and CAL values significantly decreased in the test group (p < 0.05) and were statistically lower (p < 0.05) compared to control group. PPD reduction of 2.42 mm was obtained in the test group and could be generally considered as clinically significant. A PPD reduction greater than 2 mm indicated that clindamycin gel could be used efficiently as an adjunct to SRP. Also, between-group difference in BOP and PI scores was statistically significant 6 months after treatment. In conclusion, the application of clindamycin gel in combination with SRP enhanced the efficacy of non surgical periodontal therapy in reducing pocket depth and improving attachment levels in chronic periodontitis subjects and had additional benefits over mechanical therapy alone. PMID- 26058244 TI - Risk factors for surgical site infection in laryngeal cancer surgery. AB - Surgical site infection (SSI) is a significant factor of morbidity and mortality in patients surgically treated for laryngeal carcinoma. The aim of this prospective study in 277 patients was to determine the incidence of SSI in patients surgically treated for laryngeal squamous cell carcinoma and to identify risk factors for development of SSI. Patients with previous chemotherapy and/or radiotherapy were excluded. All patients had tracheostomy postoperatively and received antibiotic prophylaxis with cephalosporin, aminoglycoside and metronidazole. The overall incidence of SSIs in our cohort was 6.5% (18 patients): 4 (22.22%) patients with superficial infections, 11 (61.11%) with deep infections and 3 (16.66%) with organ-space infections. The remaining infections included pneumonia (1 case) and Clostridium difficile colitis (2 cases). The median hospital stay in patients having developed SSIs was longer than in those without SSIs (33.5 vs. 16 days, p < 0.001). By using univariate analysis American Society of Anesthesiologists score > 3, duration of surgery longer than 120 minutes and National Nosocomial Infections Surveillance risk index > 1 were found to be significantly associated with the occurrence of SSI. Age, sex, body mass index, history of smoking, underlying diabetes and preoperative length of stay were found not to be associated with SSI. The most frequently isolated microorganism was Klebsiella spp. PMID- 26058245 TI - Frequency of radial artery anatomic variations in patients undergoing transradial heart catheterization. AB - Over the last ten years, transradial cardiac catheterization has been increasingly applied, primarily because of its lower incidence of complications compared to the femoral approach. However, one of the greatest flaws of the transradial approach is a relatively high incidence of catheterization failure (1%-5%). Anatomic variations of radial artery are ranked second among the reasons for this. Previous studies have not provided unambiguous data on the frequency of these anomalies. It was therefore the aim of this study to determine the frequency of anatomic variations using routine angiographies of radial artery during left heart catheterization. This was a retrospective study involving examination of 602 images of routine angiographies of radial artery performed during cardiac catheterization. The frequency of anatomic variations of radial artery was 8.8%, exclusive of tortuosities with a frequency of 12.7%. The most frequent anatomic variation was the high origin of radial artery, found in 31 (5.1%) subjects. Radioulnar loops, being one of the potential contraindications for the procedure, were reported in 2% of cases. Regression analysis revealed that age (p < 0.001), female sex (p = 0.015) and high origin (p = 0.034) considerably contributed to the development of tortuosity. The results indicated the incidence of tortuosity to increase linearly with age. Although it is not a contraindication for continuing with the procedure, we recommend that elderly patients have angiography of radial artery performed at the beginning of the procedure due to the higher frequency of tortuosity. PMID- 26058246 TI - Depression and dementia in Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder causing not only motor dysfunction but also cognitive, psychiatric, autonomic and sensory disturbances. Depression is the most common psychiatric disturbance identified in patients with PD and has been shown to be more common in PD than in other chronic and disabling disorders, occurring in approximately 40% of PD patients. However, the prevalence and clinical features associated with depression in PD remain controversial. Dementia is increasingly recognized as a symptom associated with idiopathic PD, and is found in up to 40% of all patients suffering from that condition. The aim of this study was to estimate the prevalence of depressive and dementia symptoms in PD patients. The study included 35 consecutive patients with PD, 13 (37.4%) male and 22 (62.6%) female (mean age 62.9 +/- 11.0, range 36-85 years), mean duration of disease 4.7 +/- 2.9 (range 1-10) years, hospitalized during one year at Clinical Department of Neurology, Tuzla University Clinical Center, Tuzla, Bosnia and Herzegovina. The Mini Mental State Examination (MMSE) was used for assessment of cognitive deterioration and Beck Depression Inventory (BDI) for depression. Computerized tomography was performed in all patients. According to BDI scale, depressive symptoms were present in all 35 PD patients: minimal in 4 (11.4%), low in 7 (20%), moderate in 8 (22.8%), severe in 9 (25.4%) and extreme in 7 (20%) patients. On MMSE scale, 9 (25.4%) patients were free from cognitive deterioration and 26 (74.6%) patients had moderate to severe deterioration, but 21 (60%) patients (7 (33.33%) male and 14 (66.66%) female) had symptoms of dementia (MMSE score <= 23). Using MMSE scale, 8 (22.8%) patients were free from dementia and 27 (77.2%) patients had some cognitive deterioration. Very mild symptoms of dementia were found in 6 (25.9%) and overt features of dementia in 21 (74.1%) PD patients. So, out of 35 PD study patients, 21 (60%) (7 (33.3%) male and 14 (66.7%) female) had symptoms of dementia (MMSE score <= 23). In conclusion, depressive and dementia symptoms are common in PD patients. PMID- 26058247 TI - Dental infection and dermatological diseases: analysis of ninety-two patients and review of the literature. AB - Dental disease has long been proposed as a potential causative agent in certain dermatological diseases. However, literature data on this association are scarce. The aim of this retrospective study was to evaluate dental status in 92 patients with various dermatological diseases who were referred to our Department for elimination of dental disease and to assess the relationship between dental infection and dermatological diseases. Dermatological conditions due to which patients were referred were alopecia, urticaria, eczematoid dermatitis, psoriasis, edema, etc. Out of 92 patients, 42 (45.7%) patients were referred for further dental treatment, while the remaining 50 (54.3%) patients had no observable dental pathology. None of the patients reported improvement following dental treatment. Based on the results of this study, we might conclude that dental infection does not play any role in the development of dermatological disease. PMID- 26058248 TI - The novella about diabetic nephropathy. AB - Diabetic nephropathy is a common complication in patients with diabetes mellitus and one of the major reasons for renal replacement therapy in Croatia, Europe and the United States. It is characterized by proteinuria, decline in glomerular filtration, hypertension, and high risk of cardiovascular morbidity and mortality. Deterioration of renal function in diabetic nephropathy develops through five clinical stages characterized by the respective histologic description. Genetic susceptibility, hyperglycemia, high blood pressure and duration of diabetes mellitus definitely play a role in the pathogenetic sequence. Early diagnosis, appropriate patient follow up and treatment are essential to improve the outcomes. Interdisciplinary approach and close collaboration of nephrologists and diabetologists are essential for timely detection of disease progression. Tight glycemic control under the supervision of diabetologists, screening of patients, and once a year report of albuminuria and glomerular filtration allow for detection of renal damage in the early stages and timely referral to a nephrologist. The points of interest given in this overview are description of clinical staging in relation to pathologic classification, repetition of basic causal features, and brief analysis of treatment. PMID- 26058249 TI - Epithelioid hemangioma of the orbit: case report. AB - Epithelioid hemangioma (EH) and Kimura's disease (KD) were once considered different stages of the same disease, as they share many clinical and histopathologic similarities. Nowadays, they are considered as two different entities, but some authors still confuse these terms. Our objective is to present a case of EH occurring in a very uncommon location and to emphasize the microscopic and clinical differences between EH and KD. We present a case of EH of the orbit in an 83-year-old man diagnosed after histopathologic evaluation of a mass that was surgically removed from the orbit. The tumor showed typical microscopic appearance with pathognomonic epithelioid endothelial cells. The diagnosis was also confirmed by immunohistochemical analysis. Our case clearly illustrates typical appearance of EH and the main differences between EH and KD are thoroughly discussed. PMID- 26058250 TI - Jejunoileal perforation and volvulus caused by multiple magnet ingestion. AB - Foreign body ingestion is a common problem in children, but magnet ingestion is relatively rare. However, when it occurs, it tends to have a high rate of complications. This is a case report of a 3-year-old child who swallowed multiple magnetic toys, subsequently developing jejunoileal perforation and volvulus. This case report indicates that it is best to surgically remove multiple ingested magnets without delay to avoid intestinal perforation, fistula, and other complications such as volvulus. PMID- 26058251 TI - Pyridoxine induced rosacea-like dermatitis. AB - Rosacea is a common chronic inflammatory cutaneous disease of unknown etiology, characterized by remissions and exacerbations, presenting with centrofacial erythema and telangiectasias. It affects mainly adults around the age of 30 years and classically predominates in females. The pathophysiology of rosacea has not yet been fully understood. Risk factors are positive family history, very light skin phototype, sun exposure and consumption of spicy food or alcohol. Recently, there has been some evidence that some drugs or vitamins could be potential factors that can aggravate rosacea or induce rosacea-like symptoms. In this context, we present a 53-year-old female developing rosacea-like dermatitis due to a fixed combination of isoniazid and pyridoxine, which she was receiving along with rifampicin for the treatment of pulmonary tuberculosis. PMID- 26058252 TI - Coexistence of ruptured ectopic tubal pregnancy, dermoid and endometriotic cyst with tubo-ovarian abscess in the same adnexa: case report. AB - A 32-year-old pregnant woman presented to the hospital with abdominal pain and minimal vaginal bleeding. Transvaginal ultrasound revealed visible fluid in pelvic region with suspected tubal rupture, and subsequently laparoscopy was performed. During laparoscopy, additional gynecologic pathologies were noticed. Histopathologic finding showed dermoid and endometriotic cyst, as well as tubo ovarian abscess in the same adnexa. This case report highlights the necessity of considering multiple diagnoses in the same organic system, which may be encountered by surgeon and histopathologist. PMID- 26058253 TI - An interesting case of childhood brucellosis with unusual features. AB - Brucellosis is a zoonotic infection, which is still a major public health concern worldwide. Common clinical findings are usually nonspecific involving fever, arthralgia, myalgia, weakness and malaise. Since none of the symptoms of brucellosis is pathognomonic, it may have a similar course with various multisystemic diseases. In terms of focal involvement, sacroiliitis is the most common musculoskeletal manifestation in adult patients, while it is quite rare in pediatric patients. Blood culture is the gold standard in the diagnosis of brucellosis. In the absence of culture facilities, the diagnosis traditionally relies on serologic testing with a variety of agglutination tests such as the Rose Bengal test and the serum agglutination test. However, these agglutination tests are accompanied by frequent false negative results such as seen in prozone phenomenon, which may lead to diagnostic delays. In this article we present a rarely encountered pediatric brucellosis patient who had sacroiliitis spondylitis, which are rarely reported in children, and exhibited prozone phenomenon in agglutination tests. PMID- 26058255 TI - A year I'll always treasure. PMID- 26058256 TI - Scholarship fundraiser an opportunity to support medical students. PMID- 26058257 TI - Faculty development. PMID- 26058258 TI - Science achievement in secondary school students across rural and urban South Dakota locales. AB - While many efforts have been made at the graduate level to train physicians for rural South Dakota, there has been little work to identify how geographic locale affects the science achievement of high school students. This study utilized the urban-central locale code system to analyze South Dakota high school student ACT science scores. Rural student achievement was significantly lower than students from city and town locales. By analyzing such correlations, unique strategies can be developed to improve secondary rural science education and increase the number of students pursuing careers in rural medicine. PMID- 26058259 TI - A previously asymptomatic 52-year-old male with congenitally corrected transposition of the great vessels presenting with arrhythmia related cardiac arrest--case report and a brief review of literature. PMID- 26058260 TI - Atrial fibrillation: a primer for the primary care physician. PMID- 26058261 TI - COPD inhaler selection--factors to consider. PMID- 26058262 TI - DAKOTACARE update: Antibiotic stewardship: a payer's perspective. PMID- 26058263 TI - Patient education: The most important diagnostic test. PMID- 26058264 TI - Quality focus: Health care payment change. PMID- 26058265 TI - [Considerations on cardiac rehabilitation: the paradigm of complexity]. PMID- 26058266 TI - [First definition of minimal care model: the role of nurses, physiotherapists, dietitians and psychologists in preventive and rehabilitative cardiology]. AB - Rehabilitative and preventive cardiology (CRP) is configured as intervention prevention to "gain health" through a process of multifactorial care that reduces disability and the risk of subsequent cardiovascular events. It makes use of an interdisciplinary team in which every professional needs to have multiple intervention paths because of the different levels of clinical and functional complexity of cardiac patients who currently have access to the rehabilitation. The document refers to the use of interventions by nurses, physiotherapists, dietitians and psychologists that are part of the rehabilitation team of CRP. Interventions of which have been documented, on scientific bases and clinical practice, empirical effectiveness and organizational efficiency. The methodological approach of this paper is a first attempt to define, through the model of consensus, the minimum standards for a CRP evidence based characterized by clearly defined criteria that can be used by operators of CRP. The document describes the activities to be carried out in each of the phases included in the pathways of care by nurses, physiotherapists, dietitians and psychologists. The routes identified were divided, according to the type of patients who have access to the CRP and to the phases of care, including the initial assessment, intervention, evaluation and final reporting, in high medium and low complexity. Examples of models of reporting, used by the operators of the team according to the principles of good clinical practice, are provided. This is made to allow traceability of operations, encourage communication inside the working group and within the patient and the caregiver. Also to give any possible indication for the post-rehabilitation. PMID- 26058267 TI - Ten years differences in recently onset atrial fibrillation and flutter incidence and management. AB - ABSTRACT: Ten years differences in recently onset atrial OBJECTS AND BACKGROUND: Atrial fibrillation (AF) and atrial flutter (AFl) are the most common arrhythmias in day-life clinical practice. Purpose of our study was to verify differences occurred in the last ten years in AF and AFI incidence and treatment in the emergency room (ER). METHODS: from the 17th January to the 15th February 2000 and from the 18th January to the 16th February 2010 all the consecutive patients with AF or AFl referring to the ER of our hospital were included in the study. Epidemiological data were collected along with information about treatment, admission to hospital wards, days of hospital stay and therapy. Data from the year 2000 were compared to these collected ten years later. RESULTS: incidence of AF and AFl has increased in the years (50%), patients are older (73.5 vs. 65.2 years; p 0.029) and refer late to the ER (45.6% in 2010 and 23.7% in 2000 with a delay of > 48 hours from arrhythmias onset; p 0.054). In 2010 only a minority of these patients is directly discharged from the ER (15.8% vs 14.4%) and there is an increased admission rate due to AF or AFl (67.5%; p 0.026), if compared to the whole admissions of the hospital. The median duration of hospital stay decreased from 6 days to 4.5 days in the year 2010 (NS). CONCLUSION: AF and AFl incidence is still increasing and account for a high admission rate from the ER to the hospital wards. Costs are consequently continuously increasing. PMID- 26058268 TI - Obstructive sleep apnea: one more target in cardiac rehabilitation. AB - ABSTRACT: Obstructive sleep apnea: one more target in Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder, often unrecognized and undiagnosed, in patients with established cardiovascular diseases. Considerable evidence is now available in support of a significant association between OSA and increased risk for cardiovascular disease morbidity. OSA has also been recognised as a potential public health issue associated with societal consequences including accidents and work economics. Treatment of OSA would reduce cardiovascular risk and the overall usage of health care resources. OSA might be a modifiable risk factor and screening for OSA should be implemented in cardiac rehabilitation settings. PMID- 26058269 TI - [Nonsteroid anti-inflammatory drugs (NSAID) and risk of cardiovascular events. Literature review and clinical implications]. AB - Non steroid anti-inflammatory drugs (NSAIDs) are largely used for treatment of acute and chronic pain, even for long periods of time (months or years). While it is known that their use is frequently associated with gastrointestinal damage, including major bleedings from peptic ulcer, the risk of cardiovascular events related to NSAID has received much less attention. However, there is a large body of evidence showing that NSAIDs (both "traditional", such as diclofenac or indobufen, and selective cyclooxygenase inhibitors, COX-2) are associated with a significant increase of risk of cardiovascular events, both fatal and nonfatal. Consequently, several options have been proposed for the treatment of pain, including the use of analgesic drugs with different mechanisms of action, such as the opiates. Of interest, the Italian Drug Agency (AIFA) published a few years ago a warning (Nota 66) on the careful prescription of NSAIDs in patients with overt heart disease, such as coronary artery disease and heart failure. Aim of this paper is to present the current status of knowledge on the proper use of NSAIDs and other analgesic drugs in the management of acute and chronic pain. PMID- 26058270 TI - Associated factors of prenatal depression among teenage pregnant women at King Chulalongkorn Memorial Hospital. AB - OBJECTIVE: Depression during pregnancy is associated with deteriorating maternal health and increasing risk of preterm birth, fetal growth restriction, and suicidal attempt. The problems may be worse in adolescents who are more vulnerable. This study was conducted to determine the percentage of depression among teenage mothers and its associated factors. MATERIAL AND METHOD: Two hundred teenage pregnant women aged between 13 and 19 years who visited King Chulalongkorn Memorial Hospital (KCMH) participated in the present study. They were asked to complete the validated Thai Edinburgh Postnatal Depression Scale (EPDS) questionnaire for depression screening. The cut-offscore of 11 was used for the diagnosis of prenatal depression. RESULTS: Ninety-two (46%) teenage pregnant women were found to have prenatal depression using the EPDS cut-off score of 11. The mean age of participants was 17.5 years with the mean gestational ages of 23 weeks. Most of the participants (67%) resignedfrom school and 16% had history of attempted abortion during current pregnancy. There was no significant association between prenatal depression and unplanned pregnancy, unemployment, leaving school, or trimester at screening. Logistic regression analyses showed that history of attempted abortion and inadequate income were significantly associated with prenatal depression (odd ratio = 8.03, 95% CI 1.59 to 40.37 and 4.16, 95% CI 1.35 to 12.83, respectively). CONCLUSION: Prenatal depression was common among teenage pregnant women who visited KCMH. Attempted abortion and inadequate income were found to be significantly associated with prenatal depression. PMID- 26058271 TI - The effects of promoting self-efficacy program on the oral contraceptive used behavior among adolescent mothers. AB - OBJECTIVE: To study the effects of a promoting self-efficacy program on the oral contraceptive used behavior among adolescent mothers. MATERIAL AND METHOD: This is a quasi-experimental study which based on a pretest-posttest design with group comparison. The participants were primiparous adolescent mothers aged 15-19 years who attended at antenatal care clinic, delivered and came for postpartum check-up at 6 weeks after delivery at Thammasat University Hospital from December 2013 to March 2014. RESULTS: Sixty adolescent mothers were selected through inclusion criteria and divided equally to study and control group. Study group participated in the effects of the promoting self-efficacy program combined with standard nursing care. Control group received only standard nursing care from the same nursing staff Demographic data of both groups had no statistical difference. Mean scores on oral contraceptive self-efficacy (OCSE) and oral contraceptive used behavior (OCUB) ofstudy group were higher than control group with a statistical significance (p < 0.001) at 12 weeks postpartum. CONCLUSION: Adolescent mothers had a high risk of unintended pregnancy due to inconsistent oral contraceptive usage. Promoting self-efficacy program regarding oral contraceptive behavior should be integrated to standard nursing care practice. This program could encourage adolescent mothers to engage correct and continuous oral contraceptive usage. PMID- 26058272 TI - The effects of systematic management on maternal and neonatal complications in gestational diabetes subjects. AB - OBJECTIVE: To compare maternal and neonatal complications ofgestational diabetes mellitus (GDM) between conservative and systematic management. MATERIAL AND METHOD: This retrospective cohort study was conducted at Thammasat University Hospital, Thailand. GDM subjects who were diagnosed and treated from October 2004 to March 2007 were classified as the conservative management group (CMG). The participants who were diagnosed and treated from April 2007 to September 2009 were classified as the systematic management group (SMG). SMG was ambulatory managed per standard protocol by a multidisciplinary team (physician, diabetes nurse case manager nutritionist and pharmacologist). RESULTS: There were 87 and 118 subjects in CMG and SMG, respectively. Mean age and body mass index before pregnancy in CMG and SMG were not statistical different. Oral glucose tolerance tests (50 and 100 gram) were similar in both groups. The prevalence of GDM A2 was 57.5 and 55.1% in CMG and SMG, respectively. Mean gestational age at DM clinic consultation and number of hospital admission of SMG was less than CMG (p < 0.001). Neonatal hypoglycemic episode in SMG was less than CMG (1.7 vs. 10.3; p = 0.007). Postpartum 75-gram glucose tolerance test appointments and percentages of underwent in SMG were more than CMG (p < 0.001). Other composite maternal and neonatal outcomes were not different in either group. CONCLUSION: Systematic management by a multidisciplinary team conducted according to a practical guideline has the benefit of neonatal hypoglycemia reduction and hospital admission included postpartum DM surveillance increments. PMID- 26058273 TI - Health-related quality of life in Thai children with allergic respiratory diseases. AB - BACKGROUND: Childhood asthma and allergic rhinitis (AR) are major chronic respiratory diseases affecting health-related quality of life (HRQOL). Few school based studies have reported the HRQOL of individuals with asthma or AR. OBJECTIVE: The study measured HRQOL among primary school pupils with asthma, AR and both diseases combined in Thailand. MATERIAL AND METHOD: Two thousand and eight school pupils, aged 6-9 years, from six primary schools were randomly studied. The self-reported Pediatric Quality of Life Inventory Core Scales (PedsQL) questionnaires were used to evaluate pupils' HRQOL in their classrooms. The parent-reported PedsQL questionnaires and the parent-reported International Study of Asthma and Allergies in Childhood (ISAAC) written questionnaire were sent to their parents to evaluate pupils' HRQOL and identify asthma and AR respectively. RESULTS: One thousand nine hundred and twenty-four of 2,008 (95.8%) pupils completed the self-reported PedsQL questionnaire and 1,789/2,008 (89.1%) parent-reported questionnaires were returned for analysis. By child self-reports, asthmatic pupils with or without AR had significant impairment in all domains of PedsQL questionnaire (p <= 0.049) compared to healthy pupils. Pupils with combined asthma and AR had significantly lower summary (p = 0.015) and emotional functioning mean scores (p = 0.001) than pupils with AR alone. By parent-reports, pupils with asthma alone, AR alone, and combined diseases had significant impairment in emotional functioning (p <= 0.047), compared to healthy pupils. CONCLUSION: Allergic respiratory diseases significantly reduced HRQOL in Thai school pupils, especially for emotional functioning. AR alone minimal impairs HRQOL while asthma with or without AR significantly reduce HRQOL in all domains. PMID- 26058274 TI - Reliability and validity of Thai version Quality of Life Questionnaire (OSA-18) for pediatric obstructive sleep apnea. AB - BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is a chronic illness affecting either cardiopulmonary or neuropsychiatric function. Besides the functional health, the quality of life of patients with obstructive sleep apnea (OSA) is of interest in literature. In children, the quality of life questionnaire, which consists of 18 items (OSA-18), has been widely accepted as a reliable, valid, and simple to administer. This questionnaire may also be useful in Thai children with OSA. OBJECTIVE: To assess the reliability and validity of the Thai version of OSA-18 in Thai children. MATERIAL AND METHOD: This was a cross-sectional study. The original English version of the 18-item pediatric obstructive sleep apnea quality of life questionnaire was translated into Thai following the guidelines of cross-cultural adaptation with permission from Rosenfeld RM, Department of Otolaryngology, SUNY Health Science Center at Brooklyn, USA. The questionnaire was divided into five domains, sleep disturbance, physical suffering, emotional distress, daytime problems, and caregiver concerns. The suspected obstructive sleep apnea children, aged less than 15 years, who did not have cardiovascular diseases, lung diseases, or neuromuscular diseases, and who underwent standardfull night polysomnography were included. The child's caregiver was asked to complete the questionnaire without assistance to determine its reliability and validity. RESULTS: Forty-three children (30 boys, and 13 girls) were enrolled in the present study. The median age was five years (range 2 to 14 years). The median apnea hypopnea index (AHI) was six events/hour and median OSA-18 total score was 66.7 (range 25 to 107). There were excellent test-retest reliability (Cronbach's alpha = 0.91) and internal consistency (Cronbach's alpha = 0.77) between each domain. Correlation between the Thai OSA-18 total scores and AHI was r = 0.48, p = 0.001, which was similar to the original English version (r = 0.43, p < 0.001). CONCLUSION: The level of reliability and validity of the Thai version of the OSA-18 has been found to be satisfactory. Therefore, this instrument can be used in future research for measuring the quality of life in Thai children with OSA and assess the benefit of treatment. PMID- 26058275 TI - Incidence and associated factors of deep vein thrombosis in Thai surgical ICU patients without chemoprophylaxis: one year study. AB - BACKGROUND: Deep vein thrombosis (DVT) is a major problem in the intensive care unit (ICU) patients, especially in Western countries. However; because the incidence of DVT in Asia ICU is lower, chemoprophylaxis (i.e., anticoagulant) is not routinely utilized. The aim of the present study was to identify the incidence and associated factors of DVT in Thai surgical ICU (SICU) patients without chemoprophylaxis. MATERIAL AND METHOD: SICU patients admitted between June 2011 and July 2012 were screenedfor lower extremity DVT using doppler ultrasonography. Stepwise logistic regression was performed to identify associated factors for the development of DVT. RESULTS: Three hundred andfive patients were included in the study, 174 were male (57%) and 131 were female (43%), with ages ranged from 15 to 99 years (mean 62.8 years). Eleven patients had DVT identified (DVT rate 3.6%), two of these had symptomatic pulmonary embolisms. The associated factors for the development of D VT were prior history of venous thromboembolism (p < 0.001, OR 34.3, 95% CI 14.6-80.5), orthopedics group (p < 0.001, OR 27.2, 95% CI 5.2-142.1), and female (p = 0.034, OR 14.3, 95% CI 1.7-102.5). CONCLUSION: The incidence of D VT in Thai SICU patients was 3.6%. Further study is required to identify method and effectiveness of DVT prophylaxis in Asian ICU patients. PMID- 26058277 TI - A comparative study of corneal endothelial structure between diabetes and non diabetes. AB - BACKGROUND: The corneal endothelial structure may be changed in diabetic patients, but the results were variable. OBJECTIVE: To compare the corneal endothelial structure including endothelial cell density, polymorphism, andpleomorphism, in diabetic and non-diabetic subjects. MATERIAL AND METHOD: The corneal endothelial structure of diabetic and non-diabetic subjects were measured by specular microscope (Confoscan4 (CS4), Nidek) for endothelial cell density, percentage of polymegathism, and percentage of hexagonal cells. The data were analyzed using the descriptive statistics and the unpaired t-test. RESULTS: There were 171 eyes of 90 diabetic patients with the mean age of 58.49 +/- 9.78 years, and 156 eyes of 90 non-diabetic subjects with the mean age of 58.98 +/- 13.12 years. Three parameters of measurement revealed no significant difference (p > 0.05). The over one year diabetic patients, however demonstrated a decreased percentage of hexagonal cells statistically significant (p < 0.05), while the over two years diabetic patients demonstrated a decreased percentage of hexagonal cell and an increased percentage of polymegathism statistically signifcant (p < 0.05). CONCLUSION: The corneal endothelial structure is not different between diabetic and non-diabetic groups. When the disease progresses, however the hexagonal cells decrease at first, followed by the polymegathism. No difference shows in endothelial cell density. PMID- 26058276 TI - Surgical correction of vascular ring in Thai patients at a tertiary hospital. AB - BACKGROUND: Vascular ring is a rare congenital vascular disease. The result of vascular ring surgery in Thailand remains unknown as it lacks serial data. The purpose of the present study was to evaluate the result of vascular ring surgery at Siriraj Hospital and demonstrate the usefulness of the computed tomograph angiographic scanning (CTA) for preoperative anatomical diagnosis of the vascular ring for planning the surgical correction. MATERIAL AND METHOD: We reviewed our experiences for all patients that underwent vascular rings surgery at our institute between 1979 and 2009, about preoperative diagnostic imaging, operative technique, and clinical outcome. RESULTS: Twelve medical records of patients that underwent vascular rings surgery were reviewed. The age at time of operation ranged from one month to two years (median 3 months). The surgical approaches were eight median sternotomies, three left thoracotomies, and one right thoracotomy. There were two cases ofpostoperative complication (residual tracheal and left pulmonary artery stenosis and surgical bleeding). There was one hospital mortality (pneumonia and sepsis). CONCLUSION: Surgical correction of vascular ring is effective and safe. CTA can give the precise anatomic diagnosis of the vascular rings, lead to good surgical planning, proper surgical approach, and good outcome. PMID- 26058278 TI - Incidence of post-intravitreal anti-VEGF endophthalmitis at Thammasat University Hospital. AB - BACKGROUND: Anti-vascular endothelial growth factor (anti-VEGF) drugs have been used as ophthalmic injections to treat various eye diseases. Recently, the use of this drug has gradually increased as awareness of potential complications, especially the occurrence of endophthalmitis. OBJECTIVE: To report the incidence rate, clinicalfeatures, management, and presumed risk factors of acute post intravitreal anti-VEGF drug injection endophthalmitis secondary to therapeutic intravitreal ranibizumab and bevacizumab injections. MATERIAL AND METHOD: A retrospective review of all consecutive eyes after intravitreal injections was performed at Thammasat University Hospital, Pathumthani, from June 2008 to September 2013. Data collected at diagnosis included patient demographics, intravitreal injection details, pre- and post-injection management, visual acuity, clinical features and managements, causative organisms, and clinical outcomes. RESULTS: During the 5-year-study interval, 1,169 intravitreal injections were performed. The overall incidence rate of endophthalmitis was 0.17% (2 of 1,169 injections). In our series, the endophthalmitis occurred after the 1st and 2nd injection. Bacterial cultures and gram stain revealed coagulase negative Staphylococcus species (n = 1) and no organism found (n = 1). All cases were treated efficiently in limiting the devastating sequels by intravitreal antibiotics, steroids andparsplana vitrectomy. The result showed that recovery of useful vision was found in one case and devastating vision in another case. CONCLUSION: Acute endophthalmitis is a rare potential complication after intravitreal injection. Prognosis of endophthalmitis varies widely depending upon the severity of the infection, the organism involved and the amount of damage the eye sustains from inflammation and scarring. Further studies are required to clarify the best prophylactic techniques to prevent this rare complication. PMID- 26058279 TI - The results of pterygium excision at Thammasat Hospital. AB - BACKGROUND: Pterygium is a common ocular disease. Outcomes ofpterygium surgery are variable. OBJECTIVE: To evaluate the results ofpterygium excision, particularly the recurrence rate and complications of surgery. MATERIAL AND METHOD: Patient data who had pterygium excision at Thammasat Hospital from October 2010 to September 2013 were reviewed. Age, sex, primary or secondary pterygium, methods of surgery and complications were analyzed. RESULTS: Three hundred and thirty-four eyes (307 patients) were studied. One hundred and ninety two (62.5%) were in women. The mean age +/- SD was 57.1 +/- 12.2 years. Three hundred and twenty-two eyes (96.4%) were primary pterygium. Amniotic membrane graft technique was performed in 323 eyes (96.7%). Pterygium recurred after surgery in 80 eyes (24.0%). Intra-ocular pressure increased more than five mmHg in 34 eyes (10.2%) after steroids use. Scleral thinning was found infive eyes (1.5%) and four in this group were treated with Mitomycin C. There was granulation tissue formation in one eye (0.3%). CONCLUSION: Pterygium excision with amniotic membrane graft technique was widely operated at Thammasat Hospital and recurrence after surgery was rather high. Increased intra-ocular pressure after steroids use was common complication. Scleral thinning was a critical problem with the application of Mitomycin C. PMID- 26058280 TI - Transthoracic imaging-guided biopsy of lung lesions: evaluation of benign non specific pathologic diagnoses. AB - OBJECTIVE: Explore the definitive diagnoses of imaging-guided transthoracic needle biopsies (TNB) with a pathological result of benign non-specific diagnosis in a tuberculosis-endemic area. The secondary goal was to characterize the initial CT imaging findings between malignancy and benign lesions. MATERIAL AND METHOD: All TNB diagnoses considered to have benign non-specific features at the Radiology Department between January 2007 andDecember 2011 were retrospectively reviewedfor definitive diagnosis based on clinical impressions andfor CT imaging characteristics. RESULTS: Sixty-seven cases with TNB were given a benign non specific diagnosis and had complete pathologic or radiologic follow-ups. Of these 67 cases, 16 (23.9%) were malignant and 51 were benign. Two main definitive diagnoses of benign cases were pulmonary tuberculosis (32.8%) and pneumonia/lung abscess (23.9%). On the CT images, most of lesions in the group of pulmonary tuberculosis (14/22, 63.6%) were not enhanced after contrast administration (p < 0.005), and necrotic mediastinal lymph nodes were significantly found more in final malignancy diagnoses (p < 0.005). CONCLUSION: The definitive diagnoses of benign non-specific diagnoses based on TNB in this tuberculosis-endemic area had a high rate of both malignancy and pulmonary tuberculosis. Hence, repeated biopsies or radiological follow-ups are advised. PMID- 26058281 TI - Ginkgo biloba for prevention of dementia: a systematic review and meta-analysis. AB - OBJECTIVE: To determine the efficacy of Ginkgo biloba for the prevention of dementia in individuals without dementia. MATERIAL AND METHOD: English databases including Medline, Embase, Cochrane Library and PsycINFO, were searched, and randomized double-blind controlled studies comparing Ginkgo biloba with placebo in prevention of dementia were considered. Two trials met inclusion criteria. Methodological quality was assessed using the Jadad criteria. RESULTS: Meta analysis of the two trials involving 5,889 participants indicated no significant difference in dementia rate between Ginkgo biloba and the placebo (347/2,951 vs. 330/2,938, odds ratio = 1.05, 95% CI 0.89-1.23) and there was no considerable heterogeneity between the trials. The two studies revealed no statistically significant differences in the rate of serious adverse effect between Ginko biloba and the placebo. CONCLUSION: There is no convincing evidence from this review that demonstrated Ginkgo biloba in late-life can prevent the development of dementia. Using it for this indication is not suggested at present. PMID- 26058282 TI - Mucosa-associated lymphoid tissue lymphoma with large cell transformation on the background of Hashimoto's thyroiditis: a case report and review literature. AB - Primary thyroid lymphoma (PTL) is a rare cause of malignancy that occurs in 0.5% of cases with Hashimoto's thyroiditis. The most common subtype is diffuse large B cell lymphoma (DLBCL), followed by mucosa-associated lymphoid tissue (MALT) lymphoma. We described the case of a 70-year-old man who was diagnosed with MALT lymphoma in the background of autoimmune thyroiditis with focal area of DLBCL transformation. The patient was a 70-year-old man with rapidly growing mass of the thyroid gland with compressive symptom over two months. The laboratory data revealed primary hypothyroidism with positively anti-thyroid antibodies. The computerized tomography scan showed right thyroid mass extended to anterior mediastinum and compressed adjacent airway with multiple cervical and mediastinal lymphadenopathies. The pathology from incisional biopsy showed extranodal marginal zone B-cell lymphoma of MALT lymphoma with large cell transformation. The patient received four courses of systemic chemotherapy combined with involved field radiation therapy. The mass was dramatically decreased in size after treatment, leading to a complete resolution of compressive symptoms. Thyroid lymphoma is quite rare; however the incidence may be higher in patients with Hashimoto's thyroiditis. A rapidly growing thyroid gland should be considered as PTL. Chemotherapy and radiation are the mainstays of treatment. PMID- 26058283 TI - Intra-operative femoral neck fracture during attempted dislocation of a reduced hemi-arthroplasty. AB - Fragility hip fractures are increasingly common and hemiarthroplasty is one of the standard treatments. Although a common surgery, it should be performed with great caution because of the poor premorbid and bone quality in this demographic. Intra-operative fractures can occur while attempting press fit of the femoral implant. However; vigilance often steps down once the implant is secured and the hip reduced. This case report reminds surgeons that a large amount of torque can be transmitted during intra-operative positioning, such as during an attempt of hip dislocation. This torque, in addition to the risk factor of osteoporotic bone, can result in iatrogenic fractures. Published literature regarding management of an intra-operative fracture while the prosthetic hip is still reduced is lacking. The authors propose that temporary prophylactic cerclage wiring is a prudent and safe procedure prior to hip dislocation. PMID- 26058284 TI - Leadership and innovation in Asia. PMID- 26058285 TI - Implementing successful strategic plans: a simple formula. AB - Strategic planning is a process. One way to think of strategic planning is to envision its development and design as a framework that will help your hospital navigate through internal and external changing environments over time. Although the process of strategic planning can feel daunting, following a simple formula involving five steps using the mnemonic B.E.G.I.N. (Begin, Evaluate, Goals & Objectives, Integration, and Next steps) will help the planning process feel more manageable, and lead you to greater success. PMID- 26058286 TI - The seven common pitfalls of customer service in hospitals. AB - Operating simultaneously like a repair shop, prison, and hotel, hospitals are prone to seven common pitfalls in customer service. Patient care is often fragmented, inscrutable, inflexible, insensitive, reactive, myopic, and unsafe. Hospitals are vying to be more high-tech, rather than high-touch even though staff engagement with patients rather than facilities and equipment strongly influence patient satisfaction. Unless processes, policies, and people are made customer-centered, the high quality of the hospital's human and hardware resources will not translate into high patient satisfaction and patient loyalty. PMID- 26058287 TI - Prosocial motivation and physicians' work attitudes. Effects of a triple synergy on prosocial orientation in a healthcare organization. AB - Employees work attitudes are key determinants to organizational performance. This article proposes a model integrating servant leadership, prosocial motivation, and corporate social responsibility (CSR) in order to explain a mechanism through which prosocial motivation plays a central role in enhanding physicians' work attitudes. A cross sectional survey from a sample of physicians indicates that (1) prosocial motivation can be shaped from servant leadership when physicians perceive high value fit with their supervisors, (2) prosocial motivation improves physicians' job satisfaction. Its effects is strengthened when physicians perceive high CSR, and (3) job satisfaction improves organizational commitment. The results provide meaningful insights that a triple synergy of prosocial orientation among physicians, supervisors and organization enhances physicians' work attitudes. PMID- 26058288 TI - Development, empowerment and accountability of front line employees. AB - Facilitating patient-focused, cost-effective care throughout the continuum is a challenge that requires creativity of healthcare administrators. At BLK Super Specialty Hospital, a Guest Relationship Executive (GRE) and Patient Care Coordinator (PCC) role was developed to improve communication and linkage among clinical and non-clinical departments. Management also innovated various other processes which needed improvement for facilitating the improvement of services provided to the patients. Empowering PCC and GRE to take the initiative, make decisions and take actions to prevent and resolve service issues has elevated service levels and lead to an enhanced patient experience. PMID- 26058289 TI - Saving lives together. AB - Established 20 years ago with a single dialysis center assisting only 20 patients with 6 hemodialysis machines, Medicare has grown leaps and bounds to assist thousands of poor patients to obtain a highly subsidized rate for quality treatment. Millions of ringgit raised via various fundraising projects and events have been well utilized to serve the growing number of kidney patients in Malaysia who simply cannot bear the exorbitant cost of treatment. Staying true to its mission, Medicare extends its assistance to needy kidney patients and their families, who indirectly have become part of the Medicare family. PMID- 26058290 TI - Quality improvement initiatives by Aga Khan Health Service in the mountains of northern Pakistan. AB - Improving health care quality in a resource constraint environment in an emerging economy that is in a hard-to-reach geographic terrain can become a challenge especially when it has to follow the international standard which AKHS, P envisions to implement across the nation in all of its health facilities. Healthcare of the nation is a responsibility which is shouldered by both the government and the private sector. Private-sector, however, remains under pressure as its resource size is limited and it remains subject to stringent regulation and quality control requirements regardless of whether it is in the remotest corner of the country where proper land routes are either lacking or not safe. This article shares the unique experience of AKHS, P in achieving ISO 9001:2008 International Quality Management System Certification. Particularly at one of the "world's highest valleys -situated at Gilgit Baltistan at an altitude of 13,083 ft. above sea level in Northern Pakistan. The experience was unique in terms of demonstrating and recording how a quality management system can be implemented in one of the most difficult to reach areas where compliance to international quality standards was previously unthinkable. PMID- 26058291 TI - Built environment and wellbeing in Italian psychiatric wards. AB - The healthcare built environment has effects on patient's wellbeing. These effects are even heavier on sensitive patient such as psychiatric ones. Therefore the environment design can be a key factor in promoting the patients' well-being and the care process. This paper investigates how this vision is influencing the design of psychiatric facilities in the Italian context, known for its radical innovation of mental health services due to Law 180 (1978). The article identifies the current built environment issues of the psychiatric ward, the design indications available and the possible future actions to meet the needs of users and to improve wellbeing and care process. PMID- 26058292 TI - Fast track surgery, a strategy to improve operational efficiency in a high complexity hospital in Latin America. AB - Fast Track surgery is designed to optimize time in low-complexity procedures, thus improving efficiency in care provision, and preserving patient safety. METHOD: Before and after intervention study in a surgical setting, with failure mode and effects analysis, identification and prioritization of improvement opportunities, process measurement before the intervention, improvement implementation, practical application, process measurement after the intervention, and surgical time comparisons. RESULTS: With the Fast Track program, 19% of the operating room capacity available was freed per day; before surgical FastTrack implementation, 50% of the procedures started 23 minutes behind schedule. After the Fast Track program was implemented, procedures start 5 minutes ahead of schedule. Anesthesia induction time was reduced by 50%, and skin to-skin surgical time dropped by 28%. The number of surgical procedures performed in the day increased by 33-50%. There were noincidents or adverse events. CONCLUSIONS: Fast Track surgery is a useful strategy for improving operating room efficiency and reducing surgical time. Procedures start on time, with increased timely care, patient and practitioner satisfaction, and lower service costs. PMID- 26058293 TI - We met as strangers; left as friends. PMID- 26058294 TI - We should not sue a broke Illinois. PMID- 26058295 TI - Dentists are our brothers' keeper. PMID- 26058296 TI - Harness social media to grow your practice. PMID- 26058297 TI - The post-op phone call is a good idea. PMID- 26058298 TI - Our legislators don't understand. PMID- 26058299 TI - Keep up with Dr. Jones. PMID- 26058300 TI - Dr. McDaniel saves a piece of our history. PMID- 26058301 TI - Holocaust survivors still face burdens. PMID- 26058302 TI - Words can bite back. PMID- 26058303 TI - Nursing considerations when caring for the obese patient. PMID- 26058304 TI - Computer-assisted intraosseous anaesthesia for molar and incisor hypomineralisation teeth. A preliminary study. AB - Anesthetizing MIH (Molar and Incisor Hypomineralisation) teeth is one of the major challenges in paediatric dentistry. Computer-assisted IO injection (CAIO) of 4% articaine with 1:200,000 epinephrine (Alphacaine, Septodont) has been shown to be an efficient way to anesthetize teeth in children. The aim of this study was to assess the efficacy of this method with MIH teeth. This preliminary study was performed using the Quick Sleeper system (Dental Hi Tec, Cholet, France) that allows computer-controlled rotation of the needle to penetrate the bone and computer-controlled injection of the anaesthetic solution. Patients (39) of the department of Paediatric Dentistry were included allowing 46 sessions (including 32 mandibular first permanent molars) to be assessed. CAIO showed efficacy in 93.5% (43/46) of cases. Failures (3) were due to impossibility to reach the spongy bone (1) and to achieve anaesthesia (2). This prospective study confirms that CAIO anaesthesia is a promising method to anesthetize teeth with MIH that could therefore be routinely used by trained practitioners. PMID- 26058305 TI - [Post-dental extraction tetanus. About an observation]. AB - The authors report a case of tetanus diagnosed in the aftermath of tooth extraction, in the absence of any other front door. OBSERVATION: A patient showed a persistent trismus several days after the extraction of tooth 38 performed at the dental office. The diffusion of tension and the appearance of paroxysms allowed the diagnosis of tetanus. DISCUSSION: The possibility of occurrence of tetanus after a tooth extraction should be kept in mind before a persistent trismus with rapid expansion in the neck and limbs. The dentist should be aware of the symptoms of tetanus to refer the patient to a specialized department. PMID- 26058306 TI - A preliminary study of a new endodontic irrigation system: Clean Jet Endo. AB - The purpose of the present study was to assess the irrigant penetration and cleaning ability of a new irrigation system, the Clean Jet Endo (Produits Dentaires SA, Switzerland) in comparison to conventional irrigation followed or not by sonic activation. Irrigant penetration was evaluated on resin blocks simulators by measuring the methylene blue absorbance thanks to a UV/visible spectrophotometer and cleaning ability was assessed in an ex vivo experiment according to the debris score in an artificial canal extension before and after the final irrigation protocol. A statistical analysis was carried out in order to highlight the significant differences between the irrigation techniques. Clean Jet Endo permitted to better eliminate the methylene blue into the simulated canals. A significant difference between the 2 techniques was observed in the middle third (p = 0.005) as well as in the apical third (p < 0.2). An additional microscope observation (16X) confirmed that Clean Jet Endo@ usage led to a better penetration of irrigant within the lateral canals of the simulators. Likewise, this irrigating system permitted to better eliminate the debris in the lateral groove than the other techniques. In conclusion, our findings implied the potential of this new irrigation system to enhance root canal debridement and disinfection. PMID- 26058307 TI - [Relationship between the obstructive character of the tonsils and the sagittal cephalometric measurements]. AB - INTRODUCTION: The role of obstructive tonsils in the sagittal dimension of the skeleton-dental abnormalities is widely discussed in the literature but remains controversial. Data on the probable relationship between obstructive tonsils and the presence of these abnormalities were subjective. The objective of this study was to quantify the relationship between the obstructive character of the tonsils and the sagittal cephalometric measurements. MATERIALS AND METHODS: A cross sectional study was performed in children aged between 6 to 12 years divided into 2 groups (A and B) according to the obstructive character of the tonsils. Cephalometric measurements were recorded on each child. Data were analyzed using SPSS 20.0 for Windows. At Student test was used to compare quantitative variables according to the obstructive character of the tonsils. Significance was set at p = 0.05. RESULTS: Subjects with obstructive tonsils (group B) are significantly more trend to have a convex facial profile and a skeletal class II with more mandibular retrusion and retroclined incisor compared with subjects without obstructive tonsils (group A). CONCLUSION: Early evaluation of children with obstructive tonsils can prevent sagittal dimension of the squeleto-dental abnormalities caused by upper airway obstruction. Thus late and more aggressive treatments which are not always as efficient as when they were performed during childhood will be avoided. PMID- 26058308 TI - Parental perceptions of dental visits and access to dental care among disabled schoolchildren in Kuwait. AB - The objective of this study was to describe dental visiting habits and access to dental care among the disabled schoolchildren in Kuwait. A total of 308 parents of children with a physical disability (n = 211), Down syndrome (n = 97) and teachers, who had normal children (n = 112) participated in the study. Less than one-fourth (21%) of the disabled children and 37% of the normal children had never visited a dentist (p = 0.003). Majority of Down syndrome (72%) and physically disabled children (59%) received curative dental care compared to 47% of normal children (p = 0.016). A bigger proportion of disabled children (42%) visited the dentist due to tooth ache than the normal ones (25%) (p < 0.01). Only 9.6% of Down syndrome children perceived no barriers to seek the dental care compared to 26.2% of physically disabled and 32.2% of normal children (p = 0.008). Difficulty to get an appointment was the most common perceived barrier to dental care by parents of Down syndrome children and the normal children (37.3%). Parents of disabled children considered difficulty in cooperation as a more important barrier to treatment (34.7%) than the parents of normal children (20.3%). Larger proportion of parents of normal children (82%) rated the present dental services as excellent/good compared to 52% of the parents of disabled children (p < 0.001). Toothache and curative treatment need were the main reasons for dental visits among disabled children. Regular dental check-ups and preventive oral health care should be encouraged for comprehensive coverage of the national school oral health program for the disabled in Kuwait. PMID- 26058309 TI - [Ectodermal Capdepont syndrome and oral prosthetic rehabilitation. About a clinical case]. AB - The authors describe the ectodermal Capdepont syndrome as an anomaly characterized by anhidrosis, hypotrichosis and anodontia diagnosed in a 22 year old adult. In front of this anodontia, oral prosthetic rehabilitation remains the only solution. PMID- 26058310 TI - Dental caries prevalence and bilateral occurrence in premolars and molars of adolescent school children in Ibadan, Nigeria. AB - The aim of the study was to determine the prevalence of dental caries in premolars and molars of adolescent school children in Ibadan, Nigeria with a view of comparing findings from this study with previous African studies. A cross section of 12-19 year-old school children from the five local government areas in Ibadan were examined over a period of three months by two examiners (OD and DA), using the WHO criteria for diagnosing dental caries. Only premolars and molars were examined but the third molars were excluded because they were not fully erupted in most children. The mean age of the children under study was 16.2 +/- 0.83 years. Dental caries was detected in 10.8% of the children. Overall, 225 teeth had dental caries, out of which 13.3% were premolars while 86.67% were molars. Among the molars, first molars were mostly affected by caries (68.72%) while 31.28% second molars were affected. Second premolars were more affected by caries among the premolars. Also bilateral caries occurrence was highest in the mandibular first molars. In conclusion since the first molars were the most vulnerable teeth to decay, caries preventive programs on them need to be drawn up. PMID- 26058311 TI - Antioxidant and renoprotective activity of 2-hydroxypropyl-beta-cyclodextrin in nephrectomized rats. AB - OBJECTIVES: Oxidative stress is known to be involved in the pathogenesis of chronic renal failure (CRF). In this study, the effect of cyclodextrins (CDs) on oxidative stress and CRF was investigated using 5/6 nephrectomized rats as model animals. METHODS: CRF model rats were divided into five groups and treated for 8 weeks as follows: control, alpha-CD, beta-CD, gamma-CD and 2-hydroxypropyl-beta CD (HP-beta-CD). Blood was collected from the rats after 4 and 8 weeks for an analysis of renal function and oxidative stress tests were carried out. KEY FINDINGS: An oral administration of HP-beta-CD over an 8-week period resulted in a significant decrease in serum indoxyl sulphate, creatinine and urea nitrogen levels, compared with the other CDs. The ingestion of HP-beta-CD also resulted in an increase in antioxidant potential, compared with the other CDs. In in vitro studies, the interaction of HP-beta-CD with a uremic toxin, indole molecule, was much higher than that for the other CDs, as evidenced by Proton nuclear magnetic resonance ((1) H NMR) measurements. CONCLUSIONS: These results suggest that the ingestion of HP-beta-CD might result in a significant reduction in the levels of pro-oxidants in the gastrointestinal tract, such as uremic toxins, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation. PMID- 26058312 TI - Minimizing chemotherapy-induced peripheral neuropathy: preclinical and clinical development of new perspectives. AB - INTRODUCTION: Chemotherapy-induced peripheral neuropathies (CIPN) are a dose limiting adverse effect of certain anticancer drugs (platinum salts, vinca alkaloids, taxanes, bortezomib, thalidomide, epothilones, eribulin). CIPN are mainly responsible for sensory disturbances and are associated with a decrease in quality of life. After the end of chemotherapy, CIPN can last for several months and even years. Unfortunately, recent meta-analyses of clinical trials have demonstrated that there is no univocal gold standard for the prevention and treatment of CIPN. AREAS COVERED: Using animal models of CIPN, several new strategies to prevent or treat CIPN are under development. These new strategies involve several pathways, including ion channels, neuroprotectants, glutamatergic neurotransmission, oxidative stress, cannabinoid system, inflammation, and mitochondrial functions. EXPERT OPINION: To date, based on meta-analyses of clinical trials, no drug can be proposed as a gold standard to prevent or treat CIPN. Consequently, there is a strong discrepancy between the optimistic results of animal studies and the poor outcomes of clinical trials. Pain assessment in preclinical and clinical studies is probably not the best outcome measurement tool and all these studies should include composite outcomes including the full complexity of CIPN symptoms, such as positive symptoms (pain, paresthesia, and dysesthesia) and negative ones (numbness). PMID- 26058314 TI - Observing practice leadership in intellectual and developmental disability services. AB - BACKGROUND: Improving staff performance is an issue in services for people with intellectual disability. Practice leadership, where the front line leader of a staff team focuses on service user outcomes in everything they do and provides coaching, modeling, supervision and organisation to the team, has been identified as important in improving staff performance. To date this finding is based only on self-report measures. METHODS: This paper describes and tests an observational measure of practice leadership based on an interview with the front-line manager, a review of paperwork and observations in 58 disability services in Australia. RESULTS: The measure showed good internal consistency and acceptable inter-rater reliability. Practice leadership was associated with staff practice and outcomes for service users. The observed measure of practice leadership appears to be a useful tool for assessing whether leadership within a service promotes enabling and empowering support by staff. It was found to discriminate higher and lower performing services in terms of active support. CONCLUSIONS: The measure had good reliability and validity although some further testing is required to give a complete picture of the possible uses and reliability of the measure. The measure is potentially useful in contexts of both research and service development. The confirmation of previous findings from self-report measures that practice leadership is related to the quality of staff practice and outcomes for service users has implications for policy and practice in terms of the training of managers and structures for organisational management. PMID- 26058313 TI - Do oral bacteria alter the regenerative potential of stem cells? A concise review. AB - Mesenchymal stem cells (MSCs) are widely recognized as critical players in tissue regeneration. New insights into stem cell biology provide evidence that MSCs may also contribute to host defence and inflammation. In case of tissue injury or inflammatory diseases, e.g. periodontitis, stem cells are mobilized towards the site of damage, thus coming in close proximity to bacteria and bacterial components. Specifically, in the oral cavity, complex ecosystems of commensal bacteria live in a mutually beneficial state with the host. However, the formation of polymicrobial biofilm communities with pathogenic properties may trigger an inadequate host inflammatory-immune response, leading to the disruption of tissue homoeostasis and development of disease. Because of their unique characteristics, MSCs are suggested as crucial regulators of tissue regeneration even under such harsh environmental conditions. The heterogeneous effects of bacteria on MSCs across studies imply the complexity underlying the interactions between stem cells and bacteria. Hence, a better understanding of stem cell behaviour at sites of inflammation appears to be a key strategy in developing new approaches for in situ tissue regeneration. Here, we review the literature on the effects of oral bacteria on cell proliferation, differentiation capacity and immunomodulation of dental-derived MSCs. PMID- 26058315 TI - Early Computed Tomography Frontal Abnormalities Predict Long-Term Neurobehavioral Problems But Not Affective Problems after Moderate to Severe Traumatic Brain Injury. AB - Behavioral problems are serious consequences of moderate to severe traumatic brain injury (TBI) and have a negative impact on outcome. There may be two types: neurobehavioral problems, manifesting as inadequate social behavior resulting from prefrontal system damage, and affective behavioral problems, resulting from emotional distress as a reaction to the brain injury. In the present study we investigated whether these two types of behavioral problems, as indicated by proxies, could be distinguished in a group of chronic TBI patients and whether early indicators of prefrontal damage on imaging could predict long-term neurobehavioral problems. Computed tomography (CT) imaging data on admission were used to identify frontal lesions. Three hundred twenty-three moderate to severe TBI survivors received 2 to 16 years post-trauma an aftercare survey with seven questions asking for changes in behavior and affect, presented both to patients and their proxies. One hundred eighty-six patients (59%) answered the behavioral questions; 42% had frontal lesions on CT. Ordinal common factor analysis on proxy scores yielded two factors, with behavior and affective items clearly separated and the anger item mediocre related to both factors. Three scales were created: Behavior, Affective and Anger. Frontal patients scored significantly higher on the Behavior and Anger scales. Logistic regression analysis showed a fourfold increase of long-term neurobehavioral problems in patients with frontal lesions. Long-term neurobehavioral problems were significantly correlated to one-year outcome and return to work in the long term. We conclude that in patients with moderate to severe TBI neurobehavioral and affective problems can be distinguished. Early CT frontal abnormalities predict long-term neurobehavioral problems, but not affective problems. PMID- 26058316 TI - A pilot study of team learning on in-patient rounds. AB - BACKGROUND: Medical trainees often do not receive structured teaching during in patient rounds. OBJECTIVE: To assess whether the addition of a collaborative team learning technique would improve the learning experience on a general medicine in patient team. METHODS: Eight learners participated in this pilot study. Learning teams consisted of internal medicine residents and third-year medical students on a general medicine in-patient rotation. The experimental curriculum covered four common topics: cardiac stress testing; syncope; pneumonia; and valvular heart disease. Sessions had the following format: (1) each learner answered five self assessment questions using an immediate feedback technique; (2) learners were divided into groups of two or three to discuss their answers; (3) the teaching doctor led a discussion to clarify and summarise, and also distributed a handout delineating key learning points. Control sessions consisted of the usual teaching rounds. Learners were e-mailed a daily online survey asking them to rate the rounds and handouts on a Likert scale. Medical trainees often do not receive structured teaching during in-patient rounds RESULTS: All of the learners rated the collaborative team learning intervention as either 'excellent' or 'very good'. Learners also indicated that they found the take-away handout valuable, and positive responses were also noted in the survey comments. DISCUSSION: A novel collaborative team learning technique resulted in high ratings of teaching rounds by medical residents and medical students. Learners found the sessions engaging, high yield, and educationally valuable. This interactive discussion based teaching method could be used to enhance the learning experience during teaching rounds on medical, surgical and subspecialty services. PMID- 26058317 TI - A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma. AB - The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as "GliomaFF." We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy. PMID- 26058318 TI - Pregnancy Hyperglycaemia and Risk of Prenatal and Postpartum Depressive Symptoms. AB - BACKGROUND: Glucose dysregulation in pregnancy may affect maternal depressive symptoms during the prenatal and postpartum periods via both physiologic and psychological pathways. METHODS: During mid-pregnancy, a combination of 50-g 1-h non-fasting glucose challenge test (GCT) and 100-g 3-h fasting oral glucose tolerance test was used to determine pregnancy glycaemic status among women participating in Project Viva: normal glucose tolerance (NGT), isolated hyperglycaemia (IHG), impaired glucose tolerance (IGT) and gestational diabetes mellitus (GDM). Using the Edinburgh Postnatal Depression Scale (EPDS), we assessed depressive symptoms at mid-pregnancy and again at 6 months postpartum. We used logistic regression, adjusted for sociodemographic, anthropometric and lifestyle factors, to estimate the odds of elevated prenatal and postpartum depressive symptoms (EPDS >= 13 on 0-30 scale) in relation to GCT glucose levels and GDM status in separate models. RESULTS: A total of 9.6% of women showed prenatal and 8.4% postpartum depressive symptoms. Women with higher GCT glucose levels were at greater odds of elevated prenatal depressive symptoms [multivariable-adjusted odds ratio (OR) per standard deviation (SD) increase in glucose levels (27 mg/dL): 1.25; 95%: 1.07, 1.48]. Compared with NGT women, the association appeared stronger among women with IHG [OR: 1.80; 95% confidence interval (CI): 1.08, 3.00] than among those with GDM (OR: 1.45; 95% CI: 0.72, 2.91) or IGT (OR: 1.43; 95% CI: 0.59, 3.46). Neither glucose levels assessed from the GCT nor pregnancy glycaemic status were significantly associated with elevated postpartum depressive symptoms. CONCLUSION: Pregnancy hyperglycaemia was cross-sectionally associated with higher risk of prenatal depressive symptoms, but not with postpartum depressive symptoms. PMID- 26058319 TI - Transient elastography and aspartate aminotransferase to platelet ratio predict liver injury in paediatric intestinal failure. AB - BACKGROUND & AIMS: We aimed to evaluate the value of AST to platelet ratio (APRI) and transient elastography (TE) as predictors of liver histopathology in children with intestinal failure (IF). METHODS: Altogether 93 liver biopsies from 57 children with parenteral nutrition (PN) duration >=3 months were analysed. APRI measurement and TE (n = 46) were performed at the time of biopsy. RESULTS: IF was caused by short bowel syndrome in 75% of patients. At the time of liver biopsy, PN dependent patients (n = 42) were younger with longer PN duration compared to those weaned off PN (n = 51) (2.2 vs. 7.6 years, P < 0.001; 26 vs. 10.5 months, P = 0.043). Elevated transaminase or bilirubin levels were found in 51%, splenomegaly in 26%, and oesophageal varices in 3.5%. Histological fibrosis was present in 61% (Metavir stage F1; 27%, F2; 26%, F3-4; 9%), cholestasis in 25% and steatosis in 22% of biopsy specimens. TE was superior to APRI in prediction of any liver histopathology (fibrosis, cholestasis or steatosis) with areas under the receiving operating curve (AUROC) of 0.86 (95% CI 0.74-0.97) and 0.67 (95% CI 0.58-0.78) respectively. For prediction of >=F1 and >=F2 fibrosis, AUROC values for TE were 0.78 (95% CI 0.64-0.93) and 0.73 (95% CI 0.59-0.88), whereas APRI did not correlate with fibrosis stages. For detection of histological cholestasis, the AUROC for APRI was 0.77 (95% CI 0.64-0.89). CONCLUSIONS: Both TE and APRI are promising noninvasive methods for monitoring the development of IF-related liver histopathology. TE values reflected the degree of fibrosis better while APRI detected histological cholestasis more accurately. PMID- 26058320 TI - Psychoanalysis of maturescence (definition, metapsychology, and clinical practice). AB - This article offers an entirely new way of addressing middle age or mid-life. It uses the neologism maturescence to denote this process's metapsychological feature, and it proposes a meta-psychology of maturescence in order to allow a 'direct understanding of maturescence' instead of the 'indirect understanding of maturescence', which psychoanalytic literature generally alludes to. The paper examines somatic processes specific to male and female climacterics and is focused on to the tension between the soma and the body. It examines the drive increase that Freud posed in climacterics and the somatic climacteric imbalance that begets specific drive activity demanding psychic work, with very different pathways depending on the individual's specific working-through activity. It discusses what happens to the individual when he/she is no longer able to procreate and begins to age; why this process is equivalent for individuals who had children and for others who could not or did not. This somatic event provides a universal constant from which it is possible to understand any individual variable. PMID- 26058321 TI - Efficacy and safety of pharmacological treatments for acute Lyme neuroborreliosis - a systematic review. AB - BACKGROUND AND PURPOSE: Our aim was to evaluate the available evidence for pharmacological treatment of acute Lyme neuroborreliosis as a basis for evidence based clinical recommendations in a systematic review. METHODS: A systematic literature search of Medline, EMBASE, the Cochrane Library and three trial registries was performed. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were evaluated. Risk of bias was assessed using the Cochrane risk of bias tools. The primary outcome was 'residual neurological symptoms' whilst the secondary outcomes were disability, quality of life, pain, fatigue, depression, cognition, sleep, adverse events and cerebrospinal fluid pleocytosis. The quality of the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: After screening 5779 records, eight RCTs and eight NRS were included. Risk of bias was generally high. No statistically significant difference was found between doxycycline and beta-lactam antibiotics in a meta-analysis regarding residual neurological symptoms at 4-12 months [risk ratio (RR) 1.27, 95% confidence interval (CI) 0.98 1.63, P = 0.07] or adverse events (RR 0.82, 95% CI 0.54-1.25, P = 0.35). Significantly fewer neurological symptoms for cefotaxime compared with penicillin were found (RR 1.81, 95% CI 1.10-2.97, P = 0.02). Adverse events were significantly fewer for penicillin (RR 0.56, 95% CI 0.38-0.84, P = 0.005). CONCLUSIONS: Evidence regarding pharmacological treatment of acute Lyme neuroborreliosis is scarce and therefore insufficient to recommend preference of beta-lactam antibiotics over doxycycline or vice versa. However, due to considerable imprecision, relevant differences between treatments cannot be excluded. No evidence suggesting benefits of extended antibiotic treatments could be identified. Further well-designed trials are needed. Individual treatment decisions should address patients' preferences and individual conditions like prior allergic reactions. PMID- 26058322 TI - In vitro activity of the protegrin IB-367 alone and in combination compared with conventional antifungal agents against dermatophytes. AB - The occurrence of resistance or side effects in patients receiving antifungal agents leads to failure in the treatment of mycosis. The aim of this experimental study was to investigate the in vitro effects of IB-367 alone and in combination with three standard antifungal drugs, fluconazole (FLU), itraconazole (ITRA) and terbinafine (TERB), against 20 clinical isolates of dermatophytes belonging to three species. Minimum inhibitory concentrations (MICs), minimal fungicidal concentrations (MFCs), synergy test, time-kill curves, fungal biomass (FB) and hyphal damage using 2,3-bis-(2-methoxy-4-nitro-5-sulfenylamino carbonil)-2H tetrazolium hydroxide assay (XTT) were performed to study the efficacy of IB-367. In this study, we observed that TERB and ITRA had MICs lower values for all the strains compared to IB-367 and FLU. Synergy was found in 35%, 30% and 25% of IB 367/FLU, IB-367/ITRA and IB-367/TERB interactions respectively. IB-367 exerted a fungicidal activity against Trichophyton mentagrophytes, T. rubrum and Microsporum canis at concentrations starting from 1x MIC. At a concentration of 5x MIC, IB-367 showed the highest rates of hyphae damage for M. canis 53% and T. mentagrophytes 50%; against the same isolates it caused a reduction of 1 log of the total viable count cell hyphae damage. We propose IB-367 as a promising candidate for the future design of antifungal drugs. PMID- 26058323 TI - Night-time continence care in Australian residential aged care facilities: findings from a grounded theory study. AB - BACKGROUND: Continence care commonly disrupts sleep in residential aged care facilities, however, little is known about what staff do when providing continence care, and the factors that inform their practice. AIMS: To describe nurses' and personal careworkers' beliefs and experiences of providing continence care at night in residential aged care facilities. METHODS/DESIGN: Eighteen nurses and personal careworkers were interviewed about continence care, and 24 hours of observations were conducted at night in two facilities. RESULTS/FINDINGS: Most residents were checked overnight. This practice was underpinned by staffs' concern that residents were intractably incontinent and at risk of pressure injuries. Staff believed pads protected and dignified residents. Decisions were also influenced by beliefs about limited staff-to-resident ratios. CONCLUSION: Night-time continence care should be audited to ensure decisions are based on residents' preferences, skin health, sleep/wake status, ability to move in bed, and the frequency, severity and type of residents' actual incontinence. PMID- 26058324 TI - Reductions in post-hepatectomy liver failure and related mortality after implementation of the LiMAx algorithm in preoperative work-up: a single-centre analysis of 1170 hepatectomies of one or more segments. AB - OBJECTIVES: Post-hepatectomy liver failure has a major impact on patient outcome. This study aims to explore the impact of the integration of a novel patient centred evaluation, the LiMAx algorithm, on perioperative patient outcome after hepatectomy. METHODS: Trends in perioperative variables and morbidity and mortality rates in 1170 consecutive patients undergoing elective hepatectomy between January 2006 and December 2011 were analysed retrospectively. Propensity score matching was used to compare the effects on morbidity and mortality of the integration of the LiMAx algorithm into clinical practice. RESULTS: Over the study period, the proportion of complex hepatectomies increased from 29.1% in 2006 to 37.7% in 2011 (P = 0.034). Similarly, the proportion of patients with liver cirrhosis selected for hepatic surgery rose from 6.9% in 2006 to 11.3% in 2011 (P = 0.039). Despite these increases, rates of post-hepatectomy liver failure fell from 24.7% in 2006 to 9.0% in 2011 (P < 0.001) and liver failure related postoperative mortality decreased from 4.0% in 2006 to 0.9% in 2011 (P = 0.014). Propensity score matching was associated with reduced rates of post hepatectomy liver failure [24.7% (n = 77) versus 11.2% (n = 35); P < 0.001] and related mortality [3.8% (n = 12) versus 1.0% (n = 3); P = 0.035]. CONCLUSIONS: Postoperative liver failure and postoperative liver failure-related mortality decreased in patients undergoing hepatectomy following the implementation of the LiMAx algorithm. PMID- 26058326 TI - Microbial diversity and community structure along a lake elevation gradient in Yosemite National Park, California, USA. AB - Microbial communities are key components of lake ecosystems and play central roles in lake biogeochemical cycles. Freshwater lakes, in turn, have a disproportionate influence on global carbon and nitrogen cycling, while also acting as 'sentinels' of environmental change. Determining what factors regulate microbial community dynamics and their relationship to lake biogeochemistry is therefore essential to understanding global change feedbacks. We used Illumina sequencing of >2 million 16S rRNA genes to examine microbial community structure and diversity in relation to spatial, temporal and biogeochemical variation, within and across lakes located along a 871 m elevation gradient in Yosemite National Park, California, USA. We captured a rich microbial community that included many rare operational taxonomic units (OTUs), but was dominated by a few bacterial classes and OTUs frequently detected in other freshwater ecosystems. Neither richness, evenness nor overall diversity was directly related to elevation. However, redundancy analysis showed that changes in microbial community structure were significantly related to elevation. Along with sampling period and dissolved nutrient concentrations, 29% of the variation in community structure could be explained by measured variables - in congruence with studies in other lakes using different techniques. We also found a distance-decay relationship in microbial community structure across lakes, suggesting that both local environmental factors and dispersal play a role in structuring communities. PMID- 26058327 TI - Gender Differences in Predrinking Behavior Among Nightclubs' Patrons. AB - BACKGROUND: Drinking before entering nightclubs (predrinking) seems to be associated with an increase in alcohol-related harm. This study aims to investigate gender differences in predrinking behavior and to evaluate its association with risk behaviors practiced inside nightclubs. METHODS: Individual level data were collected by a portal survey of 2,422 patrons at the entrance and 1,833 patrons at the exit of 31 nightclubs located at Sao Paulo, Brazil. The nightclubs were selected by 2-stage sampling with probability proportional to the establishments' capacity in the first stage and a systematic sample of patrons in the entrance line in the second stage. Breath alcohol concentration (BrAC) was measured at the entrance and exit. Face-to-face interviews identified predrinking characteristics and risk behaviors. Weighted analyses were stratified by gender. RESULTS: Predrinking was practiced by 49.2% (95% confidence interval [CI] = 42.7 to 55.8) of the male patrons and 29.0% (95% CI = 20.6 to 38.9) of the female patrons (p < 0.001) on the day of the interview. When considering only predrinkers, men and women showed similar BrAC at entrance and exit and similar proportion of alcoholic intoxication (BrAC >= 0.38 mg/l). In both genders, people who practiced predrinking on the day of the interview were more likely to drink inside the nightclub, compared to those who did not practice predrinking (p < 0.001). Among men, the practice of predrinking increased the chance of "drinking and driving" after leaving the nightclub (odds ratio [OR] = 6.9, 95% CI = 4.1 11.5, p < 0.001). Among women, the practice of predrinking increased the chances of experiencing sexual harassment in the nightclub (OR = 2.9, 95% CI = 1.3 to 6.6, p = 0.010). CONCLUSIONS: Predrinking is more prevalent among men; however, men and women who engaged in predrinking have a similar pattern of alcohol consumption and exit BrAC. The fact that risk behaviors and illicit drug use were associated with predrinking but differ between genders suggests that a gender specific approach should be used in tailored interventions to prevent alcohol related harm in nightclubs. PMID- 26058328 TI - Pediatric epilepsy following neonatal seizures symptomatic of stroke. AB - BACKGROUND: Neonatal seizures are a risk factor for later epilepsy and their etiology is known to be implicated in the outcome but, little is known about this issue in the subgroup of seizures symptomatic of perinatal arterial ischemic stroke. The aim of this study was to describe the long term risk of epilepsy after electroencephalographic confirmed neonatal seizures symptomatic of perinatal arterial ischemic stroke. DESIGN/SUBJECT: Fifty-five patients with electroclinical ictal data, vascular territory confirmed by neuroimaging and a minimum follow up of 3.5 years were identified from a multi-centre prospective neonatal seizures registry. Primary outcome was occurrence of post-neonatal epilepsy. The association of outcome with family history of epilepsy, gender, location of the infarct, neonatal clinical and electroencephalogram data were also studied. RESULTS: During a mean follow up of 8 years and 5 months, 16.4% of the patients developed post neonatal epilepsy. The mean age at first post neonatal seizure was 4 years and 2 months (range 1-10 years and 6 months). Location of the infarct was the only statistically significant risk factor (p=0.001); epilepsy was more represented in males but the difference was not statistically significant. CONCLUSIONS: Neonatal seizures symptomatic of perinatal arterial ischemic stroke had lower risk and later onset of post neonatal epilepsy, compared to seizures described in the setting of other perinatal brain insults. Our data have implications for counseling to the family at discharge from neonatal intensive care unit. PMID- 26058329 TI - Phosphonate derivatives of tetraazamacrocycles as new inhibitors of protein tyrosine phosphatases. AB - alpha,alpha-Difluoro-beta-ketophosphonated derivatives of tetraazamacrocycles were synthesized and found to be potential inhibitors of protein tyrosine phosphatases. N-Substituted conjugates of cyclam and cyclen with bioisosteric phosphonate groups displayed good activities toward T-cell protein tyrosine phosphatase with IC50 values in the micromolar to nanomolar range and showed selectivity over PTP1B, CD45, SHP2, and PTPbeta. Kinetic studies indicated that the inhibitors can occupy the region of the active site of TC-PTP. This study demonstrates a new approach which employs tetraazamacrocycles as a molecular platform for designing inhibitors of protein tyrosine phosphatases. PMID- 26058330 TI - New Pustular Lesions in an Infant with Fever. PMID- 26058331 TI - Beyond stress: describing the experiences of families during neonatal intensive care. AB - AIM: To determine whether parents of critically ill premature infants feel that neonatal intensive care unit (NICU) therapy is worthwhile, independent of their infant's outcome. METHODS: The parent(s) of ventilated infants in the NICU were interviewed. Prominent themes were identified within the text of transcribed interviews and the frequency of each theme tabulated. RESULTS: The parents of 10 infants were interviewed. All parents experienced stress and understood the uncertain future of their infants. Parents remained optimistic and uniformly expressed that NICU intervention was 'worth it'. No parent described concern about 'torture', 'cruelty' or 'futile care'. CONCLUSION: Although parents experience significant stress while their infant is in the NICU, their emotional experiences are much more broad. They feel confident in their decision to give their child a chance, a responsibility to be informed and to make the best decisions they can and remain hopeful for a good outcome regardless of their child's condition. PMID- 26058332 TI - Ageing does not result in a decline in cell synthetic activity in an injury prone tendon. AB - Advancing age is a well-known risk factor for tendon disease. Energy-storing tendons [e.g., human Achilles, equine superficial digital flexor tendon (SDFT)] are particularly vulnerable and it is thought that injury occurs following an accumulation of micro-damage in the extracellular matrix (ECM). Several authors suggest that age-related micro-damage accumulates due to a failure of the aging cell population to maintain the ECM or an imbalance between anabolic and catabolic pathways. We hypothesized that ageing results in a decreased ability of tendon cells to synthesize matrix components and matrix-degrading enzymes, resulting in a reduced turnover of the ECM and a decreased ability to repair micro-damage. The SDFT was collected from horses aged 3-30 years with no signs of tendon injury. Cell synthetic and degradative ability was assessed at the mRNA and protein levels. Telomere length was measured as an additional marker of cell ageing. There was no decrease in cellularity or relative telomere length with increasing age, and no decline in mRNA or protein levels for matrix proteins or degradative enzymes. The results suggest that the mechanism for age-related tendon deterioration is not due to reduced cellularity or a loss of synthetic functionality and that alternative mechanisms should be considered. PMID- 26058334 TI - Detecting Nonlinearity and Edge-of-Chaos Phenomena in Ordinal Data. AB - Some but not all algorithms for detecting nonlinearity in experimental data, such as prediction methods and Lyapunov spectra, require a much larger amount of stable continuous data than is generally available from individual human participants. A new method for detecting nonlinearity in relatively short data sets, Monotonic Ectropy, computes the change in Shannon information as ordinal scale values evolve over time by comparing runs of various lengths and directions. This method compares two successive ordinal scale changes with similar monotonic changes for three successive ordinal scale values. The resulting index discriminates a chaotic Henon series from both Gaussian noise and phase-randomised surrogate series, the latter containing the stochastic structure of the Henon series but without the nonlinearity. The empirical utility of the technique is illustrated using mood rating data obtained from two participants, one suffering from chronic depression, the other showing no signs of the disorder. Although Monotonic Ectropy discriminated between the mood ratings of the depressed and nondepressed subjects, evidence for nonlinearity was only obtained using Lempel-Ziv complexity, a measure based on symbolic dynamics. This was probably due to Monotonic Ectropy's unique sensitivity to edge-of-chaos phenomena. PMID- 26058333 TI - Classical and atypical Fibrodysplasia Ossificans Progressiva in India. AB - Fibrodysplasia Ossificans Progressiva (FOP) is a rare debilitating disorder characterized by congenital deformity of the great toes from infancy and postnatal heterotopic ossification. Activating mutations in the activin A receptor type 1 (ACVR1) gene are responsible for the disease. The most common allelic variant leading to FOP is c.617 G>A; p.R206H, however, other alleles have been reported with atypical phenotypes. We report 14 cases presenting to a referral institution in South India over a 3-year period. The patients were clinically diagnosed based on foot abnormality or abnormal ectopic ossification and were screened for ACVR1. The genetic analysis of ACVR1 identified the recurrent allelic variant in 12 of 14 patients. One of the remaining patients had a previously reported allele c.1067G>A; p.G356D in the 9th exon and the second allele c.983G>A; p.G328E in the 8th exon of ACVR1. The most common recurrent allele c.617 G>A; p.R206H is also the most common in Indian patients with FOP. PMID- 26058335 TI - Modeling Outcomes of Partner Violence Using Cusp Catastrophe Modeling. AB - Research suggests that intimate partner violence (IPV) is a complex, nonlinear phenomenon. In addition to the violence trajectory itself, IPV decision-making, help-seeking and leaving are nonlinear processes as well. The purpose of this study was to determine whether outcomes were best modeled as cusp catastrophic phenomena with measures of violence nonlinearity and wife-perpetrated violence serving as bifurcation variables. This 12-week time series study was conducted among 200 adult women in violent relationships. Women completed daily assessments of household environment and marital relationship using Interactive Verbal Response; missing violence data was imputed using TISEAN software to maintain its nonlinear characteristics. LZ complexity, approximate entropy, and largest Lyapunov exponents were used as measures of violence nonlinearity. Asymmetry variables included violence frequency and severity as well as its onset and duration. Factor-analyzed outcomes included coping and appraisals, hope and support, symptomatology, functional status, readiness-for-change, and medical utilization. When severity of wife's violence and nonlinearity of husband's violence were used as bifurcation variables, cusp catastrophe modeling helped explain positive and negative coping as well as readiness-for-change. In conclusion, measures of nonlinearity of husband's violence and wife's violence contributed to the variance of three outcomes in cusp catastrophe modeling. Sudden changes in coping and readiness-for-change in IPV should be expected and knowledge of violence nonlinearity may have applications when working with violent couples. PMID- 26058336 TI - The Complexity of Primary Care Psychology: Theoretical Foundations. AB - How does primary care psychology deal with organized complexity? Has it escaped Newtonian science? Has it, as Weaver (1991) suggests, found a way to 'manage problems with many interrelated factors that cannot be dealt by statistical techniques'? Computer simulations and mathematical models in psychology are ongoing positive developments in the study of complex systems. However, the theoretical development of complex systems in psychology lags behind these advances. In this article we use complexity science to develop a theory on experienced complexity in the daily practice of primary care psychologists. We briefly answer the ontological question of what we see (from the perspective of primary care psychology) as reality, the epistemological question of what we can know, the methodological question of how to act, and the ethical question of what is good care. Following our empirical study, we conclude that complexity science can describe the experienced complexity of the psychologist and offer room for personalized client-centered care. Complexity science is slowly filling the gap between the dominant reductionist theory and complex daily practice. PMID- 26058337 TI - Estimating Appropriate Lag Length for Synchronized Physiological Time Series: The Electrodermal Response. AB - Physiological synchronization of autonomic arousal between people is thought to be an important component of work team dynamics, therapist-client relationships, and other interpersonal dynamics. This article examines concepts and mathematical models of synchronization that could be relevant to work teams. Before it is possible to deploy nonlinear modeling, however, it is necessary to develop a strategy for determining appropriate lag lengths. If a measurement at time 2 is a function of itself at time 1 and a coupling effect from another source, what is the appropriate amount of real time that should be allowed to elapse between the two measurements in order to observe the coupling effect? This study examined four strategies for doing so. In the experiment, 78 undergraduates worked in pairs to perform a vigilance dual task for 90 min while galvanic skin responses (GSR) were recorded. Lags based on mutual entropy and the natural rate criteria produced corroborating results, whereas strategies based on a critical decline in the linear autocorrelation (max r/e) and Theiler's W did not produce usable results for this situation. Some connections were uncovered between linear autocorrelation strength and lag based on mutual entropy with performance on the tasks and subjective ratings of workload. PMID- 26058338 TI - A Model of Animal Spirits via Sentiment Spreading. AB - In order to incorporate animal spirits in a scientifically rigorous inquiry about the causes of aggregate business cycles, one needs to explore the foundations of human behavior, namely concerning the process through which sentiment switching occurs. Which factors drive human sentiments? In what conditions a pessimistic individual becomes an optimist, or the other way around? Is it possible to justify persistent waves of optimism and pessimism under reasonable assumptions concerning social behavior? This article proposes a framework to address the posed questions. The setup is based on rumor propagation theory and it explains how social interaction may lead individuals to change from one sentiment state to the other, eventually triggering a rotation between periods of dominant optimism and periods of dominant pessimism. PMID- 26058339 TI - [Chediak-Higashi syndrome: Optical microscopy of hair]. PMID- 26058340 TI - [Is there vitamin D deficiency in children in a sunny Mediterranean city?]. AB - INTRODUCTION: Despite the increasing interest in vitamin D functions, new cases of deficiency have been reported in sunny regions where optimal levels are expected. The aim of this study was to analyze 25-hydroxivitamin D levels in children younger than 2 years admitted for acute mild diseases in a tertiary hospital in Valencia and its relationship with factors that can be associated with its deficiency. METHODS: This one year prospective and observational study was conducted on 169 children admitted for acute mild diseases. 25-hydroxivitamin D levels were analyzed. A standardized physical examination and structured interviews to the parents were performed. Children were classified into two groups, according to 25-hydroxivitamin D levels (cut-off 30 ng/mL). RESULTS: A total of 169 children were included, with a median age of 9 months, being more prevalent Caucasians (75.7%) and youger than one year old (79.3%). Almost one quarter (24.3%) of the children had 25-hydroxivitamin D levels <30 ng/mL, more frequently in winter/spring, and in children with higher skin phototypes (P<.01). Levels >30 ng/mL were associated with vitamin D prophylaxis during the first year, in children of a Caucasian mother, and those who did not wear a hijab. No statistical differences were found in diet characteristics (P=.65). Prophylaxis was given to 47% of the breastfed children younger than one year. CONCLUSIONS: In Valencia, Spain, 25-hydroxivitamin D levels lower than 30 ng/mL were found in a quarter of the children younger than two years. Our results emphasize the importance of vitamin D prophylaxis during the first year of life, even in sunny Mediterranean regions. PMID- 26058342 TI - Genomic characterization of two novel HIV-1 unique (CRF01_AE/B) recombinant forms among men who have sex with men in Beijing, China. AB - We report here two novel HIV-1 recombinant forms (CRF01_AE/B) isolated from two HIV-positive male subjects infected through homosexual contact in Beijing, China. Recombination contributes substantially to the genetic diversity of HIV-1, and is likely to occur in populations in which multiple subtypes circulate. Molecular epidemiological studies showed that subtype B, CRF01_AE, and CRF07_BC are currently cocirculating in parallel among men who have sex with men (MSM) in China, providing the opportunity for the emergence of new recombinants. Phylogenetic analysis of near full-length genome (NFLG) sequences showed that the unique recombinant forms (URFs) were composed of gene regions from CRF01_AE and subtype B. The CRF01_AE region of the recombinants clustered together with a previously described cluster 4 lineage of CRF01_AE. The B regions of both the recombinants clustered within the B strains. The two recombinants were quite similar with six breakpoints in common. These data highlight the importance of continuous surveillance of the dynamic change of HIV-1 subtypes and new recombinants among the MSM population. PMID- 26058343 TI - Large scale fabrication of well-aligned CdS/p-Si shell/core nanowire arrays for photodetectors using solution methods. AB - We report a facile approach for the preparation of the vertically aligned, large scale CdS/p-Si shell/core nanowire heterojunction arrays based on successive ionic layer adsorption and reaction deposition. The results indicate that the rectifying characteristics of CdS/Si shell/core nanowire arrays can be tailored by changing the number of SILAR cycles, and the CdS/Si shell-core nanowire heterojunctions have good photo-sensitivity (the ratio of photocurrent to dark current could reach 14.96 at -1 V reverse bias) under AM 1.5 (1 Sun) illumination. Furthermore, the electron transport mechanism across the CdS/Si nano-heterojunctions is also discussed in detail. This reported CdS/p-Si shell/core nanowire structure offers a generic approach for the integration of new functional materials for photo-electronics applications. PMID- 26058344 TI - Alteration of heme metabolism in a cellular model of Diamond-Blackfan anemia. AB - Diamond-Blackfan anemia (DBA) is a congenital pure red cell aplasia often associated with skeletal malformations. Mutations in ribosomal protein coding genes, mainly in RPS19, account for the majority of DBA cases. The molecular mechanisms underlying DBA pathogenesis are still not completely understood. Alternative spliced isoforms of FLVCR1 (feline leukemia virus subgroup C receptor 1) transcript coding for non-functional proteins have been reported in some DBA patients. Consistently, a phenotype very close to DBA has been described in animal models of FLVCR1 deficiency. FLVCR1 gene codes for two proteins: the plasma membrane heme exporter FLVCR1a and the mitochondrial heme exporter FLVCR1b. The coordinated expression of both FLVCR1 isoforms regulates an intracellular heme pool, necessary for proper expansion and differentiation of erythroid precursors. Here, we investigate the role of FLVCR1 isoforms in a cellular model of DBA. RPS19-downregulated TF1 cells show reduced FLVCR1a and FLVCR1b mRNA levels associated with heme overload. The downregulation of FLVCR1 isoforms affects cell cycle progression and apoptosis in differentiating K562 cells, a phenotype similar to DBA. Taken together, these data suggest that alteration of heme metabolism could play a role in the pathogenesis of DBA. PMID- 26058346 TI - Quantifying harmful effects of psoriatic diseases on quality of life: Cardio metabolic outcomes in psoriatic arthritis study (COMPASS). AB - OBJECTIVE: Up to 30% of patients with psoriasis suffer from concurrent psoriatic arthritis, and both the diseases have worse quality-of-life outcomes compared to the general population. There is limited literature comparing quality-of-life outcomes between these diseases. We seek to compare quality-of-life outcomes between both these groups. METHODS: The current study is a cross-sectional analysis of a cohort of 252 patients with psoriatic diseases, who were recruited from 2 tertiary-care centers. A self-administered questionnaire was used to collect demographic and validated quality-of-life data using short form-12 (SF 12), health assessment questionnaire (HAQ), and dermatology life quality index (DLQI). Univariate and multivariate analyses were conducted to compare the quality-of-life outcomes. RESULTS: We included 107 (42.5%) psoriatic arthritis and 145 (57.5%) psoriasis patients in the cohort. The groups had comparable gender distribution and co-morbid diseases prevalence, but arthritis patients were older and received biologics/DMARDs more frequently than psoriasis patients. The physical indices (identified by HAQ and SF 12 PCS) were worse for psoriatic arthritis, whereas the mental/psychometric indices (identified by DLQI and SF 12 MCS) were comparable between both the groups. CONCLUSIONS: Despite aggressive therapy, physical quality of life was worse in psoriatic arthritis patients compared to psoriasis patients. The mental quality-of-life indices were comparable in both the groups and were still below the population norm. These results suggest need for screening for psoriatic arthritis in patients with psoriasis to reduce the burden of physical quality of life and screening for early signs of psychiatric illnesses in both these disease populations. PMID- 26058347 TI - Preparation by mandatory E-modules improves learning of practical skills: a quasi experimental comparison of skill examination results. AB - BACKGROUND: Until recently, students at UMC Utrecht Faculty of Medicine prepared for practical skills training sessions by studying recommended literature and making written assignments, which was considered unsatisfactory. Therefore, mandatory e-modules were gradually introduced as substitute for the text based preparation. This study aimed to investigate whether this innovation improved students' performance on the practical skills (OSCE) examination. METHOD: In both the 2012 and 2013 OSCEs, e-modules were available for some skill stations whereas others still had text based preparation. We compared students' performance, both within and between cohorts, for skill stations which had e-module preparation versus skill stations with text based preparation. RESULTS: We found that performance on skill stations for which students had prepared by e-modules was significantly higher than on stations with text based preparation, both within and between cohorts. This improvement cannot be explained by overall differences between the two cohorts. CONCLUSION: Our results show that results of skills training can be improved, by the introduction of e-modules without increasing teacher time. Further research is needed to answer the question whether the improved performance is due to the content of the e-modules of to their obligatory character. PMID- 26058348 TI - The effect of sulfur on the electrical properties of S and N co-doped ZnO thin films: experiment and first-principles calculations. AB - P-type sulphur-nitrogen (S-N) co-doped ZnO thin films are deposited and the effect of sulphur on the electrical properties is discussed. First-principles calculations indicate that the structure is most stable when the S atom is close to the N atom in the (0002) plane, implying that dual-doped ZnO is relatively feasible to approach. The partial density of states of S-N co-doped ZnO shows that the S impurity plays a vital role in forming the p-type conductivity. PMID- 26058349 TI - Number of years of participation in some, but not all, types of physical activity during adolescence predicts level of physical activity in adulthood: Results from a 13-year study. AB - BACKGROUND: Adolescent physical activity (PA) levels track into adulthood. However it is not known if type of PA participated in during adolescence is associated with PA levels later in life. We aimed to identify natural groupings of types of PA and to assess whether number of years participating in these different groupings during adolescence is related to PA level in early adulthood. METHODS: 673 adolescents in Montreal, Canada, age 12-13 years at baseline (54% female), reported participation in 29 physical activities every 3 months over 5 years (1999-2005). They also reported their PA level at age 24 years (2011-12). PA groupings among the 29 physical activities were identified using factor analysis. The association between number of years participating in each grouping during adolescence and PA level at age 24 was estimated using linear regression within a general estimating equation framework. RESULTS: Three PA groupings were identified: "sports", "fitness and dance", and "running". There was a positive linear relationship between number of years participating in sports and running in adolescence and PA level at age 24 years (beta (95% confidence interval) = 0.09 (0.04-0.15); 0.08 (0.01-0.15), respectively). There was no relationship between fitness and dance in adolescence and PA level at age 24. CONCLUSIONS: The association between PA participation in adolescence and PA levels in young adulthood may be specific to certain PA types and to consistency of participation during adolescence. Results suggest that efforts to establish the habit of participation in sports and running in adolescence may promote higher PA levels in adulthood. PMID- 26058350 TI - General Practitioners' vitamin K antagonist monitoring is associated with better blood pressure control in patients with hypertension--a cross-sectional database study. AB - BACKGROUND: Patients requiring anticoagulation suffer from comorbidities such as hypertension. On the occasion of INR monitoring, general practitioners (GPs) have the opportunity to control for blood pressure (BP). We aimed to evaluate the impact of Vitamin-K Antagonist (VKA) monitoring by GPs on BP control in patients with hypertension. METHODS: We cross-sectionally analyzed the database of the Swiss Family Medicine ICPC Research using Electronic Medical Records (FIRE) of 60 general practices in a primary care setting in Switzerland. This database includes 113,335 patients who visited their GP between 2009 and 2013. We identified patients with hypertension based on antihypertensive medication prescribed for >= 6 months. We compared patients with VKA for >= 3 months and patients without such treatment regarding BP control. We adjusted for age, sex, observation period, number of consultations and comorbidity. RESULTS: We identified 4,412 patients with hypertension and blood pressure recordings in the FIRE database. Among these, 569 (12.9%) were on Phenprocoumon (VKA) and 3,843 (87.1%) had no anticoagulation. Mean systolic and diastolic BP was significantly lower in the VKA group (130.6 +/- 14.9 vs 139.8 +/- 15.8 and 76.6 +/- 7.9 vs 81.3 +/- 9.3 mm Hg) (p < 0.001 for both). The difference remained after adjusting for possible confounders. Systolic and diastolic BP were significantly lower in the VKA group, reaching a mean difference of -8.4 mm Hg (95% CI -9.8 to -7.0 mm Hg) and -1.5 mm Hg (95% CI -2.3 to -0.7 mm Hg), respectively (p < 0.001 for both). CONCLUSIONS: In a large sample of hypertensive patients in Switzerland, VKA treatment was independently associated with better systolic and diastolic BP control. The observed effect could be due to better compliance with antihypertensive medication in patients treated with VKA. Therefore, we conclude to be aware of this possible benefit especially in patients with lower expected compliance and with multimorbidity. PMID- 26058351 TI - Erratum to: Incidentally found giant thymomas by SPECT myocardial perfusion imaging. PMID- 26058345 TI - Cardiovascular morbidity and associated risk factors in Spanish patients with chronic inflammatory rheumatic diseases attending rheumatology clinics: Baseline data of the CARMA Project. AB - OBJECTIVE: To establish the cardiovascular (CV) morbidity and associated risk factors for CV disease (CVD) in Spanish patients with chronic inflammatory rheumatic diseases (CIRD) and unexposed individuals attending rheumatology clinics. METHODS: Analysis of data from the baseline visit of a 10-year prospective study [CARdiovascular in rheuMAtology (CARMA) project] that includes a cohort of patients with CIRD [rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriatic arthritis (PsA)] and another cohort of matched individuals without CIRD attending outpatient rheumatology clinics from 67 hospitals in Spain. Prevalence of CV morbidity, CV risk factors, and systematic coronary risk evaluation (SCORE) assessment were analyzed. RESULTS: A total of 2234 patients (775 RA, 738 AS, and 721 PsA) and 677 unexposed subjects were included. Patients had low disease activity at the time of recruitment. PsA patients had more commonly classic CV risk factors and metabolic syndrome features than did the remaining individuals. The prevalence of CVD was higher in RA (10.5%) than in AS (7.6%), PsA (7.2%), and unexposed individuals (6.4%). A multivariate analysis adjusted for the presence of classic CV risk factors and disease duration revealed a positive trend for CVD in RA (OR = 1.58; 95% CI: 0.90-2.76; p = 0.10) and AS (OR = 1.77; 95% CI: 0.96-3.27; p = 0.07). Disease duration in all CIRD groups and functional capacity (HAQ) in RA were associated with an increased risk of CVD (OR = 2.15; 95% CI: 1.29-3.56; p = 0.003). Most patients had a moderate CV risk according to the SCORE charts. CONCLUSIONS: Despite recent advances in the management of CIRD, incidence of CVD remains increased in Spanish subjects with CIRD attending outpatient rheumatology clinics. PMID- 26058352 TI - Results and complications of operative and non-operative navicular fracture treatment. AB - BACKGROUND: Navicular fractures (NF) are uncommon. The purpose of this study was to compare results of operative (ORIF) and non-operative (NOT) treatment in NF. METHODS: A retrospective analysis was undertaken on patients diagnosed with NF between March 2002 and June 2007 at a Level I teaching trauma centre. Clinical outcome consisted of functional ability and complications. RESULTS: Eighty-eight patients with 90 fractures were identified including 56 males and 32 females with a mean age of 38 (range 17-72) and body mass index of 28.2 (range 18.7-48.9). Twenty-one of 90 (23.3%) injuries were isolated. Ten of 90 (11.1%) injuries were open. Treatment was 49/90 (55%) NOT and 41/90 (45.6%) ORIF. 11/41 (30%) ORIF required bone grafting. Complications included one ipsilateral deep vein thrombosis, one avascular necrosis, one nonunion, seven infections (two deep and five superficial), and 56 cases of secondary osteoarthrosis (SOA). ORIF had significantly more SOA (chi(2)=0.000). Secondary surgery was 25 hardware removals (16 for irritation, five for prominent or broken plates), nine arthrodeses/ plasties, two debridements for infection, and one tarsal tunnel release. Pain was present at final follow up in 39/90 (43.3%) feet. Work status was 64 without restrictions, 17 with restrictions, and 5 did not return to work. Sixty-two of 88 (69%) patients were able to wear normal shoes, which were related to return to work without restrictions (rho=-0.508, p=0.000). Inability to return to previous work was related to pain (rho=-0.394), SOA (rho=-0.280), and poor reduction quality (rho=-0.384) with significance at p<0.01. Increased BMI (>35) related to pain (rho=0.250) and poor reduction quality (rho=0.326) at a sigma<0.05. CONCLUSIONS: Despite modern surgical techniques, operative treatment of displaced fractures is at high risk for complications. Obesity, pain, and secondary osteoarthrosis determine shoe wear, return to function, and employment status. LEVEL OF EVIDENCE: Level III. PMID- 26058353 TI - Delay in auditory behaviour and preverbal vocalization in infants with unilateral hearing loss. AB - AIM: To evaluate the impact of unilateral hearing loss (UHL) on early aural/oral communication skills of infants by comparing performance to infants with bilateral normal hearing (BNH). METHOD: Thirty-four infants with UHL (median age 9.4mo, 25th-75th centile 7.34-12.15) and 331 control infants with BNH (median age 9mo, 6.0-13.38) were divided into two subgroups based on risk factors known to cause developmental delay: low risk and high risk. Early auditory skills and preverbal vocalizations were assessed using two parent questionnaires: the Infant Toddler Meaningful Auditory Integration Scale and the Production of Infants Scale Evaluation. RESULTS: Of the infants with UHL, 21% showed delays in auditory behaviour and 41% delays in preverbal vocalizations, compared to their peers with BNH (p<0.01). After adjusting for risk level, delayed auditory behaviour and preverbal vocalizations were approximately four and nine times more common in infants with UHL compared to BNH respectively (p<0.01). INTERPRETATION: This is the first study to show that infants with UHL are at higher risk of delay in early aural/oral communication abilities compared to infants with BNH even in the absence of other known risk factors for developmental delay. This has important implications for early intervention and habilitation of infants with UHL, in order to reduce some of the negative long-term consequences of what was once considered 'minor' hearing loss. PMID- 26058354 TI - In vitro digestion of emulsions: high spatiotemporal resolution using synchrotron SAXS. AB - Although the biochemical processes of lipid digestion are well-known, the biophysical ones, responsible for the assembly of molecules into functional structures, lack studies resolving both time and space scales. About 35 years ago, the seminal microscopy study of Patton and Carey constituted a major advance to reach this goal. Nowadays, new perspectives arise from the availability of large facilities scattering techniques, able to monitor the dynamics of multi scale assemblies with unprecedented resolutions. The present small angle X-ray scattering (SAXS) study focused on the roles of the emulsifier and triglyceride in the formation of lipid assemblies during emulsion digestion in vitro. By developing several interpretations of the data in the whole space range (qualitative, shape-dependent and shape-independent models), the characteristic size of the assemblies and their transition times were obtained, which depended on the triglyceride, but not on the emulsifier. The major assembly formed was found to be a spherical mixed micelle, but vesicle was also found to coexist throughout the digestion, although in a lower proportion. The quantitative determination of the sizes and proportions of these assemblies, as well as the evolution of these characteristics during digestion are precious information for nutritional sciences, as these assemblies are the vehicles of lipophilic nutrients and micronutrients towards their absorption site. PMID- 26058355 TI - From affective blindsight to emotional consciousness. AB - Following destruction or denervation of the primary visual cortex (V1) cortical blindness ensues. Affective blindsight refers to the uncanny ability of such patients to respond correctly, or above chance level, to visual emotional expressions presented to their blind fields. Fifteen years after its original discovery, affective blindsight still fascinates neuroscientists and philosophers alike, as it offers a unique window on the vestigial properties of our visual system that, though present in the intact brain, tend to be unnoticed or even actively inhibited by conscious processes. Here we review available studies on affective blindsight with the intent to clarify its functional properties, neural bases and theoretical implications. Evidence converges on the role of subcortical structures of old evolutionary origin such as the superior colliculus, the pulvinar and the amygdala in mediating affective blindsight and nonconscious perception of emotions. We conclude that approaching consciousness, and its absence, from the vantage point of emotion processing may uncover important relations between the two phenomena, as consciousness may have evolved as an evolutionary specialization to interact with others and become aware of their social and emotional expressions. PMID- 26058357 TI - Synthesis and in vitro anti-cancer evaluation of luteinizing hormone-releasing hormone-conjugated peptide. AB - Luteinizing hormone-releasing hormone (LHRH) is a decapeptide hormone released from the hypothalamus and shows high affinity binding to the LHRH receptors. It is reported that several cancer cells also express LHRH receptors such as breast, ovarian, prostatic, bladder and others. In this study, we linked B1, an anti cancer peptide, to LHRH and its analogs to improve the activity against cancer cells with LHRH receptor. Biological evaluation revealed that TB1, the peptide contains triptorelin sequence, present favorable anti-cancer activity as well as plasma stability. Further investigations disclosed that TB1 trigger apoptosis by activating the mitochondria-cytochrome c-caspase apoptotic pathway, it also exhibited the anti-migratory effect on cancer cells. PMID- 26058356 TI - Three-minute method for amino acid analysis by UHPLC and high-resolution quadrupole orbitrap mass spectrometry. AB - Amino acid analysis is a powerful bioanalytical technique for many biomedical research endeavors, including cancer, emergency medicine, nutrition and neuroscience research. In the present study, we present a 3 min analytical method for underivatized amino acid analysis that employs ultra high-performance liquid chromatography and high-resolution quadrupole orbitrap mass spectrometry. This method has demonstrated linearity (mM to nM range), reproducibility (intra-day <5 %, inter-day <20 %), sensitivity (low fmol) and selectivity. Here, we illustrate the rapidity and accuracy of the method through comparison with conventional liquid chromatography-mass spectrometry methods. We further demonstrate the robustness and sensitivity of this method on a diverse range of biological matrices. Using this method we were able to selectively discriminate murine pancreatic cancer cells with and without knocked down expression of hypoxia inducible factor 1alpha; plasma, lymph and bronchioalveolar lavage fluid samples from control versus hemorrhaged rats; and muscle tissue samples harvested from rats subjected to both low-fat and high-fat diets. Furthermore, we were able to exploit the sensitivity of the method to detect and quantify the release of glutamate from sparsely isolated murine taste buds. Spiked in light or heavy standards ((13)C6-arginine, (13)C6-lysine, (13)C 5 (15) N2-glutamine) or xenometabolites (5-fluorouracil) were used to determine coefficients of variation, confirm linearity of relative quantitation in four different matrices, and overcome matrix effects for absolute quantitation. The presented method enables high-throughput analysis of low-abundance samples requiring only one percent of the material extracted from 100,000 cells, 10 ul of biological fluid, or 2 mg of muscle tissue. PMID- 26058358 TI - Conversion of 2-Iodobiaryls into 2,2'-Diiodobiaryls via Oxidation-Iodination Sequences: A Versatile Route to Ladder-Type Heterofluorenes. AB - Even though 2,2'-diiodo- and 2,2'-dibromobiaryls represent accomplished precursors for heterofluorenes and other extended pi-conjugated systems, their preparation still remains nontrivial when structural diversity of the biaryl backbone is required. Herein, we report a convenient method for the preparation of various 2,2'-diiodobiaryls from 2-iodobiaryls via cyclic diaryliodonium intermediates. An iodinative ring-opening of the diaryliodonium salts, mediated by a copper/diamine catalyst system, is able to afford the corresponding 2,2' diiodobiaryls under mild conditions. The versatility of this two-step approach is demonstrated by the preparation of hitherto unexplored tetraiodoteraryls and their conversion into ladder-type pi-conjugated systems. PMID- 26058359 TI - Claudin-4 controls the proliferation, apoptosis, migration and in vivo growth of MCF-7 breast cancer cells. AB - Previous studies have shown that the expression of claudin-4 is upregulated in breast cancer. The aim of the present study was to investigate the role and the regulation of claudin-4 in MCF-7 breast cancer cells. For the in vitro experiments, MCF-7 cells were treated with recombinant vectors carrying cDNA for claudin-4 overexpression or short hairpin RNAs (shRNAs) for claudin-4 silencing. Cell proliferation was determined by an MTT assay and cell migration ability was measured by a wound-healing assay. The cell cycle profile and apoptotic rate were analyzed using flow cytometry. The effect of methylation status on claudin-4 expression was determined by PCR and western blotting. For the in vivo tumorigenesis analysis, MCF-7 cells with or without claudin-4 silencing were transplanted into nude mice. In vivo cell growth was evaluated 14 days after transplantation. We found that claudin-4 overexpression increased MCF-7 cell proliferation and migration, and reduced the rate of cell apoptosis. Silencing of claudin-4 induced the opposite effects in MCF-7 cells. In addition, claudin-4 expression was upregulated by demethylation. Moreover, the size of tumor formation was reduced in nude mice transplanted with claudin-4 silenced MCF-7 cells. These observations suggested that claudin-4, which was regulated by methylation status, plays an important role in breast cancer growth and malignancy via the control of cell proliferation, migration and apoptosis. PMID- 26058360 TI - Split pedicle roll envelope technique around implants and pontics: a prospective case series study. AB - Recreating a harmonious gingival contour for contiguous missing teeth in the anterior maxilla is challenging. The aim of this study was to evaluate a split pedicle roll envelope technique designed for pontics. Twelve patients presented a labial flat or concave profile at the implant and pontic sites before second stage surgery. The contour deficiency was compensated with a palatal split pedicle flap with the implant part rolled into the labial envelope and the pontic part covering the denuded ridge. Interim restorations were screwed in to guide tissue remodelling. The labial convex profile (CPF) and facial mucosal level (FML) at the implant and pontic sites, the Jemt papilla index (PIS) in the different restorative environments, and peri-implant bone levels were recorded at baseline and at 1 week, 3 months, and 6 months postoperative. Results showed that the CPF had increased by 1.4mm at the implant site and 1.5mm at the pontic site at 6 months after surgery. PIS had increased by 2 at the implant-tooth/pontic tooth sites and by 2.6 at the implant-pontic site. FML was coordinated with that of the contralateral teeth. All indices were favourable at 3 months and then remained stable. Within the limitations identified, this combined therapy can be considered as an alternative to achieve aesthetic success when contiguous maxillary anterior teeth are missing. PMID- 26058361 TI - Rugae-like FeP nanocrystal assembly on a carbon cloth: an exceptionally efficient and stable cathode for hydrogen evolution. AB - There is a strong demand to replace expensive Pt catalysts with cheap metal sulfides or phosphides for hydrogen generation in water electrolysis. Earth abundant Fe can be electroplated on carbon cloth (CC) to form high surface area rugae-like FeOOH assembly. Subsequent gas phase phosphidation converts the FeOOH to FeP or FeP2 and the morphology of the crystal assembly is controlled by the phosphidation temperature. FeP prepared at 250 degrees C presents lower crystallinity and that prepared at higher temperatures of 400 degrees C and 500 degrees C possesses higher crystallinity, but lower surface area. The phosphidation at 300 degrees C produces nanocrystalline FeP and preserves the high-surface area morphology; thus, it exhibits the highest HER efficiency in 0.5 M H2SO4, i.e., the required overpotential to reach 10 and 20 mA cm(-2) is 34 and 43 mV, respectively. These values are lowest among the reported non-precious metal phosphides on CC. The Tafel slope for FeP prepared at 300 degrees C is around 29.2 mV dec(-1), which is comparable to that of Pt/CC; this indicates that the hydrogen evolution for our best FeP is limited by the Tafel reaction (same as Pt). Importantly, the FeP/CC catalyst exhibits much better stability in a wide range working current density (up to 1 V cm(-2)), suggesting that it is a promising replacement of Pt for HER. PMID- 26058362 TI - Comprehensive phenotypic analysis and quantitative trait locus identification for grain mineral concentration, content, and yield in maize (Zea mays L.). AB - KEY MESSAGE: Understanding the correlations of seven minerals for concentration, content and yield in maize grain, and exploring their genetic basis will help breeders to develop high grain quality maize. Biofortification by enhanced mineral accumulation in grain through genetic improvement is an efficient way to solve global nutrient malnutrition, in which one key step is to detect the underlying quantitative trait loci (QTL). Herein, a maize recombinant inbred population (RIL) was field grown to maturity across four environments (two locations * two years). Phenotypic data for grain mineral concentration, content and yield were determined for copper (Cu), iron (Fe), manganese (Mn), zinc (Zn), magnesium (Mg), potassium (K) and phosphorus (P). Significant effects of genotype, location and year were observed for all investigated traits. The strongest location effects were found for Zn accumulation traits probably due to distinct soil Zn availabilities across locations. Heritability (H (2)) of different traits varied with higher H (2) (72-85 %) for mineral concentration and content, and lower (48-63 %) for mineral yield. Significant positive correlations for grain concentration were revealed between several minerals. QTL analysis revealed 28, 25, and 12 QTL for mineral concentration, content and yield, respectively; and identified 8 stable QTL across at least two environments. All these QTL were assigned into 12 distinct QTL clusters. A cluster at chromosome Bin 6.07/6.08 contained 6 QTL for kernel weight, mineral concentration (Mg) and content (Zn, K, Mg, P). Another cluster at Bin 4.05/4.06 contained a stable QTL for Mn concentration, which were previously identified in other maize and rice RIL populations. These results highlighted the phenotypic and genetic performance of grain mineral accumulation, and revealed two promising chromosomal regions for genetic improvement of grain biofortification in maize. PMID- 26058363 TI - Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug. AB - Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells. PMID- 26058365 TI - [Academic teaching at the department of ophthalmology of the University Clinic of Saarland (UKS) : The Homburg "Ophthalmo-Week"]. AB - BACKGROUND: Academic teaching activities at the department of ophthalmology of the University Clinic of Saarland (UKS) include the teaching of students during the "Ophthalmo-Week" with lectures and bedside teaching according to the academic conditions given by the law for medical schools in Germany, a spezialized course "Anterior Pole to Posterior Pole", teaching of locum students, students in their final year and tuition of PhD students. PURPOSE: Demonstration of the development of a structured teaching concept for medical students in ophthalmology including blended learning. Description of the problems encountered and the changes made during the transition from ex cathedra teaching to a mixture of lectures and practical hands-on and patient-centered teaching of the current Homburg "Ophthalmo-Week". In addition, the aim is to emphasize the importance of structured and detailed evaluation as a means to continually improve academic teaching. CONCLUSION: In the light of the current demographic changes and the relative lack of young trainees in many medical specialities in Germany, good academic teaching is becoming more and more important. Good academic teaching including positive evaluations can elucidate the interest of medical students for non-mainstream medical specialties such as ophthalmology. In addition, good and profiled academic teaching promotes research by attracting medical students to apply for PhD work at these hospitals. Furthermore, the profile of the department can be improved in comparison to departments of the same specialty in neighboring universities. Transferability of methods of academic teaching is as important as sustainability. To keep up the high standards of blended learning all medical personnel of the hospital need to be involved during the short-term focused teaching periods. PMID- 26058364 TI - Studies on metabolism of total glucosides of paeony from Paeoniae Radix Alba in rats by UPLC-Q-TOF-MS/MS. AB - Total glucosides of paeony are the active constituents of Paeoniae Radix Alba. In this study, a novel strategy was proposed to find more metabolites and the differences between paeoniflorin, albiflorin and total glucosides of paeony (TGP). This strategy was characterized as follows: firstly, the animals were divided into three groups (paeoniflorin, albiflorin and TGP) to identify the source of TGP metabolites from paeoniflorin or albiflorin; secondly, a generic information-dependent acquisition scan for the low-level metabolites was triggered by the multiple mass defect filter and dynamic background subtraction; thirdly, the metabolites were identified with a combination of data-processing methods including mass defect filtering, neutral loss filtering and product ion filtering; finally, a comparative study was used in the metabolism of paeoniflorin, albiflorin and TGP. Based on the strategy, 18 metabolites of TGP, 10 metabolites of paeoniflorin and 13 metabolites of albiflorin were identified respectively. The results indicated that the hydrolysis, conjugation reaction and oxidization were the major metabolic pathways, and the metabolic sites were the glycosidic linkage, the ester bond and the benzene ring. This study is first to explore the metabolism of TGP, and these findings enhance our understanding of the metabolism and the interactions of paeoniflrin and albiflorin in TGP. PMID- 26058366 TI - [Not Available]. PMID- 26058367 TI - Public health perspectives in cross-system practice: past, present and future. AB - Cross-system practice is widely prevalent in Indian settings. The recent policy decisions of the Government of India and the legalisation of cross-system practice in various states have brought this issue into the limelight once again. We aim to critically evaluate this issue from the philosophical, academic, and public health perspectives, as well as with reference to training. On the one hand, students of traditional Indian medicine are being introduced to allopathy without philosophical backing, practice based on the aetiological model and training in modern pharmacology. In addition, pharmaceutical industries are wooing AYUSH practitioners and their prescription patterns have already been "allopathised". As for the allopathic system, it is witnessing enormous scientific advances and growing increasingly complicated. The medicines are risky and also associated with many life-threatening side-effects. Meanwhile, the government is grappling with the humungous problem of ensuring health services for all. The government's intention is to expand the reach of health services by allowing cross-system practice, but the issue has much wider ramifications. The authors believe that before cross-system practice is allowed, there is a need for a comprehensive and deeper understanding of all the benefits and pitfalls of such as system. A few of these are discussed in this article. Specifically, we delve into the philosophical issues, syllabus and training, advances in medical technology, and larger public health perspectives. We end by suggesting a few steps that may help to improve public health in the country. PMID- 26058368 TI - A genome-wide SNP scan accelerates trait-regulatory genomic loci identification in chickpea. AB - We identified 44844 high-quality SNPs by sequencing 92 diverse chickpea accessions belonging to a seed and pod trait-specific association panel using reference genome- and de novo-based GBS (genotyping-by-sequencing) assays. A GWAS (genome-wide association study) in an association panel of 211, including the 92 sequenced accessions, identified 22 major genomic loci showing significant association (explaining 23-47% phenotypic variation) with pod and seed number/plant and 100-seed weight. Eighteen trait-regulatory major genomic loci underlying 13 robust QTLs were validated and mapped on an intra-specific genetic linkage map by QTL mapping. A combinatorial approach of GWAS, QTL mapping and gene haplotype-specific LD mapping and transcript profiling uncovered one superior haplotype and favourable natural allelic variants in the upstream regulatory region of a CesA-type cellulose synthase (Ca_Kabuli_CesA3) gene regulating high pod and seed number/plant (explaining 47% phenotypic variation) in chickpea. The up-regulation of this superior gene haplotype correlated with increased transcript expression of Ca_Kabuli_CesA3 gene in the pollen and pod of high pod/seed number accession, resulting in higher cellulose accumulation for normal pollen and pollen tube growth. A rapid combinatorial genome-wide SNP genotyping-based approach has potential to dissect complex quantitative agronomic traits and delineate trait-regulatory genomic loci (candidate genes) for genetic enhancement in crop plants, including chickpea. PMID- 26058369 TI - Conserved Omp85 lid-lock structure and substrate recognition in FhaC. AB - Omp85 proteins mediate translocation of polypeptide substrates across and into cellular membranes. They share a common architecture comprising substrate interacting POTRA domains, a C-terminal 16-stranded beta-barrel pore and two signature motifs located on the inner barrel wall and at the tip of the extended L6 loop. The observation of two distinct conformations of the L6 loop in the available Omp85 structures previously suggested a functional role of conformational changes in L6 in the Omp85 mechanism. Here we present a 2.5 A resolution structure of a variant of the Omp85 secretion protein FhaC, in which the two signature motifs interact tightly and form the conserved 'lid lock'. Reanalysis of previous structural data shows that L6 adopts the same, conserved resting state position in all available Omp85 structures. The FhaC variant structure further reveals a competitive mechanism for the regulation of substrate binding mediated by the linker to the N-terminal plug helix H1. PMID- 26058370 TI - Apgar Score at 5 Minutes Is Associated with Mortality in Extremely Preterm Infants Even after Transfer to an All Referral NICU. AB - OBJECTIVE: The Apgar score has been shown to have utility in predicting mortality in the extremely preterm infant in delivery hospital populations, where most mortality occurs within 12 hours of birth. We tested the hypothesis that the 5 minute Apgar score would remain associated with mortality in extremely preterm infants after transfer from the delivery hospital to an all referral neonatal intensive care unit at an average age of 10 days. STUDY DESIGN: A retrospective analysis of 454 infants born at < 27 weeks gestation. RESULTS: The median Apgar score was 3 at 1 minute (interquartile range [IQR] 2-6) and 6 at 5 minutes (IQR 4 7). The Apgar score increased from 1 to 5 minutes by 2.0 +/- 1.7 (p < 0.001). In logistic regression modeling, an Apgar score of < 5 at 5 minutes was associated with an increased mortality (odds ratio 1.76 [95% confidence interval 1.06-2.94], p < 0.05), but not morbidities. CONCLUSION: Infants born at < 27 weeks gestation admitted to an all referral children's hospital at a mean age of 10 days with a 5 minute Apgar < 5 are at an increased risk of mortality. Our findings continue to support the importance of the Apgar score given at delivery even in the extremely preterm infant referred to a nondelivery children's hospital. PMID- 26058371 TI - Association between Cerebral Palsy or Death and Umbilical Cord Blood Magnesium Concentration. AB - OBJECTIVE: This study aims to evaluate whether magnesium sulfate (MgSO4) infusion at the time of delivery or magnesium cord blood concentration is associated with cerebral palsy (CP) or death diagnosed by the age of 2 years. METHODS: Secondary analysis of data from a randomized trial of MgSO4 versus placebo for prevention of CP or death among offspring of women with anticipated preterm delivery. This study cohort included singleton, nonanomalous fetuses, whose mothers received MgSO4 as neuroprophylaxis. The primary outcomes were CP or death diagnosed by the age of 2 years. RESULTS: A total of 936 neonates (93 with CP or death, 843 controls) were included in the analysis. Infants in the group with CP or death had MgSO4 infusing at delivery at a similar frequency to that of controls (49 [52.7%] vs. 463 [54.9%], p = 0.68). Mean concentrations of cord blood magnesium, available for 596 neonates, also were not different between the two groups (2.7 +/- 0.9 vs. 2.6 +/- 0.9 mEq/L, p = 0.66, respectively). Multivariable analyses did not alter these findings. CONCLUSION: Among the offspring of women exposed to MgSO4, in utero, neither MgSO4 infusion at the time of delivery nor magnesium cord blood concentration is associated with CP or death. PMID- 26058372 TI - Association of Antegrade Pulmonary Artery Diastolic Velocity with Spontaneous Closure of the Patent Ductus Arteriosus in Extremely Low-Birth-Weight Infants. AB - OBJECTIVE: This study aims to determine echocardiographic parameters associated with spontaneous patent ductus arteriosus (PDA) closure in extremely low-birth weight (ELBW) infants. STUDY DESIGN: Retrospective demographic review and analysis of echocardiograms from 189 ELBW infants with suspected and confirmed hemodynamically significant PDA identified on an initial echocardiogram was performed. Comparison of echocardiographic parameters was made between infants with spontaneous closure versus those who received treatment. RESULTS: The mean birth weight (787 +/- 142 vs. 724 +/- 141 g, p = 0.04) and gestational age (27.4 +/- 2.8 vs. 26.2 +/- 1.6 weeks, p = 0.03) were higher in the spontaneous closure versus the treatment group. Antegrade pulmonary artery (PA) diastolic velocity was lower in infants with spontaneous PDA closure versus those who received treatment (0.15 +/- 0.06 vs. 0.22 +/- 0.12 m/s, p = 0.009). CONCLUSION: Heavier and more mature ELBW infants with a lower antegrade PA diastolic velocity were likely to have spontaneous closure of the PDA. PMID- 26058374 TI - The Challenge of Online Gambling: The Effect of Legalization on the Increase in Online Gambling Addiction. AB - It is possible that the growth and promotion of online gambling will result in substantially increased use of these types of games in countries where they are legal. This may be especially true for young people due to their interest in such games. In this context, it is important to note that online gambling is more addictive than any other type of game due its structural characteristics, such as immediacy, accessibility, ease of betting, and so on. This study examined the effect of online gambling in Spain 2 years after its legalization. The sample included 1277 pathological gamblers in recovery at 26 gambling addiction treatment centers. Our results showed a significant increase in young pathological gamblers since the legalization of this activity. This is a very relevant issue because, as in the case of Spain, many countries are currently in process of legalization of many types of online games. Scientific research can be useful to adapt the adequate gambling policies in order to prevent the gambling addiction. PMID- 26058373 TI - Reexamining the Surfaces of Bone in Boys and Girls During Adolescent Growth: A 12 Year Mixed Longitudinal pQCT Study. AB - We revisit Stanley Garn's theory related to sex differences in endocortical and periosteal apposition during adolescence using a 12-year mixed longitudinal study design. We used peripheral quantitative computed tomography to examine bone parameters in 230 participants (110 boys, 120 girls; aged 11.0 years at baseline). We assessed total (Tt.Ar, mm(2)), cortical (Ct.Ar, mm(2)), and medullary canal area (Me.Ar, mm(2)), Ct.Ar/Tt.Ar, cortical bone mineral density (Ct.BMD, mg/cm(3)), and polar strength-strain index (SSIp , mm(3)) at the tibial midshaft (50% site). We used annual measures of height and chronological age to identify age at peak height velocity (APHV) for each participant. We compared annual accrual rates of bone parameters between boys and girls, aligned on APHV using a linear mixed effects model. At APHV, boys demonstrated greater Tt.Ar (ratio = 1.27; 95% confidence interval [CI] 1.21, 1.32), Ct.Ar (1.24 [1.18, 1.30]), Me.Ar (1.31 [1.22, 1.40]), and SSIp (1.36 [1.28, 1.45]) and less Ct.Ar/Tt.Ar (0.98 [0.96, 1.00]) and Ct.BMD (0.97 [0.96, 0.97]) compared with girls. Boys and girls demonstrated periosteal bone formation and net bone loss at the endocortical surface. Compared with girls, boys demonstrated greater annual accrual rates pre-APHV for Tt.Ar (1.18 [1.02, 1.34]) and Me.Ar (1.34 [1.11, 1.57]), lower annual accrual rates pre-APHV for Ct.Ar/Tt.Ar (0.56 [0.29, 0.83]) and Ct.BMD (-0.07 [-0.17, 0.04]), and similar annual accrual rates pre-APHV for Ct.Ar (1.10 [0.94, 1.26]) and SSIp (1.14 [0.98, 1.30]). Post-APHV, boys demonstrated similar annual accrual rates for Ct.Ar/Tt.Ar (1.01 [0.71, 1.31]) and greater annual accrual rates for all other bone parameters compared with girls (ratio = 1.23 to 2.63; 95% CI 1.11 to 3.45). Our findings support those of Garn and others of accelerated periosteal apposition during adolescence, more evident in boys than girls. However, our findings challenge the notion of greater endocortical apposition in girls, suggesting instead that girls experience diminished endocortical resorption compared with boys. PMID- 26058376 TI - Re-evaluating the role of activin-betaC in cancer biology. AB - Transforming growth factor-beta (TGF-beta) superfamily signaling pathway and its ligands are essential regulators of cellular processes such as proliferation, differentiation, migration, and survival. Alteration of this pathway results in uncontrolled proliferation and cancer progression. This review focuses on a specific member of the TGF-beta superfamily: activin-betaC. After its initial discovery, activin-betaC has been considered non-biologically relevant. Therefore, for years several experimental designs have ignored the potential contribution of this molecule to the final biological outcome. Here we focus on recent advances in the activin field, with a particular emphasis on activin betaC, its antagonistic mechanism, and the physiological relevance of activin betaC actions in reproductive and cancer biology. Covering a novel and previously unexplored function of activin-betaC on cancer associated weight loss and muscle metabolism, this review suggests an imminent need to re-evaluate the function of activin-betaC in biological systems and advances the understanding of how activin betaC antagonizes the activin signaling pathway. Thus, challenging activin biologists to consider the impact of activin-betaC when interpreting their work. PMID- 26058377 TI - A Novel Danshensu Derivative Prevents Cardiac Dysfunction and Improves the Chemotherapeutic Efficacy of Doxorubicin in Breast Cancer Cells. AB - Doxorubicin (Dox) is an anthracycline antibiotic widely used in clinics as an anticancer agent. However, the use of Dox is limited by its cardiotoxicity. We have previously shown that a Danshensu (DSS) derivative, ADTM, displayed strong cardioprotective effects. With improved chemical stability and activity, a novel DSS derivative, D006, based on the structure of ADTM, was synthesized. In the present study, the protective effects of D006, indexed by attenuation of the cardiotoxicity induced by Dox as well as chemosensitizing effects that increase the antitumor activity of Dox, were investigated. Our results showed that D006 was more potent than either parental compound, or their use in combination, in ameliorating Dox-induced toxicity in H9c2 cells. In our zebrafish model, D006, but not DSS, alone significantly preserved the ventricular function of zebrafish after Dox treatment. Moreover, D006 upregulated mitochondrial biogenesis and increased mtDNA copy number after Dox treatment of H9c2 cells. D006 promoted the expression of HO-1 protein in a time-dependent manner while the HO-1 inhibitor, Znpp, reversed the protective effects of D006. In human breast tumor MCF-7 cells, D006 enhanced Dox-induced cytotoxicity by increasing apoptosis. In conclusion, our results indicate that a new DSS derivative exhibits promising protective effects against Dox-induced cardiotoxicity both in vivo and in vitro, an effect at least partially mediated by induction of HO-1 expression and the activation of mitochondrial biogenesis. Meanwhile, D006 also potentiated the anti-cancer effects of Dox in breast tumor cells. PMID- 26058378 TI - A one-million-year-old hominid distal ulna from Olduvai Gorge, Tanzania. AB - OBJECTIVE: Our aim was to recover new evidence of the evolution of the hominid lineage. METHODS: We undertook paleontological fieldwork at Olduvai Gorge, Tanzania, in one of the richest paleoanthropological sites in the world, documenting the evolution of our lineage and its environmental contexts over the last 2 million years. RESULTS: During field work in 2012, the Olduvai Vertebrate Paleontology Project discovered the distal end of a hominid ulna (OH 82) on the north side of Olduvai Gorge a few meters west of the Third Fault, eroding from Bed III sediments that are ~1 million years in age. DISCUSSION: The size and morphology of this distal ulna falls within the normal range of variation seen in humans, although at the larger end of the distribution. PMID- 26058375 TI - Insights into the evolution of enzyme substrate promiscuity after the discovery of (betaalpha)8 isomerase evolutionary intermediates from a diverse metagenome. AB - BACKGROUND: Current sequence-based approaches to identify enzyme functional shifts, such as enzyme promiscuity, have proven to be highly dependent on a priori functional knowledge, hampering our ability to reconstruct evolutionary history behind these mechanisms. Hidden Markov Model (HMM) profiles, broadly used to classify enzyme families, can be useful to distinguish between closely related enzyme families with different specificities. The (betaalpha)8-isomerase HisA/PriA enzyme family, involved in L-histidine (HisA, mono-substrate) biosynthesis in most bacteria and plants, but also in L-tryptophan (HisA/TrpF or PriA, dual-substrate) biosynthesis in most Actinobacteria, has been used as model system to explore evolutionary hypotheses and therefore has a considerable amount of evolutionary, functional and structural knowledge available. We searched for functional evolutionary intermediates between the HisA and PriA enzyme families in order to understand the functional divergence between these families. RESULTS: We constructed a HMM profile that correctly classifies sequences of unknown function into the HisA and PriA enzyme sub-families. Using this HMM profile, we mined a large metagenome to identify plausible evolutionary intermediate sequences between HisA and PriA. These sequences were used to perform phylogenetic reconstructions and to identify functionally conserved amino acids. Biochemical characterization of one selected enzyme (CAM1) with a mutation within the functionally essential N-terminus phosphate-binding site, namely, an alanine instead of a glycine in HisA or a serine in PriA, showed that this evolutionary intermediate has dual-substrate specificity. Moreover, site-directed mutagenesis of this alanine residue, either backwards into a glycine or forward into a serine, revealed the robustness of this enzyme. None of these mutations, presumably upon functionally essential amino acids, significantly abolished its enzyme activities. A truncated version of this enzyme (CAM2) predicted to adopt a (betaalpha)6-fold, and thus entirely lacking a C-terminus phosphate-binding site, was identified and shown to have HisA activity. CONCLUSION: As expected, reconstruction of the evolution of PriA from HisA with HMM profiles suggest that functional shifts involve mutations in evolutionarily intermediate enzymes of otherwise functionally essential residues or motifs. These results are in agreement with a link between promiscuous enzymes and intragenic epistasis. HMM provides a convenient approach for gaining insights into these evolutionary processes. PMID- 26058379 TI - Hepatocellular adenoma with malignant transformation in male patients with non cirrhotic livers. AB - INTRODUCTION: Hepatocellular adenomas (HCAs), with a risk of malignant transformation into hepatocellular carcinoma (HCC), classically develop in young women who are taking oral contraceptives. It is now clear that HCAs may also occur in men. However, it is rarely reported that HCAs with malignant transformation occur in male patients with non-cirrhotic livers. This study aimed to characterize the malignancy of HCAs occurring in male patients. METHODS: All patients with HCAs with malignant transformation who underwent hepatectomy at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 1, 1999 and December 31, 2011 were enrolled in the study. The clinical characteristics as well as radiologic and pathologic data were reviewed. RESULTS: HCAs with malignant transformation were observed in 5 male patients with non-cirrhotic livers, but not in female patients. The alpha fetoprotein (AFP) levels were higher in patients with HCAs with malignant transformation than in patients with HCAs without malignant transformation. The diameters of the tumors with malignant transformation were larger than 5 cm in 3 cases and smaller than 5 cm in 2 cases. The 5 patients were all alive without recurrence by the end of the study period. The disease-free survival times of the 5 patients were 26, 48, 69, 69, and 92 months. CONCLUSION: Our results indicate that resection would be advised even if the presumptive diagnosis is adenoma smaller than 5 cm in diameter, especially in male patients. PMID- 26058380 TI - Alteration and localization of glycan-binding proteins in human hepatic stellate cells during liver fibrosis. AB - Glycan-binding proteins (GBPs) play an important role in cell adhesion, bacterial/viral infection, and cellular signaling pathways. However, little is known about the precision alteration of GBPs referred to pathological changes in hepatic stellate cells (HSCs) during liver fibrosis. Here, the carbohydrate microarrays were used to probe the alteration of GBPs in the activated HSCs and quiescent HSCs. As a result, 12 carbohydrates (e.g. Gal, GalNAc, and Man-9Glycan) showed increased signal, while seven carbohydrates (e.g. NeuAc, Lac, and GlcNAc-O Ser) showed decreased signal in activated HSCs. Three carbohydrates (Gal, GalNAc, and NeuAc) were selected and subsequently used to validate the results of the carbohydrate microarrays as well as assess the distribution and localization of their binding proteins in HSCs and liver tissues by cy/histochemistry; the results showed that GBPs mainly distributed in the cytoplasma membrane and perinuclear region of cytoplasm. The immunocytochemistry was further used to verify some GBPs really exist in Golgi apparatus of the cells. The precision alteration and localization of GBPs referred to pathological changes in HSCs may provide pivotal information to help understand the biological functions of glycans how to exert through their recognition by a wide variety of GBPs. This study could lead to the development of new anti-fibrotic strategies. PMID- 26058381 TI - A bifunctional colorimetric fluorescent probe for Hg(2+) and Cu(2+) based on a carbazole-pyrimidine conjugate: chromogenic and fluorogenic recognition on TLC, silica-gel and filter paper. AB - A bifunctional fluorescent probe based on a carbazole-pyrimidine conjugate for Hg(2+) and Cu(2+) detection was designed and synthesized. Probe 3 exhibits red shifts in its absorption and fluorescence spectra with significant visual color changes in the presence of these ions. The detection limits of probe 3 for these metal ions were in the nanomolar range. The probe could also be useful as a solid optical sensor for Hg(2+) and Cu(2+). PMID- 26058382 TI - The health action process approach applied to African American breast cancer survivors. AB - BACKGROUND: The health action process approach (HAPA) is a relevant model for understanding physical activity (PA), yet it has not been examined in cancer survivors or minorities. In this study, we assessed the HAPA in African American breast cancer survivors using covariance modeling. METHODS: A total of 304 African American breast cancer survivors (mean age = 54 years) participated in a Web-based survey assessing demographic and medical characteristics as well as constructs of the HAPA. A two-step covariance modeling approach was used to assess the structural relationships among the constructs. RESULTS: The hypothesized measurement model fit the data; however, general severity was not significantly associated with the remaining constructs. General severity was removed, and the fit did not change significantly. The final adjusted model provided a reasonable fit to the data and accounted for significant variance in intentions (49%) and PA (42%). Action (beta = 0.1, p < 0.01) and coping (beta = 0.3, p < 0.01) planning mediated the relationship between intentions and behavior. CONCLUSIONS: The HAPA appears to be a relevant model for understanding PA in African American breast cancer survivors. However, more work is needed to determine whether these relationships can be replicated in other breast cancer survivors. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26058383 TI - Generation of Multishell Magnetic Hybrid Nanoparticles by Encapsulation of Genetically Engineered and Fluorescent Bacterial Magnetosomes with ZnO and SiO2. AB - Magnetic nanoparticles (MNPs) have great potential in biomedical applications, but the chemical synthesis of size-controlled and functionalized core-shell MNPs remain challenging. Magnetosomes produced by the magnetotactic bacterium Magnetospirillum gryphiswaldense are naturally uniform and chemically pure magnetite MNPs with superior magnetic characteristics. Here, additional functionalities are made possible by the incorporation of biomolecules on the magnetosome surface; the magnetosome system is then chemically encapsulated with an inorganic coating. The novel multishell nanoparticles consist of the magnetosome core-which includes the magnetite crystal, the magnetosome membrane, and additional moieties, such as the enhanced green fluorescent protein (EGFP) and peptides-and an outer shell, comprising either silica or zinc oxide. Coating the functionalized magnetosomes with silica improves their colloidal stability and preserves the EGFP fluorescence in the presence of proteases and detergents. In addition, the surface charge of magnetosomes can be adjusted by varying the coating. This method will be useful for the versatile generation of new, multifunctional, multishell, and magnetic hybrid nanomaterials with potential applications in various biotechnological fields. PMID- 26058384 TI - Alpinia katsumadai Extracts Inhibit Adhesion and Invasion of Campylobacter jejuni in Animal and Human Foetal Small Intestine Cell Lines. AB - Alpinia katsumadai is used in traditional Chinese medicine for abdominal distention, pain, and diarrhoea. Campylobacter jejuni is the most common cause of bacterial food-borne diarrhoeal illnesses worldwide. Adhesion to gut epithelium is a prerequisite in its pathogenesis. The antimicrobial, cytotoxic, and anti adhesive activities of a chemically characterised extract (SEE) and its residual material of hydrodistillation (hdSEE-R) from A. katsumadai seeds were evaluated against C. jejuni. Minimal inhibitory concentrations for SEE and hdSEE-R were 0.5 mg/mL and 0.25 mg/mL, respectively, and there was no cytotoxic influence in the anti-adhesion tests, as these were performed at much lower concentrations of these tested plant extracts. Adhesion of C. jejuni to pig (PSI) and human foetal (H4) small-intestine cell lines was significantly decreased at lower concentrations (0.2 to 50 ug/mL). In the same concentration range, the invasiveness of C. jejuni in PSI cells was reduced by 45% to 65% when they were treated with SEE or hdSEE-R. The hdSEE-R represents a bioactive waste with a high phenolic content and an anti-adhesive activity against C. jejuni and thus has the potential for use in pharmaceutical and food products. PMID- 26058385 TI - Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. AB - BACKGROUND: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. METHODS: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. RESULTS: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had >10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with <=10% sarcomatoid histology (P = .04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7). CONCLUSIONS: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation. PMID- 26058386 TI - Comparative biology and pesticide susceptibility of Amblydromella caudiglans and Galendromus occidentalis as spider mite predators in apple orchards. AB - The successful integrated mite management program for Washington apples was based on conservation of the mite predator Galendromus occidentalis (Nesbitt). In the 1960s, this mite was assumed to be the only phytoseiid in Washington commercial apple orchards, due to its preference for the most common mite pest of that period, Tetranychus mcdanieli McGregor, as well as its resistance to organophosphate pesticides. A recent survey of phytoseiids in Washington apple found that another phytoseiid, Amblydromella caudiglans (Schuster) has become common. It is a more generalized predator than G. occidentalis (it is not a Tetranychus spp. specialist) and is not known to be organophosphate-resistant. A series of experiments was conducted to compare the life history, prey consumption, and pesticide tolerance of these two species. Galendromus occidentalis developed more quickly than A. caudiglans, but had slightly lower egg survival. Although A. caudiglans attacked more Tetranychus urticae Koch eggs than G. occidentalis, it could not reproduce on this diet. Both predators performed equally well on a diet of T. urticae protonymphs. Unlike G. occidentalis, A. caudiglans experienced significant mortality when exposed to carbaryl, azinphosmethyl, and bifenazate. Both predators experienced significant mortality due to imidacloprid and spinetoram. These results highlight the key differences between these two predators; the shift away from organophosphate use as well as the change in dominant mite pest to Panonychus ulmi (Koch) may be driving factors for the observed increased abundance of A. caudiglans in Washington apple. PMID- 26058387 TI - Cloning and differential expression of five heat shock protein genes associated with thermal stress and development in the polyphagous predatory mite Neoseiulus cucumeris (Acari: Phytoseiidae). AB - In order to explore the role of heat shock proteins (Hsps) during thermal stress and development in the predatory mite Neoseiulus cucumeris (Oudemans), we cloned and characterized five full-length Hsp genes. We investigated the expression levels of these genes by quantitative real-time PCR. The five genes characterized here were NcHsp90, NcHsp75, NcHsp70, NcHsp60, and NcHsp40. These Hsps showed high sequence conservation and had greatest identity with heat shock proteins of Metaseiulus occidentalis and other mite and insect species. All five NcHsp genes showed changes in their levels of expression during development. Higher levels of expression were observed in adult females than in adult males, but there were no significant changes between pre-oviposition and post-oviposition stages in the females. NcHsp90, NcHsp75, and NcHsp70 expression levels were up-regulated after a heat shock, and the increases in NcHsp75 and NcHsp70 expression levels were maintained for at least 3 h. Up-regulation of NcHsp60 and NcHsp40 was not detected after 1 h at a high temperature (35-45 degrees C); however, a significant down-regulation was observed after 3 h heat exposure at 35 degrees C and 3 h recovery at 25 degrees C. Cold shock treatment (-5 to 15 degrees C) for 1 h did not acute elicit changes in the expression levels of any of the genes. At 5 degrees C, the expression levels of NcHsp90 significantly increased after 6 or 24 h exposure compared to the levels after 1 h exposure. Thus, expression of Hsp genes in N. cucumeris reflected developmental changes, sexual difference, and variable induced response to thermal stress. Increased expression of Hsps might protect N. cucumeris individuals under extreme temperature conditions. Therefore, it may be possible to enhance the thermal tolerance of commercially available N. cucumeris using temperature acclimation. Treatment at 35 degrees C should be suitable for such acclimation. PMID- 26058388 TI - Genetic footprints reveal geographic patterns of expansion in Fennoscandian red foxes. AB - Population expansions of boreal species are among the most substantial ecological consequences of climate change, potentially transforming both structure and processes of northern ecosystems. Despite their importance, little is known about expansion dynamics of boreal species. Red foxes (Vulpes vulpes) are forecasted to become a keystone species in northern Europe, a process stemming from population expansions that began in the 19th century. To identify the relative roles of geographic and demographic factors and the sources of northern European red fox population expansion, we genotyped 21 microsatellite loci in modern and historical (1835-1941) Fennoscandian red foxes. Using Bayesian clustering and Bayesian inference of migration rates, we identified high connectivity and asymmetric migration rates across the region, consistent with source-sink dynamics, whereby more recently colonized sampling regions received immigrants from multiple sources. There were no clear clines in allele frequency or genetic diversity as would be expected from a unidirectional range expansion from south to north. Instead, migration inferences, demographic models and comparison to historical red fox genotypes suggested that the population expansion of the red fox is a consequence of dispersal from multiple sources, as well as in situ demographic growth. Together, these findings provide a rare glimpse into the anatomy of a boreal range expansion and enable informed predictions about future changes in boreal communities. PMID- 26058389 TI - Implantation of an Iliac Branch Device After EVAR via a Femoral Approach Using a Steerable Sheath. AB - PURPOSE: To describe a contralateral femoral approach for iliac branch device implantation using a steerable sheath in the setting of an existing bifurcated stent-graft. TECHNIQUE: The method is demonstrated in an 80-year-old man who developed a 4-cm iliac aneurysm 3 years after implantation of an Endurant bifurcated stent-graft. Both femoral arteries were cannulated after surgical cutdown. The steerable sheath was advanced from the contralateral side over the neobifurcation of the bifurcated stent-graft. A 0.014-inch Roadrunner wire was used as a through-and-through wire to stabilize the curve of the sheath and to get proper push. The bridging stent-graft for the iliac branch was advanced over this sheath to seal the iliac aneurysm. During the entire procedure, the sheath was stable over the neobifurcation without pulling it down. CONCLUSION: The contralateral femoral approach for iliac branch graft implantation is feasible in cases with an extant bifurcated stent-graft using a steerable sheath and a through-and-through wire. PMID- 26058390 TI - Medical abortions more common than surgery for first time in 2014 in England and Wales. PMID- 26058391 TI - Body mass index, cardiorespiratory fitness and cardiometabolic risk factors in youth from Portugal and Mozambique. AB - OBJECTIVES: The objectives of this study are to examine differences in cardiometabolic risk indicators, as well as their prevalences, in Portuguese and Mozambican youth, and to investigate the associations between weight status and cardiorespiratory fitness levels with cardiometabolic risk. METHODS: The sample comprises 721 adolescents (323 Mozambican and 398 Portuguese), aged 10-15 years. Anthropometry (height, sitting height, weight and waist circumference), blood pressure, serum-fasting triglycerides, high-density lipoprotein cholesterol and glucose, and cardiorespiratory fitness were measured. Maturity offset was estimated and a cardiometabolic risk score adjusted for sex, age and biological maturity was computed. Adolescents were classified as normal weight and overweight/obese as well as fit or unfit (cardiorespiratory fitness). RESULTS: Portuguese youth have better cardiometabolic and cardiorespiratory fitness profiles. About 32% and 30% of Portuguese boys and girls, respectively, are overweight/obese; in Mozambicans, these prevalences are 7.5% for boys and 21% for girls; in addition, 81.6% of Portuguese boys and 77.7% of Portuguese girls were classified as cardiorespiratory fit, against 54% and 44.4% of Mozambican boys and girls, respectively. No statistically significant differences (P>0.05) were found between Mozambicans and Portuguese for the cluster of three or more cardiometabolic risk indicators. A positive relationship (P<0.001) was found between weight status and cardiometabolic risk in adolescents from both countries; however, a negative association (P<0.001) between cardiorespiratory fitness and cardiometabolic risk was only found among Portuguese youth. CONCLUSIONS: Portuguese and Mozambican youth differ in their cardiometabolic risk profiles, body weight and cardiorespiratory fitness, favoring Portuguese. Overweight/obesity and low cardiorespiratory fitness levels are related to a worse cardiometabolic risk profile, being relevant to design public health intervention strategies to reduce excess weight and increase cardiorespiratory fitness. PMID- 26058392 TI - Spider Transcriptomes Identify Ancient Large-Scale Gene Duplication Event Potentially Important in Silk Gland Evolution. AB - The evolution of specialized tissues with novel functions, such as the silk synthesizing glands in spiders, is likely an influential driver of adaptive success. Large-scale gene duplication events and subsequent paralog divergence are thought to be required for generating evolutionary novelty. Such an event has been proposed for spiders, but not tested. We de novo assembled transcriptomes from three cobweb weaving spider species. Based on phylogenetic analyses of gene families with representatives from each of the three species, we found numerous duplication events indicative of a whole genome or segmental duplication. We estimated the age of the gene duplications relative to several speciation events within spiders and arachnids and found that the duplications likely occurred after the divergence of scorpions (order Scorpionida) and spiders (order Araneae), but before the divergence of the spider suborders Mygalomorphae and Araneomorphae, near the evolutionary origin of spider silk glands. Transcripts that are expressed exclusively or primarily within black widow silk glands are more likely to have a paralog descended from the ancient duplication event and have elevated amino acid replacement rates compared with other transcripts. Thus, an ancient large-scale gene duplication event within the spider lineage was likely an important source of molecular novelty during the evolution of silk gland-specific expression. This duplication event may have provided genetic material for subsequent silk gland diversification in the true spiders (Araneomorphae). PMID- 26058393 TI - Selective proximal renal denervation guided by autonomic responses evoked via high-frequency stimulation in a preclinical canine model. AB - BACKGROUND: Electric stimulation has been proved to be available to monitor the efficacy of renal denervation (RDN). This study was to evaluate the effectiveness of high-frequency stimulation (HFS)-guided proximal RDN. METHODS AND RESULTS: A total of 13 Chinese Kunming dogs were included and allocated to proximal RDN group (n=8) and control group (n=5). HFS (20 Hz, 8 V, pulse width 2 ms) was performed from proximal to distal renal artery in all dogs. Radiofrequency ablations were delivered in proximal RDN group and only at the proximal positive sites where systolic blood pressure (BP) increased >=10 mm Hg during HFS. Postablation HFS was performed over the previously stimulated sites. BP, heart rate, and plasma norepinephrine were analyzed. In 8 denervated dogs, preablation HFS caused significant BP increases of 6.0+/-5.0/3.4+/-5.5, 16.9+/-11.7/11.1+/ 8.5, and 17.1+/-8.4/8.5+/-5.3 mm Hg during the first, second, and third 20 s of HFS at the proximal positive sites. After ablation, these sites showed a negative response to postablation HFS with increases of BP by 1.3+/-3.0/1.0+/-2.5, 0.8+/ 3.9/1.5+/-3.4, and 1.5+/-4.5/0.7+/-3.8 mm Hg. Of note, no radiofrequency applications were delivered at the positive sites of middle renal artery, repeated HFS increased BP only by 3.3+/-5.3/2.8+/-4.2, 5.3+/-6.6/3.8+/-4.7, and 2.9+/-4.6/1.3+/-3.2 mm Hg, failed to reproduce the previous BP increases of 6.2+/ 5.6/5.3+/-4.4, 15.0+/-9.3/10.2+/-6.2, and 14.9+/-7.7/8.4+/-4.7 mm Hg. At 3 months, BP and plasma norepinephrine substantially decreased in proximal RDN group. Whereas controls showed minimal BP decreases and had similar plasma norepinephrine concentrations as baseline. CONCLUSIONS: Renal afferent nerves can be mapped safely, and HFS-guided targeted proximal RDN can achieve apparent BP reduction and sympathetic inhibition. PMID- 26058395 TI - Metformin Suppresses Prostaglandin E2-Induced Cytochrome P450 Aromatase Gene Expression and Activity via Stimulation of AMP-Activated Protein Kinase in Human Endometriotic Stromal Cells. AB - BACKGROUND: Cytochrome P450 aromatase (encoded by the CYP19A1/aromatase gene) plays a critical physiologic role in endometriosis. Metformin is known to suppress prostaglandin E2 (PGE2)-induced CYP19A1 messenger RNA (mRNA) expression in human endometriotic stromal cells (ESCs). However, the possible mechanism behind this suppression remains to be determined. METHODS: In this study, ESCs were cultured with metformin, PGE2, and adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitors. Expression of CYP19A1 mRNA and aromatase activity were measured by quantitative polymerase chain reaction and aromatase activity assay, respectively. The binding of the cyclic AMP response element binding (CREB) protein to CYP19A1 promoter II (PII) was assessed by chromatin immunoprecipitation assay. RESULTS: We demonstrated that metformin downregulated the expression of aromatase mRNA (32%) and activity (25%) stimulated by PGE2 (4.18-fold and 2.14-fold) in ESCs via stimulation of AMPK. Following PGE2 treatment, there was a marked increase in CREB binding to aromatase PII, while metformin attenuated the above-mentioned stimulation by 67%. CONCLUSION: Metformin could inhibit PGE2-induced CYP19A1 mRNA expression and aromatase activity via AMPK activation and inhibition of CREB to CYP19A1 PII in human ESCs. The results of the present study suggest that metformin may have unique therapeutic potential as an antiendometriotic drug in the future. PMID- 26058394 TI - Potential for Stem Cell-Based Periodontal Therapy. AB - Periodontal diseases are highly prevalent and are linked to several systemic diseases. The goal of periodontal treatment is to halt the progression of the disease and regenerate the damaged tissue. However, achieving complete and functional periodontal regeneration is challenging because the periodontium is a complex apparatus composed of different tissues, including bone, cementum, and periodontal ligament. Stem cells may represent an effective therapeutic tool for periodontal regeneration due to their plasticity and their ability to regenerate different tissues. This review presents and critically analyzes the available information on stem cell-based therapy for the regeneration of periodontal tissues and suggests new avenues for the development of more effective therapeutic protocols. PMID- 26058396 TI - Identification of small molecules that inhibit the histone chaperone Asf1 and its chromatin function. AB - The eukaryotic genome is packed into chromatin, which is important for the genomic integrity and gene regulation. Chromatin structures are maintained through assembly and disassembly of nucleosomes catalyzed by histone chaperones. Asf1 (anti-silencing function 1) is a highly conserved histone chaperone that mediates histone transfer on/off DNA and promotes histone H3 lysine 56 acetylation at globular core domain of histone H3. To elucidate the role of Asf1 in the modulation of chromatin structure, we screened and identified small molecules that inhibit Asf1 and H3K56 acetylation without affecting other histone modification. These pyrimidine-2,4,6-trione derivative molecules inhibited the nucleosome assembly mediated by Asf1 in vitro, and reduced the H3K56 acetylation in HeLa cells. Furthermore, production of HSV viral particles was reduced by these compounds. As Asf1 is implicated in genome integrity, cell proliferation, and cancer, current Asf1 inhibitor molecules may offer an opportunity for the therapeutic development for treatment of diseases. PMID- 26058397 TI - Naturally occurring reoviruses for human cancer therapy. AB - Naturally occurring reoviruses are live replication-proficient viruses that specifically infect human cancer cells while sparing their normal counterpart. Since the discovery of reoviruses in 1950s, they have shown various degrees of safety and efficacy in pre-clinical or clinical applications for human anti cancer therapeutics. I have recently discovered that cellular tumor suppressor genes are also important in determining reoviral tropism. Carcinogenesis is a multi-step process involving the accumulation of both oncogene and tumor suppressor gene abnormalities. Reoviruses can exploit abnormal cellular tumor suppressor signaling for their oncolytic specificity and efficacy. Many tumor suppressor genes such as p53, ataxia telangiectasia mutated (ATM), and retinoblastoma associated (RB) are known to play important roles in genomic fidelity/maintenance. Thus, a tumor suppressor gene abnormality could affect host genomic integrity and likely disrupt intact antiviral networks due to the accumulation of genetic defects which in turn could result in oncolytic reovirus susceptibility. This review outlines the discovery of oncolytic reovirus strains, recent progresses in elucidating the molecular connection between oncogene/tumor suppressor gene abnormalities and reoviral oncotropism, and their clinical implications. Future directions in the utility of reovirus virotherapy is also proposed in this review. PMID- 26058399 TI - Drug-drug interactions that interfere with statin metabolism. AB - INTRODUCTION: Lipid-lowering drugs, especially hydroxymethylglutaryl-CoA reductase inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic diseases. The benefits of statins are well documented. However, myotoxic side effects, which can sometimes be severe, including myopathy or rhabdomyolysis, have been associated with the use of statins. In some cases, this toxicity is associated with pharmacokinetic alterations. Potent inhibitors of CYP 3A4 significantly increase plasma concentrations of the active forms of simvastatin, lovastatin and atorvastatin. Fluvastatin is metabolized by CYP2C9, while pravastatin, rosuvastatin and pitavastatin are not susceptible to inhibition by any CYP. AREAS COVERED: This review discusses the pharmacokinetic aspects of the drug-drug interaction with statins and genetic polymorphisms in CYPs, which are involved in the metabolism of statins, and highlights the importance of establishing a system utilizing electronic medical information practically to avoid adverse drug reactions. EXPERT OPINION: An understanding of the mechanisms underlying statin interactions will help to minimize drug interactions and develop statins that are less prone to adverse interactions. Quantitatively analyzed information for the low-density lipoprotein cholesterol lowering effects of statin based on electronic medical records may be useful for avoiding the adverse effect of statins. PMID- 26058398 TI - Phosphorylation-dependent regulation of Notch1 signaling: the fulcrum of Notch1 signaling. AB - Notch signaling plays a pivotal role in cell fate determination, cellular development, cellular self-renewal, tumor progression, and has been linked to developmental disorders and carcinogenesis. Notch1 is activated through interactions with the ligands of neighboring cells, and acts as a transcriptional activator in the nucleus. The Notch1 intracellular domain (Notch1-IC) regulates the expression of target genes related to tumor development and progression. The Notch1 protein undergoes modification after translation by posttranslational modification enzymes. Phosphorylation modification is critical for enzymatic activation, complex formation, degradation, and subcellular localization. According to the nuclear cycle, Notch1-IC is degraded by E3 ligase, FBW7 in the nucleus via phosphorylation-dependent degradation. Here, we summarize the Notch signaling pathway, and resolve to understand the role of phosphorylation in the regulation of Notch signaling as well as to understand its relation to cancer. PMID- 26058400 TI - Computational and Technological Innovations for Epilepsy Diagnosis and Control. Introduction. PMID- 26058401 TI - Gap Junctions as Common Cause of High-Frequency Oscillations and Epileptic Seizures in a Computational Cascade of Neuronal Mass and Compartmental Modeling. AB - High frequency oscillations (HFO) appear to be a promising marker for delineating the seizure onset zone (SOZ) in patients with localization related epilepsy. It remains, however, a purely observational phenomenon and no common mechanism has been proposed to relate HFOs and seizure generation. In this work we show that a cascade of two computational models, one on detailed compartmental scale and a second one on neural mass scale can explain both the autonomous generation of HFOs and the presence of epileptic seizures as emergent properties. To this end we introduce axonal-axonal gap junctions on a microscopic level and explore their impact on the higher level neural mass model (NMM). We show that the addition of gap junctions can generate HFOs and simultaneously shift the operational point of the NMM from a steady state network into bistable behavior that can autonomously generate epileptic seizures. The epileptic properties of the system, or the probability to generate epileptic type of activity, increases gradually with the increase of the density of axonal-axonal gap junctions. We further demonstrate that ad hoc HFO detectors used in previous studies are applicable to our simulated data. PMID- 26058404 TI - Pharmaceutical and biomedical applications of quantum dots. AB - Quantum dots (QDs) have captured the fascination and attention of scientists due to their simultaneous targeting and imaging potential in drug delivery, in pharmaceutical and biomedical applications. In the present study, we have exhaustively reviewed various aspects of QDs, highlighting their pharmaceutical and biomedical applications, pharmacology, interactions, and toxicological manifestations. The eventual use of QDs is to dramatically improve clinical diagnostic tests for early detection of cancer. In recent years, QDs were introduced to cell biology as an alternative fluorescent probe. PMID- 26058402 TI - Pre-Clinical Traumatic Brain Injury Common Data Elements: Toward a Common Language Across Laboratories. AB - Traumatic brain injury (TBI) is a major public health issue exacting a substantial personal and economic burden globally. With the advent of "big data" approaches to understanding complex systems, there is the potential to greatly accelerate knowledge about mechanisms of injury and how to detect and modify them to improve patient outcomes. High quality, well-defined data are critical to the success of bioinformatics platforms, and a data dictionary of "common data elements" (CDEs), as well as "unique data elements" has been created for clinical TBI research. There is no data dictionary, however, for preclinical TBI research despite similar opportunities to accelerate knowledge. To address this gap, a committee of experts was tasked with creating a defined set of data elements to further collaboration across laboratories and enable the merging of data for meta analysis. The CDEs were subdivided into a Core module for data elements relevant to most, if not all, studies, and Injury-Model-Specific modules for non generalizable data elements. The purpose of this article is to provide both an overview of TBI models and the CDEs pertinent to these models to facilitate a common language for preclinical TBI research. PMID- 26058403 TI - American Thyroid Association Statement on Surgical Application of Molecular Profiling for Thyroid Nodules: Current Impact on Perioperative Decision Making. AB - BACKGROUND: Recent advances in research on thyroid carcinogenesis have yielded applications of diagnostic molecular biomarkers and profiling panels in the management of thyroid nodules. The specific utility of these novel, clinically available molecular tests is becoming widely appreciated, especially in perioperative decision making by the surgeon regarding the need for surgery and the extent of initial resection. METHODS: A task force was convened by the Surgical Affairs Committee of the American Thyroid Association and was charged with writing this article. RESULTS/CONCLUSIONS: This review covers the clinical scenarios by cytologic category for which the thyroid surgeon may find molecular profiling results useful, particularly for cases with indeterminate fine-needle aspiration cytology. Distinct strengths of each ancillary test are highlighted to convey the current status of this evolving field, which has already demonstrated the potential to streamline decision making and reduce unnecessary surgery, with the accompanying benefits. However, the performance of any diagnostic test, that is, its positive predictive value and negative predictive value, are exquisitely influenced by the prevalence of cancer in that cytologic category, which is known to vary widely at different medical centers. Thus, it is crucial for the clinician to know the prevalence of malignancy within each indeterminate cytologic category, at one's own institution. Without this information, the performance of the diagnostic tests discussed below may vary substantially. PMID- 26058405 TI - The efficacy of cold-gel packing for relieving episiotomy pain - a quasi randomised control trial. AB - PURPOSES: This study evaluated the effectiveness of cold-gel packing on episiotomy pain among postpartum women who had normal spontaneous deliveries. METHODS: A quasi-randomised control trial was conducted in a maternity ward of a regional teaching hospital in northern Taiwan. Seventy postpartum women were recruited, choosing to be in either the experimental or control group (35 women per group). Subjects in the experimental group received at least six interventions of cold-gel packing applied to the perineal wound and were provided oral analgesics routinely. The subjects in the control group received oral analgesics routinely. FINDINGS: Pain intensity, pain interference on daily activities and satisfaction levels with pain management were assessed using Brief Pain Inventory (BPI) and pain management questionnaire, respectively. The results showed that women in the experimental group reported significantly lower mean pain intensity score, pain interference on daily activities scores at 48 hours post-delivery, and higher level of satisfaction with pain management at 24 and 48 hours post-delivery than the control group after adjusting for demographic and obstetric data. CONCLUSIONS: Cold-gel packing on the perineum is a cost effective, convenient, easy-to-deploy and non-pharmacologic approach to pain reduction, with an overall positive impact on postpartum recovery for parturients. PMID- 26058406 TI - Tree mortality from drought, insects, and their interactions in a changing climate. AB - Climate change is expected to drive increased tree mortality through drought, heat stress, and insect attacks, with manifold impacts on forest ecosystems. Yet, climate-induced tree mortality and biotic disturbance agents are largely absent from process-based ecosystem models. Using data sets from the western USA and associated studies, we present a framework for determining the relative contribution of drought stress, insect attack, and their interactions, which is critical for modeling mortality in future climates. We outline a simple approach that identifies the mechanisms associated with two guilds of insects - bark beetles and defoliators - which are responsible for substantial tree mortality. We then discuss cross-biome patterns of insect-driven tree mortality and draw upon available evidence contrasting the prevalence of insect outbreaks in temperate and tropical regions. We conclude with an overview of tools and promising avenues to address major challenges. Ultimately, a multitrophic approach that captures tree physiology, insect populations, and tree-insect interactions will better inform projections of forest ecosystem responses to climate change. PMID- 26058407 TI - Clear principles are needed for integrity in gambling research. AB - Commercial gambling is expanding rapidly across the globe. However, the field of gambling research has not kept pace with this expansion, and continues to focus on prevalence studies and individuated treatment regimes, with little attention to the political, economic or technological underpinnings of commercial gambling. The implications of this lack of sophistication in the research agenda are that society is ill-equipped to understand the nature and underlying causes of gambling harms, and how these might best be avoided, minimized or ameliorated. Around the world, various levels of government benefit from gambling revenue, with consequences for the independent regulation of gambling. Further, there is considerable industry influence on the research agenda, often involving similar techniques to those employed previously by the tobacco and alcohol industries to engage researchers. This influence is compounded by a failure of many gambling researchers and journals to adopt traditional academic safeguards, such as the disclosure of conflicts of interest, and by many arguing for a 'partnership model' with industry to advance the research agenda. This paper identifies five basic principles to restore reasonable standards of integrity in gambling studies: (1) research should not be funded by the proceeds of gambling; (2) research priorities should not be influenced by the beneficiaries of gambling; (3) conferences and other research fora should not be influenced by industry; (4) funding sources should be disclosed in journals and at conferences; and (5) meaningful access to gambling products and environments must be part of licensing. We also propose a range of actions to promote greater transparency and independence in the gambling research field. PMID- 26058408 TI - Fracture resistance of weakened bovine teeth after long-term use of calcium hydroxide. AB - BACKGROUND/AIM: In some parts of the world, revascularization may not be the most feasible treatment option for necrotic immature teeth. Therefore, apexification remains the most widely utilized treatment option for these cases. This study aimed to evaluate the fracture resistance of weakened bovine tooth roots treated with various irrigant solutions as well as long-term application of calcium hydroxide intracanal medication (ICM). MATERIAL AND METHODS: One hundred seventy bovine teeth were randomly divided into three experimental groups (n = 50) and two control groups (n = 10). Group SS was irrigated with physiologic solution; group CHX was treated with 2% chlorhexidine gel and group NaOCl was irrigated with 1% sodium hypochlorite. After instrumentation, root canals were dressed with calcium hydroxide and evaluated at different periods (15, 60, 90, 180, and 360 days). The specimens were loaded at a 45 degrees angle to measure fracture resistance through the use of an EMIC test machine. RESULTS: A decrease in fracture resistance was observed during the time of ICM dressing. The highest values of fracture resistance were observed in group SS with 15 days of ICM, not differing from the control group. Irrigation with NaOCl associated with ICM for 15 days presented the lowest fracture resistance; however, a statistically significant difference was not observed when compared with SS and CHX in the same time period. In longer periods of exposure to ICM (180 and 360 days), root canals irrigated with NaOCl and CHX showed significantly lower fracture resistance than SS (P < 0.05). CONCLUSION: Apexification with periodic changes of calcium hydroxide medicament leads to weakness of the teeth independent of the irrigation solution used. PMID- 26058409 TI - Transmembrane Helix Assembly by Max-Min Ant System Algorithm. AB - Because of the rapid progress in biochemical and structural studies of membrane proteins, considerable attention has been given on developing efficient computational methods for solving low-to-medium resolution structures using sparse structural data. In this study, we demonstrate a novel algorithm, max-min ant system (MMAS), designed to find an assembly of alpha-helical transmembrane proteins using a rigid helix arrangement guided by distance constraints. The new algorithm generates a large variety with finite number of orientations of transmembrane helix bundle and finds the solution that is matched with the provided distance constraints based on the behavior of ants to search for the shortest possible path between their nest and the food source. To demonstrate the efficiency of the novel search algorithm, MMAS is applied to determine the transmembrane packing of KcsA and MscL ion channels from a limited distance information extracted from the crystal structures, and the packing of KvAP voltage sensor domain using a set of 10 experimentally determined constraints, and the results are compared with those of two popular used stochastic methods, simulated annealing Monte Carlo method and genetic algorithm. PMID- 26058411 TI - Acute effects of exercise on specific and global coagulation parameters in severe haemophilia A. PMID- 26058412 TI - Enhanced LL-37 expression following vitamin D supplementation in patients with cirrhosis and spontaneous bacterial peritonitis. AB - BACKGROUND & AIMS: The morbidity and mortality of spontaneous bacterial peritonitis (SBP) are high among patients with cirrhosis; however, the mechanisms of SBP pathogenesis are poorly understood. This study aimed to determine the role of the vitamin D-LL-37 pathway in the pathogenesis and treatment in patients with cirrhosis and SBP. METHODS: Serum 25-hydroxyvitamin D concentrations of 119 patients with chronic liver diseases were tested. Vitamin D receptor (VDR) and LL 37 in peritoneal leucocytes of cirrhotic and ascitic patients with SBP were detected and compared with those without SBP. Then the peritoneal macrophages of non-infected patients were cultured and activated by lipopolysaccharide (LPS) to analyse the changes of VDR and LL-37 expressions after incubation with vitamin D. RESULTS: Vitamin D deficiency or insufficiency was found in all of patients with cirrhosis. LPS inhibited VDR and LL-37 expression in peritoneal macrophages [1.3 fold decrease (P = 0.003) and 20-fold decrease (P = 0.010) respectively]. However, vitamin D could reverse the inhibition of both VDR and LL-37 [1.5-fold increase (P = 0.001) and 2000-fold increase (P < 0.001) respectively]. The effect of the incubation time following vitamin D supplementation was significant for LL 37 expression, with a peak expression found at 36 h (P < 0.001). CONCLUSIONS: When vitamin D levels were low, bacteria inhibited VDR and LL-37 responses in peritoneal macrophages as a mechanism to evade antibacterial defence. Vitamin D supplementation could up-regulate peritoneal macrophage VDR and LL-37 expressions, which resulted in an enhanced immunological defence against SBP in patients with cirrhosis and ascites. PMID- 26058413 TI - Healthcare professionals under pressure in involuntary admission processes. AB - The main objective of this paper is to describe how quality of care may be improved during an involuntary admission process of patients suffering from Korsakoff's syndrome. It presents an empirically grounded analysis with different perspectives on 'doing good' during this process. Family carers', healthcare professionals' and legal professionals' ways of understanding and ordering this problematic situation appear very different. This could prevent patients from getting the proper care they need, with risk of more suffering and quality of life below the minimum acceptable. All this possibly lead to immoral dehumanizing situations. Firstly, the background of our empirical study is sketched. Secondly, the different perspectives on 'doing good' are summarized and compared. Thirdly, the tensions arising from the different conceptualizations of autonomy and different types of responsibilities of the actors are clarified. A common 'doing good' during involuntary admission necessitates removal of any tensions within the relational network by weighing and balancing the different perspectives on autonomy and the resulting responsibilities. With this in mind, we propose a renewed time/action table for involuntary admission, which tends to address all patients' needs at the right time. The solution presented might help healthcare professionals, who are squeezed in between patients, family carers, legal professionals and overall rules, to create practices in which patients suffering from Korsakoff's syndrome can maintain their dignity and receive the care they need. Earlier interventions, timely and adequate diagnosis, and diminishment of tensions between the different actors by fine-tuning their paradigmatic frameworks are suggested to be part of a solution. PMID- 26058414 TI - Functional assessment of the elderly with the use of EASY-Care Standard 2010 and Comprehensive Geriatric Assessment. AB - BACKGROUND: The wide variation in performance among the elderly leads to the search for a suitable instrument to identify the necessary support. The aim of this study was to examine the scope of independent functioning of the elderly and to indicate the necessary support using basic instruments, Comprehensive Geriatric Assessment (CGA) and EASY-Care Standard 2010. METHODS: For statistical analysis were qualified 101 questionnaires of patients from oncological surgery clinic. RESULTS: The study group was dominated by women (79.2%). The average age for the entire group was 74.7 +/- 7.5 years. In terms of basic life activities (Barthel Index), 75.2% of the elderly performed most of their activities independently. The Lawton IADL (Instrumental Activity of Daily Living Scale) median was 25 points. Moderate depression (Geriatric Depression Scale) reported 37.6% of the group. The influence of age, education, mode of movement and efficiency in basic and instrumental life activities and depression (Geriatric Depression Scale) was demonstrated in the results in three scales of the EASY Care Standard 2010 questionnaire: Independence score, Risk of break down in care and Risk of falls. There was no difference in terms of gender and the nature of the residence. CONCLUSION: The study group of the elderly was characterised by a good level of efficiency in basic and instrumental activities of daily living. Questionnaire EASY-Care Standard 2010 enables to identify functional limitations of the elderly that may form the basis for planning individual support. PMID- 26058415 TI - Species-specific diversity of novel bacterial lineages and differential abundance of predicted pathways for toxic compound degradation in scorpion gut microbiota. AB - Scorpions are considered 'living fossils' that have conserved ancestral anatomical features and have adapted to numerous habitats. However, their gut microbiota diversity has not been studied. Here, we characterized the gut microbiota of two scorpion species, Vaejovis smithi and Centruroides limpidus. Our results indicate that scorpion gut microbiota is species-specific and that food deprivation reduces bacterial diversity. 16S rRNA gene phylogenetic analysis revealed novel bacterial lineages showing a low level of sequence identity to any known bacteria. Furthermore, these novel bacterial lineages were each restricted to a different scorpion species. Additionally, our results of the predicted metagenomic profiles revealed a core set of pathways that were highly abundant in both species, and mostly related to amino acid, carbohydrate, vitamin and cofactor metabolism. Notably, the food-deprived V. smithi shotgun metagenome matched almost completely the metabolic features of the prediction. Finally, comparisons among predicted metagenomic profiles showed that toxic compound degradation pathways were more abundant in recently captured C. limpidus scorpions. This study gives a first insight into the scorpion gut microbiota and provides a reference for future studies on the gut microbiota from other arachnid species. PMID- 26058416 TI - Synergistic targeted therapy for acute promyelocytic leukaemia: a model of translational research in human cancer. AB - Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. It has been found that all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML-RARalpha fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of 'bench to bedside' and 'bedside to bench', which can serve as a valuable example for the diagnosis and treatment of other malignancies. PMID- 26058417 TI - Positive impact of dietary water on in vivo epidermal water physiology. AB - BACKGROUND/PURPOSE: The importance of water in human physiology is well known, also for skin functionality. This study was conducted to assess the effects of dietary water on epidermal skin hydration in healthy females. METHODS: Thirty four healthy females (mean 24.5 +/- 6.34 years old) were selected and characterized according to their dietary daily habits, by a previously validated Food Frequency Questionnaire. For 1 month, these subjects were asked to add 2 L/day of water to their regular dietary habits. Measurements took place at day D0, D15, and D30, and involved general variables (body weight, blood pressure, Body Mass Index) and specific skin physiological variables in five anatomical sites (ventral forearm, anterior leg, dorsal hand, zygomatic area, and forehead) involving epidermal superficial and deep hydration, by capacitance and transepidermal water loss (TEWL). RESULTS: This water overload (2 L/day/30 days) did not change the blood volume or weight of the individuals. However, both superficial and deep skin hydration were clearly in those individuals that regularly consumed lees water per day. No significant effect was observed in the TEWL. CONCLUSIONS: This study clearly suggests that dietary water intake seems to influence skin water content. Nevertheless further in vivo investigations involving other variables, such as biomechanical descriptors, should follow to look deeper into this aspect of skin physiology. PMID- 26058418 TI - Neurometabolic Effect of Altaian Fungus Ganoderma lucidum (Reishi Mushroom) in Rats Under Moderate Alcohol Consumption. AB - BACKGROUND: The medications produced from natural products are widely used as prophylactics for sickness induced by alcohol consumption. One such prophylactic is produced from the Reishi mushroom, Ganoderma lucidum. Because of the antioxidant properties of these preparations, we expect neuroprotective prophylactic effects of Reishi-based medications in alcohol-treated animals. METHODS: The Reishi (R) suspension was produced as water extract from Altaian mushrooms. Sprague-Dawley male rats were separated into the following 3 experimental groups: Group A + R received R (6 days per week) starting 1 week before alcohol exposure, and during the next 3 weeks, they received both R and alcohol; group A received alcohol; and group C received water. At the end of experiment, we determined the metabolic profile using proton magnetic resonance spectroscopy ((1) H MRS) of the brain cortex and phosphorus magnetic resonance spectroscopy of the liver. Additionally, the blood cells were collected, and the serum biochemistry and liver histology were performed after euthanasia. RESULTS: Partial least squares discriminant analysis processing of the brain (1) H MRS gave 2 axes, the Y1 axis positively correlated with the level of taurine and negatively correlated with the level of lactate, and the Y2 axis positively correlated with the content of GABA and glycine and negatively correlated with the sum of the excitatory neurotransmitters, glutamate and glutamine. The Y1 values reflecting the brain energetics for the A + R group exceeded the corresponding values for groups C and A. The maximal level of Y2 reflecting the prevalence of inhibitory metabolites in the brain was observed in the rats exposed to alcohol. Moderate alcohol consumption did not cause significant pathological changes in the livers of the experimental animals. However, 20 days of alcohol consumption significantly increased the number of binuclear hepatocytes compared to the control. This effect was mitigated in the rats that received the Reishi extract. CONCLUSIONS: Regular administration of the Reishi suspension improved the energy supply to the brain cortex and decreased the prevalence of inhibitory neurotransmitters that are characteristic of alcohol consumption. The alcohol-induced increase in liver proliferation was significantly suppressed by regular administration of the G. lucidum water suspension. PMID- 26058419 TI - Pediatric Lichen Planopilaris: Clinicopathologic Study of Four New Cases and a Review of the Literature. AB - Lichen planopilaris (LPP) is a rare form of cicatricial alopecia that has occasionally been reported in children. Because of the limited number of patients reported, little information is available about demographic characteristics, clinical presentation, or treatment options for these patients. A retrospective chart review of LPP cases in patients under 18 years of age from 1976 to 2013 was performed to further define clinicopathologic features of pediatric LPP. Four pediatric LPP patients ages 13 to 16 years were identified (three male, one female). One patient had scalp pruritus and one had other cutaneous findings of lichen planus (LP). Perifollicular scale and scarring were the most common physical examination findings, although changes mimicking those of alopecia areata were observed. Three patients were treated with topical or intralesional steroids. One patient was treated with minocycline. Histopathologic findings included perifollicular interface and perifollicular fibrosis in all cases. There was focal interfollicular interface in two cases and mild dermal mucin in one case. LPP is exceedingly rare in children. It may be misdiagnosed as alopecia areata in children because of the lack of symptoms and other features of LP. There should be a high index of suspicion for LPP in children with alopecia that is unresponsive to standard treatment or who have findings that are atypical for more common childhood alopecias. PMID- 26058420 TI - Unilateral renal phaeohyphomycosis due to Bipolaris spicifera in an immunocompetent child - rare case presentation and review of literature. AB - Phaeohyphomycosis refers to infections caused by phaeoid fungi that can have an aggressive course in normal hosts. We report a case of left-sided renal phaeohyphomycosis due to Bipolaris spicifera in a 7-year-old immunocompetent male child. He presented with fever, dysuria, nausea, vomiting and flank pain. Examination revealed tenderness at the left costovertebral angle. Histological examination and culture of biopsy from left kidney and blood yielded the fungal pathogen Bipolaris spicifera. His past history revealed that he was diagnosed perinatally with bilateral hydronephrosis due to bilateral pelvic ureteric junction obstruction. He underwent an open dismembered pyeloplasty on the left side followed by the right side pyeloplasty at the age of 6 months and 1.5 years respectively. He was on a regular follow-up for 5 years and had been doing well. Now he was diagnosed as a case of unilateral renal phaeohyphomycosis. The patient was managed successfully with antifungal drugs amphotericin B and itraconazole. A review of previously reported bipolaris cases with their clinical manifestations, treatment and outcome is presented. Renal phaeohyphomycosis remains an unusual disease. Aggressive diagnostic approaches and careful management helped in survival of the patient. PMID- 26058421 TI - A regionwide intervention to promote appropriate antibiotic use in children reversed trends in erythromycin resistance to Streptococcus pyogenes. PMID- 26058422 TI - The effect of maternal subclinical hypothyroidism on IQ in 7- to 8-year-old children: A case-control review. AB - BACKGROUND: In Ireland, pregnant women are not routinely screened for subclinical hypothyroidism (SCH). AIM: Our objective was to compare the intelligence quotient (IQ) of children whose mothers had been diagnosed with SCH prenatally with matched controls using a case-control retrospective study. MATERIALS AND METHODS: In a previous study from our group, 1000 healthy nulliparous women were screened anonymously for SCH. This was a laboratory diagnosis involving elevated TSH with normal fT4 or normal TSH with hypothyroxinaemia. We identified 23 cases who agreed to participate. These were matched with 47 controls. All children underwent neurodevelopmental assessment at age 7-8. Wechsler Intelligence Scale for Children IV assessment scores were used to compare the groups. Our main outcome measure was to identify whether there was a difference in IQ between the groups. RESULTS: From the cohort of cases, 23 mothers agreed to the assessment of their children as well as 47 controls. The children in the control group had higher mean scores than those in the case group across Verbal Comprehension Intelligence, Perceptual Reasoning Intelligence, Working Memory Intelligence, Processing Speed Intelligence and Full Scale IQ. Mann-Whitney U-test confirmed a significant difference in IQ between the cases (composite score 103.87) and the controls (composite score 109.11) with a 95% confidence interval (0.144, 10.330). CONCLUSIONS: Our results highlight significant differences in IQ of children of mothers who had unrecognised SCH during pregnancy. While our study size and design prevents us from making statements on causation, our data suggest significant potential public health implications for routine prenatal screening. PMID- 26058423 TI - Staphylococcus lugdunensis endocarditis following vasectomy--report of a case history and review of the literature. AB - Staphylococcus lugdunensis is a coagulase-negative Staphylococcus (CoNS), and part of the normal skin flora. The bacterium is an emerging pathogen that, unlike other CoNS, resembles coagulase-positive Staphylococcus aureus infections in virulence, tissue destruction, and clinical course. We report a fatal case following minor surgery. The frequency of S. lugdunensis infections has probably been underestimated and under-reported in the past as few clinical laboratories routinely identify coagulase-negative Staphylococci. PMID- 26058424 TI - More funding, better lives: the case for cerebral palsy research. PMID- 26058425 TI - A novel method to identify pathways associated with renal cell carcinoma based on a gene co-expression network. AB - The aim of the present study was to develop a novel method for identifying pathways associated with renal cell carcinoma (RCC) based on a gene co-expression network. A framework was established where a co-expression network was derived from the database as well as various co-expression approaches. First, the backbone of the network based on differentially expressed (DE) genes between RCC patients and normal controls was constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The differentially co-expressed links were detected by Pearson's correlation, the empirical Bayesian (EB) approach and Weighted Gene Co-expression Network Analysis (WGCNA). The co expressed gene pairs were merged by a rank-based algorithm. We obtained 842; 371; 2,883 and 1,595 co-expressed gene pairs from the co-expression networks of the STRING database, Pearson's correlation EB method and WGCNA, respectively. Two hundred and eighty-one differentially co-expressed (DC) gene pairs were obtained from the merged network using this novel method. Pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the network enrichment analysis (NEA) method were performed to verify feasibility of the merged method. Results of the KEGG and NEA pathway analyses showed that the network was associated with RCC. The suggested method was computationally efficient to identify pathways associated with RCC and has been identified as a useful complement to traditional co-expression analysis. PMID- 26058426 TI - The stress hormone norepinephrine increases migration of prostate cancer cells in vitro and in vivo. AB - The metastatic process is the most serious cause of cancer death. Norepinephrine, secreted in chronic stress conditions, stimulates the motility of breast and colon cells through beta-adrenergic receptor. On these bases, we examined its possible role in metastasis formation and development in vitro and in vivo. Treatments with norepinephrine (beta2-adrenoreceptor agonist) in mice xenografted with human DU145 prostate cancer cells increased the metastatic potential of these cells. Specifically, we showed that treatment of mice with norepinephrine induced a significant increase of the migratory activity of cancer cells in a concentration-dependent manner and that this process was blocked by propanolol (beta-adrenergic antagonist). Mice treated with norepinephrine, displayed an increased number of metastatic foci of DU145 cells in inguinal lymph nodes and also showed an increased expression of MMP2 and MMP9 in tumor samples compared to controls. Moreover, we demonstrated that propanolol induced in norepinephrine treated DU145 cells a E-cadherin finger-like membrane protrusions driven by vimentin remodeling. Altogether these data suggest that beta2-AR plays an important role in prostate cancer metastasis formation and that the treatment with antagonist propanolol, could represents an interesting tool to control this process in cells overexpressing beta2AR. PMID- 26058427 TI - Cognitive Impairment in Diabetes: Rationale and Design Protocol of the Cog-ID Study. AB - BACKGROUND: Cognitive impairment frequently co-occurs with type 2 diabetes but is often undiagnosed. Cognitive impairment affects self-management leading to treatment-related complications. OBJECTIVE: The aim of this study is to develop a stepped diagnostic procedure, consisting of a screening test complemented by an evaluation by a general practitioner (GP), to detect undiagnosed cognitive impairment in older people with type 2 diabetes. METHODS: The accuracy of two self-administered cognitive tests, the "Test Your Memory" (TYM) and "Self Administered Gerocognitive Examination" (SAGE) alone, and in combination with an evaluation by a GP will be assessed. A diagnosis of mild cognitive impairment (MCI) or dementia at a memory clinic will serve as reference standard. This cognitive impairment in diabetes (Cog-ID) study will include 513 people from primary care facilities aged >=70 with type 2 diabetes. The participants will first fill out the TYM and SAGE tests, followed by a standardized GP evaluation for cognitive impairment, including a mini mental state examination (MMSE). Subsequently, participants suspected of cognitive impairment (on either test or the GP assessment) and a random sample of 15% (65/435) of participants without suspected cognitive impairment will be referred to the memory clinic. At the memory clinic, a medical examination, neuropsychological examination, and magnetic resonance imaging (MRI) of the brain will be performed. Participants will also fill out questionnaires assessing health status and depressive symptoms at baseline and after 6 and 24 months. RESULTS: This research obtained funding and ethical approval. Enrolment started in August, 2012, and all study-related activities will be completed in September, 2016. CONCLUSIONS: With the results from this study, physicians will be able to detect cognitive impairment affecting type 2 diabetes patients through case-finding, and can use tailored care to reduce associated complications. Additionally, the results may stimulate discussions about cognitive impairment and whether early recognition is desirable. PMID- 26058428 TI - Quasi-intrinsic colossal permittivity in Nb and In co-doped rutile TiO2 nanoceramics synthesized through a oxalate chemical-solution route combined with spark plasma sintering. AB - Nb and In co-doped rutile TiO2 nanoceramics (n-NITO) were successfully synthesized through a chemical-solution route combined with a low temperature spark plasma sintering (SPS) technique. The particle morphology and the microstructure of n-NITO compounds were nanometric in size. Various techniques such as X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), thermogravimetric (TG)/differential thermal analysis (DTA), Fourier transform infrared (FTIR), and Raman spectroscopy were used for the structural and compositional characterization of the synthesized compound. The results indicated that the as-synthesized n-NITO oxalate as well as sintered ceramic have a co doped single phase of titanyl oxalate and rutile TiO2, respectively. Broadband impedance spectroscopy revealed that novel colossal permittivity (CP) was achieved in n-NITO ceramics exhibiting excellent temperature-frequency stable CP (up to 10(4)) as well as low dielectric loss (~5%). Most importantly, detailed impedance data analyses of n-NITO compared to microcrystalline NITO (MU-NITO) demonstrated that the origin of CP in NITO bulk nanoceramics might be related with the pinned electrons in defect clusters and not to extrinsic interfacial effects. PMID- 26058429 TI - Control of the 1,2-rearrangement process by oxidosqualene cyclases during triterpene biosynthesis. AB - Oxidosqualene cyclases (OSCs) catalyze the cyclization of an acyclic substrate into various polycyclic triterpenes through a series of cation-pi cyclization and 1,2-rearrangement processes. The mechanisms by which OSCs control the fate of intermediate carbocation to generate each specific triterpene product have not yet been determined. The formation of ubiquitous sterol precursors in plants, cycloartenol and Cucurbitaceae-specific cucurbitadienol, only differs by the extent of the 1,2-rearrangement of methyl and hydride. In the present study, we identified critical residues in cycloartenol synthase and cucurbitadienol synthase that were primarily responsible for switching product specificities between the two compounds. The mutation of tyrosine 118 to leucine in cycloartenol synthase resulted in the production of cucurbitadienol as a major product, while the mutation of the corresponding residue leucine 125 to tyrosine in cucurbitadienol synthase resulted in the production of parkeol. Our discovery of this "switch" residue will open up future possibilities for the rational engineering of OSCs to produce the desired triterpenes. PMID- 26058430 TI - How does the plasmonic enhancement of molecular absorption depend on the energy gap between molecular excitation and plasmon modes: a mixed TDDFT/FDTD investigation. AB - A real-time time-dependent density functional theory coupled with the classical electrodynamics finite difference time domain technique is employed to systematically investigate the optical properties of hybrid systems composed of silver nanoparticles (NPs) and organic adsorbates. The results demonstrate that the molecular absorption spectra throughout the whole energy range can be enhanced by the surface plasmon resonance of Ag NPs; however, the absorption enhancement ratio (AER) for each absorption band differs significantly from the others, leading to the quite different spectral profiles of the hybrid complexes in contrast to those of isolated molecules or sole NPs. Detailed investigations reveal that the AER is sensitive to the energy gap between the molecular excitation and plasmon modes. As anticipated, two separate absorption bands, corresponding to the isolated molecules and sole NPs, have been observed at a large energy gap. When the energy gap approaches zero, the molecular excitation strongly couples with the plasmon mode to form the hybrid exciton band, which possesses the significantly enhanced absorption intensity, a red-shifted peak position, a surprising strongly asymmetric shape of the absorption band, and the nonlinear Fano effect. Furthermore, the dependence of surface localized fields and the scattering response functions (SRFs) on the geometrical parameters of NPs, the NP-molecule separation distance, and the external-field polarizations has also been depicted. PMID- 26058431 TI - Single ZnO nanocactus gas sensor formed by etching of ZnO nanorod. AB - Etching of materials on the nanoscale is a challenging but necessary process in nanomaterials science. Gas sensing using a single ZnO nanocactus (NC), which was prepared by facile isotropic nanoetching of zinc oxide nanorods (NR) grown by chemical vapor deposition (CVD) using an organic photoresist (PR) by a thermochemical reaction, is reported in this work. PR consists of carboxylic acid groups (COOH) and cyclopentanone (C5H8O), which can react with zinc and oxygen atoms, respectively, on the surface of a ZnO NR. The thermochemical reaction is controllable by varying the concentration of PR and reaction time. A gas sensor was fabricated using a single NC. Gas sensing was tested using different gases such as CH4, NH3 and carbon monoxide (CO). It was estimated that the surface area of a ZnO NC in the case of 50% PR was found to increase four-fold. When compared with a single ZnO NR gas sensor, the sensitivity of a ZnO NC was found to increase four-fold. This increase in sensitivity is attributed to the increase in surface area of the ZnO NC. The formed single ZnO NC gas sensor has good stability, response and recovery time. PMID- 26058432 TI - Biologics in spondyloarthritis: TNFalpha inhibitors and other agents. AB - TNFalpha inhibitors are currently the only class of biological agent that has proven to be effective in the treatment of patients with ankylosing spondylitis and/or spondyloarthritis (SpA). These agents have been shown to control inflammatory pain of the axial skeleton, peripheral clinical manifestations, certain extra-articular manifestations as well as systemic and spinal MRI inflammation. Conversely, they are unable to slow radiographic progression in the spine. Since around 20-30% of patients with SpA are considered as nonmajor responders to TNFalpha inhibitors, there is a need for alternative therapies. Biological agents that target IL-1, IL-6, B cells and costimulatory pathways are not effective in SpA. Conversely, novel biological agents blocking IL-23 or IL-17 are promising in SpA, especially secukinumab, an anti-IL-17A monoclonal antibody. PMID- 26058433 TI - Our Experience with Totally Ultrasonography-Guided Percutaneous Nephrolithotomy in Children. AB - PURPOSE: To present the safety and efficacy of totally ultrasonography-guided percutaneous nephrolithotomy (PCNL) for managing urinary stones in pediatric patients. PATIENTS AND METHODS: Ten children with a mean age of 5.4 (3-11) years underwent totally ultrasonography-guided PCNL from March 2013 to November 2013. The pyelocaliceal system was punctured with the patient in the prone position by using ultrasonographic guidance, and the tract was dilated using a single-shot dilation technique. All steps of renal access were performed by using ultrasonography; no fluoroscopy was used. PCNL in all cases was performed by using adult instruments. RESULTS: The mean stone size was 28.9+/-6.7 mm (range 17 35 mm). The mean access time to stone was 4.45+/-2.25 minutes (range 3-10 min). The mean nephroscopic time was 45.9+/-17 minutes (range 20-80 min). The stone free rate was 83%. Mean hospital stay of patients was 3 days (range 2-5 days). No major complications were happened. Only one patient needed ureteral stent insertion because of urinary leakage from the nephrostomy tract. CONCLUSION: Our experience with totally ultrasonography-guided PCNL using adult size instruments in children revealed proper results and acceptable complications compared with the standard technique of PCNL. Likewise, this alternative method has the advantage of preventing radiation hazard. PMID- 26058434 TI - [Aspiration of blood does not verify intravenous location of central venous catheters]. AB - This case which involves a misplaced central venous catheter demonstrates the importance of certain recognition of intravenous placement before the administration of fluids and medicine. PMID- 26058435 TI - [No effect of the use of varicose vein treatment compression after more than seven days]. AB - The aim of this article is to review the current use of compression after varicose vein treatment. Five randomized controlled trials and one systematic review was chosen for evaluation. No benefit was found when comparing either long duration compression with short duration, or compression with no compression. Additionally, patient compliance was low. The evidence is based on underpowered and heterogeneous groups. Thus, no contribution to a consensus regarding the use of post varicose vein treatment compression can be made. PMID- 26058436 TI - [Screening for cervical cancer in women older than 65 years will probably reduce the incidence and mortality]. AB - The age-specific cervical cancer incidence in Denmark is bimodal with peaks at ages 35-40 years and 75 years. Yet, Danish women >= 65 years are not offered screening for cervical cancer. Screening women beyond the age of 65 years may reduce cervical cancer incidence as well as mortality, and seems to be cost effective. Older women may benefit more from human papillomavirus screening rather than by cytology. Thus, more research on cervical cancer screening in older women is warranted. PMID- 26058437 TI - [In case of pelvic pain desquamative inflammatory vaginitis is an important differential diagnosis]. AB - Desquamative inflammatory vaginitis (DIV) is an uncommon, severe form of chronic vaginitis of unknown aetiology. The syndrome is characterised by profuse vaginal discharge, vulvovaginal irritation, dyspareunia and vaginal erythema. As the symptoms and signs are nonspecific, other causes of purulent discharge have to be excluded first. Definition necessitates specific wet smear findings. The purpose of this case report is to consider DIV as a diagnosis in women presenting with persistent vaginitis. An effective treatment using clindamycin and/or glucocorticoids is available. PMID- 26058438 TI - [Fatal intracerebral haemorrhage possibly caused by interaction between paracetamol and warfarin]. AB - This is a case report of an 83-year-old man in warfarin treatment with stable international normalised ratio (INR) after aortic valve replacement and atrial fibrillation. Due to back pain he took paracetamol (acetaminophen) 4 g/day, morphine 30 mg/day and diclofenac as rescue medication for two weeks. After 14 days of treatment he was admitted to a hospital with acute neurological deficits, and a blood sample showed INR levels above 10. A CT-scan of the brain showed an intracerebral haemorrhage. The patient died eight days after admission. Mechanisms of the possible interaction between paracetamol and warfarin are discussed. PMID- 26058439 TI - [Chemotherapy in the second and third trimester of pregnancy is compatible with the delivery of a healthy infant]. AB - This case report describes the delay in diagnosis and treatment of a diffuse large B-cell lymphoma in pregnancy of a 27-year-old woman. Chemotherapy was initiated in week 21 of pregnancy - the tumour regressed and the foetus had linear growth. The patient had caesarean section in week 34, and after delivery she received high doses of methotrexate and obtained complete remission. The two year-old infant had a normal development. PMID- 26058440 TI - [Transient epileptic amnesia]. AB - Transient epileptic amnesia (TEA) is a presumably underdiagnosed syndrome belonging to the group of temporal lobe epilepsies. It can easily be misdiagnosed as transient global amnesia (TGA), transient ischaemic attack, psychogenic amnesia or even dementia. Many patients complain of loss of autobiographical memory and accelerated long-term forgetting. We present a case to emphasize both the importance of diagnosing TEA and the pitfalls between TEA and TGA syndrome. PMID- 26058441 TI - Influence of habitual high dietary fat intake on endothelium-dependent vasodilation. AB - High-fat diets are associated with an increased risk of cardiovascular disease. A potential underlying mechanism for the increased cardiovascular risk is endothelial dysfunction. Nitric oxide (NO)-mediated endothelium-dependent vasodilation is critical in the regulation of vascular tone and overall vascular health. The aim of this study was to determine the influence of dietary fat intake on endothelium-dependent vasodilation. Forty-four middle-aged and older sedentary, healthy adults were studied: 24 consumed a lower fat diet (LFD; 29% +/ 1% calories from fat) and 20 consumed a high-fat diet (HFD; 41% +/- 1% calories from fat). Four-day diet records were used to assess fat intake, and classifications were based on American Heart Association guidelines (<35% of total calories from fat). Forearm blood flow (FBF) responses to acetylcholine, in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl l-arginine (L-NMMA), as well as responses to sodium nitroprusside were determined by plethysmography. The FBF response to acetylcholine was lower (~15%; P < 0.05) in the HFD group (4.5 +/- 0.2 to 12.1 +/- 0.8 mL/100 mL tissue/min) than in the LFD group (4.6 +/- 0.2 to 14.4 +/- 0.6 mL/100 mL tissue/min). L-NMMA significantly reduced the FBF response to acetylcholine in the LFD group (~25%) but not in the HFD group. There were no differences between groups in the vasodilator response to sodium nitroprusside. These data indicate that a high-fat diet is associated with endothelium-dependent vasodilator dysfunction due, in part, to diminished NO bioavailability. Impaired NO-mediated endothelium dependent vasodilation may contribute to the increased cardiovascular risk with high dietary fat intake. PMID- 26058442 TI - Conversion Equation between the Drop Height in the New York University Impactor and the Impact Force in the Infinite Horizon Impactor in the Contusion Spinal Cord Injury Model. AB - There are several widely used devices for controlled contusion of the spinal cord, including the Ohio State University device, the University of British Columbia multi-mechanisms injury device, the New York University (NYU) impactor, and the Infinite Horizon (IH) impactor. Although various devices and protocols have been used to generate consistent injury severities, further investigation of the relationship between the key parameters of different spinal cord injury (SCI) contusion devices (e.g., drop height in the NYU impactor and impact force in the IH impactor) will improve our understanding of SCI mechanisms. A three dimensional finite element model of the rat spinal cord from T9 to T10 that included the white and gray matters, dura mater, and cerebrospinal fluid was developed to investigate the von-Mises stress, maximum principal strain, and maximum displacement of the spinal cord for the drop height in the NYU impactor and the impact force in the IH impactor. A quantitative relationship was established as a conversion equation between two key parameters--i.e., the drop height and the impact force--in the NYU and IH impactors from regression equations for peak von-Mises stress, peak maximum principal strain, and maximum displacement in the spinal cord with respect to drop height and impact force with very high coefficients of determination. The consistent correlation was represented as a simple equation (Force = (28.2 +/- 3.2) . Height((0.83 +/- 0.07))) under the experimental conditions of a 10-g rod in the NYU impactor and an impact velocity of 125 mm/sec in the IH impactor. Thus, the key biomechanical parameter for a contusion device can be converted or translated to that of another device to analyze experimental results from multiple contusion devices. PMID- 26058444 TI - Designing a medical records review tool: an instructional guide. AB - BACKGROUND: Medical Records Reviews (MRR) are commonly used in research and quality activities in health care, however, there is a paucity of literature offering a step by step guide to devising a reliable, user-friendly tool. AIM: This instructional paper focuses on the stages used to design and implement successful MRR using examples from two reviews in Australian rural hospitals investigating the responses of Registered Nurses to patient deterioration, and guided by time series principals. METHODS: The MRR were conducted in two rural hospitals in conjunction with a simulation learning intervention where nurses rehearsed clinical management of a deteriorating patient. A six-step template is presented to guide practitioners on how to design and use a MRR tool. CONCLUSION: When well-planned and appropriately used, MRR provides an excellent means for examining patient outcomes in addition to safety and quality of care. PMID- 26058445 TI - Dentists' self-estimation of their competence to treat avulsion and root fracture injuries. AB - AIM: The purpose of this study was to evaluate the knowledge of Norwegian dentists on avulsion and root fracture injuries. METHOD: An electronic questionnaire (QuestBack) was sent in 2012 to all dentists (n = 255) employed in the Public Dental Service (PDS) in three counties of Norway. The dentists were asked to state whether they felt they had sufficient competence to treat avulsion and root fractures immediately and long term. Based on international guidelines, the authors achieved a consensus for ideal treatment. Based on two cases, the clinicians were to assess their own competence. They were classified into either a 'sufficient competence' (SC) group or an 'insufficient competence' (ISC) group. The data were evaluated by descriptive statistics and chi-square bivariate analysis. RESULTS: The response rate was 64%, 95 dentists (62%) in the SC group and 58 (38%) in the ISC group. Significantly more young dentists responded (P < 0.001). Correct treatment (reposition and splint) for a one-day-old fracture in the middle third of the root with luxation of the coronal fragment was chosen more often by the SC group compared with the ISC group (P = 0.03), but estimating the long-term prognosis, there was no difference (P = 0.14). In a case with a previous avulsion injury and obvious signs of pulp necrosis and external infection-related root resorption, the majority (n = 97, 63%) would choose root canal treatment with a Ca(OH)2 dressing which was considered correct treatment, but fewer than half of the clinicians (40%) diagnosed the external infection related to root resorption which was visible on a radiograph. There was no difference between the groups (P = 0.81). CONCLUSION: The study shows that overall knowledge among Norwegian dentists is good, but more knowledge on detecting and diagnosing external root resorption is needed. Self-estimation of own competence does not reflect level of knowledge. PMID- 26058446 TI - An international perspective of advanced practice nursing regulation. AB - BACKGROUND: There is no common understanding about the role of the advanced practice nurse across the globe and there is wide variation in the regulation of advanced practice nursing roles as well as their educational, licensing and credentialing requirements. AIM: The goal of this research was to examine the status of advanced practice nursing regulation globally. METHODS: An online survey link was emailed to National Nursing Associations and nursing health policy makers worldwide from June to December 2011. Questions focused on regulation, education, scope of practice, and barriers and opposition. Analysis included frequency statistics and descriptive data for survey questions and content analysis for two open-ended questions. LIMITATIONS: The survey was offered online and only in English. Therefore, technology and language barriers may have influenced the results. RESULTS: There is wide variation in educational requirements, regulation and scope of practice of advanced practice nurses. The barriers to advanced practice nursing are often linked to the status of legislation and credentialing in specific jurisdictions. CONCLUSION: A database of advanced practice nursing regulation and issues related to practice has the potential to become a valuable resource for individual countries. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Each country has unique challenges related to health policy for advanced practice nursing roles. International nursing organizations have established programmes for regulation development; however, a stronger focus on monitoring regulation and more effective dissemination of information about available supports may have a bigger impact on the development and revision of health policy related to advanced practice nursing. PMID- 26058443 TI - Health effects of World Trade Center (WTC) Dust: An unprecedented disaster's inadequate risk management. AB - The World Trade Center (WTC) twin towers in New York City collapsed on 9/11/2001, converting much of the buildings' huge masses into dense dust clouds of particles that settled on the streets and within buildings throughout Lower Manhattan. About 80-90% of the settled WTC Dust, ranging in particle size from ~2.5 MUm upward, was a highly alkaline mixture of crushed concrete, gypsum, and synthetic vitreous fibers (SVFs) that was readily resuspendable by physical disturbance and low-velocity air currents. High concentrations of coarse and supercoarse WTC Dust were inhaled and deposited in the conductive airways in the head and lungs, and subsequently swallowed, causing both physical and chemical irritation to the respiratory and gastroesophageal epithelia. There were both acute and chronic adverse health effects in rescue/recovery workers; cleanup workers; residents; and office workers, especially in those lacking effective personal respiratory protective equipment. The numerous health effects in these people were not those associated with the monitored PM2.5 toxicants, which were present at low concentrations, that is, asbestos fibers, transition and heavy metals, polyaromatic hydrocarbons or PAHs, and dioxins. Attention was never directed at the very high concentrations of the larger-sized and highly alkaline WTC Dust particles that, in retrospect, contained the more likely causal toxicants. Unfortunately, the initial focus of the air quality monitoring and guidance on exposure prevention programs on low-concentration components was never revised. Public agencies need to be better prepared to provide reliable guidance to the public on more appropriate means of exposure assessment, risk assessment, and preventive measures. PMID- 26058447 TI - The impact of paying treatment providers for outcomes: difference-in-differences analysis of the 'payment by results for drugs recovery' pilot. AB - AIMS: To estimate the effect on drug misuse treatment completion of a pilot scheme to pay service providers according to rates of recovery. DESIGN: A controlled, quasi-experimental (difference-in-differences) observational study using multi-level random effects logistic regression. SETTING: Drug misuse treatment providers in all 149 commissioning areas in England in the financial years 2011-12 and 2012-13. PARTICIPANTS: Service users treated in England in 2011 12 and 2012-13. INTERVENTION AND COMPARATORS: Linkage of provider payments to performance indicators in eight pilot commissioning areas in England compared with all 141 non-pilot commissioning areas in England. MEASUREMENTS: Recovery was measured by successful completion of treatment (free from drugs of dependence) and engagement with services was measured by rates of declining to continue with treatment. FINDINGS: Following the introduction of the pilot scheme, service users treated in pilot areas were 1.3 percentage points [odds ratio (OR) = 0.859; 95% confidence interval (CI) = 0.788, 0.937] less likely to complete treatment compared with those treated in comparison areas. Service users treated in pilot areas were 0.9 percentage points (OR = 2.934; 95% CI = 2.094, 4.113) more likely to decline to continue with treatment compared with those treated in comparison areas. CONCLUSIONS: In the first year of the pilot 'Payment by Results for Drugs Recovery' scheme in England, linking payments to outcomes reduced the probability of completing drug misuse treatment and increased the proportion service users declining to continue with treatment. PMID- 26058448 TI - Synthesis and Antiproliferative Activity of Silybin Conjugates with Salinomycin and Monensin. AB - Aiming at development of multitarget drugs for the anticancer treatment, new silybin (SIL) conjugates with salinomycin (SAL) and monensin (MON) were synthesized, in mild esterification conditions, and their antiproliferative activity was studied. The conjugates obtained exhibit anticancer activity against HepG2, LoVo and LoVo/DX cancer cell lines. Moreover, MON-SIL conjugate exhibits higher anticancer potential and better selectivity than the corresponding SAL-SIL conjugate. PMID- 26058449 TI - High-Frequency Spinal Cord Stimulation and Pregnancy: A Case Report. AB - INTRODUCTION: High-frequency spinal cord stimulation (HF SCS) is a relatively new modality of SCS. The present general advice concerning pregnancy and SCS, in general, is to turn the device off because of insufficient knowledge concerning the impact on the developing fetus. As HF stimulation generates higher energies, potential adverse fetal effects could be theoretically stronger. CASE: This case report describes a 36-year-old woman who had two pregnancies with an active HF SCS system. Her first pregnancy ended in a miscarriage. During her second pregnancy, she continued stimulation treatment during the whole pregnancy. She gave birth to a healthy baby. CONCLUSIONS: This case describes both a miscarriage and the birth of a healthy baby in a patient treated with HF SCS. It is not possible to rule out that the HF SCS could have caused the miscarriage. Also, the birth of the healthy baby after the second pregnancy in which HF SCS was used the whole period, is not a valid reason to declare HF SCS and SCS, in general, safe during pregnancy. As no sufficient data are available, we must remain cautious about any unknown possible adverse effects or delayed adverse events because of SCS and maybe especially HF stimulation. All outcome data on pregnancies during all types of SCS ideally should be collected and analyzed. PMID- 26058450 TI - Haemophilia care in Central and Eastern Europe: challenges and ways forward from clinicians' perspective. PMID- 26058451 TI - Low-memory iterative density fitting. AB - A new low-memory modification of the density fitting approximation based on a combination of a continuous fast multipole method (CFMM) and a preconditioned conjugate gradient solver is presented. Iterative conjugate gradient solver uses preconditioners formed from blocks of the Coulomb metric matrix that decrease the number of iterations needed for convergence by up to one order of magnitude. The matrix-vector products needed within the iterative algorithm are calculated using CFMM, which evaluates them with the linear scaling memory requirements only. Compared with the standard density fitting implementation, up to 15-fold reduction of the memory requirements is achieved for the most efficient preconditioner at a cost of only 25% increase in computational time. The potential of the method is demonstrated by performing density functional theory calculations for zeolite fragment with 2592 atoms and 121,248 auxiliary basis functions on a single 12-core CPU workstation. PMID- 26058453 TI - A green capillary zone electrophoresis method for the simultaneous determination of piperacillin, tazobactam and cefepime in pharmaceutical formulations and human plasma. AB - A green, novel, rapid, accurate and reliable capillary zone electrophoresis method was developed and validated for the simultaneous determination of piperacillin, tazobactam and cefepime in pharmaceutical preparations. Separation was carried out using fused silica capillary (50 um i.d. * 48.6 cm and 40.2 cm detection length) and applied potential of 20 kV (positive polarity) and a running buffer containing 15 m m sodium borate buffer adjusted to pH 9.3 with UV detection at 215 nm. Amoxicillin was used as an internal standard. The method was suitably validated according to International Conference on Harmonization guidelines. The method showed good linearity in the ranges of 10-100, 20-400 and 10-400 ug/mL with limits of quantitation of 1.87, 3.17 and 6.97 ug/mL and limits of detection of 0.56, 0.95 and 2.09 ug/mL for tazobactam, piperacillin and cefepime, respectively. The proposed method was successfully applied for the analysis of these drugs in their synthetic mixtures and co-formulated injection vials. The method was extended to the in vitro determination of the two drugs in spiked human plasma. It is considered a 'green' method as it consumes no organic solvents. PMID- 26058454 TI - Vaccine associated paralytic poliomyelitis cases from children presenting with acute flaccid paralysis in Uganda. AB - A retrospective study to identify VAPP cases from the entire Uganda was conducted between January 2003 and December 2011. Eleven of the 106 AFP cases were VAPPs. The VAPP rate ranged from 0 to 3.39 cases per 1,000,000 birth cohorts and the peak was in 2009 when there was scaling up of OPV immunization activities following an importation of wild poliovirus in the country. All the subsequent polio suspect cases since then have been vaccine-associated polio cases. Our data support the strategy to withdraw OPV and introduce IPV progressively in order to mitigate against the paralysis arising from Sabin polioviruses. PMID- 26058455 TI - Effect of chewing betel nut (Areca catechu) on salivary cortisol measurement. AB - OBJECTIVES: Cultural practices may compromise the accuracy of salivary hormone measurements and must be considered when designing human biology research protocols. This study aims to evaluate the acute effect of one common human practice-chewing betel nut-on the measurement of salivary cortisol levels under field conditions. MATERIALS AND METHODS: Data were collected from 17 adult habitual betel nut users (males = 11; females = 6; mean age = 32.8 years) from a small rural community in Papua New Guinea. Saliva was collected in time series from each participant before and at 0, 15, 30, 45, 60, and 75 min after chewing betel nut. Samples were analyzed by radioimmunoassay and cortisol levels were compared across time using linear mixed effects modeling. RESULTS: Measured mean cortisol concentration fell nearly 40% immediately following betel nut use and remained significantly below baseline levels for the following 45 min (all P < 0.05). Cortisol concentrations measured at 60 min and 75 min were indistinguishable from baseline levels (all P > 0.16). DISCUSSION: Chewing betel nut is associated with a transient but significant reduction in measured levels of salivary cortisol. Future research must take this into account in populations where betel nut use is prevalent. PMID- 26058456 TI - What does height tell us about the risk of dementia? PMID- 26058452 TI - Analyzing pathways from childhood maltreatment to internalizing symptoms and disorders in children and adolescents (AMIS): a study protocol. AB - BACKGROUND: Effective interventions for maltreated children are impeded by gaps in our knowledge of the etiopathogenic mechanisms leading from maltreatment to mental disorders. Although some studies have already identified individual risk factors, there is a lack of large-scale multilevel research on how psychosocial, neurobiological, and genetic factors act in concert to modulate risk of internalizing psychopathology in childhood following maltreatment. To help close this gap, we aim to delineate gender-specific pathways from maltreatment to psychological disorder/resilience. To this end, we examine the interplay of specific maltreatment characteristics and psychological, endocrine, metabolomic, and (epi-)genomic stress response patterns as well as cognitive-emotional/social processes as determinants of developmental outcome. Specifically, we will explore endocrine, metabolomic, and epigenetic mechanisms leading from maltreatment to a higher risk of depression and anxiety disorders. METHODS/DESIGN: Four large samples amounting to a total of N = 920 children aged 4-16 years will be assessed: Two cohorts with prior internalizing psychopathology and controls will be checked for maltreatment and two cohorts with substantiated maltreatment will be checked for internalizing (and externalizing) psychopathology. We will apply a multi-source (interview, questionnaires, official records), multi-informant strategy (parents, children, teachers) to assess maltreatment characteristics (e.g., subtypes, developmental timing, chronicity) and psychopathological symptoms, supplemented with multiple measurements of risk and protective factors and cutting-edge laboratory analyses of endocrine, steroid metabolomic and epigenetic factors. As previous assessments in the two largest samples are already available, longitudinal data will be generated within the three year study period. DISCUSSION: Our results will lay the empirical foundation for (a) detection of early biopsychosocial markers, (b) development of screening measures, and PMID- 26058457 TI - Implications of changing the Six-item Cognitive Impairment Test cutoff. PMID- 26058458 TI - Pim Kinase Inhibitors Evaluated with a Single-Molecule Engineered Nanopore Sensor. AB - Protein kinases are critical therapeutic targets. Pim kinases are implicated in several leukaemias and cancers. Here, we exploit a protein nanopore sensor for Pim kinases that bears a pseudosubstrate peptide attached by an enhanced engineering approach. Analyte binding to the sensor peptide is measured through observation of the modulation of ionic current through a single nanopore. We observed synergistic binding of MgATP and kinase to the sensor, which was used to develop a superior method to evaluate Pim kinase inhibitors featuring label-free determination of inhibition constants. The procedure circumvents many sources of bias or false-positives inherent in current assays. For example, we identified a potent inhibitor missed by differential scanning fluorimetry. The approach is also amenable to implementation on high throughput chips. PMID- 26058459 TI - Concurrent pulmonary hemorrhage and deep vein thrombosis in a child with ANCA associated vasculitis: case report and review of literature. AB - Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is an uncommon but potentially life threatening disease in children. Pulmonary hemorrhage (PH) is a well recognized but lethal complication. The incidence of venous thromboembolism (VTE) is higher in patients with AAV, especially in those with active disease. However, the simultaneous occurrence of both PH and VTE has rarely been reported. Herein, we describe a 14-year-old female with AAV who developed concomitant deep vein thrombosis (DVT) and PH within 3 days after hospitalization. She was successfully treated with timely plasmapheresis and methylprednisolone pulse therapy. VTE did not occur during discontinuation of anticoagulant. On reviewing the English literature, 5 AAV patients with coexisting VTE and PH have been reported. When faced with PH, whether or not to keep anti-coagulation treatment is a dilemma. Some of the patients kept receiving anti-coagulation treatment, whereas others undergoing inferior vena cava filter implantation. Glucocorticoids and cyclophosphamide or other immunosuppressant agents were prescribed in all patients. All of the cases survived after treatment for concurrent VTE and PH, and received short- or long-term anticoagulation treatment after discharge. To the best of our knowledge, this is the first report of a pediatric patient with AAV presenting with coexistent VTE and PH. VTE should be considered to be a sign of disease flare-up, and early plasmapheresis with immunosuppressant therapy can rescue this fatal complication. PMID- 26058460 TI - Selenoprotein S Is Highly Expressed in the Blood Vessels and Prevents Vascular Smooth Muscle Cells From Apoptosis. AB - Atherosclerosis and related cardiovascular diseases (CVD) represent one of the greatest threats to human health worldwide. The protection of vascular smooth muscle cells (VSMCs) from apoptosis in the plaque has become an important therapeutic target for atherosclerotic plaque stabilization. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism remains unknown. In this paper, SelS expression in the thoracic aorta and its role in the protection of VSMCs from apoptosis have been studied. Western blot analysis showed that SelS was highly expressed in rat thoracic aorta. SelS gene silence by small interference RNA (siRNA) rendered VSMCs more sensitive to hydrogen peroxide or tunicamycin- induced injury and apoptosis, as determined by MTT assay, Hoechst staining, and annexin V/propidium iodide staining. SelS silence aggravated hydrogen peroxide-induced oxidative stress and phosphorylation of p38 MAPK and c-Jun N-terminal kinase (JNK) in VSMCs. Furthermore, SelS silence enhanced endoplasmic reticulum (ER) stress induced by hydrogen peroxide or tunicamycin, as showed by the increased protein levels of ER chaperone 78 kDa glucose-regulated protein (GRP78), ER stress transducer phosphorylated protein kinase RNA like ER kinase (PERK), and the proapoptotic transcription factor C/EBP homologous protein (CHOP). In conclusion, the present study suggested that SelS highly expressed in the blood vessel might protect VSMCs from apoptosis by inhibiting oxidative stress and ER stress. Our finding provided mechanistic insights for the potential preventive role of SelS in atherosclerotic CVD. PMID- 26058461 TI - Quantitative sodium MRI of the human brain at 9.4 T provides assessment of tissue sodium concentration and cell volume fraction during normal aging. AB - Sodium ion homeostasis is a fundamental property of viable tissue, allowing the tissue sodium concentration to be modeled as the tissue cell volume fraction. The modern neuropathology literature using ex vivo tissue from selected brain regions indicates that human brain cell density remains constant during normal aging and attributes the volume loss that occurs with advancing age to changes in neuronal size and dendritic arborization. Quantitative sodium MRI performed with the enhanced sensitivity of ultrahigh-field 9.4 T has been used to investigate tissue cell volume fraction during normal aging. This cross-sectional study (n = 49; 21 80 years) finds that the in vivo tissue cell volume fraction remains constant in all regions of the brain with advancing age in individuals who remain cognitively normal, extending the ex vivo literature reporting constant neuronal cell density across the normal adult age range. Cell volume fraction, as measured by quantitative sodium MRI, is decreased in diseases of cell loss, such as stroke, on a time scale of minutes to hours, and in response to treatment of brain tumors on a time scale of days to weeks. Neurodegenerative diseases often have prodromal periods of decades in which regional neuronal cell loss occurs prior to clinical presentation. If tissue cell volume fraction can detect such early pathology, this quantitative parameter may permit the objective measurement of preclinical disease progression. This current study in cognitively normal aging individuals provides the basis for the pursuance of investigations directed towards such neurodegenerative diseases. PMID- 26058463 TI - Hepato-pancreatectomy: how morbid? Results from the national surgical quality improvement project. AB - BACKGROUND: Simultaneous resection of both the liver and the pancreas carries significant complexity. The objective of this study was to investigate peri operative outcomes after a synchronous hepatectomy and pancreatectomy (SHP). METHODS: The American College of Surgeons National Surgical Quality Improvement Project database was queried to identify patients who underwent SHP. Resections were categorized as '< hemihepatectomy', '>= hemihepatectomy' (hemihepatectomy and trisectionectomy), 'PD' (pancreaticoduodenectomy and total pancreatectomy) and 'distal' (distal pancreatectomy and enucleation). RESULTS: From 2005 to 2013, 480 patients underwent SHP. Patients were stratified based on the extent of resection: '< hemihepatectomy + distal (n = 224)', '>= hemihepatectomy + distal' (n = 49), '< hemihepatectomy + PD' (n = 83) and '>= hemihepatectomy + PD' (n = 24). Although the first three groups had a reasonable and comparable safety profile (morbidity 33-51% and mortality 0-6.6%), the '>= hemihepatectomy + PD' group was associated with an 87.5% morbidity (organ space infection 58.3%, re intubation 12.5%, reoperation 25% and septic shock 25%), 8.3% 30-day mortality and 18.2% in-hospital mortality. CONCLUSIONS: A synchronous hemihepatectomy (or trisectionectomy) with PD remains a highly morbid combination and should be reserved for patients who have undergone extremely cautious selection. PMID- 26058462 TI - Clinicopathological indices to predict hepatocellular carcinoma molecular classification. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is the second most lethal cancer caused by lack of effective therapies. Although promising, HCC molecular classification, which enriches potential responders to specific therapies, has not yet been assessed in clinical trials of anti-HCC drugs. We aimed to overcome these challenges by developing clinicopathological surrogate indices of HCC molecular classification. METHODS: Hepatocellular carcinoma classification defined in our previous transcriptome meta-analysis (S1, S2 and S3 subclasses) was implemented in an FDA-approved diagnostic platform (Elements assay, NanoString). Ninety-six HCC tumours (training set) were assayed to develop molecular subclass-predictive indices based on clinicopathological features, which were independently validated in 99 HCC tumours (validation set). Molecular deregulations associated with the histopathological features were determined by pathway analysis. Sample sizes for HCC clinical trials enriched with specific molecular subclasses were determined. RESULTS: Hepatocellular carcinoma subclass predictive indices were steatohepatitic (SH)-HCC variant and immune cell infiltrate for S1 subclass, macrotrabecular/compact pattern, lack of pseudoglandular pattern, and high serum alpha-foetoprotein (>400 ng/ml) for S2 subclass, and microtrabecular pattern, lack of SH-HCC and clear cell variants, and lower histological grade for S3 subclass. Macrotrabecular/compact pattern, a predictor of S2 subclass, was associated with the activation of therapeutically targetable oncogene YAP and stemness markers EPCAM/KRT19. BMP4 was associated with pseudoglandular pattern. Subclass-predictive indices-based patient enrichment reduced clinical trial sample sizes from 121, 184 and 53 to 30, 43 and 22 for S1, S2 and S3 subclass-targeting therapies respectively. CONCLUSIONS: Hepatocellular carcinoma molecular subclasses can be enriched by clinicopathological indices tightly associated with deregulation of therapeutically targetable molecular pathways. PMID- 26058464 TI - Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: Comparison of efficacy and search for predictive factors guiding treatment choice. AB - BACKGROUND: The alkylating agents (ALKYs) streptozotocin, dacarbazine, and temozolomide currently are the main drugs used in systemic chemotherapy for neuroendocrine tumors (NETs). The promising activity shown by gemcitabine and oxaliplatin (GEMOX) in previous studies prompted this study 1) to confirm the use of GEMOX in a larger population of NET patients, 2) to compare its efficacy with that of ALKYs, and 3) to explore whether the O(6) -methylguanine-DNA methyltransferase (MGMT) status could help in selecting the chemotherapy regimen. METHODS: One hundred four patients with metastatic NETs (37 pancreatic NETs, 33 gastrointestinal NETs, 23 bronchial NETs, and 11 NETs of other/unknown origin) were treated with GEMOX between 2004 and 2014. Among these patients, 63 also received ALKYs. MGMT promoter gene methylation was assessed via pyrosequencing in 42 patients. RESULTS: Patients received a median of 6 courses of GEMOX. Twenty four (23%) had an objective response (OR). The median progression-free survival (PFS) and overall survival were 7.8 and 31.6 months, respectively. In the 63 patients treated with both ALKYs and GEMOX, the ORs (22% and 22%) and the PFSs (7.5 and 7.3 months) were similar. The response was concordant in 53% of the patients. Promoter gene methylation of MGMT was associated with better outcomes with ALKYs (P = .03 for OR and P = .04 for PFS) but not GEMOX. CONCLUSIONS: GEMOX is effective against NETs; its activity is comparable to that of ALKYs, and it is not influenced by the MGMT status. Our data suggest that GEMOX might be preferred for patients with unmethylated MGMT tumors. Cancer 2015;121:3435-43. (c) 2015 American Cancer Society. PMID- 26058466 TI - Cellular stage specific functional analysis of REX1: In human embryonic stem cells. AB - As transcription and translation are dynamic and can vary among the cell types and conditions, proteomics may reveal the tissue-specific functions of a protein, more relevant to its genuine functions on cellular mechanisms. The new proteome analysis by Son et al. [Proteomics 2015, 15, 2220-2229] identified the functions of the pluripotency marker protein, REX1 in hESCs, and unraveling its regulatory network orchestrating pluripotency. Compared to the previous transcriptome analysis that showed mechanisms irrelevant to pluripotency, Son et al. employed a proteome analysis determined convincing and meaningful mechanisms of REX. In addition to demonstrating the biological importance of REX1, this research by Son et al. is also a compelling example of the conceptual significance of connecting proteomics with stem cell biology. PMID- 26058465 TI - Hepatitis B virus reactivation and hepatitis in diffuse large B-cell lymphoma patients with resolved hepatitis B receiving rituximab-containing chemotherapy: risk factors and survival. AB - INTRODUCTION: Hepatitis B virus (HBV) reactivation has been reported in B-cell lymphoma patients with resolved hepatitis B (hepatitis B surface antigen [HBsAg] negative and hepatitis B core antibody [HBcAb]-positive). This study aimed to assess HBV reactivation and hepatitis occurrence in diffuse large B-cell lymphoma (DLBCL) patients with resolved hepatitis B receiving rituximab-containing chemotherapy compared with HBsAg-negative/HBcAb-negative patients to identify risk factors for HBV reactivation and hepatitis occurrence and to analyze whether HBV reactivation and hepatitis affect the survival of DLBCL patients with resolved hepatitis B. METHODS: We reviewed the clinical data of 278 patients with DLBCL treated with rituximab-containing therapy between January 2004 and May 2008 at Sun Yat-sen University Cancer Center, China. Predictive factors for HBV reactivation, hepatitis development, and survival were examined by univariate analysis using the chi-square or Fisher's exact test and by multivariate analysis using the Cox regression model. RESULTS: Among the 278 patients, 165 were HBsAg negative. Among these 165 patients, 6 (10.9%) of 55 HBcAb-positive (resolved HBV infection) patients experienced HBV reactivation compared with none (0%) of 110 HBcAb-negative patients (P = 0.001). Patients with resolved hepatitis B had a higher hepatitis occurrence rate than HBsAg-negative/HBcAb-negative patients (21.8% vs. 8.2%, P = 0.013). HBcAb positivity and elevated baseline alanine aminotransferase (ALT) levels were independent risk factors for hepatitis. Among the 55 patients with resolved hepatitis B, patients with elevated baseline serum ALT or aspartate aminotransferase (AST) levels were more likely to develop hepatitis than those with normal serum ALT or AST levels (P = 0.037, P = 0.005, respectively). An elevated baseline AST level was an independent risk factor for hepatitis in these patients. Six patients with HBV reactivation recovered after immediate antiviral therapy, and chemotherapy was continued. HBcAb positivity, HBV reactivation, or hepatitis did not negatively affect the survival of DLBCL patients. CONCLUSIONS: DLBCL patients with resolved hepatitis B may have a higher risk of developing HBV reactivation and hepatitis than HBsAg-negative/HBcAb negative patients. Close monitoring and prompt antiviral therapy are required in these patients. PMID- 26058467 TI - Contrasting effects of climate on juvenile body size in a Southern Hemisphere passerine bird. AB - Despite extensive research on the topic, it has been difficult to reach general conclusions as to the effects of climate change on morphology in wild animals: in particular, the effects of warming temperatures have been associated with increases, decreases or stasis in body size in different populations. Here, we use a fine-scale analysis of associations between weather and offspring body size in a long-term study of a wild passerine bird, the cooperatively breeding superb fairy-wren, in south-eastern Australia to show that such variation in the direction of associations occurs even within a population. Over the past 26 years, our study population has experienced increased temperatures, increased frequency of heatwaves and reduced rainfall - but the mean body mass of chicks has not changed. Despite the apparent stasis, mass was associated with weather across the previous year, but in multiple counteracting ways. Firstly, (i) chick mass was negatively associated with extremely recent heatwaves, but there also positive associations with (ii) higher maximum temperatures and (iii) higher rainfall, both occurring in a period prior to and during the nesting period, and finally (iv) a longer-term negative association with higher maximum temperatures following the previous breeding season. Our results illustrate how a morphological trait may be affected by both short- and long-term effects of the same weather variable at multiple times of the year and that these effects may act in different directions. We also show that climate within the relevant time windows may not be changing in the same way, such that overall long-term temporal trends in body size may be minimal. Such complexity means that analytical approaches that search for a single 'best' window for one particular weather variable may miss other relevant information, and is also likely to make analyses of phenotypic plasticity and prediction of longer-term population dynamics difficult. PMID- 26058468 TI - The multifaceted vigilance - nurses' experiences of caring encounters with patients suffering from substance use disorder. AB - BACKGROUND: Nursing care is guided by a value base focusing on promoting dignity and health by means of the caring relationship. However, previous research has revealed that negative attitudes towards 'addicted' patients, as well as these patients' behaviour, can give rise to negative emotions such as frustration and disappointment among nurses. This can contribute to a judgmental and controlling attitude towards patients. To preserve order, nursing interventions focusing on creating structure and stability could be applied in a way that challenges caring values. AIMS AND OBJECTIVES: This study aimed to describe how nurses' working in inpatient psychiatric care experience caring encounters with patients suffering from substance use disorder (SUD). DESIGN: This qualitative study is part of a clinical application project focusing on value-based care of patients suffering from SUD. Data were obtained during four reflective group dialogues with six nurses in a psychiatric hospital. METHODS: The transcribed dialogues were subjected to latent qualitative content analysis. RESULTS: The analysis facilitated the organisation of the findings into a coherent pattern. A common thread of meaning was conceptualised as a theme labelled 'the multifaceted vigilance', describing how nurses strived to deliver good care, while at the same time being vigilant towards patients' behaviour as well as their own reactions to it. Within that theme, four categories described experiences related to different challenges nurses face in caring encounters. CONCLUSION: We suggest that this perhaps unavoidable aspect of caring encounters can be an asset. Thus, if acknowledged and subject to reflection, being vigilant could be understood as a strength enabling nurses to safeguard caring values, and to use their authority to promote patients' health and alleviate suffering. PMID- 26058469 TI - Bacterial sensing underlies artificial sweetener-induced growth of gut Lactobacillus. AB - Disruption in stable establishment of commensal gut microbiota by early weaning is an important factor in susceptibility of young animals to enteric disorders. The artificial sweetener SUCRAM [consisting of neohesperidin dihydrochalcone (NHDC) and saccharin] included in piglets' feed reduces incidence of enteric disease. Pyrosequencing of pig caecal 16S rRNA gene amplicons identified 25 major families encompassing seven bacterial classes with Bacteroidia, Clostridia and Bacilli dominating the microbiota. There were significant shifts in microbial composition in pigs maintained on a diet containing SUCRAM, establishing SUCRAM as a major influence driving bacterial community dynamics. The most notable change was a significant increase of Lactobacillaceae population abundance, almost entirely due to a single phylotype, designated Lactobacillus 4228. The sweetener-induced increase in Lactobacillaceae was observed in two different breeds of pigs signifying a general effect. We isolated Lactobacillus 4228, sequenced its genome and found it to be related to Lactobacillus amylovorus. In vitro analyses of Lactobacillus 4228 growth characteristics showed that presence of NHDC significantly reduces the lag phase of growth and enhances expression of specific sugar transporters, independently of NHDC metabolism. This study suggests that sensing of NHDC by a bacterial plasma membrane receptor underlies sweetener-induced growth of a health promoting gut bacterium. PMID- 26058470 TI - Core Binding Factor beta Plays a Critical Role During Chondrocyte Differentiation. AB - Core binding factor beta (Cbfbeta) is a partner protein of Runx family transcription factors with minimally characterized function in cartilage. Here we address the role of Cbfbeta in cartilage by generating chondrocyte-specific Cbfbeta-deficient mice (Cbfb(Deltach/Deltach) ) from Cbfb-floxed mice crossed with mice expressing Cre from the Col2a1 promoter. Cbfb(Deltach/Deltach) mice died soon after birth and exhibited delayed endochondral bone formation, shorter appendicular skeleton length with increased proliferative chondrocytes, and nearly absent hypertrophic chondrocyte zones. Immunohistochemical and quantitative real-time PCR analyses showed that the number and size of proliferative chondrocytes increased and the expression of chondrocyte maturation markers at the growth plates, including Runx2, osterix, and osteopontin, significantly diminished in Cbfb(Deltach/Deltach) mice compared to wild type mice. With regard to signaling pathways, both PTHrP-Ihh and BMP signaling were compromised in Cbfb(Deltach/Deltach) mice. Mechanistically, Cbfbeta deficiency in chondrocytes caused a decrease of protein levels of Runx transcription factors by accelerating polyubiquitination-mediated proteosomal degradation in vitro. Indeed, Runx2 and Runx3, but not Runx1, decreased in Cbfb(Deltach/Deltach) mice. Collectively, these findings indicate that Cbfbeta plays a critical role for chondrocyte differentiation through stabilizing Runx2 and Runx3 proteins in cartilage. PMID- 26058472 TI - Screening for At-Risk Drinking in a Population Reporting Symptoms of Depression: A Validation of the AUDIT, AUDIT-C, and AUDIT-3. AB - BACKGROUND: Excessive alcohol use is common in patients presenting with symptoms of depression. The aim of this study was to evaluate how the Alcohol Use Disorders Identification Test (AUDIT) and its most commonly used abbreviated versions perform in detecting at-risk drinking among subjects reporting symptoms of depression. METHODS: A subsample (n = 390; 166 men, 224 women) of a general population survey, the National FINRISK 2007 Study, was used. Symptoms of depression were measured with the Beck Depression Inventory-Short Form and alcohol consumption with the Timeline Follow-back (TLFB). At-risk drinking was defined as >=280 g weekly or >=60 g on at least 1 occasion in the previous 28 days for men, 140 and 40 g, respectively, for women. The AUDIT, AUDIT-C, and AUDIT-3 were tested against the defined gold standard, that is, alcohol use calculated from the TLFB. An optimal cutoff was designated as having a sensitivity and specificity of over 0.75, with emphasis on specificity. The AUDIT and its abbreviations were compared with carbohydrate-deficient transferrin (CDT) and gamma-glutamyltransferase. RESULTS: At-risk drinking was common. The AUDIT and AUDIT-C performed quite consistently. Optimal cutoffs for men were >=9 for the AUDIT and >=6 for AUDIT-C. The optimal cut-offs for women with mild symptoms of depression were >=5 for the AUDIT and >=4 for AUDIT-C. Optimal cutoffs could not be determined for women with moderate symptoms of depression (specificity <0.75). A nearly optimal cutoff for women was >=5 for the AUDIT. The AUDIT-3 failed to perform in women, but in men, a good level of sensitivity and specificity was reached at a cutoff of >=2. With standard threshold values, the biochemical markers demonstrated very low sensitivity (9 to 28%), but excellent specificity (83 to 98%). CONCLUSIONS: Screening for at-risk drinking among patients presenting with symptoms of depression using the full AUDIT is recommended, although the AUDIT-C performed almost equally well. Cut-offs should be adjusted according to gender, but not according to the severity of depressive symptoms. The AUDIT and its abbreviations were superior to biochemical markers. PMID- 26058471 TI - Long-term stability of axonal boutons in the mouse barrel cortex. AB - Many lines of evidence indicate that postsynaptic dendritic spines are plastic during development and largely stable in adulthood. It remains unclear to what degree presynaptic axonal terminals undergo changes in the developing and mature cortex. In this study, we examined the formation and elimination of fluorescently labeled axonal boutons in the living mouse barrel cortex with transcranial two photon microscopy. We found that the turnover of axonal boutons was significantly higher in 3-week-old young mice than in adult mice (older than 3 months). There was a slight but significant net loss of axonal boutons in mice from 1 to 2 months of age. In both young and adult barrel cortex, axonal boutons existed for at least 1 week were less likely to be eliminated than those recently-formed boutons. In adulthood, 80% of axonal boutons persisted over 12 months and enriched sensory experience caused a slight but not significant increase in the turnover of axonal boutons over 2-4 weeks. Thus, similar to postsynaptic dendritic spines, presynaptic axonal boutons show remarkable stability after development ends. This long-term stability of synaptic connections is likely important for reliable sensory processing in the mature somatosensory cortex. PMID- 26058474 TI - Generic Biocombinatorial Strategy to Select Tailor-Made Stabilizers for Sol-Gel Nanoparticle Synthesis. AB - A generic route for the selection of nanoparticle stabilizers via biocombinatorial means of phage display peptide screening is presented, providing magnesium fluoride nanoparticle synthesis as example. Selected sequence-specific MgF2 binders are evaluated for their adsorption behavior. Peptide-polymer conjugates derived from the best binding peptide are used for the stabilization of MgF2 sol nanoparticles, yielding fully redispersable dry states and improoving processability significantly. PMID- 26058473 TI - Detection of central venous catheter-related bloodstream infections in haematooncological patients. AB - BACKGROUND: Catheter-related bloodstream infections (CRBSIs) are currently detected in patients with clinically suspicion. The aim of our study was to evaluate whether CRBSIs could be anticipated and detected in a subclinical stage by peptide nucleic acid fluorescence in situ hybridization (PNA FISH) using universal hybridization probes or acridine orange leucocyte cytospin (AOLC) tests in haematooncological patients with central venous catheters (CVCs) in situ. MATERIALS AND METHODS: Peptide nucleic acid fluorescence in situ hybridization and AOLC tests using blood samples from one CVC lumen/port chamber in haematooncological patients were continuously performed. These results were compared to those obtained from routinely performed CRBSI diagnostic tests. RESULTS: One hundred and eighty-two patients with 342 catheter periods were investigated. Seventeen CRBSI cases were detected in 6466 CVC days by routine measures resulting in a CRBSI rate of 2.6/1000 catheter days. Two of 17 showed positive PNA FISH tests, and five positive AOLC test results before the diagnosis were established with routine measures. The screening revealed further seven patients with positive universal PNA FISH tests and 10 positive AOLC tests without symptoms indicative for infection and were therefore considered not to have CRBSI. CONCLUSIONS: Sampling of only one CVC lumen/port chamber screening for CRBSI in haematooncological patients seems not to be a useful tool for anticipative diagnosis of CRBSI. Reasons for false-negative results might include origin of CRBSIs from the other CVC lumina not sampled for screening, and false positive results might origin from catheter colonization without subsequent spread of micro-organisms into the peripheral bloodstream. PMID- 26058475 TI - Candida albicans chronic colonisation in cystic fibrosis may be associated with inhaled antibiotics. AB - Candida albicans is increasingly recognised as a coloniser of the respiratory tract in cystic fibrosis (CF) patients. Yet, the potential role, if any, of the micro-organism in the progress of the disease remains unclear. In this study, we investigated the association between inhaled antibiotics and C. albicans chronic colonisation in patients with CF. A cohort of 121 CF patients born from 1988 to 1996 was, respectively, studied. The medical records of each patient were reviewed from the first time they attended the CF Centre until the occurrence of C. albicans chronic colonisation or their last visit for the year 2010. Chronic colonisation was defined as the presence of C. albicans in more than 50% of cultures in a given year. A number of possible confounders were included in the multivariate logistic regression analysis to identify an independent association between inhaled antibiotics and C. albicans chronic colonisation. Fifty-four (44.6%) of the 121 patients enrolled in the study developed chronic colonisation by the micro-organism. Multivariate logistic regression analysis determined the independent effect of inhaled antibiotic treatment on the odds of chronic colonisation (OR 1.112, 95% CI [1.007-1.229], P = 0.036). Candida albicans chronic colonisation may be associated with the duration of inhaled antibiotic treatment. PMID- 26058476 TI - Silent cerebral infarcts in very young children with sickle cell anaemia are associated with a higher risk of stroke. AB - Silent cerebral infarctions (SCI) are the most common neurological injury in children with sickle cell anaemia (SCA), but their incidence/prognosis in early childhood has not been well described. We report clinical, neuroradiological, psychometric and academic follow-up over an average period of 14 years in 37 children with SCA who had magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the brain between ages 7 and 48 months. Ten patients (27%) younger than age 5 years (Group I) had SCI, as did 12 (32%) older than 5 years (Group II). Fifteen (41%) had no lesions (Group III). Overt stroke or transient ischaemic attack occurred in 5/9 (56%) in Group I. Most Group I patients had progressive MRI abnormalities, concurrent stenosis, decreased cognitive ability, attention/executive function deficits and hindered academic attainment. The proportions of subjects in Group I with subsequent neurological events (P <= 0.006), progressive ischaemia (P <= 0.001) and vascular stenosis (P <= 0.006) were greater than in Groups II and III. Thus, SCI in young children with SCA may predict overt central nervous system events, progressive MRI abnormalities, stenosis, cognitive dysfunction and poor academic performance. Children younger than 5 years may benefit from MRI/MRA testing and should be considered for aggressive intervention when SCI are detected. PMID- 26058477 TI - Randomised trial of early neonatal hydrocortisone demonstrates potential undesired effects on neurodevelopment at preschool age. AB - AIM: We evaluated the neurodevelopment and growth of five- to seven-year-old children who had participated in a randomised trial of early low-dose hydrocortisone treatment to prevent bronchopulmonary dysplasia. METHODS: The 51 infants in the original study had birthweights of 501-1250 g and gestational ages of 23-30 weeks, required mechanical ventilation during the first 24 hours and received hydrocortisone or a placebo for 10 days. The majority (80%) of the 90% who survived to five- to seven years of age participated in this follow-up study and their growth, neuromotor, cognitive and speech development were evaluated. RESULTS: Some neurodevelopment impairment was observed in 61% of the hydrocortisone group and 39% of the placebo group, ranging from minor neurological dysfunction to severe neurological conditions (p = 0.182). The mean full-scale intelligence quotient (IQ) was 87.8 (15.3) in the hydrocortisone group and 95.7 (15.0) in the placebo group (p = 0.135), and the mean performance IQ was 88.3 (14.5) and 99.1 (14.0) (p = 0.034), respectively. A fifth (22%) of the hydrocortisone group required physiotherapy, but none of the placebo group did (p = 0.034). The age-standardised growth was comparable between both groups. CONCLUSION: Early hydrocortisone treatment may have undesired effects on neurodevelopment at preschool age, and further safety studies are required. PMID- 26058478 TI - Dermatitis Artefacta in Childhood: A Retrospective Analysis of 44 Patients, 1976 2006. AB - BACKGROUND: Dermatitis artefacta (DA) consists of self-inflicted skin lesions that the patient denies having produced. OBJECTIVES: To conduct a single-center retrospective clinical review of children and adolescents diagnosed with DA. METHODS: From 1976 to 2006, data were collected on children diagnosed with DA who were seen in the Department of Dermatology in our hospital. Clinical and epidemiologic features are described. Forty-four children (mean age 12.9 yrs) were selected, representing 21.9% of the total patients with DA recorded (n = 201) during this period. RESULTS: The most frequent clinical forms were excoriations (16 [36.4%]) and ulcers (10 [22.7%]), followed by blisters (7 [15.9%]), burns (3 [6.8%]), contact dermatitis (3 [6.8%]), hematomas (2 [4.5%]), panniculitis (1 [2.3%]), cheilitis (1 [2.3%]), and hyperpigmentation (1 [2.3%]). Sixteen were located exclusively on the face and neck, whereas 28 also had other locations (upper limbs, n = 10; lower limbs, n = 9; thorax, n = 5; abdomen, n = 4). Cutaneous lesions were treated with occlusive bandages using zinc paste or a plaster splint when necessary. CONCLUSION: To our knowledge, this is the largest reported series of DA in childhood. This complicated psychodermatologic condition requires correct diagnosis, appropriate management, and psychiatric assessment. PMID- 26058479 TI - Are the Beneficial Effects of Ischemic Preconditioning on Performance Partly a Placebo Effect? AB - The acute effect of ischemic preconditioning (IPC) on the maximal performance in the 100-m freestyle event was studied in recreational swimmers. 15 swimmers (21.0+/-3.2 years) participated in a random crossover model on 3 different days (control [CON], IPC or SHAM), separated by 3-5 days. IPC consisted of 4 cycles of 5-min occlusion (220 mmHg)/5-min reperfusion in each arm, and the SHAM protocol was similar to IPC but with only 20 mmHg during the occlusion phase. The subjects were informed that both maneuvers (IPC and SHAM) would improve their performance. After IPC, CON or SHAM, the volunteers performed a maximal 100-m time trial. IPC improved performance (p=0.036) compared to CON. SHAM performance was only better than CON (p=0.059) as a tendency but did not differ from IPC performance. The individual response of the subjects to the different maneuvers was very heterogeneous. We conclude that IPC may improve performance in recreational swimmers, but this improvement could mainly be a placebo effect. PMID- 26058481 TI - Facile Preparation of Molybdenum Bronzes as an Efficient Hole Extraction Layer in Organic Photovoltaics. AB - We proposed a facile and green one-pot strategy to synthesize Mo bronzes nanoparticles to serve as an efficient hole extraction layer in polymer solar cells. Mo bronzes were obtained through reducing the fractional self-aggregated ammonium heptamolybdate with appropriate reducing agent ascorbic acid, and its optoelectronic properties were fully characterized. The synthesized Mo bronzes displayed strong n-type semiconductor characteristics with a work function of 5.2 5.4 eV, matched well with the energy levels of current donor polymers. The presented gap states of the Mo bronzes near the Fermi level were beneficial for facilitating charge extraction. The as-synthesized Mo bronzes were used as hole extraction layer in polymer solar cells and significantly enhanced the photovoltaic performance and stability. The power conversion efficiency was increased by more than 18% compared with the polyethylene dioxythiophene:polystyrenesulfonate-based reference cell. The excellent performance and facile preparation render the as-synthesized solution-processed Mo bronzes nanoparticles a promising candidate for hole extraction layer in low cost and efficient polymer solar cells. PMID- 26058480 TI - Phylogeography of the sand dune ant Mycetophylax simplex along the Brazilian Atlantic Forest coast: remarkably low mtDNA diversity and shallow population structure. AB - BACKGROUND: During past glacial periods, many species of forest-dwelling animals experienced range contractions. In contrast, species living outside such moist habitats appear to have reacted to Quaternary changes in different ways. The Atlantic Forest represents an excellent opportunity to test phylogeographic hypotheses, because it has a wide range of vegetation types, including unforested habitats covered predominantly by herbaceous and shrubby plants, which are strongly influenced by the harsh environment with strong wind and high insolation. Here, we investigated the distribution of genetic diversity in the endemic sand dune ant Mycetophylax simplex across its known range along the Brazilian coast, with the aim of contributing to the understanding of alternative phylogeographic patterns. We used partial sequences of the mitochondrial gene cytochrome oxidase I and nuclear gene wingless from 108 specimens and 51 specimens, respectively, to assess the phylogeography and demographic history of this species. To achieve this we performed different methods of phylogenetic and standard population genetic analyses. RESULTS: The observed genetic diversity distribution and historical demographic profile suggests that the history of M. simplex does not match the scenario suggested for other Atlantic Forest species. Instead, it underwent demographic changes and range expansions during glacial periods. Our results show that M. simplex presents a shallow phylogeographic structure with isolation by distance among the studied populations, living in an almost panmictic population. Our coalescence approach indicates that the species maintained a stable population size until roughly 75,000 years ago, when it underwent a gradual demographic expansion that were coincident with the low sea level during the Quaternary. Such demographic events were likely triggered by the expansion of the shorelines during the lowering of the sea level. CONCLUSIONS: Our data suggest that over evolutionary time M. simplex did not undergo dramatic range fragmentation, but rather it likely persisted in largely interconnected populations. Furthermore, we add an important framework about how both glacial and interglacial events could positively affect the distribution and diversification of species. The growing number of contrasting phylogeographic patterns within and among species and regions have shown that Quaternary events influenced the distribution of species in more ways than first supposed. PMID- 26058482 TI - Diagnostic and prognostic role of procalcitonin (PCT) and MR-pro-Adrenomedullin (MR-proADM) in bacterial infections. AB - Rapid diagnosis of bacterial infections is crucial for adequate antibiotic treatment. Serum molecules such as Procalcitonin (PCT) have been used as biomarkers of infection. Recently, the mid-regional pro-Adrenomedullin (MR proADM) has been evaluated in combination with PCT for sepsis diagnosis. The diagnostic role of PCT and MR-proADM both in sepsis and in localized infections together with their contribution to effective antibiotic therapy has been evaluated. One hundred and eighty-two patients with bacterial infection has been enrolled: PCT and MR-proADM were measured at admission (T = 0), at 12-24 h (T = 1) and in the third or fifth day of antibiotic therapy (T = 3-5). ROC curve (receiver operating characteristic) and post-test probability were calculated. MR proADM increased with the severity of the infection. PCT resulted significantly higher in sepsis than localized infection. After antibiotic therapy, PCT significantly decreased in localized respiratory infections and in sepsis, while MR-proADM decreased significantly after antibiotic therapy only in patients with severe sepsis/septic shock. The threshold values of PCT and MR-proADM were >0.1 ng/mL and >0.8 nmol/L, respectively. The combined use of PCT and MR-proADM increased the post-test probability of the diagnosis of bacterial infections compared to PCT alone. In conclusion, PCT and MR-proADM combination improves the diagnosis of bacterial infection and contribute to prognosis and antibiotic therapy effectiveness. PMID- 26058483 TI - Autophagy is involved in recombinant Newcastle disease virus (rL-RVG)-induced cell death of stomach adenocarcinoma cells in vitro. AB - Oncolytic viruses can kill malignant cells while sparing normal cells. Multiple pathways are involved in this action. The antitumor effects of viral infection on SGC-7901 and AGS cells were investigated. We measured endoplasmic reticulum stress and autophagy caused by the recombinant avirulent Newcastle disease virus (NDV) LaSota strain expressing the rabies virus glycoprotein (rL-RVG) and the NDV wild-type strain. The dose-response curves were analyzed using the MTT assay. The expression of RVG was detected by western blotting, RT-PCR and immunofluorescence analyses. Cell death and autophagy were observed using transmission electron microscopy, TUNEL and western blotting. Endoplasmic reticulum stress and the mitochondrial transmembrane potential were detected by western blotting and immunofluorescence, respectively. Immunofluorescence, western blot and RT-PCR analyses indicated that RVG gene and protein were expressed in SGC-7901 and AGS cells infected by rL-RVG. MTT and TUNEL analyses showed that the growth of SGC 7901 and AGS cells in the rL-RVG-infected group was significantly inhibited compared with the wild-type NDV-infected group (p<0.05). Western blot analysis indicated that rL-RVG and NDV induced increases in apoptosis, endoplasmic reticulum stress, and autophagy in the SGC-7901 and AGS cells. However, apoptosis and autophagy decreased in these cells after the application of the autophagy pathway inhibitor 3-MA or ATG-5-specific siRNA. Immunofluorescence analysis showed that the mitochondrial membrane potential collapsed. Taken together, these results indicate that the rL-RVG virus group is much more powerful compared with the NDV-infected group (p<0.05). rL-RVG and NDV are potent antitumor agents that induce autophagy. PMID- 26058484 TI - Dermal anchoring structures: convex matrix structures at the bottom of the dermal layer that contribute to the maintenance of facial skin morphology. AB - BACKGROUND/PURPOSE: Facial skin must be linked to underlying structures to maintain facial morphology and prevent sagging, but the mechanism of facial skin retention is largely unknown. We aimed to elucidate this mechanism. METHODS: Twenty-two cheek skin specimens (age range: 10s-60s, both genders) were observed histologically. And 30 cheek of healthy Japanese volunteers (age range: 30s-50s, female) was photographed and the severity of sagging was graded. Dermal layer morphology was observed non-invasively with ultrasound. Skin-retaining force was measured with a Cutometer MPA 580((r)) , and sagging severity was evaluated by grading criteria. RESULTS: Histological observation revealed characteristic convex structures at the bottom of the dermal layer. Non-invasive study showed that the depth of the convex structures, measured by ultrasonography, was significantly negatively related to the ratio of viscoelastic to elastic distention (Uv/Ue) and positively related to the ratio of elastic recovery to total deformation (Ur/Uf) at the cheek of female volunteers, measured by cutometer. It was also negatively related to sagging severity. Further, Ur/Uf was negatively and Uv/Ue was positively related to sagging severity. CONCLUSION: Characteristic convex structures at the bottom of the dermal layer serve as anchoring structures to maintain skin morphology. PMID- 26058485 TI - MicroRNA-429 inhibits the migration and invasion of colon cancer cells by targeting PAK6/cofilin signaling. AB - MicroRNAs (miRs), a class of non-coding RNAs 18-25 nucleotides in length, can lead to mRNA degradation or inhibit protein translation by directly binding to the 3'-untranslational region (UTR) of their target mRNAs. The deregulation of miR-429 has been suggested to be involved in the development and progression of colon cancer. However, the detailed molecular mechanism involved remains to be determined. The aim of the present study was to investigate the role of miR-429 in the regulation of migration and invasion of colon cancer cells using RT-qPCR and western blotting. The results showed that the expression of miR-429 was reduced in colon cancer cell lines, when compared to a normal colon epithelial cell line. Treatment with DNA demethylation agent 5-aza-2'-deoxycytidine and histone deacetylase inhibitor phenylbutyrate (PBA), or transfection with the pre miR-429 lentivirus plasmid led to the upregulation of miR-429 expression, as well as inhibition of migration and invasion in colon cancer cells. Investigation of the molecular mechanism showed that PAK6 was a novel target of miR-429, and the expression of PAK6 was upregulated in colon cancer tissues and cell lines, and was negatively regulated by miR-429 in colon cancer cells. Moreover, the cofilin signaling acted as a downstream effector of miR-429 in colon cancer cells. In conclusion, the results of the present study suggested that miR-429 inhibits the migration and invasion of colon cancer cells, partly at least, by mediating the expression of PAK6, as well as the activity of cofilin signaling. Therefore, miR 429 is as a potential molecular target for the treatment of colon cancer. PMID- 26058486 TI - Tunable aromaticity in bicalicenes. AB - The unusual aromatic stability of cyclic bicalicene has been suggested to come from a tetraionic structure, where positive and negative charges are located on the cyclopropene and cyclopentadiene rings, respectively. Energetic, magnetic, geometric and electron delocalization analysis performed on a series of bicalicene derivatives, incorporating different electron donating and withdrawing groups, and electrically perturbed bicalicene structures provide additional proof of the role played by this tetraionic structure in the aromatic stability of bicalicene. In this work the aromatic stabilization is chemically and electrically tuned, enhancing or disrupting the electron delocalization and aromatic stability of the cyclopropene and cyclopentadiene rings by increasing or decreasing their corresponding charges. It is shown how the electron delocalization within these rings is similar to that of cyclopropene cation and cyclopentadiene anion for a perfect polarization of one electron. PMID- 26058487 TI - Loop nucleotides impact the stability of intrastrand i-motif structures at neutral pH. AB - The stability of i-motif structures at neutral pH is of interest due to the potential of these structures to impact gene expression. A systematic investigation of loop sequence and length revealed that certain loop nucleobases stabilize i-motif quadruplexes. PMID- 26058488 TI - Association of dietary patterns with serum adipokines among Japanese: a cross sectional study. AB - BACKGROUND: Diet may influence disease risk by modulating adipokines. Although some foods and nutrients have been linked to circulating adipokine levels, little is known about the role of dietary patterns on adipokines. We investigated the association between major dietary patterns and circulating levels of adiponectin, leptin, resistin, visfatin, and plasminogen activator inhibitor-1 (PAI-1) in a working population. METHODS: The subjects were 509 employees (296 men and 213 women), aged 20 to 65 years, of two municipal offices. Serum adipokines were measured using a Luminex suspension bead-based multiplexed array. Dietary patterns were derived by using principal component analysis of the consumption of 52 food and beverage items, which were ascertained by a validated diet history questionnaire. Multiple regression analysis was performed to assess the association between dietary pattern scores and adipokine concentrations, with adjustment for potential confounders. RESULTS: Three major dietary patterns were extracted: a Japanese, a Westernized breakfast, and a meat food patterns. Of these, we found significant, inverse associations of the Westernized breakfast pattern, which was characterized by higher intake of confectioneries, bread, and milk and yogurt but lower intake of alcoholic beverages and rice, with serum leptin and PAI-1 concentrations in a fully adjusted model (P for trend = 0.04 for both leptin and PAI-1). The other adipokines were not significantly associated with any dietary pattern. CONCLUSION: The Westernized breakfast dietary pattern may be associated with lower circulating levels of leptin and PAI-1. PMID- 26058490 TI - Minor Physical Anomalies as a Window into the Prenatal Origins of Pedophilia. AB - Evidence is steadily accumulating to support a neurodevelopmental basis for pedophilia. This includes increased incidence of non-right-handedness, which is a result primarily of prenatal neural development and solidified very early in life. Minor physical anomalies (MPAs; superficial deviations from typical morphological development, such as un-detached earlobes) also develop only prenatally, suggesting them as another potential marker of atypical physiological development during the prenatal period among pedophiles. This study administered the Waldrop Physical Anomaly Scale to assess the prevalence of MPAs in a clinical sample of men referred for assessment following a sexual assault, or another illegal or clinically significant sexual behavior. Significant associations emerged between MPA indices and indicators of pedophilia, including penile responses to depictions of children, number of child victims, and possession of child pornography. Moreover, greater sexual attraction to children was associated with an elevated craniofacial-to-peripheral anomalies ratio. The overall sample demonstrated a greater number of MPAs relative to prior samples of individuals with schizophrenia as well as to healthy controls. PMID- 26058489 TI - Pulsed electromagnetic fields for postmenopausal osteoporosis and concomitant lumbar osteoarthritis in southwest China using proximal femur bone mineral density as the primary endpoint: study protocol for a randomized controlled trial. AB - BACKGROUND: Osteoporosis (OP) and osteoarthritis (OA) are prevalent skeletal disorders among postmenopausal women. Coexistence is common especially that of postmenopausal osteoporosis (PMO) and lumbar OA. An hypothesis has been raised that OP and OA might share the same pathogenic mechanism, and pulsed electromagnetic fields (PEMFs) were reported to have anti-osteoporosis and anti osteoarthritis properties, but this suggestion was based primarily on biomarker data. Therefore, whether these two effects could take place simultaneously has not yet been investigated. This randomized controlled trial (RCT) is designed to explore the effect of PEMFs for PMO and concomitant lumbar OA. METHODS/DESIGN: The study will include PMO patients (postmenopausal women; aged between 50 and 70 years; have been postmenopausal for at least 5 years and diagnosed with OP using proximal femur T-score) with concomitant lumbar OA (patients with confounding disorders like diabetes, hypertension, hyperlipidemia, and previous fracture history, etcetera, will be excluded) will be randomly assigned to two arms: PEMFs group and sham PEMFs group. There will be 25 participants in each arm (50 in total) and the outcome assessment, including the primary endpoint (proximal femur bone mineral density), will be performed at 5 weeks, 3 months and 6 months after enrollment. DISCUSSION: PMO and lumbar OA are prominent public health problem, especially for postmenopausal women. We hope this RCT will provide scientific evidence to primary care of the postmenopausal women regarding the use of these nonpharmaceutical, noninvasive modalities, PEMFs, in managing PMO and lumbar OA. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR-TRC-14005156 (28 August 2014). PMID- 26058491 TI - Dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and micro-computed tomography techniques are discordant for bone density and geometry measurements in the guinea pig. AB - This study aims to examine agreement among bone mineral content (BMC) and density (BMD) estimates obtained using dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and micro-computed tomography (MUCT) against high-resolution MUCT and bone ash of the guinea pig femur. Middle-aged (n = 40, 86 weeks) male guinea pigs underwent in vivo followed by ex vivo DXA (Hologic QDR 4500A) scanning for intact and excised femur BMC and areal density. To assess bone architecture and strength, excised femurs were scanned on pQCT (Stratec XCT 2000L) as well as on two MUCT scanners (LaTheta LCT-200; Skyscan 1174), followed by three-point bending test. Reproducibility was determined using triplicate scans; and agreement assessed using Bland-Altman plots with reference methods being high-resolution MUCT (Skyscan) for BMD and bone ashing for BMC. All techniques showed satisfactory ex vivo precision (CV 0.05-4.3 %). However, bias compared to the reference method was highest (207.5 %) in trabecular bone volume fraction (BV/TV) measured by LaTheta, and unacceptable in most total femur and cortical bone measurements. Volumetric BMD (vBMD) and BV/TV derived by LaTheta and pQCT at the distal metaphysis were biased from the Skyscan by an average of 49.3 and 207.5 %, respectively. Variability of vBMD, BV/TV and cross-sectional area at the diaphysis ranged from -5.5 to 30.8 %. LaTheta best quantified total femur BMC with an upper bias of 3.3 %. The observed differences among imaging techniques can be attributable to inherent dissimilarity in construction design, calibration, segmentation and scanning resolution used. These bone imaging tools are precise but are not comparable, at least when assessing guinea pig bones. PMID- 26058494 TI - Enhanced crystalline morphology of a ladder-type polymer bulk-heterojunction device by blade-coating. AB - A blade-coating process was employed to fabricate bulk-heterojunction (BHJ) polymer solar cells based on a ladder-type polymer (PIDT-PhanQ) with low crystallinity. Compared to the devices processed by a conventional spin-coating method, an intriguing morphology with enhanced phase-separation and increased crystallinity was achieved. As a result, power conversion efficiency up to 7.25% could be achieved from the blade-coated PIDT-PhanQ:PC71BM BHJ film, surpassing the original value obtained by spin-coating (6.29%). This improved photovoltaic performance is attributed to the improved charge carrier mobilities, which correlates well with the increased crystallinity and the organized network of the donor-acceptor phases that produce efficient charge-transporting pathways. PMID- 26058492 TI - Different reference BMDs affect the prevalence of osteoporosis. AB - The T score represents the degree of deviation from the peak bone mineral density (BMD) (reference standard) in a population. Little has been investigated concerning the age at which the BMD reaches the peak value and how we should define the reference standard BMD in terms of age ranges. BMDs of 9,800 participants were analyzed from the Korean National Health and Nutrition Examination Survey database. Five reference standards were defined: (1) the reference standard of Japanese young adults provided by the dual-energy X-ray absorptiometry machine manufacturer, (2) peak BMD of the Korean population evaluated by statistical analysis (second-order polynomial regression models), (3) BMD of subjects aged 20-29 years, (4) BMD of subjects aged 20-39 years, and (5) BMD of subjects aged 30-39 years. T-scores from the five reference standards were calculated, and the prevalence of osteoporosis was evaluated and compared for males and females separately. The peak BMD in the polynomial regression model was achieved at 26 years in males and 36 years in females in the total hip, at 20 years in males and 27 years in females in the femoral neck, and at 20 years in males and 30 years in females in the lumbar spine. The prevalence of osteoporosis over the age of 50 years showed significant variation of up to two fold depending on the reference standards adopted. The age at which peak BMD was achieved was variable according to the gender and body sites. A consistent definition of peak BMD needs to be established in terms of age ranges because this could affect the prevalence of osteoporosis and healthcare policies. PMID- 26058493 TI - Strain differences in the attenuation of bone accrual in a young growing mouse model of insulin resistance. AB - Skeletal fractures are considered a chronic complication of type 2 diabetes mellitus (T2DM), but the etiology of compromised bone quality that develops over time remains uncertain. This study investigated the concurrent alterations in metabolic and skeletal changes in two mouse strains, a responsive (C57BL/6) and a relatively resistant (C3H/HeJ) strain, to high-fat diet-induced glucose intolerance. Four-week-old male C57BL/6 and C3H/HeJ mice were randomized to a control (Con = 10 % kcal fat) or high-fat (HF = 60 % kcal fat) diet for 2, 8, or 16 weeks. Metabolic changes, including blood glucose, plasma insulin and leptin, and glucose tolerance were monitored over time in conjunction with alterations in bone structure and turn over. Elevated fasting glucose occurred in both the C57BL/6 and C3H/HeJ strains on the HF diet at 2 and 8 weeks, but only in the C57BL/6 strain at 16 weeks. Both strains on the HF diet demonstrated impaired glucose tolerance at each time point. The C57BL/6 mice on the HF diet exhibited lower whole-body bone mineral density (BMD) by 8 and 16 weeks, but the C3H/HeJ strain had no evidence of bone loss until 16 weeks. Analyses of bone microarchitecture revealed that trabecular bone accrual in the distal femur metaphysis was attenuated in the C57BL/6 mice on the HF diet at 8 and 16 weeks. In contrast, the C3H/HeJ mice were protected from the deleterious effects of the HF diet on trabecular bone. Alterations in gene expression from the femur revealed that several toll-like receptor (TLR)-4 targets (Atf4, Socs3, and Tlr4) were regulated by the HF diet in the C57BL/6 strain, but not in the C3H/HeJ strain. Structural changes observed only in the C57BL/6 mice were accompanied with a decrease in osteoblastogenesis after 8 and 16 weeks on the HF diet, suggesting a TLR-4-mediated mechanism in the suppression of bone formation. Both the C57BL/6 and C3H/HeJ mice demonstrated an increase in osteoclastogenesis after 8 weeks on the HF diet; however, bone turnover was decreased in the C57BL/6 with prolonged hyperglycemia. Further investigation is needed to understand how hyperglycemia and hyperinsulinemia suppress bone turnover in the context of T2DM and the role of TLR-4 in this response. PMID- 26058495 TI - A method to analyze low signal-to-noise ratio functional magnetic resonance imaging data. AB - The current practice of using a single, representative hemodynamic response function (canonical HRF) to model functional magnetic resonance imaging (fMRI) data is questionable given the trial-to-trial variability of the brain's responses. In addition, the changes in blood-oxygenation level due to sensory stimulation may be small, especially when auditory stimuli are used. Here we introduce a correlation-based single trial analysis method for fMRI data analysis to deal with the low signal-to-noise (SNR) ratio and variability of the HRF in response to repeated, identical auditory stimuli. The correlation technique identifies the "active" trials, i.e., those showing a robust hemodynamic response among all single trials. Using data collected from 14 healthy subjects, it was found that the correlation method can find significant differences between brain areas and brain states in actual fMRI data. Also, the correlation-based method confirmed that the superior temporal gyrus (STG), inferior frontal gyrus (IFG), dorsolateral prefrontal cortex (DLPFC) and thalamus (THA) are involved in auditory information processing in general, and the involvement of the bilateral STG, right THA and left DLPFC in sensory gating. In contrast, conventional analysis failed to find any regions involved in sensory gating. The findings suggest that our single trial analysis method can increase the sensitivity of fMRI data analysis. PMID- 26058496 TI - Comparison of Outcomes Between Preoperatively Potent Men Treated with Focal Versus Whole Gland Cryotherapy in a Matched Population. AB - BACKGROUND AND PURPOSE: The refinement in the localization of prostate cancer tumor foci through transperineal template-mapping biopsies and MRI has led to an increased interest in lesion-directed focal prostatic cryoablation. Data are lacking, however, that compare the outcomes of whole-gland (WG) to focal ablation therapy (FT). The aim of our study was to assess both oncologic and functional outcomes between WG and FT cryoablation of the prostate after having matched patients for preoperative characteristics. PATIENTS AND METHODS: We matched with a 1:1 ratio 317 men who underwent FT with 317 who underwent WG treatment in the Cryo Online Data (COLD) registry between 2007 and 2013. All patients were low risk according to the D'Amico risk groups and were matched according to age at surgery. We only included preoperatively potent men. Oncologic outcomes were biochemical recurrence (BCR) free-survival defined according to the American Society for Radiation Oncology (ASTRO) and Phoenix criteria and assessed by Kaplan-Meier curves. Only patients with prostate-specific antigen (PSA) nadir data were included in oncologic outcome analysis. Functional outcomes were assessed at 6, 12, and 24 months after the procedure for erectile function (defined as ability to have intercourse with or without erectile aids), urinary continence, urinary retention, and rates of fistula formation. RESULTS: Median age at the time of the procedure was 66.5 years (standard deviation [SD] 6.6 y), and median follow-up time was 58.3 months. After surgery, 30% (n=95) and 17% (n=55) of the men who received WG and FT, respectively, underwent biopsy, with positive biopsy rates of 11.6% and 14.5%, respectively. BCR-free survival rates at 60 months according to the Phoenix definition were 80.1% and 71.3% in the WG and FT cohorts, respectively, with a hazard ratio of 0.827; according to the ASTRO definition, they were 82.1% and 73%, respectively (all P >= 0.1). Erectile function data at 24 months was available for 172 WG and 160 FT treated men. Recovery of erection was achieved in 46.8% and 68.8% of patients in the WG and FT cohorts, respectively (P=0.001). Urinary function data at 24 months was available for 307 WG and 313 FT patients. Continence rates were 98.7% and 100% for WG and FT groups, respectively (P=0.02). Urinary retention at 6, 12, and 24 months was reported in 7.3%, 1.9%, and 0.6%, respectively, in the WG arm, and in 5%, 1.3%, and 0.9%, respectively, in the FT arm. Finally, only one fistula was reported in each group. CONCLUSIONS: Men with low-risk prostate cancer who underwent FT cryoablation had comparable BCR-survival rates at 60 months to patients treated with WG. However, FT patients had higher erectile function preservation rates at 24 months post-procedure. Urinary continence, retention and fistula rates were similar between the two treatment groups. PMID- 26058497 TI - Time and Causation in Discourse: Temporal Proximity, Implicit Causality, and Re mention Biases. AB - Using referential processing in discourse featuring implicit causality verbs as a test case, we demonstrate how a discourse's causal and temporal dimensions interact. We show that referential processing is affected by multiple discourse biases, and that these biases do not have uniform effects. In three discourse continuation experiments, we show that the bias to re-mention a particular referent in discourse involving implicit causality verbs is not only affected by the verb's implicit causality bias, but also by the discourse's temporal structure, which at times, can even override the implicit causality bias. Our results add to the growing number of studies that show how various discourse dimensions interact in discourse processing. PMID- 26058498 TI - Palladium-catalyzed ortho-C-H alkenylation of 2-benzyl-1,2,3-triazoles. AB - A mild and efficient method for the direct alkenylation of 2-benzyl-1,2,3 triazoles via Pd-catalyzed C-H bond activation was developed. This protocol was compatible with various substrates and gave the corresponding products in good to excellent yields. Thus, the present study provides a novel and valuable method for the synthesis of 2-benzyl-1,2,3-triazole derivatives. PMID- 26058499 TI - Impact of galactosylceramides on the nanomechanical properties of lipid bilayer models: an AFM-force spectroscopy study. AB - Galactosylceramides (GalCer) are glycosphingolipids bound to a monosaccharide group, responsible for inducing extensive hydrogen bonds that yield their alignment and accumulation in the outer leaflet of the biological membrane together with cholesterol (Chol) in rafts. In this work, the influence of GalCer on the nanomechanical properties of supported lipid bilayers (SLBs) based on DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) and DLPC (1,2-didodecanoyl-sn glycero-3-phosphocoline) as model systems was assessed. Phosphatidylcholine (PC):GalCer SLBs were characterized by means of differential scanning calorimetry (DSC) and atomic force microscopy (AFM), in both imaging and force spectroscopy (AFM-FS) modes. Comparing both PC systems, we determined that the behaviour of SLB mixtures is governed by the PC phase-like state at the working temperature. While a phase segregated system is observed for DLPC:GalCer SLBs, GalCer are found to be dissolved in DPPC SLBs for GalCer contents up to 20 mol%. In both systems, the incorporation of GalCer intensifies the nanomechanical properties of SLBs. Interestingly, segregated domains of exceptionally high mechanical stability are formed in DLPC:GalCer SLBs. Finally, the role of 20 mol% Chol in GalCer organization and function in the membranes was assessed. Both PC model systems displayed phase segregation and remarkable nanomechanical stability when GalCer and Chol coexist in SLBs. PMID- 26058500 TI - Bedside Doppler ultrasound for the assessment of renal perfusion in the ICU: advantages and limitations of the available techniques. AB - Three Doppler-derived techniques have been proposed to assess renal perfusion at bedside: Doppler-based renal resistive index (RI) which has been extensively but imperfectly studied in assessing renal allograft status and changes in renal perfusion in critically ill patients and for predicting the reversibility of an acute kidney injury (AKI), semi-quantitative evaluation of renal perfusion using colour-Doppler which may be easier to perform and may give similar information than RI and contrast-enhanced sonography that may allow more precise renal and cortical perfusion assessment. These promising tools have several obvious advantages including their feasibility, non-invasiveness, repeatability and potential interest in assessing renal function or perfusion. However, several limits need to be taken into account with these techniques, and promising results remain associated with large areas of uncertainty. This editorial will describe more carefully advantages and limits of these techniques and will discuss their potential interest in assessing renal perfusion. PMID- 26058501 TI - Vagus Nerve Stimulation Delivered with Motor Training Enhances Recovery of Function after Traumatic Brain Injury. AB - Traumatic Brain Injury (TBI) is one of the largest health problems in the United States, and affects nearly 2 million people every year. The effects of TBI, including weakness and loss of coordination, can be debilitating and last years after the initial injury. Recovery of motor function is often incomplete. We have developed a method using electrical stimulation of the vagus nerve paired with forelimb use by which we have demonstrated enhanced recovery from ischemic and hemorrhagic stroke. Here we have tested the hypothesis that vagus nerve stimulation (VNS) paired with physical rehabilitation could enhance functional recovery after TBI. We trained rats to pull on a handle to receive a food reward. Following training, they received a controlled-cortical impact (CCI) in the forelimb area of motor cortex opposite the trained forelimb, and were then randomized into two treatment groups. One group of animals received VNS paired with rehabilitative therapy, whereas another group received rehabilitative therapy without VNS. Following CCI, volitional forelimb strength and task success rate in all animals were significantly reduced. VNS paired with rehabilitative therapy over a period of 5 weeks significantly increased recovery of both forelimb strength and success rate on the isometric pull task compared with rehabilitative training without VNS. No significant improvement was observed in the Rehab group. Our findings indicate that VNS paired with rehabilitative therapy enhances functional motor recovery after TBI. PMID- 26058502 TI - Misleading data in Shastin et al.'s paper. PMID- 26058503 TI - Metabolite profiling in plasma and tissues of ob/ob and db/db mice identifies novel markers of obesity and type 2 diabetes. AB - AIMS/HYPOTHESIS: Metabolomics approaches in humans have identified around 40 plasma metabolites associated with insulin resistance (IR) and type 2 diabetes, which often coincide with those for obesity. We aimed to separate diabetes associated from obesity-associated metabolite alterations in plasma and study the impact of metabolically important tissues on plasma metabolite concentrations. METHODS: Two obese mouse models were studied; one exclusively with obesity (ob/ob) and another with type 2 diabetes (db/db). Both models have impaired leptin signalling as a cause for obesity, but the different genetic backgrounds determine the susceptibility to diabetes. In these mice, we profiled plasma, liver, skeletal muscle and adipose tissue via semi-quantitative GC-MS and quantitative liquid chromatography (LC)-MS/MS for a wide range of metabolites. RESULTS: Metabolite profiling identified 24 metabolites specifically associated with diabetes but not with obesity. Among these are known markers such as 1,5 anhydro-D-sorbitol, 3-hydroxybutyrate and the recently reported marker glyoxylate. New metabolites in the diabetic model were lysine, O-phosphotyrosine and branched-chain fatty acids. We also identified 33 metabolites that were similarly altered in both models, represented by branched-chain amino acids (BCAA) as well as glycine, serine, trans-4-hydroxyproline, and various lipid species and derivatives. Correlation analyses showed stronger associations for plasma amino acids with adipose tissue metabolites in db/db mice compared with ob/ob mice, suggesting a prominent contribution of adipose tissue to changes in plasma in a diabetic state. CONCLUSIONS/INTERPRETATION: By studying mice with metabolite signatures that resemble obesity and diabetes in humans, we have found new metabolite entities for validation in appropriate human cohorts and revealed their possible tissue of origin. PMID- 26058505 TI - Design of Modern Reactors for Synthesis of Thermally Expanded Graphite. AB - One of the most progressive trends in the development of modern science and technology is the creation of energy-efficient technologies for the synthesis of nanomaterials. Nanolayered graphite (thermally exfoliated graphite) is one of the key important nanomaterials of carbon origin. Due to its unique properties (chemical and thermal stability, ability to form without a binder, elasticity, etc.), it can be used as an effective absorber of organic substances and a material for seal manufacturing for such important industries as gas transportation and automobile. Thermally expanded graphite is a promising material for the hydrogen and nuclear energy industries. The development of thermally expanded graphite production is resisted by high specific energy consumption during its manufacturing and by some technological difficulties. Therefore, the creation of energy-efficient technology for its production is very promising. PMID- 26058504 TI - Stereocomplex micelle from nonlinear enantiomeric copolymers efficiently transports antineoplastic drug. AB - Nanoscale polymeric micelles have attracted more and more attention as a promising nanocarrier for controlled delivery of antineoplastic drugs. Herein, the doxorubicin (DOX)-loaded poly(D-lactide)-based micelle (PDM/DOX), poly(L lactide)-based micelle (PLM/DOX), and stereocomplex micelle (SCM/DOX) from the equimolar mixture of the enantiomeric four-armed poly(ethylene glycol) polylactide (PEG-PLA) copolymers were successfully fabricated. In phosphate buffered saline (PBS) at pH 7.4, SCM/DOX exhibited the smallest hydrodynamic diameter (D h) of 90 +/- 4.2 nm and the slowest DOX release compared with PDM/DOX and PLM/DOX. Moreover, PDM/DOX, PLM/DOX, and SCM/DOX exhibited almost stable D hs of around 115, 105, and 90 nm at above normal physiological condition, respectively, which endowed them with great potential in controlled drug delivery. The intracellular DOX fluorescence intensity after the incubation with the laden micelles was different degrees weaker than that incubated with free DOX . HCl within 12 h, probably due to the slow DOX release from micelles. As the incubation time reached to 24 h, all the cells incubated with the laden micelles, especially SCM/DOX, demonstrated a stronger intracellular DOX fluorescence intensity than free DOX . HCl-cultured ones. More importantly, all the DOX-loaded micelles, especially SCM/DOX, exhibited potent antineoplastic efficacy in vitro, excellent serum albumin-tolerance stability, and satisfactory hemocompatibility. These encouraging data indicated that the loading micelles from nonlinear enantiomeric copolymers, especially SCM/DOX, might be promising in clinical systemic chemotherapy through intravenous injection. PMID- 26058507 TI - Characteristics of the Energetic Igniters Through Integrating B/Ti Nano Multilayers on TaN Film Bridge. AB - The energetic igniters through integrating B/Ti nano-multilayers on tantalum nitride (TaN) ignition bridge are designed and fabricated. The X-ray diffraction (XRD) and temperature coefficient of resistance (TCR) results show that nitrogen content has a great influence on the crystalline structure and TCR. TaN films under nitrogen ratio of 0.99 % exhibit a near-zero TCR value of approximately 10 ppm/ degrees C. The scanning electron microscopy demonstrates that the layered structure of the B/Ti multilayer films is clearly visible with sharp and smooth interfaces. The electrical explosion characteristics employing a capacitor discharge firing set at the optimized charging voltage of 45 V reveal an excellent explosion performance by (B/Ti) n /TaN integration film bridge with small ignition delay time, high explosion temperature, much more bright flash of light, and much large quantities of the ejected product particles than TaN film bridge. PMID- 26058508 TI - A Facile One-Pot Synthesis of Au/Cu2O Nanocomposites for Nonenzymatic Detection of Hydrogen Peroxide. AB - Au/Cu2O nanocomposites were successfully synthesized by a facile one-pot redox reaction without additional reducing agent under room temperature. The morphologies and structures of the as-prepared products were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), and X ray diffraction (XRD). The electrocatalytic performance of Au/Cu2O nanocomposites towards hydrogen peroxide was evaluated by cyclic voltammetry (CV) and chronoamperometry (CA). The prepared Au/Cu2O nanocomposite electrode showed a wide linear range from 25 to 11.2 mM (R = 0.9989) with a low detection limit of 1.05 MUM (S/N = 3) and high sensitivity of 292.89 mA mM(-1) cm(-2). The enhanced performance for H2O2 detection can be attributed to the introduction of Au and the synergistic effect between Au and Cu2O. It is demonstrated that the Au/Cu2O nanocomposites material could be a promising candidate for H2O2 detection. PMID- 26058512 TI - Near-Infrared Emitting AgInTe2 and Zn-Ag-In-Te Colloidal Nanocrystals. AB - The synthesis of AgInTe2 nanocrystals emitting between 1095 and 1160 nm is presented. Evolution of the Ag:In:Te ratio shows progressive incorporation of In(3+) in Ag2Te, leading to the formation of orthorhombic AgInTe2. When zinc is added to the synthesis, the photoluminescence quantum yield reaches 3.4 %. PMID- 26058506 TI - Characterization and Effect of Thermal Annealing on InAs Quantum Dots Grown by Droplet Epitaxy on GaAs(111)A Substrates. AB - We report the study on formation and thermal annealing of InAs quantum dots grown by droplet epitaxy on GaAs (111)A surface. By following the changes in RHEED pattern, we found that InAs quantum dots arsenized at low temperature are lattice matched with GaAs substrate, becoming almost fully relaxed when substrate temperature is increased. Morphological characterizations performed by atomic force microscopy show that annealing process is able to change density and aspect ratio of InAs quantum dots and also to narrow size distribution. PMID- 26058509 TI - The Role of Groove Periodicity in the Formation of Site-Controlled Quantum Dot Chains. AB - Structural and optical properties of InAs quantum dot (QD) chains formed in etched GaAs grooves having different periods from 200 to 2000 nm in [010] orientation are reported. The site-controlled QDs were fabricated by molecular beam epitaxy on soft UV-nanoimprint lithography-patterned GaAs(001) surfaces. Increasing the groove periods decreases the overall QD density but increases the QD size and the linear density along the groove direction. The effect of the increased QD size with larger periods is reflected in ensemble photoluminescence measurements as redshift of the QD emission. Furthermore, we demonstrate the photoluminescence emission from single QD chains. PMID- 26058515 TI - Revealing the complex conduction heat transfer mechanism of nanofluids. AB - Nanofluids are two-phase mixtures consisting of small percentages of nanoparticles (sub 1-10 %vol) inside a carrier fluid. The typical size of nanoparticles is less than 100 nm. These fluids have been exhibiting experimentally a significant increase of thermal performance compared to the corresponding carrier fluids, which cannot be explained using the classical thermodynamic theory. This study deciphers the thermal heat transfer mechanism for the conductive heat transfer mode via a molecular dynamics simulation code. The current findings are the first of their kind and conflict with the proposed theories for heat transfer propagation through micron-sized slurries and pure matter. The authors provide evidence of a complex new type of heat transfer mechanism, which explains the observed abnormal heat transfer augmentation. The new mechanism appears to unite a number of popular speculations for the thermal heat transfer mechanism employed by nanofluids as predicted by the majority of the researchers of the field into a single one. The constituents of the increased diffusivity of the nanoparticle can be attributed to mismatching of the local temperature profiles between parts of the surface of the solid and the fluid resulting in increased local thermophoretic effects. These effects affect the region surrounding the solid manifesting interfacial layer phenomena (Kapitza resistance). In this region, the activity of the fluid and the interactions between the fluid and the nanoparticle are elevated. Isotropic increased nanoparticle mobility is manifested as enhanced Brownian motion and diffusion effects. PMID- 26058511 TI - Synthesis of Pt3Ni microspheres with high performance for rapid degradation of organic dyes. AB - In this study, Pt3Ni microspheres consisted of nanoparticles were synthesized without addition of surfactants via the solvothermal route. The obtained sample was characterized by X-ray diffraction (XRD), inductively coupled plasma-atomic emission spectrometer (ICP-AES), X-ray photoelectron spectroscopy (XPS), and field-emission scanning electron microscopy (FESEM). Furthermore, the catalytic performance of as-synthesized Pt3Ni microspheres was evaluated on the degradation of different organic dyes (methylene blue, methyl orange, Congo red, and rhodamine B). The results show that different dyes were rapidly decomposed by Pt3Ni microspheres in different pathways. Among different dyes, the formation and further degradation of the intermediates was observed during the degradation of methylene blue and methyl orange, suggesting the indirect degradation process of these dyes. This study provides not only a promising catalyst for the removal of organic contaminants for environment remediation, but also new insights for Pt3Ni alloy as a high-performance catalyst in organic synthesis. PMID- 26058513 TI - Magnetically Separable Fe3O 4/AgBr Hybrid Materials: Highly Efficient Photocatalytic Activity and Good Stability. AB - Magnetically separable Fe3O4/AgBr hybrid materials with highly efficient photocatalytic activity were prepared by the precipitation method. All of them exhibited much higher photocatalytic activity than the pure AgBr in photodegradation of methyl orange (MO) under visible light irradiation. When the loading amount of Fe3O4 was 0.5 %, the hybrid materials displayed the highest photocatalytic activity, and the degradation yield of MO reached 85 % within 12 min. Silver halide often suffers serious photo-corrosion, while the stability of the Fe3O4/AgBr hybrid materials improved apparently than the pure AgBr. Furthermore, depositing Fe3O4 onto the surface of AgBr could facilitate the electron transfer and thereby leading to the elevated photocatalytic activity. The morphology, phase structure, and optical properties of the composites were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), UV visible diffuse reflectance spectra (UV-vis DRS), and photoluminescence (PL) techniques. PMID- 26058516 TI - Electronic Structure and Carrier Mobilities of Arsenene and Antimonene Nanoribbons: A First-Principle Study. AB - Arsenene and antimonene, i.e. two-dimensional (2D) As and Sb monolayers, are the recently proposed cousins of phosphorene (Angew. Chem. Int. Ed., 54, 3112 (2015)). Through first-principle calculations, we systematically investigate electronic and transport properties of the corresponding As and Sb nanoribbons, which are cut from the arsenene and antimonene nanosheets. We find that different from the 2D systems, band features of As and Sb nanoribbons are dependent on edge shapes. All armchair As/Sb nanoribbons keep the indirect band gap feature, while the zigzag ones transfer to direct semiconductors. Quantum confinement in nanoribbons enhances the gap sizes, for which both the armchair and zigzag ones have a gap scaling rule inversely proportional to the ribbon width. Comparing to phosphorene, the large deformation potential constants in the As and Sb nanoribbons cause small carrier mobilities in the orders of magnitude of 10(1) 10(2) cm(2)/Vs. Our study demonstrates that the nanostructures of group-Vb elements would possess different electronic properties for the P, As, and Sb ones, which have diverse potential applications for nanoelectronics and nanodevices. PMID- 26058510 TI - Gold Nanohole Array with Sub-1 nm Roughness by Annealing for Sensitivity Enhancement of Extraordinary Optical Transmission Biosensor. AB - Nanofabrication technology plays an important role in the performance of surface plasmonic devices such as extraordinary optical transmission (EOT) sensor. In this work, a double liftoff process was developed to fabricate a series of nanohole arrays of a hole diameter between 150 and 235 nm and a period of 500 nm in a 100-nm-thick gold film on a silica substrate. To improve the surface quality of the gold film, thermal annealing was conducted, by which an ultra-smooth gold film with root-mean-square (RMS) roughness of sub-1 nm was achieved, accompanied with a hole diameter shrinkage. The surface sensitivity of the nanohole arrays was measured using a monolayer of 16-mercaptohexadecanoic acid (16-MHA) molecule, and the surface sensitivity was increased by 2.5 to 3 times upon annealing the extraordinary optical transmission (EOT) sensor. PMID- 26058514 TI - Carboxylic Acid Fullerene (C60) Derivatives Attenuated Neuroinflammatory Responses by Modulating Mitochondrial Dynamics. AB - Fullerene (C60) derivatives, a unique class of compounds with potent antioxidant properties, have been reported to exert a wide variety of biological activities including neuroprotective properties. Mitochondrial dynamics are an important constituent of cellular quality control and function, and an imbalance of the dynamics eventually leads to mitochondria disruption and cell dysfunctions. This study aimed to assess the effects of carboxylic acid C60 derivatives (C60-COOH) on mitochondrial dynamics and elucidate its associated mechanisms in lipopolysaccharide (LPS)-stimulated BV-2 microglial cell model. Using a cell based functional screening system labeled with DsRed2-mito in BV-2 cells, we showed that LPS stimulation led to excessive mitochondrial fission, increased mitochondrial localization of dynamin-related protein 1 (Drp1), both of which were markedly suppressed by C60-COOH pretreatment. LPS-induced mitochondria reactive oxygen species (ROS) generation and collapse of mitochondrial membrane potential (DeltaPsim) were also significantly inhibited by C60-COOH. Moreover, we also found that C60-COOH pretreatment resulted in the attenuation of LPS-mediated activation of nuclear factor (NF)-kappaB and mitogen-activated protein kinase (MAPK) signaling, as well as the production of pro-inflammatory mediators. Taken together, these findings demonstrated that carboxylic acid C60 derivatives may exert neuroprotective effects through regulating mitochondrial dynamics and functions in microglial cells, thus providing novel insights into the mechanisms of the neuroprotective properties of carboxylic acid C60 derivatives. PMID- 26058517 TI - Effect of Extra-Framework Cations of LTL Nanozeolites to Inhibit Oil Oxidation. AB - Lubricant oils take significant part in current health and environmental considerations since they are an integral and indispensable component of modern technology. Antioxidants are probably the most important additives used in oils because oxidative deterioration plays a major role in oil degradation. Zeolite nanoparticles (NPs) have been proven as another option as green antioxidants in oil formulation. The anti-oxidative behavior of zeolite NPs is obvious; however, the phenomenon is still under investigation. Herein, a study of the effect of extra-framework cations stabilized on Linde Type L (LTL) zeolite NPs (ca. 20 nm) on inhibition of oxidation in palm oil-based lubricant oil is reported. Hydrophilic LTL zeolites with a Si/Al ratio of 3.2 containing four different inorganic cations (Li(+), Na(+), K(+), Ca(2+)) were applied. The oxidation of the lubricant oil was followed by visual observation, colorimetry, fourier transform infrared (FTIR) spectroscopy, (1)H NMR spectroscopy, total acid number (TAN), and rheology analyses. The effect of extra-framework cations to slow down the rate of oil oxidation and to control the viscosity of oil is demonstrated. The degradation rate of the lubricant oil samples is decreased considerably as the polarizability of cation is increased with the presence of zeolite NPs. More importantly, the microporous zeolite NPs have a great influence in halting the steps that lead to the polymerization of the oils and thus increasing the lifetime of oils. PMID- 26058520 TI - [In Process Citation]. PMID- 26058518 TI - Myeloperoxidase-Hepatocyte-Stellate Cell Cross Talk Promotes Hepatocyte Injury and Fibrosis in Experimental Nonalcoholic Steatohepatitis. AB - AIMS: Myeloperoxidase (MPO), a highly oxidative enzyme secreted by leukocytes has been implicated in human and experimental nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unknown. In this study, we investigated how MPO contributes to progression from steatosis to NASH. RESULTS: In C57Bl/6J mice fed a diet deficient in methionine and choline to induce NASH, neutrophils and to a lesser extent inflammatory monocytes are markedly increased compared with sham mice and secrete abundant amounts of MPO. Through generation of HOCl, MPO directly causes hepatocyte death in vivo. In vitro experiments demonstrate mitochondrial permeability transition pore induction via activation of SAPK/JNK and PARP. MPO also contributes to activation of hepatic stellate cells (HSCs), the most important source of collagen in the liver. In vitro MPO-activated HSCs have an activation signature (MAPK and PI3K-AKT phosphorylation) and upregulate COL1A1, alpha-SMA, and CXCL1. MPO-derived oxidative stress also activates transforming growth factor beta (TGF-beta) in vitro, and TGF-beta signaling inhibition with SB-431542 decreased steatosis and fibrosis in vivo. Conversely, congenital absence of MPO results in reduced hepatocyte injury, decreased levels of TGF-beta, fewer activated HSCs, and less severe fibrosis in vivo. INNOVATION AND CONCLUSION: Cumulatively, these findings demonstrate important cross talk between inflammatory myeloid cells, hepatocytes, and HSCs via MPO and establish MPO as part of a proapoptotic and profibrotic pathway of progression in NASH, as well as a potential therapeutic target to ameliorate this disease. PMID- 26058519 TI - Poor responder to plasma exchange therapy in acquired thrombotic thrombocytopenic purpura is associated with ADAMTS13 inhibitor boosting: visualization of an ADAMTS13 inhibitor complex and its proteolytic clearance from plasma. AB - BACKGROUND: Plasma exchange (PE) is the first-line treatment for primary acquired thrombotic thrombocytopenic purpura (aTTP) with severe deficiency of ADAMTS13 activity (ADAMTS13:AC). Some patients are poor responders to PE, raising concern over multiple pathogenetic pathways. STUDY DESIGN AND METHODS: Based on 52 aTTP patients in our national cohort study, we monitored plasma levels of ADAMTS13, clinical and laboratory findings, and outcomes. In a representative poor responder to PE, we examined an ADAMTS13 inhibitor (ADAMTS13:INH) complex in plasma milieu, by means of a large-pore isoelectric focusing (IEF) analysis. RESULTS: Of 52 aTTP patients, 20 were good responders and 32 were poor responders. In the latter group, plasma ADAMTS13:AC levels never increased to more than 10% of normal during 14 days after PE initiation. Mean (+/-SD) plasma ADAMTS13:INH titers (Bethesda unit/mL) were 5.7 (+/-4.5) before PE, but decreased to 1.4 (+/-0.8) on the fourth PE day and then remarkably increased to 14.8 (+/ 10.0) on the 10th PE day, termed "inhibitor boosting," and then slowly decreased to undetectable level over 1 month. On admission, none of the routinely available clinical and laboratory markers differentiated these two groups. However, elevated pre-PE levels of ADAMTS13:INH were correlated with a poor response. We visualized an ADAMTS13:INH (immunoglobulin G) complex in a patient plasma by an IEF analysis and found proteolytic fragment of ADAMTS13 antigen by a two dimensional IEF and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis. CONCLUSION: Findings from this cohort of aTTP patients demonstrated that inhibitor boosting often occurs in aTTP patients in Japan. Poor responders could be predicted by elevated pre-PE ADAMTS13:INH levels on admission, but not by routinely collected clinical or laboratory data. PMID- 26058522 TI - [In Process Citation]. PMID- 26058523 TI - [In Process Citation]. PMID- 26058524 TI - [Increased post-stroke risk of suicide]. AB - The purpose of this work is to illustrate a possible cohesion between stroke and subsequent risk of suicide, presenting a review of the literature covering the past 26 years. 80% of the primary studies find that the risk of suicide increases post-stroke. The first five years post-stroke is the most risky period of time. Furthermore, the risk appears to be greatest among patients below the age 60 years. Recommended is attention towards these specific risks. Some of the literature show limitations due to the lack of consideration of confounders such as depression and sociodemographic data. PMID- 26058525 TI - [An active sex life is possible for men undergoing androgen deprivation therapy for prostate cancer]. AB - Sexual function is diminished in the majority of men undergoing androgen deprivation therapy for prostate cancer. However, about 20% seem to retain some degree of libido and erectile function. In addition, the intimacy of sexual relations is important for many couples. Therefore, sexuality should be addressed when patients express an interest in this. In some men, erections can be re established with normal erectogenic aids. Others will benefit from counselling on alternative sexual practices. The goal should be to make the couple as satisfied as possible with their situation. PMID- 26058526 TI - [Biomarkers for early diagnosis of Alzheimer's disease]. AB - Alzheimer's disease is responsible for 40-50% of dementia cases. Future treatment may include disease-modifying compounds unlikely to be efficient if administered late in the course, thus necessitating early diagnosis. Furthermore, revised diagnostic research criteria that include biomarkers of pathological accumulation of cortical beta-amyloid (decreased beta-amyloid in cerebrospinal fluid and amyloid imaging) and neurodegeneration (structural MRI and 18F-FDG-PET), have been published. Future research is needed to determine specific evidence-based application of these biomarkers in the clinic as well as discovery of novel biomarkers. PMID- 26058527 TI - [A structured multidisciplinary approach ensures correct anticoagulation therapy to patients with atrial fibrillation]. AB - Atrial fibrillation (AF) is associated with an increased risk of stroke and mortality. Anticoagulation therapy reduces the risk of stroke in patients with AF. In a structured multidisciplinary AF-clinic correct anticoagulation treatment according to guidelines was achieved in 99% (170 out of 172 patients) compared to 79% (143 out of 179 patients) in the "usual care" period (p < 0.001). We propose establishment of structured multidisciplinary AF-clinics in Denmark to ensure optimal antithrombotic treatment and adherence to current guidelines. PMID- 26058528 TI - Diagnosis of acute dental trauma: the importance of standardized documentation: a review. AB - In 1985 Andreasen and Andreasen published a paper on the diagnosis of luxation injuries and outlined the importance of standardized clinical, radiographic, and photographic techniques. Now 30 years later, these recommendations remain current in the International Association of Dental Traumatology (IADT) guidelines for the management of dental trauma and describe circumstances surrounding the time of injury, the extent of trauma (e.g., type of luxation injury), healing potential (e.g., stage of root development) as well as information concerning subsequent treatment. The purpose of this review was to include findings for other types of trauma and to discuss more recent studies that augment and/or improve on the original findings from 30 years ago. The present review discusses the use of a standardized clinical registration (pulpal sensibility testing, laser Doppler flowmetry, mobility testing), radiographic survey, and photographic registration of the traumatized patient. Moreover, the value of digital radiographs and recent developments in computer tomography with respect to possible enhancement of the trauma diagnosis are discussed. PMID- 26058529 TI - The free and cued selective reminding test for predicting progression to Alzheimer's disease in patients with mild cognitive impairment: A prospective longitudinal study. AB - Amnestic mild cognitive impairment (aMCI) patients carry a greater risk of conversion to Alzheimer's disease (AD). Therefore, the International Working Group (IWG) on AD aims to consider some cases of aMCI as symptomatic prodromal AD. The core diagnostic marker of AD is a significant and progressive memory deficit, and the Free and Cued Selective Reminding Test (FCSRT) was recommended by the IWG to test memory in cases of possible prodromal AD. This study aims to investigate whether the performance on the FCSRT would enhance the ability to predict conversion to AD in an aMCI group. A longitudinal study was conducted on 88 aMCI patients, and neuropsychological tests were analysed on the relative risk of conversion to AD. During follow-up (23.82 months), 33% of the aMCI population converted to AD. An impaired FCSRT TR was significantly associated with the risk of conversion to dementia, with a mean time to conversion of 25 months. The FCSRT demonstrates utility for detecting AD at its prodromal stage, thus supporting its use as a valid clinical marker. PMID- 26058530 TI - Decision-to-delivery intervals and perinatal outcomes following emergency cesarean delivery in a Nigerian tertiary hospital. AB - OBJECTIVE: To determine the decision-to-delivery interval (DDI) for emergency cesarean deliveries (CDs) at a tertiary center in Nigeria, to evaluate causes of delay, and to assess the effects of delays on perinatal outcomes. METHODS: Between September and November 2010, a prospective, observational study was undertaken at University College Hospital, Ibadan. Events that occurred after a decision to perform an emergency CD were recorded. Associations between outcomes and the DDI were analyzed. RESULTS: Among 235 emergency CDs included, 5 (2.1%) occurred within 30 minutes and 86 (36.6%) within 75 minutes. The mean DDI was 119.2+/-95.0 minutes. Among CDs with a DDI of more than 75 minutes, logistic factors were the reason for delay in 65 (43.6 %) cases. No significant associations were recorded between DDI and the 5-minute Apgar score, admission to the special-care baby unit, or perinatal mortality (P>0.05 for all). In multivariate analysis, neonates delivered after 75 minutes were significantly less likely to die during the perinatal period than were those delivered within this period (odds ratio 0.13, 95% confidence interval 0.03-0.66; P=0.01). CONCLUSION: Institutional delays in CDs need to be addressed. However, the DDI could be less important for perinatal outcome than are some other factors, such as the severity of the indication. PMID- 26058531 TI - Expression profiling and functional analyses of BghPTR2, a peptide transporter from Blumeria graminis f. sp. hordei. AB - The obligate ascomycete parasitic fungus Blumeria graminis f. sp. hordei (Bgh) has a unique lifestyle as it is completely dependent on living barley leaves as substrate for growth. Genes involved in inorganic nitrogen utilization are notably lacking, and the fungus relies on uptake of host-derived peptides and amino acids. The PTR2 transporter family takes up di- and tri- peptides in a proton coupled process and filamentous fungi typically have two or more di/tri peptide transporters. Here we show that Bgh appear to have one PTR2 that can restore dipeptide uptake in a Saccharomyces cerevisiae PTR2 deletion strain. The Bgh PTR2 gene is expressed in conidia and germinating conidia. During Bgh infection of barley the expression level of the BghPTR2 gene is high in the appressorial germ tube, low in the haustoria and high again during conidiation and secondary infection in the compatible and intermediate resistant interactions. BghPTR2 appears to be important for the initial establishment of fungal infection but not for uptake of di-tri-peptides at the haustorial interface. Based on the expression profile we suggest that BghPTR2 is active in internal transport of nutrient reserves and/or uptake of break down products from the plant surface during the early infection stages. PMID- 26058532 TI - Functional analysis of AoAtg11 in selective autophagy in the filamentous fungus Aspergillus oryzae. AB - Autophagy is a highly conserved cellular degradation process in eukaryotes and consists of both non-selective and selective types. Selective autophagic processes include pexophagy, mitophagy, and the cytoplasm-to-vacuole targeting (Cvt) pathway of yeast, in which particular vacuolar proteins, such as aminopeptidase I (Ape1), are selectively transported to vacuoles. Although selective autophagy has been mainly studied in the yeasts Saccharomyces cerevisiae and Pichia pastoris, there is evidence for selective autophagy in filamentous fungi; however, the details are poorly understood. In S. cerevisiae, Atg11 is a selective autophagy-specific protein that recognizes and transports substrates to the pre-autophagosomal structure (PAS). Here, we first identified an ATG11 homologue in the filamentous fungus Aspergillus oryzae and analyzed the localization of the corresponding protein, designated AoAtg11, fused to enhanced green fluorescent protein (EGFP). Imaging analysis revealed that AoAtg11-EGFP was localized to PAS-like structures. We next constructed an Aoatg11 disruptant of A. oryzae and showed that AoAtg11 is involved in pexophagy and mitophagy. In addition, AoAtg11 was found to be dispensable for non-selective autophagy and for transporting AoApe1 to vacuoles. Taken together, these results suggest that AoAtg11 is a selective autophagy-specific protein in A. oryzae, and has distinct molecular functions from that of S. cerevisiae Atg11. PMID- 26058533 TI - Saprophytic growth of the alder rust fungus Melampsoridium hiratsukanum on artificial media. AB - The first axenic culture of a free living saprophytic stage of the exotic rust fungus Melampsoridium hiratsukanum is reported. Colonies were obtained from one celled, dikaryotic urediniospores on eight nutrient media out of twelve. Modified Harvey and Grasham (HG) and Schenk and Hildebrandt (HS) media HG1 and SH1 and their bovine serum albumin (BSA)-enriched derivatives gave abundant mycelial growth, but modified Murashige and Skoog (MS) QMS media and their BSA-enriched modifications performed poorly, colony growth being low on QMS-1 and QMS1+BSA, and nil on QMS-5 and QMS-6, with or without BSA. Colonies initially grew poorly when subcultured for one month in purity, but much better after re-transfer to fresh media later: presumably because only the most exploitative genotypes survived, best able to cope with an uncongenial medium. Stabilised cultures survived, and remained vegetative, but only few reproductive colonies produced spore-like bodies. Though the agarised medium remains an inhospitable environment for this biotrophic parasite, it is shown that non-living media can nevertheless sustain the growth and sporulation of this fungus outside its natural hosts and habitat. Axenic culture promises important advances in basic and applied research on this rust, leading to a better understanding of its nutrition, metabolism, diversity and pathogenicity. PMID- 26058534 TI - High osmolarity glycerol (HOG) signalling in Magnaporthe oryzae: Identification of MoYPD1 and its role in osmoregulation, fungicide action, and pathogenicity. AB - This study comprises a first functional analysis of an YPD1-homologue in filamentous phytopathogenic fungi and its role in the HOG signalling pathway. We generated a gene deletion mutant of the gene MoYPD1 in Magnaporthe oryzae and characterized the resulting mutant strain. We have shown that MoYpd1p is a component of the phosphorelay system acting in the HOG pathway due to its Y2H protein interaction with the HKs MoHik1p and MoSln1p as well as with the response regulator MoSsk1p. Fungicidal activity of fludioxonil was reported to be based on the inhibition of MoHik1p resulting in hyperactivation of the HOG signalling pathway and lethality. Western analysis proved that both, osmotic stress and fludioxonil application resulted in the phosphorylation of the MoHog1p in a MoYpd1p-dependent manner. We therefore consider MoYpd1p to be essential for the regulation capability of the HOG pathway and the fungicide action of fludioxonil, but dispensible for viability. The results indicate that MoYpd1p functions as signal transfer protein between MoSln1p, MoHik1p, and MoSsk1p. Manipulations of the HOG signalling pathway affects the infection-related morphogenesis in M. oryzae, since the mutant strain DeltaMoypd1 has a white and fluffy phenotype on complete media, is not able to form spores in various conditions and fails to colonize rice plants. PMID- 26058535 TI - Multilocus genotyping of Amylostereum spp. associated with Sirex noctilio and other woodwasps from Europe reveal clonal lineage introduced to the US. AB - Sirex noctilio is a woodwasp of Eurasian origin that was inadvertently introduced to the southern hemisphere in the 1900s and to North America over a decade ago. Its larvae bore in Pinus spp. and can cause significant mortality in pine plantations. S noctilio is associated with a symbiotic white rot fungus, Amylostereum areolatum, which females inject into trees when they oviposit and which is required for survival of developing larvae. We compared the genetic diversity of A. areolatum isolated from S. noctilio and other woodwasps collected from Europe and from northeastern North America to determine the origin of introduction(s) into the United States. Multilocus genotyping of nuclear ribosomal regions and protein coding genes revealed two widespread multilocus genotypes (MLGs) among the European samples, one of which is present in the US. The other two MLGs associated with S. noctilio in the US represented unique haplotypes. These latter two haplotypes were likely from unrepresented source populations, and together with the introduced widespread haplotype reveal multiple A. areolatum MLGs introduced by S. noctilio and indicate possible multiple S. noctilio introductions to North America from Europe. Our results also showed a lack of fidelity between woodwasp hosts and Amylostereum species. PMID- 26058536 TI - Coexistence of and interaction relationships between an aflatoxin-producing fungus and a bacterium. AB - The interactions between aflatoxin-producing fungi and bacteria have opened up a new avenue for identifying biological agents suitable for controlling aflatoxin contamination. In this study, we analysed the interactions between A. flavus and the bacterium Burkholderia gladioli M3 that coexist in rice that is naturally contaminated with A. flavus. Our results showed that a cell-free culture filtrate (CCF) and the metabolite bongkrekic acid of the M3 strain potently suppressed the mycelial growth and spore production, and then affected the production of aflatoxin of A. flavus. Bongkrekic acid secreted by the M3 strain exhibited higher antifungal activity than did analogues. The CCF of the M3 strain and its metabolite bongkrekic acid can inhibit the growth of A. flavus, but the metabolites of A. flavus, aflatoxins, exerted no inhibitory effect on the growth of the M3 strain. Furthermore, we determined that the M3 cells could use the dead mycelia of A. flavus as energy sources for reproduction, while A. flavus could not grow in a solution containing dead M3 cells. In summary, these results indicated that B. gladioli has a competitive advantage in survival when it coexists with its fungal partner A. flavus. PMID- 26058537 TI - Cornuvesica: A little known mycophilic genus with a unique biology and unexpected new species. AB - Little is known about the biology of the monotypic genus Cornuvesica (Microascales), apart from that isolates are notoriously difficult to culture on artificial media. A recent collection of material resembling this genus from freshly made wounds on Gmelina arborea in Indonesia, provided an opportunity to reconsider all available material of Cornuvesica falcata, type species of the genus. In addition to morphological comparisons, multigene phylogenetic analyses were made using sequences of the SSU, ITS, LSU and TEF-1alpha genes. Our results showed that the holotype of Cor. falcata from pine in Canada differed from all other material previously considered to represent this species and also from the new Indonesian collections. The collections considered represented three additional species that we describe here as new. Three New Zealand isolates and an isolate from UK were respectively described as Cor. acuminata and Cor. crypta, while the Indonesian isolates were described as Cor. magnispora. Phylogenies based on the SSU and LSU data sets showed that Cornuvesica spp. do not belong in the Ceratocystidaceae as previously suggested, but represent a distinct lineage in the Microascales that has yet to be named. Results showed that culture filtrates from other fungi or ferric chloride markedly stimulated the growth of Cor. magnispora. PMID- 26058538 TI - Genome-wide analysis of small RNAs in the wheat pathogenic fungus Zymoseptoria tritici. AB - Small non-coding RNAs constitute a large family of regulatory molecules with diverse function. Knowledge about small RNAs in fungi remains limited. Here, a RNA-seq-based analysis of small RNA transcriptome from the wheat pathogenic fungus Zymoseptoria tritici under nutrient-stress and nutrient-rich growth conditions is presented. Small RNAs mapped to Z. tritici genomic features including sense and antisense strands of genes, repetitive elements, rRNAs, snRNA, snoRNA and tRNA loci throughout the chromosomes. The majority of small RNAs from rich condition mapped to all the chromosomes, primarily the sense strand of chromosome seven, but under stress condition, small RNAs were enriched in accessory genome. Inspection of the predominant small RNAs matching to protein coding genes, repeats and rRNAs revealed that intron and LTP retrotransposon derived small RNAs accumulated upon stress, whereas rRNA-derived small RNAs were enriched for nutrient-rich condition. U enrichment at position 1 of small RNAs mapping to repeats and antisense-strand genes was only observed from stress library. Additionally, target analysis of one predicted milRNA suggests its potential role in fungal pathogenesis and manipulation of host immunity. Taken together, the findings provide a new insight into the function of small RNAs in regulating growth and development, stress adaptation, and possibly pathogenesis in Z. tritici. PMID- 26058539 TI - Heterologous expression and characterization of alpha-L-arabinofuranosidase 4 from Penicillium purpurogenum and comparison with the other isoenzymes produced by the fungus. AB - Penicillium purpurogenum secretes at least four arabinofuranosidases. In this work, the gene of alpha-L-arabinofuranosidase 4 (ABF4) has been sequenced and expressed in Pichia pastoris. The gene is 1521 pb long, has no introns and codes for a protein of 506 amino acid residues including a signal peptide of 26 residues. Mature protein has a calculated molecular mass of 55.4 kDa, shows 77% identity with alpha-L-arabinofuranosidase 1 from P. purpurogenum and belongs to family 54 of the glycosyl hydrolases. Purified enzyme has a molecular mass near 68 kDa, is active on p-nitrophenyl alpha-L-arabinofuranoside and p-nitrophenyl beta-D-galactofuranoside, and follows Michaelis-Menten kinetics with KM of 1.58 +/- 0.13 mM and 5.3 +/- 1.18 mM, respectively. The pH optimum is 4.6 and optimal temperature is 50 degrees C. The enzyme is active on sugar beet arabinan and wheat flour arabinoxylan but does not act on short arabinooligosaccharides or debranched arabinan. It shows synergistic effect on arabinose liberation from wheat arabinoxylan when combined with endoxylanase from P. purpurogenum. The properties of ABF4 have been compared with those of the other arabinofuranosidases produced by the fungus. P. purpurogenum is the first fungus possessing four biochemically characterized arabinofuranosidases. The availability of four different ABFs may be valuable for biotechnological applications. PMID- 26058540 TI - Copper (II) lead (II), and zinc (II) reduce growth and zoospore release in four zoosporic true fungi from soils of NSW, Australia. AB - This study examined the responses of a group of four zoosporic true fungi isolated from soils in NSW Australia, to concentrations of toxic metals in the laboratory that may be found in polluted soils. All isolates showed greatest sensitivity to Cu and least sensitivity to Pb. All isolates showed significant reduction in growth at 60 ppm (0.94 mmol m(-3)) for Cu, while three declined significantly at 60 ppm (0.92 mmol m(-3)) Zn. The growth of two isolates declined significantly at 100 ppm (0.48 mmol m(-3)) Pb and one at 200 ppm (0.96 mmol m( 3)) Pb. The rate of production of zoospores for all isolates was reduced when sporangia were grown in solid PYG media with 60 ppm Cu. Three isolates significantly declined in production at 60 ppm Zn and three at 100 ppm Pb. All isolates recovered growth after incubation in solid media with 60 ppm Zn or 100 ppm Pb. Two isolates did not recover growth after incubation in 60 ppm Cu. If these metals cause similar effects in the field, Cu, Pb, and Zn contamination of NSW soils is likely to reduce biomass of zoosporic true fungi. Loss of the fungi may reduce the rate of mineralisation of soil organic matter. PMID- 26058541 TI - Nucleus-independent chemical shift analysis of the electronic states of the (CO)4, (CS)4, and (CSe)4 molecules. AB - NICS(1) calculations have been performed on the 8pi and 10pi singlet states and the 9pi triplet state of (CO)4, (CS)4, and (CSe)4. The results show that transfer of electrons from the b2g sigma MO into the a2u pi MO decreases the NICS(1) value, indicating an increase in the diamagnetic ring current. The decreases in the calculated NICS(1) values are substantially larger in (CO)4 than in (CS)4 or (CSe)4. This finding is rationalized by the larger coefficients on the carbons in the a2u MO of (CO)4 than in the a2u MOs of (CS)4 and (CSe)4. PMID- 26058542 TI - Caregiver burden for informal caregivers of patients with dementia: A systematic review. AB - BACKGROUND: Dementia is an irreversible illness. The caregiver is expected to assume increased responsibility as the condition of the person with dementia declines. It is important to explore the factors constituting caregiver burden on the informal caregivers of people with dementia. AIMS: The purpose of this article is to identify the factors constituting caregiver burden on the informal caregivers of people with dementia living in the community. METHODS: A systematic review of the four databases, including PubMed, PsycINFO, CINAHL and the Cochrane Library, was carried out to access relevant articles published between 2003 and 2012. Twenty-one articles met the inclusion criteria of this study. RESULTS: Behavioural problems or psychological symptoms were the primary factor of the person with dementia that is associated with caregiver burden. Caregiver socio demographical factors and psychological factors were the two primary factors of the caregiver burden. LIMITATIONS: Several results of this study were based on studies that had their own limitations. Furthermore, the concept of caregiver 'burden' was not clearly defined in some of the studies; instead, the term was broadly defined. CONCLUSION: Factors of caregiver burden in regard to people with dementia living in the community were clarified in this review study. By identifying all of the factors, healthcare professionals can deliver appropriate assistance to relieve caregiver burden and improve the quality of caregiving for people with dementia. IMPLICATIONS FOR NURSING AND HEALTH POLICY: It is important to identify the factors of the burden on the caregivers of people with dementia living in the community to prevent early nursing home placement, deterioration of caregiver's health and reduce the adverse health outcomes for care recipients. A health-related policy should be formulated to help informal caregivers receive more professional assistance. Training opportunities should be provided for family caregivers to reduce the impact of caregiving on the delivery of effective care. PMID- 26058543 TI - Cocktail of Four Active Components Derived from Sheng Mai San Inhibits Hydrogen Peroxide-Induced PC12 Cell Apoptosis Linked with the Caspase-3/ROCK1/MLC Pathway. AB - SMXZF, a combination of four active components including ginsenoside Rb1, ginsenoside Rg1, schizandrin, and DT-13 (6:9:5:4) that is derived from Sheng Mai San, has previously been shown to exhibit a neuroprotective effect against focal ischemia/reperfusion injury. Due to the key role of oxidative stress-induced neuronal apoptosis in the pathogenesis of stroke, we examined the effect of SMXZF in oxidative stress responses and related signaling pathways in differentiated pheochromocytoma (PC12) cells. Our results showed that incubation with 100 MUM hydrogen peroxide (H2O2) for 12 hr could reduce cell viability and superoxide dismutase (SOD) activity with an increase of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA). In contrast, SMXZF alleviated oxidative stress by reducing the over-production of ROS and MDA in parallel to concentration dependently increasing SOD activity. In addition, SMXZF significantly attenuated H2O2-induced caspase-3 cleavage, Rho-associated coiled coil-containing protein kinase-1 (ROCK1) activation, and myosin light-chain (MLC) phosphorylation. Inhibiting either caspase-3 or ROCK1 mimicked the effect. Consequently, our results suggest that SMXZF inhibits H2O2-induced neuronal apoptosis linked with the caspase-3/ROCK1/MLC pathway, which has also been confirmed to be a positive feedback loop in oxidative stress-injured PC12 cells. These findings support the pharmacological potential of SMXZF for neurodegenerative diseases and stroke. PMID- 26058545 TI - A comprehensive study of current haemophilia care and outcomes in Singapore. PMID- 26058546 TI - Circulating heart-type fatty acid-binding protein levels predict ventricular fibrillation in Brugada syndrome. AB - BACKGROUND: The association between ongoing myocardial damage and outcomes in patients with Brugada syndrome who had received an implantable cardioverter defibrillator (ICD) is unclear. METHODS: Consecutive patients with Brugada syndrome (n=31, 50+/-13 years) who had received an ICD were prospectively enrolled. Minor myocardial membrane injury [heart-type fatty acid-binding protein (H-FABP) >2.4ng/mL] and myofibrillar injury (troponin T >0.005ng/mL) were defined using receiver operating characteristic curves. Patients were followed for a median period of 5 years to an endpoint of appropriate ICD shock. RESULTS: Myocardial membrane injury (29%) and myofibrillar injury (26%) were similarly prevalent among patients with Brugada syndrome who had received ICDs. Appropriate ICD shocks occurred in 19% of patients during the follow-up period. Multivariate Cox regression analysis showed that serum H-FABP level >2.4ng/mL, but not troponin T level, was an independent prognostic factor for appropriate ICD shock due to ventricular fibrillation [hazard ratio (HR) 25.2, 95% confidence interval (CI) 1.33-1686, p=0.03]. CONCLUSIONS: Evaluating myocardial damage using H-FABP may be a promising tool for predicting ventricular arrhythmia in patients with Brugada syndrome who have received ICDs. PMID- 26058544 TI - Adequacy of prenatal care among women living with human immunodeficiency virus: a population-based study. AB - BACKGROUND: Prenatal care reduces perinatal morbidity. However, there are no population-based studies examining the adequacy of prenatal care among women living with HIV. Accordingly, we compared the prevalence of adequate prenatal care among women living with and without HIV infection in Ontario, Canada. METHODS: Using administrative data in a universal single-payer setting, we determined the proportions of women initiating care in the first trimester and receiving adequate prenatal care according to the Revised-Graduated Prenatal Care Utilization Index . We also determined the proportion of women with HIV receiving adequate prenatal care by immigration status. We used generalized estimating equations with a logit link function to derive adjusted odds ratios (aORs) and 95% confidence intervals (CI) for all analyses. RESULTS: Between April 1, 2002 and March 31, 2011, a total of 1,132,135 pregnancies were available for analysis, of which 634 (0.06%) were among women living with HIV. Following multivariable adjustment, women living with HIV were less likely to receive adequate prenatal care (36.1% versus 43.3%; aOR 0.74, 95% CI 0.62 to 0.88) or initiate prenatal care in the first trimester (50.8% versus 70.0%; aOR 0.51, 95% CI 0.43 to 0.60) than women without HIV. Among women with HIV, recent (i.e. <= 5 years) immigrants from Africa and the Caribbean were less likely to receive adequate prenatal care (25.5% versus 38.5%; adjusted odds ratio 0.51; 95% CI, 0.32 to 0.81) than Canadian-born women. CONCLUSION: Despite universal health care, disparities exist in the receipt of adequate prenatal care between women living with and without HIV. Interventions are required to ensure that women with HIV receive timely and adequate prenatal care. PMID- 26058547 TI - Research on the change of chemical composition in productive process of Re Du Ning injection by HPLC/Q-TOF MS. AB - A high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC/Q-TOF MS) was developed for the analysis of chemical composition change in the production process of Re Du Ning injection, a Chinese medicine preparation with a combination of Lonicera japonica Thunb., Gardenia jasminoides Ellis and Artemisia annua L. A total of 90 compounds from raw materials-intermediates-Re Du Ning injection were detected; among them, 55 compounds were identified or tentatively characterized, and the characteristic ions of different types of compounds were described. Based on these studies, the different types of compounds in the various process routes were analyzed. A total of 28 compounds, including seven iridoid glycosides and six monoterpenes from G. jasminoides Ellis, five iridoid glycosides, nine phenolic acids and one unknown compound from L. japonica Thunb., were transferred to Re Du Ning injection, and two unknown compounds were generated in the production process of Re Du Ning injection. The results indicated that the Chinese Medicine Pharmaceutical process control is very important. This method could provide some reference for other Chinese medicine preparations. PMID- 26058548 TI - Introduction and commentary: Biosimilars-clinical trial and safety considerations. PMID- 26058549 TI - Inflammatory diseases: Integrating biosimilars into clinical practice. AB - OBJECTIVES: To discuss considerations regarding the selection, prescribing, and monitoring of biosimilars in the clinical management of patients with inflammatory disorders. METHODS: A search of the Internet as well as PubMed was conducted through August 2014 for information related to the clinical use of biosimilars in chronic inflammatory disorders using the keywords biosimilar, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and ankylosing spondylitis. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were searched for biosimilar guidelines. RESULTS: Articles and guidelines relating to integrating biosimilars into the clinical management of patients with inflammatory disorders have been published by regulatory agencies, professional associations, healthcare providers, and others. CONCLUSIONS: The recent approval of the biosimilar infliximab in some countries makes biosimilars a reality for rheumatologists and others involved in the care of patients with inflammatory disorders. To successfully and confidently integrate biosimilars into clinical practice, physicians must understand factors such as variation in innovator/reference products, extrapolation of data, naming and labeling, interchangeability and automatic substitution, and pharmacovigilance. PMID- 26058550 TI - Clinical trial development for biosimilars. AB - OBJECTIVES: Discuss issues regarding clinical trial design for the development of biosimilars in the European Union and the United States, with special focus on monoclonal antibodies used in the treatment of inflammatory diseases. METHODS: A search of the Internet as well as PubMed was conducted through June 2014 for information related to the clinical development of biosimilars using the keywords biosimilar, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and ankylosing spondylitis. The European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) websites were searched for biosimilar guidelines. RESULTS: The EMA began issuing draft guidelines for the development of biosimilars almost a decade ago and has approved numerous biosimilars. The US FDA has issued draft guidances providing stepwise considerations for the nonclinical and clinical development of biosimilars but has yet to approve a biosimilar under this pathway. CONCLUSIONS: Clinical trials aim to resolve uncertainties that may remain following nonclinical development regarding the similarity of the proposed biosimilar with the reference product. Pharmacokinetic and pharmacodynamic studies form the backbone of early clinical development and serve to inform phase 3 clinical development. Factors to be considered in clinical development include study population, design, end points, sample size, duration, and analytical methods. PMID- 26058551 TI - Biosimilar safety factors in clinical practice. AB - OBJECTIVES: This article provides insight into the guidelines issued by the European Medicines Agency (EMA) and the draft guidances issued by the US Food and Drug Administration (FDA) regarding potential safety considerations associated with the development and use of biosimilars. METHODS: EMA and FDA guidelines and the literature were reviewed to identify recommendations and experience of manufacturers regarding the safety of biosimilars. RESULTS: Recent results of phase 3 comparability clinical trials comparing biosimilars with their reference products, and the approval of a biosimilar infliximab by several regulatory agencies, demonstrate the growing importance of biosimilars in inflammatory diseases. The safety profiles of biosimilars developed according to regulatory guidelines appear to be highly similar to the reference product, and postmarketing pharmacovigilance programs are in place. Additional topics related to biosimilars, such as interchangeability, automatic substitution, and nomenclature, are discussed. CONCLUSIONS: Safety considerations in the development of biosimilars are an important focus of regulatory guidelines, although topics such as interchangeability, automatic substitution, and nomenclature are still being debated. PMID- 26058552 TI - Plasma adiponectin and carotid intima-media thickness in non-obese patients with type 2 diabetes. AB - AIM: We assessed the correlation between plasma adiponectin levels and carotid intima media thickness (IMT), as a marker of atherosclerosis, in non-obese patients with type 2 diabetes. METHODS: The study group included 112 (60 males and 52 females) non-obese Egyptian patients with type 2 diabetes. Fasting plasma adiponectin was measured using ELISA technique. Carotid IMT was assessed using high-resolution color- coded Doppler ultrasonography. Forty age, sex and weight matched normal Egyptian subjects were included in the study as a control group. RESULTS: A non-significant inverse correlation was found between plasma adiponectin levels and carotid IMT in the study group (p=0.054). Multiple regression analysis revealed that plasma adiponectin was not a determinant of carotid IMT in the study group (p=0.061). CONCLUSION: The inverse relation between plasma adiponectin and carotid IMT in type 2 diabetes could be explained, at least partially, by obesity. PMID- 26058553 TI - Reversal of neuromuscular block in companion animals. AB - OBJECTIVE: To review the evidence regarding the reversal of neuromuscular block (NMB) in companion animals with emphasis on the development and use of newer agents. DATABASE USED: Data sources include scientific reviews and original research publications in both human and veterinary literature using Pubmed and Scopus as search data bases. Unpublished and locally published data on reversal of NMB are presented. CONCLUSIONS: Residual NMB has been shown to increase morbidity and mortality in humans and needs to be avoided. It can be detected only by adequate neuromuscular monitoring. The proper use of reversal agents avoids residual NMB and recurarization should not occur. Anticholinesterase inhibitors, such as edrophonium and neostigmine have been used to reverse NMB when the need for this has been established. Reversal is influenced by several factors and a number of undesirable side- effects of these drugs have been reported. Sugammadex, a gamma-cyclodextrin, which was designed specifically to encapsulate rocuronium, is more rapid in its actions, has fewer side effects and can reverse profound NMB induced by aminosteroidal muscle relaxants. PMID- 26058554 TI - Fundamental and molecular composition characteristics of biochars produced from sugarcane and rice crop residues and by-products. AB - Biochar conversion of sugarcane and rice harvest residues provides an alternative for managing these crop residues that are traditionally burned in open field. Sugarcane leaves, bagasse, rice straw and husk were converted to biochar at four pyrolysis temperatures (PTs) of 450 degrees C, 550 degrees C, 650 degrees C, and 750 degrees C and evaluated for various elemental, molecular and surface properties. The carbon content of biochars was highest for those produced at 650 750 degrees C. Biochars produced at 550 degrees C showed the characteristics of biochar that are commonly interpreted as being stable in soil, with low H/C and O/C ratios and pyrolysis fingerprints dominated by aromatic and polyaromatic hydrocarbons. At 550 degrees C, all biochars also exhibited maximum CEC values with sugarcane leaves biochar (SLB) > sugarcane bagasse biochar (SBB) > rice straw biochar (RSB) > rice husk biochar (RHB). The pore size distribution of biochars was dominated by pores of 20 nm and high PT increased both smaller and larger than 50 nm pores. Water holding capacity of biochars increased with PT but the magnitude of the increase was limited by feedstock types, likely related to the hydrophobicity of biochars as evident by molecular composition, besides pore volume properties of biochars. Py-GC/MS analysis revealed a clear destruction of lignin with decarboxylation and demethoxylation at 450 degrees C and dehydroxylation at above 550 degrees C. Overall, biochar molecular compositions became similar as PT increased, and the biochars produced at 550 degrees C demonstrated characteristics that have potential benefit as soil amendment for improving both C sequestration and nutrient dynamics. PMID- 26058555 TI - Development of a rotary disc voltammetric sensor system for semi-continuous and on-site measurements of Pb(II). AB - Atomic absorption spectrometry and inductively coupled plasma-mass spectrometry are widely used for determination of heavy metals due to their low detection limits. However, they are not applicable to on-site measurements of heavy metals as bulky equipment, and highly skilled laboratory staffs are needed as well. In this study, a novel analytical method using a rotary disc voltammetric (RDV) sensor has been successfully designed, fabricated and characterized for semi continuous and on-site measurements of trace levels of Pb(II) in non deoxygenating solutions. The square wave anodic stripping voltammetry was used to improve the sensitivity of the Pb(II) detection level with less than 10nM (2MUgL( 1)). The RDV sensor has 24-sensing holes to measure concentrations of Pb(II) semi continuously at sampling sites. Each sensing hole consists of a silver working electrode, an integrated silver counter, and a quasi-reference electrode, which requires only a small amount of samples (<30MUL) for measurement of Pb(II) without disturbing and/or clogging the sensing environment. In addition, the RDV sensor showed a correlation coefficient of 0.998 for the Pb(II) concentration range of 10nM-10MUM at the deposition time of 180s and its low detection limit was 6.19nM (1.3MUgL(-1)). These results indicated that the advanced monitoring technique using a RDV sensor might provide environmental engineers with a reliable way for semi-continuous and on-site measurements of Pb(II). PMID- 26058556 TI - Temporal MRI characterization, neurobiochemical and neurobehavioral changes in a mouse repetitive concussive head injury model. AB - Single and repeated sports-related mild traumatic brain injury (mTBI), also referred to as concussion, can result in chronic post-concussive syndrome (PCS), neuropsychological and cognitive deficits, or chronic traumatic encephalopathy (CTE). However PCS is often difficult to diagnose using routine clinical, neuroimaging or laboratory evaluations, while CTE currently only can be definitively diagnosed postmortem. We sought to develop an animal model to simulate human repetitive concussive head injury for systematic study. In this study, mice received single or multiple head impacts by a stereotaxic impact device with a custom-made rubber tip-fitted impactor. Dynamic changes in MRI, neurobiochemical markers (Tau hyperphosphorylation and glia activation in brain tissues) and neurobehavioral functions such as anxiety, depression, motor function and cognitive function at various acute/subacute (1-7 day post-injury) and chronic (14-60 days post-injury) time points were examined. To explore the potential biomarkers of rCHI, serum levels of total Tau (T-Tau) and phosphorylated Tau (P-Tau) were also monitored at various time points. Our results show temporal dynamics of MRI consistent with structural perturbation in the acute phase and neurobiochemical changes (P-Tau and GFAP induction) in the subacute and chronic phase as well as development of chronic neurobehavioral changes, which resemble those observed in mTBI patients. PMID- 26058557 TI - Understanding older women's decision making and coping in the context of breast cancer treatment. AB - BACKGROUND: Primary endocrine therapy (PET) is a recognised alternative to surgery followed by endocrine therapy for a subset of older, frailer women with breast cancer. Choice of treatment is preference-sensitive and may require decision support. Older patients are often conceptualised as passive decision makers. The present study used the Coping in Deliberation (CODE) framework to gain insight into decision making and coping processes in a group of older women who have faced breast cancer treatment decisions, and to inform the development of a decision support intervention (DSI). METHODS: Semi-structured interviews were carried out with older women who had been offered a choice of PET or surgery from five UK hospital clinics. Women's information and support needs, their breast cancer diagnosis and treatment decisions were explored. A secondary analysis of these interviews was conducted using the CODE framework to examine women's appraisals of health threat and coping throughout the deliberation process. RESULTS: Interviews with 35 women aged 75-98 years were analysed. Appraisals of breast cancer and treatment options were sometimes only partial, with most women forming a preference for treatment relatively quickly. However, a number of considerations which women made throughout the deliberation process were identified, including: past experiences of cancer and its treatment; scope for choice; risks, benefits and consequences of treatment; instincts about treatment choice; and healthcare professionals' recommendations. Women also described various strategies to cope with breast cancer and their treatment decisions. These included seeking information, obtaining practical and emotional support from healthcare professionals, friends and relatives, and relying on personal faith. Based on these findings, key questions were identified that women may ask during deliberation. CONCLUSIONS: Many older women with breast cancer may be considered involved rather than passive decision-makers, and may benefit from DSIs designed to support decision making and coping within and beyond the clinic setting. PMID- 26058558 TI - The c-Jun N-terminal kinase inhibitor SP600125 inhibits human cytomegalovirus replication. AB - Human cytomegalovirus (HCMV) is an opportunistic pathogen that causes severe diseases in congenitally infected newborns and immunocompromised patients. Currently, no vaccine is available to prevent HCMV infection. Anti-viral drugs are limited by their side effects and drug resistance. In this study, by performing a medium-sized, anti-HCMV chemical screening, we identified SP600125, CC-401, and the c-Jun N-terminal kinase (JNK) inhibitor VIII, three structurally different small molecule JNK inhibitors that effectively inhibited HCMV replication in cultured human fibroblasts (HFs). SP600125 showed its potential by inhibiting the viral replication of a HCMV laboratory strain in HFs and a HCMV clinical strain in human retinal pigment epithelial cells. Knockdown of JNK expression by RNA interference significantly impaired HCMV replication, mimicking the effect of the chemical inhibitors on virus infection. Mechanistically, SP600125 affects a very early step of the viral life cycle. Viral binding, entry, and the delivery of viral DNA into the cells were not inhibited by the compound. Instead, it suppressed the transcription of the immediate-early viral genes IE1/2 and the accumulation of their gene products. IE1/2 are among the first genes expressed after viral entry, and they are the master regulators of late phase viral gene expression. Consistent with this notion, the expression of other viral genes was also reduced after SP600125 treatment. We propose that JNK inhibitors have the potential to become a new class of anti-HCMV drug candidates, and JNK is a feasible target for the development of anti-HCMV drugs. PMID- 26058559 TI - Intrahepatic biliary mucinous cystic neoplasms: clinicoradiological characteristics and surgical results. AB - BACKGROUND: Intrahepatic biliary mucinous cystic neoplasms are rare hepatic tumors and account for less than 5% of intrahepatic cystic lesions. Accurate preoperative diagnosis is difficult and the outcome differs among various treatment modalities.The aim of this study is to investigate the clinico radiological characteristics of intrahepatic biliary mucinous cystic neoplasms and to establish eligible diagnostic and treatment suggestions. METHODS: Nineteen patients with intrahepatic biliary cystadenomas and two patients with biliary cystadenocarcinomas were retrospectively reviewed. Their clinico-radiological variables and survival outcome were analyzed. RESULTS: Of the 19 patients with biliary cystadenoma, 16 (84.2 %) were female. 11 (57.9 %) patients had symptoms before operation with the most common presenting symptom being abdominal pain. Among the patients with available data, serum and cystic fluid CA 19-9 levels were invariably elevated and the CA 19-9 level in the cystic fluid was significantly higher than that in the serum. Loculations (84.2 %) and septations (63.2 %) were the most common radiologic findings. For treatment, 11 (57.9 %) patients received radical resection by either enucleation or hepatic resection, while the remaining 8 (42.1 %) patients underwent only fenestration of liver cysts. Radical resection provided a significantly better clinical outcome than fenestration in terms of tumor recurrence (p = 0.018). The only two male patients with biliary cystadenocarcinoma received radical hepatic resection and achieved a disease-free survival of 16.5 months and 33 months, respectively. CONCLUSION: Intrahepatic biliary mucinous cystic neoplasms are rare and preoperative diagnosis is difficult. Internal septations and loculations on radiologic examinations should raise some suspicion of this diagnosis. Complete tumor excision is the standard treatment that may provide patients with better long term results after the operation. PMID- 26058560 TI - Gadolinium-Catalyzed Regio- and Enantioselective Aminolysis of Aromatic trans-2,3 Epoxy Sulfonamides. AB - The first enantioselective aminolysis of aromatic trans-2,3-epoxy sulfonamides has been accomplished, which was efficiently catalyzed by a Gd-N,N'-dioxide complex. Under the directing effect of the sulfonamide moiety the ring-opening reaction proceeded selectively at the C-3 position in a highly enantioselective manner furnishing various Ts- and SES-protected 3-amino-3-phenylpropan-2-olamines as products. PMID- 26058561 TI - Pathophysiology of juvenile idiopathic arthritis induced pes planovalgus in static and walking condition: a functional view using 3D gait analysis. AB - BACKGROUND: Patients suffering from juvenile idiopathic arthritis (JIA) frequently have affected ankle joints, which can lead to foot deformities such as pes planovalgus (JIA-PPV). Usually, JIA-PPV is diagnosed by examining the foot in non-weightbearing or in weightbearing, static condition. However, functional limitations typically appear during dynamic use in daily activities such as walking. The aim of this study was to quantify the pathophysiology of JIA-PPV in both static and dynamic condition, i.e. in upright standing and during the stance phase of walking using three-dimensional (3d) gait analysis. METHODS: Eleven JIA patients (age = 12y) with at least one affected ankle joint and fixed pes planovalgus (>=5 degrees ) were compared to healthy controls (CG) (n = 14, age = 11y). Kinematic and kinetic data were obtained in barefoot standing and walking condition (1.1-1.3 m/s) with an 8-camera 3d motion analysis system including two force-plates and one pressure distribution plate. All participants were prepared using reflecting markers according to the Oxford Foot and Plug-in-Gait Model. Results were compared using the Mann-Whitney-U-test and Wilcoxon signed-rank test (p < 0.05). RESULTS: In comparison to CG, JIA-PPV had an excessive hindfoot/tibia eversion (p < 0.001) and a forefoot/hindfoot supination (p < 0.001) in both static and walking condition. JIA-PPV showed a greater hindfoot/tibia eversion during walking (midstance) compared to standing (p = 0.021) in contrast to CG. The arch index, measured by plantar pressure distribution, indicates a reduced arch height in JIA-PPV (p = 0.007). Patients had a lower maximum dorsiflexion of hindfoot/tibia (p = 0.001) and a lower plantarflexion of forefoot/hindfoot (p = 0.028), both when standing and walking. The kinetic results showed lower maximum ankle dorsiflexion moments (p < 0.037) as well as generated ankle power (p = 0.086) in JIA-PPV. CONCLUSIONS: The pathophysiology of JIA-PPV during walking indicated that excessive hindfoot eversion produces accessory symptoms such as a reduced arch height, increased forefoot supination and reduced propulsion effect of the ankle. Muscular and coordinative insufficiency caused by arthritis can lead to the observed increased hindfoot eversion from static to dynamic condition. Conventional static or passive foot examination techniques probably underestimate deformity in JIA pes planovalgus. 3d gait analysis might be helpful in early diagnosis of this condition, especially in JIA patients with affected ankle joints. PMID- 26058562 TI - Intelligent MnO2 Nanosheets Anchored with Upconversion Nanoprobes for Concurrent pH-/H2O2-Responsive UCL Imaging and Oxygen-Elevated Synergetic Therapy. PMID- 26058563 TI - Dosimetric benefit to organs at risk following margin reductions in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy. AB - INTRODUCTION: It is important to decrease the radiation exposure of normal tissue in intensity-modulated radiation therapy (IMRT). Minimizing planning target volume (PTV) margins with more precise target localization techniques can achieve this goal. This study aimed to quantify the extent to which organs at risk (OARs) are spared when using reduced margins in the treatment of nasopharyngeal carcinoma (NPC). METHODS: Two IMRT plans were regenerated for 40 patients with NPC based on two PTV margins, which were reduced or unchanged following cone beam computed tomography online correction. The reduced-margin plan was optimized based on maximal dose reduction to OARs without compromising target coverage. Dosimetric comparisons were evaluated in terms of target coverage and OAR sparing. RESULTS: Improvements in target coverage occurred with margin reduction, and significant improvements in dosimetric parameters were observed for all OARs (P < 0.05) except for the right optic nerve, chiasm, and lens. Doses to OARs decreased at a rate of 1.5% to 7.7%. Sparing of the left parotid and right parotid, where the mean dose (Dmean) decreased at a rate of 7.1% and 7.7%, respectively, was greater than the sparing of other OARs. CONCLUSIONS: Significant improvements in OAR sparing were observed with margin reduction, in addition to improvement in target coverage. The parotids benefited most from the online imaging-guided approach. PMID- 26058564 TI - Disparities in survival by insurance status in patients with Hodgkin lymphoma. AB - BACKGROUND: The association between insurance status and outcomes has not been well established for patients with Hodgkin lymphoma (HL). The purpose of this study was to examine the disparities in overall survival (OS) by insurance status in a large cohort of patients with HL. METHODS: The National Cancer Data Base (NCDB) was used to evaluate patients with stage I to IV HL from 1998 to 2011. The association between insurance status, covariables, and outcomes was assessed in a multivariate Cox proportional hazards model. Survival was estimated with the Kaplan-Meier method. RESULTS: Among the 76,681 patients within the NCDB, 45,777 patients with stage I to IV HL were eligible for this study (median follow-up, 6.0 years). The median age was 39 years (range, 18-90 years). The insurance status was as follows: 3247 (7.1%) were uninsured, 7962 (17.4%) had Medicaid, 30,334 (66.3%) had private insurance, 3746 (8.2%) had managed care, and 488 (1.1%) had Medicare. Patients with an unfavorable insurance status (Medicaid/uninsured) were at a more advanced stage, had higher comorbidity scores, had B symptoms, and were in a lower income/education quartile (all P < .01). These patients were less likely to receive radiotherapy and start chemotherapy promptly and were less commonly treated at academic/research centers (all P < .01). Patients with unfavorable insurance had a 5-year OS of 54% versus 87% for those favorably insured (P < .01). When adjustments were made for covariates, an unfavorable insurance status was associated with significantly decreased OS (hazard ratio, 1.60; 95% confidence interval, 1.34-1.91; P < .01). The unfavorable insurance status rate increased from 22.8% to 28.8% between 1998 and 2011. CONCLUSIONS: This study reveals that HL patients with Medicaid and uninsured patients have outcomes inferior to those of patients with more favorable insurance. Targeting this subset of patients with limited access to care may help to improve outcomes. Cancer 2015;121:3435-43. (c) 2015 American Cancer Society. PMID- 26058565 TI - Synthesis, drug release, and biological evaluation of new anticancer drug bioconjugates containing somatostatin backbone cyclic analog as a targeting moiety. AB - Peptide conjugates containing somatostatin (SST) cyclic analogs as a targeting moiety are able to deliver chemotherapeutic agents specifically to cancer cells expressing SST receptors (SSTRs), and hence increasing their local efficacy while limiting the peripheral toxicity. Here, we report on the synthesis and biochemical characterization of new SSTR-specific anticancer peptide conjugates, with different anticancer payloads acting through different oncogenic mechanisms to evaluate their biological activities and to provide a comparative study of their drug release profiles. The SSTR2-specific backbone cyclic peptide 3207-86 was chosen for the synthesis of a variety of novel anticancer drug conjugates with a broad drug release capabilities. The N-terminus of 3207-86 was equipped with GABA to generate free amino group available for the conjugation of chlorambucil, Camptothecin (CPT), Combretastatin 4A, ABT-751, and Amonafide through the formation of various biodegradable bonds. The chemo- and biostability/drug release of all the synthetic compounds was investigated at various pHs and in the presence of mouse liver homogenate, respectively. Their selective cytotoxic effect was evaluated on several human cancer cell lines that overexpress SSTR2. Compared with the free drugs, our peptide-drug conjugates exhibited considerable cytotoxic effect on cancer cell lines versus low SSTR2 expressed human embryonic kidney cells. Functional versatility of the conjugates was reflected in the variability of their drug release profiles, whereas the conserved sequence of a selective binding to the SSTR2 likely preserved their binding to the receptor and consequently their favorable toxicity toward targeted cancer cells. PMID- 26058566 TI - Different Effects of p52SHC1 and p52SHC3 on the Cell Cycle of Neurons and Neural Stem Cells. AB - SHC3 is exclusively expressed in postmitotic neurons, while SHC1 is found in neural stem cells and neural precursor cells but absent in mature neurons. In this study, we discovered that suppression of p52SHC1 expression by RNA interference resulted in proliferation defects in neural stem cells, along with significantly reduced protein levels of cyclin E and cyclin A. At the same time, p52SHC3 RNAi caused cell cycle re-entry (9.54% in S phase and 5.70% in G2-M phase) in primary neurons with significantly up-regulated expression of cyclin D1, cyclin E, cyclin A, CDK2, and phosphorylated CDK2. When p52SHC3 was overexpressed, the cell cycle of neural stem cells was arrested with reduced protein levels of cyclin D1, cyclin E, and cyclin A, while overexpression of p52SHC1 did not result in significant changes in postmitotic neurons. Our results indicate that p52SHC3 plays an important role in maintaining the mitotic quiescence of neurons, while p52SHC1 regulates the proliferation of neural stem cells. PMID- 26058567 TI - Phenylpyropenes E and F: new meroterpenes from the marine-derived fungus Penicillium concentricum ZLQ-69. AB - Two new meroterpenes, phenylpyropenes E (1) and F (2), together with seven known phenylpyropenes (3-5) and pyripyropenes (6-9) were isolated from the marine derived fungus Penicillium concentricum ZLQ-69. Their structures including the absolute configurations were elucidated using a combination of spectroscopic methods and electronic circular dichroism calculation. Bioactivity evaluation showed that compounds 1 and 4 were cytotoxic to the MGC-803 cell line with IC50 values of 19.1 and 13.6 MUM, respectively. PMID- 26058568 TI - A new sarkomycin analog from Streptomyces sp. HS-HY-144. PMID- 26058569 TI - New ansamycin analogues from the mutant strain of Streptomyces seoulensis. PMID- 26058570 TI - Impact of fibrosis progression on clinical outcome in patients treated for post transplant hepatitis C recurrence. AB - BACKGROUND & AIMS: Patients who achieve sustained virological response (SVR) following the treatment of post-liver transplant (LT) recurrence of hepatitis C virus (HCV) infection have improved outcomes. The full impact of eradication of HCV on allograft histology is, however, not clearly known. METHODS: We studied allograft histology in protocol-based paired liver biopsies in consecutive LT recipients who underwent post-LT treatment of recurrence of HCV. RESULTS: A total of 116 patients were treated with interferon-based therapy for recurrent HCV. Paired pre-treatment baseline biopsies and post-treatment biopsies were available in 83.2% of patients. SVR was achieved in 37.9% of patients. Among the patients who achieved SVR, 20.5% had progression of fibrosis on post-treatment biopsies vs. 65.5% of patients with non-response/relapse (P < 0.001). The impact of virological response on fibrosis progression was sustained and a similar outcome was observed in the subset of patients who had 4-5 year post-treatment biopsies available. In the SVR group, 12.8% progressed to fibrosis stage >=3 on post treatment biopsies vs. 37.9% in the non-response/relapse group (P = 0.001). The 5 year survival in patients with progression of fibrosis 86% vs. 98% among patients who had improvement/stable fibrosis [P = 0.003; HR 3.8 (1.2-11.8)]. A small subset of patients who achieve SVR unfortunately still experience progression of fibrosis, most commonly associated with plasma cell hepatitis. CONCLUSIONS: In post-transplant patients treated for HCV, SVR is associated with improved graft survival and also with sustained and significant improvement in histological outcome. Importantly, progression of fibrosis still occurred in a small subset of patients who achieved SVR. PMID- 26058571 TI - Internal phosphorus load in a Mexican reservoir: forecast and validation. AB - To determine the internal phosphorus load (IPL) as a function of redox potential (Eh) in a Mexican reservoir, the results from a phosphorus (P) release experiment were extrapolated to temporal and spatial variations of Eh in sediments, and an IPL-Eh of 24.2 +/- 2.5 t/yr was obtained. This result is compared with the P mass balance (MB) in the reservoir, where the IPL-MB is determined as the difference between P inputs to the reservoir and the outputs. Inputs of P are the sum of the external P load from the hydrological basin, the IPL, and P in atmospheric precipitation; outputs of P are the sum of sedimented P, and the removal of P in water and biomass, and the resulting IPL-MB, is 26.4 +/- 4.9 t/yr. In addition, P concentrations in sediment cores (SCs) are analyzed, and the historical release of P from sediments determined, resulting in an IPL-SC of 23.5 +/- 1.4 t/yr. The different IPL results are similar, as average values are within the standard deviation of IPL-MB. It is concluded that analysis of the variations in Eh in sediments allows determination of the reservoir's IPL. Six-weekly IPL-Eh and IPL MB values are analyzed, and it can be seen that IPL occurs mainly during the period from May to August, when the water column is thermally stratified. PMID- 26058572 TI - Changes in intrinsic connectivity of the brain's reading network following intervention in children with autism. AB - While task-based neuroimaging studies have identified alterations in neural circuitry underlying language processing in children with autism spectrum disorders [ASD], resting state functional magnetic resonance imaging [rsfMRI] is a promising alternative to the constraints posed by task-based fMRI. This study used rsfMRI, in a longitudinal design, to study the impact of a reading intervention on connectivity of the brain regions involved in reading comprehension in children with ASD. Functional connectivity was examined using group independent component analysis (GICA) and seed-based correlation analysis of Broca's and Wernicke's areas, in three groups of participants: an experimental group of ASD children (ASD-EXP), a wait list control group of ASD children (ASD WLC), and a group of typically developing (TD) control children. Both GICA and seed-based analyses revealed stronger functional connectivity of Broca's and Wernicke's areas in the ASD-EXP group postintervention. Additionally, improvement in reading comprehension in the ASD-EXP group was correlated with greater connectivity in both Broca's and Wernicke's area in the GICA identified reading network component. In addition, increased connectivity between the Broca's area and right postcentral and right STG, and the Wernicke's area and LIFG, were also correlated with greater improvement in reading comprehension. Overall, this study revealed widespread changes in functional connectivity of the brain's reading network as a result of intervention in children with ASD. These novel findings provide valuable insights into the neuroplasticity of brain areas underlying reading and the impact of intensive intervention in modifying them in children with ASD. PMID- 26058573 TI - Parental Separation and Offspring Alcohol Involvement: Findings from Offspring of Alcoholic and Drug Dependent Twin Fathers. AB - BACKGROUND: We examined associations between parental separation during childhood and offspring alcohol involvement, adjusting for genetic and environmental risks specific to parental alcohol (AD) and cannabis/other illicit drug dependence (DD). METHODS: The sample consisted of 1,828 offspring of male twins from the Vietnam Era Twin (VET) Registry, who completed a telephone diagnostic interview. Cox proportional hazards regression analyses were conducted predicting onset of first use, transition from first use to first AD symptom, and transition from first use to AD diagnosis from paternal and avuncular AD and DD history, parental separation, and offspring and family background characteristics. Paternal/avuncular DD/AD was based on the DSM-III-R; offspring and maternal AD were based on DSM-IV criteria. RESULTS: Paternal DD/AD predicted increased offspring risk for all transitions, with genetic effects suggested on rate of transitioning to AD diagnosis. Parental separation was predictive of increased risk for early alcohol use, but a reduced rate of transition to both AD symptom onset and onset of AD. No interactions between separation and familial risk (indexed by paternal or avuncular DD/AD) were found. CONCLUSIONS: Findings highlight the contribution of both parental separation and paternal substance dependence in predicting timing of offspring alcohol initiation and problems across adolescence into early adulthood. PMID- 26058576 TI - Patient explanations for non-attendance at type 2 diabetes self-management education: a qualitative study. AB - AIM: To explore reasons for non-attendance at type 2 diabetes self-management education. METHODS: To elicit the main themes explaining non-attendance, 15 semi structured interviews were conducted with persons referred to, but not attending, self-management education. Systematic text condensation was applied to code and generate themes subsequently organised under individual and organisational factors. RESULTS: Individual (illness, lack of perceived benefit) and organisational factors relating to schedule (four whole days, time of day, notification) and content (supermarket visit) were cited as reasons for non attendance. CONCLUSIONS: In this study, patients cited both individual and organisational factors as explaining non-attendance at type 2 diabetes self management education. Further studies should take into account the importance of timing and of tailoring schedules and content to individuals' life situations and resources. As organisational factors are likely to vary across programmes and settings, more case studies are needed to further elucidate the dynamic relationship between individual and organisational factors to explain non attendance at type 2 diabetes self-management education. PMID- 26058574 TI - Comparative genomics and mutagenesis analyses of choline metabolism in the marine Roseobacter clade. AB - Choline is ubiquitous in marine eukaryotes and appears to be widely distributed in surface marine waters; however, its metabolism by marine bacteria is poorly understood. Here, using comparative genomics and molecular genetic approaches, we reveal that the capacity for choline catabolism is widespread in marine heterotrophs of the marine Roseobacter clade (MRC). Using the model bacterium Ruegeria pomeroyi, we confirm that the betA, betB and betC genes, encoding choline dehydrogenase, betaine aldehyde dehydrogenase and choline sulfatase, respectively, are involved in choline metabolism. The betT gene, encoding an organic solute transporter, was essential for the rapid uptake of choline but not glycine betaine (GBT). Growth of choline and GBT as a sole carbon source resulted in the re-mineralization of these nitrogen-rich compounds into ammonium. Oxidation of the methyl groups from choline requires formyltetrahydrofolate synthetase encoded by fhs in R. pomeroyi, deletion of which resulted in incomplete degradation of GBT. We demonstrate that this was due to an imbalance in the supply of reducing equivalents required for choline catabolism, which can be alleviated by the addition of formate. Together, our results demonstrate that choline metabolism is ubiquitous in the MRC and reveal the role of Fhs in methyl group oxidation in R. pomeroyi. PMID- 26058575 TI - Dynamic oxygen challenge evaluated by NMR T1 and T2*--insights into tumor oxygenation. AB - There is intense interest in developing non-invasive prognostic biomarkers of tumor response to therapy, particularly with regard to hypoxia. It has been suggested that oxygen sensitive MRI, notably blood oxygen level-dependent (BOLD) and tissue oxygen level-dependent (TOLD) contrast, may provide relevant measurements. This study examined the feasibility of interleaved T2*- and T1 weighted oxygen sensitive MRI, as well as R2* and R1 maps, of rat tumors to assess the relative sensitivity to changes in oxygenation. Investigations used cohorts of Dunning prostate R3327-AT1 and R3327-HI tumors, which are reported to exhibit distinct size-dependent levels of hypoxia and response to hyperoxic gas breathing. Proton MRI R1 and R2* maps were obtained for tumors of anesthetized rats (isoflurane/air) at 4.7 T. Then, interleaved gradient echo T2*- and T1 weighted images were acquired during air breathing and a 10 min challenge with carbogen (95% O2 -5% CO2). Signals were stable during air breathing, and each type of tumor showed a distinct signal response to carbogen. T2* (BOLD) response preceded T1 (TOLD) responses, as expected. Smaller HI tumors (reported to be well oxygenated) showed the largest BOLD and TOLD responses. Larger AT1 tumors (reported to be hypoxic and resist modulation by gas breathing) showed the smallest response. There was a strong correlation between BOLD and TOLD signal responses, but DeltaR2* and DeltaR1 were only correlated for the HI tumors. The magnitude of BOLD and TOLD signal responses to carbogen breathing reflected expected hypoxic fractions and oxygen dynamics, suggesting potential value of this test as a prognostic biomarker of tumor hypoxia. PMID- 26058577 TI - CRISPR/Cas9-mediated genome engineering of CHO cell factories: Application and perspectives. AB - Chinese hamster ovary (CHO) cells are the most widely used production host for therapeutic proteins. With the recent emergence of CHO genome sequences, CHO cell line engineering has taken on a new aspect through targeted genome editing. The bacterial clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) system enables rapid, easy and efficient engineering of mammalian genomes. It has a wide range of applications from modification of individual genes to genome-wide screening or regulation of genes. Facile genome editing using CRISPR/Cas9 empowers researchers in the CHO community to elucidate the mechanistic basis behind high level production of proteins and product quality attributes of interest. In this review, we describe the basis of CRISPR/Cas9-mediated genome editing and its application for development of next generation CHO cell factories while highlighting both future perspectives and challenges. As one of the main drivers for the CHO systems biology era, genome engineering with CRISPR/Cas9 will pave the way for rational design of CHO cell factories. PMID- 26058578 TI - Intraskeletal Variability of Relative Cortical Area in Humans. AB - Histomorphometric and cross-sectional geometric studies of bone have provided valuable information about age at death, behavioral and activity patterns, and pathological conditions for past and present human populations. While a considerable amount of exploratory and applied research has been completed using histomorphometric and cross-sectional geometric properties, the effects of intraskeletal variability on interpreting observed histomorphometric data have not been fully explored. The purpose of this study is to quantify intraskeletal variability in the relative cortical area of long bones and ribs from modern humans. To examine intraskeletal variability, cross-sections of the femur, tibia, fibula, humerus, radius, ulna, and rib when present, were examined within individuals from a cadaveric collection (N = 34). Relative cortical area was compared within individuals using a repeated measurements General Linear Model, which shows significant differences between bones, particularly between the rib and the remaining long bones. Complementarily, correlations between bones' relative cortical area values suggest an important allometric component affecting this aspect of long bones, but not of the rib. This study highlights the magnitude of intraskeletal variability in relative cortical area in the human skeleton, and because the relative cortical area of any particular bone is affected by a series of confounding factors, extrapolation of relative cortical area values to infer load history for other skeletal elements can be misleading. PMID- 26058579 TI - Metaproteomic analysis using the Galaxy framework. AB - Metaproteomics characterizes proteins expressed by microorganism communities (microbiome) present in environmental samples or a host organism (e.g. human), revealing insights into the molecular functions conferred by these communities. Compared to conventional proteomics, metaproteomics presents unique data analysis challenges, including the use of large protein databases derived from hundreds or thousands of organisms, as well as numerous processing steps to ensure high data quality. These challenges limit the use of metaproteomics for many researchers. In response, we have developed an accessible and flexible metaproteomics workflow within the Galaxy bioinformatics framework. Via analysis of human oral tissue exudate samples, we have established a modular Galaxy-based workflow that automates a reduction method for searching large sequence databases, enabling comprehensive identification of host proteins (human) as well as "meta-proteins" from the nonhost organisms. Downstream, automated processing steps enable basic local alignment search tool analysis and evaluation/visualization of peptide sequence match quality, maximizing confidence in results. Outputted results are compatible with tools for taxonomic and functional characterization (e.g. Unipept, MEGAN5). Galaxy also allows for the sharing of complete workflows with others, promoting reproducibility and also providing a template for further modification and enhancement. Our results provide a blueprint for establishing Galaxy as a solution for metaproteomic data analysis. All MS data have been deposited in the ProteomeXchange with identifier PXD001655 (http://proteomecentral.proteomexchange.org/dataset/PXD001655). PMID- 26058580 TI - Allele frequency of somatic mutations in individuals reveals signatures of cancer related genes. PMID- 26058581 TI - Application of intra-molecular fluorescence complementation in the topology examination of polytopic proteins in living cells. PMID- 26058582 TI - Involvement of cannabinoid receptors in infrasonic noise-induced neuronal impairment. AB - Excessive exposure to infrasound, a kind of low-frequency but high-intensity sound noise generated by heavy transportations and machineries, can cause vibroacoustic disease which is a progressive and systemic disease, and finally results in the dysfunction of central nervous system. Our previous studies have demonstrated that glial cell-mediated inflammation may contribute to infrasound induced neuronal impairment, but the underlying mechanisms are not fully understood. Here, we show that cannabinoid (CB) receptors may be involved in infrasound-induced neuronal injury. After exposure to infrasound at 16 Hz and 130 dB for 1-14 days, the expression of CB receptors in rat hippocampi was gradually but significantly decreased. Their expression levels reached the minimum after 7- to 14-day exposure during which the maximum number of apoptotic cells was observed in the CA1. 2-Arachidonoylglycerol (2-AG), an endogenous agonist for CB receptors, reduced the number of infrasound-triggered apoptotic cells, which, however, could be further increased by CB receptor antagonist AM251. In animal behavior performance test, 2-AG ameliorated the infrasound-impaired learning and memory abilities of rats, whereas AM251 aggravated the infrasound-impaired learning and memory abilities of rats. Furthermore, the levels of proinflammatory cytokines tumor necrosis factor alpha and interleukin-1beta in the CA1 were upregulated after infrasound exposure, which were attenuated by 2-AG but further increased by AM251. Thus, our results provide the first evidence that CB receptors may be involved in infrasound-induced neuronal impairment possibly by affecting the release of proinflammatory cytokines. PMID- 26058583 TI - Characterization of the doublesex gene within the Culex pipiens complex suggests regulatory plasticity at the base of the mosquito sex determination cascade. AB - BACKGROUND: The doublesex gene controls somatic sexual differentiation of many metazoan species, including the malaria mosquito Anopheles gambiae and the dengue and yellow fever vector Aedes aegypti (Diptera: Culicidae). As in other studied dipteran dsx homologs, the gene maintains functionality via evolutionarily conserved protein domains and sex-specific alternative splicing. The upstream factors that regulate splicing of dsx and the manner in which they do so however remain variable even among closely related organisms. As the induction of sex ratio biases is a central mode of action in many emerging molecular insecticides, it is imperative to elucidate as much of the sex determination pathway as possible in the mosquito disease vectors. RESULTS: Here we report the full-length gene sequence of the doublesex gene in Culex quinquefasciatus (Cxqdsx) and its male and female-specific isoforms. Cxqdsx maintains characteristics possibly derived in the Culicinae and present in the Aedes aegypti dsx gene (Aeadsx) such as gain of exon 3b and the presence of Rbp1 cis-regulatory binding sites, and also retains presumably ancestral attributes present in Anopheles gambiae such as maintenance of a singular female-specific exon 5. Unlike in Aedes aegypti, we find no evidence for intron gain in the female transcript(s), yet recover a second female isoform generated via selection of an alternate splice donor. Utilizing next-gen sequence (NGS) data, we complete the Aeadsx gene model and identify a putative core promoter region in both Aeadsx and Cxqdsx. Also utilizing NGS data, we construct a full-length gene sequence for the dsx homolog of the northern house mosquito Culex pipiens form pipiens (Cxpipdsx). Analysis of peptide evolutionary rates between Cxqdsx and Cxpipdsx (both members of the Culex pipiens complex) shows the male-specific portion of the transcript to have evolved rapidly with respect to female-specific and common regions. CONCLUSIONS: As in other studied insects, doublesex maintains sex-specific splicing and conserved doublesex/mab-3 domains in the mosquitoes Culex quinquefasciatus and Cx. pipiens. The cis-regulated splicing of Cxqdsx does not appear to follow either currently described mosquito model (for An. gambiae and Ae. aegypti); each of the three mosquito genera exhibit evidence of unique cis-regulatory mechanisms. The male-specific dsx terminus exhibits rapid peptide evolutionary rates, even among closely related sibling species. PMID- 26058584 TI - First recovery of Rasamsonia argillacea species complex isolated in adolescent patient with cystic fibrosis in Slovenia--case report and review of literature. AB - We report the isolation of the emerging fungal pathogen Rasamsonia aegroticola, which belongs Rasamsonia argillacea species complex, from a respiratory sample of a patient with cystic fibrosis. This filamentous fungus, resembling members of a Penicillium and Paecilomyces spp., was identified by morphology and confirmed by DNA sequence analysis. Susceptibility pattern showed high minimal inhibitory concentration of voriconazole and amphotericin B but low minimal inhibitory concentration of caspofungin, micafungin and itraconazole. PMID- 26058586 TI - Survival in cats with primary and secondary cardiomyopathies. AB - OBJECTIVES: Feline cardiomyopathies (CMs) represent a heterogeneous group of myocardial diseases. The most common CM is hypertrophic cardiomyopathy (HCM), followed by restrictive cardiomyopathy (RCM). Studies comparing survival and outcome for different types of CM are scant. Furthermore, little is known about the cardiovascular consequences of systemic diseases on survival. The aim of this retrospective study was to compare survival and prognostic factors in cats affected by HCM, RCM or secondary CM referred to our institution over a 10 year period. METHODS: The study included 94 cats with complete case records and echocardiographic examination. Fifty cats presented HCM, 14 RCM and 30 secondary CM. RESULTS: A statistically significant difference in survival time was identified for cats with HCM (median survival time of 865 days), RCM (273 days) and secondary CM (<50% cardiac death rate). In the overall population and in the primary CM group (HCM + RCM), risk factors in the multivariate analysis, regardless of the CM considered, were the presence of clinical signs, an increased left atrial to aortic root (LA/Ao) ratio and a hypercoagulable state. CONCLUSIONS AND RELEVANCE: Primary CMs in cats share some common features (ie, LA dimension and hypercoagulable state) linked to feline cardiovascular physiology, which influence survival greatly in end-stage CM. The presence of clinical signs has to be regarded as a marker of disease severity, regardless of the underlying CM. Secondary CMs are more benign conditions, but if the primary disease is not properly managed, the prognosis might also be poor in this group of patients. PMID- 26058585 TI - Use of low-dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease: study protocol for a randomised controlled trial. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with high morbidity, mortality, and health-care costs. An incomplete response to the anti inflammatory effects of inhaled corticosteroids is present in COPD. Preclinical work indicates that 'low dose' theophylline improves steroid responsiveness. The Theophylline With Inhaled Corticosteroids (TWICS) trial investigates whether the addition of 'low dose' theophylline to inhaled corticosteroids has clinical and cost-effective benefits in COPD. METHOD/DESIGN: TWICS is a randomised double blind placebo-controlled trial conducted in primary and secondary care sites in the UK. The inclusion criteria are the following: an established predominant respiratory diagnosis of COPD (post-bronchodilator forced expiratory volume in first second/forced vital capacity [FEV1/FVC] of less than 0.7), age of at least 40 years, smoking history of at least 10 pack-years, current inhaled corticosteroid use, and history of at least two exacerbations requiring treatment with antibiotics or oral corticosteroids in the previous year. A computerised randomisation system will stratify 1424 participants by region and recruitment setting (primary and secondary) and then randomly assign with equal probability to intervention or control arms. Participants will receive either 'low dose' theophylline (Uniphyllin MR 200 mg tablets) or placebo for 52 weeks. Dosing is based on pharmacokinetic modelling to achieve a steady-state serum theophylline of 1-5 mg/l. A dose of theophylline MR 200 mg once daily (or placebo once daily) will be taken by participants who do not smoke or participants who smoke but have an ideal body weight (IBW) of not more than 60 kg. A dose of theophylline MR 200 mg twice daily (or placebo twice daily) will be taken by participants who smoke and have an IBW of more than 60 kg. Participants will be reviewed at recruitment and after 6 and 12 months. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids or antibiotics during the 52-week treatment period. DISCUSSION: The demonstration that 'low dose' theophylline increases the efficacy of inhaled corticosteroids in COPD by reducing the incidence of exacerbations is relevant not only to patients and clinicians but also to health-care providers, both in the UK and globally. TRIAL REGISTRATION: Current Controlled Trials ISRCTN27066620 was registered on Sept. 19, 2013, and the first subject was randomly assigned on Feb. 6, 2014. PMID- 26058587 TI - Clinical safety of robenacoxib in feline osteoarthritis: results of a randomized, blinded, placebo-controlled clinical trial. AB - OBJECTIVES: The objective of this study was to evaluate the clinical safety of the non-steroidal anti-inflammatory drug (NSAID) robenacoxib in cats with osteoarthritis. Degenerative joint disease, including osteoarthritis, is highly prevalent in cats and many cases have associated pain and impaired mobility. Although NSAIDs are used routinely to control pain and inflammation in cats with osteoarthritis, there are safety concerns because of the high concurrent prevalence of chronic kidney disease (CKD) and the paucity of data on the safety of these drugs in target clinical populations. METHODS: A total of 194 cats with osteoarthritis were recruited and randomly allocated to receive either robenacoxib at a dosage of 1.0-2.4 mg/kg (n = 95) or placebo (n = 99) tablets PO q24h for 28 days. Safety was assessed in 193 cats, including a subgroup of 40 animals with concurrent CKD, defined as serum creatinine concentration ?1.6 mg/dl and urine specific gravity <1.030. Safety endpoints included reports of adverse events, results of clinical examinations, including body weight, and clinical chemistry and hematology variables. RESULTS: In all 193 cats and the subgroup of 40 animals with concurrent CKD, there were no differences between groups in frequencies of reported adverse events, body weight change or results of serum or urine chemistry or hematology variables. CONCLUSIONS AND RELEVANCE: Robenacoxib was well tolerated when administered daily for 1 month in cats with osteoarthritis, including cats with evidence of concurrent CKD. There was no clinical indication of damage to the gastrointestinal tract, kidney or liver. PMID- 26058588 TI - Greater number of group identifications is associated with lower odds of being depressed: evidence from a Scottish community sample. AB - PURPOSE: Group identification has been shown to be associated with reduced risk of depression, but this research has important limitations. Our aim was to establish a robust link between group identification and depression whilst overcoming previous studies' shortcomings. METHODS: 1824 participants, recruited from General Practice throughout Scotland, completed a questionnaire measuring their identification with three groups (family, community, and a group of their choice), as well as their intensity of contact with each group. They also completed a self-rated depression measure and provided demographic information. Their medical records were also accessed to determine if they had been prescribed antidepressants in the previous 6 months. RESULTS: The number of group identifications was associated with both lower self-rated depression and lower odds of having received a prescription for antidepressants, even after controlling for the number of contact-intensive groups, level of education, gender, age, and relationship status. CONCLUSIONS: Identifying with multiple groups may help to protect individuals against depression. This highlights the potential importance of social prescriptions, where health professionals encourage a depressed patient to become a member of one or more groups with which the patient believes he/she would be likely to identify. PMID- 26058590 TI - Structure Activity Relationship Studies of Gymnemic Acid Analogues for Antidiabetic Activity Targeting PPARgamma. AB - Diabetes accounts for high mortality rate worldwide affecting million of lives annually. Global prevalence of diabetes and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of quantitative structure activity relationship model against PPARgamma, a promising drug target for diabetes. Multiple linear regression approach was adopted for statistical model development and the QSAR relationship suggested the regression coefficient (r2) of 0.84 and the cross validation coefficient (rCV2) of 0.77. Further, the study suggested that chemical descriptors viz., dipole moment, electron affinity, dielectric energy, secondary amine group count and LogP correlated well with the activity. The docking studies showed that most active gymnemic acid analogues viz., gymnemasin D and gymnemic acid VII possess higher binding affinity to PPARgamma. QSAR and ADMET studies based other predicted active gymnemc acid analogues were gymnemic acid I, gymnemic acid II, gymnemic acid III, gymnemic acid VIII, gymnemic acid X, gymnemic acid XII, gymnemic acid XIV, gymnemic acid XVIII and gymnemoside W2. Predicted activity results of three query compounds were found comparable to experimental in vivo data. Oral bioavailability of these active analogues is still a limiting factor and therefore further lead optimization required. Also, such study would be of great help in active pharmacophore discovery and lead optimization, and offering new insights into therapeutics for diabetes mellitus. PMID- 26058589 TI - Lenalidomide and vorinostat maintenance after autologous transplant in multiple myeloma. AB - Single-agent post-autologous transplant maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma. The tolerability and effectiveness of combination post-transplant maintenance therapy is unknown, so we investigated lenalidomide and vorinostat (suberoylanilide hydroxamic acid) in this setting, hypothesizing that the regimen would be well tolerated and associated with an improved post-transplant response. This trial followed a standard 3 * 3 dose escalation phase 1 design. Vorinostat was administered beginning day +90 post-haematopoietic stem cell transplantation for days 1-7 and 15-21, and lenalidomide was started at 10 mg days 1-21, both on a 28-d cycle. The primary endpoint was maximum tolerated dose and dose limiting toxicities were assessed during the first cycle. Treatment was well tolerated in 16 enrolled patients. During Cycle 1, the most common toxicities included cytopenias, gastrointestinal complaints and fatigue. Seven patients improved their transplant response after starting combination therapy. The median follow-up was 38.4 months, and the median progression-free survival and overall survival have yet to be reached. This oral post-transplant maintenance regimen was well tolerated. This is the first trial to publish results on the use of a histone deacetylase inhibitor in the maintenance setting, and it provides rationale for the ongoing randomized trial in maintenance (ISRCTN 49407852). TRIAL REGISTRATION: NCT00729118. PMID- 26058591 TI - The relationship between irritable bowel syndrome, functional dyspepsia, chronic fatigue and overactive bladder syndrome: a controlled study 6 years after acute gastrointestinal infection. AB - BACKGROUND: To investigate in a cohort with previous gastrointestinal infection and a control group the prevalence of overactive bladder syndrome (OAB), and how it was associated with three other functional disorders; irritable bowel syndrome (IBS), functional dyspepsia (FD) and chronic fatigue (CF). METHODS: Controlled historic cohort study including 724 individuals with laboratory confirmed giardiasis six years earlier, and 847 controls matched by gender and age. Prevalence and odds ratios (OR) with 95 % confidence intervals (CI) were calculated. RESULTS: The prevalence of OAB was 18.7 % (134/716) in the exposed group and 13.6 % (113/833) in the control group (p = 0.007). The association between OAB and IBS was strong in the control group (OR: 2.42; 95 % CI: 1.45 to 4.04), but insignificant in the Giardia exposed (OR: 1.29; 95 % CI: 0.88 to 1.88). The association between OAB and FD was weak in both groups. CF was strongly associated with OAB (OR: 2.73; 95 % CI: 1.85 to 4.02 in the exposed and OR: 2.79; 95 % CI: 1.69 to 4.62 in the controls), and this association remained when comorbid conditions were excluded. CONCLUSIONS: Sporadic IBS was associated with increased risk of OAB, whereas post-infectious IBS was not. An apparent association between OAB and previous Giardia infection can be ascribed to comorbid functional disorders. PMID- 26058592 TI - A new monoclonal antibody for detecting degalactosylated IgA1 as serum biomarker of IgA nephropathy. PMID- 26058593 TI - Human proximal tubule epithelial cells modulate autologous B-cell function. AB - BACKGROUND: Descriptions of inflammatory cells infiltrating the human kidney rarely mention B cells, other than in the specific scenario of transplantation. In these reports, B cells are localized almost exclusively within the kidney tubulointerstitium where they are ideally placed to interact with proximal tubule epithelial cells (PTEC). We have previously shown that activated PTEC down modulate autologous T lymphocyte and dendritic cell function. In this report, we extend these prior studies to describe PTEC-B cell interactions. METHODS: Stimulated B cells were cultured in the absence or presence of activated autologous human PTEC and monitored for proliferation, surface antigen expression, cytokine secretion and antibody (Ab) production. RESULTS: PTEC decreased B cell proliferative responses, whilst B cells cultured in the presence of PTEC displayed decreased levels of CD27, a marker of plasma B cells and memory cells. Interestingly, autologous PTEC also significantly decreased the number of B cells secreting both IgG and IgM and overall levels of Ab production. Transwell studies demonstrated that this modulation was primarily contact-dependent, and blocking studies with anti-PD-L1 led to partial restoration in Ab production. Further blocking studies targeting soluble HLA-G (sHLA-G) and IDO, two other immunoinhibitory molecules also up-regulated in our activated PTEC, demonstrated minor restoration of Ab responses. DISCUSSION: We report, for the first time, that PTEC are also able to modulate autologous B-cell phenotype and function via complex contact-dependent (PD-L1), soluble (sHLA-G) and intracellular (IDO) factors. We hypothesize that such mechanisms may have evolved to maintain peripheral immune-homeostasis, especially within the inflammatory milieu that exists within many kidney diseases. PMID- 26058594 TI - Uncertainty in sample estimates: standard error. PMID- 26058596 TI - National Partnership for Maternal Safety: Consensus Bundle on Obstetric Hemorrhage. PMID- 26058595 TI - Impact of oral anti-hepatitis B therapy on the survival of patients with hepatocellular carcinoma initially treated with chemoembolization. AB - INTRODUCTION: Most hepatocellular carcinomas (HCC) develop in a background of underlying liver disease including chronic hepatitis B. However, the effect of antiviral therapy on the long-term outcome of patients with hepatitis B virus (HBV)-related HCC treated with chemoembolization is unclear. This study aimed to evaluate the survival benefits of anti-HBV therapy after chemoembolization for patients with HBV-related HCC. METHODS: A total of 224 HCC patients who successfully underwent chemoembolization were identified, and their survival and other relevant clinical data were reviewed. Kaplan-Meier and Cox regression analyses were performed to validate possible effects of antiviral treatment on overall survival (OS). RESULTS: The median survival time (MST) was 15.9 (95% confidence interval [CI], 9.5-27.7) months in the antiviral group and 9.6 (95% CI, 7.8-13.7) months in the non-antiviral group (log-rank test, P = 0.044). Cox multivariate analysis revealed that antiviral treatment was a prognostic factor for OS (P = 0.008). Additionally, a further analysis was based on the stratification of the TNM tumor stages. In the subgroup of early stages, MST was significantly longer in the antiviral-treatment group than in the non-antiviral group (61.8 months [95% CI, 34.8 months to beyond the follow-up period] versus 26.2 [95% CI, 14.5-37.7] months, P = 0.012). Multivariate analysis identified antiviral treatment as a prognostic factor for OS in the early-stage subgroup (P = 0.006). However, in the subgroup of advanced stages, MST of the antiviral treated group was comparable to that of the non-antiviral group (8.4 [95% CI, 5.2 13.5] months versus 7.4 [95% CI, 5.9-9.3] months, P = 0.219). Multivariate analysis did not indicate that antiviral treatment was a significant prognostic factor in this subgroup. CONCLUSION: Antiviral treatment is associated with prolonged OS time after chemoembolization for HCC, especially in patients with early-stage tumors. PMID- 26058597 TI - Phytochemicals determination and classification in purple and red fleshed potato tubers by analytical methods and near infrared spectroscopy. AB - BACKGROUND: Over the last two decades, the attractive colours and shapes of pigmented tubers and the increasing concern about the relationship between nutrition and health have contributed to the expansion of their consumption and a specialty market. Thus, we have quantified the concentration of health promoting compounds such as soluble phenolics, monomeric anthocyanins, carotenoids, vitamin C, and hydrophilic antioxidant capacity, in a collection of 18 purple- and red fleshed potato accessions. RESULTS: Cultivars and breeding lines high in vitamin C, such as Blue Congo, Morada and Kasta, have been identified. Deep purple cultivars Violet Queen, Purple Peruvian and Vitelotte showed high levels of soluble phenolics, monomeric anthocyanins, and hydrophilic antioxidant capacity, whereas relatively high carotenoid concentrations were found in partially yellow coloured tubers, such as Morada, Highland Burgundy Red, and Violet Queen. CONCLUSION: The present characterisation of cultivars and breeding lines with high concentrations of phytochemicals is an important step both to support the consideration of specialty potatoes as a source of healthy compounds, and to obtain new cultivars with positive nutritional characteristics. Moreover, by using near infrared spectroscopy a non-destructive identification and classification of samples with different levels of phytochemicals is achieved, offering an unquestionable contribution to the potato industry for future automatic discrimination of varieties. PMID- 26058599 TI - Aligning Islamic Spirituality to Medical Imaging. AB - This paper attempts to conceptualize Islamic spirituality in medical imaging that deals with the humanistic and technical dimensions. It begins with establishing an understanding concerning spirituality, an area that now accepted as part of patient-centred care. This is followed by discussions pertaining to Islamic spirituality, related to the practitioner, patient care and the practice. Possible avenues towards applying Islamic spirituality in medical imaging are proposed. It is hoped that the resultant harmonization between Islamic spirituality and the practice will trigger awareness and interests pertaining to the role of a Muslim practitioner in advocating and enhancing Islamic spirituality. PMID- 26058598 TI - Levitational Image Cytometry with Temporal Resolution. AB - A simple, yet powerful magnetic-levitation-based device is reported for real time, label-free separation, as well as high-resolution monitoring of cell populations based on their unique magnetic and density signatures. This method allows a wide variety of cellular processes to be studied, accompanied by transient or permanent changes in cells' fundamental characteristics as a biological material. PMID- 26058600 TI - Uterine leiomyoma confounding a noninvasive prenatal test result. PMID- 26058601 TI - Cardiomyopathy in Duchenne Muscular Dystrophy: Current Value of Clinical, Electrophysiological and Imaging Findings in Children and Teenagers. AB - BACKGROUND: Progressive cardiomyopathy (CMP) is one main cause of death in DMD. This cross-sectional assessment of different cardiac diagnostic procedures focusses on preterm diagnosis of cardiac dysfunction. PATIENTS: 39 male DMD patients aged 6-20 years were included. 6 patients were still ambulatory, 21 patients received corticosteroid therapy. METHODS: All patients were investigated by ECG, Holter ECG and heart rate variability (HRV), B-type natriuretic peptide (BNP), echocardiography (TTE), tissue Doppler Imaging (TD) and magnetic resonance imaging (MRI) with Late Gadolinium enhancement (LE) and segmental wall motion analysis (WMA). RESULTS: 56% of the patients showed repolarization abnormalities and 76% altered HRV. Subnormal ventricular function was found in 25% by TTE and in 34% by MRI. TD differed from normal controls only in the apical septum. In MRI 89% of the patients showed different distribution and intensity of LE and WM restriction. The extent of LE was less in patients after steroid treatment (p<0.05). DISCUSSION: MRI with segmental LE- and WM-analysis seems to be superior to TTE and TD in exploring regional distribution and severity of damage of the myocardium. ECG and HRV abnormalities are common in DMD-patients but not tightly predictive for segmental and global left ventricular dysfunction. Targeted treatment of CMP in DMD needs prospective evaluation. CONCLUSION: A timely cardiac MRI is the most sensitive investigation for the identification of early myocardial changes in DMD which is a prerequisite for early interventions and therapeutic strategies. PMID- 26058602 TI - Comparison of lidocaine, lidocaine-morphine, lidocaine-tramadol or bupivacaine for neural blockade of the brachial plexus in fat-tailed lambs. AB - OBJECTIVE: To evaluate the onset time and duration of action of lidocaine, lidocaine-morphine, lidocaine-tramadol or bupivacaine for a neural blockade of the brachial plexus in fat-tailed lambs. STUDY DESIGN: Prospective, randomized, crossover, experimental study. ANIMALS: Seven healthy female fat-tailed Ghezel lambs weighing 27.0 +/- 2.2 kg (mean +/- SD). METHODS: Each lamb was administered four treatments for brachial plexus block (BPB): lidocaine 2% (5 mg kg(-1)) (LID), lidocaine 2% combined with morphine (0.1 mg kg(-1)) (LIDMO), lidocaine 2% combined with tramadol (1 mg kg(-1)) (LIDTR) or bupivacaine 0.5% (1.25 mg kg(-1)) (BUP), for a total treatment volume of 0.25 mL kg(-1). The brachial plexus was located with a peripheral nerve stimulator, and the treatment volume was injected in increments. Treatments were randomized and separated by at least 7 days. Onset and duration of a sensory block of the distal thoracic limb were evaluated using superficial and deep pin pricks and pinching of the skin with haemostatic forceps. RESULTS: The mean duration of sensory block was 100 +/- 38 minutes in LID, 103 +/- 35 minutes in LIDMO, 79 +/- 28 minutes in LIDTR, and 335 +/- 134 minutes in BUP. The mean duration of sensory and motor blocks in BUP were significantly longer compared with other treatments (p < 0.05). No clinical signs of local anaesthetic toxicity were noticed, and the rectal temperature did not differ significantly from baseline values in any treatments. CONCLUSIONS AND CLINICAL RELEVANCE: The addition of morphine or tramadol to lidocaine did not affect the duration of antinociception of lidocaine for brachial plexus block in fat-tailed lambs. Administration of bupivacaine provided a prolonged duration of action without obvious adverse effects. PMID- 26058603 TI - Low-energy electron interaction with retusin extracted from Maackia amurensis: towards a molecular mechanism of the biological activity of flavonoids. AB - The antioxidant isoflavone retusin efficiently attaches low-energy electrons in vacuo, generating fragment species via dissociative electron attachment (DEA), as has been shown by DEA spectroscopy. According to in silico results obtained by means of density functional theory, retusin is able to attach solvated electrons and could be decomposed under reductive conditions in vivo, for instance, near the mitochondrial electron transport chain, analogous to gas-phase DEA. The most intense decay channels of retusin temporary negative ions were found to be associated with the elimination of H atoms and H2 molecules. Doubly dehydrogenated fragment anions were predicted to possess a quinone structure. It is thought that molecular hydrogen, known for its selective antioxidant properties, can be efficiently generated via electron attachment to retusin in mitochondria and may be responsible for its antioxidant activity. The second abundant species, i.e., quinone bearing an excess negative charge, can serve as an electron carrier and can return the captured electron back to the respiration cycle. The number of OH substituents and their relative positions are crucial for the present molecular mechanism, which can explain the radical scavenging activity of polyphenolic compounds. PMID- 26058604 TI - Flexible Coding of Task Rules in Frontoparietal Cortex: An Adaptive System for Flexible Cognitive Control. AB - How do our brains achieve the cognitive control that is required for flexible behavior? Several models of cognitive control propose a role for frontoparietal cortex in the structure and representation of task sets or rules. For behavior to be flexible, however, the system must also rapidly reorganize as mental focus changes. Here we used multivoxel pattern analysis of fMRI data to demonstrate adaptive reorganization of frontoparietal activity patterns following a change in the complexity of the task rules. When task rules were relatively simple, frontoparietal cortex did not hold detectable information about these rules. In contrast, when the rules were more complex, frontoparietal cortex showed clear and decodable rule discrimination. Our data demonstrate that frontoparietal activity adjusts to task complexity, with better discrimination of rules that are behaviorally more confusable. The change in coding was specific to the rule element of the task and was not mirrored in more specialized cortex (early visual cortex) where coding was independent of difficulty. In line with an adaptive view of frontoparietal function, the data suggest a system that rapidly reconfigures in accordance with the difficulty of a behavioral task. This system may provide a neural basis for the flexible control of human behavior. PMID- 26058605 TI - A Neural Decomposition of Visual Search Using Voxel-based Morphometry. AB - The ability to search efficiently for visual targets among distractors can break down after a variety of brain lesions, but the specific processes affected by the lesions are unclear. We examined search over space (conjunction search) and over time plus space (preview search) in a consecutive series of patients with acquired brain lesions. We also assessed performance on standard neuropsychological measures of visuospatial short-term memory (Corsi Block), sustained attention and memory updating (the contrast between forward and backward digit span), and visual neglect. Voxel-based morphometry analyses revealed regions in the occipital (middle occipital gyrus), posterior parietal (angular gyrus), and temporal cortices (superior and middle temporal gyri extending to the insula), along with underlying white matter pathways, associated with poor search. Going beyond standard voxel-based morphometry analyses, we then report correlation measures of structural damage in these regions and the independent neuropsychological measures of other cognitive functions. We find distinct patterns of correlation in areas linked to poor search, suggesting that the areas play functionally different roles in search. We conclude that neuropsychological disorders of search can be linked to necessary and distinct cognitive functions, according to the site of lesion. PMID- 26058606 TI - Increased phosphorylation on residue S795 of the retinoblastoma protein in esophageal adenocarcinoma. AB - Due to its increasing incidence and relatively poor prognosis, esophageal adenocarcinoma (EAC) is becoming a significant health problem. Elucidating the mechanisms underlying EAC development is of great importance to improve upon current conventional treatment strategies. Insight into phosphorylation has proven to be useful for the development of diagnostic and molecular treatment strategies in cancer. A pathway largely dependent on phosphorylation and frequently deregulated in cancer is the cell cycle regulating p16-retinoblastoma (Rb) pathway. We investigated kinase activity, specifically phosphorylation within the p16-Rb pathway, in EAC. A high-throughput peptide tyrosine kinase array containing short peptides representing 100 proteins with known phosphorylation sites, was used to assess phosphorylation activity in EAC. Also, specific phosphorylation changes of the cell cycle protein Rb and its upstream regulator P16 were validated through immunoblotting in EAC and normal esophageal cells and tissues. Phosphorylation activity was higher in EAC tissues as compared to normal squamous esophageal tissues. A majority of the proteins significantly higher phosphorylated in EAC were found to be involved in cell structure maintenance and immunity. Validation of Rb phosphorylation in EAC biopsy specimens and cell lines showed hyper phosphorylation of Rb associated with aberrant P16 expression in the cancer tissues. The specific Rb (S795) residue was significantly higher phosphorylated in EAC compared to normal esophageal tissue (Wilcoxon paired rank test, p=0.004). Investigation of Rb (S795) phosphorylation may indicate targets for intervention and give more molecular insight in EAC. PMID- 26058607 TI - Decreasing ADHD phenotypic heterogeneity: searching for neurobiological underpinnings of the restrictive inattentive phenotype. AB - During the process of developing the DSM-5, a new phenotype of ADHD was proposed the ADHD restrictive inattentive presentation (ADHD-RI), describing subjects with high endorsement of inattentive symptoms and a low level of hyperactivity. However, this phenotype was not included in the DSM-5 because of the lack of robust neurobiological data. We aimed to assess the specific neurobiological underpinnings of individuals presenting ADHD-RI. We compared a sample of 301 subjects (101 ADHD-Combined; 50 ADHD-RI; 50 ADHD predominantly inattentive type and 100 typically developing subjects) aged 8-15 years, using a complete neuropsychological battery, molecular genetic data (DRD4 and DAT1 most studied polymorphisms) and functional MRI during a Go-No/Go task. Subjects with ADHD-RI had a significantly different neuropsychological profile compared with the other groups, including lower psychomotor speeds, longer reaction times and the worst overall performance in the global neurocognitive index. The proportion of subjects with the presence of DRD4-7 repeat allele was significantly higher in ADHD-RI. The fMRI data suggested that more attention-related posterior brain regions (especially temporo-occipital areas) are activated in ADHD-RI during both Go and No-Go cues compared to TD controls and ADHD predominantly inattentive type. ADHD-RI may represent a different phenotype than other types of ADHD. In addition, our results suggest that reducing the phenotypic heterogeneity may aid in the search for the neurobiological underpinnings of ADHD. PMID- 26058609 TI - Safe staffing sidestep makes the task harder. AB - Of all the issues that concerned Nursing Standard readers in the run up to the general election, two stood head and shoulders above the others. Pay, which will always feature prominently in such surveys, and safe staffing levels. PMID- 26058608 TI - The temporal build-up of hummingbird/plant mutualisms in North America and temperate South America. AB - BACKGROUND: The 361 species of hummingbirds that occur from Alaska to Patagonia pollinate ~7,000 plant species with flowers morphologically adapted to them. To better understand this asymmetric diversity build-up, this study analyzes the origin of hummingbird/plant mutualisms in North America and temperate South America, based on new compilations of the 184 hummingbird-adapted species in North America, the 56 in temperate South America, and complete species-level phylogenies for the relevant hummingbirds in both regions, namely five in temperate South America and eight in North America. Because both floras are relatively well sampled phylogenetically, crown or stem ages of many representative clades could be inferred. The hummingbird chronogram was calibrated once with fossils, once with substitutions rates, while plant chronograms were taken from the literature or in 13 cases newly generated. RESULTS: The 184 North American hummingbird-adapted species belong to ca. 70 lineages for 19 of which (comprising 54 species) we inferred divergence times. The 56 temperate South American hummingbird-adapted species belong to ca. 35 lineages, for 17 of which (comprising 25 species) we inferred divergence times. The oldest hummingbirds and hummingbird-adapted plant lineages in the South American assemblage date to 16-17 my, those in the North American assemblage to 6 7 my. Few hummingbird-pollinated clades in either system have >4 species. CONCLUSIONS: The asymmetric diversity build-up between hummingbirds and the plants dependent on them appears to arise not from rapid speciation within hummingbird-pollinated clades, but instead from a gradual and continuing process in which independent plant species switch from insect to bird pollination. Diversification within hummingbird-pollinated clades in the temperate regions of the Americas appears mainly due to habitat specialization and allopatric speciation, not bird pollination per se. Interaction tanglegrams, even if incomplete, indicate a lack of tight coevolution as perhaps expected for temperate-region mutualisms involving nectar-feeding vertebrates. PMID- 26058610 TI - NICE decision to suspend work on safe staffing is a 'backward step'. AB - Nursing leaders have reacted with dismay to the decision by the National Institute for Health and Care Excellence to shelve work on safe staffing guidance. PMID- 26058611 TI - New RCN leader vows to ensure nursing talent is recognised. AB - The RCN has appointed its head of nursing and service delivery as chief executive and general secretary. PMID- 26058612 TI - 'Hello trust, my name is Dr Granger'. AB - Healthcare campaigner and founder of the #hellomynameis campaign Kate Granger has welcomed a London trust's support for the initiative. PMID- 26058613 TI - Hunt's schedule for cutting agency spend is too ambitious, warn unions. AB - Unions have cast doubt on the timetable set by the Department of Health for reducing the use of agency nurses. PMID- 26058614 TI - Welsh staffing bill takes another step forward as assembly embraces principles. AB - Members of the Welsh assembly have approved the general principles of a bill that would place a legal duty on hospitals to make sure there are enough nurses to provide safe care. PMID- 26058615 TI - NMC unlikely to implement training changes in next year. AB - Changes to nurse education recommended in the Shape of Caring review are unlikely to be introduced within the next year, Nursing and Midwifery Council chief executive Jackie Smith has said. PMID- 26058616 TI - New approach needed for more BME leadership. AB - The NHS needs to rethink its approach to tackling race equality if it wants to see more leaders from black and minority ethnic (BME) backgrounds, according to a clinical commissioning group (CCG) director. PMID- 26058617 TI - Nurses spend two weeks a year on admin, review finds. AB - Nurses are spending up to two working weeks a year on administration tasks, a review to be published shortly has found. PMID- 26058618 TI - NHS must invest in staff development. AB - Plans to make L22 billion in savings and create a seven-day NHS by 2020 will not be realised unless the health service reconnects with staff and develops their skills, warns a leading think tank. PMID- 26058620 TI - Freya delivers anti-smoking message. AB - Seven-year-old Freya Jones (pictured above) has won the opportunity to be the voice of a trust's speaker system delivering 'no smoking' messages. PMID- 26058621 TI - Lack of post-acute stroke services hindering some patients' recovery. AB - An audit of post-acute stroke services across England, Wales and Northern Ireland has found wide variations in standards - with 'too many areas failing to commission comprehensive care', according to the authors. PMID- 26058622 TI - Is the NHS ripped off by agencies or its own workforce planning? AB - Health secretary Jeremy Hunt pitted the NHS against 'rip-off staffing agencies' last week in a bid to save the health service millions of pounds. PMID- 26058628 TI - Syphilis. AB - Essential facts Syphilis is caused by infection with the bacterium Treponema pallidum. It is transmitted by direct contact with an infectious lesion or by vertical transmission during pregnancy. Although the number of diagnoses of syphilis in the UK has risen substantially in the past decade, it remains one of the less common sexually transmitted infections, with fewer than 3,000 people diagnosed in 2012. PMID- 26058629 TI - Do branches make it hard to be holistic? PMID- 26058639 TI - National Osteoporosis Society. AB - Established in 1986, the National Osteoporosis Society has 25,000 members and employs 50 staff. With an estimated three million people in the UK living with osteoporosis, this website performs a valuable information service. PMID- 26058630 TI - Rewriting the rules for outstanding care. PMID- 26058641 TI - School Nurse Matters. AB - Devised by the Bexley and Greenwich school nursing team in London, this app is aimed at secondary school pupils. Easy to download and simple to navigate, with appealing colours and graphics, themes can be changed via the settings button. PMID- 26058643 TI - Losing unsocial hours pay would cause a mass exodus of vital HCAs. AB - The recent discussion about nurses losing their unsocial hours payments has ignored one vital factor. PMID- 26058644 TI - What you're saying on our Facebook page.... PMID- 26058645 TI - Patients are people with names, not a bed number or an ailment. AB - Ensuring patients are called by their preferred name is vital to compassionate care, yet I still hear staff refer to patients as 'bed 16' or 'the chest infection'. PMID- 26058647 TI - The contribution made by nurses from overseas is irreplaceable. AB - I was upset to read that new immigration rules mean nurses and healthcare assistants from countries such as the Philippines and India, and those from the Commonwealth, will be sent home after five years if they earn less than L35,000 (News, June 3). PMID- 26058648 TI - NHS professionals plays a vital role in workforce management. AB - NHS Professionals is part of the NHS family and we fully support the need for NHS organisations to have greater control over agency spend. PMID- 26058649 TI - The setting of nurse staffing levels must be evidence-based. AB - The suspension of NICE's vital work on safe nurse staffing levels is a damaging step back, not only for nursing but for all who use the NHS and care about its future. PMID- 26058651 TI - Case study research. AB - This article describes case study research for nursing and healthcare practice. Case study research offers the researcher an approach by which a phenomenon can be investigated from multiple perspectives within a bounded context, allowing the researcher to provide a 'thick' description of the phenomenon. Although case study research is a flexible approach for the investigation of complex nursing and healthcare issues, it has methodological challenges, often associated with the multiple methods used in individual studies. These are explored through examples of case study research carried out in practice and education settings. An overview of what constitutes 'good' case study research is proposed. PMID- 26058652 TI - Signs and symptoms of dementia. AB - The clinical features of dementia are usually considered in two groups: cognitive and non-cognitive symptoms. Among cognitive symptoms, problems with memory are typical of most forms of dementia, but problems with language and executive functioning are also prevalent. Non-cognitive symptoms is a somewhat unsatisfactory general term for a group of problems that include mood disorders, psychotic symptoms and various other changes in behaviour. In assessment and management, it is important to look for underlying causes of symptoms and try to understand the perspective of the individual with dementia, because their behaviour may be communicating an important message. PMID- 26058653 TI - Patient advocacy: the role of the nurse. AB - The role of nurses as patient advocates is well recognised by healthcare professionals, yet the processes and practices involved in patient advocacy are not clearly understood. A suboptimal level of advocacy is often apparent in the literature, encompassing paternalistic concepts of protecting patients from harm. This article examines the concept of patient advocacy and its relevance to nursing, associated goals and outcomes of advocacy and the processes and practices involved. It provides insights into how nurses practise patient advocacy in healthcare settings and how they may develop this role further, through formal education, workplace learning, role modelling by expert nurses and promoting an organisational culture conducive to patient advocacy. PMID- 26058654 TI - Chronic pain in adults. AB - Reading the CPD article helped improve my understanding of the importance of identifying chronic pain. Chronic pain may occur on its own or as a feature of other chronic conditions, and it may be nociceptive or neuropathic, or a combination of the two. PMID- 26058655 TI - Be heard in high places. AB - Giving evidence to MPs on a House of Commons select committee is not usually part of Karla Wilson-Palmer's job, but the opportunity was one she relished. PMID- 26058657 TI - Notice board. AB - Courses, events, grants, and awards to progress your career. PMID- 26058656 TI - Non-EU nurses face early exit. AB - Clive Banzon came to the UK from the Philippines in April 2012, but is likely to be told to leave in a couple of years. PMID- 26058658 TI - More than meets the eye. AB - In my work as a research nurse for more than four years, I gained experience in a range of tasks and roles. These included recruiting patients, gaining informed consent, collecting research data, dispensing trial medication, collecting and overall study co-ordination (see box ). PMID- 26058659 TI - Student life - Hello, how are you? What can I do to help? AB - As a nursing student, approaching a patient for the first time can be nerve racking. Not only will you be conscious of the need to be professional, you will be aware of your status as a student and your lack of experience when communicating with patients. PMID- 26058660 TI - Dyadic Short Forms of the Wechsler Adult Intelligence Scale-IV. AB - Full Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) administration can be time-consuming and may not be necessary when intelligence quotient estimates will suffice. Estimated Full Scale Intelligence Quotient (FSIQ) and General Ability Index (GAI) scores were derived from nine dyadic short forms using individual regression equations based on data from a clinical sample (n = 113) that was then cross validated in a separate clinical sample (n = 50). Derived scores accounted for 70%-83% of the variance in FSIQ and 77%-88% of the variance in GAI. Predicted FSIQs were strongly associated with actual FSIQ (rs = .73-.88), as were predicted and actual GAIs (rs = .80-.93). Each of the nine dyadic short forms of the WAIS-IV was a good predictor of FSIQ and GAI in the validation sample. These data support the validity of WAIS-IV short forms when time is limited or lengthier batteries cannot be tolerated by patients. PMID- 26058661 TI - Myeloid cell leukemia-1 promotes epithelial-mesenchymal transition of human gastric cancer cells. AB - Epithelial-mesenchymal transition (EMT) is a critical process that occurs during cancer progression, and cancer stem cells have been shown to acquire the EMT phenotype. Myeloid cell leukemia-1 (Mcl-1) has been implicated in cancer progression and is overexpressed in a variety of human cancers. However, the interaction between Mcl-1 and EMT in human gastric cancer (GC) is unclear. We investigated the impact of Mcl-1 expression levels on EMT and the underlying signaling pathways in human GC cells. We used the human GC cell lines, AGS and SNU638, and small interfering RNAs (siRNAs) to evaluate the effects of Mcl-1 knockdown on cell adhesion, migration and invasion. Expression of Mcl-1 and other target genes was determined using reverse transcription-polymerase chain reaction assays and western blotting. The results revealed that expression levels of Mcl-1 mRNA and protein in the AGS and SNU638 cells were reduced following transfection with Mcl-1 siRNAs. Knockdown of Mcl-1 led to increased cellular adhesion to fibronectin and collagen. Expression levels of vimentin, MMP-2, MMP-9 and Snail protein were decreased following knockdown of Mcl-1. However, expression of E cadherin was increased in the AGS cells following knockdown of Mcl-1. The expression of cancer stemness markers, such as CD44 and CD133, was not altered by knockdown of Mcl-1. Knockdown of Mcl-1 suppressed tumor cell migration and invasion in both human GC cell lines. Signaling cascades, including the beta catenin, MEK1/2, ERK1/2 and p38 pathways, were significantly blocked by knockdown of Mcl-1. Our results indicate that Mcl-1 expression induces EMT via beta catenin, MEK1/2 and MAPK signaling pathways, which subsequently stimulates the invasive and migratory capacity of human GC cells. PMID- 26058662 TI - Immediate and Persistent Effects of Salvinorin A on the Kappa Opioid Receptor in Rodents, Monitored In Vivo with PET. AB - Monitoring changes in opioid receptor binding with positron emission tomography (PET) could lead to a better understanding of tolerance and addiction because altered opioid receptor dynamics following agonist exposure has been linked to tolerance mechanisms. We have studied changes in kappa opioid receptor (KOR) binding availability in vivo with PET following kappa opioid agonist administration. Male Sprague-Dawley rats (n=31) were anesthetized and treated with the (KOR) agonist salvinorin A (0.01-1.8 mg/kg, i.v.) before administration of the KOR selective radiotracer [(11)C]GR103545. When salvinorin A was administered 1 min prior to injection of the radiotracer, [(11)C]GR103545 binding potential (BPND) was decreased in a dose-dependent manner, indicating receptor binding competition. In addition, the unique pharmacokinetics of salvinorin A (half-life ~8 min in non-human primates) allowed us to study the residual impact on KOR after the drug had eliminated from the brain. Salvinorin A was administered up to 5 h prior to [(11)C]GR103545, and the changes in BPND were compared with baseline, 2.5 h, 1 h, and 1 min pretreatment times. At lower doses (0.18 mg/kg and 0.32 mg/kg) we observed no prolonged effect on KOR binding but at 0.60 mg/kg salvinorin A induced a sustained decrease in KOR binding (BPND decreased by 40-49%) which persisted up to 2.5 h post administration, long after salvinorin A had been eliminated from the brain. These data point towards an agonist-induced adaptive response by KOR, the dynamics of which have not been previously studied in vivo with PET. PMID- 26058663 TI - White Matter Hyperintensity Accumulation During Treatment of Late-Life Depression. AB - White matter hyperintensities (WMHs) have been shown to be associated with the development of late-life depression (LLD) and eventual treatment outcomes. This study sought to investigate longitudinal WMH changes in patients with LLD during a 12-week antidepressant treatment course. Forty-seven depressed elderly patients were included in this analysis. All depressed subjects started pharmacological treatment for depression shortly after a baseline magnetic resonance imaging (MRI) scan. At 12 weeks, patients underwent a follow-up MRI scan, and were categorized as either treatment remitters (n=23) or non-remitters (n=24). Among all patients, there was as a significant increase in WMHs over 12 weeks (t(46)=2.36, P=0.02). When patients were stratified by remission status, non remitters demonstrated a significant increase in WMHs (t(23)=2.17, P=0.04), but this was not observed in remitters (t(22)=1.09, P=0.29). Other markers of brain integrity were also investigated including whole brain gray matter volume, hippocampal volume, and fractional anisotropy. No significant differences were observed in any of these markers during treatment, including when patients were stratified based on remission status. These results add to existing literature showing the association between WMH accumulation and LLD treatment outcomes. Moreover, this is the first study to demonstrate similar findings over a short interval (ie 12 weeks), which corresponds to the typical length of an antidepressant trial. These findings serve to highlight the acute interplay of cerebrovascular ischemic disease and LLD. PMID- 26058664 TI - Effects of Cortisol on Reconsolidation of Reactivated Fear Memories. AB - The return of conditioned fear after successful extinction (eg, following exposure therapy) is a significant problem in the treatment of anxiety disorders and posttraumatic stress disorder (PTSD). Targeting the reconsolidation of fear memories may allow a more lasting effect as it intervenes with the original memory trace. Indeed, several pharmacological agents and behavioral interventions have been shown to alter (enhance, impair, or otherwise update) the reconsolidation of reactivated memories of different types. Cortisol is a stress hormone and a potent modulator of learning and memory, yet its effects on fear memory reconsolidation are unclear. To investigate whether cortisol intervenes with the reconsolidation of fear memories in healthy males and how specific this effect might be, we built a 3-day reconsolidation design with skin conductance response (SCR) as a measure of conditioned fear: Fear acquisition on day 1; reactivation/no-reactivation of one conditioned stimulus and pharmacological intervention on day 2; extinction learning followed by reinstatement and reinstatement test on day 3. The groups differed only in the experimental manipulation on day 2: Reactivation+Cortisol Group, Reactivation+Placebo Group, or No-reactivation+Cortisol Group. Our results revealed an enhancing effect of cortisol on reconsolidation of the reactivated memory. The effect was highly specific, strengthening only the memory of the reactivated conditioned stimulus and not the non-reactivated one. Our findings are in line with previous findings showing an enhancing effect of behavioral stress on the reconsolidation of other types of memories. These results have implications for the understanding and treatment of anxiety disorders and PTSD. PMID- 26058665 TI - fNIRS-based investigation of the Stroop task after TBI. AB - To evaluate neural changes during a Stroop task among individuals with TBI using functional near-infrared spectroscopy (fNIRS). Thirteen healthy controls and 14 patients with moderate to severe TBI were included in this study. Oxygenated hemoglobin (HbO) was recorded every tenth of a second using a 52-channel fNIRS unit. Data were acquired using a block design during a Stroop task (i.e., Condition A = Dot Color Naming, Condition B = Incongruent Condition). Visual stimuli were presented on a computer monitor. Behaviorally, response accuracy was similar between groups for condition A, but the TBI group made more errors than the control group during condition B. During condition A, the patient group demonstrated significant increases in HbO within bilateral frontal regions compared to controls (p < 0.01). When examining the Stroop interference effect (B A), controls showed increased HbO in bilateral frontal lobes and left inferior parietal region suggesting increased neural response to increased cognitive demand, whereas no differences were detected among the TBI group (p < 0.05). No between group differences in latency of HbO response was observed during either condition. While the TBI group performed as accurately as controls on the simpler dot color naming condition of the Stroop task, neural activity was greater within the frontal lobes during this relatively simple task among the TBI group suggesting neural inefficiency. Furthermore, the spatial distribution of neural activity related to the interference effect was not different among patients, suggesting the neural demand for the simpler task was comparable to that of the more cognitive demanding task among the TBI sample. The results suggest that fNIRS can identify frontal lobe inefficiency in TBI commonly observed with fMRI. PMID- 26058666 TI - Association of dental trauma experience and first-aid knowledge among rugby players in Malaysia. AB - OBJECTIVES: To assess and compare the knowledge of rugby players regarding first aid measures for dental injuries. METHODS: A cross-sectional study was conducted at rugby tournaments in 2009 and 2010 on players aged 16 and over. Convenient sampling was performed. A total of 456 self-administered questionnaires were returned. Data collected were analysed using SPSS 21. Descriptive analysis was undertaken for the demographic data. The subjects were classified according to their experience of sustaining each type of injury. Cross-tabulation and chi square tests were carried out to compare the responses. When the expected cell count was less than five, Fisher's exact test was used. The level of significance was set at P < 0.05. RESULTS: The prevalence of self-reported dental injuries was as follows: tooth fracture (19.3%), luxation (6.6%) and avulsion (1.1%). Significant differences were found, whereby 52.2% of those who had no history of tooth fracture were more likely to seek immediate treatment (P < 0.001), whereas 42% of those who previously experienced tooth fracture claimed that they would only visit a dentist if they experienced pain (P = 0.001). Management of luxation and avulsion did not differ significantly between the groups. However, about half of those who did not have a history of tooth avulsion admitted to not knowing the correct answer, while three of five casualties would keep the tooth iced. CONCLUSIONS: Knowledge of the management of tooth fracture and storage medium differs between previous casualties and non-casualties. Overall, knowledge of dental trauma management was insufficient, suggesting the need to educate and train the players. PMID- 26058668 TI - Warm Ischemia-Related Postoperative Renal Dysfunction in Elective Laparoscopic Partial Nephrectomy Recovers During Intermediate-Term Follow-Up. AB - PURPOSE: To analyze the impact of warm ischemia time (WIT) on early postoperative and ultimate renal function after elective laparoscopic partial nephrectomy (LPN). PATIENTS AND METHODS: One hundred and twenty-seven patients who underwent elective, ischemia-applied LPN were investigated in this study. The study patients were without stage 3 or greater chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m(2)) before LPN. Initially, the patients were grouped using the criteria of postoperative de novo stage 3 or greater CKD: Group A (n=104, eGFR >=60 mL/min/1.73 m(2)) and group B (n=23, eGFR <60 mL/min/1.73 m(2)). The patients were also divided into two groups using 27.75 minute cutoff value obtained by receiver operating curve (ROC) analysis for WIT: Group 1 (n=69, WIT <27.75 min) and group 2 (n=58, WIT >=27.75 min). The groups were compared with regard to demographic, perioperative, histopathologic, and renal functional outcomes. RESULTS: The decreased preoperative eGFR (P<0.001) and increased WIT (P=0.007), operative time (P=0.015), diabetes mellitus (DM) rate (P=0.019) and pathologic tumor size (P=0.031) were significantly different in group B. Multivariate analysis determined that independent predictors of de novo stage 3 or greater CKD in the early postoperative period were preoperative eGFR (P<0.001), WIT (P=0.014), and DM (P=0.030); meanwhile, preoperative eGFR (P=0.006) was the only independent predictor at last follow-up. Decreased median postoperative eGFR (P=0.018) and percent preserved postoperative eGFR (P=0.001) were significantly different in the increased WIT group, as well as elevated median postoperative eGFR loss (P=0.001). After similar follow-up (26 vs 23.5 months, P=0.913), the increased and limited WIT groups were not significantly different with regard to final eGFR (P=0.936), final eGFR loss (P=0.749) and percent preserved final eGFR (P=0.690). CONCLUSIONS: In elective LPN, increased WIT plays an important role in renal functional loss in the early postoperative period. This functional loss, however, recovered after an intermediate term follow-up period, similar to that of patients undergoing limited WIT. PMID- 26058669 TI - Exploring carbonic anhydrase inhibition with multimeric coumarins displayed on a fullerene scaffold. AB - Carbonic anhydrases (CAs) are ubiquitous Zn metallo-enzymes that catalyze the reversible hydration/dehydration of CO2/HCO3(-). CAs are involved in many key biological processes, therefore their inhibition has become an attractive research field. Distinct families of CA inhibitors (CAIs) have been reported, most of them interacting with the Zn(II) at the active site. Some compounds such as the coumarins are hydrolyzed before binding the entrance of the active site cavity, and thus behave as "suicide" inhibitors. This study reports the first synthesis of multimeric suicide inhibitors, designed to address the selectivity and the potency of CA multivalent inhibition. Twelve coumarin units have been grafted to a central fullerene scaffold thanks to a CuAAC reaction and the final dodecamers were assayed against 4 relevant CAs. The multimers were always stronger inhibitors than the monomeric species but no strong "multivalent effect" was found. However, our study showed that the multimeric presentation of the coumarin around the C60, indeed affected the selectivity of the relative inhibition among the 4 CAs assayed. PMID- 26058667 TI - The Interplay Between Peroxiredoxin-2 and Nuclear Factor-Erythroid 2 Is Important in Limiting Oxidative Mediated Dysfunction in beta-Thalassemic Erythropoiesis. AB - AIMS: beta-Thalassemia is a common inherited red cell disorder characterized by ineffective erythropoiesis and severe oxidative stress. Peroxiredoxin-2 (Prx2), a typical 2-cysteine peroxiredoxin, is upregulated during beta-thalassemic erythropoiesis, but its contribution to stress erythropoiesis, a common feature of thalassemia, is yet to be fully defined. RESULTS: Here, we showed that Prx2(-/ ) mice displayed reactive oxygen species related abnormalities in erythropoiesis similar to that of Hbb(th3/+) mice associated with activation of redox response transcriptional factor nuclear factor-erythroid 2 (Nrf2). We generated beta thalassemic mice genetically lacking Prx2 (Prx2(-/-)Hbb(th3/+)) and documented a worsened beta-thalassemic hematological phenotype with severe ineffective erythropoiesis. To further validate a key role of Prx2 in stress erythropoiesis, we administrated fused recombinant PEP1Prx2 to Hbb(th3/+) mice and documented a decrease in ineffective erythropoiesis. We further show that Prx2 effects are mediated by activation of Nrf2 and upregulation of genes that protect against oxidative damage such as gluthatione S-transferase, heme-oxygenase-1, and NADPH dehydrogenase quinone-1. INNOVATION: We propose Prx2 as a key antioxidant system and Nrf2 activation is a cellular adaptive process in response to oxidative stress, resulting in upregulation of antioxidant (antioxidant responsive element) genes required to ensure cell survival. CONCLUSION: Our data shed new light on adaptive mechanisms against oxidative damage through the interplay of Prx2 and Nrf2 during stress erythropoiesis and suggest new therapeutic options to decrease ineffective erythropoiesis by modulation of endogenous antioxidant systems. PMID- 26058670 TI - A multi-Gaussian model for apparent diffusion coefficient histogram analysis of Wilms' tumour subtype and response to chemotherapy. AB - Wilms' tumours (WTs) are large heterogeneous tumours, which typically consist of a mixture of histological cell types, together with regions of chemotherapy induced regressive change and necrosis. The predominant cell type in a WT is assessed histologically following nephrectomy, and used to assess the tumour subtype and potential risk. The purpose of this study was to develop a mathematical model to identify subregions within WTs with distinct cellular environments in vivo, determined using apparent diffusion coefficient (ADC) values from diffusion-weighted imaging (DWI). We recorded the WT subtype from the histopathology of 32 tumours resected in patients who received DWI prior to surgery after pre-operative chemotherapy had been administered. In 23 of these tumours, DWI data were also available prior to chemotherapy. Histograms of ADC values were analysed using a multi-Gaussian model fitting procedure, which identified 'subpopulations' with distinct cellular environments within the tumour volume. The mean and lower quartile ADC values of the predominant viable tissue subpopulation (ADC(1MEAN), ADC(1LQ)), together with the same parameters from the entire tumour volume (ADC(0MEAN), ADC(0LQ)), were tested as predictors of WT subtype. ADC(1LQ) from the multi-Gaussian model was the most effective parameter for the stratification of WT subtype, with significantly lower values observed in high-risk blastemal-type WTs compared with intermediate-risk stromal, regressive and mixed-type WTs (p < 0.05). No significant difference in ADC(1LQ) was found between blastemal-type and intermediate-risk epithelial-type WTs. The predominant viable tissue subpopulation in every stromal-type WT underwent a positive shift in ADC(1MEAN) after chemotherapy. Our results suggest that our multi-Gaussian model is a useful tool for differentiating distinct cellular regions within WTs, which helps to identify the predominant histological cell type in the tumour in vivo. This shows potential for improving the risk-based stratification of patients at an early stage, and for guiding biopsies to target the most malignant part of the tumour. PMID- 26058671 TI - Severe Sunburn After a Hot Air Balloon Ride: A Case Report and Literature Review. AB - Hot air balloon tours are very popular among travelers worldwide. Preventable burn injuries associated with hot air balloon rides have been reported during crashes into power lines, in propane burner explosions, and following contact with the propane burner tanks. We present a case of severe repeated sunburn, which poses another risk of preventable injury during hot air balloon rides, and briefly discuss the injury epidemiology of hot air balloon rides. PMID- 26058672 TI - Does Inflammation Have a Role in the Pathogenesis of Cardiac Syndrome X? A Genetic-Based Clinical Study With Assessment of Multiple Cytokine Levels. AB - We compared Turkish patients with cardiac syndrome X (CSX) and controls with respect to serum pro- and anti-inflammatory cytokine levels, as well as the single-nucleotide polymorphisms located in the promoter regions of their related genes. This study included 111 consecutive patients angiographically diagnosed with CSX and 111 healthy controls with similar demographic characteristics. Serum interleukin (IL) 6, tumor necrosis factor alpha (TNF-alpha), and IL-10 levels were measured, and the genotypes of the patients and controls were determined using standard methods. Serum IL-6 and IL-10 levels were significantly higher in the CSX group than in the control group (P < .01, respectively). Serum TNF-alpha level was lower in the CSX group than in the control group (P < .001). On the other hand, participants with CSX and healthy controls were not significantly different with respect to the genotype distributions of IL-6, TNF-alpha, and IL 10 genes. As a result of our study, both pro-inflammatory and anti-inflammatory cytokines may play a role in the pathogenesis of CSX. In contrast, the studied gene polymorphisms did not influence CSX pathogenesis. PMID- 26058673 TI - The Ankle-Brachial Index is Associated With Cardiovascular Complications After Noncardiac Surgery. AB - BACKGROUND: This study evaluated the association of the ankle-brachial index (ABI) and cardiovascular complications after noncardiac surgery. METHODS: We prospectively evaluated patients referred for noncardiac surgery. The ABI was performed before surgery. Patients with abnormal ABI (<= 0.9) were included in the peripheral artery disease (PAD) group and the remaining constituted the control group. Cardiac troponin and electrocardiogram were obtained 72 hours after surgery. Patients were followed up to 30 days, and primary end point was the occurrence of any cardiovascular event: cardiovascular death, acute coronary syndrome, isolated troponin elevation (ITE), decompensated heart failure, cardiogenic shock, unstable arrhythmias, nonfatal cardiac arrest, pulmonary edema, stroke, or PAD symptoms increase. RESULTS: We evaluated 124 patients (61.3% male; mean age 65.4 years). During the study, 57.9% of patients in the PAD group had an event versus 25.7% in the control group (P = .011). The ITE was the most observed event (24.2%). After logistic regression, the odds ratio for ITE was 7.4 (95% confidence interval 2.2-25.0, P = .001). CONCLUSIONS: In patients submitted to noncardiac surgery, abnormal ABI is associated with a higher occurrence of a cardiovascular event. PMID- 26058674 TI - Association of the Derived Neutrophil-Lymphocyte Ratio With Critical Limb Ischemia. AB - Neutrophil and leukocyte counts are laboratory parameters that reflect the systemic inflammatory response in patients with atherosclerotic diseases. Based on the means of these parameters, the derived neutrophil-lymphocyte ratio (dNLR) can be calculated. We investigated a possible association of critical limb ischemia (CLI) and the dNLR in patients with peripheral arterial disease (PAD). We performed a retrospective data analysis including 1995 patients with PAD treated at our department in the years 2005 to 2010. The cohort was divided into tertiles according to dNLR. Higher dNLR values were associated with an increased CLI rate. In the tertile with lowest dNLR, the CLI rate was 20.4%, in the second tertile the CLI rate was 26.1%, and in the third tertile the CLI rate was 36.1%. Statistical significance was shown using a Jonckheere-Terpstra test (P < .001). A high dNLR is associated with an increased rate of CLI in patients with PAD. This might be a useful parameter to highlight patients at increased risk of CLI. PMID- 26058675 TI - Obsessive-compulsive symptoms in adjunctive therapy with lamotrigine in clozapine medicated patients. PMID- 26058677 TI - Synthesis of 3D structured graphene as a high performance catalyst support for methanol electro-oxidation. AB - A simple process for preparing 3D structured graphene (3D-G) by a solution combustion method is reported. The product was deposited with platinum and used for methanol electro-oxidation. The catalyst shows a considerable enhancement in both the activity and stability towards methanol electro-oxidation reaction. Characterization reveals that the Pt/3D-G catalyst has a more negative onset potential as well as a higher electrochemically active specific surface area than a commercial Pt/C catalyst. Moreover, the catalyst exhibits higher tolerance to corrosion than carbon black. This work provides an efficient way for preparing 3D G as a promising support for the oxidation of small organic molecules in fuel cells. PMID- 26058676 TI - A consumer-targeted, pharmacist-led, educational intervention to reduce inappropriate medication use in community older adults (D-PRESCRIBE trial): study protocol for a cluster randomized controlled trial. AB - BACKGROUND: Medication safety for older persons represents an ongoing challenge. Inappropriate prescriptions--those with a high risk of evidence-based harm- persist in up to 25% of seniors, and account for a significant proportion of avoidable emergency department visits. This project is the sequel to the EMPOWER study, in which a novel consumer-targeted written knowledge transfer tool aimed at empowering older adults to act as drivers of benzodiazepine de-prescription resulted in a 27% reduction of inappropriate benzodiazepine use at 6-month follow up (number needed to treat (NNT) = 4). Failure to discontinue in the EMPOWER study was attributable to re-emerging symptoms among participants, prescribing inertia, and lack of knowledge and skills for substituting alternate therapy among physicians and pharmacists. To maximize de-prescription of inappropriate therapy, educational medication-risk reduction initiatives should be tested that simultaneously include patients, physicians and pharmacists. The objective of this trial is to: 1) test the beneficial effect of a new de-prescribing paradigm enlisting pharmacists to transfer knowledge to both patients and prescribers in a 2-pronged approach to reduce inappropriate prescriptions, compared to usual care and 2) evaluate the transferability of the EMPOWER study concept to other classes of inappropriate prescriptions. METHODS: We intend to conduct a 3-year pragmatic cluster randomized parallel-group controlled trial to test the effect of the new de-prescribing intervention compared to usual care for reducing 4 classes of inappropriate prescriptions from the 2012 Beers criteria among 450 community dwelling older adults with polypharmacy. Inappropriate prescriptions will include benzodiazepines, sulfonylurea hypoglycemic agents, first generation antihistamines and non-steroidal anti-inflammatory drugs. The study population is community-dwelling older adults recruited from community pharmacies in Quebec, Canada. The intervention was developed based on a systematic review of the evidence for each medication. Participants in the experimental group will receive the written educational program following randomization and have their pharmacist send their physicians an evidence-based pharmaceutical opinion to recommend de prescription and be followed for a year. The control group will be wait-listed for 6 months. DISCUSSION: System change to effectively reduce medication risk among community-dwelling seniors requires a coordinated approach targeting physicians, pharmacists and patients. This trial will test the feasibility and effectiveness of a tripartite approach to de-prescribing. TRIAL REGISTRATION: Registered via ClinicalTrials.gov on 31 January 2014, identifier: NCT02053194. PMID- 26058678 TI - Cytokine responses and correlations thereof with clinical profiles in children with enterovirus 71 infections. AB - BACKGROUND: Severe complications associated with EV71 infections caused many infants death. However, the pathogenesis of EV71 infection in the severe cases remained poorly understood. METHODS: In this study we collected plasma and cerebrospinal fluid (CSF) specimens drawn in the acute and/or recovery phases from EV71-infected individuals, and plasma specimens from healthy children served as normal controls. We compared the levels of cytokines and chemokines determined by a Luminex-based cytokine bead array. RESULTS: The plasma levels of IL-1beta and IL-6 were significantly higher in severe and critical cases than in mild patients and normal controls. Higher plasma levels of IL-6, IL-10, and IL-8 were evident in critical than severe cases. The CSF levels of IL-6, IL-8, and IP-10 were higher, and that of RANTES lower (compared to plasma), in severe and critical patients. Significantly lower CSF levels of cytokines and chemokines were recorded in the recovery than the acute phase in severe and critical cases treated with intravenous immunoglobulin (IVIG) and glucocorticoids. Only the CSF levels of IL-6, IP-10, and IL-8 were significantly correlated with white blood cell counts, and absolute neutrophil and monocyte counts, in severe cases. Furthermore, the CSF levels of IL-6 were correlated with temperature in both cases. CONCLUSIONS: These data indicate that a major cytokine response and inflammation, in both plasma and the CNS, are features of disease caused by EV71 infection. Systemic inflammation caused by EV71 infection exacerbated the deterioration of the disease, and resulted in the disease progression to the critical illness stage. PMID- 26058679 TI - Incidence trend of nasopharyngeal carcinoma from 1987 to 2011 in Sihui County, Guangdong Province, South China: an age-period-cohort analysis. AB - INTRODUCTION: In the past several decades, declining incidences of nasopharyngeal carcinoma (NPC) have been observed in Chinese populations in Hong Kong, Taiwan, Los Angeles, and Singapore. A previous study indicated that the incidence of NPC in Sihui County, South China remained stable until 2002, but whether age, diagnosis period, and birth cohort affect the incidence of NPC remains unknown. METHODS: Age-standardized rates (ASRs) of NPC incidence based on the world standard population were examined in both males and females in Sihui County from 1987 to 2011. Joinpoint regression analysis was conducted to quantify the changes in incidence trends. A Poisson regression age-period-cohort model was used to assess the effects of age, diagnosis period, and birth cohort on the risk of NPC. RESULTS: The ASRs of NPC incidence during the study period were 30.29/100,000 for males and 13.09/100,000 for females. The incidence of NPC remained stable at a non-significant average annual percent change of 0.2% for males and -1.6% for females throughout the entire period. A significantly increased estimated annual percent change of 6.8% (95% confidence interval, 0.1%-14.0%) was observed from 2003 to 2009 for males. The relative risk of NPC increased with advancing age up to 50-59 and decreased at ages >60 years. The period effect curves on NPC were nearly flat for males and females. The birth cohort effect curve for males showed an increase from the 1922 cohort to the 1957 cohort and a decrease thereafter. In females, there was an undulating increase in the relative risk from the 1922 cohort to the 1972 cohort. CONCLUSIONS: The incidence trends for NPC remained generally stable in Sihui from 1987 to 2011, with an increase from 2003 to 2009. The relative risks of NPC increased in younger females. PMID- 26058680 TI - Hepatosplenic schistosomiasis is characterised by high blood markers of translocation, inflammation and fibrosis. AB - BACKGROUND & AIMS: Cirrhosis is the main cause of portal hypertension worldwide but schistosomiasis dominates in much of the tropics. The seroprevalence of Schistosoma mansoni is up to 77% in endemic parts of Zambia. Morbidity is attributed to portal hypertension causing variceal bleeding which can be fatal. Bacterial translocation is associated with portal hypertension in cirrhosis but this is almost unexplored in hepatosplenic schistosomiasis. Liver biopsy is usually used to assess fibrosis although it is invasive and prone to sampling error. We aimed to investigate translocation, fibrosis and inflammatory makers in a case-control study of schistosomiasis at the University Teaching Hospital, Lusaka, Zambia. METHODS: Patients had oesophageal varices, but were negative for human immunodeficiency virus, hepatitis B and C viruses. Plasma lipopolysaccharide binding protein was used as a marker of translocation while hyaluronan and laminin measured liver fibrosis. Inflammatory markers were measured in blood. Controls were patients with non-specific abdominal pain who had normal endoscopy. RESULTS: Median (interquartile range) lipopolysaccharide binding protein was elevated in patients [44.3 ng/ml (35.7, 57.1)] compared to controls [30.7 ng/ml (30.4, 35.5), P < 0.0001]. Hyaluronan was higher in patients [111.6 ng/ml (39.1, 240.3)] compared to controls [21.0 ng/ml (12.4, 37.6), P < 0.0001] and so was laminin [2.2 MUg/ml (1.0, 3.7)] compared to controls [0.9 MUg/ml (0.7, 1.2), P = 0.0015]. Inflammatory markers, except C-reactive protein, were elevated in patients. CONCLUSIONS: These data suggest that the bacterial translocation contributes to systemic inflammation in hepatosplenic schistosomiasis. Elevated fibrotic markers suggest they may be useful in diagnosing and monitoring periportal fibrosis. PMID- 26058681 TI - A Review of the Effectiveness of Breast Surgical Oncology Fellowship Programs Utilizing Kirkpatrick's Evaluation Model. AB - It has been 10 years since the first class of Society of Surgical Oncology (SSO) fellowship trained Breast Surgical Oncologist entered practice. To date, there has been no publications examining the effectiveness of these training programs that are today throughout North America and Europe. This evaluative review examines the effectiveness of these fellowship training programs through the lens of the Kirkpatrick Evaluation Model. An extensive review of the literature was performed, and articles were categorized to capture how fellows are reacting to the program, what they are learning, and how the program is effecting their career path and impacting their patients. We can conclude that there is both direct and indirect evidence to support the effectiveness of this training program, but there is a paucity of direct evidence as one progresses from a level 1 Kirkpatrick analysis to a level 4. This review sets the framework for program evaluation in surgical fellowships and should encourage stakeholders to constantly evaluate the impact their program is having on trainees and oncology patients. PMID- 26058682 TI - Reflectance confocal microscopy of extra-genital lichen sclerosus atrophicus. PMID- 26058683 TI - Nutrition and health in hotel staff on different shift patterns. AB - BACKGROUND: Limited research is available that examines the nutritional behaviour and health of hotel staff working alternating and regular shifts. AIMS: To analyse the nutritional behaviour and health of employees working in alternating and regular shifts. METHODS: The study used an ex post facto cross-sectional analysis to compare the nutritional behaviour and health parameters of workers with alternating shifts and regular shift workers. Nutritional behaviour was assessed with the Food Frequency Questionnaire. Body dimensions (body mass index, waist hip ratio, fat mass and active cell mass), metabolic values (glucose, triglyceride, total cholesterol and low- and high-density lipoprotein), diseases and health complaints were included as health parameters. RESULTS: Participants worked in alternating (n = 53) and regular shifts (n = 97). The average age of subjects was 35 +/- 10 years. There was no significant difference in nutritional behaviour, most surveyed body dimensions or metabolic values between the two groups. However, alternating shift workers had significantly lower fat mass and higher active cell mass but nevertheless reported more pronounced health complaints. Sex and age were also confirmed as influencing the surveyed parameters. CONCLUSIONS: Shift-dependent nutritional problems were not conspicuously apparent in this sample of hotel industry workers. Health parameters did not show significantly negative attributes for alternating shift workers. Conceivably, both groups could have the same level of knowledge on the health effects of nutrition and comparable opportunities to apply this. Further studies on nutritional and health behaviour in the hotel industry are necessary in order to create validated screening programmes. PMID- 26058684 TI - What are the implications of the big data paradigm shift for disability and health? PMID- 26058685 TI - Obesity in children with developmental and/or physical disabilities. AB - Children with developmental or physical disabilities, many of whom face serious health-related conditions, also are affected by the current obesity crisis. Although evidence indicates that children with disabilities have a higher prevalence of obesity than do children without disabilities, little is known of the actual magnitude of the problem in this population. To address this concern, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) held a conference on obesity in children with intellectual, developmental, or physical disabilities, bringing together scientists and practitioners in the fields of obesity and disability to foster collaboration, identify barriers to healthy weight status in populations with disabilities, propose avenues to solutions through research and practice, and develop a research agenda to address the problem. This article describes current knowledge about prevalence of obesity in this population, discusses factors influencing obesity risk, and summarizes recommendations for research presented at the conference. PMID- 26058686 TI - Differential Scaling Patterns in Maxillary Sinus Volume and Nasal Cavity Breadth Among Modern Humans. AB - Among modern humans, nasal cavity size and shape reflect its vital role in air conditioning processes. The ability for the nasal cavity to augment its shape, particularly in inferior breadth, likely relates to the surrounding maxillary sinuses acting as zones of accommodation. However, much is still unknown regarding how nasal and sinus morphology relate to each other and to overall craniofacial form, particularly across diverse populations with varying respiratory demands. As such, this study uses computed tomographic (CT) scans of modern human crania (N = 171) from nine different localities to investigate ecogeographic differences in (1) the interaction between maxillary sinus volume (MSV) and nasal cavity breadth (NCB) and (2) scaling patterns of MSV and NCB in relation to craniofacial size. Reduced major axis (RMA) regression reveals that all samples exhibit an inverse relationship between MSV and NCB, but statistical significance and the strength of that relationship is sample dependent. Individuals from cold-dry climates have larger MSVs with narrower NCBs, while smaller MSVs are associated with wider NCBs in hot-humid climates. MSV and NCB each scale with positive allometry relative to overall craniofacial size. However, sample differences are evident in the both the interaction between MSV and NCB, as well as their correlation with craniofacial size. While these results provide further support that the maxillary sinus and nasal cavity are integrated among populations from opposite ends of the climatic spectrum, additional epigenetic factors are needed to explain variation of these structures among populations from more intermediate climates. PMID- 26058687 TI - Stifle arthrodesis using a locking plate system in six dogs. AB - OBJECTIVES: To describe the use of the Fixin locking plate system for stifle arthrodesis in dogs and to retrospectively report the clinical and radiographic outcomes in six cases. MATERIALS AND METHODS: Medical records of dogs that had arthrodesis with the Fixin locking plate system were reviewed. For each patient, data pertaining to signalment and implant used were recorded. Plate series and thickness, number of screws placed, number of cortices engaged, and screw diameters were also recorded. The outcome was determined from clinical and radiographic follow-ups. Radiographic outcomes assessed included the measurement of the postoperative femoral-tibial angle in the sagittal plane. RESULTS: Six dogs met the inclusion criteria for the study. Mean body weight was 13 kg (range: 3 - 34 kg). Radiographic follow-up (mean: 32 weeks, range: 3 - 52 weeks) was available for all dogs. In one case, an intra-operative complication occurred. In another case, a tibial fracture occurred 20 days after surgery. All arthrodeses healed and no implant complication was detected although all cases had mechanical lameness. CLINICAL SIGNIFICANCE: Stifle arthrodesis can be performed successfully using a Fixin locking plate system. PMID- 26058688 TI - Does inhibitory control training improve health behaviour? A meta-analysis. AB - OBJECTIVES: Inhibitory control training has been hypothesised as a technique that will improve an individual's ability to overrule impulsive reactions in order to regulate behaviour consistent with long-term goals. METHODS: A meta-analysis of 19 studies of inhibitory control training and health behaviours was conducted to determine the effect of inhibitory control training on reducing harmful behaviours. Theoretically driven moderation analyses were also conducted to determine whether extraneous variables account for heterogeneity in the effect; in order to facilitate the development of effective intervention strategies. Moderators included type of training task, behaviour targeted, measurement of behaviour and training duration. RESULTS: A small but homogeneous effect of training on behaviour was found, d(+) = 0.378, CI95 = [0.258, 0.498]. Moderation analyses revealed that the training paradigm adopted, and measurement type influenced the size of the effect such that larger effects were found for studies that employed go/no-go (GNG) training paradigms rather than stop-signal task paradigms, and objective outcome measures that were administered immediately yielded the largest and most consistent effects on behaviour. CONCLUSIONS: Results suggest that GNG inhibitory control training paradigms can influence health behaviour, but perhaps only in the short-term. Future research is required to systematically examine the influence of training duration, and the longevity of the training effect. Determining these factors could provide the basis for cost-effective and efficacious health-promoting interventions. PMID- 26058689 TI - Hippocrates on Pediatric Dermatology. AB - Hippocrates of Kos is well known in medicine, but his contributions to pediatric dermatology have not previously been examined. A systematic study of Corpus Hippocraticum was undertaken to document references of clinical and historical importance of pediatric dermatology. In Corpus Hippocraticum, a variety of skin diseases are described, along with proposed treatments. Hippocrates rejected the theory of the punishment of the Greek gods and supported the concept that dermatologic diseases resulted from a loss of balance in the body humors. Many of the terms that Hippocrates and his pupils used are still being used today. Moreover, he probably provided one of the first descriptions of skin findings in smallpox, Henoch-Schonlein purpura (also known as anaphylactoid purpura, purpura rheumatica, allergic purpura), and meningococcal septicemia. PMID- 26058690 TI - Lack of age-dependent decrease in dopamine D3 receptor availability: a [(11)C] (+)-PHNO and [(11)C]-raclopride positron emission tomography study. AB - Positron emission tomography with antagonist radiotracers has showed that striatal dopamine D2/3 receptor (D2/3R) availability decreases with age. However, no study has specifically assessed whether D2/3R availability decreases with age in healthy persons as measured with agonist radiotracers. Moreover, it is unknown whether D3R availability changes with age in healthy humans. Thus, we explored the relationship between age and D2/3R availability in healthy humans using the D3 receptor (D3R)-preferential agonist radiotracer [(11)C]-(+)-PHNO (n=72, mean+/ s.d. age=40+/-15, range=18 to 73) and the antagonist [(11)C]-Raclopride (n=70, mean+/-s.d. age =40+/-14, range=18 to 73) (both, n=33). The contribution of D3R to the [(11)C]-(+)-PHNO signal varies across regions of interest; the substantia nigra and hypothalamus represent D3R-specific regions, the ventral pallidum, globus pallidus, and ventral striatum represent D2/3R-mixed regions, and the caudate and putamen represent D2 receptor (D2R)-specific regions. With [(11)C] (+)-PHNO, a negative correlation was observed between age and nondisplaceable binding potential (BPND) in the caudate (r(70)=-0.32, P=0.005). No correlations were observed in the other regions. With [(11)C]-Raclopride, negative correlations were observed between age and BPND in the caudate (r(68)=-0.50, P<0.001), putamen (r(68)=-0.41, P<0.001), and ventral striatum (r(68)=-0.43, P<0.001). In conclusion, in contrast with the age-dependent decrease in D2R availability, these findings suggest that D3R availability does not change with age. PMID- 26058691 TI - 20-Hydroxyeicosatetraenoic Acid Inhibition by HET0016 Offers Neuroprotection, Decreases Edema, and Increases Cortical Cerebral Blood Flow in a Pediatric Asphyxial Cardiac Arrest Model in Rats. AB - Vasoconstrictive and vasodilatory eicosanoids generated after cardiac arrest (CA) may contribute to cerebral vasomotor disturbances and neurodegeneration. We evaluated the balance of vasodilator/vasoconstrictor eicosanoids produced by cytochrome P450 (CYP) metabolism, and determined their role on cortical perfusion, functional outcome, and neurodegeneration after pediatric asphyxial CA. Cardiac arrest of 9 and 12 minutes was induced in 16- to 18-day-old rats. At 5 and 120 minutes after CA, we quantified the concentration of CYP eicosanoids in the cortex and subcortical areas. In separate rats, we inhibited 20 hydroxyeicosatetraenoic acid (20-HETE) synthesis after CA and assessed cortical cerebral blood flow (CBF), neurologic deficit score, neurodegeneration, and edema. After 9 minutes of CA, vasodilator eicosanoids markedly increased versus sham. Conversely, after 12 minutes of CA, vasoconstrictor eicosanoid 20-HETE increased versus sham, without compensatory increases in vasodilator eicosanoids. Inhibition of 20-HETE synthesis after 12 minutes of CA decreased cortical 20-HETE levels, increased CBF, reduced neurologic deficits at 3 hours, and reduced neurodegeneration and edema at 48 hours versus vehicle-treated rats. In conclusion, cerebral vasoconstrictor eicosanoids increased after a pediatric CA of 12 minutes. Inhibition of 20-HETE synthesis improved cortical perfusion and short-term neurologic outcome. These results suggest that alterations in CYP eicosanoids have a role in cerebral hypoperfusion and neurodegeneration after CA and may represent important therapeutic targets. PMID- 26058692 TI - Reduced uptake of 18F-FDG and 15O-H2O in Alzheimer's disease-related regions after glucose loading. AB - Increased plasma glucose levels are known to reduce fluorine-18-labeled fluorodeoxyglucose ((18)F-FDG) uptake in Alzheimer's disease (AD)-related regions, resulting in the appearance of an AD-like pattern. However, the relationships of its appearance with cerebral blood flow and insulin levels are uncertain. We performed (18)F-FDG and oxygen-15-labeled water ((15)O-H2O) positron emission tomography in the fasting and glucose-loading conditions on nine young healthy volunteers with no cognitive impairments. Measurement of plasma glucose and insulin levels confirmed that all subjects were free of insulin resistance, and that glucose loading significantly increased plasma glucose and insulin levels. Fluorine-18-labeled fluorodeoxyglucose and (15)O-H2O images were compared between the two conditions, focusing on AD-related regions: precuneus/posterior cingulate (PP), lateral parietal cortex (LPC), and frontal cortex (FC). Volume-of-interest analyses showed significantly lower uptake of both (18)F-FDG and (15)O-H2O in PP, LPC, and FC after glucose loading (P<0.05). Whole-brain voxel-wise analyses also revealed the PP, LPC, and FC areas where uptake of both (18)F-FDG and (15)O-H2O decreased (P<0.05, familywise error rate corrected). We concluded that increased plasma glucose and insulin levels can cause the appearance of the AD-like pattern in both (18)F-FDG and (15)O-H2O images, and this phenomenon can occur even in subjects without insulin resistance. PMID- 26058693 TI - Abnormal metabolic pattern associated with cognitive impairment in Parkinson's disease: a validation study. AB - Cognitive deficits in Parkinson's disease (PD) have been associated with a specific metabolic covariance pattern. Although the expression of this PD cognition-related pattern (PDCP) correlates with neuropsychological performance, it is not known whether the PDCP topography is reproducible across PD populations. We therefore sought to identify a PDCP topography in a new sample comprised of 19 Dutch PD subjects. Network analysis of metabolic scans from these individuals revealed a significant PDCP that resembled the original network topography. Expression values for the new PDCP correlated (P=0.001) with executive dysfunction on the Frontal Assessment Battery (FAB). Subject scores for the new PDCP correlated (P<0.001) with corresponding values for the original pattern, which also correlated (P<0.005) with FAB scores in this patient group. For further validation, subject scores for the new PDCP were computed in an independent group of 86 American PD patients. In this cohort, subject scores for the new and original PDCP topographies were closely correlated (P<0.001); significant correlations between pattern expression and cognitive performance (P<0.05) were observed for both PDCP topographies. These findings suggest that the PDCP is a replicable imaging marker of PD cognitive dysfunction. PMID- 26058694 TI - Dysfunction of mouse cerebral arteries during early aging. AB - Aging leads to a gradual decline in the fidelity of cerebral blood flow (CBF) responses to neuronal activation, resulting in an increased risk for stroke and dementia. However, it is currently unknown when age-related cerebrovascular dysfunction starts or which vascular components and functions are first affected. The aim of this study was to examine the function of microcirculation throughout aging in mice. Microcirculation was challenged by inhalation of 5% and 10% CO2 or by forepaw stimulation in 6-week, 8-month, and 12-month-old FVB/N mice. The resulting dilation of pial vessels and increase in CBF was measured by intravital fluorescence microscopy and laser Doppler fluxmetry, respectively. Neurovascular coupling and astrocytic endfoot Ca(2+) were measured in acute brain slices from 18-month-old mice. We did not reveal any changes in CBF after CO2 reactivity up to an age of 12 months. However, direct visualization of pial vessels by in vivo microscopy showed a significant, age-dependent loss of CO2 reactivity starting at 8 months of age. At the same age neurovascular coupling was also significantly affected. These results suggest that aging does not affect cerebral vessel function simultaneously, but starts in pial microvessels months before global changes in CBF are detectable. PMID- 26058695 TI - Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. AB - The term cerebral small vessel disease (SVD) refers to a group of pathologic processes with various etiologies that affect small arteries, arterioles, venules, and capillaries of the brain. Magnetic resonance imaging (MRI) correlates of SVD are lacunes, recent small subcortical infarcts, white-matter hyperintensities, enlarged perivascular spaces, microbleeds, and brain atrophy. Endothelial dysfunction is thought to have a role in the mechanisms leading to SVD-related brain changes, and the study of endothelial dysfunction has been proposed as an important step for a better comprehension of cerebral SVD. Among available methods to assess endothelial function in vivo, measurement of molecules of endothelial origin in peripheral blood is currently receiving selective attention. These molecules include products of endothelial cells that change when the endothelium is activated, as well as molecules that reflect endothelial damage and repair. This review examines the main molecular factors involved in both endothelial function and dysfunction, and the evidence linking endothelial dysfunction with cerebral SVD, and gives an overview of clinical studies that have investigated the possible association between endothelial circulating biomarkers and SVD-related brain changes. PMID- 26058696 TI - Exendin-4-loaded PLGA microspheres relieve cerebral ischemia/reperfusion injury and neurologic deficits through long-lasting bioactivity-mediated phosphorylated Akt/eNOS signaling in rats. AB - Glucagon-like peptide-1 (GLP-1) receptor activation in the brain provides neuroprotection. Exendin-4 (Ex-4), a GLP-1 analog, has seen limited clinical usage because of its short half-life. We developed long-lasting Ex-4-loaded poly(D,L-lactide-co-glycolide) microspheres (PEx-4) and explored its neuroprotective potential against cerebral ischemia in diabetic rats. Compared with Ex-4, PEx-4 in the gradually degraded microspheres sustained higher Ex-4 levels in the plasma and cerebrospinal fluid for at least 2 weeks and improved diabetes-induced glycemia after a single subcutaneous administration (20 MUg/day). Ten minutes of bilateral carotid artery occlusion (CAO) combined with hemorrhage-induced hypotension (around 30 mm Hg) significantly decreased cerebral blood flow and microcirculation in male Wistar rats subjected to streptozotocin induced diabetes. CAO increased cortical O2(-) levels by chemiluminescence amplification and prefrontal cortex edema by T2-weighted magnetic resonance imaging analysis. CAO significantly increased aquaporin 4 and glial fibrillary acidic protein expression and led to cognition deficits. CAO downregulated phosphorylated Akt/endothelial nitric oxide synthase (p-Akt/p-eNOS) signaling and enhanced nuclear factor (NF)-kappaBp65/intercellular adhesion molecule-1 (ICAM-1) expression, endoplasmic reticulum (ER) stress, and apoptosis in the cerebral cortex. PEx-4 was more effective than Ex-4 to improve CAO-induced oxidative injury and cognitive deficits. The neuroprotection provided by PEx-4 was through p-Akt/p-eNOS pathways, which suppressed CAO-enhanced NF-kappaB/ICAM-1 signaling, ER stress, and apoptosis. PMID- 26058697 TI - Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke. AB - Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD(+)/NADH ratio. In this study, we investigated whether mitochondrial NAD(+) dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD(+)-dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway. PMID- 26058698 TI - Early disrupted neurovascular coupling and changed event level hemodynamic response function in type 2 diabetes: an fMRI study. AB - Type 2 diabetes (T2DM) patients develop vascular complications and have increased risk for neurophysiological impairment. Vascular pathophysiology may alter the blood flow regulation in cerebral microvasculature, affecting neurovascular coupling. Reduced fMRI signal can result from decreased neuronal activation or disrupted neurovascular coupling. The uncertainty about pathophysiological mechanisms (neurodegenerative, vascular, or both) underlying brain function impairments remains. In this cross-sectional study, we investigated if the hemodynamic response function (HRF) in lesion-free brains of patients is altered by measuring BOLD (Blood Oxygenation Level-Dependent) response to visual motion stimuli. We used a standard block design to examine the BOLD response and an event-related deconvolution approach. Importantly, the latter allowed for the first time to directly extract the true shape of HRF without any assumption and probe neurovascular coupling, using performance-matched stimuli. We discovered a change in HRF in early stages of diabetes. T2DM patients show significantly different fMRI response profiles. Our visual paradigm therefore demonstrated impaired neurovascular coupling in intact brain tissue. This implies that functional studies in T2DM require the definition of HRF, only achievable with deconvolution in event-related experiments. Further investigation of the mechanisms underlying impaired neurovascular coupling is needed to understand and potentially prevent the progression of brain function decrements in diabetes. PMID- 26058699 TI - Positron emission tomography/magnetic resonance hybrid scanner imaging of cerebral blood flow using (15)O-water positron emission tomography and arterial spin labeling magnetic resonance imaging in newborn piglets. AB - Abnormality in cerebral blood flow (CBF) distribution can lead to hypoxic ischemic cerebral damage in newborn infants. The aim of the study was to investigate minimally invasive approaches to measure CBF by comparing simultaneous (15)O-water positron emission tomography (PET) and single TI pulsed arterial spin labeling (ASL) magnetic resonance imaging (MR) on a hybrid PET/MR in seven newborn piglets. Positron emission tomography was performed with IV injections of 20 MBq and 100 MBq (15)O-water to confirm CBF reliability at low activity. Cerebral blood flow was quantified using a one-tissue-compartment-model using two input functions: an arterial input function (AIF) or an image-derived input function (IDIF). The mean global CBF (95% CI) PET-AIF, PET-IDIF, and ASL at baseline were 27 (23; 32), 34 (31; 37), and 27 (22; 32) mL/100 g per minute, respectively. At acetazolamide stimulus, PET-AIF, PET-IDIF, and ASL were 64 (55; 74), 76 (70; 83) and 79 (67; 92) mL/100 g per minute, respectively. At baseline, differences between PET-AIF, PET-IDIF, and ASL were 22% (P<0.0001) and -0.7% (P=0.9). At acetazolamide, differences between PET-AIF, PET-IDIF, and ASL were 19% (P=0.001) and 24% (P=0.0003). In conclusion, PET-IDIF overestimated CBF. Injected activity of 20 MBq (15)O-water had acceptable concordance with 100 MBq, without compromising image quality. Single TI ASL was questionable for regional CBF measurements. Global ASL CBF and PET CBF were congruent during baseline but not during hyperperfusion. PMID- 26058700 TI - Quantification of [(11)C]PIB PET for imaging myelin in the human brain: a test retest reproducibility study in high-resolution research tomography. AB - An accurate in vivo measure of myelin content is essential to deepen our insight into the mechanisms underlying demyelinating and dysmyelinating neurological disorders, and to evaluate the effects of emerging remyelinating treatments. Recently [(11)C]PIB, a positron emission tomography (PET) tracer originally conceived as a beta-amyloid marker, has been shown to be sensitive to myelin changes in preclinical models and humans. In this work, we propose a reference region methodology for the voxelwise quantification of brain white-matter (WM) binding for [(11)C]PIB. This methodology consists of a supervised procedure for the automatic extraction of a reference region and the application of the Logan graphical method to generate distribution volume ratio (DVR) maps. This approach was assessed on a test-retest group of 10 healthy volunteers using a high resolution PET tomograph. The [(11)C]PIB PET tracer binding was shown to be up to 23% higher in WM compared with gray matter, depending on the image reconstruction. The DVR estimates were characterized by high reliability (outliers <1%) and reproducibility (intraclass correlation coefficient (ICC) >0.95). [(11)C]PIB parametric maps were also found to be significantly correlated (R(2)>0.50) to mRNA expressions of the most represented proteins in the myelin sheath. On the contrary, no correlation was found between [(11)C]PIB imaging and nonmyelin-associated proteins. PMID- 26058701 TI - Understanding the United States and Brazil's response to obesity: institutional conversion, policy reform, and the lessons learned. AB - BACKGROUND: In the United States (US) and Brazil, obesity has emerged as a health epidemic. This article is driven by the following research questions: how did the US and Brazil's federal institutions respond to obesity? And how did these responses affect policy implementation? The aim of this article is therefore to conduct a comparative case study analysis of how these nations' institutions responded in order to determine the key lessons learned. METHODS: This study uses primary and secondary qualitative data to substantiate causal arguments and factual claims. RESULTS: Brazil shows that converting preexisting federal agencies working in primary healthcare to emphasize the provision of obesity prevention services can facilitate policy implementation, especially in rural areas. Brazil also reveals the importance of targeting federal grant support to the highest obesity prevalence areas and imposing grant conditionalities, while illustrating how the incorporation of social health movements into the bureaucracy facilitates the early adoption of nutrition and obesity policies. None of these reforms were pursued in the US. CONCLUSIONS: Brazil's government has engaged in innovative institutional conversion processes aiding its ability to sustain its centralized influence when implementing obesity policy. The US government's adoption of Brazil's institutional innovations may help to strengthen its policy response. PMID- 26058702 TI - Comparison of diffusion tractography and tract-tracing measures of connectivity strength in rhesus macaque connectome. AB - With the mapping of macroscale connectomes by means of in vivo diffusion-weighted MR Imaging (DWI) rapidly gaining in popularity, one of the necessary steps is the examination of metrics of connectivity strength derived from these reconstructions. In the field of human macroconnectomics the number of reconstructed fiber streamlines (NOS) is more and more used as a metric of cortico-cortical interareal connectivity strength, but the link between DWI NOS and in vivo animal tract-tracing measurements of anatomical connectivity strength remains poorly understood. In this technical report, we communicate on a comparison between DWI derived metrics and tract-tracing metrics of projection strength. Tract-tracing information on projection strength of interareal pathways was extracted from two commonly used macaque connectome datasets, including (1) the CoCoMac database of collated tract-tracing experiments of the macaque brain and (2) the high-resolution tract-tracing dataset of Markov and Kennedy and coworkers. NOS and density of reconstructed fiber pathways derived from DWI data acquired across 10 rhesus macaques was found to positively correlate to tract tracing based measurements of connectivity strength across both the CoCoMac and Markov dataset (both P < 0.001), suggesting DWI NOS to form a valid method of assessment of the projection strength of white matter pathways. Our findings provide confidence of in vivo DWI connectome reconstructions to represent fairly realistic estimates of the wiring strength of white matter projections. Our cross modal comparison supports the notion of in vivo DWI to be a valid methodology for robust description and interpretation of brain wiring. PMID- 26058703 TI - Reliable mortality statistics for Turkey: Are we there yet? AB - BACKGROUND: The Turkish government has implemented several reforms to improve the Turkish Statistical Institute Death Reporting System (TURKSTAT-DRS) since 2009. However, there has been no assessment to evaluate the impact of these reforms on causes of death statistics. This study attempted to analyse the impact of these reforms on the TURKSTAT-DRS for Turkey, and in the case of Izmir, one of the most developed provinces in Turkey. METHODS: The evaluation framework comprised three main components each with specific criteria. Firstly, data from TURKSTAT for Turkey and Izmir for the periods 2001-2008 and 2009-2013 were assessed in terms of the following dimensions that represent quality of mortality statistics (a. completeness of death registration, b. trends in proportions of deaths with ill defined causes). Secondly, the quality of information recorded on individual death certificates from Izmir in 2010 was analysed for a. missing information, b. timeliness of death notifications and c. characteristics of deaths with ill defined causes. Finally, TURKSTAT data were analysed to estimate life tables and summary mortality indicators for Turkey and Izmir, as well as the leading causes of-death in Turkey in 2013. RESULTS: Registration of adult deaths in Izmir as well as at the national level for Turkey has considerably improved since the introduction of reforms in 2009, along with marked decline in the proportions of deaths assigned ill-defined causes. Death certificates from Izmir indicated significant gaps in recorded information for demographic as well as epidemiological variables, particularly for infant deaths, and in the detailed recording of causes of death. Life expectancy at birth estimated from local data is 3-4 years higher than similar estimates for Turkey from international studies, and this requires further investigation and confirmation. CONCLUSION: The TURKSTAT-DRS is now an improved source of mortality and cause of death statistics for Turkey. The reliability and validity of TURKSTAT data needs to be established through a detailed research program to evaluate completeness of death registration and validity of registered causes of death. Similar evaluation and data analysis of mortality indicators is required at regular intervals at national and sub-national level, to increase confidence in their utility as primary data for epidemiology and health policy. PMID- 26058704 TI - Species sensitivity weighted distribution for ecological risk assessment of engineered nanomaterials: the n-TiO2 case study. AB - Societal concerns about the environmental risks of engineered nanomaterials (ENMs) have recently increased, but nano-ecological risk assessments are constrained by significant gaps in basic information on long-term effects and exposures, for example. An approach to the ecological risk assessment of ENMs is proposed that can operate in the context of high uncertainty. This approach further develops species sensitivity weighted distribution (SSWD) by including 3 weighting criteria (species relevance, trophic level abundance, and nanotoxicity data quality) to address nano-specific needs (n-SSWD). The application of n-SSWD is illustrated for nanoscale titanium dioxide (n-TiO2 ), which is available in different crystal forms; it was selected because of its widespread use in consumer products (e.g., cosmetics) and the ample availability of data from ecotoxicological studies in the literature (including endpoints for algae, invertebrates, bacteria, and vertebrates in freshwater, saltwater, and terrestrial compartments). The n-SSWD application resulted in estimation of environmental quality criteria (hazard concentration affecting 5% and 50% of the species) and ecological risk (potentially affected fraction of species), which were then compared with similar results obtained by applying the traditional species sensitivity distribution (SSD) approach to the same dataset. The n-SSWDs were also built for specific trophic levels (e.g., primary producers) and taxonomic groups (e.g., algae), which helped to identify the most sensitive organisms. These results showd that n-SSWD is a valuable risk tool, although further testing is suggested. PMID- 26058705 TI - Ammonia-based intermittent aeration control optimized for efficient nitrogen removal. AB - This work describes the development of an intermittently aerated pilot-scale process (V = 0.45 m(3) ) operated for optimized efficient nitrogen removal in terms of volume, supplemental carbon and alkalinity requirements. The intermittent aeration pattern was controlled using a strategy based on effluent ammonia concentration set-points. The unique feature of the ammonia-based aeration control was that a fixed dissolved oxygen (DO) set-point was used and the length of the aerobic and anoxic time (anoxic time >=25% of total cycle time) were changed based on the effluent ammonia concentration. Unlike continuously aerated ammonia-based aeration control strategies, this approach offered control over the aerobic solids retention time (SRT) to deal with fluctuating ammonia loading without solely relying on changes to the total SRT. This approach allowed the system to be operated at a total SRT with a small safety factor. The benefits of operating at an aggressive SRT were reduced hydraulic retention time (HRT) for nitrogen removal. As a result of such an operation, nitrite oxidizing bacteria (NOB) out-selection was also obtained (ammonia oxidizing bacteria [AOB] maximum activity: 400 +/- 79 mgN/L/d, NOB maximum activity: 257 +/- 133 mgN/L/d, P < 0.001) expanding opportunities for short-cut nitrogen removal. The pilot demonstrated a total inorganic nitrogen (TIN) removal rate of 95 +/- 30 mgN/L/d at an influent chemical oxygen demand: ammonia (COD/NH4 (+) -N) ratio of 10.2 +/- 2.2 at 25 degrees C within the hydraulic retention time (HRT) of 4 h and within a total SRT of 5-10 days. The TIN removal efficiency up to 91% was observed during the study, while effluent TIN was 9.6 +/- 4.4 mgN/L. Therefore, this pilot-scale study demonstrates that application of the proposed on-line aeration control is capable of relatively high nitrogen removal without supplemental carbon and alkalinity addition at a low HRT. PMID- 26058706 TI - Caution When Diagnosing Your Mouse With Schizophrenia: The Use and Misuse of Model Animals for Understanding Psychiatric Disorders. AB - Animal models are widely used in biomedical research, but their applicability to psychiatric disorders is less clear. There are several reasons for this, including 1) emergent features of psychiatric illness that are not captured by the sum of individual symptoms, 2) a lack of equivalency between model animal behavior and human psychiatric symptoms, and 3) the possibility that model organisms do not have (and may not be capable of having) the same illnesses as humans. Here, we discuss the effective use, and inherent limitations, of model animals for psychiatric research. As disrupted-in-schizophrenia 1 (DISC1) is a genetic risk factor across a spectrum of psychiatric disorders, we focus on the results of studies using mice with various mutations of DISC1. The data from a broad range of studies show remarkable consistency with the effects of DISC1 mutation on developmental/anatomical endophenotypes. However, when one expands the phenotype to include behavioral correlates of human psychiatric diseases, much of this consistency ends. Despite these challenges, model animals remain valuable for understanding the basic brain processes that underlie psychiatric diseases. We argue that model animals have great potential to help us understand the core neurobiological dysfunction underlying psychiatric disorders and that marrying genetics and brain circuits with behavior is a good way forward. PMID- 26058707 TI - Taiwanese Women's Experiences of Lactation Suppression After Stillbirth. AB - OBJECTIVE: To explore the experiences of lactation suppression (LS) among Taiwanese women who experienced stillbirth after 20-weeks gestation. DESIGN: Qualitative research combining practitioner ethnography and the observ-view method (participant observation and unstructured interviews while caring for participants). SETTING: Participants were recruited from a medical center in central Taiwan between June 2013 and November 2014. PARTICIPANTS: Seven Taiwanese women who had stillbirths. METHODS: Data were collected by the observ-view method. Recorded interviews were analyzed by content analysis. RESULTS: Participants described three core experiences: deciding to use LS without careful deliberation; psychological pain is substantially stronger than physical pain; and not regretting their choice regarding method of LS. CONCLUSION: Physical pain often remains unaddressed because of the greater psychological pain following fetal death. Therefore, LS should be an essential component of follow-up care as part of the discharge plan. Follow-up should be for at least 14 days. More research is needed on nonpharmacological LS to address cultural differences and personal beliefs about methods of LS. PMID- 26058708 TI - Reply to finasteride and dutasteride may reduce melanoma risk. PMID- 26058709 TI - Quantum cognition: a new theoretical approach to psychology. AB - What type of probability theory best describes the way humans make judgments under uncertainty and decisions under conflict? Although rational models of cognition have become prominent and have achieved much success, they adhere to the laws of classical probability theory despite the fact that human reasoning does not always conform to these laws. For this reason we have seen the recent emergence of models based on an alternative probabilistic framework drawn from quantum theory. These quantum models show promise in addressing cognitive phenomena that have proven recalcitrant to modeling by means of classical probability theory. This review compares and contrasts probabilistic models based on Bayesian or classical versus quantum principles, and highlights the advantages and disadvantages of each approach. PMID- 26058710 TI - Oxidative stress factors and C-reactive protein in patients with oral lichen planus before and 2 weeks after treatment. AB - OBJECTIVES: Oral lichen planus (OLP) is an inflammatory disease with an unknown origin. Oxidative stress is suspected to play a role in its pathogenesis. The aim of this study was to evaluate serum levels of oxidative stress factors and C reactive protein in patients with OLP. MATERIALS & METHODS: In this case-control study, 25 patients with OLP and 23 control subjects were enrolled. Serum levels of C-reactive protein (CRP), malondialdehyde (MDA), and total antioxidant capacity (TAC) were investigated in both groups. In case group, all these factors were re-evaluated after 14 days of treatment. The characteristics of the lesions were also recorded at each visit. RESULTS: Serum levels of MDA were significantly higher (P = 0.009), and TAC was significantly lower (P < 0.001) in patients with OLP. There were no significant differences between serum levels of TAC, CRP, and MDA in patients with OLP before and after treatment (P = 0.174, P = 0.556, P = 0.194, respectively). However, the difference in serum levels of TAC between erosive and atrophic patients with keratotic OLP was significant (P = 0.024). CONCLUSION: We concluded patients with OLP have increased of serum MDA and the decrease of serum TAC compared with the healthy subjects, and 14-day treatment of OLP did not have any effect on serum levels of oxidative stress factors. PMID- 26058712 TI - Seroprevalence of past dengue virus infection among children and adolescents in Singapore. AB - We conducted a pediatric seroprevalence study of dengue virus (DENV) infection in Singapore, a dengue endemic city-state. Residual sera from 1,200 Singapore residents aged 1-17 years seen in two hospitals between 2008 and 2010 were tested for anti-DENV IgG antibodies. The overall seroprevalence was 10.4% (95%CI: 8.7 12.1%). There had been a marked decline in seroprevalence in the 15-19-year age group over the last three decades, while the prevalence in the 1-5-year olds (12.6%) was significantly higher than that of the 1996-1997 pediatric survey (0.8%). The overall dengue seroprevalence in children and adolescents remained low. PMID- 26058711 TI - A live attenuated vaccine prevents replication and transmission of H7N9 virus in mammals. AB - The continued spread of the newly emerged H7N9 viruses among poultry in China, together with the emergence of drug-resistant variants and the possibility of human-to-human transmission, has spurred attempts to develop an effective vaccine. An MF59-adjuvant H7N9 inactivated vaccine is reported to be well tolerated and immunogenic in humans; however a study in ferrets indicated that while a single dose of the inactivated H7N9 vaccine reduced disease severity, it did not prevent virus replication and transmission. In this study, we used reverse genetics to produce a cold-adapted, live attenuated H7N9 vaccine (H7N9/AAca) that contains wild-type HA and NA genes from AH/1, and the backbone of the cold-adapted influenza H2N2 A/Ann Arbor/6/60 virus (AAca). H7N9/AAca was attenuated in mice and ferrets, and induced robust neutralizing antibody responses in rhesus mice, ferrets, and guinea pigs immunized once or twice intranasally. The animals immunized twice were completely protected from H7N9 virus challenge. Importantly, the animals vaccinated once were fully protected from transmission when exposed to or in contact with the H7N9 virus-inoculated animals. These results demonstrate that a cold-adapted H7N9 vaccine can prevent H7N9 virus transmission; they provide a compelling argument for further testing of this vaccine in human trials. PMID- 26058713 TI - The profiling and identification of the metabolites of 8-prenylkaempferol and a study on their distribution in rats by high-performance liquid chromatography with diode array detection combined with electrospray ionization ion trap time-of flight multistage mass spectrometry. AB - 8-Prenylkaempferol is a prenylflavonoid that has various bioactivities and benefits for human health. A high-performance liquid chromatography with a diode array detector combined with electrospray ionization ion trap time-of-flight multistage mass spectrometry (HPLC-DAD-ESI-IT-TOF-MS(n) ) method was established to profile and identify the metabolites of 8-prenylkaempferol in rat in vivo and in vitro, and to study the distribution of these metabolites in rats for the first time. A total of 38 metabolites were detected and tentatively identified, 30 of which were identified as new compounds. The new in vivo metabolic reactions in rats of prenylflavonoids of isomerization, polymerization, sulfation, amino acid conjugation, vitamin C conjugation and other known metabolic reactions were found in the metabolism of 8-prenylkaempferol. The numbers of detected metabolites in feces, urine, plasma, small intestine, stomach, kidneys, liver, heart, lungs, spleen and hepatic S9 fraction were 31, 19, 1, 20, 13, 8, 7, 3, 3, 1 and 11, respectively. This indicated that small intestine and stomach were the major organs in which the 8-prenylkaempferol metabolites were distributed. Furthermore, 16 metabolites were determined to have bioactivities based on the literature and 'PharmMapper' analysis. These findings are useful for better comprehension of the effective forms, target organs and pharmacological actions of 8-prenylkaempferol. Moreover, they provide a reference for the study of the metabolism and distribution of prenylflavonoid aglycone compounds. PMID- 26058714 TI - ATP Release and P2 Y Receptor Signaling are Essential for Keratinocyte Galvanotaxis. AB - Repair to damaged tissue requires directional cell migration to heal the wound. Immediately upon wounding an electrical guidance cue is created with the cathode of the electric field (EF) located at the center of the wound. Previous research has demonstrated directional migration of keratinocytes toward the cathode when an EF of physiological strength (100-150 mV/mm) is applied in vitro, but the "sensor" by which keratinocytes sense the EF remains elusive. Here we use a customized chamber design to facilitate the application of a direct current (DC) EF of physiological strength (100 mV/mm) to keratinocytes whilst pharmacologically modulating the activation of both connexin hemichannels and purinergic receptors to determine their role in EF-mediated directional keratinocyte migration, galvanotaxis. In addition, keratinocytes were exposed to DiSCAC2 (3) dye to visualize membrane potential changes within the cell upon exposure to the applied DC EF. Here we unveil ATP-medicated mechanisms that underpin the initiation of keratinocyte galvanotaxis. The application of a DC EF of 100 mV/mm releases ATP via hemichannels activating a subset of purinergic P2 Y receptors, locally, to initiate the directional migration of keratinocytes toward the cathode in vitro, the center of the wound in vivo. The delineation of the mechanisms underpinning galvanotaxis extends our understanding of this endogenous cue and will facilitate the optimization and wider use of EF devices for chronic wound treatment. J. Cell. Physiol. 230: 181-191, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26058715 TI - Lipid Liquid-Crystal Phase Change Induced through near-Infrared Irradiation of Entrained Graphene Particles. AB - Lipid packing is intimately related to the geometry of the lipids and the forces that drive self-assembly. Here, the photothermal response of a cubic liquid crystalline phase formed using phytantriol in the presence of low concentrations of pristine graphene was evaluated. Small-angle X-ray scattering showed the reversible phase changes from cubic to hexagonal to micellar due to localized heating through irradiation with near-infrared (NIR) light and back to cubic after cooling. PMID- 26058716 TI - The experience of older people living independently in Singapore. AB - BACKGROUND: Globally, older people are living independently either alone or with their spouse, population continues to age. In Singapore, some may live with an unrelated older person in a public rental apartment. In Asia, these older people are associated with increased risks of poor health and social isolation, have poorer social support and a poor quality of life. Few studies have explored why these older people choose such living arrangements, the challenges they encountered and what has helped or may help them overcome these challenges. AIM: To explore older people's experiences of living independently or with an unrelated older person. METHODS: This descriptive qualitative study involved face to-face interviews with 25 informants, 65 years or older in Singapore. Thematic analysis was adopted. RESULTS: Five themes emerged: (1) making own choice- participants decided to live apart from their families, (2) contending with concerns--the availability of external resources for participants was shrinking, (3) coping with the available assistance--depending on available external resources from the community, (4) holding on to their values--participants rely on their internal resources to manage, and (5) preparing for the inevitable- participants were planning for their final years of life and for their death. CONCLUSION: Older people have such living arrangements for many reasons. They attain well-being and quality of life by devising strategies, tapping on their limited external resources and relying on their values to manage their diminishing resources and the foreseeable death. IMPLICATIONS FOR NURSING AND/OR HEALTH POLICY: Understanding older people's experiences may help nurses and health professionals to develop health promotion programmes that support older people's everyday needs and help them to stay healthy. Public health policy must support older people to live in a safe environment near their extended family to reduce their need to relocate. PMID- 26058717 TI - Improvement in Interstage Survival in a National Pediatric Cardiology Learning Network. PMID- 26058718 TI - Temporal Trends in Quality of Life Outcomes After Transapical Transcatheter Aortic Valve Replacement: A Placement of AoRTic TraNscathetER Valve (PARTNER) Trial Substudy. AB - BACKGROUND: In the Placement of AoRTic TraNscathetER Valve (PARTNER) randomized controlled trial (RCT), which represented the first exposure to transapical transcatheter aortic valve replacement (TA-TAVR) for many clinical sites, high risk patients undergoing TA-TAVR derived similar health-related quality of life (HRQoL) outcomes when compared with surgical aortic valve replacement (SAVR). With increasing experience, it is possible that HRQoL outcomes of TA-TAVR may have improved. METHODS AND RESULTS: We evaluated HRQoL outcomes at 1-, 6-, and 12 month follow-ups among 875 patients undergoing TA-TAVR in the PARTNER nonrandomized continued access (NRCA) registry and compared these outcomes with those of the TA-TAVR and SAVR patients in the PARTNER RCT. HRQoL was assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Medical Outcomes Study Short-Form 12, and the EuroQoL-5D, with the KCCQ overall summary score serving as the primary end point. The NRCA TA-TAVR and RCT TA-TAVR and SAVR groups were generally similar. The primary outcome, the KCCQ summary score, did not differ between the NRCA TA-TAVR and the RCT TA-TAVR group at any follow-up timepoints, although there were small differences in favor of the NRCA cohort on several KCCQ subscales at 1 month. There were no significant differences in follow-up HRQOL between the NRCA-TAVR and the RCT SAVR cohorts on the KCCQ overall summary scale or any of the disease-specific or generic subscales. CONCLUSIONS: Despite greater experience with TA-TAVR in the NRCA registry, HRQoL outcomes remained similar to those of TA-TAVR in the original RCT cohort and no better than those with SAVR. These findings have important implications for patient selection for TAVR when transfemoral access is not an option. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894. PMID- 26058719 TI - Effect of the Lookback Period's Length Used to Identify Incident Acute Myocardial Infarction on the Observed Trends on Incidence Rates and Survival: Cardiovascular Disease in Norway Project. AB - BACKGROUND: In studies using patient administrative data, the identification of the first (incident) acute myocardial infarction (AMI) in an individual is based on retrospectively excluding previous hospitalizations for the same condition during a fixed time period (lookback period [LP]). Our aim was to investigate whether the length of the LP used to identify the first AMI had an effect on trends in AMI incidence and subsequent survival in a nationwide study. METHODS AND RESULTS: All AMI events during 1994 to 2009 were retrieved from the Cardiovascular Disease in Norway project. Incident AMIs during 2004 to 2009 were identified using LPs of 10, 8, 7, 5, and 3 years. For each LP, we calculated time trends in incident AMI and subsequent 28-day and 1-year mortality rates. Results obtained from analyses using the LP of 10 years were compared with those obtained using shorter LPs. In men, AMI incidence rates declined by 4.2% during 2004 to 2009 (incidence rate ratio, 0.958; 95% confidence interval, 0.935-0.982). The use of other LPs produced similar results, not significantly different from the LP of 10 years. In women, AMI incidence rates declined by 7.3% (incidence rate ratio, 0.927; 95% confidence interval, 0.901-0.955) when an LP of 10 years was used. The decline was statistically significantly smaller for the LP of 5 years (6.2% versus 7.3%; P=0.02) and 3 years (5.9% versus 7.3%; P=0.03). The choice of LP did not influence trends in 28-day and 1-year mortality rates. CONCLUSIONS: The length of LP may influence the observed time trends in incident AMIs. This effect is more evident in older women. PMID- 26058720 TI - Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). AB - BACKGROUND: Instruments to assess symptom burden and quality of life among patients with atrial fibrillation (AF) have not been well evaluated in community practice or associated with patient outcomes. METHODS AND RESULTS: Using data from 10 087 AF patients in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), symptom severity was evaluated using the European Heart Rhythm Association (EHRA) classification system, and quality of life was assessed using the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire. The association between AF-related symptoms, quality of life, and outcomes was assessed using Cox regression. The majority of AF patients (61.8%) were symptomatic (EHRA >2) and 16.5% had severe or disabling symptoms (EHRA 3-4). EHRA symptom class was well correlated with the AFEQT score (Spearman correlation coefficient -0.39). Over 1.8 years of follow-up, AF symptoms were associated with a higher risk of hospitalization (adjusted hazard ratio for EHRA >=2 versus EHRA 1 1.23, 95% confidence interval, 1.15-1.31) and a borderline higher risk of major bleeding. Lower quality of life was associated with a higher risk of hospitalization (adjusted hazard ratio for lowest quartile of AFEQT versus highest 1.49, 95% confidence interval, 1.2-1.84), but not other major adverse events, including death. CONCLUSIONS: In a community-based study, most patients with AF were symptomatic and had impaired quality of life. Quality of life measured by the AFEQT correlated closely with symptom severity measured by the EHRA class. AF symptoms and lower quality of life were associated with higher risk of hospitalization but not mortality during follow-up. PMID- 26058722 TI - Metals in Some Edible Fish and Shrimp Species Collected in Dry Season from Subarnarekha River, India. AB - The concentration of As, Cd, Cu, Fe, Pb, Ni, Zn, Cr, Co and Sr were determined in five fish and one shrimp species collected from the Subarnarekha River during pre monsoon season using inductively coupled plasma-mass spectrometry for a risk assessment and source apportionment study. Concentrations of metals in the fish and shrimp exceeded the recommended food standards for As, Cu, Ni, Cd and Zn in many samples. Principal component analysis suggested both innate and anthropogenic activities as contributing sources of metal in the fish and shrimp. The calculated target hazard quotients and hazard indices indicated that high concentrations of metals in some species at some locations present an appreciable risk to the health of consumers of these species. PMID- 26058721 TI - Novel Oral Anticoagulant Use Among Patients With Atrial Fibrillation Hospitalized With Ischemic Stroke or Transient Ischemic Attack. AB - BACKGROUND: Novel oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for preventing stroke or transient ischemic attack in patients with atrial fibrillation, yet diffusion of these therapies and patterns of use among atrial fibrillation patients with ischemic stroke and transient ischemic attack have not been well characterized. METHODS AND RESULTS: Using data from Get With The Guidelines-Stroke, we identified a cohort of 61 655 atrial fibrillation patients with ischemic stroke or transient ischemic attack hospitalized between October 2010 and September 2012 and discharged on warfarin or NOAC (either dabigatran or rivaroxaban). Multivariable logistic regression was used to identify factors associated with NOAC versus warfarin therapy. In our study population, warfarin was prescribed to 88.9%, dabigatran to 9.6%, and rivaroxaban to 1.5%. NOAC use increased from 0.04% to a 16% to 17% plateau during the study period, although anticoagulation rates among eligible patients did not change appreciably (93.7% versus 94.1% from first quarter 2011 to second quarter 2012), suggesting a trend of switching from warfarin to NOACs rather than increased rates of anticoagulation among eligible patients. Several bleeding risk factors and CHA2DS2-VASc scores were lower among those discharged on NOAC versus warfarin therapy (47.9% versus 40.9% with CHA2DS2-VASc <=5, P<0.001 for difference in CHA2DS2-VASc). CONCLUSIONS: NOACs have had modest but growing uptake over time among atrial fibrillation patients hospitalized with stroke or transient ischemic attack and are prescribed to patients with lower stroke risk compared with warfarin. PMID- 26058723 TI - Association of sagittal spinal alignment with thickness and echo intensity of lumbar back muscles in middle-aged and elderly women. AB - OBJECTIVE: Quantitative changes, such as a decrease in muscle mass, and qualitative changes, such as an increase in the amount of intramuscular non contractile tissue, occur with aging. However, it is unclear whether quantitative or qualitative changes in back muscles are associated with spinal alignment in the standing position. We investigated the association of sagittal spinal alignment with muscle thickness as an index of the mass of lumbar back muscles and muscle echo intensity as an index of the amount of non-contractile tissue within these muscles. METHODS: Study participants comprised 36 middle-aged and elderly women. Thickness and echo intensity of erector spinae, psoas major, and lumbar multifidus muscles were measured using an ultrasound imaging device. Standing sagittal spinal alignment, determined from thoracic kyphosis and lumbar lordosis angles, and the sacral anterior inclination angle was measured using the Spinal Mouse. RESULTS: Stepwise regression analysis performed using muscle thickness, echo intensity, and age as independent variables showed that erector spinae muscle thickness was a significant determinant of the thoracic kyphosis angle. Psoas major muscle thickness and echo intensity of the lumbar multifidus muscle were significant determinants of the sacral anterior inclination angle. CONCLUSION: Our results suggest that an increase in thoracic kyphosis is associated with a decrease in the mass of the erector spinae muscle, and that a decrease in pelvic anterior inclination is associated with a decrease in the mass of the psoas major muscle and an increase in the amount of non-contractile tissue within the lumbar multifidus muscle. PMID- 26058724 TI - Kinetic Nature of Grain Boundary Formation in As-Grown MoS2 Monolayers. AB - Grain boundaries in as-grown polycrystalline MoS2 monolayers are revealed by second-harmonic-generation microscopy. Through the anisotropic polarization pattern and phase interference at the grain boundary, grain edge termination and boundary types are identified. Statistical analysis on hundreds of grains shows that grain-boundary formation is driven by kinetics and can be nicely described by the edge attachment growth model. PMID- 26058725 TI - Webinar: A useful tool in plastic surgery specialty trainee education. PMID- 26058726 TI - Referral patterns to a surgical lymphoedema service: 10 years of experience. AB - INTRODUCTION: Liposuction for lymphoedematous limbs is an effective treatment for chronic lymphoedema, with excellent long-term results in well-selected patients. In 2008 NICE produced guidelines 'Liposuction for Chronic lymphoedema', acknowledging this treatment modality. However, there remain very few centers that provide this service in the United Kingdom. We aim to share our experience of our referral system at Ninewells Hospital, Dundee, Scotland. METHODS: A 10 year prospective database from 2005 to 2014 was analysed. Referral sources, patient demographics, diagnosis and treatment offered were examined. RESULTS: There were 221 referrals in total, 190 (86%) female and 31 (14%) male. The mean age was 51 (range 7-86 years). 127 (58%) were referred via their general practitioners, 72 (33%) from a hospital consultant and 22 (10%) from a lymphoedema nurse specialist. 153 (69%) referrals were from Scotland, 61 (28%) from England and 7 (3%) from Northern Ireland. The majority of patients 165 (75%) were referred with lower limb swelling. Following assessment in clinic, 146 (66%) were found to have lymphoedema whilst the rest were deemed to have other non lymphoedematous diagnoses which include lipoedema (47, 21%), dependent oedema (8, 4%) and obesity (5, 2%). 131 (59%) were offered liposuction- 74 (34%) have received liposuction, 18 (8%) are awaiting their procedure, 3 (1%) have declined surgery, 27 (12%) are awaiting funding approval and 9 (4%) have been declined funding by their primary care trust/clinical commissioning group (PCT/CCG). 4 (2%) are awaiting investigations to further evaluate the cause of their swelling, whilst the remaining 86 (39%) were felt unsuitable for surgery and were treated conservatively. CONCLUSION: Chronic lymphoedema is a challenging condition to treat, with few specialist centers offering surgical treatment. We hereby share our referral process, diagnosis and management. PMID- 26058728 TI - Morphologic characteristics of the placental basal plate in in vitro fertilization pregnancies: a possible association with the amount of bleeding in delivery. AB - The aim of the present study was to investigate the relationship between assisted reproductive technology procedures, the morphology of the basal plate of placentas, and amount of bleeding in deliveries. Fifty-five whole placentas (fresh-embryo transfer in the in vitro fertilization cycle [n = 6], frozen-thawed embryo transfer in the natural cycle [n = 13] or in the hormonal cycle [n = 10], and age-matched spontaneously conceived pregnancies [n = 26]) were retrospectively enrolled and histologically analyzed. The whole placentas were stored in our pathological division among 512 singleton pregnancies with vaginal deliveries (34-41 weeks of gestation) at Hamamatsu University Hospital. The morphology of the placental basal plate was examined using Azan staining. A total of 20 digital images (each 0.53 mm(2)) of microscopic fields were analyzed per placenta to measure the mean values of the vertical maximum thickness of Rohr and Nitabuch fibrinoid layers and % loss of decidua. The thickness of Rohr fibrinoid layer and % loss of decidua were significantly higher in the frozen-thawed embryo transfer in the hormonal cycle group than in the frozen-thawed embryo transfer in the natural cycle and spontaneously conceived pregnancy groups (each P < .01). The z scores for both the thickness of Rohr fibrinoid layer and % loss of decidua positively correlated with those for the amount of bleeding in deliveries (P < .05 each). Assisted reproductive technology procedures changed the morphology of the placental basal plate, suggesting a possible association with an increase in the amount of bleeding in deliveries. PMID- 26058727 TI - Utility of BRAF V600E Immunohistochemistry Expression Pattern as a Surrogate of BRAF Mutation Status in 154 Patients with Advanced Melanoma. AB - Successful BRAF inhibitor therapy depends on the accurate assessment of the mutation status of the BRAF V600 residue in tissue samples. In melanoma, immunohistochemical (IHC) analysis with monoclonal anti-BRAF V600E has emerged as a sensitive and specific surrogate of BRAF V600E mutation, particularly when BRAF V600E protein expression is homogeneous and strong. A subset of melanomas exhibit heterogeneous labeling for BRAF V600E, but our understanding of the significance of heterogeneous BRAF V600E IHC expression is limited. We used next-generation sequencing to compare BRAF V600E IHC staining patterns in 154 melanomas: 79 BRAF(WT) and 75 BRAF (including 53 V600E) mutants. Agreement among dermatopathologists on tumor morphology, IHC expression, and intensity was excellent (rho = 0.99). A predominantly epithelioid cell phenotype significantly correlated with the BRAF V600E mutation (P = .0085). Tumors demonstrating either heterogeneous or homogeneous IHC expression were significantly associated with the BRAF V600E mutation (P < .0001), as was increased intensity of staining (P < .0001). The positive predictive value was 98% for homogenous IHC expression compared with 70% for heterogeneous labeling. Inclusion of both heterogeneous and homogeneous BRAF V600E IHC expression as a positive test significantly improved IHC test sensitivity from 85% to 98%. However, this reduced BRAF V600E IHC test specificity from 99% to 96%. Cautious evaluation of heterogeneous BRAF V600E IHC expression is warranted and comparison with sequencing results is critical, given its reduced test specificity and positive predictive value for detecting the BRAF V600E mutation. PMID- 26058729 TI - CXCL5/CXCR2 axis promotes bladder cancer cell migration and invasion by activating PI3K/AKT-induced upregulation of MMP2/MMP9. AB - Bladder cancer (BCa) is the most common malignant disease of the urinary tract system, yet the etiology is still poorly understood. Clinically, the majority of BCa patients progress to invasive disease at the final stage, leading to death. Previous investigations have demonstrated that matrix metal-loproteinases (MMPs) play irreplaceable roles in tumor cell extravasation and implantation. In addition, increasing numbers of reports provide evidence that MMPs, especially MMP2 and MMP9 are monitored by various signal transduction pathways targeting tumor metastasis. Seed-and-soil theory has called to attention the importance of the tumor microenvironment in disease progression. To that end, we previously reported the key role of hypoxia in BCa progression. Herein, we report the role of chemokines, specifically CXCL5, is involved in BCa development. Though it has been reported that CXCL5 promotes BCa metastasis and progression, the exact mechanisms are still unknown, necessitating the need for further investigation into the role of CXCL5 in BCa. In this study, IHC staining of BCa tumor sections showed elevated expression of CXCL5 in BCa, which correlated with disease stage. Our mechanistic studies show that CXCL5 contributes to BCa migration and invasion by binding to its receptor, CXCR2, leading to the upregulation of MMP2/MMP9 by activating PI3K/AKT signaling. This study offers vital evidence of how CXCL5 promotes BCa metastasis, and thus may potentially be used as a therapeutic target against BCa. PMID- 26058730 TI - Long-term patterns of safety and efficacy of bleeding prophylaxis with turoctocog alfa (NovoEight((r)) ) in previously treated patients with severe haemophilia A: interim results of the guardian(TM) 2 extension trial. PMID- 26058731 TI - Recent developments and future prospects of all-metal aromatic compounds. AB - The usefulness of aromaticity/antiaromaticity concepts to foresee structural stability patterns and salient features of the electronic structure of small inorganic and all-metal rings has been put forward. A critical revision of the advances made in the theoretical methods to assess the aromaticity/antiaromaticity of these compounds has also been made. In particular, the performance of local versus non-local indices has been reviewed. Finally, the passivation of these rings has been put forward as a key issue in order to prevent them from collapsing into larger aggregates and to provide them protection against the environment. PMID- 26058732 TI - Physico-chemical properties of starches isolated from potato cultivars grown in soils with different phosphorus availability. AB - BACKGROUND: Starch is the major component of potato tubers, amounting approximately to 150-200 g kg (-1) of the tuber weight. Starch is considered to be a major factor for the functionality of the potato in food applications. This study evaluated the physical characteristics of potato starches isolated from tubers of different potato cultivars grown in soil with three levels of phosphorus (P) availability. All potatoes were growing according the same method. The starches were isolated by physical methods and the samples were analyzed for the amylose, P content, paste properties (RVA) and thermal properties of gelatinization and retrogradation (DSC). Experimental data were analyzed considering the potato cultivars and the three soil P availability. RESULTS: For all measured parameters significant impact of cultivar and soil P availability was determined. Phosphorus contents in potato starches ranged from 0.252 to 0.647 g kg(-1) and amylose from 27.18 to 30.8%. Starches from different potato cultivars independent of soil showed a small range of gelatinization temperature. All starches showed low resistance heating and shear stress. CONCLUSION: The results showed the influence of growing conditions (soil P availability) and also of the differences between the potato cultivars on important characteristics of applicability of starches. PMID- 26058733 TI - Effects of a prolonged infusion of fentanyl, with or without atropine, on the minimum alveolar concentration of isoflurane in dogs. AB - OBJECTIVES: To evaluate the effect of a prolonged constant rate infusion (CRI) of fentanyl on the minimum alveolar concentration (MAC) of isoflurane (ISOMAC ) and to establish whether concurrent atropine administration influences ISOMAC in dogs. STUDY DESIGN: Prospective, crossover study. ANIMALS: Six healthy dogs weighing 13.0 +/- 4.1 kg. METHODS: Dogs were anesthetized with isoflurane under conditions of normocapnia and normothermia. Arterial blood pressure was monitored invasively. Each dog was administered two treatments, on different occasions, in a crossover design. The dogs were administered intravenously (IV) an atropine bolus 0.02 mg kg(-1) and CRI at 0.04 mg kg(-1) hour(-1) (fentanyl-atropine treatment) or no atropine (fentanyl treatment). For each dog, baseline ISOMAC was measured in duplicate using a tail clamp technique. Subsequently, all dogs were administered a fentanyl bolus (5 MUg kg(-1)) and CRI (9 MUg kg(-1) hour(-1)) IV, and ISOMAC was re-determined at 120 and 300 minutes after initiation of the fentanyl CRI. RESULTS: Baseline ISOMAC values in the fentanyl and fentanyl atropine treatments were 1.38 +/- 0.16% and 1.39 +/- 0.14%, respectively. Fentanyl significantly decreased the ISOMAC by 50 +/- 9% and 47 +/- 13% after 120 minutes and by 51 +/- 14% and 50 +/- 9% after 300 minutes (p < 0.001) in the fentanyl and fentanyl-atropine treatments, respectively. Compared with baseline, heart rate decreased significantly in the fentanyl treatment by 35% and 43% at 120 and 300 minutes, respectively. In the fentanyl-atropine treatment, heart rate did not change significantly over time. In both treatments, systolic arterial pressure increased from baseline after fentanyl. CONCLUSIONS AND CLINICAL RELEVANCE: In this study, fentanyl reduced the ISOMAC by approximately 50%. The ISOMAC remained stable throughout the 300 minute CRI of fentanyl, suggesting no cumulative effect of the opioid. Atropine did not influence ISOMAC in dogs. PMID- 26058734 TI - Meanings of at-homeness at end-of-life among older people. AB - Maintaining the well-being of older people who are approaching the end-of-life has been recognised as a significant aspect of well-being in general. However, there are few studies that have explicitly focused on at-homeness among older people. This study aims to illuminate meanings of at-homeness among older people with advancing illnesses. Twenty men and women, aged 85 or older, with advancing illnesses and who lived in their own homes, in nursing homes or in short-term nursing homes in three urban areas of Sweden were strategically sampled in the study. Data were generated in narrative interviews, and the analysis was based on a phenomenological hermeneutical method. After obtaining a naive understanding and conducting structural analyses, two aspects of the phenomenon were revealed: at-homeness as being oneself and at-homeness as being connected. At-homeness as being oneself meant being able to manage ordinary everyday life as well as being beneficial to one's life. At-homeness as being connected meant being close to significant others, being in affirming friendships and being in safe dependency. Here, at-homeness is seen as a twofold phenomenon, where being oneself and being connected are interrelated aspects. Being oneself and being connected are further interpreted by means of the concepts of agency and communion, which have been theorised as two main forces of the human being. PMID- 26058735 TI - Parameter determination procedure for extended Huckel approximation and its application for solid-state electrolytes. AB - A determination procedure of transferable tight-binding parameters of extended Huckel approximation with charge self-consistency is explained, which is applicable to both molecules and crystalline solids. The parameters are adjusted by optimizing evaluation functions, compared with reference results of energy levels or band structure calculated by, for example, the density functional theory. By introducing the evaluation function, the automatic optimization of the parameters for small molecules and clusters is achieved, which makes it easy to determine an accurate parameter set and a wide application of the TB scheme. A practical procedure of parameter optimization is demonstrated for solid-state electrolytes of Li4GeS4 and Li3PS4. PMID- 26058736 TI - Structural and electronic properties of an [(Al2O3)4](+) cluster. AB - Density functional theory (DFT) has been applied to investigate the structural and electronic properties of an [(Al2O3)4](+) cluster. Since there is no structural data available from experiment, the geometry of the cluster was obtained based on a model which produced the best agreement with vibrational IR MPD data. A range of different exchange-correlation functionals were tested, and it was concluded that the best spectral agreement was produced using the CAM B3LYP and B3LYP functionals, respectively. To further characterize the properties of the cluster, natural bond order analysis was performed, and it was concluded that an appropriate description for the system is [Al8O12](+). The frontier orbitals and spin densities of both cation and neutral systems were considered, and it was concluded that the unrestricted singlet and triplet spin densities of the neutral [Al8O12] system were nearly degenerate, representing a di-radical, with the triplet state being lower in energy. PMID- 26058737 TI - Etiology and Long-Term Outcomes of Late-Onset Infantile Spasms. AB - OBJECTIVES: The purpose of the study was to evaluate the etiology and long-term outcomes of late-onset epileptic spasms (LOS). METHODS: This is a retrospective analysis of all consecutive patients seen at our center with onset of clusters of epileptic spasms between 1 and 3 years of age in 1995 through 2005. RESULTS: Overall, 17 children with LOS were identified. Overall, 14 children (82%) had structural etiology. Six patients received resective surgical treatment. Five had focal cortical dysplasia type 1 (FCD1) histology (29% of all the patients). Overall, 16 children were followed for 2 to 18 years. At the latest follow-up, seizure freedom was observed in 67% of the operated and in 50% of the nonoperated patients. Normal cognition or only mild mental deficiency was observed in nine patients (56%), of whom eight were seizure-free. All patients with intractable spasms had a severe mental deficiency. CONCLUSION: The overall cognitive outcome of LOS was more favorable than in the previous reports and was associated with seizure freedom. FCD1 is a frequent etiology for LOS and the cognitive outcome of patients with FCD1 seemed to be favorable. PMID- 26058738 TI - A Case Report on Juvenile Neuromyelitis Optica: Early Onset, Long Remission Period, and Atypical Treatment Response. AB - Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the central nervous system and preferentially targets the optic nerves and spinal cord. NMO is rare in children and clinical course of the disease is highly variable as described in studies. Here, we present a case report of a young girl presenting with a rare course of pediatric NMO with an early disease onset at the age of 12 years, a relapse free interval of 4 years, evidence of NMO immunoglobulin G (IgG) and an unusual response against immunosuppressive therapy. The aim of this report is to highlight the potentially long remission period between relapses complicating proper diagnosis despite well defined diagnostic criteria. In addition, we want to encourage the use of rituximab in pediatric NMO, although larger cohorts are warranted to establish B cell depleting therapies in juvenile NMO. PMID- 26058739 TI - Towards next generation CHO cell biology: Bioinformatics methods for RNA-Seq based expression profiling. AB - High throughput, cost effective next generation sequencing (NGS) has enabled the publication of genome sequences for Cricetulus griseus and several Chinese hamster ovary (CHO) cell lines. RNA-Seq, the utilization of NGS technology to study the transcriptome, is expanding our understanding of the CHO cell biological system in areas ranging from the analysis of transcription start sites to the discovery of small noncoding RNAs. The analysis of RNA-Seq data, often comprised of several million short reads, presents a considerable challenge. If the CHO cell biology field is to fully exploit the potential of RNA-Seq, the development of robust data analysis pipelines is critical. In this manuscript, we outline bioinformatics approaches for the stages of a typical RNA-Seq expression profiling experiment including quality control, pre-processing, alignment and de novo transcriptome assembly. Algorithms for the analysis of mRNA and microRNA (miRNA) expression as well as methods for the detection of alternative splicing from RNA-Seq data are also presented. At this relatively early stage of Cricetulus griseus genome assembly and annotation, it is likely that a combination of isoform deconvolution and raw count based methods will provide the most complete picture of transcript expression patterns in CHO cell RNA-Seq experiments. PMID- 26058740 TI - Spontaneously Formed Nanopatterns on Polymer Films for Flexible Organic Light Emitting Diodes. PMID- 26058742 TI - Out of a creative jumble of ideas in the middle of last Century: Wiener, interdisciplinarity, and all that. AB - Is Biophysics an interdisciplinary science? In order to answer this rhetorical question, it can be useful to look back at history of disciplines, as well as that of the scientific institutions helping their development. In this contribution some aspects of the unusual hodgepodge of concepts involving Biophysics, the legacy of Cybernetics, cognitive science and the central figure of Norbert Wiener are presented and discussed. PMID- 26058741 TI - Natural progression of atherosclerosis from pathologic intimal thickening to late fibroatheroma in human coronary arteries: A pathology study. AB - OBJECTIVE: Smooth muscle cells, macrophage infiltration and accumulation of lipids, proteoglycans, collagen matrix and calcification play a central role in atherosclerosis. The early histologic changes of plaque progression from pathologic intimal thickenings (PIT) to late fibroatheroma lesions have not been fully characterized. METHODS: A total of 151 atherosclerotic coronary lesions were collected from 67 sudden death victims. Atherosclerotic plaques were classified as PIT without macrophage infiltration, PIT with macrophages, and early and late fibroatheromas. Presence of macrophages and proteoglycans (versican, decorin and biglycan) were recognized by specific antibodies while hyaluronan was detected by affinity histochemistry. Lipid deposition was identified by oil-red-O, and calcification was assessed following von Kossa and alizarin red staining. RESULTS: Lesion progression from PIT to late fibroatheroma was associated with increase in macrophage accumulation (p < 0.001) and decreasing apoptotic body clearance by macrophages (ratio of engulfed-to-total apoptotic bodies) (p < 0.001). Lipid deposition in lipid pool of PIT had a microvesicular appearance whereas those in the necrotic core were globular in nature. Overall, the accumulation of hyaluronan (p < 0.001), and proteoglycan versican (p < 0.001) and biglycan (p = 0.013) declined along with lesion progression from PIT to fibroatheromas. Microcalcification was first observed only within areas of lipid pools and its presence and size increased in lesions with necrotic core. CONCLUSIONS: PIT to fibroatheroma lesions are accompanied by early lipid accumulation, followed by macrophage infiltration with defective clearance of apoptotic bodies along with decrease in proteoglycan and hyaluronan in lipid pools that convert to necrotic cores. Calcification starts in PIT and increases with plaque progression. PMID- 26058743 TI - Thalassaemia major and infectious risk: High Mobility Group Box-1 represents a novel diagnostic and prognostic biomarker. AB - High mobility group box -1 (HMGB1) represents a common causal agent for various types of diseases, including infective pathologies. This study aimed to investigate the role of HMGB1 in beta-thalassemia major (TM) by evaluating its diagnostic and prognostic role. Fifty-one TM patients and 30 healthy subjects (HS) were enrolled. Receiver operating characteristics (ROC) analysis was employed to calculate the area under the curve (AUC) for HMGB1 to determine the best cut-off values capable of identifying infectious episodes. Adjusted risk estimates for infective events were calculated using univariate followed by multivariate Cox proportional hazard regression analysis. Serum HMGB1 levels were higher in TM patients than in HS (14.6 +/- 8.7 vs. 2.08 +/- 0.9 ng/ml, P < 0.0001). Patients who underwent splenectomy were characterized by lower levels of HMGB1, when compared with patients with an intact spleen (10.2 +/- 8 vs. 19.1 +/- 7 ng/ml, P = 0.004). ROC analyses revealed an AUC for serum HMGB1 of 0.801, with a sensitivity and specificity of 92.3% and 68.2% to detect an infectious episode. Low HMGB1 levels predicted high risk of infective events (HR: 0.81; P = 0.006). HMGB1 represents a prognostic marker for TM patients and a predictive factor for infectious events. PMID- 26058744 TI - Vitamin D and tuberculosis: a review on a hot topic. AB - The aim of this study is to critically summarize the available data on the correlation between vitamin D level and tuberculosis (TB) infection. A literature search covering English language articles published up to 20 October 2014 was conducted in MEDLINE database. Three hundred ninety-seven articles were initially identified, of which 147 studies were initially selected, and other 13 pertinent studies were included. A significant association between low vitamin D levels and susceptibility to TB infection has been found. PMID- 26058745 TI - Enhancing the Acyltransferase Activity of Candida antarctica Lipase A by Rational Design. AB - A few lipases, such as Candida antarctica lipase A (CAL-A), are known to possess acyltransferase activity. This enables the enzyme to synthesize fatty acid esters from natural oils and alcohols even in the presence of bulk water. Unfortunately, fatty acids are still formed in these reactions as undesired side-products. To reduce the amount of fatty acids, several CAL-A variants were rationally designed based on its crystal structure. These variants were expressed in Escherichia coli and Pichia pastoris, purified, and their acyltransferase/hydrolase activities were investigated by various biocatalytic approaches. Among the investigated variants, mutant Asp122Leu showed a significant decrease in the hydrolytic activity, thus reducing the side-product yield during acylation. As desired, this variant retained wild-type process-relevant features like pH profile and thermostability. PMID- 26058746 TI - Performance of prenatal diagnosis in esophageal atresia. AB - OBJECTIVE: The aim of this study was to evaluate the performance of prenatal diagnosis of esophageal atresia (EA) and its associated abnormalities. METHODS: We conducted a retrospective study from a pediatric database of EA managed postnatally in a single center. Prenatal data included ultrasound and magnetic resonance imaging parameters including amniotic fluid (AF) volume, stomach visualization, AF biochemistry, and associated malformations. Postnatal data included type of EA, mortality, and postnatal diagnosis of associated malformations. RESULTS: One hundred twenty-two cases were included. The diagnosis was suspected prenatally in 39/122 (32%) cases. Polyhydramnios was noted in 64/122 (52.4%), and the stomach was not visualized or small in 39 (32%). There was 14 (11.5%), 2 (1.6%), 101 (82.8%), 5 (4.1%), and 0 (0%) types I, II, III, IV, and V, respectively. EA was suspected prenatally in 12/14 (85.7%) in type I and in 27/108 (25%) in cases with tracheoesophageal fistula (II + III + IV + V). Magnetic resonance imaging was performed in 28 cases, which confirmed EA in 19/28 (sensitivity 67.8%). AF biochemistry was performed in 17 cases, which confirmed EA in 15/17 (sensitivity 88.2%) cases. Of the 69 syndromic associations, 41/69 (59.4%) cases were detected prenatally. Associated malformation was a strong predictor of postnatal death [19/69 vs 3/53, odds ratio 6.33 (1.76; 22.75), p < 0.01]. CONCLUSION: Prenatal diagnosis of EA remains challenging. MRI and AF biochemistry may prove useful in the diagnosis of EA. Prenatal ultrasound and MRI examination should also focus on associated anomalies. (c) 2015 John Wiley & Sons, Ltd. PMID- 26058747 TI - The risk of revision in total knee arthroplasty is not affected by previous high tibial osteotomy. AB - BACKGROUND AND PURPOSE: Previous studies have found different outcomes after revision of knee arthroplasties performed after high tibial osteotomy (HTO). We evaluated the risk of revision of total knee arthroplasty with or without previous HTO in a large registry material. PATIENTS AND METHODS: 31,077 primary TKAs were compared with 1,399 TKAs after HTO, using Kaplan-Meier 10-year survival percentages and adjusted Cox regression analysis. RESULTS: The adjusted survival analyses showed similar survival in the 2 groups. The Kaplan-Meier 10-year survival was 93.8% in the primary TKA group and 92.6% in the TKA-post-HTO group. Adjusted RR was 0.97 (95% CI: 0.77-1.21; p = 0.8). INTERPRETATION: In this registry-based study, previous high tibial osteotomy did not appear to compromise the results regarding risk of revision after total knee arthroplasty compared to primary knee arthroplasty. PMID- 26058748 TI - An assessment of oral cancer curricula in dental hygiene programmes: implications for cancer control. AB - PURPOSE: To assess oral cancer prevention and early detection curricula in Illinois associate-degree dental hygiene programmes and highlight global health applications. METHODS: An email invitation was sent to each Illinois associate degree granting dental hygiene programme's oral cancer contact to participate in a survey via a SurveyMonkeyTM link to a 21-item questionnaire. Questions elicited background information on each programme and inquired about curriculum and methods used for teaching oral cancer prevention and early detection. RESULTS: Eight of the 12 (67%) programmes responded. Three (37.5%) reported having a specific oral cancer curriculum. Five (62.5%) require students to perform examinations for signs and symptoms of oral cancer at each clinic visit. Variations exist across the programmes in the number of patients each student sees annually and the number of oral cancer examinations each student performs before graduation. Seven programmes (87.5%) conduct early detection screening in community settings. All programmes included risk assessment associated with tobacco. All other risk factors measured were treated inconsistently. CONCLUSION: Significant differences in training and experience were reported across Illinois dental hygiene programmes. Training is neither standardized nor uniformly comprehensive. Students' preparation for delivering prevention and early detection services to their patients could be strengthened to ensure competence including reflection of risk factors and behaviours in a global context. Regular review of curricular guidelines and programme content would help dental hygienists meet the expectations of the Crete Declaration on Oral Cancer Prevention. PMID- 26058750 TI - Selenoprotein K and protein palmitoylation. AB - SIGNIFICANCE: Selenoprotein K (SelK) is an endoplasmic reticulum (ER) membrane protein, and its expression is sensitive to dietary selenium levels. A recently described role for SelK as a cofactor in catalyzing protein palmitoylation reactions provides an important link between low dietary selenium intake and suboptimal cellular functions that depend on this selenoprotein for palmitoylation. RECENT ADVANCES: A recent breakthrough provided insight into the contribution of SelK to calcium (Ca(2+)) flux in immune cells. In particular, SelK is required for palmitoylation of the Ca(2+) channel protein, inositol-1,4,5 triphosphate receptor (IP3R) in the ER membrane. Without this post-translational modification, expression and function of the IP3R is impaired. SelK is required for palmitoylation of another transmembrane protein, CD36, and very likely other proteins. SelK serves as a cofactor during protein palmitoylation by binding to the protein acyltransferase, DHHC6, thereby facilitating addition of the palmitate via a thioester bond to the sulfhydryl group of cysteine residues of target proteins. CRITICAL ISSUES: The association of DHHC6 and SelK is clearly important for immune cell functions and possibly other cell types. The step in the DHHC6 catalyzed S-acylation reaction on which SelK acts remains unclear and possible mechanisms of how the kinetics of the reaction are impacted by SelK binding to DHHC6 are presented here. FUTURE DIRECTIONS: Uncovering the specific role of SelK in promoting DHHC6 catalyzed protein palmitoylation may open a new line of inquiry into other selenoproteins playing similar roles as cofactors for different enzymatic processes. PMID- 26058751 TI - Development and validation testing of a short nutrition questionnaire to identify dietary risk factors in preschoolers aged 12-36 months. AB - BACKGROUND: Although imbalances in dietary intakes can have short and longer term influences on the health of preschool children, few tools exist to quickly and easily identify nutritional risk in otherwise healthy young children. OBJECTIVES: To develop and test the validity of a parent-administered questionnaire (NutricheQ) as a means of evaluating dietary risk in young children (12-36 months). DESIGN: Following a comprehensive development process and internal reliability assessment, the NutricheQ questionnaire was validated in a cohort of 371 Irish preschool children as part of the National Preschool Nutrition Survey. Dietary risk was rated on a scale ranging from 0 to 22 from 11 questions, with a higher score indicating higher risk. RESULTS: Children with higher NutricheQ scores had significantly (p<0.05) lower mean daily intakes of key nutrients such as iron, zinc, vitamin D, riboflavin, niacin, folate, phosphorous, potassium, carotene, retinol, and dietary fibre. They also had lower (p<0.05) intakes of vegetables, fish and fish dishes, meat and infant/toddler milks and higher intakes of processed foods and non-milk beverages, confectionery, sugars and savoury snack foods indicative of poorer dietary quality. Areas under the curve values of 84.7 and 75.6% were achieved for 'medium' and 'high' dietary risk when compared with expert risk ratings indicating good consistency between the two methods. CONCLUSION: NutricheQ is a valid method of quickly assessing dietary quality in preschoolers and in identifying those at increased nutritional risk. PMID- 26058752 TI - Downregulation of miR-19a exhibits inhibitory effects on metastatic renal cell carcinoma by targeting PIK3CA and inactivating Notch signaling in vitro. AB - Metastasis seriously affects the clinical outcome of renal cell carcinoma patients. Despite the approval of several targeted therapies that have led to an improvement in the progression-free survival rate for these patients, advanced and metastatic renal cell carcinoma remains difficult to treat. Recently, microRNAs have been found to play a critical role in the metastatic dissemination of renal cell carcinoma cells. In the present study, we found that miR-19a expression was significantly upregulated in metastatic clear cell renal carcinoma than that in adjacent and primary carcinoma tissues using qPCR and in situ hybridization experiments. In addition, the results were confirmed in renal carcinoma cell lines. miR-19a expression in the cell lines derived from a metastatic site was higher than that in cell lines derived from a primary site. By gain- and loss-of-function experiments, we found that miR-19a acted as an oncogenic miRNA regulating renal cancer cell proliferation, migration and invasion by directly targeting PIK3CA. Furthermore, we also explored the downstream molecules of miR-19a/PIK3CA signaling. We found that Notch signaling was induced by upregulation of miR-19a, and inactivation of Notch signaling attenuated the cell proliferation, migration and invasion promoted by miR-19a. Thus, we provide evidence demonstrating that downregulation of miR-19a may be therapeutically beneficial for metastatic renal carcinoma. PMID- 26058753 TI - Primordial Influence of Post-operative Compliance on Weight Loss After Adolescent Laparoscopic Adjustable Gastric Banding. AB - BACKGROUND: Accumulating evidence suggests that the benefits seen in adult bariatric surgery can be reproduced in adolescents. In contrast with North America, bariatric surgery in adolescents is still not well accepted in Europe and indications and protocols have still to be formulated. METHODS: This prospective study tested the gastric banding procedure in 49 patients operated in a single French institution since 2008. The mean age at surgery was 16.2 +/- 0.9 years with a weight of 118.8 +/- 22.3 kg and body mass index of 42.5 +/- 5.9 kg/m(2). RESULTS: At 6, 12 and 24 months after surgery, weight was 103.7 +/- 20.8 kg, 98.7 +/- 21 kg and 93.6 +/- 19.3 kg, respectively (p < 0.001), corresponding to excess weight loss (EWL) of 31.6 +/- 17.2 %, 41.8 +/- 21.4 % and 59.1 +/- 24.9 % (p < 0.001), respectively. Multivariate analysis showed that the number of consultations per year was the only variable significantly associated to weight loss. Metabolic disorders were corrected, with a decreased prevalence of insulin resistance from 100 to 17 % and normalisation of homeostasis model assessment insulin resistance (HOMA-IR) at 24 months (2.09 +/- 0.95). Band-related complications were five slippages, one psychological intolerance and two ports repositioning. Six patients (12 %) had the device explanted. The death of a patient was an exceptionally severe adverse event. CONCLUSION: Given frequent follow-up support by a multidisciplinary team, laparoscopic adjustable gastric banding (LAGB) surgery in adolescent results in sustained weight loss. However, even exceptional, potentially serious complications are possible and long-term follow-up is needed to evaluate the risk/benefit ratio at 5 or 10 years after LAGB surgery. PMID- 26058754 TI - Complications After Laparoscopic Roux-en-Y Gastric Bypass in 1573 Consecutive Patients: Are There Predictors? AB - BACKGROUND: Roux-en-Y gastric bypass (RYGBP), one of the commonest performed bariatric procedures, remains a technically challenging operation associated with significant morbidity in high-risk patients. This study was conducted in order to identify predictors of complications after laparoscopic RYGBP. METHODS: Our prospectively established database has been assessed to review 30-day and in hospital complications graded according to a validated scoring system (Clavien Dindo) and separated into minor (Clavien-Dindo I-IIIa) and major (Clavien-Dindo IIIb-IV) complications. Patient- and procedure-related factors were analyzed using univariate analysis. Significant factors associated with morbidity were introduced into a multivariate analysis to identify independent predictors. RESULTS: Between 1999 and 2012, 1573 patients underwent laparoscopic RYGBP, 374 male and 1199 female. Mean age was 41 years, and mean body mass index (BMI) was 44.5 kg/m(2). One hundred fifty-nine procedures were reoperations. One hundred fifty (9.5 %) patients developed at least one complication, and 43 (2.7 %) had major complications, leading to death in one case (0.06 %). Risk factors for morbidity were male gender (p = 0.006) and overall experience of the team (p < 0.0001). Prolonged 3-day antibiotic therapy was associated with significantly reduced overall (p < 0.0001) and major (p = 0.005) complication rates. Major complications were associated with smoking (p = 0.016). CONCLUSIONS: The most significant individual risk factors for early complications after RYGBP are male gender, limited surgical experience, and single dose of antibiotics. RYGBP should be performed by experienced teams. Smoking should be discontinued before surgery. Prolonged antibiotic therapy could be considered, especially if a circular stapled gastrojejunostomy is performed with the anvil introduced transorally. PMID- 26058757 TI - The association between breast cancer and thyroid cancer: a meta-analysis. AB - Previous studies have suggested an association between breast cancer and thyroid cancer; however, there has not been a formal meta-analysis which collates the existing evidence supporting the hypothesis that breast cancer or thyroid cancer predisposes an individual to developing the other. A systematic search was carried out using PubMed and Medline. We searched for articles containing epidemiological evidence of breast cancer following thyroid cancer and vice versa. Additionally, we searched for articles that included epidemiological data involving the incidence of all second primary malignancies (SPMs) following both breast cancer and thyroid cancer, and compared the datasets. The meta-analysis performed in a total of 18 studies showed that there is a significantly increased risk of developing thyroid cancer as a second primary malignancy of breast cancer (SIR = 1.59, 95 % confidence interval (CI) 1.28-1.99). Additionally, there was marginally increased risk of developing breast cancer as a second primary malignancy of thyroid cancer (SIR = 1.24, 95 % CI 1.16-1.33), compared to the general risk of developing a second primary malignancy following thyroid cancer. The findings suggest that the risk of developing thyroid cancer as a second primary malignancy of breast cancer and vice versa is increased compared to the background risk of developing other SPMs. The risk of developing thyroid cancer after a primary breast cancer was higher than the risk of developing breast cancer as a second primary malignancy of thyroid cancer. This suggests that the effects of treatment-related factors and specific pathological processes of each cancer may contribute to the increased risk rather than common risk factors including genetic factors. Elucidation of the common mechanisms between breast cancer and thyroid cancer will have important implications in both diagnostic and therapeutic management of these cancers. Benefit of thyroid ultrasound screening after breast cancer surgery needs to be assessed. PMID- 26058755 TI - Comparative phylogeography between two generalist flea species reveal a complex interaction between parasite life history and host vicariance: parasite-host association matters. AB - BACKGROUND: In parasitic taxa, life history traits such as microhabitat preference and host specificity can result in differential evolutionary responses to similar abiotic events. The present study investigates the influence of vicariance and host association on the genetic structure of two generalist flea species, Listropsylla agrippinae, and Chiastopsylla rossi. The taxa differ in the time spent on the host (predominantly fur vs. nest) and level of host specificity. RESULTS: A total of 1056 small mammals were brushed to collect 315 fleas originating from 20 geographically distinct localities in South Africa. Phylogeographic genetic structure of L. agrippinae and C. rossi were determined by making use of 315 mitochondrial COII and 174 nuclear EF1-alpha sequences. Both parasites show significant genetic differentiation among the majority of the sampling sites confirming limited dispersal ability for fleas. The generalist fur flea with a narrower host range, L. agrippinae, displayed geographic mtDNA spatial genetic structure at the regional scale and this pattern is congruent with host vicariance. The dating of the divergence between the L. agrippinae geographic clades co-insides with paleoclimatic changes in the region approximately 5.27 Ma and this provides some evidence for a co-evolutionary scenario. In contrast, the more host opportunistic nest flea, C. rossi, showed a higher level of mtDNA and nDNA spatial genetic structure at the inter populational scale, most likely attributed to comparatively higher restrictions to dispersal. CONCLUSIONS: In the present study, the evolutionary history of the flea species could best be explained by the association between parasite and host (time spent on the host). The phylogeographic pattern of the fur flea with a narrower host range correspond to host spatial genetic structures, while the pattern in the host opportunistic nest flea correspond to higher genetic divergences between sampling localities that may also be associated with higher effective population sizes. These findings suggest that genetic exchange among localities are most likely explained by differences in the dispersal abilities and life histories of the flea species. PMID- 26058760 TI - Editorial Comment for Chopra et al. PMID- 26058758 TI - Immunological Biomarkers in Postinfectious Irritable Bowel Syndrome. AB - BACKGROUND: There is a recognized need for biological markers to facilitate diagnoses of irritable bowel syndrome (IBS) and to distinguish it from other functional and organic disorders. As postinfectious IBS (PI-IBS) is believed to account for as many as one third of all IBS cases, here we sought to identify differences in specific cytokines and serologic responses across patients with idiopathic IBS and PI-IBS and healthy controls. METHODS: At total of 120 US military personnel were identified from the Defense Medical Surveillance System based International Classification of Diseases, 9th Revision, Clinical Modification (ICD9-CM) codes recorded during medical encounters and were grouped based on infectious gastroenteritis (IGE) episode (Shigella, Campylobacter, Salmonella, or an unspecified pathogen) followed by IBS, IBS without antecedent IGE, or IGE without subsequent IBS within 2 years of the IGE exposure. Sera from subjects were assayed for cytokine levels and antibodies against a panel of microbiome antigens. RESULTS: In total, 10 of 118 markers considered were shown to differ between IBS patients and healthy controls, including cytokines interleukin-6 (IL-6), IL-8, IL-1beta, and macrophage inflammatory protein-1beta (MIP-1beta), as well as antibody responses to microbial antigens. Antimicrobial antibody response profiles also differed between PI-IBS cases compared with IBS cases without an antecedent episode of acute IGE. Comparisons also suggest that immunoglobulin A (IgA) and IgG profiles may point to pathogen-specific origins among PI-IBS cases. CONCLUSION: Taken together, these results provide further evidence as to the molecular distinctness of classes of IBS cases and that serum biomarkers may prove useful in elucidating their pathobiological pathways. PMID- 26058761 TI - [A woman with hyperkeratotic papules on arms and legs]. AB - A 50-year old woman with hyperkeratotic verrucous papules and plaques visited the outpatient clinic of Dermatology. Histopathology showed hyperplasia of verrucous epithelia, orthokeratosis and an infiltrate, leading to the diagnosis 'verrucous (hypertrophic) lichen planus'. This skin condition is often misdiagnosed as psoriasis. Squamous cell carcinoma can develop within skin lesions. PMID- 26058762 TI - [Rosacea fulminans in pregnancy]. AB - We present a 38-year-old woman who suddenly developed erythema with follicular papules and pustules on her face during the second trimester of pregnancy. The diagnosis 'rosacea fulminans' was made. This is an uncommon skin condition that predominantly affects younger women. Treatment with erythromycin was successful. PMID- 26058763 TI - [Fibrosing disorders: insights into pathogenesis and new treatment options]. AB - Fibrosis is one of the leading causes of morbidity and mortality in the Western world. This disorder is characterised by an abnormal and increased rate of fibroblast proliferation and by an excessive deposition of connective tissue. The key player in fibrosis is the myofibroblast. Fibrosis leads to loss of organ structure and, eventually, to decrease in organ function. To date, there are hardly any effective therapies for the treatment of patients with fibrosis. Pirfenidone targets the myofibroblast and is effective in the treatment of idiopathic pulmonary fibrosis. Tyrosine kinase inhibitors are effective for the treatment of patients with some forms of systemic sclerosis. Here we describe various novel therapeutic targets, such as transforming growth factor beta (TGF beta), platelet-derived growth factor (PDGF), interleukin-13 (IL-13), lysyloxidase-2 and macrophage-fibroblast interactions. These new therapies are currently under investigation in pre-clinical and clinical studies. PMID- 26058764 TI - [Prevention of infections with highly resistant microorganisms: maximizing transparency by using outcome indicators]. AB - In the Netherlands the quality of health care is supervised by the Health Care Inspectorate. Since 2013 the Health Care Inspectorate has been specifically checking hospital practices for reducing transmission of highly resistant microorganisms. Its mode of operation, using process indicators, has been criticised. Here, it is proposed that this quality control be based on relevant outcome parameters of infection prevention strategies. This would also maximise transparency regarding the occurrence of infections caused by highly resistant microorganisms in Dutch hospitals. PMID- 26058765 TI - [Pneumorachis and pneumopericardium after ecstasy use: an uncommon complication]. AB - BACKGROUND: Over the past few years there has been an increase in the use of ecstasy among the Dutch population. A number of complications are associated with this drug, hyperthermia being the most well-known. A less commonly-occurring complication is pneumomediastinum. CASE DESCRIPTION: A 20-year-old man presented at the emergency department with extensive subcutaneous emphysema, pneumomediastinum, pneumopericardium and pneumorachis (air within the spinal canal), which had developed after visiting a festival. After excluding the most likely causes, it was concluded that it was due to a combination of ecstasy use and intensive activity (dancing). He was managed conservatively and after two days of observation in the ICU the patient fully recovered. CONCLUSION: This case illustrates a rare complication that seems - indirectly - related to using ecstasy. In most cases conservative treatment is adequate but the presence of pneumopericardium means that given the risk of cardiovascular complications, cardiopulmonary monitoring is essential to trace them. PMID- 26058766 TI - [A treatment plan as method and compass]. AB - For elderly people with complex care needs, working with a treatment plan is a method for offering personalized, proactive, integrated care. The treatment plan works as a 'compass' because it indicates the key points to focus on in the care for the elderly person. It can take personal wishes and preferences into account, improve the person's ability to cope independently and involve family and caregivers in the process. The treatment plan provides an overview of the most important problems in all domains and of the professional caregivers involved. In this article we describe the potential opportunities and action points within working with treatment plans. Opportunities include shared decision making, paying attention to functioning and independent coping, and stimulation of care in the community. Action points include organization of care, registration, education and privacy. Drawing up a treatment plan is not an end in itself, but a working method, which takes into account the diversity of the elderly population and the complexity of care giving. PMID- 26058767 TI - [Lactococcus garvieae endocarditis]. AB - BACKGROUND: Lactococcus garvieae, a Gram-positive lactococcus with a short incubation period and high virulence, is a known fish pathogen responsible for serious outbreaks in both marine and freshwater aquaculture. The first human infection was documented in 1991. This is the first case report of L. garvieae endocarditis in the Netherlands. CASE DESCRIPTION: A 68-year-old woman presented with a three-week history of intermittent fever, increased bleeding tendency and weight loss. Blood tests showed prolonged clotting times and diffuse liver dysfunction. Transoesophageal ultrasound showed a vegetation on the aortic valve. Blood cultures were positive for L. garvieae, leading to a diagnosis of 'infective endocarditis'. Additional examination revealed liver cirrhosis and pandiverticulosis. The patient was treated with intravenous antibiotics for six weeks and made a good recovery. CONCLUSION: Consumption of raw fish, immunosuppression and an abnormality in the gastrointestinal tract are risk factors for L. garvieae infection. Improved determination techniques are likely to lead to more frequent identification of the bacterium. PMID- 26058768 TI - [Post-partum psychosis: an acute illness requiring resolute action]. AB - A 34-year-old woman was seen in our hospital, where she had been brought after jumping from the window together with her 3-month-old son. She had survived the jump with severe foot fractures, but her son had died. In the weeks after giving birth she had suffered from sleep disturbances and fluctuating affective symptoms. After initial response to benzodiazepines, she developed psychotic symptoms that lead her to jump from the window. Psychotic symptoms had developed within just 3 days, and medical action came too late. Here we urge clinicians to be alert to psychotic symptoms in the first months of maternity, and to instantly refer young mothers with these symptoms to a closed ward for adequate treatment. Treatment starts with benzodiazepines to restore sleep, followed by an antipsychotic agent if symptoms fail to improve with this treatment; if psychosis and affective symptoms do not improve after 2 weeks this regimen should be followed by lithium augmentation. PMID- 26058769 TI - [Are we on the verge of lung-cancer screening in the Netherlands?]. AB - Previous studies of low-dose computed tomography (CT) screening for lung cancer have shown a decrease in lung-cancer-related deaths. Data from the NELSON trial, using new thresholds for defining a positive test, resulted in less over diagnosis without a decrease in test-specific sensitivity. However, in our opinion it is still too early to implement screening in the Netherlands. Further development of the optimal screening algorithm based on defined volumetric thresholds and stratified by personal characteristics such as age, smoking habits, gender and comorbidities, will probably result in a better balance between the harms and benefits of lung-cancer screening to individuals and society. PMID- 26058770 TI - [Reading research articles]. AB - Keeping up with the latest developments is not easy, but neither is reading articles on research. There are too many medical journals that contain information that is irrelevant to clinical practice. From this mass of articles you have to decide which are important for your own clinical practice and which are not. Most articles naturally fall into the latter category as spectacular findings with important consequences for medical practice do not occur every week. The most important thing in a research article is the research question. If you begin with this, then you can put aside much scientific literature. The methodology section is essential; reading this can save you a lot of time. In this article we take you step-by-step through the process of reading research articles. The articles in our Methodology series can be used as background information. These articles have been combined in a tablet app, which is available via www.ntvg.nl/methodologie. PMID- 26058771 TI - [Strict treatment of hypertension during pregnancy: safe but not obviously better]. AB - The CHIPS (Control of Hypertension In Pregnancy Study) trial showed that tight blood pressure control in women with hypertension during pregnancy was safe with respect to neonatal outcome. However it was not linked to improvement of the predefined maternal composite outcome. The CHIPS trial is without doubt a landmark study in this field; however some questions are still unresolved. The study population consists of pregnant women with pre-existing hypertension and those with gestational hypertension. As these groups differ regarding pathophysiology and are however covered in separate guidelines in the Netherlands. Unfortunately no sub-analyses were performed for these groups. Moreover the primary neonatal endpoint is defined too broadly because of the inclusion of the rather vague component "higher than usual neonatal care". An endpoint combining major neonatal and maternal comorbidities would have been more clinically relevant. It is unlikely that the results of this trial will influence the Dutch guidelines. PMID- 26058772 TI - [Conducting your own research: a revised recipe for a clinical research training project]. AB - Learning to conduct good research demands a considerable investment in terms of time from a young investigator but this is sometimes difficult to achieve alongside studying or training. In 1989, the Dutch Journal of Medicine (NTvG) printed a 'recipe' for conducting a clinical research training project, which made some recommendations for the successful completion of such a project even with limited time and resources. This article reviews these three recommendations and adds another two. The final recommendations are: limit the research question, conduct a pilot study, write the article before you collect the data, streamline the research process and be accountable. PMID- 26058773 TI - [Sidelined under the Participation Act]. AB - In January this year, a new law was introduced in the Netherlands aimed at improving opportunities for people who cannot find work, among them young people with impairments who still have - limited - ability to work. This law, the Participation Act, is executed by municipalities. All young people with the ability to work despite their impairments are entitled to support from the municipalities in finding a job. At present, only a small percentage of these young people are in paid employment. Bureaucracy threatens the proper implementation of the Participation Act and young people with impairments are particularly affected. Integrated action by municipalities and employers, and patience, are important for the promotion of work participation by young workers. The only way to accomplish the objective of the Participation Act is to make the participation in work of the youngster with impairments a central issue. PMID- 26058775 TI - Electron nanoprobe induced oxidation: a simulation of direct-write purification. AB - Electron beam direct-write has recently taken a large step forward with the advent of methods to purify deposits. This development has opened the door for future direct-write device prototyping and editing. In one such approach, an additional beam scanning procedure removes carbonaceous impurities via oxidation from metal-carbon deposits (e.g., PtC5) in the presence of H2O or O2 after deposition. So far, critical aspects of the oxidation reaction remain unclear; experiments reveal clearly that electron stimulated oxidation drives the process yet it is not understood why H2O purifies by a bottom-up mechanism while O2 purifies from the top-down. The simulation results presented here suggest that the chemisorption of dissolved O2 at buried Pt nanoparticle surfaces controls purification in the top-down case while both the high relative solubility coupled with weak physisorption of H2O explains the bottom-up process. Crucial too is the role that the carbonaceous contaminant itself has on the dissolution and diffusion of O2 and H2O. These results pave the way for simulation driven experiments where (1) the transient densification of the deposit can be accounted for in the initial deposit design stage and (2) the deposition and purification steps can be combined. PMID- 26058776 TI - The need for cost-effectiveness analyses of antimicrobial stewardship programmes: A structured review. AB - The cost effectiveness of antimicrobial stewardship (AMS) programmes was reviewed in hospital settings of Organisation for Economic Co-operation and Development (OECD) countries, and limited to adult patient populations. In each of the 36 studies, the type of AMS strategy and the clinical and cost outcomes were evaluated. The main AMS strategy implemented was prospective audit with intervention and feedback (PAIF), followed by the use of rapid technology, including rapid polymerase chain reaction (PCR)-based methods and matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) technology, for the treatment of bloodstream infections. All but one of the 36 studies reported that AMS resulted in a reduction in pharmacy expenditure. Among 27 studies measuring changes to health outcomes, either no change was reported post-AMS, or the additional benefits achieved from these outcomes were not quantified. Only two studies performed a full economic evaluation: one on a PAIF-based AMS intervention; and the other on use of rapid technology for the selection of appropriate treatment for serious Staphylococcus aureus infections. Both studies found the interventions to be cost effective. AMS programmes achieved a reduction in pharmacy expenditure, but there was a lack of consistency in the reported cost outcomes making it difficult to compare between interventions. A failure to capture complete costs in terms of resource use makes it difficult to determine the true cost of these interventions. There is an urgent need for full economic evaluations that compare relative changes both in clinical and cost outcomes to enable identification of the most cost-effective AMS strategies in hospitals. PMID- 26058777 TI - Successful treatment of meticillin-resistant Staphylococcus aureus (MRSA) aortic prosthetic valve endocarditis with prolonged high-dose daptomycin plus ceftaroline therapy. PMID- 26058778 TI - Promoting knowledge utilisation, translation, integration, and application in practice: reasons why to write and publish research reviews. PMID- 26058779 TI - An eighteen-month follow-up of a pilot parent-delivered play-based intervention to improve the social play skills of children with attention deficit hyperactivity disorder and their playmates. AB - BACKGROUND: Children with attention deficit hyperactivity disorder (ADHD) experience significant ongoing social difficulties which occur in multiple contexts. Interventions designed to improve these social difficulties have demonstrated minimal effectiveness. Thus, there is a clear need to establish interventions that are effective in addressing the social difficulties of children with ADHD across contexts and in the long term. AIM: To examine the long term effectiveness and appropriateness of a pilot parent-delivered intervention designed to improve the social play skills of children with ADHD and their playmates. METHOD: Participants included five children with ADHD who had completed the intervention 18-months prior, their typically developing playmates and mothers of children with ADHD. Blinded ratings from the Test of Playfulness were used to measure children's social play: post-intervention and 18-months following the intervention in the home and clinic. Wilcoxon signed-ranks and Cohen's-d calculations were used to measure effectiveness. Parents' perspectives of the appropriateness of the intervention were explored through semi-structured interviews and data were analysed thematically. RESULTS: The social play skills of children with ADHD and their playmates were maintained following the intervention in the home and clinic. Thematic analysis revealed four core-themes against an intervention appropriateness framework: new parenting tools, a social shift, adapting strategies over time and the next developmental challenge. CONCLUSION: The parent-delivered intervention demonstrated long-term effectiveness and appropriateness for improving children's social play skills. SIGNIFICANCE: These preliminary results are promising as maintaining treatment effects and achieving generalisation across contexts has remained an unachieved goal for most psycho-social interventions. PMID- 26058780 TI - Occupare, to seize: expanding the potential of occupation in contemporary practice. PMID- 26058781 TI - Computerised cognitive training programs improved the cognitive performance of healthy older adults on some cognitive tests including memory, speed of information processing and visuospatial skills. PMID- 26058782 TI - Strong evidence from a small number of medium quality studies, support technology use in improving everyday task performance requiring memory, in neurological conditions. PMID- 26058784 TI - hCLP46 increases Smad3 protein stability via inhibiting its ubiquitin-proteasomal degradation. PMID- 26058785 TI - Acute kidney injury after near drowning: The way from the beach to hemodialysis. AB - Acute kidney injury (AKI) occurs in many different situations and may have a variable prognosis influenced by clinical setting, underlying cause, and comorbidity. This is important because of the high mortality and morbidity risk affecting many people around the world. Near-drowning related AKI requiring hemodialysis is very seldom reported in literature. Although cardiovascular and respiratory disorders are more frequently seen after this entity, we aimed to emphasize this rare but dangerous complication in near-drowning patients. PMID- 26058786 TI - Netrin-1 directs dendritic growth and connectivity of vertebrate central neurons in vivo. AB - BACKGROUND: Netrins are a family of extracellular proteins that function as chemotropic guidance cues for migrating cells and axons during neural development. In the visual system, netrin-1 has been shown to play a key role in retinal ganglion cell (RGC) axon growth and branching at the target, where presynaptic RGC axons form partnerships with the dendrites of tectal neurons. However, the signals that guide the connections between RGC axons and their postsynaptic partners are yet unknown. Here, we explored dynamic cellular mechanisms by which netrin-1 influences visual circuit formation, particularly those that impact postsynaptic neuronal morphology and connectivity during retinotectal wiring. RESULTS: Time-lapse in vivo imaging of individual Xenopus laevis optic tectal neurons co-expressing tdTomato and PSD95-GFP revealed rapid remodeling and reorganization of dendritic arbors following acute manipulations in netrin-1 levels. Effects of altered netrin signaling on developing dendritic arbors of tectal neurons were distinct from its effects on presynaptic RGC axons. Within 4 h of treatment, tectal injection of recombinant netrin-1 or sequestration of endogenous netrin with an UNC-5 receptor ectodomain induced significant changes in the directionality and orientation of dendrite growth and in the maintenance of already established dendrites, demonstrating that relative levels of netrin are important for these functions. In contrast, altering DCC mediated netrin signaling with function-blocking antibodies induced postsynaptic specialization remodeling and changed growth directionality of already established dendrites. Reducing netrin signaling also decreased avoidance behavior in a visually guided task, suggesting that netrin is essential for emergent visual system function. CONCLUSIONS: These in vivo findings together with the patterns of expression of netrin and its receptors reveal an important role for netrin in the early growth and guidance of vertebrate central neuron dendritic arbors. Collectively, our studies indicate that netrin shapes both pre- and postsynaptic arbor morphology directly and in multiple ways at stages critical for functional visual system development. PMID- 26058787 TI - Benzodiazepines may reduce the effectiveness of ketamine in the treatment of depression. PMID- 26058788 TI - Cell wall proteomics contributes to explore the functional proteins of Brachypodium distachyon grains. AB - The plant cell wall is the first barrier in response to external stimuli and cell wall proteins (CWPs) can play an important role in the modulation of plant growth and development. In the past 10 years, the plant cell wall proteomics has increasingly become a very active research filed, which provides a broader understanding of CWPs for people. The cell wall proteome of Arabidopsis, rice, and other model plants has begun to take shape, and proteomic technology has become an effective way to identify the candidate functional CWPs in large scale. The challenging work of Francin-Allami et al. (Proteomics 2015, 15, 2296-2306) is a vital step toward building the most extensive cell wall proteome of a monocot species. They identified 299 cell wall proteins in Brachypodium distachyon grains, and also compared the grain cell wall proteome with those of B. distachyon culms and leaves, which provides a new perspective for further explaining the plant cell wall structures and remodeling mechanism. PMID- 26058789 TI - Focal adhesion kinase activation is required for TNF-alpha-induced production of matrix metalloproteinase-2 and proinflammatory cytokines in cultured human periodontal ligament fibroblasts. AB - Since focal adhesion kinase (FAK) was proposed as a mediator of the inflammatory response, we have investigated the role of this molecule in the release of inflammatory cytokines by cultured human periodontal ligament fibroblasts (HPDLFs), cells that are thought to be important in the patient's response to periodontal infection. Human periodontal ligament fibroblasts were stimulated by tumor necrosis factor alpha (TNF-alpha) and its effects on interleukin (IL)-6 and IL-8 release were measured by ELISA. Expression of matrix metalloproteinase 2 (MMP-2) protein was analysed by western blotting. The levels of IL6, IL8, and MMP2 mRNA were evaluated by real-time PCR. Tumor necrosis factor alpha dose dependently induced the phosphorylation of FAK, whereas small interfering FAK (siFAK) inhibited TNF-alpha-induced FAK phosphorylation. Tumor necrosis factor alpha also stimulated the production of IL-6, IL-8, and MMP-2 in a dose-dependent manner. Knockdown of FAK significantly suppressed TNF-alpha-induced expression of IL6 and IL8 mRNA and release of IL-6 and IL-8 protein in HPDLFs. Similarly, MMP-2 down-regulation was significantly prevented by siFAK. Our results strongly suggest that knockdown of FAK can decrease the production of TNF-alpha-induced IL 6, IL-8, and MMP-2 in HPDLFs. These effects may help in understanding the mechanisms that control expression of inflammatory cytokines in the pathogenesis of periodontitis. PMID- 26058791 TI - Foreword. PMID- 26058790 TI - Effects of spironolactone on ventricular-arterial coupling in patients with chronic systolic heart failure and mild symptoms. AB - BACKGROUND: Several studies demonstrated that mineralocorticoid receptor antagonists (MRAs) are able to prevent myocardial and vascular fibrosis, and left ventricular (LV) remodeling in patients with systolic chronic heart failure (HF) and mild symptoms. Ventricular-arterial coupling (VAC) should be influenced by anti-fibrotic interventions. We have assessed the effects of spironolactone on VAC and its components, aortic elastance (Ea) and end-systolic LV elastance (Ees), in patients with HF. METHODS AND RESULTS: Changes from baseline in VAC were compared between 65 patients treated with spironolactone and 32 controls not receiving MRAs. All patients had HF, reduced LVEF with reduced LV ejection fraction (LVEF) and New York Heart Association (NYHA) functional class I-II symptoms, and underwent transthoracic echocardiography at baseline and after 6 months. VAC was estimated by the modified single-beat method as Ea/Ees. Parameters of LV function improved after 6 month treatment with spironolactone with an increase in the LVEF from 34 +/- 8 to 39 +/- 8 % (p < 0.001). Spironolactone increased Ees from 1.32 +/- 0.38 to 1.57 +/- 0.42 mmHg/mL (p < 0.001) and reduced VAC from 2.03 +/- 0.59 to 1.66 +/- 0.31 (p < 0.001), but did not affect Ea and V0 (LV volume at end-systolic pressure of 0 mmHg). No change in any of these parameters occurred in the control group. CONCLUSIONS: 6-month therapy with spironolactone improved VAC mainly through its effect on Ees in patients with mild HF. PMID- 26058793 TI - Evolving options for breast reconstruction. AB - In summary, if the abdomen cannot be used for a donor site, alternative flap selection is based on individual patient anatomy and body habitus, targeting the buttocks and upper thigh. Intraoperative repositioning may be required for ease in flap harvest and donor site closure, adding time to the procedure. Flap dissection is performed in the subfascial plane to avoid injury to the perforator vessels. Deep suspension sutures may be required to maintain the gluteal fold location. PMID- 26058794 TI - Change in interpersonal functioning during psychological interventions for borderline personality disorder-a systematic review of measures and efficacy. AB - OBJECTIVE: To provide a systematic review of measures of interpersonal functioning used in treatments for people diagnosed with borderline personality disorder (BPD) and to report the effectiveness of treatments on these measures of interpersonal functioning. METHOD: Literature was reviewed using the online databases and reference lists of previous systematic reviews. Selected studies were randomized controlled trials (RCTs) that examined psychotherapeutic interventions for people with BPD and contained quantitative outcomes on various aspects of interpersonal functioning and reported their results in peer-reviewed journals. Reliability and validity of the results were evaluated. RESULTS: Nineteen RCTs met our inclusion criteria. We found 16 different (sub)scales that measured some aspect of interpersonal functioning. Only four instruments were used by more than one research team. There is some evidence that psychotherapeutic interventions have beneficial effects on some aspects of interpersonal functioning in people diagnosed with BPD, both after individual and group therapy. Generalizability of these findings is limited. CONCLUSION: There is preliminary evidence that psychotherapeutic interventions have beneficial effects on various aspects of interpersonal reactivity that characterize people diagnosed with BPD. However, none of these effects have a robust evidence base. There are serious concerns about the lack of agreed-upon concepts and instruments. PMID- 26058795 TI - Cold-water immersion alters muscle recruitment and balance of basketball players during vertical jump landing. AB - The purpose of this study was to evaluate the effects of cold-water immersion on the electromyographic (EMG) response of the lower limb and balance during unipodal jump landing. The evaluation comprised 40 individuals (20 basketball players and 20 non-athletes). The EMG response in the lateral gastrocnemius, tibialis anterior, fibular longus, rectus femoris, hamstring and gluteus medius; amplitude and mean speed of the centre of pressure, flight time and ground reaction force (GRF) were analysed. All volunteers remained for 20 min with their ankle immersed in cold-water, and were re-evaluated immediately post and after 10, 20 and 30 min of reheating. The Shapiro-Wilk test, Friedman test and Dunn's post test (P < 0.05) were used. The EMG response values decreased for the lateral gastrocnemius, tibialis anterior, fibular longus and rectus femoris of both athletes and non-athletes (P < 0.05). The comparison between the groups showed that the EMG response was lower for the athletes. Lower jump flight time and GRF, greater amplitude and mean speed of centre of pressure were predominant in the athletes. Cold-water immersion decreased the EMG activity of the lower limb, flight time and GRF and increased the amplitude and mean speed of centre of pressure. PMID- 26058796 TI - Relationship between parathyroid mass and parathyroid hormone level in hemodialysis patients with secondary hyperparathyroidism. AB - BACKGROUND: To evaluate the influence of parathyroid mass on the regulation of parathyroid hormone (PTH) secretion, we investigated the relationship between the resected parathyroid gland in total parathyroidectomy and the parathyroid hormone level in hemodialysis patients with secondary hyperparathyroidism. METHODS: From January 2009 to July 2014, 223 patients undergoing total parathyroidectomy were included. The size and the weight of parathyroid gland were measured during the operation. RESULTS: 874 parathyroid glands were removed. A positive correlation was identified between the size and the weight of resected parathyroid glands. We found that both the preoperative PTH and the reduction of PTH were significantly correlated with the size and the weight of parathyroid glands in a positive manner. However, in the subgroup of patients with PTH < 1000 pg/ml, no significant correlation was found. CONCLUSIONS: Larger parathyroid gland secretes more PTH and high level of serum PTH usually indicated that surgical removal might be required. However, since PTH levels could be influenced by the pharmaceutical drug, the large size of parathyroid gland might be used as a much more appropriate guide that indicates the requirement of surgery treatment even when the parathyroid hormone was less than 1000 pg/ml. PMID- 26058797 TI - Changes in D-aspartic acid and D-glutamic acid levels in the tissues and physiological fluids of mice with various D-aspartate oxidase activities. AB - D-Aspartic acid (D-Asp) and D-glutamic acid (D-Glu) are currently paid attention as modulators of neuronal transmission and hormonal secretion. These two D-amino acids are metabolized only by D-aspartate oxidase (DDO) in mammals. Therefore, in order to design and develop new drugs controlling the D-Asp and D-Glu amounts via regulation of the DDO activities, changes in these acidic D-amino acid amounts in various tissues are expected to be clarified in model animals having various DDO activities. In the present study, the amounts of Asp and Glu enantiomers in 6 brain tissues, 11 peripheral tissues and 2 physiological fluids of DDO(+/+), DDO(+/-) and DDO(-/-) mice were determined using a sensitive and selective two dimensional HPLC system. As a result, the amounts of D-Asp were drastically increased with the decrease in the DDO activity in all the tested tissues and physiological fluids. On the other hand, the amounts of D-Glu were almost the same among the 3 strains of mice. The present results are useful for designing new drug candidates, such as DDO inhibitors, and further studies are expected. PMID- 26058798 TI - Analysis of lactate concentrations in canine synovial fluid. AB - OBJECTIVE: To report synovial fluid lactate concentrations in normal and pathological canine joints. STUDY DESIGN: Controlled, prospective study. METHODS: Lactate was measured in synovial fluid using a hand-held meter and the rest of the fluid was sent to a commercial laboratory for analysis. Samples were divided into four groups; group 1: control, group 2: osteoarthritis, group 3: immune mediated inflammatory arthritis, and group 4: septic arthritis. Statistical analysis was performed to compare lactate concentrations between the four groups and to examine the predictive value of lactate in the diagnosis of septic arthritis. A correlation was sought between synovial fluid lactate and synovial fluid total nucleated cell count and total protein. RESULTS: Seventy-four samples were investigated from 55 dogs. Statistical analysis found that lactate concentrations were significantly higher in the septic arthritis group than in each of the other three groups. No significant correlation could be found between synovial fluid lactate concentrations and synovial fluid total nucleated cell count or synovial fluid total protein. Lactate concentration was found to be a useful predictor of septic arthritis, with a low concentration pointing towards exclusion rather than a high concentration to the diagnosis of septic arthritis. CLINICAL SIGNIFICANCE: Synovial fluid lactate concentration is not a good marker for osteoarthritis or immune-mediated inflammatory arthritis, but it is significantly increased in septic arthritis and could help the clinician in ruling out this condition in a quick and cost-effective way. PMID- 26058799 TI - Influence of Asian dust storms on daily acute myocardial infarction hospital admissions. AB - OBJECTIVE: This study was the first to explore the relationship between Asian dust storm events (ADS) and acute myocardial infarction (AMI) hospital admissions by applying time series models. DESIGN AND SAMPLE: Nationwide population-based hospitalization claims data in Taiwan were used. There were 143,063 AMI admissions during 2000-2009. MEASURES: An autoregressive with exogenous variables (ARX) time series model was used to investigate the dynamic connection between AMI hospital admissions and ADS events. RESULTS: AMI hospitalizations significantly spiked on post-ADS day three. Among the total population, 3.2 more cases of AMI admissions occurred on post-ADS day three. When the data were stratified by age and gender, the same delayed effect was present in the male population, especially those aged 45-64 and over 74. CONCLUSIONS: Our study shows that although an ADS event does not cause an immediate incidence of AMI, storms may increase AMI incidence through a delayed effect. Hence, AMI prevention is not only important during a dust storm, but particularly so in subsequent days. During the days after an ADS, exposure to dust should be minimized by staying indoors as much as possible and by wearing a mask when exposure to dust is unavoidable. This is especially true for working and older adults. Nurses at local public health centers can increase awareness and promote public safety by providing health information to local communities regarding the link between dust storms and AMI. PMID- 26058800 TI - Role of clothing in both accelerating and impeding dermal absorption of airborne SVOCs. AB - To assess the influence of clothing on dermal uptake of semi-volatile organic compounds (SVOCs), we measured uptake of selected airborne phthalates for an individual wearing clean clothes or air-exposed clothes and compared these results with dermal uptake for bare-skinned individuals under otherwise identical experimental conditions. Using a breathing hood to isolate dermal from inhalation uptake, we measured urinary metabolites of diethylphthalate (DEP) and di-n butylphthalate (DnBP) from an individual exposed to known concentrations of these compounds for 6 h in an experimental chamber. The individual wore either clean (fresh) cotton clothes or cotton clothes that had been exposed to the same chamber air concentrations for 9 days. For a 6-h exposure, the net amounts of DEP and DnBP absorbed when wearing fresh clothes were, respectively, 0.017 and 0.007 MUg/kg/(MUg/m(3)); for exposed clothes the results were 0.178 and 0.261 MUg/kg/(MUg/m(3)), respectively (values normalized by air concentration and body mass). When compared against the average results for bare-skinned participants, clean clothes were protective, whereas exposed clothes increased dermal uptake for DEP and DnBP by factors of 3.3 and 6.5, respectively. Even for non occupational environments, wearing clothing that has adsorbed/absorbed indoor air pollutants can increase dermal uptake of SVOCs by substantial amounts relative to bare skin. PMID- 26058801 TI - Balanced modulation of striatal activation from D2 /D3 receptors in caudate and ventral striatum: Disruption in cannabis abusers. AB - Proper communication between dorsal caudate (CD) and ventral striatum (VS) is likely to be crucial for on-time responses and its disruption might result in impulsivity. Here, we used functional magnetic resonance imaging (fMRI) with a sensorimotor reaction time task and positron emission tomography (PET) with [(11)C]raclopride in 14 healthy controls and 18 cannabis abusers to contrast the modulation of striatal fMRI responses by dopamine receptors (D2 /D3 R) in CD and VS. In controls, we show that the fMRI signals in VS that occurs concomitantly with on-time responses showed opposite modulation from D2 /D3 R in CD (inhibitory) and D2 /D3 R in VS (stimulatory). In contrast, this modulation was not significant in cannabis abusers. Findings suggest that action speed requires balanced VS-inhibition from D2 /D3 R in CD and VS-facilitation from D2 /D3 R in VS. PMID- 26058802 TI - Mid-term results of ligament tenodesis in treatment of scapholunate dissociation: a retrospective study of 20 patients. AB - The purpose of this retrospective study was to assess the modified Brunelli technique for the treatment of chronic irreparable complete scapholunate ligament rupture, causing a reducible carpal malalignment without secondary osteoarthritis. A total of 20 patients were treated using this technique. At a mean follow-up period of 24 months (range 6-53, SD 15), pain on a visual analogue scale had improved from 6 (range 3-10) to 3 (range 0-7). Function measured with the DASH score had improved from 37 (range 11-90) to 20 (range 0-53). Range of motion was reduced in flexion by a mean of 19 degrees (range 10-45), and in extension by a mean of 14 degrees (range 0-35). Mean grip strength at last follow-up was 81% of the uninjured hand (range 50-100%) Three patients developed scapholunate advanced collapse (stage II) requiring salvage surgery. Scapholunate ligament reconstruction with the modified Brunelli technique showed satisfactory results in this study. Extended studies are needed to determine the long-term benefits of this reconstructive procedure. LEVEL OF EVIDENCE: IV. PMID- 26058803 TI - Hair Growth: Focus on Herbal Therapeutic Agent. AB - This review presents an overview on plants identified to possess hair growth activity in various ethno-botanical studies and surveys of tradition medicinal plants. It also highlights the developments in hair rejuvenation strategies from 1926 till-date and reviews the potential of herbal drugs as safer and effective alternatives. There are various causes for hair loss and the phenomenon is still not fully understood. The treatments offered include both natural or synthetic products to treat the condition of hair loss (alopecia), nonetheless natural products are continuously gaining popularity mainly due to their fewer side effects and better formulation strategies for natural product extracts. Plants have been widely used for hair growth promotion since ancient times as reported in Ayurveda, Chinese and Unani systems of medicine. This review covers information about different herbs and herbal formulation that are believed to be able to reduce the rate of hair loss and at the same time stimulate new hair growth. A focus is placed on their mechanism of action and the review also covers various isolated phytoconstituents possessing hair growth promoting effect. PMID- 26058804 TI - Bioinspired production of magnetic laccase-biotitania particles for the removal of endocrine disrupting chemicals. AB - Microbial laccases are powerful enzymes capable of degrading lignin and other recalcitrant compounds including endocrine disrupting chemicals (EDCs). Efficient EDC removal on an industrial scale requires robust, stable, easy to handle and cost-effective immobilized biocatalysts. In this direction, magnetic biocatalysts are attractive due to their easy separation through an external magnetic field. Recently, a bioinspired immobilization technique that mimics the natural biomineralization reactions in diatoms has emerged as a fast and versatile tool for generating robust, cheap, and highly stable (nano) biocatalysts. In this work, bioinspired formation of a biotitania matrix is triggered on the surface of magnetic particles in the presence of laccase in order to produce laccase biotitania (lac-bioTiO2 ) biocatalysts suitable for environmental applications using a novel, fast and versatile enzyme entrapment technique. Highly active lac bioTiO2 particles have been produced and the effect of different parameters (enzyme loading, titania precursor concentration, pH, duration of the biotitania formation, and laccase adsorption steps) on the apparent activity yield of these biocatalysts were evaluated, the concentration of the titania precursor being the most influential. The lac-bioTiO2 particles were able to catalyze the removal of bisphenol A, 17alpha-ethinylestradiol and diclofenac in a mixture of six model EDCs and retained 90% of activity after five reaction cycles and 60% after 10 cycles. PMID- 26058805 TI - The initiation of nocturnal dormancy in Synechococcus as an active process. AB - BACKGROUND: Most organisms, especially photoautotrophs, alter their behaviours in response to day-night alternations adaptively because of their great reliance on light. Upon light-to-dark transition, dramatic and universal decreases in transcription level of the majority of the genes in the genome of the unicellular cyanobacterium, Synechococcus elongatus PCC 7942 are observed. Because Synechococcus is an obligate photoautotroph, it has been generally assumed that repression of the transcription in the dark (dark repression) would be caused by a nocturnal decrease in photosynthetic activities through the reduced availability of energy (e.g. adenosine triphosphate (ATP)) needed for mRNA synthesis. RESULTS: However, against this general assumption, we obtained evidence that the rapid and dynamic dark repression is an active process. Although the addition of photosynthesis inhibitors to cells exposed to light mimicked transcription profiles in the dark, it did not significantly affect the cellular level of ATP. By contrast, when ATP levels were decreased by the inhibition of both photosynthesis and respiration, the transcriptional repression was attenuated through inhibition of RNA degradation. This observation indicates that Synechococcus actively downregulates genome-wide transcription in the dark. Even though the level of total mRNA dramatically decreased in the dark, Synechococcus cells were still viable, and they do not need de novo transcription for their survival in the dark for at least 48 hours. CONCLUSIONS: Dark repression appears to enable cells to enter into nocturnal dormancy as a feed forward process, which would be advantageous for their survival under periodic nocturnal conditions. PMID- 26058806 TI - MAGEA10 gene expression in non-small cell lung cancer and A549 cells, and the affinity of epitopes with the complex of HLA-A(*)0201 alleles. AB - MAGEA10, a cancer/testis antigens expressed in tumors but not in normal tissues with the exception of testis and placenta, represents an attractive target for cancer immunotherapy. However, suppressive cytoenvironment and requirement of specific HLA-alleles presentation frequently led to immunotherapy failure. In this study MAGEA10 was scarcely expressed in cancer patients, but enhanced by viili polysaccharides, which indicates a possibility of increasing epitopes presentation. Furthermore the correlation of gene expression with methylation, indicated by R(2) value for MAGEA10 that was 3 times higher than the value for other MAGE genes tested, provides an explanation of why MAGEA10 was highly inhibited, this is also seen by Kaplan-Meier analysis because MAGEA10 did not change the patients' lifespan. By using Molecular-Docking method, 3 MAGEA10 peptides were found binding to the groove position of HLA-A(*)0210 as same as MAGEA4 peptide co-crystallized with HLA-A(*)0210, which indicates that they could be promising for HLA-A(*)0201 presentation in immunotherapy. PMID- 26058808 TI - Structured Dance as a Healing Modality for Women. PMID- 26058807 TI - A 40-bp VNTR polymorphism in the 3'-untranslated region of DAT1/SLC6A3 is associated with ADHD but not with alcoholism. AB - BACKGROUND: ADHD and alcoholism are psychiatric diseases with pathophysiology related to dopamine system. DAT1 belongs to the SLC6 family of transporters and is involved in the regulation of extracellular dopamine levels. A 40 bp variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region of DAT1/SLC6A3 gene was previously reported to be associated with various phenotypes involving disturbed regulation of dopaminergic neurotransmission. METHODS: A total of 1312 subjects were included and genotyped for 40 bp VNTR polymorphism of DAT1/SLC6A3 gene in this study (441 alcoholics, 400 non-alcoholic controls, 218 ADHD children and 253 non ADHD children). Using miRBase software, we have performed a computer analysis of VNTR part of DAT1 gene for presence of miRNA binding sites. RESULTS: We have found significant relationships between ADHD and the 40 bp VNTR polymorphisms of DAT1/SLC6A3 gene (P < 0.01). The 9/9 genotype appeared to reduce the risk of ADHD about 0.4-fold (p < 0.04). We also noted an occurrence of rare genotypes in ADHD (frequency different from controls at p < 0.01). No association between alcoholism and genotype frequencies of 40 bp VNTR polymorphism of DAT1/SLC6A3 gene has been detected. CONCLUSIONS: We have found an association between 40 bp VNTR polymorphism of DAT1/SLC6A3 gene and ADHD in the Czech population; in a broad agreement with studies in other population samples. Furthermore, we detected rare genotypes 8/10, 7/10 and 10/11 present in ADHD boys only and identified miRNAs that should be looked at as potential novel targets in the research on ADHD. PMID- 26058809 TI - Steroids therapy for eosinophilic esophagitis: Systematic review and meta analysis. AB - OBJECTIVE: We designed this systematic review and meta-analysis aiming to clarify the advantage of steroid therapy compared with non-steroid therapy for the treatment of eosinophilic esophagitis (EoE). METHODS: PubMed, EMBASE, Medline, ISI Web of Science and the Cochrane Database of Systematic Reviews were searched to identify relevant randomized controlled trials (RCTs) comparing steroid and non-steroid therapy, and retrospective and prospective trials on steroid therapy for EoE. RevMan 5.2 was used for the analysis. Weighted mean difference and 95% confidence interval (CI) were estimated and pooled using meta-analysis methods. RESULTS: Six RCTs including 193 participants fulfilled the inclusion criteria for meta-analysis, and another two RCTs, three prospective and five retrospective trials were included in systematic review. Meta-analysis showed that topical steroids significantly decreased the mean and peak esophageal eosinophils (EOS) count compared to non-steroid therapy (MDmean = -23.41, 95% CImean -42.08--4.73, P = 0.01 and MDpeak = -51.27, 95% CIpeak -78.62--23.92, P = 0.0002). There were 14 trials showing the efficacy of steroids on decreasing the EOS count, 10 showing the amelioration of symptoms, and five showing endoscopic improvement. Only mild adverse events were reported for topical steroids. CONCLUSIONS: Steroids are effective on decreasing the EOS count in EoE patients. Its value in ameliorating symptoms and endoscopic changes remains undetermined due to the lack of comparable criteria. PMID- 26058810 TI - Variations in observable lid wiper epitheliopathy (LWE) staining patterns in wearers of silicone hydrogel lenses. PMID- 26058811 TI - Finasteride and dutasteride may reduce melanoma risk. PMID- 26058812 TI - Novel Function of Rev-erbalpha in Promoting Brown Adipogenesis. AB - Brown adipose tissue is a major thermogenic organ that plays a key role in maintenance of body temperature and whole-body energy homeostasis. Rev-erbalpha, a ligand-dependent nuclear receptor and transcription repressor of the molecular clock, has been implicated in the regulation of adipogenesis. However, whether Rev-erbalpha participates in brown fat formation is not known. Here we show that Rev-erbalpha is a key regulator of brown adipose tissue development by promoting brown adipogenesis. Genetic ablation of Rev-erbalpha in mice severely impairs embryonic and neonatal brown fat formation accompanied by loss of brown identity. This defect is due to a cell-autonomous function of Rev-erbalpha in brown adipocyte lineage commitment and terminal differentiation, as demonstrated by genetic loss- and gain-of-function studies in mesenchymal precursors and brown preadipocytes. Moreover, pharmacological activation of Rev-erbalpha activity promotes, whereas its inhibition suppresses brown adipocyte differentiation. Mechanistic investigations reveal that Rev-erbalpha represses key components of the TGF-beta cascade, an inhibitory pathway of brown fat development. Collectively, our findings delineate a novel role of Rev-erbalpha in driving brown adipocyte development, and provide experimental evidence that pharmacological interventions of Rev-erbalpha may offer new avenues for the treatment of obesity and related metabolic disorders. PMID- 26058813 TI - Molecular epidemiology of an outbreak of hand, foot, and mouth disease associated with subgenotype C4a of enterovirus A71 in Nanchang, China in 2014. AB - An outbreak of hand, foot, and mouth disease was reported through hospital-based surveillance in Nanchang, China in 2014. A total of 244 cases were reported, 176 (72.1%) cases were tested positive for enteroviruses by direct reverse transcription-polymerase chain reaction, in which enterovirus A71 (EV-A71), coxsackievirus A16 (CV-A16), and untyped enteroviruses (UEV) accounted for 84.1%, 3.4%, and 12.5%, respectively. In this outbreak, children under 5 years old constituted more than 98% of the positive cases, and the ratio of male to female cases was 2.6 to 1 (P < 0.01). Phylogenetic analysis indicated that the Nanchang EV-A71 strains belonged to subgenotype C4a undergoing continuously evolutionary changes. PMID- 26058814 TI - Alternative splicing of the cell fate determinant Numb in hepatocellular carcinoma. AB - The cell fate determinant Numb is aberrantly expressed in cancer. Numb is alternatively spliced, with one isoform containing a long proline-rich region (PRR(L) ) compared to the other with a short PRR (PRR(S) ). Recently, PRR(L) was reported to enhance proliferation of breast and lung cancer cells. However, the importance of Numb alternative splicing in hepatocellular carcinoma (HCC) remains unexplored. We report here that Numb PRR(L) expression is increased in HCC and associated with early recurrence and reduced overall survival after surgery. In a panel of HCC cell lines, PRR(L) generally promotes and PRR(S) suppresses proliferation, migration, invasion, and colony formation. Knockdown of PRR(S) leads to increased Akt phosphorylation and c-Myc expression, and Akt inhibition or c-Myc silencing dampens the proliferative impact of Numb PRR(S) knockdown. In the cell models explored in this study, alternative splicing of Numb PRR isoforms is coordinately regulated by the splicing factor RNA-binding Fox domain containing 2 (RbFox2) and the kinase serine/arginine protein-specific kinase 2 (SRPK2). Knockdown of the former causes accumulation of PRR(L) , while SRPK2 knockdown causes accumulation of PRR(S) . The subcellular location of SRPK2 is regulated by the molecular chaperone heat shock protein 90, and heat shock protein 90 inhibition or knockdown phenocopies SRPK2 knockdown in promoting accumulation of Numb PRR(S) . Finally, HCC cell lines that predominantly express PRR(L) are differentially sensitive to heat shock protein 90 inhibition. CONCLUSION: Alternative splicing of Numb may provide a useful prognostic biomarker in HCC and is pharmacologically tractable. PMID- 26058815 TI - Translating Regenerative Biomaterials Into Clinical Practice. AB - Globally health care spending is increasing unsustainably. This is especially true of the treatment of musculoskeletal (MSK) disease where in the United States the MSK disease burden has doubled over the last 15 years. With an aging and increasingly obese population, the surge in MSK related spending is only set to worsen. Despite increased funding, research and attention to this pressing health need, little progress has been made toward novel therapies. Tissue engineering and regenerative medicine (TERM) strategies could provide the solutions required to mitigate this mounting burden. Biomaterial-based treatments in particular present a promising field of potentially cost-effective therapies. However, the translation of a scientific development to a successful treatment is fraught with difficulties. These barriers have so far limited translation of TERM science into clinical treatments. It is crucial for primary researchers to be aware of the barriers currently restricting the progression of science to treatments. Researchers need to act prospectively to ensure the clinical, financial, and regulatory hurdles which seem so far removed from laboratory science do not stall or prevent the subsequent translation of their idea into a treatment. The aim of this review is to explore the development and translation of new treatments. Increasing the understanding of these complexities and barriers among primary researchers could enhance the efficiency of biomaterial translation. PMID- 26058816 TI - Community-based case management effectiveness in populations that abuse substances. AB - BACKGROUND: The number of persons who are substance abusing has been increasing globally. A majority of them remain in their communities, untreated. Empirical studies have shown some positive impacts of case management on substance abuse. However, studies that systematically synthesize the effectiveness of community based case management with populations that abuse substances are limited. AIM: To review evidence of the impact of case management in improving treatment of substance abuse among adults in community settings. METHODS: The Cochrane processes guided this systematic review. PubMed, CINAHL, PsycINFO, Ovid and the Web of Science were searched to retrieve primary studies published from 2000 to 2013. All randomized controlled trials were considered for review. The methodological quality of the studies was assessed. RESULTS: The initial unfiltered search identified 506 references. A total of seven randomized controlled trials were selected for review. Findings show that, compared with clinical case management and usual care, community-based case management services significantly improved clients' ability to abstain from drug use, reduced social problems, supported unmet service needs and improved satisfaction. Studies also showed reduced use of healthcare services, but results were mixed. CONCLUSIONS: There is an evidence base for practicing case management among adults who are substance abusing. In general, studies concluded that case management is an active and assertive method of care coordination for formal substance abuse treatment. Further research is needed to assess case management's cost effectiveness and the impact of dosage on client outcomes. IMPLICATIONS FOR NURSING POLICY: Because of the complexity of population health management across settings and over long time frames, evidence-based strategies are required to achieve health improvements. Because it provides continuous and timely care, healthcare leaders and policymakers should consider community-based case management as an important strategy for coordinating the care in populations that are substance abusing. PMID- 26058817 TI - Treatment of Chronic Plantar Fasciitis With Percutaneous Latticed Plantar Fasciotomy. AB - Plantar fasciitis, the most common cause of pain in the inferior heel, accounts for 11% to 15% of all foot symptoms requiring professional care among adults. The present study reports the results of a minimally invasive surgical treatment of chronic plantar fasciitis. All patients with plantar fasciitis who had undergone percutaneous latticed plantar fasciotomy at 3 clinical sites from March 2008 to March 2009 were included in the present study. The follow-up evaluations for this treatment were conducted using the Mayo clinical scoring system. We investigated 17 patients with recalcitrant chronic plantar fasciitis who had undergone this treatment within a follow-up period of >=13 months. All procedures were performed in the clinic with the patient under local anesthesia. No wound infections or blood vessel or nerve damage occurred. At a mean follow-up period of 16.0 +/- 2.29 (range 13 to 21) months, significant improvement was seen in the preoperative mean Mayo score (from 12.06 +/- 2.54 to 89.76 +/- 4.28, p < .001) and no patient had developed symptom recurrence. Also, none of the patients had developed complex regional pain syndrome. All patients were able to return to regular shoe wear by 3 weeks postoperatively. The technique of plantar fasciitis with percutaneous latticed plantar fasciotomy could be a promising treatment option for patients with recalcitrant chronic plantar fasciitis. PMID- 26058818 TI - Biomechanical Evaluation of Custom Foot Orthoses for Hallux Valgus Deformity. AB - The purpose of the present study was to compare the hallux valgus deformity pressure parameters seen in standard footwear (no orthosis) versus the pressure observed in the same footwear with the addition of 3 different length orthoses. The forefoot pressure at a hallux valgus deformity was recorded with pressure sensors placed on the plantar, medial, and dorsal surface of the first metatarsal head. The participants performed walking trials without an orthosis and with orthoses of 3 different lengths. The average pressure and maximum pressure of each area was recorded for each orthosis, and comparisons were made across the groups. The plantar pressures were decreased in the full length and 3/4 length orthoses, and the dorsal pressures were increased with the use of the full-length and sulcus-length orthoses. Significant changes in medial pressure were not seen with the addition of any orthosis compared with standard footwear alone. However, a trend toward increased medial pressures was seen with the full- and sulcus length orthoses, and the 3/4-length orthoses exhibited a trend toward decreased medial pressures. We were unable to demonstrate that the use of a custom foot orthosis significantly decreases the medial pressures on the first metatarsal head in patients with hallux valgus deformity. The 3/4-length orthosis was less likely to negatively affect the dorsal or medial pressures, which were noted to increase with the sulcus- and full-length orthoses. Our data suggest that if a clinician uses this treatment option, a 3/4-length orthosis might be a better choice than a sulcus- or full-length orthosis. PMID- 26058819 TI - Degenerative mitral valve disease: Survival of dogs attending primary-care practice in England. AB - This study aimed to evaluate survival of dogs with degenerative mitral valve disease (DMVD). A retrospective cohort study of dogs with DMVD attending primary care practices in England was undertaken. Cases of DMVD were identified within the electronic patient records (EPRs) of practices sharing data with VetCompass. Kaplan-Meier curves were used to explore survival and Cox regression models identified factors associated with hazard of death. The EPRs from 111,967 dogs, attending 93 veterinary practices between January 2010 and December 2011 identified 405 cases diagnosed with DMVD giving a prevalence of diagnosed DMVD of 0.36% (95% CI: 0.29-0.45%). A further 3557 dogs were classified as possible cases (heart murmurs consistent with DMVD). Overall, a total of 3962 dogs were classified as heart murmur cases (possible and diagnosed DMVD), giving a prevalence of 3.54% (95% CI: 3.26-3.84%). One hundred and sixteen (28.6%) of the diagnosed DMVD cases were incident, newly diagnosed with DMVD. The mean age at diagnosis was 9.52 years (95% CI: 8.98-10.14 years). Fifty-eight (50.0%) of the incident cases died during the study period. The median survival time (MST) for all-cause mortality was 25.4 months (95% CI: 20.4-34.4 months) after disease detection for DMVD cases. For possible cases, 121 (29.7%) from a random sample of 407 possible DMVD cases were incident cases (newly detected heart murmur consistent with DMVD during the study period). The mean age at which a heart murmur was first recorded in possible cases was 9.73 years (95% CI: 9.02-10.44 years). Forty-nine (40.5%) possible cases died during the study period. The MST for all-cause mortality was 33.8 months (95% CI: 23.7-43.1 months) after a heart murmur was initially detected. In the multivariable survival analysis for possible and diagnosed cases, Cavalier King Charles Spaniels (CKCSs) and other purebreds had higher hazards of death than crossbreds. Dogs weighing >=20.0kg and older dogs had an increased hazard of death compared with those <20.0kg and younger dogs, respectively. The study highlights poorer survival for all-cause mortality in CKCSs and larger dogs. The reported survival characteristics could aid veterinary surgeons' advice on the prognosis for dogs with DMVD and help the assessment of the impact of the condition at a population level. PMID- 26058820 TI - Regression based quasi-experimental approach when randomisation is not an option: interrupted time series analysis. PMID- 26058821 TI - Oligomeric Donor Material for High-Efficiency Organic Solar Cells: Breaking Down a Polymer. PMID- 26058822 TI - Lucy's back: Reassessment of fossils associated with the A.L. 288-1 vertebral column. AB - The Australopithecus afarensis partial skeleton A.L. 288-1, popularly known as "Lucy" is associated with nine vertebrae. The vertebrae were given provisional level assignments to locations within the vertebral column by their discoverers and later workers. The continuity of the thoracic series differs in these assessments, which has implications for functional interpretations and comparative studies with other fossil hominins. Johanson and colleagues described one vertebral element (A.L. 288-1am) as uniquely worn amongst the A.L. 288-1 fossil assemblage, a condition unobservable on casts of the fossils. Here, we reassess the species attribution and serial position of this vertebral fragment and other vertebrae in the A.L. 288-1 series. When compared to the other vertebrae, A.L. 288-1am falls well below the expected size within a given spinal column. Furthermore, we demonstrate this vertebra exhibits non-metric characters absent in hominoids but common in large-bodied papionins. Quantitative analyses situate this vertebra within the genus Theropithecus, which today is solely represented by the gelada baboon but was the most abundant cercopithecoid in the KH-1s deposit at Hadar where Lucy was discovered. Our additional analyses confirm that the remainder of the A.L. 288-1 vertebral material belongs to A. afarensis, and we provide new level assignments for some of the other vertebrae, resulting in a continuous articular series of thoracic vertebrae, from T6 to T11. This work does not refute previous work on Lucy or its importance for human evolution, but rather highlights the importance of studying original fossils, as well as the efficacy of the scientific method. PMID- 26058823 TI - The development of bystander intentions and social-moral reasoning about intergroup verbal aggression. AB - A developmental intergroup approach was taken to examine the development of prosocial bystander intentions among children and adolescents. Participants as bystanders (N = 260) aged 8-10 and 13-15 years were presented with scenarios of direct aggression between individuals from different social groups (i.e., intergroup verbal aggression). These situations involved either an ingroup aggressor and an outgroup victim or an outgroup aggressor and an ingroup victim. This study focussed on the role of intergroup factors (group membership, ingroup identification, group norms, and social-moral reasoning) in the development of prosocial bystander intentions. Findings showed that prosocial bystander intentions declined with age. This effect was partially mediated by the ingroup norm to intervene and perceived severity of the verbal aggression. However, a moderated mediation analysis showed that only when the victim was an ingroup member and the aggressor an outgroup member did participants become more likely with age to report prosocial bystander intentions due to increased ingroup identification. Results also showed that younger children focussed on moral concerns and adolescents focussed more on psychological concerns when reasoning about their bystander intention. These novel findings help explain the developmental decline in prosocial bystander intentions from middle childhood into early adolescence when observing direct intergroup aggression. PMID- 26058824 TI - C-reactive protein is a biomarker of AFP-negative HBV-related hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most aggressive cancers worldwide and is associated with the high rates of morbidity and mortality. alpha fetoprotein (AFP) is common used in diagnosis of HCC; however, a growing body of research is questioning the diagnostic power of AFP. There is, therefore, an urgent need to develop additional novel non-invasive techniques for the early diagnosis of HCC, particularly for patients with AFP-negative [AFP(-)] HCC. Accordingly, in the present study, we employed iTRAQ-based mass spectro-metry to analyze the plasma proteins of subjects with AFP(-) HBV-related HCC, AFP(+) HBV related HCC and non-malignant cirrhosis. We identified 14 aberrantly expressed proteins specific to the HCC patients, including 10 upregulated and 4 downregulated proteins. We verified C-reactive protein (CRP) overexpression by ELISA and immunohistochemical staining of clinical samples. Per ROC curve analyses, CRP was positive in 73.3% of patients with HBV-related HCC, and CRP overexpression had significant diagnostic power for AFP(-) HBV-related HCC. Furthermore, we found that silencing CRP caused a >2-fold decease in HBV replication. Additionally, we determined that this reduction in HBV replication involved the interferon-signaling pathway. However, silencing CRP also promoted HCC invasion and migration in vitro. In conclusion, we demonstrated that CRP can serve as a diagnostic biomarker for AFP(-) HBV-related HCC. PMID- 26058825 TI - On estimation of covariate-specific residual time quantiles under the proportional hazards model. AB - Estimation and inference in time-to-event analysis typically focus on hazard functions and their ratios under the Cox proportional hazards model. These hazard functions, while popular in the statistical literature, are not always easily or intuitively communicated in clinical practice, such as in the settings of patient counseling or resource planning. Expressing and comparing quantiles of event times may allow for easier understanding. In this article we focus on residual time, i.e., the remaining time-to-event at an arbitrary time t given that the event has yet to occur by t. In particular, we develop estimation and inference procedures for covariate-specific quantiles of the residual time under the Cox model. Our methods and theory are assessed by simulations, and demonstrated in analysis of two real data sets. PMID- 26058826 TI - Effect of pulse width on transesophageal atrial pacing in dogs. AB - OBJECTIVE: To determine the impact of stimulus pulse width (PW) on pacing threshold (PT), zone of capture (ZOC) and extraneous muscular stimulation (EMS). STUDY DESIGN: Experimental trial in client-owned dogs. ANIMALS: Seventeen dogs, median weight 16.1 kg (interquartile range: 11.4-21.5). METHODS: Transesophageal atrial pacing (TAP) involved a 6 Fr pacing catheter inserted trans-orally into the esophagus to a position aboral to the heart in anesthetized dogs. The catheter was slowly withdrawn until atrial pacing was noted on an electrocardiogram. The catheter was withdrawn in 1 cm increments until TAP could not be achieved. PTs were recorded at each pacing site using PWs of 10.0, 5.0, 2.0 and 1.8 ms, always in that order. RESULTS: The overall lowest mean PTs for all dogs were 6 +/- 3 mA, 9 +/- 4 mA, 11 +/- 5 mA and 13 +/- 5 mA at PWs of 10.0, 5.0, 2.0 and 1.8 ms, respectively. A significant decrease in overall minimum PT was noted using a PW of 10.0 ms compared with either 2.0 or 1.8 ms (p = 0.043 and p = 0.001, respectively) and pacing using 5.0 ms compared with 1.8 ms (p = 0.028). A significant increase in ZOC was noted using a PW of 10.0 ms compared with PWs of 5.0, 2.0 and 1.8 ms (p = 0.0047, p = 0.0006 and p = 0.0003, respectively), using a PW of 5.0 ms compared with PWs of 2.0 and 1.8 ms (p = 0.0011 and p = 0.0003, respectively) and using a PW of 2.0 compared with one of 1.8 ms (p = 0.0084). CONCLUSIONS AND CLINICAL RELEVANCE: Use of 10.0 or 5.0 ms PW to perform TAP minimized the power required to pace the atria, while a PW of 10.0 ms maximized the size of the ZOC. PMID- 26058827 TI - pH and heat-dependent behaviour of glucose oxidase down to single molecule level by combined fluorescence spectroscopy and molecular modelling. AB - BACKGROUND: In the food industry, glucose oxidase (GOX) is used to improve the shelf life of food materials. The pH- and heat-induced conformational changes of glucose oxidase from Aspergillus niger were quantified by means of fluorescence spectroscopy and molecular dynamics simulations. RESULTS: The phase diagram showed an all-or-none transition process, indicating that pH and temperature largely influence the conformational state of GOX. Shifts in maximum wavelength of Trp, Tyr were registered as the protein encounters a lower pH (pH 4.0), suggesting significant changes of the polarity around the chromophore molecule. Quenching experiments using KI showed higher quenching constants of Trp and flavin adenine dinucleotide upon heating or by changing pH value, and were mainly correlated with the conformational changes upon protein matrix. Finally, valuable insights into the thermal behaviour of GOX were obtained from molecular modelling results. CONCLUSIONS: The conformation and structure of GOX protein is dependent upon the pH and heat treatment applied. Molecular dynamics simulation indicated significant changes in the substrate binding region at temperatures over 60 degrees C that might affect enzyme activity. Moreover, an important alteration of the small pocket hosting the positively charged His(516) residue responsible for oxygen activation appears evident at high temperatures. PMID- 26058828 TI - Across-Species Transfer of Protection by Remote Ischemic Preconditioning With Species-Specific Myocardial Signal Transduction by Reperfusion Injury Salvage Kinase and Survival Activating Factor Enhancement Pathways. AB - RATIONALE: Reduction of myocardial infarct size by remote ischemic preconditioning (RIPC), that is, cycles of ischemia/reperfusion in an organ remote from the heart before sustained myocardial ischemia/reperfusion, was confirmed in all species so far, including humans. OBJECTIVE: To identify myocardial signal transduction of cardioprotection by RIPC. METHODS AND RESULTS: Anesthetized pigs were subjected to RIPC (4*5/5 minutes hindlimb ischemia/reperfusion) or placebo (PLA) before 60/180 minutes coronary occlusion/reperfusion. Phosphorylation of protein kinase B, extracellular signal regulated kinase 1/2 (reperfusion injury salvage kinase [RISK] pathway), and signal transducer and activator of transcription 3 (survival activating factor enhancement [SAFE] pathway) in the area at risk was determined by Western blot. Wortmannin/U0126 or AG490 was used for pharmacological RISK or SAFE blockade, respectively. Plasma sampled after RIPC or PLA, respectively, was transferred to isolated bioassay rat hearts subjected to 30/120 minutes global ischemia/reperfusion. RIPC reduced infarct size in pigs to 16+/-11% versus 43+/ 11% in PLA (% area at risk; mean+/-SD; P<0.05). RIPC increased the phosphorylation of signal transducer and activator of transcription 3 at early reperfusion, and AG490 abolished the protection, whereas RISK blockade did not. Signal transducer and activator of transcription 5 phosphorylation was decreased at early reperfusion in both RIPC and PLA. In isolated rat hearts, pig plasma taken after RIPC reduced infarct size (25+/-5% of ventricular mass versus 38+/-5% in PLA; P<0.05) and activated both RISK and SAFE. RISK or SAFE blockade abrogated this protection. CONCLUSIONS: Cardioprotection by RIPC in pigs causally involves activation of signal transducer and activator of transcription 3 but not of RISK. Protection can be transferred with plasma from pigs to isolated rat hearts where activation of both RISK and SAFE is causally involved. The myocardial signal transduction of RIPC is the same as that of ischemic postconditioning. PMID- 26058829 TI - An examination of quality of care in Norwegian nursing homes - a change to more activities? AB - BACKGROUND: Studies on Norwegian nursing homes have shown that the general care is at a relatively high level, while the level of physical and social activities is relatively low. As a response to these findings, the Norwegian government has stressed the importance of activities in various white papers and circulars and, in recent years, has launched several campaigns specifically aimed at increasing the level of activities. AIM: The aim of the study was to examine the following: (i) how the government has succeeded in increasing the level of physical and social activities in Norwegian nursing homes; (ii) how the level of activities compares to the general care; and (iii) how the level of activities and the general care are influenced by the following facility characteristics: residents' mobility level, total staffing levels, ratio of RNs, ratio of unlicensed staff and ward size. METHOD: A cross-sectional survey of forty nursing home wards throughout Norway was used to collect the data. RESULTS: On a scale ranging from 1 to 7, the staff members assess the activity dimension to be 4.31 and the general care dimension to be 5.66. The activity dimension was significantly negatively correlated with the ratio of unlicensed staff, the ratio of Registered Nurses and the residents' mobility level, while the general care dimension was significantly negatively correlated with the ratio of unlicensed staff. CONCLUSION: The study shows that the level of physical and social activities offered to the residents is relatively low, while the general care level is significantly higher, in line with earlier studies. Consequently, the government has not succeeded with its current policy to increase the level of activities in nursing homes. The relationship between the two quality dimensions and the explanatory variables shows that nursing home quality is a complicated phenomenon. PMID- 26058830 TI - Performance evaluation of developed polysulfone membrane hemodiafilters, ABH-F and ABH-P, in post- and pre-dilution hemodiafiltration. AB - ABH-F and ABH-P have been developed for hemodiafiltration (HDF) therapy. In this study, we evaluated the solute removal characteristics of the hemodiafilters in a bovine blood in vitro study. The hemodiafilters were examined for 120 min at various filtration flow rates (Q F) (31.2-250 mL/min) under a constant blood flow rate of 250 mL/min and constant dialysate flow rates of 500/250 mL/min in pre dilution HDF (pre-HDF) and post-dilution HDF (post-HDF). Creatinine clearance in pre-HDF was approximately 85% of that in post-HDF because it was removed by molecular diffusion dominantly. The initial clearances of beta2-microglobulin and alpha1-microglobulin increased with Q F and these values slightly and steeply decreased with time due to membrane fouling. Under a same Q F of 62.5 mL/min, higher clearance values in post-HDF were obtained compared with those in pre-HDF. All clearance values of ABH-P were higher than those of ABH-F under the same Q F. It seems that the ABH-P has a larger pore size of membrane than that in ABH-F. The creatinine and alpha1-microglobulin clearance values were obtained as highest at post-Q F62.5, the beta2-microglobulin clearance values and transmembrane pressure were obtained as highest at pre-Q F250. Large solute clearances such as alpha1-microglobulin and albumin decreased with time in all HDF experiments. Time decay of large solute clearance values was observed in the HDF modality that had a higher clearance of the solute at 5 min later after the start of experiment. PMID- 26058831 TI - Relative permittivity measurement during the thrombus formation process using the dielectric relaxation method for various hematocrit values. AB - The relative permittivity epsilon' and the dielectric loss epsilon" for various hematocrit values H for static bovine blood condition have been measured using the dielectric relaxation method to detect thrombosis in real time. The suitable measurement frequency f m ranged within 60 kHz to 1 MHz, and the relaxation frequency of red blood cells (RBCs) f rc was observed to be 2 MHz. In the f m, the temporal change of normalized epsilon' exhibited a minimum (called as bottom point). The bottom point was observed to be exponentially shortened as H increased. This characteristic of the epsilon'* minimum is discussed from three viewpoints: during fibrin formation, direct thrombus formation, and rouleaux formation processes. epsilon'* during the fibrin formation process decreased over time, irrespective of f. However, epsilon'* in f m during the direct thrombus formation process and during the aggregation formation process increased immediately and rapidly over time. Therefore, the epsilon'* bottom point in f m might be the indication of micrometer-scale thrombus formation by RBC aggregation due to fibrin formation. PMID- 26058832 TI - Low glucose depletes glycan precursors, reduces site occupancy and galactosylation of a monoclonal antibody in CHO cell culture. AB - Controlled feeding of glucose has been employed previously to enhance the productivity of recombinant glycoproteins but there is a concern that low concentrations of glucose could limit the synthesis of precursors of glycosylation. Here we investigate the effect of glucose depletion on the metabolism, productivity and glycosylation of a chimeric human-llama monoclonal antibody secreted by CHO cells. The cells were inoculated into media containing varying concentrations of glucose. Glucose depletion occurred in cultures with an initial glucose <=5.5 mM and seeded at low density (2.5 * 10(5) cells/mL) or at high cell inoculum (>=2.5 * 10(6) cells/mL) at higher glucose concentration (up to 25 mM). Glucose-depleted cultures produced non-glycosylated Mabs (up to 51%), lower galactosylation index (GI <0.43) and decreased sialylation (by 85%) as measured by mass spectrometry and HPLC. At low glucose a reduced intracellular pool of nucleotides (0.03-0.23 fmoles/cell) was measured as well as a low adenylate energy charge (<0.57). Low glucose also reduced GDP-sugars (by 77%) and UDP-hexosamines (by 90%). The data indicate that under glucose deprivation, low levels of intracellular nucleotides and nucleotide sugars reduced the availability of the immediate precursors of glycosylation. These results are important when applied to the design of fed-batch cultures. PMID- 26058833 TI - Nanofibers Comprising Yolk-Shell Sn@void@SnO/SnO2 and Hollow SnO/SnO2 and SnO2 Nanospheres via the Kirkendall Diffusion Effect and Their Electrochemical Properties. AB - Nanofibers with a unique structure comprising Sn@void@SnO/SnO2 yolk-shell nanospheres and hollow SnO/SnO2 and SnO2 nanospheres are prepared by applying the nanoscale Kirkendall diffusion process in conventional electrospinning process. Under a reducing atmosphere, post-treatment of tin 2-ethylhexanoate polyvinylpyrrolidone electrospun nanofibers produce carbon nanofibers with embedded spherical Sn nanopowders. The Sn nanopowders are linearly aligned along the carbon nanofiber axis without aggregation of the nanopowders. Under an air atmosphere, oxidation of the Sn-C composite nanofibers produce nanofibers comprising Sn@void@SnO/SnO2 yolk-shell nanospheres and hollow SnO/SnO2 and SnO2 nanospheres, depending on the post-treatment temperature. The mean sizes of the hollow nanospheres embedded within tin oxide nanofibers post-treated at 500 degrees C and 600 degrees C are 146 and 117 nm, respectively. For the 250th cycle, the discharge capacities of the nanofibers prepared by the nanoscale Kirkendall diffusion process post-treated at 400 degrees C, 500 degrees C, and 600 degrees C at a high current density of 2 A g(-1) are 663, 630, and 567 mA h g(-1), respectively. The corresponding capacity retentions are 77%, 84%, and 78%, as calculated from the second cycle. The nanofibers prepared by applying the nanoscale Kirkendall diffusion process exhibit superior electrochemical properties compared with those of the porous-structured SnO2 nanofibers prepared by the conventional post-treatment process. PMID- 26058834 TI - The Arabidopsis root stele transporter NPF2.3 contributes to nitrate translocation to shoots under salt stress. AB - In most plants, NO(3)(-) constitutes the major source of nitrogen, and its assimilation into amino acids is mainly achieved in shoots. Furthermore, recent reports have revealed that reduction of NO(3)(-) translocation from roots to shoots is involved in plant acclimation to abiotic stress. NPF2.3, a member of the NAXT (nitrate excretion transporter) sub-group of the NRT1/PTR family (NPF) from Arabidopsis, is expressed in root pericycle cells, where it is targeted to the plasma membrane. Transport assays using NPF2.3-enriched Lactococcus lactis membranes showed that this protein is endowed with NO(3)(-) transport activity, displaying a strong selectivity for NO(3)(-) against Cl(-). In response to salt stress, NO(3)(-) translocation to shoots is reduced, at least partly because expression of the root stele NO(3)(-) transporter gene NPF7.3 is decreased. In contrast, NPF2.3 expression was maintained under these conditions. A loss-of function mutation in NPF2.3 resulted in decreased root-to-shoot NO(3)(-) translocation and reduced shoot NO(3)(-) content in plants grown under salt stress. Also, the mutant displayed impaired shoot biomass production when plants were grown under mild salt stress. These mutant phenotypes were dependent on the presence of Na(+) in the external medium. Our data indicate that NPF2.3 is a constitutively expressed transporter whose contribution to NO(3)(-) translocation to the shoots is quantitatively and physiologically significant under salinity. PMID- 26058835 TI - Effect of orally administered collagen hydrolysate on gene expression profiles in mouse skin: a DNA microarray analysis. AB - Dietary collagen hydrolysate has been hypothesized to improve skin barrier function. To investigate the effect of long-term collagen hydrolysate administration on the skin, we evaluated stratum corneum water content and skin elasticity in intrinsically aged mice. Female hairless mice were fed a control diet or a collagen hydrolysate-containing diet for 12 wk. Stratum corneum water content and skin elasticity were gradually decreased in chronologically aged control mice. Intake of collagen hydrolysate significantly suppressed such changes. Moreover, we used DNA microarrays to analyze gene expression in the skin of mice that had been administered collagen hydrolysate. Twelve weeks after the start of collagen intake, no significant differences appeared in the gene expression profile compared with the control group. However, 1 wk after administration, 135 genes were upregulated and 448 genes were downregulated in the collagen group. This suggests that gene changes preceded changes of barrier function and elasticity. We focused on several genes correlated with functional changes in the skin. Gene Ontology terms related to epidermal cell development were significantly enriched in upregulated genes. These skin function-related genes had properties that facilitate epidermal production and differentiation while suppressing dermal degradation. In conclusion, our results suggest that altered gene expression at the early stages after collagen administration affects skin barrier function and mechanical properties. Long-term oral intake of collagen hydrolysate improves skin dysfunction by regulating genes related to production and maintenance of skin tissue. PMID- 26058836 TI - Genetic variation in alpha2-adrenoreceptors and heart rate recovery after exercise. AB - Heart rate recovery (HRR) after exercise is an independent predictor of adverse cardiovascular outcomes. HRR is mediated by both parasympathetic reactivation and sympathetic withdrawal and is highly heritable. We examined whether common genetic variants in adrenergic and cholinergic receptors and transporters affect HRR. In our study 126 healthy subjects (66 Caucasians, 56 African Americans) performed an 8 min step-wise bicycle exercise test with continuous computerized ECG recordings. We fitted an exponential curve to the postexercise R-R intervals for each subject to calculate the recovery constant (kr) as primary outcome. Secondary outcome was the root mean square residuals averaged over 1 min (RMS1min), a marker of parasympathetic tone. We used multiple linear regressions to determine the effect of functional candidate genetic variants in autonomic pathways (6 ADRA2A, 1 ADRA2B, 4 ADRA2C, 2 ADRB1, 3 ADRB2, 2 NET, 2 CHT, and 1 GRK5) on the outcomes before and after adjustment for potential confounders. Recovery constant was lower (indicating slower HRR) in ADRA2B 301-303 deletion carriers (n = 54, P = 0.01), explaining 3.6% of the interindividual variability in HRR. ADRA2A Asn251Lys, ADRA2C rs13118771, and ADRB1 Ser49Gly genotypes were associated with RMS1min. Genetic variability in adrenergic receptors may be associated with HRR after exercise. However, most of the interindividual variability in HRR remained unexplained by the variants examined. Noncandidate gene-driven approaches to study genetic contributions to HRR in larger cohorts will be of interest. PMID- 26058838 TI - Aortic valve dynamics using a fluid structure interaction model--The physiology of opening and closing. AB - Comparative study among aortic valves requires the use of an unbiased and relevant boundary condition. Pressure and flow boundary conditions used in literature are not sufficient for an unbiased analysis. We need a different boundary condition to analyze the valves in an unbiased, relevant environment. The proposed boundary condition is a combination of the pressure and flow boundary condition methods, which is chosen considering the demerits of the pressure and flow boundary conditions. In order to study the valve in its natural environment and to give a comparative analysis between different boundary conditions, a fluid-structure interaction analysis is made using the pressure and the proposed boundary conditions for a normal aortic valve. Commercial software LS-DYNA is used in all our analysis. The proposed boundary condition ensures a full opening of the valve with reduced valve regurgitation. It is found that for a very marginal raise in the ventricular pressure caused by pumping a fixed stroke volume, the cardiac output is considerably raised. The mechanics of the valve is similar between these two boundary conditions, however we observe that the importance of the root to raise the cardiac output may be overstated, considering the importance of the fully open nodule of arantius. Our proposed boundary condition delivers all the insights offered by the pressure and flow boundary conditions, along with providing an unbiased framework for the analysis of different valves and hence, more suitable for comparative analysis. PMID- 26058837 TI - PADPIN: protein-protein interaction networks of angiogenesis, arteriogenesis, and inflammation in peripheral arterial disease. AB - Peripheral arterial disease (PAD) results from an obstruction of blood flow in the arteries other than the heart, most commonly the arteries that supply the legs. The complexity of the known signaling pathways involved in PAD, including various growth factor pathways and their cross talks, suggests that analyses of high-throughput experimental data could lead to a new level of understanding of the disease as well as novel and heretofore unanticipated potential targets. Such bioinformatic analyses have not been systematically performed for PAD. We constructed global protein-protein interaction networks of angiogenesis (Angiome), immune response (Immunome), and arteriogenesis (Arteriome) using our previously developed algorithm GeneHits. The term "PADPIN" refers to the angiome, immunome, and arteriome in PAD. Here we analyze four microarray gene expression datasets from ischemic and nonischemic gastrocnemius muscles at day 3 posthindlimb ischemia (HLI) in two genetically different C57BL/6 and BALB/c mouse strains that display differential susceptibility to HLI to identify potential targets and signaling pathways in angiogenesis, immune, and arteriogenesis networks. We hypothesize that identification of the differentially expressed genes in ischemic and nonischemic muscles between the strains that recovers better (C57BL/6) vs. the strain that recovers more poorly (BALB/c) will help for the prediction of target genes in PAD. Our bioinformatics analysis identified several genes that are differentially expressed between the two mouse strains with known functions in PAD including TLR4, THBS1, and PRKAA2 and several genes with unknown functions in PAD including EphA4, TSPAN7, SLC22A4, and EIF2a. PMID- 26058839 TI - Intermittent theta burst stimulation over left BA10 enhances virtual reality based prospective memory in healthy aged subjects. AB - Prospective memory (PM) refers to a complex cognitive ability that underpins the delayed execution of previously formulated intentions. PM performance declines early in normal aging and this process is accentuated in Alzheimer's disease. The left frontopolar cortex (BA10) has been consistently assigned a major role in PM functioning, but whether it can be noninvasively modulated to enhance PM performance in aged people has not been addressed so far. Here, we investigated the effects of modulating left BA10 by means of theta burst stimulation (TBS), using either excitatory (intermittent TBS), inhibitory (continuous TBS) or control (vertex) TBS in healthy aged subjects. The behavioral effects were assessed using a reliable and ecological virtual reality PM task that included both event- and time-based retrievals. As compared with vertex stimulation, event based PM performance significantly improved after excitatory stimulation, whereas inhibitory stimulation had no significant effect. Additionally, and across the different types of stimulation, performance for congruent links between the event based PM cue and the action to be performed was significantly better as compared with incongruent links. In conclusion, intermittent TBS might provide a relevant interventional strategy to counteract the decline of cognitive functions and memory abilities in normal aging. PMID- 26058842 TI - Intense focused ultrasound stimulation of the rotator cuff: evaluation of the source of pain in rotator cuff tears and tendinopathy. AB - The objective of this preliminary study was to evaluate the ability of individual 0.1-s long pulses of intense focused ultrasound (iFU) emitted with a carrier frequency of 2 MHz to evoke diagnostic sensations when applied to patients whose shoulders have rotator cuff tears or tendinopathy. Patients were adults with painful shoulders and clinical and imaging findings consistent with rotator cuff disease. iFU stimulation of the shoulder was performed using B-mode ultrasound coupled with a focused ultrasound transducer that allowed image-guided delivery of precisely localized pulses of energy to different anatomic areas around the rotator cuff. The main outcome measure was iFU spatial average-temporal average intensity (I_SATA), and location required to elicit sensation. In control patients, iFU produced no sensation throughout the range of stimulation intensities (<=2000 W/cm(2) I_SATA). In patients with rotator cuff disease, iFU was able to induce sensation in the tendons of the rotator cuff, the subacromial bursa, and the subchondral bone in patients with chronic shoulder pain and rotator cuff disease, with an average +/- standard deviation intensity equaling 680 +/- 281 W/cm(2) I_SATA. This result suggests a primary role for these tissues in the pathogenesis of shoulder pain related to rotator cuff tendinopathy. PMID- 26058841 TI - More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer's disease risk. AB - Over 20 risk loci have been identified for late-onset Alzheimer's disease (LOAD), most of which display relatively small effect sizes. Recently, a rare missense (R47H) variant, rs75932628 in TREM2, has been shown to mediate LOAD risk substantially in Icelandic and Caucasian populations. Here, we present more evidence for the association of the R47H with LOAD risk in a Caucasian population comprising 4567 LOAD cases and controls. Our results show that carriers of the R47H variant have a significantly increased risk for LOAD (odds ratio = 7.40, p = 3.66E-06). In addition to Alzheimer's disease risk, we also examined the association of R47H with Alzheimer's disease-related phenotypes, including age-at onset, psychosis, and amyloid deposition but found no significant association. Our results corroborate those of other studies implicating TREM2 as an LOAD risk locus and indicate the need to determine its biological role in the context of neurodegeneration. PMID- 26058840 TI - Dexmedetomidine increases tau phosphorylation under normothermic conditions in vivo and in vitro. AB - There is developing interest in the potential association between anesthesia and the onset and progression of Alzheimer's disease. Several anesthetics have, thus, been demonstrated to induce tau hyperphosphorylation, an effect mostly mediated by anesthesia-induced hypothermia. Here, we tested the hypothesis that acute normothermic administration of dexmedetomidine (Dex), an intravenous sedative used in intensive care units, would result in tau hyperphosphorylation in vivo and in vitro. When administered to nontransgenic mice, Dex-induced tau hyperphosphorylation persisting up to 6 hours in the hippocampus for the AT8 epitope. Pretreatment with atipamezole, a highly specific alpha2-adrenergic receptor antagonist, blocked Dex-induced tau hyperphosphorylation. Furthermore, Dex dose-dependently increased tau phosphorylation at AT8 in SH-SY5Y cells, impaired mice spatial memory in the Barnes maze and promoted tau hyperphosphorylation and aggregation in transgenic hTau mice. These findings suggest that Dex: (1) increases tau phosphorylation, in vivo and in vitro, in the absence of anesthetic-induced hypothermia and through alpha2-adrenergic receptor activation, (2) promotes tau aggregation in a mouse model of tauopathy, and (3) impacts spatial reference memory. PMID- 26058843 TI - Mycophenolate mofetil and Sirolimus as second or further line treatment in children with chronic refractory Primitive or Secondary Autoimmune Cytopenias: a single centre experience. AB - The management of refractory autoimmune cytopenias in childhood is challenging due to the lack of established evidence on escalating treatments. The long-term efficacy of immunosuppressive drugs was evaluated in children with refractory autoimmune cytopenias referred to the Haematology Unit of the Gaslini Children's Hospital between 2001 and 2014. Patients were grouped into three categories: autoimmune lymphoproliferative syndrome (ALPS), ALPS-related syndrome (at least one absolute/primary additional criterion for ALPS) and primary autoimmune cytopenia (PAC, cytopenia with no other immunological symptoms/signs). Fifty eight children (aged 1-16 years) entered the study: 12 were categorized with ALPS, 24 were ALPS-related and 22 had PAC. Five didn't receive treatment. Fifty three were initially treated with steroids/intravenous immunoglobulin. Fourteen responded, whereas 39 did not. Of these 39 patients, 34 (87%) received mycophenolate mofetil (MMF) as second/further-line treatment and 22 (65%) responded. Within these 34 subjects, ALPS patients responded better (11/11, 100%) than the two other groups pooled together (11/23, 48%; P = 0.002). Sirolimus was given as second/further-line treatment to 16 children, and 12 (75%) responded, including 8 who previously failed MMF therapy. Median follow-up was 3.46 years. MMF and Sirolimus were well-tolerated and enabled partial/complete and sustained remission in most children. These drugs may be successfully and safely used in children with refractory autoimmune cytopenias with or without ALPS/ALPS-related disorders and may represent a valid second/further line option. PMID- 26058844 TI - Telavancin activity tested against Gram-positive clinical isolates from European, Russian and Israeli hospitals (2011-2013) using a revised broth microdilution testing method: redefining the baseline activity of telavancin. AB - OBJECTIVES: To reassess the activity of telavancin when tested against Gram positive clinical pathogens recovered from hospitalized patients in European and adjacent regions using a revised broth microdilution method. METHODS: 11 601 consecutive, non-duplicate isolates originating from 36 institutions among 18 countries recovered between 2011 and 2013 were tested for susceptibility using a revised broth microdilution method for telavancin. Interpretive telavancin breakpoints appropriate for the method were those recently approved by the FDA and EUCAST, as available. RESULTS: Telavancin (MIC50/90, 0.03/0.06 mg/l; 100.0% susceptible) was equally potent against methicillin-susceptible ((MSSA) and methicillin-resistant (MRSA) Staphylococcus aureus. All Enterococcus faecalis was susceptible to telavancin (MIC50/90, 0.12/0.12 mg/l) and inhibited at the susceptibility breakpoint (i.e. <= 0.25 mg/l), except for VanA-phenotype vancomycin-resistant isolates (telavancin MIC, >1 mg/l). Telavancin ( <= 0.015/0.03 mg/l) was active against vancomycin-susceptible Enterococcus faecium, while higher MIC values were obtained for VanA strains. Telavancin (both MIC50 and MIC90, <= 0.015 mg/l) was potent against Streptococcus pneumoniae, beta haemolytic streptococci (MIC50/90, <= 0.015/0.06 mg/l) and viridans group streptococci (MIC50/90, <= 0.015/0.03 mg/l). CONCLUSIONS: Telavancin exhibited potent activity against this contemporary (2011-2013) collection of organisms, inhibiting indicated pathogens at or below the FDA/EUCAST-approved breakpoints for susceptibility. VanA-phenotype enterococci were less susceptible to telavancin, a feature observed using the previous testing method. These results redefine telavancin's activity against isolates from Europe. PMID- 26058845 TI - Robotic hysterectomy or myomectomy without power morcellation: A single-port assisted three-incision technique with manual morcellation. AB - BACKGROUND: The purpose of this study was to evaluate the feasibility and safety of a single-port assisted three-incision robotic hysterectomy or myomectomy with manual morcellation using a scalpel, and to introduce our novel surgical technique. METHODS: Between October 2010 and July 2014, 16 patients underwent robotic hysterectomy and 50 patients underwent robotic myomectomy using a single port assisted three-incision technique. Manual morcellation through a single-port site without power morcellation was used to remove the uterus or uterine fibroids. RESULTS: The mean operative times were 130.2 +/- 32.6 min in the hysterectomy group and 178.8 +/- 77.9 min in the myomectomy group. Intraoperative complications, including a rectal serosa injury and a small bowel injury, occurred in two cases. Three febrile morbidities occurred postoperatively. Finally, no complications were associated with manual morcellation. CONCLUSIONS: Uterine tissues could be removed without any complications by manual morcellation within an endobag, using a scalpel. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26058846 TI - Anticancer properties of carotenoids in prostate cancer. A review. AB - Prostate cancer is the most common noncutaneous cancer of men in the world. Several epidemiological studies have linked increased carotenoids consumption with decreased prostate cancer risk. These findings are supported by in vitro and in vivo experiments showing that carotenoids not only enhance the antioxidant response of prostate cells, but that they are able to inhibit proliferation, induce apoptosis and decrease the metastatic capacity of prostate cancer cells. However, clear clinical evidence supporting the use of carotenoids in prevention or treatment of prostate cancer is not available, due to the limited number of published randomized clinical trials, and the varying protocols used in the existing studies. The scope of the present review is to discuss the potential impact of carotenoids on prostate cancer by giving an overview of the molecular mechanisms and in vitro / in vivo effects. PMID- 26058847 TI - Retention of Ejaculate by Drosophila melanogaster Females Requires the Male Derived Mating Plug Protein PEBme. AB - Within the mated reproductive tracts of females of many taxa, seminal fluid proteins (SFPs) coagulate into a structure known as the mating plug (MP). MPs have diverse roles, including preventing female remating, altering female receptivity postmating, and being necessary for mated females to successfully store sperm. The Drosophila melanogaster MP, which is maintained in the mated female for several hours postmating, is comprised of a posterior MP (PMP) that forms quickly after mating begins and an anterior MP (AMP) that forms later. The PMP is composed of seminal proteins from the ejaculatory bulb (EB) of the male reproductive tract. To examine the role of the PMP protein PEBme in D. melanogaster reproduction, we identified an EB GAL4 driver and used it to target PEBme for RNA interference (RNAi) knockdown. PEBme knockdown in males compromised PMP coagulation in their mates and resulted in a significant reduction in female fertility, adversely affecting postmating uterine conformation, sperm storage, mating refractoriness, egg laying, and progeny generation. These defects resulted from the inability of females to retain the ejaculate in their reproductive tracts after mating. The uncoagulated MP impaired uncoupling by the knockdown male, and when he ultimately uncoupled, the ejaculate was often pulled out of the female. Thus, PEBme and MP coagulation are required for optimal fertility in D. melanogaster. Given the importance of the PMP for fertility, we identified additional MP proteins by mass spectrometry and found fertility functions for two of them. Our results highlight the importance of the MP and the proteins that comprise it in reproduction and suggest that in Drosophila the PMP is required to retain the ejaculate within the female reproductive tract, ensuring the storage of sperm by mated females. PMID- 26058848 TI - Drosophila Hook-Related Protein (Girdin) Is Essential for Sensory Dendrite Formation. AB - The dendrite of the sensory neuron is surrounded by support cells and is composed of two specialized compartments: the inner segment and the sensory cilium. How the sensory dendrite is formed and maintained is not well understood. Hook related proteins (HkRP) like Girdin, DAPLE, and Gipie are actin-binding proteins, implicated in actin organization and in cell motility. Here, we show that the Drosophila melanogaster single member of the Hook-related protein family, Girdin, is essential for sensory dendrite formation and function. Mutations in girdin were identified during a screen for fly mutants with no mechanosensory function. Physiological, morphological, and ultrastructural studies of girdin mutant flies indicate that the mechanosensory neurons innervating external sensory organs (bristles) initially form a ciliated dendrite that degenerates shortly after, followed by the clustering of their cell bodies. Importantly, we observed that Girdin is expressed transiently during dendrite morphogenesis in three previously unidentified actin-based structures surrounding the inner segment tip and the sensory cilium. These actin structures are largely missing in girdin mutant. Defects in cilia are observed in other sensory organs such as those mediating olfaction and taste, suggesting that Girdin has a general role in forming sensory dendrites in Drosophila. These suggest that Girdin functions temporarily within the sensory organ and that this function is essential for the formation of the sensory dendrites via actin structures. PMID- 26058849 TI - Gene Level Meta-Analysis of Quantitative Traits by Functional Linear Models. AB - Meta-analysis of genetic data must account for differences among studies including study designs, markers genotyped, and covariates. The effects of genetic variants may differ from population to population, i.e., heterogeneity. Thus, meta-analysis of combining data of multiple studies is difficult. Novel statistical methods for meta-analysis are needed. In this article, functional linear models are developed for meta-analyses that connect genetic data to quantitative traits, adjusting for covariates. The models can be used to analyze rare variants, common variants, or a combination of the two. Both likelihood ratio test (LRT) and F-distributed statistics are introduced to test association between quantitative traits and multiple variants in one genetic region. Extensive simulations are performed to evaluate empirical type I error rates and power performance of the proposed tests. The proposed LRT and F-distributed statistics control the type I error very well and have higher power than the existing methods of the meta-analysis sequence kernel association test (MetaSKAT). We analyze four blood lipid levels in data from a meta-analysis of eight European studies. The proposed methods detect more significant associations than MetaSKAT and the P-values of the proposed LRT and F-distributed statistics are usually much smaller than those of MetaSKAT. The functional linear models and related test statistics can be useful in whole-genome and whole-exome association studies. PMID- 26058850 TI - Moderate varus/valgus malalignment after total knee arthroplasty has little effect on knee function or muscle strength. AB - BACKGROUND AND PURPOSE: Postoperative muscle strength and component alignment are important factors affecting functional results after total knee arthroplasty (TKA). We are not aware of any studies that have investigated the relationship between them. We therefore investigated whether coronal malalignment of the mechanical axis and/or of individual implant components would affect knee muscle strength and function 1 year after TKA surgery. PATIENTS AND METHODS: We included 120 consecutive osteoarthritis (OA) patients admitted for TKA. Preoperative active range of motion (ROM) of the knee, patient age, sex, and BMI were recorded and the Knee Society score (KSS) and knee joint extensor/flexor muscle strength were assessed. At 1-year follow-up, the mechanical and coronal component alignment was measured from a postoperative long standing radiograph, and ROM, KSS, and muscle strength measurements were taken in 91 patients. Functional outcome and muscle strength measurements were compared between normally aligned and malaligned TKA groups. RESULTS: 29 of 91 TKAs were malaligned, i.e. they deviated more than 3 degrees from the neutral mechanical axis. 18 femoral components and 15 tibial components were malaligned. Before surgery, the malaligned and normally aligned groups were similar regarding sex distribution, BMI, ROM, KSS, and muscle strength. At the 1-year follow-up, the differences between the groups regarding knee joint function and muscle strength were small, not statistically significant, and barely clinically relevant. INTERPRETATION: Moderate varus/valgus malalignment of the mechanical axis or of individual components has no relevant clinical effect on function or muscle strength 1 year after TKA surgery. PMID- 26058851 TI - Occupational EMF exposure from radar at X and Ku frequency band and plasma catecholamine levels. AB - Workers in certain occupations such as the military may be exposed to technical radiofrequency radiation exposure above current limits, which may pose a health risk. The present investigation intended to find the effect of chronic electromagnetic field (EMF) exposure from radar on plasma catecholamines in the military workforce. In the study, 166 male personnel selected randomly were categorized into three groups: control (n = 68), exposure group-I (X-band, 8-12 GHz, n = 40), and exposure group-II (Ku-band, 12.5-18 GHz, n = 58). The three clusters were further divided into two groups according to their years of service (YOS) (up to 9 years and >=10 years) to study the effect of years of radar exposure. Enzyme immunoassay was employed to assess catecholamine concentrations. EMF levels were recorded at different occupational distances from radar. Significant adrenaline diminution was registered in exposure group-II with no significant difference in exposure group-I when both groups were weighed against control. Nor-adrenaline and dopamine levels did not vary significantly in both exposure groups when compared to controls. Exposure in terms of YOS also did not yield any significant alteration in any of the catecholamines and in any of the exposure groups when compared with their respective control groups. The shift from baseline catecholamine values due to stress has immense significance for health and well-being. Their continual alteration may prove harmful in due course. Suitable follow-up studies are needed to further strengthen these preliminary observations and for now, exposures should be limited as much as possible with essential safeguards. PMID- 26058852 TI - Treatment of anti-laminin gamma1 pemphigoid with mycophenolate mofetil. PMID- 26058853 TI - Pediatric hematopoietic stem cell transplantation in China: Data and trends during 1998-2012. AB - The success of treating a wide variety of pediatric diseases with HSCT, hematologic malignancies in particular, has resulted in an increased number of long-term survivors. This study is the first large-scale, multicentre report that describes the evolution of pediatric HSCTs in China during the period of 1998 2012. Of all 1052 patients, 266 cases were treated with autologous HSCs and 786 used allogeneic HSCs. The disease indications for HSCTs mainly included leukemias, lymphoma, solid tumors, and non-malignant disorders. The total number of HSCTs, especially unrelated donor transplants, appeared to be increasing year by year. For patients with neuroblastoma, the therapeutic efficacy seemed to be poor, with a five-yr OS and DFS rate of 34.5 +/- 14.3% and 20.7 +/- 9.6%, respectively. In contrast, the survival of patients with SAA was prominently improved, and their five-yr OS and DFS rates were 82.8 +/- 4% and 80.7 +/- 4.1%, respectively. Patients who received cord blood transplants had a lower incidence of acute GVHD than that of PB and/or BM transplants from unrelated donors. This report offers us a valuable resource for evaluating the changes in HSCTs in China over the past 14 yr. PMID- 26058854 TI - The retinoic acid-metabolizing enzyme CYP26A1 upregulates fascin and promotes the malignant behavior of breast carcinoma cells. AB - The retinoic acid (RA)-metabolizing enzyme CYP26A1 has been shown to efficiently enhance the oncogenic potential of breast cancer, suggesting a potential oncogenic function. We previously demonstrated that CYP26A1 confers unique cell survival properties by modulating the expression of a variety of genes and identified a number of genes that drive the cells into the oncogenic state. Accumulating evidence suggested that fascin is overexpressed in various types of cancer, primarily leading to increased cell motility. Therefore, in the present study, we examined fascin, an actin-bundling protein, using immunohistochemical and SA-beta-gal staining as well as TUNEL and colony forming assays. The results of the present study showed that the expression levels of fascin increased significantly in response to CYP26A1 overexpression and, conversely, treatment with all-trans RA downregulated the expression of fascin. In addition, primary breast carcinoma samples, particularly hormone receptor-negative carcinomas and CYP26A1-overexpressing cancers, expressed elevated levels of fascin. Notably, fascin contributed to the ability of breast carcinoma cells to escape premature senescence and exhibit enhanced cell apoptotic resistance, promoting anchorage independent growth properties. Fascin also promoted cell motility and the invasiveness of CYP26A1-expressing breast carcinoma cells. These data suggest that fascin expression is modulated by the intracellular RA status regulated by the expression of CYP26A1 and plays a significant role in the malignant behavior of CYP26A1-expressing breast carcinoma cells. CYP26A1 exerts oncogenic functions during breast carcinogenesis. Therefore, CYP26A1-mediated oncogenic characteristics may be partially responsible for the elevated expression of fascin. PMID- 26058855 TI - A modified surgical approach of the hip in children: is it safe and reliable in patients with developmental hip dysplasia? AB - PURPOSE: Treatment is easier and complications are less likely to occur if developmental dysplasia of the hip (DDH) is diagnosed early. In this study, we examined the early results of open reduction using a medial approach which we had modified for DDH and analyzed the success of this technique and the associated complication rates, with a focus on avascular necrosis (AVN). METHODS: This is an Institutional Review Board-approved retrospective review of all patients diagnosed with DDH and treated with a modified medial approach at a single institution from July 1999 to December 2010. The patients' charts were analyzed for clinical and radiographic features. RESULTS: Fifty-five hips of 41 patients, all of whom were treated by open reduction using a modified medial approach due to DDH, were evaluated retrospectively. The mean age of the patients at surgery was 19 (range 11-28) months, and the average follow-up was 5.5 (range 3-9.5) years. AVN was the most important complication in terms of radiological outcomes as assessed according to the Kalamchi-McEwen classification. Radiologic results were excellent or good in 51 hips (92.7 %) and fair-plus in four (7.3 %). Type 1 temporary AVN was detected in only two hips (3.6 %), and the lesions had disappeared completely in the final control graphs of these two patients. A secondary intervention was needed for two hips (3.6 %) of the same patients who were operated on due to bilateral DDH. No other complications, such as infection, re-dislocation, or subluxation, were seen in the operated patients. CONCLUSIONS: We believe that treatment for DDH using a modified medial approach during early childhood is an effective and reliable method with low AVN rates. As shown here, this method achieves great success in radiological and clinical outcomes after a minimum 3-year follow-up. PMID- 26058857 TI - Safety and tolerability of iopromide in patients undergoing cardiac catheterization: real-world multicenter experience with 17,513 patients from the TRUST trial. AB - To assess the incidence of and risk factors for acute adverse drug reactions (ADRs) (occurring within 1 h) following iopromide administration in cardiac catheterization in Chinese 'real-world' practice. Acute ADRs following iopromide administration during coronary angiography or percutaneous coronary intervention (PCI) have not been systematically evaluated in China. TRUST was a prospective, multicenter, observational study conducted at 63 centers in China. Patients received iopromide (300 or 370 mgI/mL) during coronary angiography or PCI (n = 17,513). Acute ADRs occurred in 66 patients (0.38%); ADRs were mild in 58 patients (0.33%) and severe in two patients (0.01%). Most acute ADRs manifested as allergy-like symptoms such as nausea/vomiting [39 patients (0.22%)] and/or rash [15 patients (0.09%)]. The rate of acute ADRs was lower among patients who received premedication (6/3349; 0.18 %) than those who did not (60/14,164; 0.42%; p = 0.0379), and among those who did receive pre-procedural hydration (10/7993; 0.13%) compared with those who did not (56/9520; 0.59%; p < 0.0001). Age <50 years, left main coronary disease and history of ADRs to contrast media increased the risk of ADRs, while premedication with corticosteroids, pre-procedural hydration and contrast volume <100 mL versus >=100 mL reduced the risk. Contrast quality was rated as 'Excellent' in 99.1% of patients. The incidence of acute ADRs was very low with iopromide in cardiac catheterization in China. The risk of acute ADRs increased in patients <50 years and in those with a history of ADRs to contrast media. Premedication with corticosteroids and pre-procedural hydration may prevent acute ADRs in at-risk patients. PMID- 26058858 TI - Correlates of previous couples' HIV counseling and testing uptake among married individuals in three HIV prevalence strata in Rakai, Uganda. AB - BACKGROUND: Studies show that uptake of couples' HIV counseling and testing (couples' HCT) can be affected by individual, relationship, and socioeconomic factors. However, while couples' HCT uptake can also be affected by background HIV prevalence and awareness of the existence of couples' HCT services, this is yet to be documented. We explored the correlates of previous couples' HCT uptake among married individuals in a rural Ugandan district with differing HIV prevalence levels. DESIGN: This was a cross-sectional study conducted among 2,135 married individuals resident in the three HIV prevalence strata (low HIV prevalence: 9.7-11.2%; middle HIV prevalence: 11.4-16.4%; and high HIV prevalence: 20.5-43%) in Rakai district, southwestern Uganda, between November 2013 and February 2014. Data were collected on sociodemographic and behavioral characteristics, including previous receipt of couples' HCT. HIV testing data were obtained from the Rakai Community Cohort Study. We conducted multivariable logistic regression analysis to identify correlates that are independently associated with previous receipt of couples' HCT. Data analysis was conducted using STATA (statistical software, version 11.2). RESULTS: Of the 2,135 married individuals enrolled, the majority (n=1,783, 83.5%) had been married for five or more years while (n=1,460, 66%) were in the first-order of marriage. Ever receipt of HCT was almost universal (n=2,020, 95%); of those ever tested, (n=846, 41.9%) reported that they had ever received couples' HCT. There was no significant difference in previous receipt of couples' HCT between low (n=309, 43.9%), middle (n=295, 41.7%), and high (n=242, 39.7%) HIV prevalence settings (p=0.61). Marital order was not significantly associated with previous receipt of couples' HCT. However, marital duration [five or more years vis-a-vis 1-2 years: adjusted odds ratio (aOR): 1.06; 95% confidence interval (95% CI): 1.04-1.08] and awareness about the existence of couples' HCT services within the Rakai community cohort (aOR: 7.58; 95% CI: 5.63-10.20) were significantly associated with previous receipt of couples' HCT. CONCLUSIONS: Previous couples' HCT uptake did not significantly differ by HIV prevalence setting. Longer marital duration and awareness of the existence of couples' HCT services in the community were significantly correlated with previous receipt of couples' HCT. These findings suggest a need for innovative demand-creation interventions to raise awareness about couples' HCT service availability to improve couples' HCT uptake among married individuals. PMID- 26058859 TI - Expressions of mRNA for innate immunity-associated functional molecules in urinary sediment in immunoglobulin A nephropathy. AB - AIM: It has been reported that the innate immune system plays a pivotal role in the pathogenesis of immunoglobulin A nephropathy (IgAN). To explore non-invasive monitoring of disease activity in children with IgAN, we examined whether expressions of mRNA for innate immunity-associated functional molecules: CC ligand chemokine 5 (CCL5), fractalkine/CX3CL1, interferon-gamma-induced protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), retinoic acid-inducible gene-I (RIG-I), and toll-like receptor 3 (TLR3) in urinary sediment from patients with IgAN correlate with histologic parameters. METHODS: Twenty consecutive children with IgAN and four children with thin basement membrane disease (serving as a non-inflammatory control) were enrolled in this pilot study. Urinary mRNA expressions of target genes were examined real-time quantitative polymerase chain reaction. RESULTS: The expressions of CCL5, fractalkine and RIG-I were significantly increased in IgAN (all P < 0.05). Although no significant correlation was observed between mRNA expressions of these three molecules and clinical parameters, such as levels of urinary protein excretion, degrees of occult blood in urine and serum albumin, the expression of fractalkine was significantly correlated with the histological activity index (P = 0.022) and the chronicity index (P = 0.005). Furthermore, intense glomerular immune activity of fractalkine was observed in biopsy specimens in patients with moderately to severe proliferative IgAN. CONCLUSION: Regional expression of fractalkine may be involved in the pathogenesis of childhood IgAN. Although our present findings remain preliminary, measurement of mRNA expression of fractalkine in urinary sediment could be used as a non-invasive method for predicting histologic severity in IgAN in children. Further studies of this issue are needed. PMID- 26058860 TI - The optimal combination therapy for the treatment of early rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune condition traditionally viewed as a severe destructive disease affecting physical health and global wellbeing. The treatment strategies for RA have changed in the last decades from mainly symptomatic towards a more vigorous and targeted approach. AREA COVERED: Reviewing recent literature enhanced by own expertise and research, a case is made for starting early with an intensive combination treatment with glucocorticoids, followed by a treat to target approach in a tight control setting. Implementation issues that need to be addressed to make optimal use of the 'window of opportunity' are highlighted. EXPERT OPINION: There is strong evidence in favor of traditional synthetic disease-modifying anti rheumatic drugs (DMARDs) combined with a remission induction scheme of glucocorticoids to achieve adequate efficacy in controlling early rheumatoid arthritis with good safety and feasibility in daily clinical practice. Furthermore, the most optimal RA treatment should address not only the physician oriented clinical disease outcomes but also the patient perspective. There is still a need for working on improving implementation of this approach in daily practice in order to provide optimal treatment benefit to more patients. PMID- 26058861 TI - Central effects of humanin on hepatic triglyceride secretion. AB - Humanin (HN) is an endogenous mitochondria-associated peptide that has been shown to protect against various Alzheimer's disease-associated insults, myocardial ischemia-reperfusion injury, and reactive oxygen species-induced cell death. We have shown previously that HN improves whole body glucose homeostasis by improving insulin sensitivity and increasing glucose-stimulated insulin secretion (GSIS) from the beta-cells. Here, we report that intraperitoneal treatment with one of HN analogs, HNG, decreases body weight gain, visceral fat, and hepatic triglyceride (TG) accumulation in high-fat diet-fed mice. The decrease in hepatic TG accumulation is due to increased activity of hepatic microsomal triglyceride transfer protein (MTTP) and increased hepatic TG secretion. Both intravenous (iv) and intracerebroventricular (icv) infusion of HNG acutely increase TG secretion from the liver. Vagotomy blocks the effect on both iv and icv HNG on TG secretion, suggesting that the effects of HNG on hepatic TG flux are centrally mediated. Our data suggest that HN is a new player in central regulation of peripheral lipid metabolism. PMID- 26058862 TI - Dual actions of a novel bifunctional compound to lower glucose in mice with diet induced insulin resistance. AB - Docosahexaenoic acid (DHA 22:6n-3) and salicylate are both known to exert anti inflammatory effects. This study investigated the effects of a novel bifunctional drug compound consisting of DHA and salicylate linked together by a small molecule that is stable in plasma but hydrolyzed in the cytoplasm. The components of the bifunctional compound acted synergistically to reduce inflammation mediated via nuclear factor kappaB in cultured macrophages. Notably, oral administration of the bifunctional compound acted in two distinct ways to mitigate hyperglycemia in high-fat diet-induced insulin resistance. In mice with diet-induced obesity, the compound lowered blood glucose by reducing hepatic insulin resistance. It also had an immediate glucose-lowering effect that was secondary to enhanced glucagon-like peptide-1 (GLP-1) secretion and abrogated by the administration of exendin(9-39), a GLP-1 receptor antagonist. These results suggest that the bifunctional compound could be an effective treatment for individuals with type 2 diabetes and insulin resistance. This strategy could also be employed in other disease conditions characterized by chronic inflammation. PMID- 26058863 TI - Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis. AB - Adipose tissue has the largest capacity to store energy in the body and provides energy through the release of free fatty acids during times of energy need. Different types of immune cells are recruited to adipose tissue under various physiological conditions, indicating that these cells contribute to the regulation of adipose tissue. One major pathway influenced by a number of immune cells is the release of free fatty acids through lipolysis during both physiological (e.g., cold stress) and pathophysiological processes (e.g., obesity, type 2 diabetes). Adipose tissue expansion during obesity leads to immune cell infiltration and adipose tissue remodeling, a homeostatic process that promotes inflammation in adipose tissue. The release of proinflammatory cytokines stimulates lipolysis and causes insulin resistance, leading to adipose tissue dysfunction and systemic disruptions of metabolism. This review focuses on the interactions of cytokines and other inflammatory molecules that regulate adipose tissue lipolysis during physiological and pathophysiological states. PMID- 26058864 TI - Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease. AB - Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance. Furthermore, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR) based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated upregulation of the TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD. PMID- 26058866 TI - Classification of the mechanisms of photoinduced electron transfer from aromatic amino acids to the excited flavins in flavoproteins. AB - In many flavoproteins photoinduced electron transfer (ET) efficiently takes place from aromatic amino acids such as tryptophan or tyrosine to the excited isoalloxazine, so that the fluorescence lifetimes of isoalloxazine in some flavoproteins become ultrashort. The mechanism of ET in the flavoproteins was classified into four classes from the relationship between logarithmic ET rates (ln Rate) and the donor-acceptor distances (Rc), using reported data. The physical quantity, GT, is defined as the sum of solvent reorganization energy, electrostatic energy between a donor cation and an Iso anion, the standard free energy gap between the photoproducts and reactants, and net electrostatic energy between the photoproducts and other ionic groups in the flavoproteins (NetES). When GT fluctuates around zero with Rc, the ET rate becomes fastest (faster than 1 ps(-1)) in Kakitani and Mataga rates. In the ultrafast ET processes, the ln Rate becomes a parabolic function (category 1) of Rc as in FMN binding proteins and pyranose 2-oxidase at the shorter emission wavelengths, when NetES is negligible compared to the other quantities in the GT function. In the ultrafast ET processes, the ln Rate does not display any clear function of Rc (category 2) when NetES is dominant in the GT function, because of no direct relation between NetES and Rc. ET in flavodoxin from Helicobacter pylori may be classified into category 2. When GT linearly varies with Rc around a certain positive value, the ET rates become much slower (<1 ps(-1)). In this case the ln Rate linearly decreases with Rc (category 3), as Tyr224 in d-amino acid oxidase dimers. It is also conceivable that the ln Rate decreases with much scattered function of Rc (category 4), when NetES is dominant in the GT function, as Tyr314 in d-amino acid oxidase dimers. In ET processes of category 1, ET rates decrease as Rc becomes shorter than the distance at the maximum values of ln Rates, where GT is negative. Conditions and physical meanings were discussed for the GT-negative region. PMID- 26058865 TI - Differential epigenetic and transcriptional response of the skeletal muscle carnitine palmitoyltransferase 1B (CPT1B) gene to lipid exposure with obesity. AB - The ability to increase fatty acid oxidation (FAO) in response to dietary lipid is impaired in the skeletal muscle of obese individuals, which is associated with a failure to coordinately upregulate genes involved with FAO. While the molecular mechanisms contributing to this metabolic inflexibility are not evident, a possible candidate is carnitine palmitoyltransferase-1B (CPT1B), which is a rate limiting step in FAO. The present study was undertaken to determine if the differential response of skeletal muscle CPT1B gene transcription to lipid between lean and severely obese subjects is linked to epigenetic modifications (DNA methylation and histone acetylation) that impact transcriptional activation. In primary human skeletal muscle cultures the expression of CPT1B was blunted in severely obese women compared with their lean counterparts in response to lipid, which was accompanied by changes in CpG methylation, H3/H4 histone acetylation, and peroxisome proliferator-activated receptor-delta and hepatocyte nuclear factor 4alpha transcription factor occupancy at the CPT1B promoter. Methylation of specific CpG sites in the CPT1B promoter that correlated with CPT1B transcript level blocked the binding of the transcription factor upstream stimulatory factor, suggesting a potential causal mechanism. These findings indicate that epigenetic modifications may play important roles in the regulation of CPT1B in response to a physiologically relevant lipid mixture in human skeletal muscle, a major site of fatty acid catabolism, and that differential DNA methylation may underlie the depressed expression of CPT1B in response to lipid, contributing to the metabolic inflexibility associated with severe obesity. PMID- 26058867 TI - Iodised salt contribution to iodine nutrition status of pregnant and lactating women. AB - Sufficient iodine intake by pregnant and lactating women is crucial to their offspring's cognitive development. The aim of the present study was to explore the impact of iodised salt intake on the iodine status of pregnant and lactating women. Thirty towns were selected from 211 towns in the rural areas of Shijiazhuang city using probability proportionate to size sampling in this cross sectional survey. In each selected town, forty pregnant women and forty lactating women were randomly selected to contribute urine samples to determine iodine content. The median urinary iodine content (UIC) of 1200 pregnant women in all was 146 (interquartile range (IQR) 88-239) MUg/l. The median UIC in the first, second and third trimesters were 166 (IQR 92-276) MUg/l, 145 (IQR 83-248) MUg/l and 134 (IQR 79-221) MUg/l, respectively. The median UIC in the first trimester was significantly higher than that in the third trimester (P= 0.04). The median UIC of 1200 lactating women in all was 120 (IQR 66-195) MUg/l. Their median UIC in every 4-week block was higher than the WHO criteria except in weeks 25-28 and weeks 33-36 of lactation. Pregnant women's median UIC did not correlate with median salt iodine (MSI) (P= 0.402); however, there was a linear correlation between MSI and the lactating women's median UIC (P= 0.007). Iodised salt failed to provide adequate iodine to pregnant women possibly due to limited intake of iodised salt during pregnancy, though it was found to provide adequate iodine to lactating women in the rural areas of Shijiazhuang city. PMID- 26058868 TI - Editorial: conflicts of interest in publication about families and family therapy. PMID- 26058869 TI - Upregulation of vascular endothelial growth factor mRNA level is significantly related to progression and prognosis of oral squamous cell carcinomas. AB - BACKGROUND/PURPOSE: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. This study evaluated whether the VEGF mRNA level in oral squamous cell carcinoma (OSCC) tissue could be a biomarker to predict the progression and prognosis of OSCCs in Taiwan. METHODS: This study used quantitative real-time reverse transcription-polymerase chain reaction (quantitative RT-PCR) to detect the VEGF mRNA levels in 60 OSCC specimens. Threshold cycle (CT) was defined as the PCR cycle number needed to generate a predetermined amount of DNA (threshold). The relative amount of tissue VEGF mRNA, standardized against the amount of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA, was expressed as DeltaCT = (VEGF CT - GAPDH CT). For a chosen threshold, a smaller starting copy number of mRNA results in a higher CT value. Thus, the lower the DeltaCT, the greater the copy number of VEGF mRNA in tissues. RESULTS: The lower mean VEGF mRNA DeltaCT value was significantly associated with OSCCs with larger tumor size (p = 0.040), positive lymph node metastasis (p = 0.023), and more advanced clinical stages (p = 0.008). VEGF mRNA DeltaCT value < 4.2 (p = 0.026) was identified as an independent unfavorable prognosis factor using multivariate regression analyses. Moreover, Kaplan-Meier curve showed that OSCC patients with a VEGF mRNA DeltaCT value < 4.2 had a significantly poorer overall survival than those with a VEGF mRNA DeltaCT value >=4.2 (log-rank test, p = 0.0427). CONCLUSION: The OSCC tissue VEGF mRNA level can be used to predict the progression and prognosis of OSCCs in Taiwan. PMID- 26058871 TI - Occupational Therapy Australia, 26th National Conference and Exhibition, 1-3 July 2015, Melbourne Convention and Exhibition Centre. PMID- 26058870 TI - Natural history of renal cell carcinoma: An immunohistochemical analysis of growth rate in patients with delayed treatment. AB - BACKGROUND/PURPOSE: To investigate the natural history of renal cell carcinoma (RCC) with delayed treatment and to immunohistochemically analyze the correlation between some biomarkers and the growth rate of RCC. METHODS: We reviewed our institutional databases to identify renal tumors which were confirmed to be RCC by delayed surgical treatment after at least 12 months of active surveillance (AS). Growth rate was defined as the average growth rate of the maximal diameter on computed tomography or magnetic resonance imaging. The clinicopathological characteristics and immunohistochemical biomarkers (Ki-67, p53, bcl-2, and vascular endothelial growth factor) were analyzed the correlation with the growth rate of RCC. RESULTS: We identified 45 RCCs from 45 patients. The mean patient age was 54 years (range, 26-78 years). The mean tumor size increased from 2.39 cm (range, 0.10-6.70 cm) at presentation to 4.54 cm (range, 1.40-11.80 cm) after a mean time of 45.4 months (range, 12-155 months) of AS. The mean growth rate was 0.79 cm/y (range, 0.10-4.74 cm), and 36 (80.0%) tumors presented a growth rate <= 1.00 cm/y. Clear cell RCC had a trend of growing faster than other histological subtypes. Pathological grade was significantly correlated with the growth rate of RCC (p = 0.043). High positive ratio of Ki-67 (r = 0.351, p = 0.018) and being p53 positive (p = 0.019) were significantly correlated to the fast growth rate of RCC. CONCLUSION: In general, RCCs under AS are slow growing with a wide variation of growth rate, with a portion of RCCs presenting rapid growth kinetics. RCC with rapid growth during AS is characterized by a high histological grade, high positive ratio of Ki-67, and being p53 positive. PMID- 26058872 TI - Bimodal Modulation of Ipsilateral Spinal-Coeruleo-Spinal Pathway in CRPS: A Novel Model for Explaining Different Clinical Features of the Syndrome. AB - OBJECTIVE: The objective is to present a hypothesis to explain the sensory, autonomic, and motor disturbances associated with complex regional pain syndrome (CRPS) syndrome. METHODS: The author reviewed the available and relevant literature, which was supplemented with research on experimental animal models, with a focus on how they may translate into humans, particularly in areas about pathophysiologic mechanisms of CRPS. RESULTS: We propose that different CRPS subtypes may result from facilitative or inhibitory influences exerted by the spinal-coeruleo-spinal pathway in three sites at the spinal cord: the dorsal horn (DH), intermediolateral cell column (IML) and ventral horn (VH). A facilitatory influence over DH may have a pronociceptive effect that explains exacerbated pain, sensory disturbances, and spreading sensitization and neuroinflammation. Conversely, a facilitatory influence over preganglionic neurons located in IML cell column may increase sympathetic outflow with peripheral vasoconstriction, which leads to cold skin, ipsilateral limb ischaemia, and sympathetically maintained pain (SMP). For patients presenting with these symptoms, a descending inhibitory influence would be predicted to result in decreased sympathetic outflow and warm skin, as well as impairment of peripheral vasoconstrictor reflexes. Finally, a descending inhibitory influence over VH could explain muscle weakness and decreased active range of motion, while also facilitating motor reflexes, tremor and dystonia. CONCLUSIONS: The proposed model provides a mechanistically based diagnostic scheme for classifying and explaining the sensory, autonomic and motor disturbances associated with CRPS syndrome. PMID- 26058873 TI - MEK inhibitor diminishes nasopharyngeal carcinoma (NPC) cell growth and NPC induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions. AB - Nasopharyngeal carcinoma (NPC) is a common malignancy in southern China and Southeast Asia. NPC frequently metastasizes to the bone in advanced patients resulting in high mortality. The molecular mechanisms for NPC development and cancer-induced bone lesions are unclear. In this study, we firstly determined chemokine receptor CCR2 and CXCR6 expressions in clinical specimens and CNE2, SUNE1, CNE1, and HK1 cell lines. Then, we measured chemokine CCL2 and CXCL16 production in these NPC cell lines by ELISA. Expression levels of these chemokines and their receptors were observed to positively correlate with tumor aggressiveness. Furthermore, U0126 (MEK inhibitor) was used to treat these NPC cell lines. CCL2 and CXCL16 expression levels and cell proliferation were significantly inhibited by U0126 in a dose- and time-dependent manner. Finally, we collected conditioned medium (CM) from NPC cell cultures in the presence of U0126 treatment. When mouse bone marrow non-adherent cells were treated with the CM, the numbers of multinucleated osteoclast formation were dramatically diminished. These results indicate that MEK inhibitor diminishes NPC cell proliferation and NPC-induced osteoclastogenesis via modulating CCL2 and CXCL16 expressions. This study provides novel therapeutic targets such as CCL2/CCR2 and CXCL16/CXCR6 for advanced NPC patients. PMID- 26058874 TI - Imbalance in systemic inflammation and immune response following transarterial chemoembolization potentially increases metastatic risk in huge hepatocellular carcinoma. AB - Inflammation plays a critical role in tumor metastasis. However, few inflammation related biomarkers are currently available to predict the risk of metastasis for advanced hepatocellular carcinoma (HCC). Using huge tumors (diameter >10 cm) as a model, we evaluated the potential risk of pre- and post-treatment inflammatory responses in the development of metastasis of HCC patients undergoing transarterial chemoembolization (TACE). A logistic regression model was used to analyze the risk factors. One hundred and sixty-five patients with huge HCC were enrolled in the study. Metastases were identified in 25.5% (42/165) patients by imaging evaluation post-TACE. Neutrophils increased, whereas lymphocytes decreased significantly post-TACE. Univariate analysis showed that high post treatment neutrophil-to-lymphocyte ratio (NLR; p = 0.003), low post-treatment lymphocyte count (p = 0.047), and high baseline NLR (p = 0.100) were potential risk factors for metastasis. Further, multivariate analysis showed that high post treatment NLR, but not pre-treatment NLR, was an independent risk factor for metastasis; this was confirmed by receiver operating characteristic curve analysis. Post-treatment NLR, however, had no correlation to tumor response and overall survival of patients. In conclusion, post-treatment NLR but not pre treatment NLR independently increases the risk of metastasis in huge HCC. Our findings suggest the potential contribution of treatment-related inflammation to metastasis in advanced HCC. PMID- 26058875 TI - Long non-coding RNA HOTTIP is correlated with progression and prognosis in tongue squamous cell carcinoma. AB - Long non-coding RNAs (lncRNAs) have been demonstrated to be a critical role in cancer progression and prognosis. However, little is known about the pathological role of lncRNA HOXA transcript at the distal tip (HOTTIP) in tongue squamous cell carcinoma (TSCC) patients. The aim of this study is to measure the expression of lncRNA HOTTIP in TSCC patients and to explore the clinical significance of the lncRNA HOTTIP. The expression of lncRNA HOTTIP was measured in 86 TSCC tissues and 14 adjacent non-malignant tissues using qRT-PCR. In our study, results indicated that lncRNA HOTTIP was highly expressed in TSCC compared with adjacent non-malignant tissues (P < 0.001) and positively correlated with T stage (T1-2 vs. T3-4, P = 0.023), clinical stage (I-II stages vs. III-IV stages, P = 0.018), and distant metastasis (absent vs. present, P = 0.031) in TSCC patients. Furthermore, we also found that lncRNA HOTTIP overexpression was an unfavorable prognostic factor in TSCC patients (P < 0.001), regardless of T stage, distant metastasis, and clinical stage. Finally, overexpression of lncRNA HOTTIP was supposed to be an independent poor prognostic factor for TSCC patients through multivariate analysis (P = 0.023). In conclusion, increased lncRNA HOTTIP expression may be serve as an unfavorable prognosis predictor for TSCC patients. Nevertheless, further investigation with a larger sample size is needed to support our results. PMID- 26058876 TI - Relevance of Colonic Gas Analysis and Transit Study in Patients With Chronic Constipation. AB - BACKGROUND/AIMS: Colon transit time (CTT) is a useful diagnostic tool in chronic constipation, but requires good patient compliance. We analyzed the correlation between the gas volume score (GVS) and CTT in patients with chronic constipation. METHODS: The study included 145 consecutive patients (65 men) with chronic constipation. The primary outcome was the correlation be-tween the colon GVS and CTT. Secondary outcomes were the differences in colon GVS according to CTT and subtypes of chronic constipation. RESULTS: There were 81 patients with "CTT < 45 hours" and 64 patients with "CTT >= 45 hours." In addition, 88 patients were classi-fied as having functional constipation and 57 were classified as having constipation predominant irritable bowel syndrome (IBS-C). There was no significant correlation between CTT and colon GVS. However, the right colon GVS showed a positive cor-relation with right CTT (r = 0.255, P = 0.007). The median total colon GVS was significantly higher in patients with "CTT >= 45 hours" than in those with "CTT < 45 hours" (5.65% vs 4.15%, P = 0.010). There were no significant differences in colon GVS between the functional constipation and IBS C. CONCLUSIONS: We were unable to detect a correlation between GVS and CTT in patients with chronic constipation. However, total colon GVS may be a method of predicting slow transit in patients with chronic constipation. PMID- 26058877 TI - Proteomic profiling of human plasma identifies apolipoprotein E as being associated with smoking and a marker for squamous metaplasia of the lung. AB - Biomarkers to identify subjects at high-risk for developing lung cancer will revolutionize the disease outlook. Most biomarker studies have focused on patients already diagnosed with lung cancer and in most cases the disease is often advanced and incurable. The objective of this study was to use proteomics to identify a plasma biomarker for early detection of lung lesions that may subsequently be the harbinger for cancer. Plasma samples were obtained from subjects without lung cancer grouped as never, current, or ex-smokers. An iTRAQ based proteomic analysis was performed on these pooled plasma samples. We identified 31 proteins differentially abundant in current smokers or ex-smokers relative to never smokers. Western blot and ELISA analyses confirmed the iTRAQ results that demonstrated an increase of apolipoprotein E (APOE) in current smokers as compared to both never and ex-smokers. There was a strong and significant correlation of the plasma APOE levels with development of premalignant squamous metaplasia. Additionally, we also showed that higher tissue levels of APOE are seen with squamous metaplasia, supporting a direct relationship. Our analysis reveals that elevated plasma APOE is associated with smoking, and APOE is a novel predictive protein biomarker for early morphological changes of squamous metaplasia in the lung. PMID- 26058879 TI - Proliferation and differentiation characteristics of neural stem cells during course of cerebral cortical histogenesis. AB - Recent advancements in the research field of stem cell biology have enabled the realization of regenerative medicine in various systems of the body, including the central nervous system. However, fundamental knowledge regarding how neural stem cells divide and generate young neurons in mammals, especially in vivo, is still inadequate. In this article, we shall summarize the concept of cell cycle/division of neural stem cells that generate projection neurons in the murine cerebral cortex. We shall also review the molecular mechanisms that modulate the critical parameters related to the cell cycle regulatory mechanisms, with special reference to the cell cycle regulatory protein p27(Kip1) , an inhibitor of progression of the cell cycle at the G1 phase. A better understanding of the mechanisms controlling cell cycle progression is expected to contribute to the development of novel strategies to increase the efficiency of neural cell/tissue production, both in vivo and in vitro. PMID- 26058878 TI - Synthesis and summary of patient-reported outcome measures to inform the development of a core outcome set in colorectal cancer surgery. AB - AIM: Patient-reported outcome (PRO) measures (PROMs) are standard measures in the assessment of colorectal cancer (CRC) treatment, but the range and complexity of available PROMs may be hindering the synthesis of evidence. This systematic review aimed to: (i) summarize PROMs in studies of CRC surgery and (ii) categorize PRO content to inform the future development of an agreed minimum 'core' outcome set to be measured in all trials. METHOD: All PROMs were identified from a systematic review of prospective CRC surgical studies. The type and frequency of PROMs in each study were summarized, and the number of items documented. All items were extracted and independently categorized by content by two researchers into 'health domains', and discrepancies were discussed with a patient and expert. Domain popularity and the distribution of items were summarized. RESULTS: Fifty-eight different PROMs were identified from the 104 included studies. There were 23 generic, four cancer-specific, 11 disease specific and 16 symptom-specific questionnaires, and three ad hoc measures. The most frequently used PROM was the EORTC QLQ-C30 (50 studies), and most PROMs (n = 40, 69%) were used in only one study. Detailed examination of the 50 available measures identified 917 items, which were categorized into 51 domains. The domains comprising the most items were 'anxiety' (n = 85, 9.2%), 'fatigue' (n = 67, 7.3%) and 'physical function' (n = 63, 6.9%). No domains were included in all PROMs. CONCLUSION: There is major heterogeneity of PRO measurement and a wide variation in content assessed in the PROMs available for CRC. A core outcome set will improve PRO outcome measurement and reporting in CRC trials. PMID- 26058880 TI - Amelioration of oxidative and inflammatory status in hearts of cholesterol-fed rats supplemented with oils or oil-products with extra virgin olive oil components. AB - PURPOSE: The contribution of extra virgin olive oil (EVOO) macro- and micro constituents in heart oxidative and inflammatory status in a hypercholesterolemic rat model was evaluated. Fatty acid profile as well as alpha-tocopherol, sterol, and squalene content was identified directly in rat hearts to distinguish the effect of individual components or to enlighten the potential synergisms. METHODS: Oils and oil-products with discernible lipid and polar phenolic content were used. Wistar rats were fed a high-cholesterol diet solely, or supplemented with one of the following oils, i.e., EVOO, sunflower oil (SO), and high-oleic sunflower oil (HOSO) or oil-products, i.e., phenolics-deprived EVOO [EVOO(-)], SO enriched with the EVOO phenolics [SO(+)], and HOSO enriched with the EVOO phenolics [HOSO(+)]. Dietary treatment lasted 9 weeks; at the end of the intervention blood and heart samples were collected. RESULTS: High-cholesterol diet-induced dyslipidemia was shown by increase in serum total cholesterol, low density lipoprotein cholesterol, and triacylglycerols. Dyslipidemia resulted in increased malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-alpha) levels, while glutathione and interleukin 6 levels remained unaffected in all intervention groups. Augmentation observed in MDA and TNF-alpha was attenuated in EVOO, SO(+), and HOSO(+) groups. Heart squalene and cholesterol content remained unaffected among all groups studied. Heart alpha-tocopherol was determined by oil alpha-tocopherol content. Variations were observed for heart beta-sitosterol, while heterogeneity was reported with respect to heart fatty acid profile in all intervention groups. CONCLUSIONS: Overall, we suggest that the EVOO-polar phenolic compounds decreased MDA and TNF-alpha in hearts of cholesterol-fed rats. PMID- 26058881 TI - Mediatory effect of circulating vaspin on resting metabolic rate in obese individuals. AB - BACKGROUND/OBJECTIVE: Vaspin is a recently identified adipokine related to obesity and insulin sensitivity. The precise mechanism of vaspin in the body is not well known, and its function in resting metabolic rate (RMR) is even less understood. Therefore, the main aim of this study was to investigate the effect of circulating vaspin on RMR in obese people. MATERIALS AND METHODS: A total of 222 obese participants were included in the current comparative cross-sectional study. Body composition was measured using body composition analyzer. RMR was measured by means of indirect calorimetry. For the measurement of vaspin serum concentrations, an enzyme-linked immunosorbent assay was used. Dietary intake was assessed using 3-day 24-h dietary recall. RESULTS: Between low and high circulating vaspin groups, there was significant difference for sex (P = 0.03), fat percent (P = 0.008), RMR per weight (P < 0.001), and RMR per fat free mass (FFM) (P = 0.007). However, there was no statistical difference between the groups in dietary intake after adjustment for energy intake (P > 0.05). Furthermore, individuals with higher level of RMR had higher vaspin concentration. Weight, visceral fat, FFM, and fat mass had significant effect on increasing RMR (P < 0.05) but after adding vaspin as a covariate in the general linear model; visceral fat (P = 0.078) and fat mass (P = 0.339) missed their effectiveness. CONCLUSION: Circulating vaspin level is higher in women than in men in obese individuals. Moreover, it was found that vaspin had mediator effect between visceral fat and fat mass associations with RMR in obese participants. PMID- 26058883 TI - Population Genetic Structure of the Bonnethead Shark, Sphyrna tiburo, from the Western North Atlantic Ocean Based on mtDNA Sequences. AB - The population genetic structure of 251 bonnethead sharks, Sphyrna tiburo, from estuarine and nearshore ocean waters of the Western North Atlantic Ocean (WNA), was assessed using sequences of the mitochondrial DNA-control region. Highly significant genetic differences were observed among bonnetheads from 3 WNA regions; Atlantic coast of Florida, Gulf coast of Florida, and southwestern Gulf of Mexico (analysis of molecular variance, PhiCT = 0.137; P=0.001). Within the Gulf coast of Florida region, small but significant genetic differences were observed between bonnetheads from neighboring estuaries. These overall patterns were consistent with known latitudinal and inshore-offshore movements that occur seasonally for this species within US waters, and with the residency patterns and high site fidelity to feeding/nursery grounds reported in estuaries along the Atlantic coast of Florida and South Carolina. Historical demography also supported the occurrence of past population expansions occurring during Pleistocene glacial-interglacial cycles that caused drastic reductions in bonnethead population size, as a consequence of the eustatic processes that affected the Florida peninsula. This is the first population genetics study for bonnetheads to report genetic divergence among core abundance areas in US and Mexican waters of the WNA. These results, coupled with recent advances in knowledge regarding regional differences in life-history parameters of this species, are critical for defining management units to guide future management strategies for bonnetheads within US waters and across international boundaries into Mexico. PMID- 26058882 TI - Local brain connectivity across development in autism spectrum disorder: A cross sectional investigation. AB - There is a general consensus that autism spectrum disorder (ASD) is accompanied by alterations in brain connectivity. Much of the neuroimaging work has focused on assessing long-range connectivity disruptions in ASD. However, evidence from both animal models and postmortem examination of the human brain suggests that local connections may also be disrupted in individuals with the disorder. Here, we investigated how regional homogeneity (ReHo), a measure of similarity of a voxel's timeseries to its nearest neighbors, varies across age in individuals with ASD and typically developing (TD) individuals using a cross-sectional design. Resting-state fMRI data obtained from a publicly available database were analyzed to determine group differences in ReHo between three age cohorts: children, adolescents, and adults. In typical development, ReHo across the entire brain was higher in children than in adolescents and adults. In contrast, children with ASD exhibited marginally lower ReHo than TD children, while adolescents and adults with ASD exhibited similar levels of local connectivity as age-matched neurotypical individuals. During all developmental stages, individuals with ASD exhibited lower local connectivity in sensory processing brain regions and higher local connectivity in complex information processing regions. Further, higher local connectivity in ASD corresponded to more severe ASD symptomatology. These results demonstrate that local connectivity is disrupted in ASD across development, with the most pronounced differences occurring in childhood. Developmental changes in ReHo do not mirror findings from fMRI studies of long-range connectivity in ASD, pointing to a need for more nuanced accounts of brain connectivity alterations in the disorder. PMID- 26058889 TI - T Lymphocyte Prestimulation Impairs in a Time-Dependent Manner the Capacity of Adipose Mesenchymal Stem Cells to Inhibit Proliferation: Role of Interferon gamma, Poly I:C, and Tryptophan Metabolism in Restoring Adipose Mesenchymal Stem Cell Inhibitory Effect. AB - The immunomodulatory properties of mesenchymal stem/stromal cells (MSCs) make them an attractive therapeutic tool to treat chronic inflammatory diseases, such as rheumatoid arthritis or Crohn's disease. These indications are characterized by a chronic activation of immune cells that perpetuates the disease. In vitro, when adipose mesenchymal stem cells (ASCs) are cultured with T lymphocytes at the time of stimulation, their proliferation is inhibited. However, these experimental settings do not necessarily fit with what ASCs will face in inflammatory conditions in vivo, where ASCs will likely encounter and interact with already activated immune cells which might affect their immunomodulatory capacity. In most in vitro studies, MSCs have been cultured with peripheral blood mononuclear cells at the time of lymphocyte stimulation and information about the interaction between MSCs and prestimulated lymphocytes in vitro is scarce. Therefore, a better understanding of the capacity of MSCs to modulate the responses of preactivated immune cells is needed. In this study we focused on the effects of ASCs on prestimulated lymphocytes and systematically investigated the potential mechanisms involved. We report that prestimulation of T lymphocytes 48 h before the coculture with ASCs impairs the capacity of ASCs to inhibit proliferation. Preactivation of ASCs with interferon gamma or the toll-like receptor ligand Poly I:C, but not other stimuli tested, enhanced the ability to inhibit the proliferation of 48 h-stimulated T lymphocytes. The inhibitory effect of ASCs was shown to be time dependent and mediated through the actual magnitude of tryptophan degradation by indoleamine 2,3-dioxygenase. PMID- 26058890 TI - Can emergency physicians diagnose and correctly classify diastolic dysfunction using bedside echocardiography? AB - OBJECTIVES: The goal of this study was to determine if emergency physicians (EPs) can correctly perform a bedside diastology examination (DE) and correctly grade the level of diastolic function with minimal additional training in echocardiography beyond what is learned in residency. We hypothesize that EPs will be accurate at detecting and grading diastolic dysfunction (DD) when compared to a criterion standard interpretation by a cardiologist. METHODS: We conducted a prospective, observational study on a convenience sample of adult patients who presented to an urban emergency department with a chief concern of dyspnea. All patients had a bedside echocardiogram, including a DE, performed by an EP-sonographer who had 3 hours of didactic and hands-on echocardiography training with a cardiologist. The DE was interpreted as normal, grade 1 to 3 if DD was present, or indeterminate, all based on predefined criteria. This interpretation was compared to that of a cardiologist who was blinded to the EPs' interpretations. RESULTS: We enrolled 62 patients; 52% had DD. Using the cardiology interpretation as the criterion standard, the sensitivity and specificity of the EP-performed DE to identify clinically significant diastolic function were 92% (95% confidence interval [CI], 60-100) and 69% (95% CI, 50-83), respectively. Agreement between EPs and cardiology on grade of DD was assessed using kappa and weighted kappa: kappa = 0.44 (95% CI, 0.29-0.59) and weighted kappa = 0.52 (95% CI, 0.38-0.67). Overall, EPs rated 27% of DEs as indeterminate, compared with only 15% by cardiology. For DEs where both EPs and cardiology attempted an interpretation (indeterminates excluded) kappa = 0.45 (95% CI, 0.26 to 0.65) and weighted kappa = 0.54 (95% CI, 0.36-0.72). CONCLUSION: After limited diastology-specific training, EPs are able to accurately identify clinically significant DD. However, correct grading of DD, when compared to a cardiologist, was only moderate, at best. Our results suggest that further training is necessary for EPs to achieve expertise in grading DD. PMID- 26058891 TI - Influence of two types of self-retaining retractors on multifidus muscle blood flow during dorsolateral thoracolumbar hemilaminectomy in dogs. AB - OBJECTIVES: To assess the influence of the use of Gelpi and Grevel retractors on multifidus muscle blood flow during hemilaminectomy, using a dorsolateral approach, for acute disc extrusion in dogs as measured by laser speckle contrast imaging (LSCI). METHODS: Blood flow in the multifidus muscles was measured intra operatively using LSCI prior to insertion of the retractors, immediately after hemilaminectomy and removal of the retractors, and after 10 minutes of lavage of the surgical site. Plasma creatine kinase levels were measured preoperatively and 12-24 hours postoperatively. RESULTS: Muscular blood flow was significantly decreased following retraction and remained lower than initial values 10 minutes after lavage in all dogs. The decrease in blood flow was significantly greater with Gelpi retractors (n = 8) than with Grevel retractors (n = 10). No significant relation was found between the duration of retraction and postoperative changes in creatine kinase levels or blood flow. CLINICAL SIGNIFICANCE: Findings in this study demonstrate a drop in blood flow within the multifidus muscles using the dorsolateral approach regardless of retractor type used. Gelpi retractors seem to have greater influence on muscular blood flow than Grevel retractors. Further studies are warranted to confirm this second finding. PMID- 26058892 TI - JHH change in leadership. PMID- 26058893 TI - Neural circuitry underlying effects of context on human pain-related fear extinction in a renewal paradigm. AB - OBJECTIVES: The role of context in pain-related extinction learning remains poorly understood. We analyzed the neural mechanisms underlying context-dependent extinction and renewal in a clinically relevant model of conditioned abdominal pain-related fear. EXPERIMENTAL DESIGN: In this functional magnetic resonance imaging study, two groups of healthy volunteers underwent differential fear conditioning with painful rectal distensions as unconditioned stimuli (US) and visual conditioned stimuli (CS(+) ; CS(-) ). The extinction context was changed in an experimental group (context group), which was subsequently returned into the original learning context to test for renewal. No context changes occurred in the control group. Group differences in CS-induced differential neural activation were analyzed along with skin conductance responses (SCR), CS valence and CS-US contingency ratings. PRINCIPAL OBSERVATIONS: During extinction, group differences in differential neural activation were observed in dorsolateral (dlPFC) and ventromedial (vmPFC) prefrontal cortex and amygdala, mainly driven by enhanced activation in response to the CS(-) in the control group. During renewal, observed group differences in activation of dlPFC and orbitofrontal cortex (OFC) resulted primarily from differential modulation of the CS(-) in the absence of group differences in response to CS(+) or SCR. CONCLUSION: The extinction context affects the neural processing of nonpain predictive safety cues, supporting a role of safety learning in pain-related memory processes. PMID- 26058894 TI - Left Atrial Dysfunction Assessed by Two-Dimensional Speckle Tracking Echocardiography in Patients with Impaired Left Ventricular Ejection Fraction and Sleep-Disordered Breathing. AB - AIMS: To evaluate the relationship between left atrial (LA) structure and deformation obtained by two-dimensional speckle tracking echocardiography (2DSTE): peak longitudinal systolic strain (LAs), peak longitudinal systolic strain rate (LAS-SR), peak longitudinal early diastolic strain rate (LAE-SR), peak longitudinal late diastolic strain rate (LAA-SR), and sleep-disordered breathing (SDB) estimated by means of apnea-hypopnea index (eAHI). METHODS: Thirty-two individuals with ischemic heart disease (IHD) and impaired left ventricular ejection fraction (EF < 50%) were included in the study. LA function was assessed using 2DSTE. eAHI index was calculated by means of the 24-hour ambulatory Holter electrocardiogram monitoring. Patients were categorized into two subgroups: SDB group (eAHI >= 15; n = 15) and non-SDB group (eAHI < 15; n = 17). RESULTS: All 2DSTE parameters were decreased in the SDB group: LAS-SR (0.90 [0.60-1.25] 1/sec vs. 1.25 [1.00-1.27] 1/sec, P = 0.043), LAE-SR (-0.76 +/- 0.49 1/sec vs. -1.18 +/- 0.55 1/sec, P = 0.033), and LAA-SR (-1.26 +/- 0.71 1/sec vs. 1.48 +/- 0.75 1/sec, P = 0.049). The eAHI was negatively correlated with LA reservoir function: LAS (r = -0.53, P = 0.002) and LAS-SR (r = -0.47, P = 0.006), while it is positively correlated with LAE-SR (r = 0.67, P < 0.001) and LAA-SR (r = 0.46, P = 0.009). Moreover, SDB severity was an independent predictor of impaired LA compliance (P = 0.016) and conduit function (P = 0.002) in multivariate linear regression model, even after adjustment for age, BMI, gender, LV systolic (EF), and diastolic (E/e') function and comorbidities. CONCLUSIONS: LA dysfunction and remodeling assessed using 2DSTE in patients with impaired systolic LV function, and IHD is influenced by the severity of sleep apnea independently from LV function. PMID- 26058895 TI - Cortical reorganisation of cerebral networks after childhood stroke: impact on outcome. AB - BACKGROUND: Recovery after arterial ischaemic stroke is known to largely depend on the plastic properties of the brain. The present study examines changes in the network topography of the developing brain after stroke. Effects of brain damage are best assessed by examining entire networks rather than single sites of structural lesions. Relating these changes to post-stroke neuropsychological variables and motor abilities will improve understanding of functional plasticity after stroke. Inclusion of healthy controls will provide additional insight into children's normal brain development. Resting state functional magnetic resonance imaging is a valid approach to topographically investigate the reorganisation of functional networks after a brain lesion. Transcranial magnetic stimulation provides complementary output information. This study will investigate functional reorganisation after paediatric arterial ischaemic stroke by means of resting state functional magnetic resonance imaging and transcranial magnetic stimulation in a cross-sectional plus longitudinal study design. The general aim of this study is to better understand neuroplasticity of the developing brain after stroke in order to develop more efficacious therapy and to improve the post stroke functional outcome. METHODS: The cross-sectional part of the study will investigate the functional cerebral networks of 35 children with chronic arterial ischaemic stroke (time of the lesion >2 years). In the longitudinal part, 15 children with acute arterial ischaemic stroke (shortly after the acute phase of the stroke) will be included and investigations will be performed 3 times within the subsequent 9 months. We will also recruit 50 healthy controls, matched for age and sex. The neuroimaging and neurophysiological data will be correlated with neuropsychological and neurological variables. DISCUSSION: This study is the first to combine resting state functional magnetic resonance imaging and transcranial magnetic stimulation in a paediatric population diagnosed with arterial ischaemic stroke. Thus, this study has the potential to uniquely contribute to the understanding of neuronal plasticity in the brains of healthy children and those with acute or chronic brain injury. It is expected that the results will lead to the development of optimal interventions after arterial ischaemic stroke. PMID- 26058896 TI - Expression of the human cytomegalovirus pentamer complex for vaccine use in a CHO system. AB - Human cytomegalovirus (HCMV) causes significant disease worldwide. Multiple HCMV vaccines have been tested in man but only partial protection has been achieved. The HCMV gH/gL/UL128/UL130/UL131A complex (Pentamer) is the main target of neutralizing antibodies in HCMV seropositive individuals and raises high titers of neutralizing antibodies in small animals and non-human primates (NHP). Thus, Pentamer is a promising candidate for an effective HCMV vaccine. Development of a Pentamer-based subunit vaccine requires expression of high amounts of a functional and stable complex. We describe here the development of a mammalian expression system for large scale Pentamer production. Several approaches comprising three different CHO-originated cell lines and multiple vector as well as selection strategies were tested. Stable cell pools expressed the HCMV Pentamer at a titer of approximately 60 mg/L at laboratory scale. A FACS-based single cell sorting approach allowed selection of a highly expressing clone producing Pentamer at the level of approximately 400 mg/L in a laboratory scale fed-batch culture. Expression in a 50 L bioreactor led to the production of HCMV Pentamer at comparable titers indicating the feasibility of further scale-up for manufacturing at commercial scale. The CHO-produced HCMV Pentamer bound to a panel of human neutralizing antibodies and raised potently neutralizing immune response in mice. Thus, we have generated an expression system for the large scale production of functional HCMV Pentamer at high titers suitable for future subunit vaccine production. PMID- 26058899 TI - Effects of Prepregnancy Body Mass Index and Gestational Weight Gain on Pregnancy Outcomes. AB - To investigate the single and joint effects of prepregnancy body mass index (BMI) and gestational weight gain (GWG) on pregnancy outcomes, electronic medical records of 14,196 women who delivered singleton live infant at a maternal and child health hospital in Beijing, China, in 2012 were reviewed. Logistic regression was used to assess the associations, adjusting for maternal age, height, education, parity, and offspring sex. Women of high prepregnancy BMI or excessive GWG had higher risks of gestational diabetes mellitus, hypertensive disorders in pregnancy, postpartum hemorrhage, caesarean delivery, macrosomia, and large for gestational age infant, while women of inadequate GWG had higher risks of preterm delivery, low birth weight, and small for gestational age infant. Findings suggest that antenatal care providers should help pregnant women control their GWG to normal. PMID- 26058898 TI - Telomere protein Rap1 is a charge resistant scaffolding protein in chromosomal bouquet formation. AB - BACKGROUND: Chromosomes reorganize in early meiotic prophase to form the so called telomere bouquet. In fission yeast, telomeres localize to the nuclear periphery via interaction of the telomeric protein Rap1 with the membrane protein Bqt4. During meiotic prophase, the meiotic proteins Bqt1-2 bind Rap1 and tether to the spindle pole body to form the bouquet. Although it is known that this polarized chromosomal arrangement plays a crucial role in meiotic progression, the molecular mechanisms of telomere bouquet regulation are poorly understood. RESULTS: Here, we detected high levels of Rap1 phospho-modification throughout meiotic prophase, and identified a maximum of 35 phosphorylation sites. Concomitant phosphomimetic mutation of the modification sites suggests that Rap1 hyper-phosphorylation does not directly regulate telomere bouquet formation or dissociation. Despite the negative charge conferred by its highly phosphorylated state, Rap1 maintains interactions with its binding partners. Interestingly, mutations that change the charge of negatively charged residues within the Bqt1-2 binding site of Rap1 abolished the affinity to the Bqt1-2 complex, suggesting that the intrinsic negative charge of Rap1 is crucial for telomere bouquet formation. CONCLUSIONS: Whereas Rap1 hyper-phosphorylation observed in meiotic prophase does not have an apparent role in bouquet formation, the intrinsic negative charge of Rap1 is important for forming interactions with its binding partners. Thus, Rap1 is able to retain bouquet formation under heavily phosphorylated status. PMID- 26058900 TI - The Physical Activity Scale for the Elderly (PASE): Validity and Reliability Among Community-Dwelling Older Adults in Malaysia. AB - Physical Activity Scale for the Elderly (PASE) is among the frequently used self reported physical activity assessment for older adults. This study aims to assess the validity and reliability of a Malay version of this scale (PASE-M). A total of 408 community-dwelling older adults were enrolled. Concurrent validity was evaluated by Spearman's rank correlation coefficients between PASE with physical and psychosocial measures. Test-retest reliability was determined by the intraclass correlation coefficient (ICC). The mean PASE-M scores at baseline and follow-up were 94.96 (SD 62.82) and 92.19 (SD 64.02). Fair to moderate correlation were found between PASE-M and physical function scale, IADL (rs = 0.429, P < .001), walking speed (rs = 0.270, P < .001), grip strength (rs = 0.313 0.339, P < .001), and perceived health status (rs = -0.124, P = .016). Test retest reliability was adequate (ICC = 0.493). The Malay version of PASE was shown to have acceptable validity and reliability. This tool is useful for assessing the physical activity level of elderly Malaysians. PMID- 26058901 TI - Constrictive pericarditis post-lung transplant. AB - Constrictive pericarditis is a rare entity following lung transplant, with only seven previous cases reported in the literature. We present two additional cases and review the literature on this subject. Constrictive pericarditis should be considered in lung transplant patients who present with dyspnea and evidence of cardiac failure. Pericardiectomy remains the treatment of choice irrespective of the etiology. PMID- 26058902 TI - Caring for Adolescents on Their Journey to Adulthood. PMID- 26058904 TI - Health Care Workers' Beliefs and Practices Around Pap Screening for Adolescents Seeking Contraception. AB - Adolescents often avoid seeing a health care provider to obtain contraception because they do not want to undergo a pelvic exam and Pap screening for fear of stress, pain or embarrassment. The purpose of this quality improvement project was to study health care workers, attitudes and beliefs about Pap screening and to educate them on the latest evidence-based guidelines, with the hope of ultimately decreasing unnecessary screening. Results showed a modest reduction in the frequency of Pap screening; however, many adolescents continued to undergo unnecessary Pap screening. The reluctance of health care workers to change their practice demonstrates the need for better methods of translating evidence-based guidelines into practice. PMID- 26058905 TI - The Meaning of Food and Multicultural Implications for Perinatal Palliative Care. AB - Feeding an infant is a bonding experience for parents, particularly for women from cultures in which breastfeeding is the norm. When an infant is unexpectedly ill, or his or her life is expected to be brief, challenges surrounding infant feeding can occur. Regardless of ethnicity or culture, parents facing the death of their infant have difficult decisions to make and need time to process those decisions. Given the social, cultural and spiritual nature of food and water, withdrawing or withholding nutrition and/or hydration for infants can be one of the most difficult decisions for parents. This article considers the clinical and cultural ramifications of infant feeding decisions when a shift occurs from curative interventions to palliative care. PMID- 26058906 TI - Care of the Childbearing Family With Intrauterine Fetal Demise. AB - Intrauterine fetal demise (IUFD), or stillbirth, is the death of a fetus greater than 20 weeks gestation. Several factors contribute to risk for IUFD, although in many cases the exact etiology is unknown. Nurses are a vital part of the interdisciplinary health care team caring for families with IUFD, who require timely and sensitive care to enable an uncomplicated birth and grieving process. PMID- 26058907 TI - Myasthenia Gravis in Pregnancy. AB - Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease and is the most common disorder of neuromuscular transmission. MG is caused by a defect in the transmission of nerve impulses to muscles in which communication from nerves to muscles is interrupted at the neuromuscular junction. This interruption can cause significant impact to muscle functions, which can have serious consequences for a pregnant woman, especially during labor. This brief article, which is meant to be used as an easy-reference tool in the clinical setting, examines the disease process and its effect on the antepartum, intrapartum and postpartum periods. PMID- 26058908 TI - Long-Acting Reversible Contraception for Adolescents. AB - In 2013 and 2014, the Centers for Disease Control and Prevention (CDC) publicized its recommendations for the use of long-acting reversible contraception (LARC) (including intrauterine devices and implants) as first-line, highly effective options for pregnancy prevention. The use of LARC by adolescents has had growing support by national health and women's health organizations. Ongoing research is beginning to uncover facilitators and barriers to LARC use in adolescents. The purpose of this column is to highlight two recent U.S.-based studies in which researchers examined perspectives related to and factors associated with LARC use in adolescent and young adult women. PMID- 26058897 TI - TrxR1 as a potent regulator of the Nrf2-Keap1 response system. AB - SIGNIFICANCE: All cells must maintain a balance between oxidants and reductants, while allowing for fluctuations in redox states triggered by signaling, altered metabolic flow, or extracellular stimuli. Furthermore, they must be able to rapidly sense and react to various challenges that would disrupt the redox homeostasis. RECENT ADVANCES: Many studies have identified Keap1 as a key sensor for oxidative or electrophilic stress, with modification of Keap1 by oxidation or electrophiles triggering Nrf2-mediated transcriptional induction of enzymes supporting reductive and detoxification pathways. However, additional mechanisms for Nrf2 regulation are likely to exist upstream of, or in parallel with, Keap1. CRITICAL ISSUES: Here, we propose that the mammalian selenoprotein thioredoxin reductase 1 (TrxR1) is a potent regulator of Nrf2. A high chemical reactivity of TrxR1 and its vital role for the thioredoxin (Trx) system distinguishes TrxR1 as a prime target for electrophilic challenges. Chemical modification of the selenocysteine (Sec) in TrxR1 by electrophiles leads to rapid inhibition of thioredoxin disulfide reductase activity, often combined with induction of NADPH oxidase activity of the derivatized enzyme, thereby affecting many downstream redox pathways. The notion of TrxR1 as a regulator of Nrf2 is supported by many publications on effects in human cells of selenium deficiency, oxidative stress or electrophile exposure, as well as the phenotypes of genetic mouse models. FUTURE DIRECTIONS: Investigation of the role of TrxR1 as a regulator of Nrf2 activation will facilitate further studies of redox control in diverse cells and tissues of mammals, and possibly also in animals of other classes. PMID- 26058909 TI - What Parents Need to Know About Vitamin K Administration at Birth. AB - Prophylactic treatment of newborns with intramuscular vitamin K has been the standard of care for many years in the United States. However, instances of parental refusal of routine prophylaxis are currently on the rise. Refusal of routine prophylaxis can have serious long-term neurodevelopmental consequences for some newborns, who may subsequently develop vitamin K deficiency-associated hemorrhagic disease of the newborn (HDN). PMID- 26058910 TI - Changes to Pregnancy and Lactation Risk Labeling for Prescription Drugs. AB - Safe medication use by women during pregnancy and lactation is an area of concern for women and their health care providers. In December 2014, the U.S. Food and Drug Administration (FDA) issued a final rule on new labeling changes, which go into effect in June 2015 and eliminate the current letter system of A-D, X. The new labeling will include a summary of risks to using the medication during pregnancy and lactation, and supporting data and relevant information to assist health care providers in counseling pregnant and lactating women. PMID- 26058911 TI - A Cultural Immersion Experience in Indonesia for U.S. Nursing Students. AB - Cultural immersion experiences as part of the education of health care professionals are important as our global focus expands through technology, natural disasters, pandemics, wars and the mobility of the world population. This is the story of a recent cultural immersion experience to Indonesia by U.S. nursing students. Student groups each chose an Indonesian health topic for an in depth focus. Students critically evaluated published research and discussed evidence-based practice ideas applicable to their selected health issues. Using this knowledge, they developed PICO posters for presentation at an international nursing conference in Indonesia. The students greatly valued their opportunity to experience a different culture firsthand and to spend time with Indonesian students and faculty. PMID- 26058912 TI - Updated Obstetric Hemorrhage Toolkit. PMID- 26058913 TI - Update on Newborn Screening. PMID- 26058914 TI - Positive Impact. PMID- 26058916 TI - The effect of exercise therapy in head and neck cancer patients in the treatment of radiotherapy-induced trismus: A systematic review. AB - Trismus is characterized by a reduced ability to open the mouth, directly affecting many aspects of daily life, such as chewing, swallowing, speaking and maintaining oral hygiene. Several studies have shown that trismus affects health related quality of life. Radiotherapy in the head and neck area is identified as one of the most frequent causes of trismus in head and neck cancer (HNC) patients. Currently, there is no standard treatment for trismus. Several stretching techniques and jaw mobilizing devices are available, but their effect in radiotherapy-induced trismus is still largely unknown. With this review we give an overview of the present relevant literature and compare the effect of exercise therapy versus no exercise therapy on jaw mobility, expressed in millimeters mouth opening, in HNC patients with radiotherapy-induced trismus. A systematic literature search in four electronic bibliographic databases was conducted in July 2014. Selected articles were critically appraised on relevance and validity. Best available evidence was analyzed and compared. Three of the four selected articles show a significant increase (p-value<0.05) in maximal interincisal opening (MIO) after exercise therapy using a jaw-mobilizing device. One article reports a significant decrease in MIO. However, this decrease is less in the intervention group, which implies a positive effect of exercise therapy. Based on this current best clinical evidence, it can be assumed that exercise therapy with a jaw-mobilizing device yields better results than no exercise, with regards to opening of the mouth in HNC patients with radiotherapy-induced trismus. PMID- 26058915 TI - Genetic loci for serum magnesium among African-Americans and gene-environment interaction at MUC1 and TRPM6 in European-Americans: the Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Low serum magnesium levels have been associated with multiple chronic diseases. The regulation of serum magnesium homeostasis is not well understood. A previous genome-wide association study (GWAS) of European ancestry (EA) populations identified nine loci for serum magnesium. No such study has been conducted in African-Americans, nor has there been an evaluation of the interaction of magnesium-associated SNPs with environmental factors. The goals of this study were to identify genetic loci associated with serum magnesium in an African-American (AA) population using both genome-wide and candidate region interrogation approaches and to evaluate gene-environment interaction for the magnesium-associated variants in both EA and AA populations. We conducted a GWAS of serum magnesium in 2737 AA participants of the Atherosclerosis Risk in Communities (ARIC) Study and interrogated the regions of the nine published candidate loci in these results. Literature search identified the influence of progesterone on MUC1 expression and insulin on TRPM6 expression. RESULTS: The GWAS approach in African-American participants identified a locus near MUC1 as genome-wide significant (rs2974937, beta=-0.013, p=6.1x10(-9)). The candidate region interrogation approach identified two of the nine loci previously discovered in EA populations as containing SNPs that were significantly associated in African-American participants (SHROOM3 and TRPM6). The index variants at these three loci together explained 2.8 % of the variance in serum magnesium concentration in ARIC African-American participants. On the test of gene-environment interaction in ARIC EA participants, the index variant at MUC1 had 2.5 times stronger association in postmenopausal women with progestin use (beta=-0.028, p=7.3x10(-5)) than in those without any hormone use (beta=-0.011, p=7.0x10(-8), p for interaction 0.03). At TRPM6, the index variant had 1.6 times stronger association in those with lower fasting insulin levels (<80 pmol/L: beta=-0.013, p=1.6x10(-7); >=80 pmol/L: beta=-0.008, p=1.8x10(-2), p for interaction 0.03). CONCLUSIONS: We identified three loci that explained 2.8% of the variance in serum magnesium concentration in ARIC African-American participants. Following-up on functional studies of gene expression identified gene-environment interactions between progestin use and MUC1 and between insulin and TRPM6 on serum magnesium concentration in ARIC European-American participants. These results extend our understanding of the metabolism of serum magnesium. PMID- 26058917 TI - Autoimmunity and regulatory T cells in 22q11.2 deletion syndrome patients. PMID- 26058919 TI - Application of an ELISA Milk Pregnancy Test in Beef Cows. AB - Pregnancy-associated glycoproteins (PAG) are secreted by the binucleate giant cells of the ruminant placenta and enter maternal circulation at the time of placental attachment. The IDEXX Milk Pregnancy Test (IDEXX, Westbrook, ME) detects a subset of PAG in milk. Although designed as a management tool for dairy cows, there is potential for using the milk PAG test in beef cows. Our objective was to compare the performance of the milk PAG ELISA with a gold standard method for pregnancy diagnosis and determine the agreement between milk and serum PAG analysis in lactating beef cows. Angus and Angus-crossed cows (n = 332) from two Michigan beef herds were enrolled in this study. Cows were subjected either to timed artificial insemination followed by exposure to a bull or exclusively exposed to a bull. The bulls and cows were separated 30 days prior to examination. Serum and milk samples were collected and submitted within 24 h of collection to a commercial laboratory for PAG analysis using the IDEXX Milk Pregnancy Assay (milk) and the IDEXX Bovine Pregnancy Assay (serum). Concurrently with milk and serum collection, each cow was examined transrectally by palpation or ultrasonography. When compared to transrectal examination, the performance (and 95% confidence intervals) of the milk PAG ELISA was sensitivity of 99.7% (99.0-100.0%) and specificity of 80.8% (65.6-95.9%). The lower specificity is likely due to the low prevalence (9.9%) of open cows (n = 30) in the herds examined. Of the 332 cows examined, 1.8% (n = 6) were classified as rechecks using the milk PAG ELISA. Results of the milk and serum PAG ELISA were in high agreement (kappa coefficient = 0.91). The milk PAG ELISA was accurate in predicting pregnancy status using milk collected from beef cattle between days 37 and 125 post-insemination and may be useful for aiding management decisions in beef herds. PMID- 26058918 TI - Genetic determinants of fetal opiate exposure and risk of neonatal abstinence syndrome: Knowledge deficits and prospects for future research. AB - Opiate-dependent pregnant women receive opiate maintenance medications to prevent illicit use and withdrawal. Fetal opiate exposure causes central nervous system (CNS) alterations which manifest as postnatal physical withdrawal. The extensive variability in the Neonatal Abstinence Syndrome phenotype remains unexplained and may be related to variability in fetal exposure and response. Improved understanding of functionally significant genetic variants in pathways influencing placental opiate transfer and fetal response can lead to personalized maternal therapy and optimized neonatal outcomes. PMID- 26058920 TI - Detection and phylogenetic analysis of human pegivirus (GBV-C) among blood donors and patients infected with hepatitis B virus (HBV) in Qatar. AB - Human Pegivirus (HPgV), formerly GB virus-C/Hepatitis G virus (GBV-C/HGV), collectively known as GBV-C, is widely spread and has been reported to be associated with non-A-E hepatitis. To our knowledge, no previous study was conducted about HPgV in Qatar. Thus, the objectives of this study were as follows: (i) to determine the rates of HPgV infection in Qatar among healthy blood donors and HBV-infected patients, and (ii) to determine the most predominant HPgV genotype in Qatar. A total of 714 blood plasma samples from healthy donors (612) and HBV-infected patients (102) were collected. RNA was extracted, reversed transcribed, and then subjected for HPgV detection by two round-nested PCR using primers amplifying a 208 bp of 5'-UTR of the HPgV. For genotyping, the 5'-UTR PCR products (from 25 randomly picked samples) were cloned and sequenced. The overall infection rate of HPgV in Qatar was 13.3%. There was no significant difference (P = 0.41) in the infection rates between healthy donor (13.7%) and in HBV-infected patients (10.7%). Moreover, we did not find any significant association between HPgV infection rates and nationality, sex, or age (P > 0.05). Sequence analysis of 40 5'-UTR PCR amplicons yielded the European genotype 2 as most predominant in Qatar, although other genotypes (5 and 7) were also present. Our results indicate that there is no strong correlation between HPgV infection rate, condition, nationality, age, and sex, and genotype 2 is most predominant in Qatar. PMID- 26058922 TI - The new hepatitis C virus bottleneck: Can delaying therapy be justified? PMID- 26058921 TI - PsANT, the adenine nucleotide translocase of Puccinia striiformis, promotes cell death and fungal growth. AB - Adenine nucleotide translocase (ANT) is a constitutive mitochondrial component that is involved in ADP/ATP exchange and mitochondrion-mediated apoptosis in yeast and mammals. However, little is known about the function of ANT in pathogenic fungi. In this study, we identified an ANT gene of Puccinia striiformis f. sp. tritici (Pst), designated PsANT. The PsANT protein contains three typical conserved mitochondrion-carrier-protein (mito-carr) domains and shares more than 70% identity with its orthologs from other fungi, suggesting that ANT is conserved in fungi. Immuno-cytochemical localization confirmed the mitochondrial localization of PsANT in normal Pst hyphal cells or collapsed cells. Over-expression of PsANT indicated that PsANT promotes cell death in tobacco, wheat and fission yeast cells. Further study showed that the three mito carr domains are all needed to induce cell death. qRT-PCR analyses revealed an in planta induced expression of PsANT during infection. Knockdown of PsANT using a host-induced gene silencing system (HIGS) attenuated the growth and development of virulent Pst at the early infection stage but not enough to alter its pathogenicity. These results provide new insight into the function of PsANT in fungal cell death and growth and might be useful in the search for and design of novel disease control strategies. PMID- 26058923 TI - Editorial: Research Domain Criteria (RDoC): a new psychiatric nosology whose time has not yet come. AB - In developing new ways of classifying mental disorders, RDoC is developing a new nosology, a new way of dividing nature at its seams. Given the NIMH influence on research agendas across the world, this scientific agenda will have important consequences for researchers and clinicians worldwide. Defining discrete neural systems and the behavioral and cognitive functions they subserve is scientifically important. Understanding how these systems relate to clinical problems, patient suffering, and improved treatments has immense potential practical value for clinical care worldwide. This Editorial places the RDoC framework in context and then sets out a series of conceptual, empirical, and developmental challenges for RDoC. Together these challenges suggest that RDoC is premature as a nosology and, as currently implemented, risks being reified and overly rigid in its application. PMID- 26058924 TI - Commentary: A glass half full or half empty? Cognitive bias modification for mental health problems in children and adolescents--reflections on the meta analysis by Cristea et al. (2015). AB - The last decade has cognitive bias modification (CBM) training paradigms, emerging first as an experimental test of the causal role of information processing biases on mood and anxiety symptoms, and then, as the clinical implications of these findings were realised, as a potential clinical 'vaccine' that could be used to modify biases and reduce symptoms. CBM is an umbrella term for methods designed to modify cognitive factors that maintain psychiatric conditions such as anxiety and depression through simple repetitive learning. Two biases that have most often been targeted by these training programs are the tendency to orient attention towards threat and distortions in the interpretation of ambiguous situations. This commentary reflects on an accompanying meta analysis by Crsitea et al., which pooled effect sizes from over 20 statistical comparisons between a CBM group and a control group on post-training measures of mental health (mostly anxiety and depression). Cristea et al. reported that any CBM training-associated difference on measures of anxiety and depression were weak and non-significant (although training effects were generally evident on measures of cognitive biases). Heterogeneity across studies was high, but with exception to the setting in which CBM was delivered (home, school, laboratory or mental health facility), there was no persuasive evidence for significant moderation of training effects by other key variables. In their conclusions the authors suggested that CBM had little clinical utility and that it was unclear whether positive results in any individual study arose from experimenter or participant bias. So if the glass is half empty, what should the next stage of CBM research usefully focus on? PMID- 26058925 TI - Molecular Beam Epitaxy-Grown SnSe in the Rock-Salt Structure: An Artificial Topological Crystalline Insulator Material. PMID- 26058926 TI - Synergistic action of laccases from Trametes hirsuta Bm2 improves decolourization of indigo carmine. AB - Laccase isoenzymes (LacI,II,III) produced on wheat bran from Trametes hirsuta were partially purified through anion exchange chromatography. The three isoenzymes had the same MW of 65 kDa, and their main physico-chemical properties were studied. As single isoenzymes, laccases were unable to decolourize dye. Among several mediators evaluated, syringaldehyde was the most effective in dye decolourization (100%). A remarkable increase in dye decolourization was observed when LacI, II, III in mixture or crude enzyme were added to the reaction system, indicating that the laccases acted synergistically. SIGNIFICANCE AND IMPACT OF THE STUDY: Laccases have a great potential of application in bioremediation processes. White rot fungi produces several laccase isoenzymes and many of them have been purified and characterized. However, the additive or synergic action between laccase isoenzymes in dye decolourization has not yet been described. Such studies will help to better understand their action and to improve the process with isoenzymes mixtures. This study showed synergistic action between isoenzymes laccases produced by Trametes hirsuta Bm2 during decolourization of indigo carmine. PMID- 26058928 TI - Simultaneous Detection of Mycoplasma pneumoniae, Mycoplasma hominis and Mycoplasma arthritidis in Synovial Fluid of Patients with Rheumatoid Arthritis by Multiplex PCR. AB - BACKGROUND: It has been recognized that infectious agents, such as different bacteria and viruses, may play a role in the developing of rheumatoid arthritis (RA). Recently, the mycoplasma species has been implicated in the pathogenesis of RA. AIM: The aim of this study was to design a multiplex PCR for rapid and simultaneous detection of Mycoplasma pneumoniae, Mycoplasma hominis, and Mycoplasma arthritidis in the synovial fluid of patients with rheumatoid arthritis (RA). METHODS: A total of 131 synovial fluid (SF) samples from patients with RA were assayed. Mycoplasma pneumoniae (ATCC: 29342), M. hominis (native strain), and the synthetic complete genome of M. arthritidis mitogen (MAM) superantigen were used as controls. All SF samples were subjected to DNA extraction separately and multiplex PCR was performed. The PCR products were confirmed by sequencing. RESULTS: The designed multiplex PCR was able to detect M. pneumoniae, M. hominis, and M. arthritidis in the SF of patients with RA with a frequency of 30 (22.9%), 23 (17.5%) and 13 (9.9%), respectively. CONCLUSION: In this study, the overall detection of the Mycoplasma species in RA patients was 53.4%; thus, we recommend the application of multiplex PCR assays when searching for a specific anti mycoplasma treatment for RA patients. PMID- 26058927 TI - Long-Term Follow-up of Intra-articular Injection of Autologous Mesenchymal Stem Cells in Patients with Knee, Ankle, or Hip Osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is a debilitating disease that typically affects a large number of the middle-aged and elderly population. Current treatment strategies have had limited success in these patients. This study aims to investigate the safety of treatment with autologous bone marrow (BM)-derived mesenchymal stem cells (MSCs) transplanted in patients with OA of the knee, ankle, or hip. METHODS: We enrolled 18 patients with different joint involvements (knee, ankle, or hip OA) and one was lost to follow-up. BM samples were taken from the patients, after which BM-derived MSCs were isolated and cultured. Each patient received one MSC injection. Patients were followed with clinical examinations, MRI and laboratory tests at 2, 6, 12, and 30 months post transplantation. RESULTS: We observed no severe adverse events such as pulmonary embolism, death, or systemic complications. A limited number of patients had very minor localized adverse effects such as rash and erythema. There were no changes in liver function, hematology, or biochemistry analyses before and after cell therapy. There was no evidence of tumor or neoplastic changes in the patients during the 30-month follow-up period. All patients exhibited therapeutic benefits such as increased walking distance, decreased visual analog scale (VAS), and total Western Ontario and McMaster Universities OA Index (WOMAC) scores which were confirmed by MRI. CONCLUSIONS: Our study has shown that injection of MSCs in different OA affected joints is safe and therapeutically beneficial. However, further studies are needed with larger sample sizes and longer follow-up periods to confirm these findings. PMID- 26058929 TI - Decreased Expressions of STING but not IRF3 Molecules in Chronic HBV Infected Patients. AB - CONTEXT: The stimulator of interferon genes (STING) induces the activation of interferon regulatory factor 3 (IRF3) in response to intracellular viral double stranded (ds) DNA. The aim of this study was to evaluate mRNA levels of STING and its downstream transcription factor, IRF3, in the isolated peripheral blood mononuclear cells (PBMCs) of patients with chronic HBV (CHB) infection. METHODS: This study was performed on 60 healthy controls and 60 CHB patients. The mRNA levels of STING and IRF3 were determined using Real-Time polymerase chain reaction (PCR) techniques. The SPSS software version 18 was used to analyze raw data. RESULTS: The results revealed that mRNA levels of STING were significantly decreased in CHB patients in comparison to healthy controls (P = 0.013). Our results also revealed that expression levels of IRF3 were not different between CHB patients and healthy controls (P = 0.828). CONCLUSIONS: In the present study, we found that CHB patients were unable to express appropriate levels of STING. Thus, it may result in impairment of HBV-DNA recognition and subsequently disruption of immune responses. These results suggest a plausible mechanism which may partially define the fact that immune responses are impaired in CHB patients. PMID- 26058930 TI - Trends in Suicide Mortality Rates for Turkey from 1987 to 2011: A Joinpoint Regression Analysis. AB - BACKGROUND: Suicide is among the top 20 leading causes of death globally in all age groups and it is still a significant social and public health problem. METHODS: Data on suicide deaths in 1987-2011 were extracted from the Turkish Statistical Institute mortality dataset based on ICD-9 and ICD-10 codes. The temporal trend in age-standardized suicide rates was tested for age, gender and methods using Joinpoint Regression Analysis. RESULTS: The average of age standardized suicide rates of the period 1987-2011 were 3.08 per 100,000 people, 3.95 for male and 2.21 for female. Significant increases were observed in males in all age groups, but no significant changes were observed in females over the age of 45. The most common methods of suicide among people who live in Turkey were hanging, poisoning, firearms and jumping. CONCLUSION: High-risk groups could benefit from targeted strategies of suicide prevention. To understand the important influences on suicide risk in different age groups, future studies must investigate the experiences of older and younger individuals separately. PMID- 26058931 TI - Vitamin D Improves Learning and Memory Impairment in Streptozotocin-Induced Diabetic Mice. AB - INTRODUCTION: Diabetes mellitus (DM) is associated with memory and learning deficits. Evidence has been provided that vitamin D is involved in brain function. The aim of the present study was to determine the potential effect of vitamin D on acquisition and retention of memory and learning in streptozotocin (STZ)-induced diabetic mice. METHODS: Experiments were performed in four groups of mice (each group; n = 7). Male mice were induced to diabetes by single dose (60 mg/kg, i.p.) injection of freshly prepared STZ dissolved in cold normal saline. Treatment with vitamin D (5ug/kg daily, i.p. dissolved in tween80) was begun at three days after diabetes induction. Passive avoidance (PA) learning method was used four weeks later. Retrieval test was carried out 24 h after training. RESULTS: Our results demonstrate significant impairment in acquisition and retrieval processes of PA learning in STZ- induced diabetic mice. Treatment with vitamin D improved learning and memory compared to the control group, both in acquisition and retrieval stages and reversed learning deficits in diabetic mice. In acquisition test, there were significant differences in the initial latency among the DM+Vit. D treated and control groups (P < 0.05). There was a significant difference in step-through latency between diabetic group treated with vitamin D compared to diabetic non-treated groups (P < 0.05). CONCLUSION: It is possible that the effects of Vitamin D on cognitive deficits in STZ-induced diabetic mice could be mediated through calcium homeostasis modulation. These findings suggest a potential role for vitamin D in the treatment of diabetes associated cognition deficits. The positive effect of vitamin D on the avoidance task may be attributed to its neuronal protective roles metabolic regulating roles of prolonged vitamin D administration. PMID- 26058932 TI - Chondromyxoid Fibroma of Pelvis, Surgical Management of 8 Cases. AB - BACKGROUND: Chondromyxoid fibroma is a rare benign primary bone tumor of cartilaginous origin, which most commonly involves the metaphyseal bone of proximal tibia and distal femur. The purpose of the study is to report our experience with diagnosis and surgical management of Chondromyxoid fibroma in the pelvic region. METHODS: Eight consecutive patients with a final diagnosis of pelvic Chondromyxoid fibroma were treated from 2001 to 2010. We considered the presentations and outcome for surgical complications and local recurrence after extended curettage and allogenic corticocancellous bone grafting. RESULTS: Three patients were female and five were male. The median follow up period was 72 (30 126) months. The mean age of cases was 31.9 (20-41) years. Five patients had left side involvement and in the remaining three, the right side was involved. Four involved periacetabulum, two involved the ilium and the remaining two cases were ischiopubic. The mean Musculoskeletal Tumor Society Score was 94.1%. The major complications were recurrence in one case and herniation after pubic rami resection in another case. CONCLUSION: Chondromyxoid fibroma should be distinguished from chondrosarcoma. Management recommendation includes extensive curettage and corticocancellous bone grafting. We also advocate use of fibular strut allograft for reconstruction of pubic rami after its resection to prevent hernia in cases with pubic rami involvement. PMID- 26058933 TI - Diagnostic Efficacy of UBI Scan in Musculoskeletal Infections. AB - BACKGROUND: Limited recent studies have demonstrated that 99mTc-UBI scan can be a helpful method in precise diagnosis of infection. In the current study, we aimed to investigate the diagnostic efficacy of 99mTc-UBI scan in detection of musculoskeletal infections. METHODS: Fifty patients with suspected musculoskeletal infections (painful THA, TKA, implant and nonunion) were enrolled in this study. After injection of 99mTc-Ubiquicidin 29-41, up to 30 minutes, dynamic imaging was performed every 1 minute. Whole body anterior and posterior images were acquired at 60 and 120 min (5 min/frame). A polygonal region of interest (ROI) was drawn manually around the area of increased accumulation of tracer (lesion) and anatomically similar area on the contralateral side (background) and the lesion to background ratio (LBR) was calculated. Then, patients underwent surgical procedures to assess infection by tissue sampling and histopathologic studies as gold standard. The receiver operating characteristics (ROC) analysis was performed to find a cut-off value for LBR and determining the diagnostic efficacy of UBI scan in musculoskeletal infections. RESULTS: Histopathologic studies revealed infection in 38 patients. The mean LBR was significantly higher in infected patients (2.05 +/- 0.41 vs. 1.52 +/- 0.22; P < 0.001). ROC analysis showed that a cut-off point of 1.74 for LBR will have 94.7% sensitivity, 83.3% specificity and 92% accuracy for diagnosis of musculoskeletal infections. CONCLUSION: UBI scan is a useful diagnostic tool for evaluation of patients with suspected musculoskeletal infection. However, UBI imaging has some limitations which result in some incorrect diagnoses. It is important to interpret the results of the scan with regard to the clinical findings. PMID- 26058934 TI - Association of rs12255372 (TCF7L2) and D76N (PDX-1) Polymorphisms with Type 2 Diabetes in a Population Living in Northeast Iran. AB - The aim of this study was to investigate whether the rs12255372 (TCF7L2) and D76N (PDX-1) polymorphisms are associated with type 2 diabetes mellitus (T2DM) in Mashhad, northeast Iran. A hundred twenty seven patients with T2DM and 71 non diabetic controls in Mashhad were genotyped by PCR-RFLP and ARMS-PCR methods. Single nucleotide polymorphisms (SNPs) were confirmed by sequencing in some samples and allelic and genotypic frequencies were then analyzed in each group. The T-allele of the SNP rs12255372 of TCF7L2 (OR = 2.70, 95% CI = 1.12-6.49, P = 0.027) and the A-allele of PDX-1 D76N (OR = 3.93, 95% CI = 1.60-7.68, P = 0.002) were significantly associated with an increased risk of T2DM. The rs12255372 SNP of TCF7L2 and D76N of PDX-1 genes may confer susceptibility to T2DM in the population living in Mashhad. PMID- 26058935 TI - Capsule Endoscopy in Inflammatory Bowel Disease: Current Applications. AB - Since its introduction to clinical practice in 2001, small-bowel capsule endoscopy (SBCE) has become an important investigation procedure in many small bowel pathologies, including both suspected and known Crohn's disease (CD). SBCE has higher diagnostic yield than other radiologic and endoscopic modalities used in evaluation of patients with suspected CD. In addition, SBCE has proved useful, in a non-invasive and safe manner, as a monitoring method for evaluating the severity and extent of lesions, postoperative recurrence, and mucosal healing in patients with known CD. Monitoring of colonic inflammation in patients with ulcerative colitis (UC) using second-generation of colon capsule endoscopy (CCE 2) has also been reported. Besides its advantages, CE also has several limitations such as the inability to obtain biopsies and lack of therapeutic capabilities, hopefully to be overcome in the near future by advances in modern technologies. PMID- 26058936 TI - Acute Esophageal Necrosis: A Case of Black Esophagus with DKA. AB - Acute esophageal necrosis is a rare cause of upper gastrointestinal bleeding, usually caused by hypoperfusion. In this report, we present a 34-year-old male patient suffering from acute esophageal necrosis presenting as hematemesis in a patient with Diabetic ketoacidosis. Diabetic ketoacidosis is rarely reported as a cause of acute esophageal necrosis and it is vital to diagnose it in a patient with Diabetic Ketoacidosis as a potential cause of mortality. PMID- 26058937 TI - Neonatal Testicular Hemangiolymphangioma: A Case Report. AB - A 30-day-old neonate was brought to our hospital due to testicular neoplasm in the right scrotum. Scrotal ultrasonography revealed a mixed cystic and solid mass in the testis. Analysis of testicular tumor markers was negative. Scrotal exploration was performed. A red nodular tumor was removed from the testis by surgery. Histological examination of the specimen showed it to be hemangiolymphangioma (HLA). PMID- 26058938 TI - Interventional Therapy for Infective Pseudoaneurysm is a Hope for a Patient in an Undeveloped Area. AB - Patient, a 59-year-old male coming from an undeveloped area of Sichuan Province, China, was admitted because of chest pain for one month. Compute tomography angiography showed descending aorta pseudoaneurysm at the level of the 6th thoracic vertebra (T6). History of bone tuberculosis and tuberculosis DNA test had confirmed diagnosis of tuberculosis. Interventional surgery was performed 3 days after admission. A covered stent (Medtronic TF 3030C200EE) was deployed slowly and accurately. Digital subtraction angiography showed that the pseudoaneurysm was isolated successfully and completely. The chest pain syndrome was relieved considerably. On the day after surgery, the patient was discharged. Fourteen months later, a recent CT revealed that the stent was in the right place and fluent and no infective clue was detected. The patient did not have any discomfort. Interventional therapy for infective pseudoaneurysm still has long promising prognosis. At the same time, anti-infection therapy is also essential. PMID- 26058939 TI - Photoclinic. PMID- 26058940 TI - The History of the Foundation of the Iranian National Blood Transfusion Service in 1974 and the Biography of its Founder; Professor Fereydoun Ala. AB - The history of early attempts of blood transfusion in Iran traces back to the 1940s; however, around three decades later in 1974, the Iranian National Blood Transfusion Service (Sazeman-e Melli-e Enteqal-e Khun-e Iran) was founded by the outstanding hematologist, Professor Fereydoun Ala. The main goals of this centralized organization were to collect blood from healthy voluntary donors, to screen the donated blood and to provide various safe blood products based on scientific and ethical standards. In due course, a new era of blood transfusion service in Iran had begun to such a degree that after more than four decades of its activity, it is now considered the best-developed blood service in the eastern Mediterranean region. Here, a brief historical account of the early blood transfusion efforts and the establishment of the modern Iranian National Blood Transfusion Service in Iran is discussed in addition to the life and career of its founder and first director, Professor Fereydoun Ala. PMID- 26058941 TI - Is anti-factor Xa chromogenic assay for Rivaroxaban appropriate in clinical practice? Advantages and comparative drawbacks. AB - INTRODUCTION: No routine monitoring is required with factor Xa inhibitor rivaroxaban. Yet, its titration must be adapted, and its misuse may lead to increased risk of bleeding; therefore, therapeutic rivaroxaban monitoring might help in specific situations. MATERIAL AND METHODS: As asked by clinicians of our medical center, we measured rivaroxaban plasma concentrations in real conditions of use and checked their corresponding prescriptions. Measurement of 112 samples from 94 consecutive patients was performed with a Biophen LRT(r) anti-Xa chromogenic assay and compared blindly to the HPLC-MSMS "gold standard" method. Rivaroxaban was effectively given to 80 out of 94 patients but a mere 57% through an adequate prescription (within the scope of indications/titration). All chromogenic measurements were over the pre-specified 30ng/ml LOQ, whereas only 98 /114 samples had quantifiable rivaroxaban with HPLC-MSMS (LOQ 1ng/ml). Correlation between the two methods and linear regression were highly significant (p<0.0001). However, chromogenic values (mean 141.6ng/ml[96.6]) overestimated HPLC-MSMS values (119.7ng/ml[79.5]) by 22ng/ml according to Bland-Altman analysis (p<0.001). After re-assessing the chromogenic LOQ at 52ng/ml, 83 quantifiable samples had a mean concentration of 176.9ng/ml as compared to 158.5ng/ml with HPLC-MSMS, with no false positive anymore. CONCLUSIONS: In our medical center, rivaroxaban concentrations could be assessed by a rapid chromogenic method. Its pre-specified LOQ proved too high after being checked "on site" against HPLC MSMS. Prescriptions for rivaroxaban were not optimal. An overestimated LOQ may impair observance monitoring or predispose patients to either risky thrombolysis or otherwise adjournable surgery in clinical practice. PMID- 26058942 TI - In vitro thromboelastometric evaluation of the efficacy of frozen platelet transfusion. AB - BACKGROUND: Although frozen platelets are extensively used in remote locations and military environments, scientific evidence of their efficacy is scarce. The objective of this study was to evaluate the in vitro hemostatic efficacy of frozen versus fresh platelet transfusions by rotational thromboelastometry (ROTEM) to ascertain whether the freezing and thawing process impaired platelet contribution to clot strength. METHODS: An experimental study was performed using platelet in vitro transfusions. Blood samples were collected from 12 patients with non-autoimmune thrombocytopenia. The samples were each transfused with one of 6 pairs of fresh platelet concentrates and platelet concentrates frozen with dimethylsulfoxyde. Optical platelet counts, coagulation studies and ROTEM (EXTEM and FIBTEM) were performed for the baseline and the post-transfusion samples. RESULTS: Only fresh platelet transfusions significantly increased the EXTEM maximum clot firmness (MCF) and maximum clot elasticity (MCE) over baseline (p<0.001), achieving values within the normal range. The frozen platelet contribution to MCE was negligible. However, the EXTEM clotting time (CT) was significantly (p<0.001) shorter after the frozen platelet transfusion compared with the fresh platelet transfusion. The EXTEM clot formation time (CFT) was significantly shortened after the transfusion of fresh platelets (p=0.002). CONCLUSION: The ROTEM analysis assessment indicates a dual effect in frozen platelet transfusion: it produces a hypercoagulable state (shortening of CT), and a second, more predominant effect of frozen platelets' functionality impairment compared with fresh platelets (shorter MCF/MCE and longer CFT). PMID- 26058943 TI - NADPH oxidase-derived production of reactive oxygen species is involved in learning and memory impairments in 16-month-old female rats. AB - Women undergoing the natural menopause can experience progressive cognitive dysfunction, particularly in the form of memory impairment. However, the mechanisms underlying memory impairments in the menopause remain to be elucidated. There is increasing evidence that oxidative damage caused by excessive reactive oxygen species (ROS) production may correlate with age associated cognitive impairment. The nicotinamide adenosine dinucleotide phosphate oxidase (NOX) family is important in the generation of ROS in the brain. It has been hypothesized that the accumulation of ROS, derived from NOX, may be involved in menopause-associated learning and memory impairments. The present study investigated whether NOX-derived ROS generation affected the learning and memory ability in 3-month and 16-month-old female rats. The results of a morris water maze assessment revealed that there were significant learning and memory impairments in the 16-month-old female rats. Furthermore, the activity of superoxide dismutase (SOD), level of malondialdehyde (MDA), production of ROS and expression levels of NOX2, p47phox, Ras-related C3 botulinum toxin substrate 1 (RAC1) and protein kinase C alpha (PKCalpha) were investigated in the cortex and hippocampus of 3-month and 16-month old female rats. The results demonstrated that the activity of SOD was significantly decreased, whereas the levels of MDA, production of ROS and expression levels of NOX2, p47phox, RAC1 and PKCalpha were significantly increased in the 16-month old female rats. These results suggested that NOX-mediated oxidative stress may be important in menopause-associated learning and memory impairments. PMID- 26058944 TI - TargetFreeze: Identifying Antifreeze Proteins via a Combination of Weights using Sequence Evolutionary Information and Pseudo Amino Acid Composition. AB - Antifreeze proteins (AFPs) are indispensable for living organisms to survive in an extremely cold environment and have a variety of potential biotechnological applications. The accurate prediction of antifreeze proteins has become an important issue and is urgently needed. Although considerable progress has been made, AFP prediction is still a challenging problem due to the diversity of species. In this study, we proposed a new sequence-based AFP predictor, called TargetFreeze. TargetFreeze utilizes an enhanced feature representation method that weightedly combines multiple protein features and takes the powerful support vector machine as the prediction engine. Computer experiments on benchmark datasets demonstrate the superiority of the proposed TargetFreeze over most recently released AFP predictors. We also implemented a user-friendly web server, which is openly accessible for academic use and is available at http://csbio.njust.edu.cn/bioinf/TargetFreeze. TargetFreeze supplements existing AFP predictors and will have potential applications in AFP-related biotechnology fields. PMID- 26058945 TI - Antibody-Drug Conjugate (ADC) Research in Ophthalmology--a Review. AB - Similar to cancer, many ocular proliferative disorders could be treated with a specific antibody conjugated to a toxin. Active targeting to inhibit epithelial and endothelial cell proliferation in the eye has been tested using antibody-drug conjugates (ADC) both pre-clinically and clinically. Achieving efficacious drug concentrations in the eye, in particular to treat back of the eye disorders is challenging, and the promise of targeted antibody mediated delivery holds great potential. In this review, we describe the research efforts in drug targeting using ADC for the treatment of choroidal neovascularization (CNV), posterior lens capsule opacification, and proliferative vitreoretinopathy. Among these disorders, CNV represents a more active research focus, with more target antigens tested, given the disease prevalence and wider target antigen selection based on current understanding of the pathophysiology of the disease. However, the only research advancing to testing in clinical stage is for posterior lens capsule opacification. Compared to oncology, ADC research and development in ophthalmology is much more limited, possibly due to availability of successful therapies that could be administered locally with limited concern of off-target drug toxicity. PMID- 26058946 TI - Effects of Maillard reaction on flavor and safety of Chinese traditional food: roast duck. AB - BACKGROUND: Roast duck is one kind of representative roast food whose flavor is mainly produced by the Maillard reaction. However, some potentially toxic compounds are generated in the thermal process and are a potential health risk. The aim of this work was to analyze the effects of the Maillard reaction on flavor and safety of a Chinese traditional food: roast duck. RESULTS: Ducks with different roasting times (0, 10, 20, 30, 40, 50 and 60 min) were analyzed. The 40 and 50 min roast ducks exhibited an acceptable degree of sensory attributes, but the 60 min roast duck showed the most abundant aroma compounds. Antioxidant activities were observed to increase with roasting, and the 60 min roast duck showed the highest antioxidant activities (1,1-diphenylpicryhydrazyl, 39.3 umol Trolox g(-1) sample). The highest content of acrylamide (0.21 ug g(-1)) and 5 hydroxymethylfurfural (0.089 ug g(-1)) were detected in the 50 and 60 min roast duck extract, respectively. Furthermore, water extract from 60 min roast ducks manifested a higher lactose dehydrogenase release ratio (51.9%) and greatly increased cell apoptosis. CONCLUSION: The drastic Maillard reaction in duck induced by long roasting time could be advantageous for color, aroma and antioxidant activities in roast ducks, but might be not beneficial to health. PMID- 26058947 TI - Preoperative Detection and Intraoperative Visualization of Brain Tumors for More Precise Surgery: A New Dual-Modality MRI and NIR Nanoprobe. AB - In clinical practice, it is difficult to identify tumor margins during brain surgery due to its inherent infiltrative character. Herein, a unique dual modality nanoprobe (Gd-DOTA-Ag2S QDs, referred as Gd-Ag2S nanoprobe) is reported, which integrates advantages of the deep tissue penetration of enhanced magnetic resonance (MR) imaging of Gd and the high signal-to-noise ratio and high spatiotemporal resolution of fluorescence imaging in the second near-infrared window (NIR-II) of Ag2S quantum dots (QDs). Due to the abundant tumor angiogenesis and the enhanced permeability and retention effect in the tumor, a brain tumor (U87MG) in a mouse model is clearly delineated in situ with the help of the Gd assisted T1 MR imaging and the intraoperative resection of the tumor is precisely accomplished under the guidance of NIR-II fluorescence imaging of Ag2S QDs after intravenous injection of Gd-Ag2S nanoprobe. Additionally, no histologic changes are observed in the main organs of the mouse after administration of Gd Ag2S nanoprobe for 1 month, indicating the high biocompatibility of the nanoprobe. We expect that such a novel "Detection and Operation" strategy based on Gd-Ag2S nanoprobe is promising in future clinical applications. PMID- 26058948 TI - Metabolic engineering of sugarcane to accumulate energy-dense triacylglycerols in vegetative biomass. AB - Elevating the lipid content in vegetative tissues has emerged as a new strategy for increasing energy density and biofuel yield of crops. Storage lipids in contrast to structural and signaling lipids are mainly composed of glycerol esters of fatty acids, also known as triacylglycerol (TAG). TAGs are one of the most energy-rich and abundant forms of reduced carbon available in nature. Therefore, altering the carbon-partitioning balance in favour of TAG in vegetative tissues of sugarcane, one of the highest yielding biomass crops, is expected to drastically increase energy yields. Here we report metabolic engineering to elevate TAG accumulation in vegetative tissues of sugarcane. Constitutive co-expression of WRINKLED1 (WRI1), diacylglycerol acyltransferase1-2 (DGAT1-2) and oleosin1 (OLE1) and simultaneous cosuppression of ADP-glucose pyrophosphorylase (AGPase) and a subunit of the peroxisomal ABC transporter1 (PXA1) in transgenic sugarcane elevated TAG accumulation in leaves or stems by 95 or 43-fold to 1.9% or 0.9% of dry weight (DW), respectively, while expression or suppression of one to three of the target genes increased TAG levels by 1.5- to 9.5-fold. Accumulation of TAG in vegetative progeny plants was consistent with the results from primary transgenics and contributed to a total fatty acid content of up to 4.7% or 1.7% of DW in mature leaves or stems, respectively. Lipid droplets were visible within mesophyll cells of transgenic leaves by confocal fluorescence microscopy. These results provide the basis for optimizations of TAG accumulation in sugarcane and other high yielding biomass grasses and will open new prospects for biofuel applications. PMID- 26058949 TI - Catalyst-free direct decarboxylative coupling of alpha-keto acids with thiols: a facile access to thioesters. AB - A novel, efficient, and catalyst-free strategy has been initially developed for the construction of thioesters via the direct radical oxidative decarboxylation of alpha-keto acids with thiols, and the corresponding target products were obtained in moderate to good yields. It offers an alternative approach for the synthesis of useful diverse thioesters. PMID- 26058950 TI - Rapid and mild purification method for nanoparticles from a dispersed solution using a monolithic silica disk. AB - A rapid and mild purification method for nanoparticles using the commercially available monolithic silica disk, MonoSpin((r)), was developed. The nanoparticles were purified from a dispersed solution by filtration with the aid of centrifugation at 2290*g for 2min. The purification conditions were rapid, mild, and simple compared with those of the conventional purification methods such as ultracentrifugation, dialysis, size exclusion chromatography, and ultrafiltration. The method was shown to be applicable for the purification of various nanoparticles, regardless of their size (from 21 to 100nm), composition material (silica, polyethylene glycol, and pegylated liposome), and encapsulated molecule (rhodamine 110 and doxorubicin). It was shown that this method is applicable to the purification of a wide range of nanoparticles in many different fields. PMID- 26058951 TI - Evaluation of reversible interconversion in comprehensive two-dimensional gas chromatography using enantioselective columns in first and second dimensions. AB - The reversible molecular interconversion behaviour of a synthesised oxime (2 phenylpropanaldehyde oxime; (C6H5)CH(CH3)CHN(OH)) was investigated by both, single dimensional gas chromatography (1D GC) and comprehensive two-dimensional gas chromatography (GC*GC). Previous studies on small molecular weight oximes were extended to this larger aromatic oxime (molar mass 149.19gmol(-1)) with interest in the extent of interconversion, enantioselective resolution, and retention time. On a polyethylene glycol (PEG; wax-type) column, a characteristic interconversion zone between two antipodes of E and Z isomers was formed by molecules which have undergone isomerisation on the column (E?Z). The extent of interconversion was investigated by varying chromatographic conditions (oven temperature and carrier flow rate) to understand the nature of the behaviour observed. The extent of interconversion was negligible in both enantioselective and methyl-phenylpolysiloxane phase-columns, correlating with the low polarity of the stationary phase. In order to obtain isomerisation along with enantio resolution, a wax-type and an enantioselective column were coupled in either enantioselective-wax or wax-enantioselective order. The most appropriate column arrangement was selected for study by using a GC*GC experiment with either a wax phase or phenyl-methylpolysiloxane phase as (2)D column. In addition to evaluation of these fast elution columns, a long narrow-bore enantioselective column (10m) was introduced as (2)D, providing an enantioselective-PEG (coupled column ensemble: (1)D1+(1)D2)*enantioselective ((2)D) column combination. In this instance, the (1)D1 enantioselective column provides enantiomeric separation of the corresponding enantiomers ((R) and (S)) of (E)- and (Z)-2 phenylpropanaldehyde oxime, followed by E/Z isomerisation in the coupled (1)D2 PEG (reactor) column. The resulting chromatographic interconversion region was modulated and separated into either E/Z isomers (achiral (2)D column) or into the respective (R) and (S) enantiomers of the E/Z isomers when using a (2)D enantioselective column. With this arrangement, the isomers underneath the broad interconversion plateau in 1D elution profiles, including the enantiomers, could be resolved, illuminating salient features and understanding of the molecular reversible process of the interconverting molecules during the chromatographic elution. The two-dimensional patterns (contour plots), resulting from the combination of interconversion process and chiral separation, are discussed phenomenologically. PMID- 26058952 TI - CCR1, an enzyme required for lignin biosynthesis in Arabidopsis, mediates cell proliferation exit for leaf development. AB - After initiation, leaves first undergo rapid cell proliferation. During subsequent development, leaf cells gradually exit the proliferation phase and enter the expansion stage, following a basipetally ordered pattern starting at the leaf tip. The molecular mechanism directing this pattern of leaf development is as yet poorly understood. By genetic screening and characterization of Arabidopsis mutants defective in exit from cell proliferation, we show that the product of the CINNAMOYL CoA REDUCTASE (CCR1) gene, which is required for lignin biosynthesis, participates in the process of cell proliferation exit in leaves. CCR1 is expressed basipetally in the leaf, and ccr1 mutants exhibited multiple abnormalities, including increased cell proliferation. The ccr1 phenotypes are not due to the reduced lignin content, but instead are due to the dramatically increased level of ferulic acid (FeA), an intermediate in lignin biosynthesis. FeA is known to have antioxidant activity, and the levels of reactive oxygen species (ROS) in ccr1 were markedly reduced. We also characterized another double mutant in CAFFEIC ACID O-METHYLTRANSFERASE (comt) and CAFFEOYL CoA 3-O METHYLTRANSFERASE (ccoaomt), in which the FeA level was dramatically reduced. Cell proliferation in comt ccoaomt leaves was decreased, accompanied by elevated ROS levels, and the mutant phenotypes were partially rescued by treatment with FeA or another antioxidant (N-acetyl-L-cysteine). Taken together, our results suggest that CCR1, FeA and ROS coordinate cell proliferation exit in normal leaf development. PMID- 26058953 TI - A systematic analysis of TCA Escherichia coli mutants reveals suitable genetic backgrounds for enhanced hydrogen and ethanol production using glycerol as main carbon source. AB - Biodiesel has emerged as an environmentally friendly alternative to fossil fuels; however, the low price of glycerol feed-stocks generated from the biodiesel industry has become a burden to this industry. A feasible alternative is the microbial biotransformation of waste glycerol to hydrogen and ethanol. Escherichia coli, a microorganism commonly used for metabolic engineering, is able to biotransform glycerol into these products. Nevertheless, the wild type strain yields can be improved by rewiring the carbon flux to the desired products by genetic engineering. Due to the importance of the central carbon metabolism in hydrogen and ethanol synthesis, E. coli single null mutant strains for enzymes of the TCA cycle and other related reactions were studied in this work. These strains were grown anaerobically in a glycerol-based medium and the concentrations of ethanol, glycerol, succinate and hydrogen were analysed by HPLC and GC. It was found that the reductive branch is the more relevant pathway for the aim of this work, with malate playing a central role. It was also found that the putative C4-transporter dcuD mutant improved the target product yields. These results will contribute to reveal novel metabolic engineering strategies for improving hydrogen and ethanol production by E. coli. PMID- 26058954 TI - A rare cause of infertility: intratesticular varicocele associated with ipsilateral extratesticular varicocele. AB - Intratesticular varicocele is an uncommon condition with variable sonographic appearence and identified as dilated intratesticular veins lying from the mediastinum through testicular parenchyma. We present a case of a 20-year-old male, married and unable to conceive for 2 years. Routine scrotal sonography disclosed extratesticular varicocele which was associated with ipsilateral intratesticular varicocele. Colour Doppler ultrasonography should be the first choice modality of imaging to confirm the diagnosis. Detection of intratesticular varicocele is essential because it is one of the most common recoverable reasons of male infertility. PMID- 26058955 TI - Assessment of TREM2 rs75932628 association with Parkinson's disease and multiple system atrophy in a Chinese population. AB - Although rs75932628 in triggering receptor expressed on myeloid cells 2 (TREM2) was shown to increase the risk for Alzheimer's disease, there is no agreement on the association between this variant and the risk for Parkinson's disease (PD). Considering the overlapping of clinical manifestation and pathologic characteristics of PD and multiple system atrophy (MSA), we conducted a large sample study to investigate the associations between this variant and these two neurodegenerative diseases in a Chinese population. A total of 1216 PD, 406 MSA patients, and 869 healthy controls were included. All cases were genotyped for the Single Nucleotide Polymorphisms (SNP) using Sequenom iPLEX Assay technology. The rs75932628-T variant of the TREM2 gene was not identified in PD patients and controls. The genotype frequency of rs75932628-T SNP in MSA patients was 0.25% (1/406). However, no significant correlation was identified between this variant and the risk for MSA. TREM2 rs75932628 is unlikely to play a major role in the pathogenesis of these neurodegenerative diseases. Our findings argue against a generalized immune dysfunction triggered by the variant in the TREM2 gene. PMID- 26058956 TI - An anti-GAD autoantibody-associated cerebellar syndrome case: a curable cause of ataxia. PMID- 26058957 TI - Reply to Pascal Mouracade's letter to the editor re: R. Houston Thompson, Tom Atwell, Grant Schmit, et al. Comparison of partial nephrectomy and percutaneous ablation for cT1 renal masses. Eur Urol 2015;67:252-9. PMID- 26058958 TI - Are we targeting the right outcome for sexual health after prostate cancer treatment? AB - Satisfaction with sex life is a patient-centered, attainable sexual health outcome after prostate cancer treatment. Its achievement combines the necessary components of erectile dysfunction prevention and treatment and reliance on patients' and partners' psychosocial strengths, regardless of either partner's sexual function. PMID- 26058959 TI - Tissue-based Genomics Augments Post-prostatectomy Risk Stratification in a Natural History Cohort of Intermediate- and High-Risk Men. AB - BACKGROUND: Radical prostatectomy (RP) is a primary treatment option for men with intermediate- and high-risk prostate cancer. Although many are effectively cured with local therapy alone, these men are by definition at higher risk of adverse pathologic features and clinical disease recurrence. It has been shown that the Decipher test predicts metastatic progression in cohorts that received adjuvant and salvage therapy following RP. OBJECTIVE: To evaluate the Decipher genomic classifier in a natural history cohort of men at risk who received no additional treatment until the time of metastatic progression. DESIGN, SETTING, AND PARTICIPANTS: Retrospective case-cohort design for 356 men who underwent RP between 1992 and 2010 at intermediate or high risk and received no additional treatment until the time of metastasis. Participants met the following criteria: (1) Cancer of the Prostate Risk Assessment postsurgical (CAPRA-S) score >=3; (2) pathologic Gleason score >=7; and (3) post-RP prostate-specific antigen nadir <0.2 ng/ml. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was defined as regional or distant metastases. Time-dependent receiver operating characteristic (ROC) curves, extension of decision curve analysis to survival data, and univariable and multivariable Cox proportional-hazards models were used to measure the discrimination, net benefit, and prognostic potential of genomic and pathologic risk factors. Cumulative incidence curves were constructed using Fine-Gray competing-risks analysis with appropriate weighting of the controls to account for the case-cohort study design. RESULTS AND LIMITATIONS: Ninety six patients had unavailable tumor blocks or failed microarray quality control. Decipher scores were then obtained for 260 patients, of whom 99 experienced metastasis. Decipher correlated with increased cumulative incidence of biochemical recurrence, metastasis, and prostate cancer-specific mortality (p<0.01). The cumulative incidence of metastasis was 12% and 47% for patients with low and high Decipher scores, respectively, at 10 yr after RP. Decipher was independently prognostic of metastasis in multivariable analysis (hazard ratio 1.26 per 10% increase; p<0.01). Decipher had a c-index of 0.76 and increased the c-index of Eggener and CAPRA-S risk models from 0.76 and 0.77 to 0.86 and 0.87, respectively, at 10 yr after RP. Although the cohort was large, the single-center retrospective design is an important limitation. CONCLUSIONS: In a patient population that received no adjuvant or salvage therapy after prostatectomy until metastatic progression, higher Decipher scores correlated with clinical events, and inclusion of Decipher scores improved the prognostic performance of validated clinicopathologic risk models. These results confirm the utility already reported for Decipher. PATIENT SUMMARY: The Decipher test improves identification of patients most at risk of metastatic progression and death from prostate cancer after radical prostatectomy. PMID- 26058960 TI - 4-Phenylphenalenones as a template for new photodynamic compounds against Mycosphaerella fijiensis. AB - BACKGROUND: Evaluation of 4-phenylphenalenones and structural analogues against the fungal pathogen Mycosphaerella fijiensis (causal agent of black sigatoka disease in bananas) under light-controlled conditions uncovered some key structural features for the design of photodynamic compounds. RESULTS: Structure activity relationship analysis revealed the importance of a chromophoric aryl ketone and a steroidomimetic structural motif in the activity of the assayed compounds. The results pointed to 1,2-dihydro-3H-naphtho[2',1':3,4]cyclohepta[1,2 b]furan-3-one, which displayed an activity in the range of propiconazole but with photodynamic behaviour. CONCLUSION: The present work demonstrates that 1,2 dihydro-3H-naphtho[2',1':3,4]cyclohepta[1,2-b]heterocyclic-3-one derivatives can be used as potential lead compounds for the development of fungicides, relying on a dual mode of action. (c) 2015 Society of Chemical Industry. PMID- 26058961 TI - MAPK8-mediated stabilization of SP1 is essential for RUNX1-RUNX1T1 - driven leukaemia. PMID- 26058962 TI - Taxane-containing regimens for metastatic breast cancer. AB - BACKGROUND: It is generally accepted that taxanes are among the most active chemotherapy agents in the management of metastatic breast cancer. This is an update of a Cochrane review first published in 2003. OBJECTIVES: The objective of this review was to compare taxane-containing chemotherapy regimens with regimens not containing a taxane in the management of women with metastatic breast cancer. SEARCH METHODS: In this review update, we searched the Cochrane Breast Cancer Group Specialised Register, MEDLINE, EMBASE, the World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 14 February 2013 using keywords such as 'advanced breast cancer' and 'chemotherapy'. We searched reference lists of articles, contacted study authors, and did not apply any language restrictions. SELECTION CRITERIA: Randomised controlled trials comparing taxane-containing chemotherapy regimens to regimens without taxanes in women with metastatic breast cancer. We included published and unpublished studies. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We derived hazard ratios (HRs) for overall survival, time to progression, and time to treatment failure where possible, and used a fixed-effect model for meta analysis. We represented objective tumour response rates and toxicity as risk ratios (RRs). We extracted quality of life data where present. MAIN RESULTS: This review included 28 studies. The updated analysis included 6871 randomised women, while the original review had 3643 women. Of the 28 included studies, we considered 19 studies to be at low risk of bias overall; however, some studies failed to report details on allocation concealment and methods of outcome assessment for those outcomes that are more likely to be influenced by a lack of blinding (for example tumour response rate). Studies varied in the taxane containing chemotherapy backbone, and the comparator arms and were categorised into three groups: Regimen A plus taxane versus Regimen A (2 studies); Regimen A plus taxane versus Regimen B (14 studies); and single-agent taxane versus Regimen C (13 studies). Thirteen studies used paclitaxel, 14 studies used docetaxel, and 1 study allowed the investigator to decide on the type of taxane; the majority of studies delivered a taxane every 3 weeks. Twenty studies administered taxanes as first-line treatment, and 21 studies involved anthracycline naive women in the metastatic setting. The combined HR for overall survival and time to progression favoured the taxane-containing regimens (HR 0.93, 95% confidence interval (CI) 0.88 to 0.99, P = 0.002, deaths = 4477; and HR 0.92, 95% CI 0.87 to 0.97, P = 0.002, estimated 5122 events, respectively) with moderate to substantial heterogeneity across trials. If the analyses were restricted to studies of first line chemotherapy, this effect persisted for overall survival (HR 0.93, 95% CI 0.87 to 0.99, P = 0.03) but not for time to progression (HR 0.96, 95% CI 0.90 to 1.02, P = 0.22). Tumour response rates appeared to be better with taxane containing chemotherapy in assessable women (RR 1.20, 95% CI 1.14 to 1.27, P < 0.00001) with substantial heterogeneity across studies. Taxanes were associated with an increased risk of neurotoxicity (RR 4.84, 95% CI 3.18 to 7.35, P < 0.00001, 24 studies) and hair loss (RR 2.37, 95% CI 1.45 to 3.87, P = 0.0006, 11 studies) but less nausea/vomiting compared to non-taxane-containing regimens (RR 0.62, 95% CI 0.46 to 0.83, P = 0.001, 26 studies). Leukopaenia and treatment related death did not differ between the two groups (RR 1.07, 95% CI 0.97 to 1.17, P = 0.16, 28 studies; and RR 1.00, 95% CI 0.63 to 1.57, P = 0.99, 23 studies, respectively). For quality of life measures, none of the individual studies reported a difference in overall or any of quality of life subscales between taxane-containing and non-taxane chemotherapy regimens. AUTHORS' CONCLUSIONS: Taxane-containing regimens appear to improve overall survival, time to progression, and tumour response rate in women with metastatic breast cancer. Taxanes are also associated with an increased risk of neurotoxicity but less nausea and vomiting compared to non-taxane-containing regimens. The considerable heterogeneity encountered across studies probably reflects the varying efficacy of the comparator regimens used in these studies and indicates that taxane containing regimens are more effective than some, but not all, non-taxane containing regimens. PMID- 26058963 TI - Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy. AB - BACKGROUND: With improvements in neonatal intensive care, more preterm infants are surviving the neonatal period and presenting for surgery in early infancy. Inguinal hernia is the most common condition requiring early surgery, appearing in 38% of infants whose birth weight is between 751 grams and 1000 grams. Approximately 20% to 30% of otherwise healthy preterm infants having general anaesthesia for inguinal hernia surgery at a postmature age have at least one apnoeic episode within the postoperative period. Research studies have failed to adequately distinguish the effects of apnoeic episodes from other complications of extreme preterm gestation on the risk of brain injury, or to investigate the potential impact of postoperative apnoea upon longer term neurodevelopment. In addition to episodes of apnoea, there are concerns that anaesthetic and sedative agents may have a direct toxic effect on the developing brain of preterm infants even after reaching postmature age. It is proposed that regional anaesthesia may reduce the risk of postoperative apnoea, avoid the risk of anaesthetic-related neurotoxicity and improve neurodevelopmental outcomes in preterm infants requiring surgery for inguinal hernia at a postmature age. OBJECTIVES: To determine if regional anaesthesia reduces postoperative apnoea, bradycardia, the use of assisted ventilation, and neurological impairment, in comparison to general anaesthesia, in preterm infants undergoing inguinal herniorrhaphy at a postmature age. SEARCH METHODS: The following databases and resources were searched: the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2015, Issue 2), MEDLINE (December 2002 to 25 February 2015), EMBASE (December 2002 to 25 February 2015), controlled-trials.com and clinicaltrials.gov, reference lists of published trials and abstracts published in Pediatric Research and Pediatric Anesthesia. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of regional (spinal, epidural, caudal) versus general anaesthesia, or combined regional and general anaesthesia, in former preterm infants undergoing inguinal herniorrhaphy in early infancy. DATA COLLECTION AND ANALYSIS: At least two of three review authors (LJ, JF, AL) independently extracted data and performed analyses. Authors were contacted to obtain missing data. The methodological quality of each study was assessed according to the criteria of the Cochrane Neonatal Review Group. Data were analysed using Review Manager 5. Meta-analyses were performed with calculation of risk ratios (RR) and risk difference (RD), along with their 95% confidence intervals (CI) where appropriate. MAIN RESULTS: Seven small trials comparing spinal with general anaesthesia in the repair of inguinal hernia were identified. Two trial reports are listed as 'Studies awaiting classification' due to insufficient information on which to base an eligibility assessment. There was no statistically significant difference in the risk of postoperative apnoea/bradycardia (typical RR 0.72, 95% CI 0.48 to 1.06; 4 studies, 138 infants), postoperative oxygen desaturation (typical RR 0.82, 95% CI 0.61 to 1.11; 2 studies, 48 infants), the use of postoperative analgesics (RR 0.42, 95% CI 0.15 to 1.18; 1 study, 44 infants), or postoperative respiratory support (typical RR 0.09, 95% CI 0.01 to1.64; 3 studies, 98 infants) between infants receiving spinal or general anaesthesia. When infants who had received preoperative sedatives were excluded, the meta-analysis supported a reduction in the risk of postoperative apnoea in the spinal anaesthesia group (typical RR 0.53, 95% CI 0.34 to 0.82; 4 studies, 129 infants). Infants with no history of apnoea in the preoperative period and receiving spinal anaesthesia (including a subset of infants who had received sedatives) had a reduced risk of postoperative apnoea and this reached statistical significance (typical RR 0.34, 95% CI 0.14 to 0.81; 4 studies, 134 infants). Infants receiving spinal rather than general anaesthesia had a statistically significant increased risk of anaesthetic agent failure (typical RR 7.83, 95% CI 1.51 to 40.58; 3 studies, 92 infants). Infants randomised to receive spinal anaesthesia had an increased risk of anaesthetic placement failure of borderline statistical significance (typical RR 7.38, 95% CI 0.98 to 55.52; typical RD 0.15, 95% CI 0.03 to 0.27; 3 studies, 90 infants). AUTHORS' CONCLUSIONS: There is moderate-quality evidence to suggest that the administration of spinal in preference to general anaesthesia without pre- or intraoperative sedative administration may reduce the risk of postoperative apnoea by up to 47% in preterm infants undergoing inguinal herniorrhaphy at a postmature age. For every four infants treated with spinal anaesthesia, one infant may be prevented from having an episode of postoperative apnoea (NNTB=4). In those infants without preoperative apnoea, there is low-quality evidence that spinal rather than general anaesthesia may reduce the risk of preoperative apnoea by up to 66%. There was no difference in the effect of spinal compared with general anaesthesia on the overall incidence of postoperative apnoea, bradycardia, oxygen desaturation, need for postoperative analgesics or respiratory support. Limitations on these results included varying use of sedative agents, or different anaesthetic agents, or combinations of these factors, in addition to trial quality aspects such as allocation concealment and inadequate blinding of intervention and outcome assessment. The meta-analyses may have inadequate power to detect a difference between groups for some outcomes, with estimates of effect based on a total population of fewer than 140 infants.The effect of newer, rapidly acting, quickly metabolised general anaesthetic agents on safety with regard to the risk of postoperative apnoea and neurotoxic exposure has not so far been established in randomised trials. There is potential for harm from postoperative apnoea and direct brain toxicity from general anaesthetic agents superimposed upon pre-existing altered brain development in infants born at very to extreme preterm gestation. This highlights the clear need for the examination of neurodevelopmental outcomes in the context of large randomised controlled trials of general, compared with spinal, anaesthesia, in former preterm infants undergoing surgery for inguinal hernia.There is a particular need to examine the impact of the choice of spinal over general anaesthesia on respiratory and neurological outcomes in high-risk infant subgroups with severe respiratory disease and previous brain injury. PMID- 26058964 TI - Vitamin K for upper gastrointestinal bleeding in people with acute or chronic liver diseases. AB - BACKGROUND: Upper gastrointestinal bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. Several treatments are used for upper gastrointestinal bleeding in people with liver diseases. One of them is vitamin K administration, but it is not known whether it benefits or harms people with acute or chronic liver disease and upper gastrointestinal bleeding. This is an update of this Cochrane review. OBJECTIVES: To assess the beneficial and harmful effects of vitamin K for people with acute or chronic liver disease and upper gastrointestinal bleeding. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Controlled Trials Register (February 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2 of 12, 2015), MEDLINE (Ovid SP) (1946 to February 2015), EMBASE (Ovid SP) (1974 to February 2015), Science Citation Index EXPANDED (1900 to February 2015), and LILACS (1982 to 25 February 2015). We sought additional randomised trials from two registries of clinical trials: the World Health Organization Clinical Trials Search Portal and the metaRegister of Controlled Trials. We looked through the reference lists of the retrieved publications and review articles. SELECTION CRITERIA: Randomised clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms. We considered observational studies for assessment of harms only. DATA COLLECTION AND ANALYSIS: ?We aimed to summarise data from randomised clinical trials using Standard Cochrane methodology and assess them according to the GRADE approach. MAIN RESULTS: We found no randomised trials on vitamin K for upper gastrointestinal bleeding in people with liver diseases assessing benefits and harms of the intervention. We identified no quasi randomised studies, historically controlled studies, or observational studies assessing harms. AUTHORS' CONCLUSIONS: This updated review found no randomised clinical trials of vitamin K for upper gastrointestinal bleeding in people with liver diseases. The benefits and harms of vitamin K need to be tested in randomised clinical trials. Until randomised clinical trials are conducted to assess the trade-off between benefits and harms, we cannot recommend or refute the use of vitamin K for upper gastrointestinal bleeding in people with liver diseases. PMID- 26058965 TI - Antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or chronic liver disease. AB - BACKGROUND: Upper gastrointestinal bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. People with liver disease frequently have haemostatic abnormalities such as hyperfibrinolysis. Therefore, antifibrinolytic amino acids have been proposed to be used as supplementary interventions alongside any of the primary treatments for upper gastrointestinal bleeding in people with liver diseases. This is an update of this Cochrane review. OBJECTIVES: To assess the beneficial and harmful effects of antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or chronic liver disease. SEARCH METHODS: We searched The Cochrane Hepato Biliary Controlled Trials Register (February 2015), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 2 of 12, 2015), MEDLINE (Ovid SP) (1946 to February 2015), EMBASE (Ovid SP) (1974 to February 2015), Science Citation Index EXPANDED (1900 to February 2015), LILACS (1982 to February 2015), World Health Organization Clinical Trials Search Portal (accessed 26 February 2015), and the metaRegister of Controlled Trials (accessed 26 February 2015). We scrutinised the reference lists of the retrieved publications. SELECTION CRITERIA: Randomised clinical trials irrespective of blinding, language, or publication status for assessment of benefits and harms. Observational studies for assessment of harms. DATA COLLECTION AND ANALYSIS: We planned to summarise data from randomised clinical trials using standard Cochrane methodologies and assessed according to the GRADE approach. MAIN RESULTS: We found no randomised clinical trials assessing antifibrinolytic amino acids for treating upper gastrointestinal bleeding in people with acute or chronic liver disease. We did not identify quasi randomised, historically controlled, or observational studies in which we could assess harms. AUTHORS' CONCLUSIONS: This updated Cochrane review identified no randomised clinical trials assessing the benefits and harms of antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or chronic liver disease. The benefits and harms of antifibrinolytic amino acids need to be tested in randomised clinical trials. Unless randomised clinical trials are conducted to assess the trade-off between benefits and harms, we cannot recommend or refute antifibrinolytic amino acids for upper gastrointestinal bleeding in people with acute or chronic liver diseases. PMID- 26058966 TI - Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcomes. AB - BACKGROUND: Maternal caffeine consumption during pregnancy may have adverse effects on fetal, neonatal and maternal outcomes. OBJECTIVES: This review investigates the effects of restricting caffeine intake by mothers on fetal, neonatal and pregnancy outcomes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (16 January 2015), scanned bibliographies of published studies and corresponded with investigators. SELECTION CRITERIA: Randomised controlled trials (RCTs) including quasi-RCTs investigating the effect of caffeine and/or supplementary caffeine versus restricted caffeine intake or placebo on pregnancy outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. MAIN RESULTS: Two studies met the inclusion criteria but only one contributed data for the prespecified outcomes. Caffeinated instant coffee (568 women) was compared with decaffeinated instant coffee (629 women) and it was found that reducing the caffeine intake of regular coffee drinkers (3+ cups/day) during the second and third trimester by an average of 182 mg/day did not affect birthweight (g) (mean difference (MD) 20.00, 95% confidence interval (CI) -48.68 to 88.68; one study, 1197 participants; low quality evidence), preterm birth (risk ratio (RR) 0.81, 95% CI 0.48 to 1.37; one study, 1153 participants; low quality evidence) or small-for-gestational age (RR 0.97, 95% 0.57 to 1.64; one study, 1150 participants). Risk of bias was moderate in both studies.Two outcomes were assessed and assigned a quality rating using the GRADE methods. Evidence for these two outcomes (birthweight and preterm birth) was assessed as of low quality, with downgrading decisions due to the relatively small sample sizes and the wide confidence interval of the one included trial that contributed data. Neither of the studies reported on any of the other primary outcomes (low birthweight; first trimester fetal loss; perinatal mortality; fetal hypoxia; fetal tachycardia) or on any of the reviews neonatal or maternal outcomes. AUTHORS' CONCLUSIONS: There is insufficient evidence to confirm or refute the effectiveness of caffeine avoidance on birthweight or other pregnancy outcomes. There is a need to conduct high-quality, double-blinded RCTs to determine whether caffeine has any effect on pregnancy outcome. PMID- 26058967 TI - Snake antivenom for snake venom induced consumption coagulopathy. AB - BACKGROUND: Snake venom induced consumption coagulopathy is a major systemic effect of envenoming. Observational studies suggest that antivenom improves outcomes for venom induced consumption coagulopathy in some snakebites and not others. However, the effectiveness of snake antivenom in all cases of venom induced consumption coagulopathy is controversial. OBJECTIVES: To assess the effect of snake antivenom as a treatment for venom induced consumption coagulopathy in people with snake bite. SEARCH METHODS: The search was done on 30 January 2015. We searched the Cochrane Injuries Group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), three other sources, clinical trials registers, and we also screened reference lists. SELECTION CRITERIA: All completed, published or unpublished, randomised, controlled trials with a placebo or no treatment arm, where snake antivenom was administered for venom induced consumption coagulopathy in humans with snake bites. DATA COLLECTION AND ANALYSIS: Two authors reviewed the identified trials and independently applied the selection criteria. MAIN RESULTS: No studies met the inclusion criteria for this review. AUTHORS' CONCLUSIONS: Randomised placebo controlled trials are required to investigate the effectiveness of snake antivenom for clinically relevant outcomes in patients with venom induced consumption coagulopathy resulting from snake bite. Although ethically difficult, the routine administration of a treatment that has a significant risk of anaphylaxis cannot continue without strong evidence of benefit. PMID- 26058968 TI - Antidepressant drugs and teenage suicide in Hungary: Time trend and seasonality analysis. AB - OBJECTIVE: The aim of the present study was to analyze the relationship between increasing utilization of antidepressants and lithium, and suicide rate of persons less than 20 years of age in Hungary, with particular regard to seasonal patterns. METHODS: Time trend analysis was carried out to determine the correlation between antidepressant and lithium prescription patterns in Hungarian persons under age of 20 years as well as seasonal variations within the study period from January 1998 to December 2006. RESULTS: There was a significant correlation (P = 0.03) between the eight-fold increase in antidepressant + lithium prescriptions and decreasing suicides in young Hungarian people under 20 years of age within the study period. Lithium, selective serotonin reuptake inhibitors (SSRIs) and the group of "other antidepressant drugs" rather than nonselective monoamine reuptake inhibitors and monoamine oxidase-A inhibitors were responsible for this association. No significant association could be drawn from seasonal variation with boys (P = 0.964), girls (P = 0.140), or both genders (P = 0.997). LIMITATION: Ecological study design. CONCLUSION: Our findings are in good agreement with large-scale ecological studies showing that the beneficial effect of more widely used antidepressants at a given point could appear on the level of suicide rate of the general population even among patients under the age of 20 years. PMID- 26058969 TI - Modelling the Transport of Nanoparticles under Blood Flow using an Agent-based Approach. AB - Blood-mediated nanoparticle delivery is a new and growing field in the development of therapeutics and diagnostics. Nanoparticle properties such as size, shape and surface chemistry can be controlled to improve their performance in biological systems. This enables modulation of immune system interactions, blood clearance profile and interaction with target cells, thereby aiding effective delivery of cargo within cells or tissues. Their ability to target and enter tissues from the blood is highly dependent on their behaviour under blood flow. Here we have produced an agent-based model of nanoparticle behaviour under blood flow in capillaries. We demonstrate that red blood cells are highly important for effective nanoparticle distribution within capillaries. Furthermore, we use this model to demonstrate how nanoparticle size can selectively target tumour tissue over normal tissue. We demonstrate that the polydispersity of nanoparticle populations is an important consideration in achieving optimal specificity and to avoid off-target effects. In future this model could be used for informing new nanoparticle design and to predict general and specific uptake properties under blood flow. PMID- 26058970 TI - De novo development of antibodies to kidney-associated self-antigens angiotensin II receptor type I, collagen IV, and fibronectin occurs at early time points after kidney transplantation in children. AB - Chronic rejection is the leading cause of graft loss following pediatric kidney transplantation. Our group and others have demonstrated an association between the development of Abs to self-antigens and chronic rejection following adult lung and heart transplantation. The goal of this study was to determine whether Abs to kidney-associated self-antigens develop following pediatric renal transplantation. We investigated post-transplant development of Abs to kidney associated self-antigens angiotensin II receptor type I, Fn, and collagen IV in a pediatric cohort. Using ELISA, we measured Abs to kidney-associated self-antigens in serum. Our cohort included 29 subjects with samples collected pretransplant and for 12 months post-transplant. No samples had Abs to kidney-associated self antigen pretransplant. In contrast, 50% (10/20) of subjects developed Abs to one or more kidney-associated self-antigen post-transplantation. The median time to antibody appearance and duration of persistence were 103 and 61 days, respectively. Development of Abs did not correlate with graft function. Half of subjects developed Abs to kidney-associated self-antigens angiotensin II receptor type I, Fn, or collagen IV in the first year after kidney transplantation--a higher rate of early antibody development than expected. In this small study, Abs did not correlate with worse clinical outcomes. PMID- 26058971 TI - Isolation and identification of chemical constituents from the bacterium Bacillus sp. and their nematicidal activities. AB - A strain SMrs28 was isolated from the rhizosphere soil of a toxic plant Stellera chamaejasme and identified as Bacillus sp. on the basis of morphological and partial 16S rRNA gene sequence analysis. The crude extract of SMrs28 fermentation broth showed strong nematocidal activities in preliminary test. To define the active nematocidal metabolites of SMrs28, a novel compound (1), 4 oxabicyclo[3.2.2]nona-1(7), 5,8-triene, along with five known compounds (2-6), were isolated from the strain by various column chromatographic techniques and characterized on the basis of spectroscopic analysis. Results of the in vitro nematicidal tests showed that the metabolites presented different levels of activity at certain exposure conditions. Compounds (1-3) displayed LC50 values of 904.12, 451.26, 232.98 ug/ml and 1594.0, 366.62, 206.38 ug/ml against Bursaphelenchus xylophilus and Ditylenchus destructor at 72 h, respectively. This is the first report of the nematicidal activity of the compounds as constituents of Bacillus sp.. Our findings help to find potential chemical structures to develop nematicides from microbial source for the management of nematode-infected plant diseases. PMID- 26058972 TI - Prostaglandin E2 promotes human cholangiocarcinoma cell proliferation, migration and invasion through the upregulation of beta-catenin expression via EP3-4 receptor. AB - Prostaglandin E2 (PGE2) is involved in cholangiocarcinoma cell proliferation, migration and invasion through E prostanoid receptors, including EP1, EP2 and EP4. However, the functions and the mechanisms of those splice variants of EP3 receptors in promoting liver cancer cell growth and invasion remain to be elucidated. In our previous studies, four isoforms of EP3 receptors, EP3-4, EP3 5, EP3-6 and EP3-7 receptors, were detected in CCLP1 and HuCCT1 cells. However, the functions of these receptors in these cells have yet to be determined. It was reported that beta-catenin is closely correlated with malignancy, including cholangiocarcinoma. The present study was designed to examine the effects of 4-7 isoforms of EP3 in promoting cholangiocarcinoma progression and the mechanisms by which PGE2 increases beta-catenin protein via EP3 receptors. The results showed that PGE2 promotes cholangiocarcinoma progression via the upregulation of beta catenin protein, and the EP3-4 receptor pathway is mainly responsible for this regulation. These findings reveal that PGE2 upregulated the cholangiocarcinoma cell beta-catenin protein through the EP3-4R/Src/EGFR/PI3K/AKT/GSK-3beta pathway. The present study identified the functions of EP3 and the mechanisms by which PGE2 regulates beta-catenin expression and promoted cholangiocarcinoma cell growth and invasion. PMID- 26058975 TI - Irish Society of Gastroenterology - Winter Meeting 2014. PMID- 26058973 TI - Two cases of intralymphatic histiocytosis following hip replacement. PMID- 26058977 TI - Treating Substance Abuse and Trauma Symptoms in Incarcerated Women: An Effectiveness Study. AB - Incarcerated women report high rates of trauma exposure and substance use. The present study evaluated an integrated treatment program, Helping Women Recover/Beyond Trauma (HWR/BT), supplemented with additional modules on domestic violence, relapse prevention, and a 12-step program. The HWR/BT combined treatment program was compared with a matched comparison sample that did not receive the target treatment. Self-report measures were collected from 95 incarcerated women, with 56 women in the completer sample. Women in the treatment condition attended a 4-month group treatment. Results indicated statistically significant between-group differences, favoring the treatment condition, for negative posttraumatic cognitions. Pre-post, but not between-group, differences were also observed for posttraumatic stress disorder (PTSD) symptoms and substance-related self-efficacy, whereas no differences were observed for depression, dissociation, tension reduction, or anxious arousal. The present study indicates some promise for specific aspects of the treatment, although results question the overall benefit of the program over standard prison services. PMID- 26058976 TI - Revisiting nephrocalcinosis: A single-centre perspective. A northern Italian experience. AB - AIM: Nephrocalcinosis is a clinical-pathological entity characterized by the deposition of calcium salts within the kidney parenchyma. Both the protean presentation and multiple causes may explain the lack of data regarding its prevalence. The aim of this study is to report the prevalence and main clinical features of nephrocalcinosis diagnosed in a newly opened nephrology outpatient unit. METHODS: Analysis on the data we prospectively gathered from the start of activity (2007-2013) was carried out. Clinical and laboratory data were collected from the medical records and from the general laboratory; diagnosis was based upon imaging data reviewed by the same radiologists. RESULTS: Sixty-five of 2695 patients referred to our unit were diagnosed with nephrocalcinosis (2.4%). The affected patients were younger than the overall out-patient population (median: 37.7 (min-max: 8-82) vs 63 years (2-102) P < 0.001), with higher female prevalence (68% vs 51.4%: P < 0.05) and better preserved kidney function (CKD-EPI 103 (23-165) vs 60 mL/min (3.2-169) P < 0.001). Kidney stones were the main reason for referral (35.4%), followed by electrolyte disturbances (22.7%), acute pyelonephritis (4.6%), AKI or CKD (4.6%). Nephrocalcinosis was associated with autoimmune diseases in 29% and with microcythaemia in 23%, while positive family history was present in 23% of patients. Various electrolyte disturbances were observed, with hypercalciuria being the hallmark of beta thalassaemic patients. CONCLUSIONS: Nephrocalcinosis is a rare, but not exceptional disease in nephrology. In Mediterranean countries, microcythaemia would appear to be a major cause of this disease. Greater awareness of nephrocalcinosis is needed for an integrated approach involving various branches of internal medicine and radiology. PMID- 26058978 TI - Social Desirability in Intimate Partner Violence and Relationship Satisfaction Reports: An Exploratory Analysis. AB - The social desirability bias can be considered a two-dimensional construct, consisting of impression management and self-deception. Although social desirability is often considered a threat to the validity of intimate partner violence (IPV) reports, little is known about which dimension is most responsible for this distortion. Furthermore, it is unclear whether social desirability distorts the report of relationship satisfaction. In this study, two instruments that claim to measure social desirability are investigated on their ability to measure impression management and self-deception. Afterward, which dimension (if any) is responsible for a distortion in IPV and relationship satisfaction reports is examined. The survey consisted of the following measures: the Revised Conflict Tactics Scales for IPV, the Couples Satisfaction Index for relationship satisfaction and the Balanced Inventory of Desirable Responding, the Limited Disclosure Scale, and the Idealistic Distortion Scale for social desirability. The Limited Disclosure Scale was found to predominantly measure impression management. The Idealistic Distortion Scale did not measure social desirability well and appeared to be a bad measure for relationship satisfaction. Both the reports of IPV and relationship satisfaction were influenced by impression management, but not by self-deception. However, impression management and self deception only accounted for a small portion of the variance in IPV and relationship satisfaction reports. These results indicate that the social desirability bias, when reporting IPV and relationship satisfaction, is a conscious process, but that its influence on IPV and relationship satisfaction reports might be overrated. PMID- 26058979 TI - Physical Health Conditions and Intimate Partner Violence Perpetration Among Offenders With Alcohol Use Diagnoses. AB - Intimate partner violence (IPV) is prevalent among samples with diagnosed alcohol use disorders (AUDs), but few studies have evaluated the factors that account for this increased risk, and none have systematically evaluated the risk posed by comorbid physical health conditions. The present study evaluated the likelihood of perpetrating IPV among alcohol diagnosed offenders with medical health problems relative to healthy counterparts. Physical health and partner violence data provided by 655 criminal offenders with AUDs diagnosed during a court ordered substance abuse evaluation were examined. One third of participants (35.3%) endorsed a physical health condition, and 46.4% reported perpetrating physical IPV. The odds of perpetrating IPV among participants with a physical health condition were 2.29 times larger than among healthy participants. Specific conditions emerged as risk factors for IPV, including brain injury, cardiac issues, chronic pain, liver issues, gastrointestinal symptoms, hepatitis, and recent injury. Findings highlight the importance of identifying and managing physical health conditions that may complicate IPV treatment efforts. Integrated behavioral and medical health treatment approaches may increase treatment compliance and reduce the risk of future partner violence among offenders with co occurring issues, such as mental illness, addiction, and physical health conditions. PMID- 26058980 TI - Secure Attachment Moderates the Relation of Sexual Trauma With Trauma Symptoms Among Adolescents From an Inpatient Psychiatric Facility. AB - Experiencing sexual trauma has been linked to internalizing and externalizing psychopathologies. Insecure attachment has been shown to moderate the relation between sexual trauma and trauma symptoms among adults. However, few studies have explored relations among sexual trauma, attachment insecurity, and trauma symptoms in adolescence, and none have used developmentally appropriate measures. The present study sought to examine attachment security as a potential moderator of the relation between having a history of sexual trauma (HST) and trauma symptoms among adolescents at an inpatient psychiatric facility. Attachment to caregivers was measured by the Child Attachment Interview (CAI) and trauma symptoms by the Trauma Symptoms Checklist for Children (TSCC). HST was assessed with responses to two separate interviews that asked about traumatic experiences: the Computerized Diagnostic Interview Schedule for Children (C-DISC) and the CAI. Moderation analyses were conducted using univariate General Linear Modeling (GLM). Of the 229 study participants, 50 (21.8%) had a HST. The relation between HST and trauma symptoms was significantly moderated by insecure attachment with both mother, F(1, 228) = 4.818, p = .029, and father, F(1, 228) = 6.370, p = .012. Specifically, insecurely attached adolescents with a HST exhibited trauma symptoms at levels significantly greater than securely attached adolescents with a HST and adolescents with no HST. Results are consistent with previous research that suggests secure attachment may protect against the development of trauma symptoms among those who have experienced a sexual trauma. PMID- 26058981 TI - Clinical applications and prognostic implications of strain and strain rate imaging. AB - Strain and strain rate imaging (also known as deformation imaging) are techniques used to measure myocardial deformation. These newer echocardiographic modalities overcome the limitations of conventional echocardiography and provide a sensitive means of objectively quantifying regional and global myocardial function. It has enabled us to better understand regional myocardial function and risk stratify patients with coronary artery disease, cardiomyopathies and valvular heart disease. Also, they have been used to assess left ventricular dyssynchrony, predict responders and optimize cardiac resynchronization therapy. However, the lack of standardization and inter-vendor variability in measurements are major roadblocks to using deformation imaging in routine clinical practice. This article discusses the fundamental concept of deformation, in particular relating to strain and strain rate imaging using speckle tracking imaging and tissue Doppler imaging, the clinical applications and its prognostic implications. PMID- 26058982 TI - Decomposition pathways of formamide in the presence of vanadium and titanium monoxides. AB - Thermally feasible decomposition pathways of formamide (FM) in the presence of vanadium VO(X(4)Sigma(-)) and titanium TiO(X(3)Delta) monoxides are determined using density functional theory (BP86 functional) and coupled-cluster theory (CCSD(T)) computations with large basis sets. These diatomic metal oxides have been shown to be present in the prebiotic conditions. The dehydration, decarbonylation and dehydrogenation reactions of the molecular and dissociative complexes of FM and MO (M = V, Ti) turn out to be more favourable than those of the ground state isolated FM. The effect of addition of one or two water molecules on energy barriers is also probed for these reaction pathways. In some cases, a combined catalytic effect when adding water is observed. This enhanced catalytic effect was not observed in previously reported cases of FM transformation, for example, when adding water molecules into the mineral catalyzed isomerizations of FM. The dehydration process of MO-FM complexes without the presence of water is found to be more feasible than the decarbonylation and dehydrogenation. The overall energy barrier for the non-water VO-FM dehydration is ~3 kcal mol(-1) lower than the reference energy of the separated systems, whereas those of the two latter reactions are higher than the reference. Although the TiO-FM dehydration has a larger overall barrier of 14 kcal mol(-1) as compared to the VO-FM counterpart, the two other decomposition pathways still have much higher energy barriers. Direct formation of urea and H2CO from a FM dimer and indirect formation of urea from FM via the intermediate HNCO are also established. Urea formation in an indirect pathway is preferred. These low-energy-barrier pathways leading to the formation of important prebiotic molecules suggest that metal monoxides MO could play an important catalytic role in the prebiotic reactions of FM. PMID- 26058984 TI - Characterization of Human Dermal Fibroblasts in Fabry Disease. AB - Fabry disease (FD) is a hereditary X-linked metabolic lysosomal storage disorder due to insufficient amounts or a complete lack of the lysosomal enzyme alpha galactosidase A (alpha-GalA). The loss of alpha-GalA activity leads to an abnormal accumulation of globotriaosylcerami (Gb3) in lysosomes and other cellular components of different tissues and cell types, affecting the cell function. However, whether these biochemical alterations also modify functional processes associated to the cell mitotic ability is still unknown. The goal of the present study was to characterize lineages of human dermal fibroblasts (HDFs) of FD patients and healthy controls focusing on Gb3 accumulation, expression of chloride channels that regulate proliferation, and proliferative activity. The biochemical and functional analyses indicate the existence of quantitative differences in some but not all the parameters of cytoskeletal organization, proliferation, and differentiation processes. PMID- 26058983 TI - Linkage to care following a home-based HIV counselling and testing intervention in rural South Africa. AB - INTRODUCTION: Efforts to increase awareness of HIV status have led to growing interest in community-based models of HIV testing. Maximizing the benefits of such programmes requires timely linkage to care and treatment. Thus, an understanding of linkage and its potential barriers is imperative for scale-up. METHODS: This study was conducted in rural South Africa. HIV-positive clients (n=492) identified through home-based HIV counselling and testing (HBHCT) were followed up to assess linkage to care, defined as obtaining a CD4 count. Among 359 eligible clients, we calculated the proportion that linked to care within three months. For 226 clients with available data, we calculated the median CD4. To determine factors associated with the rate of linkage, Cox regression was performed on a subsample of 196 clients with additional data on socio-demographic factors and personal characteristics. RESULTS: We found that 62.1% (95% CI: 55.7 to 68.5%) of clients from the primary sample (n=359) linked to care within three months of HBHCT. Among those who linked, the median CD4 count was 341 cells/mm(3) (interquartile range [IQR] 224 to 542 cells/mm(3)). In the subsample of 196 clients, factors predictive of increased linkage included the following: believing that drugs/supplies were available at the health facility (adjusted hazard ratio [aHR] 1.78; 95% CI: 1.07 to 2.96); experiencing three or more depression symptoms (aHR 2.09; 95% CI: 1.24 to 3.53); being a caregiver for four or more people (aHR 1.93; 95% CI: 1.07 to 3.47); and knowing someone who died of HIV/AIDS (aHR 1.68; 95% CI: 1.13 to 2.49). Factors predictive of decreased linkage included the following: younger age - 15 to 24 years (aHR 0.50; 95% CI: 0.28 to 0.91); living with two or more adults (aHR 0.52; 95% CI: 0.35 to 0.77); not believing or being unsure about the test results (aHR 0.48; 95% CI: 0.30 to 0.77); difficulty finding time to seek health care (aHR 0.40; 95% CI: 0.24 to 0.67); believing that antiretroviral treatment can make you sick (aHR 0.56; 95% CI: 0.35 to 0.89); and drinking alcohol (aHR 0.52; 95% CI: 0.34 to 0.80). CONCLUSIONS: The findings highlight barriers to linkage following an increasingly popular model of HIV testing. Further, they draw attention to ways in which practical interventions and health education strategies could be used to improve linkage to care. PMID- 26058986 TI - Heart Failure in Women: Does Sex Matter? PMID- 26058985 TI - Initial Impacts of the Patient Care Networks of Alabama Initiative. AB - OBJECTIVES: To estimate the effects of medical home support on the use of clinical services and Medicaid expenditures. DATA SOURCE: Medicaid claims. STUDY DESIGN: A difference-in-differences model where changes in utilization and expenditures of the intervention group are compared to changes in the nonintervention group. EXTRACTION METHODS: Using Medicaid claims from October 2010 through September 2013, service use and expenditures are measured for 12 months before and 21 months after implementation. Changes for four health status groups are examined separately. PRINCIPAL FINDINGS: The introduction of community based support was associated with a small reduction in use and no statistically significant overall effect on expenditures. However, among those with chronic and/or mental health conditions, there were modest, statistically significant increases in use of and expenditures for a range of ambulatory and inpatient health care services, while service use for those without these conditions declined. Emergency department use increased for all groups. CONCLUSIONS: Community-based support for medical home practices is associated with a shift in the service mix provided to higher cost, more vulnerable subgroups in Medicaid. Such systems are unlikely to be associated with significant overall cost savings, at least in the short term, but may have other benefits. PMID- 26058987 TI - Chronic osteomyelitis correlates with increased risk of acute pancreatitis in a case-control study in Taiwan. AB - OBJECTIVES: The objective of this study was to examine the relationship between chronic osteomyelitis and acute pancreatitis in Taiwan. METHODS: This was a population-based case-control study utilizing the database of the Taiwan National Health Insurance Program. We identified 7678 cases aged 20-84 with newly diagnosed acute pancreatitis during the period of 1998 to 2011. From the same database, 30,712 subjects without diagnosis of acute pancreatitis were selected as controls. The cases and controls were matched with sex, age and index year of diagnosing acute pancreatitis. The odds ratio with 95% confidence interval of acute pancreatitis associated with chronic osteomyelitis was examined by the multivariable unconditional logistic regression analysis. RESULTS: After adjustment for multiple confounders, the multivariable analysis showed that the adjusted odds ratio of acute pancreatitis was 1.93 for subjects with chronic osteomyelitis (95% confidence interval 1.01, 3.69), when compared with subjects without chronic osteomyelitis. CONCLUSIONS: Chronic osteomyelitis correlates with increased risk of acute pancreatitis. Patients with chronic osteomyelitis should be carefully monitored about the risk of acute pancreatitis. PMID- 26058988 TI - Does coronary Atherosclerosis Deserve to be Diagnosed earlY in Diabetic patients? The DADDY-D trial. Screening diabetic patients for unknown coronary disease. AB - OBJECTIVES: To evaluate if screening and treatment of asymptomatic coronary artery disease (CAD) are effective in preventing first cardiac event in diabetics. METHODS: Diabetic patients without known CAD were randomly assigned to undergo a screening for silent myocardial ischemia followed by revascularization or to continue follow-up. The reduction of cardiac death (CD) or nonfatal myocardial infarction (MI) represented the primary aim; secondary aim was the prevention of heart failure (HF). RESULTS: From September 2007 to May 2012, 520 patients (62 years; 104 female) were enrolled. Silent CAD was found in 20 of 262 patients (7.6%), revascularization was performed in 12 (4.6%). After a mean follow-up of 3.6 years 12 events (4.6%) occurred in the study group and 14 (5.4%) in the follow-up (HR=0.849, 95% CI: 0.393-1.827, P=0.678). The occurrence of first HF episode did not differ between groups: 2 (0.8%) in screened and 7 (2.7%) in follow-up (HR=0.273, 95% CI: 0.057-1.314, P=0.083). Subgroup analysis revealed a significantly lower HF episodes among patients with intermediate cardiovascular risk (Log rank P=0.022). Additionally, when CD and MI were analysed within subgroups, a significant lower number of CDs was observed among older than 60 years (P=0.044). CONCLUSION: Screening and revascularization of silent CAD in diabetics, failed to demonstrate a significant reduction in cardiac events and HF episodes. However, our data indicate that further research is warranted in patients older than 60 years and those with an intermediate cardiovascular risk. CLINICALTRIALS.GOV: NCT00547872. PMID- 26058989 TI - New onset of diabetes after transplantation is associated with improved patient survival after liver transplantation due to confounding factor. AB - BACKGROUND: The influence of NODAT on survival of liver transplant recipients has not been clarified. Therefore, we evaluated the effect of NODAT on survival in LT recipients. METHODS: Data from 352 LT patients were totally analyzed. 97 patients with pretransplant diabetes mellitus were excluded, and 255 patients without diabetes mellitus at time of transplantation were included. RESULTS: NODAT was diagnosed in 41 patients (16.1%). There was no difference in frequency of NODAT according to the etiology of liver cirrhosis. NODAT was associated with a higher body weight (p=0.004) and BMI (p=0.002) 5years after LT, but not with weight gain (p=0.201) or increase in BMI (p=0.335) 5years after LT. HbA1c 5years after LT was significantly higher in patients with NODAT (p=0.001), but mean HbA1c still remained lower than 6.5% (6.4(+/-1.2) %). Patients with NODAT showed better survival rates (log rank: p=0.002) compared to LT recipients without diabetes. According to all existing knowledge of diabetes mellitus (DM) better survival cannot be a direct effect of this disease. Our results are rather influenced by an not known confounding factor (possibly recovery from cachexia) associated with better survival and NODAT, while complications of NODAT will not appear during the relatively short postoperative time and observation period (mean follow up 6.08 (+/-2.67) years). CONCLUSION: NODAT is frequently diagnosed in LT recipients and is associated with an improved 5year survival after LT due to a not exactly known confounding factor. PMID- 26058990 TI - Cell-mediated anti-Gag immunity in pharmacologically induced functional cure of simian AIDS: a 'bottleneck effect'? AB - BACKGROUND: Administration of antiretroviral therapy and two experimental drugs, auranofin and buthionine sulfoximine (BSO), was previously shown to be followed by drug-free control of chronic SIVmac251 infection, decreased immune activation and increased cell-mediated anti-Gag responses. METHODS: Phylogeny was analysed with Phylogeny.fr. Entropy was calculated with the specific tool of the HIV Sequence Database. The capsid Gag structure was computed using SPDBV. The bottleneck effect was simulated through an appropriate online tool. RESULTS: The region of Gag predominantly targeted during control of SIVmac251 infection is highly conserved in primate lentiviruses and plays an important role in capsid architecture. Computer-aided simulations support the view that the preferential development of immune responses against this region is derived from a 'bottleneck effect' after restriction, by auranofin and BSO, of the activated lymphocyte pool. CONCLUSIONS: Restriction of immune activation through auranofin/BSO may result in stochastic selection of cell clones targeting conserved epitopes leading to a functional cure-like condition. PMID- 26058991 TI - High-dose and fractionation effects in stereotactic radiation therapy: Analysis of tumor control data from 2965 patients. AB - BACKGROUND AND PURPOSE: Two aspects of stereotactic radiotherapy (SRT) require clarification: First, are tumoricidal mechanisms at high-doses/fraction the same as at lower doses? Second, is single high-dose SRT treatment advantageous for tumor control (TCP) vs. multi-fraction SRT? MATERIAL AND METHODS: We analyzed published TCP data for lung tumors or brain metastases from 2965 SRT patients, covering a wide range of doses and fraction numbers. We used: (a) a linear quadratic model (including heterogeneity), which assumes the same mechanisms at all doses, and (b) alternative models with terms describing distinct tumoricidal mechanisms at high doses. RESULTS: Both for lung and brain data, the LQ model provided a significantly better fit over the entire range of treatment doses than did any of the models requiring extra terms at high doses. Analyzing the data as a function of fractionation (1 fraction vs. >1 fraction), there was no significant effect on TCP in the lung data, whereas for brain data multi-fraction SRT was associated with higher TCP than single-fraction treatment. CONCLUSION: Our analysis suggests that distinct tumoricidal mechanisms do not determine tumor control at high doses/fraction. In addition, there is evidence suggesting that multi-fraction SRT is superior to single-dose SRT. PMID- 26058992 TI - The Effect of Combined Skin and Deep Tissue Inflammatory Pain Models. AB - OBJECTIVE: Cutaneous hyperalgesia is prominent in the ultraviolet-B (UVB) model of inflammatory pain. This study investigated possible interactions between cutaneous and deep tissues hyperalgesia. METHODS: A total of 16 healthy volunteers participated in the study. Skin inflammation was induced unilaterally by UVB irradiation (three times of the individual minimal erythema dose) in square-shaped areas on the upper-trapezius and lower-back. Moderate delayed onset muscle soreness (DOMS) was induced bilaterally in the low-back by eccentric exercise. Cutaneous blood flow, mechanical thresholds, pressure pain thresholds (PPTs), temporal summation to repetitive pressure stimulation, and stimulus response functions (SR curve) relating graded pressure stimulations and pain intensity were measured within and outside the irradiated areas, before and 24 hours after irradiation and eccentric muscle exercise. RESULTS: Compared with baseline (P < 0.05): the assessments 24 hours after irradiation demonstrated: 1) increased superficial blood flow inside and outside the irradiated areas and in the DOMS site; 2) reduced mechanical thresholds within the irradiated areas; 3) left-shifted SR curve function within and outside the irradiated areas; and 4) facilitated temporal summation of pain inside the irradiated areas and in the DOMS site. There was no significant influence of muscle hyperalgesia on skin measures in normal or UVB-inflamed skin. CONCLUSIONS: Moderate degrees of muscle sensitization could not facilitate UVB-induced cutaneous mechanical sensitivity, whereas UVB-induced neurogenic inflammation is enhanced when the DOMS is present. PMID- 26058993 TI - Design, Degradation Mechanism and Long-Term Cytotoxicity of Poly(L-lactide) and Poly(Lactide-co-epsilon-Caprolactone) Terpolymer Film and Air-Spun Nanofiber Scaffold. AB - Degradable nanofiber scaffold is known to provide a suitable, versatile and temporary structure for tissue regeneration. However, synthetic nanofiber scaffold must be properly designed to display appropriate tissue response during the degradation process. In this context, this publication focuses on the design of a finely-tuned poly(lactide-co-epsilon-caprolactone) terpolymer (PLCL) that may be appropriate for vascular biomaterials applications and its comparison with well-known semi-crystalline poly(l-lactide) (PLLA). The degradation mechanism of polymer film and nanofiber scaffold and endothelial cells behavior cultured with degradation products is elucidated. The results highlights benefits of using PLCL terpolymer as vascular biomaterial compared to PLLA. PMID- 26058994 TI - Drug-Drug Interactions of a Novel kappa-Opioid Receptor Agonist, Nalfurafine Hydrochloride, Involving the P-Glycoprotein. AB - BACKGROUND AND OBJECTIVE: Nalfurafine hydrochloride (TRK-820), which exhibits strong kappa-opioid agonistic activity, has an antipruritic effect on uremic pruritus. The permeability of nalfurafine across human P-glycoprotein (P-gp) expressing LLC-PK1 cells was investigated to evaluate drug-drug interactions (DDI) involving the P-gp efflux transporter of nalfurafine. Furthermore, we assessed the ratio of brain/plasma concentrations (K p) as an indicator to investigate the changes in the blood-brain barrier (BBB) transport through P-gp when digoxin or verapamil was concomitantly administered with nalfurafine in mice. METHODS: All samples were analyzed by liquid chromatography-tandem mass spectrometry or a liquid scintillation counter. RESULTS: The cleared volume ratio (cleared volume from basal to apical/cleared volume from apical to basal) of nalfurafine in P-gp-expressing cells was higher than that in the control cells; however, no concentration-dependent decrease in the cleared volume ratio of digoxin was observed in the presence of nalfurafine. The K p value in mice showed similar profiles to those observed with nalfurafine alone and when co administered with digoxin or verapamil. CONCLUSIONS: From these results, nalfurafine was found to be a substrate for P-gp, but had no inhibitory effect on P-gp-mediated transport. Furthermore, it is unlikely that nalfurafine transport via the BBB is affected by P-gp substrates in humans. PMID- 26058995 TI - Incidence of cervical dysplasia and cervical cancer in women living with HIV in Denmark: comparison with the general population. AB - OBJECTIVES: Women living with HIV (WLWH) are reportedly at increased risk of invasive cervical cancer (ICC). A recent publication found that WLWH in Denmark attend the national ICC screening programme less often than women in the general population. We aimed to estimate the incidence of cervical dysplasia and ICC in WLWH in Denmark compared with that in women in the general population. METHODS: We studied a nationwide cohort of WLWH and a cohort of 15 age-matched women per WLWH from the general population for the period 1999-2010. Pathology samples were obtained from The Danish Pathology Data Bank, which contains nationwide records of all pathology specimens. The cumulative incidence and hazard ratios (HRs) for time from inclusion to first cervical intraepithelial neoplasia (CIN)/ICC and time from first normal cervical cytology result to first CIN/ICC were estimated. Sensitivity analyses were performed to include prior screening outcome, screening intensity and treatment of CIN/ICC in the interpretation of results. RESULTS: We followed 1140 WLWH and 17 046 controls with no prior history of ICC or hysterectomy for 9491 and 156 865 person-years, respectively. Compared with controls, the overall incidences of CIN1 or worse (CIN1+), CIN2+ and CIN3+, but not ICC, were higher in WLWH and predicted by young age and a CD4 count < 200 cells/MUL. In women with normal baseline cytology, incidences of CIN1+ and CIN2+ were higher in WLWH. However, when we compared subgroups of WLWH and controls where women in both groups were adherent to the national ICC screening programme and had a normal baseline cytology, incidences of CIN and ICC were comparable. CONCLUSIONS: Overall, WLWH developed more cervical disease than controls. Yet, in WLWH and controls adherent to the national ICC screening programme and with normal baseline cytology, incidences of CIN and ICC were comparable. PMID- 26058996 TI - Michel Mirowski and the beginning of a new era of fighting sudden arrhythmic death. AB - Prior to the implantable cardioverter-defibrillator (ICD), life-threatening ventricular arrhythmias were treated using anti-arrhythmic drugs. The concept of an implantable defibrillator to prevent sudden arrhythmic death was first published by Michel Mirowski in 1970. Despite critical opinions by leading physicians, Michel Mirowski continued development of his vision. Hallmarks in the development of the ICD include the following: internal-external defibrillator used during surgery on humans in 1971/1972; fully implantable defibrillator tested in canines in 1975; defibrillator successfully implanted in a 57-year-old woman in 1980; second generation devices introduced in 1982; US Food and Drug Administration device approved in 1985. Today it is hard to imagine modern medicine without ICD therapy. This article provides the reader a history of the development of the ICD. PMID- 26058997 TI - [The subcutaneous cardioverter-defibrillator: When less is more]. AB - INTRODUCTION: In the last few decades, defibrillator therapy has revolutionized treatment of patients at risk for sudden cardiac death. Multiple clinical trials have shown the benefit of implantable cardioverter-defibrillators (ICD) for primary and secondary prevention of sudden cardiac death. Being an entirely subcutaneous system, the S-ICD(r) avoids important periprocedural and long-term complications associated with transvenous implantable cardioverter-defibrillator (TV-ICD) systems as well as the need for fluoroscopy during implant surgery. METHODS AND RESULTS: In patients with challenging anatomic conditions or after infection, the S-ICD(r) might be reasonable. In multicenter studies and registries efficacy and safety of the S-ICD(r) was equal or better to transvenous implantable defibrillators. The cardiac rhythm is detected by the use of 1 of the 3 potential vectors. The S-ICD(r) automatically selects the most suitable vector for rhythm detection. If ventricular tachyarrhythmia is detected, the device is able to deliver up to five shocks of 80 J, while postshock pacing is available at 50 bpm for 30 s. The implantation technique is different from that of conventional ICDs, but easily learnable by experienced cardiologists. Initially observed hurdles (e.g., inappropriate shocks or infections) have been overcome by standardized implantation techniques, operator learning curves, and modification of algorithms. CONCLUSIONS: The S-ICD(r) predominately might be suitable in all patients with ICD indication except patients with pacing or cardiac resynchronization therapy (CRT) indication, ventricular tachycardia < 170 bpm, negative screening, or in the occasional patient whose arrhythmia might be suppressed by overdrive pacing. The system received CE certification in 2009 and was approved by the FDA in 2012. Currently, in Germany the S-ICD(r) has been integrated into the DRG system and can be reimbursed as a single chamber ICD. PMID- 26058998 TI - Judging the Intensity of Emotional Expression in Faces: the Effects of Colored Tints on Individuals With Autism Spectrum Disorder. AB - Individuals with autism spectrum disorder (ASD) often show atypical processing of facial expressions, which may result from visual stress. In the current study, children with ASD and matched controls judged which member of a pair of faces displayed the more intense emotion. Both faces showed anger, disgust, fear, happiness, sadness or surprise but to different degrees. Faces were presented on a monitor that was tinted either gray or with a color previously selected by the participant individually as improving the clarity of text. Judgments of emotional intensity improved significantly with the addition of the preferred colored tint in the ASD group but not in controls, a result consistent with a link between visual stress and impairments in processing facial expressions in individuals with ASD. PMID- 26058999 TI - The pitfall of pulse pressure variation in the cardiac dysfunction condition. PMID- 26059000 TI - Experts question IARC report saying benefits of mammography in older women outweigh risks. PMID- 26059001 TI - Mesenchymal Stem Cells Improve Heart Rate Variability and Baroreflex Sensitivity in Rats with Chronic Heart Failure. AB - Heart failure induced by myocardial infarct (MI) attenuates the heart rate variability (HRV) and baroreflex sensitivity, which are important risk factors for life-threatening cardiovascular events. Therapies with mesenchymal stem cells (MSCs) have shown promising results after MI. However, the effects of MSCs on hemodynamic (heart rate and arterial pressure) variability and baroreflex sensitivity in chronic heart failure (CHF) following MI have not been evaluated thus far. Male Wistar rats received MSCs or saline solution intravenously 1 week after ligation of the left coronary artery. Control (noninfarcted) rats were also evaluated. MI size was assessed using single-photon emission computed tomography (SPECT). The left ventricular ejection fraction (LVEF) was evaluated using radionuclide ventriculography. Four weeks after MSC injection, the animals were anesthetized and instrumented for chronic ECG recording and catheters were implanted in the femoral artery to record arterial pressure. Arterial pressure and HRVs were determined in time and frequency domain (spectral analysis) while HRV was also examined using nonlinear methods: DFA (detrended fluctuation analysis) and sample entropy. The initial MI size was the same among all infarcted rats but was reduced by MSCs. CHF rats exhibited increased myocardial interstitial collagen and sample entropy combined with the attenuation of the following cardiocirculatory parameters: DFA indices, LVEF, baroreflex sensitivity, and HRV. Nevertheless, MSCs hampered all these alterations, except the LVEF reduction. Therefore, 4 weeks after MSC therapy was applied to CHF rats, MI size and myocardial interstitial fibrosis decreased, while baroreflex sensitivity and HRV improved. PMID- 26059003 TI - IFN-gamma in Vitiligo, Is It the Fuel or the Fire? PMID- 26059002 TI - Evaluation of WaySafe: A Disease-Risk Reduction Curriculum for Substance-Abusing Offenders. AB - With a focus on reducing disease risk behavior in the community, a six-session curriculum, WaySafe, was developed to increase positive decision-making skills among soon-to-be-released inmates participating in a therapeutic community substance abuse treatment program. The intervention used TCU Mapping-Enhanced Counseling as an approach to focus on cognitive aspects of risky sexual and drug use behaviors in an effort to improve problem recognition, commitment to change, and strategies for avoiding behavioral risks of infections. A total of 1393 inmates from eight different institutions in two states were randomly assigned to receive WaySafe or treatment as usual (TAU). Baseline and follow-up surveys measured knowledge, confidence, and motivation regarding general HIV information, risky sex and drug use, HIV testing, and risk reduction skills. WaySafe participants had significantly better scores on all measures at follow-up than did TAU participants, supporting the efficacy of WaySafe in improving knowledge, motivation, and confidence in avoiding risky behaviors. PMID- 26059004 TI - Influence of fish oil supplementation and strength training on some functional aspects of immune cells in healthy elderly women. AB - Immune function changes with ageing and is influenced by physical activity (strength training, ST) and diet (fish oil, FO). The present study investigated the effect of FO and ST on the immune system of elderly women. Forty-five women (64 (sd 1.4) years) were assigned to ST for 90 d (ST; n 15), ST plus 2 g/d FO for 90 d (ST90; n 15) or 2 g/d FO for 60 d followed by ST plus FO for 90 d (ST150; n 15). Training was performed three times per week, for 12 weeks. A number of innate (zymosan phagocytosis, lysosomal volume, superoxide anion, peroxide of hydrogen) and adaptive (cluster of differentiation 4 (CD4), CD8, TNF-alpha, interferon-gamma (IFN-gamma), IL-2, IL-6 and IL-10 produced by lymphocytes) immune parameters were assessed before supplementation (base), before (pre-) and after (post-) training. ST induced no immune changes. FO supplementation caused increased phagocytosis (48 %), lysosomal volume (100 %) and the production of superoxide anion (32 %) and H2O2(70 %) in the ST90. Additional FO supplementation (ST150) caused no additive influence on the immune system, as ST150 and ST90 did not differ, but caused greater changes when compared to the ST (P< 0.05). FO increased CD4+ and CD8+ lymphocytes in the ST150, which remained unchanged when training was introduced. The combination of ST and FO reduced TNF-alpha in the ST150 from base to post-test. FO supplementation (ST150, base-pre) when combined with exercise (ST150, pre-post) increased IFN-gamma, IL-2, IL-6 and IL-10 production. The immune parameters improved in response to FO supplementation; however, ST alone did not enhance the immune system. PMID- 26059005 TI - Divergent behavior of mucosal memory T cells. AB - Memory CD4 T cells are strategically positioned at mucosal surfaces to initiate a robust adaptive immune response. The detection of specific antigen via the T-cell receptor causes these memory T cells to unleash a potent antimicrobial response that includes rousing local innate immune populations for tissue-specific defense. Paradoxically, these same memory T cells can also be stimulated by nonantigen-specific signals that are generated by the activity of local innate immune cells. This versatility of mucosal memory T cells in both the initiation and the sensing of local innate immunity could be a vitally important asset during pathogen defense but alternatively could be responsible for initiating and maintaining chronic inflammation in sensitive mucosal tissues. PMID- 26059006 TI - Increase in glutamate/glutamine concentration in the medial prefrontal cortex during mental imagery: A combined functional mrs and fMRI study. AB - Recent functional magnetic resonance spectroscopy (fMRS) studies have shown changes in glutamate/glutamine (Glx) concentrations between resting-state and active-task conditions. However, the types of task used have been limited to sensory paradigms, and the regions from which Glx concentrations have been measured limited to sensory ones. This leaves open the question as to whether the same effect can be seen in higher-order brain regions during cognitive tasks. Cortical midline structures, especially the medial prefrontal cortex (MPFC), have been suggested to be involved in various such cognitive tasks. We, therefore set out to use fMRS to investigate the dynamics of Glx concentrations in the MPFC between resting-state and mental imagery task conditions. The auditory cortex was used as a control region. In addition, functional magnetic resonance imaging was used to explore task-related neural activity changes. The mental imagery task consisted of imagining swimming and was applied to a large sample of healthy participants (n = 46). The participants were all competitive swimmers, ensuring proficiency in mental-swimming. Glx concentrations in the MPFC increased during the imagery task, as compared to resting-state periods preceding and following the task. These increases mirror BOLD activity changes in the same region during the task. No changes in either Glx concentrations or BOLD activity were seen in the auditory cortex. These findings contribute to our understanding of the biochemical basis of generating or manipulating mental representations and the MPFC's role in this. PMID- 26059007 TI - Post-crisis efforts towards recovery and resilience after the Fukushima Daiichi Nuclear Power Plant accident. AB - One of the well-known radiation-associated late-onset cancers is childhood thyroid cancer as demonstrated around Chernobyl apparently from 1991. Therefore, immediately after the Fukushima Daiichi Nuclear Power Plant accident on March 2011, iodine thyroid blocking was considered regardless of its successful implementation or not at the indicated timing and places as one of the radiation protection measurements, in addition to evacuation and indoor sheltering, because a short-lived radioactive iodine was massively released into the environment which might crucially affect thyroid glands through inhalation and unrestricted consumption of contaminated food and milk. However, very fortunately, it is now increasingly believed that the exposure doses on the thyroid as well as whole body are too low to detect any radiation-associated cancer risk in Fukushima. Although the risk of radiation-associated health consequences of residents in Fukushima is quite different from that of Chernobyl and is considerably low based on the estimated radiation doses received during the accident for individuals, a large number of people have received psychosocial and mental stresses aggravated by radiation fear and anxiety, and remained in indeterminate and uncertain situation having been evacuated but not relocated. It is, therefore, critically important that best activities and practices related to recovery and resilience should be encouraged, supported and implemented at local and regional levels. Since psychosocial well-being of individuals and communities is the core element of resilience, local individuals, health professionals and authorities are uniquely positioned to identify and provide insight into what would provide the best resolution for their specific needs. PMID- 26059008 TI - Assessment of Myocardial Function in Children before and after Autologous Peripheral Blood Stem Cell Transplantation. AB - BACKGROUND: Increased interest is focused on the long-term adverse effects of bone marrow transplantation. Subclinical cardiac involvement appears common in adults, but only a few reports have examined pediatric patients. MATERIALS AND METHODS: A prospective case-control study of 19 children with normal cardiac function undergoing autologous hematopoietic stem cell transplantation (HSCT) was performed. Tissue Doppler imaging (TDI) and echocardiographic measurements were obtained according to the guidelines of the American Society of Echocardiography before and 3 months after HSCT. RESULTS: Lateral mitral annulus before HSCT showed significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P < 0.0001), late diastolic annular velocity (P = 0.02) and prolonged isovolumetric relaxation time (IRT) (P < 0.0001) compared with control. Significant reduced mitral systolic annular velocity (P < 0.0001), early diastolic annular velocity (P = 0.0005) and Em/Am ratio (P = 0.004), with higher late diastolic annular velocity (P = 0.02) and prolonged isovolumetric contraction time (ICT) (P = 0.003) and IRT (P = 0.002) after HSCT, were observed. Investigation of lateral tricuspid annulus showed nearly similar results as the lateral mitral annulus. LV and RV Tei indices were higher before HSCT compared with control and remained high after HSCT. CONCLUSION: TDI detected subtle abnormalities in systolic and diastolic functions before and after HSCT, which suggests that a conditioning regimen may affect cardiac function. PMID- 26059009 TI - Implementing bacterial acid resistance into cell-free protein synthesis for buffer-free expression and screening of enzymes. AB - Cell-free protein synthesis utilizes translational machinery isolated from the cells for in vitro expression of template genes. Because it produces proteins without gene cloning and cell cultivation steps, cell-free protein synthesis can be used as a versatile platform for high-throughput expression of enzyme libraries. Furthermore, the open nature of cell-free protein synthesis allows direct integration of enzyme synthesis with subsequent screening steps. However, the presence of high concentration of chemical buffers in the conventional reaction mixture makes it difficult to streamline cell-free protein synthesis with pH-based assay of the synthesized enzymes. In this study, we have implemented an enzyme-assisted bacterial acid resistance mechanism into an Escherichia coli (E.coli) extract-based cell-free protein synthesis system in place of chemical buffers. When deployed in the reaction mixture for cell-free synthesis of enzymes, through proton-consuming conversion of glutamate into gamma aminobutyric acid (GABA), an engineered glutamate decarboxylase (GADbeta) was able to maintain the pH of reaction mixture during enzyme synthesis. Because the reaction mixture becomes free of buffering capacity upon the depletion of glutamate, synthesized enzyme could be directly assayed without purification steps. The designed method was successfully applied to the screening of mutant library of sialyltransferase genes to identify mutants with improved enzymatic activity. PMID- 26059010 TI - Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding: A Nationwide Cohort Study. AB - BACKGROUND: Intracranial hemorrhage is the most feared complication of oral anticoagulant treatment. The optimal treatment option for patients with atrial fibrillation who survive an intracranial hemorrhage remains unknown. We hypothesized that restarting oral anticoagulant treatment was associated with a lower risk of stroke and mortality in comparison with not restarting. METHODS AND RESULTS: Linkage of 3 Danish nationwide registries in the period between 1997 and 2013 identified patients with atrial fibrillation on oral anticoagulant treatment with incident intracranial hemorrhage. Patients were stratified by treatment regimens (no treatment, oral anticoagulant treatment, or antiplatelet therapy) after the intracranial hemorrhage. Event rates were assessed 6 weeks after hospital discharge and compared with Cox proportional hazard models. In 1752 patients (1 year of follow-up), the rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for patients treated with oral anticoagulants was 13.6, in comparison with 27.3 for nontreated patients and 25.7 for patients receiving antiplatelet therapy. The rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for recurrent intracranial hemorrhage, the rate of ischemic stroke/systemic embolism, and all cause mortality (per 100 person-years) patients treated with oral anticoagulants was 8.0, in comparison with 8.6 for nontreated patients and 5.3 for patients receiving antiplatelet therapy. The adjusted hazard ratio of ischemic stroke/systemic embolism and all-cause mortality was 0.55 (95% confidence interval, 0.39-0.78) in patients on oral anticoagulant treatment in comparison with no treatment. For ischemic stroke/systemic embolism and for all-cause mortality, hazard ratios were 0.59 (95% confidence interval, 0.33-1.03) and 0.55 (95% confidence interval, 0.37-0.82), respectively. CONCLUSIONS: Oral anticoagulant treatment was associated with a significant reduction in ischemic stroke/all-cause mortality rates, supporting oral anticoagulant treatment reintroduction after intracranial hemorrhage as feasible. Future trials are encouraged to guide clinical practice in these patients. PMID- 26059011 TI - Outcomes and Predictors of Perinatal Mortality in Fetuses With Ebstein Anomaly or Tricuspid Valve Dysplasia in the Current Era: A Multicenter Study. AB - BACKGROUND: Ebstein anomaly and tricuspid valve dysplasia are rare congenital tricuspid valve malformations associated with high perinatal mortality. The literature consists of small, single-center case series spanning several decades. We performed a multicenter study to assess the outcomes and factors associated with mortality after fetal diagnosis in the current era. METHODS AND RESULTS: Fetuses diagnosed with Ebstein anomaly and tricuspid valve dysplasia from 2005 to 2011 were included from 23 centers. The primary outcome was perinatal mortality, defined as fetal demise or death before neonatal discharge. Of 243 fetuses diagnosed at a mean gestational age of 27+/-6 weeks, there were 11 lost to follow up (5%), 15 terminations (6%), and 41 demises (17%). In the live-born cohort of 176 live-born patients, 56 (32%) died before discharge, yielding an overall perinatal mortality of 45%. Independent predictors of mortality at the time of diagnosis were gestational age <32 weeks (odds ratio, 8.6; 95% confidence interval, 3.5-21.0; P<0.001), tricuspid valve annulus diameter z-score (odds ratio, 1.3; 95% confidence interval, 1.1-1.5; P<0.001), pulmonary regurgitation (odds ratio, 2.9; 95% confidence interval, 1.4-6.2; P<0.001), and a pericardial effusion (odds ratio, 2.5; 95% confidence interval, 1.1-6.0; P=0.04). Nonsurvivors were more likely to have pulmonary regurgitation at any gestational age (61% versus 34%; P<0.001), and lower gestational age and weight at birth (35 versus 37 weeks; 2.5 versus 3.0 kg; both P<0.001). CONCLUSION: In this large, contemporary series of fetuses with Ebstein anomaly and tricuspid valve dysplasia, perinatal mortality remained high. Fetuses with pulmonary regurgitation, indicating circular shunt physiology, are a high-risk cohort and may benefit from more innovative therapeutic approaches to improve survival. PMID- 26059013 TI - From Phosphaturia to Cardiovascular Protection: Is Fibroblast Growth Factor-23 the Heart of the Matter? PMID- 26059014 TI - Multi-VENC acquisition of four-dimensional phase-contrast MRI to improve precision of velocity field measurement. AB - PURPOSE: The present study aims to improve precision of four-dimensional (4D) phase-contrast (PC) MRI technique by using multiple velocity encoding (VENC) parameters. THEORY AND METHODS: The 3D flow fields in an in vitro stenosis phantom and an in vivo ascending aorta were determined using a 4D PC-MRI sequence with multiple VENC values. The velocity field obtained for large VENC was combined with that from small VENC, unless velocity data were lost by phase aliasing and phase dispersion. Noise levels of the combined velocity fields were compared with the increasing overlapping number of VENC parameters. RESULTS: The phantom measurement showed that the multi-VENC acquisition reduced the noise levels in radial and axial velocities (> 24 cm/s at VENC = 300 cm/s) down to 0.80 +/- 0.45 cm/s and 5.60 +/- 2.63 cm/s, respectively. This increased the velocity to-noise ratio (VNR) by approximately two-fold to six-fold depending on the locations. As a result, the multi-VENC measurement could visualize the low velocity recirculating flows more clearly. CONCLUSION: The multi-VENC measurement of 4D PC-MRI sequence increased the VNR distribution by reducing velocity noise. The improved VNR can be beneficial for investigating blood flow structures in a flow field with a high velocity dynamic range. PMID- 26059015 TI - Aggregation-Induced Emission Active Metal-Free Chemosensing Platform for Highly Selective Turn-On Sensing and Bioimaging of Pyrophosphate Anion. AB - We report the synthesis of a metal-free chemosensor for highly selective sensing of pyrophosphate (PPi) anion in physiological medium. The novel phenylbenzimidazole functionalized imine containing chemosensor (L; [2,6-bis(((4 (1H-benzo[d]imidazol-2-yl)phenyl)imino) methyl)-4 methyl phenol]) could sense PPi anion through "turn-on" colorimetric and fluorimetric responses in a very competitive environment. The overall sensing mechanism is based on the aggregation-induced emission (AIE) phenomenon. Moreover, a real time in-field device application was demonstrated by sensing PPi in paper strips coated with L. Interestingly, detection of intracellular PPi ions in model human cells could also be possible by fluorescence microscopic studies without any toxicity to these cells. PMID- 26059016 TI - Off-pump coronary artery bypass grafting in patients with mirror-imaging dextrocardia. AB - Dextrocardia requires alterations in techniques during coronary artery bypass graft (CABG) surgery. We report two cases undergoing off-pump coronary artery bypass graft (OPCAB) surgery and discuss techniques for the operative management of these patients. PMID- 26059017 TI - Examination of peripheral blood smears: performance evaluation of a digital microscope system using a large-scale leukocyte database. PMID- 26059018 TI - Ground zero: not asthma at all. AB - Upper airway obstruction is commonly misdiagnosed as asthma. We report on four children with recurrent respiratory symptoms who had been erroneously diagnosed as having asthma and who received anti-asthma medication for several years. The evaluation of spirometry tracing was neglected in all cases. Subglottic stenosis, tracheomalacia secondary to tracheo-esophageal fistula, double aortic arch, and vocal cord dysfunction were suspected by direct inspection of the flow-volume curves and eventually diagnosed. The value of clinical history and careful evaluation of spirometry tracing in children with persistent respiratory symptoms is critically discussed. PMID- 26059019 TI - Sensory stimulation in post-stroke postural imbalance: A novel treatment approach? PMID- 26059020 TI - Endogenous Progesterone Concentrations Affect Progesterone Release from Intravaginal Devices Used for Oestrous Synchronization in Cattle. AB - Intravaginal progesterone-releasing devices are largely used both as contraceptives in humans and as a component of oestrous synchronization protocols in cattle. To reduce costs in large-scale timed artificial insemination, the reuse of these releasing devices is common. Passive hormone diffusion, however, depends on the concentration gradient, which could affect the amount of residual progesterone present in these devices after a first use. To evaluate the effect of the presence of a corpus luteum in the release of progesterone from intravaginal devices, three synchronization protocols were designed to simulate the effects of inserting the device in the early dioestrus, late dioestrus or anoestrus. Holstein-Zebu cross-bred heifers were randomly allocated into one of these three treatments, and a series of blood samples was taken to evaluate the plasma progesterone concentrations. After 8 days, the intravaginal devices were removed and underwent a previously validated alcoholic extraction technique to measure the residual progesterone. Non-used devices were used as controls. As expected, the simultaneous presence of the intravaginal device and a corpus luteum resulted in increased plasma progesterone concentrations. Conversely, the amount of residual progesterone in the devices after use was inversely proportional to the plasma progesterone concentration. These results demonstrate that the release rate of progesterone from intravaginal devices is affected by the endogenous concentration of this hormone; consequently, the strategy for reuse should account for the category and expected luteal cyclic activity of the animals undergoing synchronization protocols. PMID- 26059021 TI - The association of both self-reported and behavioral impulsivity with the annual prevalence of substance use among early adolescents. AB - BACKGROUND: In relation to substance use, Spanish adolescents aged 12 to 14 can be largely classified in four groups, from highest to lowest prevalence: (a) No substance use, (b) Only alcohol use, (c) Alcohol and tobacco use, and (d) Alcohol, tobacco and cannabis use. The aim of the present study is to analyze the possible relationship between impulsivity and the substance-use group to which the young person belongs METHODS: One thousand three hundred and forty-eight adolescents aged 12 to 14 in northern and eastern Spain reported their drug use, completed impulsivity self-reports (BIS-11-A and ImpSS) and performed behavioral tasks (Stroop Test and Delay Discounting). RESULTS: Results from both measurement approaches were related to early drug use. An increasing impulsivity trend is found across groups from less to more substance involvement, except in the case of Delay Discounting, which is sensitive only for those with more substance involved. CONCLUSIONS: Impulsivity is a key factor for early drug use, especially as regards more substance-involved. This should be taken into account in designing prevention programs or as a key variable for interventions aimed at delaying the onset of substance use. PMID- 26059022 TI - Gallic acid induces apoptosis in human cervical epithelial cells containing human papillomavirus type 16 episomes. AB - The high-risk human papillomaviruses (HPV) that infect the anogenital tract are strongly associated with the development of cervical carcinoma, which is the second most common cancer in women worldwide. Therapeutic drugs specifically targeting HPV are not available. Polyphenolic compounds have gained considerable attention because of their cytotoxic effects against a variety of cancers and certain viruses. In this study, we examined the effects of several polyphenols on cellular proliferation and death of the human cervical cancer cells and human cervical epithelial cells containing stable HPV type 16 episomes (HPVep). Our results show that three polyphenols inhibited proliferation of HeLa cells dose dependently. Furthermore, one of the examined polyphenols, gallic acid (GA), also inhibited the proliferation of HPVep cells and exhibited significant specificity towards HPV-positive cells. The anti-proliferative effect of GA on HPVep and HeLa cells was associated with apoptosis and upregulation of p53. These results suggest that GA can be a potential candidate for the development of anti-HPV agents. PMID- 26059023 TI - Electronic polymers in lipid membranes. AB - Electrical interfaces between biological cells and man-made electrical devices exist in many forms, but it remains a challenge to bridge the different mechanical and chemical environments of electronic conductors (metals, semiconductors) and biosystems. Here we demonstrate soft electrical interfaces, by integrating the metallic polymer PEDOT-S into lipid membranes. By preparing complexes between alkyl-ammonium salts and PEDOT-S we were able to integrate PEDOT-S into both liposomes and in lipid bilayers on solid surfaces. This is a step towards efficient electronic conduction within lipid membranes. We also demonstrate that the PEDOT-S@alkyl-ammonium:lipid hybrid structures created in this work affect ion channels in the membrane of Xenopus oocytes, which shows the possibility to access and control cell membrane structures with conductive polyelectrolytes. PMID- 26059024 TI - Sensory Characterization and Consumer Preference Mapping of Fresh Sausages Manufactured with Goat and Sheep Meat. AB - The main objective of this study was the sensory characterization, by a taste and a consumers' panel, of fresh sausages from 140 culled goats and 140 culled ewes. Species and type of preparation effects were studied. All data were previously analyzed by analysis of variance. Taste panel data were analyzed by a Generalized Procrustes Analysis (GPA). Consumers' panel data were analyzed by Preference Mapping. The 1st 2 factors explained 88.22% of total variation in GPA. Different sausages samples were perfectly differentiated by assessors. Goat sausages have been considered harder, more fibrous, and less juicy than sheep sausages. The panelists observed that sheep sausages without paprika had greater intensity of flavor, tasted spicy, and had an off-odor, while goat sausages with paprika were considered sweeter. Consumers' panel did not show any preference for the different types of sausages. This means that all types of sausages can have market opportunity. PRACTICAL APPLICATION: The present study was a result of a project in co-promotion between 2 breeder associations, an industry unit and a research center. Results indicated that the meat from animals out of quality commercial brands could be useful as processed meat in a product with consumer acceptability. Also these new meat products brought diversity to meat industry to reach new markets and originating 2 new meat brands recorded at INPI (Instituto Nacional da Propriedade Industrial-Natl. Industrial Property Inst.) with the numbers of 489664 and 489662 of National Brands of sheep and goat meat, respectively. PMID- 26059025 TI - The Stereochemical Course of the alpha-Hydroxyphosphonate-Phosphate Rearrangement. AB - The phosphonate-phosphate rearrangement is an isomerisation of alpha hydroxyphosphonates bearing electron-withdrawing substituents at the alpha-carbon atom. We studied the stereochemical course of this rearrangement with respect to phosphorus. A set of four diastereomeric alpha-hydroxyphosphonates was prepared by a Pudovik reaction from two diastereomeric cyclic phosphites. The hydroxyphosphonates were separated and rearranged with Et3 N as base. In analogy to trichlorphon, which was the first reported compound undergoing this rearrangement. All four hydroxyphosphonates could be rearranged to 2,2 dichlorovinyl phosphates. Single-crystal X-ray structure analyses of the alpha hydroxyphosphonates and the corresponding phosphates allowed us to show that the rearrangement proceeds with retention of configuration on the phosphorus atom. PMID- 26059029 TI - Glial fibrillary acidic protein-immunoreactive enteroglial cells in the jejunum of cattle. AB - Enteroglial cells (EGCs) play critical roles in human health and disease, however, EGC-dependent neuropathies also affect commercially important animal species. Due to the lack of data on the distribution and phenotypic characterization of the EGCs throughout the bovine gastrointestinal tract, in this study the topographic localization of EGCs in the jejunum of healthy cattle was investigated by immunofluorescence using the glial specific marker glial fibrillary acidic protein (GFAP) and the panneuronal marker PGP 9.5. This analysis was conducted on both cryosections and whole mount preparations including the myenteric and the submucous plexuses of the bovine jejunum. The results obtained showed the presence of a large subpopulation of GFAP-expressing EGCs in the main plexuses and within the muscle layers, whereas only few GFAP positive glial processes were found within the deeper layer of the mucosa, and they never reached the mucosal epithelium. Three different EGC subtypes, namely I, III and IV types were recognized in the examined tract of the bovine intestine. Overall, our results provide the basis for future investigations aimed at elucidating the functional role of the GFAP-containing EGCs which is crucial for a better understanding of the physio-pathology of the bovine intestine. PMID- 26059026 TI - Whey peptide-based enteral diet attenuated elastase-induced emphysema with increase in short chain fatty acids in mice. AB - BACKGROUND: Systemic inflammation is present in chronic obstructive pulmonary disease (COPD). A whey peptide-based enteral diet reduce inflammation in patients with COPD, but its effect on COPD development has not been determined. On the other hand, it is known that short chain fatty acids (SCFAs), which are produced by micro-flora in the gut, attenuates bronchial asthma in mice model. METHODS: Mice with elastase-induced emphysema were fed with 1 of 3 diets (control diet, whey peptide-based enteral diet, or standard enteral diet) to determine the effects of whey peptide-based enteral diet on emphysema and on cecal SCFAs. RESULTS: The whey peptide-based enteral diet group exhibited fewer emphysematous changes; significantly lower total cell counts in bronchoalveolar lavage fluid (BALF); and significantly higher cecal SCFA levels than either the control or standard enteral diet groups. The total cell count was inversely correlated with total cecal SCFA levels in these three diet groups. CONCLUSIONS: The whey peptide based enteral diet attenuates elastase-induced emphysema through the suppression of inflammation in the lung. This may be related to the increase in cecal SCFA. PMID- 26059028 TI - Methylation of KvDMR1 involved in regulating the imprinting of CDKN1C gene in cattle. AB - The CDKN1C gene encodes a cyclin-dependent kinase inhibitor and is one of the key genes involved in the development of Beckwith-Wiedemann syndrome and cancer. In this study, using a direct sequencing approach based on a single nucleotide polymorphism (SNP) at genomic DNA and cDNA levels, we show that CDKN1C exhibits monoallelic expression in all seven studied organs (heart, liver, spleen, lung, kidney, muscle and subcutaneous fat) in cattle. To investigate how methylation regulates imprinting of CDKN1C in cattle, allele-specific methylation patterns in two putative differential methylation regions (DMRs), the CDKN1C DMR and KvDMR1, were analyzed in three tissues (liver, spleen and lung) using bisulfite sequencing PCR. Our results show that in the CDKN1C DMR both parental alleles were unmethylated in all three analyzed tissues. In contrast, KvDMR1 was differentially methylated between the two parental alleles in the same tissues. Statistical analysis showed that there is a significant difference in the methylation level between the two parental alleles (P < 0.01), confirming that this region is the DMR of KvDMR1 and that it may be correlated with CDKN1C imprinting. PMID- 26059012 TI - Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. AB - BACKGROUND: Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor 23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. METHODS AND RESULTS: This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone >=300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had >=30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a >=30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69 0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS: Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839. PMID- 26059030 TI - Adipose-derived stem cells improve the viability of nucleus pulposus cells in degenerated intervertebral discs. AB - Patients with degenerative disc disease (DDD) experience serious clinical symptoms, including chronic low back pain. A series of therapies have been developed to treat DDD, including physical therapy and surgical treatment. However, the therapeutic effect of such treatments has remained insufficient. Recently, stem cell-based therapy, in which stem cells are injected into the nucleus pulposus in degenerated intervertebral disc tissue, has appeared to be effective in the treatment of DDD. In the present study, the effect of adipose derived stem cells on degenerated nucleus pulposus cells was investigated using a co-culture system to evaluate the biological activity of degenerated nucleus pulposus cells. Human degenerated nucleus pulposus tissue was obtained from surgical specimens and the adipose-derived stem cells were derived from adipose tissue. The degenerated nucleus pulposus cells were cultured in a mono-culture or in a co-culture with adipose-derived stem cells using 0.4-um Transwell inserts. The results indicated that adipose-derived stem cells were able to stimulate matrix synthesis and the cell proliferation of degenerated nucleus pulposus cells, promoting the restoration of nucleus pulposus cells in the degenerated intervertebral disc. PMID- 26059031 TI - Neural control of submucosal gland and apical membrane secretions in airways. AB - The mechanisms that lay behind the low-level secretions from airway submucosal glands and the surface epithelium in the absence of external innervation have been investigated in small areas (1.0-1.5 cm(2)) of mucosa from sheep tracheas, freshly collected from a local abattoir. Glandular secretion was measured by an optical method while short circuit current was used as a measure of surface secretion. Activation of neurones in the intrinsic nerve net by veratrine alkaloids caused an immediate increase in both glandular secretion and short circuit current, both effects being blocked by the addition of tetrodotoxin. However, agents known to be acting directly on the glands, such as muscarinic agonists (e.g., carbachol) or adenylate cyclase activators (e.g., forskolin) were not influenced by tetrodotoxin. The toxin alone had no discernable effect on the low-level basal secretion shown by unstimulated glands. Calu-3 cell monolayers, generally agreed to be a surrogate for the secretory cells of submucosal glands, showed no sensitivity to veratrine alkaloids, strengthening the view that the veratrine-like drugs acted exclusively on the intrinsic nerve net. The data are discussed in relation way in which transplanted lungs can maintain mucociliary clearance and hence a sterile environment in the absence of external innervation, as in transplanted lungs. PMID- 26059032 TI - Higher vascular endothelial growth factor-C concentration in plasma is associated with increased forearm capillary filtration capacity in breast cancer-related lymphedema. AB - Breast cancer-related lymphedema (BCRL) is a frequent, chronic and debilitating swelling that mainly affects the ipsilateral arm and develops as a complication to breast cancer treatment. The pathophysiology is elusive opposing development of means for prediction and treatment. We have earlier shown that the forearm capillary filtration coefficient (CFC) is increased bilaterally in BCRL. In this study, we aimed to elucidate if increased CFC is associated with low-grade inflammation and/or vascular endothelial growth factor-c (VEGF-C) signaling. Fourteen patients with unilateral BCRL and nine matched breast cancer controls without BCRL participated. Forearm CFC was measured by venous congestion strain gauge plethysmography, and suction blisters were induced medially on the upper arms. Concentrations of 17 selected cytokines, VEGF-C, and total protein were measured in blister fluid and in plasma. Forearm CFC was higher bilaterally in BCRL subjects (P <= 0.036). No differences between forearms were found in either group. Plasma VEGF-C concentrations were significantly higher in the BCRL subjects (P < 0.001). In BCRL subjects, monocyte chemotactic protein 1 (MCP-1) (P = 0.009) and total protein (P = 0.035) concentrations were higher in blister fluid from edematous arms compared with nonedematous arms. No differences were found in interstitial cytokine or total protein concentrations between arms in control subjects. Higher plasma concentration of VEGF-C is a possible cause of bilaterally increased forearm CFC in BCRL subjects. Interstitially increased MCP 1 levels may augment local microvascular protein permeability in BCRL. PMID- 26059033 TI - Exercise efficiency relates with mitochondrial content and function in older adults. AB - Chronic aerobic exercise has been shown to increase exercise efficiency, thus allowing less energy expenditure for a similar amount of work. The extent to which skeletal muscle mitochondria play a role in this is not fully understood, particularly in an elderly population. The purpose of this study was to determine the relationship of exercise efficiency with mitochondrial content and function. We hypothesized that the greater the mitochondrial content and/or function, the greater would be the efficiencies. Thirty-eight sedentary (S, n = 23, 10F/13M) or athletic (A, n = 15, 6F/9M) older adults (66.8 +/- 0.8 years) participated in this cross sectional study. VO2peak was measured with a cycle ergometer graded exercise protocol (GXT). Gross efficiency (GE, %) and net efficiency (NE, %) were estimated during a 1-h submaximal test (55% VO2peak). Delta efficiency (DE, %) was calculated from the GXT. Mitochondrial function was measured as ATPmax (mmol/L/s) during a PCr recovery protocol with (31)P-MR spectroscopy. Muscle biopsies were acquired for determination of mitochondrial volume density (MitoVd, %). Efficiencies were 17% (GE), 14% (NE), and 16% (DE) higher in A than S. MitoVD was 29% higher in A and ATPmax was 24% higher in A than in S. All efficiencies positively correlated with both ATPmax and MitoVd. Chronically trained older individuals had greater mitochondrial content and function, as well as greater exercise efficiencies. GE, NE, and DE were related to both mitochondrial content and function. This suggests a possible role of mitochondria in improving exercise efficiency in elderly athletic populations and allowing conservation of energy at moderate workloads. PMID- 26059034 TI - Impaired arousal in rat pups with prenatal alcohol exposure is modulated by GABAergic mechanisms. AB - Prenatal alcohol exposure (PAE) increases the risk for The Sudden Infant Death Syndrome (SIDS) in human infants. In rat pups, the arousal response to hypoxia is modulated by medullary raphe GABAergic mechanisms. We hypothesized that arousal to hypoxia is impaired by PAE, and is associated with an increase in medullary GABA and enhanced GABAergic activity. Pregnant dams received an ethanol liquid diet (ETOH), an iso-caloric pair fed diet (PF) or a standard chow diet (CHOW). We first measured the time to arousal (latency), during four episodes of hypoxia in P5, P15, and P21 CHOW, PF, and ETOH pups. We also measured brainstem GABA concentration in the same groups of pups. Finally, we injected artificial cerebrospinal fluid (aCSF), nipecotic acid (NIP) or gabazine into the medullary raphe of P15 and P21 pups receiving the three diets. For statistical analysis, the PF and CHOW groups were combined into a single CONTROL group. Our main finding was that compared to CONTROL, arousal latency to hypoxia is increased in ETOH pups at P15 and P21, and the concentration of brainstem GABA is elevated at P21. NIP administration in CONTROL pups led to arousal latencies similar in magnitude to those in ETOH pups after aCSF injection. NIP injected ETOH pups had no further increases in arousal latency. We conclude that PAE impairs arousal latency and this is mediated or modulated by medullary GABAergic mechanisms. PMID- 26059035 TI - Thresholds of skin sensitivity are partially influenced by mechanical properties of the skin on the foot sole. AB - Across the foot sole, there are vibration and monofilament sensory differences despite an alleged even distribution of cutaneous afferents. Mechanical property differences across foot sole sites have been proposed to account for these differences. Vibration (VPT; 3 Hz, 40 Hz, 250 Hz), and monofilament (MF) perception threshold measurements were compared with skin hardness, epidermal thickness, and stretch response across five foot sole locations in young healthy adults (n = 22). Perceptual thresholds were expected to correlate with all mechanical property measurements to help address sensitivity differences between sites. Following this hypothesis, the MedArch was consistently found to be the thinnest and softest site and demonstrated the greatest sensitivity. Conversely, the Heel was found to be the thickest and hardest site, and was relatively insensitive across perceptual tests. Site differences were not observed for epidermal stretch response measures. Despite an apparent trend of elevated sensory threshold at harder and thicker sites, significant correlations between sensitivity measures and skin mechanical properties were not observed. Skin hardness and epidermal thickness appeared to have a negligible influence on VPT and minor influence on MF within this young healthy population. When normalized (% greater or smaller than subject mean) to the subject mean for each variable, significant positive correlations were observed between MF and skin hardness (R(2) = 0.422, P < 0.0001) and epidermal thickness (R(2) = 0.433, P < 0.0001) providing evidence that skin mechanics can influence MF threshold. In young healthy adults, differences in sensitivity are present across the foot sole, but cannot solely be accounted for by differences in the mechanical properties of the skin. PMID- 26059036 TI - How should we manage anxiety in patients with schizophrenia? AB - OBJECTIVE: We aim to provide a selective clinically focused review of the epidemiology, aetiology and management of comorbid anxiety in people with schizophrenia. METHOD: The following databases were reviewed: PubMed, Medline and Embase. RESULTS: Anxiety is highly prevalent throughout course of schizophrenia, but is often not identified or its clinical significance is under-appreciated. Also, there is a paucity of rigorous data to support specific treatment guidelines for people with schizophrenia and concurrent anxiety disorders. Psychological treatments such as cognitive behavioural therapy appear effective if targeted carefully, and preliminary data suggest that mindfulness approaches and progressive muscle relaxation may be beneficial. Pharmacological interventions need to be tailored to the individual and target specific symptom sets. There is a growing evidence base about the neurobiology of schizophrenia and concurrent anxiety symptoms or disorders which will hopefully enhance treatment options. CONCLUSIONS: Further research is required to guide treatment guidelines for anxiety in people with schizophrenia. PMID- 26059037 TI - The relationship between bipolar disorders, anxiety, and trauma - implications for clinical practice. AB - OBJECTIVE: To assess the relationship between bipolar spectrum disorders, anxiety disorders, trauma, and personality function. METHOD: A cohort of 37 diagnostically challenging bipolar spectrum patients, including both bipolar and personality disordered patients, were assessed using the Structured Combined Interview for DSM-IV to establish diagnosis of bipolarity and anxiety. Diagnoses were then quantitatively related to personality function, using the DSM-5 Level of Personality Function Scale, and to attachment, using the Relationship Questionnaire and Relationship Style Questionnaire. RESULTS: Number of comorbid anxiety disorders was significantly related to both personality and attachment, but not to bipolar status. Patients with more than one anxiety disorder were significantly more likely to have an underlying disturbance of personality. CONCLUSIONS: The presence of multiple anxiety disorders in bipolar spectrum patients may indicate heightened risk of an underlying personality disorder. Replication in a larger and more representative sample is needed. PMID- 26059039 TI - Forage legumes rich in condensed tannins may increase n-3 fatty acid levels and sensory quality of lamb meat. AB - BACKGROUND: Tannins intensively interact with rumen microbes, which is expected to have consequences for meat quality. RESULTS: Silages prepared from birdsfoot trefoil (BT), sainfoin (SF), alfalfa (AF) or red clover (RC) were fed alone to 48 lambs. The SF contained five times more condensed tannins than BT, the other tanniferous plant. Growth and carcass performance, but not general meat quality, was reduced with BT and SF compared to AF and RC. Lambs fed SF had half the skatole levels in the perirenal fat than AF-fed lambs. The longissimus thoracis et lumborum muscle of the SF-fed lambs, compared to RC and BT, had a lower intensity for 'livery' and 'sheepy' flavors but a stronger 'grassy' flavor. The intramuscular fat of BT- and SF-fed lambs contained less saturated and more polyunsaturated fatty acids, especially 20:4n-6, 20:3n-6, 20:5n-3 and 22:5n-3, with SF being more efficient than BT. CONCLUSION: The SF was most promising to increase beneficial fatty acids and to reduce skatole content in lamb meat. PMID- 26059043 TI - Superhydrophobic "Aspirator": Toward Dispersion and Manipulation of Micro/Nanoliter Droplets. PMID- 26059040 TI - Involvement of genes encoding ABI1 protein phosphatases in the response of Brassica napus L. to drought stress. AB - In this report we characterized the Arabidopsis ABI1 gene orthologue and Brassica napus gene paralogues encoding protein phosphatase 2C (PP2C, group A), which is known to be a negative regulator of the ABA signaling pathway. Six homologous B. napus sequences were identified and characterized as putative PP2C group A members. To gain insight into the conservation of ABI1 function in Brassicaceae, and understand better its regulatory effects in the drought stress response, we generated transgenic B. napus plants overexpressing A. thaliana ABI1. Transgenic plants subjected to drought showed a decrease in relative water content, photosynthetic pigments content and expression level of RAB18- and RD19A-drought responsive marker genes relative to WT plants. We present the characterization of the drought response of B. napus with the participation of ABI1-like paralogues. The expression pattern of two evolutionarily distant paralogues, BnaA01.ABI1.a and BnaC07.ABI1.b in B. napus and their promoter activity in A. thaliana showed differences in the induction of the paralogues under dehydration stress. Comparative sequence analysis of both BnaABI1 promoters showed variation in positions of cis-acting elements that are especially important for ABA- and stress-inducible expression. Together, these data reveal that subfunctionalization following gene duplication may be important in the maintenance and functional divergence of the BnaABI1 paralogues. Our results provide a framework for a better understanding of (1) the role of ABI1 as a hub protein regulator of the drought response, and (2) the differential involvement of the duplicated BnaABI1 genes in the response of B. napus to dehydration related stresses. PMID- 26059041 TI - Impact of bacterial coinfection on clinical outcomes in pneumococcal pneumonia. AB - The aim of this study was to investigate the influence of bacterial coinfection on patients with pneumococcal pneumonia. We retrospectively analyzed the incidence, clinical features, microbial distributions, and outcomes of patients with bacterial coinfection in a cohort of 433 hospitalized patients with pneumococcal pneumonia. Eighty-five patients (19.6 %) were diagnosed with bacterial coinfection; the most frequent pathogens were Haemophilus influenzae (25 patients, 33.3 %), methicillin-susceptible Staphylococcus aureus (MSSA) (15 patients, 20.0 %), and Moraxella catarrhalis (13 patients, 17.3 %). The CURB-65 score and pneumonia severity index (PSI) were significantly higher in patients with bacterial coinfection (both P < 0.001). In addition, the proportion of patients with bacterial coinfection who met the Infectious Disease Society of America (IDSA)/American Thoracic Society (ATS) severe pneumonia criteria was significantly higher (P < 0.001). Multivariate logistic regression analysis identified three risk factors for bacterial coinfection in patients with pneumococcal pneumonia: alcoholism (odds ratio [OR], 5.12; 95 % confidence interval (95 % CI), 1.60-16.4; P = 0.006), hospitalization for 2 days or more within 90 days preceding admission (OR, 2.02; 95 % CI, 1.03-3.98; P = 0.041), and residence in a nursing home or extended care facility (OR, 3.22; 95 % CI, 1.48 6.97; P = 0.003). Multivariate analysis for 30-day mortality showed that bacterial coinfection was a significant adverse prognostic factor (OR, 2.50; 95 % CI, 1.13-5.53; P = 0.023), independent of IDSA/ATS severe pneumonia, PSI, or healthcare-associated pneumonia. In conclusion, bacterial coinfection may have an adverse impact on severity and outcomes of pneumococcal pneumonia. PMID- 26059044 TI - The N-glycan on Asn54 affects the atypical N-glycan composition of plant-produced interleukin-22, but does not influence its activity. AB - Human interleukin-22 (IL-22) is a member of the IL-10 cytokine family that has recently been shown to have major therapeutic potential. IL-22 is an unusual cytokine as it does not act directly on immune cells. Instead, IL-22 controls the differentiation, proliferation and antimicrobial protein expression of epithelial cells, thereby maintaining epithelial barrier function. In this study, we transiently expressed human IL-22 in Nicotiana benthamiana plants and investigated the role of N-glycosylation on protein folding and biological activity. Expression levels of IL-22 were up to 5.4 MUg/mg TSP, and N-glycan analysis revealed the presence of the atypical Lewis A structure. Surprisingly, upon engineering of human-like N-glycans on IL-22 by co-expressing mouse FUT8 in DeltaXT/FT plants a strong reduction in Lewis A was observed. Also, core alpha1,6 fucoylation did not improve the biological activity of IL-22. The combination of site-directed mutagenesis of Asn54 and in vivo deglycosylation with PNGase F also revealed that N-glycosylation at this position is not required for proper protein folding. However, we do show that the presence of a N-glycan on Asn54 contributes to the atypical N-glycan composition of plant-produced IL-22 and influences the N glycan composition of N-glycans on other positions. Altogether, our data demonstrate that plants offer an excellent tool to investigate the role of N glycosylation on folding and activity of recombinant glycoproteins, such as IL 22. PMID- 26059045 TI - Clonal analysis of individual human embryonic stem cell differentiation patterns in microfluidic cultures. AB - Heterogeneity in the clonal outputs of individual human embryonic stem cells (hESCs) confounds analysis of their properties in studies of bulk populations and how to manipulate them for clinical applications. To circumvent this problem we developed a microfluidic device that supports the robust generation of colonies derived from single ESCs. This microfluidic system contains 160 individually addressable chambers equipped for perfusion culture of individual hESCs that could be shown to match the growth rates, marker expression and colony morphologies obtained in conventional cultures. Use of this microfluidic device to analyze the clonal growth kinetics of multiple individual hESCs induced to differentiation revealed variable shifts in the growth rate, area per cell and expression of OCT4 in the progeny of individual hESCs. Interestingly, low OCT4 expression, a slower growth rate and low nuclear to cytoplasmic ratios were found to be correlated responses. This study demonstrates how microfluidic systems can be used to enable large scale live-cell imaging of isolated hESCs exposed to changing culture conditions, to examine how different aspects of their variable responses are correlated. PMID- 26059046 TI - A de novo 1.58 Mb deletion, including MAP2K6 and mapping 1.28 Mb upstream to SOX9, identified in a patient with Pierre Robin sequence and osteopenia with multiple fractures. AB - Defects of long-range regulatory elements of dosage-sensitive genes represent an under-recognized mechanism underlying genetic diseases. Haploinsufficiency of SOX9, the gene essential for development of testes and differentiation of chondrocytes, results in campomelic dysplasia, a skeletal malformation syndrome often associated with sex reversal. Chromosomal rearrangements with breakpoints mapping up to 1.6 Mb up- and downstream to SOX9, and disrupting its distant cis regulatory elements, have been described in patients with milder forms of campomelic dysplasia, Pierre Robin sequence, and sex reversal. We present an ~1.58 Mb deletion mapping ~1.28 Mb upstream to SOX9 that encompasses its putative long-range cis-regulatory element(s) and MAP2K6 in a patient with Pierre Robin sequence and osteopenia with multiple fractures. Low bone mass panel testing using massively parallel sequencing of 23 nuclear genes, including COL1A1 and COL1A2 was negative. Based on the previous mouse model of Map2k6, suggesting that Sox9 is likely a downstream target of the p38 MAPK pathway, and our previous chromosome conformation capture-on-chip (4C) data showing potential interactions between SOX9 promoter and MAP2K6, we hypothesize that deletion of MAP2K6 might have affected SOX9 expression and contributed to our patient's phenotype. PMID- 26059047 TI - Hydrogen sulfide mediated cascade reaction forming an iminocoumarin: applications in fluorescent probe development and live-cell imaging. AB - The study on a fluorescent probe that undergoes a H2S mediated cascade reaction to form an iminocoumarin fluorophore is reported. The probe features better water solubility and fast sensing time (t1/2 = 6.1 min and response time = 24 min) as key advances compared to the reported probe that works on a similar mechanism. The sensing mechanism of the probe was demonstrated by mass spectrometric, HPLC titration and FT-IR titration methods. H2S sensing by the probe was characterized by a 31-fold fluorescence enhancement and alimit of detection of 169 nM. Application of the probe was demonstrated by imaging of H2S in live cells. PMID- 26059048 TI - Uncultured adipose-derived regenerative cells (ADRCs) seeded in collagen scaffold improves dermal regeneration, enhancing early vascularization and structural organization following thermal burns. AB - OBJECTIVE: Advances in tissue engineering have yielded a range of both natural and synthetic skin substitutes for burn wound healing application. Long-term viability of tissue-engineered skin substitutes requires the formation and maturation of neo-vessels to optimize survival and biointegration after implantation. A number of studies have demonstrated the capacity of Adipose Derived Regenerative Cells (ADRCs) to promote angiogenesis and modulate inflammation. On this basis, it was hypothesized that adding ADRCs to a collagen based matrix (CBM) (i.e. Integra) would enhance formation and maturation of well organized wound tissue in the setting of acute thermal burns. The purpose of this study was to evaluate whether seeding uncultured ADRCs onto CBM would improve matrix properties and enhance healing of the grafted wound. METHODS: Full thickness thermal burns were created on the backs of 8 Gottingen mini-swine. Two days post-injury wounds underwent fascial excision and animals were randomized to receive either Integra seeded with either uncultured ADRCs or control vehicle. Wound healing assessment was performed by digital wound imaging, histopathological and immunohistochemical analyses. RESULTS: In vitro analysis demonstrated that freshly isolated ADRCs adhered and propagated on the CBM. Histological scoring revealed accelerated maturation of wound bed tissue in wounds receiving ADRCs-loaded CBM compared to vehicle-loaded CBM. This was associated with a significant increase in depth of the wound bed tissue and collagen deposition (p<0.05). Blood vessel density in the wound bed was 50% to 69.6% greater in wounds receiving ADRCs-loaded CBM compared to vehicle-loaded CBM (p=0.05) at day 14 and 21. In addition, ADRCs delivered with CBM showed increased blood vessel lumen area and blood vessel maturation at day 21(p=0.05). Interestingly, vascularity and overall cellularity within the CBM were 50% and 45% greater in animals receiving ADRC loaded scaffolds compared to CBM alone (p<0.05). CONCLUSIONS: These data demonstrate that seeding uncultured ADRCs onto CBM dermal substitute enhances wound angiogenesis, blood vessel maturation and matrix remodeling. PMID- 26059049 TI - Epidemiology of a decade of Pediatric fatal burns in Colombia, South America. AB - BACKGROUND: Burns represent a serious problem around the world especially in low- and middle-income countries. The aim was to determine the epidemiological characteristics, causes and mortality rate of burn deaths in the Colombian pediatric population as well as to guide future education and prevention programs. METHODS: We conducted an observational, analytical, retrospective population-based study. It was based upon official death certificate data using diagnosis codes for burns (scalds, thermal, electrical, intentional self-harm and not specified), that occurred between January 1, 2000 and December 31, 2009. Official death certificates of the pediatric population of up to 15 years of age were obtained from the National Administrative Department of Statistics. RESULTS: A total of 1197 fatal pediatric injuries related to burns were identified. The crude and adjusted mortality rate for burns in the pediatric population in Colombia during the length of the study was 0.899 and 0.912 per 100,000, respectively. The mortality rate tended to decrease (-5.17% annual) during the duration of the study. Children under 5 years of age were the most affected group (59.5%). Almost half of them died before arriving at a health facility (47.1%). Fire is the principal cause of death attributable to burns in Colombia, followed by electric burns and hot liquids. CONCLUSIONS: This is a first step study in researching the epidemiological features of pediatric deaths after burns. The Public Health's strategies should be oriented toward community awareness about these kind of injuries, and to teach children and families about risk factors and first aid. PMID- 26059050 TI - Modification, cultural adaptation and validation of burn specific health scale brief (BSHS-B) for Hindi speaking population. AB - BACKGROUND: The burn specific health scale-brief (BSHS-B) has found wide acceptance as a quality of life (Qol) assessment tool. However, BSHS has rarely been employed in a very low income country like India, where burns is endemic and burns are more severe. AIM: To modify, culturally adapt and to translate BSHS-B in Hindi. METHODS: Five questions were added to the original BSHS-B (40 questions). Two questions on walking and squatting were added to the domain 'simple abilities' which was renamed 'simple abilities and mobility'; a question on itching was added to domain of 'heat sensitivity' which was renamed 'skin sensitivity'; and two questions on family income and assets were added to the domain of 'work', which was renamed 'work and economic impact'. The modified assessment scale was accorded an acronym BSHS-RBA (revised brief and adapted). Twenty patients of thermal burns (mean age 30.95 yr) with mean TBSA burns of 39.75%, and who were between six months to a year from healing of burn wounds were included in this validation study. All questionnaires were filled by interviews. RESULTS: The kappa value for inter-rater variability was 0.748. The Cronbach's alpha for internal consistency of various domains ranged from 0.443 (simple abilities and mobility) to 0.908 (sexuality), the scale showed good discriminant validity in 31 of 36 domain correlations, which confirms the construct validity of the instrument. CONCLUSIONS: BSHS-RBA with five additional items, on mobility, economic impact and itch is a reliable and valid instrument. It is currently seen to be very useful in assessment of Qol in low income countries. PMID- 26059051 TI - Impact of Haemophilus influenzae type B (Hib) and viral influenza vaccinations in pregnancy for improving maternal, neonatal and infant health outcomes. AB - BACKGROUND: Infections during pregnancy confers increased risk of maternal and perinatal morbidity and mortality. However, the case for advocating Haemophilus influenzae type B (Hib) and viral Influenza vaccinations in pregnancy is still debatable. OBJECTIVES: To assess the impact of Hib and viral Influenza vaccinations during pregnancy on maternal, neonatal and infant health outcomes compared to placebo/control. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (29 January 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised controlled clinical trials (including cluster-randomised trials) and quasi-randomised trials evaluating Hib or viral influenza vaccination during pregnancy compared with no vaccination or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion, risk of bias and extracted data. Data were checked for accuracy. MAIN RESULTS: Two trials were included this review. One (involving 213 women and 213 neonates) evaluated the impact of Hib vaccination during pregnancy and the other study (involving 2116 women and 2049 neonates) evaluated the impact of viral influenza vaccination during pregnancy. Overall, the HiB vaccination trial was judged to be at 'high risk of bias' due to inadequate randomisation while the other trial was judged to be at 'low risk of bias'. Hib vaccination during pregnancy versus placeboOne trial involving 213 women and 213 neonates evaluating the impact of Hib vaccination during pregnancy was included under this comparison. The study did not report on any of this review's prespecified primary outcomes (including mortality, respiratory tract infection and sepsis) or secondary outcomes (including adverse events) except preterm delivery. There was no clear difference between the Hib vaccination and placebo control groups in terms of preterm delivery (risk ratio (RR) 1.28, 95% confidence interval (CI) 0.12 to 13.86, one study, 213 participants), fetal distress (RR 1.23, 95% CI 0.67 to 2.26, one study, 213 infants), intubation (RR 1.03, 95% CI 0.55 to 1.95, one study, 213 infants) and neonatal jaundice (RR 1.01, 95% CI 0.52 to 1.97, one study, 213 infants). We could not grade the evidence for quality due to lack of outcome data. Viral influenza vaccination during pregnancy versus placeboOne trial involving 2116 women and 2049 infants evaluating the impact of trivalent inactivated influenza vaccine (IIV3) during pregnancy was included under this comparison.There was no clear difference between the viral influenza and placebo control group in terms of most of this review's primary outcomes: maternal death (RR 4.96, 95% CI 0.24 to 103.24, moderate quality evidence), infant death up to 175 days after birth (RR 0.71, 95% CI 0.37 to 1.37, moderate quality evidence), perinatal death (stillbirth and death in the first week of life) (RR 1.32, 95% CI 0.73 to 2.38, moderate quality evidence), influenza-like illness in women (RR 0.96, 95% CI 0.79 to 1.16) or their babies (RR 1.02, 95% CI 0.94 to 1.09), any respiratory illness in women (RR 0.97, 95% CI 0.91 to 1.04, high quality evidence) or their babies (RR 1.01, 95% CI 0.95 to 1.07, high quality evidence). There were also no clear differences between vaccination and placebo control groups in terms of maternal hospitalisation for any infection (RR 2.27, 95% CI 0.94 to 5.49; 2116 women, moderate quality evidence), and neonatal hospitalisation for sepsis (RR 1.60, 95% CI 0.73 to 3.50; 2049 infants, moderate quality evidence). However, viral influenza vaccination during pregnancy was associated with a reduction in reverse-transcriptase-polymerase-chain-reaction (RT-PCR) confirmed influenza among infants (RR 0.51, 95% CI 0.30 to 0.88, one study, 2049 infants) and women (RR 0.50, 95% CI 0.29 to 0.86, one study, 2116 women).In terms of this review's secondary outcomes, there were no clear differences in terms of the impact on pregnancy outcomes (miscarriage, preterm labour and stillbirth), hospitalisation for respiratory infection among women and infants. Similarly, there was no difference between the viral influenza vaccine and placebo control groups in terms of any adverse systemic reactions. AUTHORS' CONCLUSIONS: There is limited evidence (from one small trial at a high risk of bias) on the effectiveness on Hib during pregnancy for improving maternal, neonatal and infant health outcomes.Evidence from one large high quality trial on the effectiveness of viral influenza vaccine during pregnancy suggests reduced RT PCR confirmed influenza among women and their babies, suggesting the potential of this strategy for scale up but further evidence from varying contexts is required.Further trials for both Hib and viral influenza vaccines with appropriate study designs and suitable comparison groups are required. There are currently two 'ongoing' studies - these will be incorporated into the review in future updates. PMID- 26059052 TI - Latent growth curve analysis with dichotomous items: Comparing four approaches. AB - A Monte Carlo study was used to compare four approaches to growth curve analysis of subjects assessed repeatedly with the same set of dichotomous items: A two step procedure first estimating latent trait measures using MULTILOG and then using a hierarchical linear model to examine the changing trajectories with the estimated abilities as the outcome variable; a structural equation model using modified weighted least squares (WLSMV) estimation; and two approaches in the framework of multilevel item response models, including a hierarchical generalized linear model using Laplace estimation, and Bayesian analysis using Markov chain Monte Carlo (MCMC). These four methods have similar power in detecting the average linear slope across time. MCMC and Laplace estimates perform relatively better on the bias of the average linear slope and corresponding standard error, as well as the item location parameters. For the variance of the random intercept, and the covariance between the random intercept and slope, all estimates are biased in most conditions. For the random slope variance, only Laplace estimates are unbiased when there are eight time points. PMID- 26059054 TI - Free intra-osseous muscle transfer for treatment of chronic osteomyelitis. AB - BACKGROUND: Chronic osteomyelitis is still a big reconstructive challenge. Even with standard care, therapeutic failures and recurrences are common. Multiple techniques of tissue transfer have increased the success rate. This study recommends free muscle transfers into the intramedullary bone cavities for treatment of chronic osteomyelitis. PATIENTS AND METHODS: The review included 29 patients that were treated for chronic osteomyelitis. Osteomyelitis was located at the femur in four patients, the tibia in 22 patients, and the foot in three patients. Dead bone and scar tissue were replaced with durable free muscle flap with special attention to fill the dead space. RESULTS: The average age of these patients was 48.5 years old (range = 23-70 years old). The average duration of osteomyelitis was 8.2 years (range = 1-45 years). Gracilis was applied in 20 cases (69%), latissimus dorsi was used in five cases (17.2%), and rectus abdominis was performed in four cases (13.8%). There was one flap failure, one partial superficial flap necrosis, two arterial thrombosis, and one venous thrombosis. All the remaining 28 muscle flaps survived. From 1-10 years follow up, there was one recurrence of the osteomyelitis in the distal end of the intra medullary cavity of a femur after reconstructing using the gracilis flap. CONCLUSION: The present study demonstrated that free intramedullary muscle transfers are effective in providing a high rate of success in the treatment of chronic osteomyelitis. The secondary filling of the intramedullary cavity after extensive removal of all infected bony sequesters has proven to give a long-term arrest of chronic osteomyelitis. PMID- 26059053 TI - Combinatorial chemistry in nematodes: modular assembly of primary metabolism derived building blocks. AB - The nematode Caenorhabditis elegans was the first animal to have its genome fully sequenced and has become an important model organism for biomedical research. However, like many other animal model systems, its metabolome remained largely uncharacterized, until recent investigations demonstrated the importance of small molecule-based signalling cascades for virtually every aspect of nematode biology. These studies have revealed that nematodes are amazingly skilled chemists: using simple building blocks from conserved primary metabolism and a strategy of modular assembly, C. elegans and other nematode species create complex molecular architectures to regulate their development and behaviour. These nematode-derived modular metabolites (NDMMs) are based on the dideoxysugars ascarylose or paratose, which serve as scaffolds for attachment of moieties from lipid, amino acid, carbohydrate, citrate, and nucleoside metabolism. Mutant screens and comparative metabolomics based on NMR spectroscopy and MS have so-far revealed several 100 different ascarylose ("ascarosides") and a few paratose ("paratosides") derivatives, many of which represent potent signalling molecules that can be active at femtomolar levels, regulating development, behaviour, body shape, and many other life history traits. NDMM biosynthesis appears to be carefully regulated as assembly of different modules proceeds with very high specificity. Preliminary biosynthetic studies have confirmed the primary metabolism origin of some NDMM building blocks, whereas the mechanisms that underlie their highly specific assembly are not understood. Considering their functions and biosynthetic origin, NDMMs represent a new class of natural products that cannot easily be classified as "primary" or "secondary". We believe that the identification of new variants of primary metabolism-derived structures that serve important signalling functions in C. elegans and other nematodes provides a strong incentive for a comprehensive re-analysis of metabolism in higher animals, including humans. PMID- 26059055 TI - Cardiac sarcoidosis predominantly involved in right ventricle: An autopsy case. PMID- 26059056 TI - Curcumin inhibits the invasion of lung cancer cells by modulating the PKCalpha/Nox-2/ROS/ATF-2/MMP-9 signaling pathway. AB - Invasion and metastasis are the major causes of tumor-related mortality in lung cancer. It is believed that curcumin is an effective drug possessing anti invasive and anti-metastatic activities in the treatment of cancer. However, the specific mechanisms remain unclear. In the present study, we investigated whether the PKCalpha/Nox-2/ATF-2/MMP-9 signaling pathway is involved in the invasive behavior of lung cancer and whether curcumin could inhibit invasion by modulating this pathway. The cytotoxic effect of curcumin was evaluated by MTT assay and the capacity of invasion was assessed by Transwell assay. siRNA and plasmid transfection techniques were used to study the function of targeted genes. Real time PCR and western blot analysis were used to evaluate the expression levels of PKCalpha, Nox-2, MMP-9 and the phosphorylation of ATF-2. The results showed that curcumin inhibited the proliferation and invasion of A549 cells in a dose dependent manner. Overexpression of MMP-9 enhanced the invasion of A549 cells. However, inhibition of MMP-9 by siRNA or curcumin suppressed cell invasion. Moreover, we also demonstrated the catalytic role of PKCalpha in expression of MMP-9 and cellular invasion in A549 cells, which was dependent on the expression of Nox-2 and phosphorylation of ATF-2. Finally, we also showed that curcumin dose dependently reduced the expression of PKCalpha, P47phox, Nox-2 and phosphorylated ATF-2, as well as intracellular ROS generation, suggesting the inhibitory effect of curcumin on the activation of the PKCalpha/Nox-2/ROS/ATF-2 pathway. In conclusion, the PKCalpha/Nox-2/ROS/ATF-2/MMP-9 signaling pathway is activated in lung cancer A549 cells, which could be modulated by curcumin to inhibit cell invasiveness. PMID- 26059057 TI - Nondestructive and intuitive determination of circadian chlorophyll rhythms in soybean leaves using multispectral imaging. AB - The circadian clock, synchronized by daily cyclic environmental cues, regulates diverse aspects of plant growth and development and increases plant fitness. Even though much is known regarding the molecular mechanism of circadian clock, it remains challenging to quantify the temporal variation of major photosynthesis products as well as their metabolic output in higher plants in a real-time, nondestructive and intuitive manner. In order to reveal the spatial-temporal scenarios of photosynthesis and yield formation regulated by circadian clock, multispectral imaging technique has been employed for nondestructive determination of circadian chlorophyll rhythms in soybean leaves. By utilizing partial least square regression analysis, the determination coefficients R(2), 0.9483 for chlorophyll a and 0.8906 for chlorophyll b, were reached, respectively. The predicted chlorophyll contents extracted from multispectral data showed an approximately 24-h rhythm which could be entrained by external light conditions, consistent with the chlorophyll contents measured by chemical analyses. Visualization of chlorophyll map in each pixel offers an effective way to analyse spatial-temporal distribution of chlorophyll. Our results revealed the potentiality of multispectral imaging as a feasible nondestructive universal assay for examining clock function and robustness, as well as monitoring chlorophyll a and b and other biochemical components in plants. PMID- 26059058 TI - The effect of extracorporeal photopheresis on T cell response in chronic graft versus-host disease. AB - Extracorporeal photopheresis (ECP) is a safe and effective immunoregulatory therapy for steroid-refractory chronic graft-versus-host disease (cGVHD) but its mechanism of action is poorly understood. In this study, we evaluated the effect of ECP in a sample of cGVHD patients. Our data showed that ECP-treated patients had lower CD4 T and B cells, and substantially higher NK cells than untreated patients. T regulatory (Treg) cells were similar between the two groups of patients. Interestingly, Treg cells were higher in ECP-treated patients and ECP responders who had no history of aGVHD or sclerosis, than in those who had one of them or both. These findings suggest that at least one of the mechanisms of immunomodulation by ECP targets the Treg cell population and that an increase in Treg cells may be associated with response in patients with cGVHD. Together, the results of ECP are different depending on the patients' clinical condition. PMID- 26059059 TI - High-dose thiotepa-based conditioning regimens for relapsed lymphoma involving the central nervous system: from "orphan drug" to a standard-of-care? PMID- 26059060 TI - Spontaneous regression of a systemic ALK (+) anaplastic large cell lymphoma carrying ALK gene rearrangement that developed after PPD tuberculin skin test. PMID- 26059061 TI - Splitting livers: Trans-hilar or trans-umbilical division? Technical aspects and comparative outcomes. AB - Controversy remains about the best line of division for liver splitting, through Segment IV or through the umbilical fissure. Both techniques are currently used, with the choice varying between surgical teams in the absence of an evidence based choice. We conducted a single-center retrospective analysis of 47 left split liver grafts that were procured with two different division techniques: "classical" (N = 28, Group A) or through the umbilical fissure and plate (N = 19, Group B). The allocation of recipients to each group was at random; a single transplant team performed all transplantations. Demographics, characteristics, technical aspects, and outcomes were similar in both groups. The grafts in Group A, prepared with the classical technique, were procured more often with a single BD orifice compared with the grafts in Group B; however, this was not associated with a higher incidence of biliary problems in this series of transplants (96% actual graft survival rate [median +/- s.d. FOLLOW-UP: 26 +/- 20 months]). Both techniques provide good quality split grafts and an excellent outcome; surgical expertise with a given technique is more relevant than the technique itself. The classical technique, however, seems to be more flexible in various ways, and surgeons may find it to be preferable. PMID- 26059062 TI - Mitochondria as targets of drug toxicity: Lessons from the R118 phase I experience. AB - Low Wang et al. report the results of the phase I program for R118 in this issue.(2) R118 was designed as an activator of adenosine monophosphate activated protein kinase (AMPK) to treat claudication. The single ascending dose study in healthy subjects was characterized by an unacceptable number of serious adverse events and substantial risk to the participants. The probable mitochondrial mechanism underlying these adverse events suggests important lessons for future drug development. PMID- 26059063 TI - Targeting roles of inflammatory microenvironment in lung cancer and metastasis. AB - Inflammatory cells and mediators are essential components in tumor microenvironment and play decisive roles in the initiation, proliferation, survival, promotion, invasion, or metastasis of lung cancer. Clinical and epidemiologic studies suggested a strong association between inflammation and lung cancer and an influence of immune surveillances and tumor responses to chemotherapeutic drugs, although roles of inflammation in lung cancer remain unclear. The present review outlined roles of inflammation in lung cancer, with particular focus on inflammatory components, types, biomarkers, or principal mechanisms by which the inflammation contributes to the development of lung cancer. The cancer-associated inflammatory cells (CICs) should be furthermore defined and include cancer-specific and interacted cells with inflammatory or inflammation-like characteristics, e.g., innate or adaptive immune cells and cancer tissue cells. We also discuss targeting potentials of inflammation in the prevention and treatment of lung cancer. The diversity of cancer-related inflammatory microenvironment is instrumental to design novel therapeutic approaches for lung cancer. PMID- 26059064 TI - T-cell plasticity in inflammatory skin diseases--the good, the bad, and the chameleons. AB - According to the concept of T-cell plasticity, peripheral T cells - once differentiated into a specific T cell subset - may, in response to new environmental cues or signaling alterations, adopt the phenotype of a different helper cell subset with regard to cytokine production and regulatory functions. In a variety of T cell-mediated inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and psoriasis, T-cell plasticity - in particular the conversion of regulatory T cells (Tregs) to IL-17 producing inflammatory cells - has recently been described as key pathomechanism contributing to the aggravation of inflammatory symptoms and disease chronification. Apart from psoriasis, the phenomenon of immune cell plasticity may also have a role in other inflammatory conditions of the skin showing a T cell component and/or an IL-17-mediated pathology, such as lichen planus, lupus erythematosus, blistering diseases, allergic disorders, and others. This review summarizes the basic molecular mechanisms regulating T-cell fate decisions and plasticity in inflamed skin and in other lymphoid organs. Moreover, it explores the effect of established targeted therapies as well as alternative concepts with a focus on how to prevent the unwanted conversion of "helpful" T cells and other beneficial immune cells to pathological inflammatory vermin. PMID- 26059065 TI - Effects of volatile organic compounds from Streptomyces albulus NJZJSA2 on growth of two fungal pathogens. AB - A Streptomyces albulus strain NJZJSA2 was isolated from the forest soil sample of Tzu-chin Mountain (Nanjing China) and identified based on its morphological and physiological properties and 16S rDNA gene sequence analysis. The strain S. albulus NJZJSA2 was evaluated for the production of antifungal volatile organic compounds (VOCs) against two fungal pathogens. Results showed that the VOCs generated by S. albulus NJZJSA2 inhibited mycelial growth of Sclerotinia sclerotiorum (SS) and Fusarium oxysporum (FO) by 100 and 56.3%, respectively. The germination of SS sclerotia and FO conidia was completely inhibited in the presence of VOCs produced by S. albulus NJZJSA2 in vitro. In soil, the VOCs delayed the germination of SS sclerotia and inhibited the germination of FO conidia for 45 days. The strain S. albulus NJZJSA2 was able to produce 13 VOCs based on GC/MS analyses. Among those, six compounds were purchased and used for the antifungal activity assay. Three relatively abundant VOCs, 4-methoxystyrene, 2-pentylfuran, and anisole were proved to have antifungal activity. Microscopy analysis showed that the pathogen hyphae were shriveled and damaged after treatment with 4-methoxystyrene. These results suggest that the S. albulus strain NJZJSA2 produce VOCs that not only reduce the growth of SS and FO, but also significantly inhibit the SS sclerotia and FO conidia. The results are useful for the better understanding of biocontrol mechanisms by S. albulus strains and will help to improve the biological control efficiency of lethal plant diseases. PMID- 26059067 TI - Purification and Characterization of a Cysteine-Rich 14-kDa Antibacterial Peptide from the Granular Hemocytes of Mangrove Crab Episesarma tetragonum and Its Antibiofilm Activity. AB - Antimicrobial peptide (AMP) crustin is a type of immune molecule present in the immune system of crustaceans and response against microbial invasion. In the present study, we have identified and characterized the cationic, amphipathic structure consisting of AMP crustin from a mangrove crab Episesarma tetragonum using CM Sepharose-based cation exchange column chromatography. E. tetragonum crustin showed a single band of 14 kDa on SDS-PAGE and the homogeneity showed retention time of 8.4 min in RP-HPLC. Functional studies of E. tetragonum crustin exhibits the antibacterial activity (2-4 MUg/ml) and biofilm inhibition (20 MUg/ml) against the Gram-positive bacteria Staphylococcus aureus and Enterococcus faecalis. Hydrophobicity and extrapolysaccharide production of Gram-positive bacteria were inhibited through the bactericidal inhibitory concentration. In situ visualization analysis of biofilm inhibition was observed through light and confocal laser scanning microscopy. Surface morphology and the bacterial biofilm inhibition were viewed by scanning electron and atomic force microscopy. This study emphasizes the potential activity of E. tetragonum crustin, an interesting candidate for the development of novel broad-spectrum antimicrobial agent against bacterial pathogens. Graphical Abstract Antimicrobial peptide synthesis and host pathogen interaction lead to production of immune molecules directed to destruction of pathogens. PMID- 26059068 TI - Bonding of heme Fe(III) with dioxygen: observation and characterization of an incipient bond. AB - While ferrous heme (Fe(II)) within hemoproteins binds dioxygen efficiently, it has not yet been possible to observe the analog complex with ferric heme (Fe(III)). We present the first observation and characterization of the latter complex in a cooled ion trap. The bond formation enthalpy of ferric heme-O2 has been derived from the Van't Hoff equation by means of temperature dependent measurements. The binding energy of the [heme Fe(III)-O2](+) ionic complex is rather strong as compared to that of [heme Fe(III)-N2](+), showing the formation of an incipient Fe-O bond, which is confirmed by the electronic absorption spectra of the two complexes. This first observation of the [heme Fe(III)-O2](+) complex lays the basis for the precise description of its electronic states. PMID- 26059069 TI - Participation of TNF-alpha in Inhibitory Effects of Adipocytes on Osteoblast Differentiation. AB - Mesenchymal stem cells from bone marrow (BM-MSCs) and adipose tissue (AT-MSCs) are attractive tools for cell-based therapies to repair bone tissue. In this study, we investigated the osteogenic and adipogenic potential of BM-MSCs and AT MSCs as well as the effect of crosstalk between osteoblasts and adipocytes on cell phenotype expression. Rat BM-MSCs and AT-MSCs were cultured either in growth, osteogenic, or adipogenic medium to evaluate osteoblast and adipocyte differentiation. Additionally, osteoblasts and adipocytes were indirectly co cultured to investigate the effect of adipocytes on osteoblast differentiation and vice versa. BM-MSCs and AT-MSCs exhibit osteogenic and adipogenic potential under non-differentiation-inducing conditions. When exposed to osteogenic medium, BM-MSCs exhibited higher expression of bone markers compared with AT-MSCs. Conversely, under adipogenic conditions, AT-MSCs displayed higher expression of adipose tissue markers compared with BM-MSCs. The presence of adipocytes as indirect co-culture repressed the expression of the osteoblast phenotype, whereas osteoblasts did not exert remarkable effect on adipocytes. The inhibitory effect of adipocytes on osteoblasts was due to the release of tumor necrosis factor alpha (TNF-alpha) in culture medium by adipocytes. Indeed, the addition of exogenous TNF-alpha in culture medium repressed the differentiation of BM-MSCs into osteoblasts mimicking the indirect co-culture effect. In conclusion, our study showed that BM-MSCs are more osteogenic while AT-MSCs are more adipogenic. Additionally, we demonstrated the key role of TNF-alpha secreted by adipocytes on the inhibition of osteoblast differentiation. Thus, we postulate that the higher osteogenic potential of BM-MSCs makes them the first choice for inducing bone repair in cell-based therapies. PMID- 26059071 TI - The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on therapy to metformin in patients with Type 2 diabetes: A systematic review and meta-analysis. AB - There is no consensus on the selection of specific drug therapies when metformin fails in Type 2 diabetes (T2D). This meta-analysis was performed to determine the efficacy and safety of Dipeptidyl peptidase-4 inhibitors (DPP4-I) compared to sulfonylurea (SU) as add-on therapy to metformin in inadequately controlled T2D patients. We searched MEDLINE, CENTRAL, EMBASE, and CINAHL for randomized trials comparing DPP4-I to SU as add-on therapy to metformin and reported a change in hemoglobin A1c (HbA1c). Sixteen articles were included. There was a significantly greater reduction in HbA1c from baseline to 12 weeks with SU versus DPP4-I (MD[95% CI]=0.21%(2 mmol/mol) [0.06, 0.35]) but no significant difference at 52 and 104 weeks (MD[95% CI]=0.06%(-1 mmol/mol) [-0.03, 0.15] and 0.02%(-1 mmol/mol) [-0.13,0.18] respectively). SU was associated with weight gain and DPP4-I with weight loss at all time-points. The incidence of hypoglycemia at 12, 52, and 104 weeks was significantly greater with SU (20%, 24%, and 27% respectively) compared to DPP4-I (6%, 3%, and 4% respectively). The proportion of patients with HbA1c<7%(53 mmol/mol) without hypoglycemia was significantly higher at 52 and 104 weeks among patients on DPP4-I (RR[95% CI]=1.20 [1.05, 1.37] and 1.53 [1.16, 2.02] respectively). There was no significant difference between the two groups in the incidence of other side effects. While both SU and DPP4-I can be considered as options for add-on therapy to metformin in inadequately controlled T2D, SU results in a significantly increased risk of hypoglycemia and weight gain. By contrast, DPP4-I produce 0.4-0.6% (4-7 mmol/mol) reduction in HbA1c, lower risk of hypoglycemia, and weight loss. PMID- 26059070 TI - Partners in crime: The role of tandem modules in gene transcription. AB - Histones and their modifications play an important role in the regulation of gene transcription. Numerous modifications, such as acetylation, phosphorylation, methylation, ubiquitination, and SUMOylation, have been described. These modifications almost always co-occur and thereby increase the combinatorial complexity of post-translational modification detection. The domains that recognize these histone modifications often occur in tandem in the context of larger proteins and complexes. The presence of multiple modifications can positively or negatively regulate the binding of these tandem domains, influencing downstream cellular function. Alternatively, these tandem domains can have novel functions from their independent parts. Here we summarize structural and functional information known about major tandem domains and their histone binding properties. An understanding of these interactions is key for the development of epigenetic therapy. PMID- 26059072 TI - The cutoffs and performance of glycated hemoglobin for diagnosing diabetes and prediabetes in a young and middle-aged population and in an elderly population. AB - The aims were to compare the appropriate cutoffs of glycated hemoglobin (HbA1c) in a population of varying ages and to evaluate the performance of HbA1c for diagnosing diabetes and prediabetes. A total of 1064 participants in the young and middle-aged group and 1671 in the elderly group were included and underwent HbA1c testing and an oral glucose tolerance test (OGTT). Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated to evaluate the optimal HbA1c cutoffs. Kappa coefficients were used to test for agreement between HbA1c categorization and OGTT-based diagnoses. The optimal HbA1c cutoffs for diagnosing diabetes were 5.7% (39 mmol/mol) in the young and middle-aged group with a sensitivity of 66.7%, specificity of 86.7%, and AUC of 0.821 (95% CI: 0.686, 0.955) and 5.9% (41 mmol/mol) in the elderly group with a sensitivity of 80.4%, specificity of 73.3%, and AUC of 0.831 (0.801, 0.861). The optimal cutoffs for diagnosing prediabetes were 5.6% (38 mmol/mol) and 5.7% (39 mmol/mol) in the young and middle-aged group and in the elderly group, respectively. Agreement between the OGTT-based diagnosis of diabetes or prediabetes and the optimal HbA1c cutoff was low (all kappa coefficients <0.4). The combination of HbA1c and fasting plasma glucose increased diagnostic sensitivities or specificities. In conclusion, age-specific HbA1c cutoffs for diagnosing diabetes or prediabetes were appropriate. Furthermore, the performance of HbA1c for diagnosing diabetes and prediabetes was poor. HbA1c should be used in combination with traditional glucose criteria when detecting and diagnosing diabetes or prediabetes. PMID- 26059073 TI - Sorting Out the Health Risk in California's State-Based Marketplace. AB - OBJECTIVE: To characterize the health risk of enrollees in California's state based insurance marketplace (Covered California) by metal tier, region, month of enrollment, and plan. DATA SOURCE/STUDY SETTING: 2014 Open-enrollment data from Covered California linked with 2012 hospitalization and emergency department (ED) visit records from statewide all-payer administrative databases. DATA COLLECTION/EXTRACTION METHODS: Chronic Illness and Disability Payment System (CDPS) health risk scores derived from an individual's age and sex from the enrollment file and the diagnoses captured in the hospitalization and ED records. CDPS scores were standardized by setting the average to 1.00. PRINCIPAL FINDINGS: Among the 1,286,089 enrollees, 120,573 (9.4 percent) had at least one ED visit and/or a hospitalization in 2012. Higher risk enrollees chose plans with greater actuarial value. The standardized CDPS health risk score was 11 percent higher in the first month of enrollment (1.08; 99 percent CI: 1.07-1.09) than the last month (0.97; 99 percent CI: 0.97-0.97). Four of the 12 plans enrolled 91 percent of individuals; their average health risk scores were each within 3 percent of the marketplace's statewide average. CONCLUSIONS: Providing health plans with a means to assess the health risk of their year 1 enrollees allowed them to anticipate whether they would receive or contribute payments to a risk-adjustment pool. After receiving these findings as a part of their negotiations with Covered California, health plans covering the majority of enrollees decreased their initially proposed 2015 rates, saving consumers tens of millions of dollars in potential premiums. PMID- 26059074 TI - Challenges in legislation, recycling system and technical system of waste electrical and electronic equipment in China. AB - Waste electrical and electronic equipment (WEEE) has been one of the fastest growing waste streams worldwide. Effective and efficient management and treatment of WEEE has become a global problem. As one of the world's largest electronic products manufacturing and consumption countries, China plays a key role in the material life cycle of electrical and electronic equipment. Over the past 20 years, China has made a great effort to improve WEEE recycling. Centered on the legal, recycling and technical systems, this paper reviews the progresses of WEEE recycling in China. An integrated recycling system is proposed to realize WEEE high recycling rate for future WEEE recycling. PMID- 26059075 TI - Developing an Internet-Based Decision Aid for Women Choosing Between Vaginal Birth After Cesarean and Planned Repeat Cesarean. AB - INTRODUCTION: In response to the call to develop strategies to engage women and providers in shared decision making, this article outlines a framework and process used to create an Internet-based decision aid about birth choices after previous cesarean. Recognizing the potential benefits of mobile health information technology, a paper-based decision aid was transformed into a secure, interactive Web site to meet the diverse needs of women and providers in this often challenging health care decision. METHODS: An iterative and participatory research approach was used, engaging targeted users (pregnant women and pregnancy care providers) in the design and development process. RESULTS: Women recommended that features and functions of the decision aid should include individualized information, trustworthy evidence, a secure and private site, quizzes to check knowledge, and a way to share values and preferences with their providers. Providers recommended individualized information for women, a process for women to share and document values and preferences with providers, and balanced, straightforward and complete information about the risks and benefits of each option. DISCUSSION: There is great potential for direct linkage between Internet based decision aids and the electronic medical record. Work is currently underway to integrate and evaluate the Internet-based decision aid within busy practice settings to support shared decision making. This article is part of a special series of articles that address midwifery innovations in clinical practice, education, interprofessional collaboration, health policy, and global health. PMID- 26059076 TI - Active surveillance for low-risk prostate cancer: Need for intervention and survival at 10 years. AB - INTRODUCTION: To describe the need for treatment and cancer-specific and overall survival in a contemporary active surveillance (AS) cohort. PATIENTS AND METHODS: Historical cohort study of men diagnosed with localized prostate cancer between 1997 and 2009 and managed with AS at a tertiary care center. Inclusion criteria were Gleason score <= 6 (Gleason score of 7 in select patients),<= 3/12 cores positive, and prostate-specific antigen (PSA) level< 20 ng/ml. Survival analyses were conducted using the Kaplan-Meier method. RESULTS: A total of 469 men with median age at diagnosis of 68.1 years (interquartile range [IQR]: 62.5-73.4) were followed up for a median of 4.8 years (IQR: 3.4-7.3). Median PSA level at diagnosis was 5.1 ng/ml (IQR: 4.0-6.9), with 94% of them having PSA level<10 ng/ml. Overall, 98.3% (461/469) of patients had a Gleason score of 6 and 1.7% (8/469) had a Gleason score of 3+4 = 7, and 94.0% (441/469) had T1c stage disease. Freedom from treatment was 77% at 5 years and 62% at 10 years. A total of 116 (24.7%) patients received treatment during the course of surveillance. Reasons for treatment included 44.8% (52/116) for pathologic reclassification, 30.2% (35/116) for PSA progression, 12.1% (14/116) for patient preference, 5.2% (6/116) for digital rectal examination progression, and 4.3% (5/116) for metastatic disease. Of the patients treated, 59 (50.1%) received radiation, 26 (22.4%) underwent surgery, 17 (14.7%) received brachytherapy, and 14 (12.1%) received androgen-deprivation therapy. Cancer-specific survival was 100% at 5 and 10 years. Overall survival was 95% at 5 years and 88% at 10 years. CONCLUSION: In a contemporary cohort of men with low-risk prostate cancer, AS allowed avoidance of treatment most of them. Common reasons for change in management were Gleason upgrading and volume progression on prostate rebiopsy. PMID- 26059077 TI - Shifting paradigms in the estimation of survival for castration-resistant prostate cancer: A tertiary academic center experience. AB - OBJECTIVES: Castration-resistant prostate cancer (CRPC) has retained a guarded prognosis, with historical survival estimates of 18 to 24 months. However, the landscape of available therapy has changed, and the emphasis has altered from supportive to active treatment. Few large series from real-world populations exist in the contemporary era with fully mature survival data to confirm the indication based on clinical trials that patients with CRPC are surviving far longer than the historical estimates. We aim to review a large patient cohort with CRPC and provide mature survival data. METHODS AND MATERIALS: Using the electronic histopathology database at Queen Elizabeth Hospital, Birmingham, UK, all prostate-specific antigentest results between April 2006 and September 2007 were extracted, and patients satisfying the American Society for Radiation Oncology (ASTRO) definition of hormone failure were identified. Electronic records were reviewed and variables were collected, including survival, treatment, biochemistry, histopathology, and demographics. Probability of survival, and of developing metastasis or CRPC, was determined using the Kaplan Meier method. Patients were stratified into 3 groups, namely, D0--no metastasis at diagnosis but later appearance, D1--no metastasis at diagnosis or at last follow-up, and D2--metastasis at diagnosis. RESULTS: From 8,062 patient-prostate specific antigen episodes, we identified 447 patients meeting the criteria. A notes review revealed 147 patients with CRPC. Median overall survival (OS) from diagnosis was 84.7 months (95% CI: 73-89), and 129 deaths had occurred (88%). Median OS from diagnosis for D0, D1, and D2 patients was 100.4, 180.1, and 58.9 months, respectively (P< 0.0001), and median OS from CRPC was 40 months (95% CI: 31-58), 82.9 (95% CI: 72-94; P = 0.0125), and 38.7 months (95% CI: 33-46), respectively. One-quarter of patients survived 6 years after development of CRPC. Metastasis is the key prognostic event. CONCLUSIONS: Some current international guidelines quote <=19 months as a survival figure for patients with metastatic CRPC. In our study, median survival is more than double this. We have shown survival more than previously reported figures and believe that these data benefit clinicians and patients in understanding prognosis and treatment choices. Importantly, our patients were diagnosed before the current wave of novel therapeutics for CRPC, so survival for men diagnosed today may be more than our findings. PMID- 26059079 TI - Synergistic Effects of SDF-1alpha and BMP-2 Delivery from Proteolytically Degradable Hyaluronic Acid Hydrogels for Bone Repair. AB - In order to achieve bone repair, bone morphogenetic protein-2 (BMP-2) is typically delivered in non-physiological doses and can result in significant adverse side effects. To reduce the amount of BMP-2 necessary for bone formation, we delivered a known chemokine (stromal cell derived factor-1alpha, SDF-1alpha) in combination with BMP-2 using proteolytically degradable hydrogels. A critical sized calvarial defect was used to determine the effect of biomolecule delivery on bone formation in vivo. The treatment group with combined SDF-1alpha and BMP-2 hydrogel delivery showed significantly higher bone formation when compared to hydrogels loaded with the same BMP-2 or SDF-1alpha concentrations alone, suggesting the combined delivery of both biomolecules synergistically improves osteogenesis. PMID- 26059081 TI - Doctor told to repay L98,000 to NHS after working as locum while on paid sick leave. PMID- 26059080 TI - Critical analysis of the published literature about the effects of Ramadan intermittent fasting on healthy children's physical capacities. PMID- 26059082 TI - Individual differences in the perceptual span during reading: evidence from the moving window technique. AB - We report the results of an eye tracking experiment that used the gaze-contingent moving window technique to examine individual differences in the size of readers' perceptual span. Participants read paragraphs while the size of the rightward window of visible text was systematically manipulated across trials. In addition, participants completed a large battery of individual-difference measures representing two cognitive constructs: language ability and oculomotor processing speed. Results showed that higher scores on language ability measures and faster oculomotor processing speed were associated with faster reading times and shorter fixation durations. More interestingly, the size of readers' perceptual span was modulated by individual differences in language ability but not by individual differences in oculomotor processing speed, suggesting that readers with greater language proficiency are more likely to have efficient mechanisms to extract linguistic information beyond the fixated word. PMID- 26059084 TI - Low-molecular-weight heparin plus aspirin versus aspirin alone in pregnant women with hereditary thrombophilia to improve live birth rate: meta-analysis of randomized controlled trials. AB - PURPOSE: To determine in women with hereditary thrombophilia whether the use of the combination of low-molecular-weight heparin (LMWH) and aspirin (ASA) is better than ASA alone. METHODS: Meta-analysis of randomized controlled trials evaluating LMWH + ASA compared to ASA in pregnant women with hereditary thrombophilia in order to improve live birth rate. A systematic literature search was conducted in 5 databases (PubMed, Cochrane Controlled Trials Register, EMBASE, Scopus and ISI Web of Knowledge). Trial selection, data extraction, and quality assessment were performed independently by two authors. The main outcome measure was live birth rate. Secondary outcomes included rates of first-trimester miscarriage, prematurity, pre-eclampsia, and low birth weight for gestational age babies. RESULTS: Four trials were included in the quantitative synthesis in a total of 222 randomized women. Effect of LMWH + ASA versus ASA with regard to live births was evaluable in all four randomized controlled trials with a similar overall treatment effect for the therapies OR 1.7 (95 % CI 0.72-4.0) and without heterogeneity (I (2) = 0 %). No significant differences or heterogeneity were observed between groups for secondary outcomes, namely first-trimester miscarriages OR 0.69 (0.22-2.16), prematurity OR 0.99 (0.4-2.08), pre-eclampsia OR 1.49 (0.63-3.5), and small for gestational age babies OR 2.08 (0.96-4.47). CONCLUSIONS: There were no significant differences in live birth weight and other pregnancy outcomes between LMWH + ASA versus ASA. However, these findings were based on few trials presenting methodological limitations. Therefore, there is no evidence to support any incremental benefit of adding LMWH to ASA alone in women with inherited thrombophilia. PMID- 26059085 TI - Dermatitis herpetiformis: pathognomonic transglutaminase IgA deposits in the skin and excellent prognosis on a gluten-free diet. AB - Dermatitis herpetiformis (DH) is an itchy, blistering skin disease with sites of predilection at the elbows, knees and buttocks. Although DH is mostly asymptomatic, all patients exhibit small bowel villous atrophy or at least coeliac-type inflammatory changes. Deposition of immunoglobulin A (IgA) in the papillary dermis is a key diagnostic feature of DH. Epidermal transglutaminase (TG3) is the antigen for IgA deposited in the skin, and tissue transglutaminase (TG2) is the antigen for IgA deposited in the small bowel mucosa. Clinically silent, but immunologically active coeliac disease in the gut appears to result in IgA TG3 antibody complexes aggregated into DH skin. The prevalence of DH in northern Europe is high (30-75/100,000), but its incidence is decreasing, possibly due to increased recognition of subclinical coeliac disease. The rash and small bowel heal on a gluten-free diet, which is a life-long treatment. The risk of non-Hodgkin's lymphoma is increased, but in patients with DH who adhere strictly to a gluten-free diet long-term prognosis is excellent. PMID- 26059086 TI - Intervention in informal caregivers who take care of older people after a stroke (InCARE): study protocol for a randomised trial. AB - AIM: This study aims at describing an intervention based on informal caregivers' skills when taking care of older people after a stroke (InCARE). BACKGROUND: Most informal caregivers feel unprepared to deliver assistance in activities of daily living at home. This lack of preparedness can lead to misconceptions, burden and affect their health, which, consequently, may imply hospital readmissions or early institutionalization of the older adults. DESIGN: A single blinded randomised trial. METHODS: This study will recruit 198 dyads, comprising old stroke survivors and their caregivers, who will be divided into two groups: intervention and control (protocol approved in May 2013). INCLUSION CRITERIA: (informal caregivers) absence of cognitive impairment; resident in the Cavado Region; to return the informed consent (older people) are over 65 years of age; have had a first stroke and; be dependent on at least one of the self-care activities post hospital discharge. PRIMARY OUTCOME: informal caregivers' skills. SECONDARY OUTCOMES: include burden and Health Quality of Life in informal caregivers; functionality, hospital readmission and institutionalization of older people stroke survivors, measured 1 and 3 months after InCARE programme. DISCUSSION: The InCARE programme will highlight new ways to understand the feasibility of a large trial, which supports caregivers who take care of older people after a stroke. It will be expected that the level of burden decreases, thus helping informal caregivers enhance their quality of life. Also, it is expected that older people's functionality will be improved and that hospital readmission or institutionalization may be avoided. PMID- 26059087 TI - Magnetoresistance oscillations in topological insulator Bi2Te3 nanoscale antidot arrays. AB - Nanoscale antidot arrays were fabricated on a single-crystal microflake of topological insulator Bi2Te3. The introduction of antidot arrays significantly increased the resistance of the microflake, yet the temperature dependence of the resistance remains metallic. We observed that small oscillations that are periodic in magnetic field B appeared on top of the weak anti-localization magnetoresistance. Since the electron coherence length at low temperature becomes comparable to the feature size in our device, we argued that the magnetoresistance oscillations are the manifestation of quantum interference induced by the nanostructure. Our work demonstrates that the transport of topological insulators could indeed be controlled by artificially created nanostructures, and paves the way for future technological applications of this class of materials. PMID- 26059088 TI - Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in mice. AB - Huperzia serrata has been used as a Chinese folk medicine for many years. It contains huperzine A, which has a protective effect against memory deficits in animal models; however, it is unclear if H. serrata extract exerts any effects in Alzheimer's disease (AD) models. We used H. serrata collected in Japan and determined its huperzine A content using HPLC. We determined its inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. H. serrata extract (30 mg/kg/day) and donepezil (10 mg/kg/day) were orally administrated for 7 days. After repeated administration, we performed the Y-maze and passive avoidance tests. H. serrata extract contained 0.5% huperzine A; H. serrata extract inhibited AChE, but not BuChE. H. serrata extract ameliorated cognitive function in mice. These results indicate that Japanese H. serrata extract ameliorates cognitive function deficits by inhibiting AChE. Therefore, H. serrata extract may be valuable for the prevention or treatment of dementia in AD. PMID- 26059089 TI - Dietary ratio of animal:plant protein is associated with 24-h urinary iodine excretion in healthy school children. AB - Adequate dietary iodine intake in children is essential for optimal physical and neurological development. Whether lower dietary animal food and salt intake may adversely affect iodine status is under discussion. We examined the association between dietary animal:plant protein ratio with 24-h urinary iodine excretion (24 h UI, MUg/d), and whether this is modified by salt intake. A 24-h UI was measured in 1959 24-h urine samples from 516 6- to 12-year-old participants of the Dortmund Nutritional and Anthropometric Longitudinally Designed Study. Parallel 3 d weighed food records were used to estimate dietary intakes. Protein sources were classified as dairy, animal and plant. A repeated-measures regression model (PROC MIXED) was used to analyse the effect of animal:plant protein ratios on 24 h UI. ANIMAL: plant protein ratios ranged from 0.5 (95 % CI 0.4, 0.6) to 1.6 (95 % CI 1.4, 1.9) (lowest and highest quartile). After adjustment for total energy intake, main dietary iodine sources (dairy and salt intake), and further covariates, the inter-individual variation in animal:plant protein ratio was significantly associated with variation in 24-h UI. One unit higher animal:plant protein ratio predicted 6 MUg/d higher 24-h UI (P= 0.002) in boys and 5 MUg/d (P= 0.03) in girls. This relationship was partially mediated by a higher salt intake at higher animal:plant protein ratios. These results suggest that lower consumption of animal protein is associated with a small decline in iodine excretion, partially mediated by decreased salt intake. Because limited salt and increased intake of plant-based foods are part of a preferable healthy food pattern, effective nutrition political strategies will be required in the future to ensure appropriate iodine nutrition in adherent populations. PMID- 26059090 TI - Multiple Septal Coronary-Cameral Fistulae after Septal Myectomy. PMID- 26059091 TI - Quantitative home-based assessment of Parkinson's symptoms: the SENSE-PARK feasibility and usability study. AB - BACKGROUND: Currently, assessment of symptoms associated with Parkinson's disease is mainly performed in the clinic. However, these assessments have limitations because they provide only a snapshot of the condition. METHODS: The feasibility and usability of an objective, continuous and relatively unobtrusive system (SENSE-PARK System), which consists of wearable sensors (three worn during the day and one worn at night), a smartphone-based App, a balance board and computer software, was tested 24/7 over 12 weeks in a study including 22 PD patients. During the first four weeks of the study, patients did not get feedback about their performance, during the last eight weeks they did. The study included seven clinical visits with standardized interviews, and regular phone contact. The primary outcome was the number of drop-outs during the study. As secondary outcomes, the Post-Study System Usability Questionnaire (PSSUQ), score and information obtained from the standardized interviews were used to evaluate the usability of the system. RESULTS: All patients completed the study. The participants rated the usability of the SENSE-PARK System with a mean score of 2.67 (+/-0.49) on the PSSUQ. The interviews revealed that most participants liked using the system and appreciated that it signaled changes in their health condition. CONCLUSIONS: This 12 week controlled study demonstrates that the acceptance level of PD patients using the SENSE-PARK System as a home-based 24/7 assessment is very good. Particular emphasis should be given to a user-friendly design. Motivation to wear such a system can be increased by providing direct feedback about the individual health condition. PMID- 26059092 TI - A simple and rapid method for the determination of nicotine in third-hand smoke by liquid chromatography and its application for the assessment of contaminated outdoor communal areas. AB - This is the first report on the determination of nicotine in third-hand smoke (THS) in outdoor communal areas. The term THS can be defined as the contamination of surfaces by second-hand smoke. This can remain for extended periods of time and undergo further chemical reactions to produce further pollutants which can be re-suspended in dust or re-emitted into the gas phase. As THS is a rather complex mixture, studies have focused on using nicotine as a marker of THS, as it is the most abundant organic compound emitted during smoking. In this present study, the extraction of dust-wipe samples and the subsequent chromatographic conditions required for the separation of nicotine by hydrophilic interaction liquid chromatography were optimized. The optimum chromatographic conditions were identified as a 150 mm x 4.6 mm, 5 um Zorbax Carbohydrate Analysis column with a mobile phase consisting of 90 % acetonitrile, 10 % water at a flow rate of 1.0 mL/min with UV detection at 259 nm. Further investigations were made on samples collected from surfaces of public entrance ways. Under these conditions, a linear range for nicotine of 0.05 to 24 ug/mL (1.0-480 ng on column) was obtained, with a detection limit of 1.0 ng on column based on a signal-to-noise ratio of three. Acetone, naphthalene, phenol, musk ketone, and palmitic acid were found not to interfere. Communal entrance ways were found to be contaminated with THS nicotine levels of between 5.09 ug/m(2) and 309 ug/m(2) comparable to that found in other previous studies of indoor environments. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26059093 TI - Three-year outcome of the heparin-bonded Viabahn for superficial femoral artery occlusive disease. AB - OBJECTIVE: Self-expanding covered stents for superficial femoral artery (SFA) occlusive disease have undergone an evolution during the years. Early results of the latest generation, the heparin-bonded Viabahn (W. L. Gore & Associates, Flagstaff, Ariz) with a contoured proximal edge, were promising, with reported 1 year primary patency rates of 73% to 78% in long lesions. The aim of this study was to present the 3-year outcome of the heparin-bonded Viabahn for SFA occlusive disease. METHODS: All patients treated with a heparin-bonded Viabahn in three centers between April 2009 and December 2011 were included in the study and retrospectively analyzed. Clinical state in Rutherford category, ankle-brachial indexes, and duplex ultrasound scans were the features of follow-up at 6 weeks and 6, 12, 24, and 36 months. Primary end points of the study were the 3-year primary, primary assisted, and secondary patency rates. RESULTS: A total of 73 SFAs in 70 patients were treated with a heparin-bonded Viabahn and included in the study. Fifty-four patients were male (77%), and the mean age was 70.0 +/- 9.1 years. The mean lesion length was 17.4 +/- 7.0 cm, and 84% were classified TransAtlantic Inter-Society Consensus II types C and D. The median follow-up was 25 months (range, 2-55 months). The 3-year primary, primary assisted, and secondary patency rates were 59%, 71%, and 82%, respectively, with a 3-year freedom from amputation of 100%. CONCLUSIONS: The use of a heparin-bonded Viabahn for SFA occlusive disease is related to patency rates within limits of surgical reconstruction. The procedure is related to low morbidity and amputation rates. PMID- 26059095 TI - Real-Time, Quantitative Lighting-up Detection of Telomerase in Urines of Bladder Cancer Patients by AIEgens. AB - As a biomarker for early cancer diagnosis, telomerase are one of the promising targets for cancer therapeutics. Inspired by the fluorescent emission principle of aggregation-induced emission fluorogens, we creatively designed an AIE-based turn-on method to detect telomerase activity from cell extracts. A positively charged fluorogen (TPE-Z) is not fluorescent when freely diffused in solution. The fluorescence of TPE-Z is enhanced with the elongation of the DNA strand which could light up telomere elongation process. By exploitation of it, we can detect telomerase activity from different cell lines (E-J, HeLa, MCF-7, and HLF) with high sensitivity and specificity. Moreover, our method is successfully employed to demonstrate the applications in bladder cancer diagnosis (41 urine specimens from bladder cancer patients and 15 urine specimens from normal people are detected). The AIE-based method provides a simple one-pot technique for quantification and monitoring of the telomerase activity and shows great potential for future use in clinical tests. PMID- 26059094 TI - Type II endoleak with or without intervention after endovascular aortic aneurysm repair does not change aneurysm-related outcomes despite sac growth. AB - OBJECTIVE: There is considerable controversy about the significance and appropriate treatment of type II endoleaks (T2Ls) after endovascular aneurysm repair (EVAR). We report our long-term experience with T2L management in a large multicenter registry. METHODS: Between 2000 and 2010, 1736 patients underwent EVAR, and we recorded the incidence of T2L. Primary outcomes were mortality and aneurysm-related mortality (ARM). Secondary outcomes were change in aneurysm sac size, major adverse events, and reintervention. RESULTS: During the follow-up (median of 32.2 months; interquartile range, 14.2-52.8 months), T2L was identified in 474 patients (27.3%). There were no late abdominal aortic aneurysm ruptures attributable to a T2L. Overall mortality (P = .47) and ARM (P = .26) did not differ between patients with and without T2L. Sac growth (median, 5 mm; interquartile range, 2-10 mm) was seen in 213 (44.9%) of the patients with T2L. Of these patients with a T2L and sac growth, 36 (16.9%) had an additional type of endoleak. Of all patients with T2L, 111 (23.4%) received reinterventions, including 39 patients who underwent multiple procedures; 74% of the reinterventions were performed in patients with sac growth. Reinterventions included lumbar embolization in 66 patients (59.5%), placement of additional stents in 48 (43.2%), open surgical revision in 14 (12.6%), and direct sac injection in 22 (19.8%). The reintervention was successful in 35 patients (31.5%). After patients with other types of endoleak were excluded, no difference in overall all-cause mortality (P = .57) or ARM (P = .09) was observed between patients with T2L-associated sac growth who underwent reintervention and those in whom T2L was left untreated. CONCLUSIONS: In our multicenter EVAR registry, overall all-cause mortality and ARM were unaffected by the presence of a T2L. Moreover, patients who were simply observed for T2L-associated sac growth had aneurysm-related outcomes similar to those in patients who underwent reintervention. Our future work will investigate the most cost-effective ways to select patients for intervention besides sac growth alone. PMID- 26059096 TI - Hyperpolarized [(13)C]ketobutyrate, a molecular analog of pyruvate with modified specificity for LDH isoforms. AB - PURPOSE: The purpose of this study was to investigate (13) C hyperpolarization of alpha-ketobutyrate (alphaKB), an endogenous molecular analog of pyruvate, and its in vivo enzymatic conversion via lactate dehydrogenase (LDH) using localized MR spectroscopy. METHODS: Hyperpolarized (HP) (13) C MR experiments were conducted using [(13) C]alphaKB with rats in vivo and with isolated LDH enzyme in vitro, along with comparative experiments using [(13) C]pyruvate. Based on differences in the kinetics of its reaction with individual LDH isoforms, HP [(13) C]alphaKB was investigated as a novel MR probe, with added specificity for activity of LDHB expressed H ("heart"-type) subunits of LDH (e.g., constituents of LDH-1 isoform). RESULTS: Comparable T1 and polarization values to pyruvate were attained (T1 = 52 s at 3 tesla [T], polarization = 10%, at C1 ). MR experiments showed rapid enzymatic conversion with substantially increased specificity. Formation of product HP [(13) C]alpha-hydroxybutyrate (alphaHB) from alphaKB in vivo was increased 2.7-fold in cardiac slabs relative to liver and kidney slabs. In vitro studies resulted in 5.0-fold higher product production from alphaKB with bovine heart LDH-1, as compared with pyruvate. CONCLUSIONS: HP [(13) C]alphaKB may be a useful MR probe of cardiac metabolism and other applications where the role of H subunits of LDH is significant (e.g., renal cortex and brain). PMID- 26059098 TI - The semantic anatomical network: Evidence from healthy and brain-damaged patient populations. AB - Semantic processing is central to cognition and is supported by widely distributed gray matter (GM) regions and white matter (WM) tracts. The exact manner in which GM regions are anatomically connected to process semantics remains unknown. We mapped the semantic anatomical network (connectome) by conducting diffusion imaging tractography in 48 healthy participants across 90 GM "nodes," and correlating the integrity of each obtained WM edge and semantic performance across 80 brain-damaged patients. Fifty-three WM edges were obtained whose lower integrity associated with semantic deficits and together with their linked GM nodes constitute a semantic WM network. Graph analyses of this network revealed three structurally segregated modules that point to distinct semantic processing components and identified network hubs and connectors that are central in the communication across the subnetworks. Together, our results provide an anatomical framework of human semantic network, advancing the understanding of the structural substrates supporting semantic processing. PMID- 26059097 TI - Tryptophan derivatives regulate the transcription of Oct4 in stem-like cancer cells. AB - The aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that responds to environmental toxicants, is increasingly recognized as a key player in embryogenesis and tumorigenesis. Here we show that a variety of tryptophan derivatives that act as endogenous AhR ligands can affect the transcription level of the master pluripotency factor Oct4. Among them, ITE enhances the binding of the AhR to the promoter of Oct4 and suppresses its transcription. Reduction of endogenous ITE levels in cancer cells by tryptophan deprivation or hypoxia leads to Oct4 elevation, which can be reverted by administration with synthetic ITE. Consequently, synthetic ITE induces the differentiation of stem-like cancer cells and reduces their tumorigenic potential in both subcutaneous and orthotopic xenograft tumour models. Thus, our results reveal a role of tryptophan derivatives and the AhR signalling pathway in regulating cancer cell stemness and open a new therapeutic avenue to target stem-like cancer cells. PMID- 26059099 TI - Long-term outcome in anorexia nervosa in the community. AB - OBJECTIVE: Few studies have assessed outcomes of anorexia nervosa (AN) outside clinical settings. We aimed to assess mortality, recovery, and socio-demographic outcomes of AN in a community sample. METHOD: Women in the nationwide FinnTwin16 cohort (born 1975-1979) were followed for 10 years after baseline diagnostic assessment (mean age at follow-up 34 years, N = 2188). We compared women with lifetime DSM-IV AN (N = 40) with unaffected women from the same cohort. RESULTS: None of the women with AN had died and 88% were weight-recovered (BMI >= 18.5 kg/m(2) ), but their mean BMI (22.0 kg/m(2) ) was lower than among unaffected women (24.0 kg/m(2) , p = 0.008). University degrees (38 vs. 29%, p = 0.26), sickness absence during the past year (median 5 vs. 3 days, p = 0.21), or unemployment or disability pension (5 vs. 4%, p = 0.62) did not significantly differ between AN probands and their unaffected peers. More women with AN were still studying (15 vs. 4%, p = 0.003), and half of them had children, as compared to 66% of unaffected women (p = 0.05). DISCUSSION: The long-term prognosis of AN in the community appears promising. Weight-restoration is common and socio demographic outcomes are generally favorable. However, women with a history of AN may be less likely to have children. PMID- 26059101 TI - A three-dimensional computational fluid dynamics model of shear stress distribution during neotissue growth in a perfusion bioreactor. AB - Bone tissue engineering strategies use flow through perfusion bioreactors to apply mechanical stimuli to cells seeded on porous scaffolds. Cells grow on the scaffold surface but also by bridging the scaffold pores leading a fully filled scaffold following the scaffold's geometric characteristics. Current computational fluid dynamic approaches for tissue engineering bioreactor systems have been mostly carried out for empty scaffolds. The effect of 3D cell growth and extracellular matrix formation (termed in this study as neotissue growth), on its surrounding fluid flow field is a challenge yet to be tackled. In this work a combined approach was followed linking curvature driven cell growth to fluid dynamics modeling. The level-set method (LSM) was employed to capture neotissue growth driven by curvature, while the Stokes and Darcy equations, combined in the Brinkman equation, provided information regarding the distribution of the shear stress profile at the neotissue/medium interface and within the neotissue itself during growth. The neotissue was assumed to be micro-porous allowing flow through its structure while at the same time allowing the simulation of complete scaffold filling without numerical convergence issues. The results show a significant difference in the amplitude of shear stress for cells located within the micro porous neo-tissue or at the neotissue/medium interface, demonstrating the importance of taking along the neotissue in the calculation of the mechanical stimulation of cells during culture.The presented computational framework is used on different scaffold pore geometries demonstrating its potential to be used a design as tool for scaffold architecture taking into account the growing neotissue. Biotechnol. Bioeng. 2015;112: 2591-2600. (c) 2015 Wiley Periodicals, Inc. PMID- 26059100 TI - Comparative transcriptomics analysis reveals difference of key gene expression between banana and plantain in response to cold stress. AB - BACKGROUND: Banana and plantain (Musa spp.) comprise an important part of diets for millions of people around the globe. Low temperature is one of the key environmental stresses which greatly affects the global banana production. To understand the molecular mechanism of the cold-tolerance in plantain we used RNA Seq based comparative transcriptomics analyses for both cold-sensitive banana and cold-tolerant plantain subjected to the cold stress for 0, 3 and 6 h. RESULTS: The cold-response genes at early stage are identified and grouped in both species by GO analysis. The results show that 10 and 68 differentially expressed genes (DEGs) are identified for 3 and 6 h of cold stress respectively in plantain, while 40 and 238 DEGs are identified respectively in banana. GO classification analyses show that the majority of DEGs identified in both banana and plantain belong to 11 categories including regulation of transcription, response to stress signal transduction, etc. A similar profile for 28 DEGs was found in both banana and plantain for 6 h of cold stress, suggesting both share some common adaptation processes in response to cold stress. There are 17 DEGs found uniquely in cold tolerance plantain, which were involved in signal transduction, abiotic stress, copper ion equilibrium, photosynthesis and photorespiration, sugar stimulation, protein modifications etc. Twelve early responsive genes including ICE1 and MYBS3 were selected and further assessed and confirmed by qPCR in the extended time course experiments (0, 3, 6, 24 and 48 h), which revealed significant expression difference of key genes in response to cold stress, especially ICE1 and MYBS3 between cold-sensitive banana and cold-tolerant plantain. CONCLUSIONS: We found that the cold-tolerance pathway appears selectively activated by regulation of ICE1 and MYBS3 expression in plantain under different stages of cold stress. We conclude that the rapid activation and selective induction of ICE1 and MYBS3 cold tolerance pathways in plantain, along with expression of other cold-specific genes, may be one of the main reasons that plantain has higher cold resistance than banana. PMID- 26059102 TI - Enrichment and specific quantification of Methanocalculus in anaerobic digestion. AB - Members of the genus Methanocalculus are characterized as hydrogenotrophic methanogens and present in diverse natural and engineered environments. Methanocalculus populations were enriched from anaerobic digesters treating dairy waste using formate as the substrate. Methanocalculus sequences retrieved from the enrichment cultures were subsequently used to develop a Methanocalculus specific TaqMan qPCR assay to determine the abundance of Methanocalculus populations in the environment, representing the first quantitative tool specifically targeting Methanocalculus. The Methanocalculus-specific primer/probe set was shown to have high coverage with perfect match to >80% of all Methanocalculus 16S rRNA gene sequences in the Ribosomal Database Project (RDP). High specificity of the qPCR assay was also validated by both in silico and experimental analyses. Amplification efficiency of the qPCR assay was determined to be 91.9%, which is satisfactory for quantitative applications. Results from the Methanocalculus-specific qPCR analysis of formate-enriched methanogenic cultures were consistent with those from clone library analysis of the same cultures, validating the accuracy of the qPCR assay. Subsequent field application of the qPCR assay found low relative abundance of Methanocalculus in anaerobic digesters treating dairy waste, accounting for 0.01% of the archaeal populations. The qPCR results were consistent with the lack of detection of Methanocalculus in previous studies of the same anaerobic digesters with clone library analyses, which are less sensitive than qPCR. Thus, the Methanocalculus-specific qPCR assay developed in this study is a highly sensitive tool for the rapid and efficient quantification of Methanocalculus populations in methanogenic environments and understanding of the ecological functions of these methanogens. PMID- 26059103 TI - Bovine Surfactant Replacement Therapy in Neonates of Less than 32 Weeks' Gestation: A Multicenter Controlled Trial of Prophylaxis versus Early Treatment in China--a Pilot Study. AB - BACKGROUND: A domestic surfactant preparation has been used in China for a number of years. However, as for other surfactant preparations, there is debate among neonatologists regarding the optimal dose, mode of administration, and the best time of intervention. OBJECTIVE: To evaluate whether prophylactic administration of surfactant is superior to early treatment in preterm infants < 32 weeks with a high risk of respiratory distress syndrome (RDS). METHODS: We prospectively compared small premature infants (< 32 weeks) receiving 70 mg/kg bovine surfactant within 30 minutes after birth (prophylactic group, N = 116) with infants who received surfactant therapy for established RDS (early treatment group, N = 91). The primary outcome assessed was the incidence of RDS. The secondary outcomes assessed were severity of RDS, mortality, and bronchopulmonary dysplasia morbidity. RESULTS: Compared with the early treatment group, the prophylactic group had a significantly better PaO2 (at 1 hour, 4 hours, and 12 hours postdose, respectively), better a/APO2 (at 1 hour, 4 hours, 12 hours, and 24 hours postdose, respectively), lower PaCO2 (at 1 hour postdose), and a significantly decreased need for mean airway pressure (MAP) and FiO2 on ventilation (p < 0.05). The prophylactic group had shorter durations for mechanical ventilation and supplemental oxygen compared with the early treatment group (p < 0.01 and p < 0.05, respectively). The incidence of RDS was comparable between the groups; however, the prophylactic group had a significantly lower incidence of severe RDS and significantly lower rate of repeated doses of surfactant than the early treatment group (p < 0.05). The incidences of bronchopulmonary dysplasia and patent ductus arteriosus were also lower in the prophylactic group than the early treatment group (p < 0.05). The two groups were comparable in mortality rate. CONCLUSION: In preterm infants under 32 weeks' gestation, prophylactic use of a domestic surfactant preparation is better than early surfactant treatment in improving pulmonary status and in decreasing the incidence of severe RDS and duration on mechanical ventilation. PMID- 26059104 TI - Resection of right ventricular metastasis subsequent to liver transplant for hepatocellular carcinoma. AB - We report a case of a 54-year-old Caucasian male with exertional dyspnea who underwent palliative resection of a solitary right ventricular metastasis one year after liver transplant for a multifocal HBV-related hepatocellular carcinoma (HCC). After nine months the patient remains asymptomatic and cardiac MRI shows no local progression of the tumor. PMID- 26059105 TI - A population-based study of animal component sensitization, asthma, and rhinitis in schoolchildren. AB - BACKGROUND: Animal sensitization is a major determinant of asthma in children. Component-resolved studies of unselected pediatric populations are lacking. The aim was to describe sensitization to animal components and the association with asthma and rhinitis in animal-sensitized schoolchildren. METHODS: A random sample of 696 children (11-12 years) from a Swedish population-based cohort was tested for sensitization to cat, dog, and horse dander using ImmunoCAP. Sera from animal sensitized children were further analyzed by microarray including three allergen components from cat, four from dog, and two from horse. The parents completed an expanded ISAAC questionnaire. RESULTS: Of 259 animal-sensitized children (>=0.1 kUA /l), 51% were sensitized to all three, 23% to two, and 25% to one species. Current asthma and asthma symptoms following contact with cats were associated with co-sensitization to Fel d 1 and Fel d 4. This association was seen already at moderate-level sensitization (1-15 ISU) to Fel d 4, at which level most children were sensitized to Fel d 1, as well. In dog-sensitized children, the majority was sensitized to more than one dog component, and co-sensitization to Can f 5 and Can f 1/f 2 conferred the greatest risk for asthma. Sensitization to the highly cross-reactive serum albumins was uncommon and not associated with asthma. CONCLUSIONS: Among schoolchildren in northern Sweden, where mite allergy is uncommon, furry animals were the primary perennial sensitizers. Asthma was associated with higher levels of component sensitization, and sensitization to more than one component from the same animal conferred the greatest risk. PMID- 26059106 TI - Sildenafil Improves Vascular Endothelial Structure and Function in Renovascular Hypertension. AB - In translational medicine, the discovery of new drugs or new potential uses for currently available drugs is crucial for treating the resistant hypertension associated with renal artery stenosis. The phosphodiesterase 5 inhibitor sildenafil has been shown to reduce blood pressure and to improve the endothelium dependent relaxation in the two kidney, one clip (2K1C) mouse model of renovascular hypertension. In the present study, we evaluated the effects of sildenafil (40 mg/kg/day for two weeks) on the endothelial structure and contractile function in mesenteric resistance arteries 28 days after clipping the renal artery. The data showed an enhanced vascular contractile response to norepinephrine in 2K1C hypertensive mice (56%) when compared with Sham mice, which was associated with increased oxidative stress and with a thinning of endothelial cells. Sildenafil treatment caused a significant amelioration in the enhanced contractile responsiveness (18%), which was associated to the recovery of the endothelial surface and abolishment of the oxidative stress. These data suggest that sildenafil could be considered a promising therapeutic option to manage endothelial dysfunction and hypertension in resistant patients. PMID- 26059107 TI - Anti-Oxidative Polyphenolic Compounds of Cocoa. AB - Oxidative stress plays a key role in the pathogenesis of different serious chronic diseases such as cancer, diabetes, cardiovascular and neurodegenerative disorders, etc. Recent research has been focused on the beneficial role of dietary antioxidants against oxidative stress both under in vitro and in vivo conditions. Theobroma cacao L. (cacao tree) is an evergreen tree which is native to South America. It is a plant of great economic importance and its seeds are commonly used to produce cocoa powder and chocolate. In addition to its uses in food industry, cocoa is a rich source of polyphenolic antioxidants. There is a plethora of in vitro and in vivo studies that report cocoa antioxidant capacity. The protective activity of cocoa seems to be due to its phytochemical constituents, especially catechins. However, bioavailability of cocoa polyphenolic constituents following oral administration is very low (nanomolar concentrations). In the present paper, we critically reviewed the available literature on the antioxidant and free radical scavenging activities of cocoa and its polyphenolic constituents. In addition to these, we provide brief information about cultivation, phytochemistry, bioavailability and clinical impacts of cocoa. PMID- 26059108 TI - Monometallic Ni(0) and Heterobimetallic Ni(0) /Au(I) Complexes of Tripodal Phosphine Ligands: Characterization in Solution and in the Solid State and Catalysis. AB - The tridentate chelate nickel complexes [(CO)Ni{(PPh2 CH2 )3 CMe}] (2), [(CO)Ni{(PPh2 CH2 CH2 )3 SiMe}] (6), and [Ph3 PNi{(PPh2 CH2 CH2 )3 SiMe}] (7), as well as the bidentate complex [(CO)2 Ni{(PPh2 CH2 )2 CMeCH2 PPh2 }] (3) and the heterobimetallic complex [(CO)2 Ni{(PPh2 CH2 )2 CMeCH2 Ph2 PAuCl}] (4), have been synthesized and fully characterized in solution. All (1) H and (13) C NMR signal assignments are based on 2D-NMR methods. Single crystal X-ray structures have been obtained for all complexes. Their (31) P CP/MAS (cross polarization with magic angle spinning) NMR spectra have been recorded and the isotropic lines identified. The signals were assigned with the help of their chemical shift anisotropy (CSA) data. All complexes have been tested regarding their catalytic activity for the cyclotrimerization of phenylacetylene. Whereas complexes 2-4 display low catalytic activity, complex 7 leads to quantitative conversion of the substrate within four hours and is highly selective throughout the catalytic reaction. PMID- 26059109 TI - Maternal genealogical patterns of chicken breeds sampled in Europe. AB - The aim of this study was to investigate the maternal genealogical pattern of chicken breeds sampled in Europe. Sequence polymorphisms of 1256 chickens of the hypervariable region (D-loop) of mitochondrial DNA (mtDNA) were used. Median joining networks were constructed to establish evolutionary relationships among mtDNA haplotypes of chickens, which included a wide range of breeds with different origin and history. Chicken breeds which have had their roots in Europe for more than 3000 years were categorized by their founding regions, encompassing Mediterranean type, East European type and Northwest European type. Breeds which were introduced to Europe from Asia since the mid-19th century were classified as Asian type, and breeds based on crossbreeding between Asian breeds and European breeds were classified as Intermediate type. The last group, Game birds, included fighting birds from Asia. The classification of mtDNA haplotypes was based on Liu et al.'s (2006) nomenclature. Haplogroup E was the predominant clade among the European chicken breeds. The results showed, on average, the highest number of haplotypes, highest haplotype diversity, and highest nucleotide diversity for Asian type breeds, followed by Intermediate type chickens. East European and Northwest European breeds had lower haplotype and nucleotide diversity compared to Mediterranean, Intermediate, Game and Asian type breeds. Results of our study support earlier findings that chicken breeds sampled in Europe have their roots in the Indian subcontinent and East Asia. This is consistent with historical and archaeological evidence of chicken migration routes to Europe. PMID- 26059110 TI - Study of the association of the T869C polymorphism of the transforming growth factor-beta1 gene with polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common multifactorial disorder characterized by hyperandrogenism, insulin resistance and chronic oligoanovulation. In addition, a number of females with PCOS have ovaries with multiple cysts, an irregular or no menstrual cycle and an imbalance of female hormones compared with normal controls. The transforming growth factor beta1 (TGF beta1) gene is one of the genes associated with obesity and type 2 diabetes, which are characteristic symptoms of PCOS. The present study, therefore, investigated the association between the T869C polymorphism of the TGF-beta1 gene, a single nucleotide polymorphism (SNP) of TGF-beta1 and PCOS. The genomic DNA from 285 patients with PCOS and 129 healthy control individuals was used in the present study. P<0.05 was considered to indicate a statistically significant difference between the groups. The present study findings suggested that the frequency of genotypes provided no significant association between the T869C polymorphism in the TGF-beta1 gene and patients with PCOS. Although the present study concluded that the T869C polymorphism in the TGF-beta1 gene is not associated with the pathogenesis of PCOS, further studies regarding the correlation between other SNPs of the TGF-beta1 gene and PCOS are required. PMID- 26059111 TI - Delivery of heliox with a semi-closed circuit during spontaneous breathing: a comparative economic theoretical study. AB - BACKGROUND: Heliox is a mixture of oxygen and helium which reduces airway resistance in patients with airway obstruction. In clinical practice, patients breathing spontaneously receive heliox via an open circuit. Recently, a semi closed circuit for heliox administration has been proposed which minimizes consumption of heliox and therefore cost of the heliox therapy; although, the semi-closed circuit is associated with additional costs. The aim of the study is to conduct an economical analysis comparing total cost of heliox therapy using an open versus a semi-closed circuit in spontaneously breathing patients with airway obstruction. METHODS: Four different systems for heliox administration were analyzed: an open circuit and three alternatives of a semi-closed circuit involving a custom made semi-closed circuit and two standard anesthesia machines. Total costs of heliox therapy were calculated for all the systems. For calculation of gas consumption, the clinical procedures limiting continuous heliox therapy including the aerosol therapy, personal hygiene and nutrition were taken into account. A sensitivity analysis was conducted for main input variables that may influence the results of the study. RESULTS: Price of gases consumed by a semi-closed system represents less than 20 % of price of gases when a standard open circuit is used. This represents a saving of approximately 540 EUR per patient. The initial cost of the custom-made semi-closed circuit recuperates after treatment of 18 patients. The corresponding number of patients is 32 when a low-cost anesthesia machine is initially acquired and rises to 69 when a highly advanced anesthesia machine is considered. CONCLUSIONS: Heliox therapy in spontaneously breathing patients using a semi-closed circuit becomes more cost effective compared to the open circuit, currently used in clinical practice, when applied in a sufficient number of cases. The impact of finding a cheaper way of heliox administration on the clinical practice needs to be ascertained. PMID- 26059112 TI - Trichoderma saturnisporum, a new biological control agent. AB - BACKGROUND: Biocontrol agents (BCAs) could be a viable alternative to chemicals in the management of fungal crop diseases. Screening for potential biocontrol and plant growth promoter isolates from a soil in Cadiz (Spain) was conducted. Several isolates showed antagonism in in vitro tests to several plant pathogens. RESULTS: Two isolates of Trichoderma saturnisporum (Ascomycetes, Hypocreales) were identified by sequencing of the rDNA region. One isolate was selected for further in vivo plant growth promotion and biological control assays. Results indicate that substrate application of T. saturnisporum improved plant quality and showed biological control activity against Phytophthora capsici and Phytophthora parasitica (Peronosporales, Peronosporaceae). CONCLUSION: There are a few references to T. saturnisporum isolated from different media but not its ability to promote plant growth or biocontrol. This is the first report of T. saturnisporum as a seedling growth promoter and as biological control agent. PMID- 26059113 TI - Effect of Malting and Nixtamalization Processes on the Physicochemical Properties of Instant Extruded Corn Flour and Tortilla Quality. AB - This research aimed to prepare instant flour from malted and raw (un-malted) corn flours nixtamalized by the extrusion process and evaluate the effect on the physicochemical properties of tortillas prepared using these flours. White maize was malted for 24 h, dried at 50 +/- 1 degrees C, and ground. Subsequently, 0.3 % lime and 25 or 30 % water were added to ground malted or un-malted corn, and the mixture was refrigerated (4 degrees C) for 12 h. These samples were nixtamalized by an extrusion process in a single screw extruder at two temperature profiles within four heating zones, TP1 (60, 60, 70, and 80 degrees C) and TP2 (60, 70, 80, and 90 degrees C), to obtain corn flour. Water was added to the extruded corn flours to make a dough, or masa, and the masa was then molded and baked to obtain tortillas. The corn flours were characterized according to their ability to absorb water and viscosity profile (RVA). The firmness and rollability after 2 and 24 h of storage were determined, and a sensory evaluation was conducted. The malted corn flour extruded with a 25 % moisture content and TP2 temperature profile yielded tortillas with the best firmness and rollability. In conclusion, the changes during the malting of corn grain and the nixtamalization by the extrusion process improved the water absorption capacity of flours and textural properties of the tortilla and produced a product with acceptable sensory properties. PMID- 26059114 TI - Combined dynamic predictions using joint models of two longitudinal outcomes and competing risk data. AB - Nowadays there is an increased medical interest in personalized medicine and tailoring decision making to the needs of individual patients. Within this context our developments are motivated from a Dutch study at the Cardio-Thoracic Surgery Department of the Erasmus Medical Center, consisting of patients who received a human tissue valve in aortic position and who were thereafter monitored echocardiographically. Our aim is to utilize the available follow-up measurements of the current patients to produce dynamically updated predictions of both survival and freedom from re-intervention for future patients. In this paper, we propose to jointly model multiple longitudinal measurements combined with competing risk survival outcomes and derive the dynamically updated cumulative incidence functions. Moreover, we investigate whether different features of the longitudinal processes would change significantly the prediction for the events of interest by considering different types of association structures, such as time-dependent trajectory slopes and time-dependent cumulative effects. Our final contribution focuses on optimizing the quality of the derived predictions. In particular, instead of choosing one final model over a list of candidate models which ignores model uncertainty, we propose to suitably combine predictions from all considered models using Bayesian model averaging. PMID- 26059115 TI - Association between overweight/obesity and increased risk of periodontitis. AB - OBJECTIVE: To investigate periodontitis as a co-morbidity of overweight/obesity in an age-matched sample of periodontitis cases or periodontally healthy controls. METHODS: Participants were periodontally assessed using whole mouth clinical periodontal measures. Multivariable conditional logistic regression was used to calculate the odds ratio for diagnosis of periodontitis when body mass index (kg/m2 ), overweight (BMI 25-29.99 kg/m2 , or obese BMI >= 30 kg/m2 ) were the explanatory variables. A receiver operating characteristic (ROC) curve was generated of all possible BMI (kg/m2 ) cut-off points discriminating individuals for diagnosis of periodontitis. RESULTS: The study comprised 286 participants. BMI showed a dose-response association with increased odds (1.12 per increase of 1 kg/m2 , 95% CI 1.05-1.20, p = 0.001) of being a case compared to a control independent of gender, ethnicity, smoking status and dental plaque level. Similarly overweight/obese were independently associated with increased odds of diagnosis of periodontitis for overweight (OR = 2.56, 95% CI 1.210-5.400, p = 0.014) and for obese (OR = 3.11, 95% CI 1.052-6.481, p = 0.015) compared to normal weight individuals. The ROC curve analysis confirmed diagnosis of periodontitis was 1.6 times more likely in an individual with the BMI >= 24.32 kg/m2 . CONCLUSIONS: Overweight/obese individuals are more likely to suffer from periodontitis compared to normal weight individuals in this case-control sample. PMID- 26059117 TI - From OR to office: a cost-effective move. PMID- 26059118 TI - Enhancing anti-inflammation activity of curcumin through O/W nanoemulsions. AB - High-speed and high-pressure homogenized O/W emulsions using medium chain triacylglycerols (MCT) as oil and Tween 20 as emulsifier, with mean droplet sizes ranging from 618.6nm to 79.5nm, have been successfully prepared. The enhanced anti-inflammation activity of curcumin encapsulated in O/W emulsions is evidenced by the mouse ear inflammation model. There is a 43% or 85% inhibition effect of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced edema of mouse ear for 618.6nm and 79.5nm 1% curcumin O/W emulsions, respectively, but a negligible effect is found for 1% curcumin in 10% Tween 20 water solution. PMID- 26059119 TI - Nutritional methodologies and their use in inter-disciplinary antioxidant research. AB - There has been a significant increase in the volume of research relating to antioxidants and health. The very nature of this research is inter-disciplinary, yet the full potential of such an approach, whereby nutritionists (clinicians), chemists, pharmacists and others all bring their expertise to bear in a concerted way, is rarely achieved. This is perhaps due to a lack of understanding of the methodology and terminology of the various disciplines. In this review, the terminology and features of nutritional studies are examined with particular emphasis on the confounders that may often be ignored by laboratory-based researchers. Attention is drawn to the potential role that ethics approval processes may have in directing outcomes. PMID- 26059120 TI - Purification and characterization of type II collagen from chick sternal cartilage. AB - Type II collagen was purified from sternal cartilage of the chick using a combination of pepsin digestion, NaCl precipitation and DEAE-sepharose CL 6B ion exchange chromatography. Pepsin-solubilized type II collagen of higher stability can be obtained with the extraction time of 32h, 0.5% pepsin concentration at 20 degrees C. The purified preparation showed a single peak on RP-HPLC and a single band (alpha-chain) and its dimers (beta-chains) on SDS-PAGE with a subunit Mr of 110kDa. The amino acid composition of the type II collagen derived from chick cartilage was closer to that of reference Sigma-Aldrich type II collagen which contains more imino acid. Analysis by differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FTIR) revealed that type II collagen from chick sternal cartilage retains more intermolecular crosslinks during the purification process. Collagen purified from chick sternal cartilage was typical type II collagen and may find applications in functional foods. PMID- 26059121 TI - Chemical changes in extra virgin olive oils from Slovenian Istra after thermal treatment. AB - Changes in the physico-chemical parameters of extra virgin olive oils after heating for 142h at 100 degrees C with an air flow 10L/h were investigated. The experimental study was carried out on the two predominant olive cultivars in Slovenian Istra - cv. Istrska belica and cv. Leccino. The data obtained showed that oils from Istrska belica were more stable than those from Leccino. Peroxide values and spectrophotometric data showed higher amounts of oxidation products in oils from Leccino than in those from Istrska belica. After thermal treatment fatty acid composition was changed more in Leccino oils; particularly the amounts of polyunsaturated fatty acids dropped significantly, while alpha-tocopherol was completely depleted in all samples. The content of total biophenols decreased from 598mg/kg to 241mg/kg in Istrska belica oils and from 391mg/kg to 176mg/kg in Leccino oils. HPLC data showed that transformation of secoiridoid biophenols to the simple biophenols, tyrosol and hydroxytyrosol took place. PMID- 26059122 TI - Concordance between antioxidant activities and flavonol contents in different extracts and fractions of Cuscuta chinensis. AB - Chinese herbs employed in traditional Chinese medicine (TCM) have been used for centuries in the practice of medicated diet and dietetic therapy. The seed of Cuscuta chinensis Lam. (Convolvulaceae), a commonly used traditional Chinese herb, is frequently added in Chinese cooking and preparation of refreshments, including porridge and alcoholic beverages, to nourish the human body. In the present study, we compared the antioxidant activities of water and ethanol extracts from the seeds C. chinensis and also of its different organic fractions, including n-hexane, ethyl acetate, n-butanol and organic water, by assessing their DPPH (1,1-diphenyl-2-picryl hydrazine) free radical-scavenging, superoxide anion scavenging, anti-superoxide anion formation and anti-lipid peroxidation abilities. The flavonol contents of all test samples were analyzed by high performance liquid chromatography with an ultraviolet (HPLC-UV) detector. The results showed that there is a direct correlation of the flavonol content with the antioxidant activities from the extracts and fractions of C. chinensis. Moreover, the ethyl acetate fraction demonstrated significantly better and higher antioxidant effects, and also had a higher flavonol content than had the remaining samples (P<0.05). The water fractions, however, exhibited the weakest antioxidant activity, and had low concentrations of flavonols. Thus, we suggest that the ethanol extract of C. chinensis, but not its water extract, could be used as a dietary nutritional supplement to promote human health and prevent oxidation-related diseases, due to its antioxidant properties. PMID- 26059123 TI - Characterisation of pectins extracted from banana peels (Musa AAA) under different conditions using an experimental design. AB - An experimental design was used to study the influence of pH (1.5 and 2.0), temperature (80 and 90 degrees C) and time (1 and 4h) on extraction of pectin from banana peels (Musa AAA). Yield of extracted pectins, their composition (neutral sugars, galacturonic acid, and degree of esterification) and some macromolecular characteristics (average molecular weight, intrinsic viscosity) were determined. It was found that extraction pH was the most important parameter influencing yield and pectin chemical composition. Lower pH values negatively affected the galacturonic acid content of pectin, but increased the pectin yield. The values of degree of methylation decreased significantly with increasing temperature and time of extraction. The average molecular weight ranged widely from 87 to 248kDa and was mainly influenced by pH and extraction time. PMID- 26059124 TI - Thermal characterisation of gelatin extracted from yellowfin tuna skin and commercial mammalian gelatin. AB - Glass transition and other thermal characteristics of gelatin from different sources were studied by differential scanning calorimetry (DSC) and modulated DSC (MDSC). The initial glass transition temperatures of equilibrated gelatin samples at 11.3% relative humidity, determined from reversible heat flow thermogram of MDSC, were 23, 75 and 59 degrees C, respectively, for tuna skin, bovine and porcine gelatin. When gelatin samples were equilibrated at higher relative humidity of 52.9%, glass transition temperature of fish skin and bovine gelatin decreased to -3 and 57 degrees C, respectively. Further increase of equilibration relative humidity to 75.3% showed increased value in the case of tuna skin, whereas bovine and porcine did not show any significant change. DSC and MDSC results indicated that tuna gelatin showed lower glass transition compared to mammalian source gelatin equilibrated at the same constant relative humidity. In general glass transition measured by DSC was found lower than the values measured by MDSC. The results in this study showed that the degree of plasticization varied with the source of gelatin as well as their extraction methods. PMID- 26059125 TI - Free radical scavenging and total phenolic contents from methanolic extracts of Ulmus davidiana. AB - A methanolic (MeOH) extract of Ulmus davidiana was analyzed for antioxidant activity using model systems, including 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging, hydroxyl radical (OH) scavenging, reducing power, and total phenolic content. The MeOH extract exhibited strong antioxidant activity in the tested model systems. Among fractions using several solvents, the ethyl acetate (EtOAc)-soluble fraction, which exhibited strong antioxidant activity, was further purified by silica-gel and Sephadex LH-20 column chromatography. The (-) Catechin (1) and (-)-catechin-7-O-beta-d-apiofuranoside (2) were isolated as the active principles. Compounds 1 and 2 exhibited strong antioxidant activity on DPPH radicals, with IC50 values of 6.37+/-0.02MUM and 6.41+/-0.03MUM, respectively, and strong activity on OH radicals at 10MUg/ml, with 53.65+/-0.01% and 52.56+/-0.01% inhibition. U. davidiana extracts may be exploited as biopreservatives in food applications as well as for health supplements of functional food, to alleviate oxidative stress. PMID- 26059126 TI - Antiulcerative properties of crude polyphenols and juice of apple, and Chinese quince extracts. AB - Effects of Chinese quince extract, apple juice, semi-purified phenolics and soluble pectin from these fruits on ethanol-induced gastric ulcers in rats were investigated. In rats given Chinese quince extract or apple juice, ulcer induction was strongly suppressed, and the effect was stronger for Chinese quince extract than for apple juice. Myeloperoxidase activity in gastric mucosa showed a similar tendency. The DPPH radical scavenging activity and total phenolic content were 4 times higher in Chinese quince extract than in apple juice. Semi-purified phenolics from both fruits strongly suppressed ulcer induction at doses of 5 10mg; however, a 20mg dose of apple phenolics showed a pro-ulcerative effect. The soluble pectin fraction also showed moderate activity. These results suggest that phenolic compounds are responsible for antiulcerative activity of Chinese quince extract and apple juice, and that concentration may be an important factor in the case of apple phenolics. PMID- 26059127 TI - Partial properties of an aspartic protease in bitter gourd (Momordica charantia L.) fruit and its activation by heating. AB - Bitter gourd (BG fruit) is usually heated in hot water to reduce bitterness and improve flavour before being served. Protein extract from BG was analyzed for protease activity by gelatin-gel electrophoresis. The study showed that the proteolytic activity in BG flesh was enhanced by heat-treatment at temperatures ranging from 50 degrees C to 75 degrees C. An aspartic protease (AP) was characterized by gel electrophoresis. The optimal AP activity was at pH 7; the pI of the AP was demonstrated to be 4.8; the protein molecular weight of the BG-AP was estimated to be 60KD by SDS-PAGE. The AP was implicated in the proteolysis of the photosynthetic enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase. The AP was further purified and submitted for analysis of peptide mass fingerprint (PMF). The Mascot peptide mass fingerprint of the AP protein hit no existing protein (score>60), and it proved to be a novel AP. PMID- 26059128 TI - Thermal stability of soy protein isolate and hydrolysate ingredients. AB - The objective of this study was to characterize the effects of pH, protein concentration and calcium supplementation on thermal stability, at 140 degrees C, of soy protein isolate (SPI) and soy protein hydrolysate (SPH) ingredients. Increasing pH between 6.4 and 7.5 led to significantly (p<0.05) higher mean heat coagulation times (HCTs) at 140 degrees C, for all soy protein ingredients at 1.8, and 3.6% (w/v) protein. Increasing protein concentration from 1.8 to 7.2% (w/v) led to shorter HCTs for protein dispersions. Calcium supplementation up to 850mg/L, except in the case of supplementation of SPI 1 with calcium citrate (CaCit), decreased HCT for soy protein ingredient dispersions, at pH 6.4 - 7.5. No significant differences (p<0.05) were found in mean HCT for dispersions supplemented with calcium chloride (CaCl2) and those supplemented with CaCit at 450, 650 and 850mg/L Ca(2+), in the pH range 6.4-7.5. PMID- 26059129 TI - Composition and antioxidant activity of raisin extracts obtained from various solvents. AB - Experiments were conducted to determine if the contents of phenolics and browning reaction products and antioxidant activity of raisin extracts were closely dependent on the extraction solvent. Enhanced extraction yields were obtained from solvent containing higher water concentrations. However, total phenolic content (TPC) was highest for extracts obtained from solvent to water ratios of 60:40 (v/v), whereby the extract obtained from ethanol:water (60:40, v/v) had the highest TPC of 375mg gallic acid equivalents (GAE)/100g extract. HMF content was highest in extracts obtained from 60% solvent, regardless of solvent type. The extract obtained from 60% methanol had the highest HMF content at 199MUg/g extract. Although the 60% solvents provided extract with high antioxidant components, the antioxidant activity of raisin extracts obtained from 80:20 (v/v) solvent/water was significantly higher than other raisin extracts obtained from different solvent concentrations. Phenolic acids, HMF, and low-molecular-weight flavonoids were responsible for the antioxidant activity, but not the high molecular-weight flavonoids. PMID- 26059130 TI - Chemical characterization and antioxidant activities of oligomeric and polymeric procyanidin fractions from grape seeds. AB - Two procyanidin fractions, namely oligomers and polymers isolated from grape seed methanolic extract were characterized. Phenolic composition and procyanidin purity of these fractions were determined by normal-phase and reverse-phase HPLC, thioacidolysis-HPLC, ESI-MS analyses, formaldehyde-HCl precipitation and elemental analysis. Antioxidant activities of these fractions and other well known antioxidants were measured using xanthine-xanthine oxidase system for generating superoxide radical ({O2(-)}), the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical method and the Fenton system for generating hydroxyl radical (HO). The results showed that both oligomeric and polymeric procyanidin fractions were highly pure, with the degree of polymerization ranging from 2 to 17-18 and 12 to 32-37, respectively. On the basis of molar concentration, polymeric procyanidins appeared the highest antioxidant activities, followed by oligomeric procyanidins, whereas catechins presented a lower antioxidant activity than its oligomers and polymers. These results indicate that the antioxidant activities of grape seed procyanidins are positively related to their degree of polymerization. Moreover, grape seed procyanidins presented higher antioxidant activities than other well known antioxidants such as vitamin C, suggesting that grape seed procyanidins might be of interest to be used as alternative antioxidants. PMID- 26059131 TI - Kinetics of color development, pH decreasing, and anti-oxidative activity reduction of Maillard reaction in galactose/glycine model systems. AB - Galactose/glycine model systems of sugar concentration 0.035, 0.069, 0.139, and 0.278M were incubated at 60, 75, and 90 degrees C separately for studying the reaction kinetics of color development, pH change, and system anti-oxidative activity change in Maillard reaction. The results indicated that system color development followed first-ordered kinetics on galactose concentration; system pH went linearly down with a logarithm-ordered kinetics on galactose concentration; and anti-oxidative activity reduced linearly with a first-ordered kinetics on galactose concentration. The values of Q10 and activation energy ranged from 1.98 to 2.00 and from 68.8 to 69.5kJ/mol, respectively, for these three properties. PMID- 26059132 TI - Study on formation of acrylamide in asparagine-sugar microwave heating systems using UPLC-MS/MS analytical method. AB - Microwave heating can be regarded as a possible way to produce a considerable amount of acrylamide. The present study investigated the formation of acrylamide in asparagine-glucose, asparagine-fructose and asparagine-sucrose microwave heating systems by the response surface methodology (RSM) and the orthogonal array methodology (OAM). The acrylamide content was rapidly quantified by a validated ultra-performance liquid chromatography tandem mass spectrometry (UPLC MS/MS) method. Results of RSM study indicated that in the asparagine-glucose system, the acrylamide content increased in the combined condition of high temperature accompanying with short heating time (>190 degrees C, <20min) or low temperature accompanying with long heating time (<180 degrees C, >30min). In the asparagine-fructose system, the similar conclusion was made in the combined condition of high temperature accompanying with short heating time (>175 degrees C, <20min) or low temperature accompanying with long heating time (<170 degrees C, >25min). In the asparagine-sucrose system, the amount of acrylamide enhanced with the increase of both heating temperature and heating time. The fitted mathematic models were successfully applied to the quantification of acrylamide formation when the heating temperature and heating time fell into the ranges of 120-240 degrees C and 5-35min simultaneously. OAM study showed that acrylamide is readily formed via heating binary precursors 5min at 180 degrees C in the asparagine-glucose and asparagine-fructose systems. However, acrylamide is readily generated when the binary precursors are heated 15min at 180 degrees C in the asparagine-sucrose system. PMID- 26059133 TI - Diallyl sulfides: Selective inhibitors of family X DNA polymerases from garlic (Allium sativum L.). AB - Diallyl sulfides, organosulfur compounds isolated from garlic (Allium sativum L.), selectively inhibit the activities of mammalian family X DNA polymerases (pols), such as pol beta, pol lambda and terminal deoxynucleotidyl transferase (TdT), in vitro. The purified fraction (i.e., Sample-A) consisted of diallyl trisulfide, diallyl tetrasulfide and diallyl pentasulfide (molecular ratio: 5.3:3:1). Commercially purchased diallyl sulfides also inhibited the activities of family X pols, and the order of their effect was as follows: Sample-A>diallyl trisulfide>diallyl disulfide>diallyl monosulfide, suggesting that the number of sulfur atoms in the compounds might play an important structural role in enzyme inhibition. The suppression of human cancer cell (promyelocytic leukaemia cell line, HL-60) growth had the same tendency as the inhibition of pol X family among the compounds. Diallyl sulfides were suggested to bind to the pol beta-like region of family X pols. PMID- 26059134 TI - Physicochemical properties of hull-less barley fibre-rich fractions varying in particle size and their potential as functional ingredients in two-layer flat bread. AB - The performance of barley fibre-rich fractions (FRF), as high dietary fibre ingredients, in two-layer flat bread was investigated. In addition, the effects of particle size reduction by pin milling on functional properties of FRF were studied. FRF enriched in non-starch polysaccharides (beta-glucans and arabinoxylans) were obtained by roller milling of hull-less barley. Pin milling (PM) of FRF significantly reduced their particle size, slightly increased the solubility of beta-glucans and arabinoxylans, and increased the viscosity of water slurries containing FRF. The addition of 20% of barley FRF to wheat flour significantly increased dough water absorption and weakened the dough properties, as indicated by farinograph mixing curves, but the FRF-enriched doughs exhibited good handling characteristics at the dividing and sheeting stages. The appearance, diameter, layer separation, crumb, and aroma of the FRF-enriched flat breads were comparable to that of the control. The PM of FRF did not significantly affect the dough handling or the quality characteristics of flat breads. The addition of 20% of barley FRF to wheat flour flat bread provided substantial health benefits by significantly increasing the total and soluble dietary fibre contents and by decreasing starch digestibility. PMID- 26059135 TI - Immunoreactivity reduction of soybean meal by fermentation, effect on amino acid composition and antigenicity of commercial soy products. AB - Food allergy has become a public health problem that continues to challenge both the consumer and the food industry. The objectives of this study were to evaluate the reduction of immunoreactivity by natural and induced fermentation of soybean meal (SBM) with Lactobacillus plantarum, Bifidobacterium lactis, Saccharomyces cereviseae, and to assess the effect on amino acid concentration. Immunoreactivity of commercially available fermented soybean products and ingredients was also evaluated. ELISA and western blot were used to measure IgE immunoreactivity using plasma from soy sensitive individuals. Commercial soy products included tempeh, miso and yogurt. Fermented SBM showed reduced immunoreactivity to human plasma, particularly if proteins were <20kDa. S. cereviseae and naturally fermented SBM showed the highest reduction in IgE immunoreactivity, up to 89% and 88%, respectively, against human pooled plasma. When SBM was subjected to fermentation with different microorganisms, most of the total amino acids increased significantly (p<0.05) and only few of them suffered a decrease depending on the type of fermentation. All commercial soy containing products tested showed very low immunoreactivity. Thus, fermentation can decrease soy immunoreactivity and can be optimized to develop nutritious hypoallergenic soy products. However, the clinical relevance of these findings needs to be determined by human challenge studies. PMID- 26059136 TI - Effect of reaction pH on enolization and racemization reactions of glucose and fructose on heating with amino acid enantiomers and formation of melanoidins as result of the Maillard reaction. AB - This study investigates the effect of reaction pH on enolization and racemization reactions of glucose and fructose on heating with amino acid enantiomers, can influence the formation of melanoidins as result of the Maillard reaction. Remarkable enolization reaction of sugars was observed in the course of the Maillard reaction. Especially, the degree of sugar enolization was increased as the pH levels increased, which was higher in fructose than glucose systems. Otherwise, enolization of sugars on heating with amino acid was higher in glucose than fructose systems. Formation of isomer in Glc/d-Lys, Fru/d-Asn and Fru/d-Lys were increased upon increase of pH levels. The relative amounts of isomers in Glc/l-Asn and Glc/d-Asn were decreased upon increase of pH levels. Browning development was dependent on the pH levels, being more significant for model systems apart from heated glucose solution alone. Browning development of fructose systems was higher than glucose-amino acid systems. The l- and d-isomers both showed different absorption in the UV-vis spectra and that these occur at similar shape. Every peak has a stable absorbance appeared in the range between 260 and 320nm, characteristic of melanoidins. PMID- 26059137 TI - Survey: Ochratoxin A in European special wines. AB - The occurrence of Ochratoxin A (OTA) was examined in 121 special wines made using different winemaking techniques and from many European origins. The wine groups with the highest OTA content and occurrence, above 90%, were those were the must was fortified before fermentation (mean: 4.48MUg/l) and those made from grapes dried by means of sun exposure (mean: 2.77MUg/l). Fortified wines with long aging in wooden casks were about 50% contaminated, with OTA levels below 1.00MUg/l. Wines affected by noble rot, late harvest wines and ice wines did not contain OTA. Overall, 19.8% of the wines studied contained OTA levels above the maximum permissible limit for the European Union (2MUg/kg) in wine (excluding liqueur wines). PMID- 26059138 TI - Effect of genotype and environment on fatty acid composition of Lupinus albus L. seed. AB - Six cultivars of Lupinus albus L. (white lupin) were grown in two subcontinental climate environments and one Mediterranean-climate environment in Italy, to assess the influence of genotypic (G) and genotype*environment (GE) interaction effects on grain yield and grain content of oil, total saturated fatty acids (FAs), polyunsaturated FAs, monounsaturated FAs, and omega-3/omega-6 FA ratio. The variance of genotypic effects was much larger than the GE interaction variance for all variables, except for grain yield, indicating that oil content and FA composition of different varieties can be assessed reliably in just a few test environments. Gas-chromatographic analyses highlighted that linoleic acid and alpha-linolenic acid were in the range 1.76-4.76mg/g flour (7.79-15.81% of total FAs) and 1.17-3.14mg/g flour (5.40-10.36% of total FAs), respectively. As a consequence, the analysed lupin seeds exhibited a very favourable omega-3/omega-6 FA ratio, ranging from 0.49 to 0.79. PMID- 26059139 TI - Effects of toasting procedures on the levels of polycyclic aromatic hydrocarbons in toasted bread. AB - Some polycyclic aromatic hydrocarbons (PAHs), particularly those with a high molecular weight, have been classified as probably carcinogens to humans by the International Agency for Research on Cancer (IARC). The significance of the determination of PAHs is reflected by the special attention of the European Union, which is paying to regulate the maximum allowed levels of PAHs in foodstuffs such as smoked foods. Like other thermally processed foodstuffs, toasted bread can contain these carcinogenic chemicals, not only due to a contamination at source but also during toasting. In order to check PAHs generated from toasting in sandwich bread, several treatment conditions were evaluated: direct toasting (flame-toasting, coal-grilling or gas oven-toasting) or indirect toasting (electric oven-toasting). PAHs were extracted by solid liquid extraction (SLE) and determined by liquid chromatography with fluorescence detection (LC-FD). Based on the results, the used toasted technique would strongly affect in PAH levels in the final product. No samples obtained by electric oven and toaster were polluted; otherwise the samples toasted by charcoal and flame grilling presented very important levels. Up to 350MUg/kg of total PAHs were detected in toasted samples by wood flame. Differences between different ways of toasting could be ascribed to deposition of PAHs from smoke. Finally, several commercial toasted samples of bread were tested to determine PAHs. Overall, the PAH levels were very low. Benzo[a]pyrene ranged from no detectable to 0.23MUg/kg. PMID- 26059140 TI - Isolation and characterisation of collagens from the skin, scale and bone of deep sea redfish (Sebastes mentella). AB - To make more effective use of underutilised resources, collagens from skin, scale and bone (SKC, SCC and BOC) of deep-sea redfish were isolated with acetic acid and characterised for their potential in commercial applications. The abundant ash and fat in the materials could be removed effectively by EDTA and hexane treatment in 24h, with high recoveries of protein. The yield of SKC (47.5%) was significantly higher than that of SCC and BOC (6.8% and 10.3%, respectively). The denaturation temperatures of SKC, SCC and BOC were 16.1 degrees C, 17.7 degrees C and 17.5 degrees C, respectively, which were lower than those of most other fish species. The amino acid profiles of these collagens were similar with a low imino acid content, which might be the reason for the low denaturation temperature. All the collagens were type I mainly and maintained their triple helical structures well with slight molecular structure differences. SKC possessed a higher degree of intermolecular cross-linking and molecular order, but the extent of peptide chain unwinding was also higher, due to the existence of fewer hydrogen bonds, compared to SCC and BOC. PMID- 26059141 TI - Evidence of an active laccase-like enzyme in deepwater pink shrimp (Parapenaeus longirostris). AB - This paper demonstrates the presence of an active laccase-like enzyme from deepwater pink shrimp (Parapenaeus longirostris) using polyacrylamide gel electrophoresis. This enzyme was found in all anatomical parts of the deepwater pink shrimp, but particularly in the cephalothorax, and became active during the course of storage. Gel staining with laccase-specific substrates such as ADA, DMP and DAB was used to characterize a protein of around 44kDa as containing laccase activity. The enzyme was inhibited by a specific inhibitor, CTAB. 4 Hexylresorcinol, a specific inhibitor of polyphenoloxidase (PPO), did not inhibit the laccase-like enzyme. Low concentrations of antioxidants ascorbic acid or sodium metabisulphite were sufficient to inhibit the laccase-like enzyme. ABTS and DMP were subsequently used to characterize the enzyme. Given the evidence of this enzyme in deepwater pink shrimp, new melanosis-inhibiting compounds that are suitable for consumption need to be found to complement specific inhibitors of PPO activity. PMID- 26059142 TI - Improving the antioxidant activity of buckwheat (Fagopyrum tataricm Gaertn) sprout with trace element water. AB - Trace element water (TEW) (100, 200, 300, 400 and 500ppm) was used to grow buckwheat (Fagopyrum tataricm Gaertn) to evaluate whether the beneficial effects of trace elements on the antioxidant activity could be accomplished with the supplement of TEW. At 300ppm, TEW significantly increased the Cu, Zn and Fe contents in buckwheat sprout, but not the Se and Mn contents. The levels of rutin, quercitrin and quercetin did not differ between buckwheat sprouts grown in TEW and de-ionized water (DIW). The ethanolic extract from buckwheat sprout grown in 300ppm TEW showed higher DPPH radical scavenging activity, ferrous ion chelating activity, superoxide anion scavenging activity and inhibitory activity toward lipid peroxidation than that grown in DIW. The extract of the TEW group also enhanced intracellular superoxide dismutase activity and resulted in lower level of reactive oxygen species in human Hep G2 cells. PMID- 26059143 TI - The amino acid composition of kale (Brassica oleracea L. var. acephala), fresh and after culinary and technological processing. AB - The aim of the investigation was to evaluate the level of amino acids and the quality of protein in fresh and cooked leaves of kale and in two types of frozen product prepared for consumption after 12-months storage at -20 degrees C. Kale blanched before freezing (the traditional method) was cooked after refrigerated storage, while that cooked before freezing (the modified method) was defrosted and heated in a microwave oven. Both fresh and processed leaves of kale were a good source of amino acids. In all the samples, glutamic acid, proline and aspartic acid were the dominant, while lysine and leucine were the limiting amino acids. Cooked leaves contained 78% of the total amino acid content found in fresh leaves, while the traditional and modified frozen products contained 76% and 78%, respectively. The proportion of essential amino acids in total amino acids was 44% and 43%, respectively for fresh and cooked leaves and 46% for the frozen products. The lowest EAA index was found for the traditional frozen product (99); it was higher for the remaining samples, which were broadly similar to each other (105-106). PMID- 26059144 TI - Total and individual carotenoids and phenolic acids content in fresh, refrigerated and processed spinach (Spinacia oleracea L.). AB - The carotenoid and phenolic acid contents in fresh, stored and processed (blanched, frozen and boiled) spinach were comparatively determined by spectrophotometric and HPLC analyses. The major carotenoids identified after HPLC analysis in saponified samples were lutein (37-53MUg/kg), beta-carotene (18 31MUg/kg), violaxanthin (9-23MUg/kg) and neoxanthin (10-22MUg/kg). These carotenoids were all affected by storage and/or heating. The content of carotenoids was best preserved after storage for one day at 4 degrees C. The total phenolic content in the fresh spinach was 2088mg GAE/kg FW. After LC-MS analysis three phenolic acids were identified and quantified. These being ortho coumaric acid (28-60mg/kg FW), ferulic acid (10-35mg/kg) and para-coumaric acid (1-30mg/kg) depending on the sample type. After storage of spinach at different temperatures (4 degrees C or -18 degrees C) the amount of total phenolic compounds decreased by around 20%, while the amount of individual phenolic acids increased by four times on average. PMID- 26059145 TI - Effect of Glycine and Triton X-100 on secretion and expression of ZZ-EGFP fusion protein. AB - Two-factor and three-level fractional factorial design was employed for evaluation of the effect of Glycine and Triton X-100 on the secretion and expression of ZZ-EGFP fusion proteins. Varying contents of glycine (0%, 1%, 2%) and Triton X-100 (0%, 1%, 2%) were added into shaking flasks, respectively, and supplied with appropriate volume of ampicillin (total 9 combinations; group at concentration zero serving as control) to promote more ZZ-EGFP diffuse into liquid culture medium. Fluorescent intensity in the culture supernatant was detected. A standard curve could be generated on the basis of fluorescent intensity and protein concentration. The expression level of ZZ-EGFP fusion proteins was estimated by checking the protein standard curve concentration fluorescene intensity. Results show that when the culture medium contains 2% Glycine and 1% Triton X-100, the expression level of ZZ-EGFP was able to be greatly increased. Further experiments revealed that absorbance value (A600) in the experiment group, whose culture medium contains 2% Glycine and 2% Triton X 100, is significantly lower than other groups in the present experiment. These results indicate that the culture medium containing appropriate quantity of Glycine and Triton X-100 is favourable to the secretion and expression level of ZZ-EGFP in gene-engineering bacteria Escherichia coli HB101. PMID- 26059146 TI - Inhibitory effect of Turkish Rosmarinus officinalis L. on acetylcholinesterase and butyrylcholinesterase enzymes. AB - In the current study, we have tested acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity of the petroleum ether, ethyl acetate, chloroform, and methanol extracts, rosmarinic acid as well as the essential oil obtained from Rosmarinus officinalis L. growing in Turkey by a spectrophotometric method of Ellman using ELISA microplate-reader at 0.2,0.5, and 1.0mg/mL concentrations. In addition, quantification of rosmarinic acid, a common phenolic acid found in rosemary, was carried out by reversed-phase HPLC in the methanolic extract of the plant, which was found to have 12.21+/-0.95% (122.1+/ 9.5mg/g extract) of rosmarinic acid. Rosmarinic acid was also tested for its AChE and BChE inhibitory effect and found to cause 85.8% of inhibition against AChE at only 1.0mg/mL. Besides, the essential oil was analyzed by GC-MS technique, which was shown to be dominated by 1,8-cineol (44.42%) and followed by alpha-pinene (12.57%). PMID- 26059147 TI - Applications of sample preparation techniques in the analysis of pesticides and PCBs in food. AB - Pesticides and polychlorinated biphenyls (PCBs) are found in various parts of the environment in quite small concentrations, but they accumulate and thus become a threat to human health and life. A review is focused on the application of some popular techniques for sample preparation in analysis of these compounds in food. Even with the emergence of advanced techniques of final analysis, complex matrices, such as food, require extensive sample extraction and purification. Traditional sample preparation techniques are time consuming and require large amount of solvents, which are expensive, generate considerable waste, contaminate the sample and can enrich it for analytes. There have been many sample preparation techniques proposed to meet the requirements connected with the multiplicity of food. Optimal sample preparation can reduce analysis time, sources of error, enhance sensitivity and enable unequivocal identification and quantification. Sample extraction and purification techniques are discussed and their most recent applications in food analysis are provided. This review pointed out that sample preparation is the critical step. PMID- 26059148 TI - Freshness monitoring of sea bream (Sparus aurata) with a potentiometric sensor. AB - Freshness in one of the main quality attributes for fish commercialization and consumption. The traditional method for fish freshness evaluation is sensory analysis. However, instrumental methods such as electrical, texture and colour measurements, image analysis, VIS spectroscopy and electronic noses have been widely studied as objective alternatives. Each of these methods has advantages and disadvantages, but none of them can be universally proposed for defining and measuring fish freshness. This work evaluated the correlation of potentiometric measurements, obtained with gold and silver electrodes, with physicochemical, microbiological and biochemical analyses of sea bream stored under refrigeration. Results showed a strong correlation of the potentiometric measurements with the determined changes in fish, and an important correlation with the K1 index, dependent on the nucleoside degradation, which is used as a good indicator of post-mortem time and freshness. PMID- 26059149 TI - Determination of the seasonal changes on total fatty acid composition and omega3/omega6 ratios of carp (Cyprinus carpio L.) muscle lipids in Beysehir Lake (Turkey). AB - The muscle lipid and fatty acid composition of carp, Cyprinus carpio in Beysehir Lake the largest freshwater lake in Turkey, was determined. Polyunsaturated fatty acids (PUFA) of carp, the most abundant fish species in Beysehir Lake, were found to be higher than those of saturated fatty acids (SFA) in spring, summer and autumn and also the monounsaturated fatty acids (MUFA) in spring and summer. Palmitic acid was the major SFA (14.6-16.6%) in all seasons. Oleic acid was identified as the major MUFA (15.1-20.3%). Docosahexaenoic acid (DHA) was the major PUFA in summer and winter, whereas linoleic acid (LA) was the major PUFA in spring and autumn. The percentages of total omega3 fatty acid were higher than those of total omega6 fatty acid in the fatty acid composition of carp in winter. It was shown that the fatty acid composition in the muscle of carp was significantly influenced by feeding period and seasons. PMID- 26059150 TI - Determination of total phenols in tea infusions, tomato and apple juice by terbium sensitized fluorescence method as an alternative approach to the Folin Ciocalteu spectrophotometric method. AB - A fast screening of total phenols in tea infusions, tomato and apple juice samples using terbium sensitized fluorescence is described. The proposed method is based on the fluorescence sensitization of terbium (Tb(3+)) by complexation with flavonols (quercein as a reference standard) (at pH 7.0), which fluoresces intensely with an emission maximum at 545nm when excited at 310nm. Quercetin and terbium cations (at pH 7.0) form a stable complex and the resulted emission at 545nm can be used for the determination of the total phenols concentration expressed in terms of "quercetin equivalent". Based on the obtained results, a sensitive, simple and rapid spectrofluorimetric method was developed for the determination of total phenols. In the optimum conditions, the calibration graph was linear from 0.01 to 2MUgmL(-1), with the limit of detection of 0.002MUgmL( 1). The relative standard deviation values were in the range of 0.75-2.3%. The total concentrations of quercetin equivalent in five tested samples were found in the range of 6.6-27.9MUgmL(-1) and the results compare favorably with those obtained by spectrophotometric method (r=0.999). PMID- 26059151 TI - Isolation and purification of phenylethanoid glycosides from Cistanche deserticola by high-speed counter-current chromatography. AB - Five phenylethanoid glycosides (PhGs), echinacoside, cistanoside A, acteoside, isoacteoside and 2'-acetylacteoside, were isolated and purified from Cistanche deserticola for the first time by high-speed counter-current chromatography (HSCCC) using two biphasic systems, one consisting of ethyl acetate-ethanol-water (5:0.5:4.5, v/v/v) and another of ethyl acetate-n-butanol-ethanol-water (0.5:0.5:0.1:1, v/v/v/v). A total of 28.5mg of echinacoside, 18.4mg of cistanoside A, 14.6mg of acteoside, 30.1mg of isoacteoside and 25.2mg of 2' acetylacteoside were purified from 1412mg of the n-butanol extract of C. deserticola, each at over 92.5% purity as determined by HPLC. The structures were identified by their retention time, UV, LC-ESI-MS in the negative ion mode, and confirmed by NMR experiments. The characteristic LC-ESI-MS(n) fragmentation pattern of the five compounds is discussed, and found to be a very specific and useful tool for the structural identification of PhGs from this important medicinal plant. PMID- 26059152 TI - Effect of extraction conditions on lycopene extractions from tomato processing waste skin using response surface methodology. AB - Skin, rich in lycopene, is an important component of waste originating from tomato paste manufacturing plants. A central composite design with five independent variables, namely solvent/meal ratio (20:1, 30:1, 40:1, 50:1, and 60:1v/w); number of extractions (1, 2, 3, 4 and 5); temperature (20, 30, 40, 50 and 60 degrees C); particle size (0.05, 0.15, 0.25, 0.35 and 0.43mm); extraction time (4, 8, 12, 16 and 20min) was used to study their effects on lycopene extraction. The experimental values of lycopene ranged between 0.639 and 1.98mg/100g. The second order model obtained for extracted lycopene revealed a coefficient of determination (R(2)) of 0.99 and a standard error of 0.03. Maximum lycopene (1.98mg/100g) was extracted when the solvent/meal ratio, number of extractions, temperature, particle size and extraction time were 30:1v/w, 4, 50 degrees C, 0.15mm and 8min, respectively. PMID- 26059153 TI - Determination of the differential estrogenicity of isoflavonoids by E2-ER-ERE dependent gene expression in recombinant yeast and MCF-7 human breast cancer cells. AB - The use of phytoestrogens-containing natural sources as alternative hormone replacement therapy (HRT) has been a subject of debate for decades. Development of assays to characterize these phytoestrogens is required. In this study, differential estrogenicities of five isoflavonoids found in red clover and soy, including biochanin A, daidzein, formononetin, genistein and glycitein were examined in a yeast-based screen system with a classical palindromic estrogen response element (ERE)-ADE2 reporter and in a MCF-7 cell culture system with mRNA levels of ER-dependent genes compared. In a yeast-based assay, five isoflavonoids showed various extents of estrogenic potencies. A collection of primary estrogen receptor (ER)-regulated genes by estradiol (E2), including hTERT, c-MYC, BCL2 and Ha-ras (oncogenic) and quinone reductase (QR), human complement 3 (C3) and COX7RP (non-oncogenic) were selected as marker genes for a MCF-7 cell-based endogenous gene expression assay. The results indicated that the mRNA levels of these E2-ER ERE-dependent marker genes were regulated differentially by five isoflavonoids, leading to distinct expression patterns, which are also significantly different from that of E2. Moreover, the anti-estrogenic effects of biochanin A and formononetin on E2-induced transcriptions of marker genes in MCF-7 cells were also displayed. Taken together, these results are significant for these naturally occurring isoflavonoids regarding the issues of safety and efficacy. PMID- 26059154 TI - Purification and identification of antioxidant peptides from grass carp muscle hydrolysates by consecutive chromatography and electrospray ionization-mass spectrometry. AB - Grass carp muscles were hydrolyzed with various proteases (papain, bovine pancreatin 6.0, bromelain, neutrase 1.5MG and alcalase 2.4L) to extract antioxidant peptides. The hydrolysates were assessed using methods of hydroxyl radical scavenging ability and lipid peroxidation inhibition activity. Hydrolysate prepared with alcalase 2.4L was found to have the highest antioxidant activity. It was purified using ultrafiltration and consecutive chromatographic methods including ion-exchange chromatography, multilayer coil high-speed counter current chromatography, and gel filtration chromatography. The purified peptide, as a potent antioxidant, was identified as Pro-Ser-Lys-Tyr-Glu-Pro-Phe-Val (966.3Da) using RP-HPLC connected on-line to an electrospray ionization mass spectrometry. As well, it was found that basic peptides had greater capacity to scavenge hydroxyl radical than acidic or neutral peptides and that hydrophobic peptides contributed more to the antioxidant activities of hydrolysates than the hydrophilic peptides. In addition, the amino acid sequence of the peptide might play an important role on its antioxidant activity. PMID- 26059155 TI - Optimisation of supercritical fluid extraction of flavonoids from Pueraria lobata. AB - Supercritical carbon dioxide extraction was employed to extract flavonoids from Pueraria lobata. The optimal conditions for flavonoid extraction were determined by response surface methodology. Box-Behnken design was applied to evaluate the effects of three independent variables (pressure, temperature and co-solvent amount) on the flavonoid yield of P. lobata. Correlation analysis of the mathematical-regression model indicated that a quadratic polynomial model could be employed to optimise the supercritical carbon dioxide extraction of flavonoids. From response surface plots, pressure, temperature and co-solvent amount exhibited independent and interactive effects on the extraction of flavonoids. The optimal conditions to obtain the highest flavonoid yield of P. lobata were a pressure of 20.04MPa, a temperature of 50.24 degrees C and a co solvent amount of 181.24ml. Under these optimal conditions, the experimental values agreed with the predicted values, using analysis of variance, indicating a high goodness of fit of the model used and the success of response surface methodology for optimising supercritical carbon dioxide extraction of flavonoids from P. lobata. PMID- 26059156 TI - Authentication of pomegranate juice concentrate using FTIR spectroscopy and chemometrics. AB - Fourier transform infrared (FTIR) spectroscopy and chemometric techniques were used to detect the adulteration of pomegranate juice concentrate (PJC) with grape juice concentrate (GJC). The main differences between PJC and GJC infrared spectra occurred in the 1780-1685cm(-1) region, which corresponds to CO stretching. Principal component analysis of the spectra was used to: (1) differentiate pure PJC and GJC samples and (2) classify adulterated (containing 2 14% vol/vol GJC) and pure PJC samples. Two principal components explained 99% of the variability in each of these applications. Partial least square analysis of the spectra resulted in prediction of the GJC adulterant concentration in PJC with a correlation coefficient, R(2), of 0.9751. Partial least square analysis of spectra could also predict % titratable acidity and total solids in PJC with correlation coefficients of 0.9114 and 0.9916, respectively. Therefore, FTIR and chemometrics provide a useful approach for authenticating pomegranate juice concentrate. PMID- 26059157 TI - Geographical traceability of propolis by high-performance liquid-chromatography fingerprints. AB - A rapid fingerprint method was developed for investigating and inferring geographical origin of Chinese propolis by using high performance liquid chromatography-ultraviolet detection (HPLC-UV). 120 samples were analyzed from 17 different locations of 10 provinces of China in this study. In the HPLC chromatograms, eight major compounds were identified as flavonoids, including rutin, myricetin, quercetin, kaempferol, apigenin, pinocembrine, chrysin and galangin. Both correlation coefficient of similarity in chromatograms and relative peak areas of characteristic compounds were calculated for quantitative expression of the HPLC fingerprints. Our results revealed that the presence or absence of specific peaks and similarity evaluation in simulative mean chromatograms among different regions could efficiently identify and distinguish Chinese propolis from different geographical origins. PMID- 26059158 TI - Quantitative analysis of acrylamide in tea by liquid chromatography coupled with electrospray ionization tandem mass spectrometry. AB - An effective sample preparation procedure was optimized and a liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the quantitative analysis of acrylamide in tea. [(13)C3]-acrylamide was used as internal standard. Acrylamide was extracted at 25 degrees C for 20min by 10ml water followed by 10ml acetonitrile, and then 4g of magnesium sulfate and 0.5g of sodium chloride were added to the above mixture under stirring thoroughly. In order to increase the response of acrylamide, 9ml acetonitrile layer was taken and concentrated to 0.5ml. Solid-phase extraction with an Oasis MCX cartridge was carried out for clean-up. The limit of detection (LOD) and limit of quantification (LOQ) were 1 and 5ng/ml, respectively. The recovery efficiency of the extraction procedure ranged between 74% and 79%. The levels of acrylamide in 30 tea samples were less than 100ng/g. Black, oolong, white and yellow tea samples had quite low acrylamide contents (<20ng/g). Higher acrylamide levels occurred in baked, roasted, and one sun-dried green tea samples (46-94ng/g). PMID- 26059159 TI - Sulfamethazine detection with direct-binding optical waveguide lightmode spectroscopy-based immunosensor. AB - A direct-binding optical waveguide lightmode spectroscopy-based immunosensor detecting sulfamethazine (SMZ) was prepared, followed by the measurement of its specificity and sensitivity. System construction was undertaken with a peristaltic pump, an injector and the main unit comprising a sensor holder, two signal-harvesting photodiodes, a beam mirror, shutter and He-Ne laser source emitting a monochrome light (lambda=632.8nm), plus a PC. Antibody immobilization was performed in situ by covalent binding of an anti-SMZ antibody over the surface of a glutaraldehyde-activated 3-aminopropyltriethoxysilane-treated sensor chip. The reaction buffer for the system was 4mM Tris-HCl (pH 7.2) that showed a medium surface coverage and stable baseline. Sensor response was quite specific to antibody-antigen complexation, as judged from no sensor response caused by bovine serum albumin immobilization. The sensor responses according to SMZ concentrations from 10(-8) to 10(-2)M increased linearly in a semi-logarithmic scale, with the limit of detection of 10(-8)M. The immunosensor was favorably reusable for SMZ screening. PMID- 26059160 TI - Automatic determination of nickel in foods by flame atomic absorption spectrometry. AB - A new sensitive and low cost flow injection method that combines acid extraction, preconcentration and flame atomic absorption spectrometric determination of nickel in food samples at MUg/g levels is described. The dynamic acid extraction step was carried out by using a continuous ultrasound-assisted extraction system. The acid extract was preconcentrated on-line on a minicolumn packed with a chelating resin (Serdolit Che, with iminodiacetic groups) and nickel was eluted with diluted hydrochloric acid, being continuously monitored by flame atomic absorption spectrometry. An experimental design (Plackett-Burman 2(6)*3/16) is used to optimise the methodology proposed. The method allowed a total sampling frequency of 13-28 samples per hour. Good precision of the whole procedure (1.9 3.6% expressed as relative standard deviation) and a detection limit of 0.12MUg/g, for 60mg of sample were achieved. The method was successfully applied to the determination of trace amounts of nickel in food samples. PMID- 26059161 TI - Spectrophotometric determination of total serotonin derivatives in the safflower seeds with Ehrlich's reagent and the underlying color reaction mechanism. AB - A new spectrophotometric method for the determination of total serotonin derivatives in the safflower (Carthamus tinctorius L.) seeds is described. The determination is based upon a color reaction between serotonin derivatives and p dimethylaminobenzaldehyde (Ehrlich's reagent), which follows the electrophilic substitution reaction mechanism at the indole ring. The main factors affecting correct measurement of total serotonin derivatives concentration were studied. The maximum absorption wavelength of the complex was determined at 625nm. Lambert Beer's law is obeyed in the concentration range of 0.025-0.5mmol/l, with a correlation coefficient (R(2)) of 0.9996, a recovery of 99.7%, and a relative standard derivation (RSD) of 1.5%, respectively. The proposed method presented satisfactory results in the determination of total serotonin derivatives in the extract from a strain of safflower seeds, and thus is recommended as a routine method for total serotonin derivatives quantitation. PMID- 26059162 TI - Amino acids profile of sugar cane spirit (cachaca), rum, and whisky. AB - An analytical procedure for the separation and quantification of 20 amino acids in cachacas has been developed involving C18 solid phase cleanup, derivatization with o-phthalaldehyde/2-mercaptoethanol, and reverse phase liquid chromatography with fluorescence detection. The detection limit was between 0.0050 (Cys) and 0.25 (Ser)mgL(-1), whereas the recovery index varies from 69.5 (Lys) to 100 (Tyr)%. Relative standard deviations vary from 1.39 (Trp) to 13.4 (Glu)% and from 3.08 (Glu) to 13.5 (His) for the repeatability and intermediate precision, respectively. From the quantitative profile of amino acids in 41 cachacas, 5 rums, and 12 whisky samples, the following order of amino acids in significant quantities is observed: Gly=Ser60 was associated with mortality (P = 0.019), while lymphopenia on admission trended toward an association with death (P = 0.054). HSCT patients were less likely to be admitted to an intensive care unit (odds ratio [OR] 0.26, P = 0.04), but were significantly more likely to receive ribavirin therapy (OR 11.62, P < 0.0001). CONCLUSION: Adults hospitalized with RSV LRTI are at significant risk of mortality, and this risk may be increased in patients age >60 or with lymphopenia on admission. This study did not identify any significant increased mortality or morbidity associated with RSV infection in immune suppressed transplant recipients vs. patients who had not received a transplant. PMID- 26059181 TI - Challenges for Transformation: A Situational Analysis of Mental Health Care Services in Sehore District, Madhya Pradesh. AB - The proportion of individuals with mental disorders receiving evidence based treatments in India is very small. In order to address this huge treatment gap, programme for improving mental health care is being implemented in Sehore district of Madhya Pradesh, India. The aim of this study was to complete the situational analysis consisting of two parts; document review of Sehore district mental health programme followed by a qualitative study. The findings suggest that there are major health system challenges in developing and implementing the mental health care plan to be delivered through primary health care system in Sehore district. PMID- 26059182 TI - 'This little piranha': a qualitative analysis of the language used by health professionals and mothers to describe infant behaviour during breastfeeding. AB - Exclusive breastfeeding for the first 6 months of life offers the recommended best start in the life for a newborn baby. Yet, in Australia only a small number of babies receive breast milk exclusively for the first 6 months. Reasons for the introduction of formula milk are multi-factorial including access to appropriate support and the woman's experience of breastfeeding. The language and practices of health professionals can impact upon how a woman feels about breastfeeding and her breastfeeding body. One aspect of breastfeeding support that has had scarce attention in the literature is the language used by health professionals to describe the behaviour of the breastfeeding infant during the early establishment phase of breastfeeding. This paper reveals some of the ways in which midwives, lactation consultants and breastfeeding women describe the newborn baby during the first week after birth. The study was conducted at two maternity units in New South Wales. Interactions between midwives and breastfeeding women were observed and audio recorded on the post-natal ward and in women's homes, in the first week after birth. The transcribed data were analysed using discourse analysis searching for recurring words, themes and metaphors used in descriptions of the breastfeeding baby. Repeated negative references to infant personality and unfavourable interpretations of infant behaviour influenced how women perceived their infant. The findings revealed that positive language and interpretations of infant breastfeeding behaviour emerged from more relationship-based communication. PMID- 26059183 TI - CAN Canopy Addition of Nitrogen Better Illustrate the Effect of Atmospheric Nitrogen Deposition on Forest Ecosystem? AB - Increasing atmospheric nitrogen (N) deposition could profoundly impact community structure and ecosystem functions in forests. However, conventional experiments with understory addition of N (UAN) largely neglect canopy-associated biota and processes and therefore may not realistically simulate atmospheric N deposition to generate reliable impacts on forest ecosystems. Here we, for the first time, designed a novel experiment with canopy addition of N (CAN) vs. UAN and reviewed the merits and pitfalls of the two approaches. The following hypotheses will be tested: i) UAN overestimates the N addition effects on understory and soil processes but underestimates those on canopy-associated biota and processes, ii) with low-level N addition, CAN favors canopy tree species and canopy-dwelling biota and promotes the detritus food web, and iii) with high-level N addition, CAN suppresses canopy tree species and other biota and favors rhizosphere food web. As a long-term comprehensive program, this experiment will provide opportunities for multidisciplinary collaborations, including biogeochemistry, microbiology, zoology, and plant science to examine forest ecosystem responses to atmospheric N deposition. PMID- 26059184 TI - Assessment of rhizospheric culturable bacteria of Phragmites australis and Juncus effusus from polluted sites. AB - This study aimed at the isolation and characterization of metal(loid)-tolerant bacteria from the rhizosphere of Phragmites australis and Juncus effusus plants growing in two long-term contaminated sites in Northern Portugal. Site 1 had higher contamination than Site 3. Bacteria were isolated using metal(loid) supplemented (Cd, Zn, and As) media. Isolates were grouped by random amplified polymorphic DNA and identified by 16S rRNA gene sequencing. Strains were also examined for their metal(loid) tolerance. The counts of metal(loid)-tolerant bacteria were higher in Site 1 and ranged between log 7.17 CFU g(-1) soil in As containing medium and log 7.57 CFU g(-1) soil in Zn-containing medium, while counts at Site 3 varied between log 5.33 CFU g(-1) soil in Cd-containing medium and log 6.97 CFU g(-1) soil in As-containing medium. The composition of bacterial populations varied between locations. In Site 1, the classes Actinobacteria (36%) and Bacilli (24%) were well represented, while in Site 3 strains were mainly affiliated to classes Actinobacteria (35%), gamma-Proteobacteria (35%), and beta Proteobacteria (12%). The order of metal(loid) toxicity for the isolated strains was Cd > As > Zn. Overall, 10 strains grew at 500 mg Cd L(-1) , 1000 mg Zn L(-1) , and 500 mg As L(-1) , being considered the most metal(loid)-tolerant bacteria. These strains belonged to genera Cupriavidus, Burkholderia, Novosphingobium, Sphingobacterium, Castellaniella, Mesorhizobium, Chryseobacterium, and Rhodococcus and were mainly retrieved from Site 1. The multiple metal(loid) tolerant strains isolated in this study have potential to be used in bioremediation/phytoremediation. PMID- 26059185 TI - Study of the influence of actin-binding proteins using linear analyses of cell deformability. AB - The actin cytoskeleton plays a key role in the deformability of the cell and in mechanosensing. Here we analyze the contributions of three major actin cross linking proteins, myosin II, alpha-actinin and filamin, to cell deformability, by using micropipette aspiration of Dictyostelium cells. We examine the applicability of three simple mechanical models: for small deformation, linear viscoelasticity and drop of liquid with a tense cortex; and for large deformation, a Newtonian viscous fluid. For these models, we have derived linearized equations and we provide a novel, straightforward methodology to analyze the experiments. This methodology allowed us to differentiate the effects of the cross-linking proteins in the different regimes of deformation. Our results confirm some previous observations and suggest important relations between the molecular characteristics of the actin-binding proteins and the cell behavior: the effect of myosin is explained in terms of the relation between the lifetime of the bond to actin and the resistive force; the presence of alpha actinin obstructs the deformation of the cytoskeleton, presumably mainly due to the higher molecular stiffness and to the lower dissociation rate constants; and filamin contributes critically to the global connectivity of the network, possibly by rapidly turning over cross-links during the remodeling of the cytoskeletal network, thanks to the higher rate constants, flexibility and larger size. The results suggest a sophisticated relationship between the expression levels of actin-binding proteins, deformability and mechanosensing. PMID- 26059186 TI - Salusin beta Within the Nucleus Tractus Solitarii Suppresses Blood Pressure Via Inhibiting the Activities of Presympathetic Neurons in the Rostral Ventrolateral Medulla in Spontaneously Hypertensive Rats. AB - Salusin beta is a newly identified bioactive peptide, which shows peripheral hypotensive, mitogenic and proatherosclerotic effects. The present study was undertaken to investigate the role of salusin beta within the nucleus tractus solitarii (NTS) and the underlying mechanism in regulating blood pressure and heart rate (HR) in spontaneously hypertensive rats (SHR). Our results showed that bilateral or unilateral microinjection of salusin beta (0.4-40 pmol) into the NTS in SHR decreased mean arterial pressure and HR in a dose-dependent manner. Bilateral microinjection of salusin beta (4 pmol) within NTS improved baroreflex sensitivity functions in SHR. Pretreatment with glutamate receptors antagonist kynurenic acid (5 nmol) into the NTS in SHR did not alter the salusin beta (4 pmol) induced hypotension and bradycardia. Likewise, bilateral vagotomy also did not alter the salusin beta (4 pmol) induced hypotension and bradycardia. However, pretreatment with GABAA receptors agonist muscimol (100 pmol) within the rostral ventrolateral medulla (RVLM) in SHR almost completely abolished the hypotension and bradycardia evoked by intra-NTS salusin beta (4 pmol). Our findings suggested that microinjection of salusin beta into the NTS produced hypotension and bradycardia, as well as improved baroreflex sensitivity functions, via inhibiting the activities of presympathetic neurons in the RVLM in SHR. PMID- 26059187 TI - Deep Sequencing Reveals Occurrence of Subclonal ALK Mutations in Neuroblastoma at Diagnosis. AB - PURPOSE: In neuroblastoma, activating ALK receptor tyrosine kinase point mutations play a major role in oncogenesis. We explored the potential occurrence of ALK mutations at a subclonal level using targeted deep sequencing. EXPERIMENTAL DESIGN: In a clinically representative series of 276 diagnostic neuroblastoma samples, exons 23 and 25 of the ALK gene, containing the F1174 and R1275 mutation hotspots, respectively, were resequenced with an extremely high depth of coverage. RESULTS: At the F1174 hotspot (exon 23), mutations were observed in 15 of 277 samples (range of fraction of mutated allele per sample: 0.562%-40.409%). At the R1275 hotspot (exon 25), ALK mutations were detected in 12 of 276 samples (range of fraction of mutated allele: 0.811%-73.001%). Altogether, subclonal events with a mutated allele fraction below 20% were observed in 15/27 ALK-mutated samples. The presence of an ALK mutation was associated with poorer 5-year overall survival (OS: 75% vs. 57%, P = 0.0212 log rank test), with a strong correlation between F1174 ALK mutations and MYCN amplification being observed. CONCLUSIONS: In this series, deep sequencing allows the detection of F1174 and R1275 ALK mutational events at diagnosis in 10% of cases, with subclonal events in more than half of these, which would have gone undetected by Sanger sequencing. These findings are of clinical importance given the potential role of ALK mutations in clonal evolution and relapse. These findings also demonstrate the importance of deep sequencing techniques for the identification of patients especially when considering targeted therapy. PMID- 26059188 TI - Hepatitis B Virus X Protein (HBx) Is Responsible for Resistance to Targeted Therapies in Hepatocellular Carcinoma: Ex Vivo Culture Evidence. AB - PURPOSE: Molecular targeted therapy is an important approach for advanced hepatocellular carcinoma (HCC). Hepatitis B virus-related HCC (HBV-HCC) accounts for approximately 50% of all HCC cases. Bortezomib, a proteasome inhibitor (PI), is used extensively for the treatment of hematologic malignancies, but its application in HCC, particularly in HBV-HCC, has not been fully explored. EXPERIMENTAL DESIGN: The effects of bortezomib on HCC tissues were evaluated by TUNEL assays. The growth inhibitory activity was measured using cell viability assays, and apoptosis was measured using flow cytometry. The levels of HBx, P Raf/Raf, and P-Erk/Erk expression were measured by Western blot analysis. The ability of the MEK inhibitor PD98059 to enhance the cell killing activity of bortezomib was evaluated using ex vivo and in vivo methods. RESULTS: The potency of bortezomib varied among HCC samples and cell lines, and HBV/HBx expression was associated with resistance to bortezomib. Bortezomib increased the levels of P Raf and P-Erk in HBV/HBx-positive cells but not in HBV/HBx-negative HCC cells or in breast cancer or glioblastoma multiform cells. HBx was also upregulated after exposure to bortezomib, which was associated with the inhibition of proteasome activity. P-Erk upregulation mediated by bortezomib was effectively suppressed by the addition of the MEK inhibitor PD98059. Moreover, bortezomib and PD98059 synergistically inhibited HCC cell proliferation, as measured using both ex vivo and in vivo models. CONCLUSIONS: Our studies demonstrate for the first time that HBx causes resistance to bortezomib in HCC, and this resistance can be antagonized by a MEK signaling inhibitor, providing a novel therapeutic approach. PMID- 26059189 TI - Refining the Mantle Cell Lymphoma Paradigm: Impact of Novel Therapies on Current Practice. AB - Although mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma, proactive research efforts fueled by challenges in the management of MCL have led to an increase in median overall survival (OS) of 2.5 years in the mid 1990s to beyond 5 years nowadays. This improvement is due mostly to the use of dose intensive strategies, particularly cytarabine-containing regimens [with or without high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) consolidation], which are associated with deeper remission (and higher molecular complete response rate), as well as better salvage therapies. Along this line, MCL became the first lymphoma for which four novel agents have been approved in the relapsed/refractory setting: temsirolimus, lenalidomide, ibrutinib, and bortezomib (the last agent approved both in relapsed/refractory disease and in first-line combination therapy). In addition, the use of rituximab maintenance has helped reduce relapse rates and improve outcome. However, in routine practice (i.e., outside clinical trials), the outcome of MCL remains overall unchanged with standard immunochemotherapy, and even after HDT-ASCT, most patients still relapse and frequently develop chemoresistance. The persistent lack of consensus for the treatment of MCL explains the rather impressive variability in management of these patients. The integration of newer therapies, either in combination with immunochemotherapy or as consolidation/maintenance postinduction, offers new opportunities for patients with MCL. This review highlights how such developments can help refine the current MCL paradigm. PMID- 26059192 TI - Telavancin (VIBATIV) for the treatment of complicated skin and skin structure infections. AB - Methicillin-resistant Staphylococcus aureus has emerged as a major causative pathogen in complicated skin and skin structure infections (cSSSIs). Unfortunately, treatment failure with vancomycin has been increasingly reported. Over the past decade, several alternative antimicrobial agents have been studied and approved for the treatment of cSSSIs. One such agent is the lipoglycopeptide telavancin, which was approved by the US FDA 2009. Given its dual mechanism of action, telavancin is characterized by a highly bactericidal activity and low potential for resistance selection. In addition, in clinical trials, it was efficacious and safe in the treatment of cSSSI. The purpose of this review is to give a background overview of telavancin, highlighting its microbiological, pharmacokinetic and pharmacodynamics characteristics, to summarize the available evidence for its use in the treatment of cSSSIs, and to provide an updated evaluation of its safety profile. PMID- 26059193 TI - Origins of optical absorption characteristics of Cu(2+) complexes in aqueous solutions. AB - Many transition metal complexes exhibit infrared or visible optical absorption arising from d-d transitions that are the key to functionality in technological applications and biological processes. The observed spectral characteristics of the absorption spectra depend on several underlying physical parameters whose relative contributions are still not fully understood. Although conventional arguments based on ligand-field theory can be invoked to rationalize the peak absorption energy, they cannot describe the detailed features of the observed spectral profile such as the spectral width and shape, or unexpected correlations between the oscillator strength and absorption peak position. Here, we combine experimental observations with first-principles simulations to investigate origins of the absorption spectral profile in model systems of aqueous Cu(2+) ions with Cl(-), Br(-), NO2(-) and CH3CO2(-) ligands. The ligand identity and concentration, fine structure in the electronic d-orbitals of Cu(2+), complex geometry, and solvation environment are all found to play key roles in determining the spectral profile. Moreover, similar physiochemical origins of these factors lead to interesting and unexpected correlations in spectral features. The results provide important insights into the underlying mechanisms of the observed spectral features and offer a framework for advancing the ability of theoretical models to predict and interpret the behavior of such systems. PMID- 26059190 TI - Bioactivity and Safety of IL13Ralpha2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma. AB - PURPOSE: A first-in-human pilot safety and feasibility trial evaluating chimeric antigen receptor (CAR)-engineered, autologous primary human CD8(+) cytotoxic T lymphocytes (CTL) targeting IL13Ralpha2 for the treatment of recurrent glioblastoma (GBM). EXPERIMENTAL DESIGN: Three patients with recurrent GBM were treated with IL13(E13Y)-zetakine CD8(+) CTL targeting IL13Ralpha2. Patients received up to 12 local infusions at a maximum dose of 10(8) CAR-engineered T cells via a catheter/reservoir system. RESULTS: We demonstrate the feasibility of manufacturing sufficient numbers of autologous CTL clones expressing an IL13(E13Y)-zetakine CAR for redirected HLA-independent IL13Ralpha2-specific effector function for a cohort of patients diagnosed with GBM. Intracranial delivery of the IL13-zetakine(+) CTL clones into the resection cavity of 3 patients with recurrent disease was well-tolerated, with manageable temporary brain inflammation. Following infusion of IL13-zetakine(+) CTLs, evidence for transient anti-glioma responses was observed in 2 of the patients. Analysis of tumor tissue from 1 patient before and after T-cell therapy suggested reduced overall IL13Ralpha2 expression within the tumor following treatment. MRI analysis of another patient indicated an increase in tumor necrotic volume at the site of IL13-zetakine(+) T-cell administration. CONCLUSIONS: These findings provide promising first-in-human clinical experience for intracranial administration of IL13Ralpha2-specific CAR T cells for the treatment of GBM, establishing a foundation on which future refinements of adoptive CAR T-cell therapies can be applied. PMID- 26059194 TI - Enhancement of the catalytic activity of ferulic acid decarboxylase from Enterobacter sp. Px6-4 through random and site-directed mutagenesis. AB - The enzyme ferulic acid decarboxylase (FADase) from Enterobacter sp. Px6-4 catalyzes the decarboxylation reaction of lignin monomers and phenolic compounds such as p-coumaric acid, caffeic acid, and ferulic acid into their corresponding 4-vinyl derivatives, that is, 4-vinylphenol, 4-vinylcatechol, and 4 vinylguaiacol, respectively. Among various ferulic acid decarboxylase enzymes, we chose the FADase from Enterobacter sp. Px6-4, whose crystal structure is known, and produced mutants to enhance its catalytic activity by random and site directed mutagenesis. After three rounds of sequential mutations, FADase(F95L/D112N/V151I) showed approximately 34-fold higher catalytic activity than wild-type for the production of 4-vinylguaiacol from ferulic acid. Docking analyses suggested that the increased activity of FADase(F95L/D112N/V151I) could be due to formation of compact active site compared with that of the wild-type FADase. Considering the amount of phenolic compounds such as lignin monomers in the biomass components, successfully bioengineered FADase(F95L/D112N/V151I) from Enterobacter sp. Px6-4 could provide an ecofriendly biocatalytic tool for producing diverse styrene derivatives from biomass. PMID- 26059195 TI - Does the Relationship of the Proxy to the Target Person Affect the Concordance between Survey Reports and Medicare Claims Measures of Health Services Use? AB - OBJECTIVES: To compare concordance of survey reports of health service use versus claims data between self respondents and spousal and nonspousal relative proxies. DATA SOURCES: 1995-2010 data from the Survey on Assets and Health Dynamics among the Oldest Old and 1993-2010 Medicare claims for 3,229 individuals (13,488 person years). STUDY DESIGN: Regression models with individual fixed effects were estimated for discordance of any hospitalizations and outpatient surgery and for the numbers of under- and over-reported physician visits. PRINCIPAL FINDINGS: Spousal proxies were similar to self respondents on discordance. Nonspousal proxies, particularly daughters/daughters-in-law and sons/sons-in-law, had less discordance, mainly due to reduced under-reporting. CONCLUSIONS: Survey reports of health services use from nonspousal relatives are more consistent with Medicare claims than spousal proxies and self respondents. PMID- 26059196 TI - Patients' and doctors' preferences for adjuvant chemotherapy in resected non small-cell lung cancer: What makes it worthwhile? AB - BACKGROUND: Adjuvant chemotherapy (ACT) in non-small-cell lung cancer (NSCLC) improves overall survival, but the benefits must be weighed against its harms. We sought to determine the survival benefits that patients and their doctors judged sufficient to make ACT in NSCLC worthwhile. METHODS: 122 patients completed a self-administered questionnaire at baseline and 6 months (before & after ACT, if they had it); 82 doctors completed the questionnaire once only. The time trade off method was used to determine the minimum survival benefits judged sufficient in four hypothetical scenarios. Baseline survival times were 3 years & 5 years and baseline survival rates (at 5 years) were 50% & 65%. RESULTS: At baseline, the median benefits judged sufficient by patients were an extra 9 months (Interquartile range (IQR) 1-12 months) beyond 3 years & 5 years and an extra 5% (IQR 0.1-10%) beyond 50% & 65%. At 6 months (n=91), patients' preferences had the same median benefit (9 months & 5%) but varied more (IQRs 0-18 months & 0-15%) than at baseline. Factors associated with judging smaller benefits sufficient were deciding to have ACT (P=0.01, 0.02) and better well-being (P=0.01, 0.006) during ACT. Doctors' preferences, compared with patients' preferences, had similar median benefits (9 months & 5%) but varied less (IQR 6-12 months versus 1 12 months, P<0.001; 5%-10% versus 0.1-10%, P<0.001). CONCLUSION: Most patients and doctors judged moderate survival benefits sufficient to make ACT in NSCLC worthwhile, but the preferences of doctors varied less than those of patients. Doctors should endeavour to elicit patients' preferences during discussions about ACT in NSCLC. PMID- 26059198 TI - Commentary on 'Remote Ischemic Preconditioning to Reduce Contrast Induced Nephropathy: A Randomized Controlled Trial'. PMID- 26059197 TI - Molecular changes in endometriosis-associated ovarian clear cell carcinoma. AB - BACKGROUND: Endometriosis is frequently associated with and thought of having propensity to develop into ovarian clear cell carcinoma (OCCC), although the molecular transformation mechanism is not completely understood. METHODS: We employed immunohistochemical (IHC) staining for marker expression along the potential progression continuum. Expression profiling of microdissected endometriotic and OCCC cells from patient-matched formalin-fixed, paraffin embedded samples was performed to explore the carcinogenic pathways. Function of novel biomarkers was confirmed by knockdown experiments. RESULTS: PTEN was significantly lost in both endometriosis and invasive tumour tissues, while oestrogen receptor (ER) expression was lost in OCCC relative to endometriosis. XRCC5, PTCH2, eEF1A2 and PPP1R14B were significantly overexpressed in OCCC and associated endometriosis, but not in benign endometriosis (p ? 0.004). Knockdown experiments with XRCC5 and PTCH2 in a clear cell cancer cell line resulted in significant growth inhibition. There was also significant silencing of a panel of target genes with histone H3 lysine 27 trimethylation, a signature of polycomb chromatin-remodelling complex in OCCC. IHC confirmed the loss of expression of one such polycomb target gene, the serous ovarian cancer lineage marker Wilms' tumour protein 1 (WT1) in OCCC, while endometriotic tissues showed significant co expression of WT1 and ER. CONCLUSIONS: Loss of PTEN expression is proposed as an early and permissive event in endometriosis development, while the loss of ER and polycomb-mediated transcriptional reprogramming for pluripotency may play an important role in the ultimate transformation process. Our study provides new evidence to redefine the pathogenic programme for lineage-specific transformation of endometriosis to OCCC. PMID- 26059199 TI - National Partnership for Maternal Safety Consensus Bundle on Obstetric Hemorrhage. AB - Hemorrhage is the most frequent cause of severe maternal morbidity and preventable maternal mortality and therefore is an ideal topic for the initial national maternity patient safety bundle. These safety bundles outline critical clinical practices that should be implemented in every maternity unit. They are developed by multidisciplinary work groups of the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care. The safety bundle is organized into 4 domains: Readiness, Recognition and Prevention, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged. References contain sample resources and "Potential Best Practices" to assist with implementation. PMID- 26059201 TI - Size does matter! Perceptual stimulus properties affect event-related potentials during feedback processing. AB - The current study investigated whether or not the physical aspect of stimulus size has an effect on neuronal correlates of feedback processing. A time estimation task was administered applying three different feedback stimulus categories: small, middle, and large size stimuli. Apart from early visual ERPs such as P1 and N1 components, later feedback processing stages were also affected by the size of feedback stimuli. In particular, small size stimuli compared to middle and large size ones led to diminished amplitudes in both FRN and P300 components, despite intact discrimination between negative and positive outcomes in these two ERPs. In contrast, time estimation performance was not influenced by feedback size. The current results indicate that small size feedback stimuli were perceived as less salient and hence were processed less deeply than the others. This suggests that future feedback studies could manipulate feedback salience simply by presenting differently sized feedback stimuli, at least when the focus lies on FRN and P300 amplitude variation. PMID- 26059202 TI - Extraordinary solute-stress tolerance contributes to the environmental tenacity of mycobacteria. AB - Mycobacteria are associated with a number of well-characterized diseases, yet we know little about their stress biology in natural ecosystems. This study focuses on the isolation and characterization of strains from Yellowstone National Park (YNP) and Glacier National Park (GNP; USA), the majority of those identified were Mycobacterium parascrofulaceum, Mycobacterium avium (YNP) or Mycobacterium gordonae (GNP). Generally, their windows for growth spanned a temperature range of > 60 degrees C; selected isolates grew at super-saturated concentrations of hydrophobic stressors and at levels of osmotic stress and chaotropic activity (up to 13.4 kJ kg(-1) ) similar to, or exceeding, those for the xerophilic fungus Aspergillus wentii and solvent-tolerant bacterium Pseudomonas putida. For example, mycobacteria grew down to 0.800 water activity indicating that they are, with the sole exception of halophiles, more xerotolerant than other bacteria (or any Archaea). Furthermore, the fatty-acid composition of Mycobacterium cells grown over a range of salt concentrations changed less than that of other bacteria, indicating a high level of resilience, regardless of the stress load. Cells of M. parascrofulaceum, M. smegmatis and M. avium resisted the acute, potentially lethal challenges from extremes of pH (< 1; > 13), and saturated MgCl2 solutions (5 M; 212 kJ kg(-1) chaotropicity). Collectively, these findings challenge the paradigm that bacteria have solute tolerances inferior to those of eukaryotes. PMID- 26059200 TI - Genetic variation of the growth hormone secretagogue receptor gene is associated with alcohol use disorders identification test scores and smoking. AB - The multifaceted gut-brain peptide ghrelin and its receptor (GHSR-1a) are implicated in mechanisms regulating not only the energy balance but also the reward circuitry. In our pre-clinical models, we have shown that ghrelin increases whereas GHSR-1a antagonists decrease alcohol consumption and the motivation to consume alcohol in rodents. Moreover, ghrelin signaling is required for the rewarding properties of addictive drugs including alcohol and nicotine in rodents. Given the hereditary component underlying addictive behaviors and disorders, we sought to investigate whether single nucleotide polymorphisms (SNPs) located in the pre-proghrelin gene (GHRL) and GHSR-1a gene (GHSR) are associated with alcohol use, measured by the alcohol use disorders identification test (AUDIT) and smoking. Two SNPs located in GHRL, rs4684677 (Gln90Leu) and rs696217 (Leu72Met), and one in GHSR, rs2948694, were genotyped in a subset (n = 4161) of a Finnish population-based cohort, the Genetics of Sexuality and Aggression project. The effect of these SNPs on AUDIT scores and smoking was investigated using linear and logistic regressions, respectively. We found that the minor allele of the rs2948694 SNP was nominally associated with higher AUDIT scores (P = 0.0204, recessive model) and smoking (P = 0.0002, dominant model). Furthermore, post hoc analyses showed that this risk allele was also associated with increased likelihood of having high level of alcohol problems as determined by AUDIT scores >= 16 (P = 0.0043, recessive model). These convergent findings lend further support for the hypothesized involvement of ghrelin signaling in addictive disorders. PMID- 26059203 TI - Asthma Management Disparities: A Photovoice Investigation with African American Youth. AB - Disparities in asthma management are a burden on African American youth. The objective of this study is to describe and compare the discourses of asthma management disparities (AMDs) in African American adolescents in Seattle to existing youth-related asthma policies in Washington State. Adolescents participated in a three-session photovoice project and presented their phototexts to the Washington State asthma planning committee. Critical discourse analysis methodology was used to analyze adolescent phototexts and the State asthma plan. We found that the State plan did not address AMD in African American adolescents. Adolescents discussed more topics on AMD than the State plan presented, and they introduced new topics concerning residential mobility, poor nutrition, inadequate athletic opportunities, and schools with stairs. Current health policy may be constraining effective responses to asthma disparities in youth. School nursing leadership can use photovoice to advance youth voice in transforming structural inequities in urban school environments. PMID- 26059204 TI - The Arabidopsis Transcription Factor NAC016 Promotes Drought Stress Responses by Repressing AREB1 Transcription through a Trifurcate Feed-Forward Regulatory Loop Involving NAP. AB - Drought and other abiotic stresses negatively affect plant growth and development and thus reduce productivity. The plant-specific NAM/ATAF1/2/CUC2 (NAC) transcription factors have important roles in abiotic stress-responsive signaling. Here, we show that Arabidopsis thaliana NAC016 is involved in drought stress responses; nac016 mutants have high drought tolerance, and NAC016 overexpressing (NAC016-OX) plants have low drought tolerance. Using genome-wide gene expression microarray analysis and MEME motif searches, we identified the NAC016-specific binding motif (NAC16BM), GATTGGAT[AT]CA, in the promoters of genes downregulated in nac016-1 mutants. The NAC16BM sequence does not contain the core NAC binding motif CACG (or its reverse complement CGTG). NAC016 directly binds to the NAC16BM in the promoter of ABSCISIC ACID-RESPONSIVE ELEMENT BINDING PROTEIN1 (AREB1), which encodes a central transcription factor in the stress responsive abscisic acid signaling pathway and represses AREB1 transcription. We found that knockout mutants of the NAC016 target gene NAC-LIKE, ACTIVATED BY AP3/PI (NAP) also exhibited strong drought tolerance; moreover, NAP binds to the AREB1 promoter and suppresses AREB1 transcription. Taking these results together, we propose that a trifurcate feed-forward pathway involving NAC016, NAP, and AREB1 functions in the drought stress response, in addition to affecting leaf senescence in Arabidopsis. PMID- 26059205 TI - Efficiency of a mechanical device in controlling tracheal cuff pressure in intubated critically ill patients: a randomized controlled study. AB - BACKGROUND: Cuff pressure (P cuff) control is mandatory to avoid leakage of oral secretions passing the tracheal tube and tracheal ischemia. The aim of the present trial was to determine the efficacy of a mechanical device (PressureEasy(r)) in the continuous control of P cuff in patients intubated with polyvinyl chloride (PVC)-cuffed tracheal tubes, compared with routine care using a manometer. METHODS: This is a prospective, randomized, controlled, cross-over study. All patients requiring intubation with a predicted duration of mechanical ventilation >=48 h were eligible. Eighteen patients randomly received continuous control of P cuff with PressureEasy(r) device for 24 h, followed by discontinuous control (every 4 h) with a manual manometer for 24 h, or vice versa. P cuff and airway pressure were continuously recorded. P cuff target was 25 cmH2O during the two periods. RESULTS: The percentage of time spent with P cuff 20-30 cmH2O (median (IQR) 34 % (17-57) versus 50 % (35-64), p = 0.184) and the percentage of time spent with P cuff <20 cmH2O (23 % (5-63) versus 43 % (16-60), p = 0.5) were similar during continuous control of P cuff and routine care, respectively. However, the percentage of time spent with P cuff >30 cmH2O was significantly higher during continuous control compared with routine care of tracheal cuff (26 % (14-39) versus 7 % (1-18), p = 0.002). No significant difference was found in P cuff (25 (18-28) versus 21 (18-26), p = 0.17), mean airway pressure (14 (10-17) versus 14 (11-16), p = 0.679), or coefficient of variation of P cuff (19 % (11 26) versus 20 % (11-25), p = 0.679) during continuous control compared with routine care of tracheal cuff, respectively. CONCLUSIONS: PressureEasy(r) did not demonstrate a better control of P cuff between 20 and 30 cmH2O, compared with routine care using a manometer. Moreover, the device use resulted in significantly higher time spent with overinflation of tracheal cuff, which might increase the risk for tracheal ischemic lesions. TRIAL REGISTRATION: Clinicaltrial.gov: NCT02109003. PMID- 26059206 TI - Severe but not mild hypercapnia affects the outcome in patients with severe cardiogenic pulmonary edema treated by non-invasive ventilation. AB - BACKGROUND: Patients with severe cardiogenic pulmonary edema (CPE) are frequently hypercapnic, possibly because of associated underlying chronic lung disease (CLD). Since hypercapnia has been associated with outcome, we aimed to identify factors associated to hypercapnia and its role on outcome of patients with CPE and no underlying CLD. METHODS: Observational cohort study using data prospectively collected over a 3-year period. After excluding patients with any CLD or obstructive sleep apneas, all patients treated by non-invasive ventilation (NIV) for severe CPE were included. Hypercapnia was defined as PaCO2 >45 mmHg and non-rapid favorable outcome was defined as the need for intubation or continuation of NIV for more than 48 h. RESULTS: After excluding 60 patients with underlying CLD or sleep apneas, 112 patients were studied. The rates of intubation and of prolonged NIV were 6.3 % (n = 7) and 21.4 % (n = 24), respectively. Half of the patients (n = 56) had hypercapnia upon admission. Hypercapnic patients were older, more frequently obese, and were more likely to have a respiratory tract infection than non-hypercapnic patients. Hypercapnia had no influence on intubation rate or the need for prolonged NIV. However, patients with severe hypercapnia (PaCO2 >60 mmHg) needed longer durations of NIV and intensive care unit (ICU) stay than the others. CONCLUSIONS: Among the patients admitted for severe CPE without CLD, half of them had hypercapnia at admission. Hypercapnic patients were older and more frequently obese but their outcome was similar compared to non-hypercapnic patients. Patients with severe hypercapnia needed longer durations of NIV than the others without increase in intubation rate. PMID- 26059207 TI - Transition of myosin heavy chain isoforms in human laryngeal abductors following denervation. AB - The objective of this study was to investigate the myofiber subtype transition of human posterior cricoarytenoid (PCA) muscle after the injury to recurrent laryngeal nerve (RLN). PCA muscle specimens were obtained from 38 bilateral vocal fold paralysis patients underwent arytenoidectomy. According to the duration of RLN injury, all the cases were divided into five denervation groups: 6-12 months, 1-2, 2-3, 3-6, and >6 years. The normal PCA muscles from total laryngectomy patients were chosen as controls. Immunofluorescence was adopted to detect the expression level of myosin heavy chain (MHC)-I and MHC-II in PCA muscle. Quantitative real-time PCR was also used to assess the transcriptional level of MHC subtypes (MHC-I, MHC-IIa, MHC-IIb, MHC-IIx, embryonic-MHC, and peri-natal MHC). Immunofluorescence showed that MHC-I-positive myofibers in denervation groups were much lower than control group, respectively, while MHC-II-positive myofibers were significantly higher than control group (P < 0.05). With the extension of denervation, the number of MHC-I-positive myofibers gradually decreased, while MHC-II gradually increased and peaked in 1- to 2-year group. Transcriptional level of MHC-I, MHC-IIa, and MHC-IIb in denervation groups significantly down-regulated compared with the control (P < 0.05), respectively. However, MHC-IIx, embryonic-MHC, and peri-natal-MHC significantly up-regulated in all denervation groups, and the highest level was in 1- to 2-year denervation group. Data from the present study demonstrated that the maximum transition of MHC subtypes in human PCA muscles occurred in 1-2 years after denervation, suggesting that laryngeal reinnervation before the occurrence of irreversible transition of MHC subtypes could maintain the structural integrity of laryngeal PCA muscles. PMID- 26059208 TI - No benefit for regional control and survival by planned neck dissection in primary irradiated oropharyngeal cancer irrespective of p16 expression. AB - The aim of the study was to assess regional control and survival in primary irradiated oropharyngeal cancer patients with advanced neck disease (>=cN2a) receiving planned neck dissection (PND) irrespective of the nodal response compared to salvage neck dissection (SND) in case of regional persistence or reccurence in relation to tumoral p16 overexpression. 96 consecutive patients treated at the University Hospital of Zurich, Switzerland were included. Tissue microarray-based scoring of p16 expression was obtained. 5 years overall (OS) and disease-specific survival (DSS) in the PND and SND cohort were 70 vs. 57 % (p = 0.20) and 80 vs. 65 % (p = 0.14), respectively. Regional control in PND and SND achieved 95 vs. 87 % (p = 0.29), respectively. There was no statistically significant impact of neck treatment (PND vs. SND) on regional control or survival among patients with p16-negative tumors (5 years OS 59 vs. 50 %, p = 0.66; 5 years DSS 59 vs. 57 %, p = 0.89) nor among patients with p16-positive tumors (5 years OS 84 vs. 67 %, p = 0.21; 5 years DSS 95 vs. 81 %, p = 0.24). The type of neck dissection after primary intensity-modulated radiotherapy (IMRT) had no impact on regional control and survival even in human papillomavirus (HPV) associated disease. Therefore we are convinced that based on the accuracy of newer diagnostic modalities the surveillance of a radiologically negative neck after primary chemoradiation (CRT) is oncologically safe irrespective of p16 expression of the tumor. PMID- 26059209 TI - GJB2 mutations in deaf population of Ilam (Western Iran): a different pattern of mutation distribution. AB - Hearing loss is the most common sensory defect caused by heterogeneous factors. Up to now, more than 60 mutations in genes have been documented for nonsyndromic hearing loss. Hence, finding the causal gene in affected families could be a laborious and time-consuming process. GJB2 mutations, here, were investigated among deaf subjects of Ilam for the first time. In this study, we studied 62 unrelated patients with non-syndromic autosomal recessive deafness from 62 families. The most common mutation of GJB2, 35delG was checked, followed by direct sequencing of the GJB2 gene for determination of other mutations. In silico analyses were also performed using available software. In nine families, mutations in the connexin 26 gene were observed. In the studied population, R32H was the most common mutation. 35delG, W24X, and R127H were other mutations found in this study. In silico analyses showed pathogenicity of 35delG, R32H, and W24X but not R127H. Low frequency of GJB2 mutations in this population is probably indicative of the fact that other genes may be involved in nonsyndromic hearing loss in Ilam populations. In the other hand, the vicinity of Ilam and Iraq suggests that GJB2 mutations have likely a low frequency in this population. PMID- 26059210 TI - Influence of niche similarity on hybridization between Myriophyllum sibiricum and M. spicatum. AB - The impact of ecological factors on natural hybridization is of widespread interest. Here, we asked whether climate niche influences hybridization between the two closely related plant species Myriophyllum sibiricum and M. spicatum. Eight microsatellite loci and two chloroplast fragments were used to investigate the occurrence of hybridization between these two species in two co-occurring regions: north-east China (NEC) and the Qinghai-Tibetan Plateau (QTP). The climate niches of the species were quantified by principal component analysis with bioclimatic data, and niche comparisons were performed between the two species in each region. Reciprocal hybridization was observed, and M. sibiricum was favoured as the maternal species. Furthermore, hybrids were rare in NEC but common in the QTP. Accordingly, in NEC, the two species were climatically distinct, and hybrids only occurred in the narrow geographical or ecological transition zone, whereas in the QTP, obvious niche overlaps were found for the two species, and hybrids occurred in multiple contact zones. This association between hybridization pattern and climate niche similarity suggests that the level of hybridization was promoted by niche overlap. Compared with the parental species, similar climate niches were found for the hybrid populations in the QTP, indicating that other environmental factors rather than climate were important for hybrid persistence. Our findings highlight the significance of climate niche with respect to hybridization patterns in plants. PMID- 26059211 TI - Anetoderma in a patient with terminal osseous dysplasia with pigmentary defects. AB - Terminal osseous dysplasia with pigmentary defects (TODPD) is a rare, X-linked syndrome classically characterized by distal limb anomalies, pigmented skin defects of the face, and recurrent digital fibromas. X-inactivation plays a major role in determining the range of phenotypic expression. Thus, patients can demonstrate a wide spectrum of disease severity, making accurate diagnosis more challenging. Recent studies have identified a FLNA c.5217G>A mutation as the cause of TODPD, allowing for diagnostic genetic testing. We present a case of molecularly confirmed TODPD in a girl with the 47,XXX chromosomal complement and deformities of the hands and feet, craniofacial abnormalities, and discolored, linear facial lesions. Skin biopsy of the patient's facial lesion revealed absent papillary dermal elastic fibers, consistent with anetoderma, which contrasts with the dermal hypoplasia described in the only other such facial biopsy reported in the literature. The finding of absent elastic fibers in the skin lesions suggests that mutated filamin A, in part, exerts its effects through dysregulated elastin biology, which may explain the nature of many connective tissue pleotropic effects in FLNA-related disorders. PMID- 26059212 TI - Ectopic Adipose Tissue with Vasculitis in the Calf Muscle Explaining Systemic Symptoms in Leg-limited Cutaneous Polyarteritis Nodosa. PMID- 26059213 TI - Enhancing pediatric residents' scholar role: the development of a Scholarly Activity Guidance and Evaluation program. AB - BACKGROUND: Research training is essential to the development of well-rounded physicians. Although many pediatric residency programs require residents to complete a research project, it is often challenging to integrate research training into educational programs. OBJECTIVE: We aimed to develop an innovative research program for pediatric residents, called the Scholarly Activity Guidance and Evaluation (SAGE) program. METHODS: We developed a competency-based program which establishes benchmarks for pediatric residents, while providing ongoing academic mentorship. RESULTS: Feedback from residents and their research supervisors about the SAGE program has been positive. Preliminary evaluation data have shown that all final-year residents have met or exceeded program expectations. CONCLUSIONS: By providing residents with this supportive environment, we hope to influence their academic career paths, increase their research productivity, promote evidence-based practice, and ultimately, positively impact health outcomes. PMID- 26059214 TI - Applying the transtheoretical model to promote functional fitness of community older adults participating in elastic band exercises. AB - AIMS: The transtheoretical model was applied to promote behavioural change and test the effects of a group senior elastic band exercise programme on the functional fitness of community older adults in the contemplation and preparation stages of behavioural change. BACKGROUND: Forming regular exercise habits is challenging for older adults. The transtheoretical model emphasizes using different strategies in various stages to facilitate behavioural changes. DESIGN: Quasi-experimental design with pre-test and post-tests on two groups. METHODS: Six senior activity centres were randomly assigned to either the experimental or control group. The data were collected during 2011. A total of 199 participants were recruited and 169 participants completed the study (experimental group n = 84, control group n = 85). The elastic band exercises were performed for 40 minutes, three times per week for 6 months. The functional fitness of the participants was evaluated at baseline and at the third and sixth month of the intervention. Statistical analyses included a two-way mixed design analysis of variance, one-way repeated measures analysis of variance and an analysis of covariance. RESULTS: All of the functional fitness indicators had significant changes at post-tests from pre-test in the experimental group. The experimental group had better performances than the control group in all of the functional fitness indicators after three months and 6 months of the senior elastic band exercises. CONCLUSION: The exercise programme provided older adults with appropriate strategies for maintaining functional fitness, which improved significantly after the participants exercising regularly for 6 months. PMID- 26059215 TI - Postnatal nutritional restriction affects growth and immune function of piglets with intra-uterine growth restriction. AB - Postnatal rapid growth by excess intake of nutrients has been associated with an increased susceptibility to diseases in neonates with intra-uterine growth restricted (IUGR). The aim of the present study was to determine whether postnatal nutritional restriction could improve intestinal development and immune function of neonates with IUGR using piglets as model. A total of twelve pairs of normal-birth weight (NBW) and IUGR piglets (7 d old) were randomly assigned to receive adequate nutrient intake or restricted nutrient intake (RNI) by artificially liquid feeding for a period of 21 d. Blood samples and intestinal tissues were collected at necropsy and were analysed for morphology, digestive enzyme activities, immune cells and expression of innate immunity-related genes. The results indicated that both IUGR and postnatal nutritional restriction delayed the growth rate during the sucking period. Irrespective of nutrient intake, piglets with IUGR had a significantly lower villous height and crypt depth in the ileum than the NBW piglets. Moreover, IUGR decreased alkaline phosphatase activity while enhanced lactase activity in the jejunum and mRNA expressions of Toll-like receptor 9 (TLR-9) and DNA methyltransferase 1 (DNMT1) in the ileum of piglets. Irrespective of body weight, RNI significantly decreased the number and/or percentage of peripheral leucocytes, lymphocytes and monocytes of piglets, whereas the percentage of neutrophils and the ratio of CD4+ to CD8+ were increased. Furthermore, RNI markedly enhanced the mRNA expression of TLR-9 and DNMT1, but decreased the expression of NOD2 and TRAF-6 in the ileum of piglets. In summary, postnatal nutritional restriction led to abnormal cellular and innate immune response, as well as delayed the growth and intestinal development of IUGR piglets. PMID- 26059216 TI - Complexation-triggerable liposome mixed with silk protein and chitosan. AB - Complexation-triggerable liposomes were prepared by modifying the surface of egg phosphatidylcholine (EPC) liposomes with hydrophobicized silk fibroin (HmSF) and hydrophobicized chitosan (HmCh). Maximum complexation, determined by measuring the diameter of complexation, was found when the ratio of HmSF to HmCh was 14:1, so they were immobilized on the surface of liposomes at the same ratio. The degree of fluorescence quenching of calcein in liposomal suspension was as high as 68% when the ratio of surface modifier (HmSF + HmCh) to EPC was 1:15. When the ratio was increased to 1:5, the degree of quenching decreased to 32%, indicating the inefficient formation of liposome. Liposome mixed with the surface modifier was multi-lamellar vesicle on TEM photo. And, the mean diameter was larger than those of liposome mixed with either HmSF or HmCh, possibly due to insoluble complex on the liposomal surface. The liposome exhibited a pH-sensitive release and triggered the release at pH 5.5 and 6.0. It is believed that complexation is responsible for the promoted release at those pH values. PMID- 26059217 TI - Thermal-electric model for piezoelectric ZnO nanowires. AB - The behavior of ZnO nanowires under uniaxial loading is characterized by means of a numerical model that accounts for all coupled mechanical, electrical, and thermal effects. The paper shows that thermal effects in the nanowires may greatly impact the predicted performance of piezoelectric and piezotronic nanodevices. The pyroelectric effect introduces new equivalent volumic charge in the body of the nanowire and surface charges at the boundaries, where Kapitza resistances are located, that act together with the piezoelectric charges to improve the predicted performance. It is shown that the proposed model is able to reproduce several effects experimentally observed by other research groups, and is a promising tool for the design of ultra-high efficient nanodevices. PMID- 26059218 TI - Gestational diabetes mellitus and life assurance: the United Kingdom perspective. PMID- 26059219 TI - Prolonged androgenic anabolic steroid (AAS) induced QT interval shortening: a suitable screening tool? AB - Androgenic anabolic steroid (AAS) abuse is associated with changes in cardiac electrophysiology. Recently heart rate corrected QT interval (QTc) has been suggested as a method of screening for AAS use in athletes despite conflicting reports. This study aimed to further investigate the effect of AAS on QTc in a cohort of long-term AAS users in whom the affects may be more pronounced. Using a cross-sectional cohort design with AAS using resistance trained athletes (AS n = 15) and a group of non-AAS using resistance trained, age matched controls (C n = 15). AS had a long history of AAS use (18 +/- 2 yrs) and AS and C both had >19 years of resistance training. Participants underwent a resting electrocardiogram (ECG), from which, the QTc interval was calculated using the Bazett formula. The main outcome measure was significant differences in mean corrected QTc between groups. A secondary outcome was to calculate a QTc that best differentiated between C and AS. Results indicated that QTc was shorter in AS than in C (382.0 +/- 21.01 ms versus 409 +/- 18.77 ms for AS and C respectively p < 0.001). Chi squared analyses revealed a greater incidence of QTc < 380 ms in AS versus C p < 0.01, specificity 93% sensitivity 60%). In conclusion these results supports previous findings that AAS use causes a reduction in QTc, however, the specificity and sensitivity in our sample is lower than reported previously and precludes use as a screening tool. PMID- 26059220 TI - Transfer of services from NHS to private provider was "unmitigated disaster," report says. PMID- 26059222 TI - External-Cavity Quantum Cascade Laser Spectroscopy for Mid-IR Transmission Measurements of Proteins in Aqueous Solution. AB - In this work, we report mid-IR transmission measurements of the protein amide I band in aqueous solution at large optical paths. A tunable external-cavity quantum cascade laser (EC-QCL) operated in pulsed mode at room temperature allowed one to apply a path length of up to 38 MUm, which is four times larger than that applicable with conventional FT-IR spectrometers. To minimize temperature-induced variations caused by background absorption of the nu2 vibration of water (HOH-bending) overlapping with the amide I region, a highly stable temperature control unit with relative temperature stability within 0.005 degrees C was developed. An advanced data processing protocol was established to overcome fluctuations in the fine structure of the emission curve that are inherent to the employed EC-QCL due to its mechanical instabilities. To allow for wavenumber accuracy, a spectral calibration method has been elaborated to reference the acquired IR spectra to the absolute positions of the water vapor absorption bands. Employing this setup, characteristic spectral features of five well-studied proteins exhibiting different secondary structures could be measured at concentrations as low as 2.5 mg mL(-1). This concentration range could previously only be accessed by IR measurements in D2O. Mathematical evaluation of the spectral overlap and comparison of second derivative spectra confirm excellent agreement of the QCL transmission measurements with protein spectra acquired by FT-IR spectroscopy. This proves the potential of the applied setup to monitor secondary structure changes of proteins in aqueous solution at extended optical path lengths, which allow experiments in flow through configuration. PMID- 26059221 TI - Corticostriatal circuitry and habitual ethanol seeking. AB - The development of alcohol-use disorders is thought to involve a transition from casual alcohol use to uncontrolled alcohol-seeking behavior. This review will highlight evidence suggesting that the shift toward inflexible alcohol seeking that occurs across the development of addiction consists, in part, of a progression from goal-directed to habitual behaviors. This shift in "response strategy" is thought to be largely regulated by corticostriatal network activity. Indeed, specific neuroanatomical substrates within the prefrontal cortex and the striatum have been identified as playing opposing roles in the expression of actions and habits. A majority of the research on the neurobiology of habitual behavior has focused on non-drug reward seeking. Here, we will highlight recent research identifying corticostriatal structures that regulate the expression of habitual alcohol seeking and a comparison will be made when possible to findings for non-drug rewards. PMID- 26059223 TI - Targeting of anti-citrullinated protein/peptide antibodies in rheumatoid arthritis using peptides mimicking endogenously citrullinated fibrinogen antigens. AB - INTRODUCTION: We have previously identified endogenously citrullinated peptides derived from fibrinogen in rheumatoid arthritis (RA) synovial tissues. In this study, we have investigated the auto-antigenicity of four of those citrullinated peptides, and explored their feasibility to target anti-citrullinated protein/peptide antibodies (ACPA). METHODS: The autoantigenic potential of the fibrinogen peptides was investigated by screening 927 serum samples from the Epidemiological Investigation of RA (EIRA) cohort on a peptide microarray based on the ImmunoCAP ISAC(r) system. In order to assay for ACPA blocking, two independent pools of purified ACPA were incubated with the respective targeting peptide prior to binding to cyclic citrullinated peptide (CCP)2 using the CCPlus(r) ELISA kit. RESULTS: Two peptides derived from the fibrinogen alpha chain, Arg573Cit (563-583) and Arg591Cit (580-600), referred to as Cit573 and Cit591, and two peptides from the fibrinogen beta chain, Arg72Cit (62-81) and Arg74Cit (62-81) (Cit72 and Cit74), displayed 65%, 15%, 35%, and 53% of immune reactivity among CCP2-positive RA sera, respectively. In CCP2-negative RA sera, a positive reactivity was detected in 5% (Cit573), 6% (Cit591), 8% (Cit72), and 4% (Cit74). In the competition assay, Cit573 and Cit591 peptides reduced ACPA binding to CCP2 by a maximum of 84% and 63% respectively. An additive effect was observed when these peptides were combined. In contrast, Cit74 and Cit72 were less effective. Cyclization of the peptide structure containing Cit573 significantly increased the blocking efficiency. CONCLUSIONS: Here we demonstrate extensive autoantibody reactivity against in vivo citrullinated fibrinogen epitopes, and further show the potential use of these peptides for antagonizing ACPA. PMID- 26059224 TI - Polymorphism and expression of insulin-like growth factor 1 (IGF1) gene and its association with growth traits in chicken. AB - 1. The objectives of the study were to detect polymorphism in the coding region of the IGF1 gene, explore the expression profile and estimate association with growth traits in indigenous and exotic chickens. 2. A total of 12 haplotypes were found in Cornish, control layer and Aseel breeds of chicken in which the h1 haplotype was most frequent. 3. Nucleotide substitutions among haplotypes were found at 21 positions in the IGF1 gene in which 4 substitutions resulted in non synonymous mutations in the receptor binding domain of the IGF1 protein. 4. The haplogroup showed a significant effect on body weight at 24 and 42 d of age in the control layer line, body weight at 42 d and daily weight gain between 29 and 42 d in the control broiler line, daily weight gain between 29 and 42 d in Cornish, and body weights at 42 d as well as daily weight gain between 29 and 42 d in Aseel birds. 5. IGF1 expression varied among the breeds during embryonic and post-hatch periods. The expression among the haplogroups varied in different chicken tissues. The effect of haplogroup on myofibre number in pectoral muscle was non-significant, although there was significant variation in numbers between d 1 and d 42, and between broiler and layer lines. 6. It was concluded that the coding region of the IGF1 gene was polymorphic, expressed differentially during the pre-hatch and post-hatch periods, and haplogroups showed significant association with growth traits in chicken. PMID- 26059225 TI - Pharmacodynamics and pharmacokinetics of fluticasone furoate/vilanterol in healthy Chinese subjects. AB - STUDY OBJECTIVE: To investigate the pharmacodynamic and pharmacokinetic profiles of fluticasone furoate (FF)/vilanterol (VI) - a fixed-dose combination of an inhaled corticosteroid (ICS) and a long-acting beta2 -agonist for the treatment of asthma and chronic obstructive pulmonary disease - after single and repeat administration in healthy Chinese subjects. DESIGN: Double-blind, placebo controlled, single-site, randomized, four-way crossover study. SETTING: The Clinical Pharmacological Research Centre at Peking Union Medical College Hospital [PUMCH]) in Beijing, China. SUBJECTS: Sixteen healthy, nonsmoking Chinese adults. INTERVENTION: Subjects were randomized to receive FF/VI 50/25, 100/25, or 200/25 MUg, or placebo once/daily in the morning, delivered by the Ellipta dry powder inhaler, for 7 consecutive days. The subjects then received the other three treatments, with each treatment period separated by a 7-day washout period. MEASUREMENTS AND MAIN RESULTS: The co-primary outcome measures reflected pharmacodynamic responses relating to recognized class effects of the two drug classes: reduced serum cortisol level (ICSs), and increased Fridericia's corrected QT interval (QTcF) and reduced serum potassium level (long-acting beta2 -agonists). Co-primary pharmacodynamic endpoints were 0-24-hour weighted mean serum cortisol level on day 7 (cortisol0-24 hr, Day 7 ), and 0-4-hour weighted mean and maximum QTcF and weighted mean and minimum serum potassium level on days 1 and 7. Fluticasone furoate and VI plasma concentrations, derived pharmacokinetic parameters, and safety were also assessed. Of the 16 subjects randomized, 15 completed the study. Reductions in cortisol0-24 hour, Day 7 of 15% and 25% were observed with FF/VI 100/25 and 200/25 MUg, respectively, versus placebo. Minor increases (< 10 msec) in maximum QTcF on day 7 were seen with FF/VI 50/25 and 100/25 MUg but not with 200/25 MUg. Slight decreases in serum potassium level were only observed in subjects receiving FF/VI 50/25 MUg on day 1 and FF/VI 50/25 and 200/25 MUg on day 7. Fluticasone furoate accumulation (day 7 vs day 1) for FF/VI 50/25-200/25 MUg ranged from 38 to 54% for maximum observed concentration and 63-71% for area under the concentration-time curve from 0 to 4 hours. Fluticasone furoate pharmacokinetics were less than dose proportional. The VI pharmacokinetic profiles were similar for all three FF/VI doses. Adverse events were all mild in intensity and were reported by 13 (81%) of the 16 subjects. CONCLUSION: In healthy Chinese subjects, minimal and non-clinically relevant beta-adrenergic pharmacodynamic effects were observed with FF/VI doses ranging from 50/25 to 200/25 MUg. FF dose-dependent reductions in serum cortisol levels of 15-25% were seen after administration of FF/VI 100/25 and 200/25 MUg. FF/VI was safe and well tolerated in these subjects at doses ranging from 50/25 to 200/25 MUg. PMID- 26059226 TI - HIV-1 Rev downregulates Tat expression and viral replication via modulation of NAD(P)H:quinine oxidoreductase 1 (NQO1). AB - HIV-1 gene expression and replication largely depend on the regulatory proteins Tat and Rev, but it is unclear how the intracellular levels of these viral proteins are regulated after infection. Here we report that HIV-1 Rev causes specific degradation of cytoplasmic Tat, which results in inhibition of HIV-1 replication. The nuclear export signal (NES) region of Rev is crucial for this activity but is not involved in direct interactions with Tat. Rev reduces the levels of ubiquitinated forms of Tat, which have previously been reported to be important for its transcriptional properties. Tat is stabilized in the presence of NAD(P)H: quinine oxidoreductase 1 (NQO1), and potent degradation of Tat is induced by dicoumarol, an NQO1 inhibitor. Furthermore, Rev causes specific reduction in the levels of endogenous NQO1. Thus, we propose that Rev is able to induce degradation of Tat indirectly by downregulating NQO1 levels. Our findings have implications in HIV-1 gene expression and latency. PMID- 26059228 TI - Intelligence-related differences in the asymmetry of spontaneous cerebral activity. AB - Recent evidence suggests the spontaneous BOLD signal synchronization of corresponding interhemispheric, homotopic regions as a stable trait of human brain physiology, with emerging differences in such organization being also related to some pathological conditions. To understand whether such brain functional symmetries play a role into higher-order cognitive functioning, here we correlated the functional homotopy profiles of 119 healthy subjects with their intelligence level. Counterintuitively, reduced homotopic connectivity in above average-IQ versus average-IQ subjects was observed, with significant reductions in visual and somatosensory cortices, supplementary motor area, rolandic operculum, and middle temporal gyrus, possibly suggesting that a downgrading of interhemispheric talk at rest could be associated with higher cognitive functioning. These regions also showed an increased spontaneous synchrony with medial structures located in ipsi- and contralateral hemispheres, with such pattern being mostly detectable for regions placed in the left hemisphere. The interactions with age and gender have been also tested, with different patterns for subjects above and below 25 years old and less homotopic connectivity in the prefrontal cortex and posterior midline regions in female participants with higher IQ scores. These findings support prior evidence suggesting a functional role for homotopic connectivity in human cognitive expression, promoting the reduction of synchrony between primary sensory regions as a predictor of higher intelligence levels. PMID- 26059227 TI - Soluble receptors for advanced glycation end products and receptor activator of NF-kappaB ligand serum levels as markers of premature labor. AB - BACKGROUND: This study aimed to determine the relationships between secretory and endogenous secretory receptors for advanced glycation end products (sRAGE, esRAGE), sRANKL, osteoprotegerin and the interval from diagnosis of threatened premature labor or premature rupture of the fetal membranes to delivery, and to evaluate the prognostic values of the assessed parameters for preterm birth. METHODS: Ninety women between 22 and 36 weeks' gestation were included and divided into two groups: group A comprised 41 women at 22 to 36 weeks' gestation who were suffering from threatened premature labor; and group B comprised 49 women at 22 to 36 weeks' gestation with preterm premature rupture of the membranes. Levels of sRAGE, esRAGE, sRANKL, and osteoprotegerin were measured. The Mann-Whitney test was used to assess differences in parameters between the groups. For statistical analysis of relationships, correlation coefficients were estimated using Spearman's test. Receiver operating characteristics were used to determine the cut-off point and predictive values. RESULTS: In group A, sRAGE and sRANKL levels were correlated with the latent time from symptoms until delivery (r = 0.422; r = -0.341, respectively). The sensitivities of sRANKL and sRAGE levels for predicting preterm delivery were 0.895 and 0.929 with a negative predictive value (NPV) of 0.857 and 0.929, respectively. In group B, sRAGE and sRANKL levels were correlated with the latent time from pPROM until delivery (r = 0.381; r = -0.439). The sensitivity of sRANKL and sRAGE for predicting delivery within 24 h after pPROM was 0.682 and 0.318, with NPVs of 0.741 and 0.625, respectively. Levels of esRAGE and sRANKL were lower in group A than in group B (median = 490.2 vs 541.1 pg/mL; median = 6425.0 vs 11362.5 pg/mL, respectively). CONCLUSIONS: Correlations between sRAGE, sRANKL, and pregnancy duration after the onset of symptoms suggest their role in preterm delivery. The high prognostic values of these biomarkers indicate their usefulness in diagnosis of pregnancies with threatened premature labor. PMID- 26059229 TI - The use of 'Omics technology to rationally improve industrial mammalian cell line performance. AB - Biologics represent an increasingly important class of therapeutics, with 7 of the 10 top selling drugs from 2013 being in this class. Furthermore, health authority approval of biologics in the immuno-oncology space is expected to transform treatment of patients with debilitating and deadly diseases. The growing importance of biologics in the healthcare field has also resulted in the recent approvals of several biosimilars. These recent developments, combined with pressure to provide treatments at lower costs to payers, are resulting in increasing need for the industry to quickly and efficiently develop high yielding, robust processes for the manufacture of biologics with the ability to control quality attributes within narrow distributions. Achieving this level of manufacturing efficiency and the ability to design processes capable of regulating growth, death and other cellular pathways through manipulation of media, feeding strategies, and other process parameters will undoubtedly be facilitated through systems biology tools generated in academic and public research communities. Here we discuss the intersection of systems biology, 'Omics technologies, and mammalian bioprocess sciences. Specifically, we address how these methods in conjunction with traditional monitoring techniques represent a unique opportunity to better characterize and understand host cell culture state, shift from an empirical to rational approach to process development and optimization of bioreactor cultivation processes. We summarize the following six key areas: (i) research applied to parental, non-recombinant cell lines; (ii) systems level datasets generated with recombinant cell lines; (iii) datasets linking phenotypic traits to relevant biomarkers; (iv) data depositories and bioinformatics tools; (v) in silico model development, and (vi) examples where these approaches have been used to rationally improve cellular processes. We critically assess relevant and state of the art research being conducted in academic, government and industrial laboratories. Furthermore, we apply our expertise in bioprocess to define a potential model for integration of these systems biology approaches into biologics development. PMID- 26059230 TI - An evaluation of hand hygiene in an intensive care unit: Are visitors a potential vector for pathogens? AB - Patients in an intensive care unit (ICU) are frequently immunocompromised and might be highly susceptible to infection. Visitors to an ICU who do not adequately clean their hands could carry pathogenic organisms, resulting in risk to a vulnerable patient population. This observational study identifies pathogens carried on the hands of visitors into an ICU and investigates the effect of hand hygiene. Two observers, one stationed outside and one inside the ICU, evaluated whether visitors performed hand hygiene at any of the wall-mounted alcohol-based hand sanitizer dispensers prior to reaching a patient's room. Upon reaching a patient's room, the dominant hand of all of the participants was cultured. Of the 55 participating visitors, 35 did not disinfect their hands. Among the cultures of those who failed to perform hand hygiene, eight cultures grew Gram-negative rods and one grew methicillin-resistant Staphylococcus aureus. Of the cultures of the 20 individuals who performed hand hygiene, 14 (70%) had no growth on the cultures, and the remaining six (30%) showed only the usual skin flora. The visitors who do not perform hand hygiene might carry pathogens that pose a risk to ICU patients. PMID- 26059231 TI - Symmetry, not asymmetry, of abdominal muscle morphology is associated with low back pain in cricket fast bowlers. AB - OBJECTIVES: Although abdominal muscle morphology is symmetrical in the general population, asymmetry has been identified in rotation sports. This asymmetry includes greater thickness of obliquus internus abdominis (OI) on the non dominant side in cricketers. Cricket fast bowlers commonly experience low back pain (LBP) related to bowling action, and this depends on trunk muscle control. This study aimed to compare abdominal muscle thickness between fast bowlers with and without LBP. DESIGN: Cross sectional descriptive study. METHODS: Twenty-five adolescent provincial league specialist fast bowlers (16 with and 9 without LBP) participated. Static ultrasound images (US) of OI, and obliquus externus (OE) and transversus abdominis (TrA) were captured on the dominant and non-dominant side in supine. RESULTS: Total combined thickness of OE, OI and TrA muscles was greater on the non-dominant than dominant side (p=0.02) for fast bowlers without LBP, but symmetrical for those with pain. Total thickness was less on the non dominant side for bowlers with pain than those without (p=0.03). When individual muscles were compared, only the thickness of OI was less in bowlers with LBP than those without (p=0.02). All abdominal muscles were thicker on the non-dominant side in controls (p<0.001) but symmetrical in LBP. CONCLUSIONS: Asymmetry of abdominal muscle thickness in fast bowlers is explained by the asymmetrical biomechanics of fast bowling. Lesser OI muscle thickness in fast bowlers with LBP suggests modified trunk control in the transverse/frontal plane and may underpin the incidence of lumbar pathology. The implications for rehabilitation following LBP in fast bowlers require further investigation. PMID- 26059232 TI - Impact of the calculation algorithm on biexponential fitting of diffusion weighted MRI in upper abdominal organs. AB - PURPOSE: To compare the variability, precision, and accuracy of six different algorithms (Levenberg-Marquardt, Trust-Region, Fixed-Dp , Segmented Unconstrained, Segmented-Constrained, and Bayesian-Probability) for computing intravoxel-incoherent-motion-related parameters in upper abdominal organs. METHODS: Following the acquisition of abdominal diffusion-weighted magnetic resonance images of 10 healthy men, six distinct algorithms were employed to compute intravoxel-incoherent-motion-related parameters in the left and right liver lobe, pancreas, spleen, renal cortex, and renal medulla. Algorithms were evaluated regarding inter-reader and intersubject variability. Comparability of results was assessed by analyses of variance. The algorithms' precision and accuracy were investigated on simulated data. RESULTS: A Bayesian-Probability based approach was associated with very low inter-reader variability (average Intraclass Correlation Coefficients: 96.5-99.6%), the lowest inter-subject variability (Coefficients of Variation [CV] for the pure diffusion coefficient Dt : 3.8% in the renal medulla, 6.6% in the renal cortex, 10.4-12.1% in the left and right liver lobe, 15.3% in the spleen, 15.8% in the pancreas; for the perfusion fraction Fp : 15.5% on average; for the pseudodiffusion coefficient Dp : 25.8% on average), and the highest precision and accuracy. Results differed significantly (P < 0.05) across algorithms in all anatomical regions. CONCLUSION: The Bayesian Probability algorithm should be preferred when computing intravoxel-incoherent motion-related parameters in upper abdominal organs. PMID- 26059233 TI - Global population collapse in a superabundant migratory bird and illegal trapping in China. AB - Persecution and overexploitation by humans are major causes of species extinctions. Rare species, often confined to small geographic ranges, are usually at highest risk, whereas extinctions of superabundant species with very large ranges are rare. The Yellow-breasted Bunting (Emberiza aureola) used to be one of the most abundant songbirds of the Palearctic, with a very large breeding range stretching from Scandinavia to the Russian Far East. Anecdotal information about rapid population declines across the range caused concern about unsustainable trapping along the species' migration routes. We conducted a literature review and used long-term monitoring data from across the species' range to model population trend and geographical patterns of extinction. The population declined by 84.3-94.7% between 1980 and 2013, and the species' range contracted by 5000 km. Quantitative evidence from police raids suggested rampant illegal trapping of the species along its East Asian flyway in China. A population model simulating an initial harvest level of 2% of the population, and an annual increase of 0.2% during the monitoring period produced a population trajectory that matched the observed decline. We suggest that trapping strongly contributed to the decline because the consumption of Yellow-breasted Bunting and other songbirds has increased as a result of economic growth and prosperity in East Asia. The magnitude and speed of the decline is unprecedented among birds with a comparable range size, with the exception of the Passenger Pigeon (Ectopistes migratorius), which went extinct in 1914 due to industrial-scale hunting. Our results demonstrate the urgent need for an improved monitoring of common and widespread species' populations, and consumption levels throughout East Asia. PMID- 26059234 TI - Evaluation of reduced subsets of single nucleotide polymorphisms for the prediction of age at puberty in sows. AB - Genomic information could be used efficiently to improve traits that are expensive to measure, sex limited or expressed late in life. This study analyzed the phenotypic variation explained by major SNPs and windows for age at puberty in gilts, an indicator of reproductive longevity. A genome-wide association study using 56, 424 SNPs explained 25.2% of the phenotypic variation in age at puberty in a training set (n = 820). All SNPs from the top 10% of 1-Mb windows explained 33.5% of the phenotypic variance compared to 47.1% explained by the most informative markers (n = 261). In an evaluation population, consisting of subsequent batches (n = 412), the predictive ability of all SNPs from the major 1 Mb windows was higher compared to the variance captured by the most informative SNP from each of these windows. The phenotypic variance explained in the evaluation population varied from 12.3% to 36.8% when all SNPs from major windows were used compared to 6.5-23.7% explained by most informative SNPs. The correlation between phenotype and genomic prediction values based on SNP effects estimated in the training population was marginal compared to their effects retrained in the evaluation population for all (0.46-0.81) or most informative SNPs (0.30-0.65) from major windows. An increase in genetic gain of 20.5% could be obtained if genomic selection included both sexes compared to females alone. The pleiotropic role of major genes such as AVPR1A could be exploited in selection of both age at puberty and reproductive longevity. PMID- 26059235 TI - The Mechanism of N-O Bond Cleavage in Rhodium-Catalyzed C-H Bond Functionalization of Quinoline N-oxides with Alkynes: A Computational Study. AB - Metal-catalyzed C-H activation not only offers important strategies to construct new bonds, it also allows the merge of important research areas. When quinoline N oxide is used as an arene source in C-H activation studies, the N-O bond can act as a directing group as well as an O-atom donor. The newly reported density functional theory method, M11L, has been used to elucidate the mechanistic details of the coupling between quinoline N-O bond and alkynes, which results in C-H activation and O-atom transfer. The computational results indicated that the most favorable pathway involves an electrophilic deprotonation, an insertion of an acetylene group into a Rh-C bond, a reductive elimination to form an oxazinoquinolinium-coordinated Rh(I) intermediate, an oxidative addition to break the N-O bond, and a protonation reaction to regenerate the active catalyst. The regioselectivity of the reaction has also been studied by using prop-1-yn-1 ylbenzene as a model unsymmetrical substrate. Theoretical calculations suggested that 1-phenyl-2-quinolinylpropanone would be the major product because of better conjugation between the phenyl group and enolate moiety in the corresponding transition state of the regioselectivity-determining step. These calculated data are consistent with the experimental observations. PMID- 26059236 TI - Transcriptome sequencing and annotation of the polychaete Hermodice carunculata (Annelida, Amphinomidae). AB - BACKGROUND: The amphinomid polychaete Hermodice carunculata is a cosmopolitan and ecologically important omnivore in coral reef ecosystems, preying on a diverse suite of reef organisms and potentially acting as a vector for coral disease. While amphinomids are a key group for determining the root of the Annelida, their phylogenetic position has been difficult to resolve, and their publically available genomic data was scarce. RESULTS: We performed deep transcriptome sequencing (Illumina HiSeq) and profiling on Hermodice carunculata collected in the Western Atlantic Ocean. We focused this study on 58,454 predicted Open Reading Frames (ORFs) of genes longer than 200 amino acids for our homology search, and Gene Ontology (GO) terms and InterPro IDs were assigned to 32,500 of these ORFs. We used this de novo assembled transcriptome to recover major signaling pathways and housekeeping genes. We also identify a suite of H. carunculata genes related to reproduction and immune response. CONCLUSIONS: We provide a comprehensive catalogue of annotated genes for Hermodice carunculata and expand the knowledge of reproduction and immune response genes in annelids, in general. Overall, this study vastly expands the available genomic data for H. carunculata, of which previously consisted of only 279 nucleotide sequences in NCBI. This underscores the utility of Illumina sequencing for de novo transcriptome assembly in non-model organisms as a cost-effective and efficient tool for gene discovery and downstream applications, such as phylogenetic analysis and gene expression profiling. PMID- 26059237 TI - Diagnosis and minimally invasive surgical treatment of bleeding Meckel's diverticulum in children using double-balloon enteroscopy. AB - BACKGROUND/PURPOSE: To demonstrate the diagnosis of bleeding Meckel's diverticulum (MD) using double-balloon enteroscopy (DBE) and to highlight the utility of this technique for guidance in minimally invasive surgery. MATERIALS AND METHODS: From August 2011 to September 2014, 21 pediatric patients with bloody diarrhea underwent transanal DBE examinations. When a lesion such as MD or a tumor was detected, the enteroscopic light source was brought as close to the umbilicus as possible. A small incision was made at the umbilicus, and the lesion indicated by the enteroscopic light source was pulled out of the umbilicus for lesion removal and intestinal anastomosis. If no lesion was detected, the DBE exam was ended after the scope had been advanced at least 200 cm into the ileum. All patients were followed closely after discharge. RESULTS: Fourteen children were diagnosed with MD and underwent successful removal via an umbilical incision using enteroscopic light guidance; a standard resection was then performed. Two patients were diagnosed with lymphoma and successfully treated using the same method. Five patients had negative enteroscopic findings. Of these, a 4-year-old boy had recurrent bloody diarrhea and a negative laparoscopic evaluation after 7 months. In 4 patients, bloody diarrhea did not recur during follow-up. CONCLUSIONS: DBE is an ideal tool for the diagnosis and minimally invasive treatment of bleeding MD in children. PMID- 26059238 TI - Neural versus pneumatic control of pressure support in patients with chronic obstructive pulmonary diseases at different levels of positive end expiratory pressure: a physiological study. AB - INTRODUCTION: Intrinsic positive end-expiratory pressure (PEEPi) is a "threshold" load that must be overcome to trigger conventional pneumatically-controlled pressure support (PSP) in chronic obstructive pulmonary disease (COPD). Application of extrinsic PEEP (PEEPe) reduces trigger delays and mechanical inspiratory efforts. Using the diaphragm electrical activity (EAdi), neurally controlled pressure support (PSN) could hypothetically eliminate asynchrony and reduce mechanical inspiratory effort, hence substituting the need for PEEPe. The primary objective of this study was to show that PSN can reduce the need for PEEPe to improve patient-ventilator interaction and to reduce both the "pre trigger" and "total inspiratory" neural and mechanical efforts in COPD patients with PEEPi. A secondary objective was to evaluate the impact of applying PSN on breathing pattern. METHODS: Twelve intubated and mechanically ventilated COPD patients with PEEPi >= 5 cm H2O underwent comparisons of PSP and PSN at different levels of PEEPe (at 0 %, 40 %, 80 %, and 120 % of static PEEPi, for 12 minutes at each level on average), at matching peak airway pressure. We measured flow, airway pressure, esophageal pressure, and EAdi, and analyzed neural and mechanical efforts for triggering and total inspiration. Patient-ventilator interaction was analyzed with the NeuroSync index. RESULTS: Mean airway pressure and PEEPe were comparable for PSP and PSN at same target levels. During PSP, the NeuroSync index was 29 % at zero PEEPe and improved to 21 % at optimal PEEPe (P < 0.05). During PSN, the NeuroSync index was lower (<7 %, P < 0.05) regardless of PEEPe. Both pre-trigger (P < 0.05) and total inspiratory mechanical efforts (P < 0.05) were consistently higher during PSP compared to PSN at same PEEPe. The change in total mechanical efforts between PSP at PEEPe0% and PSN at PEEPe0% was not different from the change between PSP at PEEPe0% and PSP at PEEPe80%. CONCLUSION: PSN abolishes the need for PEEPe in COPD patients, improves patient ventilator interaction, and reduces the inspiratory mechanical effort to breathe. TRIAL REGISTRATION: Clinicaltrials.gov NCT02114567 . Registered 04 November 2013. PMID- 26059239 TI - Downregulation of Meg3 enhances cisplatin resistance of lung cancer cells through activation of the WNT/beta-catenin signaling pathway. AB - Maternally expressed gene 3 (Meg3) has been shown to promote tumor progression. However, the role of Meg3 in the development of a chemoresistant phenotype of human lung cancer has remains. Reverse transcription-quantitative polymerase chain reaction analysis was used to determine the expression of Meg3. Flow cytometric analysis and MTT assay were also used to investigate the cell cycle and apoptosis. The present study detected that the expression levels of Meg3 were significantly lower in cisplatin-resistant A549/DDP lung cancer cells, compared with those in parental A549 cells. Furthermore, upregulation of Meg3 was able to re-sensitize the A549/DDP cells to cisplatin in vitro. Whereas downregulation of Meg3, by RNA interference, decreased the sensitivity of A549 cells to cisplatin. The results of the present study also demonstrated that the Meg3-mediated chemosensitivity enhancement was associated with the induction of cell-cycle arrest and increased apoptosis, through regulation of p53, beta-catenin and survivin, which is a target gene of the WNT/beta-catenin signaling pathway. In conclusion, these results suggested that Meg3 may have a crucial role in the development of cisplatin resistance in non-small cell lung cancer. PMID- 26059240 TI - The Schwickerath adhesion test: A fracture mechanics analysis. AB - OBJECTIVES: The Schwickerath three point bending adhesion test is the basis of the International Standard ISO 9693:1999 procedure for assessing porcelain bonding to metals [1]. It has also been used to evaluate the adhesion of porcelain to zirconia. The purpose of this paper is a fracture mechanics analysis of this test, which allows determination of the crack-length load-displacement and toughness dependence of cracks extending along or near the interface. METHODS: Linear elastic mechanics is used to develop expressions for the strain energy and compliance of Schwickerath geometry specimens as a function of crack extension along or near the interface. From the derivative of the compliance as a function of crack growth the strain energy release rate (G, N/m) is determined. RESULTS: The energy release rate for interface crack extension of Schwickerath geometry specimens is determined. It is found that a simple relationship between the minima of the force-displacement response and the strain energy release rate G exists. Further development enables the predicted force-displacement response as a function of crack length to be derived for different values of G. Experimental results of porcelain bonded to zirconia with and without notches of various lengths machined along the interface verify the expressions and analysis developed. SIGNIFICANCE: With the fracture mechanics analysis developed in this paper it is possible to determine the quality of adhesion in Schwickerath specimens by the interface toughness in addition to the nominal interface shear bond strength. As the toughness of brittle materials has much less scatter than its strength, the interface toughness characterization of the adhesion should allow for a better distinction between the adhesion quality of bonding. PMID- 26059241 TI - In situ antibiofilm effect of glass-ionomer cement containing dimethylaminododecyl methacrylate. AB - OBJECTIVE: The aim of this study was to investigate antibiofilm effects of a recently developed glass ionomer cement (GIC) containing dimethylaminododecyl methacrylate (DMADDM) under oral conditions. METHODS: Biofilms were allowed to form in situ on GIC specimens (n=216) which contained DMADDM (1.1wt.% or 2.2wt.%). Samples without DMADDM served as control (n=108). GIC specimens were fixed on custom made splints and exposed to the oral cavity in six healthy volunteers for 24, 48 and 72h, respectively. Biofilm viability and coverage were analyzed by fluorescence microscopy (FM) and evaluated by red/green ratios and an established scoring system. Bacterial morphology and biofilm accumulation were determined by scanning electron microscopy (SEM). Additionally, material properties as surface charge density of quaternary ammonium groups, surface roughness and DMADDM release were recorded. RESULTS: FM results showed a higher ratio (24h: 0%: 0.5, 1.1%: 1.2, 2.2%: 2.5) of red/green fluorescence on GIC samples containing DMADDM. Biofilm coverage and viability scores were significantly reduced (24h: q1/median/q3 for: 0%: 3/4/5, 1.1%: 2/3/3, 2.2%: 1/2/2) on DMADDM containing samples compared to controls after 24h as well as 48 and 72h in situ (p<0.05). While surface charge density of quaternary ammonium groups and DMADDM release increased with the DMADDM concentration, surface roughness was lowest on specimens containing 2.2wt.% DMADDM. SIGNIFICANCE: An in situ dental biofilm model was used to evaluate the novel GIC containing DMADDM. This material strongly inhibited biofilms in situ and is promising to prevent bacterial colonization on the surface of restorations. PMID- 26059242 TI - Pilot safety study of intrabronchial instillation of bone marrow-derived mononuclear cells in patients with silicosis. AB - BACKGROUND: Silicosis is an occupational disease for which no effective treatment is currently known. Systemic administration of bone marrow-derived mononuclear cells (BMDMCs) has shown to be safe in lung diseases. However, so far, no studies have analyzed whether bronchoscopic instillation of autologous BMDMCs is a safe route of administration in patients with silicosis. METHODS: We conducted a prospective, non-randomized, single-center longitudinal study in five patients. Inclusion criteria were age 18-50 years, chronic and accelerated silicosis, forced expiratory volume in 1 s <60 % and >40 %, forced vital capacity >=60 % and arterial oxygen saturation >90 %. The exclusion criteria were smoking, active tuberculosis, neoplasms, autoimmune disorders, heart, liver or renal diseases, or inability to undergo bronchoscopy. BMDMCs were administered through bronchoscopy (2 * 10(7) cells) into both lungs. Physical examination, laboratory evaluations, quality of life questionnaires, computed tomography of the chest, lung function tests, and perfusion scans were performed before the start of treatment and up to 360 days after BMDMC therapy. Additionally, whole-body and planar scans were evaluated 2 and 24 h after instillation. RESULTS: No adverse events were observed during and after BMDMC administration. Lung function, quality of life and radiologic features remained stable throughout follow-up. Furthermore, an early increase of perfusion in the base of both lungs was observed and sustained after BMDMC administration. CONCLUSION: Administration of BMDMCs through bronchoscopy appears to be feasible and safe in accelerated and chronic silicosis. This pilot study provides a basis for prospective randomized trials to assess the efficacy of this treatment approach. CLINICAL TRIALS. GOV IDENTIFIER: NCT01239862 Date of Registration: November 10, 2010. PMID- 26059244 TI - Long-term impacts of grazing intensity on soil carbon sequestration and selected soil properties in the arid Eastern Cape, South Africa. AB - BACKGROUND: Little is known about how basic soil properties respond to contrasting grazing intensities in the Karoo biome, South Africa. The aim of this study was to investigate impacts of long-term (>75 years) grazing at 1.18 heads ha(-1) (heavy; CGH), 0.78 heads ha(-1) (light; CGL), and exclosure on selected soil properties. Soil samples were collected to a depth of 60 cm from the long term experimental site of Grootfontein Agricultural Development Institute, Eastern Cape. The samples were analyzed for C, N, bulk density and infiltration rate, among others. RESULTS: Generally, heavy and light grazing reduced soil N storage by 27.5% and 22.6%, respectively, compared with the exclosure. Animal exclusion improved water infiltration rate and C stocks significantly (P < 0.05), which was 0.128, 0.097, and 0.093 Mg ha(-1) yr(-1) for exclosure, CGL and CGH, respectively. Soil penetration resistance was higher for grazing treatments in the top 3-7 cm soil layer but for exclosure at the top 1 cm soil surface. CONCLUSION: Although livestock exclusion has the potential to improve C sequestration, a sufficient resting period for 1-2 years followed by three consecutive grazing years at light stocking rate would be ideal for sustainable livestock production in this arid region of South Africa. PMID- 26059246 TI - Factors influencing the process of medication (non-)adherence and (non )persistence in breast cancer patients with adjuvant antihormonal therapy: a qualitative study. AB - Non-adherence and non-persistence in breast cancer patients taking antihormonal therapy (AHT) is common. However, the complex patterns and dynamics of adherence and persistence are still not fully understood. This study aims to give insight into the process of (non-)adherence and (non-)persistence by researching influencing factors and their interrelatedness in breast cancer patients taking AHT by means of a qualitative study with semi-structured interviews. The sample consisted of 31 breast cancer patients treated with AHT. Purposive and theoretical sampling and the constant comparison method based on a grounded theory approach were used. Expectations regarding the impact of AHT, social support from family and friends, and recognition from healthcare professionals were found to influence the process of non-adherence and non-persistence. The results of this study can help healthcare professionals understand why breast cancer patients taking AHT do not always adhere to or persist in taking the therapy and may facilitate patient-tailored interventions. PMID- 26059245 TI - Production of human lactoferrin and lysozyme in the milk of transgenic dairy animals: past, present, and future. AB - Genetic engineering, which was first developed in the 1980s, allows for specific additions to animals' genomes that are not possible through conventional breeding. Using genetic engineering to improve agricultural animals was first suggested when the technology was in the early stages of development by Palmiter et al. (Nature 300:611-615, 1982). One of the first agricultural applications identified was generating transgenic dairy animals that could produce altered or novel proteins in their milk. Human milk contains high levels of antimicrobial proteins that are found in low concentrations in the milk of ruminants, including the antimicrobial proteins lactoferrin and lysozyme. Lactoferrin and lysozyme are both part of the innate immune system and are secreted in tears, mucus, and throughout the gastrointestinal (GI) tract. Due to their antimicrobial properties and abundance in human milk, multiple lines of transgenic dairy animals that produce either human lactoferrin or human lysozyme have been developed. The focus of this review is to catalogue the different lines of genetically engineered dairy animals that produce either recombinant lactoferrin or lysozyme that have been generated over the years as well as compare the wealth of research that has been done on the in vitro and in vivo effects of the milk they produce. While recent advances including the development of CRISPRs and TALENs have removed many of the technical barriers to predictable and efficient genetic engineering in agricultural species, there are still many political and regulatory hurdles before genetic engineering can be used in agriculture. It is important to consider the substantial amount of work that has been done thus far on well established lines of genetically engineered animals evaluating both the animals themselves and the products they yield to identify the most effective path forward for future research and acceptance of this technology. PMID- 26059247 TI - Targeted therapies for ER+/HER2- metastatic breast cancer. AB - The majority of breast cancers present with estrogen receptor (ER)-positive and human epidermal growth factor receptor (HER2)-negative features and might benefit from endocrine therapy. Although endocrine therapy has notably evolved during the last decades, the invariable appearance of endocrine resistance, either primary or secondary, remains an important issue in this type of tumor. The improvement of our understanding of the cancer genome has identified some promising targets that might be responsible or linked to endocrine resistance, including alterations affecting main signaling pathways like PI3K/Akt/mTOR and CCND1/CDK4-6 as well as the identification of new ESR1 somatic mutations, leading to an array of new targeted therapies that might circumvent or prevent endocrine resistance. In this review, we have summarized the main targeted therapies that are currently being tested in ER+ breast cancer, the rationale behind them, and the new agents and combinational treatments to come. PMID- 26059248 TI - Recent advances in robotic surgery for rectal cancer. AB - Robotic technology, which has recently been introduced to the field of surgery, is expected to be useful, particularly in treating rectal cancer where precise manipulation is necessary in the confined pelvic cavity. Robotic surgery overcomes the technical drawbacks inherent to laparoscopic surgery for rectal cancer through the use of multi-articulated flexible tools, three-dimensional stable camera platforms, tremor filtering and motion scaling functions, and greater ergonomic and intuitive device manipulation. Assessments of the feasibility and safety of robotic surgery for rectal cancer have reported similar operation times, blood loss during surgery, rates of postoperative morbidity, and circumferential resection margin involvement when compared with laparoscopic surgery. Furthermore, rates of conversion to open surgery are reportedly lower with increased urinary and male sexual functions in the early postoperative period compared with laparoscopic surgery, demonstrating the technical advantages of robotic surgery for rectal cancer. However, long-term outcomes and the cost effectiveness of robotic surgery for rectal cancer have not been fully evaluated yet; therefore, large-scale clinical studies are required to evaluate the efficacy of this new technology. PMID- 26059249 TI - Social skills programmes for schizophrenia. AB - BACKGROUND: Social skills programmes (SSP) are treatment strategies aimed at enhancing the social performance and reducing the distress and difficulty experienced by people with a diagnosis of schizophrenia and can be incorporated as part of the rehabilitation package for people with schizophrenia. OBJECTIVES: The primary objective is to investigate the effects of social skills training programmes, compared to standard care, for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register (November 2006 and December 2011) which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. We inspected references of all identified studies for further trials.A further search for studies has been conducted by the Cochrane Schizophrenia Group in 2015, 37 citations have been found and are currently being assessed by review authors. SELECTION CRITERIA: We included all relevant randomised controlled trials for social skills programmes versus standard care involving people with serious mental illnesses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RRs) and their 95% confidence intervals (CI) on an intention-to-treat basis. For continuous data, we calculated mean differences (MD) and 95% CIs. MAIN RESULTS: We included 13 randomised trials (975 participants). These evaluated social skills programmes versus standard care, or discussion group. We found evidence in favour of social skills programmes compared to standard care on all measures of social functioning. We also found that rates of relapse and rehospitalisation were lower for social skills compared to standard care (relapse: 2 RCTs, n = 263, RR 0.52 CI 0.34 to 0.79, very low quality evidence), (rehospitalisation: 1 RCT, n = 143, RR 0.53 CI 0.30 to 0.93, very low quality evidence) and participants' mental state results (1 RCT, n = 91, MD -4.01 CI -7.52 to -0.50, very low quality evidence) were better in the group receiving social skill programmes. Global state was measured in one trial by numbers not experiencing a clinical improvement, results favoured social skills (1 RCT, n = 67, RR 0.29 CI 0.12 to 0.68, very low quality evidence). Quality of life was also improved in the social skills programme compared to standard care (1 RCT, n = 112, MD -7.60 CI -12.18 to -3.02, very low quality evidence). However, when social skills programmes were compared to a discussion group control, we found no significant differences in the participants social functioning, relapse rates, mental state or quality of life, again the quality of evidence for these outcomes was very low. AUTHORS' CONCLUSIONS: Compared to standard care, social skills training may improve the social skills of people with schizophrenia and reduce relapse rates, but at present, the evidence is very limited with data rated as very low quality. When social skills training was compared to discussion there was no difference on patients outcomes. Cultural differences might limit the applicability of the current results, as most reported studies were conducted in China. Whether social skills training can improve social functioning of people with schizophrenia in different settings remains unclear and should be investigated in a large multi-centre randomised controlled trial. PMID- 26059250 TI - Is fructose malabsorption a cause of irritable bowel syndrome? AB - Irritable Bowel Syndrome (IBS) is a condition that may be marked by abdominal pain, bloating, fullness, indigestion, belching, constipation and/or diarrhea. IBS symptoms can result from malabsorption of fructose. Fructose is a monosaccharide found naturally in small quantities in fruits and some vegetables, and in much larger quantities in industrially manufactured sweets with added sugars (e.g. sucrose and high fructose corn syrup). Fructose malabsorption leads to osmotic diarrhea as well as gas and bloating due to fermentation in the colon. A low-fructose diet has been found to improve IBS symptoms in some patients. This paper discusses the prevalence of fructose malabsorption and considers fructose ingestion as a possible cause of--and fructose restriction as a possible dietary treatment for--IBS. PMID- 26059251 TI - Effect of sludge age on methanogenic and glycogen accumulating organisms in an aerobic granular sludge process fed with methanol and acetate. AB - The influence of sludge age on granular sludge formation and microbial population dynamics in a methanol- and acetate-fed aerobic granular sludge system operated at 35 degrees C was investigated. During anaerobic feeding of the reactor, methanol was initially converted to methane by methylotrophic methanogens. These methanogens were able to withstand the relatively long aeration periods. Lowering the anaerobic solid retention time (SRT) from 17 to 8 days enabled selective removal of the methanogens and prevented unwanted methane formation. In absence of methanogens, methanol was converted aerobically, while granule formation remained stable. At high SRT values (51 days), gamma-Proteobacteria were responsible for acetate removal through anaerobic uptake and subsequent aerobic growth on storage polymers formed [so called metabolism of glycogen-accumulating organisms (GAO)]. When lowering the SRT (24 days), Defluviicoccus-related organisms (cluster II) belonging to the alpha-Proteobacteria outcompeted acetate consuming gamma-Proteobacteria at 35 degrees C. DNA from the Defluviicoccus related organisms in cluster II was not extracted by the standard DNA extraction method but with liquid nitrogen, which showed to be more effective. Remarkably, the two GAO types of organisms grew separately in two clearly different types of granules. This work further highlights the potential of aerobic granular sludge systems to effectively influence the microbial communities through sludge age control in order to optimize the wastewater treatment processes. PMID- 26059252 TI - Synthesis and Evaluation of a Series of Long-Acting Glucagon-Like Peptide-1 (GLP 1) Pentasaccharide Conjugates for the Treatment of Type 2 Diabetes. AB - The present study details the development of a family of novel D-Ala(8) glucagon like peptide-1 (GLP-1) peptide conjugates by site specific conjugation to an antithrombin III (ATIII) binding carrier pentasaccharide through tetraethylene glycol linkers. All conjugates were found to possess potent insulin-releasing activity. Peptides with short linkers (<25 atoms) conjugated at Lys(34) and Lys(37) displayed strong GLP-1 receptor (GLP-1-R) binding affinity. All D-Ala(8) GLP-1 conjugates exhibited prominent glucose-lowering action. Biological activity of the Lys(37) short-linker peptide was evident up to 72 h post-injection. In agreement, the pharmacokinetic profile of this conjugate (t1/2 , 11 h) was superior to that of the GLP-1-R agonist, exenatide. Once-daily injection of the Lys(37) short-linker peptide in ob/ob mice for 21 days significantly decreased food intake and improved HbA1c and glucose tolerance. Islet size was decreased, with no discernible change in islet number. The beneficial effects of the Lys(37) short-linker peptide were similar to or better than either exenatide or liraglutide, another GLP-1-R agonist. In conclusion, GLP-1 peptides conjugated to an ATIII binding carrier pentasaccharide have a substantially prolonged bioactive profile compatible for possible once-weekly treatment of type 2 diabetes in humans. PMID- 26059253 TI - Effectiveness of a Multidimensional Randomized Control Intervention to Reduce Quartz Exposure Among Construction Workers. AB - There is little evidence with respect to the effectiveness of intervention programs that focus on the reduction of occupational quartz exposure in the construction industry. This article evaluates the effectiveness of a multidimensional intervention which was aimed at reducing occupational quartz exposure among construction workers by increasing the use of technical control measures. Eight companies participating in the cluster randomized controlled trial were randomly allocated to the intervention (four companies) or control condition (four companies). The multidimensional intervention included engineering, organizational, and behavioural elements at both organizational and individual level. Full-shift personal quartz exposure measurements and detailed observations were conducted before and after the intervention among bricklayers, carpenters, concrete drillers, demolishers, and tuck pointers (n = 282). About 59% of these workers measured at baseline were reassessed during follow-up. Bayesian hierarchical models were used to evaluate the intervention effect on exposure levels. Concrete drillers in the intervention group used technical control measures, particularly water suppression, for a significantly greater proportion of the time spent on abrasive tasks during follow-up compared to baseline (93 versus 62%; P < 0.05). A similar effect, although not statistically significant, was observed among demolishers. A substantial overall reduction in quartz exposure (73 versus 40% in the intervention and control group respectively; P < 0.001) was observed for concrete drillers, demolishers, and tuck pointers. The decrease in exposure in the intervention group compared to controls was significantly larger for demolishers and tuck pointers, but not for concrete drillers. The observed effect could at least partly be explained by the introduced interventions; the statistically significant increased use of control measures among concrete drillers explains the observed effect to some extent in this job category only. Sensitivity analyses indicated that the observed decrease in exposure may also partly be attributable to changes in work location and abrasiveness of the tasks performed. Despite the difficulties in assessing the exact magnitude of the intervention, this study showed that the structured intervention approach at least partly contributed to a substantial reduction in quartz exposure among high exposed construction workers. PMID- 26059254 TI - A near-wearless and extremely long lifetime amorphous carbon film under high vacuum. AB - Prolonging wear life of amorphous carbon films under vacuum was an enormous challenge. In this work, we firstly reported that amorphous carbon film as a lubricant layer containing hydrogen, oxygen, fluorine and silicon (a-C:H:O:F:Si) exhibited low friction (~0.1), ultra-low wear rate (9.0 * 10(-13) mm(3) N(-1) mm( 1)) and ultra-long wear life (>2 * 10(6) cycles) under high vacuum. We systematically examined microstructure and composition of transfer film for understanding of the underlying frictional mechanism, which suggested that the extraordinarily excellent tribological properties were attributed to the thermodynamically and structurally stable FeF2 nanocrystallites corroborated using first-principles calculations, which were induced by the tribochemical reaction. PMID- 26059255 TI - What are the treatment options for paroxysmal extreme pain disorder? PMID- 26059256 TI - Comparison of eosinophil density in staging bone marrow biopsies from Malawi and the United States. PMID- 26059257 TI - Recovery after brain damage: Is there any indication for generalization between different cognitive functions? AB - INTRODUCTION: The question whether recovery in various cognitive functions is supported by one or two more fundamental functions (for instance, attentional or working memory functions) is a long-standing problem of cognitive rehabilitation. One possibility to answer this question is to analyze the recovery pattern in different cognitive domains and to see whether improvement in one domain is related to performance in another domain. METHOD: Ninety-two inpatients with stroke or other brain lesions (Barthel Index >75) were included. Neuropsychological assessment was done at the beginning and the end of a rehabilitation stay. Cognitive performance was analyzed at test and at domain level using conceptually and statistically defined composite scores for attention, immediate and delayed memory, working memory, prospective memory, and word fluency. We used regression analysis to look for generalization between cognitive domains. RESULTS: Effect sizes of improvement varied largely (from d = 0.18 in attention and d = 1.36 in episodic memory). Age, gender, and time since injury had no impact on recovery. Impaired patients showed significantly more improvement than nonimpaired patients. Regression analysis revealed no effect of initial performance in one cognitive domain on improvements in other cognitive domains. CONCLUSION: Significant recovery in impaired cognitive domains can be expected during neuropsychological rehabilitation. It depends more or less exclusively on improvement in the specific functions itself, and there was no evidence for generalization between cognitive domains. PMID- 26059258 TI - Characteristics of maturity onset diabetes of the young in a large diabetes center. AB - Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes caused by a mutation in a single gene, often not requiring insulin. The aim of this study was to estimate the frequency and clinical characteristics of MODY at the Barbara Davis Center. A total of 97 subjects with diabetes onset before age 25, a random C-peptide >=0.1 ng/mL, and negative for all diabetes autoantibodies (GADA, IA-2, ZnT8, and IAA) were enrolled, after excluding 21 subjects with secondary diabetes or refusal to participate. Genetic testing for MODY 1-5 was performed through Athena Diagnostics, and all variants of unknown significance were further analyzed at Exeter, UK. A total of 22 subjects [20 (21%) when excluding two siblings] were found to have a mutation in hepatocyte nuclear factor 4A (n = 4), glucokinase (n = 8), or hepatocyte nuclear factor 1A (n = 10). Of these 22 subjects, 13 had mutations known to be pathogenic and 9 (41%) had novel mutations, predicted to be pathogenic. Only 1 of the 22 subjects had been given the appropriate MODY diagnosis prior to testing. Compared with MODY negative subjects, the MODY-positive subjects had lower hemoglobin A1c level and no diabetic ketoacidosis at onset; however, these characteristics are not specific for MODY. In summary, this study found a high frequency of MODY mutations with the majority of subjects clinically misdiagnosed. Clinicians should have a high index of suspicion for MODY in youth with antibody-negative diabetes. PMID- 26059260 TI - Retraction. PMID- 26059259 TI - Selective distributions of functionalized single-walled carbon nanotubes in a polymeric reverse hexagonal phase. AB - We have investigated the distributions of individually isolated and hydrophilically functionalized single-walled carbon nanotubes (p-SWNTs) in the Pluronic L121-water system at the reverse hexagonal phase using small-angle X-ray scattering (SAXS) and contrast-matched small-angle neutron scattering (SANS) measurements. As the p-SWNT-L121-water system is transitioned from the lamellar phase to the reverse hexagonal phase with temperature, p-SWNTs which were selectively distributed in the polar layers of the lamellar structure become selectively distributed in the cylindrical polar cores of the reverse hexagonal structure, forming a hexagonal array of p-SWNTs. This was clearly confirmed by the contrast-matched SANS measurements. The selective distribution of p-SWNTs in the reverse hexagonal phase is driven by the selective affinity of p-SWNTs to the polar domains of the block copolymer system. The method demonstrated in this study provides a new route for fabricating ordered SWNT superstructures and may be applicable for inorganic 1D nanoparticles such as semiconducting, metallic and magnetic nanorods which are of great interest. PMID- 26059262 TI - Synthesis of phase-pure and monodisperse iron oxide nanoparticles by thermal decomposition. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) are used for a wide range of biomedical applications requiring precise control over their physical and magnetic properties, which are dependent on their size and crystallographic phase. Here we present a comprehensive template for the design and synthesis of iron oxide nanoparticles with control over size, size distribution, phase, and resulting magnetic properties. We investigate critical parameters for synthesis of monodisperse SPIONs by organic thermal decomposition. Three different, commonly used, iron containing precursors (iron oleate, iron pentacarbonyl, and iron oxyhydroxide) are evaluated under a variety of synthetic conditions. We compare the suitability of these three kinetically controlled synthesis protocols, which have in common the use of iron oleate as a starting precursor or reaction intermediate, for producing nanoparticles with specific size and magnetic properties. Monodisperse particles were produced over a tunable range of sizes from approximately 2-30 nm. Reaction parameters such as precursor concentration, addition of surfactant, temperature, ramp rate, and time were adjusted to kinetically control size and size-distribution, phase, and magnetic properties. In particular, large quantities of excess surfactant (up to 25 : 1 molar ratio) alter reaction kinetics and result in larger particles with uniform size; however, there is often a trade-off between large particles and a narrow size distribution. Iron oxide phase, in addition to nanoparticle size and shape, is critical for establishing magnetic properties such as differential susceptibility (dm/dH) and anisotropy. As an example, we show the importance of obtaining the required size and iron oxide phase for application to Magnetic Particle Imaging (MPI), and describe how phase purity can be controlled. These results provide much of the information necessary to determine which iron oxide synthesis protocol is best suited to a particular application. PMID- 26059263 TI - Damage to the Brain Serotonergic System Increases the Expression of Liver Cytochrome P450. AB - Genes coding for cytochrome P450 are regulated by endogenous hormones such as the growth hormone, corticosteroids, thyroid, and sex hormones. Secretion of these hormones is regulated by the respective hypothalamus-pituitary-secretory organ axes. Since the brain sends its serotonergic projections from the raphe nuclei to the hypothalamus, we have assumed that damage to these nuclei may affect the neuroendocrine regulation of cytochrome P450 expression in the liver. Thereby, 5,7-dihydroxytryptamine (5,7-DHT), a serotonergic neurotoxin, was injected into the dorsal and median raphe nuclei of male Wistar rats. Ten days after the neurotoxin injections, the brain concentrations of neurotransmitters, serum hormone, and cytokine levels, as well as the expression of cytochrome P450 in the liver were measured. Injection of 5,7-DHT decreased serotonin concentration in the brain followed by a significant rise in the levels of the growth hormone, corticosterone, and testosterone, and a drop in triiodothyronine concentration in the serum. No changes in interleukin (IL) levels (IL-2 and IL-6) were observed. Simultaneously, the activity and protein level of liver CYP1A, CYP3A1, and CYP2C11 rose (the activity of CYP2A/2B/2C6/2D was not significantly changed). Similarly, the mRNA levels of CYP1A1, CYP1A2, CYP2C11, and CYP3A1 were elevated. This is the first report demonstrating the effect of intracerebral administration of serotonergic neurotoxin on liver cytochrome P450. The obtained results indicate involvement of the brain serotonergic system in the neuroendocrine regulation of liver cytochrome P450 expression. The physiologic and pharmacological significance of the findings is discussed. PMID- 26059265 TI - Comparative evaluation of 111In-labeled NOTA-conjugated affibody molecules for visualization of HER3 expression in malignant tumors. AB - Expression of human epidermal growth factor receptor type 3 (HER3) in malignant tumors has been associated with resistance to a variety of anticancer therapies. Several anti-HER3 monoclonal antibodies are currently under pre-clinical and clinical development aiming to overcome HER3-mediated resistance. Radionuclide molecular imaging of HER3 expression may improve treatment by allowing the selection of suitable patients for HER3-targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. In a recent study, we selected affibody molecules with affinity to HER3 at a low picomolar range. The aim of the present study was to develop an anti-HER3 affibody molecule suitable for labeling with radiometals. The HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA HER3-specific affibody molecules were labeled with indium-111 (111In) and assessed in vitro and in vivo for imaging properties using single photon emission computed tomography (SPECT). Labeling of HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA with 111In provided stable conjugates. In vitro cell tests demonstrated specific binding of the two conjugates to HER3-expressing BT-474 breast carcinoma cells. In mice bearing BT 474 xenografts, the tumor uptake of the two conjugates was receptor-specific. Direct in vivo comparison of 111In-HEHEHE-Z08698-NOTA and 111In-HEHEHE-Z08699 NOTA demonstrated that the two conjugates provided equal radioactivity uptake in tumors, although the tumor-to-blood ratio was improved for 111In-HEHEHE-Z08698 NOTA [12 +/- 3 vs. 8 +/- 1, 4 h post injection (p.i.)] due to more efficient blood clearance. 111In-HEHEHE-Z08698-NOTA is a promising candidate for imaging of HER3-expression in malignant tumors using SPECT. Results of the present study indicate that this conjugate could be used for patient stratification for anti HER3 therapy. PMID- 26059264 TI - Feasibility and impact of implementing a private care system's diabetes quality improvement intervention in the safety net: a cluster-randomized trial. AB - BACKGROUND: Integrated health care delivery systems devote considerable resources to developing quality improvement (QI) interventions. Clinics serving vulnerable populations rarely have the resources for such development but might benefit greatly from implementing approaches shown to be effective in other settings. Little trial-based research has assessed the feasibility and impact of such cross setting translation and implementation in community health centers (CHCs). We hypothesized that it would be feasible to implement successful QI interventions from integrated care settings in CHCs and would positively impact the CHCs. METHODS: We adapted Kaiser Permanente's successful intervention, which targets guideline-based cardioprotective prescribing for patients with diabetes mellitus (DM), through an iterative, stakeholder-driven process. We then conducted a cluster-randomized pragmatic trial in 11 CHCs in a staggered process with six "early" CHCs implementing the intervention one year before five "'late" CHCs. We measured monthly rates of patients with DM currently prescribed angiotensin converting enzyme (ACE)-inhibitors/statins, if clinically indicated. Through segmented regression analysis, we evaluated the intervention's effects in June 2011-May 2013. Participants included ~6500 adult CHC patients with DM who were indicated for statins/ACE-inhibitors per national guidelines. RESULTS: Implementation of the intervention in the CHCs was feasible, with setting specific adaptations. One year post-implementation, in the early clinics, there were estimated relative increases in guideline-concordant prescribing of 37.6 % (95 % confidence interval (CI); 29.0-46.2 %) among patients indicated for both ACE-inhibitors and statins and 38.7 % (95 % CI; 23.2-54.2 %) among patients indicated for statins. No such increases were seen in the late (control) clinics in that period. CONCLUSIONS: To our knowledge, this was the first clinical trial testing the translation and implementation of a successful QI initiative from a private, integrated care setting into CHCs. This proved feasible and had significant impact but required considerable adaptation and implementation support. These results suggest the feasibility of adapting diverse strategies developed in integrated care settings for implementation in under-resourced clinics, with important implications for efficiently improving care quality in such settings. CLINICALTRIALS.gov: NCT02299791 . PMID- 26059266 TI - Human bocavirus in acute gastroenteritis in children in Brazil. AB - Epidemiological surveillance for Human Bocavirus (HBoV) was conducted on 105 fecal specimens from children with acute gastroenteritis in Bahia, Brazil. Among of a total 105 stool samples, 44 samples were positive for HBoV as detected by nested-PCR. Of the 44 positive samples, co-infections with other enteric viruses (Norovirus, Adenovirus, and Rotavirus) were found in 12 pediatric patients. Mixed infections among HBoV with Norovirus were frequently observed in this population. The phylogenetic analysis identified the presence of HBoV-1, and HBoV 2A species. This study shows that HBoV is another viral pathogen in the etiology of acute gastroenteritis in children in Bahia, Brazil. PMID- 26059267 TI - Relapses from acute malnutrition and related factors in a community-based management programme in Burkina Faso. AB - Community-based management of acute malnutrition (CMAM) is effective in treating acute malnutrition. However, post-discharge follow-up often lacks. We aimed at assessing the relapse rate and the associated factors in a CMAM programme in Burkina Faso. Discharged children from the community nutrition centre were requested to return at least every 3 months for follow-up. The data of recovered children (weight-for-height z-score >=-2) who were discharged between July 2010 and June 2011 were collected in 45 villages, randomly selected out of 210 in January 2012. Sociodemographic data, economic variables, information on household food availability and the child's food consumption in the last 24 h were collected from the parents. A multivariate Cox proportional hazards regression was used to identify the factors associated to relapse. Of the 637 children, 14 (2.2%) died and 218 (34.2%) were lost to follow-up. The relapse rate [95% confidence interval] among the children who returned for follow-up was 15.4 [11.8 19.0] per 100 children-years. The associated factors to relapses in multivariate Cox regression model were mid-upper arm circumference (MUAC) at discharge below 125 mm, no oil/fat consumption during the last 24 h and incomplete vaccination. To limit relapses, CMAM programmes should avoid premature discharge before a MUAC of at least 125 mm. Nutrition education should emphasize fat/oil as inexpensive energy source for children. Promoting immunization is essential to promote child growth. Periodic monitoring of discharged children should be organized to detect earlier those who are at risk of relapse. The relapse rate should be a CMAM effectiveness indicator. PMID- 26059268 TI - The MRI features of placental adhesion disorder and their diagnostic significance: systematic review. AB - AIM: To identify the most frequently used MRI features in the diagnosis of placenta adhesion disorder (PAD) in the antenatal period and their significance. MATERIALS AND METHODS: The online databases Medline via PubMed and Ovid, Google Scholar, and Scopus were searched using the keywords and subject headings MRI*, magnetic resonance imaging*, prenatal diagnosis and placenta accreta*, morbidly adherent placenta* or placenta. Cases where MRI was carried out at/after 20 weeks gestation with detailed information available in relation to criteria and sequences used were included in the review. Exclusion criteria were case report study and studies that used intravenous contrast agents. Information regards sensitivity and specificity for each feature was taken, or calculated where possible, from the papers. Any new features were identified. The overall contribution of each feature to the diagnostic process was noted. RESULTS: Six hundred and fourteen potentially relevant articles were identified of which only 11 met the inclusion criteria. The commonest MRI criteria used were T2 dark intraplacental bands, heterogeneity of placenta, abnormal uterine bulging, and disruption of the uteroplacental zone. A newly described criterion is disorganised vasculature of placenta. MRI sensitivity and specificity varied between 75-100% and 65-100% respectively. CONCLUSION: MRI diagnosis of PAD relies on unstandardised criteria of diagnosis that enable systematic image interpretation of invasion status in all studies and enable the reproducibility. However, it is still has a high diagnostic accuracy and frequently aids in surgical planning, emphasising its value in supporting ultrasound. Most studies are of a small sample size. Additional multicentre studies are recommended to enhance the generalisability of the findings and asses the value of the newly described criteria. PMID- 26059269 TI - Retrospective preoperative assessment of the axillary lymph nodes in patients with breast cancer and literature review. AB - AIM: To evaluate the accuracy of axillary ultrasound, compared with published literature, identify women at low risk for lymph node (LN) involvement, and to determine which clinical, pathological, and imaging findings best predict LN involvement. MATERIAL AND METHODS: From June 2010 to April 2012, 288 women with breast lesions that were suspicious of malignancy (category 4) or malignant (category 5) underwent axillary ultrasound examination. A 3 mm LN cortical thickness was used as the threshold to prompt fine-needle aspiration biopsy (FNAB) of the LN. Data were gathered regarding size, site, and grade of the index breast lesion and cortical thickness of the LN. RESULTS: Using a cut-off point of <3 mm versus >=3 mm, abnormal cortical thickness had a sensitivity and specificity of 56.3% and 86.7%, respectively. Breast cancer size was significantly associated with the odds of LN metastasis (p<0.001). There were 69 patients with breast cancers of <=10 mm and 18% had positive axillary LNs. A much higher rate of malignancy was observed in breast cancers located in multiple sites and in a central location. CONCLUSION: The likelihood of axillary LN metastasis increases with cortical thickness >=3 mm and this concurs with the literature. A low-risk group of women was identified with screen-detected, low grade small cancers with LNs with a cortical thickness of <3 mm. Additional features other than cortical thickness >3 mm (such as shape [rounding], echogenicity [markedly hypo-echoic cortex], and morphology [hilar compressional displacement, loss of echogenic outer capsule and angular margins]) should be used to indicate FNAB in patients with a palpable lump, multiple or central cancers, and cancers >20 mm. PMID- 26059270 TI - Collateral circulation via the circle of Willis in patients with carotid artery steno-occlusive disease: evaluation on 3-T 4D MRA using arterial spin labelling. AB - AIM: To evaluate whether 3-T four-dimensional (4D) arterial spin-labelling (ASL) based magnetic resonance angiography (MRA) is useful for assessing the collateral circulation via the circle of Willis in patients with carotid artery steno occlusive disease. MATERIALS AND METHODS: Institutional review board approval and prior written informed consent from all patients were obtained. The inclusion criteria were fulfilled by 13 patients with carotid artery steno-occlusive disease. All underwent 4D-ASL MRA at 3 T and digital subtraction angiography (DSA). The flow-sensitive alternating inversion recovery (FAIR) preparation scheme with look-locker sampling was used for spin labeling. At 300-ms intervals seven dynamic scans were obtained with a spatial resolution of 0.5*0.5*0.6 mm(3). The collateral flow via the circle of Willis was read on 4D-ASL MRA and DSA images by two sets of two independent readers each. kappa statistics were used to assess interobserver and intermodality agreement. RESULTS: On DSA, collateral flow via the anterior communicating artery (AcomA) was observed in six patients, via the posterior communicating artery (PcomA) in four patients, and via both the AcomA and PcomA in three patients. With respect to the qualitative evaluation of 4D-ASL MRA images, interobserver agreement was excellent for all items (kappa=1). 4D-ASL MRA and DSA consensus readings agreed on the type of collateral flow pattern in 10 of the 13 patients (77%). Intermodality agreement was good (kappa=0.606; 95% confidence interval (CI): 0.215-0.997). CONCLUSION: 3 T 4D-ASL MRA may be a useful tool for the evaluation of the collateral circulation in patients with carotid artery steno-occlusive disease. PMID- 26059271 TI - The Effect of a Novel form of Extended-Release Gabapentin on Pain and Sleep in Fibromyalgia Subjects: An Open-Label Pilot Study. AB - INTRODUCTION: We assessed the efficacy and safety of extended-release gabapentin in a 15-week, open-label, single-arm, single-center study in patients with fibromyalgia (FM). METHODS: Subjects with documented diagnosis of FM were allowed to participate in the study. We opened enrollment to those who have tried and failed gabapentinoids such as gabapentin or pregabalin due to side effects. Subjects with autoimmune conditions, and or taking opioids for management of their FM pain, were excluded from the study. Subjects were given an extended release gabapentin starter pack and treated for total of 12 weeks. The primary study endpoint of pain relief was measured using Numeric Pain Rating System (NPRS) scores, and secondary study endpoints were measured with Fibromyalgia Impact Questionnaire (FIQ), Patient's Global Impression of Change (PGIC), and Medical Outcome Sleep questionnaires (MOS). RESULTS: A total of 34 subjects were enrolled and 29 subjects completed the starter pack (85%). Patients reported significant pain relief on NPRS by end of 4 weeks (P < 0.0001) on NPRS. Subjects also reported similar magnitude of improvements in FM and its impact on daily life by end of 4 weeks on FIQ (P < 0.0001). Survey of MOS showed our subjects reporting improved sleep quantity (on average, 1.2 hours over baseline) with gradual and statistically significant improvement in quality. Improvements in primary and secondary measurements were reflected in PGIC, with significant improvement in patient's impression of FM by week 8. LIMITATIONS: Small sample size, geographical bias, relatively short duration of treatment, and single-arm study without control group. CONCLUSIONS: Extended-release gabapentin relieved FM pain symptoms and improved quality-of-life for the FM subjects studied. Subjects reported improvements in both quantity and quality of sleep. PMID- 26059273 TI - Methods for treating IL-6-related diseases (US2015010554A1): a patent evaluation. AB - INTRODUCTION: IL-6 is involved in a variety of diseases such as acute or chronic inflammation and autoimmune diseases, and the modulation of IL-6 level is recognized as an important target. Therefore, the blocking agent of IL-6 receptor (IL-6R), particularly anti-IL-6R antibody, was invented and its clinical efficacy was well resolved. However, it has not been shown that synergistic effects can be achieved by the combination of anti-IL-6R antibody with immunosuppressants. AREAS COVERED: This patent assessed the possible use of anti-IL-6R antibody (tocilizumab) plus methotrexate (MTX) for the treatment of acute or chronic inflammatory diseases and autoimmune diseases including nephritis, Crohn's disease, ulcerative colitis, pancreatitis, juvenile idiopathic arthritis, rheumatoid arthritis, and psoriasis. A large Phase II trial of tocilizumab to determine the optimum dose of tocilizumab alone and in combination with MTX for the treatment of rheumatoid arthritis was carried out and its result was analyzed. In conclusion, the combination use of tocilizumab plus MTX was confirmed as clinically effective and safe for the treatment of rheumatoid arthritis whereas substantial evidence regarding superiority to tocilizumab monotherapy is still lacking. EXPERT OPINION: To prove synergistic effect or enhancement of tocilizumab plus MTX therapy, more diverse diseases related to IL 6 and tocilizumab therapy, not limited to rheumatoid arthritis, have to be evaluated, along with its safety. PMID- 26059272 TI - Identification of a critical determinant that enables efficient fatty acid synthesis in oleaginous fungi. AB - Microorganisms are valuable resources for lipid production. What makes one microbe but not the other able to efficiently synthesize and accumulate lipids is poorly understood. In the present study, global gene expression prior to and after the onset of lipogenesis was determined by transcriptomics using the oleaginous fungus Mortierella alpina as a model system. A core of 23 lipogenesis associated genes was identified and their expression patterns shared a high similarity among oleaginous microbes Chlamydomonas reinhardtii, Mucor circinelloides and Rhizopus oryzae but was dissimilar to the non-oleaginous Aspergillus nidulans. Unexpectedly, Glucose-6-phosphate dehydrogenase (G6PD) and 6-phosphogluconate dehydrogenase (PGD) in the pentose phosphate pathway (PPP) were found to be the NADPH producers responding to lipogenesis in the oleaginous microbes. Their role in lipogenesis was confirmed by a knockdown experiment. Our results demonstrate, for the first time, that the PPP plays a significant role during fungal lipogenesis. Up-regulation of NADPH production by the PPP, especially G6PD, may be one of the critical determinants that enables efficiently fatty acid synthesis in oleaginous microbes. PMID- 26059274 TI - Non-small cell lung cancer recurrence following surgery and perioperative chemotherapy: Comparison of two chemotherapy regimens (IFCT-0702: A randomized phase 3 final results study). AB - INTRODUCTION: This study compared the efficacy of docetaxel alone vs. docetaxel plus cisplatin/carboplatin in resected NSCLC patients relapsing after preoperative, adjuvant, or perioperative platinum-based chemotherapy. MATERIALS AND METHODS: Patients were randomly assigned to receive docetaxel plus cisplatin/carboplatin (Arm A) or docetaxel alone (Arm B). Primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate at 6 weeks, toxicity, quality of life, and overall survival (OS). RESULTS: From November 2007 to August 2012, 88 patients were enrolled. Due to an unexpectedly slow accrual, the trial was prematurely stopped. Adding platinum to docetaxel caused a non-significant increase in PFS. Median PFS was 8.0 months (95% CI: 5.3 10.4) for Arm A vs. 5.6 months (95% CI: 4.0-7.3) for Arm B (HR: 0.71, 95% CI: 0.45-1.1, p=0.15). Median OS was 16.0 months (95% CI: 10.1-23.9) for Arm A vs. 12.4 months (95% CI: 8.2-19.6) for Arm B. In pre-planned subgroup analyses, a time to recurrence >=12 months and non-squamous histology favorably influenced OS (HR: 0.51, 95% CI: 0.29-0.91, p=0.02 and HR: 0.54, 95% CI: 0.33-0.91, p=0.02, respectively). There were no unexpected adverse events, and Grade 3-4 toxicity was comparable in both groups. CONCLUSIONS: Our study failed to demonstrate significant PFS improvement with the docetaxel-platinum doublet compared to single-agent docetaxel. The 3.6-month improvement in OS with the cisplatin-based doublet proves, however, appealing and merits further investigation. PMID- 26059276 TI - SNP microarray abnormalities in a cohort of 28 infants with congenital diaphragmatic hernia. AB - Chromosomal abnormalities are an important factor in the pathogenesis of congenital diaphragmatic hernia (CDH), a relatively common congenital defect associated with high morbidity and mortality. The adoption of array-based platforms for chromosome analysis has resulted in the identification of numerous copy number variants (CNVs) in infants with CDH, highlighting the potential pathogenic role of many novel genes. We identified a retrospective cohort of 28 infants treated for CDH at a single institution who had microarray testing to determine the proportion of microarray abnormalities and whether these were contributory to CDH pathogenesis. Eight patients (29%) had microarray abnormality. Seven (25%) were considered likely contributory to CDH pathogenesis, including two mosaic trisomy 9s, a 9q22.31q22.32 microduplication, two atypical 22q11.21 microdeletions, a 2q35q36.1 microdeletion, and a 15q11.2 microdeletion, offering insights into the genetic mechanisms underlying CDH development. PMID- 26059275 TI - Disease reclassification risk with stringent criteria and frequent monitoring in men with favourable-risk prostate cancer undergoing active surveillance. AB - OBJECTIVES: To determine the frequency of disease reclassification and to identify clinicopathological variables associated with it in patients with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We assessed 191 men, selected by what may be the most stringent criteria used in AS studies yet conducted, who were enrolled in a prospective cohort AS trial. Clinicopathological characteristics were analysed in a multivariate Cox proportional hazards regression model. Key features were an extended biopsy with a single core positive for Gleason score (GS) 3 + 3 (<3 mm) or 3 + 4 (<2 mm) and a prostate-specific antigen (PSA) level <4 ng/mL (adjusted for prostate volume). Biopsies were repeated every 1-2 years and clinical evaluations every 6 months. Disease was reclassified when PSA level increased by 30% from baseline, or when biopsy tumour length increased beyond the enrolment criteria, more than one positive core was detected or any grade increased to a dominant 4 pattern or any 5 pattern. RESULTS: Disease was reclassified in 32 patients (16.8%) including upgrading to GS 4 + 3 in five patients (2.6%). The median (interquartile range) follow-up time among survivors was 3 (1.9-4.6) years. Overall, 13 of the 32 (40.6%) had incremental increases in GS. Tumour length (hazard ratio 2.95, 95% confidence interval [CI] 1.34-6.46; P = 0.007) and older age (hazard ratio 1.05, 95% CI 1.00-1.09; P = 0.05) were identified as significant and marginally significant predictors of disease reclassification, respectively. Disease remained stable in 83.2% of patients. CONCLUSION: The need persists for improvements in risk stratification and predictive indicators of cancer progression. PMID- 26059277 TI - Compression asphyxia from a human pyramid. AB - In compression asphyxia, respiration is stopped by external forces on the body. It is usually due to an external force compressing the trunk such as a heavy weight on the chest or abdomen and is associated with internal injuries. In present case, the victim was trapped and crushed under the falling persons from a human pyramid formation for a "Dahi Handi" festival. There was neither any severe blunt force injury nor any significant pathological natural disease contributing to the cause of death. The victim was unable to remove himself from the situation because his cognitive responses and coordination were impaired due to alcohol intake. The victim died from asphyxia due to compression of his chest and abdomen. Compression asphyxia resulting from the collapse of a human pyramid and the dynamics of its impact force in these circumstances is very rare and is not reported previously to the best of our knowledge. PMID- 26059278 TI - Making reasonable decisions: a qualitative study of medical decision making in the care of patients with a clinically significant haemoglobin disorder. AB - RATIONALE, AIMS AND OBJECTIVES: Therapies utilized in patients with clinically significant haemoglobin disorders appear to vary between clinicians and units. This study aimed to investigate the processes of evidence implementation and medical decision making in the care of such patients in NSW, Australia. METHODS: Using semi-structured interviews, 11 haematologists discussed their medical decision-making processes with particular attention paid to the use of published evidence. Transcripts were thematically analysed by a single investigator on a line-by-line basis. RESULTS: Decision making surrounding the care of patients with significant haemoglobin disorders varied and was deeply contextual. Three main determinants of clinical decision making were identified - factors relating to the patient and to their illness, factors specific to the clinician and the institution in which they were practising and factors related to the notion of evidence and to utility and role of evidence-based medicine in clinical practice. CONCLUSIONS: Clinicians pay considerable attention to medical decision making and evidence incorporation and attempt to tailor these to particular patient contexts. However, the patient context is often inferred and when discordant with the clinician's own contexture can lead to discomfort with decision recommendations. Clinicians strive to improve comfort through the use of experience and trustworthy evidence. PMID- 26059280 TI - Retraction: Characterization of cellulolytic activities of newly isolated Thelephora sowerbyi from North-Western Himalayas on different lignocellulosic substrates. AB - Characterization of cellulolytic activities of newly isolated Thelephora sowerbyi from North-Western Himalayas on different lignocellulosic substrate J. Basic Microbiol. 2015, 55, 1-11 - DOI: 10.1002/jobm.201500107 The above article from the Journal of Basic Microbiology, published online on 08 June 2015 in Wiley Online Library as Early View (http://onlinelibrary.wiley.com/doi/10.1002/jobm.201500107/pdf), has been retracted by agreement between the authors, the Editor-in-Chief and Wiley-VCH GmbH & Co. KGaA. The retraction has been agreed because the microorganism studied in the described experiments has been identified as the fungus Cotylidia pannosa (Gene Accession No. KT008117) instead of Thelephora sowerbyi. The culture has been identified on the basis of the sequence of the amplified ITS region of the microorganism which was submitted by the authors to the NCBI database. PMID- 26059279 TI - Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies? AB - Several age-associated changes in natural killer (NK) cell phenotype have been reported that contribute to the defective NK cell response observed in elderly patients. A remodelling of the NK cell compartment occurs in the elderly with a reduction in the output of immature CD56(bright) cells and an accumulation of highly differentiated CD56(dim) NK cells. Acute myeloid leukaemia (AML) is generally a disease of older adults. NK cells in AML patients show diminished expression of several activating receptors that contribute to impaired NK cell function and, in consequence, to AML blast escape from NK cell immunosurveillance. In AML patients, phenotypic changes in NK cells have been correlated with disease progression and survival. NK cell-based immunotherapy has emerged as a possibility for the treatment of AML patients. The understanding of age-associated alterations in NK cells is therefore necessary to define adequate therapeutic strategies in older AML patients. PMID- 26059282 TI - Erratum. PMID- 26059281 TI - 16th Pacific Rim College of Psychiatrists Scientific Meeting, October 5 - 7, 2014, Vancouver, Canada. PMID- 26059283 TI - Pyrimidine and s-triazine as structural motifs for ordered adsorption on Si(100): a first principles study. AB - The chemisorption of pyrimidine and s-triazine, two aromatic molecules with N atoms in the aromatic ring, is studied by first principles calculations to examine not only the chemisorption energy, but also the reaction barriers and the cooperative effects. Among the reaction paths at low coverage, the formation of a cross-bridge structure with two N-Si dative bonds is almost barrierless and should be dominant at low temperature. At higher coverage and low temperature, these cross-row structures should produce an ordered zig-zag pattern, even though it is not the energetically most stable arrangement. Upon heating, the zig-zag pattern could be transformed into lines along dimer rows. These two molecules also provide structural motifs that could facilitate the formation of ordered adsorption structures on Si(100). By symmetry, the complexity of tight-bridge structures could be greatly reduced, while the X-C-X motif, with X being an electronegative atom, could provide the building blocks for cross-row bridges. PMID- 26059284 TI - Vitamin D status and health-related quality of life in patients with Type 2 diabetes. AB - AIMS: To test whether vitamin D status was associated with health-related quality of life in people with Type 2 diabetes mellitus. METHODS: Demographic and clinical characteristics, including health-related quality of life scores, were obtained from 241 adult patients with Type 2 diabetes managed with oral hypoglycaemic agents. Health-related quality of life was assessed using the Short Form 36 Health Survey. Multiple logistic regression analysis was used to investigate the association between vitamin D status and health-related quality of life, with adjustment for confounders. RESULTS: The mean age of the patients included in the study was 67 +/- 8 years. Their mean HbA1c concentration was 52 +/- 8 mmol/mol (6.9 +/- 0.7%) and their mean serum 25-hydroxyvitamin D concentration was 59 +/- 23 nmol/l. Vitamin D deficiency (serum 25-hydroxyvitamin D < 50 nmol/l) was present in 38% of patients. No significant associations were found between vitamin D status and health-related quality of life. CONCLUSIONS: Vitamin D status was not associated with health-related quality of life in patients with Type 2 diabetes. This could be explained by the relatively high serum 25-hydroxyvitamin D concentration, good glycaemic control and relatively good health-related quality of life of all patients. A prospective study among patients with vitamin D deficiency and poor glycaemic control would be interesting for future research. PMID- 26059285 TI - An Insight into Different Stabilization Mechanisms of Phenytoin Derivatives Supersaturation by HPMC and PVP. AB - In this study, we examined the stabilization mechanism of drug supersaturation by hypromellose (HPMC) and polyvinylpirrolidone (PVP). The poorly water-soluble drugs, phenytoin (diphenylhydantoin, DPH), and its synthesized derivatives monomethylphenytoin (MDPH) and dimethylphenytoin (DMDPH) were used. DPH supersaturation was efficiently maintained by both HPMC and PVP. HPMC maintained the supersaturation of MDPH and DMDPH in a similar manner to that of DPH, whereas the ability of PVP to maintain drug supersaturation increased as follows: DPH > MDPH > DMDPH. Caco-2 permeation studies and nuclear magnetic resonance measurements revealed that the permeability and molecular state of the drug in a HPMC solution barely changed. In fact, the solubilization of the drug into PVP changed its apparent permeability and molecular state. The drug solubilization efficiency by PVP was higher and followed the order: DPH > MDPH > DMDPH. The different drug solubilization efficiencies most likely result from the different strengths in the intermolecular interaction between the DPH derivatives and PVP. The difference in the stabilization mechanism of drug supersaturation by HPMC and PVP could determine whether the efficient maintenance of the drug supersaturation was dependent on the drug species. PMID- 26059286 TI - Inflammatory Cytokines Contribute to Asbestos-Induced Injury of Mesothelial Cells. AB - BACKGROUND: Several diseases have been related to asbestos exposure, including the pleural tumor mesothelioma. The mechanism of pleural injury by asbestos fibers is not yet fully understood. The inflammatory response with release of mediators leading to a dysregulation of apoptosis may play a pivotal role in the pathophysiology of asbestos-induced pleural disease. OBJECTIVE: To determine whether pro-inflammatory cytokines produced by asbestos-exposed pleural mesothelial cells modify the injury induced by the asbestos. METHODS: Mouse pleural mesothelial cells (PMC) were exposed to crocidolite or chrysotile asbestos fibers (3.0 MUg/cm(2)) for 4, 24, or 48 h and assessed for viability, necrosis and apoptosis, and the production of cytokines IL-1beta, IL-6 and macrophage inflammatory protein-2 (MIP-2). Cells exposed to fibers were also treated with antibodies anti-IL-1beta, anti-IL-6, anti- IL-1beta+anti-IL-6 or anti-MIP-2 or their irrelevant isotypes, and assessed for apoptosis and necrosis. Non-exposed cells and cells treated with wollastonite, an inert particle, were used as controls. RESULTS: Mesothelial cells exposed to either crocidolite or chrysotile underwent both apoptosis and necrosis and released cytokines IL-1beta, IL-6 and MIP-2. In the crocidolite group, apoptosis and the levels of all cytokines were higher than in the chrysotile group, at comparable concentrations. Neutralization of IL-1beta andIL-6, but not MIP-2, inhibited apoptosis and necrosis, especially in the cells exposed to crocidolite fibers. CONCLUSIONS: Both crocidolite and chrysotile asbestos fibers induced apoptosis and produced an acute inflammatory response characterized by elevated levels of IL-1beta, IL-6 and MIP-2 in cultured mouse PMC. IL-1beta and IL-6, but not MIP-2, were shown to contribute to asbestos-induced injury, especially in the crocidolite group. PMID- 26059287 TI - HPLC-MS/MS analysis of steroid hormones in environmental water samples. AB - Today, freshwaters, such as lakes and rivers, are subject to controlled pollution. Steroid hormones are chemically very stable highly lipophilic molecules. Their biological properties have a strong impact on the endocrine regulation of species. Steroids have estrogenic, androgenic, thyroidogenic or progestogenic effects and based on them, they could disturb the physiological mechanisms of freshwater species. We focused on progestins as they are the main active ingredients of contraceptive pharmaceuticals. Progestins have been shown to impair reproduction in fish, amphibians, and mollusks at low ng/L concentrations. Certain progestins, such as levonorgestrel (LNG) have androgenic properties also. We selected the most used active substances drospirenone (DRO), LNG, and progesterone (PRG) and then developed and optimized a liquid chromatographic-mass spectrometric method with solid-phase extraction to measure them. Using our sensitive method (LOQ 0.03-0.11 ng/L) we could measure steroids even between 0.1 and 1 ng/L. Analyzing freshwater samples from the Lake Balaton catchment area, we found influents where the concentration of these hormones was 0.26-4.30 (DRO), 0.85-3.40 (LNG), and 0.23-13.67 (PRG) ng/L. Out of 53 collecting places, 21 contained measurable progestin levels, which clearly demonstrates the applicability of our method, legitimates toxicology experiments with effected species, and indicates monitoring efforts. PMID- 26059288 TI - Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir: A Review in Chronic HCV Genotype 1 Infection. AB - A fixed-dose tablet comprising ombitasvir (an NS5A replication complex inhibitor), paritaprevir (an NS3/4A protease inhibitor) and ritonavir (a cytochrome P450 inhibitor) taken in combination with dasabuvir (an NS5B polymerase inhibitor) is indicated for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection in several countries, including the USA (copackaged as Viekira Pak(TM)) and those of the EU (Viekirax((r)) and Exviera((r))). In phase II and III trials, this interferon-free regimen, taken +/- ribavirin, provided high rates of sustained virological response 12 weeks post-treatment in adults with chronic HCV genotype 1a or 1b infection, including those with compensated cirrhosis, liver transplants or HIV-1 co-infection. The regimen was generally well tolerated, with nausea, insomnia, asthenia, pruritus, other skin reactions and fatigue being among the most common tolerability issues. Thus, ombitasvir/paritaprevir/ritonavir plus dasabuvir is an effective interferon-free, direct-acting antiviral regimen for use +/- ribavirin in a broad range of adults chronically infected with HCV genotype 1. PMID- 26059290 TI - [Global health, a new concept? Some teachings about Ebola virus epidemics]. PMID- 26059291 TI - [The HER3/ERBB3 receptor: the dark side of the ERBB planet]. PMID- 26059292 TI - [From fly to man: RACK1, an essential actor of the dependent viral translation of IRES]. PMID- 26059289 TI - Therapeutic Use of Metformin in Prediabetes and Diabetes Prevention. AB - People with elevated, non-diabetic, levels of blood glucose are at risk of progressing to clinical type 2 diabetes and are commonly termed 'prediabetic'. The term prediabetes usually refers to high-normal fasting plasma glucose (impaired fasting glucose) and/or plasma glucose 2 h following a 75 g oral glucose tolerance test (impaired glucose tolerance). Current US guidelines consider high-normal HbA1c to also represent a prediabetic state. Individuals with prediabetic levels of dysglycaemia are already at elevated risk of damage to the microvasculature and macrovasculature, resembling the long-term complications of diabetes. Halting or reversing the progressive decline in insulin sensitivity and beta-cell function holds the key to achieving prevention of type 2 diabetes in at-risk subjects. Lifestyle interventions aimed at inducing weight loss, pharmacologic treatments (metformin, thiazolidinediones, acarbose, basal insulin and drugs for weight loss) and bariatric surgery have all been shown to reduce the risk of progression to type 2 diabetes in prediabetic subjects. However, lifestyle interventions are difficult for patients to maintain and the weight loss achieved tends to be regained over time. Metformin enhances the action of insulin in liver and skeletal muscle, and its efficacy for delaying or preventing the onset of diabetes has been proven in large, well-designed, randomised trials, such as the Diabetes Prevention Program and other studies. Decades of clinical use have demonstrated that metformin is generally well-tolerated and safe. We have reviewed in detail the evidence base supporting the therapeutic use of metformin for diabetes prevention. PMID- 26059294 TI - [The last surge of dying cells, a key stage during the tissular morphogenesis]. PMID- 26059293 TI - [Impact of VEGF-A in exhaustion of intratumoral T cells]. PMID- 26059295 TI - [Hell after the pleasure: drug-induced negative symptoms involve lateral habenula]. PMID- 26059296 TI - [Discovery of Toddler/Elabela ligand and the double life of the apelin receptor]. PMID- 26059297 TI - [Clinical consequences of immunosenescence in chronic kidney diseases]. PMID- 26059298 TI - [View of the inside: genetic circuits for the analysis of intracellular molecular profiles]. PMID- 26059299 TI - [Chemerin: a pro-inflammatory adipokine involved in the reproduction function?]. AB - Chemerin is a pro-inflammatory adipokine secreted and expressed predominantly by adipocytes. Chemerin is initially involved in the regulation of the immune system, the adipogenesis and the energy metabolism. However, several recent studies show that this adipokine and its receptors are present in the gonads. In vitro, chemerin reduces steroidogenesis in ovarian and testicular cells in rodents and humans. Chemerin and its receptors are also present in the placenta. Chemerin plays an important role in the regulation of fetal and maternal metabolism, fetal growth and metabolic homeostasis during pregnancy. This review describes the role of chemerin in metabolism and reproduction. PMID- 26059301 TI - [Herpes simplex virus type 1 latency and reactivation: an update]. AB - Following primary infections HSV-1 replicates productively in epithelial cells and enters sensory neurons via nerve termini. After retrograde transport the virus genome is delivered into the cell nucleus, where it establishes lifelong latent infections. During latency, the virus genome remains as a chromatinized episome expressing only a set of latency-associated transcripts (LAT) and a group of microRNAs that inhibit expression of key lytic viral functions. Periodically the virus can reactivate to reinitiate lytic, secondary infections at peripheral tissues. The ability to establish both lytic and latent infections relies on the coexistence in the virus genome of two alternative gene expression programs, under the control of epigenetic mechanisms. Latency is an adaptive phenotype that allows the virus to escape immune host responses and to reactivate and disseminate to other hosts upon recognizing danger signals such as stress, neurologic trauma or growth factor deprivation. PMID- 26059300 TI - [Galectins, a class of unconventional lectins]. AB - Galectins constitute a family of soluble animal lectins defined by their evolutionary conserved carbohydrate recognition domain and their affinity for beta-galactosides containing glycoconjugates. Each galectin is characterized by a specific spatio-temporal distribution and a unique set of ligands and molecular partners. Interestingly, galectins are found both extracellularly and intracellularly and modulate various cellular processes. Knock-out mutant mice for galectins-1, 3 or 7 are viable but display a wide range of defects under various stress conditions. Indeed, galectins are multifunctional proteins involved in cell-cell and cell-extracellular matrix interactions, organization of membrane domains, cell signalling and also in intracellular trafficking, apoptosis, regulation of cell cycle. Galectins represent potential therapeutic targets, especially in the context of cancer and inflammatory diseases. PMID- 26059302 TI - [Enamel: a unique self-assembling in mineral world]. AB - Enamel is a unique tissue in vertebrates, acellular, formed on a labile scaffolding matrix and hypermineralized. The ameloblasts are epithelial cells in charge of amelogenesis. They secrete a number of matrix proteins degraded by enzymes during enamel mineralization. This ordered cellular and extracellular events imply that any genetic or environmental perturbation will produce indelible and recognizable defects. The specificity of defects will indicate the affected cellular process. Thus, depending on the specificity of alterations, the teratogenic event can be retrospectively established. Advances in the field allow to use enamel defects as diagnostic tools for molecular disorders. The multifunctionality of enamel peptides is presently identified from their chemical roles in mineralization to cell signaling, constituting a source of concrete innovations in regenerative medicine. PMID- 26059303 TI - [Atomic force microscopy: a tool to analyze the viral cycle]. AB - Each step of the HIV-1 life cycle frequently involves a change in the morphology and/or mechanical properties of the viral particle or core. The atomic force microscope (AFM) constitutes a powerful tool for characterizing these physical changes at the scale of a single virus. Indeed, AFM enables the visualization of viral capsids in a controlled physiological environment and to probe their mechanical properties by nano-indentation. Finally, AFM force spectroscopy allows to characterize the affinities between viral envelope proteins and cell receptors at the single molecule level. PMID- 26059304 TI - [Developments in gene delivery vectors for ocular gene therapy]. AB - Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Its remarkable success in safety and efficacy, in clinical trials for Leber's congenital amaurosis (LCA) type II generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was mainly due to the favorable characteristics of the retina as a target organ. The eye offers several advantages as it is readily accessible and has some degree of immune privilege making it suitable for application of viral vectors. The viral vectors most frequently used for retinal gene delivery are lentivirus, adenovirus and adeno-associated virus (AAV). Here we will discuss the use of these viral vectors in retinal gene delivery with a strong focus on favorable properties of AAV. Thanks to its small size, AAV diffuses well in the inter-neural matrix making it suitable for applications in neural retina. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases using AAV as a vector. This article will discuss what are some of the most imminent cellular targets for such therapies and the AAV toolkit that has been built to target these cells successfully. We will also discuss some of the challenges that we face in translating AAV-based gene therapies to the clinic. PMID- 26059305 TI - [Screening marine resources to find novel chemical inhibitors of disease-relevant protein kinases]. AB - Since the early 1970's, investigators at Station Biologique de Roscoff (SBR), France, have been using marine organisms as models to describe molecular pathways conserved through evolution in mammalian cells (e.g. the cyclin-dependent kinases involved in the control of the cell division cycle). Some kinases are misregulated in various human pathologies, including cancers. Using a specialized screening approach, chemical libraries were analysed, using on-site facilities at Roscoff, in order to identify small chemical inhibitors of protein kinases. Eight chemical scaffolds produced by marine organisms were characterized as candidate drugs by our screening facility, some of which are being considered as chemical tools to pinpoint specific cellular functions of the targeted kinases. In this review, we describe our existing screening facilities and we discuss new perspectives related to marine bioprospecting. PMID- 26059306 TI - [Depression and addiction comorbidity: towards a common molecular target?]. AB - The comorbidity of depression and cocaine addiction suggests shared mechanisms and anatomical pathways. Specifically, the limbic structures, such as the nucleus accumbens (NAc), play a crucial role in both disorders. P11 (S100A10) is a promising target for manipulating depression and addiction in mice. We summarized the recent genetic and viral strategies used to determine how the titration of p11 levels within the NAc affects hedonic behavior and cocaine reward learning in mice. In particular, p11 in the ChAT+ cells or DRD1+ MSN of the NAc, controls depressive-like behavior or cocaine reward, respectively. Treatments to counter maladaptation of p11 levels in the NAc could provide novel therapeutic opportunities for depression and cocaine addiction in humans. PMID- 26059307 TI - [Hepatitis B vaccination: a review]. PMID- 26059308 TI - [Genetic diagnostic: to know or not to know?]. PMID- 26059309 TI - [Utterly unanticipated findings]. AB - There are now a number of cases in which non-invasive prenatal testing (NIPT) has detected signs of cancer in pregnant women. These unexpected findings raise a number of difficult questions regarding their communication to the patient as well as the wording of informed consent forms. PMID- 26059310 TI - The Continuity of Metaphor: Evidence From Temporal Gestures. AB - Reasoning about bedrock abstract concepts such as time, number, and valence relies on spatial metaphor and often on multiple spatial metaphors for a single concept. Previous research has documented, for instance, both future-in-front and future-to-right metaphors for time in English speakers. It is often assumed that these metaphors, which appear to have distinct experiential bases, remain distinct in online temporal reasoning. In two studies we demonstrate that, contra this assumption, people systematically combine these metaphors. Evidence for this combination was found in both directly elicited (Study 1) and spontaneous co speech (Study 2) gestures about time. These results provide first support for the hypothesis that the metaphorical representation of time, and perhaps other abstract domains as well, involves the continuous co-activation of multiple metaphors rather than the selection of only one. PMID- 26059311 TI - Health-care costs of underweight, overweight and obesity: Australian population based study. AB - AIM: Child health varies with body mass index (BMI), but it is unknown by what age or how much this attracts additional population health-care costs. We aimed to determine the (1) cross-sectional relationships between BMI and costs across the first decade of life and (2) in longitudinal analyses, whether costs increase with duration of underweight or obesity. METHODS: PARTICIPANTS: Baby (n = 4230) and Kindergarten (n = 4543) cohorts in the nationally representative Longitudinal Study of Australian Children. OUTCOME: Medicare Benefits Scheme (including all general practitioner plus a large proportion of paediatrician visits) plus prescription medication costs to federal government from birth to sixth (Baby cohort) and fourth to tenth (Kindergarten cohort) birthdays. PREDICTOR: biennial BMI measurements over the same period. RESULTS: Among Australian children under 10 years of age, 5-6% were underweight, 11-18% overweight and 5-6% obese. Excess costs with low and high BMI became evident from age 4-5 years, with normal weight accruing the least, obesity the most, and underweight and overweight intermediate costs. Relative to overall between-child variation, these excess costs per child were very modest, with a maximum of $94 per year at age 4-5 years. Nonetheless, this projects to a substantial cost to government of approximately $13 million per annum for all Australian children aged less than 10 years. CONCLUSIONS: Substantial excess population costs provide further economic justification for promoting healthy body weight. However, obese children's low individual excess health-care costs mean that effective treatments are likely to increase short term costs to the public health purse during childhood. PMID- 26059312 TI - Effect of preoperative treatment strategies on the outcome of patients with clinical T3, non-metastasized rectal cancer: A comparison between Dutch and Canadian expert centers. AB - AIM: High-dose-rate brachytherapy (HDRBT) appears to be associated with less treatment-related toxicity compared with external beam radiotherapy in patients with rectal cancer. The present study compared the effect of preoperative treatment strategies on overall survival, cancer-specific deaths, and local recurrences between a Dutch and Canadian expert center with different preoperative treatment strategies. PATIENTS AND METHODS: We included 145 Dutch and 141 Canadian patients with cT3, non-metastasized rectal cancer. All patients from Canada were preoperatively treated with HDRBT. The preoperative treatment strategy for Dutch patients consisted of either no preoperative treatment, short course radiotherapy, or chemoradiotherapy. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CIs) comparing overall survival. We adjusted for age, cN stage, (y)pT stage, comorbidity, and type of surgery. Primary endpoint was overall survival. Secondary endpoints were cancer-specific deaths and local recurrences. RESULTS: Five-year overall survival was 70.9% (95% CI 62.6%-77.7%) in Dutch patients compared with 86.9% (80.1% 91.6%) in Canadian patients, resulting in an adjusted HR of 0.70 (95% CI 0.39 1.26; p = 0.233). Of 145 Dutch patients, 6.9% (95% CI 2.8%-11.0%) had a local recurrence and 17.9% (95% CI 11.7%-24.2%) patients died of rectal cancer, compared with 4.3% (95% CI 0.9%-7.5%) local recurrences and 10.6% (95% CI 5.5% 15.7%) rectal cancer deaths out of 141 Canadian patients. CONCLUSION: We did not detect statistically significant differences in overall survival between a Dutch and Canadian expert center with different treatment strategies. This finding needs to be further investigated in a randomized controlled trial. PMID- 26059313 TI - The effect of tensile and bending strain on the electrical properties of p-type <110> silicon nanowires. AB - In this study, electromechanical responses induced by uniaxial tensile and bending deformation were obtained for p-type <110>-oriented Si whiskers by in situ transmission electron microscopy (TEM). Ohmic contacts between the nanowires (NWs) and electrodes were achieved using electron-beam-induced carbon deposition. Results show that enhancements in the carrier transport properties were achieved under both uniaxial tensile and bending strains. With the strain increased to 1.5% before fracture, the improvement in the conductance reached a maximum, which was as large as 24.2%, without any sign of saturation. On the other hand, under 5.8% bending strain, a 67% conductivity enhancement could be achieved. This study should provide important insight into the performance of nanoscale-strained Si. PMID- 26059314 TI - Lasers in stapes surgery: a review. AB - BACKGROUND: Lasers in stapes surgery are used to divide the anterior and posterior crus of the stapes, divide the stapedius tendon and perforate the footplate. The ideal laser should not penetrate deeply into the perilymph (thereby increasing its temperature). It should be conducted through optical fibres, allowing easy manipulation, and should have good water absorption, equating to high bone ablation efficiency. OBJECTIVES: This review discusses the various different lasers used in stapes surgery with regard to their properties and suitability for this type of surgery. In particular, the laser parameters used are discussed to facilitate their clinical use. PMID- 26059315 TI - Fractional Microneedling Radiofrequency Treatment for Acne-related Post inflammatory Erythema. AB - Post-inflammatory erythema is a common result of acne inflammation and is cosmetically unacceptable without effective treatment. Fractional microneedling radiofrequency (FMR) has potential for treatment of post-inflammatory erythema. The aim of this study was to evaluate the efficacy and safety of this treatment. A retrospective chart review was undertaken of 25 patients treated with 2 sessions of radiofrequency at 4-week intervals and 27 patients treated with oral antibiotics and/or topical agents. Efficacy was assessed through an investigator's global assessment of photographs, and the analysis of erythema with image analysis software and photometric devices. Histological changes resulting from the treatment were evaluated by skin biopsy. FMR treatment resulted in significant improvements in erythema with no severe adverse effects. Histological study revealed a reduction in vascular markers and inflammation. FMR is a safe and effective treatment for post-inflammatory erythema, with potential anti-inflammatory and anti-angiogenetic properties. PMID- 26059316 TI - Creating a customized intracellular niche: subversion of host cell signaling by Legionella type IV secretion system effectors. AB - The Gram-negative facultative intracellular pathogen Legionella pneumophila infects a wide range of different protozoa in the environment and also human alveolar macrophages upon inhalation of contaminated aerosols. Inside its hosts, it creates a defined and unique compartment, termed the Legionella-containing vacuole (LCV), for survival and replication. To establish the LCV, L. pneumophila uses its Dot/Icm type IV secretion system (T4SS) to translocate more than 300 effector proteins into the host cell. Although it has become apparent in the past years that these effectors subvert a multitude of cellular processes and allow Legionella to take control of host cell vesicle trafficking, transcription, and translation, the exact function of the vast majority of effectors still remains unknown. This is partly due to high functional redundancy among the effectors, which renders conventional genetic approaches to elucidate their role ineffective. Here, we review the current knowledge about Legionella T4SS effectors, highlight open questions, and discuss new methods that promise to facilitate the characterization of T4SS effector functions in the future. PMID- 26059318 TI - Formation of Silver Nanostructures by Rolling Circle Amplification Using Boranephosphonate-Modified Nucleotides. AB - We investigate the efficiency of incorporation of boranephosphonate-modified nucleotides by phi29 DNA polymerase and present a simple method for forming large defined silver nanostructures by rolling circle amplification (RCA) using boranephosphonate internucleotide linkages. RCA is a linear DNA amplification technique that can use specifically circularized DNA probes for detection of target nucleic acids and proteins. The resulting product is a collapsed single stranded DNA molecule with tandem repeats of the DNA probe. By substituting each of the natural nucleotides with the corresponding 5'-(alpha-P borano)deoxynucleosidetriphosphate, only a small reduction in amplification rate is observed. Also, by substituting all four natural nucleotides, it is possible to enzymatically synthesize a micrometer-sized, single-stranded DNA molecule with only boranephosphonate internucleotide linkages. Well-defined silver particles are then readily formed along the rolling circle product. PMID- 26059317 TI - Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease thought to employ cell non-autonomous mechanisms where neuronal injury engages immune responses to influence disease progression. Here we show that the expression of mutant proteins causative for ALS in Caenorhabditis elegans motor neurons induces an innate immune response via TIR-1/Sarm1. Loss of function mutations in tir-1, associated downstream kinases, and the transcription factor atf-7 all suppress motor neuron degeneration. The neurosecretory proteins UNC-13 and UNC-31 are required for induction of the immune response as well as the degeneration of motor neurons. The human orthologue of UNC-13, UNC13A, has been identified as a genetic modifier of survival in ALS, and we provide functional evidence of UNC 13/UNC13A in regulating motor neuron degeneration. We propose that the innate immune system reacts to the presence of mutant proteins as a contagion, recruiting a pathogen resistance response that is ultimately harmful and drives progressive neurodegeneration. PMID- 26059319 TI - Towards using a full spectrum of early clinical trial data: a retrospective analysis to compare potential longitudinal categorical models for molecular targeted therapies in oncology. AB - Following the pattern of phase I clinical trials for cytotoxic drugs, dose finding clinical trials in oncology of molecularly targeted agents (MTA) aim at determining the maximum tolerated dose (MTD). In classical phase I clinical trials, MTD is generally defined by the number of patients with short-term major treatment toxicities (usually called dose-limiting toxicities, DLT), occurring during the first cycle of study treatment (e.g. within the first 3weeks of treatment). However, S. Postel-Vinay (2011) highlighted that half of grade 3 to 4 toxicities, usually considered as DLT, occur after the first cycle of MTA treatment. In addition, MTAs could induce other moderate (e.g. grade 2) toxicities which could be taken into account depending on their clinical importance, chronic nature and duration. Ignoring these late toxicities may lead to an underestimation of the drug toxicity and to wrong dose recommendations for phase II and III clinical trials. Some methods have been proposed, such as the time-to-event continuous reassessment method (Cheung 2000 and Mauguen 2011), to take into account the late toxicities. We suggest approaches based on longitudinal models (Doussau 2013). We compare several models for longitudinal data, such as transitional or marginal models, to take into account all relevant toxicities occurring during the entire length of the patient treatment (and not just the events within a predefined short-term time-window). These models allow the statistician to benefit from a larger amount of safety data which could potentially improve that accuracy in MTD assessment. PMID- 26059321 TI - Modeling the competition between PHA-producing and non-PHA-producing bacteria in feast-famine SBR and staged CSTR systems. AB - Although the enrichment of specialized microbial cultures for the production of polyhydroxyalkanoates (PHA) is generally performed in sequencing batch reactors (SBRs), the required feast-famine conditions can also be established using two or more continuous stirred-tank reactors (CSTRs) in series with partial biomass recirculation. The use of CSTRs offers several advantages, but will result in distributed residence times and a less strict separation between feast and famine conditions. The aim of this study was to investigate the impact of the reactor configuration, and various process and biomass-specific parameters, on the enrichment of PHA-producing bacteria. A set of mathematical models was developed to predict the growth of Plasticicumulans acidivorans-as a model PHA producer-in competition with a non-storing heterotroph. A macroscopic model considering lumped biomass and an agent-based model considering individual cells were created to study the effect of residence time distribution and the resulting distributed bacterial states. The simulations showed that in the 2-stage CSTR system the selective pressure for PHA-producing bacteria is significantly lower than in the SBR, and strongly affected by the chosen feast-famine ratio. This is the result of substrate competition based on both the maximum specific substrate uptake rate and substrate affinity. Although the macroscopic model overestimates the selective pressure in the 2-stage CSTR system, it provides a quick and fairly good impression of the reactor performance and the impact of process and biomass specific parameters. PMID- 26059320 TI - SWI/SNF-Mediated Lineage Determination in Mesenchymal Stem Cells Confers Resistance to Osteoporosis. AB - Redirecting the adipogenic potential of bone marrow-derived mesenchymal stem cells to other lineages, particularly osteoblasts, is a key goal in regenerative medicine. Controlling lineage selection through chromatin remodeling complexes such as SWI/SNF, which act coordinately to establish new patterns of gene expression, would be a desirable intervention point, but the requirement for the complex in essentially every lineage pathway has generally precluded selectivity. However, a novel approach now appears possible by targeting the subset of SWI/SNF powered by the alternative ATPase, mammalian brahma (BRM). BRM is not required for development, which has hindered understanding of its contributions, but knockdown genetics here, designed to explore the hypothesis that BRM-SWI/SNF has different regulatory roles in different mesenchymal stem cell lineages, shows that depleting BRM from mesenchymal stem cells has a dramatic effect on the balance of lineage selection between osteoblasts and adipocytes. BRM depletion enhances the proportion of cells expressing markers of osteoblast precursors at the expense of cells able to differentiate along the adipocyte lineage. This effect is evident in primary bone marrow stromal cells as well as in established cell culture models. The altered precursor balance has major physiological significance, which becomes apparent as protection against age-related osteoporosis and as reduced bone marrow adiposity in adult BRM-null mice. PMID- 26059322 TI - Perceptions about cancer-related fatigue among cancer patients using Q methodology. AB - PURPOSE: Cancer-related fatigue (CRF) is a common subjective feeling and disabling symptom complex experienced by patients with cancer. This study aimed to identify the subjective perceptions of Korean patients with cancer about CRF to help the development of basic intervention strategies for these patients. METHODS: Q methodology was used to examine the subjective perceptions of patients with cancer about CRF. Thirty-one patients with cancer, hospitalized at a university hospital in Seoul, Korea, were recruited into this study and classified 41 selected Q statements using a nine-point scale. Data were analysed using PC-QUANL for Windows. RESULTS: Data analysis revealed that distinct perceptions about CRF do exist among Korean patients with cancer. Three types of perceptions were identified: dominant self-reliance, positive-conformist and self deprecating exhaustion. These three types explained 53.0% of the variance (40.2%, 8.2% and 4.6%, respectively). CONCLUSIONS: This study identified three types of perceptions about CRF among Korean patients with cancer. These findings provide baseline data to develop customised interventions for caring strategies. This study also informs health professionals in other countries about the perceptions of Korean patients with cancer about CRF. PMID- 26059323 TI - The role of advanced nursing in lung cancer: A framework based development. AB - PURPOSE: Advanced Practice Lung Cancer Nurses (APLCN) are well-established in several countries but their role has yet to be established in Switzerland. Developing an innovative nursing role requires a structured approach to guide successful implementation and to meet the overarching goal of improved nursing sensitive patient outcomes. The "Participatory, Evidence-based, Patient-focused process, for guiding the development, implementation, and evaluation of advanced practice nursing" (PEPPA framework) is one approach that was developed in the context of the Canadian health system. The purpose of this article is to describe the development of an APLCN model at a Swiss Academic Medical Center as part of a specialized Thoracic Cancer Center and to evaluate the applicability of PEPPA framework in this process. METHOD: In order to develop and implement the APLCN role, we applied the first seven phases of the PEPPA framework. RESULTS: This article spreads the applicability of the PEPPA framework for an APLCN development. This framework allowed us to i) identify key components of an APLCN model responsive to lung cancer patients' health needs, ii) identify role facilitators and barriers, iii) implement the APLCN role and iv) design a feasibility study of this new role. CONCLUSIONS: The PEPPA framework provides a structured process for implementing novel Advanced Practice Nursing roles in a local context, particularly where such roles are in their infancy. Two key points in the process include assessing patients' health needs and involving key stakeholders. PMID- 26059324 TI - Sterile v aseptic non-touch technique for needle-less connector care on central venous access devices in a bone marrow transplant population: A comparative study. AB - PURPOSE: The aim of this study was to determine whether a variation in practice from an aseptic non-touch technique (ANTT) to a sterile technique when changing needleless connectors on central venous access devices (CVAD) was associated with any change in catheter related bloodstream infection (CRBSI) rates in the bone marrow transplant (BMT) population. METHODS: A two group comparative study without concurrent controls using a retrospective cohort was conducted in a large metropolitan hospital in Brisbane, Australia. INCLUSION CRITERIA: haematological malignancy, Hickman catheter inserted, age >=18. A tool was developed to extract historical data from medical records and pathology results. PRIMARY OUTCOME: CRBSI. SECONDARY OUTCOMES: laboratory confirmed bloodstream infection, mucosal barrier injury laboratory confirmed bloodstream infection and skin contaminants. RESULTS: One hundred and fifty patients were assessed, 73/150 (49%) in the ANTT group. DEMOGRAPHICS: males 95/150 (63%), with 71/150 (47%) receiving an autologous BMT. No difference in CRBSI rates between groups was observed (ANTT n = 3 (4%) vs Sterile n = 1 (2.7%), p = 0.357 Fishers Exact Test). Infection by skin contaminants were identified in a similar number of cases across both groups (ANTT n = 9 (12.3%) vs Sterile n = 6 (7.8%)). CONCLUSIONS: No causal effect can be deduced from this small study; nevertheless results imply that an ANTT was not associated with increased CRBSI. Poor hand hygiene and ANTT were perceived across both groups. Quality and consistent ANTT is a safe method for managing intravascular devices, however education and awareness of pathogen transfer from healthcare worker and patient to their device is required. PMID- 26059325 TI - Happiness and its relation to psychological well-being of adolescents. AB - In the present decade, adolescents' mental problems are known as critical problems which have many destructive consequences. This study aimed to measure students' happiness and psychological well-being status in a sample of high school students. The cross sectional study consisted of 403 randomly selected high school students in Tabriz, Iran. Numerous variables including general health status, happiness, self-efficacy, perceived stress, hopefulness and life satisfaction were measured by using self-reported written questionnaires. Significant relation observed between happiness and psychological well-being (r=0.48). Those students with good relationship and those who had reported to enjoy attending social events indicated better mental health status. No causal inferences were investigated due to the non-experimental nature of the study. The findings also revealed that students with higher happiness score have a better school performance. Integration of happiness promotion initiatives into the comprehensive school health programs is recommended to have pleasant environments for a healthy population of adolescents. PMID- 26059326 TI - Quantification of myocardial blood flow using non-electrocardiogram-triggered MRI with three-slice coverage. AB - PURPOSE: Accurate quantification of myocardial perfusion is dependent on reliable electrocardiogram (ECG) triggering. Measuring myocardial blood flow (MBF) in patients with arrhythmias or poor ECGs is currently infeasible with MR. The purpose of this study was to demonstrate the feasibility of a non-ECG-triggered method with clinically useful three-slice ventricular coverage for measurement of MBF in healthy volunteers. METHODS: A saturation recovery magnetization-prepared gradient recalled echo acquisition was continuously repeated during first-pass imaging. A slice-interleaved radial trajectory was employed to enable image-based retrospective triggering. The arterial input function was generated using a beat by-beat T1 estimation method. The proposed technique was validated against a conventional ECG-triggered dual-bolus technique in 10 healthy volunteers. The technique was further demonstrated under adenosine stress in 12 healthy volunteers. RESULTS: The proposed method produced MBF with no significant difference compared with the ECG-triggered technique. The proposed method yielded mean myocardial perfusion reserve comparable to published literature. CONCLUSION: We have developed a non-ECG-triggered quantitative perfusion imaging method. In this preliminary study, our results demonstrate that our method yields comparable MBF compared with the conventional ECG-triggered method and that it is feasible for stress imaging. PMID- 26059327 TI - Evaluation of a Computer-aided Lung Auscultation System for Diagnosis of Bovine Respiratory Disease in Feedlot Cattle. AB - BACKGROUND: A computer-aided lung auscultation (CALA) system was recently developed to diagnose bovine respiratory disease (BRD) in feedlot cattle. OBJECTIVES: To determine, in a case-control study, the level of agreement between CALA and veterinary lung auscultation and to evaluate the sensitivity (Se) and specificity (Sp) of CALA to diagnose BRD in feedlot cattle. ANIMALS: A total of 561 Angus cross-steers (initial body weight = 246 +/- 45 kg) were observed during the first 50 day after entry to a feedlot. METHODS: Case-control study. Steers with visual signs of BRD identified by pen checkers were examined by a veterinarian, including lung auscultation using a conventional stethoscope and CALA that produced a lung score from 1 (normal) to 5 (chronic). For each steer examined for BRD, 1 apparently healthy steer was selected as control and similarly examined. Agreement between CALA and veterinary auscultation was assessed by kappa statistic. CALA's Se and Sp were estimated using Bayesian latent class analysis. RESULTS: Of the 561 steers, 35 were identified with visual signs of BRD and 35 were selected as controls. Comparison of veterinary auscultation and CALA (using a CALA score >=2 as a cut off) revealed a substantial agreement (kappa = 0.77). Using latent class analysis, CALA had a relatively high Se (92.9%; 95% credible interval [CI] = 0.71-0.99) and Sp (89.6%; 95% CI = 0.64-0.99) for diagnosing BRD compared with pen checking. CONCLUSIONS: CALA had good diagnostic accuracy (albeit with a relatively wide CI). Its use in feedlots could increase the proportion of cattle accurately diagnosed with BRD. PMID- 26059328 TI - Ultra percutaneous dilation tracheotomy vs mini open tracheotomy. A comparison of tracheal damage in fresh cadaver specimens. AB - BACKGROUND: To compare the ultra percutaneous dilation tracheostomy (PDT) and mini open techniques (MOT) in randomized fixed and fresh cadavers. Assess degrees of damage to tracheal cartilage and mucosa via tracheal lumen and external dissection. METHOD: Comparative cadaver study was performed, tracheostomy was placed in 36 cadavers (16 fixed, 20 fresh) from July 2004 to December 2004, in University of Alberta, Canada. PDT (size 7) were placed by intensivist and MOT (size 7) otolaryngologist. Both fixed and fresh cadavers were randomized. Evaluation was done according to gender, ease of landmark, mucosal and cartilage injuries. RESULTS: Significant differences in mucosal injury (7 of 9 in UPDT VS 0 of 7 in MOT, p value 0.008), and cartilage injury (8 of 9 in UPDT VS 1 of 7 in MOT p value 0.012) were seen in fixed cadavers; and in fresh cadavers, mucosal injury (5 of 10 in UPDT VS 0 of 10 in MOT, p value 0.043), and cartilage injury (5 of 10 in UPDT VS 0 of 10 in MOT, p value 0.043). CONCLUSIONS: PDT resulted in severe damage to mucosa and cartilage, that might contribute to subglottic stenosis preventing decannulation. Considering the injury, MOT has better outcome than UPDT. PMID- 26059329 TI - A novel pathway for outer membrane protein biogenesis in Gram-negative bacteria. AB - The understanding of the biogenesis of the outer membrane of Gram-negative bacteria is of critical importance due to the emergence of bacteria that are becoming resistant to available antibiotics. A problem that is most serious for Gram-negative bacteria, with essentially few antibiotics under development or likely to be available for clinical use in the near future. The understanding of the Gram-negative bacterial outer membrane is therefore critical to developing new antimicrobial agents, as this membrane makes direct contact with the external milieu, and the proteins present within this membrane are the instruments of microbial warfare, playing key roles in microbial pathogenesis, virulence and multidrug resistance. To date, a single outer membrane complex has been identified as essential for the folding and insertion of proteins into the outer membrane, this is the beta-barrel assembly machine (BAM) complex, which in some cases is supplemented by the Translocation and Assembly Module (TAM). In this issue of Molecular Microbiology, Dunstan et al. have identified a novel pathway for the insertion of a subset of integral membrane proteins into the Gram negative outer membrane that is independent of the BAM complex and TAM. PMID- 26059330 TI - A composite method for mapping quantitative trait loci without interference of female achiasmatic and gender effects in silkworm, Bombyx mori. AB - The silkworm, Bombyx mori, is an economically important insect that was domesticated more than 5000 years ago. Its major economic traits focused on by breeders are quantitative traits, and an accurate and efficient QTL mapping method is necessary to explore their genetic architecture. However, current widely used QTL mapping models are not well suited for silkworm because they ignore female achiasmate and gender effects. In this study, we propose a composite method combining rational population selection and special mapping methods to map QTL in silkworm. By determining QTL for cocoon shell weight (CSW), we demonstrated the effectiveness of this method. In the CSW mapping process, only 56 markers were used and five loci or chromosomes were detected, more than in previous studies. Additionally, loci on chromosomes 1 and 11 dominated and accounted for 35.10% and 15.03% of the phenotypic variance respectively. Unlike previous studies, epistasis was detected between loci on chromosomes 11 and 22. These mapping results demonstrate the power and convenience of this method for QTL mapping in silkworm, and this method may inspire the development of similar approaches for other species with special genetic characteristics. PMID- 26059331 TI - Heterolysis of Dihydrogen by Silver Alkoxides and Fluorides. AB - Alkoxide-bridged disilver cations react with dihydrogen to form hydride-bridged cations, releasing free alcohol. Hydrogenolysis of neutral silver fluorides affords hydride-bridged disilver cations as their bifluoride salts. These reactions proceed most efficiently when the supporting ligands are expanded N heterocyclic carbenes (NHCs) derived from 6- and 7-membered cyclic amidinium salts. Kinetics studies show that silver fluoride hydrogenolysis is first-order in both silver and dihydrogen. PMID- 26059333 TI - One in four US children exposed to weapon violence, study finds. PMID- 26059332 TI - Study design and rationale for a randomised, placebo-controlled, double-blind study to assess the efficacy of selumetinib (AZD6244; ARRY-142886) in combination with dacarbazine in patients with metastatic uveal melanoma (SUMIT). AB - BACKGROUND: Uveal melanoma is characterised by mutations in GNAQ and GNA11, resulting in Ras/Raf/MEK/ERK pathway activation. Treatment with selumetinib (AZD6244, ARRY-142886), a MEK1/2 inhibitor, results in antitumour effects in uveal melanoma pre-clinical models. A randomised phase II trial demonstrated improved progression-free survival (PFS) and response rate (RR) with selumetinib monotherapy versus chemotherapy with temozolomide or dacarbazine in patients with metastatic uveal melanoma. Pre-clinically, selumetinib in combination with alkylating agents enhanced antitumour activity compared with chemotherapy alone. We hypothesise that selumetinib in combination with dacarbazine will result in improved clinical outcomes in patients with metastatic uveal melanoma versus dacarbazine alone. METHODS/DESIGN: SUMIT is a randomised, international, double blind, placebo-controlled, phase III study assessing the efficacy and safety of selumetinib in combination with dacarbazine in patients with metastatic uveal melanoma who have not received prior systemic therapy. Primary endpoint is PFS. Secondary endpoints include objective RR, duration of response, change in tumour size at Week 6, overall survival, safety and tolerability. Exploratory endpoints include efficacy in tumours with GNAQ or GNA11 mutations. Eligible patients must have: >=1 lesion that can be accurately measured at baseline, and is suitable for accurate repeated measurements; ECOG performance status 0-1; life expectancy>12 weeks. Mutation status for GNAQ/GNA11 will be assessed retrospectively. An estimated 128 patients from approximately 50 sites globally will be randomised (3:1) to selumetinib 75 mg twice daily or placebo in combination with dacarbazine 1000 mg/m(2) on Day 1 of every 21-day cycle until objective disease progression, intolerable toxicity or occurrence of another discontinuation criterion. Randomisation will be stratified by the presence/absence of liver metastases. Tumours will be evaluated by RECIST v1.1 every 6 weeks. All patients have the option of receiving selumetinib with or without dacarbazine at disease progression. Study enrolment began in April 2014 and is expected to complete in early 2015. DISCUSSION: Treatment of patients with metastatic uveal melanoma represents an area of high unmet medical need. This study evaluating selumetinib in combination with dacarbazine was designed with input from the US FDA, and is the first potential registration trial to be conducted in patients with metastatic uveal melanoma. TRIAL REGISTRATION: Clinicaltrials.gov (Date of registration, October 10, 2013) REGISTRATION NUMBER: NCT01974752 Trial abbreviation: SUMIT. PMID- 26059334 TI - Presurgical assessment of bariatric patients with the Patient Health Questionnaire (PHQ)--a screening of the prevalence of psychosocial comorbidity. AB - BACKGROUND: Bariatric surgery has gained increasing relevance due to the dramatic rise in morbid obesity prevalence. A sound body of scientific literature demonstrates positive long-term outcome of bariatric surgery in decreasing mental and physical health morbidity. Still, there is a need for a manageable presurgical screening to assess major mental disorders. The aim of this study was to assess the frequency of common psychiatric syndromes in bariatric surgery candidates using a computerized version of the Patient Health Questionnaire (PHQ). METHODS: In a prospective cohort study from August 2009 to July 2011 morbidly obese individuals seeking bariatric treatment were evaluated for mental health disorders using the PHQ (computerized German version). RESULTS: A total of 159 patients were included in this study. The median age of participants was 42 years, the median BMI was 49 kg/m(2). The PHQ revealed a prevalence of 84 % for mental health disorders, 50 % of the participants had three or more mental health disorders. A high somatic symptom burden (46 %), depressive syndromes (62 %) and anxiety disorders (29 %) were the most frequent psychiatric syndromes. The median number of psychiatric syndromes was 3 for women and 1 for men (p = 0.007). No correlation between BMI and a single syndrome or the sum of syndromes was observed. CONCLUSION: 84 % of the patients seeking bariatric treatment were screened positive for at least one mental health disorder. The computerized PHQ with automated reporting appears to be a useful instrument for presurgical assessment of bariatric patients in routine medical settings. PMID- 26059335 TI - Lateral Organ Boundaries Domain16 and 18 Act Downstream of the AUXIN1 and LIKE AUXIN3 Auxin Influx Carriers to Control Lateral Root Development in Arabidopsis. AB - Several members of the Lateral Organ Boundaries Domain (LBD)/Asymmetric Leaves2 Like (ASL) gene family have been identified to play important roles in Arabidopsis (Arabidopsis thaliana) lateral root (LR) development during auxin response, but their functional relationship with auxin transporters has not been established yet. Here, we show that the AUXIN1 (AUX1) and LIKE-AUXIN3 (LAX3) auxin influx carriers are required for auxin signaling that activates LBD16/ASL18 and LBD18/ASL20 to control LR development. The lax3 mutant phenotype was not significantly enhanced when combined with lbd16 or lbd18. However, LBD18 overexpression could rescue the defects in LR emergence in lax3 with concomitant expression of the LBD18 target genes. Genetic and gene expression analyses indicated that LBD16 and LBD18 act with AUX1 to regulate LR initiation and LR primordium development, and that AUX1 and LAX3 are needed for auxin-responsive expression of LBD16 and LBD18. LBD18:SUPERMAN REPRESSIVE DOMAIN X in the lbd18 mutant inhibited LR initiation and LR primordium development in response to a gravitropic stimulus and suppressed promoter activities of the cell cycle genes Cyclin-Dependent Kinase A1;1 and CYCLINB1;1. Taken together, these results suggest that LBD16 and LBD18 are important regulators of LR initiation and development downstream of AUX1 and LAX3. PMID- 26059336 TI - Expansion and Functional Divergence of Jumonji C-Containing Histone Demethylases: Significance of Duplications in Ancestral Angiosperms and Vertebrates. AB - Histone modifications, such as methylation and demethylation, are crucial mechanisms altering chromatin structure and gene expression. Recent biochemical and molecular studies have uncovered a group of histone demethylases called Jumonji C (JmjC) domain proteins. However, their evolutionary history and patterns have not been examined systematically. Here, we report extensive analyses of eukaryotic JmjC genes and define 14 subfamilies, including the Lysine Specific Demethylase3 (KDM3), KDM5, JMJD6, Putative-Lysine-Specific Demethylase11 (PKDM11), and PKDM13 subfamilies, shared by plants, animals, and fungi. Other subfamilies are detected in plants and animals but not in fungi (PKDM12) or in animals and fungi but not in plants (KDM2 and KDM4). PKDM7, PKDM8, and PKDM9 are plant-specific groups, whereas Jumonji, AT-Rich Interactive Domain2, KDM6, and PKDM10 are animal specific. In addition to known domains, most subfamilies have characteristic conserved amino acid motifs. Whole-genome duplication (WGD) was likely an important mechanism for JmjC duplications, with four pairs from an angiosperm-wide WGD and others from subsequent WGDs. Vertebrates also experienced JmjC duplications associated with the vertebrate ancestral WGDs, with additional mammalian paralogs from tandem duplication and possible transposition. The sequences of paralogs have diverged in both known functional domains and other regions, showing evidence of selection pressure. The increases of JmjC copy number and the divergences in sequence and expression might have contributed to the divergent functions of JmjC genes, allowing the angiosperms and vertebrates to adapt to a great number of ecological niches and contributing to their evolutionary successes. PMID- 26059337 TI - Efficacy and Safety of Pitavastatin in Children and Adolescents at High Future Cardiovascular Risk. AB - OBJECTIVES: To assess the safety and efficacy of pitavastatin in children and adolescents with hyperlipidemia. STUDY DESIGN: A total of 106 children and adolescents with hyperlipidemia, ages 6 to 17 years, were enrolled in a 12-week randomized, double-blind, placebo-controlled study and randomly assigned to pitavastatin 1 mg, 2 mg, 4 mg, or placebo. During a 52-week extension period, subjects were up-titrated from 1 mg pitavastatin to a maximum dose of 4 mg in an effort to achieve an optimum low-density lipoprotein cholesterol (LDL-C) treatment target of <110 mg/dL (2.8 mmol/L). Adverse events rates, including abnormal clinical laboratory variables, vital signs, and physical examination were assessed. RESULTS: Compared with placebo, pitavastatin 1, 2, and 4 mg significantly reduced LDL-C from baseline by 23.5%, 30.1%, and 39.3%, respectively, and in the open-label study 20.5% of the subjects reached the LDL-C goal <110 mg/dL (2.8 mmol/L). No safety issues were evident. CONCLUSIONS: Pitavastatin at doses up to 4 mg is well tolerated and efficacious in children and adolescents aged 6-17 years. TRIAL REGISTRATION: Registered with EudraCT 2011 004964-32 and EudraCT 2011-004983-32. PMID- 26059340 TI - Wake-promoting actions of median nerve stimulation in TBI-induced coma: An investigation of orexin-A and orexin receptor 1 in the hypothalamic region. AB - A coma is a serious complication, which can occur following traumatic brain injury (TBI), for which no effective treatment has been established. Previous studies have suggested that neural electrical stimulation, including median nerve stimulation (MNS), may be an effective method for treating patients in a coma, and orexin-A, an excitatory hypothalamic neuropeptide, may be involved in wakefulness. However, the exact mechanisms underlying this involvement remain to be elucidated. The present study aimed to examine the arousal-promoting role of MNS in rats in a TBI-induced coma and to investigate the potential mechanisms involved. A total of 90 rats were divided into three groups, comprising a control group, sham-stimulated (TBI) group and a stimulated (TBI + MNS) group. MNS was performed on the animals, which were in a TBI-induced comatose state. Changes in the behavior of the rats were observed following MNS. Subsequently, hypothalamic tissues were extracted from the rats 6, 12 and 24 h following TBI or MNS, respectively. The expression levels of orexin-A and orexin receptor-1 (OX1R) in the hypothalamus were examined using immunohistochemistry, western blotting and an enzyme-linked immunosorbent assay. The results demonstrated that 21 rats subjected to TBI-induced coma exhibited a restored righting reflex and response to pain stimuli following MNS. In addition, ignificant differences in the expression levels of orexin-A and OXIR were observed among the three groups and among the time-points. Orexin-A and OX1R were upregulated following MNS. The rats in the stimulated group reacted to the MNS and exhibited a re-awakening response. The results of the present study indicated that MNS may be a therapeutic option for TBI-induced coma. The mechanism may be associated with increasing expression levels of the excitatory hypothalamic neuropeptide, orexin-A, and its receptor, OX1R, in the hypothalamic region. PMID- 26059338 TI - Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome. AB - OBJECTIVES: To assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL in patients with ALGS. STUDY DESIGN: Within the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory (PedsQL) questionnaires were administered to 70 children with ALGS, 95 children with alpha-1-antitrypsin deficiency (A1ATD), and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent proxy PedsQL scores were recorded for children aged 2-18 years (98 ALGS, 123 A1ATD, and 68 IHC). RESULTS: Mean ages and total bilirubin (mg/dL) were ALGS 9.4 years; 4.4, A1ATD 9.5 years; 0.7, and IHC 10.3 years; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs 83; P = .001). Children with ALGS and IHC were similar, except in physical scores (73 vs 79; P = .05). Parents of children with ALGS perceived their children to have worse HRQOL than A1ATD (P <= .001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated international normalized ratio, and an intracardiac defect were predictive of poor parental scores (P <= .05). In multivariate analysis, only weight z-score remained significant for child- and parent-reported scores. CONCLUSIONS: HRQOL is impaired in children with ALGS compared with healthy and children with A1ATD, similar to children with IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL. PMID- 26059339 TI - Genome-wide identification of the Phaseolus vulgaris sRNAome using small RNA and degradome sequencing. AB - BACKGROUND: MiRNAs and phasiRNAs are negative regulators of gene expression. These small RNAs have been extensively studied in plant model species but only 10 mature microRNAs are present in miRBase version 21, the most used miRNA database, and no phasiRNAs have been identified for the model legume Phaseolus vulgaris. Thanks to the recent availability of the first version of the common bean genome, degradome data and small RNA libraries, we are able to present here a catalog of the microRNAs and phasiRNAs for this organism and, particularly, we suggest new protagonists in the symbiotic nodulation events. RESULTS: We identified a set of 185 mature miRNAs, including 121 previously unpublished sequences, encoded by 307 precursors and distributed in 98 families. Degradome data allowed us to identify a total of 181 targets for these miRNAs. We reveal two regulatory networks involving conserved miRNAs: those known to play crucial roles in the establishment of nodules, and novel miRNAs present only in common bean, suggesting a specific role for these sequences. In addition, we identified 125 loci that potentially produce phased small RNAs, with 47 of them having all the characteristics of being triggered by a total of 31 miRNAs, including 14 new miRNAs identified in this study. CONCLUSIONS: We provide here a set of new small RNAs that contribute to the broader knowledge of the sRNAome of Phaseolus vulgaris. Thanks to the identification of the miRNA targets from degradome analysis and the construction of regulatory networks between the mature microRNAs, we present here the probable functional regulation associated with the sRNAome and, particularly, in N2-fixing symbiotic nodules. PMID- 26059341 TI - Cryopreserved human amniotic membrane and a bioinspired underwater adhesive to seal and promote healing of iatrogenic fetal membrane defect sites. AB - INTRODUCTION: We investigated the ability of cryopreserved human amniotic membrane (hAM) scaffold sealed with an underwater adhesive, bio-inspired by marine sandcastle worms to promote healing of iatrogenic fetal membrane defects in a pregnant swine model. METHODS: Twelve Yucatan miniature pigs underwent laparotomy under general anesthesia at 70 days gestation (term = 114 days). The gestational sacs were assigned to uninstrumented (n = 24) and instrumented with 12 Fr trocar, which was further randomized into four different arms-no hAM patch, (n = 22), hAM patch secured with suture (n = 16), hAM patch with no suture (n = 14), and hAM patch secured with adhesive (n = 9). The animals were euthanized 20 days after the procedure. Gross and histological examination of the entry site was performed for fetal membrane healing. RESULTS: There were no differences in fetal survival, amniotic fluid levels, or dye-leakage from the amniotic cavity between the groups. The fetal membranes spontaneously healed in instrumented sacs without hAM patches. In sacs with hAM patches secured with sutures, the patch was incorporated into the swine fetal membranes. In sacs with hAM patches without sutures, 100% of the patches were displaced from the defect site, whereas in sacs with hAM patches secured with adhesive 55% of the patches remained in place and showed complete healing (p = 0.04). DISCUSSION: In contrast to humans, swine fetal membranes heal spontaneously after an iatrogenic injury and thus not an adequate model. hAM patches became incorporated into the defect site by cellular ingrowth from the fetal membranes. The bioinspired adhesive adhered the hAM patches within the defect site. PMID- 26059342 TI - Laminin alpha4 (LAMA4) expression promotes trophoblast cell invasion, migration, and angiogenesis, and is lowered in preeclamptic placentas. AB - INTRODUCTION: The laminin alpha4 subunit (LAMA4) has been shown to promote migration, proliferation, and survival of various cell types. This study investigated LAMA4's role in trophoblast cells during placental development. METHODS: LAMA4 expression was immunohistochemically assessed in the first trimester and term human placentas. LAMA4 siRNA was applied to silence LAMA4 expression in extravillous explants and HTR8/SVneo cells. Hypoxia-reoxygenation (H/R) conditions were applied to mimic preeclampsia. LAMA4 expression and trophoblast cell invasion, migration, and tube formation (a measure of angiogenesis) were assessed in HTR8/SVneo cells. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 was used to study the mechanism underlying LAMA4 activity. LAMA4 promoter methylation was assessed by bisulfite sequencing polymerase chain reaction (PCR) or methylation-specific PCR. RESULTS: LAMA4 levels in preeclamptic placentas were significantly lower than those in controls. LAMA4 silencing significantly inhibited extravillous explant outgrowth as well as HTR8/SVneo cell invasion and migration. H/R conditions significantly lowered LAMA4 expression. Application of either H/R conditions or LAMA4 silencing both significantly decreased HTR8/SVneo cell invasion, migration, and tube formation, decreased MMP2 and MMP9 expression, and increased TIMP2 expression. SB203580 significantly reduced LAMA4 expression. LAMA4 silencing significantly decreased p-p38, p-c-Jun N-terminal kinase (JNK), and p-extracellular signal regulated kinase (ERK) expressions; by contrast, H/R conditions induced significant upregulation of p-p38 and p-ERK but decreased p-JNK. LAMA4 promoter methylation was not significantly altered in preeclamptic placentas compared to controls. CONCLUSIONS: LAMA4 expression is lowered in preeclamptic placentas and promotes trophoblast cell invasion, migration, and angiogenesis. H/R conditions decrease LAMA4 expression and appear to decouple the positive relationship between LAMA4 expression and p38 and ERK activation. PMID- 26059343 TI - Intestinal seromuscular tunneling: a novel method for ureteral replacement--an experimental design. AB - BACKGROUND: Long-segment ureteral injuries may have different etiologies. Although multiple procedures have been previously used for ureteral replacement, none of them had optimum results, and replacement of long segments of injured ureter is still a challenging surgical problem. In this article, we have hypothesized that it may be possible to use intestinal seromuscular tunneling as a novel method for ureteral replacement. METHODS: This experimental study was conducted on eight dogs. After cutting the ureter at about its mid-part and ligating the distal part, a 10-cm tunnel was made in the seromuscular layer of small intestine using a metallic probe, and a catheter was passed through it. Proximal and distal ends of the tunnel were anastomosed to proximal end of ureter and urinary bladder, respectively. After 8 weeks, the dogs were killed, and their whole urinary system was sent for histopathologic examinations. RESULTS: No complication was noted during the post-op period. Histopathologic examinations confirmed that the seromuscular tunnel was well patent, lined by pseudostratified transitional epithelium and without any inflammatory reaction. CONCLUSION: Our study shows that ureteral replacement by intestinal seromuscular tunneling is anatomically possible at least in animal model. However, more well-designed prospective studies are needed to confirm its long-term functional results. PMID- 26059344 TI - Management of the thyroid gland during total laryngectomy in patients with laryngeal squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: The goal of the study was to determine the role of routine total thyroidectomy and hemithyroidectomy in patients undergoing total laryngectomy for laryngeal squamous cell carcinoma. STUDY DESIGN: The study group consisted of 343 patients who underwent total laryngectomy (98 treated with surgery alone, 136 treated following radiation failure, and 109 following chemoradiation failure). Total thyroidectomy was performed in all obstructing and bilateral lesions or if there was suspicion of contralateral lobe involvement. Hemithyroidectomy was performed in all lateralized lesions. Retrospective histopathologic analysis of thyroid specimens was subsequently performed. RESULTS: In all, 262 patients underwent total thyroidectomy during total laryngectomy, six of which demonstrated squamous cell carcinoma evident within the thyroid gland (4 from transglottic lesions, 2 from subglottic lesions). Hemithyroidectomy was performed in 81 patients, with only one patient demonstrating evidence of squamous cell carcinoma within the thyroid gland. Hypothyroidism was observed in 88% (n = 61) of patients who underwent thyroid lobectomy alone, requiring hormone supplementation. CONCLUSION: Routine surgical management of the thyroid gland should not be performed, except in cases of subglottic primary lesions, lesions with significant subglottic extension, or transglottic lesions. Despite efforts to preserve the contralateral thyroid lobe in cases of selective lobectomy, these patients often have a high rate of hypothyroidism, and a total thyroidectomy should be considered when involvement of the thyroid gland is suspected. LEVEL OF EVIDENCE: N/A. PMID- 26059345 TI - Neutrophil CD64 expression as a diagnostic marker for sepsis in adult patients: a meta-analysis. AB - INTRODUCTION: Neutrophil CD64 (nCD64) expression appears to be a promising marker of bacterial infections. The aim of this meta-analysis was to assess the accuracy of nCD64 expression for the diagnosis of sepsis in critically ill adult patients. METHODS: We systematically searched PubMed, Embase, ISI Web of Knowledge, and the Cochrane Library for literature published between database inception and 19 May 2014, as well as reference lists of identified primary studies. Studies were included if they included assessment of the accuracy of nCD64 expression for sepsis diagnosis in adult patients and provided sufficient information to construct a 2*2 contingency table. RESULTS: A total of 8 studies comprising 1986 patients fulfilled the inclusion criteria for the final analysis. The pooled sensitivity and specificity were 0.76 (95 % confidence interval [CI], 0.73-0.78) and 0.85 (95 % CI, 0.82-0.87), respectively. The positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 8.15 (95 % CI, 3.82 17.36), 0.16 (95 % CI, 0.09-0.30), and 60.41 (95 % CI, 15.87-229.90), respectively. The area under the summary receiver operating characteristic curve of nCD64 expression with Q* value were 0.95 (Q* =0.89). CONCLUSIONS: On the basis of our meta-analysis, nCD64 expression is a helpful marker for early diagnosis of sepsis in critically ill patients. The results of the test should not be used alone to diagnose sepsis, but instead should be interpreted in combination with medical history, physical examination, and other test results. PMID- 26059346 TI - Linking sedimentary sulfur and iron biogeochemistry to growth patterns of a cold water coral mound in the Porcupine Basin, S.W. Ireland (IODP Expedition 307). AB - Challenger Mound, a 150-m-high cold-water coral mound on the eastern flank of the Porcupine Seabight off SW Ireland, was drilled during Expedition 307 of the Integrated Ocean Drilling Program (IODP). Retrieved cores offer unique insight into an archive of Quaternary paleo-environmental change, long-term coral mound development, and the diagenetic alteration of these carbonate fabrics over time. To characterize biogeochemical carbon-iron-sulfur transformations in the mound sediments, the contents of dithionite- and HCl-extractable iron phases, iron monosulfide and pyrite, and acid-extractable calcium, magnesium, manganese, and strontium were determined. Additionally, the stable isotopic compositions of pore water sulfate and solid-phase reduced sulfur compounds were analyzed. Sulfate penetrated through the mound sequence and into the underlying Miocene sediments, where a sulfate-methane transition zone was identified. Small sulfate concentration decreases (<7 mM) within the top 40 m of the mound suggested slow net rates of present-day organoclastic sulfate reduction. Increasing delta(34)S sulfate values due to microbial sulfate reduction mirrored the decrease in sulfate concentrations. This process was accompanied by oxygen isotope exchange with water that was indicated by increasing delta(18)O-sulfate values, reaching equilibrium with pore-water at depth. Below 50 mbsf, sediment intervals with strong (34)S-enriched imprints on chromium-reducible sulfur (pyrite S), high degree-of-pyritization values, and semi-lithified diagenetic carbonate-rich layers characterized by poor coral preservation, were observed. These layers provided evidence for the occurrence of enhanced microbial sulfate-reducing activity in the mound in the past during periods of rapid mound aggradation and subsequent intervals of non-deposition or erosion when geochemical fronts remained stationary. During these periods, especially during the Early Pleistocene, elevated sulfate reduction rates facilitated the consumption of reducible iron oxide phases, coral dissolution, and the subsequent formation of carbonate cements. PMID- 26059348 TI - Migraine equivalents and related symptoms, psychological profile and headache features: which relationship? AB - BACKGROUND: Migraine equivalents are common clinical conditions in children suffering from headache. Very few studies dealt with the psychological profile of children/adolescents with migraine equivalents. Our main aim was to compare the psychological profile between migraine children with and without migraine equivalents. Moreover, as secondary aim, exclusively in children with migraine equivalents, we investigated the possible relationship between migraine attack frequency and intensity and psychological factors. METHODS: We enrolled 136 young migraineurs. They were divided in two groups (patients with and without migraine equivalents). The psychological profile was assessed by means of SAFA Anxiety and Somatization questionnaires. RESULTS: Migraine equivalents were present in 101 patients (74.3%). Anxiety (p = 0.024) and somatization (p = 0.001) levels, but not hypochondria (p = 0.26), were higher in patients with migraine equivalents. In children with migraine equivalents, a low frequency of attacks was related to separation anxiety (p = 0.034). CONCLUSIONS: Migraine equivalents patients tend to feel more fearful and to experience more shyness. This, together with the tendency to somatization, may lead them to become vigilant in attachment relationships with their caregivers. PMID- 26059349 TI - Evaluation of headache service quality indicators: pilot implementation in two specialist-care centres. AB - BACKGROUND: Evaluating quality of health care is increasingly recognized as an important contributor to the advancement of health-care delivery. We recently developed a set of quality indicators for headache care, intended to be applicable across countries, cultures and settings so that deficiencies in headache care worldwide might be recognized and rectified. These indicators themselves require evaluation and proof of fitness for purpose. This pilot study begins this process. METHODS: We tested the quality indicators in the tertiary headache centres of the University of Duisburg-Essen in Essen, Germany, and the Hospital da Luz in Lisbon, Portugal. Using seven previously-developed enquiry instruments, we interrogated health-care providers (HCPs), including doctors, nurses, psychologists and physiotherapists, as well as consecutive patients and their medical records. RESULTS: The questionnaires were easily understood by both HCPs and patients and were not unduly time-consuming. The results from the two headache centres were comparable despite their differences in structure, staffing and language. These findings met the purpose of the study. Diagnoses were made according to ICHD criteria and critically evaluated during follow-up. However, diagnostic diaries and instruments assessing burden and response to treatment were not always in place or routinely utilised. Triage systems adjusted waiting times to urgency of need. Treatment plans included pathways to other specialities. Patients felt welcomed, reassured and educated, and were mostly satisfied. Discussion points arose over inclusion of psychological therapies in treatment plans; over recording of outcomes; over indicators of efficiency and equitability (protocols to limit wastage of resources, systems to measure input costs and means of ensuring equal access to the services); and over protocols for reporting serious adverse events. CONCLUSION: This pilot study to assess feasibility of the methods and acceptability of the instruments of headache service quality evaluation was successful. The project is ready to be taken into its next stages. PMID- 26059350 TI - Efflux pump-deficient mutants as a platform to search for microbes that produce antibiotics. AB - Pseudomonas putida DOT-T1E-18 is a strain deficient in the major antibiotic efflux pump (TtgABC) that exhibits an overall increased susceptibility to a wide range of drugs when compared with the wild-type strain. We used this strain as a platform to search for microbes able to produce antibiotics that inhibit growth. A collection of 2400 isolates from soil, sediments and water was generated and a drop assay developed to identify, via growth inhibition halos, strains that prevent the growth of DOT-T1E-18 on solid Luria-Bertani plates. In this study, 35 different isolates that produced known and unknown antibiotics were identified. The most potent inhibitor of DOT-T1E-18 growth was an isolate named 250J that, through multi-locus sequence analysis, was identified as a Pseudomonas sp. strain. Culture supernatants of 250J contain four different xantholysins that prevent growth of Gram-positive bacteria, Gram-negative and fungi. Two of the xantholysins were produced in higher concentrations and purified. Xantholysin A was effective against Bacillus, Lysinibacillus and Rhodococcus strains, and the effect against these microbes was enhanced when used in combination with other antibiotics such as ampicillin, gentamicin and kanamycin. Xantholysin C was also efficient against Gram-positive bacteria and showed an interesting antimicrobial effect against Pseudomonas strains, and a synergistic inhibitory effect with ampicillin, chloramphenicol and gentamicin. PMID- 26059351 TI - Persistent DNA Damage in Spermatogonial Stem Cells After Fractionated Low-Dose Irradiation of Testicular Tissue. AB - PURPOSE: Testicular spermatogenesis is extremely sensitive to radiation-induced damage, and even low scattered doses to testis from radiation therapy may pose reproductive risks with potential treatment-related infertility. Radiation induced DNA double-strand breaks (DSBs) represent the greatest threat to the genomic integrity of spermatogonial stem cells (SSCs), which are essential to maintain spermatogenesis and prevent reproduction failure. METHODS AND MATERIALS: During daily low-dose radiation with 100 mGy or 10 mGy, radiation-induced DSBs were monitored in mouse testis by quantifying 53 binding protein 1 (53BP-1) foci in SSCs within their stem cell niche. The accumulation of DSBs was correlated with proliferation, differentiation, and apoptosis of testicular germ cell populations. RESULTS: Even very low doses of ionizing radiation arrested spermatogenesis, primarily by inducing apoptosis in spermatogonia. Eventual recovery of spermatogenesis depended on the survival of SSCs and their functional ability to proliferate and differentiate to provide adequate numbers of differentiating spermatogonia. Importantly, apoptosis-resistant SSCs resulted in increased 53BP-1 foci levels during, and even several months after, fractionated low-dose radiation, suggesting that surviving SSCs have accumulated an increased load of DNA damage. CONCLUSIONS: SSCs revealed elevated levels of DSBs for weeks after radiation, and if these DSBs persist through differentiation to spermatozoa, this may have severe consequences for the genomic integrity of the fertilizing sperm. PMID- 26059352 TI - Addition of the Neurokinin-1-Receptor Antagonist (RA) Aprepitant to a 5 Hydroxytryptamine-RA and Dexamethasone in the Prophylaxis of Nausea and Vomiting Due to Radiation Therapy With Concomitant Cisplatin. AB - PURPOSE: To assess, in a prospective, observational study, the safety and efficacy of the addition of the neurokinin-1-receptor antagonist (NK1-RA) aprepitant to concomitant radiochemotherapy, for the prophylaxis of radiation therapy-induced nausea and vomiting. PATIENTS AND METHODS: This prospective observational study compared the antiemetic efficacy of an NK1-RA (aprepitant), a 5-hydroxytryptamine-RA, and dexamethasone (aprepitant regimen) versus a 5 hydroxytryptamine-RA and dexamethasone (control regimen) in patients receiving concomitant radiochemotherapy with cisplatin at the Department of Radiation Oncology, University Hospital Halle (Saale), Germany. The primary endpoint was complete response in the overall phase, defined as no vomiting and no use of rescue therapy in this period. RESULTS: Fifty-nine patients treated with concomitant radiochemotherapy with cisplatin were included in this study. Thirty one patients received the aprepitant regimen and 29 the control regimen. The overall complete response rates for cycles 1 and 2 were 75.9% and 64.5% for the aprepitant group and 60.7% and 54.2% for the control group, respectively. Although a 15.2% absolute difference was reached in cycle 1, a statistical significance was not detected (P=.22). Furthermore maximum nausea was 1.58 +/- 1.91 in the control group and 0.73 +/- 1.79 in the aprepitant group (P=.084); for the head-and-neck subset, 2.23 +/- 2.13 in the control group and 0.64 +/- 1.77 in the aprepitant group, respectively (P=.03). CONCLUSION: This is the first study of an NK1-RA-containing antiemetic prophylaxis regimen in patients receiving concomitant radiochemotherapy. Although the primary endpoint was not obtained, the absolute difference of 10% in efficacy was reached, which is defined as clinically meaningful for patients by international guidelines groups. Randomized phase 3 studies are necessary to further define the potential role of an NK1-RA in this setting. PMID- 26059353 TI - Computer Aided Drug Design Studies in the Discovery of Secondary Metabolites Targeted Against Age-Related Neurodegenerative Diseases. AB - Secondary metabolites are plant products that occur usually in differentiated cells, generally not being necessary for the cells themselves, but likely useful for the plant as a whole. Neurodegeneration can be found in many different levels in the neurons, it always begins at the molecular level and progresses toward the systemic levels. Usually, alterations are observed such as decreasing cholinergic impulse, toxicity related to reactive oxygen species (ROS, inflammatory "amyloid plaque" related processes, catecholamine disequilibrium, etc. Computer aided drug design (CADD has become relevant in the drug discovery process; technological advances in the areas of molecular structure characterization, computational science, and molecular biology have contributed to the planning of new drugs against neurodegenerative diseases. This review discusses scientific CADD studies of the secondary metabolites. Flavonoids, alkaloids, and xanthone compounds have been studied by various researchers (as inhibitory ligands in molecular docking; mainly with three enzymes: acetylcholinesterase (AChE; EC 3.1.1.7, butyrylcholinesterase (BChE; EC 3.1.1.8, and monoamine oxidase (MAO; EC 1.4.3.4. In addition, we have applied ligand-based-virtual screening (using Random Forest, associated with structure-based- virtual screening (docking of a small dataset of 469 alkaloids of the Apocynaceae family from an in-house data bank to select structures with potential inhibitory activity against human AChE. This computer aided drug design study selected certain alkaloids that might be useful in further studies for the treatment of neurological disorders such as Alzheimer's and Parkinson's disease. PMID- 26059355 TI - Neuroprotective Effects of Ginkgolide B Against Ischemic Stroke: A Review of Current Literature. AB - Extensive evidences has shown the promising effects of Ginkgo biloba consumption on several diseases such as Alzheimer's and Parkinson's diseases, and ischemic stroke, etc. Several studies also have reported its beneficial role on motor activity and cognitive functions. This species contain a unique class of diterpenes, namely Ginkgolide B, which possess several pharmacological activities such as protective effect against cardiovascular disease; the most important causes of death worldwide. The promising effects of Ginkgolide B on stroke, both ischemic and hemorrhagic, are suggested by an overwhelming body of scientific evidences. Many studies have shown that the increase of sirt1 expression, the suppression of nuclear factor kappa-B (NF-kB, the inhibition of the PI3K/Akt pathway and toll-like receptor 4 (TLR4/NF-kB, the up-regulation of heme oxygenase 1, erythropoietin secretion and anti-apoptotic protein expression, the inhibition of pro-apoptotic proteins expression, and the improvement of endothelial NO synthesis are the main molecular mechanisms involved in the protective effect of Ginkgolide B on ischemic stroke. In this review, all the available data on the chemistry, mechanisms of neuroprotection and clinical impacts of Ginkgolide B are critically discussed. PMID- 26059354 TI - The Role of Uric Acid and Methyl Derivatives in the Prevention of Age-Related Neurodegenerative Disorders. AB - High uric acid (UA levels have been correlated with a reduced risk of many neurodegenerative diseases through mechanisms involving chelating Fenton reaction transitional metals, antioxidant quenching of superoxide and hydroxyl free radicals, and as an electron donor that increases antioxidant enzyme activity (e.g. SOD. However, the clinical usefulness of UA is limited by its' low water solubility and propensity to form inflammatory crystals at hyperuricemic levels. This review focuses on the role of UA in neuroprotection, as well as potential strategies aimed at increasing UA levels in the soluble range, and the potential therapeutic use of more water-soluble methyl-UA derivatives from the natural catabolic end-products of dietary caffeine, theophylline, and theobromine. PMID- 26059357 TI - Collateral Damage: Contribution of Peripheral Inflammation to Neurodegenerative Diseases. AB - Neurodegenerative diseases are characterized by a progressive deterioration of brain function, with a consequent significant decline in the quality of life of patients and their families. Due to the concurrent increase in life expectancy, the incidence of these diseases has been increasing over the last years and thus there is a growing interest in finding potential risk factors. This review focuses on the correlation between peripheral inflammatory diseases and neurodegeneration, in particular on the relationship between gastrointestinal disorders and Parkinson's disease, especially through the so called gut-brain axis. PMID- 26059358 TI - Adult Hippocampal Neurogenesis, Aging and Neurodegenerative Diseases: Possible Strategies to Prevent Cognitive Impairment. AB - The adult brain of humans and other mammals continuously generates new neurons throughout life. However, this neurogenic capacity is limited to two brain areas, the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ of the lateral ventricle. Although the DG generates new neurons, its neurogenic capacity declines with age and neurodegenerative diseases such as Alzheimer's disease (AD and Huntington's disease (HD. This review focuses on the role of newly-born neurons in cognitive processes, and discusses some of the strategies proposed in humans and animals to enhance neurogenesis and counteract age-related cognitive deficits, such as physical exercise and intake of natural products like omega-3 fatty acids, curcumin and flavanols. PMID- 26059356 TI - The Role of Nicotinamide Phosphoribosyltransferase in Cerebral Ischemia. AB - As recombinant tissue plasminogen activator is the only drug approved for the clinical treatment of acute ischemic stroke, there is an urgent unmet need for novel stroke treatments. Endogenous defense mechanisms against stroke may hold the key to new therapies for stroke. A large number of studies suggest that nicotinamide phosphoribosyl-transferase (NAMPT is an attractive candidate to improve post-stroke recovery. NAMPT is a multifunctional protein and plays important roles in immunity, metabolism, aging, inflammation, and stress responses. NAMPT exists in both the intracellular and extracellular space. As a rate-limiting enzyme, the intracellular form (iNAMPT catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD from nicotinamide. iNAMPT closely regulates energy metabolism, enhancing the proliferation of endothelial cells, inhibiting apoptosis, regulating vascular tone, and stimulating autophagy in disease conditions such as stroke. Extracellular NAMPT (eNAMPT is also known as visfatin (visceral fat-derived adipokine and has pleotropic effects. It is widely believed that the diverse biological functions of eNAMPT are attributed to its NAMPT enzymatic activity. However, the effects of eNAMPT on ischemic injury are still controversial. Some authors have argued that eNAMPT exacerbates ischemic neuronal injury non-enzymatically by triggering the release of TNF-alpha from glial cells. In addition, NAMPT also participates in several pathophysiological processes such as hypertension, atherosclerosis, and ischemic heart disease. Thus, it remains unclear under what conditions NAMPT is beneficial or destructive. Recent work using in vitro and in vivo genetic/ pharmacologic manipulations, including our own studies, has greatly improved our understanding of NAMPT. This review focuses on the multifaceted and complex roles of NAMPT under both normal and ischemic conditions. PMID- 26059359 TI - Is the Modulation of Autophagy the Future in the Treatment of Neurodegenerative Diseases? AB - The pathogenesis of neurodegenerative diseases involves altered activity of proteolytic systems and accumulation of protein aggregates. Autophagy is an intracellular process in which damaged organelles and long-lived proteins are degraded and recycled for maintaining normal cellular homeostasis. Disruption of autophagic activity in neurons leads to modify the cellular homeostasis, causing deficient elimination of abnormal and toxic protein aggregates that promotes cellular stress and death. Therefore, induction of autophagy has been proposed as a reasonable strategy to help neurons to clear abnormal protein aggregates and survive. This review aims to give an overview of some of the main modulators of autophagy that are currently being studied as possible alternatives in the search of therapies that slow the progression of neurodegenerative diseases, which are incurable to date. PMID- 26059361 TI - Longevity Pathways (mTOR, SIRT, Insulin/IGF-1) as Key Modulatory Targets on Aging and Neurodegeneration. AB - Recent data from epidemiologic studies have shown that the majority of the public health costs are related to age-related disorders, and most of these diseases can lead to neuronal death. The specific signaling mechanisms underpinning neurodegeneration and aging are incompletely understood. Much work has been directed to the search for the etiology of neurodegeneration and aging and to new therapeutic strategies, including not only drugs but also non-pharmacological approaches, such as physical exercise and low-calorie dietary intake. The most important processes in aging-associated conditions, including neurodegeneration, include the mammalian (or mechanistic target of rapamycin (mTOR, sirtuin (SIRT and insulin/insulin growth factor 1 signaling (IIS pathways. These longevity pathways are involved in an array of different processes, including metabolism, cognition, stress response and brain plasticity. In this review we focus on the current advances involving the mTOR, SIRT and IIS longevity pathways during the course of healthy aging processes and neurodegenerative diseases, bringing new insights in the form of a better understanding of the signaling mechanisms underpinning neurodegeneration and how these differ from physiological normal aging processes. This also provides new targets for the therapeutic management and/or prevention of these devastating age-related disorders. PMID- 26059362 TI - A Bright Future for Evolutionary Methods in Drug Design. AB - Most medicinal chemists understand that chemical space is extremely large, essentially infinite. Although high-throughput experimental methods allow exploration of drug-like space more rapidly, they are still insufficient to fully exploit the opportunities that such large chemical space offers. Evolutionary methods can synergistically blend automated synthesis and characterization methods with computational design to identify promising regions of chemical space more efficiently. We describe how evolutionary methods are implemented, and provide examples of published drug development research in which these methods have generated molecules with increased efficacy. We anticipate that evolutionary methods will play an important role in future drug discovery. PMID- 26059360 TI - Age-Related Neurodegeneration Prevention Through mTOR Inhibition: Potential Mechanisms and Remaining Questions. AB - With the global aging population, Alzheimer's disease, Parkinson's disease and mild cognition impairment are increasing in prevalence. The success of rapamycin as an agent to extend lifespan in various organisms, including mice, brings hope that chronic mTOR inhibition could also refrain age-related neurodegeneration. Here we review the evidence suggesting that mTOR inhibition - mainly with rapamycin - is a valid intervention to delay age-related neurodegeneration. We discuss the potential mechanisms by which rapamycin may facilitate neurodegeneration prevention or restoration of cognitive function. We also discuss the known side effects of rapamycin and provide evidence to alleviate exaggerated concerns regarding its wider clinical use. We explore the small molecule alternatives to rapamycin and propose future directions for their development, mainly by exploring the possibility of targeting the downstream effectors of mTOR: S6K1 and especially S6K2. Finally, we discuss the strengths and weaknesses of the models used to determine intervention efficacy for neurodegeneration. We address the difficulties of interpreting data using the common way of investigating the efficacy of interventions to delay/prevent neurodegeneration by observing animal behavior while these animals are under treatment. We propose an experimental design that should isolate the variable of aging in the experimental design and resolve the ambiguity present in recent literature. PMID- 26059363 TI - Proteome-wide characterization of signalling interactions in the hippocampal CA4/DG subfield of patients with Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia; however, mechanisms and biomarkers remain unclear. Here, we examined hippocampal CA4 and dentate gyrus subfields, which are less studied in the context of AD pathology, in post mortem AD and control tissue to identify possible biomarkers. We performed mass spectrometry-based proteomic analysis combined with label-free quantification for identification of differentially expressed proteins. We identified 4,328 proteins, of which 113 showed more than 2-fold higher or lower expression in AD hippocampi than in control tissues. Five proteins were identified as putative AD biomarkers (MDH2, PCLO, TRRAP, YWHAZ, and MUC19 isoform 5) and were cross validated by immunoblotting, selected reaction monitoring, and MALDI imaging. We also used a bioinformatics approach to examine upstream signalling interactions of the 113 regulated proteins. Five upstream signalling (IGF1, BDNF, ZAP70, MYC, and cyclosporin A) factors showed novel interactions in AD hippocampi. Taken together, these results demonstrate a novel platform that may provide new strategies for the early detection of AD and thus its diagnosis. PMID- 26059364 TI - Exercise and oxidative stress: potential effects of antioxidant dietary strategies in sports. AB - Free radicals are produced during aerobic cellular metabolism and have key roles as regulatory mediators in signaling processes. Oxidative stress reflects an imbalance between production of reactive oxygen species and an adequate antioxidant defense. This adverse condition may lead to cellular and tissue damage of components, and is involved in different physiopathological states, including aging, exercise, inflammatory, cardiovascular and neurodegenerative diseases, and cancer. In particular, the relationship between exercise and oxidative stress is extremely complex, depending on the mode, intensity, and duration of exercise. Regular moderate training appears beneficial for oxidative stress and health. Conversely, acute exercise leads to increased oxidative stress, although this same stimulus is necessary to allow an up-regulation in endogenous antioxidant defenses (hormesis). Supporting endogenous defenses with additional oral antioxidant supplementation may represent a suitable noninvasive tool for preventing or reducing oxidative stress during training. However, excess of exogenous antioxidants may have detrimental effects on health and performance. Whole foods, rather than capsules, contain antioxidants in natural ratios and proportions, which may act in synergy to optimize the antioxidant effect. Thus, an adequate intake of vitamins and minerals through a varied and balanced diet remains the best approach to maintain an optimal antioxidant status. Antioxidant supplementation may be warranted in particular conditions, when athletes are exposed to high oxidative stress or fail to meet dietary antioxidant requirements. Aim of this review is to discuss the evidence on the relationship between exercise and oxidative stress, and the potential effects of dietary strategies in athletes. The differences between diet and exogenous supplementation as well as available tools to estimate effectiveness of antioxidant intake are also reported. Finally, we advocate the need to adopt an individualized diet for each athlete performing a specific sport or in a specific period of training, clinically supervised with inclusion of blood analysis and physiological tests, in a comprehensive nutritional assessment. PMID- 26059365 TI - Vitamin E has a beneficial effect on nonalcoholic fatty liver disease: a meta analysis of randomized controlled trials. AB - OBJECTIVES: Vitamin E is often used in the treatment of nonalcoholic fatty liver disease (NAFLD), including nonalcoholic steatohepatitis (NASH); however, the magnitude of treatment response associated with vitamin E in improving liver function and histology in NAFLD/NASH has not, to our knowledge, been quantified systematically. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) using vitamin E in the treatment of NAFLD/NASH. METHODS: PubMed, Medline, and Cochrane Library Full Text Database, and Japan Medical-Literature Database (Igaku Chuo Zasshi) were searched until March 2014, and five RCTs were identified for meta-analysis. RESULTS: According to a random effect model analysis of the five studies, vitamin E significantly reduced aspartate transaminase (AST) by -19.43 U/L, alanine aminotransferase (ALT) by -28.91 U/L, alkaline phosphatase (ALP) by -10.39 U/L, steatosis by -0.54 U/L, inflammation by -0.20 U/L, and hepatocellular ballooning by -0.34 U/L compared with the control group. Vitamin E treatment with NASH adult patients showed obvious reductions in not only AST of -13.91 U/L, ALT by -22.44 U/L, steatosis of -0.67 U/L, inflammation of -0.20 U/L, but also fibrosis of -0.30 U/L compared to the control treatment. CONCLUSIONS: Vitamin E significantly improved liver function and histologic changes in patients with NAFLD/NASH. PMID- 26059366 TI - Utility of novel body indices in predicting fat mass in elite athletes. AB - OBJECTIVE: Recently, new body indices, including body adiposity (BAI), a body shape (ABSI), and body roundness (BRI) indices have been developed to estimate adiposity. The aim of this study was to compare percent fat mass (%FM) with novel indices in an elite athlete population. METHODS: Using a cross-sectional design, %FM in 159 male and 50 female athletes using a four-component model was assessed. The %FM was compared with body mass index (BMI), BAI, ABSI, BRI, and with other %FM field methods (bioimpedance spectroscopy and skinfold prediction equation). These associations were determined using multilinear regression analysis, which resulted in predictive models of %FM in athletes. Cross-validation was performed using the prediction residual error sum of squares (PRESS) statistics method. RESULTS: Although higher associations than other indices were observed, BRI still presented low coefficients of determination (men: R(2) = 0.36; women: R(2) = 0.25) when comparing with other field methods (R(2) range, 0.33-0.75). Using BAI as the independent variable, the R(2) was 0.07 for men and 0.14 for women. ABSI did not result in a significant association with %FM in women (R(2) = 0.05) while in men a significant association was found (R(2) = 0.22). The BMI model resulted in a R(2) = 0.20 for men and R(2) = 0.22 for women. Waist circumference and the sum of skinfolds were the anthropometric variables with the highest association with adiposity. New alternatives were presented with higher coefficients of determination (PRESS R(2) ranged from 0.47 to 0.71). CONCLUSIONS: The newly developed body indices are limited in predicting %FM in elite athletes, particularly when compared with other commonly and readily available field methods like bioimpedance analysis or skinfold prediction models. PMID- 26059367 TI - Adiponectin may be a biomarker of early atherosclerosis of smokers and decreased by nicotine through KATP channel in adipocytes. AB - OBJECTIVE: Plasm adiponectin is decreased in smokers. Adiponectin is emerging as a potential key molecular marker in atherosclerosis and other cardiovascular diseases. The aim of this study was to investigate the association between serum adiponectin levels and early atherosclerosis in smokers. Furthermore, the role of the KATP channel in the down-regulation of adiponectin by smoking was preliminarily explored. METHODS: We consecutively enrolled 96 men, including 50 smokers with atherosclerosis and 46 nonsmokers. Serum adiponectin was detected with enzyme-linked immunosorbent assay - in all participants. Large (C1) and small (C2) artery elasticity indices and carotid intima-media thickness (IMT) were measured as evaluation indexes of early atherosclerosis in smokers. Finally, the effect of nicotine via ATP-dependent potassium (KATP) channels on adiponectin secretion by 3T3-L1 preadipocytes was examined in vitro. RESULTS: Adiponectin levels of smokers were statistically negatively correlated to IMT (r = -.440; P < 0.001) and positively correlated to C1 (r = 0.448; P < 0.001) as well as C2 (r = 0.426; P = 0.002). In 3-T3-L1 preadipocytes, nicotine treatment significantly decreased adiponectin levels (P = 0.003), whereas the adiponectin level was rescued by the inhibition of KATP channel (P < 0.001). CONCLUSION: Serum adiponectin level was an independent predictor of early atherosclerosis in smokers. Nicotine might decrease adiponectin in part through altering KATP channels in adipocytes. PMID- 26059368 TI - Plasma vitamin D status in patients with type 2 diabetes with and without retinopathy. AB - OBJECTIVE: Diabetic retinopathy (DR) is a common cause of blindness. Although an association between hypovitaminosis D and type 1 diabetes is known, the association between vitamin D (VD) and type 2 diabetes (T2D) and its complications such as DR has been unclear. The aim of this study was to investigate the status of VD in T2D patients with and without DR. METHODS: A cross-sectional case-control study was conducted with 99 normal control (CN) participants and 164 patients with T2D, of which 82 had retinopathy (DR) and 82 did not (DNR). After a complete ophthalmic examination, inclusive of fundus fluorescein angiography, the clinical profile and the plasma levels of VD and calcium were analyzed. RESULTS: Although the mean plasma VD levels were significantly lower in the DNR and DR groups compared with the CN group, no significant differences were observed between the groups with diabetes. Although the mean levels of VD in all three groups were below the normal range, the prevalence of VD deficiency (VDD) was higher in the DNR and DR groups (66% and 63%) than in the CN group (45%), suggesting that the prevalence of VDD was higher in individuals with diabetes, regardless of the presence or absence of retinopathy. However, there were no group differences in the plasma levels of calcium. Additionally, VDD did not seem to be related to patient's age or body mass index, but was related to the duration of diabetes. CONCLUSION: Results from this study suggest a possible association between VDD and T2D, but not specifically with DR. Further investigations are warranted. PMID- 26059369 TI - Undernutrition status and associated factors in under-5 children, in Tigray, Northern Ethiopia. AB - OBJECTIVE: The aim of this study was to assess the nutritional status and associated factors in children <5 y in the Medebay Zana District, northern Ethiopia. METHODS: A community-based cross-sectional study was conducted in the Medebay Zana District from September 8 to 29, 2013. A two-stage cluster-sampling technique was used to select 605 children age <5 y. Descriptive, binary, and multiple logistic regression analyses were performed. RESULTS: The results of this study demonstrated that the level of stunting was 56.6%, underweight 45.3%, and wasting 34.6%. Stunting was predicted by having mothers who attended high school (adjusted odds ratio [AOR], 0.75; 95% confidence interval [CI], 0.09 0.85), living in a household where providing priority food was given to the father (AOR, 4.32; 95% CI, 2.10-9.05), and water was taken from unprotected sources (AOR, 2.13; 95% CI, 1.09-4.14). In all children, initiation of breast feeding within 1 to 3 h after birth (AOR, 4.06; 95% CI, 1.77-9.33), having mothers who could make financial decisions (AOR, 0.09; 95% CI, 0.02-0.51), and being breast-fed for 12 to 23 mo (AOR, 0.07; 95% CI, 0.01-0.40) were predictors of wasting. Moreover, in girls (AOR, 1.84; 95% CI, 1.25, 2.69), initiation of breast-feeding 6 h after birth (AOR, 12.94; 95% CI, 4.04-41.49) and having mothers who could make financial decisions (AOR, 0.33; 95% CI, 0.15-0.74) were predictors of being underweight. CONCLUSION: The undernutrition status among children <5 y was high. Children's age group, time initiation of breast-feeding, child's sex, source of water, parents' educational status, type of food used for starting of complementary feeding, and mothers' financial decision-making ability could have an influence in undernutrition of children in this age group. PMID- 26059370 TI - Functional status and heart rate variability in end-stage liver disease patients: association with nutritional status. AB - OBJECTIVES: Muscle dysfunction and reduced heart rate variability (HRV) are common in patients with advanced liver disease, and both are related to poor outcomes. Malnutrition is also highly prevalent in these patients, however, the association between the malnutrition and HRV has not yet been assessed. The aim of this study was to evaluate the short-term HRV, functional and nutritional statuses in patients with advanced liver disease. METHODS: The nutritional and functional statuses were determined by subjective global assessment, handgrip strength (dynamometer, JAMAR) and gait speed during a 6-minute walk text (6MWT), respectively. The cardiac workload index (CWI) was used to evaluate the cardiac response to the 6MWT. The time domain (SD of all normal-to-normal intervals [SDNN]) and very-low, low-, and high-frequency domains of short-term HRV were evaluated with RS800 CX (Polar, Finland) and Cardioseries software (Brazil). RESULTS: The study evaluated 42 patients with liver disease (62% men) and malnutrition was found in 62% of this population. The malnourished participants presented with reduced functional status, 41% decreased SDNN, and 14% greater CWI compared with well-nourished individuals (P < 0.05). Additionally, the CWI was negatively associated to SDNN (r = 0.414; P < 0.05) and gait speed (r = 0.598; P < 0.05), especially in malnourished individuals (r = 0.650; P < 0.05). These data indicate that malnourished patients with liver disease have higher cardiovascular risk related to reduced functional status, which may be associated to poor outcomes during the course of the disease before and after transplant. Another relevant aspect is that the 6MWT associated to HRV could be a useful tool to screen liver disease patients who have a higher risk for cardiovascular complications. PMID- 26059371 TI - Associations of serum beta-carotene and retinol concentrations with insulin resistance: the Toon Health Study. AB - OBJECTIVE: Although green and yellow vegetables have beneficial effects against type 2 diabetes, the relationship of their nutritive content with insulin resistance is poorly understood. The aim of this study was to examine the associations of serum beta-carotene and retinol concentrations with glucose and insulin concentrations. METHODS: We recruited 951 Japanese men and women ages 30 to 79 y who were not undergoing treatment for diabetes and measured their serum beta-carotene and retinol concentrations. A 75-g oral glucose tolerance test was performed and the homeostasis model assessment for insulin resistance (HOMA-IR) and the Matsuda Index were calculated as measures of insulin resistance. Several confounding factors were adjusted for with multivariable logistic models. RESULTS: Multivariable-adjusted odds ratios of the highest quartile of serum beta carotene compared with the lowest quartile for HOMA-IR >1.6 and Matsuda Index <4.9 were 0.56 (95% confidence interval, 0.34-0.94) and 0.62 (0.37-1.02), respectively. When stratified by sex and overweight status, these associations were observed for women and non-overweight individuals. Serum retinol concentration was not associated with either index. Furthermore, according to the nutritional survey, serum beta-carotene concentration was associated with green and yellow vegetable intake (P = 0.01). CONCLUSION: Our findings suggest that higher serum beta-carotene levels, associated with higher intake of green and yellow vegetables, confer beneficial effects against insulin resistance. PMID- 26059372 TI - Short-term effects of ketogenic diet on anthropometric parameters, body fat distribution, and inflammatory cytokine production in GLUT1 deficiency syndrome. AB - OBJECTIVE: The aim of this study was to evaluate the effects of a 12-wk ketogenic diet (KD) on inflammatory status, adipose tissue activity biomarkers, and abdominal visceral (VAT) and subcutaneous fat (SAT) in children affected by glucose transporter 1 deficiency syndrome GLUT1 DS. METHODS: We carried out a short-term longitudinal study on 10 children (mean age: 8.4 y, range 3.3-12 y, 5 girls, 5 boys) to determine fasting serum proinflammatory cytokines (high sensitivity C-reactive protein, tumor necrosis factor-alpha interleukin-6), adipocyte-derived chemokines (leptin and adiponectin), lipid profile, homeostatic model assessment-insulin resistance (HOMA-IR), quantitative insulin sensitivity index (QUICKI), anthropometric measurements, and VAT and SAT (by ultrasonography). RESULTS: Children showed no significant changes in inflammatory and adipose tissue activity biomarkers, blood glucose, lipid profile, anthropometric measurements, VAT, and SAT. Fasting insulin decreased (6 +/- 3.2 MUU/mL versus 3 +/- 2 MUU/mL; P = 0.001), and both HOMA-IR and QUICKI indexes were significantly modified (1.2 +/- 0.6 versus 0.6 +/- 0.4; P = 0.002; 0.38 +/- 0.03 versus 0.44 +/- 0.05; P = 0.002, respectively). CONCLUSIONS: Only HOMA-IR and QUICKI indexes changed after 12 wk on a KD, suggesting that over a short period of time KD does not affect inflammatory cytokines production and abdominal fat distribution despite being a high-fat diet. Long-term studies are needed to provide answers concerning adaptive metabolic changes during KD. PMID- 26059373 TI - Influence of dietary intake of fish oil, magnesium, and zinc on metabolic parameters among individuals tested for diabetes. AB - OBJECTIVE: The aim of this study was to assess the significance and degree of correlation between the intake of fish oil, magnesium (Mg), and zinc (Zn) and metabolic parameters. METHODS: Correlation coefficients among nutrient intake and physical and laboratory parameters were determined using Spearman's rho (rho) test or a multiple regression model among Japanese individuals (male:female, 37:66; median age, 55 y) who completed a semiquantitative food questionnaire and underwent testing for diabetes. Individuals with diabetes were excluded. RESULTS: Spearman's test revealed several weak but significant correlations between intake of fish oil including omega-3 polyunsaturated fatty acids (PUFAs) and various metabolic parameters. The test showed that Zn intake in women significantly correlated with reduced systolic blood pressure (SBP), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (gamma-GPT), and homeostasis model assessment-insulin resistance (HOMA-IR). Multivariate analysis revealed that intake of fish oil, eicosapentaenoic acid (EPA), and Zn was significantly associated with increased serum levels of high-density lipoprotein cholesterol (HDL-C; fish oil versus HDL-C, P = 0.0438; 95% confidence interval [CI], 0.0055 0.3724; EPA versus HDL-C, P = 0.0439; 95% CI, 0.0053-0.3724; Zn versus HDL-C, P = 0.0041; 95% CI, 0.0890-0.4609). Multivariate analysis revealed that omega-3 PUFAs were associated with decreased serum ALT levels (P = 0.0240; 95% CI, -5.000 to 0.0367) and that Zn correlated with SBP (P = 0.0239; 95% CI, -0.5149 to -0.0377) in women. CONCLUSION: Intake of fish oil, Mg, and Zn was associated with some metabolic parameters. Abundant intake of fish oil including omega-3 PUFAs and Zn can exert antiarteriosclerotic effects through increasing serum levels of HDL-C. omega-3 PUFAs can reduce liver inflammation and Zn can reduce SBP in women. PMID- 26059374 TI - The nondietary determinants of vitamin D status in pediatric inflammatory bowel disease. AB - OBJECTIVES: The aim of this study was to investigate the relationships between 25 hydroxy vitamin D (25[OH]D) and markers of vitamin D status in inflammatory bowel disease (IBD). METHODS: We conducted a retrospective case-control study of 59 pediatric patients with IBD (age 16.4 +/- 2.2 y) and 116 controls (age 14.6 +/- 4.4 y), to investigate the association between 25(OH)D and albuminemia for protein-losing enteropathy (PLE) and hepatic dysfunction; alanine transaminase (ALT) for hepatic inflammation; erythrocyte sedimentation rate (ESR) for intestinal inflammation; body mass index (BMI) for adiposity; seasons and skin pigmentation for insolation. Vitamin D deficiency was defined as 25(OH)D < 50 nmol/L; abnormal liver enzyme by ALT >40 U/L; overweight status by BMI of >=85th but <95th percentile, and obesity by BMI >=95th percentile. Seasons were categorized as summer, winter, spring, and fall. RESULTS: Patients with IBD had a higher prevalence of vitamin D deficiency (42.4% versus 26.7%; P = 0.04), elevated ALT (16.9% versus 2.6%; P < 0.001), and lower albumin (41.1 +/- 4.8 versus 45.1 +/- 3.8; P < 0.001) than controls. In both the IBD cohort and controls, 25(OH)D was highest in summer and lowest in winter, and significantly higher in white than in non-white patients. ESR varied significantly with 25(OH)D (R(2) = 0.24; beta = -0.32; P = 0.010), and only patients with IBD with elevated ESR had lower 25(OH)D than controls (49.5 +/- 25.2 versus 65.3 +/- 28.0 nmol/L; P = 0.045). CONCLUSION: Intestinal inflammation, not the loss of albumin-bound vitamin D in the gut, is the primary intestinal determinant of vitamin D status in IBD. The extraintestinal determinants are seasons and skin pigmentation, but not adiposity and hepatic inflammation. PMID- 26059375 TI - Lactobacillus casei CRL 431 administration decreases inflammatory cytokines in a diet-induced obese mouse model. AB - OBJECTIVES: Obesity is a chronic disease associated with an inflammatory process in which cytokines play an important role. Probiotic microorganisms have been associated with modulation of the host immune system. The aim of this study was to evaluate the influence of the probiotic bacterium Lactobacillus casei CRL 431 on the cytokine response in a model of mice under high-fat diet (HFD) conditions. METHODS: BALB/c mice received a conventional balanced diet or an HFD. The test groups received milk, milk fermented by L. casei (FM), or L. casei as suspension in the drinking water. Proinflammatory and regulatory cytokine producer cells were evaluated in the small intestine and liver; the cytokine levels in the intestinal fluids were also evaluated. The percentages of immune cells as macrophages (F4/80), NKT, CD4+, CD8+ populations were determined in the liver. Adipocytes were also isolated and cultured to evaluate cytokines and the chemokine monocyte chemoattractant protein (MCP)-1 produced by them. RESULTS: The administration of probiotic L. casei CRL 431 exerted an anti-inflammatory response in mice fed an HFD, evidenced mainly by decreasing proinflammatory cytokines, such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha. Probiotic administration also was associated with fewer immune-infiltrating cells in the liver of mice that received the HFD and decreased secretion of MCP-1 by the adipocytes. This last observation could be associated with less macrophage accumulation in the adipose tissues, which is characteristic in the obese host and contributes to maintaining the inflammatory response in this organ. The results obtained show an anti-inflammatory effect of L. casei CRL 431 when it is administered as a supplement of the HFD in a mouse model. PMID- 26059376 TI - LC-MS/MS profiling and neuroprotective effects of Mentat(r) against transient global ischemia and reperfusion-induced brain injury in rats. AB - OBJECTIVE: The aim of this study was to evaluate the possible beneficial effects of Mentat against transient global ischemia and reperfusion-induced brain injury in rats. METHODS: The neuroprotective effects of Mentat were evaluated against transient global ischemia and reperfusion (I/R)-induced brain injury in rats. Various neurobehavioral and biochemical parameters were assessed, followed by morphologic and histopathologic evaluation of brain tissue to conclude the protective effect of Mentat. Additionally, in vitro antioxidant assays were performed to explore the antioxidant capacity of Mentat and detailed liquid chromatography-mass spectrometry (LC-MS/MS) profiling was carried out to identify the active phytoconstituents responsible for the protective effects of Mentat. RESULTS: Sixty minutes of transient global ischemia followed by 24 h reperfusion (I/R) caused significant alterations in the cognitive and neurologic functions in the ischemia control group (P < 0.01) compared with the sham control. Furthermore, 2,3,5-triphenyltetrazolium chloride staining of the ischemia control group showed 20.85% +/- 0.39% of cerebral infarct area (P < 0.01), increased brain volume (% edema 17.81% +/- 1.576%; P < 0.01), and increased lipid peroxidation (P < 0.01) in the brain homogenate. Additionally, the histopathology of the ischemia control group showed severe brain injury compared with the sham control group. Interestingly, pretreatment with Mentat (250 and 500 mg/kg, p.o.) and quercetin (20 mg/kg, p.o.) for 7 d has alleviated all pathological changes observed due to I/R injury. Mentat also showed very good antioxidant activity in in vitro assays (2,2-diphenyl-l-picrylhydrazyl, ferric-reducing antioxidant power, and oxygen radical absorbance capacity assays). Furthermore, the detailed LC-MS/MS analysis of Mentat was performed and enclosed for identifying the actives responsible for its protective effects. CONCLUSIONS: These findings suggest that Mentat is a neuroprotective agent that may be a useful adjunct in the management of ischemic stroke and its rehabilitation especially with respect to associated memory impairment and other related neurologic conditions. PMID- 26059378 TI - Docosahexaenoic acid alters Gsalpha localization in lipid raft and potentiates adenylate cyclase. AB - OBJECTIVE: Supplementation with docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (PUFA), recently has become popular for the amelioration of depression; however the molecular mechanism of DHA action remains unclear. The aim of this study was to investigate the mechanism underlying the antidepressant effect of DHA by evaluating Gsalpha localization in lipid raft and the activity of adenylate cyclase in an in vitro glioma cell model. METHODS: Lipid raft fractions from C6 glioma cells treated chronically with DHA were isolated by sucrose gradient ultracentrifugation. The content of Gsalpha in lipid raft was analyzed by immunoblotting and colocalization of Gsalpha with lipid raft was subjected to confocal microscopic analysis. The intracellular cyclic adenosine monophosphate (cAMP) level was determined by cAMP immunoassay kit. RESULTS: DHA decreased the amount of Gsalpha in lipid raft, whereas whole cell lysate Gsalpha was not changed. Confocal microscopic analysis demonstrated that colocalization of Gsalpha with lipid raft was decreased, whereas DHA increased intracellular cAMP accumulation in a dose-dependent manner. Interestingly, we found that DHA increased the lipid raft level, instead of disrupting it. CONCLUSIONS: The results of this study suggest that DHA may exert its antidepressant effect by translocating Gsalpha from lipid raft and potentiating the activity of adenylate cyclase. Importantly, the reduced Gsalpha in lipid raft by DHA is independent of disruption of lipid raft. Overall, the study provides partial preclinical evidence supporting a safe and effective therapy using DHA for depression. PMID- 26059377 TI - The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTor signaling in vivo and the expression of myogenic genes in vitro. AB - OBJECTIVES: Nutrition plays a key role in the maintenance of muscle and bone mass, and dietary protein deficiency has in particular been associated with catabolism of both muscle and bone tissue. One mechanism thought to link protein deficiency with loss of muscle mass is deficiency in specific amino acids that play a role in muscle metabolism. The aim of this study was to test the hypothesis that the essential amino acid tryptophan, and its metabolite kynurenine, might directly affect muscle metabolism in the setting of protein deficiency. METHODS: Adult mice (12 mo) were fed a normal diet (18% protein), as well as diets with low protein (8%) supplemented with increasing concentrations (50, 100, and 200 uM) of kynurenine (Kyn) or with tryptophan (Trp; 1.5 mM) for 8 weeks. Myoprogenitor cells were also treated with Trp and Kyn in vitro to determine their effects on cell proliferation and expression of myogenic differentiation markers. RESULTS: All mice on the low-protein diets weighed less than the group fed normal protein (18%). Lean mass measured by dual-energy X-ray absorptiometry was lowest in mice on the high Kyn diet, whereas percent lean mass was highest in mice receiving Trp supplementation and percent body fat was lowest in mice receiving Trp. Enzyme-linked immunosorbent assays showed significant increases in skeletal muscle insulin-like growth factor-1, leptin, and the myostatin antagonist follistatin with Trp supplementation. mRNA microarray and gene pathway analysis performed on muscle samples demonstrate that mTor/eif4/p70s6k pathway molecules are significantly up-regulated in muscles from mice on Kyn and Trp supplementation. In vitro, neither amino acid affected proliferation of myoprogenitors, but Trp increased the expression of the myogenic markers MyoD, myogenin, and myosin heavy chain. CONCLUSION: These findings suggest that dietary amino acids can directly affect molecular signaling in skeletal muscle, further indicating that dietary manipulation with specific amino acids could potentially attenuate muscle loss with dietary protein deficiency. PMID- 26059380 TI - Iron supplementation effectively suppresses gastrocnemius muscle lesions to improve exercise capacity in chronic heart failure rats with anemia. AB - OBJECTIVE: For patients with chronic heart failure (CHF), exertional fatigue is one of the most common and debilitating symptoms. However, the poor relationship between heart dysfunction and exercise capacity has been ascribed to peripheral abnormalities. Several previous studies confirmed that iron supplementation could significantly improve the exercise capacity of patients with CHF, although they did not analyze effects in the musculoskeletal system. The aim of this study was to investigate the effect of iron treatment on gastrocnemius muscles of CHF rats with anemia. METHODS: Male Sprague-Dawley rats were subjected to coronary ligation to induce heart failure. At the same time, blood (1-1.5 mL) was withdrawn from the retro-orbital plexus once every week to induce anemia. After 6 wk of this process, iron dextran was administered to the CHF rats with anemia (CHFa rats) at the dose of 8, 16, 32, or 64 mg/kg every 2 d for 2 wk. RESULTS: Iron dextran (8 mg/kg every 2 d) effectively improved hemodynamic parameters (P < 0.05) compared with CHFa rats. Similarly, this dose of iron dextran significantly reduced the ratio of heart weight to body weight (P < 0.01), whereas it significantly increased the distance run (m) to exhaustion (P < 0.01). Iron dextran effectively inhibited sarcoplasmic vacuolation and muscle atrophy of gastrocnemius muscles in CHFa rats, as evaluated by pathologic examinations. Other iron treatments, however, were found to be ineffective on the same parameters, so particular focus was placed on the iron dextran (8 mg/kg every 2 d) group in subsequent analyses. Consistently, phospho-p38 in gastrocnemius muscles of CHFa rats was markedly suppressed by iron dextran. Additionally, iron dextran significantly decreased c-fos and c-jun and up-regulated cellular FLICE inhibitory protein expression levels. PMID- 26059379 TI - Role of diallyl disulfide-mediated cleavage of c-Myc and Sp-1 in the regulation of telomerase activity in human lymphoma cell line U937. AB - OBJECTIVE: Garlic (Allium sativum) has been considered a wonder herb for years with a reputation of disease prevention. Telomerase, a ribonucleoprotein enzyme responsible for telomere integrity, is strongly up-regulated in different types of cancers. The aim of this study was to reveal the role of diallyl disulfide (DADS), an organosulfur component of garlic, on telomerase activity in human lymphoma with an emphasis on key transcription factors c-Myc and Sp-1. METHODS: Human lymphoma cell line U937 was used as model cell line. Telomerase activity was measured by telomerase repeat amplification protocol assay, levels of related proteins and mRNAs were measured by Western blot and reverse transcriptase polymerase chain reaction, respectively. Moreover, in vitro binding assay was performed using radiolabeled double-stranded DNA having specific sequences to detect involvement of transcription factors in DADS-dependent modulation of telomerase activity. RESULTS: The present study demonstrated DADS-mediated decrease in telomerase activity in U937 cells with concomitant transcriptional down-regulation of human telomerase reverse transcriptase (hTERT) that is caused by reduced binding of c-Myc and Sp-1 to their respective binding sites on hTERT promoter. Lowering of DNA-binding activity of c-Myc and Sp-1 due to DADS treatment is caused by the deactivation of these transcription factors due to cleavage. Additionally, Mad1-the repressor protein of hTERT expression-is also overexpressed in DADS-treated U937 cells. CONCLUSIONS: These findings strongly suggest that DADS down-regulate telomerase activity through c-Myc-, Sp-1-, and Mad1-dependent transcriptional down-regulation of hTERT. PMID- 26059381 TI - Conjugated linoleic acid reduces visceral and ectopic lipid accumulation and insulin resistance in chronic severe hypertriacylglycerolemia. AB - OBJECTIVE: The metabolic health effects of conjugated linoleic acid (CLA), which is one of the principal polyunsaturated fatty acids, are controversial and still not fully accepted. The aim of this study was to examine the effects of CLA on adiposity, ectopic lipid accumulation, and insulin-resistant states in a metabolic syndrome model of non-obese hereditary rats with hypertriacylglycerolmia (HHTg). METHODS: Groups of adult male HHTg rats were fed a high-carbohydrate diet (70% sucrose) with a 2% mixture of CLA isomers, or with the same amount of sunflower oil (control group) for 2 mo. RESULTS: CLA supplementation decreased body weight gain (P < 0.05) and visceral adipose tissue weight (P < 0.01), and distinctively reduced serum triacylglycerols (P < 0.01) and triacylglycerol accumulation in the liver, heart, muscle, and aorta. CLA treated rats exhibited increased insulin sensitivity in the adipose (P < 0.01), a higher release of fatty acids (P < 0.001), and increased adiponectin secretion (P < 0.01).In the skeletal muscle, CLA supplementation was associated with increased glucose oxidation (P < 0.01) and an elevated anti-inflammatory index (P < 0.05), according to phospholipid fatty acid composition. In the liver, CLA reduced the oxidized form of glutathione and elevated the activity of glutathione-dependent antioxidant enzymes. CONCLUSION: Results suggest that CLA supplementation may protect against HHTg-induced dyslipidemia, ectopic lipid deposition, and insulin resistance. Increased glucose oxidation in the skeletal muscle as well as adiponectin secretion may play a role in the mechanism of the CLA action. Results suggest that CLA could reduce the negative consequences of HHTg and metabolic syndrome. PMID- 26059382 TI - Nutritional strategies to reduce inflammation in chronic kidney disease patients. PMID- 26059383 TI - How to treat type 2 diabetes-induced encephalopathy: regulating the autophagic pathway? PMID- 26059384 TI - Correction of data errors and reanalysis of "The effect of glucomannan on body weight in overweight or obese children and adults: a systematic review of randomized controlled trials". PMID- 26059385 TI - Food at will after pancreaticoduodenectomies. Re. "Perioperative nutritional support of patients undergoing pancreatic surgery in the age of ERAS". PMID- 26059386 TI - Early oral nutrition after major pancreatic surgery. Author response to "Food at will after pancreaticoduodenectomies". PMID- 26059387 TI - Ethical pain management in the emergency department: the canary in the coal mine. AB - The emergency department serves as the gateway to the acute healthcare system. In the USA and increasingly worldwide, patients view the emergency department as the venue where both diagnostic and therapeutic modalities will be brought to bear regardless of condition or socioeconomic status. At the same time, the emergency department is the canary in the coal mine--the warning location for difficulties in how healthcare is delivered to patients in both the outpatient and inpatient settings. In no area is this more apparent than pain management. Emergency departments are expected to treat patient's pain aggressively, often in the face of incomplete or contradictory histories and the inability to ensure outpatient follow-up. These factors create an ethical challenge for emergency departments in how to approach pain treatment. This paper will provide a framework for how emergency departments can address the ethical challenges posed by pain management. PMID- 26059388 TI - An analysis of England's nursing policy on compassion and the 6Cs: the hidden presence of M. Simone Roach's model of caring. AB - In 2012, chief nursing officers (CNO) in England published a policy on compassion in response to serious criticisms of patients' care. Because their objective is fundamentally to shape nursing, this study argues, following Popper, that the policy should be analysed. An appraisal tool, developed from Popper, Gadamer, Jauss and Thiselton, is the framework for this analysis. The CNO policy document identified six values and behaviours, termed '6Cs', required by all nurses, midwives and care staff. The document contains no data, references or acknowledgements, but is similar to the 6Cs defined by the Canadian nursing nun, Sister M. Simone Roach, in her theory of caring published 30 years earlier. Roach considered caring and the components of it, including compassion, to be moral virtues, an inner motivation to care. This study suggests that without explicit reference to Roach's ideas, and her underlying theoretical base, the CNO requirement has the effect of turning virtues into commodities and a form of external control, described by Ritzer as a McDonaldized dehumanization. This study, which has international relevance beyond England and the UK, suggests that the CNO revise their policy by acknowledging Roach's 6Cs and openly discuss the implications of her work for their policy. PMID- 26059389 TI - Impact of functional magnetic resonance imaging (fMRI) scanner noise on affective state and attentional performance. AB - INTRODUCTION: Previous research has shown that performance on cognitive tasks administered in the scanner can be altered by the scanner environment. There are no previous studies that have investigated the impact of scanner noise using a well-validated measure of affective change. The goal of this study was to determine whether performance on an affective attentional task or emotional response to the task would change in the presence of distracting acoustic noise, such as that encountered in a magnetic resonance imaging (MRI) environment. METHOD: Thirty-four young adults with no self-reported history of neurologic disorder or mental illness completed three blocks of the affective Posner task outside of the scanner. The task was meant to induce frustration through monetary contingencies and rigged feedback. Participants completed a Self-Assessment Manikin at the end of each block to rate their mood, arousal level, and sense of dominance. During the task, half of the participants heard noise (recorded from a 4T MRI system), and half heard no noise. RESULTS: The affective Posner task led to significant reductions in mood and increases in arousal in healthy participants. The presence of scanner noise did not impact task performance; however, individuals in the noise group did report significantly poorer mood throughout the task. CONCLUSIONS: The results of the present study suggest that the acoustic qualities of MRI enhance frustration effects on an affective attentional task and that scanner noise may influence mood during similar functional magnetic resonance imaging (fMRI) tasks. PMID- 26059390 TI - Group sessions with Paro in a nursing home: Structure, observations and interviews. AB - AIM: We recently reported that a companion robot reduced residents' loneliness in a randomised controlled trial at an aged-care facility. This report aims to provide additional, previously unpublished data about how the sessions were run, residents' interactions with the robot and staff perspectives. METHODS: Observations were conducted focusing on engagement, how residents treated the robot and if the robot acted as a social catalyst. In addition, 16 residents and 21 staff were asked open-ended questions at the end of the study about the sessions and the robot. RESULTS: Observations indicated that some residents engaged on an emotional level with Paro, and Paro was treated as both an agent and an artificial object. Interviews revealed that residents enjoyed sharing, interacting with and talking about Paro. CONCLUSION: This study supports other research showing Paro has psychosocial benefits and provides a guide for those wishing to use Paro in a group setting in aged care. PMID- 26059391 TI - Investigation of pH-induced conformational change and hydration of poly(methacrylic acid) by analytical ultracentrifugation. AB - Analytical ultracentrifugation was performed on poly(methacrylic acid) (PMAA) with a series of weight average molar masses (Mw) in aqueous solutions as a function of pH. The scales of the sedimentation coefficient (s) and the diffusion coefficient (D) to Mw at infinite dilutions were obtained at different pH values, indicating that PMAA chains adopt a collapsed structure at low pH values, and stretch at pH higher than 5.2. Our results show that the sedimentation coefficient exhibits a minimum at pH ~ 6.0, presumably due to the effect of the conformational change and the hydration state of PMAA chains. When pH increases from 6.0 to 8.5, PMAA chains with high molar mass shrink a little bit, presumably because the sodium ions act as a bridging agent between nonadjacent carboxylate groups. Furthermore, the weight average molar mass of PMAA at pH 8.5 increases by one fold than that at pH 4.0, indicating the condensation of sodium ions and the increase in the number of hydration water molecules around carboxylate groups at high pH values. PMID- 26059392 TI - Commentary on: Use of Quilting Sutures During Abdominoplasty to Prevent Seroma Formation: Are They Really Effective? PMID- 26059393 TI - Drift-corrected nanoplasmonic hydrogen sensing by polarization. AB - Accurate and reliable hydrogen sensors are an important enabling technology for the large-scale introduction of hydrogen as a fuel or energy storage medium. As an example, in a hydrogen-powered fuel cell car of the type now introduced to the market, more than 15 hydrogen sensors are required for safe operation. To enable the long-term use of plasmonic sensors in this particular context, we introduce a concept for drift-correction based on light polarization utilizing symmetric sensor and sensing material nanoparticles arranged in a heterodimer. In this way the inert gold sensor element of the plasmonic dimer couples to a sensing-active palladium element if illuminated in the dimer-parallel polarization direction but not the perpendicular one. Thus the perpendicular polarization readout can be used to efficiently correct for drifts occurring due to changes of the sensor element itself or due to non-specific events like a temperature change. Furthermore, by the use of a polarizing beamsplitter, both polarization signals can be read out simultaneously making it possible to continuously correct the sensor response to eliminate long-term drift and ageing effects. Since our approach is generic, we also foresee its usefulness for other applications of nanoplasmonic sensors than hydrogen sensing. PMID- 26059394 TI - Sesamol suppresses the inflammatory response by inhibiting NF-kappaB/MAPK activation and upregulating AMP kinase signaling in RAW 264.7 macrophages. AB - OBJECTIVES AND DESIGN: Sesamol is a lignan isolated from sesame seed oil. In recent years, it was found that sesamol could decrease lung inflammation and lipopolysaccharide (LPS)-induced lung injury in rats. In this study, we investigated whether sesamol exhibited anti-inflammatory activity in LPS stimulated macrophages. MATERIALS AND METHODS: RAW 264.7 cells were treated with sesamol, then treated with LPS to induce inflammation. The levels of proinflammatory cytokines were analyzed with ELISA. The gene and protein expression of cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), and nuclear factor erythroid-2-related factor 2 (Nrf2) were evaluated with real-time PCR and Western blots, respectively. We also examined inflammatory signaling pathways, including nuclear transcription factor kappa-B (NF-kappaB) and mitogen activated protein kinase (MAPK) pathways. RESULTS: Sesamol inhibited production of nitric oxide, prostaglandin E2 (PGE2), and proinflammatory cytokines. Sesamol markedly suppressed mRNA and protein expression of iNOS and COX-2. Sesamol enhanced the protective antioxidant pathway represented by Nrf2 and HO-1. Moreover, sesamol suppressed NF-kappaB transport into the nucleus and decreased MAPK activation, but it promoted adenosine monophosphate-activated protein kinase (AMPK) activation. CONCLUSIONS: These data suggested that sesamol ameliorated inflammatory and oxidative damage by upregulating AMPK activation and Nrf2 signaling and blocking the NF-kappaB and MAPK signaling pathways. PMID- 26059396 TI - Erratum to: ISCEV Standard for full-field clinical electroretinography (2015 update). PMID- 26059395 TI - Local immunosuppression induced by high viral load of human papillomavirus: characterization of cellular phenotypes producing interleukin-10 in cervical neoplastic lesions. AB - A specific immune response to human papillomavirus (HPV) in the cervical microenvironment plays a key role in eradicating infection and eliminating mutated cells. However, high-risk HPVs modulate immune cells to create an immunosuppressive microenvironment, and induce these immune cells to produce interleukin 10 (IL-10). This production of IL-10, in conjunction with HPV infection, contributes to the appearance of cervical neoplastic lesions. We sought to characterize the IL-10-producing cellular phenotype, and investigate the influence of host and HPV factors upon the induction of an immunosuppressive microenvironment. Immunohistochemical analysis demonstrated an increase in IL-10 production by keratinocytes, macrophages and Langerhans cells in high-grade cervical lesions and cervical cancer. This increase was more pronounced in patients older than 30 years, and was also correlated with high viral load, and infection with a single HPV type, particularly high-risk HPVs. Our results indicate the existence of a highly immunosuppressive microenvironment composed of different IL-10-producing cellular phenotypes in cervical cancer samples, and samples classified as high-grade cervical lesions (cervical intraepithelial neoplasia stages II and III). The immunosuppressive microenvironment that developed for these different cellular phenotypes favours viral persistence and neoplastic progression. PMID- 26059397 TI - Staff understanding of recovery-orientated mental health practice: a systematic review and narrative synthesis. AB - BACKGROUND: Mental health policy is for staff to transform their practice towards a recovery orientation. Staff understanding of recovery-orientated practice will influence the implementation of this policy. The aim of this study was to conduct a systematic review and narrative synthesis of empirical studies identifying clinician and manager conceptualisations of recovery-orientated practice. METHODS: A systematic review of empirical primary research was conducted. Data sources were online databases (n = 8), journal table of contents (n = 5), internet, expert consultation (n = 13), reference lists of included studies and references to included studies. Narrative synthesis was used to integrate the findings. RESULTS: A total of 10,125 studies were screened, 245 full papers were retrieved, and 22 were included (participants, n = 1163). The following three conceptualisations of recovery-orientated practice were identified: clinical recovery, personal recovery and service-defined recovery. Service-defined recovery is a new conceptualisation which translates recovery into practice according to the goals and financial needs of the organisation. CONCLUSIONS: Organisational priorities influence staff understanding of recovery support. This influence is leading to the emergence of an additional meaning of recovery. The impact of service-led approaches to operationalising recovery-orientated practice has not been evaluated. TRIAL REGISTRATION: The protocol for the review was pre registered (PROSPERO 2013: CRD42013005942 ). PMID- 26059398 TI - Extracellular signaling cues for nuclear actin polymerization. AB - Contrary to cytoplasmic actin structures, the biological functions of nuclear actin filaments remain largely enigmatic. Recent progress in the field, however, has determined nuclear actin structures in somatic cells either under steady state conditions or in response to extracellular signaling cues. These actin structures differ in size and shape as well as in their temporal appearance and dynamics. Thus, a picture emerges that suggests that mammalian cells may have different pathways and mechanisms to assemble nuclear actin filaments. Apart from serum- or LPA-triggered nuclear actin polymerization, integrin activation by extracellular matrix interaction was recently implicated in nuclear actin polymerization through the linker of nucleoskeleton and cytoskeleton (LINC) complex. Some of these extracellular cues known so far appear to converge at the level of nuclear formin activity and subsequent regulation of myocardin-related transcription factors. Nevertheless, as the precise signaling events are as yet unknown, the regulation of nuclear actin polymerization may be of significant importance for different cellular functions as well as disease conditions caused by altered nuclear dynamics and architecture. PMID- 26059399 TI - Recycling of galectin-3 in epithelial cells. AB - Galectins, a family of beta-galactoside binding proteins, do not possess a signalling sequence to enter the endoplasmic reticulum as a starting point for the classical secretory pathway. They use a so-called unconventional secretion mechanism for translocation across the plasma membrane and/or into the lumen of transport vesicles. The beta-galactoside binding protein galectin-3 is highly expressed in a variety of epithelial cell lines. Polarized MDCK cells secrete this lectin predominantly into the apical medium. The lectin re-enters the cell by non-clathrin mediated endocytosis and passages through endosomal organelles. This internalized galectin-3 plays an important role in apical protein trafficking by directing the subcellular targeting of apical glycoproteins via oligomerization into high molecular weight clusters, a process that can be fine tuned by changes in the environmental pH. Following release at the apical plasma membrane, the lectin can reenter the cell for another round of recycling and apical protein sorting. This review will briefly address galectin-3-functions in epithelia and focus on distinct phases in apical recycling of the lectin. PMID- 26059400 TI - Nipah virus fusion protein: Importance of the cytoplasmic tail for endosomal trafficking and bioactivity. AB - Nipah virus (NiV) is a highly pathogenic paramyxovirus which encodes two surface glycoproteins: the receptor-binding protein G and the fusion protein F. As for all paramyxoviruses, proteolytic activation of the NiV-F protein is an indispensable prerequisite for viral infectivity. Interestingly, proteolytic activation of NiV-F differs principally from other paramyxoviruses with respect to protease usage (cathepsins instead of trypsin- or furin-like proteases), and the subcellular localization where cleavage takes place (endosomes instead of Golgi or plasma membrane). To allow efficient F protein activation needed for productive virus replication and cell-to-cell fusion, the NiV-F cytoplasmic tail contains a classical tyrosine-based endocytosis signal (Y525RSL) that we have shown earlier to be needed for F uptake and proteolytic activation. In this report, we furthermore revealed that an intact endocytosis signal alone is not sufficient for full bioactivity. The very C-terminus of the cytoplasmic tail is needed in addition. Deletions of more than four residues did not affect F uptake or endosomal cleavage but downregulated the surface expression, likely by delaying the intracellular trafficking through endosomal-recycling compartments. Given that the NiV-F cytoplasmic tail is needed for timely and correct intracellular trafficking, endosomal cleavage and fusion activity, the influence of tail truncations on NiV-mediated cell-to-cell fusion and on pseudotyping lentiviral vectors is discussed. PMID- 26059401 TI - The value of SATB2 in the differential diagnosis of intestinal-type mucinous tumors of the ovary: primary vs metastatic. AB - Primary mucinous adenocarcinomas of the ovary are a diagnostic challenge because their histologic and immunohistochemical features usually overlap with metastatic tumors. SATB2 is a recently identified protein with restricted expression in the glandular cells lining the lower gastrointestinal tract. The aim of this study is to examine the differential expression of SATB2 in primary and metastatic tumors of the ovary. Mucinous ovarian tumors of intestinal type were retrieved from the pathology files of the Instituto Nacional de Cancerologia de Mexico. A double reading of the hematoxylin and eosin-stained slides was performed to confirm the diagnosis, and a detailed review of the clinical chart was performed to define the primary origin of the tumor (ovarian vs metastatic). Immunohistochemical staining for CK20, CDX2, and SATB2 was performed and evaluated by 2 gynecopathologists. A total of 106 mucinous tumors were identified, 26 of which were considered to be metastatic, and 80 of which were primary ovarian tumors. All of the primary tumors that were not associated with cystic teratomas were negative for SATB2, and the 4 that were associated with a teratoma were positive for SATB2. All 20 of the metastatic tumors of the colon and appendix were positive for CK20, and 4 were positive for CK7. In addition, all 20 of these tumors were positive for SATB2, and 19 were positive for CDX2. SATB2 appears to be a useful marker for the diagnosis of primary vs metastatic mucinous intestinal type neoplasms and is highly sensitive in detecting lower gastrointestinal tract metastasis. PMID- 26059402 TI - Potential cost-savings may be considerable with management of hypertension according to updated US hypertension guidelines, but for women aged 35-44 years these benefits are unlikely. PMID- 26059403 TI - Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report. AB - We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-beta and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose positron emission tomography, and thus could not completely exclude occult FGF23 producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction. PMID- 26059404 TI - Treatment choices for patients with invasive lobular breast cancer: a doctor survey. AB - RATIONALE, AIMS AND OBJECTIVES: Invasive lobular breast cancer (ILC) has distinct features that present challenges for management. We surveyed doctors regarding management approaches, opinions on quality of evidence supporting their practice, and future research needs. METHODS: An online questionnaire was developed and circulated to breast cancer surgical, radiation and medical oncologists. RESULTS: The questionnaire was completed by 88/428 doctors (20.6%); 22/56 (39.3%) surgeons, 21/64 (32.8%) radiation oncologists and 45/308 (14.6%) medical oncologists. The majority (65%) of surgeons were comfortable treating ILC patients using the same surgical management as patients with invasive ductal cancers (IDC). Furthermore, 25% would perform a similar surgery but would obtain larger gross margins. There was equipoise for radiation oncologists regarding whether or not ILC was an independent risk factor for local-regional recurrence after either breast-conserving surgery or mastectomy. Of those radiation oncologists who believe ILC is an independent risk factor for recurrence after mastectomy, 44.4% would offer radiation in the absence of usual indications. Medical oncologists approached systemic therapy for ILC patients similarly to those with comparable IDCs. Areas identified as most controversial and requiring future research were preoperative magnetic resonance imaging, radiotherapy post mastectomy and the responsiveness of ILC to adjuvant chemotherapy compared with endocrine therapy. CONCLUSIONS: There is a variation in doctors' beliefs, management and opinions regarding the quality of evidence for the management of ILC. Clinical trials specifically assessing the management of ILC are required to guide clinical practice. PMID- 26059405 TI - Effect of NaCl induced floc disruption on biological disintegration of sludge for enhanced biogas production. AB - In the present study, the influence of NaCl mediated bacterial disintegration of waste activated sludge (WAS) was evaluated in terms of disintegration and biodegradability of WAS. Floc disruption was efficient at 0.03 g/g SS of NaCl, promoting the shifts of extracellular proteins and carbohydrates from inner layers to extractable--soluble layers (90 mg/L), respectively. Outcomes of sludge disintegration reveal that the maximum solubilization achieved was found to be 23%, respectively. The model elucidating the parameter evaluation, explicates that floc disrupted--bacterially disintegrated sludge (S3) showed superior biodegradability of about 0.23 (gCOD/gCOD) than the bacterially disintegrated (S2) and control (S3) sludges of about 0.13 (gCOD/gCOD) and 0.05 (gCOD/gCOD), respectively. Cost evaluation of the present study affords net profits of approximately 2.5 USD and -21.5 USD in S3 and S2 sludge. PMID- 26059406 TI - Surgical Resection for Hepatocellular Carcinoma with Concomitant Esophageal Varices. AB - BACKGROUND: The management of hepatocellular carcinoma (HCC) in patients with concomitant esophageal varices (EV) remains controversial. We assessed the surgical outcome of hepatectomy and aimed to clarify the indications and management of HCC in patients with concomitant EV. METHODS: We retrospectively enrolled 502 patients with HCC (100 with and 402 without EV), who underwent curative hepatectomy. We analyzed the prognostic outcomes and risk factors for EV bleeding after hepatectomy. RESULTS: Overall survival (OS) was significantly lower in HCC patients with EV than in those without EV (p = 0.003), although recurrence-free survival was similar in both groups. Multivariate analysis showed that indocyanine green retention test at 15 min (ICGR15) >17 % (p = 0.007) and alpha-fetoprotein >12.5 ng/ml (p = 0.003) was independent predictors of poorer OS. Among patients with EV who underwent hepatectomy, multivariate analysis identified ICGR15 >17 % (p = 0.03) as the only independent predictor of poorer OS. There was no significant difference in OS between HCC patients with EV and ICGR15 <=17.0 % and HCC patients without EV. Ten patients experienced EV bleeding after hepatectomy. Multivariate analysis showed that preoperative endoscopic findings of blue color EV (p = 0.008) and red color sign (p = 0.0005) were independent predictors of EV bleeding in patients with HCC after hepatectomy. CONCLUSIONS: These results suggest that HCC patients with EV and ICGR15 <=17 % may be suitable for surgery, but patients with preoperative endoscopic blue color EV and red color sign need to be managed appropriately. PMID- 26059407 TI - The Effect of Body Mass Index on Perioperative Outcomes After Major Surgery: Results from the National Surgical Quality Improvement Program (ACS-NSQIP) 2005 2011. AB - BACKGROUND: Obesity is associated with poor surgical outcomes and disparity in access-to-care. There is a lack of quality data on the effect of body mass index (BMI) on perioperative outcomes. Accordingly, we sought to determine the procedure specific, independent-effect of BMI on 30-day perioperative outcomes in patients undergoing major surgery. METHODS: Participants included individuals undergoing one of 16 major surgery (cardiovascular, orthopedic, oncologic; n = 141,802) recorded in the ACS-NSQIP (2005-2011). Outcomes evaluated included complications, blood transfusion, length-of-stay (LOS), re-intervention, readmission, and perioperative mortality. Multivariable-regression models assessed the independent-effect of BMI on outcomes. RESULTS: Nearly, 74 % of patients had a BMI disturbance; the majority being overweight (35.3 %) or obese (29.8 %). Morbidly obese patients constituted a small but significant proportion of the patients (5.7 %; n = 8067). In adjusted-analyses, morbidly obese patients had significantly increased odds of wound complications in 15 of the examined procedures, of renal complications after 6-procedures, of thromboembolism after 5 procedures, of pulmonary, septic and UTI complications after 2-procedures, and of cardiovascular complications after CABG. Conversely, obese/overweight patients, except for increased odds of wound complications after select procedures, had significantly decreased odds of perioperative mortality, prolonged-LOS and blood transfusion relative to normal BMI patients after 4, 8, and 9 of the examined procedures. CONCLUSIONS: The prevalence of BMI derangements in surgical patients is high. The effect of BMI on outcomes is procedure specific. Patients with BMI between 18.5 and 40-kg/m(2) at time of surgery fare equally well with regard to complications and mortality. However, morbidly obese patients are at-risk for postsurgical complications and targeted preoperative-optimization may improve outcomes and attenuate disparity in access-to-care. PMID- 26059408 TI - Determinants of Surgical Site Infections Following Pancreatoduodenectomy. AB - BACKGROUND: Surgical site infections (SSI) following pancreatoduodenectomy (PD) contribute to adverse perioperative and long-term outcomes. Hence, the need to determine the modifiable factors related to their causation. AIM: To identify demographic, nutritional, surgical and histopathological factors significantly associated with incisional SSIs. METHODS: A retrospective analysis of a prospectively maintained database of consecutive patients who underwent PD for pancreatic and periampullary lesions at a tertiary care referral centre, between April 2010 and June 2014 was carried out. Patients were divided into two groups based on the SSIs (Group 1-With SSI; Group 2-No SSI). All patients were administered three, once daily doses of Ertapenem (1 g) as follows: within 1 h prior to induction, and on day 1 and day 2 following surgery. No further antibiotics were given prior to discharge unless clinically indicated. RESULTS: 35 out of 277 patients (12.6 %) developed SSIs. No demographic (age, sex, BMI), nutritional (serum albumin), surgical (pancreatic duct size and texture, surgical duration and intraoperative blood transfusions) and histopathological factors (malignancy vs. benign) were noted between the two groups. However, SSIs were significantly higher in patients with endocrine co-morbidities (other than diabetes mellitus), in those patients who had undergone prior ERCP and stenting, as well as an end-to-side pancreaticojejunostomy. Patients with diabetes mellitus had a significantly lower incidence of wound infections (P = .014). CONCLUSION: Preoperative ERCP and stenting, end-to-side PJ and the presence of non-diabetic endocrine co-morbidity may result in a significantly higher risk of SSIs. Further studies targeting these patient subpopulations are warranted to enable a better understanding of how these factors contribute to the incidence of SSIs following PD. PMID- 26059409 TI - Predictors of the Effectiveness of Prophylactic Drains After Hepatic Resection. AB - BACKGROUND: Randomized clinical trials have demonstrated the limited efficacy of prophylactic drains following hepatic resection. However, many surgeons still insist on using prophylactic drains. This study was designed to identify patients who require prophylactic drains to manage or monitor postoperative complications after hepatic resection. METHODS: Data were retrospectively collected from 316 patients who underwent hepatic resection and received a prophylactic drain. The patients were divided into two groups according to whether the drain was used to manage or monitor the following postoperative complications: bile leakage (prophylactic drains were used to monitor and treat bile leakage) and postoperative hemorrhage (the drainage fluid was macroscopically bloody and required drain fluid blood counts and monitoring to assess the need for transfusion or reoperation). The results were then validated in a separate cohort of 101 patients. RESULTS: In 25/316 patients (7.9 %), the prophylactic drains were clinically effective, being used to manage bile leakage in 18 patients and hemorrhage in 8. Intraoperative bile leakage (P = 0.021) and long operation time (>= 360 min) (P = 0.017) were independent predictors of bile leakage. Intraoperative blood loss (>= 650 ml) (P = 0.0009) was an independent predictor of hemorrhage. In the subsequent 101 patients, prophylactic drains were clinically effective in patients with one of these predictors with sensitivity, specificity, and false-negative rates of 88.9, 62.0, and 1.7 %, respectively. CONCLUSION: A prophylactic drain should be considered following hepatic resection for patients with intraoperative bile leakage, operation time of >= 360 min, or blood loss of >= 650 ml. PMID- 26059410 TI - What are the True Advantages of Devices for Hepatic Parenchymal Transection in Open Surgery? PMID- 26059411 TI - Bik subcellular localization in response to oxidative stress induced by chemotherapy, in Two different breast cancer cell lines and a Non-tumorigenic epithelial cell line. AB - Cancer chemotherapy remains one of the preferred therapeutic modalities against malignancies despite its damaging side effects. An expected outcome while utilizing chemotherapy is apoptosis induction. This is mainly regulated by a group of proteins known as the Bcl-2 family, usually found within the endoplasmic reticulum or the mitochondria. Recently, these proteins have been located in other sites and non-canonic functions have been unraveled. Bik is a pro-apoptotic protein, which becomes deregulated in cancer, and as apoptosis is associated with oxidative stress generation, our objective was to determine the subcellular localization of Bik either after a direct oxidative insult due to H2 O2 , or indirectly by cisplatin, an antineoplastic agent. Experiments were performed in two human transformed mammary gland cell lines MDA-MB-231 and MCF-7, and one non tumorigenic epithelial cell line MCF-10A. Our results showed that in MCF-7, Bik is localized within the cytosol and that after oxidative stress treatment it translocates into the nucleus. However, in MDA-MB-231, Bik localizes in the nucleus and translocates to the cytosol. In MCF10A Bik did not change its cellular site after either treatment. Interestingly, MCF10A were more resistant to cisplatin than transformed cell lines. This is the first report showing that Bik is located in different cellular compartments depending on the cancer stage, and it has the ability to change its subcellular localization in response to oxidative stress. This is associated with increased sensitivity when exposed to toxic agents, thus rendering novel opportunities to study new therapeutic targets allowing the development of more active and less harmful agents. PMID- 26059412 TI - Generation of Isogenic Human iPS Cell Line Precisely Corrected by Genome Editing Using the CRISPR/Cas9 System. AB - Genome engineering and human iPS cells are two powerful technologies, which can be combined to highlight phenotypic differences and identify pathological mechanisms of complex diseases by providing isogenic cellular material. However, very few data are available regarding precise gene correction in human iPS cells. Here, we describe an optimized stepwise protocol to deliver CRISPR/Cas9 plasmids in human iPS cells. We highlight technical issues especially those associated to human stem cell culture and to the correction of a point mutation to obtain isogenic iPS cell line, without inserting any resistance cassette. Based on a two steps clonal isolation protocol (mechanical picking followed by enzymatic dissociation), we succeed to select and expand corrected human iPS cell line with a great efficiency (more than 2% of the sequenced colonies). This protocol can also be used to obtain knock-out cell line from healthy iPS cell line by the NHEJ pathway (with about 15% efficiency) and reproduce disease phenotype. In addition, we also provide protocols for functional validation tests after every critical step. PMID- 26059413 TI - Thermodynamics of Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs-Impact of a Second Drug on the Solution Phase Behavior and Implications for Combination Products. AB - There is increasing interest in formulating combination products that contain two or more drugs. Furthermore, it is also common for different drug products to be taken simultaneously. This raises the possibility of interactions between different drugs that may impact formulation performance. For poorly water-soluble compounds, the supersaturation behavior may be a critical factor in determining the extent of oral absorption. The goal of the current study was to evaluate the maximum achievable supersaturation for several poorly water-soluble compounds alone, and in combination. Model compounds included ritonavir, lopinavir, paclitaxel, felodipine, and diclofenac. The "amorphous solubility" for the pure drugs was determined using different techniques and the change in this solubility was then measured in the presence of differing amounts of a second drug. The results showed that "amorphous solubility" of each component in aqueous solution is substantially decreased by the second component, as long as the two drugs are miscible in the amorphous state. A simple thermodynamic model could be used to predict the changes in solubility as a function of composition. This information is of great value when developing co-amorphous or other supersaturating formulations and should contribute to a broader understanding of drug-drug physicochemical interactions in in vitro assays as well as in the gastrointestinal tract. PMID- 26059415 TI - Formation of Au and tetrapyridyl porphyrin complexes in superfluid helium. AB - Binary clusters containing a large organic molecule and metal atoms have been formed by the co-addition of 5,10,15,20-tetra(4-pyridyl)porphyrin (H2TPyP) molecules and gold atoms to superfluid helium nanodroplets, and the resulting complexes were then investigated by electron impact mass spectrometry. In addition to the parent ion H2TPyP yields fragments mainly from pyrrole, pyridine and methylpyridine ions because of the stability of their ring structures. When Au is co-added to the droplets the mass spectra are dominated by H2TPyP fragment ions with one or more Au atoms attached. We also show that by switching the order in which Au and H2TPyP are added to the helium droplets, different types of H2TPyP-Au complexes are clearly evident from the mass spectra. This study suggests a new route for the control over the growth of metal-organic compounds inside superfluid helium nanodroplets. PMID- 26059416 TI - Occupational Safety, Health, and Well-being Among Home-based Workers in the Informal Economy of Thailand. AB - The objective of this article is to provide a summary of the issues related to occupational safety and health and well-being among workers in the informal economy of Thailand, with a special emphasis on home-based workers. The reviewed literature includes documents and information sources developed by the International Labour Organization, the National Statistical Office of Thailand, peer-reviewed scientific publications, and master's theses conducted in Thailand. This work is part of a needs and opportunities analysis carried out by the Center for Work, Environment, Nutrition and Development--a partnership between Mahidol University and University of Massachusetts Lowell to identify the gaps in knowledge and research to support government policy development in the area of occupational and environmental health for workers in the informal economy. PMID- 26059414 TI - Integrative epigenomic and genomic filtering for methylation markers in hepatocellular carcinomas. AB - BACKGROUND: Epigenome-wide studies in hepatocellular carcinoma (HCC) have identified numerous genes with aberrant DNA methylation. However, methods for triaging functional candidate genes as useful biomarkers for epidemiological study have not yet been developed. METHODS: We conducted targeted next-generation bisulfite sequencing (bis-seq) to investigate associations of DNA methylation and mRNA expression in HCC. Integrative analyses of epigenetic profiles with DNA copy number analysis were used to pinpoint functional genes regulated mainly by altered DNA methylation. RESULTS: Significant differences between HCC tumor and adjacent non-tumor tissue were observed for 28 bis-seq amplicons, with methylation differences varying from 12% to 43%. Available mRNA expression data in Oncomine were evaluated. Two candidate genes (GRASP and TSPYL5) were significantly under-expressed in HCC tumors in comparison with precursor and normal liver tissues. The expression levels in tumor tissues were, respectively, 1.828 and - 0.148, significantly lower than those in both precursor and normal liver tissue. Validations in an additional 42 paired tissues showed consistent under-expression in tumor tissue for GRASP (-7.49) and TSPYL5 (-9.71). A highly consistent DNA hypermethylation and mRNA repression pattern was obtained for both GRASP (69%) and TSPYL5 (73%), suggesting that their biological function is regulated by DNA methylation. Another two genes (RGS17 and NR2E1) at Chr6q showed significantly decreased DNA methylation in tumors with loss of DNA copy number compared to those without, suggesting alternative roles of DNA copy number losses and hypermethylation in the regulation of RGS17 and NR2E1. CONCLUSIONS: These results suggest that integrative analyses of epigenomic and genomic data provide an efficient way to filter functional biomarkers for future epidemiological studies in human cancers. PMID- 26059417 TI - MicroRNA-205 inhibits cancer cell migration and invasion via modulation of centromere protein F regulating pathways in prostate cancer. AB - OBJECTIVES: To investigate the functional roles of microRNA-205 in the modulation of novel cancer pathways in prostate cancer cells. METHODS: Functional studies of microRNA-205 were carried out to investigate cell proliferation, migration and invasion in prostate cancer cell lines (PC3 and DU145) by restoration of mature microRNA. In silico database and genome-wide gene expression analyses were carried out to identify molecular targets and pathways mediated by microRNA-205. Loss-of-function studies were applied to microRNA-205 target genes. RESULTS: Restoration of microRNA-205 in cancer cell lines significantly inhibited cancer cell migration and invasion. Our data showed that the centromere protein F gene was overexpressed in prostate cancer clinical specimens and was a direct target of microRNA-205 regulation. Silencing of centromere protein F significantly inhibited cancer cell migration and invasion. Furthermore, MCM7, an oncogenic gene functioning downstream of centromere protein F, was identified by si centromere protein F transfectants in prostate cancer cells. CONCLUSIONS: Loss of tumor-suppressive microRNA-205 seems to enhance cancer cell migration and invasion in prostate cancer through direct regulation of centromere protein F. Our data describing pathways regulated by tumor-suppressive microRNA-205 provide new insights into the potential mechanisms of prostate cancer oncogenesis and metastasis. PMID- 26059419 TI - Shape-dependent microwave permeability of Fe3O4 nanoparticles: a combined experimental and theoretical study. AB - Shape anisotropy is crucial for the microwave permeability of magnetic nanoparticles. In this work, we conduct a systematic study on the shape-dependent microwave permeability of magnetic nanoparticles. Three kinds of Fe3O4 nanoparticles with different geometric shapes (rod, disc, and octahedron) are fabricated by chemical methods and their permeability is investigated through both theoretical calculation and experiment. The results suggest that the rod could exhibit the highest resonance frequency (fr), while the lowest resonance frequency could be found in the octahedron. An opposite trend is observed in the initial permeability (MU0). In order to confirm the experimental permeability, we establish an improved LL-G model, which could take both the shape anisotropy and magnetic domain structure into account by introducing a local effective anisotropy field (Heff). The good agreement between the calculated and experimental permeability proves that the model can reproduce shape-dependent microwave permeability of magnetic nanoparticles. More importantly, no fitting process is involved in this model, enabling us to predict the permeability of magnetic nanostructures independent of experiment results. PMID- 26059418 TI - Systemic, but not cardiomyocyte-specific, deletion of the natriuretic peptide receptor guanylyl cyclase A increases cardiomyocyte number in neonatal mice. AB - Guanylyl cyclase A (GC-A), the receptor for atrial and B-type natriuretic peptides, is implicated in the regulation of blood pressure and cardiac growth. We used design-based stereological methods to examine the effect of GC-A inactivation on cardiomyocyte volume, number and subcellular composition in postnatal mice at day P2. In mice with global, systemic GC-A deletion, the cardiomyocyte number was significantly increased, demonstrating that hyperplasia is the main cause for the increase in ventricle weight in these early postnatal animals. In contrast, conditional, cardiomyocyte-restricted inactivation of GC-A had no significant effect on ventricle weight or cardiomyocyte number. The mean volume of cardiomyocytes and the myocyte-related volumes of the four major cell organelles (myofibrils, mitochondria, nuclei and sarcoplasm) were similar between genotypes. Taken together, systemic GC-A deficiency induces cardiac enlargement based on a higher number of normally composed and sized cardiomyocytes early after birth, whereas cardiomyocyte-specific GC-A abrogation is not sufficient to induce cardiac enlargement and has no effect on number, size and composition of cardiomyocytes. We conclude that postnatal cardiac hyperplasia in mice with global GC-A inactivation is provoked by systemic alterations, e.g., arterial hypertension. Direct GC-A-mediated effects in cardiomyocytes seem not to be involved in the regulation of myocyte proliferation at this early stage. PMID- 26059420 TI - Pressure placed on paediatric haematopoietic stem cell donors: Views from health professionals. AB - AIM: Paediatric haematopoietic stem cell donors undergo non-therapeutic procedures and endure known and unknown physical and psychosocial risks for the benefit of a family member. One ethical concern is the risk that they may be pressured by parents or health professionals to act as a donor. This paper adds to what is known about this topic by presenting the views of health professionals. METHODS: This qualitative study involved semi-structured interviews with 14 health professionals in Australasia experienced in dealing with paediatric donors. Transcripts were analysed using established qualitative methodologies. RESULTS: Health professionals considered that some paediatric donors experience pressure to donate. Situations that were likely to increase the risk of pressure being placed on donors were identified, and views were expressed about the ethical 'appropriateness' of these practices within the family setting. CONCLUSIONS: Children may be subject to pressure from family and health professionals to be tested and act as donors, Therefore, our ethical obligation to these children extends to implementing donor-focused processes - including independent health professionals and the appointment of a donor advocate - to assist in detecting and addressing instances of inappropriate pressure being placed on a child. PMID- 26059421 TI - Kommerell's Diverticulum: Unusual Case Expanding the Horizon. PMID- 26059422 TI - Analysis of clinical trials with biologics using dose-time-response models. AB - Biologics such as monoclonal antibodies are increasingly and successfully used for the treatment of many chronic diseases. Unlike conventional small drug molecules, which are commonly given as tablets once daily, biologics are typically injected at much longer time intervals, that is, weeks or months. Hence, both the dose and the time interval have to be optimized during the drug development process for biologics. To identify an adequate regimen for the investigated biologic, the dose-time-response relationship must be well characterized, based on clinical trial data. The proposed approach uses semi mechanistic nonlinear regression models to describe and predict the time-changing response for complex dosing regimens. Both likelihood-based and Bayesian methods for inference and prediction are discussed. The methodology is illustrated with data from a clinical study in an auto-immune disease. PMID- 26059423 TI - Protective efficacy of carnosic acid against hydrogen peroxide induced oxidative injury in HepG2 cells through the SIRT1 pathway. AB - Carnosic acid (CA), found in rosemary, has been reported to have antioxidant and antiadipogenic properties. Here, we investigate the molecular mechanism by which CA inhibits hydrogen peroxide (H2O2)-induced injury in HepG2 cells. Cells were pretreated with 2.5-10 MUmol/L CA for 2 h and then exposed to 3 mmol/L H2O2 for an additional 4 h. CA dose-dependently increased cell viability and decreased lactate dehydrogenase activities. Pretreatment with CA completely attenuated the inhibited expression of manganese superoxide dismutase (MnSOD) and the B-cell lymphoma-extra large (Bcl-xL), and reduced glutathione activity caused by H2O2, whereas it reversed reactive oxygen species accumulation and the increase in cleaved caspase-3. Importantly, sirtuin 1 (SIRT1), a NAD(+)-dependent deacetylase, was significantly increased by CA. Considering the above results, we hypothesized that SIRT1 may play important roles in the protective effects of CA in injury induced by H2O2. As expected, SIRT1 suppression by Ex527 (6-chloro 2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide) and siRNA-mediated SIRT1 silencing (si-SIRT1) significantly aggravated the H2O2-induced increased level of cleaved caspase-3 but greatly reduced the decreased expression of MnSOD and Bcl-xL. Furthermore, the positive regulatory effect of CA was inhibited by si-SIRT1. Collectively, the present study indicated that CA can alleviate H2O2-induced hepatocyte damage through the SIRT1 pathway. PMID- 26059424 TI - Targeting IgE in Severe Atopic Dermatitis with a Combination of Immunoadsorption and Omalizumab. AB - Patients with atopic dermatitis (AD) tend to have greatly elevated levels of serum immunoglobulin E (IgE). However, the role of IgE in the pathogenesis of AD is debated. This investigator-initiated open-label pilot study evaluates an anti IgE-treatment approach by combining extracorporeal immunoadsorption and anti-IgE antibody omalizumab in 10 patients with severe, therapy-refractory AD. IgE levels decreased after immunoadsorption and decreased continuously in all patients during anti-IgE therapy. The reverse trend was observed during 6 months follow-up without treatment. In parallel with these observations, an improvement in AD was observed during the treatment period, with aggravation during follow-up. Further research is needed, based on the principle of reducing IgE levels in order to improve clinical symptoms, using a combination anti-IgE treatment approach, adjusted according to IgE levels. PMID- 26059425 TI - Orbital infections: five-year case series, literature review and guideline development. AB - BACKGROUND: Periorbital infections represent a spectrum of sepsis that carries potentially significant morbidity and mortality. Early recognition, systematic assessment and aggressive treatment of the condition are essential. METHODS: A retrospective five-year case note review on the management of periorbital infections was performed at a tertiary centre. A literature review on the management of periorbital infections was also undertaken. A multidisciplinary guideline on the management of periorbital infections was developed based on the findings of the case and literature reviews. RESULTS: The results of the retrospective case series correlate well with those of recent reports. CONCLUSION: The new multidisciplinary guideline has been finalised and approved for practice and future auditing. PMID- 26059426 TI - Dynamic Proteomic Profiling of Extra-Embryonic Endoderm Differentiation in Mouse Embryonic Stem Cells. AB - During mammalian preimplantation development, the cells of the blastocyst's inner cell mass differentiate into the epiblast and primitive endoderm lineages, which give rise to the fetus and extra-embryonic tissues, respectively. Extra-embryonic endoderm (XEN) differentiation can be modeled in vitro by induced expression of GATA transcription factors in mouse embryonic stem cells. Here, we use this GATA inducible system to quantitatively monitor the dynamics of global proteomic changes during the early stages of this differentiation event and also investigate the fully differentiated phenotype, as represented by embryo-derived XEN cells. Using mass spectrometry-based quantitative proteomic profiling with multivariate data analysis tools, we reproducibly quantified 2,336 proteins across three biological replicates and have identified clusters of proteins characterized by distinct, dynamic temporal abundance profiles. We first used this approach to highlight novel marker candidates of the pluripotent state and XEN differentiation. Through functional annotation enrichment analysis, we have shown that the downregulation of chromatin-modifying enzymes, the reorganization of membrane trafficking machinery, and the breakdown of cell-cell adhesion are successive steps of the extra-embryonic differentiation process. Thus, applying a range of sophisticated clustering approaches to a time-resolved proteomic dataset has allowed the elucidation of complex biological processes which characterize stem cell differentiation and could establish a general paradigm for the investigation of these processes. PMID- 26059427 TI - Production of active glycosylation-deficient gamma-secretase complex for crystallization studies. AB - Alzheimer's disease (AD)-associated gamma-secretase is a ubiquitously expressed multi-subunit protease complex embedded in the lipid bilayer of cellular compartments including endosomes and the plasma membrane. Although gamma secretase is of crucial interest for AD drug discovery, its atomic structure remains unresolved. gamma-Secretase assembly and maturation is a multistep process, which includes extensive glycosylation on nicastrin (NCT), the only gamma-secretase subunit having a large extracellular domain. These posttranslational modifications lead to protein heterogeneity that likely prevents the three-dimensional (3D) crystallization of the protease complex. To overcome this issue, we have engineered a Chinese hamster ovary (CHO) cell line deficient in complex sugar modifications (CHO lec1) to overexpress the four subunits of gamma-secretase as a functional complex. We purified glycosylation deficient gamma-secretase from this recombinant cell line (CL1-9) and fully glycosylated gamma-secretase from a recombinant CHO DG44-derived cell line (SS20). We characterized both complexes biochemically and pharmacologically in vitro. Interestingly, we found that the complex oligosaccharides, which largely decorate the extracellular domain of fully glycosylated NCT, are not involved in the proper assembly and maturation of the complex, and are dispensable for the specific generation, in physiological ratios, of the amyloid precursor protein (APP) cleavage products. In conclusion, we propose a novel bioengineering approach for the production of functional glycosylation-deficient gamma secretase, which may be suitable for crystallization studies. We expect that these findings will contribute both to solving the high-resolution 3D structure of gamma-secretase and to structure-based drug discovery for AD. PMID- 26059428 TI - Identification of a Mutation in FGF23 Involved in Mandibular Prognathism. AB - Mandibular prognathism (MP) is a severe maxillofacial disorder with undetermined genetic background. We collected a Chinese pedigree with MP which involved in 23 living members of 4 generations. Genome-wide linkage analysis were carried out to obtain the information in this family and a new MP-susceptibility locus, 12pter p12.3 was identified. Whole-exome sequencing identified a novel heterozygous mutation in fibroblast growth factor (FGF) 23 (; p.A12D) which well segregated with MP in this pedigree within the locus. The mutation was also detected in 3 cases out of 65 sporadic MP patients, but not in any of the 342 control subjects. The p.A12D mutation may disrupt signal peptide function and inhibit secretory in FGF23. Furthermore, mutant FGF23 was overexpressed in 293T cells, increased cytoplasmic accumulation was observed compared with the wild type. We have discovered that c.35C>A mutation in FGF23 strongly associated with MP, which expand our understanding of the genetic contribution to MP pathogenesis. PMID- 26059429 TI - Caring behaviours of student nurses: Effects of pre-registration nursing education. AB - In an increasing technologised and cost-constrained healthcare environment, the role of pre-registration nursing education in nurturing and developing the professional caring disposition of students is becoming far more critical than before. In view of this growing demand, the aim of this study was to evaluate the impact of Singapore's pre-registration nursing programmes on students' concept of caring. A descriptive quantitative cross-sectional survey collected data using the Caring Behaviour Inventory from first and final year student nurses, nurse lecturers and nurses in practice. The findings based on student surveys indicated a statistically significant reduction in the overall level of caring behaviour in first to final year students. When compared with the findings of lecturers and nurses, less variance to lecturers than to nurses was found amongst the first years' score, and the lowest variance to nurses was demonstrated amongst the final year. A greater reduction was evidenced amongst Singaporean students, which was exaggerated with exposure to pre-enrolled nursing education and magnified with caring job experience. This study indicates more effort is necessary to harness student caring attributes in students' entire educational journey so that expressive caring is not subsumed in the teaching of students to meet demands of complicated contemporary care. PMID- 26059430 TI - Accelerating magnetic resonance fingerprinting (MRF) using t-blipped simultaneous multislice (SMS) acquisition. AB - PURPOSE: We incorporate simultaneous multislice (SMS) acquisition into MR fingerprinting (MRF) to accelerate the MRF acquisition. METHODS: The t-Blipped SMS-MRF method is achieved by adding a Gz blip before each data acquisition window and balancing it with a Gz blip of opposing polarity at the end of each TR. Thus the signal from different simultaneously excited slices are encoded with different phases without disturbing the signal evolution. Furthermore, by varying the Gz blip area and/or polarity as a function of repetition time, the slices' differential phase can also be made to vary as a function of time. For reconstruction of t-Blipped SMS-MRF data, we demonstrate a combined slice direction SENSE and modified dictionary matching method. RESULTS: In Monte Carlo simulation, the parameter mapping from multiband factor (MB) = 2 t-Blipped SMS MRF shows good accuracy and precision when compared with results from reference conventional MRF data with concordance correlation coefficients (CCC) of 0.96 for T1 estimates and 0.90 for T2 estimates. For in vivo experiments, T1 and T2 maps from MB=2 t-Blipped SMS-MRF have a high agreement with ones from conventional MRF. CONCLUSION: The MB=2 t-Blipped SMS-MRF acquisition/reconstruction method has been demonstrated and validated to provide more rapid parameter mapping in the MRF framework. PMID- 26059431 TI - Comparison between Urine Protein: Creatinine Ratios of Samples Obtained from Dogs in Home and Hospital Settings. AB - BACKGROUND: The urine protein:creatinine ratio (UPC) is used to quantify urine protein excretion and guide recommendations for monitoring and treatment of proteinuria. HYPOTHESIS/OBJECTIVES: Home urine samples will have lower UPCs than hospital samples. The objectives were to compare UPCs of samples collected in each setting and to determine whether environment of sample collection might affect staging, monitoring or treatment recommendations. ANIMALS: Twenty-four client-owned dogs. METHODS: Prospective, nonmasked study. Clients collected a urine sample from their dog at home and a second sample was collected at the hospital. Dogs receiving corticosteroids or angiotensin-converting enzyme inhibitors were excluded, as were those with urine samples of inadequate volume, no protein on dipstick analysis, or active urine sediment. Samples were refrigerated after collection, dipstick and sediment evaluations were completed and each sample was frozen at -80 degrees C within 12 hours. UPCs were performed on frozen samples within 2 months. RESULTS: From 81 paired samples, 57 were excluded. Of the remaining 24, 12/24 (50%) had higher hospital sample UPCs, 9/24 (38%) had identical UPCs, and 3/24 (12%) had lower hospital UPCs. The UPCs of hospital samples were higher than home samples for the total population (P = .005) and the subset with UPC > 0.5 (P = .001). CONCLUSIONS: Setting and related circumstances of urine collection in dogs is associated with UPC differences; results are usually higher in hospital than in home samples. This difference has the potential to affect clinical interpretation. PMID- 26059432 TI - Revisiting the membrane interaction mechanism of a membrane-damaging beta-barrel pore-forming toxin Vibrio cholerae cytolysin. AB - Vibrio cholerae cytolysin (VCC) permeabilizes target cell membranes by forming transmembrane oligomeric beta-barrel pores. VCC has been shown to associate with the target membranes via amphipathicity-driven spontaneous partitioning into the membrane environment. More specific interaction(s) of VCC with the membrane components have also been documented. In particular, specific binding of VCC with the membrane lipid components is believed to play a crucial role in determining the efficacy of the pore-formation process. However, the structural basis and the functional implications of the VCC interaction with the membrane lipids remain unclear. Here we show that the distinct loop sequences within the membrane proximal region of VCC play critical roles to determine the functional interactions of the toxin with the membrane lipids. Alterations of the loop sequences via structure-guided mutagenesis allow amphipathicity-driven partitioning of VCC to the membrane lipid bilayer. Alterations of the loop sequences, however, block specific interactions of VCC with the membrane lipids and abort the oligomerization, membrane insertion, pore-formation and cytotoxic activity of the toxin. Present study identifies the structural signatures in VCC implicated for its functional interactions with the membrane lipid components, a process that presumably acts to drive the subsequent steps of the oligomeric beta barrel pore-formation and cytotoxic responses. PMID- 26059433 TI - Initiation and termination of DNA replication during S phase in relation to cyclins D1, E and A, p21WAF1, Cdt1 and the p12 subunit of DNA polymerase delta revealed in individual cells by cytometry. AB - During our recent studies on mechanism of the regulation of human DNA polymerase delta in preparation for DNA replication or repair, multiparameter imaging cytometry as exemplified by laser scanning cytometry (LSC) has been used to assess changes in expression of the following nuclear proteins associated with initiation of DNA replication: cyclin A, PCNA, Ki-67, p21(WAF1), DNA replication factor Cdt1 and the smallest subunit of DNA polymerase delta, p12. In the present review, rather than focusing on Pol delta, we emphasize the application of LSC in these studies and outline possibilities offered by the concurrent differential analysis of DNA replication in conjunction with expression of the nuclear proteins. A more extensive analysis of the data on a correlation between rates of EdU incorporation, likely reporting DNA replication, and expression of these proteins, is presently provided. New data, specifically on the expression of cyclin D1 and cyclin E with respect to EdU incorporation as well as on a relationship between expression of cyclin A vs. p21(WAF1) and Ki-67 vs. Cdt1, are also reported. Of particular interest is the observation that this approach makes it possible to assess the temporal sequence of degradation of cyclin D1, p21(WAF1), Cdt1 and p12, each with respect to initiation of DNA replication and with respect to each other. Also the sequence or reappearance of these proteins in G2 after termination of DNA replication is assessed. The reviewed data provide a more comprehensive presentation of potential markers, whose presence or absence marks the DNA replicating cells. Discussed is also usefulness of these markers as indicators of proliferative activity in cancer tissues that may bear information on tumor progression and have a prognostic value. PMID- 26059434 TI - Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition. AB - We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/Arf(-/-) PDGF-beta model. The tumoricidal and TMZ sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti neoplastic effect of EGFR inhibitors in the Ink4a/Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a "multi-orthogonal" combination tailored to the molecular physiology associated with the target cancer genome. PMID- 26059435 TI - HIF-1alpha and TAZ serve as reciprocal co-activators in human breast cancer cells. AB - Hypoxia-inducible factor 1alpha (HIF-1alpha) expression is a hallmark of intratumoral hypoxia that is associated with breast cancer metastasis and patient mortality. Previously, we demonstrated that HIF-1 stimulates the expression and activity of TAZ, which is a transcriptional effector of the Hippo signaling pathway, by increasing TAZ synthesis and nuclear localization. Here, we report that direct protein-protein interaction between HIF-1alpha and TAZ has reciprocal effects: HIF-1alpha stimulates transactivation mediated by TAZ and TAZ stimulates transactivation mediated by HIF-1alpha. Inhibition of TAZ expression impairs the hypoxic induction of HIF-1 target genes, such as PDK1, LDHA, BNIP3 and P4HA2 in response to hypoxia, whereas inhibition of HIF-1alpha expression impairs TAZ mediated transactivation of the CTGF promoter. Taken together, these results complement our previous findings and establish bidirectional crosstalk between HIF-1alpha and TAZ that increases their transcriptional activities in hypoxic cells. PMID- 26059436 TI - AMP-activated protein kinase is dispensable for maintaining ATP levels and for survival following inhibition of glycolysis, but promotes tumour engraftment of Ras-transformed fibroblasts. AB - Lactic acid generated by highly glycolytic tumours is exported by the MonoCarboxylate Transporters, MCT1 and MCT4, to maintain pHi and energy homeostasis. We report that MCT1 inhibition combined with Mct4 gene disruption severely reduced glycolysis and tumour growth without affecting ATP levels. Because of the key role of the 5'-AMP-activated protein kinase (AMPK) in energy homeostasis, we hypothesized that targeting glycolysis (MCT-blockade) in AMPK null (Ampk(-/-)) cells should kill tumour cells from 'ATP crisis'. We show that Ampk(-/-)-Ras-transformed mouse embryonic fibroblasts (MEFs) maintained ATP levels and viability when glycolysis was inhibited. In MCT-inhibited MEFs treated with OXPHOS inhibitors the ATP level and viability collapsed in both Ampk(+/+) and Ampk(-/-) cells. We therefore propose that the intracellular acidification resulting from lactic acid sequestration mimicks AMPK by blocking mTORC1, a major component of an ATP consuming pathway, thereby preventing 'ATP crisis'. Finally we showed that genetic disruption of Mct4 and/or Ampk dramatically reduced tumourigenicity in a xenograft mouse model suggesting a crucialrolefor these two actors in establishment of tumours in a nutrient-deprived environment. These findings demonstrated that blockade of lactate transport is an efficient anti cancer strategy that highlights the potential in targeting Mct4 in a context of impaired AMPK activity. PMID- 26059437 TI - Meta-analysis of organ-specific differences in the structure of the immune infiltrate in major malignancies. AB - Anticancer immunosurveillance is one of the major endogenous breaks of tumor progression. Here, we analyzed gene expression pattern indicative of the presence of distinct leukocyte subtypes within four cancer types (breast cancer, colorectal carcinoma, melanoma, and non-small cell lung cancer) and 20 different microarray datasets corresponding to a total of 3471 patients. Multiple metagenes reflecting the presence of such immune cell subtypes were highly reproducible across distinct cohorts. Nonetheless, there were sizable differences in the correlation patterns among such immune-relevant metagenes across distinct malignancies. The reproducibility of the correlations among immune-relevant metagenes was highest in breast cancer (followed by colorectal cancer, non-small cell lung cancer and melanoma), reflecting the fact that mammary carcinoma has an intrinsically better prognosis than the three other malignancies. Among breast cancer patients, we found that the expression of a lysosomal enzyme-related metagene centered around ASAH1 (which codes for N-acylsphingosine amidohydrolase 1, also called acid ceramidase) exhibited a higher correlation with multiple immune-relevant metagenes in patients that responded to neoadjuvant chemotherapy than in non-responders. Altogether, this meta-analysis revealed novel organ specific features of the immune infiltrate in distinct cancer types, as well as a strategy for defining new prognostic biomarkers. PMID- 26059438 TI - Epidermal growth factor receptor mutation mediates cross-resistance to panitumumab and cetuximab in gastrointestinal cancer. AB - Acquired resistance to epidermal growth factor receptor (EGFR) targeted antibodies represents a clinical challenge in the treatment of gastrointestinal tumors such as metastatic colorectal cancer, but its molecular mechanisms are incompletely understood. We scanned KRAS exon 2/3/4, NRAS exon 2/3/4 and the overlapping epitopes of the EGFR antibodies cetuximab and panitumumab for mutations in pre- and post-treatment tumor tissue of 21 patients with gastrointestinal cancer treated with chemotherapy +/- EGFR antibodies by next generation sequencing ("tumor tissue" cohort). We describe a novel EGFR exon 12 mutation acquired in tumors of 1 out of 3 patients treated with panitumumab. The EGFR G465R mutation introduces a positive charge within the overlap of the panitumumab and cetuximab epitopes. It abrogates antibody binding and mediates cross-resistance to both antibodies in EGFR G465R-transfected Ba/F3 cells. In circulating tumor DNA from an independent "liquid biopsy" cohort of 27 patients, we found this novel mutation in 1 out of 6 panitumumab-treated cases while about one third of patients show acquired RAS mutations. We show that acquired resistance by epitope-changing mutations also emerges during panitumumab treatment, which can be easily detected by a liquid biopsy approach even before clinical resistance occurs and this may help in tailoring EGFR-targeted therapies. PMID- 26059439 TI - Quercetin-induced apoptosis prevents EBV infection. AB - Epstein-Barr virus (EBV) is a human gamma-1 herpesvirus that establishes a lifelong latency in over 90% of the world's population. During latency, virus exists predominantly as a chromatin-associated, multicopy episome in the nuclei of a variety of tumor cells derived from B cells, T cells, natural killer (NK) cells, and epithelial cells. Licorice is the root of Glycyrrhiza uralensis or G. glabra that has traditionally cultivated in eastern part of Asia. Licorice was reported to have anti-viral, anti-inflammatory, anti-atopic, hepatoprotective, anti-neurodegenerative, anti-tumor, anti-diabetic effects and so forth. Quercetin and isoliquiritigenin are produced from licorice and highly similar in molecular structure. They have diverse bioactive effects such as antiviral activity, anti asthmatic activity, anti-cancer activity, anti-inflammation activity, monoamine oxidase inhibitor, and etc. To determine anti-EBV and anti-EBVaGC (Epstein-Barr virus associated gastric carcinoma) effects of licorice, we investigated antitumor and antiviral effects of quercetin and isoliquiritigenin against EBVaGC. Although both quercetin and isoliquiritigenin are cytotoxic to SNU719 cells, quercetin induced more apoptosis in SNU719 cells than isoliquiritigenin, more completely eliminated DNMT1 and DNMT3A expressions than isoliquiritigenin, and more strongly affects the cell cycle progression of SNU719 than isoliquiritigenin. Both quercetin and isoliquiritigenin induce signal transductions to stimulate apoptosis, and induce EBV gene transcription. Quercetin enhances frequency of F promoter use, whereas isoliquiritigenin enhances frequency of Q promoter use. Quercetin reduces EBV latency, whereas isoliquiritigenin increases the latency. Quercetin increases more the EBV progeny production, and inhibits more EBV infection than isoliquiritigenin. These results indicate that quercetin could be a promising candidate for antiviral and antitumor agents against EBV and human gastric carcinoma. PMID- 26059441 TI - Isolation of CeLu2 N@Ih -C80 through a Non-Chromatographic, Two-Step Chemical Process and Crystallographic Characterization of the Pyramidalized CeLu2 N within the Icosahedral Cage. AB - By combining two chemical methods of purification, 4 mg of purified CeLu2 N@C80 was readily isolated from 500 mg of carbon soot extract without the use of recycling HPLC, a method which has previously been necessary to obtain pure samples of endohedral fullerenes. In stage 1, CeLu2 N@C80 was selectively precipitated by virtue of its low first oxidation potential (+0.01 V) and the judicious choice of MgCl2 as the Lewis acid precipitant. For stage 2, we used a stir and filter approach (SAFA), which employed the electron-rich NH2 groups immobilized on silica gel to selectively bind residual endohedrals and higher cage fullerenes that were contaminants from stage 1. Crystallographic analysis of CeLu2 N@C80 in the co-crystal CeLu2 N@Ih -C80 ?Ni(octaethylporphyrin)?2(toluene) reveals that the Ih -C80 cage is present with a pyramidalized CeLu2 N unit inside. PMID- 26059440 TI - Maritoclax and dinaciclib inhibit MCL-1 activity and induce apoptosis in both a MCL-1-dependent and -independent manner. AB - The anti-apoptotic BCL-2 family proteins are important targets for cancer chemotherapy. Specific and potent inhibitors of the BCL-2 family, such as ABT-263 (navitoclax) and ABT-199, are only effective against some members of the BCL-2 family but do not target MCL-1, which is commonly amplified in tumors and associated with chemoresistance. In this report, the selectivity and potency of two putative MCL-1 inhibitors, dinaciclib and maritoclax, were assessed. Although both compounds induced Bax/Bak- and caspase-9-dependent apoptosis, dinaciclib was more potent than maritoclax in downregulating MCL-1 and also in inducing apoptosis. However, the compounds induced apoptosis, even in cells lacking MCL-1, suggesting multiple mechanisms of cell death. Furthermore, maritoclax induced extensive mitochondrial fragmentation, and a Bax/Bak- but MCL-1-independent accumulation of mitochondrial reactive oxygen species (ROS), with an accompanying loss of complexes I and III of the electron transport chain. ROS scavengers, such as MitoQ, could not salvage maritoclax-mediated effects on mitochondrial structure and function. Taken together, our data demonstrate that neither dinaciclib nor maritoclax exclusively target MCL-1. Although dinaciclib is clearly not a specific MCL-1 inhibitor, its ability to rapidly downregulate MCL-1 may be beneficial in many clinical settings, where it may reverse chemoresistance or sensitize to other chemotherapeutic agents. PMID- 26059442 TI - A novel KIT variant in an Icelandic horse with white-spotted coat colour. PMID- 26059443 TI - Detection of peri-implant bone defects with different radiographic techniques - a human cadaver study. AB - OBJECTIVES: Two- and three-dimensional radiographic techniques are available to determine peri-implantitis-related bone loss around dental implants. PURPOSE: To compare the performance of detecting different peri-implant bone defects in intraoral radiography (IR), panoramic radiography (PR), Cone Beam Computer Tomography (CBCT) and Computer Tomography (CT). MATERIAL AND METHODS: Six implants were inserted under ideal conditions into the lower jaw of an edentulous human cadaver. IR, PR, CBCT and CT were performed. Two-wall, three-wall and four wall defects with 1 mm depth were artificially created around two of the implants (one anterior and one posterior), and radiographies were repeated. The identical set-up was used for 3-mm-deep bone defects. All images were presented to seven observers. Sensitivity (SN) and specificity (SP) were determined for each modality, defect type and depths, and likelihood ratios were calculated. RESULTS: The highest sensitivity was found with IR and CBCT for 1 mm (0.67; 0.68) and 3-mm defects (0.81; 0.79). The highest specificity was found with IR for both defect depths (0.51). The best classification of defect type revealed PR for both 1-mm and 3-mm-deep defects. Both likelihood ratios (LR+ and LR-) were best for IR with 1-mm (1.37 and 0.65) and with 3-mm defects (1.65 and 0.37). CONCLUSIONS: IR should still be recommended as favourable method evaluating bone loss around dental implants, while CT demonstrated the lowest performance in detecting peri implant bone defects. PMID- 26059444 TI - Knowledge and perception of tuberculosis and the risk to become treatment default among newly diagnosed pulmonary tuberculosis patients treated in primary health care, East Nusa Tenggara: a retrospective study. AB - BACKGROUND: Despite the high efficacy of tuberculosis (TB) drug regiments, one of the barriers in the TB control program is the non-compliance to treatment. Morbidity, mortality, and risk to become resistant to drugs are emerging among defaulters. Thus, the aim of this study is to identify the factors, especially knowledge and perceptions of TB and association with treatment default among patients treated in primary care settings, East Nusa Tenggara. METHODS: This study was part of a bigger cohort community-based controlled trial study. The subjects were newly diagnosed pulmonary TB patients from four districts in East Nusa Tenggara. Knowledge, perception of TB, and other related factors were assessed prior to the treatment. Patients who interrupted the treatment in two consecutive months were classified as defaulters, as World Health Organization stated. Odds ratio (OR) looking for factors associated with becoming defaulter was analyzed. RESULTS: A total of 300 patients were recruited for this study. At the end of the treatment, 255 patients (85%) completed the treatment without interruption from regular visit. In univariate analysis, none of the socio demographic factors attributed to treatment default yet lack of knowledge and incorrect perception of TB prior therapy (OR 2.49 1.30-4.79 95% CI, p = 0.006; OR 5.40 2.64-11.04 95% CI, p < 0.001, respectively). In multivariate analysis, only incorrect perception of TB showed significant association with treatment default (OR 4.75 2.30-9.86 95% CI). CONCLUSIONS: Assessing the knowledge and perception of TB prior to the treatment in newly pulmonary TB patients is important as both of them were known as risk factor for treatment default. Education and counseling may be required to improve patients' compliance to treatment. PMID- 26059445 TI - Spontaneous activity in electromyography may differentiate certain benign lower motor neuron disease forms from amyotrophic lateral sclerosis. AB - There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%-77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage. PMID- 26059446 TI - Epidemiology and in-hospital outcome of stroke in South Ethiopia. AB - INTRODUCTION: Although the burden of stroke in Sub-Saharan Africa, including Ethiopia, is increasing, there are few available data on stroke in Ethiopia. OBJECTIVE: To describe the magnitude of risk factors, sub-types and in-hospital outcome of stroke at Hawassa University Referral Hospital, Ethiopia. METHODS: A prospective hospital-based study was conducted with all adult patients admitted to Hawassa University Referral Hospital with stroke diagnosis between May 2013 and April 2014. Computerized tomography scan was performed in all patients to confirm the type of stroke. Stroke severity at admission was assessed by the National Institute of Health Stroke Scale. Stroke outcome at discharge was measured using the modified Rankin stroke scale. RESULTS: A total of 163 stroke patients were recruited during the study period, of which 82 (50.3%) patients had ischemic stroke while 81 (49.7%) had hemorrhagic stroke. Stroke risk factors included hypertension (50.9%), cardiac diseases (16.6%), diabetes mellitus (7.4%), alcohol (10.4%), cigarette smoking (4.9%) and tuberculous meningitis (3.1%). In-hospital stroke mortality was 14.7%. The main predictors of in hospital stroke mortality were stroke severity at admission, hemorrhagic stroke, decreased level of consciousness and seizure. CONCLUSION: The proportion of hemorrhagic stroke is higher than in Western countries. Hypertension is the most common risk factor for stroke. More than half of the patients were discharged with severe disability. We recommend establishing stroke units in resource limited countries like Ethiopia in order to reduce stroke mortality and post stroke disability. PMID- 26059447 TI - Conventional transarterial chemoembolization versus drug-eluting bead transarterial chemoembolization for the treatment of hepatocellular carcinoma. AB - BACKGROUND: To compare the overall survival of patients with hepatocellular carcinoma (HCC) who were treated with lipiodol-based conventional transarterial chemoembolization (cTACE) with that of patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE). METHODS: By an electronic search of our radiology information system, we identified 674 patients that received TACE between November 2002 and July 2013. A total of 520 patients received cTACE, and 154 received DEB-TACE. In total, 424 patients were excluded for the following reasons: tumor type other than HCC (n=91), liver transplantation after TACE (n=119), lack of histological grading (n=58), incomplete laboratory values (n=15), other reasons (e.g., previous systemic chemotherapy) (n=114), or were lost to follow-up (n=27). Therefore, 250 patients were finally included for comparative analysis (n=174 cTACE; n=76 DEB-TACE). RESULTS: There were no significant differences between the two groups regarding sex, overall status (Barcelona Clinic Liver Cancer classification), liver function (Child-Pugh), portal invasion, tumor load, or tumor grading (all p>0.05). The mean number of treatment sessions was 4+/-3.1 in the cTACE group versus 2.9+/-1.8 in the DEB TACE group (p=0.01). Median survival was 409 days (95% CI: 321-488 days) in the cTACE group, compared with 369 days (95% CI: 310-589 days) in the DEB-TACE group (p=0.76). In the subgroup of Child A patients, the survival was 602 days (484-792 days) for cTACE versus 627 days (364-788 days) for DEB-TACE (p=0.39). In Child B/C patients, the survival was considerably lower: 223 days (165-315 days) for cTACE versus 226 days (114-335 days) for DEB-TACE (p=0.53). CONCLUSION: The present study showed no significant difference in overall survival between cTACE and DEB-TACE in patients with HCC. However, the significantly lower number of treatments needed in the DEB-TACE group makes it a more appealing treatment option than cTACE for appropriately selected patients with unresectable HCC. PMID- 26059448 TI - Adiponectin affects vascular smooth muscle cell proliferation and apoptosis through modulation of the mitofusin-2-mediated Ras-Raf-Erk1/2 signaling pathway. AB - Vascular smooth muscle cells (VSMCs) undergo cell biological changes in response to a variety of cytokines and growth factors. Adiponectin inhibits neointimal formation through suppressing the proliferation and migration of VSMCs. However, the mechanisms underlying the effect of adiponectin on VSMC proliferation and apoptosis require further investigation. The present study was designed to investigate the mechanisms of adiponectin on VSMC proliferation and apoptosis, focusing on the mitofusin-2 (MFN2) mediated Ras-Raf-extracellular signal regulated kinase (Erk)1/2 signaling pathway. The results of western blot analysis revealed that adiponectin increased the expression of MFN2 in a concentration dependent manner. Adiponectin also suppressed VSMC proliferation and induced VSMC apoptosis. However, transfection of the VSMCs with small interfering (si)RNA, to knock down the expression of MFN2 attenuated the effect of adiponectin on VSMC proliferation and apoptosis. The decreased expression levels of Ras, phosphorlated (p)-c-Raf and p-Erk1/2, observed in the VSMCs treated with adiponectin were also reversed by the transfection of the VSMCs with MFN2 siRNA to knock down the expression of MFN2. The results of the present study demonstrated for the first time, to the best of our knowledge, that adiponectin exhibits an inhibitory effect on VSMC proliferation and induces cell proliferation via regulation of the expression levels of MFN2. Adiponectin upregulated the expression of MFN2, inhibiting the Ras-Raf-Erk1/2 signaling pathway, which led to the inhibition of VSMC proliferation and the induction of VSMC apoptosis. The results of the present study may provide a novel basis for the therapy of vascular disease. PMID- 26059450 TI - HOXA9 and MEIS1 gene overexpression in the diagnosis of childhood acute leukemias: Significant correlation with relapse and overall survival. AB - Homeobox genes HOXA9 and MEIS1 are evolutionarily conserved transcription factors with essential roles in both hematopoiesis and leukemogenesis. They act as dominant cooperating oncoproteins that cause acute leukemias bearing MLL translocations and to a lesser extent T-cell acute lymphocytic leukemia (ALL) characterized by other gene fusions. Overexpression is associated with an adverse prognosis in adults. In childhood, the genes have only been investigated in leukemias bearing MLL translocations. The aim of this study was to determine whether overexpression extends to leukemic subtypes other than the MLL-positive subtype in childhood. We use quantitative real-time PCR methodology to investigate gene expression in 100 children with acute leukemias and compare them to those of healthy controls. We show that abnormally high HOXA9 and MEIS1 gene expression is associated with a variety of leukemic subtypes, including various maturation stages of B-cell ALL and cytogenetic types other than the MLL-positive population, thus suggesting that the genes are implicated in the development of a broad range of leukemic subtypes in childhood. In addition, we show that HOXA9 and MEIS1 overexpression are inversely correlated with relapse and overall survival, so the genes could become useful predictive markers of the clinical course of pediatric acute leukemias. PMID- 26059451 TI - STAT5A regulates DNMT3A in CD34(+)/CD38(-) AML cells. AB - Signal transducer and activator of transcription 5 (STAT5) is activated in CD34(+)/CD38(-) acute myelogenous leukemia (AML) cells. Inhibition of STAT5 induced apoptosis and sensitized these cells to the growth inhibition mediated by conventional chemotherapeutic agents. The present study attempted to identify molecules that are regulated by STAT5 in CD34(+)/CD38(-) AML cells by utilizing cDNA microarrays, comparing the gene expression profiles of control and STAT5A shRNA-transduced CD34(+)/CD38(-) AML cells. Interestingly, DNA methyltransferase (DNMT) 3A was downregulated after depletion of STAT5A in CD34(+)/CD38(-) AML cells. Reporter gene assays found that an increase in activity of DNMT3A occurred in response to activation of STAT5A in leukemia cells. On the other hand, dephosphorylation of STAT5A by AZ960 decreased this transcriptional activity. Further studies utilizing a chromatin immunoprecipitation assay identified a STAT5A-binding site on the promoter region of DNMT3A gene. Forced expression of STAT5A in leukemia cells caused hypermethylation on the promoter region of the tumor suppressor gene, PTEN, and downregulated its mRNA levels, as measured by methylation-specific and real-time polymerase chain reaction, respectively. Taken together, these data suggest that STAT5A positively regulates levels of DNMT3A, resulting in inactivation of tumor suppressor genes by epigenetic mechanisms in AML cells. PMID- 26059449 TI - Comparative genomic and phenomic analysis of Clostridium difficile and Clostridium sordellii, two related pathogens with differing host tissue preference. AB - BACKGROUND: Clostridium difficile and C. sordellii are two anaerobic, spore forming, gram positive pathogens with a broad host range and the ability to cause lethal infections. Despite strong similarities between the two Clostridial strains, differences in their host tissue preference place C. difficile infections in the gastrointestinal tract and C. sordellii infections in soft tissues. RESULTS: In this study, to improve our understanding of C. sordellii and C. difficile virulence and pathogenesis, we have performed a comparative genomic and phenomic analysis of the two. The global phenomes of C. difficile and C. sordellii were compared using Biolog Phenotype microarrays. When compared to C. difficile, C. sordellii was found to better utilize more complex sources of carbon and nitrogen, including peptides. Phenotype microarray comparison also revealed that C. sordellii was better able to grow in acidic pH conditions. Using next generation sequencing technology, we determined the draft genome of C. sordellii strain 8483 and performed comparative genome analysis with C. difficile and other Clostridial genomes. Comparative genome analysis revealed the presence of several enzymes, including the urease gene cluster, specific to the C. sordellii genome that confer the ability of expanded peptide utilization and survival in acidic pH. CONCLUSIONS: The identified phenotypes of C. sordellii might be important in causing wound and vaginal infections respectively. Proteins involved in the metabolic differences between C. sordellii and C. difficile should be targets for further studies aimed at understanding C. difficile and C. sordellii infection site specificity and pathogenesis. PMID- 26059453 TI - Minocycline-induced hyperpigmentation of tympanic membrane, sclera, teeth, and pinna. AB - A 40-year-old woman was referred by her primary care physician for evaluation after a routine physical exam revealed bilateral brownish pigmentation of the tympanic membrane. Head and neck examination in the otolaryngology clinic revealed bluish hue of both sclera, teeth, and portions of her pinnae. A hearing test revealed bilateral mild sensorineural hearing loss. The patient had a history of taking minocycline for 14 years, and the hyperpigmentation that she had is known to be a rare complication of prolonged minocycline use. However, to our knowledge, this is the first case showing photographic evidence of minocycline-induced tympanic membrane hyperpigmentation. Minocycline-induced hyperpigmentation should be considered when a patient presents with brown or blue discoloration of the tympanic membrane. PMID- 26059452 TI - Beyond ecto-nucleotidase: CD39 defines human Th17 cells with CD161. AB - CD39/ENTPD1 is a prototypic member of the ectonucleoside triphosphate diphosphohydrolase (ENTPDase) family on cell surface. CD39 has been reported to be a marker of regulatory immune cells and catalyzes extracellular hydrolysis of nucleotides to generate AMP and, in tandem with CD73, adenosine. We have recently found in addition that co-expression of CD39 and CD161 by human CD4(+) T cells may become a biomarker of human Th17 cells. CD39 and CD161 have direct interactions that are further linked with acid sphingomyelinase (ASM). Upon activation of CD39 and CD161, the molecular interactions boost ASM bio-activity, which generates cellular ceramide to further mediate downstream signals inclusive of STAT3 and mTOR. We suggest modulation of human Th17 responsiveness by CD39 and CD161 and describe novel molecular mechanisms integrating elements of both extracellular nucleotide and sphingolipid homeostasis that are pivotal in the control of human Th17 cells and which could have therapeutic potential. PMID- 26059454 TI - Evidence-based outcomes following inferior alveolar and lingual nerve injury and repair: a systematic review. AB - The inferior alveolar nerve (IAN) and lingual (LN) are susceptible to iatrogenic surgical damage. Systematically review recent clinical evidence regarding IAN/LN repair methods and to develop updated guidelines for managing injury. Recent publications on IAN/LN microsurgical repair from Medline, Embase and Cochrane Library databases were screened by title/abstract. Main texts were appraised for exclusion criteria: no treatment performed or results provided, poor/lacking procedural description, cohort <3 patients. Of 366 retrieved papers, 27 were suitable for final analysis. Treatment type for injured IANs/LNs depended on injury type, injury timing, neurosensory disturbances and intra-operative findings. Best functional nerve recovery occurred after direct apposition and suturing if nerve ending gaps were <10 mm; larger gaps required nerve grafting (sural/greater auricular nerve). Timing of microneurosurgical repair after injury remains debated. Most authors recommend surgery when neurosensory deficit shows no improvement 90 days post-diagnosis. Nerve transection diagnosed intra operatively should be repaired in situ; minor nerve injury repair can be delayed. No consensus exists regarding optimal methods and timing for IAN/LN repair. We suggest a schematic guideline for treating IAN/LN injury, based on the most current evidence. We acknowledge that additional RCTs are required to provide definitive confirmation of optimal treatment approaches. PMID- 26059456 TI - Should thorough Debridement be used in Fibular Allograft with impaction bone grafting to treat Femoral Head Necrosis: a biomechanical evaluation. AB - BACKGROUND: Fibular allograft with impaction bone grafting (FAIBG) is an effective hip-preservation method for avoiding total hip arthroplasty in the early stage of femoral head necrosis. However, whether thorough debridement should be used with FAIBG is controversial. This study compared the mechanical performance between FAIBG with and without thorough debridement, which provides a biomechanical basis for selecting the proper treatment in clinical settings. METHODS: Eighteen computational models were constructed and used to simulate two subtypes of femoral head collapse with seven debridement radii. The initial model was validated using the bony density distribution from X-ray images and a photograph of the cadaver bone cross-section. The stress of the anterolateral column and the debridement efficiency were computed and analyzed. RESULTS: (1) The peak stress of the anterolateral column in all conditions could return to the physiological level, and in two cases, the decrement/increment of stress was almost less than 0.1 % when the debridement radius increased. (2) The load share ratio (LSR) of the cortical and cancellous bone was markedly decreased in the untreated condition and increases with an increase in the debridement radius. (3) A debridement radius greater than 1/2r yields a LSR value larger than that obtained in the normal condition. CONCLUSIONS: The simulation results provide specific biomechanical evidence to support the finding that FAIBG with a debridement region of 3/8 -1/2 appears to be a better choice for resisting femoral head collapse (FHC). Furthermore, FAIBG without thorough debridement, which requires relatively simple surgical devices and reduces artificial damage, appears to be a better method for resisting FHC than FAIBG with thorough debridement. PMID- 26059457 TI - Deregulation of selective autophagy during aging and pulmonary fibrosis: the role of TGFbeta1. AB - Aging constitutes a significant risk factor for fibrosis, and idiopathic pulmonary fibrosis (IPF) is characteristically associated with advancing age. We propose that age-dependent defects in the quality of protein and cellular organelle catabolism may be causally related to pulmonary fibrosis. Our research found that autophagy diminished with corresponding elevated levels of oxidized proteins and lipofuscin in response to lung injury in old mice and middle-aged mice compared to younger animals. More importantly, older mice expose to lung injury are characterized by deficient autophagic response and reduced selective targeting of mitochondria for autophagy (mitophagy). Fibroblast to myofibroblast differentiation (FMD) is an important feature of pulmonary fibrosis in which the profibrotic cytokine TGFbeta1 plays a pivotal role. Promotion of autophagy is necessary and sufficient to maintain normal lung fibroblasts' fate. On the contrary, FMD mediated by TGFbeta1 is characterized by reduced autophagy flux, altered mitophagy, and defects in mitochondrial function. In accord with these findings, PINK1 expression appeared to be reduced in fibrotic lung tissue from bleomycin and a TGFbeta1-adenoviral model of lung fibrosis. PINK1 expression is also reduced in the aging murine lung and biopsies from IPF patients compared to controls. Furthermore, deficient PINK1 promotes a profibrotic environment. Collectively, this study indicates that an age-related decline in autophagy and mitophagy responses to lung injury may contribute to the promotion and/or perpetuation of pulmonary fibrosis. We propose that promotion of autophagy and mitochondrial quality control may offer an intervention against age-related fibrotic diseases. PMID- 26059458 TI - R-acetoin accumulation and dissimilation in Klebsiella pneumoniae. AB - Klebsiella pneumoniae is a 2,3-butanediol producer, and R-acetoin is an intermediate of 2,3-butanediol production. R-acetoin accumulation and dissimilation in K. pneumoniae was studied here. A budC mutant, which has lost 2,3-butanediol dehydrogenase activity, accumulated high levels of R-acetoin in culture broth. However, after glucose was exhausted, the accumulated R-acetoin could be reused by the cells as a carbon source. Acetoin dehydrogenase enzyme system, encoded by acoABCD, was responsible for R-acetoin dissimilation. acoABCD mutants lost the ability to grow on acetoin as the sole carbon source, and the acetoin accumulated could not be dissimilated. However, in the presence of another carbon source, the acetoin accumulated in broth of acoABCD mutants was converted to 2,3-butanediol. Parameters of R-acetoin production by budC mutants were optimized in batch culture. Aerobic culture and mildly acidic conditions (pH 6-6.5) favored R-acetoin accumulation. At the optimized conditions, in fed-batch fermentation, 62.3 g/L R-acetoin was produced by budC and acoABCD double mutant in 57 h culture, with an optical purity of 98.0 %, and a substrate conversion ratio of 28.7 %. PMID- 26059459 TI - Non-Vitamin K Oral Anticoagulants (NOACs) A Review of Clinical Management and Laboratory Issues. AB - The non-vitamin K oral anticoagulants (NOACs) are set to replace vitamin K antagonists (principally warfarin), unfractionated heparin and low molecular weight heparin as the leading antithrombotic prophylaxis in several medical and surgical settings. As a group, NOACs have a better safety profile and at least an equivalent (and sometimes superior) efficacy profile than their comparator. The objective of this review is to provide the practitioner with a comprehensive, balanced and contemporary view of these drugs and their applications. More specifically, it focuses on the evidence base for their licences, use in clinical practice (such as in renal dysfunction, orthopaedic surgery, atrial fibrillation, and venous thromboembolism, and the effects of co-medications), responses to actual or perceived haemorrhage, and the role of the laboratory. PMID- 26059460 TI - IHS: sustaining momentum, fostering collaboration, facilitating advocacy. PMID- 26059461 TI - Integrative approaches for predicting microRNA function and prioritizing disease related microRNA using biological interaction networks. AB - MicroRNAs (miRNA) play critical roles in regulating gene expressions at the posttranscriptional levels. The prediction of disease-related miRNA is vital to the further investigation of miRNA's involvement in the pathogenesis of disease. In previous years, biological experimentation is the main method used to identify whether miRNA was associated with a given disease. With increasing biological information and the appearance of new miRNAs every year, experimental identification of disease-related miRNAs poses considerable difficulties (e.g. time-consumption and high cost). Because of the limitations of experimental methods in determining the relationship between miRNAs and diseases, computational methods have been proposed. A key to predict potential disease related miRNA based on networks is the calculation of similarity among diseases and miRNA over the networks. Different strategies lead to different results. In this review, we summarize the existing computational approaches and present the confronted difficulties that help understand the research status. We also discuss the principles, efficiency and differences among these methods. The comprehensive comparison and discussion elucidated in this work provide constructive insights into the matter. PMID- 26059462 TI - Across language families: Genome diversity mirrors linguistic variation within Europe. AB - OBJECTIVES: The notion that patterns of linguistic and biological variation may cast light on each other and on population histories dates back to Darwin's times; yet, turning this intuition into a proper research program has met with serious methodological difficulties, especially affecting language comparisons. This article takes advantage of two new tools of comparative linguistics: a refined list of Indo-European cognate words, and a novel method of language comparison estimating linguistic diversity from a universal inventory of grammatical polymorphisms, and hence enabling comparison even across different families. We corroborated the method and used it to compare patterns of linguistic and genomic variation in Europe. MATERIALS AND METHODS: Two sets of linguistic distances, lexical and syntactic, were inferred from these data and compared with measures of geographic and genomic distance through a series of matrix correlation tests. Linguistic and genomic trees were also estimated and compared. A method (Treemix) was used to infer migration episodes after the main population splits. RESULTS: We observed significant correlations between genomic and linguistic diversity, the latter inferred from data on both Indo-European and non-Indo-European languages. Contrary to previous observations, on the European scale, language proved a better predictor of genomic differences than geography. Inferred episodes of genetic admixture following the main population splits found convincing correlates also in the linguistic realm. DISCUSSION: These results pave the ground for previously unfeasible cross-disciplinary analyses at the worldwide scale, encompassing populations of distant language families. PMID- 26059463 TI - Acute opioid withdrawal is associated with increased neural activity in reward processing centers in healthy men: A functional magnetic resonance imaging study. AB - BACKGROUND: Opioid analgesics are frequently prescribed for chronic pain. One expected consequence of long-term opioid use is the development of physical dependence. Although previous resting state functional magnetic resonance imaging (fMRI) studies have demonstrated signal changes in reward-associated areas following morphine administration, the effects of acute withdrawal on the human brain have been less well-investigated. In an earlier study by our laboratory, ondansetron was shown to be effective in preventing symptoms associated with opioid withdrawal. The purpose of this current study was to characterize neural activity associated with acute opioid withdrawal and examine whether these changes are modified by ondansetron. METHODS: Ten participants were enrolled in this placebo-controlled, randomized, double-blind, crossover study and attended three acute opioid withdrawal sessions. Participants received either placebo or ondansetron (8Ymg IV) before morphine administration (10Ymg/70Ykg IV). Participants then underwent acute naloxone-precipitated withdrawal during a resting state fMRI scan. Objective and subjective opioid withdrawal symptoms were assessed. RESULTS: Imaging results showed that naloxone-precipitated opioid withdrawal was associated with increased neural activity in several reward processing regions, including the right pregenual cingulate, putamen, and bilateral caudate, and decreased neural activity in networks involved in sensorimotor integration. Ondansetron pretreatment did not have a significant effect on the imaging correlates of opioid withdrawal. CONCLUSIONS: This study presents a preliminary investigation of the regional changes in neural activity during acute opioid withdrawal. The fMRI acute opioid withdrawal model may serve as a tool for studying opioid dependence and withdrawal in human participants. PMID- 26059464 TI - Charge-ordering cascade with spin-orbit Mott dimer states in metallic iridium ditelluride. AB - Spin-orbit coupling results in technologically-crucial phenomena underlying magnetic devices like magnetic memories and energy-efficient motors. In heavy element materials, the strength of spin-orbit coupling becomes large to affect the overall electronic nature and induces novel states such as topological insulators and spin-orbit-integrated Mott states. Here we report an unprecedented charge-ordering cascade in IrTe2 without the loss of metallicity, which involves localized spin-orbit Mott states with diamagnetic Ir(4+)-Ir(4+) dimers. The cascade in cooling, uncompensated in heating, consists of first order-type consecutive transitions from a pure Ir(3+) phase to Ir(3+)-Ir(4+) charge-ordered phases, which originate from Ir 5d to Te 5p charge transfer involving anionic polymeric bond breaking. Considering that the system exhibits superconductivity with suppression of the charge order by doping, analogously to cuprates, these results provide a new electronic paradigm of localized charge-ordered states interacting with itinerant electrons through large spin-orbit coupling. PMID- 26059466 TI - The language needs of residents from linguistically diverse backgrounds in Victorian aged care facilities. AB - OBJECTIVES: To investigate the language needs of residents of aged care facilities within the State of Victoria, Australia, and determine what language resources were accessible to them. METHODS: Postal questionnaires were sent to 586 aged care facilities, enquiring about residents' and staff members' languages and language-specific resources. RESULTS: The response rate was 38%. The majority of facilities had residents who spoke non-English languages, and 55 different languages were represented. Three-quarters of the facilities employed staff members who spoke to residents in non-English languages and employed language specific resources. The metropolitan and ethnospecific facilities had a greater presence of non-English-speaking residents and staff and more commonly used language-specific resources in comparison with regional and mainstream facilities. CONCLUSION: We found a large number of languages used by many residents from non-English-speaking backgrounds, with evidence of a large unmet language resource need. Unmet need was greatest in rural areas. PMID- 26059465 TI - The thymoprotective function of leptin is indirectly mediated via suppression of obesity. AB - Leptin is an adipokine that regulates metabolism and plays an important role as a neuroendocrine hormone. Leptin mediates these functions via the leptin receptor, and deficiency in either leptin or its receptor leads to obesity in humans and mice. Leptin has far reaching effects on the immune system, as observed in obese mice, which display decreased thymic function and increased inflammatory responses. With expression of the leptin receptor on T cells and supporting thymic epithelium, aberrant signalling through the leptin receptor has been thought to be the direct cause of thymic involution in obese mice. Here, we demonstrate that the absence of leptin receptor on either thymic epithelial cells or T cells does not lead to the loss of thymic function, demonstrating that the thymoprotective effect of leptin is mediated by obesity suppression rather than direct signalling to the cellular components of the thymus. PMID- 26059467 TI - Key safety considerations when administering epidural steroid injections. AB - Neurological and other complications of epidural steroid injections have been widely discussed in recent years. Consequently, the US FDA issued a warning about serious neurological events, some resulting in death, and consequently is requiring label changes. Neurological adverse events numbering 131, including 41 cases of arachnoiditis, have been identified by the FDA, and 700 cases of fungal meningitis following injection of contaminated steroids. A review of the literature reveals an overwhelming proportion of the complications are related to transforaminal epidural injections, with the majority of them to cervical transforaminal epidural injections. This perspective describes the prevalence of administering epidural injections, complications, pathoanatomy, mechanism of injury and various preventive strategies. PMID- 26059468 TI - Assessment of heavy metals mobility and toxicity in contaminated sediments by sequential extraction and a battery of bioassays. AB - The aim of this study was to assess heavy metals mobility and toxicity in sediments collected from a dam reservoir in the conditions of intensive human impact by using chemical fractionation and a battery of bioassays. In the studies, the test organisms were exposed to substances dissolved in water (Microtox, Phytotestkit) as well to substances absorbed on the surface of solid particles (Phytotoxkit, Ostracodtoxkit F). The studies showed that sediments from the Rybnik reservoir are toxic, but the tested organisms showed different sensitivity to heavy metals occurring in the bottom sediments. The sediment samples were classified as toxic and very toxic. Moreover, the studies showed a higher toxicity in solid phases and whole sediment than in pore water. The lowest sensitivity was observed in H. incongruens (solid phases) and V. fischeri (pore water, whole sediment). The studies revealed that the toxicity of the sediments is caused mainly by heavy metal forms associated with the solid phase of the sediments. The studies did not confirm the metals occurring in fraction I (exchangeable) to be bioavailable and toxic to living organisms because most correlations between the metal concentration in fraction I and the response of the organisms were negative. The highest mobility from the bottom sediments was found in zinc, average mobility--in copper, cadmium and nickel, and low mobility- in chromium and lead. Organic matter is likely to be the most important factor controlling metal distribution and mobility in the studied sediments. PMID- 26059469 TI - Biosurfactant activity, heavy metal tolerance and characterization of Joostella strain A8 from the Mediterranean polychaete Megalomma claparedei (Gravier, 1906). AB - The effect of heavy metals on the activity of biosurfactants produced by Joostella strain A8 from the polychaete Megalomma claparedei was investigated. Biosurfactant activity was first improved by evaluating the influence of abiotic parameters. Higher E(24) indices were achieved at 25 degrees C in mineral salt medium supplemented with 2 % glucose, 3 % sodium chloride (w/v) and 0.1 % ammonium chloride (w/v). Considerable surface tension reduction was never recorded. Heavy metal tolerance was preliminarily assayed by plate diffusion method resulting in the order of toxicity Cd > Cu > Zn. The activity of biosurfactants was then evaluated in the presence of heavy metals at different concentrations in liquid cultures that were incubated under optimal conditions for biosurfactant activity. The production of stable emulsions resulted generally higher in the presence of metals. These findings suggest that biosurfactant production could represent a bacterial adaptive strategy to defend cells from a stress condition derived from heavy metals in the bulk environment. PMID- 26059470 TI - Phylogenetic relationships of subfamilies in the family Hesperiidae (Lepidoptera: Hesperioidea) from China. AB - Hesperiidae is one of the largest families of butterflies. Our knowledge of the higher systematics on hesperiids from China is still very limited. We infer the phylogenetic relationships of the subfamilies of Chinese skippers based on three mitochondrial genes (cytochrome b (Cytb), the NADH dehydrogenase subunit 1 (ND1) and cytochrome oxidase I (COI)). In this study, 30 species in 23 genera were included in the Bayesian and maximum likelihood analyses. The subfamily Coeliadinae, Eudaminae, Pyrginae and Heteropterinae were recovered as a monophyletic clade with strong support. The subfamily Hesperiinae formed a clade, but support for monophyly was weak. Our results imply that the five subfamilies of Chinese Hesperiidae should be divided into: Coeliadinae, Eudaminae, Pyrginae, Heteropterinae and Hesperiinae. The relationships of the five subfamilies should be as follows: Coeliadinae + (Eudaminae + (Pyrginae + (Heteropterinae + Hesperiinae))). PMID- 26059471 TI - Flexible copper-stabilized sulfur-carbon nanofibers with excellent electrochemical performance for Li-S batteries. AB - By rational design, we fabricated a flexible and free-standing copper-immobilized sulfur-porous carbon nanofiber (denoted as S@PCNFs-Cu) electrode by simply impregnating sulfur into electrospun derived Cu embedded porous carbon nanofibers (PCNFs-Cu). The PCNF film with a 3D interconnected structure is used as a conducting matrix to encapsulate sulfur. In addition, the introduction of Cu leads to the formation of a chemical bond between Cu and S, preventing the dissolution of polysulfide during cycling. The micropores and mesopores of PCNF hosts provide free space to accommodate the volume change of S and polysulfide. When used as a cathode material for Li-S batteries, the S@PCNFs-Cu (S content: 52 wt%) exhibits much better electrochemical performance compared to the Cu-free S@PCNF electrode. The S@PCNFs-Cu displays high reversible capacity (680 mA h g( 1) after 100 cycles at 50 mA g(-1)), excellent rate capability (415 mA h g(-1) at 1 A g(-1)) and super Coulombic efficiency of 100%. This strategy of stabilizing S with a small amount of copper nanoparticles can be a very promising method to prepare free-standing cathode material for high-performance Li-S batteries. PMID- 26059472 TI - MicroRNA: master controllers of intracellular signaling pathways. AB - Signaling pathways are essential intracellular networks that coordinate molecular outcomes to external stimuli. Tight regulation of these pathways is essential to ensure an appropriate response. MicroRNA (miRNA) is a class of small, non-coding RNA that regulates gene expression at a post-transcriptional level by binding to the complementary sequence on target mRNA, thus limiting protein translation. Intracellular pathways are controlled by protein regulators, such as suppressor of cytokine signaling and A20. Until recently, expression of these classical protein regulators was thought to be controlled solely by transcriptional induction and proteasomal degradation; however, there is a growing body of evidence describing their regulation by miRNA. This new information has transformed our understanding of cell signaling by adding a previously unknown layer of regulatory control. This review outlines the miRNA regulation of these classical protein regulators and describes their broad effects at both cellular and disease levels. We review the regulation of three important signaling pathways, including the JAK/STAT, NF-kappaB, and TGF-beta pathways, and summarize an extensive catalog of their regulating miRNAs. This information highlights the importance of the miRNA regulon and reveals a previously unknown regulatory landscape that must be included in the identification and development of novel therapeutic targets for clinical disorders. PMID- 26059474 TI - Invalid assumptions in clustering analyses of category fluency data: Reply to Sung, Gordon and Schretlen (2015). PMID- 26059475 TI - Write less, write well. PMID- 26059473 TI - Splitting up the powerhouse: structural insights into the mechanism of mitochondrial fission. AB - Mitochondria are dynamic organelles whose shape is regulated by the opposing processes of fission and fusion, operating in conjunction with organelle distribution along the cytoskeleton. The importance of fission and fusion homeostasis has been highlighted by a number of disease states linked to mutations in proteins involved in regulating mitochondrial morphology, in addition to changes in mitochondrial dynamics in Alzheimer's, Huntington's and Parkinson's diseases. While a number of mitochondrial morphology proteins have been identified, how they co-ordinate to assemble the fission apparatus is not clear. In addition, while the master mediator of mitochondrial fission, dynamin related protein 1, is conserved throughout evolution, the adaptor proteins involved in its mitochondrial recruitment are not. This review focuses on our current understanding of mitochondrial fission and the proteins that regulate this process in cell homeostasis, with a particular focus on the recent mechanistic insights based on protein structures. PMID- 26059476 TI - A trial-by-trial analysis reveals more intense physical activity is associated with better cognitive control performance in attention-deficit/hyperactivity disorder. AB - Hyperactivity is a key symptom and the most observable manifestation of attention deficit/hyperactivity disorder (ADHD). The over-activity associated with ADHD can cause specific challenges in academic settings, extracurricular activities and social relationships. Cognitive control challenges are also well established in ADHD. The current study included 44 children between the ages of 10 and 17 diagnosed with ADHD or who were typically developing (TD), all of whom had no psychiatric co-morbidity or significant learning disorders. Participants wore an actometer on their ankle while performing a flanker paradigm in order to objectively measure their rates of activity in association with cognitive control. Analyses assessed the relationship between frequency and intensity of activity to task accuracy on a trial-by-trial basis. A significant interaction effect between group and performance revealed that more intense movement was associated with better performance in the ADHD group but not in the TD group. The ADHD group demonstrated more intense activity than the TD group during correct (but not error) trials. Within-group, children with ADHD generated higher intensity movements in their correct trials compared to their error trials, whereas the TD group did not demonstrate any within-group differences. These findings suggest that excessive motoric activity associated with clinically significant ADHD symptoms may reflect compensatory efforts to modulate attention and alertness. Future research should systematically explore the relationship between motion in ADHD and how it might be used to improve cognitive performance. PMID- 26059477 TI - Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations. AB - beta-Ketoacyl-ACP-synthase III (FabH or KAS III) has become an attractive target for the development of new antibacterial agents which can overcome the multidrug resistance. Unraveling the fatty acid biosynthesis (FAB) metabolic pathway and understanding structural coordinates of FabH will provide valuable insights to target Streptococcus gordonii for curing oral infection. In this study, we designed inhibitors against therapeutic target FabH, in order to block the FAB pathway. As compared to other targets, FabH has more interactions with other proteins, located on the leading strand with higher codon adaptation index value and associated with lipid metabolism category of COG. Current study aims to gain in silico insights into the structural and dynamical aspect of S. gordonii FabH via molecular docking and molecular dynamics (MD) simulations. The FabH protein is catalytically active in dimerization while it can lock in monomeric state. Current study highlights two residues Pro88 and Leu315 that are close to each other by dimerization. The active site of FabH is composed of the catalytic triad formed by residues Cys112, His249, and Asn279 in which Cys112 is involved in acetyl transfer, while His249 and Asn279 play an active role in decarboxylation. Docking analysis revealed that among the studied compounds, methyl-CoA disulfide has highest GOLD score (82.75), binding affinity (-11 kcal/mol) and exhibited consistently better interactions. During MD simulations, the FabH structure remained stable with the average RMSD value of 1.7 A and 1.6 A for undocked protein and docked complex, respectively. Further, crucial hydrogen bonding of the conserved catalytic triad for exhibiting high affinity between the FabH protein and ligand is observed by RDF analysis. The MD simulation results clearly demonstrated that binding of the inhibitor with S. gordonii FabH enhanced the structure and stabilized the dimeric FabH protein. Therefore, the inhibitor has the potential to become a lead compound. PMID- 26059478 TI - Conformational properties of chiral tobacco alkaloids by DFT calculations and vibrational circular dichroism: (-)-S-anabasine. AB - A thorough DFT and MM study of the conformational landscape, molecular and electronic structures of (-)-S-anabasine is reported aimed to reveal the mechanism controlling its conformational preference. Although the conformational flexibility and diversity of this system is quite extensive, only two structures are populated both in gas-phase and solution (CCl4 and DMSO). NBO-aided electronic structure analyses performed for the eight conformers representing minima in the potential energy surface of (-)-S-anabasine indicate that both steric and electrostatic factors are determinant in the conformational distribution of the sample in gas phase. Nonetheless, hyperconjugative effects are the key force tipping the balance in the conformational equilibrium between the two main rotamers. Increasing the polarity of the medium (using the IEF-PCM formalism) barely affect the conformational energy profile, although a slight increase in the theoretical population of those structures more affected by electrostatic interactions is predicted. The validity of the theoretical models and calculated conformers populations are endorsed by the accurate reproduction of the IR and VCD spectra (recorded in pure liquid and in CCl4 solution) of the sample (that have been firstly recorded and assigned in the present work) which are consistent with the occurrence of a 2:1 conformational ratio. PMID- 26059479 TI - Understanding the self-assembly of Fmoc-phenylalanine to hydrogel formation. AB - Hydrogels of low molecular weight molecules are important in biomedical applications. Multiple factors are responsible for hydrogel formation, but their role in governing self-assembly to hydrogel formation is poorly understood. Herein, we report the hydrogel formation of fluorenylmethyloxycarbonyl phenylalanine (FmocF) molecule. We used physical and thermal stimuli for solubilizing FmocF above the critical concentration to induce gel formation. The key role of Fmoc, Fmoc and phenylalanine covalent linkage, flexibility of phe side chain, pH, and buffer ions in self-assembly of FmocF to gel formation is described. We found that the collective action of different non-covalent interactions play a role in making FmocF hydrogel. Using powder diffraction and infrared spectroscopy, we also report a new polymorphic form of FmocF after transitioning to hydrogel. In addition, we are proposing a model for drug release from FmocF hydrogel. PMID- 26059480 TI - A normative analysis of nursing knowledge. AB - This study addresses the question of normative analysis of the value-based aspects of nursing. In our perspective, values in science may be distinguished into (i) epistemic when related to the goals of truth and objectivity and (ii) non-epistemic when related to social, cultural or political aspects. Furthermore, values can be called constitutive when necessary for a scientific enterprise, or contextual when contingently associated with science. Analysis of the roles of the various forms of values and models of knowledge translation provides the ground to understand the specific role of values in nursing. A conceptual framework has been built to classify some of the classical perspectives on nursing knowledge and to examine the relationships between values and different forms of knowledge in nursing. It follows that adopting a normative perspective in the analysis of nursing knowledge provides key elements to identify its proper dimension. PMID- 26059481 TI - Lipophilic Muramyl Dipeptide-Antigen Conjugates as Immunostimulating Agents. AB - Muramyl dipeptide (MDP) is the smallest peptidoglycan fragment capable of triggering the innate immune system through interaction with the intracellular NOD2 receptor. To develop synthetic vaccine modalities composed of an antigenic entity (typically a small peptide) and a molecular adjuvant with well-defined activity, we previously assembled covalent MDP-antigen conjugates. Although these were found to be capable of stimulating the NOD2 receptor and were processed by dendritic cells (DCs) leading to effective antigen presentation, DC maturation- required for an apt immune response--could not be achieved with these conjugates. To improve the efficacy of these vaccine modalities, we equipped the MDP moiety with lipophilic tails, well-known modifications to enhance the immune-stimulatory activity of MDPs. Herein we report the design and synthesis of a lipophilic MDP antigen conjugate and show that it is a promising vaccine modality capable of stimulating the NOD2 receptor, maturing DCs, and delivering antigen cargo into the MHC-I cross-presentation pathway. PMID- 26059483 TI - One ring (or two) to hold them all - on the structure and function of protein nanotubes. AB - Understanding the structural determinants relevant to the formation of supramolecular assemblies of homo-oligomeric proteins is a traditional and central scope of structural biology. The knowledge thus gained is crucial both to infer their physiological function and to exploit their architecture for bionanomaterials design. Protein nanotubes made by one-dimensional arrays of homo oligomers can be generated by either a commutative mechanism, yielding an 'open' structure (e.g. actin), or a noncommutative mechanism, whereby the final structure is formed by hierarchical self-assembly of intermediate 'closed' structures. Examples of the latter process are poorly described and the rules by which they assemble have not been unequivocally defined. We have collected and investigated examples of homo-oligomeric circular arrangements that form one dimensional filaments of stacked rings by the noncommutative mechanism in vivo and in vitro. Based on their quaternary structure, circular arrangements of protein subunits can be subdivided into two groups that we term Rings of Dimers (e.g. peroxiredoxin and stable protein 1) and Dimers of Rings (e.g. thermosome/rosettasome), depending on the sub-structures that can be identified within the assembly (and, in some cases, populated in solution under selected experimental conditions). Structural analysis allowed us to identify the determinants by which ring-like molecular chaperones form filamentous-like assemblies and to formulate a novel hypothesis by which nanotube assembly, molecular chaperone activity and macromolecular crowding may be interconnected. PMID- 26059484 TI - A wearable smartphone-enabled camera-based system for gait assessment. AB - Quantitative assessment of gait parameters provides valuable diagnostic and prognostic information. However, most gait analysis systems are bulky, expensive, and designed to be used indoors or in laboratory settings. Recently, wearable systems have attracted considerable attention due to their lower cost and portability. In this paper, we present a simple wearable smartphone-enabled camera-based system (SmartGait) for measurement of spatiotemporal gait parameters. We assess the concurrent validity of SmartGait as compared to a commercially available pressure-sensing walkway (GaitRite). Fifteen healthy young adults (25.8+/- 2.6 years) were instructed to walk at slow, preferred, and fast speed. The measures of step length (SL), step width (SW), step time (ST), gait speed, double support time (DS) and their variability were assessed for agreement between the two systems; absolute error and intra-class correlation coefficients (ICC) were determined. Measured gait parameters had modest to excellent agreements (ICCs between 0.731 and 0.982). Overall, SmartGait provides many advantages and is a strong alternative wearable system for laboratory and community-based gait assessment. PMID- 26059482 TI - Gene set analysis: A step-by-step guide. AB - To maximize the potential of genome-wide association studies, many researchers are performing secondary analyses to identify sets of genes jointly associated with the trait of interest. Although methods for gene-set analyses (GSA), also called pathway analyses, have been around for more than a decade, the field is still evolving. There are numerous algorithms available for testing the cumulative effect of multiple SNPs, yet no real consensus in the field about the best way to perform a GSA. This paper provides an overview of the factors that can affect the results of a GSA, the lessons learned from past studies, and suggestions for how to make analysis choices that are most appropriate for different types of data. (c) 2015 Wiley Periodicals, Inc. PMID- 26059485 TI - Comparing clinical and economic outcomes of biologic and conventional medications in postmenopausal women with osteoporosis. AB - RATIONALE, AIMS AND OBJECTIVES: Biologics are substantially more expensive than their conventional counterparts but it is unclear whether extra costs deliver better health outcomes. We compare clinical and economic outcomes between teriparatide (monthly costs $1120) and bisphosphonates (monthly costs $14) among postmenopausal women with osteoporosis. METHODS: From a 5% random sample of Medicare beneficiaries, we selected women newly diagnosed with osteoporosis between 1 January 2007 and 31 December 2011 and who initiated teriparatide or bisphosphonates after the diagnosis. We followed them up until one of these events: switching osteoporosis treatment, death, or the end of study period - 31 December 2011. Clinical outcomes included hip fracture, vertebral fracture, fracture of radius, ulna or carpal bones, other upper limb fractures, other lower limb fractures and any fracture. Economic outcomes included medical costs, pharmacy costs, and total costs associated with osteoporosis. Using conventional propensity score, high-dimensional propensity score and instrumental variable analysis, we constructed Cox proportional hazards models to evaluate the risk of fracture and two-part models to compare costs. RESULTS: Teriparatide users had higher risk of fracture and higher costs, compared with similar bisphosphonates users. The hazard ratios of fracture for teriparatide relative to bisphosphonates ranged from 1.37 to 2.12, depending on methods. There was no difference in the risk of hip fracture between treatment groups. Total annual costs related to osteoporosis were between $2733 and $3352 higher for teriparatide users. CONCLUSIONS: The biological agent, teriparatide, is more expensive yet less effective than conventional treatment, bisphosphonates. PMID- 26059486 TI - Global Emergency Medicine Journal Club: A Social Media Discussion About the Outpatient Management of Patients With Spontaneous Pneumothorax by Using Pigtail Catheters. AB - Annals of Emergency Medicine collaborated with an educational Web site, Academic Life in Emergency Medicine (ALiEM) to host a public discussion featuring the 2014 Annals article on the outpatient management of patients with a spontaneous pneumothorax by using pigtail catheters. The objective was to curate a 14-day (November 10 to 23, 2014) worldwide academic dialogue among clinicians about the article. Four online facilitators hosted the multimodal discussion on the ALiEM Web site, Twitter, and Google Hangout. Comments across the social media platforms were curated for this report, as framed by 4 preselected questions. Engagement was tracked through Web analytic tools. Blog comments, tweets, and video expert commentary involving the featured article are summarized and reported. The dialogue resulted in 1,023 page views from 347 cities in 49 countries on the ALiEM Web site, 279,027 Twitter impressions, and 88 views of the video interview with experts. This Global Emergency Medicine Journal Club created a virtual community of practice from around the world and identified common themes around the management of spontaneous pneumothorax, which included substantial practice variation in regard to inpatient versus outpatient management, location of chest tube, the use of aspiration, and chest radiography after placement. PMID- 26059487 TI - Are Steroids Effective for Severe Chronic Obstructive Pulmonary Disease Requiring Intensive Care? PMID- 26059488 TI - Emergency Care at the Crossroads: Emergency Department Crowding, Payment Reform, and One Potential Future. PMID- 26059489 TI - Comparison of the effect of raw and blanched-frozen broccoli on DNA damage in colonocytes. AB - Consumption of cruciferous vegetables may protect against colorectal cancer. Cruciferous vegetables are rich in a number of bioactive constituents including polyphenols, vitamins and glucosinolates. Before consumption, cruciferous vegetables often undergo some form of processing that reduces their content of bioactive constituents and may determine whether they exert protective effects. The aim of this study was to compare the ability of raw and blanched-frozen broccoli to protect colonocytes against DNA damage, improve antioxidant status and induce xenobiotic metabolizing enzymes (XME). Fifteen Landrace * Large White male pigs were divided into five age-matched and weight-matched sets (79 days, SD 3, and 34.7 kg, SD 3.9, respectively). Each set consisted of siblings to minimize genetic variation. Within each set, pigs received a cereal-based diet, unsupplemented (control) or supplemented with 600 g day(-1) of raw or blanched frozen broccoli for 12 days. The consumption of raw broccoli caused a significant 27% increase in DNA damage in colonocytes (p = 0.03) relative to the control diet, whereas blanched-frozen broccoli had no significant effect. Both broccoli diets had no significant effect on plasma antioxidant status or hepatic and colonic XME. This study is the first to report that the consumption of raw broccoli can damage DNA in porcine colonocytes. PMID- 26059490 TI - The role of qualitative elastography in thyroid nodule evaluation: exploring its target populations. PMID- 26059491 TI - An unusual, duplicate origin of the anterior choroidal artery with aneurysm: a case report. AB - BACKGROUND AND IMPORTANCE: Aneurysms of the anterior choroidal artery (AChoA) are rare and often difficult to treat. Variations may be present and must be identified prior to treatment. We report a unique case of a ruptured aneurysm located at the origin of a duplicate branch of the AChoA. CLINICAL PRESENTATION: A 56-year-old male was admitted to our university hospital for coma. A brain CT scan showed a subarachnoid hemorrhage, and CT angiography revealed a duplication of the right AChoA, with an aneurysm located at the branch's origin. We decided to embolize this aneurysm. Four weeks later, our patient was able to transfer to the rehabilitation unit. CONCLUSION: To the best of our knowledge, this is one of the first descriptions of an aneurysm located at the origin of a duplicate branch of the AChoA. PMID- 26059492 TI - Retrospective head motion correction approaches for diffusion tensor imaging: Effects of preprocessing choices on biases and reproducibility of scalar diffusion metrics. AB - PURPOSE: To evaluate how retrospective head motion correction strategies affect the estimation of scalar metrics commonly used in clinical diffusion tensor imaging (DTI) studies along with their across-session reproducibility errors. MATERIALS AND METHODS: Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD) and their respective across-session reproducibility errors were measured on a 4T test-retest dataset of healthy participants using five processing pipelines. These differed in: 1) the number of b0 volumes used for motion correction reference (one or five); 2) the estimations of the gradient matrix rotation (based on 6 or 12 degrees of freedom derived from coregistration); and 3) the software packages used (FSL or DTIPrep). Biases and reproducibility were evaluated in three regions of interest (ROIs) (bilateral arcuate fasciculi, cingula, and the corpus callosum) and also at the full brain level with tract based skeleton images. RESULTS: Preprocessing choices affected DTI measures and their reproducibility. The DTIPrep pipeline exhibited higher DTI metrics: FA/MD and AD (P < 0.05) relative to FSL pipelines both at the ROI and full brain level, and lower RD estimates (P < 0.05) at the ROI level. Within FSL pipelines no such effects were found (P-values ranging between 0.25 and 0.97). The DTIPrep pipeline showed the highest number of white matter skeleton voxels, with significantly higher reproducibility (P < 0.001) relative to the other pipelines (tested on P < 0.01 uncorrected maps). CONCLUSION: The use of an iteratively averaged b0 image as motion correction reference (as performed by DTIPrep) affects both scalar values and improves test-retest reliability relative to the other tested pipelines. These considerations are potentially relevant for data analysis in longitudinal DTI studies. PMID- 26059493 TI - Fluorinated polymer-grafted organic dielectrics for organic field-effect transistors with low-voltage and electrical stability. AB - The electrical stabilities of low-voltage organic field-effect transistors (OFETs) were improved by applying graftable fluorinated polymer (gPFS) layers onto poly(4-vinyl phenol)-based cross-linked dielectrics (cPVP). As a result, a smooth and hydrophobic surface was formed, and the dielectric film displayed a low-leakage current density. The chemisorbed gPFS groups enabled the solution processing of an overlying 5,11-bis(triethylsilylethynyl)anthradithiophene semiconductor, which formed favorable terrace-like crystalline structures after solvent annealing. The top-contact OFETs showed superior operational stability compared to cPVP-based OFETs. Hysteresis was negligible, and the off-current of the transfer curve was one order of magnitude lower than that obtained from cPVP based OFETs. The threshold voltage shift measured after a sustained gate bias stress for 1 h decreased significantly after introduction of the hydrophobic gPFS treatment; the energetic barrier to creating charge trapping sites increased, and the trap distribution narrowed, as supported by the stretched exponential function model. PMID- 26059494 TI - Editorial Comment to Stenting for malignant ureteral obstruction: Tandem, metal or metal-mesh stents. PMID- 26059495 TI - Non-uniform recruitment along human rectus femoris muscle during transcutaneous electrical nerve stimulation. AB - PURPOSE: To test the hypothesis that motor units with different axonal excitability levels are localized in specific portions of the rectus femoris (RF) muscle using transcutaneous electrical nerve stimulation. METHODS: M-waves were elicited by transcutaneous electrical nerve stimulation and detected from 24 sites along longitudinal line of the muscle. The stimulation was applied to the femoral nerve, and the current level was gradually increased. RESULTS: The central locus activation, which is calculated from the spatial distribution of M waves, appeared at the proximal regions at low stimulation level and then moved to the middle site of the muscle with an increase in the stimulation level. The results reveal that groups of motor units activated at different stimulation levels are located in different positions in the proximal-distal muscle direction. CONCLUSION: Our results suggest that motor unit properties in proximal and other regions are not uniform within the RF muscle. PMID- 26059496 TI - Tabletability Modulation Through Surface Engineering. AB - Poor powder tabletability is a common problem that challenges the successful development of high-quality tablet products. Using noncompressible microcrystalline cellulose beads, we demonstrate that surface coating is an effective strategy for modulating tabletability, almost at will, through judicious selection of coating material. This strategy has broad applicability as tabletability of such particles is dictated by the properties of the outermost layer coat regardless the nature of the core. PMID- 26059497 TI - Effect of a chlorhexidine/thymol and a fluoride varnish on caries development in erupting permanent molars: a comparative study. AB - AIM: To compare the caries preventive effect of a chlorhexidine/thymol-containing antibacterial varnish with a fluoride varnish when topically applied during the eruption of permanent molars. METHODS: The study group consisted of 189 patients, 5-14 years of age, with one 1st or 2nd permanent molar in the process of eruption. After stratification for type of molar and stage of eruption, the patients were randomised to either quarterly topical applications with an antibacterial varnish (Cervitec((r)) Plus; CV group) or biannual applications with a fluoride varnish plus biannual treatments with placebo varnish (Fluor Protector; FV group). The duration of the study was 2 years. The primary endpoint was caries incidence (initial and cavitated) in the erupting molars and the secondary outcome was salivary mutans streptococci (MS) counts. RESULTS: The groups were balanced with respect to socio-economy, oral hygiene, dietary habits and caries experience at baseline. The dropout rate was 11.6 %. The caries incidence was low (< 10 %) in both groups and there was no significant difference between the CV and FV groups with respect to occlusal caries development in the erupting molars (relative risk 1.08, 95 % CI 0.94-1.25). Significantly lower levels of salivary MS were disclosed in the CV group at the end of the study (p < 0.05). CONCLUSIONS: No difference in occlusal caries development in young permanent molars was displayed after topical applications of either a chlorhexidine/thymol varnish or a fluoride varnish during tooth eruption. PMID- 26059498 TI - Variable selection for zero-inflated and overdispersed data with application to health care demand in Germany. AB - In health services and outcome research, count outcomes are frequently encountered and often have a large proportion of zeros. The zero-inflated negative binomial (ZINB) regression model has important applications for this type of data. With many possible candidate risk factors, this paper proposes new variable selection methods for the ZINB model. We consider maximum likelihood function plus a penalty including the least absolute shrinkage and selection operator (LASSO), smoothly clipped absolute deviation (SCAD), and minimax concave penalty (MCP). An EM (expectation-maximization) algorithm is proposed for estimating the model parameters and conducting variable selection simultaneously. This algorithm consists of estimating penalized weighted negative binomial models and penalized logistic models via the coordinated descent algorithm. Furthermore, statistical properties including the standard error formulae are provided. A simulation study shows that the new algorithm not only has more accurate or at least comparable estimation, but also is more robust than the traditional stepwise variable selection. The proposed methods are applied to analyze the health care demand in Germany using the open-source R package mpath. PMID- 26059499 TI - Low vitamin D is associated with hypertension in paediatric obesity. AB - AIM: The aim of this paper was to investigate the relationship between circulating 25-hydroxyvitamin D (25(OH)D) and cardio-metabolic risk factors in a large cohort of obese youth attending tertiary paediatric obesity services. METHODS: We conducted a retrospective cross-sectional study. Data were retrospectively collected from all new consultations of children and adolescents attending obesity outpatient clinics between 2008 and 2011 at the two major paediatric hospitals in Melbourne, Australia. Information collected included demographics, anthropometry, blood pressure, pubertal staging, body composition and fasting serum levels of 25(OH)D, glucose, insulin, cholesterol, triglyceride, high-density lipoprotein, liver function, calcium and phosphate. RESULTS: 25(OH)D data were available in 229 patients (age 3-18 years; 116 men; mean (standard deviation) body mass index ( BMI) Z-score 2.5 (0.5) ). One hundred four (45%) participants were 25(OH)D deficient (<50 nmol/L). Lower serum 25(OH)D levels were associated with higher BMI Z-score (P-trend = 0.001), total fat mass (P-trend = 0.009), systolic (P-trend = 0.03) and diastolic blood pressures(P-trend = 0.009). In multivariable-adjusted regression analysis, 25(OH)D was significantly lower in those with elevated blood pressure after adjustment for BMI(P-trend = 0.004) or total fat mass (P-trend = 0.01). CONCLUSION: Overweight and obese youth attending specialist obesity services have a high prevalence of vitamin D deficiency. In this population, lower levels of vitamin D were seen in those with greater adiposity, and independent of this, in those who had higher blood pressure. PMID- 26059500 TI - Cartilage Status at Time of Arthroscopy Predicts Failure in Patients With Hip Dysplasia. AB - The purpose of our study was to determine whether chondral damage at the time of arthroscopy predicted conversion to THA in patients with dysplasia. We identified 166 patients with dysplasia who underwent hip arthroscopy. Forty-seven went on to receive THA. The articular cartilage of three regions of the acetabulum and femoral head were assessed for signs of chondral damage (absent, mild, or severe]). A stepwise multivariable logistic regression analysis revealed mild damage on the posterior femoral head (P=0.001) and severe damage on the anterior acetabulum (P=0.007) made a significant contribution to the predictor. The presence of mild posterior femoral head chondral changes was indicative of more global cartilage damage in this series of patients. Our findings show that chondral damage on the posterior femoral head and anterior acetabulum is a strong predictor of ultimate conversion to THA in dysplastic patients. PMID- 26059501 TI - Prolonged Length of Stay Is Not an Acceptable Alternative to Coded Complications in Assessing Hospital Quality in Elective Joint Arthroplasty. AB - We sought to determine if prolonged length of stay (pLOS) is an accurate measure of quality in total hip and knee arthroplasty (THA and TKA). Coded complications and pLOS for 5967 TKA and 4518 THA patients in our hospital discharged between 2009 and 2011 were analyzed. Of 727 patients with pLOS, only 170 also had a complication, yielding a sensitivity of 41.4% (95% CI: 36.7, 46.2) with a positive predictive value (PPV) of just 23.4% (95% CI: 20.3, 26.4). Specificity (94.5% [95% CI: 94.0, 94.9]) and negative predictive value (NPV) (97.5% [95% CI: 97.2, 97.8]) were high, due to the large number of patients without complications or pLOS. This suggests that risk-adjusted pLOS is an inadequate measure of patient safety in primary THA and TKA. PMID- 26059502 TI - Prevalence and Perioperative Outcomes of Off-Label Total Hip and Knee Arthroplasty in the United States, 2000-2010. AB - "Off-label use" refers to medical device utilization for purposes or subpopulations other than those approved by the United States Food and Drug Administration. The primary goal of this study was to determine the current epidemiology of off-label total hip and knee arthroplasties (THA and TKA, respectively) in the United States and to project further off-label use through 2040. Over the past decade, the prevalence of off-label THA and TKA was 30.4% and 37.0%, respectively, growing ~70% from 2000 to 2010. By 2040, the majority of THAs (86.1%) and TKAs (91.5%) could be off-label. The high prevalence of off label arthroplasty and the dramatically shifting patient profile illustrated by these results highlight the need for continued medical device surveillance among on- and off label patients. PMID- 26059503 TI - The Survival Analysis in Third-Generation Ceramic-On-Ceramic Total Hip Arthroplasty. AB - A total of 527 patients (577 hips) who underwent primary THA using third generation ceramic-on-ceramic (CoC) articulation were retrospectively reviewed. They were followed up for an average of 5.9 years. Seven hips experienced liner fracture and 14 hips experienced head fracture. Squeaking occurred in eight hips. The revision rate in this study was 5.2%, but excluding the cases of ceramic head and liner fracture, there were nine cases (1.6%) of revision surgery. Considering revision for any reason as the end point, mean survivorship was 93% at 10 years. According to the femoral head size and neck length, 28 mm head with short neck has the worst survivorship of 89% at 10 years. Overall, our study showed a higher rate of ceramic fracture compared with other studies. PMID- 26059504 TI - Altered exosomal protein expression in the serum of NF-kappaB knockout mice following skeletal muscle ischemia-reperfusion injury. AB - BACKGROUND: The NF-kappaB signaling pathway plays a role in local and remote tissue damage following ischemia-reperfusion (I/R) injury to skeletal muscles. Evidence suggests that exosomes can act as intercellular communicators by transporting active proteins to remote cells and may play a role in regulating inflammatory processes. This study aimed to profile the exosomal protein expression in the serum of NF-kappaB knockout mice following skeletal muscle ischemia-reperfusion injury. RESULTS: To investigate the potential changes in protein expression mediated by NF-kappaB in secreted exosomes in the serum following I/R injury, the levels of circulating exosomal proteomes in C57BL/6 and NF-kappaB(-/-) mice were compared using two dimensional differential in-gel electrophoresis (2-DE), liquid chromatography tandem mass spectrometry (LC MS/MS), and proteomic analysis. In C57BL/6 mice, the levels of circulating exosomal proteins, including complement component C3 prepropeptide, PK-120 precursor, alpha-amylase one precursor, beta-enolase isoform 1, and adenylosuccinate synthetase isozyme 1, increased following I/R injury. However, in the NF-kappaB(-/-) mice, the expression of the following was upregulated in the exosomes: protease, serine 1; glyceraldehyde-3-phosphate dehydrogenase-like isoform 1; glyceraldehyde-3-phosphate dehydrogenase; and pregnancy zone protein. In contrast, the expression of apolipoprotein B, complement component C3 prepropeptide, and immunoglobulin kappa light chain variable region was downregulated in NF-kappaB(-/-) mice. Bioinformatic annotation using the Protein Analysis Through Evolutionary Relationships (PANTHER) database revealed that the expression of the exosomal proteins that participate in metabolic processes and in biological regulation was lower in NF-kappaB(-/-) mice than in C57BL/6 mice, whereas the expression of proteins that participate in the response to stimuli, in cellular processes, and in the immune system was higher. CONCLUSIONS: The data presented in this study suggest that NF-kappaB might regulate exosomal protein expression at a remote site via circulation following I/R injury. PMID- 26059505 TI - A mathematical model of pH, based on the total stoichiometric concentration of acids, bases and ampholytes dissolved in water. AB - In chemistry and in acid-base physiology, the Henderson-Hasselbalch equation plays a pivotal role in studying the behaviour of the buffer solutions. However, it seems that the general function to calculate the valence of acids, bases and ampholytes, N = f(pH), at any pH, has only been provided by Kildeberg. This equation can be applied to strong acids and bases, pluriprotic weak acids, bases and ampholytes, with an arbitrary number of acid strength constants, pKA, including water. By differentiating this function with respect to pH, we obtain the general equation for the buffer value. In addition, by integrating the titration curve, TA, proposed by Kildeberg, and calculating its Legendre transform, we obtain the Gibbs free energy of pH (or pOH)-dependent titratable acid. Starting from the law of electroneutrality and applying suitable simplifications, it is possible to calculate the pH of the buffer solutions by numerical methods, available in software packages such as Excel. The concept of buffer capacity has also been clarified by Urbansky, but, at variance with our approach, not in an organic manner. In fact, for each set of monobasic, dibasic, tribasic acids, etc., various equations are presented which independently fit each individual acid-base category. Consequently, with the increase in acid groups (pKA), the equations become more and more difficult, both in practice and in theory. Some examples are proposed to highlight the boundary that exists between acid-base physiology and the thermodynamic concepts of energy, chemical potential, amount of substance and acid resistance. PMID- 26059506 TI - Impact of short-term exposure of antifungal agents on hemolysin activity of oral Candida dubliniensis isolates from Kuwait and Sri Lanka. AB - OBJECTIVE: Ability to produce hemolysin by Candida species is an important determinant of its pathogenicity. Candida dubliniensis is implicated in the causation of oral candidosis, which can be treated with polyene, echinocandin, and azole groups of antifungal agents as well as chlorhexidine. After oral application, however, the concentrations of these agents tend to decrease quickly to subtherapeutic levels due to the peculiarity of the oral environment. In this study, we have evaluated the effect of short-term exposure of sublethal concentrations of these drugs on hemolysin production by oral C. dubliniensis isolates obtained from two different geographical locale. MATERIALS AND METHODS: Twenty C. dubliniensis oral isolates obtained from Kuwait and Sri Lanka were exposed to sublethal concentrations of nystatin, amphotericin B, caspofungin, ketoconazole, fluconazole, and chlorhexidine for 1 h. Thereafter, the drugs were removed by dilution and the hemolysin production determined by a previously described plate assay. RESULTS: Hemolysin production of these isolates was significantly suppressed with a percentage reduction of 17.09, 16.45, 17.09, 11.39, 8.23 and 12.03 following exposure to nystatin, amphotericin B, caspofungin, ketoconazole, fluconazole, and chlorhexidine, respectively. CONCLUSION: Brief exposure to sublethal concentrations of drugs with antifungal properties appears to reduce the pathogenic potential of C. dubliniensis isolates by suppressing hemolysin production. PMID- 26059507 TI - Host demographic predicts ectoparasite dynamics for a colonial host during pre hibernation mating. AB - Parasite dynamics can be mediated by host behaviours such as sociality, and seasonal changes in aggregation may influence risk of parasite exposure. We used little brown bats (Myotis lucifugus) captured during the autumn mating/swarming period to test the hypothesis that seasonal and demographic-based variation in sociality affect ectoparasitism. We predicted that ectoparasitism would: (1) be higher for adult females and young of the year (YOY) than adult males because of female coloniality; (2) increase for adult males throughout swarming because of increasing contact with females; (3) decrease for adult females and YOY throughout swarming because of reduced coloniality and transmission of individual ectoparasites to males; (4) be similar for male and female YOY because vertical transmission from adult females should be similar. Ectoparasitism was lowest for adult males and increased for males during swarming, but some effects of demographic were unexpected. Contrary to our prediction, ectoparasitism increased for adult females throughout swarming and YOY males also hosted fewer ectoparasites compared with adult and YOY females. Interestingly, females in the best body condition had the highest parasite loads. Our results suggest that host energetic constraints associated with future reproduction affect pre-hibernation parasite dynamics in bats. PMID- 26059509 TI - High-dose-rate stereotactic body radiation therapy for postradiation therapy locally recurrent prostatic carcinoma: Preliminary prostate-specific antigen response, disease-free survival, and toxicity assessment. AB - PURPOSE: Patients with locally recurrent adenocarcinoma of the prostate following radiation therapy (RT) present a challenging problem. We prospectively evaluated the use of "high-dose-rate-like" prostate stereotactic body RT (SBRT) salvage for this circumstance, evaluating prostate-specific antigen response, disease-free survival, and toxicity. METHODS AND MATERIALS: Between February 2009 and March 2014, 29 patients with biopsy-proven recurrent locally prostate cancer >2 years post-RT were treated. Median prior RT dose was 73.8 Gy and median interval to SBRT salvage was 88 months. Median recurrence Gleason score was 7 (79% was >=7). Pre-existing RT toxicity >grade 1 was a reason for exclusion. Magnetic resonance imaging-defined prostate volume including any suspected extraprostatic extension, comprising the planning target volume. A total of 34 Gy/5 fractions was given, delivering a heterogeneous, high-dose-rate-like dose-escalation pattern. Toxicities were assessed using Common Terminology Criteria for Adverse Events, version 3.0, criteria. RESULTS: Twenty-nine treated patients had a median 24 month follow-up (range, 3-60 months). A median pre-SBRT salvage baseline prostate specific antigen level of 3.1 ng/mL decreased to 0.65 ng/mL and 0.16 ng/mL at 1 and 2 years, respectively. Actuarial 2-year biochemical disease-free survival measured 82%, with no local failures. Toxicity >grade 1 was limited to the genitourinary domain, with 18% grade 2 or higher and 7% grade 3 or higher. No gastrointestinal toxicity >grade 1 occurred. CONCLUSIONS: Two-year disease-free survival is encouraging, and the prostate-specific antigen response kinetic appears comparable with that seen in de novo patients treated with SBRT, albeit still a preliminary finding. Grade >=2 genitourinary toxicity was occasionally seen with no obvious predictive factor. Noting that our only brachytherapy case was 1 of the 2 cases with >=grade 3 genitourinary toxicity, caution is recommended treating these patients. SBRT salvage of post-RT local recurrence appears clinically feasible, with longer term evaluation required to assess ultimate efficacy and late toxicity rates. PMID- 26059508 TI - Core Pluripotency Factors Directly Regulate Metabolism in Embryonic Stem Cell to Maintain Pluripotency. AB - Pluripotent stem cells (PSCs) have distinct metabolic properties that support their metabolic and energetic needs and affect their stemness. In particular, high glycolysis is critical for the generation and maintenance of PSCs. However, it is unknown how PSCs maintain and acquire this metabolic signature. In this study, we found that core pluripotency factors regulate glycolysis directly by controlling the expression of glycolytic enzymes. Specifically, Oct4 directly governs Hk2 and Pkm2, which are important glycolytic enzymes that determine the rate of glycolytic flux. The overexpression of Hk2 and Pkm2 sustains high levels of glycolysis during embryonic stem cell (ESC) differentiation. Moreover, the maintenance of high glycolysis levels by Hk2 and Pkm2 overexpression hampers differentiation and preserves the pluripotency of ESCs in the absence of leukemia inhibitory factor. Overall, our study identifies a direct molecular connection between core pluripotency factors and ESC metabolic signatures and demonstrates the significance of metabolism in cell fate determination. PMID- 26059510 TI - Multiparametric magnetic resonance imaging for prostate cancer improves Gleason score assessment in favorable risk prostate cancer. AB - PURPOSE: Magnetic resonance imaging (MRI) guidance may improve the accuracy of Gleason score (GS) determination by directing the biopsy to regions of interest (ROI) that are likely to harbor high-grade prostate cancer (CaP). The aim of this study was to determine the frequency and predictors of GS upgrading when a subsequent MRI-guided biopsy is performed on patients with a diagnosis of GS 6 disease on the basis of conventional, transrectal ultrasound-guided biopsy. METHODS AND MATERIALS: A consecutive series of 245 men with a diagnosis of low risk CaP (ie, cT1c, GS 6, prostate-specific antigen <10) based on transrectal ultrasound-guided biopsy was enrolled in an active surveillance protocol that used subsequent MRI-guided biopsy for confirmation of GS. ROIs were categorized on a scale of 1 to 5. The Artemis ultrasound-MRI fusion device was used to perform targeted biopsies of ROIs as well as systematic biopsies from a software based 12-point map. Predictors of GS upgrading were analyzed using univariate and multivariate analyses. RESULTS: Fusion biopsy resulted in 26% of patients having GS upgrading (GS 3+4 in 18%, 4+3 in 5%, and 8-9 in 3%). Of the 72% of patients with ROIs appropriate for targeting, targeted cores upgraded the GS in 18%, whereas systematic cores upgraded the GS in 24%. In patients without targeted biopsy, GS upgrading was seen in 14%. On multivariate analysis, a category 5 ROI was the most significant predictor of GS upgrading with an odds ratio of 10.56 (P < .01). CONCLUSIONS: Nearly 25% of men with GS 6 CaP diagnosed by standard transrectal ultrasound biopsy may experience GS upgrading when a subsequent MRI ultrasound fusion biopsy is performed. The most important single predictor of upgrading is a category 5 ROI on multiparametric MRI. GS upgrading may influence treatment decisions. Therefore, MRI-guided biopsy should be considered prior to formulating a management strategy in patients whose conventional biopsy reveals low-risk CaP. PMID- 26059511 TI - Design and engineering of intracellular-metabolite-sensing/regulation gene circuits in Saccharomyces cerevisiae. AB - The development of high-throughput phenotyping tools is lagging far behind the rapid advances of genotype generation methods. To bridge this gap, we report a new strategy for design, construction, and fine-tuning of intracellular metabolite-sensing/regulation gene circuits by repurposing bacterial transcription factors and eukaryotic promoters. As proof of concept, we systematically investigated the design and engineering of bacterial repressor based xylose-sensing/regulation gene circuits in Saccharomyces cerevisiae. We demonstrated that numerous properties, such as induction ratio and dose-response curve, can be fine-tuned at three different nodes, including repressor expression level, operator position, and operator sequence. By applying these gene circuits, we developed a cell sorting based, rapid and robust high-throughput screening method for xylose transporter engineering and obtained a sugar transporter HXT14 mutant with 6.5-fold improvement in xylose transportation capacity. This strategy should be generally applicable and highly useful for evolutionary engineering of proteins, pathways, and genomes in S. cerevisiae. PMID- 26059512 TI - Diagnostic value of a plasma microRNA signature in gastric cancer: a microRNA expression analysis. AB - The differential expression of microRNAs (miRNAs) in plasma of gastric cancer (GC) patients may serve as a diagnostic biomarker. A total of 33 miRNAs were identified through the initial screening phase (3 GC pools vs. 1 normal control (NC) pool) using quantitative reverse transcription polymerase chain reaction (qRT-PCR) based Exiqon panel (miRCURY-Ready-to-Use-PCR-Human-panel-I + II-V1.M). By qRT-PCR, these miRNAs were further assessed in training (30 GC VS. 30 NCs) and testing stages (71 GC VS. 61 NCs). We discovered a plasma miRNA signature including five up-regulated miRNAs (miR-185, miR-20a, miR-210, miR-25 and miR 92b), and this signature was evaluated to be a potential diagnostic marker of GC. The areas under the receiver operating characteristic curve of the signature were 0.86, 0.74 and 0.87 for the training, testing and the external validation stages (32 GC VS. 18 NCs), respectively. The five miRNAs were consistently dysregulated in GC tissues (n = 30). Moreover, miR-185 was decreased while miR-20a, miR-210 and miR-92b were increased in arterial plasma (n = 38). However, none of the miRNAs in the exosomes showed different expression between 10 GC patients and 10 NCs. In conclusion, we identified a five-miRNA signature in the peripheral plasma which could serve as a non-invasive biomarker in detection of GC. PMID- 26059513 TI - Curing Both Virulent Mega-Plasmids from Bacillus anthracis Wild-Type Strain A16 Simultaneously Using Plasmid Incompatibility. AB - Plasmid-cured derivative strains of Bacillus anthracis are frequently used in laboratory studies. Plasmid incompatibility, which does not increase the risk of chromosomal mutation, is a useful method for plasmid curing. However, in bacteria containing multiple plasmids, it often requires the sequential introduction of multiple, specific incompatibility plasmids. This lengthy process renders the traditional plasmid incompatibility method inefficient and mutation-prone. In this study, we successfully cured plasmids pXO1 and pXO2 from B. anthracis A16 simultaneously using only one recombinant incompatible plasmid, pKORT, to obtain a plasmid-free strain, designated A16DD. This method may also be useful for the simultaneous, one-step curing of multiple plasmids from other bacteria, including Bacillus thuringiensis and Yersinia pestis. PMID- 26059514 TI - A New Multiplex-PCR for Urinary Tract Pathogen Detection Using Primer Design Based on an Evolutionary Computation Method. AB - This work describes a new strategy for optimal design of Multiplex-PCR primer sequences. The process is based on the Particle Swarm Optimization-Simplex algorithm (Mult-PSOS). Diverging from previous solutions centered on heuristic tools, the Mult-PSOS is selfconfigured because it does not require the definition of the algorithm's initial search parameters. The successful performance of this method was validated in vitro using Multiplex- PCR assays. For this validation, seven gene sequences of the most prevalent bacteria implicated in urinary tract infections were taken as DNA targets. The in vitro tests confirmed the good performance of the Mult-PSOS, with respect to infectious disease diagnosis, in the rapid and efficient selection of the optimal oligonucleotide sequences for Multiplex-PCRs. The predicted sequences allowed the adequate amplification of all amplicons in a single step (with the correct amount of DNA template and primers), reducing significantly the need for trial and error experiments. In addition, owing to its independence from the initial selection of the heuristic constants, the Mult-PSOS can be employed by non-expert users in computational techniques or in primer design problems. PMID- 26059515 TI - Expression and Characterization of a Novel Nitrilase from Hyperthermophilic Bacterium Thermotoga maritima MSB8. AB - The present study describes the gene cloning, overexpression and characterization of a novel nitrilase from hyperthermophilic bacterium Thermotoga maritima MSB8. The nitrilase gene consisted of 804 base pairs, encoding a protein of 268 amino acid residues with a molecular mass of 30.07 kDa after SDS-PAGE analysis. The optimal temperature and pH of the purified enzyme were 45 degrees C and 7.5, respectively. The enzyme demonstrated good temperature tolerance, with 40% residual activity after 60 min of heat treatment at 75 degrees C. The kinetic constants Vmax and Km of this nitrilase toward 3-cyanopyridine were 3.12 MUmol/min/mg and 7.63 mM, respectively. Furthermore, this novel nitrilase exhibited a broad spectrum toward the hydrolysis of the aliphatic nitriles among the tested substrates, and particularly was specific to aliphatic dinitriles like succinonitrile, which was distinguished from most nitrilases ever reported. The catalytic efficiency kcat/Km was 0.44 /mM/s toward succinonitrile. This distinct characteristic might enable this nitrilase to be a potential candidate for industrial applications for biosynthesis of carboxylic acid. PMID- 26059516 TI - Biosynthesis of Polymyxins B, E, and P Using Genetically Engineered Polymyxin Synthetases in the Surrogate Host Bacillus subtilis. AB - The development of diverse polymyxin derivatives is needed to solve the toxicity and resistance problems of polymyxins. However, no platform has generated polymyxin derivatives by genetically engineering a polymyxin synthetase, which is a nonribosomal peptide synthetase. In this study, we present a two-step approach for the construction of engineered polymyxin synthetases by substituting the adenylation (A) domains of polymyxin A synthetase, which is encoded by the pmxABCDE gene cluster of Paenibacillus polymyxa E681. First, the seventh L threonine-specific A-domain region in pmxA was substituted with the Lleucine- specific A-domain region obtained from P. polymyxa ATCC21830 to make polymyxin E synthetase, and then the sixth D-leucine-specific A-domain region (A6-D-Leu domain) was substituted with the D-phenylalanine-specific A-domain region (A6-D Phe-domain) obtained from P. polymyxa F4 to make polymyxin B synthetase. This step was performed in Escherichia coli on a pmxA-containing fosmid, using the lambda Red recombination system and the sacB gene as a counter-selectable marker. Next, the modified pmxA gene was fused to pmxBCDE on the chromosome of Bacillus subtilis BSK4dA, and the resulting recombinant strains BSK4-PB and BSK4-PE were confirmed to produce polymyxins B and E, respectively. We also succeeded in constructing the B. subtilis BSK4-PP strain, which produces polymyxin P, by singly substituting the A6-D-Leu-domain with the A6-D-Phe-domain. This is the first report in which polymyxin derivatives were generated by genetically engineering polymyxin synthetases. The two recombinant B. subtilis strains will be useful for improving the commercial production of polymyxins B and E, and they will facilitate the generation of novel polymyxin derivatives. PMID- 26059517 TI - Mucin2 is Required for Probiotic Agents-Mediated Blocking Effects on Meningitic E. coli-Induced Pathogenicities. AB - Mucin2 (MUC2), an important regulatory factor in the immune system, plays an important role in the host defense system against bacterial translocation. Probiotics known to regulate MUC2 gene expression have been widely studied, but the interactions among probiotic, pathogens, and mucin gene are still not fully understood. The aim of this study was to investigate the role of MUC2 in blocking effects of probiotics on meningitic E. coli-induced pathogenicities. In this study, live combined probiotic tablets containing living Bifidobacterium, Lactobacillus bulgaricus, and Streptococcus thermophilus were used. MUC2 expression was knocked down in Caco-2 cells by RNA interference. 5-Aza-2' deoxycytidine (5-Aza-CdR), which enhances mucin-promoted probiotic effects through inducing production of Sadenosyl- L-methionine (SAMe), was used to up regulate MUC2 expression in Caco-2 cells. The adhesion to and invasion of meningitic E. coli were detected by competition assays. Our studies showed that probiotic agents could block E. coli-caused intestinal colonization, bacteremia, and meningitis in a neonatal sepsis and meningitis rat model. MUC2 gene expression in the neonatal rats given probiotic agents was obviously higher than that of the infected and uninfected control groups without probiotic treatment. The prohibitive effects of probiotic agents on MUC2-knockdown Caco-2 cells infected with E44 were significantly reduced compared with nontransfected Caco-2 cells. Moreover, the results also showed that 5- Aza-CdR, a drug enhancing the production of SAMe that is a protective agent of probiotics, was able to significantly suppress adhesion and invasion of E44 to Caco-2 cells by upregulation of MUC2 expression. Taken together, our data suggest that probiotic agents can efficiently block meningitic E. coli-induced pathogenicities in a manner dependent on MUC2. PMID- 26059518 TI - In Vitro Inhibition of 4-Nitroquinoline-1-Oxide Genotoxicity by Probiotic Lactobacillus rhamnosus IMC501. AB - Inhibition of 4-nitroquinoline-1-oxide (4-NQO) genotoxicity by a probiotic strain of Lactobacillus rhamnosus (IMC501) was assessed by the prokaryotic short-term bioassay SOSChromotest, using Escherichia coli PQ37 as the target organism. Results showed the ability of strain IMC501 to rapidly and markedly counteract, in vitro, the DNA damage originated by the considered genotoxin. The inhibition was associated with a spectroscopic hypsochromic shift of the original 4-NQO profile and progressive absorbance increase of a new peak. IR-Raman and GC-MS analyses confirmed the disappearance of 4-NQO after contact with the microorganism, showing also the absence of any genotoxic molecule potentially available for metabolic activation (i.e., 4-hydroxyaminoquinoline-1-oxide and 4 nitrosoquinoline-1-oxide). Furthermore, we have shown the presence of the phenyl quinoline and its isomers as major non-genotoxic conversion products, which led to the hypothesis of a possible pattern of molecular transformation. These findings increase knowledge on lactobacilli physiology and contribute to the further consideration of antigenotoxicity as a nonconventional functional property of particular probiotic strains. PMID- 26059519 TI - Identification of Actinobacillus pleuropneumoniae Genes Preferentially Expressed During Infection Using In Vivo-Induced Antigen Technology (IVIAT). AB - Porcine pleuropneumonia is an infectious disease caused by Actinobacillus pleuropneumoniae. The identification of A. pleuropneumoniae genes, specially expressed in vivo, is a useful tool to reveal the mechanism of infection. IVIAT was used in this work to identify antigens expressed in vivo during A. pleuropneumoniae infection, using sera from individuals with chronic porcine pleuropneumonia. Sequencing of DNA inserts from positive clones showed 11 open reading frames with high homology to A. pleuropneumoniae genes. Based on sequence analysis, proteins encoded by these genes were involved in metabolism, replication, transcription regulation, and signal transduction. Moreover, three function-unknown proteins were also indentified in this work. Expression analysis using quantitative real-time PCR showed that most of the genes tested were up regulated in vivo relative to their expression levels in vitro. IVI (in vivoinduced) genes that were amplified by PCR in different A. pleuropneumoniae strains showed that these genes could be detected in almost all of the strains. It is demonstrated that the identified IVI antigen may have important roles in the infection of A. pleuropneumoniae. PMID- 26059520 TI - Identification of Plasmid-Free Chlamydia muridarum Organisms Using a Pgp3 Detection-Based Immunofluorescence Assay. AB - Chlamydia possesses a conserved 7.5 kb plasmid that is known to play an important role in chlamydial pathogenesis, since some chlamydial organisms lacking the plasmid are attenuated. The chlamydial transformation system developed recently required the use of plasmid-free organisms. Thus, the generation and identification of plasmid-free organisms represent a key step in understanding chlamydial pathogenic mechanisms. A tricolor immunofluorescence assay for simultaneously detecting the plasmid-encoded Pgp3 and whole organisms plus DNA staining was used to screen C. muridarum organisms selected with novobiocin. PCR was used to detect the plasmid genes. Next-generation sequencing was then used to sequence the genomes of plasmid-free C. muridarum candidates and the parental C. muridarum Nigg strain. We generated five independent clones of plasmid-free C. muridarum organisms by using a combination of novobiocin treatment and screening plaque-purified clones with anti-Pgp3 antibody. The clones were confirmed to lack plasmid genes by PCR analysis. No GlgA protein or glycogen accumulation was detected in cells infected with the plasmid-free clones. More importantly, whole genome sequencing characterization of the plasmid-free C. muridarum organism and the parental C. muridarum Nigg strain revealed no additional mutations other than loss of the plasmid in the plasmid-free C. muridarum organism. Thus, the Pgp3 based immunofluorescence assay has allowed us to identify authentic plasmid-free organisms that are useful for further investigating chlamydial pathogenic mechanisms. PMID- 26059521 TI - Modelling the cost-effectiveness of combination therapy for early, rapidly progressing rheumatoid arthritis by simulating the reversible and irreversible effects of the disease. AB - OBJECTIVE: To estimate the cost-effectiveness of adalimumab plus methotrexate (MTX) versus MTX monotherapy in early, aggressive rheumatoid arthritis (RA) when explicitly modelling short-term (reversible) and long-term (irreversible, ie, joint damage) disease activity and physical function. METHODS: A microsimulation model was developed to unify, in a single cost-effectiveness model, measures of reversible and irreversible disease activity and physical function based on data from the PREMIER trial. Short term, reversible disease activity was modelled using DAS28 variables, including swollen joint counts, tender joint counts, C reactive protein concentration and pain. The DAS28 variables were then used in a logistic regression to predict short-term American College of Rheumatology (ACR) responses, which informed treatment continuation and switches. Long term, irreversible, radiographically documented joint damage was modelled using modified Total Sharp Score (mTSS). The model then linked both short-term disease activity and mTSS to the Health Assessment Questionnaire score, which was used to calculate direct and indirect costs, and quality adjusted life-years (QALYs). RESULTS: When both reversible and irreversible effects of therapy were included, combination therapy was estimated to produce 6-month 50% ACR responses in 75% of patients versus 54% in MTX monotherapy. Compared to MTX monotherapy, combination therapy resulted in 2.68 and 3.04 discounted life years and QALYs gained, respectively. Combination therapy also resulted in a net increase in direct costs of L106,207 for a resulting incremental cost/QALY gain of L32,425. When indirect costs were included in the analysis, the ICER (incremental cost-effectiveness ratio) decreased to L27,238. Disregarding irreversible effects increased the incremental cost-effectiveness ratio to L78,809 (when only direct costs were included). CONCLUSIONS: Starting with adalimumab plus MTX combination therapy in early, aggressive RA is cost-effective when irreversible damage is adequately considered. PMID- 26059522 TI - Benzodiazepine prescribing in children under 15 years of age receiving free medical care on the General Medical Services scheme in Ireland. AB - OBJECTIVE: To examine the prevalence and secular trends in benzodiazepine (BZD) prescribing in the Irish paediatric population. In addition, we examine coprescribing of antiepileptic, antipsychotic, antidepressant and psychostimulants in children receiving BZD drugs and compare BZD prescribing in Ireland to that in other European countries. SETTING: Data were obtained from the Irish General Medical Services (GMS) scheme pharmacy claims database from the Health Service Executive (HSE)--Primary Care Reimbursement Services (PCRS). PARTICIPANTS: Children aged 0-15 years, on the HSE-PCRS database between January 2002 and December 2011, were included. PRIMARY AND SECONDARY OUTCOME MEASURES: Prescribing rates were reported over time (2002-2011) and duration (<= or >90 days). Age (0-4, 5-11, 12-15) and gender trends were established. Rates of concomitant prescriptions for antiepileptic, antipsychotics, antidepressants and psychostimulants were reported. European prescribing data were retrieved from the literature. RESULTS: Rates decreased from 2002 (8.56/1000 GMS population: 95% CI 8.20 to 8.92) to 2011 (5.33/1000 GMS population: 95% CI 5.10 to 5.55). Of those children currently receiving a BZD prescription, 6% were prescribed BZD for >90 days. Rates were higher for boys in the 0-4 and 5-11 age ranges, whereas for girls they were higher in the 12-15 age groups. A substantial proportion of children receiving BZD drugs are also prescribed antiepileptic (27%), antidepressant (11%), antipsychotic (5%) and psychostimulant (2%) medicines. Prescribing rates follow a similar pattern to that in other European countries. CONCLUSIONS: While BZD prescribing trends have decreased in recent years, this study shows that a significant proportion of the GMS children population are being prescribed BZD in the long term. This study highlights the need for guidelines for BZD prescribing in children in terms of clinical indication and responsibility, coprescribing, dosage and duration of treatment. PMID- 26059523 TI - Pain sensitisation and the risk of poor outcome following physiotherapy for patients with moderate to severe knee osteoarthritis: protocol for a prospective cohort study. AB - INTRODUCTION: Pain is the dominant symptom of knee osteoarthritis (OA), and recent evidence suggests factors outside of local joint pathology, such as pain sensitisation, can contribute significantly to the pain experience. It is unknown how pain sensitisation influences outcomes from commonly employed interventions such as physiotherapy. The aims of this study are, first, to provide a comprehensive description of the somatosensory characteristics of people with pain associated with knee OA. Second, we will investigate if indicators of pain sensitisation in patients with knee osteoarthritis are predictive of non-response to physiotherapy. METHODS AND ANALYSIS: This is a multicentre prospective cohort study with 140 participants. Eligible patients with moderate to severe symptomatic knee osteoarthritis will be identified at outpatient orthopaedic and rheumatology clinics. A baseline assessment will provide a comprehensive description of the somatosensory characteristics of each participant by means of clinical examination, quantitative sensory testing, and validated questionnaires measuring pain and functional capacity. Participants will then undergo physiotherapy treatment. The primary outcome will be non-response to physiotherapy on completion of the physiotherapy treatment programme as defined by the Osteoarthritis Research Society International treatment responder criteria. A principal component analysis will identify measures related to pain sensitisation to include in the predictive model. Regression analyses will explore the relationship between responder status and pain sensitisation while accounting for confounders. ETHICS AND DISSEMINATION: This study has been approved by St James' Hospital/AMNCH Research Ethics Committee and by the St Vincent's Healthcare Group Ethics and Medical Research Committee. The results will be presented at international conferences and published in a peer review journal. TRIAL REGISTRATION NUMBER: NCT02310945. PMID- 26059524 TI - Temporal trends in out-of-hospital cardiac arrest survival outcomes between two metropolitan communities: Seoul-Osaka resuscitation study. AB - OBJECTIVES: The objective of this study was to compare the temporal trends in survival after out-of-hospital cardiac arrest (OHCA) between two large metropolitan communities in Asia and evaluate the factors affecting survival after OHCA. DESIGN: A population-based prospective observational study. SETTING: The Cardiovascular Disease Surveillance (CAVAS) project in Seoul and the Utstein Osaka Project in Osaka. PARTICIPANTS: A total of 36,292 resuscitation-attempted OHCAs with cardiac aetiology from 2006 to 2011 in Seoul and Osaka (11,082 in Seoul and 25,210 in Osaka). PRIMARY OUTCOME MEASURES: The primary outcome was neurologically favourable survival. Trend analysis and multivariable Poisson regression models were conducted to evaluate the temporal trends in survival of two communities. RESULTS: During the study period, the overall neurologically favourable survival was 2.6% in Seoul and 4.6% in Osaka (p<0.01). In both communities, bystander cardiopulmonary resuscitation (CPR) rates increased significantly from 2006 to 2011 (from 0.1% to 13.1% in Seoul and from 33.3% to 41.7% in Osaka). OHCAs that occurred in public places increased in Seoul (12.5% to 20.1%, p for trend <0.01) and decreased in Osaka (13.5% to 10.5%, p for trend <0.01). The proportion of OHCAs defibrillated by emergency medical service (EMS) providers was only 0.4% in 2006 but increased to 17.5% in 2011 in Seoul, whereas the proportion in Osaka decreased from 17.7% to 13.7% (both p for trend <0.01). Age-adjusted and gender-adjusted rates of neurologically favourable survival increased significantly in Seoul from 1.4% in 2006 to 4.3% in 2011 (adjusted rate ratio per year, 1.17; p for trend <0.01), whereas no significant improvement was observed in Osaka (3.6% in 2006 and 5.1% in 2011; adjusted rate ratio per year, 1.03; p for trend=0.08). CONCLUSIONS: Survivals after OHCA were increased in Seoul while remained constant in Osaka, which may have been affected by the differences and improvements of patient, community, and EMS system factors. PMID- 26059525 TI - Diverging prevalences and different risk factors for childhood asthma and eczema: a cross-sectional study. AB - OBJECTIVE: To compare the prevalences of and risk factors for asthma, wheeze, hay fever and eczema in primary schoolchildren in Aberdeen in 2014. DESIGN: Cross sectional survey. SETTING: Primary schools in Aberdeen, North-East Scotland. PARTICIPANTS: Children in Scottish school years primary 1-7 were handed a questionnaire by their class teacher to be completed by their parents and returned to the researchers by post or online. MAIN OUTCOME MEASURES: Lifetime history of asthma, eczema and hay fever, and recent history of wheeze. RESULTS: 41 schools agreed to participate (87%). 11,249 questionnaires were distributed and 3935 returned (35%). A parent-reported lifetime history of asthma, eczema and hay fever was present in 14%, 30% and 24% of children, respectively. The odds of lifetime asthma increased with age (OR 1.1 per year, 95% CI 1.1 to 1.2), male sex (OR 1.89, 95% CI 1.4 to 2.3), parental smoking (OR 1.7, 95% CI 1.2 to 2.3) and eczema (OR 6.6, 95% CI 5.2 to 8.4). Prevalence of recent wheeze was also reported to be 14% and was positively associated with male sex, parental smoking and eczema. In contrast, parental eczema was the only identified predictor of childhood eczema risk. CONCLUSIONS: The lifetime prevalence of asthma in primary schoolchildren was 14% in this survey, approximately half the prevalence of eczema. We report diverging prevalences in relation to previous studies in our locality, and different risk factors for asthma and eczema. These findings suggest that asthma and eczema are unlikely to have a common origin. PMID- 26059526 TI - Predictive parameters of response to desmopressin in primary nocturnal enuresis. AB - INTRODUCTION/BACKGROUND: Many recent treatment guidelines have advocated the importance of a full noninvasive medical evaluation. To individualize treatment, special emphasis must be put on recording of the maximum voided volume (MVV) and nocturnal diuresis in a diary or frequency/volume chart. OBJECTIVE: The aim of this study was to identify any possible predictive factors to desmopressin response. STUDY DESIGN: This study is a re-analysis of a prospective, open-label, multinational, phase-IV study evaluating <=6 months of treatment with desmopressin tablets for children with primary nocturnal enuresis. The children were enrolled between April 2002 and December 2004 from 86 centers in four countries: UK, Canada, Germany and France. A total of 936 children were screened; 744 children aged 5-15 years participated in the study. Of these, 471 children completed the study with 6 months follow-up and recording in a frequency/volume chart. All children experienced six or more wet nights during the 14-day screening period. Exclusion criteria were: organic pathology, treatment for enuresis within the past year, previous treatment for enuresis for >4 weeks, diurnal symptoms, renal or central diabetes insipidus and the use of systemic antibiotics or other drugs known to affect desmopressin activity. The predictive value of number of wet nights a week, fluid intake, daytime voiding frequency and diuresis was investigated by performing a multinomial logistic regression. RESULTS: Of the demographic variables, age was the only significant predictor for response to desmopressin. Controlling for age, the significant predictive variables were: number of wet nights a week, average voided volume daytime, maximum voided volume daytime, total daytime diuresis, nocturnal diuresis (see Figure), maximum voided volume 24 h and total 24 h diuresis. More than 80% of the children had no nocturnal polyuria and a low maximum voided volume. DISCUSSION: Performing a secondary analysis is a limitation because the original study was not designed for that. A new prospective study is ethically hardly defendable for children if data are available from previous literature [1]; therefore, a re analysis was the appropriate choice. The study confirms the predictive value of age, number of wet nights a week and nocturnal diuresis [1,2]. CONCLUSIONS: The study demonstrates that desmopressin response rates are higher in children with greater age, limited number of wet nights a week and nocturnal polyuria. Only a minority of a primary nocturnal enuresis population, based on history alone, had nocturnal polyuria. The majority had a low maximum voided volume. The results clearly stress the importance of a frequency/volume chart for individualizing therapy to the characteristics, thereby resulting in elevated success rates. Registration number of clinical trial: Clinical Trials.gov NCT00245479. PMID- 26059528 TI - Clinical investigation of TROP-2 as an independent biomarker and potential therapeutic target in colon cancer. AB - Colon cancer is associated with a severe demographic and economic burden worldwide. The pathogenesis of colon cancer is highly complex and involves sequential genetic and epigenetic mechanisms. Despite extensive investigation, the pathogenesis of colon cancer remains to be elucidated. As the third most common type of cancer worldwide, the treatment options for colon cancer are currently limited. Human trophoblast cell-surface marker (TROP-2), is a cell surface transmembrane glycoprotein overexpressed by several types of epithelial carcinoma. In addition, TROP-2 has been demonstrated to be associated with tumorigenesis and invasiveness in solid types of tumor. The aim of the present study was to investigate the protein expression of TROP-2 in colon cancer tissues, and further explore the association between the expression of TROP-2 and clinicopathological features of patients with colon cancer. The expression and localization of the TROP-2 protein was examined using western blot analysis and immunofluorescence staining. Finally, the expression of TROP-2 expression was correlated to conventional clinicopathological features of colon cancer using a chi2 test. The results revealed that TROP-2 protein was expressed at high levels in the colon cancer tissues, which was associated with the development and pathological process of colon cancer. Therefore, TROP-2 may be used as a biomarker to determine the clinical prognosis, and as a potential therapeutic target in colon cancer. PMID- 26059527 TI - Interdisciplinary pain management is beneficial for refractory orchialgia in children. AB - INTRODUCTION: Idiopathic testicular/groin pain can be a difficult entity for children, their families, and caregivers. The role of interdisciplinary pain management has previously been demonstrated in treating chronic orchialgia at the present pediatric pain clinic. OBJECTIVE: To evaluate the role of interdisciplinary pain management in managing refractory orchialgia. It was hypothesized that children with refractory orchialgia might respond well. Interdisciplinary care was defined as that which crosses two medical disciplines such as a surgical specialty and specialist in analgesia. SUBJECTS AND METHODS: Pediatric patients were identified who were: >= 10 years old; evaluated in the pediatric urology clinic between 2002 and 2012; were diagnosed wtih ICD code 608.9 or had the diagnosis of male genital disorder NOS. Children were included if they presented with orchialgia without an identifiable cause and failed conservative management (rest, scrotal support, Sitz bath, timed voiding, constipation avoidance) including conventional anti-nociceptive analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids). Patient electronic medical records were reviewed retrospectively. RESULTS: Twenty-two children met inclusion criteria. Mean age was 13.7 years (range 10-17). Nearly half (45%) of the children had chronic medical conditions such as asthma, allergies, and obesity. Twenty-one of the 22 children were referred to the pediatric pain clinic; 15 were evaluated, and one refused treatment. All children evaluated in the pediatric pain clinic were initially offered an empiric anti neuropathic anti-convulsant (i.e. gabapentin) and/or an anti-depressant (i.e. amitriptyline) before being offered a nerve block. Of the 14 children accepting treatment in the pediatric pain clinic, six were treated solely with an empiric anti-neuropathic anti-convulsant and/or anti-depressant; eight received medications followed by nerve block (seven ilioinguinal-iliohypogastric blocks, one spinal and ilioinguinal-iliohypogastric block) (see Fig. 1). A total of eight of the 14 children (57%) treated by the pain clinic had resolution of pain, with 50% of those treated with medications alone (three out of six children) responding (two responding to gabapentin and a tricyclic antidepressant, one to gabapentin alone); and five out of eight (63%) treated with medications and then nerve block (ilioinguinal-iliohypogastric block) responding. Of the eight children undergoing nerve block, five required more than one block. The time between each block ranged from 4 to 22.6 weeks. Response to nerve block required an average of 1.4 procedures (range 1-2); mean follow-up after nerve block was 2.4 months (range 0.1-4.8). DISCUSSION: Children with refractory orchialgia often have comorbidities that suggest a multidisciplinary approach would be useful for treating them. The present study found that the majority of children with refractory orchialgia treated in the pediatric pain clinic responded to management. Major limitations, however, included small cohort size and short follow-up, particularly in those children undergoing nerve block. There was also no objective assessment of pain improvement or improvement in quality of life, which could be rectified with a prospective study. CONCLUSION: Collaboration and early referral for interdisciplinary pain management as one of these multidisciplinary approaches may help to coordinate care and ease patient suffering. PMID- 26059529 TI - Determination of the in vivo NAD:NADH ratio in Saccharomyces cerevisiae under anaerobic conditions, using alcohol dehydrogenase as sensor reaction. AB - With the current quantitative metabolomics techniques, only whole-cell concentrations of NAD and NADH can be quantified. These measurements cannot provide information on the in vivo redox state of the cells, which is determined by the ratio of the free forms only. In this work we quantified free NAD:NADH ratios in yeast under anaerobic conditions, using alcohol dehydrogenase (ADH) and the lumped reaction of glyceraldehyde-3-phosphate dehydrogenase and 3 phosphoglycerate kinase as sensor reactions. We showed that, with an alternative accurate acetaldehyde determination method, based on rapid sampling, instantaneous derivatization with 2,4 diaminophenol hydrazine (DNPH) and quantification with HPLC, the ADH-catalysed oxidation of ethanol to acetaldehyde can be applied as a relatively fast and simple sensor reaction to quantify the free NAD:NADH ratio under anaerobic conditions. We evaluated the applicability of ADH as a sensor reaction in the yeast Saccharomyces cerevisiae, grown in anaerobic glucose-limited chemostats under steady-state and dynamic conditions. The results found in this study showed that the cytosolic redox status (NAD:NADH ratio) of yeast is at least one order of magnitude lower, and is thus much more reduced, under anaerobic conditions compared to aerobic glucose-limited steady state conditions. The more reduced state of the cytosol under anaerobic conditions has major implications for (central) metabolism. Accurate determination of the free NAD:NADH ratio is therefore of importance for the unravelling of in vivo enzyme kinetics and to judge accurately the thermodynamic reversibility of each redox reaction. PMID- 26059531 TI - A Highly Efficient Chirality Switchable Synthesis of Dihydropyran-Fused Benzofurans by Fine-Tuning the Phenolic Proton of beta-Isocupreidine (beta-ICD) Catalyst with Methyl. AB - A highly enantioselective beta-isocupreidine (beta-ICD) catalyzed synthesis of dihydropyran-fused benzofurans through [4+2] cycloaddition of allenoates and benzofuranone alkenes was developed. Switchable chirality inversion of cycloaddition products was achieved by replacing the phenolic proton of the catalyst with a methyl, demonstrating an amazing effect of minimal structural variation on inverting enantioselectivity. DFT calculations were utilized to elucidate the origin of the observed phenomena. Computation also provided a clue for a rational design in which the multi-hydrogen bond with the alcohol additive was found to improve the enantioselectivity of the cycloaddition. Finally, the substrate scope was examined, in which a number of functionalized dihydropyran fused benzofurans could be obtained in high yields (up to 97 %) with very good regio- (>20:1) and enantioselectivities (up to 98:2 e.r.). PMID- 26059530 TI - Dual modes of membrane binding direct pore formation by Streptolysin O. AB - Effector translocation is central to the virulence of many bacterial pathogens, including Streptococcus pyogenes, which utilizes the cholesterol-dependent cytolysin Streptolysin O (SLO) to translocate the NAD(+) glycohydrolase SPN into host cells during infection. SLO's translocation activity does not require host cell membrane cholesterol or pore formation by SLO, yet SLO does form pores during infection via a cholesterol-dependent mechanism. Although cholesterol was considered the primary receptor for SLO, SLO's membrane-binding domain also encodes a putative carbohydrate-binding site, implicating a potential glycan receptor in binding and pore formation. Analysis of carbohydrate-binding site SLO mutants and carbohydrate-defective cell lines revealed that glycan recognition is involved in SLO's pore formation pathway and is an essential step when SLO is secreted by non-adherent bacteria, as occurs during lysis of erythrocytes. However, SLO also recognizes host cell membranes via a second mechanism when secreted from adherent bacteria, which requires co-secretion of SPN but not glycan binding by SLO. This SPN-mediated membrane binding of SLO correlates with SPN translocation, and requires SPN's non-enzymatic domain, which is predicted to adopt the structure of a carbohydrate-binding module. SPN-dependent membrane binding also promotes pore formation by SLO, demonstrating that pore formation can occur by distinct pathways during infection. PMID- 26059532 TI - Pathological tendons maintain sufficient aligned fibrillar structure on ultrasound tissue characterization (UTC). AB - Structural disorganization in the tendon is associated with tendinopathy, with little research investigating whether disorganization overwhelms the overall structural integrity of the tendon. This study investigated the mean cross sectional area (CSA) of aligned fibrillar structure as detected by ultrasound tissue characterization (UTC) in the pathological and normal Achilles and patellar tendons. Ninety-one participants had their Achilles and/or patellar tendons scanned using UTC to capture a three-dimensional image of the tendon and allow a semi-quantification of the echopattern. The mean CSA of aligned fibrillar structure (echo type I + II) and disorganized structure (echo type III + IV) was calculated based on UTC algorithms. Each tendon was classified as either pathological or normal based solely on gray-scale ultrasound. The mean CSA of aligned fibrillar structure was significantly greater (P <= 0.001) in the pathological tendon compared with the normal tendon, despite the pathological tendon containing greater amounts of disorganized structure (P <= 0.001). A significant relationship was observed between the mean CSA of disorganized structure and anteroposterior diameter of the Achilles (R(2) = 0.587) and patellar (R(2) = 0.559) tendons. This study is the first to show that pathological tendons have sufficient levels of aligned fibrillar structure. Pathological tendons may compensate for areas of disorganization by increasing in tendon thickness. PMID- 26059533 TI - Humanitarian Surgical Missions: Planning for Success. AB - Humanitarian surgical missions can provide much needed care for those who are otherwise unable to receive such care because of limited local health care resources and cost. These missions also offer excellent training opportunities and can be life-changing experiences for those who participate in them. A successful humanitarian surgical mission requires careful planning and coordination and can be challenging for those tasked with the responsibilities to organize and lead these missions. This article addresses many of the issues and challenges encountered when planning and leading humanitarian surgical missions and offers a template to be used by those who take on these challenges. PMID- 26059534 TI - A Novel Endoscopic Technique for Failed Nasogastric Tube Placement. AB - Direct visualization of the nasopharynx gives the otolaryngologist a unique advantage for addressing difficult nasopharyngeal anatomy. One common situation is being consulted to assist when the blind placement of a nasogastric tube has failed. A novel technique for managing a patient with a nasogastric tube embedded in the adenoid remnant is described with illustrations. The atraumatic method is easily employed by a resident armed with a portable nasolaryngoscope and plain suture. By using a repeated pull-through technique, the nasogastric tube can be guided past difficult nasopharyngeal anatomy and into a position from where it can be advanced into the patient's esophagus. PMID- 26059535 TI - Neuromyelitis optica with linear enhancement of corpus callosum in brain magnetic resonance imaging with contrast: a case report. AB - INTRODUCTION: Neuromyelitis optica is a demyelinating disease of the central nervous system with various patterns of brain lesions. Corpus callosum may be involved in both multiple sclerosis and neuromyelitis optica. Previous case reports have demonstrated that callosal lesions in neuromyelitis optica are usually large and edematous and have a heterogeneous intensity showing a "marbled pattern" in the acute phase. Their size and intensity may reduce with time or disappear in the chronic stages. CASE PRESENTATION: In this report, we describe a case of a 25-year-old Caucasian man with neuromyelitis optica who presented clinically with optic neuritis and myelitis. His brain magnetic resonance imaging demonstrated linear enhancement of the corpus callosum. Brain images with contrast agent added also showed linear ependymal layer enhancement of the lateral ventricles, which has been reported in this disease previously. CONCLUSIONS: Linear enhancement of corpus callosum in magnetic resonance imaging with contrast agent could help in diagnosing neuromyelitis optica and differentiating it from other demyelinating disease, especially multiple sclerosis. PMID- 26059536 TI - The patient's journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life. AB - BACKGROUND: Interferon and ribavirin negatively impact health-related quality of life (HRQL) during treatment. AIM: To compare the impact of interferon and/or ribavirin-containing regimens on HRQL to interferon- and ribavirin-free regimens. METHODS: HRQL data from nine multinational phase 3 clinical trials of sofosbuvir (SOF)-based regimens with and without ledipasvir (LDV), pegylated interferon (IFN) or ribavirin (RBV) were used. The Short Form-36 (SF-36) HRQL questionnaire was administered to subjects prospectively at baseline, during treatment, and 12 and 24 weeks after treatment cessation. RESULTS: A total of 3460 CH-C with SF-36 data were included (52.2 +/- 10.3 years, 62.6% male, 73.6% treatment-naive, 15.0% cirrhotic, 68.2% HCV genotype 1 and 20.1% genotype 3). Compared to baseline HRQL, at the end of treatment, severe HRQL decrements were noted in IFN + RBV +/- SOF regimens (on average, -3.8 to -24.3 on a 0-100 scale for different HRQL domains), while moderate decrements were noted in SOF + RBV +/- LDV (-2.8 to -8.6). In contrast, in SOF/LDV without RBV, HRQL improvements were noted during treatment (+2.3 to +5.2). By 12 weeks post-treatment, HRQL returned to baseline in IFN + RBV +/- SOF (P > 0.05) and improved in all IFN-free arms (+2.6 to +7.8). In multivariate analysis, a lower end of treatment HRQL was associated with IFN + RBV + SOF and a higher end of treatment HRQL was associated with SOF/LDV. By post treatment-12, SOF/LDV was additionally associated with higher mental health scores. These improvements in HRQL scores were maintained 24 weeks post treatment. CONCLUSIONS: Removing interferon and ribavirin has led to substantial improvement of health-related quality of life during treatment. This may result in better patient experience and higher adherence to treatment regimen. PMID- 26059537 TI - Pathways from childhood abuse and other adversities to adult health risks: The role of adult socioeconomic conditions. AB - Adverse childhood experiences (ACEs), including child abuse, have been linked with poor health outcomes in adulthood. The mechanisms that explain these relations are less understood. This study assesses whether associations of ACEs and health risks are mediated by adult socioeconomic conditions, and whether these pathways are different for maltreatment than for other types of adversities. Using the Behavioral Risk Factor Surveillance System 2012 survey (N=29,229), we employ structural equation modeling to (1) estimate associations of the number and type of ACEs with five health risks-depression, obesity, tobacco use, binge drinking, and self-reported sub-optimal health; and (2) assess whether adult socioeconomic conditions-marriage, divorce and separation, educational attainment, income and insurance status-mediate those associations. Findings suggest both direct and indirect associations between ACEs and health risks. At high numbers of ACEs, 15-20% of the association between number of ACEs and adult health risks was attributable to socioeconomic conditions. Associations of three ACEs (exposure to domestic violence, parental divorce, and residing with a person who was incarcerated) with health risks were nearly entirely explained by socioeconomic conditions in adulthood. However, child physical, emotional, and sexual abuse were significantly associated with several adult health risks, beyond the effects of other adversities, and socioeconomic conditions explained only a small portion of these associations. These findings suggest that the pathways to poor adult health differ by types of ACEs, and that childhood abuse is more likely than other adversities to have a direct impact. PMID- 26059538 TI - Effect of hypnosis on masseter EMG recorded during the 'resting' and a slightly open jaw posture. AB - The aim of this experimental study was to determine whether minimal levels of electromyographic activity in the masseter muscle are altered when individuals are in a verified hypnotic state. Experiments were performed on 17 volunteer subjects (8 male, 9 female) all of whom gave informed consent. The subjects were dentate and had no symptoms of pain or masticatory dysfunction. Surface electromyograms (EMGs) were made from the masseter muscles and quantified by integration following full-wave rectification and averaging. The EMGs were obtained (i) with the mandible in 'resting' posture; (ii) with the mandible voluntarily lowered (but with the lips closed); (iii) during maximum voluntary clenching (MVC). The first two recordings were made before, during and after the subjects were in a hypnotic state. Susceptibility to hypnosis was assessed with Spiegel's eye-roll test, and the existence of the hypnotic state was verified by changes in ventilatory pattern. On average, EMG levels expressed as percentages of MVC were less: (i) when the jaw was deliberately lowered as opposed to being in the postural position: (ii) during hypnosis compared with during the pre- and post-hypnotic periods. However, analysis of variance followed by post hoc tests with multiple comparison corrections (Bonferroni) revealed that only the differences between the level during hypnosis and those before and after hypnosis were statistically significant (P < 0.05). As the level of masseter EMG when the mandible was in 'resting' posture was reduced by hypnosis, it appears that part of that EMG is of biological origin. PMID- 26059539 TI - Histopathology of idiopathic lateral skull base defects. AB - OBJECTIVES/HYPOTHESIS: The objective of this study was to utilize techniques of otopathology to gain insight into the pathogenesis, sites of origin, and associated findings in idiopathic lateral skull base defects. STUDY DESIGN: Histopathologic analysis of temporal bones from an otopathology repository. METHODS: Specimens from a human temporal bone repository were investigated for clinical or otopathologic evidence of occult bony dehiscence indicating communication between the subarachnoid space and air cells of the temporal bone. Specimens were examined by light microscopy, organized by fistula site, and histopathologically described. Premortem patient demographics and clinical history was reviewed. RESULTS: Specimens from 52 individuals met inclusion criteria. Three distinct fistula pathways were determined: transdural, labyrinthine, and perilabyrinthine. Transdural fistulae occur most commonly as the result of arachnoid granulations along the middle or posterior fossa dura (n = 30) and are frequently incidental findings in specimens of older individuals (median age at death: 81 years). Labyrinthine fistulae (n = 10) were noted with cochlear malformations when modiolar atresia permits cerebrospinal fluid (CSF) flow into a common intracochlear scala and oval window perilymphatic fistula results. Perilabyrinthine fistulae (n = 7) were observed through three congenitally unfused tracts: the tympanomeningeal fissure, the petromastoid canal, or an extension of the subarachnoid space into the fallopian canal. CONCLUSIONS: Idiopathic lateral skull base defects occur in three distinct anatomic locations with consistent histopathologic findings. In the absence of clear radiographic localization, patient age and associated cochlear defects may assist in the determination of the site of CSF leak. These data have implications for surgical approaches of CSF fistula repair. LEVEL OF EVIDENCE: NA PMID- 26059541 TI - Formalizing the definition of meta-analysis in Molecular Ecology. AB - Meta-analysis, the statistical synthesis of pertinent literature to develop evidence-based conclusions, is relatively new to the field of molecular ecology, with the first meta-analysis published in the journal Molecular Ecology in 2003 (Slate & Phua 2003). The goal of this article is to formalize the definition of meta-analysis for the authors, editors, reviewers and readers of Molecular Ecology by completing a review of the meta-analyses previously published in this journal. We also provide a brief overview of the many components required for meta-analysis with a more specific discussion of the issues related to the field of molecular ecology, including the use and statistical considerations of Wright's FST and its related analogues as effect sizes in meta-analysis. We performed a literature review to identify articles published as 'meta-analyses' in Molecular Ecology, which were then evaluated by at least two reviewers. We specifically targeted Molecular Ecology publications because as a flagship journal in this field, meta-analyses published in Molecular Ecology have the potential to set the standard for meta-analyses in other journals. We found that while many of these reviewed articles were strong meta-analyses, others failed to follow standard meta-analytical techniques. One of these unsatisfactory meta analyses was in fact a secondary analysis. Other studies attempted meta-analyses but lacked the fundamental statistics that are considered necessary for an effective and powerful meta-analysis. By drawing attention to the inconsistency of studies labelled as meta-analyses, we emphasize the importance of understanding the components of traditional meta-analyses to fully embrace the strengths of quantitative data synthesis in the field of molecular ecology. PMID- 26059540 TI - Cripto-1 as a novel therapeutic target for triple negative breast cancer. AB - Triple-negative breast cancer (TNBC) presents the poorest prognosis among the breast cancer subtypes and no current standard therapy. Here, we performed an in depth molecular analysis of a mouse model that establishes spontaneous lung metastasis from JygMC(A) cells. These primary tumors resembled the triple negative breast cancer (TNBC) both phenotypically and molecularly. Morphologically, primary tumors presented both epithelial and spindle-like cells but displayed only adenocarcinoma-like features in lung parenchyma. The use of laser-capture microdissection combined with Nanostring mRNA and microRNA analysis revealed overexpression of either epithelial and miRNA-200 family or mesenchymal markers in adenocarcinoma and mesenchymal regions, respectively. Cripto-1, an embryonic stem cell marker, was present in spindle-like areas and its promoter showed activity in primary tumors. Cripto-1 knockout by the CRISPR-Cas9 system inhibited tumor growth and pulmonary metastasis. Our findings show characterization of a novel mouse model that mimics the TNBC and reveal Cripto-1 as a TNBC target hence may offer alternative treatment strategies for TNBC. PMID- 26059542 TI - Effects of Communication Partner Instruction on the Communication of Individuals using AAC: A Meta-Analysis. AB - The purpose of this study was to conduct a systematic review and meta-analysis of the augmentative and alternative communication (AAC) partner instruction intervention literature to determine (a) the overall effects of partner interventions on the communication of individuals using AAC, and (b) any possible moderating variables relating to participant, intervention, or outcome characteristics. Seventeen single-case experimental design studies (53 participants) met the inclusion criteria and were advanced to the full coding and analysis phase of the investigation. Descriptive analyses and effect size estimations using the Improvement Rate Difference (IRD) metric were conducted. Overall, communication partner interventions were found to be highly effective across a range of participants using AAC, intervention approaches, and outcome measure characteristics, with more evidence available for participants less than 12 years of age, most of whom had a diagnosis of autism spectrum disorder or intellectual/developmental disability. Aided AAC modeling, expectant delay, and open-ended question asking were the most frequently targeted communication partner interaction skills. Providing a descriptive overview, instructor modeling, guided practice, and role plays were the most frequently incorporated communication partner intervention activities within the included studies. PMID- 26059543 TI - Delayed neutrophil apoptosis mediates intermittent hypoxia-induced progressive heart failure in pressure-overloaded rats. AB - BACKGROUND AND OBJECTIVE: Obstructive sleep apnea (OSA) and heart failure (HF) are common coexisting diseases. Intermittent hypoxia (IH), caused by repeated apnea/hypopnea events, accompanied by increased systemic inflammation, might contribute to the promotion of HF. METHODS: To assess the hypothesis, rats were exposed to IH or normal air condition 4 weeks on the basis of normal heart function or pre-existing HF, which was induced by pressure overload caused by abdominal aortic constriction surgery performed 12 weeks earlier. Echocardiography was performed before and after IH exposure to evaluate left ventricular (LV) function. Serum concentrations of pro-inflammatory cytokines TNF alpha and IL-6 were detected by enzyme-linked immunosorbent assay. Flow cytometric analysis was used to determine the apoptotic rate of polymorphonuclear neutrophils (PMNs). RESULTS: The echocardiographic study showed a significant decrease in LV fractional shortening (FS) and ejection fraction (EF) as well as an increase in the LV relative wall thickness (RWT) index in HF rats, which was aggravated by further exposure to IH compared with single-handed HF-only and sham IH and sham-control groups. A reduced PMN apoptotic rate was observed in HF-IH rats compared with HF-only, sham-IH, and sham-control rats. Serum concentrations of TNF-alpha and IL-6 were also increased in HF-IH rats, accompanied by delayed PMN apoptosis, indicating significant systemic inflammation induced by IH. CONCLUSION: The results of this study demonstrated that IH aggravates LV remodeling and heart dysfunction in rats with pre-existing HF. Delayed neutrophil apoptosis, which was revealed in HF rats following exposure to IH, contributed to the exacerbation of myocardial damage and progression of heart dysfunction. PMID- 26059544 TI - Congenital CLN disease in two siblings. AB - BACKGROUND: Neuronal ceroid lipofuscinoses (NCL) is characterized by a combination of retinopathy, dementia, and epilepsy. As a group, they encompass ten distinct biological and clinical entities and are the most common type of childhood neurodegenerative disease. PATIENTS AND METHODS: Case reports. RESULTS: We demonstrate the clinical course of two neonates (brother and sister) with infantile neuronal ceroid lipofuscinoses (NCL) (CLN 10 disease) presenting with intractable seizures and respiratory insufficiency immediately after birth. Characteristic clinical, radiological and pathological findings of this form of NCL are presented. CONCLUSIONS: We conclude that the diagnosis of CLN10 should be kept in mind as a differential diagnosis in newborns presenting with respiratory insufficiency and severe epilepsy that is largely refractory to anti-epileptic drugs (AED) treatment. Because of the severity of CLN10 disease and futility of treatment, important ethical issues arise when caring for children with this clinical entity. PMID- 26059546 TI - Asia Oceania Algae Innovation Summit, AOAIS-2014. PMID- 26059545 TI - A 3D-microtissue-based phenotypic screening of radiation resistant tumor cells with synchronized chemotherapeutic treatment. AB - BACKGROUND: Radiation resistance presents a challenge to the effective treatment of cancer. If therapeutic compounds were capable of resensitizing resistant tumours then a concurrent chemo-radiation treatment could be used to overcome radiation resistance. METHODS: We have developed a phenotypic assay to investigate the response of radiation resistant breast cancer cells grown in 3D microtissue spheroids to combinations of radiation and established chemotherapeutic drugs. The effects were quantified by real time high content imaging of GFP detection area over 14 days. Ten established chemotherapeutic drugs were tested for their ability to enhance the effects of radiation. RESULTS: Of ten analysed chemotherapeutics, vinblastine was the most effective compound, with docetaxel and doxorubicine being less effective in combination with radiation. To investigate the response in a model closer to the in vivo situation we investigated the response of heterotypic 3D microtissues containing both fibroblasts and breast cancer cells. Drug treatment of these heterotypic 3D cultures confirmed treatment with radiation plus vinblastine to be additive in causing breast cancer growth inhibition. We have validated the screen by comparing radiation sensitizing effects of known chemotherapeutic agents. In both monotypic and heterotypic models the concurrent treatment of vinblastine and radiation proved more effective inhibitors of mammary cancer cell growth. The effective concentration range of both vinblastine and radiation are within the range used in treatment, suggesting the 3D model will offer a highly relevant screen for novel compounds. CONCLUSIONS: For the first time comfortable 3D cell based phenotypic assay is available, that allows high throughput screening of compounds with radiation therapy modulating capacity, opening the field to drug discovery. PMID- 26059547 TI - Image-guided percutaneous renal cryoablation for stage 1 renal cell carcinoma with high surgical risk. AB - BACKGROUND: This study was undertaken to evaluate the feasibility, safety, and therapeutic effects of percutaneous renal cryoablation under local anesthesia with conscious sedation for patients who have unresectable stage 1 (T1NoMo) renal cell carcinoma (RCC) in high surgical risk. METHODS: Eighteen patients who were not candidates for surgery underwent primary cryosurgery guided by gray-scale ultrasound. Contrast-enhanced ultrasonography (CEUS) and contrast-enhanced computed tomography (CT) were performed to evaluate treatment at completion. RESULTS: The mean follow-up period was 26.8 months (range, 12-56 months). All tumors were biopsied before cryosurgery. Seventeen tumors remained free of enhancement during follow-up period. No major complications associated with cryoablation procedures were found though two instances of subcapsular hematomas, one of retroperitoneal errhysis and one of nausea, were seen after cryoablation. One patient had a local recurrence of tumor and received additional cryoablation. Local tumor control rate was 100 % of T1NoMo tumors including the recurrence case who underwent additional cryoablation. CONCLUSIONS: Percutaneous cryoablation can be recommended as a feasible, safe, and promising therapy for the treatment of renal tumor, especially those unresectable stage 1 RCC, with a low risk of complications. PMID- 26059548 TI - Co-cultivation and transcriptome sequencing of two co-existing fish pathogens Moritella viscosa and Aliivibrio wodanis. AB - BACKGROUND: Aliivibrio wodanis and Moritella viscosa have often been isolated concurrently from fish with winter-ulcer disease. Little is known about the interaction between the two bacterial species and how the presence of one bacterial species affects the behaviour of the other. RESULTS: The impact on bacterial growth in co-culture was investigated in vitro, and the presence of A. wodanis has an inhibitorial effect on M. viscosa. Further, we have sequenced the complete genomes of these two marine Gram-negative species, and have performed transcriptome analysis of the bacterial gene expression levels from in vivo samples. Using bacterial implants in the fish abdomen, we demonstrate that the presence of A. wodanis is altering the gene expression levels of M. viscosa compared to when the bacteria are implanted separately. CONCLUSIONS: From expression profiling of the transcriptomes, it is evident that the presence of A. wodanis is altering the global gene expression of M. viscosa. Co-cultivation studies showed that A. wodanis is impeding the growth of M. viscosa, and that the inhibitorial effect is not contact-dependent. PMID- 26059550 TI - The greenhouse gas balance of European grasslands. AB - The greenhouse gas (GHG) balance of European grasslands (EU-28 plus Norway and Switzerland), including CO2 , CH4 and N2 O, is estimated using the new process based biogeochemical model ORCHIDEE-GM over the period 1961-2010. The model includes the following: (1) a mechanistic representation of the spatial distribution of management practice; (2) management intensity, going from intensively to extensively managed; (3) gridded simulation of the carbon balance at ecosystem and farm scale; and (4) gridded simulation of N2 O and CH4 emissions by fertilized grassland soils and livestock. The external drivers of the model are changing animal numbers, nitrogen fertilization and deposition, land-use change, and variable CO2 and climate. The carbon balance of European grassland (NBP) is estimated to be a net sink of 15 +/- 7 g C m(-2 ) year(-1) during 1961 2010, equivalent to a 50-year continental cumulative soil carbon sequestration of 1.0 +/- 0.4 Pg C. At the farm scale, which includes both ecosystem CO2 fluxes and CO2 emissions from the digestion of harvested forage, the net C balance is roughly halved, down to a small sink, or nearly neutral flux of 8 g C m(-2 ) year(-1) . Adding CH4 and N2 O emissions to net ecosystem exchange to define the ecosystem-scale GHG balance, we found that grasslands remain a net GHG sink of 19 +/- 10 g C-CO2 equiv. m(-2 ) year(-1) , because the CO2 sink offsets N2 O and grazing animal CH4 emissions. However, when considering the farm scale, the GHG balance (NGB) becomes a net GHG source of -50 g C-CO2 equiv. m(-2 ) year(-1) . ORCHIDEE-GM simulated an increase in European grassland NBP during the last five decades. This enhanced NBP reflects the combination of a positive trend of net primary production due to CO2 , climate and nitrogen fertilization and the diminishing requirement for grass forage due to the Europe-wide reduction in livestock numbers. PMID- 26059549 TI - Type II collagen and glycosaminoglycan expression induction in primary human chondrocyte by TGF-beta1. AB - BACKGROUND: A localized non-surgical delivery of allogeneic human chondrocytes (hChonJ) with irradiated genetically modified chondrocytes (hChonJb#7) expressing transforming growth factor-beta1 (TGF-beta1) showed efficacy in regenerating cartilage tissue in our pre-clinical studies and human Phase I and II clinical trials. These previous observations led us to investigate the molecular mechanisms of the cartilage regeneration. METHODS: Genetically modified TGF beta1preprotein was evaluated by monitoring cell proliferation inhibition activity. The effect of modified TGF-beta1 on chondrocytes was evaluated based on the type II collagen mRNA levels and the amount of glycosaminoclycan (GAG) formed around chondrocytes, which are indicative markers of redifferentiated chondrocytes. Among the cartilage matrix components produced by hChonJb#7 cells, type II collagen and proteoglycan, in addition to TGF-beta1, were also tested to see if they could induce hChonJ redifferentiation. The ability of chondrocytes to attach to artificially induced defects in rabbit cartilage was tested using fluorescent markers. RESULTS: Throughout these experiments, the TGF-beta1 produced from hChonJb#7 was shown to be equally as active as the recombinant human TGF-beta1. Type II collagen and GAG production were induced in hChonJ cells by TGF-beta1 secreted from the irradiated hChonJb#7 cells when the cells were co cultured in micro-masses. Both hChonJ and hChonJb#7 cells could attach efficiently to the defect area in the rabbit cartilage. CONCLUSIONS: This study suggests that the mixture (TG-C) of allogeneic human chondrocytes (hChonJ) and irradiated genetically modified human chondrocytes expressing TGF-beta1 (hChonJb#7) attach to the damaged cartilage area to produce type II collagen-GAG matrices by providing a continuous supply of active TGF-beta1. PMID- 26059551 TI - Perikymata distribution in Homo with special reference to the Xujiayao juvenile. AB - OBJECTIVES: This study investigates where the Xujiayao juvenile (I(1) and C(1) ) fits into the array of perikymata distribution patterns found within the genus Homo. MATERIALS AND METHODS: In addition to the I(1) and the C(1) of the Xujiayao juvenile, this study includes samples of early Homo (H. rudolfensis and H. erectus), Neandertals, early modern humans (Qafzeh), and recent modern humans from Southern Africa, Newcastle (UK), and North America (Inupiaq, AK). Three sets of analyses were undertaken, including a comparison of percentage of perikymata in the cervical half of the crown, repeated measures analysis of the percentage of total perikymata in each decile, and canonical variates analysis using both total perikymata number and the percentage of perikymata in the cervical half of the crown. RESULTS: The I(1) and C(1) of early Homo and Neandertals have a lower percentage of perikymata in the cervical half of the crown than modern human samples. Repeated measures analysis reveals clear distinctions in the distribution of perikymata between the modern human and fossil samples. Canonical variates analysis suggests greater differences between modern humans and the fossil samples than within the fossil samples, and classifies the Xujiayao teeth among modern humans. DISCUSSION: The present study further clarifies variation of perikymata distribution patterns within the genus Homo. The perikymata distribution of the Xujiayao juvenile tends to be more similar to that of modern humans than to either early Homo or Neandertals. PMID- 26059552 TI - Highly active oxygen reduction non-platinum group metal electrocatalyst without direct metal-nitrogen coordination. AB - Replacement of noble metals in catalysts for cathodic oxygen reduction reaction with transition metals mostly create active sites based on a composite of nitrogen-coordinated transition metal in close concert with non-nitrogen coordinated carbon-embedded metal atom clusters. Here we report a non-platinum group metal electrocatalyst with an active site devoid of any direct nitrogen coordination to iron that outperforms the benchmark platinum-based catalyst in alkaline media and is comparable to its best contemporaries in acidic media. In situ X-ray absorption spectroscopy in conjunction with ex situ microscopy clearly shows nitrided carbon fibres with embedded iron particles that are not directly involved in the oxygen reduction pathway. Instead, the reaction occurs primarily on the carbon-nitrogen structure in the outer skin of the nitrided carbon fibres. Implications include the potential of creating greater active site density and the potential elimination of any Fenton-type process involving exposed iron ions culminating in peroxide initiated free-radical formation. PMID- 26059554 TI - Screening in delirium: A pilot study of two screening tools, the Simple Query for Easy Evaluation of Consciousness and Simple Question in Delirium. AB - AIM: Delirium is poorly recognised and inadequately treated in medical settings. This research aimed to determine the psychometric properties of a newly developed tool, SQeeC against another emergent instrument, SQiD, in the screening of delirium. METHODS: The SQeeC was administered to 100 patients and SQiD administered to their informants in the general medical wards of a General Hospital. Data were compared with the reference standard geriatric consultant assessment of delirium. RESULTS: Compared with the reference standard, the SQeeC was found to have a sensitivity of 83% (95% CI 52-98%) and a specificity of 81% (95% CI 72-89%) with a negative predictive value of 97% (95% CI 90-100%) while the SQiD was found to have a sensitivity of 77% (95% CI 56-91%), a specificity of 51% (95% CI 37-64%) and a negative predictive value of 83% (95% CI 66-93%). CONCLUSION: The SQeeC and SQiD are simple and time efficient screening tools with encouraging psychometric properties. PMID- 26059555 TI - Spatial and temporal dynamics of visual search tasks distinguish subtypes of unilateral spatial neglect: Comparison of two cases with viewer-centered and stimulus-centered neglect. AB - We developed a computerised test to evaluate unilateral spatial neglect (USN) using a touchscreen display, and estimated the spatial and temporal patterns of visual search in USN patients. The results between a viewer-centered USN patient and a stimulus-centered USN patient were compared. Two right-brain-damaged patients with USN, a patient without USN, and 16 healthy subjects performed a simple cancellation test, the circle test, a visuomotor search test, and a visual search test. According to the results of the circle test, one USN patient had stimulus-centered neglect and a one had viewer-centered neglect. The spatial and temporal patterns of these two USN patients were compared. The spatial and temporal patterns of cancellation were different in the stimulus-centered USN patient and the viewer-centered USN patient. The viewer-centered USN patient completed the simple cancellation task, but paused when transferring from the right side to the left side of the display. Unexpectedly, this patient did not exhibit rightward attention bias on the visuomotor and visual search tests, but the stimulus-centered USN patient did. The computer-based assessment system provided information on the dynamic visual search strategy of patients with USN. The spatial and temporal pattern of cancellation and visual search were different across the two patients with different subtypes of neglect. PMID- 26059553 TI - C5a alters blood-brain barrier integrity in a human in vitro model of systemic lupus erythematosus. AB - The blood-brain barrier (BBB) plays a crucial role in brain homeostasis, thereby maintaining the brain environment precise for optimal neuronal function. Its dysfunction is an intriguing complication of systemic lupus erythematosus (SLE). SLE is a systemic autoimmune disorder where neurological complications occur in 5 50% of cases and is associated with impaired BBB integrity. Complement activation occurs in SLE and is an important part of the clinical profile. Our earlier studies demonstrated that C5a generated by complement activation caused the loss of brain endothelial layer integrity in rodents. The goal of the current study was to determine the translational potential of these studies to a human system. To assess this, we used a two dimensional in vitro BBB model constructed using primary human brain microvascular endothelial cells and astroglial cells, which closely emulates the in vivo BBB allowing the assessment of BBB integrity. Increased permeability monitored by changes in transendothelial electrical resistance and cytoskeletal remodelling caused by actin fiber rearrangement were observed when the cells were exposed to lupus serum and C5a, similar to the observations in mice. In addition, our data show that C5a/C5aR1 signalling alters nuclear factor-kappaB translocation into nucleus and regulates the expression of the tight junction proteins, claudin-5 and zonula occludens 1 in this setting. Our results demonstrate for the first time that C5a regulates BBB integrity in a neuroinflammatory setting where it affects both endothelial and astroglial cells. In addition, we also demonstrate that our previous findings in a mouse model, were emulated in human cells in vitro, bringing the studies one step closer to understanding the translational potential of C5a/C5aR1 blockade as a promising therapeutic strategy in SLE and other neurodegenerative diseases. PMID- 26059556 TI - Metal assisted anodic etching of silicon. AB - Metal assisted anodic etching (MAAE) of Si in HF, without H2O2, is demonstrated. Si wafers were coated with Au films, and the Au films were patterned with an array of holes. A Pt mesh was used as the cathode while the anodic contact was made through either the patterned Au film or the back side of the Si wafer. Experiments were carried out on P-type, N-type, P(+)-type and N(+)-type Si wafers and a wide range of nanostructure morphologies were observed, including solid Si nanowires, porous Si nanowires, a porous Si layer without Si nanowires, and porous Si nanowires on a thick porous Si layer. Formation of wires was the result of selective etching at the Au-Si interface. It was found that when the anodic contact was made through P-type or P(+)-type Si, regular anodic etching due to electronic hole injection leads to formation of porous silicon simultaneously with metal assisted anodic etching. When the anodic contact was made through N type or N(+)-type Si, generation of electronic holes through processes such as impact ionization and tunnelling-assisted surface generation were required for etching. In addition, it was found that metal assisted anodic etching of Si with the anodic contact made through the patterned Au film essentially reproduces the phenomenology of metal assisted chemical etching (MACE), in which holes are generated through metal assisted reduction of H2O2 rather than current flow. These results clarify the linked roles of electrical and chemical processes that occur during electrochemical etching of Si. PMID- 26059557 TI - Pentamethylquercetin (PMQ) reduces thrombus formation by inhibiting platelet function. AB - Flavonoids exert both anti-oxidant and anti-platelet activities in vitro and in vivo. Pentamethylquercetin (PMQ), a polymethoxylated flavone derivative, has been screened for anti-carcinogenic and cardioprotective effects. However, it is unclear whether PMQ has anti-thrombotic effects. In the present study, PMQ (20 mg/kg) significantly inhibited thrombus formation in the collagen- epinephrine- induced acute pulmonary thrombosis mouse model and the ferric chloride-induced carotid injury model. To explore the mechanism, we evaluated the effects of PMQ on platelet function. We found that PMQ inhibited platelet aggregation and granule secretion induced by low dose agonists, including ADP, collagen, thrombin and U46619. Biochemical analysis revealed that PMQ inhibited collagen-, thrombin- and U46619-induced activation of Syk, PLCgamma2, Akt, GSK3beta and Erk1/2. Therefore, we provide the first report to show that PMQ possesses anti-thrombotic activity in vivo and inhibited platelet function in vitro, suggesting that PMQ may represent a potential therapeutic candidate for the prevention or treatment of thrombotic disorders. PMID- 26059558 TI - Caspian Rapid Assessment Method: a localized procedure for assessment of wetlands at southern fringe of the Caspian Sea. AB - Although Iran is of founders of the Ramsar Convention, there is no comprehensive information available in the country on the status of wetlands in the past or at present. There is also no specific guideline for assessing the status of wetlands in the basin of the Caspian Sea as an ecosystem with unique ecological features. The main aim of this study was to develop a new procedure called "Caspian Rapid Assessment Method" (CRAM) for assessment of wetlands at southern fringe of the Caspian Sea. To this end, 16 rapid assessment methods analyzed by US EPA in 2003 were reviewed to provide an inventory of rapid assessment indices. Excluding less important indices, the inventory was short-listed based on Delphi panelists' consensus. The CRAM was developed with 6 main criteria and 12 sub-criteria. The modified method was used to assess three important wetlands of Anzali, Boojagh and Miyankaleh at the southern border of the Caspian Sea. According to the obtained results, the highest score of 60 was assigned to the Anzali Wetland. Obtaining the scores of 56 and 47, Miyankaleh and Boojagh wetlands were ranked in the next priorities, respectively. At final stage, the accuracy of CRAM prioritization values was confirmed using the Friedman test. All of the wetlands were classified into category II, which indicates destroyed wetlands with rehabilitation potentials. In recent years, serious threats have deteriorated the wetlands from class III (normal condition) to the class II. PMID- 26059559 TI - Estimation of soil erosion risk within an important agricultural sub-watershed in Bursa, Turkey, in relation to rapid urbanization. AB - This paper integrates the Revised Universal Soil Loss Equation (RUSLE) with a GIS model to investigate the spatial distribution of annual soil loss and identify areas of soil erosion risk in the Uluabat sub-watershed, an important agricultural site in Bursa Province, Turkey. The total soil loss from water erosion was 473,274 Mg year(-1). Accordingly, 60.3% of the surveyed area was classified into a very low erosion risk class while 25.7% was found to be in high and severe erosion risk classes. Soil loss had a close relationship with land use and topography. The most severe erosion risk typically occurs on ridges and steep slopes where agriculture, degraded forest, and shrubs are the main land uses and cover types. Another goal of this study was to use GIS to reveal the multi-year urbanization status caused by rapid urbanization that constitutes another soil erosion risk in this area. Urbanization has increased by 57.7% and the most areal change was determined in class I lands at a rate of 80% over 25 years. Urbanization was identified as one of the causes of excessive soil loss in the study area. PMID- 26059561 TI - Neutrophil-to-lymphocyte ratio as a diagnostic biomarker for the diagnosis of acute mesenteric ischemia. AB - PURPOSE: Due to the diagnostic challenges and dreadful consequences of delayed treatment of acute mesenteric ischemia (AMI), a variety of diagnostic markers have been previously studied. However, the diagnostic value of neutrophil-to lymphocyte ratio (NLR), which has been suggested to be a predictor of inflammation, has never been studied for AMI. METHODS: The data of 70 patients who underwent laparotomy (n = 8) and/or bowel resection (n = 62) for AMI (n = 70) between January 2009 and March 2014 were retrospectively analyzed. To investigate the studied parameters' role in the differential diagnosis of AMI, control groups were selected from most common reasons of inflammation-related emergent surgery, acute appendicitis (AA, n = 62) and normal appendix (NA, n = 61). White blood cell (WBC), red cell distribution width (RDW), NLR and mean platelet volume (MPV) values were recorded. Outcome variables of the study were defined as diagnostic and prognostic role of NLR in AMI. RESULTS: RDW and NLR values were found to be higher in the AMI group than the AA group (p < 0.001 and p < 0.001). Also, WBC and MPV values were higher in the AMI group than the NA group (p = 0.001 and p < 0.001). Combined sensitivity, specificity, positive predictive value and negative predictive value of RDW and NLR for recommended cut-off values were 69.4, 71.2, 57.8 and 80.4 %, respectively. CONCLUSION: High NLR value (>9.9) seems to be a valuable diagnostic marker of acute mesenteric ischemia. Combined use of NLR, RDW and other clinical assessment, could help the diagnosis of AMI, especially in the absence of advanced imaging modalities and expert radiologic interpretation. PMID- 26059562 TI - Novel loss-of-function mutation of the HINT1 gene in a patient with distal motor axonal neuropathy without neuromyotonia. PMID- 26059560 TI - Bedside ultrasound procedures: musculoskeletal and non-musculoskeletal. AB - The widespread availability of ultrasound (US) technology has increased its use for point of care applications in many health care settings. Focused (point of care) US is defined as the act of bringing US evaluation to the bedside for real time performance. These images are collected immediately by the practitioner, allowing for direct integration into the physician's medical decision-making process. The real-time bedside diagnostic ability of US becomes a key tool for the management of patients. The purpose of this review is to (1) provide a general description of the use of focused US for bedside procedures; (2) specify the indications and common techniques used in bedside US procedures; and (3) describe the techniques used for each bedside intervention. PMID- 26059563 TI - Cardiac Nav 1.5 is modulated by ubiquitin protein ligase E3 component n-recognin UBR3 and 6. AB - The voltage-gated Na(+) channel Nav 1.5 is essential for action potential (AP) formation and electrophysiological homoeostasis in the heart. The ubiquitin proteasome system (UPS) is a major degradative system for intracellular proteins including ion channels. The ubiquitin protein ligase E3 component N-recognin (UBR) family is a part of the UPS; however, their roles in regulating cardiac Nav 1.5 channels remain elusive. Here, we found that all of the UBR members were expressed in cardiomyocytes. Individual knockdown of UBR3 or UBR6, but not of other UBR members, significantly increased Nav 1.5 protein levels in neonatal rat ventricular myocytes, and this effect was verified in HEK293T cells expressing Nav 1.5 channels. The UBR3/6-dependent regulation of Nav 1.5 channels was not transcriptionally mediated, and pharmacological inhibition of protein biosynthesis failed to counteract the increase in Nav 1.5 protein caused by UBR3/6 reduction, suggesting a degradative modulation of UBR3/6 on Nav 1.5. Furthermore, the effects of UBR3/6 knockdown on Nav 1.5 proteins were abolished under the inhibition of proteasome activity, and UBR3/6 knockdown reduced Nav 1.5 ubiquitylation. The double UBR3-UBR6 knockdown resulted in comparable increases in Nav 1.5 proteins to that observed for single knockdown of either UBR3 or UBR6. Electrophysiological recordings showed that UBR3/6 reduction-mediated increase in Nav 1.5 protein enhanced the opening of Nav 1.5 channels and thereby the amplitude of the AP. Thus, our findings indicate that UBR3/6 regulate cardiomyocyte Nav 1.5 channel protein levels via the ubiquitin-proteasome pathway. It is likely that UBR3/6 have the potential to be a therapeutic target for cardiac arrhythmias. PMID- 26059565 TI - Comparison of DXA Scans and Conventional X-rays for Spine Morphometry and Bone Age Determination in Children. AB - Conventional lateral spine and hand radiographs are the standard tools to evaluate vertebral morphometry and bone age in children. Beside bone mineral density analyses, dual-energy X-ray absorptiometry (DXA) measurements with lower radiation exposure provide high-resolution scans which are not approved for diagnostic purposes. Data about the comparability of conventional radiographs and DXA in children are missing yet. The purpose of the trial was to evaluate whether conventional hand and spine radiographs can be replaced by DXA scans to diminish radiation exposure. Thirty-eight children with osteogenesis imperfecta or secondary osteoporosis or short stature (male, n=20; age, 5.0-17.0 yr) were included and assessed once by additional DXA (GE iDXA) of the spine or the left hand. Intraclass correlation coefficients (ICCs) were used to express agreement between X-ray and iDXA assessment. Evaluation of the spine morphometry showed reasonable agreement between iDXA and radiography (ICC for fish-shape, 0.75; for wedge-shape, 0.65; and for compression fractures, 0.70). Bone age determination showed excellent agreement between iDXA and radiography (ICC, 0.97). IDXA-scans of the spine in a pediatric population should be used not only to assess bone mineral density but also to evaluate anatomic structures and vertebral morphometry. Therefore, iDXA can replace some radiographs in children with skeletal diseases. PMID- 26059564 TI - Cannabinoid-dopamine interactions in the physiology and physiopathology of the basal ganglia. AB - Endocannabinoids and their receptors play a modulatory role in the control of dopamine transmission in the basal ganglia. However, this influence is generally indirect and exerted through the modulation of GABA and glutamate inputs received by nigrostriatal dopaminergic neurons, which lack cannabinoid CB1 receptors although they may produce endocannabinoids. Additional evidence suggests that CB2 receptors may be located in nigrostriatal dopaminergic neurons, and that certain eicosanoid-related cannabinoids may directly activate TRPV1 receptors, which have been found in nigrostriatal dopaminergic neurons, thus allowing in both cases a direct regulation of dopamine transmission by specific cannabinoids. In addition, CB1 receptors form heteromers with dopaminergic receptors which provide another pathway to direct interactions between both systems, in this case at the postsynaptic level. Through these direct mechanisms or through indirect mechanisms involving GABA or glutamate neurons, cannabinoids may interact with dopaminergic transmission in the basal ganglia and this is likely to have important effects on dopamine-related functions in these structures (i.e. control of movement) and, particularly, on different pathologies affecting these processes, in particular, Parkinson's disease, but also dyskinesia, dystonia and other pathological conditions. The present review will address the current literature supporting these cannabinoid-dopamine interactions at the basal ganglia, with emphasis on aspects dealing with the physiopathological consequences of these interactions. LINKED ARTICLES: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. PMID- 26059566 TI - Nutrition and Sarcopenia. AB - From 50 yr, men and women are at an increased risk of developing sarcopenia, a disorder that increases the risk of falls and fractures. The development of sarcopenia may be attenuated through healthy lifestyle changes, which include adequate dietary protein and vitamin D intakes, and regular physical activity/exercise. Protein intake and physical activity are the main anabolic stimuli for muscle protein synthesis. Exercise training leads to increased muscle mass and strength, and the combination of optimal protein intake and exercise produces a greater degree of muscle protein accretion than either intervention alone. Recommendations for optimal dietary protein intake are 1.0-1.2 g/kg body weight/d with an optimal repartition over each daily meal, together with adequate vitamin D intake at 800 IU/d to maintain serum 25-hydroxyvitamin D levels >50 nmol/L (20 ng/mL), alongside regular physical activity/exercise 3-5 times/wk combined with protein intake in close proximity to exercise. PMID- 26059567 TI - Vitamin D and Sarcopenia/Falls. AB - Maintenance of adequate vitamin D status is a stratagem to consider for sarcopenia prevention and treatment. Vitamin D deficiency is common and involves all ages of most racial/ethnic groups and both sexes. Evidence suggests that vitamin D is important for muscle strength and function, and prospective studies are underway to further define these effects. This article summarizes the potential effects of vitamin D on skeletal muscle structure and function and provides guidance for vitamin D supplementation in prevention and treatment of sarcopenia and falls. PMID- 26059568 TI - Novel Approaches to the Diagnosis of Sarcopenia. AB - Sarcopenia is common in older people and is associated with disability, reduced mobility, hospitalization, and various comorbidities. Although it has been recognized for over a quarter of a century, we do not currently have a universally adopted definition. This limits our ability to compare results from different studies and impedes the development of novel therapies. Although sarcopenia was initially defined purely based on low muscle mass, the importance of measures of muscle function has been realized and these have been included in recent operational definitions. These continue to evolve with some including an assessment of adiposity and others adding further components of musculoskeletal health in a score-based approach. This review describes the importance of reaching a widely accepted method to define sarcopenia in both research and clinical practice. It details the ways in which the definition has changed since its initial inception and explores how it may continue to evolve in the future. The different methods by which components of sarcopenia can be measured are described, and the various advantages and disadvantages of these techniques are evaluated. Clearly, there are several other similar syndromes in older people, such as frailty and cachexia; their relationships and overlap with sarcopenia are also explored. PMID- 26059569 TI - Child health must be a priority. PMID- 26059572 TI - Northern Ireland recognises dedication of children's nurses. PMID- 26059571 TI - Babies from Pakistani communities eat high sugar diets, study finds. PMID- 26059573 TI - Monkey's story aims to improve families' asthma management. PMID- 26059574 TI - Pledge for national strategy to tackle obesity gains support. PMID- 26059575 TI - Young patients' involvement in research vital for improving treatment and services. PMID- 26059581 TI - Research essentials. PMID- 26059576 TI - Nurses stress need for long-term planning and support for looked after children. PMID- 26059583 TI - Research and commentary. Internal emergency admissions shown to have better outcomes. PMID- 26059584 TI - Febrile convulsions in children. PMID- 26059585 TI - The author replies. PMID- 26059586 TI - Use of a food allergy care management pathway in adolescents. AB - The prevalence of allergic diseases is increasing, parents/carers. Healthcare staff also need training on with estimates suggesting that 3.9% of 0-19 year olds how best to deliver information to this age group and have a food allergy. Adolescents are seen as a high-risk to monitor them. More technically stylish adrenaline group for anaphylaxis because of their risk-taking auto-injectors, designed with the involvement of behaviours and challenges in using adrenaline adolescents, together with clearer food labelling, auto-injectors. The Royal College of Paediatrics would also help avoid episodes of anaphylaxis. and Child Health provides an allergy care pathway to assist health professionals with these issues. The pathway could be implemented more effectively with the adolescent age group if education on how to follow it was improved for young people and their parents/carers. Healthcare staff also need training on how best to deliver information to this age group and to monitor them. More technically stylish adrenaline auto-injectors, designed with the involvement of adolescents, together with clearer food labelling, would also help avoid episodes of anaphylaxis. PMID- 26059587 TI - Overcoming the barriers to using kangaroo care in neonatal settings. AB - Skin-to-skin contact, or kangaroo care (KC), has benefits for babies and parents, improving clinical outcomes, temperature control, breastfeeding rates and child parent bonding; it reduces morbidity and mortality. Barriers to KC for neonates may include a lack of training for nurses, lack of time, maternal or child physical or mental ill health, and inappropriate settings. With education and helpful management, neonatal nurses can advocate for KC for all babies. Parents may need information and encouragement to begin with. Therefore, nurses can improve the experiences of their patients and, in the long run, free time to perform clinical procedures. PMID- 26059588 TI - Effective nursing care of children and young people outside hospital. AB - AIM: To assess the preparation required to ensure a workforce of nurses who can provide high quality out-of-hospital services for children and young people. METHODS: Using mixed methods, questionnaires were sent to young people and community children's nursing teams, interviews were conducted with academic staff and clinical nurses, and focus groups were undertaken with pre-registration children's nursing students. FINDINGS: Nurses' communication skills and clinical abilities were most important to young people. There is a range of opinions about optimum out-of-hospital clinical experience. Pre- and post-qualification education and recruitment in this area, therefore, need attention. CONCLUSION: Out-of-hospital care presents problems, but is developing rapidly. Adequate, updated training, supervision and resources are needed. PMID- 26059589 TI - Cyberchondria: emerging themes for children's nurses in the internet age. AB - In many countries, anxious adults and young people are increasingly searching the web for information about their health or ill health and that of their family. This activity often increases their anxiety and confusion. Cyberchondria refers to the resulting match with real or imagined symptoms, and may lead to unnecessary medical consultation. Advantages of online searching include knowledge, empowerment, autonomy and self-responsibility. Disadvantages are increased fears and possible misinformation and misdiagnosis and inappropriate self-treatment. There is also loss of placebo-style trust in, and concordance with, professionals, who may experience reduced confidence, authority and effectiveness. However, a new and more collaborative style of consultation has developed, with the practitioner confirming or refuting information rather than protecting it. PMID- 26059590 TI - Combined effects of underlying substrate and evaporative cooling on the evaporation of sessile liquid droplets. AB - The evaporation of pinned, sessile droplets resting on finite thickness substrates was investigated numerically by extending the combined field approach to include the thermal properties of the substrate. By this approach, the combined effects of the underlying substrate and the evaporative cooling were characterized. The results show that the influence of the substrate on the droplet evaporation depends largely on the strength of the evaporative cooling. When the evaporative cooling is weak, the influence of substrate is also weak. As the strength of evaporative cooling increases, the influence of the substrate becomes more and more pronounced. Further analyses indicated that it is the cooling at the droplet surface and the temperature dependence of the saturation vapor concentration that relate the droplet evaporation to the underlying substrate. This indicates that the evaporative cooling number, Ec, can be used to identify the influence of the substrate on the droplet evaporation. The theoretical predictions by the present model are compared and found to be in good agreement with the experimental measurements. The present work may contribute to the body of knowledge concerning droplet evaporation and may have applications in a wide range of industrial and scientific processes. PMID- 26059591 TI - MDT lung cancer care: input from the Surgical Oncologist. AB - Although there have been many advancements in the multidisciplinary management of non-small cell lung cancer (NSCLC), surgery remains the primary modality of choice for resectable lung cancer when the patient is able to tolerate lung resection physiologically. There have been recent advances in surgical diagnosis and treatment of lung cancer. Increasing use of low-dose computed tomography (CT) screening for lung cancer has resulted in increased detection of small peripheral nodules or semi-solid ground glass opacities. Here, we review different modalities of localization techniques that have been used to aid surgical excisional biopsy when needle biopsy has failed to provide tissue diagnosis. We also report on the current debates regarding the use of sublobar resections for Stage I NSCLC as well as the surgical management of locally advanced NSCLC. Finally, we discuss the complex surgical management of T4 NSCLC lung cancers. PMID- 26059592 TI - Closing the gap between brain banks and proteomics to advance the study of neurodegenerative diseases. AB - Neurodegenerative diseases (NDs), such as Alzheimer's disease and Parkinson's disease, are among the most debilitating neurological disorders, and as life expectancy rises quickly around the world, the scientific and clinical challenges of dealing with them will also increase dramatically, putting increased pressure on the biomedical community to come up with innovative solutions for the understanding, diagnosis, and treatment of these conditions. Despite several decades of intensive research, there is still little that can be done to prevent, cure, or even slow down the progression of NDs in most patients. There is an urgent need to develop new lines of basic and applied research that can be quickly translated into clinical application. One way to do this is to apply the tools of proteomics to well-characterized samples of human brain tissue, but a closer partnership must still be forged between proteomic scientists, brain banks, and clinicians to explore the maximum potential of this approach. Here, we analyze the challenges and potential benefits of using human brain tissue for proteomics research toward NDs. PMID- 26059593 TI - Identification of peptidic substrates for the human kinase Myt1 using peptide microarrays. AB - Myt1 kinase is a member of the Wee-kinase family involved in G2/M checkpoint regulation of the cell cycle. So far, no peptide substrate suitable for activity based screening has been reported, hampering systematic development of Myt1 kinase inhibitors. Myt1 inhibitors had to be identified by using either binding assays or activity assays with expensive proteinous substrates. Here, a peptide microarray approach was used to identify peptidic Myt1 substrates. Wee1 kinase was profiled for comparison using the same technology. Myt1 hits from peptide microarray experiments were verified in solution by a fluorescence polarization assay and several peptide substrates derived from cellular proteins were identified. Subsequently, phosphorylation site determination was carried out by MS fragmentation studies and identified substrates were validated by kinase inhibitor profiling. PMID- 26059594 TI - Synthesis and bioevaluation of heterocyclic derivatives of Cleistanthin-A. AB - The vacuolar H(+)-ATPase (V-ATPase) was proposed as a key target for new strategies in cancer treatment recently. We have synthesized a novel class of derivatives of Cleistanthin-A bearing heterocyclic moieties. Most of these compounds displayed potent antiproliferative effects on four cancer cells at submicromolar concentration, and they have no cytotoxicity on normal WRL-68 cells at 200 nM. The most potent compound 3a has been shown to inhibit the activity of vacuolar H(+)-ATPase at submicromolar concentration, and it could also significantly decrease the cytosolic pH values in HepG2 cells. The current findings provide valuable insights for future development of novel V-ATPase inhibitors as anticancer agents. PMID- 26059595 TI - Discovery of substituted 1,4-dihydroquinolines as novel class of ABCB1 modulators. AB - Transmembrane efflux pumps are one main cause for multidrug resistance (mdr) of cancer. One hopeful approach to combate the mdr has been the development of inhibitors of the efflux pump activity. A novel class of small-molecule inhibitors of the most important efflux pump ABCB1 (P-glycoprotein) has been discovered. Inhibitory activities are discussed in relation to substituent effects. Most active compounds have been evaluated in first bioanalytical studies to reverse the mdr of an anticancer drug. Cellular toxicity and ABCB1 substrate properties of the compounds were investigated. A cellular induction of relevant efflux pump protein expressions was not observed under inhibitor application, so that our compounds are perspective candidates for further preclinical studies. PMID- 26059596 TI - Discovery of 3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one derivatives as novel JAK inhibitors. AB - Because Janus kinases (JAKs) play a crucial role in cytokine-mediated signal transduction, JAKs are an attractive target for the treatment of organ transplant rejection and autoimmune diseases such as rheumatoid arthritis (RA). To identify JAK inhibitors, we focused on the 1H-pyrrolo[2,3-b]pyridine derivative 3, which exhibited moderate JAK3 and JAK1 inhibitory activities. Optimization of 3 identified the tricyclic imidazo-pyrrolopyridinone derivative 19, which exhibited potent JAK3 and JAK1 inhibitory activities (IC50=1.1 nM, 1.5 nM, respectively) with favorable metabolic stability. PMID- 26059597 TI - Stage-specific reference genes significant for quantitative PCR during mouse retinal development. AB - Developing mouse retina has been serving as an ideal model for investigating the molecular mechanism of neural development and angiogenesis, because several significant events associated with these physiological phenomena are drastically occurring in conjunction with retinal development. However, as many genes are influencing on each other to establish mature retina within 21 days from E10 to P12, we must carefully design the experiments, such as in the case of quantitating the amount of altered gene expression toward the establishment of retina by quantitative PCR. As we have seen considerable variations of quantitative results in different developmental stages of retina depending on the reference genes used for compensation, we here attempted to determine a reliable reference gene to accurately quantitate the target genes in each stage. According to the results of in silico prediction and comparison with a database of SAGE, we found that the most stable gene from early to late stages was Sdha, whereas one of the most popular housekeeping genes, Actb, was the one that could mislead the quantitative results even in the adult stage. Consequently, we pointed out the importance of selecting an appropriate reference gene, especially to quantitate the amount of gene expression in the developmental stages of a certain tissue. PMID- 26059598 TI - Molecular mechanism of PdxR - a transcriptional activator involved in the regulation of vitamin B6 biosynthesis in the probiotic bacterium Bacillus clausii. AB - Pyridoxal 5'-phosphate (PLP), the well-known active form of vitamin B6 , is an essential enzyme cofactor involved in a large number of metabolic processes. PLP levels need to be finely tuned in response to cell requirements; however, little is known about the regulation of PLP biosynthesis and recycling pathways. The transcriptional regulator PdxR activates transcription of the pdxST genes encoding PLP synthase. It is characterized by an N-terminal helix-turn-helix motif that binds DNA and an effector-binding C-terminal domain homologous to PLP dependent enzymes. Although it is known that PLP acts as an anti-activator, the mechanism of action of PdxR is unknown. In the present study, we analyzed the biochemical and DNA-binding properties of PdxR from the probiotic Bacillus clausii. Spectroscopic measurements showed that PLP is the only B6 vitamer that acts as an effector molecule of PdxR. Binding of PLP to PdxR determines a protein conformational change, as detected by gel filtration chromatography and limited proteolysis experiments. We showed that two direct repeats and one inverted repeat are present in the DNA promoter region and PdxR is able to bind DNA fragments containing any combination of two of them. However, when PLP binds to PdxR, it modifies the DNA-binding properties of the protein, making it selective for inverted repeats. A molecular mechanism is proposed in which the two different DNA binding modalities of PdxR determined by the presence or absence of PLP are responsible for the control of pdxST transcription. PMID- 26059599 TI - Tumour promotion versus tumour suppression in chronic hepatic iron overload. AB - Although iron-catalysed oxidative damage is presumed to be a major mechanism of injury leading to cirrhosis and hepatocellular carcinoma in hemochromatosis, these events have been difficult to recapitulate in an animal model. In this study, we evaluated regulators of hepatocarcinogenesis in a rodent model of chronic iron overload. Sprague-Dawley rats were iron loaded with iron dextran over 6 months. Livers were harvested and analysed for markers of oxidative stress, as well as the following proteins: p53, murine double minute 2, the Shc proteins p66, p52, p46; beta-catenin, CHOP, C/EBPalpha and Yes-associated protein. In this model, iron loading is associated with hepatocyte proliferation, and indices of oxidative damage are mildly increased in tandem with augmented antioxidant defenses. Alterations potentially favouring carcinogenesis included a modest but significant decrease in p53 levels and increases in p52, p46 and beta catenin levels compared with control livers. Countering these factors, the iron loaded livers demonstrated a significant decrease in CHOP, which has recently been implicated in the development of hepatocellular carcinoma, as well as a reciprocal increase in C/EBPalpha and decrease in Yes-associated protein. Our results suggest that chronic iron overload elicits both tumour suppressive as well as tumour-promoting mechanisms in rodent liver. PMID- 26059600 TI - An automated hand hygiene training system improves hand hygiene technique but not compliance. AB - INTRODUCTION: The hand hygiene technique that the World Health Organization recommends for cleansing hands with soap and water or alcohol-based handrub consists of 7 poses. We used an automated training system to improve clinicians' hand hygiene technique and test whether this affected hospitalwide hand hygiene compliance. METHODS: Seven hundred eighty-nine medical and nursing staff volunteered to participate in a self-directed training session using the automated training system. The proportion of successful first attempts was reported for each of the 7 poses. Hand hygiene compliance was collected according to the national requirement and rates for 2011-2014 were used to determine the effect of the training system on compliance. RESULTS: The highest pass rate was for pose 1 (palm to palm) at 77% (606 out of 789), whereas pose 6 (clean thumbs) had the lowest pass rate at 27% (216 out of 789). One hundred volunteers provided feedback to 8 items related to satisfaction with the automated training system and most (86%) expressed a high degree of satisfaction and all reported that this method was time-efficient. There was no significant change in compliance rates after the introduction of the automated training system. Observed compliance during the posttraining period declined but increased to 82% in response to other strategies. CONCLUSIONS: Technology for training clinicians in the 7 poses played an important education role but did not affect compliance rates. PMID- 26059601 TI - Effect of proactive infection control measures on benchmarked rate of hospital outbreaks: An analysis of public hospitals in Hong Kong over 5 years. AB - BACKGROUND: Hospital outbreaks of epidemiologically important pathogens are usually caused by lapses in infection control measures and result in increased morbidity, mortality, and cost. However, there is no benchmark to compare the occurrence of hospital outbreaks across hospitals. METHODS: We implemented proactive infection control measures with an emphasis on timely education of health care workers and hospitalized patients at Queen Mary Hospital, a teaching hospital. Our benchmarked performance (outbreak episodes per 1 million patient discharges and 1 million patient-days) was compared with those of other regional public hospitals without these additional proactive measures in place between 2010 and 2014. RESULTS: During the study period, Queen Mary Hospital had 1 hospital outbreak resulting in 1.48 and 0.45 outbreak episodes per 1 million patient discharges and patient-days, respectively, values significantly lower than the corresponding overall rates in the 7 acute regional hospitals (24.26 and 6.70 outbreak episodes per 1 million patient discharges and patient-days, respectively; P < .001) and that of all 42 public hospitals in Hong Kong (41.62 and 8.65 outbreak episodes per 1 million patient discharges and patient-days, respectively; P < .001). CONCLUSIONS: The results of this large study on benchmarked rate of hospital outbreaks per patient discharges or patient-days suggests that proactive infection control interventions may minimize the risk of hospital outbreaks. PMID- 26059602 TI - A novel anti-TNF scFv constructed with human antibody frameworks and antagonistic peptides. AB - The introduction of TNF inhibitors has revolutionized the treatment of some chronic inflammatory diseases, e.g., rheumatoid arthritis and Crohn's disease. However, immunogenicity is one of the important mechanisms behind treatment failure, and generally, switching to another TNF inhibitor will be the first choice for patients and doctors, which results in unmet need for novel anti-TNF agents. Small antibody molecules with less number of epitope may be valuable in less immunogenicity. In this study, with the help of computer-guided molecular design, single-chain variable fragment (scFv) TSA2 was designed using consensus frameworks of human antibody variable region as scaffold to display anti-TNF antagonistic peptides. TSA2 showed evidently improved bioactivity over TSA1 (anti TNF scFv explored before) and almost similar activity as S-Remicade (the scFv form of Remicade, anti-TNF antibody approved by FDA), especially in inhibiting TNF-induced cytotoxicity and NF-kappaB activation. Human antibody consensus frameworks with less immunogenicity have been used in the designing of VH domain antibody, scFv TSA1 and TSA2. A serial of TNF-related works convinced us that the novel design strategy was feasible and could be used to design inhibitors targeting more other molecules than TNF-alpha. More importantly, these designed inhibitors derived from computer modeling may form a virtual antibody library whose size depends on the number of candidate antagonistic peptides. It will be molecular-targeted virtual antibody library because of the specific antagonistic peptides and the potential antibodies could be determined by virtual screening and then confirmed by biologic experiments. PMID- 26059604 TI - De novo DNA Methyltransferases Dnmt3a and Dnmt3b regulate the onset of Igkappa light chain rearrangement during early B-cell development. AB - Immunoglobulin genes V(D)J rearrangement during early lymphopoiesis is a critical process involving sequential recombination of the heavy and light chain loci. A number of transcription factors act together with temporally activated recombinases and chromatin accessibility changes to regulate this complex process. Here, we deleted the de novo DNA methyltransferases Dnmt3a and Dnmt3b in early B cells of conditionally targeted mice, and monitored the process of V(D)J recombination. Dnmt3a and Dnmt3b deletion resulted in precocious recombination of the immunoglobulin kappa light chain without impairing the differentiation of mature B cells or overall B-cell development. Ex vivo culture of IL-7 restricted early B-cell progenitors lacking Dnmt3a and Dnmt3b showed precocious Vkappa Jkappa rearrangements that are limited to the proximal Vkappa genes. Furthermore, B-cell progenitors deficient in Dnmt3a and Dnmt3b showed elevated levels of germline transcripts at the proximal Vkappa genes, alterations in methylation patterns at Igkappa enhancer sites and increased expression of the transcription factor E2A. Our data suggest that Dnmt3a and Dnmt3b are critical to regulate the onset of Igkappa light chain rearrangement during early B-cell development. PMID- 26059603 TI - Reliability of 7T (1) H-MRS measured human prefrontal cortex glutamate, glutamine, and glutathione signals using an adapted echo time optimized PRESS sequence: A between- and within-sessions investigation. AB - PURPOSE: To ascertain the mechanisms of neuropsychiatric illnesses and their treatment, accurate and reliable imaging techniques are required; proton magnetic resonance spectroscopy ((1) H-MRS) can noninvasively measure glutamatergic function. Evidence suggests that aberrant glutamatergic signaling plays a role in numerous psychopathologies. Until recently, overlapping glutamatergic signals (glutamate, glutamine, and glutathione) could not easily be separated. However, the advent of novel pulse sequences and higher field magnetic resonance imaging (MRI) allows more precise resolution of overlapping glutamatergic signals, although the question of signal reliability remains undetermined. MATERIALS AND METHODS: At 7T MR, we acquired (1) H-MRS data from the medial pregenual anterior cingulate cortex of healthy volunteers (n = 26) twice on two separate days. An adapted echo time optimized point-resolved spectroscopy sequence, modified with the addition of a J-suppression pulse to attenuate N-acetyl-aspartate multiplet signals at 2.49 ppm, was used to excite and acquire the spectra. In-house software was used to model glutamate, glutamine, and glutathione, among other metabolites, referenced to creatine. Intraclass correlation coefficients (ICCs) were computed for within- and between-session measurements. RESULTS: Within session measurements of glutamate, glutamine, and glutathione were on average reliable (ICCs >=0.7). As anticipated, ICCs for between-session values of glutamate, glutamine, and glutathione were slightly lower but nevertheless reliable (ICC >0.62). A negative correlation was observed between glutathione concentration and age (r(24) = -0.37; P < 0.05), and a gender effect was noted on glutamine and glutathione. CONCLUSION: The adapted sequence provides good reliability to measure glutamate, glutamine, and glutathione signals. PMID- 26059605 TI - The fungal endophyte Epichloe typhina improves photosynthesis efficiency of its host orchard grass (Dactylis glomerata). AB - MAIN CONCLUSION: According to the results presented in this paper the fungal endophyte Epichloe typhina significantly improves the growth, PSII photochemistry and C assimilation efficiency of its host Dactylis glomerata. In this paper, we present a comprehensive study of the impact of the endophytic fungi Epichloe typhina on its plant hosts' photosynthesis apparatus. Chlorophyll a fluorescence, gas exchange, immuno-blotting and spectrophotometric measurements were employed to assess photosynthetic performance, changes in pigment content and mechanisms associated with light harvesting, carbon assimilation and energy distribution in Dactylis glomerata colonized with Epichloe typhina. According to the results presented in this study, colonization of D. glomerata results in improved photosynthesis efficiency. Additionally, we propose a new mechanism allowing plants to cope with the withdrawal of a significant fraction of its energy resources by the endophytic fungi. The abundance of LHCI, LHCII proteins as well as chlorophyll b was significantly higher in E+ plants. Malate export out of the chloroplast was shown to be increased in colonized plants. To our knowledge, we are the first to report this phenomenon. Epichloe colonization improved PSII photochemistry and C assimilation efficiency. Elevated energy demands of E+ D. glomerata plants are met by increasing the rate of carbon assimilation and PSII photochemistry. PMID- 26059606 TI - BTH and BABA induce resistance in pea against rust (Uromyces pisi) involving differential phytoalexin accumulation. AB - MAIN CONCLUSION: Systemic acquired resistance elicitors, BTH and BABA, reduce rust penetration in pea through phytoalexins pathway but differing in their mode of action. It has been previously shown that rust (Uromyces pisi) infection can be reduced in pea (Pisum sativum) by exogenous applications of systemic acquired resistance elicitors such as BTH and BABA. This protection is known to be related with the induction of the phenolic pathway but the particular metabolites involved have not been determined yet. In this work, we tackled the changes induced in phytoalexin content by BTH and BABA treatments in the context of the resistance responses to pea rust. Detailed analysis through high-performance liquid chromatography (HPLC) showed qualitative and quantitative differences in the content, as well as in the distribution of phytoalexins. Thus, following BTH treatment, we observed an increase in scopoletin, pisatin and medicarpin contents in all, excreted, soluble and cell wall-bound fraction. This suggests fungal growth impairment by both direct toxic effect as well as plant cell wall reinforcement. The response mediated by BTH was genotype-dependent, since coumarin accumulation was observed only in the resistant genotype whereas treatment by BABA primed phytoalexin accumulation in both genotypes equally. Exogenous application to the leaves of scopoletin, medicarpin and pisatin lead to a reduction of the different fungal growth stages, confirming a role for these phytoalexins in BTH- and BABA-induced resistance against U. pisi hampering pre- and postpenetration fungal stages. PMID- 26059607 TI - A natural rice rhizospheric bacterium abates arsenic accumulation in rice (Oryza sativa L.). AB - MAIN CONCLUSION: A natural rice rhizospheric isolate abates arsenic uptake in rice by increasing Fe plaque formation on rice roots. Rice (Oryza sativa L.) is the staple food for over half of the world's population, but its quality and yield are impacted by arsenic (As) in some regions of the world. Bacterial inoculants may be able to mitigate the negative impacts of arsenic assimilation in rice, and we identified a nonpathogenic, naturally occurring rice rhizospheric bacterium that decreases As accumulation in rice shoots in laboratory experiments. We isolated several proteobacterial strains from a rice rhizosphere that promote rice growth and enhance the oxidizing environment surrounding rice root. One Pantoea sp. strain (EA106) also demonstrated increased iron (Fe) siderophore in culture. We evaluated EA106's ability to impact rice growth in the presence of arsenic, by inoculation of plants with EA106 (or control), subsequently grew the plants in As-supplemented medium, and quantified the resulting plant biomass, Fe and As concentrations, localization of Fe and As, and Fe plaque formation in EA106-treated and control plants. These results show that both arsenic and iron concentrations in rice can be altered by inoculation with the soil microbe EA106. The enhanced accumulation of Fe in the roots and in root plaques suggests that EA106 inoculation improves Fe uptake by the root and promotes the formation of a more oxidative environment in the rhizosphere, thereby allowing more expansive plaque formation. Therefore, this microbe may have the potential to increase food quality through a reduction in accumulation of toxic As species within the aerial portions of the plant. PMID- 26059608 TI - Establishment and value assessment of efficacy prediction model about transurethral prostatectomy. AB - OBJECTIVES: To establish and to evaluate discriminant models to predict the outcomes of transurethral prostatectomy. METHODS: Clinical data of patients treated with transurethral prostatectomy between January and December 2013 were collected, including medical history, symptoms, biochemical tests, ultrasonography and urodynamics. Surgical efficacy was evaluated at 6-month follow up. Predictive models were constructed by logistic regression. Receiver operating characteristic curve and diagnostic tests were used to test the accuracy of models before the predictive value between models was compared. RESULTS: A total of 182 patients were included, with 73.6% having an effective outcome. History of recurrent urinary tract infection (OR 1.33), score of storage phase (OR 2.58), maximum flow rate (OR 2.11) and detrusor overactivity (OR 3.13) were found to be risk factors. International Prostate Symptom Score (OR 0.13), transitional zone index (OR 0.58), resistive index of prostatic artery (OR 0.46), bladder wall thickness (OR 0.78), ultrasonic estimation of bladder weight (OR 0.28), bladder outlet obstruction index (OR 0.20) and bladder contractility index (OR 0.83) were found to be protective factors. The areas under the curve of models using factors from ultrasonography and urodynamics were 0.792 and 0.829 respectively, with no significant difference being found between them (P = 0.348). CONCLUSIONS: Surgical efficacy of transurethral prostatectomy is positively correlated to severe voiding phase symptoms, outlet obstruction and better detrusor contractility, and negative correlated with urinary infection, severe storage phase symptoms and excessive detrusor contractibility. Ultrasonography might replace urodynamics in selecting patients for whom transurethral prostatectomy is more likely to be beneficial. PMID- 26059610 TI - Regarding Paper "Stratified Fisher's exact test and its sample size calculation". PMID- 26059609 TI - 5-Thiocyanato-2'-deoxyuridine as a possible radiosensitizer: electron-induced formation of uracil-C5-thiyl radical and its dimerization. AB - In this work, we have synthesized 5-thiocyanato-2'-deoxyuridine (SCNdU) along with the C6-deuterated nucleobase 5-thiocyanatouracil (6-D-SCNU) and studied their reactions with radiation-produced electrons. ESR spectra in gamma irradiated nitrogen-saturated frozen homogeneous solutions (7.5 M LiCl in H2O or D2O) of these compounds show that electron-induced S-CN bond cleavage occurs to form a thiyl radical (dU-5-S or 6-D-U-5-S) and CN(-)via the initial pi-anion radical (SCNdU(-)) intermediate in which the excess electron is on the uracil base. HPLC and LC-MS/MS studies of gamma-irradiated N2-saturated aqueous solutions of SCNdU in the presence of sodium formate as a OH-radical scavenger at ambient temperature show the formation of the dU-5S-5S-dU dimer in preference to dU by about 10 to 1 ratio. This shows that both possible routes of electron induced bond cleavage (dUC5-SCN and S-CN) in SCNdU(-) and dU-5-S formation are preferred for the production of the sigma-type uracilyl radical (dU) by 10 fold. DFT/M06-2x/6-31++G(d,p) calculations employing the polarizable continuum model (PCM) for aqueous solutions show that dU-5-S and CN(-) formation was thermodynamically favored by over 15 kcal mol(-1) (DeltaG) compared to dU and SCN(-) production. The activation barriers for C5-S and S-CN bond cleavage in SCNdU(-) amount to 8.7 and 4.0 kcal mol(-1), respectively, favoring dU-5-S and CN(-) formation. These results support the experimental observation of S-CN bond cleavage by electron addition to SCNdU that results in the formation of dU-5-S and the subsequent dU-5S-5S-dU dimer. This establishes SCNdU as a potential radiosensitizer that could cause intra- and inter-strand crosslinking as well as DNA-protein crosslinking via S-S dimer formation. PMID- 26059611 TI - Disimpaction of children with severe constipation in 3-4 days in a suburban clinic using polyethylene glycol with electrolytes and sodium picosulphate. AB - AIM: Constipation is a common cause of admission to hospital for disimpaction, as oral laxatives are often inadequate. High-dose oral laxative protocols are used for complete bowel clearance prior to colonoscopy, but have not been reported for treating faecal impaction. The aim of this study was to assess the effectiveness of a high-dose oral protocol using polyethylene glycol with electrolytes (PEG + E) (Movicol Rx) combined with sodium picosulphate (SP) (Dulcolax SP Rx) in faecal impaction in children presenting to a suburban clinic. METHODS: Forty-four children presented with acute/chronic faecal impaction were given six to eight sachets of PEG + E were given on day 1, with decreasing doses on subsequent 3 days, while 15-20 SP drops were given on days 2 and 3. Compliance with medication was achieved using a simple method of motivation, with the child drinking the laxatives in a race. On day 4, PEG + E was reduced to one sachet and SP to 10 drops as an ongoing maintenance dose. Defecation, soiling, diet and water intake was monitored daily for 7 days in a diary. RESULTS: Forty-four children (aged 2 17 years) seen over 8 months were reviewed retrospectively. Children began defecating within 10-12 h reaching a maximum volume of stool/day (four cups) on day 2. All patients were disimpacted successfully and in the week following disimpaction there was no reported faecal soiling or complications. CONCLUSIONS: A high-dose oral protocol combining PEG + E sachets and SP drops successfully and safely disimpacted a cohort of children with acute/chronic constipation presenting to a suburban continence clinic. This protocol appears to be useful to control faecal disimpaction in an outpatient setting, thereby avoiding hospital admission. PMID- 26059612 TI - Predicting positive mental health in internally displaced persons in Indonesia: the roles of economic improvement and exposure to violent conflict. AB - Positive mental health, rather than just the absence of mental illness, is rarely investigated among the internally displaced persons (IDPs) affected by violent conflict in low-income countries. The purpose of this study was to investigate a model that could explain the interrelationship between factors contributing to positive mental health in displaced populations. In a longitudinal study we examine poverty, exposure to traumatic events and the change of material well being after one year. We collected data in two consecutive years (2005 and 2006) from a community-based sample of IDPs in Ambon, Indonesia, through face-to-face structured interviews with consenting adults. Participants of this study were IDPs lived in Ambon during the violent conflict period. We interviewed 471 IDPs in the first year and reinterviewed 399 (85%) of the same subjects in the second year. The IDPs possessed good sense of coherence and subjective well-being. Our final model, which was generated by the use of structural equation modeling, fits the data well (chi(2) = 52.51, df = 45, p = .21, CFI = .99, RMSEA = .019). Exposure to violent conflict had a negative impact on IDPs' mental health initially and better economic conditions improved it (r = -.30 and .29 respectively). Mental health status one year previously was a strong predictor of future mental health, followed by individual economic growth in the past year (r = .43 and .29 respectively). On a group level the IDPs were resilient and adaptive to survive in adverse living conditions after devastating violent conflict, and the economic improvement contributed to it. PMID- 26059613 TI - Achilles tendinopathy in elderly subjects with type II diabetes: the role of sport activities. AB - BACKGROUND: Exercise is an important therapeutic tool in the management of diabetes in older people. Aim of this study was to assess the relationship among type II diabetes, sport, overweight, and symptomatic Achilles tendinopathy in elderly subjects. METHODS: Thirty-eight patients suffering from Achilles tendinopathy and thirty-eight controls were enrolled. The prevalence of diabetes and sport practice as well as BMI and Glycated Hemoglobin (HbA1c) values were registered. An ultrasound evaluation of Achilles tendon was performed. RESULTS: Patients showed an increased prevalence of diabetes (42 vs. 13.1 %, p = 0.004), and practice of sport (60.5 vs. 28.9 %, p = 0.0001), and higher BMI values (26.8 +/- 3 vs. 24.8 +/- 2.3, p = 0.001). Sonographic abnormalities, being diagnostic criteria, were present in all the patients with Achilles tendinopathy, but signs of degeneration were also found in 36.8 % of asymptomatic controls. Symptomatic subjects with diabetes, compared to those without, showed a higher prevalence of severe degeneration (75 vs. 36.3 %, p = 0.01). HbA1c values were significantly lower in sport practitioners, both diabetics and non-diabetics. Moreover, patients practicing sport showed a trend towards lower BMI values, compared to the sedentary counterpart. CONCLUSIONS: Sport practice in elderly diabetics provides relevant metabolic advantages, reducing HbA1c and BMI. However, some sport activities (e.g., speed walking, jogging or tennis) can expose to the risk of Achilles tendinopathy. So, sport practice should be encouraged, but practitioners should follow individual training programs and be submitted to periodic sonographic controls. PMID- 26059614 TI - Latent tuberculosis infection as a target for tuberculosis control. PMID- 26059615 TI - Detection of bacteria and viruses in the pleural effusion of children and adults with community-acquired pneumonia. AB - AIM: To study the etiology and the utility of new molecular methods in the diagnosis of complicated pneumonia with empyema. MATERIALS & METHODS: Bacteria and viruses detection was performed by several traditional and molecular methods in the pleural fluid (PF) of 60 patients (38 children) with community-acquired pneumonia (CAP). RESULTS: Despite prior antimicrobial therapy in 49 (81.7%) CAP patients, an etiological diagnosis could be established in 41 (68.3%), 35 being (58.3%) Streptococcus pneumoniae. PF culture was positive in only 6 patients but each molecular test detected more than 82% of cases. CONCLUSION: Traditional culture methods have poor diagnostic sensitivity in PF because most CAP patients are under antimicrobial therapy when it is obtained. S. pneumoniae detection by molecular methods highly improves diagnosis. PMID- 26059616 TI - Antifungal activity of extracts and isolated compounds from Buchenavia tomentosa on Candida albicans and non-albicans. AB - AIM: This study aimed to evaluate the antifungal activity of Buchenavia tomentosa extract and bioactive compounds on six Candida species. MATERIALS & METHODS: The antimicrobial activity of extract was evaluated using standard strains and clinical isolates. Cytotoxicity was tested in order to evaluate cell damage caused by the extract. Extract was chemically characterized and the antifungal activity of its compounds was evaluated. RESULTS: Extract showed antifungal activity on Candida species. Candida non-albicans were more susceptible than Candida albicans. Low cytotoxicity for extract was observed. The isolated compounds presented antifungal activity at least against one Candida spp. and all compounds presented antifungal effect on Candida glabrata. CONCLUSION: Extracts from Buchenavia tomentosa showed promising antifungal activity on Candida species with low cytotoxicity. Gallic acid, corilagin and ellagic acid showed promising inhibitory activity on Candida glabrata. PMID- 26059617 TI - Antimicrobial chitosan nanodroplets: new insights for ultrasound-mediated adjuvant treatment of skin infection. AB - BACKGROUND: Chronic wounds, characterized by hypoxia, inflammation and impaired tissue remodeling, are often worsened by bacterial/fungal infections. Intriguingly, chitosan-shelled/decafluoropentane-cored oxygen-loaded nanodroplets (OLNs) have proven effective in delivering oxygen to hypoxic tissues. AIM: The present work aimed at investigating nanodroplet antimicrobial properties against methicillin-resistant Staphylococcus aureus (MRSA) or Candida albicans, toxicity on human keratinocytes (HaCaT) and ultrasound (US)-triggered transdermal delivery. MATERIALS & METHODS: Nanodroplet antibacterial/antifungal properties, human cytotoxicity, and US-triggered transdermal delivery were measured through microbiological, biochemical, and sonophoresis assays, respectively. RESULTS: OLNs and oxygen-free nanodroplets (OFNs) displayed short- or long-term cytostatic activity against MRSA or Candida albicans, respectively. OLNs were not toxic to keratinocytes, whereas OFNs slightly affected cell viability. Complementary US treatment promoted OLN transdermal delivery. CONCLUSION: As such, US-activated chitosan-shelled OLNs appear as promising, nonconventional and innovative tools for adjuvant treatment of infected chronic wounds. PMID- 26059618 TI - 5'-UTR of malS increases the invasive capacity of Salmonella enterica serovar Typhi by influencing the expression of bax. AB - AIM: An RNA-seq analysis recently identified a 236-nucleotide transcript upstream from malS in Salmonella enterica serovar Typhi. Here, we investigated its molecular characteristics and function. MATERIALS & METHODS: RACE and northern blotting were used to determine the molecular characteristics of the sequence, and mutagenesis, microarray, immunoblotting and an invasion assay were used to investigate the functions of the transcript. RESULTS: The transcript was identified as the malS 5'-untranslated region (UTR), which could influence the expression of the flagellar and SPI-1 genes and the invasion of HeLa cells by S. Typhi. Deletion of bax increased the expression of the invasion genes and the invasive capacity of S. Typhi, whereas the expression of the malS 5'-UTR reduced the expression of bax. CONCLUSION: The malS 5'-UTR reduces the expression of bax and increases the invasive capacity of S. Typhi. PMID- 26059621 TI - Residual risk of hepatocellular carcinoma after HCV eradication: more than meets the eye. AB - Eradication of HCV in patients with advanced liver fibrosis or cirrhosis reduces, but does not altogether abolish, the risk of development of hepatocellular carcinoma. The reasons underlying this residual risk remain elusive. Even if HCV clearance eliminates its direct and indirect carcinogenic effects, the persistence of cirrhosis and the possible coexistence of metabolic factors (diabetes, obesity and insulin resistance) and of alcohol abuse can promote the development of hepatocellular carcinoma acting as autonomous, nonviral carcinogenic factors. Lessons learned in the IFN era may still assist in predicting the forthcoming scenario, when IFN-free regimens will obtain high rates of viral clearance even at the most advanced stages of liver disease. PMID- 26059619 TI - Composition, structure and function of the Helicobacter pylori cag pathogenicity island encoded type IV secretion system. AB - Many Gram-negative pathogens harbor type IV secretion systems (T4SS) that translocate bacterial virulence factors into host cells to hijack cellular processes. The pathology of the gastric pathogen Helicobacter pylori strongly depends on a T4SS encoded by the cag pathogenicity island. This T4SS forms a needle-like pilus, and its assembly is accomplished by multiple protein-protein interactions and various pilus-associated factors that bind to integrins followed by delivery of the CagA oncoprotein into gastric epithelial cells. Recent studies revealed the crystal structures of six T4SS proteins and pilus formation is modulated by iron and zinc availability. All these T4SS interactions are crucial for deregulating host signaling events and disease progression. New developments in T4SS functions and their importance for pathogenesis are discussed. PMID- 26059622 TI - Genetic variation in pattern recognition receptors: functional consequences and susceptibility to infectious disease. AB - Cells of the innate immune system are equipped with surface and cytoplasmic receptors for microorganisms called pattern recognition receptors (PRRs). PRRs recognize specific pathogen-associated molecular patterns and as such are crucial for the activation of the immune system. Currently, five different classes of PRRs have been described: Toll-like receptors, C-type lectin receptors, nucleotide-binding oligomerization domain-like receptors, retinoic acid-inducible gene I-like receptors and absent in melanoma 2-like receptors. Following their discovery, many sequence variants in PRR genes have been uncovered and shown to be implicated in human infectious diseases. In this review, we will discuss the effect of genetic variation in PRRs and their signaling pathways on susceptibility to infectious diseases in humans. PMID- 26059620 TI - Histoplasma capsulatum, lung infection and immunity. AB - Histoplasma capsulatum, an environmental fungus, is the most common endemic pulmonary mycosis in the USA. Disease is most frequently observed in immunocompromised patients living in endemic areas. We present the mechanisms of fungal recognition, innate immune response and adaptive immune response that lead to protection or exacerbation of disease. Current understanding of these mechanisms is the result of a continuing dialogue between clinical observations and murine studies. Mice are a powerful model to study the immune response to H. capsulatum alone or in the presence of immunomodulatory drugs. Vigilance for histoplasmosis should be exercised with novel immunosuppressive agents that target the important immune pathways identified here. PMID- 26059623 TI - Role of virulence factors on host inflammatory response induced by diarrheagenic Escherichia coli pathotypes. AB - Pathogens are able to breach the intestinal barrier, and different bacterial species can display different abilities to colonize hosts and induce inflammation. Inflammatory response studies induced by enteropathogens as Escherichia coli are interesting since it has acquired diverse genetic mobile elements, leading to different E. coli pathotypes. Diarrheagenic E. coli secrete toxins, effectors and virulence factors that exploit the host cell functions to facilitate the bacterial colonization. Many bacterial proteins are delivered to the host cell for subverting the inflammatory response. Hereby, we have highlighted the specific processes used by E. coli pathotypes, by that subvert the inflammatory pathways. These mechanisms include an arrangement of pro- and anti-inflammatory responses to favor the appropriate environmental niche for the bacterial survival and growth. PMID- 26059624 TI - Development of broad-spectrum antibiofilm drugs: strategies and challenges. AB - The severity of many chronic bacterial infections is mainly due to the biofilm mode of life adapted by pathogenic bacteria. The bacteria in biofilm-stage exhibit high resistance to host immune responses and antimicrobials, which complicates the treatment process and results in life threatening conditions. Most of the chronic infections are polymicrobial in nature. In order to combat the polymicrobial biofilm infections and to increase the efficiency of antimicrobials, there is an urgent need for broad-spectrum antibiofilm drugs. This review discusses the clinical needs and current status of broad-spectrum antibiofilm drugs with special emphasis on prospective strategies and hurdles in the process of new drug discovery. PMID- 26059625 TI - Healthcare-associated infections, infection control and the potential of new antibiotics in development in the USA. AB - ABSTRACT Healthcare-associated infections (HAIs) caused by drug-resistant Gram negative pathogens are a significant burden on the US healthcare system. This problem has been further compounded by the recent decline in the development of new antibiotics targeting Gram-negative organisms. US healthcare agencies have been working to limit the occurrence of HAIs by several means, including surveillance systems, prevention practices, antimicrobial stewardship policies and financial incentives. Furthermore, efforts have been made to resume the development of antibiotics in the USA, with the US FDA and US government both implementing acts to boost the number of antibiotics in the clinical pipeline. This review discusses the policies instigated by the US government, including healthcare agencies and the FDA, and describes new antibiotics in development against HAIs. PMID- 26059626 TI - The changing epidemiology of hospital outbreaks due to ESBL-producing Klebsiella pneumoniae: the CTX-M-15 type consolidation. AB - Klebsiella pneumoniae is responsible for a large number of hospital outbreaks. In the 1990s, there were clonal epidemics, affecting mostly intensive care patients, which carried SHV and TEM enzyme types. With the advent of CTX-M-15 enzymes in the 2000, plasmids encoding multiple extended-spectrum beta-lactamase (ESBL) types were described and, frequently, nosocomial outbreaks reported polyclonal dissemination and involved multiple Enterobacteriaceae. Worryingly, the interface between community and hospital is becoming blurred, and there is increasing evidence for the presence of ESBL-producing K. pneumoniae in the community. Furthermore, carbapenem resistance is increasingly reported in ESBL-producing K. pneumoniae strains. Infection control measures and stewardship programs are vital weapons in controlling the pandemic evolution of multidrug-resistant K. pneumoniae. PMID- 26059628 TI - Corrigendum. PMID- 26059627 TI - Paradoxical TB-IRIS in HIV-infected adults: a systematic review and meta analysis. AB - Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) was first described almost two decades ago. We undertook this systematic review and meta-analysis to collate findings across studies that have reported the incidence, clinical features, management and outcomes of paradoxical TB-IRIS. Forty studies that cumulatively reported 1048 paradoxical TB-IRIS cases were included. The pooled estimated incidence among patients with HIV-associated TB initiating antiretroviral therapy was 18% (95% CI: 16-21%). Frequent features were pulmonary and lymph node involvement. Hospitalization occurred in 25% (95% CI: 19-30%). In studies that reported treatment, corticosteroids were prescribed more frequently (38%; 95% CI: 27-48%) than nonsteroidal anti-inflammatory drugs (28%; 95% CI: 2-53%). Case fatality was 7% (95% CI: 4-11%), but death attributed to TB-IRIS occurred in 2% of cases (95% CI: 1-3%). PMID- 26059629 TI - Current Dermatologic Care in Dutch Nursing Homes and Possible Improvements: A Nationwide Survey. AB - OBJECTIVES: To assess the provision and need of dermatologic care among Dutch nursing home patients and to obtain recommendations for improvement. DESIGN: Cross-sectional nationwide survey. SETTING: All 173 nursing home organizations in the Netherlands. PARTICIPANTS: Physicians working in nursing homes. MEASUREMENTS: Web-based questionnaire concerning the burden of skin diseases in nursing home patients, diagnostic procedures and therapy, collaboration with dermatologists, physicians' level of education, and suggestions for improvement. RESULTS: A total of 126 (72.8%) nursing home organizations, with 1133 associated physicians participated in our study and received the questionnaire. A total of 347 physicians (30.6%) completed the questionnaire. Almost all respondents (99.4%) were recently confronted with skin diseases, mostly (pressure) ulcers, eczema, and fungal infections. Diagnostic and treatment options were limited because of a lack of availability and experience of the physicians. More live consultation of dermatologists was suggested as being important to improve dermatologic care. Other suggestions were better education, more usage of telemedicine applications, and better availability of diagnostic and/or treatment procedures like cryotherapy. CONCLUSION: Physicians in nursing homes are frequently confronted with skin diseases. Several changes in organization of care and education are expected to improve dermatologic care in nursing home patients. PMID- 26059630 TI - Comparative recruitment, morphology and reproduction of a generalist trematode, Dicrocoelium dendriticum, in three species of host. AB - Epidemiological rate parameters of host generalist parasites are difficult to estimate, especially in cases where variation in parasite performance can be attributed to host species. Such cases are likely common for generalist parasites of sympatric grazing mammals. In this study, we combined data from experimental exposures in cattle and sheep and natural infections in elk to compare the recruitment, morphology and reproduction of adult Dicrocoelium dendriticum, a generalist trematode that has emerged in sympatric grazing hosts in Cypress Hills Provincial Park, Alberta. Overall, there were no significant differences in the recruitment of metacercariae and in the pre-patency period of adults in experimentally exposed cattle and sheep. All flukes reached reproductive maturity and the degree of reproductive inequality between individual flukes within each infrapopulation was moderate and approximately equal among the three host species. Neither fluke size nor per capita fecundity was constrained by density dependence. Thus, fitness parameters associated with growth and reproduction were approximately equivalent among at least three species of definitive host, two of which are sympatric on pastures in this Park. The generalist life-history strategy of this trematode, which is known to extend to other stages of its life cycle, has likely contributed to its invasion history outside its native range in Europe. PMID- 26059631 TI - MicroRNA-125b-2 overexpression represses ectodermal differentiation of mouse embryonic stem cells. AB - microRNAs (miRNAs or miRS) have been demonstrated to be essential for neural development. miR-125b-2, presented on human chromosome 21, is overexpressed in neurons of individuals with Down syndrome (DS) with cognitive impairments. It has been reported that miR-125b-2 promotes specific types of neuronal differentiation; however, the function of miR-125b-2 in the early development of the embryo has remained to be fully elucidated. In the present study, a mouse embryonic stem cell (mESC) line was stably transfected with a miR-125b-2 lentiviral expression vector and found that miR-125b-2 overexpression did not affect the self-renewal or proliferation of mESCs. However, miR-125b-2 overexpression inhibited the differentiation of mESCs into endoderm and ectoderm. Finally, miR-125b-2 overexpression was found to impair all-trans-retinoic acid induced neuron development in embryoid bodies. The findings of the present study implied that miR-125b-2 overexpression suppressed the differentiation of mESCs into neurons, which highlights that miR-125b-2 is important in the regulation of ESC differentiation. The present study provided a basis for the further identification of novel targets of miR-125b-2, which may contribute to an enhanced understanding of the molecular mechanisms of ESC differentiation. PMID- 26059632 TI - MiR-506 Over-Expression Inhibits Proliferation and Metastasis of Breast Cancer Cells. AB - BACKGROUND: This study aimed to investigate the relationship between miR-506 and proliferation and migration of breast cancer cells. MATERIAL AND METHODS: MiR-506 mimics, inhibitor, and negative control (NC) were transfected into MDA-MB-231 breast cancer cells. Cell proliferation, cell counting, colony formation assay, and Transwell assay were applied to evaluate the proliferation and migration of breast cancer cells. Data are shown as mean +/- standard deviation and the experiment was performed 3 times. Statistical analyses were performed with SPSS version 10.0. RESULTS: At 1 day after transfection, cell proliferation detected by CCK-8 assay was significantly promoted in miR-506 inhibitor when compared with the miR-506 mimics group and the NC group (P<0.05). At 3 days or 5 days after transfection, cell proliferation was markedly inhibited in the miR-506 mimics group, and miR-506 inhibitor was still significantly promoted. Cell counting with a hemocytometer showed similar results to cell proliferation. Colony formation assay showed that the number of colonies in the miR-506 mimics group was significantly smaller than that in the miR-506 inhibitor group and NC group. Transwell assay revealed that the number of migrated cells in miR-506 mimics was markedly smaller than that in the miR-506 inhibitor group and NC group. CONCLUSIONS: MiR-506 over-expression significantly inhibits the proliferation, colony formation, and migration of breast cancer cells. miR-506 over-expression may thus be able to improve the malignant phenotype of breast cancer cells. PMID- 26059633 TI - Severe and enduring anorexia nervosa (SEED-AN): a qualitative study of patients with 20+ years of anorexia nervosa. AB - Little is known about how patients with long-term eating disorders manage their clinical problems. We carried out a preliminary qualitative study (using Thematic Analysis) of patients with severe and enduring anorexia nervosa (SEED-AN) in which we undertook recorded interviews in eight participants whose conditions had lasted 20-40 years. We found 15 principle features in physical, psychological, social, family, occupational and treatment realms. Psychological and social realms were most affected. Severe physical problems were reported. They described feelings of unworthiness, frugality regarding money and obsessive time-keeping. Persisting with negligible social networks, participants described depression and hopelessness, while somehow achieving a sense of pride at their endurance and survival in spite of the eating disorder. They emphasized the importance of professional help in managing their care. The severe and enduring description, often reserved for people with psychotic illness, is appropriately applied to SEED-AN, which has major impacts in all realms. PMID- 26059634 TI - Muscle activation patterns in the Nordic hamstring exercise: Impact of prior strain injury. AB - This study aimed to determine: (a) the spatial patterns of hamstring activation during the Nordic hamstring exercise (NHE); (b) whether previously injured hamstrings display activation deficits during the NHE; and (c) whether previously injured hamstrings exhibit altered cross-sectional area (CSA). Ten healthy, recreationally active men with a history of unilateral hamstring strain injury underwent functional magnetic resonance imaging of their thighs before and after six sets of 10 repetitions of the NHE. Transverse (T2) relaxation times of all hamstring muscles [biceps femoris long head (BFlh); biceps femoris short head (BFsh); semitendinosus (ST); semimembranosus (SM)] were measured at rest and immediately after the NHE and CSA was measured at rest. For the uninjured limb, the ST's percentage increase in T2 with exercise was 16.8%, 15.8%, and 20.2% greater than the increases exhibited by the BFlh, BFsh, and SM, respectively (P < 0.002 for all). Previously injured hamstring muscles (n = 10) displayed significantly smaller increases in T2 post-exercise than the homonymous muscles in the uninjured contralateral limb (mean difference -7.2%, P = 0.001). No muscles displayed significant between-limb differences in CSA. During the NHE, the ST is preferentially activated and previously injured hamstring muscles display chronic activation deficits compared with uninjured contralateral muscles. PMID- 26059635 TI - Frequency of surgery and hospital admissions for communicable diseases in a high- and middle-income setting. AB - BACKGROUND: In high-income countries, non-communicable diseases drive the demand for surgical healthcare. Middle-income countries face a double disease burden, of both communicable and non-communicable disease. The aim of this study was to describe the role of surgery for the in-hospital care of infectious conditions in the high-income country Sweden and the middle-income country South Africa. METHODS: A retrospective cohort study was performed of 1.4 million infectious disease admissions. The study populations were the entire population of Sweden, and a cohort of 3.5 million South Africans with private healthcare insurance, during a 7-year interval. The outcome measures were frequency of surgical procedures across a spectrum of diseases, and sex and age during the medical care event. RESULTS: Some 8.1 per cent of Swedish and 15.7 per cent of South African hospital admissions were because of infectious disease. The proportion of infectious disease admissions that were associated with surgery was constant over time: 8.0 (95 per cent c.i. 7.9 to 8.1) per cent in Sweden and 21.1 (21.0 to 21.2) per cent in South Africa. The frequency of surgery was 2.6 (2.6 to 2.7) times greater in South Africa, and 2.2 (2.2 to 2.3) times higher after standardization for age, sex and disease category. CONCLUSION: The study suggests that surgical care is required to manage patients with communicable diseases, even in high-income settings with efficient prevention and functional primary care. These results further stress the importance of scaling up functional surgical health systems in low- and middle-income countries, where the disease burden is distinguished by infectious disease. PMID- 26059636 TI - Seasonal variation in detection of oesophageal eosinophilia and eosinophilic oesophagitis. AB - BACKGROUND: Seasonal variation has been reported in diagnosis of eosinophilic oesophagitis (EoE), but results are not consistent across studies and there are no national-level data in the USA. AIM: To determine if there is seasonal variation in diagnosis of oesophageal eosinophilia and EoE in the USA, while accounting for factors such as climate zone and geographic variation. METHODS: This was a cross-sectional study using a USA national pathology database. Patients with oesophageal eosinophilia (>=15 eosinophils per high-power field) comprised the primary case definition and were compared to those with normal oesophageal biopsies. We calculated the crude and adjusted odds of oesophageal eosinophilia by season, as well as by day of the year. Sensitivity analyses were performed using more restrictive case definitions of EoE, and after stratification by climate zone. RESULTS: Exactly, 14 524 cases with oesophageal eosinophilia and 90 459 normal controls were analysed. The adjusted odds of oesophageal eosinophilia were higher in the late spring and summer months, with the highest odds in July (aOR: 1.13; 95% CI: 1.03-1.24). These findings persisted with increasing levels of oesophageal eosinophilia, as well as across EoE case definitions. Seasonal variation was strongest in temperate and cold climates, and peak diagnosis varied by climate zone. CONCLUSIONS: There is a mild but consistent seasonal variation in the diagnosis of oesophageal eosinophilia and EoE, with cases more frequently diagnosed during summer months. These findings take into account climate and geographic differences, suggesting that aeroallergens may contribute to disease development or flare. PMID- 26059637 TI - A key role for TGF-beta1 in hippocampal synaptic plasticity and memory. AB - Transforming Growth Factor beta1 (TGF-beta1) is a well-known neuroprotective and neurotrophic factor demonstrated to play a role in synaptic transmission. However, its involvement in physiological mechanisms underlying synaptic plasticity and memory at hippocampal level has not been thoroughly investigated. Here, we examine the role of TGF-beta1 in hippocampal long-term potentiation (LTP) and memory in adult wild type mice. Our data provide evidence that administration of exogenous TGF-beta1 is able to convert early-phase-LTP into late-phase-LTP. Furthermore, we show that the block of the endogenous TGF-beta1 signaling pathway by the specific TGF-beta1 inhibitor SB431542, impairs LTP and object recognition memory. The latter impairment was rescued by administration of exogenous TGF-beta1, suggesting that endogenously produced TGF-beta1 plays a role in physiological mechanisms underlying LTP and memory. Finally, TGF-beta1 functional effect correlates with an increased expression of the phosphorylated transcription factor cAMP-Responsive Element Binding protein. PMID- 26059638 TI - Collagen and prostaglandin E2 regulate aromatase expression through the PI3K/AKT/IKK and the MAP kinase pathways in adipose stromal cells. AB - Excessive local estrogen production in the breast promotes estrogen-dependent breast cancer. Aromatase is a key enzyme in estrogen biosynthesis. Aromatase inhibitors used in the treatment of breast cancer are very effective, but indiscriminately reduce estrogen synthesis in all tissues, causing major side effects. It is thus desirable to develop inhibitors that selectively block aromatase and estrogen production in breast cancer. To this end, it is important to identify the mechanisms by which aromatase is activated in the tumor microenvironment. Prostaglandin E2 (PGE2) and collagen are two important factors in the tumor microenvironment, which contribute to tumor development and progression. In this study, we show that collagen-induced aromatase expression in adipose stromal cells (ASCs) was significantly reduced by inhibitors of phosphatidylinositide 3-kinase (PI3K), IkappaB kinase (IKK), mitogen-activated protein kinase kinase (MEK), c-Jun NH2-terminal kinase (JNK), protein kinase A (PKA), and by the knockdown of the JunB and AKT2 genes. In addition, PGE2-induced aromatase expression was significantly inhibited by inhibitors of IKK, MEK, JNK, p38 and PKA. These results indicate that the PI3K/AKT/IKK and the mitogen activated protein (MAP) kinase pathways are involved in collagen- and PGE2 induced aromatase expression, and also suggest that collagen and PGE2-induced signaling pathways may crosstalk in regulating aromatase expression. This study enhances our understanding on the mechanism of regulation of aromatase expression by collagen and PGE2. Furthermore, this study provides a theoretical foundation for the development of specific inhibitors of aromatase by exploiting the signaling pathways identified herein in the context of breast cancer. PMID- 26059639 TI - Insecticide applications to soil contribute to the development of Burkholderia mediating insecticide resistance in stinkbugs. AB - Some soil Burkholderia strains are capable of degrading the organophosphorus insecticide, fenitrothion, and establish symbiosis with stinkbugs, making the host insects fenitrothion-resistant. However, the ecology of the symbiotic degrading Burkholderia adapting to fenitrothion in the free-living environment is unknown. We hypothesized that fenitrothion applications affect the dynamics of fenitrothion-degrading Burkholderia, thereby controlling the transmission of symbiotic degrading Burkholderia from the soil to stinkbugs. We investigated changes in the density and diversity of culturable Burkholderia (i.e. symbiotic and nonsymbiotic fenitrothion degraders and nondegraders) in fenitrothion-treated soil using microcosms. During the incubation with five applications of pesticide, the density of the degraders increased from less than the detection limit to around 10(6)/g of soil. The number of dominant species among the degraders declined with the increasing density of degraders; eventually, one species predominated. This process can be explained according to the competitive exclusion principle using V(max) and K(m) values for fenitrothion metabolism by the degraders. We performed a phylogenetic analysis of representative strains isolated from the microcosms and evaluated their ability to establish symbiosis with the stinkbug Riptortus pedestris. The strains that established symbiosis with R. pedestris were assigned to a cluster including symbionts commonly isolated from stinkbugs. The strains outside the cluster could not necessarily associate with the host. The degraders in the cluster predominated during the initial phase of degrader dynamics in the soil. Therefore, only a few applications of fenitrothion could allow symbiotic degraders to associate with their hosts and may cause the emergence of symbiont-mediated insecticide resistance. PMID- 26059640 TI - Uptake, release, and absorption of nutrients into the marine environment by the green mussel (Perna viridis). AB - The nutrient uptake and release by the mussels in relation with amount of food consumption are emphasised in this research. Results of the study demonstrate that about 16% of the total mass dry weight food consumed by the mussels was released as faeces. The depositions of particulate carbon, nitrogen, and phosphorus in mussel faeces were found to be 26.3, 5.7, and 0.6mg/day/indv respectively. Soluble inorganic nutrients such as NH4(+)-N (2.5mg/day/indv), and PO4(3-)-P (0.6mg/day/indv) were also released as mussel excretion. The nutrient absorption efficiency for the green mussel body was found to be 65.1% for carbon, 62.1% for nitrogen, and 79.2% for phosphorus. Subsequently, green mussels can remove particulate carbon, nitrogen and phosphorus at 108.1, 13.5, and 4.6mg/day/indv from aquatic systems. Finally, the results can help in estimating the carrying capacity of mussel cultivation without deteriorating the water quality in marine ecosystems. PMID- 26059641 TI - Physical controls of hypoxia in waters adjacent to the Yangtze Estuary: A numerical modeling study. AB - A three-dimensional circulation model (the Environmental Fluid Dynamic Code) was used to examine the role that physical forcing (river discharge, wind speed and direction) plays in controlling hypoxia in waters adjacent to the Yangtze Estuary. The model assumes that the biological consumption of oxygen is constant in both time and space, which allows the role of physical forcing in modulating the oxygen dynamics to be isolated. Despite of the simplicity of this model, the simulation results showed that it can reproduce the observed variability of dissolved oxygen in waters adjacent to the Yangtze Estuary, thereby highlighting the important role of changes in physical forcing in the variation of hypoxia. The scenarios tested revealed appreciable changes in the areal extent of hypoxia as a function of wind speed and wind direction. Interestingly, well-developed hypoxia was insensitive to river discharge. PMID- 26059642 TI - Rapid deterioration of sediment surface habitats in Bellingham Bay, Washington State, as indicated by benthic foraminifera. AB - Foraminiferal assemblages in sediment grab samples were utilized to evaluate the impacts of anthropogenic activities on benthic habitats in Bellingham Bay, Washington State, U.S.A. Seventy-three samples taken in 1987, 1997, 2006 and 2010 yielded 35 species of foraminifera from 28 genera. Assemblage composition and diversity data indicate a marked deterioration between 1987 and 2010, contrary to the published Chemical Index, but analogous to the situation with macrobiota. Correlation of diversity with chemical pollutants and metals did not identify any significant correlations, however, an unrelated but highly relevant study of bottom water dissolved oxygen concentrations and pH in Bellingham Bay suggests eutrophication with accompanying hypoxia and acidification may be part of the cause. Thus, the metrics of contamination alone do not adequately characterize habitat viability, and benthic foraminiferal assemblages provide insight into the health of coastal ecosystems. PMID- 26059643 TI - The art of perception: Patients drawing their vestibular schwannoma. AB - OBJECTIVES/HYPOTHESIS: Drawings made by patients are an innovative way to assess the perceptions of patients on their illness. The objective of this study, at a university tertiary referral center, on patients who have recently been diagnosed with vestibular schwannoma, was to examine whether patients' illness perceptions can be assessed by drawings and are related to their quality of life. STUDY DESIGN: Cross-sectional study. METHODS: Patients diagnosed with vestibular schwannoma (mean age [range], 55.4 [17-85] years) between April 2011 and October 2012 were included (N = 253). Sociodemographics, illness perceptions (Brief Illness Perception Questionnaire [B-IPQ]), and disease-specific quality of life (Penn Acoustic Neuroma Quality of Life [PANQOL] scale) were assessed to evaluate the impact of being diagnosed with vestibular schwannoma. Furthermore, patients' drawings of their tumor were analyzed to explore the association between illness perceptions, drawings, and quality of life. RESULTS: Comparison of the B-IPQ scores of the current sample (N = 139; response rate 54.9%) with other disease samples shows a significantly lower score for patients with vestibular schwannoma on the Coherence dimension, indicating a low understanding of the illness. Illustration of emotions (N = 12) in the drawings gave a negative association with quality of life. Intercorrelations indicate a positive association between a low amount of physical and emotional consequences of the illness and a higher score on the Balance, Hearing, and Energy dimensions of the PANQOL. CONCLUSIONS: Patients' drawings give an insight into their perception of the tumor inside their head. Use of drawings may be helpful when developing and offering self management programs. Quality of life appears to be significantly affected by the diagnosis. LEVEL OF EVIDENCE: 4. PMID- 26059644 TI - Guest Editorial: The Professional Status of European Chemists and Chemical Engineers. AB - Which country pays its chemists and chemical engineers the highest salaries? Where can I find a new job quickest? Which chemical sub-discipline offers most jobs? Reliable answers for these and other questions have been derived from the first European employment survey for chemists and chemical engineers, which was carried out in 2013. Here we publish the first general evaluation of the results of this survey. PMID- 26059645 TI - A field survey of the partially edentate elderly: Investigation of factors related to the usage rate of removable partial dentures. AB - Although the shortened dental arch (SDA) concept has been known to all over the world, acceptance of the SDA concept as an oral health standard can be questionable from the patients' point of view, even if it is biologically reasonable. Furthermore, because the health insurance system covers removable partial dentures (RPDs) for all citizens in Japan, SDA patients seem to prefer to receive prosthetic treatment to replace the missing teeth. However, there were few field surveys to investigate the usage rate of RPDs in Japan. The purpose of this study was to determine the usage rate of RPDs in older Japanese subjects and to investigate the factors related to the usage of RPDs. Partially edentate participants (n = 390) were included in this study. Oral examinations were conducted to record several indices. The Cochran-Armitage trend test was used to evaluate the relationship between the number of missing teeth and the usage rate of RPDs. Chi-squared tests and logistic regression analysis were conducted to evaluate the factors related to the usage rate of RPDs. Usage of RPDs had a significantly positive association with the number of missing distal extension teeth and bilaterally missing teeth. The usage rate of RPDs increased as the number of missing distal extension teeth increased (P for trend < 0.001). The conclusion of this study was that participants with missing distal extension teeth had higher usage rates of RPDs than other participants, and the usage rate increased as the number of missing distal extension teeth increased. PMID- 26059646 TI - Generating Correlated, Non-normally Distributed Data Using a Non-linear Structural Model. AB - An approach to generate non-normality in multivariate data based on a structural model with normally distributed latent variables is presented. The key idea is to create non-normality in the manifest variables by applying non-linear linking functions to the latent part, the error part, or both. The algorithm corrects the covariance matrix for the applied function by approximating the deviance using an approximated normal variable. We show that the root mean square error (RMSE) for the covariance matrix converges to zero as sample size increases and closely approximates the RMSE as obtained when generating normally distributed variables. Our algorithm creates non-normality affecting every moment, is computationally undemanding, easy to apply, and particularly useful for simulation studies in structural equation modeling. PMID- 26059647 TI - Relationship Between Genital Drug Concentrations and Cervical Cellular Immune Activation and Reconstitution in HIV-1-Infected Women on a Raltegravir Versus a Boosted Atazanavir Regimen. AB - Determinants of HIV-infected women's genital tract mucosal immune health are not well understood. Because raltegravir (RAL) achieves relatively higher genital tract concentrations than ritonavir-boosted atazanavir (ATV), we examined whether an RAL-based regimen is associated with improved cervical immune reconstitution and less activation in HIV(+) women compared to an ATV-based regimen. Peripheral blood, cervical brushings, cervical-vaginal lavage (CVL), and cervical biopsies were collected from HIV(+) women on tenofovir disoproxil fumarate and emtricitabine (TDF/FTC) and either RAL (n=14) or ATV (n=19) with CD4(+) T cells>300 cells/mm(3) and HIV RNA<48 copies/ml. HLA-DR(+)CD38(+) T cells were measured in blood and cervical cells using flow cytometry, CD4(+) and CD8(+) T cells were quantified in cervical biopsies by immunofluorescent analysis, and HIV RNA (VL), ATV, and RAL concentrations were measured in CVL. In a linear regression model of log(CVL concentration) versus both log(plasma concentration) and treatment group, the RAL CVL level was 519% (95% CI: 133, 1,525%) higher than for ATV (p<0.001). Genital tract VL was undetectable in 90% of subjects and did not differ by regimen. There were no significant differences between groups in terms of cervical %HLA-DR(+)CD38(+)CD4(+) or CD8(+) T cells, CD4(+) or CD8(+) T cells/mm(2), or CD4:CD8 ratio. After adjusting for treatment time and group, the CVL:plasma drug ratio was not associated with the cervical CD4:CD8 ratio or immune activation (p>0.6). Despite significantly higher genital tract penetration of RAL compared to ATV, there were no significant differences in cervical immune activation or reconstitution between women on these regimens, suggesting both drug regimens achieve adequate genital tract levels to suppress virus replication. PMID- 26059648 TI - Abdominal cellulitis: dreadful clinical consequence after skin branding. PMID- 26059649 TI - Effectiveness of management models for facilitating self-management and patient outcomes in adults with diabetes and chronic kidney disease. AB - BACKGROUND: Self-management models can be a very powerful resource in the health system provided they are well tailored to a particular disease and setting. Patient outcomes have been demonstrated to improve when self-management practices are embedded in the care of people with certain diseases. However, it remains unclear whether self-management models and specific components of these programmes can be implemented in order to effectively improve the care of people with diabetes and/or chronic kidney disease. METHODS/DESIGN: Medline (including Medline in-process), Excerpta medica database (EMBASE), Cumulative Index to Nursing and Allied Health (CINAHL) and all evidence-based medicine (EBM) will be systematically searched for randomised controlled studies comparing self management models with usual care in patients with diabetes or chronic kidney disease. Two reviewers will independently assess articles for eligibility: extract data, evaluate risk of bias and complete quality assessment of included studies. The data will be tabulated and narratively synthesised. Meta-analyses will be performed if there is sufficient homogenous data. DISCUSSION: This protocol utilises rigorous methodology as well as pre-specified eligibility criteria to comprehensively search for diabetes and kidney disease self management models which have been compared with usual care in randomised controlled trials. The review is likely to provide insight into the effectiveness of current models for improving patient self-management, and this may address the key translational issue of how to integrate and tailor these self-management practices for patients with diabetes and chronic kidney disease. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015017316. PMID- 26059650 TI - Risk Prediction for Local Breast Cancer Recurrence Among Women with DCIS Treated in a Community Practice: A Nested, Case-Control Study. AB - BACKGROUND: Various patient, treatment, and pathologic factors have been associated with an increased risk of local recurrence (LR) following breast conserving therapy (BCT) for ductal carcinoma in situ (DCIS). However, the strength and importance of individual factors has varied; whether combining factors improves prediction, particularly in community practice, is uncertain. In a large, population-based cohort of women with DCIS treated with BCT in three community-based practices, we assessed the validity of the Memorial Sloan Kettering Cancer Center (MSKCC) DCIS nomogram, which combines clinical, pathologic, and treatment features to predict LR. METHODS: We reviewed slides of patients with unilateral DCIS treated with BCT. Regression methods were used to estimate risks of LR. The MSKCC DCIS nomogram was applied to the study population to compare the nomogram-predicted and observed LR at 5 and 10 years. RESULTS: The 495 patients in our study were grouped into quartiles and octiles to compare observed and nomogram-predicted LR. The 5-year absolute risk of recurrence for lowest and highest quartiles was 4.8 and 33.1 % (95 % CI 3.1-6.4 and 24.2-40.9, respectively; p < 0.0001). The overall correlation between 10-year nomogram predicted recurrences and observed recurrences was 0.95. Compared with observed 10-year LR rates, the risk estimates provided by the nomogram showed good correlation, and reasonable discrimination with a c-statistic of 0.68. CONCLUSIONS: The MSKCC DCIS nomogram provided good prediction of the 5- and 10 year LR when applied to a population of patients with DCIS treated with BCT in a community-based practice. This nomogram, therefore, is a useful treatment decision aid for patients with DCIS. PMID- 26059651 TI - Management and Outcomes of Patients with Recurrent Intrahepatic Cholangiocarcinoma Following Previous Curative-Intent Surgical Resection. AB - BACKGROUND: Management and outcomes of patients with recurrent intrahepatic cholangiocarcinoma (ICC) following curative-intent surgery are not well documented. We sought to characterize the treatment of patients with recurrent ICC and define therapy-specific outcomes. METHODS: Patients who underwent surgery for ICC from 1990 to 2013 were identified from an international database. Data on clinicopathological characteristics, operative details, recurrence, and recurrence-related management were recorded and analyzed. RESULTS: A total of 563 patients undergoing curative-intent hepatic resection for ICC who met the inclusion criteria were identified. With a median follow-up of 19 months, 400 (71.0 %) patients developed a recurrence. At initial surgery, treatment was resection only (98.8 %) or resection + ablation (1.2 %). Overall 5-year survival was 23.6 %; 400 (71.0 %) patients recurred with a median disease-free survival of 11.2 months. First recurrence site was intrahepatic only (59.8 %), extrahepatic only (14.5 %), or intra- and extrahepatic (25.7 %). Overall, 210 (52.5 %) patients received best supportive care (BSC), whereas 190 (47.5 %) patients received treatment, such as systemic chemotherapy-only (24.2 %) or repeat liver directed therapy +/- systemic chemotherapy (75.8 %). Repeat liver-directed therapy consisted of repeat hepatic resection +/- ablation (28.5 %), ablation alone (18.7 %), and intra-arterial therapy (IAT) (52.8 %). Among patients who recurred, median survival from the time of the recurrence was 11.1 months (BSC 8.0 months, systemic chemotherapy-only 16.8 months, liver-directed therapy 18.0 months). The median survival of patients undergoing resection of recurrent ICC was 26.7 months versus 9.6 months for patients who had IAT (p < 0.001). CONCLUSIONS: Recurrence following resection of ICC was common, occurring in up to two-thirds of patients. When there is recurrence, prognosis is poor. Only 9 % of patients underwent repeat liver resection after recurrence, which offered a modest survival benefit. PMID- 26059652 TI - Postoperative Morbidity and Mortality Rates are Not Increased for Patients with Gastric and Gastroesophageal Cancer Who Undergo Preoperative Chemoradiation Therapy. AB - BACKGROUND: This study aimed to determine whether postoperative morbidity and mortality rates increased after preoperative chemoradiation in patients who underwent gastrectomy. METHODS: The medical records of 7404 patients with gastric or gastroesophageal cancer seen from January 1995 to August 2012 were reviewed to identify patients who underwent gastrectomy. chi (2) and logistic regression analysis were used to determine differences in the 90-day postoperative morbidity and mortality rates of patients who underwent upfront surgery (SURG), preoperative chemotherapy (CHEMO), or preoperative chemoradiation (CHEMOXRT). RESULTS: Of the 500 patients included in this study, 200 underwent SURG, 65 had CHEMO, and 235 had CHEMOXRT. Respectively, 33, 43, and 58 % of these patients underwent total gastrectomy (p < 0.01). Resection of other organs was performed respectively in 19, 26, and 23 % of the patients (p = 0.37). Minor complications within 90 days (Clavien-Dindo 1 or 2) occurred for 41 % of the SURG patients, 43 % of the CHEMO patients, and 45 % of the CHEMOXRT patients (p = 0.68). Major complications or death within 90 days (Clavien-Dindo 3, 4, or 5) occurred for 21, 28, and 29 % of the patients, respectively (p = 0.15). The 90-day mortality (Clavien-Dindo 5) rates were 2 % for the SURG patients, 6 % for the CHEMO patients, and 3 % for the CHEMOXRT patients (p = 0.25). The median hospital stays were respectively 12, 12, and 13 days (p = 0.09). In the multivariate analysis, male sex, gastroesophageal junction cancer, total gastrectomy, and resection of other organs were associated with increased major morbidity and mortality rates, whereas preoperative therapy was not. CONCLUSIONS: The CHEMOXRT patients had postoperative morbidity and mortality rates similar to those for the SURG and CHEMO patients. PMID- 26059653 TI - Totally Laparoscopic Hepatic Bisegmentectomy (s4b+s5) and Hilar Lymphadenectomy for Incidental Gallbladder Cancer. AB - BACKGROUND: Gallbladder cancer is suspected preoperatively in only 30 % of all patients, while the remaining 70 % of cases are discovered incidentally by the pathologist. The increasing rate of cholecystectomies via laparoscopy has led to the detection of more gallbladder cancers in an early stage, and extended resection with regional lymph node dissection has been suggested. We present a video of a totally laparoscopic liver resection (segments 5 and 4b) with regional lymphadenectomy in a patient with an incidental gallbladder cancer. METHODS: A 50 year-old woman underwent laparoscopic cholecystectomy, and pathology revealed a T1b gallbladder carcinoma. The patient was referred for further treatment. Contact with the primary surgeon revealed that no intraoperative cholangiogram was performed, and the gallbladder was removed intact, with no perforation, and inside a plastic retrieval bag. Pathology revision confirmed T1b, and positron emission tomography/computed tomography was negative. The multidisciplinary tumor board recommended radical re-resection, and a decision was made to perform a laparoscopic extended hilar lymphadenectomy, along the resection of segments 5 and 4b. RESULTS: Operative time was 5 h, with an estimated blood loss of 240 mL. Recovery was uneventful and the patient was discharged on the fourth postoperative day. Final pathology showed no residual disease and no lymph node metastasis. CONCLUSIONS: Laparoscopic resection of liver segments 5 and 4b combined with a locoregional lymphadenectomy of the hepatoduodenal ligament is an oncologically appropriate technique, provided it is performed in a specialized center with experience in hepatobiliary surgery and advanced laparoscopic surgery. This video may help oncological surgeons to perform this complex procedure. PMID- 26059654 TI - Comparison of Lower Extremity Edema in Locally Advanced Cervical Cancer: Pretreatment Laparoscopic Surgical Staging with Tailored Radiotherapy Versus Primary Radiotherapy. AB - BACKGROUND: This study investigated the clinical manifestations of lower extremity edema (LEE) in locally advanced cervical cancer patients treated with two different strategies. METHODS: In total, 79 cervical cancer survivors with International Federation of Gynecology and Obstetrics stage IB2-IIB were included. Six survivors with stage IB1 and who had been suspicious for lymph node metastasis on pretreatment image also were included. Forty-two patients received radiotherapy after pretreatment laparoscopic surgical staging (Group 1), and 43 patients received primary radiotherapy (Group 2). The patients' medical records and survey results of the Korean version of the Gynecologic Cancer Lymphedema Questionnaire (GCLQ-K) were analyzed. RESULTS: The incidence of LEE was higher in Group 1 than in Group 2 (69.0 vs. 11.6 %; P < 0.001). The duration of LEE was longer in Group 1 (mean 77.3 vs. 9.4 months). At the time of survey, 47.6 % of the patients in Group 1 were clinically diagnosed with lymphedema compared with no patients in Group 2. In GCLQ-K, the mean symptom cluster scores for general swelling (0.74 vs. 0.09; P < 0.001), limb swelling (0.22 vs. 0.00; P = 0.006), and heaviness (0.45 vs. 0.23; P = 0.033) were significantly higher in Group 1. One patient in Group 1 developed lymphedema-related angiosarcoma that was diagnosed at 7.8 years after surgery. CONCLUSIONS: Patients with cervical cancer who underwent radiotherapy after laparoscopic surgical staging more commonly experienced LEE and related symptoms than patients who underwent primary radiotherapy. As LEE decreases patients' quality of life, it should be considered during patient consultation and surveillance. PMID- 26059656 TI - Species composition of coastal dune vegetation in Scotland has proved resistant to climate change over a third of a century. AB - Climate change is expected to have an impact on plant communities as increased temperatures are expected to drive individual species' distributions polewards. The results of a revisitation study after c. 34 years of 89 coastal sites in Scotland, UK, were examined to assess the degree of shifts in species composition that could be accounted for by climate change. There was little evidence for either species retreat northwards or for plots to become more dominated by species with a more southern distribution. At a few sites where significant change occurred, the changes were accounted for by the invasion, or in one instance the removal, of woody species. Also, the vegetation types that showed the most sensitivity to change were all early successional types and changes were primarily the result of succession rather than climate-driven changes. Dune vegetation appears resistant to climate change impacts on the vegetation, either as the vegetation is inherently resistant to change, management prevents increased dominance of more southerly species or because of dispersal limitation to geographically isolated sites. PMID- 26059657 TI - Cholesterol-rich lipid rafts play an important role in the Cyprinid herpesvirus 3 replication cycle. AB - The Cyprinus herpesvirus 3 (CyHV-3) is a member of the new Alloherpesviridae virus family in the Herpesvirales order. CyHV-3 has been implicated in a large number of disease outbreaks in carp populations causing up to 100% mortality. The aim of this study was to investigate the requirement of cholesterol-rich lipid rafts in CyHV-3 entry and replication in carp cells. Plasma membrane cholesterol was depleted from common carp brain (CCB) cells with methyl-beta-cyclodextrin (MbetaCD). Treated and non-treated cells were infected with CyHV-3 and virus binding and infection parameters were assessed using RT-qPCR, immunocytochemistry and virus titration. The effect of cholesterol reduction severely stunted virus entry in vitro, however after cholesterol replenishment virus entry and subsequent replication rates were similar to the control infection. Furthermore, cholesterol depletion did not significantly influence virus binding and the subsequent post-entry replication stage, however had an impact on virus egress. Comparative analysis of the lipid compositions of CyHV-3 and CCB membrane fractions revealed strong similarities between the lipid composition of the CyHV 3 and CCB lipid rafts. The results presented here show that cholesterol-rich lipid rafts are important for the CyHV-3 replication cycle especially during entry and egress. PMID- 26059655 TI - Network topology and functional connectivity disturbances precede the onset of Huntington's disease. AB - Cognitive, motor and psychiatric changes in prodromal Huntington's disease have nurtured the emergent need for early interventions. Preventive clinical trials for Huntington's disease, however, are limited by a shortage of suitable measures that could serve as surrogate outcomes. Measures of intrinsic functional connectivity from resting-state functional magnetic resonance imaging are of keen interest. Yet recent studies suggest circumscribed abnormalities in resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease, despite the spectrum of behavioural changes preceding a manifest diagnosis. The present study used two complementary analytical approaches to examine whole-brain resting-state functional magnetic resonance imaging connectivity in prodromal Huntington's disease. Network topology was studied using graph theory and simple functional connectivity amongst brain regions was explored using the network-based statistic. Participants consisted of gene negative controls (n = 16) and prodromal Huntington's disease individuals (n = 48) with various stages of disease progression to examine the influence of disease burden on intrinsic connectivity. Graph theory analyses showed that global network interconnectivity approximated a random network topology as proximity to diagnosis neared and this was associated with decreased connectivity amongst highly-connected rich-club network hubs, which integrate processing from diverse brain regions. However, functional segregation within the global network (average clustering) was preserved. Functional segregation was also largely maintained at the local level, except for the notable decrease in the diversity of anterior insula intermodular-interconnections (participation coefficient), irrespective of disease burden. In contrast, network-based statistic analyses revealed patterns of weakened frontostriatal connections and strengthened frontal posterior connections that evolved as disease burden increased. These disturbances were often related to long-range connections involving peripheral nodes and interhemispheric connections. A strong association was found between weaker connectivity and decreased rich-club organization, indicating that whole brain simple connectivity partially expressed disturbances in the communication of highly-connected hubs. However, network topology and network-based statistic connectivity metrics did not correlate with key markers of executive dysfunction (Stroop Test, Trail Making Test) in prodromal Huntington's disease, which instead were related to whole-brain connectivity disturbances in nodes (right inferior parietal, right thalamus, left anterior cingulate) that exhibited multiple aberrant connections and that mediate executive control. Altogether, our results show for the first time a largely disease burden-dependent functional reorganization of whole-brain networks in prodromal Huntington's disease. Both analytic approaches provided a unique window into brain reorganization that was not related to brain atrophy or motor symptoms. Longitudinal studies currently in progress will chart the course of functional changes to determine the most sensitive markers of disease progression. PMID- 26059658 TI - Socio-demographic predictors of sleep complaints in indigenous Siberians with a mixed economy. AB - OBJECTIVES: Socio-demographic indicators closely relate to sleep in industrialized populations. However we know very little about how such factors impact sleep in populations undergoing industrialization. Within populations transitioning to the global economy, the preliminary evidence has found an inconsistent relationship between socio-demographics and sleep complaints across countries and social strata. MATERIALS AND METHODS: Surveys were conducted on a sample of rural Sakha (Yakut) adults (n = 168) during the autumn of 2103 to assess variation in socio-demographics and sleep complaints, including trouble sleeping and daytime sleepiness. Socio-demographic variables included age, gender, socioeconomic measures, and markers of traditional/market-based lifestyle. We tested whether the socio-demographic variables predicted sleep complaints using bivariate analyses and multiple logistic regressions. RESULTS: Trouble sleeping was reported by 18.5% of the participants and excessive daytime sleepiness (EDS) by 17.3%. Trouble sleeping was significantly predicted by older age, female gender, and mixing traditional and market-based lifestyles. EDS was not significantly predicted by any socio-demographic variable. DISCUSSION: These findings support the few large-scale studies that found inconsistent relationships between measures of socioeconomic status and sleep complaints in transitioning populations. Employing a mix of traditional and market-based lifestyles may leave Sakha in a space of vulnerability, leading to trouble sleeping. PMID- 26059659 TI - Bruton's tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. AB - Inflammasome activation has been implicated in various inflammatory diseases including post-ischaemic inflammation after stroke. Inflammasomes mediate activation of caspase-1, which subsequently induces secretion of pro-inflammatory cytokines such as IL-1beta and IL-18, as well as a form of cell death called pyroptosis. In this study, we report that Bruton's tyrosine kinase (BTK) is an essential component of the NLRP3 inflammasome, in which BTK physically interacts with ASC and NLRP3. Inhibition of BTK by pharmacological or genetic means severely impairs activation of the NLRP3 inflammasome. The FDA-approved BTK inhibitor ibrutinib (PCI-32765) efficiently suppresses infarct volume growth and neurological damage in a brain ischaemia/reperfusion model in mice. Ibrutinib inhibits maturation of IL-1beta by suppressing caspase-1 activation in infiltrating macrophages and neutrophils in the infarcted area of ischaemic brain. Our study indicates that BTK is essential for NLRP3 inflammasome activation and could be a potent therapeutic target in ischaemic stroke. PMID- 26059661 TI - Persistent Bacillus Calmette-Guerin Reaction: A Potential Clue to Underlying Immune Deficiency. AB - Bacillus Calmette-Guerin (BCG) vaccine complications in patients with severe combined immunodeficiency (SCID) have been well documented in the literature. We present a case in which the BCG vaccine was administered to an infant who was later diagnosed with SCID and presented with worsening localized BCG reaction upon arrival in the United States. Although the BCG vaccine is not routinely administered in the United States, it is important for physicians to be aware of potential complications of BCG vaccination since prompt treatment can be lifesaving. PMID- 26059660 TI - Relevance of Foxp3+ regulatory T cells for early and late phases of murine sepsis. AB - The role of Foxp3(+) regulatory T (Treg) cells in the course of the early hyper inflammatory and subsequent hypo-inflammatory phases of sepsis is ambiguous. Whereas Nrp1 expression has been reported to discriminate natural Treg cells from induced Treg cells, the Treg cell stability depends on the methylation status of foxp3-TSDR. To specifically evaluate the role of Foxp3(+) Treg cells in the early and late phases of sepsis, we induced sepsis by caecal ligation and puncture and subsequent Pseudomonas aeruginosa lung infection in a DEREG (DEpletion of REGulatory T cells) mouse model. We found an increase of Foxp3(+) Treg cells to all CD4(+) T cells during murine sepsis. Using a new methylation-sensitive quantitative RT-PCR method and deep amplicon sequencing, we demonstrated that natural (Nrp1(+) Foxp3(+) ) Treg cells and most induced (Nrp1(-) Foxp3(+) ) Treg cells are stable and exhibit unmethylated foxp3-TSDR, and that both Treg populations are functionally suppressive in healthy and septic mice. DEREG mice depleted of Foxp3(+) Treg cells exhibit higher disease scores, mortality rates and interleukin-6 expression levels than do non-depleted DEREG mice in early phase sepsis, a finding indicating that Foxp3(+) Treg cells limit the hyper inflammatory response and accelerate recovery. Treg cell depletion before secondary infection with P. aeruginosa 1 week after caecal ligation and puncture does not influence cytokine levels or the course of secondary infection. However, a moderate Treg cell recurrence, which we observed in DEREG mice during secondary infection, may interfere with these results. In summary, Treg cells contribute to a positive outcome after early-phase sepsis, but the data do not support a significant role of Treg cells in immune paralysis during late-phase sepsis. PMID- 26059662 TI - Comparison of augmented superior rectus transposition with medial rectus recession for surgical management of esotropic Duane retraction syndrome. AB - BACKGROUND: Medial rectus recession (MRc) and vertical rectus transpositions are procedures used to treat esotropic Duane retraction syndrome. Recently superior rectus transposition (SRT) combined with MRc has also been shown to improve primary alignment and abduction. The purpose of this study is to compare the results of augmented (ie, with scleral fixation) SRT with or without MRc with either unilateral or bilateral MRc for treatment of esotropic Duane syndrome. METHODS: The medical records of patients who underwent surgery for esotropic Duane syndrome between May 2007 and February 2013 were retrospectively reviewed. Success was defined as alignment within 8(Delta) of orthotropia and abnormal head posture of <5 degrees . RESULTS: There were 8 patients in the SRT group (6 of whom had additional ipsilateral MRc) and 13 in the MRc group (6 unilateral and 7 bilateral). In the SRT group, the mean preoperative deviation was 20(Delta) of esotropia; the mean postoperative deviation, 3(Delta). In the MRc group, the mean preoperative deviation was 24(Delta) of esotropia; the mean postoperative deviation, 4(Delta). The success rate was 87% in the SRT group; 77%, in MRc group (P = 0.98). Mean abduction limitation improved from -3.6 to -2.4 units in the SRT group and from -3.6 to -3.3 units in the MRc group (P = 0.003). Induced vertical deviation or subjective torsion was not seen. Three patients in each group developed adduction limitation postoperatively. CONCLUSIONS: Although both the procedures successfully correct esotropia in Duane syndrome, SRT with or without MRc has the additional advantage of improving abduction. PMID- 26059663 TI - Eye muscle surgery for recurrent nystagmus related to head tilt after prior torsional surgery. AB - PURPOSE: To describe the usefulness of anterior nasal transposition of the inferior oblique muscle in the fixing eye to treat nystagmus-mediated head tilt recurring after prior torsional surgery. METHODS: The medical records of patients who underwent anterior nasal transposition of the inferior oblique muscle in the fixing eye to treat recurrence of head tilt after prior successful torsional surgery were retrospectively reviewed. RESULTS: Three patients met inclusion criteria. In all 3 patients head tilt was eliminated after inferior oblique anterior nasal transposition with 2, 5, and 9.5 years' follow-up. In no case did surgery result in any further intorsion of the eye. We postulate that the surgery was successful by stabilizing the normal compensatory and anticompensatory torsional movements that occur with head tilt. CONCLUSIONS: Anterior nasal transposition of the inferior oblique muscle effectively treats a recurrent nystagmus-mediated head tilt after prior successful torsional surgery. It does not, however, intort the eye further in this clinical setting and must work via a different mechanism. PMID- 26059664 TI - Canalicular laceration repair using a viscoelastic injection to locate and dilate the proximal torn edge. AB - BACKGROUND: Canalicular lacerations are common complications of eyelid trauma in the pediatric population. Irrigating air, water, and colored or viscous agents through the intact canaliculus have been suggested to identify the torn proximal edge. We report our experience in repairing canalicular lacerations using a novel viscoelastic injection technique with a Monoka monocanalicular stent. METHODS: The medical records of patients <18 years of age who underwent repair of a canalicular laceration with a monocanalicular stent using superficial viscoelastic deployment to locate the torn canaliculus were retrospectively reviewed. Demographics, cause of eyelid injury, surgical management using our novel viscoelastic injection technique, and outcome were analyzed. RESULTS: A total of 38 children with lid lacerations were identified, of whom the 17 with canalicular involvement were included (mean age, 6.27 years). Canalicular injury in these 17 was due to dog bite (9 patients) and shearing trauma (8 patients). In 11 patients, the injury was located in the lower lid; in 4, the upper lid; and in 2, combined upper and lower lids. All patients had good anatomic repair and on follow-up had negative dye disappearance tests and were free of tearing. CONCLUSIONS: Deploying viscoelastic superficially near, and injecting into the injured canaliculus can improve visualization of the operative field by retracting the surrounding tissue and tamponading any bleeding, which aids in location and dilation of the torn canaliculus initially and in subsequent steps, eases intubation into the lubricated torn canaliculus and nasolacrimal duct, and avoids iatrogenic injury to an uninjured canaliculus. PMID- 26059665 TI - Initial management of congenital canalicular atresia. AB - PURPOSE: To evaluate the initial management of pediatric patients with lacrimal canalicular atresia (CA) involving the upper or lower eyelid. METHODS: The medical records of 15 children with symptoms of nasolacrimal duct (NLD) obstruction and CA of either the upper or lower eyelid treated from 1994 to 2014 were retrospectively reviewed. Surgical treatment consisted of nasolacrimal probing through the patent canaliculus. Preoperative findings, treatment, and outcomes were reviewed. Outcomes were considered good if the patients had resolution of signs and symptoms of lacrimal obstruction, fair if the symptoms improved and additional surgery was not required, and poor if additional lacrimal surgery was performed. RESULTS: CA was found in 19 eyes of 15 patients: 11 eyes had upper CA; 8 eyes, lower. All 11 eyes with upper CA improved after NLD probing through the patent lower canaliculus. Of the 8 eyes with lower CA, 4 (50%) had good outcomes and 4 eyes had poor outcomes after NLD probing through the patent upper canaliculus. All of the latter patients improved after subsequent treatment with balloon catheter dilation (BCD), monocanalicular stent placement, or both. CONCLUSIONS: If a patient is found to have upper CA during initial surgery for NLD obstruction, NLD probing through the patent lower canaliculus has a good rate of surgical success. For patients with lower CA, the success rate of NLD probing through the upper canaliculus appears to be lower. Additional treatment during the initial surgery with either BCD or monocanalicular stent placement should be considered in these patients. PMID- 26059666 TI - Treatment of retinopathy of prematurity in Northern Ireland, 2000-2011: a population-based study. AB - PURPOSE: To evaluate the incidence of treatment-requiring retinopathy of prematurity (ROP) over a 12-year-period in Northern Ireland. METHODS: The medical records of all infants treated for ROP from January 2000 to December 2011 were retrospectively reviewed and cross-referenced with the Neonatal Intensive Care Outcomes Research and Evaluation (NICORE) database. RESULTS: The Northern Ireland population data showed an increase in the number of live births from 2000 to 2011. The proportion of babies born with a birth weight <1501 g and/or <32 weeks' gestational age remained constant (chi(2) trend = 3.220, P = 0.0727), although the proportion of these babies who died prior to 42 weeks' gestation decreased from 2000 to 2011 (P = 0.0196 using chi(2) for trend = 5.445; P = 0.0354 using chi(2) = 20.809). The prevalence of treatment-requiring ROP in these infants increased from 1.05% in 2000 to 5.78% in 2011 (P < 0.001 using chi(2) trend = 16.309; P < 0.001 using chi(2) = 31.378). CONCLUSIONS: The present population based study highlights that the incidence of treatment- requiring ROP is increasing in Northern Ireland. The increasing number of infants requiring treatment will need to be taken into consideration in the commissioning process for ROP services in Northern Ireland. PMID- 26059667 TI - Corneal collagen crosslinking in children with keratoconus. AB - PURPOSE: To report the visual, refractive, and tomographic outcomes of corneal collagen crosslinking (CXL) in pediatric patients with keratoconus. METHODS: The medical records of patients <= 18 years of age treated with corneal collagen cross-linking from December 2009 to August 2013 were retrospectively reviewed, and the following data were collected at baseline, 3 months, 6 months, and 1 year for all patients and at 2 and 3 years where available: uncorrected- and best corrected visual acuity, spherical equivalent, cylinder, and tomographic findings. RESULTS: A total of 25 eyes of 14 patients (11 males) were included. Mean age at surgery was 16.2 +/- 1.6 years (range, 13-18). Mean uncorrected visual acuity was 0.53 +/- 0.32 logMAR at baseline and 0.46 +/- 0.36 logMAR at 1 year (P = 0.07). Mean preoperative best-corrected visual acuity was 0.3 +/- 0.26 logMAR, which improved to 0.15 +/- 0.12 logMAR at 1 year (P = 0.01). Baseline spherical equivalent and cylinder values were unchanged at 1 year. Mean baseline Kmax, Kmin, and Kmean values were 49.62 +/- 4.5 D, 44.68 +/- 3.5 D, and 46.3 +/- 2.84 D, respectively; these values were stable at 1 year (P > 0.05). At 1 year, compared with preoperative Kmax values, 5 eyes (20%) showed regression; 13 eyes (52%), stabilization; and 7 eyes (18%), progression. There was a significant reduction in the mean thinnest corneal area from baseline (473.6 +/- 37.68 MUm) to 6 months (424.55 +/- 70.2 MUm), but this recovered at 1 year (452.82 +/- 53.5 MUm). There were no significant postoperative complications. CONCLUSIONS: In this patient cohort CXL effectively stabilized uncorrected visual acuity, refractive indices, and keratometry values at 1 year, while improving best-corrected visual acuity. PMID- 26059668 TI - The accuracy of anterior segment optical coherence tomography (AS-OCT) in localizing extraocular rectus muscles insertions. AB - PURPOSE: To evaluate the accuracy of the anterior segment optical coherence tomography (AS-OCT) in measuring the distance from the limbus to the insertion of primary and previously operated rectus muscles in children. METHODS: In this prospective, double masked, observational study the distance of the extraocular muscle insertion from the limbus measured by AS-OCT preoperatively was compared to intraoperative measurement using the surgical calipers. Consecutive patients 4 18 years of age undergoing primary or repeat strabismus surgery on horizontal or vertical rectus muscles between September 2013 and May 2014 were included. Patients with any condition that interfered with imaging were excluded. Participants were asked to look in the direction opposite to the muscle to ensure that the middle third of the muscle was being imaged and measured. RESULTS: A total of 65 muscles were evaluated, including 9 muscles undergoing reoperation and 10 vertical rectus muscles. Of these, 62 muscles were successfully imaged. In all reoperated eyes, the AS-OCT measurements were within 1 mm of the intraoperative measurements. Overall, 89.7% (95% CI, 78.8%-96.1%) of the measurements were within the 1 mm difference considered "clinically acceptable." The intraclass correlation coefficient comparing the reliability of the AS-OCT measurements with intraoperative measurements was 0.73 (95% CI, 0.53-0.85), or "good" agreement. CONCLUSIONS: AS-OCT can accurately detect rectus muscle insertions in primary or previously operated cases in children as young as 4 years of age. PMID- 26059669 TI - Choroidal thickness of children's eyes with anisometropic and strabismic amblyopia. AB - PURPOSE: To compare the choroidal thickness of children's eyes with amblyopia due to strabismus or anisometropia to the fellow eye and age-matched controls. METHODS: Forty patients with anisometropic amblyopia, 40 patients with strabismic amblyopia, and 40 age-matched controls were included in this cross-sectional study. Choroidal thickness was measured via the enhanced-depth imaging technique of spectral domain optical coherence tomography in all patients and controls. Choroidal thickness was measured at subfoveal area and at 500 MUm intervals to the nasal and temporal to the fovea up to 2000 MUm. Measurements were compared between the three groups. RESULTS: The mean ages were 7.9 +/- 2.6 years (range, 4 13 years) in the anisometropic group, 9.0 +/- 3.7 (range 4-15 years) years in the strabismic group, and 8.4 +/- 2.6 years (range 4-15 years) in the control group. The mean subfoveal choroidal thickness in the anisometropic group was 362 +/- 82 MUm in the amblyopic eyes and 301 +/- 54 MUm in the fellow eyes; in the strabismic group, 413 +/- 82 MUm in the amblyopic eyes and 316 +/- 54 MUm in the fellow eyes. The mean subfoveal choroidal thickness was 310 +/- 78 MUm in control eyes. The subfoveal choroids of both anisometropic and strabismic amblyopic eyes were significantly thicker than that of the fellow eyes of the corresponding groups and the control eyes (P < 0.05 for all). CONCLUSIONS: The subfoveal choroid of eyes with anisometropic and strabismic amblyopia is significantly thicker than that of the fellow eye and the age-matched controls. PMID- 26059670 TI - Evaluation of Artisan aphakic intraocular lens in cases of pediatric aphakia with insufficient capsular support. AB - PURPOSE: To evaluate the visual outcomes and complications after Artisan iris claw lens implantation in aphakic children with insufficient capsular support. METHODS: In this prospective, interventional noncontrolled study, aphakic eyes of consecutive patients >2 years of age with insufficient capsular support who underwent Artisan intraocular lens (IOL) implantation between June 2011 and December 2012 were followed for 1 year. Patients with anterior chamber depth <3 mm, central endothelial cell density (CECD) <2500 cells/mm(2), uncontrolled glaucoma, or uveitis were excluded. Best-corrected visual acuity, intraocular pressure (IOP), and CECD were measured at 1, 6, and 12 months postoperatively. RESULTS: A total of 25 aphakic eyes of 18 patients (mean age, 7.86 +/- 3.08 years) with insufficient capsular support for a standard posterior chamber IOL were included, 18 eyes with subluxated lens and 7 following trauma. The mean preoperative logMAR best-corrected visual acuity for traumatic aphakic patients was 0.95 +/- 0.36; for patients with subluxation, 0.7 +/- 0.26. Values improved at 1 year to 0.38 +/- 0.15 (P < 0.002) and 0.3 +/- 0.2 (P < 0.0001), respectively. One year after surgery the CECD (2892.64 +/- 441.79 cells/mm(2)) was significantly reduced from the preoperative and 1 month postoperative values (3573.36 +/- 468.9 cells/mm(2), 3081 +/- 495 cells/mm(2); P < 0.0001, P < 0.02 resp.). Two cases (8%) developed traumatic dislocation. Pupillary block occurred in 1 case (4%). CONCLUSIONS: Artisan IOL implantation for pediatric aphakia achieved a good visual outcome. PMID- 26059671 TI - Postoperative shift in ocular alignment following single vertical rectus recession on adjustable suture in adults without thyroid eye disease. AB - PURPOSE: To determine whether overcorrection shifts occur after vertical rectus recession on adjustable suture in the absence of thyroid eye disease. METHODS: The medical records of patients without thyroid eye disease who underwent vertical rectus recession surgery from 2001 to 2008 were retrospectively reviewed for shifts in alignment between suture adjustment at postoperative day 1 and 2 months' follow-up. Superior rectus and inferior rectus recessions were compared. In addition, we compared the use of a nonabsorbable polyester suture to an absorbable polyglactin 910 suture in nonthyroid patients undergoing inferior rectus recessions. RESULTS: A total of 59 patients were included (superior rectus, 30; inferior rectus, 29). We found a mean undercorrection shift of 1.1 (range, 17.5(Delta) undercorrection to 16(Delta) overcorrection) and 1.0(Delta) (range, 12(Delta) undercorrection shift to 6(Delta) overcorrection shift) for superior and inferior rectus recessions, respectively, between 1 day and 2 months postoperatively. CONCLUSIONS: There was no trend toward overcorrection following unilateral vertical rectus adjustable suture recessions in patients without thyroid eye disease, suggesting that thyroid myopathy may account for overcorrection shifts seen with this surgery. PMID- 26059672 TI - Causes of visual impairment in children seen at a university-based hospital low vision service in Brazil. AB - PURPOSE: To evaluate the epidemiologic characteristics of patients 0-7 years of age with visual impairment registered at a university hospital low vision service in Brazil. METHODS: The medical records of visually impaired patients were retrospectively reviewed for sociodemographic characteristics and ocular and associated deficiencies. In addition to biographical information, the following data were collected: ocular disorders, diagnosis, affected anatomic region, etiology, and avoidable or unavoidable causes. RESULTS: A total of 229 patients were included, 65% of whom were referred from rural health centers. The mean age at first appointment was 39.4 months. Associated nonophthalmic disorders were present in 47% of patients. The most prevalent disorders were congenital cataract (14%), toxoplasmosis (14%), and congenital glaucoma (13%). The most commonly affected anatomic regions were the retina (18%) and lens (15%); 33% had a normal appearing globe. Using World Health Organization classifications, the most prevalent underlying etiologies were undetermined (43%), perinatal/neonatal factors (22%), and intrauterine factors (20%). Avoidable causes were found in 64% of the children. CONCLUSIONS: The three leading causes of infant blindness in our patient cohort were congenital cataract, toxoplasmosis, and congenital glaucoma. The most commonly affected anatomic regions were retina, lens, and normal appearing globe. The percentage of avoidable causes of impairment was high and the mean age at first appointment was late. PMID- 26059673 TI - Using liquid crystal glasses to treat ambyopia in children. AB - PURPOSE: To evaluate the effectiveness of liquid crystal glasses (LCG) in the treatment of children with monocular amblyopia. METHODS: A total of 14 amblyopic eyes of 14 children with monocular amblyopia were enrolled in the study. LCG with appropriate refractive correction were ordered for each patient. Each patient was examined with the new LCG before treatment and monthly thereafter. The parents were informed about the use, care, and charging of the glasses. Best-corrected visual acuity was measured as Snellen decimal notation and converted to logarithm of the minimum angle of resolution (logMAR) for statistical analyses. RESULTS: The mean age of the study population was 7.4 +/- 1.4 years. Ten patients (71%) had anisometropic amblyopia; 2 (14%), strabismic amblyopia; and 2 (14%), mixed amblyopia. The mean follow-up period was 4.0 +/- 1.2 months (range, 3-7 months). The mean duration of using LCG was 8.2 +/- 2.5 hours daily (range, 4-12 hours). All of 14 patients used the LCG as suggested. The mean logMAR best-corrected visual acuity of the amblyopic eyes was 0.6 +/- 0.3 at baseline, improving to 0.3 +/- 0.2 at final follow-up (P < 0.001). No side effects were observed. CONCLUSIONS: The current study demonstrated that LCG wear improved visual acuity in children with monocular amblyopia. Additional studies are needed to determine whether this effect is due to the LCG on/off feature or to refractive correction alone. PMID- 26059674 TI - Trends in the incidence and causes of severe visual impairment and blindness in children from Israel. AB - PURPOSE: To describe trends in the incidence and causes of legal childhood blindness in Israel, one of the few countries worldwide that maintain a national registry of the blind. METHODS: We performed a historical cohort study of annual reports of the National Registry of the Blind (NRB) between 1999 and 2013. All data regarding demographic information, year of registration and cause of blindness of children 0-18 years of age registered for blind certification were obtained from the annual reports of the NRB. Causes of legal blindness analyzed were optic atrophy, retinitis pigmentosa, retinopathy of prematurity (ROP), albinism, other retinal disorders, cataract, and glaucoma. The main outcome measure was the incidence of new cases of certified legal blindness. RESULTS: The incidence of newly registered legally blind children in Israel almost halved from 7.7 per 100,000 in 1999 to 3.1 per 100,000 in 2013. The decline was mainly attributable to a decreased incidence of blindness resulting from retinitis pigmentosa and ROP. The incidence of registered cases due to cerebral visual impairment increased. CONCLUSIONS: During the past decade the incidence of severe childhood visual impairment and blindness declined in Israel. A continuous decline in consanguineous marriages among the Jewish and Arab populations in Israel may have contributed to the decrease in the rate of vision loss due to retinitis pigmentosa in children. PMID- 26059675 TI - Inferior oblique recession in thyroid-related orbitopathy. AB - Thyroid-related orbitopathy is a form of orbital inflammation associated with thyroid dysfunction, developing in many patients with Graves disease. Fibrosis of the inferior rectus muscle can lead to restricted elevation and vertical ocular misalignment, which may be improved by recessing this muscle. In some patients, vertical misalignment persists after surgical weakening of one or more vertical rectus muscles. In this case series, unilateral inferior oblique recession as a secondary procedure after inferior rectus recession reduced hypertropia in primary gaze from 9(Delta) +/- 3(Delta) to 1.3(Delta) +/- 1.5(Delta) (mean +/- standard deviation) and largest hypertropia in side gaze from 18.3 +/- 2.1(Delta) to 3.3(Delta) +/- 1.5(Delta). Postoperatively, all 3 patients were diplopia free in primary and downgaze. PMID- 26059676 TI - Peters anomaly in cri-du-chat syndrome. AB - The cri-du-chat syndrome is a rare genetic disorder caused by deletions in the short arm of chromosome 5. It presents with a distinctive catlike high-pitched cry, psychomotor delays, microcephaly, craniofacial abnormalities, and, in many cases, ocular findings. We report the first child with cri-du-chat and the findings of unilateral corneal staphyloma due to Peters anomaly and retinal dysplasia. PMID- 26059677 TI - Cyclic strabismus in adults. AB - Cyclic strabismus is a rare condition that usually occurs in children and is characterized by alternating intervals of straight and strabismic eyes. In adults with the condition, strabismus surgery often eliminates the cycles. We report a case of adult-onset cyclic esotropia that was converted into a cyclic exotropia. PMID- 26059678 TI - Surgical treatment of familial absence of the inferior rectus muscle. AB - Familial inferior rectus muscle aplasia is rare. Patients with this condition require surgery to correct hypertropia and anomalous head posture. We report successful surgical outcomes in a father with bilateral and his 2 children with unilateral absent inferior rectus muscle, all 3 of whom were diagnosed preoperatively by imaging. PMID- 26059679 TI - Anesthesia in young children. PMID- 26059680 TI - Reply: To PMID 25456031. PMID- 26059681 TI - Unilateral strabismus surgery in patients with exotropia results in postoperative lateral incomitance. PMID- 26059682 TI - Reply: To PMID 25498465. PMID- 26059683 TI - The effect of identical word pairs on people's metamemory judgments: What are the contributions of processing fluency and beliefs about memory? AB - Judgments of learning (JOLs) are higher for identical pairs (dog-dog) than for related pairs (dog-cat). This identical effect may be mediated (a) by processing fluency (i.e., identical pairs are processed faster than related pairs) or (b) by a belief that identical pairs are better remembered or (c) by both factors. In the present work, we assessed the contribution of both factors. We evaluated whether a measure of processing fluency (i.e., self-paced study) mediated the relationship between pair type and JOLs (Experiment 1) and attempted to disrupt processing fluency using an AlTeRnAtInG presentation format (Experiment 2). We also evaluated whether judgments made in the absence of processing fluency demonstrated the identical effect (Experiment 3), and, finally, we had participants read a vignette about an experiment that included both pair types and estimate which pairs would be best remembered (Experiment 4). Evidence from all experiments converged on the conclusion that people's beliefs about how variables affect memory--and not differential fluency--best explain the identical effect, although we cannot entirely rule out the possibility that fluency plays a small role. The outcomes were consistent with the analytic-processing theory of JOLs--namely, when instructed to make JOLs, people adopt an analytic problem solving approach that involves identifying variation across pairs that plausibly relate to memory and then use this variation to make JOLs. PMID- 26059685 TI - Three-dimensional micro/nanoscale architectures: fabrication and applications. AB - Three-dimensional (3D) functional solids with programmable hierarchical micro/nanoarchitectures are critical for several fundamental applications, including structural composites, microfluidics, photonics, and tissue engineering. Due to the broad range of application possibilities, a large amount of effort has been devoted to the in-depth exploration of various top-down and bottom-up strategies to construct these complex multi-dimensional structures. In this review, we introduce and discuss selected examples of fabrication techniques which have successfully developed large area, novel 3D functional architectures with exquisite control over their morphology at the nano/subnanolevel. Emphasis is placed on the nanofabrication techniques, their salient features as well as advantages. A summary of the emerging application possibilities of such structures, especially in biomedicine, energy, and device construction, is also discussed. PMID- 26059684 TI - Caring for acutely unwell older residents in residential aged-care facilities: Perspectives of staff and general practitioners. AB - AIM: To explore the challenges and facilitators of managing acutely unwell residents in their residential aged-care facilities (RACF) and transferring RACF residents to the emergency department of a tertiary referral hospital in Australia. METHODS: This exploratory study used a qualitative descriptive approach incorporating structured focus group interviews with nursing staff from RACFs and General Practitioners (GPs) within the local area. Four focus groups were held with staff from RACFs and one with GPs who visited one or more of the facilities during 2010. The interview data were analysed for themes relating to the study aims. RESULTS: Findings revealed both challenges and facilitators associated with managing acutely unwell older people including, communication, nursing staffing mix and numbers, use of advanced care directives, responsibilities of GPs and awareness of community services. CONCLUSION: From these findings it is possible to make recommendations for alternative ways of practising and/or new models of care. PMID- 26059686 TI - Cytotoxic effects of replication-competent adenoviruses on human esophageal carcinoma are enhanced by forced p53 expression. AB - BACKGROUND: Improvement of transduction and augmentation of cytotoxicity are crucial for adenoviruses (Ad)-mediated gene therapy for cancer. Down-regulated expression of type 5 Ad (Ad5) receptors on human tumors hampered Ad-mediated transduction. Furthermore, a role of the p53 pathways in cytotoxicity mediated by replication-competent Ad remained uncharacterized. METHODS: We constructed replication-competent Ad5 of which the E1 region genes were activated by a transcriptional regulatory region of the midkine or the survivin gene, which is expressed preferentially in human tumors. We also prepared replication-competent Ad5 which were regulated by the same region but had a fiber-knob region derived from serotype 35 (AdF35). We examined the cytotoxicity of these Ad and a possible combinatory use of the replication-competent AdF35 and Ad5 expressing the wild type p53 gene (Ad5/p53) in esophageal carcinoma cells. Expression levels of molecules involved in cell death, anti-tumor effects in vivo and production of viral progenies were also investigated. RESULTS: Replication-competent AdF35 in general achieved greater cytotoxic effects to esophageal carcinoma cells than the corresponding replication-competent Ad5. Infection with the AdF35 induced cleavages of caspases and increased sub-G1 fractions, but did not activate the autophagy pathway. Transduction with Ad5/p53 in combination with the replication competent AdF35 further enhanced the cytotoxicity in a synergistic manner. We also demonstrated the combinatory effects in an animal model. Transduction with Ad5/p53 however suppressed production of replication-competent AdF35 progenies, but the combination augmented Ad5/p53-mediated p53 expression levels and the downstream pathways. CONCLUSIONS: Combination of replication-competent AdF35 and Ad5/p53 achieved synergistic cytotoxicity due to enhanced p53-mediated apoptotic pathways. PMID- 26059687 TI - Identification of two key genes controlling chill haze stability of beer in barley (Hordeum vulgare L). AB - BACKGROUND: In bright beer, haze formation is a serious quality problem, degrading beer quality and reducing its shelf life. The quality of barley (Hordeum vulgare L) malt, as the main raw material for beer brewing, largely affects the colloidal stability of beer. RESULTS: In this study, the genetic mechanism of the factors affecting beer haze stability in barley was studied. Quantitative trait loci (QTL) analysis of alcohol chill haze (ACH) in beer was carried out using a Franklin/Yerong double haploid (DH) population. One QTL, named as qACH, was detected for ACH, and it was located on the position of about 108 cM in chromosome 4H and can explain about 20 % of the phenotypic variation. Two key haze active proteins, BATI-CMb and BATI-CMd were identified by proteomics analysis. Bioinformatics analysis showed that BATI-CMb and BATI-CMd had the same position as qACH in the chromosome. It may be deduced that BATI-CMb and BATI-CMd are candidate genes for qACH, controlling colloidal stability of beer. Polymorphism comparison between Yerong and Franklin in the nucleotide and amino acid sequence of BATI-CMb and BATI-CMd detected the corresponding gene specific markers, which could be used in marker-assisted selection for malt barley breeding. CONCLUSIONS: We identified a novel QTL, qACH controlling chill haze of beer, and two key haze active proteins, BATI-CMb and BATI-CMd. And further analysis showed that BATI-CMb and BATI-CMd might be the candidate genes associated with beer chill haze. PMID- 26059688 TI - Emergence of life: Physical chemistry changes the paradigm. AB - Origin of life research has been slow to advance not only because of its complex evolutionary nature (Franklin Harold: In Search of Cell History, 2014) but also because of the lack of agreement on fundamental concepts, including the question of 'what is life?'. To re-energize the research and define a new experimental paradigm, we advance four premises to better understand the physicochemical complexities of life's emergence: (1) Chemical and Darwinian (biological) evolutions are distinct, but become continuous with the appearance of heredity. (2) Earth's chemical evolution is driven by energies of cycling (diurnal) disequilibria and by energies of hydrothermal vents. (3) Earth's overall chemical complexity must be high at the origin of life for a subset of (complex) chemicals to phase separate and evolve into living states. (4) Macromolecular crowding in aqueous electrolytes under confined conditions enables evolution of molecular recognition and cellular self-organization. We discuss these premises in relation to current 'constructive' (non-evolutionary) paradigm of origins research - the process of complexification of chemical matter 'from the simple to the complex'. This paradigm artificially avoids planetary chemical complexity and the natural tendency of molecular compositions toward maximum disorder embodied in the second law of thermodynamics. Our four premises suggest an empirical program of experiments involving complex chemical compositions under cycling gradients of temperature, water activity and electromagnetic radiation. PMID- 26059689 TI - Research: Why and how to write a paper? AB - In this article, an internationally renowned pulmonologist with extensive experience in teaching and publishing gives practical advice to young physicians and/or residents on the importance of doing research, the steps for planning a project and also some do's and don'ts of writing and publishing a scientific paper. PMID- 26059691 TI - [Lessons learnt from the German smallpox outbreaks after World War II]. AB - BACKGROUND: Even though smallpox was declared eradicated by WHO in 1980, it cannot be ruled out that the etiological variola virus could be used as a biological weapon. Undestroyed viruses from biowarfare programmes, virus strains left undetected in a freezer or dangerous recombinant poxvirus constructs could cause dangerous outbreaks in a relatively unprotected population. OBJECTIVES: Despite an abundance of studies performed during the eradication of smallpox, epidemiological data for preparedness planning and outbreak control in modern, industrialized countries are scarce. MATERIAL AND METHODS: Full-text hand search for the period from 1945 to 1975 in the main German public health journals. RESULTS: After World War II 12 smallpox outbreaks occurred in Germany. They were studied with the focus on the period of contagiousness, the protective effect of vaccination, booster-effect of revaccination and the place of infection. A total of 95 individuals contracted smallpox, including 10 fatalities. Despite having been previously vaccinated, 81 vaccinated persons came down with smallpox, yet 91% of them developed only mild symptoms. These patients presented a high risk for spreading the infection to contact persons due to misinterpretation of symptoms and the continuing social contacts. Basically, the risk of transmission in the first 2 to 3 days after onset of symptoms was low, thus facilitating antiepidemic measures. The importance of hospital preparedness is emphasized by the fact that most infections occurred in hospitals. CONCLUSION: The data analyzed provide valuable information for today's outbreak response planning and counter bioterrorism preparedness. PMID- 26059690 TI - Skeletal muscle ultrastructure and function in statin-tolerant individuals. AB - INTRODUCTION: Statins have well-known benefits on cardiovascular mortality, though up to 15% of patients experience side effects. With guidelines from the American Heart Association, American College of Cardiology, and American Diabetes Association expected to double the number of statin users, the overall incidence of myalgia and myopathy will increase. METHODS: We evaluated skeletal muscle structure and contractile function at the molecular, cellular, and whole tissue levels in 12 statin tolerant and 12 control subjects. RESULTS: Myosin isoform expression, fiber type distributions, single fiber maximal Ca(2+) -activated tension, and whole muscle contractile force were similar between groups. No differences were observed in myosin-actin cross-bridge kinetics in myosin heavy chain I or IIA fibers. CONCLUSIONS: We found no evidence for statin-induced changes in muscle morphology at the molecular, cellular, or whole tissue levels. Collectively, our data show that chronic statin therapy in healthy asymptomatic individuals does not promote deleterious myofilament structural or functional adaptations. PMID- 26059692 TI - Detailed characterization of the O-linked glycosylation of the neuropilin-1 c/MAM domain. AB - Neuropilins are involved in angiogenesis and neuronal development. The membrane proximal domain of neuropilin-1, called c or MAM domain based on its sequence conservation, has been implicated in neuropilin oligomerization required for its function. The c/MAM domain of human neuropilin-1 has been recombinantly expressed to allow for investigation of its propensity to engage in molecular interactions with other protein or carbohydrate components on a cell surface. We found that the c/MAM domain was heavily O-glycosylated with up to 24 monosaccharide units in the form of disialylated core 1 and core 2 O-glycans. Attachment sites were identified on the chymotryptic c/MAM peptide ETGATEKPTVIDSTIQSEFPTY by electron transfer dissociation mass spectrometry (ETD-MS/MS). For highly glycosylated species consisting of carbohydrate to about 50 %, useful results could only be obtained upon partial desialylation. ETD-MS/MS revealed a hierarchical order of the initial O-GalNAc addition to the four different glycosylation sites. These findings enable future functional studies about the contribution of the described glycosylations in neuropilin-1 oligomerization and the binding to partner proteins as VEGF or galectin-1.As a spin-off result the sialidase from Clostridium perfringens turned out to discriminate between galactose- and N acetylgalactosamine-linked sialic acid. PMID- 26059694 TI - Micelle Bound Structure and Model Membrane Interaction Studies of the Peptide Hylin a1 from the Arboreal South American Frog Hypsiboas albopunctatus. AB - Antimicrobial peptides (AMPs) appear as a promising therapeutic candidate against multiresistant pathogens, because they are able to kill microorganisms and have low toxicity of resistance cells. Hylin a1 (Hy-a1, IFGAILPLALGALKNLIK-NH2) is a peptide extracted from the skin secretion of the frog Hypsiboas albopunctatus, which displays antimicrobial and hemolytic activities. We report here structural studies of Hy-a1 using different techniques such as fluorescence, CD and NMR. Our data showed that Hy-a1 acquires a well defined amphipathic alpha-helix when interacting with a membrane-like environment. Furthermore, Hy-a1 presented different affinity when compared to membranes of zwitterionic or anionic lipid composition. Finally, we proposed a molecular interaction model of this peptide with micelles. PMID- 26059693 TI - Telocytes in regenerative medicine. AB - Telocytes (TCs) are a distinct type of interstitial cells characterized by a small cell body and extremely long and thin telopodes (Tps). The presence of TCs has been documented in many tissues and organs (go to http://www.telocytes.com). Functionally, TCs form a three-dimensional (3D) interstitial network by homocellular and heterocellular communication and are involved in the maintenance of tissue homeostasis. As important interstitial cells to guide or nurse putative stem and progenitor cells in stem cell niches in a spectrum of tissues and organs, TCs contribute to tissue repair and regeneration. This review focuses on the latest progresses regarding TCs in the repair and regeneration of different tissues and organs, including heart, lung, skeletal muscle, skin, meninges and choroid plexus, eye, liver, uterus and urinary system. By targeting TCs alone or in tandem with stem cells, we might promote regeneration and prevent the evolution to irreversible tissue damage. Exploring pharmacological or non pharmacological methods to enhance the growth of TCs would be a novel therapeutic strategy besides exogenous transplantation for many diseased disorders. PMID- 26059696 TI - Quality of reporting of chemotherapy compliance in randomized controlled trials of breast cancer treatment. AB - OBJECTIVE: The Consolidated Standards of Reporting Trials statement requires detailed reporting of interventions for randomized controlled trials. We hypothesized that there was variable reporting of chemotherapy compliance in published randomized controlled trials in breast cancer, and therefore surveyed the literature to assess this parameter and determine the study characteristics associated with reporting quality. METHODS: Published Phase III randomized controlled trials (January 2005-December 2011; English language) evaluating chemotherapy in breast cancer were identified through a systematic literature search. Articles scored 1 point each for reporting of the four measures: number of chemotherapy cycles, dose modification, early treatment discontinuation and relative dose intensity. Logistic regression identified study characteristics associated with reporting quality score of >= 2. RESULTS: Of the 115 eligible randomized controlled trials, 79 (69%) were published in high-impact journals, 66 (57%) were published since 2008, 43 (37%) reported advanced-stage disease and 37 (32%) were industry sponsored. Relative dose intensity, number of cycles, dose modification and early treatment discontinuation were reported in 70 (61%), 53 (46%), 65 (57%) and 81 (70%) articles, respectively. Eighty-two (71%) articles showed a quality score of >= 2; 25 (22%) articles reported all four compliance measures. Articles published since 2008 (P = 0.035) and those reporting advanced stage disease (P < 0.001) showed significantly higher quality of compliance. CONCLUSIONS: Our results demonstrate variable reporting of chemotherapy compliance in published randomized controlled trials with a modest improvement noted in recent years. Incorporating standards for reporting chemotherapy compliance in scientific guidelines or the journal peer review process may decrease the variability and improve the quality of reporting. PMID- 26059695 TI - Investigation of the subcellular architecture of L7 neurons of Aplysia californica using magnetic resonance microscopy (MRM) at 7.8 microns. AB - Magnetic resonance microscopy (MRM) is a non-invasive diagnostic tool which is well-suited to directly resolve cellular structures in ex vivo and in vitro tissues without use of exogenous contrast agents. Recent advances in its capability to visualize mammalian cellular structure in intact tissues have reinvigorated analytical interest in aquatic cell models whose previous findings warrant up-to-date validation of subcellular components. Even if the sensitivity of MRM is less than other microscopic technologies, its strength lies in that it relies on the same image contrast mechanisms as clinical MRI which make it a unique tool for improving our ability to interpret human diagnostic imaging through high resolution studies of well-controlled biological model systems. Here, we investigate the subcellular MR signal characteristics of isolated cells of Aplysia californica at an in-plane resolution of 7.8 MUm. In addition, direct correlation and positive identification of subcellular architecture in the cells is achieved through well-established histology. We hope this methodology will serve as the groundwork for studying pathophysiological changes through perturbation studies and allow for development of disease-specific cellular modeling tools. Such an approach promises to reveal the MR contrast changes underlying cellular mechanisms in various human diseases, for example in ischemic stroke. PMID- 26059697 TI - A non-randomized confirmatory study regarding selection of fertility-sparing surgery for patients with epithelial ovarian cancer: Japan Clinical Oncology Group Study (JCOG1203). AB - Fertility-sparing treatment has been accepted as a standard treatment for epithelial ovarian cancer in stage IA non-clear cell histology grade 1/grade 2. In order to expand an indication of fertility-sparing treatment, we have started a non-randomized confirmatory trial for stage IA clear cell histology and stage IC unilateral non-clear cell histology grade 1/grade 2. The protocol-defined fertility-sparing surgery is optimal staging laparotomy including unilateral salpingo-oophorectomy, omentectomy, peritoneal cytology and pelvic and para aortic lymph node dissection or biopsy. After fertility-sparing surgery, four to six cycles of adjuvant chemotherapy with paclitaxel and carboplatin are administered. We plan to enroll 250 patients with an indication of fertility sparing surgery, and then the primary analysis is to be conducted for 63 operated patients with pathologically confirmed stage IA clear cell histology and stage IC unilateral non-clear cell histology grade 1/grade 2. The primary endpoint is 5 year overall survival. Secondary endpoints are other survival endpoints and factors related to reproduction. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000013380. PMID- 26059698 TI - Morphological distribution of liver cancer from Cancer Incidence in Five Continents Vol. X. PMID- 26059699 TI - What we have learned from the next-generation sequencing: Contributions to the genetic diagnoses and understanding of pathomechanisms of neurodegenerative diseases. AB - Since its first availability in 2009, the next-generation sequencing (NGS) has been proved to be a powerful tool in identifying disease-associated variants in many neurological diseases, such as spinocerebellar ataxias, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and amyotrophic lateral sclerosis. Whole exome sequencing and whole genome sequencing are efficient for identifying variants in novel or unexpected genes responsible for inherited diseases, whereas targeted sequencing is useful in detecting variants in previously known disease associated genes. The trove of genetic data yielded by NGS has made a significant impact on the clinical diagnoses while contributing hugely on the discovery of molecular pathomechanisms underlying these diseases. Nonetheless, elucidation of the pathogenic roles of the variants identified by NGS is challenging. Establishment of consensus guidelines and development of public genomic/phenotypic databases are thus vital to facilitate data sharing and validation. PMID- 26059700 TI - Confined self-assembly of cellulose nanocrystals in a shrinking droplet. AB - We have studied how cellulose nanocrystals (CNC) self-assemble into liquid crystalline phases in shrinking, isolated droplets. By adjusting the water dissolution rate of an aqueous CNC droplet immersed in a binary toluene-ethanol mixture we can control the final morphology of the consolidated microbead. At low ethanol concentration in the surrounding fluid dense microbeads of spherical morphology are produced while collapsed core-shell particles are obtained at high ethanol concentration. Polarized light microscopy was used to follow the spatial evolution and coalescence of birefringent spheroids during droplet shrinkage. Electron microscopy reveals the resultant nematic microstructure. This method of confined CNC assembly provides thus the possibility to prepare ordered microbeads, which can be useful as templates or for their optical properties. PMID- 26059701 TI - Zeolitic Core@Shell Adsorbents for the Selective Removal of Free Glycerol from Crude Biodiesel. AB - Selective adsorption of free glycerol from crude biodiesel was investigated by using mesoporous silica spheres coated with a thin shell of microporous silicalite-1. A polycrystalline silicalite-1 shell was formed upon first covering the external surfaces of various core templates with discrete silicalite-1 nanocrystals, and this was followed by short hydrothermal treatment to ensure shell uniformity. Batch glycerol adsorption experiments were conducted to evaluate the ability of the sorbents to remove free glycerol selectively from crude biodiesel mixtures at various temperatures, also in comparison to that of conventional sorbents, for example, bare mesoporous silica gel spheres and zeolites. The silicalite-1 shell provided a microporous membrane that hindered the diffusion of fatty acid methyl esters into the mesopores of the composite sorbent, whereas the large pore volume of the mesoporous core enabled multilayer glycerol adsorption; this ultimately substantially enhanced the performance in terms of purification yield and adsorption capacity. PMID- 26059703 TI - In harm's way: tobacco industry revenues from sales to underage tobacco users in India. AB - BACKGROUND: In 2010, the global adult tobacco survey (GATS) for India revealed that nearly 40% of current smokers and 42% of current chewers had initiated tobacco use before they were of the legal age (18 years old or over). Global evidence shows that those who initiate earlier have a lower probability of quitting the use of tobacco during their lifetime. In order to sustain its profits, the tobacco industry will make every effort to recruit underage users who become lifelong users of their products. AIMS AND OBJECTIVES: We estimate the consumer expenditure on tobacco products by underage users in India. METHODOLOGY: Using nationally representative data we estimated the number of daily underage tobacco users for a year and their annual expenditure on different types of smoked and chewed tobacco products. RESULTS: There are nearly 4.4 million underage daily tobacco users (age group 15-17 years old) in India. Approximately 7.2% of the population in the 15-17 age group are current daily users of tobacco (0.1% cigarette smokers, 0.5% bidi smokers and 6.6% tobacco chewers). Underage users spend nearly US$16.9 million and US$270.8 million respectively on smoking and chewing tobacco products. CONCLUSION: There is a substantial expenditure on tobacco products by underage individuals in India. A significant number of new users are added every year that provide an estimate for the size and nature of the future of the tobacco epidemic, one on which the tobacco industry depends on for its sustenance. The government of India's efforts to reduce sale to underage users has had limited effect and needs to be strengthened. PMID- 26059702 TI - Rivaroxaban for the treatment and prevention of thromboembolic disease. AB - OBJECTIVES: A number of direct oral anticoagulants are now available and offer alternative strategies for anticoagulation therapy. Rivaroxaban, a direct oral Factor Xa inhibitor, is approved for use across several thromboembolic indications. This article aims to provide an overview of the key pharmacological characteristics of rivaroxaban and the rationale and evidence for the use of different dose regimens across its licenced indications, and offer practical guidance to healthcare professionals on responsible use. References were sourced via PubMed searches using the search string (rivaroxaban AND (pharmacokinetics OR pharmacodynamics OR (clinical studies) OR (drug interaction)) NOT review NOT (children OR pediatrics OR paediatrics OR adolescent)). KEY FINDINGS: Rivaroxaban exhibits predictable pharmacokinetics and pharmacodynamics, and thus does not require routine coagulation monitoring, unlike vitamin K antagonists (e.g. warfarin). Rivaroxaban also has a lower potential for drug-drug and food-drug interactions compared with warfarin; however, co-administration with strong inhibitors of both cytochrome P450 3A4 and P-glycoprotein is not recommended. The data indicate that dose adjustment is not necessary for age, gender or body weight. The dosing regimens of rivaroxaban vary depending on the indication, and phase III studies have demonstrated a favourable benefit-risk profile of rivaroxaban compared with traditional standard of care. SUMMARY: Rivaroxaban may offer an anticoagulant option that could simplify and improve the management of patients with thromboembolic disorders. PMID- 26059704 TI - Unclassifiable interstitial lung disease: A review. AB - Accurate classification of interstitial lung disease (ILD) requires a multidisciplinary approach that incorporates input from an experienced respirologist, chest radiologist and lung pathologist. Despite a thorough multidisciplinary evaluation, up to 15% of ILD patients have unclassifiable ILD and cannot be given a specific diagnosis. The objectives of this review are to discuss the definition and features of unclassifiable ILD, identify the barriers to ILD classification and outline an approach to management of unclassifiable ILD. Several recent studies have described the characteristics of these patients; however, there are inconsistencies in the definition and terminology of unclassifiable ILD due to limited research in this population. Additional studies are required to determine the appropriate evaluation and management of patients with unclassifiable ILD. PMID- 26059705 TI - Nuclear localization of ubiquitin-activating enzyme Uba1 is characterized in its mammalian temperature-sensitive mutant. AB - In our previous study, a point mutation in Uba1, the gene encoding ubiquitin activating enzyme, was identified in temperature-sensitive (ts) CHO-K1 mutant tsTM3 cells, which led to a Met-to-Ile substitution at amino acid 256 in Uba1 protein. Characterization of this mutant revealed a deficiency of nuclear Uba1 and impaired ubiquitination in the nucleus. The ts defects in tsTM3 were complemented by the expression of the wild-type Uba1 tagged with green fluorescent protein (GFP). In this study, the expression and localization of Uba1 were investigated using the various forms of Uba1 tagged with GFP. Western blot analysis and confocal microscopy revealed that nuclear localization of Uba1, as well as even the modified and truncated forms of Uba1, appears to be essential to rescue tsTM3 cells. The localization of Uba1 in the nucleus, even if it was a small amount, was proportional to the efficiency of complementation of tsTM3 cells. Uba1 plays an important role in the nucleus, and a ts mutation found in tsTM3 cells appears to result in the loss of localization of Uba1 in the nucleus. PMID- 26059706 TI - SGLT-2 inhibition and glucagon: Cause for alarm? AB - Recent studies raised the alarm that the inhibition of sodium-coupled glucose transporter type-2 in humans increases endogenous glucose production rates by an unclear mechanism. Surprisingly, a potential explanation may be linked directly to the alpha-cell. Is this a mechanistic spoiler or an added benefit? PMID- 26059708 TI - Pulpectomies in primary mandibular molars: a comparison of outcomes using three root filling materials. AB - AIM: To evaluate the outcome of root canal treatment in primary teeth using three root canal filling materials - RC Fill, Vitapex and Pulpdent root canal sealer. METHODOLOGY: The study was a single-centre, double-blind, randomized controlled trial carried out on 129 primary mandibular molars with necrotic pulps or irreversible pulpitis in 4- to 9-year-old children. Participants were selected based on specific inclusion and exclusion criteria and were randomly allocated into 3 groups: Group I - RC Fill [zinc oxide-eugenol (ZOE) with iodoform]; Group II - Vitapex (calcium hydroxide with iodoform); and Group III - Pulpdent root canal sealer (ZOE). The outcome measures were evaluated both clinically and radiographically at 6, 12 and 30 months according to modified American Association of Endodontists (AAE) criteria. The radiographic outcomes were assessed by two blinded and calibrated evaluators. Pearson's chi-square analysis was performed for both intention-to-treat (ITT) and per-protocol population. RESULT: The success rates of RC Fill, Vitapex and Pulpdent were 94%, 90% and 97%, respectively, at 30 months and the differences were not significant (P = 0.137). CONCLUSION: All three materials were found to be equally effective root filling materials for primary molars with necrotic pulps and irreversible pulpitis at 30 months. However, long-term follow-up until the eruption of the permanent successor teeth is needed for more definitive assessments. PMID- 26059709 TI - Tap water versus sterile saline solution in the colonisation of skin wounds. AB - Irrigating wounds with tap water does not increase colonisation, but controlled studies are required for further evidence. Microbial colonisation was assessed in skin wounds, before and after irrigation with tap water, and was compared with irrigation using 0.9% sodium chloride sterile solution. The study included 120 subjects with chronic, traumatic, vascular, pressure or neuropathic wounds. A total of 60 wounds were randomly assigned to be irrigated with tap water (tap water group) and another 60 to be irrigated with 0.9% sodium chloride sterile solution (saline group), at a pressure of 0.46-0.54 PSI. Samples were collected from the centre of each wound using Levine's technique, before and after irrigation, and cultivated in thioglycollate, hypertonic mannitol agar, eosin methylene blue (EMB) agar, blood agar and Sabouraud agar at 37 degrees C for 72 hours. There was concordance (kappa test) and discordance (McNemar test) regarding the count of positive and/or negative samples before and after irrigation in each group. The proportion of reduction of positive samples was similar for both groups in all cultures. Colony-forming unit count before and after irrigation was similar in both groups and in all cultures, except for the culture in hypertonic mannitol agar from the tap water group, for which the count was lower after irrigation (Wilcoxon z = 2.05, P = 0.041). It is concluded that skin wound irrigation with tap water leads to further reduction of Gram-positive bacteria compared with 0.9% sodium chloride sterile solution, with no difference in colonisation of haemolytic bacteria, Gram-negative bacteria and fungi. PMID- 26059707 TI - The extracellular matrix and insulin resistance. AB - The extracellular matrix (ECM) is a highly-dynamic compartment that undergoes remodeling as a result of injury and repair. Over the past decade, mounting evidence in humans and rodents suggests that ECM remodeling is associated with diet-induced insulin resistance in several metabolic tissues. In addition, integrin receptors for the ECM have also been implicated in the regulation of insulin action. This review addresses what is currently known about the ECM, integrins, and insulin action in the muscle, liver, and adipose tissue. Understanding how ECM remodeling and integrin signaling regulate insulin action may aid in the development of new therapeutic targets for the treatment of insulin resistance and type 2 diabetes (T2D). PMID- 26059710 TI - Progress and prospects of endothelial progenitor cell therapy in coronary stent implantation. AB - Drug-eluting stents (DES) have been widely used to treat coronary artery disease (CAD) since their clinical use has significantly reduced the occurrence of in stent restenosis (ISR) as compared with the initially applied bare-metal stents (BMS). However, analyses of long-term clinical outcome have raised concerns about the serious safety problem of DES, such as ISR caused by late or very late thrombosis. Various studies showed that those complications were associated with vascular endothelial injury/dysfunction or endothelialization delaying. Recently, through biological characterization of endothelial progenitor cells (EPCs), mechanistic understanding of rapid re-endothelialization of the vascular injury sites after coronary stenting has become possible and is a new research hotspot in the prevention of ISR and late/very late stent thrombosis. It has been well recognized that the formation of a functional endothelial layer from EPCs requires a coordinated sequence of multistep and signaling events, which includes cell mobilization, adhesion, migration and finally the differentiation to vascular endothelial cells (VECs). In this review, we summarize and discuss the currently relevant information about EPCs, the mechanism of DES interfering with the natural vascular healing process in preventing or delaying the formation of a functional endothelial layer, and EPCs-mediated acceleration of re endothelialization at vascular injury sites. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1237-1247, 2016. PMID- 26059711 TI - An ex vivo model using human osteoarthritic cartilage demonstrates the release of bioactive insulin-like growth factor-1 from a collagen-glycosaminoglycan scaffold. AB - Biomimetic scaffolds hold great promise for therapeutic repair of cartilage, but although most scaffolds are tested with cells in vitro, there are very few ex vivo models (EVMs) where adult cartilage and scaffolds are co-cultured to optimize their interaction prior to in vivo studies. This study describes a simple, non-compressive method that is applicable to mammalian or human cartilage and provides a reasonable throughput of samples. Rings of full-depth articular cartilage slices were derived from human donors undergoing knee replacement for osteoarthritis and a 3 mm core of a collagen/glycosaminoglycan biomimetic scaffold (Tigenix, UK) inserted to create the EVM. Adult osteoarthritis chondrocytes were seeded into the scaffold and cultures maintained for up to 30 days. Ex vivo models were stable throughout experiments, and cells remained viable. Chondrocytes seeded into the EVM attached throughout the scaffold and in contact with the cartilage explants. Cell migration and deposition of extracellular matrix proteins in the scaffold was enhanced by growth factors particularly if the scaffold was preloaded with growth factors. This study demonstrates that the EVM represents a suitable model that has potential for testing a range of therapeutic parameters such as numbers/types of cell, growth factors or therapeutic drugs before progressing to costly pre-clinical trials. PMID- 26059714 TI - Small Bowel Metastases: Tumor Markers for Diagnosis and Role of Surgical Palliation. PMID- 26059715 TI - UniAlign: protein structure alignment meets evolution. AB - MOTIVATION: During the evolution, functional sites on the surface of the protein as well as the hydrophobic core maintaining the structural integrity are well conserved. However, available protein structure alignment methods align protein structures based solely on the 3D geometric similarity, limiting their ability to detect functionally relevant correspondences between the residues of the proteins, especially for distantly related homologous proteins. RESULTS: In this article, we propose a new protein pairwise structure alignment algorithm (UniAlign) that incorporates additional evolutionary information captured in the form of sequence similarity, sequence profiles and residue conservation. We define a per-residue score (UniScore) as a weighted sum of these and other features and develop an iterative optimization procedure to search for an alignment with the best overall UniScore. Our extensive experiments on CDD, HOMSTRAD and BAliBASE benchmark datasets show that UniAlign outperforms commonly used structure alignment methods. We further demonstrate UniAlign's ability to develop family-specific models to drastically improve the quality of the alignments. AVAILABILITY AND IMPLEMENTATION: UniAlign is available as a web service at: http://sacan.biomed.drexel.edu/unialign CONTACT: ahmet.sacan@drexel.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26059713 TI - Cross-sectional versus longitudinal estimates of age-related changes in the adult brain: overlaps and discrepancies. AB - The healthy adult brain undergoes tissue volume decline with age, but contradictory findings abound regarding rate of change. To identify a source of this discrepancy, we present contrasting statistical approaches to estimate hippocampal volume change with age based on 200 longitudinally-acquired magnetic resonance imaging in 70 healthy adults, age 20-70 years, who had 2-5 magnetic resonance imaging collected over 6 months to 8 years. Linear mixed-effects modeling using volume trajectories over age for each subject revealed significantly negative slopes with aging after a linear decline with a suggestion of acceleration in older individuals. By contrast, general linear modeling using either the first observation only of each subject or all observations treated independently (thereby disregarding trajectories) indicated no significant correlation between volume and age. Entering a quadratic term into the linear model yielded a biologically plausible function that was not supported by longitudinal analysis. The results underscore the importance of analyses that incorporate the trajectory of individuals in the study of brain aging. PMID- 26059712 TI - Amyloid burden is associated with self-reported sleep in nondemented late middle aged adults. AB - Midlife may be an ideal window for intervention in Alzheimer's disease (AD). To determine whether sleep is associated with early signs of AD neuropathology (amyloid deposition) in late midlife, we imaged brain amyloid deposits using positron emission tomography with [C-11]Pittsburgh Compound B (PiB), and assessed sleep with the Epworth Sleepiness Scale and the Medical Outcomes Study Sleep Scale in 98 cognitively healthy adults (aged 62.4 +/- 5.7 years) from the Wisconsin Registry for Alzheimer's Prevention. We used multiple regressions to test the extent to which sleep scores predicted regional amyloid burden. Participants reporting less adequate sleep, more sleep problems, and greater somnolence on the Medical Outcomes Study had greater amyloid burden in AD sensitive brain regions (angular gyrus, frontal medial orbital cortex, cingulate gyrus, and precuneus). Amyloid was not associated with reported sleep amount, symptoms of sleep-disordered breathing, trouble falling asleep, or Epworth Sleepiness Scale. Poor sleep may be a risk factor for AD and a potential early marker of AD or target for preventative interventions in midlife. PMID- 26059716 TI - DISTMIX: direct imputation of summary statistics for unmeasured SNPs from mixed ethnicity cohorts. AB - MOTIVATION: To increase the signal resolution for large-scale meta-analyses of genome-wide association studies, genotypes at unmeasured single nucleotide polymorphisms (SNPs) are commonly imputed using large multi-ethnic reference panels. However, the ever increasing size and ethnic diversity of both reference panels and cohorts makes genotype imputation computationally challenging for moderately sized computer clusters. Moreover, genotype imputation requires subject-level genetic data, which unlike summary statistics provided by virtually all studies, is not publicly available. While there are much less demanding methods which avoid the genotype imputation step by directly imputing SNP statistics, e.g. Directly Imputing summary STatistics (DIST) proposed by our group, their implicit assumptions make them applicable only to ethnically homogeneous cohorts. RESULTS: To decrease computational and access requirements for the analysis of cosmopolitan cohorts, we propose DISTMIX, which extends DIST capabilities to the analysis of mixed ethnicity cohorts. The method uses a relevant reference panel to directly impute unmeasured SNP statistics based only on statistics at measured SNPs and estimated/user-specified ethnic proportions. Simulations show that the proposed method adequately controls the Type I error rates. The 1000 Genomes panel imputation of summary statistics from the ethnically diverse Psychiatric Genetic Consortium Schizophrenia Phase 2 suggests that, when compared to genotype imputation methods, DISTMIX offers comparable imputation accuracy for only a fraction of computational resources. AVAILABILITY AND IMPLEMENTATION: DISTMIX software, its reference population data, and usage examples are publicly available at http://code.google.com/p/distmix. CONTACT: dlee4@vcu.edu SUPPLEMENTARY INFORMATION: Supplementary Data are available at Bioinformatics online. PMID- 26059717 TI - BUSCO: assessing genome assembly and annotation completeness with single-copy orthologs. AB - MOTIVATION: Genomics has revolutionized biological research, but quality assessment of the resulting assembled sequences is complicated and remains mostly limited to technical measures like N50. RESULTS: We propose a measure for quantitative assessment of genome assembly and annotation completeness based on evolutionarily informed expectations of gene content. We implemented the assessment procedure in open-source software, with sets of Benchmarking Universal Single-Copy Orthologs, named BUSCO. AVAILABILITY AND IMPLEMENTATION: Software implemented in Python and datasets available for download from http://busco.ezlab.org. CONTACT: evgeny.zdobnov@unige.ch SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26059718 TI - Automated profiling of individual cell-cell interactions from high-throughput time-lapse imaging microscopy in nanowell grids (TIMING). AB - MOTIVATION: There is a need for effective automated methods for profiling dynamic cell-cell interactions with single-cell resolution from high-throughput time lapse imaging data, especially, the interactions between immune effector cells and tumor cells in adoptive immunotherapy. RESULTS: Fluorescently labeled human T cells, natural killer cells (NK), and various target cells (NALM6, K562, EL4) were co-incubated on polydimethylsiloxane arrays of sub-nanoliter wells (nanowells), and imaged using multi-channel time-lapse microscopy. The proposed cell segmentation and tracking algorithms account for cell variability and exploit the nanowell confinement property to increase the yield of correctly analyzed nanowells from 45% (existing algorithms) to 98% for wells containing one effector and a single target, enabling automated quantification of cell locations, morphologies, movements, interactions, and deaths without the need for manual proofreading. Automated analysis of recordings from 12 different experiments demonstrated automated nanowell delineation accuracy >99%, automated cell segmentation accuracy >95%, and automated cell tracking accuracy of 90%, with default parameters, despite variations in illumination, staining, imaging noise, cell morphology, and cell clustering. An example analysis revealed that NK cells efficiently discriminate between live and dead targets by altering the duration of conjugation. The data also demonstrated that cytotoxic cells display higher motility than non-killers, both before and during contact. CONTACT: broysam@central.uh.edu or nvaradar@central.uh.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26059719 TI - Caspase-1: an integral regulator of innate immunity. AB - Caspase-1 is a unique cysteine protease playing central roles in innate immunity. Pathogens, stress, and damage signals induce activation of caspase-1, typically mediated by proximity-induced autoproteolysis in multimeric protein complexes called the inflammasome. Active caspase-1 induces secretion of pro-inflammatory cytokines and mediates pyroptosis, a programmed pro-inflammatory cell death, thereby initiating an immune response finally leading to pathogen clearance. Excessive activation of caspase-1 is the underlying cause for rare diseases such as periodic fever syndromes, and more common disorders, including atherosclerosis, type 2 diabetes, and gout. Beside these well-known pro inflammatory functions, active caspase-1 also has anti-inflammatory and protective functions contributing to cell survival, reduced inflammatory cytokine signaling, and improved outcomes in mouse models of burn injury or trauma and shock. Furthermore, naturally occurring procaspase-1 variants with reduced or abrogated enzymatic activity mediate enhanced inflammatory signaling and have been associated to autoinflammatory symptoms. Here, we review functions of caspase-1 focusing on anti-inflammatory signaling pathways and discuss the role of enzymatically inactive caspase-1 as disease-promoting factors in autoinflammatory diseases. Moreover, we illustrate differential requirements for autoproteolysis and enzymatic activity in caspase-1 functions. PMID- 26059720 TI - Regulating against the dysregulation: new treatment options in autoinflammation. AB - In autoinflammatory disorders, dysregulation of the innate immune response leads to an excessive cytokine release. The disease course is often characterized by high morbidity and mortality, treatment is mostly difficult and therapeutic options are limited. In most cases, life-long control of ongoing inflammation is necessary in order to improve clinical symptoms and prevent development of damage. Steroids are helpful in many conditions, but the development of serious side effects often limits their long-term use. Other immunosuppressive, steroid sparing medications are less effective than in the treatment of autoimmune diseases or do not show any effect. So far, anti-IL1alpha and/or beta-blocking agents as well as an IL-6 receptor-blocking monoclonal antibody and, to a lesser extent, TNF-alpha blocking agents were applied in autoinflammatory disorders and significantly improved the outcome. Although these progresses were made in the last years, there are still numerous challenges in order to improve drug therapy in autoinflammation. This review summarizes the current state of new drug development and discusses advantages and disadvantages of possible targets. PMID- 26059721 TI - Evaluation of the Effect of a Continuous Treatment: A Machine Learning Approach with an Application to Treatment for Traumatic Brain Injury. AB - For a continuous treatment, the generalised propensity score (GPS) is defined as the conditional density of the treatment, given covariates. GPS adjustment may be implemented by including it as a covariate in an outcome regression. Here, the unbiased estimation of the dose-response function assumes correct specification of both the GPS and the outcome-treatment relationship. This paper introduces a machine learning method, the 'Super Learner', to address model selection in this context. In the two-stage estimation approach proposed, the Super Learner selects a GPS and then a dose-response function conditional on the GPS, as the convex combination of candidate prediction algorithms. We compare this approach with parametric implementations of the GPS and to regression methods. We contrast the methods in the Risk Adjustment in Neurocritical care cohort study, in which we estimate the marginal effects of increasing transfer time from emergency departments to specialised neuroscience centres, for patients with acute traumatic brain injury. With parametric models for the outcome, we find that dose response curves differ according to choice of specification. With the Super Learner approach to both regression and the GPS, we find that transfer time does not have a statistically significant marginal effect on the outcomes. PMID- 26059722 TI - Cumulative deviance scores can be used as an alternative to the Hammersmith Neonatal Neurological Examination in scientific research. PMID- 26059723 TI - Development of novel radiochemotherapy approaches targeting prostate tumor progenitor cells using nanohybrids. AB - Many tumors including prostate cancer are maintained by cancer stem cells (CSCs), which might cause tumor relapse if not eradicated during the course of treatment. Specific targeting or radiosensitization of CSCs bear promise to improve tumor curability by synergistic effects in combination with radiotherapy. Carbon nanotubes (CNTs) can be used as promising drug delivery systems for anticancer drugs such as the flavonoid catechin. Catechin is an extensively studied active ingredient of the different plants, including green tea, and it is widely recognized as co-adjuvant in cancer therapy. Here we describe the synthesis of biocompatible, catechin-loaded and gelatin-conjugated CNTs (Gel_CT_CNTs) with anticancer properties and demonstrate their potential for the eradication of prostate CSCs in combination with X-ray irradiation. Gel_CT_CNTs showed a significant enhancement of in vitro anticancer activity as compared to catechin alone. Moreover, treatment of prostate cancer cells with Gel_CT_CNT nanohybrids inhibited the tumorigenic cell population defined by a high aldehyde dehydrogenase (ALDH) activity. A combination of X-ray irradiation and treatment with Gel_CT_CNTs caused a decrease in the protein level of stem cell-related transcription factors and regulators including Nanog, Oct4 and beta-catenin and led to an increase of cancer cell radiosensitivity as demonstrated by clonogenic and spherogenic cell survival assays. Taken together, our results suggest that a combination of irradiation and Gel_CT_CNTs can be potentially used for the radiosensitization and eradication of prostate CSC populations. PMID- 26059725 TI - Increased risk of aortic valve stenosis in patients with psoriasis: a nationwide cohort study. AB - AIM: Psoriasis is a chronic inflammatory disease associated with increased risk of cardiovascular disease including atherosclerosis. The pathogenesis of aortic valve stenosis (AS) also includes an inflammatory component. We therefore investigated the risk of AS in patients with psoriasis compared with the general population in a nationwide cohort. METHODS: The study comprised the entire Danish population aged >=18 years followed from 1 January 1997 until diagnosis of AS, 31 December 2011, or death. Information on comorbidity, concomitant medication, and socioeconomic status was identified by individual-level linkage of administrative registers. Incidence rates for AS were calculated and incidence rate ratios (IRRs) adjusted for age, gender, calendar year, comorbidity, medications, and socioeconomic status, were estimated in Poisson regression models. RESULTS: A total of 5 107 624 subjects were eligible for analysis. During the study period, we identified 58 747 patients with mild psoriasis and 11 918 patients with severe psoriasis. The overall incidence rates for AS were 8.09, 16.07, and 20.08 per 10 000 person-years for the reference population (48 539 cases [mean follow-up 12.3 years]), mild psoriasis (509 cases [mean follow-up 6.2 years]), and severe psoriasis (99 cases [mean follow-up 5.4 years]), respectively. Correspondingly, the fully adjusted IRRs for AS were markedly increased in patients with psoriasis with IRR 1.22 (95% confidence interval [CI] 1.12-1.33) and IRR 1.61 (CI 1.32 1.96) for subjects with mild and severe disease, respectively. CONCLUSION: In a nationwide cohort, psoriasis was associated with a disease severity-dependent increased risk of AS. The mechanisms underlying this novel finding require further study. PMID- 26059724 TI - Atrial fibrillation driven by micro-anatomic intramural re-entry revealed by simultaneous sub-epicardial and sub-endocardial optical mapping in explanted human hearts. AB - AIMS: The complex architecture of the human atria may create physical substrates for sustained re-entry to drive atrial fibrillation (AF). The existence of sustained, anatomically defined AF drivers in humans has been challenged partly due to the lack of simultaneous endocardial-epicardial (Endo-Epi) mapping coupled with high-resolution 3D structural imaging. METHODS AND RESULTS: Coronary perfused human right atria from explanted diseased hearts (n = 8, 43-72 years old) were optically mapped simultaneously by three high-resolution CMOS cameras (two aligned Endo-Epi views (330 um2 resolution) and one panoramic view). 3D gadolinium-enhanced magnetic resonance imaging (GE-MRI, 80 um3 resolution) revealed the atrial wall structure varied in thickness (1.0 +/- 0.7-6.8 +/- 2.4 mm), transmural fiber angle differences, and interstitial fibrosis causing transmural activation delay from 23 +/- 11 to 43 +/- 22 ms at increased pacing rates. Sustained AF (>90 min) was induced by burst pacing during pinacidil (30 100 uM) perfusion. Dual-sided sub-Endo-sub-Epi optical mapping revealed that AF was driven by spatially and temporally stable intramural re-entry with 107 +/- 50 ms cycle length and transmural activation delay of 67 +/- 31 ms. Intramural re entrant drivers were captured primarily by sub-Endo mapping, while sub-Epi mapping visualized re-entry or 'breakthrough' patterns. Re-entrant drivers were anchored on 3D micro-anatomic tracks (15.4 +/- 2.2 * 6.0 +/- 2.3 mm2, 2.9 +/- 0.9 mm depth) formed by atrial musculature characterized by increased transmural fiber angle differences and interstitial fibrosis. Targeted radiofrequency ablation of the tracks verified these re-entries as drivers of AF. CONCLUSIONS: Integrated 3D structural-functional mapping of diseased human right atria ex vivo revealed that the complex atrial microstructure caused significant differences between Endo vs. Epi activation during pacing and sustained AF driven by intramural re-entry anchored to fibrosis-insulated atrial bundles. PMID- 26059726 TI - The roles of stimulus and response uncertainty in forced-choice performance: an amendment to Hick/Hyman Law. AB - Hick/Hyman Law describes one of the core phenomena in the study of human information processing: mean response time is a linear function of average uncertainty. In the original work of Hick, (1952) and Hyman, (1953), along with many follow-up studies, uncertainty regarding the stimulus and uncertainty regarding the response were confounded such that the relative importance of these two factors remains mostly unknown. The present work first replicates Hick/Hyman Law with a new set of stimuli and then goes on to separately estimate the roles of stimulus and response uncertainty. The results demonstrate that, for a popular type of task-visual stimuli mapped to vocal responses-response uncertainty accounts for a majority of the effect. The results justify a revised expression of Hick/Hyman Law and place strong constraints on theoretical accounts of the law, as well as models of response selection in general. PMID- 26059727 TI - Pathophysiology and management of acne. PMID- 26059728 TI - Understanding innate immunity and inflammation in acne: implications for management. AB - Acne has long been understood to have a complex physiological basis involving several main factors: hormonally-stimulated sebum production, abnormal keratinization of the pilosebaceous duct, and an inflammatory immune response to Propionibacterium acnes. Recent studies at the molecular and cellular level have begun clarifying how all of these factors interact, and the role of the innate immune system is better appreciated. Inflammation has been demonstrated in all acne lesions - the preclinical microcomedo, comedones, inflammatory lesions, 'post-inflammatory' erythema or hyperpigmentation, and scarring. Inflammation localized to the pilosebaceous unit can be considered the defining feature of acne and should be addressed via multiple therapeutic pathways. Clinicians tend to think oral antibiotics should be used to 'calm' inflammatory acne, but there is good evidence showing that topical retinoids also have anti-inflammatory properties as a class effect. For best therapeutic outcomes, most patients with acne should be treated first line with a topical retinoid plus an antimicrobial agent, as has been demonstrated in thousands of patients involved in clinical trials and recommended by the Global Alliance to Improve Outcomes in Acne for more than a decade. Moving away from reliance on antibiotic therapy for acne is particularly important in an era of worsening antimicrobial resistance and worldwide calls to reduce antibiotic use. Improved understanding about the role of P. acnes and the innate immune system in acne should help clinicians in designing efficacious treatment strategies. PMID- 26059729 TI - Acne and quality of life - impact and management. AB - Acne is a common skin disease with a high prevalence in adolescents and young adults. In addition to physical effects such as permanent scarring and disfigurement, acne has long-lasting psychosocial effects that affect the patient's quality of life. Depression, social isolation and suicidal ideation are frequent comorbidities of acne that should not be neglected in the therapy of acne patients. Research evidence suggests that the impairment of quality of life can be alleviated by appropriate topical acne treatment. PMID- 26059730 TI - Safety and efficacy of adapalene 0.1% / benzoyl peroxide 2.5% in the long-term treatment of predominantly moderate acne with or without concomitant medication - results from the non-interventional cohort study ELANG. AB - BACKGROUND: Acne is a chronic inflammatory disease requiring long-term treatment. The fixed-dose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-BPO) is indicated for the once-daily topical treatment of Acne vulgaris when comedones, papules and pustules are present. OBJECTIVE: The main objectives of this non-interventional study were to assess long-term efficacy and safety of adapalene-BPO in moderate to severe acne with and without concomitant medication. METHODS: Patients with moderate to severe acne received adapalene-BPO alone or in combination with concomitant medication over a course of 9 months. The primary efficacy endpoint was changes in acne severity according to the Leeds Revised Acne Grading System; secondary endpoints included treatment success assessed by the patient and safety. RESULTS: In total, 5131 patients were eligible for efficacy and 5141 for safety evaluation. The majority of patients (78.8%) received adapalene-BPO alone. About 21.2% received adapalene-BPO in combination with another agent, mostly topical antibiotics (8.8%) or systemic antibiotics (8.7%). Mean (+/-SD) acne severity improved from 5.6 +/- 1.5 at baseline to 3.3 +/- 1.9 at month 3, and further to 1.9 +/- 1.9 at month 9 (both P < 0.0001). The degree of improvement correlated significantly with the severity at baseline. After 3 and 9 months of treatment, the facial skin was cleared completely (no more visible acne lesions) in 420 (8.2%) and 1326 patients (25.8%), respectively. A therapeutic effect was noted by the patients after a median time of 3 weeks (range: from 1 day to 12 weeks). No serious adverse events were reported. Facial skin irritations, mostly mild to moderate, occurred in 49.5% of patients and led to discontinuation in only 1.7% of cases. CONCLUSION: In consistence with previous clinical findings, the use of adapalene-BPO in daily practice routine is safe and effective in the long-term management of patients with moderate to severe acne. PMID- 26059732 TI - Adiabatic ionization energies of the overlapped A(2)A1 and B(2)E electronic states in CH3Cl(+)/CH3F(+) measured with double imaging electron/ion coincidence. AB - Utilizing the vacuum ultraviolet (VUV) synchrotron radiation and a double imaging photoelectron photoion coincidence (i(2)PEPICO) technique, we have measured the adiabatic ionization energies (AIEs) of the overlapped A(2)A1 and B(2)E electronic states of CH3Cl(+) and CH3F(+) ions. We show that the two overlapped electronic states can be separated in the electron and ion kinetic energy correlation diagrams based on their state-specific dissociation dynamics, leading to different kinetic energies released in dissociation, along the CH3(+) fragmentation channel. Thus the correlation diagrams yielded values of 13.67 +/- 0.03 and 14.77 +/- 0.03 eV for the AIEs of the A(2)A1 and B(2)E states of CH3Cl(+), and 16.08 +/- 0.03 and 17.00 +/- 0.05 eV for CH3F(+), respectively. This method can be generalized to separate ionic states that are otherwise overlapped in normal photoelectron spectra (PES), especially by combining VUV sources and electron/ion coincidence techniques. PMID- 26059731 TI - Effect of adapalene 0.1%/benzoyl peroxide 2.5% topical gel on quality of life and treatment adherence during long-term application in patients with predominantly moderate acne with or without concomitant medication - additional results from the non-interventional cohort study ELANG. AB - BACKGROUND: In addition to physical long-lasting effects such as permanent scarring and disfigurement, acne has acute and long-term psychosocial effects that affect the individual's quality of life. As with other chronic diseases, treatment success is often compromised by poor adherence. OBJECTIVE: Two main objectives of this non-interventional study were to assess the long-term effect of the fixed-dose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-BPO gel) on quality of life and treatment adherence. METHODS: Patients with moderate to severe facial acne receiving adapalene-BPO alone or in combination with other drugs were enrolled in this non-interventional study. Data were documented at baseline and after 3 and 9 months of adapalene-BPO treatment. The secondary outcomes reported here include quality of life determined by the Cardiff Acne Disability Index (CADI), treatment adherence assessed by the ECOB (Elaboration d'un outil d'evaluation de l'observance des traitements medicamenteux) questionnaire, and patient satisfaction. RESULTS: In total, 5131 patients were included in the efficacy evaluation. After 9 months, mean (+/-SD) quality of life (CADI) improved significantly from 5.9 +/- 3.0 to 2.4 +/- 2.7 (P < 0.0001). Patients with more severe acne at baseline tended to achieve a greater improvement in quality of life. Long-term adherence was found to be good in 83.9% of patients. Adherence had a significant effect on efficacy and quality of life (P < 0.0001 respectively). The vast majority of patients (92.1%) reported subjective improvement at the interim analysis. Accordingly, most patients (84.8%) were satisfied or very satisfied with adapalene-BPO by the end of the observation period. CONCLUSION: The clinical improvement of the disease led to an increase in quality of life among acne patients. The treatment success may be a motivation factor for patients to stay adherent over the long-term treatment course, indicating the qualification of adapalene-BPO topical gel as an appropriate medication also in the long-term usage. PMID- 26059733 TI - ABCG2 overexpression in patients with acute myeloid leukemia: Impact on stem cell transplantation outcome. AB - ABGG2 protein overexpression in acute myeloid leukemia (AML) has been associated with poor response to conventional chemotherapy and increased relapse risk. No data are available on the role of allogeneic stem cell transplantation (SCT) in reversing its negative prognostic role. We have reviewed the outcome of 142 patients with high risk AML who underwent allogeneic SCT in complete remission (n = 94) or with active disease (n = 48). Patients with ABCG2 overexpression at AML diagnosis have lower leukemia free survival (LFS) and increased cumulative incidence of relapse (CIR) compared with ABCG2- patients (5-year LFS 50% vs. 65%, P = 0.01; 5-year CIR 46% vs. 27%, P = 0.003). Five-year overall survival was not significantly different between ABCG2+ and ABCG2- patients (39% vs. 51%, P = 0.1). However, if we consider only disease-related deaths, ABCG2 maintains its negative role (64% vs. 78%, P = 0.018). The negative impact of ABCG2 overexpression was higher in patients undergoing SCT in CR compared with patients receiving transplant with active disease. Conditioning regimen did not abrogate the effect of ABCG2 overexpression, as CIR was higher in ABCG2+ patients receiving both myeloablative (44% vs. 22%, P = 0.018) or reduced intensity conditioning (50% vs. 32%, P = 0.03). In conclusion, ABCG2 overexpression at AML diagnosis identifies a subset of patients with poor outcome also after allogeneic SCT, mainly in terms of higher relapse rates. Prospective studies employing conditioning drugs or post-transplant strategies able to target ABCG2 are needed to maximize the curative potential of stem cell transplantation. PMID- 26059734 TI - Simple and Efficient System for Combined Solar Energy Harvesting and Reversible Hydrogen Storage. AB - Solar energy harvesting and hydrogen economy are the two most important green energy endeavors for the future. However, a critical hurdle to the latter is how to safely and densely store and transfer hydrogen. Herein, we developed a reversible hydrogen storage system based on low-cost liquid organic cyclic hydrocarbons at room temperature and atmospheric pressure. A facile switch of hydrogen addition (>97% conversion) and release (>99% conversion) with superior capacity of 7.1 H2 wt % can be quickly achieved over a rationally optimized platinum catalyst with high electron density, simply regulated by dark/light conditions. Furthermore, the photodriven dehydrogenation of cyclic alkanes gave an excellent apparent quantum efficiency of 6.0% under visible light illumination (420-600 nm) without any other energy input, which provides an alternative route to artificial photosynthesis for directly harvesting and storing solar energy in the form of chemical fuel. PMID- 26059736 TI - Should dobutamine be used in severe scorpion envenomation. PMID- 26059737 TI - Pedagogical Implications of Partnerships Between Psychiatry and Obstetrics Gynecology in Caring for Patients with Major Mental Disorders. AB - OBJECTIVE: Because there are no formal reviews, the authors set out to identify and describe programs that serve female patients with major mental disorders by integrating mental health care with services in obstetrics and gynecology and to describe the pedagogical implications of those programs. METHOD: The authors searched PubMed for all articles describing a program in which psychiatry was formally integrated with obstetric or gynecological services, other than standard consultation-liaison programs, in the care of patients with major mental disorders. The search terms used included interdisciplinary, interprofessional, integrated, collaborative care, psychiatry, and obstetrics-gynecology or psychosomatic obstetrics-gynecology. RESULTS: The authors found six distinct integrated programs. These included family planning clinics that were integrated into inpatient psychiatry services; inpatient and outpatient psychiatry services for pregnant mentally ill women in close collaboration with obstetric services; a day hospital for pregnant women with psychiatric disorders in an obstetric setting; an interdisciplinary training site providing care for predominantly depressed, low-income, and minority women; a primary care HIV service for women integrated with departments of obstetrics-gynecology and psychiatry; and an obstetrics-gynecology clinic-based collaborative depression care intervention for socially disadvantaged women. Residents' involvement was described in four of the programs. CONCLUSIONS: These innovative and integrated programs potentially enhance the care of vulnerable and culturally diverse women with major mental disorders. The authors discuss how these programs may contribute to the education of residents in psychiatry and obstetrics-gynecology. PMID- 26059735 TI - Methodology for AACT evidence-based recommendations on the use of intravenous lipid emulsion therapy in poisoning. AB - Intravenous lipid emulsion (ILE) therapy is a novel treatment that was discovered in the last decade. Despite unclear understanding of its mechanisms of action, numerous and diverse publications attested to its clinical use. However, current evidence supporting its use is unclear and recommendations are inconsistent. To assist clinicians in decision-making, the American Academy of Clinical Toxicology created a workgroup composed of international experts from various clinical specialties, which includes representatives of major clinical toxicology associations. Rigorous methodology using the Appraisal of Guidelines for Research and Evaluation or AGREE II instrument was developed to provide a framework for the systematic reviews for this project and to formulate evidence-based recommendations on the use of ILE in poisoning. Systematic reviews on the efficacy of ILE in local anesthetic toxicity and non-local anesthetic poisonings as well as adverse effects of ILE are planned. A comprehensive review of lipid analytical interferences and a survey of ILE costs will be developed. The evidence will be appraised using the GRADE system. A thorough and transparent process for consensus statements will be performed to provide recommendations, using a modified Delphi method with two rounds of voting. This process will allow for the production of useful practice recommendations for this therapy. PMID- 26059738 TI - Pathways to a Career in Military Psychiatry. PMID- 26059739 TI - Anti-nephrolithic potential of catechin in melamine-related urolithiasis via the inhibition of ROS, apoptosis, phospho-p38, and osteopontin in male Sprague-Dawley rats. AB - The addition of melamine to infant formula may cause urolithiasis in humans and animals. This study examined the effects of catechin, an antioxidant, on melamine cyanuric acid mixture (MCM)-induced crystallization in vitro and in vivo. In an in vitro study, crystal formation induced by an MCM was evaluated in media under various pH conditions and with catechin co-treatment. In an in vivo study, rats were administered an MCM (400 mg/kg, 1:1, via oral feeding tube) for four weeks and co-treated with catechin, after which crystal formation was observed. Oxidative stress biomarkers and nephrotoxicity were measured. Apoptotic cells were examined using the TUNEL assay. Phospho-p38 and osteopontin were evaluated via immunohistochemistry and Western blotting. MCM-induced crystal formation was pH-dependent in conditioned media, and catechin reduced the overall number of crystals. In the in vivo study, catechin suppressed MCM-induced protein expression and apoptosis in rats. Catechin consistently reduced the MCM-mediated production of renal malondialdehyde (MDA) and urinary 8-isoprostane (8-IP) in MCM treated rats. The activities of antioxidant enzymes such as superoxide dismutase (SOD) were enhanced by catechin. Catechin consistently and significantly reduced levels of renal crystals and nephrotoxicity. Our findings suggest that catechin exhibits anti-nephrolithic potential by chemically inhibiting the formation of crystals and by inhibiting reactive oxygen species, apoptosis, phospho-P38, and osteopontin signaling in rats. PMID- 26059740 TI - Excess processing of oxidative damaged bases causes hypersensitivity to oxidative stress and low dose rate irradiation. AB - Ionizing radiations such as X-ray and gamma-ray can directly or indirectly produce clustered or multiple damages in DNA. Previous studies have reported that overexpression of DNA glycosylases in Escherichia coli (E. coli) and human lymphoblast cells caused increased sensitivity to gamma-ray and X-ray irradiation. However, the effects and the mechanisms of other radiation, such as low dose rate radiation, heavy-ion beams, or hydrogen peroxide (H2O2), are still poorly understood. In the present study, we constructed a stable HeLaS3 cell line overexpressing human 8-oxoguanine DNA N-glycosylase 1 (hOGG1) protein. We determined the survival of HeLaS3 and HeLaS3/hOGG1 cells exposed to UV, heavy-ion beams, gamma-rays, and H2O2. The results showed that HeLaS3 cells overexpressing hOGG1 were more sensitive to gamma-rays, OH(*), and H2O2, but not to UV or heavy ion beams, than control HeLaS3. We further determined the levels of 8-oxoG foci and of chromosomal double-strand breaks (DSBs) by detecting gamma-H2AX foci formation in DNA. The results demonstrated that both gamma-rays and H2O2 induced 8-oxoguanine (8-oxoG) foci formation in HeLaS3 cells. hOGG1-overexpressing cells had increased amounts of gamma-H2AX foci and decreased amounts of 8-oxoG foci compared with HeLaS3 control cells. These results suggest that excess hOGG1 removes the oxidatively damaged 8-oxoG in DNA more efficiently and therefore generates more DSBs. Micronucleus formation also supported this conclusion. Low dose-rate gamma-ray effects were also investigated. We first found that overexpression of hOGG1 also caused increased sensitivity to low dose rate gamma ray irradiation. The rate of micronucleus formation supported the notion that low dose rate irradiation increased genome instability. PMID- 26059741 TI - [More than 10 years of follow up of the stop screw technique]. AB - INTRODUCTION: Infantile flexible flatfoot does not require treatment in most cases. Symptomatic flexible flat feet are treated orthopaedically and surgery is only indicated when orthosis fails. MATERIAL AND METHODS: Cases who underwent surgical treatment with the stop screw technique at the 12 de Octubre Hospital between 1995 and 2002 are reported. Patient progress is also analysed. Six angles are measured on the x-ray prior to surgery and those same x-ray angles are measured again before material extraction. They are then compared to see if the correction achieved is statistically significant. A more reduced sample is currently being assessed with the same radiological measurements and two clinical assessment scales: Lickert, and Smith and Millar. The latest x-rays are analysed by two radiologists to determine if there is subtalar arthrosis. RESULTS: In the short term, statistically significant differences are observed in all angles. The comparison between the post-surgery angles and the current angles does not show differences, except for the Giannestras angle, which has statistically significantly worsened. Clinical results and patient satisfaction is good. Incipient subtalar arthrosis is present in 68.5% of current patient x-rays. CONCLUSIONS: Stop screw method is a cheap, simple and effective technique to correct symptomatic flexible flatfoot that has not improved with conservative treatment. This technique provides short-term foot correction which can be maintained over time. PMID- 26059742 TI - Added Value of MRI over CT of the Brain in Intensive Care Unit Patients. AB - BACKGROUND: Intensive care unit (ICU) patients with neurological impairments often require neuroimaging. However, the relative sensitivity of various imaging modalities of the brain has not yet been explored in this population. METHODS: In this study, we compare the findings of CT and MRI scans in ICU patients to (1) identify the number and rate of clinically relevant lesion detected by MRI while missed by CT and vice versa and (2) determine specific lesion types for which CT versus MRI discrepancies exist. A review of medical records included CT and MRI reports of patients who underwent these procedures while they were patients in our ICUs between July 2004 and July 2009. MRI and CT were compared regarding their ability to detect clinically relevant abnormalities. Odds ratios with 95% confidence limits were calculated to compare diagnostic categories regarding the rate of discrepant MRI versus CT findings, followed by power analyses to estimate sample sizes necessary to allow for further testing in a larger trial. RESULTS: MRI revealed clinically relevant additional abnormalities over CT in 129 of 136 patients (95%) that included the detection of additional finding for 15/27 hemorrhagic lesions (55.6%), 33/36 (92%) ischemic strokes, 19/27 (70%) traumatic lesions, 8/14 (57%) infections, 15/24 (62.5%) metabolic abnormalities, and all seven neoplasms. Odds ratio analysis revealed the added sensitivity of MRI to be greater for ischemic and neoplastic lesions than for trauma, metabolic-related abnormalities, infection, or hemorrhage. CONCLUSIONS: MRI is more sensitive than CT in identifying clinically meaningful lesions in at least a subset of ICU patients, regardless of pathology. PMID- 26059743 TI - 17-ABAG, a novel geldanamycin derivative, inhibits LNCaP-cell proliferation through heat shock protein 90 inhibition. AB - Prostate cancer is one of the most common cancer types worldwide. In 2014, there were an estimated 233,000 new cases and 29,480 mortalities in the United States. Androgen deprivation therapy, also called androgen suppression therapy, targets androgen signaling and remains the standard treatment for patients with advanced prostate cancer; however, responses to treatment are not durable and most patients advance to castrate-resistant prostate cancer. Therefore, novel therapeutic strategies to treat prostate cancer are urgently required. Heat shock protein 90 (Hsp90) is a chaperone protein that has been shown to regulate the progression of tumor cells. Numerous Hsp90 inhibitors show anti-tumor activity and several of them have entered clinical trials. Geldanamycin (GA) was identified as the first Hsp90 inhibitor, but shows hepatotoxicity at its effective concentrations, limiting its clinical use. In previous studies by our group, the GA derivative 17-ABAG was designed and synthesized. The present study showed that 17-ABAG inhibits the proliferation and induces apoptosis of LNCaP, an androgen-dependent prostate cancer cell line, in vitro through a classic apoptotic pathway. 17-ABAG also downregulated the Hsp90 client protein and inhibited androgen receptor nuclear localization in LNCaP cells. In addition, 17 ABAG suppressed the growth of LNCaP xenograft tumors without any obvious side effects. The present study demonstrated that 17-ABAG is a promising anti-tumor agent and warrants further validation in prospective studies. PMID- 26059744 TI - Academic Attainment in Students with Dyslexia in Distance Education. AB - This investigation studied attainment in students with dyslexia or other specific learning difficulties who were taking modules by distance learning with the Open University in 2012. Students with dyslexia or other specific learning difficulties who had no additional disabilities were just as likely as nondisabled students to complete their modules, but they were less likely to pass the modules that they had completed and less likely to obtain good grades on the modules that they had passed. Students with dyslexia or other specific learning difficulties who had additional disabilities were less likely to complete their modules, less likely to pass the modules that they had completed and less likely to obtain good grades on the modules that they had passed than were nondisabled students. Nevertheless, around 40% of students with dyslexia or other specific learning difficulties obtained good grades (i.e. those that would lead to a bachelor's degree with first-class or upper second-class honours). PMID- 26059745 TI - A combination of isolated phytochemicals and botanical extracts lowers diastolic blood pressure in a randomized controlled trial of hypertensive subjects. AB - BACKGROUND/OBJECTIVES: Isolated phytochemicals have been shown to reduce blood pressure; however, combinations of phytochemicals have rarely been tested in humans. We hypothesized that a combination of extracts from grape seed and skin (330 mg), green tea (100 mg), resveratrol (60 mg) and a blend of quercetin, ginkgo biloba and bilberry (60 mg) would reduce blood pressure (BP) in hypertensive subjects. SUBJECTS/METHODS: Eighteen individuals meeting BP requirements (?130 mm Hg systolic or ?85 mm Hg diastolic) and criteria for metabolic syndrome were enrolled in a double-blinded, placebo-controlled, crossover trial (ClinicalTrials.gov, NCT01106170). The 28-day placebo and supplement arms were separated by a 2-week washout period, and 14 -h daytime ambulatory BP was assessed at baseline and at the end point of each arm. RESULTS: BP was not altered after placebo. After supplement treatment, diastolic pressure was reduced by 4.4 mm Hg (P=0.024, 95% CI, 0.6-8.1), systolic pressure was unchanged and mean arterial pressure trended (P=0.052) toward reduction. Serum angiotensin-converting enzyme activity was similar between placebo and supplement arms, but urinary nitrate and nitrite concentrations were significantly increased (P=0.022) after supplementation. Human aortic endothelial cells treated with metabolites of the polyphenols used in the human supplement trial had a significant increase (P=0.005) in insulin-stimulated eNOS phosphorylation and greater (P<0.001) accumulation of nitrates/nitrites. CONCLUSIONS: Our clinical and in vitro data support the theory that this combination of polyphenols reduced diastolic pressure by potentiating eNOS activation and nitric oxide production. Such supplements may have clinical relevance as stand-alone or adjunct therapy to help reduce BP. PMID- 26059746 TI - Multilayered, Hyaluronic Acid-Based Hydrogel Formulations Suitable for Automated 3D High Throughput Drug Screening of Cancer-Stromal Cell Cocultures. AB - Validation of a high-throughput compatible 3D hyaluronic acid hydrogel coculture of cancer cells with stromal cells. The multilayered hyaluronic acid hydrogels improve drug screening predictability as evaluated with a panel of clinically relevant chemotherapeutics in both prostate and endometrial cancer cell lines compared to 2D culture. PMID- 26059747 TI - Impact of co-morbidity on mortality after oesophageal cancer surgery. AB - BACKGROUND: There is limited knowledge of how co-morbidities influence survival after surgery for oesophageal cancer. This population-based cohort study investigated how Charlson co-morbidity index and specific co-morbidities influenced all-cause and disease-specific mortality. METHODS: Data from all patients who underwent oesophageal cancer surgery in Sweden in 1987-2010, with follow-up until 2012, came from histopathology records, operation charts and nationwide registers. Associations between co-morbidities (Charlson co-morbidity index) and mortality were analysed using Cox proportional hazard regression with adjustment for potential confounding, and presented as hazard ratio (HR) with 95 per cent c.i. RESULTS: Among 1822 patients there were 1474 deaths (80.9 per cent), of which 1139 (77.3 per cent) occurred between 91 days and 5 years after surgery. Overall all-cause mortality was increased in patients with a Charlson score of 2 or more (HR 1.24, 95 per cent c.i. 1.08 to 1.42), and those with a history of myocardial infarction (HR 1.23, 1.01 to 1.49) or congestive heart failure (HR 1.31, 1.04 to 1.67). Patients with squamous cell carcinoma had increased overall all-cause mortality if they had been diagnosed with cerebrovascular disease (HR 1.35, 1.00 to 1.83) or other cancers (HR 1.36, 1.09 to 1.71), whereas those with adenocarcinoma did not. A Charlson score of 1 or exposure to the co-morbidity groups peripheral vascular disease, chronic pulmonary disease, connective tissue disease, peptic ulcer disease, diabetes and liver disease did not increase mortality. The disease-specific results were generally similar to the all-cause mortality data. CONCLUSION: Co-morbidity with a Charlson score of 2 or more, previous myocardial infarction and congestive heart failure were associated with increased mortality after oesophageal cancer surgery undertaken with curative intent. PMID- 26059748 TI - The effects of aerobic endurance exercise on pulse wave velocity and intima media thickness in adults: A systematic review and meta-analysis. AB - The aim of this study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) or cohort studies that evaluated the effect of aerobic endurance exercise on pulse wave velocity (PWV) and intima media thickness (IMT) in adults. IMT and PWV were the most commonly used parameters for the assessment of arterial stiffness. The MEDLINE, Cochrane, ISI, and Ovid databases were searched between January 2000 and February 2015. A total of 1654 participants in 26 RCTs and two cohort studies were included in the meta analysis. In studies for which PWV was the outcome, aerobic endurance exercise had a significant effect on reducing PWV [-0.67, 95% CI -0.97, -0.38; I(2) = 89%; heterogeneity, P < 0.0001]. Changes in peripheral arterial PWV were statistically greater than in central arterial PWV. In the RCTs for which IMT was the outcome, changes [-0.04, 95% CI -0.12, 0.04; I(2) = 95%; heterogeneity, P < 0.00001] in IMT did not reach statistical significance. In the two cohort studies, changes [ 8.81, 95% CI -9.25, -8.37; I(2) = 22%; heterogeneity, P = 0.26] in IMT were statistically significant. Subgroup analysis indicated a longer duration aerobic exercise and a greater improvement in VO2max were associated with larger reductions in PWV. Reductions in IMT were observed in two cohort studies, but not in four RCTs. PMID- 26059749 TI - Unaltered ratio of circulating levels of growth hormone/GH isoforms in adults with Prader-Willi syndrome after GHRH plus arginine administration. AB - Human growth hormone (GH) is a heterogeneous protein hormone consisting of several isoforms, the most abundant being 22 kDa- and 20 kDa-GH. The availability of analytical methods to measure these GH isoforms might represent a valuable diagnostic tool to investigate GH hyposecretory states, including Prader-Willi syndrome (PWS), one of the most common causes of syndromic obesity. The aim of the present study was to measure circulating levels of 22 kDa- and 20 kDa-GH in PWS adults (n=14; M/F: 5/9; genotype DEL15/UPD15: 12/2; age: 19.0+/-3.7 years; BMI: 29.9+/-8.7 kg/m2) after combined GH releasing hormone (GHRH) plus arginine (ARG) administration. The results were analysed subdividing the study population in obese vs. nonobese (6/8) and GH deficient vs. nonGH deficient (GHD) (6/8) subjects, according to appropriate BMI-related diagnostic cut-off limits of GH peak response to the provocative test. Circulating levels of 22 kDa-GH were measured by a chemiluminescent method based on a detection monoclonal antibody targeting an epitope in the loop connecting helix 1 and 2 of GH, which is missing in 20 kDa-GH; the 20 kDa-GH was measured using a time resolved fluorescence assay based on two monoclonal antibodies with no cross-reactivity to 22-kDa GH. GHRH plus ARG significantly stimulated the secretions of 22 kDa- and 20 kDa-GH in nonobese (at 30, 45, 60 and 90 min and at 45, 60, 90 and 120 min vs. 0 min, p<0.05, with GH peaks of 15.8+/-10.3 ng/ml and 2.7+/-1.2 ng/ml, respectively) and in nonGHD PWS (at 30, 45 and 60 min and at 45, 60 and 90 min vs 0 min, p<0.05, with GH peaks of 12.5+/-9.0 ng/ml and 2.0+/-1.8 ng/ml, respectively). No significant GHRH plus ARG-induced changes in 22 kDa- and 20 kDa-GH were observed in obese or GHD PWS patients, the only exception being the increase of 22 kDa-GH (p<0.05) 60 min after the stimulus administration in GHD group (with GH peaks of 6.9+/-4.7 ng/ml and 0.8+/-0.6 ng/ml in obese subjects and 8.5+/-6.0 ng/ml and 1.2+/-1.0 ng/ml in GHD subjects for 22 kDa- and 20 kDa-GH, respectively). The GH responses for both isoforms were significantly higher in nonobese than in obese PWS patients (at 45 and 60 min for 22 kDa-GH and at 45, 60, 90 and 120 min for 20 kDa-GH, p<0.05), while no differences were detected between GHD vs. nonGHD groups. As previously reported in healthy subjects, the ratios of circulating levels of 22 kDa- to 20 kDa-GH remained constant after GHRH plus ARG both in obese/non-obese and GHD/non-GHD groups, thus suggesting the preservation of a normal balance in GH isoforms in PWS. PMID- 26059750 TI - The growth hormone receptor. AB - Once thought to be present only in liver, muscle and adipose tissue, the GH receptor is now known to be ubiquitously distributed, in accord with the many pleiotropic actions of GH. These include the regulation of metabolism, postnatal growth, cognition, immune, cardiac and renal systems and gut function. GH exerts these actions primarily through alterations in gene expression, initiated by activation of its membrane receptor and the resultant activation of the associated JAK2 (Janus kinase 2) and Src family kinases. Receptor activation involves hormone initiated movements within a receptor homodimer, rather than simple receptor dimerization. We have shown that binding of the hormone realigns the orientation of the two receptors both by relative rotation and by closer apposition just above the cell membrane. This is a consequence of the asymmetric placement of the binding sites on the hormone. Binding results in a conversion of parallel receptor transmembrane domains into a rotated crossover orientation, which produces separation of the lower part of the transmembrane helices. Because the JAK2 is bound to the Box1 motif proximal to the inner membrane, receptor activation results in separation of the two associated JAK2s, and in particular the removal of the inhibitory pseudokinase domain from the kinase domain of the other JAK2 (and vice versa). This brings the two kinase domains into position for trans-activation and initiates tyrosine phosphorylation of the receptor cytoplasmic domain and other substrates such as STAT5, the key transcription factor mediating most genomic actions of GH. There are a limited number of genomic actions initiated by the Src kinase family member which also associates with the upper cytoplasmic domain of the receptor, including important immune regulatory actions to dampen exuberant innate immune activation of cells involved in transplant rejection. These findings offer insights for developing specific receptor antagonists which may be valuable in cancer therapy. PMID- 26059751 TI - Magnetic resonance imaging-quantified small bowel motility is a sensitive marker of response to medical therapy in Crohn's disease. AB - BACKGROUND: Magnetic resonance enterography (MRE) can measure small bowel motility, reduction in which reflects inflammatory burden in Crohn's Disease (CD). However, it is unknown if motility improves with successful treatment. AIM: To determine if changes in segmental small bowel motility reflect response to anti-TNFalpha therapy after induction and longer term. METHODS: A total of 46 patients (median 29 years, 19 females) underwent MRE before anti-TNFalpha treatment; 35 identified retrospectively underwent repeat MRE after median 55 weeks of treatment and 11 recruited prospectively after median 12 weeks. Therapeutic response was defined by physician global assessment (retrospective group) or a >=3 point drop in the Harvey-Bradshaw Index (prospective group), C reactive protein (CRP) and the MaRIA score. Two independent radiologists measured motility using an MRE image-registration algorithm. We compared motility changes in responders and nonresponders using the Mann-Whitney test. RESULTS: Anti TNFalpha responders had significantly greater improvements in motility (median = 73.4% increase from baseline) than nonresponders (median = 25% reduction, P < 0.001). Improved MRI-measured motility was 93.1% sensitive (95%CI: 78.0-98.1%) and 76.5% specific (95% CI: 52.7-90.4%) for anti-TNFalpha response. Patients with CRP normalisation (<5 mg/L) had significantly greater improvements in motility (median = 73.4% increase) than those with persistently elevated CRP (median = 5.1%, P = 0.035). Individuals with post-treatment MaRIA scores of <11 had greater motility improvements (median = 94.7% increase) than those with post-treatment MaRIA score >11 (median 15.2% increase, P = 0.017). CONCLUSIONS: Improved MRI measured small bowel motility accurately detects response to anti-TNFalpha therapy for Crohn's disease, even as early as 12 weeks. Motility MRI may permit early identification of nonresponse to anti-TNFalpha agents, allowing personalised treatment. PMID- 26059752 TI - Population genetic structure of Oryza sativa in East and Southeast Asia and the discovery of elite alleles for grain traits. AB - We investigated the nuclear simple sequence repeat (SSR) genotypes of 532 rice (Oryza sativa L.) accessions collected from East and Southeast Asia and detected abundant genetic diversity within the population. We identified 6 subpopulations and found a tendency towards directional evolution in O. sativa from low to high latitudes, with levels of linkage disequilibrium (LD) in the 6 subpopulations ranging from 10 to 30 cM. We then investigated the phenotypic data for grain length, grain width, grain thickness and 1,000-grain weight over 4 years. Using a genome-wide association analysis, we identified 17 marker-trait associations involving 14 SSR markers on 12 chromosome arms, and 8 of the 17 associations were novel. The elite alleles were mined based on the phenotypic effects of the detected quantitative trait loci (QTLs). These elite alleles could be used to improve target traits through optimal cross designs, with the expected results obtained by pyramiding or substituting the elite alleles per QTL (independent of possible epistatic effects). Together, these results provide an in-depth understanding of the genetic diversity pattern among rice-grain traits across a broad geographic scale, which has potential use in future research work, including studies related to germplasm conservation and molecular breeding by design. PMID- 26059753 TI - Mapping of the epitopes of poliovirus type 2 in complex with antibodies. AB - The inactivated polio vaccine (IPV) contains poliovirus (PV) samples that belong to serotypes 1, 2 and 3. All three serotypes contain the D-antigen, which induces protective antibodies. The antigenic structure of PVs consists of at least four different antigenic sites and the D-antigen content represents the combined activity of multiple epitopes (Ferguson et al., 1993; Minor, 1990; Minor et al., 1986). The potency of IPV vaccines is determined by measuring the D-antigen content. Several ELISA methods have been developed using polyclonal or monoclonal antibodies (Mabs) in order to quantify the D-antigen content. Characterization of the epitopes recognized by the different Mabs is crucial to map the entire virus surface and ensure the presence of epitopes able to induce neutralizing antibodies. Using a new approach that we developed to study the interaction between monoclonal antibodies and poliovirus type 2, which combines cryo-electron microscopy, image analysis and X-ray crystallography along with identification of exposed amino acids, we have mapped in 3D the epitope sites recognized by three specific Fabs at the surface of poliovirus type 2 (PV2) and characterized precisely the antigenic sites for these Fabs. PMID- 26059754 TI - Lipoteichoic acid isolated from Lactobacillus plantarum down-regulates UV-induced MMP-1 expression and up-regulates type I procollagen through the inhibition of reactive oxygen species generation. AB - BACKGROUND: Ultraviolet (UV) irradiation from the sun is the primary environmental factor that causes human skin aging. UV irradiation induces the expressions of matrix metalloproteinases (MMPs) and extracellular matrix degrading enzymes. Among the members of MMP family, MMP-1 is an interstitial collagenase that degrades the collagen triple helix. We investigated the effect of Lactobacillus plantarum, well known as useful microorganism, on UV-induced-MMP 1 expression in human dermal fibroblasts. METHODS: Human dermal fibroblasts (HDF) was pre-stimulated with lipoteichoic acid isolated from L. plantarum followed by UV irradiation. Secreted protein level of MMP-1 was evaluated by Western blot analysis. The phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB) from the cell lysates was also examined by western blotting. Electrophoretic mobility-shift assay (EMSA) was used to detect the activated transcription factor, AP-1 and NF-kappaB. The detection of type 1 procollagen was carried with Procollagen type 1 C-peptide (PIP) EIA kit. The generation of reactive oxygen species (ROS) by LTA and UV irradiation was examined by Griess reagent assay and fluorescence microscope. RESULTS: We found that lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, isolated from L. plantarum, inhibited MMP-1 expression. Pretreatment with LTA from L. plantarum (pLTA) reduced MMP-1 expression in a dose-dependent manner and inhibited activation of extracellular signal-regulated kinases (ERK) and c-Jun N terminal kinases (JNK). It also led to the inhibition of DNA binding activity of activator protein-1 (AP-1) and of nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kappaB). Furthermore, LTA promoted type 1 procollagen synthesis and reduced the generation of ROS induced by UV irradiation. CONCLUSION: Our study demonstrates that pLTA inhibits degradation of collagen and promotes its synthesis and that pLTA contributes to a decrease in ROS production. Therefore, pLTA from L. plantarum has potential abilities to prevent and treat skin photo-aging. PMID- 26059756 TI - Involvement of glutathione and glutathione metabolizing enzymes in human colorectal cancer cell lines and tissues. AB - Reduced glutathione (GSH) is an abundant tripeptide present in the majority of cell types. GSH is highly reactive and is often conjugated to other molecules, via its sulfhydryl moiety. GSH is synthesized from glutamic acid, cysteine, and glycine via two sequential ATP-consuming steps, which are catalyzed by glutamate cysteine ligase (GCL) and GSH synthetase (GSS). However, the role of GSH in cancer remains to be elucidated. The present study aimed to determine the levels of GSH and GSH synthetic enzymes in human colorectal cancer. The mRNA and protein expression levels of GSH, the catalytic subunit of GCL (GCLC) and GSS were significantly higher in the following five colon cancer cell lines: Caco-2, SNU 407, SNU-1033, HCT-116, and HT-29, as compared with the normal colon cell line, FHC. Similarly, in 9 out of 15 patients with colon cancer, GSH expression levels were higher in tumor tissue, as compared with adjacent normal tissue. In addition, the protein expression levels of GCLC and GSS were higher in the tumor tissue of 8 out of 15, and 10 out of 15 patients with colon cancer respectively, as compared with adjacent normal tissue. Immunohistochemical analyses confirmed that GCLC and GSS were expressed at higher levels in colon cancer tissue, as compared with normal mucosa. Since GSH and GSH metabolizing enzymes are present at elevated levels in colonic tumors, they may serve as clinically useful biomarkers of colon cancer, and/or targets for anti-colon cancer drugs. PMID- 26059755 TI - ZC3H12D attenuated inflammation responses by reducing mRNA stability of proinflammatory genes. AB - Infection in airspaces and lung parenchyma may cause acute lung injury and multiple organ dysfunction syndrome due to acute inflammatory response, leading to organ failure and high mortality. ZC3H12D has been shown to modulate Toll-like receptor signaling. This study aimed to investigate the change of ZC3H12D during acute lung injury and its role in inflammation processes. Mice were challenged with lipopolysaccharides (LPS) intratracheally. The expression levels of Zc3h12d, NF-kappaB, and cytokines were analyzed by quantitative real-time PCR (qPCR), ELISA, and Western blot. The mRNA stability was assessed by qPCR after cells were treated with actinomycin D for specified times. The 3' untranslated region (3' UTR) of c-fos was cloned immediately downstream of the luciferase coding sequence driven by CMV promoter and luciferase activity was measured with a Luciferase Assay kit. Upon LPS treatment, ZC3H12D levels were reduced in mouse immune cells, whereas levels of NF-kappaB, IL-6, and TNF-alpha were significantly increased. Knockdown Zc3h12d in THP1 cells resulted in the upregulation of NF-kappaB while overexpression of Zc3h12d inhibited NF-kappaB expression. Ectopic Zc3h12d significantly reduced the mRNA stability of c-fos, NF-kappaB, TNF-alpha, IL 1beta, and IL-6. Attachment of the c-fos 3'-UTR made luciferase expression levels sensitive to levels of ZC3H12D. The data indicated that ZC3H12D could suppress both the initial inflammation storm and chronic inflammation by targeting the mRNA of cytokines as well as NF-kappaB and c-fos. PMID- 26059758 TI - Operative margin control with high-resolution optical microendoscopy for head and neck squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: High-resolution microendoscopy (HRME) provides real-time visualization of the mucosal surface in the upper aerodigestive tract. This technology allows noninvasive discrimination of benign and neoplastic epithelium and has potential applications for intraoperative margin detection. STUDY DESIGN: Single institution, prospective, feasibility trial (phase I) of in vivo optical imaging. METHODS: The study was conducted on patients with squamous cell carcinoma of the upper aerodigestive tract. High-resolution microendoscopy images obtained during surgery were correlated with histopathologic diagnosis to determine the ability of HRME to differentiate between benign and malignant mucosa. Blinded reviewers evaluated HRME images and made determinations of the status of the mucosa. Accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and interrater agreement between multiple raters were calculated to determine the accuracy of HRME imaging. RESULTS: The mean accuracy of reviewers in differentiating neoplastic or benign mucosa was 95.1% (95% confidence interval [CI], 94%-96%). Sensitivity and specificity were 96% (95% CI, 94%-99%) and 95% (95 % CI, 90%-99%), respectively. The NPV was 98% (95% CI, 97%-99%), and PPV was 91% (95% CI, 85%-98%). The Fleiss kappa statistic for interrater reliability was 0.81, with a standard error of 0.014 and a 95% CI (0.78-0.84). CONCLUSION: High-resolution microendoscopy allows real-time discrimination between benign and neoplastic mucosa. High levels of sensitivity and specificity can be obtained with this technology when interrogating mucosal surfaces. Despite several technical limitations, HRME shows promise as a technique for intraoperative margin control and platform for molecular imaging technologies. LEVEL OF EVIDENCE: 3b. PMID- 26059757 TI - Magnetic Resonance Elastography: A Novel Technique for the Detection of Hepatic Fibrosis and Hepatocellular Carcinoma After the Fontan Operation. AB - OBJECTIVE: To evaluate the utility of magnetic resonance elastography (MRE) in screening patients for hepatic fibrosis, cirrhosis, and hepatocellular carcinoma after the Fontan operation. PATIENTS AND METHODS: Hepatic MRE was performed in conjunction with cardiac magnetic resonance imaging in patients who had undergone a Fontan operation between 2010 and 2014. Liver stiffness was calculated using previously reported techniques. Comparisons to available clinical, laboratory, imaging, and histopathologic data were made. RESULTS: Overall, 50 patients at a median age of 25 years (range, 21-33 years) who had undergone a Fontan operation were evaluated. The median interval between Fontan operation and MRE was 22 years (range, 16-26 years). The mean liver stiffness values were increased: 5.5 +/- 1.4 kPa relative to normal participants. Liver stiffness directly correlated with liver biopsy-derived total fibrosis score, time since operation, mean Fontan pressure, gamma-glutamyltransferase level, Model for End-Stage Liver Disease score, creatinine level, and pulmonary vascular resistance index. Liver stiffness was inversely correlated with cardiac index. All 3 participants with hepatic nodules exhibiting decreased contrast uptake on delayed postcontrast imaging and increased nodule stiffness had biopsy-proven hepatocellular carcinoma. CONCLUSION: The association between hepatic stiffness and fibrosis scores, Model for End-Stage Liver Disease scores, and gamma-glutamyltransferase level suggests that MRE may be useful in detecting (and possibly quantifying) hepatic cirrhosis in patients after the Fontan operation. The correlation between stiffness and post-Fontan time interval, mean Fontan pressure, pulmonary vascular resistance index, and reduced cardiac index suggests a role for long-term hepatic congestion in creating these hepatic abnormalities. Magnetic resonance elastography was useful in detecting abnormal nodules ultimately diagnosed as hepatocellular carcinoma. The relationship between stiffness with advanced fibrosis and hepatocellular carcinoma provides a strong argument for additional study and broader application of MRE in these patients. PMID- 26059759 TI - Mating with an allopatric male triggers immune response and decreases longevity of ant queens. AB - In species with lifelong pair bonding, the reproductive interests of the mating partners are aligned, and males and females are expected to jointly maximize their reproductive success. Mating increases both longevity and fecundity of female reproductives (queens) of the ant Cardiocondyla obscurior, indicating a tight co-evolution of mating partners. Here, we show that mating with a male from their own population increases lifespan and reproductive success of queens more than mating with a male from a different population, with whom they could not co evolve. A comparison of transcriptomes revealed an increased expression of genes involved in immunity processes in queens, which mated with males from a different population. Increased immune response might be proximately associated with decreased lifespan. Our study suggests a synergistic co-evolution between the sexes and sheds light on the proximate mechanisms underlying the decreased fitness of allopatrically mated queens. PMID- 26059760 TI - Non-linear, cata-Condensed, Polycyclic Aromatic Hydrocarbon Materials: A Generic Approach and Physical Properties. AB - A generic approach to the regiospecific synthesis of halogenated polycyclic aromatics is made possible by the one- or two-directional benzannulation reactions of readily available (ortho-allylaryl)trichloroacetates (the "BHQ" reaction). Palladium-catalysed cross-coupling reactions of the so-formed haloaromatics enable the synthesis of functionalised polycyclic aromatic hydrocarbons (PAHs) with surgical precision. Overall, this new methodology enables the facile mining of chemical space in search of new electronic functional materials. PMID- 26059761 TI - Agreement between clinical and portable EMG/ECG diagnosis of sleep bruxism. AB - The aim of this study was to compare clinical sleep bruxism (SB) diagnosis with an instrumental diagnosis obtained with a device providing electromyography/electrocardiography (EMG/ECG) recordings. Forty-five (N = 45) subjects (19 males and 26 females, mean age 28 +/- 11 years) were selected among patients referring to the Gnathology Unit of the Dental School of the University of Torino. An expert clinician assessed the presence of SB based on the presence of one or more signs/symptoms (i.e., transient jaw muscle pain in the morning, muscle fatigue at awakening, presence of tooth wear, masseter hypertrophy). Furthermore, all participants underwent an instrumental recording at home with a portable device (Bruxoff; OT Bioelettronica, Torino, Italy) allowing a simultaneous recording of EMG signals from both the masseter muscles as well as heart frequency. Statistical procedures were performed with the software Statistical Package for the Social Science v. 20.0 (SPSS 20.0; IBM, Milan, Italy). Based on the EMG/ECG analysis, 26 subjects (11 males, 15 females, mean age 28 +/- 10 years) were diagnosed as sleep bruxers, whilst 19 subjects (7 males, 12 females, mean age 30 +/- 10 years) were diagnosed as non-bruxers. The correlation between the clinical and EMG/ECG SB diagnoses was low (phi value = 0.250), with a 62.2% agreement (28/45 subjects) between the two approaches (kappa = 0.248). Assuming instrumental EMG/ECG diagnosis as the standard of reference for definite SB diagnosis in this investigation, the false-positive and false negative rates were unacceptable for all clinical signs/symptoms. In conclusion, findings from clinical assessment are not related with SB diagnosis performed with a portable EMG/ECG recorder. PMID- 26059762 TI - Effects of untreated and treated oilfield-produced water on seed germination, seedling development, and biomass production of sunflower (Helianthus annuus L.). AB - This study aims to evaluate possible toxic effects of oil and other contaminants from oilfield-produced water from oil exploration and production, on seed germination, and seedling development of sunflower (Helianthus annuus L.). In comparison, as treated by electroflocculation, oilfield-produced water, with lower oil and organic matter content, was also used. Electroflocculation treatment of oilfield-produced water achieved significant removals of chemical oxygen demand (COD) (94 %), oil and grease (O&G) (96 %), color (97 %), and turbidity (99 %). Different O&G, COD, and salt levels of untreated and treated oilfield-produced water did not influence germination process and seedling biomass production. Normal seedlings percentage and vigor tended to decrease more intensely in O&G and COD levels, higher than 337.5 mg L(-1) and 1321 mg O2 L(-1), respectively, using untreated oilfield-produced water. These results indicate that this industrial effluent must be treated, in order to not affect adversely seedling development. This way, electroflocculation treatment appears as an interesting alternative to removing oil and soluble organic matter in excess from oilfield-produced water improving sunflower's seedling development and providing a friendly environmental destination for this wastewater, reducing its potential to harm water resources, soil, and biota. PMID- 26059763 TI - Effects of Co-Trimoxazole on Microbial Translocation in HIV-1-Infected Patients Initiating Antiretroviral Therapy. AB - Microbial translocation (MT) contributes to immune activation during HIV-1 infection, and persists after initiation of antiretroviral therapy (ART). We investigated whether levels of MT markers are influenced by the use of co trimoxazole (TMP-SMX) in HIV-1 patients. Plasma samples were obtained from HIV-1 infected patients initiating ART with (n=13) or without (n=13) TMP-SMX prophylaxis. Markers of MT [lipopolysaccharide-binding protein (LBP), lipopolysaccharide (LPS), soluble CD14 (sCD14), and intestinal fatty acid binding protein (I-FABP)] were assessed at baseline (BL), at 1 month, and at 1 year by the Limulus Amebocyte Lysate Assay or ELISA. BL levels of LBP were elevated in both categories of patients; they were highest in patients starting ART and TMP SMX (median, MUg/ml: 36.7 vs. 4.3, respectively, p=0.001) and correlated inversely with CD4(+) T cell counts (rho=-0.65; p=0.005). Patients receiving ART and TMP-SMX had a significant reduction in LBP between BL and 1 year (median, MUg/ml: 36.7 vs. 11.1; p=0.003). In contrast, levels of LPS at BL were lower in patients starting ART and TMP-SMX compared to those without TMP-SMX (median, pg/ml: 221 vs. 303 respectively; p=0.002) and did not change at 1 year. The increased BL levels of sCD14 had declined in both groups at 1 year. No difference in I-FABP levels was found between BL and 1 year. Concomitant use of ART and TMP SMX reduces microbial translocation markers LBP and sCD14, probably due to its impact on the gut microbiota. Effective ART for 1 year does not restore gut-blood barrier dysfunction. PMID- 26059765 TI - Optimising colorectal cancer screening acceptance: a review. AB - The study aims to review available evidence concerning effective interventions to increase colorectal cancer (CRC) screening acceptance. We performed a literature search of randomised trials designed to increase individuals' use of CRC screening on PubMed, Embase, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects. Small (<= 100 subjects per arm) studies and those reporting results of interventions implemented before publication of the large faecal occult blood test trials were excluded. Interventions were categorised following the Continuum of Cancer Care and the PRECEDE-PROCEED models and studies were grouped by screening model (opportunistic vs organised). Multifactor interventions targeting multiple levels of care and considering factors outside the individual clinician control, represent the most effective strategy to enhance CRC screening acceptance. Removing financial barriers, implementing methods allowing a systematic contact of the whole target population, using personal invitation letters, preferably signed by the reference care provider, and reminders mailed to all non-attendees are highly effective in enhancing CRC screening acceptance. Physician reminders may support the diffusion of screening, but they can be effective only for individuals who have access to and make use of healthcare services. Educational interventions for patients and providers are effective, but the implementation of organisational measures may be necessary to favour their impact. Available evidence indicates that organised programmes allow to achieve an extensive coverage and to enhance equity of access, while maximising the health impact of screening. They provide at the same time an infrastructure allowing to achieve a more favourable cost-effectiveness profile of potentially effective strategies, which would not be sustainable in opportunistic settings. PMID- 26059764 TI - Hypoxia-induced expression of phosducin-like 3 regulates expression of VEGFR-2 and promotes angiogenesis. AB - Expression and activation of vascular endothelial growth factor receptor 2 (VEGFR 2) by VEGF ligands are the main events in the stimulation of pathological angiogenesis. VEGFR-2 expression is generally low in the healthy adult blood vessels, but its expression is markedly increased in the pathological angiogenesis. In this report, we demonstrate that phosducin-like 3 (PDCL3), a recently identified chaperone protein involved in the regulation of VEGFR-2 expression, is required for angiogenesis in zebrafish and mouse. PDCL3 undergoes N-terminal methionine acetylation, and this modification affects PDCL3 expression and its interaction with VEGFR-2. Expression of PDCL3 is regulated by hypoxia, the known stimulator of angiogenesis. The mutant PDCL3 that is unable to undergo N-terminal methionine acetylation was refractory to the effect of hypoxia. The siRNA-mediated silencing of PDCL3 decreased VEGFR-2 expression resulting in a decrease in VEGF-induced VEGFR-2 phosphorylation, whereas PDCL3 over-expression increased VEGFR-2 protein. Furthermore, we show that PDCL3 protects VEGFR-2 from misfolding and aggregation. The data provide new insights for the chaperone function of PDCL3 in angiogenesis and the roles of hypoxia and N-terminal methionine acetylation in PDCL3 expression and its effect on VEGFR-2. PMID- 26059766 TI - May the Force Be with You: Metabolism of Arginine and Pyrimidines. PMID- 26059768 TI - Pyrimidine Metabolism: Dynamic and Versatile Pathways in Pathogens and Cellular Development. AB - The importance of pyrimidines lies in the fact that they are structural components of a broad spectrum of key molecules that participate in diverse cellular functions, such as synthesis of DNA, RNA, lipids, and carbohydrates. Pyrimidine metabolism encompasses all enzymes involved in the synthesis, degradation, salvage, interconversion and transport of these molecules. In this review, we summarize recent publications that document how pyrimidine metabolism changes under a variety of conditions, including, when possible, those studies based on techniques of genomics, transcriptomics, proteomics, and metabolomics. First, we briefly look at the dynamics of pyrimidine metabolism during nonpathogenic cellular events. We then focus on changes that pathogen infections cause in the pyrimidine metabolism of their host. Next, we discuss the effects of antimetabolites and inhibitors, and finally we consider the consequences of genetic manipulations, such as knock-downs, knock-outs, and knock-ins, of pyrimidine enzymes on pyrimidine metabolism in the cell. PMID- 26059767 TI - Genotype-Phenotype Correlations in Ornithine Transcarbamylase Deficiency: A Mutation Update. AB - Ornithine transcarbamylase (OTC) deficiency is an X-linked trait that accounts for nearly half of all inherited disorders of the urea cycle. OTC is one of the enzymes common to both the urea cycle and the bacterial arginine biosynthesis pathway; however, the role of OTC has changed over evolution. For animals with a urea cycle, defects in OTC can trigger hyperammonemic episodes that can lead to brain damage and death. This is the fifth mutation update for human OTC with previous updates reported in 1993, 1995, 2002, and 2006. In the 2006 update, 341 mutations were reported. This current update contains 417 disease-causing mutations, and also is the first report of this series to incorporate information about natural variation of the OTC gene in the general population through examination of publicly available genomic data and examination of phenotype/genotype correlations from patients participating in the Urea Cycle Disorders Consortium Longitudinal Study and the first to evaluate the suitability of systematic computational approaches to predict severity of disease associated with different types of OTC mutations. PMID- 26059769 TI - Orotic Acid, More Than Just an Intermediate of Pyrimidine de novo Synthesis. AB - It is timely to consider the many facets of the small molecule orotic acid (OA), which is well-known as an essential intermediate of pyrimidine de novo synthesis. In addition, it can be taken up by erythrocytes and hepatocytes for conversion into uridine and for use in the pyrimidine recycling pathway. We discuss the link between dietary orotate and fatty liver in rats, and the potential for the alleviation of neonatal hyperbilirubinaemia. We address the development of orotate derivatives for application as anti-pyrimidine drugs, and of complexes with metal ions and organic cations to assist therapies of metabolic syndromes. Recent genetic data link human Miller syndrome to defects in the dihydroorotate dehydrogenase (DHODH) gene, hence to depleted orotate production. Another defect in pyrimidine biosynthesis, the orotic aciduria arising in humans and cattle with a deficiency of UMP synthase (UMPS), has different symptoms. More recent work leads us to conclude that OA may have a role in regulating gene transcription. PMID- 26059770 TI - Orotidine Monophosphate Decarboxylase--A Fascinating Workhorse Enzyme with Therapeutic Potential. AB - Orotidine 5'-monophosphate decarboxylase (ODCase) is known as one of the most proficient enzymes. The enzyme catalyzes the last reaction step of the de novo pyrimidine biosynthesis, the conversion from orotidine 5'-monophosphate (OMP) to uridine 5'-monophosphate. The enzyme is found in all three domains of life, Bacteria, Eukarya and Archaea. Multiple sequence alignment of 750 putative ODCase sequences resulted in five distinct groups. While the universally conserved DxKxxDx motif is present in all the groups, depending on the groups, several characteristic motifs and residues can be identified. Over 200 crystal structures of ODCases have been determined so far. The structures, together with biochemical assays and computational studies, elucidated that ODCase utilized both transition state stabilization and substrate distortion to accelerate the decarboxylation of its natural substrate. Stabilization of the vinyl anion intermediate by a conserved lysine residue at the catalytic site is considered the largest contributing factor to catalysis, while bending of the carboxyl group from the plane of the aromatic pyrimidine ring of OMP accounts for substrate distortion. A number of crystal structures of ODCases complexed with potential drug candidate molecules have also been determined, including with 6-iodo-uridine, a potential antimalarial agent. PMID- 26059771 TI - Non-Viral Deoxyribonucleoside Kinases--Diversity and Practical Use. AB - Deoxyribonucleoside kinases (dNKs) phosphorylate deoxyribonucleosides to their corresponding monophosphate compounds. dNks also phosphorylate deoxyribonucleoside analogues that are used in the treatment of cancer or viral infections. The study of the mammalian dNKs has therefore always been of great medical interest. However, during the last 20 years, research on dNKs has gone into non-mammalian organisms. In this review, we focus on non-viral dNKs, in particular their diversity and their practical applications. The diversity of this enzyme family in different organisms has proven to be valuable in studying the evolution of enzymes. Some of these newly discovered enzymes have been useful in numerous practical applications in medicine and biotechnology, and have contributed to our understanding of the structural basis of nucleoside and nucleoside analogue activation. PMID- 26059772 TI - The Study of Carbamoyl Phosphate Synthetase 1 Deficiency Sheds Light on the Mechanism for Switching On/Off the Urea Cycle. AB - Carbamoyl phosphate synthetase 1 (CPS1) deficiency (CPS1D) is an inborn error of the urea cycle having autosomal (2q34) recessive inheritance that can cause hyperammonemia and neonatal death or mental retardation. We analyzed the effects on CPS1 activity, kinetic parameters and enzyme stability of missense mutations reported in patients with CPS1 deficiency that map in the 20-kDa C-terminal domain of the enzyme. This domain turns on or off the enzyme depending on whether the essential allosteric activator of CPS1, N-acetyl-L-glutamate (NAG), is bound or is not bound to it. To carry out the present studies, we exploited a novel system that allows the expression in vitro and the purification of human CPS1, thus permitting site-directed mutagenesis. These studies have clarified disease causation by individual mutations, identifying functionally important residues, and revealing that a number of mutations decrease the affinity of the enzyme for NAG. Patients with NAG affinity-decreasing mutations might benefit from NAG site saturation therapy with N-carbamyl-L-glutamate (a registered drug, the analog of NAG). Our results, together with additional present and prior site-directed mutagenesis data for other residues mapping in this domain, suggest an NAG triggered conformational change in the beta4-alpha4 loop of the C-terminal domain of this enzyme. This change might be an early event in the NAG activation process. Molecular dynamics simulations that were restrained according to the observed effects of the mutations are consistent with this hypothesis, providing further backing for this structurally plausible signaling mechanism by which NAG could trigger urea cycle activation via CPS1. PMID- 26059774 TI - Folding Construction of a Pentacyclic Quadruply fused Polymer Topology with Tailored kyklo-Telechelic Precursors. AB - A pentacyclic quadruply fused polymer topology has been constructed for the first time through alkyne-azide addition (click) and olefin metathesis (clip) reactions in conjunction with an electrostatic self-assembly and covalent fixation (ESA-CF) process. Thus, a spiro-type, tandem tetracyclic poly(tetrahydrofuran), poly(THF), precursor having two allyloxy groups at the opposite positions of the four ring units was prepared by the click-linking of one unit of an eight-shaped precursor having alkyne groups at the opposite positions with two units of a single-cyclic counterpart having an azide and an alkene group at the opposite positions. Both are obtainable through ESA-CF. The subsequent metathesis clip-folding of the tetracyclic precursor could afford a pentacyclic quadruply fused polymer product, of "shippo" form, in 19% yield. PMID- 26059773 TI - CTP Synthase Is Required for Optic Lobe Homeostasis in Drosophila. AB - CTP synthase (CTPsyn) is a metabolic enzyme responsible for the de novo synthesis of the nucleotide CTP. Several recent studies have shown that CTPsyn forms filamentous subcellular structures known as cytoophidia in bacteria, yeast, fruit flies and humans. However, it remains elusive whether and how CTPsyn and cytoophidia play a role during development. Here, we show that cytoophidia are abundant in the neuroepithelial stem cells in Drosophila optic lobes. Optic lobes are underdeveloped in CTPsyn mutants as well as in CTPsyn RNAi. Moreover, overexpressing CTPsyn impairs the development of optic lobes, specifically by blocking the transition from neuroepithelium to neuroblast. Taken together, our results indicate that CTPsyn is critical for optic lobe homeostasis in Drosophila. PMID- 26059775 TI - Relevance of computerized tomography in the preoperative evaluation of patients with vulvar cancer: a prospective study. AB - BACKGROUND: The purpose of the study was to determine whether inclusion of computerized tomography (CT) in the prospective evaluation of vulvar cancer changed the surgical treatment strategy in terms of detection of lymph node metastases, tumor spread and comorbidity, and additionally to examine the logistical influence of adding further examinations prior to treating out hospital patients referred from geographically distant areas. METHODS: During an 8 month period we conducted a prospective study of patients with newly diagnosed or recurrent vulvar cancer consecutively referred to Copenhagen University Hospital, Rigshospitalet. The patients underwent a gynecological examination, chest x-ray and a preoperative CT scanning of the chest, abdomen and pelvis. It was registered whether the radiological findings regarding the extent of the tumor, lymph node involvement, incidental findings and comorbidity changed the surgical treatment plan. Further, the logistical influence of the long referral distances was registered. RESULTS: Thirty patients with a median age of 69 years (range 44-93 years) were included in the study. CT did not significantly change the initial surgical treatment plan for the patients. CT did not reveal lymph node enlargement outside the inguinofemoral area and was inaccurate compared to the sentinal node examination of the local lymph nodes. CT diagnosed no cases with distant metastases from the primary malignancy, but two cases with a secondary malignant disease were found. CONCLUSIONS: CT scanning has no clinical impact as a routine screening examination prior to surgery. It may delay treatment, but can add important information when clinically indicated. PMID- 26059776 TI - Comparison of a commercial bovine pregnancy-associated glycoprotein ELISA test and a pregnancy-associated glycoprotein radiomimmunoassay test for early pregnancy diagnosis in dairy cattle. AB - The present study aimed to compare the accuracy of a commercial PAG-ELISA test (Bovine Preg Test 29) and bovine pregnancy-associated glycoprotein radioimmunoassay (PAG-RIA) for diagnosing pregnancy at Day 28 after insemination in dairy cows. Transrectal ultrasonography (TRUS) was performed in 100 Holstein Friesian cows at Day 28 after artificial insemination (AI; Day 0) to diagnose pregnancy. After TRUS examination, blood sample was collected from the coccygeal vessels of each cow to measure the concentrations of bPAGs by PAG-RIA test and Bovine Preg Test 29. Milk samples were collected at Days 0, 21 and 28 for measurement of progesterone (P4) by ELISA test. The cows were re-examined by TRUS at Day 42 to confirm the pregnancy diagnoses. The actual gold standard was based on TRUS outcomes at Day 28 that agreed with the outcomes of PAG-RIA test or PAG ELISA test. If the outcomes of TRUS at Day 28 and PAG-RIA test and PAG-ELISA test did not agree, the gold standard was based on the outcome of TRUS at Day 42. Out of 100 inseminated cows, 41 were confirmed pregnant at Day 28 after AI. Based on the actual gold standard, the sensitivity of TRUS, PAG-ELISA and PAG-RIA tests for diagnosing pregnant cows at Day 28 were 92.7%, 90.2% and 100%, while the specificity of the three tests for diagnosing non-pregnant cows were 91.5%, 98.3% and 94.4%, respectively. The overall accuracy of the three tests were 92%, 95% and 97%, respectively. The degree of agreement (Kappa+/-S.E.) between PAG-RIA and PAG-ELISA test was 0.90 +/-0.04. The degrees of agreement between PAG-RIA and PAG ELISA and TRUS at Day 28 were 0.80+/-0.05 and 0.76+/-0.06, respectively. In conclusion, the commercial PAG-ELISA test is a highly accurate method for diagnosing early pregnancy in dairy cows on Day 28 after AI and may be used as an alternative method to the TRUS and the PAG-RIA test. PMID- 26059777 TI - Prophylaxis and therapeutic potential of ozone in buiatrics: Current knowledge. AB - Ozone therapy has been in use since 1896 in the USA. As a highly reactive molecule, ozone may inactivate bacteria, viruses, fungi, yeasts and protozoans, stimulate the oxygen metabolism of tissue, treat diseases, activate the immune system, and exhibit strong analgesic activity. More recently, ozone has been used in veterinary medicine, particularly in buiatrics, but still insufficiently. Medical ozone therapy has shown effectiveness as an alternative to the use of antibiotics, which are restricted to clinical use and have been withdrawn from non-clinical use as in-feed growth promoters in animal production. This review is an overview of current knowledge regarding the preventive and therapeutic effects of ozone in ruminants for the treatment of puerperal diseases and improvement in their fertility. In particular, ozone preparations have been tested in the treatment of reproductive tract lesions, urovagina and pneumomovagina, metritis, endometritis, fetal membrane retention and mastitis, as well as in the functional restoration of endometrium in dairy cows and goats. In addition, the preventive use of the intrauterine application of ozone has been assessed in order to evaluate its effectiveness in improving reproductive efficiency in dairy cows. No adverse effects were observed in cows and goats treated with ozone preparations. Moreover, there is a lot of evidence indicating the advantages of ozone preparation therapy in comparison to the application of antibiotics. However, there are certain limitations on ozone use in veterinary medicine and buiatrics, such as inactivity against intracellular microbes and selective activity against the same bacterial species, as well as the induction of tissue inflammation through inappropriate application of the preparation. PMID- 26059778 TI - The endostructural pattern of a middle pleistocene human femoral diaphysis from the Karain E site (Southern Anatolia, Turkey). AB - OBJECTIVE: The human femur from Karain E Cave (Turkey) exhumed from a Mousterian level provided the opportunity to make an incursion into the structural morphology of a late adolescent, or a young adult, femoral shaft from the late Middle Pleistocene of Anatolia. METHODS: Considering the chrono-ecogeographical context, this study focuses particularly on the endostructural morphological similarities between Karain and Neanderthal fossils. RESULTS: Comparative analysis shows that some femoral features of the Karain specimen are frequently observed in Neanderthals, in comparison to some Middle Pleistocene Homo and Middle/Upper Paleolithic modern humans. In particular, we note a high degree of circularity and a strong midshaft posteromedial reinforcement of cortical thickness on the medial side. According to the mapping of cortical thickness, this latter feature can be related to the medial spiral distribution pattern of cortical thickness in the mid-proximal shaft, which is present at Karain and in all Neanderthals available for this study. This spiral distribution was not identified in recent modern humans and may be absent from ancient Homo with femoral pilaster. CONCLUSIONS: The endostructural signature of Karain could indicate a similar biomechanical strain system to that of Neanderthals that could be linked to body shape. However, the presence of posteromedial reinforcement in Berg Aukas may point to an ancestral feature and may be independent of latitude. A larger comparative sample should further clarify the taxonomical, biomechanical, and chrono-ecogeographical origins of the structural femoral features observed in an evolutionary Neanderthal context from MIS 7-9 in Karain. PMID- 26059779 TI - A diode for ferroelectric domain-wall motion. AB - For over a decade, controlling domain-wall injection, motion and annihilation along nanowires has been the preserve of the nanomagnetics research community. Revolutionary technologies have resulted, like racetrack memory and domain-wall logic. Until recently, equivalent research in analogous ferroic materials did not seem important. However, with the discovery of sheet conduction, the control of domain walls in ferroelectrics has become vital for the future of what has been termed 'domain-wall electronics'. Here we report the creation of a ferroelectric domain-wall diode, which allows a single direction of motion for all domain walls, irrespective of their polarity, under a series of alternating electric field pulses. The diode's sawtooth morphology is central to its function. Domain walls can move readily in the direction in which thickness increases gradually, but are prevented from moving in the other direction by the sudden thickness increase at the sawtooth edge. PMID- 26059782 TI - Shouldering the load in sport. PMID- 26059781 TI - A Prospective, Nonrandomized, Open-Label Study of the Efficacy and Safety of OnabotulinumtoxinA in Adolescents with Primary Axillary Hyperhidrosis. AB - OBJECTIVE: To evaluate the efficacy and safety of onabotulinumtoxinA in adolescents with primary axillary hyperhidrosis. METHODS: This 52-week, multicenter, nonrandomized, open-label study was conducted in 141 adolescents ages 12 to 17 years with severe primary axillary hyperhidrosis. Patients could receive up to six treatments with onabotulinumtoxinA (50 U per axilla), with re treatment occurring no sooner than 8 weeks after the prior treatment cycle and no later than 44 weeks after the initial treatment cycle. The primary efficacy measure was treatment response, based on self-assessed hyperhidrosis severity following the first two treatments using the 4-point Hyperhidrosis Disease Severity Scale (HDSS). Other efficacy measures included spontaneous resting sweat production and health outcomes. RESULTS: Fifty-six (38.9%) participants underwent one treatment, 59 (41.0%) underwent two, 20 (13.9%) underwent three, 6 (4.2%) underwent four, and 3 (2.1%) underwent five. OnabotulinumtoxinA significantly improved HDSS scores and decreased sweat production compared with treatment cycle baselines. Seventy-nine patients (54.9%) responded to treatment based on HDSS criteria. From 56.6% to 72.3% of patients experienced a two-grade or more improvement at 4 and 8 weeks after each of the first two treatments. The majority (79.4%-93.2%) had a 75% or greater reduction in sweat production at week 4 (treatments 1-3). The median duration of effect for responders ranged from 134 to 152 days. Using quality of life measures, health outcomes improved markedly. Eight patients (5.6%) had mild or moderate treatment-related adverse events. No unexpected safety signals were observed in this study. Neutralizing antibodies to onabotulinumtoxinA did not develop. CONCLUSION: OnabotulinumtoxinA injections provided beneficial effects in adolescents with primary axillary hyperhidrosis. PMID- 26059783 TI - The notion of contextual locking: Previously learnt items are not accessible as such when appearing in a less common context. AB - We examined the effect of context on the learning of spatial coding in four experiments. Two partially overlapping sets of stimuli, which had the very same stimulus-response spatial coding, were presented in unique contexts. Results show contextual locking-that is, response times to the very same item in a more common context (80%) were significantly shorter than those in a less common context (20%). Contextual locking was obtained both when the context was more salient (Experiments 1 and 2) and less salient (Experiments 3 and 4). In addition, results were obtained even when contextualization seemed less necessary (Experiments 2 and 4). Binding of information to context is discussed in relation to chunking, transfer effects, and practical applications pertaining to professional training. PMID- 26059780 TI - Mast cell-macrophage dynamics in modulation of dengue virus infection in skin. AB - Dengue virus (DENV) infection causes dengue fever, dengue haemorrhagic fever, or dengue shock syndrome. Mast cells have been speculated to play a role in DENV disease although their precise roles are unclear. In this study, we used mast cell-deficient Kit(W-sh/W-sh) mice to investigate the involvement of mast cells after intradermal DENV infection. An approximately two- to three-fold higher level of DENV NS3 antigen was detected at the skin inoculation site in DENV infected Kit(W-sh/W-sh) mice than in DENV-infected wild-type (WT) mice (using a dose of 1 * 10(9) plaque-forming units/mouse). Moreover, as an indicator of heightened pathogenesis, a more prolonged bleeding time was observed in DENV infected Kit(W-sh/W-sh) mice than in WT mice. Monocytes/macrophages are considered to be important targets for DENV infection, so we investigated the susceptibility and chemokine response of DENV-infected peritoneal macrophages from Kit(W-sh/W-sh) and WT mice both ex vivo and in vivo. There was a tendency for higher DENV infection and higher secretion of CCL2 (MCP-1) from peritoneal macrophages isolated from Kit(W-sh/W-sh) mice than those from WT mice. In vivo studies using intradermal inoculation of DENV showed about twofold higher levels of infiltrating macrophages and CCL2 (MCP-1) at the inoculation site in both mock control and DENV-inoculated Kit(W-sh/W-sh) mice than in corresponding WT mice. In summary, compared with WT mice, Kit(W-sh/W-sh) mice show enhanced DENV infection and macrophage infiltration at the skin inoculation site as well as increased DENV-associated bleeding time. The results indicate an intriguing interplay between mast cells and tissue macrophages to restrict DENV replication in the skin. PMID- 26059784 TI - Bystander attitudes toward parents? The perceived meaning of filial piety among Koreans in Australia, New Zealand and Korea. AB - AIM: The objective of this paper was to explore how present-day filial piety is understood among Koreans in geographically different settings. METHODS: Data were collected from qualitative interviews with 61 Korean participants in Australia, New Zealand and Korea and then thematically analysed and evaluated. RESULTS: The findings from this study show that filial piety for Koreans consists of family care and support, along with respect for parents. The norm of filial piety is regarded as an important aspect of intergenerational family relationships in current Korean culture, while its practice is perceived as increasingly eroded within a context of major socio-cultural and economic changes, including migration. CONCLUSION: The results show that the tension between the social and economic aspects of filial piety often creates a 'bystander' attitude toward parents and provides fertile ground for the seeds of family conflict. PMID- 26059785 TI - Heat collection and supply of interconnected netlike graphene/polyethyleneglycol composites for thermoelectric devices. AB - The key challenges in thermoelectric power conversion are creating a significant temperature difference and obtaining more heat energy through a thermoelectric device. Herein, graphene/polyethyleneglycol composites (G-PEGs) were proposed as a heat supply for thermoelectric devices. The G-PEGs not only afford a lot of conductive pathways for heat transfer but also act as highly thermally conductive reservoirs to hold phase-change materials for thermal energy collection, storage and release. The concept described in this study holds great promise in designing multifunctional composites for heat collection, transport, and supply in thermoelectric power conversion. PMID- 26059787 TI - Clinical Diagnosis and Management of Hypertension Compared With the Joint National Committee 8 Panelists' Recommendations. AB - BACKGROUND: The panelists of the Joint National Committee recently published new recommendations for the management of hypertension. Our study aims to evaluate how current practice compares. HYPOTHESIS: Current practice likely deviates from the recent JNC 8 panelists' recommendations. METHODS: A survey was sent to cardiology providers at 3 academic medical centers: Mayo Clinic, Jacksonville, Florida; Mayo Clinic, Scottsdale, Arizona; and Mayo Clinic, Rochester, Minnesota. Providers were asked to select which blood-pressure goal would be deemed appropriate in various cases based on individual practice in both the maintenance of patients already on therapy as well as threshold of when to initiate therapy. Comparisons with current recommendations were made, as well as geographic location and level of experience. RESULTS: A total of 251 survey requests were sent (May 2014), and 77 responses (30.7%) were received. Cardiologists tended not to practice according to the new guidelines, with most variation seen in patients age >60 years without comorbidities on active treatment. Providers' selection of initial pharmacologic agents in non-African American patients, African American patients, and patients with diabetes mellitus reflected congruency with guidelines. CONCLUSIONS: Our study found that clinical practice does not correlate well with the new blood-pressure goal recommendations published by the Joint National Committee 8 panelists, particularly in patients age >60 years. Practitioners are likely to follow the recommendations in regard to pharmacologic management. PMID- 26059789 TI - [Unilateral maxillary sinusitis]. PMID- 26059788 TI - [Personalized medicine in otology. The role of genetic diagnostics in patients with hearing impairment]. AB - BACKGROUND: Classification of diseases on the molecular level is the basis for personalized medicine. Personalized medicine proposes to improve efficiency and quality of care, to reduce side effects and to increase long-term cost effectiveness. OBJECTIVES: This paper is concerned with the role of genetic diagnostics in patients with a cochlear implant. MATERIAL AND METHODS: A selective literature search in PubMed was performed. RESULTS: Genetic diagnosis allows ruling out syndromic hearing loss and thus prevents follow-up studies. It allows genetic counseling, prognosis and advice on family planning and targeted prevention. Due to its minimal invasiveness, it is suitable for evaluation of factors accounting for hearing loss in children. CONCLUSIONS: Molecular medicine plays a major role in the treatment of sensorineural hearings loss with cochlear implants. PMID- 26059790 TI - [Effect of body position on coordination of breathing and swallowing]. AB - BACKGROUND: To allow passage of food, the swallowing process closes off the larynx and interrupts respiratory flow. Both the timing of the interruption of respiratory flow and the body position can affect the results of the swallowing process. OBJECTIVE: The effect of body position on the swallowing process and the coordination of breathing and swallowing is investigated. MATERIALS AND METHOD: A combined EMG/bioimpedance measurement system and a piezoelectric sensor were used to investigate coordination of breathing and swallowing of a range of food consistencies in three different body positions (90 degrees , 45 degrees and 0 degrees ) in healthy subjects. RESULTS: Investigations were carried out on 21 healthy subjects (12 ?, 9 ?). 762 swallows were recorded. Changing body position was found to have a statistically significant effect on swallow-related parameters (maximum laryngeal elevation and speed of laryngeal elevation) and breathing pattern (pre- and post-swallow breathing phases). The laryngeal elevation as well as the speed of the laryngeal elevation is influenced significantly by the consistency to be swallowed. The breathing pattern changes from saliva to solid food of inspiration/swallow/inspiration to expiration/swallow/expiration. A change of body position influences the parameters specific for swallowing and the breathing patterns significantly. CONCLUSIONS: This study demonstrates that body position affects coordination of breathing and swallowing and swallow-related parameters in healthy subjects. Our results indicate that patients should be enabled to adopt a position in which they are sitting at an angle of at least 45 degrees . PMID- 26059791 TI - [Erratum to: prevalence of deafness in northwestern Germany: results of an epidemiological study on the hearing status (HORSTAT)]. PMID- 26059793 TI - Levo-tetrahydropalmatine attenuates mouse blood-brain barrier injury induced by focal cerebral ischemia and reperfusion: Involvement of Src kinase. AB - The restoration of blood flow following thrombolytic therapy causes ischemia and reperfusion (I/R) injury leading to blood-brain barrier (BBB) disruption and subsequent brain edema in patients of ischemic stroke. Levo-tetrahydropalmatine (l-THP) occurs in Corydalis genus and some other plants. However, whether l-THP exerts protective role on BBB disruption following cerebral I/R remains unclear. Male C57BL/6N mice (23 to 28 g) were subjected to 90 min middle cerebral artery occlusion, followed by reperfusion for 24 h. l-THP (10, 20, 40 mg/kg) was administrated by gavage 60 min before ischemia. We found I/R evoked Evans blue extravasation, albumin leakage, brain water content increase, cerebral blood flow decrease, cerebral infarction and neurological deficits, all of which were attenuated by l-THP treatment. Meanwhile, l-THP inhibited tight junction (TJ) proteins down-expression, Src kinase phosphorylation, matrix metalloproteinases 2/9 (MMP-2/9) and caveolin-1 activation. In addition, surface plasmon resonance revealed binding of l-THP to Src kinase with high affinity. Then we found Src kinase inhibitor PP2 could attenuate Evans blue dye extravasation and inhibit the caveolin-1, MMP-9 activation, occludin down-expression after I/R, respectively. In conclusion, l-THP attenuated BBB injury and brain edema, which were correlated with inhibiting the Src kinase phosphorylation. PMID- 26059795 TI - Upregulated expression of ILF2 in non-small cell lung cancer is associated with tumor cell proliferation and poor prognosis. AB - ILF2 (NF45) is a sequence-specific DNA binding protein that is involved in mitosis control, transcriptional regulation, DNA breaks repair, microRNA processing and viral replication. In the present study, we aim to investigate the potential role of ILF2 in the progression of non-small cell lung cancer (NSCLC). Western blot analysis indicated that ILF2 was up-regulated in NSCLC tissues, compared with adjacent non-tumorous ones. Furthermore, immunohistochemistry analysis showed that the expression of ILF2 was correlated with histological differentiation, clinical stage and Ki-67 expression in NSCLC specimens. In addition, using Kaplan-Meier survival analysis, we found that high expression of ILF2 predicted poor outcome in NSCLC patients. Furthermore, we showed that up regulated expression of ILF2 might play a regulatory role in the proliferation of NSCLC cells using serum starvation and release assay. Moreover, knockdown of ILF2 inhibited cell proliferation and cell cycle progress of NSCLC cells. In conclusion, our results indicated that ILF2 was involved in the pathogenesis of NSCLC and might be a potential target for NSCLC therapy. PMID- 26059794 TI - Histone deacetylase 5 regulates the inflammatory response of macrophages. AB - Modifying the chromatin structure and interacting with non-histone proteins, histone deacetylases (HDAC) are involved in vital cellular processes at different levels. We here specifically investigated the direct effects of HDAC5 in macrophage activation in response to bacterial or cytokine stimuli. Using murine and human macrophage cell lines, we studied the expression profile and the immunological function of HDAC5 at transcription and protein level in over expression as well as RNA interference experiments. Toll-like receptor-mediated stimulation of murine RAW264.7 cells significantly reduced HDAC5 mRNA within 7 hrs but presented baseline levels after 24 hrs, a mechanism that was also found for Interferon-gamma treatment. If treated with lipopolysaccharide, RAW264.7 cells transfected for over-expression only of full-length but not of mutant HDAC5, significantly elevated secretion of tumour necrosis factor alpha and of the monocyte chemotactic protein-1. These effects were accompanied by increased nuclear factor-kappaB activity. Accordingly, knock down of HDAC5-mRNA expression using specific siRNA significantly reduced the production of these cytokines in RAW264.7 or human U937 cells. Taken together, our results suggest a strong regulatory function of HDAC5 in the pro-inflammatory response of macrophages. PMID- 26059796 TI - Anterior maxilla alveolar ridge dimension and morphology measurement by cone beam computerized tomography (CBCT) for immediate implant treatment planning. AB - BACKGROUND: Implants have been widely used to restore missing teeth. Limited information on applied anatomy at the anterior maxilla compromises the clinical outcome for implant placement in this region. In the current study, Cone Beam Computerized Tomography (CBCT) was used to measure alveolar ridge and buccal undercut dimension at the anterior maxilla to help develop treatment planning for immediate implant placement. METHODS: CBCT scans were screened to include 51 subjects with full dentition at right maxilla. Measurements were taken at the cross sectional views in the middle of the maxillary right central incisor, lateral incisor, and canine regions. Alveolar height was measured from the alveolar crest to floor of nasal fossa. Alveolar width was measured from the buccal to palatal cortical plate at the coronal, middle, and apical third of the distance from the alveolar crest to floor of the nasal fossa. Buccal undercut location was measured from where the buccal cortical plate started dipping to a line extending at the alveolar crest that was perpendicular to the long axis of the alveolar ridge. The buccal undercut depth was measured from the deepest point of the undercut at the buccal plate to a line tangent to the buccal plate paralleling the long axis of ridge. RESULTS: Alveolar width increased from coronal to apical direction for each tooth. Mean alveolar widths (mm) were: central incisor, 9.55; lateral incisor, 8.30; canine, 9.62. The lateral incisor had a significantly smaller alveolar width than the other anterior teeth. No significant difference in ridge height was noted among the teeth. Undercut locations from the alveolar crest (mm) were: central incisor, 5.84; lateral incisor, 3.59; canine, 5.11. Undercut depths (mm) were: central incisor, 0.76; lateral incisor, 0.87; canine, 0.73. The percentages of teeth with buccal undercuts were: central incisor, 41%, lateral incisor, 77%, and canine 33%. Male demonstrate significant larger ridge width compared with females for all three teeth. CONCLUSIONS: At anterior maxilla, the lateral incisor has the thinnest alveolar bone, and most frequently exhibits a buccal undercut which is the closest to alveolar ridge compared with other maxillary anterior teeth. PMID- 26059797 TI - Tracking single-particle rotation during macrophage uptake. AB - We investigated the rotational dynamics of single microparticles during their internalization by macrophage cells. The microparticles used were triblock patchy particles that display two fluorescent patches on their two poles. The optical anisotropy made it possible to directly visualize and quantify the orientation and rotation of the particles. We show that particles exhibit a mixture of fast and slow rotation as they are uptaken by macrophages and transiently undergo directional rotation during their entry into the cell. The size of the particles and the surface presentation of ligands exerted a negligible influence on this heterogeneity of particle rotation. PMID- 26059786 TI - IMa2p--parallel MCMC and inference of ancient demography under the Isolation with migration (IM) model. AB - IMa2 and related programs are used to study the divergence of closely related species and of populations within species. These methods are based on the sampling of genealogies using MCMC, and they can proceed quite slowly for larger data sets. We describe a parallel implementation, called IMa2p, that provides a nearly linear increase in genealogy sampling rate with the number of processors in use. IMa2p is written in OpenMPI and C++, and scales well for demographic analyses of a large number of loci and populations, which are difficult to study using the serial version of the program. PMID- 26059798 TI - Pharmacokinetics of cyclodextrins and drugs after oral and parenteral administration of drug/cyclodextrin complexes. AB - OBJECTIVES: The objective of the present study was to shed some light on pharmacokinetics of cyclodextrins (CDs) and drugs after oral and parenteral administration of inclusion complexes. KEY FINDINGS: The complex binding constant in water can predict pharmacokinetics after parenteral administration, but it has to be considered in the context of the physiological environment, where plasma proteins compete with CDs for drug binding. Neither drug/CD nor drug/protein complexes can extravasate, but differently from proteins, CDs are readily cleared through glomerular filtration. In such intricate interrelationships, for complexes with low-to-mid binding constant, binding of drug to plasma proteins will mainly dictate the pharmacokinetics. Oppositely, for drugs showing large CD complex binding constant and low protein binding, significant decrease in distribution volume and enhanced excretion of unmetabolized drug are observed; thus, relevant changes in bioavailability can be predicted. In the case of oral administration, volume for dilution/dissolution of the complexes is relatively low and hence excess CD can hamper drug absorption from the gastrointestinal (GI) tract. SUMMARY: CDs are well-established multipurpose excipients for overcoming organoleptic and biopharmaceutical deficiencies of a variety of drugs. Balances between free and complexed drug in the GI tract and between drug-CD binding and drug-protein binding in plasma seem to play a relevant role in drug pharmacokinetics. PMID- 26059799 TI - Carbon Nanotubes as Support in the Platinum-Catalyzed Hydrolytic Dehydrogenation of Ammonia Borane. AB - We report remarkable support effects for carbon nanotubes (CNTs) in the Pt/CNT catalyzed hydrolytic dehydrogenation of ammonia borane. The origin of the support dependent activity and durability is elucidated by combining the catalytic and durability testing with characterization by a range of spectroscopy and high angle annular dark-field scanning transmission electron microscopy techniques and ICP analysis. The effects mainly arise from different electronic properties and different abilities for the adsorption of boron-containing species on platinum surfaces and changes in size and shape of the platinum particles during the reaction. Defect-rich CNTs in particular are a promising support material, as it not only enhances the platinum binding energy, leading to the highest hydrogen generation rate, but also inhibits the adsorption of boron-containing species and stabilizes the platinum nanoparticles to resist the agglomeration during the reaction, leading to the highest durability. The insights revealed herein may pave the way for the rational design of highly active and durable metal/carbon catalysts for the hydrolytic dehydrogenation of ammonia borane. PMID- 26059800 TI - Codon and Propeptide Optimizations to Improve the Food-grade Expression of Bile Salt Hydrolase in Lactococcus lactis. AB - To achieve the food-grade expression of bile salt hydrolase (BSH, EC 3.5.1.24) from Lactobacillus plantarum BBE7, the nisin controlled gene expression system (NICE), food-grade selection maker and signal peptide of Lactococcus lactis were used in this study. The open reading frame of BSH was optimized based on the codon bias of L. lactis, resulting in 12-fold and 9.5% increases in the intracellular and extracellular BSH activities, respectively. Three synthetic propeptides, LEISSTCDA (acidic), LGISSTCNA (neutral) and LKISSTCHA (basic) were also fused with signal peptide SPusp45 of vector pNZ8112 and introduced into the food-grade expression vector pNZ8149, respectively. Among these propeptides, acidic propeptide was effective in increasing the secretion efficiency and yield of BSH in recombinant bacteria, while neutral propeptide had no significant effect on the secretion of BSH. In contrast, basic propeptide strongly reduced the extracellular expression of BSH. By using codon optimization and the acidic propeptide together, the extracellular BSH activity was increased by 11.3%, reaching its maximum of 3.56 U/mg. To the best of our knowledge, this is the first report on the intracellular and extracellular expression of BSH using food grade expression system, which would lay a solid foundation for large-scale production of BSH and other heterologous proteins in L. lactis. PMID- 26059801 TI - Cytocompatibility of HEMA-free resin-based luting cements according to application protocols on dentine surfaces. AB - AIM: To evaluate the transdentinal cytotoxicity of resin-based luting cements (RBLCs), with no HEMA in their composition, to odontoblast-like cells. METHODOLOGY: Human dentine discs 0.3 mm thick were adapted to artificial pulp chambers (APCs) and placed in wells of 24-well plates containing 1 mL of culture medium (DMEM). Two categories of HEMA-free RBLCs were evaluated: group 1, self adhesive Rely X Unicem (RU; 3M ESPE), applied directly to the dentine substrate; and group 2, Rely X ARC (RARC; 3M ESPE), applied to dentine previously acid etched and treated with a bonding agent. In group 3 (control), considered as representing 100% cell metabolic activity, no treatment was performed on dentine. The APC/disc sets were incubated for 24 h or 7 days at 37 degrees C and 5% CO2 . Then, the extracts (DMEM + dental materials components that diffused through dentine) were applied to cultured odontoblast-like MDPC-23 cells for 24 h. After that, the cell viability (MTT assay), cell morphology (SEM), total protein production (TP) and alkaline phosphatase (ALP) activity were assessed. Data from MTT assay and TP production were analysed by Kruskal-Wallis and Mann-Whitney tests (alpha = 5%). Data from ALP activity were analysed by one-way anova and Tukey's test (alpha = 5%). RESULTS: In group 1, a slight reduction in cell viability (11.6% and 16.8% for 24-h and 7-day periods, respectively) and ALP activity (13.5% and 17.9% for 24-h and 7-day periods, respectively) was observed, with no significant difference from group 3 (control) (P > 0.05). In group 2, a significant reduction in cell viability, TP production and ALP activity compared with group 3 (control) occurred (P < 0.05), regardless of incubation time. Alteration in MDPC-23 cell morphology was observed only in group 2. CONCLUSIONS: HEMA-free Rely X ARC cement caused greater toxicity to odontoblast-like MDPC-23 cells than did Rely X Unicem cement when both resin-based luting materials were applied to dentine as recommended by the manufacturer. PMID- 26059802 TI - Hope to reality: The future of hospitalists and palliative care. PMID- 26059803 TI - Multiple vascular malformations in a patient with microcephalic osteodysplastic primordial dwarfism type ii. PMID- 26059804 TI - Lipoid proteinosis or Urbach-Wiethe disease: Description of a new case with cerebral involvement. PMID- 26059805 TI - Utility of EEG findings in the management of a case of herpes simplex encephalitis. PMID- 26059806 TI - Innovative and effective immunosuppressive bitherapy for an unusual paraneoplastic opsoclonus-myoclonus-ataxia syndrome of the adult. PMID- 26059807 TI - Positron emission tomography/computed tomography with 18-fluorodeoxyglucose: A technique for assessing vasculitis of the central nervous system secondary to giant cell arteritis. PMID- 26059808 TI - Thunderclap headache secondary to pneumocephalus. PMID- 26059809 TI - [Standardization of the Test Your Memory and evaluation of their concordance with the outcome of the psychometric examination]. AB - OBJECTIVE: To explore the relationship between scores on the Test Your Memory (TYM) battery and findings from a more exhaustive neurocognitive assessment. METHODS: The TYM and fourteen psychometric tests were administered to 84 subjects aged 50 or older who attended an outpatient neurology clinic due to cognitive symptoms. Each patient's cognitive state was determined independently from his/her score on the TYM (CDR 0, n=25; CDR 0.5, n=45; CDR 1, n=14). We analysed concurrent validity of TYM scores and results from the psychometric tests, as well as the degree of concordance between the two types of measurement, by contrasting normalised data from each instrument. RESULTS: Although the intraclass correlation coefficient was 0.67 (confidence interval 95%, 0.53-0.77), analysis of the Bland-Altman plot and the curve on the survival-agreement plot (Luiz et al. method) demonstrates that the individual distances between the two methods exhibit excessive dispersion from a clinical viewpoint. TYM-based predictions of the mean z-score on psychometric tests differed substantially from real results in 30% of the subjects. Concordance of 95% can only be achieved by accepting absolute inter-instrument differences of up to 0.87 as identical values. Furthermore, the TYM underestimates cognitive performance for low values and overestimates it for high values. CONCLUSIONS: The TYM is a cognitive screening test which should not be used to predict results on psychometric tests or to detect cognitive changes in clinical trials. PMID- 26059810 TI - Understanding replication fork progression, stability, and chromosome fragility by exploiting the Suppressor of Underreplication protein. AB - There are many layers of regulation governing DNA replication to ensure that genetic information is accurately transmitted from mother cell to daughter cell. While much of the control occurs at the level of origin selection and firing, less is known about how replication fork progression is controlled throughout the genome. In Drosophila polytene cells, specific regions of the genome become repressed for DNA replication, resulting in underreplication and decreased copy number. Importantly, underreplicated domains share properties with common fragile sites. The Suppressor of Underreplication protein SUUR is essential for this repression. Recent work established that SUUR functions by directly inhibiting replication fork progression, raising several interesting questions as to how replication fork progression and stability can be modulated within targeted regions of the genome. Here we discuss potential mechanisms by which replication fork inhibition can be achieved and the consequences this has on genome stability and copy number control. PMID- 26059811 TI - Aspirin Promotes Oligodendroglial Differentiation Through Inhibition of Wnt Signaling Pathway. AB - Aspirin, one of the most commonly used anti-inflammatory drugs, has been recently reported to display multiple effects in the central nervous system (CNS), including neuroprotection and upregulation of ciliary neurotrophic factor (CNTF) expression in astrocytes. Although it was most recently reported that aspirin could promote the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) after white matter lesion, the underlying mechanisms remain unclear. To dissect the effects of aspirin on oligodendroglial development and explore possible mechanisms, we here demonstrated the following: (i) in vitro treatment of aspirin on OPC cultures significantly increased the number of differentiated oligodendrocytes (OLs) but had no effect on the number of proliferative OPCs, indicating that aspirin can promote OPC differentiation but not proliferation; (ii) in vivo treatment of aspirin on neonatal (P3) rats for 4 days led to a nearly twofold increase in the expression of myelin basic protein (MBP), devoid of change in OPC proliferaion, in the corpus callosum (CC); (iii) finally, aspirin treatment increased the phosphorylation level of beta-catenin and counteracted Wnt signaling pathway synergist QS11-induced suppression on OPC differentiation. Together, our data show that aspirin can directly target oligodendroglial lineage cells and promote their differentiation through inhibition of Wnt/beta-catenin signaling pathway. These findings suggest that aspirin may be a novel candidate for the treatment of demyelinating diseases. PMID- 26059813 TI - Symmetries of a generic utricular projection: neural connectivity and the distribution of utricular information. AB - Sensory contribution to perception and action depends on both sensory receptors and the organization of pathways (or projections) reaching the central nervous system. Unlike the semicircular canals that are divided into three discrete sensitivity directions, the utricle has a relatively complicated anatomical structure, including sensitivity directions over essentially 360 degrees of a curved, two-dimensional disk. The utricle is not flat, and we do not assume it to be. Directional sensitivity of individual utricular afferents decreases in a cosine-like fashion from peak excitation for movement in one direction to a null or near null response for a movement in an orthogonal direction. Directional sensitivity varies slowly between neighboring cells except within the striolar region that separates the medial from the lateral zone, where the directional selectivity abruptly reverses along the reversal line. Utricular primary afferent pathways reach the vestibular nuclei and cerebellum and, in many cases, converge on target cells with semicircular canal primary afferents and afference from other sources. Mathematically, some canal pathways are known to be characterized by symmetry groups related to physical space. These groups structure rotational information and movement. They divide the target neural center into distinct populations according to the innervation patterns they receive. Like canal pathways, utricular pathways combine symmetries from the utricle with those from target neural centers. This study presents a generic set of transformations drawn from the known structure of the utricle and therefore likely to be found in utricular pathways, but not exhaustive of utricular pathway symmetries. This generic set of transformations forms a 32-element group that is a semi-direct product of two simple abelian groups. Subgroups of the group include order-four elements corresponding to discrete rotations. Evaluation of subgroups allows us to functionally identify the spatial implications of otolith and canal symmetries regarding action and perception. Our results are discussed in relation to observed utricular pathways, including those convergent with canal pathways. Oculomotor and other sensorimotor systems are organized according to canal planes. However, the utricle is evolutionarily prior to the canals and may provide a more fundamental spatial framework for canal pathways as well as for movement. The fullest purely otolithic pathway is likely that which reaches the lumbar spine via Deiters' cells in the lateral vestibular nucleus. It will be of great interest to see whether symmetries predicted from the utricle are identified within this pathway. PMID- 26059812 TI - Long-Term Effects of Prenatal Hypoxia on Schizophrenia-Like Phenotype in Heterozygous Reeler Mice. AB - Prenatal hypoxia (PHX) is a well-known environmental factor implicated in the pathophysiology of schizophrenia. However, the long-term effects of PHX on schizophrenia-related neuroplasticity are poorly understood. Using behavioral tasks, MRI imaging, and biochemical studies, we examined the long-term effects of PHX in heterozygous reeler mice (HRM; mice deficient for reelin, a candidate gene for schizophrenia). PHX at E17 failed to induce any significant deficits in prepulse inhibition, spatial memory, anxiety-like behavior, or blood flow in wild type (WT) and HRM at 6 months of age. However, PHX induced a significant increase in frontal cortex volume in WT whereas the higher frontal cortical volume found in HRM was significantly reduced by PHX. A significant decrease in reelin levels was observed in frontal cortex of WT and HRM and hippocampus of HRM following PHX. In addition, PHX induced significant reductions in hypoxia inducible factor 1alpha (HIF-1alpha) levels in frontal cortex and hippocampus of HRM. Although no significant effect of PHX was observed in vascular endothelial growth factor (VEGF) protein levels in frontal cortex and hippocampus of WT and HRM, serum VEGF levels were found higher in HRM following PHX. Moreover, glucocorticoid receptor (GR) protein levels were significantly lower in frontal cortex of WT and HRM and hippocampus of HRM following PHX. We found a significant reduction in serum corticosterone levels of PHX-treated WT mice. These findings suggest that future experiments addressing gene-environment interaction in schizophrenia should consider age-dependent effects of the environmental factor, in addition to the specificity of the gene of interest. PMID- 26059816 TI - Elevated background TV exposure over time increases behavioural scores of 18 month-old toddlers. AB - AIM: To investigate whether trends of TV exposure from age six to 18 months and adult TV programmes were associated with behavioural concerns of 18-month-old Thai toddlers. METHODS: There were 194 healthy infants recruited at age six months and followed up until 18 months of age in this present cohort. TV exposure variables were assessed by interviewing in depth at both six- and 18-month-old visits. A mother of each participant rated the child's behaviours using the Child Behaviour Checklist. RESULTS: Infants who were increasingly exposed to TV from age six to 18 months with adult programmes since six months of age had higher pervasive developmental problems and oppositional defiant behaviours scores. Exposure to adult TV programmes at age six months was also associated with emotionally reactive problems, aggression and externalising behaviours in the final regression models. CONCLUSION: To promote appropriate toddlers' behaviours at age 18 months, elevated background TV exposure over time should be discouraged. Furthermore, paediatricians should emphasise such effects of TV exposure on child behaviours with parents at health supervision visits. As such, parents will be aware of the detrimental effect of increased background TV exposure over time on their children's behaviours. PMID- 26059817 TI - C-ing the Genome: A Compendium of Chromosome Conformation Capture Methods to Study Higher-Order Chromatin Organization. AB - Three-dimensional organization of the chromatin has important roles in transcription, replication, DNA repair, and pathologic events such as translocations. There are two fundamental ways to study higher-order chromatin organization: microscopic and molecular approaches. In this review, we briefly introduce the molecular approaches, focusing on chromosome conformation capture or "3C" technology and its derivatives, which can be used to probe chromatin folding at resolutions beyond that provided by microscopy techniques. We further discuss the different types of data generated by the 3C-based methods and how they can be used to answer distinct biological questions. PMID- 26059818 TI - Macroscopic modelling of bioethanol production from potato peel wastes in batch cultures supplemented with inorganic nitrogen. AB - Inorganic nitrogen supplementation is commonly used to boost fermentation metabolism in yeast cultures. However, an excessive addition can induce an opposite effect. Hence, it is important to ensure that the ammonia supplemented to the culture leads to an improvement of the ethanol production while avoiding undesirable inhibition effects. To this end, a macroscopic model describing the influence of ammonia addition on Saccharomyces cerevisiae metabolism during bioethanol production from potato peel wastes has been developed. The model parameters are obtained by a simplified identification methodology in five steps. It is validated with experimental data and successfully predicts the dynamics of growth, substrate consumption (ammonia and fermentable sugar sources) and bioethanol production, even in cross validation. The model is used to determine the optimal quantity of supplemented ammonia required for maximizing bioethanol production from potato peel wastes in batch cultures. PMID- 26059819 TI - From new findings in acne pathogenesis to new approaches in treatment. AB - Acne is a chronic disease of the pilosebaceous unit which is most common during adolescence. Four factors are believed to play a key role in the development of acne lesions: excess sebum production, disturbed keratinization within the follicle, colonization of the pilosebaceous duct by Propionibacterium acnes, and the release of inflammatory mediators into the skin. Consequently, in order to effectively and rapidly reduce acne lesions, treatments need to address as many of these underlying factors as possible. Currently, about half of patients have poor adherence to acne treatments. To overcome this limitation, treatments need to be developed which are well tolerated by patients, and easy for them to use, handle and apply. Topical monotherapies for acne such as retinoids and antimicrobials by themselves have a restricted range of actions against the pathogenic factors of acne. Instead, the Global Alliance to Improve Outcomes in Acne Group recommends combination therapy with a topical retinoid and an antimicrobial agent as the preferred approach for almost all acne patients. The principal advantage of such combinations is that they target more of the underlying pathogenic factors of acne than individual monotherapies and this results in faster and more complete clearing of acne lesions. Fixed-dose combinations are also more convenient than applying two medications separately, which leads to improved adherence with the regimen. By normalizing desquamation, the retinoid component of these combinations allows entry of the antimicrobial agent into the pilosebaceous unit resulting in faster clearance of P. acnes. In conclusion, topical retinoid/antimicrobial fixed-dose combinations represent a rational approach for the treatment of acne. They should be considered as the cornerstone of acne management and should be used much more in the future. PMID- 26059820 TI - Clindamycin phosphate 1.2% / tretinoin 0.025%: a novel fixed-dose combination treatment for acne vulgaris. AB - The Global Alliance to Improve Outcomes in Acne Group recommends retinoid-based combination therapy as first-line therapy and the preferred treatment approach for almost all acne patients except those with the most severe disease. Clindamycin 1% (as clindamycin phosphate 1.2%)/tretinoin 0.025% (Clin-RA) is a new fixed-dose retinoid-based combination therapy. The aqueous-based gel formulation of Clin-RA was designed to minimize skin irritation and optimize adherence with the therapy. It contains both solubilized and crystalline tretinoin which allows the retinoid to be slowly released onto the skin surface and decreases the potential for cutaneous irritation. A pooled analysis of three pivotal studies involving 4550 acne patients showed that Clin-RA is well tolerated and effective at treating both inflammatory and non-inflammatory acne lesions. The onset of action of Clin-RA is rapid occurring within 2 weeks of treatment initiation. It is not associated with acne flaring or an increase in clindamycin-resistant Propionibacterium acnes counts. Clin-RA is considered as effective as adapalene 0.1%/benzoyl peroxide (BPO) 2.5%, whereas Clin-RA has a more favourable tolerability profile. Clin-RA may be more effective than clindamycin 1%/BPO 5% at treating non-inflammatory acne lesions since the latter does not contain a retinoid to target comedones. Clin-RA is also easy for patients to handle and apply, and has the advantage of not containing BPO which can bleach hair and fabrics. Taken together, the profile of Clin-RA suggests Clin RA to be a first-line treatment for patients with facial acne. PMID- 26059821 TI - Treatment of adult female acne: a new challenge. AB - Acne is affecting an increasing number of adult females and so can no longer be considered as a disease of adolescence. The disease has a greater negative impact on the quality of life of adult females than their younger counterparts. Adult female acne may persist from adolescence or may have its first occurrence once adulthood has been reached. The clinical presentation and pathogenesis of adult female acne may be somewhat different to that of adolescent acne and this may require a different treatment approach. Genetic and hormonal factors are thought to play key roles in the pathogenesis of adult female acne and the disease is characterized by a chronic evolution with frequent relapses requiring long-term maintenance therapy. Fixed-dose retinoid/antimicrobial combinations may be of interest for the treatment of adult female acne given that subgroup analysis of clinical trials has indicated that they are effective against both inflammatory and non-inflammatory lesions in these patients. These treatments may also be of interest, given the chronic course of the disease in adult females, the high likelihood of the presence of antibiotic-resistant P. acnes and the poor adherence of patients to other long-term therapies. Oral hormonal treatment or isotretinoin may be required in patients with severe acne or disease that is refractory to other treatments. Additional clinical studies of acne treatments specifically conducted in adult female patients are required to increase the evidence base on which future treatment recommendations can be based. PMID- 26059822 TI - Non-covalent interactions in ionic liquid ion pairs and ion pair dimers: a quantum chemical calculation analysis. AB - Ionic liquids (ILs) being composed of bulky multiatomic ions reveal a plethora of non-covalent interactions which determine their microscopic structure. In order to establish the main peculiarities of these interactions in an IL-environment, we have performed quantum chemical calculations for a set of representative model molecular clusters. These calculations were coupled with advanced methods of analysis of the electron density distribution, namely, the quantum theory of atoms in molecules (QTAIM) and the non-covalent interaction (NCI; J. Am. Chem. Soc., 2010, 132, 6499) approaches. The former allows for profound quantitative characterization of non-covalent interactions between atoms while the latter gives an overview of spatial extent, delocalization, and relative strength of such interactions. The studied systems consist of 1-butyl-3-methylimidazolium (Bmim(+)) cations and different perfluorinated anions: tetrafluoroborate (BF4( )), hexafluorophosphate (PF6(-)), trifluoromethanesulfonate (TfO(-)), and bis(trifluoromethanesulfonyl)imide (TFSI(-)). IL ion pairs and ion pair dimers were considered as model structures for the neat ILs and large aggregates. Weak electrostatic hydrogen bonding was found between the anions and the imidazolium ring hydrogen atoms of cations. Weaker but still appreciable hydrogen bonding was also noted for hydrogen atoms adjacent to the imidazolium ring alkyl groups of Bmim(+). The relative strength of the hydrogen bonding is higher in BmimTfO and BmimBF4 ILs than in BmimPF6 and BmimTFSI, whereas BmimTfO and BmimTFSI reveal higher sensitivity of hydrogen bonding at the different hydrogen atoms of the imidazolium ring. PMID- 26059823 TI - Reply: To PMID 25545807. PMID- 26059824 TI - Adrenal Gland Background Findings in CD-1 (Crl:CD-1(ICR)BR) Mice from 104-week Carcinogenicity Studies. AB - The authors performed a retrospective study to determine the incidences of spontaneous findings in the adrenal glands of control CD-1 mice. Data were collected from 2,163 mice from control dose groups in 104-week carcinogenicity studies carried out between 2000 and 2010. Adrenal gland nonproliferative lesions were more common in males than in females. In males, the most common nonproliferative lesions were cortical hypertrophy, cortical atrophy, pigment deposition/pigmentation, cysts, and extramedullary hematopoiesis. In females, the most common nonproliferative lesions were pigment deposition/pigmentation, extramedullary hematopoiesis, and cortical atrophy. Proliferative lesions were more common in females than in males. In both sexes, the most common proliferative lesions were subcapsular cell hyperplasia, focal cortical hyperplasia, and subcapsular cell tumor. Pheochromocytomas were uncommon in both sexes, with a slightly higher incidence in females, and the benign type was more frequent than the malignant type. Lymphoma was the most common metastatic tumor in both males and females, followed by histiocytic sarcoma and erythroid/myeloid leukemia. To the best knowledge of the authors, there are no recent reports on spontaneous pathological findings in the adrenal glands of CD-1 mice, and these results will facilitate the interpretation of background findings in carcinogenicity studies. PMID- 26059826 TI - Effects of the GLP-1 Receptor Agonist Dulaglutide on the Structure of the Exocrine Pancreas of Cynomolgus Monkeys. AB - Clinical and nonclinical studies have implicated glucagon-like peptide-1 (GLP-1) receptor agonist therapy as a risk factor for acute pancreatitis in patients with type 2 diabetes. Therefore, it is critical to understand the effect that dulaglutide, an approved GLP-1 receptor agonist, has on the exocrine pancreas. Dulaglutide 8.15 mg/kg (approximately 500 times the maximum recommended human dose based on plasma exposure) was administered twice weekly for 12 months to cynomolgus monkeys. Serum amylase and lipase activities were measured and 6 sections of each pancreas were examined microscopically. Ductal epithelial cell proliferation was estimated using Ki67 labeling. Dulaglutide administration did not alter serum amylase or lipase activities measured at the end of treatment compared to control values. An extensive histologic evaluation of the pancreas revealed no changes in the acinar or endocrine portions and no evidence of pancreatitis, necrosis, or pancreatic intraepithelial neoplasia. An increase in goblet cells noted in 4 of the 19 treated monkeys was considered an effect of dulaglutide but was not associated with dilation, blockage, or accumulation of mucin in the pancreatic duct. There was no difference in cell proliferation in ductal epithelium between control and dulaglutide-treated monkeys. These data reveal that chronic dosing of nondiabetic primates with dulaglutide does not induce inflammatory or preneoplastic changes in exocrine pancreas. PMID- 26059825 TI - Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal. AB - Rodent lung tumors are morphologically similar to a subtype of human lung adenocarcinomas. The objective of this study was to evaluate Kirsten rat sarcoma oncogene homolog (Kras), epidermal growth factor receptor (Egfr), and tumor protein 53 (Tp53) mutations, which are relevant to human lung cancer, in cobalt metal dust (CMD)-induced alveolar/bronchiolar tumors of B6C3F1/N mice and F344/NTac rats. Kras mutations were detected in 67% (mice) and 31% (rats) of CMD induced lung tumors and were predominantly exon 1 codon 12 G to T transversions (80% in mice and 57% in rats). Egfr mutations were detected in 17% (both mice and rats) of CMD-induced lung tumors and were predominantly in exon 20 with 50% G to A transitions (mice and rats). Tp53 mutations were detected in 19% (mice) and 23% (rats) of CMD-induced lung tumors and were predominant in exon 5 (mice, 69% transversions) and exon 6 (rats, all transitions). No mutations were observed for these genes in spontaneous lung tumors or normal lungs from untreated controls. Ames assay indicated that CMD is mutagenic in the absence but not in the presence of S9 mix. Thus, the mutation data (G to T transversions) and Ames assay results suggest that oxidative damage to DNA may be a contributing factor in CMD-induced pulmonary carcinogenesis in rodents. PMID- 26059827 TI - Drug-induced Skin Lesions in Cynomolgus Macaques Treated with Metabotropic Glutamate Receptor 5 (mGluR5) Negative Allosteric Modulators. AB - Three orally administered metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators caused skin lesions consistent with delayed type-IV hypersensitivity in cynomolgus macaques in 2- and 12-week toxicity studies. Several monkeys developed macroscopic skin lesions in multiple locations after 8 to 9 days of dosing; the most prominent effects involved the genital region of males and generalized erythema occurred in both sexes. Microscopic lesions occurred in both clinically affected and unaffected areas and were characterized by lymphocytic interface inflammation, subepidermal bullae, and individual keratinocyte vacuolation/necrosis. In the 12-week study, clinical effects in 2 animals resolved with continued dosing, whereas in others the inflammatory process progressed with 1 female exhibiting systemic lymphocytic inflammation in multiple tissues. The inflammatory infiltrate consisted of CD3 and CD4 positive T lymphocytes with minimal CD68 positive macrophages and only rare CD8 positive T lymphocytes. A subset of animals given a dosing holiday was subsequently rechallenged with similar lesions developing but with a more rapid clinical onset. These skin lesions were consistent with type-IV delayed hypersensitivity with some features comparable to bullous drug eruptions in humans. A relationship between these findings and the intended mode of action for these compounds could not be ruled out, given the occurrence across different chemotypes. PMID- 26059828 TI - Chemerin Expression in the Peritoneal Fluid, Serum, and Ovarian Endometrioma of Women with Endometriosis. AB - PROBLEM: Inflammation is an essential process in the pathogenesis of endometriosis. METHOD OF STUDY: Serum and peritoneal fluid (PF) samples were collected from women with endometriosis (n = 31) and women without endometriosis (n = 48). Chemerin, tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) levels in serum and PF samples were determined with a specific enzyme linked immunosorbent assay. Eutopic endometrial tissue from controls and ovarian endometriotic cysts were obtained during surgery. Expression of chemerin and chemerin receptors in ectopic and eutopic endometrial tissues was measured on real-time reverse transcriptase-polymerase chain reaction. Protein expression was examined with Western blot and densitometric analysis. RESULTS: Chemerin concentrations were higher in PF from women with endometriosis than that in that from controls. PF chemerin concentrations were significantly correlated with both TNF-alpha and IL-6 levels in PF. The mRNA and protein of chemerin and its receptor were significantly increased in the ovarian endometrioma tissue compared with eutopic endometrium of controls. CONCLUSION: These findings suggest that chemerin plays a role in endometriosis-related pelvic inflammation. PMID- 26059829 TI - Differential effects of IFN-beta on IL-12, IL-23, and IL-10 expression in TLR stimulated dendritic cells. AB - MS is an autoimmune disease characterized by immune cell infiltration in the CNS, leading to cumulative disability. IFN-beta, used clinically in RR-MS reduces lesion formation and rates of relapse. Although the molecular mechanisms are not entirely elucidated, myeloid cells appear to be a major target for the therapeutic effects of IFN-beta. DCs have a critical role in experimental models of MS through their effect on encephalitogenic Th1/Th17 cell differentiation and expansion. Here we focused on the effects of IFN-beta on DC expression of cytokines involved in the control of Th1/Th17 differentiation and expansion. Administration of IFN-beta to mice immunized with MOG35-55 inhibited IL-12 and IL 23 expression in splenic DC and reduced in vivo differentiation of Th1/Th17 cells. IFN-beta affected cytokine expression in TLR-stimulated DC in a similar manner in vitro, inhibiting IL-12 and IL-23 and stimulating IL-10 at both mRNA and protein levels, by signaling through IFNAR. We investigated the role of the signaling molecules STAT1/STAT2, IRF-1 and IRF-7, and of the PI3K->GSK3 pathway. IFN-beta inhibition of the IL-12 subunits p40 and p35 was mediated through STAT1/STAT2, whereas inhibition of IL-23 was STAT1 dependent, and the stimulatory effect on IL-10 expression was mediated through STAT2. IFN-beta induces IRF-7 and, to a lesser degree, IRF-1. However, neither IRF mediated the effects of IFN beta on IL-12, IL-23, or IL-10. We found that the PI3K pathway mediated IL-12 inhibition but did not interfere with the inhibition of IL-23 or stimulation of IL-10. PMID- 26059832 TI - Return to play and physical performance tests: evidence-based, rough guess or charade? PMID- 26059831 TI - Effectiveness of a Voice Training Program for Student Teachers on Vocal Health. AB - OBJECTIVES: The effectiveness of a preventive training program on vocal health for German student teachers was investigated on specific vocal parameters. METHODS: The voice quality as described by the Dysphonia Severity Index of 204 student teachers (training group: n = 123; control group: n = 81) was measured at the beginning and at the end of the student teachers training period (duration 1.5 years). Additionally, for investigating the voice-carrying capacity, a vocal loading test (VLT) was performed. Finally, participants had to provide a subjective judgment of a possible Voice Handicap Index. RESULTS: The training program improved the voice quality of the trained group compared with that of the control group, whose voice quality declined. The trained group was also able to better sustain their voice quality across the VLT than the control group. Both groups, however, reported a similar increase in subjective vocal strain. CONCLUSIONS: The presented training program clearly showed a positive impact on the voice quality and the vocal capacity. The results maintain the importance of such a training program to be integrated in the education and occupational routine of teachers. PMID- 26059830 TI - Epigenetic regulation of IL-12-dependent T cell proliferation. AB - It is well established that the cytokine IL-12 and the transcription factor STAT4, an essential part of the IL-12 signaling pathway, are critical components of the Th1 differentiation process in T cells. In response to pathogenic stimuli, this process causes T cells to proliferate rapidly and secrete high amounts of the cytokine IFN-gamma, leading to the Th1 proinflammatory phenotype. However, there are still unknown components of this differentiation pathway. We here demonstrated that the expression of the histone methyltransferase Mll1 is driven by IL-12 signaling through STAT4 in humans and mice and is critical for the proper differentiation of a naive T cell to a Th1 cell. Once MLL1 is up-regulated by IL-12, it regulates the proliferation of Th1 cells. As evidence of this, we show that Th1 cells from Mll1(+/-) mice are unable to proliferate rapidly in a Th1 environment in vitro and in vivo. Additionally, upon restimulation with cognate antigen Mll1(+/-), T cells do not convert to a Th1 phenotype, as characterized by IFN-gamma output. Furthermore, we observed a reduction in IFN gamma production and proliferation in human peripheral blood stimulated with tetanus toxoid by use of a specific inhibitor of the MLL1/menin complex. Together, our results demonstrate that the MLL1 gene plays a previously unrecognized but essential role in Th1 cell biology and furthermore, describes a novel pathway through which Mll1 expression is regulated. PMID- 26059833 TI - Safety of aromatase inhibitor therapy in breast cancer. AB - INTRODUCTION: Aromatase inhibitor (AI) therapy is the current preferred choice of endocrine therapy in postmenopausal estrogen receptor-positive breast cancer patients thanks to their improved effectiveness compared to tamoxifen. Despite the absence of increased endometrial pathology and deep venous thrombosis seen in tamoxifen-users, the safety profile of AIs consists of a variety of bothersome side effects negatively influencing daily functioning. AREAS COVERED: Besides the well-known adverse effects on joints and bone and the vasomotor system, more neglected and latent toxicity like cognitive problems and vulvovaginal atrophy will be discussed. Concern has been raised in terms of increased risk of fractures and cardiovascular events with chronic AI use. EXPERT OPINION: Placebo controlled long-term studies carefully monitoring these adverse events, together with more extensive research in the etiologies, are warranted. PMID- 26059834 TI - Gastric neuroendocrine neoplasms and proton pump inhibitors: fact or coincidence? AB - OBJECTIVE: Reporting on three cases of gastric neuroendocrine tumors (g-NETs) in patients taking long-term proton pump inhibitors (PPIs). These tumors are not classifiable considering current criteria. g-NETs are currently grouped as: types 1 and 2, related to hypergastrinemia due to chronic atrophic gastritis and Zollinger-Ellison syndrome respectively, and type 3, normogastrinemic and more aggressive. Although the g-NETs onset in patients taking PPIs is biologically plausible, only a few cases have been reported so far. MATERIALS AND METHODS: From January 2005 to July 2014, 31 g-NETs were referred to our Unit: 24 (77%), one (3%) and three (10%) resulted types 1, 2 and 3, respectively. Three cases (10%) did not meet the current classification criteria. RESULTS: The three patients were administered long-term PPIs for gastro-esophageal reflux disease. Patient 1: a 78-year-old man, with a 4-mm well-differentiated g-NET (Ki-67<1%) and marked hypergastrinemia. Patient 2: a 58-year-old man affected by a 6-mm well differentiated (Ki-67 = 4%) g-NET, with normal gastrin levels. Patients 3: a 67 year-old woman with an 18-mm well-differentiated g-NET (Ki-67 <2%), with mild hypergastrinemia. In the three patients, histology and pertinent blood tests excluded chronic atrophic gastritis, Helicobacter pylori infection or Zollinger Ellison syndrome. The first two patients underwent endoscopic polypectomy; in the third case total gastrectomy was performed. Further clinical, endoscopic and imaging follow-up did not show any g-NET recurrence. CONCLUSIONS: The present data point to the existence and epidemiological relevance of g-NETs associated with PPIs intake. These neoplasms are not included in the current classification, thus their treatment and follow-up have not been established. PMID- 26059835 TI - Reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test as a marker for glucocorticoid sensitivity in children with asthma. AB - PURPOSE: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment in children. However, there is considerable inter-individual variation in glucocorticoid sensitivity, leading to over- as well as undertreatment. A simple and fast test to predict glucocorticoid sensitivity would enable more tailored therapy in children with asthma. AIM: To study reproducibility and utility of an overnight 0.25 mg dexamethasone suppression test (DST) with salivary cortisol levels as marker for glucocorticoid sensitivity in asthmatic children. METHODS: 23 children with atopic asthma were recruited for two overnight 0.25 mg DST's, 1 month apart. RESULTS: Baseline cortisol levels correlated well between both tests. However, cortisol levels, change in cortisol levels or fractional suppression of cortisol levels after dexamethasone did not correlate between the two tests. Bland-Altman plots showed that the difference in salivary cortisol levels between test 1 and 2 of an individual patient could go up to 12 nmol/l, which is a clinically relevant difference. ICS dose did not correlate with baseline cortisol levels, height and BMI SDS. CONCLUSION: The low-dose salivary DST test in its current form is not suitable for use in clinical practice in children with asthma, due to low reproducibility. Therefore, studies using the 0.25 mg salivary DST should be interpreted cautiously. PMID- 26059836 TI - A integral treatment for attention deficit hyperactivity disorder in Europe. PMID- 26059837 TI - Gray matter characteristics associated with trait anxiety in older adults are moderated by depression. AB - BACKGROUND: Structural gray matter characteristics of anxiety remain unclear. The aim of this study was to assess the influence of current depressive symptoms and history of depression on the gray matter characteristics of trait anxiety. METHODS: Structural magnetic resonance imaging (MRI) data from 393 individuals aged 65 years or older were used. Regions of interest (ROIs) included the amygdala, anterior cingulate cortex (ACC), insula, orbitofrontal cortex (OFC), and temporal cortex. Trait anxiety was measured by the State-Trait Anxiety Inventory (STAI). Depression and depressive symptoms were measured using DSM-IV criteria and the Center for Epidemiological Studies Depression Scale (CESD). RESULTS: After adjustments for sociodemographics and health-related variables, anxiety had a significant influence on the gray matter characteristics in all cortical ROIs. First, in participants without depression antecedents, higher trait anxiety was associated with a larger cortical thickness in all cortical ROIs. Second, in participants with a previous history of depression, higher trait anxiety was associated with a smaller cortical thickness in all cortical ROIs. CONCLUSIONS: These results suggest that anxiety is related to cortical thickness differently in healthy older adults and in older adults with psychiatric antecedents. Anxiety associated with thinner cortical areas could reflect symptoms of a specific type of depression or a vulnerability to develop depression. PMID- 26059838 TI - Differential effects of tetrahydropyridinol derivatives on beta-catenin signaling and invasion in human hepatocellular and breast carcinoma cells. AB - In continuation of previous efforts to investigate the biological potency of tetrahydropyridinol derivatives, the present study synthesized three target compounds: N-(bromoacetyl)-3-carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl) Delta3-tetra-hydropyridine (5a), N-(chloroacetyl)-3-carboxyethyl-2,6-diphenyl-4-O (pentafluorobenzoyl)-Delta3-tetrahydropyridine (5b) and N-(2-bromopropanoyl)-3 carboxyethyl-2,6-diphenyl-4-O-(pentafluorobenzoyl)-Delta3-tetrahydropyridine (5c), and examined their anticancer potency. Experiments were performed using the Sk-Hep1 and Hep3B human hepatocellular carcinoma cell lines and MDA-MB-231 breast adenocarcinoma cell line. Among the three compounds, 5a and 5b were comparably and significantly cytotoxic to the Sk-Hep1, Hep3B and MDA-MB-231 cells. The highest level of cytotoxicity was detected in theSk-Hep1 cells with half maximal inhibitory concentrations for compounds 5a and 5b at 12 and 6 uM, respectively. These two compounds induced cell cycle arrest in the Sk-Hep1 and MDA-MB-231 cells through the downregulation of beta-catenin and upregulation of glycogen synthase kinase-3beta and E-cadherin. By contrast, 5a and 5b induced G1 arrest in the Hep3B cells by modulating the p21 and p27 cell cycle regulatory molecules and cyclin-dependent kinase 2. In addition, 5a and 5b significantly inhibited the invasion of Sk-Hep1 and MDA-MB-231 cells. These results suggested that the 5a and 5b compounds induce cell cycle arrest by suppressing Wnt/beta-catenin signaling in highly invasive Sk-Hep1 and MDA-MB-231 cells, and by inducing p53 independent cell cycle arrest in Hep3B cells. PMID- 26059839 TI - DOES SCREENING WITH THE MDQ AND EPDS IMPROVE IDENTIFICATION OF BIPOLAR DISORDER IN AN OBSTETRICAL SAMPLE? AB - BACKGROUND: Women with bipolar disorder (BD) are at high risk for postpartum affective episodes and psychosis. Although validated screening tools are available for postpartum unipolar depression, few screening tools for hypomania/mania exist. Screening tools for BD in the postpartum period are essential for improving detection and planning appropriate treatment. We evaluated whether adding the Mood Disorders Questionnaire (MDQ) to the Edinburgh Postnatal Depression Scale (EPDS) increased the identification of BD in the early postpartum period. METHODS: Women (N = 1,279) who delivered a live infant and screened positive on the EPDS and/or MDQ at 4-6 weeks postbirth were invited to undergo an in-home Structured Clinical Interview for DSM-IV (SCID). RESULTS: Positive EPDS and/or MDQ screens occurred in 12% of the sample (n = 155). In home SCID diagnostic interviews were completed in 93 (60%) of the mothers with positive screens. BD was the primary diagnosis in 37% (n = 34). Women with BD screened positive on the EPDS and/or MDQ as follows: EPDS+/MDQ+ (n = 14), EPDS+/MDQ- (n = 17), and EPDS-/MDQ+ (n = 3). The MDQ identified 50% (17/34) of the women with BD and 6 additional cases of BD when the MDQ question regarding how impaired the mother perceived herself was excluded from the screen criterion. CONCLUSION: Addition of the MDQ to the EPDS improved the distinction of unipolar depression from bipolar depression at the level of screening in 50% of women with traditional MDQ scoring and by nearly 70% when the MDQ was scored without the impairment criterion. PMID- 26059840 TI - STAG3 truncating variant as the cause of primary ovarian insufficiency. AB - Primary ovarian insufficiency (POI) is a distressing cause of infertility in young women. POI is heterogeneous with only a few causative genes having been discovered so far. Our objective was to determine the genetic cause of POI in a consanguineous Lebanese family with two affected sisters presenting with primary amenorrhoea and an absence of any pubertal development. Multipoint parametric linkage analysis was performed. Whole-exome sequencing was done on the proband. Linkage analysis identified a locus on chromosome 7 where exome sequencing successfully identified a homozygous two base pair duplication (c.1947_48dupCT), leading to a truncated protein p.(Y650Sfs*22) in the STAG3 gene, confirming it as the cause of POI in this family. Exome sequencing combined with linkage analyses offers a powerful tool to efficiently find novel genetic causes of rare, heterogeneous disorders, even in small single families. This is only the second report of a STAG3 variant; the first STAG3 variant was recently described in a phenotypically similar family with extreme POI. Identification of an additional family highlights the importance of STAG3 in POI pathogenesis and suggests it should be evaluated in families affected with POI. PMID- 26059841 TI - Exon skipping causes atypical phenotypes associated with a loss-of-function mutation in FLNA by restoring its protein function. AB - Loss-of-function mutations in filamin A (FLNA) cause an X-linked dominant disorder with multiple organ involvement. Affected females present with periventricular nodular heterotopia (PVNH), cardiovascular complications, thrombocytopenia and Ehlers-Danlos syndrome. These mutations are typically lethal to males, and rare male survivors suffer from failure to thrive, PVNH, and severe cardiovascular and gastrointestinal complications. Here we report two surviving male siblings with a loss-of-function mutation in FLNA. They presented with multiple complications, including valvulopathy, intestinal malrotation and chronic intestinal pseudo-obstruction (CIPO). However, these siblings had atypical clinical courses, such as a lack of PVNH and a spontaneous improvement of CIPO. Trio-based whole-exome sequencing revealed a 4-bp deletion in exon 40 that was predicted to cause a lethal premature protein truncation. However, molecular investigations revealed that the mutation induced in-frame skipping of the mutated exon, which led to the translation of a mutant FLNA missing an internal region of 41 amino acids. Functional analyses of the mutant protein suggested that its binding affinity to integrin, as well as its capacity to induce focal adhesions, were comparable to those of the wild-type protein. These results suggested that exon skipping of FLNA partially restored its protein function, which could contribute to amelioration of the siblings' clinical courses. This study expands the diversity of the phenotypes associated with loss of-function mutations in FLNA. PMID- 26059842 TI - The use of whole-exome sequencing to disentangle complex phenotypes. AB - The success of whole-exome sequencing to identify mutations causing single-gene disorders has been well documented. In contrast whole-exome sequencing has so far had limited success in the identification of variants causing more complex phenotypes that seem unlikely to be due to the disruption of a single gene. We describe a family where two male offspring of healthy first cousin parents present a complex phenotype consisting of peripheral neuropathy and bronchiectasis that has not been described previously in the literature. Due to the fact that both children had the same problems in the context of parental consanguinity we hypothesised illness resulted from either X-linked or autosomal recessive inheritance. Through the use of whole-exome sequencing we were able to simplify this complex phenotype and identified a causative mutation (p.R1070*) in the gene periaxin (PRX), a gene previously shown to cause peripheral neuropathy (Dejerine-Sottas syndrome) when this mutation is present. For the bronchiectasis phenotype we were unable to identify a causal single mutation or compound heterozygote, reflecting the heterogeneous nature of this phenotype. In conclusion, in this study we show that whole-exome sequencing has the power to disentangle complex phenotypes through the identification of causative genetic mutations for distinct clinical disorders that were previously masked. PMID- 26059843 TI - Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders. AB - Copy number variations are a common cause of intellectual disability (ID). Determining the contribution of copy number variants (CNVs), particularly gains, to disease remains challenging. Here, we report four males with ID with sub microscopic duplications at Xp11.2 and review the few cases with overlapping duplications reported to date. We established the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2 with one case also duplicating the known disease gene HUWE1. Patients with a duplication encompassing TSPYL2, KDM5C and IQSEC2 without gains of nearby SMC1A and HUWE1 genes have not been reported thus far. All cases presented with ID and significant deficits of speech development. Some patients also manifested behavioral disturbances such as hyperactivity and attention deficit/hyperactivity disorder. Lymphoblastic cell lines from patients show markedly elevated levels of TSPYL2, KDM5C and SMC1A, transcripts consistent with the extent of their CNVs. The duplicated region in our patients contains several genes known to escape X-inactivation, including KDM5C, IQSEC2 and SMC1A. In silico analysis of expression data in selected gene expression omnibus series indicates that dosage of these genes, especially IQSEC2, is similar in males and females despite the fact they escape from X-inactivation in females. Taken together, the data suggest that gains in Xp11.22 including IQSEC2 cause ID and are associated with hyperactivity and attention-deficit/hyperactivity disorder, and are likely to be dosage-sensitive in males. PMID- 26059844 TI - Compare and contrast: a cross-national study across UK, USA and Greek experts regarding return of incidental findings from clinical sequencing. AB - Return of incidental findings (IFs) from clinical sequencing has become a hotly debated topic over the past year. Efforts are being made by several bodies to provide guidance at both national and international levels; however, no studies comparing attitudes of experts across different countries have been published so far. Our goal was to investigate attitudes towards return of IFs from clinical sequencing across UK, USA and Greek experts. Thirty in-depth interviews were conducted with genetics and genomic experts with different backgrounds. Our study revealed more differences when experts were compared according to their professional background than their country. General principles guiding the decision-making and the feedback process were common across all experts but the details of integrating these tests might vary as different professionals reported different needs and attitudes. PMID- 26059845 TI - Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations. AB - Two variants (c.[301_302delAG];[301_302delAG] and c.[150delA];[150delA]) in the PROP1 gene are the most common genetic causes of recessively inherited combined pituitary hormones deficiency (CPHD). Our objective was to analyze in detail the origin of the two most prevalent variants. In the multicentric study were included 237 patients with CPHD and their 15 relatives carrying c.[301_302delAG];[301_302delAG] or c.[150delA];[150delA] or c.[301_302delAG];[ 150delA]. They originated from 21 different countries worldwide. We genotyped 21 single-nucleotide variant markers flanking the 9.6-Mb region around the PROP1 gene that are not in mutual linkage disequilibrium in the general populations--a finding of a common haplotype would be indicative of ancestral origin of the variant. Haplotypes were reconstructed by Phase and Haploview software, and the variant age was estimated using an allelic association method. We demonstrated the ancestral origin of both variants--c.[301_302delAG] was carried on 0.2 Mb long haplotype in a majority of European patients arising ~101 generations ago (confidence interval 90.1-116.4). Patients from the Iberian Peninsula displayed a different haplotype, which was estimated to have emerged 23.3 (20.1-29.1) generations ago. Subsequently, the data indicated that both the haplotypes were transmitted to Latin American patients ~13.8 (12.2-17.0) and 16.4 (14.4-20.1) generations ago, respectively. The c.[150delA] variant that was carried on a haplotype spanning about 0.3 Mb was estimated to appear 43.7 (38.4-52.7) generations ago. We present strong evidence that the most frequent variants in the PROP1 gene are not a consequence of variant hot spots as previously assumed, but are founder variants. PMID- 26059846 TI - Minimal clinically important differences in the Edmonton Symptom Assessment Scale in cancer patients: A prospective, multicenter study. AB - BACKGROUND: The Edmonton Symptom Assessment Scale (ESAS) is widely used for symptom assessment in clinical and research settings. A sensitivity-specificity approach was used to identify the minimal clinically important difference (MCID) for improvement and deterioration for each of the 10 ESAS symptoms. METHODS: This multicenter, prospective, longitudinal study enrolled patients with advanced cancer. ESAS was measured at the first clinic visit and at a second visit 3 weeks later. For each symptom, the Patient's Global Impression ("better," "about the same," or "worse") was assessed at the second visit as the external criterion, and the MCID was determined on the basis of the optimal cutoff in the receiver operating characteristic (ROC) curve. A sensitivity analysis was conducted through the estimation of MCIDs with other approaches. RESULTS: For the 796 participants, the median duration between the 2 study visits was 21 days (interquartile range, 18-28 days). The area under the ROC curve varied from 0.70 to 0.87, and this suggested good responsiveness. For all 10 symptoms, the optimal cutoff was >=1 point for improvement and <=-1 point for deterioration, with sensitivities of 59% to 85% and specificities of 69% to 85%. With other approaches, the MCIDs varied from 0.8 to 2.2 for improvement and from -0.8 to 2.3 for deterioration in the within-patient analysis, from 1.2 to 1.6 with the one-half standard deviation approach, and from 1.3 to 1.7 with the standard error of measurement approach. CONCLUSIONS: ESAS was responsive to change. The optimal cutoffs were >=1 point for improvement and <=-1 point for deterioration for each of the 10 symptoms. Our findings have implications for sample size calculations and response determination. PMID- 26059847 TI - Running away from stress: How regulatory modes prospectively affect athletes' stress through passion. AB - A prospective field study conducted with runners training for an upcoming marathon (Marathon of Rome 2013) examined the relation between regulatory modes, locomotion and assessment, and stress. Integrating regulatory mode theory and the dualistic model of passion, we hypothesized that the relation between regulatory modes (evaluated 3 months before the race) and the experience of stress approaching the marathon, is mediated by the type of passion (harmonious vs obsessive) athletes experience with regard to marathoning. Results revealed that (a) locomotion positively predicted harmonious passion, which in turn reduced athletes' experience of stress; and (b) assessment positively predicted obsessive passion, which in turn enhanced athletes' experience of stress. Overall, the present results suggest that proximal psychological mechanisms such as basic regulatory mode orientations can predict distal outcomes such as stress indirectly through their relation with motivational phenomena such as passion. PMID- 26059848 TI - Efficacy of cerebral thrombolysis in an extended 'time window'. AB - WHAT IS KNOWN AND OBJECTIVE: Cerebral systemic thrombolysis (i.v. thrombolysis) with tissue-type plasminogen activator (rt-PA) is the only proven medical therapy for ischaemic stroke. The use of i.v. thrombolysis up to 4.5 h from stroke onset was approved in certain countries in 2008, but its safety and efficacy have not been fully determined to date. OBJECTIVE: To assess the long-term outcome and complication rate of i.v. thrombolysis performed in the extended 'time window'. METHODS: The study included 403 ischaemic stroke patients consecutively treated with i.v. thrombolysis from 2006 to 2012 at three comprehensive stroke centres in Poland. The long-term outcome and the haemorrhagic complications' (HC) rate were compared between subgroups of patients treated within 3 vs. 3-4.5 h from stroke onset. RESULTS AND DISCUSSION: About 132 (32.75%) patients were treated between 3 and 4.5 h from stroke onset. Neurological deficits tended to be more severe in patients treated <=3 than in those treated 3-4.5 h (National Institutes of Health Stroke Scale, NIHSS 12 vs.10 points; P = 0.053); however, the ratio of patients with a favourable outcome (mRS 0-2 points) and mortality did not differ between the two groups (53.9 vs. 58.3, P = 0.39 and 17.7 vs. 21.2, P = 0.39, respectively). The rate of HC also did not differ between the two groups (18.8% vs. 15.1%, P = 0.46). WHAT IS NEW AND CONCLUSION: The efficacy of i.v. thrombolysis routinely performed in an extended 'time window' is not reduced when compared to procedures performed within 3 h from symptom onset. PMID- 26059849 TI - Reassessment of Scleral Depression in the Clinical Setting. PMID- 26059850 TI - Screening of targeted genes in extrahepatic bile ducts of mice with experimental biliary atresia. AB - Biliary atresia (BA) is an infantile disease resulting from a severe cholangiopathy, which can obstruct extrahepatic bile ducts, disrupt bile flow and lead to end-stage cirrhosis. The current study aimed to develop a genetic method to investigate the pathogenesis of BA. The gene expression profile of BA (GSE46967) was downloaded from the Gene Expression Omnibus database and included 18 samples from newborn mice. These samples were collected at three time points following the induction of BA with rhesus rotavirus. The differentially expressed genes (DEGs) in mice with BA were identified using the limma package in R language, followed by hierarchical clustering analysis. Gene ontology functional analysis and Kyoto Enrichment of Genes and Genomes pathway analysis of the selected common DEGs was conducted using the Database for Annotation, Visualization and Integrated Discovery. In total, 306 DEGs were identified in the samples from the 3 day time point, 721 at 7 days and 370 at 14 days. A total of 74 common DEGs were identified in these three sample groups, which are reported to function in multiple immune biological processes, including the defense response, leukocyte migration, cell chemotaxis and leukocyte chemotaxis. In addition, 'cytokine-cytokine receptor interaction' and 'chemokine signaling pathway' were observed to be significantly enriched in BA. A total of six common DEGs (CCL3, CXCL5, CXCL13, CXCR2, CCL5 and CCL6) were identified that were involved in the significantly enriched functions and the significantly enriched pathways. The data from the current study suggested that the immune response is a critical biological process in the development of BA. The six critical hub genes identified (CCL3, CXCL5, CXCL13, CXCR2, CCL5 and CCL6) may be used as specific target genes in the treatment of BA. PMID- 26059851 TI - A spontaneous depressive pattern in adult female rhesus macaques. AB - Non-human primates offer unique opportunities to study the development of depression rooted in behavioral and physiological abnormalities. This study observed adult female rhesus macaques within social hierarchies and aimed to characterize the physiological and brain abnormalities accompanying depressive like behavior. The behaviors of 31 female rhesus macaques from 14 different breeding groups were video recorded, and the footage was analyzed using the focal animal technique. There were 13 monkeys who never displayed huddling behavior (non-huddlers). The remaining 18 monkeys were divided into two groups according the mean time spent in the huddle posture. Four monkeys were designated as high huddlers, whereas the other 14 monkeys were low huddlers. An inverse relationship was discovered between social rank and depression. High huddlers spent more time engaging in physical contact and in close proximity to other monkeys, as well as less time spontaneously and reactively locomoting, than low huddlers and/or non huddlers. Cortisol levels measured from the hair were elevated significantly in high huddlers compared with low huddlers and non-huddlers, and the measured cortisol levels were specifically higher in high huddlers than subordinate or dominant control monkeys. Regional cerebral blood flow data revealed significant and widespread decreases in high huddlers compared with non-huddlers. PMID- 26059852 TI - Cyanine fluorophores for cellular protection against ROS in stimulated macrophages and two-photon ROS detection. AB - We report the first example of a novel two-photon active, biocompatible, and macrophage cell-membrane permeable carbazole-based cyanine fluorophore for the detection of three biologically important ROS, namely, OH, O2(-) and OCl(-) in solution. This versatile probe shows cellular protection not only in stimulated macrophages from phorbol-12-myristate-13-acetate-induced morphological changes but also lipopolysaccharide-induced cytotoxicity by quenching with the O2(-) and OCl(-) production, respectively. Such protection could be visualized by a distinct change in the fluorescence intensity of the probe. PMID- 26059853 TI - Sliding-scale insulin used for blood glucose control: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Sliding-scale insulin has been widely used in treating inpatient hyperglycemia. A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted to evaluate the efficacy and possible adverse effects of sliding-scale insulin in hospitalized patients. METHODS: PubMed, EMBASE, Cochrane Library, Scopus, and ClinicalTrials.gov registry were searched for studies published up to May 2015. Individual effect sizes were standardized, and a meta-analysis was performed to calculate a pooled effect size using random effects models. RESULTS: Eleven RCTs containing a total of 1322 patients were identified. Among eight studies in which the RISS was compared with other regimens, no significant difference was observed in the percentage of patients who achieved the mean blood glucose level between the two groups, which was determined according to the numbers of blood samples (RR: 2.84; 95% CI: 0.94 to 8.59) and patients (RR: 1.75; 95% CI: 0.86 to 3.55). The mean blood glucose level (weighted mean difference=27.33, 95% CI: 14.74 to 39.92) and incidence of hyperglycemic events were significantly higher in the RISS group than in the non sliding-scale group. No significant difference in the incidence of severe hypoglycemia and length of hospitalization between the groups was identified. CONCLUSIONS: The overall results of the meta-analysis indicated that applying the RISS alone or in combination with other antidiabetic medications did not provide any benefits in blood glucose control, but was accompanied by an increased incidence of hyperglycemic events. Therefore, we suggest that the use of sliding scale insulin be discontinued in hospitals. PMID- 26059854 TI - A comparison between transoral glottis-widening techniques for bilateral vocal fold immobility. AB - OBJECTIVE: Comparison of different endoscopic glottis-widening procedures designed for bilateral vocal cord immobility (BVCI) is a challenge. This is because a statistically efficient analysis and comparable clinical series is hard to obtain considering the variable aspects of the results and the evaluation methods. This study of a large number of cadaver larynges provides comparable, objective data for the evaluation of the possible postoperative breathing and voicing function. STUDY DESIGN: A morphometric study was performed on 50 male and 50 female larynges to compare the different suture lateralization and resection procedures. METHODS: The postoperative characteristic of glottic configuration was evaluated following vocal cord laterofixation, endolaryngeal arytenoid abduction lateropexy (EAAL), Schobel's external lateralization procedure (SELP), transverse cordotomy (TC), and medial and total arytenoidectomies (AE). The glottic area and the parameters determining the phoniatric outcomes were assessed by a digital image analyzer program. RESULTS: Improvement of glottic area was observed after all procedures, but arytenoid abduction procedures were significantly the most effective. However, the smallest vocal cord angles were found in TC and AE; the injury of the voicing structures results in a deterioration of vocal mechanics and can be reasonably assumed to negatively influence the voice. Endolaryngeal arytenoid abduction lateropexy and SELP may provide the best phonation closure when residual adduction regeneration can occur. CONCLUSION: This study demonstrates the complexity of the correct surgical decision making in BVCI. Procedures that utilize physiological abduction of the arytenoid cartilage seem to be more advantageous, especially if recovery of adductor function occurs. LEVEL OF EVIDENCE: N/A. PMID- 26059855 TI - How sleep and wakefulness influence circadian rhythmicity: effects of insufficient and mistimed sleep on the animal and human transcriptome. AB - The mammalian circadian system is a multi-oscillator, hierarchically organised system where a central pacemaker synchronises behavioural, physiological and gene expression rhythms in peripheral tissues. Epidemiological studies show that disruption of this internal synchronisation by short sleep and shift work is associated with adverse health outcomes through mechanisms that remain to be elucidated. Here, we review recent animal and human studies demonstrating the profound effects of insufficient and mistimed sleep on the rhythms of gene expression in central and peripheral tissues. In mice, sleep restriction leads to an ~80% reduction in circadian transcripts in the brain and profound disruption of the liver transcriptome. In humans, sleep restriction leads to a 1.9% reduction in circadian transcripts in whole blood, and when sleep is displaced to the daytime, 97% of rhythmic genes become arrhythmic and one-third of all genes show changes in temporal expression profiles. These changes in mice and humans include a significant reduction in the circadian regulation of transcription and translation and core clock genes in the periphery, while at the same time rhythms within the suprachiasmatic nucleus are not disrupted. Although the physiological mediators of these sleep disruption effects on the transcriptome have not been established, altered food intake, changes in hormones such as cortisol, and changes in body and brain temperature may play important roles. Processes and molecular pathways associated with these disruptions include metabolism, immune function, inflammatory and stress responses, and point to the molecular mechanisms underlying the established adverse health outcomes associated with short sleep duration and shift work, such as metabolic syndrome and cancer. PMID- 26059856 TI - Inhibition of Osteoclast Differentiation by Ginsenoside Rg3 in RAW264.7 Cells via RANKL, JNK and p38 MAPK Pathways Through a Modulation of Cathepsin K: An In Silico and In Vitro Study. AB - Various studies have demonstrated that overexpression of cathepsin K (Cat-K) causes excessive bone loss, which ultimately leads to a variety of bone diseases including osteoporosis. Therefore, inhibition of Cat-K signifies a potential therapeutic target in osteoporosis treatment. Ginsenoside Rg3 is one of the most promising compound of Panax ginseng Meyer (P. ginseng) with numerous biological activities. Thus, in recent study the inhibitory effect of Rg3 isolated from P. ginseng was investigated in order to impede the osteoclast activity by an in silico approach followed by in vitro study validation using RAW264.7 cells through the investigation of different biological activity prediction such as absorption distribution metabolism and excretion (ADMET) properties against Cat-K protein. The docking results of our study showed that Rg3 is a non-toxic compound and may act as a drug-like molecule. Additionally, the molecular interaction of Rg3 with the active residues of Cat-K markedly describes its inhibitory effects on osteoclastogenesis. Findings of the present study exhibited that Rg3 significantly reduced receptor activator of nuclear factor kappa B ligand (RANKL) induced tartrate-resistant acid phosphatase (TRAP) activity, pit formation (actin rings), and TRAP-positive multinucleated cells development in RAW264.7 cells. Furthermore, Rg3 dose-dependently reduced the mRNA expression levels of osteoclast-specific markers such as RANK, TRAP, and Cat-K induced by RANKL through the down regulation of p38, extracellular signal-regulated kinase, and c Jun N-terminal kinase (JNK) pathways. In conclusion, in silico docking study and in vitro validation together suggested that Rg3 inhibits osteoclastogenesis and reduces bone resorption through the inhibition of Cat-K. Therefore, Rg3 might be a useful therapeutic agent for the treatment of osteoporosis and proper bone formation. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26059857 TI - Manual therapy for the management of pain and limited range of motion in subjects with signs and symptoms of temporomandibular disorder: a systematic review of randomised controlled trials. AB - There is a lack of knowledge about the effectiveness of manual therapy (MT) on subjects with temporomandibular disorders (TMD). The aim of this systematic review is to synthetise evidence regarding the isolated effect of MT in improving maximum mouth opening (MMO) and pain in subjects with signs and symptoms of TMD. MEDLINE((r)) , Cochrane, Web of Science, SciELO and EMBASE(TM) electronic databases were consulted, searching for randomised controlled trials applying MT for TMD compared to other intervention, no intervention or placebo. Two authors independently extracted data, PEDro scale was used to assess risk of bias, and GRADE (Grading of Recommendations Assessment, Development and Evaluation) was applied to synthetise overall quality of the body of evidence. Treatment effect size was calculated for pain, MMO and pressure pain threshold (PPT). Eight trials were included, seven of high methodological quality. Myofascial release and massage techniques applied on the masticatory muscles are more effective than control (low to moderate evidence) but as effective as toxin botulinum injections (moderate evidence). Upper cervical spine thrust manipulation or mobilisation techniques are more effective than control (low to high evidence), while thoracic manipulations are not. There is moderate-to-high evidence that MT techniques protocols are effective. The methodological heterogeneity across trials protocols frequently contributed to decrease quality of evidence. In conclusion, there is widely varying evidence that MT improves pain, MMO and PPT in subjects with TMD signs and symptoms, depending on the technique. Further studies should consider using standardised evaluations and better study designs to strengthen clinical relevance. PMID- 26059858 TI - Decoding the transcriptome and DNA methylome of human primordial germ cells. PMID- 26059859 TI - The efficacy and safety of maraviroc addition to a stable antiretroviral regimen in subjects with suppressed plasma HIV-RNA is not influenced by age. AB - There are few data about the immunovirological efficacy, safety/tolerability, and durability of maraviroc (MVC) addition to aging patients on suppressive antiretroviral therapy (cART) and undetectable viral load (<50 copies/ml). The aging population is underrepresented in most HIV clinical trials. This study included 80 patients aged >=50 years and 161 aged <50 years and showed that after 48 weeks of treatment, there was no between-group differences in the median increase of CD4(+) T cells or the virological suppression rate. Safety and tolerability were also comparable. In multivariable analysis, the effect of age was not modified and was independent of the response to MVC. An immunological recovery of >=100 CD4(+) T cells was significantly less common in those with a longer HIV history (>=15 years) (OR 0.43; p=0.016) or having <200/mm(3) CD4(+) T cells at MVC initiation (OR 0.27; p=0.004). Meanwhile, achieving a CD4/CD8 ratio >=0.5 at week 48 was less likely in those with CD4(+) T cell counts <200 at MVC initiation (OR 0.09; p<0.0001) or with a previous AIDS event (OR 0.43; p=0.028). In summary, the immunovirological efficacy, safety/tolerability, and durability of MVC addition in patients virologically suppressed were independent of the patient's age at treatment onset. PMID- 26059860 TI - The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study. AB - BACKGROUND: Interferon- and ribavirin (RBV)-free regimens can improve patient reported outcomes (PROs) during treatment. AIM: To compare PROs during treatment with ledipasvir and sofosbuvir (LDV/SOF) to placebo and to LDV/SOF + RBV. METHODS: Treatment-experienced CH-C genotype 1 patients with compensated cirrhosis (N = 154) were randomized to receive 24 weeks of LDV/SOF or 12 weeks of placebo followed by 12 weeks of LDV/SOF + RBV (the SIRIUS clinical trial). While blinded to their HCV RNA level and study treatment, patients completed PRO questionnaires (SF-36, FACIT-F, CLDQ-HCV, WPAI:SHP) at baseline, during and post treatment. RESULTS: Baseline PRO scores were similar between the two study arms. Patients receiving LDV/SOF showed improvement in a number of PROs (predominantly related to mental health) starting as early as 4 weeks after treatment initiation; no PRO decrement from baseline were noted, and no PRO scores were inferior to placebo (all P > 0.05). In the second 12 weeks, patients who were receiving LDV/SOF continued to improve PROs (up to +9.2% from a 100% maximum possible score, P < 0.05), while patients receiving LDV/SOF + RBV had less gains or no improvement in their PRO scores. However, regardless of the regimen, patients who successfully cleared the virus (N = 149) had significant improvement in all aspects of PROs (up to +12.2% by post-treatment week 12, up to +16.9% by week 24). CONCLUSIONS: Treatment-experienced cirrhotic patients experience a notable improvement of their PROs during treatment with LDV/SOF. Furthermore, achieving SVR-12 is associated with significant PRO improvement, which further improves at post-treatment week 24 in this difficult to treat group of patients with chronic hepatitis C. PMID- 26059861 TI - Changing composition of microbial communities indicates seepage fluid difference of the Thuwal Seeps in the Red Sea. AB - Cold seeps are unique ecosystems that are generally characterized by high salinity and reducing solutions. Seepage fluid, the major water influx of this system, contains hypersaline water, sediment pore water, and other components. The Thuwal cold seeps were recently discovered on the continental margin of the Red Sea. Using 16S rRNA gene pyro-sequencing technology, microbial communities were investigated by comparing samples collected in 2011 and 2013. The results revealed differences in the microbial communities between the two sampling times. In particular, a significantly higher abundance of Marine Group I (MGI) Thaumarchaeota was coupled with lower salinity in 2013. In the brine pool, the dominance of Desulfobacterales in 2011 was supplanted by MGI Thaumarchaeota in 2013, perhaps due to a reduced supply of hydrogen sulfide from the seepage fluid. Collectively, this study revealed a difference in water components in this ecosystem between two sampling times. The results indicated that the seawater in this cold seep displayed a greater number of characteristics of normal seawater in 2013 than in 2011, which might represent the dominant driving force for changes in microbial community structures. This is the first study to provide a temporal comparison of the microbial biodiversity of a cold seep ecosystem in the Red Sea. PMID- 26059862 TI - Halosimplex litoreum sp. nov., isolated from a marine solar saltern. AB - A halophilic archaeal strain, YGH94(T), was isolated from the Yinggehai marine solar saltern near the Shanya city of Hainan Province, China. Cells of the strain were observed to be short rods, stain Gram-negative and to form red-pigmented colonies on solid media. Strain YGH94(T) was found to grow at 25-50 degrees C (optimum 40 degrees C), at 0.9-4.8 M NaCl (optimum 3.1 M), at 0-1.0 M MgCl2 (optimum 0.05 M) and at pH 5.0-9.0 (optimum pH 7.5). The cells were found to lyse in distilled water and the minimal NaCl concentration to prevent cell-lysis was determined to be 5 % (w/v). The major polar lipids were identified as phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and four major glycolipids (disulfated mannosyl glucosyl diether, sulfated mannosyl glucosyl diether and two unidentified glycolipids chromatographically identical to glycolipids in Halosimplex carlsbadense JCM 11222(T)). Strain YGH94(T) was found to possess two heterogeneous 16S rRNA genes (rrnA and rrnB) and both are related to those of Hsx. carlsbadense JCM 11222(T) (92.7-98.6 % similarities), Halosimplex pelagicum R2(T) (94.6-99.2 % similarities) and Halosimplex rubrum R27(T) (92.9-98.8 % similarities). The rpoB' gene similarity between strain YGH94(T) and Hsx. carlsbadense JCM 11222(T), Hsx. pelagicum R2(T) and Hsx. rubrum R27(T) are 95.4, 94.9 and 95.1 %, respectively. The DNA G+C content of strain YGH94(T) was determined to be 64.0 mol%. Strain YGH94(T) showed low DNA-DNA relatedness (35-39 %) with the current three members of the genus Halosimplex. The phenotypic, chemotaxonomic and phylogenetic properties suggest that strain YGH94(T) (=CGMCC 1.12235(T) = JCM 18647(T)) represents a new species of the genus Halosimplex, for which the name Halosimplex litoreum sp. nov. is proposed. PMID- 26059864 TI - Construction of photoswitchable rotaxanes and catenanes containing dithienylethene fragments. AB - Mechanically interlocked structures such as rotaxanes and catenanes provide a novel backbone for constructing functional materials with unique structural characteristics. In this study, we have designed and synthesized a series of photoswitchable rotaxanes and catenanes containing photochromic dithienylethene fragments using a template-directed clipping approach based on dynamic imine chemistry. Their structures have been confirmed using NMR, mass spectrometry and elemental analysis. Investigations into their photoisomerization properties indicated that these dithienylethene-based mechanically interlocked molecules have good reversibility and excellent fatigue resistance upon irradiation with UV or visible light. Interestingly, the mechanically interlocked molecules containing two dithienylethene backbones display around a 2-fold increase in the molar absorption coefficient compared with that of the mono dithienylethene derivative. Furthermore, the introduction of the fluorophore pyrene in the dithienylethene component facilitates these molecules to serve as fluorescent switches. PMID- 26059863 TI - Isoprenyl caffeate, a major compound in manuka propolis, is a quorum-sensing inhibitor in Chromobacterium violaceum. AB - The emergence of antibiotic-resistant bacterial pathogens, especially Gram negative bacteria, has driven investigations into suppressing bacterial virulence via quorum sensing (QS) inhibition strategies instead of bactericidal and bacteriostatic approaches. Here, we investigated several bee products for potential compound(s) that exhibit significant QS inhibitory (QSI) properties at the phenotypic and molecular levels in Chromobacterium violaceum ATCC 12472 as a model organism. Manuka propolis produced the strongest violacein inhibition on C. violaceum lawn agar, while bee pollen had no detectable QSI activity and honey had bactericidal activity. Fractionated manuka propolis (pooled fraction 5 or PF5) exhibited the largest violacein inhibition zone (24.5 +/- 2.5 mm) at 1 mg dry weight per disc. In C. violaceum liquid cultures, at least 450 ug/ml of manuka propolis PF5 completely inhibited violacein production. Gene expression studies of the vioABCDE operon, involved in violacein biosynthesis, showed significant (>=two-fold) down-regulation of vioA, vioD and vioE in response to manuka propolis PF5. A potential QSI compound identified in manuka propolis PF5 is a hydroxycinnamic acid-derivative, isoprenyl caffeate, with a [M-H] of 247. Complete violacein inhibition in C. violaceum liquid cultures was achieved with at least 50 ug/ml of commercial isoprenyl caffeate. In silico docking experiments suggest that isoprenyl caffeate may act as an inhibitor of the violacein biosynthetic pathway by acting as a competitor for the FAD-binding pockets of VioD and VioA. Further studies on these compounds are warranted toward the development of anti-pathogenic drugs as adjuvants to conventional antibiotic treatments, especially in antibiotic-resistant bacterial infections. PMID- 26059865 TI - Reliability of Calculated Low-Density Lipoprotein Cholesterol. AB - Aggressive low-density lipoprotein cholesterol (LDL-C)-lowering strategies are recommended for prevention of cardiovascular events in high-risk populations. Guidelines recommend a 30% to 50% reduction in at-risk patients even when LDL-C concentrations are between 70 and 130 mg/dl (1.8 to 3.4 mmol/L). However, calculation of LDL-C by the Friedewald equation is the primary laboratory method for routine LDL-C measurement. We compared the accuracy and reproducibility of calculated LDL-C <130 mg/dl (3.4 mmol/L) to LDL-C measured by beta quantification (considered the gold standard method) in 15,917 patients with fasting triglyceride concentrations <400 mg/dl (4.5 mmol/L). Both variation and bias of calculated LDL-C increased at lower values of measured LDL-C. The 95% confidence intervals for a calculated LDL-C of 70 mg/dl (1.8 mmol/L) and 30 mg/dl (0.8 mmol/L) were 60 to 86 mg/dl (1.6 to 2.2 mmol/L) and 24 to 60 mg/dl (0.6 to 1.6 mmol/L), respectively. Previous recommendations have emphasized the requirement for a fasting sample with triglycerides <400 mg/dl (4.5 mmol/L) to calculate LDL C by the Friedewald equation. However, no recommendations have addressed the appropriate lower reportable limit for calculated LDL-C. In conclusion, calculated LDL-C <30 mg/dl (0.8 mmol/L) should not be reported because of significant deviation from the gold standard measured LDL-C results, and caution is advised when using calculated LDL-CF values <70 mg/dl (1.8 mmol/L) to make treatment decisions. PMID- 26059866 TI - Impact of Brain Natriuretic Peptide, Calcium Channel Blockers, and Body Mass Index on Recovery Time from Left Ventricular Systolic Dysfunction in Patients With Takotsubo Cardiomyopathy. AB - Takotsubo cardiomyopathy (TC) is generally recognized to have a good prognosis, but it can be rarely aggravated. We sought to investigate the clinical characteristics of TC and to evaluate the effects of clinical parameters on predicting delayed recovery. We enrolled consecutive patients with TC admitted to our hospital from January 1991 to January 2014. We defined delayed recovery as sustained left ventricular (LV) systolic dysfunction requiring >=10 days for LV contraction to normalize. We screened 9,630 patients suspected of having acute coronary syndrome, and 60 patients (0.6%; men/women: 20/38; mean age: 69.7 +/- 11.9 years) were diagnosed as having TC. With the exception of 2 patients who died before LV systolic function improved, all patients recovered from LV systolic dysfunction within 6 months; the mean recovery period was 9.1 +/- 11.5 days. Twenty-eight patients met the criteria for delayed recovery. Univariate logistic regression analyses showed that male gender, LV end-diastolic diameter, brain natriuretic peptide (BNP) level, body mass index (BMI), and nonuse of calcium channel blockers (CCBs) at baseline were associated with delayed recovery. Among these factors, multiple logistic regression analysis identified BNP >=238 pg/ml (relative risk [RR] 11.6, p = 0.002) and nonuse of CCBs (RR 22.2, p = 0.0014) as independent risk factors for delayed recovery and leptosomic build (BMI <20 kg/m(2)) as an independent predictor of rapid recovery (RR 0.11, p = 0.02). In conclusion, BNP level, BMI, and use of CCBs are associated with recovery speed of LV systolic function in patients with TC. PMID- 26059867 TI - Coronary Embolization in Hypertrophic Cardiomyopathy With Left Ventricular Apical Aneurysm. Does Follow-Up With Cardiac Magnetic Resonance Have a Role? PMID- 26059868 TI - Reply: To PMID 25759101. PMID- 26059869 TI - Impact of Heart Disease on Maternal and Fetal Outcomes in Pregnant Women. AB - Pregnant women with underlying heart disease (HD) are at increased risk for adverse maternal and fetal outcomes. In this study, we sought to identify the risk and risk factors for adverse maternal and fetal events in pregnant women with underlying HD. Pregnant women referred for echocardiogram with known or suspected HD were categorized into those with (1) cardiomyopathy, (2) other HD (congenital, coronary, arrhythmia, or valvular), and (3) no HD. Primary outcome was major adverse cardiovascular events (MACE), defined as a composite of death, sustained arrhythmia, myocardial infarction, heart failure, and transient ischemic attack/stroke. Secondary outcome was fetal adverse clinical events (FACE), a composite of infant death, prematurity, underweight status, intracranial hemorrhage, and respiratory distress. Of the 173 pregnancies, 37 (21%) had cardiomyopathy, 65 (38%) had other HD, and 68 (39%) had no HD. MACE was higher in pregnancies with cardiomyopathy (p <0.001) because of higher rates of heart failure and cardiac arrest (up to 6 months postpartum, p <0.001 and 0.023, respectively). FACE rates were higher in cardiomyopathy pregnancies (p <0.001). In multivariate analysis, cardiomyopathy (odds ratio [OR] 11.5, 95% confidence interval [CI] 3.7 to 35.4), hypertension (OR 10.69, 95% CI 3.70 to 30.90), and arrhythmia (OR 7.6, 95% CI 2.1 to 27) were independently associated with higher MACE. Cardiomyopathy (OR 2.7, 95% CI 1.1 to 7.0) and hypertension (OR 3.6, 95% CI 1.4 to 9.0) were also independently predictive of higher FACE. In conclusion, pregnant women with cardiomyopathy had higher rates of adverse MACE and FACE rates. Cardiomyopathy, hypertension, and arrhythmia were independently associated with adverse cardiovascular and fetal clinical events, whereas other HD was not. PMID- 26059870 TI - UV-Induced Tetrazole-Thiol Reaction for Polymer Conjugation and Surface Functionalization. AB - A UV-induced 1,3-dipolar nucleophilic addition of tetrazoles to thiols is described. Under UV irradiation the reaction proceeds rapidly at room temperature, with high yields, without a catalyst, and in both polar protic and aprotic solvents, including water. This UV-induced tetrazole-thiol reaction was successfully applied for the synthesis of small molecules, protein modification, and rapid and facile polymer-polymer conjugation. The reaction has also been demonstrated for the formation of micropatterns by site-selective surface functionalization. Superhydrophobic-hydrophilic micropatterns were successfully created by sequential modifications of a tetrazole-modified porous polymer surface with hydrophobic and hydrophilic thiols. A biotin-functionalized surface could be fabricated in aqueous solutions under long-wavelength UV irradiation. PMID- 26059871 TI - Functional group diversity increases with modularity in complex food webs. AB - Biodiversity increases the ability of ecosystems to provide multiple functions. Most studies report a positive relationship between species richness and the number of ecosystem functions. However, it is not known whether the number of functional groups is related to the structure of the underlying species interaction network. Here we present food web data from 115 salt marsh islands and show that network structure is associated with the number of functional groups present. Functional group diversity is heterogeneously distributed across spatial scales, with some islands hosting more functional groups than others. Functional groups form modules within the community so that food webs with more modular architectures have more functional group diversity. Further, in communities with different interaction types, modularity can be seen as the multifunctional equivalent of trophic complementarity. Collectively, these findings reveal spatial heterogeneity in the number of functional groups that emerges from patterns in the structure of the food web. PMID- 26059873 TI - Aortic valve repair for insufficiency in older children offers unpredictable durability that may not be advantageous over a primary Ross operation?. AB - OBJECTIVES: To evaluate the durability of aortic valve (AoV) repair relative to other strategies for children with significant aortic insufficiency (AI). METHODS: From 2001 to 2012, 90 children with greater than or equal to moderate AI underwent surgery. Resulting procedures were classified according to final operative outcome: AoV repair (repair; n = 46, 51%), Ross procedure (Ross; n = 21, 23%) or replacement with mechanical or tissue prosthesis [aortic valve replacement (AVR); n = 23, 26%]. Repeated measures (n = 1081 echocardiograms) mixed-model analysis and parametric multiphase risk-adjusted hazard analysis were used to evaluate haemodynamic parameters and durability of operations. RESULTS: Mean age at operation was similar for repair and Ross groups, but slightly higher for the AVR group (10.6, 11 and 13.2, respectively; P = 0.04). Baseline annular dimensions were similar among groups. Of 46 repairs, 85% involved pericardial leaflet extensions (commonly with leaflet shaving and/or commisuroplasty). The remaining repairs were commissuroplasties. On multivariable analysis, repair was associated with increased early (~1-2 years) AI and increased outflow tract peak pressure gradients relative to Ross and AVR procedures. On univariate analysis, repairs tended to have a larger annulus size compared with Ross or AVR; however, this was not significant on multivariable analysis. There were 25 reinterventions (surgical reoperation = 16; transcatheter intervention = 9) for 22 children. Freedom from surgical reoperation was 64, 100 and 51% at 6 years for repairs, Ross and AVR, respectively (P = 0.05); however, three of five reoperations after AVR were for failed bioprosthetic devices. The freedom from reintervention was not significantly influenced by the type of AoV operation (P = 0.43). CONCLUSIONS: Durability of aortic valve repair for children is limited by recurrence of AI and/or stenosis, often within the first few years. After repair, reoperation should be anticipated within ~7 years. PMID- 26059872 TI - Can municipality-based post-discharge follow-up visits including a general practitioner reduce early readmission among the fragile elderly (65+ years old)? A randomized controlled trial. AB - OBJECTIVE: To evaluate how municipality-based post-discharge follow-up visits including a general practitioner and municipal nurse affect early readmission among high-risk older people discharged from a hospital department of internal medicine. DESIGN AND SETTING: Centrally randomized single-centre pragmatic controlled trial comparing intervention and usual care with investigator-blinded outcome assessment. INTERVENTION: The intervention was home visits with a general practitioner and municipal nurse within seven days of discharge focusing on medication, rehabilitation plan, functional level, and need for further health care initiatives. The visit was concluded by planning one or two further visits. Controls received standard health care services. PATIENTS: People aged 65 + years discharged from Holbaek University Hospital, Denmark, in 2012 considered at high risk of readmission. MAIN OUTCOME MEASURES: The primary outcome was readmission within 30 days. Secondary outcomes at 30 and 180 days included readmission, primary health care, and municipal services. Outcomes were register-based and analysis used the intention-to-treat principle. RESULTS: A total of 270 and 261 patients were randomized to intervention and control groups, respectively. The groups were similar in baseline characteristics. In all 149 planned discharge follow-up visits were carried out (55%). Within 30 days, 24% of the intervention group and 23% of the control group were readmitted (p = 0.93). No significant differences were found for any other secondary outcomes except that the intervention group received more municipal nursing services. CONCLUSION: This municipality-based follow-up intervention was only feasible in half the planned visits. The intervention as delivered had no effect on readmission or subsequent use of primary or secondary health care services. PMID- 26059874 TI - Pectus Carinatum Evaluation Questionnaire (PCEQ): a novel tool to improve the follow-up in patients treated with brace compression. AB - OBJECTIVES: A questionnaire (Pectus Carinatum Evaluation Questionnaire, PCEQ) was developed to be applied in follow-up of patients with Pectus Carinatum (PC). After validation of the PCEQ, we aimed to quantify the compliance to brace compression and to assess factors that could influence this treatment in patients with PC. METHODS: From July 2008 to July 2014, 56 patients with PC were treated with the Calgary Protocol of compressive bracing at Paediatric Surgery Department of Hospital Sao Joao. Forty patients (71%) completed the questionnaire. The PCEQ was divided into four sections: (i) compliance; (ii) symptoms; (iii) social influence; (iv) activities. For the validation process of the PCEQ, principal components analysis (PCA), orthogonal varimax or oblimin rotation and Cronbach's alpha coefficient were used. To evaluate the association between compliance and other sections of the questionnaire, we estimated the Pearson's correlation between compliance factor scores ('Compliance Days' and 'Compliance Hours') and the final score of each new questionnaire component identified by PCA ('Chest Pain', 'Dyspnoea', 'Back Pain', 'Parents' Influence', 'Friends' Influence', 'Activities', 'Time To Compliance'). For the sections 'Symptoms', 'Social Influence' and 'Activities', we estimated final scores as the sum of the questions that constitute each component. For the section 'Compliance', the factor scores were estimated by the regression method. RESULTS: After PCA analysis, the PCEQ found nine different components with high reliability. When analysing the compliance of our study group, the final score for 'Activities' revealed a significant correlation with the factor score for 'Compliance Hours' (r = 0.382, P = 0.015). The final score for 'Time To Compliance' showed a significant correlation with both factor scores for 'Compliance Hours' (r = 0.765, P < 0.001) and 'Compliance Days' (r = -0.345, P < 0.029). CONCLUSIONS: The PCEQ seems to be an important tool to follow up patients with PC treated by brace compression. Practical steps, such as developing a tight schedule in the early follow-up period or applying the PCEQ in first visits after initiating brace therapy, can be taken in order to increase compliance with brace therapy and improve the quality of life. PMID- 26059875 TI - A predictive scoring system for deep sternal wound infection after bilateral internal thoracic artery grafting. AB - OBJECTIVES: Despite long-term survival benefits, the increased risk of sternal complications limits the use of bilateral internal thoracic artery (BITA) grafts for myocardial revascularization. The aim of the present study was both to analyse the risk factors for deep sternal wound infection (DSWI), which complicates routine BITA grafting and to create a DSWI risk score based on the results of this analysis. METHODS: BITA grafts were used as skeletonized conduits in 2936 (70.6%) of 4160 consecutive patients with multivessel coronary artery disease who underwent isolated coronary bypass surgery at the authors' institution from 1 January 1999 to 2013. The outcomes of these BITA patients were reviewed retrospectively and a risk factor analysis for DSWI was performed. RESULTS: A total of 129 (4.4%) patients suffered from DSWI. Two multivariable analysis models were created to examine preoperative factors either alone or combined with intraoperative and postoperative factors. Female gender, obesity, diabetes, poor glycaemic control, chronic lung disease and urgent surgical priority were the predictors of DSWI common to both models. Two (preoperative and combined) models of a new scoring system were devised to predict DSWI after BITA grafting. The preoperative model performed better than five of six scoring systems for sternal wound infection that were considered; the combined model performed better than three considered scoring systems. CONCLUSIONS: A weighted scoring system based on risk factors for DSWI was specifically created to predict DSWI risk after BITA grafting. This scoring system outperformed the existing scoring systems for sternal wound infection after coronary bypass surgery. Prospective studies are needed for validation. PMID- 26059876 TI - Multiple valve surgery for a patient with presternal oesophageal reconstruction. AB - A 73-year old woman presented with progressive exertional dyspnoea. Echocardiography revealed severe regurgitation of the aortic, mitral and tricuspid valves, indicating the need for multiple valve surgery. The patient had a past history of oesophageal cancer that had been treated with chemoradiotherapy followed by oesophagectomy with presternal reconstruction using a gastric tube and a pedicled jejunum covered by the rectus abdominal muscle flap. She underwent aortic and mitral valve replacement with prostheses and tricuspid ring annuloplasty through a lower partial median sternotomy to avoid injury to the cervical oesophagus and a pedicled jejunum placed on the sternal manubrium. PMID- 26059877 TI - On the barriers to significant innovation in and reform of healthcare. PMID- 26059878 TI - Resolution of paraneoplastic immune thrombocytopenia following everolimus treatment for metastatic renal cell carcinoma. AB - Autoimmune thrombocytopenia is an uncommon but reported paraneoplastic manifestation of renal cell carcinoma (RCC). Treatment usually involves management of the underlying malignancy; however, steroids have shown a benefit in published case reports. Here, we describe a patient with profound thrombocytopenia secondary to metastatic RCC. It was refractory to steroid and intravenous immunoglobulin, but the platelet count improved markedly following initiation of everolimus. The possible explanation includes immunomodulation, tumour lysis or a combination of both effects. This is the first reported case of everolimus used in paraneoplastic thrombocytopenia from RCC. More studies are needed for further investigation of its potential use in secondary immune thrombocytopenia from RCC and perhaps other malignancies. PMID- 26059879 TI - Using functional magnetic resonance imaging to explore the possible mechanism of the action of acupuncture at Dazhong (KI 4) on the functional cerebral regions of healthy volunteers. AB - Acupuncture at right Dazhong (KI 4) mostly affects functional magnetic resonance imaging signal in the right inferior frontal gyrus, right insular lobe, right thalamus, right middle frontal gyrus and right orbitofrontal cortex, which are associated with governing executive functions, emotional activities and social behaviour. PMID- 26059880 TI - Novel gain of function mutation in the SLC40A1 gene associated with hereditary haemochromatosis type 4. AB - Here we report the case of a 69-year-old Chinese Han woman who presented with liver cirrhosis, diabetes mellitus, skin hyperpigmentation, hyperferritinaemia and high transferrin saturation. Subsequent genetic analyses identified a novel heterozygous mutation (p.Cys326Phe) in the SLC40A1 gene. This is the first report regarding a SLC40A1 mutation in the Chinese Han population and provides novel clinical evidence for the importance of p.Cys326 in SLC40A1 gene function. PMID- 26059881 TI - Medical use of cannabis: an addiction medicine perspective. AB - The use of cannabis for medical purposes, evident throughout history, has become a topic of increasing interest. Yet on the present medical evidence, cannabis based treatments will only be appropriate for a small number of people in specific circumstances. Experience with cannabis as a recreational drug, and with use of psychoactive drugs that are prescribed and abused, should inform harm reduction in the context of medical cannabis. PMID- 26059882 TI - Critical hyperkalaemia mimicking acute cerebral infarction in a haemodialysis patient. PMID- 26059883 TI - Extensive cerebral venous sinus thrombosis after romiplostim treatment for immune thrombocytopenia (ITP) despite severe thrombocytopenia. PMID- 26059884 TI - The makings of a bionic man: first use of osseo-integrated prostheses in a quadruple amputee. PMID- 26059885 TI - Mandatory reporting of impaired practitioners. PMID- 26059886 TI - New oral anticoagulants in the elderly: what's the evidence? PMID- 26059887 TI - Lack of harmonisation in the classification of renal impairment in European Summaries of Product Characteristics. PMID- 26059888 TI - Modern technology and infectious diseases activity data: how can we use this for service planning? PMID- 26059890 TI - Erratum. PMID- 26059889 TI - Erratum. PMID- 26059891 TI - [Vaccinations from the pulmonologist's point of view]. AB - BACKGROUND: The best strategy for prevention of acute respiratory tract infections is primary prophylaxis against diseases preventable by vaccination. From the pulmonologist's point of view, vaccinations against pneumococci, influenza A and B viruses and Bordetella pertussis are of particular clinical relevance. OBJECTIVES: This review article discusses the disease burden of these pathogens and the recommendations for immunization in adults. CURRENT DATA: For immunization against pneumococci a less immunogenic but broad-spectrum 23-valent polysaccharide vaccine (PPV23) and a highly immunogenic 13-valent conjugate vaccine (PCV13) with a more narrow-spectrum are approved. A sequential vaccination with PCV13 followed by PPV23 is a new option in adults. In the US this vaccination strategy is recommended as routine vaccination for all adults over 65. In Germany sequential pneumococcal vaccination is proposed only in special indications such as patients with asplenia. Trivalent and quadrivalent split-virus vaccines are the standard vaccines against seasonal influenza in adults. The Standing Committee on Vaccinations (STIKO) recommends a yearly vaccination as standard over 60 and in indications for special risk groups (e.g. infants with underlying diseases, immunocompromised patients, chronically ill patients and pregnant women). For the primary prophylaxis of pertussis only an acellular vaccine is available. Neither vaccination nor a previous infection provide lifelong immunity; therefore, the STIKO recommends an additional booster vaccine for all adults. CONCLUSION: Vaccination against pneumococci, influenza A and B viruses as well as Bordetella pertussis are recommended as standard and in special indications for adults by the STIKO at the Robert Koch Institute. For selection of the various vaccines individual factors such as age, immune status, comorbidities and pregnancy have to be considered. PMID- 26059892 TI - The influence of birth season on height: Evidence from Indonesia. AB - OBJECTIVES: Literature on the effect of birth month on height has generally considered regions in temperate climates. However, because many climatic conditions there change with seasons, it is difficult to isolate potential causes. This study estimated the effect of birth month and season on terminal height by analyzing the population of a country with only a few factors driving its climate. MATERIALS AND METHODS: The sample was derived from nationally representative data of the Indonesian population. We considered 9,262 men and 10,314 women 20-50 years of age. We applied cosinor analysis to a time series of height by birth month. We then applied a more flexible approach by regressing height on a series of dummy variables for birth month (and, subsequently, season) and birth year fixed effects by sex. RESULTS: There was no statistically significant difference in height by birth month. However, although weakly significant, men born in the dry season (June-September) were 2.3 mm shorter than those born in the wet season (the remaining months). The corresponding figure for women was 2.6 mm, a statistically significant difference. DISCUSSION: We eliminated some potential factors previously suggested in the literature, including insolation, the position of our planet with respect to the sun, food availability, and maternal workload. We speculate that babies born in the dry season were affected in the third trimester by the high disease burden that characterizes the wet season. PMID- 26059894 TI - Recent advances in hybrid Cu2O-based heterogeneous nanostructures. AB - Hybrid Cu2O-based heterogeneous nanostructures possess novel synergistic properties that arise from the integrated interaction between the disparate components, thereby showing promising potential for various important applications including solar cells, carbon monoxide oxidation, photocatalysts, field emission, sensors, templates and so on. With the rapid progress in nanomaterials science and nanotechnology, hybrid Cu2O-based heterogeneous nanostructures with well-controlled compositions, shapes and sizes have been rationally designed and synthesized. This review attempts to summarize the important advances in the development of different types of hybrid Cu2O-based heterogeneous nanostructures, such as hybrid Cu2O-metal nanostructures, hybrid Cu2O-metal oxide nanostructures and hybrid Cu2O-carbon nanostructures. The correlations between the improved performances and interfacial structures of the hybrid Cu2O-based heterogeneous nanostructures are discussed based on some important and representative examples. Several key scientific issues and perspective research directions in this field are also given. PMID- 26059893 TI - Incidence of Melanoma in Children: A Population-Based Study in Olmsted County, Minnesota. AB - BACKGROUND: The incidence of melanoma has been rising in the United States, with conflicting evidence regarding trends in children. METHODS: We identified patients 0 to 17 years old with a diagnosis of melanoma from January 1, 1970, through December 31, 2010, in Olmsted County, Minnesota. Information on survival and demographic characteristics was abstracted, and estimates of true incidence were calculated. RESULTS: The estimated true incidence of melanoma in children from 1970 to 2010 was found to be 0.62 per 100,000 girls and 0.45 per 100,000 boys. The incidence of melanoma in this population did not increase with time after adjusting for age and sex. Only one case of metastatic disease (lymph node) was identified. Girls were more commonly affected and the mean age of disease onset was 14 years. Five of the seven melanomas in this population arose in association with a nevus, and none involved the trunk. Overall and disease specific survival rates were not calculated because all patients studied were alive at the last follow-up. CONCLUSION: The estimated true incidence rates of pediatric melanoma from our population-based study in Olmsted County, Minnesota, appear stable. This finding is in contrast to our prior research showing rapidly increasing incidence rates of melanoma in young and middle-aged adults from the same population. PMID- 26059895 TI - One-year outcomes of small-incision lenticule extraction (SMILE): mild to moderate myopia vs. high myopia. AB - BACKGROUND: The purpose of this study was to compare the refractive outcomes of small incision lenticule extraction (SMILE) in high-myopic patients with those of mild- to moderate-myopic patients. METHODS: This study included 183 eyes of 92 myopic patients treated with SMILE using a VisuMax 500-kHz femtosecond laser. Treated eyes were divided into two groups, according to the preoperative spherical equivalent (SE): mild to moderate myopia (A group, <-6.0 D) and high myopia (B group, >= - 6.0 D). Follow-up visits were at 1 day, 1 week, and 1, 3, 6, and 12 months. The outcome measures included uncorrected distance visual acuity (UDVA), best-corrected distance visual acuity (BDVA), postoperative SE, efficacy index, safety index, and predictability. RESULTS: Preoperative SE was 5.05 +/- 0.71 D in the A group and -7.67 +/- 1.01 D in the B group. No differences were observed between -0.13 +/- 0.38 D in the A group and -0.24 +/- 0.35 D in the B group 12 months postoperatively (p = 0.18). At 12 months postoperatively, 93.1 % and 76.8 % had an UDVA of 20/20 or better in the A and B groups, respectively. In the A group, 87.9 % and 96.6 % were within +/- 0.5 D and +/- 1.0 D, respectively, of the intended correction; in the B group, 88.0 % and 97.6 % were within +/- 0.5 D and +/- 1.0 D, respectively. The efficacy index was 1.04 +/- 0.19 in the A group and 0.99 +/- 0.19 in the B group. The safety index was 1.27 +/- 0.17 for the A group and 1.24 +/- 0.17 for the B group. The efficacy and safety index were not significantly different between the two groups 12 months postoperatively (p = 0.141 and p = 0.307, respectively). CONCLUSIONS: This study showed that SMILE is effective and safe for correcting high myopia, as well as mild to moderate myopia. PMID- 26059896 TI - Effects of Ranolazine in Patients With Chronic Angina in Patients With and Without Percutaneous Coronary Intervention for Acute Coronary Syndrome: Observations From the MERLIN-TIMI 36 Trial. AB - BACKGROUND: Ranolazine, a piperazine derivative with anti-ischemic effects, reduces the frequency of angina and improves exercise performance in patients with chronic angina. The effects of ranolazine in patients with established ischemic heart disease and chronic angina undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) is not well described. We hypothesized that ranolazine would reduce ischemic events, regardless of revascularization. METHODS: We examined the 1-year incidence of recurrent cardiovascular (CV) events in the subgroup of patients with prior chronic angina (n = 3565) enrolled in the randomized, double-blind, placebo-controlled Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST-Elevation ACS (MERLIN) Thrombolysis In Myocardial Infarction (TIMI) 36 trial who did or did not have a PCI within 30 days of the index event. RESULTS: Ranolazine reduced the risk of recurrent ischemia following admission regardless of whether patients had (hazard ratio [HR], 0.69; 95% confidence interval [CI] 0.51-0.92] or did not have PCI (HR, 0.81; 95% CI, 0.66-0.99; P interaction = 0.39). CV death, myocardial infarction, and recurrent ischemia were similarly lower with ranolazine in the PCI group (HR, 0.71; 95% CI, 0.55-0.91) vs the non-PCI group (HR, 0.91; 95% CI, 0.78-1.06; P interaction = 0.10), with a nominally significant decrease in CV death (HR, 0.39; 95% CI, 0.16-0.93) in the PCI group vs no difference in the non PCI group (HR, 1.19; 95% CI, 0.89-1.59; P interaction = 0.02). CONCLUSIONS: In patients with chronic angina, ranolazine reduced recurrent ischemic events, regardless of whether patients did or did not receive PCI within 30 days of a non ST-segment ACS. PMID- 26059897 TI - Intracellular microRNA profiles form in the Xenopus laevis oocyte that may contribute to asymmetric cell division. AB - Asymmetric distribution of fate determinants within cells is an essential biological strategy to prepare them for asymmetric division. In this work we measure the intracellular distribution of 12 maternal microRNAs (miRNA) along the animal-vegetal axis of the Xenopus laevis oocyte using qPCR tomography. We find the miRNAs have distinct intracellular profiles that resemble two out of the three profiles we previously observed for mRNAs. Our results suggest that miRNAs in addition to proteins and mRNAs may have asymmetric distribution within the oocyte and may contribute to asymmetric cell division as cell fate determinants. PMID- 26059899 TI - Clinical Trial of Vitamin D2 vs D3 Supplementation in Critically Ill Pediatric Burn Patients. AB - BACKGROUND: Hypovitaminosis D exists postburn. However, evidence-based guidelines for vitamin D repletion are unknown. This investigation examined differences between D2 and D3 supplementation on outcome in children with burn injuries. METHODS: Fifty patients with total body surface area burn of 55.7% +/- 2.6% and full-thickness injury of 40.8% +/- 3.8% were enrolled, ranging in age from 0.7 18.4 years. All participants received multivitamin supplementation per standardized clinical protocol. In addition, 100 IU/kg D2, D3, or placebo was administered daily during hospitalization using a randomized, double-blinded study design. Assay of total 25-hydroxyvitamin D (D25), 1,25-dihydroxyvitamin D (D1,25), 25-hydroxyvitamin D2 (25-OH-D2), 25-hydroxyvitamin D3 (25-OH-D3), and parathyroid hormone (PTH) was performed at 4 preplanned time intervals (baseline, midpoint, discharge, and 1 year postburn). Differences in vitamin D status were compared over time and at each specific study interval. RESULTS: There were no significant differences in serum vitamin D levels between groups, but >10% of patients had low D25 at discharge, and percent deficiency worsened by the 1-year follow up for the placebo (75%), D2 (56%), and D3 (25%) groups. There were no statistical differences in PTH or clinical outcomes between treatment groups, although vitamin D supplementation demonstrated nonsignificant but clinically relevant decreases in exogenous insulin requirements, sepsis, and scar formation. CONCLUSIONS: The high incidence of low serum D25 levels 1 year following serious thermal injury indicates prolonged compromise. Continued treatment with vitamin D3 beyond the acute phase postburn is recommended to counteract the trajectory of abnormal serum levels and associated morbidity. PMID- 26059898 TI - The Fecal Microbiome in Pediatric Patients With Short Bowel Syndrome. AB - BACKGROUND: Changes in the intestinal microbiome of patients with short bowel syndrome (SBS) are thought to significantly affect clinical outcome. These changes may not only delay enteral diet advancement but may also predispose patients to bacterial translocation, bacteremia, and liver disease. Patients with SBS are thought to be more susceptible to changes in gut microbial communities due to intestinal dysmotility and/or lack of anatomic safeguards such as the ileocecal valve. MATERIALS AND METHODS: We analyzed the bacterial composition of 21 fecal specimens from 9 children with SBS and 8 healthy children ages 4 months to 8 years by 16S ribosomal RNA gene sequencing. The sequences were quality filtered and analyzed using QIIME, the Ribosomal Database Project Classifier, and the randomForest supervised learning algorithm. RESULTS: The fecal microbiome of patients with SBS is different from that of healthy controls. Stool from patients with SBS had a significantly greater abundance of the bacterial classes Gammaproteobacteria and Bacilli. Stool from patients with SBS who experienced increased stool frequency tended to have increased abundance of Lactobacillus (P = .057) and decreased abundance of Ruminococcus. CONCLUSION: This study shows that the fecal microbiome of patients with SBS is significantly different from that of healthy controls when analyzed by 16S metagenomics. Differences in the composition and function of gut microbiomes in children with SBS may affect bowel physiology, and these findings may provide new opportunities for intestinal rehabilitation and clinical management. PMID- 26059900 TI - Lactobacillus reuteri DSM 17938 as a Probiotic for Preterm Neonates: A Strain Specific Systematic Review. AB - INTRODUCTION: Prevention of necrotizing enterocolitis (NEC) while optimizing enteral nutrition (EN) is a priority in preterm neonates. Lactobacillus reuteri DSM 17938 (L reuteri) is known to improve gut motility. Previous systematic reviews have not adequately assessed the effects of L reuteri in improving feed tolerance in preterm neonates. OBJECTIVE: To assess the effects of L reuteri in preterm neonates. DESIGN: A systematic review of randomized controlled trials (RCTs) and non-RCTs of L reuteri was conducted. We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, and CINAHL databases and proceedings of Pediatric Academic Society meetings in December 2014. RESULTS: Six RCTs (n = 1778) and 2 non-RCTs (n = 665) were included. Meta-analysis of RCTs estimated that the time to full feeds (mean difference [MD], -1.34 days; 95% confidence interval [CI], -1.81 to -0.86; 2 RCTs), duration of hospitalization ( 10.77 days; 95% CI, -13.67 to -7.86; 3 RCTs), and late-onset sepsis (LOS) (relative risk [RR], 0.66; 95% CI, 0.52 to 0.83; 4 RCTs) were reduced in the L reuteri group. Mortality (RR, 0.79; 95% CI, 0.57-1.09; 3 RCTs) and >= stage II NEC (RR, 0.69; 95% CI, 0.47-1.01; 3 RCTs) were reduced but statistically not significant. There were no adverse effects of supplementation. Both non-RCT studies showed significant improvement in the incidence of NEC with L reuteri supplementation. CONCLUSIONS: Evidence from a limited number of studies suggests that L reuteri supplementation has the potential to reduce the risk of NEC and LOS while facilitating EN in preterm infants. Larger definitive RCTs are needed to confirm these findings. PMID- 26059901 TI - Evaluating Evidence-Based Nutrition Support Practice Among Healthcare Professionals With and Without the Certified Nutrition Support Clinician Credential. AB - BACKGROUND: The National Board of Nutrition Support Certification credentials healthcare professionals and certifies that holders of the Certified Nutrition Support Clinician (CNSC) credential have specialized knowledge of safe and effective nutrition support therapy. The purpose of this pilot study was to survey healthcare professionals affiliated with the American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) regarding their approaches to nutrition support practice using a complex patient case scenario in accordance with established clinical guidelines. MATERIALS AND METHODS: An electronic survey was emailed to individuals affiliated with A.S.P.E.N. Eight multiple-choice knowledge questions addressed evidence-based nutrition support practice issues for a patient with progressing pancreatitis. Demographic and clinical characteristic data were collected. RESULTS: Of 48,093 email invitations sent, 4455 (9.1%) responded and met inclusion criteria. Most respondents were dietitians (70.8%) and in nutrition support practice for 10.3 years, and 29.3% held the CNSC credential. Respondents with the CNSC credential answered 6.18 questions correctly compared with 4.56 for non-CNSC respondents (P < .001). For all 8 questions, CNSC respondents were significantly more likely to choose the correct answer compared with non-CNSC respondents (P < .001). CONCLUSION: Professionals with the CNSC credential scored significantly higher on a complex case-based knowledge assessment of guideline recommendations for the nutrition support treatment of pancreatitis compared with those without a credential. PMID- 26059902 TI - Glutamine Administration After Sublethal Lower Limb Ischemia Reduces Inflammatory Reaction and Offers Organ Protection in Ischemia/Reperfusion Injury. AB - BACKGROUND: This study investigated the effects of intravenous glutamine (GLN) administration on the expression of adhesion molecules and inflammatory mediators in a mice model of hind limb ischemia/reperfusion (IR) injury. METHODS: There were 3 IR groups and 1 normal control (NC) group. The NC group did not undergo the IR procedure. Mice in the IR groups underwent 90 minutes of limb ischemia followed by a variable period of reperfusion. Ischemia was performed by applying a 4.5-oz orthodontic rubber band to the left thigh. Mice in one IR group were sacrificed immediately after reperfusion. The other 2 IR groups were injected once with either 0.75 g GLN/kg body weight (G group) or an equal volume of saline (S group) via tail vein before reperfusion. Mice in the S and G groups were subdivided and sacrificed at 4 or 24 hours after reperfusion. RESULTS: IR enhanced the inflammatory cytokine gene expressions in muscle. Also, plasma interleukin (IL)-6 levels, blood neutrophil percentage, and the adhesion molecule and chemokine receptors expressed by leukocytes were upregulated after reperfusion. The IR-induced muscle inflammatory mediator gene expressions, blood macrophage percentage, and plasma IL-6 concentration had declined at an early or a late phase of reperfusion when GLN was administered. Histologic findings also found that remote lung injury was attenuated during IR insult. CONCLUSIONS: A single dose of GLN administration immediately after sublethal lower limb ischemia reduces the inflammatory reaction locally and systemically; this may offer local and distant organ protection in hind limb IR injury. PMID- 26059903 TI - Usefulness and growing need for intraoperative transthoracic echocardiography: a case series. AB - BACKGROUND: Physician-performed transthoracic echocardiography (TTE) is still seldom used during anesthesia. Despite its various advantages, there are only a few reports of intraoperative TTE. We report 3 cases in which intraoperative TTE was successfully used. CASE PRESENTATION: A 75-year-old woman (Case 1) was scheduled for a posterior spinal fusion. When the wound was being closed, systolic blood pressure suddenly dropped to 30 mmHg. TTE revealed hypokinesis in the antero-septal region. Emergent coronary angiography showed 90% stenosis in left anterior descending artery (Segment 7), and a bare metal stent was implanted. A 71-year-old woman (Case 2) with hypertrophic cardiomyopathy was scheduled for brain tumor operation. During anesthesia induction, the patient developed hemodynamic instability. TTE showed systolic anterior motion of the mitral valve, and appropriate treatment was administered. A 78-year-old woman (Case 3) was scheduled for revision total hip arthroplasty. When the wound was closed, TTE revealed severe hypovolemia despite massive infusion. We insisted on reopening the wound and found additional massive hemorrhage. CONCLUSION: Intraoperative TTE is a potent tool for quick hemodynamic evaluation because it is noninvasive and has sufficient diagnostic capabilities. The successful outcomes of our cases suggest the great usefulness of intraoperative TTE, and more frequent use is to be encouraged. PMID- 26059904 TI - Management of musculoskeletal tumors during pregnancy: a retrospective study. AB - BACKGROUND: In recent years, scientific research has increasingly focused on malignancies during pregnancy. However, the development of musculoskeletal tumors during pregnancy has only been the subject of a few studies so far. The primary aim of this study was to identify the incidence of sarcomas during pregnancy at our musculoskeletal tumor center (MSTC). Secondarily we intended to analyze these cases and discuss possible recommendations regarding diagnostic work-up as well as therapy on the basis of the literature. METHODS: All female patients who had been treated for soft tissue or bone sarcoma at our academic MSTC in the period between the years 2002 and 2010 were screened retrospectively for anamnestic annotations of pregnancy or records of pregnancy in the obstetrical database of our university hospital. The patients who met the criteria for inclusion (diagnosed sarcoma and pregnancy) were enrolled. For every pregnant patient two age-matched female control patients that suffered from tumors with the same histologic type were included. RESULTS: In the period between 2002 and 2010, 240 female patients between the age of 16 and 45 were treated for sarcoma. In eight out of the 240 cases the tumor disease developed or progressed during pregnancy. The delay in diagnosis was approximately eight months and turned out to be significantly higher for pregnant patients compared to non- pregnant controls. Each woman's tumor was misdiagnosed at least once. CONCLUSIONS: Diagnostic follow up of pregnant women presenting with a growing or painful mass, which is suspected to be a musculoskeletal tumor, should be performed at a specialized tumor center. We recommend a multidisciplinary approach and discussing all possible consequences for mother and child intensively in accordance with the available literature. PMID- 26059905 TI - rIL-10 enhances IL-10 signalling proteins in foetal alveolar type II cells exposed to hyperoxia. AB - Although the mechanisms by which hyperoxia promotes bronchopulmonary dysplasia are not fully defined, the inability to maintain optimal interleukin (IL)-10 levels in response to injury secondary to hyperoxia seems to play an important role. We previously defined that hyperoxia decreased IL-10 production and pre treatment with recombinant IL-10 (rIL-10) protected these cells from injury. The objectives of these studies were to investigate the responses of IL-10 receptors (IL-10Rs) and IL-10 signalling proteins (IL-10SPs) in hyperoxic foetal alveolar type II cells (FATIICs) with and without rIL-10. FATIICs were isolated on embryonic day 19 and exposed to 65%-oxygen for 24 hrs. Cells in room air were used as controls. IL-10Rs protein and mRNA were analysed by ELISA and qRT-PCR, respectively. IL-10SPs were assessed by Western blot using phospho-specific antibodies. IL-10Rs protein and mRNA increased significantly in FATIICs during hyperoxia, but JAK1 and TYK2 phosphorylation showed the opposite pattern. To evaluate the impact of IL-8 (shown previously to be increased) and the role of IL 10Rs, IL-10SPs were reanalysed in IL-8-added normoxic cells and in the IL-10Rs' siRNA-treated hyperoxic cells. The IL-10Rs' siRNA-treated hyperoxic cells and IL 8-added normoxic cells showed the same pattern in IL10SPs with the hyproxic cells. And pre-treatment with rIL-10 prior to hyperoxia exposure increased phosphorylated IL-10SPs, compared to the rIL-10-untreated hyperoxic cells. These studies suggest that JAK1 and TYK2 were significantly suppressed during hyperoxia, where IL-8 may play a role, and rIL-10 may have an effect on reverting the suppressed JAK1 and TYK2 in FATIICs exposed to hyperoxia. PMID- 26059907 TI - Tribute. PMID- 26059906 TI - What is the value of anti-Mullerian hormone in predicting the response to ovarian stimulation with GnRH agonist and antagonist protocols? AB - BACKGROUND: Anti-Mullerian hormone (AMH) is a marker of the ovarian reserve with promising prognostic potential in reproductive medicine. We aimed to evaluate the prognostic ability of AMH for predicting excessive or poor responses to ovarian stimulation using gonadotrophin-releasing hormone (GnRH) agonist and GnRH antagonist protocols in patients undergoing medically assisted reproduction (MAR) procedures. METHODS: This retrospective analysis included 623 women who underwent ovarian stimulation for medically assisted reproduction. AMH level measurements were acquired from all couples within six months of the initiation of ovarian stimulation. RESULTS: AMH was significantly correlated with the number of retrieved oocytes, and age was not relevant in a multivariate regression analysis (unstandardized regression coefficient of 1.130, 95 % confidence interval 0.977 1.283). AMH was a better predictor of both excessive (>19 oocytes) and poor (<4 oocytes) ovarian response than age (areas under the curve (AUCs) of 0.882 and 0.816, respectively). When stratified according to the stimulation protocol (a long GnRH agonist versus a GnRH antagonist protocol), AMH retained its high predictive value for excessive and poor responses in both groups. Serum AMH levels exhibited a strong correlation with the level of the response to ovarian stimulation. CONCLUSIONS: AMH is an independent and an accurate predictor of excessive and poor responses to GnRH agonist and GnRH antagonist protocols for ovarian stimulation. PMID- 26059908 TI - Cardiac response to centrally administered echinocandin antifungals. AB - OBJECTIVES: The purpose of this study was to determine the effect of the echinocandin antifungals on the cardiac system, including cardiac output, blood pressure and heart rate, when administered in an in-vivo model. METHODS: The echinocandin antifungals were administered via central line to male Sprague Dawley rats. Cardiac imaging and functional measurements were made using a high resolution in-vivo imaging system. Statistical comparisons of the experimental antifungals versus saline control were made using a Student's t-test. KEY FINDINGS: In cardiac output (CO) measurements, caspofungin was associated with a bimodal distribution in results at 3 mg/kg. Those with little response, termed 'non-vulnerable' animals (n = 3) had no significant change in CO from baseline ( 4.6 +/- 10.7%). Other animals, termed 'vulnerable' animals (n = 3 at 3 mg/kg and those dosed at 6 mg/kg (n = 6)), experienced greater than 60% decrease in CO ( 66.4 +/- 13.1% at 3 mg/kg and -62.9 +/- 13.0% at 6 mg/kg, P < 0.05). A dose of 5 mg/kg anidulafungin was associated with no significant changes in CO (-16.1 +/- 26%), while 11.5 mg/kg decreased CO by 62.7 +/- 19.4% from baseline (P < 0.05). With micafungin 1 mg/kg and 5 mg/kg doses, changes in CO were not significant ( 16.7 +/- 2.1% and -18.2 +/- 1.9%, respectively). CONCLUSIONS: These studies provide substantial evidence to support ex-vivo Langendorff and in-vitro mitochondrial studies demonstrating a similar pharmacological event. Clinical reports of similar effects also support these findings. PMID- 26059909 TI - Concentration and temperature induced dual-responsive wormlike micelle to hydrogel transition in ionic liquid-type surfactant [C16imC9]Br aqueous solution without additives. AB - A highly viscoelastic fluid formed by the ionic liquid-type surfactant 1 hexadecyl-3-nonyl imidazolium bromide ([C16imC9]Br) in water in the absence of any additive was studied. The phase behavior and morphology of aggregates were studied by a combination of rheological techniques, small-angle X-ray scattering (SAXS), cryo-etch-scanning electron microscopy (cryo-etch-SEM) and freeze fractured transmission electron microscopy (FF-TEM). [C16imC9]Br aqueous solutions showed interesting rheological behavior as a function of both concentration and temperature, which invoked a transition between wormlike micelles and hydrogels. With the increase in [C16imC9]Br concentration, the aqueous solution could form viscoelastic wormlike micelles (50-80 mM), hydrogels (90-110 mM) and wormlike micelles (120-180 mM). As the temperature increased, the hydrogels (90-110 mM) could also transit to wormlike micelles. The unusual phase transition between wormlike micelles and elastic hydrogels was postulated to be the change of the average micellar length. PMID- 26059910 TI - Astragalin Attenuates Allergic Inflammation in a Murine Asthma Model. AB - The present study aimed to determine the protective effects and the underlying mechanisms of astragalin (AG) on ovalbumin (OVA)-induced allergic inflammation in a mouse model of allergic asthma. Our study demonstrated that AG inhibited OVA induced increases in eosinophil count; IL-4, IL-5, IL-13, and IgE were recovered in bronchoalveolar lavage fluid, and increased IFN-gamma level in bronchoalveolar lavage fluid. Histological studies demonstrated that AG substantially inhibited OVA-induced eosinophilia in lung tissue. Western blot analysis demonstrated that AG treatments markedly inhibited OVA-induced SOCS-3 expression and enhancement of SOCS-5 expression in an asthma model. Our findings support the possible use of AG as a therapeutic drug for patients with allergic asthma. PMID- 26059912 TI - Assessing effective population size, coancestry and inbreeding effects on litter size using the pedigree and SNP data in closed lines of the Iberian pig breed. AB - The complete pedigree of two closed Iberian pig lines (Gamito and Torbiscal), with 798 and 4077 reproducers, has been used to measure the evolution of coancestry (f) and inbreeding (F) for autosomal and X-linked genes along 16 and 28 respective equivalent discrete generations. At the last generation, the mean values of each line were f = 0.41 and 0.22, F = 0.35 and 0.18, fX = 0.46 and 0.22 and FX = 0.47 and 0.19, respectively. Other calculated parameters were the effective number of founders (final values, 6.8 and 35.2) and non-founders (1.5 and 2.4), founder genome equivalents (1.2 and 2.3) and effective population size (16.0 and 57.7). Measures of Torbiscal effective size based on rates of coancestry (66.1), inbreeding (65.0) and linkage disequilibrium (71.0) were estimated from whole-genome SNP genotyping data. Values of new and old inbreeding and their respective rates by generation were computed to detect purging effects of natural selection. The analysis of 6854 Torbiscal litters showed significant negative impacts of new and fast inbreeding on litter size, as expected from the purging hypothesis: -0.20 born piglets per litter by a 10% of new inbreeding, and -0.03 and -0.02 piglets by 1% of total and new inbreeding rates, respectively. The analysis performed on 1274 litters of the Gamito line failed to show purging effects. The only significant results were reductions in -0.91 and -0.17 piglets by a 10% of old and X-linked genes inbreeding, respectively. These results may be useful for some practical issues in conservation programs of farm or captive wild animals. PMID- 26059911 TI - Disproportionate effects of dementia on hospital discharge disposition in common hospitalization categories. AB - BACKGROUND: The impact of dementia on hospitalization discharge dispositions (HDDs) in the United States has not been quantified, and dementia prevalence in various hospitalization categories has not been detailed in recent years. OBJECTIVE: To characterize hospitalizations prevalent with dementia, and to examine the relationship between dementia and HDDs. DESIGN: A retrospective cross sectional study. SETTING: 2000 to 2012 National Inpatient Sample databases. PATIENTS: Hospitalizations in persons >=65 years old assigned to 1 of 12 Diagnosis Related Groups (DRGs) with a high number of dementia patients. INTERVENTION: None. MEASUREMENTS: The databases were queried for 12 DRGs (versions 18/24). Predictor effects for dementia on HDD categories were modeled adjusting for other defined comorbidities/covariates using logistic regression. Adjusted predictor effects of dementia on HDD in the DRG groupings were determined. Dementia prevalence and trends were assessed. RESULTS: Increasing proportions of dementia were noted in 4 DRGs studied. Dementia was strongly associated with being discharged to a nonhome setting. The most marked dementia effects were noted in DRGs 174 (gastrointestinal hemorrhage), 88 (chronic obstructive pulmonary disease), 182 (esophagitis/gastroenteritis), 138 (cardiac arrhythmias), 127 (congestive heart failure), and 89 (simple pneumonia and pleurisy), where there was at least a 76% reduction in the adjusted odds ratio (0.18-0.24) for home discharge. In contrast, DRGs 14 (stroke), 79 (respiratory infections/ inflammations), and 320 (kidney/urinary infections) had a smaller reduction in dementia-associated adjusted odds ratio (0.41-0.46) for home discharge. DRGs 79 and 320 had the highest proportions of dementia (>10%). CONCLUSIONS: Dementia proportions in many hospitalization categories have increased. The variable effect of dementia on home discharge suggests that dementia has a differential influence on hospital discharge disposition depending on the DRG. These findings have implications for healthcare allocation and long term care planning. PMID- 26059913 TI - The effect of external heat transfer on thermal explosion in a spherical vessel with natural convection. AB - When any exothermic reaction proceeds in an unstirred vessel, natural convection may develop. This flow can significantly alter the heat transfer from the reacting fluid to the environment and hence alter the balance between heat generation and heat loss, which determines whether or not the system will explode. Previous studies of the effects of natural convection on thermal explosion have considered reactors where the temperature of the wall of the reactor is held constant. This implies that there is infinitely fast heat transfer between the wall of the vessel and the surrounding environment. In reality, there will be heat transfer resistances associated with conduction through the wall of the reactor and from the wall to the environment. The existence of these additional heat transfer resistances may alter the rate of heat transfer from the hot region of the reactor to the environment and hence the stability of the reaction. This work presents an initial numerical study of thermal explosion in a spherical reactor under the influence of natural convection and external heat transfer, which neglects the effects of consumption of reactant. Simulations were performed to examine the changing behaviour of the system as the intensity of convection and the importance of external heat transfer were varied. It was shown that the temporal development of the maximum temperature in the reactor was qualitatively similar as the Rayleigh and Biot numbers were varied. Importantly, the maximum temperature in a stable system was shown to vary with Biot number. This has important consequences for the definitions used for thermal explosion in systems with significant reactant consumption. Additionally, regions of parameter space where explosions occurred were identified. It was shown that reducing the Biot number increases the likelihood of explosion and reduces the stabilising effect of natural convection. Finally, the results of the simulations were shown to compare favourably with analytical predictions in the classical limits of Semenov and Frank-Kamenetskii. PMID- 26059914 TI - Innovative teaching in situational awareness. AB - BACKGROUND: In the UK the publication of the Health Select Committee Report highlighted the need to incorporate human factors training in health care education. In response there has been a rise in health care professional training in human factors, focusing on non-technical skills, such as teamwork, leadership and situational awareness. CONTEXT: Using simulation and contextualised learning, we have developed a non-technical skills programme for undergraduate medical students that introduces situational awareness training in the first year. Early integration of human factors into the undergraduate programme can be built upon in a constructivist approach throughout the undergraduate curriculum. Initially no formal ethical approval was required as this was an integral part of the undergraduate teaching programme and did not involve patients; however, ethical approval was gained for the analyses of this session from the local University Research Ethics Committee. Approval included the information sheets and consent forms provided to students, which permitted use of data 'in future posters/publications/presentations'. INNOVATION: Students were introduced to hazards and cues that they may find in clinical areas, encouraged to explore the simulated clinical areas gathering information, interpret their findings and then consider future states. There has been a rise in health care professional training in human factors, focusing on non-technical skills IMPLICATIONS: Initial feedback from both the students and the tutors involved has been positive. In addition, the opportunity for linking this to other non-technical skills developments in different clinical settings and in interprofessional settings is being considered. The next stage is to explore students' perceptions of this session and their learning through questionnaires and focus-group interviews before developing further. PMID- 26059915 TI - Couples coping with cancer: exploration of theoretical frameworks from dyadic studies. AB - OBJECTIVE: A diagnosis of cancer and subsequent treatment are distressing not only for the person directly affected, but also for their intimate partner. The aim of this review is to (a) identify the main theoretical frameworks underpinning research addressing dyadic coping among couples affected by cancer, (b) summarise the evidence supporting the concepts described in these theoretical frameworks, and (c) examine the similarities and differences between these theoretical perspectives. METHODS: A literature search was undertaken to identify descriptive studies published between 1990 and 2013 (English and French) that examined the interdependence of patients' and partners' coping, and the impact of coping on psychosocial outcomes. Data were extracted using a standardised form and reviewed by three of the authors. RESULTS: Twenty-three peer-reviewed manuscripts were identified, from which seven theoretical perspectives were derived: Relationship-Focused Coping, Transactional Model of Stress and Coping, Systemic-Transactional Model (STM) of dyadic coping, Collaborative Coping, Relationship Intimacy model, Communication models, and Coping Congruence. Although these theoretical perspectives emphasised different aspects of coping, a number of conceptual commonalities were noted. CONCLUSION: This review identified key theoretical frameworks of dyadic coping used in cancer. Evidence indicates that responses within the couple that inhibit open communication between partner and patient are likely to have an adverse impact on psychosocial outcomes. Models that incorporate the interdependence of emotional responses and coping behaviours within couples have an emerging evidence base in psycho-oncology and may have greatest validity and clinical utility in this setting. PMID- 26059916 TI - Formation of a hard tissue barrier after experimental pulp capping or partial pulpotomy in humans: an updated systematic review. AB - The aim was to update a systematic review of pulp capping and partial pulpotomy by Olsson et al. (2006), by evaluating new evidence on formation of a hard tissue barrier after pulp capping and partial pulpotomy of experimental exposures in humans. PubMed (01-01-2005 to 01-03-2014) and CENTRAL were searched using specific keywords. Hand searches were made and the level of evidence for each included article was evaluated by the authors. The evidence of the conclusions was graded as strong, moderately strong, limited or insufficient. The initial search in PubMed yielded 215 abstracts. Hand searches of reference lists yielded no additional original scientific articles. After a selection process and interpretation, 22 articles were included and rated for level of evidence: no article was rated as high and seven as moderate. Overall the methodological quality of studies has improved since the previous systematic review was published in 2006. The conclusions are that there is limited scientific evidence that application of calcium hydroxide or mineral trioxide aggregate to an exposed pulp frequently results in formation of a hard tissue barrier, whereas adhesives or enamel matrix derivatives do not. There is insufficient scientific evidence that mineral trioxide aggregate promotes hard tissue formation more frequently than calcium hydroxide. PMID- 26059917 TI - Drug-drug interactions in pharmacologic management of gastroparesis. AB - BACKGROUND: Gastroparesis is a disorder characterized by delayed gastric emptying due to chronic abnormal gastric motility. The treatment of the disease often entails the co-administration of several classes of pharmacological agents. These agents may be metabolized via the same pathway. Inhibition or induction of a shared metabolic pathway leads to change in the systemic levels of prescribed drugs, possibly leading to undesired clinical outcomes. PURPOSE: This review discusses different pharmacological treatment for gastroparesis patients and describes the potential for drug-drug interactions (DDIs) in some of the combinations that are currently used. Prokinetic agents such as metoclopramide and domperidone are the cornerstone in treatment of gastroparesis. Antiemetic agents such as promethazine and ondansetron are frequently administered to gastroparesis patients to reduce nausea and vomiting. Gastroparesis is prevalent in diabetic patients and therefore antidiabetic agents are also prescribed. Many of these co-administered drugs are metabolized via common drug metabolizing enzymes and this can trigger potential DDIs. The scientific literature was reviewed from the years 1975-2014 for original research articles and reviews that evaluated DDIs in gastroparesis. Many commonly prescribed combinations were predicted to cause potential DDIs in gastroparesis patients. This review will help inform about potential hazardous combinations. This information will hopefully lead to less adverse effects and more successful gastroparesis management. PMID- 26059918 TI - 33rd Congress of the Scandinavian Society of Anaesthesiology and Intensive Care Medicine, Reykjavik, Iceland, 10 June 2015. PMID- 26059919 TI - Serum vitamin D status is associated with the presence but not the severity of primary open angle glaucoma. AB - OBJECTIVES: Vitamin D is involved in visual health and function. Our objective was to determine whether age-related vitamin D insufficiency was associated with the presence and the severity of primary open angle glaucoma (POAG) in a case control study of older adults. STUDY DESIGN: Case-control study. MAIN OUTCOME MEASURES: One hundred fifty cases diagnosed with moderate-to-severe POAG (mean, 75.1 +/- 8.5 years; 42.0% female) and 164 healthy controls (mean, 73.0 +/- 7.9 years; 59.8% female) were included. POAG diagnosis was based on classical diagnostic criteria of optic nerve cupping and/or RNFL thinning, measured with optical coherence tomography. Severe POAG was defined as Humphrey visual field mean deviation (MD) worse than -12 dB. Vitamin D insufficiency was defined as serum 25OHD <= 75 nmol/L. Age, gender, mean arterial pressure, vitamin D supplementation, visual acuity, and intraocular pressure were used as potential confounders. RESULTS: POAG cases had lower mean serum 25OHD concentration than controls (42.9 +/- 25.7 nmol/L versus 49.4 +/- 29.5 nmol/L, P=0.039) and a greater prevalence of vitamin D insufficiency (90.7% versus 82.3%, P=0.032). Increased mean serum 25OHD concentrations were associated with lower POAG frequency, even after adjustment for potential confounders (OR=0.89 per 10 nmol/L of 25OHD, P=0.045). Similarly, vitamin D insufficiency was associated with POAG (OR=2.09, P=0.034). Among POAG cases, no 25OHD difference was observed between moderate and severe POAG cases (respectively, 39.2 +/- 23.3 nmol/L versus 45.1 +/ 26.7 nmol/L, P=0.188); and no between-group difference regarding the prevalence of vitamin D insufficiency (88.9% versus 94.0%, P=0.313). CONCLUSIONS: Decreased serum 25OHD concentration was associated with POAG. There was no 25OHD difference between moderate and severe POAG. PMID- 26059920 TI - Depression and the incidence of urinary incontinence symptoms among young women: Results from a prospective cohort study. AB - OBJECTIVE: To examine the association of depressive symptoms with subsequent urinary incontinence (UI) symptoms among young women. SUBJECTS AND METHODS: Data were from a cohort of 5391 young women (born 1973-1978) from the Australian Longitudinal Study on Women's Health. Generalised Estimating Equations (GEEs) were used to link depressive symptoms, and history of doctor diagnosed depression at Survey 2 (S2) in 2000 with the incidence of UI symptoms in subsequent surveys (from S3 in 2003 to S6 in 2012). RESULTS: 24% of women reported the incidence of UI over the nine-year study period, while the prevalence rose over time from 6.8% (at S2, aged 22-27 years) to 16.5% (at S6, aged 34-39). From univariable GEE analysis, women with depressive symptoms or a history of depression were more likely to report subsequent UI symptoms. This remained after adjusting for socio demographic, body mass index, health behaviours and reproductive factors, with depressive symptoms associated with 37% higher odds (odds ratio 1.37, 95% CI 1.16 to 1.61) and history of depression with 42% higher odds (1.42, 1.17 to 1.74) of incidence of UI. CONCLUSIONS: When woman seek treatment for UI symptoms, health professionals should consider her current or history of depression. PMID- 26059921 TI - Mechanisms of Alcohol-Facilitated Intimate Partner Violence. AB - Intimate partner violence (IPV) is a critical public health problem that requires clear and testable etiological models that may translate into effective interventions. While alcohol intoxication and a pattern of heavy alcohol consumption are robust correlates of IPV perpetration, there has been limited research that examines the mediating mechanisms of how alcohol potentiates IPV. We provide a theoretical and methodological framework for researchers to conceptualize how alcohol intoxication causes IPV, and propose innovative laboratory methods that directly test mediational mechanisms. We conclude by discussing how these innovations may lead to the development of interventions to prevent or reduce alcohol-related IPV. PMID- 26059922 TI - Use of technical skills and medical devices among new registered nurses: A questionnaire study. AB - BACKGROUND: One comprehensive part of nursing practice is performing technical skills and handling of medical equipment. This might be challenging for new registered nurses (RNs) to do in patient-safe way. OBJECTIVES: The aim of this study was to describe and compare the extent to which new RNs perform various technical skills and handle medical devices in different settings, and to investigate their possibility for continued learning in this respect. A further aim was to describe their perceptions of incident reporting related to technical skills and medical devices. DESIGN: A cross-sectional study with descriptive and comparative design. PARTICIPANTS: RNs who recently graduated from a nursing programme at three Swedish universities and had worked as a RN for up to 1 year were included in the study (n=113, response rate 57%). METHOD: Data were collected by means of a postal questionnaire. RESULTS: Half of the RNs reported that they performed several of the listed tasks every day or every week, regardless of workplace. These tasks were most frequently performed in surgical departments. The majority of the participants (76%) stated a need of continued practical training. However, less than half of them (48%) had access to a training environment. Several participants (43%) had been involved in incidents related to technical skills or medical devices, which were not always reported. Nearly a third of the participants (31%) did not use the existing guidelines when performing technical skills, and reflection on performance was uncommon. CONCLUSIONS: This study highlights the importance of shared responsibilities between nurse educators and health care employers to provide learning opportunities for new RNs in technical skills, to maintain patient safety. To increase the safety culture where nursing students and new RNs understand the importance of using evidence-based guidelines and taking a reflective approach in the performance of technical tasks is needed. PMID- 26059923 TI - International clinical placements for Australian undergraduate nursing students: A systematic thematic synthesis of the literature. AB - OBJECTIVES: International clinical placements provide undergraduate nursing students with the opportunity to experience or practice nursing care in diverse countries, settings, and cultures. This systematic review aims to ascertain the current knowledge on international clinical placements offered by undergraduate nursing programs in Australia. It seeks to explore three questions: (1) How have previous experiences of nursing students' international clinical placements been described? (2) How have participants and stakeholders determined if the placement has been successful? And (3) What benefits or challenges have been identified by stakeholders as a result of participating in international clinical placements? DESIGN: A systematic thematic synthesis was undertaken. DATA SOURCES: A search of electronic databases including CINAHL, Proquest Central, Scopus, PubMed, and Health Collection was undertaken between September and October 2014. REVIEW METHODS: Key terms including 'international clinical placement', 'study abroad', 'international exchange', 'nursing', and 'Australia' were used to identify articles that appeared in peer-reviewed English language journals and that explored international clinical placements offered to undergraduate nursing students by Australian universities. RESULTS: Eight studies were identified that meet the inclusion criteria, and through thematic analysis, five key themes were identified including developing cultural awareness and competence, providing a global perspective on health care, translation of theory to practice, growing personally through reflection, and overcoming apprehension to successfully meet the challenge. A comparison search of literature from Canada and the United Kingdom revealed that similar themes occurred internationally. CONCLUSIONS: Although personal successes were identified by students undertaking international clinical placement, further research is required to identify all stakeholder experiences including those of the educators, the educational institutions, and travel providers supporting these placements and the communities where the placements take place. PMID- 26059924 TI - Water and carbon dioxide fluxes over an alpine meadow in southwest China and the impact of a spring drought event. AB - Based on the eddy covariance measurements from June 2011 to December 2013, the seasonal variations and the controls of water and CO2 fluxes were investigated over an alpine meadow in Lijiang, southwest China. The year 2012 had the largest total precipitation among years from 2011 to 2013 (1037.9, 1190.4, and 1066.1 mm, respectively). A spring drought event occurred from March to May 2012, and the peak normalized difference vegetation index (NDVI) in 2012 was the lowest. Throughout the whole year, net radiation (Rn), vapor pressure deficit, and air temperature (Ta) were the primary controls on evapotranspiration (ET), and R n is the most important factor. The influence of R n on ET was much more in the wet season (R(2) = 0.93) than in the dry season (R(2) = 0.28). In the wet season, the ratio of ET to equilibrium ET (ETeq) (0.92 +/- 0.14; mean +/- S.D.) did not show a clear seasonal pattern with NDVI when the soil water content (SWC) was usually more than 0.25 m(3) m(-3), indicating that ET could be predicted well by ETeq (or radiation and temperature). On half-hourly and daily scales, photosynthetic active radiation (PAR) and air temperature were the main meteorological factors in determining the net ecosystem production (NEP). The seasonal trends of NEP were closely related with the change of NDVI. The integrated NEP in the 2012 wet season (157.8 g C m(-2) year(-1)) was 19.5 and 23.8 % lower than in the 2011 and 2013 wet season (207.0 and 196.1 g C m(-2) year(-1)). The mean ET/ETeq for each of the wet seasons from 2011 to 2013 was 0.88. The 2012 spring drought and its reduction in NDVI decreased the total NEP significantly but had little effect on the total ET in the wet season. The different response of NEP and ET to the spring drought was attributed to the high SWC and small vapor pressure deficit during the wet season. PMID- 26059925 TI - Breast Cancer Survivorship: Where Are We Today? AB - Breast cancer is the most common cancer in women, and survivors with this diagnosis account for almost one fourth of the over 14 million cancer survivors in the US. After several decades of basic and clinical trials research, we have learned much about the heterogeneity of breast cancer and have evolved a complex and multidisciplinary treatment approach to the disease. Increasingly, we are paying attention to the long term and late effects of breast cancer treatment, and this is largely the subject of this volume. In this chapter, the authors introduce the topic of breast cancer survivorship and highlight the organization and content of this volume, briefly describing the contents of the subsequent chapters. PMID- 26059926 TI - Special Issues in Younger Women with Breast Cancer. AB - Although women less than 50 years old make up less than 25% of the patient population with breast cancer in industrialized countries, they have unique clinical and psychosocial issues that must be addressed as part of their oncology care to ensure the best health and psychosocial outcomes after treatment. Preserving fertility is a major issue for many younger women who have either not had children or would like to have additional children after treatment. Dealing with the disruption of a cancer diagnosis at a young age is challenging physically, socially and emotionally, and the health care system does not always address these patients' concerns. Because younger women have the potential for a long life expectancy after cancer treatment, preventing and reducing the risk for late effects of cancer treatment is very important. We discuss these and a range of other issues throughout this chapter. PMID- 26059927 TI - Special Issues in Older Women with Breast Cancer. AB - The true face of breast cancer is more commonly that of an older woman. The rapid aging of the US population is contributing to an increasing number of breast cancer cases in older adults today, as well as an increase in the number of breast cancer survivors who carry the long-term side effects of breast cancer treatment. The number one problem facing older women with breast cancer today is that they are not receiving the same benefits from treatment advances as younger women. This disparity in outcomes highlights the great need for studies that specially include older women with breast cancer in order to guide informed decisions regarding the most efficacious treatment options. Novel study designs are needed to fill these gaps in knowledge which include metrics that provide a detailed understanding of the individual beyond chronologic age, and which identify areas of vulnerability for which targeted interventions can be employed. In studying cancer therapeutics in older adults, metrics of success, beyond disease-free and overall survival should be included, such as the feasibility of delivering the therapy, as well as the impact of treatment on functional independence and cognition. Ultimately, this framework will lead to evidence based "personalized" medicine for the older adult. PMID- 26059928 TI - Breast Cancer Among Special Populations: Disparities in Care Across the Cancer Control Continuum. AB - Disparities in breast cancer risk factors, access, and treatment patterns are responsible for disparities in incidence, mortality and other measures of the impact of breast cancer among different population groups. Moreover, differences in culture and role definition impact various areas of aging and quality of life. Populations most impacted by disparities include women of racial/ethnic groups, older women, and women from rural and urban areas. More research is needed to document and address disparities across the cancer control continuum among a variety of populations that suffer disparities. PMID- 26059929 TI - Symptoms: Fatigue and Cognitive Dysfunction. AB - Fatigue and cognitive complaints commonly occur during adjuvant chemotherapy treatment of breast cancer. Fatigue is also associated with radiation therapy, and can occur with surgery alone. Both of these symptoms may persist beyond the initial treatment of breast cancer and they have taken on greater prominence with the growing number of breast cancer survivors. These symptoms are most troublesome when patients try to resume their pre-illness activities (e.g., work, household responsibilities) and find that they are limited. Recovery may take months to years, but in some women these symptoms persist indefinitely and can be very distressing. In this chapter we review what is known about the etiology and biology of these two common symptoms, discuss potential interventions, and describe future research challenges. PMID- 26059930 TI - Symptoms: Chemotherapy-Induced Peripheral Neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic, treatment induced toxicity that has the potential to impact quality of life and limit the doses of curative intent therapy. This therapy-induced side effect is one of the most troublesome in oncology clinical practices, considering the morbidity, the frequency, and the potential irreversibility of this problem. Patients with breast cancer are particularly impacted by this side effect as multiple agents commonly used for this disease can cause neuropathy. In this chapter, we provide an overview of CIPN, including: clinical predictors, frequency, and its impact on quality of life. Further, we highlight the pathophysiology and review the literature to date for agents designed to prevent or treat CIPN. We also highlight the most important ongoing clinical and translational research questions that hope to help better predict and prevent this toxicity. This includes optimizing the methods of assessment, using host specific factors (Race and genetics) to predict those more likely to experience CIPN, and determining how CIPN might impact clinical decisions toward therapy. PMID- 26059931 TI - Symptoms: Aromatase Inhibitor Induced Arthralgias. AB - Recent clinical trials have demonstrated that aromatase inhibitors (AIs) are slightly more effective than tamoxifen at reducing breast cancer recurrences. However, breast cancer patients receiving AIs have a higher incidence of musculoskeletal symptoms, particularly joint pain and stiffness. Musculoskeletal pain and stiffness can lead to noncompliance and increased utilization of health care resources. There is a suggestion that the syndrome is the result of estrogen deprivation and may share components with autoimmune diseases such as Sjogren's syndrome. Several factors may increase the likelihood of developing AI arthralgia, such as prior chemotherapy, prior hormone replacement therapy, and increased weight; there are inconsistencies with regard to the data on genetic predispositions to this syndrome. While several studies have been done to evaluate interventions to treat or prevent AI arthralgia, no clear treatment has emerged as being particularly beneficial. Much of the research has been limited by small sample size, difficulty blinding patients to placebo, inconsistent definitions of the syndrome, multiple patient reported outcomes, lack of objective outcome measures and heterogeneous patient populations. We are at the early stages of research in characterizing, understanding etiology, preventing and treating AI arthralgias; however much work is being done in this area which, hopefully, will ultimately improve the lives of women with breast cancer. PMID- 26059932 TI - Symptoms: Lymphedema. AB - Lymphedema is one of the main late effects from breast cancer treatment affecting 3-60% of breast cancer survivors. Primarily occurring in the hand, arm, and/or affected breast, symptoms of lymphedema include swelling, pain, redness, restriction of arm/hand movement, tightness and feelings of fullness. These symptoms not only may limit physical functioning but also negatively affect quality of life, body image, social functioning, and financial status of breast cancer survivors with lymphedema. Unfortunately, there are no standardized methods for prevention, diagnosis, and treatment of breast cancer-related lymphedema. Despite its prevalence and lack of clinical guidelines, lymphedema is one of the most poorly understood, relatively underestimated, and least researched complications of cancer treatment. This chapter reviews the current problem of breast cancer-related lymphedema by investigating prevention and risk reduction strategies, diagnosis, and treatment. In addition, this chapter identifies future research opportunities focusing on prevention and risk reduction strategies, quality of life and physical function, surveillance, patient education, cost, diagnosis, and treatment. Challenges and recommendations for future research in these areas, particularly among underserved populations, are discussed. PMID- 26059933 TI - Symptoms: Menopause, Infertility, and Sexual Health. AB - By 2022, the number of survivors is expected to grow to nearly 18 million. Therefore, addressing acute and chronic negative sequelae of a cancer diagnosis and its treatments becomes a health imperative. For women with a history of breast cancer, one of the common goals of treatment and prevention of recurrence is to reduce circulating concentrations of estradiol, especially in women with hormone receptor positive breast cancer. Hormone deprivation after a diagnosis of breast cancer impacts physiological targets other than in the breast tissue and can result in unwanted side effects, all of which can negatively impact quality of life and function and cause distress. Symptoms that are most strongly linked by evidence to hormone changes after cancer diagnosis and treatment include hot flashes, night sweats, sleep changes, fatigue, mood changes, and diminishing sexual function, including vaginal atrophy (decreased arousal, dryness and dyspareunia), infertility, decreased desire and negative self-image. Weight gain and resulting body image changes are often concomitants of the abrupt onset of treatment-induced menopause. The purpose of this chapter is to briefly review what is known about the advent of premature menopause in women treated for breast cancer, menopausal symptoms that are exacerbated by endocrine treatments for breast cancer, and the associated concerns of hot flashes and related menopausal symptoms, sexual health and fertility issues. We will discuss limitations in the current research and propose strategies that address current limitations in order to move the science forward. PMID- 26059934 TI - Host Factors and Risk of Breast Cancer Recurrence: Genetic, Epigenetic and Biologic Factors and Breast Cancer Outcomes. AB - Among women with breast cancer, there is wide variability in outcomes, both in treatment-related toxicities and disease-free survival (DFS). Primary predictors of DFS are those related to the extent of the disease and tumor characteristics, associated not only with tumor aggressiveness, but also responsiveness to targeted therapies. Inherited germline variation may also play a role in cancer treatment outcomes, and there have been studies targeting drug metabolism and other candidate pathways as well as genome-wide association studies (GWAS), which take a more agnostic approach and interrogate hundreds of thousands single nucleotide polymorphisms (SNPs) to determine those that modify response to breast cancer treatment. While this field of pharmacogenetics and pharmacogenomics has held exciting promise for personalized medicine, the results have not been as consistent, or the effects as profound, as first hoped. An emerging field in studies of cancer prognosis is epigenetics, which regulates DNA expression and can be influenced by numerous biologic processes as well as environmental exposures. Although young, this field of research likely holds promise for understanding of epigenetic mechanisms driving cancer and cancer outcomes, with a potential to modify these factors through drugs or other approaches. Finally, circulating markers in blood that reflect some lifestyle factors have also been studies in relation to cancer outcomes, particularly Vitamin D. In this chapter, we highlight advances in the areas noted above, and comment on factors that can impact interpretation of results from observational studies. We also discuss future directions, and avenues necessary to move the field forward. PMID- 26059935 TI - Comorbidities and Their Management: Potential Impact on Breast Cancer Outcomes. AB - Pre-existing comorbidities negatively impacts overall breast cancer prognosis, increasing both breast cancer specific deaths as well as death from competing causes. Improvements in breast cancer survival in recent decades, however, have primarily been experienced among cancer patients without comorbidities, and less so among those with moderate or severe comorbidities. As guidelines for the treatment of breast cancer are mostly based on studies excluding patients with moderate and severe comorbidities with under-representation of older women with comorbid conditions, information regarding treatment effectiveness in breast cancer patients with comorbidities is currently lacking. This chapter describes the impact of comorbidities on breast cancer treatment and outcomes, previous research approaches taken, and specific populations that may be most susceptible to the effects of comorbidities on breast cancer outcomes. Future research directions are suggested that may help to improve understanding of comorbidity related factors that underlie disparities in breast cancer outcomes, and to examine the potential role of effective management of comorbidities among breast cancer patients as a strategy to help close gaps in disease prognosis. PMID- 26059936 TI - Modifiable Lifestyle Factors and Breast Cancer Outcomes: Current Controversies and Research Recommendations. AB - Lifestyle factors, particularly obesity, have been associated with poor breast cancer outcomes in a large number of observational studies. Despite a growing body of research, controversy exists regarding obesity associations across breast cancer subtypes and the importance of obesity versus physical activity and dietary composition in determining breast cancer outcome. These controversies are reviewed and the complex biologic nature of the association of obesity with breast cancer addressed. Potential mediators, including insulin, estrogens, adipokines and inflammation markers are identified. Relevant prognostic findings of previous research involving dietary, physical activity and weight loss interventions are summarized. A broad-based program of research is outlined, highlighting the need for a randomized trial of weight loss that is adequately powered to examine survival effects, as well as correlative and preclinical research to investigate mediators and mechanisms of obesity effects on breast cancer outcomes. Finally, potential contributions of alcohol intake and tobacco use in breast cancer survivors are discussed. PMID- 26059937 TI - Risk Reduction from Weight Management and Physical Activity Interventions. AB - Obesity and low levels of physical activity are associated with a higher risk of breast cancer recurrence and mortality. Currently, over 65% of breast cancer survivors are overweight or obese, and fewer than 30% engage in recommended levels of physical activity. The reason for low adherence to lifestyle guidelines is likely multifactorial. Given the continuing trend of increased obesity and physical inactivity in the United States, worldwide and in breast cancer survivors, more research showing the direct effect of weight loss and/or exercise on breast cancer recurrence and mortality is needed. Many exercise interventions have examined the impact of increasing exercise on changes in quality of life, with most studies showing a favorable effect of exercise on quality of life. Smaller Phase II randomized trials using biomarkers as surrogate endpoints is likely appropriate to answer questions regarding mechanisms of action, exercise type, volume, and intensity, yet a definitive trial of weight loss and exercise on disease-free survival is critical for moving the field forward. Research is also necessary on how to disseminate lifestyle interventions into the clinic and community that lead to clinically meaningful weight losses of at least 5% that are maintained over time, and favorable sustained changes in physical activity levels. Changes in referrals, access, and reimbursement of lifestyle programs may lead to favorable changes in the prevalence of obesity and physical activity in breast cancer survivors and in turn rates of breast cancer recurrence and mortality. PMID- 26059938 TI - Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors. AB - As recurrence free survival following a breast cancer diagnosis continues to improve, cardiovascular morbidity and mortality will assume greater importance in the breast cancer survivorship research agenda particularly for women receiving potentially cardiotoxic therapy. Development of (1) tools to readily identify pre diagnostic risk factors for cardiac dysfunction, (2) well-tolerated prophylactic treatments to reduce the risk of cardiac injury, and (3) sensitive and affordable monitoring techniques which can identify subclinical toxicity prior to a drop in left ventricular ejection fraction are or should be focus areas of cardio oncology research. Since weight as well as cardiorespiratory fitness generally decline after a breast cancer diagnosis, behavioral approaches which can improve energy balance and fitness are important to optimize cardiovascular health in all breast cancer survivors not just those undergoing cardiotoxic therapy. These goals are likely best achieved by partnerships between cardiologists, oncologists and internists such as those initiated with the formation of the International CardiOncology Society (ICOS) and the NCI Community Cardiotoxicity Task Force. PMID- 26059939 TI - Psychological Adjustment in Breast Cancer Survivors. AB - Women living with a diagnosis of breast cancer constitute more than 20 % of the cancer survivor population in the United States. Research on trajectories of psychological adjustment in women recently diagnosed with breast suggests that the largest proportion of women evidences relatively low psychological distress either from the point of diagnosis or after a period of recovery. Substantial heterogeneity exists, however, and some women are at risk for lingering depression, anxiety, fear of cancer recurrence and other long-term psychological effects. Most women diagnosed with breast cancer also report a number of benefits that arise from their experience of cancer. Longitudinal studies have illuminated risk and protective factors for psychological adjustment in breast cancer survivors, which we describe in this chapter. Effective psychosocial interventions, as evidenced in randomized controlled trials, also are available for bolstering breast cancer-related adjustment. We offer directions for research to deepen the understanding of biological, psychological, and social contributors to positive adjustment in the context of breast cancer, as well as suggestions for the development of optimally efficient evidence-based psychosocial interventions for women living with the disease. PMID- 26059940 TI - Living with Metastatic Breast Cancer. AB - Although prevalence estimates are imprecise, growing numbers of women in the United States are living longer with metastatic breast cancer, attributable at least in part to the availability of effective targeted therapies. Women living with metastatic disease are understudied, however, and substantial heterogeneity exists in both the clinical characteristics of metastatic tumors and the physical and psychological experience of patients living with the disease. Survivorship issues are complex for patients who are living with metastatic disease over extended periods of time, from years to decades. Newly diagnosed patients with stage IV disease are confronting cancer for the first time, while others have metastatic disease as a result of breast cancer recurrence. Many patients are able to live for years on stable medical regimens, and yet others live with a moving target of aggressive disease with arduous treatments and uneven response. The psychological common denominator is the experience of profound life threat and the accompanying uncertainty, for both the affected woman and her loved ones. Maintaining life balance in the face of metastatic disease, as well as managing pain, fatigue, and other physical and psychological symptoms are major challenges. Increasingly, the clinical approach to metastatic disease reflects the consensus that palliative and supportive care are essential from the point of diagnosis. To remedy the paucity of systematic research on women living with metastatic breast cancer for extended periods, we offer directions for research to understand the experience of metastatic breast cancer and to provide evidence based inter-professional care. PMID- 26059941 TI - Quality of Care, Including Survivorship Care Plans. AB - With the expectation of prolonged survival in the vast majority of women diagnosed with breast cancer, making initial treatment decisions that minimize or prevent late complications, and maximize the quality as well as quantity of life, is absolutely critical. Unfortunately, such care is not uniformly delivered. Patient, provider, and system barriers contribute to delays in cancer care, lower quality of care, and poorer outcomes in vulnerable populations, including low income, underinsured, and racial/ethnic minority populations. Covering the costs of cancer care is a major concern for many cancer survivors, and as a result, a major challenge will be to provide cost-effective follow-up care by reducing overuse of unnecessary tests and procedures so that access to effective medications can be preserved. One of the recently promoted means of improving the coordination of care for breast cancer survivors has been the use of survivorship care planning, as coordination of care will be absolutely essential to deliver high-quality care. Patient navigation is another approach to help overcome healthcare system barriers and facilitate timely access to quality medical care. Understanding the challenges and opportunities in delivering high-quality cancer care is one of the most critical issues of the day. With the large numbers of breast cancer patients and the tremendous advances in our understanding of the disease and treatments (leading to large numbers of survivors), breast cancer will likely be the focus of new models for the delivery of better and more efficient cancer care. PMID- 26059942 TI - Comparison of the Charlson Comorbidity Index derived from self-report and medical record review in Asian patients with rheumatic diseases. AB - The aim of the study was to compare the agreement between self-report Charlson Comorbidity Index (SR-CCI) and the medical record-based CCI (MR-CCI) and to examine the impact of both instruments on health-related quality of life (HRQoL) amongst Asian patients with rheumatic diseases. This cross-sectional study surveyed a convenience sample of patients seen at rheumatology specialty outpatient clinics. Patients completed the SR-CCI and Short Form 36, while two research assistants completed the MR-CCI. Item-level agreement between the SR-CCI and MR-CCI was evaluated using kappa coefficients. Adjusted linear regression models evaluated the independent effect of the SR-CCI/MR-CCI on HRQoL. The study included 301 patients (median age 51, range 21-79, 61.5 % female, 68.8 % Chinese, 17.6 % Indian, 6.0 % Malay). Kappa statistics for cerebrovascular disease (0.433), chronic pulmonary disease (0.509), connective tissue disease/rheumatoid arthritis (0.506), ulcer disease (0.461), and tumour (0.541) reflected moderate agreement between the SR-CCI and MR-CCI (all p < 0.0001). There was substantial agreement in the reporting of diabetes (0.764, p < 0.0001) but poor/fair agreement for that of myocardial infarction (0.359, p < 0.0001) and diabetes with end-organ damage (0.189, p = 0.0002). Increases in SR-CCI were associated with significant reductions in both physical (beta coefficient -2.56, p < 0.0001) and mental HRQoL (beta coefficient -1.24, p = 0.044). However, such associations were not observed with the MR-CCI. The SR-CCI demonstrated moderate concordance with the MR-CCI, and the SR-CCI but not MR-CCI scores were associated with lower HRQoL. Assessment of comorbidities amongst rheumatology patients remains complex, and more efficient methods of quantifying these conditions are needed for clinical and research purposes. PMID- 26059943 TI - Platelet and red blood cell interactions and their role in rheumatoid arthritis. AB - Cytokines, lymphocytes, platelets and several biomolecules have long been implicated in the pathology of rheumatoid arthritis (RA), and the influences of antibody production and tagging, and cytokine, chemokine and enzyme production at specific rheumatoid joints were thought to be exclusive to the advancement of disease parameters. Another role player in RA is red blood cells (RBCs) which, of late, have been found to be involved in RA pathobiology, as there is a positive correlation between RBC counts and joint pathology, as well as with inflammatory biomarkers in the disease. There is also an association between RBC distribution width and the incidence of myocardial infarction amongst RA patients, and there is a change in the lipid distribution within RBC membranes. Of late, certain RBC associated factors with previously obscure roles and cell-derived particles thought to be inconsequential to the other constituents of plasma were found to be active biomolecular players. Several of these have been discovered to be present in or originating from RBCs. Their influences have been shown to involve in membrane dynamics that cause structural and functional changes in both platelets and RBCs. RBC-derived microparticles are emerging entities found to play direct roles in immunomodulation via interactions with other plasma cells. These correlations highlight the direct influences of RBCs on exacerbating RA pathology. This review will attempt to shed more light on how RBCs, in the true inflammatory milieu of RA, are playing an even greater role than previously assumed. PMID- 26059945 TI - IMAGING DIAGNOSIS - UNILATERAL TRIGEMINAL NEURITIS MIMICKING PERIPHERAL NERVE SHEATH TUMOR IN A HORSE. AB - A 16-year old Warmblood gelding presented with a nonhealing corneal ulcer and absent corneal sensation in the left eye. A lesion affecting the maxillary and ophthalmic branches of the left trigeminal nerve was suspected. Magnetic resonance (MR) imaging identified marked thickening of the ophthalmic and maxillary branches of the left trigeminal nerve. The nerve was iso- to hypointense on T1-weighted and T2-weighted images with heterogeneous enhancement. A peripheral nerve sheath tumor was suspected, however granulomatous neuritis was histopathologically confirmed. These inflammatory changes can result in severe nerve enlargement and should be considered with MR findings suggestive of peripheral nerve sheath tumor. PMID- 26059946 TI - Deciphering the protein-RNA recognition code: combining large-scale quantitative methods with structural biology. AB - RNA binding proteins (RBPs) are key factors for the regulation of gene expression by binding to cis elements, i.e. short sequence motifs in RNAs. Recent studies demonstrate that cooperative binding of multiple RBPs is important for the sequence-specific recognition of RNA and thereby enables the regulation of diverse biological activities by a limited set of RBPs. Cross-linking immuno precipitation (CLIP) and other recently developed high-throughput methods provide comprehensive, genome-wide maps of protein-RNA interactions in the cell. Structural biology gives detailed insights into molecular mechanisms and principles of RNA recognition by RBPs, but has so far focused on single RNA binding proteins and often on single RNA binding domains. The combination of high throughput methods and detailed structural biology studies is expected to greatly advance our understanding of the code for protein-RNA recognition in gene regulation, as we review in this article. PMID- 26059944 TI - Differences in the prevalence and characteristics of metabolic syndrome in rheumatoid arthritis and osteoarthritis: a multicentric study. AB - The purpose of the study was to examine whether rheumatoid arthritis (RA) patients have higher prevalence of metabolic syndrome (MetS) than osteoarthritis (OA) patients in association with a higher level of chronic systemic inflammation in rheumatoid arthritis. A total of 583 RA and 344 OA outpatients were analyzed in this multicentric study. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A 1.6-fold higher prevalence of MetS was found in patients with OA compared with the RA patients. Among the parameters of MetS, patients with OA had significantly higher levels of waist circumference, systolic blood pressure, fasting blood glucose and triglycerides, whereas HDL cholesterol and diastolic blood pressure values were similar in both groups of patients. Higher values of inflammatory markers [C reactive protein (CRP), erythrocyte sedimentation rate (ESR)] in MetS than in non MetS patients and higher prevalence of MetS in patients with CRP level >=5 mg/L in both RA and OA patients were found. In multivariate logistic regression analysis, significant predictors of MetS were type of arthritis (OA vs. RA; OR 2.5 [95 % CI 1.82-3.43]), age (OR 1.04 [95 % CI 1.03-1.06]) and ESR (OR 1.01; [95 % CI 1.00-1.01]). The significant association between OA and MetS was maintained in the regression model that controlled for body mass index (OR 1.87 [95 % CI 1.34-2.61]). The present analysis suggests that OA is associated with an increased risk of MetS, which may be due to a common underlying pathogenic mechanism. PMID- 26059949 TI - Does Trastuzumab Cause Cardiotoxicity in the Treatment of Patients with Breast Cancer? PMID- 26059947 TI - Dynamic regulation of CD24 expression and release of CD24-containing microvesicles in immature B cells in response to CD24 engagement. AB - The glycophosphatidylinositol-anchored cell surface receptor CD24 (also called heat-stable antigen) promotes the apoptosis of progenitor and precursor B lymphocytes. However, the immediate proximal events that occur after engagement of CD24 in B cells are not precisely understood. Using a bioinformatics analysis of mouse (Mus musculus) gene expression data from the Immunological Genome Project, we found that known vesicle trafficking and cellular organization genes have similar expression patterns to CD24 during B-cell development in the bone marrow. We therefore hypothesized that CD24 regulates vesicle trafficking. We first validated that antibody-mediated engagement of CD24 induces apoptosis in the mouse WEHI-231 cell line and mouse primary bone marrow-derived B cells. We next found that CD24 surface protein expression is rapidly and dynamically regulated in both WEHI-231 cells and primary immature B cells in response to engagement of CD24. The change in surface expression was not mediated by classical endocytosis or exocytosis. However, we found that CD24-bearing plasma membrane-derived extracellular microvesicles were released in response to CD24 engagement. Furthermore, in response to CD24 engagement we observed a clear exchange of CD24 between different populations of B cells. Hence, we show that engagement of CD24 in immature B cells results in a dynamic regulation of surface CD24 protein and a redistribution of CD24 within the population. PMID- 26059948 TI - Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. AB - Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was 8.3 months; 46% of patients were treated for >12 months, and 22% were treated for >=2 years. The ORR was 67% (23% complete response), with a median duration of response of 17.5 months. The 24-month progression-free survival and overall survival rates were 31% (95% confidence interval [CI], 22.3-40.4) and 47% (95% CI, 37.1-56.9), respectively. The most common adverse events (AEs) in >30% of patients included diarrhea (54%), fatigue (50%), nausea (33%), and dyspnea (32%). The most frequent grade >=3 infections included pneumonia (8%), urinary tract infection (4%), and cellulitis (3%). Grade >=3 bleeding events in >=2% of patients were hematuria (2%) and subdural hematoma (2%). Common all-grade hematologic AEs were thrombocytopenia (22%), neutropenia (19%), and anemia (18%). The prevalence of infection, diarrhea, and bleeding was highest for the first 6 months of therapy and less thereafter. With longer follow-up, ibrutinib continues to demonstrate durable responses and favorable safety in relapsed/refractory MCL. The trial is registered to www.ClinicalTrials.gov as #NCT01236391. PMID- 26059950 TI - How I lost--or found?--my way in bioethics. PMID- 26059951 TI - Addressing ethical issues in health information technology. PMID- 26059952 TI - Selling health data: de-identification, privacy, and speech. AB - Two court cases that involve selling prescription data for pharmaceutical marketing affect biomedical informatics, patient and clinician privacy, and regulation. Sorrell v. IMS Health Inc. et al. in the United States and R v. Department of Health, Ex Parte Source Informatics Ltd. in the United Kingdom concern privacy and health data protection, data de-identification and reidentification, drug detailing (marketing), commercial benefit from the required disclosure of personal information, clinician privacy and the duty of confidentiality, beneficial and unsavory uses of health data, regulating health technologies, and considering data as speech. Individuals should, at the very least, be aware of how data about them are collected and used. Taking account of how those data are used is needed so societal norms and law evolve ethically as new technologies affect health data privacy and protection. PMID- 26059953 TI - Epistocracy for online deliberative bioethics. AB - The suggestion that deliberative democratic approaches would suit the management of bioethical policymaking in democratic pluralistic societies has triggered what has been called the "deliberative turn" in health policy and bioethics. Most of the empirical work in this area has focused on the allocation of healthcare resources and priority setting at the local or national level. The variety of the more or less articulated theoretical efforts behind such initiatives is remarkable and has been accompanied, to date, by an overall lack of method specificity. We propose a set of methodological requirements for online deliberative procedures for bioethics. We provide a theoretical motivation for these requirements. In particular, we discuss and adapt an "epistocratic" proposal and argue that, regardless of its merits as a general political theory, a more refined version of its normative claims can generate a useful framework for the design of bioethical forums that combine maximal inclusiveness with informed and reasonable deliberation. PMID- 26059954 TI - The use of data mining by private health insurance companies and customers' privacy. AB - This article examines privacy threats arising from the use of data mining by private Australian health insurance companies. Qualitative interviews were conducted with key experts, and Australian governmental and nongovernmental websites relevant to private health insurance were searched. Using Rationale, a critical thinking tool, the themes and considerations elicited through this empirical approach were developed into an argument about the use of data mining by private health insurance companies. The argument is followed by an ethical analysis guided by classical philosophical theories-utilitarianism, Mill's harm principle, Kant's deontological theory, and Helen Nissenbaum's contextual integrity framework. Both the argument and the ethical analysis find the use of data mining by private health insurance companies in Australia to be unethical. Although private health insurance companies in Australia cannot use data mining for risk rating to cherry-pick customers and cannot use customers' personal information for unintended purposes, this article nonetheless concludes that the secondary use of customers' personal information and the absence of customers' consent still suggest that the use of data mining by private health insurance companies is wrong. PMID- 26059955 TI - Developing a research agenda on ethical issues related to using social media in healthcare. AB - The consequences of using publicly available social media applications specifically for healthcare purposes are largely unaddressed in current research. Where they are addressed, the focus is primarily on issues of privacy and data protection. We therefore use a case study of the first live Twitter heart operation in the Netherlands, in combination with recent literature on social media from other academic fields, to identify a wide range of ethical issues related to using social media for health-related purposes. Although this case reflects an innovative approach to public education and patient centeredness, it also illustrates the need for institutions to weigh the various aspects of use and to develop a plan to deal with these on a per case basis. Given the continual development of technologies, researchers may not yet be able to oversee and anticipate all of the potential implications. Further development of a research agenda on this topic, the promotion of guidelines and policies, and the publication of case studies that reveal the granularity of individual situations will therefore help raise awareness and assist physicians and institutions in using social media to support existing care services. PMID- 26059956 TI - Ethics issues in social media-based HIV prevention in low- and middle-income countries. AB - Questions have been raised regarding participants' safety and comfort when participating in e-health education programs. Although researchers have begun to explore this issue in the United States, little research has been conducted in low- and middle-income countries, where Internet and social media use is rapidly growing. This article reports on a quantitative study with Peruvian men who have sex with men who had previously participated in the Harnessing Online Peer Education (HOPE) program, a Facebook-based HIV education program. The survey assessed participants' ethics-relevant perspectives during recruitment, consent, intervention, and follow-up. PMID- 26059957 TI - Emerging ethical issues in digital health information. AB - The problems of poor or biased information and of misleading health and well being advice on the Internet have been extensively documented. The recent decision by the Internet Corporation for Assigned Names and Numbers to authorize a large number of new generic, top-level domains, including some with a clear connection to health or healthcare, presents an opportunity to bring some order to this chaotic situation. In the case of the most general of these domains, ".health," experts advance a compelling argument in favor of some degree of content oversight and control. On the opposing side, advocates for an unrestricted and open Internet counter that this taken-for-granted principle is too valuable to be compromised, and that, once lost, it may never be recovered. We advance and provide evidence for a proposal to bridge the credibility gap in online health information by providing provenance information for websites in the .health domain. PMID- 26059958 TI - The medicalization of love and narrow and broad conceptions of human well-being. AB - Would a "medicalization" of love be a "good" or "bad" form of medicalization? In discussing this question, Earp, Sandberg, and Savulescu primarily focus on the potential positive and negative consequences of turning love into a medical issue. But it can also be asked whether there is something intrinsically regrettable about medicalizing love. It is argued here that the medicalization of love can be seen as an "evaluative category mistake": it treats a core human value (love) as if it were mainly a means to other ends (viz. physical health and hedonic well-being). It is also argued that Earp et al's closing argument (that a scientific perspective on love actually adds more value to love) can be seen as involving another evaluative category mistake: it treats an object of desire and practical interest (namely, love) as if it mainly were an object of scientific contemplation and theoretical interest. It is concluded that, to relate love to health and well-being in a more satisfying way, we should construe the latter two in broader ways, whereby love is itself a component or element of human flourishing. PMID- 26059959 TI - Normality, therapy, and enhancement. AB - According to human enhancement advocates, it is morally permissible (and sometimes obligatory) to use biomedical means to modulate or select certain biological traits in order to increase people's welfare, even when there is no pathology to be treated or prevented. Some authors have recently proposed to extend the use of biomedical means to modulate lust, attraction, and attachment. I focus on some conceptual implications of this proposal, particularly with regard to bioconservatives' understanding of the notions of therapy and enhancement I first explain what makes the proposal of medicalizing love interesting and unique, compared to the other forms of bioenhancement usually advocated. I then discuss how the medicalization of love bears on the more general debate on human enhancement, particularly with regard to the key notion of "normality" that is commonly used to define the therapy-enhancement distinction. This analysis suggests that the medicalization of love, in virtue of its peculiarity, requires bioconservatives to reconsider their way of understanding and applying the notions of "therapy" and "enhancement." More in particular, I show that, because a non-arbitrary and value-free notion of "therapy" cannot be applied to the case of love, bioconservatives have the burden of either providing some new criterion that could be used for drawing a line between permissible and impermissible medicalization, or demonstrating that under no circumstances-including the cases in which love is already acknowledged to require medical intervention-can love fall within the domain of medicine. PMID- 26059960 TI - Unrequited: neurochemical enhancement of love. AB - I raise several concerns with Earp and colleagues' analysis of enhancement through neurochemical modulation of love as a key issue in contemporary neuroethics. These include: (i) strengthening their deflation of medicalization concerns by showing how the objection that love should be left outside of the scope of medicine would directly undermine the goal of medicine; (ii) developing stronger analysis of the social and political concerns relevant to neurochemical modulation of love, by exploring and suggesting possible counters to ways in which 'wellbeing' may be used as a tool of oppression; (iii) providing reasons to support a broad need for ecological investigation of, and indeed ecological education concerning, neurotechnology; (iv) suggesting ways in which philosophy, and the humanities more broadly, remain directly relevant to responding effectively to issues in contemporary neuroethics. PMID- 26059961 TI - Clipping the angel's wings: why the medicalization of love may still be worrying. AB - This is a critique of Earp, Sandberg and Savulescu's argument in support of a possible future neuromodulation of love and love-related relationships. I argue that, contrary to what is suggested by Earp, Sandberg and Savulescu, we do have good reason to be concerned about that possibility as well as about the medicalization of love that its pursuit would bring about. PMID- 26059962 TI - Reconsidering the ethical permissibility of the use of unregistered interventions against Ebola virus disease. AB - Ethical considerations for the use of unregistered interventions for Ebola virus disease have sparked considerable debate among academic and clinical ethicists. In August 2014 the World Health Organization (WHO) convened a panel of experts to discuss approaches to the outbreak in West Africa, with the goal of determining "whether it is ethical to use unregistered interventions with unknown adverse effects for possible treatment or prophylaxis". 1 The panel concluded that there would be an ethical imperative to provide such unregistered interventions if specific criteria could be met. This paper evaluates the WHO conclusion and argues that although it may be reasonable to provide unregistered interventions considering the circumstance, there is no clear ethical imperative to do so. PMID- 26059963 TI - The Association Between p38 MAPK-Mediated TNF-alpha/TNFR2 up-Regulation and 2-(4 Aminophenyl)-7-Methoxybenzothiazole-Induced Apoptosis in Human Leukemia U937 Cells. AB - The primary cause of treatment failures in acute myeloid leukemia is usually associated with defects in the apoptotic pathway. Several studies suggest that 2 (4-aminophenyl)-7-methoxybenzothiazole (7-OMe-APBT) may potentially induce apoptosis of cancer cells. Thus, the present study was conducted to explore the cytotoxic effect of 7-OMe-APBT on human leukemia U937 cells. The apoptosis of human leukemia U937 cells induced by 7-OMe-APBT was characterized by an increase in mitochondrial membrane depolarization, procaspase-8 degradation, and tBid production. Down-regulation of FADD blocked 7-OMe-APBT-induced procaspase-8 degradation and rescued the viability of 7-OMe-APBT-treated cells, suggesting the involvement of a death receptor-mediated pathway in 7-OMe-APBT-induced cell death. Increased TNF-alpha expression, TNFR2 expression, and p38 MAPK phosphorylation were noted in 7-OMe-APBT-treated cells. Pretreatment with a p38 MAPK inhibitor abolished 7-OMe-APBT-induced TNF-alpha and TNFR2 up-regulation. 7 OMe-APBT stimulated p38 MAPK/c-Jun-mediated transcriptional up-regulation of TNFR2, while the increased TNF-alpha mRNA stability led to TNF-alpha up regulation in 7-OMe-APBT-treated cells. Treatment with 7-OMe-APBT up-regulated protein phosphatase 2A catalytic subunit alpha (PP2Acalpha) expression via the p38 MAPK/c-Jun/ATF-2 pathway, which, in turn, promoted tristetraprolin (TTP) degradation. Pretreatment with a protein phosphatase 2A inhibitor or TTP over expression abrogated TNF-alpha up-regulation in 7-OMe-APBT-treated cells. Abolishment of TNF-alpha up-regulation or knock-down of TNFR1/TNFR2 by siRNA restored the viability of 7-OMe-APBT-treated cells. Taken together, our data indicate a connection between p38 MAPK-mediated TNF-alpha and TNFR2 up-regulation and 7-OMe-APBT-induced TNF-alpha-mediated death pathway activation in U937 cells. The same pathway also elucidates the mechanism underlying 7-OMe-APBT-induced death of human leukemia HL-60 cells. PMID- 26059964 TI - Safety of anticoagulant treatment in cancer patients. AB - INTRODUCTION: Patients with cancer are at increased risk of (recurrent) venous thromboembolism. They are also at increased risk of bleeding. This makes treatment of venous thromboembolisms (VTE) in cancer patients challenging. AREAS COVERED: In this review, we will focus on the safety of anticoagulant treatment of VTE in cancer patients. We will discuss the absolute and relative bleeding risks associated with the various types of anticoagulants, specifically focusing on low-molecular-weight heparins (LMWH), vitamin K antagonist (VKA) and the new oral anticoagulants (NOACs). EXPERT OPINION: Monotherapy with LMWH is recommended for treatment of acute VTE in cancer patients. The bleeding risk associated with LMWH is comparable to VKAs, but LMWH are more effective in preventing recurrent VTE. More evidence on the efficacy and safety of NOACs in cancer patients is needed. PMID- 26059965 TI - Health-related quality of life may deteriorate from adolescence to young adulthood after extremely preterm birth. AB - AIM: This study examined the development of health-related quality of life (HRQoL) and health from adolescence to adulthood after extremely preterm birth. METHODS: We assessed a population-based cohort of extremely preterm-born (EPB) infants (gestational age of <=28 weeks or birthweight of <=1000 grams) and term born (TB) controls at 17 and 24 years of age. They completed the Child Health Questionnaire-Child Form 87 at 17 years of age, the Short Form Health Survey-36 (SF-36) at 24 years of age and the Health Behaviour in School-aged Children Symptom Checklist at both ages. RESULTS: Of the 51 eligible EPB subjects, 46 (90%) were included and nine had severe neurosensory disabilities. On the whole, EPB and TB subjects gave their HRQoL and health similar ratings, but EPB subjects with disabilities reported poorer physical functioning at 17 and EPB subjects without disabilities reported lower scores on three of the eight SF-36 scales for social functioning and mental health and reported more psychological health complaints at 24. Differences remained in adjusted analyses. Changes from 17 to 24 years of age were minor in EPB subjects with disabilities. CONCLUSION: Our comparison of EPB and TB subjects at the ages of 17 and 24 indicated that psychosocial HRQoL may deteriorate for EPB subjects when they enter adulthood. PMID- 26059966 TI - Acute celiac trunk thrombosis revealed by biliary peritonitis. AB - Acute thrombosis of the celiac trunk is a very uncommon condition, which is a life-threatening emergency. The clinical presentation is highly variable depending on the extent of the ischemic territory. We report a case of biliary peritonitis related to an acute thrombosis of the celiac trunk. This case highlights the role of abdominal computed tomography in the diagnosis of acute upper abdominal pain. PMID- 26059967 TI - Treatment preferences of originator versus biosimilar drugs in Crohn's disease; discrete choice experiment among gastroenterologists. AB - OBJECTIVE: To explore preferences of gastroenterologists for biosimilar drugs in Crohn's disease. MATERIAL AND METHODS: Discrete choice experiment was carried out involving 51 Hungarian gastroenterologists in May 2014. The following attributes were used to describe hypothetical choice sets: 1) type of the treatment (biosimilar/originator), 2) severity of disease, 3) availability of continuous medicine supply, 4) frequency of the efficacy check-ups. Multinomial logit model was used to differentiate between three attitude types: 1) always opting for the originator, 2) willing to consider biosimilar for biological-naive patients only, 3) willing to consider biosimilar treatment for both types of patients. Conditional logit model was used to estimate the probabilities of choosing a given profile. RESULTS: Men, senior consultants, working in inflammatory bowel disease center and treating more patients were more likely willing to consider biosimilar for biological-naive patients only. Treatment type (originator/biosimilar) was the most important determinant of choice for patients already treated with biologicals, and the availability of continuous medicine supply in case of biological-naive patients. The probabilities of choosing the biosimilar with all the benefits offered over the originator under current reimbursement conditions are 89% versus 11% for new patients, and 44% versus 56% for patients already treated with biological. CONCLUSIONS: For gastroenterologist, the continuous medical supply would be one of the major benefits of biosimilars. However, benefits offered in the scenarios do not compensate for the change from the originator to the biosimilar treatment of patients already treated with biologicals. PMID- 26059968 TI - Identification of quantitative genetic components of fitness variation in farmed, hybrid and native salmon in the wild. AB - Feral animals represent an important problem in many ecosystems due to interbreeding with wild conspecifics. Hybrid offspring from wild and domestic parents are often less adapted to local environment and ultimately, can reduce the fitness of the native population. This problem is an important concern in Norway, where each year, hundreds of thousands of farm Atlantic salmon escape from fish farms. Feral fish outnumber wild populations, leading to a possible loss of local adaptive genetic variation and erosion of genetic structure in wild populations. Studying the genetic factors underlying relative performance between wild and domesticated conspecific can help to better understand how domestication modifies the genetic background of populations, and how it may alter their ability to adapt to the natural environment. Here, based upon a large-scale release of wild, farm and wild x farm salmon crosses into a natural river system, a genome-wide quantitative trait locus (QTL) scan was performed on the offspring of 50 full-sib families, for traits related to fitness (length, weight, condition factor and survival). Six QTLs were detected as significant contributors to the phenotypic variation of the first three traits, explaining collectively between 9.8 and 14.8% of the phenotypic variation. The seventh QTL had a significant contribution to the variation in survival, and is regarded as a key factor to understand the fitness variability observed among salmon in the river. Interestingly, strong allelic correlation within one of the QTL regions in farmed salmon might reflect a recent selective sweep due to artificial selection. PMID- 26059969 TI - Inbreeding depression across a nutritional stress continuum. AB - Many natural populations experience inbreeding and genetic drift as a consequence of nonrandom mating or low population size. Furthermore, they face environmental challenges that may interact synergistically with deleterious consequences of increased homozygosity and further decrease fitness. Most studies on inbreeding environment (I-E) interactions use one or two stress levels, whereby the resolution of the possible stress and inbreeding depression interaction is low. Here we produced Drosophila melanogaster replicate populations, maintained at three different population sizes (10, 50 and a control size of 500) for 25 generations. A nutritional stress gradient was imposed on the replicate populations by exposing them to 11 different concentrations of yeast in the developmental medium. We assessed the consequences of nutritional stress by scoring egg-to-adult viability and body mass of emerged flies. We found: (1) unequivocal evidence for I-E interactions in egg-to-adult viability and to a lesser extent in dry body mass, with inbreeding depression being more severe under higher levels of nutritional stress; (2) a steeper increase in inbreeding depression for replicate populations of size 10 with increasing nutritional stress than for replicate populations of size 50; (3) a nonlinear norm of reaction between inbreeding depression and nutritional stress; and (4) a faster increase in number of lethal equivalents in replicate populations of size 10 compared with replicate populations of size 50 with increasing nutritional stress levels. Our data provide novel and strong evidence that deleterious fitness consequences of I-E interactions are more pronounced at higher nutritional stress and at higher inbreeding levels. PMID- 26059970 TI - Measuring individual inbreeding in the age of genomics: marker-based measures are better than pedigrees. AB - Inbreeding (mating between relatives) can dramatically reduce the fitness of offspring by causing parts of the genome to be identical by descent. Thus, measuring individual inbreeding is crucial for ecology, evolution and conservation biology. We used computer simulations to test whether the realized proportion of the genome that is identical by descent (IBDG) is predicted better by the pedigree inbreeding coefficient (FP) or by genomic (marker-based) measures of inbreeding. Genomic estimators of IBDG included the increase in individual homozygosity relative to mean Hardy-Weinberg expected homozygosity (FH), and two measures (FROH and FE) that use mapped genetic markers to estimate IBDG. IBDG was more strongly correlated with FH, FE and FROH than with FP across a broad range of simulated scenarios when thousands of SNPs were used. For example, IBDG was more strongly correlated with FROH, FH and FE (estimated with ?10 000 SNPs) than with FP (estimated with 20 generations of complete pedigree) in populations with a recent reduction in the effective populations size (from Ne=500 to Ne=75). FROH, FH and FE generally explained >90% of the variance in IBDG (among individuals) when 35 K or more SNPs were used. FP explained <80% of the variation in IBDG on average in all simulated scenarios, even when pedigrees included 20 generations. Our results demonstrate that IBDG can be more precisely estimated with large numbers of genetic markers than with pedigrees. We encourage researchers to adopt genomic marker-based measures of IBDG as thousands of loci can now be genotyped in any species. PMID- 26059971 TI - Heterosis and outbreeding depression in crosses between natural populations of Arabidopsis thaliana. AB - Understanding the causes and architecture of genetic differentiation between natural populations is of central importance in evolutionary biology. Crosses between natural populations can result in heterosis if recessive or nearly recessive deleterious mutations have become fixed within populations because of genetic drift. Divergence between populations can also result in outbreeding depression because of genetic incompatibilities. The net fitness consequences of between-population crosses will be a balance between heterosis and outbreeding depression. We estimated the magnitude of heterosis and outbreeding depression in the highly selfing model plant Arabidopsis thaliana, by crossing replicate line pairs from two sets of natural populations (C<->R, B<->S) separated by similar geographic distances (Italy<->Sweden). We examined the contribution of different modes of gene action to overall differences in estimates of lifetime fitness and fitness components using joint scaling tests with parental, reciprocal F1 and F2, and backcross lines. One of these population pairs (C<->R) was previously demonstrated to be locally adapted, but locally maladaptive quantitative trait loci were also found, suggesting a role for genetic drift in shaping adaptive variation. We found markedly different genetic architectures for fitness and fitness components in the two sets of populations. In one (C<->R), there were consistently positive effects of dominance, indicating the masking of recessive or nearly recessive deleterious mutations that had become fixed by genetic drift. The other set (B<->S) exhibited outbreeding depression because of negative dominance effects. Additional studies are needed to explore the molecular genetic basis of heterosis and outbreeding depression, and how their magnitudes vary across environments. PMID- 26059972 TI - Variation in symptom distress in underserved Chinese American cancer patients. AB - BACKGROUND: Cancer is prevalent in the rapidly growing Chinese American community, yet little is known about the symptom experience to guide comprehensive treatment planning. This study evaluated symptom prevalence and patient subgroups with symptom distress in a large sample of Chinese American cancer patients. METHODS: Patients were consecutively recruited from 4 oncology practices, and they completed a translated cancer symptom scale. Latent class cluster analysis was used to identify subgroups of patients with distinct symptom distress profiles. RESULTS: There were 1436 patients screened; 94.4% were non English-speaking, and 45.1% were undergoing cancer therapy. The cancers included breast (32.6%), lung (14.8%), head and neck (12.5%), and hematologic cancer (10.1%). Overall, 1289 patients (89.8%) had 1 or more symptoms, and 1129 (78.6%) had 2 or more. The most prevalent symptoms were a lack of energy (57.0%), dry mouth (55.6%), feeling sad (49.3%), worrying (47.5%), and difficulty sleeping (46.8%). Symptoms causing "quite a bit" or "very much" distress included difficulty sleeping (37.9%), a lack of appetite (37.2%), feeling nervous (35.8%), pain (35.2%), and worrying (34.0%). Four patient subgroups were identified according to the probability of reporting moderate to high symptom distress: very low physical and psychological symptom distress (49.5%), low physical symptom distress and moderate psychological symptom distress (25.2%), moderate physical and psychological symptom distress (17.4%), and high physical and psychological symptom distress (7.8%). CONCLUSIONS: Symptom prevalence is high in community dwelling Chinese American cancer patients, and nearly half experience severe distress (rated as "quite a bit" or "very much" distressing) from physical symptoms, psychological symptoms, or both. These data have important implications for the development of effective symptom control interventions. PMID- 26059973 TI - Neutrophil and monocyte responses to downhill running: Intracellular contents of MPO, IL-6, IL-10, pstat3, and SOCS3. AB - High-intensity exercise results in immune activation. This study determined whether (a) there is concordance between serum MPO and neutrophil and/or monocyte intracellular MPO content; (b) peripheral blood mononuclear cells respond to inflammatory interleukins (ILs) by increasing intracellular signaling. Healthy male (n = 12) volunteers participated in high-intensity running (12 * 5 min, 10% decline, 15 km/h). Blood sample (pre, post, 4 h) analyses included serum concentrations of IL-1beta, IL-1ra, IL-4, IL-6, IL-8, IL-10, matrix metalloprotease-9 (MMP-9) and creatine kinase (CK). Intracellular IL-6, IL-10, MPO and STAT3/SOCS3 signaling were assessed in mononuclear cells. CK (1573 +/- 756 u/L), MMP-9 (101 +/- 27 ng/mL), neutrophil (9.89 +/- 0.76 * 10(9) cells/L) and monocyte counts (1 +/- 0.08 * 10(9) cells/L) increased at 4 h. At 4 h serum (7.1 +/- 1.3 ng/mL) and monocyte MPO (1.7-fold) increased, whereas neutrophil MPO decreased (0.8-fold). Intracellular monocyte IL-10 and IL-6 decreased by 15% and 20-30%, respectively, coinciding with elevations in serum IL-10 of 14.5 +/- 4.7 pg/mL and IL-6 of 5.4 +/- 2.9 pg/mL, suggesting immune cell cytokine release in response to exercise. Intracellular PBMC p-STAT3 to total STAT3 ratio increased from pre to 4 h. Circulating monocytes are responsive to increased serum IL-6 suggesting a negative feedback loop via STAT3 signaling. PMID- 26059975 TI - Systematic review of topical amitriptyline for the treatment of neuropathic pain. AB - WHAT IS KNOWN AND OBJECTIVE: Neuropathic pain is a common disorder for which patients seek treatment. The most common causes of neuropathic pain are diabetes, herpetic infection and chemotherapy-induced neuropathy. Oral administration of amitriptyline has traditionally been used for treating neuropathic pain; however, it has dose-related anticholinergic effects, which may limit its use in some individuals. Pharmacotherapeutic agents that are commonly used to treat neuropathic pain include antidepressants, anticonvulsants, opioids and opioid like substances, and topical medications. The objective of this paper is to review the effectiveness of topical amitriptyline in patients with neuropathic pain. METHODS: We utilized the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to provide a systematic and transparent reporting method. The literature search was performed using PubMed (1966 through October 2014) applying the MeSH 'amitriptyline' and 'drug administration, topical' and 'neuropathy'. Web of Science (1945 through October 2014) was searched using the text words 'amitriptyline' and 'neuropathy'. Bibliographies of retrieved articles were scanned for relevant articles. Cochrane databases were also searched for methods to treat neuropathic pain. Broad subject headings, including 'neuropathic pain', were used to search the database for review articles. All data sources in English and in humans were considered for inclusion. RESULTS AND DISCUSSION: Topical application of amitriptyline has the theoretical advantage of local effects with fewer systemic side effects. The clinical trials and case reports describing the use of topical amitriptyline we reviewed show mixed results concerning the efficacy and the presence of adverse reactions. Controlled clinical trials reveal that topical amitriptyline is not effective in treating neuropathic pain. The uncontrolled clinical trials did support efficacy of topical amitriptyline; however, the data from these trials may be biased due to the nature of the study design. Finally, there have been several case reports that claim patients achieved pain relief with the use of topical amitriptyline. Data from these cases are limited due to the fact that there were no controls to which the amitriptyline treatments could be compared, and the majority of the patients in these cases were on other analgesics. WHAT IS NEW AND CONCLUSION: Although there are reports that describe the benefits of topical amitriptyline for neuropathic pain, data from evidence-based controlled clinical trials do not support efficacy in patients who use topical amitriptyline for neuropathic pain control. PMID- 26059974 TI - Identification of telomere dysfunction in Friedreich ataxia. AB - BACKGROUND: Friedreich ataxia (FRDA) is a progressive inherited neurodegenerative disorder caused by mutation of the FXN gene, resulting in decreased frataxin expression, mitochondrial dysfunction and oxidative stress. A recent study has identified shorter telomeres in FRDA patient leukocytes as a possible disease biomarker. RESULTS: Here we aimed to investigate both telomere structure and function in FRDA cells. Our results confirmed telomere shortening in FRDA patient leukocytes and identified similar telomere shortening in FRDA patient autopsy cerebellar tissues. However, FRDA fibroblasts showed significantly longer telomeres at early passage, occurring in the absence of telomerase activity, but with activation of an alternative lengthening of telomeres (ALT)-like mechanism. These cells also showed accelerated telomere shortening as population doubling increases. Furthermore, telomere dysfunction-induced foci (TIF) analysis revealed that FRDA fibroblasts have dysfunctional telomeres. CONCLUSIONS: Our finding of dysfunctional telomeres in FRDA cells provides further insight into FRDA molecular disease mechanisms, which may have implications for future FRDA therapy. PMID- 26059976 TI - Intravenous Bisphosphonate Therapy of Young Children With Osteogenesis Imperfecta: Skeletal Findings During Follow Up Throughout the Growing Years. AB - Cyclical intravenous bisphosphonate therapy is widely used to treat children with osteogenesis imperfecta (OI), but little is known about long-term treatment outcomes. We therefore reviewed 37 children with OI (OI type I, n = 1; OI type III, n = 14; and OI type IV, n = 22) who started intravenous bisphosphonate therapy before 5 years of age (median 2.2 years; range, 0.1 to 4.8 years), and who had a subsequent follow-up period of at least 10 years (median 14.8 years; range, 10.7 to 18.2 years), during which they had received intravenous bisphosphonate treatment (pamidronate or zoledronic acid) for at least 6 years. During the observation period, the mean lumbar spine areal bone mineral density Z score increased from -6.6 (SD 3.1) to -3.0 (SD 1.8), and weight Z-score increased from -2.3 (SD 1.5) to -1.7 (SD 1.7) (p < 0.001 and p = 0.008). At the time of the last assessment, patients with OI type IV had significantly higher height Z scores than a control group of patients matched for age, gender, and OI type who had not received bisphosphonates. Patients had a median of six femur fractures (range, 0 to 18) and five tibia fractures (range, 0 to 17) during the follow-up period. At baseline, 35% of vertebra were affected by compression fractures, whereas only 6% of vertebra appeared compressed at the last evaluation (p < 0.001), indicating vertebral reshaping during growth. Spinal fusion surgery was performed in 16 patients (43%). Among the 21 patients who did not have spinal fusion surgery, 13 had scoliosis with a curvature ranging from 10 to 56 degrees. In conclusion, long-term intravenous bisphosphonate therapy was associated with higher Z-scores for lumbar spine areal bone mineral density and vertebral reshaping, but long-bone fracture rates were still high and the majority of patients developed scoliosis. PMID- 26059977 TI - Regulation of mitochondrial ceramide distribution by members of the BCL-2 family. AB - Apoptosis is an intricately regulated cellular process that proceeds through different cell type- and signal-dependent pathways. In the mitochondrial apoptotic program, mitochondrial outer membrane permeabilization by BCL-2 proteins leads to the release of apoptogenic factors, caspase activation, and cell death. In addition to protein components of the mitochondrial apoptotic machinery, an interesting role for lipids and lipid metabolism in BCL-2 family regulated apoptosis is also emerging. We used a comparative lipidomics approach to uncover alterations in lipid profile in the absence of the proapoptotic proteins BAX and BAK in mouse embryonic fibroblasts (MEFs). We detected over 1,000 ions in these experiments and found changes in an ion with an m/z of 534.49. Structural elucidation of this ion through tandem mass spectrometry revealed that this molecule is a ceramide with a 16-carbon N-acyl chain and sphingadiene backbone (d18:2/16:0 ceramide). Targeted LC/MS analysis revealed elevated levels of additional sphingadiene-containing ceramides (d18:2-Cers) in BAX, BAK-double knockout MEFs. Elevated d18:2-Cers are also found in immortalized baby mouse kidney epithelial cells lacking BAX and BAK. These results support the existence of a distinct biochemical pathway for regulating ceramides with different backbone structures and suggest that sphingadiene-containing ceramides may have functions that are distinct from the more common sphingosine-containing species. PMID- 26059979 TI - Demographic, clinical and psychosocial factors identify a high-risk group for depression screening among predominantly Hispanic patients with Type 2 diabetes in safety net care. AB - OBJECTIVE: Identify biopsychosocial factors associated with depression for patients with Type 2 diabetes. METHOD: A quasi-experimental clinical trial of 1293 patients was predominantly Hispanic (91%) female (62%), mean age 53 and average diabetes duration 10 years; 373 (29%) patients were depressed and assessed by Patient Health Questionnaire-9. Demographic, baseline clinical and psychosocial variables were compared between depressed and nondepressed patients. RESULTS: Bivariate analyses found depression significantly associated (p<0.05) with female gender, diabetes emotional burden and regimen distress, BMI >= 30, lack of an A1C test, diabetes duration, poor self-care, number of diabetes symptoms and complications, functional and physical characteristics (pain, self rated health condition, Short-Form Health Survey SF-physical, disability score and comorbid illnesses), as well as higher number of ICD-9 diagnoses and emergency room use. A multivariable regression model with stepwise selection identified six key risk factors: greater disability, diabetes symptoms and regimen distress, female gender, less diabetes self-care and lack of A1C. In addition, after controlling for identified six factors, the number of psychosocial stressors significantly associated with increased risk of depression (adjusted odds ratio=1.37, 95% confidence intervals: 1.18-1.58, p<.0001). CONCLUSION: Knowing biopsychosocial factors could help primary care physicians and endocrinologists identify a high-risk group of patients needing depression screening. PMID- 26059978 TI - Macrophage SR-BI mediates efferocytosis via Src/PI3K/Rac1 signaling and reduces atherosclerotic lesion necrosis. AB - Macrophage apoptosis and efferocytosis are key determinants of atherosclerotic plaque inflammation and necrosis. Bone marrow transplantation studies in ApoE- and LDLR-deficient mice revealed that hematopoietic scavenger receptor class B type I (SR-BI) deficiency results in severely defective efferocytosis in mouse atherosclerotic lesions, resulting in a 17-fold higher ratio of free to macrophage-associated dead cells in lesions containing SR-BI(-/-) cells, 5-fold more necrosis, 65.2% less lesional collagen content, nearly 7-fold higher dead cell accumulation, and 2-fold larger lesion area. Hematopoietic SR-BI deletion elicited a maladaptive inflammatory response [higher interleukin (IL)-1beta, IL 6, and TNF-alpha lower IL-10 and transforming growth factor beta]. Efferocytosis of apoptotic thymocytes was reduced by 64% in SR-BI(-/-) versus WT macrophages, both in vitro and in vivo. In response to apoptotic cells, macrophage SR-BI bound with phosphatidylserine and induced Src phosphorylation and cell membrane recruitment, which led to downstream activation of phosphoinositide 3-kinase (PI3K) and Ras-related C3 botulinum toxin substrate 1 (Rac1) for engulfment and clearance of apoptotic cells, as inhibition of Src decreased PI3K, Rac1-GTP, and efferocytosis in WT cells. Pharmacological inhibition of Rac1 reduced macrophage efferocytosis in a SR-BI-dependent fashion, and activation of Rac1 corrected the defective efferocytosis in SR-BI(-/-) macrophages. Thus, deficiency of macrophage SR-BI promotes defective efferocytosis signaling via the Src/PI3K/Rac1 pathway, resulting in increased plaque size, necrosis, and inflammation. PMID- 26059980 TI - Prevalence of psychosis in tuberculosis patients and their nontuberculosis family contacts in a multidrug treatment-resistant treatment center in Nigeria. AB - OBJECTIVE: This study aimed at determining the prevalence of psychosis in tuberculosis (TB) patients in comparison to nontuberculosis control and its correlation with disease pattern. METHOD: One hundred and fifteen patients with TB and 112 family members visiting the multidrug treatment-resistant treatment center at University College Hospital Ibadan Centre were screened for psychological distress with the General Health Questionnaire (GHQ-12). Presence of a psychotic condition was determined by the Psychosis Screening Questionnaire and the Structured Clinical Interview for DSM-IV Axis I Disorder and was compared with severity of pulmonary TB. RESULTS: After adjusting for age, predictors of high/positive GHQ include the following: duration of TB >=4years [odds ratio (OR)=4.02, 95% confidence interval (CI)=1.29-11.13], extrapulmonary TB (OR=3.45, 95% CI=1.02-14.11), severe disease extent (OR=5.27, 95% CI=1.05-13.01) and disease category 2 (OR=2.38, 95% CI=1.01-7.99), and predictors of psychosis are as follows: duration of TB >=4years (OR=3.99, 95% CI=1.51-9.88), extrapulmonary TB (OR=3.88, 95% CI=1.55-9.98), severe disease extent (OR=9.55, 95% CI=2.15 18.05) and disease category 2 (OR=2.86, 95% CI=1.14-7.55). CONCLUSION: In view of high prevalence of psychological distress and psychosis in TB, care of TB patients should include consultative-liaison psychiatric care. PMID- 26059981 TI - Recombinant LH supplementation during IVF cycles with a GnRH-antagonist in estimated poor responders: A cross-matched pilot investigation of the optimal daily dose and timing. AB - Although it is widely accepted that patients, who are considered poor responders to in vitro fertilization (IVF) benefit from recombinant luteinizing hormone (rLH) supplementation during an in vitro fertilization cycle, particularly when gonadotropin-releasing hormone (GnRH)-antagonist (ant) treatment is used the optimal administration timing and daily dose of rLH remains to be elucidated. The aim of the present study was to investigate the optimal timing of rLH supplementation to improve ovarian response, embryo quality, endometrial thickness and pregnancy rate in infertile, estimated poor responders to IVF, undergoing GnRH-ant treatment. In addition, the present study aimed to evaluate the optimal daily dose to achieve the same outcomes. A prospective-randomized cross-matched investigation was performed on 40 patients undergoing a GnRH-ant treatment-cycle The patients were randomly assigned to either group A (rLH-75 IU/day) or group B (rLH-150 IU/day) and further randomized into subgroup A1/B1, in which rLH was administered at recombinant follicle stimulating hormone (rFSH) administration, and subgroup A2/B2, in which rLH was administered at GnRH-ant administration. Patients who did not become pregnant during the first cycle (35 patients), were treated a second time, cross-matched for groups and subgroups. Improved ovarian response, embryo quality and pregnancy rate were achieved by administering rLH at 150 IU/day, starting from GnRH-ant administration, independently from the total rLH dose administered. Improved endometrial thickness at oocyte retrieval day was achieved by administering rLH at 150 IU from the start of rFSH administration. These data led to the hypothesis that ovarian responses are affected by the timing of administration more than the total-dose of rLH. The optimal window to administer rLH appears to be the mid-to late follicular phase, despite the fact that rLH-supplementation in the early follicular phase appeared to increase endometrial thickness and to enhance its morphology. Standardization of the optimal daily dose and supplementation timing of rLH may resolve the debate regarding its efficacy in increasing the number of pregnancies and neonatal survival rates. PMID- 26059982 TI - The role of calcineurin signaling in microcystin-LR triggered neuronal toxicity. AB - Microcystin-LR (MCLR) is a commonly acting potent hepatotoxin and has been pointed out of potentially causing neurotoxicity, but the exact mechanisms of action still remain unclear. Using proteomic analysis, forty-five proteins were identified to be significantly altered in hippocampal neurons of rats treated with MCLR. Among them, Ca(2+)-activated phosphatase calcineurin (CaN) and the nuclear factor of activated T-cells isoform c3 (NFATc3) were up-regulated remarkably. Validation of the changes in CaN and NFATc3 expression by Western blotting demonstrated CaN cleavage and subsequent NFATc3 nuclear translocation were generated, suggesting that exposure to MCLR leads to activation of CaN, which in turn activates NFATc3. Activation of CaN signaling has been reported to result in apoptosis via dephosphorylation of the proapoptotic Bcl-2 family member Bad. In agreement with this, our results revealed that treatment of neurons with the CaN inhibitor FK506 blocked the reduction in Bad dephosphorylation and cytochrome c (cyt c) release triggered by MCLR. Consistent with these biochemical results, we observed a marked decrease in apoptotic and necrotic cell death after MCLR exposure in the presence of FK506, supporting the hypothesis that MCLR appeared to cause neuronal toxicity by activation of CaN and the CaN-mediated mitochondrial apoptotic pathway. PMID- 26059983 TI - Gender and BCR-ABL transcript type are correlated with molecular response to imatinib treatment in patients with chronic myeloid leukemia. AB - OBJECTIVES: Achieving a major molecular response (MMR) is the goal of imatinib therapy for chronic myeloid leukemia. However, the association between gender, BCR-ABL transcript type, and age with MMR is not well understood and often controversial. METHODS: We retrospectively analyzed 166 patients who have been treated with imatinib for up to 10 yr. RESULTS: Men had a lower MMR rate than women (63.3% vs. 81.6%, P = 0.006) and a shorter time to relapse (median 354 vs. 675 d, P = 0.049), while patients with b3a2 or with both b3a2 and b2a2 break point transcripts had higher MMR rate than those with b2a2 (81.8%, 77.1% vs. 60.7%, P = 0.023 for b3a2 vs. b2a2, P = 0.043 for both vs. b2a2). A striking difference was found between men with b2a2 and women with both b2a2 and b3a2 in terms of MMR rate (43.8% vs. 88.9%), MMR rate within 6 months (7.1% vs. 62.5%) and the time to MMR (median d 493 vs. 159, P = 0.036). CONCLUSIONS: Both gender and BCR-ABL transcript, but not age, were significantly associated with the molecular response. Men with b2a2 represent a less favorable group in their response to imatinib treatment and may need alternative therapy regimen and closer monitoring. PMID- 26059984 TI - Environmental enrichment rescues the degraded auditory temporal resolution of cortical neurons induced by early noise exposure. AB - The accurate processing of sound temporal information is crucial to human speech perception and other species-specific communication. During postnatal development, the auditory cortex shows environmental and experience-dependent plasticity. However, how the postnatal environment affects cortical processing of sound temporal information is not fully understood. The aim of the present study was to determine whether postnatal noise exposure impairs neural temporal resolution in the auditory cortex, and, if so, whether environmental enrichment can rescue this degraded neural temporal acuity. Using the neural gap detection threshold determined in anesthetized rats as an index of temporal acuity, we found that exposure of juvenile rats to moderate-level noise induced much higher neural gap detection thresholds in adulthood than exposure of adult rats to the same noise. Environmental enrichment did not affect cortical neural gap detection thresholds in normally developing rats. However, rearing of rats with early noise exposure in an enriched environment promoted recovery from the noise-induced degraded neural temporal resolution. In addition, the tonal stimuli in the enriched environment contributed to only a portion of the recovery. These results provide evidence for noise-induced developmental impairment in neural gap detection thresholds in the auditory cortex, and suggest a therapeutic potential for environmental enrichment as a non-invasive approach to rescue developmentally degraded auditory temporal processing. PMID- 26059985 TI - Early enforced mobilisation following surgery for gastrointestinal cancer: feasibility and outcomes. AB - OBJECTIVES: To evaluate the feasibility and outcomes of early enforced mobilisation following surgery for gastrointestinal cancer. DESIGN: Feasibility study with a separate-sample pre-post-test design. SETTING: Surgical gastrointestinal ward. PARTICIPANTS: Patients with various types of gastrointestinal cancer, before and after implementation of postoperative enforced mobilisation (n=55 and n=61, respectively). INTERVENTION: The enforced mobilisation protocol included structured mobilisation by a nurse and walking supervised by a physiotherapist, starting within 24hours of surgery. MAIN OUTCOME MEASURES: The enforced mobilisation protocol was deemed to be feasible if at least 50% of patients were able to walk the scheduled distance on postoperative day 1. Pre- and postimplementation differences in postoperative pulmonary complications (PPCs), length of hospital stay (LOS) and re-admission rate were analysed using regression analyses, adjusting for relevant co-variables. RESULTS: In the various surgical groups, between 48% and 56% of patients were able to walk the scheduled distance on postoperative day 1, which was regarded as feasible. However, none of the patients who had undergone oesophageal resection were able to walk on postoperative day 1. Excluding these patients from the analyses, a significant decrease in PPCs was found (odds ratio 0.08, 95% confidence interval 0.010 to 0.71, P=0.023) following implementation of enforced mobilisation. Differences in LOS and re-admission rate were not significant. CONCLUSIONS: Early enforced mobilisation seems to be feasible in patients following surgery for gastrointestinal cancer, except for those undergoing oesophageal resection. The occurrence of PPCs was reduced after implementation of enforced mobilisation. Further research is needed to confirm these results. PMID- 26059986 TI - Exploring the Paradox of Intimate Partner Violence and Increased Contraceptive Use in sub-Saharan Africa. AB - We question the positive effect of intimate partner violence on women's modern contraceptive use in sub-Saharan Africa found in previous studies. The explanations offered for this counter-intuitive result are either that women make greater efforts to avoid childbearing in conflictual relationships, or that endogeneity bias exists. Endogeneity bias stems from the inability of researchers to attribute a specific cause to one variable when they are unable to control for related missing covariates. Demographic and Health Survey data from 13 countries in sub-Saharan Africa provide evidence for the latter but not the former. Indeed, using simple probit regression models, we observe a positive relationship between intimate partner violence and modern contraceptive use in Burkina Faso, Mali, Nigeria, Tanzania, and Zimbabwe. This effect remains unchanged when controlling for various measures of women's autonomy in the household, showing that these two variables interact with contraceptive use independently. However, the use of recursive bivariate probit and Rosenbaum bounds sensitivity analysis to control for endogeneity biases erodes the initial positive effect in the five countries, although only partially in Burkina Faso. Our research shows that the previously reported findings arise from poor model specification and highlights the need for more appropriate data to assess the effect of intimate partner violence on modern contraceptive use in sub-Saharan Africa. PMID- 26059987 TI - Teenage Childbearing and Educational Attainment in South Africa. AB - The relationship between teenage childbearing and school attainment is investigated using nationally representative longitudinal data drawn from South Africa's National Income Dynamics Study. The analysis focuses on the outcomes by 2010 of a panel of 673 young women who were aged 15-18 and childless in 2008. Controlling for other factors, girls who went on to give birth had twice the odds of dropping out of school by 2010 and nearly five times the odds of failing to matriculate. Few girls from households in the highest-income quintile gave birth. Girls who attended schools in higher-income areas and were behind at school were much more likely to give birth than those who were in the appropriate grade for their age or were in no-fee schools. New mothers were much more likely to have re enrolled in school by 2010 if they were rural residents, they belonged to relatively well-off households, or their own mother had attended secondary school. These findings suggest that, in South Africa, interventions that address poor school attainment would also reduce teenage childbearing. PMID- 26059988 TI - An Assessment of Childbearing Preferences in Northern Malawi. AB - Fertility preferences are an essential component of family planning program evaluation; however, doubts about their validity in sub-Saharan Africa exist and little methodological assessment has been carried out. This study investigates prospective fertility intentions in terms of their temporal stability, intensity, degree of spousal agreement, and association with future childbearing in northern Malawi. A total of 5,222 married women participated in the three-round study. The odds of having a child or becoming pregnant within 36 months were 4.2 times higher when both wife and husband wanted a child within three years and 2 times higher when both wanted to wait at least three years, compared with the odds when both wanted to cease childbearing. The influence of husbands' and wives' preferences on subsequent fertility was equal. Compared with the intention to stop, the intention to postpone childbearing was less stable, recorded less spousal agreement, and was much less strongly predictive of fertility. PMID- 26059989 TI - Fertility Limitation and Child Schooling in Ouagadougou: Selective Fertility or Resource Dilution? AB - Using original data collected in Ouagadougou, Burkina Faso, this study investigates evidence for the competing theories that fertility reductions increase children's education through either the quantity-quality tradeoff (intentionally choosing smaller families to make greater investments in education and other indicators of child quality) or resource dilution (having more children reduces resources available per child, regardless of intentionality of family size). The results provide evidence for both hypotheses: children having four or fewer siblings were significantly more likely to be enrolled in school if their mothers had intentionally stopped childbearing relative to those whose mothers wanted more children but whose childbearing was limited by subfecundity. The difference between intentional and unintentional family limitation was not significant for parities greater than five. In addition, the relationship between number of siblings and their schooling is negative, regardless of the intentionality of family-size limitation, but the strength of this negative relationship is approximately twice as high among children whose mothers intentionally limited fertility (reflecting both selection and dilution effects) than among children whose mothers were subfecund (reflecting the pure dilution effect). PMID- 26059990 TI - Men's Perspectives on Their Role in Family Planning in Nyanza Province, Kenya. AB - Research has indicated that gender dynamics-and in particular men's disapproval of family planning-have had an influence on the low levels of contraceptive use in sub-Saharan Africa. Limited evidence exists, however, on effective strategies to increase male approval. We conducted 12 focus group discussions with married men aged 20-66 (N = 106) in Kenya to explore FP perceptions. Men's disapproval of FP was associated with anxieties regarding male identity and gender roles. Men often distrusted FP information provided by their wives because they suspected infidelity or feared being viewed as "herded." Men also feared that providers might pressure them into vasectomies or into disclosing extramarital sexual activity or HIV diagnoses to their wives. Suggested strategies include programs targeting couples jointly and FP education for men provided by male outreach workers. To encourage men's acceptance, community-based programs directly targeting men are needed to reduce stigma and misconceptions and to increase awareness of the benefits of FP. PMID- 26059991 TI - Jordan 2012 DHS. PMID- 26059992 TI - Mali 2012-13 DHS. PMID- 26059994 TI - Tyrosinase and Cholinesterase Inhibitory Potential and Flavonoid Characterization of Viola odorata L. (Sweet Violet). AB - Inhibitory potential of the dichloromethane, ethyl acetate, ethanol, and aqueous extracts of Viola odorata L. (VO) was investigated against tyrosinase (TYR) and cholinesterases by microplate assays. The antioxidant activity was tested using six in vitro assays. Only the ethanol extract inhibited TYR (80.23 +/- 0.87% at 100 ug mL-1 ), whereas none of them were able to inhibit cholinesterases. The extracts were more able to scavenge NO radical (31.98 +/- 0.53-56.68 +/- 1.10%) than other radicals tested, and displayed low to moderate activity in the rest of the assays. HPLC analysis revealed that the aqueous extract of VO contained a substantial amount of vitexin (18.81 +/- 0.047 mg g-1 extract), while the ethanol extract also possessed rutin (1.31 +/- 0.013 mg g-1 extract) and vitexin (4.65 +/ 0.103 mg g-1 extract). Furthermore, three flavonoids (rutin, isovitexin, and kaempferol-6-glucoside) were isolated from the ethanol extract. This is the first report on TYR inhibitory activity of VO as well as presence of vitexin and isovitexin in this species. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26059996 TI - Effects of CT resolution and radiodensity threshold on the CFD evaluation of nasal airflow. AB - The article focuses on the robustness of a CFD-based procedure for the quantitative evaluation of the nasal airflow. CFD ability to yield robust results with respect to the unavoidable procedural and modeling inaccuracies must be demonstrated to allow this tool to become part of the clinical practice in this field. The present article specifically addresses the sensitivity of the CFD procedure to the spatial resolution of the available CT scans, as well as to the choice of the segmentation level of the CT images. We found no critical problems concerning these issues; nevertheless, the choice of the segmentation level is potentially delicate if carried out by an untrained operator. PMID- 26059995 TI - Full Length Single Chain Fc Protein (FLSC IgG1) as a Potent Antiviral Therapy Candidate: Implications for In Vivo Studies. AB - We have previously shown that FLSC, a chimeric protein containing HIV-1BAL gp120 and the D1 and D2 domains of human CD4, blocks the binding and entry of HIV-1 into target cells by occluding CCR5, the major HIV-1 coreceptor. In an effort to improve the antiviral potential of FLSC, we fused it with the hinge-CH2-CH3 region of human IgG1. The IgG moiety should increase both the affinity and stability in vivo of FLSC, due to the resultant bivalency and an extended serum half-life, thereby increasing its antiviral potency. We previously showed that (FLSC) IgG1 indeed had greater antiviral activity against T cell infections. Here we extend these results to macrophages, for which (FLSC) IgG1 has a more potent antiviral activity than FLSC alone, due in part to its higher binding affinity for CCR5. We also test both compounds in a relevant humanized mouse model and show that, as anticipated, the IgG1 moiety confers a greatly extended half-life. These data, taken together with previous results, suggest potential clinical utility for (FLSC) IgG1 and support further developmental work toward eventual clinical trials. PMID- 26059997 TI - Behavioural assessment of autism spectrum disorders in people with multiple disabilities. AB - BACKGROUND: It is difficult to diagnose autism spectrum disorder (ASD) in people with a combination of intellectual and sensory disabilities because of overlap in behaviour. The ASD typical behaviours of people with combined intellectual and sensory disabilities are often caused by their disabilities and not by ASD. Current diagnostic tools are inadequate to differentiate between people with and without ASD when they have these combined disabilities, because tools lack norms for this population or are subjective, indirect or unable to adapt to the variety of disabilities that these people may have. Because giving a correct diagnosis is necessary for treatment and support, a new observational tool was developed to diagnose ASD in people with multiple disabilities, observation of autism in people with sensory and intellectual disabilities (OASID). METHOD: Observation of autism in people with sensory and intellectual disabilities was tested on 18 participants with moderate to profound intellectual disabilities, one or dual sensory impairment, with and without ASD. Two independent experts diagnosed these participants as well in order to test the psychometric properties and differentiating abilities of OASID. RESULTS: Observation of autism in people with sensory and intellectual disabilities showed high inter-rater reliability, internal consistency of scales and content and construct validity. OASID could differentiate people with and without ASD without overlap. CONCLUSIONS: Observation of autism in people with sensory and intellectual disabilities could differentiate people with intellectual disabilities combined with sensory impairments, who clearly had or did not have signs of ASD. People with unclear signs of ADS scored in between those two groups with regard to their OASID scores. Psychometric properties of OASID are promising. PMID- 26059998 TI - Yoga for Heart Rate Variability: A Systematic Review and Meta-analysis of Randomized Clinical Trials. AB - The objective of this systematic review is to summarize and critically assess the effects of yoga on heart rate variability (HRV). Nine databases were searched from their inceptions to June 2014. We included randomized clinical trials (RCTs) comparing yoga against any type of control intervention in healthy individuals or patients with any medical condition. Risk of bias was assessed using the Cochrane criteria. Two reviewers performed the selection of studies, data extraction, and quality assessments independent of one another. Fourteen trials met the inclusion criteria. Only two of them were of acceptable methodological quality. Ten RCTs reported favourable effects of yoga on various domains of HRV, whereas nine of them failed to do so. One RCT did not report between-group comparisons. The meta analysis (MA) of two trials did not show favourable effects of yoga compared to usual care on E:I ratio (n = 61, SMDs = 0.63; 95% CIs [-0.72 to 1.99], p = 0.36; heterogeneity: r(2) = 0.79, chi(2) = 5.48, df = 1, (p = 0.02); I(2) = 82%). The MA also failed to show statistically significant differences between the groups regarding the 30:15 ratio (n = 61, SMDs = 0.20; 95% CIs [-0.43 to 0.84], p = 0.53; heterogeneity: r(2) = 0.07, chi(2) = 1.45, df = 1, (p = 0.23); I(2) = 31%). The data from the remaining RCTs were too heterogeneous for pooling. These results provide no convincing evidence for the effectiveness of yoga in modulating HRV in patients or healthy subjects. Future investigations in this area should overcome the multiple methodological weaknesses of the previous research. PMID- 26059999 TI - No association of TREM1 rs6910730 and TREM2 rs7759295 with Alzheimer disease. PMID- 26060000 TI - Predictors of recurrence of umbilical hernias following primary tissue repair in obese veterans. AB - BACKGROUND: Factors that determine recurrence and complications following primary tissue repair of umbilical hernias (UHs) and the approach to repair UHs in obese patients need further analysis. METHODS: A retrospective review of UH repair (UHR) conducted at our institution was undertaken. Patients were grouped by body mass index (BMI) and compared for recurrence and complications. Univariate and multivariate analyses were performed. RESULTS: In total, 199 patients (BMI 32.3 kg/m(2), 97% male, 77% Caucasian, American Society of Anesthesiologists class III/IV 59.2%) underwent primary tissue UHR. There were 8 recurrences (4.0%); average follow-up 3.9 +/- 2.4 years (range 30 days to 9.2 years). There were no recurrences among normal BMI patients (0/11); 3 in overweight (3/54), 2 in class I obese (2/73), 2 in class II obese (2/47), and 1 in morbidly obese (1/14) patients (P = .84). Albumin and American Society of Anesthesiologists were similar in all groups. Recurrence rates among obese and nonobese patients were not significantly different (3.7% vs 4.6%, P = .72). There were 18 (9.0%) complications. BMI was not associated with complications. CONCLUSION: Primary tissue repair is a feasible approach for UHR in obese patients. PMID- 26060001 TI - Increasing organ donation after cardiac death in trauma patients. AB - BACKGROUND: Organ donation after cardiac death (DCD) is not optimal but still remains a valuable source of organ donation in trauma donors. The aim of this study was to assess national trends in DCD from trauma patients. METHODS: A 12 year (2002 to 2013) retrospective analysis of the United Network for Organ Sharing database was performed. Outcome measures were the following: proportion of DCD donors over the years and number and type of solid organs donated. RESULTS: DCD resulted in procurement of 16,248 solid organs from 8,724 donors. The number of organs donated per donor remained unchanged over the study period (P = .1). DCD increased significantly from 3.1% in 2002 to 14.6% in 2013 (P = .001). There was a significant increase in the proportion of kidney (2002: 3.4% vs 2013: 16.3%, P = .001) and liver (2002: 1.6% vs 2013: 5%, P = .041) donation among DCD donors over the study period. CONCLUSIONS: DCD from trauma donors provides a significant source of solid organs. The proportion of DCD donors increased significantly over the last 12 years. PMID- 26060002 TI - Surgical care checklists to optimize patient care following postoperative complications. AB - BACKGROUND: Postoperative complications are common. Inconsistency in the care of complications is reflected in variable rates of failure to rescue. This study aims to develop and validate checklists for treatment of common postoperative complications. METHODS: Initial checklists were based on best evidence, with expert clinician review. Casenote review was performed, comparing checklist item completion with outcomes. Logistic regression was performed for risk of further morbidity, considering American Society of Anesthesiology grade, age, sex, and checklist compliance. Checklists were finalized through end user multidisciplinary review. RESULTS: Evidence-based checklists were developed. Retrospective casenote review revealed management of 86% (31/37) of these complications to be noncompliant with checklist-mandated care. This resulted in delays and errors in 65% (24/37) of cases, with median treatment delay of 6 hours (interquartile range 5.4 hours). Regression analysis revealed poor checklist compliance to be to only significant factor (odds ratio 6.75, 95% confidence interval 1.11 to 41.00, P = .038) for developing further morbidity. CONCLUSIONS: Management of complications is highly variable, with failure to adhere to best practice principles significantly associated with an increased risk of further morbidity. This study presents an evidence-based framework for the development of checklists to standardize care. PMID- 26060003 TI - Boron-Containing Polycyclic Aromatic Hydrocarbons: Facile Synthesis of Stable, Redox-Active Luminophores. AB - Herein we show that replacing the two meso carbon atoms of the polycyclic aromatic hydrocarbon (PAH) bisanthene by boron atoms transforms a near-infrared dye into an efficient blue luminophore. This observation impressively illustrates the impact of boron doping on the frontier orbitals of PAHs. To take full advantage of this tool for the targeted design of organic electronic materials, the underlying structure-property relationships need to be further elucidated. We therefore developed a modular synthesis sequence based on a Peterson olefination, a stilbene-type photocyclization, and an Si-B exchange reaction to substantially broaden the palette of accessible polycyclic aromatic organoboranes and to permit a direct comparison with their PAH congeners. PMID- 26060004 TI - Historical perspectives of The American Association for Thoracic Surgery: Timothy Joseph Gardner. PMID- 26060005 TI - Imagine all the people.... PMID- 26060007 TI - Aortic filtration system's impact on preventing adverse clinical events. PMID- 26060006 TI - Trends, clinical outcomes, and cost implications of mitral valve repair versus replacement, concomitant with aortic valve replacement. AB - OBJECTIVE: This study evaluated national trends, clinical outcomes, and cost implications of mitral valve (MV) repair, versus replacement, concomitant with aortic valve replacement (AVR). METHODS: Patients who underwent MV surgery concomitant with AVR, between 1999 and 2008, were identified in the Nationwide Inpatient Sample (NIS) registry. Mitral stenosis, endocarditis, and emergency cases were excluded. Inpatient clinical outcomes and costs were compared. Costs were derived using cost-to-charge ratios supplied by the dataset for each individual hospital. Multivariable logistic and linear regression analyses were used for risk adjustment. RESULTS: A total of 41,417 concomitant cases were identified, of which 11,472 (28%) were MV repairs. Repair rates increased from 15.3% in 1999 to 43.5% in 2008 (P < .001). Major postoperative morbidity rates were similar with MV repair, versus replacement, concomitant with AVR (each 29%, P = .54). Unadjusted inpatient mortality (7.9% vs 10.1%, P = .005); length of hospital stay (median: 8 vs 9 days, P < .001); and costs (median: $45,455 vs $49,648, P < .001) were lower with MV repair. After risk adjustment, MV repair was associated with lower odds of inpatient mortality, and with lower costs (each P < .001). CONCLUSIONS: Mitral valve repair concomitant with AVR is associated with reduced inpatient mortality and costs, compared with MV replacement, supporting its use when technically feasible. Although use has increased substantially, MV repair continues to comprise a minority of concomitant AVR cases, in centers reporting to the NIS registry. Increasing repair rates, particularly in NIS-participating hospitals, seems prudent. PMID- 26060008 TI - Aortic surgery and spinal collateral flow: A call for structured approaches to functional characterization of the intraspinal collateral system. PMID- 26060009 TI - Neurologic impact of using embol-x intraaortic filter. PMID- 26060010 TI - Are there really differences between acute aortic dissections in Eastern and Western populations? PMID- 26060011 TI - Reply to the Editor. PMID- 26060012 TI - The STICH trial data: Keep it simple. PMID- 26060013 TI - A balanced assessment of the STICH trial. PMID- 26060014 TI - Infant euthanasia is morally unacceptable. PMID- 26060015 TI - The ethical case against assisted euthanasia has not been made. PMID- 26060016 TI - More than one way to skin a cat. PMID- 26060017 TI - ITGBL1 Is a Runx2 Transcriptional Target and Promotes Breast Cancer Bone Metastasis by Activating the TGFbeta Signaling Pathway. AB - Bone metastasis affects more than 70% of advanced breast cancer patients, but the molecular mechanisms of this process remain unclear. Here, we present clinical and experimental evidence to clarify the role of the integrin beta-like 1 (ITGBL1) as a key contributor to bone metastasis of breast cancer. In an in vivo model system and in vitro experiments, ITGBL1 expression promoted formation of osteomimetic breast cancers, facilitating recruitment, residence, and growth of cancer cells in bone microenvironment along with osteoclast maturation there to form osteolytic lesions. Mechanistic investigations identified the TGFbeta signaling pathway as a downstream effector of ITGBL1 and the transcription factor Runx2 as an upstream activator of ITGBL1 expression. In support of these findings, we also found that ITGBL1 was an essential mediator of Runx2-induced bone metastasis of breast cancer. Overall, our results illuminate how bone metastasis occurs in breast cancer, and they provide functional evidence for new candidate biomarkers and therapeutic targets to identify risk, to prevent, and to treat this dismal feature of advanced breast cancer. PMID- 26060018 TI - Androgen Receptor Splice Variants Dimerize to Transactivate Target Genes. AB - Constitutively active androgen receptor splice variants (AR-V) lacking the ligand binding domain have been implicated in the pathogenesis of castration-resistant prostate cancer and in mediating resistance to newer drugs that target the androgen axis. AR-V regulates expression of both canonical AR targets and a unique set of cancer-specific targets that are enriched for cell-cycle functions. However, little is known about how AR-V controls gene expression. Here, we report that two major AR-Vs, termed AR-V7 and AR(v567es), not only homodimerize and heterodimerize with each other but also heterodimerize with full-length androgen receptor (AR-FL) in an androgen-independent manner. We found that heterodimerization of AR-V and AR-FL was mediated by N- and C-terminal interactions and by the DNA-binding domain of each molecule, whereas AR-V homodimerization was mediated only by DNA-binding domain interactions. Notably, AR-V dimerization was required to transactivate target genes and to confer castration-resistant cell growth. Our results clarify the mechanism by which AR Vs mediate gene regulation and provide a pivotal pathway for rational drug design to disrupt AR-V signaling as a rational strategy for the effective treatment of advanced prostate cancer. PMID- 26060019 TI - Correlation between Density of CD8+ T-cell Infiltrate in Microsatellite Unstable Colorectal Cancers and Frameshift Mutations: A Rationale for Personalized Immunotherapy. AB - Colorectal cancers with microsatellite instability (MSI) represent 15% of all colorectal cancers, including Lynch syndrome as the most frequent hereditary form of this disease. Notably, MSI colorectal cancers have a higher density of tumor infiltrating lymphocytes (TIL) than other colorectal cancers. This feature is thought to reflect the accumulation of frameshift mutations in sequences that are repeated within gene coding regions, thereby leading to the synthesis of neoantigens recognized by CD8(+) T cells. However, there has yet to be a clear link established between CD8(+) TIL density and frameshift mutations in colorectal cancer. In this study, we examined this link in 103 MSI colorectal cancers from two independent cohorts where frameshift mutations in 19 genes were analyzed and CD3(+), CD8(+), and FOXP3(+) TIL densities were quantitated. We found that CD8(+) TIL density correlated positively with the total number of frameshift mutations. TIL densities increased when frameshift mutations were present within the ASTE1, HNF1A, or TCF7L2 genes, increasing even further when at least one of these frameshift mutations was present in all tumor cells. Through in vitro assays using engineered antigen-presenting cells, we were able to stimulate peripheral cytotoxic T cells obtained from colorectal cancer patients with peptides derived from frameshift mutations found in their tumors. Taken together, our results highlight the importance of a CD8(+) T cell immune response against MSI colorectal cancer-specific neoantigens, establishing a preclinical rationale to target them as a personalized cellular immunotherapy strategy, an especially appealing goal for patients with Lynch syndrome. PMID- 26060020 TI - Ligand regulation of a constitutively dimeric EGF receptor. AB - Ligand-induced receptor dimerization has traditionally been viewed as the key event in transmembrane signalling by epidermal growth factor receptors (EGFRs). Here we show that the Caenorhabditis elegans EGFR orthologue LET-23 is constitutively dimeric, yet responds to its ligand LIN-3 without changing oligomerization state. SAXS and mutational analyses further reveal that the preformed dimer of the LET-23 extracellular region is mediated by its domain II dimerization arm and resembles other EGFR extracellular dimers seen in structural studies. Binding of LIN-3 induces only minor structural rearrangements in the LET 23 dimer to promote signalling. Our results therefore argue that EGFR can be regulated by allosteric changes within an existing receptor dimer--resembling signalling by insulin receptor family members, which share similar extracellular domain compositions but form covalent dimers. PMID- 26060021 TI - Single-cell genomics of uncultivated deep-branching magnetotactic bacteria reveals a conserved set of magnetosome genes. AB - While magnetosome biosynthesis within the magnetotactic Proteobacteria is increasingly well understood, much less is known about the genetic control within deep-branching phyla, which have a unique ultrastructure and biosynthesize up to several hundreds of bullet-shaped magnetite magnetosomes arranged in multiple bundles of chains, but have no cultured representatives. Recent metagenomic analysis identified magnetosome genes in the genus 'Candidatus Magnetobacterium' homologous to those in Proteobacteria. However, metagenomic analysis has been limited to highly abundant members of the community, and therefore only little is known about the magnetosome biosynthesis, ecophysiology and metabolic capacity in deep-branching MTB. Here we report the analysis of single-cell derived draft genomes of three deep-branching uncultivated MTB. Single-cell sorting followed by whole genome amplification generated draft genomes of Candidatus Magnetobacterium bavaricum and Candidatus Magnetoovum chiemensis CS-04 of the Nitrospirae phylum. Furthermore, we present the first, nearly complete draft genome of a magnetotactic representative from the candidate phylum Omnitrophica, tentatively named Candidatus Omnitrophus magneticus SKK-01. Besides key metabolic features consistent with a common chemolithoautotrophic lifestyle, we identified numerous, partly novel genes most likely involved in magnetosome biosynthesis of bullet shaped magnetosomes and their arrangement in multiple bundles of chains. PMID- 26060022 TI - Preface. PMID- 26060023 TI - History of cardiopulmonary bypass (CPB). AB - The development of cardiopulmonary bypass (CPB), thereby permitting open-heart surgery, is one of the most important advances in medicine in the 20th century. Many currently practicing cardiac anesthesiologists, cardiac surgeons, and perfusionists are unaware of how recently it came into use (60 years) and how much the practice of CPB has changed during its short existence. In this paper, the development of CPB and the many changes and progress that has taken place over this brief period of time, making it a remarkably safe endeavor, are reviewed. The many as yet unresolved questions are also identified, which sets the stage for the other papers in this issue of this journal. PMID- 26060024 TI - Inflammatory response and extracorporeal circulation. AB - Patients undergoing cardiac surgery with extracorporeal circulation (EC) frequently develop a systemic inflammatory response syndrome. Surgical trauma, ischaemia-reperfusion injury, endotoxaemia and blood contact to nonendothelial circuit compounds promote the activation of coagulation pathways, complement factors and a cellular immune response. This review discusses the multiple pathways leading to endothelial cell activation, neutrophil recruitment and production of reactive oxygen species and nitric oxide. All these factors may induce cellular damage and subsequent organ injury. Multiple organ dysfunction after cardiac surgery with EC is associated with an increased morbidity and mortality. In addition to the pathogenesis of organ dysfunction after EC, this review deals with different therapeutic interventions aiming to alleviate the inflammatory response and consequently multiple organ dysfunction after cardiac surgery. PMID- 26060026 TI - Myocardial injury and protection related to cardiopulmonary bypass. AB - During cardiac surgery with cardiopulmonary bypass, the heart is isolated from the circulation. This inevitably induces myocardial ischemia. In addition to this ischemic insult, an additional hit will occur upon reperfusion, which may worsen the extent of tissue damage and organ dysfunction. Over the years, several strategies have been developed that aim to attenuate and/or modulate the extent of this ischemia-reperfusion injury related to the episode of cardiopulmonary bypass. This article reviews the pathophysiology of myocardial injury related to cardiopulmonary bypass and summarizes potential therapeutic strategies that may modulate the extent of this myocardial injury. PMID- 26060025 TI - Neurocognitive outcomes after extracorporeal membrane oxygenation. AB - Extracorporeal membrane oxygenation (ECMO) has been a therapy of last resort for the treatment of severe cardiorespiratory failure since the 1970s [1]. In recent years, ECMO has seen a resurgence in its use in adults. Recent work examining rates of ECMO use in the US adult population, using Nationwide Inpatient Sample data, quotes an increase in use of 433% from 2006 to 2011 [2]. While much research has focused on neurologic injury after cardiac surgery and cardiopulmonary bypass (CPB), the effects of ECMO on neurocognitive function are less well described. This review aims to summarize recent findings as they pertain to pathophysiology, monitoring techniques, prevention, therapy, and emerging experimental concepts in the context of ECMO for adult patients. Given that neurocognitive outcomes after cardiac surgery have been recently reviewed [3,4], we will limit the discussion of findings from the cardiac surgery/CPB literature to those especially relevant for ECMO. PMID- 26060027 TI - Hepatic and renal effects of cardiopulmonary bypass. AB - Although associated with low morbidity and mortality, cardiopulmonary bypass remains a "non-physiologic" device that carries a set of complications. Hepatic and renal impairment are associated with a poor outcome. The knowledge of pathophysiology, risk factors and therapeutic interventions can help the anaesthesiologist in preventing these complications in daily practice. The present narrative review provides an update of the literature on the effects of cardiopulmonary bypass on hepatic and renal functions, focussing on markers of hepatic and renal injuries, perioperative strategies in preserving organ function and replacement therapies. PMID- 26060028 TI - Pulmonary complications of cardiopulmonary bypass. AB - Pulmonary complications after the use of extracorporeal circulation are common, and they range from transient hypoxemia with altered gas exchange to acute respiratory distress syndrome (ARDS), with variable severity. Similar to other end-organ dysfunction after cardiac surgery with extracorporeal circulation, pulmonary complications are attributed to the inflammatory response, ischemia reperfusion injury, and reactive oxygen species liberated as a result of cardiopulmonary bypass. Several factors common in cardiac surgery with extracorporeal circulation may worsen the risk of pulmonary complications including atelectasis, transfusion requirement, older age, heart failure, emergency surgery, and prolonged duration of bypass. There is no magic bullet to prevent or treat pulmonary complications, but supportive care with protective ventilation is important. Targets for the prevention of pulmonary complications include mechanical, surgical, and anesthetic interventions that aim to reduce the contact activation, systemic inflammatory response, leukocyte sequestration, and hemodilution associated with extracorporeal circulation. PMID- 26060030 TI - Anticoagulation management associated with extracorporeal circulation. AB - The use of extracorporeal circulation requires anticoagulation to maintain blood fluidity throughout the circuit, and to prevent thrombotic complications. Additionally, adequate suppression of hemostatic activation avoids the unnecessary consumption of coagulation factors caused by the contact of blood with foreign surfaces. Cardiopulmonary bypass represents the greatest challenge in this regard, necessitating profound levels of anticoagulation during its conduct, but also quick, efficient reversal of this state once the surgical procedure is completed. Although extracorporeal circulation has been around for more than half a century, many questions remain regarding how to best achieve anticoagulation for it. Although unfractionated heparin is the predominant agent used for cardiopulmonary bypass, the amount required and how best to monitor its effects are still unresolved. This review discusses the use of heparin, novel anticoagulants, and the monitoring of anticoagulation during the conduct of cardiopulmonary bypass. PMID- 26060029 TI - Glycemic control and outcome related to cardiopulmonary bypass. AB - Perioperative hyperglycemia, aggravated by cardiopulmonary bypass, is associated with adverse outcome in adult and pediatric patients. Whereas hyperglycemia was originally perceived as an adaptive response to surgical stress, it is now clear that glycemic control is a strategy to reduce adverse outcomes after cardiac surgery and cardiopulmonary bypass. The optimal blood glucose target, whether or not glycemic control should be initiated already intraoperatively, and whether or not perioperative glucose administration affects the impact of glycemic control on ischemia-reperfusion damage remain open questions. Hypoglycemia, the risk of which is increased with glycemic control, is also associated with adverse outcomes. However, it remains controversial whether brief episodes of hypoglycemia, rapidly corrected during glycemic control, have adverse effects on outcome. This review gives an overview of the currently available literature on glycemic control during and after cardiac surgery and focuses on the indicated open questions about this intervention for this specific patient population. PMID- 26060031 TI - Mechanical circulatory support. AB - Heart failure (HF) is a condition in which the heart is not able to pump enough blood and oxygen required for organ systems to function. According to recent statistics from the American Heart Association (AHA), about 5.1 million people in the nation suffer from HF; one in nine deaths in 2009 included HF as a contributing cause. About half of people who develop HF die within 5 years of diagnosis. HF costs the nation an estimated $32 billion each year. This total includes the cost of health-care services, medications to treat HF, and missed days of work [1]. Despite several recent promising developments in medical therapy for HF, many patients still progress to advanced stages of HF. The annual mortality rate for patients with advanced HF remains high [2]. Heart transplantation (HT) is the definitive therapy for advanced HF, but it is limited by the availability of donors and strict recipient criteria applied to avoid poor outcomes. Therefore, the alternate treatment of mechanically supporting the ventricles, ventricular assist device (VAD) therapy, has gained an important role in the management of advanced HF (stage D). This chapter discusses the indications, contraindications, and various classifications of mechanical circulatory support (MCS) and individual features of commonly used VADs. Perioperative management of patients undergoing MCS will also be described in detail. PMID- 26060032 TI - Extracorporeal life support for adult cardiopulmonary failure. AB - The use of extracorporeal life support (ECLS) or extracorporeal membrane oxygenation (ECMO), as it is also known, has rapidly expanded over the past decade. The increase in ECMO use is a consequence of multiple factors including significant advancements in extracorporeal technology, the emergence of data supporting its use, and a growing number of potential clinical applications. This review focuses on the various modes of ECLS as well as the clinical indications and available evidence for the use of extracorporeal support. PMID- 26060033 TI - Cardiopulmonary bypass in the pediatric population. AB - Cardiopulmonary bypass (CPB) facilitates the repair of cardiac lesions in adults and children. Surgical mortality has decreased with improvements in technique allowing for the successful repair of complex heart defects in neonates of increasingly low body weight and gestational age. The physiological effects of CPB are more significant in children. The presence of intracardiac shunts and other anatomic variants further complicates CPB in patients with congenital heart disease. Special techniques and monitors are often necessary. Protocols are often established within individual institutions to standardize the approach to CPB. The anesthesiologist caring for the patient must understand the physiology of CPB to facilitate the initiation and separation from bypass, and to be able to treat complications. Evidence supporting a particular technique of CPB in pediatric population is still largely from uncontrolled or nonrandomized trials, observational studies, extrapolation from adult studies, and expert opinion. The heterogeneity of congenital heart disease makes randomized controlled trials or meta-analyses challenging, and thus they are limited in the literature. PMID- 26060034 TI - Pharmacologic approaches to weaning from cardiopulmonary bypass and extracorporeal membrane oxygenation. AB - Cardiopulmonary bypass (CBP) and extracorporeal membrane oxygenation (ECMO) are two modalities of mechanical circulatory support. They provide hemodynamic stability for patients undergoing invasive cardiothoracic interventions, and they can be lifesaving in emergencies resulting from cardiogenic shock or respiratory failure. Unlike implantable ventricular assist devices, CPB and ECMO are short term solutions meant to last from hours to days, and the patient will need to be weaned from the mechanical support once the intervention has completed or when the underlying condition has improved. Weaning imposes major physiological strain upon the recovering cardiovascular and pulmonary systems, and it usually requires pharmacological support. This article focuses on the proper diagnosis of the underlying pathophysiology, an understanding of the pharmacology of available agents, and a rational approach to the management of patients weaning from CPB and ECMO. PMID- 26060035 TI - Social status and helminth infections in female forest guenons (Cercopithecus mitis). AB - OBJECTIVE: When resource competition within primate social groups is effective, high-ranking individuals generally gain fitness benefits. Contrary to expectations, female Cercopithecus mitis form linear dominance hierarchies without evidence for rank-related variation in fitness-relevant measures, raising questions about the evolution of guenon social structure. Here, we test whether social status predicts gastrointestinal helminth infections, known to influence health and morbidity in other mammalian hosts. In addition, we assess whether infections contribute to stress responses as indicated by fecal glucocorticoid (fGC) levels. METHODS: We quantified infections and hormone levels in 382 fecal samples from 11 adult female Sykes' monkeys (C. m. albogularis) over four months in one wild study group at Gede Ruins, Kenya. Using a generalized estimating equations technique, we modeled the odds of infection, relative infection intensity, and fGC variation. RESULTS: High-ranking females were less likely infected with Trichuris and Trichostrongylus, had lower fecal egg counts for both taxa, and overall lower helminth richness than low-ranking females. An inverse relationship between rank and Trichuris egg counts existed also in a study population of blue monkeys (C. m. stuhlmanni), where we collected comparable data over a shorter period. Regardless of rank, lactating females were more likely than non-lactating females to be infected with Trichuris, and had higher fecal egg counts for both Trichuris and Oesophagostomum. Lastly, we report evidence that Trichuris infections exacerbated energetic stress and that food supplementation by tourists increased infection levels. CONCLUSION: Our findings suggest that high-rank may provide long-term health and energetic benefits for female C. mitis, with potential fitness implications. PMID- 26060036 TI - Desmoplastic Trichoepithelioma: An Infrequent Entity not to be Missed: Report of Two Cases. AB - Desmoplastic trichoepitheliomas are rare benign tumors with follicular differentiation. They have rarely been described in children. We report two children with this uncommon condition. PMID- 26060037 TI - Layered double hydroxide nanoparticles promote self-renewal of mouse embryonic stem cells through the PI3K signaling pathway. AB - Embryonic stem cells (ESCs) hold great potential for regenerative medicine due to their two unique characteristics: self-renewal and pluripotency. Several groups of nanoparticles have shown promising applications in directing the stem cell fate. Herein, we investigated the cellular effects of layered double hydroxide nanoparticles (LDH NPs) on mouse ESCs (mESCs) and the associated molecular mechanisms. Mg-Al-LDH NPs with an average diameter of ~100 nm were prepared by hydrothermal methods. To determine the influences of LDH NPs on mESCs, cellular cytotoxicity, self-renewal, differentiation potential, and the possible signaling pathways were explored. Evaluation of cell viability, lactate dehydrogenase release, ROS generation and apoptosis demonstrated the low cytotoxicity of LDH NPs. The alkaline phosphatase activity and the expression of pluripotency genes in mESCs were examined, which indicated that exposure to LDH NPs could support self-renewal and inhibit spontaneous differentiation of mESCs under feeder-free culture conditions. The self-renewal promotion was further proved to be independent of the leukemia inhibitory factor (LIF). Furthermore, cells treated with LDH NPs maintained the potential to differentiate into all three germ layers both in vitro and in vivo through formation of embryoid bodies and teratomas. In addition, we observed that LDH NPs initiated the activation of the PI3K/Akt pathway, while treatment with the PI3K inhibitor LY294002 could block the effects of LDH NPs on mESCs. The results confirmed that the promotion of self-renewal by LDH NPs was associated with activation of the PI3K/Akt signaling pathway. Altogether, our studies identified a new role of LDH NPs in maintaining self renewal of mouse ES cells which could potentially be applied in stem cell research. PMID- 26060039 TI - The footprint of urban heat island effect in China. AB - Urban heat island (UHI) is one major anthropogenic modification to the Earth system that transcends its physical boundary. Using MODIS data from 2003 to 2012, we showed that the UHI effect decayed exponentially toward rural areas for majority of the 32 Chinese cities. We found an obvious urban/rural temperature "cliff", and estimated that the footprint of UHI effect (FP, including urban area) was 2.3 and 3.9 times of urban size for the day and night, respectively, with large spatiotemporal heterogeneities. We further revealed that ignoring the FP may underestimate the UHI intensity in most cases and even alter the direction of UHI estimates for few cities. Our results provide new insights to the characteristics of UHI effect and emphasize the necessity of considering city- and time-specific FP when assessing the urbanization effects on local climate. PMID- 26060038 TI - In ovo administration of human recombinant leptin shows dose dependent angiogenic effect on chicken chorioallantoic membrane. AB - BACKGROUND: Leptin, the cytokine produced by white adipose tissue is known to regulate food energy homeostasis through its hypothalamic receptor. In vitro studies have demonstrated that leptin plays a major role in angiogenesis through binding to the receptor Ob-R present on ECs by stimulating and initiating new capillary like structures from ECs. Various in vivo studies indicate that leptin has diverse effect on angiogenesis. A few reports have showed that leptin exerts pro angiogenic effects while some suggested that it has antiangiogenic potential. It is theoretically highly important to understand the effect of leptin on angiogenesis to use as a therapeutic molecule in various angiogenesis related pathological conditions. Chicken chorio allantoic membrane (CAM) on 9th day of incubation was incubated with 1, 3 and 5 MUg concentration of HRL for 72 h using gelatin sponge. Images where taken after every 24 h of incubation and analysed with Angioguant software. The treated area was observed under microscope and histological evaluation was performed for the same. Tissue thickness was calculated morphometrically from haematoxylin and eosin stained cross sections. Reverse transcriptase PCR and immunohistochemistry were also performed to study the gene and protein level expression of angiogenic molecules. RESULTS: HRL has the ability to induce new vessel formation at the treated area and growth of the newly formed vessels and cellular morphological changes occur in a dose dependent manner. Increase in the tissue thickness at the treated area is suggestive of initiation of new capillary like structures. Elevated mRNA and protein level expression of VEGF165 and MMP2 along with the activation of ECs as demonstrated by the presence of CD34 expression supports the neovascularization potential of HRL. CONCLUSION: Angiogenic potential of HRL depends on the concentration and time of incubation and is involved in the activation of ECs along with the major interaction of VEGF 165 and MMP2. It is also observed that 3 MUg of HRL exhibits maximum angiogenic potential at 72 h of incubation. Thus our data suggest that dose dependent angiogenic potential HRL could provide a novel role in angiogenic dependent therapeutics such as ischemia and wound healing conditions. PMID- 26060040 TI - Clinical applications of next-generation sequencing-based gene panel in patients with muscular dystrophy: Korean experience. AB - Muscular dystrophy (MD) is a genetically and clinically heterogeneous group of disorders. Here, we performed targeted sequencing of 18 limb-girdle MD (LGMD) related genes in 35 patients who were highly suspected of having MD. We identified one or more pathogenic variants in 23 of 35 patients (65.7%), and a genetic diagnosis was performed in 20 patients (57.1%). LGMD2B was the most common LGMD type, followed by LGMD1B, LGMD2A, and LGMD2G. Among the three major LGMD types in this group, LGMD1B was correlated with the lowest creatine kinase (CK) levels and the earliest onset, whereas LGMD2B was correlated with the highest CK levels and the latest onset. Thus, next-generation sequencing-based gene panels can be a helpful tool for the diagnosis of MDs, particularly in young children and those displaying atypical symptoms. PMID- 26060041 TI - Effect of vaginal self-sampling on cervical cancer screening rates: a community based study in Newfoundland. AB - BACKGROUND: Cervical cancer is highly preventable and treatable if detected early through regular screening. Women in the Canadian province of Newfoundland & Labrador have relatively low rates of cervical cancer screening, with rates of around 40 % between 2007 and 2009. Persistent infection with oncogenic human papillomavirus (HPV) is a necessary cause for the development of cervical cancer, and HPV testing, including self-sampling, has been suggested as an alternative method of cervical cancer screening that may alleviate some barriers to screening. Our objective was to determine whether offering self-collected HPV testing screening increased cervical cancer screening rates in rural communities. METHODS: During the 2-year study, three community-based cohorts were assigned to receive either i) a cervical cancer education campaign with the option of HPV testing; ii) an educational campaign alone; iii) or no intervention. Self collection kits were offered to eligible women at family medicine clinics and community centres, and participants were surveyed to determine their acceptance of the HPV self-collection kit. Paired proportions testing for before-after studies was used to determine differences in screening rates from baseline, and Chi Square analysis of three dimensional 2 * 2 * 2 tables compared the change between communities. RESULTS: Cervical cancer screening increased by 15.2 % (p < 0.001) to 67.4 % in the community where self-collection was available, versus a 2.9 % increase (p = 0.07) in the community that received educational campaigns and 8.5 % in the community with no intervention (p = 0.193). The difference in change in rates was statistically significant between communities A and B (p < 0.001) but not between communities A and C (p = 0.193). The response rate was low, with only 9.5 % (168/1760) of eligible women opting to self-collect for HPV testing. Of the women who completed self-collection, 15.5 % (26) had not had a Pap smear in the last 3 years, and 88.7 % reported that they were somewhat or very satisfied with self-collection. CONCLUSIONS: Offering self-collected HPV testing increased the cervical cancer screening rate in a rural NL community. Women who completed self-collection had generally positive feelings about the experience. Offering HPV self-collection may increase screening compliance, particularly among women who do not present for routine Pap smears. PMID- 26060042 TI - Tracheostomy in intensive care unit patients can be performed without bleeding complications in case of normal thromboelastometry results (EXTEM CT) despite increased PT-INR: a prospective pilot study. AB - BACKGROUND: Coagulopathy is often accompanied by prolongation of prothrombin time (PT) in septic and nonseptic patients in intensive care unit (ICU). The conventional way to correct the coagulopathy is to administer fresh frozen plasma (FFP) before invasive procedures to minimise the risk of bleeding. However, prolonged PT can be present even in hypercoagulation status, resulting in unnecessary administration of FFP. In the present study, we have assessed the reliability of thromboelastometry in case of prolonged PT and the relationship to bleeding complications during surgical tracheostomy. METHODS: The study was conducted during the period between April 2013 and April 2014 in patients undergoing surgical tracheostomy. Coagulation status was assessed using PT, and the status was reassessed by thromboelastometry for prolonged PT. Tracheostomy was performed in patients with normal thromboelastometry results without administering FFP. RESULTS: Tracheostomy was performed in total 119 patients. Normal value of PT as measured by international normalized ratio (INR) <= 1.2 was found in 64 (54%) patients, while prolonged INR > 1.2 was found in 55 (46%) patients. Patients with INR >= 1.3 (with INR min- 1.3, max- 1.84, and median- 1.48) were further analysed by thromboelastometry. Despite prolonged INR, thromboelastometry results were in normal ranges in all cases except one. With normal thromboelastometry, tracheostomy was performed safely without any bleeding complication. CONCLUSIONS: Surgical tracheostomy in septic and nonseptic patients can be performed without bleeding complications in case of normal thromboelastometry results (EXTEM CT) despite increased PT-INR. This method can help physicians to reduce unnecessary administration of FFP in patients. PMID- 26060043 TI - Bioactive natural products with anti-herpes simplex virus properties. AB - OBJECTIVES: In this review, we highlight and summarise the most promising extracts, fractions and pure compounds as potential anti-herpes simplex virus (HSV) agents derived from microorganisms, marine organisms, fungi, animals and plants. The role of natural products in the development of anti-HSV drugs will be discussed. KEY FINDINGS: Herpes simplex viruses (HSV-1 and -2) are common human pathogens that remain a serious threat to human health. In recent years, a great interest has been devoted to the search for integrated management of HSV infections. Acyclovir and related nucleoside analogues have been licensed for the therapy that target viral DNA polymerase. Although these drugs are currently effective against HSV infections, the intensive use of these drugs has led to the problem of drug-resistant strains. Therefore, the search for new sources to develop new antiherpetic agents has gained major priority to overcome the problem. SUMMARY: Natural products as potential, new anti-HSV drugs provide several advantages such as reduced side effects, less resistance, low toxicity and various mechanisms of action. This paper aims to provide an overview of natural products that possess antiviral activity against HSV. PMID- 26060044 TI - Discrete Boltzmann modeling of multiphase flows: hydrodynamic and thermodynamic non-equilibrium effects. AB - A discrete Boltzmann model (DBM) is developed to investigate the hydrodynamic and thermodynamic non-equilibrium (TNE) effects in phase separation processes. The interparticle force drives changes and the gradient force, induced by gradients of macroscopic quantities, opposes them. In this paper, we investigate the interplay between them by providing a detailed inspection of various non equilibrium observables. Based on the TNE features, we define TNE strength which roughly estimates the deviation amplitude from the thermodynamic equilibrium. The time evolution of the TNE intensity provides a convenient and efficient physical criterion to discriminate the stages of the spinodal decomposition and domain growth. Via the DBM simulation and this criterion, we quantitatively study the effects of latent heat and surface tension on phase separation. It is found that the TNE strength attains its maximum at the end of the spinodal decomposition stage, and it decreases when the latent heat increases from zero. The surface tension effects are threefold, prolong the duration of the spinodal decomposition stage, decrease the maximum TNE intensity, and accelerate the speed of the domain growth stage. PMID- 26060046 TI - Combined action of the major secreted exo- and endopolygalacturonases is required for full virulence of Fusarium oxysporum. AB - The genome of the tomato pathogen Fusarium oxysporum f. sp. lycopersici encodes eight different polygalacturonases (PGs): four endoPGs and four exoPGs. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) revealed that endoPGs pg1 and pg5 and exoPGs pgx4 and pgx6 are expressed at significant levels during growth on citrus pectin, polygalacturonic acid or the monomer galacturonic acid, as well as during the infection of tomato plants. The remaining PG genes exhibit low expression levels under all the conditions tested. Secreted PG activity was decreased significantly during growth on pectin in the single deletion mutants lacking either pg1 or pgx6, as well as in the double mutant. Although the single deletion mutants did not display a significant virulence reduction on tomato plants, the Deltapg1Deltapgx6 double mutant was significantly attenuated in virulence. The combined action of exoPGs and endoPGs is thus essential for plant infection by the vascular wilt fungus F. oxysporum. PMID- 26060045 TI - Determination of HER2 and p53 Mutations by Sequence Analysis Method and EGFR/Chromosome 7 Gene Status by Fluorescence in Situ Hybridization for the Predilection of Targeted Therapy Modalities in Immunohistochemically Triple Negative Breast Carcinomas in Turkish Population. AB - Triple negative breast cancer (TNBC), an agressive subtype accounts nearly 15 % of all breast carcinomas. Conventional chemotherapy is the only treatment modality thus new, effective targeted therapy methods have been investigated. Epidermal growth factor receptor (EGFR) inhibitors give hope according to the recent studies results. Also therapeutic agents have been tried against aberrant p53 signal activity as TNBC show high p53 mutation rates. Our aim was to detect the incidence of mutations/amplifications identified in TNBC in our population. Here we used sequence analysis to detect HER2 (exon 18-23), p53 (exon 5-8) mutations; fluorescence in situ hybridization (FISH) method to analyse EGFR/chromosome 7 centromere gene status in 82 immunohistochemically TNBC. Basaloid phenotype was identified in 49 (59.8 %) patients. EGFR amplification was noted in 5 cases (6.1 %). All EGFR amplified cases showed EGFR overexpression by immunohistochemistry (IHC). p53 mutations were identified in 33 (40.2 %) cases. Almost 60 % of the basal like breast cancer cases showed p53 mutation. Only one case showed HER2 mutation (exon 20:g.36830_3). Our results showed that gene amplification is not the unique mechanism in EGFR overexpression. IHC might be used in the decision of anti-EGFR therapy in routine practice. p53 mutation rate was lower than the rates reported in the literature probably due to ethnic differences and low sensitivity of sanger sequences in general mutation screening. We also established the rarity of HER2 mutation in TNBC. In conclusion EGFR and p53 are the major targets in TNBC also for our population. PMID- 26060047 TI - Gender differences in vocational rehabilitation service predictors of successful competitive employment for transition-aged individuals with autism. AB - As males and females with autism spectrum disorder (ASD) experience different symptomology, their needs for vocational rehabilitation (VR) are unique as they transition into adulthood. This study examined the effects of gender differences in VR service predictors on employment outcomes for transition-aged individuals with ASD. A total of 1696 individuals (857 males and 839 females) were analyzed from a sample of RSA-911 data of FY 2011. Hierarchical logistic regression analyses were conducted. Results revealed both gender-independent VR service predictors (with job placement and on-the-job supports more beneficial for both genders) and gender-specific predictors of employment (with counseling and guidance, job search assistance, and other services more beneficial for the male group). This study provides support for individualized gender-specific VR services for people with ASD. PMID- 26060048 TI - Individuals with autistic-like traits show reduced lateralization on a greyscales task. AB - Individuals with autism spectrum conditions attend less to the left side of centrally presented face stimuli compared to neurotypical individuals, suggesting a reduction in right hemisphere activation. We examined whether a similar bias exists for non-facial stimuli in a large sample of neurotypical adults rated above- or below-average on the autism spectrum quotient (AQ). Using the "greyscales" task, we found the typical leftward bias in the below-average group was significantly reduced in the above-average group. Moreover, a negative correlation between leftward bias and the social skills factor of the AQ suggested a link between atypical hemispheric activation and social difficulties in high-AQ trait individuals that extends to non-facial stimuli. PMID- 26060049 TI - Bio-inspired Hierarchical Nanowebs for Green Catalysis. AB - Bio-inspired 3D hierarchical nanowebs are fabricated using silicon micropillars, carbon nanotubes (CNT), and manganese oxide. The Si pillars act as artificial branches for growing CNTs and the secondary metal coating strengthens the structures. The simple but effective structure provides both chemical and mechanical stability to be used as a green catalyst for recycling waste polymers into raw materials. PMID- 26060050 TI - Characterization of microRNA profile in mammary tissue of dairy and beef breed heifers. AB - MicroRNAs (miRNAs) are small non-coding RNAs that participate in the regulation of gene expression. Their role during mammary gland development is still largely unknown. In this study, we performed a microarray analysis to identify miRNAs associated with high mammogenic potential of the bovine mammary gland. We identified 54 significantly differentially expressed miRNAs between the mammary tissue of dairy (Holstein-Friesian, HF) and beef (Limousin, LM) postpubertal heifers. Fifty-two miRNAs had higher expression in the mammary tissue of LM heifers. The expression of the top candidate miRNAs (bta-miR-10b, bta-miR-29b, bta-miR-101, bta-miR-375, bta-miR-2285t, bta-miR-146b, bta-let7b, bta-miR-107, bta-miR-1434-3p) identified in the microarray experiment was additionally evaluated by qPCR. Enrichment analyses for targeted genes revealed that the major differences between miRNA expression in the mammary gland of HF versus LM were associated with the regulation of signalling pathways that are crucial for mammary gland development, such as TGF-beta, insulin, WNT and inflammatory pathways. Moreover, a number of genes potentially targeted by significantly differentially expressed miRNAs were associated with the activity of mammary stem cells. These data indicate that the high developmental potential of the mammary gland in dairy cattle, leading to high milk productivity, depends also on a specific miRNA expression pattern. PMID- 26060051 TI - Constipation: an overlooked, unmanaged symptom of patients with pheochromocytoma and sympathetic paraganglioma. AB - OBJECTIVE: Pheochromocytomas (PHs) and sympathetic paragangliomas (PGs) are tumors that produce catecholamines, predisposing patients to cardiovascular disease and gastrointestinal effects such as constipation. OBJECTIVES: i) determine the prevalence of constipation, its risk factors, and its impact on survival; ii) identify whether a systematic combination of fiber, water, and laxatives was effective for treatment of constipation. DESIGN AND METHODS: We retrospectively studied 396 patients with PH/PG diagnosed in 2005-2014. The study population was patients with constipation as a presenting symptom; the control group was patients without constipation as a presenting symptom. The MD Anderson Symptom Inventory was used to assess constipation and quality of life. RESULTS: Twenty-three patients (6%) had constipation. Constipation was associated with headaches, palpitations, diaphoresis, weight loss, and excessive noradrenaline production (P<0.0001). Eighteen of these patients had non-metastatic primary tumors larger than 5 cm and/or extensive metastases. No statistically significant differences in age, sex, and genotype were noted between the study and control groups. In patients without metastases, resection of the primary tumor led to symptom disappearance. A systematic combination of fiber, water, and laxatives was associated with symptom improvement. Two patients who presented unmanaged constipation died because of sepsis from toxic megacolon. CONCLUSIONS: Constipation is a rare and potentially lethal complication in patients with PH/PGs. Severe constipation can be prevented by recognizing and treating mild symptoms. PMID- 26060052 TI - Metabolic comorbidities in Cushing's syndrome. AB - Cushing's syndrome (CS) patients have increased mortality primarily due to cardiovascular events induced by glucocorticoid (GC) excess-related severe metabolic changes. Glucose metabolism abnormalities are common in CS due to increased gluconeogenesis, disruption of insulin signalling with reduced glucose uptake and disposal of glucose and altered insulin secretion, consequent to the combination of GCs effects on liver, muscle, adipose tissue and pancreas. Dyslipidaemia is a frequent feature in CS as a result of GC-induced increased lipolysis, lipid mobilisation, liponeogenesis and adipogenesis. Protein metabolism is severely affected by GC excess via complex direct and indirect stimulation of protein breakdown and inhibition of protein synthesis, which can lead to muscle loss. CS patients show changes in body composition, with fat redistribution resulting in accumulation of central adipose tissue. Metabolic changes, altered adipokine release, GC-induced heart and vasculature abnormalities, hypertension and atherosclerosis contribute to the increased cardiovascular morbidity and mortality. In paediatric CS patients, the interplay between GC and the GH/IGF1 axis affects growth and body composition, while in adults it further contributes to the metabolic derangement. GC excess has a myriad of deleterious effects and here we attempt to summarise the metabolic comorbidities related to CS and their management in the perspective of reducing the cardiovascular risk and mortality overall. PMID- 26060054 TI - High thermopower and ultra low thermal conductivity in Cd-based Zintl phase compounds. AB - By combining first principles density functional theory and electronic as well as lattice Boltzmann transport calculations, we unravel the excellent thermoelectric properties of Zintl phase compounds ACd2Sb2 (where, A = Ca, Ba, Sr). The calculated electronic structures of these compounds show charge carrier pockets and heavy light bands near the band edge, which lead to a large power factor. Furthermore, we report large Gruneisen parameters and low phonon group velocity indicating essential strong anharmonicity in these compounds, which resulted in low lattice thermal conductivity. The combination of low thermal conductivity and the excellent transport properties give a high ZT value of ~1.4-1.9 in CaCd2Sb2 and BaCd2Sb2 at moderate p and n-type doping. Our results indicate that well optimized Cd-based Zintl phase compounds have the potential to match the performance of conventional thermoelectric materials. PMID- 26060053 TI - Grasping the 'teachable moment': time since diagnosis, symptom burden and health behaviors in breast, colorectal and prostate cancer survivors. AB - BACKGROUND: A cancer diagnosis may provide a 'teachable moment' in cancer recovery. To better understand factors influencing lifestyle choices following diagnosis, we examined associations between time since diagnosis and symptom burden with recommended dietary (e.g., five or more fruit/vegetable servings/day), physical activity (e.g., >150 active min, 3-5 times/week), and smoking behaviors (i.e., eliminate tobacco use) in cancer survivors. METHODS: We analyzed cross-sectional survey data collected from breast (n = 528), colorectal (n = 106), and prostate (n = 419) cancer survivors following active treatment at The University of Texas MD Anderson Cancer Center. Four regression models were tested for behaviors of interest. Additionally, we assessed symptom burden as a potential moderator and/or mediator between time since diagnosis and behaviors. RESULTS: Respondents were mostly female (55%) and non-Hispanic White (68%) with a mean age of 62.8 +/- 11.4 years and mean time since diagnosis of 4.6 +/- 3.1 years. In regression models, greater time since diagnosis predicted lower fruit and vegetable consumption (B = -0.05, p = 0.02) and more cigarette smoking (B = 0.06, p = 0.105). Greater symptom burden was a significant negative predictor for physical activity (B = -0.08, p < .001). We did not find evidence that symptom burden moderated or mediated the association between time since diagnosis and health behaviors. CONCLUSION: We assessed the prevalence of recommended behaviors in the context of other challenges that survivors face, including time since diagnosis and symptom burden. Our results provide indirect evidence that proximity to a cancer diagnosis may provide a teachable moment to improve dietary and smoking behaviors and that symptom burden may impede physical activity following diagnosis. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26060055 TI - Genetic manipulation of cardiac ageing. AB - Ageing in humans is associated with a significant increase in the prevalence of cardiovascular disease. We still do not fully understand the molecular mechanisms underpinning this correlation. However, a number of insights into which genes control cardiac ageing have come from studying hearts of the fruit fly, Drosophila melanogaster. The fly's simple heart tube has similar molecular structure and basic physiology to the human heart. Also, both fly and human hearts experience significant age-related morphological and functional decline. Studies on the fly heart have highlighted the involvement of key nutrient sensing, ion channel and sarcomeric genes in cardiac ageing. Many of these genes have also been implicated in ageing of the mammalian heart. Genes that increase oxidative stress, or are linked to cardiac hypertrophy or neurodegenerative diseases in mammals also affect cardiac ageing in the fruit fly. Moreover, fly studies have demonstrated the potential of exercise and statins to treat age related cardiac disease. These results show the value of Drosophila as a model to discover the genetic causes of human cardiac ageing. PMID- 26060056 TI - Study on the performance of different craniofacial superimposition approaches (I). AB - As part of the scientific tasks coordinated throughout The 'New Methodologies and Protocols of Forensic Identification by Craniofacial Superimposition (MEPROCS)' project, the current study aims to analyse the performance of a diverse set of CFS methodologies and the corresponding technical approaches when dealing with a common dataset of real-world cases. Thus, a multiple-lab study on craniofacial superimposition has been carried out for the first time. In particular, 26 participants from 17 different institutions in 13 countries were asked to deal with 14 identification scenarios, some of them involving the comparison of multiple candidates and unknown skulls. In total, 60 craniofacial superimposition problems divided in two set of females and males. Each participant follow her/his own methodology and employed her/his particular technological means. For each single case they were asked to report the final identification decision (either positive or negative) along with the rationale supporting the decision and at least one image illustrating the overlay/superimposition outcome. This study is expected to provide important insights to better understand the most convenient characteristics of every method included in this study. PMID- 26060057 TI - Deep sequencing of dsRNAs recovered from mosaic-diseased pigeonpea reveals the presence of a novel emaravirus: pigeonpea sterility mosaic virus 2. AB - Deep-sequencing analysis of double-stranded RNA extracted from a mosaic-diseased pigeonpea plant (Cajanus cajan L., family Fabaceae) revealed the complete sequence of six emaravirus-like negative-sense RNA segments of 7009, 2229, 1335, 1491, 1833 and 1194 nucleotides in size. In the order from RNA1 to RNA6, these genomic RNAs contained ORFs coding for the RNA-dependent RNA polymerase (RdRp, p1 of 266 kDa), the glycoprotein precursor (GP, p2 of 74.5 kDa), the nucleocapsid (NC, p3 of 34.9 kDa), and the putative movement protein (MP, p4 of 40.7 kDa), while p5 (55 kDa) and p6 (27 kDa) had unknown functions. All RNA segments showed distant relationships to viruses of the genus Emaravirus, and in particular to pigeonpea sterility mosaic virus (PPSMV), with which they shared nucleotide sequence identity ranging from 48.5 % (RNA3) to 62.5 % (RNA1). In phylogenetic trees constructed from the sequences of the proteins encoded by RNA1, RNA2 and RNA3 (p1, p2 and p3), this new viral entity showed a consistent grouping with fig mosaic virus (FMV) and rose rosette virus (RRV), which formed a cluster of their own, clearly distinct from PPSMV-1. In experimental greenhouse trials, this novel virus was successfully transmitted to pigeonpea and French bean seedlings by the eriophyid mite Aceria cajani. Preliminary surveys conducted in the Hyderabad region (India) showed that the virus in question is widespread in pigeonpea plants affected by sterility mosaic disease (86.4 %) but is absent in symptomless plants. Based on molecular, biological and epidemiological features, this novel virus is the second emaravirus infecting pigeonpea, for which the provisional name pigeonpea sterility mosaic virus 2 (PPSMV-2) is proposed. PMID- 26060058 TI - Association between a naturally arising polymorphism within a functional region of HIV-1 Nef and disease progression in chronic HIV-1 infection. AB - HIV-1 Nef mediates downregulation of HLA class I (HLA-I) through a number of highly conserved sequence motifs. We investigated the in vivo implication(s) of naturally arising polymorphisms in functional motifs in HIV-1 Nef that are associated with HLA-I downregulation, including the acidic cluster, polyproline, di-arginine and Met-20 regions. Plasma samples from treatment-naive, chronically HIV-1 infected subjects were collected after obtaining informed consent, and viral RNA was extracted and amplified by nested RT-PCR. The resultant nef amplicons were sequenced directly, and subtype-B sequences with an intact open reading frame (n = 406) were included in our analyses. There was over representation of isoleucine at position 20 (Ile-20) in our dataset when compared to sequences in the Los Alamos sequence database (17.7 vs. 6.9 %, p = 0.0309). The presence of having Ile-20 in Nef was found to be associated with higher median plasma viral load (p = 0.013), independent of associated codons or viral lineage effects, whereas no clinical association was found with polymorphisms in the other functional motifs. Moreover, introduction of a Met-20-to-Ile mutation in a laboratory strain SF2 Nef resulted in a modest, albeit not statistically significant, increase in HLA class I downregulation activity (p = 0.06). Taken together, we have identified a naturally arising polymorphism, Ile-20, within HIV 1 subtype B Nef that is associated with poorer disease outcome. PMID- 26060059 TI - Role of IL28B genotyping in patients with hepatitis C virus-associated mixed cryoglobulinemia and response to PEG-IFN and ribavirin treatment. AB - The role of interleukin (IL) 28B in the treatment of chronic hepatitis C (CHC) has recently been examined in many studies, while a possible relationship between IL28B and the presence of mixed cryoglobulinemia (MC) remains to be clarified. In this study, we analyzed the influence of IL28B rs8099917/rs12979860 on the presence of MC and the role in treatment with PEG-IFN. We retrospectively examined 541 patients affected by CHC who were treated with pegylated interferon (PEG-IFN) and ribavirin from 2003 to 2012. We included all treatment-naive patients without other viral co-infections or major contraindications to the PEG IFN and ribavirin standard of care. One hundred seventy-five patients (32.3 %) had MC; 49 of these (33.3 %) had symptomatic MC. The IL28B rs8099917/rs12979860 TT/CC genotype was the most frequent in MC-positive patients with sustained virological response (SVR) (p < 0.001), while the TG/TC genotype was most frequent in non-SVR (p < 0.001). The TT/CC genotype was found to be the main positive predictive factor of MC in HCV patients (OR = 11.914; IQR = 7.092 18.776; p < 0.001); HCV genotype 2/3 was the strongest positive predictive factor of SVR (OR = 10.448; IQR = 8.352-21.561; p < 0.001); IL28B rs8099917/rs12979860 TT/CC was a better predictive factor than rs12979860 CC alone (OR = 9.829 vs. 2.663). Negative predictive factors were Metavir score F3-F4 (OR = 0.625; IQR = 0.416-0.779; p = 0.008), insulin-resistance (OR = 0.315; IQR = 0.224-0.585; p < 0.001) and presence of symptoms (OR = 0.716; IQR = 0.492-0.855; p < 0.001). IL28B rs8099917/rs12979860 is useful in the treatment of MC-positive HCV patients with PEG-IFN and ribavirin; the TT/CC genotype is associated with SVR, the TG/TC with non-SVR; TT/CC is also predictive of MC in HCV patients. PMID- 26060060 TI - The effects of different hygiene procedures in reducing bacterial contamination in a model domestic kitchen. AB - AIMS: Few studies have compared the effectiveness of hygienic cleaning under simulated use conditions. This study compares commonly used and novel cleaning methods for food contact and hand contact surfaces in kitchens. METHODS AND RESULTS: We report results from two surveys on Norwegian consumers' cleaning procedures. Laboratory models involving cutting boards, tap handles and mobile phones contaminated with Escherichia coli and Staphylococcus aureus were used to compare the hygiene efficacy of commonly used cleaning methods together with new technologies (sprays, single-use wipes, and chlorine-based disinfectants). Commonly used cleaning methods produced a mean log10 reduction (LR) in contamination of 1.5-2.5. The efficacy could be improved by drying or including a disinfection step (mean LR 3.1-4.6). Cleaning of mobile phones was common and was improved by including humidity (1.5-1.9 mean LR). CONCLUSIONS: In many situations, traditional methods used by consumers may be sufficient to hygienically clean surfaces. However, in some situations, such as where there are infected or immune-compromised individuals, or where high risk foods are being handled, hygiene practices resulting in higher LR should be recommended. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates that data from models simulating use conditions are required to estimate the effectiveness of detergent-based removal practices and how these can be enhanced by inactivation processes such as drying and disinfection to ensure that contamination from food borne pathogens is reduced to acceptable levels to prevent infection transmission. PMID- 26060061 TI - Anatomy of the lymph node venous networks of the groin and their investigation by ultrasonography. AB - OBJECTIVE: To describe the anatomy of the lymph node venous networks of the groin and their assessment by ultrasonography. MATERIAL AND METHODS: Anatomical dissection of 400 limbs in 200 fresh cadavers following latex injection as well as analysis of 100 CT venograms. Routine ultrasound examinations were done in patients with chronic venous disease. RESULTS: Lymph node venous networks were found in either normal subjects or chronic venous disease patients with no history of operation. These networks have three main characteristics: they cross the nodes, are connected to the femoral vein by direct perforators, and join the great saphenous vein and/or anterior accessory great saphenous vein. After groin surgery, lymph node venous networks are commonly seen as a dilated and refluxing network with a dystrophic aspect. We found dilated lymph node venous networks in about 15% of the dissected cadavers. CONCLUSION: It is likely that lymph node venous networks represent remodeling and dystrophic changes of a normal pre existing network rather than neovessels related to angiogenic factors that occur as a result of an inflammatory response to surgery. The so-called neovascularization after surgery could, in a number of cases, actually be the onset of dystrophic lymph node venous networks.Lymph node venous networks are an ever-present anatomical finding in the groin area. Their dilatation as well as the presence of reflux should be ruled out by US examination of the venous system as they represent a contraindication to a groin approach, particularly in recurrent varicose veins after surgery patients. A refluxing lymph node venous network should be treated by echo-guided foam injection. PMID- 26060062 TI - First epidemiological data for venotonics in pregnancy from the EFEMERIS database. AB - OBJECTIVE: There are few published data about possible effects of veinotonics in pregnant women. The present study investigates potential adverse drug reactions of veinotonics in pregnancy. METHOD: EFEMERIS is a database including prescribed and dispensed reimbursed drugs during pregnancy (data from Caisse Primaire d'Assurance Maladie) and outcomes (data from Maternal and Infant Protection Service and Antenatal diagnostic Centre). Women who delivered from 1 July 2004 to December 2007 in Haute-Garonne and were registered in the French Health Insurance Service have been included in the EFEMERIS database. We compared pregnancy outcomes and newborn health between women exposed to veinotonics during pregnancy and unexposed women. RESULTS: We found that 8998 women (24%) had received at least one prescription for venotonic agents during their pregnancy, corresponding to the period of organogenesis in 1200 cases. We compared data for these women with those for the 27,963 women for whom these drugs were not prescribed during pregnancy. The most widely used veinotonics were hesperidin, diosmin and troxerutin. Pregnancies led to 98.4% versus 93.6% of live births, 0.2% versus 0.2% of postnatal deaths and 1.6% versus 6.4% of pregnancy termination (miscarriage, ectopic pregnancy, medical termination, intrauterine death) in exposed and non-exposed groups, respectively. The risks of pregnancy termination (HR = 0.71 (0.60-0.84)) and prematurity (HR = 0.82 (0.73-0.93)) remained significantly lower in the women exposed to venotonics than in unexposed women. In the group of newborns whose mother had a prescription of veinotonics during organogenesis, 39 out of 1200 (3.4%) had a malformation versus 789 (3.0%) in the control group (ORa = 1.134 (0.873-1.472)). The risk of neonatal diseases was not increased by exposure to venotonic agents in the third trimester (4.9% versus 6.1% for the controls, ORa = 1.07 (0.95-1.20)). CONCLUSION: We found no increased risk of adverse pregnancy outcome among women exposed to veinotonics compared with unexposed pregnant women. PMID- 26060063 TI - Clinical evaluation of a computer-aided diagnosis system for determining cancer aggressiveness in prostate MRI. AB - OBJECTIVES: To investigate the added value of computer-aided diagnosis (CAD) on the diagnostic accuracy of PIRADS reporting and the assessment of cancer aggressiveness. METHODS: Multi-parametric MRI and histopathological outcome of MR guided biopsies of a consecutive set of 130 patients were included. All cases were prospectively PIRADS reported and the reported lesions underwent CAD analysis. Logistic regression combined the CAD prediction and radiologist PIRADS score into a combination score. Receiver-operating characteristic (ROC) analysis and Spearman's correlation coefficient were used to assess the diagnostic accuracy and correlation to cancer grade. Evaluation was performed for discriminating benign lesions from cancer and for discriminating indolent from aggressive lesions. RESULTS: In total 141 lesions (107 patients) were included for final analysis. The area-under-the-ROC-curve of the combination score was higher than for the PIRADS score of the radiologist (benign vs. cancer, 0.88 vs. 0.81, p = 0.013 and indolent vs. aggressive, 0.88 vs. 0.78, p < 0.01). The combination score correlated significantly stronger with cancer grade (0.69, p = 0.0014) than the individual CAD system or radiologist (0.54 and 0.58). CONCLUSIONS: Combining CAD prediction and PIRADS into a combination score has the potential to improve diagnostic accuracy. Furthermore, such a combination score has a strong correlation with cancer grade. KEY POINTS: * Computer-aided diagnosis helps radiologists discriminate benign findings from cancer in prostate MRI. * Combining PIRADS and computer-aided diagnosis improves differentiation between indolent and aggressive cancer. * Adding computer-aided diagnosis to PIRADS increases the correlation coefficient with respect to cancer grade. PMID- 26060064 TI - Polymer film-nanoparticle composites as new multimodality, non-migrating breast biopsy markers. AB - OBJECTIVES: To develop a breast biopsy marker that resists fast and slow migration and has permanent visibility under commonly used imaging modalities. METHODS: A polymer-nanoparticle composite film was prepared by embedding superparamagnetic iron oxide nanoparticles and a superelastic Nitinol wire within a flexible polyethylene matrix. MRI, mammography, and ultrasound were used to visualize the marker in agar, ex vivo chicken breast, bovine liver, brisket, and biopsy training phantoms. Fast migration caused by the "accordion effect" was quantified after simulated stereotactic, vacuum-assisted core biopsy/marker placement, and centrifugation was used to simulate accelerated long-term (i.e., slow) migration in ex vivo bovine tissue phantoms. RESULTS: Clear marker visualization under MRI, mammography, and ultrasound was observed. After deployment, the marker partially unfolds to give a geometrically constrained structure preventing fast and slow migration. The marker can be deployed through an 11G introducer without fast migration occurring, and shows substantially less slow migration than conventional markers. CONCLUSION: The polymer-nanoparticle composite biopsy marker is clearly visible on all clinical imaging modalities and does not show substantial migration, which ensures multimodal assessment of the correct spatial information of the biopsy site, allowing for more accurate diagnosis and treatment planning and improved breast cancer patient care. KEY POINTS: Polymer-nanoparticle composite biopsy markers are visualized using ultrasound, MRI, and mammography. Embedded iron oxide nanoparticles provide tuneable contrast for MRI visualization. Permanent ultrasound visibility is achieved with a non-biodegradable polymer having a distinct ultrasound signal. Flexible polymer-based biopsy markers undergo shape change upon deployment to minimize migration. Non-migrating multimodal markers will help improve accuracy of pre/post-treatment planning studies. PMID- 26060065 TI - Improved stability of lipiodol-drug emulsion for transarterial chemoembolisation of hepatocellular carcinoma results in improved pharmacokinetic profile: Proof of concept using idarubicin. AB - OBJECTIVES: To investigate the relationship between the improved stability of an anticancer drug-lipiodol emulsion and pharmacokinetic (PK) profile for transarterial chemoembolisation (TACE) of hepatocellular carcinoma (HCC). METHODS: The stability of four doxorubicin- or idarubicin-lipiodol emulsions was evaluated over 7 days. PK and clinical data were recorded after TACE with the most stable emulsion in eight unresectable HCC patients, after institutional review board approval. RESULTS: The most stable emulsion was the one that combined idarubicin and lipiodol (1:2 v:v). At 7 days, the percentages of aqueous, persisting emulsion and oily phases were 50-0-50, 33-0-67, 31-39-30, and 10-90-0 for the doxorubicin-lipiodol (1:1 v:v), doxorubicin-lipiodol (1:2 v:v), idarubicin-lipiodol (1:1 v:v), and the idarubicin-lipiodol (1:2 v:v) emulsion, respectively. After TACE, mean idarubicin Cmax and AUC0-24h were 12.5 +/- 9.4 ng/mL and 52 +/- 16 ng/mL*h. Within 24 h after injection, 40% of the idarubicin was in the liver, either in vessels, tumours, or hepatocytes. During the 2 months after TACE, no clinical grade >3 adverse events occurred. One complete response, five partial responses, one stabilisation, and one progression were observed at 2 months. CONCLUSION: This study showed a promising and favourable PK and safety profile for the idarubicin-lipiodol (1:2 v:v) emulsion for TACE. KEY POINTS: * Transarterial chemoembolisation (TACE) regimens that improve survival in hepatocellular carcinoma are needed. * Improved emulsion stability for TACE resulted in a favourable pharmacokinetic profile. * Preliminary safety and efficacy data for the idarubicin-lipiodol emulsion for TACE were encouraging. PMID- 26060067 TI - Protein Engineering and Selection Using Yeast Surface Display. AB - Yeast surface display is a powerful technology for engineering a broad range of protein scaffolds. This protocol describes the process for de novo isolation of protein binders from large combinatorial libraries displayed on yeast by using magnetic bead separation followed by flow cytometry-based selection. The biophysical properties of isolated single clones are subsequently characterized, and desired properties are further enhanced through successive rounds of mutagenesis and flow cytometry selections, resulting in protein binders with increased stability, affinity, and specificity for target proteins of interest. PMID- 26060066 TI - MR elastography of the liver at 3.0 T in diagnosing liver fibrosis grades; preliminary clinical experience. AB - OBJECTIVES: To clarify the usefulness of 3.0-T MR elastography (MRE) in diagnosing the histological grades of liver fibrosis using preliminary clinical data. MATERIALS AND METHODS: Between November 2012 and March 2014, MRE was applied to all patients who underwent liver MR study at a 3.0-T clinical unit. Among them, those who had pathological evaluation of liver tissue within 3 months from MR examinations were retrospectively recruited, and the liver stiffness measured by MRE was correlated with histological results. Institutional review board approved this study, waiving informed consent. RESULTS: There were 70 patients who met the inclusion criteria. Liver stiffness showed significant correlation with the pathological grades of liver fibrosis (rho = 0.89, p < 0.0001, Spearman's rank correlation). Areas under the receiver operating characteristic curve were 0.93, 0.95, 0.99 and 0.95 for fibrosis score greater than or equal to F1, F2, F3 and F4, with cut-off values of 3.13, 3.85, 4.28 and 5.38 kPa, respectively. Multivariate analysis suggested that grades of necroinflammation also affected liver stiffness, but to a significantly lesser degree as compared to fibrosis. CONCLUSIONS: 3.0-T clinical MRE was suggested to be sufficiently useful in assessing the grades of liver fibrosis. KEY POINTS: MR elastography may help clinicians assess patients with chronic liver diseases. Usefulness of 3.0-T MR elastography has rarely been reported. Measured liver stiffness correlated well with the histological grades of liver fibrosis. Measured liver stiffness was also affected by necroinflammation, but to a lesser degree. 3.0-T MRE could be a non-invasive alternative to liver biopsy. PMID- 26060068 TI - Isolation and Validation of Anti-B7-H4 scFvs from an Ovarian Cancer scFv Yeast Display Library. AB - B7-H4 (VTCN1, B7x, B7s) is an inhibitory modulator of T-cell response implicated in antigen tolerization. As such, B7-H4 is an immune checkpoint of potential therapeutic interest. To generate anti-B7-H4 targeting reagents, we isolated antibodies by differential cell screening of a yeast-display library of recombinant antibodies (scFvs) derived from ovarian cancer patients and we screened for functional scFvs capable to interfere with B7-H4-mediated inhibition of antitumor responses. We found one antibody binding to B7-H4 that could restore antitumor T cell responses. This chapter gives an overview of the methods we developed to isolate a functional anti-B7-H4 antibody fragment. PMID- 26060069 TI - Combining Phage and Yeast Cell Surface Antibody Display to Identify Novel Cell Type-Selective Internalizing Human Monoclonal Antibodies. AB - Using phage antibody display, large libraries can be generated and screened to identify monoclonal antibodies with affinity for target antigens. However, while library size and diversity is an advantage of the phage display method, there is limited ability to quantitatively enrich for specific binding properties such as affinity. One way of overcoming this limitation is to combine the scale of phage display selections with the flexibility and quantitativeness of FACS-based yeast surface display selections. In this chapter we describe protocols for generating yeast surface antibody display libraries using phage antibody display selection outputs as starting material and FACS-based enrichment of target antigen-binding clones from these libraries. These methods should be widely applicable for the identification of monoclonal antibodies with specific binding properties. PMID- 26060070 TI - Yeast Display-Based Antibody Affinity Maturation Using Detergent-Solubilized Cell Lysates. AB - It is often desired to identify or engineer antibodies that target membrane proteins (MPs). However, due to their inherent insolubility in aqueous solutions, MPs are often incompatible with in vitro antibody discovery and optimization platforms. Recently, we adapted yeast display technology to accommodate detergent solubilized cell lysates as sources of MP antigens. The following protocol details the incorporation of cell lysates into a kinetic screen designed to obtain antibodies with improved affinity via slowed dissociation from an MP antigen. PMID- 26060071 TI - Yeast Endoplasmic Reticulum Sequestration Screening for the Engineering of Proteases from Libraries Expressed in Yeast. AB - There is significant interest in engineering proteases with desired proteolytic properties. We describe a high-throughput fluorescence-activated cell sorting (FACS) assay for detecting altered proteolytic activity of protease in yeast, at the single cell level. This assay relies on coupling yeast endoplasmic reticulum (ER) retention, yeast surface display, and FACS analysis. The method described here allows facile screening of large libraries, and of either protease or substrate variants, including the screening of protease libraries against substrate libraries. We demonstrate the application of this technique in the screening of libraries of Tobacco Etch Virus protease (TEV-P) for altered proteolytic activities. In addition, the generality of this method is also validated by other proteases such as human granzyme K and the hepatitis C virus protease, and the human Abelson tyrosine kinase. PMID- 26060072 TI - T Cell Receptor Engineering and Analysis Using the Yeast Display Platform. AB - The alphabeta heterodimeric T cell receptor (TCR) recognizes peptide antigens that are transported to the cell surface as a complex with a protein encoded by the major histocompatibility complex (MHC). T cells thus evolved a strategy to sense these intracellular antigens, and to respond either by eliminating the antigen-presenting cell (e.g., a virus-infected cell) or by secreting factors that recruit the immune system to the site of the antigen. The central role of the TCR in the binding of antigens as peptide-MHC (pepMHC) ligands has now been studied thoroughly. Interestingly, despite their exquisite sensitivity (e.g., T cell activation by as few as 1-3 pepMHC complexes on a single target cell), TCRs are known to have relatively low affinities for pepMHC, with K D values in the micromolar range. There has been interest in engineering the affinity of TCRs in order to use this class of molecules in ways similar to now done with antibodies. By doing so, it would be possible to harness the potential of TCRs as therapeutics against a much wider array of antigens that include essentially all intracellular targets. To engineer TCRs, and to analyze their binding features more rapidly, we have used a yeast display system as a platform. Expression and engineering of a single-chain form of the TCR, analogous to scFv fragments from antibodies, allow the TCR to be affinity matured with a variety of possible pepMHC ligands. In addition, the yeast display platform allows one to rapidly generate TCR variants with diverse binding affinities and to analyze specificity and affinity without the need for purification of soluble forms of the TCRs. The present chapter describes the methods for engineering and analyzing single-chain TCRs using yeast display. PMID- 26060073 TI - Epitope-Specific Binder Design by Yeast Surface Display. AB - Yeast surface display is commonly used to engineer affinity and design novel molecular interaction. By alternating positive and negative selections, yeast display can be used to engineer binders that specifically interact with the target protein at a defined site. Epitope-specific binders can be useful as inhibitors if they bind the target molecule at functionally important sites. Therefore, an efficient method of engineering epitope specificity should help with the engineering of inhibitors. We describe the use of yeast surface display to design single domain monobodies that bind and inhibit the activity of the kinase Erk-2 by targeting a conserved surface patch involved in protein-protein interaction. The designed binders can be used to disrupt signaling in the cell and investigate Erk-2 function in vivo. The described protocol is general and can be used to design epitope-specific binders of an arbitrary protein. PMID- 26060075 TI - Identification of Novel Protein-Ligand Interactions by Exon Microarray Analysis of Yeast Surface Displayed cDNA Library Selection Outputs. AB - Yeast surface display is widely utilized to screen large libraries for proteins or protein fragments with specific binding properties. We have previously constructed and utilized yeast surface displayed human cDNA libraries to identify protein fragments that bind to various target ligands. Conventional approaches employ monoclonal screening and sequencing of polyclonal outputs that have been enriched for binding to a target molecule by several rounds of affinity-based selection. Frequently, a small number of clones will dominate the selection output, making it difficult to comprehensively identify potentially important interactions due to low representation in the selection output. We have developed a novel method to address this problem. By analyzing selection outputs using high density human exon microarrays, the full potential of selection output diversity can be revealed in one experiment. FACS-based selection using yeast surface displayed human cDNA libraries combined with exon microarray analysis of the selection outputs is a powerful way of rapidly identifying protein fragments with affinity for any soluble ligand that can be fluorescently detected, including small biological molecules and drugs. In this report we present protocols for exon microarray-based analysis of yeast surface display human cDNA library selection outputs. PMID- 26060074 TI - Applications of Yeast Surface Display for Protein Engineering. AB - The method of displaying recombinant proteins on the surface of Saccharomyces cerevisiae via genetic fusion to an abundant cell wall protein, a technology known as yeast surface display, or simply, yeast display, has become a valuable protein engineering tool for a broad spectrum of biotechnology and biomedical applications. This review focuses on the use of yeast display for engineering protein affinity, stability, and enzymatic activity. Strategies and examples for each protein engineering goal are discussed. Additional applications of yeast display are also briefly presented, including protein epitope mapping, identification of protein-protein interactions, and uses of displayed proteins in industry and medicine. PMID- 26060076 TI - Identification of Posttranslational Modification-Dependent Protein Interactions Using Yeast Surface Displayed Human Proteome Libraries. AB - The identification of proteins that interact specifically with posttranslational modifications such as phosphorylation is often necessary to understand cellular signaling pathways. Numerous methods for identifying proteins that interact with posttranslational modifications have been utilized, including affinity-based purification and analysis, protein microarrays, phage display, and tethered catalysis. Although these techniques have been used successfully, each has limitations. Recently, yeast surface-displayed human proteome libraries have been utilized to identify protein fragments with affinity for various target molecules, including phosphorylated peptides. When coupled with fluorescently activated cell sorting and high throughput methods for the analysis of selection outputs, yeast surface-displayed human proteome libraries can rapidly and efficiently identify protein fragments with affinity for any soluble ligand that can be fluorescently detected, including posttranslational modifications. In this review we compare the use of yeast surface display libraries to other methods for the identification of interactions between proteins and posttranslational modifications and discuss future applications of the technology. PMID- 26060078 TI - Enzyme Evolution by Yeast Cell Surface Engineering. AB - Artificial evolution of proteins with the aim of acquiring novel or improved functionality is important for practical applications of the proteins. We have developed yeast cell surface engineering methods (or arming technology) for evolving enzymes. Here, we have described yeast cell surface engineering coupled with in vivo homologous recombination and library screening as a method for the artificial evolution of enzymes such as firefly luciferases. Using this method, novel luciferases with improved substrate specificity and substrate reactivity were engineered. PMID- 26060077 TI - Utilizing Yeast Surface Human Proteome Display Libraries to Identify Small Molecule-Protein Interactions. AB - The identification of proteins that interact with small bioactive molecules is a critical but often difficult and time-consuming step in understanding cellular signaling pathways or molecular mechanisms of drug action. Numerous methods for identifying small molecule-interacting proteins have been developed and utilized, including affinity-based purification followed by mass spectrometry analysis, protein microarrays, phage display, and three-hybrid approaches. Although all these methods have been used successfully, there remains a need for additional techniques for analyzing small molecule-protein interactions. A promising method for identifying small molecule-protein interactions is affinity-based selection of yeast surface-displayed human proteome libraries. Large and diverse libraries displaying human protein fragments on the surface of yeast cells have been constructed and subjected to FACS-based enrichment followed by comprehensive exon microarray-based output analysis to identify protein fragments with affinity for small molecule ligands. In a recent example, a proteome-wide search has been successfully carried out to identify cellular proteins binding to the signaling lipids PtdIns(4,5)P2 and PtdIns(3,4,5)P3. Known phosphatidylinositide-binding proteins such as pleckstrin homology domains were identified, as well as many novel interactions. Intriguingly, many novel nuclear phosphatidylinositide binding proteins were discovered. Although the existence of an independent pool of nuclear phosphatidylinositides has been known about for some time, their functions and mechanism of action remain obscure. Thus, the identification and subsequent study of nuclear phosphatidylinositide-binding proteins is expected to bring new insights to this important biological question. Based on the success with phosphatidylinositides, it is expected that the screening of yeast surface displayed human proteome libraries will be of general use for the discovery of novel small molecule-protein interactions, thus facilitating the study of cellular signaling pathways and mechanisms of drug action or toxicity. PMID- 26060079 TI - Electrochemical Glucose Biosensor Based on Glucose Oxidase Displayed on Yeast Surface. AB - The conventional enzyme-based biosensor requires chemical or physical immobilization of purified enzymes on electrode surface, which often results in loss of enzyme activity and/or fractions immobilized over time. It is also costly. A major advantage of yeast surface display is that it enables the direct utilization of whole cell catalysts with eukaryote-produced proteins being displayed on the cell surface, providing an economic alternative to traditional production of purified enzymes. Herein, we describe the details of the display of glucose oxidase (GOx) on yeast cell surface and its application in the development of electrochemical glucose sensor. In order to achieve a direct electrochemistry of GOx, the entire cell catalyst (yeast-GOx) was immobilized together with multiwalled carbon nanotubes on the electrode, which allowed sensitive and selective glucose detection. PMID- 26060080 TI - Coupling Binding to Catalysis: Using Yeast Cell Surface Display to Select Enzymatic Activities. AB - We find yeast cell surface display can be used to engineer enzymes by selecting the enzyme library for high affinity binding to reaction intermediates. Here we cover key steps of enzyme engineering on the yeast cell surface including library design, construction, and selection based on magnetic and fluorescence-activated cell sorting. PMID- 26060081 TI - The Use of Yeast Surface Display in Biofuel Cells. AB - Biofuel cells are electrochemical devices which convert chemical energy to electricity using biochemical pathways and redox enzymes. In enzymatic fuel cells purified redox enzymes catalyze the reactions in the anode and cathode compartments whereas in microbial fuel cells (MFCs) the entire metabolism of the microorganisms is exploited. Here, a hybrid biofuel cell concept is presented, which is based on yeast surface display (YSD) of redox enzymes to catalyze the different cell reactions. PMID- 26060082 TI - Postprandial effects on arterial stiffness parameters in healthy young adults. AB - Postprandial lipemia has been associated with acute endothelial dysfunction. Endothelial dysfunction, in turn, is associated with increased arterial stiffness. However, the relationship between postprandial lipemia and acute changes in arterial stiffness has not been extensively investigated. Therefore, we conducted a pilot study on the effects of postprandial lipemia on arterial stiffness in 19 healthy young adults before and after consumption of a high-fat mixed meal. Arterial stiffness was assessed locally with echo-tracking carotid arterial strain (CAS) and globally with carotid-femoral pulse wave velocity (PWV). As assessed by these two benchmark parameters, arterial stiffness did not differ significantly postprandially. However, the arterial distension period (ADP) was significantly lower 2 hours after mixed meal ingestion. In addition, slopes of carotid artery area (CAA) curves were significantly steeper postprandially. Therefore, we concluded that ADP may be a more sensitive marker of arterial stiffness in healthy young adults when compared to PWV and CAS. PMID- 26060083 TI - Many paths lead chromatin to the nuclear periphery. AB - It is now well accepted that defined architectural compartments within the cell nucleus can regulate the transcriptional activity of chromosomal domains within their vicinity. However, it is generally unclear how these compartments are formed. The nuclear periphery has received a great deal of attention as a repressive compartment that is implicated in many cellular functions during development and disease. The inner nuclear membrane, the nuclear lamina, and associated proteins compose the nuclear periphery and together they interact with proximal chromatin creating a repressive environment. A new study by Harr et al. identifies specific protein-DNA interactions and epigenetic states necessary to re-position chromatin to the nuclear periphery in a cell-type specific manner. Here, we review concepts in gene positioning within the nucleus and current accepted models of dynamic gene repositioning within the nucleus during differentiation. This study highlights that myriad pathways lead to nuclear organization. PMID- 26060085 TI - Statistical shape model reconstruction with sparse anomalous deformations: Application to intervertebral disc herniation. AB - Many medical image processing techniques rely on accurate shape modeling of anatomical features. The presence of shape abnormalities challenges traditional processing algorithms based on strong morphological priors. In this work, a sparse shape reconstruction from a statistical shape model is presented. It combines the advantages of traditional statistical shape models (defining a 'normal' shape space) and previously presented sparse shape composition (providing localized descriptors of anomalies). The algorithm was incorporated into our image segmentation and classification software. Evaluation was performed on simulated and clinical MRI data from 22 sciatica patients with intervertebral disc herniation, containing 35 herniated and 97 normal discs. Moderate to high correlation (R=0.73) was achieved between simulated and detected herniations. The sparse reconstruction provided novel quantitative features describing the herniation morphology and MRI signal appearance in three dimensions (3D). The proposed descriptors of local disc morphology resulted to the 3D segmentation accuracy of 1.07+/-1.00mm (mean absolute vertex-to-vertex mesh distance over the posterior disc region), and improved the intervertebral disc classification from 0.888 to 0.931 (area under receiver operating curve). The results show that the sparse shape reconstruction may improve computer-aided diagnosis of pathological conditions presenting local morphological alterations, as seen in intervertebral disc herniation. PMID- 26060084 TI - Lanthanum Chloride Attenuates Osteoclast Formation and Function Via the Downregulation of Rankl-Induced Nf-kappab and Nfatc1 Activities. AB - The biological activities of lanthanum chloride (LaCl3 ) and the molecular mechanisms of action underlying its anti-inflammatory, anti-hyperphosphatemic, and osteoblast-enhancing effects have been studied previously, but less is known about the effects of LaCl3 on osteoclasts. The present study used in vivo and in vitro approaches to explore the effects of LaCl3 on osteoclasts and osteolysis. The results indicated that LaCl3 concentrations that were non-cytotoxic to mouse bone marrow-derived monocytes attenuated receptor activator of nuclear factor kappaB ligand (RANKL)-stimulated osteoclastogenesis, bone resorption, mRNA expression of osteoclastogenic genes in these cells, including cathepsin K, calcitonin receptor, and tartrate-resistant acid phosphatase (TRAP). Further, LaCl3 inhibited RANKL-mediated activation of the nuclear factor-kappaB (NF kappaB) signaling pathway, and downregulated mRNA and protein levels of nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NFATc1), and c fos. In vivo, LaCl3 attenuated titanium (Ti) particle-induced bone loss in a murine calvarial osteolysis model. Histological analyses revealed that LaCl3 ameliorated bone destruction and decreased the number of TRAP-positive osteoclasts in this model. These results demonstrated that LaCl3 inhibited osteoclast formation, function, and osteoclast-specific gene expression in vitro, and attenuated Ti particle-induced mouse calvarial osteolysis in vivo, where the inhibition of NF-kappaB signaling and downregulation of NFATc1 and c-fos played an important role. PMID- 26060086 TI - How to overcome a scary complication: a mesh-trapped balloon during a CoreValve implantation procedure. PMID- 26060087 TI - Final results of a self-apposing paclitaxel-eluting stent fOr the PErcutaNeous treatment of de novo lesions in native bifurcated coronary arteries study. AB - AIMS: We aimed to evaluate the long-term safety and efficacy of the STENTYS self apposing paclitaxeleluting stent (STENTYS-PES) in bifurcation lesions in routine clinical practice. METHODS AND RESULTS: The primary endpoint of the study was the composite major adverse cardiac events (MACE: cardiac death, myocardial infarction, clinically driven target lesion revascularisation, or emergent bypass surgery) assessed at six months after enrolment. This was reported in 21 patients (10.1%), mainly due to clinically driven target lesion revascularisation (TLR). At 12 months, 27 patients experienced MACE (13.0%). CONCLUSIONS: The long-term results of OPEN II show that the STENTYS-PES is safe and effective in the treatment of all-comers with coronary bifurcation lesions. PMID- 26060088 TI - The aetiology of paediatric bloodstream infections changes after pneumococcal vaccination and group B streptococcus prophylaxis. AB - AIM: This study explored the incidence and aetiology of bloodstream infections after patients received the pneumococcal conjugate vaccination and a risk-based intrapartum antibiotic prophylaxis against early onset sepsis caused by group B streptococcus. We also monitored clinically relevant antimicrobial resistance. METHOD: We studied 3986 positive blood cultures from children up to 17 years of age at a paediatric hospital in Stockholm, Sweden, using data from medical records before and after the initiatives, to reduce early onset sepsis, were introduced in 2007 and 2008. RESULTS: Bloodstream infections caused by Streptococcus pneumoniae declined by 42% overall (5.6 to 3.2/100 000) and by 62% in previously healthy children under 36 months of age (24.2 to 9.2/100 000). Early onset sepsis caused by group B streptococcus declined by 60% (0.5 to 0.2/1000 live born children). Bacterial meningitis caused by these bacteria decreased by 70%. Staphylococcus aureus and various Gram-negative bacteria became the dominant pathogens, in both previously healthy children and those with underlying disease. Overall, antimicrobial resistance remained low between the two 5-year study periods. CONCLUSION: Pneumococcal conjugate vaccination and risk based intrapartum antibiotic prophylaxis against group B streptococcus effectively decreased the incidence of bloodstream infections. Empirical antibiotic therapy should target Staphylococcus aureus in both community and hospital-acquired invasive bacterial infections. PMID- 26060089 TI - MicroRNA profiles in cisplatin-induced apoptosis of hepatocellular carcinoma cells. AB - Cisplatin [cis-diamminedichloroplatinum (II)], is a platinum coordination compound that is commonly used to treat hepatocellular carcinoma (HCC). It is also one of the most compelling anticancer drugs. Recent studies suggest that cisplatin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of cisplatin in several types of cancers, including HCC, has not been elucidated. The goal of the present study was to evaluate the effects of cisplatin on the proliferation of HCC cells in vitro and to determine which microRNAs (miRNAs) are associated with the anticancer effects of cisplatin in vitro. We used various human HCC-derived cell lines to study the effects of cisplatin on human HCC cells. Cisplatin led to a strong dose- and time- dependent inhibition of cell proliferation in HLE, HLF, HuH7, Li-7, Hep3B and HepG2 cells in vitro. Cisplatin also blocked the progression of the cell cycle in the G0/G1 phase, which inhibited cyclin D1 and induced apoptosis. In addition, miRNA expression was markedly altered by treatment with cisplatin in vitro. Therefore, various miRNAs induced by cisplatin may also contribute to the suppression of cellular proliferation and apoptosis. Our results demonstrate that cisplatin inhibits the growth of HCC, possibly through the induction of G1 cell cycle arrest and apoptosis through the alteration of microRNA expression. PMID- 26060091 TI - Surgery for low grade ductal carcinoma in situ does not improve survival, study finds. PMID- 26060090 TI - Heat shock protein 60 levels in tissue and circulating exosomes in human large bowel cancer before and after ablative surgery. AB - BACKGROUND: Heat shock protein 60 (Hsp60) is a chaperonin involved in tumorigenesis, but its participation in tumor development and progression is not well understood and its value as a tumor biomarker has not been fully elucidated. In the current study, the authors presented evidence supporting the theory that Hsp60 has potential as a biomarker as well as a therapeutic target in patients with large bowel cancer. METHODS: The authors studied a population of 97 subjects, including patients and controls. Immunomorphology, Western blot analysis, and quantitative real-time polymerase chain reaction were performed on tissue specimens. Exosomes were isolated from blood and characterized by electron microscopy, biochemical tests, and Western blot analysis. RESULTS: Hsp60 was found to be increased in cancerous tissue, in which it was localized in the tumor cell plasma membrane, and in the interstitium associated with cells of the immune system, in which it was associated with exosomes liberated by tumor cells and, as such, circulated in the blood. An interesting finding was that these parameters returned to normal shortly after tumor removal. CONCLUSIONS: The data from the current study suggested that Hsp60 is a good candidate for theranostics applied to patients with large bowel carcinoma and encourage similar research among patients with other tumors in which Hsp60 has been implicated. PMID- 26060092 TI - Higher rate of fat oxidation during rowing compared with cycling ergometer exercise across a range of exercise intensities. AB - The relative contribution of carbohydrate and fat oxidation to energy expenditure during exercise is dependent on variables including exercise intensity, mode, and recruited muscle mass. This study investigated patterns of substrate utilization during two non-weightbearing exercise modalities, namely cycling and rowing. Thirteen young, moderately trained males performed a continuous incremental (3 min stages) exercise test to exhaustion on separate occasions on an electronically braked cycle (CYC) ergometer and an air-braked rowing (ROW) ergometer, respectively. On two further occasions, participants performed a 20 min steady-state exercise bout at ~50%VO2peak on the respective modalities. Despite similar oxygen consumption, rates of fat oxidation (FATox ) were ~45% higher during ROW compared with CYC (P < 0.05) across a range of power output increments. The crossover point for substrate utilization occurred at a higher relative exercise intensity for ROW than CYC (57.8 +/- 2.1 vs 42.1 +/- 3.6%VO2peak , P < 0.05). During steady-state submaximal exercise, the higher FATox during ROW compared with CYC was maintained (P < 0.05), but absolute FATox were 42% (CYC) and 28% (ROW) lower than during incremental exercise. FATox is higher during ROW compared with CYC exercise across a range of exercise intensities matched for energy expenditure, and is likely as a consequence of larger muscle mass recruited during ROW. PMID- 26060093 TI - Classification of hemopericardium on postmortem CT. AB - Postmortem CT (PMCT) is increasingly used in forensic practice, and knowledge and classification of typical hemopericardium on PMCT would help to assure correct radiological interpretation. The goal of this study was to evaluate the pericardial and pleural space fluid volumetry, and to evaluate the signs on PMCT pointing to cardiac tamponade as the cause of death, and their pitfalls. Fourteen cadavers (eleven male, three female, 49-87 [mean, 70.9] years) were examined by PMCT. The pericardial volume and pericardial findings with/without pleural space fluid collection were compared with autopsy findings. In addition, the appearance of pericardial lesions on PMCT was documented and compared with the autopsy findings. The respective volumes of pericardial space, and right and left pleural space fluid showed as 172.0-711.0 (mean 368.7) ml, 0-1830.0 (266.1) ml, 0-231.0 (75.2) ml on PMCT, and were 136.0-652.0 (311.1) ml, 0-2100 (299.0) ml, and 0 300.0 (61.3) ml on autopsy. In statistical evaluation, the pericardial space volume was significantly greater on PMCT (p<0.05), but there was no significant difference in pleural space fluid volume. The hemopericardium PMCT showed 3 patterns: double band, single band, and horizontal level, and the former two patterns presented as coagulated blood at autopsy. Single band and horizontal level patterns were thought to result from CPR-related causes and/or postmortem manipulation. In conclusion, double and single band patterns on PMCT were indicative findings of cardiac tamponade. An understanding of the pericardial PMCT appearance and its significance can help to avoid misreading, and is important for making correct radiological interpretation. PMID- 26060095 TI - Versatile control of metal-assisted chemical etching for vertical silicon microwire arrays and their photovoltaic applications. AB - A systematic study was conducted into the use of metal-assisted chemical etching (MacEtch) to fabricate vertical Si microwire arrays, with several models being studied for the efficient redox reaction of reactants with silicon through a metal catalyst by varying such parameters as the thickness and morphology of the metal film. By optimizing the MacEtch conditions, high-quality vertical Si microwires were successfully fabricated with lengths of up to 23.2 MUm, which, when applied in a solar cell, achieved a conversion efficiency of up to 13.0%. These solar cells also exhibited an open-circuit voltage of 547.7 mV, a short circuit current density of 33.2 mA/cm(2), and a fill factor of 71.3% by virtue of the enhanced light absorption and effective carrier collection provided by the Si microwires. The use of MacEtch to fabricate high-quality Si microwires therefore presents a unique opportunity to develop cost-effective and highly efficient solar cells. PMID- 26060094 TI - Multiscale Predictors of Femoral Neck In Situ Strength in Aging Women: Contributions of BMD, Cortical Porosity, Reference Point Indentation, and Nonenzymatic Glycation. AB - The diagnosis of fracture risk relies almost solely on quantifying bone mass, yet bone strength is governed by factors at multiple scales including composition and structure that contribute to fracture resistance. Furthermore, aging and conditions such as diabetes mellitus alter fracture incidence independently of bone mass. Therefore, it is critical to incorporate other factors that contribute to bone strength in order to improve diagnostic specificity of fracture risk. We examined the correlation between femoral neck fracture strength in aging female cadavers and areal bone mineral density, along with other clinically accessible measures of bone quality including whole-bone cortical porosity (Ct.Po), bone material mechanical behavior measured by reference point indentation (RPI), and accumulation of advanced glycation end-products (AGEs). All measurements were found to be significant predictors of femoral neck fracture strength, with areal bone mineral density (aBMD) being the single strongest correlate (aBMD: r = 0.755, p < 0.001; Ct.Po: r = -0.500, p < 0.001; RPI: r = -0.478, p < 0.001; AGEs: r = -0.336, p = 0.016). RPI-derived measurements were not correlated with tissue mineral density or local cortical porosity as confirmed by micro-computed tomography (MUCT). Multiple reverse stepwise regression revealed that the inclusion of aBMD and any other factor significantly improve the prediction of bone strength over univariate predictions. Combining bone assays at multiple scales such as aBMD with tibial Ct.Po (r = 0.835; p < 0.001), tibial difference in indentation depth between the first and 20th cycle (IDI) (r = 0.883; p < 0.001), or tibial AGEs (r = 0.822; p < 0.001) significantly improves the prediction of femoral neck strength over any factor alone, suggesting that this personalized approach could greatly enhance bone strength and fracture risk assessment with the potential to guide clinical management strategies for at-risk populations. PMID- 26060096 TI - Anaesthetic management for balloon dilation of cor triatriatum dexter in a dog. AB - A three-month-old female Rottweiler puppy was referred for intravascular correction of a previously identified cor triatriatum dexter. Echocardiography confirmed the presence of a hyperechoic membrane that divided the right atrium into a cranial and caudal chamber. A foramen in this membrane allowed the blood to flow from the caudal to the cranial chamber. Balloon dilation of the defect under transthoracic echocardiographic guidance was scheduled for the following day. The dog was premedicated with 0.5 MUg/kg sufentanil and 0.2 mg/kg midazolam administered intravenously. General anaesthesia was induced with 2 mg/kg propofol and maintained with inhaled isoflurane in oxygen; at the same time, a constant rate infusion of 0.5 MUg/kg/h sufentanil was administered by means of an infusion pump. Uneventful ventricular and supraventricular tachyarrhythmias developed during the placement of catheters and balloon dilation. At the end of procedure, when the guide wire and balloon catheter were removed, normal sinus rhythm was observed. To the authors' knowledge, no previous reports have described the anaesthetic management of a balloon dilation procedure for cor triatriatum dexter in dogs. PMID- 26060097 TI - Array of piezoelectric lateral electric field excited resonators. AB - An array containing two resonators placed on X-cut lithium niobate plate has been experimentally investigated. The resonator's lateral electric field was directed along the Y-crystallographic axis. It has been shown that stable resonance exists for a longitudinal acoustic wave propagating along the X-axis in the area between the electrodes. A layer of special damping coating was deposited around the resonators and on the part of electrodes to suppress parasitic oscillations induced mainly by Lamb waves. Frequency dependences of the real and imaginary parts of electric impedance/admittance were measured for every resonator to find resonant frequency and Q-factor with series and parallel resonances. The optimal values of width of electrode coating for every resonator were revealed which provide good resonance quality. The measurements of parameter S12, which characterizes a degree of acoustical coupling between the resonators, have shown its value to be higher than 50dB in the absolute value in all the cases considered. This means that the resonators under study are entirely acoustically decoupled. Thus it has been demonstrated that the damping layer not only provides a sufficiently good quality of every resonator's resonance, but it also assures their entire acoustical decoupling. PMID- 26060098 TI - From Birds to Bacteria: Generalised Velocity Jump Processes with Resting States. AB - There are various cases of animal movement where behaviour broadly switches between two modes of operation, corresponding to a long-distance movement state and a resting or local movement state. Here, a mathematical description of this process is formulated, adapted from Friedrich et al. (Phys Rev E, 74:041103, 2006b). The approach allows the specification any running or waiting time distribution along with any angular and speed distributions. The resulting system of integro-partial differential equations is tumultuous, and therefore, it is necessary to both simplify and derive summary statistics. An expression for the mean squared displacement is derived, which shows good agreement with experimental data from the bacterium Escherichia coli and the gull Larus fuscus. Finally, a large time diffusive approximation is considered via a Cattaneo approximation (Hillen in Discrete Continuous Dyn Syst Ser B, 5:299-318, 2003). This leads to the novel result that the effective diffusion constant is dependent on the mean and variance of the running time distribution but only on the mean of the waiting time distribution. PMID- 26060099 TI - Applying User Input to the Design and Testing of an Electronic Behavioral Health Information System for Wraparound Care Coordination. AB - Health information technology (HIT) and care coordination for individuals with complex needs are high priorities for quality improvement in health care. However, there is little empirical guidance about how best to design electronic health record systems and related technologies to facilitate implementation of care coordination models in behavioral health, or how best to apply user input to the design and testing process. In this paper, we describe an iterative development process that incorporated user/stakeholder perspectives at multiple points and resulted in an electronic behavioral health information system (EBHIS) specific to the wraparound care coordination model for youth with serious emotional and behavioral disorders. First, we review foundational HIT research on how EBHIS can enhance efficiency and outcomes of wraparound that was used to inform development. After describing the rationale for and functions of a prototype EBHIS for wraparound, we describe methods and results for a series of six small studies that informed system development across four phases of effort predevelopment, development, initial user testing, and commercialization-and discuss how these results informed system design and refinement. Finally, we present next steps, challenges to dissemination, and guidance for others aiming to develop specialized behavioral health HIT. The research team's experiences reinforce the opportunity presented by EBHIS to improve care coordination for populations with complex needs, while also pointing to a litany of barriers and challenges to be overcome to implement such technologies. PMID- 26060100 TI - The Leukemia Inhibitory Factor Receptor Gene Is a Direct Target of RUNX1. AB - Activation of cytokine signaling via the leukemia inhibitory factor receptor (LIFR) plays an integral role in hematopoiesis, osteogenesis, and placental development, along with mediating neurotrophic mechanisms. However, the regulatory control of the LIFR gene has remained largely unexplored. Here, we characterize the LIFR gene as a novel target of the RUNX1 transcription factor. The RUNX1 transcription factor is an essential regulator of hematopoiesis and is a frequent target of point mutations and chromosomal alterations in leukemia. RUNX1 regulates hematopoiesis through its control of genes important for hematopoietic cell growth, proliferation, and differentiation, including a number of cytokines and cytokine receptors. LIFR is regulated by two alternate promoters: a placental-specific and a ubiquitously active general promoter. We show that both of these promoters are regulated by RUNX1. However, in myeloid cells LIFR expression is driven solely by the general LIFR promoter with our data indicating that the placental promoter is epigenetically silenced in these cells. While RUNX1 activates the LIFR general promoter, the oncogenic RUNX1-ETO fusion protein generated by the t(8;21) translocation commonly associated with acute myeloid leukemia represses promoter activity. The data presented here establish LIFR as a transcriptional target of RUNX1 and suggest that disruption of RUNX1 activity in myeloid cells may result in altered LIFR signaling in these cells. PMID- 26060101 TI - Palladium(II)-Catalyzed meta-C-H Olefination: Constructing Multisubstituted Arenes through Homo-Diolefination and Sequential Hetero-Diolefination. AB - Divinylbenzene derivatives represent an important class of molecular building blocks in organic chemistry and materials science. Reported herein is the palladium-catalyzed synthesis of divinylbenzenes by meta-C-H olefination of sulfone-based arenes. Successful sequential olefinations in a position-selective manner provided a novel route for the synthesis of hetero-dialkenylated products, which are difficult to access using conventional methods. Additionally, 1,3,5 trialkenylated compounds can be generated upon successful removal of the directing group. PMID- 26060102 TI - Preface. PMID- 26060103 TI - Celiac disease from a global perspective. AB - Celiac disease (CD) is one of the commonest lifelong disorders in countries populated by individuals of European origin, affecting approximately 1% of the general population. This is a common disease also in North Africa, Middle East and India. The widespread diffusion of CD is not surprising given that its causal factors (HLA predisposing genotypes and consumption of gluten-containing cereals) show a worldwide distribution. Further studies are needed to quantify the incidence of CD in apparently "celiac-free" areas such as Sub-Saharan Africa and Far East. Several reports have shown that CD is increasing in frequency in different geographic areas. Genetic factors do not explain the rising incidence during the last decades; environmental or lifestyle factors may be responsible for these changes over time. The majority of patients with CD are still undiagnosed all over the world, leading to debate about the need of screening program. PMID- 26060104 TI - Adaptive diagnosis of coeliac disease. AB - Coeliac disease has for a long time simply been regarded as a gluten-dependent enteropathy and a duodenal biopsy was required in all patients for the diagnosis. It is now accepted that autoimmunity against transglutaminase 2 is an earlier, more universal and more specific feature of coeliac disease than histologic lesions. Moreover, high serum levels of combined anti-transglutaminase 2 and anti endomysium antibody positivity have excellent predictive value for the presence of enteropathy with villous atrophy. This makes the histology evaluation of the gut no longer necessary in well defined symptomatic paediatric patients with compatible HLA-DQ2 and/or DQ8 background. The biopsy-sparing diagnostic route is not yet recommended by gastroenterologists for adults, and certain clinical circumstances (immunodeficiency conditions, extraintestinal manifestations, type 1 diabetes mellitus, age less than 2 years) may require modified diagnostic approaches. Coeliac patients with preserved duodenal villous structure do exist and these need a more extended evaluation by immunologic and molecular biology tools. PMID- 26060105 TI - Genetics of celiac disease. AB - New insights into the underlying molecular pathophysiology of celiac disease (CeD) over the last few years have been guided by major advances in the fields of genetics and genomics. The development and use of the Immunochip genotyping platform paved the way for the discovery of 39 non-HLA loci associated to CeD, and for follow-up functional genomics studies that pinpointed new disease genes, biological pathways and regulatory elements. By combining information from genetics with gene expression data, it has become clear that CeD is a disease with a dysregulated immune response, which can probably occur in a variety of immune cells. This type of information is crucial for our understanding of the disease and for providing leads for developing alternative therapies to the current gluten-free diet. In this review, we place these genetic findings in a wider context and suggest how they can assist the clinical care of CeD patients. PMID- 26060106 TI - T-cell and B-cell immunity in celiac disease. AB - Celiac disease is an inflammatory disorder with leukocyte infiltration and changes of tissue architecture of the small intestine. The condition develops in genetically susceptible individuals as the result of an inappropriate immune response to gluten proteins of wheat, barley and rye. The clinical manifestations and the histological changes normalize when gluten is eliminated from the diet. CD4(+) T cells that recognize gluten peptides bound to predisposing HLA-DQ molecules play a key role in the pathogenesis. These T cells recognize better gluten peptides that are deamidated, and this posttranslational modification is mediated by the enzyme transglutaminase 2 (TG2). Another hallmark of celiac disease is the production of antibodies to gluten as well as to TG2. A role for B cells in celiac disease pathogenesis is receiving increased recognition. This review will discuss the main discoveries in the field of T-cell and B-cell biology of celiac disease. PMID- 26060107 TI - Innate immunity: actuating the gears of celiac disease pathogenesis. AB - Celiac disease is a T cell mediated immune disorder characterized by the loss of oral tolerance to dietary gluten and the licensing of intraepithelial lymphocytes to kill intestinal epithelial cells, leading to villous atrophy. Innate immunity plays a critical role in both of these processes and cytokines such as interleukin-15 and interferon-alpha can modulate innate processes such as polarization of dendritic cells as well as intraepithelial lymphocyte function. These cytokines can be modulated by host microbiota, which can also influence dendritic cell function and intraepithelial lymphocyte homeostasis. We will elaborate on the role of interleukin-15, interferon-alpha, and the microbiota in modulating the processes that lead to loss of tolerance to gluten and tissue destruction in celiac disease. PMID- 26060108 TI - The role of animal models in unravelling therapeutic targets in coeliac disease. AB - Coeliac disease is a complex small intestinal enteropathy that develops consequently to a breach of tolerance to gliadin, a storage protein abundantly found in cereals such as wheat, rye and barley. The understanding of the mechanisms underlying the development of coeliac disease in HLA-DQ2 and HLA-DQ8 genetically susceptible individuals has greatly improved during the last decades but so far did not allow to develop curative therapeutics, leaving a long-life gluten free diet as the only treatment option for the patients. In order to bring new therapeutic targets to light and to test the safety and efficacy of putative drugs, animal models recapitulating features of the disease are needed. Here, we will review the existing animal models and the clinical features of coeliac disease they reflect and discuss their relevance for modelling immune pathways that may lead to potential therapeutic approaches. PMID- 26060109 TI - Complications of coeliac disease. AB - Within the past 20 years the spectrum of complications of coeliac disease (CD) has been considerably extended. Besides the classic complications, autoimmune diseases and osteopenia, numerous forms of CD non-responsive to a gluten-free diet have been recently identified. Among the non-responsive CD, the majority of patients presents as long term responders. However a small subset of CD patients becomes refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy. Whereas refractory coeliac disease type I (RCDI) is hardly distinguishable from active CD, the type II (RCDII) has a severe clinical presentation and a very poor prognosis. Enteropathy Associated T cell Lymphoma (EATL) is even more aggressive with a five year survival of 20%. Classic adriamycin-based chemotherapy is poorly efficient in the lymphomatous complications of CD and current therapeutic strategies focus on more intensive regimen with autologous or allogenic stem cell transplantation. Notable pathogenic advances let us to test targeted therapy both in low (RCDII) and high grade lymphomatous (EATL) complications associated with CD. PMID- 26060110 TI - Preventing complications in celiac disease: our experience with managing adult celiac disease. AB - Celiac disease is, as we know it, rather than being a rare and incurable disease until the 1950's, both quite common in screening studies and readily treatable. Three conditions are triggered by gluten consumption: celiac disease, the skin rash dermatitis herpetiformis and gluten ataxia. We describe our follow up for out clinic management, as evidence based data about such an approach are lacking in current literature. No food, beverages or medications containing any amount of gluten can be taken. Compliance is often difficult especially when patients are asymptomatic. We control a cohort, in daily practice, of over 700 adult patients. The majority of patients manage the diet without any problems. We describe our follow up in general, for serology, laboratory and histology. Forty percent of our newly diagnosed celiac patients do have a BMI over 25 kg/m(2). An appropriate attitude for this problem is lacking. The problem of slowly weaning off Dapsone over 5-10 years in DH is recognized. The bone density is checked in all newly diagnosed celiac patients. We control, if necessary, by telephone and lab controls done in local cities and see our patients only every two years face-to face for follow up. The main question is if the adherence to a GFD, quality of life and prevention of complications is improved by visiting a dedicated celiac clinic. We hope to standardize this attitude on evidence data in the years to come. PMID- 26060111 TI - Non-celiac wheat sensitivity: differential diagnosis, triggers and implications. AB - Non allergy-non-celiac wheat sensitivity (NCWS) has become a common and often overrated diagnosis. Skepticism mainly relates to patients with prominent intestinal symptoms in the absence of general or intestinal signs of inflammation. There is consensus that the major wheat sensitivities, celiac disease and wheat allergy, have to be ruled out which may be difficult for wheat allergy. The non-inflammatory intolerances to carbohydrates, mainly lactose and FODMAPs (fermentable oligi-, di-, monosaccharides and polyols), which cause bloating or diarrhoea, can usually be excluded clinically or by simple tests. Recent studies and experimental data strongly indicate that NCWS exists in a substantial proportion of the population, that it is an innate immune reaction to wheat and that patients often present with extraintestinal symptoms, such as worsening of an underlying inflammatory disease in clear association with wheat consumption. Wheat amylase-trypsin inhibitors (ATIs) have been identified as the most likely triggers of NCWS. They are highly protease resistant and activate the toll-like receptor 4 (TLR4) complex in monocytes, macrophages and dendritic cells of the intestinal mucosa. Non-gluten containing cereals or staples display no or little TLR4 stimulating activity. Wheat ATIs are a family of up to 17 similar proteins of molecular weights around 15 kD and represent 2-4% of the wheat protein. With oral ingestion they costimulate antigen presenting cells and promote T cell activation in celiac disease, but also in other immune-mediated diseases within and outside the GI tract. PMID- 26060112 TI - Non-celiac gluten sensitivity: a work-in-progress entity in the spectrum of wheat related disorders. AB - Non-celiac gluten sensitivity is an undefined syndrome with gastrointestinal and extra-intestinal manifestations triggered by gluten in patients without celiac disease and wheat allergy. The pathogenesis involves immune-mediated mechanisms requiring further research. Symptoms disappear in a few hours or days after gluten withdrawal and recur rapidly after gluten ingestion. Besides gluten, other wheat proteins as well as fermentable oligo-, di-, mono-saccharides and polyols (FODMAPs) may contribute to this syndrome. This syndrome occurs mainly in young women, being rare in children. Its prevalence ranges from 0.6% to 6%, based on primary or tertiary care center estimates. No biomarker is available, but half of patients tests positive for IgG anti-gliadin antibodies, which disappear quickly after gluten-free diet together with symptoms. Also, genetic markers are still undefined. Although currently limited to a research setting, double-blind, placebo-controlled, cross-over trial strategy is recommended to confirm the diagnosis. Treatment is based on dietary restriction with special care to nutrient intake. PMID- 26060113 TI - The prevention of coeliac disease. AB - Primary prevention of coeliac disease is currently not possible. Previously, a 'window of opportunity' was suggested for primary prevention, by introducing gluten between four and six months of age. However, results from recent prospective studies establish that the timing of gluten introduction and the duration or maintenance of breastfeeding do not influence the development of the disease. Secondary prevention is possible through early diagnosis and treatment. Since coeliac disease is severely underdiagnosed, the only way to achieve large scale secondary prevention is by mass screening. Prospective studies indicate that important health problems, such as reduced foetal growth and birth weight, delayed growth in height and weight in children, and reduced bone mineral density in both children and adults can be prevented by mass screening. Adherence to a strict gluten-free diet may be considered as tertiary prevention. PMID- 26060115 TI - Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes. AB - Predicting evolutionary paths to antibiotic resistance is key for understanding and controlling drug resistance. When considering a single final resistant genotype, epistatic contingencies among mutations restrict evolution to a small number of adaptive paths. Less attention has been given to multi-peak landscapes, and while specific peaks can be favoured, it is unknown whether and how early a commitment to final fate is made. Here we characterize a multi-peaked adaptive landscape for trimethoprim resistance by constructing all combinatorial alleles of seven resistance-conferring mutations in dihydrofolate reductase. We observe that epistatic interactions increase rather than decrease the accessibility of each peak; while they restrict the number of direct paths, they generate more indirect paths, where mutations are adaptively gained and later adaptively lost or changed. This enhanced accessibility allows evolution to proceed through many adaptive steps while delaying commitment to genotypic fate, hindering our ability to predict or control evolutionary outcomes. PMID- 26060114 TI - Therapeutic approaches for celiac disease. AB - Celiac disease is a common, lifelong autoimmune disorder for which dietary control is the only accepted form of therapy. A strict gluten-free diet is burdensome to patients and can be limited in efficacy, indicating there is an unmet need for novel therapeutic approaches to supplement or supplant dietary therapy. Many molecular events required for disease pathogenesis have been recently characterized and inspire most current and emerging drug-discovery efforts. Genome-wide association studies (GWAS) confirm the importance of human leukocyte antigen genes in our pathogenic model and identify a number of new risk loci in this complex disease. Here, we review the status of both emerging and potential therapeutic strategies in the context of disease pathophysiology. We conclude with a discussion of how genes identified during GWAS and follow-up studies that enhance susceptibility may offer insight into developing novel therapies. PMID- 26060117 TI - Declining trends in acute myocardial infarction attack and mortality rates, celebrating progress and ensuring future success. PMID- 26060116 TI - Ectopic clustering of Cajal-Retzius and subplate cells is an initial pathological feature in Pomgnt2-knockout mice, a model of dystroglycanopathy. AB - Aberrant glycosylation of dystroglycan causes congenital muscular dystrophies associated with cobblestone lissencephaly, classified as dystroglycanopathy. However, pathological features in the onset of brain malformations, including the precise timing and primary cause of the pial basement membrane disruption and abnormalities in the migration of pyramidal neurons, remain unexplored. Using the Pomgnt2-knockout (KO) mouse as a dystroglycanopathy model, we show that breaches of the pial basement membrane appeared at embryonic day 11.5, coinciding with the ectopic clustering of Cajal-Retzius cells and subplate neurons and prior to the migration onset of pyramidal neurons. Furthermore, in the Pomgnt2-KO cerebral cortex, preplate splitting failure likely occurred due to the aggregation of Cajal-Retzius and subplate cells, and migrating pyramidal neurons lost polarity and radial orientation. Our findings demonstrate the initial pathological events in dystroglycanopathy mice and contribute to our understanding of how dystroglycan dysfunction affects brain development and progresses to cobblestone lissencephaly. PMID- 26060118 TI - Palpitations in a 46-year-old man. PMID- 26060119 TI - A 42-year-old woman collapses in a park. PMID- 26060120 TI - Myocardial fibrosis on cardiac magnetic resonance and cardiac outcomes in hypertrophic cardiomyopathy: a meta-analysis. AB - OBJECTIVE: Late gadolinium enhancement (LGE) on cardiac MRI that indicates the extent of myocardial fibrosis in hypertrophic cardiomyopathy (HCM) is a potential risk factor of sudden cardiac death (SCD) in non-high-risk patients according to conventional clinical markers. METHODS: The present study was designed to systematically review prospective trials and assess the association between LGE and SCD in HCM. We systematically searched the electronic databases, MEDLINE, PubMed, Embase and Cochrane for prospective cohort studies of the effects of LGE on clinical outcomes (SCD/aborted SCD, all-cause mortality, cardiac and heart failure death) in HCM. RESULTS: We identified six clinical studies, examining 1414 patients without LGE and 1653 with LGE and an average follow-up of 3.05 years. The incidence of SCD/aborted SCD in patients with HCM and LGE was significantly increased as compared with patients without LGE (OR 2.52, 95% CI 1.44 to 4.4, p=0.001). The all-cause mortality and cardiac death rates were also significantly increased in patients with LGE. The extent of LGE was not significantly related to the risk of SCD. CONCLUSIONS: LGE is significantly associated with SCD risk, cardiac mortality and all-cause mortality in patients with non-high-risk HCM according to conventional risk factors. PMID- 26060121 TI - Clinical impact and evolution of mitral regurgitation following transcatheter aortic valve replacement: a meta-analysis. AB - OBJECTIVES: Mitral regurgitation (MR) is a common entity in patients with aortic stenosis undergoing transcatheter aortic valve replacement (TAVR), but its influence on outcomes remains controversial. The purpose of this meta-analysis was to assess the clinical impact of and changes in significant (moderate-severe) MR in patients undergoing TAVR, overall and according to valve design (self expandable (SEV) vs balloon-expandable (BEV)). METHODS: All national registries and randomised trials were pooled using meta-analytical guidelines to establish the impact of moderate-severe MR on mortality after TAVR. Studies reporting changes in MR after TAVR on an individual level were electronically searched and used for the analysis. RESULTS: Eight studies including 8015 patients (SEV: 3474 patients; BEV: 4492 patients) were included in the analysis. The overall 30-day and 1-year mortality was increased in patients with significant MR (OR 1.49, 95% CI 1.16 to 1.92; HR 1.32, 95% CI 1.12 to 1.55, respectively), but a significant heterogeneity across studies was observed (p<0.05). The impact of MR on mortality was not different between SEV and BEV in meta-regression analysis for 30-day (p=0.360) and 1-year (p=0.388) mortality. Changes in MR over time were evaluated in nine studies including 1278 patients. Moderate-severe MR (SEV: 326 patients; BEV: 192 patients) improved in 50.5% of the patients at a median follow-up of 180 (30-360) days after TAVR, and the degree of improvement was greater in patients who had received a BEV (66.7% vs 40.8% in the SEV group, p=0.001). CONCLUSIONS: Concomitant moderate-severe MR was associated with increased early and late mortality following TAVR. A significant improvement in MR severity was detected in half of the patients following TAVR, and the degree of improvement was greater in those patients who had received a BEV. PMID- 26060122 TI - Predictors of bleeding in patients with acute coronary syndromes treated with prasugrel. AB - BACKGROUND: When considering antiplatelet therapy for acute coronary syndrome (ACS), it is essential to balance benefits (less thrombotic/ischaemic events) versus bleeding risks related to intense platelet inhibition via antagonism of P2Y12 receptors. This analysis aimed to identify predictors of bleeding events among A Comparison of Prasugrel at the Time of PCI or as Pretreatment at the Time of Diagnosis in Patients with NSTEACS (ACCOAST) study population. METHODS AND RESULTS: The ACCOAST study randomised 4033 patients with non-ST-segment elevation myocardial infarction (NSTEMI) to (A) a 30 mg prasugrel loading dose (LD) followed by coronary angiography with an additional 30 mg prasugrel at the time of percutaneous coronary intervention (PCI) or (B) a placebo LD followed by a 60 mg prasugrel at the time of PCI. Patients received standard of care, including use of aspirin. Independent predictors of Thrombolysis in Myocardial Infarction (TIMI) major bleeding not related to coronary artery bypass grafting (CABG) within 7 days were assessed using stepwise Cox proportional model for time to first occurrence of the event. Non-CABG-related TIMI major or minor bleeding was similarly analysed. Non-CABG-related TIMI major bleeding occurred in 36 (0.9%) patients, and TIMI major or minor bleeding occurred in 81 (2.0%) patients. Independent predictors for TIMI major bleeding alone were pretreatment with prasugrel LD (HR 3.02; 95% CI 1.42 to 6.43), femoral access (HR 2.45; 95% CI 1.11 to 5.38), female sex (HR 2.57; 95% CI 1.32 to 5.00), placement of >1 stent (HR 2.50; 95% CI 1.26 to 4.95) and age (HR 1.05; 95% CI 1.02 to 1.09). Pretreatment with prasugrel LD (HR 3.05; 95% CI 1.84 to 5.07), femoral access (HR 3.06; 95% CI 1.74 to 5.38), female sex (HR 2.62; 95% CI 1.67 to 4.12), performed PCI (HR 2.21; 95% CI 1.23 to 3.99), therapy with glycoprotein IIb/IIIa inhibitors (HR 1.88; 95% CI 1.06 to 3.33) and age (increased bleed per year of age HR 1.04; 95% CI 1.02 to 1.06) were independent predictors of TIMI major or minor bleeding through 7 days. CONCLUSIONS: Pretreatment, age, gender and procedural variables predicted bleeding risk in patients with NSTEMI. CLINICAL REGISTRATION NO: NCT01015287. PMID- 26060123 TI - Breast Cancer Risk in Sexual Minority Women during Routine Screening at an Urban LGBT Health Center. AB - BACKGROUND: Sexual minority women (SMW) may experience elevated breast cancer risk, yet limited research has assessed the utility of the Gail breast cancer risk model in this population. Using data from screening mammography patients at an urban health center specializing in sexual minority health, we calculated and compared Gail risk scores of SMW with heterosexual women and identified factors associated with elevated risk. METHODS: This retrospective study reviewed medical records from all patients who underwent screening mammography during 12 months (2013-2014) at a federally qualified community health center in the Northeast United States. Descriptive statistics compared risk scores and other characteristics of patients reporting female only or female and male sex partners ("SMW") with patients reporting only male sex partners ("heterosexual"). Linear regression identified correlates of increased lifetime risk. FINDINGS: Among 423 patients, SMW (n=162) were more likely to be nulliparous than heterosexual women (79% vs. 40%; p<.01) and had significantly higher lifetime Gail scores (10.7% vs. 8.9%; p<.01). In multivariable regression, being SMW was independently associated with 1.43% higher lifetime Gail scores (95% CI, 0.69%-2.17%), and having private health insurance was associated with 1.52% higher lifetime Gail scores (95% CI, 0.62-2.42). CONCLUSIONS: Using the Gail model to assess breast cancer risk routinely in a clinical setting is feasible. Risk scores may be higher among SMW, who are more likely to be nulliparous, and among patients who are privately insured. Additional research on breast cancer risk assessment among SMW is needed. PMID- 26060124 TI - A Growing Problem: Sizing Up the Burden of Non-melanoma Skin Cancer. PMID- 26060125 TI - Is Safety Psoriasis Patients' Overriding Concern? PMID- 26060126 TI - Erythema Annulare Centrifugum in the Era of Triple Therapy With Boceprevir Plus Pegylated Interferon alpha-2b and Ribavirin for Hepatitis C Virus Infection. PMID- 26060127 TI - Spatio-temporal analysis of female breast cancer incidence in Shenzhen, 2007 2012. AB - INTRODUCTION: Breast cancer is a leading tumor with a high mortality in women. This study examined the spatio-temporal distribution of the incidence of female breast cancer in Shenzhen between 2007 and 2012. METHODS: The data on breast cancer incidence were obtained from the Shenzhen Cancer Registry System. To describe the temporal trend, the average annual percentage change (AAPC) was analyzed using a joinpoint regression model. Spatial autocorrelation and a retrospective spatio-temporal scan approach were used to detect the spatio temporal cluster distribution of breast cancer cases. RESULTS: Breast cancer ranked first among different types of cancer in women in Shenzhen between 2007 and 2012 with a crude incidence of 20.0/100,000 population. The age-standardized rate according to the world standard population was 21.1/100,000 in 2012, with an AAPC of 11.3%. The spatial autocorrelation analysis showed a spatial correlation characterized by the presence of a hotspot in south-central Shenzhen, which included the eastern part of Luohu District (Donghu and Liantang Streets) and Yantian District (Shatoujiao, Haishan, and Yantian Streets). Five spatio-temporal cluster areas were detected between 2010 and 2012, one of which was a Class 1 cluster located in southwestern Shenzhen in 2010, which included Yuehai, Nantou, Shahe, Shekou, and Nanshan Streets in Nanshan District with an incidence of 54.1/100,000 and a relative risk of 2.41; the other four were Class 2 clusters located in Yantian, Luohu, Futian, and Longhua Districts with a relative risk ranging from 1.70 to 3.25. CONCLUSIONS: This study revealed the spatio-temporal cluster pattern for the incidence of female breast cancer in Shenzhen, which will be useful for a better allocation of health resources in Shenzhen. PMID- 26060128 TI - Inhibition of penicillin-binding protein 2a (PBP2a) in methicillin resistant Staphylococcus aureus (MRSA) by combination of ampicillin and a bioactive fraction from Duabanga grandiflora. AB - BACKGROUND: The inhibition of penicillin-binding protein 2a (PBP2a) is a promising solution in overcoming resistance of methicillin resistance Staphylococcus aureus (MRSA). A potential approach in achieving this is by combining natural product with currently available antibiotics to restore the activity as well as to amplify the therapeutic ability of the drugs. We studied inhibition effects of a bioactive fraction, F-10 (isolated from the leaves of Duabanga grandiflora) alone and in combination with a beta-lactam drug, ampicillin on MRSA growth and expression of PBP2a. Additionally, phytochemical analysis was conducted on F-10 to identify the classes of phytochemicals present. METHODS: Fractionation of the ethyl acetate leaf extract was achieved by successive column chromatography which eventually led to isolation of an active fraction, F-10. Both extract and F-10 were analyzed for the presence of major classes of phytochemicals in addition to obtaining a high performance liquid chromatography (HPLC) profile to reveal the complexity of the fraction F-10. Broth microdilution method was employed to determine minimum inhibitory concentration (MIC) of the extract and fractions against MRSA. Evaluation of synergistic activity of the active fraction with ampicillin was determined using checkerboard methodand kinetic growth experiments. Effect of combination treatments on expression of PBP2a, a protein that confers resistance to beta lactam antibiotics, was elucidated with the Western blot assay. RESULTS: MIC of F 10 against MRSA was 750 mg/L which showed an improved activity by 4-fold compared to its crude extract (MIC = 3000 mg/L). Phytochemical analysis revealed occurrence of tannins, saponin, flavonoids, sterols, and glycosides in F10 fraction. In FIC index interpretation, the most synergistic activity was achieved for combinations of 1/64 * MIC ampicillin + 1/4 * MIC F-10. The combination also evidently inhibited MRSA growth in kinetic growth curve assay. As a result of this synergistic interaction, MIC of ampicillin against MRSA was reduced to 0.78 mg/L (64-fold) from initial value of 50 mg/L. Western blot analysis suggested inhibition of PBP2a in MRSA cultures grown in synergistic combination treatment in which no PBP2a band was expressed. CONCLUSIONS: The results demonstrated synergism between fraction F-10 of D. grandiflora with ampicillin in suppressing MRSA growth via PBP2a inhibition. PMID- 26060129 TI - Retrospective review of in hospital use of mineralocorticoid receptor antagonists for high risk patients following myocardial infarction. AB - BACKGROUND: There is little data regarding use of mineralocorticoid antagonists (MRAs) for patients reduced LV ejection fraction (LVEF) following acute myocardial infarction (MI). We determined the frequency and temporal trends of MRA use in these patients. METHODS: We performed a retrospective review of all cases of acute MI between June 1, 2010 and April 1, 2012. Patients were considered eligible for MRA therapy if they were admitted with acute MI with LVEF <= 40 % and had heart failure symptoms or a history of diabetes. RESULTS: Of 3910 cases of acute MI, 332 patients were considered eligible for MRA therapy. MRA therapy was prescribed for 92/332 (28 %) eligible patients, while 66 of 1142 (6 %) of ineligible patients were so treated. Over the study period, usage in eligible and ineligible patients rose significantly (22 to 30 %, p = 0.08 and 4 to 7 %, p = 0.04 respectively). CONCLUSIONS: Prescription of MRAs for eligible patients occurred in a minority of patients, and demonstrated a modest increase over time. In patients without an indication for MRAs, a similar trend was observed. Further study is required to better understand barriers to appropriate use of MRAs in this patient population. PMID- 26060130 TI - Ternary B2X2H2 (X = O and S) rhombic clusters and their potential use as inorganic ligands in sandwich-type (B2X2H2)2Ni complexes. AB - Based upon global searches and electronic structure calculations at the B3LYP and CCSD(T) levels, we present the global-minimum structures of two ternary B-O-H and B-S-H rhombic clusters: D2h B2O2H2 (1, (1)Ag) and C2v B2S2H2 (2, (1)A1). Both species feature a B2X2 (X = O or S) four-membered ring as the core, with two H atoms attached terminally. The former cluster is perfectly planar, whereas the latter undergoes a slight butterfly distortion. Bonding analyses reveal a four center four-electron (4c-4e) o-bond in these clusters, which are 4pi systems in a nonbonding/bonding combination, in contrast to an antibonding/bonding combination in a classical 4pi antiaromatic hydrocarbon such as cyclobutadiene (C4H4). Clusters 1 and 2 are considered to be aromatic. The present results also help elucidate the bonding nature in the relevant heteroatomic ring B2N2H4 system and suggest that it is not appropriate to consider B2N2H4 as an inorganic cyclobutadiene, a conception that has been in existence in the literature for over 40 years. The electronic properties of the global-minimum clusters 1 and 2 are predicted. It is shown that B2O2H2 (1) and B2S2H2 (2) may serve as effective inorganic ligands to form sandwich-type transition metal complexes, such as D2d [B2O2H2]2Ni (3) and D2d [B2S2H2]2Ni (4). PMID- 26060131 TI - Reproductive and obstetric outcomes in mosaic Turner's Syndrome: a cross sectional study and review of the literature. AB - BACKGROUND: Turner's syndrome (TS) is depicted as a total or partial absence of one X chromosome that results in ovarian dysgenesis. Chances of spontaneous pregnancy in TS are rare and the outcome of the pregnancies is known to be poor with an increased risk of miscarriage and stillbirths. Our aim is to evaluate reproductive and obstetric outcomes of natural conception and in-vitro fertilization (IVF) cycles in mosaic TS patients. METHODS: A total of 22 mosaic TS cases (seventeen 45,X/46,XX and five 45,X/46,XX/47,XXX karyotypes) were evaluated. RESULTS: Live birth and abortion rates were found as 32.7 % and 67.3 %, respectively in 52 pregnancies. Implantation, clinical pregnancy and take home baby rates were detected as 3.7 %, 8.6 % and 5.7 %, respectively per IVF cycle as a result of 35 cycles. Fecundability analysis revealed that 5 % of the cases experienced first pregnancy within 6 months and 8 % within the first 2 years. Mosaicism ratio did not have an effect on the time to the first pregnancy (p = .149). CONCLUSION: Only a small proportion of the mosaic TS patients conceive in the first 2 years of the marriage. Age of menarche and age of marriage appear not to have any impact on the chance of conceiving. Mosaic TS cases should counseled about the low odds of pregnancy and high miscarriage rates. PMID- 26060132 TI - Nasal manifestations of IgG4-related disease: A report of two cases. AB - IgG4-related disease (IgG4-RD) is a recently recognized clinical disease entity characterized by elevated serum IgG4, tumefaction, tissue infiltration of IgG4 positive plasma cells and fibrosis. IgG4-RD may occur, either synchronously or metachronously, in a variety of organs throughout the body. We describe herein two representative cases of the nasal manifestations of IgG4-RD, characterized by diffuse, crusty, erosive lesions on nasal mucosa. Oral steroid administration was effective in treating these nasal manifestations. We report a decrease in IgG4 positive plasma cell infiltrates in nasal mucosa biopsy specimens after steroid therapy, demonstrating that infiltration of IgG4-positive cells is reversible. PMID- 26060133 TI - A phase II trial of perioperative chemotherapy involving a single intraperitoneal administration of paclitaxel followed by sequential S-1 plus intravenous paclitaxel for serosa-positive gastric cancer. AB - BACKGROUND AND OBJECTIVES: We carried out a phase II trial to evaluate the feasibility, efficacy, and tolerability of perioperative chemotherapy including single intraperitoneal(IP) administration of paclitaxel(PTX) followed by intravenous(IV) administrations of PTX with S-1 in a neoadjuvant setting for serosa-positive gastric cancer. METHODS: Patients with cT4a gastric cancer were enrolled. A laparoscopic survey was performed before study inclusion for the confirmation of serosal invasion, negative lavage cytology, and negative peritoneal metastasis. IP PTX (80 mg/m(2)) was administered, followed by systemic chemotherapy. Surgery was performed after the completion of chemotherapy. The primary endpoint was the treatment completion rate. RESULTS: 37 patients were recruited. The treatment completion rate was 67.6% (25/37; 90% CI, 52.8-80.1%), which was significantly higher than 50%; we set this as a threshold value (P = 2.4% [one-sided]). 14 patients had target lesions; of these, 10 showed a partial response (71.4%), three had stable disease (21.4%), and one had progressive disease(7.2%). The response rate was 71.4% (10/14). All patients underwent gastrectomy with D2 lymph node dissection. The 3- and 5-year OS rates were 78.0 and 74.9%, respectively. CONCLUSIONS: Perioperative chemotherapy including neoadjuvant IP PTX followed by sequential IV PTX with S-1 for serosa-positive gastric cancer is feasible, safe, and efficient. PMID- 26060135 TI - Mini-instruments for minimally invasive arthroscopy of the temporomandibular joint: a technical note. PMID- 26060136 TI - Emerging developments in the use of bioactive glass for reconstruction of craniofacial bone. AB - For decades, researchers have investigated the use of bioactive glasses as synthetic substitutes for bone grafts that can bond with bone, and recent discoveries have shown that their clinical performance in osteoplastic and reconstructive surgery has exceeded that of traditional synthetic materials. Craniofacial reconstructions with bioactive glass were associated with good functional and aesthetic results with no donor-site morbidity, and the material's unique ability to inhibit bacterial growth was advantageous when used in dead spaces that were chronically infected. Treatment of large defects in the head and neck with these multifunctional biomaterials is a suitable alternative to conventional methods. PMID- 26060134 TI - Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in plants. AB - Being a major factory for protein synthesis, assembly, and export, the endoplasmic reticulum (ER) has a precise and robust ER quality control (ERQC) system monitoring its product line. However, when organisms are subjected to environmental stress, whether biotic or abiotic, the levels of misfolded proteins may overwhelm the ERQC system, tilting the balance between the capacity of and demand for ER quality control and resulting in a scenario termed ER stress. Intense or prolonged ER stress may cause damage to the ER as well as to other organelles, or even lead to cell death in extreme cases. To avoid such serious consequences, cells activate self-rescue programs to restore protein homeostasis in the ER, either through the enhancement of protein-folding and degradation competence or by alleviating the demands for such reactions. These are collectively called the unfolded protein response (UPR). Long investigated in mammalian cells and yeasts, the UPR is also of great interest to plant scientists. Among the three branches of UPR discovered in mammals, two have been studied in plants with plant homologs existing of the ER-membrane-associated activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1). This review discusses the molecular mechanisms of these two types of UPR in plants, as well as the consequences of insufficient UPR, with a focus on experiments using model plants. PMID- 26060137 TI - Feasibility of performing dynamic sentinel lymph node biopsy as a delayed procedure in penile cancer. AB - INTRODUCTION: Patients diagnosed with penile cancer and clinically impalpable inguinal lymph nodes (cN0), normally undergo dynamic sentinel lymph node biopsy (DSNB) at the same time as the primary penile surgery. The aim of this study is to investigate the diagnostic accuracy and clinical outcomes of performing DSNB in patients who have already undergone surgery for the primary penile cancer. METHODS: Ninety-two patients with unilateral or bilateral impalpable inguinal lymph nodes (LNs) who had already undergone primary resection of the penile tumour (stage >= T1G2) were included in this study. All patients underwent a preoperative USS of the groin(s) with fine needle aspiration cytology (FNAC). Provided that the FNAC was clear, DSNB was performed. Radical inguinal lymphadenectomy was performed if the histological analysis of the SLN confirmed the presence of micrometastatic disease. RESULTS: DSNB was undertaken in 165 groins with a nonvisualisation rate of 4.8 % (8/165 groins). The SLN was positive for micrometastatic disease in nine groins (5.5 %) from a total of eight patients (8.7 %). One patient developed regional recurrence in a prepubic LN after excision of bilateral negative SLN (1.1 %). The three-year disease-specific survival for patients with negative and positive SLN was 98.8 and 87.5 %, respectively (p = 0.042). Using DSNB, occult LN metastases in penile cancer can be detected with a sensitivity of 88.9 % and specificity of 100 %. CONCLUSIONS: We have demonstrated that DSNB is feasible as a delayed procedure to localise the SLN. Surgical resection of the primary penile lesion does not appear to change the lymphatic drainage. PMID- 26060138 TI - Considerations in the modern management of stress urinary incontinence resulting from intrinsic sphincter deficiency. AB - PURPOSE: Intrinsic sphincter deficiency (ISD) is a common cause of stress urinary incontinence and is associated with more severe symptoms, often being associated with failed previous surgery. Due to the impaired sphincteric function, alternative surgical approaches are often required. The purpose of this review is to appraise the contemporary literature on the diagnosis and management of ISD. METHODS: A PubMed search was performed to identify articles published between 1990 and 2014 using the following terms: ISD, stress urinary incontinence and type III stress urinary incontinence. Publications were screened for relevance, and full manuscripts were retrieved. RESULTS: Most studies base the diagnosis of ISD upon urodynamic appearances using recognized criteria (Valsalva leak point pressure <60 cm H2O or a maximum urethral closure pressure <20 cm H2O) in addition to clinical features. A range of non-surgical and surgical treatment options are available for the patient. Pubovaginal slings are more effective than retropubic colposuspensions with outcomes comparable to those reported with midurethral slings. The artificial urinary sphincter provides long-term cure rates; however, it is associated with specific morbidity including device erosion, mechanical failure and revision. The benefits of bulking agents, however, are not sustained beyond 1 year. CONCLUSIONS: There are few randomized controlled trials that compare accepted treatments specifically for patients with ISD. The lack of standardization in the definition and diagnostic criteria used limits inter-study comparisons. An assessment of urethral pressure profile when combined with the clinical features may help predict outcomes of surgical intervention. PMID- 26060140 TI - COMMD7 as a novel NEMO interacting protein involved in the termination of NF kappaB signaling. AB - NEMO/IKKgamma is the regulatory subunit of the IkappaB Kinase (IKK) complex, required for the activation of the NF-kappaB pathway, which is involved in a variety of key processes, including immunity, inflammation, differentiation, and cell survival. Termination of NF-kappaB activity on specific -kappaB responsive genes, which is crucial for the resolution of inflammatory responses, can be achieved by direct degradation of the chromatin-bound NF-kappaB subunit RelA/p65, a process mediated by a protein complex that contains Copper Metabolism Murr1 Domain 1 (COMMD1). In this study, we identify COMMD7, another member of the COMMDs protein family, as a novel NEMO-interacting protein. We show that COMMD7 exerts an inhibitory effect on NF-kappaB activation upon TNFalpha stimulation. COMMD7 interacts with COMMD1 and together they cooperate to down-regulate NF kappaB activity. Accordingly, termination of TNFalpha-induced NF-kappaB activity on the -kappaB responsive gene, Icam1, is defective in cells silenced for COMMD7 expression. Furthermore, this impairment is not greatly increased when we silence the expression of both COMMD7 and COMMD1 indicating that the two proteins participate in the same pathway of termination of TNFalpha-induced NF-kappaB activity. Importantly, we have demonstrated that COMMD7's binding to NEMO does not interfere with the binding to the IKKs, and that the disruption of the IKK complex through the use of the NBP competitor impairs the termination of NF kappaB activity. We propose that an intact IKK complex is required for the termination of NF-kappaB-dependent transcription and that COMMD7 acts as a scaffold in the IKK-mediated NF-kappaB termination. PMID- 26060141 TI - Use of phosphodiesterase type 5 inhibitors in assistive living and home care settings. AB - The purpose of this descriptive study was to assess frequency of phosphodiesterase type (PDE-5) inhibitor use (sildenafil, tadalafil, ardenafil) in community settings. METHODS: A retrospective record review was conducted to determine PDE-5 inhibitor use in older males (mean age 79.2) residing in three assisted living communities (n=126), or living in private homes with home care services (n=109). RESULTS: Two participants from assisted living had PDE-5 inhibitors listed on medication profiles, while no participants from the home care setting had any listed. IMPLICATIONS: Many factors may have contributed to the absence of PDE-5 inhibitors in records, including comorbidities precluding use; fear of side effects; reluctance to report use; and lack of erectile dysfunction diagnosis to name a few. It is unknown whether sexual function, or the need for PDE-5 inhibitors was ever assessed by providers. Future research is warranted given the aging population and the benefits of holistic assessments. PMID- 26060142 TI - Change in sexual activity after a cardiac event: the role of medications, comorbidity, and psychosocial factors. AB - AIM: The aim of this study was to examine change in sexual activity before and after cardiac diagnosis in men and women by medication class. BACKGROUND: Decline in sexual activity after cardiac diagnosis frequently occurs, with adverse effects of medications believed to play a role, although literature by subclass of drugs are conflicting. METHODS: Mixed methods approach was used to evaluate cardiac patients' (N=211) self-reported medications and changes in sexual activity before and after cardiac diagnosis via mailed survey. Chi square, logistic regression, and thematic analysis were used. RESULTS: First and third generation beta blockers, class 1 calcium channel blockers, vasodilators, diuretics, and loop diuretics adversely affected sexual activity. Significant predictors of change in sexual activity were number of medications, education level, and income; the overall model predicted 25.7% of the variance in sexual activity. CONCLUSIONS: Sexual assessment and discussion of sexual concerns and side effects of medications by nurses are important to support sexual function. PMID- 26060143 TI - Sexual dysfunction and anxiety levels of type 2 male diabetics. AB - AIM: This descriptive study aims to identify sexual dysfunction and anxiety levels of male patients with type 2 diabetes. METHOD: The sample is composed of 150 patients who were seen at the Endocrinology and Diabetes Clinic of one university hospital in Istanbul, Turkey. The data were collected using an "Information Form", the "International Index of Erectile Function", and the "State-Trait Anxiety Inventory (STAI)". RESULTS: The mean age of the sample was 56.2+/-8.71, the sexual dysfunction total score was on average 46.44+/-15.66, and 82% of the sample experienced erectile dysfunction. According to the STAI, the patients had "mild" anxiety on average, whereas according to the TAI, they had "moderate" anxiety levels. There were no statistically significant differences between the sexual dysfunction total scores and the State Anxiety Scores (p>0.05), whereas there was a negative weak correlation between the trait anxiety levels (p<0.05). CONCLUSION: These results show that the sexual function and anxiety of diabetic patients should be evaluated at regular intervals. PMID- 26060144 TI - Conflict of interest in public health: should there be a law to prevent it? AB - "Conflict of interest", now being commonly cited, is a set of circumstances that creates a risk that professional judgement or actions regarding a primary interest will be unduly influenced by a secondary interest. Conflict of interest situations can be institutional or personal, and can stem from financial or other interests including post-employment opportunities or during public -private partnerships. Conflicts of interest in the creation of public policy, especially health or nutrition related policies such as the vaccine policy, tobacco control, and research related to health, can have negative impact on the lives of millions of people. While the UN Convention Against Corruption, to which India is a signatory, identifies conflict of interest as often being a precursor to corruption, there is no serious action being taken in this direction by the Indian government, in spite of the fact there are instances of serious nature coming to light that affect our peoples lives. If conflict of interest situations are allowed to continue especially in health policy it could be detrimental to millions of people; therefore, it would be in public interest that India enacts a law to prevent conflict of interest in the making of public policies, comprehensive enough to include financial and institutional conflicts of interest. PMID- 26060145 TI - Nontyphoidal Salmonella urinary tract infection among elderly patients. PMID- 26060146 TI - Earlier versus later subthalamic deep brain stimulation in Parkinson's disease. AB - INTRODUCTION: Subthalamic nucleus deep brain stimulation (STN-DBS) has been recently compared to a possible "second therapeutic honeymoon" for Parkinson's disease, as it might prevent the development of severe motor complications and lessen the social adjustment associated to disease progression. This study aims to evaluate whether an early surgical treatment could result in better long-term outcomes, comparing the follow-up evolution of 203 parkinsonian patients, treated at different stages of the disease course. METHODS: The retrospective allocation to Early- or Late-Stimulated groups was performed in accordance to disease severity at the time of surgery and motor fluctuations duration. Then, the two groups clinical outcomes were compared after more than 8 years of follow-up by means of the Unified Parkinson's Disease Rating Scale, reporting the overall disability experienced by patients during the entire observational period. RESULTS: Subjects receiving an earlier STN-DBS showed a sustained improvement in the activities of daily living and motor complications, never reaching the severe levels of disability reported by Late-Stimulated patients at the time of surgical selection. After >=8 years of follow-up the Early-Stimulated group still reported a 28.7% lower impairment in activities of daily living and 43.8% lower duration of waking day spent in OFF compared to their pre-surgical basal scores. CONCLUSION: Although the limitation of a retrospective study design should be considered in the interpretation of data, our findings suggest that an earlier STN-DBS treatment might result in a more precocious stabilization of motor complications, with beneficial effects on the patient's social and professional life autonomy. PMID- 26060147 TI - Searching for a rat model of chronic tympanic membrane perforation: Healing delayed by mitomycin C/dexamethasone but not paper implantation or iterative myringotomy. AB - OBJECTIVES: Surgical intervention such as myringoplasty or tympanoplasty is an option in the current clinical management of chronic tympanic membrane perforation (TMP). Animal models of chronic TMP are needed for pre-clinical testing of new materials and to improve existing techniques. We evaluated several reported animal model techniques from the literature for the creation of chronic TMPs. The aim of this study was to evaluate production of chronic TMPs in a rat model using topical mitomycin C/dexamethasone, paper insertion into middle ear cavity (MEC) or re-myringotomy. METHODS: Forty male Sprague-Dawley rats underwent myringotomy of the right tympanic membrane (TM) and were randomly divided into 3 experimental groups: application of topical mitomycin C/dexamethasone, paper insertion into middle ear cavity, or re-myringotomy. Control perforations were allowed to close spontaneously. TMs were assessed regularly with otoscopy for 8 weeks. At the end of 8 weeks, animals were sacrificed for histology. RESULTS: The closure of TMPs was significantly delayed by mitomycin C/dexamethasone (mean patency, 18.9 days; P<=0.01) compared with the control (mean patency, 7 days), but was not significantly delayed in the paper insertion group (mean patency, 9.4 days; P=0.74). Repeated myringotomy of closed perforations (mean number of myringotomies, 8.9 per ear) stimulated acceleration of closure rather than delay. Histologically, the mitomycin C/dexamethasone group had almost normal TM morphology, while the paper insertion group revealed inflammatory and granulomatous responses. The re-myringotomy group had a thickened TM fibrous layer with collagen deposition. CONCLUSIONS: Mitomycin C/dexamethasone delayed TMP closure in rats but the effect was not sufficiently long-lasting to be defined as a chronic TMP. Neither paper insertion into middle ear cavity nor re myringotomy created chronic TMP in rats. PMID- 26060148 TI - Grisel syndrome, acute otitis media, and temporo-mandibular reactive arthritis: A rare association. AB - We present a case report of a four-year-old boy with torcicollis and trismus after acute otitis media. Grisel Syndrome diagnosis in association with temporo mandibular reactive arthritis was admitted, leading to early conservative treatment. GS should be suspected in a child presenting with torticollis after an upper respiratory tract infection or an ENT surgical procedure. The association with temporo-mandibular reactive findings is somehow rarer but not impossible, due to the close vascular communication between retropharyngeal and pterigoid spaces. PMID- 26060149 TI - Age related changes in auditory processes in children aged 6 to 10 years. AB - OBJECTIVES: The study evaluated age related changes in auditory processing (separation/auditory closure, binaural auditory integration abilities, temporal processing abilities) and higher order cognitive function (auditory memory & sequencing abilities) in children. Additionally, the study aimed to assess the effect of gender on the auditory processes/higher cognitive function as well as ear effect for the monaural tests that were administered. METHODS: The cross sectional experimental study evaluated 280 typically developing children aged 6 to 10 years, divided into five age groups. They were evaluated on auditory processes/higher order cognitive functions reported to be frequently affected in children with auditory processing disorders (Speech-in-Noise Test in Indian English, Dichotic consonant-vowel test, Duration pattern test, & Revised Auditory Memory and Sequencing Test in Indian-English). RESULTS: ANOVA and MANOVA revealed no significant gender effect in all four tests. However, a significant age effect was seen, with the rate at which maturation occurred, varying across the tests. CONCLUSIONS: Thus, the findings indicate that different auditory processes have different rates of development. This reflects that the areas responsible for different auditory processes/higher cognitive function do not develop at the same pace. PMID- 26060150 TI - Effects of nutrition on educational standards of school children of a developing country. PMID- 26060151 TI - Comparison of risk-taking behaviour and frequency of piercing and tattooing among university students. AB - OBJECTIVE: To assess the frequency of piercing and tattooing among university students and to determine the extent of risk-taking behaviour in this age group. METHODS: The descriptive cross-sectional study was conducted at a university in Istanbul, Turkey, from December 2009 to February 2010. Data was obtained from students through a questionnaire. SPSS 20 was used for statistical analysis. RESULTS: Of the 1303 subjects, 838(64.3%) were girls. The overall mean age of the sample was 21.7+/-1.9 years. A total of 107 (8.2%) had piercings and 56(4.3%) had tattoos. It was seen that young people who had piercings and tattoos were significantly more likely (p<0.05) to exhibit certain types of risk behaviour including smoking, alcohol, substance abuse, extreme sports, carrying switchblades/knives, unprotected sexuality and having multiple sex partners. CONCLUSIONS: In the face of the steadily increasing fads of piercing and tattooing among the youth, families, teachers and health professionals need to be constantly on the alert. PMID- 26060152 TI - Clinical outcomes of intermittent antegrade warm versus cold blood cardioplegia. AB - OBJECTIVE: To compare clinical outcome in patients undergoing conventional coronary artery bypass graft surgery who received intermittent antegrade warm blood cardioplegia or intermittent antegrade cold blood cardioplegia for myocardial protection. METHODS: The observational, prospective non-randomised analytical comparative study was conducted at the Punjab Institute of Cardiology, Lahore, and Chaudhry Pervaiz Elahi Institute of Cardiology, Multan, from September 2012 to October 2013, and comprised patients undergoing coronary artery bypass graft surgery. They were divided into two groups, with Group I having those who received intermittent antegrade warm blood cardioplegia, and Group II having those who received intermittent antegrade cold blood cardioplegia. SPSS 16 was used for statistical analysis. RESULTS: Of the 215 patients, 94(44%) were in Group I, and 121(56%) in Group II. Total surgical time in Group II was 119.26+/ 22.24 minutes compared to 105.73+/-31.34 in Group I (p >0.0001). Spontaneous resumption of sinus rhythm and peri-operative myocardial infarction was statistically insignificant (p>0.05). There were 21(17.4%) patients in Group II to whom peri-operative myocardial infarction occurred compared to 9(9.6%) in Group I (p=0.10). CONCLUSIONS: Intermittent antegrade warm blood cardioplegia showed better myocardial protection in early postoperative period compared to intermittent antegrade cold blood cardioplegia. PMID- 26060153 TI - Relationship of CD95 and COX-2 in renal cell carcinomas with survival and other prognostic parameters: A tissue microarray study. AB - OBJECTIVE: To investigate the expression of cyclooxygenase-2 and cluster of differentiation 95 in renal cell carcinomas having different clinico-pathological characteristics. METHODS: The study entailed histopathological diagnoses carried out on paraffin blocks at the Department of Pathology of the Medical Hospital of Duzce University, Turkey, between 2005 and 2011. Immunohistochemical staining for cyclooxygenase-2 and cluster of differentiation 95was performed on tissue microarray using standard procedures. Each patient's age and gender as well as the tumour's grade, stage, diameter, ureteral surgical margins, vascular invasion, capsule invasion and subtype were assessed. In order to determine if the cases were still alive, relatives were telephoned and identity registration records were checked. SPSS 18 was used for statistical analysis. RESULTS: There were 49 paraffin blocks in the study.Significant correlations were found between cyclooxygenase-2 and tumour subtype (p=0.044) as well as between cyclooxygenase-2 and tumour diameter (p=0.026). There was a significant correlation between cluster of differentiation 95and the Fuhrman grade (p=0.050). CONCLUSIONS: Expression of cluster of differentiation 95and cyclooxygenase-2 may be correlated with prognostic parameters in renal cell carcinoma and may also be associated with tumour progression. PMID- 26060154 TI - The effect of massage on neonatal jaundice in stable preterm newborn infants: a randomized controlled trial. AB - OBJECTIVE: To evaluate the effects of massage therapy on transcutaneous bilirubin of stable preterm infants. METHODS: The controlled clinical trial was conducted in 2014 at Shahid Hasheminejhad Hospital, Iran, and comprised preterm neonatal children in the neonatal intensive care unit. The newborns were divided into two groups of massage and control via random allocation. The children in the control group received the routine therapy whereas those in the massage group underwent the same four days of routine plus 20 minutes of massage twice a day. The transcutaneous bilirubin and the number of excretions of the newborns were noted from the first to the fourth day of the intervention and results were compared between the two groups. RESULTS: There were 40 newborns in the study l 20(50%) each in the two groups. There was a significant difference in the number of times of defecation (p=0.002) and in the level of bilirubin (p=0.003) between the groups with those in the massage group having a higher number of defecations as well as a lower level of transcutaneous bilirubin. CONCLUSIONS: Through massage therapy the bilirubin level in preterm newborns can be controlled and a need for phototherapy can also be delayed. PMID- 26060155 TI - Comparing neonatal respiratory morbidity in neonates delivered at term by elective Caesarean section with and without dexamethasone: retrospective cohort study. AB - OBJECTIVE: To assess the effect of dexamethasone on neonatal respiratory morbidity in babies delivered by early term elective lower segment Caesarean section. METHODS: The retrospective cohort study was conducted at a secondary level hospital in Karachi. It reviewed the medical record of pregnant women and their babies who were delivered by elective lower segment Caesarean section between January 1 and June 30, 2013, at 37-38+6 weeks of pregnancy. The women were divided into exposed group (Group A) who received prophylactic dexamethasone, and non-exposed group (Group B) who did not receive dexamethasone Neonatal respiratory morbidity was compared between the two groups. Data was analysed using SPSS 19. RESULTS: The 196 subjects in the study were equally divided in two groups. In Group A, only 1(1%) baby developed transient tachypnoea compared to 10(10%) babies in Group B (p=0.005). Besides, 11(11%) babies were admitted to nursery in Group B compared to 1(1%) in Group A (p=0.005). No baby was referred to any tertiary care hospital for intensive care. CONCLUSIONS: Beneficial effects of prophylactic dexamethasone in neonatal respiratory morbidity were found, but further prospective studies with large sample size are required. PMID- 26060156 TI - The incidence of nasal septal deviation and its relation with chronic rhinosinusitis in patients undergoing functional endoscopic sinus surgery. AB - OBJECTIVE: To investigate the correlation of nasal septal deviations and chronic rhinosinusitis. METHODS: The study was conducted at Department of Otolaryngology, Head and Neck Surgery, Boali Hospital, Sari, Iran from January 2012 to September 2014 and comprised subjects aged from 5 to 68 years who had undergone elective functional endoscopic sinus surgery for chronic rhinosinusitis. SPSS 17 was used for statistical analysis. RESULTS: Of the 60 subjects in the study, 41(68.3%) were males and 19(31.7%) females with overall median age of 27. Nasal septal deviation was found in 49(81.7%) subjects; 11(18.3%) had it in both right and left sides, 16(26.7%) in right alone and 22(36.7%) in the left side. The commonest type of septal deviations in the left side were posteroinferior 10(16.66%) and anteroinferior 7(11.7%). In the right side, the corresponding numbers were 9(15%) and 7(11.7%). CONCLUSIONS: Nasal septal deviations are of particular interest in majority of patients with chronic rhinosinusitis. PMID- 26060157 TI - Students' perception of mentoring at Bahria University Medical and Dental College, Karachi. AB - OBJECTIVE: To assess the students' perception regarding mentoring at different stages of their studies at a private-sector medical college. METHODS: The cross sectional study was conducted from April 2012 to July 2014 at Bahria University Medical and Dental College, Karachi, and comprised students from first to fourth year. Data was collected through a self-administered questionnaire, which was developed after literature search and discussion. The total score for the 35 questions was used as the 'perception score' for the students. The perceptions among all students in an academic year were compared using the Kruskall-Wallis test for median score differences. RESULTS: Of the 401 students approached, 341(85%) completed the survey. The median perception scores for personal support (p=0.81) and career advice (p=0.07) were not different across the four years. There was a significant difference in the perception scores for role modelling (p<0.001) and research collaboration (p=0.002). Students in pre-clinical years (1st/2nd years) rated their mentors higher on role modelling aspects of mentoring (p<0.001) compared to those in the clinical years (3rd/4th years). CONCLUSIONS: Agreement for personal support had the highest score out of the four categories which was not different among all the four years. However, students' perception varied among preclinical and clinical groups when it came to the matter of career advising and role modelling. PMID- 26060158 TI - The hepatoprotective role of Silymarin in isoniazid induced liver damage of rabbits. AB - OBJECTIVE: To evaluate the hepatoprotective role of Silymarin against isonicotinylhydrazine-induced hepatotoxicity in rabbit model. METHODS: The experimental animal study was held at Jinnah Postgraduate Medical Centre, Karachi, from April to September 2013 and comprised rabbits weighing 1-1.5kgof either gender. The animals were divided randomly into equal groups: group I underwent liver function test without any drug; in group II effects of Silymarin (50mg/kg/day orally) was observed; in group III isoniazid (50mg/kg/dayorally) was administered; and in group IV combined effects of isoniazid and silymarin were observed. Liver function tests were performed at day0 and after the treatment at day19. SPSS 16 was used for statistical analysis. RESULTS: The 28 rabbits in the study were divided in four groups of 7(25%) each. No mortality was recorded in any group. In group III, bilirubin level was increased and alanine transaminase was decreased significantly (p<0.05 each). In group IV, there was significant improvement in serum billirubin and serum alanine transaminase (p<0.05 each). CONCLUSIONS: Isonicotinylhydrazine-induced hepatotoxicity was well treated by concurrent administration of Silymarin. PMID- 26060159 TI - The reasons for using and not using alternative medicine in Khorramabad women, west of Iran. AB - OBJECTIVE: To evaluate reasons for using and not using alternative medicines. METHODS: The cross-sectional study was conducted in 2009 on women over 18 years of age in Khorramabad, Iran. The subjects were selected by using cluster and simple random sampling method. The data were recorded in a questionnaire that involved questions about the subjects' age, marital status, their opinions on their general health, and advantages and disadvantages of conventional and alternative medicine. RESULTS: Of the 1600 women initially selected, 1551(97%) represented the final sample. The mean age of the participants was 35.04+/-10.71 years. Overall, 435(28%) spoke of disadvantages of alternative medicine; 277(18%) about the advantages of alternative medicine; 523(34%) about the advantages of conventional treatments; and 316(20%) about the disadvantages of conventional treatments. The most prevalent reason for not using the conventional treatments was the cost factor in 159(50.3%). Trust in physicians 328(62.7%) and distrust in alternative medicine therapists 317(73%) were the most prevalent reasons for using conventional treatments and not using alternative medicine. CONCLUSIONS: Similar studies should be done on the reasons for using and not using each medication of alternative medicines separately. PMID- 26060160 TI - Association between knee pain and low back pain. AB - OBJECTIVE: To evaluate the association between knee pain and lumbar disorders. METHODS: The case-control study was conducted at Physical Medicine and Rehabilitation Department, Tabriz University of Medical Sciences, Iran, from December 2009 to March 2011, and comprised patients with primary complaint of knee pain. A separate group worked as controls. The coincidence of knee pain and lumbar disorders were assessed and compared between the two groups SPSS 15 was used for statistical analysis. RESULTS: Of the 170 patients, 90(53%) were in the case group having 20(22.2%) males and 70(77.7%) females, and 80(47%) in the control group having 18(22.5%) males and 62(77.5%) females. The overall mean age was 46.9+/-8.9 (range: 25-61years). Age and gender difference between two groups was not significant (p>0.05 each). Lifetime prevalence of radicular, chronic and recurrent low back pain and its point prevalence in the case group were significantly higher than the control group (p<0.05 each). Range of movement of the lower limb and lumbar region in the case group was less than the controls (p<0.05). Local subcutaneous tissue oedema of the lumbar region was more prevalent in the case group (p<0.05). There was no significant difference in vertebral column posture between the two groups (p>0.05). CONCLUSIONS: The relationship between lumbar and knee pain disorders should be considered in the assessment and management of patients with knee pain. PMID- 26060162 TI - MPV and other inflammatory markers in diagnosing acute appendicitis. AB - OBJECTIVE: To investigate whether mean platelet volume can be used as an inflammatory marker for the diagnosis of acute appendicitis, and to determine the role, if any, of white blood cell count, C-reactive protein and neutrophil count in this regard. METHODS: The retrospective study was conducted at Mersin University (MEU) Health Research and Application Center, Emergency Department, Mersin, Turkey, and included medical record of patients having gone appendectomy between April 2012 to July 2013. Based on pathology examination, the cases were grouped as uncomplicated, complicated, and non-appendicitis cases. Preoperative white blood cell, neutrophil, C-reactive protein and mean platelet volume were noted. SPSS 16 was used for statistical analysis. RESULTS: Records of 275 patients were studied. Overall, 90(32.7%) patients were uncomplicated, 120(43.7%) complicated, and 65(23.6%) were non-appendicitis cases. The first two groups had a significantly higher white blood cell (p=0.001) and neutrophil (p<0.001) counts than the third one. Mean platelet volume levels were not statistically different (p=0.478).The neutrophil count had a sensitivity of 76.19%, specificity of 56.92%, positive predictive value of 85.11%, and negative predictive value of 42.53%; white blod cell count had sensitivity 68.10%, specificity 61.54%, positive predictive value 85.12%, and negative predictive value 37.38%; mean platelet volume level had sensitivity 74.76%, specificity 35.38%, positive predictive value 78.89%, and negative predictive value 30.26%; and C-reactive protein level had sensitivity 84.29%, specificity 30.77%, positive predictive value 79.73%, and negative predictive value 37.74%. CONCLUSIONS: Elevated white blood cell and neutrophil counts may be used as diagnostic tests in cases of acute appendicitis, while C-reactive protein and mean platelet volume levels were not useful as diagnostic markers. PMID- 26060161 TI - The effect of methyl palmitate on treatment of experimental asthma. AB - OBJECTIVE: To determine the effects of methyl palmitate on murine model of chronic asthma. METHODS: The experimental study was conducted in the animal laboratory of DokuzEylul University, Turkey, from October to December, 2012, and comprised BALB/c mice whowere divided into four equal groups: three experimental and one control group. All groups except the control group were sensitised and challenged with ovalbumin. Mice with experimentally-induced asthma in Group I received saline; Group II dexamethasone 1mg/kg; Group III methyl palmitate300mg/kg intraperitoneally three times per week in the last four weeks of the study period. Animals were sacrificed 24h after the last administration of study drugs. Histological findings of airways were evaluated by light microscopic examination. Blood samples from vena cava inferior were taken for measurement of interleukin-5 levels. SPSS 15 was used for statistical analysis. RESULTS: The 28 female mice in the study were divided into 4 groups of 7(25%) each. The age range of the animals was 6-8weeks, and the weight range was 18-20g. All histological parameters and interleukin-5 levels of asthma in the Group III were significantly ameliorated compared to the Group I (p<0.05). All histological parameters and interleukin-5 levels were similar between Group III and Group II. CONCLUSIONS: Methyl palmitate exhibited anti-inflammatory effects by resolving the histological changes and reducing the interleukin-5 levels in murine model of chronic asthma. PMID- 26060163 TI - Activities of daily living, quality of life, social support and depression levels of elderly individuals in Turkish society. AB - OBJECTIVE: To determine activities of daily living, quality of life, social support and depression levels of elderly individuals and the factors affecting each of these items. METHODS: The cross-sectional study was conducted from August 2009 to June 2012 in Edirne, Turkey, and included elderly individuals over 60 years of age. Data was collected using a survey form, the Katz Activities of Daily Living Scale, the Multidimensional Scale of Perceived Social Support, the European Quality of Life-5 Dimensions scale and the Geriatric Depression Scale. Data was analysed using Spearman's correlation analysis. RESULTS: Of the 912 subjects in the study, 509(55.8%) were females and 402(44.2%) were males, with an overall mean age of 68.05 +/- 6.6 years (range: 60-94 years). Besides, 644(70.6%) of the subjects were married and 595(65.2%) were living with their spouse. The levels of social support and activities of daily living of elderly individuals with a high quality of life were higher, and their levels of depression were lower (p<0.05). CONCLUSIONS: Older age, chronic health problems and polypharmacy should be taken into account when planning healthcare services for the elderly to ensure that they maintain a better quality of life. PMID- 26060164 TI - Risk factors of childhood asthma in children attending Lyari General Hospital. AB - OBJECTIVE: To determine the factors associated with asthma in children. METHODS: The case-control study was conducted in the paediatrics clinic of Lyari General Hospital, Karachi, from May to October 2010. Children 1-15 years of age attending the clinic represented the cases, while the control group had children who were closely related (sibling or cousin) to the cases but did not have the symptoms of disease at the time. Data was collected through a proforma and analysed using SPSS 10. RESULTS: Of the total 346 subjects, 173(50%) each comprised the two groups. According to univariable analysis the risk factors were presence of at least one smoker (odds ratio: 3.6; 95% confidence interval: 2.3-5.8), resident of kacha house (odds ratio: 16.2; 95% confidence interval: 3.8-69.5),living in room without windows (odds ratio: 9.3; 95% confidence interval: 2.1-40.9) and living in houses without adequate sunlight (odds ratio: 1.6; 95% confidence interval: 1.2-2.4).Using multivariable modelling, family history of asthma (odds ratio: 5.9; 95% confidence interval: 3.1-11.6), presence of at least one smoker at home (odds ratio: 4.1; 95% confidence interval: 2.3-7.2), people living in a room without a window (odds ratio: 5.5; 95% confidence interval: 1.15-26.3) and people living in an area without adequate sunlight (odds ratio: 2.2; 95% confidence interval: 1.13-4.31) were found to be independent risk factors of asthma in children adjusting for age, gender and history of weaning. CONCLUSIONS: Family history of asthma, children living with at least one smoker at home, room without windows and people living in an area without sunlight were major risk factors of childhood asthma. PMID- 26060165 TI - Cost of care in a paediatric intensive care unit of a tertiary-care university hospital of Pakistan. AB - OBJECTIVE: To assess the cost of treatment for families of children hospitalised in paediatric intensive care unit of a tertiary care teaching hospital. METHODS: The retrospective cohort study was conducted in Aga Khan University Hospital, Karachi, and comprised record of all children admitted to the paediatric intensive care unit from January 1 to June 30, 2013. Demographic data, diagnosis at the time of admission, co-morbidity, length of stay in intensive care and outcome were recorded. The record of all hospital charges for each day the patient was cared for were also recorded. The finance department itemised the cost into major categories like pharmacy, radiology, laboratory, etc. SPSS 19 was used for statistical analysis. RESULTS: Record of 148 patients represented the study sample. Of them, 98(66%) were males. Overall median age was 2.7 yrs (interquartile range: 1 month to 16 years) and 93(62.8%) were below 5 years of age. Median length of stay was 3.5 days (range: 2-5 days) and total patient days in intensive care were 622. The median cost per admission was PKR 217,238 (range: (114,550-368,808) and mean cost per day was PKR 57,535 (43,911-85,527). The major cost distributions were bed charges PKR 8,092,080 (18.02%), physician charges PKR 6,398653(14.25%), medical-surgical supplies PKR 8,000772(17.8%), laboratory charges PKR 8,403,615(18.9%) and pharmacy charges PKR 5,852.226(13.03%). CONCLUSIONS: The cost of paediatric intensive care unit was expensive. Cost distribution was almost evenly distributed. Hence, a better admission policy is needed for resource utilisation and cost-effectiveness. PMID- 26060166 TI - Hepatitis E -- A preventable health issue -- endangering pregnant women's life and foetal outcomes. AB - OBJECTIVE: To observe the clinical spectrum, complications and pregnancy outcome in women with Hepatitis E. METHODS: The descriptive prospective study was conducted at the Liaquat University of Medical and Health Sciences, Jamshoro, Red Crescent General Hospital and Saint Elizabeth Hospital, Hyderabad, from January 1, 2011, to December 31, 2013. All pregnant women with Hepatitis E positive on virology screening were included. The subjects were enrolled from the out-patient department as well as from among those admitted in either Obstetrics or Medical wards. Data was obtained through a predesigned proforma, and analysed using SPSS 20. RESULTS: The overall mean age of the 45 women in the study was 27.78+/-6.742. There were 21(46.7%) women in 21-30 years age group, 22(48.9) were multiparous, 31(68.9%) were uneducated, and 29(64.4%) were from poor social class. Besides, late second trimester and third trimester of pregnancy was found in 27(60%), unstable condition 10(22.22%), disturbed liver function test 24(53.3%) and raised serum glutamic pyruvic transaminase level >101u/l 27(60%), deranged coagulation profile such as raised prothrombin time 25(55.5%), and activated partial thromboplastin time 18(40%)cases. Overall 36(80%) women were discharged, while 9 (20%) died. Besides, 10(24.4%) babies needed intensive care, 13(42.2%) foetuses died during intrauterine life, 5(11%) were stillborn, while 17(37.8%) were alive and were discharged home. CONCLUSIONS: Pregnant women with Hepatitis E were more vulnerable as their life, health and foetal outcome suffered a lot. PMID- 26060167 TI - The case for family medicine in Pakistan. AB - The specialty of Family Medicine enjoys a special position in the medical practice of the West, serving as one of the key primary care specialties. Family physicians act as providers of first contact catering to the medical needs of the entire family in all aspects of preventive, curative and rehabilitative stages of illness and to health maintenance. The growth of this specialty, however, has lagged behind in Pakistan for various reasons. Having both a high burden of communicable and non-communicable diseases in Pakistan; family physicians should form the frontline force in dealing with these health issues. Several success stories of Family Medicine forming the base of medical services have been noted, validating its presence and propagation. The World Health Organisation also supported this in its 2008 report that discusses primary care for all. Growth of family practice needs to be encouraged at both undergraduate and postgraduate levels to ensure adequate training and provision of quality of medical care to our society. The need of the hour is that both medical institutions and the government develop policies to strengthen Family Medicine and incentivise family practice in rural and urban settings to cater to the needs of society at large. PMID- 26060168 TI - How to conduct a workshop on medical writing: Tips, advice and experience sharing. AB - Medical writing has become an essential skill for anybody in academia and engaged in teaching. Workshops on medical writing are an effective way to teach the essential skills of medical writing to students and faculty members. There is a huge demand for these workshops all around the globe. Usually there is no curriculum of medical writing for the undergraduates or dedicated structured training sessions for the faculty members. One of the authors won an Author AID grant to conduct a series of workshops on medical writing. Eight workshops were conducted in three months, benefitting more than 200 students and faculty staff. We share our experience of holding this successful series of workshops with the aim that it might serve as a guide for researchers and faculty members who are eager to share and transfer their skills and knowledge. We also offer lessons learnt during this educational activity, tips to improve the quality and delivery of the content with limited resources and maximizing the impact. Experienced medical writers need to conduct these workshops to transfer their skills and to facilitate their colleagues and students to become better medical writers. Planning, rehearsal, motivation, resource management, good team work, audience analysis and feedback can make a workshop successful. Well prepared workshop content delivered in an interactive way with a variety of activities makes the workshop an engaging and interesting educational activity. PMID- 26060169 TI - Haemosuccus pancreaticus, an uncommon cause of upper gastro intestinal bleeding: Case report and review of the literature. AB - Haemosuccus Pancreaticus is defined as upper gastro intestinal (GI) bleeding from the ampula of vater via the pancreatic duct. It is most commonly associated with pancreatic inflammation, erosion of the pancrease by aneurysm or pseudo-aneurysm of the splenic artery. We report a 69 year old man with previous history of acute pancreatitis who was admitted with recurrent haematemesis. Initial upper GI endocopy was normal, while admitted, he collapse with abdominal pain and hypotension. He was resuscitated with blood and intravenous fluid. Repeat upper GI endocopy showed fresh blood in the duodenum, but no active bleeding site was demonstrated. An urgent coeliac axis CT angiogram was done which showed an splenic artery pseudo-aneurysm, which was successfully embolized. Patient is well 9 months after the procedure. This case highlights the importance of considering coeliac axis CT angiogram as part of investigation for obscure GI bleeding. PMID- 26060170 TI - Schwannoma of stomach. AB - Gastrointestinal mesenchymal tumours are a group of tumours originating from the mesenchymal stem cells of the gastrointestinal (GI) tract. Digestive tract Schwannomas are rare mesenchymal tumours occurring most frequently in the stomach. We report the case of a 40-year-old woman with gastric Schwannoma located at the posterior wall of the antrum. PMID- 26060171 TI - Central acetabular fracture with dislocation treated by minimally invasive plate osteosynthesis. AB - Central acetabular fractures with dislocation are usually the result of high energy trauma, resulting in joint incongruity, and are frequently associated with other injuries. Open reduction and internal fixation has been the standard treatment for acetabular fractures, but it is associated with extensive surgical trauma, and complications such as haematoma formation, iatrogenic nerve injury, and heterotopic ossification. We present the case of a 63-year-old female who sustained a central acetabular fracture of the hip with dislocation as a result of an automobile collision. Closed reduction of the dislocation was performed, and the fracture was managed by minimally invasive plate osteosynthesis using a specially prepared plate. At 01 year postoperatively, radiographs showed the fracture to have been well-healed with good congruity of the joint. However, heterotopic ossification of the joint was noted. The technique allowed reduction of the fracture with minimal surgical trauma. PMID- 26060172 TI - Pain management with retrobulbar alcohol injection in absolute glaucoma. AB - Ocular pain can be multi-factorial and often refractory to treatment, in spite of the myriad options available to the ophthalmologist for its management. Initial therapy entails the use of topical and systemic pressure lowering agents as well as anti-inflammatory/analgesics for the provision of relief. Those refractory to medical therapy may require surgical intervention in the form of cyclodestructive procedures, retrobulbar injection of absolute alcohol and evisceration or enucleation. A case series of 5 patients of absolute glaucoma who were successfully treated with retrobulbar alcohol injection is reported. Pain was recorded on a verbal analogue score (VAS).All the patients were pain free twelve months after the injection. No significant long term complications were observed. This case series emphasizes the fact that retrobulbar alcohol injection can play an important role in the alleviation of pain in patients with absolute glaucoma. PMID- 26060174 TI - Self-management of diabetes in primary care. AB - This article defines and discusses diabetes self-management education and diabetes self-management support in the context of primary care. It offers practical advice to help primary care physicians begin and enhance the quality of self-management education and support services in their practice. PMID- 26060173 TI - Type 1 diabetes: Syndromes in resource-challenged settings. AB - Type 1 Diabetes is a complex disorder that is made more complex by the myriad of co-morbid conditions associated with it. Mauriac Syndrome is a well-known but nowadays uncommon condition that presents with growth retardation secondary to poor glycaemic control. Limited Joint Mobility is an often-missed association of diabetes. Its importance lies in the fact that it can cause significant impairment of fine movements in T1DM children. It also indicates poor glycaemic control over a long period of time and can be used as a surrogate marker for development of diabetic microvascular complications. Anaemia in T1DM is protean and can develop due to a combination of nutritional factors, chronic renal disease, coeliac disease and worm infestation. Management is etiological. Vitamin deficiencies are ubiquitous in T1DM and if left untreated, can lead to neurological, haematological and skeletal dysfunction. The best-known co-morbid conditions are the local site reactions clubbed together under the moniker lipodystrophies. These can be either atrophic or hypertrophic and are usually due to repeated injections at the same site, improper technique and needle re-use. Management is often difficult and they are best prevented by appropriate diabetes education and emphasis on proper injection techniques at the time of T1DM diagnosis, with periodic reinforcement. Amyloidosis is a little known condition that shares a lot of features in common with the lipodystrophies and often needs to be differentiated from lipohypertrophy. T1DM is a disease which is often associated with a poor quality of life and these co-morbid conditions also need to be treated for effective general and psychological well-being. PMID- 26060175 TI - Cancer illustrations and warning labels on cigarette packs: perceptions of teenagers from high socioeconomic status in Lahore. AB - Smoking is linked with adverse health outcomes and multi-organ diseases with six million deaths every year. The smoking population includes both genders and the habit is seen in minors as well. The cross-sectional study was conducted in Lahore among teenagers belonging to high socioeconomic class. A sample of 191 students was recruited by convenience sampling. The teenagers were questioned on their perceptions relating to prohibition labels, factors that led them to smoke, and ideas to make health warnings more effective. Overall, 66(34.55%) teenagers were smokers, and of them, 50(75.75%) were boys and 16(24.24%) were girls. Besides, 25(37.9%) smokers were of the view that smoking is a bad habit; 40(60.6%) said prohibition labels would not change the mindset of the smoker; 35(53%)believed that a smoker is completely uninfluenced by prohibition labels. Results suggest that the warning labels on cigarette packs should be made more comprehensible and alarming for smokers. PMID- 26060176 TI - The economic evidence for advance care planning: Systematic review of evidence. AB - BACKGROUND: Advance care planning is a process of discussion and review concerning future care in the event of losing capacity. Aimed at improving the appropriateness and quality of care, it is also often considered a means of making better use of healthcare resources at the end of life. AIM: To review and summarise economic evidence on advance care planning. DESIGN: A systematic review of the academic literature. DATA SOURCES: We searched for English language, peer reviewed journal articles, 1990-2014, using relevant research databases: PubMed, ProQuest, CINAHL Plus with Full Text; EconLit, PsycINFO, SocINDEX with Full Text and International Bibliography of the Social Sciences. Empirical studies using statistical methods in which advance care planning and costs are variables were included. RESULTS: There are no published cost-effectiveness studies. Included studies focus on healthcare savings, usually associated with reduced demand for hospital care. Advance care planning appears to be associated with healthcare savings for some people in some circumstances, such as people living with dementia in the community, people in nursing homes or in areas with high end-of life care spending. There is no evidence that advance care planning is likely to be more expensive. CONCLUSION: There is need for clearer articulation of the likely mechanisms by which advance care planning can lead to reduced care costs or improved cost-effectiveness, particularly for people who retain capacity. There is also a need to consider wider costs, including the costs of advance care planning facilitation or interventions and the costs of substitute health, social and informal care. Economic outcomes need to be considered in the context of quality benefits. PMID- 26060178 TI - A positive complement. AB - This brief editorial article introduces the special series, Positive Body Image: Avenues for Assessment, Application, and Advancement. This special series serves as "a positive complement" to help round out the body image literature, which has been heavily slanted towards understanding, measuring, preventing, and treating negative body image. More precisely, this special series offers a guide for conceptualizing, assessing, and promoting positive body image; highlights expressions of positive body image among various social groups; and articulates numerous directions for future research. This editorial describes the need for this special series and its development, and provides a synopsis of the six articles of the series, written by world-renowned positive body image theorists, researchers, clinicians, and change agents. PMID- 26060177 TI - Investigating the efficacy of attention bias modification in reducing high spider fear: The role of individual differences in initial bias. AB - BACKGROUND AND OBJECTIVES: Attention Bias Modification (ABM) targets attention bias (AB) towards threat and is a potential therapeutic intervention for anxiety. The current study investigated whether initial AB (towards or away from spider images) influenced the effectiveness of ABM in spider fear. METHODS: AB was assessed with an attentional probe task consisting of spider and neutral images presented simultaneously followed by a probe in spider congruent or spider incongruent locations. Response time (RT) differences between spider and neutral trials > 25 ms was considered 'Bias Toward' threat. RT difference < - 25 ms was considered 'Bias Away' from threat, and a difference between -25 ms and +25 ms was considered 'No Bias'. Participants were categorized into Initial Bias groups using pre-ABM AB scores calculated at the end of the study. 66 participants' (Bias Toward n = 27, Bias Away n = 18, No Bias n = 21) were randomly assigned to ABM-active training designed to reduce or eliminate a bias toward threat and 61 (Bias Toward n = 17, Bias Away n = 18, No Bias n = 26) to ABM-control. RESULTS: ABM-active had the largest impact on those demonstrating an initial Bias Towards spider images in terms of changing AB and reducing Spider Fear Vulnerability, with the Bias Away group experiencing least benefit from ABM. However, all Initial Bias groups benefited equally from active ABM in a Stress Task. LIMITATIONS: Participants were high spider fearful but not formally diagnosed with a specific phobia. Therefore, results should be confirmed within a clinical population. CONCLUSIONS: Individual differences in Initial Bias may be an important determinant of ABM efficacy. PMID- 26060179 TI - Architecture of TFIIIC and its role in RNA polymerase III pre-initiation complex assembly. AB - In eukaryotes, RNA Polymerase III (Pol III) is specifically responsible for transcribing genes encoding tRNAs and other short non-coding RNAs. The recruitment of Pol III to tRNA-encoding genes requires the transcription factors (TF) IIIB and IIIC. TFIIIC has been described as a conserved, multi-subunit protein complex composed of two subcomplexes, called tauA and tauB. How these two subcomplexes are linked and how their interaction affects the formation of the Pol III pre-initiation complex (PIC) is poorly understood. Here we use chemical crosslinking mass spectrometry and determine the molecular architecture of TFIIIC. We further report the crystal structure of the essential TPR array from tauA subunit tau131 and characterize its interaction with a central region of tauB subunit tau138. The identified tau131-tau138 interacting region is essential in vivo and overlaps with TFIIIB-binding sites, revealing a crucial interaction platform for the regulation of tRNA transcription initiation. PMID- 26060180 TI - Cognitive behavioural therapy can help chronic insomnia, review finds. PMID- 26060182 TI - Financial Incentives for Living Kidney Donors: Are They Necessary? AB - In the face of the perceived failure of altruistic organ donation programs to generate sufficient kidneys to meet demand, introducing financial incentives for living donors is sometimes argued as the only effective strategy by which lives currently lost while awaiting kidney transplantation might be saved. This argument from life-saving necessity is implicit in many incentive proposals, but rarely challenged by opponents. The core empirical claims on which it rests are thus rarely interrogated: that the gap between supply of and demand for donor kidneys is large and growing, the current system cannot meet demand, and financial incentives would increase the overall supply of kidneys and thus save lives. We consider these claims in the context of the United States. While we acknowledge the plausibility of claims that incentives, if sufficiently large, may successfully recruit greater numbers of living donors, we argue that strategies compatible with the existing altruistic system may also increase the supply of kidneys and save lives otherwise lost to kidney failure. We conclude that current appeals to the life-saving necessity argument have yet to establish sufficient grounds to justify trials of incentives. PMID- 26060183 TI - Creatine Kinase, Coenzyme Q10, Race, and Risk of Rhabdomyolysis. PMID- 26060184 TI - Onco-nephrology: Core Curriculum 2015. PMID- 26060181 TI - Protective effects of dietary avocado oil on impaired electron transport chain function and exacerbated oxidative stress in liver mitochondria from diabetic rats. AB - Electron transport chain (ETC) dysfunction, excessive ROS generation and lipid peroxidation are hallmarks of mitochondrial injury in the diabetic liver, with these alterations also playing a role in the development of non-alcoholic fatty liver disease (NAFLD). Enhanced mitochondrial sensitivity to lipid peroxidation during diabetes has been also associated to augmented content of C22:6 in membrane phospholipids. Thus, we aimed to test whether avocado oil, a rich source of C18:1 and antioxidants, attenuates the deleterious effects of diabetes on oxidative status of liver mitochondria by decreasing unsaturation of acyl chains of membrane lipids and/or by improving ETC functionality and decreasing ROS generation. Streptozocin-induced diabetes elicited a noticeable increase in the content of C22:6, leading to augmented mitochondrial peroxidizability index and higher levels of lipid peroxidation. Mitochondrial respiration and complex I activity were impaired in diabetic rats with a concomitant increase in ROS generation using a complex I substrate. This was associated to a more oxidized state of glutathione, All these alterations were prevented by avocado oil except by the changes in mitochondrial fatty acid composition. Avocado oil did not prevented hyperglycemia and polyphagia although did normalized hyperlipidemia. Neither diabetes nor avocado oil induced steatosis. These results suggest that avocado oil improves mitochondrial ETC function by attenuating the deleterious effects of oxidative stress in the liver of diabetic rats independently of a hypoglycemic effect or by modifying the fatty acid composition of mitochondrial membranes. These findings might have also significant implications in the progression of NAFLD in experimental models of steatosis. PMID- 26060185 TI - Computer-aided combined movement examination of the lumbar spine and manual therapy implications: Case report. AB - Combined movement examination (CME) of the lumbar spine has been recommended for clinical examination as it confers information about mechanical pain patterns. However, little quantitative study has been undertaken to validate its use in manual therapy practice. This study used computer aided CME to develop a normal reference range, and to guide provisional diagnosis and management. Two cases were assessed, before and after manual therapy using CME, a pain Visual Analogue Scale, the Roland Morris Low Back Pain and Disability Questionnaire and the Short Form (SF-12) Health Survey. Diagnosis and management were guided by comparing each CME pattern with the age and gender matched reference range. Self-reports data and CME total change scores were markedly improved for both cases, particularly for the most painful and restricted CME directions. This report describes how computer-aided CME and a normal reference range may be used objectively to inform a diagnosis and as an outcome measure in cases of mechanical LBP. Future investigations of cases with specific lumbar pathologies are required to validate this concept. PMID- 26060186 TI - Stakeholder Perceptions of the Provision of Reproductive Health Services by School-Based Health Centers as They May Inform Public Policy. AB - The provision of reproductive health services (RHS) by school-based health centers (SBHCs) is the subject of much controversy. Ideological differences about the role of schools in health care and the sexual activity of youth frame this debate. The purpose of this study was to determine the perspectives of key stakeholders related to access to RHS in SBHCs. Individual, semistructured interviews were conducted with 50 adult stakeholders. Template analysis yielded rich answers to the interview questions. Nine overarching themes emerged during thematic analysis. Subthemes and exemplar quotes revealed important insights into public opinion about RHS at SBHCs. Findings reflect strong stakeholder support for the inclusion of RHS in SBHCs as a way to promote teen sexual health. Nurses have an important role in influencing policies related to teen reproductive health such as those addressed in this study. PMID- 26060187 TI - When drugs don't make it to market. PMID- 26060188 TI - Sepsis in children. PMID- 26060189 TI - Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies. AB - Therapy-responsive biomarkers are an important and unmet need in the muscular dystrophy field where new treatments are currently in clinical trials. By using a comprehensive high-resolution mass spectrometry approach and western blot validation, we found that two fragments of the myofibrillar structural protein myomesin-3 (MYOM3) are abnormally present in sera of Duchenne muscular dystrophy (DMD) patients, limb-girdle muscular dystrophy type 2D (LGMD2D) and their respective animal models. Levels of MYOM3 fragments were assayed in therapeutic model systems: (1) restoration of dystrophin expression by antisense oligonucleotide-mediated exon-skipping in mdx mice and (2) stable restoration of alpha-sarcoglycan expression in KO-SGCA mice by systemic injection of a viral vector. Following administration of the therapeutic agents MYOM3 was restored toward wild-type levels. In the LGMD model, where different doses of vector were used, MYOM3 restoration was dose-dependent. MYOM3 fragments showed lower inter individual variability compared with the commonly used creatine kinase assay, and correlated better with the restoration of the dystrophin-associated protein complex and muscle force. These data suggest that the MYOM3 fragments hold promise for minimally invasive assessment of experimental therapies for DMD and other neuromuscular disorders. PMID- 26060190 TI - Reversibility of neuropathology and motor deficits in an inducible mouse model for FXTAS. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting carriers of the fragile X-premutation, who have an expanded CGG repeat in the 5'-UTR of the FMR1 gene. FXTAS is characterized by progressive development of intention tremor, ataxia, parkinsonism and neuropsychological problems. The disease is thought to be caused by a toxic RNA gain-of-function mechanism, and the major hallmark of the disease is ubiquitin-positive intranuclear inclusions in neurons and astrocytes. We have developed a new transgenic mouse model in which we can induce expression of an expanded repeat in the brain upon doxycycline (dox) exposure (i.e. Tet-On mice). This Tet-On model makes use of the PrP-rtTA driver and allows us to study disease progression and possibilities of reversibility. In these mice, 8 weeks of dox exposure was sufficient to induce the formation of ubiquitin-positive intranuclear inclusions, which also stain positive for the RAN translation product FMRpolyG. Formation of these inclusions is reversible after stopping expression of the expanded CGG RNA at an early developmental stage. Furthermore, we observed a deficit in the compensatory eye movements of mice with inclusions, a functional phenotype that could be reduced by stopping expression of the expanded CGG RNA early in the disease development. Taken together, this study shows, for the first time, the potential of disease reversibility and suggests that early intervention might be beneficial for FXTAS patients. PMID- 26060192 TI - Subnuclear re-localization of SOX10 and p54NRB correlates with a unique neurological phenotype associated with SOX10 missense mutations. AB - SOX10 is a transcription factor with well-known functions in neural crest and oligodendrocyte development. Mutations in SOX10 were first associated with Waardenburg-Hirschsprung disease (WS4; deafness, pigmentation defects and intestinal aganglionosis). However, variable phenotypes that extend beyond the WS4 definition are now reported. The neurological phenotypes associated with some truncating mutations are suggested to be the result of escape from the nonsense mediated mRNA decay pathway; but, to date, no mechanism has been suggested for missense mutations, of which approximately 20 have now been reported, with about half of the latter shown to be redistributed to nuclear bodies of undetermined nature and function in vitro. Here, we report that p54NRB, which plays a crucial role in the regulation of gene expression during many cellular processes including differentiation, interacts synergistically with SOX10 to regulate several target genes. Interestingly, this paraspeckle protein, as well as two other members of the Drosophila behavior human splicing (DBHS) protein family, co localize with SOX10 mutants in nuclear bodies, suggesting the possible paraspeckle nature of these foci or re-localization of the DBHS members to other subnuclear compartments. Remarkably, the co-transfection of wild-type and mutant SOX10 constructs led to the sequestration of wild-type protein in mutant-induced foci. In contrast to mutants presenting with additional cytoplasmic re localization, those exclusively found in the nucleus alter synergistic activity between SOX10 and p54NRB. We propose that such a dominant negative effect may contribute to or be at the origin of the unique progressive and severe neurological phenotype observed in affected patients. PMID- 26060193 TI - Strategic exploration of battery waste management: A game-theoretic approach. AB - Electronic waste or e-waste is the fastest growing stream of solid waste today. It contains both toxic substances as well as valuable resources. The present study uses a non-cooperative game-theoretic approach for efficient management of e-waste, particularly batteries that contribute a major portion of any e-waste stream and further analyses the economic consequences of recycling of these obsolete, discarded batteries. Results suggest that the recycler would prefer to collect the obsolete batteries directly from the consumer rather than from the manufacturer, only if, the incentive return to the consumer is less than 33.92% of the price of the battery, the recycling fee is less than 6.46% of the price of the battery, and the price of the recycled material is more than 31.08% of the price of the battery. The manufacturer's preferred choice of charging a green tax from the consumer can be fruitful for the battery recycling chain. PMID- 26060191 TI - Rett syndrome: disruption of epigenetic control of postnatal neurological functions. AB - Loss-of-function mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2) cause a devastating pediatric neurological disorder called Rett syndrome. In males, these mutations typically result in severe neonatal encephalopathy and early lethality. On the other hand, owing to expression of the normal allele in ~50% of cells, females do not suffer encephalopathy but instead develop Rett syndrome. Typically females with Rett syndrome exhibit a delayed onset of neurologic dysfunction that manifests around the child's first birthday and progresses over the next few years. Features of this disorder include loss of acquired language and motor skills, intellectual impairment and hand stereotypies. The developmental regression observed in patients with Rett syndrome arises from altered neuronal function and is not the result of neurodegeneration. Maintenance of an appropriate level of MeCP2 appears integral to the function of healthy neurons as patients with increased levels of MeCP2, owing to duplication of the Xq28 region encompassing the MECP2 locus, also present with intellectual disability and progressive neurologic symptoms. Despite major efforts over the past two decades to elucidate the molecular functions of MeCP2, the mechanisms underlying the delayed appearance of symptoms remain unclear. In this review, we will highlight recent findings that have expanded our knowledge of MeCP2's functions, and we will discuss how epigenetic regulation, chromatin organization and circuit dynamics may contribute to the postnatal onset of Rett syndrome. PMID- 26060194 TI - Esterification of sludge palm oil as a pretreatment step for biodiesel production. AB - Acid esterification of sludge palm oil, having 50 mas.% free fatty acids, i.e., 50 g of dominant free fatty acid per 100 g of oil, was investigated with the objective of determining conditions for the efficient reduction of free fatty acids. The influences of sulphuric acid dosage and molar ratio of methanol to oil were studied, with the final intention to obtain feedstock with a free fatty acids content acceptable for biodiesel production by alkali-transesterification. Esterification was performed using different molar ratios of methanol to oil (3:1, 6:1 and 9:1) and varying the amount of H2SO4 catalyst (0.92 mas.%, 1.84 mas.% and 4.60 mas.%). Under the applied conditions, the sulphuric acid dosage of 4.60 mas.% resulted in the satisfactory decrease of the feedstock's free fatty acids for 6:1 and 9:1 molar ratios of methanol to oil. Thus, taking into account the economic reasoning, it can be concluded that approximately 5 mas.% of H2SO4 with 6:1 molar ratio of methanol to oily feedstock, might be regarded as the dosage necessary for satisfactory pretreatment of the feedstock to be further subjected to the alkaline transesterification. Finally, the effort to consolidate the information on acid esterification available in literature was made, contributing to knowledge on sustainable biodiesel production using the low-grade and low-cost sources. PMID- 26060195 TI - Properties of ceramics prepared using dry discharged waste to energy bottom ash dust. AB - The fine dust of incinerator bottom ash generated from dry discharge systems can be transformed into an inert material suitable for the production of hard, dense ceramics. Processing involves the addition of glass, ball milling and calcining to remove volatile components from the incinerator bottom ash. This transforms the major crystalline phases present in fine incinerator bottom ash dust from quartz (SiO(2)), calcite (CaCO(3)), gehlenite (Ca(2)Al(2)SiO(7)) and hematite (Fe(2)O(3)), to the pyroxene group minerals diopside (CaMgSi(2)O(6)), clinoenstatite (MgSi(2)O(6)), wollastonite (CaSiO(3)) together with some albite (NaAlSi(3)O(8)) and andradite (Ca(3)Fe(2)Si(3)O(12)). Processed powders show minimal leaching and can be pressed and sintered to form dense (>2.5 g cm(-3)), hard ceramics that exhibit low firing shrinkage (<7%) and zero water absorption. The research demonstrates the potential to beneficially up-cycle the fine incinerator bottom ash dust from dry discharge technology into a raw material suitable for the production of ceramic tiles that have potential for use in a range of industrial applications. PMID- 26060196 TI - Corrigendum. AB - Removal performance of elemental mercury by low-cost adsorbents prepared through facile methods of carbonization and activation of coconut husk by Johari et al., Waste Manag Res January 2015 33: 81-88, doi: 10.1177/0734242X14562660. PMID- 26060197 TI - Iron and aluminium oxides containing industrial wastes as adsorbents of heavy metals: Application possibilities and limitations. AB - Industrial wastes with a high iron or aluminium oxide content are produced in huge quantities as by-products of water treatment (water treatment residuals), bauxite processing (red mud) and hard and brown coal burning in power plants (fly ash). Although they vary in their composition, the wastes have one thing in common--a high content of amorphous iron and/or aluminium oxides with a large specific surface area, whereby this group of wastes shows very good adsorbability towards heavy metals, arsenates, selenates, etc. But their physical form makes their utilisation quite difficult, since it is not easy to separate the spent sorbent from the solution and high bed hydraulic resistances occur in dynamic regime processes. Nevertheless, because of the potential benefits of utilising the wastes in industrial effluent treatment, this issue attracts much attention today. This study describes in detail the waste generation processes, the chemical structure of the wastes, their physicochemical properties, and the mechanisms of fixing heavy metals and semimetals on the surface of iron and aluminium oxides. Typical compositions of wastes generated in selected industrial plants are given. A detailed survey of the literature on the adsorption applications of the wastes, including methods of their thermal and chemical activation, as well as regeneration of the spent sorbents, is presented. The existing and potential ways of modifying the physical form of the discussed group of wastes, making it possible to overcome the basic limitation on their practical use, are discussed. PMID- 26060198 TI - Possibilities of municipal solid waste incinerator fly ash utilisation. AB - Properties of the waste treatment residual fly ash generated from municipal solid waste incinerator fly ash were investigated in this study. Six different mortar blends with the addition of the municipal solid waste incinerator fly ash were evaluated. The Portland cement replacement levels of the municipal solid waste incinerator fly ash used were 25%, 30% and 50%. Both, raw and washed municipal solid waste incinerator fly ash samples were examined. According to the mineralogical composition measurements, a 22.6% increase in the pozzolanic/hydraulic properties was observed for the washed municipal solid waste incinerator fly ash sample. The maximum replacement level of 25% for the washed municipal solid waste incinerator fly ash in mortar blends was established in order to preserve the compressive strength properties. Moreover, the leaching characteristics of the crushed mortar blend was analysed in order to examine the immobilisation of its hazardous contents. PMID- 26060199 TI - Comparison of cardio-protective effects induced by different modalities of sevoflurane conditioning in isolated rat hearts. AB - OBJECTIVE: To examine whether the combination of anesthetic preconditioning and anesthetic postconditioning could elicit additional cardio-protection as compared to either anesthetic preconditioning or anesthetic postconditioning alone and its underlying mechanism. METHODS: Isolated rat hearts were randomized into one of four groups: CTRL group (30 min of ischemia followed by 120 min of reperfusion alone); SpreC group (3% sevoflurane preconditioning was administered for 15 min followed by 10 min of washout before ischemia); SpostC group (3% sevoflurane postconditioning was administered during the first 15 min of reperfusion after ischemia); SpreC+SpostC group (the protocols of SpreC and SpostC were combined). Hemodynamics, myocardial infarct size, lactate dehydrogenase and creatine kinase MB in collected effluent, phosphorylation of PKB/Akt and ERK 1/2 and content of nicotinamide adenine dinucleotide in the left ventricular tissue were compared among the four groups. RESULTS: When compared with unprotected Control hearts, those in the sevoflurane-treated groups (SpreC, SpostC and SpreC+SpostC) showed significantly better functional recovery, reduced myocardial infarct size and decreased lactate dehydrogenase and creatine kinase-MB release. Comparison of the above-mentioned variables among the three sevoflurane-treated groups showed that maximal cardio-protection was obtained in the SpreC+SpostC group. Both SpreC and SpreC+SpostC induced a biphasic response in protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK 1/2) phosphorylation, while SpostC induced only one phase. The effects on phosphorylation of both PKB/Akt and ERK 1/2 induced by SpreC and SpostC were found to be additive during reperfusion. The combination of SpreC and SpostC also had additive effects on inhibiting mitochondrial permeability transition pore (mPTP) opening induced by ischemia reperfusion. CONCLUSION: These findings suggested that the cardio-protection induced by SpreC and SpostC could be additive via the involvement of PKB/Akt, ERK 1/2 and mPTP. PMID- 26060200 TI - Anticoagulation strategies and difficulties in neonatal and paediatric extracorporeal membrane oxygenation (ECMO). AB - OBJECTIVE: The aim of this review is to highlight an emerging problem with anticoagulation-related complications in neonatal and paediatric ECMO, to explore for flaws in the currently recommended anticoagulation management responsible for these problems and to discuss possible strategies mitigating further escalation of the issue. DATA SOURCES: Pertinent neonatal and paediatric literature on the topic of interest and international Extracorporeal Life Support Organisation (ELSO) registry data request. CONCLUSIONS: The international ELSO registry data reveals increasing rates of anticoagulation-related complications during neonatal and paediatric ECMO worldwide. The causes are multifactorial and the proposed solution to the problem is to match anticoagulation management to the pathophysiological complexity of haemostasis on ECMO. PMID- 26060201 TI - Changes in electrical activation modify the orientation of left ventricular flow momentum: novel observations using echocardiographic particle image velocimetry. AB - AIMS: Changes in electrical activation sequence are known to affect the timing of cardiac mechanical events. We aim to demonstrate that these also modify global properties of the intraventricular blood flow pattern. We also explore whether such global changes present a relationship with clinical outcome. METHODS AND RESULTS: We investigated 30 heart failure patients followed up after cardiac resynchronization therapy (CRT). All subjects underwent echocardiography before implant and at follow-up after 6+ months. Left ventricular mechanics was investigated at follow-up during active CRT and was repeated after a temporary interruption <5 min later. Strain analysis, performed by speckle tracking, was used to assess the entity of contraction (global longitudinal strain) and its synchronicity (standard deviation of time to peak of radial strain). Intraventricular fluid dynamics, by echographic particle image velocimetry, was used to evaluate the directional distribution of global momentum associated with blood motion. The discontinuation of CRT pacing reflects into a reduction of deformation synchrony and into the deviation of blood flow momentum from the base apex orientation with the development of transversal flow-mediated haemodynamic forces. The deviation of flow momentum presents a significant correlation with the degree of volumetric reduction after CRT. CONCLUSION: Changes in electrical activation alter the orientation of blood flow momentum. The long-term CRT outcome correlates with the degree of re-alignment of haemodynamic forces. These preliminary results suggest that flow orientation could be used for optimizing the biventricular pacing setting. However, larger prospective studies are needed to confirm this hypothesis. PMID- 26060202 TI - QRS complex distortion (Grade 3 ischaemia) as a predictor of myocardial damage assessed by cardiac magnetic resonance imaging and clinical prognosis in patients with ST-elevation myocardial infarction. AB - AIMS: Distortion of the terminal portion of the QRS complex (so-called Grade 3 ischaemia, G3I) has been associated with adverse outcomes in ST-elevation myocardial infarction (STEMI) populations. However, the correlation of G3I with infarct size and microvascular injury as defined by cardiac magnetic resonance (CMR) is not well defined. Aim of this study was to assess the relation of G3I with myocardial damage as assessed by CMR and clinical outcomes in STEMI patients. METHODS AND RESULTS: We analysed the ECGs of 572 consecutive STEMI patients regarding the presence or absence of G3I. CMR was performed within 1 week after infarction for comprehensive assessment of myocardial damage using a standardized protocol. The primary clinical endpoint was major adverse cardiac events (MACE) within 12 months after infarction. G3I was present in 186 (32%) patients. The presence of G3I was associated with larger infarct size (P = 0.01), the presence of late microvascular obstruction (P = 0.05), the presence of intramyocardial haemorrhage (P = 0.04), and impaired myocardial salvage (P = 0.01). G3I was associated with a higher incidence of MACE (P = 0.01) and was identified as an independent predictor of MACE in Cox regression analysis (HR 2.19; 95% CI 1.10 to 4.38, P = 0.03). CONCLUSION: This largest study to date correlating G3I on the admission ECG with CMR markers of myocardial damage demonstrates that G3I is significantly associated with infarct size, impaired myocardial salvage, and reperfusion injury in a reperfused STEMI population. Moreover, G3I was independently associated with MACE. CLINICALTRIALS.GOV: NCT00712101. PMID- 26060203 TI - Left ventricular regional function and maximal exercise capacity in aortic stenosis. AB - AIMS: The objective assessment of maximal exercise capacity (MEC) using peak oxygen consumption (VO2) measurement may be helpful in the management of asymptomatic aortic stenosis (AS) patients. However, the relationship between left ventricular (LV) function and MEC has been relatively unexplored. We aimed to identify which echocardiographic parameters of LV systolic function can predict MEC in asymptomatic AS. METHODS AND RESULTS: Asymptomatic patients with moderate to severe AS (n = 44, aortic valve area <1.5 cm(2), 66 +/- 13 years, 75% of men) and preserved LV ejection fraction (LVEF > 50%) were prospectively referred for resting echocardiography and cardiopulmonary exercise test. LV longitudinal strain (LS) of each myocardial segment was measured by speckle tracking echocardiography (STE) from the apical (aLS) 4-, 2-, and 3-chamber views. An average value of the LS of the analysable segments was provided for each myocardial region: basal (bLS), mid (mLS), and aLS. LV circumferential and radial strains were measured from short-axis views. Peak VO2 was 20.1 +/- 5.8 mL/kg/min (median 20.7 mL/kg/min; range 7.2-32.3 mL/kg/min). According to the median of peak VO2, patients with reduced MEC were significantly older (P < 0.001) and more frequently females (P = 0.05). There were significant correlations between peak VO2 and age (r = -0.44), LV end-diastolic volume (r = 0.35), LV stroke volume (r = 0.37), indexed stroke volume (r = 0.32), and E/e' ratio (r = -0.37, all P < 0.04). Parameters of AS severity and LVEF did not correlate with peak VO2 (P = NS for all). Among LV deformation parameters, bLS and mLS were significantly associated with peakVO2 (r = 0.43, P = 0.005, and r = 0.32, P = 0.04, respectively). With multivariable analysis, female gender (beta = 4.9; P = 0.008) and bLS (beta = 0.50; P = 0.03) were the only independent determinants (r(2) = 0.423) of peak VO2. CONCLUSION: In asymptomatic AS, impaired LV myocardial longitudinal function determines reduced MEC. Basal LS was the only parameter of LV regional function independently associated with MEC. PMID- 26060204 TI - Use of left ventricular flow mapping in echocardiographic optimization of atrioventricular delay. PMID- 26060205 TI - Tricuspid valve remodelling in functional tricuspid regurgitation: multidetector row computed tomography insights. AB - AIMS: Multidetector row computed tomography (MDCT) may help to understand the underlying mechanisms of functional tricuspid regurgitation (TR), a highly prevalent valve disease with novel transcatheter therapies under development. The purpose of the present study was to assess the geometrical changes of the tricuspid valve in patients with functional TR using MDCT and to correlate these changes with the TR grade assessed with echocardiography. METHODS AND RESULTS: In 114 patients undergoing transcatheter aortic valve implantation (47 men, age 81 +/- 8 years), including 33 (28.9%) patients with TR >= 3+, the tricuspid valve and right ventricle (RV) were geometrically analysed with 320-slice MDCT. The antero-posterior and septal-lateral diameters, perimeter and area of the annulus, degree of tethering of the anterior, septal and posterior tricuspid valve leaflets, and RV volumes and ejection fraction were assessed and subsequently correlated with TR grade in multivariate models. Patients with pacemaker or implantable cardioverter defibrillator leads were excluded.Patients with TR >= 3+ had larger tricuspid annulus area (1539.7 +/- 260.2 vs.1228.4 +/- 243.5 mm(2), P < 0.001), larger septal and anterior leaflet angles, and larger RV end-systolic volumes (93.2 +/- 29.8 vs. 64.2 +/- 23.6 mL, P < 0.001) compared with patients with TR < 3+.The antero-posterior tricuspid annulus diameter was independently correlated with TR >= 3+ (odds ratio 1.35; 95% confidence interval 1.07-1.69, P = 0.010), after adjusting for estimated pulmonary pressure and RV end-systolic volume. CONCLUSION: In patients with TR >= 3+, MDCT demonstrated larger tricuspid annulus and RV dimensions and pronounced tethering of the anterior and septal tricuspid leaflet. The antero-posterior annulus diameter was independently correlated with the grade of functional TR. PMID- 26060206 TI - Coronary anatomy and function: a story of Yin and Yang. PMID- 26060207 TI - Shifts in myocardial fatty acid and glucose metabolism in pulmonary arterial hypertension: a potential mechanism for a maladaptive right ventricular response. AB - AIMS: We investigated the role of metabolic alterations in the development of a maladaptive right ventricular (RV) response in pulmonary arterial hypertension (PAH), which has not previously been undertaken. This study evaluated relationships between glucose and fatty acid metabolism obtained using PET with invasive pulmonary haemodynamics, RV measurements, and RV function to gain insight into the mechanism of RV maladaptation. METHODS AND RESULTS: Seventeen consecutive PAH patients (mean age 56 +/- 15) who underwent right heart catheterization [mean pulmonary arterial pressure (mPAP) 43 +/- 12 mmHg] had cardiac 18F-fluoro-2-deoxyglucose (FDG) and (18)F-fluoro-6-thioheptadecanoic acid (FTHA) PET imaging. RV and left ventricular (LV) FDG and FTHA uptake standard uptake values (SUVs) were measured. The SUV was corrected for the partial volume effect (SUVPVE) based on cardiac magnetic resonance imaging (CMR). Right ventricular ejection fraction (RVEF) was determined by CMR. There was a significant positive correlation between mPAP and RV/LV FDG SUVPVE (r = 0.68, P = 0.003), and the ratio of RV/LV FDG SUV : RV/LV FTHA SUV (r = 0.60, P = 0.02). RVEF was negatively correlated with RV/LV FDG SUVPVE uptake (r = -0.56, P = 0.02) and RV/LV FTHA SUVPVE (r = -0.62, P = 0.019). CONCLUSION: Increased pulmonary arterial pressures are associated with increases in the ratio of FDG/FTHA uptake in the RV. Inverse correlation between the uptake of the metabolic tracers and RV function may reflect a shift towards increased fatty acid oxidation and glycolysis associated with RV failure in maladaptive remodelling. PMID- 26060208 TI - Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of lifestyle modification + metformin with lifestyle modification +/- placebo, and of metformin alone with lifestyle modification +/- placebo in PCOS on anthropometric, metabolic, reproductive and psychological outcomes. METHODS: Databases including MEDLINE, EMBASE, Pubmed, Scopus, Cochrane, PsycINFO, CINAHL, Clinical Trials registry and ANZCTR were searched for RCTs conducted on humans and published in English up to August 2014. Inclusion criteria were diagnosis of PCOS based on Rotterdam criteria (inclusive of National Institutes of Health criteria) at any age and with any BMI. Interventions of interest included lifestyle + metformin (with any dose and any duration) or metformin alone compared with lifestyle +/- placebo. RESULTS: Of 2372 identified studies, 12 RCTs were included for analysis comprising 608 women with PCOS. Lifestyle + metformin were associated with lower BMI (mean difference (MD) -0.73 kg/m(2), 95% confidence intervals (CI) -1.14, 0.32, P = 0.0005) and subcutaneous adipose tissue (MD -92.49 cm(2), 95% CI 164.14, -20.84, P = 0.01) and increased number of menstrual cycles (MD 1.06, 95% CI 0.30, 1.82, P = 0.006) after 6 months compared with lifestyle +/- placebo. There were no differences in other anthropometric, metabolic (surrogate markers of insulin resistance, fasting and area under the curve glucose, lipids and blood pressure), reproductive (clinical and biochemical hyperandrogenism), and psychological (quality of life) outcomes after 6 months between lifestyle + metformin compared with lifestyle +/- placebo. With metformin alone compared with lifestyle +/- placebo, weight and BMI were similar after 6 months, but testosterone was lower with metformin. CONCLUSIONS: Lifestyle + metformin is associated with lower BMI and subcutaneous adipose tissue and improved menstruation in women with PCOS compared with lifestyle +/- placebo over 6 months. Metformin alone compared with lifestyle showed similar BMI at 6 months. These results suggest the combination of lifestyle with metformin has a role to play in weight management: a key concern for women with PCOS. Existing study limitations include small sample sizes, short durations and risk of bias. With international guidelines now acknowledging that lifestyle and pharmacotherapy are required for weight loss and maintenance in obesity, future studies of appropriate size and duration are vital to clarify the role of metformin in PCOS management. PMID- 26060209 TI - Permanent pacing after transcatheter aortic valve implantation of a CoreValve prosthesis as determined by electrocardiographic and electrophysiological predictors: a single-centre experience. AB - AIM: The most frequent conduction complications with transcatheter aortic valve implantation (TAVI) are complete atrioventricular (AV) block and new bundle branch block (BB). The purpose of this study was to assess clinical, electrocardiographic, and electrophysiological predictors of conduction abnormalities in patients (pts) undergoing TAVI with the CoreValve prosthesis. The secondary end points were the long-term rhythm follow-up and the recovery of conduction. METHODS AND RESULTS: Forty-five consecutive pts with severe aortic stenosis, New York Heart Association II/III, and normal or slightly impaired left ventricular function who underwent CoreValve transcatheter implantation were randomized 2:1 to electrocardiographic and electrocardiographic plus electrophysiological evaluations. Pacemakers were implanted in pts with complete AV block. Follow-up was performed at 1, 6, 12, and 24 months. Conduction was affected in the total group of pts undergoing TAVI. The PR lengthened compared with the baseline but did not exceed the normal cut-off of 200 ms, and the QRS widened, basically due to new left bundle branch blocks (LBBBs). Within 1 month of follow-up, 10 pts (22%) developed complete AV block (9 peri-procedurally-20%) and 15 pts (33%) developed a new bundle BB, with LBBBs being the most common (14 31%). In the 30 pts who underwent an electrophysiological study, analysis showed that prolonged HV intervals were prognostic for pacemaker implantation. Follow-up in the total study group revealed that only 4 of the 10 (9%) initial implantations remained completely pacemaker dependent. CONCLUSION: Conduction was affected in all pts undergoing TAVI, but serious complications that required permanent pacing generally occurred in pts with pre-existing conduction abnormalities. PMID- 26060210 TI - Acute low back pain management in primary care: a simulated patient approach. AB - BACKGROUND: Recent medical guidelines for acute low back pain (aLBP) are unevenly followed. Based on financial criteria or associated with a desirability bias, studies incompletely describe the actual management provided by general practitioners (GPs) in terms of diagnosis, treatment and prevention of progression towards chronicity. OBJECTIVE: To compare actual practices of French GPs for aLBP management with clinical guidelines. METHODS: A young simulated patient (SP) consulted, using a single scenario of aLBP, in 30 primary care practices in the Paris region. RESULTS: Heterogeneous data were collected according to the grid items: during the questioning, 29 GPs (97%) asked for age and 1 GP (3%) for pregnancy; during the clinical examination, 21 GPs (70%) asked for spinal stiffness and 3 GPs (10%) for cauda equina syndrome. Non-steroidal anti-inflammatory drugs were prescribed by 27 GPs (90%). Imaging (2 GPs or 7%) and physiotherapy (3 GPs or 10%) was rarely prescribed. A sick leave was prescribed by 22 GPs (73%). Twenty-seven GPs (90%) reassured the patient. CONCLUSION: aLBP management was in line with international guidelines in terms of clinical examination, physiotherapy and imaging prescriptions and some risk factors for chronicity were taken into account. However, patient questioning was brief, and drug and sick leave prescriptions did not meet international guidelines. The SP approach seems to be a useful tool for assessing actual GP practices. PMID- 26060212 TI - Stability Design and Response to Waves by Batoids. AB - Unsteady flows in the marine environment can affect the stability and locomotor costs of animals. For fish swimming at shallow depths, waves represent a form of unsteady flow. Waves consist of cyclic oscillations, during which the water moves in circular or elliptical orbits. Large gravity waves have the potential to displace fish both cyclically and in the direction of wave celerity for animals floating in the water column or holding station on the bottom. Displacement of a fish can exceed its stability control capability when the size of the wave orbit is equivalent to the size of the fish. Previous research into compensatory behaviors of fishes to waves has focused on pelagic osteichthyan fishes with laterally compressed bodies. However, dorsoventrally compressed batoid rays must also contend with waves. Examination of rays subjected to waves showed differing strategies for stability between pelagic and demersal species. Pelagic cownose rays (Rhinoptera bonasus) would glide through or be transported by waves, maintaining a positive dihedral of the wing-like pectoral fins. Demersal Atlantic stingrays (Dasyatis sabina) and freshwater rays (Potamotrygon motoro) maintained contact with the bottom and performed compensatory fin motions and body postures. The ability to limit displacement due to wave action by the demersal rays was also a function of the bottom texture. The ability of rays to maintain stability due to wave action suggests mechanisms to compensate for the velocity flux of the water impinging on the large projected area of the enlarged pectoral fins of rays. PMID- 26060211 TI - Alligators and Crocodiles Have High Paracellular Absorption of Nutrients, But Differ in Digestive Morphology and Physiology. AB - Much of what is known about crocodilian nutrition and growth has come from animals propagated in captivity, but captive animals from the families Crocodilidae and Alligatoridae respond differently to similar diets. Since there are few comparative studies of crocodilian digestive physiology to help explain these differences, we investigated young Alligator mississippiensis and Crocodylus porosus in terms of (1) gross and microscopic morphology of the intestine, (2) activity of the membrane-bound digestive enzymes aminopeptidase-N, maltase, and sucrase, and (3) nutrient absorption by carrier-mediated and paracellular pathways. We also measured gut morphology of animals over a larger range of body sizes. The two species showed different allometry of length and mass of the gut, with A. mississippiensis having a steeper increase in intestinal mass with body size, and C. porosus having a steeper increase in intestinal length with body size. Both species showed similar patterns of magnification of the intestinal surface area, with decreasing magnification from the proximal to distal ends of the intestine. Although A. mississippiensis had significantly greater surface-area magnification overall, a compensating significant difference in gut length between species meant that total surface area of the intestine was not significantly different from that of C. porosus. The species differed in enzyme activities, with A. mississippiensis having significantly greater ability to digest carbohydrates relative to protein than did C. porosus. These differences in enzyme activity may help explain the differences in performance between the crocodilian families when on artificial diets. Both A. mississippiensis and C. porosus showed high absorption of 3-O methyl d-glucose (absorbed via both carrier-mediated and paracellular transport), as expected. Both species also showed surprisingly high levels of l-glucose-uptake (absorbed paracellularly), with fractional absorptions as high as those previously seen only in small birds and bats. Analyses of absorption rates suggested a relatively high proportional contribution of paracellular (i.e., non-mediated) uptake to total uptake of nutrients in both species. Because we measured juveniles, and most paracellular studies to date have been on adults, it is unclear whether high paracellular absorption is generally high within crocodilians or whether these high values are specific to juveniles. PMID- 26060213 TI - Holistic analysis of seven active ingredients by micellar electrokinetic chromatography from three medicinal herbs composing Shuanghuanglian. AB - A simple and reliable method has been developed with a new strategy named holistic analysis of multiple constituents to evaluate the quality of the well known traditional Chinese medicine (TCM) Shuanghuanglian (SHL) oral liquid and soft capsule. Seven main constituents of the medicine, i.e., baicalein, baicalin, chlorogenic acid, wogonin, scutellarin, forsythin and hyperin, were selected as the evaluation markers and analyzed by micellar electrokinetic chromatography. The effects of buffer pH, concentration of electrolyte, organic modifier and applied voltage on migration behavior were studied systematically. The optimum conditions for the separation were achieved in a 12.5 mM borate-10 mM sodium dihydrogen phosphate-10 mM sodium dodecyl sulfate buffer at pH 9.1 containing 10% (v/v) acetonitrile under 15 kV. The analytes were identified by their relative time with regard to para-hydroxybenzoic acid migration time used as an internal standard. The method was validated in terms of linearity, limit of detection and quantification, precision, accuracy and recoveries. The correlation coefficient ranged from 0.9962 to 0.9992. The limits of detection (S/N = 3) were from 0.15 to 3.95 MUg mL(-1). Recoveries of seven analytes in the SHL samples ranged from 89.00 to 103.04%. The proposed method was successfully applied for the quality control of complicated TCM SHL. PMID- 26060215 TI - Evaluation of aegerolysins as novel tools to detect and visualize ceramide phosphoethanolamine, a major sphingolipid in invertebrates. AB - Ceramide phosphoethanolamine (CPE), a sphingomyelin analog, is a major sphingolipid in invertebrates and parasites, whereas only trace amounts are present in mammalian cells. In this study, mushroom-derived proteins of the aegerolysin family-pleurotolysin A2 (PlyA2; K(D) = 12 nM), ostreolysin (Oly; K(D) = 1.3 nM), and erylysin A (EryA; K(D) = 1.3 nM)-strongly associated with CPE/cholesterol (Chol)-containing membranes, whereas their low affinity to sphingomyelin/Chol precluded establishment of the binding kinetics. Binding specificity was determined by multilamellar liposome binding assays, supported bilayer assays, and solid-phase studies against a series of neutral and negatively charged lipid classes mixed 1:1 with Chol or phosphatidylcholine. No cross-reactivity was detected with phosphatidylethanolamine. Only PlyA2 also associated with CPE, independent of Chol content (K(D) = 41 MUM), rendering it a suitable tool for visualizing CPE in lipid-blotting experiments and biologic samples from sterol auxotrophic organisms. Visualization of CPE enrichment in the CNS of Drosophila larvae (by PlyA2) and in the bloodstream form of the parasite Trypanosoma brucei (by EryA) by fluorescence imaging demonstrated the versatility of aegerolysin family proteins as efficient tools for detecting and visualizing CPE. PMID- 26060214 TI - Extracellular ATP protects against sepsis through macrophage P2X7 purinergic receptors by enhancing intracellular bacterial killing. AB - Extracellular ATP binds to and signals through P2X7 receptors (P2X7Rs) to modulate immune function in both inflammasome-dependent and -independent manners. In this study, P2X7(-/-) mice, the pharmacological agonists ATP-magnesium salt (Mg-ATP; 100 mg/kg, EC50 ~ 1.32 mM) and benzoylbenzoyl-ATP (Bz-ATP; 10 mg/kg, EC50 ~ 285 MUM), and antagonist oxidized ATP (oxi-ATP; 40 mg/kg, IC50 ~ 100 MUM) were used to show that P2X7R activation is crucial for the control of mortality, bacterial dissemination, and inflammation in cecal ligation and puncture-induced polymicrobial sepsis in mice. Our results with P2X7(-/-) bone marrow chimeric mice, adoptive transfer of peritoneal macrophages, and myeloid-specific P2X7(-/-) mice indicate that P2X7R signaling on macrophages is essential for the protective effect of P2X7Rs. P2X7R signaling protects through enhancing bacterial killing by macrophages, which is independent of the inflammasome. By using the connexin (Cx) channel inhibitor Gap27 (0.1 mg/kg, IC50 ~ 0.25 MUM) and pannexin channel inhibitor probenecid (10 mg/kg, IC50 ~ 11.7 MUM), we showed that ATP release through Cx is important for inhibiting inflammation and bacterial burden. In summary, targeting P2X7Rs provides a new opportunity for harnessing an endogenous protective immune mechanism in the treatment of sepsis. PMID- 26060216 TI - Barrientosiimonas endolithica sp. nov., isolated from pebbles, reclassification of the only species of the genus Tamlicoccus, Tamlicoccus marinus Lee 2013, as Barrientosiimonas marina comb. nov. and emended description of the genus Barrientosiimonas. AB - Strain JC268(T) was isolated from pebbles collected from a dam located in Lalitpur, Uttar Pradesh, India. Cells of strain JC268(T) were coccoid, appeared in pairs/triads/tetrads or short chains and were Gram-stain-positive, non-spore forming, non-motile and obligately aerobic. Strain JC268(T) was catalase- and oxidase-positive and utilized citrate for growth. The genomic DNA G+C content of strain JC268(T) was 65.3 mol%. The cell-wall peptidoglycan contained L-lysine-L serine-D-aspartic acid as interpeptide bridge with the type A4alpha. The major menaquinone was MK-8(H4). Major (>10%) fatty acids were iso-C16 : 0, iso-C16 : 1H and anteiso-C17 : 1omega9c. Diphosphatidylglycerol, phosphoglycolipid, phosphatidylinositol, glycolipid, four unidentified lipids, an amino lipid and phospholipid were the polar lipids of strain JC268(T). EzTaxon-e blast search of 16S rRNA gene sequences showed that strain JC268(T) has highest similarity to Barrientosiimonas humi 39(T) (98.65%) and Tamlicoccus marinus MSW-24(T) (97.8%) of the family Dermacoccaceae. Genome reassociation (based on DNA-DNA hybridization) of strain JC268(T) with Barrientosiimonas humi CGMCC 4.6864(T) ( = 39(T)) and T. marinus KCTC 19485(T) ( = MSW-24(T)) yielded values of 32.5 +/- 2% and 27.3 +/- 2%, respectively. Based on the data from phylogenetic and polyphasic taxonomic analyses, strain JC268(T) represents a novel species of the genus Barrientosiimonas for which the name Barrientosiimonas endolithica sp. nov., is proposed. The type strain of Barrientosiimonas endolithica is JC268(T) ( = KCTC 29672(T) = NBRC 110608(T)). Our data suggest that T. marinus should be reclassified within the genus Barrientosiimonas. Thus, a reclassification is proposed for T. marinus, the type and only species of the genus Tamlicoccus, as Barrientosiimonas marina comb. nov., which implies the emendation of the description of the genus Barrientosiimonas. PMID- 26060217 TI - Average nucleotide identity of genome sequences supports the description of Rhizobium lentis sp. nov., Rhizobium bangladeshense sp. nov. and Rhizobium binae sp. nov. from lentil (Lens culinaris) nodules. AB - Rhizobial strains isolated from effective root nodules of field-grown lentil (Lens culinaris) from different parts of Bangladesh were previously analysed using sequences of the 16S rRNA gene, three housekeeping genes (recA, atpD and glnII) and three nodulation genes (nodA, nodC and nodD), DNA fingerprinting and phenotypic characterization. Analysis of housekeeping gene sequences and DNA fingerprints indicated that the strains belonged to three novel clades in the genus Rhizobium. In present study, a representative strain from each clade was further characterized by determination of cellular fatty acid compositions, carbon substrate utilization patterns and DNA-DNA hybridization and average nucleotide identity (ANI) analyses from whole-genome sequences. DNA-DNA hybridization showed 50-62% relatedness to their closest relatives (the type strains of Rhizobium etli and Rhizobium phaseoli) and 50-60% relatedness to each other. These results were further supported by ANI values, based on genome sequencing, which were 87-92% with their close relatives and 88-89% with each other. On the basis of these results, three novel species, Rhizobium lentis sp. nov. (type strain BLR27(T) = LMG 28441(T) = DSM 29286(T)), Rhizobium bangladeshense sp. nov. (type strain BLR175(T) = LMG 28442(T) = DSM 29287(T)) and Rhizobium binae sp. nov. (type strain BLR195(T) = LMG 28443(T) = DSM 29288(T)), are proposed. These species share common nodulation genes (nodA, nodC and nodD) that are similar to those of the symbiovar viciae. PMID- 26060218 TI - Factors associated with RTCs among for-hire three-wheeler drivers in Sri Lanka: a case-control study. AB - OBJECTIVE: For-hire three-wheeler crashes are a growing burden in Sri Lanka. We conducted this study to examine the factors associated with road traffic crashes (RTCs) among for-hire three-wheeler drivers in Sri Lanka. METHODS: We conducted a case-control study in Kandy, Sri Lanka between August 2008 and March 2009. Cases were all the for-hire three-wheeler drivers involved in crashes in Kandy between 1 January and 31 December 2007 (n=88). Controls were non-crash-involved for-hire three-wheeler drivers in Kandy, matched to the ages of the cases (n=88). We examined participants' sociodemographic characteristics, job characteristics, driving behaviours and the characteristics of their three wheelers. We used conditional logistic regression analysis to examine the factors associated with for-hire three-wheeler crashes. RESULTS: Three factors were positively associated with for-hire three-wheeler crashes. They were as follows: taking more than three passengers in the passenger seat (adjusted OR (AOR)=8.03, 95% CI 1.16 to 55.71), higher age of the three wheelers (AOR=1.38, 95% CI 1.04 to 1.84), and being convicted by police for traffic law violations during the past 12 months (AOR=1.74, 95% CI 1.16 to 2.58). CONCLUSIONS: We identified three factors that might lead to for-hire three-wheeler crashes in Sri Lanka. They were as follows: carrying excessive passengers, higher three-wheeler age and drivers' traffic law violations. To prevent three-wheeler crashes, laws should prevent three wheelers carrying more than three passengers. Yearly examinations should be mandated to ensure proper driving conditions of for-hire three wheelers. Police should enforce traffic laws to prevent traffic law violations by three-wheeler drivers. PMID- 26060219 TI - L-Phenylalanine catabolism and 2-phenylethanol synthesis in Yarrowia lipolytica- mapping molecular identities through whole-proteome quantitative mass spectrometry analysis. AB - A world-wide effort is now being pursued towards the development of flavors and fragrances (F&F) production independently from traditional sources, as well as autonomously from depleting fossil fuel supplies. Biotechnological production of F&F by microbes has emerged as a vivid solution to the current market limitations. Amongst a wide variety of fragrant chemicals, 2-PE is of significant interest to both scientific and industrial community. Although the general overview of the 2-PE synthesis pathway is commonly known, involvement of particular molecular identities in this pathway has not been elucidated in Yarrowia lipolytica to date. The aim of this study was mapping molecular identities involved in 2-PE synthesis in Y. lipolytica. To acquire a comprehensive landscape of the proteins that are directly and indirectly involved in L-Phe degradation and 2-PE synthesis, we took advantage of comprehensibility and sensitivity of high-throughput LC-MS/MS-quantitative analysis. Amongst a number of proteins involved in amino acid turnover and the central carbon metabolism, enzymes involved in L-Phe conversion to 2-PE have been identified. Results on yeast-to-hyphae transition in relation to the character of the provided nitrogen source have been presented. PMID- 26060220 TI - Spillover effect of HIV-specific foreign aid on immunization services in Nigeria. AB - BACKGROUND: Health aid to Nigeria increased tremendously in the last decade and a significant portion of the funds were earmarked for HIV-associated programs. Studies on the impact of HIV-specific aid on the delivery of non-HIV health services in sub-Saharan Africa have yielded mixed results. This study assessed if there is a spillover effect of HIV-specific aid on childhood vaccinations in Nigeria. METHODS: Multivariate logistic regression models were used to estimate the effect of aid disbursements in a previous year on the receipt of vaccines at the individual level in a given year. Estimations were done for approximately 11 700 children using data from demographic and health surveys conducted in Nigeria in 2003 and 2008. RESULTS: US$1 increase in HIV aid per capita was associated with a decrease in the probability of receipt of vaccines by 8-31%: polio first dose decreased by 8%; polio final dose by 9%; diphtheria-pertussis-tetanus (DPT) first dose by 11%; DPT final dose by 19%; measles by 31%; final doses of polio and DPT plus measles vaccine by 8%. CONCLUSIONS: HIV-specific aid had a negative spillover effect on immunization services in Nigeria over the study period. Donors may need to rethink their funding strategies in favour of more horizontal approaches. PMID- 26060221 TI - Oncology Care Model: Short- and Long-Term Considerations in the Context of Broader Payment Reform. PMID- 26060222 TI - Inpatient Hematology-Oncology Rotation Is Associated With a Decreased Interest in Pursuing an Oncology Career Among Internal Medicine Residents. AB - PURPOSE: The demand for hematologists and oncologists is not being met. We hypothesized that an inpatient hematology-oncology ward rotation would increase residents' interest. Potential reasons mitigating interest were explored and included differences in physician distress, empathy, resilience, and patient death experiences. METHODS: Agreement with the statement "I am interested in pursuing a career/fellowship in hematology and oncology" was rated by residents before and after a hematology-oncology rotation, with 0 = not true at all, 1 = rarely true, 2 = sometimes true, 3 = often true, and 4 = true nearly all the time. House staff rotating on a hematology-oncology service from November 2013 to October 2014 also received questionnaires before and after their rotations containing the Connors-Davidson Resilience Scale, the Impact of Events Scale Revised, the Interpersonal Reactivity Index, demographic information, and number of dying patients cared for and if a sense of meaning was derived from that experience. RESULTS: Fifty-six residents completed both before- and after rotation questionnaires (response rate, 58%). The mean interest score was 1.43 initially and decreased to 1.24 after the rotation (P = .301). Female residents' mean score was 1.13 initially and dropped to 0.81 after the rotation (P = .04). Male residents' mean score was 1.71 initially and 1.81 after the rotation (P = .65). Decreased hematology-oncology interest correlated with decreased empathy; male interest decrease correlated with decreased resilience. CONCLUSION: An inpatient hematology-oncology ward rotation does not lead to increased interest and, for some residents, may lead to decreased interest in the field. Encouraging outpatient hematology-oncology rotations and the cultivation of resilience, empathy, and meaning regarding death experiences may increase resident interest. PMID- 26060223 TI - Use of Bevacizumab in Community Settings: Toxicity Profile and Risk of Hospitalization in Patients With Advanced Non-Small-Cell Lung Cancer. AB - PURPOSE: Little is known regarding toxicities and hospitalizations in community based settings for patients with advanced non-small-cell lung cancer (NSCLC) who received commonly prescribed carboplatin-paclitaxel (CP) or carboplatin paclitaxel-bevacizumab (CPB) chemotherapy. METHODS: Patients with stages IIIB-IV NSCLC age >= 21 years diagnosed between 2005 and 2010 who received first-line CP or CPB were identified at four health maintenance organizations (N = 1,109). Using patient and tumor characteristics and hospital and ambulatory encounters from automated data in the 180 days after chemotherapy initiation, the association between CP and CPB and toxicities and hospitalizations were evaluated with chi(2) tests and propensity score-adjusted regression models. RESULTS: Patients who received CPB were significantly younger and had significantly more bleeding, proteinuria, and GI perforation events (all P < .05). For these patients, the unadjusted odds ratio associated with the likelihood of having a hospitalization was 0.46 (95% CI, 0.32 to 0.67). As shown by multivariable and propensity score-adjusted models, patients who received CPB were less likely to have been hospitalized (odds ratio, 0.48; 95% CI, 0.32 to 0.71) and had fewer total hospitalizations (rate ratio, 0.62; 95% CI, 0.47 to 0.82) and hospital days (rate ratio, 0.53; 95% CI, 0.47 to 0.60) than patients who received CP. CONCLUSION: Consistent with earlier randomized clinical trials, significantly more toxicity events were identified in patients treated with CPB. However, both unadjusted and adjusted models showed that patients who received CPB were less likely than patients who received CP to experience a hospital-related event after the initiation of chemotherapy. Findings here confirm the need for adherence to clinical recommendations for judicious use of CPB, but provide reassurance regarding the relative risk for hospitalizations. PMID- 26060224 TI - How Do Payers Respond to Regulatory Actions? The Case of Bevacizumab. AB - PURPOSE: In February 2008, the US Food and Drug Administration (FDA) granted accelerated approval for bevacizumab for metastatic breast cancer. After public hearings in July 2010, and June 2011, the FDA revoked this approved indication in November 2011, on the basis of additional evidence regarding its risk/benefit profile. The Centers for Medicare and Medicaid Services, local Medicare contractors, and commercial payers varied in their stated intentions to cover bevacizumab after FDA's regulatory actions. We examined payer-specific trends in bevacizumab use after the FDA's regulatory actions. METHODS: We used outpatient medical claims compiled by IMS Health to evaluate trends in bevacizumab use for breast cancer for Medicare-insured and commercially insured patients (N = 102,906) using segmented regression. Given that Medicare coverage policies may vary across regional contractors, we estimated trends in bevacizumab use across 10 local coverage areas. In a sensitivity analysis, we estimated trends in bevacizumab use for breast cancer compared with trends in use for lung cancer using difference-in-differences models. RESULTS: Among chemotherapy infusions for breast cancer, bevacizumab use decreased from 31% in July 2010, to 4% in September 2012. Use decreased by 11% among commercially insured and 13% among Medicare-insured patients after July 2010 (interaction P = .68) and continued to decline by 9% per month (interaction P = .61). We observed no contractor-level variation in bevacizumab use among Medicare beneficiaries. During the same period, bevacizumab use for lung cancer was stable. CONCLUSION: Although insurers varied in public statements regarding coverage intentions, bevacizumab use declined similarly among all payers, suggesting that provider decision making, rather than payer-specific coverage policies, drove reductions. PMID- 26060225 TI - Baseline Estimates of Adherence to American Society of Clinical Oncology/American Board of Internal Medicine Choosing Wisely Initiative Among Patients With Cancer Enrolled With a Large Regional Commercial Health Insurer. AB - PURPOSE: The American Society of Clinical Oncology (ASCO)/American Board of Internal Medicine (ABIM) Choosing Wisely (CW) measures aim to reduce the use of interventions that lack evidence of benefit in cancer care. The study presented here characterized adherence to the 2012 ASCO/ABIM CW recommendations by linking health plan claims data with a regional cancer registry and sought to identify areas for research interventions to improve adherence. METHODS: SEER records for patients diagnosed with cancer in Western Washington State between 2007 and 2014 were linked with enrollment and claims from a large regional commercial insurance plan. Using claims and SEER records, algorithms were developed to characterize adherence to each CW measure. In addition, we calculated differences in total reimbursements and procedure-specific reimbursements for patients receiving adherent and nonadherent care. RESULTS: A total of 22,359 unique individuals with cancer were linked with insurance enrollment records and met basic eligibility criteria. Overall adherence varied from 53% (breast surveillance) to 78% (breast staging). Within each measure, adherence varied substantially by stage at diagnosis and by cancer site in situations in which the CW measure affected multiple types of cancer. The difference in reimbursements between adherent and nonadherent populations across all five measures was approximately $29 million. CONCLUSION: Adherence to the ASCO/ABIM CW measures varies widely, as does the cost implication of nonadherence. A structured approach to evaluating adherence and cost impact is needed before developing programs aimed at improving adherence to the ASCO/ABIM CW measures. PMID- 26060226 TI - Do Wise Choices Translate Into Cost Savings and Improved Outcomes? PMID- 26060227 TI - Lifestyle Behaviors in Elderly Cancer Survivors: A Comparison With Middle-Age Cancer Survivors. AB - PURPOSE: Improved cancer screening and treatment have led to a greater focus on cancer survivorship care. Older cancer survivors may be a unique population. We evaluated whether older cancer survivors (age >= 65 years) had lifestyle behaviors, attitudes, and knowledge distinct from younger survivors. PATIENTS AND METHODS: Adult cancer survivors with diverse cancer subtypes were recruited from Princess Margaret Cancer Centre (Toronto, Ontario, Canada). Multivariable models evaluated the effect of age on smoking, alcohol, and physical activity habits, attitudes toward and knowledge of these habits on cancer outcomes, and lifestyle information and recommendations received from health care providers, adjusted for sociodemographic and clinicopathologic covariates. RESULTS: Among the 616 survivors recruited, 23% (n = 139) were older. Median follow-up since diagnosis was 24 months. Older survivors were more likely ex-smokers and less likely current smokers than younger survivors, but they were less likely to know that smoking could affect cancer treatment (adjusted odds ratio [OR], 0.53; P = .007) or prognosis (adjusted OR, 0.53; P = .008). Older survivors were more likely to perceive alcohol as improving overall survival (adjusted OR, 2.39; P = .02). Rates of meeting moderate-to-vigorous physical activity guidelines 1 year before diagnosis (adjusted OR, 0.55; P = .02) and maintaining and improving their exercise levels to meet these guidelines after diagnosis (adjusted OR, 0.48; P = .02) were lower in older survivors. Older and younger cancer survivors reported similar rates of receiving lifestyle behavior information from health care providers (P = .36 to .98). CONCLUSION: Older cancer survivors reported being less aware of the impact of smoking on their overall health, more likely perceived alcohol as beneficial to survival, and were less likely to meet exercise goals compared with younger survivors. Survivorship programs need to consider age when counseling on lifestyle behaviors. PMID- 26060228 TI - Towards excellence in cardiac surgery: experience from a developing country. AB - OBJECTIVE: The objective of this study is an attempt to measure the performance in terms of comparing results with a large internationally recognized database used as a benchmark. DESIGN: Cross-sectional (prospectively collected data analysed and compared retrospectively). SETTING: Aga Khan University Hospital, Karachi, Pakistan. PARTICIPANTS, INTERVENTIONS AND MAIN OUTCOME MEASURES: From January 2006 to December 2010, information of the 2198 CABGs performed at Aga Khan University Hospital (AKU) was collected prospectively. This included patient characteristics and specific intra- and post-operative outcomes and compared with findings from the American Society of Thoracic Surgeons' National Cardiac Database (STS-NCD). RESULTS: There were more male patients in the AKU cohort and more diabetics. In AKU, more cases involved three or more grafts (85 vs. 78%), and in both groups, an internal mammary artery graft was used over 90% of the time. The overall 30-day mortality was 2.7% at AKU, compared with 1.5% in the STS NCD data. AKU had a lower incidence of permanent stroke (0.5 vs. 1.2%), prolonged ventilation (10.5 vs. 11.0%), deep sternal wound infection (0.2 vs. 0.4%) and reoperation (4.0 vs. 4.7%). It had more cases of renal failure (5.4 vs. 3.6%). Readmission rates within 30 days were also less in AKU (3.9 vs. 9.1%). CONCLUSIONS: The outcomes of this study compare very favourably with the benchmark (STS). This demonstrates that high level of quality care can be achieved in this part of the world. PMID- 26060229 TI - Processes and outcomes of ischemic stroke care: the influence of hospital level of care. AB - OBJECTIVE: Processes of stroke care play an increasingly important role in comparing hospital performance. The relationship between processes of care and outcomes for stroke is unclear. Moreover, in terms of stroke care regionalization, little information is available with regard to the relationships among hospital level of care, processes and outcomes of stroke care. We used nationwide population-based data to examine the relationship between processes of care and mortality and the relationships among hospital level of care, processes and mortality for ischemic stroke. DESIGN: Cross-sectional study. SETTING: General acute care hospitals throughout Taiwan. PARTICIPANTS: A total of 31 274 ischemic stroke patients admitted in 2010 through Taiwan's National Health Insurance Research Database. MAIN OUTCOME MEASURES: Processes of care and 30-day mortality. Multilevel models were used after adjustment for patient and hospital characteristics to test the relationship between processes of care and 30-day mortality and the relationships among hospital level of care, processes and 30 day mortality. RESULTS: The use of thrombolytic therapy, antithrombotic therapy, statin treatment and rehabilitation assessment was associated with lower mortality. Hospital level of care was associated with the use of thrombolytic therapy, antithrombotic therapy, statin treatment and rehabilitation assessment, and mortality. These processes of care were mediators of the relationship between hospital level of care and mortality. CONCLUSIONS: Outcomes among patients with ischemic stroke can be improved by thrombolytic therapy, antithrombotic therapy, statin treatment and rehabilitation assessment. Among patients with ischemic stroke, admission to designated stroke center hospitals may be associated with lower mortality through better processes of care. PMID- 26060231 TI - Transient Receptor Potential Channel Opening Releases Endogenous Acetylcholine, which Contributes to Endothelium-Dependent Relaxation Induced by Mild Hypothermia in Spontaneously Hypertensive Rat but Not Wistar-Kyoto Rat Arteries. AB - Mild hypothermia causes endothelium-dependent relaxations, which are reduced by the muscarinic receptor antagonist atropine. The present study investigated whether endothelial endogenous acetylcholine contributes to these relaxations. Aortic rings of spontaneously hypertensive rats (SHRs) and normotensive Wistar Kyoto (WKY) rats were contracted with prostaglandin F2 alpha and exposed to progressive mild hypothermia (from 37 to 31 degrees C). Hypothermia induced endothelium-dependent, Nomega-nitro-l-arginine methyl ester-sensitive relaxations, which were reduced by atropine, but not by mecamylamine, in SHR but not in WKY rat aortae. The responses in SHR aortae were also reduced by acetylcholinesterase (the enzyme responsible for acetylcholine degradation), bromoacetylcholine (inhibitor of acetylcholine synthesis), hemicholinium-3 (inhibitor of choline uptake), and vesamicol (inhibitor of acetylcholine release). The mild hypothermia-induced relaxations in both SHR and WKY rat aortae were inhibited by AMTB [N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2 thienylmethyl)-benzamide; the transient receptor potential (TRP) M8 inhibitor]; only those in SHR aortae were inhibited by HC-067047 [2-methyl-1-[3-(4 morpholinyl)propyl]-5-phenyl-N-[3-(trifluoromethyl)phenyl]-1H-pyrrole-3 carboxamide; TRPV4 antagonist] while those in WKY rat aortae were reduced by HC 030031 [2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4 isopropylphenyl)acetamide; TRPA1 antagonist]. The endothelial uptake of extracellular choline and release of cyclic guanosine monophosphate was enhanced by mild hypothermia and inhibited by HC-067047 in SHR but not in WKY rat aortae. Compared with WKY rats, the SHR preparations expressed similar levels of acetylcholinesterase and choline acetyltransferase, but a lesser amount of vesicular acetylcholine transporter, located mainly in the endothelium. Thus, mild hypothermia causes nitric oxide-dependent relaxations by opening TRPA1 channels in WKY rat aortae. By contrast, in SHR aortae, TRPV4 channels are opened, resulting in endothelial production of acetylcholine, which, in an autocrine manner, activates muscarinic receptors on neighboring cells to elicit endothelium-dependent relaxations in response to mild hypothermia. PMID- 26060230 TI - Engaging staff to improve quality and safety in an austere medical environment: a case-control study in two Sierra Leonean hospitals. AB - QUALITY PROBLEM OR ISSUE: Inadequate observance of basic processes in patient care such as patient monitoring and documentation practices are potential impediments to the timely diagnoses and management of patients. These gaps exist in low resource settings such as Sierra Leone and can be attributed to a myriad of factors such as workforce and technology deficiencies. INITIAL ASSESSMENT: In the study site, only 12.4% of four critical vital signs were documented in the pre-intervention period. CHOICE OF SOLUTION: Implement a failure mode and effects analysis (FMEA) to improve documentation of four patient vital signs: temperature, blood pressure, pulse rate and respiratory rate. IMPLEMENTATION: FMEA was implemented among a subpopulation of health workers who are involved in monitoring and documenting patient vital signs. Pre- and post-FMEA monitoring and documentation practice were compared with a control site. EVALUATION: Participants identified a four-step process to monitoring and documenting vital signs, three categories of failure modes and four potential solutions. Based on 2100 patient days of documentation compliance data from 147 patients between July and November 2012, staff members at the study site were 1.79 times more likely to document all four patient vital signs in the post-implementation period (95% CI [1.35, 2.38]). LESSONS LEARNED: FMEA is a feasible and effective strategy for improving quality and safety in an austere medical environment. Documentation compliance improved at the intervention facility. To evaluate the scalability and sustainability of this approach, programs targeting the development of these types of process improvement skills in local staff should be evaluated. PMID- 26060232 TI - Hidden dilemma in household e-waste management. PMID- 26060233 TI - Application of MFA as a decision support tool for waste management in small municipalities--case study of Serbia. AB - In this paper, attention is shifted from larger cities and regions to the important role of small municipalities in large-scale capacity waste management systems. The motivation of this analysis is to understand how small municipalities can be prepared for future inclusion in regional waste management. For the first time, solutions that include integrated treatment of municipal, agricultural, and industrial waste generated by small-scale municipalities are developed and assessed. For this purpose, five small Serbian municipalities with populations up to 30,000 inhabitants were chosen as case studies. The methodology integrates field data with material flow analysis (MFA) to analyze and evaluate future scenarios. A set of indicators which reflect the goals of waste management, including the total costs, was chosen for scenario comparison and evaluation. It was found that delivering generated waste to regional waste management centers can result in the most affordable environmental benefits for the representative municipalities. More advanced solutions, which include composting and joint treatment of municipal, agricultural, and industrial waste, can contribute to reaching waste management goals, but are more costly (217% and 652% comparing to delivering generated waste to regions). These results can be regarded as a representative for similar municipalities and can serve to support pre-planning decisions in other countries with problems in establishing regional waste management systems. PMID- 26060234 TI - Feasibility analysis of municipal solid waste mass burning in the Region of East Macedonia--Thrace in Greece. AB - The present work conducts a preliminary techno-economic feasibility study for a single municipal solid waste mass burning to an electricity plant for the total municipal solid waste potential of the Region of Eastern Macedonia - Thrace, in Greece. For a certain applied and highly efficient technology and an installed capacity of 400,000 t of municipal solid waste per year, the available electrical power to grid would be approximately 260 GWh per year (overall plant efficiency 20.5% of the lower heating value). The investment for such a plant was estimated at ?200m. Taking into account that 37.9% of the municipal solid waste lower heating value can be attributed to their renewable fractions, and Greek Law 3851/2010, which transposes Directive 2009/28/EC for Renewable Energy Sources, the price of the generated electricity was calculated at ?53.19/MWhe. Under these conditions, the economic feasibility of such an investment depends crucially on the imposed gate fees. Thus, in the gate fee range of 50-110 ? t(-1), the internal rate of return increases from 5% to above 15%, whereas the corresponding pay-out time periods decrease from 11 to about 4 years. PMID- 26060235 TI - Recycling and utilisation of industrial solid waste: an explorative study on gold deposit tailings of ductile shear zone type in China. AB - Tailings are solid waste arising from mineral processing. This type of waste can cause severe damage to the environment during stockpiling as a result of the leaching of something harmful into the ecosystem. Gold deposit of ductile shear zone type is an important type of gold deposit, and the recycling of its tailings has been challenging researchers for a long time. In this article, the characteristics of this type of tailings were systematically studied by using modern technical means. Considering the characteristics of the tailings, clay was selected to make up for the shortcomings of the tailings and improve their performance. Water and raw materials were mixed to produce green bodies, which are subsequently sintered into ceramic bodies at 980 degrees C~1020 degrees C (sintering temperature). The results showed that some new kinds of mineral phases, such as mullite, anorthite and orthoclase, appear in ceramic bodies. Furthermore, the ceramic bodies have a surface hardness of 5 to 6 (Mohs scale), and their water absorption and modulus of rupture can meet some technical requirements of ceramic materials described in ISO 13006-2012 and GB 5001-1985. These gold mine tailings can be made into ceramic tiles, domestic ceramic bodies, and other kinds of ceramic bodies for commercial and industrial purposes after further improvements. PMID- 26060236 TI - Medication misuse in India: a major public health issue in India. AB - BACKGROUND: In India, it has been estimated that 50% of family spending on healthcare is on unnecessary medications or investigations. This, combined with the wide availability of medications, has seemingly contributed to increasing rates of antibiotic resistance and further impoverishment. In this literature review, we aim to characterize the extent of misuse and describe underlying factors contributing to the misuse of medication in India. METHODS: This literature review included relevant articles published after 2000 that assessed medication use and misuse in India. A narrative review framework was used to analyse each article, confirm its inclusion, extract relevant information and group the findings under thematic areas. RESULTS: There were 115 articles included in this literature review. The literature demonstrated that the misuse of medications in India is widespread. The factors resulting in this involves all levels of the health system including regulation, enforcement and policy, healthcare providers and consumers. CONCLUSIONS: This is one of the most comprehensive reviews of medication misuse in India. It indicates the widespread nature of the problem and so highlights the need for action. This review provides a detailed understanding as to the complex interplay of factors that result in medication misuse in India. PMID- 26060237 TI - Effect of Display Technology on Perceived Scale of Space. AB - OBJECTIVE: Our goal was to evaluate the degree to which display technologies influence the perception of size in an image. BACKGROUND: Research suggests that factors such as whether an image is displayed stereoscopically, whether a user's viewpoint is tracked, and the field of view of a given display can affect users' perception of scale in the displayed image. METHOD: Participants directly estimated the size of a gap by matching the distance between their hands to the gap width and judged their ability to pass unimpeded through the gap in one of five common implementations of three display technologies (two head-mounted displays [HMD] and a back-projection screen). RESULTS: Both measures of gap width were similar for the two HMD conditions and the back projection with stereo and tracking. For the displays without tracking, stereo and monocular conditions differed from each other, with monocular viewing showing underestimation of size. CONCLUSIONS: Display technologies that are capable of stereoscopic display and tracking of the user's viewpoint are beneficial as perceived size does not differ from real-world estimates. Evaluations of different display technologies are necessary as display conditions vary and the availability of different display technologies continues to grow. APPLICATIONS: The findings are important to those using display technologies for research, commercial, and training purposes when it is important for the displayed image to be perceived at an intended scale. PMID- 26060239 TI - Coexistence of an intracranial meningioma and an arteriovenous malformation. AB - The occurrence of a primary brain tumour in association with a cerebral arteriovenous malformation (AVM) is a recognized but rarely reported finding. A 56-year-old female presented following a single tonic clonic seizure. Radiological investigations revealed a left posterior frontal parafalcine meningioma and a left parietal AVM. Both were uneventfully resected. Whether there is a causal relationship is unproven, however, this case report might lend some support to this hypothesis given the relatively close proximity of the two lesions. PMID- 26060238 TI - Influencing Trust for Human-Automation Collaborative Scheduling of Multiple Unmanned Vehicles. AB - OBJECTIVE: We examined the impact of priming on operator trust and system performance when supervising a decentralized network of heterogeneous unmanned vehicles (UVs). BACKGROUND: Advances in autonomy have enabled a future vision of single-operator control of multiple heterogeneous UVs. Real-time scheduling for multiple UVs in uncertain environments requires the computational ability of optimization algorithms combined with the judgment and adaptability of human supervisors. Because of system and environmental uncertainty, appropriate operator trust will be instrumental to maintain high system performance and prevent cognitive overload. METHOD: Three groups of operators experienced different levels of trust priming prior to conducting simulated missions in an existing, multiple-UV simulation environment. RESULTS: Participants who play computer and video games frequently were found to have a higher propensity to overtrust automation. By priming gamers to lower their initial trust to a more appropriate level, system performance was improved by 10% as compared to gamers who were primed to have higher trust in the automation. CONCLUSION: Priming was successful at adjusting the operator's initial and dynamic trust in the automated scheduling algorithm, which had a substantial impact on system performance. APPLICATION: These results have important implications for personnel selection and training for futuristic multi-UV systems under human supervision. Although gamers may bring valuable skills, they may also be potentially prone to automation bias. Priming during training and regular priming throughout missions may be one potential method for overcoming this propensity to overtrust automation. PMID- 26060240 TI - The many faces of somatosensory amplification: The relative contribution of body awareness, symptom labeling, and anxiety. AB - The questionnaire study aimed to evaluate the relative contribution of body awareness, subjective symptoms, and anxiety to the construct of somatosensory amplification in both healthy controls (n = 475) and patients visiting their general practitioner (n = 236). Regression analysis explained 52.0 percent of total variance of the somatosensory amplification scale scores. Body awareness was the most influential predictor (beta = 0.489, p < 0.001) when considering all predictors simultaneously. The results suggest that dispositional interoceptive focus, as indicated by body awareness, may be an important aspect of somatosensory amplification, over and above dispositional anxiety or subjective symptom report. PMID- 26060241 TI - Healthy eating beliefs and intentions of mothers and their adult children: An intergenerational transmission perspective. AB - This study examined the possible intergenerational transmission of eating beliefs and intentions between 60 mothers and their adult children. Maternal restrictive feeding practices were correlated with mothers' own healthy eating attitudes and subjective norms, and with their adult children's subjective norms. Mothers' beliefs and intentions were correlated with their adult children. Adult children's intentions to eat healthily were predicted by their attitudes and perceived behavioural control, and also by their mothers' intentions and perceived behavioural control. Mothers' own beliefs and intentions may be involved in shaping their children's beliefs and intentions into adulthood but their child feeding practices may have less of an influence. PMID- 26060242 TI - Lived experiences and illness representation of Taiwanese patients with late stage chronic kidney disease. AB - This qualitative study was designed to identify patients' experiences and perceptions related to living with late-stage chronic kidney disease. Interviews were held for 15 patients with late-stage chronic kidney disease from two medical centers in Taiwan. Five themes were identified using content analysis: experiencing moderate to severe symptoms and signs; tracing back to causes; realizing the long-term, irreversible nature of the disease; facing the consequence of unavoidable deterioration; and coping with the disease. The findings present the special lived experiences of Taiwanese chronic kidney disease patients and highlight the need for healthcare providers to assess patients' illness representation before offering interventions for patients coping with chronic kidney disease. PMID- 26060243 TI - The patient. PMID- 26060245 TI - Selective Vulnerability of Cortical Border Zone to Microembolic Infarct. AB - BACKGROUND AND PURPOSE: Endovascular procedures, including atrial fibrillation transcatheter ablation, may cause microembolization of brain arteries. Microemboli often cause small sized and clinically silent cerebral ischemias (SCI). These lesions are clearly visible on early postoperative magnetic resonance diffusion-weighted images. We analyzed SCI distribution in a population of patients submitted to atrial fibrillation transcatheter ablation. METHODS: Seventy-eight of 927 consecutive patients submitted to atrial fibrillation transcatheter ablation were found positive for acute SCI on a postoperative magnetic resonance. SCI were identified and marked, and their coordinates were transformed from native space into the International Consortium for Brain Mapping/Montreal Neurological Institute space. We then computed the voxel-wise probability distribution map of the SCI using the activation likelihood estimation approach. RESULTS: SCI were more commonly found in the cortex. In supratentorial regions, SCI selectively involved cortical border zone between anterior, middle, and posterior cerebral arteries; in infratentorial regions, distal territory of posteroinferior cerebellar artery. Possible explanations include selective embolization, linked to the vascular anatomy of pial arteries supplying those territories, reduced clearance of emboli in a relatively hypoperfused zone, or a combination of both. This particular distribution of lesions has been reported in both animal models and in patients with microemboli of different sources. CONCLUSIONS: A selective vulnerability of cortical border zone to microemboli occurring during atrial fibrillation transcatheter ablation was observed. We hypothesize that such selectivity may apply to microemboli of different sources. PMID- 26060244 TI - Prophylactic Edaravone Prevents Transient Hypoxic-Ischemic Brain Injury: Implications for Perioperative Neuroprotection. AB - BACKGROUND AND PURPOSE: Hypoperfusion-induced thrombosis is an important mechanism for postsurgery stroke and cognitive decline, but there are no perioperative neuroprotectants to date. This study investigated whether prophylactic application of Edaravone, a free radical scavenger already used in treating ischemic stroke in Japan, can prevent infarct and cognitive deficits in a murine model of transient cerebral hypoxia-ischemia. METHODS: Adult male C57BL/6 mice were subjected to transient hypoxic-ischemic (tHI) insult that consists of 30-minute occlusion of the unilateral common carotid artery and exposure to 7.5% oxygen. Edaravone or saline was prophylactically applied to compare their effects on cortical oxygen saturation, blood flow, coagulation, oxidative stress, metabolites, and learning-memory using methods that include photoacoustic imaging, laser speckle contrast imaging, solid-state NMR, and Morris water maze. The effects on infarct size by Edaravone application at different time points after tHI were also compared. RESULTS: Prophylactic administration of Edaravone (4.5 mg/kg*2, IP, 1 hour before and 1 hour after tHI) improved vascular reperfusion, oxygen saturation, and the maintenance of brain metabolites, reducing oxidative stress, thrombosis, white-matter injury, and learning impairment after tHI insult. Delayed Edaravone treatment after 3 h post tHI became unable to reduce infarct size. CONCLUSIONS: Acute application of Edaravone may be a useful strategy to prevent postsurgery stroke and cognitive impairment, especially in patients with severe carotid stenosis. PMID- 26060246 TI - Regenerative Neurogenesis After Ischemic Stroke Promoted by Nicotinamide Phosphoribosyltransferase-Nicotinamide Adenine Dinucleotide Cascade. AB - BACKGROUND AND PURPOSE: Nicotinamide adenine dinucleotide (NAD) is a ubiquitous fundamental metabolite. Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme for mammalian NAD salvage synthesis and has been shown to protect against acute ischemic stroke. In this study, we investigated the role of Nampt-NAD cascade in brain regeneration after ischemic stroke. METHODS: Nampt transgenic (Nampt-Tg) mice and H247A mutant enzymatic-dead Nampt transgenic (DeltaNampt-Tg) mice were subjected with experimental cerebral ischemia by middle cerebral artery occlusion. Activation of neural stem cells, neurogenesis, and neurological function recovery were measured. Besides, nicotinamide mononucleotide and NAD, two chemical enzymatic product of Nampt, were administrated in vivo and in vitro. RESULTS: Compared with wild-type mice, Nampt Tg mice showed enhanced number of neural stem cells, improved neural functional recovery, increased survival rate, and accelerated body weight gain after middle cerebral artery occlusion, which were not observed in DeltaNampt-Tg mice. A delayed nicotinamide mononucleotide administration for 7 days with the first dose at 12 hours post middle cerebral artery occlusion did not protect acute brain infarction and neuronal deficit; however, it still improved postischemic regenerative neurogenesis. Nicotinamide mononucleotide and NAD(+) promoted proliferation and differentiation of neural stem cells in vitro. Knockdown of NAD dependent deacetylase sirtuin 1 (SIRT1) and SIRT2 inhibited the progrowth action of Nampt-NAD axis, whereas knockdown of SIRT1, SIRT2, and SIRT6 compromised the prodifferentiation effect of Nampt-NAD axis. CONCLUSIONS: Our data demonstrate that the Nampt-NAD cascade may act as a centralizing switch in postischemic regeneration through controlling different sirtuins and therefore represent a promising therapeutic target for long-term recovery of ischemic stroke. PMID- 26060247 TI - Influence of Cardiovascular Fitness and Muscle Strength in Early Adulthood on Long-Term Risk of Stroke in Swedish Men. AB - BACKGROUND AND PURPOSE: Low cardiovascular fitness (fitness) in mid- and late life is a risk factor for stroke. However, the respective effects on long-term stroke risk of fitness and muscle strength in early adulthood are unknown. Therefore, we analyzed these in a large cohort of young men. METHOD: We performed a population-based longitudinal cohort study of Swedish male conscripts registered in 1968 to 2005. Data on fitness (by the cycle ergometric test; n=1 166 035) and muscle strength (n=1,563,750) were trichotomized (low, medium, and high). During a 42-year follow-up, risk of stroke (subarachnoidal hemorrhage, intracerebral hemorrhage, and ischemic stroke) and fatality were calculated with Cox proportional hazards models. To identify cases, we used the International Classification of Diseases-Eighth to Tenth Revision in the Hospital Discharge Register and the Cause of Death Register. RESULTS: First-time stroke events were identified (subarachnoidal hemorrhage, n=895; intracerebral hemorrhage, n=2904; ischemic stroke, n=7767). For all stroke and fatality analysis any type of first time stroke was recorded (n=10,917). There were inverse relationships in a dose response fashion between fitness and muscle strength with any stroke (adjusted hazard ratios for the lowest, compared with the highest, tertile of each 1.70 [1.50-1.93] and 1.39 [1.27-1.53], respectively). There were stronger associations for fatal stroke. All 3 stroke types displayed similar associations. Associations between fitness and stroke remained when adjusted for muscle strength, whereas associations between muscle strength and stroke weakened/disappeared when adjusted for fitness. CONCLUSIONS: At the age of 18 years, low fitness and to a lesser degree low muscle strength were independently associated with an increased future stroke risk. PMID- 26060249 TI - Fukushima effects in Germany? Changes in media coverage and public opinion on nuclear power. AB - Based on a literature review on factors that explain media effects and previous findings on media coverage and public opinion on nuclear power, this article examines the effects of Fukushima on media coverage and public opinion in Germany in two studies. The first study uses content analysis data to analyse changes in media coverage, and the second one is based on panel survey data to examine attitude changes on an individual level. The results of both studies show changes in media coverage and public opinion on nuclear power. Furthermore, the second study reveals that individual attitude changes cannot necessarily be explained by the same factors as the distribution of attitudes. PMID- 26060248 TI - Relationship Between Lesion Topology and Clinical Outcome in Anterior Circulation Large Vessel Occlusions. AB - BACKGROUND AND PURPOSE: Diffusion-weighted imaging (DWI) Alberta Stroke Program Early CT Score (ASPECTS), a surrogate of infarct volume, predicts outcome in anterior large vessel occlusion strokes. We aim to determine whether topological information captured by DWI ASPECTS contributes additional prognostic value. METHODS: Adults with intracranial internal carotid artery, M1 or M2 middle carotid artery occlusions who underwent endovascular therapy were included. The primary outcome measure was poor clinical outcome (3-month modified Rankin Scale score, 3-6). Prognostic value of the 10 DWI ASPECTS regions in predicting poor outcome was determined by multivariable logistic regression, controlling for final infarct volume, age, and laterality. RESULTS: Two hundred and thirteen patients (mean age, 66.1+/-14.5 years; median National Institutes of Health Stroke Scale, 15) were included. Inter-rater reliability was good for DWI ASPECTS (deep regions, kappa=0.72; cortical regions, kappa=0.63). All DWI ASPECTS regions with the exception of the putamen were significant predictors (P<0.05) of poor outcome in univariate analyses. Statistical collinearity among ASPECTS regions was not observed. Using penalized multivariable logistic regression, only M4 (odds ratio, 2.82; 95% confidence interval, 1.39-5.76) and M6 (odds ratio, 2.45; 95% confidence interval, 1.15-5.3) involvement were associated with poor outcome. M6 involvement independently predicted poor outcome in right hemispheric strokes (odds ratio, 5.8; 95% confidence interval, 1.9-20.3), whereas M4 (odds ratio, 4.3; 95% confidence interval, 1.3-15.0) involvement predicted poor outcome in left hemispheric strokes adjusting for infarct volume. Topologic information modestly improved the predictive ability of a prognostic score that incorporates age, infarct volume, and hemorrhagic transformation. CONCLUSIONS: Involvement of the right parieto-occipital (M6) and left superior frontal (M4) regions affect clinical outcome in anterior large vessel occlusions over and above the effect of infarct volume and should be considered during prognostication. PMID- 26060250 TI - Regulation and Quality Control of Adiponectin Assembly by Endoplasmic Reticulum Chaperone ERp44. AB - Adiponectin, a collagenous hormone secreted abundantly from adipocytes, possesses potent antidiabetic and anti-inflammatory properties. Mediated by the conserved Cys(39) located in the variable region of the N terminus, the trimeric (low molecular weight (LMW)) adiponectin subunit assembles into different higher order complexes, e.g. hexamers (middle molecular weight (MMW)) and 12-18-mers (high molecular weight (HMW)), the latter being mostly responsible for the insulin sensitizing activity of adiponectin. The endoplasmic reticulum (ER) chaperone ERp44 retains adiponectin in the early secretory compartment and tightly controls the oxidative state of Cys(39) and the oligomerization of adiponectin. Using cellular and in vitro assays, we show that ERp44 specifically recognizes the LMW and MMW forms but not the HMW form. Our binding assays with short peptide mimetics of adiponectin suggest that ERp44 intercepts and converts the pool of fully oxidized LMW and MMW adiponectin, but not the HMW form, into reduced trimeric precursors. These ERp44-bound precursors in the cis-Golgi may be transported back to the ER and released to enhance the population of adiponectin intermediates with appropriate oxidative state for HMW assembly, thereby underpinning the process of ERp44 quality control. PMID- 26060251 TI - NMR-based Structural Analysis of Threonylcarbamoyl-AMP Synthase and Its Substrate Interactions. AB - The hypermodified nucleoside N(6)-threonylcarbamoyladenosine (t(6)A37) is present in many distinct tRNA species and has been found in organisms in all domains of life. This post-transcriptional modification enhances translation fidelity by stabilizing the anticodon/codon interaction in the ribosomal decoding site. The biosynthetic pathway of t(6)A37 is complex and not well understood. In bacteria, the following four proteins have been discovered to be both required and sufficient for t(6)A37 modification: TsaC, TsaD, TsaB, and TsaE. Of these, TsaC and TsaD are members of universally conserved protein families. Although TsaC has been shown to catalyze the formation of L-threonylcarbamoyl-AMP, a key intermediate in the biosynthesis of t(6)A37, the details of the enzymatic mechanism remain unsolved. Therefore, the solution structure of Escherichia coli TsaC was characterized by NMR to further study the interactions with ATP and L threonine, both substrates of TsaC in the biosynthesis of L-threonylcarbamoyl AMP. Several conserved amino acids were identified that create a hydrophobic binding pocket for the adenine of ATP. Additionally, two residues were found to interact with L-threonine. Both binding sites are located in a deep cavity at the center of the protein. Models derived from the NMR data and molecular modeling reveal several sites with considerable conformational flexibility in TsaC that may be important for L-threonine recognition, ATP activation, and/or protein/protein interactions. These observations further the understanding of the enzymatic reaction catalyzed by TsaC, a threonylcarbamoyl-AMP synthase, and provide structure-based insight into the mechanism of t(6)A37 biosynthesis. PMID- 26060252 TI - Evidence That Antibiotics Bind to Human Mitochondrial Ribosomal RNA Has Implications for Aminoglycoside Toxicity. AB - Aminoglycosides are a well known antibiotic family used to treat bacterial infections in humans and animals, but which can be toxic. By binding to the decoding site of helix44 of the small subunit RNA of the bacterial ribosome, the aminoglycoside antibiotics inhibit protein synthesis, cause misreading, or obstruct peptidyl-tRNA translocation. Although aminoglycosides bind helix69 of the bacterial large subunit RNA as well, little is known about their interaction with the homologous human helix69. To probe the role this binding event plays in toxicity, changes to thermal stability, base stacking, and conformation upon aminoglycoside binding to the human cytoplasmic helix69 were compared with those of the human mitochondrial and Escherichia coli helix69. Surprisingly, binding of gentamicin and kanamycin A to the chemically synthesized terminal hairpins of the human cytoplasmic, human mitochondrial, and E. coli helix69 revealed similar dissociation constants (1.3-1.7 and 4.0-5.4 MUM, respectively). In addition, aminoglycoside binding enhanced conformational stability of the human mitochondrial helix69 by increasing base stacking. Proton one-dimensional and two dimensional NMR suggested significant and specific conformational changes of human mitochondrial and E. coli helix69 upon aminoglycoside binding, as compared with human cytoplasmic helix69. The conformational changes and similar aminoglycoside binding affinities observed for human mitochondrial helix69 and E. coli helix69, as well as the increase in structural stability shown for the former, suggest that this binding event is important to understanding aminoglycoside toxicity. PMID- 26060253 TI - IPO3-mediated Nonclassical Nuclear Import of NF-kappaB Essential Modulator (NEMO) Drives DNA Damage-dependent NF-kappaB Activation. AB - Activation of IkappaB kinase (IKK) and NF-kappaB by genotoxic stresses modulates apoptotic responses and production of inflammatory mediators, thereby contributing to therapy resistance and premature aging. We previously reported that genotoxic agents induce nuclear localization of NF-kappaB essential modulator (NEMO) via an undefined mechanism to arbitrate subsequent DNA damage dependent IKK/NF-kappaB signaling. Here we show that a nonclassical nuclear import pathway via IPO3 (importin 3, transportin 2) mediates stress-induced NEMO nuclear translocation. We found putative nuclear localization signals in NEMO whose mutations disrupted stress-inducible nuclear translocation of NEMO and IKK/NF-kappaB activation in stably reconstituted NEMO-deficient cells. RNAi screening of both importin alpha and beta family members, as well as co immunoprecipitation analyses, revealed that a nonclassical importin beta family member, IPO3, was the only importin that was able to associate with NEMO and whose reduced expression prevented genotoxic stress-induced NEMO nuclear translocation, IKK/NF-kappaB activation, and inflammatory cytokine transcription. Recombinant IPO3 interacted with recombinant NEMO but not the nuclear localization signal mutant version and induced nuclear import of NEMO in digitonin-permeabilized cells. We also provide evidence that NEMO is disengaged from IKK complex following genotoxic stress induction. Thus, the IPO3 nuclear import pathway is an early and crucial determinant of the IKK/NF-kappaB signaling arm of the mammalian DNA damage response. PMID- 26060254 TI - Src Kinase Is the Connecting Player between Protein Kinase A (PKA) Activation and Hyperpolarization through SLO3 Potassium Channel Regulation in Mouse Sperm. AB - Plasma membrane hyperpolarization is crucial for mammalian sperm to acquire acrosomal responsiveness during capacitation. Among the signaling events leading to mammalian sperm capacitation, the immediate activation of protein kinase A plays a pivotal role, promoting the subsequent stimulation of protein tyrosine phosphorylation that associates with fertilizing capacity. We have shown previously that mice deficient in the tyrosine kinase cSrc are infertile and exhibit improper cauda epididymis development. It is therefore not clear whether lack of sperm functionality is due to problems in epididymal maturation or to the absence of cSrc in sperm. To further address this problem, we investigated the kinetics of cSrc activation using anti-Tyr(P)-416-cSrc antibodies that only recognize active cSrc. Our results provide evidence that cSrc is activated downstream of PKA and that inhibition of its activity blocks the capacitation induced hyperpolarization of the sperm plasma membrane without blocking the increase in tyrosine phosphorylation that accompanies capacitation. In addition, we show that cSrc inhibition also blocks the agonist-induced acrosome reaction and that this inhibition is overcome by pharmacological hyperpolarization. Considering that capacitation-induced hyperpolarization is mediated by SLO3, we evaluated the action of cSrc inhibitors on the heterologously expressed SLO3 channel. Our results indicate that, similar to SLO1 K(+) channels, cSrc blockers significantly decreased SLO3-mediated currents. Together, these results are consistent with findings showing that hyperpolarization of the sperm plasma membrane is necessary and sufficient to prepare the sperm for the acrosome reaction and suggest that changes in sperm membrane potential are mediated by cSrc activation. PMID- 26060255 TI - Increased NF-kappaB Activity and Decreased Wnt/beta-Catenin Signaling Mediate Reduced Osteoblast Differentiation and Function in DeltaF508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mice. AB - The prevalent human DeltaF508 mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) is associated with reduced bone formation and bone loss in mice. The molecular mechanisms by which the DeltaF508-CFTR mutation causes alterations in bone formation are poorly known. In this study, we analyzed the osteoblast phenotype in DeltaF508-CFTR mice and characterized the signaling mechanisms underlying this phenotype. Ex vivo studies showed that the DeltaF508 CFTR mutation negatively impacted the differentiation of bone marrow stromal cells into osteoblasts and the activity of osteoblasts, demonstrating that the DeltaF508-CFTR mutation alters both osteoblast differentiation and function. Treatment with a CFTR corrector rescued the abnormal collagen gene expression in DeltaF508-CFTR osteoblasts. Mechanistic analysis revealed that NF-kappaB signaling and transcriptional activity were increased in mutant osteoblasts. Functional studies showed that the activation of NF-kappaB transcriptional activity in mutant osteoblasts resulted in increased beta-catenin phosphorylation, reduced osteoblast beta-catenin expression, and altered expression of Wnt/beta-catenin target genes. Pharmacological inhibition of NF kappaB activity or activation of canonical Wnt signaling rescued Wnt target gene expression and corrected osteoblast differentiation and function in bone marrow stromal cells and osteoblasts from DeltaF508-CFTR mice. Overall, the results show that the DeltaF508-CFTR mutation impairs osteoblast differentiation and function as a result of overactive NF-kappaB and reduced Wnt/beta-catenin signaling. Moreover, the data indicate that pharmacological inhibition of NF-kappaB or activation of Wnt/beta-catenin signaling can rescue the abnormal osteoblast differentiation and function induced by the prevalent DeltaF508-CFTR mutation, suggesting novel therapeutic strategies to correct the osteoblast dysfunctions in cystic fibrosis. PMID- 26060256 TI - Chest radiographic abnormalities in HIV-infected African children: a longitudinal study. AB - BACKGROUND: There is limited knowledge of chest radiographic abnormalities over time in HIV-infected children in resource-limited settings. OBJECTIVE: To investigate the natural history of chest radiographic abnormalities in HIV infected African children, and the impact of antiretroviral therapy (ART). METHODS: Prospective longitudinal study of the association of chest radiographic findings with clinical and immunological parameters. Chest radiographs were performed at enrolment, 6-monthly, when initiating ART and if indicated clinically. Radiographic abnormalities were classified as normal, mild or moderate severity and considered persistent if present for 6 consecutive months or longer. An ordinal multiple logistic regression model assessed the association of enrolment and time-dependent variables with temporal radiographic findings. RESULTS: 258 children (median (IQR) age: 28 (13-51) months; median CD4+%: 21 (15 24)) were followed for a median of 24 (18-42) months. 70 (27%) were on ART at enrolment; 130 (50%) (median age: 33 (18-56) months) commenced ART during the study. 154 (60%) had persistent severe radiographic abnormalities, with median duration 18 (6-24) months. Among children on ART, 69% of radiographic changes across all 6-month transition periods were improvements, compared with 45% in those not on ART. Radiographic severity was associated with previous radiographic severity (OR=120.80; 95% CI 68.71 to 212.38), lack of ART (OR=1.72; 95% CI 1.29 to 2.27), enrolment age <18 months (OR=1.39; 95% CI 1.06 to 1.83), diffuse, severe radiographic abnormality at enrolment (OR=2.18; 95% CI 1.33 to 3.56), hospitalisation for lower respiratory tract infection during the previous 6 months (OR=1.88; 95% CI 1.06 to 3.30) and length of follow-up: at 18-24 months (OR=0.66; 95% CI 0.49 to 0.90), and at 30-54 months (OR=0.42; 95% CI 0.32 to 0.56). CONCLUSIONS: Most children had severe radiographic abnormalities persisting for at least 18 months. ART was beneficial, reducing the risk of radiographic deterioration or increasing the likelihood of radiological improvement. PMID- 26060257 TI - Pituitary volumes of the patients with borderline personality disorder are not changed. AB - Although it has important relationships with psychiatric symptoms via the hypothalamic-pituitary-adrenal axis, there have been limited investigations of pituitary neuroimaging in psychiatric disorder. Moreover, there have been no studies of borderline personality disorder. In the present investigation, we examined pituitary gland volumes in patients with borderline personality disorder. Seventeen right-handed female patients with borderline personality disorder, selected among the patients who had presented to Firat University School of Medicine Department of Psychiatry outpatient and inpatient clinics, and the same number of healthy control subjects were included in the present investigation. Pituitary gland volumes were manually detected. The results demonstrated that the mean volumes of the gland of the patients with borderline personality disorder were not significantly different than those of healthy control subjects (mean volume of 0.79 cm3 in the patient group, with a value of SD+/-0.11 and 0.81 cm3 in the healthy control group, with a value of SD+/-0.23; t=-0.21; p>0.05). PMID- 26060258 TI - Psychotic and depressive symptoms after gabapentin treatment. AB - Gabapentin, one of the antiepileptics, shows its effects via voltage-gated calcium channels. Sedation and mood elevation are among its side effects. The positive effects of antiepileptics such as valproate and carbamazepine as mood stabilizers have raised the hope that other antiepileptics may as well be efficacious in the treatment of mood disorders. However, relevant research data have not proven success of newer antiepileptics. This article presents the negative side effects of gabapentin such as psychotic and depressive symptoms, which occur shortly after its use. The use of gabapentin in mood disorders is discussed through these side effects. PMID- 26060259 TI - Prevalence of suicidal ideation and suicide attempts in the general population of China: A meta-analysis. AB - OBJECTIVE: The objective of this meta-analysis is to estimate the pooled prevalence of suicidal ideation and suicide attempts in the general population of Mainland China. METHODS: A systematic literature search was conducted via the following databases: PubMed, PsycINFO, MEDLINE, China Journals Full-Text Databases, Chongqing VIP database for Chinese Technical Periodicals, and Wan Fang Data. Statistical analysis used the Comprehensive Meta-Analysis program. RESULTS: Eight studies met the inclusion criteria for the analysis; five reported on the prevalence of suicidal ideation and seven on that of suicide attempts. The estimated lifetime prevalence figures of suicidal ideation and suicide attempts were 3.9% (95% confidence interval: 2.5%-6.0%) and 0.8% (95% confidence interval: 0.7%-0.9%), respectively. The estimated female-male ratio for lifetime prevalence of suicidal ideation and suicide attempts was 1.7 and 2.2, respectively. Only the difference of suicide attempts between the two genders was statistically significant. CONCLUSION: This was the first meta-analysis of the prevalence of suicidal ideation and suicide attempts in the general population of Mainland China. The pooled lifetime prevalence of both suicidal ideation and suicide attempts are relatively low; however, caution is required when assessing these self-report data. Women had a modestly higher prevalence for suicide attempts than men. The frequency for suicidal ideation and suicide attempts in urban regions was similar to those in rural areas. PMID- 26060260 TI - Effects of religious and spiritual variables on outcomes in violent relationships. AB - OBJECTIVE: Religious and spiritual factors in intimate partner violence have received increasing attention. But are such factors related to outcomes in violent relationships? The purpose of this study was to assess the relative impact of spiritual symptoms and religious coping on attitudinal/behavioral and clinical outcomes among women in violent relationships. METHODS: Adult women with a recent history of husband-to-wife physical abuse were recruited from six primary care clinics. Once enrolled, 200 subjects completed a baseline interview and daily assessment of level of violence, using the Interactive Verbal Response for 12 weeks. At the completion of the study, contact with each participant was attempted to determine whether she had either sought professional help or left the relationship. Three religious/spiritual variables were assessed at baseline number of visits to a religious/spiritual counselor, religious coping, and severity of spiritual symptoms. Stepped multiple linear regression was used to explain factor-analyzed outcomes (coping and appraisals, hope and support, symptomatology, functional status, readiness for change, and medical utilization), adjusting for demographic, marital, childhood, mental health, and violence variables. RESULTS: After controlling for duration, severity and dynamics of violence, the use of spiritual resources, and the level of spiritual symptoms were associated with most attitudinal/behavioral and clinical outcomes, while religious coping was only associated with staying in the relationship. CONCLUSIONS: Religious and spiritual factors were associated with most outcomes. Spiritual symptoms had a consistently negative effect on outcomes while use of spiritual resources had variable effects. Religious coping was only associated with refraining from leaving the relationship. PMID- 26060261 TI - Insecure attachment strategies are associated with cognitive alexithymia in patients with severe somatoform disorder. AB - OBJECTIVE: In light of interpersonal difficulties and their relation to alexithymia in patients with somatoform disorder, the primary aim of this study was to explore the association between two insecure attachment strategies (deactivation and hyperactivation strategies), and affective and cognitive alexithymia in a sample of 128 patients with severe somatoform disorder, over and above the levels of negative affectivity and personality pathology. METHOD: In a cross-sectional study among patients with somatoform disorder, self-report data were obtained using measures for alexithymia (Bermond-Vorst Alexithymia Questionnaire), attachment (Experiences in Close Relationships Questionnaire), personality pathology (Inventory of Personality Organization), and negative affectivity (Dutch Short Form of the MMPI). We used hierarchical regression analyses to test main effects of attachment deactivation and hyperactivation strategies in the prediction of both cognitive and affective alexithymia, while controlling for the levels of negative affectivity and personality pathology. RESULTS: Only cognitive alexithymia, i.e., the inability to analyze, identify, and verbalize emotions, was associated with personality dysfunction, in particular insecure attachment strategies. Affective alexithymia, i.e., the inability to fantasize and to experience emotions, was associated (negatively) with negative affectivity but not with the personality variables. CONCLUSIONS: This study, therefore, indicates that both types of alexithymia are relevant for the assessment and treatment of severe somatoform disorder, yet each type may tap into different features of somatoform disorder. PMID- 26060262 TI - Associations between comorbid anxiety, diabetes control, and overall medical burden in patients with serious mental illness and diabetes. AB - OBJECTIVE: While previous work has demonstrated elevation of both comorbid anxiety disorders and diabetes mellitus type II in individuals with serious mental illness, little is known regarding the impact of comorbid anxiety on diabetes mellitus type II outcomes in serious mental illness populations. We analyzed baseline data from patients with serious mental illness and diabetes mellitus type II to examine relationships between comorbid anxiety, glucose control as measured by hemoglobin A1c score, and overall illness burden. METHODS: Using baseline data from an ongoing prospective treatment study involving 157 individuals with serious mental illness and diabetes mellitus type II, we compared individuals with and without a comorbid anxiety disorder and compared hemoglobin A1c levels between these groups to assess the relationship between anxiety and management of diabetes mellitus type II. We conducted a similar analysis using cumulative number of anxiety diagnoses as a proxy for anxiety load. Finally, we searched for associations between anxiety and overall medical illness burden as measured by Charlson score. RESULTS: Anxiety disorders were seen in 33.1% (N=52) of individuals with serious mental illness and diabetes mellitus type II and were associated with increased severity of depressive symptoms and decreased function. Hemoglobin A1c levels were not significantly different in those with or without anxiety, and having multiple anxiety disorders was not associated with differences in diabetes mellitus type II control. However, depressive symptoms were significantly associated with higher hemoglobin A1c levels. Neither comorbid anxiety nor anxiety load was significantly associated with overall medical burden. CONCLUSION: One in three people with serious mental illness and diabetes mellitus type II had anxiety. Depressive symptoms were significantly associated with Hb1Ac levels while anxiety symptoms had no relation to hemoglobin A1c; this is consistent with previously published work. More studies are needed to better understand the relationship between depression, anxiety, and health management in people with serious mental illness and diabetes mellitus type II. PMID- 26060263 TI - Menstrual cycle could affect Ki67 expression in estrogen receptor-positive breast cancer patients. AB - BACKGROUND: Ki67 is a potent prognostic marker for determining systemic treatment of patients with hormone receptor-positive breast cancer. However, evaluation of Ki67 expression can be difficult, due mostly to its heterogeneity. The Ki67 expression level, which indicates that a cell is undergoing division (cell cycle), rises when proliferation activity increases. Thus, Ki67 expression might be affected by hormonal stimuli. We hypothesised that Ki67 expression level might change during the menstrual cycle. We examined pairs of biopsy and surgical specimens from individual patients to evaluate this hypothesis. METHODS: First, the effects of estradiol on Ki67 expression in breast cancer cell lines were examined employing immunocytochemistry and Western blotting. Next, differences in Ki67 expression between biopsy and surgical specimens from 131 patients with estrogen receptor-positive tumours were retrospectively examined. RESULTS: In vitro experiments showed Ki67 expression in estrogen receptor-positive cancer cells to be dependent on estradiol stimulation. Ki67 expression was higher in biopsy samples collected in the luteal phase than in those from other phases. When biopsy and surgical samples were obtained at different times during the menstrual cycle in the same individual, there were differences in Ki67 expression between these samples. Those collected in the luteal phase showed higher Ki67 expression than samples obtained during other phases (p<0.01). CONCLUSIONS: Ki67 expression varied in the same patients according to menstrual cycle phase. Our results suggest that Ki67 expression in estrogen receptor-positive breast cancer should be carefully assessed bearing in mind the patient's menstrual cycle, since the interpretation of expression could affect treatment decisions. PMID- 26060264 TI - Pseudohypercreatininaemia in two patients caused by monoclonal IgM interference with enzymatic assay of creatinine. PMID- 26060265 TI - ERG protein expression over time: from diagnostic biopsies to radical prostatectomy specimens in clinically localised prostate cancer. AB - AIMS: We evaluated the consistency in ERG protein expression from diagnostic specimens through rebiopsies to radical prostatectomies in patients with clinically localised prostate cancer to investigate the validity of ERG status in biopsies. METHODS: ERG expression was assessed by immunohistochemistry (IHC) in 625 biopsy sets and 86 radical prostatectomy specimens from 265 patients with prostate cancer managed on active surveillance. For IHC, a rabbit monoclonal primary antibody was used (clone: EPR3864). TMPRSS2-ERG fluorescence in situ hybridisation (FISH) analyses were performed in 74 biopsies using the FISH ZytoLight TriCheck Probe (SPEC ERG/TMPRSS2). FISH results were correlated with IHC findings. RESULTS: The concordance between FISH and IHC was 97.3% and IHC demonstrated a sensitivity and specificity for ERG rearrangement of 100% and 95.5%, respectively. Applying IHC, 38.1% of patients were ERG-positive, 53.6% were ERG-negative and 8.3% showed both ERG-positive and negative tumour foci (ERG heterogeneous) at diagnosis. When ERG status was dichotomised (ERG-positive or heterogeneous vs ERG-negative), 95.6%-97.1% of patients did not experience ERG reclassification during the first two rounds of rebiopsies. The concordance in ERG status between biopsies and surgical specimen was 89.5%-94.2% depending on the number of rebiopsies included. Sampling bias was assumed to explain most (81.3%) of the mismatches in ERG status. CONCLUSIONS: Consistency in ERG status ranged from 90% to 95% for patients undergoing serial biopsies and radical prostatectomy. This indicates that biopsies can be used reliably to investigate ERG's prognostic and predictive value. PMID- 26060266 TI - Biomass recalcitrance: a multi-scale, multi-factor, and conversion-specific property. AB - Recalcitrance of plant biomass to enzymatic hydrolysis for biofuel production is thought to be a property conferred by lignin or lignin-carbohydrate complexes. However, chemical catalytic and thermochemical conversion pathways, either alone or in combination with biochemical and fermentative pathways, now provide avenues to utilize lignin and to expand the product range beyond ethanol or butanol. To capture all of the carbon in renewable biomass, both lignin-derived aromatics and polysaccharide-derived sugars need to be transformed by catalysts to liquid hydrocarbons and high-value co-products. We offer a new definition of recalcitrance as those features of biomass which disproportionately increase energy requirements in conversion processes, increase the cost and complexity of operations in the biorefinery, and/or reduce the recovery of biomass carbon into desired products. The application of novel processing technologies applied to biomass reveal new determinants of recalcitrance that comprise a broad range of molecular, nanoscale, and macroscale factors. Sampling natural genetic diversity within a species, transgenic approaches, and synthetic biology approaches are all strategies that can be used to select biomass for reduced recalcitrance in various pretreatments and conversion pathways. PMID- 26060267 TI - Toxicokinetic Model Development for the Insensitive Munitions Component 3-Nitro 1,2,4-Triazol-5-One. AB - 3-Nitro-1,2,4-triazol-5-one (NTO) is a component of insensitive munitions that are potential replacements for conventional explosives. Toxicokinetic data can aid in the interpretation of toxicity studies and interspecies extrapolation, but only limited data on the toxicokinetics and metabolism of NTO are available. To supplement these limited data, further in vivo studies of NTO in rats were conducted and blood concentrations were measured, tissue distribution of NTO was estimated using an in silico method, and physiologically based pharmacokinetic models of the disposition of NTO in rats and macaques were developed and extrapolated to humans. The model predictions can be used to extrapolate from designated points of departure identified from rat toxicology studies to provide a scientific basis for estimates of acceptable human exposure levels for NTO. PMID- 26060268 TI - Mercury Exposure and Endothelial Dysfunction: An Interplay Between Nitric Oxide and Oxidative Stress. AB - Vascular endothelium plays a vital role in the organization and function of the blood vessel and maintains homeostasis of the circulatory system and normal arterial function. Functional disruption of the endothelium is recognized as the beginning event that triggers the development of consequent cardiovascular disease (CVD) including atherosclerosis and coronary heart disease. There is a growing data associating mercury exposure with endothelial dysfunction and higher risk of CVD. This review explores and evaluates the impact of mercury exposure on CVD and endothelial function, highlighting the interplay of nitric oxide and oxidative stress. PMID- 26060269 TI - Two Proteins Form a Heteromeric Bacterial Self-Recognition Complex in Which Variable Subdomains Determine Allele-Restricted Binding. AB - Self- versus nonself-recognition in bacteria has been described recently through genetic analyses in multiple systems; however, understanding of the biochemical properties and mechanisms of recognition-determinant proteins remains limited. Here we extend the molecular and biochemical understanding of two recognition determinant proteins in bacteria. We have found that a heterotypic complex is formed between two bacterial self-recognition proteins, IdsD and IdsE, the genes of which have been shown to genetically encode the determinants for strain specific identity in the opportunistic bacterial pathogen Proteus mirabilis. This IdsD-IdsE complex forms independently of other P. mirabilis-encoded self recognition proteins. We have also shown that the binding between IdsD and IdsE is strain- and allele-specific. The specificity for interactions is encoded within a predicted membrane-spanning subdomain within each protein that contains stretches of unique amino acids in each P. mirabilis variant. Finally, we have demonstrated that this in vitro IdsD-IdsE binding interaction correlates to in vivo population identity, suggesting that the binding interactions between IdsD and IdsE are part of a cellular pathway that underpins self-recognition behavior in P. mirabilis and drives bacterial population sociality. IMPORTANCE: Here we demonstrate that two proteins, the genes of which were genetically shown to encode determinants of self-identity in bacteria, bind in vitro in an allele restricted interaction, suggesting that molecular recognition between these two proteins is a mechanism underpinning self-recognition behaviors in P. mirabilis. Binding specificity in each protein is encapsulated in a variable region subdomain that is predicted to span the membrane, suggesting that the interaction occurs in the cell envelope. Furthermore, conversion of binding affinities in vitro correlates with conversion of self-identity in vivo, suggesting that this molecular recognition might help to drive population behaviors. PMID- 26060270 TI - Cathepsin W Is Required for Escape of Influenza A Virus from Late Endosomes. AB - Human cathepsin W (CtsW) is a cysteine protease, which was identified in a genome wide RNA interference (RNAi) screen to be required for influenza A virus (IAV) replication. In this study, we show that reducing the levels of expression of CtsW reduces viral titers for different subtypes of IAV, and we map the target step of CtsW requirement to viral entry. Using a set of small interfering RNAs (siRNAs) targeting CtsW, we demonstrate that knockdown of CtsW results in a decrease of IAV nucleoprotein accumulation in the nuclei of infected cells at 3 h postinfection. Assays specific for the individual stages of IAV entry further show that attachment, internalization, and early endosomal trafficking are not affected by CtsW knockdown. However, we detected impaired escape of viral particles from late endosomes in CtsW knockdown cells. Moreover, fusion analysis with a dual-labeled influenza virus revealed a significant reduction in fusion events, with no detectable impact on endosomal pH, suggesting that CtsW is required at the stage of viral fusion. The defect in IAV entry upon CtsW knockdown could be rescued by ectopic expression of wild-type CtsW but not by the expression of a catalytically inactive mutant of CtsW, suggesting that the proteolytic activity of CtsW is required for successful entry of IAV. Our results establish CtsW as an important host factor for entry of IAV into target cells and suggest that CtsW could be a promising target for the development of future antiviral drugs. IMPORTANCE: Increasing levels of resistance of influenza viruses to available antiviral drugs have been observed. Development of novel treatment options is therefore of high priority. In parallel to the classical approach of targeting viral enzymes, a novel strategy is pursued: cell-dependent factors of the virus are identified with the aim of developing small-molecule inhibitors against a cellular target that the virus relies on. For influenza A virus, several genome-wide RNA interference (RNAi) screens revealed hundreds of potential cellular targets. However, we have only limited knowledge on how these factors support virus replication, which would be required for drug development. We have characterized cathepsin W, one of the candidate factors, and found that cathepsin W is required for escape of influenza virus from the late endosome. Importantly, this required the proteolytic activity of cathepsin W. We therefore suggest that cathepsin W could be a target for future host cell-directed antiviral therapies. PMID- 26060272 TI - Acetic Acid Acts as a Volatile Signal To Stimulate Bacterial Biofilm Formation. AB - Volatiles are small air-transmittable chemicals with diverse biological activities. In this study, we showed that volatiles produced by the bacterium Bacillus subtilis had a profound effect on biofilm formation of neighboring B. subtilis cells that grew in proximity but were physically separated. We further demonstrated that one such volatile, acetic acid, is particularly potent in stimulating biofilm formation. Multiple lines of genetic evidence based on B. subtilis mutants that are defective in either acetic acid production or transportation suggest that B. subtilis uses acetic acid as a metabolic signal to coordinate the timing of biofilm formation. Lastly, we investigated how B. subtilis cells sense and respond to acetic acid in regulating biofilm formation. We showed the possible involvement of three sets of genes (ywbHG, ysbAB, and yxaKC), all encoding putative holin-antiholin-like proteins, in cells responding to acetic acid and stimulating biofilm formation. All three sets of genes were induced by acetate. A mutant with a triple mutation of those genes showed a severe delay in biofilm formation, whereas a strain overexpressing ywbHG showed early and robust biofilm formation. Results of our studies suggest that B. subtilis and possibly other bacteria use acetic acid as a metabolic signal to regulate biofilm formation as well as a quorum-sensing-like airborne signal to coordinate the timing of biofilm formation by physically separated cells in the community. IMPORTANCE: Volatiles are small, air-transmittable molecules produced by all kingdoms of organisms including bacteria. Volatiles possess diverse biological activities and play important roles in bacteria-bacteria and bacteria host interactions. Although volatiles can be used as a novel and important way of cell-cell communication due to their air-transmittable nature, little is known about how the volatile-mediated signaling mechanism works. In this study, we demonstrate that the bacterium Bacillus subtilis uses one such volatile, acetic acid, as a quorum-sensing-like signal to coordinate the timing of the formation of structurally complex cell communities, also known as biofilms. We further characterized the molecular mechanisms of how B. subtilis responds to acetic acid in stimulating biofilm formation. Our study also suggests that acetic acid may be used as a volatile signal for cross-species communication. PMID- 26060273 TI - Examination of the Enterotoxigenic Escherichia coli Population Structure during Human Infection. AB - Enterotoxigenic E. coli (ETEC) can cause severe diarrhea and death in children in developing countries; however, bacterial diversity in natural infection is uncharacterized. In this study, we explored the natural population variation of ETEC from individuals with cholera-like diarrhea. Genomic sequencing and comparative analysis of multiple ETEC isolates from twelve cases of severe diarrhea demonstrated clonal populations in the majority of subjects (10/12). In contrast, a minority of individuals (2/12) yielded phylogenomically divergent ETEC isolates. Detailed examination revealed that isolates also differed in virulence factor content. These genomic data suggest that severe, cholera-like ETEC infections are largely caused by a clonal population of organisms within individual patients. Additionally, the isolation of similar clones from geographically and temporally dispersed cases with similar clinical presentations suggests that some isolates are particularly suited for virulence. The identification of multiple genomically diverse isolates with variable virulence factor profiles from a single subject highlights the dynamic nature of ETEC, as well as a potential weakness in the examination of cultures obtained from a single colony in clinical settings. These findings have implications for vaccine design and provide a framework for the study of population variation in other human pathogens. IMPORTANCE: Enterotoxigenic Escherichia coli (ETEC) has been identified as one of the major causes of diarrheal diseases in children as well as travelers. It has been previously appreciated that this pathogenic variant of E. coli is diverse, both at the genomic level, as defined with multilocus sequence typing, and with regard to the presence or absence of virulence factors within clonal groups. Using whole-genome sequencing and comparative analysis, we identified and characterized diverse enterotoxigenic E. coli isolates from individual patients. In 17% of patients, we identified multiple distinct ETEC isolates, each with unique genomic features and in some cases diverse virulence factor profiles. These studies ascertained that any one person may be colonized by multiple pathogenic ETEC isolates, which may impact how we think about the development of vaccines and therapeutics against these organisms. PMID- 26060274 TI - The Atypical Occurrence of Two Biotin Protein Ligases in Francisella novicida Is Due to Distinct Roles in Virulence and Biotin Metabolism. AB - The physiological function of biotin requires biotin protein ligase activity in order to attach the coenzyme to its cognate proteins, which are enzymes involved in central metabolism. The model intracellular pathogen Francisella novicida is unusual in that it encodes two putative biotin protein ligases rather than the usual single enzyme. F. novicida BirA has a ligase domain as well as an N terminal DNA-binding regulatory domain, similar to the prototypical BirA protein in E. coli. However, the second ligase, which we name BplA, lacks the N-terminal DNA binding motif. It has been unclear why a bacterium would encode these two disparate biotin protein ligases, since F. novicida contains only a single biotinylated protein. In vivo complementation and enzyme assays demonstrated that BirA and BplA are both functional biotin protein ligases, but BplA is a much more efficient enzyme. BirA, but not BplA, regulated transcription of the biotin synthetic operon. Expression of bplA (but not birA) increased significantly during F. novicida infection of macrophages. BplA (but not BirA) was required for bacterial replication within macrophages as well as in mice. These data demonstrate that F. novicida has evolved two distinct enzymes with specific roles; BplA possesses the major ligase activity, whereas BirA acts to regulate and thereby likely prevent wasteful synthesis of biotin. During infection BplA seems primarily employed to maximize the efficiency of biotin utilization without limiting the expression of biotin biosynthetic genes, representing a novel adaptation strategy that may also be used by other intracellular pathogens. IMPORTANCE: Our findings show that Francisella novicida has evolved two functional biotin protein ligases, BplA and BirA. BplA is a much more efficient enzyme than BirA, and its expression is significantly induced upon infection of macrophages. Only BplA is required for F. novicida pathogenicity, whereas BirA prevents wasteful biotin synthesis. These data demonstrate that the atypical occurrence of two biotin protein ligases in F. novicida is linked to distinct roles in virulence and biotin metabolism. PMID- 26060275 TI - csrR, a Paralog and Direct Target of CsrA, Promotes Legionella pneumophila Resilience in Water. AB - Critical to microbial versatility is the capacity to express the cohort of genes that increase fitness in different environments. Legionella pneumophila occupies extensive ecological space that includes diverse protists, pond water, engineered water systems, and mammalian lung macrophages. One mechanism that equips this opportunistic pathogen to adapt to fluctuating conditions is a switch between replicative and transmissive cell types that is controlled by the broadly conserved regulatory protein CsrA. A striking feature of the legionellae surveyed is that each of 14 strains encodes 4 to 7 csrA-like genes, candidate regulators of distinct fitness traits. Here we focus on the one csrA paralog (lpg1593) that, like the canonical csrA, is conserved in all 14 strains surveyed. Phenotypic analysis revealed that long-term survival in tap water is promoted by the lpg1593 locus, which we name csrR (for "CsrA-similar protein for resilience"). As predicted by its GGA motif, csrR mRNA was bound directly by the canonical CsrA protein, as judged by electromobility shift and RNA-footprinting assays. Furthermore, CsrA repressed translation of csrR mRNA in vivo, as determined by analysis of csrR-gfp reporters, csrR mRNA stability in the presence and absence of csrA expression, and mutation of the CsrA binding site identified on the csrR mRNA. Thus, CsrA not only governs the transition from replication to transmission but also represses translation of its paralog csrR when nutrients are available. We propose that, during prolonged starvation, relief of CsrA repression permits CsrR protein to coordinate L. pneumophila's switch to a cell type that is resilient in water supplies. IMPORTANCE: Persistence of L. pneumophila in water systems is a public health risk, and yet there is little understanding of the genetic determinants that equip this opportunistic pathogen to adapt to and survive in natural or engineered water systems. A potent regulator of this pathogen's intracellular life cycle is CsrA, a protein widely distributed among bacterial species that is understood quite well. Our finding that every sequenced L. pneumophila strain carries several csrA paralogs-including two common to all isolates--indicates that the legionellae exploit CsrA regulatory switches for multiple purposes. Our discovery that one paralog, CsrR, is a target of CsrA that enhances survival in water is an important step toward understanding colonization of the engineered environment by pathogenic L. pneumophila. PMID- 26060276 TI - Insertion Sequence IS26 Reorganizes Plasmids in Clinically Isolated Multidrug Resistant Bacteria by Replicative Transposition. AB - Carbapenemase-producing Enterobacteriaceae (CPE), which are resistant to most or all known antibiotics, constitute a global threat to public health. Transposable elements are often associated with antibiotic resistance determinants, suggesting a role in the emergence of resistance. One insertion sequence, IS26, is frequently associated with resistance determinants, but its role remains unclear. We have analyzed the genomic contexts of 70 IS26 copies in several clinical and surveillance CPE isolates from the National Institutes of Health Clinical Center. We used target site duplications and their patterns as guides and found that a large fraction of plasmid reorganizations result from IS26 replicative transpositions, including replicon fusions, DNA inversions, and deletions. Replicative transposition could also be inferred for transposon Tn4401, which harbors the carbapenemase blaKPC gene. Thus, replicative transposition is important in the ongoing reorganization of plasmids carrying multidrug-resistant determinants, an observation that carries substantial clinical and epidemiological implications for understanding how such extreme drug resistance phenotypes evolve. IMPORTANCE: Although IS26 is frequently reported to reside in resistance plasmids of clinical isolates, the characteristic hallmark of transposition, target site duplication (TSD), is generally not observed, raising questions about the mode of transposition for IS26. The previous observation of cointegrate formation during transposition implies that IS26 transposes via a replicative mechanism. The other possible outcome of replicative transposition is DNA inversion or deletion, when transposition occurs intramolecularly, and this would also generate a specific TSD pattern that might also serve as supporting evidence for the transposition mechanism. The numerous examples we present here demonstrate that replicative transposition, used by many mobile elements (including IS26 and Tn4401), is prevalent in the plasmids of clinical isolates and results in significant plasmid reorganization. This study also provides a method to trace the evolution of resistance plasmids based on TSD patterns. PMID- 26060277 TI - Genome-Wide Identification of Klebsiella pneumoniae Fitness Genes during Lung Infection. AB - Klebsiella pneumoniae is an urgent public health threat because of resistance to carbapenems, antibiotics of last resort against Gram-negative bacterial infections. Despite the fact that K. pneumoniae is a leading cause of pneumonia in hospitalized patients, the bacterial factors required to cause disease are poorly understood. Insertion site sequencing combines transposon mutagenesis with high-throughput sequencing to simultaneously screen thousands of insertion mutants for fitness defects during infection. Using the recently sequenced K. pneumoniae strain KPPR1 in a well-established mouse model of pneumonia, insertion site sequencing was performed on a pool of >25,000 transposon mutants. The relative fitness requirement of each gene was ranked based on the ratio of lung to inoculum read counts and concordance between insertions in the same gene. This analysis revealed over 300 mutants with at least a 2-fold fitness defect and 69 with defects ranging from 10- to >2,000-fold. Construction of 6 isogenic mutants for use in competitive infections with the wild type confirmed their requirement for lung fitness. Critical fitness genes included those for the synthesis of branched-chain and aromatic amino acids that are essential in mice and humans, the transcriptional elongation factor RfaH, and the copper efflux pump CopA. The majority of fitness genes were conserved among reference strains representative of diverse pathotypes. These results indicate that regulation of outer membrane components and synthesis of amino acids that are essential to its host are critical for K. pneumoniae fitness in the lung. IMPORTANCE: Klebsiella pneumoniae is a bacterium that commonly causes pneumonia in patients after they are admitted to the hospital. K. pneumoniae is becoming resistant to all available antibiotics, and when these infections spread to the bloodstream, over half of patients die. Since currently available antibiotics are failing, we must discover new ways to treat these infections. In this study, we asked what genes the bacterium needs to cause an infection, since the proteins encoded by these genes could be targets for new antibiotics. We identified over 300 genes that K. pneumoniae requires to grow in a mouse model of pneumonia. Many of the genes that we identified are found in K. pneumoniae isolates from throughout the world, including antibiotic-resistant forms. If new antibiotics could be made against the proteins that these genes encode, they may be broadly effective against K. pneumoniae. PMID- 26060279 TI - Endovascular treatment of an infected pseudoaneurysm secondary to retropharyngeal abscess in a child. AB - We describe a rare case of carotid pseudoaneurysm secondary to a retropharyngeal abscess, treated with coil embolization in a 2-year-old boy. The patient presented to an emergency department with symptoms suggesting meningitis but was subsequently diagnosed with streptococcal pharyngitis. He was discharged home on oral antibiotics after a short hospitalization. He returned to the emergency department two weeks later with limited neck motion and pain. Neck CT demonstrated a retropharyngeal abscess with a large left cervical internal carotid artery (ICA) pseudoaneurysm. The petrous ICA distal to the pseudoaneurysm had thrombosed prior to treatment. The ICA proximal to the pseudoaneurysm was sacrificed with coil embolization. Post-treatment imaging demonstrated complete thrombosis of the pseudoaneurysm but also demonstrated acute strokes in the left MCA/ACA watershed distribution. His parents noted that the patient was clumsier and exhibited some mild speech changes and a steppage gait prior to evaluation in the ED; therefore, these were thought to be secondary to emboli from partial thrombosis of the pseudoaneurysm prior to treatment. The patient was discharged home in good condition and his neurological function improved. PMID- 26060271 TI - Cryptococcosis Serotypes Impact Outcome and Provide Evidence of Cryptococcus neoformans Speciation. AB - Cryptococcus neoformans is a human opportunistic fungal pathogen causing severe disseminated meningoencephalitis, mostly in patients with cellular immune defects. This species is divided into three serotypes: A, D, and the AD hybrid. Our objectives were to compare population structures of serotype A and D clinical isolates and to assess whether infections with AD hybrids differ from infections with the other serotypes. For this purpose, we analyzed 483 isolates and the corresponding clinical data from 234 patients enrolled during the CryptoA/D study or the nationwide survey on cryptococcosis in France. Isolates were characterized in terms of ploidy, serotype, mating type, and genotype, utilizing flow cytometry, serotype- and mating type-specific PCR amplifications, and multilocus sequence typing (MLST) methods. Our results suggest that C. neoformans serotypes A and D have different routes of multiplication (primarily clonal expansion versus recombination events for serotype A and serotype D, respectively) and important genomic differences. Cryptococcosis includes a high proportion of proven or probable infections (21.5%) due to a mixture of genotypes, serotypes, and/or ploidies. Multivariate analysis showed that parameters independently associated with failure to achieve cerebrospinal fluid (CSF) sterilization by week 2 were a high serum antigen titer, the lack of flucytosine during induction therapy, and the occurrence of mixed infection, while infections caused by AD hybrids were more likely to be associated with CSF sterilization. Our study provides additional evidence for the possible speciation of C. neoformans var. neoformans and grubii and highlights the importance of careful characterization of causative isolates. IMPORTANCE: Cryptococcus neoformans is an environmental fungus causing severe disease, estimated to be responsible for 600,000 deaths per year worldwide. This species is divided into serotypes A and D and an AD hybrid, and these could be considered two different species and an interspecies hybrid. The objectives of our study were to compare population structures of serotype A and serotype D and to assess whether infections with AD hybrids differ from infections with serotype A or D isolates in terms of clinical presentation and outcome. For this purpose, we used clinical data and strains from patients diagnosed with cryptococcosis in France. Our results suggest that, according to the serotype, isolates have different routes of multiplication and high genomic differences, confirming the possible speciation of serotypes A and D. Furthermore, we observed a better prognosis for infections caused by AD hybrid than those caused by serotype A or D, at least for those diagnosed in France. PMID- 26060278 TI - Cyclic Rhamnosylated Elongation Factor P Establishes Antibiotic Resistance in Pseudomonas aeruginosa. AB - Elongation factor P (EF-P) is a ubiquitous bacterial protein that is required for the synthesis of poly-proline motifs during translation. In Escherichia coli and Salmonella enterica, the posttranslational beta-lysylation of Lys34 by the PoxA protein is critical for EF-P activity. PoxA is absent from many bacterial species such as Pseudomonas aeruginosa, prompting a search for alternative EF-P posttranslation modification pathways. Structural analyses of P. aeruginosa EF-P revealed the attachment of a single cyclic rhamnose moiety to an Arg residue at a position equivalent to that at which beta-Lys is attached to E. coli EF-P. Analysis of the genomes of organisms that both lack poxA and encode an Arg32 containing EF-P revealed a highly conserved glycosyltransferase (EarP) encoded at a position adjacent to efp. EF-P proteins isolated from P. aeruginosa DeltaearP, or from a DeltarmlC::acc1 strain deficient in dTDP-L-rhamnose biosynthesis, were unmodified. In vitro assays confirmed the ability of EarP to use dTDP-L-rhamnose as a substrate for the posttranslational glycosylation of EF-P. The role of rhamnosylated EF-P in translational control was investigated in P. aeruginosa using a Pro4-green fluorescent protein (Pro4GFP) in vivo reporter assay, and the fluorescence was significantly reduced in Deltaefp, DeltaearP, and DeltarmlC::acc1 strains. DeltarmlC::acc1, DeltaearP, and Deltaefp strains also displayed significant increases in their sensitivities to a range of antibiotics, including ertapenem, polymyxin B, cefotaxim, and piperacillin. Taken together, our findings indicate that posttranslational rhamnosylation of EF-P plays a key role in P. aeruginosa gene expression and survival. IMPORTANCE: Infections with pathogenic Salmonella, E. coli, and Pseudomonas isolates can all lead to infectious disease with potentially fatal sequelae. EF-P proteins contribute to the pathogenicity of the causative agents of these and other diseases by controlling the translation of proteins critical for modulating antibiotic resistance, motility, and other traits that play key roles in establishing virulence. In Salmonella spp. and E. coli, the attachment of beta-Lys is required for EF-P activity, but the proteins required for this posttranslational modification pathway are absent from many organisms. Instead, bacteria such as P. aeruginosa activate EF-P by posttranslational modification with rhamnose, revealing a new role for protein glycosylation that may also prove useful as a target for the development of novel antibiotics. PMID- 26060280 TI - Rampant Parasexuality Evolves in a Hospital Pathogen during Antibiotic Selection. AB - Horizontal gene transfer threatens the therapeutic success of antibiotics by facilitating the rapid dissemination of resistance alleles among bacterial species. The conjugative mobile element Tn916 provides an excellent context for examining the role of adaptive parasexuality as it carries the tetracycline resistance allele tetM and has been identified in a wide range of pathogens. We have used a combination of experimental evolution and allelic frequency measurements to gain insights into the adaptive trajectories leading to tigecycline resistance in a hospital strain of Enterococcus faecalis and predict what mechanisms of resistance are most likely to appear in the clinical setting. Here, we show that antibiotic selection led to the near fixation of adaptive alleles that simultaneously altered TetM expression and produced remarkably increased levels of Tn916 horizontal gene transfer. In the absence of drug, approximately 1 in 120,000 of the nonadapted E. faecalis S613 cells had an excised copy of Tn916, whereas nearly 1 in 50 cells had an excised copy of Tn916 upon selection for resistance resulting in a more than 1,000-fold increase in conjugation rates. We also show that tigecycline, a translation inhibitor, selected for a mutation in the ribosomal S10 protein. Our results show the first example of mutations that concurrently confer resistance to an antibiotic and lead to constitutive conjugal-transfer of the resistance allele. Selection created a highly parasexual phenotype and high frequency of Tn916 jumping demonstrating how the use of antibiotics can lead directly to the proliferation of resistance in, and potentially among, pathogens. PMID- 26060281 TI - An ecological analysis of secondary school students' drug use in Hong Kong: A case-control study. AB - BACKGROUND: Youth drug use is a significant at-risk youth behaviour and remains as one of the top priorities for mental health services, researchers and policy planners. The ecological characteristics of secondary school students' behaviour in Hong Kong are understudied. AIM: To examine individual, familial, social and environmental correlates of drug use among secondary students in Hong Kong. METHOD: Data were extracted from a school survey with 3078 students. Among the 3078 students, 86 students reported to have used drugs in the past 6 months. A total of 86 age- and gender-matched controls with no drug-use behaviour in the past 6 months were randomly selected from the remaining students. Multiple logistic analysis was used to examine differential correlates between those who used and did not use substance in the past 6 months. RESULT: Positive school experience and perspective to school and parental support are protective factors of drug use. Lower self-esteem, lower self-efficacy against using drugs and higher level of permissive attitude towards drugs were associated with drug use. Students who were low in self-esteem and rather impulsive tend to use drugs. CONCLUSION: To prevent students from drug use, efforts in individual, family, school and community-levels should be addressed. PMID- 26060282 TI - Examination of a Parent-Assisted, Friendship-Building Program for Adolescents With ADHD. AB - OBJECTIVE: Youth with ADHD experience significant impairment in peer functioning. Based on recommendations from the literature, the current pilot study examined the effectiveness of a parent-assisted, friendship-building program at establishing mutual friendships and improving peer relationships in adolescents with ADHD. METHOD: Participants included 20 adolescents with ADHD (ages 11-16 years) and their parent(s). Families completed the Program for the Evaluation and Enrichment of Relational Skills (PEERS). Measures of friendship quality, social knowledge, social self-efficacy, get-togethers, and peer conflict were completed at baseline and post-treatment. At post-treatment, participants also reported on the initiation of a new friendship. RESULTS: Baseline to post-treatment differences were examined using paired-samples t tests. The majority of participants reported the initiation of a new friendship at post-treatment. Adolescents also demonstrated significantly improved social knowledge and increased get-togethers. Effect sizes were large. CONCLUSION: Following participation in PEERS, adolescents improved in several peer functioning domains and many initiated new friendships. PMID- 26060283 TI - Clinical Characteristics, Diagnosis, Management, and Outcomes of Disseminated Emmonsiosis: A Retrospective Case Series. AB - BACKGROUND: We describe the geographic distribution, clinical characteristics, and management of patients with disease caused by Emmonsia sp., a novel dimorphic fungal pathogen recently described in South Africa. METHODS: We performed a multicenter, retrospective chart review of laboratory-confirmed cases of emmonsiosis diagnosed across South Africa from January 2008 through February 2015. RESULTS: Fifty-four patients were diagnosed in 5/9 provinces. Fifty-one patients (94%) were human immunodeficiency virus coinfected (median CD4 count 16 cells/uL [interquartile range, 6-40]). In 12 (24%) of these, antiretroviral therapy had been initiated in the preceding 2 months. All patients had disseminated disease, most commonly involving skin (n = 50/52, 96%) and lung (n = 42/48, 88%). Yeasts were visualized on histopathologic examination of skin (n = 34/37), respiratory tissue (n = 2/4), brain (n = 1/1), liver (n = 1/2), and bone marrow (n = 1/15). Emmonsia sp. was cultured from skin biopsy (n = 20/28), mycobacterial/fungal and aerobic blood culture (n = 15/25 and n = 9/37, respectively), bone marrow (n = 12/14), lung (n = 1/1), lymph node (n = 1/1), and brain (n = 1/1). Twenty-four of 34 patients (71%) treated with amphotericin B deoxycholate, 4/12 (33%) treated with a triazole alone, and none of 8 (0%) who received no antifungals survived. Twenty-six patients (48%) died, half undiagnosed. CONCLUSIONS: Disseminated emmonsiosis is more widespread in South Africa and carries a higher case fatality rate than previously appreciated. Cutaneous involvement is near universal, and skin biopsy can be used to diagnose the majority of patients. PMID- 26060284 TI - Bordetella pertussis Isolates Circulating in China Where Whole Cell Vaccines Have Been Used for 50 Years. PMID- 26060286 TI - HIV Coinfected Have Similar SVR Rates as HCV Monoinfected With DAAs: It's Time to End Segregation and Integrate HIV Patients Into HCV Trials. AB - Phase 3 trials of direct acting antiviral drugs (DAAs) for hepatitis C virus (HCV) excluded patients coinfected with human immunodeficiency virus (HIV). After approval, small trials were done in HIV-HCV coinfected patients. The status quo results in delayed access to DAAs for HIV coinfected patients, a group with more rapid progression of liver disease. This article reviews all approved DAAs and compares sustained virological response (SVR) rates in the HIV coinfected with those in the HCV monoinfected treated with the same regimen for the same HCV genotype. SVR rates in HCV genotype 1 to 4 are virtually identical in the HIV co infected as in the HCV monoinfected, regardless of whether the regimens contain interferon. Because HIV coinfection does not affect SVR rates or toxicity with DAA-containing therapy, excluding HIV coinfected patients from clinical trials of DAA-containing anti-HCV therapy is discriminatory and unnecessary. Rather, HIV coinfection is one of many comorbidities that occur in some patients with HCV infection. PMID- 26060285 TI - Lower Newborn Bone Mineral Content Associated With Maternal Use of Tenofovir Disoproxil Fumarate During Pregnancy. AB - BACKGROUND: Fetal bone effects of maternal tenofovir use have not been well studied. We sought to compare whole-body bone mineral content (BMC) of newborns exposed vs not exposed to tenofovir in utero. METHODS: We enrolled participants from April 2011 to June 2013 at 14 US clinical sites. Singleton infants of women with human immunodeficiency virus (HIV) infection who took tenofovir in late pregnancy (tenofovir-exposed) or no tenofovir during pregnancy (tenofovir unexposed) were enrolled during late pregnancy or within 72 hours of birth. Infants born before 36 weeks gestation or with confirmed HIV infection were excluded. Whole-body BMC was measured in the first month of life and compared with that of the tenofovir-exposed and tenofovir-unexposed newborns, unadjusted and adjusted for covariates. RESULTS: Seventy-four tenofovir-exposed and 69 tenofovir-unexposed infants had evaluable BMC measurements. Tenofovir-exposed mothers were more likely to be married (31% vs 22%; P = .04) and to use boosted protease inhibitors (84% vs 62%; P = .004). Tenofovir-exposed newborns did not differ from unexposed newborns on mean gestational age (38.2 vs 38.1 weeks) or mean length (-0.41 vs -0.18) or weight (-0.71 vs -0.48) Z-scores. The mean (standard deviation) BMC of tenofovir-exposed infants was 12% lower than for unexposed infants (56.0 [11.8] vs 63.8 [16.6] g; P = .002). The adjusted mean bone mineral content was 5.3 g lower (95% confidence interval, -9.5, -1.2; P = .013) in the tenofovir-exposed infants. CONCLUSIONS: Maternal tenofovir use is associated with significantly lower neonatal BMC. The duration and clinical significance of this finding should be evaluated in longitudinal studies. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01310023. PMID- 26060287 TI - Mortality Associated With Seasonal and Pandemic Influenza Among Pregnant and Nonpregnant Women of Childbearing Age in a High-HIV-Prevalence Setting-South Africa, 1999-2009. AB - BACKGROUND: Information on the mortality burden associated with seasonal and pandemic influenza virus infection among pregnant women is scarce in most settings, particularly in sub-Saharan Africa where pregnancy and maternal mortality rates as well as human immunodeficiency virus (HIV) prevalence are elevated. METHODS: We used an ecological study design to estimate the seasonal and A(H1N1)pdm09 influenza-associated mortality among pregnant and nonpregnant women of childbearing age (15-49 years) by HIV serostatus during 1999-2009 in South Africa. Mortality rates were expressed per 100 000 person-years. RESULTS: During 1999-2009, the estimated mean annual seasonal influenza-associated mortality rates were 12.6 (123 deaths) and 7.3 (914 deaths) among pregnant and nonpregnant women, respectively. Among pregnant women, the estimated mean annual seasonal influenza-associated mortality rates were 74.9 (109 deaths) among HIV infected and 1.5 (14 deaths) among HIV-uninfected individuals. Among nonpregnant women, the estimated mean annual seasonal influenza-associated mortality rate was 41.2 (824 deaths) among HIV-infected and 0.9 (90 deaths) among HIV-uninfected individuals. Pregnant women experienced an increased risk of seasonal influenza associated mortality compared with nonpregnant women (relative risk [RR], 2.8; 95% confidence interval [CI], 1.7-3.9). In 2009, the estimated influenza A(H1N1)pdm09-associated mortality rates were 19.3 (181 deaths) and 9.4 (1189 deaths) among pregnant and nonpregnant women, respectively (RR, 3.2; 95% CI, 2.3 4.1). CONCLUSIONS: Among women of childbearing age, the majority of estimated seasonal influenza-associated deaths occurred in HIV-infected individuals. Pregnant women experienced an increased risk of death associated with seasonal and A(H1N1)pdm09 influenza infection compared with nonpregnant women. PMID- 26060288 TI - Editorial Commentary: Different Strains of Bacillus Calmette-Guerin Vaccine Have Very Different Effects on Tuberculosis and on Unrelated Infections. PMID- 26060289 TI - Study of Ebola Virus Disease Survivors in Guinea. AB - BACKGROUND: There is a paucity of data regarding health consequences of Ebola virus disease among survivors. METHODS: We surveyed 105 Ebola virus disease survivors postdischarge from an Ebola treatment unit in Guinea using a standard data collection form. Patients rated recovery as the percentage of improvement in functional status, where 0% represents "unable to perform" and 100% represents "able to perform at prior level." RESULTS: The mean +/- standard deviation time interval between hospital discharge and administration of questionnaire was 103.5 +/- 47.9 days in 105 survivors. Anorexia was reported by 103 patients, with varying severity levels: mild (n = 33), moderate (n = 65), or severe (n = 5). Reported pain according to site was chest (30.7%), joint (86.7%), muscle (26.7%), and back (45.7%), among others. Recovery in functional status was graded as mild (10%-30%) (n = 2 [1.9%]), moderate (40%-70%) (n = 52 [50.0%]), and excellent (80% 100%) (n = 50 [48.1%]). Severity of arthralgia (R(2) = 0.09; P = .008) was directly associated with lower recovery in functional status in multivariate analysis. CONCLUSIONS: Ebola virus disease survivors frequently reported anorexia and arthralgia. Severity of arthralgia was related to lower functional recovery. There may be a role for focused screening and intervention for symptoms identified in this study of survivors. PMID- 26060290 TI - Role of Treatment Cost on Transmission of Multidrug-Resistant Tuberculosis Into Iran. PMID- 26060291 TI - Immunity to Measles, Mumps, and Rubella in US Children With Perinatal HIV Infection or Perinatal HIV Exposure Without Infection. AB - BACKGROUND: Children with perinatal human immunodeficiency virus (HIV) infection (PHIV) may not be protected against measles, mumps, and rubella (MMR) because of impaired initial vaccine response or waning immunity. Our objectives were to estimate seroimmunity in PHIV-infected and perinatally HIV-exposed but uninfected (HEU) children and identify predictors of immunity in the PHIV cohort. METHODS: PHIV and HEU children were enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS) at ages 7-15 years from 2007 to 2009. At annual visits, demographic, laboratory, immunization, and clinical data were abstracted and serologic specimens collected. Most recent serologic specimen was used to determine measles seroprotection by plaque reduction neutralization assay and rubella seroprotection and mumps seropositivity by enzyme immunoassay. Sustained combination antiretroviral therapy (cART) was defined as taking cART for at least 3 months. RESULTS: Among 428 PHIV and 221 HEU PHACS participants, the prevalence was significantly lower in PHIV children for measles seroprotection (57% [95% confidence interval {CI}, 52%-62%] vs 99% [95% CI, 96%-100%]), rubella seroprotection (65% [95% CI, 60%-70%] vs 98% [95% CI, 95%-100%]), and mumps seropositivity (59% [95% CI, 55%-64%] vs 97% [95% CI, 94%-99%]). On multivariable analysis, greater number of vaccine doses while receiving sustained cART and higher nadir CD4 percentage between last vaccine dose and serologic testing independently improved the cumulative prediction of measles seroprotection in PHIV. Predictors of rubella seroprotection and mumps seropositivity were similar. CONCLUSIONS: High proportions of PHIV-infected children, but not HEU children, lack serologic evidence of immunity to MMR, despite documented immunization and current cART. Effective cART before immunization is a strong predictor of current seroimmunity. PMID- 26060292 TI - Use of Acid Suppression Medication is Associated With Risk for C. difficile Infection in Infants and Children: A Population-based Study. AB - BACKGROUND: Acid suppression medication is associated with Clostridium difficile infection (CDI) in adults and is increasingly prescribed to children. This study evaluated the relationship between acid suppression medication and incident CDI in children. METHODS: This was a population-based, nested case-control study. Patients were eligible if they were aged 0-17 years with 3 or more visits or 1 year or more of follow-up in the dataset. Patients were excluded if they had comorbidities that associate with CDI and might also associate with acid suppression medication. Patients with codes for CDI were matched 1:5 with control patients by age, sex, medical practice, time of entry into the dataset, and follow-up time. The primary exposure was use of acid suppression medication with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) within 8-90 days. RESULTS: We identified 650 CDI cases and 3200 controls. The adjusted odds ratio (OR) for CDI and acid suppression medication was 7.66 (95% confidence interval [CI], 3.24-18.1). Acid suppression medication was associated with CDI in infants aged <1 year (OR, 5.24; 95% CI, 1.13-24.4) and children aged 1-17 years (OR, 9.33; 95% CI, 3.25-26.8). There was increased risk for CDI with PPIs compared with H2RAs and with recent compared with distant exposure. CONCLUSIONS: Acid suppression medication associated with CDI in infants and children in the outpatient setting, with an effect based on medication timing. Increased risk for CDI should be factored into the decision to use acid suppression medication in children. PMID- 26060293 TI - Development of BCG Scar and Subsequent Morbidity and Mortality in Rural Guinea Bissau. AB - BACKGROUND: Previous studies have found that BCG vaccination has nonspecific beneficial effects on child survival, especially among children who developed a BCG scar. These studies have mostly been done in settings with a high scar frequency. In rural Guinea-Bissau, many children do not develop a scar; we tested the hypothesis that among BCG-vaccinated children, a vaccination scar was associated with lower mortality and fewer hospital admissions. METHODS: During 2009-2011, children <5 years of age in villages followed by Bandim Health Project's demographic surveillance system had their scar status assessed at semiannual visits. We compared mortality and hospital admission rates of scar positive and scar-negative BCG-vaccinated children during 6 months of follow-up in Cox proportional hazards models. RESULTS: Among 15 911 BCG-vaccinated children, only 52% had a scar. There were 106 non-injury-related deaths among scar-positive children and 137 among scar-negative children. The mortality rate ratio (MRR) was 0.74 (95% confidence interval [CI], .56-.96) overall; 0.48 (95% CI, .26-.90) in infancy, 0.69 (95% CI, .45-1.05) in the second year of life, and 0.89 (95% CI, .61-1.31) in the third-fifth year of life. The association between scar positivity and lower mortality differed significantly by cause of death and was strongest for respiratory infections (MRR, 0.20 [95% CI, .07-.55]). There were 99 hospital admissions among scar-positive children and 125 admissions among scar-negative children, resulting in an incidence rate ratio of 0.74 (95% CI, .60 .92). CONCLUSIONS: Among BCG-vaccinated children in a setting with low scar prevalence, having a scar is associated with lower mortality and morbidity. BCG scar prevalence may be an important marker of vaccination program quality. PMID- 26060294 TI - Advanced Clinical Decision Support for Vaccine Adverse Event Detection and Reporting. AB - BACKGROUND: Reporting of adverse events (AEs) following vaccination can help identify rare or unexpected complications of immunizations and aid in characterizing potential vaccine safety signals. We developed an open-source, generalizable clinical decision support system called Electronic Support for Public Health-Vaccine Adverse Event Reporting System (ESP-VAERS) to assist clinicians with AE detection and reporting. METHODS: ESP-VAERS monitors patients' electronic health records for new diagnoses, changes in laboratory values, and new allergies following vaccinations. When suggestive events are found, ESP-VAERS sends the patient's clinician a secure electronic message with an invitation to affirm or refute the message, add comments, and submit an automated, prepopulated electronic report to VAERS. High-probability AEs are reported automatically if the clinician does not respond. We implemented ESP-VAERS in December 2012 throughout the MetroHealth System, an integrated healthcare system in Ohio. We queried the VAERS database to determine MetroHealth's baseline reporting rates from January 2009 to March 2012 and then assessed changes in reporting rates with ESP-VAERS. RESULTS: In the 8 months following implementation, 91 622 vaccinations were given. ESP-VAERS sent 1385 messages to responsible clinicians describing potential AEs. Clinicians opened 1304 (94.2%) messages, responded to 209 (15.1%), and confirmed 16 for transmission to VAERS. An additional 16 high-probability AEs were sent automatically. Reported events included seizure, pleural effusion, and lymphocytopenia. The odds of a VAERS report submission during the implementation period were 30.2 (95% confidence interval, 9.52-95.5) times greater than the odds during the comparable preimplementation period. CONCLUSIONS: An open-source, electronic health record-based clinical decision support system can increase AE detection and reporting rates in VAERS. PMID- 26060296 TI - Correction: Synergistic Induction of Apoptosis in Multiple Myeloma Cells by Bortezomib and Hypoxia-Activated Prodrug TH-302, In Vivo and In Vitro. PMID- 26060297 TI - Opinion: What makes things humorous. PMID- 26060300 TI - Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic resistant bacteria. AB - The increasing threat of pathogen resistance to antibiotics requires the development of novel antimicrobial strategies. Here we present a proof of concept for a genetic strategy that aims to sensitize bacteria to antibiotics and selectively kill antibiotic-resistant bacteria. We use temperate phages to deliver a functional clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system into the genome of antibiotic-resistant bacteria. The delivered CRISPR-Cas system destroys both antibiotic resistance conferring plasmids and genetically modified lytic phages. This linkage between antibiotic sensitization and protection from lytic phages is a key feature of the strategy. It allows programming of lytic phages to kill only antibiotic-resistant bacteria while protecting antibiotic-sensitized bacteria. Phages designed according to this strategy may be used on hospital surfaces and hand sanitizers to facilitate replacement of antibiotic-resistant pathogens with sensitive ones. PMID- 26060299 TI - Gradual decline in mobility with the adoption of food production in Europe. AB - Increased sedentism during the Holocene has been proposed as a major cause of decreased skeletal robusticity (bone strength relative to body size) in modern humans. When and why declining mobility occurred has profound implications for reconstructing past population history and health, but it has proven difficult to characterize archaeologically. In this study we evaluate temporal trends in relative strength of the upper and lower limb bones in a sample of 1,842 individuals from across Europe extending from the Upper Paleolithic [11,000 33,000 calibrated years (Cal y) B.P.] through the 20th century. A large decline in anteroposterior bending strength of the femur and tibia occurs beginning in the Neolithic (~ 4,000-7,000 Cal y B.P.) and continues through the Iron/Roman period (~ 2,000 Cal y B.P.), with no subsequent directional change. Declines in mediolateral bending strength of the lower limb bones and strength of the humerus are much smaller and less consistent. Together these results strongly implicate declining mobility as the specific behavioral factor underlying these changes. Mobility levels first declined at the onset of food production, but the transition to a more sedentary lifestyle was gradual, extending through later agricultural intensification. This finding only partially supports models that tie increased sedentism to a relatively abrupt Neolithic Demographic Transition in Europe. The lack of subsequent change in relative bone strength indicates that increasing mechanization and urbanization had only relatively small effects on skeletal robusticity, suggesting that moderate changes in activity level are not sufficient stimuli for bone deposition or resorption. PMID- 26060295 TI - Less Bone Loss With Maraviroc- Versus Tenofovir-Containing Antiretroviral Therapy in the AIDS Clinical Trials Group A5303 Study. AB - BACKGROUND: There is a need to prevent or minimize bone loss associated with antiretroviral treatment (ART) initiation. We compared maraviroc (MVC)- to tenofovir disoproxil fumarate (TDF)-containing ART. METHODS: This was a double blind, placebo-controlled trial. ART-naive subjects with human immunodeficiency virus type 1 RNA load (viral load [VL]) >1000 copies/mL and R5 tropism were randomized to MVC 150 mg or TDF 300 mg once daily (1:1), stratified by VL <100 000 or >=100 000 copies/mL and age <30 or >=30 years. All subjects received darunavir 800 mg, ritonavir 100 mg, and emtricitabine 200 mg daily. Dual-energy X ray absorptiometry scanning was done at baseline and week 48. The primary endpoint was percentage change in total hip bone mineral density (BMD) from baseline to week 48 in the as-treated population. RESULTS: We enrolled 262 subjects. A total of 259 subjects (130 MVC, 129 TDF) contributed to the analyses (91% male; median age, 33 years; 45% white, 30% black, 22% Hispanic). Baseline median VL was 4.5 log10 copies/mL and CD4 count was 390 cells/uL. The decline in hip BMD (n = 115 for MVC, n = 109 for TDF) at week 48 was less with MVC (median [Q1, Q3] of -1.51% [-2.93%, -0.11%] vs -2.40% [-4.30%, -1.32%] for TDF (P < .001). Lumbar spine BMD decline was also less with MVC (median -0.88% vs -2.35%; P < .001). Similar proportions of subjects in both arms achieved VL <=50 copies/mL in as-treated and ITT analyses. CONCLUSIONS: MVC was associated with less bone loss at the hip and lumbar spine compared with TDF. MVC may be an option to attenuate ART-associated bone loss. CLINICAL TRIALS REGISTRATION: NCT01400412. PMID- 26060301 TI - A survey of human brain transcriptome diversity at the single cell level. AB - The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level. Healthy adult temporal lobe tissue was obtained during surgical procedures where otherwise normal tissue was removed to gain access to deeper hippocampal pathology in patients with medical refractory seizures. We were able to classify individual cells into all of the major neuronal, glial, and vascular cell types in the brain. We were able to divide neurons into individual communities and show that these communities preserve the categorization of interneuron subtypes that is typically observed with the use of classic interneuron markers. We then used single cell RNA sequencing on fetal human cortical neurons to identify genes that are differentially expressed between fetal and adult neurons and those genes that display an expression gradient that reflects the transition between replicating and quiescent fetal neuronal populations. Finally, we observed the expression of major histocompatibility complex type I genes in a subset of adult neurons, but not fetal neurons. The work presented here demonstrates the applicability of single cell RNA sequencing on the study of the adult human brain and constitutes a first step toward a comprehensive cellular atlas of the human brain. PMID- 26060302 TI - On overvaluing parental overvaluation as the origins of narcissism. PMID- 26060303 TI - Reply to Kealy et al.: Theoretical precision in the study of narcissism and its origins. PMID- 26060304 TI - Progressive Movement Disorder in Brothers Carrying a GNAO1 Mutation Responsive to Deep Brain Stimulation. AB - GNAO1, located on chromosome 16q12.2, encodes for 1 of the heterotrimeric guanine binding proteins subunits (G proteins), specifically Galphao, which has been implicated as having an important role in brain function. GNAO1 mutations have been shown to impart oncogene properties as well as cause epileptic encephalopathy. The authors report 2 cases of brothers with a severe movement disorder and hypotonia without epilepsy who have been confirmed by whole exome sequencing to have a novel mutation in GNAO1. Their movement disorder improved significantly with deep brain stimulation. PMID- 26060305 TI - Study of Posterior Reversible Encephalopathy Syndrome in Children With Acute Lymphoblastic Leukemia After Induction Chemotherapy. AB - Increasing occurrence of posterior reversible encephalopathy syndrome has been reported in children with acute lymphoblastic leukemia. However, the etiology of posterior reversible encephalopathy syndrome is not clear. To study the possible pathogenetic mechanisms and treatment of this complication, we reported 11 cases of pediatric acute lymphoblastic leukemia who developed posterior reversible encephalopathy syndrome after induction chemotherapy. After appropriate treatment, the clinical symptoms of posterior reversible encephalopathy syndrome in most cases disappeared even though induction chemotherapy continued. During the 1-year follow-up, no recurrence of posterior reversible encephalopathy syndrome was observed. Although the clinical and imaging features of posterior reversible encephalopathy syndrome may be diverse, posterior reversible encephalopathy syndrome should be recognized as a possible important complication of acute lymphoblastic leukemia when neurologic symptoms appear. In line with previous reports, our study also indicated that posterior reversible encephalopathy syndrome was reversible when diagnosed and treated at an early stage. Thus, the occurrence of posterior reversible encephalopathy syndrome should be considered and investigated to optimize the early induction scheme of acute lymphoblastic leukemia treatment. PMID- 26060306 TI - Medical Marijuana in Pediatric Neurological Disorders. AB - Marijuana and marijuana-based products have been used to treat medical disease. Recently, derivatives of the plant have been separated or synthesized to treat various neurological disorders, many of them affecting children. Unfortunately, data are sparse in regard to treating children with neurologic illness. Therefore, formal conclusions about the potential efficacy, benefit, and adverse effects for these products cannot be made at this time. Further robust research using strong scientific methodology is desperately needed to formally evaluate the role of these products in children. PMID- 26060307 TI - Methionyl-tRNA Formyltransferase (MTFMT) Deficiency Mimicking Acquired Demyelinating Disease. AB - Disease-related mutations in the mitochondrial methionyl-tRNA formyltransferase (MTFMT) gene encoding a critical enzyme for mitochondrial translation have been rarely reported and are described in association with Leigh syndrome and combined oxidative phosphorylation deficiency. Symptoms include developmental delay, followed by ataxia and spasticity manifesting at later stages. A man had a clinical picture suggestive of an acquired demyelinating disease. Brain magnetic resonance imaging (MRI) demonstrated extensive involvement of the optic nerves, cerebral white matter, brain stem, and spinal cord. Whole-exome sequencing detected a pathologic homozygous c.626C>T mutation in the MTFMT gene. These findings expand the clinical features and neuroimaging spectrum associated with MTFMT mutations to include a relapsing-remitting phenotype. PMID- 26060308 TI - The Clinical Implications of Todd Paralysis in Children With Benign Rolandic Epilepsy. AB - The aim of this study was to describe the clinical and electroencephalographic (EEG) findings of postictal Todd paralysis in benign rolandic epilepsy of childhood and find out the possible correlation with migraine. Based on International Headache Society pediatric migraine criteria, patients were investigated for migraine, and 12 of the 108 patients with benign rolandic epilepsy (6 girls and 6 boys, 11.1%) were found to have postictal Todd paralysis. Ten of these 12 patients (83.3%) had pediatric migraine based on the diagnostic criteria. We showed comorbidity of migraine and benign rolandic epilepsy with postictal Todd paralysis in children. Increased incidence of migraine in the present study suggest that children who have benign rolandic epilepsy and postictal Todd paralysis are more likely to have migraines. PMID- 26060309 TI - Identification of a triplet pair intermediate in singlet exciton fission in solution. AB - Singlet exciton fission is the spin-conserving transformation of one spin-singlet exciton into two spin-triplet excitons. This exciton multiplication mechanism offers an attractive route to solar cells that circumvent the single-junction Shockley-Queisser limit. Most theoretical descriptions of singlet fission invoke an intermediate state of a pair of spin-triplet excitons coupled into an overall spin-singlet configuration, but such a state has never been optically observed. In solution, we show that the dynamics of fission are diffusion limited and enable the isolation of an intermediate species. In concentrated solutions of bis(triisopropylsilylethynyl)[TIPS]--tetracene we find rapid (<100 ps) formation of excimers and a slower (~ 10 ns) break up of the excimer to two triplet exciton bearing free molecules. These excimers are spectroscopically distinct from singlet and triplet excitons, yet possess both singlet and triplet characteristics, enabling identification as a triplet pair state. We find that this triplet pair state is significantly stabilized relative to free triplet excitons, and that it plays a critical role in the efficient endothermic singlet fission process. PMID- 26060311 TI - Correction for Campbell et al., Humoral response to a viral glycan correlates with survival on PROSTVAC-VF. PMID- 26060312 TI - Correction for Stoveken et al., Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist. PMID- 26060310 TI - Inflammation negatively regulates FOXP3 and regulatory T-cell function via DBC1. AB - Forkhead box P3 (FOXP3)-positive Treg cells are crucial for maintaining immune homeostasis. FOXP3 cooperates with its binding partners to elicit Treg cells' signature and function, but the molecular mechanisms underlying the modulation of the FOXP3 complex remain unclear. Here we report that Deleted in breast cancer 1 (DBC1) is a key subunit of the FOXP3 complex. We found that DBC1 interacts physically with FOXP3, and depletion of DBC1 attenuates FOXP3 degradation in inflammatory conditions. Treg cells from Dbc1-deficient mice were more resistant to inflammation-mediated abrogation of Foxp3 expression and function and delayed the onset and severity of experimental autoimmune encephalomyelitis and colitis in mice. These findings establish a previously unidentified mechanism regulating FOXP3 stability during inflammation and reveal a pathway for potential therapeutic modulation and intervention in inflammatory diseases. PMID- 26060313 TI - Empirical inference of circuitry and plasticity in a kinase signaling network. AB - Our understanding of physiology and disease is hampered by the difficulty of measuring the circuitry and plasticity of signaling networks that regulate cell biology, and how these relate to phenotypes. Here, using mass spectrometry-based phosphoproteomics, we systematically characterized the topology of a network comprising the PI3K/Akt/mTOR and MEK/ERK signaling axes and confirmed its biological relevance by assessing its dynamics upon EGF and IGF1 stimulation. Measuring the activity of this network in models of acquired drug resistance revealed that cells chronically treated with PI3K or mTORC1/2 inhibitors differed in the way their networks were remodeled. Unexpectedly, we also observed a degree of heterogeneity in the network state between cells resistant to the same inhibitor, indicating that even identical and carefully controlled experimental conditions can give rise to the evolution of distinct kinase network statuses. These data suggest that the initial conditions of the system do not necessarily determine the mechanism by which cancer cells become resistant to PI3K/mTOR targeted therapies. The patterns of signaling network activity observed in the resistant cells mirrored the patterns of response to several drug combination treatments, suggesting that the activity of the defined signaling network truly reflected the evolved phenotypic diversity. PMID- 26060315 TI - Mindfulness for neurologists. PMID- 26060314 TI - Extracapsular cataract extraction training: junior ophthalmology residents' self reported satisfaction level with their proficiency and initial learning barrier. AB - PURPOSE: To investigate residents' self-reported satisfaction level with their proficiency in extracapsular cataract extraction (ECCE) surgery and the initial barriers to learning the procedure. METHODS: This is a single-centre prospective descriptive case series involving eight first-year ophthalmology residents in Singapore National Eye Center. We recorded the demographics, frequency of review by the residents of their own surgical videos and their satisfaction level with their proficiency at each of the ECCE steps using a 5-point Likert scale. All ECCE surgical videos between October 2013 and May 2014 were collected and analysed for the overall time taken for the surgery and the time taken to perform the individual steps of the procedure. RESULTS: The mean age of the residents was 27.6 +/- 1.5 years and 62.5% (5/8) were women. More than half (62.5%, 5/8) reviewed their own surgical videos while 37.5% (3/8) discussed the surgical videos with their peers or supervisors. Of the ECCE steps, the residents were most dissatisfied with their proficiency in performing irrigation and aspiration (87.5%, 7/8), followed by suturing (62.5%, 5/8), intraocular lens insertion (62.5%, 5/8) and tin can capsulotomy (62.5%, 5/8). The average time taken for each ECCE case was 55.0 +/- 12.2 min and, of all the steps, most time was spent on suturing (20.5 +/- 6.8 min), followed by irrigation and aspiration (5.5 +/- 3.6 min) and tin can capsulotomy (3.3 +/- 1.8 min). CONCLUSIONS: The first-year ophthalmology residents were most dissatisfied with their proficiency in irrigation/aspiration, suturing and tin can capsulotomy. More training needs to be directed to these areas during teaching sessions in the operating room, wet laboratory or cataract simulation training sessions. PMID- 26060316 TI - Curious turns in the night-time. PMID- 26060317 TI - Placental changes caused by food restriction during early pregnancy in mice are reversible. AB - In a previous study, 50% calorie restriction in mice from d1.5 to 11.5 of pregnancy resulted in reduced placental weights and areas,relative sparing of labyrinth zone area compared to junctional zone area, and dramatic changes in global gene expression profiles.However, little lasting effect was seen on adult offspring of these pregnancies, with a slight reduction in adiposity in males and some changes in liver gene expression in both sexes. The goals of the present study were to determine whether the placental changes induced by caloric restriction in early pregnancy had permanent, irreversible effects on the placenta, and whether the changes in liver gene expression in adult offspring were present before birth. There were no differences in placental weights or areas, or the areas of individual placental zones near term in mice that had previously been food restricted. Global gene expression profiles at d18.5 were indistinguishable in placentas from control and previously food-restricted mothers. In fetuses from restricted dams at d18.5, liver expression of Gck, a key regulator of glycogen synthesis, was reduced, whereas its expression was increased in livers from adult offspring of restricted dams. Ppara expression was also reduced in fetal livers from restricted dams at d18.5, but not in adult offspring livers. We conclude that alterations in the placenta caused by nutrient restriction in early pregnancy are reversible, and that alterations in gene expression in livers of adult offspring are not a result of changes initiated during pregnancy and maintained through adulthood. PMID- 26060318 TI - Lactate Dehydrogenase as a Biomarker for Prediction of Refractory Mycoplasma pneumoniae Pneumonia in Children. AB - BACKGROUND: Corticosteroids have been used for refractory Mycoplasma pneumoniae pneumonia and have beneficial effects. The aim of this study was to identify the biomarkers for predicting refractory M. pneumoniae pneumonia in a timely fashion to initiate steroid therapy. METHODS: This was a prospective cohort study of children with M. pneumoniae pneumonia admitted to the Children's Hospital of Fudan University from September 2012 to August 2013. Lactate dehydrogenase (LDH) and other laboratory tests, including complete blood counts, C-reactive protein, erythrocyte sedimentation rate (ESR), alanine aminotransferase, aspartate aminotransferase, alpha-hydroxybutyrate dehydrogenase (HBDH), creatine kinase, and creatine kinase MB, were performed on admission. Based on the definition of refractory M. pneumoniae pneumonia, subjects were divided into 2 groups: refractory M. pneumoniae pneumonia and usual M. pneumoniae pneumonia. The diagnostic values of laboratory findings were analyzed. RESULTS: In total, 653 subjects were enrolled, including 300 in the refractory pneumonia group and 353 in the usual pneumonia group. There was no significant difference in sex distribution between the 2 groups. The average age in the refractory M. pneumoniae pneumonia group was greater than that in the usual M. pneumoniae pneumonia group. Compared with the usual pneumonia group, the refractory pneumonia group showed significantly higher levels of C-reactive protein, serum LDH, serum HBDH, serum alanine aminotransferase, serum aspartate aminotransferase, and neutrophils and higher ESRs. Logistic regression showed that age, LDH, and ESR were the significant factors in predicting refractory M. pneumoniae pneumonia. In addition, LDH and HBDH were strongly correlated, and receiver operating characteristic curve analysis showed that the area under the curve of LDH was 0.718 with a cutoff of 379 IU/L, that of ESR was 0.683 with a cutoff of 32.5 IU/L, and that of HBDH was 0.691 with a cutoff of 259.5 IU/L. CONCLUSIONS: Serum LDH can be used as a biomarker to predict refractory M. pneumoniae pneumonia at the early stage of hospitalization. PMID- 26060319 TI - Inflammatory Responses, Spirometry, and Quality of Life in Subjects With Bronchiectasis Exacerbations. AB - BACKGROUND: Bronchiectasis exacerbations are critical events characterized by worsened symptoms and signs (ie, cough frequency, sputum volume, malaise). OBJECTIVES: Our goal was to examine variations in airway and systemic inflammation, spirometry, and quality of life during steady state, bronchiectasis exacerbations, and convalescence (1 week following a 2-week antibiotic treatment) to determine whether potentially pathogenic microorganisms, including Pseudomonas aeruginosa, were associated with poorer conditions during bronchiectasis exacerbations. METHODS: Peripheral blood and sputum were sampled to detect inflammatory mediators and bacterial densities. Spirometry and quality of life (St George Respiratory Questionnaire [SGRQ]) were assessed during the 3 stages. RESULTS: Forty-eight subjects with bronchiectasis (43.2 +/- 14.2 y of age) were analyzed. No notable differences in species and density of potentially pathogenic microorganisms were found during bronchiectasis exacerbations. Except for CXCL8 and tumor necrosis factor alpha (TNF-alpha), serum inflammation was heightened during bronchiectasis exacerbations and recovered during convalescence. Even though sputum TNF-alpha was markedly higher during bronchiectasis exacerbations and remained heightened during convalescence, the variations in miscellaneous sputum markers were unremarkable. Bronchiectasis exacerbations were associated with notably higher SGRQ symptom and total scores, which recovered during convalescence. FVC, FEV1, and maximum mid-expiratory flow worsened during bronchiectasis exacerbations (median change from baseline of -2.2%, -0.8%, and 1.3%) and recovered during convalescence (median change from baseline of 0.6%, 0.7%, and -0.7%). Compared with no bacterial isolation, potentially pathogenic microorganism or P. aeruginosa isolation at baseline did not result in poorer clinical condition during bronchiectasis exacerbations. CONCLUSIONS: Bronchiectasis exacerbations are characterized by heightened inflammatory responses and poorer quality of life and spirometry, but not by increased bacterial density, which applies for subjects with and without potentially pathogenic microorganism isolation when clinically stable. (ClinicalTrials.gov registration NCT01761214.). PMID- 26060320 TI - High-Flow Nasal Cannula in a Mixed Adult ICU. AB - BACKGROUND: Humidified, high-flow nasal cannula (HFNC) enables mucociliary clearance, accurate oxygen measurement, precise control of flow, and low-level positive airway pressure. There is sparse information concerning the timing of HFNC on patient outcomes such as incidence of adverse events during hospitalization, ICU stay, and post-ICU stay. METHODS: This is a retrospective analysis of a heterogeneous population of medical and trauma ICU patients who received HFNC therapy in a critical care setting. The study sample included 145 subjects who were admitted to the ICU and received HFNC therapy between March 2012 and February 2014. HFNC was delivered by the Fisher & Paykel Optiflow system. RESULTS: Of the 145 subjects who received HFNC, 35 (24.1%) received mechanical ventilation before HFNC, 21 (14.5%) received mechanical ventilation after HFNC, and 89 (61.3%) never received mechanical ventilation. Delay to first HFNC was moderately associated with unplanned ICU admission and was strongly correlated with the development of ventilator-associated pneumonia. Subjects with a greater length of time between ICU admission and first use of HFNC experienced significantly longer stays in the ICU and post-ICU periods, even after controlling for adverse events and mechanical ventilation. CONCLUSIONS: Study results provide preliminary evidence that early use of HFNC is beneficial in a medical and trauma ICU population, as it was associated with decreased ICU and post-ICU lengths of stay and reduced incidence of adverse events. This suggests that HFNC should be considered early in the ICU as first-line oxygen therapy. PMID- 26060321 TI - Use of High-Flow Nasal Cannula for Acute Dyspnea and Hypoxemia in the Emergency Department. AB - BACKGROUND: Acute dyspnea and hypoxemia are 2 of the most common problems in the emergency room. Oxygen therapy is an essential supportive treatment to correct these issues. In this study, we investigated the physiologic effects of high-flow nasal oxygen cannula (HFNC) compared with conventional oxygen therapy (COT) in subjects with acute dyspnea and hypoxemia in the emergency room. METHODS: A prospective randomized comparative study was conducted in the emergency department of a university hospital. Forty subjects were randomized to receive HFNC or COT for 1 h. The primary outcome was level of dyspnea, and secondary outcomes included change in breathing frequency, subject comfort, adverse events, and rate of hospitalization. RESULTS: Common causes of acute dyspnea and hypoxemia were congestive heart failure, asthma exacerbation, COPD exacerbation, and pneumonia. HFNC significantly improved dyspnea (2.0 +/- 1.8 vs 3.8 +/- 2.3, P = .01) and subject comfort (1.6 +/- 1.7 vs 3.7 +/- 2.4, P = .01) compared with COT. No statistically significant difference in breathing frequency was found between the 2 groups at the end of the study. HFNC was well tolerated, and no serious adverse events were found. The rate of hospitalization in the HFNC group was lower than in the COT group, but there was no statistically significant difference (50% vs 65%, P = .34). CONCLUSIONS: HFNC improved dyspnea and comfort in subjects presenting with acute dyspnea and hypoxemia in the emergency department. HFNC may benefit patients requiring oxygen therapy in the emergency room. PMID- 26060322 TI - Cathepsin S and cathepsin L in serum and synovial fluid in rheumatoid arthritis with and without autoantibodies. AB - OBJECTIVES: Cathepsin S and cathepsin L are endosomal proteolytic enzymes involved in the degradation of extracellular matrixes, angiogenesis and antigen presentation. Cathepsins could thus play several roles in the disease process of RA. The aim of this study was to examine differences in cathepsin S and cathepsin L levels in serum and SF of RA patients with and without ACPA and RF. METHODS: In this study 121 patients with RA and clinical signs of knee synovitis were recruited. Patient characteristics were collected and matched samples of serum and SF were analysed for cathepsin S, cathepsin L, ACPA, IgA and IgM RF, CRP and MMP3. RESULTS: SF levels of cathepsin L, cathepsin S and MMP3 were significantly higher than in serum. Serum levels of both cathepsins were significantly higher in patients with ACPA, IgM-RF and IgA-RF compared with patients without these antibodies. SF levels of both cathepsins correlated with DAS28 and CRP in ACPA- and RF-positive but not in seronegative patients. CONCLUSION: The differences in cathepsin S and cathepsin L between RA patients with and without autoantibodies indicate that these cathepsins have a specific role in the disease process of seropositive RA. In this phenotype, cathepsin serum levels may reflect the autoimmune activity, whereas the levels in SF may reflect the local inflammatory and matrix degrading process in the joint. PMID- 26060323 TI - Estimating the diagnostic accuracy of rheumatoid factor in UK primary care: a study using the Clinical Practice Research Datalink. AB - OBJECTIVE: To investigate the diagnostic accuracy of RF as a test for RA in primary care and its impact on referral times using the Clinical Practice Research Datalink. METHODS: We identified all patients with a first RF test recorded in the Clinical Practice Research Datalink between 1 January 2000 and 31 December 2008 and those diagnosed with RA within 2 years of testing. We calculated likelihood ratios (LRs), sensitivity, specificity and predictive values of RF for a diagnosis of RA. We compared time to hospital referral in those testing positive and negative using Kaplan-Meier failure curves and log rank tests. RESULTS: Of 62 436 first RF tests, 4679 (7.5%) were positive. There were 1753 incident cases of RA, of which 57.8% were seropositive. The positive LR for RF was 9.5 (95% CI 9.0, 10.0) and the negative LR was 0.5 (95% CI 0.4, 0.5). Sensitivity and specificity were 57.8% (95% CI 55.4%, 60.1%) and 93.9% (95% CI 93.7%, 94.1%) and the positive predictive value and negative predictive value were 21.4% (95% CI 20.3%, 22.6%) and 98.7% (95% CI 98.6%, 98.8%), respectively. Median time to first hospital contact after the first RF test in those with seropositive vs seronegative results was 54 days (95% CI 49, 58) vs 150 (95% CI 147, 152). CONCLUSION: Only 2.8% of patients undergoing RF testing were diagnosed with RA, suggesting that RF is used to screen patients with musculoskeletal symptoms rather than those with more specific features of RA. A positive RF test may be helpful in diagnosing RA in primary care but performs badly in excluding RA and may delay referral. PMID- 26060324 TI - The dual nature of eye contact: to see and to be seen. AB - Previous research has shown that physiological arousal and attentional responses to eye contact are modulated by one's knowledge of whether they are seen by another person. Recently it was shown that this 'eye contact effect' can be elicited without seeing another person's eyes at all. We aimed to investigate whether the eye contact effect is actually triggered by the mere knowledge of being seen by another individual, i.e. even in a condition when the perceiver does not see the other person at all. We measured experienced self-awareness and both autonomic and brain activity responses while participants were facing another person (a model) sitting behind a window. We manipulated the visibility of the model and the participants' belief of whether or not the model could see them. When participants did not see the model but believed they were seen by the model, physiological responses were attenuated in comparison to when both parties saw each other. However, self-assessed public self-awareness was not attenuated in this condition. Thus, two requirements must be met for physiological responses to occur in response to eye contact: an experience of being seen by another individual and an experience of seeing the other individual. PMID- 26060325 TI - Memory and reward systems coproduce 'nostalgic' experiences in the brain. AB - People sometimes experience an emotional state known as 'nostalgia', which involves experiencing predominantly positive emotions while remembering autobiographical events. Nostalgia is thought to play an important role in psychological resilience. Previous neuroimaging studies have shown involvement of memory and reward systems in such experiences. However, it remains unclear how these two systems are collaboratively involved with nostalgia experiences. Here, we conducted a functional magnetic resonance imaging study of healthy females to investigate the relationship between memory-reward co-activation and nostalgia, using childhood-related visual stimuli. Moreover, we examined the factors constituting nostalgia and their neural correlates. We confirmed the presence of nostalgia-related activity in both memory and reward systems, including the hippocampus (HPC), substantia nigra/ventral tegmental area (SN/VTA), and ventral striatum (VS). We also found significant HPC-VS co-activation, with its strength correlating with individual 'nostalgia tendencies'. Factor analyses showed that two dimensions underlie nostalgia: emotional and personal significance and chronological remoteness, with the former correlating with caudal SN/VTA and left anterior HPC activity, and the latter correlating with rostral SN/VTA activity. These findings demonstrate the cooperative activity of memory and reward systems, where each system has a specific role in the construction of the factors that underlie the experience of nostalgia. PMID- 26060326 TI - Dysfunctional error-related processing in female psychopathy. AB - Neurocognitive studies of psychopathy have predominantly focused on male samples. Studies have shown that female psychopaths exhibit similar affective deficits as their male counterparts, but results are less consistent across cognitive domains including response modulation. As such, there may be potential gender differences in error-related processing in psychopathic personality. Here we investigate response-locked event-related potential (ERP) components [the error-related negativity (ERN/Ne) related to early error-detection processes and the error related positivity (Pe) involved in later post-error processing] in a sample of incarcerated adult female offenders (n = 121) who performed a response inhibition Go/NoGo task. Psychopathy was assessed using the Hare Psychopathy Checklist Revised (PCL-R). The ERN/Ne and Pe were analyzed with classic windowed ERP components and principal component analysis (PCA). Consistent with previous research performed in psychopathic males, female psychopaths exhibited specific deficiencies in the neural correlates of post-error processing (as indexed by reduced Pe amplitude) but not in error monitoring (as indexed by intact ERN/Ne amplitude). Specifically, psychopathic traits reflecting interpersonal and affective dysfunction remained significant predictors of both time-domain and PCA measures reflecting reduced Pe mean amplitude. This is the first evidence to suggest that incarcerated female psychopaths exhibit similar dysfunctional post error processing as male psychopaths. PMID- 26060328 TI - Small molecules with big effects: Cyclic di-GMP-mediated stimulation of cellulose production by the amino acid L-arginine. AB - In this issue of Science Signaling, Mills et al. show that the amino acid L arginine increases the concentration of the second messenger c-di-GMP in Salmonella enterica serovar Typhimurium through a specific diguanylate cyclase, leading to increased production of the exopolysaccharide cellulose, which is an extracellular matrix component of environmental and host-associated biofilms. PMID- 26060327 TI - Social support, stress and the aging brain. AB - Social support benefits health and well-being in older individuals, however the mechanism remains poorly understood. One proposal, the stress-buffering hypothesis states social support 'buffers' the effects of stress on health. Alternatively, the main effect hypothesis suggests social support independently promotes health. We examined the combined association of social support and stress on the aging brain. Forty healthy older adults completed stress questionnaires, a social network interview and structural MRI to investigate the amygdala-medial prefrontal cortex circuitry, which is implicated in social and emotional processing and negatively affected by stress. Social support was positively correlated with right medial prefrontal cortical thickness while amygdala volume was negatively associated with social support and positively related to stress. We examined whether the association between social support and amygdala volume varied across stress level. Stress and social support uniquely contribute to amygdala volume, which is consistent with the health benefits of social support being independent of stress. PMID- 26060330 TI - A direct screen for c-di-GMP modulators reveals a Salmonella Typhimurium periplasmic L-arginine-sensing pathway. AB - Cyclic-di-GMP (c-di-GMP) is a bacterial second messenger that transduces internal and external signals and regulates bacterial motility and biofilm formation. Some organisms encode more than 100 c-di-GMP-modulating enzymes, but only for a few has a signal been defined that modulates their activity. We developed and applied a high-throughput, real-time flow cytometry method that uses a fluorescence resonance energy transfer (FRET)-based biosensor of free c-di-GMP to screen for signals that modulate its concentration within Salmonella Typhimurium. We identified multiple compounds, including glucose, N-acetyl-d-glucosamine, salicylic acid, and L-arginine, that modulated the FRET signal and therefore the free c-di-GMP concentration. By screening a library of mutants, we identified proteins required for the c-di-GMP response to each compound. Furthermore, low micromolar concentrations of L-arginine induced a rapid translation-independent increase in c-di-GMP concentrations and c-di-GMP-dependent cellulose synthesis, responses that required the regulatory periplasmic domain of the diguanylate cyclase STM1987. L-Arginine signaling also required the periplasmic putative L arginine-binding protein ArtI, implying that L-arginine sensing occurred in the periplasm. Among the 20 commonly used amino acids, S. Typhimurium specifically responded to L-arginine with an increase in c-di-GMP, suggesting that L-arginine may serve as a signal during S. Typhimurium infection. Our results demonstrate that a second-messenger biosensor can be used to identify environmental signals and define pathways that alter microbial behavior. PMID- 26060329 TI - SUMO deconjugation is required for arsenic-triggered ubiquitylation of PML. AB - Acute promyelocytic leukemia is characterized by a chromosomal translocation that produces an oncogenic fusion protein of the retinoic acid receptor alpha (RARalpha) and promyelocytic leukemia protein (PML). Arsenic trioxide chemotherapy of this cancer induces the PML moiety to organize nuclear bodies, where the oncoprotein is degraded. This process requires the participation of two SUMO paralogs (SUMO1 and SUMO2) to promote PML ubiquitylation mediated by the ubiquitin E3 ligase RNF4 and reorganization of PML nuclear bodies. We demonstrated that the ubiquitylation of PML required the SUMO deconjugation machinery, primarily the deconjugating enzyme SENP1, and was suppressed by expression of non-deconjugatable SUMO2. We hypothesized that constitutive SUMO2 conjugation and deconjugation occurred basally and that arsenic trioxide treatment caused the exchange of SUMO2 for SUMO1 on a fraction of Lys(65) in PML. On the basis of data obtained with mutational analysis and quantitative proteomics, we propose that the SUMO switch at Lys(65) of PML enhanced nuclear body formation, subsequent SUMO2 conjugation to Lys(160), and consequent RNF4 dependent ubiquitylation of PML. Our work provides insights into how the SUMO system achieves selective SUMO paralog modification and highlights the crucial role of SENPs in defining the specificity of SUMO signaling. PMID- 26060331 TI - Targeted phosphoproteomics of insulin signaling using data-independent acquisition mass spectrometry. AB - A major goal in signaling biology is the establishment of high-throughput quantitative methods for measuring changes in protein phosphorylation of entire signal transduction pathways across many different samples comprising temporal or dose data or patient samples. Data-independent acquisition (DIA) mass spectrometry (MS) methods, which involve tandem MS scans that are collected independently of precursor ion information and then are followed by targeted searching for known peptides, may achieve this goal. We applied DIA-MS to systematically quantify phosphorylation of components in the insulin signaling network in response to insulin as well as in stimulated cells exposed to a panel of kinase inhibitors targeting key downstream effectors in the network. We accurately quantified the effect of insulin on phosphorylation of 86 protein targets in the insulin signaling network using either stable isotope standards (SIS) or label-free quantification (LFQ) and mapped signal transmission through this network. By matching kinases to specific phosphorylation events (based on linear consensus motifs and temporal phosphorylation) to the quantitative phosphoproteomic data from cells exposed to inhibitors, we investigated predicted kinase-substrate relationships of AKT and mTOR in a targeted fashion. Furthermore, we applied this approach to show that AKT2-dependent phosphorylation of GAB2 promoted insulin signaling but inhibited epidermal growth factor (EGF) signaling in a manner dependent on 14-3-3 binding. Because DIA-MS can increase throughput and improve the reproducibility of peptide detection across multiple samples, this approach should facilitate more accurate, comprehensive, and quantitative assessment of signaling networks under various experimental conditions than are possible using other MS proteomic methods. PMID- 26060333 TI - High-Throughput Screening for Biomarker Discovery. PMID- 26060332 TI - Novel Serum Biomarkers to Differentiate Cholangiocarcinoma from Benign Biliary Tract Diseases Using a Proteomic Approach. AB - BACKGROUND AND AIM: Cholangiocarcinoma (CCA) is the most frequent biliary malignancy, which poses high mortality rate due to lack of early detection. Hence, most CCA cases are present at the advanced to late stages with local or distant metastasis at the time of diagnosis. Currently available tumor markers including CA19-9 and CEA are inefficient and of limited usage due to low sensitivity and specificity. Here, we attempt to identify serum tumor markers for CCA that can effectively distinguish CCA from benign biliary tract diseases (BBTDs). METHODS: Serum samples from 19 CCA patients and 17 BBTDs were separated by SDS-PAGE followed with LC-MS/MS and were subjected to statistical analysis and cross-validation to identify proteins whose abundance was significantly elevated or suppressed in CCA samples compared to BBTDs. RESULTS: In addition to identifying several proteins previously known to be differentially expressed in CCA and BBTDs, we also discovered a number of molecules that were previously not associated with CCA. These included FAM19A5, MAGED4B, KIAA0321, RBAK, and UPF3B. CONCLUSIONS: Novel serum biomarkers to distinguish CCA from BBTDs were identified using a proteomic approach. Further validation of these proteins has the potential to provide a biomarker for differentiating CCA from BBTDs. PMID- 26060334 TI - Acute effect of whole body vibration on isometric strength, squat jump, and flexibility in well-trained combat athletes. AB - The purpose of this study was to investigate the effect of whole body vibration (WBV) training on maximal strength, squat jump, and flexibility of well-trained combat athletes. Twelve female and 8 male combat athletes (age: 22.8 +/- 3.1 years, mass: 65.4 +/- 10.7 kg, height: 168.8 +/- 8.8 cm, training experience: 11.6 +/- 4.7 years, training volume: 9.3 +/- 2.8 hours/week) participated in this study. The study consisted of three sessions separated by 48 hours. The first session was conducted for familiarization. In the subsequent two sessions, participants performed WBV or sham intervention in a randomized, balanced order. During WBV intervention, four isometric exercises were performed (26 Hz, 4 mm). During the sham intervention, participants performed the same WBV intervention without vibration treatment (0 Hz, 0 mm). Hand grip, squat jump, trunk flexion, and isometric leg strength tests were performed after each intervention. The results of a two-factor (pre-post[2] * intervention[2]) repeated measures ANOVA revealed a significant interaction (p = 0.018) of pre-post * intervention only for the hand grip test, indicating a significant performance increase of moderate effect (net increase of 2.48%, d = 0.61) after WBV intervention. Squat jump, trunk flexion, and isometric leg strength performances were not affected by WBV. In conclusion, the WBV protocol used in this study potentiated hand grip performance, but did not enhance squat jump, trunk flexion, or isometric leg strength in well-trained combat athletes. PMID- 26060335 TI - Effects of general, specific and combined warm-up on explosive muscular performance. AB - The purpose of this study was to compare the acute effects of general, specific and combined warm-up (WU) on explosive performance. Healthy male (n = 10) subjects participated in six WU protocols in a crossover randomized study design. Protocols were: passive rest (PR; 15 min of passive rest), running (Run; 5 min of running at 70% of maximum heart rate), stretching (STR; 5 min of static stretching exercise), jumping [Jump; 5 min of jumping exercises - 3x8 countermovement jumps (CMJ) and 3x8 drop jumps from 60 cm (DJ60)], and combined (COM; protocols Run+STR+Jump combined). Immediately before and after each WU, subjects were assessed for explosive concentric-only (i.e. squat jump - SJ), slow stretch-shortening cycle (i.e. CMJ), fast stretch-shortening cycle (i.e. DJ60) and contact time (CT) muscle performance. PR significantly reduced SJ performance (p =0.007). Run increased SJ (p =0.0001) and CMJ (p =0.002). STR increased CMJ (p =0.048). Specific WU (i.e. Jump) increased SJ (p =0.001), CMJ (p =0.028) and DJ60 (p =0.006) performance. COM increased CMJ performance (p =0.006). Jump was superior in SJ performance vs. PR (p =0.001). Jump reduced (p =0.03) CT in DJ60. In conclusion, general, specific and combined WU increase slow stretch-shortening cycle (SSC) muscle performance, but only specific WU increases fast SSC muscle performance. Therefore, to increase fast SSC performance, specific fast SSC muscle actions must be included during the WU. PMID- 26060336 TI - Acute effects of prolonged intermittent low-intensity isometric warm-up schemes on jump, sprint, and agility performance in collegiate soccer players. AB - The aim of the present study was to compare the effects of different warm-up interventions on jump, sprint and agility performance in collegiate soccer players. Twenty-one healthy male college soccer players (age: 20.14 +/- 1.65 years; body height: 179.9 +/- 8.34 cm; body mass: 74.4 +/- 13.0 kg; % body fat: 9.45 +/- 4.8) participated in the study. Subjects underwent four different randomized warm-up protocols separated by at least 48 hours. The warm-up schemes were: 1. no conditioning contraction protocol (NCC); 2. dynamic stretching (DS); 3. prolonged intermittent low-intensity isometric exercise (ST); and, 4. ST with an additional external load equal to 30% of body weight (ST + 30% BW). All interventions were preceded by a general warm-up. Results from one-way repeated measures ANOVA demonstrated a significant difference in countermovement jump (CMJ) at F(3,60) = 10.2, etarho(2) = 0.337, p < 0.01. Post hoc analysis revealed a significant difference in CMJ performance in DS when compared to NCC and ST + 30% BW. No significant difference in CMJ was observed between DS and ST. CMJ scores in NCC, ST, and ST + 30% BW were non-significant. There was a significant difference in speed; F(3, 60) = 6.61, etarho(2) = 0.248, p < 0.01. Post hoc analysis revealed significantly better time in DS than NCC and ST. However, no difference in speed was observed between DS and ST + 30% BW. Similarly, speed was similar in NCC, ST and ST + 30% BW. A significant difference in agility performance was also observed; F(3, 60) = 24.1, etarho(2)= 0.546, p < 0.01. Post hoc analysis revealed significantly greater performance gains in DS than NCC. No significant difference in agility was observed in DS, ST and ST + 30% BW. In conclusion, a prolonged intermittent low-intensity isometric protocol using bodyweight only showed similar benefits with dynamic stretching in countermovement jump performance. When the same isometric condition with additional load equal to 30% of bodyweight was applied, effects in speed and agility were similar to dynamic stretching. PMID- 26060337 TI - Anthropometric and physiological characteristics of Melanesian futsal players: a first approach to talent identification in Oceania. AB - This study assessed the anthropometric and physiological characteristics of elite Melanesian futsal players in order to determine the best performance predictors. Physiological parameters of performance were measured in 14 Melanesian (MEL-G, 24.4+/-4.4 yrs) and 8 Caucasian (NMEL-G, 22.9+/-4.9) elite futsal players, using tests of jump-and-reach (CMJ), agility (T-Test), repeated sprint ability (RSA), RSA with change-of-direction (RSA-COD), sprints with 5 m, 10 m, 15 m, and 30 m lap times, and aerobic fitness with the 30-15 intermittent fitness test (30-15 IFT). The anthropometric data revealed significantly lower height for MEL-G compared with NMEL-G: 1.73+/-0.05 and 1.80+/-0.08 m, respectively; P = 0.05. The CMJ was significantly higher for MEL-G than NMEL-G: 50.4+/-5.9 and 45.2+/-4.3 cm, respectively; P = 0.05. T-Test times were significantly lower for MEL-G than NMEL G: 10.47+/-0.58 and 11.01+/-0.64 seconds, respectively; P = 0.05. MEL-G height was significantly related to CMJ (r = 0.706, P = 0.01), CMJpeakP (r = 0.709, P = 0.01) and T-Test (r = 0.589, P = 0.02). No significant between-group differences were observed for sprint tests or 30-15 IFT, including heart rate and estimated VO2max. Between groups, the percentage decrement (%Dec) in RSA-COD was significantly lower in MEL-G than NMEL-G (P = 0.05), although no significant difference was noted between RSA and RSA-COD. Within groups, no significant difference was observed between %Dec in RSA or RSA-COD; P = 0.697. This study presents specific anthropometric (significantly lower height) and physiological (significantly greater agility) reference values in Melanesians, which, taken together, might help coaches and physical fitness trainers to optimize elite futsal training and talent identification in Oceania. PMID- 26060338 TI - Overrepresentation of the COL3A1 AA genotype in Polish skiers with anterior cruciate ligament injury. AB - Although various intrinsic and extrinsic risk factors for anterior cruciate ligament (ACL) rupture have been identified, the exact aetiology of the injury is not yet fully understood. Type III collagen is an important factor in the repair of connective tissue, and certain gene polymorphisms may impair the tensile strength. The aim of this study was to examine the association of the COL3A1 rs1800255 polymorphism with ACL rupture in Polish male recreational skiers. A total of 321 male Polish recreational skiers were recruited for this study; 138 had surgically diagnosed primary ACL ruptures (ACL-injured group) and 183 were apparently healthy male skiers (control group - CON) who had no self-reported history of ligament or tendon injury. Both groups had a comparable level of exposure to ACL injury. Genomic DNA was extracted from the oral epithelial cells. All samples were genotyped on a real-time polymerase chain reaction instrument. The genotype distribution in the ACL-injured group was significantly different than in CON (respectively: AA=10.1 vs 2.2%, AG=22.5 vs 36.1, GG=67.4 vs 61.8%; p=0.0087). The AA vs AG+GG genotype of COL3A1 (odds ratio (OR)=5.05; 95% confidence interval (CI), 1.62-15.71, p=0.003) was significantly overrepresented in the ACL-injured group compared with CON. The frequency of the A allele was higher in the ACL-injured group (21.4%) compared with CON (20.2%), but the difference was not statistically significant (p=0.72). This study revealed an association between the COL3A1 rs1800255 polymorphism and ACL ruptures in Polish skiers. PMID- 26060339 TI - Effect of training in minimalist footwear on oxygen consumption during walking and running. AB - The present study sought to examine the effect of 5 weeks of training with minimalist footwear on oxygen consumption during walking and running. Thirteen college-aged students (male n = 7, female n = 6, age: 21.7+/-1.4 years, height: 168.9+/-8.8 cm, weight: 70.4+/-15.8 kg, VO2max: 46.6+/-6.6 ml.kg(-1).min(-1)) participated in the present investigation. The participants did not have experience with minimalist footwear. Participants underwent metabolic testing during walking (5.6 km.hr(-1)), light running (7.2 km.hr(-1)), and moderate running (9.6 km.hr(-1)). The participants completed this assessment barefoot, in running shoes, and in minimalist footwear in a randomized order. The participants underwent 5 weeks of training with the minimalist footwear. Afterwards, participants repeated the metabolic testing. Data was analyzed via repeated measures ANOVA. The analysis revealed a significant (F4,32= 7.576, [Formula: see text]=0.408, p <= 0.001) interaction effect (time * treatment * speed). During the initial assessment, the minimalist footwear condition resulted in greater oxygen consumption at 9.6 km.hr(-1) (p <= 0.05) compared to the barefoot condition, while the running shoe condition resulted in greater oxygen consumption than both the barefoot and minimalist condition at 7.2 and 9.6 km.hr( 1). At post-testing the minimalist footwear was not different at any speed compared to the barefoot condition (p> 0.12). This study suggests that initially minimalist footwear results in greater oxygen consumption than running barefoot, however; with utilization the oxygen consumption becomes similar. PMID- 26060340 TI - Better economy in field running than on the treadmill: evidence from high-level distance runners. AB - Given the ongoing interest in ways to improve the specificity of testing elite athletes in their natural environment, portable metabolic systems provide an opportunity to assess metabolic demand of exercise in sport-specific settings. Running economy (RE) and maximal oxygen uptake ([Formula: see text]O2max) were compared between track and treadmill (1% inclination) conditions in competitive level European distance runners who were fully habituated to treadmill running (n = 13). All runners performed an exercise test on running track and on treadmill. While [Formula: see text]O2max was similar on the track and on the treadmill (68.5 +/- 5.3 vs. 71.4 +/- 6.4 ml.kg(-1).min(-1), p = 0.105, respectively), superior RE was found on the track compared to the treadmill (215.4 +/- 12.4 vs. 236.8 +/- 18.0 O2 ml.kg(-1).km(-1), p < 0.001). RE on the track was strongly correlated with RE on the treadmill (r = 0.719, p = 0.006). The present findings indicate that high-level distance runners have significantly better RE but not [Formula: see text]O2max on the track compared to treadmill. This difference may be due to biomechanical adjustments. As RE is strongly correlated between the two conditions, it would be reasonable to assume that interventions affecting RE on the treadmill will also affect RE on the track. PMID- 26060341 TI - Effects of supplementation with acai (Euterpe oleracea Mart.) berry-based juice blend on the blood antioxidant defence capacity and lipid profile in junior hurdlers. A pilot study. AB - The purpose of this pilot study was to examine whether regular consumption of an acai berry-based juice blend would affect sprint performance and improve blood antioxidant status and lipid profile in junior athletes. Seven junior hurdlers (17.5+/-1.2 years) taking part in a pre-season conditioning camp were supplemented once a day, for six weeks, with 100 ml of the juice blend. At the start and the end of the camp the athletes performed a 300-m sprint running test on an outdoor track. Blood samples were taken before and immediately after the test and after 1 h of recovery. Blood antioxidant status was evaluated based on activities of antioxidant enzymes (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GSH-Px], glutathione reductase [GR]), concentrations of non-enzymatic antioxidants (reduced glutathione [GSH], uric acid), total plasma polyphenols, ferric reducing ability of plasma (FRAP), thiobarbituric acid reactive substances (TBARS) and activities of creatine kinase (CK) and lactate dehydrogenase (LDH) as muscle damage markers. In order to evaluate potential health benefits of the acai berry, the post-treatment changes in lipid profile parameters (triglycerides, cholesterol and its fractions) were analysed. Six weeks' consumption of acai berry-based juice blend had no effect on sprint performance, but it led to a marked increase in the total antioxidant capacity of plasma, attenuation of the exercise-induced muscle damage, and a substantial improvement of serum lipid profile. These findings strongly support the view of the health benefits of supplementation with the acai berry-based juice blend, mainly attributed to its high total polyphenol content and the related high in vivo antioxidant and hypocholesterolaemic activities of this supplement. PMID- 26060342 TI - Ecdysteroids: A novel class of anabolic agents? AB - Increasing numbers of dietary supplements with ecdysteroids are marketed as "natural anabolic agents". Results of recent studies suggested that their anabolic effect is mediated by estrogen receptor (ER) binding. Within this study the anabolic potency of ecdysterone was compared to well characterized anabolic substances. Effects on the fiber sizes of the soleus muscle in rats as well the diameter of C2C12 derived myotubes were used as biological readouts. Ecdysterone exhibited a strong hypertrophic effect on the fiber size of rat soleus muscle that was found even stronger compared to the test compounds metandienone (dianabol), estradienedione (trenbolox), and SARM S 1, all administered in the same dose (5 mg/kg body weight, for 21 days). In C2C12 myotubes ecdysterone (1 uM) induced a significant increase of the diameter comparable to dihydrotestosterone (1 uM) and IGF 1 (1.3 nM). Molecular docking experiments supported the ERbeta mediated action of ecdysterone. To clarify its status in sports, ecdysterone should be considered to be included in the class "S1.2 Other Anabolic Agents" of the list of prohibited substances of the World Anti-Doping Agency. PMID- 26060343 TI - Efficiency of quantification of cardiac electrical heterogeneity: via QT dispersion, transmural dispersion, or both. PMID- 26060344 TI - Chemical conversion of human fibroblasts into neuronal cells: dawn of future clinical trials. PMID- 26060345 TI - Highly efficient direct conversion of human fibroblasts to neuronal cells by chemical compounds. AB - Direct conversion of mammalian fibroblasts into induced neuronal (iN) cells has been attained by forced expression of pro-neural transcriptional factors, or by combining defined factors with either microRNAs or small molecules. Here, we show that neuronal cells can be converted from postnatal human fibroblasts into cell populations with neuronal purities of up to >80% using a combination of six chemical compounds. The chemical compound-induced neuronal cells (CiNCs) express neuron-specific proteins and functional neuron markers. The efficiency of CiNCs is unaffected by either the donor's age or cellular senescence (passage number). We propose this chemical direct converting strategy as a potential approach for highly efficient generation of neuronal cells from human fibroblasts for such uses as in neural disease modeling and regenerative medicine. PMID- 26060346 TI - Anti-inflammatory effects of astaxanthin in the human gingival keratinocyte line NDUSD-1. AB - Oral lichen planus is a chronic inflammatory disease that affects the mucous membrane of the oral cavity and can contribute to the development of other diseases. Inflammation in oral lichen planus is a T-cell-mediated autoimmune disease that acts through cytotoxic CD8(+) T cells to trigger apoptosis of keratinocytes. However, the specific cause of oral lichen planus remains unknown and no effective medical treatment has yet been established. Astaxanthin is a carotenoid pigment with capacity for anti-inflammatory and anti-oxidant activities. In this study, we evaluated whether astaxanthin could be used to improve the pathology of oral lichen planus by reducing inflammation. In particular, the anti-inflammatory effects of astaxanthin on the chronic inflammation caused by lipopolysaccharide derived from Escherichia coli O55 in human gingival keratinocytes (NDUSD-1) were evaluated. Following astaxanthin treatment, localization of nuclear factor kappaB/p65 and the level of inflammatory cytokines (interleukin-6, tumor necrosis factor-alpha) tended to decrease, and cell proliferation significantly increased in vitro. These results suggest that astaxanthin could be useful for improving chronic inflammation such as that associated with oral lichen planus. PMID- 26060347 TI - Therapeutic administration of an ingredient of aged-garlic extracts, S-allyl cysteine resolves liver fibrosis established by carbon tetrachloride in rats. AB - S-allyl cysteine (SAC) is the most abundant compound in aged garlic extracts (AGEs). AGE has been reported to ameliorate the oxidative damage implicated in a variety of diseases. However, the effects of SAC have not been established in liver cirrhosis. The aim of this study was to examine the effect of therapeutic administration of SAC in liver cirrhosis by chronic carbon tetrachloride (CCl4) administration in rats. SAC or other cysteine compounds were administered from 4 weeks when liver fibrosis was confirmed to be in process. CCl4 administration elevated plasma alanine aminotransferase, plasma lipid peroxidation, liver hydroxyproline, and liver transforming growth factor (TGF)-beta at 12 weeks. SAC prevented these changes induced by CCl4. Furthermore, SAC improved survival in a dose-dependent manner following consecutive CCl4 administration. The inhibitory mechanisms may be associated with a decrease in the profibrogenic cytokine, TGF beta as well as the antioxidative properties of SAC. PMID- 26060348 TI - Pruni cortex ameliorates skin inflammation possibly through HMGB1-NFkappaB pathway in house dust mite induced atopic dermatitis NC/Nga transgenic mice. AB - Pruni cortex, the bark of Prunus jamasakura Siebold ex Koidzumi, has been used in the Japanese systems of medicine for many years for its anti-inflammatory, antioxidant and antitussive properties. In this study, we investigated the effect of pruni cortex on atopic dermatitis NC/Nga mouse model. Atopic dermatitis-like lesion was induced by the application of house dust mite extract to the dorsal skin. After induction of atopic dermatitis, pruni cortex aqueous extract (1 g/kg, p.o.) was administered daily for 2 weeks. We evaluated dermatitis severity, histopathological changes and cellular protein expression by Western blotting for nuclear and cytoplasmic high mobility group box 1, receptor for advanced glycation end products, nuclear factor kappaB, apoptosis and inflammatory markers in the skin of atopic dermatitis mice. The clinical observation confirmed that the dermatitis score was significantly lower when treated with pruni cortex than in the atopic dermatitis group. Similarly pruni cortex inhibited hypertrophy and infiltration of inflammatory cells as identified by histopathology. In addition, pruni cortex significantly inhibited the protein expression of cytoplasmic high mobility group box 1, receptor for advanced glycation end products, nuclear p nuclear factor kappa B, apoptosis and inflammatory markers. These results indicate that pruni cortex may have therapeutic potential in the treatment of atopic dermatitis by attenuating high mobility group box 1 and inflammation possibly through the nuclear factor kappaB pathway. PMID- 26060349 TI - Altered retinol status and expression of retinol-related proteins in streptozotocin-induced type 1 diabetic model rats. AB - Diabetes is a metabolic disorder characterized by chronic hyperglycemia. Advanced diabetes is associated with severe complications and impaired nutritional status. Here, we assessed the expression of retinol-associated proteins, including beta carotene 15,15'-monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), and cytochrome P450 26A1 (CYP26A1), and measured retinol levels in the plasma and liver of streptozotocin (STZ)-induced type 1 diabetic model rats. Compared to the levels in the control rats, retinol levels in the plasma and liver of STZ rats were decreased and increased, respectively. Hepatic expression of the LRAT gene in STZ rats was lower than that in the controls. In the liver of STZ rats, the expression of ALDH1A1, a retinal metabolizing enzyme was higher, whereas ALDH1A2 expression was lower than in the controls. Hepatic CYP26A1 expression in STZ rats was significantly higher than in the control rats. BCMO expression levels in the liver and intestine of STZ rats were much lower than those of the controls. Altered BCMO expression might affect retinol status. It is considered that the metabolic availability of retinol was lessened despite the accelerated catabolism of retinol; therefore, retinol mobilization may be unbalanced in the liver of rats in the type 1 diabetic state. PMID- 26060350 TI - l-Arginine administration attenuates airway inflammation by altering l-arginine metabolism in an NC/Nga mouse model of asthma. AB - Changes in l-arginine metabolism, including increased arginase levels and decreased nitric oxide production, are involved in the pathophysiology of asthma. In this study, using an intranasal mite-induced NC/Nga mouse model of asthma, we examined whether administration of l-arginine ameliorated airway hyperresponsiveness and inflammation by altering l-arginine metabolism. Experimental asthma was induced in NC/Nga mice via intranasal administration of mite crude extract (50 ug/day) on 5 consecutive days (days 0-4, sensitization) and on day 11 (challenge). Oral administration of l-arginine (250 mg/kg) was performed twice daily on days 5-10 for prevention or on days 11-13 for therapy. On day 14, we evaluated the inflammatory airway response (airway hyperresponsiveness, the number of cells in the bronchoalveolar lavage fluid, and the changes in pathological inflammation of the lung), arginase expression and activity, l-arginine bioavailability, and the concentration of NOx, the end products of nitric oxide. Treatment with l-arginine ameliorated the mite-induced inflammatory airway response. Furthermore, l-arginine administration attenuated the increases in arginase expression and activity and elevated the NOx levels by enhancing l-arginine bioavailability. These findings indicate that l-arginine administration may contribute to the improvement of asthmatic symptoms by altering l-arginine metabolism. PMID- 26060351 TI - Comparison of energy metabolism and nutritional status of hospitalized patients with Crohn's disease and those with ulcerative colitis. AB - This study aimed to compare the nutritional status and energy expenditure of hospitalized patients with Crohn's disease (CD) and those with ulcerative colitis (UC). Twenty-two hospitalized patients with CD and 18 patients with UC were enrolled in this study. We analyzed nutritional status upon admission by using nutritional screening tools including subjective global assessment, malnutrition universal screening tool, and laboratory tests. We measured resting energy expenditure (mREE) of the patients with indirect calorimetry and predicted resting energy expenditure (pREE) was calculated by using the Harris-Benedict equation. Results presented here indicate no significant difference in nutritional parameters and energy metabolism between CD and UC patients. In UC patients, a significant correlation was observed between mREE/body weight and disease activity detected by the Lichtiger and Seo indices. However, there was no correlation between mREE/body weight and Crohn's disease activity index in CD patients. Inflammatory cytokine interleukin-6 levels correlated with mREE/pREE in CD and UC patients while tumor necrosis factor-alpha was not. In conclusion, energy expenditure significantly correlated with disease activity in UC patients but not in CD patients. These results indicate that establishing daily energy requirements based on disease activity of UC is imperative for improving the nutritional status of patients. PMID- 26060352 TI - Changes in energy metabolism after induction therapy in patients with severe or moderate ulcerative colitis. AB - We investigated the changes in energy expenditure during induction therapy in patients with severe or moderate ulcerative colitis. Thirteen patients (10 men, 3 women; mean age, 36.5 years) with ulcerative colitis admitted to the Shiga University Hospital were enrolled in this study. We measured the resting energy expenditure and respiratory quotients of these patients before and after induction therapy with indirect calorimetry. We analyzed the changes of nutritional status and serum inflammatory cytokine levels and also evaluated the relationship between energy metabolism and disease activity by using the Seo index and Lichtiger index. The resting energy expenditure was 26.3 +/- 3.8 kcal/kg/day in the active stage and significantly decreased to 23.5 +/- 2.4 kcal/kg/day after induction therapy (p<0.01). The resting energy expenditure changed in parallel with the disease activity index and C-reactive protein and inflammatory cytokine levels. The respiratory quotient significantly increased after induction therapy. Thus, moderate to severe ulcerative colitis patients had a hyper-metabolic status, and the energy metabolism of these patients significantly changed after induction therapy. Therefore, we recommend that nutritional management with 30-34 kcal/kg/day (calculated as measured resting energy expenditure * activity factor, 1.3) may be optimal for hospitalized ulcerative colitis patients. PMID- 26060353 TI - Biological impacts of resveratrol, quercetin, and N-acetylcysteine on oxidative stress in human gingival fibroblasts. AB - In periodontitis, production of reactive oxygen species (ROS) by neutrophils induces oxidative stress and deteriorates surrounding tissues. Antioxidants reduce damage caused by ROS and are used to treat diseases involving oxidative stress. This study summarizes the different effects of resveratrol, quercetin, and N-acetylcysteine (NAC) on human gingival fibroblasts (HGFs) under oxidative stress induced by hydrogen peroxide. Real-time cytotoxicity analyses reveals that resveratrol and quercetin enhanced cell proliferation even under oxidative stress. Of the antioxidants tested, resveratrol is the most effective at inhibiting ROS production. HGFs incubated with resveratrol and quercetin up regulate the transcription of type I collagen gene after 3 h, but only resveratrol sustained this up-regulation for 24 h. A measurement of the oxygen consumption rate (OCR, mitochondrial respiration) shows that resveratrol generates the highest maximal respiratory capacity, followed by quercetin and NAC. Simultaneous measurement of OCR and the extracellular acidification rate (non-mitochondrial respiration) reveals that resveratrol and quercetin induce an increase in mitochondrial respiration when compared with untreated cells. NAC treatment consumes less oxygen and enhances more non-mitochondrial respiration. In conclusion, resveratrol is the most effective antioxidant in terms of real time cytotoxicity analysis, reduction of ROS production, and enhancement of type I collagen synthesis and mitochondrial respiration in HGFs. PMID- 26060354 TI - Long-term efficacy and safety of rabeprazole in patients taking low-dose aspirin with a history of peptic ulcers: a phase 2/3, randomized, parallel-group, multicenter, extension clinical trial. AB - A 24-week, double-blind, clinical trial of rabeprazole for the prevention of recurrent peptic ulcers caused by low-dose aspirin (LDA) has been reported, but trials for longer than 24 weeks have not been reported. The aim of this study is to assess the long-term efficacy and safety of rabeprazole for preventing peptic ulcer recurrence on LDA therapy. Eligible patients had a history of peptic ulcers on long-term LDA (81 or 100 mg/day) therapy. Patients with no recurrence of peptic ulcers at the end of the 24-week double-blind phase with rabeprazole (10- or 5-mg once daily) or teprenone (50 mg three times daily) entered the extension phase. Rabeprazole doses were maintained for a maximum of 76 weeks, including the double-blind 24-week period and the extension phase period (long-term rabeprazole 10- and 5-mg groups). Teprenone was randomly switched to rabeprazole 10 or 5 mg for a maximum of 52 weeks in the extension phase (newly-initiated rabeprazole 10- and 5-mg groups). The full analysis set consisted of 151 and 150 subjects in the long-term rabeprazole 10- and 5-mg groups, respectively, and the cumulative recurrence rates of peptic ulcers were 2.2 and 3.7%, respectively. Recurrent peptic ulcers were not observed in the newly-initiated rabeprazole 10- and 5-mg groups. No bleeding ulcers were reported. No clinically significant safety findings, including cardiovascular events, emerged. The use of long-term rabeprazole 10- and 5-mg once daily prevents the recurrence of peptic ulcers in subjects on low-dose aspirin therapy, and both were well-tolerated. PMID- 26060355 TI - Lactobacillus rhamnosus GG improves glucose tolerance through alleviating ER stress and suppressing macrophage activation in db/db mice. AB - Although recent studies have reported that Lactobacillus rhamnosus GG (LGG), the most extensively studied probiotic strain, exerts an anti-hyperglycemic effect on several rodent models, the underlying mechanism remains unclear. In this study, twenty male C57BL/KsJ-db/db (db/db) mice were divided into 2 groups, LGG-treated and control group, which received a daily dose of LGG (1 * 10(8) CFU per mouse) and PBS orally for 4 weeks, respectively. We observed that glucose tolerance was significantly improved in LGG-treated db/db mice. Insulin-stimulated Akt phosphorylation and GLUT4 translocation were higher in skeletal muscle of LGG treated mice relative to their controls. It was also observed that LGG treatment caused significant reductions in endoplasmic reticulum (ER) stress in skeletal muscle and M1-like macrophage activation in white adipose tissues. Our results indicate that the anti-diabetic effect of LGG in db/db mice is associated with alleviated ER stress and suppressed macrophage activation, resulting in enhanced insulin sensitivity. These findings suggest a therapeutic potential of probiotics for prevention and treatment of type 2 diabetes. PMID- 26060356 TI - Cognitive Impairment and Brain Imaging Characteristics of Patients with Congenital Cataracts, Facial Dysmorphism, Neuropathy Syndrome. AB - Congenital cataracts, facial dysmorphism, neuropathy (CCFDN) syndrome is a complex autosomal recessive multisystem disorder. The aim of the current study is to evaluate the degree of cognitive impairment in a cohort of 22 CCFDN patients and its correlation with patients' age, motor disability, ataxia, and neuroimaging changes. Twenty-two patients with genetically confirmed diagnosis of CCFDN underwent a detailed neurological examination. Verbal and nonverbal intelligence, memory, executive functions, and verbal fluency were assessed in all the patients aged 4 to 47 years. Brain magnetic resonance imaging was performed in 20 affected patients. Eighteen affected were classified as having mild intellectual deficit, whereas 4 had borderline intelligence. In all psychometric tests, evaluating different cognitive domains, CCFDN patients had statistically significant lower scores when compared to the healthy control group. All cognitive domains seemed equally affected. The main abnormalities on brain MRI found in 19/20 patients included diffuse cerebral atrophy, enlargement of the lateral ventricles, and focal lesions in the subcortical white matter, different in number and size, consistent with demyelination more pronounced in the older CCFDN patients. The correlation analysis of the structural brain changes and the cognitive impairment found a statistically significant correlation only between the impairment of short-term verbal memory and the MRI changes. PMID- 26060358 TI - Vitamin D Potentiates the Inhibitory Effect of MicroRNA-130a in Hepatitis C Virus Replication Independent of Type I Interferon Signaling Pathway. AB - Calcitriol, the bioactive metabolite of vitamin D, was reported to inhibit HCV production in a synergistic fashion with interferon, a treatment in vitro. Our previous study established that miR-130a inhibits HCV replication by restoring the host innate immune response. We aimed to determine whether there is additive inhibitory effect of calcitriol and miR-130a on HCV replication. Here we showed that calcitriol potentiates the anti-HCV effect of miR-130a in both Con1b replicon and J6/JFH1 culture systems. Intriguingly, this potentiating effect of calcitriol on miR-130a was not through upregulating the expression of cellular miR-130a or through increasing the miR-130a-mediated IFNalpha/beta production. All these findings may contribute to the development of novel anti-HCV therapeutic strategies although the antiviral mechanism needs to be further investigated. PMID- 26060357 TI - T Regulatory and T Helper 17 Cells in Primary Sjogren's Syndrome: Facts and Perspectives. AB - Historically, primary Sjogren's syndrome (pSS) was thought to be a T helper (h) 1 driven disease due to the predominance of CD4(+)T lymphocytes and their products in target organs and peripheral blood of patients. In the last decades, the identification of a number of T cell subsets, including Th17, T regulatory (Treg), and follicular helper T cells, challenged this long-standing paradigm and prompted to identify their role in pSS pathogenesis. In addition the impact of abnormal proinflammatory cytokine production, such as IL-6, IL-17, IL-22, and IL 23, has also attracted considerable attention. However, although several studies have been carried out in experimental models and patients with pSS, many aspects concerning the role of Treg cells and IL-17/Th17 cell system in pSS pathogenesis are not fully elucidated. In particular, the role played by different IL-17 producing T cell subsets as well as the effects of pharmacological therapies on Treg/Th17 cell balance represents an intriguing issue. The aim of this review article is to provide an overview of current knowledge on Treg cells and IL-17 producing T cells in pSS pathogenesis. We believe that these insights into pSS pathogenesis may provide the basis for successful therapeutic intervention in this disease. PMID- 26060359 TI - Percutaneous native kidney biopsy in patients receiving antiplatelet agents- is it necessary to stop them routinely? AB - Percutaneous renal biopsy plays an important role in the investigational approach of the nephrologist. Though the technique and the safety of the procedure has improved over the last two decades it remains an invasive procedure and can be associated with bleeding complications. To minimize the risk of bleeding, it has been the practice of many centers and nephrologists to advise patients receiving antiplatelet agents to discontinue them 5-7 days before planned procedure. This advice is based on opinion and pre-established procedure or norms rather than sound evidence based guidelines. This article aims to be a critical appraisal of this unnecessary and sometimes not so safe practice of routine stoppage of antiplatelet agents prior to kidney biopsy. PMID- 26060360 TI - Prevalence of chronic kidney disease in India - Where are we heading? PMID- 26060361 TI - Oral prostacycline analog and clopidogrel combination provides early maturation and long-term survival after arteriovenous fistula creation: A randomized controlled study. AB - Vascular access is used as a lifeline for hemodialysis in patients with end stage renal disease failure (ESRD). Failure of arteriovenous fistula (AVF) maturation is still high. The purpose of this study was to research the effects of clopidogrel in combination with oral iloprost, a synthetic analog of prostacyclin PGI2. Ninety-six diabetic ESRD patients were divided into two groups. In the first group (Group 1, N = 50), clopidogrel (75 mg daily dose) and an oral prostacycline analog (200 mg daily dose) were administered. In the second group (Group 2, N = 46), placebo was given. All patients took study medication 7-10 days prior to surgery. A Doppler ultrasound (USG) was performed for measurement of arterial and venous diameters, and peak systolic velocity of arterial flow based on subsequent fistula adequacy. Autogenous AVFs were constructed in forearm as distally as possible in all patients. Both groups were followed-up for a year. In the placebo group, early AVF thrombosis was detected in two patients (4.3%). AVF maturation failure was noted in 14 patients (30.4%) in placebo group and in four patients (8%) in clopidogrel plus oral prostacycline analog group in the early postoperative period (P = 0.001). The mean maturation time was 38 +/- 6.5 and 53 +/- 12.8 days in study and placebo groups, respectively (P = 0.023). The mean blood flow was 352 +/- 94 mL/min in placebo group and 604 +/- 125 mL/min in study group (P = 0.001). The arterial end diastolic velocity was 116 +/- 14 cm/s in study group and 72 +/- 21 cm/s in placebo group (P = 0.036) 1 year after the surgery. Our data indicated that clopidogrel and oral prostacycline analog combination is effective and safe for the prevention of primary AVF failure in hemodialysis patients and decreased acute and chronic thrombotic events. PMID- 26060362 TI - Cystatin C: An alternative dialysis adequacy marker in high flux hemodialysis. AB - The conventional, low flux (LF) dialyzer allows the removal of small molecular solutes like urea and creatinine. High flux (HF) dialyzers allow the effective removal of middle molecules (MM) as well, and are associated with reduced hemodialysis-related morbidity and mortality. Cystatin C has attractive characteristics as a representative MM. The aim of this study was to determine cystatin C reduction ratio (CysCRR) in both LF and HF groups and to compare it with other markers of dialysis adequacy. Thirty-seven patients were subjected to both LF and HF hemodialysis 2 weeks apart. Serum urea, creatinine and cystatin C were measured pre- and post-dialysis. Cystatin C was measured by latex-enhanced immunoturbidimetry. Urea and creatinine reduction ratios were 72.3 +/- 14.7% and 62.5 +/- 13%, respectively in the LF group. The CysCRR was -9.7 +/- 6.7% and 29.2 +/- 11% in LF and HF hemodialysis, respectively. The statistically significant decrease in CysCRR in the HF group shows the effective clearance of MM by HF dialyzers. Hence, CysCRR could be applied to measure the MM clearance in HF hemodialysis. This study highlights the significance of cystatin C as an important dialysis adequacy marker replacing the conventional markers such as urea and creatinine in HF hemodialysis. Among the middle molecules cystatin C scores over beta-2 microglobulin. PMID- 26060363 TI - Dehydration and malaria augment the risk of developing chronic kidney disease in Sri Lanka. AB - Chronic kidney disease (CKD) of unknown etiology (CKDu) is a serious health issue in Sri Lanka. One-to-one age and sex-matched two sample comparative study was carried out in the Medawachchiya divisional secretariat area of the North Central Province (NCP) of Sri Lanka, by randomly selecting 100 CKDu patients and 100 age and sex-matched subjects from non-CKDu affected families from the same area. An interviewer-administered questionnaire was used for the collection of data pertaining to occupation, medical history and lifestyle. Data were analyzed using a conditional linear logistic model. Working for >6 h in the field per day, exposure to sun, drinking water only from well, consumption of <3 L of water per day, and having a history of malaria were found to be having significant (P < 0.05) likelihood toward the development of CKDu. Treatment of water prior to consumption had a significant protective effect against CKDu. Dehydration, history of malaria and drinking untreated well water from are likely contribute to the development of CKD of unknown etiology among the inhabitants of NCP, Sri Lanka. PMID- 26060364 TI - Liver biopsy in patients on hemodialysis with hepatitis C virus infection: An important tool. AB - Hepatitis C virus (HCV) infection is commonest blood borne infection amongst hemodialysis patients. Still, there is paucity of data on liver biopsy in these patients. Our center is doing regular liver biopsy in these patients and thus thought of sharing our experience. In this retrospective study, all patients with HCV infection on hemodialysis were subjected to liver biopsy. Serum bilirubin, liver enzyme, HCV-PCR, genotype and viral load measurement were done in all. Biopsy specimen was stained with H and E, Periodic Acid Schiff, Gomori Stain, Masson Trichrome and Perls Stain. International Working Group scoring system of Ishak et al. was used for Grading and Staging. Of the 270 liver biopsies, mean age of patients was 34.05 +/- 10.28 years and 233 (85.3%) were males. Mean duration of hemodialysis was 10.9 +/- 7.4 months while of known HCV infection was 5.2 +/- 4.0 months. Genotype 3 was commonest followed by 1. All had normal bilirubin and 64 (23.1%) had normal ALT. In 37 (13.3%) patients anti-HCV was not detectable. Mean histology grade was 4.03 +/- 1.65 (1-10) and stage was 0.75 +/- 0.98 (0-3). Only one patient had cirrhosis on histology. Associated hemosiderosis was seen 10 patients. Only minor complications were observed with no mortality. In conclusion, our study shows that in one-fourth patients with active liver disease, liver enzymes are persistently normal in patients on hemodialysis. Further, carefully performed liver biopsy is reasonably safe procedure though some patients do have non-fatal complications. Liver biopsy helps in assessing disease activity, which otherwise cannot be assessed. Histological grade and stage in these patients is usually mild and cirrhosis is rare. Till such time other non-invasive test is validated, liver biopsy will remain an important test in these patients. PMID- 26060365 TI - Awareness level of kidney functions and diseases among adults in a Nigerian population. AB - The prevalence of kidney diseases is on the increase in Nigeria. The cost of its management is far beyond the reach of an average patient. Prevention is thus of paramount importance and awareness of kidney diseases will help in its prevention. The aim of this study is to assess the level of awareness of kidney functions and diseases among adults in a Nigerian population. A semi-structured, researcher - administered questionnaire was the tool for data collection. Four hundred and thirty-five questionnaires were analyzed. There were 160 males (36.8%) and 275 females (63.2%). The mean age was 42.8 +/- 14 years with a range of 18-78 years. Among these, 82.1% were aware of the kidneys' involvement in waste removal from the body through urine while 36% and 29% were aware of kidneys' role in blood pressure regulation and blood production, respectively. Only 26.6% correctly identified at least two basic functions of the kidneys. Also, 32.6% of the respondents were aware of at least three common causes of kidney diseases in our environment. Majority of the respondents (70.7%) did not know that kidney diseases could be inherited. Furthermore, belief in alternative therapy for kidney disease was documented in 83.2%, while unawareness of dialysis as a treatment modality was recorded in 68% of the respondents. The awareness of kidney functions and diseases among the population is poor. Measures are needed to improve this to stem the rising prevalence of chronic kidney disease in Nigeria. PMID- 26060366 TI - Membranous nephropathy as a rare renal manifestation of IgG4-related disease. AB - IgG4-related disease, a newly described immune-mediated disorder with tissue infiltration of IgG4-positive plasma cells, has been reported in nearly every organ. In the kidney, it manifests as IgG4-related tubulointerstitial nephritis (TIN) but may also present as membranous nephropathy. We report a patient with IgG4 renal disease who had membranous nephropathy as well as TIN. PMID- 26060367 TI - Immunoglobulin A dominant membranoproliferative glomerulonephritis in an elderly man: A case report and review of the literature. AB - Immunoglobulin A (IgA) dominant membranoproliferative glomerulonephritis (MPGN) is rare, described only as case reports. We report a rare case of an elderly man presenting with rapidly progressive renal failure and nephrotic range proteinuria with histological, immunofluorescence, and ultrastructural findings supporting a diagnosis of IgA dominant MPGN. Autoimmune disease, cryoglobulinemia and infection-associated glomerulonephritis were excluded. Remission was achieved within 3 months of treatment. This case highlights an uncommon diagnosis with a good response to therapy. The differential diagnosis of IgA nephropathy with MPGN like pattern is discussed. PMID- 26060368 TI - Primary hyperparathyroidism in a child. AB - Primary hyperparathyroidism is rare in children. We report a 12-year-old girl who presented with recurrent renal calculi, muscular weakness and inability to walk; was diagnosed to have parathyroid adenoma and underwent parathyroidectomy. PMID- 26060369 TI - Gloriosa superba ingestion: Hair loss and acute renal failure. AB - Gloriosa superba is a plant that grows wild in several parts of South India. Tubers of this plant contain several alkaloids. Acute intoxication following the ingestion of G. superba results in gastrointestinal and haematological abnormalities, hepatic and renal insufficiency, cardiotoxicity and hair loss. We present a case with typical features of G superba toxicity. PMID- 26060370 TI - Successful catheter reinsertion in a case of Paecilomyces varioti peritonitis in a patient on continuous ambulatory peritoneal dialysis. AB - Peritonitis is one of the most common and important complications in patients on continuous ambulatory peritoneal dialysis (CAPD). Fungal peritonitis isreported in 4-8% of peritonitis episodes. Fungal peritonitis due to Paecilomyces species is not common. We report a case of CAPD peritonitis due to P. varioti. We immediately removed the CAPD catheter and IV amphotericin was administered for 4 weeks along with temporary hemodialytic support followed by successful catheter reinsertion. PMID- 26060372 TI - Terry's nails. PMID- 26060371 TI - Adefovir nephrotoxicity in a renal allograft recipient. AB - Adefovir dipivoxil, an oral prodrug of adefovir, is used in the treatment of lamivudine-resistant hepatitis B virus (HBV) infection. Nephrotoxicity manifesting as proximal renal tubular dysfunction and acute tubular necrosis (ATN) were commonly reported in the past, when higher doses were used for the treatment of human immunodeficiency virus infection. However, nephrotoxicity is rare at lower doses that are currently recommended for the treatment of HBV infection. A 31-year-old female was detected to be hepatitis B surface antigen positive months after a kidney transplant. The patient was initiated on lamivudine, but developed resistance after 1 year of treatment, at which time low dose adefovir was added. The patient developed renal allograft dysfunction after 10 months of starting adefovir. Serum creatinine increased from 1.1 mg/dl to 1.9 mg/dl, along with progressively increasing sub-nephrotic proteinuria. Renal allograft biopsy revealed features of ATN. After discontinuation of adefovir, proteinuria resolved and renal dysfunction improved slowly over the next 2 years. Adefovir-induced nephrotoxicity, although uncommon at lower doses, needs to be considered in the differential diagnosis of renal dysfunction and sub-nephrotic proteinuria occurring in patients receiving adefovir for prolonged periods. PMID- 26060373 TI - Allograft and remnant kidneys display a difference in size 5 years after transplantation. PMID- 26060374 TI - Effect of improved periodontal health in renal recipients. PMID- 26060375 TI - Glomerulonephritis with monoclonal IgG deposits. PMID- 26060377 TI - JETSTREAM Atherectomy: A Review of Technique, Tips, and Tricks in Treating the Femoropopliteal Lesions. AB - JETSTREAM (Bayer, Whippany, NJ) atherectomy is a highly effective rotational atherectomy device with active aspiration capacity approved in the United States to treat infrainguinal obstructive peripheral arterial disease. The technique in using the JETSTREAM is critical and relies on appropriate wire use, appropriate sizing, and speed in advancing the cutter as well as the use of fluoroscopic imaging and tactile and auditory senses. Using the right technique, the device appears to have a low rate of distal embolization and complications and results in high procedural success. We describe our own experience with the JETSTREAM device and the techniques used in our endovascular laboratory. PMID- 26060376 TI - Role of Advanced Glycation End Products and Its Receptors in the Pathogenesis of Cigarette Smoke-Induced Cardiovascular Disease. AB - The interaction of advanced glycation end products (AGEs) with its cell-bound receptor RAGE increases gene expression and release of proinflammatory cytokines and increase generation of reactive oxygen species (ROS). Circulating receptors, soluble RAGE (sRAGE), and endosecretory RAGE (esRAGE) by binding with RAGE ligands have protective effects against AGE-RAGE interaction. Cigarette smoking is a risk factor for coronary artery disease, stroke, and peripheral vascular disease. This article reviews; if the AGE-RAGE axis is involved in the cigarette smoke-induced cardiovascular diseases. There are various sources of AGEs in smokers including, gas/tar of cigarette, activation of macrophages and polymorphonuclear leukocytes, uncoupling of endothelial isoform of nitric oxide synthase (eNOS) and xanthine oxidase. The levels of AGEs are elevated in smokers. Serum levels of sRAGE have been reported to be reduced, elevated, or unchanged in smokers. Mostly the levels are reduced. There is one article which shows an elevation of levels of sRAGE in smokers. Serum levels of esRAGE are unaltered in smokers. Mechanism of AGE-RAGE-induced atherosclerosis has been discussed. Atherosclerosis leads to the cardiovascular diseases. It has been suggested that ratio of AGE/sRAGE or AGE/esRAGE is useful in determining the deleterious effects of AGE-RAGE interaction in smokers. sRAGE alone is not a good marker for smoke induced cardiovascular disease. In conclusion cigarette smoke induces formation of AGEs and reduces sRAGE resulting in the development of atherosclerosis and related coronary heart disease, stroke, and peripheral vascular disease. Ratio of AGEs/sRAGE is a better marker for cardiovascular disease than AGEs or sRAGE alone in smokers. PMID- 26060378 TI - Effects of Parvovirus B19 Infection in Renal Transplant Recipients: A Retrospective Review of Three Cases. AB - Parvovirus B19 (PVB19) is a DNA virus which causes clinically relevant infection in renal transplant recipients (RTR) leading to significant morbidity. Manifestations include erythropoietin resistant anemia, proteinuria, and glomerulosclerosis in the allograft. Severe infection may require administration of intravenous immunoglobulin, reduction in immunosuppression and transfusions. The major challenge in managing and preventing the infection in RTR involves the act of balancing the decreased level of immunosuppression and the risk of rejection. The objective of this article is to understand the importance of PVB19 infection and its outcome in RTR. We reviewed the medical records of three RTR with confirmed PVB19 infection and recorded patient information including demographics, clinical and laboratory data, management, and outcome. The average time of occurrence of PVB19 infection as transplant was 8.6 weeks and they presented with symptomatic anemia. Elevated creatinine values were noted in two of them. Following treatment, anemia improved and creatinine values returned to baseline. One of them developed an early relapse and had to be treated once again similarly. We emphasize the importance of maintaining a high index of suspicion for PVB19 infection in patients with anemia in the posttransplant phase, especially in patients on higher doses of immunosuppressants. Early and proper treatment can prevent worsening clinical condition and possible effects on the allograft. PMID- 26060379 TI - Effects of Gender on Outcomes and Survival Following Repair of Acute Type A Aortic Dissection. AB - Previous studies have demonstrated gender-related differences in early and late outcomes following type A dissection diagnosis. However, it is widely unknown whether gender affects early clinical outcomes and survival after repair of type A aortic dissection. The goal of this study was to compare the early and late clinical outcomes in women versus men after repair of acute type A aortic dissections. Between January 2000 and October 2010 a total of 251 patients from four academic medical centers underwent repair of acute type A aortic dissection. Of those, 79 were women and 172 were men with median ages of 67 (range, 20-87 years) and 58 years (range, 19-83 years), respectively (p < 0.001). Major morbidity, operative mortality, and 10-year actuarial survival were compared between the groups. Operative mortality was not significantly influenced by gender (19% for women vs. 17% for men, p = 0.695). There were similar rates of hemodynamic instability (12% for women vs. 13% men, p = 0.783) between the two groups. Actuarial 10-year survival rates were 58% for women versus 73% for men (p = 0.284). Gender does not significantly impact early clinical outcomes and actuarial survival following repair of acute type A aortic dissection. PMID- 26060380 TI - Percutaneous Transcatheter Closure of Ruptured Sinus of Valsalva Aneurysm: Immediate Result and Long-Term Follow-Up. AB - There is scarcity of data on closure and long-term follow-up of percutaneous treatment of ruptured sinus of Valsalva aneurysm (RSOVA). In this article, we present our experience in percutaneous closure of this defect. Between December 2009 and July 2014, 11 cases of RSOVA were referred to our hospital. Eight of the 11 cases (72.7%) were considered for percutaneous closure. Seven of the eight (87.5%) patients underwent successful percutaneous closure. There were four females and three males in the age group of 16 to 48 years (mean 24.7 +/- 6.1 years). Associated defects were bicuspid aortic valve in one patient, mild preexisting aortic regurgitation in two patients, and healed infective endocarditis in one patient. Echocardiography revealed RSOVA from right coronary sinus (RCS) to right atrium (RA) in one patient (14.3%), RCS to right ventricular outflow in three patients (42.8%), and noncoronary sinus ruptured into RA in three patients (42.8%). All patients were symptomatic in New York Heart Association (NYHA) class II to IV. The defect size ranged from 7 to 10 mm (mean 8.4 +/- 1.3 mm). The defects were closed from the venous side with device selection 2 to 4 mm higher than the defect size under fluoroscopy and transesophageal echocardiography guidance. Technical success was 87.5%. The mean device size was 12.0 +/- 1.6 mm/10.0 +/- 1.6 mm. Six out of seven patients (85.7%) had complete disappearance of shunt before discharge. During 1 to 55 months follow-up, all patients were in NYHA class I. There was no residual shunt, progression of AR or new AR, infective endocarditis or device embolization. Percutaneous closure of RSOVA appears to be a safe alternative to surgical therapy, with high technical success and excellent long-term outcome. PMID- 26060381 TI - Survival Benefit of Statins in Hemodialysis Patients Awaiting Renal Transplantation. AB - End-stage renal disease (ESRD) patients have extraordinarily high cardiovascular risk and mortality, yet the benefit of statins in this population remains unclear based on the randomized trials. We investigated the prognostic value of statins in a large, pure cohort of prospectively recruited patients with ESRD awaiting renal transplantation, and being followed up in a dedicated cardiac clinic. We prospectively collected demographic, clinical, laboratory, and pharmacological data on 423 consecutive ESRD patients on hemodialysis awaiting renal transplantation. Survival analysis was performed as a function of statin therapy. The baseline characteristics were as follows: age 57 +/- 11 years, males 64%, diabetes mellitus in 68%, known coronary artery disease in 30%, left ventricular (LV) ejection fraction 61 +/- 11%. Over a mean follow-up of 2 years, there were 43 deaths. Adjusted for age, gender, hypertension, body mass index, diabetes mellitus, coronary artery disease, smoking, and treatment with angiotensin converting enzyme inhibitor, beta blocker, and antiplatelet medications, statin use was a predictor of lower mortality (hazard ratio 0.30, 95% confidence interval 0.11-0.79, p = 0.01). This beneficial effect of statin was supported by propensity score analysis (p = 0.02) and was consistent across all clinical subgroups. The benefit of statins seemed to be greater in those with LV hypertrophy and smoking. Statin therapy in hemodialysis patients awaiting renal transplant is independently associated with better survival supporting its use in this high-risk population. PMID- 26060382 TI - Abdominal Aortic Diameter and the Risk for Asymptomatic Peripheral Arterial Disease in Patients with Type 2 Diabetes. AB - Peripheral arterial disease (PAD) is common among older people because it often results from atherosclerosis, which becomes more common with age. The disease is particularly common among people who have diabetes. Little information is available on the relation between abdominal aortic diameter and PAD in elderly patients with diabetes. This article studies the relationships between abdominal aortic diameter, PAD, and the cardiovascular risk factors in asymptomatic elderly patients suffering from type 2 diabetes mellitus. A case-control study was conducted on 90 participants aged 60 years and older divided into 60 cases (30 males and 30 females) and 30 age-matched healthy controls (15 males and 15 females). The relationships between the size of the abdominal aorta and ankle brachial index (ABI), plasma cholesterol, triglycerides (TG), and high sensitivity C-reactive protein were examined. Approximately, 15% of patients with diabetes had asymptomatic PAD. The patients with diabetes with PAD were of older age (70.4 +/- 3.6 vs. 63.4 +/- 3.9 years; p = 0.000), had larger abdominal aortic diameter (22.4 +/- 3.08 vs. 18.7 +/- 2 mm; p = 0.000), and higher CRP levels (8.3 +/- 1.1 vs. 5.8 +/- 2.2 mg/L; p = 0.002), while other variables revealed no significant difference. Abdominal aortic diameter correlated well with ABI measured by Doppler method in diabetic patients (r = - 0.471, p = 0.000). Older age and larger abdominal aorta are independent risk factors for asymptomatic PAD in the elderly with type 2 diabetes mellitus. PMID- 26060383 TI - How to Treat Obstructions in Patients with Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is characterized by the presence of increased thickness of the left ventricular wall that is not solely explained by abnormal loading conditions. Two-thirds of the patients with HCM have an obstruction in the left ventricle after provocation or even while at rest. This obstruction is associated with more symptoms and a worse prognosis. The two main therapeutic approaches for treating a left ventricular obstruction are alcohol septal ablation and surgical myectomy. Both these techniques are discussed in this article. Currently, the final decision concerning the optimal invasive therapy for patients with obstructive HCM must be individualized to each patient depending on his/her wishes and expectations, way of life, age, heart morphology, and hemodynamics, as well as the experience of the treating center. PMID- 26060384 TI - Blood Leukocyte Count on Admission Predicts Cardiovascular Events in Patients with Acute Non-ST Elevation Myocardial Infarction. AB - We aim to test the hypothesis that blood leukocyte count adds prognostic information in patients with acute non-ST-elevation myocardial infarction (non STEMI). A total of 585 patients with acute non-STEMI (thrombolysis in myocardial infarction risk score >= 3) were enrolled in this cohort retrospective study. Blood leukocyte count was measured immediately after admission in the emergency department. The composite of death, reinfarction, urgent revascularization, and stroke during hospitalization were defined as the primary end point of the study. The mean age of the patients was 61 +/- 9.6 years and most of them were male (79%). Using multivariate Cox regression analysis involving seven variables (history of smoking, hypertension, heart rate > 100 beats/minute, serum creatinine level > 1.5 mg/dL, blood leukocyte count > 11,000/uL, use of beta blocker, and use of angiotensin-converting enzyme inhibitor), leukocyte count > 11,000/uL demonstrated to be a strong predictor of the primary end point (hazard ratio = 3.028; 95% confidence interval = 1.69-5.40, p < 0.001). The high blood leukocyte count on admission is an independent predictor of cardiovascular events in patients with acute non-STEMI. PMID- 26060385 TI - Comparison of Angioseal and Manual Compression in Patients Undergoing Transfemoral Coronary and Peripheral Vascular Interventional Procedures. AB - Vascular closure devices (VCDs) were introduced in the early 1990s with the goal of limiting the time, labor, bed rest, and patient discomfort associated with manual compression (MC) for hemostasis after cardiovascular interventions. However, its advantage over MC has not been extensively studied after interventional procedures. The aim of this study was to do prospective, randomized study comparing the safety and efficacy of the Angio-Seal (AS) to that of MC in patients undergoing transfemoral coronary and peripheral vascular interventional procedure. A prospective, randomized trial was undertaken on consecutive series of patients admitted to King Fahd Hospital of the University for transfemoral coronary and peripheral vascular interventional procedures over 1 year. The study was designed to compare the hemostasis time in minutes and the incidence of vascular complications in patients receiving AS with those undergoing MC. All patients were on antiplatelets and received heparin during the procedure. During the study period, 160 patients were included, 80 in each group. There was a significant difference in mean time to hemostasis in minutes (15.83 +/- 1.63 minutes for MC and 0.42 +/- 0.04 minutes for the AS; p < 0.001), time to ambulation in minutes (280 +/- 15 for MC and 120 for AS; p = 0.04) and in minor complications (33.8% in MC vs. AS 5%; p < 0.001). However, the major complication rate did not significantly differ between the two groups (0% in AS vs. 2.5% in MC; p = 0.15). AS was found to achieve rapid closure of the femoral access site safely in patients undergoing coronary and peripheral vascular interventional procedures under antiplatelets and systemic heparinization. PMID- 26060386 TI - Preliminary Report of Endovascular Treatment for Critical Limb Ischemia Patients with Connective Tissue Disease: Cases Series and Review of the Literature. AB - Only few studies have addressed the surgical revascularization in patients with both connective tissue disease (CTD) and critical limb ischemia (CLI), and the evidence for the endovascular treatment (EVT) is lacking in such patients. The main purpose of this study is to assess our outcome of EVT in patients with CTD and ischemic leg ulcers and review the current situation of the revascularization in such patients. Medical records of 10 consecutive patients with coexistent CTD and CLI-related leg ulcers (in 11 limbs) treated endovascularly at our institution between 2009 and 2013 were reviewed retrospectively. The patients had rheumatoid arthritis (n = 5), systemic lupus erythematosus (n = 1), progressive systemic scleroderma (n = 3), or polyarteritis nodosa (n = 1). EVT was technically successful in all the cases. No procedure-related morbidity or mortality occurred. During the mean follow-up period of 26 months, there were no major amputations, and sustained clinical improvement (ulcer healing and reduction in Rutherford category) was observed in eight limbs. The overall 1-year rates of amputation-free survival and freedom from reintervention were 89 and 81%, respectively. In our series of patients with CTD and ischemic leg ulcers, EVT had acceptable outcomes and may be recommended as a safe and reasonably effective initial treatment option for such patients. PMID- 26060387 TI - An Extremely Rare Coronary Variation: Direct Communication between the Circumflex and Right Coronary Arteries. AB - Coronary collateral circulation frequently develops in the presence of obstructive coronary lesions as an alternative source of blood supply. We present a case of rare direct communication between the circumflex and right coronary arteries in a 30-year-old male with continuity between the distal segments of the circumflex and right coronary artery and no coronary artery stenoses. Direct intercoronary connections may be seen in the absence of an occlusive coronary lesion, as a remnant of the fetal circulation in adult life. We present this case to increase awareness of this rare coronary variation and its clinical implications. PMID- 26060388 TI - Kikuchi-Fujimoto Disease Masquerading as Metastatic Papillary Carcinoma of the Thyroid. AB - Kikuchi-Fujimoto disease also known as histiocytic necrotizing lymphadenitis is a rare cervical inflammatory lymphadenitis that is most commonly seen in young Asian women. It is mainly characterized by lymphadenopathy, hepatosplenomegaly, fever, nocturnal sweats, myalgia, weight loss, and arthralgia, and commonly follows a self-limited course. The differential diagnosis is challenging as many other conditions such as malignant lymphoma, metastatic disease, tuberculosis and infectious lymphadenopathies can present in a similar way. We present an unusual case of Kikuchi-Fujimoto disease masquerading as metastatic papillary carcinoma of the thyroid. A 30-year-old young female presented, 2 months post-partum, with complaints of neck pain and fever. A computed tomography scan showed enlarged right-sided lymph nodes and a thyroid nodule. Subsequent biopsy of a thyroid nodule revealed papillary thyroid carcinoma and reactive inflammation in one of the lymph nodes. She underwent an elective total thyroidectomy, central node dissection and a right modified lymph node dissection for enlarged lymph nodes. Her recovery was uneventful and the pathology report was consistent with a papillary carcinoma of the thyroid with one lymph node positive for metastatic disease and several other lymph nodes showing histiocytic necrotizing lymphadenitis. This coexistence of Kikuchi-Fujimoto disease with localized metastatic papillary thyroid cancer is unusual and presents an interesting, challenging, and complex management dilemma. PMID- 26060389 TI - Thoracoplasty for Postpneumonectomy Empyema Associated with Bronchopleural Fistula: A Case Series. AB - Thoracoplasty is a historical procedure, initially devised for the treatment of refractory tuberculous empyema. Advances in medical treatments have nearly eliminated the need for this surgical procedure in pulmonary tuberculosis and it is rarely performed or taught in modern day surgical practice. However, few indications still exist, most prominently, in the treatment of postpneumonectomy refractory empyema often but not always associated with a bronchopleural fistula. In this case report, we present two cases of postpneumonectomy refractory empyema treated by thoracoplasty with long-term follow-up. PMID- 26060390 TI - Scotoma analysis of 10-2 visual field testing with a white target in screening for hydroxychloroquine retinopathy. AB - OBJECTIVE: To quantify the variability of scotomas detected by 10-2 visual field (VF) testing in patients taking hydroxychloroquine without and with retinopathy. DESIGN: Retrospective review of clinical charts and visual fields. SUBJECTS: Twenty-one patients taking hydroxychloroquine without retinopathy, and nine patients taking hydroxychloroquine and one patient taking chloroquine with retinopathy. METHODS: Retinopathy was defined by annular scotomas on 10-2 VF testing with corroborative spectral domain optical coherence tomographic outer retinal changes and multifocal electroretinographic changes leading to cessation of hydroxychloroquine or chloroquine. Location and depth of scotoma points on 10 2 VF testing were recorded and their fates followed in serial, reliable 10-2 VFs performed with a white target over time. MAIN OUTCOME MEASURES: Number of scotoma points and locations, percentage of persistent scotoma points, size of scotomas, location of scotomas, and percentage of scotomas deepening. RESULTS: A median of five, interquartile range (IQR) 3-8 scotoma points per VF occurred in patients without retinopathy. A median of 86%, IQR 63%-100% of these points resolve on the subsequent field. For patients with retinopathy, a median of 22%, IQR 10%-59% resolve. The median percentage of scotoma points in the zone 2-8 degrees from fixation in eyes with retinopathy was 79%, IQR 68%-85% compared to 60%, IQR 54% 75% in eyes without retinopathy (P=0.0094). Single-point scotomas were more common in eyes without than with retinopathy. Scotomas consisting of more than four contiguous scotoma points were generally indicative of retinopathy. CONCLUSION: Point scotomas are common and variable in 10-2 VF testing with a white target for hydroxychloroquine retinopathy in subjects without retinopathy. The annular zone 2 to 8 degrees from fixation was useful for distinguishing the significance of scotoma points. Scotomas with more contiguous scotoma points were more often associated with retinopathy. PMID- 26060391 TI - Human adenovirus type 8 epidemic keratoconjunctivitis with large corneal epithelial full-layer detachment: an endemic outbreak with uncommon manifestations. AB - Epidemic viral conjunctivitis is a highly contagious disease that is encountered year-round. The causative agents are mainly adenoviruses and enteroviruses. It occurs most commonly upon infection with subgroup D adenoviruses of types 8, 19, or 37. For common corneal involvement of human adenovirus type 8 epidemic keratoconjunctivitis, full-layer epithelial detachment is rarely seen. Herein, we report three cases of epidemic keratoconjunctivitis during an outbreak which manifested as large corneal epithelial full-layer detachment within a few days. The lesions healed without severe sequelae under proper treatment. The unique manifestation of this outbreak may indicate the evolution of human adenovirus type 8. PMID- 26060392 TI - Visual outcomes of age-related macular degeneration patients undergoing intravitreal ranibizumab monotherapy in an urban population. AB - AIM: To compare the visual outcomes of an urban population with age-related macular degeneration (AMD) undergoing ranibizumab monotherapy to the results from major clinical trials. PROCEDURES: Prospective data was collected from 164 wet AMD patients receiving intravitreal ranibizumab. Visual acuities were obtained with the Early Treatment Diabetic Retinopathy Study chart. All patients underwent a loading phase of three monthly treatments of ranibizumab. Patients were monitored monthly using a retreatment criterion. Treatment was further individualized by sequentially lengthening follow-up intervals when stable. RESULTS: At 12 and 24 months, respectively, the percentage of eyes that maintained vision was 91% and 88.6%. We found that 20.3% of eyes had improved vision at 12 months and 20% at 24 months. At 12 months, 8.3% of eyes' vision worsened and 12% worsened at 24 months. CONCLUSION: Individualized ranibizumab monotherapy is effective in preserving vision in wet AMD and follows the same trends as the pivotal trials. PMID- 26060393 TI - Population pharmacokinetics of methylphenidate hydrochloride extended-release multiple-layer beads in pediatric subjects with attention deficit hyperactivity disorder. AB - A new multilayer-bead formulation of extended-release methylphenidate hydrochloride (MPH-MLR) has been evaluated in pharmacokinetic studies in healthy adults and in Phase III efficacy/safety studies in children and adolescents with attention deficit hyperactivity disorder (ADHD). Using available data in healthy adults, a two-input, one-compartment, first-order elimination population pharmacokinetic model was developed using nonlinear mixed-effect modeling. The model was then extended to pediatric subjects, and was found to adequately describe plasma concentration-time data for this population. A pharmacokinetic/pharmacodynamic model was also developed using change from baseline in the ADHD Rating Scale (ADHD-RS)-IV total scores from a pediatric Phase III trial and simulated plasma concentration-time data. During simulations for each MPH-MLR dose level (10-80 mg), increased body weight resulted in decreased maximum concentration. Additionally, as maximum concentration increased, ADHD-RS-IV total score improved (decreased). Knowledge of the relationship between dose, body weight, and clinical response following the administration of MPH-MLR in children and adolescents may be useful for clinicians selecting initial dosing of MPH-MLR. Additional study is needed to confirm these results. PMID- 26060394 TI - Role of sodium tungstate as a potential antiplatelet agent. AB - PURPOSE: Platelet inhibition is a key strategy in the management of atherothrombosis. However, the large variability in response to current strategies leads to the search for alternative inhibitors. The antiplatelet effect of the inorganic salt sodium tungstate (Na2O4W), a protein tyrosine phosphatase 1B (PTP1B) inhibitor, has been investigated in this study. METHODS: Wild-type (WT) and PTP1B knockout (PTP1B(-/-)) mice were treated for 1 week with Na2O4W to study platelet function with the platelet function analyzer PFA-100, a cone-and-plate analyzer, a flat perfusion chamber, and thrombus formation in vivo. Human blood aliquots were incubated with Na2O4W for 1 hour to measure platelet function using the PFA-100 and the annular perfusion chamber. Aggregometry and thromboelastometry were also performed. RESULTS: In WT mice, Na2O4W treatment prolonged closure times in the PFA-100 and decreased the surface covered (%SC) by platelets on collagen. Thrombi formed in a thrombosis mice model were smaller in animals treated with Na2O4W (4.6+/-0.7 mg vs 8.9+/-0.7 mg; P<0.001). Results with Na2O4W were similar to those in untreated PTP1B(-)/(-) mice (5.0+/-0.3 mg). Treatment of the PTP1B(-)/(-) mice with Na2O4W modified only slightly this response. In human blood, a dose-dependent effect was observed. At 200 MUM, closure times in the PFA-100 were prolonged. On denuded vessels, %SC and thrombi formation (%T) decreased with Na2O4W. Neither the aggregating response nor the viscoelastic clot properties were affected. CONCLUSION: Na2O4W decreases consistently the hemostatic capacity of platelets, inhibiting their adhesive and cohesive properties under flow conditions in mice and in human blood, resulting in smaller thrombi. Although Na2O4W may be acting on platelet PTP1B, other potential targets should not be disregarded. PMID- 26060395 TI - Clinical evaluation of the efficacy and safety of a medical device in various forms containing Triticum vulgare for the treatment of venous leg ulcers - a randomized pilot study. AB - This study was carried out to assess the efficacy and tolerability of the topical application of an aqueous extract of Triticum vulgare (TV) in different vehicles (cream, impregnated gauzes, foam, hydrogel, and dressing gel) for the treatment of venous lower leg ulcers. Fifty patients were randomized to receive one of the five investigational vehicles. Treatment was performed up to complete healing or to a maximum of 29 days. The wound size reduction from baseline was the primary efficacy variable, which was measured by means of a noninvasive laser scanner instrument for wound assessment. In all groups, apart from the foam group, a similar trend toward the reduction of the surface area was observed. The cream showed the greatest effect on the mean reduction of the lesion size. At last visit, six ulcers were healed: two in the cream group, three in the gauze group, and one in the dressing gel group. In the patients treated with the cream, the gauzes, the hydrogel, and the dressing gel, the reduction of lesion size was 40% 50%; the reduction was smaller in the foam group. No impact in terms of age on the healing process was found. The Total Symptoms Score decreased in all groups during the study; a greater efficacy in terms of signs/symptoms was observed in the patients treated with the gauzes. In the dressing gel group, one patient had an infection of the wound after 3 weeks of treatment and 2 of colonization, leading to a systemic antibiotic treatment. The events were judged as nonrelated to the device used. On the basis of the results, it could be argued that the medical device may be useful in the treatment of chronic venous ulcers. PMID- 26060396 TI - Isolation and evaluation of anticancer efficacy of stigmasterol in a mouse model of DMBA-induced skin carcinoma. AB - Stigmasterol (99.9% pure) was isolated from Azadirachta indica and its chemopreventive effect on 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin cancer was investigated in Swiss albino mice. Skin tumors were induced by topical application of DMBA and promoted by croton oil. To assess the chemopreventive potential of stigmasterol, it was orally administered at a concentration of 200 mg/kg and 400 mg/kg three times weekly for 16 weeks. Reduction in tumor size and cumulative number of papillomas were seen as a result of treatment with stigmasterol. The average latency period was significantly increased as compared with the carcinogen-treated control. Stigmasterol induced a significant decrease in the activity of serum enzymes, such as aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and bilirubin as compared with the control. Stigmasterol significantly increased glutathione, superoxide dismutase, and catalase as compared with the control. Elevated levels of lipid peroxide and DNA damage in the control group were significantly inhibited by administration of stigmasterol. From the present study, it can be inferred that stigmasterol has chemopreventive activity in an experimental model of cancer. This chemopreventive activity may be linked to the oxidative stress of stigmasterol. The antigenotoxic properties of stigmasterol are also likely to contribute to its chemopreventive action. PMID- 26060397 TI - Itraconazole solid dispersion prepared by a supercritical fluid technique: preparation, in vitro characterization, and bioavailability in beagle dogs. AB - This research aimed to develop a supercritical fluid (SCF) technique for preparing a particulate form of itraconazole (ITZ) with good dissolution and bioavailability characteristics. The ITZ particulate solid dispersion was formulated with hydroxypropyl methylcellulose, Pluronic F-127, and L-ascorbic acid. Aggregated particles showed porous structure when examined by scanning electron microscopy. Powder X-ray diffraction and Fourier transform infrared spectra indicated an interaction between ITZ and excipients and showed that ITZ existed in an amorphous state in the composite solid dispersion particles. The solid dispersion obtained by the SCF process improved the dissolution of ITZ in media of pH 1.0, pH 4.5, and pH 6.8, compared with a commercial product (Sporanox((r))), which could be ascribed to the porous aggregated particle shape and amorphous solid state of ITZ. While the solid dispersion did not show a statistical improvement (P=0.50) in terms of oral bioavailability of ITZ compared with Sporanox((r)), the C max (the maximum plasma concentration of ITZ in a pharmacokinetic curve) of ITZ was raised significantly (P=0.03) after oral administration. Thus, the SCF process has been shown to be an efficient, single step process to form ITZ-containing solid dispersion particles with good dissolution and oral bioavailability characteristics. PMID- 26060400 TI - Effectiveness of high-intensity interval training on the mental and physical health of people with chronic schizophrenia. AB - BACKGROUND: Low-volume high-intensity interval training (HIIT) is emerging as a time-efficient exercise strategy for improving cardiorespiratory fitness and for controlling blood sugar levels and hypertension. In addition, patient acceptance of HIIT may improve adherence to exercise programs. This study evaluated the effectiveness of HIIT for improving the mental and physical health of people with chronic schizophrenia. METHODS: Twenty patients attending a psychiatric day care unit volunteered for an 8-week program of HIIT. Blood pressure, resting heart rate, body weight, body mass index, waist and hip circumference, and waist-to-hip ratio were measured weekly. The Positive and Negative Syndrome Scale score was recorded at baseline and at the end of the study. Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) scores were recorded every 2 weeks. RESULTS: Statistically significant changes occurred in the physical and mental parameters measured in the 18 patients who completed the study. Body weight, body mass index, resting heart rate, and pulse pressure decreased significantly. Mean arterial pressure and diastolic blood pressure increased significantly. Mental health scores improved, with the Negative Scale score decreasing from 31.17+/ 5.95 to 27.78+/-3.57 (P<0.01) and the General Psychopathology Scale score from 14.28+/-2.16 to 13.00+/-1.72 (P<0.01). Positive Scale scores changed, but not significantly, from 12.28+/-2.27 to 12.33+/-2.00 (P=0.729). Scores on the BDI (from 19.56+/-15.28 to 15.89+/-14.33, P<0.001) and BAI (from 13.67+/-13.83 to 10.06+/-11.18, P=0.003) both improved significantly. CONCLUSION: This study demonstrated that HIIT has positive effects on the physical and mental health of patients with chronic schizophrenia. PMID- 26060399 TI - GX1-conjugated poly(lactic acid) nanoparticles encapsulating Endostar for improved in vivo anticolorectal cancer treatment. AB - Tumor angiogenesis plays a key role in tumor growth and metastasis; thus, targeting tumor-associated angiogenesis is an important goal in cancer therapy. However, the efficient delivery of drugs to tumors remains a key issue in antiangiogenesis therapy. GX1, a peptide identified by phage-display technology, is a novel tumor vasculature endothelium-specific ligand and possesses great potential as a targeted vector and antiangiogenic agent in the diagnosis and treatment of human cancers. Endostar, a novel recombinant human endostatin, has been shown to inhibit tumor angiogenesis. In this study, we developed a theranostic agent composed of GX1-conjugated poly(lactic acid) nanoparticles encapsulating Endostar (GPENs) and labeled with the near-infrared dye IRDye 800CW to improve colorectal tumor targeting and treatment efficacy in vivo. The in vivo fluorescence molecular imaging data showed that GPENs (IRDye 800CW) more specifically targeted tumors than free IRDye 800CW in colorectal tumor-bearing mice. Moreover, the antitumor efficacy was evaluated by bioluminescence imaging and immunohistology, revealing that GPENs possessed improved antitumor efficacy on subcutaneous colorectal xenografts compared to other treatment groups. Thus, our study showed that GPENs, a novel GX1 peptide guided form of nanoscale Endostar, can be used as a theranostic agent to facilitate more efficient targeted therapy and enable real-time monitoring of therapeutic efficacy in vivo. PMID- 26060401 TI - Olanzapine-valproate combination versus olanzapine or valproate monotherapy in the treatment of bipolar I mania: a randomized controlled study in a Chinese population group. AB - BACKGROUND: Bipolar disorder (BP) is a mental illness that has a high social burden estimated by disability-adjusted life years. In the present study, we investigated the efficacy of olanzapine-valproate combination therapy versus olanzapine or valproate monotherapy in the treatment of bipolar I mania in a Chinese population group. SUBJECTS AND METHODS: Patients aged 19-58 years who had had an acute manic episode of BP were enrolled in the present study and randomly assigned to receive 600 mg sodium valproate daily (group A), 10 mg olanzapine daily (group B), or a combination of 600 mg olanzapine and 10 mg sodium valproate daily (group C) for 4 weeks. The primary outcome was reduction in Young Mania Rating Scale (YMRS) scores. The secondary outcome was assessed with the Clinical Global Impression - Bipolar (CGI-BP) scale. Adverse reactions, such as weight gain, sleepy, and dizziness were also evaluated. Statistical analysis was carried out on a per-protocol basis. RESULTS: Patients in groups B and C showed significant improvement in YMRS scores compared with those in group A (P<0.01) during weeks 1-4 of treatment. Patients in group C showed significant improvement in YMRS scores compared with those in group B (P<0.01) only after 4 weeks of treatment. Furthermore, after 3-4 weeks of treatment, patients in groups B and C showed significantly greater improvement in CGI-BP scale scores compared with group A (P<0.05), while Group C demonstrated significantly greater improvement in CGI-BP scale scores than group B (P<0.01). No significant difference existed in extrapyramidal reactions among these groups. Adverse reactions, including weight gain, drowsiness, dizziness, and constipation, were stronger in groups B and C than in group A (P<0.05). CONCLUSION: The combination therapy with olanzapine and sodium valproate had higher efficacy than monotherapy in patients with bipolar mania, which provides a crucial insight of the treatment regimen during clinical practice. PMID- 26060402 TI - The interventional effects of loving-kindness meditation on positive emotions and interpersonal interactions. AB - The study aimed to investigate the effects of loving-kindness meditation on positive emotions, intragroup interactions, and complex understanding of others. A total of 50 freshmen not receiving any training in meditation intervention were randomly divided into the meditation group (25 subjects) and the control group (25 subjects). The meditation group was implemented with group meditation intervention for 4 weeks, three times a week, about 30 minutes each time. The results revealed that the effect sizes in interpersonal interaction and complex understanding of others in the meditation group were both above 0.8, indicating strong effects. It was concluded that loving-kindness meditation can effectively improve positive emotions, interpersonal interactions, and complex understanding of others in college students. PMID- 26060398 TI - Value of phagocyte function screening for immunotoxicity of nanoparticles in vivo. AB - Nanoparticles (NPs) present in the environment and in consumer products can cause immunotoxic effects. The immune system is very complex, and in vivo studies are the gold standard for evaluation. Due to the increased amount of NPs that are being developed, cellular screening assays to decrease the amount of NPs that have to be tested in vivo are highly needed. Effects on the unspecific immune system, such as effects on phagocytes, might be suitable for screening for immunotoxicity because these cells mediate unspecific and specific immune responses. They are present at epithelial barriers, in the blood, and in almost all organs. This review summarizes the effects of carbon, metal, and metal oxide NPs used in consumer and medical applications (gold, silver, titanium dioxide, silica dioxide, zinc oxide, and carbon nanotubes) and polystyrene NPs on the immune system. Effects in animal exposures through different routes are compared to the effects on isolated phagocytes. In addition, general problems in the testing of NPs, such as unknown exposure doses, as well as interference with assays are mentioned. NPs appear to induce a specific immunotoxic pattern consisting of the induction of inflammation in normal animals and aggravation of pathologies in disease models. The evaluation of particle action on several phagocyte functions in vitro may provide an indication on the potency of the particles to induce immunotoxicity in vivo. In combination with information on realistic exposure levels, in vitro studies on phagocytes may provide useful information on the health risks of NPs. PMID- 26060403 TI - Adult children of parents with young-onset dementia narrate the experiences of their youth through metaphors. AB - BACKGROUND: Limited research exists on the development and needs of children of parents with young-onset dementia (YOD) (<65 years old). There is scarce knowledge of how these children experience the situation of growing up with a parent with dementia. This study investigates the stories of children of persons with YOD and interprets their metaphorical expressions of their experiences as a source of understanding their situation and needs during the development and course of their parent's dementia. METHODS: Qualitative interviews with 14 informants (aged 18-30 years; nine daughters, five sons) were conducted in 2014 and subsequently analyzed by the informants' use of metaphors. Steger's three step method for analyzing metaphors was applied. RESULTS: The analysis identified four themes in the metaphors: the informants' relations to the disease, to the self, to the parent, and to others. From these themes, four core metaphors were abstracted: "my parent is sliding away"; "emotional chaos"; "becoming a parent to my parent"; and "a battle". CONCLUSION: The study revealed that growing up with a parent with dementia has a great impact on the children's situation and their experiences of their personal development. Children of a parent with YOD are a group with unmet needs for support. A formalized system where the children can get into contact with service providers to receive tailored information and individual follow-up needs to be established. The service providers must listen to the children's stories, perceive how metaphors convey their experiences, and recognize their need for support for their own development. PMID- 26060404 TI - The impact of anesthesia providers on major morbidity following screening colonoscopies. AB - BACKGROUND AND AIMS: Few studies evaluate the impact of anesthesia providers during procedures, such as colonoscopy, on low-risk patients. The objective of this study was to compare the effect of anesthesia providers on several outcome variables, including major morbidity, following screening colonoscopies. METHODS: A propensity-matched cohort study of 14,006 patients who enrolled with a national insurer offering health maintenance organization (HMO), preferred provider organization (PPO), and Medicare Advantage plans for a screening colonoscopy between July 1, 2005 and June 30, 2007 were studied. Records were evaluated for completion of the colonoscopy, new cancer diagnosis (colon, anal, rectal) within 6 months of the colonoscopy, new primary diagnosis of myocardial infarction (MI), new primary diagnosis of stroke, hospital admission within 7 days of the colonoscopy, and adherence to guidelines for use of anesthesia providers. RESULTS: The presence of an anesthesia provider did not affect major morbidity or the percent of completed exams. Overall morbidity within 7 days was very low. When an anesthesia provider was present, a nonsignificant trend toward greater cancer detection within 6 months of the procedure was observed. Adherence to national guidelines regarding the use of anesthesia providers for low-risk patients was poor. CONCLUSION: A difference in outcome associated with the presence or absence of an anesthesia provider during screening colonoscopy in terms of MI, stroke, or hospital admission within 7 days of the procedure was not observed. Adherence to published guidelines for the use of anesthesia providers is low. The incidence of completed exams was unaffected by the presence of an anesthesia provider. However, a nonstatistically significant trend toward increased cancer detection requires further study. PMID- 26060405 TI - Oral treatment with the herbal formula B307 alleviates cardiac toxicity in doxorubicin-treated mice via suppressing oxidative stress, inflammation, and apoptosis. AB - OBJECTIVE: This study aimed to investigate whether the herbal formula B307 could alleviate doxorubicin (DOX)-induced acute cardiotoxicity. If so, we further unraveled possible molecular mechanisms of cardiac protection under treatment with the herbal formula B307. METHODS: Before the animal experiment, we examined relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307. To test whether oral treatment with the herbal formula B307 could alleviate cardiotoxicity, equal volumes of B307 (50 mg/kg) or saline (sham treatment) were administered to 20-week-old male mice once daily for 14 consecutive days. Then, DOX (10 mg/kg; ip) was administered to male mice under B307 and sham treatments at 22-23 weeks of age. Cardiac functions in these mice were assessed via echocardiography at 23-24 weeks of age. Then, expressions of oxidative stress, inflammation, and apoptosis-related proteins were examined in the heart tissue by immunohistochemistry and Western blotting at 24-25 weeks of age. Apart from this, mortality rate and body weight were measured during the experiment. RESULTS: In vitro, the relative viabilities of Huh7 cancer cells under treatment with the herbal formula B307 had shown no obvious change at doses of 10-160 ng/mL. Furthermore, the relative viabilities of Huh7 cancer cells were significantly reduced under DOX treatment but showed no significant change under DOX only and DOX plus B307 treatment. In vivo, the mortality rate, body weight, and cardiac function of DOX-treated mice were obviously improved under oral treatment with the herbal formula B307. Furthermore, cardiac expressions of endothelial nitric oxide synthase, superoxide dismutase 2, and B-cell lymphoma 2 were significantly enhanced, but tumor necrosis factor alpha, NFKB1 (p50 and its precursor, p105), neurotrophin-3, Bcl-2-associated X protein, calpain, caspase 12, caspase 9, and caspase 3 were significantly suppressed in DOX-treated mice under oral treatment with the herbal formula B307. CONCLUSION: Our results revealed that oral treatment with the herbal formula B307 may provide cardioprotection in DOX treated mice via suppressing oxidative stress, inflammation, and apoptosis in heart tissue. We believe that the herbal formula B307 may be developed as a potential alternative treatment for cancer patients under DOX treatment. PMID- 26060406 TI - Antiproliferative effects and molecular mechanisms of troglitazone in human cervical cancer in vitro. AB - We investigated the effects of troglitazone on human cervical cancer SiHa cells and its mechanisms of action. SiHa cells were incubated with different concentrations of troglitazone (100, 200, or 400 MUg/mL) for 24, 48, and 72 hours. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl) 2,5 diphenyltetrazolium bromide (MTT) assay; cell cycle and apoptosis were detected by flow cytometry; and morphology of SiHa cells was observed under an inverted microscope. pcDNA3.1 and pcDNA3.1-Skp2 plasmids were constructed and then transfected into SiHa cells. Protein expression was analyzed by Western blotting. Troglitazone inhibited the proliferation of SiHa cells in a time- and concentration-dependent manner. Troglitazone caused G0/1 phase arrest but failed to reduce apoptosis in SiHa cells. Troglitazone significantly increased expression of p27 but decreased Skp2 expression. Skp2 overexpression inhibited the role of troglitazone in increasing expression of p27, and the cell cycle inhibitory effect of troglitazone. Troglitazone can inhibit SiHa cell viability by affecting cell cycle distribution but not apoptosis, and Skp2 and p27 may play a critical role. PMID- 26060407 TI - Clinical analysis of 50 Eastern Asian patients with primary pulmonary large-cell neuroendocrine carcinoma. AB - BACKGROUND: To understand the clinicopathological features of patients with primary pulmonary large-cell neuroendocrine carcinoma (LCNEC), including the frequency of epidermal growth factor receptor (EGFR) mutation, and to explore prognostic factors. METHODS: We investigated a cohort of 50 individuals from our center database who were diagnosed with operable pulmonary LCNEC and treated in Sun Yat-sen University Cancer Center. Serum albumin (ALB) and neuron-specific enolase (NSE) were also collected. Survival curves were obtained with the Kaplan Meier method, and the differences between groups in survival were tested by the log-rank test. RESULTS: The median age was 59 years (range, 40-80 years). Fourteen patients underwent mutational analysis of EGFR; of these, 12 had wild type EGFR and the remaining two had EGFR mutations in exons. The median disease free survival (DFS) of pulmonary LCNEC was 49.3 months and that of overall survival (OS) was not reached. DFS and OS were shorter for patients with decreased serum ALB than for patients with normal serum ALB (P=0.003 and P=0.004, respectively). Meanwhile, a high level of NSE was also significantly associated with short DFS and OS (P=0.005 and P=0.000, respectively). Multivariate analysis showed that decrease in serum ALB was an independent prognostic factor for OS (P=0.046). CONCLUSION: The frequency of EGFR mutation in LCNEC patients is low. Serum ALB and NSE levels are valuable prognostic factors for LCNEC patients. PMID- 26060408 TI - Positive feedback between oncogenic KRAS and HIF-1alpha confers drug resistance in colorectal cancer. AB - Approximately 30%-50% of colorectal cancers (CRCs) harbor the somatic mutated KRAS gene. KRAS G12V, one of the most common KRAS mutations in CRCs, is linked to increased tumor aggressiveness, less response to anti-epidermal growth factor receptor (EGFR) therapy, and poor survival rate. In this study, we sought to determine whether resistance to EGFR inhibitors in colorectal cancer cells harboring KRAS G12V mutation is associated with hypoxia. Our data indicated that HIF-1alpha was induced by KRAS G12V signaling at transcription level. Hypoxia or HIF-1alpha overexpression could increase KRAS G12V activity. Therefore, a positive feedback between hypoxia and KRAS G12V activation was formed. Cetuximab, an EGFR inhibitor, which has a minor effect on KRAS-mutant CRCs, could effectively inhibit the proliferation of CRC cells harboring KRAS G12V mutation when combined with HIF-1alpha inhibitor PX-478. Our data indicated that hypoxia was involved in resistance to anti-EGFR therapy, and a combination therapy might be necessary for CRC patients with KRAS mutation. PMID- 26060409 TI - Value of detection of serum human epididymis secretory protein 4 and carbohydrate antigen 125 in diagnosis of early endometrial cancer of different pathological subtypes. AB - This study explored the value of detection of human epididymis secretory protein 4 (HE4) and carbohydrate antigen 125 (CA125) from serum in diagnosis of early endometrial cancer of different pathological subtypes and discussed the mechanism of HE4 and CA125 in diagnosis. In this study, enzyme-linked immunosorbent assay and chemiluminescent immunoassay were used to detect HE4 and CA125 from serum in endometrial cancer and control groups. Besides, the concentration of HE4 and CA125 was compared in these two groups, and the expression of CA125 and HE4 and clinicopathological characteristics in patients with endometrial cancer were also analyzed. Compared with the control group, the expression of HE4 was much higher in serum of patients with endometrial cancer, while there was no obvious change in the expression of CA125. The threshold detection value was acquired by receiver operating characteristic analysis method, that is, 141.5 pmol/L and 54.5 U/L, respectively. When comparing the concentration of HE4 in patients with endometrial cancer at the early stage (stage I) with healthy people, the difference therein had statistical significance, but there was no obvious difference in CA125. HE4 and CA125 in diagnosis of endometrial cancer in the stages I and II were found with no statistically significant difference. The difference of HE4 in the stages II and III had statistical significance while the difference of CA125 had no statistical significance. The specificity of both HE4 and CA125 was 95%, and the sensitivity of HE4 to uterine papillary serous carcinomas was higher than that to endometrioid adenocarcinoma. Thus, the serum HE4 is much better than CA125 in detecting the endometrial cancer at an early stage. PMID- 26060410 TI - Percutaneous microwave ablation combined with simultaneous transarterial chemoembolization for the treatment of advanced intrahepatic cholangiocarcinoma. AB - AIM: To retrospectively evaluate the safety and efficacy of ultrasound-guided percutaneous microwave ablation (MWA) combined with simultaneous transarterial chemoembolization (TACE) in the treatment of patients with advanced intrahepatic cholangiocarcinoma (ICC). METHODS: All patients treated with ultrasound-guided percutaneous MWA combined with simultaneous TACE for advanced ICC at our institution were included. Posttreatment contrast-enhanced computed tomography and/or magnetic resonance imaging were retrieved and reviewed for tumor response to the treatment. Routine laboratory studies, including hematology and liver function tests were collected and analyzed. Procedure-related complications were reviewed and survival rates were analyzed. RESULTS: From January 2011 to December 2014, a total of 26 advanced ICC patients were treated at our single institute with ultrasound-guided percutaneous MWA combined with simultaneous TACE. There were 15 males and eleven females with an average age of 57.9+/-10.4 years (range, 43-75 years). Of 26 patients, 20 (76.9%) patients were newly diagnosed advanced ICC without any treatment, and six (23.1%) were recurrent and treated with surgical resection of the original tumor. The complete ablation rate was 92.3% (36/39 lesions) for advanced ICC. There were no major complications observed. There was no death directly from the treatment. Median progression-free survival and overall survival were 6.2 and 19.5 months, respectively. The 6-, 12-, and 24 month survival rates were 88.5%, 69.2%, and 61.5%, respectively. CONCLUSION: The study suggests that ultrasound-guided percutaneous MWA combined with simultaneous TACE therapy can be performed safely in all patients with advanced ICC. The complete ablation rate was high and there was no major complication. The overall 24-month survival was 61.5%. PMID- 26060412 TI - Pyoderma gangrenosum: challenges and solutions. AB - Pyoderma gangrenosum (PG) is a rare disease, but commonly related to important morbidity. PG was first assumed to be infectious, but is now considered an inflammatory neutrophilic disease, often associated with autoimmunity, and with chronic inflammatory and neoplastic diseases. Currently, many aspects of the underlying pathophysiology are not well understood, and etiology still remains unknown. PG presents as painful, single or multiple lesions, with several clinical variants, in different locations, with a non specific histology, which makes the diagnosis challenging and often delayed. In the classic ulcerative variant, characterized by ulcers with inflammatory undermined borders, a broad differential diagnosis of malignancy, infection, and vasculitis needs to be considered, making PG a diagnosis of exclusion. Moreover, there are no definitively accepted diagnostic criteria. Treatment is also challenging since, due to its rarity, clinical trials are difficult to perform, and consequently, there is no "gold standard" therapy. Patients frequently require aggressive immunosuppression, often in multidrug regimens that are not standardized. We reviewed the clinical challenges of PG in order to find helpful clues to improve diagnostic accuracy and the treatment options, namely topical care, systemic drugs, and the new emerging therapies that may reduce morbidity. PMID- 26060411 TI - Mycoplasma genitalium infection: current treatment options, therapeutic failure, and resistance-associated mutations. AB - Mycoplasma genitalium is an important cause of non-gonococcal urethritis, cervicitis, and related upper genital tract infections. The efficacy of doxycycline, used extensively to treat non-gonococcal urethritis in the past, is relatively poor for M. genitalium infection; azithromycin has been the preferred treatment for several years. Research on the efficacy of azithromycin has primarily focused on the 1 g single-dose regimen, but some studies have also evaluated higher doses and longer courses, particularly the extended 1.5 g regimen. This extended regimen is thought to be more efficacious than the 1 g single-dose regimen, although the regimens have not been directly compared in clinical trials. Azithromycin treatment failure was first reported in Australia and has subsequently been documented in several continents. Recent reports indicate an upward trend in the prevalence of macrolide-resistant M. genitalium infections (transmitted resistance), and cases of induced resistance following azithromycin therapy have also been documented. Emergence of antimicrobial resistant M. genitalium, driven by suboptimal macrolide dosage, now threatens the continued provision of effective and convenient treatments. Advances in techniques to detect resistance mutations in DNA extracts have facilitated correlation of clinical outcomes with genotypic resistance. A strong and consistent association exists between presence of 23S rRNA gene mutations and azithromycin treatment failure. Fluoroquinolones such as moxifloxacin, gatifloxacin, and sitafloxacin remain highly active against most macrolide resistant M. genitalium. However, the first clinical cases of moxifloxacin treatment failure, due to bacteria with coexistent macrolide-associated and fluoroquinolone-associated resistance mutations, were recently published by Australian investigators. Pristinamycin and solithromycin may be of clinical benefit for such multidrug-resistant infections. Further clinical studies are required to determine the optimal therapeutic dosing schedules for both agents to effect clinical cure and minimize the risk of emergent antimicrobial resistance. Continual inappropriate M. genitalium treatments will likely lead to untreatable infections in the future. PMID- 26060413 TI - Vasomotor sympathetic outflow in the muscle metaboreflex in low birth weight young adults. AB - A growing body of evidence suggests that low birth weight (LBW) offspring are associated with long-term structural and functional changes in cardiovascular and neuroendocrine systems. We tested the hypothesis that muscle metaboreflex activation produces exaggerated responses in cardiac autonomic tone (represented by heart rate variability ratio) and cutaneous vascular sympathetic tone (represented by plethysmography pulse wave amplitude) in LBW compared to normal birth weight (NBW) young adults. We recruited 23 LBW (18 females and five males) and 23 NBW (14 females and nine males) University of Zimbabwe students with neonatal clinical cards as proof of birth weight at term. Resting electrocardiogram, pulse waves, and blood pressures were recorded. Participants then underwent a static/isometric handgrip exercise until fatigue and a post exercise circulatory arrest period of 2 minutes. We observed (results mean +/- standard deviation) a greater mean increase in heart rate variability ratio from baseline to exercise for LBW compared to NBW individuals (1.015+/-1.034 versus [vs] 0.119+/-0.789, respectively; P<0.05). We also observed a greater mean decrease in plethysmography pulse wave amplitude from baseline to exercise ( 1.32+/-1.064 vs -0.735+/-0.63; P<0.05) and from baseline to post-exercise circulatory arrest (-0.932+/-0.998 vs -0.389+/-0.563; P<0.05) for LBW compared to NBW individuals. We conclude that LBW may be associated with an exaggerated sympathetic discharge in response to muscle metaboreflex. PMID- 26060414 TI - The VariLift((r)) Interbody Fusion System: expandable, standalone interbody fusion. AB - Intervertebral fusion cages have been in clinical use since the 1990s. Cages offer the benefits of bone graft containment, restored intervertebral and foraminal height, and a more repeatable, stable procedure compared to interbody fusion with graft material alone. Due to concerns regarding postoperative stability, loss of lordosis, and subsidence or migration of the implant, interbody cages are commonly used with supplemental fixation such as pedicle screw systems or anterior plates. While providing additional stability, supplemental fixation techniques increase operative time, exposure, cost, and morbidity. The VariLift((r)) Interbody Fusion System (VariLift((r)) system) has been developed as a standalone solution to provide the benefits of intervertebral fusion cages without the requirement of supplemental fixation. The VariLift((r)) system, FDA-cleared for standalone use in both the cervical and lumbar spine, is implanted in a minimal profile and then expanded in situ to provide segmental stability, restored lordosis, and a large graft chamber. Preclinical testing and analyses have found that the VariLift((r)) System is durable, and reduces stresses that may contribute to subsidence and migration of other standalone interbody cages. Fifteen years of clinical development with the VariLift((r)) system have demonstrated positive clinical outcomes, continued patient maintenance of segmental stability and lordosis, and no evidence of implant migration. The purpose of this report is to describe the VariLift((r)) system, including implant characteristics, principles of operation, indications for use, patient selection criteria, surgical technique, postoperative care, preclinical testing, and clinical experience. The VariLift((r)) System represents an improved surgical option for a stable interbody fusion without requiring supplemental fixation. PMID- 26060415 TI - Technology update: intracardiac echocardiography - a review of the literature. AB - The development of new imaging tools helps in better investigation of cardiac structures and function by showing detailed images during interventional procedures. Intracardiac echocardiography plays a pivotal role as an intraoperative real-time imaging tool during invasive cardiac procedures. Initially, this echocardiographic technique was particularly useful when transthoracic image quality was insufficient and to avoid general anesthesia for transesophageal imaging. Nowadays, intracardiac echocardiography is routinely used in several cardiac invasive laboratories to support several types of procedures, such as extraction and implantation of cardiac devices, electrophysiological mapping, ablation, and endomyocardial biopsies. This review gives an overview of the basic principles of intracardiac echocardiography and examines its applications in the different settings of invasive cardiology. PMID- 26060416 TI - Post-market clinical research conducted by medical device manufacturers: a cross sectional survey. AB - BACKGROUND: In the US, once a medical device is made available for use, several requirements have been established by the US Food and Drug Administration (FDA) to ensure ongoing post-market surveillance of device safety and effectiveness. Our objective was to determine how commonly medical device manufacturers initiate post-market clinical studies or augment FDA post-market surveillance requirements for higher-risk devices that are most often approved via the FDA's pre-market approval (PMA) pathway. METHODS AND RESULTS: We conducted a cross-sectional survey of 47 manufacturers with operations in California, Minnesota, and Massachusetts who market devices approved via the PMA pathway. Among 22 respondents (response rate =47%), nearly all self-reported conducting post-market clinical research studies, commonly between 1 and 5; only 1 respondent reported never conducting post-market clinical research studies. While manufacturers most often engaged in these studies to satisfy FDA requirements, other reasons were reported, including performance monitoring and surveillance and market acceptance initiatives. Risks of conducting and not conducting post-market clinical research studies were described through open-ended response to questions. CONCLUSION: Medical device manufacturers commonly initiate post-market clinical studies at the request of the FDA. Clinical data from these studies should be integrated into national post-market surveillance initiatives. PMID- 26060417 TI - Peyton's four-step approach: differential effects of single instructional steps on procedural and memory performance - a clarification study. AB - BACKGROUND: Although Peyton's four-step approach is a widely used method for skills-lab training in undergraduate medical education and has been shown to be more effective than standard instruction, it is unclear whether its superiority can be attributed to a specific single step. PURPOSE: We conducted a randomized controlled trial to investigate the differential learning outcomes of the separate steps of Peyton's four-step approach. METHODS: Volunteer medical students were randomly assigned to four different groups. Step-1 group received Peyton's Step 1, Step-2 group received Peyton's Steps 1 and 2, Step-3 group received Peyton's Steps 1, 2, and 3, and Step-3mod group received Peyton's Steps 1 and 2, followed by a repetition of Step 2. Following the training, the first independent performance of a central venous catheter (CVC) insertion using a manikin was video-recorded and scored by independent video assessors using binary checklists. The day after the training, memory performance during delayed recall was assessed with an incidental free recall test. RESULTS: A total of 97 participants agreed to participate in the trial. There were no statistically significant group differences with regard to age, sex, completed education in a medical profession, completed medical clerkships, preliminary memory tests, or self-efficacy ratings. Regarding checklist ratings, Step-2 group showed a superior first independent performance of CVC placement compared to Step-1 group (P<0.001), and Step-3 group showed a superior performance to Step-2 group (P<0.009), while Step-2 group and Step-3mod group did not differ (P=0.055). The findings were similar in the incidental free recall test. CONCLUSION: Our study identified Peyton's Step 3 as being the most crucial part within Peyton's four step approach, contributing significantly more to learning success than the previous steps and reaching beyond the benefit of a mere repetition of skills demonstration. PMID- 26060418 TI - Dengue Hemorrhagic Fever in a Japanese Traveler with Pre-existing Japanese Encephalitis Virus Antibody. AB - An adult Japanese man who had just returned from Thailand developed dengue hemorrhagic fever (DHF). A primary infection of dengue virus (DENV) was confirmed, specifically DENV serotype 2 (DENV-2), on the basis of the detection of the virus genome, a significant increase in the neutralizing antibody and the isolation of DENV-2. DHF is often observed following a secondary infection from another serotype of dengue virus, particularly in children, but this case was a primary infection of DENV. Japan is a non-endemic country for dengue disease. In fact, only Japanese encephalitis (JE) is known to be a member of the endemic flavivirus family. In this study, IgG antibody against Japanese encephalitis virus (JEV) was detected. JEV belongs to the family of dengue virus and prevails in Japan, particularly Kyushu. Among many risk factors for the occurrence of DHF, a plausible candidate could be a cross-reactive antibody-dependent enhancement (ADE) mechanism caused by JEV antibody. This indicates that most Japanese travelers who living in dengue non-endemic areas, particularly Kyushu, should be aware of the occurrence of DHF. PMID- 26060419 TI - Re: Treatment of Parasitic Skin Diseases with Dimeticones A New Family of Compounds with a Purely Physical Mode of Action. AB - The article on use of dimeticone for treatment of epidermal parasitic skin diseases is potentially confusing and misleading because, in a practical sense, only head louse infestation can be treated with this material. Scabies mites are unaffected by silicones and use of dimeticone against other ectoparasites may have unwanted side effects such as anaphylactiform reactions or increased risk of pathogen transmission. PMID- 26060420 TI - Author's Response to Burgess. PMID- 26060421 TI - Mediastinal Lymphadenopathy: Melioidosis Mimicking Tuberculosis. AB - Melioidosis has protean manifestations and often mimics other disease processes. We present a case of a gentleman presenting with chronic cough whose initial radiographic findings of a cavitatory lung lesion and mediastinal lymphadenopathy were suggestive of tuberculosis. This case highlights the important role that bronchoscopy and endobronchial ultrasound can play in the diagnosis of melioidosis in patients presenting with mediastinal lymphadenopathy whose initial microbiological findings from sputum are negative for tuberculosis. PMID- 26060422 TI - Households with Insufficient Bednets in a Village with Sufficient Bednets: Evaluation of Household Bednet Coverage Using Bednet Distribution Index in Xepon District, Lao PDR. AB - In Lao PDR, the National Malaria Control Program (NMCP) evaluates bednet coverage, often at the village level, using a coverage target of one net per 2.5 (or fewer) persons in a given population. However, in villages that meet the target, not all households necessarily meet the target or utilize all available bednets. This study explored households that fell short of the target and household utilization of bednets in villages that met the target of bednet coverage set by the NMCP. The person per net ratio (PPNR), which is defined as the population divided by the number of available bednets in a household/village, was used to determine whether a household/village met the NMCP target. Using a household survey, we collected and analyzed the data of 635 households in 17 villages in Xepon district in 2012. Households that fell short of the target (households with a PPNR of > 2.5 or no bednet) existed in every village. The proportion of these households differed greatly among the villages, ranging from 3.4-50%, with some households falling far short. Of the 635 households, 275 (43.5%) had at least one bednet that was not being used on the night preceding the survey and 131 (20.6%) had at least two. In conclusion, in villages that met the NMCP target, a considerable number of households fell short of the target, and the available bednets were not fully utilized in many of the surveyed households. PMID- 26060423 TI - Abundant Aedes (Stegomyia) aegypti aegypti mosquitoes in the 2014 dengue outbreak area of Mozambique. AB - In early 2014, dengue cases were reported from northern Mozambique, 30 years after the last outbreak. We identified potential dengue vector species in three northern towns, Pemba, Nampula and Nacala, and one southern town, Maputo, during the outbreak in April 2014. A major dengue vector species, Aedes (Stegomyia) aegypti, was found in all these towns. The dominant vector subspecies in the northern towns was Aedes aegypti aegypti, while Ae. aegypti formosus was dominant in Maputo. Considering the high proportion of Ae. aegypti aegypti and its high vector competence, the findings from this study suggest that Ae. aegypti aegypti was responsible for the outbreak in northern Mozambique. PMID- 26060424 TI - Evaluation of Rapid Neutralizing Antibody Detection Test against Rabies Virus in Human Sera. AB - Rapid and easy determination of protective neutralization antibody (NAb) against rabies in the field is very important for an early and effective response to rabies in both animal and human health sectors. The rapid neutralizing antibody detection test (RAPINA), first developed in 2009 and then improved in 2012, is a quick test allowing detection of 0.5 IU/ml antibodies in human and animal sera or plasma. This study aimed to assess the RAPINA test by comparison with rapid focus fluorescence inhibition test (RFFIT), using 214 sera of vaccinated and unvaccinated professional dog butchers, laboratory workers and rabies patients in Vietnam. The sensitivity, specificity, false negative rate, false positive rate and concordance of the RAPINA test as compared to RFFIT were 100%, 98.34%, 0%, 1.66% and 98.6%, respectively. The positive predictive value and negative predictive value were 91.7% and 100%, respectively when RAPINA test was used. With its remarkable sensitivity, specificity and easy implementation, RAPINA test can be used for rapid determination of NAb in the field. PMID- 26060425 TI - Motivations of nursing students regarding their educational preparation for mental health nursing in Australia and the United Kingdom: a survey evaluation. AB - BACKGROUND: There has been much debate by both academics and clinical agencies about the motivations and abilities of nurse graduates to work in mental health nursing. The aim of this study was to recruit student nurses from a dedicated mental health nursing program in the United Kingdom (UK) and a comprehensive nursing program in Australia and illuminate their motivations towards considering mental health nursing as a career choice. METHODS: This study comprised of two UK and four Australian Schools of Nursing within Universities. A 12 item survey was developed for the purpose of this study and was checked for face validity by experienced mental health nurses. Convenience sampling was used and 395 responses were received. RESULTS: The comprehensive program represented by the Australian sample, revealed a third of respondents indicated that mental health nursing was definitely not a career option, while only 8 % of the UK specialised program reported mental health nursing was not seven for them. In both groups a higher level of motivation to work in mental health emanated from personal experience and/or work experience/exposure to mental health care. CONCLUSIONS: A greater focus on clinical exposure in comprehensive programs could enhance professional experience needed to increase student motivations for mental health nursing. PMID- 26060426 TI - Paracrine factors from adipose-mesenchymal stem cells enhance metastatic capacity through Wnt signaling pathway in a colon cancer cell co-culture model. AB - BACKGROUND: Mesenchymal stem cells (MSCs) in tumors have emerged as progenitors involved in stroma formation and metastasis of cancers, partially owing to their abilities to differentially express paracrine factors related to the proliferation and invasion of cancer cells. In this regard, increasing evidence has shown that MSCs have impacts on the malignancy of colon cancer, however, the underpinning mechanisms by which MSCs promote cancer metastasis remain elusive. METHODS: To investigate the crosstalk between adipose-derived MSCs (AMSCs) isolated from adipose tissues and colon cancer cells, a co-culture transwell model of AMSCs and colon cancer cells was employed, and the activation of Wnt signaling and paracrine factors in colon cancer cells and AMSCs were measured. RESULTS: The results showed that AMSCs could enhance the metastatic capacity of colon cancer cells with an elevated expression of mesenchymal-epithelial transition (EMT)-associated genes in a contact-dependent manner. Reciprocally, colon cancer cells were able to induce AMSCs to produce metastasis-related factors and cytokines, such as FGF10, VEGFC and matrix metalloproteinases (MMPs) in part through a mechanism of an activation of Wnt signaling, by which these factors in turn activate Wnt signaling of colon cancer cells. Intriguingly, an inhibition of Wnt signaling leads a reduced capacity of invasion and colony formation of colon cancer cells in vitro, and the tumorigenicity of cancer cells in a murine model. CONCLUSIONS: These findings thus suggest that the crosstalk between the Wnt signaling of cancer cells and paracrine factors of AMSCs has an implication in colon cancer malignancy. This study thus uncovers a novel Wnt paracrine factors mediated-crosstalk between colon cancer cells and AMSCs in cancer malignancy. PMID- 26060427 TI - Application of Novel Amino-Functionalized NZVI@SiO2 Nanoparticles to Enhance Anaerobic Granular Sludge Removal of 2,4,6-Trichlorophenol. AB - A novel amino-functionalized silica-coated nanoscale zerovalent iron (NZVI@SiO2 NH2) was successfully synthesized by using one-step liquid-phase method with the surface functionalization of nanoscale zerovalent iron (NZVI) to enhance degradation of chlorinated organic contaminants from anaerobic microbial system. NZVI@SiO2-NH2 nanoparticles were synthesized under optimal conditions with the uniform core-shell structure (80-100 nm), high loading of amino functionality (~0.9 wt%), and relatively large specific surface area (126.3 m(2)/g). The result demonstrated that well-dispersed NZVI@SiO2-NH2 nanoparticle with nFe(0)-core and amino-functional silicon shell can effectively remove 2,4,6-trichlorophenol (2,4,6-TCP) in the neutral condition, much higher than that of NZVI. Besides, the surface-modified nanoparticles (NZVI@SiO2-NH2) in anaerobic granule sludge system also showed a positive effect to promote anaerobic biodechlorination system. More than 94.6% of 2,4,6-TCP was removed from the combined NZVI@SiO2-NH2-anaerobic granular sludge system during the anaerobic dechlorination processes. Moreover, adding the appropriate concentration of NZVI@SiO2-NH2 in anaerobic granular sludge treatment system can decrease the toxicity of 2,4,6-TCP to anaerobic microorganisms and improved the cumulative amount of methane production and electron transport system activity. The results from this study clearly demonstrated that the NZVI@SiO2-NH2/anaerobic granular sludge system could become an effective and promising technology for the removal of chlorophenols in industrial wastewater. PMID- 26060428 TI - Alteration of Genetic Make-up in Karnal Bunt Pathogen (Tilletia indica) of Wheat in Presence of Host Determinants. AB - Alteration of genetic make-up of the isolates and monosporidial strains of Tilletia indica causing Karnal bunt (KB) disease in wheat was analyzed using DNA markers and SDS-PAGE. The generation of new variation with different growth characteristics is not a generalized feature and is not only dependant on the original genetic make up of the base isolate/monosporidial strains but also on interaction with host. Host determinant(s) plays a significant role in the generation of variability and the effect is much pronounced in monosporidial strains with narrow genetic base as compared to broad genetic base. The most plausible explanation of genetic variation in presence of host determinant(s) are the recombination of genetic material from two different mycelial/sporidia through sexual mating as well as through para-sexual means. The morphological and development dependent variability further suggests that the variation in T. indica strains predominantly derived through the genetic rearrangements. PMID- 26060429 TI - Construction of a High-Quality Yeast Two-Hybrid Library and Its Application in Identification of Interacting Proteins with Brn1 in Curvularia lunata. AB - Curvularia lunata is an important maize foliar fungal pathogen that distributes widely in maize growing area in China, and several key pathogenic factors have been isolated. An yeast two-hybrid (Y2H) library is a very useful platform to further unravel novel pathogenic factors in C. lunata. To construct a high quality full length-expression cDNA library from the C. lunata for application to pathogenesis-related protein-protein interaction screening, total RNA was extracted. The SMART (Switching Mechanism At 5' end of the RNA Transcript) technique was used for cDNA synthesis. Double-stranded cDNA was ligated into the pGADT7-Rec vector with Herring Testes Carrier DNA using homologous recombination method. The ligation mixture was transformed into competent yeast AH109 cells to construct the primary cDNA library. Eventually, a high qualitative library was successfully established according to an evaluation on quality. The transformation efficiency was about 6.39 *10(5) transformants/3 MUg pGADT7-Rec. The titer of the primary cDNA library was 2.5*10(8) cfu/mL. The numbers for the cDNA library was 2.46*10(5). Randomly picked clones show that the recombination rate was 88.24%. Gel electrophoresis results indicated that the fragments ranged from 0.4 kb to 3.0 kb. Melanin synthesis protein Brn1 (1,3,8-hydroxynaphthalene reductase) was used as a "bait" to test the sufficiency of the Y2H library. As a result, a cDNA clone encoding VelB protein that was known to be involved in the regulation of diverse cellular processes, including control of secondary metabolism containing melanin and toxin production in many filamentous fungi was identified. Further study on the exact role of the VelB gene is underway. PMID- 26060430 TI - Analysis of Fungicide Sensitivity and Genetic Diversity among Colletotrichum Species in Sweet Persimmon. AB - Anthracnose, caused by Colletotrichum gloeosporioides (C. gloeosporioides; Teleomorph: Glomerella cingulata), is the most destructive disease that affects sweet persimmon production worldwide. However, the biology, ecology, and genetic variations of C. gloeosporioides remain largely unknown. Therefore, in this study, the development of fungicide resistance and genetic diversity among an anthracnose pathogen population with different geographical origins and the exposure of this population to different cultivation strategies were investigated. A total of 150 pathogen isolates were tested in fungicide sensitivity assays. Five of the tested fungicides suppressed mycelial pathogen growth effectively. However, there were significant differences in the sensitivities exhibited by the pathogen isolates examined. Interestingly, the isolates obtained from practical management orchards versus organic cultivation orchards showed no differences in sensitivity to the same fungicide. PCR restriction fragment length polymorphism (RFLP) analyses were performed to detect internal transcribed spacer regions and the beta-tubulin and glutamine synthetase genes of the pathogens examined. Both the glutamine synthetase and beta-tubulin genes contained a complex set of polymorphisms. Based on these results, the pathogens isolated from organic cultivation orchards were found to have more diversity than the isolates obtained from the practical management orchards. PMID- 26060431 TI - Validation and Application of a Real-time PCR Protocol for the Specific Detection and Quantification of Clavibacter michiganensis subsp. sepedonicus in Potato. AB - Clavibacter michiganensis subsp. sepedonicus (Cms) multiplies very rapidly, passing through the vascular strands and into the stems and petioles of a diseased potato. Therefore, the rapid and specific detection of this pathogen is highly important for the effective control of the pathogen. Although several PCR assays have been developed for detection, they cannot afford specific detection of Cms. Therefore, in this study, a computational genome analysis was performed to compare the sequenced genomes of the C. michiganensis subspecies and to identify an appropriate gene for the development of a subspecies-specific PCR primer set (Cms89F/R). The specificity of the primer set based on the putative phage-related protein was evaluated using genomic DNA from seven isolates of Cms and 27 other reference strains. The Cms89F/R primer set was more specific and sensitive than the existing assays in detecting Cms in in vitro using Cms cells and its genomic DNA. This assay was also able to detect at least 1.47*10(2) copies/MUl of cloned-amplified target DNA, 5 fg of DNA using genomic DNA or 10( 6) dilution point of 0.12 at OD600 units of cells per reaction using a calibrated cell suspension. PMID- 26060432 TI - Evaluation of Bt-cotton Genotypes for Resistance to Cotton Leaf Curl Disease under High Inoculum Pressure in the Field and Using Graft Inoculation in Glasshouse. AB - Bt-cotton germplasm, consisting of 75 genotypes was evaluated against cotton leaf curl disease (CLCuD) under high inoculum pressure in the field and using graft inoculation in glasshouse by visual symptom scoring assessments. None of the tested genotype was found disease free under both evaluation tests. Under field conditions in 2011, 3 genotypes were found resistant, 4 moderately resistant, 3 tolerant, 2 moderately susceptible and one susceptible; in 2012, 3 genotypes were tolerant, 7 moderately susceptible, 5 susceptible and 38 highly susceptible; in 2013, one was moderately susceptible and 51 were highly susceptible with varying degree of percent disease index (PDI) and severity index (SI). However, through graft evaluation in glasshouse, none of the graft inoculated plant was symptomless. All tested genotypes showed disease symptoms with SI values ranging between 5.0 and 6.0, and latent period between 12 and 14 days. Of the 75 genotypes evaluated using graft inoculation, 11 were found susceptible with SI values of 5.0 to 5.4 while remaining 64 were highly susceptible with SI values of 5.5 to 6.0. Inoculated plants of all tested genotypes exhibited severe disease symptoms within 10 days after the appearance of initial symptoms. No reduction in SI value was observed until the end of the experiment i.e., 90 days after grafting. Information generated under the present study clearly demonstrates that no sources of resistance to CLCuD are available among the tested Bt-cotton genotypes. So, a breeding programme is needed to introgress the CLCuD-resistance from other resistant sources to agronomically suitable Bt-cotton genotypes. PMID- 26060433 TI - Rhizosphere Inhibition of Cucumber Fusarium Wilt by Different Surfactin- excreting Strains of Bacillus subtilis. AB - Bacillus subtilis B006 strain effectively suppresses the cucumber fusarium wilt caused by Fusarium oxysporum f. sp. cucumerinum (Foc). The population dynamics of Foc, strain B006 and its surfactin over-producing mutant B841 and surfactin deficient mutant B1020, in the rhizosphere were determined under greenhouse conditions to elucidate the importance of the lipopeptides excreted by these strains in suppressing Foc. Results showed that B. subtilis strain B006 effectively suppressed the disease in natural soil by 42.9%, five weeks after transplanting, whereas B841 and B1020 suppressed the disease by only 22.6% and 7.1%, respectively. Quantitative PCR assays showed that effective colonization of strain B006 in the rhizosphere suppressed Foc propagation by more than 10 times both in nursery substrate and in field-infected soil. Reduction of Foc population at the cucumber stems in a range of 0.96 log10 ng/g to 2.39 log10 ng/g was attained at the third and the fifth weeks of B006 treatment in nursery substrate. In field-infected soil, all three treatments with B. subtilis suppressed Foc infection, indicated by the reduction of Foc population at a range of 2.91 log10 ng/g to 3.36 log10 ng/g at the stem base, one week after transplanting. This study reveals that the suppression of fusarium wilt disease is affected by the effective colonization of the surfactin-producing B. subtilis strain in the rhizosphere. These results improved our understanding of the biocontrol mechanism of the B. subtilis strain B006 in the natural soil and facilitate its application as biocontrol agent in the field. PMID- 26060434 TI - Bacillus oryzicola sp. nov., an Endophytic Bacterium Isolated from the Roots of Rice with Antimicrobial, Plant Growth Promoting, and Systemic Resistance Inducing Activities in Rice. AB - Biological control of major rice diseases has been attempted in several rice growing countries in Asia during the last few decades and its application using antagonistic bacteria has proved to be somewhat successful for controlling various fungal diseases in field trials. Two novel endophytic Bacillus species, designated strains YC7007 and YC7010(T), with anti-microbial, plant growth promoting, and systemic resistance-inducing activities were isolated from the roots of rice in paddy fields at Jinju, Korea, and their multifunctional activities were analyzed. Strain YC7007 inhibited mycelial growth of major rice fungal pathogens strongly in vitro. Bacterial blight and panicle blight caused by Xanthomonas oryzae pv. oryzae (KACC 10208) and Burkholderia glumae (KACC 44022), respectively, were also suppressed effectively by drenching a bacterial suspension (10(7) cfu/ml) of strain YC7007 on the rhizosphere of rice. Additionally, strain YC7007 promoted the growth of rice seedlings with higher germination rates and more tillers than the untreated control. The taxonomic position of the strains was also investigated. Phylogenetic analyses based on 16S rRNA gene sequences indicated that both strains belong to the genus Bacillus, with high similarity to the closely related strains, Bacillus siamensis KACC 15859(T) (99.67%), Bacillus methylotrophicus KACC 13105(T) (99.65%), Bacillus amyloliquefaciens subsp. plantarum KACC 17177(T) (99.60%), and Bacillus tequilensis KACC 15944(T) (99.45%). The DNA-DNA relatedness value between strain YC7010(T) and the most closely related strain, B. siamensis KACC 15859(T) was 50.4+/-3.5%, but it was 91.5+/-11.0% between two strains YC7007 and YC7010(T), indicating the same species. The major fatty acids of two strains were anteiso C15:0 and iso C15:0. Both strains contained MK-7 as a major respiratory quinone system. The G+C contents of the genomic DNA of two strains were 50.5 mol% and 51.2 mol%, respectively. Based on these polyphasic studies, the two strains YC7007 and YC7010(T) represent novel species of the genus Bacillus, for which the name Bacillus oryzicola sp. nov. is proposed. The type strain is YC7010(T) (= KACC 18228(T)). Taken together, our findings suggest that novel endophytic Bacillus strains can be used for the biological control of rice diseases. PMID- 26060436 TI - Effects of Ionizing Radiation on Postharvest Fungal Pathogens. AB - Postharvest diseases cause losses in a wide variety of crops around the world. Irradiation, a useful nonchemical approach, has been used as an alternative treatment for fungicide to control plant fungal pathogens. For a preliminary study, ionizing radiations (gamma, X-ray, or e-beam irradiation) were evaluated for their antifungal activity against Botrytis cinerea, Penicillium expansum, and Rhizopus stolonifer through mycelial growth, spore germination, and morphological analysis under various conditions. Different fungi exhibited different radiosensitivity. The inhibition of fungal growth showed in a dose-dependent manner. Three fungal pathogens have greater sensitivity to the e-beam treatment compared to gamma or X-ray irradiations. The inactivation of individual fungal viability to different irradiations can be considered between 3-4 kGy for B. cinerea and 1-2 kGy for P. expansum and R. stolonifer based on the radiosensitive and radio-resistant species, respectively. These preliminary data will provide critical information to control postharvest diseases through radiation. PMID- 26060435 TI - Antagonistic Activities of Bacillus spp. Strains Isolated from Tidal Flat Sediment Towards Anthracnose Pathogens Colletotrichum acutatum and C. gloeosporioides in South Korea. AB - Anthracnose is a fungal disease caused by Colletotrichum species that is detrimental to numerous plant species. Anthracnose control with fungicides has both human health and environmental safety implications. Despite increasing public concerns, fungicide use will continue in the absence of viable alternatives. There have been relatively less efforts to search antagonistic bacteria from mudflats harboring microbial diversity. A total of 420 bacterial strains were isolated from mudflats near the western sea of South Korea. Five bacterial strains, LB01, LB14, HM03, HM17, and LB15, were characterized as having antifungal properties in the presence of C. acutatum and C. gloeosporioides. The three Bacillus atrophaeus strains, LB14, HM03, and HM17, produced large quantities of chitinase and protease enzymes, whereas the B. amyloliquefaciens strain LB01 produced protease and cellulase enzymes. Two important antagonistic traits, siderophore production and solubilization of insoluble phosphate, were observed in the three B. atrophaeus strains. Analyses of disease suppression revealed that LB14 was most effective for suppressing the incidence of anthracnose symptoms on pepper fruits. LB14 produced antagonistic compounds and suppressed conidial germination of C. acutatum and C. gloeosporioides. The results from the present study will provide a basis for developing a reliable alternative to fungicides for anthracnose control. PMID- 26060437 TI - Reaction of Cauliflower Genotypes to Black Rot of Crucifers. AB - This study aimed to evaluate six cauliflower genotypes regarding their resistance to black rot and their production performance. To do so, it was conducted two field experiments in Ipameri, Goias, Brazil, in 2012 and 2013. It was used a randomized block design, with four replications (total of 24 plots). Each plot consisted of three planting lines 2.5 m long (six plants/line), spaced 1.0 m apart, for a total area of 7.5 m(2). Evaluations of black rot severity were performed at 45 days after transplanting, this is, 75 days after sowing (DAS), and yield evaluations at 90 to 105 DAS. The Verona 184 genotype was the most resistant to black rot, showing 1.87 and 2.25% of leaf area covered by black rot symptom (LACBRS) in 2012 and 2013. However, it was not among the most productive materials. The yield of the genotypes varied between 15.14 and 25.83 t/ha in both years, Lisvera F1 (21.78 and 24.60 t/ha) and Cindy (19.95 and 23.56 t/ha) being the most productive. However, Lisvera F1 showed 6.37 and 9.37% of LACBRS and Cindy showed 14.25 and 14.87% of LACBRS in 2012 and 2013, being both considered as tolerant to black rot. PMID- 26060438 TI - Isolation and Physiological Characterization of a Novel Algicidal Virus Infecting the Marine Diatom Skeletonema costatum. AB - Diatoms are a major component of the biological community, serving as the principal primary producers in the food web and sustaining oxygen levels in aquatic environments. Among marine planktonic diatoms, the cosmopolitan Skeletonema costatum is one of the most abundant and widespread species in the world's oceans. Here, we report the basic characteristics of a new diatom infecting S. costatum virus (ScosV) isolated from Jaran Bay, Korea, in June 2008. ScosV is a polyhedral virus (45-50 nm in diameter) that propagates in the cytoplasm of host cells and causes lysis of S. costatum cultures. The infectivity of ScosV was determined to be strain- rather than species-specific, similar to other algal viruses. The burst size and latent period were roughly estimated at 90-250 infectious units/cell and <48 h, respectively. PMID- 26060439 TI - NPR1 is Instrumental in Priming for the Enhanced flg22-induced MPK3 and MPK6 Activation. AB - Pathogen-associated molecular patterns (PAMPs) activate mitogen-activated protein kinases (MAPKs), essential components of plant defense signaling. Salicylic acid (SA) is also central to plant resistance responses, but its specific role in regulation of MAPK activation is not completely defined. We have investigated the role of SA in PAMP-triggered MAPKs pathways in Arabidopsis SA-related mutants, specifically in the flg22-triggered activation of MPK3 and MPK6. cim6, sid2, and npr1 mutants exhibited wild-type-like flg22-triggered MAPKs activation, suggesting that impairment of SA signaling has no effect on the flg22-triggered MAPKs activation. Pretreatment with low concentrations of SA enhanced flg22 induced MPK3 and MPK6 activation in all seedlings except npr1, indicating that NPR1 is involved in SA-mediated priming that enhanced flg22-induced MAPKs activation. PMID- 26060440 TI - Activation of Pathogenesis-related Genes by the Rhizobacterium, Bacillus sp. JS, Which Induces Systemic Resistance in Tobacco Plants. AB - Plant growth promoting rhizobacteria (PGPR) are known to confer disease resistance to plants. Bacillus sp. JS demonstrated antifungal activities against five fungal pathogens in in vitro assays. To verify whether the volatiles of Bacillus sp. JS confer disease resistance, tobacco leaves pre-treated with the volatiles were damaged by the fungal pathogen, Rhizoctonia solani and oomycete Phytophthora nicotianae. Pre-treated tobacco leaves had smaller lesion than the control plant leaves. In pathogenesis-related (PR) gene expression analysis, volatiles of Bacillus sp. JS caused the up-regulation of PR-2 encoding beta-1,3 glucanase and acidic PR-3 encoding chitinase. Expression of acidic PR-4 encoding chitinase and acidic PR-9 encoding peroxidase increased gradually after exposure of the volatiles to Bacillus sp. JS. Basic PR-14 encoding lipid transfer protein was also increased. However, PR-1 genes, as markers of salicylic acid (SA) induced resistance, were not expressed. These results suggested that the volatiles of Bacillus sp. JS confer disease resistance against fungal and oomycete pathogens through PR genes expression. PMID- 26060441 TI - Is perioperative home the future of surgical patient care? PMID- 26060442 TI - Prevention of fatal hepatic complication in schistosomiasis by inhibition of CETP. AB - Schistosoma japonicum, once endemic all the East Asia, remains as a serious public health problem in certain regions. Ectopic egg embryonation in the liver causes granulomatosis and eventually fatal cirrhosis, so that prevention of this process is one of the keys to reduce its mortality. The embryonation requires cholesteryl ester from HDL of the host blood for egg yolk formation, and this reaction is impaired from the abnormal large HDL in genetic cholesteryl ester transfer protein (CETP) deficiency. When CETP was expressed in mice that otherwise lack this protein, granulomatosis of the liver was shown increased compared to the wild type upon infection of Schistosoma japonicum. The CETP deficiencies accumulated exclusively in East Asia, from Indochina to Siberia, so that Shistosomiasis can be a screening factor for this accumulation. CD36 related protein (CD36RP) was identified as a protein for this reaction, cloned from the cDNA library of Schistosoma japonicum with 1880-bp encoding 506 amino acids. The antibody against the extracellular loop of CD36RP inhibited cholesteryl ester uptake from HDL and suppressed egg embryonation in culture. Therefore, inhibition of CETP is a potential approach to prevent liver granulomatosis and thereby fatal liver cirrhosis in the infection of Schistosoma japonicum. PMID- 26060443 TI - Growing applications of FDG PET-CT imaging in non-oncologic conditions. AB - As the number of clinical applications of 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET-CT) grows, familiarity with the conditions that can be diagnosed by this modality and when relevant pieces of additional information can be obtained becomes increasingly important for both requesting physicians and nuclear medicine physicians or radiologists who interpret the findings. Apart from its heavy use in clinical oncology, FDG PET-CT is widely used in a variety of non-oncologic conditions interconnecting to such disciplines as general internal medicine, infectious diseases, cardiology, neurology, surgery, traumatology, orthopedics, pediatrics, endocrinology, rheumatology, psychiatry, neuropsychology, and cognitive neuroscience. The aim of this review was to summarize the current evidence of FDG PET-CT applications in evaluating non-oncologic pathologies and the relevant information it can add to achieve a final diagnosis. PMID- 26060444 TI - GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats. AB - Hydrogen sulfide (H2S) is a gasotransmitter that regulates cardiovascular functions. The present study aimed to determine the protective effect of slow releasing H2S donor GYY4137 on myocardial ischemia and reperfusion (I/R) injury and to investigate the possible signaling mechanisms involved. Male Sprague Dawley rats were treated with GYY4137 at 12.5 mg/(kg.day), 25 mg/(kg.day) or 50 mg/(kg.day) intraperitoneally for 7 days. Then, rats were subjected to 30 minutes of left anterior descending coronary artery occlusion followed by reperfusion for 24 hours. We found that GYY4137 increased the cardiac ejection fraction and fractional shortening, reduced the ischemia area, alleviated histological injury and decreased plasma creatine kinase after myocardial I/R. Both H2S concentration in plasma and cystathionine-gamma-lyase (CSE) activity in the myocardium were enhanced in the GYY4137 treated groups. GYY4137 also decreased malondialdehyde and myeloperoxidase levels in serum, attenuated superoxide anion level and suppressed phosphorylation of mitogen activated protein kinases in the myocardium after I/R. Meanwhile, GYY4137 increased the expression of Bcl-2 but decreased the expression of Bax, caspase-3 activity and apoptosis in the myocardium. The data suggest that GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis. PMID- 26060445 TI - In vitro activity and in vivo efficacy of a combination therapy of diminazene and chloroquine against murine visceral leishmaniasis. AB - The present study evaluated the in vitro activity and in vivo efficacy of diminazene combined with chloroquine as a potential drug against Leishmania donovani. Amphotericin B was used as a positive control drug. In vitro activity involved incubation of various drug concentrations with promastigotes or vero cells in culture before determination of parasite growth inhibition or cell death while in vivo evaluations involved infection of various mice groups with virulent L. donovani parasites and treatment with test drug compounds following disease establishment. Weight changes in experimental mice were also evaluated before infection and throughout the experiment. The results indicated that the diminazene-chloroquine combination was at least nine times more efficacious than individual drugs in killing promastigotes in culture. The diminazene-chloroquine combination was safer (Ld50 = 0.03+/-0.04) than Amphotericin B (Ld50 = 0.02+/ 0.01). Body weight in infected mice increased significantly (P = 0.0007) from day 7 to day 37 following infection (P = 0.026). However, body weight remained comparable in all mice groups during treatment (P = 0.16). The diminazene chloroquine combination significantly reduced splenic parasite numbers as compared to individual drug therapies (P = 0.0001) although Amphotericin B was still more efficacious than any other treatment (P = 0.0001). Amongst the test compounds, the diminazene-chloroquine combination showed the lowest level of IgG antibody responses with results indicating significant negative correlation between antileishmanial antibody responses and protection against disease. These findings demonstrate the positive advantage and the potential use of a combined therapy of diminazene-chloroquine over the constituent drugs. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds. PMID- 26060446 TI - Technetium-99m-labeled annexin V imaging for detecting prosthetic joint infection in a rabbit model. AB - Accurate and timely diagnosis of prosthetic joint infection is essential to initiate early treatment and achieve a favorable outcome. In this study, we used a rabbit model to assess the feasibility of technetium-99m-labeled annexin V for detecting prosthetic joint infection. Right knee arthroplasty was performed on 24 New Zealand rabbits. After surgery, methicillin-susceptible Staphylococcus aureus was intra-articularly injected to create a model of prosthetic joint infection (the infected group, n = 12). Rabbits in the control group were injected with sterile saline (n = 12). Seven and 21 days after surgery, technetium-99m-labeled annexin V imaging was performed in 6 rabbits of each group. Images were acquired 1 and 4 hours after injection of technetium-99m-labeled annexin V (150 MBq). The operated-to-normal-knee activity ratios were calculated for quantitative analysis. Seven days after surgery, increased technetium-99m-labeled annexin V uptake was observed in all cases. However, at 21 days a notable decrease was found in the control group, but not in the infected group. The operated-to-normal knee activity ratios of the infected group were 1.84 +/- 0.29 in the early phase and 2.19 +/- 0.34 in the delay phase, both of which were significantly higher than those of the control group (P = 0.03 and P = 0.02). The receiver operator characteristic curve analysis showed that the operated-to-normal-knee activity ratios of the delay phase at 21 days was the best indicator, with an accuracy of 80%. In conclusion, technetium-99m-labeled annexin V imaging could effectively distinguish an infected prosthetic joint from an uninfected prosthetic joint in a rabbit model. PMID- 26060447 TI - Increased serum IL-10 in lupus patients promotes apoptosis of T cell subsets via the caspase 8 pathway initiated by Fas signaling. AB - We sought to investigate the expression of Fas and FasL on T cell surface and caspase 8 involvement in T cell apoptosis promoted by serum IL-10 in systemic lupus erythematosus (SLE) patients. Cells and sera were obtained from 35 SLE patients. Apoptosis of T cells in patients with SLE was increased and associated with the SLE disease activity index (SLEDAI). Elevated expression of Fas and FasL on T cell surface contributed to increased apoptosis of T cells. Increased IL-10 in the sera of SLE patients was capable of inducing Fas and FasL expression on CD4(+)T cell surface, promoting apoptosis of this cell subset. Decreased IL-10 serum levels and low expression of Fas were found in 5 patients of the first follow-up group after 2-month treatment. In another group with one-year treatment, the SLEDAI declined to inactive scores. Serum IL-10 was decreased significantly, and expression of Fas and FasL on T cells was also reduced. Declined apoptosis was predominant only in CD4(+)T cell subset. When sera with high level of IL-10 were used to culture PBMCs from healthy controls, activated caspase 8 was elevated in CD3(+)T, CD4(+)T and CD8(+)T cells. The study showed that serum IL-10 induced apoptosis of T cell subsets via the caspase 8 pathway initiated by Fas signaling. Increased apoptosis of T cells contributes to autoantigen burden, which is pathogenic in the development of SLE. PMID- 26060448 TI - PKMzeta knockdown disrupts post-ischemic long-term potentiation via inhibiting postsynaptic expression of aminomethyl phosphonic acid receptors. AB - Post-ischemic long-term potentiation (i-LTP) is a pathological form of plasticity that was observed in glutamate receptor-mediated neurotransmission after stroke and may exert a detrimental effect via facilitating excitotoxic damage. The mechanism underlying i-LTP, however, remains less understood. By employing electrophysiological recording and immunofluorescence assay on hippocampal slices and cultured neurons, we found that protein kinase Mzeta (PKMzeta), an atypical protein kinase C isoform, was involved in enhancing aminomethyl phosphonic acid (AMPA) receptor (AMPAR) expression after i-LTP induction. PKMzeta knockdown attenuated postsynaptic expression of AMPA receptors and disrupted i-LTP. Consistently, we observed less neuronal death of cultured hippocampal cells with PKMzeta knockdown. Meanwhile, these findings indicate that PKMzeta plays an important role in i-LTP by regulating postsynaptic expression of AMPA receptors. This work adds new knowledge to the mechanism of i-LTP, and thus is helpful to find the potential target for clinical therapy of ischemic stroke. PMID- 26060450 TI - The future of simulation in medical education. PMID- 26060449 TI - Hypothalamic-pituitary-adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A. AB - Accumulating studies have proved that perinatal exposure to environmental dose causes long-term potentiation in anxiety/depression-related behaviors in rats. Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent biological findings in anxiety- and depression-related disorders. The HPA axis is reported to be susceptible to developmental reprogramming. The present study focused on HPA reactivity in postnatal day (PND) 80 male rats exposed perinatally to environmental-dose BPA. When female breeders were orally administered 2 MUg/(kg.day) BPA from gestation day 10 to lactation day 7, their offspring (PND 80 BPA-exposed rats) showed obvious anxiety/depression-like behaviors. Notably, significant increase in serum corticosterone and adrenocorticotropin, and corticotropin-releasing hormone mRNA were detected in BPA-exposed rats before or after the mild stressor. Additionally, the level of glucocorticoid receptor mRNA in the hippocampus, but not the hypothalamus, was decreased in BPA-exposed rats. The levels of hippocampal mineralocorticoid receptor mRNA, neuronal nitric oxide synthase and phosphorylated cAMP response element binding protein were increased in BPA-exposed rats. In addition, the testosterone level was in BPA-exposed rats. The results indicate that reprogramming-induced hyperactivity of the HPA axis is an important link between perinatal BPA exposure and persistent potentiation in anxiety and depression. PMID- 26060451 TI - Treatment non-adherence among patients with poorly controlled type 2 diabetes in ambulatory care settings in southwestern Nigeria. AB - BACKGROUND: Poor adherence to prescribed therapy among patients with chronic diseases is a growing concern which undermines the benefits of current medical care. OBJECTIVES: To evaluate the pattern of treatment non-adherence among ambulatory patients with poorly controlled type 2 diabetes in southwestern Nigeria, and to determine the possible factor(s) that accounted for such non adherence with a view to identifying areas of future intervention to improve outcome. METHODS: A prospective cross-sectional interview using the concept of RIM (Recognize, Identify and Manage) model was used to evaluate adherence to treatment recommendations among 176 consented patients recruited from the endocrinology out-patient clinics of two teaching hospitals in southwestern Nigeria between November, 2010 and January, 2011. RESULTS: Overlaps of non adherence behavior were obtained. More than three-quarter (153; 88.4%) were not aware of indication for each of the prescribed medications, 26 (15.3%) correctly described regimen as prescribed. The factorsidentified as possible barriers to medication adherence include practical (145; 40.1%), knowledge (103; 28.5%), and attitudinal (114; 31.5%) barriers. Dietary non-adherence was mostly due to inappropriate guidance (62; 33.7%). CONCLUSIONS: The arrays of non-adherence behavior among the cohort further emphasize the need for patient-centered approach as a reasonable strategy in resolving non-adherence problems in routine clinical practice. PMID- 26060452 TI - Impact of mild versus moderate intensity aerobic walking exercise training on markers of bone metabolism and hand grip strength in moderate hemophilic A patients. AB - BACKGROUND: Patients with hemophilia A have low bone density than healthy controls. It is now widely recognized that physical activity and sports are beneficial for patients with hemophilia. OBJECTIVE: To compare the effects of mild and moderate intensity treadmill walking exercises on markers of bone metabolism and hand grip strength in male patients with moderate hemophilia A. MATERIAL AND METHODS: Fifty male patients with moderate hemophilia, and age range from 25 to 45 years. The subjects were randomly assigned into 2 equal groups; the first group (A) received moderate intensity aerobic exercise training. The second group (B) received mild intensity aerobic exercise training. RESULTS: There was a 32.1% and 24.8% increase in mean values of serum calcium and hand grip strength respectively and 22.7 % reduction in mean values of parathyroid hormone in moderate exercise training group (A). While there was a 15.1 % and 15 % increase in mean values of Serum Calcium and Hand grip strength respectively and 10.3 % reduction in mean values of parathyroid hormone in mild exercise training group(B). The mean values of serum calcium and hand grip strength were significantly increased, while the mean values of parathyroid hormone were significantly decreased in both groups . There were significant differences between mean levels of the investigated parameters in group (A) and group (B) after treatment. CONCLUSION: Moderate intensity aerobic exercise training on treadmill is appropriate to improve markers of bone metabolism and hand grip strength in male patients with hemophilia A. PMID- 26060453 TI - Cancer of the esophagus: histopathological sub-types in northern Uganda. AB - BACKGROUND: Esophageal cancer is the eighth most common cause of cancer death worldwide with squamous cell carcinoma and adenocarcinoma carcinoma as the main histopathological subtypes. Esophageal cancer is known for its marked variation by geographic region, ethnicity, and gender. Hitherto, the histopathological subtype of this cancer in Northern Uganda were not known. Therefore the aim of the study was to describe the characteristics of esophageal cancer with respect to the histopathologic subtypes, different sites of occurrence, age and gender in this region since its distribution varies with location. METHODS: The study was carried out at Lacor Hospital, in northern part of Uganda. The record of 71 patients who had endoscopic and histopathological diagnosis of cancer of esophagus over a period of 3 years between January 2009 and December 2011 were retrospectively analyzed. RESULTS: A total of 140 patients had endoscopic diagnosis of cancer of the esophagus and of these, 71 patients had both endoscopic and histopathological diagnosis of cancer of esophagus during the three-year period covered in the study between January 2009 to December 2011. The female to male ratio was 1:3 with mean age of 55.5 years +/- SD 11.8. The common histopathological pattern of cancer of esophagus was squamous cell carcinoma of esophageal consisting of 66 patients (93.o%). The ratio of squamous cell carcinoma to adenocarcinoma was 13:1.The majority of the esophageal cancers were found in the middle third with 38 patients (53.52%), followed by lower third with 27 patients (38.0%) and the upper third which was only 6 patients (8.5%). CONCLUSSIONS: Squamous cell carcinoma is the most common histopathological subtype in this geographical location with overall cancer of the esophagus mainly affecting the lower 2/3 of the esophagus with the majority in the middle third. PMID- 26060454 TI - Enrichment and purification process of astragalosides and their anti-human gastric cancer MKN-74 cell proliferation effect. AB - BACKGROUND: Radix astragali mainly contains saponins, polysaccharides, flavonoids, amino acids and other chemical constituents of which total astragalosides have immunomodulatory, anti-viral, hepatoprotective, and gastric mucosa protective effects. OBJECTIVE: To investigate the process conditions for extraction, purification and enrichment of total astragalosides by macroporous adsorption resin, and to study the inhibitory effect of total astragalosides on growth of human gastric cancer cell line MKN-74. METHODS: UV spectrophotometry was applied to determine the adsorption and desorption capacity of macroporous adsorption resin on total astragaloside content, MTT assay was used to determine the inhibition of MKN-74 cell growth by total astragalosides. RESULTS: The dynamic adsorption performance of DA201 adsorption resin was examined, and the dynamic adsorption curve of total astragalosides on DA201 resin column was plotted. Meanwhile, eluent and elution flow rate were investigated, the results showed that the choice of eluent of 80% ethanol, and a flow rate of 5 BV/h could maximize the yield of total astragalosides. MTT assay found that astragalosides could relatively pronouncedly inhibit the proliferation of MKN-74 cells, and the inhibitory effect was enhanced with the increase of astragaloside dose and the extension of processing time, which showed a dose-and time-dependence. CONCLUSION: DA201 resin can effectively enrich total astragalosides, total astragalosides have an inhibitory effect on growth of MKN-74 cells. PMID- 26060455 TI - Quality of life in rectal cancer patients with permanent colostomy in Xi'an. AB - OBJECTIVES: To observe the quality of life (QOL) in rectal cancer patients with permanent colostomy in different periods after operation. METHODS: A 1-,3-,6 month prospective study of QOL in 51 rectal cancer patients with permanent colostomy and 50 without permanent colostomy was assessed using European Organization for Research and Treatment of Cancer (EORTC) QOL-30 and CR38 questionnaires. RESULTS: The variation of QOL in different periods was "v" type. In the 1st postoperative month, these patients had the lowest quality of life scores, accompanied significantly varied functions and severe symptoms. Almost of all indexes of these patients had improved consistently in the postoperative period. The scores of global QOL even better than pre-operative level at 6th months post-operation, but the social function, body image, chemotherapy side effects and financial difficulties had not restored to the baseline level. Patients without permanent colostomy had a better score in most of categories of QOL-30 and CR38. CONCLUSIONS: The 1st postoperative month was crucial for patients' recovery, in which we should pay great attention to these problems which relate to the recovery of rectal cancer patients with permanent colostomy. PMID- 26060456 TI - Effect of Ginkgo biloba extract on the expressions of Cox-2 and GST-Pi in rats with hepatocellular carcinoma risk. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common and aggressive cancers worldwide, and the pathogenesis is complicated at present. There iare few effective therapeutic measures, and novel therapeutic strategies are urgently required to improve clinical outcome. Ginkgo biloba extract (EGb) is reported to have an anti-cancer activity. OBJECTIVES: To explore the effect of EGb on expressions of cyclooxygenase-2 (Cox-2) and glutathione S-transferase Pi (GST-Pi) in the pathogenesis of HCC. METHODS: 120 Wistar rats were divided into three groups at random: normal control group (control group), HCC risk group without treatment (HCC risk group), HCC risk group treated with EGb (EGb group); n=40, respectively. The HCC risk in rat was induced by aflatoxin B1 injection. At the end of 13-week, 33-week, 53-week and 73-week, 10 rats in each group were killed and the relevant samples were collected. RESULTS: The mRNA and protein expressions of Cox-2 and GST-Pi were measured by real-time reverse transcription polymerase chain reaction, immunohistochemical analysis and western-blot. When compared with those in the control group in 73-week, the mRNA and protein expressions of GST-Pi in EGb group were weaker than those in HCC risk group in 73 week. However, the mRNA and protein expressions of Cox-2 in HCC risk group were increased than that of control group, and there was no statistical difference for mRNA and protein expressions of Cox-2 between HCC risk group and EGb group. CONCLUSION: EGb can regulate the expression of GST-Pi, but it does not seem to have an effect on Cox-2 expression in the liver of HCC risk rats. PMID- 26060457 TI - Symptom clusters and quality of life in China patients with lung cancer undergoing chemotherapy. AB - OBJECTIVE: To explore the symptom clusters and quality of life in patients with lung cancer undergoing chemotherapy. METHODS: A cross-sectional survey was completed with 183 patients from three public hospitals in Xi'an, China. Patients completed a demographic questionnaire, the Functional Assessment of Cancer Therapy-Lung Cancer (FACT-L) and the M. D. Anderson Symptom Inventory (MDASI-C). Factor analysis was used to identify symptom clusters based on the severity of patients' symptom experiences. The resulting clusters were correlated with quality-of-life measures. RESULTS: The QOL scores of lung cancer patients on the functioning subscale were the lowest (9.70+/-5.30), while those of the family subscale were the highest (19.28+/-3.24). Three symptom clusters were identified: gastrointestinal, emotional and fatigue-related symptoms. There was a negative relationship between the symptom clusters and multiple dimensions of quality of life (r -0.178 ~-0.805, p< 0. 05). Females, especially those women with low education level /chronic diseases, were experienced greater symptom distress than others. CONCLUSIONS: The clusters had a negative relationship with QOL. Identifying symptom clusters helped clarify possible inter-relationships which may lead to the establishment of more effective symptom management interventions for patients with lung cancer in order to improve the quality of life. PMID- 26060458 TI - Maxillofacial tumors and tumor-like lesions in a Nigerian teaching hospital: an eleven year retrospective analysis. AB - BACKGROUND: This paper reviews the types, prevalence and demographic distribution of maxillofacial tumors, cysts and tumor-like lesions in a Nigerian population. METHODS: A retrospective analysis of the medical records and histological reports of patients with oral and maxillofacial tumors and cystic lesions who presented to the Maxillofacial Unit of our institution over an eleven year period was undertaken. Information on demographics, histological diagnosis and clinical presentation were obtained and analyzed. A p value of less than 0.05 was considered significant. RESULTS: A total o:f 146 patients, aged 5-70 years (mean 30.5+/- 12.9) were seen over the period of study. There were 96 males (65.8%) and 50 females (34.2%) giving a male to female ratio of almost 2:1. Benign tumors accounted for 124, 86.3% and malignant tumors (22, 13.7%). Ameloblastoma was the most prevalent benign tumor observed (53, 36.3%) while squamous cell carcinoma was the most common malignant tumor. The peak age of ameloblastoma was the fourth decade and squamous cell carcinomas the sixth and seventh decades of life. Jaw swellings were the most common presentation (98, 67.1%), followed by pain (23, 15.9). The duration of symptoms on presentation ranged from 1 to 96 months (mean 23.32 +/-15.72) and this was not different for malignant or benign tumors (P=0.886). CONCLUSION: Late presentation still remains the main challenging factor in the early detection and management of maxillofacial tumors in our environment. More awareness campaign is necessary, especially at the primary health care level, to educate the populace on the need for early presentation at treatment centers. PMID- 26060459 TI - Removal of metallic foreign bodies embedded in soft tissues by stereotaxic approach. AB - BACKGROUND: A trial fibrillation (AF) is the most common cardiac arrhythmia and increases the risk of stroke and death. Patients with hypertensive have an increased risk of developing atrial fibrillation. RDW (Red blood cell distribution width) levels are elevated in cardiovascular disorders including heart failure, stable coronary disease, acute coronary syndrome, slow coronary flow and stroke. OBJECTIVE: To investigate the relation between RDW and AF in patients with hypertensive. METHOD: We retrospectively examined 126 consecutive hypertensive patients (63 hypertensive patients with AF and 63 hypertensive patients without AF matched with age and sex. RESULTS: The mean age of the study population was 71,09+/- 8,50 (af group) and 70,97+/-8,24 (non-af group) years. RDW level was different among patients with atrial fibrillation and without atrial fibrillation.(15,13+/-1,58 and 14,05+/-1,15 p<001). Logistic regression analysis showed that RDW and left atrial dimension were only independently risk factory associated with atrial fibrillation. (Rdw odds ratio:1,846 CI; 1,221 2,793 p<0,05). Roc curve analyses were applied to determine the cut-off point. Cut-off point was at 14,195 and Sensitive, specificity was %71,4, %56 respectively. CONCLUSION: RDW levels were higher in hypertensive patients with atrial fibrillation. An increased RDW level in the patient with hypertension may alert physician on developing or presence of atrial fibrillation. PMID- 26060460 TI - Young patient's age determines pterygium recurrence after surgery. AB - BACKGROUND: It is not clear whether demographic or pterygium characteristics or limbal stem cell deficiency determine pterygium recurrence after surgery. PURPOSE: To determine whether the demographic, pterygium characteristics, or limbal stem cell deficiency determine pterygium recurrence after excision. METHODS: Of 190 patients operated and followed-up for 6 months, 101 and 89 underwent free conjunctival autotransplant (CAT) or limbal conjunctival autotransplant (LCAT) respectively. The age, gender, occupation, grade of pterygium extent and degree of fleshiness, and laterality were compared between recurrent and no recurrent pterygia. Multivariate analysis was performed to determine the predictors of pterygium recurrence. Recurrence rates after surgery were compared between CAT and LCAT. RESULTS: The age range of the 190 patients was 22-65 years, mean +/-SD 46.4 +/-10.8 years. Pterygium recurred in 52 (27.4%). Thirty-nine (75%) of 52 patients with pterygia that recurred were aged <50 years (young) vs. 72 (52%) of 138 young patients with no recurrence; odds ratio (OR) = 1.54; 95% confidence interval (95% CI) = 0.70-3.36; p = 0.28. Thirty-one (60%) of 52 participants with post-surgical recurrent pterygia had large pre-operative pterygium (grade >=3) vs. 130 (94%) of 138 patients with large pterygia that did not recur; OR = 0.11; 95% CI = 0.04-0.28; p <0.001. Of 101 patients undergoing CAT, 29 (28.7%) experienced recurrence vs. 23 (25.8%) of 89 undergoing LCAT; p = 0.66. CONCLUSIONS: Young age seems to be associated with pterygium recurrence after excision followed by conjunctival graft. Large pterygia were protective. PMID- 26060461 TI - Dentofacial injuries in commercial motorcycle accidents in Cameroon: pattern and cost implication of care. AB - OBJECTIVE: To assess the pattern of dentofacial injuries in commercial motorcycle accidents among riders and passengers in Cameroon. METHODS: This was a hospital based study conducted in 6 out of 10 regional capitals in the months of December 2011 to September 2012. Analyzed information included age, gender, residence, role on the motorcycle (rider or passenger), type, pattern and month of injury, cost, duration and patient's perception about the cost of treatment. RESULTS: A total of 387 patients were studied with majority of the patients being 21-30 years (39.8%), males (63.8%), passengers (57.3%) and urban dwellers (85.8%). Most of the injuries occurred in December (20.7%), January (19.4%) and February (20.2%). Soft tissue injuries were most frequent (91.2%) followed by trauma to the teeth (83.5%), of which 62.3% were tooth loss. Mandibular fracture was commoner than maxillary fracture; (45% versus 25.3%). A total of 44.2% of patients received their treatment as in-patients. The treatment of the dentofacial injuries among 64.3% of the patients lasted for more than a month. A total of 51.9% of the patients spent 100,000 francs ($200) or more for their treatment. More than half (51.4%) of the patients perceived the cost of treatment as expensive. CONCLUSION: Dentofacial injuries in commercial motorcycle accidents necessitated hospital admission and lengthy treatment time with high attendant cost. Preventing these injuries will serves as a form of poverty reduction as money that will be used by the victim to better their life is not used to correct deformities or treat injuries. PMID- 26060462 TI - Relationship between the morphology of A-1 segment of anterior cerebral artery and anterior communicating artery aneurysms. AB - BACKGROUND: The anterior communicating artery (ACoA) is one of the most frequent sites for cerebral aneurysm. The peculiar directions of projection of aneurysms offer great challenges to clinical treatment. OBJETIVES: To establish the relationship between morphology of A-1 segment of anterior cerebral artery (ACA) and aneurismal projection. METHODS: Randomly selected digital subtraction angiography data of 264 anterior communicating artery aneurysms (ACoAA) cases and 296 cases of other cerebral vascular diseases in the same period were retrospectively analyzed. RESULTS: Among 264 ACoAA patients, the morphology of A 1 segment showed type 1a in 158 sides, type 1b in 11, type 2a in 35, type 1 2b in 87, type 3 in 171 and absence in 66. The morphology of A-1 segment in 296 patients with other cerebral vascular diseases displayed type 1a in 195 sides, type 1b in 20, type 2a in 47, type 2b in 74, type 3 in 217 and absence in 39. The non-visualization of A-1 segment in the group of ACoAA occurred more than in the control group (chi(2)=11.482, p=0.001). The classifications of ACoAAs in 264 patients were confirmed as anterior-superior type in 121 cases, anterior-inferior type in 105, complicated type in 16, posterior-inferior type in 12 and posterior superior type in 10. The correlation between morphology of A-1 segment of ACA and classifications of ACoAA was significant (p=0.000; C=0.619, p=0.000). The direction of ACoAA was downward when the A-1 segment of ACA was Type 1a or Type 2a, and was upward when it was Type 1a or Type 2a and was upward or downward or complicated when it was Type 3. CONCLUSION: The relationship between morphology of A-1 segment of ACA and classification of ACoAA is clarified in the present study, which is helpful to surgical treatment. PMID- 26060463 TI - Endovascular treatment of ruptured distal posterior inferior cerebellar artery aneurysms: report of 11 cases. AB - OBJECTIVE: To investigate the clinical characteristics and endovascular treatment of ruptured distal posterior inferior cerebellar artery (PICA) aneurysms. METHODS: 11 consecutive patients (7 women, 4 men, mean age of 49.2 years) with ruptured distal PICA aneurysms were studied retrospectively. All had onset of acute intraventricular or cerebellar haemorrhage, and subarachnoid hemorrhage (SAH). Hunt-Hess (HH) grades were H-H I in 1 patient, H-H II in 5 patients, H-H 111 in 4 patients and H-H IV in 1 patient on admission. RESULTS: All patients were treated by endovascular treatment, seven cases got endosaccular coiling and four cases got parent artery occlusion at the same time. All the patients were followed up one to four years. Recurrences occurred in 1 patient two years post treatment, and were successfully retreated by endosaccular coiling and parent artery occlusion. The occluded PICA was recanalized one year post-treatment but without any growth of the aneurysm in one case. One year post-treatment, 2 patients had a modified Rankin Scale (mRS) score of 0, 8 patients had a mRS score of 1 and 1 patient had a mRS score of 2. CONCLUSIONS: Coiling of ruptured distal PICA aneury, with or without parent vessel occlusion, was feasible, relatively safe and effective in preventing early/medium-term rebleeding. A strict angiographic follow-up, however, was necessary to detect recurrence. PMID- 26060464 TI - A new diagnostic marker for acute pulmonary embolism in emergency department: mean platelet volume. AB - OBJECTIVE: To investigate the diagnostic importance of mean platelet volume (MPV) on acute pulmonary embolism (APE) in the emergency Department (ED). METHODS: Subjects were selected from patients admitted to ED with clinically suspected APE. Demographic, anthropometric and serologic data were collected for each patient. RESULTS: A total of 315 consecutive patients were analyzed, including 150 patients (53.44 +/- 15.14 y; 92 men/58 women) in APE group and 165 patients (49.80 +/-13.76y; 94 men/71 women) in the control group. MPV in the APE group was significantly higher than in the control group (9.42+/-1.22 fl vs. 8.04+/-0.89 fl, p<0.0001). The best cut-off values for MPV when predicting APE in patients with clinically suspected APE presenting at the ED were 8.55 fl (sensitivity 82.2%; specificity 52.3%). CONCLUSIONS: MPV is a helpful parameter for the diagnosis of APE in ED, for the first time in the literature. PMID- 26060465 TI - The phenomenon of diminishing -returns in the use of bed nets and indoor house spraying and the emerging place of antimalarial medicines in the control of malaria in Uganda. AB - BACKGROUND: The mosquito net existed long before it was known that mosquitoes transmitted malaria. Therefore it was not intended for malaria control. OBJECTIVES: To scrutinise the patterns of prevalence and identify any hitherto unknown factors that could explain the findings. METHODS: Retrieval of records on malaria prevalence. FINDINGS: Households sprayed in the previous 12 months or owning at least one ITN: 77.8% and IRS: 31.6% in mid-northern districts. Paradoxically, this was the highest malaria prevalence at 80.1%, hence the phenomenon of diminishing-returns. The urban children (28.6%), those of post secondary education mothers (14.3%) and in the highest wealth quintile (33.3%) had a lower malaria prevalence than those without education (55.8%) and the less wealthy (67.6%), (p < 0.001). In all, the connection was that the urban (77.4%) and the wealthy (63.8%) sought health care first from hospitals, for proper treatment. Hence the low prevalence is most likely to be due to anti-malarial medicines and not to bed-nets and IRS, since the other findings of the survey show that there are no significant differences in bed nets ownership and usage and IRS in both groups. RECOMMENDATION: Antimalarial medicines should therefore be used to control malaria instead of the nets and IRS. PMID- 26060466 TI - Synergistic effect of aqueous extract of Telfaria occidentalis on the biological activities of artesunate in Plasmodium berghei infected mice. AB - BACKGROUND: Resistance to most antimalarial drugs has encouraged the use of herbal preparations along with prescribed orthodox drugs. OBJECTIVE: this study investigated effect of co-administration of aqueous extract of T. occidentalis leaves, commonly used as antimalarial and haematinic agent in Nigeria, and artesunate using P. berghei animal model. METHODS: In vivo curative antiplasmodial effect of T. occidentalis (200mg/kg) alone and in combination with artesunate (2mg/kg) were evaluated using albino mice infected with 10(6) parasitized erythrocytes of P. berghei intraperitoneally. The haematological parameters: haemoglobin level, red blood cells and white blood cells and packed cell volume were monitored using standard methods. RESULTS: Aqueous extract of T. occidentalis, artesunate and the combination gave 72.17+/-4.07%, 70.43+/- 4.27% and 85.43+/-3.65% reduction in parasitaemia after 48hours respectively. A significant enhancement of the PCV was obtained with the co-administration of artesunate and aqueous extract (p < 0.01). Similar trends were also observed with heamatological parameters at 72 hours of administration. CONCLUSION: This study revealed a synergistic effect of the co-administration on parasite clearance rate of P. berghei infection in mice, with a significant enhancement of haematological parameters within 48 hours of administration. This indicates a rapid rate of recovery from plasmodial infections with the co-administration. PMID- 26060467 TI - A three year retrospective study on seroprevalence of syphilis among pregnant women at Gondar University Teaching Hospital, Ethiopia. AB - BACKGROUND: Sexually transmitted infections (STIs) are a serious public health problem in low income countries, including Ethiopia. Syphilis caused by Treponema pallidum remains a major cause of reproductive morbidity and poor pregnancy outcomes in low income countries. Stillbirth, perinatal death, serious neonatal infection and low-birth weight babies are common among seropositive mothers. OBJECTIVE: To assess the seroprevalence of syphilis and risk factor correlates of this infection at Gondar University Teaching Hospital, Ethiopia. METHODS: The study was done on 2385 pregnant women attending the antenatal care clinic (ANC) from January 2009 to December 2011. Data was abstracted from the antenatal care clinic medical database. Chi-square test was used, using SPSS version 16 and significance level was chosen at 0.05 level with a two-tailed test. RESULTS: Of the total, 69(2. 9%) of pregnant women were confirmed as seropositive for syphilis. Pregnant women with an age group of 21-25 years of old were the most seropositive (3.4%), followed by 26-30 years of old (3.1%). The prevalence of syphilis infection was 3.2% in urban and 2.2% in rural pregnant women. Relatively high prevalence of syphilis infection were identified among students (4.2%) followed by governmental employees (3.8%). CONCLUSION: The seroprevalence of syphilis among pregnant women attending ANC is declining. However, syphilis is more prevalent in the young and urban pregnant women. Emphasis on education to young people on STI risk behavioral change and partner follow up and notification for exposure to syphilis and treatment should be given. PMID- 26060468 TI - Seroprevalence of cytomegalovirus among pregnant women attending Murtala Mohammed Specialist Hospital Kano, Nigeria. AB - BACKGROUND: Primary Cytomegalovirus (CMV) infection during pregnancy is a frequent and serious threat to the fetus. As there is no vaccine alternative measures are needed to prevent congenital CMV infection. OBJECTIVE: This study determined CMV Immunoglobulin G (IgG) antibody among pregnant women in order to ascertain the immune status of mothers to guide policy makers. METHODS: A semi structured questionnaire was initially administered to obtain information on demographic details, stage of pregnancy and risk factors. Blood was collected by venipuncture from 180 women attending the antenatal clinic in Murtala Mohammed Specialist Hospital Kano, Kano State, Nigeria. Sera samples were screened using CMV IgG ELISA kit (Dialab, Austria). RESULTS: Out of 180 pregnant women, 164 (91.1%) were seropositive. Based on stages of pregnancy 6/6(100%), 52/60(86.7%) and 106/114(93.0%) were seropositive among women in the first, second and third trimesters respectively. CONCLUSION: Seroprevalence of pregnant women to CMV Ig G is high, hence the need for CMV - IgM screening to know the extent of active infection. There is also need for public enlightenment on the methods of transmission, effective prevention and control strategies. PMID- 26060469 TI - Effects of supplemental measles immunization on cases of measles admitted at the Wesley Guild Hospital, Ilesa, Nigeria. AB - BACKGROUND: Measles is a highly contagious vaccine-preventable infection which continues to be a significant cause of childhood morbidity and mortality in developing countries particularly those with poor routine immunisation coverage. Supplemental immunisation activities (SIAs) were thus introduced to improve vaccine coverage. OBJECTIVE: This study was carried out to assess the impact of the supplemental measles vaccinations on the cases of measles admitted at a tertiary health facility in South west Nigeria. METHODS: Weretrospectivelylooked at therecords of cases of measles in children admitted to the Wesley Guild Hospital, Ilesa over a ten year period (2001 - 2010); five years before and five years after the nationwide commencement of supplemental measles immunisation activities (SIAs) in the region in 2006. Measles cases were defined using the WHO case definition. RESULTS: Over the ten year study period, a total of 12,139 children were admitted andmanaged; out of which 302 (2.5%) were cases of complicated measles. There was no difference in the mean (SD) of children admitted in the years before and after the introduction of the SIAs {6040 (122.7) vs.6099 (120.2); t-test 0.02, p =0.988.} There was however a remarkable reduction in the proportion of the cases of measles admitted after the introduction of SIAs compared to the period before SIAs (4.3% vs. 0.6% x2=169.580; p < 0.001). CONCLUSION: SIAs have remarkably reduced morbidity and mortality associated with measles in the region. We advocate for sustenance of these efforts as well as improvement in routine immunisation coverage to avoid a backlash which can lead to devastating measles outbreak. PMID- 26060470 TI - Serum zinc levels in hospitalized children with acute lower respiratory infections in the north-central region of Nigeria. AB - BACKGROUND: Macronutrient deficiency has continued to attract significant research interest, where as the import of micronutrients like zinc has only recently become the focus of interest. Thus against the background of a dearth of data on zinc levels in Nigerian children with Acute Lower Respiratory Infection (ALRI), this study was carried out in Ilorin, Nigeria to determine the serum zinc levels in hospitalized children with ALRI. METHODOLOGY: A comparative cross sectional hospital based study involving 120 children aged two months to five years with ALRI recruited as subjects, and 120 age-appropriate controls without ALRI was carried out. Socio-demographic, clinical and laboratory data were obtained. The serum zinc was analyzed with a JenwayTM spectrophotometer after an initial preparation with the QuantiChromTM zinc assay kit. RESULTS: The male/ female ratio was 1.6:1. The mean (SD) serum zinc level in subjects with ALRI of 18.7(11.8)ug/dl was significantly lower than the corresponding value of 53.1(18.5)ug/dl recorded in the controls, p=0.001. The prevalence of 98.3% for low serum zinc levels recorded in children with ALRI was significantly higher than that recorded in controls of 64.2%, p=0.001. CONCLUSION: Low serum zinc levels are significantly associated with ALRI. There is a need to determine whether hospitalized children managed for ALRI might benefit from post discharge zinc supplementation. PMID- 26060471 TI - Presentation and outcome of tuberculous meningitis among children: experiences from a tertiary children's hospital. AB - BACKGROUND: Diagnosis of tuberculous meningitis (TBM) is complicated and outcome is poor especially in resource limited settings. Early diagnosis and prompt treatment are vital in effective treatment. We set out to describe experiences in the management and immediate outcome of TBM a tertiary-level children's hospital in a high HIV and tuberculosis co-infection setting. METHODS: This retrospective study included children who were diagnosed with TBM in the year 2009. A pre-coded questionnaire was used to extract data on presentation, diagnostics, treatment and outcome at the time of hospital discharge. Data was analyzed using STATA statistical package (StataCorp, Version 11). RESULTS: Of the 40 children diagnosed with TBM, 6 (15%) had definitive TBM, 17 (42.5%) had probable TBM and 17 (42.5%) had possible TBM. The cerebrospinal fluid (CSF) chemistry and cells were abnormal in 39/40 (98%). Mantoux test was reactive in 16/29 (55%) and 17/30 (57%) had Chest X-rays suggestive of tuberculosis. Only 3/21 (14%) had positive sputum tuberculosis culture and 89% (32/36) had neuro-imaging abnormalities. Outcome at discharge was; 8% died, 49% improved with neurological sequelae and 43% improved without sequelae. Having TBM stage 3 at admission was associated with mortality (p=0.001). CONCLUSIONS: Most children had early diagnosis of TBM and mortality was lower than in previous studies. We recommend a larger prospective study to further understand the outcome of TBM. PMID- 26060472 TI - Effectiveness of counseling at primary health facilities: level of knowledge of antenatal attendee and their attitude on Prevention of Mother to Child Transmission of HIV in primary health facilities in Dar es Salaam, Tanzania. AB - BACKGROUND: Children living with HIV worldwide majority are infected through mother to child transmission of HIV (MTCT) acquired during pregnancy. Knowledge, attitude and behavioral changes are pivot tools towards success of any interventions. OBJECTIVES: To determine the effectiveness of counseling on HIV done in primary health facilities (PHF), level of knowledge gained and attitude changes towards PMTCT. METHODS: A cross sectional study assessing pregnant women's knowledge and their attitude towards PMTCT was conducted in Temeke district from October 2010 to Jan 2011 using a structured questionnaire. RESULTS: A total of 383 antenatal attendees were referred to Temeke district for management after counselled and tested for HIV in PHFs. Majority (86.9%) had primary education and good knowledge on MTCT. Correct timing of ARVs prophylaxis (15.7%) as preventive measures for MTCT was poor. Education and employment were associated with good knowledge on MTCT of HIV. Women had positive attitudes towards HIV counseling and testing, but stigma was a barrier to disclosure of one's serostatus. CONCLUSION: There is knowledge gap in routine PMTCT counseling among antenatal attendees in our PHFs. Effective counseling on PMTCT in the PHFs will bridge the identified knowledge gap and help in reduction of pediatric HIV. PMID- 26060473 TI - Prevalence and factors associated with tuberculosis treatment outcome among hazardous or harmful alcohol users in public primary health care in South Africa. AB - BACKGROUND: Tuberculosis (TB) remains a chronic infectious disease with high morbidity and mortality. OBJECTIVE: The aim of this study was to assess the prevalence and associated factors of tuberculosis treatment failure, death and default among hazardous or harmful alcohol users. METHOD: We conducted a prospective study with TB patients in 40 public health clinics in three districts in South Africa. All consecutively new tuberculosis and retreatment patients presenting at the 40 primary health care facilities with hazardous or harmful alcohol use were included in this study. Logistic regression was used to assess determinants of TB treatment failure, death and default. RESULTS: The findings of our study showed that 70% of TB patients were either cured or had completed their TB treatment by the end of 6 months. In multivariate analysis participants living in a shack or traditional housing (Odds Ratio=OR: 0.63, Confidence Interval=CI: 0.45-0.89), being a TB retreatment patient (OR: 1.61, CI: 1.15-2.26) and residing in the eThekwini district (OR: 1.82, CI: 1.27-2.58) were significant predictors of treatment failure, death and default. CONCLUSION: A high rate of treatment failure, death and default were found in the TB patients. Several factors were identified that can guide interventions for the prevention of treatment failure, death and default. PMID- 26060474 TI - Activities of selected medicinal plants against multi-drug resistant Gram negative bacteria in Cameroon. AB - BACKGROUND: Medicinal plants are used worldwide for several human ailments including bacterial infections. The present work was designed to assess the in vitro antibacterial activities of some Cameroonian medicinal plants including Entada abyssinica, Entada africana, Pentaclethra macrophylla, Allexis cauliflora, Anthocleista leibrechtsiana, Carapa procera, Carica papaya and Persea americana against Gram-negative bacteria expressing multidrug resistant (MDR) phenotypes. METHODS: The microbroth dilution was used to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of the samples against eight bacterial strains belonging to four species, Escherichia coli, Enterobacter aerogenes, Klebsiella pneumoniae and Providencia stuartii. RESULTS: The extracts displayed selective antibacterial activities with the minimal inhibitory concentrations (MIC) values ranges of 64 to 1024 ug/mL. The most active extract was that from Pentaclethra macrophylla (TPM) that showed inhibitory activities against five of the eight (62.5%) tested bacteria. The lowest MIC value (64 ug/mL) was recorded with the crude extract of Entada africana against E. coli AG100A whilst the best MBC (256 ug/mL) value was also obtained with methanol extract of Persea americana against this bacterial strain. CONCLUSION: The results of the present work provide baseline information on the possible use of Pentaclethra macrophylla, Entada africana and Entada abyssinica in the treatment of selected bacterial infections. PMID- 26060475 TI - In vitro evidence of baicalein's inhibition of the metabolism of zidovudine (AZT). AB - BACKGROUND: Herb-drug interaction (HDI) has been regarded as a key factor limiting the clinical application of herbs and drugs. AIMS: Potential baicalein zidovudine (AZT) interaction was predicted in the present study. METHODS: In vitro evaluation of baicalein's inhibition towards human liver microsomes (HLMs) catalyzed metabolism of zidovudine (AZT) was performed. Dixon and Lineweaver-Burk plots were used to determine the inhibition kinetic type, and second plot with the slopes from Lineweaver-Burk plot versus the concentrations of baicalein was employed to calculate the inhibition parameter (Ki). In combination with the in vivo concentration of baicalein, in vitro-in vivo extrapolation (IVIVE) was carried out to predict in vivo baicalein-AZT interaction. RESULTS: Competitive inhibition of baicalein towards AZT metabolism was demonstrated, and the Ki value was calculated to be 101.2 uM. The value of AUCi/AUC was calculated to be 2. CONCLUSION: Potential baicalein-AZT interaction was indicated in the present study, indicating the need for monitoring when AZT is co-administrated with baicalein or baicalein-containing herbs. PMID- 26060476 TI - Evaluation of haematological, hepatic and renal functions of petroleum tanker drivers in Lagos, Nigeria. AB - BACKGROUND: Hydrocarbons which are among the major components of petroleum products are considered toxic and have been implicated in a number of human diseases. Tanker drivers are continuously exposed to hydrocarbons by inhalation and most of these drivers do not use protective devices to prevent inhalation of petroleum products; nor do they visit hospital regularly for routine check-up. OBJECTIVE: In view of this occupational hazard, we investigated the haematological, renal and hepatic functions of workers of petroleum tankers drivers in Lagos, Nigeria. METHOD: Twenty-five tanker drivers' and fifteen control subjects were randomly selected based on the selection criteria of not smoking and working for minimum of 5 years as petroleum tanker driver. The liver, renal and haematological parameters were analyzed using automated clinical and haematological analyzers while the lipid peroxidation and antioxidant level tests were assayed using standard methods. RESULTS: There were significant (p <= 0.05) increases in the levels of serum alanine amino transferase (31.14+/-13.72; 22.38+/-9.89), albumin (42.50+/-4.69; 45.36+/-1.74) and alkaline phosphatase (84.04+/-21.89; 62.04+/-23.33) of petroleum tanker drivers compared with the controls. A significant (p<=0.05) increase in the levels of creatinine, urea and white blood cells of the tanker drivers, compared with the controls, were also obtained. CONCLUSION: The results have enormous health implications of continuous exposure to petroleum products reflected hepatic and renal damage of petroleum tanker drivers. Therefore, there is need for this group of workers to be sensitized on the importance of protective devises, regular medical checkup and management. PMID- 26060477 TI - In vitro evidence for endocrine-disrupting chemical (EDC)'s inhibition of drug metabolism. AB - BACKGROUND: Humans can be frequently exposed to Bisphenol A (BPA) via multiple sources, and babies are considered to be the most sensitive group to exposure of BPA. AIMS: To investigate the inhibition potential of BPA towards human liver microsomes (HLMs)-catalyzed zidovudine (AZT) glucuronidation. MATERIALS AND METHODS: In vitro HLMs incubation system was used to investigate the inhibition potential of BPA towards AZT glucuronidation. Both Dixon and Lineweaver-Burk plots were employed to determine the inhibition kinetic type, and nonlinear repression was utilized to calculate the inhibition kinetic parameters (Ki). RESULTS: Concentration-dependent inhibition of BPA towards AZT glucuronidation was observed. Both Dixon and Lineweaver-Burk plots showed that BPA exerted competitive inhibition towards the glucuronidation of AZT, and nonlinear repression with competitive equation was used to calculate the Ki value to be 3.2 uM. CONCLUSION: Potential BPA-AZT interaction might occur when the patients administered with AZT is also exposed to BPA. PMID- 26060478 TI - Correlation between the cystathionine-gamma-lyase (CES) and the severity of peptic ulcer disease. AB - BACKGROUND: The infection of Helicobacter pylori (H. pylori) is one of the most important causes of gastric ulcer disease. The role of hydrogen sulfide (H2S) production in H. pylori-induced gastric ulcer disease. AIM: The expression of cystathionine-gamma-lyase (CSE) was determined, and correlated with the severity of gastric ulcer disease. METHODS: One hundred and eight patients were selected based on the determination of gastric ulcer and the infection of Helicobacter pylori (H. pylori), including 36 normal control, 36 patients with H. Pylori negative gastric ulcer, and 36 patients with H. Pylori-positive gastric ulcer. RT PCR determination was performed to determine the expression of CSE, NF-kappaB and IL-8. RESULTS: The expression of CSE, NF-kappaB and IL-8 was higher in the gastric ulcer group than control group (p<0.05). Compared with the H. pylori negative gastric ulcer, the expression of CSE, NF-kappaB and IL-8 was higher than H. pylori-positive gastric ulcer group (p<0.05). For H. pylori-negative gastric ulcer group, the expression of CSE positively correlated with the expression of NF-kappaB (r=0.98, p<0.05) and IL-8 (r=0.95, p<0.05). For H. pylori-positive gastric ulcer group, the expression of CSE also positively correlated with the expression of NF-kappaB (r=0.99, p<0.05) and IL-8 (r=0.85, p<0.05). CONCLUSION: The expression of CSE was positively correlated with the severity of gastric ulcer. PMID- 26060479 TI - Locomotor differences in Mongolian gerbils with the effects of midazolam administration in the form of eye drops. AB - BACKGROUND: Midazolam is a sedative-hypnotic agent with amnestic and anticonvulsant properties that can be administrated to mammals through various routes, such as intravenous, intramuscular, oral, intrathecal, rectal, and buccal. Midazolam administration in the form of eye drops through the conjunctiva is not reported in the literature. AIM: This study aims to demonstrate the possible central nervous system effects of midazolam administration as eyes drops in Mongolian gerbils. MATERIALS AND METHODS: Fourteen gerbils were randomly assigned to one of two equal sized groups. The active arm received 2 ml of 10 mg midazolam as eye drops in both eyes. Control group received a total of 2 ml of physiological saline (0.9% NaCl). We subjected the gerbils to an adapted "Open Field" to determine the possible effects on central nervous system of midazolam. Gerbils were allowed to move freely in the open field. Before and after the drug administration, locomotor activities of each gerbil have been recorded. Frequency of loss of righting reflex was quantified. RESULTS: Conjunctival midazolam administration resulted with the transient loss of righting reflex (p=0.017) and suppressed exploration motion (p=0.018) in the open field test compared to control subjects. CONCLUSIONS: In the present study, administration of conjunctival midazolam as an eye drop may affect gerbil's locomotor activities and open field behaviors. We argue that, using a sedative and anticonvulsive drug such as midazolam via conjunctival route may be useful in some clinical situations. Therefore, it could be beneficial to develop a new conjunctival formulation of midazolam. Also, there is a need for trials in humans with pharmacokinetic studies. PMID- 26060480 TI - Review of the chemistry and pharmacology of 7-Methyljugulone. AB - BACKGROUND: Naphthoquinone is a class of phenolic compounds derived from naphthalene. 7-Methyljuglone (7-MJ) is a naphthoquinone also known as ramentaceone or 6-Methyl-8-hydroxy-1,4-naphthoquinone or 5-Hydroxy-7-methyl-1,4 naphthoquinone or 7-Methyl-5-hydroxy-1,4-naphthoquinone or 5-Hydroxy-7-methyl ,1,4-naphtoquinone or 7-Methyl-5-hydroxynaphthalene-1,4-dione. This compound is a biologically active naphtoquinone, with a molecular weight of 188 g/mol mostly isolated in the genus Diospyros and Euclea. OBJECTIVES: This review was aimed at providing available chemically and pharmacological data on 7-MJ. METHODS: The chemical and pharmacological data were retrieved from the well-known scientific websites such as Pubmed, Google Scholar, Reaxys, Scirus, Scopus, Sciencedirect, Web-of-knowledge and Scifinder. RESULTS: 7-MJ was reported to have a variety of pharmacological activities such as antibacterial, antifungal, anticancer, antitubercular, anti-inflammatory and antiviral activities. The hemi-synthesis of the compound have been described. CONCLUSIONS: The present review pooled out together the knowledge on 7-MJ, and can serve as the start point for future research and valorization accomplishments. PMID- 26060481 TI - The influence of bile acids homeostasis by cryptotanshinone-containing herbs. AB - BACKGROUND: Herbs might affect the homeostasis of bile acids through influence of multiple metabolic pathways of bile acids. OBJECTIVE: To investigate the inhibition of cryptotanshinone towards the glucuronidation of LCA, trying to indicate the possible influence of cryptotanshinone-containing herbs towards the homeostasis of bile acids. METHODS: The LCA-3-glucuronidation and LCA-24 glucuronidation reaction was monitored by LC-MS. RESULTS: Initial screening showed that 100 uM of cryptotanshinone inhibited LCA-24-glucuronidation and LCA-3 glucuronidation reaction activity by 82.6% and 79.1%, respectively. This kind of inhibition behaviour exerted cryptotanshinone concentrations-dependent and LCA concentrations-independent inhibition behaviour. CONCLUSION: All these data indicated the possibility of cryptotanshinone's influence towards bile acids metabolism and homeostasis of bile acids. PMID- 26060482 TI - India, Laos and South Africa reject sponsorship and gifts from formula companies. PMID- 26060484 TI - A case of anomalous origin of the left coronary artery presenting with acute myocardial infarction and cardiovascular collapse. AB - BACKGROUND: Though a rare clinical entity, anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) a common cause of myocardial infarction in children. Unrecognized and untreated it leads to progressive left ventricular dilatation and systolic dysfunction. In settings of high infectious burden, ALCAPA may erroneously be diagnosed as myocarditis, dilated cardiomyopathy or other common childhood disorders. CLINICAL CASE: We present the case of a 10 weeks old male infant who presented to the inpatient unit with marked restlessness and irritability. He was inconsolable, had marked respiratory distress, cool extremities, central and peripheral cyanosis oxygen. The radial and brachial pulses were absent. The mean arterial pressure was 65mmHg, Heart rate of 160 beats per minute with a third heart sound. The liver was enlarged 4cm below the costal margin and tender, with a splenomegaly. He had an elevated Creatinine Kinase-MB of 112.5 u/L. ECG revealed deep Q waves in leads I, aVL, V5, V6 with ST elevation in the anterolateral leads. Echo showed a dilated left ventricle LVEDd of 40mm, with paradoxical interventricular septal motion, severe LV systolic dysfunction (FS=15%, EF=28%), LV anterolateral wall echo brightness and flow reversal in the Left coronary artery with its origin from the pulmonary trunk. He was admitted to the coronary care unit as a case of acute myocardial infarction with cardiovascular collapse. He received fluid resuscitation, inotropic support and standard management of heart failure. Six days later he was discharged home with a plan to refer abroad. He died at home after one week. CONCLUSION: A combination of a high index of suspicion, typical ECG and echocardiographic findings in a young infant presenting with LV dysfunction could lead to an earlier diagnosis of ALCAPA. PMID- 26060483 TI - Evaluation of chromosomal abnormalities and common trombophilic mutations in cases with recurrent miscarriage. AB - BACKGROUND: Recurrent miscarriage (RM) is a frequent obstetric problem. Its' pathophysiology is poorly understood. Infections, genetic, endocrine, anatomic and immunologic problems have been suggested as causes for RM. OBJECTIVE: To evaluate the frequency of chromosomal abnormalities and 3 common thrombophilic mutations in couples with RM. METHODS: A retrospective data collection was performed for the results of the cytogenetic analysis of the couples and Methylenetetrahydrofolate Reductase (MTHFR) C677T, Factor V Leiden (FVL) G1691A and Prothrombin (PTm) G20210A mutations of the mother in 142 couples suffering from RM. RESULTS: Prevalence of FVL, MTHFR, and PTm gene mutations were similar between cases shaving 2 or >=3 abortions (P=0.528; P=0.233; P=0.375). In patients with FVL, MTHFR and PTm gene mutations, the OR's of having >=3 abortions when compared to having 2 abortions were 1.515 (95% CI: 0.414-5.552), 0.573 (95% CI: 0.228-1.441), and 2.848 (95% CI: 0.355-22.871). All cases with PTm mutation had >=3 abortions and all abortions occurred between 6-8 gestational weeks. CONCLUSION: Chromosomal abnormalities and thrombophilic mutations (especially PTm) seem to have an important role in RM. Additional larger studies involving investigation of more genes that may have a role in pregnancy are needed to assess this association. PMID- 26060485 TI - How medical education can contribute towards the reduction of maternal mortality in Angola: the teaching/learning process of Gynecology and Obstetrics. AB - BACKGROUND: In Angola the maternal mortality ratio is among the highest in the world. Medical students are an important target for intervention. OBJECTIVES: To evaluate how students perceive the curricular unit of Gynecology and Obstetrics (G&O) in a public institution of reference in Angola. METHODS: The study involved a sample of 147 students of the faculty of Medicine of the University Agostinho Neto, Luanda, Angola, attending the curricular unit of G&O in the 5th and 6th years of the medical course. Data were obtained through surveys of opinion. The information of the scales was summarized through the construction of scores from the original items using the Principal Components Analysis. RESULTS: Students evaluated positively the curricular unit although emphasizing the lack of human and physical resources. The 5th year scored with higher values Teacher Performance and 6th year Students' Performance. Both years considered to have insufficient skills to meet the learning objectives. CONCLUSION: Constraints were identified in the outcomes of the teaching/learning program. Several points emerged as crucial from this study: widespread the areas of teaching/learning, increase the number and quality of teaching staff, improve the monitoring of students and provide adequate infrastructures and medical equipment to support the teaching/learning program. PMID- 26060486 TI - Burnout and psychological distress among nurses in a Nigerian tertiary health institution. AB - BACKGROUND: The role of nurses in the health care delivery system cannot be overemphasized. Nurses are needed at all levels of healthcare and the profession requires a lot of dedication, time and energy with regards to patient management and service delivery. This time investment and dedication to duty is likely to lead to burnout and psychological distress among the nurses. OBJECTIVE: This study assesses the prevalence of burnout and psychological distress among nurses working in Nigerian tertiary health institution. METHOD: The Maslach Burnout Inventory (MBI) and the General Health Questionnaire (GHQ-12) were used to assess 210 nurses working in this health institution for symptoms of burnout and psychological distress. RESULTS: High levels of burnout were identified in 42.9% of the respondents in the area of emotional exhaustion, 47.6% in the area of depersonalization and 53.8% in the area of reduced personal accomplishment, while 44.1% scored positive in the GHQ-12 indicating presence of psychological distress. CONCLUSION: Prevalence of burnout and psychological distress is high among nurses. PMID- 26060487 TI - Sonographic determination of spleen to left kidney ratio among Igbo school age children of south east Nigeria. AB - BACKGROUND: Clinical determination of mild splenomegaly is notoriously inaccurate. OBJECTIVES: To determine sonographically the spleen to left kidney ratio according to age and somatometric parameters among school age children in a tropical environment. METHODS: A cross sectional study and convenience sampling were done on 947 apparently healthy subjects (496 boys and 451 girls) aged 6-17 years at the University of Nigeria Medical Centre, Nsukka. The sonographic examination was performed on Shenzhen DP-1100 machine with 3.5 and 5 MHz convex transducers. Spleen and left kidney lengths were obtained using appropriate techniques. The weight and height of the subjects were obtained with the participants wearing light weight street clothes without shoes. RESULTS: Measurement of spleen and left kidney lengths were reliable within and between sonographers. The spleen and left kidney lengths were not statistically different in boys and girls (p > 0.05). The spleen to left kidney ratio according to age and somatometric parameters is constant at about 1.13 with 1.3 as the upper limit of normal in the studied population. CONCLUSION: Sonography can be used to detect mild splenomegaly if the spleen to left kidney ratio is greater than 1.3 in the absence of renal disease among school age children. PMID- 26060488 TI - Compliance with iron-folic acid (IFA) therapy among pregnant women in an urban area of south India. AB - BACKGROUND: Anaemia is highly prevalent among pregnant women and iron deficiency is the most important cause. Like many other countries, India has policies to give pregnant women iron supplements. Non-compliance is one important challenging factor in combating anaemia. OBJECTIVE: To estimate the compliance for IFA tablets among pregnant women and to study the social factors influencing it. METHODOLOGY: This study included 190 pregnant women seeking ante-natal care in tertiary health Centres in the Mangalore city in South India. After Institutional Ethics Committee (IEC) approval, data was collected by personal interview. Missing >=2 doses consecutively was considered non-compliance. The data was analyzed using SPSS (Statistical Package for Social Sciences) version 11.5. RESULTS: The mean age of the study population was 25.8 years (SD: 4.1). Majority of the subjects consumed mixed diet and 72.1% belonged to lower socioeconomic status. Overall, compliance with IFA tablets was 64.7%. Compliance increased with the increase in age, birth order and single daily dose. Forgetfulness and both perceived as well as experienced side effects of IFA therapy were the important factors for non-compliance. CONCLUSION: There was a moderate level of Compliance towards IFA tablets with key social and demographic factors playing important role. PMID- 26060489 TI - The importance of the mean platelet volume in the diagnosis of supraventricular tachycardia. AB - BACKGROUND: The diagnosis of palpitation can be difficult in the emergency department (ED) and the waiting time for a first appointment with an arrhythmia clinic can be very long. The inflammation is sufficient to facilitate the initiation of supraventricular tachyarrhythmia (SVT). The increased mean platelet volume (MPV) is closely correlated with inflammation and to reflect inflammatory burden in different condition. OBJECTIVE: In this study, we aimed to investigate the relation between MPV and SVT in patient with documented atrial tachyarrhythmia in ED. METHODS: Two study groups were compared; a SVT group with arrive at the ED with documented SVT (n=122) and 100 healthy adult without any palpitation symptom, arrhythmic disease, and with normal physical examination results that were brought for checkups to the cardiology polyclinic were classified as control group. Blood samples were obtained from all patients for determining the hematologic counts and MPV during first hour in ED period. RESULTS: In terms of the focus of the study, hemoglobin, neutrophil count, mean cell volume (MCV), red cell distribution width (RDW), platelet, white blood cell (WBC), and lymphocyte counts were similar in both group (p>0.05). MPV in the SVT group was signifi cantly higher than in the control group (9.12+/-1.22 fl vs 8.64+/-0.89 fl , p<0.001). Multivariate logistic regression analysis showed that just MPV was independent predictor of SVT in patients with palpitation in ED (odds ratio [OR] 8.497, 95% confidence interval (6.181 to 12.325), p=0.012). CONCLUSIONS: Our study described that MPV is helpful parameter for the diagnosis of SVT in emergency department, for the first time in the literature. PMID- 26060490 TI - Is there any relationship between RDW levels and atrial fibrillation in hypertensive patient? AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia and increases the risk of stroke and death. Patients with hypertensive have an increased risk of developing atrial fibrillation. RDW (Red blood cell distribution width) levels are elevated in cardiovascular disorders including heart failure, stable coronary disease, acute coronary syndrome, slow coronary flow and stroke. OBJECTIVE: We aimed to investigate the relation between RDW and AF in patients with hypertensive. METHOD: We retrospectively examined 126 consecutive hypertensive patients (63 hypertensive patients with AF and 63 hypertensive patients without AF matched with age and sex. RESULTS: The mean age of the study population was 71,09+/- 8,50 (af group) and 70,97+/-8,24 (non-af group) years. RDW level was different among patients with atrial fibrillation and without atrial fibrillation.(15,13+/-1,58 and 14,05+/-1,15 p<001) . Logistic regression analysis showed that RDW and left atrial dimension were only independently risk factory associated with atrial fibrillation. (Rdw odds ratio:1,846 CI; 1,221-2,793 p<0,05). Roc curve analyses were applied to determine the cut-off point. Cut-off point was at 14,195 and Sensitive, specificity was %71,4, %56 respectively. CONCLUSION: RDW levels were higher in hypertensive patients with atrial fibrillation. An increased RDW level in the patient with hypertension may alert physician on developing or presence of atrial fibrillation. PMID- 26060491 TI - Non communicable diseases and infections refuse to go away despite current knowledge and scientific advances. PMID- 26060492 TI - Bacteremia after Endoscopic Submucosal Excavation for Treating the Gastric Muscular Layer Tumors. AB - Background. The bacteremia is reported as being infrequent and transient in gastric EMR and ESD for treating gastric mucosa lesions or superficial gastric neoplastic lesion. There was no report of it being investigated in ESD for treating gastric muscular layer tumors (endoscopic submucosal excavation, ESE). This study aimed to determine the frequency of bacteremia in gastric ESE. Patients and Methods. A prospective study, in 122 consecutive patients who underwent gastric ESE for treating gastric muscular layer tumors, investigated the frequency of bacteremia before and 15 minutes after the procedure. Results. The median time for the total ESE procedure was 29 min (range from 8 to 62 min). The mean size of the biggest diameter of each resected specimen was 10 +/- 2.7 mm (range from 5 mm to 30 mm). Blood cultures obtained before ESE were positive in 0% (0/122) of cases. Blood cultures obtained 15 min after ESE were positive in 2.5% (3/122) of cases. Six blood samples contained Staphylococcus with coagulase negative, which was considered contaminant. No signs of sepsis were seen in all patients. Conclusions. The frequency of bacteremia after gastric ESE was low. ESE for treating gastric lesions is thought to have a low risk of infectious complications; therefore, prophylactic administration of antibiotics may not be warranted. PMID- 26060493 TI - Correlations of Human Epithelial Growth Factor Receptor 2 Overexpression with MUC2, MUC5AC, MUC6, p53, and Clinicopathological Characteristics in Gastric Cancer Patients with Curative Resection. AB - Background. The purpose of this study was to evaluate the relationships between HER2 overexpression in the tumor and MUC2, MUC5AC, MUC6, and p53 status and clinicopathological characteristics of gastric cancer patients. Methods. This retrospective study included 282 consecutive patients with gastric cancer who underwent surgery at the Kosin University Gospel Hospital between April 2011 and December 2012. All tumor samples were examined for HER2 expression by immunohistochemistry (IHC) and MUC2, MUC5AC, MUC6, and p53 expression by staining. A retrospective review of the medical records was conducted to determine the correlation between the presence of HER2 overexpression and clinicopathological factors. Results. The HER2-positive rate was 18.1%. Although no association was found between HER2 expression and MUC5AC, the expression of MUC2, MUC6, and p53 was significantly correlated with HER2 positivity, respectively (P = 0.004, 0.037, 0.002). Multivariate analysis revealed that HER2 overexpression and nodal status were independent prognostic factors. Conclusions. HER2 overexpression in gastric carcinoma is an independent poor prognostic factor. PMID- 26060495 TI - Awareness of Prediabetes and Diabetes among Persons with Clinical Depression. AB - Background. Major depressive disorder (MDD) is highly comorbid with diabetes, a relationship underappreciated by clinicians. Purpose. Examine the proportion of nonpregnant individuals >=20 years with MDD and elevated glucose and the demographic and clinical characteristics associated with unrecognized elevated glucose. Methods. 14,373 subjects who participated in the National Health and Nutrition Examination Survey (2007-2012) completed the PHQ-9 depression screen and had hemoglobin A1C (HbA1c) measured. PHQ-9 scores >=10 and HbA1c scores >=5.7% were defined as MDD and elevated HbA1c, respectively. Data were analyzed using complex survey sampling software. Results. 38.4% of the sample with MDD had elevated HbA1c readings. Compared with nondepressed subjects, they were significantly more likely to have elevated glucose readings (P = 0.003) and to be aware of their elevated glucose levels if they had a higher body mass index, family history of diabetes, more doctor visits in the past year, a usual care source, health insurance, or were taking hypertension or hypercholesterolemia medications. Conclusions. Many adults with MDD have elevated HbA1c levels, have never been advised of elevated HbA1c, have not received diabetes screening, and have minimal contact with a healthcare provider. Additional opportunities for diabetes risk screening in people with MDD are needed. PMID- 26060496 TI - Unusual Synchronous Methimazole-Induced Agranulocytosis and Severe Hepatotoxicity in Patient with Hyperthyroidism: A Case Report and Review of the Literature. AB - Context. To report a patient with hyperthyroidism who developed concurrent occurrence of agranulocytosis and severe hepatotoxicity after taking methimazole (MMI). Case. A 51-year-old Chinese male was diagnosed as hyperthyroidism with normal white blood count and liver function. After 4 weeks' treatment with MMI 20 mg/d, it developed to agranulocytosis and severe cholestatic hepatotoxicity. The patient's symptoms and laboratory abnormalities disappeared after the withdrawal of MMI; his white blood count and liver function recover to normal in 2 weeks and 5 weeks, respectively. 296 MBq dose of (131)I was given to the patient 3 weeks after the withdrawal of MMI and his thyroid function was back to normal in 6 months. As we know through literature review, only 5 previous cases reported the synchronous ATD-induced agranulocytosis and severe hepatotoxicity in patients with hyperthyroidism. Methods. Review of the patient's clinical course. Literature review of cases of hyperthyroidism with agranulocytosis and severe hepatotoxicity demonstrated that these complications occurred after taking antithyroid drug (ATD). Conclusions. Patient with hyperthyroidism can have synchronous ATD-induced agranulocytosis and severe hepatotoxicity. This case is extremely rare, but the adverse effects with ATDs is clinically significant. The clinicians need to be careful about this and monitor biochemical of patients who take ATDs. PMID- 26060494 TI - Diabetes Mellitus, Cognitive Impairment, and Traditional Chinese Medicine. AB - Diabetes mellitus (DM) is a metabolic disorder affecting a large number of people worldwide. Numerous studies have demonstrated that DM can cause damage to multiple systems, leading to complications such as heart disease, cancer, and cerebrovascular disorders. Numerous epidemiological studies have shown that DM is closely associated with dementia and cognition dysfunction, with recent research focusing on the role of DM-mediated cerebrovascular damage in dementia. Despite the therapeutic benefits of antidiabetic agents for the treatment of DM-mediated cognitive dysfunction, most of these pharmaceutical agents are associated with various undesirable side-effects and their long-term benefits are therefore in doubt. Early evidence exists to support the use of traditional Chinese medicine (TCM) interventions, which tend to have minimal toxicity and side-effects. More importantly, these TCM interventions appear to offer significant effects in reducing DM-related complications beyond blood glucose control. However, more research is needed to further validate these claims and to explore their relevant mechanisms of action. The aims of this paper are (1) to provide an updated overview on the association between DM and cognitive dysfunction and (2) to review the scientific evidence underpinning the use of TCM interventions for the treatment and prevention of DM-induced cognitive dysfunction and dementia. PMID- 26060497 TI - Evolving Concepts: Immunity in Oncology from Targets to Treatments. AB - Cancer is associated with global immune suppression of the host. Malignancy induced immune suppressive effect can be circumvented by blocking the immune checkpoint and tip the immune balance in favor of immune stimulation and unleash cytotoxic effects on cancer cells. Human antibodies directed against immune checkpoint proteins: cytotoxic T lymphocytes antigen-4 (CTLA-4) and programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), have shown therapeutic efficacy in advanced melanoma and non-small-cell lung cancer and other malignancies. Immune check point blockade antibodies lead to diminished tolerance to self and enhanced immune ability to recognize and eliminate cancer cells. As a class these agents have immune-related adverse events due to decreased ability of effector immune cells to discriminate between self and non-self. Seventy percent of patients participating in clinical trials have experienced anticancer activities and varying degrees of immune mediated dose-limiting side effects. PMID- 26060499 TI - Slum Sanitation and the Social Determinants of Women's Health in Nairobi, Kenya. AB - Inadequate urban sanitation disproportionately impacts the social determinants of women's health in informal settlements or slums. The impacts on women's health include infectious and chronic illnesses, violence, food contamination and malnutrition, economic and educational attainment, and indignity. We used household survey data to report on self-rated health and sociodemographic, housing, and infrastructure conditions in the Mathare informal settlement in Nairobi, Kenya. We combined quantitative survey and mapping data with qualitative focus group information to better understand the relationships between environmental sanitation and the social determinants of women and girls' health in the Mathare slum. We find that an average of eighty-five households in Mathare share one toilet, only 15% of households have access to a private toilet, and the average distance to a public toilet is over 52 meters. Eighty-three percent of households without a private toilet report poor health. Mathare women report violence (68%), respiratory illness/cough (46%), diabetes (33%), and diarrhea (30%) as the most frequent physical burdens. Inadequate, unsafe, and unhygienic sanitation results in multiple and overlapping health, economic, and social impacts that disproportionately impact women and girls living in urban informal settlements. PMID- 26060498 TI - Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells. AB - The immunosuppressive properties of mesenchymal stromal/stem cells (MSC) rendered them an attractive therapeutic approach for immune disorders and an increasing body of evidence demonstrated their clinical value. However, the influence of MSC on the function of specific immune cell populations, namely, monocyte subpopulations, is not well elucidated. Here, we investigated the influence of human bone marrow MSC on the cytokine and chemokine expression by peripheral blood classical, intermediate and nonclassical monocytes, and myeloid dendritic cells (mDC), stimulated with lipopolysaccharide plus interferon (IFN)gamma. We found that MSC effectively inhibit tumor necrosis factor- (TNF-) alpha and macrophage inflammatory protein- (MIP-) 1beta protein expression in monocytes and mDC, without suppressing CCR7 and CD83 protein expression. Interestingly, mDC exhibited the highest degree of inhibition, for both TNF-alpha and MIP-1beta, whereas the reduction of TNF-alpha expression was less marked for nonclassical monocytes. Similarly, MSC decreased mRNA levels of interleukin- (IL-) 1beta and IL-6 in classical monocytes, CCL3, CCL5, CXCL9, and CXCL10 in classical and nonclassical monocytes, and IL-1beta and CXCL10 in mDC. MSC do not impair the expression of maturation markers in monocytes and mDC under our experimental conditions; nevertheless, they hamper the proinflammatory function of monocytes and mDC, which may impede the development of inflammatory immune responses. PMID- 26060501 TI - Traditional Herbal Medicine and Allergic Asthma. PMID- 26060500 TI - An Exploratory Analysis of Public Awareness and Perception of Ionizing Radiation and Guide to Public Health Practice in Vermont. AB - Exposure to ionizing radiation has potential for acute and chronic health effects. Within the general public of the United States, there may be a discrepancy between perceived and actual health risks. In conjunction with the Vermont Department of Health, a survey designed to assess public perception and knowledge of ionizing radiation was administered at 6 Vermont locations (n = 169). Descriptive and inferential statistical analyses were conducted. Eighty percent of respondents underestimated the contribution of medical imaging tests to total ionizing radiation exposure. Although only thirty-nine percent of participants were confident in their healthcare professional's knowledge of ionizing radiation, most would prefer to receive information from their healthcare professional. Only one-third of individuals who received a medical imaging test in the past year were educated by their healthcare professional about the risks of these tests. Those who tested their home for radon were twice as likely to choose radon as the greatest ionizing radiation risk to self. Although respondents had an above-average education level, there were many misperceptions of actual risks of exposure to ionizing radiation, particularly of medical imaging tests. Educating healthcare professionals would therefore have a profound and positive impact on public understanding of ionizing radiation. PMID- 26060502 TI - Flos Puerariae Extract Ameliorates Cognitive Impairment in Streptozotocin-Induced Diabetic Mice. AB - Objective. The effects of Flos Puerariae extract (FPE) on cognitive impairment associated with diabetes were assessed in C57BL/6J mice. Methods. Experimental diabetic mice model was induced by one injection of 50 mg/kg streptozotocin (STZ) for 5 days consecutively. FPE was orally administrated at the dosages of 50, 100, or 200 mg/kg/day, respectively. The learning and memory ability was assessed by Morris water maze test. Body weight, blood glucose, free fatty acid (FFA) and total cholesterol (TCH) in serum, malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and acetylcholinesterase (AChE) activities in cerebral cortex and hippocampus were also measured. Results. Oral administration of FPE significantly improved cognitive deficits in STZ induced diabetic mice. FPE treatment also maintained body weight and ameliorated hyperglycemia and dyslipidemia in diabetic mice. Additionally, decreased MDA level, enhanced CAT, and GSH-Px activities in cerebral cortex or hippocampus, as well as alleviated AChE activity in cerebral cortex, were found in diabetic mice supplemented with FPE. Conclusion. This study suggests that FPE ameliorates memory deficits in experimental diabetic mice, at least partly through the normalization of metabolic abnormalities, ameliorated oxidative stress, and AChE activity in brain. PMID- 26060503 TI - Acupuncture for Frequent Migraine: A Randomized, Patient/Assessor Blinded, Controlled Trial with One-Year Follow-Up. AB - Objectives. This study aimed to evaluate the efficacy and safety of manual acupuncture as a prophylaxis for frequent migraine. Methods. Fifty frequent migraineurs were randomly allocated to receive 16 sessions of either real acupuncture (RA = 26) or sham acupuncture (SA = 24) during 20 weeks. The primary outcomes were days with migraine over four weeks, duration, and intensity of migraine and the number of responders with more than 50% reduction of migraine days. The secondary outcomes were the relief medication, quality of migraine, quality of life, and pressure pain thresholds. Results. The two groups were comparable at baseline. At the end of the treatment, when compared with the SA group, the RA group reported significant less migraine days (RA: 5.2 +/- 5.0; SA: 10.1 +/- 7.1; P = 0.008), less severe migraine (RA: 2.18 +/- 1.05; SA: 2.93 +/- 0.61; P = 0.004), more responders (RA: 19 versus SA: 7), and increased pressure pain thresholds. No other group difference was found. Group differences were maintained at the end of the three-month follow-up, but not at the one-year follow-up. No severe adverse event was reported. Blinding was successful. Discussion. Manual acupuncture was an effective and safe treatment for short-term relief of frequent migraine in adults. Larger trials are warranted. PMID- 26060504 TI - Automated Segmentation of Cerebellum Using Brain Mask and Partial Volume Estimation Map. AB - While segmentation of the cerebellum is an indispensable step in many studies, its contrast is not clear because of the adjacent cerebrospinal fluid, meninges, and cerebra peduncle. Thus, various cerebellar segmentation methods, such as a deformable model or a template-based algorithm might exhibit incorrect segmentation of the venous sinuses and the cerebellar peduncle. In this study, we propose a fully automated procedure combining cerebellar tissue classification, a template-based approach, and morphological operations sequentially. The cerebellar region was defined approximately by removing the cerebral region from the brain mask. Then, the noncerebellar region was trimmed using a morphological operator and the brain-stem atlas was aligned to the individual brain to define the brain-stem area. The proposed method was validated with the well-known FreeSurfer and ITK-SNAP packages using the dice similarity index and recall and precision scores. As a result, the proposed method was significantly better than the other methods for the dice similarity index (0.93, FreeSurfer: 0.92, ITK SNAP: 0.87) and precision (0.95, FreeSurfer: 0.90, ITK-SNAP: 0.93). Therefore, it could be said that the proposed method yielded a robust and accurate segmentation result. Moreover, additional postprocessing with the brain-stem atlas could improve its result. PMID- 26060505 TI - Fair evaluation of global network aligners. AB - BACKGROUND: Analogous to genomic sequence alignment, biological network alignment identifies conserved regions between networks of different species. Then, function can be transferred from well- to poorly-annotated species between aligned network regions. Network alignment typically encompasses two algorithmic components: node cost function (NCF), which measures similarities between nodes in different networks, and alignment strategy (AS), which uses these similarities to rapidly identify high-scoring alignments. Different methods use both different NCFs and different ASs. Thus, it is unclear whether the superiority of a method comes from its NCF, its AS, or both. We already showed on state-of-the-art methods, MI-GRAAL and IsoRankN, that combining NCF of one method and AS of another method can give a new superior method. Here, we evaluate MI-GRAAL against a newer approach, GHOST, by mixing-and-matching the methods' NCFs and ASs to potentially further improve alignment quality. While doing so, we approach important questions that have not been asked systematically thus far. First, we ask how much of the NCF information should come from protein sequence data compared to network topology data. Existing methods determine this parameter more less arbitrarily, which could affect alignment quality. Second, when topological information is used in NCF, we ask how large the size of the neighborhoods of the compared nodes should be. Existing methods assume that the larger the neighborhood size, the better. RESULTS: Our findings are as follows. MI-GRAAL's NCF is superior to GHOST's NCF, while the performance of the methods' ASs is data dependent. Thus, for data on which GHOST's AS is superior to MI-GRAAL's AS, the combination of MI-GRAAL's NCF and GHOST's AS represents a new superior method. Also, which amount of sequence information is used within NCF does not affect alignment quality, while the inclusion of topological information is crucial for producing good alignments. Finally, larger neighborhood sizes are preferred, but often, it is the second largest size that is superior. Using this size instead of the largest one would decrease computational complexity. CONCLUSION: Taken together, our results represent general recommendations for a fair evaluation of network alignment methods and in particular of two-stage NCF-AS approaches. PMID- 26060506 TI - Prediction of neurosurgical intervention after mild traumatic brain injury using the national trauma data bank. AB - INTRODUCTION: Patients with mild traumatic brain injury (TBI) as defined by an admission Glasgow Coma Score (GCS) of 14-15 often do not require neurosurgical interventions, but which patients will go on to require neurosurgical care has been difficult to predict. We hypothesized that injury patterns would be associated with need for eventual neurosurgical intervention in mild TBI. METHODS: The National Trauma Databank (2007-2012) was queried for patients with blunt injury and a diagnosis of TBI with an emergency department GCS of 14-15. Patients were stratified by age and injury type. Multiple logistic regression for neurosurgical intervention was run with patient demographics, physiologic variables, and injury diagnoses as dependent variables. RESULTS: The study included 50,496 patients, with an overall 8.8 % rate of neurosurgical intervention. Neurosurgical intervention rates varied markedly according to injury type, and were only correlated with age for patients with epidural and subdural hemorrhage. In multiple logistic regression, TBI diagnoses were predictive of need for neurosurgical interventions; moreover, after controlling for injury type and severity score, age was not significantly associated with requiring neurosurgical intervention. CONCLUSIONS: We found that in mild TBI, injury pattern is associated with eventual need for neurosurgical intervention. Patients with cerebral contusion or subarachnoid hemorrhage are much less likely to require neurosurgical intervention, and the effects of age are not significant after controlling for other patient factors. Prospective studies should validate this finding so that treatment guidelines can be updated to better allocate ICU resources. PMID- 26060507 TI - Membrainy: a 'smart', unified membrane analysis tool. AB - BACKGROUND: The study of biological membranes using Molecular Dynamics has become an increasingly popular means by which to investigate the interactions of proteins, peptides and potentials with lipid bilayers. These interactions often result in changes to the properties of the lipids which can modify the behaviour of the membrane. Membrainy is a unified membrane analysis tool that contains a broad spectrum of analytical techniques to enable: measurement of acyl chain order parameters; presentation of 2D surface and thickness maps; determination of lateral and axial headgroup orientations; measurement of bilayer and leaflet thickness; analysis of the annular shell surrounding membrane-embedded objects; quantification of gel percentage; time evolution of the transmembrane voltage; area per lipid calculations; and quantification of lipid mixing/demixing entropy. RESULTS: Each analytical component within Membrainy has been tested on a variety of lipid bilayer systems and was found to be either comparable to or an improvement upon existing software. For the analytical techniques that have no direct comparable software, our results were confirmed with experimental data. CONCLUSIONS: Membrainy is a user-friendly, intelligent membrane analysis tool that automatically interprets a variety of input formats and force fields, is compatible with both single and double bilayers, and capable of handling asymmetric bilayers and lipid flip-flopping. Membrainy has been designed for ease of use, requiring no installation or configuration and minimal user-input to operate. PMID- 26060508 TI - Evaluation of multiplex ligation dependent probe amplification (MLPA) for identification of acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21 (iAMP21) in a Brazilian population. AB - BACKGROUND: An intrachromosomal amplification of chromosome 21 (iAMP21) defines a unique subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The finding of three or more extra copies of the RUNX1 gene by fluorescence in situ hybridization (FISH) is internationally used to define an iAMP21. Genomic profiling of chromosome 21 has been suggested for assisting diagnostic case identification. Due to limitations of comparative genomic hybridization, in terms of a routine application as first line-screening tests we evaluated the multiplex ligation-dependent probe amplification (MLPA) SALSA P327_A1 and P327_B1 probe sets for detecting chromosome 21 copy number alterations in Brazilian childhood BCP-ALL. RESULTS: In 74 out of 368 patients gain of genetic material was detected. For data confirmation RUNX1 directed FISH was performed. Cells with >=5 RUNX1 signals (n = 9) were considered as "true iAMP21" while <5 RUNX1 signals (n = 41) were counted as evidence for additional copies of intact chromosomes 21. All patients with an iAMP21 had high MLPA peak ratios (>=1.8), while the majority of patients with <5 RUNX1 presented low MLPA peak ratios (<1.8). Observed differences gained statistical strength by comparing probes located within the common region of amplification. Next, a principal component analysis was performed in order to illustrate distribution of cases according to their MLPA peak profile in two dimensions. Cases with an iAMP21 mostly clustered together, however additional cases with <5 RUNX1 signals or no available FISH data located in proximity. CONCLUSIONS: MLPA qualified as a high throughput technique that could be employed in future studies for a critical comparison with data obtained by FISH, especially in cases where metaphase nuclei are not available. Taking submicroscopic aberrations into account examined by MLPA, cases exhibiting an "iAMP21 like" peak ratio profile but <5 RUNX1 signals should be considered as candidates for this chromosomal abnormality. PMID- 26060509 TI - Language impairment in a case of a complex chromosomal rearrangement with a breakpoint downstream of FOXP2. AB - BACKGROUND: We report on a young female, who presents with a severe speech and language disorder and a balanced de novo complex chromosomal rearrangement, likely to have resulted from a chromosome 7 pericentromeric inversion, followed by a chromosome 7 and 11 translocation. RESULTS: Using molecular cytogenetics, we mapped the four breakpoints to 7p21.1-15.3 (chromosome position: 20,954,043 21,001,537, hg19), 7q31 (chromosome position: 114,528,369-114,556,605, hg19), 7q21.3 (chromosome position: 93,884,065-93,933,453, hg19) and 11p12 (chromosome position: 38,601,145-38,621,572, hg19). These regions contain only non-coding transcripts (ENSG00000232790 on 7p21.1 and TCONS_00013886, TCONS_00013887, TCONS_00014353, TCONS_00013888 on 7q21) indicating that no coding sequences are directly disrupted. The breakpoint on 7q31 mapped 200 kb downstream of FOXP2, a well-known language gene. No splice site or non-synonymous coding variants were found in the FOXP2 coding sequence. We were unable to detect any changes in the expression level of FOXP2 in fibroblast cells derived from the proband, although this may be the result of the low expression level of FOXP2 in these cells. CONCLUSIONS: We conclude that the phenotype observed in this patient either arises from a subtle change in FOXP2 regulation due to the disruption of a downstream element controlling its expression, or from the direct disruption of non-coding RNAs. PMID- 26060510 TI - Precision cancer mouse models through genome editing with CRISPR-Cas9. AB - The cancer genome is highly complex, with hundreds of point mutations, translocations, and chromosome gains and losses per tumor. To understand the effects of these alterations, precise models are needed. Traditional approaches to the construction of mouse models are time-consuming and laborious, requiring manipulation of embryonic stem cells and multiple steps. The recent development of the clustered regularly interspersed short palindromic repeats (CRISPR)-Cas9 system, a powerful genome-editing tool for efficient and precise genome engineering in cultured mammalian cells and animals, is transforming mouse-model generation. Here, we review how CRISPR-Cas9 has been used to create germline and somatic mouse models with point mutations, deletions and complex chromosomal rearrangements. We highlight the progress and challenges of such approaches, and how these models can be used to understand the evolution and progression of individual tumors and identify new strategies for cancer treatment. The generation of precision cancer mouse models through genome editing will provide a rapid avenue for functional cancer genomics and pave the way for precision cancer medicine. PMID- 26060511 TI - The impact of diabetes on cognitive decline: potential vascular, metabolic, and psychosocial risk factors. AB - Older people with type 2 diabetes are at increased risk of developing cognitive impairment, for which several potential risk factors have been proposed. The present article reviews evidence in people with type 2 diabetes for associations of cognitive impairment with a range of vascular, metabolic, and psychosocial risk factors, many of which have a higher prevalence in people with type 2 diabetes than in non-diabetic adults of a similar age. Definitive research studies in this field are few in number. The risk factors may be involved in causal pathways or may act as useful markers of cerebrovascular damage (or both), and for which relatively consistent evidence is available, include poor glycemic control, hypoglycemia, microvascular disease, inflammation, and depression. For macrovascular disease, the strength of the association with cognitive impairment appears to depend on which vascular system has been examined. A role for pre morbid ability in young adulthood as influencing the risk of both diabetes and cognitive impairment has also been suggested. The importance of considering inter relationships between risk factors when investigating their potential contribution to cognitive impairment in future investigations is discussed. PMID- 26060512 TI - Person-centred healthcare and medicine paradigm: it's time to clarify. AB - The person-centred healthcare and medicine paradigm is in need of a strong theoretical framework not only to explain what it is but to prevent dangerous confusions of terminology or reductive oversimplification of its true scope: for example, it may be integrated into biomedicine, whereas person-centred medicine and Traditional Systems and Complementary and Alternative Medicine (TCAM) actually stand in the position of interacting with the conventional health system. Emphasis on person-centred care is also in line with World Health Organization (WHO) policy and the International Declarations of Beijing and Alma Ata. Interaction of TCAM and person-centred approach to all forms of medicine will ensure variety of therapy in tackling the intrinsically complex and multifaceted issue of health and healing. It will also prevent inestimable traditional knowledge from being lost. PMID- 26060513 TI - Safety and Efficacy of Bimatoprost for Eyelash Growth in Postchemotherapy Subjects. AB - OBJECTIVE: To evaluate long-term efficacy and safety of bimatoprost for treatment of chemotherapy-induced eyelash hypotrichosis. DESIGN: One-year, multicenter, double-masked, parallel-group study. SETTING: Twenty-one centers in the United States and one center in the United Kingdom. PARTICIPANTS: This study randomized (3:1) 130 subjects to bimatoprost 0.03% or vehicle applied topically to upper eyelid margins for six months. All subjects used bimatoprost for a second six months. MEASUREMENTS: Responders for the primary composite end point achieved >=1 grade improvement in Global Eyelash Assessment score and >=3-point improvement in Confidence, Attractiveness, and Professionalism domain score of the Eyelash Satisfaction Questionnaire at Month 4. Secondary assessments included eyelash length, thickness, and darkness, using digital image analysis. RESULTS: The responder rate was significantly higher with bimatoprost versus vehicle at Month 4 (37.5% vs. 18.2%; p=0.041) and Month 6 (46.9% vs. 18.2%; p=0.004). Significant improvements favoring bimatoprost occurred in eyelash length (p=0.008), thickness (p<0.001), or darkness (p=0.029) at Month 4, with similar results at Month 6 (p<0.001, length; p<0.001, thickness; p=0.002, darkness). Responder rates reached 61.5 percent at Month 12 for subjects continuing bimatoprost and 67.6 percent for those switched from vehicle to bimatoprost. Conjunctival hyperemia (16.7%) and punctate keratitis (9.4%) were the most common adverse events. CONCLUSION: Bimatoprost provides rapid eyelash recovery, whether started shortly after chemotherapy (4 to 12 weeks) or delayed for six months, with minimal adverse events. CLINICAL TRIAL REGISTRY: NCT00907426. PMID- 26060514 TI - The Efficacy and Tolerability of a Fixed Combination Clindamycin (1.2%) and Benzoyl Peroxide (3.75%) Aqueous Gel in Adult Female Patients with Facial Acne Vulgaris. AB - OBJECTIVE: To investigate the efficacy and tolerability of clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel or vehicle monotherapy in adult female acne patients. METHODS: A post hoc analysis in 72 adult female patients (aged >=25 years) with moderate-to-severe acne receiving clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel or vehicle for 12 weeks. RESULTS: The efficacy of clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel was significantly greater than vehicle. The mean percent change from baseline in inflammatory and noninflammatory lesion counts and the percentage of patients who achieved a 2-grade reduction in the Evaluator's Global Severity Score was 68.7%, 60.4, and 52.7 percent, respectively (P=0.019, 0.020 and 0.074 versus vehicle). In addition, 44 percent of patients reported their acne to be "clear" or "almost clear" at Week 12 (P=0.026 versus vehicle). No substantive differences were seen in cutaneous tolerability among treatment groups, and no patients discontinued treatment because of adverse events. LIMITATIONS: It is not possible to determine the contributions of the individual active ingredients, and this study was not set up specifically to investigate the treatment of adult female acne. CONCLUSION: Clindamycin phosphate 1.2%/benzoyl peroxide 3.75% gel provides statistically significant greater efficacy than vehicle in treating acne in adult female patients and has a favorable safety and tolerability profile. PMID- 26060515 TI - Treatment Satisfaction Among Patients with Moderate-to-severe Psoriasis. AB - OBJECTIVE: Various treatment options are available for the management of psoriasis; however, there remains a scarcity of literature regarding satisfaction levels among these patients. Given that treatment dissatisfaction is associated with lower levels of adherence, the objective of the present study was to establish satisfaction levels among patients with psoriasis. DESIGN: A modified version of a previously validated satisfaction questionnaire was completed by patients. SETTING: Dermatology outpatient department (Solihull, United Kingdom). PARTICIPANTS: Thirty-eight patients with psoriasis (median age 43). MEASUREMENTS: The questionnaire addressed various domains of satisfaction including satisfaction with safety, convenience, information provision, and finally global satisfaction with 1) topical treatments, 2) phototherapy, and 3) systemic treatments. RESULTS: Mean global satisfaction with phototherapy and systemic treatments was significantly higher than with topical treatments. The authors' findings also showed that 20 percent of patients receiving topical treatment were dissatisfied with the convenience of the treatment. Interestingly, the only domain causing dissatisfaction among patients receiving systemic therapies (largely biologies) was safety. Despite this, satisfaction with both systemic treatment and phototherapy was higher than has been previously reported. CONCLUSION: The findings of this study indicate that levels of satisfaction with phototherapy and systemic treatments are high, which is encouraging for both clinicians and patients. However, there are undoubtedly higher levels of dissatisfaction with topical treatments. Given that topical treatments have the greatest safety profile, they will continue to be the first-line treatment for psoriasis. Advances that focus on patient concerns should become a priority in order to improve compliance and reduce the need for more costly intervention. PMID- 26060517 TI - Comprehensive Tuberculosis Testing for the Dermatologist. AB - Tuberculosis remains a noteworthy disease worldwide, rendering detection of latent tuberculosis of great importance. As healthcare workers, dermatologists should be aware of the available testing options and how they compare. In general, the tuberculin skin test has been around longer and, thus, there have been more studies performed on its sensitivity and specificity compared to interferon gamma release assays, which are newer to the market. The tuberculin skin test requires more office visits, takes longer to obtain results, is subject to healthcare worker bias, and can cause a booster phenomenon; whereas, interferon gamma release assays have a higher cost and less data available on their use in children under five years old. Both the tuberculin skin test and interferon gamma release assays fail to differentiate between recent and remote infections, have a low predictive value for active tuberculosis, and a lower sensitivity in people living with human immunodeficiency virus/acquired immunodeficiency syndrome. PMID- 26060516 TI - Sports Dermatology: Part 1 of 2 Traumatic or Mechanical Injuries, Inflammatory Conditions, and Exacerbations of Pre-existing Conditions. AB - Competitive athletes endure extreme bodily stress when participating in sports related activities. An athlete's skin is particularly susceptible to a wide array of repetitive physical and environmental stressors that challenge the skin's protective function. Many unique dermatoses are well-known to the serious athlete due to countless hours of intense physical training, but are frequently unrecognized by many healthcare professionals. Sports dermatology is a distinctive, budding field of dermatology that focuses on dermatoses frequently encountered in athletes. Athletic skin problems are notoriously infectious in nature due to the inherent environment of close-contact physical activity. Nonetheless, other skin conditions can manifest or worsen with recurring mechanical or traumatic injury or exposure to environmental hazards. Additionally, sports-related activities may exacerbate other pre-existing dermatological conditions that may possibly be unknown to the athlete or clinician. The objective of this two-part review is to arm the astute physician with the fundamental knowledge of the range of dermatological conditions distinct to the competitive athlete. Knowledge of these cutaneous conditions in the context of specific sporting events will permit the clinician to manage these unique patients most effectively. Part one will focus on traumatic or mechanical injuries, inflammatory conditions, and exacerbations of pre-existing conditions frequently seen in athletes. PMID- 26060518 TI - Differentiating Early Stage Cystic Keratoacanthoma, Nodular Basal Cell Carcinoma, and Excoriated Acne Vulgaris by Clinical Exam, Dermoscopy, and Optical Coherence Tomography: A Report of 3 Cases. AB - Making accurate diagnoses when certain lesions are in a relatively young stage can prove challenging, as their "textbook descriptions" are often not fully apparent, and may in fact be markedly different. The authors present three interesting cases of early lesions that were clinically difficult to differentiate from one another: a cystic variation of a keratoacanthoma squamous cell carcinoma, a basal cell carcinoma, and an excoriated facial acne vulgaris. The subtle clinical nuances found in each of these cases demonstrated the importance of a careful clinical evaluation; however, this was not sufficient for adequate assessment of whether or not to biopsy. With early lesions such as these, the use of the noninvasive imaging modalities of dermoscopy and optical coherence tomography becomes critical in order to avoid unnecessary biopsy. The discussion of the clinically and dermoscopically challenging features is both instructive and enlightening. Oftentimes, "textbook descriptions" of lesions focus on the description of an already mature stage of growth, despite the fact that we continue to strive toward earlier detection of potential malignancies. With this in mind, the features found with optical coherence tomography proved essential to the elucidation of these difficult lesions. These three interesting cases illustrated the challenges encountered when dealing with early lesions specifically. The authors bring to light features in each of these cases that are often not thought of as being the "typical" presentation in each lesion category and demonstrate the clinical utility of noninvasive devices in difficult-to diagnose cases such as these. PMID- 26060519 TI - Brain Magnetic Resonance Imaging in a Patient with Entrapped Echelon Microcatheter within Onyx Cast. PMID- 26060520 TI - Stent-Assisted Coil Embolization of a Wide-Neck Aneurysm at the Vertebral Artery Terminus Using a Contralateral Approach: A Technical Report. AB - BACKGROUND: Aneurysms of the vertebrobasilar junction (VBJ) are especially uncommon but carry a significant risk of hemorrhage and historically have been difficult to treat. In recent years, however, advancements in stent-assisted embolization have allowed better access and stabilization of complicated posterior circulation aneurysms. METHODS: We describe a novel approach in the treatment of a wide-neck aneurysm at the terminus of the left vertebral artery by a contralateral approach in a patient with ipsilateral subclavian artery occlusion. RESULTS: A complex, wide-neck aneurysm at the verterbrobasilar junction hindered by ipsilateral subclavian occlusion can successfully be treated with stent-assisted coil embolization using a contralateral approach. CONCLUSION: Contralateral U-shaped stenting offers a viable endovascular option for patients with complex aneurysms of the vertebral basilar junction but should be reserved for appropriate cases with favorable anatomy when the ipsilateral approach from the subclavian artery is unobtainable. PMID- 26060521 TI - Can the World Federation of Neurosurgical Societies Classification Accurately Predict Outcomes in Intracerebral Hemorrhage? AB - BACKGROUND: Many scoring systems have been developed for the purpose of estimating of mortality and outcomes in intracerebral hemorrhage (ICH). However, the utility of the World Federation of Neurosurgical Society (WFNS) classification, which is routinely used in patients with subarachnoid hemorrhage, has never been specifically assessed in ICH. METHODS: A retrospective review of the records of consecutive ICH patients admitted over a 2-year period was carried out. Collected data included ICH size, location, intraventricular hemorrhage, age, admission Glasgow Coma Scale scores, and outcomes on discharge. Linear regression was performed to confirm correlations of the WFNS scale and the ICH score separately with good outcome, poor outcome, and in-hospital mortality. Receiver-operator characteristic (ROC) curve was employed to plot WFNS and ICH scores each in relation to in-hospital mortality and poor outcome. Accuracy was estimated by calculating the area under the curves (AUC). RESULTS: In this study, 128 patients were included. The overall mortality rate was 34.4%. Linear regression showed appropriate fit for both the ICH Score and the WFNS in relation to poor outcome and mortality. The ROC curves for the scales in relation to in hospital death produced an AUC estimate 0.93 for WFNS and 0.92 for the ICH Score (p = 0.81). For poor outcome, the AUC values were 0.91 and 0.90 for the WFNS and the ICH Score, respectively (p = 0.9). For good outcome, the AUC for WFNS was 0.86 and for the ICH score, 0.85 (p = 0.74). CONCLUSION: The WFNS classification is as accurate as the ICH score in predicting discharge outcomes and in-hospital mortality. It is a simple clinical scale that can be used to predict outcomes in both ICH and subarachnoid hemorrhage patients. PMID- 26060522 TI - Mechanical Thrombectomy Using Solitaire in a 6-Year-Old Child. AB - A six-year-old boy was diagnosed as recurrent posterior circulation stroke secondary to basilar artery occlusion with rapid progression of symptoms. Etiology of stroke was a dissection of V3 segment of left vertebral artery, which was treated using endovascular technique 26 hours after worsening of symptoms. Since the guidelines for acute revascularization in pediatric stroke are not well established, there is limited experience in the use of mechanical devices for acute ischemic stroke revascularization in children. To our knowledge, this is one of the youngest reported cases of acute ischemic stroke from Asia managed with newer mechanical clot removal devices. PMID- 26060523 TI - Fusiform Basilar Artery Aneurysm Associated with Pontine Lacunar Infarctions. PMID- 26060524 TI - Trends in Outcome and Hospitalization Cost among Adult Patients with Acute Ischemic Stroke in the United States. AB - INTRODUCTION: New treatments for acute ischemic stroke (AIS) have been introduced and are expected to improve patients' overall outcomes. We assessed the impact of new therapeutic strategies on outcome and cost of hospitalization among adult patients with AIS in the United States. METHODS: Patients with AIS admitted in the United States in 1993-1994 and 2006-2007 were listed using the Nationwide Inpatient Survey database. We determined the rates of occurrence, hospitalization outcomes, and mean hospital charges for all patients. We further analyzed these variables in the ventilated and nonventilated patients. RESULTS: We identified 386,043 patients with AIS admitted in the United States in 1993-1994 and 749,766 patients in 2006-2007. The length of hospitalization was significantly higher in 1993-1994 compared with 2006-2007: 6.9 +/- 4.2 days versus 4.66 +/- 3 days, respectively. In-hospital mortality rate was 8.9% in 1993-1994 and 5.6% in 2006 2007 (P < 0.0001). There was a significant increase in mean hospital charges in 2006-2007 compared with 1993-1994 ($21,916 +/- $14,117 versus $9,646 +/- $5,727). The length of hospitalization was significantly shorter in 2006-2007 in nonventilated patients. There was a significant increase in mean hospital charges in 2006-2007 compared with 1993-1994 in both ventilated ($81,528 +/- $64,526 versus $25,143 +/- $17,172, P<0.0001) and nonventilated patients ($21,085 +/- $13,042 versus $10,000 +/- $6,300, P<0.0001). The mortality rate was significantly lower in 2006-2007 in both subgroups: 46.5% versus 59.8% in ventilated patients and 4.2% versus 8.2% in nonventilated patients (P < 0.0001). CONCLUSION: Our study suggests that new therapeutic strategies have improved outcomes and increased cost of hospitalization among adult patients with AIS in the United States over a period of 13 years. The hospitalization cost was significantly higher in the ventilated and nonventilated patients in 2006-2007, which may reflect the impact of new therapeutic strategies, the availability of more intensive care units and stroke centers, and the lower mortality rate in this time period. PMID- 26060525 TI - Complex Partial Epilepsy Associated with Temporal Lobe Developmental Venous Anomaly. AB - BACKGROUND: Developmental venous anomalies (DVA) are found incidentally but sometimes patients with these anomalies present with varying degrees of neurologic manifestations. OBJECTIVE: We report a patient with early onset complex partial epilepsy and associated DVA and discuss the natural history, neuroimaging and clinical characteristics, and management. CASE DESCRIPTION: A 21 year-old man presented with a history of complex partial epilepsy with secondary generalization which started at the age of 4 years. An electroencephalogram (EEG) was performed which demonstrated spike and wave discharges predominantly in the left frontotemporal region. A magnetic resonance imaging (MRI) was performed which demonstrated a linear flow void suggestive of a DVA. The angiogram demonstrated DVA that connected with the left transverse venous sinus and an anastomotic vein between the straight sinus and the transverse venous sinus traversing the brain parenchyma. He was started on carbamezipine for the treatment of complex partial seizures. CONCLUSIONS: Temporal lobe DVA may be associated with complex partial seizures and can be diagnosed by MRI and angiographic findings. PMID- 26060526 TI - Percutaneous Access to the Subarachnoid Space-An Approach to the Patient With Difficult Body Habitus. PMID- 26060527 TI - Postictal Todd's Paralysis Associated with Focal Cerebral Hypoperfusion on Magnetic Resonance Perfusion Studies. AB - BACKGROUND: The exact underlying physiology of postictal motor deficits, known as Todd's paralysis, is not well understood and its vascular perfusion physiology is not well studied. Reversible postictal perfusion abnormalities have been sparsely described in the literature. METHODS: We report abnormal brain magnetic resonance perfusion maps in a 9-year-old boy who presented with postictal left hemiparesis. This case correlates postictal hemispheric cerebral hypoperfusion with clinical evidence of Todd's paralysis. CONCLUSIONS: Our case provides an insight into the potential pathophysiology mechanism underlying Todd's paralysis and the practicality of magnetic resonance perfusion studies in localizing an epileptogenic zone in the postictal patient. PMID- 26060528 TI - A Method for Quantifying Angiographic Severity of Extracranial Vertebral Artery Stenosis. PMID- 26060529 TI - Preliminary Experience with use of Qureshi-5 Catheters for Diagnostic Cerebral Angiography. AB - BACKGROUND: A catheter technique was developed to overcome current challenges in the stabilization and manipulation of catheter in tortuous arteries such as right subclavian artery and left common carotid artery. METHODS: The new catheter has the following two lumens: first lumen can accommodate a 0.035-inch guide wire (lumen A) and a curved shape at the distal end; the second lumen can accommodate a 0.018-inch guide wire and terminates at the beginning of the distal curve of the first lumen (lumen B). The catheter is withdrawn or advanced over the 0.018 inch guide wire and the curved free end of catheter manipulated until the end engages the origin of the target artery. Subsequently, either contrast can be injected or a 0.035-inch guide wire advanced into the target artery. RESULTS: The catheters were used in two patients to perform diagnostic cerebral angiography through a 6F introducer sheath placed in the right common femoral artery. The left and right common carotid arteries and left and right vertebral arteries were catheterized in first patient (contrast used 50 ml; fluoroscopy time 20:09 min). The left and right internal carotid arteries, left and right subclavian arteries, and left external carotid artery were catheterized in second patient (contrast used 40 ml; fluoroscopy time 13:56 min). No complications were observed in either of the two patients. CONCLUSIONS: The performance of the new catheter for catheterization of multiple arteries in two patients was considered adequate with high-quality angiographic image acquisitions. PMID- 26060530 TI - Catheter-Based Transepidural Approach to Cervical and Thoracic Posterior and Perineural Epidural Spaces: A Cadaveric Feasibility Study. AB - BACKGROUND AND OBJECTIVES: Approaching the cervical and high thoracic level epidural space through transepidural route from lumbar region represents a method to lower the occurrence of complications associated with direct approach. The authors performed a cadaveric pilot project to determine the feasibility of various catheter-based manipulation and cephalad advancement using the transepidural route. STUDY DESIGN AND METHODS: Two cadavers were used to determine the following: 1. Ability to place a guide sheath over a guidewire using a percutaneous approach within the posterior lumbar epidural space; 2. The highest vertebral level catheter can be advanced within the posterior epidural space; 3. Ability to cross midline within the posterior epidural space; and 4. Ability to catheterize the perineural epidural sheaths of the nerve roots exiting at cervical and thoracic vertebral levels. RESULTS: We were able to advance the catheters up to the level of cervical vertebral level of C2 within the posterior epidural space under fluoroscopic guidance from a sheath inserted via oblique parasagittal approach at the lumbar L4-L5 intervertebral space. We were able to cross midline within the posterior epidural space and catheterize multiple perineural epidural sheaths of the nerve roots exiting at cervical vertebral level of C2, C3, and C4 on ipsilateral or contralateral sides. We also catheterized multiple epidural sheaths that surround the nerve roots exiting at the thoracic vertebral level on ipsilateral or contralateral sides. CONCLUSIONS: We were able to advance a catheter or microcatheter up to the cervical vertebral level within the posterior epidural space and catheterize the perineural epidural sheath of the nerve root exiting at cervical and thoracic vertebral levels. Such observations support further exploration of percutaneous catheter based transepidural approach to cervical and thoracic dorsal epidural spaces for therapeutic interventions. PMID- 26060531 TI - Enhanced Locomotor Activity Is Required to Exert Dietary Restriction-Dependent Increase of Stress Resistance in Drosophila. AB - Dietary restriction (DR) is known to be one of the most effective interventions to increase stress resistance, yet the mechanisms remain elusive. One of the most obvious DR-induced changes in phenotype is an increase in locomotor activity. Although it is conceptually perceivable that nutritional scarcity should prompt enhanced foraging behavior to garner additional dietary resources, the significance of enhanced movement activity has not been associated with the DR dependent increase of stress resistance. In this study, we confirmed that flies raised on DR exhibited enhanced locomotive activity and increased stress resistance. Excision of fly wings minimized the DR-induced increase in locomotive activity, which resulted in attenuation of the DR-dependent increase of stress resistance. The possibility that wing clipping counteracts the DR by coercing flies to have more intake was ruled out since it did not induce any weight gain. Rather it was found that elimination of reactive oxygen species (ROS) that is enhanced by DR-induced upregulation of expression of antioxidant genes was significantly reduced by wing clipping. Collectively, our data suggests that DR increased stress resistance by increasing the locomotor activity, which upregulated expression of protective genes including, but not limited to, ROS scavenger system. PMID- 26060532 TI - Anti-inflammatory effect of enzymatic hydrolysates from Styela clava flesh tissue in lipopolysaccharide-stimulated RAW 264.7 macrophages and in vivo zebrafish model. AB - BACKGROUND/OBJECTIVES: In this study, potential anti-inflammatory effect of enzymatic hydrolysates from Styela clava flesh tissue was assessed via nitric oxide (NO) production in lipopolysaccahride (LPS) induced RAW 264.7 macrophages and in vivo zebrafish model. MATERIALS/METHODS: We investigated the ability of enzymatic hydrolysates from Styela clava flesh tissue to inhibit LPS-induced expression of pro-inflammatory mediators in RAW 264.7 macrophages, and the molecular mechanism through which this inhibition occurred. In addition, we evaluated anti-inflammatory effect of enzymatic hydrolysates against a LPS exposed in in vivo zebrafish model. RESULTS: Among the enzymatic hydrolysates, Protamex-proteolytic hydrolysate exhibited the highest NO inhibitory effect and was fractionated into three ranges of molecular weight by using ultrafiltration (UF) membranes (MWCO 5 kDa and 10 kDa). The above 10 kDa fraction down-regulated LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), thereby reducing production of NO and prostaglandin E2 (PGE2) in LPS-activated RAW 264.7 macrophages. The above 10 kDa fraction suppressed LPS-induced production of pro-inflammatory cytokines, including interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha. In addition, the above 10 kDa fraction inhibited LPS-induced phosphorylation of extracellular signal-regulated kinases (ERKs), c-Jun N-terminal kinase (JNK), and p38. Furthermore, NO production in live zebrafish induced by LPS was reduced by addition of the above 10 kDa fraction from S. clava enzymatic hydrolysate. CONCLUSION: The results of this study suggested that hydrolysates derived from S. clava flesh tissue would be new anti-inflammation materials in functional resources. PMID- 26060533 TI - Dual effects of a mixture of grape pomace (Campbell Early) and Omija fruit ethanol extracts on lipid metabolism and the antioxidant defense system in diet induced obese mice. AB - BACKGROUND/OBJECTIVES: We investigated the effects of a combination of grape pomace (Vitis labrusca, Campbell Early) and Omija fruit (Schizandra chinensis, Baillon) ethanol extracts on lipid metabolism and antioxidant defense system in diet-induced obese mice. MATERIALS/METHODS: Forty male C57BL/6J mice were divided into four groups and fed high-fat diet (control group, CON) or high-fat diet added 0.5% grape pomace extract (GPE), 0.05% Omija fruit extract (OFE) or 0.5% GPE plus 0.05% OFE (GPE+OFE) for 12 weeks. RESULTS: In contrast to the GPE- or OFE-supplemented groups, the GPE+OFE group showed significantly lower body weight and white adipose tissue weights than the CON group. Moreover, GPE+OFE supplementation significantly decreased plasma total cholesterol and increased the plasma HDL-cholesterol/total-cholesterol ratio (HTR) compared to the control diet. The hepatic triglyceride level was significantly lower in the GPE+OFE and GPE groups by increasing beta-oxidation and decreasing lipogenic enzyme compared to the CON group. Furthermore, GPE+OFE supplementation significantly increased antioxidant enzyme activities with a simultaneous decrease in liver H2O2 content compared to the control diet. CONCLUSIONS: Together our results suggest that supplementation with the GPE+OFE mixture may be more effective in improving adiposity, lipid metabolism and oxidative stress in high-fat diet-fed mice than those with GPE and OFE alone. PMID- 26060534 TI - Inhibitory effects of Doenjang, Korean traditional fermented soybean paste, on oxidative stress and inflammation in adipose tissue of mice fed a high-fat diet. AB - BACKGROUND/OBJECTIVES: Doenjang, Korean traditional fermented soybean paste has been reported to have an anti-obesity effect. Because adipose tissue is considered a major source of inflammatory signals, we investigated the protective effects of Doenjang and steamed soybean on oxidative stress and inflammation in adipose tissue of diet-induced obese mice. MATERIALS/METHODS: Male C57BL/6J mice were fed a low fat diet (LF), a high-fat diet (HF), or a high-fat containing Doenjang diet (DJ) or a high-fat containing steamed soybean diet (SS) for 11 weeks. RESULTS: Mice fed a DJ diet showed significantly lower body and adipose tissue weights than those in the HF group. Although no significant differences in adipocyte size and number were observed among the HF diet-fed groups, consumption of Doenjang alleviated the incidence of crown-like structures in adipose tissue. Consistently, we observed significantly reduced mRNA levels of oxidative stress markers (heme oxygenase-1 and p40(phox)), pro-inflammatory adipokines (tumor necrosis factor alpha and macrophage chemoattractant protein-1), macrophage markers (CD68 and CD11c), and a fibrosis marker (transforming growth factor beta 1) by Doenjang consumption. Gene expression of anti-inflammatory adipokine, adiponectin was significantly induced in the DJ group and the SS group compared to the HF group. The anti-oxidative stress and anti-inflammatory effects observed in mice fed an SS diet were not as effective as those in mice fed a DJ diet, suggesting that the bioactive compounds produced during fermentation and aging may be involved in the observed health-beneficial effects of Doenjang. CONCLUSIONS: Doenjang alleviated oxidative stress and restored the dysregulated expression of adipokine genes caused by excess adiposity. Therefore, Doenjang may ameliorate systemic inflammation and oxidative stress in obesity via inhibition of inflammatory signals of adipose tissue. PMID- 26060535 TI - Comparison of the gut microbiota profile in breast-fed and formula-fed Korean infants using pyrosequencing. AB - BACKGROUND/OBJECTIVES: Feeding in infancy is the most significant determinant of the intestinal microbiota in early life. The aim of this study was to determine the gut microbiota of Korean infants and compare the microbiota obtained between breast-fed and formula-fed Korean infants. SUBJECTS/METHODS: We analyzed the microbial communities in fecal samples collected from twenty 4-week old Korean (ten samples in each breast-fed or formula-fed) infants using pyrosequencing. RESULTS: The fecal microbiota of the 4-week-old Korean infants consisted of the three phyla Actinobacteria, Firmicutes, and Proteobacteria. In addition, five species, including Bifidocbacterium longum, Streptococcus salivarius, Strepotococcus lactarius, Streptococcus pseudopneumoniae, and Lactobacillus gasseri were common commensal intestinal microbiota in all infants. The predominant intestinal microbiota in the breast-fed infants (BFI) included the phylum Actinobacteria (average 70.55%), family Bifidobacteriacea (70.12%), genus Bifidobacterium (70.03%) and species Bifidobacterium longum (69.96%). In the microbiota from the formula-fed infants (FFI), the proportion of the phylum Actinobacteria (40.68%) was less, whereas the proportions of Firmicutes (45.38%) and Proteobacteria (13.85%) as well as the diversity of each taxonomic level were greater, compared to those of the BFI. The probiotic species found in the 4-week old Korean infants were Bifidobacterium longum, Streptococcus salivarius, and Lactobacillus gasseri. These probiotic species accounted for 93.81% of the microbiota from the BFI, while only 63.80% of the microbiota from the FFI. In particular, B. longum was more abundant in BFI (69.96%) than in FFI (34.17%). CONCLUSIONS: Breast milk supports the growth of B. longum and inhibits others. To the best of our knowledge, this study was the first attempt to analyze the gut microbiota of healthy Korean infants according to the feeding type using pyrosequencing. Our data can be used as a basis for further studies to investigate the development of intestinal microbiota with aging and disease status. PMID- 26060536 TI - The supplementation effects of peanut sprout on reduction of abdominal fat and health indices in overweight and obese women. AB - BACKGROUD/OBJECTIVES: This study was conducted in order to investigate the effect of peanut sprout extracts (PSE) on health indices in overweight and obese women (BMI >= 23 kg/m(2)). SUBJECTS/METHODS: Subjects were divided into three groups by double-blind randomized trial; the Placebo group (n = 15) and the Low PSE group (2.6 g PSE/day, n = 15), and the High PSE group (5.8 g PSE/day, n = 15). Subjects consumed 12 capsules per day, three times a day, 30 min before meals, for 4 weeks. Anthropometric data, blood biochemical variables, and dietary intake were evaluated before and after the experiments. RESULTS: In the Low and High PSE group, the waist circumference showed a significant decrease between pre- and post-test. In the Low PSE group, the reduction of systolic blood pressure between pre- and post-test was statistically significant. Serum LDL or triglyceride levels in both Low and High PSE groups were significantly decreased, and serum alanine transaminase and aspartate transaminase were significantly decreased only in the Low PSE group. The parameters regarding erythrocyte and leucocyte counts showed no significant differences between pre- and post-test among groups, which suggested the safety of intake of peanut sprouts as a dietary supplement. CONCLUSIONS: This study indicates that PSE supplementation improves abdominal obesity and overall health indices. Therefore, an appropriate amount of peanut sprouts may be a plausible effective agent for obesity and obesity related health problems in obese women. PMID- 26060537 TI - The effect of yacon (Samallanthus sonchifolius) ethanol extract on cell proliferation and migration of C6 glioma cells stimulated with fetal bovine serum. AB - BACKGROUND/OBJECTIVES: Yacon (Samallanthus sonchifolius), a common edible plant grown throughout the world, is well known for its antidiabetic properties. It is also known to have several other pharmacological properties including anti inflammatory, anti-oxidant, anti-allergic, and anti-cancer effects. To date, the effect of yacon on gliomas has not been studied. In this study, we investigated the effects of yacon on the migration and proliferation of C6 glioma cells stimulated by fetal bovine serum (FBS). MATERIALS/METHODS: Cell growth and proliferation were determined by evaluating cell viability using an EZ-Cytox Cell Viability Assay Kit. FBS-induced migration of C6 glioma cells was evaluated by performing the scratch wound healing assay and the Boyden chamber assay. We also used western blot analysis to determine the expression levels of extracellular signal-regulated kinase 1/2 (ERK1/2), a major regulator of migration and proliferation of glioma cells. Matrix metallopeptidase (MMP) 9 and TIMP-1 levels were measured by performing reverse transcription PCR. RESULTS: Yacon (300 ug/mL) reduced both the FBS-induced proliferation of C6 glioma cells and the dose dependent migration of the FBS-stimulated C6 cells. FBS-stimulated C6 glioma cells treated with yacon (200 and 300 ug/mL) showed reduced phosphorylation of ERK1/2 and inhibition of MMP 9 expression compared to those shown by the untreated FBS-stimulated C6 cells. In contrast, yacon (200 and 300 ug/mL) induced TIMP-1 expression. CONCLUSIONS: On the basis of these results, we suggest that yacon may exert an anti-cancer effect on FBS-stimulated C6 glioma cells by inhibiting their proliferation and migration. The most likely mechanism for this is down-regulation of ERK1/2 and MMP9 and up-regulation of TIMP-1 expression levels. PMID- 26060538 TI - Hypoglycemic and antioxidant effects of Daraesoon (Actinidia arguta shoot) in animal models of diabetes mellitus. AB - BACKGROUND/OBJECTIVES: The primary objective of the treatment of diabetes mellitus is the attainment of glycemic control. Hyperglycemia increases oxidative stress which contributes to the progression of diabetic complications. Thus, the purpose of this study was to investigate the hypoglycemic and antioxidant effects of Daraesoon (Actinidia arguta shoot) in animal models of diabetes mellitus. MATERIALS/METHODS: Rats with streptozotocin-induced diabetes received an oral administration of a starch solution (1 g/kg) either with or without a 70% ethanol extract of Daraesoon (400 mg/kg) or acarbose (40 mg/kg) after an overnight fast and their postprandial blood glucose levels were measured. Five-week-old C57BL/6J mice were fed either a basal or high-fat/high-sucrose (HFHS) diet with or without Daraesoon extract (0.4%) or acarbose (0.04%) for 12 weeks after 1 week of adaptation to determine the effects of the chronic consumption of Daraesoon on fasting hyperglycemia and antioxidant status. RESULTS: Compared to the control group, rats that received Daraesoon extract (400 mg/kg) or acarbose (40 mg/kg) exhibited a significant reduction in the area under the postprandial glucose response curve after the oral ingestion of starch. Additionally, the long-term consumption of Daraesoon extract or acarbose significantly decreased serum glucose and insulin levels as well as small intestinal maltase activity in HFHS fed mice. Furthermore, the consumption of Daraesoon extract significantly reduced thiobarbituric acid reactive substances and increased glutathione levels in the livers of HFHS-fed mice compared to HFHS-fed mice that did not ingest Daraesoon. CONCLUSIONS: Daraesoon effectively suppressed postprandial hyperglycemia via the inhibition of alpha-glucosidase in STZ-induced diabetic rats. Chronic consumption of Daraesoon alleviated fasting hyperglycemia and oxidative stress in mice fed a HFHS diet. PMID- 26060539 TI - Efficacy of mid-upper arm circumference in identification, follow-up and discharge of malnourished children during nutrition rehabilitation. AB - BACKGROUND/OBJECTIVES: Although it is crucial to identify those children likely to be treated in an appropriate nutrition rehabilitation programme and discharge them at the appropriate time, there is no golden standard for such identification. The current study examined the appropriateness of using Mid-Upper Arm Circumference for the identification, follow-up and discharge of malnourished children. We also assessed its discrepancy with the Weight-for-Height based diagnosis, the rate of recovery, and the discharge criteria of the children during nutrition rehabilitation. SUBJECTS/METHODS: The study present findings from 156 children (aged 6-59 months) attending a supplementary feeding programme at Makadara and Jericho Health Centres, Eastern District of Nairobi, Kenya. Records of age, weight, height and mid-upper arm circumference were selected at three stages of nutrition rehabilitation: admission, follow-up and discharge. The values obtained were then used to calculate z-scores as defined by WHO Anthro while estimating different diagnostic indices. RESULTS: Mid-upper arm circumference single cut-off (< 12.5 cm) was found to exhibit high values of sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio at both admission and discharge. Besides, children recorded higher rate of recovery at 86 days, an average increment of 0.98 cm at the rate of 0.14mm/day, and a weight gain of 13.49gm/day, albeit higher in female than their male counterparts. Nevertheless, children admitted on basis of low MUAC had a significantly higher MUAC gain than WH at 0.19mm/day and 0.13mm/day respectively. CONCLUSIONS: Mid-upper arm circumference can be an appropriate tool for identifying malnourished children for admission to nutrition rehabilitation programs. Our results confirm the appropriateness of this tool for monitoring recovery trends and discharging the children thereafter. In principle the tool has potential to minimize nutrition rehabilitation costs, particularly in community therapeutic centres in developing countries. PMID- 26060541 TI - Breakfast skipping and breakfast type are associated with daily nutrient intakes and metabolic syndrome in Korean adults. AB - BACKGROUND/OBJECTIVES: Emerging evidence shows that eating breakfast and breakfast types may be associated with health outcomes and dietary intakes in various populations. The aim of this study was to investigate the association between breakfast types in Korean adults with their daily nutrient intakes and health outcomes. SUBJECTS/METHODS: A total of 11,801 20- to 64-year-old adults (age 42.9 +/- 11.8 yrs [mean +/- standard error of the mean]; male 41.1%, female 58.9%) in 2007-2009 Korean National Health and Nutrition Survey data were divided into 5 groups based on breakfast types in a 24-hr dietary recall: rice with 3 or more side dishes (Rice3+, 35.3%), rice with 0-2 side dishes (Rice0-2, 34.73%), noodles (1.56%), bread and cereal (6.56%), and breakfast skipping (21.63%). Daily nutrient intakes and the risk of metabolic syndrome were compared among five groups. RESULTS: Compared with Korean Recommended Nutrient Intake levels, the breakfast-skipping group showed the lowest intake level in most nutrients, whereas the Rice3+ group showed the highest. Fat intake was higher in the bread and noodle groups than in the other groups. When compared with the Rice3+ group, the odds ratios for the risk of obesity and metabolic syndrome were increased in the breakfast skipping, Rice0-2, and noodle groups after controlling for confounding variables. CONCLUSIONS: The rice-based breakfast group showed better nutritional status and health outcomes when eating with 3 or more side dishes. Nutrition education is needed to emphasize both the potential advantage of the rice-based, traditional Korean diet in terms of nutritional content and the importance of food diversity. PMID- 26060542 TI - Importance-satisfaction analysis of street food sanitation and choice factor in Korea and Taiwan. AB - BACKGROUND/OBJECTIVES: The present study investigated Korean and Taiwan adults on the importance of and the satisfaction with street food sanitation and street food choice factor, in order to present management and improvement measures for street foods. SUBJECTS/METHODS: The present study conducted a survey on 400 randomly chosen adults (200 Korean, 200 Taiwanese). General characteristics, eating habits, street food intake frequency, and preference by type of street food of respondents were checked. Respondents' importance and satisfaction of street food hygiene and selection attributes were also measured. In order to test for the difference between groups, chi(2)-test and t-test were performed. ISA was also performed to analyze importance and satisfaction. RESULTS: Results showed that the importance of sanitation was significantly higher than satisfaction on all items in both Korea and Taiwan, and the satisfaction with sanitation was higher in Taiwan than in Korea. According to ISA results with street food sanitation, satisfaction was low while importance was high in both Korea and Taiwan. In terms of street food choice factor, importance scores were significantly higher than satisfaction scores on all items. In addition, satisfaction scores on all items except 'taste' were significantly higher in Taiwan than in Korea. CONCLUSIONS: A manual on sanitation management of street foods should be developed to change the knowledge and attitude toward sanitation by putting into practice a regularly conducted education. Considering the popularity of street foods and its potential as a tourism resource to easily publicize our food culture, thorough management measures should be prepared on sanitation so that safe street food culture should be created. PMID- 26060540 TI - The relationship between household income and dietary intakes of 1-10 year old urban Malaysian. AB - BACKGROUND/OBJECTIVES: Diet plays an important role in growth and development of children. However, dietary intakes of children living in either rural or urban areas can be influenced by household income. This cross-sectional study examined energy, nutrient and food group intakes of 749 urban children (1-10 years old) by household income status. SUBJECTS/METHODS: Children's dietary intakes were obtained using food recall and record for two days. Diet adequacy was assessed based on recommended intakes of energy and nutrients and food group servings. RESULTS: For toddlers, all nutrients except dietary fiber (5.5 g) exceeded recommended intakes. Among older children (preschoolers and school children), calcium (548 mg, 435 mg) and dietary fiber (7.4 g, 9.4 g) did not meet recommendations while percentage of energy from total fat and saturated fats exceeded 30% and 10%, respectively. The mean sodium intakes of preschoolers (1,684 mg) and school children (2,000 mg) were relatively high. Toddlers in all income groups had similar energy and nutrient intakes and percentages meeting the recommended intakes. However, low income older children had lowest intakes of energy (P < 0.05) and most nutrients (P < 0.05) and highest proportions that did not meet recommended energy and nutrient intakes. For all food groups, except milk and dairy products, all age groups had mean intakes below the recommended servings. Compared to middle and high income groups, low income preschoolers had the lowest mean intake of fruits (0.07 serving), meat/poultry (0.78 serving) and milk/dairy products (1.14 serving) while low income toddlers and school children had the least mean intake of fruits (0.09 serving) and milk/dairy products (0.54 serving), respectively. CONCLUSION: Low socioeconomic status, as indicated by low household income, could limit access to adequate diets, particularly for older children. Parents and caregivers may need dietary guidance to ensure adequate quantity and quality of home food supply and foster healthy eating habits in children. PMID- 26060543 TI - Acculturation and changes in dietary behavior and anthropometric measures among Chinese international students in South Korea. AB - BACKGROUND/OBJECTIVES: International students face dissimilar food environments, which could lead to changes in dietary behaviors and anthropometric characteristics between before and after migration. We sought to examine the risk factors, including dietary behaviors, acculturation, and demographic characteristics, related to overweight subjects residing in South Korea. SUBJECTS/METHODS: We conducted a cross-sectional study, collecting data from 142 Chinese international students (63 males, 79 females) in 2013. RESULTS: The mean age of the subjects was 25.4 years, and almost half of them immigrated to South Korea to earn a master's degree or doctoral degree (n = 70, 49.3%). Chinese international students showed an increase in skipping meals and eating speed, but a decrease in the frequency of fruit and vegetable consumption in South Korea compared to when they lived in China. We found a statistically significant increase in weight (69.4 -> 73.9 kg) and BMI (22.4 -> 23.8 kg/m(2)) for male subjects (P < 0.001) but no change for female subjects. We also found that overweight subjects were more likely to be highly acculturated and male compared with normal-weight subjects. CONCLUSION: Among Chinese international students living in South Korea, male and more highly acculturated subjects are more vulnerable to weight gain. This study provides useful information to design tailored nutrition intervention programs for Chinese international students. PMID- 26060544 TI - Dietary patterns and cardio-cerebrovascular disease in a Chinese population. AB - BACKGROUND/OBJECTIVES: Dietary pattern and its association with cardio cerebrovascular disease have not been studied in Baoji city by now. This study was aimed to identify the dietary patterns among Chinese adults in Baoji, and explore the association between these dietary patterns and cardio-cerebrovascular disease. SUBJECTS/METHODS: A total of 4,968 participants were included in this study at 12 counties. With multistage stratified random sampling and semi quantitative food frequency questionnaire, the prevalence of cardio cerebrovascular disease and dietary intake were investigated in 2013. We used factor analysis to establish dietary patterns. RESULTS: A total of 4,968 participants over 15 years old were included in this study. Five dietary patterns were identified in Baoji: protein, balanced, beans, prudent, and traditional patterns. The protein dietary pattern mainly included animal and plant proteins and was negatively associated with hypertension as well as stroke. The balanced pattern included carbohydrates, protein, and fat and was negatively associated with hypertension as well as stroke. The beans pattern was mainly beans and beans products and was negatively associated with hypertension. The prudent pattern only included staple foods and pickled vegetables and was positively associated with hypertension as well as coronary heart disease. The traditional pattern was representative of local Baoji traditional recipes and was positively associated with hypertension. CONCLUSIONS: The protein, balanced, and beans dietary patterns showed many protective effects on cardio-cerebrovascular disease. Based on these results, Baoji city residents should be encouraged to choose protein, balanced, and beans dietary patterns and abandon prudent and traditional patterns to prevent incidence of hypertension, coronary heart disease, and stroke. PMID- 26060545 TI - Validity of self-reported height and weight in elderly Poles. AB - BACKGROUND/OBJECTIVES: In nutritional epidemiology, collecting self-reported respondent height and weight is a simpler procedure of data collection than taking measurements. The aim of this study was to compare self-reported and measured height and weight and to evaluate the possibility of using self-reported estimates in the assessment of nutritional status of elderly Poles aged 65 + years. SUBJECTS/METHODS: The research was carried out in elderly Poles aged 65 + years. Respondents were chosen using a quota sampling. The total sample numbered 394 participants and the sub-sample involved 102 participants. Self-reported weight (non-corrected self-reported weight; non-cSrW) and height estimates (non corrected self-reported height; non-cSrH) were collected. The measurements of weight (measured weight; mW) and height (measured height; mH) were taken. Using multiple regression equations, the corrected self-reported weight (cSrW) and height (cSrH) estimates were calculated. RESULTS: Non-cSrH was higher than mH in men on average by 2.4 cm and in women on average by 2.3 cm. In comparison to mW, non-cSrW was higher in men on average by 0.7 kg, while in women no significant difference was found (mean difference of 0.4 kg). In comparison to mBMI, non cSrBMI was lower on average by 0.6 kg/m(2) in men and 0.7 kg/m(2) in women. No differences were observed in overweight and obesity incidence when determined by mBMI (68% and 19%, respectively), non-cSrBMI (62% and 14%, respectively), cSrBMI (70% and 22%, respectively) and pcSrBMI (67% and 18%, respectively). CONCLUSIONS: Since the results showed that the estimated self-reported heights, weights and BMI were accurate, the assessment of overweight and obesity incidence was accurate as well. The use of self-reported height and weight in the nutritional status assessment of elderly Poles on a population level is therefore recommended. On an individual level, the use of regression equations is recommended to correct self-reported height, particularly in women. PMID- 26060547 TI - Erratum: A comparative study on dietary behavior, nutritional knowledge and life stress between Korean and Chinese female high school students. AB - [This corrects the article on p. 205 in vol. 8, PMID: 24741406.]. PMID- 26060546 TI - The cross-sectional relationship between dietary calcium intake and metabolic syndrome among men and women aged 40 or older in rural areas of Korea. AB - BACKGROUND/OBJECTIVES: Studies conducted in Western populations have suggested that dietary calcium may protect against metabolic abnormalities, but there is little evidence of this effect in Asians, who have relatively low calcium intake. We evaluated the cross-sectional relationship between dietary calcium and metabolic syndrome among Korean men and women aged 40 years and over. SUBJECTS/METHODS: A total of 6,375 subjects aged 40 years and over and were recruited between January 2005 and February 2010 from the baseline study of the Multi-Rural Communities Cohort Study in Rural Communities (MRCohort). A food frequency questionnaire was used to collect dietary information. Metabolic syndrome was defined using the modified criteria published in the Third Report of the National Cholesterol Education Program Adult Treatment Panel. RESULTS: Calcium intake was related inversely to metabolic syndrome in women (P-value = 0.0091), but not in men (P = 0.1842). Among metabolic components, high waist circumference (WC) (P = 0.0426) and high blood glucose (P = 0.0027) in women and hypertriglyceridemia (P = 0.0017) in men were inversely correlated with calcium intake. Excluding those who used calcium or multinutrient supplements did not attenuate the relationship between dietary calcium and metabolic abnormalities. CONCLUSION: Dietary calcium intake from foods may be inversely related to metabolic syndrome, WC, and blood glucose among women in rural areas of Korea. PMID- 26060548 TI - Gangrenous Appendicitis in a Boy with Mobile Caecum. AB - A mobile caecum and ascending colon is an uncommon congenital disorder, and it is even rarer as the cause of an acute abdomen during childhood. This report presents the case of a 6-year-old boy with acute gangrenous appendicitis with a mobile caecum and ascending colon. Data from the surgical course, as well as laboratory and imaging studies, were acquired and carefully examined. Emergency ultrasound (US) was performed and revealed no signs of appendicitis in the right lower quadrant. Serial imaging study, including non-enhanced computed tomography (CT), was performed. An imaging study identified epigastric appendicitis with mobile caecum. Surgery was executed under general anesthesia with a median incision extending from the epigastrium to the suprapubic region. The caecum was mobile and placed in the right epigastric area, next to the left lobe of the liver and gallbladder. The gangrenous appendix was discovered posterior to the caecum and transverse colon, enlarging to the left upper quadrant. Appendectomy was executed, the gangrenous appendix was confirmed pathologically, and the patient was released 4 days later. In the US, if there are unusual clinical findings or no findings in patients with abdominal pain, CT is beneficial in determining the location of the caecum and appendix and preventing misdiagnosis in children. PMID- 26060549 TI - Metastatic Adenocarcinoma Presenting as Extensive Cavoatrial Tumor Thrombus. AB - The presence of tumor thrombus in the right atrium is frequently the result of direct intraluminal extension of infra-diaphragmatic malignancy into the inferior vena cava (IVC) or supradiaphragmatic carcinoma into the superior vena cava (SVC). Right atrial tumor thrombus with extension into both SVC and IVC has not been reported in the literature. We present a patient who presented with symptoms of right atrial and SVC obstruction. Imaging revealed presence of a thrombus in the right atrium, extending to the SVC and IVC, with the additional findings of a left adrenal mass and multiple liver lesions. The histopathological examination of the right atrial mass revealed metastatic adenocarcinoma cells. The patient was given a presumptive diagnosis of metastatic adenocarcinoma, most likely adrenal in origin, with multiple hepatic lesions suspicious for metastasis. The clinical outcome of the patient was not favorable; the patient succumbed before the adrenal mass could be confirmed to be the primary tumor. This case highlights that in patients manifesting with extensive cavoatrial thrombus as, the existence of primary carcinoma should be considered especially in the adrenal cortex or in the lung. PMID- 26060550 TI - Hanging Bladder calculi Secondary to Misplaced Surgical Suture. AB - Bladder calculi, a rare condition in the pediatric population, occur most commonly as a result of either migration from the kidney or urinary stasis in the bladder. We report the case of a 3-year-old boy with recurrent urinary tract infections (UTI) secondary to bladder calculi formation on the sutures from a previous herniorrhaphy.A 3-year-old boy with previous history of herniorrhaphy presented with recurrent episodes of urinary tract infection, resistant to antibiotic therapy. Physical examination was unremarkable. Ultrasonography (US) showed an echogenic fixed intra-luminal lesion in the bladder. Cystoscopic evaluation was performed and confirmed presence of calculi forming around several permanent silk sutures fixed to the bladder wall. The patient undergone cystotomy and the calculi were resected. The stone analysis revealed 80% uric acid calculi. The final diagnosis was of bladder calculi due to remnant suture from past herniorrhaphy. PMID- 26060551 TI - A Rare Case of Calf Muscle Metastasis from a Non-Functional Pancreatic Neuroendocrine Carcinoma. AB - Pancreatic neuroendocrine tumors (PNET) are uncommon pancreatic neoplasms, accounting for 1-2% of all pancreatic tumors. However, they have a better prognosis and long-term survival compared to exocrine pancreatic cancer. PNETs can be divided into functional or non-functional based upon whether or not they excrete active substances relevant to specific clinical syndromes. Skeletal muscle metastasis is also a rare condition and differentiation between a primary soft tissue sarcoma and metastatic carcinoma is difficult without biopsy. Thus, skeletal muscle metastases from pancreatic neoplasms are exceedingly rare, with only a few cases reported in the literature. We present a 34-year-old man with metastatic pancreatic neuroendocrine carcinoma that was initially thought to be a primary soft tissue tumor. Pathology and immunohistochemistry demonstrated the tumor to be a metastasis from a pancreatic neuroendocrine carcinoma. A brief review of the literature on this subject is also presented. PMID- 26060552 TI - Prostate Biopsy Using Transrectal Ultrasonography; The Optimal Number of Cores Regarding Cancer Detection Rate and Complications. AB - BACKGROUND: Transrectal ultrasound guided biopsy of the prostate is the most common modality used to diagnose prostate cancer. OBJECTIVES: The aim of this study was to evaluate the optimal number of cores at prostate biopsy, which have the most diagnostic value with least adverse effects. PATIENTS AND MATERIALS: Transrectal ultrasonography (TRUS) guided biopsy was performed in 180 patients suspicious for prostate cancer due to either abnormal rectal examination or elevated PSA. The patients were divided randomly into three groups of six-core, twelve-core and eighteen-core biopsies. The detection rate of prostate cancer in each group with the rate of post biopsy urinary infection and prostatitis were compared. RESULTS: Prostate cancer was diagnosed in 8 (13.3%), 21 (35%) and 24 (40%) patients in six, twelve and eighteen core biopsy groups, respectively. Urinary tract infection and prostatitis occurred in 17 (28.3%), 23 (38.3%) and 35 (58.3%) patients in six, twelve and eighteen core biopsy groups, respectively. Considering the detection rate of prostate cancer, there was a significant difference between 6 and 12 core biopsy groups (P = 0.006) and 12-core biopsies detected more cases of prostate cancer, but there was no significant difference between 12 and 18 core biopsy groups (P = 0.572). Considering the infection rate, there was no significant difference between 6 and 12 core biopsy groups (P = 0.254), but there was a significant difference between 12 and 18 core biopsy groups (P = 0.028) and infectious complications occurred more frequently in 18 core biopsy group. CONCLUSIONS: The best balance between detection rate of prostate cancer and infectious complications of biopsies achieved in twelve-core biopsy protocol. Twelve-core biopsy enhances the rate of prostate cancer detection with minimum adverse effects. PMID- 26060553 TI - Complementary Role of Ultrasound in Management of Gestational Trophoblastic Disease. AB - BACKGROUND: Transvaginal Ultrasonography is a noninvasive and inexpensive medical imaging tool used for the diagnosis of various diseases. OBJECTIVES: To identify an effective method to identify high-risk patients for developing malignancy after molar evacuation. PATIENTS AND METHODS: A prospective serial assessment of 19 patients with gestational trophoblastic disease was performed. Clinical and laboratory data, transvaginal ultrasound and Doppler findings were evaluated the day before evacuation. They were followed-up in the first week after evacuation and every two weeks during the next two months, then every month until the sixth month. RESULTS: Ovarian theca lutein cysts (P = 0.018) (among pre-evacuation factors) and first week ultrasound (P = 0.02) can help in detecting high-risk patients. Even though, when beta-hCG titer is not available in a high-risk patient, post evacuation myometrial involvement (P = 0.005) is a useful sign for detecting persistency. CONCLUSIONS: Some ultrasonographic features of molar pregnancy have capability to predict malignancy in the course of disease. PMID- 26060554 TI - Radiologic Findings of Ductal Carcinoma in Situ Arising Within a Juvenile Fibroadenoma: Mammographic, Sonographic and Dynamic Contrast-Enhanced Breast MRI Features. AB - Juvenile fibroadenoma is an uncommon histologic variant of fibroadenoma that frequently shows a remarkable and rapid growth. The development of a carcinoma within a fibroadenoma, either in situ or invasive, is a rare condition. We encountered a 36-year-old woman with a palpable mass in the right breast. The radiologic findings were indicative of a fibroadenoma in the breast. Sonographic guided biopsy using a 14G core needle revealed the presence of ductal carcinoma in situ (DCIS) within the juvenile fibroadenoma. Focal excision was performed and the patient underwent radiation therapy in the right breast after surgery. PMID- 26060555 TI - The Effect of Emboss Enhancement on Reliability of Landmark Identification in Digital Lateral Cephalometric Images. AB - BACKGROUND: Evaluation of the craniofacial bones is the oldest method to measure the facial proportion ratio in orthodontics. OBJECTIVES: The purpose of this study was to evaluate the effect of emboss enhancement on the reliability of landmark identification in digital lateral cephalometric images. MATERIALS AND METHODS: Ten digital lateral cephalograms were selected from the archive of an oral and maxillofacial radiology center. Using DIGORA software, these images were saved in two formats; common images and 3D emboss images. On these images, 32 skeletal, dental, and soft tissue landmarks were marked at least twice with a 2 week interval by four observers (two radiologists and two orthodontists). In order to determine the position of the marked landmarks (in x and y coordinates), a software was designed. The statistical analysis was performed in SPSS software and the reliability of each observer was obtained by means of intraclass correlation coefficient (ICC). RESULTS: In three skeletal landmarks [Orbit (Or), condyl top (Cond), and pogonion (Pog)], the enhancement caused significant reduction in the reliability, and in four skeletal [Anterior Nasal Spine (ANS), B, A, and Basion (Ba)], two dental (U1 root, L1 incisal), and one soft tissue landmark (Menton soft tissue), the enhancement increased the reliability of landmark detection between the two phases of the study. Totally, ICC of embossed images in both x and y coordinates were greater than the typical images, but the difference was not statistically significant. However, the effect of enhancement on the improvement of the reliability of landmark identification was higher in the x-axis than the y-axis. CONCLUSIONS: Using embossed images is only effective in increasing the reliability of detection in a few numbers of cephalometric landmarks. PMID- 26060556 TI - Radiation Dose to the Thyroid and Gonads in Patients Undergoing Cardiac CT Angiography. AB - BACKGROUND: The present data show a global increase in the rate of cardiovascular disease. Cardiac CT angiography has developed as a fast and non-invasive cardiac imaging modality following the introduction of multi-slice computed tomogaraphy. OBJECTIVES: The aim of this study was to measure the radiation dose to the thyroid and pelvis regions in patients undergoing cardiac CT angiography using the Care Dose 4D method of 64-slice scanner. PATIENTS AND METHODS: Eighty-one patients (41 males and 40 females) who were diagnosed with suspected coronary artery disease and were referred to Golestan Hospital, Imaging Department were recruited. Inclusion criteria were based on the protocol of multi-slice CT coronary angiography. The radiation dose to the thyroid and pelvis regions was measured using thermo luminescent dosimeters (TLDs). RESULTS: The mean radiation dose to the thyroid in male and female subjects was 0.32 mSv and 0.41 mSv, respectively (P = 0.032) (total mean, 0.36 mSv). The mean radiation dose to the pelvis in male and female subjects was 81 MUSv and 112 MUSv, respectively (P = 0.026) (total mean, 96.5 MUSv). CONCLUSIONS: The total mean radiation dose to the thyroid and gonads was 0.36 mSv, and 96.5 MUSv, respectively for the subjects. These values were high for one organ in a single study. Gender can affect the radiation dose to the thyroid and gonads. This can be attributed to the anatomical characteristic differences of the male and female subjects. PMID- 26060557 TI - Chromosomally and Anatomically Normal Fetuses With Increased First Trimester Nuchal Translucency Conceived by ICSI. AB - Nuchal translucency (NT) measurements in the first trimester screening between 11 and 14 weeks' gestation are regarded as a clear marker for aneuploidies. The presence of a thickened NT, even if the karyotype is normal, can be associated with structural abnormalities. Having an abnormal screening of NT, parents and physicians could face dilemma over abortion particularly in a case of IVF/ICSI fetuses. Measurement of the NT thickness combined with biochemical markers has a false-positive rate of 5%. Hereby we present six cases of chromosomally normal fetuses with an increased NT thickness in the first trimester, a normal karyotype and normal follow-up scans, who had a good prognosis for a normal early childhood. This report may help increase the confidence of couples who are reluctant to terminate the pregnancy. PMID- 26060558 TI - Evaluation of Enteroneovesical Fistula by 64-Detector CT Enterography: A Case Report. AB - Enterovesical fistula is an abnormal communication between the bladder and the intestine. The accurate localization of leakage is important for accurate treatment planning. Some imaging techniques can not demonstrate the fistula; therefore, choosing the appropriate imaging technique is necessary. CT enterography (CTE) is a new technique for evaluation of the small bowel and the entire abdomen. CTE examination with multi-detector CT (MDCT) enables us to get excellent quality reformatted images with high spatial resolution. We report a patient with neobladder and enteroneovesical fistula. We showed the exact location of the fistula and its' association with the bowels and neobladder by CTE. The aim of this report is to show that CTE can be a new and effective modality in the detection of enteroneovesical fistulas and to discuss the efficacy of CTE in the detection and evaluation of enterovesical fistula referring to the literature. In conclusion, CTE may be a useful, sensitive, effective, and non-invasive technique for the evaluation of enteroneovesical fistula, leakage from the anastomose sides, and other extraintestinal complications such as urinary tract obstruction or abscess formation. PMID- 26060559 TI - Fresh Garlic Extract Enhances the Antimicrobial Activities of Antibiotics on Resistant Strains in Vitro. AB - BACKGROUND: Infections caused by strains with multi-drug resistance are difficult to treat with standard antibiotics. Garlic is a powerful remedy to protect against infections of many bacteria, fungi and viruses. However, little is known about the potentials of fresh garlic extract (FGE) to improve the sensitivity of multi-drug resistant strains to antibiotics. OBJECTIVES: In this study, we used the disk diffusion method to investigate the antimicrobial activities of FGE and the combination of antibiotics with FGE, on methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa and Candida albicans, to evaluate the interactions between antibiotics and FGE. MATERIALS AND METHODS: Clinical isolates were isolated from clinical specimens obtained from the inpatients at the First Affiliated Hospital of Xi'an Jiaotong University Health Science Center. The isolates consisted of MRSA, (n = 30), C. albicans (n = 30) and P. aeruginosa (n = 30). Quality control for CLSI (Clinical and Laboratory Standards Institute) disk diffusion was performed using S. aureus ATCC(r)25923, C. albicans ATCC(r)90028 and P. aeruginosa ATCC(r)27853. The 93 microorganisms were divided into four groups in a factorial design: control (deionized water), FGE, antibiotics without FGE, and antibiotics with FGE. Next, antibacterial activity was evaluated by measuring the diameter of inhibition zones according to performance standards for antimicrobial susceptibility testing of the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS). RESULTS: Fresh garlic extract displayed evident inhibition properties against C. albicans and MRSA, yet weak inhibition properties against P. aeruginosa. Additionally, FGE showed the potential to improve the effect of antibiotics on antibiotic resistant pathogens. The synergism of fluconazole and itraconazole with FGE on C. albicans yielded larger sized inhibition zones compared with fluconazole and itraconazole without FGE (P < 0.01). The factorial analysis represents intense positive interaction effects (P < 0.01). The synergism of cefotaxime and ceftriaxone with FGE on P. aeruginosa yielded larger sized inhibition zones than cefotaxime and ceftriaxone without FGE (P < 0.01). The factorial analysis represents intense positive interaction effects (P < 0.01). CONCLUSIONS: The results suggest that FGE can improve the antibiotic sensitivity of these pathogens to some antibiotics. PMID- 26060560 TI - In Vitro Evaluation of Enzymatic and Antifungal Activities of Soil-Actinomycetes Isolates and Their Molecular Identification by PCR. AB - BACKGROUND: Human cutaneous infection caused by a homogeneous group of keratinophilic fungi called dermatophytes. These fungi are the most common infectious agents in humans that are free of any population and geographic area. Microsporum canis is a cause of dermatophytosis (Tinea) in recent years in Iran and atypical strain has been isolated in Iran. Its cases occur sporadically due to M. canis transmission from puppies and cats to humans. Since this pathogenic dermatophyte is eukaryotes, chemical treatment with antifungal drugs may also affect host tissue cells. OBJECTIVES: The aim of the current study was to find a new antifungal agent of soil-Actinomycetes from Kerman province against M. canis and Actinomycete isolates were identified by PCR. MATERIALS AND METHODS: A number of hundred Actinomycete isolated strains were evaluated from soil of Kerman province, for their antagonistic activity against the M. canis. M. canis of the Persian Type Culture Collection (PTCC) was obtained from the Iranian Research Organization for Science and Technology (IROST). Electron microscope studies of these isolates were performed based on the physiological properties of these antagonists including lipase, amylase, protease and chitinase activities according to the relevant protocols and were identified using gene 16SrDNA. RESULTS: In this study the most antagonist of Actinomycete isolates with antifungal activity against M. canis isolates of L1, D5, Ks1m, Km2, Kn1, Ks8 and Ks1 were shown in vitro. Electron microscopic studies showed that some fungal strains form spores, mycelia and spore chain. Nucleotide analysis showed that Ks8 had maximum homology (98%) to Streptomyces zaomyceticus strain xsd08149 and L1 displayed 100% homology to Streptomyces sp. HVG6 using 16SrDNA studies. CONCLUSIONS: Our findings showed that Streptomyces has antifungal effects against M. canis. PMID- 26060561 TI - Study of Lactic Acid Bacteria Community From Raw Milk of Iranian One Humped Camel and Evaluation of Their Probiotic Properties. AB - BACKGROUND: Camel milk is amongst valuable food sources in Iran. On the other hand, due to the presence of probiotic bacteria and bacteriocin producers in camel milk, probiotic bacteria can be isolated and identified from this food product. OBJECTIVES: The objectives of the present research were the isolation and molecular identification of lactic acid bacteria from camel milk and evaluation of their probiotic properties. MATERIALS AND METHODS: A total of ten samples of camel milk were collected from the Golestan province of Iran under aseptic conditions. Bacteria were isolated by culturing the samples on selective medium. Isolates were identified by amplification of the 16S rDNA and Internal Transcribed Spacer (ITS) region between the 16S and 23S rRNA genes by Polymerase Chain Reaction (PCR) and were then screened and grouped by the Amplified Ribosomal DNA Restriction Analysis (ARDRA) method. To evaluate probiotic properties, representative isolates of different ARDRA profiles were analyzed. The antimicrobial activity of Lactic Acid Bacteria (LAB) against Pediococcus pentosaceus, Escherichia coli and Bacillus cereus was examined by the agar diffusion assay. Acid and bile tolerance of isolates were evaluated. RESULTS: A total of 64 isolates were analyzed based on biochemical tests and morphological characteristics. The most frequently isolated LAB was Enterococci. Weissella, Leuconostoc, Lactobacilli and Pediococci were less frequently found. Based on restriction analysis of the ITS, the isolates were grouped into nine different ARDRA patterns that were identified by ribosomal DNA sequencing as P. pentosaceus, Enterococcus faecium strain Y-2, E. faecium strain JZ1-1, E. faecium strain E6, E. durans, E. lactis, Leuconostoc mesenteroides, Lactobacillus casei and Weissella cibaria. The results showed that antimicrobial activity of the tested isolates was remarkable and P. pentosaceus showed the most antibacterial activity. In addition, E. durans, E. lactis, L. casei and P. pentosaceus were selected as probiotic bacteria. CONCLUSIONS: This study revealed the presence of bacteriocin-producing bacteria and probiotic bacteria in camel milk from the Golestan province of Iran. PMID- 26060562 TI - Anti-Methicillin Resistant Staphylococcus aureus Activity and Optimal Culture Condition of Streptomyces sp. SUK 25. AB - BACKGROUND: The potential of secondary metabolites extracted from Streptomyces sp. to treat bacterial infections including infections with Staphylococcus aureus is previously documented. The current study showed significant antimicrobial activities associated with endophytic Streptomyces sp. isolated from medicinal plants in Peninsular Malaysia. OBJECTIVES: The current study aimed to determine anti-methicillin-resistant-Staphylococcus aureus (MRSA) activities of Streptomyces sp. isolates. MATERIALS AND METHODS: Disc diffusion and Minimum Inhibitory Concentration (MIC) assay were used to determine the antibacterial activity of Streptomyces sp. isolates. Optimization of fermentation parameters for the most potent anti-MRSA extract in terms of medium type, pH, aeration rate, and culture period was also carried out. Lastly, toxicity of the extract against Chang liver cells was determined employing the MTT, 2- (3, 5- diphenyltetrazol-2 ium-2-yl) -4, 5-dimethyl -1, 3 - thiazole; bromide assay. RESULTS: The results indicated Streptomyces sp. SUK 25 isolates showed the most potent anti-MRSA activity. Disc diffusion assay revealed that spread plate technique was more efficient in screening anti-MRSA activity compared to pour plate (P < 0.05). To determine anti-MRSA MIC of Streptomyces sp. SUK 25, Thronton media was used. Therefore, MIC was determined as 2.44 +/- 0.01 ug/mL, and accordingly, the lowest MIC was 1.95 ug/mL based on a seven-day culture, pH7, and aeration rate of 140 rpm. The crude extract was not toxic against Chang liver cells (IC50 = 43.31 +/- 1.24 ug/mL). CONCLUSIONS: The Streptomyces sp. SUK 25 culturing was optimized using Thronton media, at pH 7 and aeration of 140 rpm. Further isolation and identification of bioactive compounds will develop anti-MRSA therapeutics. PMID- 26060563 TI - Otomycosis in Adolescent Patients Referred to the Therapeutic Centers in Babol City, Iran. AB - BACKGROUND: Otomycosis is an external ear canal infection caused by various fungi. This disease is prevalent in some tropical and subtropical regions or countries. OBJECTIVES: Given the crucial role of fungal agents in the treatment of the disease, the aim of the present study was to identify the fungi in ear canal of patients with otomycosis admitted to the hospitals in Babol City, Iran. PATIENTS AND METHODS: This study included 56 patients with otomycosis. After removal of ear infectious samples, some of them were placed on the slides for direct examination and also a portion of them was plated on the Sabouraud dextrose agar with chloramphenicol for fungal growth. The slides were studied for the presence of fungal elements. Conventional methods were performed to determine fungal colonies. RESULTS: Thirty-three patients (55.36%) were female and the rest were male. Fungal elements were observed in 11 cases (19.64%) in the direct examination, alone, and 45 specimens (80.36%) had fungi and bacteria combined. Septate mycelia, with 43 cases, had the most frequent fungal elements in direct examination. Aspergillus and Candida genera were the prevalent fungal colonies in culture media. CONCLUSIONS: According to the role of different genera of fungi in the process of otomycosis, much attention on the macroscopic and microscopic examination of the samples leads to special treatment decisions of a physician. PMID- 26060564 TI - Levels of Transforming Growth Factor-Beta After Immunization of Mice With in vivo prepared Toxoplasma gondii Excretory/Secretory Proteins. AB - BACKGROUND: Zoonotic parasite Toxoplasma gondii has a high prevalence in human populations. A suitable vaccine for animals can stop the transmission of infection between animal and human. OBJECTIVES: The aim of this study was to evaluate in vivo prepared excretory/secretory antigens (E/SA) as a potential candidate for immunization against the parasite and its effect on the production of transforming growth factor-beta (TGF-beta). MATERIALS AND METHODS: Toxoplasma gondii tachyzoites were inoculated in the peritoneal cavity of mice and E/SA was harvested and used in animal immunization with and without adjuvant. Serum levels of anti-E/SA antibodies and TGF-beta were measured in days 0, 3, 7, 14, 28 and 56 after immunization using ELISA technique. The measurements were statistically analyzed. RESULTS: Our results showed that the serum levels of anti-E/SA immunoglobulins significantly increased in all of the immunized groups. The differences of the serum levels of TGF-beta between the groups were statistically significant at days 28 and 56 after immunization with E/SA. CONCLUSIONS: Based on our study, in vivo prepared E/SA may be considered as a good candidate for animal immunization. PMID- 26060565 TI - Molecular Characterization of Vibrio cholerae Isolated From Clinical Samples in Kurdistan Province, Iran. AB - BACKGROUND: Vibrio cholerae causes diarrhoeal disease that afflicts thousands of people annually. V. cholerae is classified on the basis of somatic antigens into serovars or serogroups and there are at least 200 known serogroup. Two serogroups, O1 and O139 have been associated with epidemic diseases. Virulence genes of these bacteria are OmpW, ctxA and tcpA. OBJECTIVES: Due to the importance of V. cholerae infection and developing molecular diagnostics of this organism in medical and microbiology sciences, this study aimed to describe molecular characterization of V. cholerae isolated from clinical samples using a molecular method. MATERIALS AND METHODS: In this study, 48 samples were provided during summer 2013 (late August and early September) by reference laboratory. Samples were assessed using biochemical tests initially. The primer of OmpW, ctxA and tcpA genes was used in Polymerase Chain Reaction (PCR) protocols. Enterobacterial Repetitive Intergenic Consensus (ERIC)-PCR and Repetitive Extragenic Palindromic (REP)-PCR methods were used to subtype V. cholerae. RESULTS: In this study, from a total of 48 clinical stool samples 39 (81.2 %) were positive for V. cholerae in biochemical tests and bacteria culture tests. The PCR results showed that of 39 positive isolates 35 (89.7%), 34 (87.1%) and 37 (94.8%) were positive for ctxA, tcpA and OmpW gene, respectively. Also, in the REP-PCR method with ERIC primer strains were divided into 10 groups. In the REP PCR method with REP primer, strains were divided into 13 groups. CONCLUSIONS: Polymerase chain reaction has specificity and accuracy for identification of the organism and is able to differentiate biotypes. Enterobacterial repetitive intergenic consensus sequence is one of the informative and discriminative methods for the analysis of V. cholerae diversity. The REP-PCR is a less informative and discriminative method compared to other methods for the analysis of V. cholerae diversity. PMID- 26060566 TI - Genetic Characterization of Campylobacter Jejuni and C. coli Isolated From Broilers Using flaA PCR-Restriction Fragment Length Polymorphism Method in Shiraz, Southern Iran. AB - BACKGROUND: Thermophilic campylobacters, particularly Campylobacter jejuni and C. coli are the main agents of human campylobacteriosis. Campylobacter contaminated chicken products is the most important source of foodborne gastroenteritis. Evaluation of genetic diversity among Campylobacter population is critical for understanding the epidemiology of this bacterium and developing effective control strategies against Campylobacter infections and other related disorders. OBJECTIVES: The aim of this study was to investigate the polymorphism of thermophilic Campylobacter isolated from broiler fecal samples in Shiraz, southern Iran. MATERIALS AND METHODS: Ninety Campylobacter isolates were recovered from broiler feces using enrichment process followed by cultivation method. The isolates were species typing on the basis of polymerase chain reaction (PCR) detection of 16SrRNA and multiplex PCR for determining two thermophilic species. To evaluate strain diversity of thermophilic Campylobacter isolates, flaA PCR-Restriction Fragment Length Polymorphism (RFLP) was performed using DdeI restriction enzyme. RESULTS: All 90 Campylobacter isolates confirmed by m-PCR were successfully typed using flaA-PCR-RFLP. Eleven different types were defined according to flaA-typing method and the RFLP patterns were located at three separate clusters in RFLP image analysis dendrogram. CONCLUSIONS: Campylobacter jejuni isolates significantly showed more variety than C. coli isolates. A relatively low genetic diversity existed among C. jejuni and C. coli isolated from broilers in Shiraz, southern Iran. In our knowledge, this was the first report of genetic diversity among broiler originated human pathogen thermophilic campylobacters in Shiraz, southern Iran. PMID- 26060567 TI - Identification of Candida Species Using MP65 Gene and Evaluation of the Candida albicans MP65 Gene Expression in BALB/C Mice. AB - BACKGROUND: Systemic candidiasis is a major public health concern. In particular, in immunocompromised people, such as patients with neutropenia, patients with Acquired Immune Deficiency Syndrome (AIDS) and cancer who are undergoing antiballistic chemotherapy or bone marrow transplants, and people with diabetes. Since the clinical signs and symptoms are nonspecific, early diagnosis is often difficult. The 65-kDa mannoprotein (MP65) gene of Candida albicans is appropriate for detection and identification of systemic candidiasis. This gene encodes a putative b-glucanase mannoprotein of 65 kDa, which plays a major role in the host fungus relationship, morphogenesis and pathogenicity. OBJECTIVES: The current study aimed to identify different species of Candida (C. albicans, C. glabrata and C. parapsilosis) using the Polymerase Chain Reaction (PCR) technique and also to evaluate C. albicans MP65 gene expression in BALB/C mice. MATERIALS AND METHODS: All yeast isolates were identified on cornmeal agar supplemented with tween-80, germ tube formation in serum, and assimilation of carbon sources in the API 20 C AUX yeast identification system. Polymerase Chain Reaction was performed on all samples using species-specific primers for the MP65 65 kDa gene. After RNA extraction, cDNA synthesis was performed by the Maxime RT Pre Mix kit. Candida albicans MP65 gene expression was evaluated by quantitative Real-Time (q Real Time) and Real-Time (RT) PCR techniques. The 2-DeltaDeltaCT method was used to analyze relative changes in gene expression of MP65. For statistical analysis, nonparametric Wilcoxon test was applied using the SPSS version 16 software. RESULTS: Using biochemical methods, one hundred, six and one isolates of clinical samples were determined as C. albicans, C. glabrata and C. parapsilosis, respectively. Species-specific primers for PCR experiments were applied to clinical specimens, and in all cases a single expected band for C. albicans, C. glabrata and C. parapsilosis was obtained (475, 361 and 124 base pairs, respectively). All species isolated by culture methods (100% positivity) were evaluated with PCR using species-specific primers to identify Candida species. Relative expression of Mp65 genes increased significantly after C. albicans injection into the mice (P < 0.05). CONCLUSIONS: The results of the current study showed that the PCR method is reproducible for rapid identification of Candida species with specific primers. Mp65 gene expression of C. albicans after injection into the mice was 2.3 folds higher than before injection, with this difference being significant. These results indicated that increase of Mp65 gene expression might be an early stage of infection; however definitive conclusions require further studies. PMID- 26060568 TI - Cutaneous Alternariasis in a Patient With Renal Transplant. AB - INTRODUCTION: Alternaria is a common saprophyte, which is usually not pathogenic in humans. Generally, local wounds infections of Alternaria occur with presence of immunosuppression factors such as HIV infection and renal transplant patients. CASE PRESENTATION: We reported a case of wound infection induced by Alternaria spp. in a renal transplant patients. The main interest in this case was the rareness of the cutaneous alternariasis, its clinical aspects and good response to therapy. Recognition of Alternaria spp. as potential opportunistic pathogens is important for differential diagnosis of dermatological lesions, such as granulomatous or ulcerative lesions in immunocompromised patients. CONCLUSIONS: Alternariasis or similar cases may be increased due to the increased number of immunosuppressed patients. From this point of view, skin lesions in these patients must be planned and microbiologically evaluated considering the molds. PMID- 26060569 TI - Prevalence of Hepatitis G Virus Among Hemodialysis and Kidney Transplant Patients in Khuzestan Province, Iran. AB - BACKGROUND: Hepatitis G virus (HGV) is a member of Flaviviridae. Prevalence of HGV in healthy people is very low, but this virus is more prevalent in patients with hepatitis. Besides, relative frequency of HGV in patients undergoing hemodialysis, and kidney recipients is very high. The role of HGV in pathogenesis is not clear. Since this virus cannot be cultivated, molecular techniques such as Revers Transcription Polymerase Chain Reaction (RT-PCR) is applied to detect HGV. OBJECTIVES: The current study aimed to investigate the prevalence of HGV using determination of E2, viral envelope antigen, antibodies and the RNA by Enzyme Linked Immunosorbent Assay (ELISA) and RT-PCR techniques. The rational of the study was to determine the prevalence of HGV in patients undergoing hemodialysis and kidney transplantation in Khuzestan province, Iran. PATIENTS AND METHODS: Five hundred and sixteen serum samples of the patients undergoing hemodialysis and kidney transplantation from various cities of Khuzestan province were collected. Anti-hepatitis G E2 antibodies were investigated by ELISA method. RNAs were extracted from serums and Hepatitis G RNA was detected by RT-PCR. RESULTS: Of the 516 samples, 38 (7.36%) specimens were positive for anti-HGV by ELISA. All of these ELISA positive samples were negative for HGV genome by RT-PCR. Of the remaining 478 ELISA negative samples, 16 (3.14%) samples were positive by RT-PCR. CONCLUSIONS: Hepatitis G Virus was not prevalent in the patients undergoing hemodialysis and kidney transplantation in Khuzestan province. Although reports indicated high frequency of co-infection of HGV with hepatitis B and C viruses, in the current research, co-infection of HGV with B and C was not considerable. Since different groups and subtypes of HGV are reported, periodic epidemiologic evaluation of HGV and its co-infection with other hepatitis viruses is suggested in other populations such as the patients with thalassemia; however, periodic epidemiologic monitoring of HGV may be helpful to control future potential variations of the virus. PMID- 26060570 TI - Sex-different abnormalities in the right second to fourth digit ratio in Japanese individuals with autism spectrum disorders. AB - BACKGROUND: The prevalence of autism spectrum disorders (ASDs) is higher in men than in women. The extreme male brain theory proposes that excessive prenatal testosterone activity could be a risk factor for ASDs. However, it is unclear whether prenatal sex hormone activity is a risk factor for women. The ratio of the length of the second to fourth digits (2D:4D) is considered to be a biomarker of the prenatal ratio of testosterone to estrogen. Therefore, this study compared the 2D:4D ratios of women with and without ASDs to determine if prenatal sex hormone activity could be a risk factor for ASDs in women. METHODS: The study included 35 Japanese men with ASDs, 17 Japanese women with ASDs, 59 typically developed (TD) Japanese men, and 57 TD Japanese women. We measured digit lengths and compared the 2D:4D ratios among the four groups. We also examined the relationship between the 2D:4D ratio and the autism-spectrum quotient score of each group. RESULTS: In our cohort, men with ASDs tended to have lower right-hand 2D:4D ratios relative to TD men. In contrast, the right 2D:4D ratios in women with ASDs were higher compared to those of TD women. No significant correlations were found between the 2D:4D ratios and the autism-spectrum quotient scores in any group. The higher right 2D:4D ratios in women could not be explained by age or full-scale intelligent quotients. This group difference was not found for the left 2D:4D or right-left 2D:4D ratios. CONCLUSIONS: We found a reverse direction of abnormality in the right 2D:4D ratio for men and women with ASDs. It has been posited that high prenatal testosterone levels lead to a lower 2D:4D ratio. However, a recent animal study showed that testosterone injection to dam leads to a higher right 2D:4D ratio especially for female offspring, which might be mediated by abnormal adipose accumulation in the fingertip. Therefore, the present findings suggest that high prenatal testosterone could be a risk factor both for Japanese men and women with ASDs, elucidating one potential etiology of ASDs in women. PMID- 26060571 TI - Evaluating the Y chromosomal STR dating in deep-rooting pedigrees. AB - BACKGROUND: Y chromosomal short tandem repeat (STR) has been used in time estimations for single nucleotide polymorphism (SNP) lineages or eminent persons. But to choose which mutation rate and estimation method in the Y chromosome dating is controversial, since different rates and methods can result in several fold deviation. FINDINGS: We used two deep-rooting pedigrees with full records and reliable dates to directly evaluate the Y chromosomal STR mutation rates and dating methods. We found that the Y chromosomal genealogical mutation rates (OMRB and lmMR) in BATWING method can give the best-fit estimation for historical lineage dating. CONCLUSIONS: This study validated a very efficient and reliable way for genealogy and historical anthropology researches. PMID- 25866620 TI - A critical evaluation of science outreach via social media: its role and impact on scientists. AB - The role of scientists in social media and its impact on their careers are not fully explored. While policies and best practices are still fluid, it is concerning that discourse is often based on little to no data, and some arguments directly contradict the available data. Here, we consider the relevant but subjective questions about science outreach via social media (SOSM), specifically: (1) Does a public relations nightmare exist for science?; (2) Why (or why aren't) scientists engaging in social media?; (3) Are scientists using social media well?; and (4) Will social media benefit a scientist's career? We call for the scientific community to create tangible plans that value, measure, and help manage scientists' social media engagement. PMID- 26060573 TI - Getting the most from venous occlusion plethysmography: proposed methods for the analysis of data with a rest/exercise protocol. AB - BACKGROUND: Venous occlusion plethysmography is a simple yet powerful technique for the non-invasive measurement of blood flow. It has been used extensively in both the experimental and clinical settings. The underlying rationale is that when venous outflow from an extremity is occluded, any immediate increase in volume of this compartment must originate from the on-going arterial inflow. Mercury-in-silastic strain gauges are typically used to measure these volume changes, the rates of which are directly proportional to blood flow. RESULTS: When using a simple rest/exercise protocol to provide a local or systemic metabolic stimulus to increase blood flow, current methods for analysing the data obtained are often rather simplistic, solely considering the mean increment in blood flow induced by exercise. Previous methodological considerations have focused mainly on issues of reproducibility and accuracy (for instance, by comparing unilateral and/or bilateral measurements) but rarely on what the recorded traces may actually mean. CONCLUSIONS: In this methodological manuscript, we suggest a more detailed approach to processing venous occlusion plethysmography data, one which could provide additional physiological information. Six parameters are described, all of which are easily derived from a simple and reproducible experimental rest/exercise venous occlusion plethysmography protocol. PMID- 26060574 TI - Dexmedetomidine sedation during the nighttime reduced the incidence of postoperative atrial fibrillation in cardiovascular surgery patients after tracheal extubation. AB - BACKGROUND: Dexmedetomidine (Dex) provides sedation and analgesia by acting on central alpha-2 receptors and is suitable for use after extubation because it has little respiratory depression. Considering the sympathoinhibitory and anxiolytic action of Dex, there is the possibility that Dex might reduce the incidence of atrial fibrillation (AF), which is recognized as a common complication after cardiovascular surgery. We investigated whether the postoperative incidence of AF decreased in patients who received Dex only during the nighttime in the intensive care unit (ICU). METHODS: We retrospectively reviewed ICU charts to determine the incidence of AF and associated factors during the 2-day period after tracheal extubation in patients who underwent cardiovascular surgery from November 2009 to November 2010. The patients were divided into a Dex group (n = 16) and a non-Dex group (n = 29). RESULTS: There were no differences in AF risk factors except for diabetes between the two groups. The average rate of Dex administration was 0.3 +/- 0.2 MUg/kg/h. There were also no differences between the groups in heart rate during the daytime, central venous pressure, body temperature, white blood cell count, serum level of C-reactive protein, catecholamine use, beta-blocker use, and amount of fentanyl. AF developed in one patient in the Dex group (6.3 %) and ten patients in the non-Dex group (34.5 %) during the observation period, and the difference was significant (p = 0.035). None of the risk factors for AF was significantly associated with AF in univariate analysis; however, multivariate logistic regression analysis using age, Dex use, and beta-blocker use, extracted because their p values in univariate analysis were not exceeding 0.15, showed that Dex use was the only factor associated with the development of AF (p = 0.045, odds ratio 9.75 [1.05-90.8]). CONCLUSIONS: The results suggest that adequate sedation with Dex during the nighttime can reduce the incidence of AF in cardiovascular surgery patients after extubation. PMID- 26060575 TI - A modified Delphi process to identify process of care indicators for the identification, prevention and management of acute kidney injury after major surgery. AB - BACKGROUND: The outcomes of acute kidney injury (AKI) are well appreciated. However, valid indicators of high quality processes of care for AKI after major surgery are lacking. OBJECTIVES: To identify indicators of high quality processes of care related to AKI prevention, identification, and management after major surgery. DESIGN: A three stage modified Delphi process. SETTING: The study was conducted in Alberta, Canada using an online format. PARTICIPANTS: A panel of care providers from surgery, critical care, and nephrology. MEASUREMENTS: The degree of validity of candidate indicators were rated by panelists on a 7-point Likert scale that ranged from "strongly disagree" to "strongly agree". METHODS: A focused literature review was performed to identify candidate indicators. A modified Delphi process, with three rounds, was used to obtain expert consensus on the validity of potential process of care quality indicators. RESULTS: Thirty three physicians participated (6 from surgery, 10 from critical care, and 17 from nephrology). A list of 58 potential process of care quality indicators for AKI after surgery was generated including 28 indicators from the initial literature review and 30 indicators suggested by panelists. Following the third round of questioning, 40 process of care indicators were identified with a high level of agreement for face validity; 16 of these reached high consensus among all panelists. LIMITATIONS: The consensus of panelists from Alberta, Canada may not be generalizable to other settings. The modified Delphi process did not focus on the feasibility of measuring these process indicators. CONCLUSIONS: These indicators can be used to measure and improve the quality of care for AKI after major surgery. PMID- 26060576 TI - Quantification of severe liver iron overload using MRI offset echoes. AB - Magnetic resonance imaging (MRI) has become the clinical standard to estimate liver iron overload. The most commonly used method is to measure the transversal relaxation time, T2*, from a multi gradient recalled echo sequence (MGRE). While this technique is reliable in low to moderate liver iron concentrations (LIC), it will be inaccurate when it is severe. We report a case with severe liver hemochromatosis and show the benefit of using an easily implemented MRI offset echo sequence to more accurately estimate LIC. After adjusting treatment, both Ferritin and LIC decreased. Using standard MGRE this reduction could not have been detected. PMID- 26060577 TI - Evaluation of Optical Low Coherence Reflectometry Parameters in Patients with Exfoliation Syndrome. AB - Purpose. To evaluate optical low coherence reflectometry (OLCR) parameters in patients with exfoliation syndrome (EXS) undergoing cataract surgery. Methods. Forty-seven eyes of 47 patients with EXS (Group 1), and 55 eyes of 55 healthy subjects (Group 2) were included in the study. Anterior chamber depth (ACD), lens thickness (LT), axial length (AL), central corneal thickness (CCT), horizontal corneal length (HCL), and pupil diameter (PD) parameters were measured by OLCR (Lenstar LS 900, Haag-Streit) and compared between groups. Shapiro-Wilk test and Mann Whitney U tests were used for statistical analyses. Results. The mean ACD, HCL, and PD values were significantly lower in EXS group than in healthy subjects (P = 0.01, P = 0.04, and P < 0.001, resp.). The mean LT was significantly higher in EXS group than in healthy subjects (P = 0.007). There was no significant difference between groups in means of AXL and CCT. Conclusions. According to OLCR measures, eyes with EXS have shallower ACD, smaller PD, thicker LT, shorter HCL, and no significantly different CCT levels. PMID- 26060578 TI - Elevated Neutrophil Lymphocyte Ratio in Recurrent Optic Neuritis. AB - Purpose. To demonstrate the relation between optic neuritis (ON) and systemic inflammation markers as neutrophil lymphocyte ratio (N/L ratio), platelet count, mean platelet volume (MPV), and red cell distribution width (RDW) and furthermore to evaluate the utilization of these markers to predict the frequency of the ON episodes. Methods. Forty-two patients with acute ON and forty healthy subjects were enrolled into the study. The medical records were reviewed for age, sex, hemoglobin (Hb), Haematocrit (Htc), RDW, platelet count, MPV, white blood cell count (WBC), neutrophil and lymphocyte count, and neutrophil lymphocyte ratio (N/L ratio). Results. The mean N/L ratio, platelet counts, and RDW were significantly higher in ON group (p = 0.000, p = 0.048, and p = 0.002). There was a significant relation between N/L ratio and number of episodes (r = 0.492, p = 0.001). There was a statistically significant difference for MPV between one episode group and recurrent ON group (p = 0.035). Conclusions. Simple and inexpensive laboratory methods could help us show systemic inflammation and monitor ON patients. Higher N/L ratio can be a useful marker for predicting recurrent attacks. PMID- 26060579 TI - Corneal Epithelial Remodeling after LASIK Measured by Fourier-Domain Optical Coherence Tomography. AB - Purpose. To quantify corneal epithelial thickness changes after myopic LASIK by OCT. Methods. Epithelial thickness before and after myopic LASIK were measured by a Fourier-domain OCT system. Average central (within 1 mm diameter) and paracentral epithelial thickness (5~6 mm diameter) before and after LASIK were compared. Correlation between central epithelial thickness change and laser spherical equivalent setting was evaluated. An epithelial smoothing constant was estimated based on a mathematical model published previously. Results. Nineteen eyes from 11 subjects were included in the study. Eyes had myopic LASIK ranging from -1.69 D to -6.75 D spherical equivalent. The average central epithelial thickness was 52.6 +/- 4.1 MUm before LASIK and 56.2 +/- 4.3 MUm 3 months after LASIK (p = 0.002). The average paracentral epithelial thickness was 51.6 +/- 6.6 MUm before LASIK and 54.8 +/- 4.3 MUm 3 months after LASIK (p = 0.007). The change in average central epithelial thickness was correlated with laser spherical equivalent (R (2) = 0.40, p = 0.028). The epithelial smoothing constant was estimated to be 0.46 mm. Conclusions. Corneal epithelial thickens centrally and paracentrally after myopic LASIK. The extent of epithelial remodeling correlated with the amount of LASIK correction and could be predicted by a mathematical model. PMID- 26060580 TI - Edmonton Obesity Staging System Prevalence and Association with Weight Loss in a Publicly Funded Referral-Based Obesity Clinic. AB - OBJECTIVES: To determine the distribution of EOSS stages and differences in weight loss achieved according to EOSS stage, in patients attending a referral based publically funded multisite weight management clinic. SUBJECTS/METHODS: 5,787 obese patients were categorized using EOSS staging using metabolic risk factors, medication use, and severity of doctor diagnosis of obesity-related physiological, functional, and psychological comorbidities from electronic patient files. RESULTS: The prevalence of EOSS stages 0 (no risk factors or comorbidities), 1 (mild conditions), 2 (moderate conditions), and 3 (severe conditions) was 1.7%, 10.4%, 84.0%, and 3.9%, respectively. Prehypertension (63%), hypertension (76%), and knee replacement (33%) were the most common obesity-related comorbidities for stages 1, 2, and 3, respectively. In the models including age, sex, initial BMI, EOSS stage, and treatment time, lower EOSS stage and longer treatment times were independently associated with greater absolute (kg) and percentage of weight loss relative to initial body weight (P < 0.05). CONCLUSIONS: Patients attending this publicly funded, referral-based weight management clinic were more likely to be classified in the higher stages of EOSS. Patients in higher EOSS stages required longer treatment times to achieve similar weight outcomes as those in lower EOSS stages. PMID- 26060581 TI - Multiplex Analysis of Pro- or Anti-Inflammatory Serum Cytokines and Chemokines in relation to Gender and Age among Tanzanian Tuberculous Lymphadenitis Patients. AB - Objectives. Tuberculous lymphadenitis is the most common form of extrapulmonary tuberculosis (TB) with a female and paediatric preponderance, postulated to be due to differences in the immune response. The aim of this study was to analyze the differences in the serum cytokine levels of tuberculous lymphadenitis patients with respect to age and gender. Methods. A multiplex bead-based enzyme linked immunosorbent assay was used to measure IFN-gamma, TNF-alpha, GM-CSF, IL 1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, and IL-17 levels in sera of patients (n = 86) and healthy controls (n = 23). Results. Levels of IFN gamma, TNF-alpha, GM-CSF, IL-1beta, IL-2, IL-4, and IL-6 were higher in adult patients than in controls, while those of IL-12 were lower (P < 0.05). Children had lower levels of TNF-alpha, GM-CSF, and IL-5 and higher levels of IL-2 compared with adult patients (P < 0.05). The male adult patients had higher levels of IL-17 and lower levels of IL-12 compared with female adult patients (P < 0.05). Conclusion. There were significant differences in the levels of circulating cytokines with respect to gender and age. Children had generally lower levels of cytokines as compared to adults, which could make them more susceptible. Findings do not support that female preponderance is due to differences in immune response. PMID- 26060582 TI - SILAC-Based Quantitative Proteomic Analysis of Diffuse Large B-Cell Lymphoma Patients. AB - Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma, is a heterogeneous disease where the outcome for patients with early relapse or refractory disease is very poor, even in the era of immunochemotherapy. In order to describe possible differences in global protein expression and network patterns, we performed a SILAC-based shotgun (LC-MS/MS) quantitative proteomic analysis in fresh-frozen tumor tissue from two groups of DLBCL patients with totally different clinical outcome: (i) early relapsed or refractory and (ii) long-term progression-free patients. We could identify over 3,500 proteins; more than 1,300 were quantified in all patients and 87 were significantly differentially expressed. By functional annotation analysis on the 66 proteins overexpressed in the progression-free patient group, we found an enrichment of proteins involved in the regulation and organization of the actin cytoskeleton. Also, five proteins from actin cytoskeleton regulation, applied in a supervised regression analysis, could discriminate the two patient groups. In conclusion, SILAC-based shotgun quantitative proteomic analysis appears to be a powerful tool to explore the proteome in DLBCL tumor tissue. Also, as progression-free patients had a higher expression of proteins involved in the actin cytoskeleton protein network, such a pattern indicates a functional role in the sustained response to immunochemotherapy. PMID- 26060583 TI - Neurodevelopmental Plasticity in Pre- and Postnatal Environmental Interactions: Implications for Psychiatric Disorders from an Evolutionary Perspective. AB - Psychiatric disorders are disadvantageous behavioral phenotypes in humans. Accordingly, a recent epidemiological study has reported decreased fecundity in patients with psychiatric disorders, such as schizophrenia and autism spectrum disorders. Moreover, the fecundity of the relatives of these patients is not exceedingly higher compared to the fecundity of the relatives of normal subjects. Collectively, the prevalence of psychiatric disorders among humans is expected to decrease over generations. Nevertheless, in reality, the prevalence rates of psychiatric disorders in humans either have been constant over a long period of time or have even increased more recently. Several attempts to explain this fact have been made using biological mechanisms, such as de novo gene mutations or variants, although none of these explanations is fully comprehensive. Here, we propose a hypothesis towards understanding the biological mechanisms of psychiatric disorders from evolutionary perspectives. This hypothesis considers that behavioral phenotypes associated with psychiatric disorders might have emerged in the evolution of organisms as a neurodevelopmental adaptation against adverse environmental conditions associated with stress. PMID- 26060584 TI - Increase in Short-Interval Intracortical Facilitation of the Motor Cortex after Low-Frequency Repetitive Magnetic Stimulation of the Unaffected Hemisphere in the Subacute Phase after Stroke. AB - Low-frequency repetitive transcranial magnetic stimulation of the unaffected hemisphere (UH-LF-rTMS) in patients with stroke can decrease interhemispheric inhibition from the unaffected to the affected hemisphere and improve hand dexterity and strength of the paretic hand. The objective of this proof-of principle study was to explore, for the first time, effects of UH-LF-rTMS as add on therapy to motor rehabilitation on short-term intracortical inhibition (SICI) and intracortical facilitation (ICF) of the motor cortex of the unaffected hemisphere (M1UH) in patients with ischemic stroke. Eighteen patients were randomized to receive, immediately before rehabilitation treatment, either active or sham UH-LF-rTMS, during two weeks. Resting motor threshold (rMT), SICI, and ICF were measured in M1UH before the first session and after the last session of treatment. There was a significant increase in ICF in the active group compared to the sham group after treatment, and there was no significant differences in changes in rMT or SICI. ICF is a measure of intracortical synaptic excitability, with a relative contribution of spinal mechanisms. ICF is typically upregulated by glutamatergic agonists and downregulated by gabaergic antagonists. The observed increase in ICF in the active group, in this hypothesis-generating study, may be related to M1UH reorganization induced by UH-LF-rTMS. PMID- 26060585 TI - Biatrial Cardiac Metastases in a Patient with Uterine Cervix Malignant Melanoma. AB - Primary malignant melanomas of uterine cervix are quite rarely seen neoplasms, and long-life prognosis of patients with this disease is poor. Immunohistochemical methods and exclusion of other primary melanoma sites are used to confirm the diagnosis. As with other melanomas, cervix malignant melanomas may also cause cardiac metastases. Cardiac metastases are among rarely seen but more commonly encountered cases, compared to primary cardiac tumors. Here, we present a case of biatrial cardiac metastases in a 73-year-old patient with uterine cervix malignant melanomas. The patient underwent echocardiography, cardiac magnetic resonance imaging, and computed tomography. Our report shows the importance of advanced diagnostic techniques, such as cardiac magnetic resonance, not only for the detection of cardiac masses, but for a better anatomic definition and tissue characterization. Although the cases of malignant melanomas leading to multiple cardiac metastasis were reported in literature, the metastatic concurrence of malignant melanomas in both right and left atriums is quite rarely encountered as metastatic malignant melanomas. Also, another intriguing point in our case is that the primary lesion of our case was stemmed from uterine cervix, but not skin. PMID- 26060586 TI - Paget Disease of the Vulva: Diagnosis by Immunohistochemistry. AB - The objective of this paper is to report a case of extramammary Paget disease of the vulva, to describe its diagnosis, surgical treatment, and outcome, and to discuss the general characteristics of this pathology. This is a rare neoplasm, found principally in areas in which apocrine and eccrine glands are numerous. This case report is relevant to the literature since the differential diagnosis of extramammary Paget disease is difficult to be done only with the macroscopic appearance of the lesion and even with the microscopic characteristics, requiring further studies, immunohistochemistry, as to differentiate pathologies. The present report describes the case of a 63-year-old patient at the Santa Casa de Misericordia Hospital in Vitoria, Espirito Santo, Brazil, who presented with a hardened, ulcerated, and purplish lesion with hyperchromic and hypochromic spots, measuring 4 cm in diameter, located on the lower third of right labium majus, close to the vaginal fourchette. A right hemivulvectomy was performed, leaving wide margins all around. The patient progressed satisfactorily following surgery. Although extramammary Paget disease is rare, its incidence increases as a function of the patient's age. Patients should be followed up closely because of the risk of persistence and/or recurrence of the disease. PMID- 26060587 TI - A Broken Toothbrush in the Retropharyngeal Space in a Toddler of Sixteen Months. AB - A toddler of sixteen months fell while brushing his teeth and his mouth hit the ground. The toothbrush broke and one-third of it including the head got impacted in his throat. The attempt of his mother to remove it with her fingers further complicated the case and the toothbrush was ultimately lodged in the retropharyngeal space at the level from C1 to C5 vertebrae. It was strongly impacted due to the presence of the bristles. The broken end of the handle was just protruding into the nasopharynx and was very difficult to locate. The first attempt of its removal was unsuccessful. The toothbrush was removed safely in the second attempt without any complication. PMID- 26060588 TI - Antineutrophilic Cytoplasmic Antibody Positive Vasculitis Associated with Methimazole Use. AB - ANCA-associated vasculitis (AAV) is a rare and potentially life threatening complication associated with antithyroid drug use. It is more commonly reported with propylthiouracil, with fewer cases reported with methimazole use. We present the case of a 55-year-old man with toxic multinodular goiter which was treated with methimazole for 6 months. He developed ANCA positive leukocytoclastic vasculitis with hemorrhagic and necrotic bullous lesions of lower extremities. The vasculitis was initially thought to be secondary to recent cephalosporin use; however, the skin lesions progressed despite stopping the cephalosporin and treatment with steroids, and he developed osteomyelitis. His vasculitis resolved after cessation of methimazole use. This case highlights the importance of careful monitoring for variable manifestations of AAV in patients treated with methimazole. PMID- 26060589 TI - The Role of Inspiratory Muscle Training in Sickle Cell Anemia Related Pulmonary Damage due to Recurrent Acute Chest Syndrome Attacks. AB - Background. The sickling of red blood cells causes a constellation of musculoskeletal, cardiovascular, and pulmonary manifestations. A 32-year-old gentleman with sickle cell anemia (SCA) had been suffering from recurrent acute chest syndrome (ACS). Aim. To examine the effects of inspiratory muscle training (IMT) on pulmonary functions, respiratory and peripheral muscle strength, functional exercise capacity, and quality of life in this patient with SCA. Methods. Functional exercise capacity was evaluated using six-minute walk test, respiratory muscle strength using mouth pressure device, hand grip strength using hand-held dynamometer, pain using Visual Analogue Scale, fatigue using Fatigue Severity Scale, dyspnea using Modified Medical Research Council Scale, and health related quality of life using European Organization for Research and Treatment of Cancer QOL measurement. Results. A significant improvement has been demonstrated in respiratory muscle strength, functional exercise capacity, pain, fatigue, dyspnea, and quality of life. There was no admission to emergency department due to acute chest syndrome in the following 12 months after commencing regular erythrocytapheresis. Conclusion. This is the first report demonstrating the beneficial effects of inspiratory muscle training on functional exercise capacity, respiratory muscle strength, pain, fatigue, dyspnea, and quality of life in a patient with recurrent ACS. PMID- 26060590 TI - Brain Abscess and Keratoacanthoma Suggestive of Hyper IgE Syndrome. AB - Hyper immunoglobulin-E (IgE) syndrome is an autosomal immune deficiency disease. It is characterized by an increase in IgE and eosinophil count with both T-cell and B-cell malfunction. Here, we report an 8-year-old boy whose disease started with an unusual skin manifestation. When 6 months old he developed generalized red, nontender nodules and pathologic report of the skin lesion was unremarkable (inflammatory). Then he developed a painless, cold abscess. At the age of 4 years, he developed a seronegative polyarticular arthritis. Another skin biopsy was taken which was in favor of Keratoacanthoma. Laboratory workup for immune deficiency showed high eosinophil count and high level of immunoglobulin-E, due to some diagnostic criteria (NIH sores: 41 in 9-year-olds), he was suggestive of hyper IgE syndrome. At the age of 8, the patient developed an abscess in the left inguinal region. While in hospital, the patient developed generalized tonic colonic convulsion and fever. Brain computed tomography scan revealed an abscess in the right frontal lobe. Subsequently magnetic resonance imaging (MRI) of the brain indicated expansion of the existing abscess to contralateral frontal lobe (left side). After evacuating the abscesses and administrating intravenous antibiotic, the patient's condition improved dramatically and fever stopped. PMID- 26060591 TI - Punctate Inner Choroidopathy. AB - Purpose. To report a case of bilateral punctate inner choroidopathy (PIC). Case Report. A 26-year-old Caucasian woman presented with bilateral blurred vision with one year of evolution. There was no relevant systemic disease or family history. Best-corrected visual acuity in the right eye was 20/30 and in the left eye was 20/20; there was no clinically significant refractive error. Fundoscopy evidenced multiple, small, round, yellow-white lesions limited to the posterior pole of both eyes, with greater macular involvement in the RE. There were no signs of inflammation in the anterior chamber or vitreous cavity. Fluorescein angiography revealed the presence of multiple hyperfluorescent lesions more evident in the later stages of the angiogram in both eyes. On indocyanine green angiography, these lesions appeared hypofluorescent in both early and late phases. Optical coherence tomography showed the presence of focal elevations of the retinal pigment epithelium with underlying hyporeflective space, bilaterally. Laboratory and imaging evaluation for evidence of autoimmune and infectious diseases were negative. Conclusion. The PIC is a relatively uncommon condition. In this report, an attempt has been made to describe a classic clinic presentation of this disease in a young and female patient. PMID- 26060592 TI - Flexor Digitorum Accessorius Longus: Importance of Posterior Ankle Endoscopy. AB - Endoscopy for the posterior region of the ankle through two portals is becoming more widespread for the treatment of a large number of conditions which used to be treated with open surgery years ago. The tendon of the flexor hallucis longus (FHL) travels along an osteofibrous tunnel between the posterolateral and posteromedial tubercles of the talus. Chronic inflammation of this tendon may lead to painful stenosing tenosynovitis. The aim of this report is to describe two cases depicting an accessory tendon which is an anatomical variation of the flexor hallucis longus in patients with posterior friction syndrome due to posterior ankle impingement and associated with a posteromedial osteochondral lesion of the talus. The anatomical variation (FDAL) described was a finding during an endoscopy of the posterior region of the ankle, and we have spared it by sectioning the superior flexor retinaculum only. The accessory flexor digitorum longus is an anatomical variation and should be taken into account when performing an arthroscopy of the posterior region of the ankle. We recommend this treatment on this type of injury although we admit this does not make a definite conclusion. PMID- 26060593 TI - Mature Cystic Teratoma in Douglas' Pouch. AB - Mature cystic teratoma is one of the most common ovarian neoplasms, but extragonadal teratoma is rare. Teratoma in Douglas' pouch is extremely rare, and only 12 cases have been reported since the first case was described in 1978. We report a 20-year-old woman with a multicystic mass in Douglas' pouch that was treated via laparoscopic resection. The tumor consisted of cysts lined by stratified squamous epithelium with an accumulation of keratin debris and various mature tissues. No immature elements or malignancy was found in the tumor, confirming the pathologic diagnosis of a mature cystic teratoma. The teratoma contained no ovarian tissues and both of the ovaries were intact on laparoscopy. These findings suggest that the teratoma originated primarily in Douglas' pouch rather than being caused by autoamputation of a previously existing ovarian teratoma. This is the first case that simultaneously showed normal ovaries and a teratoma in Douglas' pouch on laparoscopy. PMID- 26060594 TI - Synchronous Bilateral Testicular Tumors with Different Histopathology. AB - A 40-year-old male presented to our outpatient department with the chief complaint of a painless mass on his right testis with gradual size increase over the past two months. Physical examination and ultrasound revealed a firm and nontender mass both on the right and on the left testis. The only elevated biomarker was b-hcG (24,7 mIU/mL) and computer tomography (CT) did not reveal any pathology. Bilateral high orchiectomies were performed, without previous frozen storage of the sperm. Histology proved typical seminoma of the left testis and embryonal carcinoma of the right testis. He received two cycles of adjuvant combination chemotherapy with bleomycin, etoposide, and cisplatin. Six months after the operation no residual tumor or recurrence was observed. PMID- 26060595 TI - CYP2A6 Polymorphisms May Strengthen Individualized Treatment for Nicotine Dependence. AB - Each CYP2A6 gene variant metabolizes nicotine differently depending on its enzymatic activities. The normal nicotine metabolizer CYP2A6(*)1A is associated with high scores of nicotine dependence (5-10) on the Fagerstrom Test for Nicotine Dependence (FTND) scale because it encodes for enzymes that catalyze nicotine 100%. Slow nicotine metabolizers (i.e., CYP2A6(*)1H, CYP2A6(*)4A, CYP2A6(*)9, and CYP2A6(*)12A) are associated with underrated nicotine metabolizing activity (50%-75%), linking them to low scores for nicotine dependence (0-4) on the FTND scale. In a clinical trial involving the use of bupropion, people who were carriers of slow nicotine metabolizers were found to have a tendency to maintain abstinence 1.7 times longer than people with normal nicotine metabolizers. An overview of CYP2A6 polymorphism enzymatic activities in nicotine dependence etiology and treatment revealed that slow nicotine metabolizers may strengthen the individualized treatment of nicotine dependence. PMID- 26060596 TI - Missing the 'window' might shut the light forever: Central retinal artery occlusion following spine surgery. PMID- 26060597 TI - A rare case of delayed subarachnoid anesthetic blockade effects in a 103-year-old female patient. AB - BACKGROUND: The elderly represent a unique challenge for the effects of regional anesthesia, and very few cases of block onset delay have been described. Their delayed response is attributed to a number of factors that include: Physiologic deterioration, musculoskeletal contractures, degenerative joint disease, autonomic regulatory dysfunction, cognitive dysfunction, altered pharmacokinetics, and pharmacodynamics of local anesthetics and adjuvants. CASE DESCRIPTION: In this report we present the rare case of 45-min delay between the administration and onset of action of a subarachnoid blockade in a 103-year-old female, who was scheduled for left hip pinning, for repair of a femoral neck fracture. Patient received an injection of hyperbaric bupivacaine, 1.5 ml of 0.75% (11.25 mg), with 15 mcg of fentanyl into the subarachnoidal space and underwent the surgical procedure without complications. CONCLUSIONS: Delayed responses to subarachnoid anesthesia can be expected in extremely elderly patients. Anesthetic procedures should be monitored and managed on a case-by-case basis. PMID- 26060598 TI - Management of infections complicating the orbitocranial approaches: Report of two cases and review of literature. AB - BACKGROUND: The orbitocranial approaches are now indispensible for treating lesions of the skull base, providing access to lesions in the anterior and middle cranial fossae, as well as the upper clivus and anterior brainstem. The management of infectious complications of the orbitocranial approaches, however, has evaded the literature. CASE DESCRIPTION: We present two cases of patients who underwent orbitocranial approach whose clinical course was complicated by wound infection and osteomyelitis. One patient was treated with antibiotics and then had a custom implant placed for cranioplasty. The other case was managed with removal of bone and wire-mesh cranioplasty. CONCLUSION: Management of orbitocraniotomy infections can be difficult due to the complex geometry of the flap and to cosmetic considerations. Once the infection involves the bone, the bone can be replaced after cleaning or discarded and a cranioplasty performed. Cranioplasty can be performed with wire-mesh or a custom implant made by computer assisted modeling. PMID- 26060599 TI - Efficacy of arachnoid plasty with collagen sheets and fibrin glue: An in vitro experiment and a case review. AB - BACKGROUND: Postoperative subdural fluid collection sometimes occurs after clipping of cerebral aneurysms. Arachnoid plasty is used to prevent such postoperative complications; however, the optimal materials for arachnoid plasty remain unclear. In this study, we aimed to clarify the optimal materials for arachnoid plasty and report our experience of arachnoid plasty after clipping of unruptured aneurysms. METHODS: In an in vitro experiment, adhesive strengths of three materials permitted for use in the intradural space, such as collagen sheets, gelatin sponge, and oxidized cellulose sheets, were measured by assessing their water pressure resistance. Then, 80 consecutive cases surgically treated unruptured cerebral aneurysms were retrospectively reviewed to examine the occurrence rate of postoperative subdural fluid collection. RESULTS: The collagen sheet exhibited the greatest adhesive strength, so we used collagen sheets for the arachnoid plasty procedures. In all of these cases, arachnoid plasty was performed with fibrin glue-soaked collagen sheets. No postoperative subdural fluid collection, inflammation, or allergic reactions occurred in any case. CONCLUSIONS: The present study suggests that collagen sheet might be one of the optimal materials for arachnoid plasty. This technique is simple and may be effective to prevent subdural fluid collection after clipping. PMID- 26060600 TI - Lateral supraorbital approach to ipsilateral PCA-P1 and ICA-PCoA aneurysms. AB - BACKGROUND: Aneurysms of the posterior cerebral artery (PCA) are rare and often associated with anterior circulation aneurysms. The lateral supraorbital approach allows for a very fast and safe approach to the ipsilateral lesions Circle of Willis. A technical note on the successful clip occlusion of two aneurysms in the anterior and posterior Circle of Willis via this less invasive approach has not been published before. The objective of this technical note is to describe the simultaneous microsurgical clip occlusion of an ipsilateral PCA-P1 and an internal carotid artery - posterior communicating artery (ICA-PCoA) aneurysm via the lateral supraorbital approach. CASE DESCRIPTION: The authors present a technical report of successful clip occlusions of ipsilateral located PCA-P1 and ICA-PCoA aneurysms. A 59-year-old female patient was diagnosed with a PCA-P1 and an ipsilateral ICA-PCoA aneurysm by computed tomography angiography (CTA) after an ischemic stroke secondary to a contralateral ICA dissection. The patient underwent microsurgical clipping after a lateral supraorbital craniotomy. The intraoperative indocyanine green (ICG) videoangiography and the postoperative CTA showed a complete occlusion of both aneurysms; the parent vessels (ICA and PCA) were patent. The patient presents postoperative no new neurologic deficit. CONCLUSION: The lateral supraorbital approach is suitable for the simultaneous microsurgical treatment of proximal anterior circulation and ipsilateral proximal PCA aneurysms. Compared to endovascular treatment, direct visual control of brainstem perforators is possible. PMID- 26060601 TI - The role of C5a in acute lung injury induced by highly pathogenic viral infections. AB - The complement system, an important part of innate immunity, plays a critical role in pathogen clearance. Unregulated complement activation is likely to play a crucial role in the pathogenesis of acute lung injury (ALI) induced by highly pathogenic virus including influenza A viruses H5N1, H7N9, and severe acute respiratory syndrome (SARS) coronavirus. In highly pathogenic virus-induced acute lung diseases, high levels of chemotactic and anaphylatoxic C5a were produced as a result of excessive complement activaiton. Overproduced C5a displays powerful biological activities in activation of phagocytic cells, generation of oxidants, and inflammatory sequelae named "cytokine storm", and so on. Blockade of C5a signaling have been implicated in the treatment of ALI induced by highly pathogenic virus. Herein, we review the literature that links C5a and ALI, and review our understanding of the mechanisms by which C5a affects ALI during highly pathogenic viral infection. In particular, we discuss the potential of the blockade of C5a signaling to treat ALI induced by highly pathogenic viruses. PMID- 26060602 TI - Evaluation of zebrafish as a model to study the pathogenesis of the opportunistic pathogen Cronobacter turicensis. AB - Bacteria belonging to the genus Cronobacter spp. have been recognized as causative agents of life-threatening systemic infections, primarily in premature, low-birth weight and/or immune-compromised neonates. Knowledge remains scarce regarding the underlying molecular mechanisms of disease development. In this study, we evaluated the use of a zebrafish model to study the pathogenesis of Cronobacter turicensis LMG 23827(T), a clinical isolate responsible for two fatal sepsis cases in neonates. Here, the microinjection of approximately 50 colony forming units (CFUs) into the yolk sac resulted in the rapid multiplication of bacteria and dissemination into the blood stream at 24 h post infection (hpi), followed by the development of a severe bacteremia and larval death within 3 days. In contrast, the innate immune response of the embryos was sufficiently developed to control infection after the intravenous injection of up to 10(4) CFUs of bacteria. Infection studies using an isogenic mutant devoid of surviving and replicating in human macrophages (DeltafkpA) showed that this strain was highly attenuated in its ability to kill the larvae. In addition, the suitability of the zebrafish model system to study the effectiveness of antibiotics to treat Cronobacter infections in zebrafish embryos was examined. Our data indicate that the zebrafish model represents an excellent vertebrate model to study virulence related aspects of this opportunistic pathogen in vivo. PMID- 26060604 TI - Kinematic Analysis of Five Different Anterior Cruciate Ligament Reconstruction Techniques. AB - Several anatomical anterior cruciate ligament (ACL) reconstruction techniques have been proposed to restore normal joint kinematics. However, the relative superiorities of these techniques with one another and traditional single-bundle reconstructions are unclear. Kinematic responses of five previously reported reconstruction techniques (single-bundle reconstruction using a bone-patellar tendon-bone graft [SBR-BPTB], single-bundle reconstruction using a hamstring tendon graft [SBR-HST], single-tunnel double-bundle reconstruction using a hamstring tendon graft [STDBR-HST], anatomical single-tunnel reconstruction using a hamstring tendon graft [ASTR-HST], and a double-tunnel double-bundle reconstruction using a hamstring tendon graft [DBR-HST]) were systematically analyzed. The knee kinematics were determined under anterior tibial load (134 N) and simulated quadriceps load (400 N) at 0 degrees , 15 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion using a robotic testing system. Anterior joint stability under anterior tibial load was qualified as normal for ASTR-HST and DBR-HST and nearly normal for SBR-BPTB, SBR-HST, and STDBR-HST as per the International Knee Documentation Committee knee examination form categorization. The analysis of this study also demonstrated that SBR-BPTB, STDBR-HST, ASTR-HST, and DBR-HST restored the anterior joint stability to normal condition while the SBR-HST resulted in a nearly normal anterior joint stability under the action of simulated quadriceps load. The medial-lateral translations were restored to normal level by all the reconstructions. The internal tibial rotations under the simulated muscle load were over-constrained by all the reconstruction techniques, and more so by the DBR-HST. All five ACL reconstruction techniques could provide either normal or nearly normal anterior joint stability; however, the techniques over-constrained internal tibial rotation under the simulated quadriceps load. PMID- 26060603 TI - Is mother-to-infant transmission the most important factor for persistent HBV infection? AB - Of the infants born to hepatitis B surface antigen (HBsAg)-positive mothers globally, 42.1% who did not receive hepatitis B virus (HBV) passive-active immunoprophylaxis and 2.9% of infants who received the immunoprophylaxis acquired HBV infection perinatally. Moreover, perinatal infection occurred in 84.2% (18.8% 100%) and 8.7% (0.0-21.0%) of infants born to hepatitis B e-antigen (HBeAg) positive mothers who did not and did receive immunoprophylaxis, respectively; by contrast, the infection rates were 6.7% (0.0-15.4%) and 0.4% (0.0-2.5%) for infants born to HBeAg-negative-carrier mothers, respectively. The chronicity rates of HBV infection acquired perinatally were 28.2% (17.4%-33.9%) in infants born to HBeAg-negative mothers and 64.5% (53.5%-100%) in infants born to HBeAg positive mothers. HBV mother-to-child transmission was more frequent in East Asia relative to other areas. In addition to differences in the endemic HBV genotype, the interchange of allelic dominance in genetic polymorphisms in HLA class II and NF-kappaB between the Chinese and European populations may explain why chronic HBV infection frequently affects the Chinese. The risk of progressing into chronic infection was inversely related to the age of children at the time of horizontal transmission. To further diminish HBV chronic infection, it is necessary to enforce antiviral treatment after the 28th week of gestation for HBeAg-positive mothers and to improve the health habits of carrier mothers and household sanitary conditions. PMID- 26060605 TI - Clinical Results of Contralateral Arthroscopic Meniscectomy Performed with Unilateral Total Knee Arthroplasty: Minimum 3-year Follow-up. AB - PURPOSE: We assessed the clinical outcome of contralateral arthroscopic meniscectomy performed with unilateral total knee arthroplasty (TKA). MATERIALS AND METHODS: From May 1999 to June 2006, 23 patients underwent unilateral total knee arthroplasty and contralateral arthroscopic meniscectomy at the same time. All patients were women and followed for at least 36 months, except 2 patients who died. For clinical assessment, range of motion of the knee joint, Hospital for Special Surgery (HSS) knee score and the Lysholm knee score were evaluated preoperatively and at the last follow-up. At arthroscopy, meniscal pathology and cartilage changes were recorded and classified according to the Outerbridge scale. Progression of osteoarthritis in the contralateral knee to subsequent TKA was also assessed. RESULTS: The mean age of the 21 patients was 67.1 years and the mean follow-up period was 5.7 years. All of the patients were diagnosed with osteoarthritis and had Outerbridge grade 3 or 4 cartilage changes. Eight of the 21 patients had subsequent TKA at an average of 3.1 years after the index operation. The other 13 patients had no further surgery and clinical results including the HSS knee score and the Lysholm score were improved from 74.5 and 60.6 preoperatively to 90.8 and 82.4 postoperatively, respectively (p<0.001). CONCLUSIONS: Contralateral arthroscopic meniscectomy performed simultaneously with unilateral TKA produces relatively good results regardless of the presence of cartilage degeneration. PMID- 26060606 TI - Two-Stage Total Knee Arthroplasty for Prosthetic Joint Infection. AB - PURPOSE: This retrospective review was conducted to identify prognostic factors for two-stage reimplantation for infected total knee arthroplasty (TKA) and the rate of reinfection following revision TKA. MATERIALS AND METHODS: Out of 88 patients diagnosed with post-TKA infection between 1998 and 2011, 76 underwent two-stage reimplantation and were reviewed in this study. The 76 patients were divided into two groups-those who experienced reinfection and those who did not. Comorbidities, culture results, and inflammation indices were analyzed and compared between the two groups. RESULTS: Of the 76 patients who underwent a two stage reimplantation, 18 (23.7%) experienced reinfection. Patients with more than three comorbidities had significantly higher reinfection rates than those with less than three comorbidities (47.1% vs. 4.8%, p=0.032). The reinfection rate between the culture positive prosthetic joint infection group and the culture negative prosthetic joint infection group was not significantly different (p=0.056). Inflammation indices (erythrocyte sedimentation rate [ESR] and C reactive protein [CRP]) showed a statistically significant difference between patients with reinfection and those without reinfection at 4 weeks after the first-stage surgery. CONCLUSIONS: Reimplantation must be carefully performed when the risk of reinfection is high, particularly in patients with more than three systemic or local comorbidities and higher inflammation indices (ESR and CRP) prior to revision TKA. PMID- 26060607 TI - Clinical Evaluation of the Root Tear of the Posterior Horn of the Medial Meniscus in Total Knee Arthroplasty for Osteoarthritis. AB - PURPOSE: To investigate the incidence of root tears of the posterior horn of the medial meniscus in total knee replacement arthroplasty for knee osteoarthritis and retrospectively analyze clinical results and factors associated with root tears. MATERIALS AND METHODS: There were 197 knees of 140 enrolled patients who had undergone total knee replacement arthroplasty between September 2010 and May 2014. The presence of a root tear of the posterior horn of the medial meniscus was confirmed in all patients. Statistical analysis was performed to investigate the correlation between root tears and the possible factors of meniscal tears including gender, age, severity of symptoms (visual analogue scale [VAS] score and medial joint line tenderness), grade of osteoarthritis (Kellgren-Lawrence grading scale), body mass index (BMI), varus deformity, and mechanical axis deviation. RESULTS: Meniscal tears were observed in 154 knees (78.17%). The root tear had correlation with the severity of osteoarthritis (p<0.05), varus deformity (p<0.05), mechanical axis deviation (p<0.05), and BMI (p<0.05). CONCLUSIONS: Factors considered to represent the severity of osteoarthritis were found to be associated with root tears of the medial meniscus posterior horn. Increased BMI seemed to be associated with the increased incidence of root tears of the medial meniscus posterior horn. PMID- 26060608 TI - Is Knee Magnetic Resonance Imaging Overutilized in Current Practice? AB - PURPOSE: To determine what proportion of patients visiting a tertiary knee clinic had pre-obtained knee magnetic resonance imaging (MRI) and to assess the impact of pre-obtained knee MRI on the selection of treatment plans. MATERIALS AND METHODS: Six hundred and eighty patients were enrolled from patients who visited our knee clinic during a 6-month period. The proportion of patients with pre obtained knee MRI was calculated, and associations of sociodemographic factors, disease category, and finally selected treatment options with knee MRI pre obtainment were investigated. A utility assessment panel of five orthopaedic surgeons was formed and established utility assessment criteria. Two rounds of utility assessment (before and after MRI review) were performed. RESULTS: Of the 680 patients, 185 (27%) had pre-obtained knee MRI. In the first round of utility assessment, 39%, 18%, and 43% of the 185 knee MRIs were evaluated as useful, equivocal, and arguably useless, respectively, and almost identical results were obtained in the second round. The proportion of assessed 'useful MRI' was higher in sports related injury (84%) and other conditions (91%) than in degenerative joint disease (18%) and nonspecific knee pain (31%). Utility assessment results among panels varied little for practice patterns and education duration. CONCLUSIONS: This study suggests clinicians should reconsider and counsel patients the expected utility of knee MRI acquisition. PMID- 26060609 TI - Lack of Correlation between Dynamic Balance and Hamstring-to-Quadriceps Ratio in Patients with Chronic Anterior Cruciate Ligament Tears. AB - PURPOSE: The purpose of this study was to evaluate the quadriceps and hamstring muscle strength and hamstring-to-quadriceps (HQ) ratio, as well as the relationships of these parameters with dynamic balance, in patients with anterior cruciate ligament (ACL) rupture. MATERIALS AND METHODS: We compared 25 patients diagnosed with chronic unilateral ACL tears and 25 age-matched healthy volunteers. The maximal torque of the quadriceps and hamstring and dynamic balance were measured. RESULTS: Although the isokinetic maximal peak torques were about 50% lower in the quadriceps (57%, p<0.001) and hamstring (56%, p=0.001) muscles in the chronic ACL tear group than in the control group, their HQ ratios were similar (56%+/-17% vs. 58%+/-6%, p=0.591). HQ ratio was significantly correlated with anterior-posterior stability index (r=-0.511, p=0.021) and overall stability index (r=-0.476, p=0.034) in control group, but these correlations were not observed in chronic ACL tear group. CONCLUSIONS: Thigh muscle strength was about 50% lower in the chronic ACL tear group than in the control group, but the HQ ratio was similar. The dynamic balance of the knee was not influenced by thigh muscle strength but was influenced by HQ ratio in healthy young individuals. However, HQ ratio was not correlated with dynamic knee balance in chronic ACL tear patients. PMID- 26060610 TI - Usefulness of Ultrasound-Guided Lower Extremity Nerve Blockade in Surgery for Patellar Fracture. AB - PURPOSE: To evaluate the usefulness of ultrasound-guided nerve blockade in patellar fracture surgery. MATERIALS AND METHODS: Twenty-three patients who underwent metal fixation under ultrasound-guided lower extremity blockade after diagnosis of patellar fracture from July 2011 to June 2012 were enrolled in this study. Under ultrasound guidance, femoral nerve, lateral femoral cutaneous nerve, obturator nerve, and sciatic nerve blockades were performed. For evaluation of anesthesia, interference with overall surgery, such as intraoperative knee pain and tourniquet pain, was checked. Individual anesthetic complications, satisfaction with nerve blocks, and choice of future anesthesia method were investigated. RESULTS: Nineteen patients underwent surgery without any pain and 4 patients with mild pain. Satisfaction was excellent in 17 patients, good in 5, and unsatisfactory in 1. No complications such as infection or nerve injury occurred. In terms of selection of future anesthesia, 22 patients chose a nerve blockade of the lower extremity under ultrasound guidance, and one chose general anesthesia. CONCLUSIONS: Overall, ultrasound-guided nerve block of the lower extremity for patellar fracture surgery showed satisfactory results. Therefore, it could be a useful method to prevent complications associated with general or spinal anesthesia. PMID- 26060611 TI - Anatomical Single-bundle Anterior Cruciate Ligament Reconstruction Using a Freehand Transtibial Technique. AB - PURPOSE: In anatomical single-bundle (SB) anterior cruciate ligament (ACL) reconstruction, the traditional transtibial approach can limit anatomical placement of the femoral tunnel. SURGICAL TECHNIQUE: We present a novel three point freehand technique that allows for anatomic SB ACL reconstruction with the transtibial technique. MATERIALS AND METHODS: Between January 2012 and December 2012, 55 ACL reconstructions were performed using the three-point freehand technique. All the patients were followed for a minimum of 12 months post operatively. Clinical evaluation was done using the Lysholm score and International Knee Documentation Committee (IKDC) grade. All patients were analyzed by 3-dimensional computed tomography (3D CT) at 1 week after surgery. RESULTS: The mean Lysholm score improved from 68.2+/-12.7 points preoperatively to 89.2+/-8.2 points at final follow-up. At final follow-up, the IKDC grade was normal in 42 patients and nearly normal in 13 patients. None of the patients had a positive pivot shift test, anterior drawer test and Lachman test at final follow-up. The anatomical position of the femoral tunnel was confirmed on 3D CT scans. CONCLUSIONS: The three-point freehand technique for SB transtibial ACL reconstruction is a simple, anatomic technique showing good clinical results. PMID- 26060612 TI - Acute Patellar Tendon Rupture after Total Knee Arthroplasty Revision. AB - Patellar tendon rupture is a catastrophic complication following total knee arthroplasty (TKA). Though revision TKA has been suspected of being a predisposing factor for the occurrence of patellar tendon rupture, there are few reports on patellar tendon rupture after revision TKA. Here, we present a case of acute patellar tendon rupture that occurred after TKA revision. In the patient, the patellar tendon was so thin and could not be repaired, and accordingly was sutured end to end. We used the anterior tibialis tendon allograft to augment the poor quality patellar tendon tissue. Fixation of the allograft was done by using the bone tunnel created through tibial tuberosity and suturing the allograft to the patellar tendon and quadriceps tendon. The patient was instructed to wear a full extension knee splint and was kept non-weight bearing for 6 weeks after operation. Full knee extension could be achieved 6 weeks postoperatively. PMID- 26060613 TI - Bilateral Medial Tibial Plateau Fracture after Arthroscopic Anterior Cruciate Ligament Reconstruction. AB - Tibial plateau fractures after arthroscopic anterior cruciate ligament (ACL) reconstruction are rare, and only isolated cases have been reported. The authors describe a case of bilateral medial tibial plateau fracture following a minor motorcycle accident in a patient who underwent arthroscopic ACL reconstruction in the past. Two years and four months before the accident, the patient underwent an arthroscopically assisted ACL reconstruction using double-bundle technique on his left knee at a hospital. He had the same surgery using single-bundle technique on his right knee about eight months ago at another hospital. The fractures in his both involved knees occurred through the tibial tunnel and required open reduction with internal fixation. At three weeks after fixation, a second-look arthroscopy revealed intact ACLs in both knees. At five months follow-up, he was able to walk without instability on physical examination. Follow-up radiographs of the patient showed callus formations with healed fractures. PMID- 26060614 TI - The Role of the Community Nurse in Promoting Health and Human Dignity-Narrative Review Article. AB - BACKGROUND: Population health, as defined by WHO in its constitution, is out "a physical, mental and social complete wellbeing". At the basis of human welfare is the human dignity. This dimension requires an integrated vision of health care. The ecosystemical vision of Bronfenbrenner allows highlighting the unexpected connections between social macro system based on values and the micro system consisting of individual and family. Community nurse is aimed to transgression in practice of education and care, the respect for human dignity, the bonds among values and practices of the community and the physical health of individuals. In Romania, the promotion of community nurse began in 2002, through the project promoting the social inclusion by developing human and institutional resources within community nursery of the National School of Public Health, Management and Education in Healthcare Bucharest. The community nurse became apparent in 10 counties included in the project. Considering the respect for human dignity as an axiomatic value for the community nurse interventions, we stress the need for developing a primary care network in Romania. The proof is based on the analysis of the concept of human dignity within health care, as well as the secondary analysis of health indicators, in the year of 2010, of the 10 counties included in the project. Our conclusions will draw attention to the need of community nurse and, will open directions for new researches and developments needed to promote primary health in Romania. PMID- 26060615 TI - A Simple Emergency Prediction Tool for Acute Aortic Dissection. AB - BACKGROUND: A simple emergency risk prediction tool should be developed for clinicians to quickly identify the prognosis of patients with acute aortic dissection. METHODS: We enrolled 280 patients with acute aortic dissection admitted to emergency department between May 2010 and February 2013. Multivariate logistic regression analysis was performed to identify independent predictors of in-hospital death. RESULTS: The in-hospital mortality of our patients with acute aortic dissection was 32.5%, in-hospital deaths with surgery less than the survived (34.1% VS 54.5%). Multivariate analysis identified that age (>=65 years old), Type A, blood pressure (mean systolic blood pressure <= 90 mmHg), neutrophil percentage (>= 80%) and serum D-dimer (>= 5.0 mg/L) were significant predictors of death. With the simple emergency risk prediction tool, scores of all in-hospital deaths were >= 3, whereas almost all of the survivors (97.9%) had scores < 15. A score of 10 offered the best threshold value, with the highest sensitivity (81.3%) and specificity (86.8%). CONCLUSIONS: The in-hospital mortality rate of patients with acute aortic dissection is high and can be predicted. Early surgery would be beneficial for in-hospital survive. This tool should be available for clinicians in the emergency department to quickly identify the prognosis of patients with acute aortic dissection. PMID- 26060616 TI - Faculty Member's Views, Attitude and Current Practice As Regards International Committee of Medical Journal Editors Criteria for Authorship. AB - BACKGROUND: The objective of this study was to assess the knowledge and views of faculty members on criteria for authorship by International Committee of Medical Journal Editors (ICMJE), their current practice of choosing the authors, views on gift authorship and problems they had faced concerning authorship. METHODS: It was a cross sectional survey from January 2011 to July 2011 among faculty members of various private and public sector medical institutions of Pakistan through a self-administered questionnaire. Main outcome measures included awareness and use of ICMJE criteria, which contribution to research merit authorship and their perceptions about gift authorship. RESULTS: Two hundred eighteen faculty members (180 males, 38 females) participated in the study. One hundred twenty eight (58.7%) were from surgery and allied disciplines. Ninety six percent had published between one to five papers while 60(27.5%) had six to ten papers to their credit. One hundred eleven (50.9%) claimed they were aware about the authorship criteria, only twenty two (19.8%) could name this document. Only four (1.8%) could correctly state this. Only one hundred twenty (55.0%) said that all three criteria's must be met to be eligible for authorship. Ninety three (42.7%) said that they were not included as authors though they deserved it while sixty three said they did not merit but were still included. Forty two (19.3%) said that they were not aware when they were listed as authors. CONCLUSION: A vast majority of young faculty members are not aware of the existence of authorship criteria and gift authorship is quite common. PMID- 26060617 TI - Elderly Peoples' Perception of Young People - A Preliminary Study. AB - BACKGROUND: Aging is becoming a more noticeable phenomenon in Poland and Europe. We analysed the perception of youth by elderly and compared attitudes of students of the University of the Third Age (SU3A) with nursing homes residents (NHR) to young people. METHODS: Our questionnaire was distributed to 140 people over the age of 50 (70 SU3A and 70 NHR). RESULTS: 85.0% of all respondents answered positively to the question "Do you enjoy contact with young people?", even though their contacts are usually limited and mostly confined to a few s a year. Vast majority of NHR (62.9%) and almost half SU3A (48.6%) believe that there is a need to integrate seniors and youth to achieve mutual benefits. CONCLUSION: Young people would benefit from the life experience of the elderly; the elderly could become more active in many areas of life. PMID- 26060618 TI - Service Users and Providers Expectations of Mental Health Care in Iran: A Qualitative Study. AB - BACKGROUND: Mental disorders are known to be an important cause of disabilities worldwide. Despite their importance, about two thirds of mentally ill people do not seek treatment, probably because of the mental health system's inability to decrease the negative side effects of the interaction with the mental health services. The World Health Organization has suggested the concept of responsiveness as a way to better understand the active interaction between the health system and the population. This study aimed to explore the expectations of mental health service users and providers. METHODS: Six focus group discussions were carried in Tehran, the capital of Iran. In total, seventy-four participants comprising twenty-one health providers and fifty-three users of mental health system were interviewed. Interviews were analyzed through content analysis. The coding was synchronized between the researchers through two discussion sessions to ensure the credibility of the findings. The results were then discussed with two senior researchers to strengthen plausibility. RESULTS: Five common domains among all groups were identified: accessibility, quality of interpersonal relationships, adequate infrastructure, participation in decisions, and continuity of care. The importance of cultural appropriateness of care was only raised by service users as an expectation of an ideal mental health service. CONCLUSIONS: Both users and providers identified the most relevant expectations from the mental health care system in Iran. More flexible community mental health services which are responsive to users' experiences may contribute to improving the process of care for mental health patients. PMID- 26060619 TI - Causal Aspects of Social Capital of Iranian Patients with Cancer: Evidence of Predictive, Modifying and Descriptive Effects in Health Inequality. AB - BACKGROUND: There is a good literature confirming the effects of social capital on different health domains. The increase in different types of cancer has caused scientists to encounter a number of issues regarding the reasons of affliction by this disease. The aim of this empirical research was to study the causal aspects of social capital of Iranian patients with cancer. METHODS: The study was a causal-comparative study conducted in the spring and summer of 2010 in Tehran. The sample consists of 212 people selected based on affliction or no affliction to cancer. Social capital emphasizes two dimensions of structure and cognition. Social participation, social trust and sense of social solidarity are considered as different dimensions of social capital. The focus has been on personal social capital. RESULTS: The effect and association of social capital are not significant with any of stomach and colon cancers. The effect and association of social trust are not significant with any of stomach, colon and breast cancers. CONCLUSION: People with similar social capital in their life have different experiences of cancer-related stress and unhealthy behaviors. Thus a specific feature of a stressful social determinant is not a reliable criterion to determine the degree of stress and the extent of its effect on affliction to cancer. PMID- 26060620 TI - Frequency and Susceptibility of Bacteria Caused Urinary Tract Infection in Neonates: Eight-Year Study at Neonatal Division of Bahrami Children's Hospital, Tehran Iran. AB - BACKGROUND: Susceptibility pattern of organisms causing urinary tract infection (UTI) in neonate would potentially improve the clinical management by enabling clinicians to choose most reasonable first line empirical antibiotics. This study aimed to this end by studying isolated organisms from neonates with UTI in an inpatient setting. METHODS: Current retrospective study has recruited all cases of neonatal UTI diagnosed through a suprapubic/catheterized sample, admitted to Neonatal Division of Bahrami Children's Hospital, Tehran, Iran, from June 2004 to June 2012. RESULTS: Escherichia coli was the dominant (64.4%) bacteria among a total of 73 cases (69.9% boys and 30.1% girls; aged 14.14 +/- 7.68 days; birth weight of 3055.85 +/- 623.00 g) and Enterobacter (19.2%), Klebsiella (12.3%), and Staphylococcus epidermdisis (4.1%) were less frequent isolated bacteria. E. coli was mostly resistant to ampicillin (93.6%), cefixime (85.7%) and cephalexin (77.3%), and sensitive to cefotaxime (63.6%). Enterobacter found to be most resistant to amikacin (100%), ampicillin (92.85%), and most sensitive to ceftizoxime (71.4%). CONCLUSION: A high ratio (> 92.85%) of resistance toward ampicillin was observed among common neonatal UTI bacterial agents. Having this finding along with previous reports of emerging resistance of neonatal uropathogensto ampicillin could be a notion that a combination of a third generation cephalosporin and an aminoglycoside would be a more reasonable first choice than ampicillin plus an aminoglycoside. PMID- 26060621 TI - Scientometrics Study of Impact of Journal Indexing on the Growth of Scientific Productions of Iran. AB - BACKGROUND: This study represents scientific production of Iran in medical sciences field at recent years, and the correlation between scientific productions with the number of indexed journals. METHODS: Data extracted from SCOPUS database between years 2000 and 2011, and Iran's performance measured in terms of different Scientometrics indexes including self-citations, percent of cited articles, number of articles with international collaboration and contribution of Iran in medical sciences in Middle East and world. Moreover correlation between the number of articles, citations, self-citations, and H index and number of indexed journals for 50 countries in all fields is included. RESULTS: In 2011 year, Iran contributed 32.77 percent of the Middle East, and accounted for 1.57 percent of the world scientific production. The most frequent document type was original journal article published in English. Retrieved records revealed preferred subject areas, including medicine miscellaneous (14.53 percent of Iran publications in 2011 year). In 2011, according to the number of articles and citations to them, Iran was at 17th and 23th position between 226 countries, respectively. After adjustment for 19708 journals from 50 countries, Iran's rank based on the number of journals in medical sciences was 24th. CONCLUSION: The number of indexed journals with number of articles, citations, self-citations, and H-index of each country showed significant correlation (P value<0.01). In recent years, by favoring quality over quantity of researches, the new rules have proven to be more effective for discriminating Iranian scientific productions. PMID- 26060622 TI - Effectiveness of Coping Skills Education Program to Reduce Craving Beliefs among Addicts Referred To Addiction Centers in Hamadan: A Randomized Controlled Trial. AB - BACKGROUND: One of the most important factors affecting relapse of addiction is craving beliefs of substance use. The goal of the present study was assessment of the effectiveness of coping skills education program to reduce craving beliefs among opium addicts. METHODS: In a randomized controlled trial, during September 2011 to August 2012, 70 opium addicted men referred to the Behavioral Disorders and Substance Abuse Research Center in Hamadan, western Iran were assigned to intervention group (receiving coping skills education program) and control groups. The study information was analyzed using SPSS software. RESULTS: Regarding craving beliefs for continuing drug use, the two groups had similar scales at the beginning of interventional program, while the level of these beliefs was significantly reduced in the intervention group (P= 0.002), but not in the control group (P= 0.105). Also, a significant correlation was also revealed between taking advantage of the educational program and increase awareness of the signs of relapse in the intervention group (P=0.003) that was not revealed in the control (P= 0.174). On the other hand, executing coping skills education program led to reducecraving beliefs and improve knowledge towards signs of relapse. CONCLUSION: Our findings demonstrate positive impact of coping skills education program after detoxification process on decrease of craving beliefs among opium addicts. PMID- 26060623 TI - Motor Skill Competence and Perceived Motor Competence: Which Best Predicts Physical Activity among Girls? AB - BACKGROUND: The main purpose of this study was to determine which correlate, perceived motor competence or motor skill competence, best predicts girls' physical activity behavior. METHODS: A sample of 352 girls (mean age=8.7, SD=0.3 yr) participated in this study. To assess motor skill competence and perceived motor competence, each child completed the Test of Gross Motor Development-2 and Physical Ability sub-scale of Marsh's Self-Description Questionnaire. Children's physical activity was assessed by the Physical Activity Questionnaire for Older Children. Multiple linear regression model was used to determine whether perceived motor competence or motor skill competence best predicts moderate-to vigorous self-report physical activity. RESULTS: Multiple regression analysis indicated that motor skill competence and perceived motor competence predicted 21% variance in physical activity (R(2)=0.21, F=48.9, P=0.001), and motor skill competence (R(2)=0.15, ?=0.33, P= 0.001) resulted in more variance than perceived motor competence (R(2)=0.06, ?=0.25, P=0.001) in physical activity. CONCLUSION: Results revealed motor skill competence had more influence in comparison with perceived motor competence on physical activity level. We suggest interventional programs based on motor skill competence and perceived motor competence should be administered or implemented to promote physical activity in young girls. PMID- 26060624 TI - Antibiotic Sensitivity Patterns and Molecular Typing of Shigella sonnei Strains Using ERIC-PCR. AB - BACKGROUND: Shigella sonnei is considered as a major cause of diarrheal disease in both developing and developed countries. Iran is one of the endemic areas of shigellosis. The present study was undertaken to investigate the antibiotic susceptibility and genetic relatedness of S. sonnei strains isolated from pediatric patients in Tehran, Iran. METHODS: The study included all S. sonnei strains isolated from pediatric patients with diarrhea admitted to several hospitals in Tehran, Iran, during 2008-2010. Shigella spp. strains were recovered from patients using standard microbiological methods. S. sonnei strains were further studied by antimicrobial susceptibility testing and Enterobacterial Repetitive Intergenic Consensus (ERIC) - PCR analysis. RESULTS: Eighty nine Shigella isolates were isolated. S. sonnei was themost prevalent Shigella species (60.7%) followed by, S. flexneri (31.5%). Eleven antimicrobial resistance patterns (R1-R11) were identified among S. sonnei isolates. The majority of the strains were resistant to trimethoprim-sulfamethoxazole, tetracycline and streptomycin. All isolates were susceptible to ciprofloxacin, ceftizoxime and chloramphenicol. All strains were typable by ERIC-PCR. Five ERIC-PCR patterns (E1 E5) were found among S. sonnei isolates; however the half of the isolates was clustered in E4 pattern. CONCLUSION: The antibiotic resistance rates are increasing among S. sonnei strains. Moreover, a predominant clone or limited clones of S. sonnei were responsible for shigellosis caused by this Shigella species in pediatric patients in Tehran, Iran. PMID- 26060625 TI - A Randomized, Controlled Trial of Levonorgestrel Vs. The Yuzpe Regimen as Emergency Contraception Method among Iranian Women. AB - BACKGROUND: We aimed to compare acceptability of Levonorgestrel with the Yuzpe regimen among Iranian women based on their side-effects and resulting changes in the amount and pattern of menses. METHODS: Five hundred twenty nine participants aged 15-49 having regular menses and one act of unprotected intercourse within 72 h were included in the double-blind, controlled trial in 2006-2007 and randomly assigned into LNG (n=263) and HD (n=266) groups, receiving Levonorgestrel 0.75 mg given 12 h apart and ethinyl estradiol 100 MUg plus 0.5 mg Levonorgestrel 0.5 mg repeated after 12 h, respectively. RESULTS: The participants receiving Levonorgestrel experienced significantly lower side-effects in the case of nausea, vomiting, and dizziness (P<0.05). The changes occurred in the amount and pattern of menses were the same for both groups (P>0.05). No significant difference was observed between the efficiencies of the treatments. CONCLUSION: Significantly lower side-effects of Levonorgestrel can be considered as greater acceptability and translated to higher efficiency. PMID- 26060626 TI - Effect of Air Pollutant Markers on Multiple Sclerosis Relapses. AB - BACKGROUND: Multiple Sclerosis (MS) is one of the autoimmune diseases with an unknown cause. The aim of this study was to explore the link between air quality and MS relapses in patients who suffer from MS. METHODS: This time-series study was conducted on patients registered at the Iranian Multiple Sclerosis Society in 2011-2012. They were randomly selected from patients lived in Tehran in the last five years, and had at least one relapse in the last three years. The link between monthly mean air pollutant levels and the relapses of MS in the participants was studied. RESULTS: Among the registered 160 participants, at least 150 had one attack during 2009 and 2012. Most air pollutants such as NO2, NO and CO are in high levels in the rainy season. Others like Pm10 and Nox are in high levels in the dry season. The correlation between NO2 levels of all markers of air quality and MS relapses (P=0.03, r=0.27) is weak. Best ARIMA model (p,d,q; 1,0,1) was determined between number of monthly relapses and living place, although this model was not significant (P=0.3) (AR; P=0.000, MA;P=0.4). CONCLUSIONS: Air pollutants might be regarded as a risk factor for MS relapse. PMID- 26060627 TI - The Effectiveness of Emotional Intelligence Training on the Mental Health of Male Deaf Students. AB - BACKGROUND: Deafness is a common neural-sensory impairment which leads to lower life quality, withdrawal, social activities reduction, and rejection feeling. So, it is important to plan suitable training programs for mental health promotion of deaf children. Emotional intelligence training is one of these programs. The present study was aimed to determine the effectiveness of emotional intelligence training on the mental health of deaf students. METHODS: In this semi experimental study with pretest and posttest design, General Health Questionnaire (GHQ) was completed in 40 randomly selected boy deaf students with mean age of (12.48) years old before and after the intervention. The aim of the questionnaire was obtaining information of somatic symptoms, anxiety, social dysfunction, and depression as well as general health. The students were assigned in experimental and control group randomly and in equal. Experimental group participated in 12 sessions (each session lasts for 50 minutes; twice a week) and were trained by emotional intelligence program, but control group did not. Multivariate analysis of covariance (MANCOVA) was used for analyzing the data. RESULTS: There was a significant difference (P<0.001) between experimental and control group according to somatic symptoms, anxiety, social dysfunction, depression and general health as a whole after participation in intervention sessions. CONCLUSION: There was a significant decrease in somatic symptoms, anxiety, social dysfunction, depression and increase in general health of experimental group. Our findings showed that emotional intelligence training program led to promote of general health of boy deaf students. PMID- 26060628 TI - Improving Trend of Adhering to Ethical Measures in Iranian Research in Human Genetics: A Survey from 2005 to 2009; and the Road Ahead. AB - BACKGROUND: The overwhelming rate of progress in biotechnological research especially in human genetics, as well as the high levels of power these researches provide us to intervene in human lives, brings serious concerns on the ethical problems that may rise from these research endeavors. To address this critical issue in Iran, we conducted a study issuing publishing authors of studies in human genetics from Iran, between years 2005 to 2011. METHODS: We contacted 116 corresponding authors of articles issuing genetics research on human subjects, asking them that whether they have gotten either informed consent from their study subjects or ethical approval from their institutional ethics committee. RESULTS: Only 13% of the authors presented both documents; 52% had not gotten any of the documents; 19% of authors felt no need for getting the mentioned documents; 13% declared that they only gotten oral consent and 3% of authors did not remember whether they have gotten any documentation or not. CONCLUSION: The trend for informed consent taking was improving over time, from 5% in year 2006 to 24% in 2009. The result was not satisfactory but showed good trend towards improvement, recommending more serious follow up concerning ethical aspects of articles published in human genetics. PMID- 26060629 TI - Myelodysplastic Syndrome with 6q Deletion as the Sole Chromosome Abnormality in an Iranian Patient: A Case Report with Review of Literature. AB - BACKGROUND: The myelodysplastic syndrome (MDS) is a highly heterogenous disorder and karyotype analysis is helpful for diagnostic and prognostic estimation. Deletion in long arm chromosome 6 (6q del) as a sole abnormality is a rare event in MDS. This is the first case report of del (6q) as the only observed diagnostic change in Iran. We also reviewed the literature of this cytogenetic lesion. PMID- 26060630 TI - Features of Carbon Monoxide Poisoning in China. PMID- 26060631 TI - Tubular Kidney Protection by Antioxidants. PMID- 26060632 TI - Increasing the Trend of Smoking in Iranian Adolescents. PMID- 26060633 TI - Intestinal Parasites and Bruxism in Children. PMID- 26060634 TI - Towards the Application of Open Source Software in Developing National Electronic Health Record-Narrative Review Article. AB - Electronic Health Record (EHR) is a repository of patient health information shared among multiple authorized users. As a modern method of storing and processing health information, it is a solution for improving quality, safety and efficiency of patient care and health system. However, establishment of EHR requires a significant investment of time and money. While many of healthcare providers have very limited capital, application of open source software would be considered as a solution in developing national electronic health record especially in countries with low income. The evidence showed that financial limitation is one of the obstacles to implement electronic health records in developing countries. Therefore, establishment of an open source EHR system capable of modifications according to the national requirements seems to be inevitable in Iran. The present study identifies the impact of application of open source software in developing national electronic health record in Iran. PMID- 26060635 TI - A Review of Pioneer Physicians' Work on Maternal Health in Pregnancy in Ancient Iran; Narrative Systematic Review. AB - Background Maternal lifestyle and behaviors during pregnancy have been associated with future health outcomes for mothers and babies. Iranian Traditional medicine, which is a holistically-oriented medical discipline, has special attitudes towards pregnancy. The purpose of the study is the investigation of maternal health in medical books of ancient Iran. This study is a systematic review scrutinizing issues concerning lifestyle during pregnancy based on "Avicenna's Canon medicine" and "Rhazes Al-Havi" and for complete discussion, other reliable sources in traditional medicine which was conducted following the categorization and analysis of the gleaned data. Based on approaches by Iranian Traditional Medicine, the most important topics in lifestyle habits during pregnancy are divided into four main groups: Nutrition, physical exercise, sexual activity and psychological stress. Then special recommendations are suggested which include a regimen to facilitate labor. Eating behaviors and other lifestyle habits have a major role in optimizing the health of women in pregnancy. Regarding to traditional medicine viewpoints paying special attention to correcting diet, life style and preventive attitude with effective and simple therapeutic procedures, it seems that traditional medicine can offer efficient managements to alleviate some pregnancy complications. PMID- 26060636 TI - Differences in Lifestyles Including Physical Activity According to Sexual Orientation among Korean Adolescents. AB - BACKGROUND: The purpose of the present study was to examine differences in lifestyle factors such as physical activity among homosexual (gay or lesbian), bisexual, and heterosexual Korean adolescents. METHODS: The sample consisted of 74,186 adolescents from grades 7-12 (ages 12-18) who participated in the 8(th) annual Korea Youth Risk Behavior Web-based Survey in 2012. Of this sample, only 11,829 provided enough information regarding their romantic and sexual experiences to define them as gay, lesbian, bisexual, or heterosexual. From this information, males were divided into gay (n = 323), bisexual (n = 243), and heterosexual (n = 6,501) groups, and females were divided into lesbian (n = 208), bisexual (n = 113), and heterosexual (n = 4,441) groups. Differences in lifestyle factors according to sexual orientation were analyzed using one-way analysis of variance. RESULTS: Males showed significant differences by sexual orientation group in terms of frequency of smoking (P = 0.029), alcohol consumption (P < 0.001), muscular strength exercises (P = 0.020), and walking for at least 10 minutes per week (P < 0.001). Females showed significant differences by sexual orientation group in terms of frequency of smoking (P < 0.001), alcohol consumption (P < 0.001), vigorous physical exercise (P < 0.001), moderate physical exercise (P < 0.001), and muscular strength exercises (P < 0.001), as well as for self-reported mental stress (P < 0.001). CONCLUSION: We concluded those gay and bisexual males and lesbian and bisexual females had significant lifestyle differences as compared with heterosexual adolescents. This effect was stronger for females than for males. PMID- 26060637 TI - Impact of Socio-Health Factors on Life Expectancy in the Low and Lower Middle Income Countries. AB - BACKGROUND: This study is concerned with understanding the impact of demographic changes, socioeconomic inequalities, and the availability of health factors on life expectancy (LE) in the low and lower middle income countries. METHODS: The cross-country data were collected from 91 countries from the United Nations agencies in 2012. LE is the response variable with demographics (total fertility rate, and adolescent fertility rate), socioeconomic status (mean year of schooling, and gross national income per capita), and health factors (physician density, and HIV prevalence rate) are as the three main predictors. Stepwise multiple regression analysis is used to extract the main factors. RESULTS: The necessity of more healthcare resources and higher levels of socioeconomic advantages are more likely to increase LE. On the other hand, demographic changes and health factors are more likely to increase LE by way of de-cease fertility rates and disease prevalence. CONCLUSION: These findings suggest that international efforts should aim at increasing LE, especially in the low income countries through the elimination of HIV prevalence, adolescent fertility, and illiteracy. PMID- 26060638 TI - Effect of Second-Hand Smoke Exposure on Lung Function among Non-Smoking Korean Women. AB - BACKGROUND: Previous literature has implicated that there might be an individual susceptibility difference in terms of race/ethnicity and gender in response to second hand smoke (SHS) exposure. This study was done to examine the effect of SHS exposure on lung function in non-smoking Korean women. METHODS: This cross sectional study was conducted using the Korea National Health and Nutrition Examination Survey (KNHANES) from 2008-2011. A total of 2,513 female participants, age 40 yr and older, with no respiratory symptoms or prior lung diseases, were included in this study. Participants' smoking status was examined using both self-reported history and measurement of urinary cotinine level. Lung function was assessed using spirometry data, including FVC and FEV1. T-test and Chi-square tests were performed to compare diverse variables between groups. Analysis of covariance (ANCOVA) adjusted for age, height, alcohol consumption, and level of exercise was used to see any statistical differences in lung function parameters between non-SHS exposed and SHS-exposed groups. RESULTS: Among 2,513 non-smoking females, 767 (30.5%) were SHS-exposed. The urinary cotinine levels clearly distinguished SHS exposure, and the mean urinary cotinine levels were 7.1+/-0.4 and 11+/-0.7 in non-SHS exposed group vs. SHS-exposed group, respectively (P < 0.001). Urinary cotinine levels were correlated with duration of SHS exposure. However, both groups had normal lung function and there was no significant difference between the two groups in lung function. CONCLUSIONS: Urinary cotinine is a valuable marker of SHS exposure. Korean women may have higher tolerance for SHS exposure-induced lung function decline. PMID- 26060639 TI - Neurobehavioral Performance of Estate Residents with Privately-Treated Water Supply. AB - BACKGROUND: Neurotoxicants present in water supply may affect human functions in terms of attention, response speed and perceptual motor speed. Neurobehavioural performance can be influenced by gender, age and education levels. This study aims to assess the neurobehavioral performance of palm oil estate residents with private water supply in southern Peninsular of Malaysia. METHODS: A total of 287 and 246 participants from estates with private (PWS) and public water supply (PUB) were recruited to complete a demographic and subjective symptom questionnaire followed by the Neurobehavioral Core Test Battery (NCTB). RESULTS: PWS participants who consumed privately-treated water performed poorly in all NCTB tests compared to PUB participants except for Santa Ana test. Significant group differences in neurobehavioral performance were found for Digit Span Backward (P=0.047), Benton Visual Retention (P=0.006) and Trail Making B tests (P<0.05); which measures the function of memory, attention and visual perception conceptual. Gender, age and years of education influenced the NCTB scores (P<0.05). Female participants performed poorly in tests measuring latency but excellently tackled those tests that determined association. Younger participants from both PWS and PUB performed better on NCTB tests when compared to other age groups (P<0.05). PWS and PUB participants in this study who received a longer duration of education excelled in the NCTB tests (P=0.000). CONCLUSION: Poor neurobehavioral performance is associated with low water supply quality which affects neurofunctions in terms of attention, memory, response and perceptual motor speed. PMID- 26060640 TI - A Study of Risk Factors and T- Score Variability in Romanian Women with Postmenopausal Osteoporosis. AB - BACKGROUND: The purpose of this study was to analyse the prevalence of postmenopausal osteoporosis risk factors and to analyse the T-score variability in spine and hip according to the associated risk factors. METHODS: This is a retrospective study (2003-2007) including 177 female patients with postmenopausal osteoporosis. The patients were separated in seven groups according to the number of risk factors per case. The T-score was compared between this groups using unpaired t-Student test. RESULTS: The most frequent risk factor was early menopause (44.63%), followed by low consumption of dairy products (37.29%), coffee consumption (25.99%), sedentary lifestyle (20.9%), smoking (19.21%), delayed menarche (15.25%), low body mass index (10.71%), nulliparity (7.91%), alcohol consumption (0.56%). The maximum number of risk factors per case was six. The T-score decreased with increasing number of risk factors. T-score differences are statistically significant when comparing cases with 6 risk factors to cases with 5 risk factors (P=0.0315 in spine; P=0.0088 in hip), 4 risk factors (P=0.0076 in spine; P=0.043 in hip), 3 risk factors (P<0.0001 in spine; P=0.0205 in hip), 2 risk factors (P=0.0012 in spine; P<0.0001 in hip), a single risk factor (P<0.001 in spine and hip) and no risk factor (P=0.0075 in spine; P=0.0006 in hip). CONCLUSION: Association of several risk factors leads to decrease of T score so being able to avoid any such factors may contribute to a better bone mineral density. This could be achieved by the education of female population regarding postmenopausal osteoporosis risk factors, followed by adopting an appropriate lifestyle and diet. PMID- 26060641 TI - Prevalence of Primary Infertility in Iran in 2010. AB - BACKGROUND: Infertility is one of the most significant medical, as well as social problems that affect psychological health of families and societies. Determining the prevalence of infertility is important for evaluating the potential of fertility. There are different reports on the prevalence of infertility in Iran, but the current research employs fertility history in order to provide an unbiased estimation of primary infertility. METHODS: Data from a national survey of Iranian women aged 20-40 years was used in this study in year 2011. Totally, 1011 clusters were randomly selected according to post office codes, proportional to the population of the province. We evaluated the history of fertility as the basis for gathering information. Accordingly, we designed a questionnaire. Subsequently, we recruited and trained nurses and obstetricians to call on married women to fill the questionnaires. Primary infertility refers to a condition in which couples have not been able to conceive a child after one year of un-protected intercourse. RESULTS: In this research, we questioned 17187 women in 1011 clusters. The mean age of the women at the time of their marriage was 20.1, and that of their husbands was 25.4 years. The mean age of women at the time of their first pregnancy was 21.1. This research revealed the prevalence of primary infertility to be 20.2% in Iran. CONCLUSION: The prevalence of primary infertility in Iran seems to be higher than the world average. Therefore, it is crucially important to support the large number of couples who face this problem. PMID- 26060642 TI - What Is the Share of the Country's Researches in Iran's National Tuberculosis Guideline? AB - BACKGROUND: Appraisal of clinical guideline, especially at the national level, has two potential benefits; one is the improvement of quality of care and the second is assessing the impact of researches on an applied setting. On the other hand, Tuberculosis (TB) is a major infectious disease which has national guideline in many countries. The present study was performed to assess sources of information and level of evidence in Iran's national TB guideline. This could explore the impact of national researches on day by day practice in the health system. METHODS: A list of main "recommendations" of the guideline was explored. Then, in cases that the cited study for any decision was available, the type of study and its evidence level was specified using a standard tool. In addition, the source of information (national/international) was determined. In other cases that no any specific citation was found, the data source of the recommendation was determined by the senior experts in the Center for Communicable Disease Control. RESULTS: Fifteen (48.3%) recommendations of the national guideline, out of 31 reviewed, had clearly cited at least one study. There was just one single national study which was utilized as the basis for the recommendations. All other sources were international guidelines, mainly World Health Organization's, and or international researches. CONCLUSION: While, the methodology of the guideline development was not clear enough appropriately; the share of national researches in development of the national guideline was insignificant. PMID- 26060643 TI - Comparison between Complementary Dietary Treatment of Alzheimer Disease in Iranian Traditional Medicine and Modern Medicine. AB - BACKGROUND: Dietary notifications have been introduced recently for Alzheimer Disease (AD). In Iranian old medical manuscripts, there are some nutritional recommendations related to Nesyan (AD equivalent). The aim of this article was to compare dietary recommendations of Iranian traditional medicine (ITM) with novel medical outcomes. METHODS: 1) Searching for dietary recommendations and abstinences described in ITM credible manuscripts; 2) Extracting fatty components of ITM diet according to the database of the Department of Agriculture of the USA; 3) Statistical analysis of fatty elements of traditionally recommended foods via Mann-Whitney Test in comparison with elements of the abstinent ones; 4) Searching for AD dietary recommendations and abstinences which currently published in medical journals; 5) Comparing traditional and new dietary suggestions with each other. RESULTS: 1) Traditionally recommended foods are fattier than abstinent ones (P<0.001). There are meaningful differences between unsaturated fatty acids (UFAs) (P<0.001), saturated fatty acids (P<0.001), and cholesterol (P<0.05) of recommended foods and abstinent ones. 2) Traditionally recommended diet is also fattier than the abstinent diet (4.5 times); UFAs of the recommended diet is 11 times more than that of the abstinent one; it is the same story for cholesterol (1.4 times); 3) Recent studies show that diets with high amounts of UFAs have positive effects on AD; a considerable number of papers emphasizes on probable positive role of cholesterol on AD; 4) Traditional recommended diet is in agreement with recent studies. CONCLUSION: ITM recommended diet which is full of unsaturated fatty acids and cholesterol can be utilized for complementary treatment of AD. PMID- 26060644 TI - Peer Education: Participatory Qualitative Educational Needs Assessment. AB - BACKGROUND: In the area of youth health, peers education is an approach to health promotion. Assess the training needs of peers educators clarifies the components, values, and quality of training protocols. Aim to that we conducted a participatory educational needs assessment of youth peer educators. METHODS: Involving youth and key informants in direct collaboration with research team, a qualitative approach was planned based on grounded theory. For data collection a semi-structured guide questioning was designed. Sixteen focus group discussions and 8 in depth interview were held. RESULTS: The majority of participants emphasized on the importance of mental health, life skills, AIDS prevention, contraception methods, and healthy nutrition as the main training topics. They were extremely interested into the comprehensive educational material among their participatory role in peer programs. CONCLUSION: The training programs should be well defined based on the knowledge, skills and behavior of peers. During the implementation, training programs should be followed to meet the ongoing educational needs of service providers. PMID- 26060645 TI - The Effectiveness of Harm Reduction Programs in Seven Prisons of Iran. AB - BACKGROUND: Starting in 1990 many programs were initiated to prevent and control the spread of HIV/AIDS in prisons in accordance with the policies of the Ministry of Health. This study attempts to evaluate the effectiveness of harm reduction programs vis-a-vis drug abuse and dependency in 7 prisons in Iran. METHODS: The methodology used is Before-After testing and the sample population is incarcerated prisoners in 7 large prisons in 7 provinces with diverse geographical, criminal, and numerical factors and the population sample is estimated at 2,200 inmates. RESULTS: Findings show that Drug addiction tests conducted on prisoners, right after their admittance indicated that 57% used at least one of the three drugs of morphine, amphetamines, and hashish (52% morphine, 4.5% ampheta-mines, and 3.9% hashish). Two months later, on the 2nd phase of the study, test results indicated that only 10% of subjects continued using drugs (P =0.05). Heroin and opium were the two most prevalent drugs. Smoking, oral in-take, and sniffing were the three most popular methods. Of those who continued to use drugs in prison, 95% admitted to drug use records. CONCLUSION: Intervention policies in prisons resulted in reduction of drug consumption, from 57% of the newly admitted inmates to 10% after two months of incarceration. PMID- 26060646 TI - Developing of National Accreditation Model for Rural Health Centers in Iran Health System. AB - BACKGROUND: The primary health care has notable effects on community health and accreditation is one of the appropriate evaluation methods that led to health system performance improvement, therefore, this study aims to developing of national accreditation model for rural health centers in Iran Health System. METHODS: Firstly the suitable accreditation models selected to benchmarking worldwide via systematic review, the related books and medical university's web site surveyed and some interviews hold with experts. Then the obtain standards surveyed from the experts' perspectives via Delphi technique. Finally, the obtainedmodel assessedvia the experts' perspective and pilot study. RESULTS: The researchers identified JCAHO and CCHSA as the most excellent models. The obtained standards and their quality accepted from experts' perspective and pilot study, and finally the number of 55 standards acquired. CONCLUSION: The designed model has standards with acceptable quality and quantity, and researchers' hopeful that its application in rural health centers led to continues quality improvement. PMID- 26060647 TI - Rheological Characterization and Cluster Classification of Iranian Commercial Foods, Drinks and Desserts to Recommend for Esophageal Dysphagia Diets. AB - BACKGROUND: In the absence of dysphagia-oriented food products, rheological characterization of available food items is of importance for safe swallowing and adequate nutrient intake of dysphagic patients. In this way, introducing alternative items (with similar ease of swallow) is helpful to improve quality of life and nutritional intake of esophageal cancer dysphagia patients. The present study aimed at rheological characterization and cluster classification of potentially suitable foodstuffs marketed in Iran for their possible use in dysphagia diets. METHODS: In this descriptive study, rheological data were obtained during January and February 2012 in Rheology Lab of National Nutrition and Food Technology Research Institute Tehran, Iran. Steady state and oscillatory shear parameters of 39 commercial samples were obtained using a Physica MCR 301 rheometer (Anton-Paar, GmbH, Graz, Austria). Matlab Fuzzy Logic Toolbox (R2012 a) was utilized for cluster classification of the samples. RESULTS: Using an extended list of rheological parameters and fuzzy logic methods, 39 commercial samples (drinks, main courses and desserts) were divided to 5 clusters and degree of membership to each cluster was stated by a number between 0 and 0.99. CONCLUSION: Considering apparent viscosity of foodstuffs as a single criterion for classification of dysphagia-oriented food products is shortcoming of current guidelines in dysphagia diets. Authors proposed to some revisions in classification of dysphagia-oriented food products and including more rheological parameters (especially, viscoelastic parameters) in the classification. PMID- 26060648 TI - Analysis of the Systematic Relationships among Social Determinants of Health (SDH) and Identification of Their Prioritization in Iran Using DEMATEL Technique. AB - BACKGROUND: Social determinants, similar to equity, have been considered by policymakers in many countries. However, there is not a correct and complete understanding of them. This study aimed to analyze the systematic relationships among social determinants of health (SDH) and identify their prioritization in Iran. METHODS: This cross-sectional descriptive-analytical study was conducted in 2012. The target population consisted of 30 experts on SDH. Required data was collected using a questionnaire, as well as, nominal group technique (NGT). Then collected data were analyzed using MATLAB 7.9.0 and SPSS 18.0. RESULTS: Determinants of early life (EL), social gradient (SG), unemployment (U), stress (S) and addiction (A) were certainly affecting determinants on the system, which were placed in the cause group and ranked as the first to fifth priorities, respectively. While social exclusion (SE), food (F), social support (SS), work (W) and transport (T) were partially affected determinants and were placed in the effect group and ranked as the sixth to tenth priorities, respectively. Early life and transport were identified as the most affecting and affected determinants with the coordinates (2.16 and 0.75) and (1.68 and -0.47) on the SDH diagram, respectively. CONCLUSION: Improving the social and economic status, considering the early life, increasing the quality of education, and reducing unemployment and stress have effects on the other social determinants of health and provide opportunities for increasing equity. PMID- 26060649 TI - A Family Clustered Nitrite Intoxication Investigation in Gaoxin District, Suzhou, China, 2013. AB - BACKGROUND: In April, 2013, a Suzhou Hospital reported a nitrite intoxication patient in coma as well as 2 family members with the similar symptom 5 days ahead. We investigated the event to identify the cause, source and possible pollution ways of the contamination. METHODS: We defined case as any person living in YSHY community who has cyanosis and with at least one of the following symptoms: dizziness, headache, fatigue, tachycardia, drowsiness, nausea, vomiting, abdominal pain or diar-rhea during April 15 to April 25, 2013. We searched for case by interviewing community residents and reviewing clinics' medical records; information was then retrospectively collected on the patient's food history, cooking procedures and food sources. RESULTS: We identified 3 nitrite intoxication cases, 1 male and 2 female from a family. The interval time between dinner and onset was < 1 hour. Retrospective survey showed 'sugar stir and mix asparagus' on April 17 and 'scrambled asparagus' on April 21 were suspected foods. Both suspected dishes had 'sugar' added, sourced from a clean-up of a neighboring rental house. Nitrite was detected in a vomitus sample, the 'sugar' and two leftover food samples. CONCLUSION: This family clustered nitrite intoxication was induced by using unidentified nitrite as sugar to cook dishes. We recommend sodium nitrite should be dyed with bright colors to avoid mistaking it for plain salt or sugar, health departments strengthen food hygiene propaganda to improve people's recognition of food safety, and to alert them the dangerous of eating unidentified or unknown source food. PMID- 26060650 TI - Evolution of Clinical Manifestations of Neck and Face due to Cutaneous Leishmaniasis Resulting In Diagnostic Errors. AB - Background Cutaneous leishmaniasis is the most common form of leishmaniasis caused by flagellate protozoa of the genus Leishmania transmitted by sand fly bites. Old World leishmaniasis is endemic in the Mediterranean Sea and the neighbouring countries. We believe, that this case is interesting by the fact that we had a very rear disease case that can be observed in nonendemic area. We present a case of a 22-year-old man with a cutaneous leishmaniasis in a localised form of ulcers on the right cheek and the right part of the neck. Histopathological examination showed diffuse dermal infiltrate predominantly of macrophages with admixture of few lymphocytes, eosinophils and plasma cells. In a very small number of macrophages amastigotes were seen. On their surface and occasionally extracellularly rod-shaped kinetoplasts were noticeable. It should be stressed that both clinical and laboratory data were not peculiar for this disease. Adults in endemic areas have stable immunity for protozoal infections. This made diagnostication and timely management of the disease very difficult. But clinical effect of drug therapy which is specific for cutaneous leishmaniasis treatment proved, in spite of the absence of ulcer soft tissues, blood and cerebrospinal puncture Leishmania, that our diagnosis was correct. The case, described by us, may be interesting for dermatologists, parasitologists, surgeons and other medical specialists. Because of higher rate of travel and work abroad increased number of sporadic cases of cutaneous leishmaniasis in non-endemic areas should be taken into account. Cutaneous leishmaniasis is a rare disease in Kazakhstan, especially in the north region. Because of higher rate of travel and work abroad increased number of sporadic cases of cutaneous leishmaniasis in non endemic areas should be taken into account. PMID- 26060651 TI - Ethical Use of Homeopathy and How Can We Use It in Dentistry. PMID- 26060652 TI - Secondary Data Analysis: Ethical Issues and Challenges. PMID- 26060653 TI - Mistake in Calculating the Positive Predictive Value. PMID- 26060655 TI - A Disaster Response and Management Competency Mapping of Community Nurses in China. AB - BACKGROUND: It is widely accepted in many parts of the world thatcommunity nurses are of vital importance in various phases of disaster response and management. In China, however, it is not clear whether the Chinese community nurses are able to assume disaster-related duties due to the lack of a systematic assessment. METHODS: A pre-designed and well-tested questionnaire was employed to evaluate the competency in disaster response and management among 205 valid registered Chinese community nurses between September and October 2009. Statistical analyses were performed with SPSS Version 13.0 using one way ANOVA, Least Significant Difference (LSD) and multiple stepwise regression analysis. RESULTS: This group of Chinese community nurses scored at an intermediate level of competency (a score of 3.68 (SD 0.48) out of a perfect score of 5) in disaster response and management, suggesting that they have the basic ability to participate in disaster-related nursing. Four factors, namely, Experiences in Disaster Relief, Participation in Disaster Training, the Age and Duration in Job, were identified to be the predominant factors contributing significantly to the integrated competency in disaster response and management of an individual. CONCLUSION: Most of the Chinese community nurses have basic qualifications and competencies to undertake the responsibilities of disaster response and management. However, more targeted disaster training including virtual-reality based drills should be provided in order to improve their competency. PMID- 26060654 TI - Oral Health of Drug Abusers: A Review of Health Effects and Care. AB - Oral health problems, among the most prevalent comorbidities related to addiction, require more attention by both clinicians and policy-makers. Our aims were to review oral complications associated with drugs, oral health care in addiction rehabilitation, health services available, and barriers against oral health promotion among addicts. Drug abuse is associated with serious oral health problems including generalized dental caries, periodontal diseases, mucosal dysplasia, xerostomia, bruxism, tooth wear, and tooth loss. Oral health care has positive effects in recovery from drug abuse: patients' need for pain control, destigmatization, and HIV transmission. Health care systems worldwide deliver services for addicts, but most lack oral health care programs. Barriers against oral health promotion among addicts include difficulty in accessing addicts as a target population, lack of appropriate settings and of valid assessment protocols for conducting oral health studies, and poor collaboration between dental and general health care sectors serving addicts. These interfere with an accurate picture of the situation. Moreover, lack of appropriate policies to improve access to dental services, lack of comprehensive knowledge of and interest among dental professionals in treating addicts, and low demand for non-emergency dental care affect provision of effective interventions. Management of drug addiction as a multi-organ disease requires a multidisciplinary approach. Health care programs usually lack oral health care elements. Published evidence on oral complications related to addiction emphasizes that regardless of these barriers, oral health care at various levels including education, prevention, and treatment should be integrated into general care services for addicts. PMID- 26060656 TI - Burnout and Coping Strategies in Male Staff from National Police in Valparaiso, Chile. AB - BACKGROUND: This cross-sectional study aimed to examine the relationship between several dimensions of the burnout syndrome with certain stress-coping strategies, seniority level and marital status in male staff from National Police in Vaparaiso, Chile. METHODS: The sample collected in 2010 was composed of 338 male officers coming from various special units of a National Police in Valparaiso. Burnout and Coping Strategies were assessed and classified according Maslach Burnout Inventory (MBI) and COPE Inventory, respectively. Data was analyzed using Pearson product-moment correlation, t-test for independent measures and Multiple Linear Regression to generate a predictive model. RESULTS: The prevalence of the burnout syndrome disaggregated by grouping criteria, the dimensions concentrated in middle levels for emotional exhaustion with a 52.1%, a 51.8% for depersonalization and finally, personal achievement with a 48.8%. Only 28% of participants showed more exacerbated dimensions of the burnout syndrome. There was a weak and direct yet statistically significant relationship between personal achievement and active coping. Mental disconnection had a weak direct relationship between both coping strategies and emotional exhaustion also existed. Certain correlations between burnout dimensions and coping strategies focused on emotion as predictor variables over the criterion variable corresponding to emotional exhaustion were mental disconnection in first place, secondly, focusing on emotions, and emotional social support. CONCLUSIONS: Burnout dimensions scored medium values focusing mainly on emotional exhaustion and reduced personal accomplishment. Coping strategies are used in parallel and in general are not mutually exclusive. Finally, there were not any relationship between variables seniority level and marital status. PMID- 26060657 TI - Maternal Mortality in Burkina Faso: A Method from Population Census 2006. AB - BACKGROUND: Estimating maternal mortality level is constantly challenging researchers and planners both in rich and poor countries. In developing countries, particularly in Burkina Faso where the registration system is not working properly, censuses and surveys are the main providers of maternal mortality estimates. However, censuses provide more reliable data about maternal mortality especially at sub-national level. Strength of this situation, the census 2006 of Burkina Faso collected information about maternal mortality. Unfortunately, the census also under reported the phenomenon. In this regard, a methodology was developed to provide adjusted estimates of the phenomenon. METHODS: This paper aims to assess the census 2006 estimates of maternal mortality through a critical review of the questionnaire, data quality, adjustment technique and outputs. Incoherencies, duplicated cases and missing data were the key aspects of the data quality assessment. The assumptions and outputs of the method were examined and comparison made with existent estimates. RESULTS: Findings highlighted weaknesses regarding the assumptions of the method and showed that the levels of the phenomenon were still under-estimated. In this research, propositions have been made concerning data cleaning, situations of adjustment coefficients less than 1 and the problem of weak assumptions. Findings led to a MMRatio of 331 [293-402] maternal deaths per 100 000 live births. CONCLUSION: The level of maternal mortality as published in the census 2006 report (MMRatio of 307) is acceptable because falling in the range 293-402. However, the questionnaire, data and method used needed improvements. PMID- 26060658 TI - Survey of Hypertension, Diabetes and Obesity in Three Nigerian Urban Slums. AB - BACKGROUND: Non-communicable diseases (NCDs) exist in slums as the inhabitants adopt an urbanized lifestyle which places them at a higher risk for. Lack of knowledge about the morbidity, complications and the method of control contributes to a large percentage of undetected and untreated cases. METHODS: This cross-sectional survey polled 2,434 respondents from Ijora Oloye, Ajegunle and Makoko, three urban slums in Lagos metropolis, southwestern Nigeria between June 2010 and October 2012. We investigated the prevalence of hypertension, diabetes and obesity. Respondents signed consent forms and their health conditions were documented based on self-reported history of diabetes, hypertension and family history using a semi-structured questionnaire. Diagnostic tests; weight and height for body mass index, blood glucose, and blood pressure were performed. RESULTS: More than one quarter of the participants were suffering from hypertension and only half of this were diagnosed earlier, while a further few were already on treatment. Therefore on screening, it had been possible to diagnose over three hundred more respondents, who were not previously aware of their health status. The respondents' BMI showed that more than half of them were either overweight or obese and are at risk for diabetes, while 3.3% were confirmed as being diabetic, with their sugar levels greater than the normal range. CONCLUSION: This study therefore revealed the near absence of screening programs for chronic diseases such as hypertension, diabetes and obesity in these urban slums. This was further confirmed by the detection of new and undiagnosed cases of hypertension in about one quarter of the respondents. PMID- 26060659 TI - The Use of Competency Models to Assess Leadership in Nursing. AB - BACKGROUND: The efficiency of the health care system is significantly dependent on the appropriate leadership and guidance of employees. One of the most frequently used new approaches in human resources management is the study of competencies and competency models. The aim of this research is to develop a competency model for leaders in nursing, and to compare it with the leadership competency model for state administration. METHODS: A survey was conducted among 141 nurse leaders in Slovenia. The respondents were asked to complete questionnaire with 95 leadership behaviours that form the leadership competency model for leaders in nursing. The data were analysed by ANOVA and Tukey's honestly significant differences test. RESULTS: The levels of competencies set for themselves by leaders at the third leadership level in nursing (leaders of small units and teams) are significantly lower than those set by all other leaders, both in nursing and in state administration. Statistically significant differences were apparent in the majority of areas. CONCLUSION: Within the context of the comparison of competency models, the greatest need for training can be observed at the third level of leadership in nursing. A comparison of models formulated in this way enables the exchange of good practices among leaders from various professional groups and easier identification of the training needs of individual groups of leaders in public administration. The proposed concept is designed to significantly simplify and unify the building of competency-based leadership models in public sector. PMID- 26060660 TI - The Impact on Family among Down syndrome Children with Early Intervention. AB - BACKGROUND: Child with Down's syndrome is an individual who is suitable and eligible to receive early intervention services. This study aimed to measure the family outcome among parents of Down syndrome children, on the impact of receiving early intervention and identify the factors influencing it. METHODS: A cross sectional was conducted from April 2009 until January 2010 with a total of 125 parents of children with Down syndrome. There are five domains of family outcomes that has been studied which are understanding the strengths, abilities and special needs of children, knowing the rights and talk on children behalf, assisting the child to grow and learn, having a support system and be involved in the community. Children with Down syndrome aged four to 15 years was chosen as the respondents when they were accompanying their children in seven rehabilitation centers or during house visits. RESULTS: Family outcomes among parents of Down syndrome children who receive early intervention is better, 67.3 percent, compared to parents of Down syndrome children who receive late intervention, 41.4 percent. There are significant relationship between the acceptance level of intervention, parents education level, family income and the family outcomes. Parents of children who receive early intervention were more positive in understanding the strengths, abilities and special needs of their children compared to other family outcomes. CONCLUSION: Families whom children received early intervention had indirectly proved the importance and benefit of early intervention, not only for children with special needs, but for their family as well. PMID- 26060661 TI - Identification of Mutation of Glucose-6-Phosphate Dehy-drogenase (G6PD) in Iran: Meta- analysis Study. AB - BACKGROUND: Glucose-6-phosphate dehydrogenase is one of the most common genetic deficiencies, which approximately 400 million people in the world suffer from. According to authors' initial search, numerous studies have been carried out in Iran regarding molecular variants of this enzyme. Thus, this meta-analysis presented a reliable estimation about prevalence of different types of molecular mutations of G6PD Enzyme in Iran. METHODS: Keywords "glucose 6 phosphate dehydrogenase or G6PD, Mediterranean or Chatham or Cosenza and mutation, Iran or Iranian and their Persian equivalents" were searched in different databases. Moreover, reference list of the published studies were examined to increase sensitivity and to select more studies. After studying titles and abstracts of retrieved articles, excluding the repeated and unrelated ones, and evaluating quality of articles, documents were selected. Data was analyzed using STATA. RESULTS: After performing systematic review, 22 papers were entered this meta analysis and 1698 subjects were examined concerning G6PD molecular mutation. In this meta-analysis, prevalence of Mediterranean mutation, Chatham mutation and Cosenza mutation in Iran was estimated 78.2%, 9.1% and 0.5% respectively. CONCLUSIONS: This meta-analysis showed that in spite of prevalence of different types of G6PD molecular mutations in center, north, north-west and west of Iran, the most common molecular mutations in people with G6PD deficiency in Iran, like other Mediterranean countries and countries around Persian Gulf, were Mediterranean mutation, Chatham mutation and Cosenza mutation. It is also recommended that future studies may focus on races and regions which haven't been taken into consideration up to now. PMID- 26060662 TI - Prevalence of Permanent Congenital Hypothyroidism in Children in Yazd, Central Iran. AB - BACKGROUND: Congenital hypothyroidism is a condition of thyroid hormone deficiency. Approximately 1 in 4000 newborn infants has a deficiency of thyroid function. The aim of this study is determination of the prevalence of permanent and transient congenital hypothyroidism (CH) in Yazd, Iran. METHODS: From May 2006 to June 2008, 35377 newborns were screened by measuring serum TSH obtained by heel prick. The neonates who had a TSH>=5mU/L were recalled for measurement of serum T4 and thyroid stimulating hormone (TSH) in venous samples. Based on the results of the secondary measurements (between days 7 and 28), neonates were considered hypothyroid if their T4 was <6.5 mg/dl and their TSH was >=10mIU/L. In 22 primarily diagnosed as cases of CH, treatment was discontinued at age 3 years for 4 weeks and T4 and TSH were measured again. Permanent or transient CH was determined from the results of these tests; Patients with TSH levels >=5 mIU/l were diagnosed with permanent CH. RESULTS: The incidence of congenital hypothyroidism was found to be 1:1608 with a female to male ratio of 0.69:1. In 22 patients with CH, 10 patients were diagnosed with permanent CH (45.5%) and 12 with transient hypothyroidism (54.5%). Permanent CH was associated with higher TSH levels at first measurement than transient hypothyroidism (P-value=0.041). CONCLUSION: The rate of transient CH in our study was higher than the comparable worldwide rate, so more and larger studies are needed to find clear information about the etiologic factors of this disease. PMID- 26060663 TI - Intensive Care Unit Staff and Resource Utilization: Is It an Effective Factor? AB - BACKGROUND: The aim of present study was to determine the impact of two different ICU management model, open and semi closed, on resources utilization in intensive care unit. METHOD: Retrospective cohort analysis using data from hospital database was applied to compare the effect of ICU management model on ICU length of stay and bed disposition of 1064 patients admitted to the general ICU of Imam Khomeini Hospital of Tehran, Iran during the two consecutive 12-month periods from Mar, 2009 to Feb, 2010. RESULTS: In open and semi closed interval 380 and 684 patients were admitted to ICU respectively. There was no significant difference in age, gender and severity of illness (based on APACHE-II score) and nurse to bed ratio between two groups. Average ICU length of stay, net mortality rate and bed turnover rate were lower in semi closed model than open model management significantly (P<0.05). CONCLUSION: Semi closed model improves patient care and lead to lower mortality rate and resources utilization too. PMID- 26060664 TI - Effect of Mindfulness Based Stress Reduction on Quality of Life (SF-36) and Spirometry Parameters, in Chemically Pulmonary Injured Veterans. AB - BACKGROUND: Studies have shown that Mindfulness Based Stress Reduction (MBSR) has positive effect on physical and psychological dimensions of chronic illnesses. In this study for the first time we examine the effect of this new technique on quality of life and pulmonary function in chemically pulmonary injured veterans who have chronic pulmonary problem, psychological problems and low quality of life. METHODS: Forty male pulmonary injured veterans were randomly replaced in two groups with 20 participants (MBSR and control Wait List (WL)). Then MBSR group received 8-weekly sessions intervention. We evaluate quality of life (used SF-36 questionnaire) and Spirometry parameters two times; before and after intervention in two group. We used "mixed factorial analyses of variance" test for analyzing data in each dependent variables. Then if we have significant interactional effect, we used -paired- sample t-test" for comparing before and after intervention data of each group, and "Independent-Sample t-test" for comparing after intervention data of two groups. RESULTS: The MBSR compare to WL group improved SF-36 total score, (F (1, 38) =12.09, P=0.001), "Role limitations due to physical problems"(F(1,38)= 6.92, P=0.01), "Role limitations due to emotional problems"(F(1,38)= 7.75, P=0.008), "Social functioning"(F(1,38)= 9.89, P=0.003), "Mental health"(F(1,38)= 15.93, P=0), "Vitality"(F(1,38)= 40.03, P<=0.001), and "Pain"(F(1,38)= 27.60, P<=0.001). MBSR had no significant effect on "FEV1" (F (1, 38) = 0.03, P=0.85),"FVC" (F (1, 38) = 0.16, P=0.69) and "FEV1/FVC" (F (1, 38) = 2.21, P=0.14). CONCLUSION: MBSR can improve individual's quality of life but not lung function in chemically pulmonary injured veterans. PMID- 26060665 TI - Burnout and Associated Factors among Iranian Emergency Medicine Practitioners. AB - BACKGROUND: Emergency physicians are at risk of burnout, which can affect their mental health, as well as patient care. We assessed burnout level among Iranian emergency physicians and investigated demographic, work-related factors and stressors associated with higher burnout. METHODS: In a cross-sectional study, we surveyed all 188 emergency medicine residents and practitioners in Iran. We measured burnout using 22-item Maslach Burnout Inventory assessing emotional exhaustion, depersonalization and personal accomplishment, also demographic factors, work related factors and sources of stress in emergency department using anonymous self-administered questionnaire. Descriptive analysis, univariate analysis to evaluate association with higher score of burnout, and multivariate logistic regression analysis to predict high burnout in 3 subscales was performed. RESULTS: Totally, 165 questionnaires were filled (response rate: 88%; mean age: 33.6 years, 91% male). Mean burnout scores were 22.94 for emotional exhaustion (95% CI=20.78-25.01; moderate), 9.3 for depersonalization (95% CI=8.24 10.36; moderate to high), and 31.47 for personal accomplishment (95% CI=29.87 33.07; moderate to high). Frequent reported sources of stress were shortage of equipment, problem with work physical environment, and relationship with other services. All 19 sources of stress were associated with higher score of emotional exhaustion and depersonalization; while twelve out of 19 were significantly associated with lower level of personal accomplishment. In logistic regression model, the significant predictors for high emotional exhaustion were work overload, feeling of insecurity for future career and difficulties to balance professional and private life. CONCLUSION: Burnout is high among Iranian emergency medicine practitioners and some interventions can be proposed to reduce stress. PMID- 26060666 TI - Is Age of Menarche Related with Body Mass Index? AB - BACKGROUND: Prediction of the onset of menstruation (menarche age) using height, weight and Body Mass Index (BMI) is a major health procedure. The present study was conducted to determine the relationship between anthropometric indices and menarche age in 488 girls 11-17 years in southern Iran (Kish Island) in 2011. METHODS: Data was collected using questionnaires as well as measurements of the children's height and weight. This data was analyzed using t-test and logistic regression. RESULTS: Median age of menarche of menstruated girls as inferred from the age of menarche cumulative distribution was 12.9 years. Mean (SD) BMI in menstruated and non-menstruated girls were 21.97 (4.5) and 19.17 (3.7), respectively. Mean (SD) weight and height of the menstruated girls were 53.65 (12.3) kg and 156.06 (5.5) cm, respectively which are higher than respective figures of the non-menstruated participants 43.70 (10.7) kg and 150.21 (6.3) cm, respectively. Our results revealed a significant correlation between BMI and menarche age. CONCLUSION: Menarche age and BMI are significantly correlated with higher BMI related to lower menarche age. PMID- 26060667 TI - A Molecular Epidemiological Survey of Clinically Important Dermatophytes in Iran Based on Specific RFLP Profiles of Beta-tubulin Gene. AB - BACKGROUND: Surveillance of dermatophytosis is essential to determine the likely changes in etiological trends and distribution profile of this infection. In this study beta tubulin gene (BT2), was used as the first time in a PCR-RFLP format to clarify the distribution of dermatophytosis agents in some parts of Iran. METHODS: A total of 603 clinical isolates was obtained from 500 patients in Tehran, Isfahan, Mazandaran and Guilan provinces. The isolates were identified using macro/micro-morphological criteria and electrophoretic patterns of PCR amplicons of BT2after digestion with each of the restriction enzymes FatI, HpyCH4V, MwoI and Alw21I. RESULTS: Among the patients, 59.2% were male and 40.8% female. The most prevalent clinical form was tinea pedis (42.4%), followed by tinea cruris (24.2%), tinea unguium (12.3%), tinea corporis (10.8%), tinea faciei (4%), tinea manuum (3.14%), tinea capitis (3%) and tinea barbae (0.16%), respectively. Trichophyton interdigitale ranked the first, followed by T. rubrum, Epidermophyton floccosum, Microsporum canis, T. tonsurans, T. erinacei and T. violaceum (each 0.49%) and the less frequent species were T. schoenleinii, M. gypseum and T.anamorph of Arthroderma benhamiae (each 0.16%). A case of scalp infection by E. floccosum was an exceptional event in the study. No case of T. verrucosum was found. CONCLUSION: Trichophyton species and E. floccosum are yet the predominant agents of infection in Iran, while Microsporum species are decreasing. T. interdigitale and Tinea pedis remain as the most causal agent and clinical form of dermatophytosis, respectively. It seems that BT2 can be a useful genetic marker for epidemiological survey of common pathogenic dermatophytes. PMID- 26060668 TI - Is Scores Derived from the Most Internationally Applied Patient Safety Culture Assessment Tool Correct? AB - BACKGROUND: Hospital Survey on Patient Safety Culture, known as HSOPS, is an internationally well known and widely used tool for measuring patient safety culture in hospitals. It includes 12 dimensions with positive and negative wording questions. The distribution of these questions in different dimensions is uneven and provides the risk of acquiescence bias. The aim of this study was to assess the questionnaire against this bias. METHODS: Three hundred nurses were assigned into study and control groups randomly. Short form of HSOPS was distributed in the control group and totally reversed form of it was given to the study group. Percent positive scores and t-test were applied for data analysis. Statistical analyses were conducted using SPSS Version 16. RESULTS: Finally a total of 272 nurses completed the questionnaire. All dimensions with positive wording items in both groups had higher scores compared with their negative worded format. The first dimension "organizational learning and continued improvement" which had the only statistically significant difference, got 16.2% less score in the study group comparing the other group. In addition six out of 18 differences in questions were statistically significant. CONCLUSION: The popular and widely used HSOPS is subject to acquiescence bias. The bias might lead to exaggerate the status of some patient safety culture composites. Balancing the number of positive and negative worded items in each composite could mitigate the mentioned bias and provide a more valid estimation of different elements of patient safety culture. PMID- 26060669 TI - Bacterial Contamination of Iranian Paper Currency. AB - BACKGROUND: Transmission of human pathogens can be occurred via inert objects. Paper currency is a further common contact surface whereby pathogens can be transferred within a population although the significance remains unknown. Hence, the aim of the present study was to investigate microbial populations associated with Iranian paper currency. METHODS: This study was carried out by getting 108 samples of the Iranian currency notes (1000, 2000, 5000, 10000, 20000 and 50000 RIALS) from food-related shops that included food service outlets, greengrocery, supermarket, bakery, confectionary and poultry meat retail outlets. All currency notes were examined for total bacterial count and identification of pathogenic bacteria. RESULTS: The average total bacterial count that was recovered from currency notes was found to be 3.27+/-0.31 colony forming unites.2000R had the highest total bacterial count, followed by 5000R, 10000R and the lowest in 50000R. In this study, the isolated bacteria recovered were Bacillus cereus (8.33%), E. coli (48.14%), Staphylococcus aureus(28.7%), Salmonella (0.92%), Listeria monocytogenes (0.92%), Yersinia entrocolitica(6.48%). It was revealed that all the pathogens screened for where encountered on currency notes were recovered from one sample. There were no significant (P>0.05) correlations between the carriage of pathogens/fecal indicator bacteria and currency note condition. CONCLUSION: Our findings demonstrate that Iranian currency notes represent a significant vehicle for human pathogens. PMID- 26060670 TI - Medicinal Plants and New Concerns in Statin Consumption. PMID- 26060671 TI - The Relationship between Vital Spirit and Fevers in the "Canon of Medicine": A Probable Solution for the Controversy over Stress-Induced Hyperthermia. PMID- 26060672 TI - Etiology of Cough in Avicenna's Canon of Medicine. PMID- 26060673 TI - Dental Diseases of Acid Factory Workers Globally-Narrative Review Article. AB - Background Industrial growth is occurring exponentially, for unimpeded growth, industrial workers are recruited on a large scale globally. There are various sectors of industries present for which laborers are trained in accordance to their requirements. As workers possess the general health risk of occupational hazards, various labor laws, schemes and policies are undertaken by the government which are implemented by industries, but very few attention for oral health is being given because of which laborers are more progressing towards hidden adverse oral effects which can affect their working efficacy. Various studies on different sector workers were carried out focusing their oral health status but for acid factory workers it is neglected and therefore unrevealed to the society. For this purpose, in this article, though, paucity of literature, still, tries to enlighten the oral health status in acid factory industrial workers with available resources. PMID- 26060674 TI - Depression, Diabetes, and Healthcare Utilization: Results from the Korean Longitudinal Study of Aging (KLoSA). AB - BACKGROUND: The aim of this study was to explore the relationship between diabetes and depression and investigate the effects of comorbid diabetes and depression on healthcare utilization. METHODS: The study sample included 10,179 Korean adults aged >= 45 years. The presence of diabetes was assessed by asking participants if the participants had ever been diagnosed with diabetes. Depression was measured using the 10-item Center for Epidemiological Studies Depression scale. Healthcare utilization was assessed by self-report. Multiple logistic regression analyses were performed. RESULTS: Diabetes was positively associated with depression after controlling socioeconomic and health variables. Diabetic patients who had low socioeconomic status, who were obese, who were smokers, and who had higher numbers of chronic diseases had a higher depression risk. Diabetes and depression was associated with increased healthcare utilization. People with both diabetes and depression had significantly increased odds of multiple physician visits, multiple hospital admissions, and prolonged hospitalization compared with individuals with neither diabetes nor depression. Patients with both diabetes and depression had greater odds of multiple hospital admissions than patients with diabetes alone. CONCLUSIONS: We found a positive association between diabetes and depression. Depression in persons with diabetes is associated with increased multiple hospital admissions. More research is warranted to clarify an association between co-occurring depression with diabetes and increased healthcare utilization. PMID- 26060675 TI - Determinants of Caesarean Risk Factor in Northern Region of Bangladesh: A Multivariate Analysis. AB - BACKGROUND: Caesarean section (c-section) rates have been increasing dramatically in the past decades around the world. This increase has been attributed to multiple factors such as maternal, socio-demographic and institutional fac-tors. Therefore, this study examines the impact of maternal, socio-demographic and relevant characteristics on caesar-ean delivery in the northern region of Bangladesh. METHODS: This study is based on a total of 1142 delivery cases from four private hospitals and four public hospitals during the period of January to March 2010. The study was carried out using a cross-sectional design where data were collected by simple random sampling. In order to data analysis, first, an initial bivariate analysis was performed by the chi-square and Fisher exact test. Secondly, the risk factors which are associated with c-section identify by logistic re-gression model. Finally, a stepwise regression analysis was carried out to isolate the most influential risk factors. RESULTS: Among the 17 risk factors, nine were found significantly associated with type of delivery. Eight of the risk factors i.e. previous c-section, pregnancy-induced swollen of leg, prolonged labour, maternal education status, mater-nal age more than 25 years, low birth order, length of baby more than 45cm and irregular intake of a balanced diet remained independently significant for caesarean delivery. The value of P<0.05 was considered statistically significant. Maternal complications were found to be more significant in public hospitals than in private ones and conversely for the demographic characteristics. CONCLUSIONS: The findings of this study suggested that the above factors may influence the health-seeking behaviour of women in the northern region of Bangladesh. PMID- 26060676 TI - Morbidity and Mortality of Malaria during Monsoon Flood of 2011: South East Asia Experience. AB - BACKGROUND: Malaria is the second most frequent clinically suspected disease entity after acute respiratory tract infection in developing countries. Active malarial transmission occurs throughout the year, while aggressive out bursts of disease are seen mainly during and after the 'monsoon' season. This study aimed to determine the morbidity and mortality associated with malaria during flood at Isra University Hospital, Hyderabad. METHODS: This prospective observational study was done at Isra University Hospital Hyderabad during monsoon flooding from July 2011 to October 2011. All 883 patients presented with symptoms of malaria (fever, headache, and vomiting) were evaluated and diagnostic tool ICT-MP was used for the detection of malaria parasite among them. RESULTS: Seventy four (8.38%) patients diagnosed for malaria. The mean age and SD was 30.11 +/- 1.67 years. Overall mortality due to malaria observed (18.9%). Mortality rate significantly observed high in pregnant women (0.005) and in those patients who developed complications such as, pneumonia (P = 0.04), renal failure (P = 0.04), Unconsciousness (P = 0.001), and Septicemia (P = 0.001). CONCLUSION: A Significant increase in the morbidity and mortality in patients with malaria after flood noticed. The probability of getting poor outcome is also associated when patient develop complications. PMID- 26060677 TI - Cadmium, Chromium, and Copper Concentration plus Semen-Quality in Environmental Pollution Site, China. AB - BACKGROUND: The environmental pollution is one of the factors contributing to the decrease of sperm quality for human beings. The aim of this study was to assess cadmium (Cd), chromium (Cr), and copper (Cu) concentration of man in environmental pollution site, and explore relationships between men exposure to Cd, Cr, and Cu and semen-quality parameters in environmental pollution site. METHODS: Ninety five men were recruited through pollution area and controls in 2011. We measured semen quality using Computer-aided Semen Quality Analysis, and Cd, Cr, and Cu levels in seminal plasma using Graphite Gurnace Atomic Absorption Spectroscopy. Spearman rank correlation analysis was used to evaluate the correlation between Cd, Cr and Cu concentration in seminal plasma and semen quality. RESULTS: The mean of seminal plasma Cd, Cr, and Cu values in pollution area was higher than the controls. Seminal plasma Cr values displayed a significant negative correlation with total motility and normomorph sperm rate. Seminal plasma Cu values also displayed a negative correlation with normomorph sperm rate. CONCLUSIONS: Male reproductive health may be threatened by environmental pollution, and it may be influence local population diathesis. PMID- 26060678 TI - Prevalence of Congenital Anomalies and Non-Communicable Diseases in Women of Age 12-75 Years in District Bhimber, Azad Jammu and Kashmir, Pakistan. AB - BACKGROUND: The advancement in the healthcare systems, stringent interventions for infectious diseases and improved diet has significantly shifted the patterns of morbidities, and consequently hereditary and congenital anomalies (CA) and non communicable diseases (NCDs) have emerged as the most common causes of morbidity and mortality. In Pakistan, there is no systematic health surveillance system to assess the impact of such diseases particularly on the young and adult populations. METHODS: In order to glean into the health and morbidity profile of Azad Jammu and Kashmir we have carried out an epidemiological study in Bhimber District in the north-east of Pakistan. A total of 1,731 female subjects of age 12-75 yr originating from Bhimber were recruited through a cross-sectional study. RESULTS: There were 74 cases (and 15 types) of CA with a prevalence estimate of 42.75/1,000. CA was significantly higher in subjects who were illiterate and married, speaking Pahari language and belonged to rural areas and nuclear families. Additionally, there were 104 cases (and 21 types) of NCDs (prevalence 60.08/1,000). NCDs were observed to have higher prevalence in subjects who were illiterate and married, speaking Punjabi language, and belonged to higher age groups and nuclear families. CONCLUSION: This study explores the types and dynamics of morbidity across the major socio-demographic parameters of adult females of Bhimber and would be helpful in estimating the impact of morbidity in this population. A comprehensive country-wide study is the need of the time to identify specific risk factors associated with certain morbidity types and help prioritize areas for interventions. PMID- 26060679 TI - Serological Survey and Associated Risk Factors of Visceral Leish-maniasis in Qom Province, Central Iran. AB - BACKGROUND: Visceral leishmaniasis (VL) or kala-azar is considered as a parasitic disease caused by the species of Leishmania donovani complex which is intracellular parasites. This systemic disease is endemic in some parts of provinc-es of Iran. The aim of this study was to determine the seroprevalence of VL in Qom Province, central Iran using di-rect agglutination test (DAT). METHODS: Overall, 1564 serum samples (800 males and 764 females) were collected from selected subjects by random-ized cluster sampling in 2011-2012. Sera were tested and analyzed by DAT. Before sampling; a questionnaire was filled out for each case. Data were analyzed using Chi-square test and multivariate logistic regression for risk factors analysis. RESULTS: Of 1564 individuals, 53 cases (3.38%) showed Leishmania specific antibodies as follows: with 1:400 titer 16 cases (1.02%), with 1:800 titer 20 cases (1.27%), with 1:1600 titer 16 cases (1.02%) whereas only one subject (0.06%) showed titers of >= 1:3200. There was no significant association between VL seropositivity and gender, age group and occupation. Binary logistic regression showed that rural areas was 0.44 times at higher risk of infection than urban areas (OR= 0.44; %95 CI= 0.25- 0.78). CONCLUSION: Although the seroprevalence of VL is relatively low in Qom Province, yet due to the importance of the disease, the surveillance system should be monitored by health authorities. PMID- 26060680 TI - Effect of PTEN Gene Mutations and Environmental Risk Factors on the Progression and Prognosis of Bladder Cancer. AB - BACKGROUND: Bladder cancer is the most frequent genitourinary malignancy in Iran. Environmental and genetic factors are the two factors linked with bladder cancer expansion. The aim of this study was to investigate the role of PTEN gene and environmental risk factors on the progression and prognosis of bladder cancer. METHODS: We evaluated 55 tumor specimens and 66 bladder mucosa samples of non cancerous patients between 2011 and 2013. All samples were analyzed for PTEN mutations using PCR and direct DNA sequencing methods. Demographic data collected, were analyzed using SPSS version 19.0 software and a P value of < 0.05 was considered statistically significant. RESULTS: Of the 55 patients examined, tumor stage was T1, T2 (T2a, T2b) in 34 (61.8%) and 21 (38.2%) and tumor grade was high, low in 34 (61.8%) and 21 (38.2%), respectively. No mutations in the PTEN gene were found in patients with bladder cancer and control. Among the risk factors studied, only the occupation and history of urinary tract stones, were significantly associated with bladder cancer (P value<0.05). However, other risk factors did not show such a relationship. CONCLUSION: No mutation was found in PTEN gene of patients with bladder cancer. Therefore, mutations in this gene cannot predict the prognosis and progression of urothelial bladder cancer. On the other hand, significant rela-tionship was found between occupation and urinary stones with bladder cancer. This communication reflects the im-pact of these factors on the risk of bladder cancer. PMID- 26060681 TI - Community Perceptions and Practices about Malaria Prevention and Control in Iran. AB - BACKGROUND: General knowledge of at risk people regarding malaria is key element to facilitate appropriate treatment and prevention behaviours. The aim of this study was to assess the family heads' understanding of malaria transmission, signs and symptoms, and preventive measures in malaria-affected districts of Iran. METHOD: In 2009 in a cluster randomized cross-sectional survey data were collected from the heads of 5,466 randomly selected households by trained interviewers and a validated questionnaire. Only one adult person was interviewed per household Once all the information collected and entered to the SPSS Ver. 18 analysis was done and descriptive statistics were used to summarize results. Point estimates and 95% confidence intervals were also estimated for indicators. RESULTS: 63.8% [95% CI: 62.2 - 65.4] of the participants recognized fever as a sign of malaria, 56.4% [95% CI: 54.6 - 58.2] reported that mosquito bites cause malaria and about 35% [95% CI: 32.7 - 37.1] of participants mentioned that the use of mosquito nets could prevent malaria. Furthermore, about one-third of selected samples in target districts did not know symptoms, transmission route and appropriate prevention method of malaria. Data also suggests a slight variation by residency, but substantial discrepancy according to the region. CONCLUSIONS: General knowledge of respondents concerning malaria is too far from the levels required to be constructive for malaria elimination. Therefore, the survey suggests developing, and implementing effective health promotion policies to increase the awareness of households about the symptoms, transmission route and control measures of malaria. PMID- 26060682 TI - Use of Health Care Services and Associated Factors among Women. AB - BACKGROUND: To estimate the prevalence and analyze factors associated with both public and private health services utilization in women population in a western district of Iran. METHOD: A cross-sectional study with 1200 individuals aged 18 49 years carried out in different districts of Sanandaj City, western Iran, in 2012. The main outcome variable was use of health service in the previous 12 months. The in-dependent variables were age, education level, place of residence, marital and pregnancy status, household wealth, oc-cupation and duration time of employment, and rating of quality of health services. RESULTS: The prevalence of public and private health services utilization were 60.8% [95%CI: 57.8, 63.8] and 53.8% [95%CI: 50.8%, 56.8%], respectively (P=0.001). After controlling other investigated factors using logistic regression; the academic educational level (OR=1.36, 95%CI: 1.03, 1.80; OR=1.76, 95%CI: 1.33, 2.33), residents of urban (OR=1.65, 95%CI: 1.10, 2.47; OR=1.60, 95%CI: 1.10, 2.42), pregnancy status (OR=2.38, 95%CI: 1.60, 3.55; OR=2.36, 95%CI: 1.61, 3.47), and high level of quality of health services (OR=1.61, 95%CI: 1.15, 2.27; OR=1.70, 95%CI: 1.20, 2.40) were found to be predictors of utilization of both public and private health care respectively. There was also statistically relation between high level of household wealth (OR=3.01, 95% CI: 2.00, 4.57) and private health services utilization. CONCLUSIONS: Prevalence of health services utilization varied according to the individual and social factors of popula-tion studied. Present study emphasizes the need to develop care models that focus on the characteristics and demands of the subjects. PMID- 26060683 TI - Polymorphism of the CLDN5 gene and Schizophrenia in an Iranian Population. AB - BACKGROUND: The gene coding claudin (CLDN5) is located on 22q11. Since the proteins of CLDN5 family are a ma-jor component for barrier-forming tight junctions, it may be important to test whether or not the CLDN5 locus could be associated with schizophrenia. METHOD: A total of 150 individuals affected with schizophrenia and 150 healthy persons were recruited. The relation-ship between the three single nucleotide polymorphism (SNPs) and schizophrenia disease was studied using polymer-ase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) technique. The PCR products were completely digested with restriction enzymes of DpnII, PvuII and BstNI, and then separated on agarose gel. The statis-tical investigations and haplotype analysis were also performed. RESULTS: The transmission disequilibrium test (TDT) exhibited weak association between rs10314 [C/G] and schizo-phrenia (v2 = 3.55, P = 0.022), but the other two SNPs did not show such an association. The global chi-square test showed that the 3-SNP haplotype system was not associated with schizophrenia although the 1 df test for individual haplotypes showed that the rs1548359(C)-rs10314(G) rs739371(C) haplotype was excessively non-transmitted (v2 = 6.33, P = 0.025). The v2 test for LD between SNPs indicated that these three SNPs were in strong LD. CONCLUSIONS: Collectively, LD analysis showed that the CLDN5 locus was associated with schizophrenia in an Iranian population. PMID- 26060684 TI - The Prevalence of Resistance to Methicillin in Staphylococcus aureus Strains Isolated from Patients by PCR Method for Detec-tion of mecA and nuc Genes. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is the main cause of hospital infection emerged over the last decades. Rapid detection of MRSA is important for patient care and proper usage of infection control. Detection of mecA genes (encoding resistance to methicillin and other similar antibiotics) and nuc genes (encoding staphylococcal thermostable nuclease) by PCR method is now considered for rapid identification of MRSA strain. The aim of this study was to determine the prevalence of MRSA isolated from patients in Tehran, Iran by PCR method for detection of mecA and nuc genes. METHOD: Phenotypic method such as microscopic and colony morphology and catalase and coagulase tests were used for identification of S. aureus isolates. DNA was extracted from all isolates and the presence of nuc and mecA gene was detected by PCR method. For determination of MRSA by phenotypic methods, oxacillin disk diffusion test were used. Data were analyzed by SPSS software. RESULTS: Out of 126 clinical sample identified by phenotypic method, 101 isolates had nuc gene. In disk diffusion tests by oxacillin disk, 78.2% of isolates were considered to be MRSA, but in PCR method for mecA gene, 69% isolates were positive. CONCLUSIONS: The results showed a high prevalence of methicillin-resistance among S. aureus isolates. Identifying MRSA strains, isolating MRSA-positive patients and carrier's treatment in a hospital to prevent MRSA infection is important in limiting the spread of MRSA. The PCR method for detection of nuc and mecA genes has potential for rapid and accurate diagnosis of MRSA strains. PMID- 26060685 TI - Investigating the Financial Performance of Universities of Medical Science and Health Services in Iran, Using Data Envelopment Analysis. AB - BACKGROUND: Universities of Medical Science and Health Services (UMSHSs) are among the main organizations in Iran's health-care section. Improving their efficiency in financial resource management through creating an appropri-ate coordination between consumption and resources is strategically vital. Investigating the financial performance as well as ranking the Iranian UMSHSs is the research objective. METHODS: The study is of descriptive and applied type. The study population includes the UMSHSs of Iran (n=42) among which 24 UMSHSs are selected. DEA is used with the aim to model and assess the financial performance in-cluding 4 inputs and 3 outputs. Also, linear regression is applied to determine the effectiveness of the applied indices as well as the level of the financial performance. Data are obtained from the Budgeting Center in the Ministry of Health and Medical Education, during 2010 mainly through forms designed based on the available balance sheets. RESULTS: The average score of financial performance assessment for UMSHSs based on the DEA of input-oriented data is 0.74, assuming a constant scale of DEA-CRS. Thus, approximately 25% of the studied UMSHSs have maxi-mum relative performance and totally, there is about a 30% capacity to increase the financial performance in these UMSHSs. CONCLUSION: Most Iranian UMSHSs do not have high financial performance. This can be due to problems in financial resource management especially in asset combining. Therefore, compilation and execution of a comprehensive pro-gram for organizational change and agility with the aim to create a kind of optimized combination of resources and assets is strongly recommended. PMID- 26060686 TI - Relationship between Health-Related Quality of Life and Social Support in HIV Infected People in Tehran, Iran. AB - BACKGROUND: The present study was conducted to determine the association between social support and health-related QOL (HRQL) for a sample of 120 patients living with HIV/AIDS in Tehran. METHOD: Eighty male and 40 female living with HIV referred to Iranian AIDS Research Center at Imam Khomini Hospital in Tehran, Iran in 2011 were randomly selected for assessment. Data was collected by means of Vaux's Social Support questionnaire and Medical Outcomes Short-Form-36 (SF-36) QOL questionnaires. Pearson (P) Correlation Coefficient and Fisher z-test were used for statistical analysis. RESULTS: In general, social support was significantly associated with overall QOL in men (P = 0.001) and women (P = 0.009) living with HIV/AIDS. In men, social support was significantly associated with mental and physical domains of QOL (P = 0.001) while in women it simply associated with mental domain of QOL (P = 0.003). CONCLUSIONS: Our findings indicate that increasing social support for HIV/AIDS persons increases their QOL. This can help those physicians who are involved in care of HIV-infected persons and it maintains QOL across the spec-trum of HIV disease. PMID- 26060688 TI - Exophthalmos Myxedema Acropachy Syndrome: A Case Report. AB - Exophthalmos, myxedema, and acropachy are collectively named Exophthalmos myxedema acropachy (EMA) syn-drome, which is a rare syndrome associated with hypertcardiotrophia. Among patients with hyperthyreosis, EMA has an incidence less than 1%. Here, we reported a case of EMA and explored its diagnosis and treatment. PMID- 26060687 TI - A Combined Approach for Estimating Health Staff Requirements. AB - BACKGROUND: Many studies have been carried out and many methods have been used for estimating health staff re-quirements in health facilities or system, each have different advantages and disadvantages. Differences in the extent to which utilization matches needs in different conditions intensify the limitations of each approach when used in iso-lation. Is the utilization-based approach efficient in a situation of over servicing? Is it sufficient in a situation of under-utilization? These questions can be similarly asked about the needs-based approach. This study is looking for a flexible approach to estimate the health staff requirements efficiently in these different conditions. METHOD: This study was carried out in 2011 in some stages: It was conducted in order to identify the formula used in the different approaches. The basic formulas used in the utilization-based approach and the needs-based approach were identified and then combined using simple mathematical principles to develop a new formula. Finally, the new formula was piloted by assessing family health staff requirements in the health posts in Kashan City, Iran. RESULTS: Comparison of the two formulas showed that the basic formulas used in the two approaches can be com-bined by including the variable 'Coverage'. The pilot study confirmed the role of coverage in the suggested combined approach. CONCLUSIONS: The variables in the developed formula allow combining needs-based, target-based and utilization-based approaches. A limitation of this approach is applicability to a given service package. PMID- 26060689 TI - Indefinite Fetal Heart Rate Pattern in a Patient with Vasa Previa: A Situation Where Guideline Is Inapplicable. AB - Most fetal heart rate patterns can be interpreted accurately so that management decisions can be made correctly. How-ever, few fetal heart rate patterns are so ambiguous that the obstetricians cannot interpret them precisely. A 27-year-old woman at 38 weeks' gestation in her first pregnancy was admitted with heavy vaginal bleeding and decrease in fetal movements. Fetal status was indeterminate according to an indefinite fetal heart rate tracing with regular decelerations. After emergent cesarean delivery, a ruptured vasa previa, traversing the fetal membrane, unsupported by either the umbilical cord or placental tissue, was clearly identified. Treatment decision-making is challenging in such patient with indefinite fetal heart rate pattern because limited data exist to guide management. Well-designed studies are needed to clarify the uncertainty about the effect of indefinite fetal heart rate pattern on clinical outcomes. PMID- 26060690 TI - Resignation of Nurses in China. PMID- 26060691 TI - Friedrich Esmarch, the Founder of Modern First Aid, and His Works. PMID- 26060692 TI - World Kidney Day 2014; Chronic Kidney Disease and Aging: A Global Health Alert. PMID- 26060693 TI - Appraisal the Output of "Iranian J Publ Health" in 2013. PMID- 26060694 TI - Neighborhood-Level Stress and Circadian Cortisol: A Systematic Review and Meta Analysis. AB - The main objective was to find association between basal cortisol and neighborhood-level stress. Systematic searches, including electronic and hand searches, were conducted. The most recent date of the search was July 26, 2013. Primary observational studies included if they considered stress related outcomes in the neighborhood context. Using the EndNote X7 advanced search option; the authors examined the abstracts and titles of the 18,092 articles to exclude obviously irrelevant studies, gray literature, discussion papers, reviews and, studies with no complete data. Two authors independently extracted data from the original reports into pre-designed data extraction forms based on the Data Extraction Template of the Cochrane Consumer and Communication Review Group (CCCRG). Ten studies with a total of 2,134 participants were synthesized and analyzed. Two studies out of ten received expanded meta-analysis. The overall effect size (95% CI) for cortisol level for residents in neighborhoods with lower stress compared to inhabitants from higher was 0.12 (0.01, 0.23). This review is demonstrating a link between psychosocial or physical stress and cortisol obtained from saliva. However, living in high disorder neighborhoods results in higher level of cortisol. This represents a biological indicator of psychosocial/physical stress exposure (i.e., neighborhood disorder) that reflects variances in stress exposure levels. PMID- 26060695 TI - Women's Health Concept: A Meta-Synthesis Study. AB - BACKGROUND: It is necessary to identify unidentified or less- concentrated issues in women's health dimension through an extended study. This study is done to identify different dimensions of women's health among qualitative research. METHOD: The present meta-synthesis study is done through a systematic review. The main criteria were to use qualitative studies issued in the same language and researches in which their participants were women. All the published and indexed articles related to women's health in Iran at SID, Magiran and Iranmedex databases from 2001 to 2013 were scrutinized. Search in these databases was done using key words "health" and "women". Finally, 29 qualitative articles were chosen. Data analysis was performed using qualitative content analysis. RESULTS: Generally, concepts extracted from women's health dimension are classified in three main categories including personal, familial and social dimensions. Each category includes some subcategories, too. Personal factors consist of physical, psychological -emotional and spiritual; familial factors consist of fertility, husband's support and women's fundamental roles, and social factors consist of cultural, socioeconomically support, and women's management issues. CONCLUSION: In this meta-synthesis study, there was an effort to present a new interpretation of the previous studies. This study helped attain a more comprehensive and deeper knowledge about women's health concept and reveal its different aspects, which are not assessed in the country. PMID- 26060696 TI - Association between Gene Polymorphisms of Seven Newly Identified Loci and Type 2 Diabetes and the Correlate Quantitative Traits in Chinese Dong Populations. AB - BACKGROUND: There are much heterogeneity in the genetic variation of type 2 diabetes (T2D). The purpose of this study was to investigate the association of seven novel genetic loci identified in a recent genome-wide association studies (GWAS) with T2D in Chinese Dong populations. METHODS: A case-controlled study was performed in individuals of Chinese Dong nationality. The genotypes of PARD3B (rs849230), LOC729993 (rs149228), EPHA4 (rs16862811), HNT (rs3099797), PTPRD (rs17584499 and rs649891), TOMM7 (rs2240727) genes were determined using Multiplex PCR-SNaPshot. The independent association between each polymorphism and T2D was assessed using unconditional binary logistic regression analysis (BLR). RESULTS: A total of 136 cases of T2D and 136 control subjects were enrolled in the study. The polymorphism of rs2240727 in TOMM7 gene was associated with T2D (odds ratio (OR) = 1.65, per copy of the risk T allele, P = 0.004). In addition, CT and TT were risk genotypes for T2D (OR (95% CIs):2.64 (1.28-5.45) and 3.42 (1.58-7.41) respectively). After correcting for multiple testing, the above results remained significant (all P < 0.05). After adjusting for the confounders of age, gender, and BMI, the association between T2D and rs2240727 remained significant (P < 0.01). There were significantly statistical difference in levels of fasting plasm glucose(FPG) among genotypes of rs2240727 in controls and patients, the levels of FPG were significantly higher in CT and TT genotypes than in CC genotype in both groups (all P < 0.05). CONCLUSIONS: The rs2240727 genetic variant in TOMM7 was associated with T2D of Chinese Dong individuals, and might enhance the risk of T2D by affecting the level of FPG. PMID- 26060697 TI - Rota Viral Infection: A Significant Disease Burden to Libya. AB - BACKGROUND: Rotavirus is a common infection causing 450,000 deaths annually primarily in children 5 years and below. Despite the high burden of disease, little is known about the epidemiology of rotavirus in Libya. The aim of this study was to estimate the rotavirus disease burden among Libyan children. METHODS: A cross-sectional study was carried out prospectively among children 5 years old and below between August 2012 and April 2013. Stool samples of children with diarrhea attending the outpatient department or admitted to the pediatric wards, at three public hospitals within the northwestern region of Libya were tested for rotavirus. The seasonality, symptomology demographics and outcomes of rotavirus cases were determined and compared to other diarrhea illnesses. An estimated incidence rate per 100,000 children aged 5 years and below was determined. RESULTS: A total of 545 children with diarrhea were identified for participation. Results of rotavirus immunoassays determined 57% of cases were caused by rotavirus. Inpatients were more likely to be rotavirus positive than outpatients (58% vs. 53%, P<0.05), Most rotavirus positive cases (86%) were found among children below 2 years of age. Rotaviral cases peaked in the winter, constituting 76% of diarrheal illness in February and very few rotavirus cases in the summer months. The incidence rate of rotavirus diarrhea was estimated at 640/100,000 children aged 5 years and below. CONCLUSION: Rotavirus infection poses a significant disease burden in Libya. Preventive measures such as proper hygiene should be emphasized. Introduction of vaccination against rotavirus into the national immunization program should be examined, as it would likely be a cost-effective investment. PMID- 26060698 TI - Genotyping and Phylogenetic Analysis of Fasciola Spp. Isolated from Sheep and Cattle Using PCR-RFLP in Ardabil Province, Northwestern Iran. AB - BACKGROUND: The aim of this study was to detect the genotype of Fasciola spp. in Meshkin-Shahr, Ardabil Province, northwestern Iran in different hosts using PCR RFLP. METHODS: The parasite hosts included cattle, and sheep. Overall, 70 adult flukes from livers of slaughtered animals were collected from the abattoirs of aforementioned area. The included 35 samples from infected sheep and 35 samples from 35 infected cattle. PCR-RFLP and sequence analysis of the first nuclear ribosomal internal transcribed spacer (ITS 1) region from Fasciola species were used to conduct the study. RESULTS: The fragment of approximately 700bp in all of the Fasciola samples was amplified. PCR products of ITS 1 were subjected for digestion by restriction enzyme. RsaI restriction enzyme was selected for RFLP method that caused the separation specifically of Fasciola species. Amplicons with the sequences of F. hepatica had a pattern of about 360, 100, and 60 bp band size, whereas F. gigantica worms had a profile of 360, 170, and 60 bp in size, respectively. Results based on PCR-RFLP analysis were confirmed by sequence analysis of representative ITS 1 amplicons. No hybrid forms were detected in the present study. All sheep were infected with F. hepatica but cattle were infected with both species. CONCLUSION: Both species of Fasciola are present in Ardabil. The method described here can be valuable for identification of Fasciola species in endemic parts for fasciolosis, regions with intermediate species and in that overlapping distribution area. PMID- 26060699 TI - Comparison of Age- Standard Incidence Rate Trends of Gynecologic and Breast Cancer in Iran and Other Countries. AB - BACKGROUND: Female cancer, especially breast and gynecologic cancers are considered multistage disease, highly influenced by risk and protective factors and/or screening preventive modalities. Consequences of all these factors result in the trend of change over time. METHODS: In this comparative study, based on data of national cancer registry of Iran 2004 published by Iranian Ministry of Health, age - standard incidence rate (ASR) according to the world population was calculated in all reported gynecologic and breast cancers. Source of all subjects are pathologic based. In the next step, the calculated ASR of Iran and those of the other countries in 2004 were compared to GLOBOCAN ASR reports of 2008. RESULTS: In Iran ASR of breast cancer 2004 (24.93) changed to 18.4 in 2008. Ovarian cancer ASR of 2004, 3.07 was 3.1 in 2008. Endometrial cancer ASR in 2004 (2.29) was 1.7 in 2008. Cervical cancer ASR of 1.71 in 2004 was 2.2 in 2008. CONCLUSIONS: In Iran incidence trend of breast and endometrium are decreasing in the same direction of USA and Australia. Increasing trend of ovary and cervix ASR in Iran is in the inverse direction of USA and Australia which are decreasing. Future studies to find out the same trend or any changes, might develop these findings and improve consequent practical decisions based on results of this study and complementary future studies. PMID- 26060700 TI - Urinary and Milk Iodine Status in Neonates and Their Mothers during Congenital Hypothyroidism Screening Program in Eastern Azerbaijan: A Pilot Study. AB - BACKGROUND: Iodine is essential element in thyroid hormones synthesis and normal growth and development of the brain. Milk and iodine concentrations can be appropriate indicator of body iodine status; in this study, we evaluated the concentrations of urine and milk iodine in newborns and their mothers. METHODS: In a cross-sectional study conducted in 2013, urine and milk iodine in 106 neonates and their mothers referred to healthcare center in Shabestar, Eastern Azerbaijan for congenital hypothyroidism screening program were determined. Median urinary iodine < 100 ug/L and milk iodine < 50 ug/L was considered as iodine deficiency. RESULTS: The median urine iodine concentrations (UIC) in mothers and infants were 142.31 ug/L (.0 - 1260) and 306.76 ug/L (23.56-1020) respectively. Urine iodine concentrations were < 100 ug/L in 33.9% of mothers and 14.2% of neonates. The median milk iodine concentration (MIC) was 58.23 ug/L (20.31- 425) and in 41.9% of mothers was <50 ug/L. A positive significant correlation was found between milk iodine and maternal urinary iodine concentration (r=0.533, P= 0.000). There was significant correlation between neonatal UIC and maternal UIC (r=0.462, P= 0.000), neonatal UIC and MIC (r=0.414, P= 0.000). CONCLUSIONS: Urinary and milk iodine concentrations in mothers and infants were within acceptable range, which indicates adequate iodine intake. However, there were moderate and marginal iodine deficiencies in about half percentage of participants. Insufficient amount of milk iodine in about half of the mothers can result in iodine deficiency in breast-fed infants. PMID- 26060702 TI - Persistence of Hemorrhage and Hypertensive Disorders of Pregnancy (HDP) as the Main Causes of Maternal Mortality: Emergence of Medical Errors in Iranian Healthcare System. AB - BACKGROUND: This study aimed to assess factors affecting substandard care and probable medical errors associated with obstetric hemorrhage and HDP at a Northwestern Iranian health care system. METHODS: In a community-based descriptive cross-sectional study, data on all maternal deaths occurred at West Azerbaijan Province, Iran during a period of 10 years from March 21, 2002 to March 20, 2011 was analyzed. The principal cause of death, main contributory factors, nature of care, main responsible staff for sub-standard care and medical error were determined. The data on maternal deaths was obtained from the national Maternal Mortality Surveillance System (MMSS) which were covered all maternal deaths. The "Three delays model" was used to recognize contributing factors of maternal deaths due to obstetric hemorrhage and HDP. RESULTS: There were 183 maternal deaths, therefore the Mean Maternal Mortality Ratio (MMR) in the province was 32.8 per 100 000 live births (95% CI, 32.64-32.88). The most common causes of maternal deaths were obstetric hemorrhage in 36.6% of cases and HDP in 25.7%. The factors that most contributed to the deaths were all types of medical errors and substandard care with different proportions in management of obstetric hemorrhage and HDP. CONCLUSION: A substandard care and medical error was the major contributing factor in both obstetric hemorrhage and HDP leading to maternal mortality, therefore, it is necessary to improve the quality of health care at all levels especially hospitals. PMID- 26060701 TI - Prioritizing High-Risk Practices and Exploring New Emerging Ones Associated With Hepatitis C Virus Infection in Egypt. AB - BACKGROUND: The aim of this study was to identify and prioritize the risky behaviors and explore the newly emerging pi related to Egyptian habits that may lead to HCV transmission. METHODS: From January 2011 until January 2012, a case control study matched on socio demographic factors was conducted comparing 540 hepatitis C patients and their contacts who were HCV serologically negative (102 subjects). They were randomly selected from six governorates representing Upper Egypt, Lower Egypt, Middle and Canal regions. The questionnaire covered demographic data, risk exposures, behaviors, and practices for HCV infection. Focus group discussions were done with groups of professionals in Hepatology to discuss the observed emerging risk practices in Egypt. RESULTS: In univariate analysis, invasive medical procedures, wound stitches, illiteracy and marriage were significantly associated with HCV infection. Among women, delivery at home by traditional birth attendant was associated with 3 times (OR=2.91, CI=1.23 6.98) and 4 times (OR=3.94, CI=1.44-11.35) increase in HCV risk than delivery at hospital and by doctors respectively. Among males, shaving at barbershops was associated with 2 fold increase in the risk of infection (OR=2.6, CI=1.44-4.89). Newly observed emerging risk practices were: sharing scarves' pins by veiled women in same houses, sharing loofah for personal cleaning and sharing toothpaste among family members. CONCLUSION: Increasing risk of HCV infection in Egypt reinforces the need for strict implementation of effective HCV prevention programs according to the prevailing risk behaviours. PMID- 26060703 TI - The Effect of Melatonin on Climacteric Symptoms in Menopausal Women; A Double Blind, Randomized Controlled, Clinical Trial. AB - BACKGROUND: Menopause is one of the most critical periods of woman's life. With reducing of ovarian estrogen; women are more prone to psychological and physical symptoms. The present study aimed to investigate the effect of melatonin on the climacteric symptoms. METHODS: The present double blind, placebo randomized controlled clinical trial was conducted on 240 menopausal women (40 - 60 years old) referring to the gynecology clinics of Shiraz University of Medical Sciences (January - November 2012). The participants were randomly divided into two groups through sortition. Demographic characteristics, Goldberg's general health questionnaire (GHQ), Greene Climacteric Scale and level of Follicle Stimulating Hormone (FSH) were determined for both groups before the intervention. The intervention group received one 3mg melatonin tablet each night for 3 months and the control group received the placebo in the same period. Changes of climacteric symptoms and drug complications were measured 1, 2 and 3 months after the intervention. RESULTS: We analyzed the data of 99 postmenopausal women in the intervention group and 101 postmenopausal women in the control group. In the melatonin group, the climacteric symptoms score decreased from 35.73+11.6 to 17.09+10.22 during the 3-month study period and regardless of time, a significant difference was observed between the two groups (P<0.001). In addition, a significant difference was found between the two groups regarding various dimensions of the climacteric symptoms over time (P<0.001). No significant difference was found regarding side effects between the two groups (P= 0.135). CONCLUSION: The study findings showed that using melatonin improved the climacteric symptoms. PMID- 26060704 TI - Effect of Vitamin E and Metformin on Fatty Liver Disease in Obese Children- Randomized Clinical Trial. AB - BACKGROUND: We evaluated the effect of vitamin E and metformin on fatty liver disease in obese children. METHODS: This interventional study has been done on 119 children with Non-alcoholic fatty liver disease (based on sonography results). Patients were divided into four treatment groups; they received metformin 1gr daily (age< 12 years), metformin 1.5 gr daily (age> 12 years), vitamin E 800 U daily and vitamin E 400 U daily. Liver sonography was performed for patients for two periods of two months. This trial was registered in Iranian Registry of Clinical Trials (IRCT), No.IRCT2013021012421N1. RESULTS: The study group comprised 119 individuals (62 females, 57 males). The mean age was 10+/- 3.19 yr. There was no significant difference in terms of sex and BMI between the groups. Overall liver sonography showed normal liver in 66 patients (55.46%), 66.63% after two months and 33.37% after four months. After two months, the most therapeutic response observed in the group which received vitamin E 800 u daily (48.1%) and the least therapeutic response was in the group which received vitamin E 400 u daily (14.3%). After four months, the greater response was seen in vitamin E 400 u daily group (45.8%) and the least response in the metformin 1 gram daily group (19%). CONCLUSION: In comparison with metformin, vitamin E is more influential in remission; however both are efficient in treatment of fatty liver. Vitamin E 400 u daily responses better in four-month treatment. PMID- 26060705 TI - Health Needs of People Living with HIV/AIDS: From the Perspective of Policy Makers, Physicians and Consultants, and People Living with HIV/AIDS. AB - BACKGROUND: HIV/AIDS has been concentrated among injecting drug users in the country. This study aimed to investigate and identify health and treatment needs of people living with HIV/AIDS in Iran. METHODS: This qualitative study was conducted in 2012 in Iran. The study groups consisted of experts, practitioners, and consultants working with People Living with HIV/AIDS and their families. Data was collected through Focus Group Discussions and deep interviews. Data were analyzed using content analysis method. RESULTS: The findings of this study included the needs of people living with HIV/AIDS, which were classified in three main categories. The first category was prevention and counseling services with several sub-groups such as education and public and available consultation, distribution of condoms to vulnerable groups, increasing counseling centers in urban areas, providing appropriate psychological and supportive counseling, and family planning services. The second category included diagnostic and treatment services and had several sub-groups such as full retroviral treatment, Tuberculosis treatment and continuing care, providing care and treatment for patients with hepatitis, and providing dental services. The third category included rehabilitation services and had some sub-categories such as home care, social and psychological support, nutritional support, and empowering positive clubs. CONCLUSIONS: This study puts emphasis on making plans based on the priorities to meet the needs of people living with HIV/AIDS in Iran. PMID- 26060706 TI - Dementia Still Diagnosed Too Late - Data from the Czech Republic. AB - BACKGROUND: The goal of the study is to evaluate the sensitivity of Czech physicians to the early diagnosis of dementia in patients with memory impairment. METHODS: A retrospective observational study was designed. We have reviewed the electronic medical records of patients who have been hospitalized for the first time due to dementia of any type at the Kromeriz Mental hospital from January 1, 2012 to December 31, 2013 (24-month period). Pluralistic methods combining the qualitative and quantitative approach were used in this study. RESULTS: Dementia of any type was diagnosed in 125 patients in the monitored period. The mean time between patient memory complaints and his / her admission to our facility for their first hospitalization due to dementia was 7.1 years (+- 3.7 years). Most patients with dementia had no prior outpatient treatment of their memory impairment (56.2%); a minority of patients (43.8%) had treatment of their memory impairment by an outpatient physician. CONCLUSION: The sensitivity of Czech physicians to the early diagnosis of dementia is very low. Any delay in starting the treatment of dementia means a worsened effectiveness of this treatment, a worsened quality of life of patients with dementia and their caregivers. Our recommendations for both the early diagnosis and treatment of dementia should be involved in guidelines and should become a part of the pregraduate and postgraduate education of all physicians. PMID- 26060707 TI - Man-Made Major Hazards Like Earthquake or Explosion; Case Study, Turkish Mine Explosion (13 May 2014). AB - In all over the world, mining is considered as a high-risk activity that is pregnant with serious disasters not only for miners, engineers, and other people into it, but also for people who live near the mines. In this article, our main purpose is to examine some major mine disasters and safety in mines and the case study is a coal mine in Turkey. Safety in mines is one of the most important issues that need attention. Therefore, it is suggested that existing deficiencies in mines should be removed by continuous monitoring in all devices, equipments, control of Methane and safe separation of coal from a mine. Moreover, we recommend that early warning systems should be installed to alert some explosions, fires and other dangerous events to the fire departments, hospitals, Red Crescent and other major reliefs. Experiences from previous events in mines can help managers and miners. With some plans and projects related to disasters in mines and solution for them, some diseases such as black lung disease or other problems in mines such as carbon monoxide poisoning can forestall a danger. Before Mine owners begin their activity, they must research about the environmental and social effects of their activities. Therefore, they should identify some important hazards and determine some essential tasks to remove them or control risks via collaboration with other scientists. PMID- 26060708 TI - Substance Use and Perceived Hassles among Junior Medical Students with High Anxiety Levels in the Republic of Macedonia. PMID- 26060709 TI - Adherence to the Mediterranean Diet in Relation to Obesity Indices before and after a Weight Reduction Program in OSAS Patients. PMID- 26060710 TI - Socio-Economic Factors Affecting Hepatitis C and Lack of Awareness: A Case Study of Pakistan. PMID- 26060711 TI - Correlation between Oral Health Status (DMFT) and BMI Index in Khuzestan Province, Iran during 2012-2013. PMID- 26060712 TI - Pharmacological Concepts of Temperament in Iranian Traditional Medicine. PMID- 26060713 TI - Happiness & Health: The Biological Factors- Systematic Review Article. AB - Happiness underlying factors are considerable from two dimensions: endogenic factors (biological, cognitive, personality and ethical sub-factors) and exogenic factors (behavioral, socialcultural, economical, geographical, life events and aesthetics sub-factors). Among all endogenic factors, biological sub-factors are the significant predictors of happiness. Existence of significant differences in temperament and happiness of infants is an indicator of biological influences. Therefore, this study aimed to consider biological factors that underlie happiness. At the first, all of the biological factors in relation with happiness were searched from following websites: PubMed, Wiley& Sons, Science direct (1990 2014). Then, the articles divided into five sub-groups (genetic, brain and neurotransmitters, endocrinology and hormones, physical health, morphology and physical attractiveness). Finally, a systematic review performed based on existing information. Results of studies on genetic factors indicated an average effectiveness of genetic about 35 -50 percent on happiness. In spite of difficulties in finding special genes, several genes distributed to emotion and mood. Neuroscience studies showed that some part of brain (e.g. amygdala, hipocamp and limbic system) and neurotransmitters (e.g. dopamine, serotonin, norepinefrine and endorphin) play a role in control of happiness. A few studies pointed to the role of cortisol and adrenaline (adrenal gland) and oxitocin (pituitary gland) in controlling happiness. Physical health and typology also concluded in most related studies to have a significant role in happiness. Therefore, according to previous research, it can be said that biological and health factors are critical in underlying happiness and its role in happiness is undeniable. PMID- 26060714 TI - The Influence Paths of Emotion on the Occupational Safety of Rescuers Involved in Environmental Emergencies- Systematic Review Article. AB - A detailed study and analysis of previous research has been carried out to illustrate the relationships between a range of environmental emergencies, and their effects on the emotional state of the rescuers involved in responding to them, by employing Pub Med, Science Direct, Web of Science, Google Scholar, CNKI and Scopus for required information with the several keywords "emergency rescue", "occupational safety", "natural disaster", "emotional management". The effect of the rescuers' emotion on their occupational safety and immediate and long-term emotional behavior is then considered. From these considerations, we suggested four research propositions related to the emotional effects at both individual and group levels, and to the responsibilities of emergency response agencies in respect of ensuring the psychological and physical occupational safety of rescuers during and after environmental emergencies. An analysis framework is proposed which could be used to study the influence paths of these different aspects of emotional impact on a range of occupational safety issues for rescue workers. The authors believe that the conclusions drawn in this paper can provide a useful theoretical reference for decision-making related to the management and protection of the occupational safety of rescuers responding to natural disasters and environmental emergencies. PMID- 26060715 TI - Factors Associated with Successful Smoking Cessation in Korean Adult Males: Findings from a National Survey. AB - BACKGROUND: Smoking cessation rates have remained stagnant globally. This study was conducted to explore the factors associated with successful smoking cessation among South Korean adult males using nationally representative data from the Korea National Health and Nutrition Examination Survey (KNHANES) from 2007 to 2012. A comparison was made between successful quitters and those who failed to quit after attempts to stop smoking. METHODS: A total of 7,839 males, aged 19-65 years, were included in this cross-sectional study. The outcome measures were the success and failure rates in smoking cessation, sociodemographic and clinical characteristics, health behaviors, perceived health status, quality of life, and mental health. Multiple logistic regression analyses were used to examine the various factors associated with smoking cessation success. RESULTS: The cessation success and failure rates were 45.5% and 54.5%, respectively. Smoking cessation was related to older age, marriage, higher income, smoking larger amounts of cigarettes, use of willpower, alcohol abstinence, cancer history, better mental health, and higher levels of quality of life, after controlling for multiple variables. Second-hand smoke exposure at home and using nicotine replacement therapy were associated with a lower likelihood of smoking cessation. CONCLUSION: A smoke-free environment, use of willpower, alcohol abstinence, and better stress management are important for smoking cessation. Unlike previous studies, not using nicotine replacement therapy and higher levels of daily cigarette consumption were associated with successful smoking cessation, suggesting that motivation appears to be important to smoking cessation in Korean adult male population. PMID- 26060716 TI - Association of Unhealthy Exercise Patterns with Overweight and Obesity in Kuwaiti Adults. AB - BACKGROUND: Our aim was to investigate the frequency of the behaviors that are most often associated with excess weight gain in Kuwaitis and to determine which gender and age groups are at highest risk for each behavior. METHODS: A questionnaire developed to identify barriers to exercise in western populations was modified for use with Kuwaitis and posted online during September through December 2012. Data from 1370 adults 18 to 59 years old with BMIs ranging from 15.1-70.8 was collected. The prevalence of seven behavior patterns was examined for age, BMI, and gender groups as well as the odds ratio of each behavior for each BMI group. RESULTS: Both individual unhealthy exercise behaviors and the sum of all such behaviors were more frequent in over-weight and obese individuals. For all behaviors the odds ratio was significantly greater for those with BMIs of 30-39 than for those with BMIs below 25 (P< 0.05). Some exercise avoidance behaviors were more frequent in older age groups and in overweight females. CONCLUSION: Unhealthy exercise behavior patterns were highly prevalent in obese individuals. Tailoring programs and counseling to the most common of these patterns in Kuwaiti obese should facilitate greater success in weight management. PMID- 26060717 TI - Association of Serum Uric Acid with Body Mass Index: A Cross-Sectional Study from Jiangsu Province, China. AB - BACKGROUND: Body mass index (BMI) has been demonstrated to be associated with serum uric acid (SUA) level in many developed countries, however, there is still a lack of large sample study in Jiangsu Province, one of the most economically developed regions in China, where fat-rich diet is common. METHODS: Through retrospective analysis in healthy subjects, we determined the association of BMI with hyperuricemia risk. Data of 39,736 participants from January 2011 to June 2013 in China were analyzed for parameters including physical examinations and biochemical blood analysis. RESULTS: On univariate analysis, SUA was positively correlated with age, SBP, DBP, BMI, FPG, red blood cell count, hemoglobin, white blood cell count, platelet, cholesterol, triglyceride, HDL-cholesterol, LDL cholesterol, ALT, AST, bilirubin, albumin, BUN and creatinine. SUA was significantly elevated in a linear fashion as BMI increased, and SUA in obesity was significantly higher than underweight. The prevalence of hyperuricemia remained approximately 2.98 times greater among individuals with overweight, and 5.96 times greater among obesity, compared to individuals with underweight. CONCLUSION: There is a positive relationship between BMI and SUA among healthy subjects in Jiangsu province, China. PMID- 26060718 TI - Factors Associated with Hepatitis C Infection among Chronic HCV Egyptian Patients. AB - BACKGROUND: Identification of risk factors of acute hepatitis C virus (HCV) infection in Egypt is crucial for developing appropriate prevention strategies. There are few community-based studies on the epidemiology and risk factors of hepatitis C infection in Egypt, which could not provide enough information. Clear identification of past and current risk factors for infection is of utmost importance so that intervention programs can be appropriately focused. This study aims to provide up-to-date information about changes in the incidence of individual risk factors for HCV infection transmission in Egypt. METHODS: A total of 396 chronic HCV patients on follow-up treatment at liver center in El-Qabbary General Hospital in Alexandria were evaluated retrospectively regarding the potential iatrogenic, community acquired and behavioral HCV risk factors. Risk factors for HCV transmission were found in all study populations. RESULTS: At least three identifiable risk factors were reported by each participant. Some behavioral and community-acquired exposures that entail several risky behaviors particularly, unsafe sexual practices were exclusively established among males. We report a significant decline in prevalence of HCV transmission through blood transfusion, parenteral treatment, hospitalization, surgery, non medicalized circumcision, Hijiama done by informal practitioner, tattooing, folk body piercing and threading, sharing hygiene and sharp items, and the use of communal barber or manicure sets among younger age cluster. CONCLUSION: The pattern of risk differed among older patients compared to younger age group suggesting improved medical care and infection control measures and raised public health awareness regarding the different modes of viral transmission. PMID- 26060719 TI - Automatic Identification of Messages Related to Adverse Drug Reactions from Online User Reviews using Feature-based Classification. AB - BACKGROUND: User-generated medical messages on Internet contain extensive information related to adverse drug reactions (ADRs) and are known as valuable resources for post-marketing drug surveillance. The aim of this study was to find an effective method to identify messages related to ADRs automatically from online user reviews. METHODS: We conducted experiments on online user reviews using different feature set and different classification technique. Firstly, the messages from three communities, allergy community, schizophrenia community and pain management community, were collected, the 3000 messages were annotated. Secondly, the N-gram-based features set and medical domain-specific features set were generated. Thirdly, three classification techniques, SVM, C4.5 and Naive Bayes, were used to perform classification tasks separately. Finally, we evaluated the performance of different method using different feature set and different classification technique by comparing the metrics including accuracy and F-measure. RESULTS: In terms of accuracy, the accuracy of SVM classifier was higher than 0.8, the accuracy of C4.5 classifier or Naive Bayes classifier was lower than 0.8; meanwhile, the combination feature sets including n-gram-based feature set and domain-specific feature set consistently outperformed single feature set. In terms of F-measure, the highest F-measure is 0.895 which was achieved by using combination feature sets and a SVM classifier. In all, we can get the best classification performance by using combination feature sets and SVM classifier. CONCLUSION: By using combination feature sets and SVM classifier, we can get an effective method to identify messages related to ADRs automatically from online user reviews. PMID- 26060720 TI - Understanding of School Related Factors Associated with Emotional Health and Bullying Behavior among Jordanian Adolescents. AB - BACKGROUND: Students emotional health and bullying behavior are receiving greater attention worldwide due to their long-term effects on students' health. The purpose of this study was to examine the relationships between perceived school climate, peer support, teacher support, school pressure and emotional health and bullying among adolescent school students in Jordan. METHODS: A cross-sectional descriptive design was used to recruit a sample of 1166 in-school adolescents in Amman between November 2013 and January 2014. A multi-stage cluster sampling technique was used to select respondents and Health Behavior in School Aged Children questionnaire was used to collect the data. Data were analyzed using Pearson Correlation to detect relationships among study variables. RESULTS: Significant correlations (P value was <=.05) were found between school climate including teacher and peer support and emotional health and bullying behavior of school students. School pressure was not correlated significantly with emotional health and bullying. CONCLUSION: Study findings emphasize the importance of school related factors in influencing students' emotional health and bullying behavior. This indicates that the issue of bullying and emotional health of students in Jordanian schools requires further attention, both for future research and preventive intervention. PMID- 26060721 TI - Health Sector Inflation Rate and its Determinants in Iran: A Longitudinal Study (1995-2008). AB - BACKGROUND: Health price inflation rate is different from increasing in health expenditures. Health expenditures contain both quantity and prices but inflation rate contains prices. This study aimed to determine the factors that affect the Inflation Rate for Health Care Services (IRCPIHC) in Iran. METHODS: We used Central Bank of Iran data. We estimated the relationship between the inflation rate and its determinants using dynamic factor variable approach. For this purpose, we used STATA software. RESULTS: The study results revealed a positive relationship between the overall inflation as well as the number of dentists and health inflation. However, number of beds and physicians per 1000 people had a negative relationship with health inflation. CONCLUSION: When the number of hospital beds and doctors increased, the competition between them increased, as well, thereby decreasing the inflation rate. Moreover, dentists and drug stores had the conditions of monopoly markets; therefore, they could change the prices easier compared to other health sectors. Health inflation is the subset of growth in health expenditures and the determinants of health expenditures are not similar to health inflation. PMID- 26060722 TI - Evaluation of Vitamin D Status in Newly Diagnosed Pemphigus Vulgaris Patients. AB - BACKGROUND: Pemphigus vulgaris (PV) is an autoimmune blistering disorder of the skin or mucosa. Since low vitamin D status has been linked to many immune disorders, we designed this study to compare the vitamin D status in PV patients with healthy controls. METHODS: In this case-control study, vitamin D status of 32 newly diagnosed PV patients was compared with 36 healthy control subjects. All patients were selected from the specialized dermatology departments of Razi Hospital, Tehran University of Medical Sciences in a 2-year period (2009-2010). The severity of the disease was estimated according to Harman's scores. Serum concentration of 25(OH)D was measured by Roche Elecsys System. Data were analyzed by independent t-test. RESULTS: Both groups were similar based on sex, age and body mass index. The mean duration of disease was 5.57+/-0.93 months. The mean oral and skin severities were 1.81+/-0.20 and 2.31+/-0.17 respectively, based on Harman's scores. Serum 25(OH)D was significantly lower in PV patients compared to controls (-8.90; 95% CI, 2.29-15.51 and P = 0.009). There was a negative correlation between vitamin D level and the oral severity of disease (r = -0.39 and P = 0.02). CONCLUSION: PV patients had significantly lower serum level of 25(OH)D compared to healthy subjects which might contribute to worsen the disease. These data indicate the importance of improving vitamin D level in pemphigus patients. PMID- 26060723 TI - Emotional Intelligence (EI) of Patients with Multiple Sclerosis (MS). AB - BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease that affects physical and emotional aspects of patient's lives. The aim of this study was to evaluate Emotional Intelligence (EI) in cases with MS. METHODS: One hundred sixty six clinically definite MS and 110 healthy subjects were enrolled in this study. All participants filled valid and reliable Persian version Emotional Quotient inventory (EQ-i) questionnaire, which had been developed due to Bar-On model. RESULTS: Mean EI total score and 12 out of 15 subscales were significantly different between patients and controls. Total EI score and most of its subscales were significantly higher in patients with RR (Relapsing Remitting) than Secondary Progressive (SP) ones. There was significant negative correlation between EDSS and total EI score (rho=-0.4, P<0.001). Multiple linear regression analysis between the EI as a dependent variable and sex, type of disease, level of education, age and marital status as independent variables in patients showed that type of disease and level of education were independent predictors of EI. CONCLUSION: Emotional intelligence as the ability to behave better and communicate with others should be considered in MS cases as their physical and psychological health are affected by their illness. PMID- 26060724 TI - Stability of Freeze-Dried Sera Stored at Different Temperatures for the Detection of Anti-Leishmania infantum Antibodies Using Direct Agglutination Test. AB - BACKGROUND: This study aimed to evaluate freeze-dried sera as an alternative to non-freeze dried for detection of anti-Leishmania infantum antibodies over the course of 11 months using the direct agglutination test (DAT). METHODS: Altogether, 60 serum samples (30 from humans and 30 from dogs) were collected from various geographical locations in Iran. All the collected sera were pooled and each pooled serum sample contained 10 different sera. In the beginning, the human and dog pooled sera were categorized as positive (weak and strong) and negative based on anti-L. infantum antibodies using the DAT. All the freeze-dried and non-freeze-dried sera were stored at -70 degrees C, -20 degrees C, 4 degrees C, 22-28 degrees C and 56 degrees C for 11 months. The positive and negative human and dog pooled sera were separately tested using the DAT each month and the results were compared to non-freeze-dried sera kept under the same conditions. RESULTS: We found strong agreement (100%) between the results obtained from freeze-dried human and dog in strong DAT positive sera kept at -70 degrees C, -20 degrees C, 4 degrees C and 22-28 degrees C during this study. The human and dog pooled sera stored at 56 degrees C were corrupted after 2 weeks. The DAT results were highly reproducible using freeze-dried human pooled sera in the beginning and month 11 of this study (CV = 0.036). CONCLUSION: Freeze-dried human and dog strong DAT positive sera are highly stable under different temperature conditions, are easy to transport and are safe for use as positive and negative serum controls in laboratories. PMID- 26060725 TI - Frequency of Human Papillumavirus among Women with High-Grade Squamous Intraepithelial Lesions and Invasive Cervical Cancer Attending Shahid Beheshti University of Medical Sciences Clinics, Tehran, Iran. AB - BACKGROUND: The previous studies reported some information about prevalence release of high-risk HPV types in HSIL or cervical cancer globally and in Iran, however, this information is not enough for final judgment about vaccination against HPV or any screening program. The aim of the present study was to assess the HPV type distribution in HSIL and ICC specimens of women attending Shahid Beheshti University of Medical Sciences teaching hospitals, Tehran, Iran for treatment during 10 years. METHODS: This retrospective- descriptive study evaluated the HPV type distribution of pathologic specimens of Iranian women with invasive cervical cancer (ICC) and high-grade squamous cell intraepithelial lesions (HSIL). Formalin-fixed tumor biopsies that were retrieved from women presenting with histological confirmation for ICC and 17 pathologic confirmation for HSIL specimens. RESULTS: The most frequently identified HPV type 16 among both groups, women with invasive cervical cancer (4-2.18%) and women with High Grade Squamous Intraepithelial Lesion (29.41%), followed by HPV18, HPV31 and 26. HPV16 and / or 18 accounted for 82.2% of all infected samples. CONCLUSION: The dominance of HPV16 over other high-risk types might be even higher than in a region with low HPV exposure. However, there was no strong evidence for any judgment that show to the policy makers; which one is cost-effectiveness and feasibility for cervical cancer prevention in Iran, vaccination, screening or both? More population based study and national meta-analysis needed for better understanding of HPV prevalence and HPV DNA patterns in Iran. PMID- 26060726 TI - Sero-Prevalence of Antibodies against Varicella Zoster Virus in Children under Seven-Years Old in 2012 in Tehran, Iran. AB - BACKGROUND: Varicella zoster virus (VZV) is a member of herpes family viruses, which causes varicella (chickenpox) after primary infection and herpes zoster (shingles) because of latent virus reactivation from dorsal root ganglia. Generally, prevalence of varicella antibodies increases with age. We aimed to compare the prevalence of anti-VZV antibody in children under seven years old, in order to obtain a preliminarily picture of general presence of these antibodies to design an immunization plan. METHODS: In this cross-sectional study, performed from September 2011 to September 2012 in Tehran, Iran, 267 serum samples including sera from 7 month old infants, n= 87; 18 month old children, n= 86; and 6 year old children, n= 94 were assessed for the presence of specific IgG antibodies against VZV, using ELISA technique. RESULTS: 4.6% of 7 month, 12.8% of 18 month and 21.3% of 6-year-old children were seropositive. No relation was found between demographic variables (e.g. age and birth weight) and seropositivity in these age groups. VZV antibodies increased with age. Serum levels of varicella antibodies were elevated in 18 months old compared to 7 months old children, significantly (P < 0.001). CONCLUSION: In view of the significant elevation of VZV antibodies in children from 7 months to 18 months of age and rate of seronegative children, our results support the necessity of varicella immunization between 7 and 18 months of age in order to prevent viral infection. PMID- 26060727 TI - Hospitals Productivity Measurement Using Data Envelopment Analysis Technique. AB - BACKGROUND: This study aimed to measure the hospital productivity using data envelopment analysis (DEA) technique and Malmquist indices. METHODS: This is a cross sectional study in which the panel data were used in a 4 year period from 2007 to 2010. The research was implemented in 12 teaching and non-teaching hospitals of Ahvaz County. Data envelopment analysis technique and the Malmquist indices with an input-orientation approach, was used to analyze the data and estimation of productivity. Data were analyzed using the SPSS.18 and DEAP.2 software. RESULTS: Six hospitals (50%) had a value lower than 1, which represents an increase in total productivity and other hospitals were non-productive. the average of total productivity factor (TPF) was 1.024 for all hospitals, which represents a decrease in efficiency by 2.4% from 2007 to 2010. The average technical, technologic, scale and managerial efficiency change was 0.989, 1.008, 1.028, and 0.996 respectively. There was not a significant difference in mean productivity changes among teaching and non-teaching hospitals (P>0.05) (except in 2009 years). CONCLUSION: Productivity rate of hospitals had an increasing trend generally. However, the total average of productivity was decreased in hospitals. Besides, between the several components of total productivity, variation of technological efficiency had the highest impact on reduce of total average of productivity. PMID- 26060728 TI - Novel Influenza A (H6N1) Virus That Infected a Person in Taiwan. PMID- 26060729 TI - Subjective Well-Being in University Students. PMID- 26060730 TI - The Influence of Dietary Energy Density on Childhood Obesity. PMID- 26060731 TI - Oral Health Policy Amicable for the South Asian Association for Regional Cooperation Nations. PMID- 26060732 TI - The Survey of Viewpoint Waste Management for Developing Methods of Education. PMID- 26060733 TI - Implementation of Performance-Based Budgeting in the Health System: Luxury or Necessity? PMID- 26060734 TI - Artificial Eye in Burnt City and Theoretical Understanding of How Vision Works. PMID- 26060735 TI - Prognostic Significance of VEGF-C Expression in Patients with Breast Cancer: A Meta-Analysis. AB - BACKGROUND: Vascular endothelial growth factor (VEGF)-C, as a lymphangiogenic factor, plays important roles in the progression of several malignancies. However, its clinical prognostic value in breast cancer still remains controversial. We performed a meta-analysis of available studies to assess the association between VEGF-C expression and the ou-tcomes of breast cancer patients. METHODS: We searched eligible studies in three English databases (MEDLINE, EMBASE, and Web of Science) and two Chinese databases (Wanfang and Chinese National Knowledge Infrastructure databases). Key words used in the research included 'VEGF-C", "breast cancer", "immunohistochemistry", "breast neoplasma(s)", "breast carcinoma", "metastasis", and "prognosis". Fourteen studies with a total of 1, 573 breast cancer cases were finally included into the meta-analysis. The pooled odds ratios (ORs) with the corresponding 95% confidence interval (95% CIs) for lymph node metastasis, overall survival, and disease-free survival were calculated by using fixed-effects or random-effects models. Heterogeneity and publication bias were also assessed. RESULTS: Meta-analysis of random-effects model showed VEGF-C expression was associated with lymph node metastasis in patients with breast cancer (random-effects, OR = 2.14; 95 % CI 1.21-3.77, P = 0.009). VEGF-C expression was associated with poorer overall survival (fixed-effects, OR = 2.46, 95% CI: 1.46-4.14, P < 0.001) and disease free survival (fixed-effects, OR = 2.10, 95% CI: 1.32-3.35, P = 0.002) in patients with breast cancer. CONCLUSION: VEGF-C expression is positively associated with lymph node metastasis in breast cancer, and VEGF-C detection in breast cancer might be an effective and feasible means to predict outcome. PMID- 26060736 TI - Predictors of Self-Medication Behavior: A Systematic Review. AB - BACKGROUND: Self-medication with over the counter (OTC) and non OTC drugs may provoke serious consequences for users and societies. Recognition of its predictors therefore, is pivotal in plans to hinder the aggregating behavior. This study aimed to identify possibly all predictors of self-medication and the range of its prevalence among different populations. METHODS: Medline, Amed, Scopus, Medlib, SID, Pub Med, Science Direct, and super searcher of Google Scholar were scrutinized using "self-medication", "self-prescription" and "self treatment" key words without a time limit with special focus on Iranian studies. Authors independently assessed the title, abstract and full text of identified articles for inclusion and any disagreement was resolved with consensus. RESULTS: The range of reported self-medication in the 70 included publications was 8.5 98.0%. Having a minor illness (15 studies), health care costs (9 studies), lack of adequate time to visit a physician (11 studies), prior experience (7 studies) in using a drug and long waiting time to visit a qualified practitioner (5 studies) were most frequently reported reasons of self-medication. CONCLUSION: The observed diversity in the reported prevalence and reasons of self-medication among different sub-groups of populations (e.g. males vs. females) and between developed and developing countries highlights the importance of explanatory behavioral chain analysis of self-medication in different population groups and countries. Even within a single country, predictors of this harmful practice could be inconsistent. Lack of sufficient quality re-search to identify precipitating factors of self-medication in developing countries is paramount. PMID- 26060737 TI - Efficacy of Microwave-Heating during Alkaline Processing of Fumonisin Contaminated Maize. AB - BACKGROUND: Fumonisins (a family of foodborne carcinogenic mycotoxins) cause health hazards to humans and animals in developing countries, and has also economic implications. Therefore, the efficacy of a novel environmental friendly nixtamalization procedure to make tortillas (the main staple food for the Mexican population) was investigated. METHODS: Maize contaminated with 2136.67 ng/g total fumonisins was processed into tortillas, starting with maize grits mixed with water and calcium hydroxide that was cooked in a microwave field at 2.45 GHz during 3.75 min, and steeped 3.5 h at room temperature. The steeped maize grits (nixtamal) was stone-ground into masa (maize dough), which was then used to make tortillas. Total fumonisin content was determined using monoclonal antibody columns. RESULTS: Masa contained 1998.33 ng/g total fumonisins, which represents 6.5% toxin reduction. Nevertheless, fumonisin concentration was reduced significantly in tortillas (up to 985.33 ng/g) due to the cooking process, corresponding to a cumulative toxin degradation of 54%. Tortillas were below the maximum tolerated level, considering the European Union regulatory limit for fumonisins in maize (1000 ng/g). The physicochemical and technological properties of tortillas were also considered within the acceptable margins of quality. CONCLUSION: Microwave nixtamalization was not a feasible method to reduce fumonisin content in masa to acceptable levels; however, an effective extra reduction occurred when masa was baking into tortillas. PMID- 26060738 TI - Epidemiological Aspects of Hepatitis B and C Markers in Blood Donors in Kazakhstan; 2000-2011. AB - BACKGROUND: Transfusion-transmissible infections such as hepatitis B and hepatitis C are among the greatest threats to blood safety for transfusion recipients and pose a serious public health problem. The aim of this study was to assess the epidemiological aspects of hepatitis B and C in Kazakhstani donor's blood over the period 2000-2011. METHODS: The data were obtained from the annual reports of the Republican Blood Center. The retrospective study was conducted from 2000 to 2011. RESULTS: Over the study period in the republic a growth of volumes of procured blood from 312.4 to 398.0 units was noted, in total equaled to 4,277.8 units. The proportion of blood wasted increased from 8.3% to 8.7%. In the dynamics the proportion of viral hepatitis among all causes of blood wasted decreased from 29% to 15.5% (HBV) and from 33.5% to 9.9% (HCV). The proportion of HBV and HCV in whole blood decreased considerably, in plasma and red cell concentrate the rates changed slightly. The average annual prevalence of HBV and HCV were 2.1% and 1.8%, respectively. CONCLUSION: Despite the reduction of viral hepatitis rates among blood donors in Kazakhstan the prevalence still remains high. The HBV prevalence is higher compared to HCV, which needs further investigations in the general population to address the issue. PMID- 26060739 TI - Occurrence of a Snail Borne Disease, Cercarial Dermatitis (Swimmer Itch) in Doon Valley (Uttarakhand), India. AB - BACKGROUND: 'Cercarial dermatitis' also known as swimmers itch (Skin allergies) is caused by a trematode parasite, Schistosoma which has two hosts - an invertebrate (snail) and a vertebrate (livestock, human being). Although the availability of both vector snails and pathogens at the selected site the Doon Valley in northern India has already been confirmed but there was a hazy picture of the disease, whether it is due to entrance of cercariae or due to wild variety of grass (Parthenium hysterophorus). The present study is an attempt to provide a way forward towards the vector snails and snail borne diseases in the study area. METHODS: Snail sampling and identification was done by applying standard methods / using Keys & Catalogues. Associated parasites and cercariometry in snails has been worked out by cercarial shedding. Human involvement at zo-onotic level has been performed in collaboration with Health centers and socio- economic aspect of inhabitants of study area. RESULTS: The snail diversity encountered 19 species including the vector species such as Indoplanorbis exustus, Gyraulus convexiusculus, Melanoides tuberculata and Lymnaea acuminata. The cercarial diversity comprised Furcocercous, Monostome, Amphistome and liver fluke / Xiphidiocercaria. During the study (2009-2010), 0.173% was found with cercarial dermatitis among human population in the selected area. The symptoms of disease recorded were red spots and swellings on effected parts of skin. Frequent visits of livestock to the water body and presence of vector snails provides a clue in completing the life cycle of the parasite of the family Schistosomatidae. CONCLUSION: Cercarial dermatitis has been considered a potential risk at those places where warm blooded and snail's hosts share a link with aquatic bodies with particular emphasis to temperature and time of year. PMID- 26060740 TI - Characterization of Domestic Wastewater Sludge in Oman from Three Different Regions and Recommendations for Alternative Reuse Applications. AB - BACKGROUND: There are more than 350 wastewater treatment plants distributed across different parts of Oman. Some of them produce large quantities of domestic sewage sludge, particularly this study focused on characterizing domestic sludge of six treatment plants that may contain various pollutants, therefore the proper management of domestic sewage sludge is essential. METHODS: Samples of domestic sewage sludge were collected for each month over a period of one year in 2010. Samples of retained/recycled activated sludge (RAS) and waste activated sludge (WAS) were analyzed for elec-trical conductivity (EC), potential of hydrogen (pH), cations, anions and volatile content. All tests were conducted according to the Standard Method for the Examination of Water and Wastewater. RESULTS: Monitoring ofelectrical conductivity, nitrite and nitrate, the presence of chloride, sulfate and phosphate were higher than the other anions, the phosphate was found very high in all domestic STPs. The average obtained values of the cations in both domestic RAS and WAS samples were within the Omani Standards. CONCLUSION: The study showed the very high concentration of phosphate, it might be worth to further investigate on the sources of phosphate. Cations in both domestic RAS and WAS samples were low and suggest that the domestic sludge can be re used in agriculture. A regular maintenance should be performed to prevent any accumulation of some harmful substances which may affect the sludge quality and the sludge drying beds should be large enough to handle the produced sludge for better management. PMID- 26060741 TI - Analysis of Range of Motion and Isokinetic Strength of Internal and External Rotation According to Humeral Retroversion of the Dominant Shoulder in Youth Baseball Players: A Pilot Study. AB - BACKGROUND: We aimed to analyze the range of motion (ROM) and internal rotation (IR) and external rotation (ER) isokinetic strength according to humeral retroversion of the dominant shoulder. METHODS: We included 40 elite baseball players in Korea (OBP group: n=20 players with careers spanning >10 years, age: 19.37+/-2.21 years, height: 181.00+/-5.41 cm, weight: 84.58+/-7.85 kg; BBP group: n=20 players with careers spanning <10 years, age: 16.55+/-1.36 years, height: 177.27+/-7.57 cm, weight: 77.27+/-8.14 kg). Radiography was performed to examine humeral retroversion, a goniometer was used to measure IROM and EROM, and a dynamometer was used to measure IR and ER isokinetic strength (speed set at 180 degrees /s or 300 degrees /s). RESULTS: The BBP and OBP groups had significantly different IR and ER isokinetic strength (180 degrees /s and 300 degrees /s) (P<0.001) and dominant shoulder retroversion (P=0.009). In the BBP group, retroversion had no correlation with ROM and with IR or ER isokinetic strength (180 degrees /s and 300 degrees /s). In the OBP group, retroversion had no correlation with ROM and with ER isokinetic strength at 180 degrees /s, but had significant correlation with IR isokinetic strength at both 180 degrees /s (r=0.483, P=0.007) and 300 degrees /s (r=0.373, P=0.043) and ER isokinetic strength at 300 degrees /s (r=0.366, P=0.046). CONCLUSION: Thus, youth players with careers spanning >10 years had significantly higher humeral retroversion, IROM, EROM, and IR and ER isokinetic strength of the dominant shoulder than youth players with careers spanning <10 years. Furthermore, humeral retroversion and ROM were not significantly related, but IR and ER isokinetic strength were significantly positively related with retroversion in both groups. PMID- 26060742 TI - The Relationship between Students' Bonding to School and Multiple Health Risk Behaviors among High School Students in South-East of Iran. AB - BACKGROUND: School is the first social institution which affects adolescents' lives, and it determines their opportunities, life quality and behavior. Thus, the aim of this study was to determine the relationship between students' bonds with their school and multiple health risk behaviors amongst high school students in Kerman City, Iran. METHODS: In this cross-sectional study, high school students of all levels participated during November and December 2001 in Kerman. The research sample included 1024 students (588 females and 436 males) aged 15 to 19 years. A CTC (Communities That Care Youth Survey) questionnaire was designed based ona standard questionnaire in order to collect a profile of students' risk behaviors. A multi-stage cluster sampling method was used to collect the data. RESULTS: In the final multivariate logistic regression, two variables including; age, (ORa=1.15, P=0.02) and male gender (ORa=2.14, P=0.001) had a significant positive association with multiple health risk behaviors (MHRB). School commitment (ORa=0.38, P=0.001) and school rewards for involvement (ORa=0.80, P=0.21), had a significant negative association with MHRB. CONCLUSION: Our results quantified the pivotal role of schools in shaping the risky behavior of students. It seems that school may minimize the risky behaviors by creating a strong link, and improving the effective communications with students. PMID- 26060743 TI - Association of Metabolic Syndrome with Body Fat Percent, Anthropometric Indices in 10 To 18 Year Old Adolescents. AB - BACKGROUND: Our aim was to evaluate the association of metabolic syndrome (MetS) and its components with body fat percentage (BFP) and anthropometric indicesin10 to 18year old adolescents. METHODS: This was a cross-sectional study conducted on 134 Tehranian adolescents, aged 10 to 18 years (66 boys and 68 girls) in 2007. The MetS definition proposed by Cook et al. was used. Logistic regression was used to determine the relationship of MetS and its components with body mass index (BMI), waist circumference (WC), waist to height ratio (WHtR), and BFP. Using the areas under the receiver operating characteristic (ROC) curve, the discriminatory ability of anthropometric measurements and BFP was evaluated. RESULTS: The mean+/-SD forage of boys and girls was14.5+/-2.3and13.0+/-2.9 years, respectively (P=0.001); the prevalence of MetS in these groups was 32.3 and6.5%, respectively (P=0.001). After adjusting for sex and physical activity, the highest odds ratios (95% CI) for MetS and hypertriglyceridemia were found for WC, 6.27 (2.63-14.94; P<0.05)and 3.14 (1.87-5.27; P<0.05), respectively, and those for low HDL-C and hypertension were found for BMI, 2.91 (1.73-4.90; P<0.05)and 2.26 (1.27-4.02; P=0.05), respectively. After adjusting for sex and physical activity, the highest area under ROC curve for MetS and hypertriglyceridemia was seen for WC (P=0.001), for hypertension it was seen for BMI (P=0.001), and for low HDL-C it was observed for both WC and BMI (P=0.001). CONCLUSIONS: In adolescents, WC was the best predictor of MetS and hypertriglyceridemia, BMI was the best predictor of hypertension, and WC and BMI were the best predictors for low HDL-C. PMID- 26060744 TI - Household Health Costs: Direct, Indirect and Intangible. AB - BACKGROUND: This study aimed at identifying components of the household health costs. METHODS: This study was a qualitative research conducted in two main phases. The first phase consisted of interviews with sample households selected in eight provinces of Iran. They were to identify components of the household health costs. In the second phase, components were determined as direct, indirect and intangible based on a content analysis. RESULTS: In the first phase of the study, 93 components of households' health costs were identified. According to the content analysis, 44 components were categorized as direct costs, 10 components were indirect and 39 components were categorized as intangible. CONCLUSION: All components of households' health costs including: direct, indirect and intangible costs, should be considered in the planning and policy making in the health system. PMID- 26060745 TI - Factors Affecting Medical Service Quality. AB - BACKGROUND: A better understanding of factors influencing quality of medical service can pinpoint better strategies for quality assurance in medical services. This study aimed to identify factors affecting the quality of medical services provided by Iranian physicians. METHODS: Exploratory in-depth individual interviews were conducted with sixty-four physicians working in various medical institutions in Iran. RESULTS: Individual, organizational and environmental factors enhance or inhibit the quality of medical services. Quality of medical services depends on the personal factors of the physician and patient, and factors pertaining to the healthcare setting and the broader environment. CONCLUSION: Differences in internal and external factors such as availability of resources, patient cooperation and collaboration among providers affect the quality of medical services and patient outcomes. Supportive leadership, proper planning, education and training and effective management of resources and processes improve the quality of medical services. This article contributes to healthcare theory and practice by developing a conceptual framework for understanding factors that influence medical services quality. PMID- 26060746 TI - Comparison the Effects of Health Indicators on Male and Female Labor Supply, Evidence from Panel Data of Eastern Mediterranean Countries 1995-2010. AB - BACKGROUND: Skilled labor force is very important in economic growth. Workers become skilled when they are healthy and able to be educated and work. In this study, we estimated the effects of health indicators on labor supply. We used labor force participation rate as the indicator of labor supply. We categorized this indicator into 2 indicators of female and male labor force participation rates and compared the results of each estimate with the other. METHODS: This study was done in eastern Mediterranean countries between 1995 and 2011. We used a panel cointegration approach for estimating the models. We used Pesaran cross sectional dependency, Pesaran unit root test, and Westerlund panel cointegration for this issue. At the end, after confirmation of having random effect models, we estimated them with random effects. RESULTS: Increasing the fertility rate decreased the female labor supply, but increased the male labor supply. However, public health expenditures increased the female labor supply, but decreased the male labor supply because of substitution effects. Similar results were found regarding urbanization. Gross domestic product had a positive relationship with female labor supply, but not with male labor supply. Besides, out of pocket health expenditures had a negative relationship with male labor supply, but no significant relationships with female labor supply. CONCLUSION: The effects of the health variables were more severe in the female labor supply model compared to the male model. Countries must pay attention to women's health more and more to change the labor supply. PMID- 26060747 TI - Prevalence of HIV and Hepatitis B, C, D Infections and Their Associated Risk Factors among Prisoners in Southern Khorasan Province, Iran. AB - BACKGROUND: Prison inmates are among the high risk population for dangerous infections such HIV, HBV, HCV and other contagious diseases. In spit of many data about the prevalence and risk factors for blood born diseases among prisoners in the world, such data are spares from Iran. The aim of this study was to determine the prevalence and associated risk factors for HIV, HBV, HCV and HDV infections among a large sample of prison inmates in Iran. METHODS: In a cross-sectional study in 2009-2010, 881 inmates in three prisons of Southern Khorasan Province in Iran were selected based on a systematic, stratified random sampling method. Sera were analyzed for HBV, HDV, HCV and HIV infections by appropriate commercial ELISA kits. An anonymous questionnaire was used to collect the demographic data and information about risk factors. RESULTS: Overall, 881 prisoners (mean age: 34.7+/-11.4 years, range: 11-84 years, M/F ratio:4.5/1) were participated in this study. The prevalence of HBV and HCV infection was 6.9% and 7.7%, respectively. Among the HBsAg positive subjects, 6.6% (4/61) and 9.8% (6/61) had HDV and HCV super-infection, respectively. Only one case (0.1%) had HIV infection that was co infection with HCV. Drug abuse and history of traditional phlebotomy were associated risk factors for HBV infection (P<0.05) and history of drug injection was associated with HCV infection (P<0.05). CONCLUSIONS: This study show fairly higher prevalence of blood borne infections among prisoners and indicate drug abuse and phlebotomy as the associated risk factor. Implementation of appropriate screening tests and preventive programs is suggested in prisons. PMID- 26060748 TI - Haplotype Frequency of G691S/S904S in the RET Proto-Onco-gene in Patients with Medullary Thyroid Carcinoma. AB - BACKGROUND: Medullary thyroid carcinoma (MTC) occurs in both sporadic (75%) and hereditary (25%) forms. The missense mutations of the REarranged during Transfection (RET) proto-oncogene in MTC development have been well demonstrated. The aim of this study was to investigate frequency of G691S/S904S haplotype in MTC patients and their relatives. METHODS: In this research 293 participants were studied, including 181 patients (102 female, 79 male) and 112 their relatives (58 female, 54 male). Genomic DNA was extracted from peripheral blood leucocytes using the standard Salting Out/Proteinase K method. Nucleotide change detection was performed using PCR and direct DNA sequencing methods. RESULTS: According to DNA sequencing results, 159 individuals (104 patients, 55 relatives) had both G691S (rs1799939) missense mutation in exon11 and S904S (rs1800863) synonymous mutation in exon 15 of RET proto-oncogene. The allele frequency of G691S/S904S haplotype was 21.15% in patients and 10.75% in their relatives. CONCLUSION: The obtained data showed the frequency of G691S/S904S RET gene haplotype among Iranian MTC patients and their relatives. The G691S and S904S nucleotide changes were in complete linkage disequilibrium, so the results were grouped together and referred to as G691S/S904S haplotype. Further analysis is need to demonstrate the association between this haplotype and MTC development. PMID- 26060749 TI - Radiological Features of Human Infection with Avian Influenza A H7N9 Virus: A Report of Three Cases. AB - Human infection with avian influenza A H7N9 virus has emerged in China with high morbidity rates. Patients usually present with severe and rapidly progressive pneumonia. Therefore, radiological findings are important to diagnose and evaluate disease severity. The clinical characteristics of three new cases of H7N9 virus infection were analyzed, especially the radiological findings, and previously published studies regarding H7N9 virus infection were summarized. Ground-glass opacification and areas of consolidation were the most common image features. Although drug resistance has been found in some H7N9 viruses, oseltamivir administration is still recommended as soon as possible. Moreover, timely epidemiological surveillance is needed, and a new vaccine is expected for the management of avian influenza. PMID- 26060750 TI - Human-Induced Radioresistance as a Possible Mechanism for Producing Biological Weapons: A Feasible Bridge between Radiore-sistance and Resistance to Antibiotics and Genotoxic Agents. PMID- 26060751 TI - First Skull Surgery in Iran: The Burned City and a 4800-Year-Old Skull. PMID- 26060752 TI - Indoor Radon Levels in Selected Houses in Isfahan, Central Iran. PMID- 26060753 TI - Medicinal Plants And Antioxidants: Why They Are Not Always Beneficial? PMID- 26060754 TI - Social Perceptions of Protection against HIV Infection among Female Street Prostitutes. PMID- 26060755 TI - The Efficient Estimation of Motor Unit Excitability Parameters in Needle Electromyography Experiments. PMID- 26060756 TI - Prevalence and Causes of Cesarean Section in Iran: Systematic Review and Meta Analysis. AB - Unfortunately, the prevalence of cesarean section has increased in recent years. Whereas awareness of the prevalence and causes is inevitable for planning and effective interventions, so aim of this study has designed and conducted for reviewing of systematic Prevalence and caesarean causes in Iran. In this meta analysis, the required information have been collected using several keywords which are Cesarean section rate, Cesarean section prevalence, delivery, childhood, childbirth, relative causes, relative frequency, Iran and their Persian equivalents have been collected from databases such as CINAHL, Science Direct, PubMed, Magiran, SID, Iranmedex. Finally, we found 706 related articles and selected 34 articles among them for studying of cesarean Prevalence. We used CMA software with random model for Meta-Analysis. The prevalence of Cesarean was estimated48%. Using content analysis, Factors influencing the incidence of cesarean section were divided to 3 categories including social and demographic factors, obstetric-medical causes and non-obstetric-medical causes. Maternal education and grand multiparity in the field of demographic and social factors, previous cesarean in the field of obstetric-medical causes and fear of normal vaginal delivery (NVD) and doctor's suggestion in the field of non-obstetric medical causes were major causes of Cesarean. According to the high prevalence of caesarean section and it upward development, it seems to be essential designing and implementing of programs and interventions effectiveness including providing of Possibility of painless childbirth and education and psychological interventions, increasing of quality of natural delivery services, proper culture and prohibiting of doctors from Personal opinions and profit. PMID- 26060757 TI - Actinomycosis in Iran: Short Narrative Review Article. AB - Actinomycosis is an indolent, slowly progressive infection caused by anaerobic or microaerophilic bacteria, primarily of genus Actinomyces, which colonize the mouth, colon and vagina. Mucosal disruption may lead to infection virtually at any sites in the body. The aim of this study was to underline different features of actinomycosis and to represent total data about etiologic agents, clinical, diagnostic and therapeutic approaches these infections. From a total of 38 case reports or series, ninety one cases were obtained by using of relevant articles reported as recorded cases in Iran (1972 to 2012). Analyzed data represented 21 cases of oral-servicofacial (23.1%), 7 cases of thoracic (7.7%), 17 cases of abdominal (18.7%), 21 cases of disseminated forms (23.1%) and 25 cases of others (27.5%). Findings indicated more common of these infections in men (61.5%). Actinomyces naeslundii (21 cases) was found as the most common causative agents in comparison with A. Israeli (15 cases), A. viscosus (3 cases) and A. bovis (1 case). The most patients had been successfully treated with penicillin although some cases needed surgery along with antibiotic therapy. Since some clinical features of actinomycosis are similar to malignancies, so the differential diagnosis of invasive forms must be considered. This report emphasizes on the importance of differential diagnosis of actinomycosis from similar diseases by clinicians. PMID- 26060758 TI - How to Make Diagnosis Related Groups Payment More Feasible in Developing Countries- A Case Study in Shanghai, China. AB - BACKGROUND: Given limited health sources, how to make DRGs (Diagnosis Related Groups) more feasible is a big question in developing countries. This study contributes to the debate on how to bridge the pay-for-service and DRGs during the transitional period of payment reform. METHODS: From 2008 to 2012, 20740 patients with cirrhosis or duodenal ulcer disease were chosen as sample. Using multiple linear regression analysis, the interrelationships between the total medical expenses of the inpatients, and age, gender of the inpatients, length of stay (LOS), region and economic level of the hospitals were examined. RESULTS: The main findings were 1) length of stay (LOS) and the economic level of treatment location had a statistically significant impact on patients with cirrhosis or duodenal ulcer disease. Meanwhile gender is not a significant factor for both of them. 2) Under the premise of limited resources, developing countries should first narrow down to screen for common and frequently occurring diseases, then study the key factors which affect the treatment cost of the diseases. CONCLUSION: Based on picking out common diseases and their key factors, Simplification of the DRGs setting process will greatly increase the efficiency of implementing DRGs in the developing world. PMID- 26060759 TI - Relationships of both Heavy and Binge Alcohol Drinking with Unhealthy Habits in Korean Adults Based on the KNHANES IV Data. AB - BACKGROUND: We conducted this cross-sectional study to examine the relationships between problematic alcohol drinking, unhealthy habits and socio-demographic factors based on the Fourth Korean National Health and Nutrition Examination Survey (KNHANES IV). METHODS: We analyzed a total of 13,488 participants based on the data collected from the KNHANES IV performed between 2007 and 2009. RESULTS: The frequency of binge and heavy drinking was significantly higher in men and the married participants with intermediate income. The frequency of binge drinking was higher in younger adults and individuals with at least high school graduates. After the adjustment of socio-demographic factors, the odds of current smoking (adjusted Odds Ratio [aOR] 4.11, 95% CI 3.35-5.03), abdominal obesity (aOR 1.26, 95% CI 1.08-1.48), stress (aOR 1.45, 95% CI 1.261.68), and depressed mood (aOR 1.31, 95% CI 1.08-1.58) were greater in heavy drinkers than in nondrinkers. The odds of current smoking (aOR 1.73, 95% CI 1.42-2.09 for infrequent binge drinking and aOR 4.95, 95% CI 4.25-5.77 for frequent binge drinking), obesity (aOR 1.22, 95% CI 1.06-1.41 for infrequent binge drinking and aOR 1.64, 95% CI 1.46-1.85 for frequent binge drinking), and abdominal obesity (aOR 1.22, 95% CI 1.04-1.43 for infrequent binge drinking and aOR 1.55, 95% CI 1.36-1.77 for frequent binge drinking) were increased with the increased frequency of the binge drinking. CONCLUSIONS: Our results would be of help for screening a specific subgroup of individuals who are vulnerable to alcohol drinking by establishing effective population-based strategies to reduce the problematic drinking. PMID- 26060760 TI - Sleep Duration and Self-Rated Health are Independently Associated with Physical Activity Level in the Korean Population. AB - BACKGROUND: The purpose of this study was to examine the relationship of physical activity levels with sleep duration (SD), and self-rated health (SRH) using the fifth Korean National Health and Nutrition Examination Survey data from 2010 and 2011. METHOD: Overall, 12,188 Korean people were evaluated in relation to meeting guidelines for vigorous PA (MVPA), moderate PA (MMPA), and low PA (MLPA) associated with SD and SRH. RESULTS: The adjusted odds ratio (AOR) of males who slept seven hours with MMPA (AOR=0.84) and MLPA (AOR=0.85) and eight hours with MMPA (AOR=0.76) and MLPA (AOR=0.78) significantly decreased compared to subjects who sleep 6 hours/day. In females, an AOR of less than 5 (AOR=1.40) and 6 hours (AOR=1.12) with MVPA was significantly increased compared to 7 hours sleep/day, while sleeping more than 8 hours/day was significantly decreased with MLPA (AOR=0.73). Compared to the very good SHR, the AORs of more negative SHR status with MVPA, MMPA, and MLPA in males and with MMVP and MLVP in females decreased significantly. CONCLUSIONS: Sleeping 6-8 hours/day for MMPA and MLPA in males and 7-8 hours/day for MVPA and MLPA in females, and a very good SRH for MVPA, MMPA, and MLPA in males and for MMPA and MLPA in females are recommended to participate physical activity for the Korean population. We therefore, the independent association between PA levels and SD or SRH according to gender supports public health program to participate physical activity for the Korean population. PMID- 26060761 TI - Trends of Blood and Plasma Donations in Kazakhstan: 12-Years Retrospective Analysis. AB - BACKGROUND: Each country faces a continuing challenge to collect enough blood to meet the national needs. According to WHO, there should be at least 20 blood donations per 1,000 population for developing countries, in Kazakhstan this indicator was only 16.8 in 2011. Thus, we conducted an epidemiological assessment and drew a map of the regional distribution of blood and plasma donations in Kazakhstan during the years 2000-2011. METHODS: The retrospective study was conducted from 2000 to 2011. Data on blood and its components donations were acquired from the Ministry of Health (annual statistical reporting form N degrees 39). RESULTS: During 2000-2011, number of blood donors decreased to 17.4% and blood donations to 6.3%. The proportion of non-remunerated blood donations and donors decreased from 97.6% to 77.9% and 97.9% to 87.7%, respectively. The paid donations had the opposite trend. Number of plasma donors increased in 2.1 times, plasma donations in 2.4 times, nevertheless the proportion of non-remunerated plasma donations decreased from 60.1% to 29.8%. The average number of blood donations per 1,000 population decreased from 19.8 (2000) to 16.8 (2011), plasma donations increased from 1.4 to 3.1. Regionally, annual average rates of blood and plasma donations per 1,000 population over 12 years varied greatly. CONCLUSION: This is the first study conducted in Kazakhstan to provide detailed information, including the regional characteristics of blood and plasma donations over an extended period of time, which can be used in blood transfusion services work. PMID- 26060762 TI - Trends of Amphetamine Type Stimulants DTR Mass Load in Poznan Based on Wastewater Analysis. AB - BACKGROUND: The aim of this study was to determine the monthly DTR mass load of amphetamine-type compounds in Poland as well as an investigation of cyclical behaviour by using time series analysis and especially trends analysis. METHODS: Amphetamine, methamphetamine and MDMA (ecstasy) were detected in wastewater samples collected from the main Wastewater Treatment Plant in the city of Poznan using liquid chromatography / tandem mass spectrometry (LC-MS-MS). Back calculations used in the sewage epidemiology approach were applied to estimate the DTR mass load level of the drugs analyzed. Trends analysis was performed by fitting the data to a simple linear regression and then by using smoothing by means of a moving average (Mat lab 2013a). Trend analysis displays a steady tendency of increase or decrease throughout time series. When we plot the observation against time, we may notice that a straight line can describe the increase or decrease in the series as time goes on. Simple linear regression and method of last squares to estimate parameters of a straight-line model were used. Additionally, a lagged plot (autocorrelation plot) was used to investigate an appearance of correlation between amphetamines throughout time. RESULTS: Trends analysis showed the slight increase in consumption of amphetamine and decreasing trend in case of ecstasy and methamphetamine within the investigated period. There is also visible, strong correlation between ecstasy and methamphetamine consumption which cannot be stated in case of amphetamine. CONCLUSION: Trends analysis is a very useful tool to analyse the increasing or decreasing tendency in consumption of illicit drugs based on the DTR mass load data. PMID- 26060763 TI - Spatial Analysis of Multiple Sclerosis Disease in Tehran Metropolitan Zone, Iran, 2001-2012. AB - BACKGROUND: Multiple Sclerosis (MS) is a disease with high disabling disorders and considerable social and economic impacts. This study was conducted to analyze the spatial distribution of MS disease in Tehran, Iran during 2001-2012. METHODS: The existing information in the MS patients' medical files who had registered in Iranian MS Society (IMSS), located in Tehran office, was used for analysis. The relationship between diseases incidences in 22 zones of Tehran based on estimated socio-economic status (SES) of each zone was evaluated. High and low clustering approach was used in order to investigate the disease's distribution pattern meanwhile, Getis Ord's Gi test and Hot Spot analysis approach has been used to detect high risk zones of the disease. RESULTS: A total of 6027 MS patients were registered between 2001- 2012 which 4580 (%75.99) were women. During the study period, zone number 6 figured as the most high risk zone for the disease (P<0.1). A heterogeneous distribution was shown for the disease. Cumulative incidence of the disease in northern zones (101.73 per 100,000 inhabitants) was two times more of Southern zones (53.79 per 100,000 inhabitants). There seems to be a direct linear relationship between estimated incidence rate of the disease in each zones with the level of SES (P<0.001). CONCLUSION: Heterogeneous geographical distribution of MS and its higher estimated incidence for northern zones in Tehran may be because of higher SES and other factors in mentioned zones. It is recommended to consider the surveillance with long-term and cost-effective interventional strategies along with disease in high risk zones. PMID- 26060764 TI - Association of Tumor Necrosis Factor Alpha Gene Polymorphisms with Inflammatory Bowel Disease in Iran. AB - BACKGROUND: Inflammatory bowel disease (IBD) is a chronic disease of unknown etiology, in which genetic factors, seem to play an important role in the disease predisposition and course. Assessment of tumor necrosis factor (TNF-alpha) gene polymorphisms in many populations showed a possible association with IBD. Considering the genetic variety in different ethnic groups, the aim of the present study was to investigate the association of five important single nucleo tide polymorphisms (SNPs) in the promoter region of (TNF-alpha) gene with IBD in Iran. METHODS: In this case-control study, 156 Ulcerative colitis (UC) patients, 50 Crohn's disease (CD) patients and 200 sex and age matched healthy controls of Iranian origin were enrolled. The study was performed during a two year period (2008-2010) at Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. DNA samples were evaluated for (TNF-alpha) gene polymorphisms (including -1031, -863, -857, -308 and -238) by PCR and RFLP methods. RESULTS: The frequency of the mutant allele of -1031 polymorphism was significantly higher in Iranian patients with Crohn's disease compared to healthy controls (P=0.01, OR=1.92; 95% CI: 1.14-3.23). None of the other evaluated polymorphisms demonstrated a significant higher frequency of mutant alleles in Iranian IBD patients compared to controls. CONCLUSION: Among the five assessed (SNPs), only -1031 polymorphism of (TNF-alpha) gene may play a role in disease susceptibility for Crohn's disease in Iran. This pattern of distribution of (TNF alpha) gene polymorphisms could be specific in this population. PMID- 26060765 TI - The Efficacy of Residual Chlorine Content on the Control of Legionella Spp. In Hospital Water Systems. AB - BACKGROUND: Outbreaks of legionellosis may be a side effect of institution-water treatment. However, the long-term outcomes and the predictive factors of Legionella prevalence in such systems have still not been fully studied. This study was therefore conducted to investigate the prevalence of Legionella spp. and to evaluate the role of bacteriological water quality parameters on its prevalence and removal in hospital water systems. METHODS: A total of 45 samples were collected from distinct sites at seven hospitals in Tehran, Iran. The prevalence of this bacterium was assayed through a sensitive and specific technique for DNA detection using PCR. Multivariable stepwise regression analysis was used to explore the independent effects of the baseline factors on the incidence of Legionella. Two positive samples were also identified for species by DNA sequencing. RESULTS: Legionella were detected in 31.1% of samples. Showerheads and cold-water taps were the most and the least contaminated sources with 55.3 and 9 percent positive samples, respectively. Total mean of residual chlorine was 0.38 mg/L, with the peak value of 1.7 mg/L. Legionella detection was proportional to the residual chlorine content of water and the results indicated that residual chlorine content is a critical factor in the incidence and proliferation of Legionella (r=-0.33). The prevalence of Legionella also coincided with the prevalence of HPC and amoeba cysts. CONCLUSION: The high positive rate of Legionella colonization shows that hospital-acquired legionellosis might be under diagnosed in studied hospitals. Further, Legionella colonization is independent of the type of water, system characteristics and of preventive maintenance measures. PMID- 26060766 TI - Coupling of Molecular Imprinted Polymer Nanoparticles by High Performance Liquid Chromatography as an Efficient Technique for Sensitive and Selective Trace Determination of 4-Chloro-2-Methylphenoxy Acetic Acid in Complex Matrices. AB - BACKGROUND: 4-chloro-2-methylphenoxy acetic acid (MCPA) is one of the most important pesticides which is extensively used to control weeds in arable farmland. Exposure to this compound occurs in general population and persons who occupationally handle it. The aim of this present work was the preparation of MCPA imprinting polymer and its application as a selective sample preparation technique for trace determination of MCPA in biological and environmental samples. METHODS: In this study, MCPA imprinting polymer was obtained by precipitation polymerization using methacrylic acid (the functional monomer), ethylene glycol dimethacrylate (the cross-linker), 2, 2'-azobisisobutyronitrile (the initiator) and MCPA (the template molecule) in acetonitrile solution. The MIP-NPs were characterized by thermogravimetric analysis and scanning electron microscopy. The optimization process was carried out applying batch method. After optimization of the parameters, affecting the adsorption and desorption of analyte, urine and different water samples were used to determine MCPA. RESULTS: Imprinted MCPA molecules were removed from the polymeric structure using acetic acid in methanol (20:80 v/v %) as the eluting solvent. Both sorption and desorption process occur within 10 min. The maximum sorbent capacity of the molecular imprinted polymer is 87.4 mg g-1. The relative standard deviation and limit of detection for water samples by introduced selective solid phase extraction were 4.8% and 0.9 MUg L-1, and these data for urine samples were 4.5% and 1.60 MUg L-1, respectively. CONCLUSION: The developed method was successfully applied to determine MCPA in urine and different water samples. PMID- 26060767 TI - Effects of Aerobic Exercise on Serum Retinol Binding Protein4, Insulin Resistance and Blood Lipids in Obese Women. AB - BACKGROUND: Retinol binding protein4 (RBP4) is a type of adipokine which transports vitamin A to serum. RBP4 could be a bridge between obesity and insulin resistance. This study aimed to investigate the effects of aerobic exercises on RBP4 serum's concentration and metabolic syndrome risk factors in obese women. METHODS: Twenty obese women with body max index 35.81+/-3.67Kg/m2, fat percentage 43.98+/-4.02, and waist to hip ratio 1.03+/-0.05 were included and were randomly assigned to experimental and control groups. The experimental group received aerobic exercises for a period of 12 weeks each three sessions on treadmill workout. The treadmill speed were based on a 60-65 and 80-85 maximal heart rate percentage and duration of 15-20 and 45-50 minutes, at the beginning and the end of exercise, respectively. Body composition, serum glucose, insulin, TG, LDL-C, HDL-C, total cholesterol, and RBP4, were measured in both groups before and after the treatment by ELISA method. Insulin resistance was measured by HOMA-IR. To compare within group differences and between group comparisons t-correlated and t independent tests were used, respectively. RESULTS: After 12 week aerobic exercises; weight, fat percentage, WHR, and BMI in the experimental group was significantly decreased (P<0.05). RBP4, insulin, insulin resistance, TG and HDL-C had significant differences between two groups. The cholesterol level, LDL-C and glucose did not have any significant changes. CONCLUSION: The aerobic exercises can decrease body composition, insulin resistance, TG, and RBP4, so it can be beneficial for obese women's health, because it. PMID- 26060768 TI - Cancer Risk Assessment in Welder's Under Different Exposure Scenarios. AB - BACKGROUND: Welders exposure to nickel and hexavalent chromium in welding fumes is associated with increase of cancer risk in welders. In this study we calculated cancer risk due to exposure to these compounds in welders. METHODS: The role of exposure parameters in welders on derived incremental lifetime cancer risk were determined by stochastic modeling of cancer risk. Input parameters were determined by field investigation in Iranian welders in 2013 and literature review. RESULTS: The 90% upper band cancer risk due to hexavalent chromium and nickel exposure was in the range of 6.03E-03 to 2.12E-02 and 7.18E-03 to 2.61E-02 respectively. Scenario analysis showed that asthmatic and project welders are significantly at higher cancer risk in comparison with other welders (P<0.05). Shift duration was responsible for 37% and 33% of variances for hexavalent chromium and nickel respectively. CONCLUSIONS: Welders are at high and unacceptable risk of cancer. Control measures according to scenario analysis findings are advisable. PMID- 26060769 TI - Assessment of Drinking Water Quality from Bottled Water Coolers. AB - BACKGROUND: Drinking water quality can be deteriorated by microbial and toxic chemicals during transport, storage and handling before using by the consumer. This study was conducted to evaluate the microbial and physicochemical quality of drinking water from bottled water coolers. METHODS: A total of 64 water samples, over a 5-month period in 2012-2013, were collected from free standing bottled water coolers and water taps in Isfahan. Water samples were analyzed for heterotrophic plate count (HPC), temperature, pH, residual chlorine, turbidity, electrical conductivity (EC) and total organic carbon (TOC). Identification of predominant bacteria was also performed by sequence analysis of 16S rDNA. RESULTS: The mean HPC of water coolers was determined at 38864 CFU/ml which exceeded the acceptable level for drinking water in 62% of analyzed samples. The HPC from the water coolers was also found to be significantly (P < 0.05) higher than that of the tap waters. The statistical analysis showed no significant difference between the values of pH, EC, turbidity and TOC in water coolers and tap waters. According to sequence analysis eleven species of bacteria were identified. CONCLUSION: A high HPC is indicative of microbial water quality deterioration in water coolers. The presence of some opportunistic pathogens in water coolers, furthermore, is a concern from a public health point of view. The results highlight the importance of a periodic disinfection procedure and monitoring system for water coolers in order to keep the level of microbial contamination under control. PMID- 26060770 TI - Tuberculosis Treatment Non-Adherence and Lost to Follow Up among TB Patients with or without HIV in Developing Countries: A Systematic Review. AB - This systematic review intended to combine factors associated with tuberculosis treatment non-adherence and lost to follow up among TB patients with/without HIV in developing countries. Comprehensive remote electronic databases (MEDLINE, (PMC, Pub Med Central), Google scholar and Web of science) search was conducted using the following keywords: Tuberculosis, treatment, compliance, adherence, default, behavioural factors and socioeconomic factors. All types of studies intended to assess TB treatment non-adherence and lost to follow up in developing countries among adult TB patient from 2008 to data extraction date were included. Twenty-six original and one-reviewed articles, which meet inclusion criteria, were reviewed. TB treatment non-adherence and lost to follow up were continued across developing countries. The main factors associated with TB treatment non adherence and lost to follow up were socioeconomic factors: lack of transportation cost, lack of social support, and patients-health care worker poor communication. Behavioural factors were Feeling better after few weeks of treatments, tobacco and alcohol use, knowledge deficit about duration of treatment and consequences of non-adherence and lost to follow up. TB treatment non-adherence and lost to follow up were continued across developing countries throughout the publication years of reviewed articles. Numerous, socioeconomic and behavioural factors were influencing TB treatment adherence and lost to follow up. Therefore, well understanding and minimizing of the effect of these associated factors is very important to enhance treatment adherence and follow up completion in developing countries. PMID- 26060771 TI - Unintended Pregnancy and Its Adverse Social and Economic Consequences on Health System: A Narrative Review Article. AB - Unintended pregnancy is among the most troubling public health problems and a major reproductive health issue worldwide imposing appreciable socioeconomic burden on individuals and society. Governments generally plan to control growth of births (especially wanted births as well as orphans and illegitimate births) imposing extra burden on public funding of the governments which inevitably affects economic efficiency and leads to economic slowdown, too. The present narrative review focuses on socioeconomic impacts of unintended pregnancy from the health system perspective. Follow of Computerized searches of Academic, 53 scientific journals were found in various databases including PubMed, EMBASE, ISI, Iranian databases, IPPE, UNFPA (1985-2013). Original articles, review articles, published books about the purpose of the paper were used. During this search, 20 studies were found which met the inclusion criteria. Unintended pregnancy is one of the most critical challenges facing the public health system that imposes substantial financial and social costs on society. On the other hand, affecting fertility indicators, it causes reduced quality of life and workforce efficiency. Therefore lowering the incidence of intended pregnancies correlates with elevating economic growth, socio-economic development and promoting public health. Regarding recent policy changes in Iran on family planning programs and adopting a new approach in increasing population may place the country at a higher risk of increasing the rate of unintended pregnancy. Hence, all governmental plans and initiatives of public policy must be regulated intelligently and logically aiming to make saving in public spending and reduce healthcare cost inflation. PMID- 26060772 TI - Achieving a Spiritual Therapy Standard for Drug Dependency in Malaysia, from an Islamic Perspective: Brief Review Article. AB - Religion is one of the protective factors that facilities positive outcomes by preventing individuals from engaging in addictive substance. A recent study has confirmed that religion inhibits drug addiction. The concept of psychospiritual therapy was to introduce drug addiction. Therefore, of the various methods of psychotherapy, the usage of Taqwa (piety) emerged as an applicable method of Islamic spiritual therapy. This study was conducted in Malaysia as a Muslim country and focuses on Islamic recommendations and its relation to spiritual therapy. PMID- 26060773 TI - The Effects of Unemployment Rate on Health Status of Chinese People. AB - BACKGROUND: The aim of the study was to estimate the short-run and long-run effects of unemployment rate on health outcomes of Chinese population, which is under studied before. METHODS: The Chinese aggregate data was analyzed (provincial data from 1990-2011). The fixed effect model and infinite distributed lag model (IDL) were applied to analyze the data. It aimed to estimate the short run and long-run association between unemployment rate and health status of population in China. The mortality was applied as an indicator for health outcomes of entire population. RESULTS: In the short run, when the unemployment rate was decreased by 1%, mortality will be reduced by approximately 4 % (P<0.01). In the long-run, mortality will be increased by 6.8% with increased unemployment rate of 1% (P <0.05). CONCLUSION: The result in China demonstrated that the unemployment rate was positively associated with mortality. The result also showed that the increased unemployment rate has been harmful to health outcomes of population. It will be significant to reduce the unemployment rate for improving potential public health benefits in developing countries like China. PMID- 26060774 TI - Secular Trends in Overweight and Obesity among Urban Children in Guangzhou China, 2007-2011. AB - BACKGROUND: No studies have been reported on children obesity prevalence of Guangzhou, one of the most urbanized areas in China. This study tracks the secular trends of obesity prevalence of children. METHODS: The data were derived from the surveys on students' constitution and health carried out by government. Randomly, 3832 students in 2007, 13141 in 2008, 14052 in 2009, 13750 in 2010, and 15225 in 2011, aged 7-12 years, from urban primary school were examined. Anthropometric parameters were measured in all students. RESULTS: The mean of body mass index increased significantly from 16.6 in 2008 to 16.8 in 2011 in the total group of children, and the total prevalence of overweight and obesity increased from 9.4 and 6.2 to 10.5 and 7.5 from 2007 to 2011, respectively. The minimum value of the mean body mass index and the overweight and obesity prevalence in the total age group all appeared in 2008. The prevalence of overweight and obesity in males was significantly higher than that in females in each year among the 5 years. CONCLUSION: Although the prevalence of children obesity in Guangzhou in 2011 is still lower than the average values of Chinese large coastal cities, a significant increase was found in their prevalence from 2007 to 2011 and the total obesity prevalence of children is even higher than that of adolescent. Furthermore, we found that the minimum value of overweight and obesity prevalence of the total group and almost all gender-specific age groups appeared in 2008. PMID- 26060775 TI - Loneliness in Elderly People, Associated Factors and Its Correlation with Quality of Life: A Field Study from Western Turkey. AB - BACKGROUND: This study examined the factors that affect loneliness of older people and their relationship with quality of life. METHODS: Data in this cross sectional study were collected through survey form, UCLA Loneliness Scale and Quality of Life (QOL) Short Form (SF-36) Scale. The total number of elderly people over the age of 65 yr from whom the study population was chosen was 4,170. The study population was determined as 190 with G-power program by taking impact size 0.362, alpha=0.05, power (1-beta) =0.80 at a confidence level of 95% and a substitute group composing of 10 individuals was added. In total, 83.2% (n=174) of the target population was reached via Multi-Stage Sampling Methods. RESULTS: UCLA Loneliness median score of the participants was 33 (25(th)p= 27, 75(th)p= 40). It was found that the existence of chronic diseases and physical handicaps, regular use of medication, lack of hobbies and living with spouse increased loneliness (P<0.05). A negative relationship was identified between all sub scales in the QOL scale and loneliness. CONCLUSION: Loneliness negatively affects QOL in old age and that the existence of chronic health problems and lack of hobbies are strong predictors for loneliness. Elderly people living alone must be evaluated as a high-risk group and thus policy makers and health personnel should be aware of the factors that can affect loneliness. In order to increase life quality of the aged population and psychological well-being of the elderly, social support systems must be taken into account and the elderly should be encouraged to participate in social activities. PMID- 26060776 TI - Epidemiological Feature of Visceral Leishmaniasis in China, 2004-2012. AB - BACKGROUND: Visceral leishmaniasis (VL) remains an important public health problem in China. It is essential to elucidate the current epidemiological characteristics of VL for designing control policy. METHODS: The data were obtained from China Disease Prevention and Control Information System from 2004 to 2012. Characteristics by major variables, such as age, gender, season and geography were analyzed using SPSS13.0. RESULTS: The incidence of VL in China remained at a lower level in recent years. The outbreak appeared in xinjiang kashgar region in 2008. A total of 3337 VL cases were reported in China from 2004 to 2012, 97.03% of cases were concentrated in Xinjiang, Gansu and Sichuan provinces. The cases under 5 year-old accounted for 59.21%. concentrated in 3 ~ 5 months each year and annual December to January of next year The ratio of males to females was 1.67:1(2088:1249). The lag time between symptom onset and diagnosis of VL appeared a marked decrease after 2008, and were shorter in endemic provinces of Xinjiang, Gansu and Sichuan than non-endemic provinces. The case fatality rate was 2.99% (10/3337) during the study period. CONCLUSION: The reported cases of VL were concentrated in Xinjiang, Gansu, Sichuan provinces in China, 2004-2012. The onset was given priority to children. The lag time between symptom onset and diagnosis of VL were difference among years and provinces. Therefore, prevention and control measures should be focused on improving awareness and capacities of diagnosis and treatment, targeting high-risk people in high-risk areas. PMID- 26060778 TI - Impacts of Social Network on Therapeutic Community Participation: A Follow-up Survey of Data Gathered after Ya'an Earthquake. AB - BACKGROUND: In recent years, natural disasters and the accompanying health risks have become more frequent, and rehabilitation work has become an important part of government performance. On one hand, social networks play an important role in participants' therapeutic community participation and physical & mental recovery. On the other hand, therapeutic communities with widespread participation can also contribute to community recovery after disaster. METHODS: This paper described a field study in an earthquake-stricken area of Ya'an. A set of 3-stage follow-up data was obtained concerning with the villagers' participation in therapeutic community, social network status, demographic background, and other factors. The Hierarchical linear Model (HLM) method was used to investigate the determinants of social network on therapeutic community participation. RESULTS: First, social networks have significantly impacts on the annual changes of therapeutic community participation. Second, there were obvious differences in education between groups mobilized by the self-organization and local government. However, they all exerted the mobilization force through the acquaintance networks. Third, local cadre networks of villagers could negatively influence the activities of self-organized therapeutic community, while with positively influence in government-organized therapeutic activities. CONCLUSION: This paper suggests that relevant government departments need to focus more on the reconstruction and cultivation of villagers' social network and social capital in the process of post-disaster recovery. These findings contribute to better understandings of how social networks influence therapeutic community participation, and what role local government can play in post-disaster recovery and public health improvement after natural disasters. PMID- 26060777 TI - Effects of Family Meal Frequency on Risk Factors for Cardiovascular Disease in Korean Elderly Males and Females. AB - BACKGROUND: In the case of the elderly who highly depend on family, serious health problems can be caused due to the reduction of family meals. Therefore, this study aims to suggest the fundamental data for management of cardiovascular disease, one of the major causes of death in elderly Koreans, by investigating the effects of family meal frequency on the risk factors for cardiovascular disease in Korean elderly males and females. METHODS: The raw data of the Fifth Korea National Health and Nutrition Examination Survey (KNHANES III) were utilized. Data of 1,236 respondents were extracted for analysis regarding anthropometry, blood, blood pressure, nutrients and total energy intake. For collected data, using SPSS 18.0 and Amos 18.0, the mean and standard deviation, and the path coefficient between groups through a multi-group analysis by structural equation model were checked. RESULTS: As family meal frequency increased, triglyceride and fasting blood glucose in Korean elderly males were likely to decrease, which led to conflicting results with those of Korean elderly females. CONCLUSION: Frequent family meal makes a positive effect on reducing several risk factors for cardiovascular disease in Korean elderly. PMID- 26060779 TI - Informal Payments for Health Care in Iran: Results of a Qualitative Study. AB - BACKGROUND: Informal payments to health care providers have been reported in many African, Asian and European countries. This study aimed to investigate different aspects of these payments that are also known as under-the-table payments in Iran. METHODS: This is an in-depth interview-based qualitative study conducted on 12 purposively chosen clinical specialists. The interviewees answered 9 questions including the ones about, definitions of informal payments, the specialties and hospitals mostly involved with the problem, how they are paid, factors involved, motivation of patients for the payments, impact of the payments on the health care system and physician-patient relationship and the ways to face up with the problem. The findings of the study were analyzed using qualitative content analysis method. RESULTS: Six topics were extracted from the interviews including definitions, commonness, varieties, motivations, outcomes and preventive measures. It was revealed that under-the-table payments are the money taken (either in private or public portions) from patients in addition to what formally is determined. This problem is mostly seen in surgical services and the most important reason for it is unrealistic tariffs. CONCLUSION: Regarding the soaring commonness of informal payments rooted in underpayments of health expenditures in some specialties, which deeply affect the poor, the government has to boost the capitation and to invest on health sectors through supporting the health insurance companies and actualizing the health care costs in accord with the real price of the health care delivered. PMID- 26060780 TI - High-Level Expression of Immunogenic Recombinant Plasmodium vivax Merozoite Surface Protein (Pvmsp-142 kDa) in pGEX 6P1 Vector. AB - BACKGROUND: Detection of Plasmodium vivax specific antibodies with serological tests could be a valuable tool for epidemiological researches. Whereas P. vivax cannot be simply obtained in vitro, serological tests using total or semi purified antigens are infrequently used. Given this restriction, the present study investigated whether recombinant P. vivax merozoite surface protein 1 (PvMSP-1 42 kDa) could be useful in detection of antibodies from the serums of a P. vivax infected person using serological tests. METHODS: Parasite DNA was extracted from blood sample of an Iranian P. vivax-infected patient. The region of PvMSP-142 kDa was amplified by PCR then cloned into pTZ57R/T vector and sequenced. The insert was sub cloned into pGEX 6P1 expression vector. Afterwards, it was transformed into E. coli BL21 and cultured massively. Sub cloning of gene was confirmed by PCR and enzyme digestion and sequencing finally. Production of recombinant protein was confirmed by SDS-PAGE. Western blot was performed by human sera to appraisal binding ability to the IgG antibodies of P. vivax infected patients. Recombinant protein was purified and estimated by Bradford assay. RESULTS: The specialty values of the Western blot determined with 10 sera from naturally infected individuals, 10 sera from healthy individuals and 7 sera from individuals with other infectious diseases. CONCLUSION: For the Iranian population, using a Western blot assay for MSP-142 recombinant protein can be used as the foundation for promotion of serological assay for the detection of P. vivax malaria such as ELISA. PMID- 26060781 TI - Factors that Contribute in the First Hookah Smoking Trial by Women: A Qualitative Study from Iran. AB - BACKGROUND: Hookah smoking is growing in popularity especially among women but little is known about the determinants influencing on hookah smoking initiation. In order to address this emerging health risk, a qualitative study was conducted to explore the factors that contribute in the first hookah smoking trial by women. METHODS: This qualitative study was conducted during 2012 to 2013 in Tehran, Iran. Participants were recruited to represent diversity in smoking status, ethnicity, age groups and residence. Data was collected through in-depth individual interviews and was analyzed through content analysis. RESULTS: Four main themes were identified from the qualitative data including: Positive attitude toward hookah smoking; Social and family facilitators; Psychosocial needs and gaps and Sensory characteristic of hookah. CONCLUSION: From this study, a variety of factors which contribute to the initiation of hookah smoking among women have been identified. Since one of the major causes of increased hookah smoking may be its ordinary use, all factors causing the ordinary use should be eliminated, and efforts should be made in opposition to hookah smoking promotions. PMID- 26060782 TI - Key Aspects of Providing Healthcare Services in Disaster Response Stage. AB - BACKGROUND: Health care management in disasters is one of the main parts of disaster management. Health in disasters is affected by performance of various sectors, and has an interactive impact on various aspects of disaster management. The aim of this study was to identify the most important themes affecting the healthcare management in disaster. METHOD: In this qualitative study with a content analysis approach, in-depth interviews in two steps with 30 disaster experts and managers were conducted to collect the data. RESULTS: Eleven themes affecting healthcare management in disasters were identified. These themes were related to human resources management, resources management, victims' management transfer, environmental hygiene monitoring, nutrition management, mental health control, inter-agency coordination, training, technology management, information and communication management, and budget management. CONCLUSION: Providing effective health care service in disasters requires a comprehensive look at the various aspects of disaster management. Effective factors on the success of healthcare in disaster are not limited to the scope of healthcare. There should be a close relationship and interaction between different sectors of disaster management. PMID- 26060783 TI - The Social Determinants of Health in Association with Women's Health Status of Reproductive Age: A Population-Based Study. AB - BACKGROUND: Prioritizing women's health helps achievement of the 4(th) and 5(th) goals of Millennium Development Program. This study aimed to investigate association between social determinants of health and women's health of reproductive age. METHODS: This population-based cross-sectional study, using multi-stage sampling procedure was conducted on 770, 15 to 49-year-old women residing in any one of the 22 municipality zones across Tehran, Iran. Eligible women were interviewed at home with SF-36 (Short Form Health Survey) and socio demographic questionnaires. Social determinants of health contains; ethnicity, education, job, income, and crowding index. Data were analyzed by ANOVA and Multiple Linear Regression using SPSS-16. The threshold of P.V was considered 0.05. RESULTS: Overall, 770 women with mean age 33.9+/-9.3 years were interviewed. Majority of them were married (72.27%), housewives (62.2%), of Persian ethnicity (64.3%), and educated to high school level (43.8%). Age with dimensions of health except role emotional, mental health, and social functioning had significant association with B from -0.65 to -0.16.educational level with dimensions of health except role emotional andsocial functioning had significant association with B from 3.61 to 6.43 (P<0.05). Income with dimensions of health except role physical had significant association with B from -9.97 to -4.42. CONCLUSION: Reflection of unfavorable economic conditions and low education level on negative women' health experiences are alarming. Interaction between social determinants of health and health status must be considered in policymaking, and there is a need for policies that would enhance health of women in the low education and income brackets. PMID- 26060784 TI - Unusual Presentation of Interventricular Hydatid Cyst: A Case Report. AB - Echinococcus infection typically affects liver and lungs while rarely occur through heart. Cardiac hydatidosis can be fatal or lead to major complications if it is not treated. The majority of patients with cardiac hydatid cysts complain from cardiac problems as their first presentation. However, this article reports an unusual case suffers from an interventricular hydatid cyst presented by abdominal pain on 2013. After the patient transferred to Tehran Heart Center, surgical cyst excision with removing germinal layer and concurrent albendazole therapy was prescribed for the management of this Iranian 15 year old female. PMID- 26060785 TI - The Trends of Puberty Onset among Chinese Children. PMID- 26060786 TI - A Secondary Analysis of Maternal Factors Determining Low Birth Weight in Pakistan. PMID- 26060787 TI - Ascorbic Acid Content of Rose Hip Fruit Depending on Altitude. PMID- 26060788 TI - A Co-relational Study of Community Midwife and Maternal Health Care System: A Questionnaire Survey in Rural Areas of Pakistan. PMID- 26060789 TI - Antioxidant Activity of Plantago Species in Vegetative and Flowering Stages. PMID- 26060790 TI - Prospects for Delivering and Managing Curative Health Services in North Darfur State, Sudan. PMID- 26060791 TI - Correlations between Stress, Anxiety and Coping Mechanisms in Orthodontic Patients. PMID- 26060792 TI - Who Is a Good Doctor? Patients & Physicians' Perspectives. PMID- 26060794 TI - A Comparative Analysis on the Trend of Submitted Manuscripts to "Iranian Journal of Public Health" During 2012-2014. PMID- 26060793 TI - Cardiotonic Drugs from the Avicenna's Point of View. PMID- 26060795 TI - Endovascular Therapy: A Standard Treatment? PMID- 26060796 TI - Evolving Concept of Small Vessel Disease through Advanced Brain Imaging. AB - Imaging plays a crucial role in studying and understanding cerebral small vessel disease. Several important findings have emerged from recent applications of advanced brain imaging methods. In patients with acute lacunar syndromes, diffusionweighted MRI studies have shown that the diagnostic precision of using clinical features alone or combined with CT scan findings to diagnose small vessel disease as the underlying cause is poor. Followup imaging studies on patients with acute infarcts related to small vessel disease have shown that the infarct may cavitate, merge into white matter disease abnormalities, or become invisible with time. High resolution MRI may demonstrate intracranial atherosclerosis in larger arteries (that may block orifices of penetrating arteries and cause small deep infarcts), but abnormalities in single penetrating arteries cannot as yet be consistently and reliably visualized for use in clinical practice. The epidemiology and risk factors of silent cerebral infarcts have been further delineated. Patterns of new incident silent infarcts appear related to existing white matter disease, suggesting similarities in pathophysiology. Silent deep infarcts causes local cortical atrophy, and can affect connectivity in the brain. Studies on cerebral microbleeds have shown consistent patterns in their effects on prognosis for a large number of outcomes, but the implications of cerebral microbleeds for treatment decisions remain to be established. Cortical microinfarcts represent the latest addition to the spectrum of small vessel disease in the brain, and appears as the most prevalent SVD entity. An important consensus document on neuroimaging standards for small vessel disease has been recently published. PMID- 26060797 TI - Prognostic Impact of Cerebral Small Vessel Disease on Stroke Outcome. AB - Cerebral small vessel disease (SVD), which includes white matter hyperintensities (WMHs), silent brain infarction (SBI), and cerebral microbleeds (CMBs), develops in a conjunction of cumulated injuries to cerebral microvascular beds, increased permeability of blood-brain barriers, and chronic oligemia. SVD is easily detected by routine neuroimaging modalities such as brain computed tomography or magnetic resonance imaging. Research has revealed that the presence of SVD markers may increase the risk of future vascular events as well as deteriorate functional recovery and neurocognitive trajectories after stroke, and such an association could also be applied to hemorrhagic stroke survivors. Currently, the specific mechanistic processes leading to the development and manifestation of SVD risk factors are unknown, and further studies with novel methodological tools are warranted. In this review, recent studies regarding the prognostic impact of WMHs, SBI, and CMBs on stroke survivors and briefly summarize the pathophysiological concepts underlying the manifestation of cerebral SVD. PMID- 26060799 TI - Endovascular Mechanical Thrombectomy for Acute Ischemic Stroke: A New Standard of Care. AB - The treatment of acute ischemic stroke (AIS) in the setting of intracranial large artery occlusion (LAO) with intravenous tissue plasminogen activator (IV-tPA) is associated with low rates of recanalization and high rates of neurological morbidity and functional dependence. Endovascular intervention, particularly mechanical thrombectomy, is a promising therapeutic adjunct to IV-tPA for the treatment of acute LAO. However, until recently, its efficacy has been controversial. In this brief review, we analyze the criticisms of three negative randomized controlled trials (RCT) of endovascular stroke treatment and evaluate the results from seven positive endovascular stroke RCTs that have recently been presented or published. IMS III, MR RESCUE, and SYTHESIS Expansion were three RCTs that failed to show a benefit from endovascular stroke therapy. Major criticisms of these studies included a lack of routine screening for LAO, resulting in the selection of AIS patients without LAO for endovascular intervention, and a low utilization rate of modern endovascular thrombectomy devices, leading to substandard rates of successful recanalization. MR CLEAN was the first phase III RCT to show a significant clinical benefit from endovascular stroke therapy. The dissemination of its findings elicited a cascade of positive results from, to date, six additional endovascular stroke RCTs, ESCAPE, EXTEND IA, SWIFT PRIME, REVASCAT, THERAPY, and THRACE, which were halted prematurely for efficacy. The cumulative evidence from these studies shows an overwhelming benefit from the endovascular treatment of acute LAO, therefore effectively establishing a new standard of care for the management of AIS. PMID- 26060798 TI - Prevention and Management of Cerebral Small Vessel Disease. AB - Lacunar infarcts/lacunes, white matter hyperintensities (WMH), and cerebral microbleeds (CMBs) are considered various manifestations of cerebral small vessel disease (SVD). Since the exact mechanisms of these manifestations differ, their associated risk factors differ. High blood pressure is the most consistent risk factor for all of these manifestations. However, a "J curve" phenomenon in terms of blood pressure probably exists for WMH. The association between cholesterol levels and lacunar infarcts/lacunes or WMH was less consistent and sometimes conflicting; a low cholesterol level probably increases the risk of CMBs. Homocysteinemia appears to be associated with WMH. It is noteworthy that the risk factors profile may also differ between different lacunar patterns and CMBs located at different parts of the brain. Thrombolysis, antihypertensives, and statins are used to treat patients with symptomatic lacunar infarction, just as in those with other stroke subtypes. However, it should be remembered that bleeding risks increase in patients with extensive WMH and CMBs after thrombolysis therapy. According to the Secondary Prevention of Small Subcortical Strokes trial results, a blood pressure reduction to <130 mmHg is recommended in patients with symptomatic lacunar infarction. However, an excessive blood pressure decrease may induce cognitive decline in older patients with extensive WMH. Dual antiplatelet therapy (aspirin plus clopidogrel) should be avoided because of the excessive risk of intracerebral hemorrhage. Although no particular antiplatelet is recommended, drugs such as cilostazol or triflusal may have advantages for patients with SVD since they are associated with less frequent bleeding complications than aspirin. PMID- 26060800 TI - Evolution of Endovascular Therapy in Acute Stroke: Implications of Device Development. AB - Intravenous thrombolysis is an effective treatment for acute ischaemic stroke. However, vascular recanalization rates remain poor especially in the setting of large artery occlusion. On the other hand, endovascular intra-arterial therapy addresses this issue with superior recanalization rates compared with intravenous thrombolysis. Although previous randomized controlled studies of intra-arterial therapy failed to demonstrate superiority, the failings may be attributed to a combination of inferior intra-arterial devices and suboptimal selection criteria. The recent results of several randomized controlled trials have demonstrated significantly improved outcomes, underpinning the advantage of newer intra arterial devices and superior recanalization rates, leading to renewed interest in establishing intra-arterial therapy as the gold standard for acute ischaemic stroke. The aim of this review is to outline the history and development of different intra-arterial devices and future directions in research. PMID- 26060801 TI - Association between Beta Adrenergic Receptor Polymorphism and Ischemic Stroke: A Meta-Analysis. AB - BACKGROUND AND PURPOSE: The purpose of this meta-analysis was to determine the precise association between beta-2 adrenergic receptor (beta2AR) polymorphism and Ischemic stroke. METHODS: Published case control studies on association between beta2AR and ischemic stroke were searched from electronic databases. Pooled Odds ratio and 95% Confidence interval were calculated by using software RevMan version 5.2. RESULTS: A total of three studies involving 1,642 cases and 1,673 controls, which were published from 2007 to 2014, were subjected to meta-analysis for allelic association and 518 cases and 510 controls for genotypic association. Pooled analysis of two studies for genotypic association suggested that subjects carrying Gln27Glu polymorphism of beta2AR had an increased risk for Ischemic stroke under recessive model (OR 2.09; 95% CI; 1.20 to 3.64) and under dominant model (OR 1.47; 95% CI 1.14 to 1.90). Pooled analysis of three studies for allelic association showed a significantly higher Glu27 allele of beta2AR in the patients with ischemic stroke (OR 1.58; 95% CI; 1.38 to 1.81). CONCLUSIONS: The present meta-analysis suggests that Gln27Glu polymorphism of beta2AR gene is associated with increased risk for ischemic stroke. PMID- 26060803 TI - Factors Associated with Early Hospital Arrival in Patients with Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Factors associated with early arrival may vary according to the characteristics of the hospital. We investigated the factors associated with early hospital arrival in two different stroke centers located in Korea and Japan. METHODS: Consecutive patients with ischemic stroke arrived hospital within 48 hours of onset between January 2011 and December 2012 were identified and the clinical and time variables were retrieved from the prospective stroke registries of Severance Hospital of Yonsei University Health System (YUHS; Seoul, Korea) and National Cerebral and Cardiovascular Center (NCVC; Osaka, Japan). Subjects were dichotomized into early (time from onset to arrival <=4.5 hours) and late (>4.5 hours) arrival groups. Univariate and multivariate analyses were performed to evaluate factors associated with early hospital arrival. RESULTS: A total of 1,966 subjects (992 from YUHS; 974 from NCVC) were included in this study. The median time from onset to arrival was 6.1 hours [interquartile range, 1.7-17.8 hours]. In multivariate analysis, the factors associated with early arrival were atrial fibrillation (Odds ratio [OR], 1.505; 95% confidence interval [CI], [1.168 1.939]), higher initial National Institute of Health Stroke Scale scores (OR, 1.037; 95% CI [1.023-1.051]), onset during daytime (OR, 2.799; 95% CI [2.173 3.605]), and transport by an emergency medical service (OR, 2.127; 95% CI [1.700 2.661]). These factors were consistently associated with early arrival in both hospitals. CONCLUSIONS: Despite differences between the hospitals, there were common factors related to early arrival. Efforts to identify and modify these factors may promote early hospital arrival and improve stroke outcome. PMID- 26060802 TI - A Functional Perspective on the Embryology and Anatomy of the Cerebral Blood Supply. AB - The anatomy of the arterial system supplying blood to the brain can influence the development of arterial disease such as aneurysms, dolichoectasia and atherosclerosis. As the arteries supplying blood to the brain develop during embryogenesis, variation in their anatomy may occur and this variation may influence the development of arterial disease. Angiogenesis, which occurs mainly by sprouting of parent arteries, is the first stage at which variations can occur. At day 24 of embryological life, the internal carotid artery is the first artery to form and it provides all the blood required by the primitive brain. As the occipital region, brain stem and cerebellum enlarge; the internal carotid supply becomes insufficient, triggering the development of the posterior circulation. At this stage, the posterior circulation consists of a primitive mesh of arterial networks that originate from projection of penetrators from the distal carotid artery and more proximally from carotid-vertebrobasilar anastomoses. These anastomoses regress when the basilar artery and the vertebral arteries become independent from the internal carotid artery, but their persistence is not uncommon in adults (e.g., persistent trigeminal artery). Other common remnants of embryological development include fenestration or duplication (most commonly of the basilar artery), hypoplasia (typically of the posterior communicating artery) or agenesis (typically of the anterior communicating artery). Learning more about the hemodynamic consequence that these variants may have on the brain territories they supply may help understand better the underlying physiopathology of cerebral arterial remodeling and stroke in patients with these variants. PMID- 26060804 TI - Low Plasma Proportion of Omega 3-Polyunsaturated Fatty Acids Predicts Poor Outcome in Acute Non-Cardiogenic Ischemic Stroke Patients. AB - BACKGROUND AND PURPOSE: Alterations in blood fatty acid (FA) composition are associated with cardiovascular diseases. We investigated whether plasma FA composition was related to stroke severity and functional outcome in acute ischemic stroke patients. METHODS: We prospectively enrolled 156 patients with first-episode cerebral infarction, within 7 days of symptom onset. The proportion of FAs was analyzed using gas chromatography, and the summation of the omega-3 polyunsaturated fatty acids (omega3-PUFA), 18:3 omega3 alpha-linolenic acid, 20:3 omega3 eicosatrienoic acid, 20:5 omega3 eicosapentaenoic acid (EPA), and 22:6 omega3 docosahexaenoic acid (DHA) was reported as Sigmaomega3-PUFAs. Stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) score on admission. Poor functional outcome was defined by modified Rankin scale (mRS) >=3 at three months after the index stroke. RESULTS: Lower proportions of EPA (beta=-0.751), DHA (beta=-0.610), and Sigmaomega3-PUFAs (beta= 0.462) were independently associated with higher NIHSS score, after adjusting for stroke subtype, hemoglobin, high density lipoprotein, high sensitivity C-reactive protein, fasting glucose, 16:0 palmitic acid, and Sigmasaturated fatty acids. Moreover, a lower proportion of DHA (odds ratio [OR]: 0.20, 95% confidence interval [CI]: 0.04-0.88), and Sigmaomega3-PUFAs (OR: 0.22, 95% CI: 0.05-0.84) showed an independent relationship with poor functional outcome after adjusting for age, sex, smoking status, NIHSS score, stroke subtype, and 16:0 palmitic acid. CONCLUSIONS: Our results demonstrate that omega3-PUFAs correlated with stroke severity on admission and functional outcomes at 3 months. omega3-PUFAs are potential blood biomarkers for prognosis of acute non-cardiogenic ischemic stroke patients. PMID- 26060805 TI - Smoking is Not a Good Prognostic Factor following First-Ever Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: There is evidence that smoking increases stroke risk; however, the effect of smoking on functional outcome after stroke is unclear. The aim of this study was to explore the effect of smoking status on outcome following acute ischemic stroke. METHODS: We assessed 1,117 patients with first ever acute cerebral infarction and no prestroke disability whose functional outcome was measured after three months. A poor outcome was defined as a modified Rankin Scale score of >=2. Smoking within one month prior to admission was defined as current smoking. Our analysis included demographics, vascular risk factors, initial National Institutes of Health Stroke Scale (NIHSS) score, stroke subtype, onset-to-admission time, thrombolytic therapy, initial blood pressure, and prognostic blood parameters as covariates. RESULTS: At baseline, current smokers were predominantly male, approximately 10 years younger than non-smokers (mean age, 58.6 vs. 68.3 years), and less likely to have hypertension and atrial fibrillation (53.9% vs. 65.4% and 8.7% vs. 25.9%, respectively), with a lower mean NIHSS score (4.6 vs. 5.7). The univariate analyses revealed that current smokers had a better functional outcome and significantly fewer deaths at three months follow-up when compared with non-smokers (functional outcome: 64.0% vs. 58.4%, P=0.082; deaths: 3.0% vs. 8.4%, P=0.001); however, these effects disappeared after adjusting for covariates (P=0.168 and P=0.627, respectively). CONCLUSIONS: In this study, smoking was not associated with a good functional outcome, which does not support the paradoxical benefit of smoking on functional outcome following acute ischemic stroke. PMID- 26060806 TI - Lack of Association of Clinical Factors (SAMe-TT2R2) with CYP2C9/VKORC1 Genotype and Anticoagulation Control Quality. AB - BACKGROUND AND PURPOSE: Advantages of new oral anticoagulations may be greater in atrial fibrillation (AF) patients of poor anticoagulation control with warfarin. The SAMe-TT2R2 scoring system, based on clinical variables, was recently developed to aid in identifying these patients. In this study, we investigated the association of this clinical composite score with genetic factors related warfarin dosing and the quality of anticoagulation control. METHODS: Clinical and genetic data were collected from 380 consecutive Korean patients with AF (CHA2DS2 VASc score, 3.5+/-1.8) who were followed for an average of 4 years. We evaluated factors associated with time in therapeutic range (TTR, INR 2-3), including the CYP2C9 and VKORC1 genotypes and the SAMe-TT2R2 score (Sex female, Age <60 years, Medical history [>two co-morbidities], Treatment [interacting drugs, e.g., amiodarone], Tobacco use within 2 years [doubled], and Race non-white [doubled]). RESULTS: The average SAMe-TT2R2 score was 3.4+/-0.9, range 2-7; and 153 patients (40.2%) had SAMe-TT2R2 scores >=4. Time in specific INR ranges varied depending on the VKORC1 genotype but not with the CYP2C9 genotype or the SAMe-TT2R2 score. TTR was higher in patients with the VKORC1 1173C>T than in VKORC1 TT (61.7+/-16% vs. 56.7+/-17.4%, P=0.031). Multivariate testing showed that VKORC1 genotype but not the SAMe-TT2R2 score was significantly associated with labile INRs. There was no correlation between the SAMe-TT2R2 scores and pharmacogenetic data. CONCLUSIONS: A genetic factor, but none of the common clinical and demographic factors, as combined in the SAMe-TT2R2 score, was associated with the quality of anticoagulation control in Korean patients with AF. PMID- 26060807 TI - A Novel Computerized Clinical Decision Support System for Treating Thrombolysis in Patients with Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Thrombolysis is underused in acute ischemic stroke, mainly due to the reluctance of physicians to treat thrombolysis patients. However, a computerized clinical decision support system can help physicians to develop individualized stroke treatments. METHODS: A consecutive series of 958 patients, hospitalized within 12 hours of ischemic stroke onset from a representative clinical center in Korea, was used to establish a prognostic model. Multivariable logistic regression was used to develop the model for global and safety outcomes. An external validation of developed model was performed using 954 patients data obtained from 5 university hospitals or regional stroke centers. RESULTS: Final global outcome predictors were age; previous modified Rankin scale score; initial National Institutes of Health Stroke Scale (NIHSS) score; previous stroke; diabetes; prior use of antiplatelet treatment, antihypertensive drugs, and statins; lacunae; thrombolysis; onset to treatment time; and systolic blood pressure. Final safety outcome predictors were age, initial NIHSS score, thrombolysis, onset to treatment time, systolic blood pressure, and glucose level. The discriminative ability of the prognostic model showed a C-statistic of 0.89 and 0.84 for the global and safety outcomes, respectively. Internal and external validation showed similar C-statistic results. After updating the model, calibration slopes were corrected from 0.68 to 1.0 and from 0.96 to 1.0 for the global and safety outcome models, respectively. CONCLUSIONS: A novel computerized outcome prediction model for thrombolysis after ischemic stroke was developed using large amounts of clinical information. After external validation and updating, the model's performance was deemed clinically satisfactory. PMID- 26060808 TI - Antithrombotic Management of Patients with Nonvalvular Atrial Fibrillation and Ischemic Stroke or Transient Ischemic Attack: Executive Summary of the Korean Clinical Practice Guidelines for Stroke. AB - Cardioembolic stroke related to nonvalvular atrial fibrillation is associated with a high recurrence rate and high mortality and morbidity. In this population, therefore, optimal anticoagulant therapy is required to prevent the occurrence of second stroke. Oral anticoagulant, warfarin has been traditionally used, but it is greatly limited by its narrow efficacy window, complex pharmacokinetics, and multiple drug interactions, thus requiring frequent blood monitoring. Recently, oral anticoagulants targeted for a specific coagulation component have been newly developed and tested in large clinical trials. Dabigatran, direct thrombin inhibitor, and rivaroxaban, apixaban, and edoxaban, inhibitors of factor Xa harbor great merits of rapid action time, short half-life, stable plasma concentration, and little drug interaction. Recently, large randomized clinical trials and meta-analyses have been published to show the efficacy and safety of the new oral anticoagulants compared with warfarin. Based on the results from recent clinical trials, we revised recommendations to apply optimal anticoagulant therapy in patients with nonvalvular atrial fibrillation and ischemic stroke or transient ischemic attack. PMID- 26060809 TI - Paradoxical Procoagulant Effect of Early Doses of Warfarin: Possible Role of Non Vitamin K Oral Anticoagulant in Patients with Atrial Fibrillation-Related Stroke. PMID- 26060810 TI - Seasonal Variations in Stroke: A Study in a Hospital in North India. PMID- 26060811 TI - microProtein Prediction Program (miP3): A Software for Predicting microProteins and Their Target Transcription Factors. AB - An emerging concept in transcriptional regulation is that a class of truncated transcription factors (TFs), called microProteins (miPs), engages in protein protein interactions with TF complexes and provides feedback controls. A handful of miP examples have been described in the literature but the extent of their prevalence is unclear. Here we present an algorithm that predicts miPs and their target TFs from a sequenced genome. The algorithm is called miP prediction program (miP3), which is implemented in Python. The software will help shed light on the prevalence, biological roles, and evolution of miPs. Moreover, miP3 can be used to predict other types of miP-like proteins that may have evolved from other functional classes such as kinases and receptors. The program is freely available and can be applied to any sequenced genome. PMID- 26060812 TI - Medication adherence in patients with rheumatoid arthritis: the effect of patient education, health literacy, and musculoskeletal ultrasound. AB - BACKGROUND: Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting <1% of the population. Incompletely controlled RA results in fatigue, joint and soft tissue pain, progressive joint damage, reduced quality of life, and increased cardiovascular mortality. Despite an increasing range of disease modifying agents which halt disease progression, poor patient adherence with medication is a significant barrier to management. OBJECTIVE: The goal of this review was to examine the effectiveness of measures to improve patient medication adherence. METHODS: Studies addressing treatment adherence in patients with RA were identified by trawling PsycINFO, Medline, Cochrane, Pubmed, and ProQuest for studies published between January 2000 and October 2014. Articles were independently reviewed to identify relevant studies. RESULTS: Current strategies were of limited efficacy in improving patient adherence with medications used to treat RA. CONCLUSION: Poor medication adherence is a complex issue. Low educational levels and limited health literacy are contributory factors. Psychological models may assist in explaining medication nonadherence. Increasing patient knowledge of their disease seems sensible. Existing educational interventions appear ineffective at improving medication adherence, probably due to an overemphasis on provision of biomedical information. A novel approach to patient education using musculoskeletal ultrasound is proposed. PMID- 26060814 TI - A survey on the computational approaches to identify drug targets in the postgenomic era. AB - Identifying drug targets plays essential roles in designing new drugs and combating diseases. Unfortunately, our current knowledge about drug targets is far from comprehensive. Screening drug targets in the lab is an expensive and time-consuming procedure. In the past decade, the accumulation of various types of omics data makes it possible to develop computational approaches to predict drug targets. In this paper, we make a survey on the recent progress being made on computational methodologies that have been developed to predict drug targets based on different kinds of omics data and drug property data. PMID- 26060813 TI - Regulatory role of small nucleolar RNAs in human diseases. AB - Small nucleolar RNAs (snoRNAs) are appreciable players in gene expression regulation in human cells. The canonical function of box C/D and box H/ACA snoRNAs is posttranscriptional modification of ribosomal RNAs (rRNAs), namely, 2' O-methylation and pseudouridylation, respectively. A series of independent studies demonstrated that snoRNAs, as well as other noncoding RNAs, serve as the source of various short regulatory RNAs. Some snoRNAs and their fragments can also participate in the regulation of alternative splicing and posttranscriptional modification of mRNA. Alterations in snoRNA expression in human cells can affect numerous vital cellular processes. SnoRNA level in human cells, blood serum, and plasma presents a promising target for diagnostics and treatment of human pathologies. Here we discuss the relation between snoRNAs and oncological, neurodegenerative, and viral diseases and also describe changes in snoRNA level in response to artificial stress and some drugs. PMID- 26060815 TI - Diffusion and persistence of multidrug resistant Salmonella Typhimurium strains phage type DT120 in southern Italy. AB - Sixty-two multidrug resistant Salmonella enterica serovar Typhimurium strains isolated from 255 clinical strains collected in Southern Italy in 2006-2008 were characterised for antimicrobial resistance genes, pulsotype, and phage type. Most strains (83.9%) were resistant to ampicillin, chloramphenicol, streptomycin, sulfamethoxazole, and tetracycline (ACSSuT) encoded in 88.5% by the Salmonella genomic island (SGI1) and in 11.5% by the InH-like integron (bla OXA-30-aadA1) and catA1, sul1, and tet(B) genes. STYMXB.0061 (75%) and DT120 (84.6%) were the prevalent pulsotype and phage type identified in these strains, respectively. Five other resistance patterns were found either in single or in a low number of isolates. The pandemic clone DT104 (ACSSuT encoded by SGI1) has been identified in Italy since 1992, while strains DT120 (ACSSuT encoded by SGI1) have never been previously reported in Italy. In Europe, clinical strains DT120 have been reported from sporadic outbreaks linked to the consumption of pork products. However, none of these strains were STYMXB.0061 and SGI1 positive. The prevalent identification and persistence of DT120 isolates would suggest, in Southern Italy, a phage type shifting of the pandemic DT104 clone pulsotype STYMXB.0061. Additionally, these findings raise epidemiological concern about the potential diffusion of these emerging multidrug resistant (SGI linked) DT120 strains. PMID- 26060816 TI - Decreased pulmonary function in school children in Western Japan after exposures to Asian desert dusts and its association with interleukin-8. AB - The objective of the study was to investigate the influence of Asian dust storms (ADS) on pulmonary function of school children and the relationship of this effect with interleukin-8. Morning peak expiratory flow (PEF) was measured daily in 399 children from April to May 2012 and in 384 of these children from March to May 2013. The data were analyzed for an association between ADS events and PEF by linear mixed models. Interleukin-8 transcriptional activity was assessed in THP G8 cells stimulated by airborne particles collected on ADS days. Seven ADS days were identified: April 23 and 24, 2012; March 8 to 10, 2013; and March 19 and 20, 2013. Changes in PEF after ADS exposure were -8.17 L/min (95% confidence interval, -11.40 to -4.93) in 2012 and -1.17 L/min (-4.07 to 1.74) in 2013, and there was a significant difference between 2012 and 2013. Interleukin-8 transcriptional activity was significantly higher in 2012 at 10.6 +/- 2.9-fold compared to 3.7 +/- 0.4 in March 8 to 10, 2013, and 2.3 +/- 0.2 in March 19 and 20, 2013. The influence of ADS events on pulmonary function of children differs with each ADS event and may be related to interleukin-8 production. PMID- 26060817 TI - The ovariectomized rat as a model for studying alveolar bone loss in postmenopausal women. AB - In postmenopausal women, reduced bone mineral density at the hip and spine is associated with an increased risk of tooth loss, possibly due to a loss of alveolar bone. In turn, having fewer natural teeth may lead to compromised food choices resulting in a poor diet that can contribute to chronic disease risk. The tight link between alveolar bone preservation, tooth retention, better nutritional status, and reduced risk of developing a chronic disease begins with the mitigation of postmenopausal bone loss. The ovariectomized rat, a widely used preclinical model for studying postmenopausal bone loss that mimics deterioration of bone tissue in the hip and spine, can also be used to study mineral and structural changes in alveolar bone to develop drug and/or dietary strategies aimed at tooth retention. This review discusses key findings from studies investigating mandible health and alveolar bone in the ovariectomized rat model. Considerations to maximize the benefits of this model are also included. These include the measurement techniques used, the age at ovariectomy, the duration that a rat is studied after ovariectomy and habitual diet consumed. PMID- 26060818 TI - Identification and characterization of Chlamydia abortus isolates from yaks in Qinghai, China. AB - Recently, the yak population has exhibited reproductive disorders, which are considered to be associated with Chlamydia abortus (C. abortus) in Qinghai, China. In this study, a total of 9 aborted fetuses (each from a different herd) and 126 vaginal swab samples from the 9 herds were collected and analyzed. C. abortus DNA was detected from all of the 9 aborted fetuses and 30 of the 126 vaginal swab samples (23.81%) from yak cows in the selected herds. Four C. abortus strains were isolated from embryonated egg yolk sacs inoculated with foetal organ suspensions. The isolated C. abortus strains were further identified, which showed identical restriction profiles with the C. abortus reference strain using AluI restriction enzyme in the RFLP test. Moreover, the isolated C. abortus strains and C. abortus-positive vaginal swab samples were genotyped by multiple loci variable number tandem repeat analysis and all belonged to the genotype 2 group. These findings suggested that C. abortus played a substantial role in yak abortion in Qinghai, China. PMID- 26060819 TI - Redesigning protein cavities as a strategy for increasing affinity in protein protein interaction: interferon- gamma receptor 1 as a model. AB - Combining computational and experimental tools, we present a new strategy for designing high affinity variants of a binding protein. The affinity is increased by mutating residues not at the interface, but at positions lining internal cavities of one of the interacting molecules. Filling the cavities lowers flexibility of the binding protein, possibly reducing entropic penalty of binding. The approach was tested using the interferon-gamma receptor 1 (IFNgammaR1) complex with IFNgamma as a model. Mutations were selected from 52 amino acid positions lining the IFNgammaR1 internal cavities by using a protocol based on FoldX prediction of free energy changes. The final four mutations filling the IFNgammaR1 cavities and potentially improving the affinity to IFNgamma were expressed, purified, and refolded, and their affinity towards IFNgamma was measured by SPR. While individual cavity mutations yielded receptor constructs exhibiting only slight increase of affinity compared to WT, combinations of these mutations with previously characterized variant N96W led to a significant sevenfold increase. The affinity increase in the high affinity receptor variant N96W+V35L is linked to the restriction of its molecular fluctuations in the unbound state. The results demonstrate that mutating cavity residues is a viable strategy for designing protein variants with increased affinity. PMID- 26060820 TI - The effect of nicotine dependence on psychopathology in patients with schizophrenia. AB - INTRODUCTION: Our study aims to determine the prevalence of nicotine dependence and investigate the effect of nicotine dependence on psychopathology among schizophrenia patients. METHODS: A cross-sectional study was carried out in an outpatient psychiatric clinic at a general hospital in Malaysia. 180 recruited subjects were administered the Malay version of Mini International Neuropsychiatric Interview (MINI), the Positive and Negative Symptom Scale (PANSS), and the Malay version of Fagerstrom Test for Nicotine Dependence (FTND M) questionnaires. RESULTS: The prevalence of nicotine dependence among the subjects was 38.1% (n = 69) and they were mainly composed of male gender, Malay ethnicity, being treated with atypical antipsychotics, and taking other illicit drugs or alcohol. Subjects with severe nicotine dependence scored less in the negative subscale of PANSS compared with the nonsmokers (P = 0.011). On performing the hierarchy multiple regressions, dependence status still significantly predicted negative scores after adjusting the confounders (t = 2.87, P = 0.005). CONCLUSION: The rate of nicotine use disorder among schizophrenia patients in this study is higher than that of the general population in Malaysia. The significant association between nicotine dependence and negative psychopathology symptoms will help the healthcare practitioners in their management of nicotine dependence among schizophrenia patients. PMID- 26060822 TI - Need for scientific rigor in the evaluation of minimally invasive alternative procedures. PMID- 26060821 TI - Rebamipide improves chronic inflammation in the lesser curvature of the corpus after Helicobacter pylori eradication: a multicenter study. AB - Background and Aim. Although many epidemiologic studies have shown that Helicobacter pylori eradication has prophylactic effects on gastric cancer, it does not completely eliminate the risk of gastric cancer. We aimed to investigate the changes in histological gastritis in patients receiving rebamipide treatment after H. pylori eradication. Methods. 206 patients who had undergone H. pylori eradication were evaluated. Of these, 169 patients who achieved successful eradication were randomly allocated to 2 groups: the rebamipide group (n = 82) and the untreated group (n = 87). The primary endpoints were histopathological findings according to the updated Sydney system at the start of the study and after 1 year. Results. Final assessment for histological gastritis was possible in 50 cases from the rebamipide group and 53 cases from the untreated group. The activity and atrophy improved in both the rebamipide and untreated groups, and no significant intergroup differences were observed. Chronic inflammation affecting the lesser curvature of the corpus was significantly improved in the rebamipide group compared to in the untreated group (1.12 +/- 0.08 versus 1.35 +/- 0.08; P = 0.043). Conclusions. Rebamipide treatment after H. pylori eradication alleviated chronic inflammation in the lesser curvature of the corpus compared to that in the untreated group. This trial is registered with UMIN000002369. PMID- 26060823 TI - Timed Bromocriptine-QR Therapy Reduces Progression of Cardiovascular Disease and Dysglycemia in Subjects with Well-Controlled Type 2 Diabetes Mellitus. AB - BACKGROUND: Type 2 diabetes (T2DM) patients, including those in good glycemic control, have an increased risk of cardiovascular disease (CVD). Maintaining good glycemic control may reduce long-term CVD risk. However, other risk factors such as elevated vascular sympathetic tone and/or endothelial dysfunction may be stronger potentiators of CVD. This study evaluated the impact of bromocriptine QR, a sympatholytic dopamine D2 receptor agonist, on progression of metabolic disease and CVD in T2DM subjects in good glycemic control (HbA1c <= 7.0%). METHODS: 1834 subjects (1219 bromocriptine-QR; 615 placebo) with baseline HbA1c <= 7.0% derived from the Cycloset Safety Trial (this trial is registered with ClinicalTrials.gov Identifier: NCT00377676), a 12-month, randomized, multicenter, placebo-controlled, double-blind study in T2DM, were evaluated. Treatment impact upon a prespecified composite CVD endpoint (first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina/congestive heart failure) and the odds of losing glycemic control (HbA1c >7.0% after 52 weeks of therapy) were determined. RESULTS: Bromocriptine-QR reduced the CVD endpoint by 48% (intention-to-treat; HR: 0.52 [0.28-0.98]) and 52% (on-treatment analysis; HR: 0.48 [0.24-0.95]). Bromocriptine-QR also reduced the odds of both losing glycemic control (OR: 0.63 (0.47-0.85), p = 0.002) and requiring treatment intensification to maintain HbA1c <= 7.0% (OR: 0.46 (0.31-0.69), p = 0.0002). CONCLUSIONS: Bromocriptine-QR therapy slowed the progression of CVD and metabolic disease in T2DM subjects in good glycemic control. PMID- 26060824 TI - Euglycemia in Diabetic Rats Leads to Reduced Liver Weight via Increased Autophagy and Apoptosis through Increased AMPK and Caspase-3 and Decreased mTOR Activities. AB - Euglycemia is the ultimate goal in diabetes care to prevent complications. However, the benefits of euglycemia in type 2 diabetes are controversial because near-euglycemic subjects show higher mortality than moderately hyperglycemic subjects. We previously reported that euglycemic-diabetic rats on calorie-control lose a critical liver weight (LW) compared with hyperglycemic rats. Here, we elucidated the molecular mechanisms underlying the loss of LW in euglycemic diabetic rats and identified a potential risk in achieving euglycemia by calorie control. Sprague-Dawley diabetic rats generated by subtotal-pancreatectomy were fed a calorie-controlled diet for 7 weeks to achieve euglycemia using 19 kcal% (19R) or 6 kcal% (6R) protein-containing chow or fed ad libitum (19AL). The diet in both R groups was isocaloric/kg body weight to the sham-operated group (19S). Compared with 19S and hyperglycemic 19AL, both euglycemic R groups showed lower LWs, increased autophagy, and increased AMPK and caspase-3 and decreased mTOR activities. Though degree of insulin deficiency was similar among the diabetic rats, Akt activity was lower, and PTEN activity was higher in both R groups than in 19AL whose signaling patterns were similar to 19S. In conclusion, euglycemia achieved by calorie-control is deleterious in insulin deficiency due to increased autophagy and apoptosis in the liver via AMPK and caspase-3 activation. PMID- 26060826 TI - Clinical and Experimental Immunomodulation 2014. PMID- 26060825 TI - Impact of Bromocriptine-QR Therapy on Glycemic Control and Daily Insulin Requirement in Type 2 Diabetes Mellitus Subjects Whose Dysglycemia Is Poorly Controlled on High-Dose Insulin: A Pilot Study. AB - BACKGROUND: The concurrent use of a postprandial insulin sensitizing agent, such as bromocriptine-QR, a quick release formulation of bromocriptine, a dopamine D2 receptor agonist, may offer a strategy to improve glycemic control and limit/reduce insulin requirement in type 2 diabetes (T2DM) patients on high-dose insulin. This open label pilot study evaluated this potential utility of bromocriptine-QR. METHODS: Ten T2DM subjects on metformin (1-2 gm/day) and high dose (TDID >= 65 U/day) basal-bolus insulin were enrolled to receive once daily (morning) bromocriptine-QR (1.6-4.8 mg/day) for 24 weeks. Subjects with at least one postbaseline HbA1c measurement (N = 8) were analyzed for change from baseline HbA(1c), TDID, and postprandial glucose area under the curve of a four-hour mixed meal tolerance test (MMTT). RESULTS: Compared to the baseline, average HbA1c decreased 1.76% (9.74 +/- 0.56 to 7.98 +/- 0.36, P = 0.01), average TDID decreased 27% (199 +/- 33 to 147 +/- 31, P = 0.009), and MMTT AUC(60-240) decreased 32% (P = 0.04) over the treatment period. The decline in HbA(1c) and TDID was observed at 8 weeks and sustained over the remaining 16-week study duration. CONCLUSION: In this study, bromocriptine-QR therapy improved glycemic control and meal tolerance while reducing insulin requirement in T2DM subjects poorly controlled on high-dose insulin therapy. PMID- 26060827 TI - Advances in Diagnosis and Treatment of HPV Ocular Surface Infections. PMID- 26060828 TI - Smartphone-based Video of Demodex folliculorum In Biopsied Human Eyelash Follicles. AB - The ability of smartphone technology to document static microscopy images has been well documented and is gaining widespread use in ophthalmology, where slit lamp biomicroscopy is frequently utilized. However, little has been described regarding the use of smartphone technology to relay video of tissue microscopy results to patients, particularly when a tissue sample integrates motility of organisms as a characteristic feature of the disease. Here, we describe the method to use smartphone video to document motility of Demodex folliculorum in human eyelashes, individual results of which can be shown to patients for education and counseling purposes. The use of smartphone video in documenting the motility of organisms may prove to be beneficial in a variety of medical fields; producers of electronic medical records, therefore, may find it helpful to integrate video drop box tools. PMID- 26060829 TI - Age-Related Macular Degeneration: A Scientometric Analysis. AB - Age-related macular degeneration (ARMD) is a major cause of central blindness among working aged adults across the world. Systematic research planning on any subject, including ARMD is in need of solid data regarding previous efforts in this field and to identify the gaps in the research. This study aimed to elucidate the most important trends, directions, and gap in this subject. The data extracted from the Institute for Scientific Information were used to perform a bibliometric analysis of the scientific productions (1993-2013) about ARMD. Specific parameters related to ARMD were analyzed to obtain a view of the topic's structure, history, and document relationships. Additionally, the trends and authors in the most influential publications were analyzed. The number of articles in this field was found constantly increasing. Most highly cited articles addressed genetic epidemiology and clinical research topics in this field. During the past 3 years, there has been a trend toward biomarker research. Through performing the first scientometric survey on ARMD research, we analyzed the characteristics of papers and the trends in scientific production. We also identified some of the critical gaps in the current research efforts that would help in large-scale research strategic planning. PMID- 26060830 TI - Psychosis, Mood and Behavioral Disorders in Usher Syndrome: Review of the Literature. AB - The aim of this review is to focus the current knowledge about mental and behavioral disorders in Usher syndrome. Previous studies described the presence of various mental disorders associated with Usher syndrome, suggesting possible mechanisms of association between these disorders. The most common manifestations are schizophrenia-like disorder and psychotic symptoms. Mood and behavioral disorders are rarely described, and often are associated with more complex cases in co-occurrence with other psychiatric disorders. Neuroimaging studies reported diffuse involvement of central nervous system (CNS) in Usher patients, suggesting a possible role of CNS damage in the pathogenesis of psychiatric manifestations. Genetic hypothesis and stress-related theories have also been proposed. PMID- 26060831 TI - Cutting Edge of Traumatic Maculopathy with Spectral-domain Optical Coherence Tomography - A Review. AB - This article reviews clinically relevant data regarding traumatic maculopathy (TM), frequently observed in clinical practice, especially due to sport or traffic accident injuries. It is characterized by transient gray-whitish retinal coloration and reduction of visual acuity (VA) with closed, blunt object globe trauma of their prior. It may be limited to the posterior pole (Berlin's edema), or peripheral areas of the retina. Spectral-domain optical coherence tomography (SD-OCT) provides detail insight using high resolution cross-sectional tomographs of the ocular tissue. It is a potent non-invasive tool for the clinician to follow-up. Clinicians are, thereby empowered with a tool that enables evaluation of the retinal status and allows for prediction of the prognosis. Spectral-domain optical coherence tomography supports the idea that the major site of injury is in the photoreceptor and layers of the retinal pigment epithelium (RPE). Depending on the severity of the trauma, SD-OCT may reveal differential optical densities of intraretinal spaces ranging from disappearance of the thin hyporeflective optical space in mild lesions, or areas of disruption of the inner segment/outer segment (IS/OS) junction and hyperreflectivity of the overlying retina, pigment disorders and retinal atrophy, in more severe cases. The prognosis for recovery of vision is generally good, and improvement occurs within 3-4 weeks. PMID- 26060832 TI - Ocular Effects of Niacin: A Review of the Literature. AB - Cystoid macular edema is a condition that involves the macula, caused by an accumulation of extracellular fluid in the macular region with secondary formation of multiple cystic spaces. This condition is provoked by a variety of pathological conditions such as intraocular inflammation, central or branch retinal vein occlusion, diabetic retinopathy and most commonly following cataract extraction, hereditary retinal dystrophies, and topical or systemic assumption of drugs. Niacin is a vitamin preparation usually used for the treatment of lipid disorders. The treatment with niacin, alone or in combination with other lipid lowering agents, significantly reduces total mortality and coronary events and slows down the progression of and induces the regression of coronary atherosclerosis. Several cases of niacin-induced cystoid macular edema have been reported with different dosages. PMID- 26060834 TI - Diabetes and end-stage renal disease; a review article on new concepts. AB - It is well established that diabetic nephropathy is the most common cause or in combination with hypertensive nephropathy are the most common causes of end-stage renal disease (ESRD) in developed and developing countries. For this review, we used a variety of sources by searching through PubMed, Embase, Scopus, Current Content and Iran Medex from January 1990 up to December 2014. Manuscripts published in English and Persian languages, as full-text articles, and or as abstract were included in the study. Patient survival in diabetics on maintenance renal replacement therapy including hemodialysis (HD), peritoneal dialysis (PD) and kidney transplantation is significantly lower than that seen in nondiabetics with ESRD. The poor prognosis of diabetic patients with ESRD is partly due to presence of significant cardiovascular disease, problems with vascular access, more susceptible to infections, foot ulcer, and hemodynamic instability during HD. Although, many complications related to kidney transplantation may occur in diabetic ESRD patients, multiple studies have found that the kidney transplantation is the preferred renal replacement therapy for diabetic patients with ESRD and it is associated with a much better survival and quality of life than dialysis among these patients. PMID- 26060833 TI - Renal ischemia/reperfusion injury; from pathophysiology to treatment. AB - Ischemia/reperfusion injury (IRI) is caused by a sudden temporary impairment of the blood flow to the particular organ. IRI usually is associated with a robust inflammatory and oxidative stress response to hypoxia and reperfusion which disturbs the organ function. Renal IR induced acute kidney injury (AKI) contributes to high morbidity and mortality rate in a wide range of injuries. Although the pathophysiology of IRI is not completely understood, several important mechanisms resulting in kidney failure have been mentioned. In ischemic kidney and subsequent of re-oxygenation, generation of reactive oxygen species (ROS) at reperfusion phase initiates a cascade of deleterious cellular responses leading to inflammation, cell death, and acute kidney failure. Better understanding of the cellular pathophysiological mechanisms underlying kidney injury will hopefully result in the design of more targeted therapies to prevent and treatment the injury. In this review, we summarize some important potential mechanisms and therapeutic approaches in renal IRI. PMID- 26060835 TI - Impact of the severity of obesity on microalbuminuria in obese normotensive nondiabetic individuals. AB - INTRODUCTION: Microalbuminuria has been now recognized as the most important risk factor for the increased morbidity and mortality in the obese population. OBJECTIVES: We aimed to know whether severity of obesity is associated with the presence of renal injury while microalbuminuria acts, independent of other risk factors as hypertension and diabetes mellitus. PATIENTS AND METHODS: The current cross-sectional study was conducted on consecutive obese normotensive nondiabetic individuals. Two groups of adult individuals were selected as controls comprised of 161 obese adults with body mass index (BMI) 30-35 kg/m(2) and 25 very obese adults as cases with BMI more than 35 kg/m(2). Microalbuminuria was defined as abnormal urinary albumin to creatinine ratio (UACR) more than 30 mg/g of creatinine. RESULTS: No significant differences in serum creatinine level, urinary albumin concentration, as well as UACR between obese and very obese individuals was seen. Using Pearson correlation coefficient analysis, no significant correlation was observed between BMI and parameters of renal function. Microalbuminuria was more prevalent in very obese individuals compared with obese group (24.0% versus 9.9%, P = 0.043) in univariate analysis. CONCLUSION: Severe obesity compared with milder obesity status cannot predict the occurrence of increased urinary albumin excretion and microalbuminuria. PMID- 26060836 TI - Urinary neutrophil gelatinase-associated lipocalin (NGAL) might be an independent marker for anticipating scar formation in children with acute pyelonephritis. AB - INTRODUCTION: Urinary tract infections (UTIs) are the most serious common bacterial infections among young children. It may affect kidneys that classified as acute pyelonephritis (APN) and may lead to renal parenchymal involvement and scarring with high prevalence rate (15%-60%) among children. This study aimed to assess the urinary concentration of neutrophil gelatinase-associated lipocalin (NGAL) in patients with APN to diagnose those with potency to scar formation. PATIENTS AND METHODS: Children who were admitted with a diagnosis of APN were enrolled and divided into two groups; APN with scar and APN without scar. Urinary levels of NGAL and its ratio to creatinine (Cr) levels were measured in the acute phase of infection. A receiver operating characteristic (ROC) curve was generated to allow calculation of cut-off values. RESULTS: Fifty-four children were enrolled across the 2 groups: group 1 consisted of 16 patients (all female); group 2 consisted of 38 children (36 female and 2 male). Urinary levels of NGAL were significantly higher in APN with scar than in APN without scar (P = 0.037). For comparison of groups 1 and 2, the cut-off values were measured as 7.32 ng/ml, sensitivity; 81.3% and specificity; 66%. CONCLUSION: Evaluation of urinary NGAL levels may help us to identify children with APN who are at risk of developing renal scarring. PMID- 26060838 TI - Prevalence, awareness and risk factors of hypertension in southwest of Iran. AB - INTRODUCTION: Hypertension is an important cause of stroke, heart and kidney disease and these diseases are the cause for about two-thirds of all mortalities around the world. OBJECTIVES: The aim of this study was to assess the prevalence, awareness and risk factors of hypertension in Ahvaz, southwest of Iran. PATIENTS AND METHODS: In this descriptive-analytical study, 944 participants older than 20 years were enrolled. Systolic blood pressure (BP) >=140 mm Hg, diastolic BP >=90 mm Hg or the use of antihypertensive medication was considered as hypertension. Systolic BP = 140-159 mm Hg or diastolic BP = 90-99 mm Hg were defined as stage 1, and systolic BP >=160 mm Hg or diastolic BP >=100 mm Hg were considered as stage 2 of hypertension. Systolic BP = 120-139 mm Hg and diastolic BP= 80-89 mm Hg were considered as prehypertensive state. RESULTS: The prevalence of hypertension in Ahvaz was 17.58% (95% CI: 15.28-20.14) (males; 45.8%, females; 54.2%). Age-adjusted prevalence of hypertension was 8.6%; age- and sex-adjusted prevalence of hypertension was 3.7%. Seventy-two cases (7.7%) were prehypertensive. The frequency of stage 1 hypertension was 10.8% and stage 2 was 5.7%. Among them, 53.6% were not aware of their disease and 22% of hypertensive cases were controlled. Logistic regression analysis showed that age, metabolic syndrome and family history of hypertension had significant relationship with hypertension. CONCLUSION: This study showed that, age, metabolic syndrome and family history of disease are risk factors of hypertension in Ahvaz population. About half of patients were unaware of their disease and about 20% had controlled BP. PMID- 26060837 TI - Protective effect of pomegranate flower extract against gentamicin-induced renal toxicity in male rats. AB - INTRODUCTION: Gentamicin (GM) as an antibiotic is used in clinic. However, its administration is limited by side effects such as nephrotoxicity. Herbal extracts could be used in therapeutic approaches. OBJECTIVES: The present study was planned to investigate whether pomegranate flower extract (PFE) could ameliorate GM-induced renal toxicity in male rats. MATERIALS AND METHODS: Twenty eight male Wistar rats were divided into 5 groups. Groups 1 and 2 respectively received PFE 25 and 50 mg/kg for 9 days. Groups 3, 4 and 5 received saline, PFE 25 mg/kg, and PFE 50 mg/kg for 9 days, respectively, and GM (100 mg/kg/day) was administered from day 3 on. Blood samples were obtained, and after sacrificing the animals, the kidneys were removed for histopathology investigations. RESULTS: GM alone increased the serum levels of creatinine (Cr) and blood urea nitrogen (BUN), and tissue damage and kidney weight (P < 0.05). However, administration of low dose of PFE accompanied with GM decreased these markers significantly (P < 0.05). Low dose of PFE also ameliorated weight loss induced by GM (P < 0.05). CONCLUSION: It is concluded that PFE 25 mg/kg is the effective dose to ameliorate nephrotoxicity induced by GM. PMID- 26060839 TI - Using Fuzzy Logic Techniques for Assertion-Based Software Testing Metrics. AB - Software testing is a very labor intensive and costly task. Therefore, many software testing techniques to automate the process of software testing have been reported in the literature. Assertion-Based automated software testing has been shown to be effective in detecting program faults as compared to traditional black-box and white-box software testing methods. However, the applicability of this approach in the presence of large numbers of assertions may be very costly. Therefore, software developers need assistance while making decision to apply Assertion-Based testing in order for them to get the benefits of this approach at an acceptable level of costs. In this paper, we present an Assertion-Based testing metrics technique that is based on fuzzy logic. The main goal of the proposed technique is to enhance the performance of Assertion-Based software testing in the presence of large numbers of assertions. To evaluate the proposed technique, an experimental study was performed in which the proposed technique is applied on programs with assertions. The result of this experiment shows that the effectiveness and performance of Assertion-Based software testing have improved when applying the proposed testing metrics technique. PMID- 26060840 TI - Review on the Risk Assessment of Heavy Metals in Malaysian Clams. AB - The current review discusses the levels of six heavy metals in different clam species from 34 sites of Malaysian coasts. The concentrations (ug/g dry weight) of these heavy metals ranged around 0.18-8.51, 0.13-17.20, 2.17-7.80, 0.84-36.00, 24.13-368.00, and 177.82-1912.00 for Cd, Pb, Ni, Cu, Zn, and Fe, respectively. It was observed that the concentrations of metals slightly depend on different clam species but mostly depend on site locations. According to Malaysian Food Regulation (1985), about 30% and more than 50% sites are safe from Cd and Pb contamination, respectively, and also the clam species from the other populations studied were safe for consumption. PMID- 26060842 TI - Acrylate formation from CO2 and ethylene: catalysis with palladium and mechanistic insight. AB - We report the first catalyst based on palladium for the reaction of CO2, alkene and a base to form sodium acrylate and derivatives. A mechanism similar to a previously reported Ni(0)-catalyst is proposed based on stoichiometric in situ NMR experiments, isolated intermediates and a parent palladalactone. Our palladium catalyst was applied to the coupling of CO2 with conjugated alkenes. PMID- 26060841 TI - Trace detection of tetrabromobisphenol A by SERS with DMAP-modified magnetic gold nanoclusters. AB - Magnetic gold nanoclusters (MGNCs) functionalized with 4-dimethylaminopyridine (DMAP) enables the trace detection of tetrabromobisphenol A (TBBPA), an environmental pollutant, using surface-enhanced Raman scattering (SERS) spectroscopy. The synthesis, cleansing, and functionalization of MGNCs are conducted in aqueous solutions; SERS samples are prepared by magnetic precipitation in the presence of trace analyte. The limit of detection (LOD) for TBBPA is greatly increased by the use of DMAP as a reporter molecule: DMAP modified MGNCs can detect TBBPA at 10 pM in water, whereas the LOD for TBBPA by unfunctionalized Au is 1 nM. The reproducibility of picomolar TBBPA detection with DMAP-modified MGNCs is confirmed by two-dimensional correlation analysis. The high SERS sensitivity for TBBPA can be attributed to its capacity to modulate the Raman spectrum of adsorbed DMAP. This indirect mode of detection can also be applied toward the detection of other hydrophobic analytes, each identifiable by its characteristic SERS identity. PMID- 26060843 TI - NIR light induced H2 evolution by a metal-free photocatalyst. AB - NIR light induced H2 evolution was realized by metal-free photocatalysis for the first time. The considerable H2 production at 808 nm and large promotion of the photocatalytic activity in both UV-Vis and Vis regions originated from the synergistic effect on spectral and electronic coupling of g-C3N4 nanosheets and carbon quantum dots. PMID- 26060844 TI - Hunting for the elusive shallow traps in TiO2 anatase. AB - Understanding electron mobility on TiO2 is crucial because of its applications in photocatalysis and solar cells. This work shows that shallow traps believed to be involved in electron migration in TiO2 conduction band are formed upon band gap excitation, i.e., are not pre-existing states. The shallow traps in TiO2 results from large polarons and are not restricted to surface. PMID- 26060845 TI - Organoaqueous calcium chloride electrolytes for capacitive charge storage in carbon nanotubes at sub-zero-temperatures. AB - Solutions of calcium chloride in mixed water and formamide are excellent electrolytes for capacitive charge storage in partially oxidised carbon nanotubes at unprecedented sub-zero-temperatures (e.g. 67% capacitance retention at -60 degrees C). PMID- 26060846 TI - Controlling the assembly of cyclotriveratrylene-derived coordination cages. AB - A review of the emerging field of cyclotriveratrylene-derived coordination cages is presented. Ligand-functionalised cyclotriveratrylene (CTV) derivatives self assemble with a range of metal cations to afford coordination cages, polymers and topologically non-trivial constructs, such as [2]catenanes and a self-entangled cube. Increased control over their self-assembly allows for the controlled and predictable formation of well-defined coordination cages for application in host guest and recognition chemistry, with surfactant binding and single-crystal-to single-crystal (SCTSC) uptake of small-molecule guests being observed. PMID- 26060847 TI - Alkoxylated dehydrobenzo[12]annulene on Au(111): from single molecules to quantum dot molecular networks. AB - We demonstrate the effective confinement of surface electrons in the pores of molecular networks formed by dehydrobenzo[12]annulene (DBA) molecules with butoxy groups (DBA-OC4) on Au(111). Investigation of the network formation starting from single molecules reveals a considerable interaction of the molecules with the substrate, which is at the origin of the observed confinement. PMID- 26060848 TI - Functional, composite polythioether nanoparticles via thiol-alkyne photopolymerization in miniemulsion. AB - Thiol-yne photopolymerization in miniemulsion is demonstrated as a simple, rapid, and one-pot synthetic approach to polythioether nanoparticles with tuneable particle size and clickable functionality. The strategy is also useful in the synthesis of composite polymer-inorganic nanoparticles. PMID- 26060849 TI - Complete reductive cleavage of CO facilitated by highly electrophilic borocations. AB - The addition of CO to [((R3N)BH2)2(MU-H)][B(C6F5)4] leads to formation of trimethylboroxine ((MeBO)3) and [(R3N)2BH2][B(C6F5)4]. When R = Et, [(Et3N)H2B(MU O)B(CH3)NEt3][B(C6F5)4], is isolated and demonstrated to be an intermediate in the formation of (MeBO)3. PMID- 26060850 TI - Supramolecular metallacycles with a 'pseudo double-paracyclophane' structure based on flexible pi-conjugated linkers. AB - The straightforward synthesis of new supramolecular metallacycles having a 'pseudo double-paracyclophane' structure is presented. They are obtained from the reaction of a pre-assembled Cu(I) bimetallic precursor bearing short intermetallic distances with cyano-capped homoditopic pi-conjugated linkers having flexible central cores. PMID- 26060851 TI - Reactivity of carbon dioxide in hydrofluoroethers: a facile access to cyclic carbonates. AB - The high solubility of CO2 in hydrofluoroethers led to various cyclic carbonates with excellent selectivities and yields. The fluorinated phase increased the amount of CO2 in contact with the reagents. Reactions could be realized under mild conditions at 80 degrees C, under atmospheric pressure or under 5 bar. PMID- 26060852 TI - Template-controlled synthesis of chiral cyclohexylhemicucurbit[8]uril. AB - Enantiomerically pure cyclohexylhemicucurbit[8]uril (cycHC[8]), possessing a barrel-shaped cavity, has been prepared in high yield on a gram scale from either (R,R,N,N')-cyclohex-1,2-diylurea and formaldehyde or cycHC[6]. In either case, a dynamic covalent library is first generated from which the desired cycHC can be amplified using a suitable anion template. PMID- 26060853 TI - A theoretical study on the molecular determinants of the affibody protein Z(Abeta3) bound to an amyloid beta peptide. AB - Amyloid beta (Abeta) peptides are small cleavage products of the amyloid precursor protein. Aggregates of Abeta peptides are thought to be linked with Alzheimer's and other neurodegenerative diseases. Strategies aimed at inhibiting amyloid formation and promoting Abeta clearance have been proposed and investigated in in vitro experiments and in vivo therapies. A recent study indicated that a novel affibody protein ZAbeta3, which binds to an Abeta40 monomer with a binding affinity of 17 nM, is able to prevent the aggregation of Abeta40. However, little is known about the energetic contribution of each residue in ZAbeta3 to the formation of the (ZAbeta3)2:Abeta complex. To address this issue, we carried out unbiased molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area calculations. Through the per-residue decomposition scheme, we identified that the van der Waals interactions between the hydrophobic residues of (ZAbeta3)2 and those at the exterior and interior faces of Abeta are the main contributors to the binding of (ZAbeta3)2 to Abeta. Computational alanine scanning identified 5 hot spots, all residing in the binding interface and contributing to the binding of (ZAbeta3)2 to Abeta through the hydrophobic effect. In addition, the amide hydrogen bonds in the 4-strand beta-sheet and the pi-pi stacking were also analyzed. Overall, our study provides a theoretical basis for future experimental improvement of the ZAbeta3 peptide binding to Abeta. PMID- 26060854 TI - [Not Available]. PMID- 26060855 TI - Characterization of splenogonadal fusion by contrast-enhanced ultrasound (CEUS) and elastography. PMID- 26060856 TI - New diet may protect against Alzheimer's. PMID- 26060857 TI - RSPH presents 'improve and protect'. PMID- 26060858 TI - Call for child mental health services to be overhauled. PMID- 26060859 TI - New work schedules could improve wellbeing. PMID- 26060860 TI - [Thoughts of murder, dissolved in pleasure]. PMID- 26060861 TI - [Job center statistics may not be altered by you]. PMID- 26060862 TI - Scientific corner. PMID- 26060863 TI - Statement of the section internal medicine of the DEGUM - ultrasound obtains pole position for clinical imaging in acute diverticulitis. AB - This paper reviews and interprets the role of ultrasonography in view of the recently published Guideline on diverticular disease of the Consensus conference of the German Societies of Gastroenterology (DGVS) and Visceral Surgery (DGAV) implying a new classification of diverticular disease (CDD). Qualified US is not only equipotent to qualified CT and frequently effectual for diagnosis but considers relevant legislation for radiation exposure protection. Unsurpassed resolution allows detailed resolution thereby allowing to differentiate and stratify the relevant types of diverticular disease. Subsequently, US is considered the first choice of imaging in diverticular disease. Vice versa, CT has definite indications in unclear / discrepant situations - or insufficient US performance. PMID- 26060864 TI - [Better lung function thanks to fixed combination]. PMID- 26060865 TI - [Prokinetic effects of artichoke extract]. PMID- 26060866 TI - [Rehabilitation claim only with continuing education]. PMID- 26060867 TI - [Intermittent facial flushing and diarrhea]. PMID- 26060868 TI - ["Weekend effect": are the patients to blame?]. PMID- 26060869 TI - Corrigendum to "Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain" [Neurosci.Lett. 580 (2014) 12 16] A possible new animal model of autism. AB - The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20 mg/kg or 100 mg/kg) continuously during the last 9-12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fraction at or and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20 mg/kg and 100 mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively, (p < 0.05) compared to controls amounting to 15.5??106 neocortical neurons (p < 0.01). There was no statistical difference between the two VPA groups. Pups exposed to 100 mg/kg, but not to 20 mg/kg VPA displayed a significant (p < 0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen inhuman autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism. PMID- 26060870 TI - Concurrent copper and iron deficiency in a gastric bypass patient: a great mimicker of MDS. PMID- 26060871 TI - Tell me. PMID- 26060872 TI - Poxvirus countermeasures during an emergency in the United States. AB - Although smallpox was eradicated worldwide by 1980, national security experts remain concerned that it could be used in a deliberate attack. The United States and other governments have given priority to developing and stockpiling vaccines and antivirals to protect their populations from the potential reintroduction of this deadly disease. Public health officials are also concerned about the spread of related zoonotic orthopoxviruses such as monkeypox and cowpox, against which smallpox vaccine provides protection. This report analyzes how medical countermeasures available in the US Strategic National Stockpile will be given priority and used in the event of an intentional or accidental release of smallpox in the United States. PMID- 26060873 TI - Preparedness for a smallpox pandemic in Japan: public health perspectives. AB - Smallpox is an acute, febrile, contagious disease caused by the Variola virus, which is a member of the Poxviridae family. Until the 1970s, smallpox had been a pandemic disease for more than 3000 years, endemic in tropical and developing areas and periodically epidemic worldwide. The World Health Organization declared smallpox to be completely eradicated in 1980 as the result of global vaccination efforts. At that time, all routine vaccination programs were terminated, given the success of thismonumental eradication. Although smallpox remains fully eradicated, uncertainty exists regarding the possibility of recurrent smallpox outbreaks. At the end of the Cold War, concerns regarding unstable international security and the feasibility of terrorism with weapons of mass destruction have been highlighted. The potential threat of intentional release of smallpox has forced regional health authorities to reconsider their political landscape and create preparedness plans to protect the community in the event of biological attacks. Here we present current countermeasures to this biological threat in Japan and discuss methods for strengthening public health preparedness both domestically and internationally. These methods include infection control, vaccination policy, and international partnerships to help deter or contain a contagious smallpox pandemic. PMID- 26060874 TI - Response: safety and trust, above all else. PMID- 26060875 TI - Strong Second-Harmonic Generation in Atomic Layered GaSe. AB - Nonlinear effects in two-dimensional (2D) atomic layered materials have recently attracted increasing interest. Phenomena such as nonlinear optical edge response, chiral electroluminescence, and valley and spin currents beyond linear orders have opened up a great opportunity to expand the functionalities and potential applications of 2D materials. Here we report the first observation of strong optical second-harmonic generation (SHG) in monolayer GaSe under nonresonant excitation and emission condition. Our experiments show that the nonresonant SHG intensity of GaSe is the strongest among all the 2D atomic crystals measured up to day. At the excitation wavelength of 1600 nm, the SHG signal from monolayer GaSe is around 1-2 orders of magnitude larger than that from monolayer MoS2 under the same excitation power. Such a strong nonlinear signal facilitates the use of polarization-dependent SHG intensity and SHG mapping to investigate the symmetry properties of this material: the monolayer GaSe shows 3-fold lattice symmetry with an intrinsic correspondence to its geometric triangular shape in our growth condition; whereas the bilayer GaSe exhibits two dominant stacking orders: AA and AB stacking. The correlation between the stacking orders and the interlayer twist angles in GaSe bilayer indicates that different triangular GaSe atomic layers have the same dominant edge configuration. Our results provide a route toward exploring the structural information and the possibility to observe other nonlinear effects in GaSe atomic layers. PMID- 26060876 TI - Cleavable Molecular Beacon for Hg(2+) Detection Based on Phosphorothioate RNA Modifications. AB - Mercury is a highly toxic heavy metal, and detection of Hg(2+) by biosensors has attracted extensive research interest in the past decade. In particular, a number of DNA-based sensing strategies have been developed. Well-known examples include thymine-Hg(2+) interactions and Hg(2+)-activated DNAzymes. However, these mechanisms are highly dependent on buffer conditions or require hybridization with another DNA strand. Herein, we report a new mechanism based on Hg(2+) induced cleavage of phosphorothioate (PS) modified RNA. Among the various metal ions tested, Hg(2+) induced the most significant cleavage (~16%), while other metals cleaved less than 2% of the same substrate. The uncleaved substrate undergoes desulfurization in the presence of Hg(2+). This cleavage reaction yields a similar amount of product from pH 3.5 to 7 and in the temperature range between 20 and 90 degrees C. Various PS RNA junctions can be cleaved with a similar efficiency, but PS DNA junctions cannot be cleaved. A molecular beacon containing three PS RNA modifications is designed, detecting Hg(2+) down to 1.7 nM with excellent selectivity. This sensor can also detect Hg(2+) in the Lake Ontario water sample, although its response is significantly masked by fish tissues. PMID- 26060879 TI - Transformation of Plasmacytoid Dendritic Cells into Giant Multinuclear Cells by HIV-1. PMID- 26060878 TI - A Simple Optical Coherence Tomography Quantification Method for Choroidal Neovascularization. AB - PURPOSE: Therapeutic efficacy is routinely assessed by measurement of lesion size using flatmounted choroids and confocal microscopy in the laser-induced choroidal neovascularization (L-CNV) rodent model. We investigated whether optical coherence tomography (OCT) quantification, using an ellipsoid volume measurement, was comparable to standard ex vivo evaluation methods for this model and whether this approach could be used to monitor treatment-related lesion changes. METHODS: Bruch's membrane was ruptured by argon laser in the dilated eyes of C57BL/6J mice, followed by intravitreal injections of anti-VEGF164 or vehicle, or no injection. In vivo OCT images were acquired using Micron III or InVivoVue systems at 7, 10, and/or 14 days post-laser and neovascular lesion volume was calculated as an ellipsoid. Subsequently, lesion volume was compared to that calculated from confocal Z-stack images of agglutinin-stained choroidal flatmounts. RESULTS: Ellipsoid volume measurement of orthogonal 2-dimensional OCT images obtained from different imaging systems correlated with ex vivo lesion volumes for L-CNV (Spearman's rho=0.82, 0.75, and 0.82 at days 7, 10, and 14, respectively). Ellipsoid volume calculation allowed temporal monitoring and evaluation of CNV lesions in response to antivascular endothelial growth factor treatment. CONCLUSIONS: Ellipsoid volume measurements allow rapid, quantitative use of OCT for the assessment of CNV lesions in vivo. This novel method can be used with different OCT imaging systems with sensitivity to distinguish between treatment conditions. It may serve as a useful adjunct to the standard ex vivo confocal quantification, to assess therapeutic efficacy in preclinical models of CNV, and in models of other ocular diseases. PMID- 26060881 TI - Wireless Hydrogen Smart Sensor Based on Pt/Graphene-Immobilized Radio-Frequency Identification Tag. AB - Hydrogen, a clean-burning fuel, is of key importance to various industrial applications, including fuel cells and the aerospace and automotive industries. However, hydrogen gas is odorless, colorless, and highly flammable; thus, appropriate safety protocol implementation and monitoring are essential. Highly sensitive hydrogen-gas leak detection and surveillance systems are needed; additionally, the ability to monitor large areas (e.g., cities) via wireless networks is becoming increasingly important. In this report, we introduce a radio frequency identification (RFID)-based wireless smart-sensor system, composed of a Pt-decorated reduced graphene oxide (Pt_rGO)-immobilized RFID sensor tag and an RFID-reader antenna-connected network analyzer to detect hydrogen gas. The Pt_rGOs, produced using a simple chemical reduction process, were immobilized on an antenna pattern in the sensor tag through spin coating. The resulting Pt_rGO based RFID sensor tag exhibited a high sensitivity to hydrogen gas at unprecedentedly low concentrations (1 ppm), with wireless communication between the sensor tag and RFID-reader antenna. The wireless sensor tag demonstrated flexibility and a long lifetime due to the strong immobilization of Pt_rGOs on the substrate and battery-independent operation during hydrogen sensing, respectively. PMID- 26060880 TI - Therapeutic Hypothermia Reduces Intracranial Pressure and Partial Brain Oxygen Tension in Patients with Severe Traumatic Brain Injury: Preliminary Data from the Eurotherm3235 Trial. AB - Traumatic brain injury (TBI) is a significant cause of disability and death and a huge economic burden throughout the world. Much of the morbidity associated with TBI is attributed to secondary brain injuries resulting in hypoxia and ischemia after the initial trauma. Intracranial hypertension and decreased partial brain oxygen tension (PbtO2) are targeted as potentially avoidable causes of morbidity. Therapeutic hypothermia (TH) may be an effective intervention to reduce intracranial pressure (ICP), but could also affect cerebral blood flow (CBF). This is a retrospective analysis of prospectively collected data from 17 patients admitted to the Western General Hospital, Edinburgh. Patients with an ICP >20 mmHg refractory to initial therapy were randomized to standard care or standard care and TH (intervention group) titrated between 32 degrees C and 35 degrees C to reduce ICP. ICP and PbtO2 were measured using the Licox system and core temperature was recorded through rectal thermometer. Data were analyzed at the hour before cooling, the first hour at target temperature, 2 consecutive hours at target temperature, and after 6 hours of hypothermia. There was a mean decrease in ICP of 4.3+/-1.6 mmHg (p<0.04) from 15.7 to 11.4 mmHg, from precooling to the first epoch of hypothermia in the intervention group (n=9) that was not seen in the control group (n=8). A decrease in ICP was maintained throughout all time periods. There was a mean decrease in PbtO2 of 7.8+/-3.1 mmHg (p<0.05) from 30.2 to 22.4 mmHg, from precooling to stable hypothermia, which was not seen in the control group. This research supports others in demonstrating a decrease in ICP with temperature, which could facilitate a reduction in the use of hyperosmolar agents or other stage II interventions. The decrease in PbtO2 is not below the suggested treatment threshold of 20 mmHg, but might indicate a decrease in CBF. PMID- 26060882 TI - Going High with Heart Disease: The Effect of High Altitude Exposure in Older Individuals and Patients with Coronary Artery Disease. AB - Levine, Benjamin D. Going high with heart disease: The effect of high altitude exposure in older individuals and patients with coronary artery disease. High Alt Med Biol 16:89-96, 2015.--Ischemic heart disease is the largest cause of death in older men and women in the western world (Lozano et al., 2012 ; Roth et al., 2015). Atherosclerosis progresses with age, and thus age is the dominant risk factor for coronary heart disease in any algorithm used to assess risk for cardiovascular events. Subclinical atherosclerosis also increases with age, providing the substrate for precipitation of acute coronary syndromes. Thus the risk of high altitude exposure in older individuals is linked closely with both subclinical and manifest coronary heart disease (CHD). There are several considerations associated with taking patients with CHD to high altitude: a) The reduced oxygen availability may cause or exacerbate symptoms; b) The hypoxia and other associated environmental conditions (exercise, dehydration, change in diet, thermal stress, emotional stress from personal danger or conflict) may precipitate acute coronary events; c) If an event occurs and the patient is far from advanced medical care, then the outcome of an acute coronary event may be poor; and d) Sudden death may occur. Physicians caring for older patients who want to sojourn to high altitude should keep in mind the following four key points: 1). Altitude may exacerbate ischemic heart disease because of both reduced O2 delivery and paradoxical vasoconstriction; 2). Adverse events, including acute coronary syndromes and sudden cardiac death, are most common in older unfit men, within the first few days of altitude exposure; 3). Ensuring optimal fitness, allowing for sufficient acclimatization (at least 5 days), and optimizing medical therapy (especially statins and aspirin) are prudent recommendations that may reduce the risk of adverse events; 4). A graded exercise test at sea level is probably sufficient for most clinical decision making and will allow for assessment of exercise capacity, and provocable ischemia. Given these considerations, most older individuals with CHD should be able to tolerate exposure to high altitude safely, and with minimal increased risk. PMID- 26060883 TI - Self-Sensitized Photooxygenation of 2H-Pyrans: Characterization of Unexpected Products Assisted by Computed Structural Elucidation and Residual Dipolar Couplings. AB - The UVA (350 nm) irradiation of an alpha-pyran in the presence of oxygen led to the unexpected formation of a tetraoxygenated compound whose structure could not be unambiguously determined on the basis of conventional (1)H-(13)C correlated experiments. 1,1-ADEQUATE (adequate double quantum transfer experiment) and 1,n ADEQUATE combined with computer-assisted structure elucidation software led to two structural possibilities involving the formation of either an epoxide or an oxetane. Residual dipolar couplings allowed not only the identification of the compound as a spiroepoxide but also the determination of its relative configuration. To account for its formation, we propose a bisepoxide intermediate that, as opposed to most alpha,beta-epoxyketones under irradiation, undergoes O Cbeta cleavage probably due to the presence of an extra oxygen substituent in the beta position. 1,2-Acyl migration would then proceed stereoselectively to the final product obtained as a single diastereomer. PMID- 26060884 TI - Corrigendum. PMID- 26060886 TI - DNA transducer-triggered signal switch for visual colorimetric bioanalysis. AB - A simple and versatile colorimetric biosensor has been developed for sensitive and specific detection of a wide range of biomolecules, such as oligonucleotides and aptamer-recognized targets. Combining the signal transducer and catalyzed hairpin assembly (CHA)-based signal amplification, the target DNA binds with the hairpin DNA to form a new nucleic acid sequence and creates a toehold in the transducer for initiating the recycle amplification reaction of CHA. The catalyzed assembly process produces a large amount of G-rich DNA. In the presence of hemin, the G-rich DNA forms G-quadruplex/hemin complex and mimic horseradish peroxidase activity, which catalyzes a colorimetric reaction. Under optimal conditions, the calibration curve of synthetic target DNA has good linearity from 50 pM to 200 nM with a detection limit of 32 pM. This strategy has been successfully applied to detect S. pneumoniae as low as 156 CFU mL(-1), and shows a good specificity against closely related streptococci and major pathogenic bacteria. In addition, the developed method enables successful visual analysis of S. pneumoniae in clinical samples by the naked eye. Importantly, this method demonstrates excellent assay versatility for sensitively detecting oligonucleotides or aptamer-recognized targets. PMID- 26060887 TI - Exceedingly Efficient Synthesis of (+/-)-Grandifloracin and Acylated Analogues. AB - A highly efficient regio- and stereoselective total synthesis of (+/-) grandifloracin via a tandem dearomative epoxidation/spontaneous Diels-Alder cyclodimerization from salicylic acid in only four steps is reported. The synthetic route allows for late-stage diversification of the core structure to give ready access to analogues of this promising agent against pancreatic cancer. PMID- 26060889 TI - The impact of psychological empowerment and organisational commitment on Chinese nurses' job satisfaction. AB - BACKGROUND: Research findings have shown that job satisfaction of Chinese nurses is at a low level. Limited studies have focused on the impact of psychological empowerment and organisational commitment on job satisfaction of Chinese nurses. AIMS: The aim of this study is to describe job satisfaction, psychological empowerment and organisational commitment of Chinese nurses and to explore the impact of psychological empowerment and organisational commitment on the nurses' job satisfaction. METHODS: A total of 726 nurses were recruited in a convenience sample from 10 tertiary hospitals. Data were collected using four questionnaires including Job Satisfaction Survey, Psychological Empowerment Scale, Organisational Commitment Scale and Demographic Questionnaire. Descriptive analysis, correlation and stepwise multiple regression were used for data analysis. RESULTS: Nurses' job satisfaction, psychological empowerment and organisational commitment were identified at moderate levels. Nurses' job satisfaction and psychological empowerment were significantly different in terms of age and length of service; nurse job satisfaction varied with respect to marital status. Findings further indicated that nurse job satisfaction was positively correlated with psychological empowerment and organisational commitment. Psychological empowerment, organisational commitment and marital status were significant predicting factors of nurse job satisfaction. CONCLUSIONS: This study provides evidence to help nursing managers and health policy-makers to develop intervention programs aimed at enhancing nurse job satisfaction and retaining nurses. PMID- 26060888 TI - Vascular replacement using a layered elastin-collagen vascular graft in a porcine model: one week patency versus one month occlusion. AB - A persistent clinical demand exists for a suitable arterial prosthesis. In this study, a vascular conduit mimicking the native 3-layered artery, and constructed from the extracellular matrix proteins type I collagen and elastin, was evaluated for its performance as a blood vessel equivalent. A tubular 3-layered graft (elastin-collagen-collagen) was prepared using highly purified type I collagen fibrils and elastin fibers, resembling the 3-layered native blood vessel architecture. The vascular graft was crosslinked and heparinised (37 +/- 4 MUg heparin/mg graft), and evaluated as a vascular graft using a porcine bilateral iliac artery model. An intra-animal comparison with clinically-used heparinised ePTFE (Propaten(r)) was made. Analyses included biochemical characterization, duplex scanning, (immuno)histochemistry and scanning electron microscopy. The tubular graft was easy to handle with adequate suturability. Implantation resulted in pulsating grafts without leakage. One week after implantation, both ePTFE and the natural acellular graft had 100% patencies on duplex scanning. Grafts were partially endothelialised (Von Willebrand-positive endothelium with a laminin-positive basal membrane layer). After one month, layered thrombi were found in the natural (4/4) and ePTFE graft (1/4), resulting in occlusion which in case of the natural graft is likely due to the porosity of the inner elastin layer. In vivo application of a molecularly-defined tubular graft, based on nature's matrix proteins, for vascular surgery is feasible. PMID- 26060890 TI - Downloading Diabetes Device Data: Empowering Patients to Download at Home to Achieve Better Outcomes. PMID- 26060892 TI - Propranolol in the Treatment of Infantile Hemangiomas: A Meta-Analysis in Chinese Patients. AB - A meta-analysis was conducted to evaluate the efficacy of propranolol in the treatment of infantile hemangiomas (IHs) in Chinese infants. A statistically significant difference was found between infants treated using propranolol and those treated using corticosteroids (p < 0.001). The total effect pooled from 26 single-arm studies using meta-analysis of propranolol on IHs in Chinese infants was 93% (95% confidence interval 0.88, 0.96). PMID- 26060891 TI - MYBL2 guides autophagy suppressor VDAC2 in the developing ovary to inhibit autophagy through a complex of VDAC2-BECN1-BCL2L1 in mammals. AB - Oogenesis is essential for female gamete production in mammals. The total number of ovarian follicles is determined early in life and production of ovarian oocytes is thought to stop during the lifetime. However, the molecular mechanisms underling oogenesis, particularly autophagy regulation in the ovary, remain largely unknown. Here, we reveal an important MYBL2-VDAC2-BECN1-BCL2L1 pathway linking autophagy suppression in the developing ovary. The transcription factors GATA1 and MYBL2 can bind to and activate the Vdac2 promoter. MYBL2 regulates the spatiotemporal expression of VDAC2 in the developing ovary. Strikingly, in the VDAC2 transgenic pigs (Sus scrofa/Ss), VDAC2 exerts its function by inhibiting autophagy in the ovary. In contrast, Vdac2 knockout promotes autophagy. Moreover, VDAC2-mediated autophagy suppression is dependent on its interactions with both BECN1 and BCL2L1 to stabilize the BECN1 and BCL2L1 complex, suggesting VDAC2 as an autophagy suppressor in the pathway. Our findings provide a functional connection among the VDAC2, MYBL2, the BECN1-BCL2L1 pathway and autophagy suppression in the developing ovary, which is implicated in improving female fecundity. PMID- 26060893 TI - Molecular architecture of the stria vascularis membrane transport system, which is essential for physiological functions of the mammalian cochlea. AB - Stria vascularis of the mammalian cochlea transports K(+) to establish the electrochemical property in the endolymph crucial for hearing. This epithelial tissue also transports various small molecules. To clarify the profile of proteins participating in the transport system in the stria vascularis, membrane components purified from the stria of adult rats were analysed by liquid chromatography tandem mass spectrometry. Of the 3236 proteins detected in the analysis, 1807 were membrane proteins. Ingenuity Knowledge Base and literature data identified 513 proteins as being expressed on the 'plasma membrane', these included 25 ion channels and 79 transporters. Sixteen of the former and 62 of the latter had not yet been identified in the stria. Unexpectedly, many Cl(-) and Ca(2+) transport systems were found, suggesting that the dynamics of these ions play multiple roles. Several transporters for organic substances were also detected. Network analysis demonstrated that a few kinases, including protein kinase A, and Ca(2+) were key regulators for the strial transports. In the library of channels and transporters, 19 new candidates for uncloned deafness related genes were identified. These resources provide a platform for understanding the molecular mechanisms underlying the epithelial transport essential for cochlear function and the pathophysiological processes involved in hearing disorders. PMID- 26060894 TI - Switchable Coupling of Vibrations to Two-Electron Carbon-Nanotube Quantum Dot States. AB - We report transport measurements on a quantum dot in a partly suspended carbon nanotube. Electrostatic tuning allows us to modify and even switch "on" and "off" the coupling to the quantized stretching vibration across several charge states. The magnetic-field dependence indicates that only the two-electron spin-triplet excited state couples to the mechanical motion, indicating mechanical coupling to both the valley degree of freedom and the exchange interaction, in contrast to standard models. PMID- 26060897 TI - Etiology of Epilepsy. PMID- 26060895 TI - Natural and induced B-1 cell immunity to infections raises questions of nature versus nurture. AB - Mouse B-1 cells are not only major producers of steady-state natural antibodies but also rapid responders to infections and inflammation. These discrete functions may be the outcomes of distinct environmental or developmental triggers that drive B-1 cells toward IgM production or an effector cell fate. Alternatively, distinct B-1 cell subsets may exist, which differ in their functional plasticity. In this paper, we summarize existing data suggesting that B-1 cells form a heterogeneous group of cells with distinct developmental requirements and nonoverlapping functions. Most spleen B-1 cells differ in development from that of bone marrow and peritoneal cavity B-1 cells, in that they develop in the absence of natural IgM. Functional heterogeneity is revealed by findings that B-1 cells in the bone marrow and spleen, but not the peritoneal cavity, generate natural serum IgM, while the latter are rapid responders to inflammatory and infectious insults, resulting in their relocation to secondary lymphoid tissues. A clearer understanding of the developmental and functional differences within the B-1 cell pool may reveal how they might be harnessed for prophylaxis or therapy. PMID- 26060898 TI - Hippocampal Sclerosis: Causes and Prevention. AB - Hippocampal sclerosis is the commonest cause of drug-resistant epilepsy in adults, and is associated with alterations to structures and networks beyond the hippocampus.In addition to being a cause of epilepsy, the hippocampus is vulnerable to damage from seizure activity. In particular, prolonged seizures (status epilepticus) can result in hippocampal sclerosis. The hippocampus is also vulnerable to other insults including traumatic brain injury, and inflammation. Hippocampal sclerosis can occur in association with other brain lesions; the prevailing view is that it is probably a secondary consequence. In such instances, successful surgical treatment usually involves the resection of both the lesion and the involved hippocampus. Experimental data have pointed to numerous neuroprotective strategies to prevent hippocampal sclerosis. Initial neuroprotective strategies aimed at glutamate receptors may be effective, but later, metabolic pathways, apoptosis, reactive oxygen species, and inflammation are involved, perhaps necessitating the use of interventions aimed at multiple targets. Some of the therapies that we use to treat status epilepticus may neuroprotect. However, prevention of neuronal death does not necessarily prevent the later development of epilepsy or cognitive deficits. Perhaps, the most important intervention is the early, aggressive treatment of seizure activity, and the prevention of prolonged seizures. PMID- 26060899 TI - Focal Cortical Dysplasia. AB - Focal cortical dysplasias are common malformations of cerebral cortical development and are highly associated with medically intractable epilepsy. They have been classified into neuropathological subtypes (type Ia, Ib, IIa, IIb, and III) based on the severity of cytoarchitectural disruption--tangential or radial dispersion, or loss of laminar structure--and the presence of unique cells types such as cytomegalic neurons or balloon cells. Most focal cortical dysplasias can be identified on neuroimaging and many require resective epilepsy surgery to cure refractory seizures. The pathogenesis of focal cortical dysplasias remains to be defined, although there is recent evidence to suggest that focal cortical dysplasias arise from de novo somatic mutations occurring during brain development. Some focal cortical dysplasia subtypes show a link to the mammalian target of rapamycin signaling cascade; this has now extended to other cortical malformations, including hemimegalencephaly. PMID- 26060900 TI - Tumors in Epilepsy. AB - Primary brain tumors are common causes of focal epilepsy, accounting for 5% of new-onset seizures in adults and over 10% of lesional focal epilepsies. These epilepsies are often refractory to medical treatment, and high rates of seizure freedom can be achieved with gross total resections. However, the management strategy is not straightforward, and should be decided on a case-by-case basis in a multidisciplinary team, considering the natural history of the tumor, the likelihood of seizure freedom following surgical resection, the risks of surgery, and the impact of seizures on quality of life. In this review, the authors summarize the crucial factors that help to decide how to manage this challenging patient group. PMID- 26060901 TI - The Epidemiology of Posttraumatic Epilepsy. AB - Traumatic brain injury is an important contributor to morbidity and mortality, and results in reduced quality of life and lifespan: An estimated 1.7 million traumatic brain injuries occur annually in the United States alone. Traumatic brain injury carries an increased risk of epilepsy that correlates with the severity of the brain injury. Posttraumatic epilepsy accounts for less than 10% of epilepsy, but traumatic brain injury is one of only a few potentially preventable causes of epilepsy. Despite several well-controlled human studies, there is no current preventive treatment available for humans. Therefore, primary prevention is the only proven way to prevent posttraumatic epilepsy. PMID- 26060902 TI - Intracranial Vascular Malformations and Epilepsy. AB - Among the spectrum of intracranial vascular malformations (IVMs), arteriovenous malformations (AVMs), and cavernous malformations (CCMs) are of particular importance for epilepsy. Seizures are a common mode of presentation for both conditions. Seizures may occur de novo or secondary to intracerebral hemorrhage. Timely imaging is thus crucial for patients with seizures and AVMs or CCMs. Patients with a first-ever AVM- or CCM-related seizure can now be considered to have epilepsy according to the International League Against Epilepsy criteria. Observational studies and case series suggest that between 45 to 78% of patients with AVM-related epilepsy and 47 to 60% of patients with CCM-related epilepsy may achieve seizure freedom through antiepileptic drugs (AEDs) alone. Invasive procedures are available although current evidence suggests that epilepsy specific preintervention evaluations are underused. Randomized controlled trials and population-based studies have demonstrated worse short-term functional outcomes after routine intervention on unruptured AVMs or CCMs when compared with conservative management. The role of invasive therapy for IVM-related epilepsy has yielded mixed results. Case series have reported high estimates of seizure freedom although these results have not been replicated in controlled observational studies. Randomized controlled trials of immediate invasive therapy versus conservative management, in addition to usual care with AEDs and of different types of treatment and their timing, are warranted for AVMs and CCM related epilepsy. PMID- 26060903 TI - Infective Causes of Epilepsy. AB - A wide range of infections of the central nervous system are responsible for both acute seizures and epilepsy. The pathogenesis and clinical semiology of the seizure disorders vary widely between the infective pathogens. The exact mechanisms underlying this are poorly understood, but appear, at least in part, to relate to the pathogen; the degree of cortical involvement; delays in treatment; and the host inflammatory response. The treatment of infective causes of seizures involves both symptomatic treatment with antiepileptic drugs and direct treatment of the underlying condition. In many cases, early treatment of the infection may affect the prognosis of the epilepsy syndrome. The greatest burden of acute and long-term infection-related seizures occurs in resource-poor settings, where both clinical and research facilities are often lacking to manage such patients adequately. Nevertheless, education programs may go a long way toward addressing the stigma, leading to improved diagnosis, management, and ultimately to better quality of life. PMID- 26060904 TI - Autoimmune Epilepsy. AB - Seizures are recognized as a common manifestation of autoimmune limbic encephalitis and multifocal paraneoplastic disorders, but accumulating evidence supports an autoimmune basis for seizures in the absence of syndromic manifestations of encephalitis. Autoimmune encephalitis and epilepsy have been linked to neural-specific autoantibodies targeting both intracellular and plasma membrane antigens. The detection of these antibodies can serve as a diagnostic marker directing physicians toward specific cancers and can assist in therapeutic decision-making, but are not necessary to establish the diagnosis. Response to an immunotherapy trial can support the diagnosis and help establish prognosis. Early recognition is important because expedited diagnosis can facilitate recovery. In this review, the authors summarize the clinical presentation, pathophysiology, and management of autoimmune epilepsies for which neural antigen-specific autoantibodies serve as diagnostic aids. PMID- 26060905 TI - Rasmussen Syndrome and Other Inflammatory Epilepsies. AB - An underlying immune basis is emerging in an increasing number of epileptic and encephalopathic syndromes. The immunopathological mechanisms may be categorized into antibody-mediated, T-cell cytotoxicity, and microglia-induced degeneration. The immune basis in Rasmussen syndrome is thought to be T-cell mediated. Antibodies to extracellular and intracellular epitopes are implicated in limbic and other encephalitides, characterized by seizures, movement disorder, sleep disorder, obtundation, psychosis, mutism, and other psychiatric symptoms. Extracellular antibodies are directed at cell-surface-expressed neuronal or glial proteins: glutamate receptors (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5 methyl-4-isoxazol-propionic acid), voltage-gated potassium channel complex (contactin-associated-protein 2 [CASPR2], contactin-2 and leucin-rich, glioma inactivated 1 [LGI1]), and gamma-aminobutyric acid (GABA) receptors (GABABR and GABAAR). Antibodies to intracellular antigens are less commonly seen (for example, glutamic acid decarboxylase). Diseases caused by antibodies to cell surface-expressed antigens are better expected to respond to immune treatments than to those where the presumed mechanism is T-cell driven. Antibodies to the folate receptor FR1 are a cause of primary cerebral folate deficiency. Febrile infection-related epilepsy syndrome (FIRES) may also have an immune basis, although this is yet to be proven. For all these epilepsies, the best treatment and the long-term outcomes are not yet clear. PMID- 26060906 TI - Epilepsy in Tuberous Sclerosis: Phenotypes, Mechanisms, and Treatments. AB - Epilepsy affects 75% to 90% of people with tuberous sclerosis, a multisystem genetic disorder. Although seizures can occur for the first time at any age, onset in infancy or childhood is usual. Around 30% of patients present with infantile spasms that often respond well to treatment with vigabatrin. Later seizures may occur as specific patterns, such as in Lennox-Gastaut syndrome, or with combinations of seizures including focal and multifocal seizures, and drop attacks. Most patients have two or more seizure types. Seizure control using current antiepileptic drugs is often unsatisfactory, leading to frequent polypharmacy. Epilepsy surgery has a place in the management of some patients. Mutations in the TSC1 and TSC2 genes that cause tuberous sclerosis lead to hyperactivation of signaling via the mammalian target of rapamycin complex 1 (mTORC1). Inhibitors of mTORC1 have recently been shown to be effective treatments for some manifestations of tuberous sclerosis; they are now being assessed as potential novel antiepileptic drugs in tuberous sclerosis and related disorders. PMID- 26060907 TI - Megalencephaly and Macrocephaly. AB - Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and behavioral problems; specific disorders have associations with overgrowth or abnormalities in other tissues. The molecular underpinnings of many of these disorders are now understood, providing insight into how dysregulation of critical pathways leads to disease. The advances in molecular understanding are leading to improved diagnosis of these conditions, as well as providing new avenues for therapeutic interventions. PMID- 26060908 TI - Genetic Causes of Generalized Epilepsies. AB - Generalized epilepsies, particularly the idiopathic or genetic generalized epilepsies (GGEs), represent some of the most common epilepsies. Clinical genetic data including family studies and twin studies provide compelling evidence for a prominent genetic impact. The first decade of the 21st century was marked by progress in understanding the basic biology of generalized epilepsies including generalized/genetic epilepsies with febrile seizures plus (GEFS+) and GGE through studies of large families, discovering causative mutations in SCN1A, SCN1B, GABRG2, and GABRA1. Subsequently, recurrent microdeletions at 15q13.3, 16p13.11, and 15q11.2 were found to be relevant risk factors for nonfamilial GGE. Genes for epileptic encephalopathies such as SLC2A1 were rediscovered in GGE, highlighting the biological continuum between different epilepsies. Genome-wide studies examining common genetic risk factors identified common variants in SCN1A, indicating a convergence of shared pathophysiological pathways in various types of epilepsies. In the era of next-generation sequencing, however, the GGEs appear more complex than expected, and small or moderately sized studies give only a limited genetic perspective. Thus, there is a strong impetus for large collaborative investigations on an international level. PMID- 26060909 TI - Progressive Myoclonus Epilepsies. AB - The progressive myoclonus epilepsies (PMEs) comprise a group of rare and heterogeneous disorders defined by the combination of action myoclonus, epileptic seizures, and progressive neurologic deterioration. Neurologic deterioration may include progressive cognitive decline, ataxia, neuropathy, and myopathy. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. The prognosis of a PME depends on the specific disease. Lafora disease, the neuronal ceroid lipofuscinoses, and the neuronopathic form of Gaucher disease have an invariably fatal course. In contrast, Unverricht-Lundborg disease has a much slower progression, and with adequate care many patients have a normal life span. The specific diseases that cause PME are diagnosed by recognition of their age of onset, the associated clinical symptoms, the clinical course, the pattern of inheritance, and by special investigations such as enzyme measurement, skin/muscle biopsy, or gene testing. PMID- 26060910 TI - Mitochondrial Causes of Epilepsy: Evaluation, Diagnosis, and Treatment. AB - Mitochondrial disorders are frequently associated with seizures. In this review, the authors discuss the seizure patterns and distinguishing features of mitochondrial epilepsy, alongside the indications for investigating, and how to investigate epilepsy from a mitochondrial perspective. Finally, they discuss management strategies for this complex group of patients. PMID- 26060911 TI - Epileptic Encephalopathies in Childhood: The Role of Genetic Testing. AB - The epileptic encephalopathies comprise a heterogeneous group of neurodevelopmental disorders characterized by marked epileptic activity associated with developmental regression. The genetic confirmation and classification of a clinical diagnosis in an individual may provide certainty in treatment decisions, prognosis, and evaluation of seizure recurrence risks and may also prevent unnecessary diagnostic investigations. Furthermore, without genetic testing it is challenging to classify the epileptic encephalopathies based on clinical and electroencephalogram features alone. The significant gain of knowledge of the past few years associated with improvement in genetic analyses allows for precise diagnoses in an increasing number of patients. As a consequence, known encephalopathies have been associated with even broader phenotypic ranges and novel entities constantly expand the spectrum of these disorders. Accordingly, many entities of this heterogeneous spectrum escape a precise classification using current nomenclatures. PMID- 26060912 TI - High Cytokine Levels in Tonsillitis Secretions Regardless of Presence of Beta Hemolytic Streptococci. AB - Acute pharyngotonsillitis denotes tonsillar inflammation caused by bacteria or viruses. Here, we investigated if beta-hemolytic streptococci (beta-HS) tonsillitis would differ in inflammatory mediator response from tonsillitis of other causes. Tonsillar secretions were obtained from 36 acute pharyngotonsillitis patients and 16 controls. Bacteria were cultured quantitatively and 18 different viruses were quantified by real-time polymerase chain reaction. Cytokine and prostaglandin E2 (PGE2) levels were determined by enzyme-linked immunosorbent assays. Almost half of the patients' tonsillar secretions yielded high counts of beta-HS, and most samples contained viruses, irrespective of whether beta-HS were present or not. The Epstein-Barr virus (EBV) was the most common virus (patients 62% and controls 13%). Compared to controls, patients' secretions had higher levels of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor (TNF), and PGE2, while few samples contained IL-12, IL-10, or interferon-gamma (IFN-gamma). The presence of beta-HS in tonsillitis secretions could not be distinguished by any of the measured mediators, while the presence of EBV DNA tended to be associated with enhanced levels of IL-1beta and IL-8. The results suggest a common inflammatory response in acute pharyngotonsillitis, regardless of causative agent. The suggested correlation between intense inflammation and the presence of EBV DNA in tonsillitis secretions may be due to reactivation of the virus and/or the EBV-containing B cells. PMID- 26060913 TI - Synthesis, Characterization, Antimicrobial Screening and Free-Radical Scavenging Activity of Some Novel Substituted Pyrazoles. AB - The present work deals with the synthesis of acetoxysulfonamide pyrazole derivatives, substituted 4,5-dihydropyrazole-1-carbothioamide and 4,5 dihydropyrazole-1-isonicotinoyl derivatives starting from substituted vanillin chalcones. Acetoxysulfonamide pyrazole derivatives were prepared from the reaction of chalcones with p-sulfamylphenylhydrazine followed by treatment with acetic anhydride. At the same time 4,5-dihydropyrazole-1-carbothioamide and 4,5 dihydropyrazole-1-isonicotinoyl derivatives were prepared from the reaction of chalcones with either thiosemicarbazide or isonicotinic acid hydrazide, respectively. The synthesized compounds were structurally characterized on the basis of IR, 1H-NMR, 13C-NMR spectral data and microanalyses. All of the newly isolated compounds were tested for their antimicrobial activities. The antimicrobial screening using the agar well-diffusion method revealed that the chloro derivatives are the most active ones. Moreover, the antioxidant and anti inflammatory activity of these chloro derivatives are also studied using the DPPH radical scavenging and NO radical scavenging methods, respectively. PMID- 26060914 TI - Efficient Esterification of Oxidized l-Glutathione and Other Small Peptides. AB - Oxidized l-glutathione was esterified to the tetra methyl ester using thionyl chloride in methanol solvent. Other alcohols were tested and the reaction progress was monitored via ESI-MS. This procedure proved to be compatible with other small peptides not containing serine and cysteine residues. In contrast to previously reported methods this procedure provided convenient access to esterified peptides requiring no purification, extended reaction times, or complicated reaction setups. PMID- 26060915 TI - Selenium Catalyzed Oxidation of Aldehydes: Green Synthesis of Carboxylic Acids and Esters. AB - The stoichiometric use of hydrogen peroxide in the presence of a selenium containing catalyst in water is here reported as a new ecofriendly protocol for the synthesis of variously functionalized carboxylic acids and esters. The method affords the desired products in good to excellent yields under very mild conditions starting directly from commercially available aldehydes. Using benzaldehyde as a prototype the gram scale synthesis of benzoic acid is described, in which the aqueous medium and the catalyst could be recycled at last five times while achieving an 87% overall yield. PMID- 26060916 TI - Role and Regulation of Glutathione Metabolism in Plasmodium falciparum. AB - Malaria in humans is caused by one of five species of obligate intracellular protozoan parasites of the genus Plasmodium. P. falciparum causes the most severe disease and is responsible for 600,000 deaths annually, primarily in Sub-Saharan Africa. It has long been suggested that during their development, malaria parasites are exposed to environmental and metabolic stresses. One strategy to drug discovery was to increase these stresses by interfering with the parasites' antioxidant and redox systems, which may be a valuable approach to disease intervention. Plasmodium possesses two redox systems-the thioredoxin and the glutathione system-with overlapping but also distinct functions. Glutathione is the most abundant low molecular weight redox active thiol in the parasites existing primarily in its reduced form representing an excellent thiol redox buffer. This allows for an efficient maintenance of the intracellular reducing environment of the parasite cytoplasm and its organelles. This review will highlight the mechanisms that are responsible for sustaining an adequate concentration of glutathione and maintaining its redox state in Plasmodium. It will provide a summary of the functions of the tripeptide and will discuss the potential of glutathione metabolism for drug discovery against human malaria parasites. PMID- 26060917 TI - Effects of Fusarium solani and F. oxysporum Infection on the Metabolism of Ginsenosides in American Ginseng Roots. AB - American ginseng (Panax quinquefolius L.) is a highly valuable herb widely used for medicinal treatments. Its pharmacologically important compounds are the ginsenosides, which are secondary metabolites in American ginseng root. The concentrations of ginsenoside in roots can be changed by fungal infection, but it is unclear what specific root tissues are impacted and whether the change is systemic. In this study, American ginseng roots were inoculated with two fungal pathogens (Fusarium solani or F. oxysporum) and the levels of six ginsenosides (Rb1, Rb2, Rc, Rd, Re, and Rg1) were then measured in the phloem and xylem around the discolored lesions and adjacent healthy areas of the root. Results indicated that the growth of Fusarium spp. was strictly limited to phloem, and correspondingly the ginsenoside concentration was only altered in this infected phloem. The concentration of Rg1, Rd, and Rc significantly changed in phloem tissues where F. solani was inoculated, while only Rg1 and Rd changed significantly after F. oxysporum inoculation. However, no changes of any ginsenoside occurred in either xylem or phloem tissue adjacent to the inoculation point. In addition, when two Fusarium spp. were grown on ginsenoside-amended Czapek medium, the majority of ginsenosides were depleted. Therefore, pathogenic Fusarium spp. may reduce ginsenoside levels by consuming them. PMID- 26060918 TI - Analysis of Flavonoids in Lotus (Nelumbo nucifera) Leaves and Their Antioxidant Activity Using Macroporous Resin Chromatography Coupled with LC-MS/MS and Antioxidant Biochemical Assays. AB - Lotus (Nelumbo nucifera) leaves, a traditional Chinese medicinal herb, are rich in flavonoids. In an effort to thoroughly analyze their flavonoid components, macroporous resin chromatography coupled with HPLC-MS/MS was employed to simultaneously enrich and identify flavonoids from lotus leaves. Flavonoids extracted from lotus leaves were selectively enriched in the macroporous resin column, eluted subsequently as fraction II, and successively subjected to analysis with the HPLC-MS/MS and bioactivity assays. Altogether, fourteen flavonoids were identified, four of which were identified from lotus leaves for the first time, including quercetin 3-O-rhamnopyranosyl-(1->2)-glucopyranoside, quercetin 3-O-arabinoside, diosmetin 7-O-hexose, and isorhamnetin 3-O-arabino- pyranosyl-(1->2)-glucopyranoside. Further bioactivity assays revealed that these flavonoids from lotus leaves possess strong antioxidant activity, and demonstrate very good potential to be explored as food supplements or even pharmaceutical products to improve human health. PMID- 26060919 TI - Continuous Polyol Synthesis of Metal and Metal Oxide Nanoparticles Using a Segmented Flow Tubular Reactor (SFTR). AB - Over the last years a new type of tubular plug flow reactor, the segmented flow tubular reactor (SFTR), has proven its versatility and robustness through the water-based synthesis of precipitates as varied as CaCO3, BaTiO3, Mn(1 x)NixC2O4.2H2O, YBa oxalates, copper oxalate, ZnS, ZnO, iron oxides, and TiO2 produced with a high powder quality (phase composition, particle size, and shape) and high reproducibility. The SFTR has been developed to overcome the classical problems of powder production scale-up from batch processes, which are mainly linked with mass and heat transfer. Recently, the SFTR concept has been further developed and applied for the synthesis of metals, metal oxides, and salts in form of nano- or micro-particles in organic solvents. This has been done by increasing the working temperature and modifying the particle carrying solvent. In this paper we summarize the experimental results for four materials prepared according to the polyol synthesis route combined with the SFTR. CeO2, Ni, Ag, and Ca3(PO4)2 nanoparticles (NPs) can be obtained with a production rate of about 1 10 g per h. The production was carried out for several hours with constant product quality. These findings further corroborate the reliability and versatility of the SFTR for high throughput powder production. PMID- 26060920 TI - Kinetics of the Reaction of Pyrogallol Red, a Polyphenolic Dye, with Nitrous Acid: Role of ?NO and ?NO2. AB - In the present work we studied the reaction under gastric conditions of pyrogallol red (PGR), a polyphenolic dye, with nitrous acid (HONO). PGR has been used as a model polyphenol due to its strong UV-visible absorption and its high reactivity towards reactive species (radicals and non-radicals, RS). The reaction was followed by UV-visible spectroscopy and high performance liquid chromatography (HPLC). A clear decrease of the PGR absorbance at 465 nm was observed, evidencing an efficient bleaching of PGR by HONO. In the initial stages of the reaction, each HONO molecule nearly consumed 2.6 PGR molecules while, at long reaction times, ca. 7.0 dye molecules were consumed per each reacted HONO. This result is interpreted in terms of HONO recycling. During the PGR-HONO reaction, nitric oxide was generated in the micromolar range. In addition, the rate of PGR consumption induced by HONO was almost totally abated by argon bubbling, emphasising the role that critical volatile intermediates, such as ?NO and/or nitrogen dioxide (?NO2), play in the bleaching of this phenolic compound. PMID- 26060921 TI - Microwave-Assisted Synthesis of Cinnamyl Long Chain Aroma Esters. AB - Cinnamyl long chain aroma esters were prepared by using the conventional and microwave-assisted methods. The esterification reaction of naturally occurring 3 phenyl-prop-2-en-1-ol and different chain lengths acidic and diol reagents was carried out at the temperature of 140 degrees C under solvent free conditions. As acidic reagents, oxolane-2,5-dione, oxane-2,6-dione, hexanedioic acid and decanedioic acid were applied. Ethane-1,2-diol and 2,2'-[oxybis(2,1 ethandiyloxy)]diethanol were used as diol reagents. The synthesis of high molecular mass cinnamyl esters under conventional method conditions requires a long time to obtain high yields. The studies confirm that by using microwave irradiation, it is possible to reduce the reaction times to only 10-20 min. The structures of prepared esters were confirmed on the basis of FTIR, 1H-NMR and 13C NMR. In addition, the newly obtained cinnamyl long chain esters were tested for their thermal properties. The TG studies proved the high thermal resistance of the obtained esters under inert and oxidative conditions. PMID- 26060922 TI - Antiviral, Antifungal and Antibacterial Activities of a BODIPY-Based Photosensitizer. AB - Antimicrobial photodynamic inactivation (aPDI) employing the BODIPY-based photosensitizer 2,6-diiodo-1,3,5,7-tetramethyl-8-(N-methyl-4-pyridyl)-4,4' difluoro-boradiazaindacene (DIMPy-BODIPY) was explored in an in vitro assay against six species of bacteria (eight total strains), three species of yeast, and three viruses as a complementary approach to their current drug-based or non existent treatments. Our best results achieved a noteworthy 5-6 log unit reduction in CFU at 0.1 MUM for Staphylococcus aureus (ATCC-2913), methicillin resistant S. aureus (ATCC-44), and vancomycin-resistant Enterococcus faecium (ATCC-2320), a 4-5 log unit reduction for Acinetobacter baumannii ATCC-19606 (0.25 MUM), multidrug resistant A. baumannii ATCC-1605 (0.1 MUM), Pseudomonas aeruginosa ATCC-97 (0.5 MUM), and Klebsiella pneumoniae ATCC-2146 (1 MUM), and a 3 log unit reduction for Mycobacterium smegmatis mc2155 (ATCC-700084). A 5 log unit reduction in CFU was observed for Candida albicans ATCC-90028 (1 MUM) and Cryptococcus neoformans ATCC-64538 (0.5 MUM), and a 3 log unit reduction was noted for Candida glabrata ATCC-15545 (1 MUM). Infectivity was reduced by 6 log units in dengue 1 (0.1 MUM), by 5 log units (0.5 MUM) in vesicular stomatitis virus, and by 2 log units (5 MUM) in human adenovirus-5. Overall, the results demonstrate that DIMPy-BODIPY exhibits antiviral, antibacterial and antifungal photodynamic inactivation at nanomolar concentrations and short illumination times. PMID- 26060923 TI - Entanglement dynamics in the presence of controlled unital noise. AB - Quantum entanglement is notorious for being a very fragile resource. Significant efforts have been put into the study of entanglement degradation in the presence of a realistic noisy environment. Here, we present a theoretical and an experimental study of the decoherence properties of entangled pairs of qubits. The entanglement dynamics of maximally entangled qubit pairs is shown to be related in a simple way to the noise representation in the Bloch sphere picture. We derive the entanglement level in the case when both qubits of a Bell state are transmitted through any arbitrary unital Pauli channel, and compare it to the case when the channel is applied only to one of the qubits. The dynamics of both cases was verified experimentally using an all-optical setup. We further investigated the evolution of partially entangled initial states. Different dynamics was observed for initial mixed and pure states of the same entanglement level. PMID- 26060924 TI - Achieving consensus and controversy around applicability of palliative care to dementia. AB - BACKGROUND: People with dementia may benefit from palliative care which specifically addresses the needs of patients and families affected by this life limiting disease. On behalf of the European Association for Palliative Care (EAPC), we recently performed a Delphi study to define domains for palliative care in dementia and to provide recommendations for optimal care. An international panel of experts in palliative care, dementia care or both, achieved consensus on almost all domains and recommendations, but the domain concerning the applicability of palliative care to dementia required revision. METHODS: To examine in detail, the opinions of the international panel of 64 experts around the applicability of palliative care, we explored feedback they provided in the Delphi process. To examine which experts found it less important or less applicable, ordinal regression analyses related characteristics of the panelists to ratings of overall importance of the applicability domain, and to agreement with the domain's four recommendations. RESULTS: Some experts expressed concerns about bringing up end-of-life issues prematurely and about relabeling dementia care as palliative care. Multivariable analyses with the two outcomes of importance and agreement with applicability indicated that younger or less experienced experts and those whose expertise was predominantly in dementia care found palliative care in dementia less important and less applicable. CONCLUSIONS: Benefits of palliative care in dementia are acknowledged by experts worldwide, but there is some controversy around its early introduction. Further studies should weigh concerns expressed around care receiving a "palliative" label versus the benefits of applying palliative care early. PMID- 26060925 TI - Interaction of different prototropic species of an anticancer drug ellipticine with HSA and IgG proteins: multispectroscopic and molecular modeling studies. AB - Studies on interactions between an anticancer alkaloid, ellipticine, and various carrier proteins in blood serum show tangible results to gain insight into the solubility and transport of the drug under physiological conditions. In this report, we extensively studied the interactions of different prototropic species of ellipticine with two prominent serum proteins namely human serum albumin (HSA) and immunoglobulin G (IgG) in their native and partially unfolded states using steady state and time resolved fluorescence spectroscopy, molecular docking and circular dichroism (CD). Both the fluorescence techniques and molecular modeling studies elucidate that only neutral species of ellipticine binds to HSA in the sudlow site II. Unlike HSA, IgG in the native state mostly binds to cationic species of ellipticine. However, in partially unfolded configuration, IgG binds to the neutral ellipticine molecules. Molecular docking studies indicate the prevalence of electrostatic interactions involving charged residues in the binding process of cationic species of ellipticine with native IgG in its Fab region. In native conformation, the hydrophobic residues of the Fab region are found to be buried completely by the ligand. This implies that the hydrophobic interaction will be favored by unfolding of IgG through which the hydrophobic pocket will be more accessible to neutral species of ellipticine. The circular dichroism measurements reveal that upon interaction with ellipticine, heat and acid treated HSA resumes its alpha-helical content. This conclusive comparative study on interactions of IgG and HSA with ellipticine yields the result that native HSA is responsible for transport of neutral species of ellipticine whereas IgG carries cationic ellipticine in its native form. PMID- 26060926 TI - The Interrater Reliability of Subjective Assessments of the Babinski Reflex. AB - The Babinski reflex is a clinical diagnostic tool; however, the interrater reliability of this tool is currently greatly contested. A comparison between rater groups with objective measurements of the Babinski reflex was therefore conducted. Fifteen recorded Babinski reflexes were assessed by 12 neurologists and 12 medical students as being either pathological or nonpathological. Kinematic and electromyographic variables were collected and used to assess which aspects of the Babinski reflex predict classification. Substantial interrater agreement within the neurologist and student groups (kappa = .72 and .67, respectively) was shown; however, there were some differing aspects between what neurologists and students used to assess the reflex as determined by objective kinematic measurements. PMID- 26060927 TI - Comparison between EGSnrc, Geant4, MCNP5 and Penelope for mono-energetic electron beams. AB - A simple geometry is chosen to highlight similarities and differences of current electron transport algorithms implemented in four Monte Carlo codes commonly used in radiation physics. Energy deposited in a water-filled sphere by mono-energetic electron beams was calculated using EGSnrc, Geant4, MCNP5 and Penelope as the radius of the sphere varied from 0.25 cm to 4.5 cm for beam energies of 0.5 MeV, 1.0 MeV and 5.0 MeV. The calculations were performed in single-scattering mode (where applicable) and in condensed history mode. A good agreement is found for the single-scattering calculations except for the in-air case at 0.5 MeV where differences increase with decreasing radius up to 5% between EGSnrc and Penelope. Differences between results calculated with the default user settings when compared to their own single-scattering modes are under 5% for all codes when the sphere is surrounded by vacuum, however, large differences occur for Geant4, MCNP5 and Penelope when air is introduced around the sphere. Finally, the parameters associated with the multiple scattering algorithms were tuned reducing these differences below 10% for these codes at the expense of increased computation time. PMID- 26060928 TI - Faciobrachial dystonic seizures associated with Hashimoto encephalopathy. PMID- 26060929 TI - Head injury, alpha-synuclein Rep1 and Parkinson's disease: a meta-analytic view of gene-environment interaction. PMID- 26060931 TI - Review and the state of the art: Sol-gel and melt quenched bioactive glasses for tissue engineering. AB - Biomaterial development is currently the most active research area in the field of biomedical engineering. The bioglasses possess immense potential for being the ideal biomaterials due to their high adaptiveness to the biological environment as well as tunable properties. Bioglasses like 45S5 has shown great clinical success over the past 10 years. The bioglasses like 45S5 were prepared using melt quenching techniques but recently porous bioactive glasses have been derived through sol-gel process. The synthesis route exhibits marked effect on the specific surface area, as well as degradability of the material. This article is an attempt to provide state of the art of the sol-gel and melt quenched bioactive bioglasses for tissue regeneration. Fabrication routes for bioglasses suitable for bone tissue engineering are highlighted and the effect of these fabrication techniques on the porosity, pore-volume, mechanical properties, cytocompatibilty and especially apatite layer formation on the surface of bioglasses is analyzed in detail. Drug delivery capability of bioglasses is addressed shortly along with the bioactivity of mesoporous glasses. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1248-1275, 2016. PMID- 26060932 TI - Ecobiotherapy Rich in Firmicutes Decreases Susceptibility to Colitis in a Humanized Gnotobiotic Mouse Model. AB - BACKGROUND: Alterations in the intestinal microbiota, characterized by depletion of anti-inflammatory bacteria, such as Firmicutes, in patients with ulcerative colitis (UC) have prompted interest in microbiota-modulating strategies for this condition. The aim of this study was to evaluate the role of fecal and synthetic human microbial ecosystems, low or enriched in Firmicutes, on colitis susceptibility and host immune responses. METHODS: The microbiota of selected healthy and UC human donors was characterized by culture method and 16S rRNA based sequencing. Germ-free mice were colonized with fecal or a synthetic ecosystem enriched (healthy donors) or low (UC donors) in Firmicutes. Experimental colitis was induced using dextran sodium sulfate. Colon transcriptome and colon lamina propria cells were evaluated in mice postcolonization by RNA-seq and flow cytometry, respectively, and T helper (TH) 17 differentiation was assessed in vitro. RESULTS: Mice colonized with microbiota from patients with UC low in Firmicutes had increased sensitivity to colitis compared with mice colonized with fecal or synthetic ecosystems rich in Firmicutes. Microbiota low in Firmicutes increased expression of TH17-related genes and expansion of interleukin-17A-expressing CD4 cells in vivo. Supplementation with bacterial isolates belonging to the Firmicutes phylum abrogated the heightened TH17 responses in vitro. CONCLUSIONS: A microbiota rich in Firmicutes derived from fecal samples of a healthy human donor, or assembled synthetically, downregulated colonic inflammation and TH17 pathways in mice. The results support the use of ecobiotherapy strategies, enriched in Firmicutes, for the prevention or treatment of UC. PMID- 26060933 TI - A Facile Surfactant-Assisted Reflux Method for the Synthesis of Single Crystalline Sb2Te3 Nanostructures with Enhanced Thermoelectric Performance. AB - Antimony telluride (Sb2Te3) and its based alloys are of importance to p-type semiconductors for thermoelectric applications near room temperature. Herein, we report a simple, low-energy intensive, and scalable surfactant-assisted reflux method for the synthesis of Sb2Te3 nanoparticles in the solvent ethylene glycol (EG) at low temperatures (120-180 degrees C). The formation mechanism of platelike Sb2Te3 nanoparticles is proposed. Also, it is found that the size, shape, and chemical composition of the products could be controlled by the introduction of organic surfactants (CTAB, PVP, etc.) or inorganic salts (EDTA Na2, NaOH, etc.). Additionally, the collected Sb2Te3 nanoparticles were further fabricated into nanostructured pellets using cold-compaction and annealing techniques. Low resistivity [(7.37-19.4) * 10(-6) Omega m], moderate Seebeck coefficient (103-141 MUV K(-1)), and high power factor (10-16 * 10(-4) W m(-1) K( 2)) have been achieved in our Sb2Te3-nanostructured bulk materials. The relatively low thermal conductivity (1.32-1.55 W m(-1) K(-1)) is attained in the nanobulk made of PVP-modified nanoparticles, and values of ZT in the range of 0.24-0.37 are realized at temperatures ranging from 50 to 200 degrees C. Our researches set forth a new avenue in promoting practical applications of Sb2Te3 based thermoelectric power generation or cooling devices. PMID- 26060934 TI - Automated drawing of network plots in network meta-analysis. AB - In systematic reviews based on network meta-analysis, the network structure should be visualized. Network plots often have been drawn by hand using generic graphical software. A typical way of drawing networks, also implemented in statistical software for network meta-analysis, is a circular representation, often with many crossing lines. We use methods from graph theory in order to generate network plots in an automated way. We give a number of requirements for graph drawing and present an algorithm that fits prespecified ideal distances between the nodes representing the treatments. The method was implemented in the function netgraph of the R package netmeta and applied to a number of networks from the literature. We show that graph representations with a small number of crossing lines are often preferable to circular representations. PMID- 26060935 TI - Thermal Stability of Ettringite Exposed to Atmosphere: Implications for the Uptake of Harmful Ions by Cement. AB - The decomposition behavior of ettringite, Ca6Al2(SO4)3(OH)12.26H2O, at different temperatures was studied by means of isothermal XRD experiments, in which the evolution of the solid is monitored as a function of time. The experiments were performed at 40, 50, 55, and 60 degrees C for a natural ettringite specimen. The experimental data were used to construct a temperature-transformation-time (TTT) diagram. Such a diagram enables the prediction of the reaction pathways during the transformation process. The decomposition behavior was also studied under nonisothermal conditions using thermogravimetry and differential scanning calorimetry, and the obtained results were correlated with the results of the XRD study. Finally, the transformation kinetics and the activation energy (Ea = 246.1 kJ.mol(-1)) of the reaction were estimated using the so-called "time to a given fraction" method. The temperature at which the initial transformation stage occurs (lower than 50 degrees C) indicates that ettringite cannot be considered a suitable host phase for the immobilization of radionuclides and other harmful elements, as is frequently proposed in the literature. PMID- 26060936 TI - Topical Application of Oleuropein Induces Anagen Hair Growth in Telogen Mouse Skin. AB - METHODOLOGY AND PRINCIPAL FINDINGS: Oleuropein promoted cultured human follicle dermal papilla cell proliferation and induced LEF1 and Cyc-D1 mRNA expression and beta-catenin protein expression in dermal papilla cells. Nuclear accumulation of beta-catenin in dermal papilla cells was observed after oleuropein treatment. Topical application of oleuropein (0.4 mg/mouse/day) to C57BL/6N mice accelerated the hair-growth induction and increased the size of hair follicles in telogenic mouse skin. The oleuropein-treated mouse skin showed substantial upregulation of Wnt10b, FZDR1, LRP5, LEF1, Cyc-D1, IGF-1, KGF, HGF, and VEGF mRNA expression and beta-catenin protein expression. CONCLUSIONS AND SIGNIFICANCE: These results demonstrate that topical oleuroepin administration induced anagenic hair growth in telogenic C57BL/6N mouse skin. The hair-growth promoting effect of oleuropein in mice appeared to be associated with the stimulation of the Wnt10b/beta-catenin signaling pathway and the upregulation of IGF-1, KGF, HGF, and VEGF gene expression in mouse skin tissue. PMID- 26060937 TI - Exploring the potential of gold(III) cyclometallated compounds as cytotoxic agents: variations on the C^N theme. AB - A series of novel (C^N) cyclometallated Au(III) complexes of general formula [Au(py(b)-H)L(1)L(2)](n+) (py(b)-H = C^N cyclometallated 2-benzylpyridine, L(1) and L(2) being chlorido, phosphane or glucosethiolato ligands, n = 0 or 1) have been synthesized and fully characterized using different techniques, including NMR, IR and far-IR, mass spectrometry, as well as elemental analysis. The crystal structure of one compound has been solved using X-ray diffraction methods. All compounds were tested in vitro in five human cancer cell lines including the lung, breast, colon and ovarian cancer cells. For comparison purposes, all compounds were also tested in a model of healthy human cells from the embryonic kidney. Notably, all new compounds were more toxic than their cyclometallated precursor bearing two chlorido ligands, and the derivative bearing one phosphane ligand presented the most promising toxicity profile in our in vitro screening, displaying a p53 dependent activity in colorectal cancer HCT116 cells. Finally, for the first time C^N cyclometallated gold(III) complexes were shown to be potent inhibitors of the zinc finger protein PARP-1, involved in the mechanism of cisplatin resistance. PMID- 26060938 TI - Habitat-mediated carry-over effects lead to context-dependent outcomes of species interactions. AB - When individuals disperse, their performance in newly colonized habitats can be influenced by the conditions they experienced in the past, leading to environmental carry-over effects. While carry-over effects are ubiquitous in animal and plant systems, their impact on species interactions and coexistence are largely ignored in traditional coexistence theory. Here we used a combination of modelling and experiments with two competing species to examine when and how such environmental carry-over effects influence community dynamics and competitive exclusions. We found that variation in the natal habitat quality of colonizing individuals created carry-over effects which altered competitive coefficients, fecundity and mortality rates, and extinction probabilities of both species. As a consequence, the dynamics of competitive exclusion within and across habitat types was contingent on the natal habitat of colonizing individuals, indicating that spatial carry-over effects can fundamentally alter the dynamics and outcome of interspecific competition. Interestingly, carry-over effects persistently influenced dynamics in systems with interspecific competition for the entire duration of the experiment while carry-over effects were transient and only influenced initial dynamics in single-species populations. Thus carry-over effects can be enhanced by species interactions, suggesting that their long-term effects may often not be accurately predicted by single-species studies. Given that carry-over effects are ubiquitous in heterogeneous landscapes, our results provide a novel mechanism that could help explain variation in the structure of natural communities. PMID- 26060939 TI - Searching for anthranilic acid-based thumb pocket 2 HCV NS5B polymerase inhibitors through a combination of molecular docking, 3D-QSAR and virtual screening. AB - A combination of the following computational methods: (i) molecular docking, (ii) 3-D Quantitative Structure Activity Relationship Comparative Molecular Field Analysis (3D-QSAR CoMFA), (iii) similarity search and (iv) virtual screening using PubChem database was applied to identify new anthranilic acid-based inhibitors of hepatitis C virus (HCV) replication. A number of known inhibitors were initially docked into the "Thumb Pocket 2" allosteric site of the crystal structure of the enzyme HCV RNA-dependent RNA polymerase (NS5B GT1b). Then, the CoMFA fields were generated through a receptor-based alignment of docking poses to build a validated and stable 3D-QSAR CoMFA model. The proposed model can be first utilized to get insight into the molecular features that promote bioactivity, and then within a virtual screening procedure, it can be used to estimate the activity of novel potential bioactive compounds prior to their synthesis and biological tests. PMID- 26060940 TI - Broadband laser polarization control with aligned carbon nanotubes. AB - We introduce a simple approach to fabricate an aligned carbon nanotube (ACNT) device for broadband polarization control in fiber laser systems. The ACNT device was fabricated by pulling from as-fabricated vertically-aligned carbon nanotube arrays. Their anisotropic properties are confirmed with various microscopy techniques. The device was then integrated into fiber laser systems (at two technologically important wavelengths of 1 and 1.5 MUm) for polarization control. We obtained a linearly-polarized light output with the maximum extinction ratio of ~12 dB. The output polarization direction could be fully controlled by the ACNT alignment direction in both lasers. To the best of our knowledge, this is the first time that the ACNT device is applied to polarization control in laser systems. Our results exhibit that the ACNT device is a simple, low-cost, and broadband polarizer to control laser polarization dynamics, for various photonic applications (such as material processing, polarization diversity detection in communications etc.), where linear polarization control is necessary. PMID- 26060941 TI - An anatomic-based approach to the iatrogenic spinal accessory nerve injury in the posterior cervical triangle: How to avoid and treat it. AB - Iatrogenic injury of the spinal accessory nerve (SAN) is a significant reducible risk with any invasive procedure involving the posterior cervical triangle. Most commonly associated with cervical lymph node biopsy, it affects 3-6% of patients and serves as a major cause of avoidable medical malpractice litigation. Medical malpractice cases not only affect the primary surgeon but also may include the repairing surgeon through a shift of blame. For this reason, we discuss the strategies all clinicians may utilize in approaching iatrogenic SAN injuries. By taking basic precautionary measures based on simple application of anatomy in the management of these patients, clinicians may protect themselves from needless malpractice litigation. A thorough knowledge of the anatomy and application in preventative strategies may provide guidance for clinicians in reducing the incidence of iatrogenic injuries, providing effective postinjury management, and ensuring the salvaging surgeon is not at fault if litigation is pursued. PMID- 26060943 TI - Challenges to preventing suicide in later life. PMID- 26060942 TI - Sex Offenders Seeking Treatment for Sexual Dysfunction--Ethics, Medicine, and the Law. AB - INTRODUCTION: The treatment of sexual dysfunction in patients with prior sexual offenses poses ethical and legal dilemmas. Sex offenders are not obligated by law to disclose this history to medical professionals. Over 20% of sex offenders experience sexual dysfunction; however, the number of sex offenders seeking evaluation for sexual dysfunction is unknown. AIMS: The aims of this study were to determine the incidence and characteristics of sex offenders seeking treatment in our clinic; and to review data regarding sex offender recidivism and ethics pertaining to the issue as it relates to treating physicians. METHODS: Sex offenders were identified via three methods: new patient screening in a dedicated sexual medicine clinic, chart review of those on intracavernosal injection (ICI) therapy for erectile dysfunction (ED), and review of patient's status-post placement of penile prosthesis. Charts were cross-referenced with the U.S. Department of Justice National Sex Offender Public Website. Patient characteristics and details of offenses were collected. MAIN OUTCOME MEASURES: The main outcome measures used were a self-reported sexual offense and national registry data. RESULTS: Eighteen male sex offenders were identified: 13 via new patient screening; 3 by review of ICI patients; 1 by review of penile prosthesis data; and 1 prior to penile prosthesis placement. All were primarily referred for ED. Of those with known offenses, 64% were level 3 offenders (most likely to re offend). The same number had committed crimes against children. All those with complete data had multiple counts of misconduct (average 3.6). Ninety-four percent (17/18) had publicly funded health care. Twelve (67%) were previously treated for sexual dysfunction. CONCLUSIONS: Registered sex offenders are seeking and receiving treatment for sexual dysfunction. It is unknown whether treatment of sexual dysfunction increases the risk of recidivism of sexual offenses. Physicians currently face a difficult choice in deciding whether to treat sexual dysfunction in sex offenders. PMID- 26060944 TI - Qualitative study on suicide attempts and ideations with 60 elderly in Brazil. AB - Sixty cases of suicidal attempts and ideations among elderly people from thirteen Brazilian municipalities were studied, with the objective of discovering, from what they had to say, their reasons and interpretations for attempting to take their own life. The study, with a hermeneutic and dialectic basis, was based on an interview guide, to steer the conversation with these individuals. It starts with a sociodemographic classification and looks in depth at the person's situation according to their social, community and family circumstances and their physical and mental health, functional capacity, and the reasons given for the suicidal ideations and attempts. This field information was first analysed locally and then cross-categorized according to the method used, severity of the events and reasons given by the elderly people, by sex, age, socioeconomic profile and risk and protection factors. A comprehensive, critical and interpretative summary was made of the material. The results show that failure to listen to and the isolation of elderly people, lack of awareness of the risks on the part of family, the association with physical and mental, functional, social and family losses and violence are predisposing factors, and concurrent in many cases. The conclusion is that vulnerability and self-neglect are reduced where there is family support, care and bonds of unity. PMID- 26060945 TI - Tools, strategies and qualitative approach in relation to suicidal attempts and ideation in the elderly. AB - The article analyses the quality and consistency of a comprehensive interview guide, adapted to study attempted suicide and its ideation among the elderly, and imparts the method followed in applying this tool. The objective is to show how the use of a semi-structured interview and the organization and data analysis set up were tested and perfected by a network of researchers from twelve universities or research centers in Brazil, Uruguay and Colombia. The method involved application and evaluation of the tool and joint production of an instruction manual on data collection, systematization and analysis. The methodology was followed in 67 interviews with elderly people of 60 or older and in 34 interviews with health professionals in thirteen Brazilian municipalities and in Montevideo and Bogota, allowing the consistency of the tool and the applicability of the method to be checked, during the process and at the end. The enhanced guide and the instructions for reproducing it are presented herein. The results indicate the suitability and credibility of this methodological approach, tested and certified in interdisciplinary and interinstitutional terms. PMID- 26060946 TI - Descriptive study of suicide attempts in the Brazilian elderly population, 2000 - 2014. AB - The study describes hospital admission rates for suicide attempts among the Brazilian elderly and discusses the weaknesses of data from information systems. Data were extracted from the Hospital Information System (HIS) and from the Violence and Injury Surveillance System (VIVA). The analyzes included: (1) temporal evolution of rates by age group (1-9; 10-19; 20-39; 40-59 and 60 or over) from 2000 to 2014 by region; (2) triennial hospital admission rates by sex for age groups 60-69, 70-79 and 80 or over by region and state; (3) hospital admission rates for the elderly from the two information systems. Temporal evolution showed higher rates in the north and lower ones in the northeast. The analysis by age group and sex showed higher rates for older men of the three investigated age groups. The comparison of rates obtained from the two information systems showed a gradual increase in rates from VIVA. After 2012, rates obtained from VIVA were higher in the Southeast, South and Midwest regions. The study highlights the need for further improvement of information on hospital morbidity and data from compulsory notification of violence. PMID- 26060947 TI - Suicide attempts and suicide ideation among the elderly in Uruguay. AB - An investigation is presented into Suicide Attempts (SA) among the Elderly in Uruguay conducted in 2014 in a Public Health institution in Montevideo linked to a Claves/Fiocruz project. Starting with an initial project, semi-structured interviews were conducted with institutionalized individuals with a history of suicide attempts, as well as a review of the literature and research into preventive norms and actions by public health authorities in the country. The results reveal difficulties of individuals in talking about SA as well as shame associated with aging. There was also a major difficulty talking about family ties, confirming gender differences in the method of SA and greater suicide ideation among women, although the possibility of SA repetition does not appear to be a concern. The study elicits reflection on the importance of attention, care, quality of life and the effects of institutionalized life upon the elderly. PMID- 26060948 TI - The influence of family problems and conflicts on suicidal ideation and suicide attempts in elderly people. AB - Family conflicts and problems involve meanings that are constructed during the course of an existence, and become associated with other factors in manifestations of suicidal thoughts and suicide attempts in elderly people. These questions are analyzed in a qualitative study of interviews with elderly people in four different locations in Brazil. A total of 63 men and women took part, and the interviews were held in 2013 and 2014. The field data showed the following factors - in order of the importance that the interviewees gave to them: significant family losses; family and inter-generation conflicts; and explicit and veiled violence. The speech of the subjects showed, as elements that led them to try to end their lives: sadness; feelings of abandonment; isolation, incomprehension of their desires by their family members, and absence of manifestations of affection and/or respect. When telling their stories, they also gave clues about what they expect from their families: welcome, acceptance, comprehension and freedom to carry out their minor wishes; to end their lives in a dignified manner without suffering; to find help and protection for the progressive reduction of their capacities; to continue to participate in family decisions, and to prolong to the maximum their social achievements and prerogatives, such as property, authority and respect. PMID- 26060949 TI - Is it possible to overcome suicidal ideation and suicide attempts? A study of the elderly. AB - This study presents a qualitative analysis of how older people who had attempted suicide began to overcome the desire and the urge to take their own life. This article is based on a survey of 87 Brazilian men and women aged 60 and over, living in different regions of Brazil, who have demonstrated suicidal behaviour; twenty of whom gave important information about their coping strategies. The analysis in this article only refers to the aforementioned twenty participants. All the participants were heard through semi-structured interviews, which included questions about the process of overcoming suicidal ideation and suicide attempts. The central focus of the analysis - overcoming suicidal ideation and suicide attempts - was based on the following concepts: coping strategies, autonomy, and emotional balance. Irrespective of the gender of the respondents, five centers of meaning emerged from the discourses of the elderly, which highlighted the effectiveness of the following factors: religiosity and religious practices; social and family support; the support of health services; contact with pets; and the recovery of the autonomy to manage their own lives. This study can help to support the primary and secondary prevention of suicidal behavior in older people. PMID- 26060950 TI - Suicide attempts by elderly women - from a gender perspective. AB - This article analyzes the presence of gender inequality and violence in the lives of elderly women who have attempted suicide. This survey is part of a qualitative research study developed in twelve municipal regions in Brazil with high levels of suicide, and is coordinated by Claves-Fiocruz. Information was obtained by means of semi-structured interviews with thirty-two women from a sampling of fifty-nine elderly women with a history of attempted suicide. It was decided not to identify the interviewees, and to construct a narrative based on events that have occurred in the lives of all these women. The study was based on the women's life cycle (infancy, youth, adult life and old age) to see if gender inequality had been an issue in each of these phases. The inequalities began in infancy with differentiated gender upbringing; these continued during their youth and with their sexual initiation, marriage and maturity these continued during their adult life through acts of violence committed by their partners and/ or other family members which culminates in old age, when they are deprived of their independence and have lost ties, possessions and points of reference. These lives permeated with violence result in a feeling of emptiness and unworthiness, and lead many elderly women to view death as their only solution. PMID- 26060951 TI - Suicidal ideation and attempted suicide in elderly people - subjective experiences. AB - We discuss the subjective experiences of elderly people who show suicidal ideation and/or attempts at suicide, based on their own reports. We understand the concept of 'subjective' as referring to intra-psychic experience resulting from social, economic, relationship or biographical conditions. Although the subject is sparsely covered in the literature, it is important, because it is in the field of subjectivity that ideations of, and attempts at, suicide develop and occur until they become a concrete act. Empirical data were collected through semi-structured interviews focusing on: social characterization, portrayal and mode of life, previous mental state, atmosphere of the attempt, effects on the health of the elderly person and family. Based on the analysis of the meanings that emerge, five empirical categories were generated: (1) subject's feeling of being in a non-place; (2) absence of acceptance of losses; (3) suffering due to ingratitude of family members; (4) feeling of uselessness of, and in, life; (5) re-signification of the situations that generate suicide-related conduct. The results point to a fundamental need to incorporate knowledge about the subjective processes into programs for prevention of suicide among the elderly who have ideation of, or attempts at, suicide. PMID- 26060952 TI - Convergence and Non-Convergence: stories of elderly who have attempted suicide and the Integrated Care System in Porto Alegre/RS, Brazil. AB - This article is the product of research undertaken in the city of Porto Alegre, in the Brazilian state of Rio Grande do Sul. The goal is to bring to light and discuss a little known phenomenon - attempted suicide by the elderly. Under reporting of suicide attempts among this population makes it difficult to place this serious public health problem on the political agenda. As part of this study, we interviewed not only elderly persons who had attempted suicide, but also their family members and mental health and emergency and urgent service professionals. These interviews took place during the course of 2014. From a textual discourse analysis of the various reports, there emerged a category we will call Convergence and Non-Convergence, which deals with the relationship between the elderly population's need for care and the healthcare model in use. This study uses three short stories of individuals to question the biomedical model of serving risk situations, stressing the concept of an Expanded Clinic to provide integrated healthcare. This concept focuses on the different types of care and the uniqueness of each user, which often the biomedical model neglects. This study also highlights the need to develop a line of care for the elderly, with investments in continued education about active aging and care in times of crises, articulating a cross-sectorial network. PMID- 26060953 TI - Suicide attempts among the elderly: a review of the literature (2002/2013). AB - A literature review was carried out focusing on the main factors associated with suicide attempts among the elderly. The research was conducted between 2002 and 2013 in the MEDLINE, Lilacs, Pubmed, PsychINFO, SciELO, the Virtual Library in Violence and Health from BIREME and the Virtual Library of Public Health databases. 105 texts were selected and 75 were analyzed. Studies are on the increase in North America, Europe and Asia, rare in Latin America and do not exist in Africa. The major causal factors for attempted suicide are degenerative and chronic diseases, physical dependence, mental disturbances and suffering, as well as severe depression. Depression is the most relevant cause found, combined with chronic physical suffering, loss, abandonment, loneliness and family conflicts. Differences in gender, ethnicity, the ageing process, social issues and cultural backgrounds are also major contributing factors. The subject of suicide attempts among the elderly is a problem that is extremely relevant to the Unified Health System (SUS); however, this problem is not addressed in Brazil in theoretical or practical terms. We trust that this review can serve as a model for empirical studies to contribute to health support for the elderly and promote health in old age. PMID- 26060954 TI - Health education as the main alternative to promote the health of the elderly. AB - This is an integrative review aimed to identify the scientific evidence on the educational health actions designed to promote the health of the elderly. A literature search was conducted in Medline, Lilacs, BDENF, CINAHL and in SciELO virtual library databases, by crossing the descriptors Education in Health, Elderly, Aging, Elderly Health, Health Promotion and Quality of Life, including articles conducted with elderly people published from 2003 to 2013, in English, Spanish and Portuguese. Eight articles, which presented quality of life and promotion of healthy aging as a result of health education strategies, were selected. Health education actions for elderly need methodologies that attend the complexity of the aging process and correlate the factors surrounding the individual, such as beliefs, values, norms and ways of life. PMID- 26060955 TI - Implementing International Health Regulation (2005) in the Brazilian legal administrative system. AB - The scope of this study was to analyze how the International Sanitary Regulation (ISR 2005)has been incorporated into the Brazilian legal-administrative system, in relation to sanitary control measures involving freight, means of transportation and travelers and possible alterations to health surveillance activities, competencies and procedures. This case study has been undertaken using a qualitative approach, of a descriptive and exploratory nature, using institutional data sources and interviews with key-informants involved in implementing ISR (2005). Alterations to the Brazilian legal-administrative system resulting from ISR (2005) were identified, in relation to standards, special competencies and procedures relating to sanitary controls for freight, modes of transportation and travelers. In its present form, the International Sanitary Regulation is an instrument that, in addition to introducing new international and national sanitary control concepts and elements, also helps to clarify questions that are helpful on a national level, relating to the specific competencies and procedures which will, to a certain extent, put pressure on administrative structures in the areas of sanitary control and surveillance. PMID- 26060956 TI - Izabel dos Santos and the training of the health workers. AB - This article discusses the career of Izabel dos Santos (1927-2010) as a means of examining the connections between health schools and agendas in contemporary Brazil. The article highlights dos Santos's training and her work in the Servico Especial de Saude Publica (SESP- Special Public Health Service), the Pan American Health Organization (PAHO) and in the formulation and implementation of national training programs for human resources within the area of health from the late 1970s onwards. The article highlights dos Santos's central role in the formulation and implementation of training policies for health workers, especially nursing technicians and assistants, and demonstrates how she occupies an important place in the history of Brazilian public health. PMID- 26060957 TI - Life stories, homeopathy and permanent education: construction of shared healthcare. AB - Taking its inspiration from the homeopathic method of collecting data, and acting in a context of permanent education in health, this study aimed to analyze the possibilities that can be offered for healthcare by construction of Life Histories, in organized encounters for collective elaboration of shared therapeutic projects. Some changes that arose from the use of this strategy are discussed: health workers and users changed their stances in relation to each other; teams looked at cases with a new approach; and both these developments appeared to have created stronger and more effective encounters to produce care. It is concluded that, in the ambit of this study, Life Histories, by intensifying the collective operation of soft technologies, in an invitation to the shared therapeutic project, increased the porosity of the teams, and the recognition of the user as a valid interlocutor. The conclusion favors reorientation of approach to the other technological levels in health work, and recognition of Life Histories as powerful elements for production of effective healthcare. PMID- 26060958 TI - The Care management Information system for the home Care Network (SI GESCAD): support for care coordination and continuity of care in the Brazilian Unified health system (SUS). AB - The present article describes the development of the initial version of the Brazilian Care Management Information System for the Home Care Network (SI GESCAD). This system was created to enhance comprehensive care, care coordination and the continuity of care provided to the patients, family and caretakers of the Home Care (HC) program. We also present a reflection on the contributions, limitations and possibilities of the SI GESCAD within the scope of the Home Care Network of the Brazilian Unified Health System (RAS-AD). This was a study on technology production based on a multi-method protocol. It discussed software engineering and human-computer interaction (HCI) based on user-centered design, as well as evolutionary and interactive software process (prototyping and spiral). A functional prototype of the GESCAD was finalized, which allowed for the management of HC to take into consideration the patient's social context, family and caretakers. The system also proved to help in the management of activities of daily living (ADLs), clinical care and the monitoring of variables associated with type 2 HC. The SI GESCAD allowed for a more horizontal work process for HC teams at the RAS-AD/SUS level of care, with positive repercussions on care coordination and continuity of care. PMID- 26060959 TI - Self-reported dyslipidemia in central-west Brazil: prevalence and associated factors. AB - Lipid disorders are risk factors for atherosclerotic disease and its control may reduce morbidity and mortality from coronary artery disease. Knowledge of the factors associated with this injury may subsidize campaigns to encourage change in the population's lifestyle. The objective of this study is to estimate the prevalence of dyslipidemia and to identify associated factors. Cross-sectional population-based study, with individual data from the Telephone Survey on Risk Factors and Protection for Chronic Diseases Surveillance System (VIGITEL). It included 7,975 individuals of both sexes, aged >= 18 years living in state capitals in the central-west of Brazil, in the year 2009. Associations were estimated using Poisson regression. The prevalence of dyslipidemia was 15%, increased with age (p = < 0.01) did and not differ significantly according to sex. After adjustments, the variables that were directly associated with the outcome were overweight (p = < 0.01), obesity (p = < 0.01) and self-rated health as poor (p = < 0.01). Regular consumption of bean (>= 5 days/week) was inversely associated with the prevalence of dyslipidemia (p = < 0.01). The prevalence of dyslipidemia in the central-west of Brazil was increased with age and was associated with bean consumption, excess weight (overweight and obesity) and self rated health as poor. PMID- 26060960 TI - [The contracting process and outsourcing in health: the scenario for dispute between public and private interests]. AB - This research analyzed the public-private composition in the municipal health network and aspects of the contracting/outsourcing process for services over the period from 2001 to 2008. The research method used was a case study with documentary research and interviews. The interviewees were former secretaries of health, directors of regulation and district managers. The categories of analysis used were public funds, care networks and public control. The results showed that the contracting was restricted to philanthropic units. With respect to the other private establishments linked to the public care network, non-compliance with programmatic aspects was detected, such as the lack of regulation of bidding processes required for contracting. Management authorities did not actively pursue building up state public services, or the formation of care networks. The contracted establishments conducted their activities without effective external and internal control mechanisms, which are paramount for the proper use of public resources. The authors conclude that the contracting process does not significantly alter the standard of buying and selling of services and indeed does not enhance the empowering process of the role of the public domain. PMID- 26060961 TI - Therapeutic workshops and psychosocial rehabilitation for institutionalised leprosy patients. AB - Leprosy is still a major public health problem and psychosocial rehabilitation services for patients suffering from the disease remain insufficient. This study aimed to assess the impact of therapeutic workshops on quality of life and symptoms of depression among institutionalised leprosy patients. The Beck Depression Inventory (BDI) and generic World Health Organization Quality of Life questionnaire (WHOQOL-BREF) were used before and after the implementation of a series of therapeutic workshops over a period of six months. Sixty-two patients participated in the study. Almost all of the sample were elderly and had a low level of education. There was a significant reduction in the symptoms of depression scores after the intervention (p < 0,001) and a positive impact was shown for the psychological (p = 0,001), physical (p = 0,03) and environment (p < 0,001) domains, but not for the social relationships (p = 0,124) domain. Therapeutic workshops appear to a useful tool for psychosocial rehabilitation work with leprosy patients. PMID- 26060962 TI - Prevalence of psychotropic drug use in military police units. AB - The present study aimed to verify the prevalence of psychoactive drug use (amphetamines, methamphetamines, cannabinoids, cocaine, opioids and benzodiazepines) among military police officers in the state of Goias. Data were obtained from urine samples voluntarily provided by the officers participating in the study, who were informed of the study methods and signed a free and informed consent form. The samples were subject to screening analysis by immunochromatography (Multi-DrugOneStep Test(r)), with positive tests confirmed by gas chromatography- mass spectrometry (GC-MS) and data analyzed by descriptive statistics. The results indicated the presence of the following drugs: amphetamines (0.33%), cannabinoids (0.67%) and benzodiazepines (1.34%); 97.66% showed negative results. The positive cases were distributed as follows: benzodiazepines (57.1%); cannabinoids (28.6%) and amphetamines (14.3%). In conclusion, the detection of psychoactive substances in voluntary sampling of military police officers indicates the need to implement drug testing among active military officers and preventive public policies aimed at eliminating the abusive consumption of psychotropic drugs. PMID- 26060963 TI - Crack cocaine users living on the streets - gender characteristics. AB - The increase in the use of crack cocaine constitutes a challenge to public health in Brazil. The objectives of this article are to identify how gender relations are constituted in the daily lives of crack users, and to analyze the dynamics that permeate the construction of these relationships involving exchange and power. This is a qualitative, descriptive, exploratory study of phenomenological orientation. The data was collected from crack users living on the streets in the Manguinhos community in the city of Rio de Janeiro. Eight focus groups (n = 31) were conducted and there were two individual interviews between June and August 2011. In the groups, the reports of the young men and women differed in terms of the establishment of bonds of affection; in the role attributed to crack as an operator in conflict mediation; in the use of the body as exchange/prostitution; and in the generation and care of offspring. Some shifts were observed with respect to traditional and hierarchical arrangements of gender. The study of the relationships established in this research reveals that it is not possible to point to simply perpetrators or victims. What emerges in the analysis is a plural and fluid universe, which is in permanent construction, with shifts that sometimes favor women and sometimes favor men. PMID- 26060964 TI - [Scale for assessment of aggressive behavior of adolescents]. AB - This study consists of the validation of a scale for the analysis of violent behavior in adolescents. It is a cross-sectional observational study. A total of 437 adolescent students from public and private schools in the city of Recife in Pernambuco state participated in the study by responding to a questionnaire. Semantic and Content Validation was performed, followed by Dimensionality, Reliability, Discriminant, Trust and Convergent Analysis. The extraction method was Principal Component Analysis with Varimax rotation and Kaiser normalization. The analysis resulted in a scale for assessment of aggressive behavior of teenagers with 39 items. Seven factors were selected and Cronbach's total alpha was 0.830. Discriminant analysis revealed groups of items that distinguish subjects between high and low level of violent behavior and between groups of items revealed a positive correlation among 17 items and the reliability of the instrument was confirmed in the retest. The scale revealed evidence of validity as a tool for assessing violent behavior among adolescents. PMID- 26060965 TI - The health care model: concepts and challenges for primary health care in Brazil. AB - This is a theoretical reflection aiming to highlight the conceptual debate about the health care model and the challenges for primay health care in Brazil. The study characterizes different concepts and terminologies relating to the expression 'care model' and shows that the Family Health Strategy has improved access to health care, and also including user reception and humanization perspectives in health practices. However, one still sees: a centralizing attitude in the treatment of pathologies, and care focused on the biological body; difficulties in implementing comprehensive care; and deficits in training of teams, and in working conditions and relations. The study concludes that the term 'care model' is interpreted as polysemic and that, although there are structuring proposals and policies for a model that can make progress in relation to the biomedical paradigm, the difficulties for its implementation are significant. PMID- 26060966 TI - [Challenges facing health professionals in the notification of violence: mandatory implementation and follow-up procedures]. AB - The notification of the occurrence or suspicion of violence is mandatory for health professionals and is a key tool for epidemiological surveillance and the definition of public policies for prevention and intervention. However, professionals feel unprepared for this assignment, which renders underreporting prevalent. To address this issue, the objective is to identify the means available to the professional to submit notification as well as ensure due process follow-up. For this purpose, research and document analysis was conducted in Brazilian legislation, ordinances, and government programs, codes of ethics and consultation of the literature in databases on the subject over a period of five years to establish a brief comparative analysis with other countries. The conclusion drawn is that while some measures are inapplicable, knowledge about the appropriate process for the notification and routing to specific organs will enable healthcare professionals to make the appropriate decisions for the protection and safety of the victim, besides the measures in order to change this situation of violence in the country. PMID- 26060967 TI - Strengths and weaknesses in the supply of school food resulting from the procurement of family farm produce in a municipality in Brazil. AB - The objective of this study was to assess compliance with school food programme recommendations for the procurement of family farm produce. This study consists of an exploratory descriptive study utilising a qualitative approach based on semistructured interviews with key informants in a municipality in the State of Santa Catarina in Brazil. Study participants were managers and staff of the school food programme and department of agriculture, and representatives of a farmers' organisation. The produce delivery and demand fulfilment stages of the procurement process were carried out in accordance with the recommendations. However, nonconformities occurred in the elaboration of the public call for proposals, elaboration of the sales proposal, and fulfilment of produce quality standards. It was observed that having a diverse range of suppliers and the exchange of produce by the cooperative with neighbouring municipalities helped to maintain a regular supply of produce. The elaboration of menus contributed to planning agricultural production. However, agricultural production was not mapped before elaborating the menus in this case study and an agricultural reform settlement was left out of the programme. A number of weaknesses in the programme were identified which need to be overcome in order to promote local family farming and improve the quality of school food in the municipality. PMID- 26060968 TI - Informal caregivers of older people recovering from surgery for hip fractures caused by a fall: fall prevention. AB - The objectives of this study were to investigate the sociodemographic characteristics of informal caregivers of elderly persons who had undergone surgery for hip fractures caused by a fall, explore the level of caregiver's knowledge regarding fall prevention, and assess the relationship between this knowledge and the use of preventative measures in practice. This investigation consists of a cross-sectional study using nonprobability sampling methods conducted over a period of 12 months and involving 89 caregivers. The majority of caregivers were female (76.4%) and sons or daughters of the patients (64%). Environmental modification was the predominant preventative measure used by caregivers (88.2%). 58.1% of caregivers believed it was possible to prevent falls in the elderly and there was a significant association (p = 0,002) between believing it was possible to prevent falls and carrying out modifications in the home and/or to the daily routine of the older person. Informal caregivers with wide or partial knowledge of fall prevention put preventative measures into practice. These findings demonstrate that the number of falls among older persons could be significantly reduced if health care programmes widened their actions to include the guiding principles of the WHO falls prevention model. PMID- 26060969 TI - [The National Comprehensive Health Policy for the Black Population: implementation, awareness and socioeconomic aspects from the perspective of this ethnic group]. AB - The scope of the National Comprehensive Health Policy for the Black Population is to ensure equitable health care to this population. This policy is to compensate for the discrimination suffered by this ethnic group throughout the history of Brazil. The black population presents higher social and economic vulnerability, leading to shorter life expectancy and an increased susceptibility to diseases. The objective of the study is to investigate the black population's knowledge about this policy, its potential benefits and the difficulties of this population regarding access to health. It involves cross-sectional, quantitative and descriptive research. Structured interviews were conducted with 391 black people in Juiz de Fora. The sample was structured according to race (black and brown). Around 90% of the sample reported not knowing the existence of a health policy for the black population, and 53% stated that this policy could enhance racial discrimination. Having completed primary education and lower income was positively associated with higher discrimination in health care. Most of the sample didn't know the existence of the PNSIPN, but was in favor of its goals, despite the possibility that it can reinforce the legacy of Brazilian racial discrimination. PMID- 26060970 TI - [The profile of fragility and associated factors among the elderly registered in a Family Health Unit]. AB - The scope of this study was to identify the profile of fragility and associated factors among the elderly registered in a Family Health Unit. It involved an observational, exploratory, household -based and cross-sectional study conducted with 139 elderly individuals. The data were collected using a structured questionnaire requesting the following information: personal history, family and self-reported diseases, socio-demographic information, level of physical activity, behavior variables, number of falls in the last year, depressive symptoms, unintentional weight loss and fatigue. Anthropometric measurements (weight and height) were also taken and the body mass index (BMI) was calculated. Descriptive analyses and Pearson's chi-square test or Fisher's exact test were performed, with a significance level of p < 0.05. SPSS software version 21.0 was used for statistical analysis. The prevalence of fragility among the elderly was: frail (16.9%), pre-frail (61.8%) and non-frail (21.3%), respectively. The fragility profile was associated with: age (p < 0.001), BMI (p = 0.018), family situation (p = 0.014), level of physical activity (p < 0.001) and falls (p = 0.043). In this study, a high prevalence was observed of pre-frail and frail elderly individuals and identified factors associated with this syndrome. PMID- 26060971 TI - Interrelationships between nursing workers' state of nutrition, socio demographic factors, work and health habits. AB - The interrelationships between professional nursing workers' state of nutrition, variables relating to their socio demographic relationships, their professional work, and health behavior, were examined based on a correspondence analysis technique. This is a sectional study carried out involving 917 nursing professionals in a public hospital in Rio de Janeiro. The results show the formation of four groups, three of them grouped under BMI (body mass index) categories. The obese individuals group included poor health, current socio economic conditions, unfavorable past conditions, and former night shift workers. The low/adequate group showed the most favorable conditions, while the group of overweight individuals also included smoking, alcohol consumption, and current night shift work (up to five nights per two-week period). Specifically, among the interrelationships between the states of nutrition levels, we highlight those relating to current and previously evaluated socio economic conditions, and underscore the life-long importance of social indicators. PMID- 26060972 TI - The impact of a nutritional intervention on the nutritional status and anthropometric profile of participants in the health Gym Programme in Brazil. AB - The objective of this study was to assess the impact of an intervention implemented under the Programa Academia da Saude (Health Gym Programme) of Belo Horizonte, MG on the nutritional status and anthropometric profile of participants. Intervention study involving participants in the Health Gym Programme which encompasses group food and nutrition education activities over a period of 11 months combined with regular physical activity. Impact was assessed by comparing nutritional and anthropometric indicators in women participants who were divided into two groups according to their participation rate in the intervention. A total of 124 women were evaluated, results showed an increase in the number of daily meals (p<0.001) among all participants. Participants whose participation rate was less than 50% (n = 61) reduced their daily consumption of sugary soft drinks (p = 0.03), while those whose participation rate was 50% and over (n = 63) reduced daily per capita intake of oil (p = 0.01) and sugar (p = 0.002), increased their consumption of fruit (p = 0. 004), and milk and dairy products (p = 0.02), and also experienced weight loss (-1.3 +/- 3.9kg; p = 0.02). The findings show the importance of combining nutritional interventions with physical activity to ensure positive impacts on the nutritional status and anthropometric profile of participants in the Health Gym Programme. PMID- 26060973 TI - [Barriers to administrative access to health services in the Colombian population, 2013]. AB - The scope of this paper is to characterize the main barriers faced by the Colombian population when they attempt to gain access to health services. It is an observational, descriptive and exploratory study using both quantitative and qualitative techniques. It was based on the records of Petitions, Complaints, Claims and Suggestions sent to the National Department of Health of Colombia between January 2102 and June 2013. In-depth interviews were conducted with users of health services, as well as officials of the Health Promoting Companies and Outlets for Right to Health of the Health Department of Bogota. The study is based on domains proposed by Frenk et al for effective access to health services. Users of this study found limitations starting at admission and search for care due to communication failures in accessing health services. For ongoing care services, they encountered barriers resulting from the need for authorizations, lack of availability of specialist medical appointments, surgical procedures and drug delivery. Based on the findings, the conclusion reached is that the barriers perceived by users generate negative perceptions and harmful consequences both for them and for their families. PMID- 26060975 TI - [In Process Citation]. PMID- 26060974 TI - [In Process Citation]. PMID- 26060976 TI - Erratum. PMID- 26060979 TI - Deformation twinning evolution from a single crystal in a face-centered-cubic ternary alloy. AB - Deformation twinning evolution from a single crystal is conducted by molecular dynamics simulations, to elucidate a twinned face-centered-cubic alloy in an experiment with hardness up to 100 times as that of single crystals, and with ductility simultaneously. Critical twinning stress of cadmium zinc telluride (CdZnTe or CZT) calculated is 1.38 GPa. All the twin boundaries are along the (11 1) orientation, except the one with the (-111) plane that supports the indentation, interpreting the unidirectional and boundary-free characteristics, confirmed in the experiment. Three twin thicknesses after unloading are 3.2, 3.5, and 16 nm, which is consistent with the experimentally repeated pattern of a lamellar twin with thickness larger than 12.7 nm, followed by one or several twins with thicknesses smaller than 12.7 nm. An inverse triangle of a twin combining with three twins generate a synergistic strengthening effect through the hardening and softening functions, illuminating the ultrahigh hardness demonstrated in the experiment. Twinning takes place in loading, and detwinning occurs in unloading, which expounds the high ductility observed in the experiment. PMID- 26060978 TI - Students helping students: Evaluating a pilot program of peer teaching for an undergraduate course in human anatomy. AB - The educational literature generally suggests that supplemental instruction (SI) is effective in improving academic performance in traditionally difficult courses. A pilot program of peer teaching based on the SI model was implemented for an undergraduate course in human anatomy. Students in the course were stratified into three groups based on the number of peer teaching sessions they attended: nonattendees (0 sessions), infrequently attended (1-3 sessions), and frequently attended (>= 4 sessions). After controlling for academic preparedness [i.e., admission grade point average (AGPA)] using an analysis of covariance, the final grades of frequent attendees were significantly higher than those of nonattendees (P = 0.025) and infrequent attendees (P = 0.015). A multiple regression analysis was performed to estimate the relative independent contribution of several variables in predicting the final grade. The results suggest that frequent attendance (beta = 0.245, P = 0.007) and AGPA (beta = 0.555, P < 0.001) were significant positive predictors, while being a first-year student (beta = -0.217, P = 0.006) was a significant negative predictor. Collectively, these results suggest that attending a certain number of sessions may be required to gain a noticeable benefit from the program, and that first year students (particularly those with a lower level of academic preparedness) would likely stand to benefit from maximally using the program. End-of-semester surveys and reports indicate that the program had several additional benefits, both to the students taking the course and to the students who served as program leaders. PMID- 26060977 TI - Thromboembolic Complications and Prophylaxis Patterns in Colorectal Surgery. AB - IMPORTANCE: Venous thromboembolism (VTE) is an important complication of colorectal surgery, but its incidence is unclear in the era of VTE prophylaxis. OBJECTIVE: To describe the incidence of and risk factors associated with thromboembolic complications and contemporary VTE prophylaxis patterns following colorectal surgery. DESIGN, SETTING, AND PARTICIPANTS: Prospective data from the Washington State Surgical Care and Outcomes Assessment Program (SCOAP) linked to a statewide hospital discharge database. At 52 Washington State SCOAP hospitals, participants included consecutive patients undergoing colorectal surgery between January 1, 2006, and December 31, 2011. MAIN OUTCOMES AND MEASURES: Venous thromboembolism complications in-hospital and up to 90 days after surgery. RESULTS: Among 16,120 patients (mean age, 61.4 years; 54.5% female), the use of perioperative and in-hospital VTE chemoprophylaxis increased significantly from 31.6% to 86.4% and from 59.6% to 91.4%, respectively, by 2011 (P < .001 for trend for both). Overall, 10.6% (1399 of 13,230) were discharged on a chemoprophylaxis regimen. The incidence of VTE was 2.2% (360 of 16,120). Patients undergoing abdominal operations had higher rates of 90-day VTE compared with patients having pelvic operations (2.5% [246 of 9702] vs 1.8% [114 of 6413], P = .001). Those having an operation for cancer had a similar incidence of 90-day VTE compared with those having an operation for nonmalignant processes (2.1% [128 of 6213] vs 2.3% [232 of 9902], P = .24). On adjusted analysis, older age, nonelective surgery, history of VTE, and operations for inflammatory disease were associated with increased risk of 90-day VTE (P < .05 for all). There was no significant decrease in VTE over time. CONCLUSIONS AND RELEVANCE: Venous thromboembolism rates are low and largely unchanged despite increases in perioperative and postoperative prophylaxis. These data should be considered in developing future guidelines. PMID- 26060980 TI - Selection of Portable Spectrometers for Planetary Exploration: A Comparison of 532 nm and 785 nm Raman Spectroscopy of Reduced Carbon in Archean Cherts. AB - Knowledge and understanding of the martian environment has advanced greatly over the past two decades, beginning with NASA's return to the surface of Mars with the Pathfinder mission and its rover Sojourner in 1997 and continuing today with data being returned by the Curiosity rover. Reduced carbon, however, is yet to be detected on the martian surface, despite its abundance in meteorites originating from the planet. If carbon is detected on Mars, it could be a remnant of extinct life, although an abiotic source is much more likely. If the latter is the case, environmental carbonaceous material would still provide a source of carbon that could be utilized by microbial life for biochemical synthesis and could therefore act as a marker for potential habitats, indicating regions that should be investigated further. For this reason, the detection and characterization of reduced or organic carbon is a top priority for both the ESA/Roscosmos ExoMars rover, currently due for launch in 2018, and for NASA's Mars 2020 mission. Here, we present a Raman spectroscopic study of Archean chert Mars analog samples from the Pilbara Craton, Western Australia. Raman spectra were acquired with a flight representative 532 nm instrument and a 785 nm instrument with similar operating parameters. Reduced carbon was successfully detected with both instruments; however, its Raman bands were detected more readily with 785 nm excitation, and the corresponding spectra exhibited superior signal-to-noise ratios and reduced background levels. PMID- 26060981 TI - Polymerization of Building Blocks of Life on Europa and Other Icy Moons. AB - The outer Solar System may provide a potential habitat for extraterrestrial life. Remote sensing data from the Galileo spacecraft suggest that the jovian icy moons -Europa, Ganymede, and possibly Callisto--may harbor liquid water oceans underneath their icy crusts. Although compositional information required for the discussion of habitability is limited because of significantly restricted observation data, organic molecules are ubiquitous in the Universe. Recently, in situ spacecraft measurements and experiments suggest that amino acids can be formed abiotically on interstellar ices and comets. These amino acids could be continuously delivered by meteorite or comet impacts to icy moons. Here, we show that polymerization of organic monomers, in particular amino acids and nucleotides, could proceed spontaneously in the cold environment of icy moons, in particular the jovian icy moon Europa as a typical example, based on thermodynamic calculations, though kinetics of formation are not addressed. Observed surface temperature on Europa is 120 and 80 K in the equatorial region and polar region, respectively. At such low temperatures, Gibbs energies of polymerization become negative, and the estimated thermal structure of the icy crust should contain a shallow region (i.e., at a depth of only a few kilometers) favorable for polymerization. Investigation of the possibility of organic monomer polymerization on icy moons could provide good constraints on the origin and early evolution of extraterrestrial life. PMID- 26060982 TI - Biogeological Analysis of Desert Varnish Using Portable Raman Spectrometers. AB - Desert varnishes are thin, dark mineral coatings found on some rocks in arid or semi-arid environments on Earth. Microorganisms may play an active role in their formation, which takes many hundreds of years. Their mineral matrix may facilitate the preservation of organic matter and is therefore of great relevance to martian exploration. Miniaturized Raman spectrometers (which allow nondestructive analysis of the molecular composition of a specimen) will equip rovers in forthcoming planetary exploration missions. In that context, and for the first time, portable Raman spectrometers operating in the green visible (532 nm as currently baselined for flight) and in the near-infrared (785 nm) were used in this study to investigate the composition (and substrate) of several samples of desert varnish. Rock samples that were suspected (and later confirmed) to be coated with desert varnish were recovered from two sites in the Mojave Desert, USA. The portable spectrometers were operated in flight-representative acquisition modes to identify the key molecular components of the varnish. The results demonstrate that the coatings typically comprise silicate minerals such as quartz, plagioclase feldspars, clays, ferric oxides, and hydroxides and that successful characterization of the samples can be achieved by using flightlike portable spectrometers for both the 532 and 785 nm excitation sources. In the context of searching for spectral signatures and identifying molecules that indicate the presence of extant and/or extinct life, we also report the detection of beta-carotene in some of the samples. Analysis complications caused by the presence of rare earth element photoluminescence (which overlaps with and overwhelms the organic Raman signal when a 785 nm laser is employed) are also discussed. PMID- 26060983 TI - Descent without Modification? The Thermal Chemistry of H2O2 on Europa and Other Icy Worlds. AB - The strong oxidant H2O2 is known to exist in solid form on Europa and is suspected to exist on several other Solar System worlds at temperatures below 200 K. However, little is known of the thermal chemistry that H2O2 might induce under these conditions. Here, we report new laboratory results on the reactivity of solid H2O2 with eight different compounds in H2O-rich ices. Using infrared spectroscopy, we monitored compositional changes in ice mixtures during warming. The compounds CH4 (methane), C3H4 (propyne), CH3OH (methanol), and CH3CN (acetonitrile) were unaltered by the presence of H2O2 in ices, showing that exposure to either solid H2O2 or frozen H2O+H2O2 at cryogenic temperatures will not oxidize these organics, much less convert them to CO2. This contrasts strongly with the much greater reactivity of organics with H2O2 at higher temperatures, and particularly in the liquid and gas phases. Of the four inorganic compounds studied, CO, H2S, NH3, and SO2, only the last two reacted in ices containing H2O2, NH3 making NH4+ and SO2 making SO(4)2- by H+ and e- transfer, respectively. An important astrobiological conclusion is that formation of surface H2O2 on Europa and that molecule's downward movement with H2O-ice do not necessarily mean that all organics encountered in icy subsurface regions will be destroyed by H2O2 oxidation. PMID- 26060984 TI - Microbial Ecology of a Crewed Rover Traverse in the Arctic: Low Microbial Dispersal and Implications for Planetary Protection on Human Mars Missions. AB - Between April 2009 and July 2011, the NASA Haughton-Mars Project (HMP) led the Northwest Passage Drive Expedition (NWPDX), a multi-staged long-distance crewed rover traverse along the Northwest Passage in the Arctic. In April 2009, the HMP Okarian rover was driven 496 km over sea ice along the Northwest Passage, from Kugluktuk to Cambridge Bay, Nunavut, Canada. During the traverse, crew members collected samples from within the rover and from undisturbed snow-covered surfaces around the rover at three locations. The rover samples and snow samples were stored at subzero conditions (-20 degrees C to -1 degrees C) until processed for microbial diversity in labs at the NASA Kennedy Space Center, Florida. The objective was to determine the extent of microbial dispersal away from the rover and onto undisturbed snow. Interior surfaces of the rover were found to be associated with a wide range of bacteria (69 unique taxa) and fungi (16 unique taxa). In contrast, snow samples from the upwind, downwind, uptrack, and downtrack sample sites exterior to the rover were negative for both bacteria and fungi except for two colony-forming units (cfus) recovered from one downwind (1 cfu; site A4) and one uptrack (1 cfu; site B6) sample location. The fungus, Aspergillus fumigatus (GenBank JX517279), and closely related bacteria in the genus Brevibacillus were recovered from both snow (B. agri, GenBank JX517278) and interior rover surfaces. However, it is unknown whether the microorganisms were deposited onto snow surfaces at the time of sample collection (i.e., from the clothing or skin of the human operator) or via airborne dispersal from the rover during the 12-18 h layovers at the sites prior to collection. Results support the conclusion that a crewed rover traveling over previously undisturbed terrain may not significantly contaminate the local terrain via airborne dispersal of propagules from the vehicle. PMID- 26060986 TI - Copper-Catalyzed Intramolecular Desymmetric Aryl C-O Coupling for the Enantioselective Construction of Chiral Dihydrobenzofurans and Dihydrobenzopyrans. AB - O-Heterocyclic structures such as 2,3-dihydrobenzofurans are key motifs in many natural compounds and pharmaceuticals. Enantioselective formation of chiral dihydrobenzofurans and analogues was achieved through a copper-catalyzed desymmetrization strategy with a chiral cyclic 1,2-diamine. A broad range of substrates are compatible with this Cu(I)-diamine catalytic system and afford the desired coupling products with chiral tertiary or quaternary carbon centers in high yields and good to excellent enantioselectivities under mild conditions. PMID- 26060985 TI - The Significance of Microbe-Mineral-Biomarker Interactions in the Detection of Life on Mars and Beyond. AB - The detection of biomarkers plays a central role in our effort to establish whether there is, or was, life beyond Earth. In this review, we address the importance of considering mineralogy in relation to the selection of locations and biomarker detection methodologies with characteristics most promising for exploration. We review relevant mineral-biomarker and mineral-microbe interactions. The local mineralogy on a particular planet reflects its past and current environmental conditions and allows a habitability assessment by comparison with life under extreme conditions on Earth. The type of mineral significantly influences the potential abundances and types of biomarkers and microorganisms containing these biomarkers. The strong adsorptive power of some minerals aids in the preservation of biomarkers and may have been important in the origin of life. On the other hand, this strong adsorption as well as oxidizing properties of minerals can interfere with efficient extraction and detection of biomarkers. Differences in mechanisms of adsorption and in properties of minerals and biomarkers suggest that it will be difficult to design a single extraction procedure for a wide range of biomarkers. While on Mars samples can be used for direct detection of biomarkers such as nucleic acids, amino acids, and lipids, on other planetary bodies remote spectrometric detection of biosignatures has to be relied upon. The interpretation of spectral signatures of photosynthesis can also be affected by local mineralogy. We identify current gaps in our knowledge and indicate how they may be filled to improve the chances of detecting biomarkers on Mars and beyond. PMID- 26060987 TI - A microfluidic dual-well device for high-throughput single-cell capture and culture. AB - In vitro culture of single cells facilitates biological studies by deconvoluting complications from cell population heterogeneity. However, there is still a lack of simple yet high-throughput methods to perform single cell culture experiments. In this paper, we report the development and application of a microfluidic device with a dual-well (DW) design concept for high-yield single-cell loading (~77%) in large microwells (285 and 485 MUm in diameter) which allowed for cell spreading, proliferation and differentiation. The increased single-cell loading yield is achieved by using sets of small microwells termed "capture-wells" and big microwells termed "culture-wells" according to their utilities for single-cell capture and culture, respectively. This novel device architecture allows the size of the "culture" microwells to be flexibly adjusted without affecting the single cell loading efficiency making it useful for cell culture applications as demonstrated by our experiments of KT98 mouse neural stem cell differentiation, A549 and MDA-MB-435 cancer cell proliferation, and single-cell colony formation assay with A549 cells in this paper. PMID- 26060988 TI - Reduced Radial Displacement of the Gastrocnemius Medialis Muscle After Electrically Elicited Fatigue. AB - CONTEXT: Assessments of skeletal-muscle functional capacity often necessitate maximal contractile effort, which exacerbates muscle fatigue or injury. Tensiomyography (TMG) has been investigated as a means to assess muscle contractile function after fatigue; however, observations have not been contextualized by concurrent physiological measures. OBJECTIVE: To measure peripheral-fatigue-induced alterations in mechanical and contractile properties of the plantar-flexor muscles through noninvasive TMG concurrently with maximal voluntary contraction (MVC) and passive muscle tension (PMT) to validate TMG as a gauge of peripheral fatigue. DESIGN: Pre- and posttest intervention with control. SETTING: University laboratory. PARTICIPANTS: 21 healthy male volunteers. INTERVENTIONS: Subjects' plantar flexors were tested for TMG parameters, along with MVC and PMT, before and after either a 5-min rest period (control) or a 5 min electrical-stimulation intervention (fatigue). MAIN OUTCOME MEASURES: Temporal (contraction velocity) and spatial (radial displacement) contractile parameters of the gastrocnemius medialis were recorded through TMG. MVC was measured as an indicator of muscle fatigue, and PMT was measured to assess muscle stiffness. RESULTS: Radial displacement demonstrated a fatigue-associated reduction (3.3 +/- 1.2 vs 4.0 +/- 1.4 mm, P = .031), while contraction velocity remained unaltered. In addition, MVC significantly declined by 122.6 +/- 104 N (P < .001) after stimulation (fatigue). PMT was significantly increased after fatigue (139.8 +/- 54.3 vs 111.3 +/- 44.6 N, P = .007). CONCLUSION: TMG successfully detected fatigue, evident from reduced MVC, by displaying impaired muscle displacement accompanied by elevated PMT. TMG could be useful in establishing skeletal-muscle fatigue status without exacerbating the functional decrement of the muscle. PMID- 26060990 TI - Assessment of MRI Contrast Agent Kinetics via Retro-Orbital Injection in Mice: Comparison with Tail Vein Injection. AB - It is not known whether administration of contrast agent via retro-orbital injection or the tail vein route affects the efficiency of dynamic contrast enhanced magnetic resonance imaging (MRI). Therefore, we compared the effects of retro-orbital and tail vein injection on the kinetics of the contrast agent used for MRI in mice. The same group of nine healthy female mice received contrast agent via either route. An extracellular contrast agent was infused via the tail vein and retro-orbital vein, in random order. Dynamic contrast-enhanced MRI was performed before and after administering the contrast agent. The contrast effects in the liver, kidney, lung, and myocardium were assessed. The average total times of venous puncture and mounting of the injection system were about 10 and 4 min for the tail vein and retro-orbital route, respectively. For all organs assessed, the maximum contrast ratio occurred 30 s after administration and the time course of the contrast ratio was similar with either routes. For each organ, the contrast ratios correlated strongly; the contrast ratios were similar. The retro orbital and tail vein routes afforded similar results in terms of the kinetics of the contrast agent. The retro-orbital route can be used as a simple efficient alternative to tail vein injection for dynamic contrast-enhanced MRI of mice. PMID- 26060989 TI - Clostridium perfringens enterotoxin C-terminal domain labeled to fluorescent dyes for in vivo visualization of micrometastatic chemotherapy-resistant ovarian cancer. AB - Identification of micrometastatic disease at the time of surgery remains extremely challenging in ovarian cancer patients. We used fluorescence microscopy, an in vivo imaging system and a fluorescence stereo microscope to evaluate fluorescence distribution in Claudin-3- and -4-overexpressing ovarian tumors, floating tumor clumps isolated from ascites and healthy organs. To do so, mice harboring chemotherapy-naive and chemotherapy-resistant human ovarian cancer xenografts or patient-derived xenografts (PDXs) were treated with the carboxyl terminal binding domain of the Clostridium perfringens enterotoxin (c-CPE) conjugated to FITC (FITC-c-CPE) or the near-infrared (NIR) fluorescent tag IRDye CW800 (CW800-c-CPE) either intraperitoneally (IP) or intravenously (IV). We found tumor fluorescence to plateau at 30 min after IP injection of both the FITC-c-CPE and the CW800-c-CPE peptides and to be significantly higher than in healthy organs (p < 0.01). After IV injection of CW800-c-CPE, tumor fluorescence plateaued at 6 hr while the most favorable tumor-to-background fluorescence ratio (TBR) was found at 48 hr in both mouse models. Importantly, fluorescent c-CPE was highly sensitive for the in vivo visualization of peritoneal micrometastatic tumor implants and the identification of ovarian tumor spheroids floating in malignant ascites that were otherwise not detectable by conventional visual observation. The use of the fluorescent c-CPE peptide may represent a novel and effective optical approach at the time of primary debulking surgery for the real time detection of micrometastatic ovarian disease overexpressing the Claudin-3 and -4 receptors or the identification of residual disease at the time of interval debulking surgery after neoadjuvant chemotherapy treatment. PMID- 26060991 TI - Precision and Disclosure in Text and Voice Interviews on Smartphones. AB - As people increasingly communicate via asynchronous non-spoken modes on mobile devices, particularly text messaging (e.g., SMS), longstanding assumptions and practices of social measurement via telephone survey interviewing are being challenged. In the study reported here, 634 people who had agreed to participate in an interview on their iPhone were randomly assigned to answer 32 questions from US social surveys via text messaging or speech, administered either by a human interviewer or by an automated interviewing system. 10 interviewers from the University of Michigan Survey Research Center administered voice and text interviews; automated systems launched parallel text and voice interviews at the same time as the human interviews were launched. The key question was how the interview mode affected the quality of the response data, in particular the precision of numerical answers (how many were not rounded), variation in answers to multiple questions with the same response scale (differentiation), and disclosure of socially undesirable information. Texting led to higher quality data-fewer rounded numerical answers, more differentiated answers to a battery of questions, and more disclosure of sensitive information-than voice interviews, both with human and automated interviewers. Text respondents also reported a strong preference for future interviews by text. The findings suggest that people interviewed on mobile devices at a time and place that is convenient for them, even when they are multitasking, can give more trustworthy and accurate answers than those in more traditional spoken interviews. The findings also suggest that answers from text interviews, when aggregated across a sample, can tell a different story about a population than answers from voice interviews, potentially altering the policy implications from a survey. PMID- 26060992 TI - Symptoms Reported by Head and Neck Cancer Patients during Radiotherapy and Association with Mucosal Ulceration Site and Size: An Observational Study. AB - BACKGROUND: Self-reported pain and impairment of oral functions varies markedly and often in spite of extensive oral mucositis (OM). The aim of the current study was to appraise how patient-reported debilitation caused by OM is influenced by the extent and possibly location of the OM lesions. METHODS: Patients with head and neck cancer undergoing radiotherapy were examined before treatment, twice weekly during 6-7 weeks of therapy, and 3-4 weeks after therapy completion. OM signs of 33 participants were evaluated using the Oral Mucositis Assessment Scale (OMAS), while OM symptoms were recorded using Patient-Reported Oral Mucositis Symptom (PROMS)-questionnaires. Changes in OM experience as a function of OM signs was undertaken by comparing the aggregated and individual PROMS scale values at the point of transition of OMAS ulceration scores between 0 to 1, 1 to 2 and 2 to 3, respectively in the nine intra-oral locations designated in the OMAS. ANOVA with pairwise contrasts using the LSD procedure was applied for comparisons of mean changes of PROMS scale values for the participants who experienced an OMAS score of 2 or more during therapy (n=24). RESULTS: Impairment of eating hard foods was more when the OMAS score for ulceration anywhere in the mouth or in the soft palate changed from 1 to 2, compared to between score 0 and 1 (p=.002 and p=.05) or between score 2 and 3 (p=.001 and p=.02). Mouth pain increased more upon transition of OMAS score anywhere in the mouth from 1 to 2 compared to 0 to 1 (p=.05). CONCLUSION: The relationship between patient-reported impairment of oral function and pain caused by OM ulceration is not linear, but rather curvilinear. Our findings should prompt investigators of future interventional trials to consider using a less severe outcome than maximum OM scores as the primary study outcome. PMID- 26060993 TI - Reusable ionic liquid-catalyzed oxidative coupling of azoles and benzylic compounds via sp(3) C-N bond formation under metal-free conditions. AB - The heterocyclic ionic liquid-catalyzed direct oxidative amination of benzylic sp(3) C-H bonds via intermolecular sp(3) C-N bond formation for the synthesis of N-alkylated azoles under metal-free conditions is reported for the first time. The catalyst 1-butylpyridinium iodide can be recycled and reused with similar efficacies for at least eight cycles. PMID- 26060994 TI - Visual and Olfactory Floral Cues of Campanula (Campanulaceae) and Their Significance for Host Recognition by an Oligolectic Bee Pollinator. AB - Oligolectic bees collect pollen from a few plants within a genus or family to rear their offspring, and are known to rely on visual and olfactory floral cues to recognize host plants. However, studies investigating whether oligolectic bees recognize distinct host plants by using shared floral cues are scarce. In the present study, we investigated in a comparative approach the visual and olfactory floral cues of six Campanula species, of which only Campanula lactiflora has never been reported as a pollen source of the oligolectic bee Ch. rapunculi. We hypothesized that the flowers of Campanula species visited by Ch. rapunculi share visual (i.e. color) and/or olfactory cues (scents) that give them a host-specific signature. To test this hypothesis, floral color and scent were studied by spectrophotometric and chemical analyses, respectively. Additionally, we performed bioassays within a flight cage to test the innate color preference of Ch. rapunculi. Our results show that Campanula flowers reflect the light predominantly in the UV-blue/blue bee-color space and that Ch. rapunculi displays a strong innate preference for these two colors. Furthermore, we recorded spiroacetals in the floral scent of all Campanula species, but Ca. lactiflora. Spiroacetals, rarely found as floral scent constituents but quite common among Campanula species, were recently shown to play a key function for host-flower recognition by Ch. rapunculi. We conclude that Campanula species share some visual and olfactory floral cues, and that neurological adaptations (i.e. vision and olfaction) of Ch. rapunculi innately drive their foraging flights toward host flowers. The significance of our findings for the evolution of pollen diet breadth in bees is discussed. PMID- 26060996 TI - Osteological Variation among Extreme Morphological Forms in the Mexican Salamander Genus Chiropterotriton (Amphibia: Plethodontidae): Morphological Evolution And Homoplasy. AB - Osteological variation is recorded among and within four of the most distinctive species of the Mexican salamander genus Chiropterotriton. Analysis of the data is consistent with the monophyletic status of the genus and documents previously unrecorded intraspecific and interspecific variation. Most of the recorded variation involves qualitative and quantitative proportional differences, but four fixed differences constitute autapomorphic states that affirm and diagnose some species (C. dimidiatus, C. magnipes). Osteological variation in 15 characters is analyzed with respect to predictions generated from four hypotheses: 1) phylogeny, 2) adaptation to specific habitats (the four species include cave-dwelling, terrestrial, and arboreal forms), 3) size-free shape, and 4) size. High levels of intraspecific variation suggest that the characters studied are not subject to rigid functional constraints in salamanders, regardless of size. The pattern predicted by the hypothesis based on size differences seen among these four Chiropterotriton species matches most closely the observed pattern of relative skull robustness. Since size change and heterochrony are often associated in plethodontid evolution, it is likely that changes in developmental timing play a role in the morphological transitions among these morphologically diverse taxa. Webbed feet, miniaturization, body shape, and an unusual tarsal arrangement are morphologies exhibited in species of Chiropterotrition that are shown to be homoplastic with other clades of tropical plethodontids. Although extensive homoplasy in salamanders might be seen as a roadblock to unraveling phylogenetic hypotheses, the homologous developmental systems that appear to underlie such homoplasy may reveal common and consistent evolutionary processes at work. PMID- 26060995 TI - Mild Staphylococcus aureus Skin Infection Improves the Course of Subsequent Endogenous S. aureus Bacteremia in Mice. AB - Staphylococcus aureus carriers with S. aureus bacteremia may have a reduced mortality risk compared to non-carriers. A role for the immune system is suggested. Here, we study in mice the effect of mild S. aureus skin infection prior to endogenous or exogenous S. aureus bacteremia, and evaluate protection in relation to anti-staphylococcal antibody levels. Skin infections once or twice by a clinical S. aureus isolate (isolate P) or S. aureus strain 8325-4 were induced in mice free of S. aureus and anti-staphylococcal antibodies. Five weeks later, immunoglobulin G (IgG) levels in blood against 25 S. aureus antigens were determined, and LD50 or LD100 bacteremia caused by S. aureus isolate P was induced. S. aureus skin infections led to elevated levels of anti-staphylococcal IgG in blood. One skin infection improved the course of subsequent severe endogenous bacteremia only. A second skin infection further improved animal survival rate, which was associated with increased pre-bacteremia IgG levels against Efb, IsaA, LukD, LukE, Nuc, PrsA and WTA. In conclusion, S. aureus isolate P skin infection in mice reduces the severity of subsequent endogenous S. aureus bacteremia only. Although cellular immune effects cannot be rules out, anti-staphylococcal IgG against specified antigens may contribute to this effect. PMID- 26060997 TI - Natural Hendra Virus Infection in Flying-Foxes - Tissue Tropism and Risk Factors. AB - Hendra virus (HeV) is a lethal zoonotic agent that emerged in 1994 in Australia. Pteropid bats (flying-foxes) are the natural reservoir. To date, HeV has spilled over from flying-foxes to horses on 51 known occasions, and from infected horses to close-contact humans on seven occasions. We undertook screening of archived bat tissues for HeV by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Tissues were tested from 310 bats including 295 Pteropodiformes and 15 Vespertilioniformes. HeV was detected in 20 individual flying-foxes (6.4%) from various tissues including spleen, kidney, liver, lung, placenta and blood components. Detection was significantly higher in Pteropus Alecto and P. conspicillatus, identifying species as a risk factor for infection. Further, our findings indicate that HeV has a predilection for the spleen, suggesting this organ plays an important role in HeV infection. The lack of detections in the foetal tissues of HeV-positive females suggests that vertical transmission is not a regular mode of transmission in naturally infected flying foxes, and that placental and foetal tissues are not a major source of infection for horses. A better understanding of HeV tissue tropism will strengthen management of the risk of spillover from flying-foxes to horses and ultimately humans. PMID- 26060998 TI - Fecal Volatile Organic Ccompound Profiles from White-Tailed Deer (Odocoileus virginianus) as Indicators of Mycobacterium bovis Exposure or Mycobacterium bovis Bacille Calmette-Guerin (BCG) Vaccination. AB - White-tailed deer (Odocoileus virginianus) serve as a reservoir for bovine tuberculosis, caused by Mycobacterium bovis, and can be a source of infection in cattle. Vaccination with M. bovis Bacille Calmette Guerin (BCG) is being considered for management of bovine tuberculosis in deer. Presently, no method exists to non-invasively monitor the presence of bovine tuberculosis in deer. In this study, volatile organic compound profiles of BCG-vaccinated and non vaccinated deer, before and after experimental challenge with M. bovis strain 95 1315, were generated using solid phase microextraction fiber head-space sampling over suspended fecal pellets with analysis by gas chromatography/mass spectrometry. Chromatograms were processed using XCMS Online to characterize ion variation among treatment groups. The principal component scores resulting from significant (alpha = 0.05) ion responses were used to build linear discriminant analysis models. The sensitivity and specificity of these models were used to evaluate the feasibility of using this analytical approach to distinguish within group comparisons between pre- and post-M. bovis challenge: non-vaccinated male or female deer, BCG-vaccinated male deer, and the mixed gender non-vaccinated deer data. Seventeen compounds were identified in this analysis. The peak areas for these compounds were used to build a linear discriminant classification model based on principal component analysis scores to evaluate the feasibility of discriminating between fecal samples from M. bovis challenged deer, irrespective of vaccination status. The model best representing the data had a sensitivity of 78.6% and a specificity of 91.4%. The fecal head-space sampling approach presented in this pilot study provides a non-invasive method to discriminate between M. bovis challenged deer and BCG-vaccinated deer. Additionally, the technique may prove invaluable for BCG efficacy studies with free-ranging deer as well as for use as a non-invasive monitoring system for the detection of tuberculosis in captive deer and other livestock. PMID- 26060999 TI - The Effects of Aging, Malingering, and Traumatic Brain Injury on Computerized Trail-Making Test Performance. AB - The trail making test (TMT) is widely used to assess speed of processing and executive function. However, normative data sets gathered at different sites show significant inconsistencies. Here, we describe a computerized version of the TMT (C-TMT) that increases the precision and replicability of the TMT by permitting a segment-by-segment analysis of performance and separate analyses of dwell-time, move-time, and error time. Experiment 1 examined 165 subjects of various ages and found that completion times on both the C-TMT-A (where subjects connect successively numbered circles) and the C-TMT-B (where subjects connect circles containing alternating letters and numbers) were strongly influenced by age. Experiment 2 examined 50 subjects who underwent three test sessions. The results of the first test session were well fit by the normative data gathered in Experiment 1. Sessions 2 and 3 demonstrated significant learning effects, particularly on the C-TMT-B, and showed good test-retest reliability. Experiment 3 examined performance in subjects instructed to feign symptoms of traumatic brain injury: 44% of subjects produced abnormal completion times on the C-TMT-A, and 18% on the C-TMT-B. Malingering subjects could be distinguished from abnormally slow controls based on (1) disproportionate increases in dwell-time on the C-TMT-A, and (2) greater deficits on the C-TMT-A than on the C-TMT-B. Experiment 4 examined the performance of 28 patients with traumatic brain injury: C-TMT-B completion times were slowed, and TBI patients showed reduced movement velocities on both tests. The C-TMT improves the reliability and sensitivity of the trail making test of processing speed and executive function. PMID- 26061000 TI - Combining Ability of Different Agronomic Traits and Yield Components in Hybrid Barley. AB - Selection of parents based on their combining ability is an effective approach in hybrid breeding. In this study, eight maintainer lines and nine restorer lines were used to obtain 72 crosses for analyzing the general combining ability (GCA) and special combining ability (SCA) for seven agronomic and yield characters including plant height (PH), spike length excluding awns (SL), inter-node length (IL), spikes per plant (SP), thousand kernel weight (TKW), kernel weight per plant (KWP) and dry matter weight per plant (DWP). The results showed that GCA was significantly different among parents and SCA was also significantly different among crosses. The performance of hybrid was significantly correlated with the sum of female and male GCA (TGCA), SCA and heterosis. Hu1154 A, Mian684 A, 86F098 A, 8036 R and 8041 R were excellent parents with greater general combining ability. Five crosses, Hu1154 A*8032 R, Humai10 A*8040 R, Mian684 A*8037 R, Mian684 A*8041 R and 86F098 A*8037 R, showed superior heterosis for most characters. PMID- 26061001 TI - Does a Warmer World Mean a Greener World? Not Likely! PMID- 26061002 TI - Research of the Dispersity of the Functional Sericite/Methylphenyl- Silicone Resin. AB - In order to improve the homogeneity and dispersity of the sericite in methylphenyl-silicone resin, the agglomerate state of the sericites was controlled effectively. The dispersive model of the sericite in methylphenyl silicone resin was designed also. First, the modified sericite was prepared using hexadecyl trimethyl ammonium bromide as the intercalating agent. Then, functional sericite was incorporated into methylphenyl-silicone by terminal hydroxyl. The structure and dispersive performance of the hybrid polymers was charactered by analytical instruments. Scanning electron microscopy and Transmission electron microscope, Laser scanning confocal microscope and X-ray diffraction analysis showed that functional sericite was dispersed homogeneously in methylphenyl silicone resin matrix. X-ray photoelectron spectroscopy analysis showed that the absorption peaks of the Si-OH band of methylphenyl-silicone resin were decreased and the Si-O-Si band was increased. This change evidently showed a significant role to enhance the reaction degree of the functional sericite in methylphenyl silicone resin. PMID- 26061003 TI - Non-Invasive Assessment of the Interrelationships of Diet, Pregnancy Rate, Group Composition, and Physiological and Nutritional Stress of Barren-Ground Caribou in Late Winter. AB - The winter diet of barren-ground caribou may affect adult survival, timing of parturition, neonatal survival, and postpartum mass. We used microhistological analyses and hormone levels in feces to determine sex-specific late-winter diets, pregnancy rates, group composition, and endocrine-based measures of physiological and nutritional stress. Lichens, which are highly digestible but contain little protein, dominated the diet (> 68%) but were less prevalent in the diets of pregnant females as compared to non-pregnant females and males. The amount of lichens in the diets of pregnant females decreased at higher latitudes and as winter progressed. Pregnancy rates (82.1%, 95% CI = 76.0 - 88.1%) of adult cows were within the expected range for a declining herd, while pregnancy status was not associated with lichen abundance in the diet. Most groups (80%) were of mixed sex. Male: female ratios (62:100) were not skewed enough to affect the decline. Levels of hormones indicating nutritional stress were detected in areas of low habitat quality and at higher latitudes. Levels of hormones indicated that physiological stress was greatest for pregnant cows, which faced the increasing demands of gestation in late winter. These fecal-based measures of diet and stress provided contextual information for the potential mechanisms of the ongoing decline. Non-invasive techniques, such as monitoring diets, pregnancy rates, sex ratios and stress levels from fecal samples, will become increasingly important as monitoring tools as the industrial footprint continues to expand in the Arctic. PMID- 26061004 TI - Necroptosis Interfaces with MOMP and the MPTP in Mediating Cell Death. AB - During apoptosis the pro-death Bcl-2 family members Bax and Bak induce mitochondrial outer membrane permeabilization (MOMP) to mediate cell death. Recently, it was shown that Bax and Bak are also required for mitochondrial permeability transition pore (MPTP)-dependent necrosis, where, in their non oligomeric state, they enhance permeability characteristics of the outer mitochondrial membrane. Necroptosis is another form of regulated necrosis involving the death receptors and receptor interacting protein kinases (RIP proteins, by Ripk genes). Here, we show cells or mice deficient for Bax/Bak or cyclophilin D, a protein that regulates MPTP opening, are resistant to cell death induced by necroptotic mediators. We show that Bax/Bak oligomerization is required for necroptotic cell death and that this oligomerization reinforces MPTP opening. Mechanistically, we observe mixed lineage kinase domain-like (MLKL) protein and cofilin-1 translocation to the mitochondria following necroptosis induction, while expression of the mitochondrial matrix isoform of the antiapoptotic Bcl-2 family member, myeloid cell leukemia 1 (Mcl-1), is significantly reduced. Some of these effects are lost with necroptosis inhibition in Bax/Bak1 double null, Ppif-/-, or Ripk3-/- fibroblasts. Hence, downstream mechanisms of cell death induced by necroptotic stimuli utilize both Bax/Bak to generate apoptotic pores in the outer mitochondrial membrane as well as MPTP opening in association with known mitochondrial death modifying proteins. PMID- 26061005 TI - A Novel Alpha Cardiac Actin (ACTC1) Mutation Mapping to a Domain in Close Contact with Myosin Heavy Chain Leads to a Variety of Congenital Heart Defects, Arrhythmia and Possibly Midline Defects. AB - BACKGROUND: A Lebanese Maronite family presented with 13 relatives affected by various congenital heart defects (mainly atrial septal defects), conduction tissue anomalies and midline defects. No mutations were found in GATA4 and NKX2 5. METHODS AND RESULTS: A set of 399 poly(AC) markers was used to perform a linkage analysis which peaked at a 2.98 lod score on the long arm of chromosome 15. The haplotype analysis delineated a 7.7 meganucleotides genomic interval which included the alpha-cardiac actin gene (ACTC1) among 36 other protein coding genes. A heterozygous missense mutation was found (c.251T>C, p.(Met84Thr)) in the ACTC1 gene which changed a methionine residue conserved up to yeast. This mutation was absent from 1000 genomes and exome variant server database but segregated perfectly in this family with the affection status. This mutation and 2 other ACTC1 mutations (p.(Glu101Lys) and p.(Met125Val)) which result also in congenital heart defects are located in a region in close apposition to a myosin heavy chain head region by contrast to 3 other alpha-cardiac actin mutations (p.(Ala297Ser),p.(Asp313His) and p.(Arg314His)) which result in diverse cardiomyopathies and are located in a totally different interaction surface. CONCLUSIONS: Alpha-cardiac actin mutations lead to congenital heart defects, cardiomyopathies and eventually midline defects. The consequence of an ACTC1 mutation may in part be dependent on the interaction surface between actin and myosin. PMID- 26061006 TI - A study of the dynamics of seizure propagation across micro domains in the vicinity of the seizure onset zone. AB - OBJECTIVE: The use of micro-electrode arrays to measure electrical activity from the surface of the brain is increasingly being investigated as a means to improve seizure onset zone (SOZ) localization. In this work, we used a multivariate autoregressive model to determine the evolution of seizure dynamics in the [Formula: see text] Hz high frequency band across micro-domains sampled by such micro-electrode arrays. We showed that a directed transfer function (DTF) can be used to estimate the flow of seizure activity in a set of simulated micro electrode data with known propagation pattern. APPROACH: We used seven complex partial seizures recorded from four patients undergoing intracranial monitoring for surgical evaluation to reconstruct the seizure propagation pattern over sliding windows using a DTF measure. MAIN RESULTS: We showed that a DTF can be used to estimate the flow of seizure activity in a set of simulated micro electrode data with a known propagation pattern. In general, depending on the location of the micro-electrode grid with respect to the clinical SOZ and the time from seizure onset, ictal propagation changed in directional characteristics over a 2-10 s time scale, with gross directionality limited to spatial dimensions of approximately [Formula: see text]. It was also seen that the strongest seizure patterns in the high frequency band and their sources over such micro-domains are more stable over time and across seizures bordering the clinically determined SOZ than inside. SIGNIFICANCE: This type of propagation analysis might in future provide an additional tool to epileptologists for characterizing epileptogenic tissue. This will potentially help narrowing down resection zones without compromising essential brain functions as well as provide important information about targeting anti-epileptic stimulation devices. PMID- 26061007 TI - Ultrasensitive Proteome Profiling for 100 Living Cells by Direct Cell Injection, Online Digestion and Nano-LC-MS/MS Analysis. AB - Single-cell proteome analysis has always been an exciting goal because it provides crucial information about cellular heterogeneity and dynamic change. Here we presented an integrated proteome analysis device (iPAD) for 100 living cells (iPAD-100) that might be suitable for single-cell analysis. Once cells were cultured, the iPAD-100 could be applied to inject 100 living cells, to transform the living cells into peptides, and to produce protein identification results with total automation. Due to the major obstacle for detection limit of mass spectrometry, we applied the iPAD-100 to analyze the proteome of 100 cells. In total, 813 proteins were identified in a DLD-cell proteome by three duplicate runs. Gene Ontology analysis revealed that proteins from different cellular compartments were well-represented, including membrane proteins. The iPAD-100 greatly simplified the sampling process, reduced sample loss, and prevented contamination. As a result, proteins whose copy numbers were lower than 1000 were identified from 100-cell samples with the iPAD-100, showing that a detection limit of 200 zmol was achieved. With increased sensitivity of mass spectrometry, the iPAD-100 may be able to reveal bountiful proteome information from a single cell in the near future. PMID- 26061008 TI - Erratum to: Cardiac Surgery in Germany during 2014: A Report on Behalf of the German Society for Thoracic and Cardiovascular Surgery [Thorac Cardiovasc Surg 2015; 63(04): 258-269]. PMID- 26061009 TI - Synthesis of 6-Hydroxysphingosine and alpha-Hydroxy Ceramide Using a Cross Metathesis Strategy. AB - In this paper, a new synthetic route toward 6-hydroxysphingosine and alpha hydroxy ceramide is described. The synthesis employs a cross-metathesis to unite a sphingosine head allylic alcohol with a long-chain fatty acid alkene that also bears an allylic alcohol group. To allow for a productive CM coupling, the sphingosine head allylic alcohol was protected with a cyclic carbonate moiety and a reactive CM catalyst system, consisting of Grubbs II catalyst and CuI, was employed. PMID- 26061011 TI - Growth of MoS(2(1-x))Se(2x) (x = 0.41-1.00) Monolayer Alloys with Controlled Morphology by Physical Vapor Deposition. AB - Transition-metal dichalcogenide (TMD) monolayer alloys are a branch of two dimensional (2D) materials which can have large-range band gap tuning as the composition changes. Synthesis of 2D TMD monolayer alloys with controlled composition as well as controlled domain size and edge structure is of great challenge. In the present work, we report growth of MoS2(1-x)Se2x monolayer alloys (x = 0.41-1.00) with controlled morphology and large domain size using physical vapor deposition (PVD). MoS2(1-x)Se2x monolayer alloys with different edge orientations (Mo-zigzag and S/Se-zigzag edge orientations) have been obtained by controlling the deposition temperature. Large domain size of MoS2(1 x)Se2x monolayer alloys (x = 0.41-1.00) up to 20 MUm have been obtained by tuning the temperature gradient in the deposition zone. Together with previously obtained MoS2(1-x)Se2x monolayer alloys (x = 0-0.40), the band gap photoluminescence (PL) is continuously tuned from 1.86 eV (i.e., 665 nm, reached at x = 0.00) to 1.55 eV (i.e., 800 nm, reached at x = 1.00). Additionally, Raman peak splitting was observed in MoS2(1-x)Se2x monolayer alloys. This work provides a way to synthesize MoS2(1-x)Se2x monolayer alloys with different edge orientations, which could be benefit to controlled growth of other 2D materials. PMID- 26061010 TI - Imine Hydrogels with Tunable Degradability for Tissue Engineering. AB - A shortage of available organ donors has created a need for engineered tissues. In this context, polymer-based hydrogels that break down inside the body are often used as constructs for growth factors and cells. Herein, we report imine cross-linked gels where degradation is controllable by the introduction of mixed imine cross-links. Specifically, hydrazide-functionalized poly(ethylene glycol) (PEG) reacts with aldehyde-functionalized PEG (PEG-CHO) to form hydrazone linked hydrogels that degrade quickly in media. The time to degradation can be controlled by changing the structure of the hydrazide group or by introducing hydroxylamines to form nonreversible oxime linkages. Hydrogels containing adipohydrazide-functionalized PEG (PEG-ADH) and PEG-CHO were found to degrade more rapidly than gels formed from carbodihydrazide-functionalized PEG (PEG-CDH). Incorporating oxime linkages via aminooxy-functionalized PEG (PEG-AO) into the hydrazone cross-linked gels further stabilized the hydrogels. This imine cross linking approach should be useful for modulating the degradation characteristics of 3D cell culture supports for controlled cell release. PMID- 26061012 TI - DMAP-Catalyzed [2 + 4] Cycloadditions of Allenoates with N-Acyldiazenes: Direct Method to 1,3,4-Oxadiazine Derivatives. AB - An efficient DMAP-catalyzed [2 + 4] cycloaddition of allenoates and N acyldiazenes is reported. The reaction involved embedding three heteroatoms into a six-membered ring and generated 1,3,4-oxadiazine derivatives in moderate to good yields. PMID- 26061013 TI - Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA Encoded Chemical Library. AB - We describe the synthesis and screening of a DNA-encoded chemical library containing 76230 compounds. In this library, sets of amines and carboxylic acids are directly linked producing encoded compounds with compact structures and drug like properties. Affinity screening of this library yielded inhibitors of the potential pharmaceutical target tankyrase 1, a poly(ADP-ribose) polymerase. These compounds have drug-like characteristics, and the most potent hit compound (X066/Y469) inhibited tankyrase 1 with an IC50 value of 250 nM. PMID- 26061014 TI - Iron-Catalyzed Directed C(sp(2))-H and C(sp(3))-H Functionalization with Trimethylaluminum. AB - Conversion of a C(sp(2))-H or C(sp(3))-H bond to the corresponding C-Me bond can be achieved by using AlMe3 or its air-stable diamine complex in the presence of catalytic amounts of an inorganic iron(III) salt and a diphosphine along with 2,3 dichlorobutane as a stoichiometric oxidant. The reaction is applicable to a variety of amide substrates bearing a picolinoyl or 8-aminoquinolyl directing group, enabling methylation of a variety of (hetero)aryl, alkenyl, and alkyl amides. The use of the mild aluminum reagent prevents undesired reduction of iron and allows the reaction to proceed with catalyst turnover numbers as high as 6500. PMID- 26061015 TI - Serum Vitamin D Levels and Polycystic Ovary syndrome: A Systematic Review and Meta-Analysis. AB - Vitamin D deficiency (VDD) is common in women with and without polycystic ovary syndrome (PCOS) and may be associated with metabolic and endocrine disorders in PCOS. The aim of this meta-analysis is to assess the associations of serum vitamin D levels with metabolic and endocrine dysregulations in women with PCOS, and to determine effects of vitamin D supplementation on metabolic and hormonal functions in PCOS patients. The literature search was undertaken through five databases until 16 January 2015 for both observational and experimental studies concerning relationships between vitamin D and PCOS. A total of 366 citations were identified, of which 30 were selected (n = 3182). We found that lower serum vitamin D levels were related to metabolic and hormonal disorders in women with PCOS. Specifically, PCOS patients with VDD were more likely to have dysglycemia (e.g., increased levels of fasting glucose and homeostatic model assessment insulin resistance index (HOMA-IR)) compared to those without VDD. This meta analysis found no evidence that vitamin D supplementation reduced or mitigated metabolic and hormonal dysregulations in PCOS. VDD may be a comorbid manifestation of PCOS or a minor pathway in PCOS associated metabolic and hormonal dysregulation. Future prospective observational studies and randomized controlled trials with repeated VDD assessment and better characterization of PCOS disease severity at enrollment are needed to clarify whether VDD is a co determinant of hormonal and metabolic dysregulations in PCOS, represents a consequence of hormonal and metabolic dysregulations in PCOS or both. PMID- 26061016 TI - Quercetin Decreases Claudin-2 Expression Mediated by Up-Regulation of microRNA miR-16 in Lung Adenocarcinoma A549 Cells. AB - Claudin-2 is highly expressed in human lung adenocarcinoma tissues and cells. Knockdown of claudin-2 decreases cell proliferation and migration. Claudin-2 may be a novel target for lung adenocarcinoma. However, there are no physiologically active substances of foods which decrease claudin-2 expression. We here found that quercetin, a flavonoid present in fruits and vegetables, time- and concentration-dependently decreases claudin-2 expression in lung adenocarcinoma A549 cells. In the present study, we examined what regulatory mechanism is involved in the decrease in claudin-2 expression by quercetin. Claudin-2 expression was decreased by LY-294002, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, and U0126, a MEK inhibitor. These drugs inhibited the phosphorylation of Akt and ERK1/2, which are downstream targets of PI3-K and MEK, respectively. In contrast, quercetin did not inhibit the phosphorylation. Both LY-294002 and U0126 inhibited promoter activity of claudin-2, but quercetin did not. The stability of claudin-2 mRNA was decreased by quercetin. Quercetin increased the expression of microRNA miR-16. An inhibitor of miR-16 rescued quercetin-induced decrease in the claudin-2 expression. These results suggest that quercetin decreases claudin-2 expression mediated by up-regulation of miR-16 expression and instability of claudin-2 mRNA in lung adenocarcinoma cells. PMID- 26061017 TI - Contribution of Food Groups to Energy and Nutrient Intakes in Five Developed Countries. AB - Economic growth in developing countries and globalization of the food sector is leading to increasingly similar food consumption patterns worldwide. The aim of this study was to describe similarities and differences in the contributions of main food groups to energy and nutrient intakes in five developed countries across three continents. We obtained summary reports of national food consumption survey data from Australia, France, Denmark, the Netherlands, and the United States. Survey years spanned 2003-2012; sample size ranged from 1444 to 17,386. To mitigate heterogeneity of food groups across countries, we recategorized each survey's reported food groups and subgroups into eight main food groups and, for three countries, a ninth "mixed dishes" group. We determined the percent contribution of each food group to mean daily intakes of energy, saturated fat, sodium, fiber, and ten vitamins and minerals that are commonly under-consumed. Differences in findings from surveys utilizing a foods-as-consumed versus a disaggregated or ingredients approach to food group composition and contributions from the milk and milk products group, a source of several under-consumed nutrients, were explored. Patterns of food group contributions to energy and nutrient intakes were generally similar across countries. Some differences were attributable to the analytical approach used by the surveys. For the meat/protein, milk and milk products, vegetables, and fruit groups, percent contributions to key nutrient intakes exceeded percent contributions to energy intake. The mixed dishes group provided 10%-20% of total daily energy and a similar 10%-25% of the daily intake of several nutrients. This descriptive study contributes to an understanding of food group consumption patterns in developed countries. PMID- 26061018 TI - Construct Validity of the DSM-5 Section III Personality Trait Profile for Borderline Personality Disorder. AB - This study evaluated the nomological network of the borderline personality disorder (BPD) trait profile in the Diagnostic and Statistical Manual of Mental Disorders (5th ed. [DSM-5]) Section III. BPD symptoms include a variety of maladaptive thoughts and behaviors, and it is important to determine if the Section III trait operationalization for BPD captures these behavioral symptoms, as well as shows similar associations as the traditional Section II version with external criteria. For this purpose, we used a sample of 285 undergraduate students and conducted correlation and regression analyses to delineate the associations between Section III BPD traits and conceptually relevant external criteria. A Section III Total score was meaningfully associated with all criteria. Moreover, externalizing psychopathology tended to be most highly associated with disinhibitory Section III BPD traits, whereas internalizing psychopathology tended to have its strongest unique associations with traits reflective of negative affectivity. These results provide support for the construct validity of the trait profile for BPD in DSM-5 Section III. PMID- 26061019 TI - Endothelial Erg expression is required for embryogenesis and vascular integrity. AB - Members of the ETS family of transcription factors are involved in several developmental processes including endothelial cell specification and blood vessel formation, but their exact roles remain unclear. The family member Erg is highly expressed in endothelial cells as compared to other developing cell types including chondrocytes, hematopoietic cells and mesodermal cells. To study the specific roles ERG plays in endothelial cell specification and function during early embryogenesis, we conditionally ablated it by mating ErgloxP/loxP and Tie2 Cre mice. We found that mutant embryos died by mid-gestation and that angiogenesis and vascular integrity were highly compromised. Our study reveals that ERG has essential and cell autonomous roles in endothelial cell development and blood vessel maintenance. PMID- 26061020 TI - Sentencing Male Sex Offenders Under the Age of 14: A Law Reform Advocacy Journey in Hong Kong. AB - The common law presumption that a boy under the age of 14 is incapable of sexual intercourse has provoked controversial debates in Hong Kong. This article describes a 6-step advocacy journey to examine how community efforts have helped modify this law so that juvenile male sexual offenders under the age of 14 who have committed the crime of having sexual intercourse with underage females can be sentenced to receive appropriate treatment. Seven court cases provided by the magistrates' courts in Hong Kong were used in this advocacy effort for the removal of the presumption in July 2012. Although this effort has yet to reveal signs of effectiveness, it represents greater public awareness about providing rehabilitation appropriate for juvenile sex offenders through a formal sentence. Restorative justice, as opposed to retributive or punitive justice, places an emphasis on rehabilitation of the offender and restoration of victims to a place of wholeness. PMID- 26061021 TI - Interpreting Child Sexual Abuse: Empathy and Offense-Supportive Cognitions among Child Sex Offenders. AB - Researchers have suggested that child sex offenders hold distorted views on social interactions with children. Misinterpreting children's behavior and intentions could lead to sexually abusive behavior toward children. It is further suggested that the interpretation process is influenced by offenders' offense supportive cognitions and levels of empathy. To examine the relationships between these three concepts, 47 contact offenders completed self-reports on offense supportive cognitions and empathy. Vignettes were developed to assess the extent to which offenders attributed responsibility, benefit, and complicity to children in hypothetical child molestation incidents. This study showed that cognitions that justify sexual offending against children seem to diminish the threshold for sexual assault by assigning more cooperation and willingness of the victim in a child molestation incident. PMID- 26061022 TI - Disclosure of Child Sexual Abuse: The Case of Pacific Islanders. AB - A number of factors influence the disclosure of child sexual abuse by survivors. While the influence of race and ethnicity on disclosure patterns is getting more attention, little has been written on abused children of Pacific Islanders, due in part to both lack of relevant data and a relatively small Pacific Islander population in the United States. Drawing on interviews with Pacific Islander women who were sexually abused in childhood and who delayed revealing their victimization, we explore the reasons for delayed disclosure. Findings suggest that cultural norms and family dynamics affect disclosure decisions. Concerns for the family and self-blame were the most common reasons for delay and lack of disclosure. We discuss implications of the findings and make policy recommendations. PMID- 26061023 TI - Pilot Study on Childhood Sexual Abuse, Diurnal Cortisol Secretion, and Weight Loss in Bariatric Surgery Patients. AB - Childhood sexual abuse increases risk for adult obesity. A potential contributing factor is altered cortisol secretion. In this pilot study, relationships among childhood sexual abuse, diurnal salivary cortisol secretion, and weight loss were explored in 17 bariatric surgery patients. Measurement points were before surgery (baseline) and 3 and 6 months after surgery. Childhood sexual abuse was measured by the Childhood Trauma Questionnaire. The results showed moderate but nonsignificant positive correlations between the childhood sexual abuse subscale score and baseline morning cortisol, evening cortisol, and daily mean cortisol. An unexpected positive correlation was noted between the Childhood Trauma Questionnaire total score and weight loss at six months. Diurnal cortisol secretion did not change over time after surgery nor correlate significantly with weight loss at six months. PMID- 26061024 TI - Prevalence of Sexual Abuse in Childhood: Some Critical Methodological Reflections. AB - This article attempts to analyze the prevalence rates of sexual abuse in childhood reported in comparative empirical studies, giving an overview of a selection of representative studies reporting high rates of abuse and comparing it to an overview of studies reporting lower rates. Extremely discrepant rates of childhood sexual abuse are reported in a number of empirical studies conducted in this field over the past 26 years, particularly those looking beyond prevalence to study the links between this type of trauma and future motherhood. To shed light on the disparities in the reported prevalence rates, the article reviews the principal methodological biases that have contaminated the findings. The authors then offer several suggestions for improvement that might be implemented in future studies. PMID- 26061025 TI - Structured Therapeutic Games for Nonoffending Caregivers of Children Who Have Experienced Sexual Abuse. AB - Game-based cognitive-behavioral therapy group model for nonoffending caregivers utilizes structured therapeutic games to assist parents following child sexual abuse. Game-based cognitive-behavioral therapy group model is a manualized group treatment approach that integrates evidence-based cognitive-behavioral therapy components with structured play therapy to teach parenting and coping skills, provide psychoeducation, and process trauma. Structured therapeutic games were designed to allow nonoffending caregivers to process their children's abuse experiences and learn skills necessary to overcome trauma in a nonthreatening, fun, and engaging manner. The implementation of these techniques allow clinicians to address a variety of psychosocial difficulties that are commonly found among nonoffending caregivers of children who have experienced sexual abuse. In addition, structured therapeutic games help caregivers develop strengths and abilities that they can use to help their children cope with abuse and trauma and facilitates the development of positive posttraumatic growth. Techniques and procedures for treatment delivery along with a description of core components and therapeutic modules are discussed. An illustrative case study is provided. PMID- 26061026 TI - Participatory Action Research on Help-Seeking Behaviors of Self-Defined Ritual Abuse Survivors: A Brief Report. AB - The existence of ritual abuse is the subject of much debate. Ritual abuse survivor perceptions of seeking help have not been explored, and studies have yet to utilize self-defined survivors as collaborative researchers. This study addresses both issues. Participatory action research was utilized to design a survey and semistructured interview to investigate ritual abuse survivor experience of seeking help. Sixty-eight participants completed the survey, and 22 were interviewed. A group approach to thematic analysis aided validity and reliability. Participants reported experiencing disbelief and a lack of ritual abuse awareness and help from support services. In contrast, participatory action research was reported by participants as educative and emancipatory. Future research should explore the benefits of participatory action research for survivors of different forms of oppression. PMID- 26061028 TI - Robust Polypropylene Fabrics Super-Repelling Various Liquids: A Simple, Rapid and Scalable Fabrication Method by Solvent Swelling. AB - A simple, rapid (10 s) and scalable method to fabricate superhydrophobic polypropylene (PP) fabrics is developed by swelling the fabrics in cyclohexane/heptane mixture at 80 degrees C. The recrystallization of the swollen macromolecules on the fiber surface contributes to the formation of submicron protuberances, which increase the surface roughness dramatically and result in superhydrophobic behavior. The superhydrophobic PP fabrics possess excellent repellency to blood, urine, milk, coffee, and other common liquids, and show good durability and robustness, such as remarkable resistances to water penetration, abrasion, acidic/alkaline solution, and boiling water. The excellent comprehensive performance of the superhydrophobic PP fabrics indicates their potential applications as oil/water separation materials, protective garments, diaper pads, or other medical and health supplies. This simple, fast and low cost method operating at a relatively low temperature is superior to other reported techniques for fabricating superhydrophobic PP materials as far as large scale manufacturing is considered. Moreover, the proposed method is applicable for preparing superhydrophobic PP films and sheets as well. PMID- 26061030 TI - Development and Validation of a Set of Palliative Medicine Entrustable Professional Activities: Findings from a Mixed Methods Study. AB - BACKGROUND: Entrustable professional activities (EPAs) are routine tasks considered essential to a professional practice. An EPA can serve as a performance-based outcome that a clinical supervisor would progressively entrust a learner to perform. OBJECTIVE: Our aim was to identify, develop, and validate a set of EPAs for the palliative medicine discipline. METHODS: The design was a sequential qualitative and quantitative mixed methods study. A working group was convened to develop a set of EPAs. Focus groups and surveys were used for validation purposes. Palliative medicine educators and content experts from across Canada participated in both the working group as well as the focus groups. Attendees of the 2014 Canadian Society of Palliative Care Physicians (CSPCP) annual conference completed surveys. A questionnaire was used to collect survey participant sociodemographic, clinical, and academic information along with ratings of the importance of the EPAs individually and collectively. Cronbach's alpha examined internal consistency of the set of EPAs. RESULTS: Focus group participants strongly endorsed the 12 EPAs. Virtually all survey participants rated the individual EPAs as being "fairly/very important" (range 94% to 100%). Of the participants, 97% agreed that residents able to perform the set of EPAs would be practicing palliative medicine and 87% indicated strong agreement that this collective set of EPAs captures activities that all palliative medicine physicians must be able to perform. A Cronbach's alpha of 0.841 confirmed good internal consistency. CONCLUSIONS: Near uniform agreement from a national group of palliative medicine physicians provides strong validation for the set of 12 EPAs. PMID- 26061031 TI - With Cytometric Bead Assay, the Interleukin-10/HBV DNA Ratio Is an Early Predictor for Response to Interferon-alpha Treatment in Chronic Hepatitis B. AB - Both host immunity and hepatitis B virus (HBV) contribute to the therapeutic response to interferon (IFN)-alpha treatment in chronic hepatitis B (CHB) based on the immune modulation function to eliminate virus, while neither viral load nor cytokine alone could reflect the complex interaction between host immune response and virus. This study aimed at exploring a parameter of combined immunological and virological indexes to predict the response profile to IFN alpha treatment in patients with CHB. Biochemical (alanine transaminase), virological (HBV DNA load, HBsAg, HBeAg), and immunological [IFN-gamma, tumor necrosis factor (TNF), interleukin (IL)-2, IL-4, IL-6, and IL-10] indexes were dynamically monitored (at baseline, 2, 4, 8, 12, 24, 36, 48, and 72 weeks) in 41 patients who received a 48-week IFN-alpha treatment. First, we found that responders displayed an elevation in both Th1 and Th2 type cytokines from baseline to 4 weeks. What is more, the HBV DNA load at the baseline and IL-10 at 4 weeks showed significant differences between responders and nonresponders and were highly associated with the response to IFN-alpha treatment. More importantly, IL-10/HBV DNA was identified as a positive predictor for response to IFN-alpha treatment (odds ratio=5.785) by logistic regression analysis. We show here that the IL-10/HBV DNA ratio, a parameter of combined immunological and virological factors, can be useful in predicting the response to IFN-alpha treatment in CHB. PMID- 26061032 TI - Immune alterations in acute bipolar depression. AB - OBJECTIVE: Immunologic abnormalities have been found in bipolar disorder and acute mania. However, there have been fewer studies of patients with acute bipolar depression. METHOD: Blood samples were obtained from individuals with acute bipolar depression, acute mania, and controls. These samples were evaluated for antibodies to human herpesviruses, gliadin, Toxoplasma gondii, and endogenous retroviruses as well as for C-reactive protein (CRP) and pentraxin-3 using immunoassay methods. Linear regression models were used to compare the levels of the markers controlling for demographic and clinical variables. A subset of the bipolar depressed group was evaluated at a 6-month follow-up. RESULTS: The sample consisted of 82 individuals with acute bipolar depression, 147 with acute mania, and 280 controls. The levels of CRP and IgG antibodies to an endogenous retrovirus, Mason-Pfizer monkey virus (MPMV), were significantly elevated in the bipolar depressed group. Levels of pentraxin-3 were reduced in both psychiatric groups. An evaluation of 32 individuals 6 months after hospitalization for bipolar depression showed a significant decrease in the levels of MPMV antibodies, but not a change in the other markers. CONCLUSION: Individuals with acute bipolar depression show immune alterations. Some of the alterations are similar to those found in acute mania. PMID- 26061033 TI - Analysis of the siRNA-Mediated Gene Silencing Process Targeting Three Homologous Genes Controlling Soybean Seed Oil Quality. AB - In the past decade, RNA silencing has gained significant attention because of its success in genomic scale research and also in the genetic improvement of crop plants. However, little is known about the molecular basis of siRNA processing in association with its target transcript. To reveal this process for improving hpRNA-mediated gene silencing in crop plants, the soybean GmFAD3 gene family was chosen as a test model. We analyzed RNAi mutant soybean lines in which three members of the GmFAD3 gene family were silenced. The silencing levels of FAD3A, FAD3B and FAD3C were correlated with the degrees of sequence homology between the inverted repeat of hpRNA and the GmFAD3 transcripts in the RNAi lines. Strikingly, transgenes in two of the three RNAi lines were heavily methylated, leading to a dramatic reduction of hpRNA-derived siRNAs. Small RNAs corresponding to the loop portion of the hairpin transcript were detected while much lower levels of siRNAs were found outside of the target region. siRNAs generated from the 318-bp inverted repeat were found to be diced much more frequently at stem sequences close to the loop and associated with the inferred cleavage sites on the target transcripts, manifesting "hot spots". The top candidate hpRNA-derived siRNA share certain sequence features with mature miRNA. This is the first comprehensive and detailed study revealing the siRNA-mediated gene silencing mechanism in crop plants using gene family GmFAD3 as a test model. PMID- 26061034 TI - Deciphering the Niches of Colonisation of Vitis vinifera L. by the Esca Associated Fungus Phaeoacremonium aleophilum Using a gfp Marked Strain and Cutting Systems. AB - INTRODUCTION: Esca disease has become a major threat for viticulture. Phaeoacremonium aleophilum is considered a pioneer of the esca complex pathosystem, but its colonisation behaviour inside plants remains poorly investigated. MATERIAL AND METHODS: In this study, P. aleophilum::gfp7 colonisation was assessed six and twelve weeks post-inoculation in two different types of tissues: in the node and the internode of one year-old rooted cuttings of Cabernet Sauvignon. These processes of colonisation were compared with the colonisation by the wild-type strain using a non-specific lectin probe Alexa Fluor 488-WGA. RESULTS: Data showed that six weeks post-inoculation of the internode, the fungus had colonised the inoculation point, the bark and xylem fibres. Bark, pith and xylem fibres were strongly colonised by the fungus twelve weeks post-inoculation and it can progress up to 8 mm from the point of inoculation using pith, bark and fibres. P. aleophilum was additionally detected in the lumen of xylem vessels in which tyloses blocked its progression. Different plant responses in specific tissues were additionally visualised. Inoculation of nodes led to restricted colonisation of P. aleophilum and this colonisation was associated with a plant response six weeks post-inoculation. The fungus was however detected in xylem vessels, bark and inside the pith twelve weeks post inoculation. CONCLUSIONS: These results demonstrate that P. aleophilum colonisation can vary according to the type of tissues and the type of spread using pith, bark and fibres. Woody tissues can respond to the injury and to the presence of this fungus, and xylem fibres play a key role in the early colonisation of the internode by P. aleophilum before the fungus can colonise xylem vessels. PMID- 26061035 TI - Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. AB - BACKGROUND AND AIMS: Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches. METHODS: Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population. RESULTS: In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09-1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07-3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000. CONCLUSIONS: Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation. PMID- 26061036 TI - Decadal Changes in the Abundance and Length of Snapper (Chrysophrys auratus) in Subtropical Marine Sanctuaries. AB - Abundance and length of the highly-targeted snapper Chysophrys auratus were compared between sites in 'no take' areas (Sanctuary Zones: SZ), partial protected areas which are fished (Habitat Protection Zones: HPZ), and areas outside (Outside) the Solitary Islands Marine Park (SIMP), Australia. Baited Remote Underwater Video (BRUV) sampling on shallow rocky reef (15 - 25 m) was conducted annually from 2002 until 2014 in the Austral-winter, covering the decade after these marine park zones were established (2002). Additional deeper sites (25 - 40 m) were sampled in 2010-2011 to assess if findings were more broadly applicable. Lengths were measured using stereo-BRUVs from 2011-2014. Snapper were significantly more abundant in SZ overall and in most years compared with the other two management types, which did not significantly differ. Snapper rapidly increased after 2 - 3 years protection in all management types, especially SZ. Snapper were present on more SZ deployments than HPZ and Outside after the same period. The positive SZ response in snapper abundance on shallower reef was also found at a broader spatial scale on deeper sites. Again the two fished management types did not show significant differences among each other. There was considerable variation in snapper abundance between years, with strong peaks in 2005, 2009 and 2014 especially in SZ. Abundances remained higher in SZ in the year or two following a strong peak, but decreased to similar abundances to fished areas before the next peak. Snapper length frequency distribution significantly differed between SZ and both fished management types, with more larger snapper within SZ including a higher proportion (58%) that were legal sized (>25.7 cm FL). HPZ and Outside did not significantly differ from each other, and were dominated by individuals below legal size. Overall, SZ's have positively influenced abundance and length of snapper on these subtropical rocky reefs. PMID- 26061037 TI - International Differences in Treatment and Clinical Outcomes for High Grade Glioma. AB - BACKGROUND: High grade gliomas are the most common type of malignant brain tumor, and despite their rarity, cause significant morbidity and mortality. This study aimed to compare the treatment patterns of high grade glioma to examine survival patterns in patients who receive specific treatments between cohorts in Ohio and Taiwan. METHOD: Patients aged 18 years and older at age of diagnosis with World Health Organization (WHO) grade III or IV astrocytoma from 2007-2012 were selected from the Ohio Brain Tumor Study and the Taiwan Cancer Registry. The treatment information was derived from medical chart reviews in Ohio and National Health Insurance Research Data in Taiwan. Treatment examined included surgical procedure (brain biopsy and/or resection), radiotherapy (radiation and/or radiosurgery), and alkylating chemotherapy. Kaplan-Meier and parametric survival models were used to examine the effect of treatment on survival, adjusted for age, sex, and comorbidities. RESULTS: 294 patients in Ohio and 1,097 patients in Taiwan met the inclusion criteria. 70.3% patients in Ohio and 51.4% in Taiwan received surgical resection, followed by concurrent chemoradiation. Patients who received this treatment had the highest survival rate, with a 1-year survival rate of 72.8% in Ohio and 73.4% in Taiwan. Patients who did not receive surgical resection, followed by concurrent chemoradiation had an increased risk of death (hazard ratio of 5.03 [95% confidence interval (CI): 3.61-7.02] in Ohio and 1.49 [95% CI: 1.31-1.71] in Taiwan) after adjustment for age, sex, and comorbidities. CONCLUSION: Surgical resection followed by concurrent chemoradiation was associated with higher survival rate of patients with high grade glioma in both Ohio and Taiwan; however, one-third of patients in Ohio and half in Taiwan did not receive this treatment. PMID- 26061038 TI - The Interplay between Environmental Filtering and Spatial Processes in Structuring Communities: The Case of Neotropical Snake Communities. AB - Both habitat filters and spatial processes can influence community structure. Space alone affects species immigration from the regional species pool, whereas habitat filters affect species distribution and inter-specific interactions. This study aimed to understand how the interplay between environmental and geographical processes influenced the structure of Neotropical snake communities in different habitat types. We selected six studies that sampled snakes in forests, four conducted in savannas and two in grasslands (the latter two are grouped in a non-forest category). We used the net relatedness and nearest taxon indices to assess phylogenetic structure within forest and non-forest areas. We also used the phylogenetic fuzzy-weighting algorithm to characterize phylogenetic structure across communities and the relation of phylogenetic composition patterns to habitat type, structure, and latitude. Finally, we tested for morphological trait convergence and phylogenetic niche conservatism using four forest and four non-forest areas for which morphological data were available. Community phylogenetic composition changed across forest and non-forest areas suggesting that environmental filtering influences community structure. Species traits were affected by habitat type, indicating convergence at the metacommunity level. Tail length, robustness, and number of ventral scales maximized community convergence among forest and non-forest areas. The observed patterns suggested environmental filtering, indicating that less vertically structured habitats represent a strong filter. Despite the fact that phylogenetic structure was not detected individually for each community, we observed a trend towards communities composed by more closely related species in higher latitudes and more overdispersed compositions in lower latitudes. Such pattern suggests that the limited distribution of major snake lineages constrained species distributions. Structure indices for each community were also related to habitat type, showing that communities from non-forest areas tend to be more clustered. Our study showed that both environmental filtering and spatial gradients play important roles in shaping the composition of Neotropical snake communities. PMID- 26061039 TI - Impact of Virgin Olive Oil and Phenol-Enriched Virgin Olive Oils on the HDL Proteome in Hypercholesterolemic Subjects: A Double Blind, Randomized, Controlled, Cross-Over Clinical Trial (VOHF Study). AB - The effects of olive oil phenolic compounds (PCs) on HDL proteome, with respect to new aspects of cardioprotective properties, are still unknown. The aim of this study was to assess the impact on the HDL protein cargo of the intake of virgin olive oil (VOO) and two functional VOOs, enriched with their own PCs (FVOO) or complemented with thyme PCs (FVOOT), in hypercholesterolemic subjects. Eligible volunteers were recruited from the IMIM-Hospital del Mar Medical Research Institute (Spain) from April 2012 to September 2012. Thirty-three hypercholesterolemic participants (total cholesterol >200 mg/dL; 19 men and 14 women; aged 35 to 80 years) were randomized in the double-blind, controlled, cross-over VOHF clinical trial. The subjects received for 3 weeks 25 mL/day of: VOO, FVOO, or FVOOT. Using a quantitative proteomics approach, 127 HDL-associated proteins were identified. Among these, 15 were commonly differently expressed after the three VOO interventions compared to baseline, with specific changes observed for each intervention. The 15 common proteins were mainly involved in the following pathways: LXR/RXR activation, acute phase response, and atherosclerosis. The three VOOs were well tolerated by all participants. Consumption of VOO, or phenol-enriched VOOs, has an impact on the HDL proteome in a cardioprotective mode by up-regulating proteins related to cholesterol homeostasis, protection against oxidation and blood coagulation while down regulating proteins implicated in acute-phase response, lipid transport, and immune response. The common observed protein expression modifications after the three VOOs indicate a major matrix effect. TRIAL REGISTRATION: International Standard Randomized Controlled Trials ISRCTN77500181. PMID- 26061041 TI - Correction: Relationship between Adiponectin Gene Polymorphisms and Late-Onset Alzheimer's Disease. PMID- 26061040 TI - Characteristics of Women Enrolled into a Randomized Clinical Trial of Dapivirine Vaginal Ring for HIV-1 Prevention. AB - INTRODUCTION: Women in sub-Saharan Africa are a priority population for evaluation of new biomedical HIV-1 prevention strategies. Antiretroviral pre exposure prophylaxis is a promising prevention approach; however, clinical trials among young women using daily or coitally-dependent products have found low adherence. Antiretroviral-containing vaginal microbicide rings, which release medication over a month or longer, may reduce these adherence challenges. METHODS: ASPIRE (A Study to Prevent Infection with a Ring for Extended Use) is a phase III, randomized, double-blind, placebo-controlled trial testing the safety and effectiveness of a vaginal ring containing the non-nucleoside reverse transcriptase inhibitor dapivirine for prevention of HIV-1 infection. We describe the baseline characteristics of African women enrolled in the ASPIRE trial. RESULTS: Between August 2012 and June 2014, 5516 women were screened and 2629 HIV 1 seronegative women between 18-45 years of age were enrolled from 15 research sites in Malawi, South Africa, Uganda, and Zimbabwe. The median age was 26 years (IQR 22-31) and the majority (59%) were unmarried. Nearly 100% of participants reported having a primary sex partner in the prior three months but 43% did not know the HIV-1 status of their primary partner; 17% reported additional concurrent partners. Nearly two-thirds (64%) reported having disclosed to primary partners about planned vaginal ring use in the trial. Sexually transmitted infections were prevalent: 12% had Chlamydia trachomatis, 7% Trichomonas vaginalis, 4% Neisseria gonorrhoeae, and 1% syphilis. CONCLUSIONS: African HIV-1 seronegative women at risk of HIV -1 infection were successfully enrolled into a phase III trial of dapivirine vaginal ring for HIV-1 prevention. PMID- 26061042 TI - Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity. AB - OBJECTIVE: Given that helminth infections have been shown to improve insulin sensitivity in animal studies, which may be explained by beneficial effects on energy balance or by a shift in the immune system to an anti-inflammatory profile, we investigated whether soil-transmitted helminth (STH)-infected subjects are more insulin sensitive than STH-uninfected subjects. DESIGN: We performed a cross-sectional study on Flores island, Indonesia, an area with high prevalence of STH infections. METHODS: From 646 adults, stool samples were screened for Trichuris trichiura by microscopy and for Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, and Strongyloides stercoralis by qPCR. No other helminth was found. We collected data on body mass index (BMI, kg/m2), waist-to-hip ratio (WHR), fasting blood glucose (FBG, mmol/L), insulin (pmol/L), high sensitive C-reactive protein (ng/ml) and Immunoglobulin E (IU/ml). The homeostatic model assessment for insulin resistance (HOMAIR) was calculated and regression models were used to assess the association between STH infection status and insulin resistance. RESULTS: 424 (66%) participants had at least one STH infection. STH infected participants had lower BMI (23.2 vs 22.5 kg/m2, p value = 0.03) and lower HOMAIR (0.97 vs 0.81, p value = 0.05). In an age-, sex- and BMI-adjusted model a significant association was seen between the number of infections and HOMAIR: for every additional infection with STH species, the HOMAIR decreased by 0.10 (p for linear trend 0.01). This effect was mainly accounted for by a decrease in insulin of 4.9 pmol/L for every infection (p for trend = 0.07). CONCLUSION: STH infections are associated with a modest improvement of insulin sensitivity, which is not accounted for by STH effects on BMI alone. PMID- 26061043 TI - Plasma Proteomic Profiling in Hereditary Breast Cancer Reveals a BRCA1-Specific Signature: Diagnostic and Functional Implications. AB - BACKGROUND: Breast cancer (BC) is a leading cause of death among women. Among the major risk factors, an important role is played by familial history of BC. Germ line mutations in BRCA1/2 genes account for most of the hereditary breast and/or ovarian cancers. Gene expression profiling studies have disclosed specific molecular signatures for BRCA1/2-related breast tumors as compared to sporadic cases, which might help diagnosis and clinical follow-up. Even though, a clear hallmark of BRCA1/2-positive BC is still lacking. Many diseases are correlated with quantitative changes of proteins in body fluids. Plasma potentially carries important information whose knowledge could help to improve early disease detection, prognosis, and response to therapeutic treatments. The aim of this study was to develop a comprehensive approach finalized to improve the recovery of specific biomarkers from plasma samples of subjects affected by hereditary BC. METHODS: To perform this analysis, we used samples from patients belonging to highly homogeneous population previously reported. Depletion of high abundant plasma proteins, 2D gel analysis, liquid chromatography-tandem mass spectrometry (LC-MS/MS) and bioinformatics analysis were used into an integrated approach to investigate tumor-specific changes in the plasma proteome of BC patients and healthy family members sharing the same BRCA1 gene founder mutation (5083del19), previously reported by our group, with the aim to identify specific signatures. RESULTS: The comparative analysis of the experimental results led to the identification of gelsolin as the most promising biomarker. CONCLUSIONS: Further analyses, performed using a panel of breast cancer cell lines, allowed us to further elucidate the signaling network that might modulate the expression of gelsolin in breast cancer. PMID- 26061044 TI - The Tumor Suppressive Effects of HPP1 Are Mediated Through JAK-STAT-Interferon Signaling Pathways. AB - HPP1, a novel tumor suppressive epidermal growth factor (EGF)-like ligand, mediates its effects through signal transducer and activators of transcription (STAT) activation. We previously demonstrated the importance of STAT1 activation for HPP1 function; however the contribution of STAT2 remains unclear. We sought to delineate the components of JAK-STAT-interferon (IFN) signaling specifically associated with HPP1s biological effects. Using stable HPP1-HCT116 transfectants, expression analyses were performed by polymerase chain reaction (PCR)/western blotting while expression knockdowns were achieved using siRNA. Growth parameters evaluated included proliferation, cell cycle distribution, and anchorage independent growth. STAT dimerization, translocation, and DNA binding were examined by reporter assays, fluorescent microscopy, and chromatin immunoprecipitation (ChIP), respectively. Forced expression of HPP1 in colon cancer cell lines results in the upregulation of total and activated levels of STAT2. We have also determined that JAK1 and JAK2 are activated in response to HPP1 overexpression, and are necessary for subsequent STAT activation. Overexpression of HPP1 was associated with significant increases in STAT1:STAT1 (p=0.007) and STAT1:STAT2 (p=0.036) dimer formation, as well as subsequent nuclear translocation. By ChIP, binding of activated STAT1 and STAT2 to the interferon-signaling regulatory element promoter sites of the selected genes, protein kinase RNA-activated (PKR), IFI44, and OAS1 was demonstrated. STAT2 knockdown resulted in partial abrogation of HPP1s growth suppressive activity with increased proliferation (p<0.0001), reduced G1/G0 phase cell cycle fraction, and a restoration of growth potential in soft agar (p<0.01). Presumably as a consequence of upregulation of IFN signaling elements, HPP1 overexpression resulted in an acquisition of exogenous IFN sensitivity. Physiologic doses of IFN alpha resulted in a significant reduction in proliferation (p<0.001) and increase in G1/G0 cell cycle arrest in HPP1 transfectants. STAT2 is necessary for HPP1 associated growth suppression, and mediates these effects through activation of IFN-alpha pathways. Given the interest in therapeutic targeting of oncogenic erbB proteins, further understanding of HPP1s role as a tumor suppressive EGF-like ligand is warranted. PMID- 26061045 TI - Lorentz force correction to the Boltzmann radiation transport equation and its implications for Monte Carlo algorithms. AB - To establish a theoretical framework for generalizing Monte Carlo transport algorithms by adding external electromagnetic fields to the Boltzmann radiation transport equation in a rigorous and consistent fashion. Using first principles, the Boltzmann radiation transport equation is modified by adding a term describing the variation of the particle distribution due to the Lorentz force. The implications of this new equation are evaluated by investigating the validity of Fano's theorem. Additionally, Lewis' approach to multiple scattering theory in infinite homogeneous media is redefined to account for the presence of external electromagnetic fields. The equation is modified and yields a description consistent with the deterministic laws of motion as well as probabilistic methods of solution. The time-independent Boltzmann radiation transport equation is generalized to account for the electromagnetic forces in an additional operator similar to the interaction term. Fano's and Lewis' approaches are stated in this new equation. Fano's theorem is found not to apply in the presence of electromagnetic fields. Lewis' theory for electron multiple scattering and moments, accounting for the coupling between the Lorentz force and multiple elastic scattering, is found. However, further investigation is required to develop useful algorithms for Monte Carlo and deterministic transport methods. To test the accuracy of Monte Carlo transport algorithms in the presence of electromagnetic fields, the Fano cavity test, as currently defined, cannot be applied. Therefore, new tests must be designed for this specific application. A multiple scattering theory that accurately couples the Lorentz force with elastic scattering could improve Monte Carlo efficiency. The present study proposes a new theoretical framework to develop such algorithms. PMID- 26061046 TI - Why Verbalization of Non-Verbal Memory Reduces Recognition Accuracy: A Computational Approach to Verbal Overshadowing. AB - Verbal overshadowing refers to a phenomenon whereby verbalization of non-verbal stimuli (e.g., facial features) during the maintenance phase (after the target information is no longer available from the sensory inputs) impairs subsequent non-verbal recognition accuracy. Two primary mechanisms have been proposed for verbal overshadowing, namely the recoding interference hypothesis, and the transfer-inappropriate processing shift. The former assumes that verbalization renders non-verbal representations less accurate. In contrast, the latter assumes that verbalization shifts processing operations to a verbal mode and increases the chance of failing to return to non-verbal, face-specific processing operations (i.e., intact, yet inaccessible non-verbal representations). To date, certain psychological phenomena have been advocated as inconsistent with the recoding-interference hypothesis. These include a decline in non-verbal memory performance following verbalization of non-target faces, and occasional failures to detect a significant correlation between the accuracy of verbal descriptions and the non-verbal memory performance. Contrary to these arguments against the recoding interference hypothesis, however, the present computational model instantiated core processing principles of the recoding interference hypothesis to simulate face recognition, and nonetheless successfully reproduced these behavioral phenomena, as well as the standard verbal overshadowing. These results demonstrate the plausibility of the recoding interference hypothesis to account for verbal overshadowing, and suggest there is no need to implement separable mechanisms (e.g., operation-specific representations, different processing principles, etc.). In addition, detailed inspections of the internal processing of the model clarified how verbalization rendered internal representations less accurate and how such representations led to reduced recognition accuracy, thereby offering a computationally grounded explanation. Finally, the model also provided an explanation as to why some studies have failed to report verbal overshadowing. Thus, the present study suggests it is not constructive to discuss whether verbal overshadowing exists or not in an all-or-none manner, and instead suggests a better experimental paradigm to further explore this phenomenon. PMID- 26061047 TI - Sodium Tanshinone IIA Sulfonate Ameliorates Bladder Fibrosis in a Rat Model of Partial Bladder Outlet Obstruction by Inhibiting the TGF-beta/Smad Pathway Activation. AB - Transforming growth factor (TGF)-beta1 is known to play a pivotal role in a diverse range of biological systems including modulation of fibrosis in several organs. The precise role of TGF-beta/Smad signaling in the progression of bladder fibrosis secondary to partial bladder outlet obstruction (PBOO) is yet to be conclusively. Using a rat PBOO model, we investigated TGF-beta1 expression and exaimined whether sodium tanshinone IIA sulfonate (STS) could inhibit TGF beta/Smad signaling pathway activation and ameliorate bladder fibrosis. Forty eight female Sprague-Dawley rats were randomly divided into three groups: sham operation group (n = 16), PBOO operation without STS treatment group (n = 16) and PBOO operation with STS treatment group (n = 16). Thirty-two rats underwent the operative procedure to create PBOO and subsequently received intraperitoneal injections of STS (10 mg/kg/d; n = 16) or vehicle (n = 16) two days after the surgery. Sham surgery was conducted on 16 rats, which received intraperitoneal vehicle injection two days later. In each of the three groups, an equal number of rats were sacrificed at weeks 4 and 8 after the PBOO or sham operation. The TGF beta/Smad signaling pathway was analyzed using western blotting, immunohistochemical staining and reverse transcriptase polymerase chain reaction (RT-PCR). One-way analysis of variance was conducted to draw statistical inferences. At 4 and 8 weeks, the expression of TGF-beta1 and phosphorylated Smad2 and Smad3 in STS-treated PBOO rats was significantly lower than in the PBOO rats not treated with STS. Alpha smooth muscle actin (alpha-SMA), collagen I and collagen III expression at 4 and 8 weeks post PBOO was lower in STS-treated PBOO rats when compared to that in PBOO rats not treated with STS. Our findings indicate that STS ameliorates bladder fibrosis by inhibiting TGF-beta/Smad signaling pathway activation, and may prove to be a potential therapeutic measure for preventing bladder fibrosis secondary to PBOO operation. PMID- 26061048 TI - p53 Represses the Oncogenic Sno-MiR-28 Derived from a SnoRNA. AB - p53 is a master tumour repressor that participates in vast regulatory networks, including feedback loops involving microRNAs (miRNAs) that regulate p53 and that themselves are direct p53 transcriptional targets. We show here that a group of polycistronic miRNA-like non-coding RNAs derived from small nucleolar RNAs (sno miRNAs) are transcriptionally repressed by p53 through their host gene, SNHG1. The most abundant of these, sno-miR-28, directly targets the p53-stabilizing gene, TAF9B. Collectively, p53, SNHG1, sno-miR-28 and TAF9B form a regulatory loop which affects p53 stability and downstream p53-regulated pathways. In addition, SNHG1, SNORD28 and sno-miR-28 are all significantly upregulated in breast tumours and the overexpression of sno-miR-28 promotes breast epithelial cell proliferation. This research has broadened our knowledge of the crosstalk between small non-coding RNA pathways and roles of sno-miRNAs in p53 regulation. PMID- 26061050 TI - God and the Welfare State - Substitutes or Complements? An Experimental Test of the Effect of Belief in God's Control. AB - Belief in God's control of the world is common to many of the world's religions, but there are conflicting predictions regarding its role in shaping attitudes toward the welfare state. While the devout are expected to support pro-social values like helping others, and thus might be supportive of the welfare state, the possibility of taking action is undermined by the belief in God's absolute control over world affairs and in a morally perfect providence, who is responsible for the fates of individuals. As the literature provides mixed results on this question, this study examines the role of belief in God's control on welfare attitudes using three priming experiments and two priming tasks, carried out with a design that is both cross-cultural (US vs. Israel) and cross religious tradition (Judaism vs. Catholicism). We find evidence that, largely, belief in God's control increases support for income redistribution among Israeli Jews (study 1), American Jews (study 2), and American Catholics (study 3). The findings suggest that the traditional and common political gap between the economic left and the religious, based on the evaluation that religious beliefs lead to conservative economic preferences, may be overstated. PMID- 26061049 TI - Reovirus FAST Proteins Drive Pore Formation and Syncytiogenesis Using a Novel Helix-Loop-Helix Fusion-Inducing Lipid Packing Sensor. AB - Pore formation is the most energy-demanding step during virus-induced membrane fusion, where high curvature of the fusion pore rim increases the spacing between lipid headgroups, exposing the hydrophobic interior of the membrane to water. How protein fusogens breach this thermodynamic barrier to pore formation is unclear. We identified a novel fusion-inducing lipid packing sensor (FLiPS) in the cytosolic endodomain of the baboon reovirus p15 fusion-associated small transmembrane (FAST) protein that is essential for pore formation during cell cell fusion and syncytiogenesis. NMR spectroscopy and mutational studies indicate the dependence of this FLiPS on a hydrophobic helix-loop-helix structure. Biochemical and biophysical assays reveal the p15 FLiPS preferentially partitions into membranes with high positive curvature, and this partitioning is impeded by bis-ANS, a small molecule that inserts into hydrophobic defects in membranes. Most notably, the p15 FLiPS can be functionally replaced by heterologous amphipathic lipid packing sensors (ALPS) but not by other membrane-interactive amphipathic helices. Furthermore, a previously unrecognized amphipathic helix in the cytosolic domain of the reptilian reovirus p14 FAST protein can functionally replace the p15 FLiPS, and is itself replaceable by a heterologous ALPS motif. Anchored near the cytoplasmic leaflet by the FAST protein transmembrane domain, the FLiPS is perfectly positioned to insert into hydrophobic defects that begin to appear in the highly curved rim of nascent fusion pores, thereby lowering the energy barrier to stable pore formation. PMID- 26061051 TI - Specific Detection and Identification of American Mulberry-Infecting and Italian Olive-Associated Strains of Xylella fastidiosa by Polymerase Chain Reaction. AB - Xylella fastidiosa causes bacterial leaf scorch in many landscape trees including elm, oak, sycamore and mulberry, but methods for specific identification of a particular tree host species-limited strain or differentiation of tree-specific strains are lacking. It is also unknown whether a particular landscape tree infecting X. fastidiosa strain is capable of infecting multiple landscape tree species in an urban environment. We developed two PCR primers specific for mulberry-infecting strains of X. fastidiosa based on the nucleotide sequence of a unique open reading frame identified only in mulberry-infecting strains among all the North and South American strains of X. fastidiosa sequenced to date. PCR using the primers allowed for detection and identification of mulberry-infecting X. fastidiosa strains in cultures and in samples collected from naturally infected mulberry trees. In addition, no mixed infections with or non-specific detections of the mulberry-infecting strains of X. fastidiosa were found in naturally X. fastidiosa-infected oak, elm and sycamore trees growing in the same region where naturally infected mulberry trees were grown. This genotype-specific PCR assay will be valuable for disease diagnosis, studies of strain-specific infections in insects and plant hosts, and management of diseases caused by X. fastidiosa. Unexpectedly but interestingly, the unique open reading frame conserved in the mulberry-infecting strains in the U. S. was also identified in the recently sequenced olive-associated strain CoDiRO isolated in Italy. When the primer set was tested against naturally infected olive plant samples collected in Italy, it allowed for detection of olive-associated strains of X. fastidiosa in Italy. This PCR assay, therefore, will also be useful for detection and identification of the Italian group of X. fastidiosa strains to aid understanding of the occurrence, evolution and biology of this new group of X. fastidiosa strains. PMID- 26061053 TI - Tackling the Health Challenge posed by Hepatitis C in Puerto Rico: A Call for Immediate Public Health Actions. AB - Within the past decade, researchers and hepatitis C specialists in Puerto Rico have highlighted the burden of hepatitis C and associated disease outcomes in the island to raise public awareness about this problem and set out a call to action to tackle prevention and control efforts, yet so far no concrete actions have taken place. The population-based studies on hepatitis C have documented that the main risk factor is the sharing of syringes and drug paraphernalia to inject drugs, that most seropositive individuals are unaware of their infection status, and that there are large knowledge deficits about the disease, its risk factors, and measures of prevention and control. The subject is further complicated by the fact that despite hepatitis C reporting is mandatory, there is no effective epidemiological surveillance system to provide the information needed for planning, implementation, monitoring, and evaluation of intervention strategies for this infection and access to medical and other existing therapies is limited. This document addresses the disparities in HC V infection and its adverse outcomes experienced among Puerto Ricans and attempts to set out strategies to address a public health response for hepatitis C at the meso and macro levels of the social-ecological model. Diverse organizations and major stakeholders are urged to mount an adequate response to hepatitis C by transforming current scientific evidence into public health actions to increase awareness, identify those who are actively infected, and link infected individuals into comprehensive care and treatment. PMID- 26061052 TI - Comparative Characterization of Cells from the Various Compartments of the Human Umbilical Cord Shows that the Wharton's Jelly Compartment Provides the Best Source of Clinically Utilizable Mesenchymal Stem Cells. AB - The human umbilical cord (UC) is an attractive source of mesenchymal stem cells (MSCs) with unique advantages over other MSC sources. They have been isolated from different compartments of the UC but there has been no rigorous comparison to identify the compartment with the best clinical utility. We compared the histology, fresh and cultured cell numbers, morphology, proliferation, viability, stemness characteristics and differentiation potential of cells from the amnion (AM), subamnion (SA), perivascular (PV), Wharton's jelly (WJ) and mixed cord (MC) of five UCs. The WJ occupied the largest area in the UC from which 4.61 +/- 0.57 x 106 /cm fresh cells could be isolated without culture compared to AM, SA, PV and MC that required culture. The WJ and PV had significantly lesser CD40+ non stem cell contaminants (26-27%) compared to SA, AM and MC (51-70%). Cells from all compartments were proliferative, expressed the typical MSC-CD, HLA, and ESC markers, telomerase, had normal karyotypes and differentiated into adipocyte, chondrocyte and osteocyte lineages. The cells from WJ showed significantly greater CD24+ and CD108+ numbers and fluorescence intensities that discriminate between MSCs and non-stem cell mesenchymal cells, were negative for the fibroblast-specific and activating-proteins (FSP, FAP) and showed greater osteogenic and chondrogenic differentiation potential compared to AM, SA, PV and MC. Cells from the WJ offer the best clinical utility as (i) they have less non stem cell contaminants (ii) can be generated in large numbers with minimal culture avoiding changes in phenotype, (iii) their derivation is quick and easy to standardize, (iv) they are rich in stemness characteristics and (v) have high differentiation potential. Our results show that when isolating MSCs from the UC, the WJ should be the preferred compartment, and a standardized method of derivation must be used so as to make meaningful comparisons of data between research groups. PMID- 26061054 TI - Association of the Intestinal Microbiota and Obesity. AB - Obesity is a condition mainly caused by an alteration in energy intake, shifting towards positive energy balance, which can be influenced by genetic and environmental factors. The human gut is heavily populated with microbial organisms. Recent evidence suggests that obesity is influenced by specific bacterial phyla present in the human gut that have increased energy harvesting capabilities. The main objective of this review is to identify the microbial taxa that are related to obesity and weight loss. In this review, we also discuss the differences between the phylum ratio of the gut microbiota population of obese individuals and that of individuals who have healthy weight. It has been shown that obese individuals have a higher ratio of Firmicutes to Bacteroidetes than healthy weight individuals. The few studies to date have shown that weight-loss treatment may change microbial population of the gut, as there is a decrease in the ratio of Firmicutes to Bacteroidetes. Treating imbalances of the gut microbiota may offer new possibilities for treating obesity. PMID- 26061056 TI - Rheumatic Manifestations in Patients with Chikungunya Infection. AB - Chikungunya virus (CHIKV) infection is a common cause of febrile arthritis. The most common manifestations of acute infection are fever, symmetrical polyarthralgias or polyarthritis, myalgias, and maculopapular rash. Up to 80% of patients may develop musculoskeletal manifestations that persist longer than 3 months, causing impairment in their quality of life. The most common chronic manifestations are persistent or relapsing-remitting polyarthralgias, polyarthritis, and myalgias. Fingers, wrists, knees, ankles, and toes are the most frequently involved, but proximal joints and axial involvement can occur in the chronic stage. Chronic manifestations of CHIKV infection may resemble those of some autoimmune connective tissue diseases. Furthermore, CHIKV infection can cause cryoglobulinemia and may induce rheumatoid arthritis and seronegative spondyloarthropathies in genetically susceptible individuals. The Centers for Disease Control and Prevention recommend acetaminophen and non steroidal anti inflammatory drugs for the acute rheumatic manifestations of CHIKV infection. However, some studies suggest that low-dose corticosteroids for about 1-2 months (depending on clinical course) are beneficial in relieving acute rheumatic symptoms. Conversely, hydroxychloroquine in combination with corticosteroids or other disease modifying anti-rheumatic drugs (DMARDs) has been successful in treating chronic rheumatic manifestations. Methotrexate and sulfasalazine (alone or in combination) have also been effective for chronic CHIKV arthritis. Patients with CHIKV infection should be closely monitored to identify those with chronic arthritis who would benefit from a rheumatologic evaluation and early treatment with DMARDs. PMID- 26061055 TI - Recent Advances in Dengue: Relevance to Puerto Rico. AB - Dengue represents an increasingly important public health challenge in Puerto Rico, with recent epidemics in 2007, 2010, and 2012-2013. Although recent advances in dengue vaccine development offer hope for primary prevention, the role of health professionals in the diagnosis and management of dengue patients is paramount. Case definitions for dengue, dengue with warning signs, and severe dengue provide a framework to guide clinical decision-making. Furthermore, the differentiation between dengue and other acute febrile illnesses, such as leptospirosis and chikungunya, is necessary for the appropriate diagnosis and management of cases. An understanding of dengue epidemiology and surveillance in Puerto Rico provides context for clinicians in epidemic and non-epidemic periods. This review aims to improve health professionals' ability to diagnose dengue, and as highlight the relevance of recent advances in dengue prevention and management in Puerto Rico. PMID- 26061057 TI - Number and Type of Meals consumed by Children in a Subset of Schools in San Juan, Puerto Rico. AB - OBJECTIVE: Eating patterns of children have been investigated in the U.S. and have been found to be changeable over extended time periods. Trends can be correlated to changes in the same periods for determinants of overall health such as body mass index (BMI). In Puerto Rico, there have been no such studies so similar correlations cannot be done. Herein, we present baseline information on the number and types of eating occasions in a convenience sample of children from the area of San Juan so that future changes in patterns can be monitored over time. METHODS: Multiple 24 hour recall questionnaires were administered to school children at 3 different grade levels. Number of eating occasions and type of meal (breakfast, lunch, dinner and snacks) were quantified. Factors considered for analysis were age, gender and BMI of the children, participation in the School Lunch Program (SLP) and if meals were eaten on a weekday or weekend day. RESULTS: Approximately 40% of children were categorized as overweight. There was a trend toward fewer eating occasions in older vs. younger children and fewer eating occasions on weekend days vs. weekdays. Lunch and dinner were consumed more frequently than breakfast and participants in the SLP had more eating occasions than non-participants. CONCLUSION: The number of eating occasions in Puerto Rican youth is maintained at about 5 for weekdays and about 4.5 per day for weekend days with a trend toward fewer meals as a function of increasing age. This data can be used as baseline information in future studies that wish to correlate changes in dietary patterns with health. PMID- 26061058 TI - Prevalence of Vitamin D Insufficiency and Deficiency among Young Physicians at University District Hospital in San Juan, Puerto Rico. AB - Vitamin D has been attracting increased attention because of higher prevalences of vitamin D insufficiency and deficiency than expected in areas with sufficient sun exposure. Even though sunlight exposure and diet are the main determinants of vitamin D status, other factors, such as age, race, the use (or not) of sunscreen, medications, and malabsorptive conditions, also affect vitamin D levels. Recent studies have found high prevalences of vitamin D deficiency and insufficiency in different populations. However, there are limited data regarding the prevalence of vitamin D deficiency and insufficiency in Puerto Rico. To shed more light on the subject, we evaluated a sample of 51 internal medicine residents and research fellows, aged from 25 to 39 years at the University District Hospital in San Juan, Puerto Rico, doing so by means of a questionnaire that explored basic socio demographic and lifestyle characteristics and collected anthropometric data; in addition, we obtained blood samples in order to determine 25-hydroxyvitamin D levels. The median 25-hydroxyvitamin D level was 21 ng/mL (range, 7-38 ng/mL). Forty-five participants (88.2%) had 25-hydroxyvitamin D concentrations of lower than 30 ng/mL. We found vitamin D deficiencies in 43.1% of the population and insufficiencies in 45.1%. Contributory factors to our findings include limited exposure to sunlight during periods of high sun intensity, increased body mass index, and a limited area of the body being exposed to sunlight. A relationship between reduced physical activity levels and hypovitaminosis D was also found. Both calcium intake and vitamin D intake, which were markedly below recommended daily allowances, were positively correlated with 25-hydroxy vitamin D levels, but with a weak association. PMID- 26061059 TI - Expression of Basal-like Biomarkers in Triple Negative Invasive Breast Carcinoma in Puerto Rico. AB - OBJECTIVE: Routine Progesterone and Estrogen hormone receptor proteins and human epidermal growth factor receptor 2 (HER-2) analysis on invasive breast carcinomas provide therapeutic and prognostic values, revealing significant subgroups: luminal A, luminal B, HER-2 and the "triple negative" tumors. The aim of this study was to determine the expression of basal cytokeratins and Epidermal Growth Factor Receptor in "triple negative" invasive breast carcinomas in Puerto Rico women. METHODS: All invasive breast carcinoma cases received from 2008 to 2010 were included. Assessment of tumoral expression of Estrogen Receptor, Progesterone Receptor and HER-2 was performed. The cases were divided into groups based on their molecular categories and analyzed according to the age. "Triple negative" tumors were further analyzed according to their expression of Epidermal Growth Factor Receptor and cytokeratins 5/6 and 14. RESULTS: From 717 cases reviewed, 487 cases of invasive breast carcinoma were included. The molecular categories were 66%, 10%, 9% and 15% for the luminal A, luminal B, Her-2 and "triple negative" groups, respectively. No significant difference (p= 0.64) was observed between the molecular categories and the age of the patients. Assessment of basal cytokeratins and Epidermal Growth Factor Receptor expression was performed on 41 "triple negative" tumors; 71% expressed at least one basal cytokeratin or Epidermal Growth Factor Receptor and 29% were negative to all markers. CONCLUSION: Prevalence and relation between the molecular categories and the expression of basal cytokeratins in "triple negative" tumors in our population is comparable to other published data. PMID- 26061060 TI - Longitudinal Observations on the Mineral Metabolism of Dialysis Patients at the University Hospital. AB - A retrospective review was performed from November 2011 through June 2012 in 49 stable patients receiving ambulatory hemodialysis at the dialysis unit of the University Hospital in San Juan. Measurements of serum phosphate, serum calcium (corrected to albumin levels), intact parathyroid hormone (PTH), and pulse pressure were obtained at 3-month intervals over the course of a 9-month observation period. These longitudinal observations assessed the efficiency of treatment, with the objective being to determine the nature of and then implement such changes as would improve the patients' outcomes. Thirty-three of the 49 patients appeared to have fairly good control of their PTH levels during the observation period. Sixteen patients had levels over 300 pg/ml, and, using Stata data analysis software, a linear relationship with phosphate levels was obtained (p = 0.021, R2 = 0.1037, adjusted R2 = 0.0855). Pulse pressure (PP) measurements obtained at each observation interval showed the following increases: 69% at 3 months, 65% at 6 months, and 57% at 9 months. Calcium-containing phosphate binders were used in one third of the population and vitamin D analogs in 50%. A trend towards a rise in PP was observed as calcium levels increased over 9.5 mg/dl. It is concluded that those patients experiencing that rise need close supervision to avoid the increasing morbidity and mortality associated with mineral metabolism derangement. Wide PPs were observed in these patients during the 9 months of observation, denoting persistent arterial stiffness suggestive of an increase in calcium balance. PMID- 26061061 TI - Trends of Respiratory Syncytial Virus Infections in Children under 2 Years of Age in Puerto Rico. AB - OBJECTIVE: The respiratory syncytial virus (RSV) is the most significant viral pathogen causing bronchiolitis and pneumonia in infants, today. In tropical climates the RSV infection may occur throughout the year. The purpose of this study was to asses RSV infections during the 2009-2010 RSV season in children under 2 years of age and to evaluate the trend of positive RSV tests in the period of 2007 to 2009. METHODS: A retrospective review of data collected from 6 hospitals in Puerto Rico was performed. Patients with confirmed RSV bronchiolitis were included in the study. RESULTS: A total of 4,678 patients were included. The mean age of the patients was 7 months. Data showed that RSV infection occurred throughout the studied months. CONCLUSION: Data confirms a year-round presence of RSV in Puerto Rico. The RSV surveillance system needs to be reinforced to establish and understand the epidemiology of RSV and to review the current immunoprophylaxis guidelines. PMID- 26061062 TI - Refractory dissecting Cellulitis of the Scalp Successfully controlled with Adalimumab. AB - Dissecting cellulitis of the scalp (DCS) is an uncommon inflammatory disease that often results in scarring alopecia. Numerous therapies have either proved ineffective or only temporarily effective in the management of this condition. Recent reports show adequate responses to tumor necrosis factor (TNF) inhibitors in cases of DCS. We report a case of severe recalcitrant DCS successfully treated with adalimumab. PMID- 26061063 TI - A 44-year-old Rhinolith: A Case Report and Review of the Literature. AB - The reported incidence of rhinolithiasis is 1 in 10,000 patients. Symptoms include rhinorrhea, epistaxis, and nasal obstruction. Diagnosis is clinical, by anterior rhinoscopy. Treatment requires the complete removal of the existing rhinolith, either by anterior rhinoscopy or nasal endoscopy, although a lateral rhinotomy has been required in some cases. Reported complications include sinusitis, septal perforation, frontal osteomyelitis, and, rarely, epidural abscess formation. We present a case of a large right nasal cavity rhinolith of 44 years of evolution that required removal under general anesthesia. The patient's chart was reviewed to compile case details, and PubMed was searched for current diagnostic and management options. PMID- 26061064 TI - Computed ABC Analysis for Rational Selection of Most Informative Variables in Multivariate Data. AB - OBJECTIVE: Multivariate data sets often differ in several factors or derived statistical parameters, which have to be selected for a valid interpretation. Basing this selection on traditional statistical limits leads occasionally to the perception of losing information from a data set. This paper proposes a novel method for calculating precise limits for the selection of parameter sets. METHODS: The algorithm is based on an ABC analysis and calculates these limits on the basis of the mathematical properties of the distribution of the analyzed items. The limits implement the aim of any ABC analysis, i.e., comparing the increase in yield to the required additional effort. In particular, the limit for set A, the "important few", is optimized in a way that both, the effort and the yield for the other sets (B and C), are minimized and the additional gain is optimized. RESULTS: As a typical example from biomedical research, the feasibility of the ABC analysis as an objective replacement for classical subjective limits to select highly relevant variance components of pain thresholds is presented. The proposed method improved the biological interpretation of the results and increased the fraction of valid information that was obtained from the experimental data. CONCLUSIONS: The method is applicable to many further biomedical problems including the creation of diagnostic complex biomarkers or short screening tests from comprehensive test batteries. Thus, the ABC analysis can be proposed as a mathematically valid replacement for traditional limits to maximize the information obtained from multivariate research data. PMID- 26061065 TI - CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis. AB - CD8+ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-alpha inhibitor therapy. The frequency of autoreactive CD8+ T cells specific to various apoptotic epitopes, as detected by both enzyme linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8+ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-alpha inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8+ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-alpha inhibitor therapy to validate in a larger cohort of patients. PMID- 26061066 TI - Rapid Assessment of Distribution of Wildlife and Human Activities for Prioritizing Conservation Actions in a Patagonian Landscape. AB - Large landscapes encompassing reserves and areas with other human uses are necessary for conservation of many species. Generating information for conservation planning over such landscapes may be expensive and time-consuming, though resources for conservation are generally limited and conservation is often urgent. We developed a sign-based occupancy survey to help prioritize conservation interventions by simultaneously assessing the distribution of 3 species, the lesser rhea, guanaco, and mara, and their association with human activities in a 20,000-km2 landscape in the northern Patagonian steppe. We used a single-season occupancy model with spatial rather than temporal replication of surveys in order to reduce costs of multiple visits to sites. We used covariates related to detectability, environmental factors, and different human activities to identify the most plausible models of occupancy, and calculated importance weights of covariates from these models to evaluate relative impacts of human activities on each species. Abundance of goats had the strongest negative association with lesser rheas and guanacos, and road density with maras. With six months of fieldwork, our results provided initial hypotheses for adaptive conservation interventions for each species. Addressing high livestock densities for rheas and guanacos, poaching by urban hunters for all three species, and hunting by rural people for rheas are priorities for conservation in this landscape. Our methodology provided new insights into the responses of these species, although low detection probabilities for maras indicate that the sampling scheme should be altered for future monitoring of this species. This method may be adapted for any large landscape where a rapid, objective means for prioritizing conservation actions on multiple species is needed and data are scarce. PMID- 26061067 TI - Associations of Pet Ownership with Wheezing and Lung Function in Childhood: Findings from a UK Birth Cohort. AB - BACKGROUND: Asthma is a heterogeneous condition and differential effects of pet ownership on non-atopic versus atopic asthma have been reported. The aim of this study was to investigate whether pet ownership during pregnancy and early childhood was associated with wheezing from birth to age 7 years and with lung function at age 8 years in a UK population-based birth cohort. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to investigate associations of pet ownership at six time-points from pregnancy to age 7 years with concurrent episodes of wheezing, wheezing trajectories (phenotypes) and lung function at age 8 years using logistic regression models adjusted for child's sex, maternal history of asthma/atopy, maternal smoking during pregnancy, and family adversity. RESULTS: 4,706 children had complete data on pet ownership and wheezing. From birth to age 7 years, cat ownership was associated with an overall 6% lower odds of wheezing (OR=0.94 (0.89-0.99)). Rabbit and rodent ownership was associated with 21% (OR=1.21 (1.12-1.31)) and 11% (OR=1.11 (1.02-1.21)) higher odds of wheezing, respectively, with strongest effects evident during infancy. Rabbit and rodent ownership was positively associated with a 'persistent wheeze' phenotype. Pet ownership was not associated with lung function at age 8 years, with the exception of positive associations of rodent and bird ownership with better lung function. CONCLUSIONS: Cat ownership was associated with reduced risk, and rabbit and rodent ownership with increased risk, of wheezing during childhood. The mechanisms behind these differential effects warrant further investigation. PMID- 26061069 TI - A New Historical Feature for the Journal: Eponyms and Entities. PMID- 26061068 TI - Thinner Cortex in Collegiate Football Players With, but not Without, a Self Reported History of Concussion. AB - Emerging evidence suggests that a history of sports-related concussions can lead to long-term neuroanatomical changes. The extent to which similar changes are present in young athletes is undetermined at this time. Here, we tested the hypothesis that collegiate football athletes with (n = 25) and without (n = 24) a self-reported history of concussion would have cortical thickness differences and altered white matter integrity relative to healthy controls (n = 27) in fronto temporal regions that appear particularly susceptible to traumatic brain injury. Freesurfer software was used to estimate cortical thickness, fractional anisotropy was calculated in a priori white matter tracts, and behavior was assessed using a concussion behavioral battery. Groups did not differ in self reported symptoms (p > 0.10) or cognitive performance (p > 0.10). Healthy controls reported significantly higher happiness levels than both football groups (all p < 0.01). Contrary to our hypothesis, no differences in fractional anisotropy were observed between our groups (p > 0.10). However, football athletes with a history of concussion had significantly thinner cortex in the left anterior cingulate cortex, orbital frontal cortex, and medial superior frontal cortex relative to healthy controls (p = 0.02, d = -0.69). Further, football athletes with a history of concussion had significantly thinner cortex in the right central sulcus and precentral gyrus relative to football athletes without a history of concussion (p = 0.03, d = -0.71). No differences were observed between football athletes without a history of concussion and healthy controls. These results suggest that previous concussions, but not necessarily football exposure, may be associated with cortical thickness differences in collegiate football athletes. PMID- 26061070 TI - Javier Arias-Stella and His Famous Reaction. PMID- 26061071 TI - Ovarian Metastasis of a Thymoma: Report of a Case and Literature Review. AB - Thymomas are infrequent, although they are the most common neoplasms in the anterior mediastinum. They are slow-growing tumors that may involve surrounding structures by direct extension. In these aggressive cases, intrathoracic recurrences are frequent. However, distant metastases are uncommon, the most common sites including liver, lymph nodes, and bones. Metastatic thymoma to the ovary is exceedingly rare, with only 6 cases reported in the literature. We report a 46-yr-old female with a metastatic thymoma to her left ovary 6 yr after the initial diagnosis of thymoma, Type B1 with pleural invasion. PMID- 26061072 TI - Lymph Node Micrometastases in Early-Stage Cervical Cancer are Not Predictive of Survival. AB - Although patients with early-stage cervical cancer have in general a favorable prognosis, 10% to 40% patients still recur depending on pathologic risk factors. The objective of this study was to evaluate if the presence of lymph node micrometastasis (LNmM) had an impact on patient's survival. We performed a multi institutional retrospective review on patients with early-stage cervical cancer, with histologically negative lymph nodes, treated with radical hysterectomy and pelvic lymphadenectomy for the study period 1994 to 2004. Tissue blocks of lymph nodes from the patient's original surgery were recut and then evaluated for the presence of micrometastases. One hundred twenty-nine patients were identified who met inclusion criteria. LNmM were found in 26 patients (20%). In an average follow-up time of 70 mo, there were 11 recurrences (8.5%). Of the 11 recurrences, 2 (18%) patients had LNmM. Patients with LNmM were more likely to have received adjuvant radiation and chemotherapy. In stratified log-rank analysis, LNmM were not associated with any other high-risk clinical or pathologic variables. Survival data analysis did not demonstrate an association between the presence of LNmM and recurrence or overall survival. The presence of LNmM was not associated with an unfavorable prognosis nor was it associated with other high-risk clinical or pathologic variables predicting recurrence. Further study is warranted to understand the role of micrometastases in cervical cancer. PMID- 26061073 TI - Percutaneous treatment of complex biliary stone disease using endourological technique and literature review. AB - Most biliary stone diseases need to be treated surgically. However, in special cases that traditional biliary tract endoscopic access is not allowed, a multidisciplinary approach using hybrid technique with urologic instrumental constitute a treatment option. We report a case of a patient with complex intrahepatic stones who previously underwent unsuccessful conventional approaches, and who symptoms resolved after treatment with hybrid technique using an endourologic technology. We conducted an extensive literature review until October 2012 of manuscripts indexed in PubMed on the treatment of complex gallstones with hybrid technique. The multidisciplinary approach with hybrid technique using endourologic instrumental represents a safe and effective treatment option for patients with complex biliary stone who cannot conduct treatment with conventional methods. PMID- 26061074 TI - Carbon dioxide as a substitute for iodine contrast in arteriography during embolectomy. AB - Acute limb ischemia can be potentially harmful to the limb and life threatening. Renal failure is a possible outcome associated with release of products of ischemic limb reperfusion. Some authors reported the benefit of performing angiography after embolectomy, even though iodine contrast is also nephrotoxic. We report a case of embolectomy on a patient with renal insufficiency in whom carbon dioxide was used as a substitute for iodine contrast. PMID- 26061075 TI - Complications in adolescent pregnancy: systematic review of the literature. AB - Sexual activity during adolescence can lead to unwanted pregnancy, which in turn can result in serious maternal and fetal complications. The present study aimed to evaluate the complications related to adolescent pregnancy, through a systematic review using the Medical Subject Headings: "pregnancy complication" AND "adolescent" OR "pregnancy in adolescence". Only full original articles in English or Portuguese with a clearly described methodology, were included. No qualitative studies, reviews or meta-analyses, editorials, case series, or case reports were included. The sample consisted of 15 articles; in that 10 were cross sectional and 5 were cohort studies. The overall prevalence of adolescent pregnancy was 10%, and among the Brazilian studies, the adolescent pregnancy rate was 26%. The cesarean delivery rate was lower than that reported in the general population. The main maternal and neonatal complications were hypertensive disorders of pregnancy, prematurity and low birth weight, respectively. Adolescent pregnancy is related to increased frequency of neonatal and maternal complications and lower prevalence of cesarean delivery. PMID- 26061076 TI - Risk factors for post-extubation stridor in children: the role of orotracheal cannula. AB - Objective To determine the risk factors associated with stridor, with special attention to the role of the cuffed orotracheal cannula. Methods Prospective analysis of all the intubated patients submitted to mechanical ventilator support from January 2008 to April 2011. The relevant factors for stridor collected were age, weight, size and type of airway tube, diagnosis, and duration of mechanical ventilation. The effects of variables on stridor were evaluated using uni- and multivariate logistic regression models. Results A total of 136 patients were included. Mean age was 1.4 year (3 days to 17 years). The mean duration of mechanical ventilation was 73.5 hours. Fifty-six patients (41.2%) presented with stridor after extubation. The total reintubation rate was 19.6% and 12.5 in patients with and without stridor, respectively. The duration of mechanical ventilation (>72 hours) was associated with a greater risk for stridor (odds ratio of 8.60; 95% confidence interval of 2.98-24.82; p<0.001). The presence of the cuffed orotracheal cannula was not associated with stridor (odds ratio of 98; 95% confidence interval of 0.46-2.06; p=0.953). Conclusion The main risk factor for stridor after extubation in our population was duration of mechanical ventilation. The presence of the cuffed orotracheal cannula was not associated with increased risk for stridor, reinforcing the use of the cuffed orotracheal cannula in children with respiratory distress. PMID- 26061077 TI - Aggressive angiomyxoma of the vulva: case report. AB - Female patient, 42-years-old, complaining of difficulty in urinating and swelling in the vulvar area for one year. Her gynecological examination showed extensive injury in the vulvar region and the biopsy done was inconclusive. The removal of the lesion was conducted. After the procedure, the patient remains free of recurrence for 15 months. This case highlights the need to consider angiomyxoma in the differential diagnosis for tumors of unknown cause in the vulvar region. PMID- 26061078 TI - Breastfeeding and protection against diarrhea: an integrative review of literature. AB - OBJECTIVE: To identify, in national and international journals, the studies conducted in Brazil related to breast feeding and reducing cases of diarrhea in children under 2 years of age, featuring health interventions more used. METHODS: Descriptive study, based on an integrative review of literature from PubMed and LILACS data published between January 1992 and August 2011. The keywords "breastfeeding AND diarrhea" was searched in Portuguese, English and Spanish in PubMed and LILACS. The guiding question was: "What was knowledge produced about breast feeding and prevention of diarrhea in children under 2 years between 1992 and 2011 in studies conducted in Brazil?" RESULTS: We selected 11 studies that showed the importance of breast feeding in the prevention and protection against diarrhea in children under 6 months, especially among children in exclusive breastfeeding. CONCLUSION: Public health policies should be directed to the context of each locality, in order to reduce the problems that involve the early weaning. PMID- 26061079 TI - Polymalformative syndrome with congenital heart defect. PMID- 26061082 TI - Taphonomic Analysis of the Faunal Assemblage Associated with the Hominins (Australopithecus sediba) from the Early Pleistocene Cave Deposits of Malapa, South Africa. AB - Here we present the results of a taphonomic study of the faunal assemblage associated with the hominin fossils (Australopithecus sediba) from the Malapa site. Results include estimation of body part representation, mortality profiles, type of fragmentation, identification of breakage patterns, and microscopic analysis of bone surfaces. The diversity of the faunal spectrum, presence of animals with climbing proclivities, abundance of complete and/or articulated specimens, occurrence of antimeric sets of elements, and lack of carnivore modified bones, indicate that animals accumulated via a natural death trap leading to an area of the cave system with no access to mammalian scavengers. The co-occurrence of well preserved fossils, carnivore coprolites, deciduous teeth of brown hyaena, and some highly fragmented and poorly preserved remains supports the hypothesis of a mixing of sediments coming from distinct chambers, which collected at the bottom of the cave system through the action of periodic water flow. This combination of taphonomic features explains the remarkable state of preservation of the hominin fossils as well as some of the associated faunal material. PMID- 26061083 TI - Longitudinal Study of the Decline in Renal Function in Healthy Subjects. AB - BACKGROUND: Chronic kidney disease is an important concern in preventive medicine, but the rate of decline in renal function in healthy population is not well defined. The purpose of this study was to determine reference values for the estimated glomerular filtration rate (eGFR) and rate of decline of eGFR in healthy subjects and to evaluate factors associated with this decline using a large cohort in Japan. METHODS: Retrospective cross-sectional and longitudinal studies were performed with healthy subjects aged >=18 years old who received a medical checkup. Reference values for eGFR were obtained using a nonparametric method and those for decline of eGFR were calculated by mixed model analysis. Relationships of eGFR decline rate with baseline variables were examined using a linear least-squares method. RESULTS: In the cross-sectional study, reference values for eGFR were obtained by gender and age in 72,521 healthy subjects. The mean (+/-SD) eGFR was 83.7+/-14.7 ml/min/1.73 m2. In the longitudinal study, reference values for eGFR decline rate were obtained by gender, age, and renal stage in 45,586 healthy subjects. In the same renal stage, there was little difference in the rate of decline regardless of age. The decline in eGFR depended on the renal stage and was strongly related to baseline eGFR, with a faster decline with a higher baseline eGFR and a slower decline with a lower baseline eGFR. The mean (+/-SD) eGFR decline rate was -1.07+/-0.42 ml/min/1.73 m2/year ( 1.29+/-0.41%/year) in subjects with a mean eGFR of 81.5+/-11.6 ml/min/1.73 m2. CONCLUSIONS: The present study clarified for the first time the reference values for the rate of eGFR decline stratified by gender, age, and renal stage in healthy subjects. The rate of eGFR decline depended mainly on baseline eGFR, but not on age, with a slower decline with a lower baseline eGFR. PMID- 26061084 TI - Sequence Analysis of Bitter Taste Receptor Gene Repertoires in Different Ruminant Species. AB - Bitter taste has been extensively studied in mammalian species and is associated with sensitivity to toxins and with food choices that avoid dangerous substances in the diet. At the molecular level, bitter compounds are sensed by bitter taste receptor proteins (T2R) present at the surface of taste receptor cells in the gustatory papillae. Our work aims at exploring the phylogenetic relationships of T2R gene sequences within different ruminant species. To accomplish this goal, we gathered a collection of ruminant species with different feeding behaviors and for which no genome data is available: American bison, chamois, elk, European bison, fallow deer, goat, moose, mouflon, muskox, red deer, reindeer and white tailed deer. The herbivores chosen for this study belong to different taxonomic families and habitats, and hence, exhibit distinct foraging behaviors and diet preferences. We describe the first partial repertoires of T2R gene sequences for these species obtained by direct sequencing. We then consider the homology and evolutionary history of these receptors within this ruminant group, and whether it relates to feeding type classification, using MEGA software. Our results suggest that phylogenetic proximity of T2R genes corresponds more to the traditional taxonomic groups of the species rather than reflecting a categorization by feeding strategy. PMID- 26061085 TI - Peptidomimetic beta-Secretase Inhibitors Comprising a Sequence of Amyloid-beta Peptide for Alzheimer's Disease. AB - Alzheimer's disease is a grave social problem in an aging population. A major problem is the passage of drugs through the blood-brain barrier. This work tests the hypothesis that the conjugation of peptidomimetic beta-secretase inhibitors with a fragment of amyloid-beta peptide facilitates entrance into the central nervous system. HVR-3 (compound 4), one of the conjugation products, was found to be as potent as OM00-3, a known peptidomimetic inhibitor, 4-fold more selective toward beta-secretase 1 in relation to beta-secretase 2 and 3-fold more resistant to in vitro metabolization in human serum. Its intravenous administration to mice and Wistar rats generated an active metabolite recovered from the rodent's brains. PMID- 26061086 TI - Macrocyclic Oligoesters Incorporating a Cyclotetrasiloxane Ring. AB - Macrocyclic oligoester structures based on a cyclotetrasiloxane core consisting of tricyclic (60+ atoms) and pentacycylic (130+ atoms) species were identified as the major components of a lipase-mediated transesterification reaction. Moderately hydrophobic solvents with log P values in the range of 2-3 were more suitable than those at lower or higher log P values. Temperature had little effect on total conversion and yield of the oligoester macrocycles, except when a reaction temperature of 100 degrees C was employed. At this temperature, the amount of the smaller macrocycle was greatly increased, but at the expense of the larger oligoester. For immobilized lipase B from Candida antarctica (N435), longer chain length esters and diols were more conducive to the synthesis of the macrocycles. Langmuir isotherms indicated that monolayers subjected to multiple compression/expansion cycles exhibited a reversible collapse mechanism different from that expected for linear polysiloxanes. PMID- 26061087 TI - The Fox and the Grapes-How Physical Constraints Affect Value Based Decision Making. AB - One fundamental question in decision making research is how humans compute the values that guide their decisions. Recent studies showed that people assign higher value to goods that are closer to them, even when physical proximity should be irrelevant for the decision from a normative perspective. This phenomenon, however, seems reasonable from an evolutionary perspective. Most foraging decisions of animals involve the trade-off between the value that can be obtained and the associated effort of obtaining. Anticipated effort for physically obtaining a good could therefore affect the subjective value of this good. In this experiment, we test this hypothesis by letting participants state their subjective value for snack food while the effort that would be incurred when reaching for it was manipulated. Even though reaching was not required in the experiment, we find that willingness to pay was significantly lower when subjects wore heavy wristbands on their arms. Thus, when reaching was more difficult, items were perceived as less valuable. Importantly, this was only the case when items were physically in front of the participants but not when items were presented as text on a computer screen. Our results suggest automatic interactions of motor and valuation processes which are unexplored to this date and may account for irrational decisions that occur when reward is particularly easy to reach. PMID- 26061088 TI - Background fish feminization effects in European remote sites. AB - Human activity has spread trace amounts of chemically stable endocrine-disrupting pollutants throughout the biosphere. These compounds have generated a background level of estrogenic activity that needs to be assessed. Fish are adequate sentinels for feminization effects as male specimens are more sensitive than humans to exogenous estrogenic compounds. High mountain lakes, the most distant environments of continental areas, only receive semi-volatile compounds from atmospheric deposition. We analyzed the expression levels of estrogen-regulated genes in male fish from these mountain lakes in Europe. Incipient feminization involving expression of estrogen receptor and zona radiata genes revealed a widespread diffuse estrogenic impact. This effect was correlated with the concentrations of some organochlorine compounds in fish and was consistent with the persistent occurrence of these tropospheric pollutants in the most remote planet regions. These results should be of general concern given the increasing endocrine disruption effects in human populations. PMID- 26061089 TI - Will Women Diagnosed with Breast Cancer Provide Biological Samples for Research Purposes? AB - BACKGROUND: Little is known about the response rates for biological sample donation and attitudes towards control recruitment, especially in younger women. The goals of this pilot study were to determine in women recently diagnosed with breast cancer, the proportion of cases willing to provide biological samples and for purposes of control recruitment, contact information for friends or colleagues. METHODS: A population-based sample of breast cancer cases (n = 417, 25-74 years) was recruited from the Ontario Cancer Registry in 2010 and self administered questionnaires were completed to determine willingness to provide samples (spot or 24-hr urine, saliva, blood) and contact information for friends/colleagues for control recruitment. Using Chi2 analyses of contingency tables we evaluated if these proportions varied by age group (<45 and 45+) and other factors such as ethnicity, education, income, body mass index (BMI), smoking status and alcohol consumption. RESULTS: Cases were willing to provide blood samples, by visiting a clinic (62%) or by having a nurse visit the home (61%). Moreover, they would provide saliva (73%), and morning or 24-hr urine samples (66% and 52%). Younger cases (<=45) were 3 times (OR) more likely more than older cases to agree to collect morning urine (95% CI: 1.15-8.35). Only 26% of cases indicated they would provide contact information of friends or work colleagues to act as controls. Educated cases were more likely to agree to provide samples, and cases who consumed alcohol were more willing to provide contact information. Ethnicity, income, BMI and smoking had little effect on response rates. CONCLUSIONS: Reasonable response rates for biological sample collection should be expected in future case controls studies in younger women, but other methods of control selection must be devised. PMID- 26061090 TI - Nonoxido Vanadium(IV) Compounds Involving Dithiocarbazate-Based Tridentate ONS Ligands: Synthesis, Electronic and Molecular Structure, Spectroscopic and Redox Properties. AB - A new series of nonoxido vanadium(IV) compounds [VL2] (L = L(1)-L(3)) (1-3) have been synthesized using dithiocarbazate-based tridentate Schiff-base ligands H2L(1)-H2L(3), containing an appended phenol ring with a tert-butyl substitution at the 2-position. The compounds are characterized by X-ray diffraction analysis (1, 3), IR, UV-vis, EPR spectroscopy, and electrochemical methods. These are nonoxido V(IV) complexes that reveal a rare distorted trigonal prismatic arrangement around the "bare" vanadium centers. Concerning the ligand isomerism, the structure of 1 and 3 can be described as intermediate between mer and sym-fac isomers. DFT methods were used to predict the geometry, g and (51)V A tensors, electronic structure, and electronic absorption spectrum of compounds 1-3. Hyperfine coupling constants measured in the EPR spectra can be reproduced satisfactorily at the level of theory PBE0/VTZ, whereas the wavelength and intensity of the absorptions in the UV-vis spectra at the level CAM-B3LYP/gen, where "gen" is a general basis set obtained using 6-31+g(d) for S and 6-31g for all the other elements. The results suggest that the electronic structure of 1-3 can be described in terms of a mixing among V-dxy, V-dxz, and V-dyz orbitals in the singly occupied molecular orbital (SOMO), which causes a significant lowering of the absolute value of the (51)V hyperfine coupling constant along the x-axis. The cyclic voltammograms of these compounds in dichloroethane solution display three one-electron processes, two in the cathodic and one in the anodic potential range. Process A (E1/2 = +1.06 V) is due to the quasi-reversible V(IV/V) oxidation while process B at E1/2 = -0.085 V is due to the quasi-reversible V(IV/III) reduction, and the third one (process C) at a more negative potential E1/2 = -1.66 V is due to a ligand centered reduction, all potentials being measured vs Ag/AgCl reference. PMID- 26061091 TI - Suitable Days for Plant Growth Disappear under Projected Climate Change: Potential Human and Biotic Vulnerability. AB - Ongoing climate change can alter conditions for plant growth, in turn affecting ecological and social systems. While there have been considerable advances in understanding the physical aspects of climate change, comprehensive analyses integrating climate, biological, and social sciences are less common. Here we use climate projections under alternative mitigation scenarios to show how changes in environmental variables that limit plant growth could impact ecosystems and people. We show that although the global mean number of days above freezing will increase by up to 7% by 2100 under "business as usual" (representative concentration pathway [RCP] 8.5), suitable growing days will actually decrease globally by up to 11% when other climatic variables that limit plant growth are considered (i.e., temperature, water availability, and solar radiation). Areas in Russia, China, and Canada are projected to gain suitable plant growing days, but the rest of the world will experience losses. Notably, tropical areas could lose up to 200 suitable plant growing days per year. These changes will impact most of the world's terrestrial ecosystems, potentially triggering climate feedbacks. Human populations will also be affected, with up to ~2,100 million of the poorest people in the world (~30% of the world's population) highly vulnerable to changes in the supply of plant-related goods and services. These impacts will be spatially variable, indicating regions where adaptations will be necessary. Changes in suitable plant growing days are projected to be less severe under strong and moderate mitigation scenarios (i.e., RCP 2.6 and RCP 4.5), underscoring the importance of reducing emissions to avoid such disproportionate impacts on ecosystems and people. PMID- 26061092 TI - Effects of physical exercise on survival after allogeneic stem cell transplantation. AB - Observational studies have suggested that physical activity may be associated with improved survival after cancer treatment. However, data from controlled clinical trials are required. We analyzed survival data of 103 patients from a previously published randomized controlled trial in allogeneic stem cell transplant patients who were randomized to either an exercise intervention (EX) or to a social contact control group. EX patients trained prior to hospital admission, during inpatient treatment, and for 6-8 weeks after discharge. Survival analyses were used to compare both total mortality (TM) and non-relapse mortality (NRM) after discharge and transplantation during an observation period of 2 years after transplantation. Analyses were corroborated with Cox and Fine & Gray regression models adjusting for potential confounders. After discharge, EX patients had a significantly lower TM rate than controls (12.0 vs. 28.3%, p = 0.030) and a numerically lower NRM rate (4.0 vs. 13.5%, p = 0.086). When the inpatient period was included, absolute risk reductions were similar but not significantly different (TM: 34.0 vs. 50.9%, p = 0.112; NRM: 26.0 vs. 36.5%, p = 0.293). The number needed to treat (NNT) to prevent one death with EX was about 6. Furthermore, regression analyses revealed that baseline fitness was protective against mortality. The data suggest that exercise might improve survival in patients undergoing allo-HCT. However, the results should be interpreted with caution as the study was not designed to detect differences in survival rates, and as no stratification on relevant prognostic factors was carried out. PMID- 26061093 TI - Nanocellulose-Zeolite Composite Films for Odor Elimination. AB - Free standing and strong odor-removing composite films of cellulose nanofibrils (CNF) with a high content of nanoporous zeolite adsorbents have been colloidally processed. Thermogravimetric desorption analysis (TGA) and infrared spectroscopy combined with computational simulations showed that commercially available silicalite-1 and ZSM-5 have a high affinity and uptake of volatile odors like ethanethiol and propanethiol, also in the presence of water. The simulations showed that propanethiol has a higher affinity, up to 16%, to the two zeolites compared with ethanethiol. Highly flexible and strong free-standing zeolite-CNF films with an adsorbent loading of 89 w/w% have been produced by Ca-induced gelation and vacuum filtration. The CNF-network controls the strength of the composite films and 100 MUm thick zeolite-CNF films with a CNF content of less than 10 vol % displayed a tensile strength approaching 10 MPa. Headspace solid phase microextraction (SPME) coupled to gas chromatography-mass spectroscopy (GC/MS) analysis showed that the CNF-zeolite films can eliminate the volatile thiol-based odors to concentrations below the detection ability of the human olfactory system. Odor removing zeolite-cellulose nanofibril films could enable improved transport and storage of fruits and vegetables rich in odors, for example, onion and the tasty but foul-smelling South-East Asian Durian fruit. PMID- 26061094 TI - From Boolean Network Model to Continuous Model Helps in Design of Functional Circuits. AB - Computational circuit design with desired functions in a living cell is a challenging task in synthetic biology. To achieve this task, numerous methods that either focus on small scale networks or use evolutionary algorithms have been developed. Here, we propose a two-step approach to facilitate the design of functional circuits. In the first step, the search space of possible topologies for target functions is reduced by reverse engineering using a Boolean network model. In the second step, continuous simulation is applied to evaluate the performance of these topologies. We demonstrate the usefulness of this method by designing an example biological function: the SOS response of E. coli. Our numerical results show that the desired function can be faithfully reproduced by candidate networks with different parameters and initial conditions. Possible circuits are ranked according to their robustness against perturbations in parameter and gene expressions. The biological network is among the candidate networks, yet novel designs can be generated. Our method provides a scalable way to design robust circuits that can achieve complex functions, and makes it possible to uncover design principles of biological networks. PMID- 26061095 TI - Ocean Acidification Has Multiple Modes of Action on Bivalve Larvae. AB - Ocean acidification (OA) is altering the chemistry of the world's oceans at rates unparalleled in the past roughly 1 million years. Understanding the impacts of this rapid change in baseline carbonate chemistry on marine organisms needs a precise, mechanistic understanding of physiological responses to carbonate chemistry. Recent experimental work has shown shell development and growth in some bivalve larvae, have direct sensitivities to calcium carbonate saturation state that is not modulated through organismal acid-base chemistry. To understand different modes of action of OA on bivalve larvae, we experimentally tested how pH, PCO2, and saturation state independently affect shell growth and development, respiration rate, and initiation of feeding in Mytilus californianus embryos and larvae. We found, as documented in other bivalve larvae, that shell development and growth were affected by aragonite saturation state, and not by pH or PCO2. Respiration rate was elevated under very low pH (~7.4) with no change between pH of ~ 8.3 to ~7.8. Initiation of feeding appeared to be most sensitive to PCO2, and possibly minor response to pH under elevated PCO2. Although different components of physiology responded to different carbonate system variables, the inability to normally develop a shell due to lower saturation state precludes pH or PCO2 effects later in the life history. However, saturation state effects during early shell development will carry-over to later stages, where pH or PCO2 effects can compound OA effects on bivalve larvae. Our findings suggest OA may be a multi-stressor unto itself. Shell development and growth of the native mussel, M. californianus, was indistinguishable from the Mediterranean mussel, Mytilus galloprovincialis, collected from the southern U.S. Pacific coast, an area not subjected to seasonal upwelling. The concordance in responses suggests a fundamental OA bottleneck during development of the first shell material affected only by saturation state. PMID- 26061097 TI - Benziporphyrins, a unique platform for exploring the aromatic characteristics of porphyrinoid systems. AB - Benziporphyrins were first discovered over 20 years ago. Although initially they were considered to be a chemical curiosity, a wide range of benzene-containing porphyrinoid systems are now known that exhibit intriguing spectroscopic, structural and chemical properties. These systems can often generate stable organometallic derivatives, and have been shown to have applications in the development of chemical sensors and in molecular recognition studies. The characteristics of these porphyrinoid macrocycles vary from nonaromatic to highly aromatic systems, and in a few cases antiaromatic structures are formed. The variations in aromatic character are insightful and provide a deeper understanding of aromaticity and conjugation in porphyrinoid structures. In this review, the synthesis and properties of benziporphyrinoid systems is presented with a particular emphasis on the variations in aromatic characteristics. PMID- 26061096 TI - Exotic Fish in Exotic Plantations: A Multi-Scale Approach to Understand Amphibian Occurrence in the Mediterranean Region. AB - Globally, amphibian populations are threatened by a diverse range of factors including habitat destruction and alteration. Forestry practices have been linked with low diversity and abundance of amphibians. The effect of exotic Eucalyptus spp. plantations on amphibian communities has been studied in a number of biodiversity hotspots, but little is known of its impact in the Mediterranean region. Here, we identify the environmental factors influencing the presence of six species of amphibians (the Caudata Pleurodeles waltl, Salamandra salamandra, Lissotriton boscai, Triturus marmoratus and the anurans Pelobates cultripes and Hyla arborea/meridionalis) occupying 88 ponds. The study was conducted in a Mediterranean landscape dominated by eucalypt plantations alternated with traditional use (agricultural, montados and native forest) at three different scales: local (pond), intermediate (400 metres radius buffer) and broad (1000 metres radius buffer). Using the Akaike Information Criterion for small samples (AICc), we selected the top-ranked models for estimating the probability of occurrence of each species at each spatial scale separately and across all three spatial scales, using a combination of covariates from the different magnitudes. Models with a combination of covariates at the different spatial scales had a stronger support than those at individual scales. The presence of predatory fish in a pond had a strong effect on Caudata presence. Permanent ponds were selected by Hyla arborea/meridionalis over temporary ponds. Species occurrence was not increased by a higher density of streams, but the density of ponds impacted negatively on Lissotriton boscai. The proximity of ponds occupied by their conspecifics had a positive effect on the occurrence of Lissotriton boscai and Pleurodeles waltl. Eucalypt plantations had a negative effect on the occurrence of the newt Lissotriton boscai and anurans Hyla arborea/meridionalis, but had a positive effect on the presence of Salamandra salamandra, while no effect on any of the other species was detected. In conclusion, eucalypts had limited effects on the amphibian community at the intermediate and broad scales, but predatory fish had a major impact when considering all the scales combined. The over-riding importance of introduced fish as a negative impact suggests that forest managers should prevent new fish introductions and eradicate fish from already-occupied ponds whenever possible. PMID- 26061098 TI - Terminal osseous dysplasia with pigmentary defects; Case and brief review of filamin A-related disorders. AB - Terminal osseous dysplasia with pigmentary defects (TOD) is an extremely rare X linked dominant disorder, which is characterised by cutaneous digital fibromas, pigmentary skin defects and skeletal abnormalities. A single mutation in the last nucleotide of exon 31 of the filamin A gene (FLNA) has recently been identified as a cause of the disease. We describe a case of an 18-month-old girl with the clinical phenotype of TOD and the disease-specific FLNA mutation confirmed by genetic testing. This report highlights the importance of recognising this distinct phenotype that can present to a wide variety of health-care professionals, and reviews the spectrum of filamin A disorders. PMID- 26061099 TI - The Relationship between the p.V37I Mutation in GJB2 and Hearing Phenotypes in Chinese Individuals. AB - The most common cause of nonsyndromic autosomal recessive hearing loss is mutations in GJB2. The mutation spectrum and prevalence of mutations vary significantly among ethnic groups, and the relationship between p.V37I mutation in GJB2 and the hearing phenotype is controversial. Among the 3,864 patients in this study, 106 (2.74%) had a homozygous p.V37I variation or a compound p.V37I plus other GJB2 pathogenic mutation, a frequency that was significantly higher than that in the control group (600 individuals, 0%). The hearing loss phenotype ranged from mild to profound in all patients with the homozygous p.V37I variation or compound p.V37I plus other GJB2 pathogenic mutation. There was no difference in the distribution of the hearing level in the group with the homozygous p.V37I variation and the group with the compound p.V37I variation plus pathogenic mutation. Most patients (66.04%) with the V37I-homozygous variation or p.V37I plus other pathogenic mutation had a mild or moderate hearing level. This study found a definite relationship between p.V37I and deafness, and most patients who carried the pathogenic combination with p.V37I mutation had mild or moderate hearing loss. Therefore, otolaryngologists should consider that the milder phenotype might be caused by the GJB2 p.V37I mutation. PMID- 26061101 TI - Natural compound renews hope for diabetes and obesity therapeutic target. PMID- 26061100 TI - TERT Promoter Mutations Are Predictive of Aggressive Clinical Behavior in Patients with Spitzoid Melanocytic Neoplasms. AB - Spitzoid neoplasms constitute a morphologically distinct category of melanocytic tumors, encompassing Spitz nevus (benign), atypical Spitz tumor (intermediate malignant potential), and spitzoid melanoma (fully malignant). Currently, no reliable histopathological criteria or molecular marker is known to distinguish borderline from overtly malignant neoplasms. Because TERT promoter (TERT-p) mutations are common in inherently aggressive cutaneous conventional melanoma, we sought to evaluate their prognostic significance in spitzoid neoplasms. We analyzed tumors labeled as atypical Spitz tumor or spitzoid melanoma from 56 patients with available follow-up data for the association of TERT-p mutations, biallelic CDKN2A deletion, biallelic PTEN deletion, kinase fusions, BRAF/NRAS mutations, nodal status, and histopathological parameters with risk of hematogenous metastasis. Four patients died of disseminated disease and 52 patients were alive and disease free without extranodal metastasis (median follow up, 32.5 months). We found TERT-p mutations in samples from the 4 patients who developed hematogenous metastasis but in none of tumors from patients who had favorable outcomes. Presence of TERT-p mutations was the most significant predictor of haematogenous dissemination (P < 0.0001) among variables analyzed. We conclude that TERT-p mutations identify a clinically high-risk subset of patients with spitzoid tumors. Application of TERT-p mutational assays for risk stratification in the clinic requires large-scale validation. PMID- 26061102 TI - Loading antimalarial drugs into noninfected red blood cells: an undesirable roommate for Plasmodium. PMID- 26061103 TI - Drug discovery and development 2014: Returning toward the norm? PMID- 26061104 TI - Pyranopyrazolotacrines as nonneurotoxic, Abeta-anti-aggregating and neuroprotective agents for Alzheimer's disease. AB - AIM: Due to the complex nature of Alzheimer's disease, there is a renewed search for multipotent, nonhepatotoxic tacrines. RESULTS: This paper describes the synthesis and in vitro biological evaluation of eight new racemic 3-methyl-4-aryl 2,4,6,7,8,9-hexahydropyrazolo[4',3':5,6]pyrano[2,3-b]quinolin-5-amines (pyranopyrazolotacrines, PPT) as nonhepatotoxic multipotent tacrine analogs. Among these compounds, PPT4 is the less hepatotoxic in the cell viability assay on HepG2 cells, showing a good neuroprotective effect in the decreased cortical neuron viability induced by oligomycin A/rotenone analysis. PPT4 is a selective and good, noncompetitive EeAChE inhibitor, able to completely inhibit the Abeta1 40 aggregation induced by acetylcholinesterase. CONCLUSION: A new family of nonhepatotoxic showing selective acetylcholinesterase inhibition, permeable tacrine analogs have been discovered for the potential treatment of Alzheimer's disease. PMID- 26061105 TI - Searching phase II enzymes inducers, from Michael acceptor-[1,2]dithiolethione hybrids, as cancer chemopreventive agents. AB - BACKGROUND: Cancer chemoprevention involves the carcinogenic process prevention, delay or reverse by the administration of chemopreventive agents, which are able to suppress or block the carcinogen metabolic activation/formation. The increased activity of phase II detoxification enzymes such as quinone-reductase (QR) and glutation-S-transferase (GST) correlates with the protection against chemically induced carcinogenesis. It has been shown that synthetic chalcones and 3H-[1,2] dithiole-3-thiones promote expression of genes involved in chemoprevention. MATERIALS & METHODS: Herein, the induction of phase II enzymes by designed Michael acceptor-dithiolethione hybrids was studied. RESULTS & DISCUSSION: Hybrids 5 and 7 displayed the induction of quinone-reductase and glutation-S transferase in vitro in the same order on the wild-type mouse-hepatoma Hepa 1c1c7 and on the aryl-hydrocarbon-nuclear-translocator (Arnt)-defective mutant BPrc1 cells indicating that 7 displays the best chemopreventive potential. PMID- 26061106 TI - Drugging ATR: progress in the development of specific inhibitors for the treatment of cancer. AB - In this article, we review the ATR inhibitor field from initial pharmacological tools to first-generation clinical candidates with the potential to bring benefit to cancer patients. ATR is a critical part of the cell DNA-damage response. Over the past decade or more, compounds with weak ATR potency and low specificity have been used as tools in early studies to elucidate ATR pharmacology. More recently highly potent, selective and in vivo active ATR inhibitors have been developed enabling detailed preclinical in vitro and in vivo target assessment to be made. The published studies reveal the potential of ATR inhibitors for use as monotherapy or in combination with DNA-damaging agents. To date, VX-970 and AZD6738, have entered clinical assessment. PMID- 26061107 TI - Microwave-assisted synthesis of chromenes: biological and chemical importance. AB - Chromenes constitute chemically important class of heterocyclic compounds having diverse biological and chemical importance. Development of environmentally benign, efficient and economical methods for the synthesis of chromenes remains a significant challenge in synthetic chemistry. The synthesis of chromenes, therefore, has attracted enormous attention from medicinal and organic chemists. Researchers have embraced the concepts of microwave (high speed) synthesis to produce biologically and chemically important chromenes in a time sensitive manner. This review will summarize the recent biological applications such as anticancer, antimicrobial, neurodegenerative and insecticidal activity of new chromenes prepared via microwave irradiation. The development of new methodologies for the synthesis of chromenes including green chemistry processes has also been discussed. PMID- 26061108 TI - Target-selective delivery and activation of platinum-based anticancer agents. PMID- 26061109 TI - P-glycoprotein and membrane roles in multidrug resistance. AB - Multidrug-resistance (MDR) phenomena are a worldwide health concern. ATP-binding cassette efflux pumps as P-glycoprotein have been thoroughly studied in a frantic run to develop new efflux modulators capable to reverse MDR phenotypes. The study of efflux pumps has provided some key aspects on drug extrusion, however the answers could not be found solely on ATP-binding cassette transporters. Its counterpart - the plasma membrane - is now emerging as a critical structure able to modify drug behavior and efflux pump activity. Alterations in the membrane surrounding P-glycoprotein are now known to modulate drug efflux, with membrane related biophysical, biochemical and mechanical aspects further increasing the complexity of an already multifaceted phenomena. This review summarizes the main knowledge comprising the plasma membrane role in MDR. PMID- 26061110 TI - Recent advances in research of natural and synthetic bioactive quinolines. AB - Many natural products that consist of quinoline core are found to be bioactive and the versatility of quinoline and its derivatives have attracted great attention in the field of drug development. As a result, in recent years, many green and sustainable synthetic approaches for the synthesis of structurally diverse quinolines have been developed. This review covers four main aspects, namely bioactive quinoline alkaloids, the biological activity and mechanism of action of quinoline-based compounds as well as various quinoline syntheses. PMID- 26061111 TI - Natural and Anthropogenic Hybridization in Two Species of Eastern Brazilian Marmosets (Callithrix jacchus and C. penicillata). AB - Animal hybridization is well documented, but evolutionary outcomes and conservation priorities often differ for natural and anthropogenic hybrids. Among primates, an order with many endangered species, the two contexts can be hard to disentangle from one another, which carries important conservation implications. Callithrix marmosets give us a unique glimpse of genetic hybridization effects under distinct natural and human-induced contexts. Here, we use a 44 autosomal microsatellite marker panel to examine genome-wide admixture levels and introgression at a natural C. jacchus and C. penicillata species border along the Sao Francisco River in NE Brazil and in an area of Rio de Janeiro state where humans introduced these species exotically. Additionally, we describe for the first time autosomal genetic diversity in wild C. penicillata and expand previous C. jacchus genetic data. We characterize admixture within the natural zone as bimodal where hybrid ancestry is biased toward one parental species or the other. We also show evidence that Sao Francisco River islands are gateways for bidirectional gene flow across the species border. In the anthropogenic zone, marmosets essentially form a hybrid swarm with intermediate levels of admixture, likely from the absence of strong physical barriers to interspecific breeding. Our data show that while hybridization can occur naturally, the presence of physical, even if leaky, barriers to hybridization is important for maintaining species genetic integrity. Thus, we suggest further study of hybridization under different contexts to set well informed conservation guidelines for hybrid populations that often fit somewhere between "natural" and "man-made." PMID- 26061112 TI - Rhodium-Catalyzed Synthesis of Benzosilolometallocenes via the Dehydrogenative Silylation of C(sp(2))-H Bonds. AB - Use of a rhodium catalyst with electron-rich and bulky chiral diphosphine ligands having C2-symmetry allowed efficient dehydrogenative silylation of the C(sp(2))-H bond of ferrocenes leading to chiral benzosiloloferrocenes. The substrate scope was expanded to hydrogermane and hydrosilanes having a ruthenocene backbone, which resulted in a new approach to benzosilole- and benzogermole-fused metallocenes. PMID- 26061114 TI - Monitoring patterned enzymatic polymerization on DNA origami at single-molecule level. AB - DNA origami has been used to orchestrate reactions with nano-precision using a variety of biomolecules. Here, the dynamics of albumin-assisted, localized single molecule DNA polymerization by terminal deoxynucleotidyl transferase on a 2D DNA origami are monitored using AFM in liquid. Direct visualization of the surface activity revealed the mechanics of growth. PMID- 26061115 TI - Muscle synergy analysis in children with cerebral palsy. AB - OBJECTIVE: To explore the mechanism of lower extremity dysfunction of cerebral palsy (CP) children through muscle synergy analysis. APPROACH: Twelve CP children were involved in this study, ten adults (AD) and eight typically developed (TD) children were recruited as a control group. Surface electromyographic (sEMG) signals were collected bilaterally from eight lower limb muscles of the subjects during forward walking at a comfortable speed. A nonnegative matrix factorization algorithm was used to extract muscle synergies. In view of muscle synergy differences in number, structure and symmetry, a model named synergy comprehensive assessment (SCA) was proposed to quantify the abnormality of muscle synergies. MAIN RESULTS: There existed larger variations between the muscle synergies of the CP group and the AD group in contrast with the TD group. Fewer mature synergies were recruited in the CP group, and many abnormal synergies specific to the CP group appeared. Specifically, CP children were found to recruit muscle synergies with a larger difference in structure and symmetry between two legs of one subject and different subjects. The proposed SCA scale demonstrated its great potential to quantitatively assess the lower-limb motor dysfunction of CP children. SCA scores of the CP group (57.00 +/- 16.78) were found to be significantly less (p < 0.01) than that of the control group (AD group: 95.74 +/- 2.04; TD group: 84.19 +/- 11.76). SIGNIFICANCE: The innovative quantitative results of this study can help us to better understand muscle synergy abnormality in CP children, which is related to their motor dysfunction and even the physiological change in their nervous system. PMID- 26061116 TI - The Neuregulin1/ErbB system is selectively regulated during peripheral nerve degeneration and regeneration. AB - The peripheral nervous system has an intrinsic capability to regenerate, crucially related to the ability of Schwann cells (SC) to create a permissive environment, for example, through production of regeneration-promoting neurotrophic factors. Survival, proliferation, migration and differentiation of SC into a myelinating phenotype during development and after injury is regulated by different Neuregulin1 (NRG1) isoforms. This study investigates the expression of different NRG1 isoforms and of their ErbB receptors in distal rat median nerve samples under regenerating conditions after a mild (crush) and more severe (end to-end repair) injury and under degenerating condition. The expression of the NRG1/ErbB system was evaluated at mRNA and protein level, and demonstrated to be specific for distinct and consecutive phases following nerve injury and regeneration or the progress in degeneration. For the first time a detailed analysis of expression profiles not only of soluble and transmembrane NRG1 isoforms, but also of alpha and beta as well as type a, b and c isoforms is presented. The results of mRNA and protein expression pattern analyses were related to nerve ultrastructure changes evaluated by electron microscopy. In particular, transmembrane NRG1 isoforms are differentially regulated and proteolytically processed under regeneration and degeneration conditions. Soluble NRG1 isoforms alpha and beta, as well as type a and b, are strongly upregulated during axonal regrowth, while type c NRG1 isoform is downregulated. This is accompanied by an upregulation of ErbB receptors. This accurate regulation suggests that each molecule plays a specific role that could be clinically exploited to improve nerve regeneration. PMID- 26061117 TI - Giant Rabi Splitting of Whispering Gallery Polaritons in GaN/InGaN Core-Shell Wire. AB - The hybrid nature of exciton polaritons opens up possibilities for developing a new concept nonlinear photonic device (e.g., polariton condensation, switching, and transistor) with great potential for controllability. Here, we proposed a novel type of polariton system resulting from strong coupling between a two dimensional exciton and whispering gallery mode photon using a core-shell GaN/InGaN hexagonal wire. High quality, nonpolar InGaN multiple-quantum wells (MQWs) were conformally formed on a GaN core nanowire, which was spatially well matched with whispering gallery modes inside the wire. Both high longitudinal transverse splitting of nonpolar MQWs and high spatial overlap with whispering gallery modes lead to unprecedented large Rabi splitting energy of ~180 meV. This structure provides a robust polariton effect with a small footprint; thus, it could be utilized for a wide range of interesting applications. PMID- 26061118 TI - A review of ethical issues in dementia. AB - Dementia raises many ethical issues. The present review, taking note of the fact that the stages of dementia raise distinct ethical issues, focuses on three issues associated with stages of dementia's progression: (1) how the emergence of preclinical and asymptomatic but at-risk categories for dementia creates complex questions about preventive measures, risk disclosure, and protection from stigma and discrimination; (2) how despite efforts at dementia prevention, important research continues to investigate ways to alleviate clinical dementia's symptoms, and requires additional human subjects protections to ethically enroll persons with dementia; and (3) how in spite of research and prevention efforts, persons continue to need to live with dementia. This review highlights two major themes. First is how expanding the boundaries of dementias such as Alzheimer's to include asymptomatic but at-risk persons generate new ethical questions. One promising way to address these questions is to take an integrated approach to dementia ethics, which can include incorporating ethics-related data collection into the design of a dementia research study itself. Second is the interdisciplinary nature of ethical questions related to dementia, from health policy questions about insurance coverage for long-term care to political questions about voting, driving, and other civic rights and privileges to economic questions about balancing an employer's right to a safe and productive workforce with an employee's rights to avoid discrimination on the basis of their dementia risk. The review highlights these themes and emerging ethical issues in dementia. PMID- 26061119 TI - How Do C-Tactile Skin Afferents Contribute to Erotic Affect? PMID- 26061120 TI - Predictive modelling of habitat selection by marine predators with respect to the abundance and depth distribution of pelagic prey. AB - Understanding the ecological processes that underpin species distribution patterns is a fundamental goal in spatial ecology. However, developing predictive models of habitat use is challenging for species that forage in marine environments, as both predators and prey are often highly mobile and difficult to monitor. Consequently, few studies have developed resource selection functions for marine predators based directly on the abundance and distribution of their prey. We analysed contemporaneous data on the diving locations of two seabird species, the shallow-diving Peruvian Booby (Sula variegata) and deeper diving Guanay Cormorant (Phalacrocorax bougainvilliorum), and the abundance and depth distribution of their main prey, Peruvian anchoveta (Engraulis ringens). Based on this unique data set, we developed resource selection functions to test the hypothesis that the probability of seabird diving behaviour at a given location is a function of the relative abundance of prey in the upper water column. For both species, we show that the probability of diving behaviour is mostly explained by the distribution of prey at shallow depths. While the probability of diving behaviour increases sharply with prey abundance at relatively low levels of abundance, support for including abundance in addition to the depth distribution of prey is weak, suggesting that prey abundance was not a major factor determining the location of diving behaviour during the study period. The study thus highlights the importance of the depth distribution of prey for two species of seabird with different diving capabilities. The results complement previous research that points towards the importance of oceanographic processes that enhance the accessibility of prey to seabirds. The implications are that locations where prey is predictably found at accessible depths may be more important for surface foragers, such as seabirds, than locations where prey is predictably abundant. Analysis of the relative importance of abundance and accessibility is essential for the design and evaluation of effective management responses to reduced prey availability for seabirds and other top predators in marine systems. PMID- 26061121 TI - Synthesis, Biological Evaluation and Molecular Modeling of Substituted Indeno[1,2 b]indoles as Inhibitors of Human Protein Kinase CK2. AB - Due to their system of annulated 6-5-5-6-membered rings, indenoindoles have sparked great interest for the design of ATP-competitive inhibitors of human CK2. In the present study, we prepared twenty-one indeno[1,2-b]indole derivatives, all of which were tested in vitro on human CK2. The indenoindolones 5a and 5b inhibited human CK2 with an IC50 of 0.17 and 0.61 uM, respectively. The indeno[1,2-b]indoloquinone 7a also showed inhibitory activity on CK2 at a submicromolar range (IC50 = 0.43 uM). Additionally, a large number of indenoindole derivatives was evaluated for their cytotoxic activities against the cell lines 3T3, WI-38, HEK293T and MEF. PMID- 26061122 TI - Terahertz Plasmonic Field-Induced Conductivity Modulation in Gold. AB - We report the observation of terahertz (THz) electric field induced conductivity modulation in sub-wavelength gold plasmonic media. Through all-THz pump-probe time-resolved transmission spectroscopy, we demonstrate that the presence of induced surface charges influences near-field mediated light propagation. The phenomenon is ascribed to the enhanced metal conductivity due to enhanced surface density of conduction electrons. The surface induced charge dynamics are revealed via phase-dependent time-resolved signatures. The phenomenon is a prelude to a wide class of ultrafast active THz plasmonic devices and paves the way for plasmonic field effects devices, similar to semiconductor ones. PMID- 26061123 TI - Selectivity hot-spots of sirtuin catalytic cores. AB - Sirtuins are NAD(+)-dependent deacetylases with several biological roles in DNA regulation, genomic stability, metabolism, longevity and immune cell functions. Numerous disease conditions are linked to sirtuins including metabolic disorders, inflammatory and autoimmune processes and cancer. Although few specific small molecule modulators have been reported to date, the need to identify selective ligands would be crucial not only for the development of active pharmaceutical ingredients for new targeted therapies but also as a tool for dissecting the biological roles of sirtuin family members. Herein, we report a comprehensive study aimed to classify and identify the selectivity hot-spots for targeting the catalytic cores of human sirtuins using small molecule modulators. Our selectivity analysis suggests that catalytic cores can be divided into different clusters that can constitute the basis for the development of selective ligands. The ensemble of hot-spot information is expected to be helpful to devise new selective chemicals targeting sirtuin family members. PMID- 26061124 TI - The Use of Decision Support Systems in Social Work: A Scoping Study Literature Review. AB - Decision support systems are known to be helpful for professionals in many medical professions. In social work, decision support systems have had modest use, accompanied by strong criticism from the profession but often by praise from political management. In this study the aim of the authors was to collect and report on the published evidence on decision support systems in social work. The conclusion of the authors is that a decision support system gives support to social workers in conducting a thorough investigation, but at the same time gives them the freedom to make autonomous decisions that might be the most helpful for and used by social workers. Their results also indicate that decision support systems focusing on atypical rather than typical cases are perceived as the most useful among experienced staff. PMID- 26061125 TI - Wrong-Site Surgery, Retained Surgical Items, and Surgical Fires : A Systematic Review of Surgical Never Events. AB - IMPORTANCE: Serious, preventable surgical events, termed never events, continue to occur despite considerable patient safety efforts. OBJECTIVE: To examine the incidence and root causes of and interventions to prevent wrong-site surgery, retained surgical items, and surgical fires in the era after the implementation of the Universal Protocol in 2004. DATA SOURCES: We searched 9 electronic databases for entries from 2004 through June 30, 2014, screened references, and consulted experts. STUDY SELECTION: Two independent reviewers identified relevant publications in June 2014. DATA EXTRACTION AND SYNTHESIS: One reviewer used a standardized form to extract data and a second reviewer checked the data. Strength of evidence was established by the review team. Data extraction was completed in January 2015. MAIN OUTCOMES AND MEASURES: Incidence of wrong-site surgery, retained surgical items, and surgical fires. RESULTS: We found 138 empirical studies that met our inclusion criteria. Incidence estimates for wrong site surgery in US settings varied by data source and procedure (median estimate, 0.09 events per 10,000 surgical procedures). The median estimate for retained surgical items was 1.32 events per 10,000 procedures, but estimates varied by item and procedure. The per-procedure surgical fire incidence is unknown. A frequently reported root cause was inadequate communication. Methodologic challenges associated with investigating changes in rare events limit the conclusions of 78 intervention evaluations. Limited evidence supported the Universal Protocol (5 studies), education (4 studies), and team training (4 studies) interventions to prevent wrong-site surgery. Limited evidence exists to prevent retained surgical items by using data-matrix-coded sponge-counting systems (5 pertinent studies). Evidence for preventing surgical fires was insufficient, and intervention effects were not estimable. CONCLUSIONS AND RELEVANCE: Current estimates for wrong-site surgery and retained surgical items are 1 event per 100,000 and 1 event per 10,000 procedures, respectively, but the precision is uncertain, and the per-procedure prevalence of surgical fires is not known. Root-cause analyses suggest the need for improved communication. Despite promising approaches and global Universal Protocol evaluations, empirical evidence for interventions is limited. PMID- 26061129 TI - Benign Arterial Calcification on Screening Mammogram: A Marker for Coronary Artery Disease? AB - BACKGROUND: Studies have shown several risk factors for coronary artery disease (CAD), such as diabetes and hypertension, are associated with benign arterial calcifications (BACs) seen on screening mammograms. However, there are few studies examining the association of BACs with women who are diagnosed with CAD. The purpose of our study was to determine whether there is an association between BACs present on routine screening digital mammograms and the presence of CAD as documented on cardiac catheterization. METHODS: A retrospective chart review was performed on women aged >=40 years who had undergone a digital screening mammogram within two years of also having a cardiac catheterization from 1999 to 2010. Mammograms were reviewed for the presence of BACs. Cardiac catheterizations were reviewed for the presence of CAD. Patients with BACs were compared with those without BACs by chi-squared or Wilcoxon rank sum tests. RESULTS: The final study cohort consisted of 198 patients with 101 patients having clinically significant cardiac vessel disease. Most patients (67.2%) did not have diabetes, while the majority was hypertensive (83.3%) and had hypercholesterolemia (80.8%). On multivariate analysis, history of smoking (p=0.003), hypercholesterolemia (p<=0.0001), and BACs (p=0.005) were significant predictors of CAD. In a second model, CAD on cardiac catheterization was a significant predictor of BACs found on mammography while a history of smoking was a negative predictor of BACs. CONCLUSIONS: BACs present on digital screening mammography, history of smoking and hypercholesterolemia were all significant predictors of CAD. Routine screening digital mammography could potentially assist in stratification of patients in consideration of CAD. PMID- 26061130 TI - Self-Assembly of Metal Phenolic Mesocrystals and Morphosynthetic Transformation toward Hierarchically Porous Carbons. AB - A facile and sustainable synthetic strategy based on the coordination of natural polyphenols with metal ions is developed for the textural engineering of mesocrystals and hierarchical carbon nanomaterials. The desired control of coordination between ellagic acid and zinc ions enables the macroscopic self assembly behavior of crystalline nanoplatelets to be tailored into round and elongated "peanut"-like micron-sized mesostructured particles. Direct carbonization of these mesocrystals generates hierarchically porous carbon particles in good yields, possessing bimodal micro- and mesoporous architecture along with a well-preserved macroscopic structure. The pore system provides both small storage sites, demonstrated by high CO2 uptake, and transport channels also accessible by larger molecules. PMID- 26061131 TI - 25(th) Anniversary State-of-the-Art Expert Discussion With Ralph C. Cohen, MBBS, BMedSci, MS, FRACS, on the Advances of Surgical Practice in Pediatric Urology. PMID- 26061132 TI - Complete Endoscopic Thyroidectomy via Oral Vestibular Approach Versus Areola Approach for Treatment of Thyroid Diseases. AB - BACKGROUND: Natural orifice translumenal endoscopic surgery (NOTES((r)); American Society for Gastrointestinal Endoscopy [Oak Brook, IL] and Society of American Gastrointestinal and Endoscopic Surgeons [Los Angeles, CA]) is gaining interest because it allows operations without skin incisions. The aim of this study was to evaluate the feasibility, safety, and cosmetic results of endoscopic thyroidectomy via the oral vestibular approach (ETOVA) compared with endoscopic thyroidectomy via the areola approach (ETAA) in patients with thyroid diseases. MATERIALS AND METHODS: Eighty-two patients with thyroid diseases were randomized to receive either ETOVA (n=41) or ETAA (n=41). Perioperative and follow-up data were assessed. RESULTS: The surgery was completed in all cases, and all patients were followed up for at least 1 year. There were no differences between the two groups in operation time, blood loss, or postoperative hospital stay. Respective pain scores were 1.7 versus 2.1 and 0.6 versus 0.8 on Days 1 and 3, respectively, postoperatively. The white blood cell counts and C-reactive protein levels were not significantly different between the two groups. Complications were the same in both groups. Oral incision scars were invisible in the ETOVA group. Rates of skin traction sensation on the surgical field were lower in the ETOVA group than in the ETAA group at 3 and 6 months postoperatively (53.7% versus 80.5% and 24.4% versus 46.3%, respectively). The respective satisfaction score was 9.61 versus 9.22 (P=.021). No recurrent cases were observed in the study. CONCLUSIONS: Both the ETOVA and the ETAA procedures are feasible for thyroid diseases. The ETOVA eliminated skin incision scars and gained better cosmetic results in the short term follow-ups, and the trauma was the same between the two approaches. However, more cases and longer-term follow-ups are needed for confirmation. PMID- 26061133 TI - Commentary on "Medium-Term Recurrence and Quality of Life Assessment Using the Hernia-Specific Carolinas Comfort Scale Following Laparoscopic Inguinal Hernia Repair": Asking the Right Questions-Evaluating Outcomes in Hernia Repair. PMID- 26061134 TI - Correction to: J Laparoendosc Adv Surg Tech 2014;24(12):883-886. PMID- 26061135 TI - A Consensus-Based Interpretation of the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure Trial. AB - Widely-varying published and presented analyses of the Benchmark Evidence From South American Trials: Treatment of Intracranial Pressure (BEST TRIP) randomized controlled trial of intracranial pressure (ICP) monitoring have suggested denying trial generalizability, questioning the need for ICP monitoring in severe traumatic brain injury (sTBI), re-assessing current clinical approaches to monitored ICP, and initiating a general ICP-monitoring moratorium. In response to this dissonance, 23 clinically-active, international opinion leaders in acute care sTBI management met to draft a consensus statement to interpret this study. A Delphi method-based approach employed iterative pre-meeting polling to codify the group's general opinions, followed by an in-person meeting wherein individual statements were refined. Statements required an agreement threshold of more than 70% by blinded voting for approval. Seven precisely-worded statements resulted, with agreement levels of 83% to 100%. These statements, which should be read in toto to properly reflect the group's consensus positions, conclude that the BEST TRIP trial: 1) studied protocols, not ICP-monitoring per se; 2) applies only to those protocols and specific study groups and should not be generalized to other treatment approaches or patient groups; 3) strongly calls for further research on ICP interpretation and use; 4) should be applied cautiously to regions with much different treatment milieu; 5) did not investigate the utility of treating monitored ICP in the specific patient group with established intracranial hypertension; 6) should not change the practice of those currently monitoring ICP; and 7) provided a protocol, used in non-monitored study patients, that should be considered when treating without ICP monitoring. Consideration of these statements can clarify study interpretation. PMID- 26061136 TI - Degradation of zinc in saline solutions, plasma, and whole blood. AB - The initial degradation of zinc has been investigated through exposures to simulated and real body fluids of increasing complexity: phosphate buffered saline (PBS), Ringer's saline solution, human plasma, and whole blood. Real body fluids were used to close the electrolyte gap between simulated and in vivo environment. Polarization of zinc in whole blood show a passive response not present in other electrolytes. The analysis shows a decrease in corrosion rate with time for plasma and whole blood and an increase for PBS and Ringer's. During exposure to plasma and whole blood a bi-layered corrosion product with poor adherence was formed over a uniformly corroding surface. The corrosion products comprise a mixture of inorganic material and biomolecules. Samples degrading in PBS were prone to localized corrosion and formed thick porous corrosion products of primarily zinc phosphates while in Ringer's solution a gel like layer of zinc carbonate was formed over an interface with shallow pits. The use of whole blood or plasma as electrolytes for short term in vitro evaluation of potential biodegradable metals may provide an improved understanding of the behavior in vivo, while Ringer's solution is preferred over PBS for long term degradation studies of zinc. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1141-1151, 2016. PMID- 26061137 TI - Performance Enhancement of Electronic and Energy Devices via Block Copolymer Self Assembly. AB - The use of self-assembled block copolymers (BCPs) for the fabrication of electronic and energy devices has received a tremendous amount of attention as a non-traditional approach to patterning integrated circuit elements at nanometer dimensions and densities inaccessible to traditional lithography techniques. The exquisite control over the dimensional features of the self-assembled nanostructures (i.e., shape, size, and periodicity) is one of the most attractive properties of BCP self-assembly. Harmonic spatial arrangement of the self assembled nanoelements at desired positions on the chip may offer a new strategy for the fabrication of electronic and energy devices. Several recent reports show the great promise in using BCP self-assembly for practical applications of electronic and energy devices, leading to substantial enhancements of the device performance. Recent progress is summarized here, with regard to the performance enhancements of non-volatile memory, electrical sensor, and energy devices enabled by directed BCP self-assembly. PMID- 26061138 TI - The return trip is felt shorter only postdictively: A psychophysiological study of the return trip effect [corrected]. AB - The return trip often seems shorter than the outward trip even when the distance and actual time are identical. To date, studies on the return trip effect have failed to confirm its existence in a situation that is ecologically valid in terms of environment and duration. In addition, physiological influences as part of fundamental timing mechanisms in daily activities have not been investigated in the time perception literature. The present study compared round-trip and non round-trip conditions in an ecological situation. Time estimation in real time and postdictive estimation were used to clarify the situations where the return trip effect occurs. Autonomic nervous system activity was evaluated from the electrocardiogram using the Lorenz plot to demonstrate the relationship between time perception and physiological indices. The results suggest that the return trip effect is caused only postdictively. Electrocardiographic analysis revealed that the two experimental conditions induced different responses in the autonomic nervous system, particularly in sympathetic nervous function, and that parasympathetic function correlated with postdictive timing. To account for the main findings, the discrepancy between the two time estimates is discussed in the light of timing strategies, i.e., prospective and retrospective timing, which reflect different emphasis on attention and memory processes. Also each timing method, i.e., the verbal estimation, production or comparative judgment, has different characteristics such as the quantification of duration in time units or knowledge of the target duration, which may be responsible for the discrepancy. The relationship between postdictive time estimation and the parasympathetic nervous system is also discussed. PMID- 26061139 TI - WISP3 (CCN6) Regulates Milk Protein Synthesis and Cell Growth Through mTOR Signaling in Dairy Cow Mammary Epithelial Cells. AB - The mTOR/S6K1 signaling pathway is the primary regulator of milk protein synthesis. While mTOR is known to be regulated at the translational level by amino acids, the mechanism by which mTOR accepts the amino acid signal is not yet clear. In this study, we describe the discovery of WISP3 as a potentially novel signaling factor that connects mTOR and amino acids. Treatment of dairy cow mammary epithelial cells with amino acids (lysine or methionine) increased both cell growth and the expression of beta-casein (CSN2), WISP3, mTOR, and phospho mTOR (p-mTOR). Notably, overexpressing WISP3 in these cells also increased both cell growth and the expression of CSN2, mTOR, and p-mTOR and decreased the expression of glycogen synthase kinase 3beta (GSK3beta), while repressing WISP3 had the opposite effect. The increase of the expression of CSN2, mTOR, and p-mTOR mediated by amino acid could be inhibited by repressing WISP3. The increase of the expression of CSN2, mTOR, and p-mTOR mediated by WISP3 overexpression could be inhibited by overexpressing GSK3beta, and vice versa. Taken together, these results reveal that through its amino acid-mediated regulation of the mTOR pathway, WISP3 is an important regulatory factor involved in the amino acid mediated regulation of milk protein synthesis and cell growth. PMID- 26061140 TI - Gene delivery of neurturin to putamen and substantia nigra in Parkinson disease: A double-blind, randomized, controlled trial. AB - OBJECTIVE: A 12-month double-blind sham-surgery-controlled trial assessing adeno associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. METHODS: We performed a 15- to 24-month, multicenter, double blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 * 10(11) vector genomes) and putamen (1.0 * 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state. RESULTS: Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 +/- 9.92; sham, -5.2 +/- 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin. INTERPRETATION: AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin. PMID- 26061141 TI - Genetic Divergence among Regions Containing the Vulnerable Great Desert Skink (Liopholis kintorei) in the Australian Arid Zone. AB - Knowledge of genetic structure and patterns of connectivity is valuable for implementation of effective conservation management. The arid zone of Australia contains a rich biodiversity, however this has come under threat due to activities such as altered fire regimes, grazing and the introduction of feral herbivores and predators. Suitable habitats for many species can be separated by vast distances, and despite an apparent lack of current geographical barriers to dispersal, habitat specialisation, which is exhibited by many desert species, may limit connectivity throughout this expansive region. We characterised the genetic structure and differentiation of the great desert skink (Liopholis kintorei), which has a patchy, but widespread distribution in the western region of the Australian arid zone. As a species of cultural importance to local Aboriginal groups and nationally listed as Vulnerable, it is a conservation priority for numerous land managers in central Australia. Analysis of mitochondrial ND4 sequence data and ten nuclear microsatellite loci across six sampling localities through the distribution of L. kintorei revealed considerable differentiation among sites, with mitochondrial FST and microsatellite F'ST ranging from 0.047 0.938 and 0.257-0.440, respectively. The extent of differentiation suggests three main regions that should be managed separately, in particular the southeastern locality of Uluru. Current genetic delineation of these regions should be maintained if future intervention such as translocation or captive breeding is to be undertaken. PMID- 26061142 TI - A Nematode Calreticulin, Rs-CRT, Is a Key Effector in Reproduction and Pathogenicity of Radopholus similis. AB - Radopholus similis is a migratory plant-parasitic nematode that causes severe damage to many agricultural and horticultural crops. Calreticulin (CRT) is a Ca2+ binding multifunctional protein that plays key roles in the parasitism, immune evasion, reproduction and pathogenesis of many animal parasites and plant nematodes. Therefore, CRT is a promising target for controlling R. similis. In this study, we obtained the full-length sequence of the CRT gene from R. similis (Rs-crt), which is 1,527-bp long and includes a 1,206-bp ORF that encodes 401 amino acids. Rs-CRT and Mi-CRT from Meloidogyne incognita showed the highest similarity and were grouped on the same branch of the phylogenetic tree. Rs-crt is a multi-copy gene that is expressed in the oesophageal glands and gonads of females, the gonads of males, the intestines of juveniles and the eggs of R. similis. The highest Rs-crt expression was detected in females, followed by juveniles, eggs and males. The reproductive capability and pathogenicity of R. similis were significantly reduced after treatment with Rs-crt dsRNA for 36 h. Using plant-mediated RNAi, we confirmed that Rs-crt expression was significantly inhibited in the nematodes, and resistance to R. similis was significantly improved in transgenic tomato plants. Plant-mediated RNAi-induced silencing of Rs crt could be effectively transmitted to the F2 generation of R. similis; however, the silencing effect of Rs-crt induced by in vitro RNAi was no longer detectable in F1 and F2 nematodes. Thus, Rs-crt is essential for the reproduction and pathogenicity of R. similis. PMID- 26061143 TI - Anatomy education for the YouTube generation. AB - Anatomy remains a cornerstone of medical education despite challenges that have seen a significant reduction in contact hours over recent decades; however, the rise of the "YouTube Generation" or "Generation Connected" (Gen C), offers new possibilities for anatomy education. Gen C, which consists of 80% Millennials, actively interact with social media and integrate it into their education experience. Most are willing to merge their online presence with their degree programs by engaging with course materials and sharing their knowledge freely using these platforms. This integration of social media into undergraduate learning, and the attitudes and mindset of Gen C, who routinely creates and publishes blogs, podcasts, and videos online, has changed traditional learning approaches and the student/teacher relationship. To gauge this, second year undergraduate medical and radiation therapy students (n = 73) were surveyed regarding their use of online social media in relation to anatomy learning. The vast majority of students had employed web-based platforms to source information with 78% using YouTube as their primary source of anatomy-related video clips. These findings suggest that the academic anatomy community may find value in the integration of social media into blended learning approaches in anatomy programs. This will ensure continued connection with the YouTube generation of students while also allowing for academic and ethical oversight regarding the use of online video clips whose provenance may not otherwise be known. PMID- 26061144 TI - Asymmetric Epoxidation Using Hydrogen Peroxide as Oxidant. AB - Asymmetric epoxidation is one of the most important transformations in organic synthesis. Although tremendous progress was achieved in this field in the 1980s and 1990s, it is still desirable from both economical and ecological views to develop environmentally friendly catalytic epoxidation with a broad substrate scope. Hydrogen peroxide is a safe and cheap oxidant, which is easy to handle and generates water as the sole byproduct. Therefore, asymmetric epoxidation of olefins using hydrogen peroxide as oxidant has been a very active research field and has been investigated by many research groups in recent years. In this review, the exciting very recent developments of this rapidly growing area are surveyed and organized according to the catalyst systems. PMID- 26061145 TI - Fast GPU-based Monte Carlo simulations for LDR prostate brachytherapy. AB - The aim of this study was to evaluate the potential of bGPUMCD, a Monte Carlo algorithm executed on Graphics Processing Units (GPUs), for fast dose calculations in permanent prostate implant dosimetry. It also aimed to validate a low dose rate brachytherapy source in terms of TG-43 metrics and to use this source to compute dose distributions for permanent prostate implant in very short times. The physics of bGPUMCD was reviewed and extended to include Rayleigh scattering and fluorescence from photoelectric interactions for all materials involved. The radial and anisotropy functions were obtained for the Nucletron SelectSeed in TG-43 conditions. These functions were compared to those found in the MD Anderson Imaging and Radiation Oncology Core brachytherapy source registry which are considered the TG-43 reference values. After appropriate calibration of the source, permanent prostate implant dose distributions were calculated for four patients and compared to an already validated Geant4 algorithm. The radial function calculated from bGPUMCD showed excellent agreement (differences within 1.3%) with TG-43 accepted values. The anisotropy functions at r = 1 cm and r = 4 cm were within 2% of TG-43 values for angles over 17.5 degrees . For permanent prostate implants, Monte Carlo-based dose distributions with a statistical uncertainty of 1% or less for the target volume were obtained in 30 s or less for 1 * 1 * 1 mm(3) calculation grids. Dosimetric indices were very similar (within 2.7%) to those obtained with a validated, independent Monte Carlo code (Geant4) performing the calculations for the same cases in a much longer time (tens of minutes to more than a hour). bGPUMCD is a promising code that lets envision the use of Monte Carlo techniques in a clinical environment, with sub-minute execution times on a standard workstation. Future work will explore the use of this code with an inverse planning method to provide a complete Monte Carlo-based planning solution. PMID- 26061146 TI - Lactobacillus rhamnosus bacteremia in a kidney transplant recipient. AB - Lactobacillus rhamnosus is a rare clinical pathogen. A case of bacteremia caused by L. rhamnosus in a kidney transplant recipient is described. Once considered only as a contaminant or a low-virulence organism, L. rhamnosus might be an opportunistic pathogen in immunocompromised patients. To our knowledge, this is the first report of primary bloodstream infection caused by L. rhamnosus in a kidney transplant recipient. PMID- 26061148 TI - In vitro activity of 1,3-bisaryloxypropanamines against Trypanosoma cruzi infected L929 cultures. AB - We describe herein the antitrypanosomal activity of 20 novel 1,3 bis(aryloxy)propan-2-amine derivatives. Compounds 2, 4, 6, 12, 15, 16 and 19 were significantly active against amastigote and trypomastigote forms, with half maximal inhibitory concentrationvalues in the range of 6-18 uM. In the cytotoxicity tests against L929 cells, only compound 4 presented selectivity index value above 10, indicating low toxicity. PMID- 26061149 TI - Trypanosoma evansi is alike to Trypanosoma brucei brucei in the subcellular localisation of glycolytic enzymes. AB - Trypanosoma evansi, which causes surra, is descended from Trypanosoma brucei brucei, which causes nagana. Although both parasites are presumed to be metabolically similar, insufficient knowledge of T. evansi precludes a full comparison. Herein, we provide the first report on the subcellular localisation of the glycolytic enzymes in T. evansi, which is a alike to that of the bloodstream form (BSF) of T. b. brucei: (i) fructose-bisphosphate aldolase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), hexokinase, phosphofructokinase, glucose-6-phosphate isomerase, phosphoglycerate kinase, triosephosphate isomerase (glycolytic enzymes) and glycerol-3-phosphate dehydrogenase (a glycolysis-auxiliary enzyme) in glycosomes, (ii) enolase, phosphoglycerate mutase, pyruvate kinase (glycolytic enzymes) and a GAPDH isoenzyme in the cytosol, (iii) malate dehydrogenase in cytosol and (iv) glucose 6-phosphate dehydrogenase in both glycosomes and the cytosol. Specific enzymatic activities also suggest that T. evansi is alike to the BSF of T. b. brucei in glycolytic flux, which is much faster than the pentose phosphate pathway flux, and in the involvement of cytosolic GAPDH in the NAD+/NADH balance. These similarities were expected based on the close phylogenetic relationship of both parasites. PMID- 26061150 TI - A sensitive, specific and reproducible real-time polymerase chain reaction method for detection of Plasmodium vivax and Plasmodium falciparum infection in field collected anophelines. AB - We describe a simple method for detection of Plasmodium vivax and Plasmodium falciparum infection in anophelines using a triplex TaqMan real-time polymerase chain reaction (PCR) assay (18S rRNA). We tested the assay on Anopheles darlingi and Anopheles stephensi colony mosquitoes fed with Plasmodium-infected blood meals and in duplicate on field collected An. darlingi. We compared the real-time PCR results of colony-infected and field collected An. darlingi, separately, to a conventional PCR method. We determined that a cytochrome b-PCR method was only 3.33% as sensitive and 93.38% as specific as our real-time PCR assay with field collected samples. We demonstrate that this assay is sensitive, specific and reproducible. PMID- 26061151 TI - Draft genome sequences of three NDM-1-producing Enterobacteriaceae species isolated from Brazil. AB - The emergence of multidrug-resistant Enterobacteriaceae strains producing carbapenemases, such as NDM-1, has become a major public health issue due to a high dissemination capacity and limited treatment options. Here we describe the draft genome of three NDM-1-producing isolates: Providencia rettgeri (CCBH11880), Enterobacter hormaechei subsp. oharae (CCBH10892) and Klebsiella pneumoniae (CCBH13327), isolated in Brazil. Besides blaNDM-1, resistance genes to aminoglycosides [aadA1, aadA2, aac(6')-Ib-cr] and quinolones (qnrA1, qnrB4) were observed which contributed to the multidrug resistance profile. The element ISAba125 was found associated to the blaNDM-1 gene in all strains. PMID- 26061152 TI - Bubble stimulation efficiency of dinoflagellate bioluminescence. AB - Dinoflagellate bioluminescence, a common source of bioluminescence in coastal waters, is stimulated by flow agitation. Although bubbles are anecdotally known to be stimulatory, the process has never been experimentally investigated. This study quantified the flash response of the bioluminescent dinoflagellate Lingulodinium polyedrum to stimulation by bubbles rising through still seawater. Cells were stimulated by isolated bubbles of 0.3-3 mm radii rising at their terminal velocity, and also by bubble clouds containing bubbles of 0.06-10 mm radii for different air flow rates. Stimulation efficiency, the proportion of cells producing a flash within the volume of water swept out by a rising bubble, decreased with decreasing bubble radius for radii less than approximately 1 mm. Bubbles smaller than a critical radius in the range 0.275-0.325 mm did not stimulate a flash response. The fraction of cells stimulated by bubble clouds was proportional to the volume of air in the bubble cloud, with lower stimulation levels observed for clouds with smaller bubbles. An empirical model for bubble cloud stimulation based on the isolated bubble observations successfully reproduced the observed stimulation by bubble clouds for low air flow rates. High air flow rates stimulated more light emission than expected, presumably because of additional fluid shear stress associated with collective buoyancy effects generated by the high air fraction bubble cloud. These results are relevant to bioluminescence stimulation by bubbles in two-phase flows, such as in ship wakes, breaking waves, and sparged bioreactors. PMID- 26061153 TI - Educating Asthmatic Children in European Ambulatory Pediatrics: Facts and Insights. AB - The aim of this study was to assess the role of European ambulatory pediatricians in caring for asthmatic children, especially in terms of their therapeutic education. We developed a survey that was observational, declarative, retrospective and anonymous in nature. 436 ambulatory pediatricians in Belgium, France, Germany, Italy, Luxembourg and Slovenia were asked to participate in the survey providing information on three children over 6 years old suffering from persistent asthma, who had been followed for at least 6 months. We considered the pediatricians' profile, and their role in the therapeutic education of children. 277 pediatricians (64%) responded: 81% were primary care pediatricians; 46% participated in networks; 4% had specific training in Therapeutic Patient Education; 69% followed more than 5 asthmatic children per month, and over long periods (7 +/- 4 years). The profiles of 684 children were assessed. Answers diverged concerning the provision of a Personalized Action Plan (60-88%), training the child to measure and interpret his Peak Expiratory Flow (31-99%), and the prescription of pulmonary function tests during the follow-up programme of consultations (62-97%). Answers converged on pediatricians' perception of their role in teaching children about their condition and its treatment (99%), about inhalation techniques (96%), and in improving the children's ability to take preventive measures when faced with risk situations (97%). This study highlights the role of European pediatricians in caring for asthmatic children, and their lack of training in Therapeutic Patient Education. Programmes and tools are required in order to train ambulatory pediatricians in Therapeutic Patient Education, and such resources should be integrated into primary health care, and harmonized at the European level. PMID- 26061154 TI - Disaster Planning: Financing a Burn Disaster, Where Do You Turn and What Are Your Options When Your Hospital Has Been Impacted by a Burn Disaster in the United States? AB - The cost associated with a single burn injured patient can be significant. The American healthcare system functions in part based on traditional market forces which include supply and demand. In addition, there are a variety of payer sources with disparate payment for the same services. Thus, when a group of patients with serious injuries needing complicated care are underinsured or uninsured, or lacks the ability to pay, the financial health of the organization providing the care can be undermined. When a medical disaster with significant numbers of burn injured patients occurs, the financial concerns can be compounded with this singular event. It is critical to be cognizant of the disaster-related financial resources available. Knowing where to turn and what may be available can help assure that the institution caring for this group of high cost patients does not simultaneously take on significant financial risk in the aftermath of the disaster. This article includes national (United States) financial data with respect to burn injury, and focuses on (United States) governmental financial resources during and after a disaster. This review includes identifying and discussing traditional financial support, as well as atypical but established programs where, during a disaster, health care institutions may be eligible for assistance to cover part or all of the associated costs. PMID- 26061155 TI - Heart Rate Variability as a Predictor of Death in Burn Patients. AB - Heart rate variability (HRV), a noninvasive technique used to quantify fluctuations in the interval between normal heart beats (NN), is a predictor of mortality in some patient groups. The aim of this study was to assess HRV in burn trauma patients as a predictor of mortality. The authors prospectively performed 24-hour Holter monitoring on burn patients and collected demographic information, burn injury details, and in-hospital clinical events. Analysis of HRV in the time and frequency domains was performed. A total of 40 burn patients with a mean age of 44 +/- 15 years were enrolled. Mean %TBSA burn was 27 +/- 22% for the overall population and was significantly higher in those who died compared with those who survived (55 +/- 23% vs 19 +/- 13%; P < .0001). There was a statistically significant inverse linear correlation between SD of NN intervals and %TBSA (r = .337, R = 0.113, 95% CI = -0.587 to -0.028, two-tailed P = .034), as well as with ultra low frequency power and %TBSA burn (r = -0.351, R = 0.123, 95% CI = -0.152 to -0.009; P = .027). The receiver-operator characteristic showed the area under the curve for %TBSA as a predictor of death was 0.82 (P < .001), for SDANN was 0.94 (P < .0001), and for ultra low frequency power was 0.96 (P < .0001). Deranged HRV in the early postburn period is a strong predictor of death. PMID- 26061156 TI - In Situ Detection of Integrin Ligands. AB - Integrins are cell surface receptors for cell adhesion. Integrin-mediated cell adhesion regulates various cellular processes, including cell survival, migration, proliferation, and differentiation. In vivo, ligands for integrins are immobilized within extracellular matrices, insoluble sheet-like or fibrous supramolecular complexes that associate with or surround cells. To better understand the molecular basis of integrin-mediated regulation of cellular behavior in vivo, it is of critical importance to collect information regarding the activities as well as spatial distributions of integrin ligands in situ. This unit describes a protocol for detecting the spatial distribution of the complement of integrin ligands in situ by overlaying soluble recombinant integrins. PMID- 26061157 TI - Recombinant messenger RNA technology and its application in cancer immunotherapy, transcript replacement therapies, pluripotent stem cell induction, and beyond. AB - In recent years, the interest in using messenger RNA (mRNA) as a therapeutic means to tackle different diseases has enormously increased. This holds true not only for numerous preclinical studies, but mRNA has also entered the clinic to fight cancer. The advantages of using mRNA compared to DNA were recognized very early on, e.g., the lack of risk for genomic integration, or the expression of the encoded protein in the cytoplasm without the need to cross the nuclear membrane. However, it was generally assumed that mRNA is just not stable enough to give rise to sufficient expression of the encoded protein. Yet, an initially small group of mRNA aficionados could demonstrate that the stability of mRNA and the efficiency, by which the encoded protein is translated, can be significantly increased by selecting the right set of cis-acting structural elements (including the 5'-cap, 5'- and 3'-untranslated regions, poly(A)-tail, and modified building blocks). In parallel, significant advances in RNA packaging and delivery have been made, extending the potential for this molecule. This paved the way for further work to prove mRNA as a promising therapeutic for multiple diseases. Here, we review the developments to optimize mRNA regarding stability, translational efficiency, and immune-modulating properties to enhance its functionality and efficacy as a therapeutic. Furthermore, we summarize the current status of preclinical and clinical studies that use mRNA for cancer immunotherapy, for the expression of functional proteins as so-called transcript (or protein) replacement therapy, as well as for induction of pluripotent stem cells. PMID- 26061158 TI - A selective prostaglandin E2 receptor subtype 2 (EP2) antagonist increases the macrophage-mediated clearance of amyloid-beta plaques. AB - A high-throughput screen resulted in the discovery of benzoxazepine 1, an EP2 antagonist possessing low microsomal stability and potent CYP3A4 inhibition. Modular optimization of lead compound 1 resulted in the discovery of benzoxazepine 52, a molecule with single-digit nM binding affinity for the EP2 receptor and significantly improved microsomal stability. It was devoid of CYP inhibition and was ~4000-fold selective against the other EP receptors. Compound 52 was shown to have good PK properties in CD-1 mice and high CNS permeability in C57Bl/6s mice and Sprague-Dawley rats. In an ex vivo assay, it demonstrated the ability to increase the macrophage-mediated clearance of amyloid-beta plaques from brain slices in a dose-dependent manner. PMID- 26061159 TI - The golden age of transfer hydrogenation. PMID- 26061160 TI - Smoking was associated with poor response to intravenous steroids therapy in Graves' ophthalmopathy. AB - BACKGROUND: Previous studies have shown that smoking is closely related to the occurrence, severity and response to orbital radiation in Graves' ophthalmopathy (GO). The aim of this study was to investigate whether smoking impacts the response to intravenous 4.5 g methylprednisolone therapy in patients with active moderate-to-severe GO. METHODS: Ninety-two individuals with active moderate-to severe GO who were treated with cumulative doses of 4.5 g intravenous methylprednisolone within 3 months were recruited. The patients were grouped as never smokers, active smokers (including smokers and quit smokers) and passive smokers. RESULTS: We observed significantly greater response rate in never smokers compared with active smokers (73.9% vs 29.0%, p=0.001). After adjusting the confounding factors such as age, sex, body mass index, clinical activity score, thyroid-stimulating hormone receptor antibody and the duration of GO, smoking was independently associated with poor intravenous glucocorticoid (GC) response (OR 12.40, 95% CI 1.20 to 128.14, p=0.035). We also found the response rate was significantly higher in never smokers than in quit smokers (73.9% vs 16.7%, p=0.001), while no statistical significance between current smokers and quit smokers (36.8% vs 16.7%, p=0.228). There was a trend of poor response for passive smokers compared with never smokers (64.7% vs 72.2%, p=0.583). CONCLUSIONS: Smoking, even past smoking, was an independent risk factor associated with impaired response to intravenous corticosteroids in patients with GO. Smokers with GO should be given optimised treatment strategy such as higher dose of GC or combined radiation therapy. PMID- 26061161 TI - Effect of mitomycin-C on contraction and migration of human nasal mucosa fibroblasts: implications in dacryocystorhinostomy. AB - AIM: To determine the effect of mitomycin-C (MMC) on the contraction and migration of human nasal mucosal fibroblasts (HNMFs) in vitro in order to identify the least concentration of MMC required to prevent cicatrix development following dacryocystorhinostomy (DCR). METHODS: Primary cultures of HNMFs were established from nasal mucosal tissues of patients undergoing DCR. Myofibroblast transformation of HNMFs was induced using transforming growth factor-beta (TGF beta1) and confirmed by immunostaining for alpha-smooth muscle actin (alpha-SMA). Collagen gel contraction assay was employed to study contraction in the presence or absence of TGF-beta1 (5 and 10 ng/mL) and MMC (0.2 and 0.4 mg/mL). Scratch wound assay was employed to determine the influence of MMC treatment on cell migration. Quantification of gel contraction and wound closure was done using Image J software. RESULTS: alpha-SMA expression increased with TGF-beta1 treatment in a time- and dose-dependent manner indicating myofibroblast transformation of HNMFs. MMC inhibited TGF-beta1- induced collagen gel contraction in a dose-dependent manner (0.4 mg/mL>0.2 mg/mL). Further, there was a decrease in the migration of MMC-treated HNMFs, resulting in delayed wound closure that corroborated with the loss of actin stress fibres. CONCLUSIONS: MMC successfully inhibited TGF-beta1-induced myofibroblast transformation, collagen gel contraction and significantly reduced the migration of HNMFs to cover the wound even at a low concentration of 0.2 mg/mL. This study provides evidence that low concentration and short duration of MMC treatment is efficient in reducing increased contraction and migration of HMNFs in response to injury. PMID- 26061162 TI - Clinical presentation and survival of retinoblastoma in Indian children. AB - OBJECTIVE: To study the clinical presentation and survival among Indian children with retinoblastoma (RB) and to determine factors predictive of poor outcome. METHODS: A retrospective review of children newly diagnosed with RB at a tertiary referral centre was undertaken. Demographic and clinical characteristics and treatment outcomes were studied. RESULTS: A total of 600 patients (unilateral 67.6%, bilateral 32.4%) was studied. 61% was boys. The median age at presentation was 29 months (18 months vs 36 months in bilateral and unilateral cases, respectively, p<0.001). leukocoria was most common (83%), followed by proptosis (17%). Tumours were intraocular in 72.3% and extraocular in 27.7% cases. In the intraocular group, 78% were advanced Group D or E disease. Metastasis to the central nervous system was noted in 15.7% of extraocular cases. A statistically significant difference was seen between intraocular and extraocular groups in the median age (24 months vs 37.5 months, p<0.001) and median lag period (2.5 months vs 7 months, p<0.001). The Kaplan-Meier survival probability was 83%, 73% and 65% at 1 year, 2 years and 5 years, respectively. On univariate analysis, age >2 years (p=0.002), lag period >6 months (p=0.004) and extraocular stage (p<0.001) were associated with poor outcome. On multivariate analysis, extraocular invasion was predictive of low survival (HR 5.04, p<0.001). CONCLUSIONS: Delayed presentation is a matter of concern. Improving awareness about the early signs and creating facilities for diagnosing and treating RB at the primary and secondary levels of healthcare are required to reduce mortality and morbidity, and lead to improved outcomes that are comparable with the developed nations. PMID- 26061163 TI - Peripherin mutations cause a distinct form of recessive Leber congenital amaurosis and dominant phenotypes in asymptomatic parents heterozygous for the mutation. AB - BACKGROUND: Dominant mutations in peripherin (PRPH2) are associated with a spectrum of retinal dystrophy phenotypes, many of which are adult onset and involve the macula. Recessive PRPH2 mutations cause retinal dystrophy associated with prominent maculopathy in adulthood; however, the presenting childhood phenotype has not been defined. We characterise this phenotype. METHODS: Retrospective case series of families harbouring bi-allelic PRPH2 mutations (2010 2014). RESULTS: Three children (two families; assessed at 2 years old) and two adults (one family; assessed at 24 and 35 years old) with homozygous PRPH2 mutations (c.497G>A (p.Cys166Tyr) or c.136C>T (p.Arg46*)) all had infantile nystagmus and decreased vision noted soon after birth and a history of staring at lights during infancy (photophilia). The three children had high hyperopia, a normal or near normal fundus, and non-recordable electroretinographies (ERGs). The two adults had slight myopia, macular and peripheral retinal changes, and non recordable ERGs. All five available carrier parents had macular+/-peripheral retinal findings, although they considered themselves asymptomatic except for one mother who had developed visual loss in one eye at 48 years old and had an associated subfoveal lesion. CONCLUSIONS: Bi-allelic PRPH2 mutations cause a distinct Leber congenital amaurosis phenotype in infancy; affected adults have prominent maculopathy. Heterozygous parents can be asymptomatic but have clinically obvious macular phenotypes with or without peripheral retinal findings, which can be helpful in making the genetic diagnosis in affected children. The difference between the heterozygous and homozygous phenotypes is likely related to gene product dosage effect. PMID- 26061164 TI - In situ characterizing membrane lipid phenotype of breast cancer cells using mass spectrometry profiling. AB - Lipid composition in cell membrane is closely associated with cell characteristics. Here, matrix-assisted laser desorption/ionization- Fourier transform ion cyclotron resonance mass spectrometry was employed to in situ determine membrane components of human mammary epithelial cells (MCF-10 A) and six different breast cancer cell lines (i.e., BT-20, MCF-7, SK-BR-3, MDA-MB-231, MDA-MB-157, and MDA-MB-361) without any lipid extraction and separation. Partial least-square discriminant analysis indicated that changes in the levels of these membrane lipids were closely correlated with the types of breast cell lines. Elevated levels of polyunsaturated lipids in MCF-10 A cells relative to six breast cancer cells and in BT-20 cells relative to other breast cancer cell lines were detected. The Western blotting assays indicated that the expression of five lipogenesis-related enzymes (i.e., fatty acid synthase 1(FASN1), stearoyl-CoA desaturase 1 (SCD1), stearoyl-CoA desaturase 5 (SCD5), choline kinase alpha (CKalpha), and sphingomyelin synthase 1) was associated with the types of the breast cells, and that the SCD1 level in MCF-7 cells was significantly increased relative to other breast cell lines. Our findings suggest that elevated expression levels of FASN1, SCD1, SCD5, and CKalpha may closely correlated with enhanced levels of saturated and monounsaturated lipids in breast cancer cell lines. PMID- 26061165 TI - X-ray Absorption and Emission Study of Dioxygen Activation by a Small-Molecule Manganese Complex. AB - Manganese K-edge X-ray absorption (XAS) and Kbeta emission (XES) spectroscopies were used to investigate the factors contributing to O-O bond activation in a small-molecule system. The recent structural characterization of a metastable peroxo-bridged dimeric Mn(III)2 complex derived from dioxygen has provided the first opportunity to obtain X-ray spectroscopic data on this type of species. Ground state and time-dependent density functional theory calculations have provided further insight into the nature of the transitions in XAS pre-edge and valence-to-core (VtC) XES spectral regions. An experimentally validated electronic structure description has also enabled the determination of structural and electronic factors that govern peroxo bond activation, and have allowed us to propose both a rationale for the metastability of this unique compound, as well as potential future ligand designs which may further promote or inhibit O-O bond scission. Finally, we have explored the potential of VtC XES as an element selective probe of both the coordination mode and degree of activation of peroxomanganese adducts. The comparison of these results to a recent VtC XES study of iron-mediated dintrogen activation helps to illustrate the factors that may determine the success of this spectroscopic method for future studies of small-molecule activation at transition metal sites. PMID- 26061166 TI - Illuminating and inspiring: using television historical drama to cultivate contemporary nursing values and critical thinking. AB - As the world prepares to commemorate the centenary of the First World War, it is timely to discuss meaningful learning activities that students of nursing could be engaged in to encourage them to reflect on the nurse's role then and now. Several films and television series about the war and featuring nursing have already been aired. No doubt there will be many more stories to come. Such stories have the potential to do more than eulogise nursing for students and practitioners. Stories, such as The crimson field, have potential to stimulate serious contemplation about values and cultural practices that have remained constant or have changed and to assist students to develop and articulate values that will be fitting for contemporary practice. Recently, excerpts from the series were examined with a group of nursing students and key learnings were found. These are shared in this paper for the benefit of educators planning to utilise public discourse as triggers to engage nursing students in discussions about nursing values, nursing history and representations of the profession. PMID- 26061168 TI - Gender and ethnic differences in incidence and survival of lymphoid neoplasm subtypes in an Asian population: Secular trends of a population-based cancer registry from 1998 to 2012. AB - Descriptive epidemiology on incidence and survival by lymphoid neoplasm (LN) subtypes using the 2008 World Health Organisation (WHO) classification remained limited in Asia. The aim of this study was to evaluate whether gender and ethnic differences in incidence and survival of LN subtypes existed using the Singapore Cancer Registry (SCR) from 1998 to 2012. We derived age standardised incidence rates (ASIRs) by the direct standardisation method and 5-year relative survival (RSR) by the Ederer II method and period approach. Five-year observed survival (OS) was obtained for each ethnicity. Malays had the highest ASIR of total LNs among the three ethnicities for each time period. The largest increase in 5-year RSR subtypes was follicular lymphoma from 43.8% in 1998-2002 to 82.3% in 2008 2012; followed by chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) from 48.1% in 1998-2002 to 77.9% in 2008-2012. Although males had higher incidence than females in each time period, females had greater 5-year RSR for follicular lymphoma (89.8% in 2008-2012 for females vs. 76.6% in 2008-2012 for males) and CLL/SLL (78.7% in 2008-2012 for females vs. 76.7% in 2008-2012 for males). All three ethnicities experienced an overall increase in 5-year OS for mature B-cell lymphoma, with Indians experiencing the greatest increase (37.1% in 1998-2002 to 61.1% in 2008-2012), followed by Malays (30.8% in 1998-2002 to 48.7% in 2008-2012) and then Chinese (36.4% in 1998-2002 to 51.3% in 2008-2012). Our study demonstrated that improved mature B-cell lymphoma survival was not only observed in the West, but also in Singapore. PMID- 26061167 TI - Zebrafish Bone and General Physiology Are Differently Affected by Hormones or Changes in Gravity. AB - Teleost fish such as zebrafish (Danio rerio) are increasingly used for physiological, genetic and developmental studies. Our understanding of the physiological consequences of altered gravity in an entire organism is still incomplete. We used altered gravity and drug treatment experiments to evaluate their effects specifically on bone formation and more generally on whole genome gene expression. By combining morphometric tools with an objective scoring system for the state of development for each element in the head skeleton and specific gene expression analysis, we confirmed and characterized in detail the decrease or increase of bone formation caused by a 5 day treatment (from 5dpf to 10 dpf) of, respectively parathyroid hormone (PTH) or vitamin D3 (VitD3). Microarray transcriptome analysis after 24 hours treatment reveals a general effect on physiology upon VitD3 treatment, while PTH causes more specifically developmental effects. Hypergravity (3g from 5dpf to 9 dpf) exposure results in a significantly larger head and a significant increase in bone formation for a subset of the cranial bones. Gene expression analysis after 24 hrs at 3g revealed differential expression of genes involved in the development and function of the skeletal, muscular, nervous, endocrine and cardiovascular systems. Finally, we propose a novel type of experimental approach, the "Reduced Gravity Paradigm", by keeping the developing larvae at 3g hypergravity for the first 5 days before returning them to 1g for one additional day. 5 days exposure to 3g during these early stages also caused increased bone formation, while gene expression analysis revealed a central network of regulatory genes (hes5, sox10, lgals3bp, egr1, edn1, fos, fosb, klf2, gadd45ba and socs3a) whose expression was consistently affected by the transition from hyper- to normal gravity. PMID- 26061169 TI - Mechanisms of Toxicity of Ag Nanoparticles in Comparison to Bulk and Ionic Ag on Mussel Hemocytes and Gill Cells. AB - Silver nanoparticles (Ag NPs) are increasingly used in many products and are expected to end up in the aquatic environment. Mussels have been proposed as marine model species to evaluate NP toxicity in vitro. The objective of this work was to assess the mechanisms of toxicity of Ag NPs on mussel hemocytes and gill cells, in comparison to ionic and bulk Ag. Firstly, cytotoxicity of commercial and maltose stabilized Ag NPs was screened in parallel with the ionic and bulk forms at a wide range of concentrations in isolated mussel cells using cell viability assays. Toxicity of maltose alone was also tested. LC50 values were calculated and the most toxic Ag NPs tested were selected for a second step where sublethal concentrations of each Ag form were tested using a wide array of mechanistic tests in both cell types. Maltose-stabilized Ag NPs showed size dependent cytotoxicity, smaller (20 nm) NPs being more toxic than larger (40 and 100 nm) NPs. Maltose alone provoked minor effects on cell viability. Ionic Ag was the most cytotoxic Ag form tested whereas bulk Ag showed similar cytotoxicity to the commercial Ag NPs. Main mechanisms of action of Ag NPs involved oxidative stress and genotoxicity in the two cell types, activation of lysosomal AcP activity, disruption of actin cytoskeleton and stimulation of phagocytosis in hemocytes and increase of MXR transport activity and inhibition of Na-K-ATPase in gill cells. Similar effects were observed after exposure to ionic and bulk Ag in the two cell types, although generally effects were more marked for the ionic form. In conclusion, results suggest that most observed responses were due at least in part to dissolved Ag. PMID- 26061170 TI - Evidence for a Shared Etiological Mechanism of Psychotic Symptoms and Obsessive Compulsive Symptoms in Patients with Psychotic Disorders and Their Siblings. AB - The prevalence of obsessive-compulsive disorder in subjects with psychotic disorder is much higher than in the general population. The higher than chance co occurrence has also been demonstrated at the level of subclinical expression of both phenotypes. Both extended phenotypes have been shown to cluster in families. However, little is known about the origins of their elevated co-occurrence. In the present study, evidence for a shared etiological mechanism was investigated in 3 samples with decreasing levels of familial psychosis liability: 987 patients, 973 of their unaffected siblings and 566 healthy controls. The association between the obsessive-compulsive phenotype and the psychosis phenotype c.q. psychosis liability was investigated. First, the association was assessed between (subclinical) obsessive-compulsive symptoms and psychosis liability. Second, in a cross-sib cross-trait analysis, it was examined whether (subclinical) obsessive-compulsive symptoms in the patient were associated with (subclinical) psychotic symptoms in the related unaffected sibling. Evidence was found for both associations, which is compatible with a partially shared etiological pathway underlying obsessive-compulsive and psychotic disorder. This is the first study that used a cross-sib cross-trait design in patients and unaffected siblings, thus circumventing confounding by disease-related factors present in clinical samples. PMID- 26061171 TI - Glucocorticoid Stress Responses of Reintroduced Tigers in Relation to Anthropogenic Disturbance in Sariska Tiger Reserve in India. AB - Tiger (Panthera tigris), an endangered species, is under severe threat from poaching, habitat loss, prey depletion and habitat disturbance. Such factors have been reported causing local extermination of tiger populations including in one of the most important reserves in India, namely Sariska Tiger Reserve (STR) in northwestern India. Consequently, tigers were reintroduced in STR between 2008 and 2010, but inadequate breeding success was observed over the years, thus invoking an investigation to ascertain physiological correlates. In the present study, we report glucocorticoid stress responses of the reintroduced tigers in relation to anthropogenic disturbance in the STR from 2011 to 2013. We found anthropogenic disturbance such as encounter rates of livestock and humans, distance to roads and efforts to kill domestic livestock associated with an elevation in fecal glucocorticoid metabolite (fGCM) concentrations in the monitored tigers. In this regard, female tigers seem more sensitive to such disturbance than males. It was possible to discern that tiger's fGCM levels were significantly positively related to the time spent in disturbed areas. Resulting management recommendations include relocation of villages from core areas and restriction of all anthropogenic activities in the entire STR. PMID- 26061172 TI - Environmentally responsive self-assembly of mixed poly(tert-butyl acrylate) polystyrene brush-grafted silica nanoparticles in selective polymer matrices. AB - Environmentally responsive self-assembly of nearly symmetric mixed poly(tert butyl acrylate) (PtBA, 22.2 kDa)/polystyrene (PS, 23.4 kDa) brushes grafted onto 67 nm silica nanoparticles in selective homopolymer matrices [PtBA for the grafted PtBA chains and poly(cyclohexyl methacrylate) (PCHMA) for the grafted PS chains] was investigated using both conventional transmission electron microscopy (TEM) and electron tomography (i.e., 3D TEM). A variety of self-assembled phase morphologies were observed for the mixed brushes in selective polymer matrices with different molecular weights, and these can be explained by entropy-driven wet- and dry-brush theories. In a low molecular weight selective matrix, the wet brush regime was formed with the miscible chains stretching out and the immiscible chains collapsing into isolated domains. In contrast, when the molecular weight of the selective matrix was higher than that of the compatible grafted polymer chains, the dry-brush regime was formed with the mixed brushes exhibiting the unperturbed morphology. In addition to the molecular weight, the size of nanoparticles (or the substrate curvature) was also observed to play an important role. For small particles (core size less than 50 nm), the wet brush like morphology with a surface-tethered micellar structure was observed. Finally, the wet- and dry-brush regimes also significantly affected the dispersion of mixed brush particles in selective polymer matrices. PMID- 26061174 TI - Combination therapy with ruxolitinib plus intensive treatment strategy is feasible in patients with blast-phase myeloproliferative neoplasms. PMID- 26061173 TI - Azotobacter Genomes: The Genome of Azotobacter chroococcum NCIMB 8003 (ATCC 4412). AB - The genome of the soil-dwelling heterotrophic N2-fixing Gram-negative bacterium Azotobacter chroococcum NCIMB 8003 (ATCC 4412) (Ac-8003) has been determined. It consists of 7 circular replicons totalling 5,192,291 bp comprising a circular chromosome of 4,591,803 bp and six plasmids pAcX50a, b, c, d, e, f of 10,435 bp, 13,852, 62,783, 69,713, 132,724, and 311,724 bp respectively. The chromosome has a G+C content of 66.27% and the six plasmids have G+C contents of 58.1, 55.3, 56.7, 59.2, 61.9, and 62.6% respectively. The methylome has also been determined and 5 methylation motifs have been identified. The genome also contains a very high number of transposase/inactivated transposase genes from at least 12 of the 17 recognised insertion sequence families. The Ac-8003 genome has been compared with that of Azotobacter vinelandii ATCC BAA-1303 (Av-DJ), a derivative of strain O, the only other member of the Azotobacteraceae determined so far which has a single chromosome of 5,365,318 bp and no plasmids. The chromosomes show significant stretches of synteny throughout but also reveal a history of many deletion/insertion events. The Ac-8003 genome encodes 4628 predicted protein encoding genes of which 568 (12.2%) are plasmid borne. 3048 (65%) of these show > 85% identity to the 5050 protein-encoding genes identified in Av-DJ, and of these 99 are plasmid-borne. The core biosynthetic and metabolic pathways and macromolecular architectures and machineries of these organisms appear largely conserved including genes for CO-dehydrogenase, formate dehydrogenase and a soluble NiFe-hydrogenase. The genetic bases for many of the detailed phenotypic differences reported for these organisms have also been identified. Also many other potential phenotypic differences have been uncovered. Properties endowed by the plasmids are described including the presence of an entire aerobic corrin synthesis pathway in pAcX50f and the presence of genes for retro-conjugation in pAcX50c. All these findings are related to the potentially different environmental niches from which these organisms were isolated and to emerging theories about how microbes contribute to their communities. PMID- 26061175 TI - Is Preoperative Vitamin D Deficiency a Risk Factor for Postoperative Symptomatic Hypocalcemia in Thyroid Cancer Patients Undergoing Total Thyroidectomy Plus Central Compartment Neck Dissection? AB - BACKGROUND: Although some studies have reported that preoperative vitamin D deficiency (VDD) is a risk factor for hypocalcemia after total thyroidectomy (TT) in patients with nontoxic multinodular goiter or Graves' disease, the association between VDD and postoperative hypocalcemia in thyroid cancer patients undergoing TT plus central compartment neck dissection (CCND) remains unclear. This study evaluated whether preoperative VDD was associated with postoperative symptomatic hypocalcemia. MATERIALS AND METHODS: Data were collected prospectively between September 2012 and May 2013. A total of 267 consecutive thyroid cancer patients who underwent TT with CCND were analyzed. Patients were divided into two groups- VDD or non-VDD--by preoperative vitamin D level of <10 or >=10 ng/mL. Symptomatic hypocalcemia was defined as serum calcium <8.2 mg/dL and symptoms or signs of hypocalcemia. The rates of postoperative symptomatic hypocalcemia and clinicopathological features were compared between the two patient groups. RESULTS: The rate of postoperative symptomatic hypocalcemia was higher in the VDD group than in the non-VDD group (43.8% vs. 30.4%, p=0.043). By logistic regression analysis, predictive factors for postoperative symptomatic hypocalcemia included a preoperative vitamin D level of <10 ng/mL (p=0.007; odds ratio=3.00). In patients who had postoperative intact parathyroid hormone (iPTH) levels <15 pg/mL, symptomatic hypocalcemia was more common in the VDD group than in the non-VDD group (77.5% vs. 53.2%, p=0.008). The findings show that a preoperative vitamin D threshold level of >20 ng/mL reduced the risk of symptomatic hypocalcemia by 72% when compared with patients with VDD (p=0.003). CONCLUSION: VDD is significantly associated with postoperative symptomatic hypocalcemia in thyroid cancer patients undergoing TT plus CCND. VDD was predictive for symptomatic hypocalcemia when patients had postoperative serum iPTH levels <15 pg/mL. Thus, preoperative supplementation with oral vitamin D should be considered to minimize postoperative symptomatic hypocalcemia. PMID- 26061176 TI - Dynamic Magnetic Responsive Wall Array with Droplet Shedding-off Properties. AB - Directional control of droplets on a surface is an important issue for tasks of long-range liquid-transport, self-cleaning and water repellency. However, it is still challenging to control the structure motions in orientations so as to control the shedding-off of droplets. Herein, we report a novel dynamic magnetic responsive wall (DMRW) array on PDMS (polydimethylsiloxane)-based surface. The walls can easily tilt through the effect of the external magnet because of the magnetic material in the DMRW. The droplets can be shed off directionally on the surface. Particularly, with the shape recovery and flexible properties, it achieves simultaneous control of the tilt angles (0-60 degrees ) of DMRW for shedding-off of droplets with different volumes (1-15 MUL) under magnetic action on DMRW. The mechanism of droplet shedding-off on DMRW is elucidated by theory of interfaces. It offers an insight into design of dynamic interface for water repellency. This strategy realizes the preparation of multifunctional, tunable and directional drive functions. PMID- 26061178 TI - Corrigendum. PMID- 26061177 TI - Alternatively Spliced Homologous Exons Have Ancient Origins and Are Highly Expressed at the Protein Level. AB - Alternative splicing of messenger RNA can generate a wide variety of mature RNA transcripts, and these transcripts may produce protein isoforms with diverse cellular functions. While there is much supporting evidence for the expression of alternative transcripts, the same is not true for the alternatively spliced protein products. Large-scale mass spectroscopy experiments have identified evidence of alternative splicing at the protein level, but with conflicting results. Here we carried out a rigorous analysis of the peptide evidence from eight large-scale proteomics experiments to assess the scale of alternative splicing that is detectable by high-resolution mass spectroscopy. We find fewer splice events than would be expected: we identified peptides for almost 64% of human protein coding genes, but detected just 282 splice events. This data suggests that most genes have a single dominant isoform at the protein level. Many of the alternative isoforms that we could identify were only subtly different from the main splice isoform. Very few of the splice events identified at the protein level disrupted functional domains, in stark contrast to the two thirds of splice events annotated in the human genome that would lead to the loss or damage of functional domains. The most striking result was that more than 20% of the splice isoforms we identified were generated by substituting one homologous exon for another. This is significantly more than would be expected from the frequency of these events in the genome. These homologous exon substitution events were remarkably conserved--all the homologous exons we identified evolved over 460 million years ago--and eight of the fourteen tissue specific splice isoforms we identified were generated from homologous exons. The combination of proteomics evidence, ancient origin and tissue-specific splicing indicates that isoforms generated from homologous exons may have important cellular roles. PMID- 26061180 TI - Mild Mn(OAc)3-Mediated Aerobic Oxidative Decarboxylative Coupling of Arylboronic Acids and Arylpropiolic Acids: Direct Access to Diaryl 1,2-Diketones. AB - A simple and efficient method for the synthesis of diaryl 1,2-diketones has been developed. The reaction represents the first example of diaryl 1,2-diketones that are synthesized directly from arylboronic acids and arylpropiolic acids by a radical pathway in moderate to good yields. This reaction proceeds under mild reaction conditions and with good tolerance of a variety of functional groups. Preliminary mechanistic studies were conducted. PMID- 26061179 TI - High Incidences of Invasive Fungal Infections in Acute Myeloid Leukemia Patients Receiving Induction Chemotherapy without Systemic Antifungal Prophylaxis: A Prospective Observational Study in Taiwan. AB - Invasive fungal infections (IFIs) is an important complication for acute myeloid leukemia (AML) patients receiving induction chemotherapy. However, the epidemiological information is not clear in Southeastern Asia, an area of potential high incidences of IFIs. To clarify it, we enrolled 298 non-M3 adult AML patients receiving induction chemotherapy without systemic anti-fungal prophylaxis from Jan 2004 to Dec 2009, when we applied a prospective diagnostic and treatment algorithm for IFIs. Their demographic parameters, IFI characters, and treatment outcome were collected for analysis. The median age of these patients was 51 years. Standard induction chemotherapy was used for 246 (82.6%) patients, and 66.8% of patients achieved complete remission (CR) or partial remission. The incidence of all-category IFIs was 34.6% (5.7% proven IFIs, 5.0% probable IFIs and 23.8% possible IFIs). Candida tropicalis was the leading pathogen among yeast, and lower respiratory tract was the most common site for IFIs (75.4%, 80/106). Standard induction chemotherapy and failure to CR were identified as risk factors for IFIs. The presence of IFI in induction independently predicted worse survival (hazard ratio 1.536 (1.100-2.141), p value = 0.012). Even in those who survived from the initial IFI insults after 3 months, the presence of IFIs in induction still predicted a poor long-term survival. This study confirms high incidences of IFIs in Southeastern Asia, and illustrates potential risk factors; poor short-term and long-term outcomes are also demonstrated. This epidemiological information will provide useful perspectives for anti-fungal prophylaxis and treatment for AML patients during induction, so that best chances of cure and survival can be provided. PMID- 26061182 TI - Effects of Row-Type, Row-Spacing, Seeding Rate, Soil-Type, and Cultivar Differences on Soybean Seed Nutrition under US Mississippi Delta Conditions. AB - The new Early Soybean Production System (ESPS), developed in the Midsouth USA, including the Mississippi delta, resulted in higher yield under irrigated and non irrigated conditions. However, information on the effects of the agricultural practices such as row-type (RT: twin- vs. single-row), row-spacing, (RS), seeding rate (SR), soil-type (ST) on seed nutrition under the ESPS environment in the Mississippi delta is very limited. Our previous research in the Mississippi delta showed these agricultural practices altered seed nutrients in one cultivar only. However, whether these effects on seed nutrients will be exhibited by other soybean cultivars with earlier and later maturities across multiple years are not yet known. Therefore, the objective of this research was to evaluate the effects of agricultural practices and cultivar (Cv) differences on seed nutrition in clay and sandy soils under ESPS environment of high heat and drought. Two field experiments were conducted; one experiment was conducted in 2009 and 2010, and the other in 2008, 2009, and 2010 under irrigated conditions. Soybean were grown on 102 cm single-rows and on 25 cm twin-rows with 102 cm centers at seeding rates of 20, 30, 40, and 50 seeds m(-2). Two soybean cultivars (94M80 with earlier maturity; and GP 533 with later maturity) were used. Results showed that increasing seeding rate resulted in increases of protein, sucrose, glucose, raffinose, B, and P concentrations on both single- and twin-rows. However, this increase became either constant or declined at the higher rates (40 and 50 seeds m(-2)). Protein and linolenic acid concentrations were higher in GP 533 than in 94M80 on both row-types, but oil and oleic acid concentrations were in 94M80 than GP 533. Generally, cultivar GP 533 accumulated more seed constituents in seeds than 94M80. In 2010, there were no clear responses of seed nutrients to SR increase in both cultivars, perhaps due to drier year and high heat in 2010. It is concluded that RT and SR can alter seed nutrition under clay and sandy soils, especially under high heat and drought conditions as in the Mississippi delta. PMID- 26061181 TI - 1,25 Dihydroxyvitamin D3 Inhibits TGFbeta1-Mediated Primary Human Cardiac Myofibroblast Activation. AB - AIMS: Epidemiological and interventional studies have suggested a protective role for vitamin D in cardiovascular disease, and basic research has implicated vitamin D as a potential inhibitor of fibrosis in a number of organ systems; yet little is known regarding direct effects of vitamin D on human cardiac cells. Given the critical role of fibrotic responses in end stage cardiac disease, we examined the effect of active vitamin D treatment on fibrotic responses in primary human adult ventricular cardiac fibroblasts (HCF-av), and investigated the relationship between circulating vitamin D (25(OH)D3) and cardiac fibrosis in human myocardial samples. METHODS AND RESULTS: Interstitial cardiac fibrosis in end stage HF was evaluated by image analysis of picrosirius red stained myocardial sections. Serum 25(OH)D3 levels were assayed using mass spectrometry. Commercially available HCF-av were treated with transforming growth factor (TGF)beta1 to induce activation, in the presence or absence of active vitamin D (1,25(OH)2D3). Functional responses of fibroblasts were analyzed by in vitro collagen gel contraction assay. 1,25(OH)2D3 treatment significantly inhibited TGFbeta1-mediated cell contraction, and confocal imaging demonstrated reduced stress fiber formation in the presence of 1,25(OH)2D3. Treatment with 1,25(OH)2D3 reduced alpha-smooth muscle actin expression to control levels and inhibited SMAD2 phosphorylation. CONCLUSIONS: Our results demonstrate that active vitamin D can prevent TGFbeta1-mediated biochemical and functional pro-fibrotic changes in human primary cardiac fibroblasts. An inverse relationship between vitamin D status and cardiac fibrosis in end stage heart failure was observed. Collectively, our data support an inhibitory role for vitamin D in cardiac fibrosis. PMID- 26061183 TI - Chemoenzymatic Conjugation of Toxic Payloads to the Globally Conserved N-Glycan of Native mAbs Provides Homogeneous and Highly Efficacious Antibody-Drug Conjugates. AB - A robust, generally applicable, nongenetic technology is presented to convert monoclonal antibodies into stable and homogeneous ADCs. Starting from a native (nonengineered) mAb, a chemoenzymatic protocol allows for the highly controlled attachment of any given payload to the N-glycan residing at asparagine-297, based on a two-stage process: first, enzymatic remodeling (trimming and tagging with azide), followed by ligation of the payload based on copper-free click chemistry. The technology, termed GlycoConnect, is applicable to any IgG isotype irrespective of glycosylation profile. Application to trastuzumab and maytansine, both components of the marketed ADC Kadcyla, demonstrate a favorable in vitro and in vivo efficacy for GlycoConnect ADC. Moreover, the superiority of the native glycan as attachment site was demonstrated by in vivo comparison to a range of trastuzumab-based glycosylation mutants. A side-by-side comparison of the copper free click probes bicyclononyne (BCN) and a dibenzoannulated cyclooctyne (DBCO) showed a surprising difference in conjugation efficiency in favor of BCN, which could be even further enhanced by introduction of electron-withdrawing fluoride substitutions onto the azide. The resulting mAb-conjugates were in all cases found to be highly stable, which in combination with the demonstrated efficacy warrants ADCs with a superior therapeutic index. PMID- 26061185 TI - Organic Carbon Burial in Lakes and Reservoirs of the Conterminous United States. AB - Organic carbon (OC) burial in lacustrine sediments represents an important sink in the global carbon cycle; however, large-scale OC burial rates are poorly constrained, primarily because of the sparseness of available data sets. Here we present an analysis of OC burial rates in water bodies of the conterminous U.S. (CONUS) that takes advantage of recently developed national-scale data sets on reservoir sedimentation rates, sediment OC concentrations, lake OC burial rates, and water body distributions. We relate these data to basin characteristics and land use in a geostatistical analysis to develop an empirical model of OC burial in water bodies of the CONUS. Our results indicate that CONUS water bodies sequester 20.8 (95% CI: 9.4-65.8) Tg C yr(-1), and spatial patterns in OC burial are strongly influenced by water body type, size, and abundance; land use; and soil and vegetation characteristics in surrounding areas. Carbon burial is greatest in the central and southeastern regions of the CONUS, where cultivation and an abundance of small water bodies enhance accumulation of sediment and OC in aquatic environments. PMID- 26061184 TI - Rapamycin Enhances the Anti-Cancer Effect of Dasatinib by Suppressing Src/PI3K/mTOR Pathway in NSCLC Cells. AB - Src and the mammalian target of rapamycin (mTOR) signaling are commonly activated in non-small cell lung cancer (NSCLC) and hence potential targets for chemotherapy. Although the combined use of Src inhibitor Dasatinib with other chemotherapeutic agents has shown superior efficacy for cancer treatment, the mechanisms that lead to enhanced sensitivity of Dasatinib are not completely understood. In this study, we found that Rapamycin dramatically enhanced Dasatinib-induced cell growth inhibition and cell cycle G1 arrest in human lung adenocarcinoma A549 cells without affecting apoptosis. The synergistic effects were consistently correlated with the up-regulation of cyclin-dependent kinases inhibitor proteins, including p16, p19, p21, and p27, as well as the repression of Cdk4 expression and nuclear translocation. Mechanistic investigations demonstrated that FoxO1/FoxO3a and p70S6K/4E-BP1, the molecules at downstream of Src-PI3K-Akt and mTOR signaling, were significantly suppressed by the combined use of Dasatinib and Rapamycin. Restraining Src and mTOR with small interfering RNA in A549 cells further confirmed that the Src/PI3K/mTOR Pathway played a crucial role in enhancing the anticancer effect of Dasatinib. In addition, this finding was also validated by a series of assays using another two NSCLC cell lines, NCI-H1706 and NCI-H460. Conclusively, our results suggested that the combinatory application of Src and mTOR inhibitors might be a promising therapeutic strategy for NSCLC treatment. PMID- 26061186 TI - Elite Athletes Refine Their Internal Clocks: A Bayesian Analysis. AB - This paper carries out a full Bayesian analysis for a data set examined in Chen & Cesari (2015). These data were collected for assessing people's ability in evaluating short intervals of time. Chen & Cesari (2015) showed evidence of the existence of two independent internal clocks for evaluating time intervals below and above the second. We reexamine here, the same question by performing a complete statistical Bayesian analysis of the data. The Bayesian approach can be used to analyze these data thanks to the specific trial design. Data were obtained from evaluation of time ranges from two groups of individuals. More specifically, information gathered from a nontrained group (considered as baseline) allowed us to build a prior distribution for the parameter(s) of interest, and data from the trained group determined the likelihood function. This paper's main goals are (i) showing how the Bayesian inferential method can be used in statistical analyses and (ii) showing that the Bayesian methodology gives additional support to the findings presented in Chen & Cesari (2015) regarding the existence of two internal clocks in assessing duration of time intervals. PMID- 26061187 TI - Micro-CT Study of Rhynchonkos stovalli (Lepospondyli, Recumbirostra), with Description of Two New Genera. AB - The Early Permian recumbirostran lepospondyl Rhynchonkos stovalli has been identified as a possible close relative of caecilians due to general similarities in skull shape as well as similar robustness of the braincase, a hypothesis that implies the polyphyly of extant lissamphibians. In order to better assess this phylogenetic hypothesis, we studied the morphology of the holotype and three specimens previously attributed to R. stovalli. With the use of micro-computed x ray tomography (MUCT) we are able to completely describe the external and internal cranial morphology of these specimens, dramatically revising our knowledge of R. stovalli and recognizing two new taxa, Aletrimyti gaskillae gen et sp. n. and Dvellacanus carrolli gen et sp. n. The braincases of R. stovalli, A. gaskillae, and D. carrolli are described in detail, demonstrating detailed braincase morphology and new information on the recumbirostran supraoccipital bone. All three taxa show fossorial adaptations in the braincase, sutural articulations of skull roof bones, and in the lower jaw, but variation in cranial morphology between these three taxa may reflect different modes of head-first burrowing behaviors and capabilities. We revisit the homology of the supraoccipital, median anterior bone, and temporal bone of recumbirostrans, and discuss implications of alternate interpretations of the homology of these elements. Finally, we evaluate the characteristics previously used to unite Rhynchonkos stovalli with caecilians in light of these new data. These proposed similarities are more ambiguous than previous descriptions suggest, and result from the composite nature of previous descriptions, ambiguities in external morphology, and functional convergence between recumbirostrans and caecilians for head-first burrowing. PMID- 26061188 TI - Incorporating advanced language models into the P300 speller using particle filtering. AB - OBJECTIVE: The P300 speller is a common brain-computer interface (BCI) application designed to communicate language by detecting event related potentials in a subject's electroencephalogram signal. Information about the structure of natural language can be valuable for BCI communication, but attempts to use this information have thus far been limited to rudimentary n-gram models. While more sophisticated language models are prevalent in natural language processing literature, current BCI analysis methods based on dynamic programming cannot handle their complexity. APPROACH: Sampling methods can overcome this complexity by estimating the posterior distribution without searching the entire state space of the model. In this study, we implement sequential importance resampling, a commonly used particle filtering (PF) algorithm, to integrate a probabilistic automaton language model. MAIN RESULT: This method was first evaluated offline on a dataset of 15 healthy subjects, which showed significant increases in speed and accuracy when compared to standard classification methods as well as a recently published approach using a hidden Markov model (HMM). An online pilot study verified these results as the average speed and accuracy achieved using the PF method was significantly higher than that using the HMM method. SIGNIFICANCE: These findings strongly support the integration of domain specific knowledge into BCI classification to improve system performance. PMID- 26061189 TI - Transient visual responses reset the phase of low-frequency oscillations in the skeletomotor periphery. AB - We recorded muscle activity from an upper limb muscle while human subjects reached towards peripheral targets. We tested the hypothesis that the transient visual response sweeps not only through the central nervous system, but also through the peripheral nervous system. Like the transient visual response in the central nervous system, stimulus-locked muscle responses (< 100 ms) were sensitive to stimulus contrast, and were temporally and spatially dissociable from voluntary orienting activity. Also, the arrival of visual responses reduced the variability of muscle activity by resetting the phase of ongoing low frequency oscillations. This latter finding critically extends the emerging evidence that the feedforward visual sweep reduces neural variability via phase resetting. We conclude that, when sensory information is relevant to a particular effector, detailed information about the sensorimotor transformation, even from the earliest stages, is found in the peripheral nervous system. PMID- 26061190 TI - Pneumonia Prevention during a Humanitarian Emergency: Cost-effectiveness of Haemophilus Influenzae Type B Conjugate Vaccine and Pneumococcal Conjugate Vaccine in Somalia. AB - BACKGROUND: Pneumonia is a leading cause of death among children less than five years old during humanitarian emergencies. Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae are the leading causes of bacterial pneumonia. Vaccines for both of these pathogens are available to prevent pneumonia. Problem This study describes an economic analysis from a publicly funded health care system perspective performed on a birth cohort in Somalia, a country that has experienced a protracted humanitarian emergency. METHODS: An impact and cost effectiveness analysis was performed comparing: no vaccine, Hib vaccine only, pneumococcal conjugate vaccine 10 (PCV10) only, and both together administered through supplemental immunization activities (SIAs). The main summary measure was the incremental cost per disability-adjusted life-years (DALYs) averted. One-way sensitivity analysis was conducted for uncertainty in parameter values. RESULTS: Each SIA would avert a substantial number of cases and deaths. Compared with no vaccine, the DALYs averted by two SIAs for two doses of Hib vaccine was US $202.93 (lower and upper limits: $121.80-$623.52), two doses of PCV10 was US $161.51 ($107.24-$227.21), and two doses of both vaccines was US $152.42 ($101.20 $214.42). Variables that influenced the cost-effectiveness for each strategy most substantially were vaccine effectiveness, case fatality rates (CFRs), and disease burden. CONCLUSIONS: The World Health Organization (WHO) defines a cost-effective intervention as costing one to three times the per capita gross domestic product (GDP; in 2011, for Somalia=US $112). Based on the presented model, Hib vaccine alone, PCV10 alone, or Hib vaccine and PCV10 given together in SIAs are cost effective interventions in Somalia. The WHO/Strategic Advisory Group of Experts decision-making factors for vaccine deployment appear to have all been met: the disease burden is large, the vaccine-related risk is low, prevention in this setting is more feasible than treatment, the vaccine duration probably is sufficient for the vulnerable period of the child's life, cost is reasonable, and herd immunity is possible. PMID- 26061191 TI - Encoded Library Synthesis Using Chemical Ligation and the Discovery of sEH Inhibitors from a 334-Million Member Library. AB - A chemical ligation method for construction of DNA-encoded small-molecule libraries has been developed. Taking advantage of the ability of the Klenow fragment of DNA polymerase to accept templates with triazole linkages in place of phosphodiesters, we have designed a strategy for chemically ligating oligonucleotide tags using cycloaddition chemistry. We have utilized this strategy in the construction and selection of a small molecule library, and successfully identified inhibitors of the enzyme soluble epoxide hydrolase. PMID- 26061192 TI - 5-Arylaminouracil Derivatives: New Inhibitors of Mycobacterium tuberculosis. AB - Three series of 5-arylaminouracil derivatives, including 5-(phenylamino)uracils, 1-(4'-hydroxy-2'-cyclopenten-1'-yl)-5-(phenylamino)uracils, and 1,3-di-(4' hydroxy-2'-cyclopenten-1'-yl)-5-(phenylamino)uracils, were synthesized and screened for potential antimicrobial activity. Most of compounds had a negative effect on the growth of the Mycobacterium tuberculosis H37Rv strain, with 100% inhibition observed at concentrations between 5 and 40 MUg/mL. Of those, 1-(4' hydroxy-2'-cyclopenten-1'-yl)-3-(4'''-hydroxy-2'''-cyclopenten-1'''-yl)-5-(4" butyloxyphenylamino)uracil proved to be the most active among tested compounds against the M. tuberculosis multidrug-resistant strain MS-115 (MIC90 5 MUg/mL). In addition, the thymidylate kinase of M. tuberculosis was evaluated as a possible enzymatic target. PMID- 26061194 TI - User Involvement in Social Work and Education--A Matter of Participation? AB - The increase in user involvement in social work practice and education can be explained by incentives toward an evidence-based practice, such as those offered by legislation and from the user movement, and those related to professional development. Still, the clients' involvement in research and practice is highlighted as a gap that needs to be filled. The aim of the author in this article is to study the presence of user involvement in social work practice, research, and education, and the level of influence of users and carers within these activities. The results reflect an expanding user involvement in social work practice. Still, projects of user involvement in social work practice are often developed on an ad hoc and inconsistent basis, and knowledge about the effects of these efforts is still limited. User involvement is not to be understood as something that is self-evidently good. On the contrary, the results present a rather complex concept that is bound up with changing and contested understandings of the role of the social worker, academia, and the users themselves. PMID- 26061193 TI - Analysis of the giant genomes of Fritillaria (Liliaceae) indicates that a lack of DNA removal characterizes extreme expansions in genome size. AB - Plants exhibit an extraordinary range of genome sizes, varying by > 2000-fold between the smallest and largest recorded values. In the absence of polyploidy, changes in the amount of repetitive DNA (transposable elements and tandem repeats) are primarily responsible for genome size differences between species. However, there is ongoing debate regarding the relative importance of amplification of repetitive DNA versus its deletion in governing genome size. Using data from 454 sequencing, we analysed the most repetitive fraction of some of the largest known genomes for diploid plant species, from members of Fritillaria. We revealed that genomic expansion has not resulted from the recent massive amplification of just a handful of repeat families, as shown in species with smaller genomes. Instead, the bulk of these immense genomes is composed of highly heterogeneous, relatively low-abundance repeat-derived DNA, supporting a scenario where amplified repeats continually accumulate due to infrequent DNA removal. Our results indicate that a lack of deletion and low turnover of repetitive DNA are major contributors to the evolution of extremely large genomes and show that their size cannot simply be accounted for by the activity of a small number of high-abundance repeat families. PMID- 26061195 TI - Asymptomatic Papular Eruption in a Teenage Boy. PMID- 26061198 TI - Ultrabright Luminescence from Gold Nanoclusters: Rigidifying the Au(I)-Thiolate Shell. AB - Luminescent nanomaterials have captured the imagination of scientists for a long time and offer great promise for applications in organic/inorganic light-emitting displays, optoelectronics, optical sensors, biomedical imaging, and diagnostics. Atomically precise gold clusters with well-defined core-shell structures present bright prospects to achieve high photoluminescence efficiencies. In this study, gold clusters with a luminescence quantum yield greater than 60% were synthesized based on the Au22(SG)18 cluster, where SG is glutathione, by rigidifying its gold shell with tetraoctylammonium (TOA) cations. Time-resolved and temperature dependent optical measurements on Au22(SG)18 have shown the presence of high quantum yield visible luminescence below freezing, indicating that shell rigidity enhances the luminescence quantum efficiency. To achieve high rigidity of the gold shell, Au22(SG)18 was bound to bulky TOA that resulted in greater than 60% quantum yield luminescence at room temperature. Optical measurements have confirmed that the rigidity of gold shell was responsible for the luminescence enhancement. This work presents an effective strategy to enhance the photoluminescence efficiencies of gold clusters by rigidifying the Au(I)-thiolate shell. PMID- 26061196 TI - Pregnancy Complications as Markers for Subsequent Maternal Cardiovascular Disease: Validation of a Maternal Recall Questionnaire. AB - BACKGROUND: We designed and tested the validity of a questionnaire to characterize maternal recall of pregnancy complications associated with increased future cardiovascular disease risk, based on the 2011 American Heart Association (AHA) guidelines. METHODS: A maternal recall questionnaire of pregnancy history was administered to 971 patients who had participated in a previous cohort study of 1,608 pregnant women. Medical records from the study pregnancy served as the gold standard. Prevalence, sensitivity (sens), specificity (spec), positive predictive value (PPV), negative predictive value (NPV), and/or Spearman's correlation coefficients (r) were calculated for each question. RESULTS: A total of 526 (54%) individuals recontacted responded. Respondents were more likely to be older, white, educated, and nulliparous and were less likely to deliver low birthweight infants in the study pregnancy than were individuals who did not respond. Mean length of recall was 4.35 years (standard deviation [SD] 0.46) postpartum. Maternal recall was most accurate for gestational diabetes (sens: 92%, spec: 98%, PPV: 79%, NPV: 99%), infant birthweight (r=0.95), and gestation length (r=0.85). Maternal recall was modest for preeclampsia (sens: 79%, spec: 97%, PPV: 68%, NPV: 98%) and pregnancy-associated hypertension, including preeclampsia or gestational hypertension (sens: 60%, spec: 95%, PPV: 64%, NPV: 94%). CONCLUSIONS: This validation study demonstrated that the majority of women could accurately recall a history of gestational diabetes, infant birthweight, and gestational age at delivery, 4 years postpartum on average. Recall of preeclampsia and pregnancy-associated hypertension overall was modest. Maternal report of these pregnancy conditions may help clinicians identify women at increased risk for cardiovascular disease. PMID- 26061199 TI - A Multi-Channel Method for Retrieving Surface Temperature for High-Emissivity Surfaces from Hyperspectral Thermal Infrared Images. AB - The surface temperature (ST) of high-emissivity surfaces is an important parameter in climate systems. The empirical methods for retrieving ST for high emissivity surfaces from hyperspectral thermal infrared (HypTIR) images require spectrally continuous channel data. This paper aims to develop a multi-channel method for retrieving ST for high-emissivity surfaces from space-borne HypTIR data. With an assumption of land surface emissivity (LSE) of 1, ST is proposed as a function of 10 brightness temperatures measured at the top of atmosphere by a radiometer having a spectral interval of 800-1200 cm(-1) and a spectral sampling frequency of 0.25 cm(-1). We have analyzed the sensitivity of the proposed method to spectral sampling frequency and instrumental noise, and evaluated the proposed method using satellite data. The results indicated that the parameters in the developed function are dependent on the spectral sampling frequency and that ST of high-emissivity surfaces can be accurately retrieved by the proposed method if appropriate values are used for each spectral sampling frequency. The results also showed that the accuracy of the retrieved ST is of the order of magnitude of the instrumental noise and that the root mean square error (RMSE) of the ST retrieved from satellite data is 0.43 K in comparison with the AVHRR SST product. PMID- 26061200 TI - Profiling of Current Transients in Capacitor Type Diamond Sensors. AB - The operational characteristics of capacitor-type detectors based on HPHT and CVD diamond have been investigated using perpendicular and parallel injection of carrier domain regimes. Simulations of the drift-diffusion current transients have been implemented by using dynamic models based on Shockley-Ramo's theorem, under injection of localized surface domains and of bulk charge carriers. The bipolar drift-diffusion regimes have been analyzed for the photo-induced bulk domain (packet) of excess carriers. The surface charge formation and polarization effects dependent on detector biasing voltage have been revealed. The screening effects ascribed to surface charge and to dynamics of extraction of the injected bulk excess carrier domain have been separated and explained. The parameters of drift mobility of the electrons MU(e) = 4000 cm2/Vs and holes MU(h) = 3800 cm2/Vs have been evaluated for CVD diamond using the perpendicular profiling of currents. The coefficient of carrier ambipolar diffusion D(a) = 97 cm2/s and the carrier recombination lifetime tau(R,CVD) ? 110 ns in CVD diamond were extracted by combining analysis of the transients of the sensor current and the microwave probed photoconductivity. The carrier trapping with inherent lifetime tauR,HPHT ? 2 ns prevails in HPHT diamond. PMID- 26061201 TI - Multiple Human Tracking Using Binary Infrared Sensors. AB - To create a context-aware environment, human locations and movement paths must be considered. In this paper, we propose an algorithm that tracks human movement paths using only binary sensed data obtained by infrared (IR) sensors attached to the ceiling of a room. Our algorithm can estimate multiple human movement paths without a priori knowledge of the number of humans in the room. By repeating predictions and estimations of human positions and links from the previous human positions to the estimated ones at each time period, human movement paths can be estimated. Simulation-based evaluation results show that our algorithm can dynamically trace human movement paths. PMID- 26061202 TI - Sorption and dissolution of bare and coated silver nanoparticles in soil suspensions--Influence of soil and particle characteristics. AB - The increasing use of silver nanoparticles (AgNPs) in consumer products triggers the need for investigations that improve the understanding of their chemical transformations upon environmental entry. Such knowledge provides crucial information for toxicological studies and risk assessments. Interactions with the soil compartment need to be explored as there are evident risks of the dispersion of both AgNPs and of released Ag ions/complexes present in wastewater-treated sludge that is distributed onto agricultural land. The dissolution and fractionation in solution of bare (AgNP-bare, noncoated) and coated AgNPs (AgNP coat, stabilized with two nonionic surfactants, polyoxyethylene glycerol trioleate and Tween 20) were investigated after 4 and 48 h in suspensions of one sandy and one clayey soil of different pHs (3.3, 5.2). Parallel experiments were performed with soil suspensions spiked with easily soluble AgNO3. Silver in the water phase was separated in a dissolved fraction (mainly Ag ions/complexes) and a particle fraction (mainly AgNP/agglomerates/Ag adsorbed on organic matter) by means of ultracentrifugation. Bare AgNPs were nonstable and dissolved to a significantly larger extent in the sandy soil mixture compared to coated AgNPs. The concentration of dissolved Ag (ions/complexes) in the water phase was similar in the case of bare AgNPs and AgNO3 (at pH 3 and 5.2) after 24 h in sandy soil, which implies a high degree of dissolution of bare AgNPs (50-100%). In contrast, approximately 50% of the coated AgNPs remained in the water phase after 48 h of equilibration in the sandy soil at pH 5.2. The clayey soil had a significantly higher sorption capacity of Ag compared with the sandy soil, as Ag in the case of coated AgNPs was only detected in the water phase of pH 5.2 (<1% of added Ag). Ultracentrifugation was proven more efficient compared with microfiltration to separate the dissolved Ag fraction (ions/complexes) and the particle fraction (AgNPs/agglomerates) of the water phase. This fractionation is not a measure of any potential toxicity. PMID- 26061203 TI - Removal of Pb(II), Cd(II), Cu(II) and trichloroethylene from water by Nanofer ZVI. AB - Zero-valent iron nanoparticle (Nanofer ZVI) is a new reagent due to its unique structure and properties. Images of scanning electron microscopy/electron dispersive spectroscopy (SEM/EDS), transmission electron microscopy and X-ray diffraction revealed that Nanofer ZVI is stable, reactive and has a unique structure. The particles exhibited a spherical shape, a chain-like structure with a particle size of 20 to 100 nm and a surface area between 25-30 m2g(-1). The time interval for particles to agglomerate and settle was between 4-6 h. SEM/EDS Images showed that particle size increased to 2 um due to agglomeration. Investigation of adsorption and oxidation behavior of Nanofer ZVI used for the removal of Cu(II), Pb(II), Cd(II) ions and trichloroethylene (TCE) from aqueous solutions showed that the optimal pH for Pb(II), Cu(II), Cd(II) and TCE removal were 4.5 and 4.8, 5.0 and 6.5, respectively. Test data were used to form Langmuir and Freundlich isotherms. The maximum contaminant loading was estimated as 270, 170, 110, 130 mg per gram of Nanofer ZVI for Cu(II), Pb(II), Cd(II) and TCE respectively. Removal of metal ions is interpreted in terms of their hydrated ionic radii and their electronegativity. TCE oxidation followed the dechlorination pathway resulting in nonhazardous by-products. PMID- 26061204 TI - Effects of titanium dioxide and zinc oxide nanoparticles on methane production from anaerobic co-digestion of primary and excess sludge. AB - Anaerobic co-digestion of primary and excess sludge is regarded as an efficient way to reuse sludge organic matter to produce methane. In this study, short-term and long-term exposure experiments were conducted to investigate the possible effects of titanium dioxide (TiO2) and zinc oxide (ZnO) nanoparticles (NPs) on methane production from anaerobic co-digestion of primary and excess sludge. The data showed that TiO2 NPs had no measurable impact on methane production, even at a high concentration (150 mg/g total suspended solids (TSS)). However, short-term (8 days) exposure to 30 or 150 mg/g-TSS of ZnO NPs significantly decreased methane production. More importantly, these negative effects of ZnO NPs on anaerobic sludge co-digestion were not alleviated by increasing the adaptation time to 105 days. Further studies indicated that the presence of ZnO NPs substantially decreased the abundance of methanogenic archaea, which reduced methane production. Meanwhile, the activities of some key enzymes involved in methane production, such as protease, acetate kinase, and coenzyme F420, were remarkably inhibited by the presence of ZnO NPs, which was also an important reason for the decreased methane production. These results provide a better understanding of the potential risks of TiO2 and ZnO NPs to methane production from anaerobic sludge co-digestion. PMID- 26061205 TI - Factors affecting lead release in sodium silicate-treated partial lead service line replacements. AB - Water quality parameters affecting sodium silicate performance in partial lead service line replacements were examined using a fractional factorial experimental design and static pipe systems. An external copper wire was used to create a galvanic connection between a former lead service line and a new copper pipe. The pipe systems were filled with lab prepared water made to mimic real water quality. Water was changed on a three times per week basis. A 2(4-1) fractional factorial design was used to evaluate the impact of alkalinity (15 mg L(-1) or 250 mg L(-1) as CaCO3), nitrate (1 mg L(-1) or 7 mg L(-1) as N), natural organic matter (1 mg L(-1) or 7 mg L(-1) as dissolved organic carbon), and disinfectant type (1 mg L(-1) chlorine or 3 mg L(-1) monochloramine), resulting in eight treatment conditions. Fractional factorial analysis revealed that alkalinity, natural organic matter and monochloramine had a significant positive effect on galvanic current. Natural organic matter and monochloramine also had a significant positive effect with respect to both total and dissolved lead release. For the treatment conditions examined, 67-98% of the lead released through galvanic currents was stored as corrosion scales and predominantly comprised of particulate lead (96.1-99.9%) for all eight treatments. The use of monochloramine and the presence of natural organic matter (7 mg L(-1)) were not favourable for corrosion control in sodium silicate-treated partial lead service line replacements, although further studies would be required to characterize optimal water quality parameters for specific water quality types. For utilities operating with sodium silicate as a corrosion inhibitor, this work offers further evidence regarding the consideration of chlorine as a secondary disinfectant instead of monochloramine, as well as the value of controlling natural organic matter in distributed water. PMID- 26061206 TI - Degradation of N,N-diethyl-m-toluamid (DEET) on lead dioxide electrodes in different environmental aqueous matrixes. AB - This study investigates the electrochemical degradation of N,N-diethyl-m toluamide (DEET) on PbO2 and Bi-PbO2 anodes. The difference in electrode crystalline structure was responsible for the better DEET degradation and TOC removal on PbO2 than on Bi-PbO2. In 1 M Na2SO4, the degradation efficiency and apparent rate constant (kapp) of DEET oxidation on PbO2 increased with the increase in current density or temperature (activation energy=24.4 kJ mol(-1)). The kapp values in DEET-spiked environmental matrixes (municipal wastewater treatment plant secondary effluent (MWTPSE), groundwater (GW), and river water (RW)) were the same (6.05*10(-4) s(-1)), but significantly smaller than that in 1 M Na2SO4 (2.23*10(-3) s(-1)). The TOC removal efficiency was better in MWTPSE than in RW and GW; however, the mineralization current efficiencies in MWTPSE and RW were similar but higher than that in GW. During electrolysis, the aromaticity was lower in GW than in RW. PMID- 26061207 TI - Distribution and possible dietary intake of radioactive 137Cs, 40K and 226Ra with the pantropical mushroom Macrocybe gigantea in SW China. AB - There is scarcity of data on contamination with radiocesium 134/137Cs of edible mushrooms from the Southwestern Asia. This study aimed to get insight into activity concentration of artificial nuclides 134/137Cs and natural 40K and 226Ra in mushrooms from Yunnan province, which is major producer in China. The specimens of pantropical mushroom Macrocybe gigantea were collected from the wild and from a farm across Yunnan land in 2012-2013 and analyzed using gamma spectrometry with hyperpure germanium coaxial detector (HPGe). M. gigantea showed low activity concentrations of 137Cs (median value for dehydrated caps was 4.5 Bq kg(-1) and 5.4 Bq kg(-1) for stipes) while 134Cs was not detected. Natural radionuclide 40K showed 2-3 orders of magnitude greater activity concentration compared to artificial 137Cs in M. gigantea. The activity concentrations of 226Ra from uranium and radium decay series for most of the consignments of M. gigantea examined were below the method's limit of detection. The nominal effective dose equivalent for the Yunnan people from the dietary intake of 137Cs was assessed to be below 0.01 MUSv per annum on the average, and that from 40K to be below 0.1 MUSv per annum. Data available for the first time on activity concentrations of 137Cs in wild-grown saprobic mushroom from this region of Asia suggest low pollution with radiocesium from fallout there. Hence, the likely health risks from intake of 137Cs from cooked M. gigantea are in practice of mushrooms absent for human consumers there. Because of abundance of mushrooms in Yunnan and high significance of the region as producer and exporter a wider study using many species is necessary to fill a gap on possible radioactive contamination and risk to mushroom consumers. PMID- 26061208 TI - Biodegradation of linear alkylbenzene sulfonate in commercial laundry wastewater by an anaerobic fluidized bed reactor. AB - The biodegradation of linear alkylbenzene sulfonate (LAS) from commercial laundry wastewater was evaluated in an anaerobic fluidized bed reactor (FBR) fed with synthetic substrate (598 mg L(-1) to 723 mg L(-1) of organic matter) supplemented with 9.5+/-3.1 mg L(-1) to 27.9+/-9.6 mg L(-1) of LAS. The average chemical oxygen demand (COD) removal efficiency was 89% and the biodegradation of LAS was 57% during the 489 days of anaerobic FBR. Higher levels of volatile fatty acids (VFA) were observed in the effluent at the stage with the best LAS removal performance. Increasing the surfactant concentration did not increase the VFA production in the effluent. The predominant VFAs after the addition of LAS were as follows: isovaleric acid and valeric acid, followed by propionic acid, caproic acid and formic acid. The similarities of 64% and 45% to Archaea and Bacteria domains were observed in the samples taken in the operating period of anaerobic FBR fed with 23.6+/-10 mg L(-1) and 27.9+/-10 mg L(-1) of LAS. During the operation stages in the reactor, Gemmatimonas, Desulfobulbus and Zoogloea were determined as the most abundant genera related to surfactant degradation using 454-Pyrosequencing. PMID- 26061209 TI - Comparative evaluation of the efficiency of low-cost adsorbents and ligninolytic fungi to remove a combination of xenoestrogens and pesticides from a landfill leachate and abate its phytotoxicity. AB - In this study, two widely available low-cost adsorbents, almond shells and a green compost, and two ligninolytic fungi, Pleurotus ostreatus and Stereum hirsutum, were used to remove organic contaminants from a landfill leachate (LLe) and abate its phytotoxicity. The methodology adopted was based on the occurrence of two simultaneous processes, such as adsorption and bioremoval. The leachate was artificially contaminated with a mixture of the xenoestrogens bisphenol A (BPA), ethynilestadiol (EE2) and 4-n-nonylphenol (NP), the herbicide linuron and the insecticide dimethoate at concentrations of 10, 1, 1, 10 and 10 mg L(-1), respectively. Three adsorption substrates were prepared: potato dextrose agar alone or the same incorporating each adsorbent. The substrates were either not inoculated or inoculated with each fungus, separately, before to be superimposed on LLe. After 2 months, the residual amount of each contaminant, the electrical conductivity, the pH and the content of total phenols were measured in treated LLe. Germination assays using lettuce, ryegrass and radish were performed to evaluate LLe phytotoxicity. The combination substrate+P. ostreatus showed the best results with average removals of 88, 96, 99, 58 and 46% for BPA, EE2, NP, linuron and dimethoate, respectively. The same treatment considerably reduced the phenol content in LLe compared to no treatment. The combination substrate+S. hirsutum produced average removals of 39, 71, 100, 61 and 32% for BPA, EE2, NP, linuron and dimethoate, respectively. Also uninoculated substrates showed relevant adsorption capacities towards the five contaminants. Most treatments significantly reduced LLe phytotoxicity, especially on lettuce. The best results were obtained with the treatment compost+S. hirsutum, which produced root and shoot lengths and seedling biomass of lettuce, respectively, 2.3, 3.3, and 1.9 times those measured in untreated LLe. In general, germination results were negatively correlated with LLe properties like the residual amount of the contaminants, the electrical conductivity and the pH. These results show that the methodology adopted in the study, i.e., combined adsorption/biodegradation, is suitable not only to remove xenobiotic contaminants from the leachate but also to reduce considerably its inhibition on seed germination. PMID- 26061210 TI - Treating separated liquid dairy manure derived from mesophilic anaerobic digester effluent to reduce indicator pathogens and Salmonella concentrations for use as organic fertilizer. AB - Dairy manure has much potential for use as an organic fertilizer in the United States. However, the levels of indicator organisms and pathogens in dairy manure can be ten times higher than stipulated use guidelines by the National Organic Standards Board (NOSB) even after undergoing anaerobic digestion at mesophilic temperatures. The objective of this study was to identify pasteurization temperatures and treatment durations to reduce fecal coliforms, E. coli, and Salmonella concentrations in separated liquid dairy manure (SLDM) of a mesophilic anaerobic digester effluent to levels sufficient for use as an organic fertilizer. Samples of SLDM were pasteurized at 70, 75, and 80 degrees C for durations of 0 to 120 min. Fecal coliforms, E. coli, and Salmonella concentrations were assessed via culture-based techniques. All of the tested pasteurization temperatures and duration combinations reduced microbial concentrations to levels below the NOSB guidelines. The fecal coliforms and E. coli reductions ranged 2from 0.76 to 1.34 logs, while Salmonella concentrations were reduced by more than 99% at all the pasteurization temperatures and active treatment durations. PMID- 26061211 TI - Removal of ammonia nitrogen from leachate of Muribeca municipal solid waste landfill, Pernambuco, Brazil, using natural zeolite as part of a biochemical system. AB - The inadequate disposal of leachate is one of the key factors in the environmental impact of urban solid waste landfills in Brazil. Among the compounds present in the leachates from Brazilian landfills, ammonia nitrogen is notable for its high concentrations. The purpose of this study was to assess the efficiency of a permeable reactive barrier filled with a natural zeolite, which is part of a biochemical system for the tertiary treatment of the leachate from Muribeca Municipal Solid Waste Landfill in Pernambuco, Brazil, to reduce its ammonia nitrogen concentration. This investigation initially consisted of kinetic studies and batch equilibrium tests on the natural zeolite to construct the sorption isotherms, which showed a high sorption capacity, with an average of 12.4 mg NH4+.L(-1), a value close to the sorption rates found for the aqueous ammonium chloride solution. A permeable reactive barrier consisting of natural zeolite, as simulated by the column test, was efficient in removing the ammonia nitrogen present in the leachate pretreated with calcium hydroxide. Nevertheless, the regenerated zeolite did not satisfactorily maintain the sorption properties of the natural zeolite, and an analysis of their cation-exchange properties showed a reduced capacity of 54 meq per 100 g for the regenerated zeolite compared to 150 meq per 100 g for the natural zeolite. PMID- 26061212 TI - Pooled Open Blocks Shorten Wait Times for Nonelective Surgical Cases. AB - OBJECTIVE: Assess the impact of the implementation of a data-driven scheduling strategy that aimed to improve the access to care of nonelective surgical patients at Massachusetts General Hospital (MGH). BACKGROUND: Between July 2009 and June 2010, MGH experienced increasing throughput challenges in its perioperative environment: approximately 30% of the nonelective patients were waiting more than the prescribed amount of time to get to surgery, hampering access to care and aggravating the lack of inpatient beds. METHODS: This work describes the design and implementation of an "open block" strategy: operating room (OR) blocks were reserved for nonelective patients during regular working hours (prime time) and their management centralized. Discrete event simulation showed that 5 rooms would decrease the percentage of delayed patients from 30% to 2%, assuming that OR availability was the only reason for preoperative delay. RESULTS: Implementation began in January 2012. We compare metrics for June through December of 2012 against the same months of 2011. The average preoperative wait time of all nonelective surgical patients decreased by 25.5% (P < 0.001), even with a volume increase of 9%. The number of bed-days occupied by nonurgent patients before surgery declined by 13.3% whereas the volume increased by 4.5%. CONCLUSIONS: The large-scale application of an open-block strategy significantly improved the flow of nonelective patients at MGH when OR availability was a major reason for delay. Rigorous metrics were developed to evaluate its performance. Strong managerial leadership was crucial to enact the new practices and turn them into organizational change. PMID- 26061213 TI - Comparison of Perioperative Radiation Therapy and Surgery Versus Surgery Alone in 204 Patients With Primary Retroperitoneal Sarcoma: A Retrospective 2-Institution Study. AB - OBJECTIVE: To compare outcomes of patients with retroperitoneal or pelvic sarcoma treated with perioperative radiation therapy (RT) versus those treated without perioperative RT. BACKGROUND: RT for retroperitoneal or pelvic sarcoma is controversial, and few studies have compared outcomes with and without RT. METHODS: Prospectively maintained databases were reviewed to retrospectively compare patients with primary retroperitoneal or pelvic sarcoma treated during 2003-2011. Multivariate Cox regression models were used to assess associations with the primary endpoints: local recurrence-free survival (LRFS) and disease specific survival. RESULTS: At 1 institution, 172 patients were treated with surgery alone, whereas at another institution 32 patients were treated with surgery and perioperative proton beam RT or intensity-modulated RT with or without intraoperative RT. The groups were similar in age, tumor size, grade, and margin status (all P > 0.08). The RT group had a higher percentage of pelvic tumors (P = 0.03) and a different distribution of histologies (P = 0.04). Perioperative morbidity was higher in the RT group (44% vs 16% of patients; P = 0.004). After a median follow-up of 39 months, 5-year LRFS was 91% (95% confidence interval, 79%-100%) in the RT group and 65% (57%-74%) in the surgery only group (P = 0.02). On multivariate analysis, RT was associated with better LRFS (hazard ratio, 0.26; P = 0.03). Five-year disease-specific survival was 93% (95% confidence interval, 82%-100%) in the RT group and 85% (78%-92%) in the surgery-only group (P = 0.3). CONCLUSIONS: The addition of advanced-modality RT to surgery for primary retroperitoneal or pelvic sarcoma was associated with improved LRFS, although this did not translate into significantly better disease specific survival. This treatment strategy warrants further investigation in a randomized trial. PMID- 26061215 TI - Correction to: J Neurotrauma 2014;31(12):1122-1128. PMID- 26061214 TI - Prospective, Randomized Assessment of Transfer of Training (ToT) and Transfer Effectiveness Ratio (TER) of Virtual Reality Simulation Training for Laparoscopic Skill Acquisition. PMID- 26061218 TI - Innate Antibacterial Activity in Female Genital Tract Secretions Is Associated with Increased Risk of HIV Acquisition. AB - Greater inhibitory activity against Escherichia coli and levels of human beta defensin (HBD)-2 in genital tract secretions predicted HIV acquisition in women in the HPTN 035 trial. We investigated whether higher levels of E. coli inhibitory activity and antimicrobial peptides in cervicovaginal lavage (CVL) samples predicted HIV acquisition in women in the CAPRISA 002 Acute Infection Study. E. coli inhibitory activity and antimicrobial peptides were quantified in CVL from a subset of CAPRISA 002 participants who did not seroconvert (n=39) and from seroconverting women prior to infection (n=17) and during acute infection (n=11). Women who acquired HIV had significantly greater preinfection CVL E. coli inhibitory activity (p=0.01) and HBD-1 levels (p=0.02) compared to women who remained uninfected. Preinfection E. coli inhibitory activity remained significantly associated with seroconversion following adjustment for the presence of bacterial vaginosis (OR 1.45; 95% CI 1.07, 1.97). Partial least squares discriminant analysis confirmed that preinfection CVL E. coli inhibitory activity, together with higher CVL concentrations of HBD-1 and secretory leukocyte protease inhibitor, distinguished seroconverters from nonseroconverters with 67% calibration accuracy. CVL concentrations of human neutrophil peptides (HNP) 1-3 increased significantly with acute infection (p=0.001) and correlated with plasma viral set point (r=0.66, p=0.03). E. coli inhibitory activity in genital tract secretions could provide a biomarker of HIV risk. The correlation between HNP 1-3 and viral set point merits further investigation of the relationship between mucosal inflammation during early HIV infection and disease progression. PMID- 26061219 TI - In vitro evaluation of thermal frontally polymerized thiol-ene composites as bone augments. AB - Because of the large number of total knee replacement (TKR) surgeries conducted per year, and with projections of increased demand to almost a million primary TKR surgeries per year by 2030 in the United States alone, there is a need to discover more efficient working materials as alternatives to current bone cements. There is a need for surgeons and hospitals to become more efficient and better control over the operative environment. One area of inefficiency is the cement steps during TKR. Currently the surgeon has very little control over cement polymerization. This leads to an increase in time, waste, and procedural inefficiencies. There is a clear need to create an extended working time, moldable, osteoconductive, and osteoinductive bone augment as a substitution for the current clinically used bone cement where the surgeon has better control over the polymerization process. This study explored several compositions of pentaerythritol-co-trimethylolpropane tris-(3-mercaptopropionate) hydroxyapatite composite materials prepared via benzoyl peroxide-initiated thermal frontal polymerization. The 4:1 acrylate to thiol ratio containing augment material shows promise with a maximal propagation temperature of 160 degrees C +/- 10 degrees C, with mechanical strength of 3.65 MPa, and 111% cytocompatibility, relative to the positive control. This frontally polymerized material may have application as an augment with controlled polymerization supporting cemented implants. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1152 1160, 2016. PMID- 26061220 TI - In situ synthesis of TiO2/SnO(x)-Au ternary heterostructures effectively promoting visible-light photocatalysis. AB - TiO2/SnOx-Au ternary heterostructures were successfully fabricated via a simple in situ reduction of AuCl4(-) on TiO2 surfaces pre-modified with Sn(2+). The samples were characterized by XRD, TEM, XPS, N2 physical absorption and UV-vis diffuse reflectance spectra. Photocatalytic activity toward degradation of methylene blue (MB) aqueous solution under visible light irradiation was investigated. The results suggested that the highly dispersive and ultrafine Au nanoparticles (NPs) covered with SnOx were deposited onto the surface of TiO2. The heterostructures significantly enhanced the photocatalytic activity compared with the traditional TiO2/Au sample prepared by the impregnation method and also enhanced the activity more than the binary TiO2/SnOx sample. Moreover, the size of the Au NPs could be well controlled by simply tuning the dosage of HAuCl4, and the optimized catalytic activity of the ternary heterostructures was obtained when the dosage of Au was 1% and the Au particle size was ~2.65 nm. The enhancement of photocatalytic performance could be attributed to the surface plasmon resonance effect of the Au NPs and the electron-sink function of the SnOx, which improve the optical absorption properties as well as photoinduced charge carrier separation, synergistically facilitating the photocatalysis. PMID- 26061221 TI - 3D WS2 Nanolayers@Heteroatom-Doped Graphene Films as Hydrogen Evolution Catalyst Electrodes. PMID- 26061222 TI - The impact of transcranial direct current stimulation (tDCS) combined with modified constraint-induced movement therapy (mCIMT) on upper limb function in chronic stroke: a double-blind randomized controlled trial. AB - PURPOSE: This pilot double-blind sham-controlled randomized trial aimed to determine if the addition of anodal tDCS on the affected hemisphere or cathodal tDCS on unaffected hemisphere to modified constraint-induced movement therapy (mCIMT) would be superior to constraints therapy alone in improving upper limb function in chronic stroke patients. METHODS: Twenty-one patients with chronic stroke were randomly assigned to receive 12 sessions of either (i) anodal, (ii) cathodal or (iii) sham tDCS combined with mCIMT. Fugl-Meyer assessment (FMA), motor activity log scale (MAL), and handgrip strength were analyzed before, immediately, and 1 month (follow-up) after the treatment. Minimal clinically important difference (mCID) was defined as an increase of >=5.25 in the upper limb FMA. RESULTS: An increase in the FMA scores between the baseline and post intervention and follow-up for active tDCS group was observed, whereas no difference was observed in the sham group. At post-intervention and follow-up, when compared with the sham group, only the anodal tDCS group achieved an improvement in the FMA scores. ANOVA showed that all groups demonstrated similar improvement over time for MAL and handgrip strength. In the active tDCS groups, 7/7 (anodal tDCS) 5/7 (cathodal tDCS) of patients experienced mCID against 3/7 in the sham group. CONCLUSION: The results support the merit of association of mCIMT with brain stimulation to augment clinical gains in rehabilitation after stroke. However, the anodal tDCS seems to have greater impact than the cathodal tDCS in increasing the mCIMT effects on motor function of chronic stroke patients. IMPLICATIONS FOR REHABILITATION: The association of mCIMT with brain stimulation improves clinical gains in rehabilitation after stroke. The improvement in motor recovery (assessed by Fugl-Meyer scale) was only observed after anodal tDCS. The modulation of damaged hemisphere demonstrated greater improvements than the modulation of unaffected hemispheres. PMID- 26061223 TI - Inconsistency in the analysis of morphological deformities in chironomidae (Insecta: Diptera) larvae. AB - The incidence of morphological deformities of chironomid larvae as an indicator of sediment toxicity has been studied for decades. However, standards for deformity analysis are lacking. The authors evaluated whether 25 experts diagnosed larval deformities in a similar manner. Based on high-quality digital images, the experts rated 211 menta of Chironomus spp. larvae as normal or deformed. The larvae were from a site with polluted sediments or from a reference site. The authors revealed this to a random half of the experts, and the rest conducted the assessment blind. The authors quantified the interrater agreement by kappa coefficient, tested whether open and blind assessments differed in deformity incidence and in differentiation between the sites, and identified those deformity types rated most consistently or inconsistently. The total deformity incidence varied greatly, from 10.9% to 66.4% among experts. Kappa coefficient across rater pairs averaged 0.52, indicating insufficient agreement. The deformity types rated most consistently were those missing teeth or with extra teeth. The open and blind assessments did not differ, but differentiation between sites was clearest for raters who counted primarily absolute deformities such as missing and extra teeth and excluded apparent mechanical aberrations or deviations in tooth size or symmetry. The highly differing criteria in deformity assignment have likely led to inconsistent results in midge larval deformity studies and indicate an urgent need for standardization of the analysis. PMID- 26061225 TI - Combinatorial nanomedicines for colon cancer therapy. AB - Colon cancer is one of the major causes of cancer deaths worldwide. Even after surgical resection and aggressive chemotherapy, 50% of colorectal carcinoma patients develop recurrent disease. Thus, the rationale of developing new therapeutic approaches to improve the current chemotherapeutic regimen would be highly recommended. There are reports on the effectiveness of combination chemotherapy in colon cancer and it has been practiced in clinics for long time. These approaches are associated with toxic side effects. Later, the drug delivery research had shown the potential of nanoencapsulation techniques and active targeting as an effective method to improve the effectiveness of chemotherapy with less toxicity. This current focus article provides a brief analysis of the ongoing research in the colon cancer area using the combinatorial nanomedicines and its outcome. PMID- 26061226 TI - Two-Photon Probes for Lysosomes and Mitochondria: Simultaneous Detection of Lysosomes and Mitochondria in Live Tissues by Dual-Color Two-Photon Microscopy Imaging. AB - Novel two-photon (TP) probes were developed for lysosomes (PLT-yellow) and mitochondria (BMT-blue and PMT-yellow). These probes emitted strong TP-excited fluorescence in cells at widely separated wavelength regions and displayed high organelle selectivity, good cell permeability, low cytotoxicity, and pH insensitivity. The BMT-blue and PLT-yellow probes could be utilized to detect lysosomes and mitochondria simultaneously in live tissues by using dual-color two photon microscopy, with minimum interference from each other. PMID- 26061224 TI - Construction of a robust and sensitive arginine biosensor through ancestral protein reconstruction. AB - Biosensors for signaling molecules allow the study of physiological processes by bringing together the fields of protein engineering, fluorescence imaging, and cell biology. Construction of genetically encoded biosensors generally relies on the availability of a binding "core" that is both specific and stable, which can then be combined with fluorescent molecules to create a sensor. However, binding proteins with the desired properties are often not available in nature and substantial improvement to sensors can be required, particularly with regard to their durability. Ancestral protein reconstruction is a powerful protein engineering tool able to generate highly stable and functional proteins. In this work, we sought to establish the utility of ancestral protein reconstruction to biosensor development, beginning with the construction of an l-arginine biosensor. l-arginine, as the immediate precursor to nitric oxide, is an important molecule in many physiological contexts including brain function. Using a combination of ancestral reconstruction and circular permutation, we constructed a Forster resonance energy transfer (FRET) biosensor for l-arginine (cpFLIPR). cpFLIPR displays high sensitivity and specificity, with a Kd of ~14 uM and a maximal dynamic range of 35%. Importantly, cpFLIPR was highly robust, enabling accurate l-arginine measurement at physiological temperatures. We established that cpFLIPR is compatible with two-photon excitation fluorescence microscopy and report l-arginine concentrations in brain tissue. PMID- 26061227 TI - Generation of Brain Microvascular Endothelial-Like Cells from Human Induced Pluripotent Stem Cells by Co-Culture with C6 Glioma Cells. AB - The blood brain barrier (BBB) is formed by brain microvascular endothelial cells (BMECs) and tightly regulates the transport of molecules from blood to neural tissues. In vitro BBB models from human pluripotent stem cell (PSCs)-derived BMECs would be useful not only for the research on the BBB development and function but also for drug-screening for neurological diseases. However, little is known about the differentiation of human PSCs to BMECs. In the present study, human induced PSCs (iPSCs) were differentiated into endothelial cells (ECs), and further maturated to BMECs. Interestingly, C6 rat glioma cell-conditioned medium (C6CM), in addition to C6 co-culture, induced the differentiation of human iPSC derived ECs (iPS-ECs) to BMEC-like cells, increase in the trans-endothelial electrical resistance, decreased in the dextran transport and up-regulation of gene expression of tight junction molecules in human iPS-ECs. Moreover, Wnt inhibitors attenuated the effects of C6CM. In summary, we have established a simple protocol of the generation of BMEC-like cells from human iPSCs, and have demonstrated that differentiation of iPS-ECs to BMEC-like cells is induced by C6CM-derived signals, including canonical Wnt signals. PMID- 26061229 TI - Drivers of Daily Routines in an Ectothermic Marine Predator: Hunt Warm, Rest Warmer? AB - Animal daily routines represent a compromise between maximizing foraging success and optimizing physiological performance, while minimizing the risk of predation. For ectothermic predators, ambient temperature may also influence daily routines through its effects on physiological performance. Temperatures can fluctuate significantly over the diel cycle and ectotherms may synchronize behaviour to match thermal regimes in order to optimize fitness. We used bio-logging to quantify activity and body temperature of blacktip reef sharks (Carcharhinus melanopterus) at a tropical atoll. Behavioural observations were used to concurrently measure bite rates in herbivorous reef fishes, as an index of activity for potential diurnal prey. Sharks showed early evening peaks in activity, particularly during ebbing high tides, while body temperatures peaked several hours prior to the period of maximal activity. Herbivores also displayed peaks in activity several hours earlier than the peaks in shark activity. Sharks appeared to be least active while their body temperatures were highest and most active while temperatures were cooling, although we hypothesize that due to thermal inertia they were still warmer than their smaller prey during this period. Sharks may be most active during early evening periods as they have a sensory advantage under low light conditions and/or a thermal advantage over cooler prey. Sharks swam into shallow water during daytime low tide periods potentially to warm up and increase rates of digestion before the nocturnal activity period, which may be a strategy to maximize ingestion rates. "Hunt warm, rest warmer" may help explain the early evening activity seen in other ectothermic predators. PMID- 26061230 TI - GGEMS-Brachy: GPU GEant4-based Monte Carlo simulation for brachytherapy applications. AB - In brachytherapy, plans are routinely calculated using the AAPM TG43 formalism which considers the patient as a simple water object. An accurate modeling of the physical processes considering patient heterogeneity using Monte Carlo simulation (MCS) methods is currently too time-consuming and computationally demanding to be routinely used. In this work we implemented and evaluated an accurate and fast MCS on Graphics Processing Units (GPU) for brachytherapy low dose rate (LDR) applications. A previously proposed Geant4 based MCS framework implemented on GPU (GGEMS) was extended to include a hybrid GPU navigator, allowing navigation within voxelized patient specific images and analytically modeled (125)I seeds used in LDR brachytherapy. In addition, dose scoring based on track length estimator including uncertainty calculations was incorporated. The implemented GGEMS-brachy platform was validated using a comparison with Geant4 simulations and reference datasets. Finally, a comparative dosimetry study based on the current clinical standard (TG43) and the proposed platform was performed on twelve prostate cancer patients undergoing LDR brachytherapy. Considering patient 3D CT volumes of 400 * 250 * 65 voxels and an average of 58 implanted seeds, the mean patient dosimetry study run time for a 2% dose uncertainty was 9.35 s (~500 ms 10(-6) simulated particles) and 2.5 s when using one and four GPUs, respectively. The performance of the proposed GGEMS-brachy platform allows envisaging the use of Monte Carlo simulation based dosimetry studies in brachytherapy compatible with clinical practice. Although the proposed platform was evaluated for prostate cancer, it is equally applicable to other LDR brachytherapy clinical applications. Future extensions will allow its application in high dose rate brachytherapy applications. PMID- 26061228 TI - Ethanol Extract of Persimmon Tree Leaves Improves Blood Circulation and Lipid Metabolism in Rats Fed a High-Fat Diet. AB - The leaves of the persimmon tree (PL) are known to have beneficial effects on hyperglycemia, dyslipidemia, and nonalcoholic fatty liver disease. We recently demonstrated that PL had antithrombotic properties in vitro. However, little is known about the antiplatelet and anticoagulant properties of PL in vivo. Omega-3 fatty acid (n-3 FA)-containing fish oil has been widely prescribed to improve blood circulation. This study compared the effects of dietary supplementation with an ethanol extract of PL or n-3 FA on blood coagulation, platelet activation, and lipid levels in vivo. Sprague-Dawley rats were fed a high-fat diet with either PL ethanol extract (0.5% w/w) or n-3 FA (2.5% w/w) for 9 weeks. Coagulation was examined by monitoring the activated partial thromboplastin time (aPTT) and prothrombin time. We examined plasma thromboxane B2 (TXB2), serotonin, and soluble P-selectin (sP-selectin) levels. The aPTT was significantly prolonged in the PL and n-3 FA supplement groups. PL also attenuated the TXB2 level and lowered arterial serotonin transporter mRNA expression, although it did not alter plasma serotonin or sP-selectin levels. C-reactive protein and leptin levels were significantly reduced by PL and n-3 FA supplementation. In addition, PL decreased plasma total- and low-density lipoprotein-cholesterol levels, as did n-3 FA treatment. These results indicated that the PL ethanol extract may have the potential to improve circulation by inhibiting blood coagulation and platelet activation and by reducing plasma cholesterol levels. PMID- 26061231 TI - Hypnotics and the Occurrence of Bone Fractures in Hospitalized Dementia Patients: A Matched Case-Control Study Using a National Inpatient Database. AB - BACKGROUND: Preventing falls and bone fractures in hospital care is an important issue in geriatric medicine. Use of hypnotics is a potential risk factor for falls and bone fractures in older patients. However, data are lacking on the association between use of hypnotics and the occurrence of bone fracture. METHODS: We used a national inpatient database including 1,057 hospitals in Japan and included dementia patients aged 50 years or older who were hospitalized during a period of 12 months between April 2012 and March 2013. The primary outcome was the occurrence of bone fracture during hospitalization. Use of hypnotics was compared between patients with and without bone fracture in this matched case-control study. RESULTS: Of 140,494 patients, 830 patients suffered from in-hospital fracture. A 1:4 matching with age, sex and hospital created 817 cases with fracture and 3,158 matched patients without fracture. With adjustment for the Charlson comorbidity index, emergent admission, activities of daily living, and scores for level walking, a higher occurrence of fractures were seen with short-acting benzodiazepine hypnotics (odds ratio, 1.43; 95% confidence interval, 1.19-1.73; P<0.001), ultrashort-acting non-benzodiazepine hypnotics (1.66; 1.37-2.01; P<0.001), hydroxyzine (1.45; 1.15-1.82, P=0.001), risperidone and perospirone (1.37; 1.08-1.73; P=0.010). Other drug groups were not significantly associated with the occurrence of in-hospital fracture. CONCLUSIONS: Short-acting benzodiazepine hypnotics and ultrashort-acting non benzodiazepine hypnotics may increase risk of bone fracture in hospitalized dementia patients. PMID- 26061232 TI - In vivo confocal microscopy for the detection of canine fungal keratitis and monitoring of therapeutic response. AB - OBJECTIVE: To describe in vivo corneal confocal microscopy of dogs during the clinical course of fungal keratitis and correlate findings with clinical evaluations and an ex vivo experimental canine fungal keratitis model. ANIMALS STUDIED: Seven dogs with naturally acquired fungal keratitis and ex vivo canine corneas experimentally infected with clinical fungal isolates. PROCEDURES: Dogs with naturally acquired fungal keratitis were examined by in vivo laser scanning confocal microscopy. Initial confocal microscopic examinations were performed to assist in establishing the diagnosis of fungal keratitis. Serial confocal microscopic examinations were performed to guide antifungal chemotherapy. Confocal microscopy images of canine corneal fungal isolates were obtained by examination of experimentally infected ex vivo canine corneas to corroborate in vivo findings. RESULTS: Fungi cultured and detected by PCR from canine corneal samples included Candida albicans, Fusarium incarnatum-equiseti, Malassezia pachydermatis, and a Rhodotorula sp. Linear, branching, interlocking, hyperreflective structures were detected by confocal microscopy in dogs with filamentous fungal keratitis and round to oval hyperreflective structures were detected in dogs with yeast fungal keratitis. Antifungal chemotherapy was associated with a progressive reduction in the distribution and density of corneal fungal elements, alterations to fungal morphology, decreased leukocyte numbers, restoration of epithelial layers, and an increased number of visible keratocyte nuclei. No dogs had a recurrence of fungal keratitis following medication discontinuation. Confocal microscopic fungal morphologies were similar between in vivo and ex vivo examinations. CONCLUSIONS: In vivo corneal confocal microscopy is a rapid method of diagnosing fungal keratitis in dogs and provides a noninvasive mechanism for monitoring therapeutic response. PMID- 26061234 TI - Molecular characterisation and disease severity of leptospirosis in Sri Lanka. AB - Leptospirosis is a re-emerging zoonotic disease all over the world, important in tropical and subtropical areas. A majority of leptospirosis infected patients present as subclinical or mild disease while 5-10% may develop severe infection requiring hospitalisation and critical care. It is possible that several factors, such as the infecting serovar, level of leptospiraemia, host genetic factors and host immune response, may be important in predisposition towards severe disease. Different Leptospira strains circulate in different geographical regions contributing to variable disease severity. Therefore, it is important to investigate the circulating strains at geographical locations during each outbreak for epidemiological studies and to support the clinical management of the patients. In this study immunochromatography, microscopic agglutination test and polymerase chain reaction were used to diagnose leptospirosis. Further restriction fragment length polymorphism and DNA sequencing methods were used to identify the circulating strains in two selected geographical regions of Sri Lanka. Leptospira interrogans, Leptospira borgpetersenii and Leptospira kirschneri strains were identified to be circulating in western and southern provinces. L. interrogans was the predominant species circulating in western and southern provinces in 2013 and its presence was mainly associated with renal failure. PMID- 26061233 TI - First report of autochthonous transmission of Zika virus in Brazil. AB - In the early 2015, several cases of patients presenting symptoms of mild fever, rash, conjunctivitis and arthralgia were reported in the northeastern Brazil. Although all patients lived in a dengue endemic area, molecular and serological diagnosis for dengue resulted negative. Chikungunya virus infection was also discarded. Subsequently, Zika virus (ZIKV) was detected by reverse transcription polymerase chain reaction from the sera of eight patients and the result was confirmed by DNA sequencing. Phylogenetic analysis suggests that the ZIKV identified belongs to the Asian clade. This is the first report of ZIKV infection in Brazil. PMID- 26061235 TI - Impact of the age of Biomphalaria alexandrina snails on Schistosoma mansoni transmission: modulation of the genetic outcome and the internal defence system of the snail. AB - Of the approximately 34 identified Biomphalariaspecies,Biomphalaria alexandrinarepresents the intermediate host of Schistosoma mansoniin Egypt. Using parasitological and SOD1 enzyme assay, this study aimed to elucidate the impact of the age of B. alexandrinasnails on their genetic variability and internal defence against S. mansoniinfection. Susceptible and resistant snails were reared individually for self-reproduction; four subgroups of their progeny were used in experiment. The young susceptible subgroup showed the highest infection rate, the shortest pre-patent period, the highest total cercarial production, the highest mortality rate and the lowest SOD1 activity. Among the young and adult susceptible subgroups, 8% and 26% were found to be resistant, indicating the inheritance of resistance alleles from parents. The adult resistant subgroup, however, contained only resistant snails and showed the highest enzyme activity. The complex interaction between snail age, genetic background and internal defence resulted in great variability in compatibility patterns, with the highest significant difference between young susceptible and adult resistant snails. The results demonstrate that resistance alleles function to a greater degree in adults, with higher SOD1 activity and provide potential implications for Biomphalariacontrol. The identification of the most susceptible snail age enables determination of the best timing for applying molluscicides. Moreover, adult resistant snails could be beneficial in biological snail control. PMID- 26061236 TI - The spatiotemporal trajectory of a dengue epidemic in a medium-sized city. AB - Understanding the transmission dynamics of infectious diseases is important to allow for improvements of control measures. To investigate the spatiotemporal pattern of an epidemic dengue occurred at a medium-sized city in the Northeast Region of Brazil in 2009, we conducted an ecological study of the notified dengue cases georeferenced according to epidemiological week (EW) and home address. Kernel density estimation and space-time interaction were analysed using the Knox method. The evolution of the epidemic was analysed using an animated projection technique. The dengue incidence was 6.918.7/100,000 inhabitants; the peak of the epidemic occurred from 8 February-1 March, EWs 6-9 (828.7/100,000 inhabitants). There were cases throughout the city and was identified space-time interaction. Three epicenters were responsible for spreading the disease in an expansion and relocation diffusion pattern. If the health services could detect in real time the epicenters and apply nimbly control measures, may possibly reduce the magnitude of dengue epidemics. PMID- 26061237 TI - Reply: To PMID 25865305. PMID- 26061238 TI - Molecular and Physiological Mechanisms of Heavy Metal Tolerance in Atriplex halimus. AB - A study was carried out to identify the mechanisms underlying stress caused by Cd and Pb accumulation in leaves of Atriplex halimus L. collected from habitats representing different kinds of pollution. Mean concentrations of Cd and Pb in aerial parts exceeded the critical levels in polluted plants as compared to reference plants. There were significant reduction in guiacol peroxidase, ascorbate peroxidase and glutathione content in most of polluted plants. The results showed increase in superoxide dismutase enzyme in all polluted plants. The significant increment in catalase enzyme, glutathione S-transeferase and ascorbic acid content were observed in most of polluted plants. Results of the nine differential expressed bands showed down regulation of NADH dehydrogenase and Sedoheptulose-bisphosphatase in polluted plants. In contrast, there were six regulated genes in highly polluted plants, representing transcription factors, membrane transporters and ROS detoxification. The transcription level of phytochelatin synthase showed a significant increase in all polluted plants, while heavy metal ATPase transporter expression significantly increased in some polluted plants. In conclusion, A. halimus may use two different strategies against Cd and Pb stress, in which the molecular and physiological features affords similar levels of Cd and Pb tolerance through binding, sequestration and the reduction of harmful effect of heavy metals. PMID- 26061239 TI - In Vitro Analysis of the Very-Low Density Lipoprotein Export from the Trans-Golgi Network. AB - The movement of mature VLDL particles from the TGN to the plasma membrane (PM) is a complex physiological process that plays a critical role in hepatic lipid homeostasis. However, the molecular mechanisms regulating these intracellular transport events had not been studied until recently because of the lack of appropriate molecular assays and techniques. This unit provides a detailed description of cell-free approaches and techniques to study the TGN-to-PM transport of the mature VLDL at the molecular level. A major emphasis is placed on the preparation and purification of sub-cellular organelles because the success of in vitro assays for the vesicle formation and fusion depends on the quality of the isolated TGN, hepatic PM and hepatic cytosol. A number of critical factors that control the formation of mature VLDL-containing vesicle, the PG-VTV, from the TGN and their subsequent targeting to and fusion with the hepatic PM have been discussed. PMID- 26061240 TI - Identification and Characterization of Tunneling Nanotubes for Intercellular Trafficking. AB - Tunneling nanotubes (TNTs) are thin membranous channels providing direct cytoplasmic connection between remote cells. They are commonly observed in different cell cultures and increasing evidence supports their role in intercellular communication and pathogen transfer. However, the study of TNTs presents several pitfalls (e.g., difficulty in preserving such delicate structures, possible confusion with other protrusions, structural and functional heterogeneity, etc.) and therefore requires thoroughly designed approaches. The methods described in this unit represent a guideline for the characterization of TNTs (or TNT-like structures) in cell culture. Specifically, optimized protocols to (1) identify TNTs and the cytoskeletal elements present inside them; (2) evaluate TNT frequency in cell culture; (3) unambiguously distinguish them from other cellular connections or protrusions; and (4) monitor their formation in living cells are provided. Finally, this unit describes how to assess TNT mediated cell-to-cell transfer of cellular components, which is a fundamental criterion for identifying functional TNTs. PMID- 26061241 TI - Visualizing G Protein-Coupled Receptor-Receptor Interactions in Brain Using Proximity Ligation In Situ Assay. AB - G protein-coupled receptors (GPCRs) constitute the largest family of plasma membrane receptors, thus representing the more investigated drug targets in the design of new therapeutic strategies. The existence of receptor-receptor interactions has revolutionized the field, since GPCR oligomerization might confer new intervention opportunities in pharmacotherapy. However, demonstrating the existence of such receptor-receptor interactions in native tissue has been a bottleneck in GPCR pharmacology. Here, we discuss an experimental approach, the proximity ligation in situ assay (P-LISA), which provides enough sensitivity to evaluate a receptor's close proximity within a named GPCR oligomer. Indeed, we provide a detailed step-by-step protocol for P-LISA experiments visualizing receptor-receptor interactions in brain slices. Additionally, we provide instructions for slide observation, data acquisition and quantification. Finally, we also discuss these critical aspects determining the success of the technique, namely the fixation process and the validation of the primary antibodies used. Overall, the P-LISA is a powerful and straightforward technique to visualize receptor-receptor interactions when performed under optimal conditions. PMID- 26061242 TI - Isolation and Culturing of Glioma Cancer Stem Cells. AB - In many human cancers including malignant glioblastoma multiforme (GBM), cancer stem cells (CSCs) are thought to be responsible for tumor initiation, metastasis and resistance to conventional anti-cancer therapies. Therefore, a CSC-targeted drug delivery strategy to eliminate CSCs is a desirable approach for developing a more effective therapeutic. Moreover, isolated CSCs will provide an invaluable tool for studying the underlying cellular mechanisms of tumor development and provide insight into therapeutic options for successful eradication of CSCs. This unit describes a method for the isolation and culture of CSCs from human GBM tumor tissue. PMID- 26061243 TI - Proteasomes: Isolation and Activity Assays. AB - In eukaryotes, damaged or unneeded proteins are typically degraded by the ubiquitin-proteasome system. In this system, the protein substrate is often first covalently modified with a chain of ubiquitin polypeptides. This chain serves as a signal for delivery to the 26S proteasome, a 2.5-MDa, ATP-dependent multisubunit protease complex. The proteasome consists of a barrel-shaped 20S core particle (CP) that is capped on one or both of its ends by a 19S regulatory particle (RP). The RP is responsible for recognizing the substrate, unfolding it, and translocating it into the CP for destruction. Here we describe simple, one step purifications scheme for isolating the 26S proteasome and its 19S RP and 20S CP subcomplexes from the yeast Saccharomyces cerevisiae, as well as assays for measuring ubiquitin-dependent and ubiquitin-independent proteolytic activity in vitro. PMID- 26061244 TI - Polarized Fluorescence Microscopy to Study Cytoskeleton Assembly and Organization in Live Cells. AB - The measurement of not only the location but also the organization of molecules in live cells is crucial to understanding diverse biological processes. Polarized light microscopy provides a nondestructive means to evaluate order within subcellular domains. When combined with fluorescence microscopy and GFP-tagged proteins, the approach can reveal organization within specific populations of molecules. This unit describes a protocol for measuring the architectural dynamics of cytoskeletal components using polarized fluorescence microscopy and OpenPolScope open-access software (http://www.openpolscope.org). The protocol describes installation of linear polarizers or a liquid crystal (LC) universal compensator, calibration of the system, polarized fluorescence imaging, and analysis. The use of OpenPolScope software and hardware allows for reliable, user friendly image acquisition to measure and analyze polarized fluorescence. PMID- 26061245 TI - Interventions for Adults With Heart Failure. PMID- 26061246 TI - Mining environmental high-throughput sequence data sets to identify divergent amplicon clusters for phylogenetic reconstruction and morphotype visualization. AB - Environmental high-throughput sequencing (envHTS) is a very powerful tool, which in protistan ecology is predominantly used for the exploration of diversity and its geographic and local patterns. We here used a pyrosequenced V4-SSU rDNA data set from a solar saltern pond as test case to exploit such massive protistan amplicon data sets beyond this descriptive purpose. Therefore, we combined a Swarm-based blastn network including 11 579 ciliate V4 amplicons to identify divergent amplicon clusters with targeted polymerase chain reaction (PCR) primer design for full-length small subunit of the ribosomal DNA retrieval and probe design for fluorescence in situ hybridization (FISH). This powerful strategy allows to benefit from envHTS data sets to (i) reveal the phylogenetic position of the taxon behind divergent amplicons; (ii) improve phylogenetic resolution and evolutionary history of specific taxon groups; (iii) solidly assess an amplicons (species') degree of similarity to its closest described relative; (iv) visualize the morphotype behind a divergent amplicons cluster; (v) rapidly FISH screen many environmental samples for geographic/habitat distribution and abundances of the respective organism and (vi) to monitor the success of enrichment strategies in live samples for cultivation and isolation of the respective organisms. PMID- 26061247 TI - Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor. AB - The bromodomain containing proteins TRIM24 (tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis, and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethylbenzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and ITC Kd = 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo. PMID- 26061252 TI - Preoperative Prediction of Ki-67 Labeling Index By Three-dimensional CT Image Parameters for Differential Diagnosis Of Ground-Glass Opacity (GGO). AB - The aim of this study was to predict Ki-67 labeling index (LI) preoperatively by three-dimensional (3D) CT image parameters for pathologic assessment of GGO nodules. Diameter, total volume (TV), the maximum CT number (MAX), average CT number (AVG) and standard deviation of CT number within the whole GGO nodule (STD) were measured by 3D CT workstation. By detection of immunohistochemistry and Image Software Pro Plus 6.0, different Ki-67 LI were measured and statistically analyzed among preinvasive adenocarcinoma (PIA), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC). Receiver operating characteristic (ROC) curve, Spearman correlation analysis and multiple linear regression analysis with cross-validation were performed to further research a quantitative correlation between Ki-67 labeling index and radiological parameters. Diameter, TV, MAX, AVG and STD increased along with PIA, MIA and IAC significantly and consecutively. In the multiple linear regression model by a stepwise way, we obtained an equation: prediction of Ki-67 LI=0.022*STD+0.001* TV+2.137 (R=0.595, R's square=0.354, p<0.001), which can predict Ki-67 LI as a proliferative marker preoperatively. Diameter, TV, MAX, AVG and STD could discriminate pathologic categories of GGO nodules significantly. Ki-67 LI of early lung adenocarcinoma presenting GGO can be predicted by radiologic parameters based on 3D CT for differential diagnosis. PMID- 26061254 TI - Zinc metal complex as a sensor for simultaneous detection of fluoride and HSO4(-) ions. AB - A Schiff base based tripodal receptor was synthesized and complexed with a zinc metal ion (n17) using a very easy single step process. The resulting complex was fully characterized by CHN and single crystal XRD. The real time application of the complex in aqueous media was devised by preparing its organic nanoparticles (ONPs) and their sensor activity was tested with various anions by observing changes in the fluorescence profile of n17. It was observed that ONPs of n17 responded excellently for fluoride and sulfate, producing two different signals, with detection limits of 4.84 * 10(-12) M and 5.67 * 10(-9) M respectively, without having any interference from each other. The real time application of the sensor was also tested using various samples collected from various daily utility items and found to respond exceptionally well. PMID- 26061253 TI - Continuous Flow Microfluidic Bioparticle Concentrator. AB - Innovative microfluidic technology has enabled massively parallelized and extremely efficient biological and clinical assays. Many biological applications developed and executed with traditional bulk processing techniques have been translated and streamlined through microfluidic processing with the notable exception of sample volume reduction or centrifugation, one of the most widely utilized processes in the biological sciences. We utilize the high-speed phenomenon known as inertial focusing combined with hydraulic resistance controlled multiplexed micro-siphoning allowing for the continuous concentration of suspended cells into pre-determined volumes up to more than 400 times smaller than the input with a yield routinely above 95% at a throughput of 240 ml/hour. Highlighted applications are presented for how the technology can be successfully used for live animal imaging studies, in a system to increase the efficient use of small clinical samples, and finally, as a means of macro-to-micro interfacing allowing large samples to be directly coupled to a variety of powerful microfluidic technologies. PMID- 26061255 TI - Copper Lanthanide Phosphonate Cages: Highly Symmetric {Cu3Ln9P6} and {Cu6Ln6P6} Clusters with C3v and D3h Symmetry. AB - Two families of copper lanthanide phosphonate clusters have been obtained through reaction of [Cu2(O2C(t)Bu)4(HO2C(t)Bu)2] and either Ln(NO3)3.nH2O or [Ln2(O2C(t)Bu)6(HO2C(t)Bu)6] and tert-butylphosphonic acid or an amino functionalized phosphonic acid. The clusters, with general formula [Cu(MeCN)4][Cu3Ln9(MU3-OH)7(O3P(t)Bu)6(O2C(t)Bu)15] and [Cu6Ln6(MU3 OH)6(O3PC(NH2)Me2)6(O2C(t)Bu)12], were structurally characterized through single crystal X-ray diffraction and possess highly symmetric metal cores with approximately C3v and D3h point symmetry, respectively. We have investigated the possible application of the isotropic analogues in magnetic cooling, where we were able to observe that up to around 70% of the theoretical magnetic entropy change is obtained. Simulation of the magnetic data shows antiferromagnetic coupling between the spin centers, which explains the magnetic entropy value observed. PMID- 26061256 TI - From margins to centre: an oral history of the wartime experience of Iranian nurses in the Iran-Iraq War, 1980-1988. AB - BACKGROUND: The extensive nature of the Iraq-Iran war converted to a human tragedy with large casualties; it has affected nursing discipline dramatically. AIM: To analyse the history of the wartime experience of Iranian nurses in Iran Iraq War. METHOD: The current study was conducted with oral history. The study sample consisted of 13 Iranian nurses who served in the war zones during the wartime. Purposive and snowball sampling were used to recruit the participants. During the face-to-face interviews, participants were asked to describe their experience in the war zones during the war years. Data collection and analysis took place from April to August 2013, when saturation was reached. All interviews were tape recorded and transcribed and then analysed with thematic content analysis. RESULTS: Finally, five themes and 18 subthemes emerged from data analysis of significant statements from 17 interviews. The five emerged themes included (1) 'From margin to centre', (2) 'Development of referral care', (3) 'Personal and professional growth and development', (4) 'The emerging pillar of culture in war nursing' and (5) 'Threats to nursing at the war'. CONCLUSION AND RELEVANCE TO CLINICAL PRACTICE: Nursing in Iran at wartime has a difficult path to development. There are powerful implications for clinical practice. It is recommended to continue collection, archiving and analysing the wartime experiences of Iranian nurses. PMID- 26061257 TI - Self-Assembly of the Second Transmembrane Domain of hCtr1 in Micelles and Interaction with Silver Ion. AB - Human copper transporter 1 (hCtr1) transports copper and silver by a homotrimer. The protein contains three transmembrane domains in which the second transmembrane domain (TMD2) is a key component lining the central pore of the trimer. The MXXXM motif in the C-terminal end of TMD2 plays a significant role in the function of hCtr1. In this study, we characterized the structure and assembly of isolated TMD2 of hCtr1 in sodium dodecyl sulfate (SDS) micelles and the interaction of the micelle-bound peptide with silver ion using nuclear magnetic resonance, circular dichroism, isothermal titration calorimetry and electrophoresis techniques. We detected the formation of a trimer of the isolated hCtr1-TMD2 in SDS micelles and the binding of the trimer to Ag(I) by a chemical stoichiometry of 3:2 of peptide:Ag(I). We showed that either an intensive pretreatment of the TMD2 peptide by 1,1,1,3,3,3-hexafluoro-2-propanol solvent or a conversion from methionine to leucine in the MXXXM motif changes the aggregation structure of the peptide and decreases the binding affinity by 1 order of magnitude. Our results suggest that the intrinsic interaction of the second transmembrane domain itself may be closely associated with the formation of hCtr1 pore in cellular membranes, and two methionine residues in the MXXXM motif may be important for TMD2 both in the trimeric assembly and in a higher affinity binding to Ag(I). PMID- 26061258 TI - Impact of aggregate formation on the viscosity of protein solutions. AB - Gaining knowledge on the stability and viscosity of concentrated therapeutic protein solutions is of great relevance to the pharmaceutical industry. In this work, we borrow key concepts from colloid science to rationalize the impact of aggregate formation on the changes in viscosity of a concentrated monoclonal antibody solution. In particular, we monitor the kinetics of aggregate growth under thermal stress by static and dynamic light scattering, and we follow the rise in solution viscosity by measuring the diffusion coefficient of tracer nanoparticles with dynamic light scattering. Moreover, we characterize aggregate morphology in the frame of the fractal geometry. We show that the curves of the increase in viscosity with time monitored at three different protein concentrations collapse on one single master curve when the reaction profiles are normalized based on an effective volume fraction occupied by the aggregates, which depends on the aggregate size, concentration and morphology. Importantly, we find that the viscosity of an aggregate sample is lower than the viscosity of a monomeric sample of a similar occupied volume fraction due to the polydispersity of the aggregate distribution. PMID- 26061259 TI - Selective stabilization of aliphatic organic carbon by iron oxide. AB - Stabilization of organic matter in soil is important for natural ecosystem to sequestrate carbon and mitigate greenhouse gas emission. It is largely unknown what factors govern the preservation of organic carbon in soil, casting shadow on predicting the response of soil to climate change. Iron oxide was suggested as an important mineral preserving soil organic carbon. However, ferric minerals are subject to reduction, potentially releasing iron and decreasing the stability of iron-bound organic carbon. Information about the stability of iron-bound organic carbon in the redox reaction is limited. Herein, we investigated the sorptive interactions of organic matter with hematite and reductive release of hematite bound organic matter. Impacts of organic matter composition and conformation on its sorption by hematite and release during the reduction reaction were analyzed. We found that hematite-bound aliphatic carbon was more resistant to reduction release, although hematite preferred to sorb more aromatic carbon. Resistance to reductive release represents a new mechanism that aliphatic soil organic matter was stabilized by association with iron oxide. Selective stabilization of aliphatic over aromatic carbon can greatly contribute to the widely observed accumulation of aliphatic carbon in soil, which cannot be explained by sorptive interactions between minerals and organic matter. PMID- 26061260 TI - Use of open-source software for adaptive measurement: Concerto as an R-based computer adaptive development and delivery platform. PMID- 26061261 TI - Recurrent High-Flow Arterio-Venous Malformation of the Thyroid Gland. AB - BACKGROUND: Vascular malformations and hemangiomas of the thyroid gland are rare disorders. The first case of a patient with recurrent high-flow arterio-venous malformation of the right thyroid gland involving the right endolarynx is presented. PATIENT FINDINGS: In June 2013, a 42-year-old female patient presented to the surgical department with recurrent hoarseness and a soft, vibrating mass on the right side of her neck. In 1993, she underwent right subtotal hemithyroidectomy with embolization on the day before surgery for a high-flow arterio-venous malformation of the thyroid gland. Diagnostic work-up in 2013 demonstrated a complex recurrent high-flow arterio-venous malformation on the right side of her neck involving the endolarynx. Full function of the right vocal fold could not be ascertained. The lesion was embolized again and excised the following day. Intraoperative gross bleeding and scar tissue prevented visualization and monitoring of the recurrent laryngeal nerve. Gross bleeding was also noted on hemithyroidectomy after embolization in 1993. No therapy was needed for the endolaryngeal part of the lesion. Histology showed large arterio-venous malformations with thyroid tissue. She remains well without signs of recurrence 18 month later but with a definitive voice handicap. SUMMARY: This is the first report of a recurrent high-flow arterio-venous malformation originally developing from the right thyroid gland involving the right endolarynx. Counseling, diagnostic, and therapeutic work-up of the patient was possible only with an interdisciplinary team. The endolaryngeal part of the hemangioma dried out after embolization and completion hemithyroidectomy. Her hoarseness has greatly improved but a definitive voice handicap remains. CONCLUSION: High-flow arterio venous malformations of the thyroid gland are a rare disease, and recurrent lesions have not been reported. Interdisciplinary management of these patients is mandatory due to the complex nature of the underlying pathology. Recurrence might develop after long free intervals. PMID- 26061262 TI - A Paleolatitude Calculator for Paleoclimate Studies. AB - Realistic appraisal of paleoclimatic information obtained from a particular location requires accurate knowledge of its paleolatitude defined relative to the Earth's spin-axis. This is crucial to, among others, correctly assess the amount of solar energy received at a location at the moment of sediment deposition. The paleolatitude of an arbitrary location can in principle be reconstructed from tectonic plate reconstructions that (1) restore the relative motions between plates based on (marine) magnetic anomalies, and (2) reconstruct all plates relative to the spin axis using a paleomagnetic reference frame based on a global apparent polar wander path. Whereas many studies do employ high-quality relative plate reconstructions, the necessity of using a paleomagnetic reference frame for climate studies rather than a mantle reference frame appears under-appreciated. In this paper, we briefly summarize the theory of plate tectonic reconstructions and their reference frames tailored towards applications of paleoclimate reconstruction, and show that using a mantle reference frame, which defines plate positions relative to the mantle, instead of a paleomagnetic reference frame may introduce errors in paleolatitude of more than 15 degrees (>1500 km). This is because mantle reference frames cannot constrain, or are specifically corrected for the effects of true polar wander. We used the latest, state-of-the-art plate reconstructions to build a global plate circuit, and developed an online, user friendly paleolatitude calculator for the last 200 million years by placing this plate circuit in three widely used global apparent polar wander paths. As a novelty, this calculator adds error bars to paleolatitude estimates that can be incorporated in climate modeling. The calculator is available at www.paleolatitude.org. We illustrate the use of the paleolatitude calculator by showing how an apparent wide spread in Eocene sea surface temperatures of southern high latitudes may be in part explained by a much wider paleolatitudinal distribution of sites than previously assumed. PMID- 26061263 TI - Distributions of Autocorrelated First-Order Kinetic Outcomes: Illness Severity. AB - Many complex systems produce outcomes having recurring, power law-like distributions over wide ranges. However, the form necessarily breaks down at extremes, whereas the Weibull distribution has been demonstrated over the full observed range. Here the Weibull distribution is derived as the asymptotic distribution of generalized first-order kinetic processes, with convergence driven by autocorrelation, and entropy maximization subject to finite positive mean, of the incremental compounding rates. Process increments represent multiplicative causes. In particular, illness severities are modeled as such, occurring in proportion to products of, e.g., chronic toxicant fractions passed by organs along a pathway, or rates of interacting oncogenic mutations. The Weibull form is also argued theoretically and by simulation to be robust to the onset of saturation kinetics. The Weibull exponential parameter is shown to indicate the number and widths of the first-order compounding increments, the extent of rate autocorrelation, and the degree to which process increments are distributed exponential. In contrast with the Gaussian result in linear independent systems, the form is driven not by independence and multiplicity of process increments, but by increment autocorrelation and entropy. In some physical systems the form may be attracting, due to multiplicative evolution of outcome magnitudes towards extreme values potentially much larger and smaller than control mechanisms can contain. The Weibull distribution is demonstrated in preference to the lognormal and Pareto I for illness severities versus (a) toxicokinetic models, (b) biologically-based network models, (c) scholastic and psychological test score data for children with prenatal mercury exposure, and (d) time-to-tumor data of the ED01 study. PMID- 26061264 TI - Residual Hearing in DFNB1 Deafness and Its Clinical Implication in a Korean Population. AB - INTRODUCTION: The contribution of Gap junction beta-2 protein (GJB2) to the genetic load of deafness and its mutation spectra vary among different ethnic groups. OBJECTIVE: In this study, the mutation spectrum and audiologic features of patients with GJB2 mutations were evaluated with a specific focus on residual hearing. METHODS: An initial cohort of 588 subjects from 304 families with varying degrees of hearing loss were collected at the otolaryngology clinics of Seoul National University Hospital and Seoul National University Bundang Hospital from September 2010 through January 2014. GJB2 sequencing was carried out for 130 probands with sporadic or autosomal recessive non syndromic hearing loss. The audiograms were evaluated in the GJB2 mutants. RESULTS: Of the 130 subjects, 22 (16.9%) were found to carry at least one mutant allele of GJB2. The c.235delC mutation was shown to have the most common allele frequency (39.0%) among GJB2 mutations, followed by p.R143W (26.8%) and p.V37I (9.8%). Among those probands without the p.V37I allele in a trans configuration who showed some degree of residual hearing, the mean air conduction thresholds at 250 and 500 Hz were 57 dB HL and 77.8 dB HL, respectively. The c.235delC mutation showed a particularly wide spectrum of hearing loss, from mild to profound and significantly better hearing thresholds at 250 Hz and 2k Hz than in the non-p.V37I and non-235delC nonsyndromic hearing loss and deafness 1(DFNB1) subjects. CONCLUSION: Despite its reputation as the cause of severe to profound deafness, c.235delC, the most frequent DFNB1 mutation in our cohort, caused a wide range of hearing loss with some residual hearing in low frequencies. This finding can be of paramount help for prediction of low frequency hearing thresholds in very young DFNB1 patients and highlights the importance of soft surgery for cochlear implantation in these patients. PMID- 26061266 TI - Activation of the interleukin-6/Janus kinase/STAT3 pathway in pleomorphic adenoma of the parotid gland. AB - The interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway is of crucial importance in promoting tumorigenesis in several malignant tumors but may also be active in benign tumors, e.g., of pleomorphic adenoma (PA). In this study we characterize the expression of the pathway components with immunohistochemistry and selected mRNAs and microRNAs (miRNAs) regulated by this pathway in isolated duct- and myoepithelial cells in PA. 46 PAs were immunostained and 10 of these were used for in situ hybridization (ISH). Six frozen specimens were analyzed using reverse transcription-polymerase chain reaction (RT-PCR). Using immunohistochemistry, IL 6, JAK1, JAK2 and STAT3 were detected significantly more frequently in PA cells than in cells from normal salivary gland tissue. Using RT-PCR cyclin D1, fibroblast growth factor 2, and p21 were found to be overexpressed while matrix metallopeptidase 9 was detected at low levels in PA compared to normal salivary gland. ISH showed significant overexpression of miR-181b in PA, while miR-21 was undetectable in PA and normal tissue. Overexpression of the pathway components and its mRNA and miRNA products provide important clues regarding the growth of PAs. Our findings brings us one step closer to targeted treatment of this tumor entity, although in vitro studies are warranted to confirm this. PMID- 26061265 TI - Construction and Immunogenicity Evaluation of Recombinant Influenza A Viruses Containing Chimeric Hemagglutinin Genes Derived from Genetically Divergent Influenza A H1N1 Subtype Viruses. AB - BACKGROUND AND OBJECTIVES: Influenza A viruses cause highly contagious diseases in a variety of hosts, including humans and pigs. To develop a vaccine that can be broadly effective against genetically divergent strains of the virus, in this study we employed molecular breeding (DNA shuffling) technology to create a panel of chimeric HA genes. METHODS AND RESULTS: Each chimeric HA gene contained genetic elements from parental swine influenza A viruses that had a history of zoonotic transmission, and also from a 2009 pandemic virus. Each parental virus represents a major phylogenetic clade of influenza A H1N1 viruses. Nine shuffled HA constructs were initially screened for immunogenicity in mice by DNA immunization, and one chimeric HA (HA-129) was expressed on both a A/Puerto Rico/8/34 backbone with mutations associated with a live, attenuated phenotype (PR8LAIV-129) and a A/swine/Texas/4199-2/98 backbone (TX98-129). When delivered to mice, the PR8LAIV-129 induced antibodies against all four parental viruses, which was similar to the breadth of immunity observed when HA-129 was delivered as a DNA vaccine. This chimeric HA was then tested as a candidate vaccine in a nursery pig model, using inactivated TX98-129 virus as the backbone. The results demonstrate that pigs immunized with HA-129 developed antibodies against all four parental viruses, as well as additional primary swine H1N1 influenza virus field isolates. CONCLUSION: This study established a platform for creating novel genes of influenza viruses using a molecular breeding approach, which will have important applications toward future development of broadly protective influenza virus vaccines. PMID- 26061267 TI - Alternative sedation for the higher risk endoscopy: a randomized controlled trial of ketamine use in endoscopic retrograde cholangiopancreatography. AB - OBJECTIVE: Sedation for endoscopy carries an element of cardiorespiratory risk, more significant for certain procedures and in certain patient groups. Ketamine has features which make it an attractive agent for sedation during the higher risk endoscopy; the objectives of this pilot trial were to assess the effectiveness and tolerability of ketamine as a primary agent for sedation during endoscopy. METHODS: The study was a prospective randomized controlled trial, in which American Society of Anesthesiologists' (ASA) class 1-3 patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) received either conventional sedation with midazolam and pethidine or a combination of midazolam and ketamine. Patients were monitored physiologically and in respect to depth of sedation (Modified Observer's Assessment of Alertness/Sedation score) and were observed post procedure for evidence of emergence reactions or other complications. After full recovery, patients completed a questionnaire on their experiences, with particular emphasis on vivid dreaming or other complications attributable to ketamine. RESULTS: Demographically, control (n = 18) and study (n = 19) groups were similar in makeup. Median midazolam dose was 2 mg (interquartile range [IQR] = 1-3) and 2 mg (IQR = 2-3), respectively (p = 0.98); median procedure duration was 25.5 min (IQR = 17-30) and 21.0 min (IQR = 15-34) (p = 0.92). Median satisfaction with sedation (scored from 0 to 4) was 3.5 (range 1-4) and 4 (range 2-4) respectively (p = 0.88). No patient in either group experienced emergence reactions, dysphoria, or vivid dreaming. CONCLUSION: In this pilot study, sedation for endoscopy with ketamine and midazolam was as effective as conventional sedation, as acceptable to patients, and was not associated with dysphoric events. Ketamine may have potential as an agent for sedation in higher risk patients. PMID- 26061268 TI - Scan-Free Absorbance Spectral Imaging A(x, y, lambda) of Single Live Algal Cells for Quantifying Absorbance of Cell Suspensions. AB - Label-free, non-invasive, rapid absorbance spectral imaging A(x,y,lambda) microscopy of single live cells at 1.2 MUm * 1.2 MUm resolution with an NA = 0.85 objective was developed and applied to unicellular green algae Chlamydomonas reinhardtii. By introducing the fiber assembly to rearrange a two-dimensional image to the one-dimensional array to fit the slit of an imaging spectrograph equipped with a CCD detector, scan-free acquisition of three-dimensional information of A(x,y,lambda) was realized. The space-resolved absorbance spectra of the eyespot, an orange organelle about 1 MUm, were extracted from the green color background in a chlorophyll-rich single live cell absorbance image. Characteristic absorbance change in the cell suspension after hydrogen photoproduction in C. reinhardtii was investigated to find a single 715-nm absorption peak was locally distributed within single cells. The formula to calculate the absorbance of cell suspensions from that of single cells was presented to obtain a quantitative, parameter-free agreement with the experiment. It is quantitatively shown that the average number of chlorophylls per cell is significantly underestimated when it is evaluated from the absorbance of the cell suspensions due to the package effect. PMID- 26061269 TI - Facile Synthesis of Carbazoles via a Tandem Iodocyclization with 1,2-Alkyl Migration and Aromatization. AB - A strategy for the synthesis of iodocarbazoles through a tandem iodocyclization with migration and aromatization is presented. This sequential cascade process is concisely conducted at room temperature and in a short time. Moreover, the obtained halides can be further applied to palladium-catalyzed coupling reactions, which act as the important intermediates for building other valuable compounds. PMID- 26061270 TI - Front Crawl Sprint Performance: A Cluster Analysis of Biomechanics, Energetics, Coordinative, and Anthropometric Determinants in Young Swimmers. AB - The aim of this study was to evaluate the determinants of front crawl sprint performance of young swimmers using a cluster analysis. 103 swimmers, aged 11- to 13-years old, performed 25-m front crawl swimming at 50-m pace, recorded by two underwater cameras. Swimmers analysis included biomechanics, energetics, coordinative, and anthropometric characteristics. The organization of subjects in meaningful clusters, originated three groups (1.52 +/- 0.16, 1.47 +/- 0.17 and 1.40 +/- 0.15 m/s, for Clusters 1, 2 and 3, respectively) with differences in velocity between Cluster 1 and 2 compared with Cluster 3 (p = .003). Anthropometric variables were the most determinants for clusters solution. Stroke length and stroke index were also considered relevant. In addition, differences between Cluster 1 and the others were also found for critical velocity, stroke rate and intracycle velocity variation (p < .05). It can be concluded that anthropometrics, technique and energetics (swimming efficiency) are determinant domains to young swimmers sprint performance. PMID- 26061271 TI - Nanostructured p-type CZTS thin films prepared by a facile solution process for 3D p-n junction solar cells. AB - Nanoporous p-type semiconductor thin films prepared by a simple solution-based process with appropriate thermal treatment and three-dimensional (3D) p-n junction solar cells fabricated by depositing n-type semiconductor layers onto the nanoporous p-type thin films show considerable photovoltaic performance compared with conventional thin film p-n junction solar cells. Spin-coated p-type Cu2ZnSnS4 (CZTS) thin films prepared using metal chlorides and thiourea show unique nanoporous thin film morphology, which is composed of a cluster of CZTS nanograins of 50-500 nm, and the obvious 3D p-n junction structure is fabricated by the deposition of n-type CdS on the nanoporous CZTS thin films by chemical bath deposition. The photovoltaic properties of 3D p-n junction CZTS solar cells are predominantly affected by the scale of CZTS nanograins, which is easily controlled by the sulfurization temperature of CZTS precursor films. The scale of CZTS nanograins determines the minority carrier transportation within the 3D p-n junction between CZTS and CdS, which are closely related with the photocurrent of series resistance of 3D p-n junction solar cells. 3D p-n junction CZTS solar cells with nanograins below 100 nm show power conversion efficiency of 5.02%, which is comparable with conventional CZTS thin film solar cells. PMID- 26061273 TI - Writing in the Air: Contributions of Finger Movement to Cognitive Processing. AB - The present study investigated the interactions between motor action and cognitive processing with particular reference to kanji-culture individuals. Kanji-culture individuals often move their finger as if they are writing when they are solving cognitive tasks, for example, when they try to recall the spelling of English words. This behavior is called kusho, meaning air-writing in Japanese. However, its functional role is still unknown. To reveal the role of kusho behavior in cognitive processing, we conducted a series of experiments, employing two different cognitive tasks, a construction task and a stroke count task. To distinguish the effects of the kinetic aspects of kusho behavior, we set three hand conditions in the tasks; participants were instructed to use either kusho, unrelated finger movements or do nothing during the response time. To isolate possible visual effects, two visual conditions in which participants saw their hand and the other in which they did not, were introduced. We used the number of correct responses and response time as measures of the task performance. The results showed that kusho behavior has different functional roles in the two types of cognitive tasks. In the construction task, the visual feedback from finger movement facilitated identifying a character, whereas the kinetic feedback or motor commands for the behavior did not help to solve the task. In the stroke count task, by contrast, the kinetic aspects of the finger movements influenced counting performance depending on the type of the finger movement. Regardless of the visual condition, kusho behavior improved task performance and unrelated finger movements degraded it. These results indicated that motor behavior contributes to cognitive processes. We discussed possible mechanisms of the modality dependent contribution. These findings might lead to better understanding of the complex interaction between action and cognition in daily life. PMID- 26061274 TI - A Cleaner Process for Selective Recovery of Valuable Metals from Electronic Waste of Complex Mixtures of End-of-Life Electronic Products. AB - In recent years, recovery of metals from electronic waste within the European Union has become increasingly important due to potential supply risk of strategic raw material and environmental concerns. Electronic waste, especially a mixture of end-of-life electronic products from a variety of sources, is of inherently high complexity in composition, phase, and physiochemical properties. In this research, a closed-loop hydrometallurgical process was developed to recover valuable metals, i.e., copper and precious metals, from an industrially processed information and communication technology waste. A two-stage leaching design of this process was adopted in order to selectively extract copper and enrich precious metals. It was found that the recovery efficiency and extraction selectivity of copper both reached more than 95% by using ammonia-based leaching solutions. A new electrodeposition process has been proven feasible with 90% current efficiency during copper recovery, and the copper purity can reach 99.8 wt %. The residue from the first-stage leaching was screened into coarse and fine fractions. The coarse fraction was returned to be releached for further copper recovery. The fine fraction was treated in the second-stage leaching using sulfuric acid to further concentrate precious metals, which could achieve a 100% increase in their concentrations in the residue with negligible loss into the leaching solution. By a combination of different leaching steps and proper physical separation of light materials, this process can achieve closed-loop recycling of the waste with significant efficiency. PMID- 26061272 TI - A systematic review and meta-analysis of randomized trials on the role of targeted therapy in the management of advanced gastric cancer: Evidence does not translate? AB - It is still uncertain if targeted therapy-based regimens in advanced gastric cancer actually produce survival benefit. To shed light on this important question, we performed a systematic review and meta-analyses on each relevant targeted-pathway. By searching literature databases and proceedings of major cancer meetings in the time-frame 2005-2014, 22 randomized clinical trials exploring targeted therapy for a total of 7022 advanced gastric cancer patients were selected and included in the final analysis. Benefit was demonstrated for antiangiogenic agents in terms of overall survival (HR 0.759; 95%CI 0.655-0.880; p < 0.001). Conversely no benefit was found for EGFR pathway (HR 1.077; 95%CI 0.847-1.370; p = 0.543). Meta-analysis of HER-2 pathway confirmed improvement in terms of survival outcome, already known for this class of drugs (HR 0.823; 95%CI 0.722-0.939; p = 0.004). Pooled analysis demonstrated a significant survival benefit (OS: HR 0.823; PFS: HR 0.762) with acceptable tolerability profile for targeted-based therapies as compared to conventional treatments. This finding conflicts with the outcome of most individual studies, probably due to poor trial design or patients selection. In conclusion, our findings demonstrate a significant survival benefit for targeted therapy in its whole, which can be ascribed to anti-angiogenic and anti-HER2 agents. PMID- 26061276 TI - Vaccination Coverage and Compliance with Three Recommended Schedules of 10-Valent Pneumococcal Conjugate Vaccine during the First Year of Its Introduction in Brazil: A Cross-Sectional Study. AB - Pneumococcal 10-valent conjugate vaccine (PCV10) was introduced to Brazil's National Immunization Program (NIP) in 2010. During the first year of vaccine introduction three schedules were used to deal with age at initiation of PCV for catch-up purposes: 3 primary doses + 1 booster (for children aged <=6 months), a catch-up schedule of 2 doses + 1 booster (7-11 months), and a catch-up schedule of a single dose (12-15 months). The purpose of this study was to assess the magnitude and associated risk factors for under-vaccination or lack of on time vaccination six to eight months after PCV10 introduction. A household survey was conducted in the municipality of Goiania with 1,237 children, who were retroactively classified into one of three age groups, as a factor of the child's age relatively to 30 days after PCV10 introduction. Socioeconomic characteristics and vaccination dates were obtained during home interviews. Vaccination coverage was defined as the percentage of children who completed the recommended number of doses. Compliance with recommended schedules was defined as the percentage of children who received all valid doses at the NIP recommended time interval. Adjusted prevalence ratios (PR) of variables independently associated with coverage and compliance were estimated by log binomial regression. Coverage of DTP-Hib was used for comparison purposes. Overall, vaccination coverage was 54.6% (95% CI 52.1-57.7%), lower than DTP-Hib coverage (93.0%; 95% CI 91.5-94.3%). Compliance with recommended schedules was 16.8% (95% CI: 14.7-18.6%). Children 7 11 months old had lower coverage (40.7%) and compliance (6.3%) compared to children aged 12-15 months (coverage: 88.8%; compliance: 35.6%) and <=6 months old (coverage: 54%; compliance: 18.8%). Having private health insurance was associated with higher PCV10 coverage (PR=1.25; 95% CI: 1.06-1.47, p=0.007), and compliance (PR=1.09; 95% CI: 1.02-1.16, p=0.015). Although PCV10 coverage rapidly increased shortly after vaccination introduction, it was not matched by compliance with recommended schedules. Public initiatives should target compliance of PCV10 because of the burden of pneumococcal diseases on childhood morbidity and mortality. PMID- 26061277 TI - One central oscillatory drive is compatible with experimental motor unit behaviour in essential and Parkinsonian tremor. AB - OBJECTIVE: Pathological tremors are symptomatic to several neurological disorders that are difficult to differentiate and the way by which central oscillatory networks entrain tremorogenic contractions is unknown. We considered the alternative hypotheses that tremor arises from one oscillator (at the tremor frequency) or, as suggested by recent findings from the superimposition of two separate inputs (at the tremor frequency and twice that frequency). APPROACH: Assuming one central oscillatory network we estimated analytically the relative amplitude of the harmonics of the tremor frequency in the motor neuron output for different temporal behaviors of the oscillator. Next, we analyzed the bias in the relative harmonics amplitude introduced by superimposing oscillations at twice the tremor frequency. These findings were validated using experimental measurements of wrist angular velocity and surface electromyography (EMG) from 22 patients (11 essential tremor, 11 Parkinson's disease). The ensemble motor unit action potential trains identified from the EMG represented the neural drive to the muscles. MAIN RESULTS: The analytical results showed that the relative power of the tremor harmonics in the analytical models of the neural drive was determined by the variability and duration of the tremor bursts and the presence of the second oscillator biased this power towards higher values. The experimental findings accurately matched the analytical model assuming one oscillator, indicating a negligible functional role of secondary oscillatory inputs. Furthermore, a significant difference in the relative power of harmonics in the neural drive was found across the patient groups, suggesting a diagnostic value of this measure (classification accuracy: 86%). This diagnostic power decreased substantially when estimated from limb acceleration or the EMG. SIGNFICANCE: The results indicate that the neural drive in pathological tremor is compatible with one central network providing neural oscillations at the tremor frequency. Moreover, the regularity of this neural oscillation varies across tremor pathologies, making the relative amplitude of tremor harmonics a potential biomarker for diagnostic use. PMID- 26061275 TI - Necrotic Cells Actively Attract Phagocytes through the Collaborative Action of Two Distinct PS-Exposure Mechanisms. AB - Necrosis, a kind of cell death closely associated with pathogenesis and genetic programs, is distinct from apoptosis in both morphology and mechanism. Like apoptotic cells, necrotic cells are swiftly removed from animal bodies to prevent harmful inflammatory and autoimmune responses. In the nematode Caenorhabditis elegans, gain-of-function mutations in certain ion channel subunits result in the excitotoxic necrosis of six touch neurons and their subsequent engulfment and degradation inside engulfing cells. How necrotic cells are recognized by engulfing cells is unclear. Phosphatidylserine (PS) is an important apoptotic cell surface signal that attracts engulfing cells. Here we observed PS exposure on the surface of necrotic touch neurons. In addition, the phagocytic receptor CED-1 clusters around necrotic cells and promotes their engulfment. The extracellular domain of CED-1 associates with PS in vitro. We further identified a necrotic cell-specific function of CED-7, a member of the ATP-binding cassette (ABC) transporter family, in promoting PS exposure. In addition to CED-7, anoctamin homolog-1 (ANOH-1), the C. elegans homolog of the mammalian Ca(2+) dependent phospholipid scramblase TMEM16F, plays an independent role in promoting PS exposure on necrotic cells. The combined activities from CED-7 and ANOH-1 ensure efficient exposure of PS on necrotic cells to attract their phagocytes. In addition, CED-8, the C. elegans homolog of mammalian Xk-related protein 8 also makes a contribution to necrotic cell-removal at the first larval stage. Our work indicates that cells killed by different mechanisms (necrosis or apoptosis) expose a common "eat me" signal to attract their phagocytic receptor(s); furthermore, unlike what was previously believed, necrotic cells actively present PS on their outer surfaces through at least two distinct molecular mechanisms rather than leaking out PS passively. PMID- 26061278 TI - Acidic Fibroblast Growth Factor Promotes Endothelial Progenitor Cells Function via Akt/FOXO3a Pathway. AB - Acidic fibroblast growth factor (FGF1) has been suggested to enhance the functional activities of endothelial progenitor cells (EPCs). The Forkhead homeobox type O transcription factors (FOXOs), a key substrate of the survival kinase Akt, play important roles in regulation of various cellular processes. We previously have shown that FOXO3a is the main subtype of FOXOs expressed in EPCs. Here, we aim to determine whether FGF1 promotes EPC function through Akt/FOXO3a pathway. Human peripheral blood derived EPCs were transduced with adenoviral vectors either expressing a non-phosphorylable, constitutively active triple mutant of FOXO3a (Ad-TM-FOXO3a) or a GFP control (Ad-GFP). FGF1 treatment improved functional activities of Ad-GFP transduced EPCs, including cell viability, proliferation, antiapoptosis, migration and tube formation, whereas these beneficial effects disappeared by Akt inhibitor pretreatment. Moreover, EPC function was declined by Ad-TM-FOXO3a transduction and failed to be attenuated even with FGF1 treatment. FGF1 upregulated phosphorylation levels of Akt and FOXO3a in Ad-GFP transduced EPCs, which were repressed by Akt inhibitor pretreatment. However, FGF1 failed to recover Ad-TM-FOXO3a transduced EPCs from dysfunction. These data indicate that FGF1 promoting EPC function is at least in part mediated through Akt/FOXO3a pathway. Our study may provide novel ideas for enhancing EPC angiogenic ability and optimizing EPC transplantation therapy in the future. PMID- 26061279 TI - Abnormal motor cortex excitability during linguistic tasks in adductor-type spasmodic dysphonia. AB - In healthy subjects (HS), transcranial magnetic stimulation (TMS) applied during 'linguistic' tasks discloses excitability changes in the dominant hemisphere primary motor cortex (M1). We investigated 'linguistic' task-related cortical excitability modulation in patients with adductor-type spasmodic dysphonia (ASD), a speech-related focal dystonia. We studied 10 ASD patients and 10 HS. Speech examination included voice cepstral analysis. We investigated the dominant/non dominant M1 excitability at baseline, during 'linguistic' (reading aloud/silent reading/producing simple phonation) and 'non-linguistic' tasks (looking at non letter strings/producing oral movements). Motor evoked potentials (MEPs) were recorded from the contralateral hand muscles. We measured the cortical silent period (CSP) length and tested MEPs in HS and patients performing the 'linguistic' tasks with different voice intensities. We also examined MEPs in HS and ASD during hand-related 'action-verb' observation. Patients were studied under and not-under botulinum neurotoxin-type A (BoNT-A). In HS, TMS over the dominant M1 elicited larger MEPs during 'reading aloud' than during the other 'linguistic'/'non-linguistic' tasks. Conversely, in ASD, TMS over the dominant M1 elicited increased-amplitude MEPs during 'reading aloud' and 'syllabic phonation' tasks. CSP length was shorter in ASD than in HS and remained unchanged in both groups performing 'linguistic'/'non-linguistic' tasks. In HS and ASD, 'linguistic' task-related excitability changes were present regardless of the different voice intensities. During hand-related 'action-verb' observation, MEPs decreased in HS, whereas in ASD they increased. In ASD, BoNT-A improved speech, as demonstrated by cepstral analysis and restored the TMS abnormalities. ASD reflects dominant hemisphere excitability changes related to 'linguistic' tasks; BoNT-A returns these excitability changes to normal. PMID- 26061280 TI - Prehospital Naloxone Administration as a Public Health Surveillance Tool: A Retrospective Validation Study. AB - BACKGROUND: Abuse or unintended overdose (OD) of opiates and heroin may result in prehospital and emergency department (ED) care. Prehospital naloxone use has been suggested as a surrogate marker of community opiate ODs. The study objective was to verify externally whether prehospital naloxone use is a surrogate marker of community opiate ODs by comparing Emergency Medical Services (EMS) naloxone administration records to an independent database of ED visits for opiate and heroin ODs in the same community. METHODS: A retrospective chart review of prehospital and ED data from July 2009 through June 2013 was conducted. Prehospital naloxone administration data obtained from the electronic medical records (EMRs) of a large private EMS provider serving a metropolitan area were considered a surrogate marker for suspected opiate OD. Comparison data were obtained from the regional trauma/psychiatric ED that receives the majority of the OD patients. The ED maintains a de-identified database of narcotic-related visits for surveillance of narcotic use in the metropolitan area. The ED database was queried for ODs associated with opiates or heroin. Cross-correlation analysis was used to test if prehospital naloxone administration was independent of ED visits for opiate/heroin ODs. RESULTS: Naloxone was administered during 1,812 prehospital patient encounters, and 1,294 ED visits for opiate/heroin ODs were identified. The distribution of patients in the prehospital and ED datasets did not differ by gender, but it did differ by race and age. The frequency of naloxone administration by prehospital providers varied directly with the frequency of ED visits for opiate/heroin ODs. A monthly increase of two ED visits for opiate-related ODs was associated with an increase in one prehospital naloxone administration (cross-correlation coefficient [CCF]=0.44; P=.0021). A monthly increase of 100 ED visits for heroin-related ODs was associated with an increase in 94 prehospital naloxone administrations (CCF=0.46; P=.0012). CONCLUSIONS: Frequency of naloxone administration by EMS providers in the prehospital setting varied directly with frequency of opiate/heroin OD-related ED visits. The data correlated both for short-term frequency and longer term trends of use. However, there was a marked difference in demographic data suggesting neither data source alone should be relied upon to determine which populations are at risk within the community. PMID- 26061281 TI - miR-135b Promotes Cancer Progression by Targeting Transforming Growth Factor Beta Receptor II (TGFBR2) in Colorectal Cancer. AB - The transforming growth factor beta (TGF-beta) signaling pathway is a tumor suppressor pathway that is commonly inactivated in colorectal cancer (CRC). The inactivation of TGFBR2 is the most common genetic event affecting the TGF-beta signaling pathway. However, the mechanism by which cancer cells downregulate TGFBR2 is unclear. In this study, we found that the TGFBR2 protein levels were consistently upregulated in CRC tissues, whereas its mRNA levels varied in these tissues, suggesting that a post-transcriptional mechanism is involved in the regulation of TGFBR2. Because microRNAs (miRNAs) are powerful post transcriptional regulators of gene expression, we performed bioinformatic analyses to search for miRNAs that potentially target TGFBR2. We identified the specific targeting site of miR-135b in the 3'-untranslated region (3'-UTR) of TGFBR2. We further identified an inverse correlation between the levels of miR 135b and TGFBR2 protein, but not mRNA, in CRC tissue samples. By overexpressing or silencing miR-135b in CRC cells, we experimentally validated that miR-135b directly binds to the 3'-UTR of the TGFBR2 transcript and regulates TGFBR2 expression. Furthermore, the biological consequences of the targeting of TGFBR2 by miR-135b were examined using in vitro cell proliferation and apoptosis assays. We demonstrated that miR-135b exerted a tumor-promoting effect by inducing the proliferation and inhibiting the apoptosis of CRC cells via the negative regulation of TGFBR2 expression. Taken together, our findings provide the first evidence supporting the role of miR-135b as an oncogene in CRC via the inhibition of TGFBR2 translation. PMID- 26061282 TI - Embryonic Medaka Model of Microglia in the Developing CNS Allowing In Vivo Analysis of Their Spatiotemporal Recruitment in Response to Irradiation. AB - Radiation therapy (RT) is pivotal in the treatment of many central nervous system (CNS) pathologies; however, exposure to RT in children is associated with a higher risk of secondary CNS tumors. Although recent research interest has focused on the reparative and therapeutic role of microglia, their recruitment following RT has not been elucidated, especially in the developing CNS. Here, we investigated the spatiotemporal dynamics of microglia during tissue repair in the irradiated embryonic medaka brain by whole-mount in situ hybridization using a probe for Apolipoprotein E (ApoE), a marker for activated microglia in teleosts. Three-dimensional imaging of the distribution of ApoE-expressing microglia in the irradiated embryonic brain clearly showed that ApoE-expressing microglia were abundant only in the late phase of phagocytosis during tissue repair induced by irradiation, while few microglia expressed ApoE in the initial phase of phagocytosis. This strongly suggests that ApoE has a significant function in the late phase of phagocytosis by microglia in the medaka brain. In addition, the distribution of microglia in p53-deficient embryos at the late phase of phagocytosis was almost the same as in wild-type embryos, despite the low numbers of irradiation-induced apoptotic neurons, suggesting that constant numbers of activated microglia were recruited at the late phase of phagocytosis irrespective of the extent of neuronal injury. This medaka model of microglia demonstrated specific recruitment after irradiation in the developing CNS and could provide a useful potential therapeutic strategy to counteract the detrimental effects of RT. PMID- 26061283 TI - Waveguide integrated superconducting single-photon detectors with high internal quantum efficiency at telecom wavelengths. AB - Superconducting nanowire single-photon detectors (SNSPDs) provide high efficiency for detecting individual photons while keeping dark counts and timing jitter minimal. Besides superior detection performance over a broad optical bandwidth, compatibility with an integrated optical platform is a crucial requirement for applications in emerging quantum photonic technologies. Here we present SNSPDs embedded in nanophotonic integrated circuits which achieve internal quantum efficiencies close to unity at 1550 nm wavelength. This allows for the SNSPDs to be operated at bias currents far below the critical current where unwanted dark count events reach milli-Hz levels while on-chip detection efficiencies above 70% are maintained. The measured dark count rates correspond to noise-equivalent powers in the 10(-19) W/Hz(-1/2) range and the timing jitter is as low as 35 ps. Our detectors are fully scalable and interface directly with waveguide-based optical platforms. PMID- 26061284 TI - Synthesis, Biological Evaluation, and Docking of Dihydropyrazole Sulfonamide Containing 2-hydroxyphenyl Moiety: A Series of Novel MMP-2 Inhibitors. AB - In this study, we synthesized a series of dihydropyrazole sulfonamide derivatives containing 2-hydroxyphenyl moiety as antitumor agents to target the matrix metalloproteinase-2 (MMP-2). All of the synthesized compounds were examined by bioactivity assays, in which compound 4c turned out as a potential antagonist of MMP-2 along with potent anticancer activity against four tumor cell lines. Structure-activity relationship analysis was also performed to examine how structural changes impacted the bioactivity. Suggested to be caused by the induction of apoptosis, the antitumor mechanism of 4c was further confirmed by PI combining with annexin V-FITC staining assay using flow cytometry analysis. These new findings along with molecular docking observations suggested that compound 4c could be developed as a potential anticancer agent. PMID- 26061285 TI - Modulating the magnetic behavior of Fe(II)-MOF-74 by the high electron affinity of the guest molecule. AB - As a new class of magnetic materials, metal-organic framework (MOF) has received a significant attention due to their functionality and porosity that can provide diverse magnetic phenomena by utilizing host-guest chemistry. For Fe-MOF-74, we here find using density functional calculations that the O2 and C2H4 adsorptions result in the ferromagnetic (FM) and antiferromagnetic (AFM) orderings along the 1D chain of an hexagonal MOF framework, respectively, while their adsorption energies, pi-complexation, and geometrical changes are all similar upon binding. We reveal that this different magnetism behavior is attributed to the different electronic effects, where the adsorbed O2 greatly withdraws a minor spin electron from the Fe centers. The latter significant back donation opens a new channel for superexchange interactions that can enhance the FM coupling between Fe centers, where the strength of calculated intrachain FM coupling constrant (Jin) in O2 adsorbed Fe-MOF-74 is more than 10 times enhanced compared to bare Fe-MOF-74. This prediction suggests a possibility for the conceptual usage of Fe-MOF-74 as a gas sensor based on its magnetic changes caused by the adsorbed gases. Furthermore, the suggested mechanism might be used to control the magnetic properties of MOFs using the guest molecules, although concrete strategies to enhance such magnetic interactions to be used in practical applications would require further significant investigation. PMID- 26061287 TI - CH(+) Destruction by Reaction with H: Computing Quantum Rates To Model Different Molecular Regions in the Interstellar Medium. AB - A detailed analysis of an ionic reaction that plays a crucial role in the carbon chemistry of the interstellar medium (ISM) is carried out by computing ab initio reactive cross sections with a quantum method and by further obtaining the corresponding CH(+) destruction rates over a range of temperatures that shows good overall agreement with existing experiments. The differences found between all existing calculations and the very-low-T experiments are discussed and explored via a simple numerical model that links these cross section reductions to collinear approaches where nonadiabatic crossing is expected to dominate. The new rates are further linked to a complex chemical network that models the evolution of the CH(+) abundance in the photodissociation region (PDR) and molecular cloud (MC) environments of the ISM. The abundances of CH(+) are given by numerical solutions of a large set of coupled, first-order kinetics equations that employs our new chemical package krome. The analysis that we carry out reveals that the important region for CH(+) destruction is that above 100 K, hence showing that, at least for this reaction, the differences with the existing laboratory low-T experiments are of essentially no importance within the astrochemical environments discussed here because, at those temperatures, other chemical processes involving the title molecule are taking over. A detailed analysis of the chemical network involving CH(+) also shows that a slight decrease in the initial oxygen abundance might lead to higher CH(+) abundances because the main chemical carbon ion destruction channel is reduced in efficiency. This might provide an alternative chemical route to understand the reason why general astrochemical models fail when the observed CH(+) abundances are matched with the outcomes of their calculations. PMID- 26061286 TI - The Arabidopsis mitogen-activated protein kinase 6 is associated with gamma tubulin on microtubules, phosphorylates EB1c and maintains spindle orientation under nitrosative stress. AB - Stress-activated plant mitogen-activated protein (MAP) kinase pathways play roles in growth adaptation to the environment by modulating cell division through cytoskeletal regulation, but the mechanisms are poorly understood. We performed protein interaction and phosphorylation experiments with cytoskeletal proteins, mass spectrometric identification of MPK6 complexes and immunofluorescence analyses of the microtubular cytoskeleton of mitotic cells using wild-type, mpk6 2 mutant and plants overexpressing the MAP kinase-inactivating phosphatase, AP2C3. We showed that MPK6 interacted with gamma-tubulin and co-sedimented with plant microtubules polymerized in vitro. It was the active form of MAP kinase that was enriched with microtubules and followed similar dynamics to gamma tubulin, moving from poles to midzone during the anaphase-to-telophase transition. We found a novel substrate for MPK6, the microtubule plus end protein, EB1c. The mpk6-2 mutant was sensitive to 3-nitro-l-tyrosine (NO2 -Tyr) treatment with respect to mitotic abnormalities, and root cells overexpressing AP2C3 showed defects in chromosome segregation and spindle orientation. Our data suggest that the active form of MAP kinase interacts with gamma-tubulin on specific subsets of mitotic microtubules during late mitosis. MPK6 phosphorylates EB1c, but not EB1a, and has a role in maintaining regular planes of cell division under stress conditions. PMID- 26061288 TI - Correction to "Author's reply to Tovey and colleagues". PMID- 26061290 TI - Proton-Induced, Reversible Interconversion of a MU-1,2-Peroxo and a MU-1,1 Hydroperoxo Dicopper(II) Complex. AB - The MU-1,2-peroxo dicopper(II) complex (2) of a compartmental bis(tetradentate) pyrazolate-based ligand is shown to convert, upon protonation, to the corresponding MU-1,1-hydroperoxo dicopper(II) complex (3). The transformation is cleanly reversed with base, and an apparent pK(a) = 22.2 +/- 0.3 for the Cu2OOH unit in MeCN has been determined. The unprecedented stability of 3 (t(1/2) = 9 h in nitrile solvents at room temperature, giving the hydroxo-bridged dicopper complex) has allowed for its structural characterization by X-ray diffraction. While the O-O bond length (1.462(3) A) barely changes upon protonation from 2 to 3, the O-O stretching frequency is much higher in the hydroperoxo complex 3 (860 cm(-1)). 3 mediates 2e(-) oxo transfer to the nucleophilic substrate PPh3 but is not activated for H-atom abstraction. PMID- 26061291 TI - Sexual Problems Among Older Women by Age and Race. AB - BACKGROUND: The purpose of our study was to examine the prevalence of sexual problems by age and race among older women in the United States and to examine quality of life correlates to sexual dysfunction among non-Hispanic white and African American older women. METHODS: A cross-sectional study using self-report surveys was conducted among community-dwelling U.S. women, aged 60 years and over. A total of 807 women aged 61-89 years were included. Self-administered questionnaires assessed sexual dysfunction, satisfaction with life, depressive symptomatology, and self-rated health. Analyses included multivariate logistic regression. RESULTS: The mean age of the sample was 66 years. Two-thirds of the sample had at least one sexual dysfunction; the most common for both African American and non-Hispanic white women were lack of interest in sex and vaginal dryness. Prevalence varied by age for each of the sexual dysfunctions. The odds of experiencing sexual dysfunction varied with age and race. Compared with non Hispanic white women, African American women had lower odds of reporting lack of interest in sex or vaginal dryness. Poor self-rated health, depressive symptomatology, and lower satisfaction with life were associated with higher odds of having some sexual dysfunction. CONCLUSIONS: Improved understanding of how sexual dysfunction affects women across multiple age ranges and racial/ethnic groups can assist providers in making recommendations for care that are patient centered. The associations that we identified with quality of life factors highlight the need to assess sexual health care in the aging female population. PMID- 26061292 TI - LDL Receptor-Related Protein-1 (LRP1) Regulates Cholesterol Accumulation in Macrophages. AB - Within the circulation, cholesterol is transported by lipoprotein particles and is taken up by cells when these particles associate with cellular receptors. In macrophages, excessive lipoprotein particle uptake leads to foam cell formation, which is an early event in the development of atherosclerosis. Currently, mechanisms responsible for foam cell formation are incompletely understood. To date, several macrophage receptors have been identified that contribute to the uptake of modified forms of lipoproteins leading to foam cell formation, but the in vivo contribution of the LDL receptor-related protein 1 (LRP1) to this process is not known [corrected]. To investigate the role of LRP1 in cholesterol accumulation in macrophages, we generated mice with a selective deletion of LRP1 in macrophages on an LDL receptor (LDLR)-deficient background (macLRP1-/-). After feeding mice a high fat diet for 11 weeks, peritoneal macrophages isolated from Lrp+/+ mice contained significantly higher levels of total cholesterol than those from macLRP1-/- mice. Further analysis revealed that this was due to increased levels of cholesterol esters. Interestingly, macLRP1-/- mice displayed elevated plasma cholesterol and triglyceride levels resulting from accumulation of large, triglyceride-rich lipoprotein particles in the circulation. This increase did not result from an increase in hepatic VLDL biosynthesis, but rather results from a defect in catabolism of triglyceride-rich lipoprotein particles in macLRP1-/- mice. These studies reveal an important in vivo contribution of macrophage LRP1 to cholesterol homeostasis. PMID- 26061293 TI - Extracting Primary Open-Angle Glaucoma from Electronic Medical Records for Genetic Association Studies. AB - Electronic medical records (EMRs) are being widely implemented for use in genetic and genomic studies. As a phenotypic rich resource, EMRs provide researchers with the opportunity to identify disease cohorts and perform genotype-phenotype association studies. The Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study, as part of the Population Architecture using Genomics and Epidemiology (PAGE) I study, has genotyped more than 15,000 individuals of diverse genetic ancestry in BioVU, the Vanderbilt University Medical Center's biorepository linked to a de-identified version of the EMR (EAGLE BioVU). Here we develop and deploy an algorithm utilizing data mining techniques to identify primary open-angle glaucoma (POAG) in African Americans from EAGLE BioVU for genetic association studies. The algorithm described here was designed using a combination of diagnostic codes, current procedural terminology billing codes, and free text searches to identify POAG status in situations where gold-standard digital photography cannot be accessed. The case algorithm identified 267 potential POAG subjects but underperformed after manual review with a positive predictive value of 51.6% and an accuracy of 76.3%. The control algorithm identified controls with a negative predictive value of 98.3%. Although the case algorithm requires more downstream manual review for use in large-scale studies, it provides a basis by which to extract a specific clinical subtype of glaucoma from EMRs in the absence of digital photographs. PMID- 26061294 TI - Visual Detection of Speckles in the Fish Xenotoca variata by the Predatory Snake Thamnophis melanogaster in Water of Different Turbidity. AB - Semi-aquatic snakes integrate visual and chemical stimuli, and prey detection and capture success are therefore linked to the display of visual predatory behavior. The snake Thamnophis melanogaster responds preferentially to individuals of the fish Xenotoca variata with a greater number of bright, colorful spots (lateral speckles) compared with those with a smaller number; however, water turbidity can reduce underwater visibility and effect the vulnerability of fish. In this study, we tested whether the presence of iridescent speckles on the flanks of male X. variata interacted with water turbidity to modify the predatory behavior displayed by the snake T. melanogaster. We predicted that in an experimental laboratory test, the snakes would increase the frequency of their predatory behavior to the extent that the water turbidity decreases. The snakes were tested at six different levels of water turbidity, in combination with three categories of male fish (with few, a median number of, or many speckles). The results showed that in a pool with high or zero turbidity, the number of speckles is not a determining factor in the deployment of the predatory behavior of the snake T. melanogaster toward X. variata. Our findings suggest that snakes can view the fish at intermediate percentages of turbidity, but the number of speckles in male X. variata is irrelevant as an interspecific visual signal in environments with insufficient luminosity. The successful capture of aquatic prey is influenced by integration between chemical and visual signals, according to environmental factors that may influence the recognition of individual traits. PMID- 26061295 TI - Asynchronous therapy targeting Nogo-A enhances neurobehavioral recovery by reducing neuronal loss and promoting neurite outgrowth after cerebral ischemia in mice. AB - Therapeutics targeting the Nogo-A signal pathway hold promise to promote recovery following brain injury. Based on the temporal characteristics of Nogo-A expression in the process of cerebral ischemia and reperfusion, we tested a novel asynchronous treatment, in which TAT-M9 was used in the early stage to decrease neuronal loss, and TAT-NEP1-40 was used in the delayed stage to promote neurite outgrowth after bilateral common carotid artery occlusion (BCCAO) in mice. Both TAT-M9 and TAT-NEP1-40 were efficiently delivered into the brains of mice by intraperitoneal injection. TAT-M9 treatment promoted neuron survival and inhibited neuronal apoptosis. Asynchronous therapy with TAT-M9 and TAT-NEP1-40 increased the expression of Tau, GAP43 and MAP-2 proteins, and enhanced short term and long-term cognitive functions. In conclusion, the asynchronous treatment had a long-term neuroprotective effect, which reduced neurologic injury and apoptosis, promoted neurite outgrowth and enhanced functional recovery after ischemia. It suggests that this asynchronous treatment could be a promising therapy for cerebral ischemia in humans. PMID- 26061297 TI - Radiolabelled nanoparticles: novel classification of radiopharmaceuticals for molecular imaging of cancer. AB - Nanotechnology has been used for every single modality in the molecular imaging arena for imaging purposes. Synergic advantages can be explored when multiple molecular imaging modalities are combined with respect to single imaging modalities. Multifunctional nanoparticles have large surface areas, where multiple functional moieties can be incorporated, including ligands for site specific targeting and radionuclides, which can be detected to create 3D images. Recently, radiolabeled nanoparticles with individual properties have attracted great interest regarding their use in multimodality tumor imaging. Multifunctional nanoparticles can combine diagnostic and therapeutic capabilities for both target-specific diagnosis and the treatment of a given disease. The future of nanomedicine lies in multifunctional nanoplatforms that combine the diagnostic ability and therapeutic effects using appropriate ligands, drugs, responses and technological devices, which together are collectively called theranostic drugs. Co-delivery of radiolabeled nanoparticles is useful in multifunctional molecular imaging areas because it comprises several advantages based on nanoparticles architecture, pharmacokinetics and pharmacodynamic properties. PMID- 26061298 TI - Nanocarriers for cancer-targeted drug delivery. AB - Nanoparticles as drug delivery system have received much attention in recent years, especially for cancer treatment. In addition to improving the pharmacokinetics of the loaded poorly soluble hydrophobic drugs by solubilizing them in the hydrophobic compartments, nanoparticles allowed cancer specific drug delivery by inherent passive targeting phenomena and adopted active targeting strategies. For this reason, nanoparticles-drug formulations are capable of enhancing the safety, pharmacokinetic profiles and bioavailability of the administered drugs leading to improved therapeutic efficacy compared to conventional therapy. The focus of this review is to provide an overview of various nanoparticle formulations in both research and clinical applications with a focus on various chemotherapeutic drug delivery systems for the treatment of cancer. The use of various nanoparticles, including liposomes, polymeric nanoparticles, dendrimers, magnetic and other inorganic nanoparticles for targeted drug delivery in cancer is detailed. PMID- 26061299 TI - Structure-based rational design of peptide hydroxamic acid inhibitors to target tumor necrosis factor-alpha converting enzyme as potential therapeutics for hepatitis. AB - The human tumor necrosis factor-alpha converting enzyme (TACE) has recently been raised as a new and promising therapeutic target of hepatitis and other inflammatory diseases. Here, we reported a successful application of the solved crystal structure of TACE complex with a peptide-like ligand INN for rational design of novel peptide hydroxamic acid inhibitors with high potency and selectivity to target and inhibit TACE. First, the intermolecular interactions between TACE catalytic domain and INN were characterized through an integrated bioinformatics approach, with which the key substructures of INN that dominate ligand binding were identified. Subsequently, the INN molecular structure was simplified to a chemical sketch of peptide hydroxamic acid compound, which can be regarded as a linear tripeptide capped by a N-terminal carboxybenzyl group (chemically protective group) and a C-terminal hydroxamate moiety (coordinated to the Zn(2+) at TACE active site). Based on the sketch, a virtual combinatorial library containing 180 peptide hydroxamic acids was generated, from which seven samples were identified as promising candidates by using a knowledge-based protein-peptide affinity predictor and were then tested in vitro with a standard TACE activity assay protocol. Consequently, three designed peptide hydroxamic acids, i.e. Cbz-Pro-Ile-Gln-hydroxamic acid, Cbz-Leu-Ile-Val-hydroxamic acid and Cbz-Phe-Val-Met-hydroxamic acid, exhibited moderate or high inhibitory activity against TACE, with inhibition constants Ki of 36 +/- 5, 510 +/- 46 and 320 +/- 26 nM, respectively. We also examined the structural basis and non-bonded profile of TACE interaction with a designed peptide hydroxamic acid inhibitor, and found that the inhibitor ligand is tightly buried in the active pocket of TACE, forming a number of hydrogen bonds, hydrophobic forces and van der Waals contacts at the interaction interface, conferring both stability and specificity for TACE inhibitor complex architecture. PMID- 26061296 TI - Targeted polymeric nanoparticles for cancer gene therapy. AB - In this article, advances in designing polymeric nanoparticles for targeted cancer gene therapy are reviewed. Characterization and evaluation of biomaterials, targeting ligands, and transcriptional elements are each discussed. Advances in biomaterials have driven improvements to nanoparticle stability and tissue targeting, conjugation of ligands to the surface of polymeric nanoparticles enable binding to specific cancer cells, and the design of transcriptional elements has enabled selective DNA expression specific to the cancer cells. Together, these features have improved the performance of polymeric nanoparticles as targeted non-viral gene delivery vectors to treat cancer. As polymeric nanoparticles can be designed to be biodegradable, non-toxic, and to have reduced immunogenicity and tumorigenicity compared to viral platforms, they have significant potential for clinical use. Results of polymeric gene therapy in clinical trials and future directions for the engineering of nanoparticle systems for targeted cancer gene therapy are also presented. PMID- 26061300 TI - A Case Report of High 18F-FDG PET/CT Uptake in Progressive Transformation of the Germinal Centers. AB - Progressive transformation of the germinal centers (PTGC) is a benign reaction pattern in lymph nodes. An association with Hodgkin disease (HD) has been reported and PTGC may precede, coexist, or present after the diagnosis of HD. This case report describes a patient who presented with unprovoked pulmonary embolism and subsequent investigations showed a solitary abdominal mass, which was subsequently proven to be PTGC. PTGC is usually avid on fluorine-18-labeled fluorodeoxyglucose positron emission tomography with computed tomography for attenuation correction and may be mistaken for neoplastic disease. Being a reactive etiology, the metabolic activity is generally low with a low maximum standardized uptake value (SUVmax), but in our case, the metabolic activity and corresponding SUVmax were relatively high making the diagnosis difficult, as most clinicians would consider a high metabolically active process more likely malignant. Recognition of PTGC is important, as it is not a malignant process. Owing to its reported associations, however, patients with this diagnosis will likely require regular surveillance. PMID- 26061301 TI - Unplanned Reoperations in Neurosurgical Patients Due to Postoperative Bleeding: A Single-Center Experience and Literature Review. AB - The aim of this study is to investigate the incidence of unplanned reoperations from all causes due to bleeding in neurosurgical patients. The medical records of patients who received neurosurgical procedures at our hospital were retrospectively reviewed and data of patients who received reoperations were extracted and summarized. A literature review was conducted of the Medline, Cochrane, EMBASE, and Google Scholar databases up to November 2013. The main outcome measure was the rate of unplanned reoperations due to bleeding. At our hospital, 68 patients with a mean age of 41.5 +/- 21.5 years (range, 7 months to 76 years) received an unplanned reoperation. More than 70% of the patients were older than 18 years, 64.7% were males, and 94.1% had cranial surgery. Almost 60% of the patients received >1 blood transfusion (58.8%) after the first surgery. Of the 68 patients, 35 (51.5%) received a second operation due to bleeding. Univariate logistic regression analysis only showed that an increasing time interval between the first and second surgery was associated with a decreased chance of the reoperation being performed due to bleeding (odds ratio [OR] = 0.843, 95% confidence interval [CI]: 0.720-0.987; P = .033). Of 229 studies identified, 5 retrospective reports with a total of 1375 patients were included in the analysis. The rate of reoperations for bleeding in the 5 studies ranged from 4.2% to 31.5%. Employing measures to reduce postoperative bleeding may help reduce the rate of unplanned neurosurgical reoperations. PMID- 26061302 TI - A Genetic Susceptibility Mechanism for Major Depression: Combinations of polymorphisms Defined the Risk of Major Depression and Subpopulations. AB - Major Depression (MD) is a highly inherited psychiatric disorder. The norepinephrine transporter (NET) gene plays important role in pathophysiology of MD. This study attempted to examine the relationship between polymorphisms of NET gene and MD. Patients with MD and healthy controls were recruited and subgrouped. The T-182C and G1287A polymorphisms of NET gene were genotyped by direct sequencing. The genotypic and allelic frequencies were compared using the Pearson chi2 analysis. The linkage disequilibrium was analyzed using the UNPHASED program. Significant differences in genotypic and allelic frequencies of T-182C polymorphism were observed between MD subgroups and controls. When referenced by TT genotype, the OR value increased gradient from TC to CC genotype; when referenced by T allele, the odds ratio value of C allele also increased. Compared with those having both -182 T/T and 1287 G/G genotypes, in patients with MD, early-onset MD, and MD with suicide concept group, the -182 C/C and 1287 G/A combinatorial genotype has significant risk; yet in patients with MD family history, the -182 C/C and 1287 A/A combinatorial genotype has significant risk. Different combinations of T-182C and the G1287A polymorphisms of NET gene might increase morbidity risk of MD subpopulations. PMID- 26061303 TI - A De Novo Arisen Case of Primary Adrenal Insufficiency in an Adolescent Patient With Crohn Disease: A Case report. AB - Several recent population-based studies have demonstrated that patients with inflammatory bowel disease are likely to have other autoimmune diseases. Here we describe the first de novo arisen case of primary adrenal insufficiency in an adolescent female patient with Crohn disease (CD). A 17-year-old female diagnosed with stricturing colonic CD received the maintenance regimen of Remicade (infliximab) 5 mg/kg every 8 weeks following the standard induction regimen. She had an ileocecostomy due to acute small bowel obstruction at 1.5-year since the last infusion of Remicade. She was presented with skin hyperpigmentation of her face, neck, upper limbs, buccal mucosa and lips, which worsened when commenced on 6-mercaptopurine treatment for prophylaxis of postoperative recurrence. An increased adrenocorticotropic hormone (20.3 pmol/L, range 2-11) measurement was obtained. Radiography of the sella turcica region showed no signs of pituitary disease, or abnormality of bilateral adrenal cortex. Since serum aldosterone was below the reference range, more importantly, assessments for both antiadrenal antibodies and anti-21-hydroxylase antibodies were positive, she was then diagnosed as primary adrenal insufficiency. The symptoms improved after supplement of hydrocortisone. This case highlights a rare immune-mediated comorbidity in an adolescent patient with CD. Recognition of a new pattern of autoimmune endocrine comorbidity enables clinicians to be alert about the possibility of concurrence of primary adrenal insufficiency with CD. PMID- 26061304 TI - Red Blood Cell Distribution Width is Independently Correlated With Diurnal QTc Variation in Patients With Coronary Heart Disease. AB - To investigate the relationship between red blood cell distribution width (RDW) and diurnal corrected QT (QTc) variation in patients with coronary heart disease. This retrospective study included 203 patients who underwent coronary angiography between February 2013 and June 2014. RDW values and dynamic electrocardiography (Holter) results were collected to investigate the relationship between RDW and diurnal QTc variation. Patients were separated into three groups (A, B, and C) by binning their RDW values in an ascending order. RDW values, coronary artery scores and diurnal QTc variations were significantly different among these groups (P < 0.05). While coronary artery scores gradually rose with increased RDW, diurnal QTc variation decreased. Pearson's correlation analysis was applied to control for confounding factors, and multiple correlation analysis showed that coronary artery score was positively correlated with RDW (r = 0.130, P = 0.020), while it was not correlated with the diurnal QTc variation (r = -0.226, P = 0.681). RDW was negatively correlated with diurnal QTc variation (r = -0.197, P = 0.035). RDW is independently associated with diurnal QTc variation in patients with coronary heart disease. PMID- 26061305 TI - Risk Factors and Consequences of Cortical Thickness in an Asian Population. AB - Cortical thickness has been suggested to be one of the most important markers of cortical atrophy. In this study, we examined potential risk factors of cortical thickness and its association with cognition in an elderly Asian population from Singapore. This is a cross-sectional study among 572 Chinese and Malay patients from the ongoing Epidemiology of Dementia in Singapore (EDIS) Study, who underwent comprehensive examinations including neuropsychological testing and brain magnetic resonance imaging (MRI). Cortical thickness (in micrometers) was measured using a model-based automated procedure. Cognitive function was expressed as composite and domain-specific Z-scores. Cognitive impairment was categorized into cognitive impairment no dementia (CIND)-mild, CIND-moderate, and dementia in accordance with accepted criteria. Linear regression models were used to examine the association between various risk factors and cortical thickness. With respect to cognition as outcome, both linear (for Z-scores) and logistic (for CIND/dementia) regression models were constructed. Initial adjustments were made for age, sex, and education, and subsequently for other cardiovascular risk factors and MRI markers. Out of 572 included patients, 171 (29.9%) were diagnosed with CIND-mild, 197 (34.4%) with CIND-moderate, and 28 (4.9%) with dementia. Risk factors related to a smaller cortical thickness were increased age, male sex, Malay ethnicity, higher blood glucose, and body mass index levels and presence of lacunar infarcts on MRI. Smaller cortical thickness was associated with CIND moderate/dementia [odds ratio (OR) per standard deviation (SD) decrease: 1.70; 95% confidence interval (CI): 1.19-2.44, P = 0.004] and with composite Z-score reflecting global cognitive functioning [mean difference per SD decrease: -0.094; 95% CI: -0.159; -0.030, P = 0.004]. In particular, smaller cortical thicknesses in the occipital and temporal lobes were related to cognitive impairment. Finally, in terms of specific cognitive domains, the most significant associations were found for executive function, visuoconstruction, and visual memory. Smaller cortical thickness is significantly associated with cognitive impairment, suggesting a contribution of diffuse cortical atrophy beyond the medial temporal lobe to cognitive function. These findings suggest that cortical thinning is a biomarker of neurodegenerative changes in the brain not only in dementia, but also in its preclinical stages. PMID- 26061306 TI - Is There a Survival Benefit in Patients With Stage IIIA (N2) Non-small Cell Lung Cancer Receiving Neoadjuvant Chemotherapy and/or Radiotherapy Prior to Surgical Resection: A Systematic Review and Meta-analysis. AB - Optimal management of clinical stage IIIA (N2) non-small cell lung cancer (NSCLC) is controversial. This study is a systematic review and meta-analysis of published randomized control trials of multimodality management strategies for NSCLC. We conducted a comprehensive literature search of the Pubmed, Embase, Medline, and CENTRAL databases for relevant studies comparing patients with stage IIIA (N2) NSCLC undergoing surgery alone, chemotherapy and/or radiotherapy alone, or surgical resection after neoadjuvant treatment with chemotherapy and/or radiotherapy. We estimated hazard ratios, odds ratios (ORs), and 95% confidence intervals (CIs) for survival data. Seven trials involving 1049 patients were included in this study. There was no significant difference in overall survival (OS) or progression-free survival (PFS) in stage IIIA (N2) NSCLC patients who received neoadjuvant chemotherapy or chemoradiotherapy prior to surgical resection compared to those who received neoadjuvant chemotherapy or chemoradiotherapy prior to radical radiotherapy. There was a significant increase in pathological complete remission in the mediastinal lymph nodes in stage IIIA (N2) NSCLC patients who received neoadjuvant chemoradiotherapy prior to surgical resection compared to those who received neoadjuvant chemotherapy (OR 3.61; 95% CI 1.07-12.15; P = 0.04), but no difference in tumor downstaging, OS, or PFS. Neoadjuvant chemotherapy and/or radiotherapy prior to surgical resection do not appear to be clinically superior to neoadjuvant chemotherapy and/or radiotherapy prior to definitive radiotherapy in IIIA (N2) NSCLC patients. Neoadjuvant chemoradiotherapy does not improve survival compared to neoadjuvant chemotherapy alone. PMID- 26061307 TI - Epidural Analgesia With Bupivacaine and Fentanyl Versus Ropivacaine and Fentanyl for Pain Relief in Labor: A Meta-Analysis. AB - The aim of this study was to compare the efficacy and safety of the combinational use of bupivacaine and fentanyl versus ropivacaine and fentanyl in epidural analgesia for labor. Multiple electronic databases were searched by using appropriate MeSH terms, and keywords for original research papers published before October 2014. Meta-analyses were based on mean differences between the groups as well as odds ratios. Statistical heterogeneity was tested by I2 index. Fifteen randomized controlled trials, recruiting 2097 parturient mothers overall, were selected for the meta-analyses. Concentrations of the preparations used (weight/volume; mean and standard deviations) were bupivacaine 0.1023% +/- 0.0375%, ropivacaine 0.1095% +/- 0.042%, and fentanyl 0.00021% +/- 0.000089%. There were no statistically significant differences between both the combinations in the mean change in Visual Analog Score for pain during labor, incidence of instrumental or cesarean delivery, neonate Apgar score of <7, maternal satisfaction, duration of either first or second stage of labor, oxytocin use for induction, onset of analgesia, and duration of analgesia. Women who received ropivacaine and fentanyl had significantly lower incidence of motor blocks (odds ratio [95% CI] = 0.38 [0.30, 0.48] P < 0.00001, fixed effect and 0.38 [0.27, 0.54] P < 0.0001, random effects I2 30%) when compared with women who received bupivacaine and fentanyl. Incidence of side effects was similar for both the combinations. Analgesia with ropivacaine in combination with fentanyl at 0.1%:0.0002% ratio for labor pain relief is associated with lower incidence of motor blocks in comparison with analgesia with bupivacaine and fentanyl at similar ratio (0.1%: 0.0002%). PMID- 26061308 TI - High Frequency of Thyroid Disorders in Patients Presenting With Neutropenia to an Outpatient Hematology Clinic STROBE-Compliant Article. AB - Granulopoiesis abnormalities have been described in association with thyroid disorders (TD). However, data regarding systematic evaluation of adult neutropenia and concurrent or prior TD are scarce. To investigate the frequency of TD among patients presenting with neutropenia, and the immunophenotypic and immunologic profile of neutropenic patients with concomitant thyroidopathy. Two hundred eighteen consecutive neutropenic patients were prospectively evaluated in our outpatient Hematology Clinic, with a detailed laboratory screen, including thyroid function tests, antineutrophil antibodies, blood lymphocytes immunophenotyping, and detection of T-cell clonality by PCR. Among 218 patients with neutropenia, 95 (43.6%) had TD, 65 chronic immunologic neutropenia, 20 clonal proliferation of T-large granular lymphocytes (T-LGL), 5 autoimmune disorders, and 33 other diagnoses. TD-patients had an increased frequency of recurrent infections compared with other patients (P = 0.045). The following correlations were found: negative correlation between FT3 and absolute neutrophil count (ANC) (r2 = -0.274, P = 0.007), negative correlation between TPO-Abs/TG-Abs and C4 (r2 = -0.16, P = 0.045; r2 = -0.266, P = 0.001), and CD4+ counts were inversely correlated to T4 and positively to TSH (r2 = -0.274, P = 0.024; r2 = 0.16, P = 0.045). In addition, TD-patients had significantly higher percentages of CD4+ lymphocytes (P = 0.003). Among TD-patients, 23.4% had Hashimoto thyroiditis (HT), 4.1%, Graves disease (GD), 8.2% nontoxic multinodular goiter (NTMG), 5% subclinical hypothyroidism, and 2.8% had undergone total thyroidectomy associated with nodules (TTM). Thirteen TD-patients displayed T-LGL. Patients with autoimmune thyroidopathy had an increased frequency of concomitant autoimmune manifestations (P = 0.03). Significant differences between the different thyroidopathies included: HT-patients had higher percentages of B lymphocytes, while the opposite was evident for the TTM-subgroup (P = 0.009, 0.02); GD-patients showed an increase of the proportion of NK cells and a decrease in the percentage of TCRgammadelta+ lymphocytes (P = 0.001, 0.045); and NTMG-patients had significantly higher ANC (P = 0.004) compared to other thyroidopathies. Antineutrophil antibodies were found in 37.2% of TD-patients tested. Anti-TPO titers were significantly higher in patients with positive antineutrophil antibodies (P = 0.04). The frequency of TD among neutropenic patients may be higher than previously reported. The existence of antineutrophil antibodies, as well as the different distribution of lymphocyte subsets among patients with different TD, suggests both humoral and cellular mechanisms in the pathophysiology of thyroid disease-associated neutropenia. PMID- 26061309 TI - Blood Pressure Reduction in the Acute Phase of an Ischemic Stroke Does Not Improve Short- or Long-Term Dependency or Mortality: A Meta-Analysis of Current Literature. AB - The purpose of this study was to perform a meta-analysis of current literature to determine whether lowering blood pressure (BP) during the acute phase of an ischemic stroke improves short- and long-term outcomes. PubMed, Cochrane, and Embase were searched until September 5, 2014 using combinations of the search terms: blood pressure reduction, reduced blood pressure, lowering blood pressure, ischemic stroke, acute stroke, and intra-cerebral hemorrhage. Inclusion criteria were randomized controlled trial and patients with acute stroke (ischemic or hemorrhagic) treated with an antihypertensive agent or placebo. Outcome measures were change in systolic and diastolic BP (SBP, DBP) after treatment, and short- and long-term dependency and mortality rates. A total of 459 studies were identified, and ultimately 22 studies were included in the meta-analysis. The total number of participants in the treatment groups was 5672 (range, 6-2308), and in the control groups was 5416 (range, 6-2033). In most studies, more than 50% of the participants were males and the mean age was more than 60 years. The mean follow-up time ranged from 5 days to 12 months. As expected, treatment groups had a greater decrease in BP than control groups, and this effect was seen with different classes of antihypertensive drugs. Short-term and long-term dependency rates were similar between treatment and control groups (short-term dependency: pooled odds ratio [OR] = 1.041, 95% confidence interval [CI]: 0.936 1.159, P = 0.457; long-term dependency: pooled OR = 1.013, 95% CI: 0.915-1.120, P = 0.806). Short-term or long-term mortality was similar between the treatment and control groups (short-term mortality: pooled OR = 1.020, 95% CI: 0.749-1.388, P = .902; long-term mortality: pooled OR = 1.039, 95% CI: 0.883-1.222, P = 0.644). Antihypertensive agents effectively reduce BP during the acute phase of an ischemic stroke, but provide no benefit with respect to short- and long-term dependency and mortality. PMID- 26061310 TI - Serum Alpha-Fetoprotein Has High Specificity for the Early Detection of Hepatocellular Carcinoma After Hepatitis C Virus Eradication in Patients. AB - Alpha-fetoprotein (AFP) has not played a large role in the surveillance of hepatocellular carcinoma due to inadequate sensitivity and specificity for active chronic hepatitis or cirrhosis. The aim of this study was to evaluate the diagnostic accuracy of AFP in small hepatocellular carcinomas after hepatitis C virus eradication to determine the optimal cutoff value. We conducted a case control study of 29 cases and 58 controls, matched for age, gender, and platelet counts. The AFP cutoff was 5 ng/mL in patients after hepatitis C virus eradication and 17 ng/mL in those without hepatitis C virus eradication. The areas under the receiver operating characteristic curve were 0.86 (95% confidence interval, 0.76-0.96) in patients after hepatitis C virus eradication and 0.83 (95% confidence interval, 0.74-0.91) in those without hepatitis C virus eradication. In patients after hepatitis C virus eradication, the sensitivity and specificity of AFP levels were 24.1% and 100%, respectively, using a cutoff value of 17 ng/mL. Using a lower cutoff value of 5 ng/mL, the sensitivity increased to 75.9%, although the specificity decreased to 89.0%. AFP is a specific tumor marker for the diagnosis of hepatocellular carcinoma after hepatitis C virus eradication when using the optimal cutoff value of 5 ng/mL. PMID- 26061311 TI - Strong Negative Interference by Calcium Dobesilate in Sarcosine Oxidase Assays for Serum Creatinine Involving the Trinder Reaction. AB - The vasoprotective drug calcium dobesilate is known to interfere with creatinine (Cr) quantifications in sarcosine oxidase enzymatic (SOE) assays. The aim of this study was to investigate this interference in 8 different commercially available assays and to determine its clinical significance. In in vitro experiments, interference was evaluated at 3 Cr levels. For this, Cr was quantified by SOE assays in pooled serum supplemented with calcium dobesilate at final concentrations of 0, 2, 4, 8, 16, 32, and 64 MUg/mL. Percent bias was calculated relative to the drug-free specimen. For in vivo analyses, changes in serum concentrations of Cr, cystatin C (CysC; a renal function marker), and calcium dobesilate were monitored in healthy participants of group I before and after oral calcium dobesilate administration. In addition, variations in interference were also examined among different SOE assays using serum obtained from healthy participants of group II. Lastly, Cr levels from the 10 patients treated with calcium dobesilate were measured using 4 SOE assays and liquid chromatography isotope dilution tandem mass spectrometry (LC-IDMS/MS) for comparison. Our in vitro analyses indicated that the presence of 8 MUg/mL calcium dobesilate resulted in a -4.4% to -36.3% reduction in Cr serum concentration compared to drug-free serum for 8 SOE assays examined. In vivo, Cr values decreased relative to the baseline level with increasing drug concentration, with the lowest Cr levels obtained at 2 or 3 hours after drug administration in participants of group I. The observed Cr concentrations for participants in group II were reduced by -28.5% to -3.1% and -60.5% to -11.6% at 0 and 2 hours after administration related to baseline levels. The Cr values of 10 patients measured by Roche, Beckman, Maker, and Merit Choice SOE assays showed an average deviation of 20.0%, -22.4%, -14.2%, and -29.6%, respectively, compared to values obtained by LC-IDMS/MS. These results revealed a clinically significant negative interference with calcium dobesilate in all sarcosine oxidase-based Cr assays, but the degree of interference varied greatly among the assays examined. Thus, extra care should be taken in evaluating Cr quantification obtained by SOE assays in patients undergoing calcium dobesilate therapy. PMID- 26061312 TI - Metastases to the Pancreas: Computed Tomography Imaging Spectrum and Clinical Features: A Retrospective Study of 18 Patients With 36 Metastases. AB - The aim of this study is to identify the key computed tomography (CT) imaging findings and clinical characteristics of pancreatic metastases for its differential diagnosis. CT images and clinical features of 18 patients with 36 histopathologically proven pancreatic metastases were retrospectively reviewed. The primary malignancy included non-small cell lung cancer (NSCLC) (n = 7), gastrointestinal carcinoma (n = 5), renal cell carcinoma (RCC) (n = 3), osteosarcoma (n = 1), cardiac sarcomas (n = 1), and neuroendocrine ethmoid sinus carcinoma (n = 1). Pancreatic metastases were metachronous in 12 patients (ranging from 4 to 72 months). Tumor markers were elevated for 8 patients, of which 7 patients had NSCLC and gastrointestinal carcinoma, and 1 patient had osteosarcoma. Metastases from NSCLC and gastrointestinal carcinoma frequently presented as small well-circumscribed lesions, with homogeneous or rim enhancement, and or local pancreatic infiltration instead of focal mass, mimicking local pancreatitis. Neuroendocrine ethmoid sinus carcinoma affecting the pancreas also exhibited local pancreatic infiltration. Metastases from RCC and cardiac sarcomas had typical characteristics of hypervascular lesions. Osteosarcoma metastasizing to pancreas had special manifestation, that is, cystic lesion with thick wall and calcification. Although pancreatic metastases have a broad spectrum of CT appearances, lesions from some types of primary tumors exhibited characteristic imaging features, which, in combination with oncological history, will contribute to correct diagnosis. PMID- 26061313 TI - Effect of Psychotropic Drugs on Development of Diabetes Mellitus in Patients With Alzheimer's Disease. AB - We aimed to examine risk of diabetes mellitus (DM) among older adults with Alzheimer's disease receiving 3 types of psychotropic drugs, that is, antipsychotics, antidepressants, and sedative anxiolytics. We retrospectively analyzed data from a hospital-based Clinical Research Center for Dementia of South Korea (CREDOS) study conducted between January 1, 2008 and December 31, 2012. Participants (n = 3042) with Alzheimer's disease were aged 65 or older and had no preexisting history of DM. Development of DM was identified using claims for initiating at least 1 prescription of antidiabetic medications or a diagnosis of DM during the follow-up period. Cox proportional hazards regression was used to demonstrate the Hazard ratio of DM in use of each psychotropic drug. Among the 3042 participants, 426 patients (14.0%) developed DM, representing an incidence rate of 5.2/100 person-years during an average 2.9 years of follow-up period. Among the 3 types of psychotropic drugs, antipsychotic users had a significantly higher risk of DM (hazard ratio = 1.74, 95% confidence interval = 1.10, 2.76) than nonusers, after adjusting covariates. Antidepressants and sedative anxiolytics did not achieve statistical significance. These results suggested that the diabetes risk was elevated in Alzheimer patients on antipsychotic treatment. Therefore, patients with Alzheimer's disease receiving antipsychotic treatment should be carefully monitored for the development of DM. PMID- 26061314 TI - Long-Term Observation of Coexistence of Posterior Polymorphous Corneal Dystrophy, Resultant High Myopia and Nonkeratoconic Developing Corneal Astigmatism: A Case Report of 7-Year Tracking in a Chinese Boy. AB - Posterior polymorphous corneal dystrophy (PPCD) is an extremely rare, bilateral, and inherited disorder, which affects the corneal endothelium and Descemet's membrane. Few PPCD cases in Chinese patients have been published so far. As far as we know, there are few studies which focused on the associations between PPCD and high myopia either. Here we report a rare case of coexistence of posterior polymorphous corneal dystrophy, resultant high myopia and with-the-rule developing corneal astigmatism in a young Chinese boy. A 6-year-old boy was first referred to our department 7 years ago, complaining of bilateral poor vision. Examinations of both eyes including ophthalmologic examination, cycloplegic refraction examination, confocal microscopy findings, and corneal topography were performed. Bilateral small aggregates of vesicular lesions and patchy hyperreflectivity were observed at the level of the Descemet's membrane on confocal microscopy, which is consistent with typical PPCD. Optometry and corneal topography examinations showed a resultant high myopia. Ocular examinations were performed annually to follow up with the patient in the past 7 years. The corneal lesions remained stable whereas an axial elongation and a sharp increase in both spherical and cylindrical equivalent power were observed. Close follow-ups including thorough scrutiny of the endothelium and systematic ocular ancillary examinations are essential for patients with PPCD. The pathological coexistence of PPCD and high myopia in our case is possibly due to a shared etiological pathway or genetic background. Advanced genetic analysis on similar cases is expected if more samples can be provided. PMID- 26061315 TI - Association of Endoscopic Sphincterotomy or Papillary Balloon Dilatation and Biliary Cancer: A Population-Based Cohort Study. AB - Endoscopic sphincterotomy (EST) and endoscopic papillary balloon dilatation (EPBD) have become the main therapeutic procedures in the treatment of biliary and pancreas disease. The risk of cholangiocarcinoma (CCA) is not well investigated among post-EST/EPBD patients with benign diseases, particularly in Asia population. A retrospective nationwide cohort study using data from Taiwan's National Health Insurance Research Database (from January 1, 1998 through December 31, 2010) was conducted. Among patients with history of biliary stone with cholangitis, there were 17,503 patients in the EST/EPBD cohort and 69,998 subjects in the comparison. The incidence rate ratio was calculated using the Poisson regression model. Multivariable Cox proportional hazard models, adjusted for potential confounding factors, were used to assess the risk of developing CCA associated with endoscopic EST/EPBD. The cumulative incidences of CCA in the 2 cohorts were calculated using Kaplan-Meier analyses, and differences between the survival curves of the 2 cohorts were analyzed using a log-rank test. The overall incidence of CCA in the EST/EPBD cohort was higher than in the controls (1.36 vs 7.37 per 1000 person-years, IRR = 5.40, 95% CI = 5.15-5.67), with an adjusted HR of 4.41 (95% CI = 3.86-5.04). There were no CCA occurrences among patients receiving EST over the follow-up period 3 year after EST performed. The cumulative incidence of extrahepatic CCA seemed to be little growing in patients receiving EPBD. The cumulative incidence of intrahepatic CCA was also steady increasing in patients treated with EPBD and was more than patients receiving EST 10 years after EPBD by Kaplan-Meier analysis. In the population-based cohort study, EST is not associated with a long-term risk of intrahepatic and extrahepatic CCA. The risk of CCA for EPBD needs further investigation. PMID- 26061316 TI - Validation of Scoring Systems That Predict Outcomes in Patients With Coronary Artery Disease Undergoing Coronary Artery Bypass Grafting Surgery. AB - Several risk stratification scores, based on angiographic or clinical parameters, have been developed to evaluate outcomes in patients with left main coronary artery disease (LMCAD) who undergo coronary artery bypass grafting (CABG). This study aims to validate the predictive ability of different risk scoring systems with regard to long-term outcomes after CABG. This single-center study retrospectively re-evaluated the Synergy Between PCI with TAXUS and Cardiac Surgery (SYNTAX) score; EuroSCORE; age, creatinine, and ejection fraction (ACEF) score; modified ACEF score; clinical SYNTAX; logistic clinical SYNTAX score (logistic CSS); and Parsonnet scores for 305 patients with LMCAD who underwent CABG. The endpoints were 5-year rate of all-cause death and major adverse cardio cerebral events (MACCEs), including cardiovascular (CV) death, myocardial infarction (MI), and stroke and target vessel revascularization (TVR). Compared with the SYNTAX score, other scores were significantly higher in discriminative ability for all-cause death (SYNTAX vs others: P < 0.01). The EuroSCORE >=6 showed significant outcome difference on all-cause death, CV death, MI, and MACCE (P < .01). Multivariate analysis indicated the SYNTAX score was a non-significant predictor for different outcomes. Adjusted multivariate analysis revealed that the EuroSCORE was the strongest predictor of all-cause death (hazard ratio[HR]: 1.17; P < 0.001), CV death (HR: 1.16; P < 0.001), and MACCE (HR: 1.09; P = 0.01). The ACEF score and logistic CSS were predictive factors for TVR (HR: 0.25, P = 0.03; HR: 0.85, P = 0.01). The EuroSCORE scoring system most accurately predicts all-cause death, CV death, and MACCE over 5 years, whereas low ACEF score and logistic CSS are independently associated with TVR over the 5-year period following CABG in patients with LMCAD undergoing CABG. PMID- 26061317 TI - Increased Risk of Dementia in Patients With Chronic Obstructive Pulmonary Disease. AB - Neurodegenerative disease in patients with chronic obstructive pulmonary disease (COPD) was observed. We aim to clarify the risk of dementia in patients with COPD. The study used claims data from Taiwan's National Health Insurance Research Database. Subjects were those who received a discharge diagnosis of COPD between January 1, 2002 and December 31, 2011. Only the first hospitalization was enrolled, and the index date was the first day of admission. Patients younger than 40 years or those with a history of Alzheimer disease (AD) or Parkinson disease (PD) before the index date were excluded. The patients with COPD were then followed until receiving a diagnosis of AD or PD, death, or the end of the study. Control subjects were selected from hospitalized patients without a history of COPD, AD, or PD and were matched according to age (+/-3 years), gender, and the year of admission at a 2:1 ratio. The comorbidities were measured from 1 year before the index date based on the ICD-9-CM codes. The study included 8640 patients with COPD and a mean age of 68.76 (+/-10.74) years. The adjusted hazard ratio of developing dementia (AD or PD) was 1.74 (95% confidence interval = 1.55-1.96) in patients with COPD compared with patients without COPD after adjusting for age, gender, and comorbidities. This nationwide cohort study demonstrates that the risk of dementia, including AD and PD, is significantly increased in patients with COPD compared with individuals in the general population. PMID- 26061318 TI - Quality of Life After Surgery or Surveillance for Asymptomatic Primary Hyperparathyroidism: A Meta-Analysis of Randomized Controlled Trials. AB - A number of studies have investigated the effects of surgery on symptoms and quality of life in patients with hyperparathyroidism. However, the results are inconsistent. We conducted this meta-analysis to quantitatively assess changes in quality of life among patients with asymptomatic primary hyperparathyroidism. Different databases were searched for randomized controlled trials comparing surgery with surveillance. Quality of life was measured by the Short Form-36 general health survey. The pooled random-effects estimates of standardized mean difference (SMD) and 95% confidence intervals (CIs) were calculated. Three trials involving 294 participants were included. At 1 year, patients undergoing parathyroidectomy had significantly better physical role functioning (SMD, 0.31; 95% CI 0.04-0.57; P = 0.02) and emotional role functioning (SMD, 0.29; 95% CI 0.02-0.55; P = 0.03). At 2 years, the surgery group had significantly better emotional role functioning (SMD, 0.35; 95% CI 0.02-0.67; P = 0.04) than the surveillance group. Furthermore, compared with baseline, emotional role functioning improved after surgery (SMD, 0.31; 95% CI 0.02-0.60; P = 0.04), whereas emotional role functioning tended to get worse in patients assigned to medical surveillance (SMD, -0.27; 95% CI -0.55 to 0.02; P = 0.07). Although Short Form-36 is a generic instrument, our results suggest that parathyroidectomy may be associated with better quality of life, especially in the emotional aspects of well-being. PMID- 26061319 TI - Pedobarographic Analysis Following Pemberton's Pericapsular Osteotomy for Unilateral Developmental Dysplasia of the Hip: An Observational Study. AB - Successful clinical and radiographic outcomes have been reported in patients with unilateral developmental dysplasia of the hip (DDH) following Pemberton pericapsular osteotomy (PPO). However, residual gait deviations are seen in both the affected and unaffected limbs. To date it is not known whether these deviations result in abnormal plantar pressure in such patients. This study investigated this possibility by performing pedobarographic, clinical, and radiographic examinations after PPO in 20 patients (age: 102.5 +/- 19.0 months) with unilateral DDH who underwent PPO at 34.2 +/- 9.8 months of age. Plantar pressure was evaluated using the Footscan pressure plate (RsScan International, Olen, Belgium). Each foot was subdivided into 10 zones and peak pressure, force time integral as a percentage of total FTI, and contact time as a percentage of total stance time was estimated. The minimum duration of follow-up was 24 months (mean: 68.3 +/- 20.3 months). The data were compared with 20 age- and weight matched healthy controls. Despite clinical and radiographic examinations showing satisfactory results according to modified McKay and Severin criteria, significant differences in plantar pressure parameters were identified between the affected limbs, the unaffected limbs, and normal controls. No significant differences were found between patients classified as "excellent or good" and those rated as "fair" according to the modified Severin criteria. Pedobarographic results showed the existence of the residual plantar pressure deviations during walking in patients treated with PPO for unilateral DDH. Longer follow-up will be needed to more fully evaluate the effect of these deviations on gait. PMID- 26061320 TI - Keratoacanthoma and Keratoacanthoma-Like Squamous Cell Carcinoma: Similar Morphology but Different Pathogenesis. AB - Differential diagnosis between keratoacanthoma (KA) and squamous cell carcinoma (SCC) is difficult due to their similarities. The mechanisms that drive their distinct biological behavior are poorly understood. To investigate whether the assessment of microvessel density (MVD) could be helpful in KA and SCC differential diagnosis and to gain insight into the pathogenesis of KA-like neoplasms, we compared the density of CD105- and CD34-stained vessels in KAs and SCCs and their relation to the expression of the p53 oncoprotein and proliferation marker Ki67. This is an observational retrospective cohort study. Forty lesions with clinical appearance of KAs (29 KAs and 11 SCCs) entered the study. A biopsy was taken from each lesion at presentation and the natural clinical course was monitored for at least 1 month. Growing or minimally regressing lesions were submitted to complete surgical excision. The diagnoses were established on combined clinical, histological, and follow-up evaluations. The MVD and p53 or Ki67 expression in neoplastic cells were assessed through morphometry. The MVD did not show discriminating power between KAs and SCCs. The Ki67 proliferation rate was significantly higher in SCCs. Although neoangiogenesis (CD105-MVD) in KAs was associated with cell proliferation, in SCCs it was not. There was significant correlation between p53 expression and neoplasia size in SCCs but not in KAs. From our results, we may conclude that KA and SCC have similarities, as CD105- and CD34-MVD. However, the low Ki67 proliferation index and the positive correlation between Ki-67 index and neovascularization in KA suggest a dependence in neovascularization to grow in KA, pointing to involvement of distinct pathogenesis. PMID- 26061321 TI - Reduced Stroke Risk After Parathyroidectomy in End-Stage Renal Disease: A 13-Year Population-Based Cohort Study. AB - Research information on the risk of stroke in patients with dialysis-dependent end-stage renal disease (ESRD) who have undergone parathyroidectomy (PTX) is scant. We used a nationwide health insurance claims database to select all patients with dialysis-dependent ESRD age 18 years and older for the study population. Of the patients with ESRD, we selected 1083 patients who had undergone PTX between 1998 and 2006 as the PTX group and frequency-matched 1083 patients with ESRD by sex, age, years since the disease diagnosis, and the year of undergoing PTX as the non-PTX group. We used a multivariate Cox proportional hazards regression analysis to measure the risk of stroke for the PTX group compared with the non-PTX group after adjusting for sex, age, premium-based income, urbanization, and comorbidity. The mean follow-up periods were 6.08 and 5.38 years for the PTX and non-PTX groups, respectively. After adjusting for previously mentioned variables, significant risk reductions of stroke (adjusted hazard ratio = 0.57, 95% confidence interval = 0.41-0.79), particularly those of hemorrhagic stroke (adjusted hazard ratio = 0.34, 95% confidence interval = 0.20 0.57), with PTX were observed. Chronologically, the risk of stroke in the PTX group decreased in the second year after PTX and persisted for >3 years. PTX reduces the risk of stroke, particularly that of hemorrhagic stroke, in patients with dialysis-dependent ESRD. Other factors for risk reduction include sex (females), an age <65 years, and the presence of comorbidity. PMID- 26061322 TI - Tusanqi-Related Sinusoidal Obstruction Syndrome in China: A Systematic Review of the Literatures. AB - In West, sinusoidal obstruction syndrome (SOS) is often complicated with hemopoietic stem cell transplantation. By comparison, in China, SOS is frequently caused by Tusanqi-containing pyrrolizidine alkaloids. A systematic review aimed to evaluate the clinical profiles, diagnostic workup, treatment, and outcomes of Tusanqi-related SOS in China. All relevant articles were searched via PubMed, China Knowledge Resource Integrated, VIP, and Wanfang databases. Case reports were defined, as the data were available in every individual patient. Otherwise, case series were defined. Overall, 106 articles were eligible. Fifty-six case reports included 84 individual patients with SOS secondary to Tusanqi alone. All of them presented with ascites, but only 1 patient presented with upper gastrointestinal bleeding. The 1-, 3-, and 6-month cumulative survival rate was 98%, 87%, and 76%, respectively. Increased bilirubin and aspartate transaminase levels were significantly associated with poor outcome. Thirty-one case series included 402 patients with SOS secondary to Tusanqi alone. Ascites was observed in 94% of patients, but upper gastrointestinal bleeding was observed in 40% of patients. Recovery, stabilization, progression, and death were observed in 41%, 30%, 14%, and 16% of patients, respectively. Nineteen case series included 281 patients with SOS secondary to mixed etiologies. The pooled proportion of Tusanqi related SOS was 66% (95% confidence interval: 56%-75%). Tusanqi is a major cause of SOS in China. Ascites is the most common clinical presentation of Tusanqi related SOS. Despite a relatively good short-term outcome, further studies should be necessary to explore the long-term outcome and refine the treatment strategy. PMID- 26061323 TI - PET/CT-Based Dosimetry in 90Y-Microsphere Selective Internal Radiation Therapy: Single Cohort Comparison With Pretreatment Planning on (99m)Tc-MAA Imaging and Correlation With Treatment Efficacy. AB - 90Y PET/CT can be acquired after 90Y-microsphere selective radiation internal therapy (SIRT) to describe radioactivity distribution. We performed dosimetry using 90Y-microsphere PET/CT data to evaluate treatment efficacy and appropriateness of activity planning from (99m)Tc-MAA scan and SPECT/CT. Twenty three patients with liver malignancy were included in the study. (99m)Tc-MAA was injected during planning angiography and whole body (99m)Tc-MAA scan and liver SPECT/CT were acquired. After SIRT using 90Y-resin microsphere, 90Y-microsphere PET/CT was acquired. A partition model (PM) using 4 compartments (tumor, intarget normal liver, out-target normal liver, and lung) was adopted, and absorbed dose to each compartment was calculated based on measurements from (99m)Tc-MAA SPECT/CT and 90Y-microsphere PET/CT, respectively, to be compared with each other. Progression-free survival (PFS) was evaluated in terms of tumor absorbed doses calculated by (99m)Tc-MAA SPECT/CT and 90Y-microsphere PET/CT results. Lung shunt fraction was overestimated on (99m)Tc-MAA scan compared with 90Y microsphere PET/CT (0.060 +/- 0.037 vs. 0.018 +/- 0.026, P < 0.01). Tumor absorbed dose exhibited a close correlation between the results from (99m)Tc-MAA SPECT/CT and 90Y-microsphere PET/CT (r = 0.64, P < 0.01), although the result from (99m)Tc-MAA SPECT/CT was significantly lower than that from 90Y-microsphere PET/CT (135.4 +/- 64.2 Gy vs. 185.0 +/- 87.8 Gy, P < 0.01). Absorbed dose to in target normal liver was overestimated on (99m)Tc-MAA SPECT/CT compared with PET/CT (62.6 +/- 38.2 Gy vs. 45.2 +/- 32.0 Gy, P = 0.02). Absorbed dose to out target normal liver did not differ between (99m)Tc-MAA SPECT/CT and 90Y microsphere PET/CT (P = 0.49). Patients with tumor absorbed dose >200 Gy on 90Y microsphere PET/CT had longer PFS than those with tumor absorbed dose <=200 Gy (286 +/- 56 days vs. 92 +/- 20 days, P = 0.046). Tumor absorbed dose calculated by (99m)Tc-MAA SPECT/CT was not a significant predictor for PFS. Activity planning based on (99m)Tc-MAA scan and SPECT/CT can be effectively used as a conservative method. Post-SIRT dosimetry based on 90Y-microsphere PET/CT is an effective method to predict treatment efficacy. PMID- 26061324 TI - The Correlation of Retinal Nerve Fiber Layer Thickness With Blood Pressure in a Chinese Hypertensive Population. AB - To investigate the association between retinal nerve fiber layer (RNFL) thickness and blood pressure (BP) in subjects with systemic hypertension. Subjects with systemic hypertension on anti-hypertensive medications were screened by fundus photography and referred for glaucoma work-up if there was enlarged vertical cup to-disc (VCDR) ratio >=0.6, VCDR asymmetry >=0.2, or optic disc hemorrhage. Workup included a complete ophthalmological examination, Humphrey visual field test, and RNFL thickness measurement by optical coherence tomography. The intraocular pressure (IOP) and RNFL thicknesses (global and quadrant) were averaged from both eyes and the means were correlated with: the systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) using Pearson correlation. Among 4000 screened hypertensive subjects, 133 were referred for glaucoma workup and 110 completed the workup. Of the 4000 screened subjects, 1.3% had glaucoma (0.9% had normal tension glaucoma [NTG], 0.2% had primary open angle glaucoma, and 0.2% had primary angle closure glaucoma), whereas 0.3% were NTG suspects. The SBP was negatively correlated with the mean superior RNFL thickness (P = 0.01). The DBP was negatively correlated with the mean global (P = 0.03), superior (P = 0.02), and nasal (P = 0.003) RNFL thickness. The MAP was negatively correlated with the mean global (P = 0.01), superior (P = 0.002), and nasal (P = 0.004) RNFL thickness while positively correlated with the mean IOP (P = 0.02). In medically treated hypertensive subjects, glaucoma was present in 1.3%, with NTG being most prevalent. MAP control may help with IOP lowering and RNFL preservation, although future prospective studies will be needed. PMID- 26061325 TI - Psychological Distress in Young Adult Males with Atopic Dermatitis: A Cross Sectional Study. AB - The relationship between atopic dermatitis (AD) and psychological distress has been well established for children and adolescents. However, it is unclear whether this relationship exists in young adults. This study aimed to assess the relationship between AD and psychological distress in young male adults in South Korea. A cross-sectional study was conducted using regional conscription data from 2008 to 2012. A dermatologist diagnosed AD based on historical and clinical features, and determined severity using the eczema area and severity index. A psychiatrist used medical records, an interview, and a psychological test to examine psychological distress (depression, anxiety, and somatization). The relationship between psychological distress and AD was assessed by multivariate logistic regression analyses. Among the 120,508 conscripts, 1517 (1.2%) presented with AD. The odds of having each type of psychological distress were significantly greater for individuals with AD compared with those without AD. The adjusted odds ratios for depression, anxiety, and somatization were 1.79 (95% CI 1.40-2.29), 1.38 (95% CI 1.08-1.76), and 1.75 (95% CI 1.40-2.20), respectively. Moderate-to-severe AD was significantly related to depression and somatization to a greater extent compared with mild AD. Depression, anxiety, and somatization are strongly and independently associated with AD in young adult males. Early treatment of skin inflammation might modify the risk of psychiatric problems. Prospective cohort studies are needed to verify causal relationships. PMID- 26061326 TI - Prognostic Implications of Antibodies to Soluble Liver Antigen in Autoimmune Hepatitis: A PRISMA-Compliant Meta-Analysis. AB - Prognostic evaluation is important for the management of patients with autoimmune hepatitis (AIH). Although some autoantibodies have been associated with disease activity and outcomes, the implication of antibodies to soluble liver antigen (anti-SLA) remains controversial. To conduct a meta-analysis of observational studies which addressed differences in clinical characteristics by anti-SLA status in patients with AIH. Three databases PUBMED, EMBASE, and OVID were systemically searched up to January 2015 using the terms "soluble liver antigen" or "liver-pancreas antigen" and "autoimmune hepatitis" with restriction to English-language. Studies were included if at least 50 patients with objective diagnosis of AIH were enrolled, anti-SLA detection was performed for the patients, and prognostic outcomes and/or disease severity were reported. Two investigators independently reviewed retrieved literature and evaluated eligibility. Discrepancy was resolved by discussion and a third investigator. Quality of included studies was evaluated using Newcastle-Ottawa Quality Assessment Scale (NOS). Data were pooled using fixed-effect or random-effect models. Prognostic outcomes included death from hepatic failure or requirement for liver transplantation, and responses to immunosuppressive therapy regarding remission or relapse. Results were combined on the odds ratio (OR) or standardized mean difference (SMD) scales. Eight studies were enrolled in this study, involving a total of 1297 AIH patients among whom 195 with anti-SLA. Pooled serum AST levels tended to be lower in anti-SLA seropositive patients. The presence of anti-SLA conferred 3.1-fold increased risk of hepatic death in AIH patients. The remission rates were comparable between anti-SLA seropositive and seronegative AIH patients, while anti-SLA positivity was associated with nearly 2 fold increased risk of relapse after drug withdrawal. Human leukocyte antigen (HLA) allotype DR3 was positively associated with anti-SLA. Antibodies to SLA may be an indicator of increased risks of hepatic death and treatment relapse for AIH patients. Our findings suggest that the anti-SLA seropositive patients should be maintained indefinitely on individually adjusted medication to improve their prognosis. PMID- 26061327 TI - A Case of Stiff Person Syndrome: Immunomodulatory Effect of Benzodiazepines: Successful Rituximab and Tizanidine Therapy. AB - Stiff person syndrome (SPS) is a rare autoimmune disease. Most patients have high titer antibodies against glutamate decarboxylase (GADAb), which is without practical value in disease monitoring. Benzodiazepines are the first line drugs, but long-term use is not well characterized. This report demonstrates ineffective benzodiazepine therapy of SPS that prompts tachyphylaxis, loss of responsiveness, and finally benzodiazepine withdrawal syndrome. Convulsion and anxiety correlate with high level of creatine phosphokinase (CK). Although tonus and spasm attacks were successfully controlled by tizanidine, glutamate release inhibitor, the immune response, and autoimmune diabetes development require the plasmapheresis, mycophenolat mofetil, and rituximab therapy that results in a significant decrease of GADAb, impaired glucose tolerance (IGT), lactate dehydrogenase (LDH), and CK normalization. Unfortunately, reintroduction of benzodiazepine was a source of rapid and high increase of CK, LDH, GADAb titer (up to 1:15,000), IGT, and SPS relapse. Contrary to previous publications, we observed IGT that correlated with high anti-GAD level, but without high immunogenetic susceptibility to haplotype human leukocyte antigens-DR3, DQw2. This preliminary observation and the last finding of immunomodulatory properties of peripheral benzodiazepine receptor suggest that increased antigenic stimulation during benzodiazepine therapy and glutamatergic hyperactivity could account for convulsions observed in SPS. Benzodiazepine withdrawal prompted alternative muscle relaxant therapy (tizanidine). Muscular and brain abnormalities observed in SPS indicate that noncardiac CK level may be a useful tool in SPS therapy monitoring. PMID- 26061328 TI - Associations of Metabolic Syndrome and its Components With Mortality in the Elderly: A Cohort Study of 73,547 Taiwanese Adults. AB - Available evidence shows that metabolic syndrome (Mets) has clear adverse effects for middle-aged and pre-elderly adults; however, the effect of Mets on mortality among elderly adults remains unclear. In addition, the comparative utility of Mets and its component for predicting mortality among the elderly has not been clearly established. Using data from a large Taiwanese cohort, we evaluated the effect of Mets and its components on subsequent all-cause and cause-specific mortality overtime among the elderly. A total of 73,547 elders (age >=65 years) participated in the Taipei Elderly Health Examination Program from 2007 to 2010. Mets was diagnosed using the adult treatment panel III criteria, and mortality was ascertained by using national death records. Time-dependent analysis was used to evaluate associations of Mets and its components with all-cause mortality, cardiovascular disease (CVD) mortality, and expanded CVD mortality. This retrospective cohort study found that 42.6% of elders had Mets. During 194,057 person-years of follow-up, 2944 deaths were observed. After adjusting for sociodemographic characteristics and comorbidities, Mets was associated with increased risk of expanded CVD mortality (hazard ratio [HR], 1.27; 95% CI, 1.10 1.46) but not all-cause or CVD mortality. Among Mets components, decreased high density lipoprotein cholesterol (HDL-C, HR 1.25, 95% CI 1.13-1.37) and hyperglycemia (HR 1.21, 95% CI 1.12-1.31) were associated with a significant increase in all-cause mortality. Hypertension and low HDL-C were predictors of CVD mortality and expanded CVD mortality, and, as compared with Mets, were associated with a higher risk of expanded CVD mortality. The present findings indicate that, in elderly adults, individual components of Mets are better predictors of all-cause and cause-specific mortality than is Mets as a whole. Our results suggest that future efforts should focus on preventing and managing individual risk factors (particularly hypertension, low HDL-C, and hyperglycemia) rather than on "diagnosing" Mets in elders. PMID- 26061329 TI - Comparison of Existing Clinical Scoring Systems in Predicting Severity and Prognoses of Hyperlipidemic Acute Pancreatitis in Chinese Patients: A Retrospective Study. AB - It is important to identify the severity of acute pancreatitis (AP) in the early course of the disease. Clinical scoring systems may be helpful to predict the prognosis of patients with early AP; however, few analysts have forecast the accuracy of scoring systems for the prognosis in hyperlipidemic acute pancreatitis (HLAP). The purpose of this study was to summarize the clinical characteristics of HLAP and compare the accuracy of conventional scoring systems in predicting the prognosis of HLAP. This study retrospectively analyzed all consecutively diagnosed AP patients between September 2008 and March 2014. We compared the clinical characteristics between HLAP and nonhyperlipidemic acute pancreatitis. The bedside index for severity of acute pancreatitis (BISAP), Ranson, computed tomography severity index (CTSI), and systemic inflammatory response syndrome (SIRS) scores were applied within 48 hours following admission. Of 909 AP patients, 129 (14.2%) had HLAP, 20 were classified as severe acute pancreatitis (SAP), 8 had pseudocysts, 9 had pancreatic necrosis, 30 had pleural effusions, 33 had SIRS, 14 had persistent organ failure, and there was 1 death. Among the HLAP patients, the area under curves for BISAP, Ranson, SIRS, and CTSI in predicting SAP were 0.905, 0.938, 0.812, and 0.834, 0.874, 0.726, 0.668, and 0.848 for local complications, and 0.904, 0.917, 0.758, and 0.849 for organ failure, respectively. HLAP patients were characterized by younger age at onset, higher recurrence rate, and being more prone to pancreatic necrosis, organ failure, and SAP. BISAP, Ranson, SIRS, and CTSI all have accuracy in predicting the prognosis of HLAP patients, but each has different strengths and weaknesses. PMID- 26061330 TI - S-1 and Cisplatin With or Without Nimotuzumab for Patients With Untreated Unresectable or Metastatic Gastric Cancer: A Randomized, Open-Label Phase 2 Trial. AB - This open-label, randomized phase II trial was performed to compare the efficacy and safety of nimotuzumab plus S-1 and cisplatin (NCS) versus S-1 and cisplatin (CS) alone in patients with untreated unresectable or metastatic gastric cancer in the first-line setting. Eligible participants were randomly assigned (1:1) to receive either NCS or CS. The treatment consisted of 3-week cycles of twice-daily S-1 40 mg/m2 (on days 1-14) and intravenous cisplatin 30 mg/m2 (on days 1, 2), with or without weekly nimotuzumab (200 mg/m2). The primary endpoint was objective response rate (ORR). The second endpoint included progression-free survival (PFS), overall survival (OS), safety and association between efficacy and tumor epidermal growth factor receptor (EGFR) expression. Between October, 2009, and February, 2012, we enrolled 62 patients in Cancer Hospital Chinese Academy of Medical Sciences (CAMS). The ORR for 31 patients allocated NCS was 54.8% compared with 58.1% for 31 patients who were allocated to receive CS alone (P = 0.798). Median PFS for patients in CS arm was significantly improved than that in NCS arm [7.2 months vs. 4.8 months HR = 2.136 (95% CI 1.193-3.826), P = 0.011]. There was also a trend toward better overall survival for patients in CS arm compared with NCS arm [14.3 months vs. 10.2 months; HR = 1.776 (95% CI 0.972 3.246), P = 0.062]. In the EGFR 2+/3+ subgroup, adding nimotuzumab also failed to show additional benefit than chemotherapy alone. Both groups were well tolerated. Less than 10% of patients in both arms developed grade 3/4 toxicity. Combination of nimotuzumab and S-1-cisplatin provided no additional benefit than chemotherapy alone in the first-line treatment of unresectable or metastatic gastric cancer. PMID- 26061331 TI - Management of Iron-Deficiency Anemia in Inflammatory Bowel Disease: A Systematic Review. AB - Anemia is the most frequent complication of inflammatory bowel disease (IBD), but anemia, mostly due to iron deficiency, has long been neglected in these patients. The aim was to briefly present the pathophysiology, followed by a balanced overview of the different forms of iron replacement available, and subsequently, to perform a systematic review of studies performed in the last decade on the treatment of iron-deficiency anemia in IBD. Given that intravenous therapies have been introduced in the last decade, a systematic review performed in PubMed, EMBASE, the Cochrane Library, and the websites of WHO, FDA, and EMA covered prospective trials investigating the management of iron-deficiency anemia in IBD published since 2004. A total of 632 articles were reviewed, and 13 articles (2906 patients) with unique content were included. In general, oral supplementation in iron-deficiency anemia should be administered with a target to restore/replenish the iron stores and the hemoglobin level in a suitable way. However, in patients with IBD flares and inadequate responses to or side effects with oral preparations, intravenous iron supplementation is the therapy of choice. Neither oral nor intravenous therapy seems to exacerbate the clinical course of IBD, and intravenous iron therapy can be administered even in active disease stages and concomitantly with biologics. In conclusion, because many physicians are in doubt as to how to manage anemia and iron deficiency in IBD, there is a clear need for the implementation of evidence-based recommendations on this matter. Based on the data presented, oral iron therapy should be preferred for patients with quiescent disease stages and trivial iron deficiency anemia unless such patients are intolerant or have an inadequate response, whereas intravenous iron supplementation may be of advantage in patients with aggravated anemia or flares of IBD because inflammation hampers intestinal absorption of iron. PMID- 26061332 TI - Serum Triglyceride Levels Independently Contribute to the Estimation of Visceral Fat Amount Among Nondiabetic Obese Adults. AB - Determining the visceral fat amount is important in the risk stratification for the prevention of type 2 diabetes and obesity-related disorders. The area-based measurement of visceral fat area (VFA) via magnetic resonance imaging (MRI) is an accurate but expensive and time-consuming method for estimating visceral fat amount. The aim of our study was to identify a practical predictive parameter for visceral obesity in clinical settings. In this cross-sectional study, we recruited 51 nondiabetic obese (body mass index [BMI] >= 27 kg/m2) adults in Taiwan (21 men and 30 women, mean age 35.6 +/- 9.2 years, mean BMI 33.3 +/- 3.9 kg/m2). VFA was quantified by a single-slice MRI image. Anthropometric indices and biochemical parameters including fasting plasma glucose, serum level of alanine aminotransferase, and lipid profiles were measured. The associations between different variables and VFA were analyzed by linear regression analysis. Increases in BMI, waist circumference, serum levels of alanine aminotransferase and triglycerides (TGs), and decreased serum levels of high-density lipoprotein cholesterol were correlated with larger VFA. After adjustment for age, sex, and anthropometric indices, only serum TG level remained as an independent correlate of VFA. Besides demographic and anthropometric indices, adding TG level may explain a greater variance of VFA. In stepwise multivariate regression analysis, male sex, age, waist circumference, and serum TG level remained significant predictors of VFA. In a subgroup analysis among subjects with BMI >=30 kg/m2, similar results were demonstrated and serum TG level remained as significant independent correlates of VFA in all of the predictive models. Among nondiabetic obese adults, serum TG level was positively associated with VFA. The combination of sex, age, anthropometric indices, and serum TG level may be used to estimate VFA in clinical settings. PMID- 26061333 TI - Development and Validation of a Prognostic Score to Predict Survival in Adult Patients With Solid Tumors and Bone Marrow Metastases. AB - Bone marrow metastasis (BMM) in patients with solid cancers is indicative of advanced-stage disease with a poor prognosis. The clinical features and outcomes remain unclear. We aimed to develop a scoring system to predict survival in these patients to help with clinical decision making. A total of 165 adult patients diagnosed with solid cancers and BMM between 2000 and 2014 were selected as the derivation cohort. A risk model was developed using multivariate logistic regression from the derivation cohort and a marrow metastases prognostic score (MMPS) was generated. An independent cohort of 156 patients from 3 other hospitals was selected using the same recruiting criteria to validate the MMPS as a predictor of survival. The MMPS was calculated based on 4 independent prognostic variables: the Eastern Cooperative Oncology Group performance scale, site of cancer, platelet count, and neutrophil-to-lymphocyte ratio. Patients in both the derivation and validation cohorts were stratified into good, intermediate, and poor prognostic groups based on their MMPS. The median survival in each risk group of the derivation cohort was 241, 58, and 11 days for the good, intermediate, and poor prognostic groups, respectively, and 305, 65, and 9 days, respectively, in the validation cohort. The c-statistic values for prediction of mortality at 3, 6, and 12 months were significantly higher for the MMPS than for the Eastern Cooperative Oncology Group performance scale in both cohorts. We developed a risk model that accurately predicted survival in adult patients with solid cancers and BMM. This scoring system may help patients and clinicians with treatment decisions. PMID- 26061334 TI - Dementia Increases Severe Sepsis and Mortality in Hospitalized Patients With Chronic Obstructive Pulmonary Disease. AB - Dementia increases the risk of morbidity and mortality in hospitalized patients. However, information on the potential effects of dementia on the risks of acute organ dysfunction, severe sepsis and in-hospital mortality, specifically among inpatients with chronic obstructive pulmonary disease (COPD), is limited. The observational analytic study was inpatient claims during the period from 2000 to 2010 for 1 million people who were randomly selected from all of the beneficiaries of the Taiwan National Health Insurance in 2000. In total, 1406 patients with COPD and dementia were admitted during the study period. Hospitalized patients with COPD and free from a history of dementia were randomly selected and served as control subjects (n = 5334). The patient groups were matched according to age (+/-3 years), gender, and the year of admission, with a control/dementia ratio of 4. Only the first-time hospitalization data for each subject was analyzed. Logistic regression models were used to calculate the odds ratio (OR) of outcome measures (acute organ dysfunction, severe sepsis, and mortality), controlling for confounding factors (age, sex, comorbidity, infection site, hospital level, and length of stay). In COPD patients with dementia, the incidence rate of severe sepsis and hospital mortality was 17.1% and 4.8%, respectively, which were higher than the controls (10.6% and 2.3%). After controlling for potential confounding factors, dementia was found to significantly increase the odds of severe sepsis and hospital mortality with an adjusted OR (OR) of 1.38 (95% confidence interval [CI] 1.10-1.72) and 1.69 (95% CI 1.18-2.43), respectively. Dementia was also significantly associated with an increased OR of acute respiratory dysfunction (adjusted OR 1.39, 95% CI 1.09 1.77). In hospitalized COPD patients, the presence of dementia may increase the risks of acute respiratory dysfunction, severe sepsis, and hospital mortality, which warrants the attention of health care professionals. PMID- 26061336 TI - The complete mitochondrial genome of the Warm Springs pupfish, Cyprinodon nevadensis pectoralis. AB - In this article we report the complete mitochondrial genome of the Warm Springs pupfish, Cyprinodon nevadensis pectoralis. The genomic DNA of a single female individual was extracted and sequenced on the Illumina HiSeq2000 platform. It contains 16,499 bp and a total of 37 genes, divided into 22 tRNA genes, 2 rRNA genes and 13 protein-coding genes. It exhibits 94% sequence similarity with the other published mitochondrion in its genus, C. rubrofluviatilis. A Tamura-Nei maximum-likelihood tree constructed from mitochondrial sequences shows expected phylogenetic relationships between C. nevadensis and sister taxa. PMID- 26061335 TI - The Chikungunya Virus Capsid Protein Contains Linear B Cell Epitopes in the N- and C-Terminal Regions that are Dependent on an Intact C-Terminus for Antibody Recognition. AB - Chikungunya virus (CHIKV) is an arthropod-borne agent that causes severe arthritic disease in humans and is considered a serious health threat in areas where competent mosquito vectors are prevalent. CHIKV has recently been responsible for several millions of cases of disease, involving over 40 countries. The recent re-emergence of CHIKV and its potential threat to human health has stimulated interest in better understanding of the biology and pathogenesis of the virus, and requirement for improved treatment, prevention and control measures. In this study, we mapped the binding sites of a panel of eleven monoclonal antibodies (mAbs) previously generated towards the capsid protein (CP) of CHIKV. Using N- and C-terminally truncated recombinant forms of the CHIKV CP, two putative binding regions, between residues 1-35 and 140-210, were identified. Competitive binding also revealed that five of the CP-specific mAbs recognized a series of overlapping epitopes in the latter domain. We also identified a smaller, N-terminally truncated product of native CP that may represent an alternative translation product of the CHIKV 26S RNA and have potential functional significance during CHIKV replication. Our data also provides evidence that the C-terminus of CP is required for authentic antigenic structure of CP. This study shows that these anti-CP mAbs will be valuable research tools for further investigating the structure and function of the CHIKV CP. PMID- 26061337 TI - Complete mitochondrial genome sequences of two Indonesian rasboras (Rasbora aprotaenia and Rasbora lateristriata). AB - Complete mitochondrial genome sequences were determined for two Indonesian freshwater fishes, Rasbora aprotaenia and Rasbora lateristriata. These genomes are 16,541 bp and 16,539 bp in length, respectively and encode 37 genes in the typical vertebrate gene arrangement. Phylogenetic analyses supported a view that these species are very closely related to each other. PMID- 26061338 TI - The mitochondrial genomes of three lineages of Asian yellow pond turtle, Mauremys mutica. AB - The complete mitochondrial genomes of three lineages (N, TW and S) of Mauremys mutica are determined in this study. The total lengths of the mitogenomes were 16,758 bp for N, 16 500bp for TW, and 16 494bp for S. The nucleotide composition was 26.3-27% for T, 26.2-26.8% for C, and 33.8-33.9% for A. The genomes encoded 37 genes typically found in other vertebrates. Three CSBs were identified, and the CSB1 were variable. A long tandem repeats of (TTATTATA) 30 were found in the control region of N mitogenome, but none in TW and S lineage. These sequences would be useful for the phylogenetic and conservation studies of Asian endangered turtles. PMID- 26061339 TI - Complete mitochondrial genome of the Chinese skipper, Polytremis jigongi (Lepidoptera: Hesperiidae). AB - The sequence of the mitochondrial genome (mitogenome) of Polytremis jigongi (Lepidoptera: Hesperiidae) has been presented in this article. It is 15,353 bp in length, with an A + T content of 80.9% containing 13 protein-coding genes, 22 tRNAs, 2 rRNAs, and a noncoding control region (D-loop). All of the 37 typical animal mitochondrial genes were found. All protein-coding genes started with ATN as a start codon except for the gene COX1 that uses CGA as in other lepidopteran species. Five protein-coding genes use incomplete stop codon TA or T, while the others use TAA as stop codons. Most of the tRNA genes can be folded into a typical cloverleaf structure. Nucleotide composition is similar to other insects, showing a high bias toward A + T. Phylogenetic analysis showed that the genome sequence of P. jigongi is close to Hesperiidae. PMID- 26061340 TI - Complete mitochondrial genomes of two ornamental fishes. AB - The complete mitochondrial genomes of two ornamental fishes, black molly (Poecilia sphenops) and blue gourami (Trichogaster trichopterus), were obtained by the traditional polymerase chain reaction (PCR)-based sequencing approach. The mitogenomes of P. sphenops and T. trichopterus are determined as 16,533 bp and 16,456 bp in length, respectively. Both the genomes include 22 transfer RNA genes, 13 protein-coding genes and 2 ribosomal RNA genes. Phylogenetic tree was constructed based on the complete mitogenomes of these two species and closely related 20 teleost species to assess their phylogenic relationship and evolution. PMID- 26061341 TI - Phylogenetic utility, and variability in structure and content, of complete mitochondrial genomes among genetic lineages of the Hawaiian anchialine shrimp Halocaridina rubra Holthuis 1963 (Atyidae:Decapoda). AB - The Atyidae are caridean shrimp possessing hair-like setae on their claws and are important contributors to ecological services in tropical and temperate fresh and brackish water ecosystems. Complete mitochondrial genomes have only been reported from five of the 449 species in the family, thus limiting understanding of mitochondrial genome evolution and the phylogenetic utility of complete mitochondrial sequences in the Atyidae. Here, comparative analyses of complete mitochondrial genomes from eight genetic lineages of Halocaridina rubra, an atyid endemic to the anchialine ecosystem of the Hawaiian Archipelago, are presented. Although gene number, order, and orientation were syntenic among genomes, three regions were identified and further quantified where conservation was substantially lower: (1) high length and sequence variability in the tRNA-Lys and tRNA-Asp intergenic region; (2) a 317-bp insertion between the NAD6 and CytB genes confined to a single lineage and representing a partial duplication of CytB; and (3) the putative control region. Phylogenetic analyses utilizing complete mitochondrial sequences provided new insights into relationships among the H. rubra genetic lineages, with the topology of one clade correlating to the geologic sequence of the islands. However, deeper nodes in the phylogeny lacked bootstrap support. Overall, our results from H. rubra suggest intra-specific mitochondrial genomic diversity could be underestimated across the Metazoa since the vast majority of complete genomes are from just a single individual of a species. PMID- 26061342 TI - The complete mitochondrial genome of the Epinephelus polyphekadion (Teleostei, Serranidae). AB - In this study, the complete mitochondrial genome of the Epinephelus polyphekadion has been sequenced by the next-generation sequencing (NGS) techniques strategy. The mitochondrial genome is 16,691 bp in length and consists of 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes and a control region. The nucleotide compositions of the light strand are 27.90% A, 29.05% T, 27.48% G and 15.58% C. With the exception of ND6 and eight tRNA genes, all other mitochondrial genes are encoded on the heavy-strand (H-strand). All the tRNAs have clover secondary structure with conservative anticodon arm, TPsiC arm and D arm except for tRNA Ser(GCT) and tRNA-Pro(TGG), which D arm consists of 13 bp and 7 bp single-base, respectively. Phylogenetic tree showed that E. latifasciatus, E. polyphekadion, E. epistictus, E. akaara and E. stictus of the Epinephelus formed a monophyletic group, whereas E. latifasciatus, E. polyphekadion and E. epistictus formed a sister group. PMID- 26061343 TI - A protocol for isolating insect mitochondrial genomes: a case study of NUMT in Melipona flavolineata (Hymenoptera: Apidae). AB - Nuclear mitochondrial DNA insertions (NUMTs) are mitochondrial DNA sequences that have been transferred into the nucleus and are recognized by the presence of indels and stop codons. Although NUMTs have been identified in a diverse range of species, their discovery was frequently accidental. Here, our initial goal was to develop and standardize a simple method for isolating NUMTs from the nuclear genome of a single bee. Subsequently, we tested our new protocol by determining whether the indels and stop codons of the cytochrome c oxidase subunit I (COI) sequence of Melipona flavolineata are of nuclear origin. The new protocol successfully demonstrated the presence of a COI NUMT. In addition to NUMT investigations, the protocol described here will also be very useful for studying mitochondrial mutations related to diseases and for sequencing complete mitochondrial genomes with high read coverage by Next-Generation technology. PMID- 26061345 TI - Variability in Findings From Adult Protective Services Investigations of Elder Abuse in California. AB - Adult Protective Services (APS) workers in California investigate complaints of elder abuse and must determine the validity of a complaint with minimal guidelines. It is unclear whether APS workers reach similar conclusions given cases with similar circumstances. To assess variation in case findings and reasons for them, we used data from monthly reports of completed investigations, and investigation outcomes from all 58 California counties from September 2004 to August 2005, telephone interviews with 54 of 58 counties, and site visits to 17 counties. We also compared the data from 2004-2005 with more recent data from 2013. Large variability was found from county to county in the proportions of cases found to be conclusive, inconclusive, and unfounded. The combined analyses revealed significant differences in how individual APS workers interpret definitions of different types of case outcomes, varying skill and experience of the APS workers, individual and county agency factors, and other reasons that influence variability in case findings. Widespread inconsistencies in the outcomes of elder abuse investigations raise issues to be addressed on multiple levels, including the use of APS data for developing policy, standardizing training of APS workers, and seeking just outcomes for the victims of elder abuse. PMID- 26061346 TI - Biodegradable HEMA-based hydrogels with enhanced mechanical properties. AB - Hydrogels are widely used in the biomedical field. Their main purposes are either to deliver biological active agents or to temporarily fill a defect until they degrade and are followed by new host tissue formation. However, for this latter application, biodegradable hydrogels are usually not capable to sustain any significant load. The development of biodegradable hydrogels presenting load bearing capabilities would open new possibilities to utilize this class of material in the biomedical field. In this work, an original formulation of biodegradable photo-crosslinked hydrogels based on hydroxyethyl methacrylate (HEMA) is presented. The hydrogels consist of short-length poly(2-hydroxyethyl methacrylate) (PHEMA) chains in a star shape structure, obtained by introducing a tetra-functional chain transfer agent in the backbone of the hydrogels. They are cross-linked with a biodegradable N,O-dimethacryloyl hydroxylamine (DMHA) molecule sensitive to hydrolytic cleavage. We characterized the degradation properties of these hydrogels submitted to mechanical loadings. We showed that the developed hydrogels undergo long-term degradation and specially meet the two essential requirements of a biodegradable hydrogel suitable for load bearing applications: enhanced mechanical properties and low molecular weight degradation products. (c) 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1161-1169, 2016. PMID- 26061344 TI - Sugar-coated sperm: Unraveling the functions of the mammalian sperm glycocalyx. AB - Mammalian spermatozoa are coated with a thick glycocalyx that is assembled during sperm development, maturation, and upon contact with seminal fluid. The sperm glycocalyx is critical for sperm survival in the female reproductive tract and is modified during capacitation. The complex interplay among the various glycoconjugates generates numerous signaling motifs that may regulate sperm function and, as a result, fertility. Nascent spermatozoa assemble their own glycans while the cells still possess a functional endoplasmic reticulum and Golgi in the seminiferous tubule, but once spermatogenesis is complete, they lose the capacity to produce glycoconjugates de novo. Sperm glycans continue to be modified, during epididymal transit by extracellular glycosidases and glycosyltransferases. Furthermore, epididymal cells secrete glycoconjugates (glycophosphatidylinositol-anchored glycoproteins and glycolipids) and glycan rich microvesicles that can fuse with the maturing sperm membrane. The sperm glycocalyx mediates numerous functions in the female reproductive tract, including the following: inhibition of premature capacitation; passage through the cervical mucus; protection from innate and adaptive female immunity; formation of the sperm reservoir; and masking sperm proteins involved in fertilization. The immense diversity in sperm-associated glycans within and between species forms a remarkable challenge to our understanding of essential sperm glycan functions. PMID- 26061348 TI - 39th Annual Congress of the Italian Urodynamic Society (Continence, Neuro Urology, Pelvic Floor), Nicolaus Hotel, Bari, Italy 18-20 June 2015. PMID- 26061347 TI - Physical function impairment of older, HIV-infected adults is associated with cytomegalovirus immunoglobulin response. AB - Cytomegalovirus (CMV) is associated with poor outcomes, including physical function impairment, in older HIV-uninfected adults. Whether CMV is associated with physical functional impairment in HIV-infected adults is unknown. The primary objective of this study was to determine the relationship between CMV specific humoral and cell-mediated immune responses with functional impairment in well-controlled HIV infection. In a case-control study, low-function cases were matched by age, gender, and time from HIV diagnosis to high-function controls. Quantitative CMV IgG and %CMV-specific CD8(+) and CD4(+) T cells (interferon gamma expression following CMV pp65 stimulation) were used to estimate physical function. Among 30 low-function cases and 48 high-function matched controls, CMV IgG ranged from <10 to 8,830 EU/ml, including four controls with results <10 EU/ml. Each log10 increase in CMV IgG was associated with 5-fold greater odds of low function (p=0.01); these findings were robust to adjustment for concomitant CD4(+) count, tobacco use, and age; to exclusion of subjects with CMV IgG <10 EU/ml; and to adjustment for hepatitis C viremia. %CMV-specific CD4(+) or CD8(+) T cells were not associated with low function. In bivariable models, the relationship between CMV IgG and physical function was attenuated and was no longer significant when including IL-6, CD4/CD8 ratio, or the Veterans Aging Cohort Study Index score. High levels of CMV-specific IgG were associated with impaired physical function. Attenuation of the strength of this association in bivariable models suggests an indirect relationship mediated by systemic inflammation and immune suppression. PMID- 26061349 TI - Shape-Controlled Synthesis of NiCo2 O4 Microstructures and Their Application in Supercapacitors. AB - The shape-controlled synthesis of NiCo2 O4 microstructures through a facile hydrothermal method and subsequent calcinations was explored. By employing CoSO4 , NiSO4 , and urea as the starting reactants, flower-like NiCo2 O4 microstructures were obtained at 100 degrees C after 5 h without the assistance of any additive and subsequent calcination at 300 degrees C for 2 h; dumbbell like NiCo2 O4 microstructures were prepared at 150 degrees C after 5 h in the presence of trisodium citrate and subsequent calcination at 300 degrees C for 2 h. The as-prepared NiCo2 O4 microstructures were characterized by X-ray powder diffraction, field-emission scanning electron microscopy, energy-dispersive X-ray spectroscopy, and (high-resolution) transmission electron microscopy. Both the flower-like and dumbbell-like NiCo2 O4 microstructures could be used as electrode materials for supercapacitors, and they exhibited excellent electrochemical performance, including high specific capacitance, good rate capability, and excellent long-term cycle stability. Simultaneously, the shape-dependent electrochemical properties of the product were investigated. PMID- 26061350 TI - A study of potential numerical pitfalls in GPU-based Monte Carlo dose calculation. AB - The purpose of this study was to evaluate the impact of numerical errors caused by the floating point representation of real numbers in a GPU-based Monte Carlo code used for dose calculation in radiation oncology, and to identify situations where this type of error arises. The program used as a benchmark was bGPUMCD. Three tests were performed on the code, which was divided into three functional components: energy accumulation, particle tracking and physical interactions. First, the impact of single-precision calculations was assessed for each functional component. Second, a GPU-specific compilation option that reduces execution time as well as precision was examined. Third, a specific function used for tracking and potentially more sensitive to precision errors was tested by comparing it to a very high-precision implementation. Numerical errors were found in two components of the program. Because of the energy accumulation process, a few voxels surrounding a radiation source end up with a lower computed dose than they should. The tracking system contained a series of operations that abnormally amplify rounding errors in some situations. This resulted in some rare instances (less than 0.1%) of computed distances that are exceedingly far from what they should have been. Most errors detected had no significant effects on the result of a simulation due to its random nature, either because they cancel each other out or because they only affect a small fraction of particles. The results of this work can be extended to other types of GPU-based programs and be used as guidelines to avoid numerical errors on the GPU computing platform. PMID- 26061351 TI - Pharmacokinetics and tissue distribution of novel platinum containing anticancer agent BP-C1 studied in rabbits using sector field inductively coupled plasma mass spectrometry. AB - A method of platinum quantification in whole blood samples after microwave digestion using sector field inductively coupled plasma mass spectrometry has been developed. The following analytical figures of merit have been established: limit of detection 1.1 ug/L for blood samples, dynamic range 3.6-200 ug/L, intra day precision (relative standard deviation, n = 9) did not exceed 5%. Spiked samples were analyzed for method validation. The method was used for pharmacokinetics studies of a novel anti-cancer drug BP-S1, a complex of cis configured platinum and benzene-poly-carboxylic acids. Main pharmacokinetic parameters (area under curve, maximum concentration, clearance, half-life times for alpha- and beta-phase) were estimated for two dosage forms of BP-C1 0.05 and 0.125 mass %. Pharmacokinetic curves were assessed for single and course administration. Studies were performed using rabbits (n = 6) as a model. BP-C1 was injected intramuscularly. The study established dose proportionality of the tested dosage forms and suggested clinical dosing schedule: 5 days of injections followed by 2 days' break. Platinum tissue distribution was studied in tissue samples collected 20 days after the last injection. Predominant platinum accumulation was observed in kidneys, liver, and muscles near injection site. 'Slow' phase of platinum excretion kinetics may be related to the muscles at the injection site. PMID- 26061352 TI - The side-by-side exploratory test: a simple automated protocol for the evaluation of adult zebrafish behavior simultaneously with social interaction. AB - The assessment of shoaling in adult zebrafish is technically difficult, but important, given their social nature. The present study aimed to characterize a new protocol using simple automated tracking software to evaluate general behavior and social interaction simultaneously. To this end, we used a single tank with a central transparent glass division and placed one zebrafish on each side for 5 min. This strategy allows fish to interact visually at the same time that individual automated evaluation of behavior can be easily performed. Our results showed that, when two fish are placed side-by-side, there is an increase in their height in the tank compared with isolated fish and they remain close to each other. The pharmacological treatments with benzodiazepines (bromazepam and clonazepam) and the serotonergic drugs buspirone, fluoxetine, and escitalopram did not affect locomotion at the concentrations tested, except for the highest concentration of buspirone. Nevertheless, benzodiazepines increased interfish distance (i.e. reduced shoaling behavior) and serotonergic drugs elevated height in the tank. These results support the use of the side-by-side exploratory test for behavioral studies with the zebrafish, including high-throughput behavioral screening for antidepressants and anxiolytics. PMID- 26061353 TI - Social stress during lactation, depressed maternal care, and neuropeptidergic gene expression. AB - Depression and anxiety can be severely detrimental to the health of both the affected woman and her offspring. In a rodent model of postpartum depression and anxiety, chronic social stress exposure during lactation induces deficits in maternal care and increases anxiety. Here, we extend previous findings by expanding the behavioral analyses, assessing lactation, and examining several neural systems within amygdalar and hypothalamic regions involved in the control of the stress response and expression of maternal care that may be mediating the behavioral changes in stressed dams. Compared with control dams, those exposed to chronic social stress beginning on day 2 of lactation show impaired maternal care and lactation and increased maternal anxiety on day 9 of lactation. Saccharin based anhedonia and maternal aggression were increased and lactation was also impaired on day 16 of lactation. These behavioral changes were correlated with a decrease in oxytocin mRNA expression in the medial amygdala, and increases in the expressions of corticotrophin-releasing hormone mRNA in the central nucleus of the amygdala, glucocorticoid receptor mRNA in the paraventricular nucleus, and orexin 2 receptor mRNA in the supraoptic nucleus of stressed compared with control dams. The increase in glucocorticoid receptor mRNA in the paraventricular nucleus was negatively correlated with methylation of a CpG site in the promoter region. In conclusion, the data support the hypothesis that social stress during lactation can have profound effects on maternal care, lactation, and anxiety, and that these behavioral effects are mediated by central changes in stress and maternally relevant neuropeptide systems. PMID- 26061354 TI - Effects of psychostimulants on social interaction in adult male rats. AB - Psychostimulants are known to have a huge impact on different forms of social behaviour. The aim of the present study was to compare the effects of three different psychostimulants [amphetamine, cocaine and 3,4 methylenedimethoxyamphetamine (MDMA)] on social interaction (SI) in adult male rats. The SI test was performed in a familiar arena and under low-stress environmental conditions. Experimental animals received amphetamine (0.5, 1.0, 1.5 mg/kg), cocaine (0.5, 1.0, 1.5, 2.5, 5.0, 10.0 mg/kg) or MDMA (2.5, 5.0, 10 mg/kg) and control animals received saline (1 ml/kg) 45 min before the SI test. Time spent in SI (individual patterns of social behaviour) and nonsocial activities (locomotion and rearing) were video recorded and then analysed offline, with the following results: (a) all doses of amphetamine decreased SI. Specifically, all doses of amphetamine decreased mutual sniffing, and the higher doses also decreased allo-grooming and following behaviours. (b) The higher doses of cocaine decreased SI, especially mutual sniffing, allo-grooming and climbing over. Cocaine at the dose of 5.0 mg/kg increased genital investigation compared with lower doses. (c) All doses of MDMA decreased mutual sniffing and climbing over; the two higher doses decreased allo-grooming behaviour, and only the highest dose decreased following. The two higher doses of amphetamine and all the doses of MDMA increased locomotion and rearing; cocaine did not affect locomotion, but increased rearing at higher doses. In conclusion, the results confirm the well-known finding that psychostimulants suppress SI, but also show novel differences in the effects of psychostimulants on specific patterns of SI. PMID- 26061355 TI - Effects of amphetamine, morphine, and CP 55, 940 on Go/No-Go task performance in rhesus monkeys. AB - In humans, impulsivity measured as false alarms in a Go/No-Go task is reportedly decreased by amphetamine and is not affected by oxycodone and delta(9) tetrahydrocannabinol. To model these findings in animals, three rhesus monkeys were trained to perform a food-reinforced Go/No-Go task. In this task, amphetamine was found to decrease false alarms (i.e. responding during No-Go trials), but only at doses that also decreased hits (i.e. responding during Go trials). Morphine generally decreased hits but not false alarms. The cannabinoid receptor agonist CP 55, 940 decreased both false alarms and hits, but only at doses that also decreased the number of trials completed. Additional studies in animals and humans are necessary to delineate the conditions under which amphetamine and other psychoactive drugs affect impulsivity in Go/No-Go tasks. PMID- 26061356 TI - Delta9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market. AB - When synthetic cannabinoid compounds became controlled by state and federal governments, different, noncontrolled compounds began to appear as marijuana substitutes. Unlike the scheduled cannabinoids, the newer compounds have not been characterized for potency and efficacy in preclinical studies. The purpose of these experiments was to determine whether some of the more recent synthetic compounds sold as marijuana substitutes have behavioral effects similar to those of Delta-tetrahydrocannabinol (Delta-THC), the pharmacologically active compound in marijuana. The compounds UR-144, XLR-11, AKB-48 (APINACA), PB-22 (QUPIC), 5F PB-22, and AB-FUBINACA were tested for locomotor depressant effects in male Swiss Webster mice and subsequently for their ability to substitute for Delta-THC (3 mg/kg, intraperitoneally) in drug discrimination experiments with male Sprague Dawley rats. UR-144, XLR-11, AKB-48, and AB-FUBINACA each decreased locomotor activity for up to 90 min, whereas PB-22 and 5F-PB-22 produced depressant effects lasting 120-150 min. Each of the compounds fully substituted for the discriminative stimulus effects of Delta-THC. These findings confirm the suggestion that these compounds have marijuana-like psychoactive effects and abuse liability. PMID- 26061357 TI - Google Search Trends and Skin Cancer: Evaluating the US Population's Interest in Skin Cancer and Its Association With Melanoma Outcomes. PMID- 26061358 TI - Harnessing NGS and Big Data Optimally: Comparison of miRNA Prediction from Assembled versus Non-assembled Sequencing Data--The Case of the Grass Aegilops tauschii Complex Genome. AB - MicroRNAs (miRNAs) are small, endogenous, non-coding RNA molecules that regulate gene expression at the post-transcriptional level. As high-throughput next generation sequencing (NGS) and Big Data rapidly accumulate for various species, efforts for in silico identification of miRNAs intensify. Surprisingly, the effect of the input genomics sequence on the robustness of miRNA prediction was not evaluated in detail to date. In the present study, we performed a homology based miRNA and isomiRNA prediction of the 5D chromosome of bread wheat progenitor, Aegilops tauschii, using two distinct sequence data sets as input: (1) raw sequence reads obtained from 454-GS FLX Titanium sequencing platform and (2) an assembly constructed from these reads. We also compared this method with a number of available plant sequence datasets. We report here the identification of 62 and 22 miRNAs from raw reads and the assembly, respectively, of which 16 were predicted with high confidence from both datasets. While raw reads promoted sensitivity with the high number of miRNAs predicted, 55% (12 out of 22) of the assembly-based predictions were supported by previous observations, bringing specificity forward compared to the read-based predictions, of which only 37% were supported. Importantly, raw reads could identify several repeat-related miRNAs that could not be detected with the assembly. However, raw reads could not capture 6 miRNAs, for which the stem-loops could only be covered by the relatively longer sequences from the assembly. In summary, the comparison of miRNA datasets obtained by these two strategies revealed that utilization of raw reads, as well as assemblies for in silico prediction, have distinct advantages and disadvantages. Consideration of these important nuances can benefit future miRNA identification efforts in the current age of NGS and Big Data driven life sciences innovation. PMID- 26061359 TI - Assembly, growth and nonlinear thermo-optical properties of nitropeptides. AB - The molecular self-assembly, growth and nonlinear thermo-optical properties of three synthetic aromatic-aliphatic hybrid nitropeptides have been investigated. The X-ray crystallography of nitropeptide 2 containing a glutamic acid moiety shows that the peptide adopts a dimeric structure using intermolecular hydrogen bonding as well as face to face pi-pi stacking interactions. Moreover, nitropeptide 2 exhibits nonlocal nonlinear optical properties. When a Gaussian laser beam passes through nitropeptide 2, the peptide shows several concentric rings due to spatial self-phase modulation (SSPM). However, the homologous peptide 1 containing an aspartic acid moiety and peptide 3 containing an achiral alpha-aminoisobutyric acid (Aib) moiety adopt sheet-like structures and have no self-phase modulation effect. The report describes the thermo-optical properties consistent with assumption and calculation and is promising for their applications in nonlinear optical modulation devices. PMID- 26061362 TI - Formation of Multicomponent Star Structures at the Liquid/Solid Interface. AB - To demonstrate key roles of multiple interactions between multiple components and multiple phases in the formation of an uncommon self-assembling pattern, we present here the construction of a porous hexagonal star (h-star) structure using a trigonal molecular building block at the liquid/solid interface. For this purpose, self-assembly of hexaalkoxy-substituted dehydrobenzo[12]annulene derivatives DBA-OCns was investigated at the tetradecane/graphite interface by means of scanning tunneling microscopy (STM). Monolayer structures were significantly influenced by coadsorbed tetradecane molecules depending on the alkyl chains length (C13-C16) of DBA-OCn. However, none of DBA-OCn molecules formed the expected trigonal complexes, indicating that an additional driving force is necessary for the formation of the trigonal complex and its assembly into the h-star structure. As a first approach, we employed the "guest induced structural change" for the formation of the h-star structure. In the presence of two guest molecules, nonsubstituted DBA and hexakis(phenylethynyl)benzene which fit the respective pores, an h-star structure was formed by DBA-OC15 at the tetradecane/graphite interface. Moreover, a tetradecane molecule was coadsorbed between a pair of alkyl chains of DBA-OC15, thereby blocking the interdigitation of the alkyl chain pairs. Therefore, the h-star structure results from the self assembly of the four molecular components including the solvent molecule. The second approach is based on aggregation of perfluoroalkyl chains via fluorophilicity of DBA-F, in which the perfluoroalkyl groups are substituted at the end of three alkyl chains of DBA-OCn via p-phenylene linkers. A trigonal complex consisting of DBA-F and three tetradecane molecules formed an h-star structure, in which the perfluoroalkyl groups that orient into the alkane solution phase aggregated at the hexagonal pore via fluorophilicity. The present result provides useful insight into the design and control of complex molecular self-assembly at the liquid/solid interface. PMID- 26061361 TI - Artemisia asiatica Nakai Attenuates the Expression of Proinflammatory Mediators in Stimulated Macrophages Through Modulation of Nuclear Factor-kappaB and Mitogen Activated Protein Kinase Pathways. AB - The present study aimed to examine the anti-inflammatory effects and potential mechanism of action of Artemisia asiatica Nakai (A. asiatica Nakai) extract in activated murine macrophages. A. asiatica Nakai extract showed dose-dependent suppression of lipopolysaccharide (LPS)-induced nitric oxide, inducible nitric oxide synthase, and cyclooxygenase-2 activity. It also showed dose-dependent inhibition of nuclear factor-kappaB (NF-kappaB) translocation from the cytosol to the nucleus and as an inhibitor of NF-kappaB-alpha phosphorylation. The extract's inhibitory effects were found to be mediated through NF-kappaB inhibition and phosphorylation of extracellular signal-regulated kinase 1/2 and p38 in LPS stimulated J774A.1 murine macrophages, suggesting a potential mechanism for the anti-inflammatory activity of A. asiatica Nakai. To our knowledge, this is the first report of the anti-inflammatory effects of A. asiatica Nakai on J774A.1 murine macrophages; these results may help develop functional foods possessing an anti-inflammatory activity. PMID- 26061364 TI - Epidemiological transition of tropical diseases in the Brazilian Amazon. PMID- 26061363 TI - Development of New Modular Genetic Tools for Engineering the Halophilic Archaeon Halobacterium salinarum. AB - Our ability to genetically manipulate living organisms is usually constrained by the efficiency of the genetic tools available for the system of interest. In this report, we present the design, construction and characterization of a set of four new modular vectors, the pHsal series, for engineering Halobacterium salinarum, a model halophilic archaeon widely used in systems biology studies. The pHsal shuttle vectors are organized in four modules: (i) the E. coli's specific part, containing a ColE1 origin of replication and an ampicillin resistance marker, (ii) the resistance marker and (iii) the replication origin, which are specific to H. salinarum and (iv) the cargo, which will carry a sequence of interest cloned in a multiple cloning site, flanked by universal M13 primers. Each module was constructed using only minimal functional elements that were sequence edited to eliminate redundant restriction sites useful for cloning. This optimization process allowed the construction of vectors with reduced sizes compared to currently available platforms and expanded multiple cloning sites. Additionally, the strong constitutive promoter of the fer2 gene was sequence optimized and incorporated into the platform to allow high-level expression of heterologous genes in H. salinarum. The system also includes a new minimal suicide vector for the generation of knockouts and/or the incorporation of chromosomal tags, as well as a vector for promoter probing using a GFP gene as reporter. This new set of optimized vectors should strongly facilitate the engineering of H. salinarum and similar strategies could be implemented for other archaea. PMID- 26061365 TI - Malaria in the State of Amazonas: a typical Brazilian tropical disease influenced by waves of economic development. AB - In Brazil, more than 99% of malaria cases are reported in the Amazon, and the State of Amazonas accounts for 40% of this total. However, the accumulated experience and challenges in controlling malaria in this region in recent decades have not been reported. Throughout the first economic cycle during the rubber boom (1879 to 1912), malaria was recorded in the entire state, with the highest incidence in the villages near the Madeira River in the Southern part of the State of Amazonas. In the 1970s, during the second economic development cycle, the economy turned to the industrial sector and demanded a large labor force, resulting in a large migratory influx to the capital Manaus. Over time, a gradual increase in malaria transmission was observed in peri-urban areas. In the 1990s, the stimulation of agroforestry, particularly fish farming, led to the formation of permanent Anopheline breeding sites and increased malaria in settlements. The estimation of environmental impacts and the planning of measures to mitigate them, as seen in the construction of the Coari-Manaus gas pipeline, proved effective. Considering the changes occurred since the Amsterdam Conference in 1992, disease control has been based on early diagnosis and treatment, but the development of parasites that are resistant to major antimalarial drugs in Brazilian Amazon has posed a new challenge. Despite the decreased lethality and the gradual decrease in the number of malaria cases, disease elimination, which should be associated with government programs for economic development in the region, continues to be a challenge. PMID- 26061366 TI - Tegumentary leishmaniasis in the State of Amazonas: what have we learned and what do we need? AB - This study evaluated the occurrence of American tegumentary leishmaniasis (ATL) in the State of Amazonas, Brazil, in the last 30 years with emphasis on the last 10 years (2001 to 2010). The disease was predominantly observed in males (76.2%), in the 21- to 30-year-old age group (26.6%) and in extractive workers (43.7%); 3.3% of the cases were the mucosal form. The endemic channel shows the disease seasonality, with a predominance of cases at the beginning and end of each year. The number of cases by municipality in the period of 2001-2010 shows the maintenance of the endemic in the localities where the highest numbers of cases have always been registered, namely, Manaus, Rio Preto da Eva, Itacoatiara and Presidente Figueiredo. The comparison of data from 2001 to 2005 and from 2006 to 2010 showed the emergence of this disease in municipalities that had been previously unaffected. In the last years, there has been a significant increase in the activities of control, diagnosis and treatment of leishmaniasis in the State of Amazonas. In conclusion, the historical series of ATL analyzed in this study suggests that the transmission foci remain and are even expanding, though without continuous transmission in the intra- or peridomicile settings. Moreover, the disease will persist in the Amazon while the factors associated with infection acquisition relative to forest exploitation continue to have economic appeal. There is a real expectation of wide variations in disease incidence that can be influenced by climate and economic aspects. PMID- 26061367 TI - Arboviral diseases in the Western Brazilian Amazon: a perspective and analysis from a tertiary health & research center in Manaus, State of Amazonas. AB - The Fundacao de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD), located in Manaus, the capital of the State of Amazonas (Western Brazilian Amazon), is a pioneering institution in this region regarding the syndromic surveillance of acute febrile illness, including arboviral infections. Based on the data from patients at the FMT-HVD, we have detected recurrent outbreaks in Manaus by the four dengue serotypes in the past 15 years, with increasing severity of the disease. This endemicity has culminated in the simultaneous circulation of all four serotypes in 2011, the first time this has been reported in Brazil. Between 1996 and 2009, 42 cases of yellow fever (YF) were registered in the State of Amazonas, and 71.4% (30/42) were fatal. Since 2010, no cases have been reported. Because the introduction of the yellow fever virus into a large city such as Manaus, which is widely infested by Aedes mosquitoes, may pose a real risk of a yellow fever outbreak, efforts to maintain an appropriate immunization policy for the populace are critical. Manaus has also suffered silent outbreaks of Mayaro and Oropouche fevers lately, most of which were misdiagnosed as dengue fever. The tropical conditions of the State of Amazonas favor the existence of other arboviruses capable of producing human disease. Under this real threat, represented by at least 4 arboviruses producing human infections in Manaus and in other neighboring countries, it is important to develop an efficient public health surveillance strategy, including laboratories that are able to make proper diagnoses of arboviruses. PMID- 26061368 TI - Chagas disease in the State of Amazonas: history, epidemiological evolution, risks of endemicity and future perspectives. AB - Chagas disease (CD) is a parasitic infection that originated in the Americas and is caused by Trypanosoma cruzi. In the last few years, the disease has spread to countries in North America, Asia and Europe due to the migration of Latin Americans. In the Brazilian Amazon, CD has an endemic transmission, especially in the Rio Negro region, where an occupational hazard was described for piacaveiros (piassaba gatherers). In the State of Amazonas, the first chagasic infection was reported in 1977, and the first acute CD case was recorded in 1980. After initiatives to integrate acute CD diagnostics with the malaria laboratories network, reports of acute CD cases have increased. Most of these cases are associated with oral transmission by the consumption of contaminated food. Chronic cases have also been diagnosed, mostly in the indeterminate form. These cases were detected by serological surveys in cardiologic outpatient clinics and during blood donor screening. Considering that the control mechanisms adopted in Brazil's classic transmission areas are not fully applicable in the Amazon, it is important to understand the disease behavior in this region, both in the acute and chronic cases. Therefore, the pursuit of control measures for the Amazon region should be a priority given that CD represents a challenge to preserving the way of life of the Amazon's inhabitants. PMID- 26061369 TI - Snakebites as a largely neglected problem in the Brazilian Amazon: highlights of the epidemiological trends in the State of Amazonas. AB - Envenoming snakebites are thought to be a particularly important threat to public health worldwide, especially in rural areas of tropical and subtropical countries. The true magnitude of the public health threat posed by snakebites is unknown, making it difficult for public health officials to optimize prevention and treatment. The objective of this work was to conduct a systematic review of the literature to gather data on snakebite epidemiology in the Amazon region and describe a case series of snakebites from epidemiological surveillance in the State of Amazonas (1974-2012). Only 11 articles regarding snakebites were found. In the State of Amazonas, information regarding incidents involving snakes is scarce. Historical trends show an increasing number of cases after the second half of the 1980s. Snakebites predominated among adults (20-39 years old; 38%), in the male gender (78.9%) and in those living in rural areas (85.6%). The predominant snake envenomation type was bothropic. The incidence reported by the epidemiological surveillance in the State of Amazonas, reaching up to 200 cases/100,000 inhabitants in some areas, is among the highest annual snakebite incidence rates of any region in the world. The majority of the cases were reported in the rainy season with a case-fatality rate of 0.6%. Snakebite envenomation is a great disease burden in the State of Amazonas, representing a challenge for future investigations, including approaches to estimating incidence under-notification and case-fatality rates as well as the factors related to severity and disabilities. PMID- 26061370 TI - Progression of the load of waterborne and intestinal parasitic diseases in the State of Amazonas. AB - In the State of Amazonas, Brazil, urban expansion together with precarious basic sanitation conditions and human settlement on river banks has contributed to the persistence of waterborne and intestinal parasitic diseases. Time series of the recorded cases of cholera, typhoid fever, hepatitis A and leptospirosis are described, using data from different levels of the surveillance systems. The sources for intestinal parasitosis prevalence data (non-compulsory reporting in Brazil) were Medical Literature Analysis and Retrieval System Online (MEDLINE), Literatura Latino-Americana (LILACS) and the annals of major scientific meetings. Relevant papers and abstracts in all languages were accessed by two independent reviewers. The references cited by each relevant paper were scrutinized to locate additional papers. Despite its initial dissemination across the entire State of Amazonas, cholera was controlled in 1998. The magnitude of typhoid fever has decreased; however, a pattern characterized by eventual outbreaks still remains. Leptospirosis is an increasing cause of concern in association with the annual floods. The overall prevalence of intestinal parasites is high regardless of the municipality and the characteristics of areas and populations. The incidence of hepatitis A has decreased over the past decade. A comparison of older and recent surveys shows that the prevalence of intestinal parasitic diseases has remained constant. The load of waterborne and intestinal parasitic diseases ranks high among the health problems present in the State of Amazonas. Interventions aiming at basic sanitation and vaccination for hepatitis A were formulated and implemented, but assessment of their effectiveness in the targeted populations is still needed. PMID- 26061371 TI - A historical overview of leprosy epidemiology and control activities in Amazonas, Brazil. AB - Leprosy is an ancient infectious disease caused by Mycobacterium leprae. According to comparative genomics studies, this disease originated in Eastern Africa or the Near East and spread with successive human migrations. The Europeans and North Africans introduced leprosy into West Africa and the Americas within the past 500 years. In Brazil, this disease arrived with the colonizers who disembarked at the first colonies, Rio de Janeiro, Salvador and Recife, at the end of the sixteenth century, after which it was spread to the other states. In 1854, the first leprosy cases were identified in State of Amazonas in the north of Brazil. The increasing number of leprosy cases and the need for treatment and disease control led to the creation of places to isolate patients, known as leprosaria. One of them, Colonia Antonio Aleixo was built in Amazonas in 1956 according to the most advanced recommendations for isolation at that time and was deactivated in 1979. The history of the Alfredo da Matta Center (AMC), which was the first leprosy dispensary created in 1955, parallels the history of leprosy in the state. Over the years, the AMC has become one of the best training centers for leprosy, general dermatology and sexually transmitted diseases in Brazil. In addition to being responsible for leprosy control programs in the state, the AMC has carried out training programs on leprosy diagnosis and treatment for health professionals in Manaus and other municipalities of the state, aiming to increase the coverage of leprosy control activities. This paper provides a historical overview of leprosy in State of Amazonas, which is an endemic state in Brazil. PMID- 26061372 TI - Temporal distribution of tuberculosis in the State of Amazonas, Brazil. AB - Tuberculosis (TB) is one of the infectious diseases that contributes most to the morbidity and mortality of millions of people worldwide. Brazil is one of 22 countries that accounts for 80% of the tuberculosis global burden. The highest incidence rates in Brazil occur in the States of Amazonas and Rio de Janeiro. The aim of this study was to describe the temporal distribution of TB in the State of Amazonas. Between 2001 and 2011, 28,198 cases of tuberculosis were reported in Amazonas, distributed among 62 municipalities, with the capital Manaus reporting the highest (68.7%) concentration of cases. Tuberculosis was more prevalent among males (59.3%) aged 15 to 34 years old (45.5%), whose race/color was predominantly pardo (64.7%) and who had pulmonary TB (84.3%). During this period, 81 cases of multidrug-resistant TB were registered, of which the highest concentration was reported from 2008 onward (p = 0.002). The municipalities with the largest numbers of indigenous individuals affected were Sao Gabriel da Cachoeira (93%), Itamarati (78.1%), and Santa Isabel do Rio Negro (70.1%). The future outlook for this region includes strengthening the TB control at the primary care level, by expanding diagnostic capabilities, access to treatment, research projects developed in collaboration with the Dr. Heitor Vieira Dourado Tropical Medicine Foundation .;Fundacao de Medicina Tropical Dr. Heitor Vieira Dourado (FMT-HVD).; and financing institutions, such as the project for the expansion of the Clinical Research Center and the creation of a hospital ward for individuals with transmissible respiratory diseases, including TB. PMID- 26061373 TI - HIV/AIDS epidemic in the State of Amazonas: characteristics and trends from 2001 to 2012. AB - A scoping review was conducted to describe the epidemiological characteristics of the human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) epidemic in the State of Amazonas, Brazil, from 2001 to 2012, and temporary patterns were estimated from surveillance data. The results suggest that in its third decade, the Amazon HIV/AIDS epidemic is far from being stabilized and displays rising AIDS incidence and mortality rates and late diagnoses. The data suggest that AIDS cases are hitting mostly young adults and have recently shifted toward men, both homosexual and heterosexual. AIDS cases among the indigenous people have remained stable and low. However, the epidemic has disseminated to the interior of the state, which adds difficulties to its control, given the geographical isolation, logistical barriers, and culturally and ethnically diverse population. Antiretroviral (ARV) therapy has been decentralized, but peripheral ARV services are still insufficient and too distant from people who need them. Recently, the expansion of point-of-care (POC) rapid HIV testing has been contributing to overcoming logistical barriers. Other new POC devices, such as the PIMA CD4 analyzer, will bring the laboratory to the patient. AIDS uniquely coexists with other tropical infections, sharing their epidemiological profiles. The increased demand for HIV/AIDS care services can only be satisfied through increased decentralization to peripheral health units, which can also naturally integrate care with other tropical infections and can promote a shift from vertical to integrated programming. Future challenges involve building surveillance data on HIV case notification and covering the spectrum of engagement in care, including adherence to treatment and follow-up loss. PMID- 26061374 TI - Epidemiology of infectious meningitis in the State of Amazonas, Brazil. AB - INTRODUCTION: In the State of Amazonas, particularly in the capital Manaus, meningitis has affected populations of different cultures and social strata over the years. Bacterial meningitis is caused by several different species and represents a major issue of public health importance. The present study reports the meningitis case numbers with different etiologies in Amazonas from January 1976 to December 2012. METHODS: Since the 1970s, the (currently named) Tropical Medicine Foundation of Doutor Heitor Vieira Dourado [Fundacao de Medicina Tropical Doutor Heitor Vieira Dourado (FMT-HVD)] has remained a reference center in Amazonas for the treatment of meningitis through the diagnosis and notification of cases and the confirmation of such cases using specific laboratory tests. RESULTS: The foundation has achieved coverage of over 90% of the state medical records for many years. Between 1990 and 2012, meningitis cases caused by Haemophilus influenzae decreased with the introduction of the H. influenzae vaccine. Meningococcal disease previously had a higher frequency of serogroup B disease, but starting in 2008, the detection of serogroup C increased gradually and has outpaced the detection of serogroup B. Recently, surveillance has improved the etiological definition of viral meningitis at FMT-HVD, with enteroviruses, Epstein-Barr virus (EBV) and varicella zoster virus (VZV) prevailing in this group of pathogens. With the advent of acquired immunodeficiency syndrome (AIDS), cryptococcal meningitis has become an important disease in Amazonas. Additionally, infectious meningitis is an important burden in the State of Amazonas. CONCLUSIONS: Changes in the epidemiological profile for the different etiology-defined cases are the result of continuous epidemiological surveillance and laboratory capacity improvements and control measures, such as Haemophilus influenzae vaccination. PMID- 26061375 TI - External quality assessment in the voluntary counseling and testing centers in the Brazilian Amazon using dried tube specimens: results of an effectiveness evaluation. AB - INTRODUCTION: In 2011, the Brazilian Ministry of Health rolled out a program for the external quality assessment of rapid human immunodeficiency virus (HIV) tests using the dried tube specimen (DTS) method (EQA-RT/DTS-HIV). Our objective was to evaluate the implementation of this program at 71 voluntary counseling and testing centers (VCTCs) in the Brazilian Legal Amazonian area one year after its introduction. METHODS: Quantitative and qualitative study that analyzed secondary data and interviews with healthcare workers (HCWs) (n=39) and VCTC coordinators (n=32) were performed. The assessment used 18 key indicators to evaluate the three dimensions of the program's logical framework: structure, process, and result. Each indicator was scored from 1-4, and the aggregate results corresponding to the dimensions were expressed as proportions. The results were compared to the perceptions of the HCWs and coordinators regarding the EQA-RT/DTS HIV program. RESULTS: The aggregate scores for the three dimensions of structure, process, and result were 91.7%, 78.6%, and 95%, respectively. The lowest score in each dimension corresponded to a different indicator: access to Quali-TR online system 39% (structure), registration in Quali-TR online system 38.7% (process), and VCTC completed the full process in the program's first round 63.4% (result). Approximately 36% of the HCWs and 52% of the coordinators reported enhanced trust in the program for its rapid HIV testing performance. CONCLUSIONS: All three program dimensions exhibited satisfactory results (>75%). Nevertheless, the study findings highlight the need to improve certain program components. Additionally, long-term follow-ups is needed to provide a more thorough picture of the process for external quality assessment. PMID- 26061376 TI - A basic introduction to fixed-effect and random-effects models for meta-analysis. AB - There are two popular statistical models for meta-analysis, the fixed-effect model and the random-effects model. The fact that these two models employ similar sets of formulas to compute statistics, and sometimes yield similar estimates for the various parameters, may lead people to believe that the models are interchangeable. In fact, though, the models represent fundamentally different assumptions about the data. The selection of the appropriate model is important to ensure that the various statistics are estimated correctly. Additionally, and more fundamentally, the model serves to place the analysis in context. It provides a framework for the goals of the analysis as well as for the interpretation of the statistics. In this paper we explain the key assumptions of each model, and then outline the differences between the models. We conclude with a discussion of factors to consider when choosing between the two models. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26061377 TI - Outlier and influence diagnostics for meta-analysis. AB - The presence of outliers and influential cases may affect the validity and robustness of the conclusions from a meta-analysis. While researchers generally agree that it is necessary to examine outlier and influential case diagnostics when conducting a meta-analysis, limited studies have addressed how to obtain such diagnostic measures in the context of a meta-analysis. The present paper extends standard diagnostic procedures developed for linear regression analyses to the meta-analytic fixed- and random/mixed-effects models. Three examples are used to illustrate the usefulness of these procedures in various research settings. Issues related to these diagnostic procedures in meta-analysis are also discussed. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26061378 TI - Evidence synthesis, economics and public policy. AB - Systematic reviews and syntheses of evidence are increasingly used to inform public policy decisions. Growing budgetary pressures mean that decision makers often need to consider evidence on the costs and efficiency of alternatives as well as their effects. There are a number of methodological challenges in the identification, appraisal, synthesis, interpretation and use of economic evidence. This article draws on a recently published edited volume to review the latest developments, proposals and controversies in these aspects of economic evidence synthesis methodology. It focuses on two broad classes of approach: systematic review to summarize and compare the findings of existing economic analyses and synthesis of new economic results using decision models. The availability and scope of economic evidence is currently limited in many fields, but improving. Increased engagement between economists, the wider evidence synthesis community, and decision makers is needed to improve both the production and use of economic evidence. Further research to improve the evidence base that underpins application of economic evidence synthesis methodology will need to embrace a broader range of methods than economic evaluation and systematic review alone. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26061379 TI - Multivariate fixed- and random-effects models for summarizing ordinal data in meta-analysis of diagnostic staging studies. AB - For many diseases (e.g. rectal cancer and the Crohn disease), more than two stages exist and as treatment mostly depends on disease stages, correctly determining this by a diagnostic test is very important. To determine their role in clinical practice, the value of these tests should be carefully evaluated, and summarizing results in meta-analysis should also be done appropriately. A multinomial model for meta-analyzing data with more than two categories has previously been developed; these data were considered as nominal categories. However, there is an ordinal character within staging data. In this study we extended this multinomial model to three ordinal models (models for the logits of adjacent-categories, for continuation-ratio logits and for proportional odds logits) to summarize the ordinal character of staging data. Both fixed- and random-effects approaches were developed and compared. The principles of the multinomial model as well as three ordinal models are shown by fitting these models using the data on staging of rectal cancer by endoluminal ultrasonography and magnetic resonance imaging. The proportions of patients correctly staged, understaged, and overstaged per stage are obtained by these models. Because of the increased interest in meta-analyses for evidence-based guidelines, these models can be helpful in summarizing staging data. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26061380 TI - Critical interpretation of Cochran's Q test depends on power and prior assumptions about heterogeneity. AB - We describe how an appropriate interpretation of the Q-test depends on its power to detect a given typical amount of between-study variance (tau(2)) as well as prior beliefs on heterogeneity. We illustrate these concepts in an evaluation of 1011 meta-analyses of clinical trials with ?4 studies and binary outcomes. These concepts can be seen as an application of the Bayes theorem. Across the 1011 meta analyses, power to detect typical heterogeneity was low in most situations. Thus, usually a non-significant Q test did not change perceptibly prior convictions on heterogeneity. Conversely, significant results for the Q test typically augmented considerably the probability of heterogeneity. The posterior probability of heterogeneity depends on what tau(2) we want to detect. With the same approach, one may also estimate the posterior probability for the presence of heterogeneity that is large enough to annul statistically significant summary effects; that is half the average within-study variance of the combined studies; and that is able to change the summary effect estimate of the meta-analysis by 20%. The discussed analyses are exploratory, and may depend heavily on prior assumptions when power for the Q-test is low. Statistical heterogeneity in meta-analyses should be cautiously interpreted considering the power to detect a specific tau(2) and prior assumptions about the presence of heterogeneity. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26061381 TI - Erratum: Robust variance estimation in meta-regression with dependent effect size estimates. PMID- 26061383 TI - The impact of active site protonation on substrate ring conformation in Melanocarpus albomyces cellobiohydrolase Cel7B. AB - The ability to utilize biomass as a feedstock for liquid fuel and value-added chemicals is dependent on the efficient and economic utilization of lignin, hemicellulose, and cellulose. In current bioreactors, cellulases are used to convert crystalline and amorphous cellulose to smaller oligomers and eventually glucose by means of cellulase enzymes. A critical component of the enzyme catalyzed hydrolysis reaction is the degree to which the enzyme can facilitate substrate ring deformation from the chair to a more catalytically active conformation (e.g. skewed boat) at the -1 subsite. Presented here is an evaluation of the impact of the protonation state for critical active site residues (i.e. Glu212, Asp214, Glu217, and His228) in Melanocarpus albomyces (Ma) Cellobiohydrolase Cel7B on the substrate's orientation and ring conformation. It is found that the protonation state of the active site can disrupt the intra enzyme hydrogen bonding network and enhance the sampling of various ring puckering conformations for the substrate ring at the +1 and -1 subsites. In particular it is observed that the protonation state of Asp214 dictates the accessibility of the glycosidic bond to the catalytic acid/base Glu217 by influencing the phi/psi dihedral angles and the puckering of the ring structure. The protonation-orientation-conformation analysis has revealed an active site that primarily utilizes two highly coupled protonation schemes; one protonation scheme to orient the substrate and generate catalytically favorable substrate geometries and ring puckering conformations and another protonation scheme to hydrolyze the glycosidic bond. In addition to identifying how enzymes utilize protonation state to manipulate substrate geometry, this study identifies possible directions for improving catalytic activity through protein engineering. PMID- 26061382 TI - Optimizing and Interpreting Insular Functional Connectivity Maps Obtained During Acute Experimental Pain: The Effects of Global Signal and Task Paradigm Regression. AB - The insula is uniquely located between the temporal and parietal cortices, making it anatomically well-positioned to act as an integrating center between the sensory and affective domains for the processing of painful stimulation. This can be studied through resting-state functional connectivity (fcMRI) imaging; however, the lack of a clear methodology for the analysis of fcMRI complicates the interpretation of these data during acute pain. Detected connectivity changes may reflect actual alterations in low-frequency synchronous neuronal activity related to pain, may be due to changes in global cerebral blood flow or the superimposed task-induced neuronal activity. The primary goal of this study was to investigate the effects of global signal regression (GSR) and task paradigm regression (TPR) on the changes in functional connectivity of the left (contralateral) insula in healthy subjects at rest and during acute painful electric nerve stimulation of the right hand. The use of GSR reduced the size and statistical significance of connectivity clusters and created negative correlation coefficients for some connectivity clusters. TPR with cyclic stimulation gave task versus rest connectivity differences similar to those with a constant task, suggesting that analysis which includes TPR is more accurately reflective of low-frequency neuronal activity. Both GSR and TPR have been inconsistently applied to fcMRI analysis. Based on these results, investigators need to consider the impact GSR and TPR have on connectivity during task performance when attempting to synthesize the literature. PMID- 26061385 TI - A mathematical model and computational framework for three-dimensional chondrocyte cell growth in a porous tissue scaffold placed inside a bi directional flow perfusion bioreactor. AB - The in vitro chondrocyte cell culture for cartilage tissue regeneration in a perfusion bioreactor is a complex process. Mathematical modeling and computational simulation can provide important insights into the culture process, which would be helpful for selecting culture conditions to improve the quality of the developed tissue constructs. However, simulation of the cell culture process is a challenging task due to the complicated interaction between the cells and local fluid flow and nutrient transport inside the complex porous scaffolds. In this study, a mathematical model and computational framework has been developed to simulate the three-dimensional (3D) cell growth in a porous scaffold placed inside a bi-directional flow perfusion bioreactor. The model was developed by taking into account the two-way coupling between the cell growth and local flow field and associated glucose concentration, and then used to perform a resolved scale simulation based on the lattice Boltzmann method (LBM). The simulation predicts the local shear stress, glucose concentration, and 3D cell growth inside the porous scaffold for a period of 30 days of cell culture. The predicted cell growth rate was in good overall agreement with the experimental results available in the literature. This study demonstrates that the bi-directional flow perfusion culture system can enhance the homogeneity of the cell growth inside the scaffold. The model and computational framework developed is capable of providing significant insight into the culture process, thus providing a powerful tool for the design and optimization of the cell culture process. PMID- 26061384 TI - The application of nanomaterials in controlled drug delivery for bone regeneration. AB - Bone regeneration is a complicated process that involves a series of biological events, such as cellular recruitment, proliferation and differentiation, and so forth, which have been found to be significantly affected by controlled drug delivery. Recently, a lot of research studies have been launched on the application of nanomaterials in controlled drug delivery for bone regeneration. In this article, the latest research progress in this area regarding the use of bioceramics-based, polymer-based, metallic oxide-based and other types of nanomaterials in controlled drug delivery for bone regeneration are reviewed and discussed, which indicates that the controlling drug delivery with nanomaterials should be a very promising treatment in orthopedics. Furthermore, some new challenges about the future research on the application of nanomaterials in controlled drug delivery for bone regeneration are described in the conclusion and perspectives part. PMID- 26061387 TI - Administration of Danhong Injection to diabetic db/db mice inhibits the development of diabetic retinopathy and nephropathy. AB - Danhong Injection (DHI), a Chinese medicine for treatment of patients with coronary heart disease, inhibits primary abdominal aortic aneurysms in apoE deficient (apoE(-/-)) mice. Formation of microaneurysms plays an important role in the development of diabetic retinopathy and nephropathy. It remains unknown if DHI can reduce these diabetic complications. In this study, diabetic db/db mice in two groups were injected with saline and DHI, respectively, for 14 weeks. Blood and tissue samples were collected to determine serum glucose, lipids and tissue structure. DHI reduced diabetes-induced body weight gain, serum cholesterol and glucose levels. In retinas, DHI blocked the shrink of whole retina and retinal sub-layers by inhibiting expression of caspase 3, matrix metalloproteinase 2 (MMP-2) and MMP-9, accumulation of carbohydrate macromolecules and formation of acellular capillaries. DHI improved renal functions by inhibiting mesangial matrix expansion, expression of vascular endothelial growth factor A, fibronectin and advanced glycation end products in kidneys. Mechanistically, DHI induced expression of glucokinase, AMPKalpha/phosphorylated AMPKalpha, insulin receptor substrate 1, fibroblast growth factor 21 and peroxisome proliferator-activated gamma. Expression of genes responsible for energy expenditure was also activated by DHI. Therefore, DHI inhibits diabetic retinopathy and nephropathy by ameliorating glucose metabolism and demonstrates a potential application in clinics. PMID- 26061388 TI - Discovery of 1-{4-[3-fluoro-4-((3s,6r)-3-methyl-1,1-dioxo-6-phenyl-[1,2]thiazinan 2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone (GNE-3500): a potent, selective, and orally bioavailable retinoic acid receptor-related orphan receptor C (RORc or RORgamma) inverse agonist. AB - Retinoic acid receptor-related orphan receptor C (RORc, RORgamma, or NR1F3) is a nuclear receptor that plays a major role in the production of interleukin (IL) 17. Considerable efforts have been directed toward the discovery of selective RORc inverse agonists as potential treatments of inflammatory diseases such as psoriasis and rheumatoid arthritis. Using the previously reported tertiary sulfonamide 1 as a starting point, we engineered structural modifications that significantly improved human and rat metabolic stabilities while maintaining a potent and highly selective RORc inverse agonist profile. The most advanced delta sultam compound, GNE-3500 (27, 1-{4-[3-fluoro-4-((3S,6R)-3-methyl-1,1-dioxo-6 phenyl-[1,2]thiazinan-2-ylmethyl)-phenyl]-piperazin-1-yl}-ethanone), possessed favorable RORc cellular potency with 75-fold selectivity for RORc over other ROR family members and >200-fold selectivity over 25 additional nuclear receptors in a cell assay panel. The favorable potency, selectivity, in vitro ADME properties, in vivo PK, and dose-dependent inhibition of IL-17 in a PK/PD model support the evaluation of 27 in preclinical studies. PMID- 26061389 TI - Circadian and Circannual Rhythms in Thyroid Hormones: Determining the TSH and Free T4 Reference Intervals Based Upon Time of Day, Age, and Sex. AB - BACKGROUND: Establishing the reference interval for thyrotropin (TSH) and free thyroxine (T4) is clinically important because a number of disease states have been linked to alterations in TSH and free T4 concentrations that are within the 95% confidence interval for normal thyroid hormone values. Age, sex, time of day, and ethnicity are known to affect circulating levels of TSH and free T4 but have not been used to establish reference intervals. The purpose of this study was to define the reference interval for TSH and free T4 taking into account age, sex, ethnicity, and circadian and circannual variability. METHODS: We performed a retrospective analysis of 465,593 TSH and 112,994 free T4 measurements from subjects ages 1-104 years with no thyroid disease using a single TSH and free T4 immunoassay method. Boundaries for the central 95% of patient values, taking into account hour of day, day of year, sex, and age were calculated. RESULTS: Females had significantly higher TSH and free T4 levels than males; the magnitude of these differences did not exceed 0.1 mIU/L or 0.1 ng/dL respectively. Although the 2.5% TSH reference interval remains constant through the day, date, and age ranges, the upper limit (97.5%) of the TSH reference interval increases from 6.45 to 7.55 mIU/L with age, due primarily to a progressive increase in the amplitude of the nocturnal TSH surge. Additionally, significant ethnic differences in TSH circadian periodicity occur between African American, Pacific Island, and Caucasian populations. CONCLUSIONS: The reference interval for TSH varies significantly by age, sex, hour of day, and ethnicity. Time of year does not affect the TSH reference interval, and age, sex, hour of day and time of year do not affect the free T4 reference interval. PMID- 26061390 TI - Unique Urchin-like Ca2Ge7O16 Hierarchical Hollow Microspheres as Anode Material for the Lithium Ion Battery. AB - Germanium is an outstanding anode material in terms of electrochemical performance, especially rate capability, but its developments are hindered by its high price because it is rare in the crust of earth, and its huge volume variation during the lithium insertion and extraction. Introducing other cheaper elements into the germanium-based material is an efficient way to dilute the high price, but normally sacrifice its electrochemical performance. By the combination of nanostructure design and cheap element (calcium) introduction, urchin-like Ca2Ge7O16 hierarchical hollow microspheres have been successfully developed in order to reduce the price and maintain the good electrochemical properties of germanium-based material. The electrochemical test results in different electrolytes show that ethylene carbonate/dimethyl carbonate/diethyl carbonate (3/4/3 by volume) with 5 wt% fluoroethylene carbonate additive is the most suitable solvent for the electrolyte. From the electrochemical evaluation, the as synthesized Ca2Ge7O16 hollow microspheres exhibit high reversible specific capacity of up to 804.6 mA h g(-1) at a current density of 100 mA g(-1) after 100 cycles and remarkable rate capability of 341.3 mA h g(-1) at a current density of 4 A g(-1). The growth mechanism is proposed based on our experimental results on the growth process. PMID- 26061391 TI - Dynamics of Energy and Electron Transfer in the FMO-Reaction Center Core Complex from the Phototrophic Green Sulfur Bacterium Chlorobaculum tepidum. AB - The reaction center core (RCC) complex and the RCC with associated Fenna-Matthews Olson protein (FMO-RCC) complex from the green sulfur bacterium Chlorobaculum tepidum were studied comparatively by steady-state and time-resolved fluorescence (TRF) and femtosecond time-resolved transient absorption (TA) spectroscopies. The energy transfer efficiency from the FMO to the RCC complex was calculated to be ~40% based on the steady-state fluorescence. TRF showed that most of the FMO complexes (66%), regardless of the fact that they were physically attached to the RCC, were not able to transfer excitation energy to the reaction center. The TA spectra of the RCC complex showed a 30-38 ps lifetime component regardless of the excitation wavelengths, which is attributed to charge separation. Excitonic equilibration was shown in TA spectra of the RCC complex when excited into the BChl a Qx band at 590 nm and the Chl a Qy band at 670 nm, while excitation at 840 nm directly populated the low-energy excited state and equilibration within the excitonic BChl a manifold was not observed. The TA spectra for the FMO-RCC complex excited into the BChl a Qx band could be interpreted by a combination of the excited FMO protein and RCC complex. The FMO-RCC complex showed an additional fast kinetic component compared with the FMO protein and the RCC complex, which may be due to FMO-to-RCC energy transfer. PMID- 26061392 TI - Photoactivatable Prodrugs of Antimelanoma Agent Vemurafenib. AB - In this study, we report on novel photoactivatable caged prodrugs of vemurafenib. This kinase inhibitor was the first approved drug for the personalized treatment of BRAF-mutated melanoma and showed impressive results in clinical studies. However, the occurrence of severe side effects and drug resistance illustrates the urgent need for innovative therapeutic approaches. To conquer these limitations, we implemented photoremovable protecting groups into vemurafenib. In general, this caging concept provides spatial and temporal control over the activation of molecules triggered by ultraviolet light. Thus, higher inhibitor concentrations in tumor tissues might be reached with less systemic effects. Our study describes the first development of caged vemurafenib prodrugs useful as pharmacological tools. We investigated their photochemical characteristics and photoactivation. In vitro evaluation proved the intended loss-of-function and the light-dependent recovery of efficacy in kinase and cellular assays. The reported vemurafenib photo prodrugs represent a powerful biological tool for novel pharmacological approaches in cancer research. PMID- 26061393 TI - Histomorphological features and prognosis of colitis-associated colorectal cancer in patients with primary sclerosing cholangitis. AB - BACKGROUND: Histomorphology of colitis-associated colorectal cancer (CAC) in patients with primary sclerosing cholangitis (PSC) remains to be systemically characterized and prognosis in these patient needs to be further defined. AIM: To examine the impact of PSC on histomorphology and to assess prognosis of CAC-PSC patients. METHODS: A cohort of CAC patients were identified from the Pathology Database (1994-2010) at Cleveland Clinic; histomorphological features and other relevant data were collected by retrospective review of pathology slides and medical records. RESULTS: A total of 87 CAC patients were included, with 11 patients having PSC (the study group) and 76 patients without PSC (the control group). The overall median follow up was 6 (range: 0-20) years. The patients in the study group had a longer median duration of inflammatory bowel disease prior to CAC diagnosis (p = 0.046). In study group, seven (63.6%) patients had right sided CAC (vs. 36.8% in the control group, p = 0.11). Background high-grade dysplasia was noted less (9.1% vs. 44.7%), while low-grade dysplasia was detected more in the study group (72.7% vs. 28.9%) (p = 0.02). All histomorphological features were comparable between groups. The overall survival (OS) and progression-free survival (PFS) showed no statistical difference between CAC patients with or without PSC. After excluding TNM stage IV patients, patients with PSC showed a trend toward shorter OS and PFS (p = 0.07 and p = 0.1). CONCLUSION: In CAC, histomorphology appeared to be independent of PSC. PSC is associated with a trend toward shorter OS and PFS in CAC patients with stage I III diseases. PMID- 26061396 TI - Numerical Simulation of Flow-Induced Noise in High Pressure Reducing Valve. AB - The main objective of this paper is to study the characteristics of flow-induced noise in high pressure reducing valve (HPRV) and to provide some guidance for noise control. Based on computational fluid dynamics (CFD), numerical method was used to compute flow field. Ffowcs Williams and Hawkings Model was applied to obtain acoustic signals. The unsteady flow field shows that noise sources are located at the bottom of plug for valve without perforated plate, and noise sources are behind the plate for valve with perforated plate. Noise directivity analysis and spectrum characteristics indicate that the perforated plate could help to reduce noise effectively. Inlet pressure has great effects on sound pressure level (SPL). The higher inlet pressure will lead to larger SPL at high frequency. When the maximum Ma is close to 1, SPL at low frequency becomes very high. PMID- 26061394 TI - Expression of Toll-like receptors in nasal epithelium in allergic rhinitis. AB - Toll-like receptors (TLRs) are important in barrier homeostasis, but their role in airborne allergies is not fully understood. The aim was to evaluate baseline and allergen-induced expression of TLR proteins in nasal epithelium during allergic rhinitis. Nineteen otherwise healthy non-smoking volunteers both allergic to birch pollen and non-allergic controls were enrolled. We took nasal biopsies before and after off-seasonal intranasal birch pollen or diluent challenge. The expression of epithelial TLR1-7, TLR9-10, and MyD88 proteins was immunohistochemically evaluated from the nasal biopsies. The TLR1-3 and TLR5-10 mRNAs were observed by RNA-microarray. Baseline epithelial expression of TLR proteins was wide and identical in controls and atopics. After off-seasonal intranasal birch pollen challenge, a negative change in the expression score of TLR1 and TLR6 proteins was detected in the atopic group. TLR mRNA expression was not affected by birch pollen challenge. Nasal epithelium seems to express all known TLRs. The mechanisms by which TLR1, and TLR6 proteins could affect pollen allergen transport need further studies. PMID- 26061395 TI - Genotyping-By-Sequencing (GBS) Detects Genetic Structure and Confirms Behavioral QTL in Tame and Aggressive Foxes (Vulpes vulpes). AB - The silver fox (Vulpes vulpes) offers a novel model for studying the genetics of social behavior and animal domestication. Selection of foxes, separately, for tame and for aggressive behavior has yielded two strains with markedly different, genetically determined, behavioral phenotypes. Tame strain foxes are eager to establish human contact while foxes from the aggressive strain are aggressive and difficult to handle. These strains have been maintained as separate outbred lines for over 40 generations but their genetic structure has not been previously investigated. We applied a genotyping-by-sequencing (GBS) approach to provide insights into the genetic composition of these fox populations. Sequence analysis of EcoT22I genomic libraries of tame and aggressive foxes identified 48,294 high quality SNPs. Population structure analysis revealed genetic divergence between the two strains and more diversity in the aggressive strain than in the tame one. Significant differences in allele frequency between the strains were identified for 68 SNPs. Three of these SNPs were located on fox chromosome 14 within an interval of a previously identified behavioral QTL, further supporting the importance of this region for behavior. The GBS SNP data confirmed that significant genetic diversity has been preserved in both fox populations despite many years of selective breeding. Analysis of SNP allele frequencies in the two populations identified several regions of genetic divergence between the tame and aggressive foxes, some of which may represent targets of selection for behavior. The GBS protocol used in this study significantly expanded genomic resources for the fox, and can be adapted for SNP discovery and genotyping in other canid species. PMID- 26061397 TI - Elevated ARG1 expression in primary monocytes-derived macrophages as a predictor of radiation-induced acute skin toxicities in early breast cancer patients. AB - Radiation therapy (RT) the front-line treatment after surgery for early breast cancer patients is associated with acute skin toxicities in at least 40% of treated patients. Monocyte-derived macrophages are polarized into functionally distinct (M1 or M2) activated phenotypes at injury sites by specific systemic cytokines known to play a key role in the transition between damage and repair in irradiated tissues. The role of M1 and M2 macrophages in RT-induced acute skin toxicities remains to be defined. We investigated the potential value of M1 and M2 macrophages as predictive factors of RT-induced skin toxicities in early breast cancer patients treated with adjuvant RT after lumpectomy. Blood samples collected from patients enrolled in a prospective clinical study (n = 49) were analyzed at baseline and after the first delivered 2Gy RT dose. We designed an ex vivo culture system to differentiate patient blood monocytes into macrophages and treated them with M1 or M2-inducing cytokines before quantitative analysis of their "M1/M2" activation markers, iNOS, Arg1, and TGFbeta1. Statistical analysis was performed to correlate experimental data to clinical assessment of acute skin toxicity using Common Toxicity Criteria (CTC) grade for objective evaluation of skin reactions. Increased ARG1 mRNA significantly correlated with higher grades of erythema, moist desquamation, and CTC grade. Multivariate analysis revealed that increased ARG1 expression in macrophages after a single RT dose was an independent prognostic factor of erythema (p = 0 .032), moist desquamation (p = 0 .027), and CTC grade (p = 0 .056). Interestingly, multivariate analysis of ARG1 mRNA expression in macrophages stimulated with IL-4 also revealed independent prognostic value for predicting acute RT-induced toxicity factors, erythema (p = 0 .069), moist desquamation (p = 0 .037), and CTC grade (p = 0 .046). To conclude, our findings underline for the first time the biological significance of increased ARG1 mRNA levels as an early independent predictive biomarker of RT induced acute skin toxicities. PMID- 26061398 TI - Genetic Affinity of the Bhil, Kol and Gond Mentioned in Epic Ramayana. AB - Kol, Bhil and Gond are some of the ancient tribal populations known from the Ramayana, one of the Great epics of India. Though there have been studies about their affinity based on classical and haploid genetic markers, the molecular insights of their relationship with other tribal and caste populations of extant India is expected to give more clarity about the the question of continuity vs. discontinuity. In this study, we scanned >97,000 of single nucleotide polymorphisms among three major ancient tribes mentioned in Ramayana, namely Bhil, Kol and Gond. The results obtained were then compared at inter and intra population levels with neighboring and other world populations. Using various statistical methods, our analysis suggested that the genetic architecture of these tribes (Kol and Gond) was largely similar to their surrounding tribal and caste populations, while Bhil showed closer affinity with Dravidian and Austroasiatic (Munda) speaking tribes. The haplotype based analysis revealed a massive amount of genome sharing among Bhil, Kol, Gond and with other ethnic groups of South Asian descent. On the basis of genetic component sharing among different populations, we anticipate their primary founding over the indigenous Ancestral South Indian (ASI) component has prevailed in the genepool over the last several thousand years. PMID- 26061400 TI - Decarboxylative Alkynylation of alpha-Keto Acids and Oxamic Acids in Aqueous Media. AB - A mild K2S2O8 promoted decarboxylative alkynylation of alpha-keto acids and oxamic acids has been developed. This process features mild reaction conditions, a broad substrate scope, and good functional-group tolerance, therefore providing a new and efficient access to a wide range of ynones and propiolamides. Furthermore, this radical process could also be successfully applied to alkynylation of the Csp(2)-H bond in DMF with hypervalent alkynyl iodide reagents. PMID- 26061399 TI - Low Abdominal NIRS Values and Elevated Plasma Intestinal Fatty Acid-Binding Protein in a Premature Piglet Model of Necrotizing Enterocolitis. AB - To identify early markers of necrotizing enterocolitis (NEC), we hypothesized that continuous abdominal near-infrared spectroscopy (A-NIRS) measurement of splanchnic tissue oxygen saturation and intermittent plasma intestinal fatty-acid binding protein (pI-FABP) measured every 6 hours can detect NEC prior to onset of clinical symptoms. Premature piglets received parenteral nutrition for 48-hours after delivery, followed by enteral feeds every three hours until death or euthanasia at 96-hours. Continuous A-NIRS, systemic oxygen saturation (SpO2), and heart rate were measured while monitoring for clinical signs of NEC. Blood samples obtained at 6-hour intervals were used to determine pI-FABP levels by ELISA. Piglets were classified as fulminant-NEC (f-NEC), non-fulminant-NEC (nf NEC) and No-NEC according to severity of clinical and histologic features. Of 38 piglets, 37% (n=14) developed nf-NEC, 18% (n=7) developed f-NEC and 45% (n=17) had No-NEC. There were significant differences in baseline heart rate (p=0.008), SpO2 (p<0.001) and A-NIRS (p<0.001) among the three groups. A-NIRS values of NEC piglets remained lower throughout the study with mean for f-NEC of 69+/-3.8%, 71.9+/-4.04% for nf-NEC, and 78.4+/-1.8% for No-NEC piglets (p<0.001). A-NIRS <75% predicted NEC with 97% sensitivity and 97% specificity. NEC piglets demonstrated greater variability from baseline in A-NIRS than healthy piglets (10.1% vs. 6.3%; p=0.04). Mean pI-FABP levels were higher in animals that developed NEC compared to No-NEC piglets (0.66 vs. 0.09 ng/mL;p<0.001). In f-NEC piglets, pI-FABP increased precipitously after feeds (0.04 to 1.87 ng/mL;p<0.001). pI-FABP levels increased in parallel with disease progression and a value >0.25ng/mL identified animals with NEC (68% sensitivity and 90% specificity). NIRS is a real-time, non-invasive tool that can serve as a diagnostic modality for NEC. In premature piglets, low A-NIRS in the early neonatal period and increased variability during initial feeds are highly predictive of NEC, which is then confirmed by rising plasma I-FABP levels. These modalities may help identify neonates with NEC prior to clinical manifestations of disease. PMID- 26061402 TI - Progress: Baby Steps Yield Leaps and Bounds. PMID- 26061403 TI - Abrupt CMS Decision May Threaten Hundreds of Thousands of Wound Care Patients with Potential Limb Loss. PMID- 26061401 TI - The Nutritional Geometry of Resource Scarcity: Effects of Lean Seasons and Habitat Disturbance on Nutrient Intakes and Balancing in Wild Sifakas. AB - Animals experience spatial and temporal variation in food and nutrient supply, which may cause deviations from optimal nutrient intakes in both absolute amounts (meeting nutrient requirements) and proportions (nutrient balancing). Recent research has used the geometric framework for nutrition to obtain an improved understanding of how animals respond to these nutritional constraints, among them free-ranging primates including spider monkeys and gorillas. We used this framework to examine macronutrient intakes and nutrient balancing in sifakas (Propithecus diadema) at Tsinjoarivo, Madagascar, in order to quantify how these vary across seasons and across habitats with varying degrees of anthropogenic disturbance. Groups in intact habitat experience lean season decreases in frugivory, amounts of food ingested, and nutrient intakes, yet preserve remarkably constant proportions of dietary macronutrients, with the proportional contribution of protein to the diet being highly consistent. Sifakas in disturbed habitat resemble intact forest groups in the relative contribution of dietary macronutrients, but experience less seasonality: all groups' diets converge in the lean season, but disturbed forest groups largely fail to experience abundant season improvements in food intake or nutritional outcomes. These results suggest that: (1) lemurs experience seasonality by maintaining nutrient balance at the expense of calories ingested, which contrasts with earlier studies of spider monkeys and gorillas, (2) abundant season foods should be the target of habitat management, even though mortality might be concentrated in the lean season, and (3) primates' within-group competitive landscapes, which contribute to variation in social organization, may vary in complex ways across habitats and seasons. PMID- 26061404 TI - The Prevalence of Anemia of Chronic Disease in Patients With Spinal Cord Injuries and Pressure Ulcers and the Impact of Erythropoietin Supplementation on Wound Healing: A Descriptive Pilot Study. AB - Anemia of chronic disease (ACD) is thought to impair the responsiveness of erythroid progenitor cells, but research has shown treatment with recombinant human erythropoietin (rhuEPO) can improve patient hemoglobin levels and, subsequently, overall patient health status and quality of life. A prospective pilot study was designed to estimate the prevalence of ACD in outpatients with spinal cord injury (SCI) and chronic pressure ulcers (PUs) and examine the impact of rhuEPO on PU healing in this population. The charts of 49 SCI patients with PUs were reviewed; of those, 17 had anemia (hemoglobin <110 g/L). The prevalence of anemia in SCI patients with PUs was found to be approximately 35%. From these 17 potential participants, 5 had improved hemoglobin levels during the screening period (rendering them ineligible), 1 withdrew due to illness, and 7 died, leaving 4 participants to complete the study. Four patients (2 men, 2 women, average age 57 +/- 16.5 years) ultimately were enrolled. Wound area and depth and cytokines were measured before, during, and after 6 weeks of treatment with rhuEPO, with a 3-month follow-up. Laboratory tests measuring hemoglobin, C reactive protein, and prealbumin were used to monitor nutritional status and treatment response. No statistically significant changes were observed with treatment. Wound surface area and depth had mean decreases of 1.35 cm(2) and 0.58 cm, respectively, immediately post-treatment. Participants' elevated C-reactive protein levels (91.1-14.2 mg/L) decreased with rhuEPO treatment, but returned to baseline levels post-treatment (83.2-14.3 mg/L). Prealbumin levels were consistently low (range of 0.1-0.21 g/L). This research indicates rhuEPO treatment may improve some outcomes for ACD-SCI PU patients, but larger randomized controlled trials are required. The results of this study suggest the prevalence of ACD in the SCI outpatient population with PUs is at least 35%, and increased vigilance of patient nutrition is recommended. PMID- 26061405 TI - Hypertonic Glucose Combined with Negative Pressure Wound Therapy to Prepare Wounds with Pseudomonas aeruginosa Infection for Skin Grafting: A Report of 3 Cases. AB - Soft tissue losses from acute or chronic trauma are a challenge for surgeons. To explore a method to expedite granulation tissue formation in preparation for a split-thickness skin graft (STSG), the medical records of 3 patients - 2 adult men with wounds related to trauma injury and 1 infant with necrotizing fasciitis, all infected with Pseudomonas aeruginosa - were reviewed. All wounds were surgically debrided and managed by applying gauze soaked in 50% glucose followed by continuous negative pressure wound therapy (NPWT) before definitive skin grafting. NPWT pressure was applied at -80 mm Hg for the 2 adult males (ages 39 and 25 years) and -50 mm Hg for the 7-month-old male infant. The dressings were changed every 2 to 3 days. No adverse events occurred, and wounds were successfully closed with a STSG after an average of 7 days. In 1 case, NPWT was able to help affix dressings in a difficult-to-dress area (genital region). The combination of hypertonic glucose and hand-made, gauze-based NPWT was found to be safe, well-tolerated, and effective in preparing the wound bed for grafting. Prospective, randomized, controlled clinical studies are needed to compare the safety, effectiveness, and efficacy of this method to other treatment approaches for P. aeruginosa-infected wounds. PMID- 26061406 TI - Implementing a Pro-forma for Multidisciplinary Management of an Enterocutaneous Fistula: A Case Study. AB - Optimal management of patients with an entercocutaneous fistula (ECF) requires utilization of the sepsis, nutrition, anatomy, and surgical procedure (SNAP) protocol. The protocol includes early detection and treatment of sepsis, optimizing patient nutrition through oral and parenteral routes, identifying the fistula anatomy, optimal fistula management, and proceeding to corrective surgery when appropriate. The protocol requires multidisciplinary team (MDT) coordination among surgeons, nurses, dietitians, stoma nurses, and physiotherapists. This case study describes a 70-year-old man who developed an ECF subsequent to a laparotomy for a small bowel obstruction. Following a period of ileus, 16 days post laparotomy the patient developed a high-output (2,000 mL per day) fistula. The patient also became pyrexial with raised inflammatory markers, requiring antibiotic treatment. Following development of his ECF, he was managed using the SNAP protocol for the duration of his admission; however, in implementing this protocol with this patient, clinicians noted fluid charts were inadequate to allow effective management of the variables. Thus, a new pro-forma was created that encompassed fluid balance, nutritional status, and pertinent blood test results, as well as perifistular skin condition, medication, and documentation of management plans from the MDT team. The pro-forma was recorded daily in the patient notes. Following implementation of the pro-forma and the SNAP protocol, the patient recovered well clinically over a period of 4 weeks with a decrease in his fistula output to 300-500 mL per day, and he was discharged with plans for further corrective surgery to resect the fistula and for bowel re-anastomoses. Although fluid charts are readily available, they do not include all pertinent variables for optimal management of patients with an ECF. Further research is needed to validate the pro-forma and evaluate its effect on patient outcomes. PMID- 26061407 TI - Quantity, Quality, and Availability of Waste Heat from United States Thermal Power Generation. AB - Secondary application of unconverted heat produced during electric power generation has the potential to improve the life-cycle fuel efficiency of the electric power industry and the sectors it serves. This work quantifies the residual heat (also known as waste heat) generated by U.S. thermal power plants and assesses the intermittency and transport issues that must be considered when planning to utilize this heat. Combining Energy Information Administration plant level data with literature-reported process efficiency data, we develop estimates of the unconverted heat flux from individual U.S. thermal power plants in 2012. Together these power plants discharged an estimated 18.9 billion GJ(th) of residual heat in 2012, 4% of which was discharged at temperatures greater than 90 degrees C. We also characterize the temperature, spatial distribution, and temporal availability of this residual heat at the plant level and model the implications for the technical and economic feasibility of its end use. Increased implementation of flue gas desulfurization technologies at coal-fired facilities and the higher quality heat generated in the exhaust of natural gas fuel cycles are expected to increase the availability of residual heat generated by 10.6% in 2040. PMID- 26061408 TI - Threading DNA through nanopores for biosensing applications. AB - This review outlines the recent achievements in the field of nanopore research. Nanopores are typically used in single-molecule experiments and are believed to have a high potential to realize an ultra-fast and very cheap genome sequencer. Here, the various types of nanopore materials, ranging from biological to 2D nanopores are discussed together with their advantages and disadvantages. These nanopores can utilize different protocols to read out the DNA nucleobases. Although, the first nanopore devices have reached the market, many still have issues which do not allow a full realization of a nanopore sequencer able to sequence the human genome in about a day. Ways to control the DNA, its dynamics and speed as the biomolecule translocates the nanopore in order to increase the signal-to-noise ratio in the reading-out process are examined in this review. Finally, the advantages, as well as the drawbacks in distinguishing the DNA nucleotides, i.e., the genetic information, are presented in view of their importance in the field of nanopore sequencing. PMID- 26061409 TI - Threat-Related Information Suggests Competence: A Possible Factor in the Spread of Rumors. AB - Information about potential danger is a central component of many rumors, urban legends, ritual prescriptions, religious prohibitions and witchcraft crazes. We investigate a potential factor in the cultural success of such material, namely that a source of threat-related information may be intuitively judged as more competent than a source that does not convey such information. In five studies, we asked participants to judge which of two sources of information, only one of which conveyed threat-related information, was more knowledgeable. Results suggest that mention of potential danger makes a source appear more competent than others, that the effect is not due to a general negativity bias, and that it concerns competence rather than a more generally positive evaluation of the source. PMID- 26061410 TI - Synthesis and Biological Evaluation of 3-Alkyl-1,5-Diaryl-1H-Pyrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative Activity. AB - A series of novel 3-alkyl-1,5-diaryl-1H-pyrazoles were synthesized as combretastatin A-4 (CA-4) analogues and evaluated for antiproliferative activity against three human cancer cell lines (SGC-7901, A549 and HT-1080). Most of the target compounds displayed moderate to potent antiproliferative activity, and 7k was found to be the most potent compound. Structure-activity relationships indicated that compounds with a trimethoxyphenyl A-ring at the N-1 position of the pyrazole skeleton were more potent than those with the A-ring at the C-5 position. Tubulin polymerization and immunostaining experiments revealed that 7k potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Computational modelling demonstrated that the binding of 7k to the colchicine binding site on microtubules may involve a similar mode as CA-4. PMID- 26061411 TI - Empirically derived dietary patterns in relation to psychological disorders. AB - OBJECTIVE: Psychological disorders are highly prevalent worldwide. The present study aimed to investigate the relationship between major dietary patterns and prevalence of psychological disorders in a large sample of Iranian adults. DESIGN: A cross-sectional study was done to identify dietary patterns derived from factor analysis. Dietary data were collected through the use of a validated dish-based semi-quantitative FFQ. Psychological health was examined by use of the Hospital Anxiety and Depression Scale and the General Health Questionnaire. SETTING: The study was conducted in Isfahan, Iran, within the framework of the Study on Epidemiology of Psychological, Alimentary Health and Nutrition (SEPAHAN). SUBJECTS: Iranian adults (n 3846) aged 20-55 years. RESULTS: After adjustment for potential confounders, greater adherence to the lacto-vegetarian dietary pattern was protectively associated with depression in women (OR=0.65; 95 % CI 0.46, 0.91). Normal-weight participants in the top quintile of this dietary pattern tended to have decreased odds of anxiety compared with those in the bottom quintile (OR=0.61; 95 % CI 0.38, 1.00). In addition, the traditional dietary pattern was associated with increased odds of depression (OR=1.42; 95 % CI 1.01, 1.99) and anxiety (OR=1.56; 95 % CI 1.00, 2.42) in women. Normal-weight participants in the highest quintile of the traditional dietary pattern had greater odds for anxiety (OR=1.89; 95 % CI 1.12, 3.08) compared with those in the lowest quintile. The Western dietary pattern was associated with increased odds of depression in men (OR=1.73; 95 % CI 1.07, 2.81) and anxiety in normal-weight participants (OR=2.05; 95 % CI 1.22, 3.46). There was a significant increasing trend in the odds of psychological distress across increasing quintiles of the fast food dietary pattern in women (P-trend=0.02). CONCLUSIONS: Recommendation to increase the intake of fruits, citrus fruits, vegetables, tomato and low-fat dairy products and to reduce the intakes of snacks, high-fat dairy products, chocolate, carbonated drinks, sweets and desserts might be associated with lower chance of psychological disorders. PMID- 26061413 TI - Individual left-hand and right-hand intra-digit representations in human primary somatosensory cortex. AB - Individual intra-digit somatotopy of all phalanges of the middle and little finger of the right and left hand was studied by functional magnetic resonance imaging in 12 healthy subjects. Phalanges were tactilely stimulated and activation in BA 3b of the human primary somatosensory cortex could be observed for each individual phalanx. Activation peaks were further analysed using the Direction/Order (DiOr) method, which identifies somatotopy, if a significantly high number of subjects exhibit ordered distal-to-proximal phalanx representions along a similar direction. Based on DiOr, ordered and similar-direction-aligned intra-digit maps across subjects were found at the left hand for the little and middle finger and at the right hand for the little finger. In these digits the proximal phalanges were represented more medially along the course of the central sulcus than the distal phalanges. This is contrasted by the intra-digit maps for the middle finger of the right hand, which showed larger inter-subject variations of phalanx alignments without a similar within-digit representation across subjects. As all subjects were right-handed and as the middle finger of the dominant hand probably plays a more individual role in everyday tactile performance than the little finger of the right hand and all left-hand digits, the observed variation might reflect a functional somatotopy based on individual use of that particular digit at the dominant hand. PMID- 26061412 TI - Replication and Active Partition of Integrative and Conjugative Elements (ICEs) of the SXT/R391 Family: The Line between ICEs and Conjugative Plasmids Is Getting Thinner. AB - Integrative and Conjugative Elements (ICEs) of the SXT/R391 family disseminate multidrug resistance among pathogenic Gammaproteobacteria such as Vibrio cholerae. SXT/R391 ICEs are mobile genetic elements that reside in the chromosome of their host and eventually self-transfer to other bacteria by conjugation. Conjugative transfer of SXT/R391 ICEs involves a transient extrachromosomal circular plasmid-like form that is thought to be the substrate for single stranded DNA translocation to the recipient cell through the mating pore. This plasmid-like form is thought to be non-replicative and is consequently expected to be highly unstable. We report here that the ICE R391 of Providencia rettgeri is impervious to loss upon cell division. We have investigated the genetic determinants contributing to R391 stability. First, we found that a hipAB-like toxin/antitoxin system improves R391 stability as its deletion resulted in a tenfold increase of R391 loss. Because hipAB is not a conserved feature of SXT/R391 ICEs, we sought for alternative and conserved stabilization mechanisms. We found that conjugation itself does not stabilize R391 as deletion of traG, which abolishes conjugative transfer, did not influence the frequency of loss. However, deletion of either the relaxase-encoding gene traI or the origin of transfer (oriT) led to a dramatic increase of R391 loss correlated with a copy number decrease of its plasmid-like form. This observation suggests that replication initiated at oriT by TraI is essential not only for conjugative transfer but also for stabilization of SXT/R391 ICEs. Finally, we uncovered srpMRC, a conserved locus coding for two proteins distantly related to the type II (actin-type ATPase) parMRC partitioning system of plasmid R1. R391 and plasmid stabilization assays demonstrate that srpMRC is active and contributes to reducing R391 loss. While partitioning systems usually stabilizes low-copy plasmids, srpMRC is the first to be reported that stabilizes a family of ICEs. PMID- 26061414 TI - Sequence Polymorphism of Cytochrome b Gene in Theileria annulata Tunisian Isolates and Its Association with Buparvaquone Treatment Failure. AB - BACKGROUND: Buparvaquone (BW 720C) is the major hydroxynaphtoquinone active against tropical theileriosis (Theileria annulata infection). Previous studies showed that buparvaquone, similarly to others hydroxynaphtoquinone, probably acts by binding to cytochrome b (cyt b) inhibiting the electron transport chain in the parasite. Several observations suggested that T. annulata is becoming resistant to buparvaquone in many endemic regions (Tunisia, Turkey and Iran), which may hinder the development of bovine livestock in these areas. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we sought to determine whether point mutations in T. annulata cytochrome b gene could be associated to buparvaquone resistance. A total of 28 clones were studied in this work, 19 of which were obtained from 3 resistant isolates (ST2/12, ST2/13 and ST2/19) collected at different time after treatment, from a field treatment failure and nine clones isolated from 4 sensitive stocks of T. annulata (Beja, Battan, Jed4 and Sousse). The cytochrome b gene was amplified and sequenced. We identified five point mutations at the protein sequences (114, 129, 253, 262 and 347) specific for the clones isolated from resistant stocks. Two of them affecting 68% (13/19) of resistant clones, are present in the drug-binding site Q02 region at the position 253 in three resistant clones and at the position 262 in 11 out of 19 resistant clones. These two mutations substitute a neutral and hydrophobic amino acids by polar and hydrophilic ones which could interfere with the drug binding capabilities. When we compared our sequences to the Iranian ones, the phylogenetic tree analyses show the presence of a geographical sub-structuring in the population of T. annulata. CONCLUSIONS/SIGNIFICANCE: Taken together, our results suggest that the cytochrome b gene may be used as a tool to discriminate between different T. annulata genotypes and also as a genetic marker to characterize resistant isolates of T. annulata. PMID- 26061415 TI - Experimental verification of electro-refractive phase modulation in graphene. AB - Graphene has been considered as a promising material for opto-electronic devices, because of its tunable and wideband optical properties. In this work, we demonstrate electro-refractive phase modulation in graphene at wavelengths from 1530 to 1570 nm. By integrating a gated graphene layer in a silicon-waveguide based Mach-Zehnder interferometer, the key parameters of a phase modulator like change in effective refractive index, insertion loss and absorption change are extracted. These experimentally obtained values are well reproduced by simulations and design guidelines are provided to make graphene devices competitive to contemporary silicon based phase modulators for on-chip applications. PMID- 26061416 TI - Time-Domain Ab Initio Analysis of Excitation Dynamics in a Quantum Dot/Polymer Hybrid: Atomistic Description Rationalizes Experiment. AB - Hybrid organic/inorganic polymer/quantum dot (QD) solar cells are an attractive alternative to the traditional cells. The original, simple models postulate that one-dimensional polymers have continuous energy levels, while zero-dimensional QDs exhibit atom-like electronic structure. A realistic, atomistic viewpoint provides an alternative description. Electronic states in polymers are molecule like: finite in size and discrete in energy. QDs are composed of many atoms and have high, bulk-like densities of states. We employ ab initio time-domain simulation to model the experimentally observed ultrafast photoinduced dynamics in a QD/polymer hybrid and show that an atomistic description is essential for understanding the time-resolved experimental data. Both electron and hole transfers across the interface exhibit subpicosecond time scales. The interfacial processes are fast due to strong electronic donor-acceptor, as evidenced by the densities of the photoexcited states which are delocalized between the donor and the acceptor. The nonadiabatic charge-phonon coupling is also strong, especially in the polymer, resulting in rapid energy losses. The electron transfer from the polymer is notably faster than the hole transfer from the QD, due to a significantly higher density of acceptor states. The stronger molecule-like electronic and charge-phonon coupling in the polymer rationalizes why the electron-hole recombination inside the polymer is several orders of magnitude faster than in the QD. As a result, experiments exhibit multiple transfer times for the long-lived hole inside the QD, ranging from subpicoseconds to nanoseconds. In contrast, transfer of the short-lived electron inside the polymer does not occur beyond the first picosecond. The energy lost by the hole on its transit into the polymer is accommodated by polymer's high-frequency vibrations. The energy lost by the electron injected into the QD is accommodated primarily by much lower-frequency collective and QD modes. The electron dynamics is exponential, whereas evolution of the injected hole through the low density manifold of states of the polymer is highly nonexponential. The time scale of the electron-hole recombination at the interface is intermediate between those in pristine polymer and QD and is closer to that in the polymer. The detailed atomistic insights into the photoinduced charge and energy dynamics at the polymer/QD interface provide valuable guidelines for optimization of solar light harvesting and photovoltaic efficiency in modern nanoscale materials. PMID- 26061417 TI - Genotype-phenotype Correlations of Hypertrophic Cardiomyopathy When Diagnosed in Children, Adolescents, and Young Adults. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease and a leading cause of identifiable sudden cardiac death (SCD) in the young. Herein, we sought to determine the genotype-phenotype correlations in a cohort of unrelated, genotyped patients diagnosed with HCM at a young age, as well as to characterize the differences between HCM diagnosed in adulthood and HCM diagnosed at a young age. METHODS AND RESULTS: From 1999 to 2011, 1053 unrelated patients diagnosed with HCM were enrolled in research-based genetic testing. The electronic medical record was reviewed to identify those with HCM diagnosed at <=21 years (N = 137, mean age at diagnosis 13.2 +/- 6 years, 64% male). From this cohort of patients recruited from a tertiary care referral center, the genetic test was positive in 71 (52%), which was significantly higher than patients diagnosed >21 years (31%; P < .001). Genotype positive patients had increased maximum left ventricular wall thickness (24.9 +/- 8.0 vs. 21.6 +/- 7.4 mm, P = .01) and higher incidence of reverse-curve ventricular septal morphology (71% vs. 40%, P < .001). Unrelated to genotype status, 26/137 patients (19%) experienced significant HCM-related morbidity/mortality including progressive heart failure symptoms in 12, transplantation in 4, and death in 10. CONCLUSIONS: Among patients diagnosed with HCM during the first two decades of life, the yield of genetic testing is significantly higher than when diagnosed at later age. While the phenotype of young HCM patients is worse than patients whose HCM is diagnosed at later age, the phenotypes of genotype-positive and genotype-negative young patients were similar. Independent of genotype, nearly 30% of the patients with follow-up in this study had symptom progression, transplant, or death. PMID- 26061418 TI - Genome-wide association mapping of cadmium accumulation in different organs of barley. AB - The threshold value of cadmium (Cd) concentration in grains of barley (Hordeum vulgare) is the lowest among cereal crops; however, it is poorly understood how Cd accumulation in barley grain is genetically controlled. We investigated genotypic variation in Cd accumulation of different organs in 100 accessions from a subset of the barley core collection using both hydroponic and Cd-contaminated soil culture. We also performed a genome-wide association (GWA) mapping for Cd accumulation in different organs. A large genotypic variation in the Cd concentration was found in all organs. There was a good correlation between shoot Cd of solution and soil culture, the shoot Cd and grain Cd, but no correlation between the root Cd and grain Cd. GWA mapping detected 9 quantitative trait loci (QTL) for root Cd, 21 for shoot Cd, 14 for root-to-shoot translocation and 15 for grain Cd. A common QTL for the shoot Cd and root-to-shoot translocation was found at 132.6 cM on chromosome 5H. Two major QTL for grain Cd were identified on chromosome 2H and chromosome 5H. The genetic variation in Cd accumulation and major QTL detected provide useful information helpful for cloning candidate genes for Cd accumulation and breeding low-Cd barley cultivars in future. PMID- 26061419 TI - Determinants of Obesity and Associated Population Attributability, South Africa: Empirical Evidence from a National Panel Survey, 2008-2012. AB - BACKGROUND: Obesity is a major risk factor for emerging non-communicable diseases (NCDS) in middle income countries including South Africa (SA). Understanding the multiple and complex determinants of obesity and their true population attributable impact is critical for informing and developing effective prevention efforts using scientific based evidence. This study identified contextualised high impact factors associated with obesity in South Africa. METHODS: Analysis of three national cross sectional (repeated panel) surveys, using a multilevel logistic regression and population attributable fraction estimation allowed for identification of contextualised high impact factors associated with obesity (BMI>30 kg/m2) among adults (15 years+). RESULTS: Obesity prevalence increased significantly from 23.5% in 2008 to 27.2% in 2012, with a significantly (p value<0.001) higher prevalence among females (37.9% in 2012) compared to males (13.3% in 2012). Living in formal urban areas, white ethnicity, being married, not exercising and/or in higher socio-economic category were significantly associated with male obesity. Females living in formal or informal urban areas, higher crime areas, African/White ethnicity, married, not exercising, in a higher socio-economic category and/or living in households with proportionate higher spending on food (and unhealthy food options) were significantly more likely to be obese. The identified determinants appeared to account for 75% and 43% of male and female obesity respectively. White males had the highest relative gain in obesity from 2008 to 2012. CONCLUSIONS: The rising prevalence of obesity in South Africa is significant and over the past 5 years the rising prevalence of Type-2 diabetes has mirrored this pattern, especially among females. Targeting young adolescent girls should be a priority. Addressing determinants of obesity will involve a multifaceted strategy and requires at individual and population levels. With rising costs in the private and public sector to combat obesity related NCDS, this analysis can inform culturally sensitive mass communications and wellness campaigns. Knowledge of social determinants is critical to develop "best buys". PMID- 26061420 TI - Chimpanzees (Pan troglodytes) Produce the Same Types of 'Laugh Faces' when They Emit Laughter and when They Are Silent. AB - The ability to flexibly produce facial expressions and vocalizations has a strong impact on the way humans communicate, as it promotes more explicit and versatile forms of communication. Whereas facial expressions and vocalizations are unarguably closely linked in primates, the extent to which these expressions can be produced independently in nonhuman primates is unknown. The present work, thus, examined if chimpanzees produce the same types of facial expressions with and without accompanying vocalizations, as do humans. Forty-six chimpanzees (Pan troglodytes) were video-recorded during spontaneous play with conspecifics at the Chimfunshi Wildlife Orphanage. ChimpFACS was applied, a standardized coding system to measure chimpanzee facial movements, based on FACS developed for humans. Data showed that the chimpanzees produced the same 14 configurations of open-mouth faces when laugh sounds were present and when they were absent. Chimpanzees, thus, produce these facial expressions flexibly without being morphologically constrained by the accompanying vocalizations. Furthermore, the data indicated that the facial expression plus vocalization and the facial expression alone were used differently in social play, i.e., when in physical contact with the playmates and when matching the playmates' open-mouth faces. These findings provide empirical evidence that chimpanzees produce distinctive facial expressions independently from a vocalization, and that their multimodal use affects communicative meaning, important traits for a more explicit and versatile way of communication. As it is still uncertain how human laugh faces evolved, the ChimpFACS data were also used to empirically examine the evolutionary relation between open-mouth faces with laugh sounds of chimpanzees and laugh faces of humans. The ChimpFACS results revealed that laugh faces of humans must have gradually emerged from laughing open-mouth faces of ancestral apes. This work examines the main evolutionary changes of laugh faces since the last common ancestor of chimpanzees and humans. PMID- 26061421 TI - Do Organometallic CH4-Me(+p) Adducts and X4H(+) (X = P, As) Clusters Undergo Two Electron Three-Center Interactions? Some Aspects of Discussion. AB - Most of the systems possessing true two-electron three-center interactions are electron deficient compounds like boron hydrids, closo-boranes, and some organic ions such as butonium cations. In this work, we perform a detailed study of the electron distribution for two different types of systems to which likewise interactions has been adjudicated: organometallic CH4-Me(+p) (p = 1, 2) adducts with Me, alkaline and earth alkaline metallic ions of Li, Na, K, Be, Mg, Ca in their stable gaseous phase and X4H(+) (X = P, As) simple clusters. For this purpose, topological analysis of the electron density decomposed into its effectively paired and unpaired contributions has been carried out looking for complex interactions. PMID- 26061423 TI - Preparedness explains some differences between Haiti and Nepal's response to earthquake. PMID- 26061422 TI - Effects of Fermented Dairy Products on Skin: A Systematic Review. AB - OBJECTIVE: Fermented dairy products, such as yogurt, have been proposed as a natural source of probiotics to promote intestinal health. Growing evidence shows that modulation of the gastrointestinal tract microbiota can modulate skin disease as well. This systematic review was conducted to examine the evidence for the use of ingested fermented dairy products to modulate skin health and function. We also sought to review the effects of the topical application of dairy products. DESIGN: The PubMed and Embase databases were systematically searched for clinical studies involving humans only that examined the relationship between fermented dairy products and skin health. RESULTS: A total of 312 articles were found and a total of 4 studies met inclusion criteria. Three studies evaluated the effects of ingestion, while one evaluated the effects of topical application. All studies noted improvement with the use of fermented dairy. CONCLUSIONS: Overall, there is early and limited evidence that fermented dairy products, used both topically and orally, may provide benefits for skin health. However, existing studies are limited and further studies will be important to better assess efficacy and the mechanisms involved. PMID- 26061424 TI - Use of Stochastic Simulation to Evaluate the Reduction in Methane Emissions and Improvement in Reproductive Efficiency from Routine Hormonal Interventions in Dairy Herds. AB - This study predicts the magnitude and between herd variation in changes of methane emissions and production efficiency associated with interventions to improve reproductive efficiency in dairy cows. Data for 10,000 herds of 200 cows were simulated. Probability of conception was predicted daily from the start of the study (parturition) for each cow up to day 300 of lactation. Four scenarios of differing first insemination management were simulated for each herd using the same theoretical cows: A baseline scenario based on breeding from observed oestrus only, synchronisation of oestrus for pre-set first insemination using 2 methods, and a regime using prostaglandin treatments followed by first insemination to observed oestrus. Cows that did not conceive to first insemination were re-inseminated following detection of oestrus. For cows that conceived, gestation length was 280 days with cessation of milking 60 days before calving. Those cows not pregnant after 300 days of lactation were culled and replaced by a heifer. Daily milk yield was calculated for 730 days from the start of the study for each cow. Change in mean reproductive and economic outputs were summarised for each herd following the 3 interventions. For each scenario, methane emissions were determined by daily forage dry matter intake, forage quality, and cow replacement risk. Linear regression was used to summarise relationships. In some circumstances improvement in reproductive efficiency using the programmes investigated was associated with reduced cost and methane emissions compared to reliance on detection of oestrus. Efficiency of oestrus detection and the time to commencement of breeding after calving influenced variability in changes in cost and methane emissions. For an average UK herd this was a saving of at least L50 per cow and a 3.6% reduction in methane emissions per L of milk when timing of first insemination was pre-set. PMID- 26061427 TI - To screen or not to screen: is the pelvic examination the answer? PMID- 26061426 TI - Solar Radiation Determines Site Occupancy of Coexisting Tropical and Temperate Deer Species Introduced to New Zealand Forests. AB - Assemblages of introduced taxa provide an opportunity to understand how abiotic and biotic factors shape habitat use by coexisting species. We tested hypotheses about habitat selection by two deer species recently introduced to New Zealand's temperate rainforests. We hypothesised that, due to different thermoregulatory abilities, rusa deer (Cervus timorensis; a tropical species) would prefer warmer locations in winter than red deer (Cervus elaphus scoticus; a temperate species). Since adult male rusa deer are aggressive in winter (the rut), we also hypothesised that rusa deer and red deer would not use the same winter locations. Finally, we hypothesised that in summer both species would prefer locations with fertile soils that supported more plant species preferred as food. We used a 250 * 250 m grid of 25 remote cameras to collect images in a 100-ha montane study area over two winters and summers. Plant composition, solar radiation, and soil fertility were also determined for each camera location. Multiseason occupancy models revealed that direct solar radiation was the best predictor of occupancy and detection probabilities for rusa deer in winter. Multistate, multiseason occupancy models provided strong evidence that the detection probability of adult male rusa deer was greater in winter and when other rusa deer were present at a location. Red deer mostly vacated the study area in winter. For the one season that had sufficient camera images of both species (summer 2011) to allow two species occupancy models to be fitted, the detection probability of rusa deer also increased with solar radiation. Detection probability also varied with plant composition for both deer species. We conclude that habitat use by coexisting tropical and temperate deer species in New Zealand likely depends on the interplay between the thermoregulatory and behavioural traits of the deer and the abiotic and biotic features of the habitat. PMID- 26061425 TI - Predictive Modeling of Drug Response in Non-Hodgkin's Lymphoma. AB - We combine mathematical modeling with experiments in living mice to quantify the relative roles of intrinsic cellular vs. tissue-scale physiological contributors to chemotherapy drug resistance, which are difficult to understand solely through experimentation. Experiments in cell culture and in mice with drug-sensitive (Eu myc/Arf-/-) and drug-resistant (Eu-myc/p53-/-) lymphoma cell lines were conducted to calibrate and validate a mechanistic mathematical model. Inputs to inform the model include tumor drug transport characteristics, such as blood volume fraction, average geometric mean blood vessel radius, drug diffusion penetration distance, and drug response in cell culture. Model results show that the drug response in mice, represented by the fraction of dead tumor volume, can be reliably predicted from these inputs. Hence, a proof-of-principle for predictive quantification of lymphoma drug therapy was established based on both cellular and tissue-scale physiological contributions. We further demonstrate that, if the in vitro cytotoxic response of a specific cancer cell line under chemotherapy is known, the model is then able to predict the treatment efficacy in vivo. Lastly, tissue blood volume fraction was determined to be the most sensitive model parameter and a primary contributor to drug resistance. PMID- 26061428 TI - Do family meals affect childhood overweight or obesity?: nationwide survey 2008 2012. AB - BACKGROUND: The prevalence of childhood obesity is increasing worldwide and this trend is no exception for South Korea. A multidisciplinary approach is needed for the prevention and management of childhood obesity. To do so, among many other strategies, managing the family unit can be a very effective strategy. OBJECTIVES: The purpose of this study was to identify the relationship between frequency of family meals and overweight/obesity in elementary students and to suggest the management and prevention strategies of childhood obesity. METHODS: Data from a total of 2904 elementary students were analyzed from the 2008-2012 Korea National Health and Nutrition Examination Survey. Multiple logistic regression analysis was used to examine the association between overweight/obesity and family meals. RESULTS: Of the total 2904 elementary students, 573 (19.4%) were overweight or obese. The odds ratio of overweight or obese students who had family dinner only was 1.21 (95% CI: 0.89-1.64), that of those who had family breakfast only was 3.20 (95% CI: 1.70-6.02), and that of those who had neither family breakfast nor family dinner was 4.17 (95% CI: 1.98 8.78) compared with those who had both family breakfast and family dinner. CONCLUSIONS: The frequency of family meals was strongly an inverse association with childhood overweight or obesity. Therefore, we suggest that the intervention of childhood obesity should include family meals. PMID- 26061429 TI - An unusual cause of hepatic encephalopathy. PMID- 26061430 TI - Goldberg Active Template Synthesis of a [2]Rotaxane Ligand for Asymmetric Transition-Metal Catalysis. AB - We report on the active template synthesis of a [2]rotaxane through a Goldberg copper-catalyzed C-N bond forming reaction. A C2-symmetric cyclohexyldiamine macrocycle directs the assembly of the rotaxane, which can subsequently serve as a ligand for enantioselective nickel-catalyzed conjugate addition reactions. Rotaxanes are a previously unexplored ligand architecture for asymmetric catalysis. We find that the rotaxane gives improved enantioselectivity compared to a noninterlocked ligand, at the expense of longer reaction times. PMID- 26061432 TI - Sertoli cell androgen receptor signalling in adulthood is essential for post meiotic germ cell development. PMID- 26061431 TI - AMPK-HDAC5 pathway facilitates nuclear accumulation of HIF-1alpha and functional activation of HIF-1 by deacetylating Hsp70 in the cytosol. AB - Hypoxia-inducible factor 1 (HIF-1) transcriptionally promotes production of adenosine triphosphate (ATP) whereas AMPK senses and regulates cellular energy homeostasis. A histone deacetylase (HDAC) activity has been proven to be critical for HIF-1 activation but the underlying mechanism and its role in energy homesostasis remain unclear. Here, we demonstrate that HIF-1 activation depends on a cytosolic, enzymatically active HDAC5. HDAC5 knockdown impairs hypoxia induced HIF-1alpha accumulation and HIF-1 transactivation, whereas HDAC5 overexpression enhances HIF-1alpha stabilization and nuclear translocation. Mechanistically, we show that Hsp70 is a cytosolic substrate of HDAC5; and hyperacetylation renders Hsp70 higher affinity for HIF-1alpha binding, which correlates with accelerated degradation and attenuated nuclear accumulation of HIF-1alpha. Physiologically, AMPK-triggered cytosolic shuttling of HDAC5 is critical; inhibition of either AMPK or HDAC5 impairs HIF-1alpha nuclear accumulation under hypoxia or low glucose conditions. Finally, we show specifically suppressing HDAC5 is sufficient to inhibit tumor cell proliferation under hypoxic conditions. Our data delineate a novel link between AMPK, the energy sensor, and HIF-1, the major driver of ATP production, indicating that specifically inhibiting HDAC5 may selectively suppress the survival and proliferation of hypoxic tumor cells. PMID- 26061434 TI - Changes in written sign-out composition across hospitalization. AB - BACKGROUND: Inaccurate or incomplete information in the written portion of the patient handoff, or sign-out, may be associated with adverse events in hospitalized patients. Little is known about what information providers actually include in written sign-out documents and how sign-outs change over time. OBJECTIVES: (1) Provide a descriptive analysis of initial and subsequent hospital day-written sign-out content, and (2) evaluate the relationship between team workload and sign-out composition. DESIGN: Retrospective review of sign-out documents from a larger observational study of general medicine patients admitted to housestaff and hospitalist teams at 3 hospitals. MAIN MEASURES: The presence of 13 components of a high-quality sign-out. We performed descriptive analyses and compared initial and subsequent day sign-outs for content. KEY RESULTS: We reviewed 200 patient hospitalizations (200 initial handoffs, 580 subsequent day handoffs). Initial sign-out entries contained a mean of 7.54 (standard deviation: 2.27) key sign-out components. Subsequent day sign-outs contained a higher percentage of certain key elements but had more vague language. The number of elements present in the sign-out was reduced as patient census increased (r = 0.295, P < 0.01). CONCLUSIONS: Sign-out composition changes over time, and is associated with workload. Future interventions to improve quality should take these factors into consideration. PMID- 26061435 TI - Urodynamics useless before surgery for female stress urinary incontinence: Are you sure? Results from a multicenter single nation database. AB - AIMS: The role of urodynamics (UDS) before surgery for stress urinary incontinence (SUI) remains a debated issue in female urology as well as in urogynaecology and it has been recently questioned on the basis of data coming from selected population of patients defined as "uncomplicated." The aim of this study was to investigate the percentage of "uncomplicated" patients undergoing urodynamic evaluations in six referral Italian centers. The secondary aim was to assess the prevalence of women, for whom the urodynamic evaluation could add new information to the pre-urodynamic picture and in how many cases these findings had a significant impact on patient management. METHODS: The data of women who underwent urodynamic evaluation prior to surgery for stress urinary incontinence between 2008 and 2013 were retrospectively analyzed. According to the definition of the Value of Urodynamic Evaluation (ValUE) trial criteria, patients presenting with SUI were classified as "uncomplicated" or "complicated." Urodynamic observations were then compared with pre-urodynamic data. RESULTS: Overall, 2,053 female patients were considered. Only 740/2,053 (36.0%) patients were defined "uncomplicated" according to the definition used in the ValUE trial. The urodynamic observations were not consistent with the pre-urodynamic diagnosis in 1,276 out of 2,053 patients (62.2%). Voiding dysfunctions were urodynamically diagnosed in 394 patients (19.2%). Planned surgery was cancelled or modified in 304 patients (19.2%), due to urodynamic findings. CONCLUSIONS: "Uncomplicated" patients represent a minority among female SUI patients evaluated before surgery. In "complicated" patients, the role of urodynamic has not been challenged yet and UDS seems still mandatory. Neurourol. Urodynam. 35:809-812, 2016. (c) 2015 Wiley Periodicals, Inc. PMID- 26061436 TI - Cardiac troponin elevation pattern in patients undergoing a primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: characterization and relationship with cardiovascular events during hospitalization. AB - HYPOTHESIS: We aimed to describe the kinetics and associated prognostic implications of the cardiac troponin release curve after a primary percutaneous coronary intervention (PPCI) in patients presenting with ST-segment elevation myocardial infarction (STEMI). PATIENTS AND METHODS: We prospectively determined, in a prespecified timely manner, serial cardiac troponin I levels and obtained clinical, ECG, and echocardiographic data from 175 consecutive patients hospitalized with STEMI who underwent PPCI. The median peak troponin levels and time until troponin peaking were determined. RESULTS: The troponin elevation curve following PPCI was single peaked, with a median value measuring 715 times the upper normal limit and a median peaking time of 8 h. Later-peaking troponin levels were associated with a TIMI flow grade of 0/1 at the initiation of angiography and with lack of at least 70% regression in the ST-elevation on the first post-PPCI ECG. Higher peak values were similarly associated with these two parameters as well as with a lower blush score and with distal embolization during PPCI. Both higher peak values and later peaking of troponin were associated independently with higher occurrence of the combined adverse cardiovascular event outcomes consisting of death, congestive heart failure, and recurrent infarction. CONCLUSION: The cardiac troponin elevation curve following PPCI for STEMI shows a single peak and is affected by the adequacy of myocardial reperfusion. This method can serve as a simple surrogate for risk stratification of patients with STEMI who undergo PPCI. PMID- 26061437 TI - Long-term prognostic value of elevated pentraxin 3 in patients undergoing primary angioplasty for ST-elevation myocardial infarction. AB - OBJECTIVES: The prognostic value of pentraxin 3 (PTX3) has been documented in patients with acute coronary syndrome. However, its long-term prognostic value in acute ST-segment elevation myocardial infarction (STEMI) remains unclear. The aim of this study was to evaluate the prognostic value of PTX3 in patients with STEMI undergoing a primary percutaneous coronary intervention (PCI). METHODS: We prospectively enrolled 499 consecutive STEMI patients undergoing primary PCI. The high-PTX3 group (n=141) was defined as having values in the third tertile (>=3.2 ng/ml) and the low-PTX3 group (n=358) included patients with values in the lower two tertiles (<3.2 ng/ml). RESULTS: The patients in the high-PTX3 group were older (mean age 54.3+/-11.8 vs. 58.5+/-13.1 years, P=0.002). Higher in-hospital cardiovascular mortality and 2-year all-cause mortality rates were observed in the high-PTX3 group (9.9 vs. 2.8%, respectively, P<0.001; 21 vs. 6.2%, respectively, P<0.001). In a Cox multivariate analysis, a high admission PTX3 value (>3.2 ng/ml) was found to be an independent predictor of 2-year all-cause mortality (odds ratio: 2.3, 95% confidence interval: 1.20-4.90, P=0.025). CONCLUSION: These results suggest that a high admission PTX3 level was associated with increased in-hospital cardiovascular mortality and 2-year all-cause mortality in patients with STEMI undergoing primary PCI. PMID- 26061438 TI - Complete remission of metastatic melanoma upon BRAF inhibitor treatment - what happens after discontinuation? AB - Treatment with BRAF inhibitors (BRAFi) leads to complete remissions (CR) in 3-6% of patients with BRAF mutant metastatic melanoma. In cases of CR, it is unclear whether BRAFi therapy should be continued. We retrospectively analyzed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a CR. In 12 patients, CR of metastatic melanoma was diagnosed after a median BRAFi treatment duration of 13 (range 0.3-32) months. Reasons for discontinuation were side effects in seven patients and patient demand in five patients. Six patients are still in CR after a median of 17 (range 2-26) months after discontinuation of BRAF inhibition. Six patients developed a melanoma recurrence after a median of 3 (range 2-17) months of discontinuation of BRAFi therapy. Subsequently, these patients were again treated with a BRAFi, which resulted in three CR, one stable disease, and one progressive disease; one patient could not be assessed. Melanoma patients achieving CR during BRAFi therapy represent a heterogeneous group. Discontinuation of BRAFi therapy after a CR has to be balanced carefully with the potential risk of nonresponding to BRAFi retreatment in the case of relapse. PMID- 26061440 TI - The Role of Flies in Disseminating Plasmids with Antimicrobial-Resistance Genes Between Farms. AB - Dissemination of antimicrobial resistance is a major global public health concern. To clarify the role of flies in disseminating antimicrobial resistance between farms, we isolated and characterized tetracycline-resistant Escherichia coli strains isolated from flies and feces of livestock from four locations housing swine (abattoir, three farms) and three cattle farms. The percentages of isolates from flies resistant to tetracycline, dihydrostreptomycin, ampicillin, and chloramphenicol (80.8%, 61.5%, 53.8%, and 50.0%, respectively) and those from animal feces (80.5%, 78.0%, 41.5%, and 46.3%, respectively) in locations housing swine were significantly higher than those from cattle farms (p<0.05). The rates of resistance in E. coli derived from flies reflected those derived from livestock feces at the same locations, suggesting that antimicrobial resistance spreads between livestock and flies on the farms. The results of pulsed-field gel electrophoresis (PFGE) analysis showed that, with a few exceptions, all E. coli isolates differed. Two pairs of tetracycline-resistant strains harbored similar plasmids with the same tetracycline-resistance genes, although the origin (fly or feces), site of isolation, and PFGE patterns of these strains differed. Therefore, flies may disseminate the plasmids between farms. Our results suggest that flies may be involved not only in spreading clones of antimicrobial resistant bacteria within a farm but also in the widespread dissemination of plasmids with antimicrobial resistance genes between farms. PMID- 26061439 TI - LASP1, a Newly Identified Melanocytic Protein with a Possible Role in Melanin Release, but Not in Melanoma Progression. AB - The LIM and SH3 protein 1 (LASP1) is a focal adhesion protein. Its expression is increased in many malignant tumors. However, little is known about the physiological role of the protein. In the present study, we investigated the expression and function of LASP1 in normal skin, melanocytic nevi and malignant melanoma. In normal skin, a distinct LASP1 expression is visible only in the basal epidermal layer while in nevi LASP1 protein is detected in all melanocytes. Melanoma exhibit no increase in LASP1 mRNA compared to normal skin. In melanocytes, the protein is bound to dynamin and mainly localized at late melanosomes along the edges and at the tips of the cell. Knockdown of LASP1 results in increased melanin concentration in the cells. Collectively, we identified LASP1 as a hitherto unknown protein in melanocytes and as novel partner of dynamin in the physiological process of membrane constriction and melanosome vesicle release. PMID- 26061441 TI - Synthesis of Mn3O 4-Based Aerogels and Their Lithium-Storage Abilities. AB - Mn3O4 aerogels and their graphene nanosheet (GN) composite aerogels were synthesized by a simple supercritical-ethanol process. In the process, supercritical ethanol acted as a reductant to reduce graphene oxide and MnO2 gels simultaneously. The synthesized aerogels consisted of 10-20 nm Mn3O4 nanocrystallites, with BET-specific surface areas around 60 m(2)/g. The performance of the aerogels as anode materials for lithium-ion batteries was also evaluated in this study. The results showed that Mn3O4 aerogels as anode materials exhibited a reversible capacity of 498.7 mAh/g after 60 charge/discharge cycles while the reversible capacity for Mn3O4/GN composite aerogels could further increase to 665 mAh/g. The mechanisms for the enhanced capacity retention could be attributed to their porous structures and improved electronic contact with GN addition. The process should also offer an effective and facile method to fabricate many other porous metal oxide/GN nanocomposites for low-cost, high-capacity, environmentally benign material for lithium-ion batteries. PMID- 26061442 TI - Morphological and SERS Properties of Silver Nanorod Array Films Fabricated by Oblique Thermal Evaporation at Various Substrate Temperatures. AB - Aligned silver nanorod (AgNR) array films were fabricated by oblique thermal evaporation. The substrate temperature during evaporation was varied from 10 to 100 degrees C using a home-built water cooling system. Deposition angle and substrate temperature were found to be the most important parameters for the morphology of fabricated films. Especially, it was found that there exists a critical temperature at ~90 degrees C for the formation of the AgNR array. The highest enhancement factor of the surface-enhanced Raman scattering (SERS), observed in the Ag films coated with benzenethiol monolayer, was ~6 * 10(7). Hot spots, excited in narrow gaps between nanorods, were attributed to the huge enhancement factor by our finite-difference time-domain (FDTD) simulation reflecting the real morphology. PMID- 26061443 TI - Durability Improvement of Pt/RGO Catalysts for PEMFC by Low-Temperature Self Catalyzed Reduction. AB - Pt/C catalyst used for polymer electrolyte membrane fuel cells (PEMFCs) displays excellent initial performance, but it does not last long because of the lack of durability. In this study, a Pt/reduced graphene oxide (RGO) catalyst was synthesized by the polyol method using ethylene glycol (EG) as the reducing agent, and then low-temperature hydrogen bubbling (LTHB) treatment was introduced to enhance the durability of the Pt/RGO catalyst. The cyclic voltammetry (CV), oxygen reduction reaction (ORR) analysis, and transmittance electron microscopy (TEM) results suggested that the loss of the oxygen functional groups, because of the hydrogen spillover and self-catalyzed dehydration reaction during LTHB, reduced the carbon corrosion and Pt agglomeration and thus enhanced the durability of the electrocatalyst. PMID- 26061444 TI - Characterization of InSb Nanoparticles Synthesized Using Inert Gas Condensation. AB - Nanoparticles (NPs) of indium antimonide (InSb) were synthesized using a vapor phase synthesis technique known as inert gas condensation (IGC). NPs were directly deposited, at room temperature and under high vacuum, on glass cover slides, TEM grids and (111) p-type silicon wafers. TEM studies showed a bimodal distribution in the size of the NPs with average particle size of 13.70 nm and 33.20 nm. The Raman spectra of InSb NPs exhibited a peak centered at 184.27 cm( 1), which corresponds to the longitudinal optical (LO) modes of phonon vibration in InSb. A 1:1 In-to-Sb composition ratio was confirmed by energy dispersive X ray (EDX). X-ray diffractometer (XRD) and high-resolution transmission electron microscopy (HRTEM) studies revealed polycrystalline behavior of these NPs with lattice spacing around 0.37 and 0.23 nm corresponding to the growth directions of (111) and (220), respectively. The average crystallite size of the NPs obtained using XRD peak broadening results and the Debye-Scherrer formula was 25.62 nm, and the value of strain in NPs was found to be 0.0015. NP's band gap obtained using spectroscopy and Fourier transform infrared (FTIR) spectroscopy was around 0.43-0.52 eV at 300 K, which is a blue shift of 0.26-0.35 eV. The effects of increased particle density resulting into aggregation of NPs are also discussed in this paper. PMID- 26061445 TI - Computational Study of the Cation-Modified GSH Peptide Interactions With Perovskite-Type BFO-(111) Membranes Under Aqueous Conditions. AB - We elucidated a number of facets regarding glutathione (GSH)-bismuth ferrite (BiFeO3, BFO) interactions and reactivity that have previously remained unexplored on a molecular level. In this approach, the cation-modified reduced GSH (or oxidised glutathione (GS.)) formed on the (111)-oriented BiFeO3 membrane (namely BFO-(111)) can serve as an efficient quencher, and the luminescence mechanism is explained in aqueous conditions. Notably, we suggest the use of Fe(2+)? ion as an electron donor and K(+) ion as an electron acceptor to exert a "gluing" effect on the glutamic acid (Glu) and glycine (Gly) side chains, producing an exposed sulfhydryl (-SH) configuration. This method may enable the rational design of a convenient platform for biosensors. PMID- 26061446 TI - Enhanced Antifungal Activity by Ab-Modified Amphotericin B-Loaded Nanoparticles Using a pH-Responsive Block Copolymer. AB - Fungal infections are an important cause of morbidity and mortality in immunocompromised patients. Amphotericin B (AMB), with broad-spectrum antifungal activity, has long been recognized as a powerful fungicidal drug, but its clinical toxicities mainly nephrotoxicity and poor solubility limit its wide application in clinical practice. The fungal metabolism along with the host immune response usually generates acidity at sites of infection, resulting in loss of AMB activity in a pH-dependent manner. Herein, we developed pH-responsive AMB-loaded and surface charge-switching poly(D,L-lactic-co-glycolic acid)-b poly(L-histidine)-b-poly(ethylene glycol) (PLGA-PLH-PEG) nanoparticles for resolving the localized acidity problem and enhance the antifungal efficacy of AMB. Moreover, we modified AMB-encapsulated PLGA-PLH-PEG nanoparticles with anti Candida albicans antibody (CDA) (CDA-AMB-NPs) to increase the targetability. Then, CDA-AMB-NPs were characterized in terms of physical characteristics, in vitro drug release, stability, drug encapsulation efficiency, and toxicity. Finally, the targetability and antifungal activity of CDA-AMB-NPs were investigated in vitro/in vivo. The result demonstrated that CDA-AMB-NPs significantly improve the targetability and bioavailability of AMB and thus improve its antifungal activity and reduce its toxicity. These NPs may become a good drug carrier for antifungal treatment. PMID- 26061447 TI - Controlled growth of polyhedral and plate-like Ag nanocrystals on a nanofiber mat as a SERS substrate. AB - We report chemical deposition of silver nanocrystals (AgNCs) of different sizes and morphologies, such as polyhedra and plates, on a polyacrylonitrile (PAN) nanofiber mat. High performance surface-enhanced Raman scattering (SERS) substrates are achieved. The effect of the experimental parameters, such as the temperature, concentration and pH of [Ag(NH3)2]OH aqueous solution, on the morphology evolution and density of AgNCs is systematically investigated. The results suggest that the optimized nanofiber mat exhibits a significant SERS performance with superior stability and reproduction, and the SERS enhancement factor (EF) can reach as high as 10(8) for 4-mercaptobenzoic acid (4-MBA). The optimized nanofiber mat also shows high SERS activity for p-aminothiophenol (4 ATP) over the whole nanofiber mat demonstrating the feasibility for detection of both analytes. The detection limit of 4-MBA and 4-ATP is as low as 10(-9) M and 10(-10) M respectively, making the nanofiber mat a promising candidate for SERS detection of chemical pollutants. PMID- 26061448 TI - Primary Cutaneous Trichosporonosis Responsive to Voriconazole. PMID- 26061451 TI - A key discovery at the TiO2/dye/electrolyte interface: slow local charge compensation and a reversible electric field. AB - Dye-sensitized mesoporous TiO2 films have been widely applied in energy and environmental science related research fields. The interaction between accumulated electrons inside TiO2 and cations in the surrounding electrolyte at the TiO2/dye/electrolyte interface is, however, still poorly understood. This interaction is undoubtedly important for both device performance and fundamental understanding. In the present study, Stark effects of an organic dye, LEG4, adsorbed on TiO2 were well characterized and used as a probe to monitor the local electric field at the TiO2/dye/electrolyte interface. By using time-resolved photo- and potential-induced absorption techniques, we found evidence for a slow (t > 0.1 s) local charge compensation mechanism, which follows electron accumulation inside the mesoporous TiO2. This slow local compensation was attributed to the penetration of cations from the electrolyte into the adsorbed dye layer, leading to a more localized charge compensation of the electrons inside TiO2. Importantly, when the electrons inside TiO2 were extracted, a remarkable reversal of the surface electric field was observed for the first time, which is attributed to the penetrated and/or adsorbed cations now being charge compensated by anions in the bulk electrolyte. A cation electrosorption model is developed to account for the overall process. These findings give new insights into the mesoporous TiO2/dye/electrolyte interface and the electron cation interaction mechanism. Electrosorbed cations are proposed to act as electrostatic trap states for electrons in the mesoporous TiO2 electrode. PMID- 26061452 TI - Installing Logic Gates to Multiresponsive Supramolecular Hydrogel Co-assembled from Phenylalanine Amphiphile and Bis(pyridinyl) Derivative. AB - Recently, logic gates based on multiresponsive hydrogel systems are attractive because of their potential biological applications. A quite simple supramolecular hydrogel co-assembled from phenylalanine-based amphiphile (LPF2) and bis(pyridinyl) derivative (AP) is constructed. The co-assembled hydrogel exhibited a macroscopic gel-sol transition in response to four distinct input stimuli: temperature, acid, base, and light. A set of techniques including microscopic, spectroscopic, and rheological measurements demonstrate this performance and confirm that the hydrogel is formed through intermolecular hydrogen bonds between amide/pyridine moieties and carbonyl groups. On the basis of its mutiple-stimulus responsiveness, installing gel-based supramolecular logic gates (OR and XOR) is achieved. It may promote the possibility to develop smart soft materials, such as gels, that can be used as tools releasing a drug quantitatively by rational design and fine control of the external stimuli. PMID- 26061453 TI - Maltitol Prevents the Progression of Fatty Liver Degeneration in Mice Fed High Fat Diets. AB - Nonalcoholic fatty liver disease (NAFLD) progresses to nonalcoholic steatohepatitis, ultimately leading to cirrhosis and liver cancer. It is important to prevent this progression during the initial stages of hepatic fatty degeneration. Maltitol is a polyol produced by the hydrogenation of maltose. We investigated the efficacy of maltitol for treating hepatic fatty degeneration in C57BL/6 male mice using a high-fat diet model. Intake of 5.0% maltitol for 8 weeks significantly suppressed weight gain, hepatic fatty degeneration, hyperglycemia, and hypercholesterolemia. With maltitol intake, sterol regulatory element-binding protein 1c (SREBP1c) mRNA expression was significantly decreased, and farnesoid X receptor (FXR), peroxisome proliferator-activated receptor alpha (PPARalpha), and hydroxymethylglutaryl-Co reductase expressions were significantly higher in the liver. The increase in SREBP1c and suppression of FXR and PPARalpha expressions are correlated with NAFLD. Our results suggest that maltitol may prevent steatosis of NAFLD with a high-fat diet. PMID- 26061454 TI - Lack of access and continuity of adult health care: a national population-based survey. AB - OBJECTIVE To describe the lack of access and continuity of health care in adults. METHODS A cross-sectional population-based study was performed on a sample of 12,402 adults aged 20 to 59 years in urban areas of 100 municipalities of 23 states in the five Brazilian geopolitical regions. Barriers to the access and continuity of health care and were investigated based on receiving, needing and seeking health care (hospitalization and accident/emergency care in the last 12 months; care provided by a doctor, by other health professional or home care in the last three months). Based on the results obtained by the description of the sample, a projection is provided for adults living in Brazilian urban areas. RESULTS The highest prevalence of lack of access to health services and to provision of care by health professionals was for hospitalization (3.0%), whilst the lowest prevalence was for care provided by a doctor (1.1%). The lack of access to care provided by other health professionals was 2.0%; to accident and emergency services, 2.1%; and to home care, 2.9%. As for prevalences, the greatest absolute lack of access occurred in emergency care (more than 360,000 adults). The main reasons were structural and organizational problems, such as unavailability of hospital beds, of health professionals, of appointments for the type of care needed and charges made for care. CONCLUSIONS The universal right to health care in Brazil has not yet been achieved. These projections can help health care management in scaling the efforts needed to overcome this problem, such as expanding the infrastructure of health services and the workforce. PMID- 26061455 TI - Metabolic syndrome in fixed-shift workers. AB - OBJECTIVE To analyze if metabolic syndrome and its altered components are associated with demographic, socioeconomic and behavioral factors in fixed-shift workers. METHODS A cross-sectional study was conducted on a sample of 902 shift workers of both sexes in a poultry processing plant in Southern Brazil in 2010. The diagnosis of metabolic syndrome was determined according to the recommendations from Harmonizing the Metabolic Syndrome. Its frequency was evaluated according to the demographic (sex, skin color, age and marital status), socioeconomic (educational level, income and work shift), and behavioral characteristics (smoking, alcohol intake, leisure time physical activity, number of meals and sleep duration) of the sample. The multivariate analysis followed a theoretical framework for identifying metabolic syndrome in fixed-shift workers. RESULTS The prevalence of metabolic syndrome in the sample was 9.3% (95%CI 7.4;11.2). The most frequently altered component was waist circumference (PR 48.4%; 95%CI 45.5;51.2), followed by high-density lipoprotein. Work shift was not associated with metabolic syndrome and its altered components. After adjustment, the prevalence of metabolic syndrome was positively associated with women (PR 2.16; 95%CI 1.28;3.64), workers aged over 40 years (PR 3.90; 95%CI 1.78;8.93) and those who reported sleeping five hours or less per day (PR 1.70; 95%CI 1.09;2.24). On the other hand, metabolic syndrome was inversely associated with educational level and having more than three meals per day (PR 0.43; 95%CI 0.26;0.73). CONCLUSIONS Being female, older and deprived of sleep are probable risk factors for metabolic syndrome, whereas higher educational level and higher number of meals per day are protective factors for metabolic syndrome in fixed shift workers. PMID- 26061456 TI - Methylphenidate use in children with attention deficit hyperactivity disorder. AB - A Brazilian Health Technology Assessment Bulletin (BRATS) article regarding scientific evidence of the efficacy and safety of methylphenidate for treating attention deficit hyperactivity disorder (ADHD) has caused much controversy about its methods. Considering the relevance of BRATS for public health in Brazil, we critically reviewed this article by remaking the BRATS search and discussing its methods and results. Two questions were answered: did BRATS include all references available in the literature? Do the conclusions reflect the reviewed articles? The results indicate that BRATS did not include all the references from the literature on this subject and also that the proposed conclusions are different from the results of the articles chosen by the BRATS authors themselves. The articles selected by the BRATS authors showed that using methylphenidate is safe and effective. However, the BRATS final conclusion does not reflect the aforementioned and should not be used to support decisions on the use of methylphenidate. PMID- 26061457 TI - Improved efficiency in Monte Carlo simulation for passive-scattering proton therapy. AB - The aim of this work was to improve the computational efficiency of Monte Carlo simulations when tracking protons through a proton therapy treatment head. Two proton therapy facilities were considered, the Francis H Burr Proton Therapy Center (FHBPTC) at the Massachusetts General Hospital and the Crocker Lab eye treatment facility used by University of California at San Francisco (UCSFETF). The computational efficiency was evaluated for phase space files scored at the exit of the treatment head to determine optimal parameters to improve efficiency while maintaining accuracy in the dose calculation. For FHBPTC, particles were split by a factor of 8 upstream of the second scatterer and upstream of the aperture. The radius of the region for Russian roulette was set to 2.5 or 1.5 times the radius of the aperture and a secondary particle production cut (PC) of 50 mm was applied. For UCSFETF, particles were split a factor of 16 upstream of a water absorber column and upstream of the aperture. Here, the radius of the region for Russian roulette was set to 4 times the radius of the aperture and a PC of 0.05 mm was applied. In both setups, the cylindrical symmetry of the proton beam was exploited to position the split particles randomly spaced around the beam axis. When simulating a phase space for subsequent water phantom simulations, efficiency gains between a factor of 19.9 +/- 0.1 and 52.21 +/- 0.04 for the FHTPC setups and 57.3 +/- 0.5 for the UCSFETF setups were obtained. For a phase space used as input for simulations in a patient geometry, the gain was a factor of 78.6 +/- 7.5. Lateral-dose curves in water were within the accepted clinical tolerance of 2%, with statistical uncertainties of 0.5% for the two facilities. For the patient geometry and by considering the 2% and 2mm criteria, 98.4% of the voxels showed a gamma index lower than unity. An analysis of the dose distribution resulted in systematic deviations below of 0.88% for 20% of the voxels with dose of 20% of the maximum or more. PMID- 26061458 TI - Should anesthesiologists be concerned with acute angle closure glaucoma? PMID- 26061459 TI - Novel Drug Targets for Food-Borne Pathogen Campylobacter jejuni: An Integrated Subtractive Genomics and Comparative Metabolic Pathway Study. AB - Campylobacters are a major global health burden and a cause of food-borne diarrheal illness and economic loss worldwide. In developing countries, Campylobacter infections are frequent in children under age two and may be associated with mortality. In developed countries, they are a common cause of bacterial diarrhea in early adulthood. In the United States, antibiotic resistance against Campylobacter is notably increased from 13% in 1997 to nearly 25% in 2011. Novel drug targets are urgently needed but remain a daunting task to accomplish. We suggest that omics-guided drug discovery is timely and worth considering in this context. The present study employed an integrated subtractive genomics and comparative metabolic pathway analysis approach. We identified 16 unique pathways from Campylobacter when compared against H. sapiens with 326 non redundant proteins; 115 of these were found to be essential in the Database of Essential Genes. Sixty-six proteins among these were non-homologous to the human proteome. Six membrane proteins, of which four are transporters, have been proposed as potential vaccine candidates. Screening of 66 essential non homologous proteins against DrugBank resulted in identification of 34 proteins with drug-ability potential, many of which play critical roles in bacterial growth and survival. Out of these, eight proteins had approved drug targets available in DrugBank, the majority serving crucial roles in cell wall synthesis and energy metabolism and therefore having the potential to be utilized as drug targets. We conclude by underscoring that screening against these proteins with inhibitors may aid in future discovery of novel therapeutics against campylobacteriosis in ways that will be pathogen specific, and thus have minimal toxic effect on host. Omics-guided drug discovery and bioinformatics analyses offer the broad potential for veritable advances in global health relevant novel therapeutics. PMID- 26061461 TI - Rhythmic control of endocannabinoids in the rat pineal gland. AB - Endocannabinoids modulate neuroendocrine networks by directly targeting cannabinoid receptors. The time-hormone melatonin synchronizes these networks with external light condition and guarantees time-sensitive and ecologically well adapted behaviors. Here, the endocannabinoid arachidonoyl ethanolamide (AEA) showed rhythmic changes in rat pineal glands with higher levels during the light period and reduced amounts at the onset of darkness. Norepinephrine, the essential stimulus for nocturnal melatonin biosynthesis, acutely down-regulated AEA and other endocannabinoids in cultured pineal glands. These temporal dynamics suggest that AEA exerts time-dependent autocrine and/or paracrine functions within the pineal. Moreover, endocananbinoids may be released from the pineal into the CSF or blood stream. PMID- 26061460 TI - Ubiquitin-specific Protease 15 Negatively Regulates Virus-induced Type I Interferon Signaling via Catalytically-dependent and -independent Mechanisms. AB - Viral infection triggers a series of signaling cascades, which converge to activate the transcription factors nuclear factor-kappaB (NF-kappaB) and interferon regulatory factor 3 (IRF3), thereby inducing the transcription of type I interferons (IFNs). Although not fully characterized, these innate antiviral responses are fine-tuned by dynamic ubiquitination and deubiquitination processes. In this study, we report ubiquitin-specific protease (USP) 15 is involved in regulation of the retinoic acid-inducible gene I (RIG-I)-dependent type I IFN induction pathway. Knockdown of endogenous USP15 augmented cellular antiviral responses. Overexpression of USP15 inhibited the transcription of IFN beta. Further analyses identified histidine 862 as a critical residue for USP15's catalytic activity. Interestingly, USP15 specifically removed lysine 63-linked polyubiquitin chains from RIG-I among the essential components in RIG-I-like receptor-dependent pathway. In addition, we demonstrated that in contrast to USP15 de-ubiquitinating (DUB) activity, USP15-mediated inhibition of IFN signaling was not abolished by mutations eliminating the catalytic activity, indicating that a fraction of USP15-mediated IFN antagonism was independent of the DUB activity. Catalytically inactive USP15 mutants, as did the wild-type protein, disrupted virus-induced interaction of RIG-I and IFN-beta promoter stimulator 1. Taken together, our data demonstrate that USP15 acts as a negative regulator of RIG-I signaling via DUB-dependent and independent mechanisms. PMID- 26061463 TI - Single-chip photonic transceiver based on bulk-silicon, as a chip-level photonic I/O platform for optical interconnects. AB - When silicon photonic integrated circuits (PICs), defined for transmitting and receiving optical data, are successfully monolithic-integrated into major silicon electronic chips as chip-level optical I/Os (inputs/outputs), it will bring innovative changes in data computing and communications. Here, we propose new photonic integration scheme, a single-chip optical transceiver based on a monolithic-integrated vertical photonic I/O device set including light source on bulk-silicon. This scheme can solve the major issues which impede practical implementation of silicon-based chip-level optical interconnects. We demonstrated a prototype of a single-chip photonic transceiver with monolithic-integrated vertical-illumination type Ge-on-Si photodetectors and VCSELs-on-Si on the same bulk-silicon substrate operating up to 50 Gb/s and 20 Gb/s, respectively. The prototype realized 20 Gb/s low-power chip-level optical interconnects for lambda ~ 850 nm between fabricated chips. This approach can have a significant impact on practical electronic-photonic integration in high performance computers (HPC), cpu-memory interface, hybrid memory cube, and LAN, SAN, data center and network applications. PMID- 26061464 TI - Meta-research: The art of getting it wrong. AB - Meta-analysis has major strengths, but sometimes it can often lead to wrong and misleading answers. In this SRSM presidential address, I discuss some case studies that exemplify these problems, including examples from meta-analyses of both clinical trials and observational associations. I also discuss issues of effect size estimation, bias (in particular significance-chasing biases), and credibility in meta-research. I examine the factors that affect the credibility of meta-analyses, including magnitude of effects, multiplicity of analyses, scale of data, flexibility of analyses, reporting, and conflicts of interest. Under the current circumstances, a survey of expert meta-analysts attending the SRSM meeting showed that most of them believe that the true effect is practically equally likely to lie within the 95% confidence interval of a meta-analysis or outside of it. Finally, I address the placement of meta-analysis in the wider current research agenda and make a plea for adoption of more prospective meta designs. In many/most/all fields, all primary original research may be designed, executed, and interpreted as a prospective meta-analysis. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061465 TI - The impact of research synthesis methods on industrial-organizational psychology: The road from pessimism to optimism about cumulative knowledge. AB - This paper presents an account of the impact that research synthesis methods, in the form of psychometric meta-analysis, has had on industrial/organizational (I/O) psychology. This paper outlines the central contributions of psychometric meta-analysis in providing a method for developing cumulative knowledge. First, this paper describes the concerns and the state of the field before the development of meta-analytic methods. Second, the paper explains how meta analysis addressed these concerns. Third, the paper details the development of psychometric meta-analysis through VG research and describes how the use of psychometric meta-analysis spread to other topic areas in the field. Finally, the paper presents illustrative example literatures, such as training and leadership, where meta-analysis had crucial impacts. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061462 TI - Luminal 5-HT stimulates colonic bicarbonate secretion in rats. AB - BACKGROUND AND PURPOSE: The bioactive monoamine 5-HT, implicated in the pathogenesis of functional gastrointestinal disorders, is abundantly synthesized and stored in rat proximal colonic mucosa and released to the gut lumen and subepithelial space. Despite much data regarding its expression and function, the effects of luminal 5-HT on colonic anion secretion have not been fully investigated. EXPERIMENTAL APPROACH: We measured short-circuit current (Isc ) as an indicator of ion transport in mucosa-submucosa or mucosa-only preparations of rat proximal colon. Total CO2 output was measured in vitro and in vivo. Immunohistochemistry was performed to investigate the localization of 5-HT4 , NOS1 and NOS2. KEY RESULTS: Luminal 5-HT gradually increased the amplitude and sustained the elevation of Isc . Luminal 5-HT-evoked DeltaIsc was acetazolamide sensitive and HCO3 (-) dependent, consistent with cytosolic carbonic anhydrase dependent electrogenic HCO3 (-) secretion, while not affected by tetrodotoxin (TTX), atropine or indomethacin. Pretreatment with the selective 5-HT4 antagonist GR113808, but not antagonists for 5-HT3 , 5-HT6 or 5-HT7 , inhibited luminal 5-HT evoked DeltaIsc . Furthermore, luminal cisapride and tegaserod increased Isc to the same extent as did 5-HT in the presence of indomethacin and TTX. Removal of the submucosa or pretreatment with NOS inhibitors enhanced luminal 5-HT-evoked DeltaIsc , suggesting that NO synthesized in the submucosa suppresses mucosal anion secretion. NOS1 and NOS2 were immunostained in the submucosal neurons and glial cells respectively. Luminal 5-HT-evoked HCO3 (-) secretion was confirmed in vivo, inhibited by co-perfusion of GR113808, but not by ondansetron. CONCLUSIONS AND IMPLICATIONS: A novel apical 5-HT4 -mediated HCO3 (-) secretory pathway and an NO-dependent inhibitory mechanism are present in the proximal colon. Luminal 5 HT-evoked HCO3 (-) secretion may be important for the maintenance of mucosal integrity by regulating luminal pH. PMID- 26061466 TI - The evolution of a new publication type: Steps and challenges of producing overviews of reviews. AB - BACKGROUND: To date, the Cochrane Child Health Field has published 18 overviews of reviews in our journal, Evidence-based Child Health: A Cochrane Review Journal. In this article, we highlight some of the logistical and methodological challenges of producing such syntheses. As this is a new and evolving publication type, we hope that our experience will benefit others who engage in this process. Current Methods: We discuss the process we have developed to produce overviews of reviews relevant to our mandate, including identification of the research question, establishment of the author team, selection of outcomes and included SRs, and presentation of findings. Ongoing Development: We discuss the lessons we have learned, outstanding challenges for overview authors, and the limitations of overviews. CONCLUSIONS: Overviews of reviews are only as good as the SRs and primary studies on which they are based; gaps or lack of currency in this evidence will weaken the overview of reviews. Future directions in this work must address questions of bias and loss of information. Methods for overviews of reviews targeted for specific groups, such as children, need more elaboration. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061467 TI - Development of a combined database for meta-epidemiological research. AB - Collections of meta-analyses assembled in meta-epidemiological studies are used to study associations of trial characteristics with intervention effect estimates. However, methods and findings are not consistent across studies. To combine data from 10 meta-epidemiological studies into a single database, and derive a harmonized dataset without overlap between meta-analyses. The database design allowed trials to be contained in different meta-analyses, multiple meta analyses in systematic reviews, overlapping meta-analyses between systematic reviews, and multiple references to the same trial or review. Unique identifiers were assigned to each reference and used to identify duplicate trials. Sets of meta-analyses with overlapping trials were identified and duplicates removed. Overlapping trials were used to examine agreement between assessments of trial characteristics. The combined database contained 427 reviews, 454 meta-analyses and 4874 trial results. Of these, 258 meta-analyses were unique, while for 196 at least one trial overlapped with another meta-analysis. Median kappa statistics for reliability of assessments were 0.60 for sequence generation, 0.58 for allocation concealment and 0.87 for blinding. Based on inspection of sets of overlapping meta-analyses, 91 meta-analyses containing 1344 trial results were removed. Additionally, 24 duplicated trial results were removed from 16 meta analyses, to derive a final database containing 363 meta-analyses and 3477 unique trial results. The final database will be used to examine the combined evidence on sources of bias in randomized controlled trials. The strategy used to remove overlap between meta-analyses may be of use for future empirical research. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26061468 TI - Bayesian model selection for meta-analysis of diagnostic test accuracy data: Application to Ddimer for deep vein thrombosis. AB - A number of statistical models have been developed for meta-analysis (MA) of diagnostic test (DT) accuracy data. Here we consider these alternative MA models, explore the relationships between them, and consider the use of the deviance information criteria (DIC) to decide which is the most appropriate model for a given dataset. A Bayesian statistical approach is adopted throughout. The alternative MA models are applied to a dataset of 198 assays of Ddimer to diagnose deep vein thrombosis. In this example, based on the DIC, a bivariate random effects model for sensitivity and specificity fitted the data best. When considering the inclusion of study level covariates, allowing sensitivity to vary by study setting further improved the fit of the model. The model fitting approach is then repeated for a subset of the data, which highlights the less decisive results obtained when using the DIC with a more limited dataset. Formal approaches to model selection are often overlooked in an MA context; however, they offer sensible rationale to the analysis, particularly for complex models such as those proposed for DT accuracy. Specifically, the use of the DIC statistic appears to be well suited for deciding between potentially complex mixed-effect MA models, possibly including covariates. Copyright (c) 2010 John Wiley & Sons, Ltd. PMID- 26061469 TI - Synthesis of survival and disease progression outcomes for health technology assessment of cancer therapies. AB - Studies of clinical efficacy commonly report more than one clinical endpoint. For example, randomized controlled trials of treatments for cancer will normally report time to disease progression as well as overall survival. It is likely that disease progression will be associated with higher mortality rates. Disease progression rates will also have consequences for the societal economic burden of the disease. Economic evaluation of the cost-effectiveness of different treatment regimes therefore requires the joint estimation of both disease progression and mortality. We describe a model to combine evidence from studies reporting time to event summaries for disease progression and/or mortality, motivated by a systematic review of 1st-line treatment for advanced breast cancer to provide inputs for an economic evaluation as part of the National Institute for Health and Clinical Excellence (NICE) clinical guideline on treatment of advanced breast cancer in England and Wales. The review identified a network of treatment comparisons, which provides the basis for indirect comparison. A variety of outcomes were reported: overall survival, time to progression (overall and responders only), and the proportion of responder, stable, progressive disease, and non-assessable patients. There were only five trials, and not all trials reported all outcomes. The scarcity of the available evidence required us to make strong assumptions in order to identify model parameters. However, this evidence structure often occurs in health technology assessment (HTA) of treatments for cancer. We discuss the validity of the assumptions made, and the potential to assess their validity in other applications of HTA of cancer therapies. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061470 TI - Network meta-analysis of parametric survival curves. AB - To inform health-care decision-making, treatments are often compared by synthesizing results from a number of randomized controlled trials. The meta analysis may not only be focused on a particular pairwise comparison, but can also include multiple treatment comparisons by means of network meta-analysis. For time-to-event outcomes such as survival, pooling is typically based on the hazard ratio (HR). The proportional hazards assumption that underlies current approaches of evidence synthesis is not only often implausible, but can also have a huge impact on decisions based on differences in expected outcomes, such as cost-effectiveness analysis. The application of a constant HR implies the assumption that the treatment only has an effect on one characteristic of the survival distribution, while commonly used survival distributions, like the Weibull distribution, have both a shape and a scale parameter. Instead of using constant HRs, this paper proposes meta-analysis of treatment effects based on the shape and scale parameters of parametric survival curves. The model for meta analysis is extended for network meta-analysis and illustrated with an example. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061471 TI - An alternative to R(2) for assessing linear models of effect size. PMID- 26061472 TI - Combining the evidence using stable weights. AB - In a meta-analysis one seeks to combine the results of several studies in order to improve the accuracy of decisions. Here we compare by simulation four methods for combining estimates of the risk difference, namely the Cochran and Mantel Haenszel (MH) methods, the inverse-variance weights approach and a recent variance-stabilized weights approach. Both the level and power of corresponding test statistics, as well as the coverage of related confidence intervals are compared over a wide range of sample size and parameter configurations. We found that the inverse-variance weights methodology is unreliable and is not recommended, while for equal risks, the Cochran test and the associated confidence intervals are the most reliable. Under alternatives of unequal risks, the coverage probabilities of the variance-stabilized confidence intervals are almost uniformly more reliable than those based on other methods except when the average risk is small in which case the MH confidence intervals are preferable. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061473 TI - Use of quality control charts for detection of outliers and temporal trends in cumulative meta-analysis. AB - Cumulative meta-analysis (CMA) aims to aggregate accumulating evidence. Essentially a visual tool, CMA should be supplemented by formal statistical methods for assessment of the significance of the accumulating evidence, and for detection of temporal trends in effect sizes. These methods should also take into account multiple testing inherent in CMA. We review the existing methods for detection of temporal trends in effect sizes and suggest a new approach, namely the use of standard quality control (QC) charts, in particular X charts and CUSUM charts, to detect possible outliers and trends over time. We discuss the application of the QC charts to four popular measures of effect size: the odds ratios, the relative risks, the correlation coefficients and the standardized mean differences. Applications of QC charts are illustrated by three meta analysis examples from medicine, ecology and evolutionary biology. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061474 TI - 'Cross hairs' plots for diagnostic meta-analysis. AB - Understanding diagnostic test accuracy (DTA) data, especially meta-analysis of this information, can be challenging for researchers and clinicians. The use of plots of receiver-operator curve (ROC) space showing individual studies and summary estimates of diagnostic accuracy has become common but can be difficult to interpret. The assessment of heterogeneity in sensitivity and specificity across studies can be particularly difficult. In this paper, we review the key concepts of assessing DTA, starting at the level of individual studies and progressing to the setting of research synthesis. We explore the standard displays of this information and then propose and explain an alternative approach to summarizing key data. These 'cross-hairs' plots display the individual studies in ROC space with paired confidence intervals representing sensitivity and specificity, and allow for the results of meta-analysis to be overlaid on the plot. We suggest that these plots are more easily interpreted, and are a more informative graphical form than common approaches. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061475 TI - Article alerts: Items from 2009, Part II. AB - This second installment of the 'Article Alerts' feature section more than doubles the collection's number of items. The print and archive versions now include 200 and 2579 items, respectively. Remarks are offered on inclusion criteria, anticipated growth of the archive version, and a related resource. Copyright 2011 John Wiley & Sons, Ltd. PMID- 26061477 TI - Trends in Robotic Thyroid Surgery in the United States from 2009 Through 2013. AB - BACKGROUND: The objective of this study was to describe national trends in robotic thyroid surgery from 2009 through 2013. METHODS: The University HealthSystem Consortium (UHC) database was searched for patients undergoing robotic thyroidectomy (RT) from 2009 through 2013. Another U.S. institution's RT data, not included in the UHC database, were also evaluated. Patient demographics, institutional volume, comorbid conditions, complications, and cost information were analyzed. RESULTS: Sixty-one institutions performed 484 RT during the study period. From 2009 through 2011, U.S. annual RT volume increased from 39 cases to 140. Annual volume dropped to 69 cases in 2012 and 93 cases in 2013. Higher-volume centers reported lower complication rates (p<0.02). Hematoma formation (3.7%) was the most common complication, and there was one death. More than 10% of patients were obese. Brachial plexus injury and axillary skin flap perforations were reported in <1% of cases. Mean cost for a total RT was $13,287 ($5,125-42,444). CONCLUSIONS: From 2009 through early 2011, there was a steady increase in RT volume, especially among high-volume institutions. In mid-to-late 2011, there was a noticeable drop in RT volume, which significantly altered the projected trajectory of the procedure in this country. Despite higher complication rates, lower-volume centers perform the majority of RT and are also responsible for recent increases in RT utilization patterns in the United States. PMID- 26061478 TI - Transferring Fungi to a Deuterium-Enriched Medium Results in Assorted, Conditional Changes in Secondary Metabolite Production. AB - Deuterium is one of the few stable isotopes that have the capacity to significantly alter a compound's chemical and biological properties. The addition of a single neutron to a protium atom results in the near doubling of its mass, which gives rise to deuterium's characteristic isotope effects. Since the incorporation of deuterium into organic substrates is known to alter enzyme/protein-substrate interactions, we tested the extent to which deuterium enrichment would modify fungal secondary metabolite production. Several fungal cultures were tested, and in all cases their secondary metabolomes were marked by changes in natural product production. Workup of one Aspergillus sp. grown under deuterium-enrichment conditions resulted in the production of several secondary metabolites not previously detected from the fungus. Bioassay testing revealed that in comparison to the inactive crude fungal extract derived from growing the fungus under non-deuterium-enriched conditions, an extract derived from the same isolate cultured in a deuterium-enriched medium inhibited methicillin-resistant Staphylococcus aureus. Using an assortment of NMR and mass spectrometry experiments, we were able to identify the bacterial inhibitor as an isotope labeled version of pigmentosin A (6). Five additional isotopically labeled metabolites were also obtained from the fungus including brevianamide F (1), stephacidin A (2), notoamide D (3), notoamide L (4), and notoamide C (5). Given the assorted changes observed in the secondary metabolite profiles of this and other fungi grown in deuterium-enriched environments, as well as the fact that 1 and 3-6 had not been previously observed from the Aspergillus sp. isolate used in this study, we propose that deuterium enrichment might offer an effective method for further expanding a fungus's chemical diversity potential. PMID- 26061479 TI - A Fluorescent Sensor and Gel Stain for Detection of Pyrophosphorylated Proteins. AB - The design and synthesis of a fluorescent sensor of diphosphate esters along with its application for in-gel detection is described. Dinuclear zinc complex 1 selectively binds diphosphate esters in the presence of various other functional groups, including monophosphate esters. Complex 1 also constitutes a competent stain for visualization of pyrophosphorylated proteins in polyacrylamide gels. This reagent will facilitate the validation and exploration of protein pyrophosphorylation. PMID- 26061480 TI - Interside Latency Differences in Brainstem Auditory and Somatosensory Evoked Potentials. Defining Upper Limits to Determine Asymmetry. AB - PURPOSE: Limits of the interside differences are invaluable when interpreting asymmetry in brainstem auditory evoked potentials and somatosensory evoked potentials (SEP) recordings. The aim of this study was to analyze the normal upper limits of interside latency differences of brainstem auditory evoked potentials and SEP from the posterior tibial nerve and median nerve to determine asymmetry. METHODS: The authors performed a prospective study in 56 healthy subjects aged 15 to 64 years with no neurological or hearing disorders. They analyzed (1) the latencies of I, III, and V waves and I-III, III-V, and I-V intervals and the amplitude ratios V/I and IV/I for brainstem auditory evoked potentials bilaterally; (2) the latencies of N8, N22, N28, and P37 waves and the interval N22-P37 and the amplitude P37 for posterior tibial nerve SEP bilaterally; and (3) the latencies and amplitudes of N9, N13, and N20 waves and N9-N13 and N13-N20 intervals for median nerve SEP bilaterally. The interside differences for these parameters were calculated and analyzed. RESULTS: The authors obtained an upper limit for the interside latency differences from brainstem auditory evoked potentials that was significantly lower than the previously published data. However, the upper limits of interside latency differences for SEP were similar to those previously reported. CONCLUSIONS: The findings of this study should be considered when laboratories analyze asymmetry using the normative data published by another center, however temporarily, in organizing new laboratories. PMID- 26061481 TI - Using Transcranial Magnetic Stimulation to Evaluate the Motor Pathways After an Intraoperative Spinal Cord Injury and to Predict the Recovery of Intraoperative Transcranial Electrical Motor Evoked Potentials: A Case Report. AB - The authors report a case of unilateral loss of intraoperative transcranial electrical motor evoked potentials (TES MEP) associated with a spinal cord injury during scoliosis correction and the subsequent use of extraoperative transcranial magnetic stimulation to monitor the recovery of spinal cord function. The authors demonstrate the absence of TES MEPs and absent transcranial magnetic stimulation responses in the immediate postoperative period, and document the partial recovery of transcranial magnetic stimulation responses, which corresponded to partial recovery of TES MEPs. Intraoperative TES MEPs were enhanced using spatial facilitation technique, which enabled the patient to undergo further surgery to stabilize the spine and correct her scoliosis. This case report supports evidence of the use of extraoperative transcranial magnetic stimulation to predict the presence of intraoperative TES responses and demonstrates the usefulness of spatial facilitation to monitor TES MEPs in a patient with a preexisting spinal cord injury. PMID- 26061482 TI - Nano-beam X-ray microscopy of dried colloidal films. AB - We report on a nano-beam small angle X-ray scattering study on densely-packed, dried binary films made out of spherical silica particles with radii of 11.2 and 19.3 nm. For these three-dimensional thin films prepared by drop casting, only a finite number of colloidal particles contributes to the scattering signal due to the small beam size of 400 * 400 nm(2). By scanning the samples, the structure and composition of the silica particle films are determined spatially resolved revealing spatial heterogeneities in the films. Three different types of domains were identified: regions containing mainly large particles, regions containing mainly small particles, and regions where both particle species are mixed. Using the new angular X-ray cross-correlations analysis (XCCA) approach, spatial maps of the local type and degree of orientational order within the silica particle films are obtained. Whereas the mixed regions have dominant two-fold order, weaker four-fold and marginal six-fold order, regions made out of large particles are characterized by an overall reduced orientational order. Regions of small particles are highly ordered showing actually crystalline order. Distinct differences in the local particle order are observed by analyzing sections through the intensity and XCCA maps. The different degree of order can be understood by the different particle size polydispersities. Moreover, we show that preferential orientations of the particle domains can be studied by cross correlation analysis yielding information on particle film formation. We find patches of preferential order with an average size of 8-10 MUm. Thus, by this combined X-ray cross-correlation microscopy (XCCM) approach the structure and orientational order of films made out of nanometer sized colloids can be determined. This method will allow to reveal the local structure and order of self-assembled structures with different degree of order in general. PMID- 26061483 TI - Product Translational and Vibrational Distributions for the OH/OD + CH4/CD4 Reactions from Quasiclassical Trajectory Calculations. Comparison with Experiment. AB - For the OH + CH4/CD4 hydrogen abstraction reactions, the methyl radical (CH3 and CD3) product translational distributions and the water (H2O and HOD) product vibrational distributions experimentally reported by Liu's group are reproduced by quasi-classical trajectory (QCT) calculations on an analytical full dimensional potential energy surface when a quantum spirit is included in the analysis. Our simulations correctly predict: (i) the vibrational excitation of the water product, (ii) the inversion of the water vibrational population, and (iii) the propensity of transfer from reactant kinetic energy to product translational energy. These reactions therefore present a marked isotopic effect. In addition, the water product vibrational distributions for the OH/OD + CH4 reactions agree reasonably well with Butkovskaya and Setser's experiments for a similar alkane reaction. The theory/experiment agreement is better for the HOD than for the H2O product due to the mode coupling in the H2O molecule, which is absent in the HOD stretching modes, which show a more "local" character. In summary, for polyatomic systems with many degrees of freedom (15 in the present reaction), QCT calculations analyzed with a quantum spirit represent a useful alternative to quantum scattering methods. PMID- 26061484 TI - Efficient Site-Specific Incorporation of Thioamides into Peptides on a Solid Support. AB - Designing bioactive peptides containing "thioamide" functionality to modulate their pharmacological properties has been thwarted so far because of various synthetic challenges. The fast, efficient, and inexpensive synthesis and incorporation of a wide range of thionated amino acids into a growing peptide chain on a solid support is reported using standard Fmoc-based chemistry. The commonly employed methodology is comprehensively investigated and optimized with significant improvements regarding the quantity of reagents and reaction conditions. The utility of the protocol is further demonstrated in the synthesis of dithionated linear and monothionated cyclic peptides, which has been a daunting task. PMID- 26061485 TI - High mobility flexible graphene field-effect transistors and ambipolar radio frequency circuits. AB - Field-effect transistors (GFETs) were fabricated on mechanically flexible substrates using chemical vapor deposition grown graphene. High current density (nearly 200 MUA MUm(-1)) with saturation, almost perfect ambipolar electron-hole behavior, high transconductance (120 MUS MUm(-1)) and good stability over 381 days were obtained. The average carrier mobility for holes (electrons) is 13,540 cm(2) V(-1) s(-1) (12,300 cm(2) V(-1) s(-1)) with the highest value over 24,000 cm(2) V(-1) s(-1) (20,000 cm(2) V(-1) s(-1)) obtained in flexible GFETs. Ambipolar radio-frequency circuits, frequency doubler, were constructed based on the high performed flexible GFET, which show record high output power spectra purity (~97%) and high conversion gain of -13.6 dB. Bending measurements show the flexible GFETs are able to work under modest strain. These results show that flexible GFETs are a very promising option for future flexible radio-frequency electronics. PMID- 26061486 TI - EUS-guided 22-gauge fine needle biopsy for the diagnosis of gastric subepithelial tumors larger than 2 cm. AB - OBJECTIVE: EUS-guided fine needle biopsy (EUS-FNB) was introduced to obtain tissue cores. However, data on the efficacy of EUS-FNB for the diagnosis of gastric subepithelial tumors (SET) are limited. This study was aimed to determine the tissue acquisition and diagnostic yield of EUS-FNB using a novel 22-gauge FNB needle. MATERIAL AND METHODS: Between May 2012 and February 2014, we retrieved data on 78 consecutive patients who underwent 22-gauge EUS-FNB for tissue sampling of gastric SET larger than 2 cm. Relevant tumor and EUS-related parameters were reviewed retrospectively. RESULTS: The median tumor diameter was 2.8 cm and tumors were punctured successfully in 77 SET (98.7%). EUS-FNB was diagnostic in 81.8% of SET (63/77), by obtaining core biopsy tissue in 96.8% (61/63) and aspirates in 27.0% (17/63). FNB specimens permitted immunostaining for the diagnosis of gastrointestinal stromal tumors (GIST) in 30 SET (47.6%), 20 leiomyomas (31.7%), and 3 schwannomas (4.8%). Diagnoses could be made without immunostaining in 10 SET (15.9%). Tissue adequacy was optimal in 85.7% of FNB specimens by endosonographers' on-site visual evaluation. Endosonographers' evaluation of tissue adequacy was the only factor significantly associated with a higher diagnostic yield in univariate analysis. No adequate high-power fields for GIST risk stratification were available in FNB specimens. There was a single case of post-procedural bleeding (1.3%). CONCLUSION: EUS-FNB using 22-gauge needle obtains a high yield for the diagnosis of gastric SET >=2 cm, mostly via core tissue acquisition. Endosonographers should pay careful attention to the adequacy of FNB specimens. PMID- 26061487 TI - Association of 14-bp insertion/deletion polymorphism of HLA-G gene with idiopathic recurrent miscarriages in infertility center patients in Yazd, Iran. AB - HLA-G is supposed to play a pivotal role in tolerance of the semi-allogeneic graft in pregnancy by inhibiting the cytotoxic functions of T and NK cells. A 14 bp insertion and/or deletion polymorphism in exon-8 has a possible role in HLA-G expression. The present study analyzed the 14-bp insertion/deletion polymorphism in normal pregnancy and recurrent miscarriage patients in order to discover a possible correlation between the 14-bp polymorphism and recurrent miscarriage (RM). In this study, genomic DNA from 200 RM patients and 200 normal fertile control individuals using the routine salting out method were isolated. Exon-8 of HLA-G gene of the two groups were amplified using polymerase chain reaction and analyzed by electrophoresis on 10% non-denaturing polyacrylamide gel electrophoresis containing ethidium bromide and visualized under ultraviolet light. HLA-G allele frequencies and genotypes in RM women and the fertile control group were compared using a Chi-square test. The results showed that there was a difference in allelic frequencies of 14-bp insertion polymorphism between fertile controls and RM patients; the frequency of +14 bp/-14 bp heterozygotes was significantly higher in RM patients as compared with fertile controls. Furthermore, the frequency of +14-bp insertion allele was significantly higher in those with RM as compared with normal fertile controls. From the findings here, it was concluded that a 14-bp insertion/deletion polymorphism in exon 8 could play a possible role in recurrent miscarriages. These results might ultimately be of significance for clinicians and those involved in understanding infertility and RM. PMID- 26061489 TI - Honey: A Biologic Wound Dressing. AB - Honey has been used as a wound dressing for thousands of years, but only in more recent times has a scientific explanation become available for its effectiveness. It is now realized that honey is a biologic wound dressing with multiple bioactivities that work in concert to expedite the healing process. The physical properties of honey also expedite the healing process: its acidity increases the release of oxygen from hemoglobin thereby making the wound environment less favorable for the activity of destructive proteases, and the high osmolarity of honey draws fluid out of the wound bed to create an outflow of lymph as occurs with negative pressure wound therapy. Honey has a broad-spectrum antibacterial activity, but there is much variation in potency between different honeys. There are 2 types of antibacterial activity. In most honeys the activity is due to hydrogen peroxide, but much of this is inactivated by the enzyme catalase that is present in blood, serum, and wound tissues. In manuka honey, the activity is due to methylglyoxal which is not inactivated. The manuka honey used in wound-care products can withstand dilution with substantial amounts of wound exudate and still maintain enough activity to inhibit the growth of bacteria. There is good evidence for honey also having bioactivities that stimulate the immune response (thus promoting the growth of tissues for wound repair), suppress inflammation, and bring about rapid autolytic debridement. There is clinical evidence for these actions, and research is providing scientific explanations for them. PMID- 26061488 TI - Using High-Resolution Satellite Aerosol Optical Depth To Estimate Daily PM2.5 Geographical Distribution in Mexico City. AB - Recent advances in estimating fine particle (PM2.5) ambient concentrations use daily satellite measurements of aerosol optical depth (AOD) for spatially and temporally resolved exposure estimates. Mexico City is a dense megacity that differs from other previously modeled regions in several ways: it has bright land surfaces, a distinctive climatological cycle, and an elevated semi-enclosed air basin with a unique planetary boundary layer dynamic. We extend our previous satellite methodology to the Mexico City area, a region with higher PM2.5 than most U.S. and European urban areas. Using a novel 1 km resolution AOD product from the MODIS instrument, we constructed daily predictions across the greater Mexico City area for 2004-2014. We calibrated the association of AOD to PM2.5 daily using municipal ground monitors, land use, and meteorological features. Predictions used spatial and temporal smoothing to estimate AOD when satellite data were missing. Our model performed well, resulting in an out-of-sample cross validation R(2) of 0.724. Cross-validated root-mean-squared prediction error (RMSPE) of the model was 5.55 MUg/m(3). This novel model reconstructs long- and short-term spatially resolved exposure to PM2.5 for epidemiological studies in Mexico City. PMID- 26061490 TI - Efficacy of a New Flowable Wound Matrix in Tunneled and Cavity Ulcers: A Preliminary Report. AB - INTRODUCTION: In chronic wounds the healing is stagnant, and regenerative surgery is often needed. Many engineered tissues with a conventional bidimensional sheet are ineffective for tunneling wounds, because adherence to the wound bed is not complete. An advanced wound matrix for treating wounds with irregular geometries has been developed (Integra Flowable Wound Matrix, Integra LifeScience Corp, Plainsboro, NJ). METHODS AND MATERIALS: Between March 2013 and December 2013 the authors treated 18 patients (11 female) with tunneled or cavity ulcers with the advanced wound matrix at the Unit of General and Geriatric Surgery of the Second University of Naples, Naples, Italy. Two patients (11.1%) had postsurgical wounds, two (11.1%) had post-traumatic wounds, and 14 (77.8%) had neuropathic ulcers. After debridement and antibiotic therapy, the lesions were filled with the wound matrix product. Surgical wound edges were either approximated with stitches or left to heal by secondary intention and covered with wet gauze. During the first week, follow-up visits were carried out every 3 days, then once a week until complete healing was achieved. All patients underwent preoperative and postoperative ultrasonography scans and plain radiograph controls. RESULTS: Twenty-one applications were performed. Engraftment was complete in all but 1 patient who had diabetes and graft failure. Three patients needed repeated applications to complete the filling of the lesions. Median (range) pain Visual Analog Scores-on a scale of 0 to 10, where 0 = no pain, and 10 = intolerable pain were 6.3 (range 3-8) preoperatively and 0.5 (range 0-2) at first follow-up (P <= 0.001). All but 2 patients showed a progressive remodeling of the tissue gap at scheduled radiographic controls. CONCLUSIONS: To the author's knowledge, the advanced wound matrix used in this study is the only available biomaterial for the treatment of tunneled lesions. It stimulates tissue regeneration by filling surfaces which cannot be repaired spontaneously or by using conventional biomaterials in the form of sheets. Its application is atraumatic, painless, and safe. PMID- 26061491 TI - Real-world Experience With a Decellularized Dehydrated Human Amniotic Membrane Allograft. AB - While randomized controlled trials (RCTs) are designed to evaluate efficacy and/or safety under controlled conditions, use of strict inclusion/ exclusion criteria are noted to exclude more than 50% of wound populations. Applicability of RCT outcomes to performance expectations in real-world wound populations raises questions about generalizing their results. The primary aim of this decellularized, dehydrated human amniotic membrane (DDHAM) Use Registry Study was to gain experience and observe outcomes with use of a DDHAM in uninfected, full thickness, or partial-thickness wounds that, in the investigators' opinions, would benefit from such treatment. METHODS: Investigators were instructed to provide usual care regarding visit and application frequencies, concomitant therapies, and change in wound-care regimens. The only exclusions were patients with actively infected wounds or known hypersensitivity to DDHAM. Fifteen sites with practicing wound care clinicians of various specialties participated in this review, enrolling chronic wounds including venous, diabetic, pressure, collagen vascular, and arterial ulcers-all of various severities, durations, sizes, and previous treatments. Twenty-eight ulcers studied had failed 32 previous treatments with advanced biologic therapies. A total of 244 wounds were observed in this study, however, this review is limited to the 179 chronic wounds in 165 patients that were enrolled at 15 of the 19 participating centers. The 4 centers that enrolled acute wounds only were excluded. RESULTS: Results from the analysis of this very heterogeneous population demonstrated that during the usual course of an average of 8 weeks of wound management, patients experienced factors that significantly affected wound closure. These factors included wound infections, noncompliance with prescribed treatments (eg, compression, off-loading, and wound care), re-injury of the wound, and systemic comorbidities. Nearly 50% of chronic wounds (including those that failed previous therapy with advanced biologics) with an average baseline area of 3.1 cm2 achieved complete closure within a median of 6.3 weeks without product-related adverse experiences. CONCLUSION: Despite the challenges of uncontrolled factors that affect healing, this registry study demonstrated the safety and clinical benefit of DDHAM to support wound closure across a variety of chronic wound types and patient conditions in real world environments. PMID- 26061493 TI - Editorial Message: An Unexpected role model for wound Care. PMID- 26061492 TI - Fox Den Disease: An Interesting Case Following Delayed Diagnosis. AB - Pyoderma fistulans sinifica, also known as fox den disease, is a rare and poorly understood inflammatory disorder of the skin and subcutaneous tissues. This disorder is often mistaken for other inflammatory skin disorders and treated inappropriately. The authors describe the case of a 53-year-old male who presented to the colorectal surgery service with a longstanding diagnosis of perirectal Crohn's disease. Despite aggressive immunosuppression and numerous surgical procedures, the patient continued to have unrelenting purulent drainage from the skin of his buttocks. Following wide excision of the affected skin and subcutaneous tissues by the colorectal surgeon, the plastic surgery team reconstructed the 30 cm x 55 cm wound using a combination of local flaps and skin grafts. The initial pathology report of the excised specimen confirmed the presence of nonspecific abscesses and inflammation. Upon special request by the plastic surgery team, the sample was resectioned with the specific intent of establishing a diagnosis of fox den disease. The additional slides met the criteria for an unequivocal diagnosis of fox den disease. Immunosuppression was discontinued and the patient healed his wounds without complication. Fox den disease is often overlooked because of the obscurity of the disease and the special histological sectioning needed to establish a diagnosis. In this case, the patient was unnecessarily treated with immunosuppressive drugs for more than 3 decades because of a misdiagnosis. With increased awareness of fox den disease, perhaps its pathophysiology can be better elucidated as more patients are appropriately diagnosed and treated. PMID- 26061494 TI - Stable Carbon Isotope Evidence for Neolithic and Bronze Age Crop Water Management in the Eastern Mediterranean and Southwest Asia. AB - In a large study on early crop water management, stable carbon isotope discrimination was determined for 275 charred grain samples from nine archaeological sites, dating primarily to the Neolithic and Bronze Age, from the Eastern Mediterranean and Western Asia. This has revealed that wheat (Triticum spp.) was regularly grown in wetter conditions than barley (Hordeum sp.), indicating systematic preferential treatment of wheat that may reflect a cultural preference for wheat over barley. Isotopic analysis of pulse crops (Lens culinaris, Pisum sativum and Vicia ervilia) indicates cultivation in highly varied water conditions at some sites, possibly as a result of opportunistic watering practices. The results have also provided evidence for local land-use and changing agricultural practices. PMID- 26061496 TI - Structure, dynamics, and function of the monooxygenase P450 BM-3: insights from computer simulations studies. AB - The monooxygenase P450 BM-3 is a NADPH-dependent fatty acid hydroxylase enzyme isolated from soil bacterium Bacillus megaterium. As a pivotal member of cytochrome P450 superfamily, it has been intensely studied for the comprehension of structure-dynamics-function relationships in this class of enzymes. In addition, due to its peculiar properties, it is also a promising enzyme for biochemical and biomedical applications. However, despite the efforts, the full understanding of the enzyme structure and dynamics is not yet achieved. Computational studies, particularly molecular dynamics (MD) simulations, have importantly contributed to this endeavor by providing new insights at an atomic level regarding the correlations between structure, dynamics, and function of the protein. This topical review summarizes computational studies based on MD simulations of the cytochrome P450 BM-3 and gives an outlook on future directions. PMID- 26061495 TI - Investigation of Gene Regulatory Networks Associated with Autism Spectrum Disorder Based on MiRNA Expression in China. AB - Autism spectrum disorder (ASD) comprise a group of neurodevelopmental disorders characterized by deficits in social and communication capacities and repetitive behaviors. Increasing neuroscientific evidence indicates that the neuropathology of ASD is widespread and involves epigenetic regulation in the brain. Differentially expressed miRNAs in the peripheral blood from autism patients were identified by high-throughput miRNA microarray analyses. Five of these miRNAs were confirmed through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. A search for candidate target genes of the five confirmed miRNAs was performed through a Kyoto encyclopedia of genes and genomes (KEGG) biological pathways and Gene Ontology enrichment analysis of gene function to identify gene regulatory networks. To the best of our knowledge, this study provides the first global miRNA expression profile of ASD in China. The differentially expressed miR-34b may potentially explain the higher percentage of male ASD patients, and the aberrantly expressed miR-103a-3p may contribute to the abnormal ubiquitin-mediated proteolysis observed in ASD. PMID- 26061497 TI - Modeling Behavior by Coastal River Otter (Lontra Canadensis) in Response to Prey Availability in Prince William Sound, Alaska: A Spatially-Explicit Individual Based Approach. AB - Effects of climate change on animal behavior and cascading ecosystem responses are rarely evaluated. In coastal Alaska, social river otters (Lontra Canadensis), largely males, cooperatively forage on schooling fish and use latrine sites to communicate group associations and dominance. Conversely, solitary otters, mainly females, feed on intertidal-demersal fish and display mutual avoidance via scent marking. This behavioral variability creates "hotspots" of nutrient deposition and affects plant productivity and diversity on the terrestrial landscape. Because the abundance of schooling pelagic fish is predicted to decline with climate change, we developed a spatially-explicit individual-based model (IBM) of otter behavior and tested six scenarios based on potential shifts to distribution patterns of schooling fish. Emergent patterns from the IBM closely mimicked observed otter behavior and landscape use in the absence of explicit rules of intraspecific attraction or repulsion. Model results were most sensitive to rules regarding spatial memory and activity state following an encounter with a fish school. With declining availability of schooling fish, the number of social groups and the time simulated otters spent in the company of conspecifics declined. Concurrently, model results suggested an elevation of defecation rate, a 25% increase in nitrogen transport to the terrestrial landscape, and significant changes to the spatial distribution of "hotspots" with declines in schooling fish availability. However, reductions in availability of schooling fish could lead to declines in otter density over time. PMID- 26061499 TI - [AMP Student: Vision and Point of View]. PMID- 26061498 TI - Validation of Perfusion Quantification with 3D Gradient Echo Dynamic Contrast Enhanced Magnetic Resonance Imaging Using a Blood Pool Contrast Agent in Skeletal Swine Muscle. AB - The purpose of our study was to validate perfusion quantification in a low perfused tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with shared k-space sampling using a blood pool contrast agent. Perfusion measurements were performed in a total of seven female pigs. An ultrasonic Doppler probe was attached to the right femoral artery to determine total flow in the hind leg musculature. The femoral artery was catheterized for continuous local administration of adenosine to increase blood flow up to four times the baseline level. Three different stable perfusion levels were induced. The MR protocol included a 3D gradient-echo sequence with a temporal resolution of approximately 1.5 seconds. Before each dynamic sequence, static MR images were acquired with flip angles of 5 degrees , 10 degrees , 20 degrees , and 30 degrees . Both static and dynamic images were used to generate relaxation rate and baseline magnetization maps with a flip angle method. 0.1 mL/kg body weight of blood pool contrast medium was injected via a central venous catheter at a flow rate of 5 mL/s. The right hind leg was segmented in 3D into medial, cranial, lateral, and pelvic thigh muscles, lower leg, bones, skin, and fat. The arterial input function (AIF) was measured in the aorta. Perfusion of the different anatomic regions was calculated using a one- and a two-compartment model with delay- and dispersion-corrected AIFs. The F-test for model comparison was used to decide whether to use the results of the one- or two-compartment model fit. Total flow was calculated by integrating volume-weighted perfusion values over the whole measured region. The resulting values of delay, dispersion, blood volume, mean transit time, and flow were all in physiologically and physically reasonable ranges. In 107 of 160 ROIs, the blood signal was separated, using a two compartment model, into a capillary and an arteriolar signal contribution, decided by the F-test. Overall flow in hind leg muscles, as measured by the ultrasound probe, highly correlated with total flow determined by MRI, R = 0.89 and P = 10-7. Linear regression yielded a slope of 1.2 and a y-axis intercept of 259 mL/min. The mean total volume of the investigated muscle tissue corresponds to an offset perfusion of 4.7mL/(min ? 100cm3). The DCE-MRI technique presented here uses a blood pool contrast medium in combination with a two-compartment tracer kinetic model and allows absolute quantification of low-perfused non cerebral organs such as muscles. PMID- 26061500 TI - [Ten Achievements for 35 Years of the Portuguese National Health Service (1979 2015): Looking Back, Planning the Future]. PMID- 26061501 TI - [Freedom of Choice in the National Health Service--the Case of HIV]. PMID- 26061502 TI - [Health Communication: Preventing the Spread of Ebola Virus Disease in the Portuguese Spoken African Countries--Methodology KISS & KEYWORDS]. AB - In this work, Health Communication is considered as an important discipline in medicine and health sciences for his role as true determinant of health. We highlight their contribution to health promotion and disease prevention. Thus, the Health Communication Plan (PCS): Preventing the spread of Ebola virus disease in the Portuguese Speaking African Countries - KISS & KEYWORDS methodology is a tool that aims to minimize the risk of infection by Ebola virus in the Portuguese Speaking African Countries and also train for a general improvement of health conditions of the local populations. In the PCS design are especially considered the social and cultural contexts of the target populations, especially the customs, traditions and religion. Health Communication is considered as an Essential Function of Public Health and its main is to provide a population-based approach. The target of communication actions are population groups in addition to the individual communication, target-audiences are people without access to the media, in Guinea Bissau, Cape Verde and Sao Tome and Principe. Under the communication plan uses the methodology, models and practices both by media professionals as health. A proximity approach and cultural mediation, previously identified key facts, are defined objectives; outlines to the Plan in concrete and its implementation methodology (target-audience and following intervention, materials to be used and key-messages and partners to mobilize) following the World Health Organisation standards. PMID- 26061503 TI - [Analysis of the Cochrane Review: Electronic Cigarettes for Smoking Cessation and Reduction. Cochrane Database Syst Rev. 2014,12: CD010216]. AB - Smoking is one of the most important risk factors for various cardiovascular, cancer and respiratory diseases. There are a number of smoking cessation techniques involving psychological, pharmacological and behavioral interventions, with varying effectiveness and different costs. The electronic cigarettes are devices which produce a nicotine aerosol but without the toxic products of tobacco smoke, and they have become popular as a potential intervention for smoking cessation. The present review analyzed the evidence published of this approach for the treatment of tobacco dependence and concluded that there is reasonable evidence of its clinical effectiveness. We present and discuss the findings of this systematic review, with practical contextualization. PMID- 26061504 TI - [Normative Database of Optical Coherence Tomography Parameters in Childhood]. AB - INTRODUCTION: Optical coherence tomography is a technology that allows obtaining high resolution images of tissues in vivo, enabling the measurement of ocular structures, including the retinal nerve fiber layer and macular thickness. As a noninvasive test it's particularly useful in children, but its applicability is limited by the existence of normative values for adults only. PURPOSE: To establish the pediatric normative values of retinal nerve fiber layer thickness and macular thickness and to investigate its relationship with sex, age, refraction, eye side and ocular dominance. MATERIAL AND METHODS: Ophthalmologic examination and Cirrus HD-optical coherence tomography (Carl Zeiss Meditec) were carried out on 153 children aged 4 to 17 years old. RESULTS: We obtained a mean retinal nerve fiber layer average thickness of 97.90 MUm. No significant differences were detected between genders, however the eye side and ocular dominance had significant influence on retinal nerve fiber layer thickness. Retinal nerve fiber layer thickness increased significantly with more positive refraction. With the Macular Cube 512 x 128 protocol we found that the average central subfield showed the smallest thickness (250.35 MUm) and boys had higher macular thickness. DISCUSSION: The values of the retinal nerve fiber layer thickness and macular thickness obtained are comparable to recent studies. The distribution of retinal nerve fiber layer thickness in quadrants is in agreement with the normal distribution of retinal nerve fiber layer. Macular thickness proved to be higher in males (center field and inner ring), data consistent with previous studies. CONCLUSION: We establish the normative retinal nerve fiber layer thickness and macular thickness in healthy Portuguese children. These data enhance the evaluation and interpretation of parameters obtained by optical coherence tomography in the diagnosis of pediatric disorders in clinical practice. PMID- 26061505 TI - [Complex Congenital Heart Disease: The Influence of Prenatal Diagnosis]. AB - INTRODUCTION: Complex congenital heart disease is a group of severe conditions. Prenatal diagnosis has implications on morbidity and mortality for most severe conditions. The purpose of this work was to evaluate the influence of prenatal diagnosis and distance of residence and birth place to a reference center, on immediate morbidity and early mortality of complex congenital heart disease. MATERIAL AND METHODS: Retrospective study of complex congenital heart disease patients of our Hospital, born between 2007 and 2012. RESULTS: There were 126 patients born with complex congenital heart disease. In 95%, pregnancy was followed since the first trimester, with prenatal diagnosis in 42%. There was a statistically significant relation between birth place and prenatal diagnosis. Transposition of great arteries was the most frequent complex congenital heart disease (45.2%), followed by pulmonary atresia with ventricular septal defect (17.5%) and hypoplastic left ventricle (9.5%). Eighty-two patients (65.1%) had prostaglandin infusion and 38 (30.2%)were ventilated before an intervention. Surgery took place in the neonatal period in 73%. Actuarial survival rate at 30 days, 12 and 24 months was 85%, 80% and 75%, respectively. There was no statistically significant relation between prenatal diagnosis and mortality. DISCUSSION: Most patients with complex congenital heart disease did not have prenatal diagnosis. All cases with prenatal diagnosis were born in a tertiary center. Prenatal diagnosis did not influence significantly neonatal mortality, as already described in other studies with heterogeneous complex heart disease. CONCLUSION: prenatal diagnosis of complex congenital heart disease allowed an adequate referral. Most patients with complex congenital heart disease werenaAot diagnosed prenatally. This data should be considered when planning prenatal diagnosis of congenital heart disease. PMID- 26061506 TI - [SAIMI Study--Health and Health Care Access by Immigrants from the Indian Subcontinent in Lisbon: What Recommendations for Equitable and Culturally Adequate Health Care?]. AB - INTRODUCTION: The growth of the immigrant population in Portugal has been consistent over the past decades. Nevertheless, information on the health of immigrant populations is scarce. This research uses data collected from the population from the Indian subcontinent living in the district of Lisbon to produce recommendations for the provision of culturally adapted health services. MATERIAL AND METHODS: Cross-sectional study with the immigrant community of the Indian subcontinent (Bangladesh, India and Pakistan) living in Lisbon, selected based on a snowball sampling technique and using privileged access interviewers. The questionnaire focused on health, health care access, lifestyle and attitudes towards death. The data were subject to a descriptive analysis and an age standardized comparison between the three nationalities was made. RESULTS: Surveys were administered to 1011 individuals with a participation rate of 97%. Most participants were adult males. Indian immigrants most frequently reported barriers to use of health services and had a higher frequency of chronic diseases. Pakistani immigrants had worse lifestyle indicators. DISCUSSION: The immigrant population from the Indian subcontinent tends to report more language difficulties in health care access when compared with other immigrant populations. Based on recommendations of the World Health Organization, it was possible to adapt this knowledge to produce recommendations adapted to the Portuguese context. CONCLUSION: There are several aspects in the management of health services in Portugal that can be better adapted to the immigrant population from the Indian subcontinent. PMID- 26061507 TI - [Fiability Study of Diabetes Empowerment Scale: Short Version]. AB - PURPOSE: To compare the final score of the scale to the levels of HbA1c. MATERIAL AND METHODS: Cross-sectional observational study by applying the Diabetes Empowerment Scale-Short Form to diabetics at three primary care units in the central region of Portugal. The test-retest (in writing first and, five minutes later, orally) was performed to access Cronbach's alpha in 20 patients not studied in the next phase. Then, the scale was applied to diabetic patients after nursing consultation and prior to entering the medical consultation. Descriptive and inferential statistics after checking for the normality of the data were performed. RESULTS: In the first phase Cronbach's alpha was 0.90 to 1.00 in all of eight scale items. The average result obtained in the written phase was 3.78 +/- 0.71 and in the oral 3.79 +/- 0.64, p = 0.629. The sample of the second stage was of 81 diabetic patients, 55.6% male. Sample's mean age was 68.5 +/- 1.1 years, mean HbA1c of 6.8 +/- 0.2 and mean time from diagnosis of 9.2 +/- 0.9 years. The average final score of the scale was 4.1+/- 0.8. There was significant correlation between the final score and HbA1c levels (p= -0.114; p = 0.312). CONCLUSION: The Portuguese version of the Diabetes Empowerment Scale-Short Form proved to be a reliable scale to measure empowerment in diabetic patients in Portugal. It was evident the presence of a statistically significant correlation between the results obtained at the end of the scale and HbA1c. PMID- 26061508 TI - [The Epidemiology of Dementia and Alzheimer Disease in Portugal: Estimations of Prevalence and Treatment-Costs]. AB - INTRODUCTION: The incidence and prevalence of global dementia and Alzheimer's disease (AD) increase with age, almost doubling every five years after the sixth decade of life. Demographic aging is a reality in Portugal, being expectable that the number of dementia cases also increases. Even so, dementia-epidemiological data in Portugal is scarce and cost-of-illness studies are almost inexistent. Our aims were to obtain up-to-date information about the prevalence of dementia/ Alzheimer's disease in Portugal, to estimate the number of cases effectively diagnosed as Alzheimer's disease and to determine illness-costs with specific dementia treatment. MATERIAL AND METHODS: The numbers of age-adjusted prevalence of dementia obtained for Occidental Europe (Alzheimer's Disease International study), where applied to the resident population in Portugal (2013). Estimations related to diagnosis and treatment-costs were based in data provided by the Intercontinental Marketing Services Health (IMSH)-2013. RESULTS: The estimated number of Portuguese people with dementia among those aged >=60 years, is 160,287, representing 5.91% of this population-stratum. Knowing Alzheimer's disease is responsible for 50-70% of all cases, we might conclude there are between 80,144 and 112,201 patients. According to IMSH-data, 76250 receive anti dementia drugs and the costs of this kind of medication is 37 M?!/year. CONCLUSIONS: As a consequence of the demographic aging, also the number of dementia cases increases. Apparently, not all Alzheimer's disease patients receive the recommended medication, suggesting this condition is still under diagnosed. However, figures indicate a positive progression with an increment of treated cases and a reduction of medication-costs. PMID- 26061509 TI - [Comparing the Application of Hema-Obs RSS to 250 Pregnancies from Obstetrics/Hematology Consultation in Centro Hospitalar Sao Joao, Portugal with the Application of Galit Sarig RSS to 90 Pregnancies from Rambam Health Care Campus, Israel]. AB - INTRODUCTION: Pregnant women with thromboembolic diseases, previous thrombotic episodes or thrombophilia family history were supervised in a multidisciplinary Obstetrics/ Hematology consultation in Centro Hospitalar Sao Joao EPE, Porto, Portugal. For the evaluation and medication of these women, a risk stratification scale was used. PURPOSES: The aim of this study was to validate a Risk Stratification Scale and thromboprophylaxis protocol by means of comparing it with a similar scale, developed and published by Sarig. MATERIAL AND METHODS: We have compared: The distribution, by risk groups, obtained through the application of the two scales on pregnant women followed at Centro Hospitalar Sao Joao, Porto, Portugal, consultation; the sensibility and specificity for each one of the scales (DeLong scale, applied to Receiver Operating Characteristic) curves; the outcomes in pregnancies followed in Hospital Sao Joao, Porto, PortugalResults: According to our Hema-Obs risk stratification scale, 29% were allocated to low-risk, 47% to high-risk and 24% to very-high-risk groups. According to Galit Sarig risk stratification scale, 24% were considered low-risk, 53% moderate, 16% high-risk and 7% as very high-risk group. In our study we observed 9% of spontaneous abortions, in comparison with 18% in the Galit Sarig cohort. From the application of Receiver Operating Characteristic curve to both risk stratification scales, the results of the calculated areas were 58,8% to our Hema-Obs risk stratification scale and 38,7% to Galit Sarig risk stratification scale, with a Delong test significancie of p = 0.0006. CONCLUSIONS: We concluded that Hema-Obs risk stratification scale is an effective support for clinical monitoring of therapeutic strategies. PMID- 26061510 TI - [Disciplinary Actions in Gynecology and Obstetrics in the North of Portugal from Year 2008 to 2012]. AB - INTRODUCTION: Disciplinary actions may have a significant impact in medical doctors' and patients' lives. The objective of this study was the assessment of the disciplinary actions in Obstetrics and Gynecology that occurred in the north of Portugal in years 2008 to 2012. MATERIAL AND METHODS: Retrospective descriptive study based on the anonymized data contained in the annual activity reports of Conselho Disciplinar da Secao Regional Norte da Ordem dos Medicos from 2008 to 2012. We calculated the proportion of disciplinary actions in Obstetrics and Gynaecology over the total number of registered specialists in that speciality. We also analysed the type of complainers, accused, institutions, complaints and decisions. For statistical inference proportions with 95% confidence intervals were estimated. RESULTS: From years 2008 to 2012, we registered 1040 complaints in all medical specialities in the north of Portugal. Obstetrics and Gynecology was the forth most affected specialty, with a total of 54 complaints. Forty-three complaints were related with medical malpractice and if we only consider this type of complaint Obstetrics and Gynecology was the most affected specialty. The most frequent complainers and accused were, respectively, patients themselves and female physicians, with 41 to 60 years of age. Fifty-two complaints were archived without punishment while two still await conclusion. DISCUSSION: The overall results of this study are in agreement with those reported by other authors. CONCLUSIONS: Obstetrics and Gynecology was the forth speciality with highest risk for any disciplinary action in the north of Portugal in years 2008 to 2012 and the first one in relation with alleged negligence. All presented and already concluded complaints were archived without penalty, except two that are still under evaluation. PMID- 26061511 TI - [Bone Fractures in a Neonatal Intensive Care Unit]. AB - INTRODUCTION: Fractures during the neonatal period are rare. Some fractures, especially long bones, may occur during birth. Moreover, neonates hospitalized in the Neonatal Intensive Care Unit have an increased risk of fractures for several reasons. OBJECTIVE: To evaluate the incidence and characterize fractures in newborns admitted in a tertiary Neonatal Intensive Care Unit. MATERIAL AND METHODS: A retrospective analysis of the newborns admitted to the Neonatal Intensive Care Unit with a diagnosis at discharge of one or more bone fractures from January 1996 to June 2013. RESULTS: Eighty neonates had one or more fractures. In 76 (95%) infants the fractures were attributed to birth injury. The most common fracture was the clavicle fracture in 60 (79%) neonates, followed by skull fracture in 6 (8%). In two (2.5%) neonates, extremely low birth weight infants, fractures were interpreted as resulting from osteopenia of prematurity. Both had multiple fractures, and one of them with several ribs. CONCLUSION: A change in obstetric practices allied to improvement premature neonateaAos care contributed to the decreased incidence of fractures in neonatal period. But in premature infants the diagnosis may be underestimated, given the high risk of fracture that these infants present. PMID- 26061513 TI - [Pharmacovigilance in Portugal: Activity of the Central Pharmacovigilance Unit]. AB - INTRODUCTION: The aim of this study was to characterize the spontaneous reports of adverse events that were received by the Central Portugal Regional Pharmacovigilance Unit. MATERIAL AND METHODS: Spontaneous reports received between 01/2001 and 12/2013 were considered. The annual reporting ratios were estimated. The cases were characterized according to their seriousness, previous description, causality assessment, origin and professional group of the reporter, type of adverse event and pharmacotherapeutic groups of the suspected drugs most frequently reported. RESULTS: The Pharmacovigilance Unit received 2408 reports that contained 5749 adverse events. In 2013, the reporting rate was estimated at 171 reports per million inhabitants. Fifty-five percent of the reports were assessed as serious. Ninety percent of the cases were assessed as being at least possibly related with the suspected drug. The suspected drugs most frequently reported were anti-infectives for systemic use (n = 809, 33%). The most frequently reported adverse events were "Skin and subcutaneous tissue disorders" (n = 1139, 20%). There were 154 (6.4%) reports resulting in life-threatening situations and/or death, and 88 (3.6%) containing at least one adverse event assessed as serious, unknown and certain or probable. DISCUSSION: The present results are in line with those found in other studies, namely the seriousness and type of the adverse events and the pharmacotherapeutic groups of the most frequently reported suspected drugs. CONCLUSION: In the last years, the Central Portugal Regional Pharmacovigilance Unit has registered a growth in the reporting rate in general, as well as an increase in the reporting of unknown and serious adverse drug reactions. PMID- 26061512 TI - [Career Satisfaction of Medical Residents in Portugal]. AB - INTRODUCTION: The satisfaction with the medical profession has been identified as an essential factor for the quality of care, the wellbeing of patients and the healthcare systems' stability. Recent studies have emphasized a growing discontent of physicians, mainly as a result of changes in labor relations. OBJECTIVES: To assess the perception of Portuguese medical residents about: correspondence of residency with previous expectations; degree of satisfaction with the specialty, profession and place of training; reasons for dissatisfaction; opinion regarding clinical practice in Portugal and emigration intents. MATERIAL AND METHODS: Cross-sectional study. Data collection was conducted through the "Satisfaction with Specialization Survey", created in an online platform, designed for this purpose, between May and August 2014. RESULTS: From a total population of 5788 medical residents, 804 (12.25 %) responses were obtained. From this sample, 77% of the responses were from residents in the first three years. Results showed that 90% of the residents are satisfied with their specialty, 85% with the medical profession and 86% with their place of training. Nevertheless, results showed a decrease in satisfaction over the final years of residency. The overall assessment of the clinical practice scenario in Portugal was negative and 65% of residents have plans to emigrate after completing their residency. CONCLUSION: Portuguese residents revealed high satisfaction levels regarding their profession. However, their views on Portuguese clinical practice and the results concerning the intent to emigrate highlight the need to take steps to reverse this scenario. PMID- 26061514 TI - [Obesity: Paradigm of Endothelial Dysfunction in Paediatric Age Groups]. AB - INTRODUCTION: Obesity is considered a global epidemic with important public health issues as it is an independent risk factor in the development of cardiovascular disorders. MATERIAL AND METHODS: Approximately 10% of the worldaAos paediatric population has excess weight or obesity and 40% of these will be obese adults. Obesity is characterized by a chronic, low grade, pro inflammatory process that ultimately results in endothelial dysfunction, the trigger lesion leading to adult cardiovascular disease. This leads to an imbalance in the synthesis of mediators that normally regulate vascular homeostasis, particularly nitric oxide bioavailability, favoring a pro atherosclerotic status, the hallmark of cardiovascular disorders. RESULTS: These changes begin early in childhood and anatomopathological studies in children with excess weight or obesity have shown endothelial changes that represent the precursors of the atherosclerotic lesion. DISCUSSION: Endothelial dysfunction is the earliest manifestation of the atherosclerotic lesion. It is evident in obese children and, as such, it potentially contributes towards cardiovascular disease in the adult. CONCLUSION: Although the clinical impact of these changes rarely manifest themselves in infancy, the presence of related biomarkers as well as vascular morphological changes can, at this early stage, be found and assessed. PMID- 26061515 TI - Prostate Cancer: The Role of Multiparametric Magnetic Resonance Imaging. AB - Multiparametric magnetic resonance imaging has been increasingly used for detection, localization and staging of prostate cancer over the last years. It combines high-resolution T2 weighted-imaging and at least two functional techniques, which include dynamic contrast-enhanced magnetic resonance imaging, diffusion-weighted imaging, and magnetic resonance imaging spectroscopy. Although the combined use of a pelvic phased-array and an endorectal coil is considered the state-of-the-art for magnetic resonance imaging evaluation of prostate cancer, endorectal coil is only absolute mandatory for magnetic resonance imaging spectroscopy at 1.5 T. Sensitivity and specificity levels in cancer detection and localization have been improving with functional technique implementation, compared to T2 weighted-imaging alone. It has been particularly useful to evaluate patients with abnormal PSA and negative biopsy. Moreover, the information added by the functional techniques may correlate to cancer aggressiveness and therefore be useful to select patients for focal radiotherapy, prostate sparing surgery, focal ablative therapy and active surveillance. However, more studies are needed to compare the functional techniques and understand the advantages and disadvantages of each one. This article reviews the basic principles of prostatic mp-magnetic resonance imaging, emphasizing its role on detection, staging and active surveillance of prostate cancer. PMID- 26061516 TI - [Deep Vein Thrombosis Prophylaxis in Patients with Traumatic Brain Injury]. AB - INTRODUCTION: The risk of deep vein thrombosis is increased in patients with head trauma, but the prophylaxis against this event is confronted with the possible risk of worsening hemorrhagic injuries. In this article, we present an overview about deep vein thrombosis prophylaxis in patients with head trauma and we propose a practical protocol for clinical management of deep vein thrombosis prophylaxis. MATERIAL AND METHODS: We reviewed relevant papers cited in the Medline/PubMed, Cochrane, and Scielo databases from January 1998 to January 2014. Based on a search with the following search expression: "deep venous thrombosis and prophylaxis and traumatic brain injury", we found 44 eligible articles. Twenty-three papers were selected using criteria as published in English or Portuguese, patients in acute phase of moderate and severe traumatic brain injury and noninvasive mechanical prophylaxis or chemistry. RESULTS: Head trauma alone is a risk factor for deep vein thrombosis. The chance of deep vein thrombosis is 2.59 times higher in patients with head trauma. The prevalence of deep vein thrombosis and pulmonary embolism in patients who have suffered head trauma is 20% in the literature, reaching 30% in some studies. DISCUSSION AND CONCLUSION: Head trauma alone is a risk factor for deep vein thrombosis and pulmonary thromboembolism and the risks inherent in this disease requires methods of prevention for these complications. Clinical trials are needed to establish the efficacy of prophylaxis and the best time to start medication for deep vein thrombosis in patients with traumatic brain injury. PMID- 26061517 TI - [Bilateral Optic Disc Edema Secondary to Amiodarone: Manifestation of an Iatrogenic Optic Neuropathy]. AB - A 69-years-old male patient was treated with amiodarone 200mg/day over the passed two months for atrial fibrillation. He presented a sudden, painless and unilateral visual loss. Ophthalmologic evaluation revealed a bilateral optic disc edema. Neurological examination was otherwise unremarkable. After properly excluding increased intracranial pressure and giant cell arteritis, the main differential diagnosis was between nonarteritic anterior ischemic optic neuropathy and optic neuropathy secondary to amiodarone. The latter diagnosis was favored due to a presence of bilateral and simultaneous optic disc edema, gradual improvement of symptoms after discontinuation of the drug, and, mostly, by persistence of optic disc edema beyond 6 weeks. Of note, an acute presentation of this disorder is common. Amiodarone optic neuropathy is a rare but potentially serious cause of optic nerve dysfunction, and its discontinuation is usually warrant. PMID- 26061519 TI - [Rickets: Emerging From the Past]. AB - In the past decade rickets has re-emerged in developed countries due to changes in lifestyles and dietary habits. We describe a case of a 28-month-old black infant with failure to thrive. He was exclusively breastfed until nine months of age, without vitamin supplementation, and never ingested milk products due to alleged cowaAos milk intolerance. His examination revealed bowlegs, rachitic rosary and wide wrists. Alkaline phosphatase and intact parathyroid hormone levels were elevated, and calcidiol was decreased. Radiographic images showed bone demineralization, fraying and cupping of the distal radius and ulna. Nutritional rickets was considered and treatment with colecalciferol and calcium carbonate was initiated, with clinical, laboratory and radiologic improvement. In this case, a group of factors contributed to severe nutritional rickets, alerting to the re-emergence of this disease. PMID- 26061518 TI - [Bronchopleurocutaneous Fistula: A Rare Complication of Pulmonary Tuberculosis]. AB - INTRODUCTION: Multiple complications can occur in tuberculosis. Bronchopleurocutaneous fistula is a pathological communication between bronchus, pleural space and skin. CLINICAL CASE: We present a 47 year-old male patient, schizophrenic, who presented with complaints of pleuritic chest pain, cough and weight loss. The patient was cachectic with purulent drainage from an orifice in the antero-lateral left chest wall. In this drainage acid-fast bacilli were identified and chest radiograph showed bilateral infiltrates. He was admitted to the Infectious Diseases Department with the diagnosis of fistulized pulmonary tuberculosis, confirmed by visualization of acid-fast bacilli, positive polymerase chain reaction and cultures for Mycobacterium tuberculosis in the sputum. The patient was started on quadruple antituberculosis therapy and had a favorable outcome. CONCLUSIONS: Bronchopleurocutaneous fistula is a rare complication of pulmonary tuberculosis. Despite pulmonary tuberculosis being a common condition in our country, the rarity of this complication prompted the authors to present it. PMID- 26061520 TI - [Endotracheal Kaposi's Sarcoma]. PMID- 26061521 TI - [Carcinoma Erysipeloides]. PMID- 26061522 TI - [Tips for a Title]. PMID- 26061523 TI - [The Hell: Some Reflexions on Moral and Deontology]. PMID- 26061525 TI - Unexpected Positive Buoyancy in Deep Sea Sharks, Hexanchus griseus, and a Echinorhinus cookei. AB - We do not expect non air-breathing aquatic animals to exhibit positive buoyancy. Sharks, for example, rely on oil-filled livers instead of gas-filled swim bladders to increase their buoyancy, but are nonetheless ubiquitously regarded as either negatively or neutrally buoyant. Deep-sea sharks have particularly large, oil-filled livers, and are believed to be neutrally buoyant in their natural habitat, but this has never been confirmed. To empirically determine the buoyancy status of two species of deep-sea sharks (bluntnose sixgill sharks, Hexanchus griseus, and a prickly shark, Echinorhinus cookei) in their natural habitat, we used accelerometer-magnetometer data loggers to measure their swimming performance. Both species of deep-sea sharks showed similar diel vertical migrations: they swam at depths of 200-300 m at night and deeper than 500 m during the day. Ambient water temperature was around 15 degrees C at 200-300 m but below 7 degrees C at depths greater than 500 m. During vertical movements, all deep-sea sharks showed higher swimming efforts during descent than ascent to maintain a given swimming speed, and were able to glide uphill for extended periods (several minutes), indicating that these deep-sea sharks are in fact positively buoyant in their natural habitats. This positive buoyancy may adaptive for stealthy hunting (i.e. upward gliding to surprise prey from underneath) or may facilitate evening upward migrations when muscle temperatures are coolest, and swimming most sluggish, after spending the day in deep, cold water. Positive buoyancy could potentially be widespread in fish conducting daily vertical migration in deep-sea habitats. PMID- 26061524 TI - Relationship between cytokine expression patterns and clinical outcomes: two population-based birth cohorts. AB - BACKGROUND: Models that incorporate patterns of multiple cytokine responses to allergens, rather than individual cytokine production, may better predict sensitization and asthma. OBJECTIVE: To characterize the patterns of peripheral blood mononuclear cells' (PBMCs) cytokine responses to house dust mite (HDM) allergens among children from two population-based birth cohorts using machine learning techniques. METHODS: PBMCs collected at 8 years of age from the UK Manchester Asthma and Allergy Study (n = 268) and at 14 years of age from the Australian Raine Study (n = 1374) were cultured with HDM extract (10 MUg/ml). Cytokine expression (IL-13, IL-5, IFN-gamma, and IL10) was measured in the supernatant. Cytokine patterns were identified using a Gaussian mixture model clustering, and classification stability was assessed by bootstrapping. RESULTS: A six-class model indicated complex latent structure of cytokine expression. Based on the characteristics of each class, we designated them as follows: 'Nonresponders' (n = 905, 55%); 'IL-10 responders' (n = 49, 3%); 'IFN-gamma and IL-13 medium responders' (n = 56, 3.4%); 'IL-13 medium responders' (n = 351, 21.4%); 'IL-5 and IL-13 medium responders' (n = 77, 4.7%); and 'IL-13 and IL-5 high responders' (n = 204, 12.4%). 'IL-13 and IL-5 high responders' were at much higher risk of HDM sensitization and asthma compared to all other classes, with 88% of children assigned to this class being sensitized and 28.5% having asthma. CONCLUSION: Using model-based clustering, we identified several distinct patterns of cytokine response to HDM and observed interplay between cytokine expression level, cytokine patterns (especially IL-13 and IL-5), and clinical outcomes. 'IL 13 and IL-5 high responders' class was strongly associated with HDM sensitization. However, among HDM-sensitized children, one-third showed no PBMC response to HDM, and the majority of HDM-sensitized children did not have asthma or wheeze. Our findings suggest that positive HDM 'allergy tests' and asthma are associated with a broad range of immunophenotypes, which may have important implications for the use of cytokine-targeted treatment approaches. PMID- 26061526 TI - Earlier Menarche Is Associated with Lower Insulin Sensitivity and Increased Adiposity in Young Adult Women. AB - OBJECTIVE: We aimed to assess whether age at menarche was associated with insulin sensitivity in young adult women. METHODS: We studied 54 healthy young women aged 20-30 years. Participants were grouped according to age at menarche: Early (<=11.0 years; n=13), Average (>12.0 and <=13.0 years; n=28), and Late (>=14.0 years, n=13). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman's minimal model. Body composition was assessed using whole-body dual-energy X-ray absorptiometry. RESULTS: Earlier menarche was associated with lower insulin sensitivity (p=0.015). There was also a continuous increase in adiposity with younger age at menarche, which was associated with increased weight (p=0.001), BMI (p=0.002), total body fat (p=0.049), and truncal fat (p=0.020). Stratified analyses showed that insulin sensitivity in Early women (5.5 x10-4.min-1(mU/l)) was lower than in Average (8.0 x10-4.min-1(mU/l), p=0.021) and Late (8.6 x10-4.min-1(mU/l), p=0.033) groups. Early women (weight=66.1 kg; BMI=24.1 kg/m2) were considerably heavier and fatter than Average (59.0 kg, p=0.004; 21.4 kg/m2, p=0.002) and Late (57.0 kg, p=0.001; 20.8 kg/m2, p=0.0009) women. CONCLUSIONS: Early menarche is associated with lower insulin sensitivity and increased adiposity in young adulthood, potentially increasing the risk of type 2 diabetes and the metabolic syndrome later in life. PMID- 26061527 TI - Prioritising Infectious Disease Mapping. AB - BACKGROUND: Increasing volumes of data and computational capacity afford unprecedented opportunities to scale up infectious disease (ID) mapping for public health uses. Whilst a large number of IDs show global spatial variation, comprehensive knowledge of these geographic patterns is poor. Here we use an objective method to prioritise mapping efforts to begin to address the large deficit in global disease maps currently available. METHODOLOGY/PRINCIPAL FINDINGS: Automation of ID mapping requires bespoke methodological adjustments tailored to the epidemiological characteristics of different types of diseases. Diseases were therefore grouped into 33 clusters based upon taxonomic divisions and shared epidemiological characteristics. Disability-adjusted life years, derived from the Global Burden of Disease 2013 study, were used as a globally consistent metric of disease burden. A review of global health stakeholders, existing literature and national health priorities was undertaken to assess relative interest in the diseases. The clusters were ranked by combining both metrics, which identified 44 diseases of main concern within 15 principle clusters. Whilst malaria, HIV and tuberculosis were the highest priority due to their considerable burden, the high priority clusters were dominated by neglected tropical diseases and vector-borne parasites. CONCLUSIONS/SIGNIFICANCE: A quantitative, easily-updated and flexible framework for prioritising diseases is presented here. The study identifies a possible future strategy for those diseases where significant knowledge gaps remain, as well as recognising those where global mapping programs have already made significant progress. For many conditions, potential shared epidemiological information has yet to be exploited. PMID- 26061529 TI - Multifunctional SA-PProDOT Binder for Lithium Ion Batteries. AB - An environmentally benign, highly conductive, and mechanically strong binder system can overcome the dilemma of low conductivity and insufficient mechanical stability of the electrodes to achieve high performance lithium ion batteries (LIBs) at a low cost and in a sustainable way. In this work, the naturally occurring binder sodium alginate (SA) is functionalized with 3,4 propylenedioxythiophene-2,5-dicarboxylic acid (ProDOT) via a one-step esterification reaction in a cyclohexane/dodecyl benzenesulfonic acid (DBSA)/water microemulsion system, resulting in a multifunctional polymer binder, that is, SA-PProDOT. With the synergetic effects of the functional groups (e.g., carboxyl, hydroxyl, and ester groups), the resultant SA-PProDOT polymer not only maintains the outstanding binding capabilities of sodium alginate but also enhances the mechanical integrity and lithium ion diffusion coefficient in the LiFePO4 (LFP) electrode during the operation of the batteries. Because of the conjugated network of the PProDOT and the lithium doping under the battery environment, the SA-PProDOT becomes conductive and matches the conductivity needed for LiFePO4 LIBs. Without the need of conductive additives such as carbon black, the resultant batteries have achieved the theoretical specific capacity of LiFePO4 cathode (ca. 170 mAh/g) at C/10 and ca. 120 mAh/g at 1C for more than 400 cycles. PMID- 26061530 TI - CdSe Nanowire-Based Flexible Devices: Schottky Diodes, Metal-Semiconductor Field Effect Transistors, and Inverters. AB - Novel CdSe nanowire (NW)-based flexible devices, including Schottky diodes, metal semiconductor field-effect transistors (MESFETs), and inverters, have been fabricated and investigated. The turn-on voltage of a typical Schottky diode is about 0.7 V, and the rectification ratio is larger than 1 * 10(7). The threshold voltage, on/off current ratio, subthreshold swing, and peak transconductance of a typical MESFET are about -0.3 V, 4 * 10(5), 78 mV/dec, and 2.7 MUS, respectively. The inverter, constructed with two MESFETs, exhibits clear inverting behavior with the gain to be about 28, 34, and 38, at the supply voltages (V(DD)) of 3, 5, and 7 V, respectively. The inverter also shows good dynamic behavior. The rising and falling times of the output signals are about 0.18 and 0.09 ms, respectively, under 1000 Hz square wave signals input. The performances of the flexible devices are stable and reliable under different bending conditions. Our work demonstrates these flexible NW-based Schottky diodes, MESFETs, and inverters are promising candidate components for future portable transparent nanoelectronic devices. PMID- 26061528 TI - Long-Term Mild, rather than Intense, Exercise Enhances Adult Hippocampal Neurogenesis and Greatly Changes the Transcriptomic Profile of the Hippocampus. AB - Our six-week treadmill running training (forced exercise) model has revealed that mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance spatial memory, while intense exercise (IE) above the LT negates such benefits. To help understand the unrevealed neuronal and signaling/molecular mechanisms of the intensity-dependent cognitive change, in this rat model, we here investigated plasma corticosterone concentration as a marker of stress, adult hippocampal neurogenesis (AHN) as a potential contributor to this ME-induced spatial memory, and comprehensively delineated the hippocampal transcriptomic profile using a whole-genome DNA microarray analysis approach through comparison with IE. Results showed that only IE had the higher corticosterone concentration than control, and that the less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis using a 4 * 44 K Agilent chip revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 41 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor. Rather, network analysis of the data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN. In contrast, IE-influenced genes linked to excessive inflammatory immune response, which is a negative regulator of hippocampal neuroadaptation, were identified. Collectively, these results in a treadmill running model demonstrate that long-term ME, but not of IE, with minimizing running stress, has beneficial effects on increasing AHN, and provides an ME-specific gene inventory containing some potential regulators of this positive regulation. This evidence might serve in further elucidating the mechanism behind ME-induced cognitive gain. PMID- 26061531 TI - Propofol Treatment Inhibits Constitutive Apoptosis in Human Primary Neutrophils and Granulocyte-Differentiated Human HL60 Cells. AB - Apoptosis regulation is essential for neutrophil homeostasis. We previously demonstrated that a process involving glycogen synthase kinase (GSK)-3beta determines neutrophil apoptosis. As for this apoptotic process, an overdose of propofol (2,6-Diisopropylphenol; 25 MUg/ml or 140 MUM) also causes GSK-3beta mediated macrophage apoptosis; however, the early deactivation of GSK-3beta with low-dose propofol has been shown. Therefore, we hypothesize that low-dose propofol may induce neutrophil survival via GSK-3beta inactivation. Following in vitro culture, the therapeutic concentration of propofol (10 MUg/ml or 56 MUM) treatment decreased constitutive apoptosis in isolated human primary neutrophils and in granulocyte-differentiated HL60 cells after all-trans retinoic acid (1 MUM) treatment. The inactivation of phosphatidylinositol 3-kinase (PI3 kinase)/AKT and the activation of GSK-3beta results in myeloid cell leukemia 1 (Mcl-1) down-regulation, the loss of the mitochondrial transmembrane potential, and caspase-3 activation in these cells, which is accompanied by apoptosis. Notably, propofol treatment attenuates these effects in a PI3-kinase-regulated manner. We found that propofol initiates PI3-kinase/AKT-mediated GSK-3beta inactivation and Mcl-1 stabilization, rescuing the constitutive apoptosis in primary neutrophils and granulocyte-differentiated acute promyelocytic leukemia HL60 cells. PMID- 26061532 TI - On-Surface Observation of the Formation of Organometallic Complex in a Supramolecular Network. AB - The on-surface formation of organometallic monomers or oligomers, especially in supramolecular network, attracts an extensive interest for chemists and material scientist. In this work, we have investigated metal coordination between zinc (II) phthalocyanine (ZnPc) and 1, 3-di (4-pyridyl) propane (dipy-pra) in the 2, 6, 11-tricarboxydecyloxy-3, 7, 10-triundecyloxy triphenylene (asym-TTT) supramolecular template by means of scanning tunneling microscopy (STM) on highly oriented pyrolytic graphite (HOPG) substrate under ambient conditions. The experimental results demonstrate that every two ZnPc molecules in one nano reactor connect with each other through one dipy-pra molecule by metal coordination interaction. In this coordinating process, the template of asym-TTT supramolecular networks plays a significant role. PMID- 26061533 TI - Vascular tortuosity may be related to intracranial artery atherosclerosis. AB - BACKGROUND: Conventional risk factors cannot explain the individual or ethnic difference in the location of cerebral atherosclerosis. Vascular geometry may play a role on this. AIM: To investigate the association between the geometrical properties of the middle cerebral artery and intracranial atherosclerosis. METHODS: Stroke patients with either symptomatic middle cerebral artery or proximal internal carotid artery diseases were enrolled. The diameter, length, and tortuosity (arc-chord ratio, by percent) of the middle cerebral artery was compared between stroke patients and the age- and gender-matched healthy subjects. The geometrical property was also compared between the symptomatic middle cerebral artery and the normal-looking contralateral middle cerebral artery, and between the contralateral middle cerebral arteries in patients with symptomatic middle cerebral artery and proximal internal carotid artery diseases. RESULTS: One hundred seventy-seven patients (101 with middle cerebral artery disease and 76 with proximal internal carotid artery disease) were studied. Symptomatic middle cerebral artery was more tortuous (119.31 +/- 16.95 vs. 112.98 +/- 14.16; P = 0.009) than the contralateral middle cerebral artery. The contralateral middle cerebral artery of patients with symptomatic middle cerebral artery disease demonstrated a smaller proximal diameter (P = 0.007) and a greater vascular tortuosity than the contralateral middle cerebral artery of patients with proximal internal carotid artery disease (112.01 +/- 12.25 vs. 107.46 +/- 9.35; P = 0.008) and corresponding middle cerebral artery of healthy control subjects (112.01 +/- 12.25 vs. 108.73 +/- 9.79; P = 0.04). Young age, female, small diameter, the absence of diabetes, and high tortuosity of the contralateral middle cerebral artery were independently associated with middle cerebral artery atherosclerotic disease. CONCLUSIONS: High tortuosity and small diameter are related to middle cerebral artery atherosclerosis, probably by altering hemodynamics. Different degree of tortuosity may be one of the reasons for individual differences in location of cerebral atherosclerosis. PMID- 26061534 TI - When Push Comes to Shove: A Comparative Concept Analysis of Motivation and Coercion in Nursing Education. AB - BACKGROUND: Understanding the fine line between motivation and coercion in nursing education may offer insight into satisfaction and autonomy in young nursing students, leading to increased retention, effectiveness, and professionalism in the workplace. PURPOSE: To compare and analyze the concepts of motivation and coercion with application to nursing academia. METHODS: Using the Walker and Avant method for concept analyses, definitions and defining attributes of motivation and coercion were identified, along with antecedents, consequences, and model cases for each concept. Comparison of the concepts noting comparative terms and notable differences are presented. CONCLUSIONS: The comparison of the concepts of motivation and coercion reveals the stark contrast in the consequences of motivational and coercive power interactions in creating professional, satisfied, and empowered nurses. Nurse educators should seek to identify the best ways to create autonomy, competence, and relatedness in their graduates while minimizing coercive power plays which foster distance and dependence. Miller. PMID- 26061535 TI - Theoretical Rovibronic Treatment of the X (2)Sigma(+) and A (2)Pi States of C2H and the X (1)Sigma(+) State of C2H(-) from Quartic Force Fields. AB - Quartic force fields (QFFs) have been shown to be an effective ab initio tool for the generation of highly accurate anharmonic spectroscopic data but have only recently been extended to the description of electronically excited states using equation-of-motion (EOM) coupled cluster theory. In this study, rovibrational data are provided for the X (2)Sigma(+) ground state of the ethynyl radical as well as the X (1)Sigma(+) ground state of the acetylide anion using traditional QFF methods in conjunction with the new EOM-based QFF method to describe the ethynyl radical's A (2)Pi excited state. These data sets include fundamental vibrational frequencies, rotational constants, and vibrationally averaged structures in addition to other spectroscopic constants. An anticipated theoretical correction (ATC) is shown to be an effective way of improving the accuracy of the fundamental modes of the ethynyl radical's A (2)Pi electronically excited state, lowering the frequencies from 2 to 9%. The anharmonic fundamental vibrational frequencies of A (2)Pi C2H are reported to be nu2 = 538.0 cm(-1) (bend), nu3 = 1832.2 cm(-1) (C-C stretch), and nu1 = 3008.1 cm(-1) (C-H stretch). These A (2)Pi frequencies match closely to predicted transitions from previous theoretical work as well as observed transitions from matrix isolation results. Electron binding energies for the X (2)Sigma(+) C2H <- X (1)Sigma(+) C2H(-) and A (2)Pi C2H <- X (1)Sigma(+) C2H(-) transitions are found to be 2.975 and 3.4 eV, respectively. Spectroscopic data are also provided for the (13)C and deuterated isotopologues of X (2)Sigma(+) C2H, A (2)Pi C2H, and X (1)Sigma(+) C2H(-). PMID- 26061537 TI - The problem of pyridinyl imidazole class inhibitors of MAPK14/p38alpha and MAPK11/p38beta in autophagy research. AB - In addition to its established role in inflammation, the stress-activated p38 MAP kinase pathway plays major roles in the regulation of cell cycle, senescence, and autophagy. Robust studies could establish mechanistic links between MAPK11 MAPK14/p38 signaling and macroautophagy converging at ATG9-trafficking and BECN1 phosphorylation. However, several reports seem to monitor MAPK11-MAPK14/p38 dependence of autophagy exclusively by the use of the SB203580/SB202190 class of MAPK14/MAPK11/p38alpha/beta inhibitors. In this "Letter to the editor" we present data to support our claim that these inhibitors interfere with autophagic flux in a MAPK11-MAPK14/p38-independent manner and hence should no longer be used as pharmacological tools in the analysis of MAPK11-MAPK14/p38-dependence of autophagy. We propose a general guideline from Autophagy with regard to this issue to avoid such misinterpretations in the future. PMID- 26061538 TI - A Review of the Genus Oecetis (Trichoptera: Leptoceridae) in the Northeastern Region of Brazil with the Description of 5 New Species. AB - Within Leptoceridae, the genus Oecetis contains about 500 species around the world, including 53 in the Neotropics. In Brazil, there are 15 recorded species of Oecetis. These species were described over several decades by numerous authors with the results that descriptions are not comparable and diagnoses are incomplete. Also, the apparently unbranched M vein, in the forewing, a diagnostic character for Oecetis pointed by McLachlan, is controversial and no consensus has been reached about its homology. Additionally, the only revision for the genus was never published; thus the information and proposed taxa are not available according to the International Code of Zoological Nomenclature. We analyzed specimens collected in the Brazilian Northeast Region and compared these with described species and literature descriptions and Oecetis from other regions. We provide herein the description of five new species, additional characters for diagnosing seven of the species recorded from Brazil, new distributional records, and a dichotomous key to the Brazilian species. Additionally, we contrast the two hypotheses of forewing M vein homology and support the unbranched hypothesis. In this way, we improve the knowledge of the genus in the Neotropics, making the species descriptions comparable in a way that facilitates species identification. PMID- 26061539 TI - Correction: The Quality of Reports on Cervical Arterial Dissection following Cervical Spinal Manipulation. PMID- 26061540 TI - Impact of obesity on outcomes of paediatric acute pancreatitis based on a national administrative database. AB - BACKGROUND: Insufficient information is available on the relationship between obesity and outcome of paediatric patients with acute pancreatitis. OBJECTIVES: This study aimed to investigate the effect of obesity on outcomes of paediatric patients with acute pancreatitis based on a national administrative database. METHODS: A total of 500 cases in 416 paediatric patients with acute pancreatitis (aged 5-17 years) were referred from 260 hospitals between 2010 and 2012 in Japan. Patients were divided into two groups according to the presence of obesity: with obesity (n = 65) and without obesity (n = 435). Patient data were collected from the administrative database to compare the prevalence of severe acute pancreatitis, in-hospital mortality, length of stay (LOS) and medical costs between the groups. RESULTS: Both prevalence of severe acute pancreatitis and in hospital mortality were significantly higher in paediatric patients with obesity than those without (36.9% vs. 16.3% and 3.1% vs. 0.0%; P < 0.001, respectively). Longer LOS and higher medical costs were also observed in paediatric patients with obesity (25.7 vs. 15.2 days, P < 0.001 and 14 169.5 vs. 7457.7 US dollars, P < 0.001, respectively). CONCLUSION: This study demonstrated that obesity significantly influenced the outcomes of paediatric acute pancreatitis. PMID- 26061541 TI - A Bright Fluorescent Probe for H2S Enables Analyte-Responsive, 3D Imaging in Live Zebrafish Using Light Sheet Fluorescence Microscopy. AB - Hydrogen sulfide (H2S) is a critical gaseous signaling molecule emerging at the center of a rich field of chemical and biological research. As our understanding of the complexity of physiological H2S in signaling pathways evolves, advanced chemical and technological investigative tools are required to make sense of this interconnectivity. Toward this goal, we have developed an azide-functionalized O methylrhodol fluorophore, MeRho-Az, which exhibits a rapid >1000-fold fluorescence response when treated with H2S, is selective for H2S over other biological analytes, and has a detection limit of 86 nM. Additionally, the MeRho Az scaffold is less susceptible to photoactivation than other commonly used azide based systems, increasing its potential application in imaging experiments. To demonstrate the efficacy of this probe for H2S detection, we demonstrate the ability of MeRho-Az to detect differences in H2S levels in C6 cells and those treated with AOAA, a common inhibitor of enzymatic H2S synthesis. Expanding the use of MeRho-Az to complex and heterogeneous biological settings, we used MeRho Az in combination with light sheet fluorescence microscopy (LSFM) to visualize H2S in the intestinal tract of live zebrafish. This application provides the first demonstration of analyte-responsive 3D imaging with LSFM, highlighting the utility of combining new probes and live imaging methods for investigating chemical signaling in complex multicellular systems. PMID- 26061542 TI - Magnesium modifies the association between serum phosphate and the risk of progression to end-stage kidney disease in patients with non-diabetic chronic kidney disease. AB - It is known that magnesium antagonizes phosphate-induced apoptosis of vascular smooth muscle cells and prevents vascular calcification. Here we tested whether magnesium can also counteract other pathological conditions where phosphate toxicity is involved, such as progression of chronic kidney disease (CKD). We explored how the link between the risk of CKD progression and hyperphosphatemia is modified by magnesium status. A post hoc analysis was run in 311 non-diabetic CKD patients who were divided into four groups according to the median values of serum magnesium and phosphate. During a median follow-up of 44 months, 135 patients developed end-stage kidney disease (ESKD). After adjustment for relevant clinical factors, patients in the lower magnesium-higher phosphate group were at a 2.07-fold (95% CI: 1.23-3.48) risk for incident ESKD and had a significantly faster decline in estimated glomerular filtration rate compared with those in the higher magnesium-higher phosphate group. There were no significant differences in the risk of these renal outcomes among the higher magnesium-higher phosphate group and both lower phosphate groups. Incubation of tubular epithelial cells in high phosphate and low magnesium medium in vitro increased apoptosis and the expression levels of profibrotic and proinflammatory cytokine; these changes were significantly suppressed by increasing magnesium concentration. Thus, magnesium may act protectively against phosphate-induced kidney injury. PMID- 26061543 TI - Once upon a time in dialysis: the last days of Kt/V? AB - After its proposal as a marker of dialysis adequacy in the eighties of last century, Kt/V(urea) helped to improve dialysis efficiency and to standardize the procedure. However, the concept was developed when dialysis was almost uniformly short and was applied thrice weekly with small pore cellulosic dialyzers. Since then dialysis evolved in the direction of many strategic alternatives, such as extended or daily dialysis, large pore high-flux dialysis, and convective strategies. Although still a useful baseline marker, Kt/V(urea) no longer properly covers up for most of these modifications so that urea kinetics are hardly if at all representative for those of other solutes with a deleterious effect on morbidity and mortality of uremic patients. This is corroborated in several clinical studies showing a dissociation between removal of urea and that of other uremic toxins. In addition, randomized controlled trials showed no benefit of increasing Kt/V(urea). Finally, this parameter also hardly is evocative for metabolic or intestinal generation of toxins, for their removal by residual renal function and for the complex interaction of dialysis length with removal pattern and patient outcomes. We conclude that apart from being a baseline parameter of dialysis adequacy, Kt/V(urea) insufficiently represents all novel strategic changes of modern dialysis. Kt/V(urea) is too simple a concept for the complexities of uremia and of today's dialysis. PMID- 26061544 TI - Recurrent IgA nephropathy is predicted by altered glycosylated IgA, autoantibodies and soluble CD89 complexes. AB - IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, frequently leads to end-stage renal disease and kidney transplantation. However, disease recurrence often occurs after transplantation. Here we evaluated the predictive value of three markers for IgAN recurrence: the presence of galactose deficient IgA1, IgG anti-IgA autoantibodies, and IgA-soluble (s) CD89 complexes. This was analyzed in 38 kidney transplant recipients with IgAN recurrence and compared with 22 patients transplanted for IgAN but without recurrence and with 17 healthy controls. Pre-transplantation galactose-deficient IgA1 serum levels were significantly higher in the recurrence compared with the no recurrence or control groups. IgA-IgG complexes were significantly elevated in the recurrence group. Both the recurrence and no recurrence groups had increased values of IgA sCD89 complexes compared with healthy controls, but values were significantly lower in patients with recurrence compared with no recurrence. Areas under the receiver operating curve of the markers in pre-transplantation sera were 0.86 for galactose-deficient-IgA, 0.82 for IgA-IgG, and 0.78 for sCD89-IgA; all significant. Disease recurrence was associated with decreased serum galactose deficient IgA1 and appearance of mesangial-galactose-deficient IgA1 deposits, whereas increased serum IgA-sCD89 complexes were associated with mesangial sCD89 deposits. Thus, galactose-deficient-IgA1, IgG autoantibodies, and IgA-sCD89 complexes are valuable biomarkers to predict disease recurrence, highlighting major pathogenic mechanisms in IgAN. PMID- 26061545 TI - Protein carbamylation and cardiovascular disease. AB - Carbamylation constitutes a posttranslational modification of proteins or amino acids and results from different pathways in vivo. First is the non-enzymatic reaction between isocyanic acid, a decomposition product of urea, and either the N-terminus or the E-amino group of lysine residues. Isocyanic acid levels, while low in vivo, are in equilibrium with urea and are thus increased in chronic and end-stage renal diseases. An alternative pathway involves the leukocyte heme protein myeloperoxidase, which catalyzes the oxidation of thiocyanate in the presence of hydrogen peroxide, producing isocyanate at inflammation sites. Notably, plasma thiocyanate levels are increased in smokers, and leukocyte-driven protein carbamylation occurs both within human and animal atherosclerotic plaques, as well as on plasma proteins. Protein carbamylation is considered a hallmark of molecular aging and is implicated in many pathological conditions. Recently, it has been shown that carbamylated low-density lipoprotein (LDL) induces endothelial dysfunction via lectin-like-oxidized LDL receptor-1 activation and increased reactive oxygen species production, leading to endothelial nitric oxide synthase uncoupling. Moreover, carbamylated LDL harbors atherogenic activities, including both binding to macrophage scavenger receptors inducing cholesterol accumulation and foam-cell formation, as well as promoting vascular smooth muscle proliferation. In contrast, high-density lipoprotein loses its anti-apoptotic activity after carbamylation, contributing to endothelial cell death. In addition to involvement in atherogenesis, protein carbamylation levels have emerged as a particularly strong predictor of both prevalent and incident cardiovascular disease risk. Recent studies also suggest that protein carbamylation may serve as a potential therapeutic target for the prevention of atherosclerotic heart disease. PMID- 26061546 TI - Heterogeneity of epigenetic changes at ischemia/reperfusion- and endotoxin induced acute kidney injury genes. AB - Aberrant gene expression is a molecular hallmark of acute kidney injury (AKI). As epigenetic processes control gene expression in a cell- and environment-defined manner, understanding the epigenetic pathways that regulate genes altered by AKI may open vital new insights into the complexities of disease pathogenesis and identify possible therapeutic targets. Here we used matrix chromatin immunoprecipitation and integrative analysis to study 20 key permissive and repressive epigenetic histone marks at transcriptionally induced Tnf, Ngal, Kim 1, and Icam-1 genes in mouse models of AKI; unilateral renal ischemia/reperfusion, lipopolysaccharide (LPS), and their synergistically injurious combination. Results revealed unexpected heterogeneity of transcriptional and epigenetic responses. Tnf and Ngal were transcriptionally upregulated in response to both treatments individually, and to combination treatment. Kim-1 was induced by ischemia/reperfusion and Icam-1 by LPS only. Epigenetic alterations at these genes exhibited distinct time-dependent changes that shared some similarities, such as reduction in repressive histone modifications, and also had major ischemia/reperfusion versus endotoxin differences. Thus, diversity of changes at AKI genes in response to different insults indicates involvement of several epigenetic pathways. This could be exploited pharmacologically through rational-drug design to alter the course and improve clinical outcomes of this syndrome. PMID- 26061547 TI - Neutrophil serine proteases exert proteolytic activity on endothelial cells. AB - Neutrophil serine proteases (NSPs) are released from activated neutrophils during inflammation. Here we studied the transfer of the three major NSPs, namely proteinase 3, human neutrophil elastase, and cathepsin G, from neutrophils to endothelial cells and used an unbiased approach to identify novel endothelial NSP substrates. Enzymatically active NSPs were released from stimulated neutrophils and internalized by endothelial cells in a dose- and time-dependent manner as shown by immunoblotting, flow cytometry, and the Boc-Ala substrate assay. Using terminal-amine isotopic labeling of substrates in endothelial cells, we identified 121 peptides from 82 different proteins consisting of 36 substrates for proteinase 3, 30 for neutrophil elastase, and 28 for cathepsin G, respectively. We characterized the extended cleavage pattern and provide corresponding IceLogos. Gene ontology analysis showed significant cytoskeletal substrate enrichment and confirmed several cytoskeletal protein substrates by immunoblotting. Finally, ANCA-stimulated neutrophils released all three active NSPs into the supernatant. Supernatants increased endothelial albumin flux and disturbed the endothelial cell cytoskeletal architecture. Serine protease inhibition abrogated this effect. Longer exposure to NSPs reduced endothelial cell viability and increased apoptosis. Thus, we identified novel NSP substrates and suggest NSP inhibition as a therapeutic measure to inhibit neutrophil mediated inflammatory vascular diseases. PMID- 26061548 TI - Macrophage-derived tumor necrosis factor-alpha mediates diabetic renal injury. AB - Monocyte/macrophage recruitment correlates strongly with the progression of diabetic nephropathy. Tumor necrosis factor-alpha (TNF-alpha) is produced by monocytes/macrophages but the direct role of TNF-alpha and/or macrophage-derived TNF-alpha in the progression of diabetic nephropathy remains unclear. Here we tested whether inhibition of TNF-alpha confers kidney protection in diabetic nephropathy via a macrophage-derived TNF-alpha-dependent pathway. Compared to vehicle-treated mice, blockade of TNF-alpha with a murine anti-TNF-alpha antibody conferred kidney protection in Ins2(Akita) mice as indicated by reductions in albuminuria, plasma creatinine, histopathologic changes, kidney macrophage recruitment, and plasma inflammatory cytokine levels at 18 weeks of age. To assess the direct role of macrophage-derived TNF-alpha in diabetic nephropathy, we generated macrophage-specific TNF-alpha-deficient mice (CD11b(Cre)/TNF alpha(Flox/Flox)). Conditional ablation of TNF-alpha in macrophages significantly reduced albuminuria, the increase in plasma creatinine and blood urea nitrogen, histopathologic changes, and kidney macrophage recruitment compared to diabetic TNF-alpha(Flox/Flox) control mice after 12 weeks of streptozotocin-induced diabetes. Thus, production of TNF-alpha by macrophages plays a major role in diabetic renal injury. Hence, blocking TNF-alpha could be a novel therapeutic approach for treatment of diabetic nephropathy. PMID- 26061549 TI - Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation. AB - Vascular calcification (VC) is a major risk factor for cardiovascular mortality in chronic renal failure (CRF) patients, but the pathogenesis remains partially unknown and effective therapeutic targets should be urgently explored. Here we pursued the therapeutic role of rapamycin in CRF-related VC. Mammalian target of rapamycin (mTOR) signal was activated in the aortic wall of CRF rats. As expected, oral rapamycin administration significantly reduced VC by inhibiting mTOR in rats with CRF. Further in vitro results showed that activation of mTOR by both pharmacological agent and genetic method promoted, while inhibition of mTOR reduced, inorganic phosphate-induced vascular smooth muscle cell (VSMC) calcification and chondrogenic/osteogenic gene expression, which were independent of autophagy and apoptosis. Interestingly, the expression of Klotho, an antiaging gene that suppresses VC, was reduced in calcified vasculature, whereas rapamycin reversed membrane and secreted Klotho decline through mTOR inhibition. When mTOR signaling was enhanced by either mTOR overexpression or deletion of tuberous sclerosis 1, Klotho mRNA was further decreased in phosphate-treated VSMCs, suggesting a vital association between mTOR signaling and Klotho expression. More importantly, rapamycin failed to reduce VC in the absence of Klotho by using either siRNA knockdown of Klotho or Klotho knockout mice. Thus, Klotho has a critical role in mediating the observed decrease in calcification by rapamycin in vitro and in vivo. PMID- 26061551 TI - YPEL1 overexpression in early avian craniofacial mesenchyme causes mandibular dysmorphogenesis by up-regulating apoptosis. AB - BACKGROUND: The YPEL (Yippee-like) gene family comprises five highly conserved members (YPEL1-5), but their biological function remains largely unknown. Early studies of YPEL1 function suggested that it plays a role in the development of structures derived from the pharyngeal arches. Human YPEL1 localises to distal chromosome 22q11.2 and copy number changes at this locus lead to diverse phenotypes that include facial dysmorphism, facial asymmetry, and palatal anomalies comprising the distal 22q11.2 deletion/duplication syndromes (OMIM 611867). We therefore investigated the role of chick YPEL1 in craniofacial development using ex vivo and in vivo approaches in the avian model. RESULTS: We found that retroviral-mediated in vivo overexpression of YPEL1 causes abnormal mandibular morphogenesis associated with increased apoptosis and involvement of the BMP/MSX pathway. CONCLUSIONS: Our results suggest that YPEL1 expression is regulated by bone morphogenetic protein signaling and suggest a role for YPEL1 in the pathogenesis of the craniofacial abnormalities observed in humans with distal chromosome 22q11.2 deletions or duplications. PMID- 26061550 TI - Quality of Life Is Related to Social Support in Elderly Osteoporosis Patients in a Chinese Population. AB - OBJECTIVE: To explore the association between quality of life and social support in elderly osteoporosis patients in a Chinese population. METHODS: A total of 214 elderly patients who underwent bone mineral density screening were divided into two groups: elderly patients with primary osteoporosis (case group, n = 112) and normal elderly patients (control group, n = 102). Quality of life and social support were compared between the two groups. RESULTS: Quality of life and social support were significantly different between the case and control groups. The physical function, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health scores in case group were significantly lower than those in the control group (P < 0.01). The objective support, subjective support, utilization of support, and total scores in case group were significantly lower than those in the control group (P < 0.01). Quality of life and social support were positively correlated in the case group (r = 0.672, P < 0.01). CONCLUSION: Quality of life and social support in elderly patients with osteoporosis in China were poorer than in elderly patients without osteoporosis and were positively correlated. Our findings indicate that increased efforts to improve the social support and quality of life in elderly osteoporosis patients are urgently needed in China. Further longitudinal studies should be conducted to provide more clinical evidence to determine causative factors for the observed association between risk factors and outcomes. PMID- 26061552 TI - A novel HLA allele, HLA-DRB1*15:116, discovered in a Taiwanese unrelated hematopoietic stem cell donor. AB - One nucleotide substitution at residue 127 of HLA-DRB1*15:01:01:01 results in a new allele, HLA-DRB1*15:116. PMID- 26061553 TI - An Effective 3D Ear Acquisition System. AB - The human ear is a new feature in biometrics that has several merits over the more common face, fingerprint and iris biometrics. It can be easily captured from a distance without a fully cooperative subject. Also, the ear has a relatively stable structure that does not change much with the age and facial expressions. In this paper, we present a novel method of 3D ear acquisition system by using triangulation imaging principle, and the experiment results show that this design is efficient and can be used for ear recognition. PMID- 26061554 TI - Axial Length Measurement Failure Rates with the IOLMaster and Lenstar LS 900 in Eyes with Cataract. AB - PURPOSE: To evaluate axial length (AL) measurement failure rate with the IOLMaster (Carl Zeiss AG, Germany) and Lenstar LS 900 (Haag-Streit AG, Switzerland) in eyes with cataract. METHODS: Two hundred and ninety-six eyes of 170 patients with cataract were enrolled. Cataract type and severity were graded using the Lens Opacities Classification System III (LOCS III) and AL measurements were attempted with IOLMaster (version 5.4) and Lenstar LS 900 (version 1.1). Chi squared analysis was used to assess if the difference in AL measurement acquisition rate was statistically significant between the two devices. The association of the different cataract types and severity with the AL measurement acquisition rate was evaluated with logistic regression analysis. RESULTS: AL measurements were obtained in 184 eyes (62.16%) using the IOLMaster and 191 eyes (64.53%) using the Lenstar, which corresponds to a failure rate of 37.84% and 35.47% respectively. Chi-square analysis indicated no significant difference between the Lenstar and IOLMaster for AL measurement failure rate (x2 = 0.356, P = 0.550). Logistic regression analysis indicated no association between acquisition rates and cortical or nuclear cataracts with either device. There was a statistically significant association between acquisition rates and increasing severity of posterior subcapsular cataracts with the IOLMaster (beta = -1.491, P<0.001) and Lenstar LS 900 (beta = -1.507, P<0.001). CONCLUSION: The IOLMaster and Lenstar LS 900 have similar AL measurement failure rates (35-38%) for Chinese public hospital cataract patients. Increasing severity of posterior subcapsular cataracts was problematic for both devices. PMID- 26061555 TI - The Authors Reply "Redesigning an inpatient pediatric service using lean to improve throughput efficiency". PMID- 26061556 TI - New insights into plasticity of pancreatic cancer: cancer to acinar cell reprogramming by the basic helix-loop-helix transcription factor E47. PMID- 26061557 TI - Pathophysiological mechanisms of acute pancreatitis define inflammatory markers of clinical prognosis. AB - Development of acute pancreatitis illustrates the need to understand the basic mechanisms of disease progression to drive the exploration of therapeutic options. Cytokines play a major role in the pathogenesis of acute pancreatitis as underlying systemic inflammatory response, tissue damage, and organ dysfunction. However, little is known about circulating concentrations of these inflammatory markers and their real impact on clinical practice. Experimental studies have suggested that the prognosis for acute pancreatitis depends on the degree of pancreatic necrosis and the intensity of multisystem organ failure generated by the systemic inflammatory response. This suggests an intricate balance between localized tissue damage with proinflammatory cytokine production and a systemic anti-inflammatory response that restricts the inappropriate movement of proinflammatory agents into the circulation. Implication of such mediators suggests that interruption or blunting of an inappropriate immune response has the potential to improve outcome. A detailed understanding of pathophysiological processes and immunological aspects in patients with acute pancreatitis is the basis for the development of therapeutic strategies that will provide significant reductions in morbidity and mortality. PMID- 26061558 TI - Response to Galassi et al, "A 5-year experience of benign pancreatic hyperenzymemia". PMID- 26061559 TI - Reply to the letter on A 5-year experience of benign pancreatic hyperenzymemia. PMID- 26061560 TI - The effects of beverage type on pancreatitis mortality rate in Russia. PMID- 26061561 TI - Endoscopic ultrasound-guided needle-based confocal laser endomicroscopy: a pilot study for use in focal pancreatic masses. PMID- 26061562 TI - Cognitive Workload of Computerized Nursing Process in Intensive Care Units. AB - The aim of this work was to measure the cognitive workload to complete printed nursing process versus computerized nursing process from International Classification Practice of Nursing in intensive care units. It is a quantitative, before-and-after quasi-experimental design, with a sample of 30 participants. Workload was assessed using National Aeronautics and Space Administration Task Load Index. Six cognitive categories were measured. The "temporal demand" was the largest contributor to the cognitive workload, and the role of the nursing process in the "performance" category has excelled that of computerized nursing process. It was concluded that computerized nursing process contributes to lower cognitive workload of nurses for being a support system for decision making based on the International Classification Practice of Nursing. The computerized nursing process as a logical structure of the data, information, diagnoses, interventions and results become a reliable option for health improvement of healthcare, because it can enhance nurse safe decision making, with the intent to reduce damage and adverse events to patients in intensive care. PMID- 26061563 TI - Electronic Personal Health Record Use Among Nurses in the Nursing Informatics Community. AB - An electronic personal health record is a patient-centric tool that enables patients to securely access, manage, and share their health information with healthcare providers. It is presumed the nursing informatics community would be early adopters of electronic personal health record, yet no studies have been identified that examine the personal adoption of electronic personal health record's for their own healthcare. For this study, we sampled nurse members of the American Medical Informatics Association and the Healthcare Information and Management Systems Society with 183 responding. Multiple logistic regression analysis was used to identify those factors associated with electronic personal health record use. Overall, 72% were electronic personal health record users. Users tended to be older (aged >50 years), be more highly educated (72% master's or doctoral degrees), and hold positions as clinical informatics specialists or chief nursing informatics officers. Those whose healthcare providers used electronic health records were significantly more likely to use electronic personal health records (odds ratio, 5.99; 95% confidence interval, 1.40-25.61). Electronic personal health record users were significantly less concerned about privacy of health information online than nonusers (odds ratio, 0.32; 95% confidence interval, 0.14-0.70) adjusted for ethnicity, race, and practice region. Informatics nurses, with their patient-centered view of technology, are in prime position to influence development of electronic personal health records. Our findings can inform policy efforts to encourage informatics and other professional nursing groups to become leaders and users of electronic personal health record; such use could help them endorse and engage patients to use electronic personal health records. Having champions with expertise in and enthusiasm for the new technology can promote the adoptionof electronic personal health records among healthcare providers as well as their patients. PMID- 26061564 TI - Rp-cAMPS Prodrugs Reveal the cAMP Dependence of First-Phase Glucose-Stimulated Insulin Secretion. AB - cAMP-elevating agents such as the incretin hormone glucagon-like peptide-1 potentiate glucose-stimulated insulin secretion (GSIS) from pancreatic beta cells. However, a debate has existed since the 1970s concerning whether or not cAMP signaling is essential for glucose alone to stimulate insulin secretion. Here, we report that the first-phase kinetic component of GSIS is cAMP-dependent, as revealed through the use of a novel highly membrane permeable para acetoxybenzyl (pAB) ester prodrug that is a bioactivatable derivative of the cAMP antagonist adenosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS). In dynamic perifusion assays of human or rat islets, a step-wise increase of glucose concentration leads to biphasic insulin secretion, and under these conditions, 8 bromoadenosine-3',5'-cyclic monophosphorothioate, Rp-isomer, 4-acetoxybenzyl ester (Rp-8-Br-cAMPS-pAB) inhibits first-phase GSIS by up to 80%. Surprisingly, second-phase GSIS is inhibited to a much smaller extent (<=20%). Using luciferase, fluorescence resonance energy transfer, and bioluminescence resonance energy transfer assays performed in living cells, we validate that Rp-8-Br-cAMPS pAB does in fact block cAMP-dependent protein kinase activation. Novel effects of Rp-8-Br-cAMPS-pAB to block the activation of cAMP-regulated guanine nucleotide exchange factors (Epac1, Epac2) are also validated using genetically encoded Epac biosensors, and are independently confirmed in an in vitro Rap1 activation assay using Rp-cAMPS and Rp-8-Br-cAMPS. Thus, in addition to revealing the cAMP dependence of first-phase GSIS from human and rat islets, these findings establish a pAB-based chemistry for the synthesis of highly membrane permeable prodrug derivatives of Rp-cAMPS that act with micromolar or even nanomolar potency to inhibit cAMP signaling in living cells. PMID- 26061566 TI - Row Ratios of Intercropping Maize and Soybean Can Affect Agronomic Efficiency of the System and Subsequent Wheat. AB - Intercropping is regarded as an important agricultural practice to improve crop production and environmental quality in the regions with intensive agricultural production, e.g., northern China. To optimize agronomic advantage of maize (Zea mays L.) and soybean (Glycine max L.) intercropping system compared to monoculture of maize, two sequential experiments were conducted. Experiment 1 was to screening the optimal cropping system in summer that had the highest yields and economic benefits, and Experiment 2 was to identify the optimum row ratio of the intercrops selected from Experiment 1. Results of Experiment 1 showed that maize intercropping with soybean (maize || soybean) was the optimal cropping system in summer. Compared to conventional monoculture of maize, maize || soybean had significant advantage in yield, economy, land utilization ratio and reducing soil nitrate nitrogen (N) accumulation, as well as better residual effect on the subsequent wheat (Triticum aestivum L.) crop. Experiment 2 showed that intercropping systems reduced use of N fertilizer per unit land area and increased relative biomass of intercropped maize, due to promoted photosynthetic efficiency of border rows and N utilization during symbiotic period. Intercropping advantage began to emerge at tasseling stage after N topdressing for maize. Among all treatments with different row ratios, alternating four maize rows with six soybean rows (4M:6S) had the largest land equivalent ratio (1.30), total N accumulation in crops (258 kg ha(-1)), and economic benefit (3,408 USD ha(-1)). Compared to maize monoculture, 4M:6S had significantly lower nitrate-N accumulation in soil both after harvest of maize and after harvest of the subsequent wheat, but it did not decrease yield of wheat. The most important advantage of 4M:6S was to increase biomass of intercropped maize and soybean, which further led to the increase of total N accumulation by crops as well as economic benefit. In conclusion, alternating four maize rows with six soybean rows was the optimum row ratio in maize || soybean system, though this needs to be further confirmed by pluri-annual trials. PMID- 26061567 TI - Psychiatric legal investigation for sickness benefits due to disability at the Brazilian Federal Social Security Special Court in Florianopolis, capital city of the State of Santa Catarina, southern Brazil. AB - OBJECTIVE: To describe the profile of insured individuals that filed claims for sickness benefits and compare the results of the administrative and legal investigations. METHOD: This case series included 114 insured persons that filed lawsuits against the Brazilian National Institute of Social Security (Instituto Nacional de Seguridade Social, INSS). They underwent psychiatric examinations required by the Brazilian Federal Social Security Special Court in Florianopolis from August to December 2010. RESULTS: Mean age was 47 years, and participant age ranged from 24 to 64 years. Most insured individuals were women (79%), and most were employed (67.5%) and self-employed (26.5%) workers. Mean contribution time was 99.9 months, ranging from 8 to 352 months. Mean benefit duration was 20.4 months, ranging from 2 to 97 months. The most prevalent category of workers was service workers, store and supermarket salespeople (54.4%), followed by administrative workers (19.3%). CONCLUSIONS: Only 17 participants were found to be unable to work after benefit cessation, a 14.9% mismatch between administrative and legal investigations. The most frequent diagnoses were mood disorders (59.6%) and anxiety disorders (17.5%). PMID- 26061565 TI - FOXO1/3 and PTEN Depletion in Granulosa Cells Promotes Ovarian Granulosa Cell Tumor Development. AB - The forkhead box (FOX), FOXO1 and FOXO3, transcription factors regulate multiple functions in mammalian cells. Selective inactivation of the Foxo1 and Foxo3 genes in murine ovarian granulosa cells severely impairs follicular development and apoptosis causing infertility, and as shown here, granulosa cell tumor (GCT) formation. Coordinate depletion of the tumor suppressor Pten gene in the Foxo1/3 strain enhanced the penetrance and onset of GCT formation. Immunostaining and Western blot analyses confirmed FOXO1 and phosphatase and tensin homolog (PTEN) depletion, maintenance of globin transcription factor (GATA) 4 and nuclear localization of FOXL2 and phosphorylated small mothers against decapentaplegic (SMAD) 2/3 in the tumor cells, recapitulating results we observed in human adult GCTs. Microarray and quantitative PCR analyses of mouse GCTs further confirmed expression of specific genes (Foxl2, Gata4, and Wnt4) controlling granulosa cell fate specification and proliferation, whereas others (Emx2, Nr0b1, Rspo1, and Wt1) were suppressed. Key genes (Amh, Bmp2, and Fshr) controlling follicle growth, apoptosis, and differentiation were also suppressed. Inhbb and Grem1 were selectively elevated, whereas reduction of Inha provided additional evidence that activin signaling and small mothers against decapentaplegic (SMAD) 2/3 phosphorylation impact GCT formation. Unexpectedly, markers of Sertoli/epithelial cells (SRY [sex determining region Y]-box 9/keratin 8) and alternatively activated macrophages (chitinase 3-like 3) were elevated in discrete subpopulations within the mouse GCTs, indicating that Foxo1/3/Pten depletion not only leads to GCTs but also to altered granulosa cell fate decisions and immune responses. Thus, analyses of the Foxo1/3/Pten mouse GCTs and human adult GCTs provide strong evidence that impaired functions of the FOXO1/3/PTEN pathways lead to dramatic changes in the molecular program within granulosa cells, chronic activin signaling in the presence of FOXL2 and GATA4, and tumor formation. PMID- 26061568 TI - Interstitial 1p32.1p32.3 deletion in a patient with multiple congenital anomalies. AB - Interstitial deletions encompassing chromosome bands 1p32.1p32.3 are rare. Only nine unrelated patients with partially overlapping 1p32.1p32.3 deletions of variable size and position have been reported to date. We report on a 17-month old boy with choanal atresia, hearing loss, urogenital anomalies, and microcephaly in whom an interstitial de novo deletion of 6.4 Mb was detected in 1p32.1p32.3 (genomic position chr1:54,668,618-61,113,264 according to GRCh37/hg19). The deleted region harbors 31 RefSeq genes. Notable genes in the region are PCSK9, haploinsufficiency of which caused low LDL cholesterol plasma levels in the patient, and DAB1, which is a candidate gene for cognitive deficits, microcephaly, and cerebral abnormalities such as ventriculomegaly and agenesis of the corpus callosum. Choanal atresia, microcephaly, and severe hearing loss were previously not known to be associated with 1p32 deletions. Our reported patient thus broadens the spectrum of clinical findings in this chromosome region and further facilitates genotype-phenotype correlations. Additional patients with overlapping deletions and/or point mutations in genes of this region need to be identified to elucidate the role of individual genes for the complex clinical manifestations. PMID- 26061569 TI - Metabolite-enabled mutualistic interaction between Shewanella oneidensis and Escherichia coli in a co-culture using an electrode as electron acceptor. AB - Mutualistic interactions in planktonic microbial communities have been extensively studied. However, our understanding on mutualistic communities consisting of co-existing planktonic cells and biofilms is limited. Here, we report a planktonic cells-biofilm mutualistic system established by the fermentative bacterium Escherichia coli and the dissimilatory metal-reducing bacterium Shewanella oneidensis in a bioelectrochemical device, where planktonic cells in the anode media interact with the biofilms on the electrode. Our results show that the transfer of formate is the key mechanism in this mutualistic system. More importantly, we demonstrate that the relative distribution of E. coli and S. oneidensis in the liquid media and biofilm is likely driven by their metabolic functions towards an optimum communal metabolism in the bioelectrochemical device. RNA sequencing-based transcriptomic analyses of the interacting organisms in the mutualistic system potentially reveal differential expression of genes involved in extracellular electron transfer pathways in both species in the planktonic cultures and biofilms. PMID- 26061570 TI - Antioxidant Opuntia ficus-indica Extract Activates AHR-NRF2 Signaling and Upregulates Filaggrin and Loricrin Expression in Human Keratinocytes. AB - Opuntia ficus-indica (OFI) is a cactus species widely used as an anti inflammatory, antilipidemic, and hypoglycemic agent. It has been shown that OFI extract (OFIE) inhibits oxidative stress in animal models of diabetes and hepatic disease; however, its antioxidant mechanism remains largely unknown. In this study, we demonstrated that OFIE exhibited potent antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the downstream antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1), which inhibited the generation of reactive oxygen species in keratinocytes challenged with tumor necrosis factor alpha or benzo[alpha]pyrene. The antioxidant capacity of OFIE was canceled in NRF2 knockdown keratinocytes. OFIE exerted this NRF2-NQO1 upregulation through activation of the aryl hydrocarbon receptor (AHR). Moreover, the ligation of AHR by OFIE upregulated the expression of epidermal barrier proteins: filaggrin and loricrin. OFIE also prevented TH2 cytokine-mediated downregulation of filaggrin and loricrin expression in an AHR-dependent manner because it was canceled in AHR knockdown keratinocytes. Antioxidant OFIE is a potent activator of AHR-NRF2-NQO1 signaling and may be beneficial in treating barrier-disrupted skin disorders. PMID- 26061572 TI - Efficacy of Benzocaine 20% Topical Anesthetic Compared to Placebo Prior to Administration of Local Anesthesia in the Oral Cavity: A Randomized Controlled Trial. AB - The aim of the present study was to compare the effects of a topical anesthetic to a placebo on pain perception during administration of local anesthesia in 2 regions of the oral cavity. A split-mouth, double-blind, randomized clinical trial design was used. Thirty-eight subjects, ages 18-50 years, American Society of Anesthesiologists I and II, received 4 anesthetic injections each in regions corresponding to the posterior superior alveolar nerve (PSA) and greater palatine nerve (GPN), totaling 152 sites analyzed. The side of the mouth where the topical anesthetic (benzocaine 20%) or the placebo was to be applied was chosen by a flip of a coin. The needle used was 27G, and the anesthetic used for administration of local anesthesia was 2% lidocaine with 1:100,000 epinephrine. After receiving the administration of local anesthesia, each patient reported pain perception on a visual analog scale (VAS) of 100-mm length. The results showed that the topical anesthetic and the placebo had similar effects: there was no statistically significant VAS difference between the PSA and the GPN pain ratings. A higher value on the VAS for the anesthesia of the GPN, relative to the PSA, was observed for both groups. Regarding gender, male patients had higher values on the VAS compared with female patients, but these differences were not meaningful. The topical anesthetic and the placebo had similar effects on pain perception for injection of local anesthesia for the PSA and GPN. PMID- 26061573 TI - Tissue Blood Flow During Remifentanil Infusion With Carbon Dioxide Loading. AB - The aim of this study was to investigate the effect of changes in end-tidal carbon dioxide tension (ETCO2) during remifentanil (Remi) infusion on oral tissue blood flow in rabbits. Eight male tracheotomized Japan White rabbits were anesthetized with sevoflurane under mechanical ventilation. The infusion rate of Remi was 0.4 MUg/kg/min. Carbon dioxide was added to the inspired gas to change the inspired CO2 tension to prevent changes in the ventilating condition. Observed variables were systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), heart rate (HR), common carotid artery blood flow (CCBF), tongue mucosal blood flow (TBF), mandibular bone marrow tissue blood flow (BBF), masseter muscle tissue blood flow (MBF), upper alveolar tissue blood flow (UBF), and lower alveolar tissue blood flow (LBF). The CCBF, TBF, BBF, UBF, and LBF values were increased, while MBF was decreased, under hypercapnia, and vice versa. The BBF, UBF, and LBF values were increased, while the MBF value was decreased, under hypercapnia during Remi infusion, and vice versa. The BBF, MBF, UBF, and LBF values, but not the CCBF and TBF values, changed along with ETCO2 changes during Remi infusion. PMID- 26061574 TI - Does the Preemptive Use of Oral Nonsteroidal Anti-inflammatory Drugs Reduce Postoperative Pain in Surgical Removal of Third Molars? A Meta-analysis of Randomized Clinical Trials. AB - The purpose of this study was to investigate the effectiveness of preemptive analgesia with nonsteroidal anti-inflammatory drugs (NSAIDs) in third-molar surgery. A PubMed literature search was conducted for articles restricted to the English language using the following terms (DeCS/MeSH) or combinations: analgesia, third molar, and preemptive. From a total of 704 articles, 6 (n=420 subjects) were selected. All studies presented a low risk of bias (Cochrane criteria) but exhibited high heterogeneity of methods. Two studies were excluded from the meta-analysis because they did not have adequate numeric values (dichotomous data) for the calculations. Preemptive analgesia showed no significant benefit (n=298, P=.2227, odds ratio: 2.30, 0.60-8.73) in reducing postoperative pain after removal of lower impacted third molars. However, there was a probable direct relationship between the effectiveness of NSAIDs in preemptive analgesia for removal of third molars and its selectivity for the cyclooxygenase-2 (COX-2). Preemptive analgesia did not have a significant effect in reducing postoperative pain after removal of lower impacted third molars. More homogeneous and well-delineated clinical studies are necessary to determine a possible association between NSAIDs' selectivity for COX-2 and treatment effectiveness. PMID- 26061575 TI - Anaphylactoid-like Reaction to Midazolam During Oral and Maxillofacial Surgery. AB - We experienced a case of life-threatening hypotension and bronchoconstriction associated with edema in a patient undergoing resection of a tumor of the right mandible following intravenous midazolam for induction of general anesthesia. We decided to postpone surgery for further examination of a possible drug-induced allergic reaction, and we rescheduled surgery for 1 week later. After administering H1 and H2 histamine antagonists, we administered a slow induction with sevoflurane in nitrous oxide and oxygen plus intravenous atropine sulfate after performing a test dose injection. We safely induced and maintained anesthesia with nitrous oxide, oxygen, and sevoflurane. PMID- 26061576 TI - Inadvertent Endobronchial Intubation in a Patient With a Short Neck Length. AB - Inadvertent placement of the endotracheal tube into the right bronchus during intubation for general anesthesia is a fairly common occurrence. Many precautions should be taken by the anesthesia provider in order to minimize the incidence of endobronchial intubation, including bilateral auscultation of the lungs, use of the 21/23 rule, and palpation of the inflated endotracheal cuff at the sternal notch. These provisions, however, are not foolproof; anesthesia providers should realize that endobronchial intubation may occur from time to time because of variations in patient anatomy, changes in patient positioning, and cephalad pressures exerted during surgery. A 58-year-old man with chronic obstructive pulmonary disease received general endotracheal anesthesia for a laparoscopic cholecystectomy. His height was 165 cm (5 ft, 5 in) and the endotracheal tube was secured at his incisors at 21 cm after placement with a rigid laryngoscope. Bilateral breath sounds were confirmed with auscultation, although they were distant because of his chronic obstructive pulmonary disease. After radiographic examination in the postanesthesia care unit, a right main-stem intubation was revealed to have taken place, resulting in complete atelectasis of the left lung. After repositioning of the endotracheal tube, radiography confirmed that the patient had an anatomically short tracheal length. PMID- 26061577 TI - Repeated General Anesthesia in a Patient With Noonan Syndrome. AB - Noonan syndrome (NS) is an autosomal dominant disorder characterized by facial anomalies, short stature, chest deformity, congenital heart diseases, and other comorbidities. The challenges faced during anesthetic management of patients with NS could be due to congenital heart diseases, hemostatic disorders, and airway anomalies. Here we describe dental treatment under general anesthesia performed for a 28-year-old man with NS. He had characteristic features of NS along with mild pulmonary valve stenosis. Dental treatment under general anesthesia was performed successfully on 13 occasions with nasotracheal intubation under curve tipped suction catheter guidance or insertion of a reinforced laryngeal mask airway. This case suggests that for patients with NS, who might present several challenges, dental anesthesiologists should consider the extent of the patient's disorders to enable them to perform dental treatment safely under general anesthesia. PMID- 26061578 TI - Airway Assessment for Office Sedation/Anesthesia. AB - Whenever a patient is about to receive sedation or general anesthesia, no matter what the technique, the preoperative assessment of the airway is one of the most important steps in ensuring patient safety and positive outcomes. This article, Part III in the series on airway management, is directed at the ambulatory office practice and focuses on predicting the success of advanced airway rescue techniques. PMID- 26061581 TI - Reply: To PMID 25517552. PMID- 26061584 TI - New Biology and United Nations Sustainable Development Goals (SDGs) 2016-2030: Values Steering the OMICS: A Journal of Integrative Biology Editorial Flight Deck. PMID- 26061583 TI - A framework for implementation of organ effect models in TOPAS with benchmarks extended to proton therapy. AB - The aim of this work was to develop a framework for modeling organ effects within TOPAS (TOol for PArticle Simulation), a wrapper of the Geant4 Monte Carlo toolkit that facilitates particle therapy simulation. The DICOM interface for TOPAS was extended to permit contour input, used to assign voxels to organs. The following dose response models were implemented: The Lyman-Kutcher-Burman model, the critical element model, the population based critical volume model, the parallel serial model, a sigmoid-based model of Niemierko for normal tissue complication probability and tumor control probability (TCP), and a Poisson-based model for TCP. The framework allows easy manipulation of the parameters of these models and the implementation of other models. As part of the verification, results for the parallel-serial and Poisson model for x-ray irradiation of a water phantom were compared to data from the AAPM Task Group 166. When using the task group dose volume histograms (DVHs), results were found to be sensitive to the number of points in the DVH, with differences up to 2.4%, some of which are attributable to differences between the implemented models. New results are given with the point spacing specified. When using Monte Carlo calculations with TOPAS, despite the relatively good match to the published DVH's, differences up to 9% were found for the parallel-serial model (for a maximum DVH difference of 2%) and up to 0.5% for the Poisson model (for a maximum DVH difference of 0.5%). However, differences of 74.5% (in Rectangle1), 34.8% (in PTV) and 52.1% (in Triangle) for the critical element, critical volume and the sigmoid-based models were found respectively. We propose a new benchmark for verification of organ effect models in proton therapy. The benchmark consists of customized structures in the spread out Bragg peak plateau, normal tissue, tumor, penumbra and in the distal region. The DVH's, DVH point spacing, and results of the organ effect models are provided. The models were used to calculate dose response for a Head and Neck patient to demonstrate functionality of the new framework and indicate the degree of variability between the models in proton therapy. PMID- 26061585 TI - Sensitive detection of atrazine in tap water using TELISA. AB - A highly sensitive flow injection analysis (FIA)-based thermal enzyme-linked immunoassay, TELISA, was developed for the rapid detection of atrazine (ATZ) in tap water. ATZ and beta-lactamase-labeled ATZ were employed in a competitive immunoassay using a monoclonal antibody (mAb). After the off-column liquid-phase competition, the mAb was captured on the Protein G SepharoseTM 4 Fast Flow (PGSFF) column support material. Injected beta-lactamase substrate ampicillin was degraded by the column-bound ATZ-beta-lactamase, generating a detectable heat signal. Several assay parameters were optimized, including substrate concentration, flow rates and regeneration conditions, as well as the mAb and ATZ beta dilution ratios and concentrations. The assay linear range was 0.73-4.83 ng mL(-1) with a detection limit of 0.66 ng mL(-1). An entire heat signal requires 10 min for generation, and the cycle time is less than 40 min. The results were reproducible and stable. ATZ-spiked tap water samples exhibited a recovery rate of 103%-116%, which correlated with the UHPLC-MS/MS measurements. We attributed this significant increase in sensitivity over our previously published work to the following factors: (i) the capture of already-formed immune complexes on the column via immobilized Protein G, which eliminated chemical immobilization of the antibody; (ii) off-column preincubation allows the formation of immune complexes under nearly ideal conditions; and (iii) multiple buffers can be used to, in one case, enhance immune-complex formation and in the other to maximize enzymatic activity. Furthermore, the scheme creates a universal assay platform in which sensing is performed in the off-column incubation and detection after capture in the enzyme thermistor (ET) detector, which opens up the possibility of detecting any antigen for which antibodies were available. PMID- 26061586 TI - Temporal trends in cardiovascular demand in EMS: Weekday versus weekend differences. AB - Diagnosed cardiovascular disease has well-reported temporal patterns, with demand distribution peaks in the late morning and greater case numbers on Mondays and in winter. We aimed to report temporal patterns of presumptive cardiovascular disease cases as determined after emergency medical services (EMS) assessment and to characterize the demand distribution by day of the week. We conducted a secondary analysis of all Ambulance Victoria cases in metropolitan Melbourne (Victoria, Australia) between January 2008 and December 2011. Analyzed data included time of call, incident mechanism, location type, final assessment (paramedic "diagnosis") and patient age. We employed Poisson's regression to analyze case numbers and trigonometric regression to quantify distribution patterns. The 182 983 cases of presumptive cardiovascular disease observed during the study period constituted 15.2% of total demand. The median age of persons attended was 72 (IQR 57-82) and there was an almost even split between genders (51% female). Peak numbers of most cardiovascular case types occurred between 09:00 and 11:00; the only exception was acute pulmonary edema, which had peak case numbers at 06:00. Trigonometric regression showed distinct time of day distribution patterns, which did not alter by season. Although weekend day demand was lower than on Mondays, due to a different distribution pattern, these differences were not constant over the 24-hour period. There were up to 27% fewer cases at 09:00 and up to 2.8% more cases at 01:00 on weekends compared to Mondays. We have shown that examination of presumptive cardiovascular disease using not only case counts but also demand distribution patterns allows for a greater understanding of ambulance demand. Monday might be the most frequent day for cardiovascular cases but different patterns of demand occur on weekends. Increased knowledge of when different types of cases are most likely to occur will help inform EMS planning, including paramedic capacity and resources. PMID- 26061587 TI - Social jetlag, academic achievement and cognitive performance: Understanding gender/sex differences. AB - Adolescents in high school suffer from circadian misalignment, undersleeping on weekdays and oversleeping on weekends. Since high schools usually impose early schedules, adolescents suffer from permanent social jetlag (SJL) and thus are a suitable population to study the effects of SJL on both academic and cognitive performance. In this study, 796 adolescents aged 12-16 years reported information about their sleep habits, morningness-eveningness (M-E), cognitive abilities and grade point average (GPA). Time in bed on both weekdays and weekends was not related to cognitive abilities, and only time in bed on weekdays was related to academic achievement. SJL was negatively related to academic achievement, cognitive abilities (except for vocabulary and verbal fluency abilities) and general cognitive ability (g), whereas M-E was slightly positively related to academic achievement and marginally negatively related to inductive reasoning. Results separated by sex/gender indicated that SJL may be more detrimental to girls' performance, as it was negatively related to a greater number of cognitive abilities and GPA. PMID- 26061589 TI - Morningness-eveningness and the environment hypothesis - A cross-cultural comparison of Turkish and German adolescents. AB - Individuals differ in morningness-eveningness, which is their preferred time for intellectual and physical activities. Although it is a basic human trait, cross cultural comparisons are scarce but interesting because they help to determine the influence of exogenous factors, such as ambient temperature, climate and photoperiod. We here compare a large sample of German and Turkish adolescents (N = 26 465) by using the Composite Scale of Morningness and the Morning Affect Factor. First, we show that the Morning Affect Factor and Morningness scores are equivalent in both countries and we report country differences with Turkish adolescents scoring higher on morningness (F1,26 038 = 1293.313, p < 0.001) and in the morning affect (F1,26 038 = 133.833, p < 0.001). This fits into the environment hypothesis suggesting that populations near the equator should be more morning oriented. Meanwhile, gender differences were small and adolescents showed a lower morningness and a lower morning affect with increasing age. PMID- 26061590 TI - Morphological Control of Anisotropic Self-Assemblies from Alternating Poly(p dioxanone)-poly(ethylene glycol) Multiblock Copolymer Depending on the Combination Effect of Crystallization and Micellization. AB - A novel and facile method was developed for morphological controlling of self assemblies prepared by crystallization induced self-assembly of crystalline-coil copolymer depending on the combination effect of crystallization and micellization. The morphological evolution of the self-assemblies of alternating poly(p-dioxanone)-block-poly(ethylene glycol) (PPDO-PEG) multiblock copolymer prepared by different solvent mixing methods in aqueous solution were investigated. "Chrysanthemum"-like and "star anise"-like self-assemblies were obtained at different rates of solvent mixing. The results suggested gradually change in solvent quality (slowly dropping water into DMF solution) leaded to a hierarchical micellization-crystallization process of core-forming PPDO blocks, and flake-like particles were formed at the initial stage of crystallization. Meanwhile, crystallization induced micellization process occurred when solvent quality changed drastically. Shuttle-like particles, which have much smaller size than those of flake-like particles, were formed at the initial stage of crystallization when quickly injecting water into DMF solution of the copolymer. Therefore, owing to the different changing rate of solvent quality, which may result in different combination effect of crystallization and micellization during self-assembly of the copolymer, PPDO-PEG self-assemblies with different hierarchical morphology in nano scale could be obtained. PMID- 26061588 TI - Irregular 24-hour activity rhythms and the metabolic syndrome in older adults. AB - Circadian rhythms - near 24 h intrinsic biological rhythms - modulate many aspects of human physiology and hence disruption of circadian rhythms may have an important impact on human health. Experimental work supports a potential link between irregular circadian rhythms and several key risk factors for cardiovascular disease including hypertension, obesity, diabetes and dyslipidemia, collectively termed the metabolic syndrome. While several epidemiological studies have demonstrated an association between shift-work and the components of the metabolic syndrome in working-age adults, there is a relative paucity of data concerning the impact of non-occupational circadian irregularity in older women and men. To address this question, we studied 7 days of actigraphic data from 1137 older woman and men participating in the Rush Memory and Aging Project, a community-based cohort study of the chronic conditions of aging. The regularity of activity rhythms was quantified using the nonparametric interdaily stability metric, and was related to the metabolic syndrome and its components obesity, hypertension, diabetes and dyslipidemia. More regular activity rhythms were associated with a lower odds of having the metabolic syndrome (OR = 0.69, 95% CI = 0.60-0.80, p = 5.8 * 10(-7)), being obese (OR = 0.73, 95% CI = 0.63-0.85, p = 2.5 * 10(-5)), diabetic (OR = 0.76, 95% CI = 0.65-0.90, p = 9.3 * 10(-4)), hypertensive (OR = 0.78, 95% CI = 0.66-0.91, p = 2.0 * 10(-3)) or dyslipidemic (OR = 0.82, 95% CI = 0.72-0.92, p = 1.2 * 10(-3)). These associations were independent of differences in objectively measured total daily physical activity or rest, and were not accounted for by prevalent coronary artery disease, stroke or peripheral artery disease. Moreover, more regular activity rhythms were associated with lower odds of having cardiovascular disease (OR = 0.83; 95% CI = 0.73-0.95, p = 5.7 * 10(-3)), an effect that was statistically mediated by the metabolic syndrome. We conclude that irregular activity rhythms are associated with several key components of the metabolic syndrome in older community-dwelling adults, and that the metabolic syndrome statistically partially mediates the association between activity rhythms and prevalent cardiovascular disease. Although additional longitudinal and experimental studies are needed to conclusively delineate the causal relationships underlying these associations, these findings are consistent with preclinical data, and add further support for investigations of the irregularity of activity rhythms as a potential therapeutic target to decrease the burden of cardiovascular disease in older adults. PMID- 26061591 TI - Incidence of In Situ and Invasive Melanoma in Denmark From 1985 Through 2012: A National Database Study of 24,059 Melanoma Cases. AB - IMPORTANCE: In Denmark, the incidence of malignant melanoma (MM) has doubled during the past 25 years, with an incidence of 29.5 and 31.7 per 100,000 person years in 2012 for men and women, respectively. Understanding the nature of this increase in incidence is important to optimize prevention, early diagnosis, and treatment of in situ and invasive melanoma in Denmark. OBJECTIVE: To describe changes over time in the incidence and clinical and pathologic characteristics of in situ and invasive melanoma in Denmark from 1985 through 2012. DESIGN, SETTING, AND PARTICIPANTS: We used the official national Danish Melanoma Group database to describe all eligible, prospectively registered cases of in situ and invasive melanoma in Denmark from January 1, 1985, through December 31, 2012. Data analyses were performed from April 1, 2012, through January 31, 2013. MAIN OUTCOMES AND MEASURES: Estimated annual percentage changes (EAPCs) for men and women in European age-standardized incidence, age at diagnosis, and tumor region for in situ melanoma and MM. For MM only, melanoma type, Breslow thickness, ulceration, and mortality. RESULTS: We included 3299 cases of in situ melanoma and 20,760 cases of MM. The incidence (95% CI) of MM increased by 4.5% (3.6% 5.3%) for men and 4.3% (3.5%-5.2%) for women, which was especially pronounced in patients older than 60 years (EAPCs, 5.8% [4.7%-6.8%] and 4.8% [3.8%-5.9%], respectively), in thin (Breslow thickness, <0.75 mm) melanoma (EAPCs, 6.6% [5.0% 8.2%] and 6.1% [6.0%-7.1%], respectively), and in superficially spreading MM (EAPCs, 5.2% [4.3%-6.2%] and 4.7% [3.9%-5.7%], respectively). We found no significant EAPC in the incidence of melanomas with Breslow thickness greater than 2.00 mm in women, and relative ulceration rates (95% CI) declined in both sexes (EAPCs, -3.3% [-4.0% to -2.6%] in men and -3.4% [-4.0% to -2.8%] in women). More proximal tumor location occurred over time (P < .001). Incidence of in situ melanoma (95% CI) greatly increased (EAPCs, 14.0% [12.2%-15.8%] in men and 11.6% [10.2%-13.2%] in women) with changes over time in age and region (defined by codes in the International Statistical Classification of Diseases, Tenth Revision) similar to those for MM. Mortality related to MM increased in men (EAPC, 0.6% [0.1% to 1.2%]), whereas mortality in women (EAPC, -0.4% [-1.0% to 0.3%]) remained stable. CONCLUSIONS AND RELEVANCE: This study confirms a worldwide increase in melanoma incidence. Results may indicate the importance of secondary melanoma prevention in Denmark. Future efforts could intensify primary prevention aimed at young adults, adolescents, and children and maintain and target secondary prevention at the population older than 60 years. PMID- 26061592 TI - Manipulating surface-plasmon-polariton launching with quasi-cylindrical waves. AB - Launching the free-space light to the surface plasmon polaritons (SPPs) in a broad bandwidth is of importance for the future plasmonic circuits. Based on the interference of the pure SPP component, the bandwidths of the unidirectional SPP launching is difficult to be further broadened. By greatly manipulating the SPP intensities with the quasi-cylindrical waves (Quasi-CWs), an ultra-broadband unidirectional SPP launcher is experimentally realized in a submicron asymmetric slit. In the nano-groove of the asymmetric slit, the excited Quasi-CWs are not totally damped, and they can be scattered into the SPPs along the metal surface. This brings additional interference and thus greatly manipulates the SPP launching. Consequently, a broadband unidirectional SPP launcher is realized in the asymmetric slit. More importantly, it is found that this principle can be extended to the three-dimensional subwavelength plasmonic waveguide, in which the excited Quasi-CWs in the aperture could be effectively converted to the tightly guided SPP mode along the subwavelength plasmonic waveguide. In the large wavelength range from about 600 nm to 1300 nm, the SPP mode mainly propagates to one direction along the plasmonic waveguide, revealing an ultra-broad (about 700 nm) operation bandwidth of the unidirectional SPP launching. PMID- 26061594 TI - Magnetic compression for treatment of large oesophageal diverticula: a new endoscopic approach for a risky surgical disease? PMID- 26061593 TI - Pathogenesis of pancreatic cancer exosome-induced lipolysis in adipose tissue. AB - BACKGROUND AND OBJECTIVES: New-onset diabetes and concomitant weight loss occurring several months before the clinical presentation of pancreatic cancer (PC) appear to be paraneoplastic phenomena caused by tumour-secreted products. Our recent findings have shown exosomal adrenomedullin (AM) is important in development of diabetes in PC. Adipose tissue lipolysis might explain early onset weight loss in PC. We hypothesise that lipolysis-inducing cargo is carried in exosomes shed by PC and is responsible for the paraneoplastic effects. Therefore, in this study we investigate if exosomes secreted by PC induce lipolysis in adipocytes and explore the role of AM in PC-exosomes as the mediator of this lipolysis. DESIGN: Exosomes from patient-derived cell lines and from plasma of patients with PC and non-PC controls were isolated and characterised. Differentiated murine (3T3-L1) and human adipocytes were exposed to these exosomes to study lipolysis. Glycerol assay and western blotting were used to study lipolysis. Duolink Assay was used to study AM and adrenomedullin receptor (ADMR) interaction in adipocytes treated with exosomes. RESULTS: In murine and human adipocytes, we found that both AM and PC-exosomes promoted lipolysis, which was abrogated by ADMR blockade. AM interacted with its receptor on the adipocytes, activated p38 and extracellular signal-regulated (ERK1/2) mitogen activated protein kinases and promoted lipolysis by phosphorylating hormone sensitive lipase. PKH67-labelled PC-exosomes were readily internalised into adipocytes and involved both caveolin and macropinocytosis as possible mechanisms for endocytosis. CONCLUSIONS: PC-secreted exosomes induce lipolysis in subcutaneous adipose tissue; exosomal AM is a candidate mediator of this effect. PMID- 26061595 TI - ABO blood type B and fucosyltransferase 2 non-secretor status as genetic risk factors for chronic pancreatitis. PMID- 26061596 TI - Applications of text mining within systematic reviews. AB - Systematic reviews are a widely accepted research method. However, it is increasingly difficult to conduct them to fit with policy and practice timescales, particularly in areas which do not have well indexed, comprehensive bibliographic databases. Text mining technologies offer one possible way forward in reducing the amount of time systematic reviews take to conduct. They can facilitate the identification of relevant literature, its rapid description or categorization, and its summarization. In this paper, we describe the application of four text mining technologies, namely, automatic term recognition, document clustering, classification and summarization, which support the identification of relevant studies in systematic reviews. The contributions of text mining technologies to improve reviewing efficiency are considered and their strengths and weaknesses explored. We conclude that these technologies do have the potential to assist at various stages of the review process. However, they are relatively unknown in the systematic reviewing community, and substantial evaluation and methods development are required before their possible impact can be fully assessed. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061597 TI - Comprehensive computer searches and reporting in systematic reviews. AB - Systematic reviews (SR) are a strategic resource for many who may assume that comprehensive computer searches are used to identify the studies that are used in SR. The current study assessed the reports of comprehensive computer searching in SR in psychology. Comprehensive computer search methods listed as basic in SR manuals and publications of major SR organizations (e.g., Cochrane Collaboration) were the "recommended methods" that became items on a checklist used to assess computer search reports. A methodology index search in PsycINFO identified SR in psychology that were compared to SR identified in the Cochrane Database of SR. Checklist item frequencies supported descriptive analyses, and Mann-Whitney U test was used to compare the PsycINFO and Cochrane SR. Two recommended computer search methods were significantly more common in Cochrane SR: truncation (z = 5.64, p < .001), controlled vocabulary (z = -5.08, p < .001 ). A third search method (Cited Reference Searching) was virtually absent (SR in psychology: 0/25; and Cochrane SR: 1/25). Confidence in SR conclusions may be undermined when evidence of recommended or empirically-based search methods is not seen. Results and suggestions might have value for those who use, evaluate, or develop guidelines for SR; research topics are also described. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061598 TI - Using logic models to capture complexity in systematic reviews. AB - Logic models have long been used to understand complex programs to improve social and health outcomes. They illustrate how a program is designed to achieve its intended outcomes. They also can be used to describe connections between determinants of outcomes, for example, low high-school graduation rates or spiraling obesity rates, thus aiding the development of interventions that target causal factors. However, these models have not often been used in systematic reviews. This paper argues that logic models can be valuable in the systematic review process. First, they can aid in the conceptualization of the review focus and illustrate hypothesized causal links, identify effect mediators or moderators, specify intermediate outcomes and potential harms, and justify a priori subgroup analyses when differential effects are anticipated. Second, logic models can be used to direct the review process more specifically. They can help justify narrowing the scope of a review, identify the most relevant inclusion criteria, guide the literature search, and clarify interpretation of results when drawing policy-relevant conclusions about review findings. We present examples that explain how logic models have been used and how they can be applied at different stages in a systematic review. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061599 TI - Linear inference for mixed treatment comparison meta-analysis: A two-stage approach. AB - Mixed treatment comparisons (MTC) meta-analysis synthesises comparative evidence on multiple treatments or other interventions from a collection of randomised controlled trials (RCT) available in a research area, while still respecting the randomisation structure in RCTs. This paper sets out to examine the properties of MTC estimates and elucidate the concept of consistency between direct and indirect evidence in MTC networks. We decompose MTC synthesis into two stages. At the first stage, ordinary meta-analysis is performed in each group of trials that have the same treatment comparators-this provides the 'direct' estimates of relative effect parameters. At the second stage, the optimal consistent estimates that minimise the distance between the direct estimates and the consistency hyper plane can be deduced as the weighted least squares solution to a linear regression model with a specific design matrix that represents the consistency conditions. The consistent MTC estimates can then be represented explicitly as linear combinations of direct estimates, and under normality assumptions the overall evidence consistency can be tested with a likelihood-ratio statistic. This two-stage framework further allows us to use the leverage statistics to diagnose influence of the first-stage evidence and use the regression residuals to assess local inconsistency. The method is illustrated with two examples from medical research. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061600 TI - Fixed effects and variance components estimation in three-level meta-analysis. AB - Meta-analytic methods have been widely applied to education, medicine, and the social sciences. Much of meta-analytic data are hierarchically structured because effect size estimates are nested within studies, and in turn, studies can be nested within level-3 units such as laboratories or investigators, and so forth. Thus, multilevel models are a natural framework for analyzing meta-analytic data. This paper discusses the application of a Fisher scoring method in two-level and three-level meta-analysis that takes into account random variation at the second and third levels. The usefulness of the model is demonstrated using data that provide information about school calendar types. sas proc mixed and hlm can be used to compute the estimates of fixed effects and variance components. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061601 TI - Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Abeta (beta-amyloid) plaques in Alzheimer's disease. AB - BACKGROUND: PET radiopharmaceuticals capable of imaging beta-amyloid (Abeta) plaque burden in the brain could offer highly valuable diagnostic tools for clinical studies of Alzheimer's disease. To further supplement existing armamentarium of FDA-approved agents as well as those under development, and to correlate multiphoton-imaging data reported earlier, herein, we describe preclinical validation of a PET tracer. METHODS: A novel PET radiopharmaceutical ((18)F-7B) was synthesized and characterized. To assess its affinity for Abeta, binding assays with Abeta1-42 fibrils, Alzheimer's disease (AD) homogenates, and autoradiography studies and their IHC correlations were performed. For assessing its overall pharmacokinetic profiles in general and its ability to cross the blood-brain barrier (BBB) in particular, biodistribution studies in normal mice were performed. Finally, for evaluating potential for (18)F-7B to serve as a targeted Abeta probe, the microPET/CT imaging was performed in age-matched amyloid precursor protein/presenilin-1 (APP/PS1) mice and wild-type (WT) counterparts. RESULTS: The radiotracer (18)F-7B shows saturable binding to autopsy-confirmed AD homogenates (K d = 17.7 nM) and Abeta1-42 fibrils (K d = 61 nM). Preliminary autoradiography studies show binding of (18)F-7B to cortical Abeta plaques in autopsy-confirmed AD tissue sections, inhibition of that binding by unlabeled counterpart 7A-indicating specificity, and a good correlation of tracer binding with Abeta immunostaining. The agent indicates high initial penetration into brains (7.23 +/- 0.47%ID/g; 5 min) of normal mice, thus indicating a 5-min/120-min brain uptake clearance ratio of 4.7, a benchmark value (>4) consistent with the ability of agents to traverse the BBB to enable PET brain imaging. Additionally, (18)F-7B demonstrates the presence of parental species in human serum. Preliminary microPET/CT imaging demonstrates significantly higher retention of (18)F-7B in brains of transgenic mice compared with their WT counterparts, consistent with expected binding of the radiotracer to Abeta plaques, present in APP/PS1 mice, compared with their age-matched WT counterparts lacking those Abeta aggregates. CONCLUSIONS: These data offer a platform scaffold conducive to further optimization for developing new PET tracers to study Abeta pathophysiology in vitro and in vivo. PMID- 26061602 TI - Radiosynthesis and first preclinical evaluation of the novel norepinephrine transporter pet-ligand [(11)C]ME@HAPTHI. AB - BACKGROUND: The norepinephrine transporter (NET) has been demonstrated to be relevant to a multitude of neurological, psychiatric and cardiovascular pathologies. Due to the wide range of possible applications for PET imaging of the NET together with the limitations of currently available radioligands, novel PET tracers for imaging of the cerebral NET with improved pharmacological and pharmacodynamic properties are needed. METHODS: The present study addresses the radiosynthesis and first preclinical evaluation of the novel NET PET tracer [(11)C]Me@HAPTHI by describing its affinity, selectivity, metabolic stability, plasma free fraction, blood-brain barrier (BBB) penetration and binding behaviour in in vitro autoradiography. RESULTS: [(11)C]Me@HAPTHI was prepared and displayed outstanding affinity and selectivity as well as excellent in vitro metabolic stability, and it is likely to penetrate the BBB. Moreover, selective NET binding in in vitro autoradiography was observed in human brain and rat heart tissue samples. CONCLUSIONS: All preclinical results and radiosynthetic key-parameters indicate that the novel benzothiadiazole dioxide-based PET tracer [(11)C]Me@HAPTHI is a feasible and improved NET radioligand and might prospectively facilitate clinical NET imaging. PMID- 26061603 TI - Hierarchical ZnCo2 O4 @NiCo2 O4 Core-Sheath Nanowires: Bifunctionality towards High-Performance Supercapacitors and the Oxygen-Reduction Reaction. AB - Increasing energy demands and worsening environmental issues have stimulated intense research on alternative energy storage and conversion systems including supercapacitors and fuel cells. Here, a rationally designed hierarchical structure of ZnCo2 O4 @NiCo2 O4 core-sheath nanowires synthesized through facile electrospinning combined with a simple co-precipitation method is proposed. The obtained core-sheath nanostructures consisting of mesoporous ZnCo2 O4 nanowires as the core and uniformly distributed ultrathin NiCo2 O4 nanosheets as the sheath, exhibit excellent electrochemical activity as bifunctional materials for supercapacitor electrodes and oxygen reduction reaction (ORR) catalysts. Compared with the single component of either ZnCo2 O4 nanowires or NiCo2 O4 nanosheets, the hierarchical ZnCo2 O4 @NiCo2 O4 core-sheath nanowires demonstrate higher specific capacitance of 1476 F g(-1) (1 A g(-1) ) and better rate capability of 942 F g(-1) (20 A g(-1) ), while maintaining 98.9 % capacity after 2000 cycles at 10 A g(-1) . Meanwhile, the ZnCo2 O4 @NiCo2 O4 core-sheath nanowires reveal comparable catalytic activity but superior stability and methanol tolerance over Pt/C as ORR catalyst. The impressive performance may originate from the unique hierarchical core-sheath structures that greatly facilitate enhanced reactivity, and faster ion and electron transfer. PMID- 26061604 TI - Mangrove dolabrane-type of diterpenes tagalsins suppresses tumor growth via ROS mediated apoptosis and ATM/ATR-Chk1/Chk2-regulated cell cycle arrest. AB - Natural compounds are an important source for drug development. With an increasing cancer rate worldwide there is an urgent quest for new anti-cancer drugs. In this study, we show that a group of dolabrane-type of diterpenes, collectively named tagalsins, isolated from the Chinese mangrove genus Ceriops has potent cytotoxicity on a panel of hematologic cancer cells. Investigation of the molecular mechanisms by which tagalsins kill malignant cells revealed that it induces a ROS-mediated damage of DNA. This event leads to apoptosis induction and blockage of cell cycle progression at S-G2 phase via activation of the ATM/ATR Chk1/Chk2 check point pathway. We further show that tagalsins suppress growth of human T-cell leukemia xenografts in vivo. Tagalsins show only minor toxicity on healthy cells and are well tolerated by mice. Our study shows a therapeutic potential of tagalsins for the treatment of hematologic malignancies and a new source of anticancer drugs. PMID- 26061608 TI - Semibullvalene and diazasemibullvalene: recent advances in the synthesis, reaction chemistry, and synthetic applications. AB - Semibullvalene (SBV) and its aza analogue 2,6-diazasemibullvalene (NSBV) are theoretically interesting and experimentally challenging organic molecules because of four unique features: highly strained ring systems, intramolecular skeletal rearrangement, extremely rapid degenerate (aza-)Cope rearrangement, and the predicted existence of neutral homoaromatic delocalized structures. SBV has received much attention in the past 50 years. In contrast, after NSBV was predicted in 1971 and the first in situ synthesis was realized in 1982, no progress on NSBV chemistry was made until our results in 2012. We have been interested in the reaction chemistry of 1,4-dilithio-1,3-butadienes (dilithio reagents for short), especially for their applications in the synthesis of SBV and NSBV, because (i) the cyclodimerization of dilithio reagents could provide the potential eight-carbon skeleton of SBV from four-carbon butadiene units and (ii) the insertion reaction of dilithio reagents with C=N bonds of two nitriles could provide a 6C + 2N skeleton that might be a good precursor for the synthesis of NSBV. Therefore, we initiated a journey into the synthesis and reaction chemistry of SBV and NSBV starting from dilithio reagents that has been ongoing since 2006. In this Account, we outline mainly our recent achievements in the synthesis, structural characterization, reaction chemistry, synthetic application, and theoretical/computational analysis of NSBV. Two efficient strategies for the synthesis of NSBV from dilithio reagents and nitriles via oxidant-induced C-N bond formation are described. Structural investigations of NSBV, including X-ray crystal structure analysis, determination of the activation barrier for the aza-Cope rearrangement, and theoretical analysis, show that the localized structure of NSBV is the predominant form and that the homoaromatic delocalized structure exists as a minor component in the equilibrium. We also discuss the reaction chemistry and synthetic applications of NSBV. Several novel reaction patterns have been explored, including thermolysis, C-N bond insertion, rearrangement-cycloaddition, oxidation, and nucleophilic ring-opening reactions. Diverse and interesting N-containing polycyclic skeletons can be constructed, such as nickelaazetidine, 1,5-diazatriquinacenes, and triazabrexadienes, which are not available by other means. Our results show that NSBV not only features a rapid aza-Cope rearrangement with a low activation barrier but also acts as unique synthetic reagent that is significantly different from aziridine. The strained rigid ring systems as a whole can be involved in the reactions. Our achievements highlight two significant advances: (i) the well-established efficient synthesis and isolation of NSBV has greatly accelerated the development of NSBV chemistry, and (ii) the previously unattainable molecules have become "normal" and routine starting materials for the synthesis of otherwise unavailable but interesting structures. We expect that our pursuits will inspire and help direct future chemical and physical research on NSBV. PMID- 26061605 TI - An Inverse Relationship Between Weight and Free Thyroxine During Early Gestation Among Women Treated for Hypothyroidism. AB - BACKGROUND: Following treatment sufficient to normalize thyrotropin (TSH), nonpregnant hypothyroid adults display higher free thyroxine (FT(4)) concentrations than a reference population. Our aim is to determine whether FT(4) concentrations are higher during pregnancy among women treated for hypothyroidism and whether their weight is associated with FT(4) levels. Weight/FT(4) relationships have not previously been reported in treated hypothyroid adults (either pregnant or nonpregnant). METHODS: Thyroid-related measurements were available from over 10,000 women at two early pregnancy time periods from the FaSTER (First and Second Trimester Evaluation of Risk for Fetal aneuploidy) trial (1999-2002). All women were receiving routine prenatal care. Present analyses were restricted to 9267 reference women and 306 treated, hypothyroid women with TSH between the 2nd and 98th reference percentiles. We compared FT(4) values between those groups at 11-14 and 15-18 weeks' gestation, using linear regression to estimate FT(4)/maternal weight relationships, after accounting for treatment and other potential covariates. RESULTS: In comparison to reference women, median FT(4) values and percent of FT(4) values >=95th reference percentile were significantly higher in treated women at both 11-14 and 15-18 weeks' gestation (p<0.001) overall and after stratification by weight into tertiles. Among both treated and reference women, median FT(4) decreased monotonically with increasing weight, regardless of anti-thyroperoxidase antibody status. Maternal age, maternal weight, and treatment status were important predictors of FT(4) levels (p<0.001, defined by partial r(2) values of 1% or higher). Anti-thyroperoxidase antibody status, TSH values (after logarithmic transformation), and all interaction terms were well below an r(2) of 1%. FT(4) levels were 1.45 pmol/L higher in treated than reference women, independent of other factors. Maternal age and weight reduced FT(4) levels by 0.0694 pmol/L/y and 0.0208 pmol/L/kg, respectively. CONCLUSIONS: FT(4) concentrations are higher among treated hypothyroid pregnant women than among reference women, and higher maternal weight is associated with lower FT(4) levels, regardless of treatment status. This inverse relationship is not associated with higher TSH levels. While no immediate clinical implications are attached to the current observations, increased peripheral deiodinase activity in the presence of higher weight might explain these findings. Further investigation appears worthy of attention. PMID- 26061610 TI - Does Combining Aripiprazole With Other Antipsychotics Worsen Psychosis? PMID- 26061609 TI - Transdermal Estradiol Treatment for Postpartum Depression: A Pilot, Randomized Trial. AB - Postpartum depression occurs in 14.5% of women in the first 3 months after birth. This study was an 8-week acute phase randomized trial with 3 cells (transdermal estradiol [E2], sertraline [SERT], and placebo [PL]) for the treatment of postpartum major depressive disorder. However, the study was stopped after batch analysis revealed that the E2 serum concentrations were lower than prestudy projections. This paper explores our experiences that will inform future investigations of therapeutic E2 use. Explanations for the low E2 concentrations were as follows: (1) study patch nonadhesion, which did not explain the low concentrations across the entire sample. (2) Ineffective transdermal patch preparations, although 2 different patch preparations were used and no significant main effect of patch type on E2 concentrations was found. (3) Obesity, at study entry, E2-treated women had body mass index of 32.9 (7.4) (mean [SD]). No pharmacokinetic data comparing E2 concentrations from transdermal patches in obese women versus normal weight controls are available. (4) Induction of cytochrome P450 (CYP450) 3A4 and other E2 elimination pathways in pregnancy. CYP4503A4 is induced in pregnancy and is a pathway for the metabolism of E2. Conversion to estrone and phase II metabolism via glucuronidation and sulfation, which also increase in pregnancy, are routes of E2 elimination. The time required for these pathways to normalize after delivery has not been elucidated. The observation that transdermal E2 doses greater than 100 MUg/d did not increase serum concentrations was unexpected. Another hypothesis consistent with this observation is suppression of endogenous E2 secretion with increasing exogenous E2 dosing. PMID- 26061611 TI - Dependence on Internet-Purchased Ethylphenidate. PMID- 26061612 TI - Paliperidone Palmitate Long-Acting Injectable Given Intramuscularly in the Deltoid Versus the Gluteal Muscle: Are They Therapeutically Equivalent? AB - Paliperidone palmitate long-acting injectable is a second-generation antipsychotic indicated for the treatment of schizophrenia. According to the product monograph, the monthly maintenance dose of paliperidone palmitate can be given in either the deltoid or gluteal muscle. Unfortunately, many clinicians may misinterpret these directions to mean that these intramuscular sites are interchangeable, and thus therapeutically equivalent. Currently, the literature on this topic is sparse, but the published pharmacokinetic studies and Food and Drug Administration submission data on paliperidone palmitate show discrepancies in the elimination half-life, peak plasma concentration, and absorption rate that are dependent on the site of injection. The degree of shifts in pharmacokinetic parameters suggests that paliperidone palmitate injections via the deltoid and gluteal muscle are not bioequivalent and therefore are not therapeutically equivalent. Thus, using the same maintenance dosing regimen at both sites or switching between sites of injection may result in unforeseen consequences in patient outcomes. PMID- 26061613 TI - Relationship between particle elasticity, glass fragility, and structural relaxation in dense microgel suspensions. AB - "Fragile" glassy materials, which include most polymeric materials and organic liquids, exhibit a steep and super-Arrhenius dependence of relaxation time with temperature upon the glass transition and have been extensively studied. Yet, a full understanding of strong glass formers that exhibit an Arrhenius dependence on temperature is still lacking. In this work, we have investigated the glassy dynamics of poly(N-isopropylacrylamide) (PNIPAM) microgel particles of varied elasticity in dense aqueous suspensions, giving rise to a full spectrum of strong to fragile glass-forming behaviors. We have observed the dependence of particle motions and structural relaxation on particle volume fraction can be weakened by decreasing particle elasticity, due to particle deformation and the resulting interparticle elastic interaction upon intimate particle contacts at high particle concentration. Both measured alpha-relaxation time scales and dynamic length scales for cooperative rearranging motions of microgels in suspensions show similarly dependence on particle volume fraction and elasticity, thereby quantifying the glass fragility of dense microgel suspension of varied particle elasticity. PMID- 26061615 TI - CAD/CAM-fabricated implant-supported restorations: a systematic review. AB - OBJECTIVES: The aim of this systematic review was to identify and summarize the available literature related to CAD/CAM-fabricated implant-supported restorations. MATERIALS AND METHODS: A systematic review of the literature was conducted using the Cochrane Library and the US Library of Medicine, National Institute of Health databases (Pubmed). Several search runs with specific search terms were performed and combined. All published papers available on the databases up to January 15, 2015 were considered with primarily no restrictions. RESULTS: About 12 of 3484 identified papers met the inclusion criteria and were analyzed in the present review. One paper reported results on implant-supported single crowns (SCs), one on partial fixed dental prostheses (FDPs), and 10 papers reported results on full-arch screw-retained FDPs. Publications on SCs and FDPs were very limited but it was possible to identify 10 papers reporting adequate results on full-arch screw-retained FDPs. Survival rates ranged between 92% and 100% with observation times of 1-10 years. CONCLUSION: The available data provided promising results for CAD/CAM-fabricated implant-supported restorations; nonetheless, current evidence is limited due to the quality of available studies and the paucity of data on long-term clinical outcomes of 5 years or more. In the sense of an evidence-based dentistry, the authors recommend further studies designed as randomized controlled clinical trials and reported according to the CONSORT statement. PMID- 26061616 TI - Melt-grafting for the synthesis of core-shell nanoparticles with ultra-high dispersant density. AB - Superparamagnetic iron oxide nanoparticles (NPs) are used in a rapidly expanding number of applications in e.g. the biomedical field, for which brushes of biocompatible polymers such as poly(ethylene glycol) (PEG) have to be densely grafted to the core. Grafting of such shells to monodisperse iron oxide NPs has remained a challenge mainly due to the conflicting requirements to replace the ligand shell of as-synthesized NPs with irreversibly bound PEG dispersants. We introduce a general two-step method to graft PEG dispersants from a melt to iron oxide NPs first functionalized with nitrodopamine (NDA). This method yields uniquely dense spherical PEG-brushes (~3 chains per nm(2) of PEG(5 kDa)) compared to existing methods, and remarkably colloidally stable NPs also under challenging conditions. PMID- 26061614 TI - Mechanisms of Damage to DNA Labeled with Electrophilic Nucleobases Induced by Ionizing or UV Radiation. AB - Hypoxia--a hallmark of solid tumors--makes hypoxic cells radioresistant. On the other hand, DNA, the main target of anticancer therapy, is not sensitive to the near UV photons and hydrated electrons, one of the major products of water radiolysis under hypoxic conditions. A possible way to overcome these obstacles to the efficient radio- and photodynamic therapy of cancer is to sensitize the cellular DNA to electrons and/or ultraviolet radiation. While incorporated into genomic DNA, modified nucleosides, 5-bromo-2'-deoxyuridine in particular, sensitize cells to both near-ultraviolet photons and gamma rays. It is believed that, in both sensitization modes, the reactive nucleobase radical is formed as a primary product which swiftly stabilizes, leading to serious DNA damage, like strand breaks or cross-links. However, despite the apparent similarity, such radio- and photosensitization of DNA seems to be ruled by fundamentally different mechanisms. In this review, we demonstrate that the most important factors deciding on radiodamage to the labeled DNA are (i) the electron affinity (EA) of modified nucleoside (mNZ), (ii) the local surroundings of the label that significantly influences the EA of mNZ, and (iii) the strength of the chemical bond holding together the substituent and a nucleobase. On the other hand, we show that the UV damage to sensitized DNA is governed by long-range photoinduced electron transfer, the efficiency of which is controlled by local DNA sequences. A critical review of the literature mechanisms concerning both types of damage to the labeled biopolymer is presented. Ultimately, the perspectives of studies on DNA sensitization in the context of cancer therapy are discussed. PMID- 26061619 TI - Rectal biopsy, rather than ileal, is appropriate to confirm the diagnosis of early gastrointestinal graft-versus-host disease. AB - OBJECTIVE: Once gastrointestinal (GI) graft-versus-host disease (GVHD) occurs after hematopoietic stem cell transplantation, it may be life-threatening. Therefore, an earlier accurate diagnosis of macroscopic and microscopic features using an appropriate modality improves the prognosis of patients with suspected GI-GVHD. PATIENTS AND METHODS: In patients experiencing watery diarrhea within 100 days after hematopoietic stem cell transplantation, we evaluated the severity of mucosal injury at the proximal ileum, terminal ileum, and rectum according to previously reported criteria using transanal single balloon endoscopy. GI-GVHD was diagnosed by the presence of gland apoptosis without inflammatory or infectious factors in the biopsied specimens obtained from their respective site regardless of the mucosal lesion. RESULTS: Consecutive suspected GI-GVHD patients with watery diarrhea (11 men and 5 women, mean age: 45.6 years, coexistent symptoms: nausea [38%] and exanthema [69%]) were enrolled. GI-GVHD was identified pathologically in 11 patients (69%), all of whom had pathological findings of GI GVHD at the rectum. However, eight patients (73%) had pathological findings of GI GVHD at both the ileum and the rectum and none had pathological findings of GI GVHD at the ileum alone. The accuracies for a pathological diagnosis of GI-GVHD based on endoscopic features were 44%, 44%, and 38% at the proximal ileum, terminal ileum, and rectum, respectively. The severity of mucosal injury had no association with the diagnostic rate of pathological GI-GVHD at any site. CONCLUSIONS: A pathological evaluation of the rectum but not the ileum may be important and useful for the accurate diagnosis of early GI-GVHD. PMID- 26061620 TI - Industry-Cost-Curve Approach for Modeling the Environmental Impact of Introducing New Technologies in Life Cycle Assessment. AB - The environmental costs and benefits of introducing a new technology depend not only on the technology itself, but also on the responses of the market where substitution or displacement of competing technologies may occur. An internationally accepted method taking both technological and market-mediated effects into account, however, is still lacking in life cycle assessment (LCA). For the introduction of a new technology, we here present a new approach for modeling the environmental impacts within the framework of LCA. Our approach is motivated by consequential life cycle assessment (CLCA) and aims to contribute to the discussion on how to operationalize consequential thinking in LCA practice. In our approach, we focus on new technologies producing homogeneous products such as chemicals or raw materials. We employ the industry cost-curve (ICC) for modeling market-mediated effects. Thereby, we can determine substitution effects at a level of granularity sufficient to distinguish between competing technologies. In our approach, a new technology alters the ICC potentially replacing the highest-cost producer(s). The technologies that remain competitive after the new technology's introduction determine the new environmental impact profile of the product. We apply our approach in a case study on a new technology for chlor-alkali electrolysis to be introduced in Germany. PMID- 26061621 TI - The assembly and disassembly of the AcrAB-TolC three-component multidrug efflux pump. AB - In Gram-negative bacteria, tripartite efflux pumps, like AcrAB-TolC from Escherichia coli, play a prominent role in the resistance against multiple antibiotics. Transport of the drugs across the outer membrane and its coupling to the electrochemical gradient is dependent on the presence of all three components. As the activity of the E. coli AcrAB-TolC efflux pump is dependent on both the concentration of substrates and the extent of the electrochemical gradient across the inner membrane, the dynamics of tripartite pump assembly and disassembly might be crucial for effective net transport of drugs towards the outside of the cell. PMID- 26061622 TI - Obesity: epigenetic regulation - recent observations. AB - Genetic and environmental factors, especially nutrition and lifestyle, have been discussed in the literature for their relevance to epidemic obesity. Gene environment interactions may need to be understood for an improved understanding of the causes of obesity, and epigenetic mechanisms are of special importance. Consequences of epigenetic mechanisms seem to be particularly important during certain periods of life: prenatal, postnatal and intergenerational, transgenerational inheritance are discussed with relevance to obesity. This review focuses on nutrients, diet and habits influencing intergenerational, transgenerational, prenatal and postnatal epigenetics; on evidence of epigenetic modifiers in adulthood; and on animal models for the study of obesity. PMID- 26061623 TI - Synonymous and nonsynonymous distances help untangle convergent evolution and recombination. AB - When estimating a phylogeny from a multiple sequence alignment, researchers often assume the absence of recombination. However, if recombination is present, then tree estimation and all downstream analyses will be impacted, because different segments of the sequence alignment support different phylogenies. Similarly, convergent selective pressures at the molecular level can also lead to phylogenetic tree incongruence across the sequence alignment. Current methods for detection of phylogenetic incongruence are not equipped to distinguish between these two different mechanisms and assume that the incongruence is a result of recombination or other horizontal transfer of genetic information. We propose a new recombination detection method that can make this distinction, based on synonymous codon substitution distances. Although some power is lost by discarding the information contained in the nonsynonymous substitutions, our new method has lower false positive probabilities than the comparable recombination detection method when the phylogenetic incongruence signal is due to convergent evolution. We apply our method to three empirical examples, where we analyze: (1) sequences from a transmission network of the human immunodeficiency virus, (2) tlpB gene sequences from a geographically diverse set of 38 Helicobacter pylori strains, and (3) hepatitis C virus sequences sampled longitudinally from one patient. PMID- 26061624 TI - Membrane tension and cytoskeleton organization in cell motility. AB - Cell membrane shape changes are important for many aspects of normal biological function, such as tissue development, wound healing and cell division and motility. Various disease states are associated with deregulation of how cells move and change shape, including notably tumor initiation and cancer cell metastasis. Cell motility is powered, in large part, by the controlled assembly and disassembly of the actin cytoskeleton. Much of this dynamic happens in close proximity to the plasma membrane due to the fact that actin assembly factors are membrane-bound, and thus actin filaments are generally oriented such that their growth occurs against or near the membrane. For a long time, the membrane was viewed as a relatively passive scaffold for signaling. However, results from the last five years show that this is not the whole picture, and that the dynamics of the actin cytoskeleton are intimately linked to the mechanics of the cell membrane. In this review, we summarize recent findings concerning the role of plasma membrane mechanics in cell cytoskeleton dynamics and architecture, showing that the cell membrane is not just an envelope or a barrier for actin assembly, but is a master regulator controlling cytoskeleton dynamics and cell polarity. PMID- 26061626 TI - Corrigendum: Clinical effectiveness and cost-effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer: a systematic review and economic evaluation. PMID- 26061625 TI - From Glacier to Sauna: RNA-Seq of the Human Pathogen Black Fungus Exophiala dermatitidis under Varying Temperature Conditions Exhibits Common and Novel Fungal Response. AB - Exophiala dermatitidis (Wangiella dermatitidis) belongs to the group of the so called black yeasts. Thanks in part to its thick and strongly melanized cell walls, E. dermatitidis is extremely tolerant to various kinds of stress, including extreme pH, temperature and desiccation. E. dermatitidis is also the agent responsible for various severe illnesses in humans, such as pneumonia and keratitis, and might lead to fatal brain infections. Due to its association with the human environment, its poly-extremophilic lifestyle and its pathogenicity in humans, E. dermatitidis has become an important model organism. In this study we present the functional analysis of the transcriptional response of the fungus at 1 degrees C and 45 degrees C, in comparison with that at 37 degrees C, for two different exposition times, i.e. 1 hour and 1 week. At 1 degrees C, E. dermatitidis uses a large repertoire of tools to acclimatize, such as lipid membrane fluidization, trehalose production or cytoskeleton rearrangement, which allows the fungus to remain metabolically active. At 45 degrees C, the fungus drifts into a replicative state and increases the activity of the Golgi apparatus. As a novel finding, our study provides evidence that, apart from the protein coding genes, non-coding RNAs, circular RNAs as well as fusion transcripts are differentially regulated and that the function of the fusion transcripts can be related to the corresponding temperature condition. This work establishes that E. dermatitidis adapts to its environment by modulating coding and non-coding gene transcription levels and through the regulation of chimeric and circular RNAs. PMID- 26061627 TI - Versatile Core-Shell Nanoparticle@Metal-Organic Framework Nanohybrids: Exploiting Mussel-Inspired Polydopamine for Tailored Structural Integration. AB - We report a versatile strategy based on the use of multifunctional mussel inspired polydopamine for constructing well-defined single-nanoparticle@metal organic framework (MOF) core-shell nanohybrids. The capability of polydopamine to form a robust conformal coating on colloidal substrates of any composition and to direct the heterogeneous nucleation and growth of MOFs makes it possible for customized structural integration of a broad range of inorganic/organic nanoparticles and functional MOFs. Furthermore, the unique redox activity of polydopamine adds additional possibilities to tailor the functionalities of the nanohybrids by sandwiching plasmonic/catalytic metal nanostructures between the core and shell via localized reduction. The core-shell nanohybrids, with the molecular sieving effect of the MOF shell complementing the intrinsic properties of nanoparticle cores, represent a unique class of nanomaterials of considerable current interest for catalysis, sensing, and nanomedicine. PMID- 26061628 TI - Understanding Water Storage Practices of Urban Residents of an Endemic Dengue Area in Colombia: Perceptions, Rationale and Socio-Demographic Characteristics. AB - INTRODUCTION: The main preventive measure against dengue virus transmission is often based on actions to control Ae. Aegypti reproduction by targeting water containers of clean and stagnant water. Household water storage has received special attention in prevention strategies but the evidence about the rationale of this human practice is limited. The objective was to identify and describe water storage practices among residents of an urban area in Colombia (Girardot) and its association with reported perceptions, rationales and socio-demographic characteristics with a mixed methods approach. METHODS: Knowledge, attitudes and practices and entomological surveys from 1,721 households and 26 semi-structured interviews were conducted among residents of Girardot and technicians of the local vector borne disease program. A multivariate analysis was performed to identify associations between a water storage practice and socio-demographic characteristics, and knowledge, attitudes and practices about dengue and immature forms of the vector, which were then triangulated with qualitative information. RESULTS: Water storage is a cultural practice in Girardot. There are two main reasons for storage: The scarcity concern based on a long history of shortages of water in the region and the perception of high prices in water rates, contrary to what was reported by the local water company. The practice of water storage was associated with being a housewife (Inverse OR: 2.6, 95% CI 1.5 -4.3). The use of stored water depends on the type of container used, while water stored in alberca (Intra household cement basins) is mainly used for domestic cleaning chores, water in plastic containers is used for cooking. CONCLUSIONS: It is essential to understand social practices that can increase or reduce the number of breeding sites of Ae. Aegypti. Identification of individuals who store water and the rationale of such storage allow a better understanding of the social dynamics that lead to water accumulation. PMID- 26061629 TI - Behavioral Immunity Suppresses an Epizootic in Caribbean Spiny Lobsters. AB - Sociality has evolved in a wide range of animal taxa but infectious diseases spread rapidly in populations of aggregated individuals, potentially negating the advantages of their social interactions. To disengage from the coevolutionary struggle with pathogens, some hosts have evolved various forms of "behavioral immunity"; yet, the effectiveness of such behaviors in controlling epizootics in the wild is untested. Here we show how one form of behavioral immunity (i.e., the aversion of diseased conspecifics) practiced by Caribbean spiny lobsters (Panulirus argus) when subject to the socially transmitted PaV1 virus, appears to have prevented an epizootic over a large seascape. We capitalized on a "natural experiment" in which a die-off of sponges in the Florida Keys (USA) resulted in a loss of shelters for juvenile lobsters over a ~2500km2 region. Lobsters were thus concentrated in the few remaining shelters, presumably increasing their exposure to the contagious virus. Despite this spatial reorganization of the population, viral prevalence in lobsters remained unchanged after the sponge die-off and for years thereafter. A field experiment in which we introduced either a healthy or PaV1-infected lobster into lobster aggregations in natural dens confirmed that spiny lobsters practice behavioral immunity. Healthy lobsters vacated dens occupied by PaV1-infected lobsters despite the scarcity of alternative shelters and the higher risk of predation they faced when searching for a new den. Simulations from a spatially-explicit, individual-based model confirmed our empirical results, demonstrating the efficacy of behavioral immunity in preventing epizootics in this system. PMID- 26061630 TI - Biodegradable Gelatin Microcarriers Facilitate Re-Epithelialization of Human Cutaneous Wounds - An In Vitro Study in Human Skin. AB - The possibility to use a suspended tridimensional matrix as scaffolding for re epithelialization of in vitro cutaneous wounds was investigated with the aid of a human in vitro wound healing model based on viable full thickness skin. Macroporous gelatin microcarriers, CultiSpher-S, were applied to in vitro wounds and cultured for 21 days. Tissue sections showed incorporation of wound edge keratinocytes into the microcarriers and thicker neoepidermis in wounds treated with microcarriers. Thickness of the neoepidermis was measured digitally, using immunohistochemical staining of keratins as epithelial demarcation. Air-lifting of wounds enhanced stratification in control wounds as well as wounds with CultiSpher-S. Immunohistochemical staining revealed expression of keratin 5, keratin 10, and laminin 5 in the neoepidermal component. We conclude that the CultiSpher-S microcarriers can function as tissue guiding scaffold for re epithelialization of cutaneous wounds. PMID- 26061631 TI - Coccidian Parasites and Conservation Implications for the Endangered Whooping Crane (Grus americana). AB - While the population of endangered whooping cranes (Grus americana) has grown from 15 individuals in 1941 to an estimated 304 birds today, the population growth is not sufficient to support a down-listing of the species to threatened status. The degree to which disease may be limiting the population growth of whooping cranes is unknown. One disease of potential concern is caused by two crane-associated Eimeria species: Eimeria gruis and E. reichenowi. Unlike most species of Eimeria, which are localized to the intestinal tract, these crane associated species may multiply systemically and cause a potentially fatal disease. Using a non-invasive sampling approach, we assessed the prevalence and phenology of Eimeria oocysts in whooping crane fecal samples collected across two winter seasons (November 2012-April 2014) at the Aransas National Wildlife Refuge along the Texas Gulf coast. We also compared the ability of microscopy and PCR to detect Eimeria in fecal samples. Across both years, 26.5% (n = 328) of fecal samples were positive for Eimeria based on microscopy. Although the sensitivity of PCR for detecting Eimeria infections seemed to be less than that of microscopy in the first year of the study (8.9% vs. 29.3%, respectively), an improved DNA extraction protocol resulted in increased sensitivity of PCR relative to microscopy in the second year of the study (27.6% and 20.8%, respectively). The proportion of positive samples did not vary significantly between years or among sampling sites. The proportion of Eimeria positive fecal samples varied with date of collection, but there was no consistent pattern of parasite shedding between the two years. We demonstrate that non-invasive fecal collections combined with PCR and DNA sequencing techniques provides a useful tool for monitoring Eimeria infection in cranes. Understanding the epidemiology of coccidiosis is important for management efforts to increase population growth of the endangered whooping crane. PMID- 26061632 TI - Defect Engineering and Phase Junction Architecture of Wide-Bandgap ZnS for Conflicting Visible Light Activity in Photocatalytic H2 Evolution. AB - ZnS is among the superior photocatalysts for H2 evolution, whereas the wide bandgap restricts its performance to only UV region. Herein, defect engineering and phase junction architecture from a controllable phase transformation enable ZnS to achieve the conflicting visible-light-driven activities for H2 evolution. On the basis of first-principle density functional theory calculations, electron spin resonance and photoluminescence results, etc., it is initially proposed that the regulated sulfur vacancies in wurtzite phase of ZnS play the key role of photosensitization units for charge generation in visible light and active sites for effective electron utilization. The symbiotic sphalerite-wurtzite phase junctions that dominate the charge-transfer kinetics for photoexciton separation are the indispensable configuration in the present systems. Neither ZnS samples without phase junction nor those without enough sulfur vacancies conduct visible light photocatalytic H2 evolution, while the one with optimized phase junctions and maximum sulfur vacancies shows considerable photocatalytic activity. This work will not only contribute to the realization of visible light photocatalysis for wide-bandgap semiconductors but also broaden the vision on the design of highly efficient transition metal sulfide photocatalysts. PMID- 26061633 TI - Ultrafast Electron Emission from a Sharp Metal Nanotaper Driven by Adiabatic Nanofocusing of Surface Plasmons. AB - We report photoelectron emission from the apex of a sharp gold nanotaper illuminated via grating coupling at a distance of 50 MUm from the emission site with few-cycle near-infrared laser pulses. We find a fifty-fold increase in electron yield over that for direct apex illumination. Spatial localization of the electron emission to a nanometer-sized region is demonstrated by point projection microscopic imaging of a silver nanowire. Our results reveal negligible plasmon-induced electron emission from the taper shaft and thus efficient nanofocusing of few-cycle plasmon wavepackets. This novel, remotely driven emission scheme offers a particularly compact source of ultrashort electron pulses of immediate interest for miniaturized electron microscopy and diffraction schemes with ultrahigh time resolution. PMID- 26061634 TI - Ubiquitin-specific protease 14 modulates degradation of cellular prion protein. AB - Prion diseases are fatal neurodegenerative disorders characterized by the accumulation of prion protein (PrP(C)). To date, there is no effective treatment for the disease. The accumulated PrP, termed PrP(Sc), forms amyloid fibrils and could be infectious. It has been suggested that PrP(Sc) is abnormally folded and resistant to proteolytic degradation, and also inhibits proteasomal functions in infected cells, thereby inducing neuronal death. Recent work indicates that the ubiquitin-proteasome system is involved in quality control of PrP(C). To reveal the significance of prion protein ubiqitination, we focused on ubiquitin-specific protease 14 (USP14), a deubiqutinating enzyme that catalyzes trimming of polyubiquitin chains and plays a role in regulation of proteasomal processes. Results from the present study showed that treatment with a selective inhibitor of USP14 reduced PrP(C), as well as PrP(Sc), levels in prion-infected neuronal cells. Overexpression of the dominant negative mutant form of USP14 reduced PrP(Sc), whereas wildtype USP14 increased PrP(Sc) in prion-infected cells. These results suggest that USP14 prevents degradation of both normal and abnormal PrP. Collectively, a better understanding about the regulation of PrP(Sc) clearance caused by USP14 might contribute greatly to the development of therapeutic strategies for prion diseases. PMID- 26061635 TI - An Examination of the Prevalence, Consumer Profiles, and Patterns of Energy Drink Use, With and Without Alcohol, in Australia. AB - BACKGROUND: There has been a significant growth in the energy drink (ED) market in Australia and around the world; however, most research investigating the popularity of ED and alcohol and energy drink (AED) use has focused on specific subpopulations such as university students. The aim of this study was to estimate the prevalence, consumption patterns, and sociodemographic correlates of ED and combined AED use among a representative Australian population sample. METHODS: A computer-assisted telephone interview survey (n = 2,000) was undertaken in March April 2013 of persons aged 18 years and over. Half of the interviews were obtained through randomly generated landline telephone numbers and half through mobile phones. Approximately half of the sample was female (55.5%; n = 1,110) and the mean age of participants was 45.9 (range 18 to 95, SD 20.0). RESULTS: Less than 1 in 6 Australians reported ED use (13.4%, n = 268) and 4.6% (n = 91) reported AED use in the past 3 months. Majority of ED and AED users consumed these beverages monthly or less. ED and AED users are more likely to be aged 18 to 24 years, live in a metropolitan area, and be moderate risk or problem gamblers. AED consumers are more likely to report moderate levels of psychological distress. CONCLUSIONS: Our findings in relation to problem gambling and psychological distress are novel and require further targeted investigation. Health promotion strategies directed toward reducing ED and AED use should focus on young people living in metropolitan areas and potentially be disseminated through locations where gambling takes place. PMID- 26061637 TI - Georeferencing deaths from stroke in Sao Paulo: an intra-city stroke belt? AB - BACKGROUND: The role of socioeconomic status in the worldwide stroke burden has been studied with various methods using vital statistics and research-generated data. AIM: The objective of our study was to describe the stroke mortality rates and the stroke mortality distribution, and to evaluate the association between stroke mortality rates and geographical distribution with the human development index in Sao Paulo, Brazil. METHODS: This ecological study evaluated a historical series of stroke mortality in Sao Paulo, Brazil, from 2004 to 2010. Standard stroke mortality rate per 100 000 inhabitants at each year, the address of residence assumed as the place of living, and the human development index applied as a social indicator were used in order to evaluate if stroke mortality correlated with socioeconomic status. RESULTS: The mean standardized stroke mortality in Sao Paulo decreased from 66 to 46.7 per 100 000 inhabitants from 2004 to 2010. Stroke mortality differed according to human development index strata with an almost three times higher stroke mortality in the lowest when compared with the highest human development index stratum. Visual inspection of the map of the districts with high stroke mortality disclosed regional clusters with high mortality in the east, northwest, and south regions, a finding suggestive of the presence of a stroke belt inside the city of Sao Paulo. CONCLUSIONS: In conclusion, between 2004 and 2010, stroke mortality rates decreased by 28.5% in Sao Paulo. A geographical pattern in stroke mortality could be observed, with considerable differences according the human development index level of the place of living. PMID- 26061636 TI - Aberrant Activation of the RANK Signaling Receptor Induces Murine Salivary Gland Tumors. AB - Unlike cancers of related exocrine tissues such as the mammary and prostate gland, diagnosis and treatment of aggressive salivary gland malignancies have not markedly advanced in decades. Effective clinical management of malignant salivary gland cancers is undercut by our limited knowledge concerning the key molecular signals that underpin the etiopathogenesis of this rare and heterogeneous head and neck cancer. Without knowledge of the critical signals that drive salivary gland tumorigenesis, tumor vulnerabilities cannot be exploited that allow for targeted molecular therapies. This knowledge insufficiency is further exacerbated by a paucity of preclinical mouse models (as compared to other cancer fields) with which to both study salivary gland pathobiology and test novel intervention strategies. Using a mouse transgenic approach, we demonstrate that deregulation of the Receptor Activator of NFkB Ligand (RANKL)/RANK signaling axis results in rapid tumor development in all three major salivary glands. In line with its established role in other exocrine gland cancers (i.e., breast cancer), the RANKL/RANK signaling axis elicits an aggressive salivary gland tumor phenotype both at the histologic and molecular level. Despite the ability of this cytokine signaling axis to drive advanced stage disease within a short latency period, early blockade of RANKL/RANK signaling markedly attenuates the development of malignant salivary gland neoplasms. Together, our findings have uncovered a tumorigenic role for RANKL/RANK in the salivary gland and suggest that targeting this pathway may represent a novel therapeutic intervention approach in the prevention and/or treatment of this understudied head and neck cancer. PMID- 26061638 TI - Negligible degradation upon in situ voltage cycling of a PEMFC using an electrospun niobium-doped tin oxide supported Pt cathode. AB - Novel platinum-catalysed, corrosion-resistant, loose-tube-structured electrocatalysts for proton exchange membrane fuel cells have been obtained using single-needle electrospinning associated with a microwave-assisted polyol method. Monodisperse platinum particles supported on Nb-SnO2 demonstrated higher electrochemical stability than conventional Pt/C electrodes during ex situ potential cycling and comparable activity in the oxygen reduction reaction. In situ fuel cell operation under accelerated stress test conditions of a membrane electrode assembly elaborated using a Pt/C anode and Pt/Nb-SnO2 cathode confirmed that the voltage loss is significantly lower for the novel cathode than for an MEA prepared using conventional Pt/C supported electrocatalysts. Furthermore, the Nb-SnO2 stabilised the supported platinum nanoparticles against dissolution, migration and reprecipitation in the membrane. Pt/Nb-SnO2 loose-tubes constitute a mitigation strategy for two known degradation mechanisms in PEMFC: corrosion of the carbon support at the cathode, and dissolution of Pt at high cell voltages. PMID- 26061640 TI - Ready or Not-Retirement Looms Near for Boomer Nurses. AB - PROBLEM: Nursing has been identified as one of the top 20 occupations that will be affected by baby boomer retirements. Boomer nurses, born between 1946 and 1964, have begun leaving the profession at an alarming rate. This nursing exodus is occurring at a time when demand for nurses is very high, the nursing shortage continues throughout the country, and financial forecasts predict very difficult financial times ahead for boomer nurses. METHODS: A literature review was conducted on research on retirement planning, habits and beliefs of boomer nurses, and the market forces that affect retirement savings. FINDINGS: Boomer nurses will face an unprecedented retirement crisis because they simply have not saved enough for a secure financial future after their retirement from the profession. CONCLUSIONS: The case studies and recommendations in this article suggest that there are actions nurses at all ages can take to improve their retirement savings. Johnson Morrissey. PMID- 26061639 TI - Airborne Transmission of Melioidosis to Humans from Environmental Aerosols Contaminated with B. pseudomallei. AB - Melioidosis results from an infection with the soil-borne pathogen Burkholderia pseudomallei, and cases of melioidosis usually cluster after rains or a typhoon. In an endemic area of Taiwan, B. pseudomallei is primarily geographically distributed in cropped fields in the northwest of this area, whereas melioidosis cases are distributed in a densely populated district in the southeast. We hypothesized that contaminated cropped fields generated aerosols contaminated with B. pseudomallei, which were carried by a northwesterly wind to the densely populated southeastern district. We collected soil and aerosol samples from a 72 km2 area of land, including the melioidosis-clustered area and its surroundings. Aerosols that contained B. pseudomallei-specific TTSS (type III secretion system) ORF2 DNA were well distributed in the endemic area but were rare in the surrounding areas during the rainy season. The concentration of this specific DNA in aerosols was positively correlated with the incidence of melioidosis and the appearance of a northwesterly wind. Moreover, the isolation rate in the superficial layers of the contaminated cropped field in the northwest was correlated with PCR positivity for aerosols collected from the southeast over a 2 year period. According to pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) analyses, PFGE Type Ia (ST58) was the predominant pattern linking the molecular association among soil, aerosol and human isolates. Thus, the airborne transmission of melioidosis moves from the contaminated soil to aerosols and/or to humans in this endemic area. PMID- 26061641 TI - Binding of Trivalent Arsenic onto the Tetrahedral Au20 and Au19Pt Clusters: Implications in Adsorption and Sensing. AB - The interaction of arsenic(III) onto the tetrahedral Au20 cluster was studied computationally to get insights into the interaction of arsenic traces (presented in polluted waters) onto embedded electrodes with gold nanostructures. Pollutant interactions onto the vertex, edge, or inner gold atoms of Au20 were observed to have a covalent character by forming metal-arsenic or metal-oxygen bonding, with adsorption energies ranging from 0.5 to 0.8 eV, even with a stable physisorption; however, in aqueous media, the Au-vertex-pollutant interaction was found to be disadvantageous. The substituent effect of a platinum atom onto the Au20 cluster was evaluated to get insights into the changes in the adsorption and electronic properties of the adsorbent-adsorbate systems due to chemical doping. It was found that the dopant atom increases both the metal-pollutant adsorption energy and stability onto the support in a water media for all interaction modes; adsorption energies were found to be in a range of 0.6 to 1.8 eV. All interactions were determined to be accompanied by electron transfer as well as changes in the local reactivity that determine the amount of transferred charge and a decrease in the HOMO-LUMO energy gap with respect to the isolated substrate. PMID- 26061642 TI - Good Samaritans in Networks: An Experiment on How Networks Influence Egalitarian Sharing and the Evolution of Inequality. AB - The fact that the more resourceful people are sharing with the poor to mitigate inequality-egalitarian sharing-is well documented in the behavioral science research. How inequality evolves as a result of egalitarian sharing is determined by the structure of "who gives whom". While most prior experimental research investigates allocation of resources in dyads and groups, the paper extends the research of egalitarian sharing to networks for a more generalized structure of social interaction. An agent-based model is proposed to predict how actors, linked in networks, share their incomes with neighbors. A laboratory experiment with human subjects further shows that income distributions evolve to different states in different network topologies. Inequality is significantly reduced in networks where the very rich and the very poor are connected so that income discrepancy is salient enough to motivate the rich to share their incomes with the poor. The study suggests that social networks make a difference in how egalitarian sharing influences the evolution of inequality. PMID- 26061644 TI - A defect of the vacuolar putative lipase Atg15 accelerates degradation of lipid droplets through lipolysis. AB - Lipid droplets (LDs) are the conserved organelles for the deposit of neutral lipids, and function as reservoirs of membrane and energy sources. To date, functional links between autophagy and LD dynamics have not been fully elucidated. Here, we report that a vacuolar putative lipase, Atg15, required for degradation of autophagic bodies, is crucial for the maintenance of LD amount in the yeast Saccharomyces cerevisiae in the stationary phase. Mutant analyses revealed that the putative lipase motif and vacuolar localization of Atg15 are important for the maintenance of LD amount. Loss of autophagosome formation by simultaneous deletion of core ATG genes cancelled the reduction in the LD amount in ATG15-deleted cells, indicating that degradation of autophagic bodies accounts for the functional involvement of Atg15 in LD dynamics. The reduced level of LDs in the mutant strain was dependent on Tgl3 and Tgl4, major lipases for lipolysis in S. cerevisiae. An altered phosphorylation status of Tgl3, higher accumulation of Tgl4, and closer associations of Tgl3 and Tgl4 with LDs were detected in the ATG15-deleted cells. Furthermore, increased levels of downstream metabolites of lipolysis in the mutant strain strongly suggested enhanced lipolytic activity caused by loss of ATG15. Our data provide evidence for a novel link between autophagic flux and LD dynamics integrated with Atg15 activity. PMID- 26061645 TI - Food insecurity and dietary intake among US youth, 2007-2010. AB - BACKGROUND: There is limited research describing associations between food insecurity and dietary intake. OBJECTIVE: To examine differences in dietary intake by food security status among a nationally representative sample of children and adolescents in the USA. METHODS: The sample included 5136 children, ages 2-15 years, from the National Nutrition and Health Examination Survey, 2007 2010. Propensity score weighting was used to improve covariate balance between food-secure and food-insecure (marginal, low or very low food security) participants. Multivariate measurement error models were used to model usual intake of various dietary components and assess differences by food security status. RESULTS: Initial analyses using multivariate measurement error models determined there were no differences between food-insecure and food-secure children across several dietary components. In sensitivity analyses, children experiencing very low food security consumed fewer whole grains and more solid fats and added sugars compared with their food-secure counterparts. Some of these differences were attenuated after propensity score weighting, although intake of whole grains and added sugars remained significantly different. CONCLUSIONS: Food insecurity was largely not associated with dietary intake among 2-15-year-old US children, although some differences were observed comparing food-secure children to those experiencing very low food security. PMID- 26061646 TI - A Multidrug-resistant Engineered CAR T Cell for Allogeneic Combination Immunotherapy. AB - The adoptive transfer of chimeric antigen receptor (CAR) T cell represents a highly promising strategy to fight against multiple cancers. The clinical outcome of such therapies is intimately linked to the ability of effector cells to engraft, proliferate, and specifically kill tumor cells within patients. When allogeneic CAR T-cell infusion is considered, host versus graft and graft versus host reactions must be avoided to prevent rejection of adoptively transferred cells, host tissue damages and to elicit significant antitumoral outcome. This work proposes to address these three requirements through the development of multidrug-resistant T cell receptor alphabeta-deficient CAR T cells. We demonstrate that these engineered T cells displayed efficient antitumor activity and proliferated in the presence of purine and pyrimidine nucleoside analogues, currently used in clinic as preconditioning lymphodepleting regimens. The absence of TCRalphabeta at their cell surface along with their purine nucleotide analogues-resistance properties could prevent their alloreactivity and enable them to resist to lymphodepleting regimens that may be required to avoid their ablation via HvG reaction. By providing a basic framework to develop a universal T cell compatible with allogeneic adoptive transfer, this work is laying the foundation stone of the large-scale utilization of CAR T-cell immunotherapies. PMID- 26061647 TI - Arylsulfatase A Overexpressing Human iPSC-derived Neural Cells Reduce CNS Sulfatide Storage in a Mouse Model of Metachromatic Leukodystrophy. AB - Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder resulting from a functional deficiency of arylsulfatase A (ARSA), an enzyme that catalyzes desulfation of 3-O-sulfogalactosylceramide (sulfatide). Lack of active ARSA leads to the accumulation of sulfatide in oligodendrocytes, Schwann cells and some neurons and triggers progressive demyelination, the neuropathological hallmark of MLD. Several therapeutic approaches have been explored, including enzyme replacement, autologous hematopoietic stem cell-based gene therapy, intracerebral gene therapy or cell-based gene delivery into the central nervous system (CNS). However, long-term treatment of the blood-brain-barrier protected CNS remains challenging. Here we used MLD patient-derived induced pluripotent stem cells (iPSCs) to generate long-term self-renewing neuroepithelial stem cells and astroglial progenitors for cell-based ARSA replacement. Following transplantation of ARSA-overexpressing precursors into ARSA-deficient mice we observed a significant reduction of sulfatide storage up to a distance of 300 um from grafted cells. Our data indicate that neural precursors generated via reprogramming from MLD patients can be engineered to ameliorate sulfatide accumulation and may thus serve as autologous cell-based vehicle for continuous ARSA supply in MLD-affected brain tissue. PMID- 26061648 TI - Human Rhinovirus Presenting 4E10 Epitope of HIV-1 MPER Elicits Neutralizing Antibodies in Human ICAM-1 Transgenic Mice. AB - Attempts at eliciting neutralizing antibodies against human immunodeficiency virus (HIV)-1 have generally failed. Computationally designed epitope-scaffold platforms allow transplantation of structural epitopes to scaffold proteins. Human rhinovirus (HRV) allows such engrafting of HIV-1 epitopes on the surface scaffold proteins. However, since HRV infects only humans and great apes, the efficacy of chimeric HRV-based live viral vaccines is difficult to assess in animal models. Here, we used human ICAM-1 transgenic (hICAM-1 Tg) mice that support productive HRV infection to assess the efficacy of chimeric HRV expressing the HIV-1 membrane proximal external region (MPER) epitope, 4E10. Intranasal immunization with chimeric HRV in transgenic mice effectively induced antibodies that recognized 4E10 peptide as well as HIV-1 Env trimer. Importantly, the immunized mouse sera were able to neutralize HIV strains including those belonging to clades B and C. Moreover, intranasal immunization could bypass pre existing immunity to HRV. Thus, chimeric HRV appears to provide a viable vaccine vehicle for HIV-1 immunization in humans. PMID- 26061650 TI - Beckwith-Wiedemann syndrome prenatal diagnosis by methylation analysis in chorionic villi. AB - Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder that can be prenatally suspected or diagnosed based on established clinical guidelines. Molecular confirmation is commonly performed on amniocytes. The possibility to use fresh (CVF) and cultured (CVC) chorionic villi has never been investigated. To verify whether CVF and CVC are reliable sources of DNA to study fetal methylation, we used pyrosequencing to test the methylation level of a number of differentially methylated regions (DMRs) at several imprinted loci (ICR1, ICR2, H19, PWS/AS-ICR, GNASXL, GNAS1A, ZAC/PLAGL1, and MEST) and at non-imprinted MGMT and RASSF1A promoters. We analyzed these regions in 19 healthy pregnancies and highlighted stable methylation levels between CVF and CVC at ICR1, ICR2, GNASXL, PWS/AS-ICR, and MEST. Conversely, the methylation levels at H19 promoter, GNAS1A and ZAC/PLAGL1 were different in CVC compared to fresh CV. We also investigated ICR1 and ICR2 methylation level of CVF/CVC of 2 BWS-suspected fetuses (P1 and P2). P1 showed ICR2 hypomethylation, P2 showed normal methylation at both ICR1 and ICR2. Our findings, although limited to one case of BWS fetus with an imprinting defect, can suggest that ICR1 and ICR2, but not H19, could be reliable targets for prenatal BWS diagnosis by methylation test in CVF and CVC. In addition, PWS/AS-ICR, GNASXL, and MEST, but not GNAS1A and ZAC/PLAGL1, are steadily hemimethylated in CV from healthy pregnancies, independently from culture. Thus, prenatal investigation of genomic imprinting in CV needs to be validated in a locus-specific manner. PMID- 26061651 TI - Development and Initial Validation of a Brief Symptom Measure. AB - Self-report measures of psychiatric symptomatology are important components of treatment monitoring and service evaluation programs. However, the currently available measures have numerous limitations including being symptom or disorder specific, suited to a limited range of clinical settings, and having excessive burden. Consequently, there is a need for a brief and psychometrically robust measure of global symptomatology that is applicable across diverse clinical settings, therapeutic modalities and patient populations. This paper presents the development and initial validation of such a scale, the Brief Symptom Measure-25 (BSM-25). We report findings from multiple samples examining the reliability, validity, sensitivity to change and factor structure of the new instrument. The results suggest that the BSM-25 has good reliability, is suitable to multiple levels of care, sensitive to treatment induced change and has promising validity. Exploratory bifactor modelling revealed that all items loaded strongly on a general factor (bifactor) while also forming two minor group factors. Potential limitations of this study along with future research and clinical applications of the BSM-25 are discussed. KEY PRACTITIONER MESSAGE: The BSM-25 is a broad measure of symptom severity that is easy to administer and score, appropriate for divers patient populations, and suitable for monitoring progress in routine clinical practice. PMID- 26061649 TI - Aptamers Selected to Postoperative Lung Adenocarcinoma Detect Circulating Tumor Cells in Human Blood. AB - Circulating tumor cells (CTCs) are rare cells and valuable clinical markers of prognosis of metastasis formation and prediction of patient survival. Most CTC analyses are based on the antibody-based detection of a few epithelial markers; therefore miss an important portion of mesenchymal cancer cells circulating in blood. In this work, we selected and identified DNA aptamers as specific affinity probes that bind to lung adenocarcinoma cells derived from postoperative tissues. The unique feature of our selection strategy is that aptamers are produced for lung cancer cell biomarkers in their native state and conformation without previous knowledge of the biomarkers. The aptamers did not bind to normal lung cells and lymphocytes, and had very low affinity to A549 lung adenocarcinoma culture. We applied these aptamers to detect CTCs, apoptotic bodies, and microemboli in clinical samples of peripheral blood of lung cancer and metastatic lung cancer patients. We identified aptamer-associated protein biomarkers for lung cancer such as vimentin, annexin A2, annexin A5, histone 2B, neutrophil defensin, and clusterin. Tumor-specific aptamers can be produced for individual patients and synthesized many times during anticancer therapy, thereby opening up the possibility of personalized diagnostics. PMID- 26061653 TI - Attack, parry and riposte: molecular fencing between the innate immune system and human herpesviruses. AB - Once individuals acquire one of the eight human-pathogenic herpesviruses, the upcoming relationship is predefined to last lifelong. Despite the fact that acute phases of herpesviral replication are usually confined and controlled by a concerted action of all branches of the healthy immune system, sterile immunity is never reached. To accomplish this, herpesviruses evolved the unique ability to outlast episodes of efficient immunity in a dormant state called latency and a remarkable array of immune antagonists which counteract most (if not all) relevant aspects of intrinsic, innate and adaptive immune responses. Certain psychological and physiological conditions (such as stress, immuno-suppression or pregnancy) predispose for viral reactivation which can lead to recurrent disease and virus spread. One important pillar of immunity is the innate immune system. The leading cytokines of the innate immune response are interferons (IFN). IFNs reinforce intrinsic immunity, induce a cell-intrinsic antiviral state and recruit and orchestrate adaptive immunity. Consistently, individuals lacking a functional IFN system suffer from otherwise harmless opportunists and live-attenuated vaccines. The selective pressure elicited by IFNs drove herpesviruses to evolve numerous IFN antagonistic gene products. A molecular in-depth understanding of (herpes-) viral IFN antagonists might allow the design of novel antiviral drugs which reconstitute IFN responses by blocking the antagonistic function and thereby help the host to help himself. Additionally, virus mutants lacking immune evasins constitute promising candidates for vaccine viruses. Here we summarize the current knowledge on IFN antagonistic strategies of the eight human herpesviruses and try to decipher common strategies. PMID- 26061652 TI - IFN-Gamma Inhibits JC Virus Replication in Glial Cells by Suppressing T-Antigen Expression. AB - OBJECTIVE: Patients undergoing immune modulatory therapies for the treatment of autoimmune diseases such as multiple sclerosis, and individuals with an impaired immune system, most notably AIDS patients, are in the high risk group of developing progressive multifocal leukoencephalopathy (PML), an often lethal disease of the brain characterized by lytic infection of oligodendrocytes in the central nervous system (CNS) with JC virus (JCV). The immune system plays an important regulatory role in controlling JCV reactivation from latent sites by limiting viral gene expression and replication. However, little is known regarding the molecular mechanisms responsible for this regulation. METHODS AND RESULTS: Here, we investigated the impact of soluble immune mediators secreted by activated PBMCs on viral replication and gene expression by cell culture models and molecular virology techniques. Our data revealed that viral gene expression and viral replication were suppressed by soluble immune mediators. Further studies demonstrated that soluble immune mediators secreted by activated PBMCs inhibit viral replication induced by T-antigen, the major viral regulatory protein, by suppressing its expression in glial cells. This unexpected suppression of T-antigen was mainly associated with the suppression of translational initiation. Cytokine/chemokine array studies using conditioned media from activated PBMCs revealed several candidate cytokines with possible roles in this regulation. Among them, only IFN-gamma showed a robust inhibition of T-antigen expression. While potential roles for IFN-beta, and to a lesser extent IFN-alpha have been described for JCV, IFN-gamma has not been previously implicated. Further analysis of IFN-gamma signaling pathway revealed a novel role of Jak1 signaling in control of viral T-antigen expression. Furthermore, IFN gamma suppressed JCV replication and viral propagation in primary human fetal glial cells, and showed a strong anti-JCV activity. CONCLUSIONS: Our results suggest a novel role for IFN-gamma in the regulation of JCV gene expression via downregulation of the major viral regulatory protein, T-antigen, and provide a new avenue of research to understand molecular mechanisms for downregulation of viral reactivation that may lead to development of novel strategies for the treatment of PML. PMID- 26061654 TI - Self-Crosslinking and Surface-Engineered Polymer Vesicles. PMID- 26061656 TI - Correction: CD36/SR-B2-TLR2 Dependent Pathways Enhance Porphyromonas gingivalis Mediated Atherosclerosis in the Ldlr KO Mouse Model. PMID- 26061655 TI - Cortical Thickness in Dementia with Lewy Bodies and Alzheimer's Disease: A Comparison of Prodromal and Dementia Stages. AB - OBJECTIVES: To assess and compare cortical thickness (CTh) of patients with prodromal Dementia with Lewy bodies (pro-DLB), prodromal Alzheimer's disease (pro AD), DLB dementia (DLB-d), AD dementia (AD-d) and normal ageing. METHODS: Study participants(28 pro-DLB, 27 pro-AD, 31 DLB-d, 54 AD-d and 33 elderly controls) underwent 3Tesla T1 3D MRI and detailed clinical and cognitive assessments. We used FreeSurfer analysis package to measure CTh and investigate patterns of cortical thinning across groups. RESULTS: Comparison of CTh between pro-DLB and pro-AD (p<0.05, FDR corrected) showed more right anterior insula thinning in pro DLB, and more bilateral parietal lobe and left parahippocampal gyri thinning in pro-AD. Comparison of prodromal patients to healthy elderly controls showed the involvement of the same regions. In DLB-d (p<0.05, FDR corrected) cortical thinning was found predominantly in the right temporo-parietal junction, and insula, cingulate, orbitofrontal and lateral occipital cortices. In AD-d(p<0.05, FDR corrected),the most significant areas affected included the entorhinal cortices, parahippocampal gyri and parietal lobes. The comparison of AD-d and DLB d demonstrated more CTh in AD-d in the left entorhinal cortex (p<0.05, FDR corrected). CONCLUSION: Cortical thickness is a sensitive measure for characterising patterns of grey matter atrophy in early stages of DLB distinct from AD. Right anterior insula involvement may be a key region at the prodromal stage of DLB and needs further investigation. PMID- 26061657 TI - Synthesis of a series of new platinum organometallic complexes derived from bidentate Schiff-base ligands and their catalytic activity in the hydrosilylation and dehydrosilylation of styrene. AB - The synthesis and properties of a novel class of platinum complexes containing Schiff bases as O,N-bidentate ligands is described as are the solution and solid state properties of the uncomplexed ligands. The platinum complexes were prepared from [PtBr2(COD)] (COD = 1,5-cyclooctadiene) and N-(2-hydroxy-1 naphthalidene)aniline derivatives in the presence of base (NaOBu(t)). Instead of a substitution reaction to afford cationic species, the addition of the Schiff base ligands results in both the formal loss of two equivalents of bromide and addition of hydroxide to the COD ligand of the complexes. It is proposed that this reaction proceeds through a cationic platinum complex [Pt(N-O)(COD)]Br which then undergoes addition of water and loss of HBr. An example of a dinuclear platinum complex in which two cyclo-octene ligands are bridged by an ether linkage is also reported. The platinum complexes were evaluated as catalysts for the hydrogenative and dehydrogenative silylation of styrene, the resulting behaviour is substituent, time and temperature dependent. PMID- 26061658 TI - Does Trapping Influence Decision-Making under Ambiguity in White-Lipped Peccary (Tayassu pecari)? AB - The white-lipped peccary (Tayassu pecari) is an endangered species whose bold anti-predator behaviour in comparison to related species may increase its vulnerability to hunting and predation. We used a judgement bias test to investigate whether captive peccaries that had recently experienced a trapping event made more 'pessimistic' decisions under ambiguity. If so, this would indicate (i) that the procedure may induce a negative affective state and hence have welfare implications, and (ii) that the species is able to adopt a cautious response style despite its bold phenotype. Eight individuals were trained to 'go' to a baited food bowl when a positive auditory cue (whistle; CS+) was given and to 'no-go' when a negative cue (horn A; CS-) was sounded to avoid a loud sound and empty food bowl. An 'ambiguous' auditory cue (bell; CSA) was presented to probe decision-making under ambiguity. Individuals were subjected to three tests in the order: T1 (control-no trap), T2 (24h after-trap procedure), and T3 (control-no trap). In each test, each animal was exposed to 10 judgement bias trials of each of the three cue types: CS+,CS-,CSA. We recorded whether animals reached the food bowl within 60s ('go' response) and their response speed (m/s). The animals varied in their responses to the CSA cue depending on test type. In all tests, animals made more 'go' responses to CS+ than CSA. During control tests (T1 and T3), the peccaries showed higher proportions of 'go' responses to CSA than to CS-. In T2, however, the animals showed similar proportions of 'go' responses to CSA and CS-, treating the ambiguous cue similarly to the negative cue. There were differences in their response speed according to cue type: peccaries were faster to respond to CS+ than to CS- and CSA. Trapping thus appeared to cause a 'pessimistic' judgement bias in peccaries, which may reflect a negative affective state with implications for the welfare and management of captive individuals, and also function to increase caution and survival chances following such an event in the wild environment. PMID- 26061659 TI - Regulation of cholesteryl ester transfer protein expression by upstream polymorphisms: reduced expression associated with rs247616. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in reverse cholesterol transport by exchanging cholesteryl esters for triglycerides between high-density lipoprotein and low-density lipoprotein particles, effectively decreasing high-density lipoprotein cholesterol levels. Variants within a large haplotype block upstream of CETP (rs247616, rs173539) have been shown to be significantly associated with reduced expression; however, the underlying mechanism has not been identified. METHODS: We analyzed the linkage structure of our top candidate single-nucleotide polymorphism (SNP), rs247616, and assessed each SNP of the haplotype block for potential interactions with transcription factor binding sites. We then used a reporter gene assay to assess the effect of three SNPs (rs247616, rs173539, and rs1723150) on expression in vitro. RESULTS: Several variants in the upstream haplotype, including rs247616, rs173539, and rs1723150, disrupt or generate transcription factor binding sites. In reporter gene assays, rs247616 and rs173539 were found to significantly affected expression in HepG2 cells, whereas rs17231506 had no effect. rs247616 decreased expression by 1.7-fold (P<0.0001), whereas rs173539 increased expression by 2.2 fold (P=0.0006). CONCLUSION: SNPs rs247616 and rs173539 are in high linkage disequilibrium (R=0.96, D'=1.00) and have the potential to regulate CETP expression. Although opposing effects suggest that regulation of CETP expression could vary between tissues, the minor allele of rs247616 and SNPs in high linkage with it were found to be associated with reduced expression across all tissues. PMID- 26061660 TI - Diarrhea, Weight Loss, and an Ampullary Mass. Intraductal papillary mucinous neoplasm. PMID- 26061661 TI - Electronic Cigarettes Efficacy and Safety at 12 Months: Cohort Study. AB - OBJECTIVE: To evaluate the safety and efficacy as a tool of smoking cessation of electronic cigarettes (e-cigarettes), directly comparing users of e-cigarettes only, smokers of tobacco cigarettes only, and smokers of both. DESIGN: Prospective cohort study. Final results are expected in 2019, but given the urgency of data to support policies on electronic smoking, we report the results of the 12-month follow-up. DATA SOURCES: Direct contact and structured questionnaires by phone or via internet. METHODS: Adults (30-75 years) were included if they were smokers of >=1 tobacco cigarette/day (tobacco smokers), users of any type of e-cigarettes, inhaling >=50 puffs weekly (e-smokers), or smokers of both tobacco and e-cigarettes (dual smokers). Carbon monoxide levels were tested in a sample of those declaring tobacco smoking abstinence. MAIN OUTCOME MEASURES: Sustained smoking abstinence from tobacco smoking at 12 months, reduction in the number of tobacco cigarettes smoked daily. DATA SYNTHESIS: We used linear and logistic regression, with region as cluster unit. RESULTS: Follow up data were available for 236 e-smokers, 491 tobacco smokers, and 232 dual smokers (overall response rate 70.8%). All e-smokers were tobacco ex-smokers. At 12 months, 61.9% of the e-smokers were still abstinent from tobacco smoking; 20.6% of the tobacco smokers and 22.0% of the dual smokers achieved tobacco abstinence. Adjusting for potential confounders, tobacco smoking abstinence or cessation remained significantly more likely among e-smokers (adjusted OR 5.19; 95% CI: 3.35-8.02), whereas adding e-cigarettes to tobacco smoking did not enhance the likelihood of quitting tobacco and did not reduce tobacco cigarette consumption. E-smokers showed a minimal but significantly higher increase in self rated health than other smokers. Non significant differences were found in self reported serious adverse events (eleven overall). CONCLUSIONS: Adding e cigarettes to tobacco smoking did not facilitate smoking cessation or reduction. If e-cigarette safety will be confirmed, however, the use of e-cigarettes alone may facilitate quitters remaining so. REGISTRATION NUMBER: NCT01785537. PMID- 26061662 TI - Diving Related Changes in the Blood Oxygen Stores of Rehabilitating Harbor Seal Pups (Phoca vitulina). AB - Harbor seal (Phoca vitulina) pups begin diving within hours of birth, stimulating the development of the blood oxygen (O2) stores necessary to sustain underwater aerobic metabolism. Since harbor seals experience a brief nursing period, the early-life development of these blood O2 stores is necessary for successful post weaning foraging. If mothers and pups become prematurely separated, the pup may be transported to a wildlife rehabilitation center for care. Previous studies suggest that the shallow pools and lack of diving in rehabilitation facilities may lead to under-developed blood O2 stores, but diving behavior during rehabilitation has not been investigated. This study aimed to simultaneously study the diving behaviors and blood O2 store development of rehabilitating harbor seal pups. Standard hematology measurements (Hct, Hb, RBC, MCV, MCH, MCHC) were taken to investigate O2 storage capacity and pups were equipped with time depth recorders to investigate natural diving behavior while in rehabilitation. Linear mixed models of the data indicate that all measured blood parameters changed with age; however, when compared to literature values for wild harbor seal pups, rehabilitating pups have smaller red blood cells (RBCs) that can store less hemoglobin (Hb) and subsequently, less O2, potentially limiting their diving capabilities. Wild pups completed longer dives at younger ages (maximum reported <25 days of age: 9 min) in previous studies than the captive pups in this study (maximum <25 days of age: 2.86 min). However, captivity may only affect the rate of development, as long duration dives were observed (maximum during rehabilitation: 13.6 min at 89 days of age). Further, this study suggests that there may be a positive relationship between RBC size and the frequency of long duration dives. Thus, rehabilitating harbor seal pups should be encouraged to make frequent, long duration dives to prepare themselves for post-release foraging. PMID- 26061663 TI - ACE-I Inhibitory Activity from Phaseolus lunatus and Phaseolus vulgaris Peptide Fractions Obtained by Ultrafiltration. AB - The involvement of angiotensin-I-converting enzyme (ACE-I) as one of the mechanisms controlling blood pressure is being studied to find alternative means of control of hypertension on human beings. On the market there are synthetic drugs that can control it, but these can cause undesirable health side effects. In this work was assessed the fractionation by ultrafiltration of the Lima bean (Phaseolus lunatus) and Jamapa bean (Phaseolus vulgaris), protein hydrolysates obtained with Alcalase((r)) and Flavourzyme((r)) on ACE-I inhibitory activity. Four membranes of different molecular cutoffs (10, 5, 3, and 1 kDa) were used. Fractions that had a higher inhibitory activity in both legumes were denominated as E (<1 kDa) with IC50 of 30.3 and 51.8 MUg/mL values for the P. lunatus with Alcalase and Flavourzyme, respectively, and for the Phaseolus vulgaris with Alcalase and Flavourzyme with about 63.8 and 65.8 MUg/mL values, respectively. The amino acid composition of these fractions showed residues in essential amino acids, which make a good source of energy and amino acids. On the other hand, the presence of hydrophobic amino acids such as V and P is a determining factor in the ACE-I inhibitor effect. The results suggest the possibility of obtaining and utilizing these peptide fractions in the development and innovation of a functional product that helps with treatment and/or prevention of hypertension. PMID- 26061664 TI - De novo 11q13.4q14.3 tetrasomy with uniparental isodisomy for 11q14.3qter. AB - Interstitial triplications in conjunction with uniparental disomy (UPD) have been rarely reported. Here we report on a patient with de novo triplication at 11q13.4 q14.3 and UPD for 11q14.3-qter. Chromosomal analysis showed a karyotype of 46, XYqh+, der (11), and normal parental karyotypes. A single nucleotide polymorphism (SNP) array detected an 18.7 Mb copy number gain consistent with tetrasomy for 11q13.4-q14.3 (chr11:71,002,347 bp-89,725,167 bp, hg19) and absence of heterozygosity for a 45 Mb stretch on 11q and consistent with uniparental isodisomy at 11q14.3-qter (chr11:89,843,477 bp-134,930,689 bp, hg19) in our patient. FISH analysis using two probes on both sides of the tetrasomic region showed an inverted 11q13.4-q14.3 region between two direct oriented 11q13.4-q14.3 segments (11q13.4-q14.3::11q14.3-q13.4::11q13.4-qter). Previously reported features of duplication overlapping 11q13-q14 showed clinical variability. Our patient presented with some of those frequently described features, such as development delay, facial dysmorphism, and microcephaly but without congenital heart disease. Moreover, our patient had in addition a brain anomaly (absence of cerebellar vermis and partial absence of corpus callosum) which has not been reported. To our knowledge, this is the sixth patient reported an intrachromosomal triplication together with UPD. Interstitial 11q duplication overlapping 11q13-q14 is associated with intellectual disability/development delay, microcephaly, and facial dysmorphism but also other malformations. PMID- 26061665 TI - An all-silicon single-photon source by unconventional photon blockade. AB - The lack of suitable quantum emitters in silicon and silicon-based materials has prevented the realization of room temperature, compact, stable, and integrated sources of single photons in a scalable on-chip architecture, so far. Current approaches rely on exploiting the enhanced optical nonlinearity of silicon through light confinement or slow-light propagation, and are based on parametric processes that typically require substantial input energy and spatial footprint to reach a reasonable output yield. Here we propose an alternative all-silicon device that employs a different paradigm, namely the interplay between quantum interference and the third-order intrinsic nonlinearity in a system of two coupled optical cavities. This unconventional photon blockade allows to produce antibunched radiation at extremely low input powers. We demonstrate a reliable protocol to operate this mechanism under pulsed optical excitation, as required for device applications, thus implementing a true single-photon source. We finally propose a state-of-art implementation in a standard silicon-based photonic crystal integrated circuit that outperforms existing parametric devices either in input power or footprint area. PMID- 26061666 TI - Extension of TOPAS for the simulation of proton radiation effects considering molecular and cellular endpoints. AB - The aim of this work is to extend a widely used proton Monte Carlo tool, TOPAS, towards the modeling of relative biological effect (RBE) distributions in experimental arrangements as well as patients. TOPAS provides a software core which users configure by writing parameter files to, for instance, define application specific geometries and scoring conditions. Expert users may further extend TOPAS scoring capabilities by plugging in their own additional C++ code. This structure was utilized for the implementation of eight biophysical models suited to calculate proton RBE. As far as physics parameters are concerned, four of these models are based on the proton linear energy transfer, while the others are based on DNA double strand break induction and the frequency-mean specific energy, lineal energy, or delta electron generated track structure. The biological input parameters for all models are typically inferred from fits of the models to radiobiological experiments. The model structures have been implemented in a coherent way within the TOPAS architecture. Their performance was validated against measured experimental data on proton RBE in a spread-out Bragg peak using V79 Chinese Hamster cells. This work is an important step in bringing biologically optimized treatment planning for proton therapy closer to the clinical practice as it will allow researchers to refine and compare pre defined as well as user-defined models. PMID- 26061667 TI - Specific G-quadruplex structure recognition of human telomeric RNA over DNA by a fluorescently activated hyperporphyrin. AB - Human telomeric repeat-containing RNA (TERRA), which has recently been found to play as important a role in living cells as its DNA counterpart, solely adopts a parallel G-quadruplex (G4) topology. However, developing a highly selective fluorescent probe specific for the TERRA G4 is a great challenge, since difficulty arises in differentiating it from the DNA G4s that possess polymorphic structures including parallel, (3 + 1) hybrid, basket, and chair topologies. In this work, 5,10,15,20-tetrakis(3,5-dihydroxyphenyl)porphyrin (TOH(d)PP) was selected out of various porphyrins as the most efficient fluorescent probe in targeting TERRA. We found that only the TERRA binding is effective in activating the hyperporphyrin spectrum of TOH(d)PP, favoring red-shifted spectral bands and an enhanced fluorescence emission. Following the previous investigations on the TERRA G4 structure and our present experiments, we anticipate that TOH(d)PP most likely interacts with the 5' tetrads of two TERRA G4s via a 1 : 2 sandwich association. The ribose 2'-OH favors the loop adenine residue-extended tetrad G4 plane that is specific for TERRA, thus besides pi-stacking with the G4 tetrads, TOH(d)PP should also interact with this substructure to trigger an efficient electron communication between the tetraphenyl substituents and the porphyrin macrocycle, as required by the hyperporphyrin effect. The hydrogen bonding interactions of the eight hydroxyl substituents in TOH(d)PP with the backbone phosphate oxygen atoms of TERRA most likely further contribute to the binding selectivity. Our work demonstrates the potential of TOH(d)PP as a selective TERRA G4 fluorescent probe and a promising TERRA-based sensor reporter. PMID- 26061670 TI - Correction to Natural Colloidal P and Its Contribution to Plant P Uptake. PMID- 26061668 TI - Stakeholder Engagement in HIV Cure Research: Lessons Learned from Other HIV Interventions and the Way Forward. AB - Clinical and basic science advances have raised considerable hope for achieving an HIV cure by accelerating research. This research is dominated primarily by issues about the nature and design of current and future clinical trials. Stakeholder engagement for HIV cure remains in its early stages. Our analysis examines timing and mechanisms of historical stakeholder engagement in other HIV research areas for HIV-uninfected individuals [vaccine development and pre exposure prophylaxis (PrEP)], and HIV-infected individuals (treatment as prevention, prevention of mother-to-child transmission, and treatment of acute HIV infection) and articulate a plan for HIV cure stakeholder engagement. The experience from HIV vaccine development shows that early engagement of stakeholders helped manage expectations, mitigating the failure of several vaccine trials, while paving the way for subsequent trials. The relatively late engagement of HIV stakeholders in PrEP research may partly explain some of the implementation challenges. The treatment-related stakeholder engagement was strong and community-led from the onset and helped translation from research to implementation. We outline five steps to initiate and sustain stakeholder engagement in HIV cure research and conclude that stakeholder engagement represents a key investment in which stakeholders mutually agree to share knowledge, benefits, and risk of failure. Effective stakeholder engagement prevents misconceptions. As HIV cure research advances from early trials involving subjects with generally favorable prognosis to studies involving greater risk and uncertainty, success may depend on early and deliberate engagement of stakeholders. PMID- 26061671 TI - An Intervention To Enhance the Food Environment in Public Recreation and Sport Settings: A Natural Experiment in British Columbia, Canada. AB - BACKGROUND: Publicly funded recreation and sports facilities provide children with access to affordable physical activities, although they often have unhealthy food environments that may increase child obesity risk. This study evaluated the impact of a capacity-building intervention (Healthy Food and Beverage Sales; HFBS) on organizational capacity for providing healthy food environments, health of vending machine products, and food policy development in recreation and sport facilities in British Columbia, Canada. METHODS: Twenty-one HFBS communities received training, resources, and technical support to improve their food environment over 8 months in 2009-2010, whereas 23 comparison communities did not. Communities self-reported organizational capacity, food policies, and audited vending machine products at baseline and follow-up. Repeated-measures analysis of variance evaluated intervention impact. RESULTS: Intervention and comparison communities reported higher organizational capacity at follow-up; however, improvements were greater in HFBS communities (p<0.001). Healthy vending products increased from 11% to 15% (p<0.05), whereas unhealthy products declined from 56% to 46% (p<0.05) in HFBS communities, with no changes in comparison communities. At baseline 10% of HFBS communities reported having a healthy food policy, whereas 48% reported one at follow-up. No comparison communities had food policies. CONCLUSIONS: This is the first large, controlled study to examine the impact of an intervention to improve recreation and sport facility food environments. HFBS communities increased their self-rated capacity to provide healthy foods, healthy vending product offerings, and food policies to a greater extent than comparison communities. Recreation and sport settings are a priority setting for supporting healthy dietary behaviors among children. PMID- 26061669 TI - Multimodal Discrimination of Alzheimer's Disease Based on Regional Cortical Atrophy and Hypometabolism. AB - Structural MR image (MRI) and 18F-Fluorodeoxyglucose-positron emission tomography (FDG-PET) have been widely employed in diagnosis of both Alzheimer's disease (AD) and mild cognitive impairment (MCI) pathology, which has led to the development of methods to distinguish AD and MCI from normal controls (NC). Synaptic dysfunction leads to a reduction in the rate of metabolism of glucose in the brain and is thought to represent AD progression. FDG-PET has the unique ability to estimate glucose metabolism, providing information on the distribution of hypometabolism. In addition, patients with AD exhibit significant neuronal loss in cerebral regions, and previous AD research has shown that structural MRI can be used to sensitively measure cortical atrophy. In this paper, we introduced a new method to discriminate AD from NC based on complementary information obtained by FDG and MRI. For accurate classification, surface-based features were employed and 12 predefined regions were selected from previous studies based on both MRI and FDG-PET. Partial least square linear discriminant analysis was employed for making diagnoses. We obtained 93.6% classification accuracy, 90.1% sensitivity, and 96.5% specificity in discriminating AD from NC. The classification scheme had an accuracy of 76.5% and sensitivity and specificity of 46.5% and 89.6%, respectively, for discriminating MCI from AD. Our method exhibited a superior classification performance compared with single modal approaches and yielded parallel accuracy to previous multimodal classification studies using MRI and FDG PET. PMID- 26061672 TI - Robust Microcompartments with Hydrophobically Gated Shells. AB - We report on robust synthetic microcompartments with hydrophobically gated shells that can reversibly swell and contract multiple times upon external stimuli. The gating mechanism relies on a hydrophilic-hydrophobic transition of a polymer layer that is grafted on inorganic colloidosomes using atom-transfer radical polymerization. As a result of such a transition, the initially tight hydrophobic shell becomes permeable to the diffusion of hydrophilic solutes across the microcompartment walls. Surprisingly, the microcompartments are strong enough to retain their spherical shape during several swelling and contraction cycles. This provides a powerful alternative platform for the creation of synthetic microreactors and protocells that interact with the surrounding media through a simple gating mechanism and are sufficiently robust for further engineering of increasingly complex compartmentalized structures. PMID- 26061674 TI - Resting-State Functional Connectivity in Psychiatric Disorders. PMID- 26061675 TI - Case Study: Symptomatic Exercise-Associated Hyponatremia in an Endurance Runner Despite Sodium Supplementation. AB - Symptomatic exercise-associated hyponatremia (EAH) is known to be a potential complication from overhydration during exercise, but there remains a general belief that sodium supplementation will prevent EAH. We present a case in which a runner with a prior history of EAH consulted a sports nutritionist who advised him to consume considerable supplemental sodium, which did not prevent him from developing symptomatic EAH during a subsequent long run. Emergency medical services were requested for this runner shortly after he finished a 17-hr, 72-km run and hike in Grand Canyon National Park during which he reported having consumed 9.2-10.6 L of water and >6,500 mg of sodium. First responders determined his serum sodium concentration with point-of-care testing was 122 mEq/L. His hyponatremia was documented to have improved from field treatment with an oral hypertonic solution of 800 mg of sodium in 200 ml of water, and it improved further after significant aquaresis despite in-hospital treatment with isotonic fluids (lactated Ringer's). He was discharged about 5 hr after admission in good condition. This case demonstrates that while oral sodium supplementation does not necessarily prevent symptomatic EAH associated with overhydration, early recognition and field management with oral hypertonic saline in combination with fluid restriction can be effective treatment for mild EAH. There continues to be a lack of universal understanding of the underlying pathophysiology and appropriate hospital management of EAH. PMID- 26061673 TI - Production of monoclonal antibodies against GPCR using cell-free synthesized GPCR antigen and biotinylated liposome-based interaction assay. AB - G-protein-coupled receptors (GPCRs) are one of the most important drug targets, and anti-GPCR monoclonal antibody (mAb) is an essential tool for functional analysis of GPCRs. However, it is very difficult to develop GPCR-specific mAbs due to difficulties in production of recombinant GPCR antigens, and lack of efficient mAb screening method. Here we describe a novel approach for the production of mAbs against GPCR using two original methods, bilayer-dialysis method and biotinylated liposome-based interaction assay (BiLIA), both of which are developed using wheat cell-free protein synthesis system and liposome technology. Using bilayer-dialysis method, various GPCRs were successfully synthesized with quality and quantity sufficient for immunization. For selection of specific mAb, we designed BiLIA that detects interaction between antibody and membrane protein on liposome. BiLIA prevented denaturation of GPCR, and then preferably selected conformation-sensitive antibodies. Using this approach, we successfully obtained mAbs against DRD1, GHSR, PTGER1 and T1R1. With respect to DRD1 mAb, 36 mouse mAbs and 6 rabbit mAbs were obtained which specifically recognized native DRD1 with high affinity. Among them, half of the mAbs were conformation-sensitive mAb, and two mAbs recognized extracellular loop 2 of DRD1. These results indicated that this approach is useful for GPCR mAb production. PMID- 26061676 TI - A further use for the Harvest plot: a novel method for the presentation of data synthesis. AB - When performing a systematic review, whether or not a meta-analysis is performed, graphical displays can be useful. Data do still need to be described, ideally in graphical form. The Harvest plot has been developed to display combined data from several studies that allows demonstration of not only effect but also study quality. We describe a modification to the Harvest plot that allows the presentation of data that normally could not be included in a forest plot meta analysis and allows extra information to be displayed. Using specific examples, we describe how the arrangement of studies, height of the bars and additional information can be used to enhance the plot. This is an important development, which by fulfilling Tufte's nine requirements for graphical presentation, allows researchers to display evidence in a flexible way. This means readers can follow an argument in a clear and efficient manner without the need for large volumes of descriptive text. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061677 TI - The problem of natural funnel asymmetries: a simulation analysis of meta-analysis in macroeconomics. AB - Effect sizes in macroeconomic are estimated by regressions on data published by statistical agencies. Funnel plots are a representation of the distribution of the resulting regression coefficients. They are normally much wider than predicted by the t-ratio of the coefficients and often asymmetric. The standard method of meta-analysts in economics assumes that the asymmetries are because of publication bias causing censoring and adjusts the average accordingly. The paper shows that some funnel asymmetries may be 'natural' so that they occur without censoring. We investigate such asymmetries by simulating funnels by pairs of data generating processes (DGPs) and estimating models (EMs), in which the EM has the problem that it disregards a property of the DGP. The problems are data dependency, structural breaks, non-normal residuals, non-linearity, and omitted variables. We show that some of these problems generate funnel asymmetries. When they do, the standard method often fails. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061678 TI - Inquisitio validus Index Medicus: A simple method of validating MEDLINE systematic review searches. AB - We offer a new method of validation for the effectiveness of MEDLINE searches used in systematic reviews, the Inquisitio Validus Index Medicus. Validation is essential to ensure that relevant studies are not missed by the MEDLINE search strategy. METHODS: To demonstrate the validation method, a sample of six updated Cochrane reviews with comprehensive searches was used. The MEDLINE searches of both the original and updated reviews were tested to determine the percent of eligible MEDLINE-indexed studies retrieved by the search (recall). RESULTS: The validation method was robust and was able to demonstrate that the retrieval of relevant studies from MEDLINE was sub-optimal. The approach to revising searches in our sample appeared unsystematic. Some poorly performing searches were used unchanged in the updates, and of the two amended strategies, one performed worse than the original when tested against studies included in the original, while the other improved recall. CONCLUSION: There is a clear need for search validation. Using this validation method can determine whether the search of the main database performs adequately or needs to be revised to improve recall, allowing the searcher an opportunity to improve their search strategy. Validation of the search is recommended for systematic reviews, where the intent is to identify all relevant studies. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061679 TI - Reliability and validity of three quality rating instruments for systematic reviews of observational studies. AB - To assess the inter-rater reliability, validity, and inter-instrument agreement of the three quality rating instruments for observational studies. Inter-rater reliability, criterion validity, and inter-instrument reliability were assessed for three quality rating scales, the Downs and Black (D&B), Newcastle-Ottawa (NOS), and Scottish Intercollegiate Guidelines Network (SIGN), using a sample of 23 observational studies of musculoskeletal health outcomes. Inter-rater reliability for the D&B (Intraclass correlations [ICC] = 0.73; CI = 0.47-0.88) and NOS (ICC = 0.52; CI = 0.14-0.76) were moderate to good and was poor for the SIGN (kappa = 0.09; CI = -0.22-0.40). The NOS was not statistically valid (p = 0.35), although the SIGN was statistically valid (p < 0.05) with medium to large effect sizes (f(2) = 0.29-0.47). Inter-instrument agreement estimates were kappa = 0.34, CI = 0.05-0.62 (D&B versus SIGN), kappa = 0.26, CI = 0.00-0.52 (SIGN versus NOS), and kappa = 0.43, CI = 0.09-0.78 (D&B versus NOS). Reliability and validity are quite variable across quality rating scales used in assessing observational studies in systematic reviews. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061680 TI - Precision of healthcare systematic review searches in a cross-sectional sample. AB - BACKGROUND: In systematic reviews, search precision is generally traded off against the desire to retrieve all relevant studies; however, there is no published evidence on typical precision values. The objective of this study is to establish typical values for the precision of systematic review searches in healthcare. METHODS: From an existing cross-sectional sample of 300 MEDLINE indexed systematic reviews, those that reported the flow of bibliographic records through the review process (n = 109) were examined. Where the ratio of the number of included studies and the number of unique retrievals could be determined, overall and median precision of the search was calculated. Subgroup analyses were conducted by review type (treatment/prevention, diagnosis/prognosis, epidemiology, other), eligible study designs, number of databases searched and for updates of existing systematic reviews. RESULTS: Precision could be calculated for 94 systematic reviews. The median [interquartile range] precision was 0.029 [0.013, 0.081] with a range of 0.007-0.358. In this sample, precision did not differ significantly in any of the subgroups examined. IMPLICATIONS: Search precision of approximately 3% was typical in this cross-section of health related systematic reviews. This finding is useful for systematic review teams to gauge review resource needs and for information specialists in evaluating their searches. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061681 TI - Article alerts: items from 2010, part I. AB - This third installment of the 'Article Alerts' feature section highlights 100 articles published in 2010 for the print component. More than 400 books and chapters and more than 100 dissertations and theses were added to the archive component since the last installment. Many items in the online supplemental material now include an identifier to facilitate online access. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061682 TI - The cost-effectiveness of celecoxib versus non-steroidal anti-inflammatory drugs plus proton-pump inhibitors in the treatment of osteoarthritis in Saudi Arabia. AB - BACKGROUND: Cyclooxygenase (COX)-2 inhibitors including celecoxib are as effective as non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs) in the treatment of osteoarthritis (OA) and have less gastrointestinal toxicity. Although they are associated with higher treatment costs, COX-2 inhibitors may simultaneously reduce costs associated with adverse events, hence, their overall economic benefit should be assessed. OBJECTIVE: To evaluate the incremental cost effectiveness ratio (ICER) of celecoxib versus ns-NSAIDs, with/without proton pump inhibitor (PPI) co-therapy, for managing OA in Saudi Arabian subjects aged >=65 years. METHODS: The National Institute for Health and Care Excellence health economic model from the UK, updated with relative risks of adverse events using CONDOR trial data, was adapted. Patients received celecoxib or ns-NSAIDs, with/without omeprazole. The effectiveness measure was quality-adjusted life years (QALYs) gained per patient. The analysis was conducted from the patient's perspective. Frequencies of resource use for adverse events were based on data collected in July 2012 from seven private hospitals in Jeddah, Saudi Arabia. Probabilistic sensitivity analysis was performed to construct cost-effectiveness acceptability curves (CEACs). RESULTS: Over a 6-month treatment duration, QALYs gained per patient were higher with celecoxib (0.37) and celecoxib plus PPI (0.40) versus comparators. Ibuprofen plus PPI showed the lowest expected cost per patient (US$ 1,314.50 versus US$ 1,422.80 with celecoxib plus PPI and US$ 1,543.50 with celecoxib). Celecoxib plus PPI was the most cost-effective option with an ICER of US$ 1,805.00, followed by celecoxib (ICER, US$ 7,633.33) versus ibuprofen plus PPI. Over 2- and 5-year treatment durations, celecoxib plus PPI, and celecoxib, showed higher QALYs gained/patient and lower ICERs versus comparators. These ICERs are <1 gross domestic product/capita in Saudi Arabia in 2013 (US$ 25,961). CEACs over 6 months' treatment showed a significantly higher likelihood that celecoxib plus PPI and celecoxib alone would be more cost effective versus comparators once the willingness to pay is over US$ 2,000.00. CONCLUSION: After considering new adverse event risks, celecoxib with/without PPI co-therapy was deemed very cost effective for medium- and long-term use in Saudi Arabian OA patients aged >=65 years. PMID- 26061683 TI - Strain-Induced Reactivity in the Dynamic Covalent Chemistry of Macrocyclic Imines. AB - The displacement of molecular structures from their thermodynamically most stable state by imposition of various types of electronic and conformational constraints generates highly strained entities that tend to release the accumulated strain energy by undergoing either structural changes or chemical reactions. The latter case amounts to strain-induced reactivity (SIR) that may enforce specific chemical transformations. A particular case concerns dynamic covalent chemistry which may present SIR, whereby reversible reactions are activated by coupling to a high-energy state. We herewith describe such a dynamic covalent chemical (DCC) system involving the reversible imine formation reaction. It is based on the formation of strained macrocyclic bis-imine metal complexes in which the macrocyclic ligand is in a high energy form enforced by the coordination of the metal cation. Subsequent demetallation generates a highly strained free macrocycle that releases its accumulated strain energy by hydrolysis and reassembly into a resting state. Specifically, the metal-templated condensation of a dialdehyde with a linear diamine leads to a bis-imine [1+1]-macrocyclic complex in which the macrocyclic ligand is in a coordination-enforced strained conformation. Removal of the metal cation by a competing ligand yields a highly reactive [1+1]-macrocycle, which then undergoes hydrolysis to transient non cyclic aminoaldehyde species, which then recondense to a strain-free [2+2] macrocyclic resting state. The process can be monitored by (1) H NMR spectroscopy. Energy differences between different conformational states have been evaluated by Hartree-Fock (HF) computations. One may note that the stabilisation of high-energy molecular forms by metal ion coordination followed by removal of the latter, offers a general procedure for producing out-of equilibrium molecular states, the fate of which may then be examined, in particular when coupled to dynamic covalent chemical processes. PMID- 26061684 TI - Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. AB - CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP-positive renal carcinogenesis. Genome (whole-exome and copy number), transcriptome and proteome (two-dimensional image converted analysis of liquid chromatography-mass spectrometry) analyses were performed using tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and corresponding specimens of non-cancerous renal cortex. Genes encoding microtubule-associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non-synonymous single-nucleotide mutations and insertions/deletions) in CIMP-positive RCCs, whereas CIMP-negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP-positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the "The metaphase checkpoint (p = 1.427 * 10(-6))," "Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 * 10(-6))" and "Spindle assembly and chromosome separation (p = 9.260 * 10(-6))" pathways. Quantitative RT-PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP-positive than in CIMP-negative RCCs. All CIMP positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP-positive RCCs. PMID- 26061686 TI - Efficacy and Safety of Radiofrequency Ablation Versus Observation for Nonfunctioning Benign Thyroid Nodules: A Randomized Controlled International Collaborative Trial. AB - BACKGROUND: Percutaneous radiofrequency thermal ablation (RFA) has been reported as an effective tool for the management of benign thyroid nodules (BTN). However, large, randomized controlled trials (RCTs) are lacking. OBJECTIVE: The aims of this study were to assess the volume reduction of BTN after a single RFA performed using the moving-shot technique and to compare the volume reduction obtained in patients treated in two centers with different experience of the moving-shot technique. METHOD: This study was an international prospective RCT. It was carried out at the Mauriziano Hospital (Turin, Italy) and the Asan Medical Center (Seoul, Korea). Eighty patients harboring solid, compressive, nonfunctioning BTN (volume 10-20 mL) were enrolled. Twenty patients in each country were treated by RFA using a 18-Gauge internally cooled electrode (group A); 20 nontreated patients in each country were followed as controls (group B). RESULTS: At six months, BTN volume significantly decreased in group A (15.1+/-3.1 mL vs. 4.2+/-2.7 mL; p<0.0001), whereas it remained unchanged in group B (14.4+/ 3.3 mL vs. 15.2+/-3.5 mL). The baseline volume was larger in the Italian series (16.4+/-2.5 mL vs. 13.9+/-3.3 mL, p=0.009). However, at six months, there was no significant difference between the Korean group and the Italian group (3.7+/-2.9 mL vs. 5.5+/-2.2 mL). Both cosmetic and compressive symptoms significantly improved (3.6+/-0.5 vs. 1.7+/-0.4 and 3.6+/-1.9 vs. 0.4+/-0.7, respectively; p<0.001). No side effects occurred. CONCLUSIONS: RFA was effective in reducing the volume of BTN. The outcome was similar in centers with different experience in the moving-shot technique. PMID- 26061688 TI - A Re-Appraisal of the Early Andean Human Remains from Lauricocha in Peru. AB - The discovery of human remains from the Lauricocha cave in the Central Andean highlands in the 1960's provided the first direct evidence for human presence in the high altitude Andes. The skeletons found at this site were ascribed to the Early to Middle Holocene and represented the oldest known population of Western South America, and thus were used in several studies addressing the early population history of the continent. However, later excavations at Lauricocha led to doubts regarding the antiquity of the site. Here, we provide new dating, craniometric, and genetic evidence for this iconic site. We obtained new radiocarbon dates, generated complete mitochondrial genomes and nuclear SNP data from five individuals, and re-analyzed the human remains of Lauricocha to revise the initial morphological and craniometric analysis conducted in the 1960's. We show that Lauricocha was indeed occupied in the Early to Middle Holocene but the temporal spread of dates we obtained from the human remains show that they do not qualify as a single contemporaneous population. However, the genetic results from five of the individuals fall within the spectrum of genetic diversity observed in pre-Columbian and modern Native Central American populations. PMID- 26061689 TI - Application of an Effective Statistical Technique for an Accurate and Powerful Mining of Quantitative Trait Loci for Rice Aroma Trait. AB - When a phenotype of interest is associated with an external/internal covariate, covariate inclusion in quantitative trait loci (QTL) analyses can diminish residual variation and subsequently enhance the ability of QTL detection. In the in vitro synthesis of 2-acetyl-1-pyrroline (2AP), the main fragrance compound in rice, the thermal processing during the Maillard-type reaction between proline and carbohydrate reduction produces a roasted, popcorn-like aroma. Hence, for the first time, we included the proline amino acid, an important precursor of 2AP, as a covariate in our QTL mapping analyses to precisely explore the genetic factors affecting natural variation for rice scent. Consequently, two QTLs were traced on chromosomes 4 and 8. They explained from 20% to 49% of the total aroma phenotypic variance. Additionally, by saturating the interval harboring the major QTL using gene-based primers, a putative allele of fgr (major genetic determinant of fragrance) was mapped in the QTL on the 8th chromosome in the interval RM223 SCU015RM (1.63 cM). These loci supported previous studies of different accessions. Such QTLs can be widely used by breeders in crop improvement programs and for further fine mapping. Moreover, no previous studies and findings were found on simultaneous assessment of the relationship among 2AP, proline and fragrance QTLs. Therefore, our findings can help further our understanding of the metabolomic and genetic basis of 2AP biosynthesis in aromatic rice. PMID- 26061690 TI - Prevalence and Incidence of Hypoglycaemia in 532,542 People with Type 2 Diabetes on Oral Therapies and Insulin: A Systematic Review and Meta-Analysis of Population Based Studies. AB - OBJECTIVE: To collate and evaluate the current literature reporting the prevalence and incidence of hypoglycaemia in population based studies of type 2 diabetes. RESEARCH DESIGN AND METHODS: Medline, Embase and Cochrane were searched up to February 2014 to identify population based studies reporting the proportion of people with type 2 diabetes experiencing hypoglycaemia or rate of events experienced. Two reviewers independently screened studies for eligibility and extracted data for included studies. Random effects meta-analyses were carried out to calculate the prevalence and incidence of hypoglycaemia. RESULTS: 46 studies (n = 532,542) met the inclusion criteria. Prevalence of hypoglycaemia was 45% (95%CI 0.34,0.57) for mild/moderate and 6% (95%CI, 0.05,0.07) for severe. Incidence of hypoglycaemic episodes per person-year for mild/moderate and for severe was 19 (95%CI 0.00, 51.08) and 0.80 (95%CI 0.00,2.15), respectively. Hypoglycaemia was prevalent amongst those on insulin; for mild/moderate episodes the prevalence was 50% and incidence 23 events per person-year, and for severe episodes the prevalence was 21% and incidence 1 event per person-year. For treatment regimes that included a sulphonylurea, mild/moderate prevalence was 30% and incidence 2 events per person-year, and severe prevalence was 5% and incidence 0.01 events per person-year. A similar prevalence of 5% was found for treatment regimes that did not include sulphonylureas. CONCLUSIONS: Current evidence shows hypoglycaemia is considerably prevalent amongst people with type 2 diabetes, particularly for those on insulin, yet still fairly common for other treatment regimens. This highlights the subsequent need for educational interventions and individualisation of therapies to reduce the risk of hypoglycaemia. PMID- 26061691 TI - Complete Chloroplast Genome of the Wollemi Pine (Wollemia nobilis): Structure and Evolution. AB - The Wollemi pine (Wollemia nobilis) is a rare Southern conifer with striking morphological similarity to fossil pines. A small population of W. nobilis was discovered in 1994 in a remote canyon system in the Wollemi National Park (near Sydney, Australia). This population contains fewer than 100 individuals and is critically endangered. Previous genetic studies of the Wollemi pine have investigated its evolutionary relationship with other pines in the family Araucariaceae, and have suggested that the Wollemi pine genome contains little or no variation. However, these studies were performed prior to the widespread use of genome sequencing, and their conclusions were based on a limited fraction of the Wollemi pine genome. In this study, we address this problem by determining the entire sequence of the W. nobilis chloroplast genome. A detailed analysis of the structure of the genome is presented, and the evolution of the genome is inferred by comparison with the chloroplast sequences of other members of the Araucariaceae and the related family Podocarpaceae. Pairwise alignments of whole genome sequences, and the presence of unique pseudogenes, gene duplications and insertions in W. nobilis and Araucariaceae, indicate that the W. nobilis chloroplast genome is most similar to that of its sister taxon Agathis. However, the W. nobilis genome contains an unusually high number of repetitive sequences, and these could be used in future studies to investigate and conserve any remnant genetic diversity in the Wollemi pine. PMID- 26061692 TI - Comprehensive Survey of Genetic Diversity in Chloroplast Genomes and 45S nrDNAs within Panax ginseng Species. AB - We report complete sequences of chloroplast (cp) genome and 45S nuclear ribosomal DNA (45S nrDNA) for 11 Panax ginseng cultivars. We have obtained complete sequences of cp and 45S nrDNA, the representative barcoding target sequences for cytoplasm and nuclear genome, respectively, based on low coverage NGS sequence of each cultivar. The cp genomes sizes ranged from 156,241 to 156,425 bp and the major size variation was derived from differences in copy number of tandem repeats in the ycf1 gene and in the intergenic regions of rps16-trnUUG and rpl32 trnUAG. The complete 45S nrDNA unit sequences were 11,091 bp, representing a consensus single transcriptional unit with an intergenic spacer region. Comparative analysis of these sequences as well as those previously reported for three Chinese accessions identified very rare but unique polymorphism in the cp genome within P. ginseng cultivars. There were 12 intra-species polymorphisms (six SNPs and six InDels) among 14 cultivars. We also identified five SNPs from 45S nrDNA of 11 Korean ginseng cultivars. From the 17 unique informative polymorphic sites, we developed six reliable markers for analysis of ginseng diversity and cultivar authentication. PMID- 26061693 TI - The Energetic Value of Land-Based Foods in Western Hudson Bay and Their Potential to Alleviate Energy Deficits of Starving Adult Male Polar Bears. AB - Climate change is predicted to expand the ice-free season in western Hudson Bay and when it grows to 180 days, 28-48% of adult male polar bears are projected to starve unless nutritional deficits can be offset by foods consumed on land. We updated a dynamic energy budget model developed by Molnar et al. to allow influx of additional energy from novel terrestrial foods (lesser snow geese, eggs, caribou) that polar bears currently consume as part of a mixed diet while on land. We calculated the units of each prey, alone and in combination, needed to alleviate these lethal energy deficits under conditions of resting or limited movement (2 km d-1) prior to starvation. We further considered the total energy available from each sex and age class of each animal prey over the period they would overlap land-bound polar bears and calculated the maximum number of starving adult males that could be sustained on each food during the ice-free season. Our results suggest that the net energy from land-based food, after subtracting costs of limited movement to obtain it, could eliminate all projected nutritional deficits of starving adult male polar bears and likely other demographic groups as well. The hunting tactics employed, success rates as well as behavior and abundance of each prey will determine the realized energetic values for individual polar bears. Although climate change may cause a phenological mismatch between polar bears and their historical ice-based prey, it may simultaneously yield a new match with certain land-based foods. If polar bears can transition their foraging behavior to effectively exploit these resources, predictions for starvation-related mortality may be overestimated for western Hudson Bay. We also discuss potential complications with stable-carbon isotope studies to evaluate utilization of land-based foods by polar bears including metabolic effects of capture-related stress and consuming a mixed diet. PMID- 26061694 TI - Human Milk Warming Temperatures Using a Simulation of Currently Available Storage and Warming Methods. AB - Human milk handling guidelines are very demanding, based upon solid scientific evidence that handling methods can make a real difference in infant health and nutrition. Indeed, properly stored milk maintains many of its unique qualities and continues to be the second and third best infant feeding alternatives, much superior to artificial feeding. Container type and shape, mode of steering, amount of air exposure and storage temperature may adversely affect milk stability and composition. Heating above physiological temperatures significantly impacts nutritional and immunological properties of milk. In spite of this knowledge, there are no strict guidelines regarding milk warming. Human milk is often heated in electrical-based bottle warmers that can exceed 80 degrees C, a temperature at which many beneficial human milk properties disappear. High temperatures can also induce fat profile variations as compared with fresh human milk. In this manuscript we estimate the amount of damage due to overheating during warming using a heat flow simulation of a regular water based bottle warmer. To do so, we carried out a series of warming simulations which provided us with dynamic temperature fields within bottled milk. We simulated the use of a hot water-bath at 80 degrees C to heat bottled refrigerated milk (60 ml and 178 ml) to demonstrate that large milk portions are overheated (above 40 degrees C). It seems that the contemporary storage method (upright feeding tool, i.e. bottle) and bottle warming device, are not optimize to preserve the unique properties of human milk. Health workers and parents should be aware of this problem especially when it relates to sick neonates and preemies that cannot be directly fed at the breast. PMID- 26061695 TI - Rapid and Specific Enrichment of Culturable Gram Negative Bacteria Using Non Lethal Copper-Free Click Chemistry Coupled with Magnetic Beads Separation. AB - Currently, identification of pathogenic bacteria present at very low concentration requires a preliminary culture-based enrichment step. Many research efforts focus on the possibility to shorten this pre-enrichment step which is needed to reach the minimal number of cells that allows efficient identification. Rapid microbiological controls are a real public health issue and are required in food processing, water quality assessment or clinical pathology. Thus, the development of new methods for faster detection and isolation of pathogenic culturable bacteria is necessary. Here we describe a specific enrichment technique for culturable Gram negative bacteria, based on non-lethal click chemistry and the use of magnetic beads that allows fast detection and isolation. The assimilation and incorporation of an analog of Kdo, an essential component of lipopolysaccharides, possessing a bio-orthogonal azido function (Kdo-N3), allow functionalization of almost all Gram negative bacteria at the membrane level. Detection can be realized through strain-promoted azide-cyclooctyne cycloaddition, an example of click chemistry, which interestingly does not affect bacterial growth. Using E. coli as an example of Gram negative bacterium, we demonstrate the excellent specificity of the technique to detect culturable E. coli among bacterial mixtures also containing either dead E. coli, or live B. subtilis (as a model of microorganism not containing Kdo). Finally, in order to specifically isolate and concentrate culturable E. coli cells, we performed separation using magnetic beads in combination with click chemistry. This work highlights the efficiency of our technique to rapidly enrich and concentrate culturable Gram negative bacteria among other microorganisms that do not possess Kdo within their cell envelope. PMID- 26061696 TI - Fabrication of bimetallic Cu/Au nanotubes and their sensitive, selective, reproducible and reusable electrochemical sensing of glucose. AB - Herein, we report a facile two-step approach to produce gold-incorporated copper (Cu/Au) nanostructures through controlled disproportionation of the Cu(+) oleylamine complex at 220 degrees C to form copper nanowires and the subsequent reaction with Au(3+) at different temperatures of 140, 220 and 300 degrees C. In comparison with copper nanowires, these bimetallic Cu/Au nanostructures exhibit their synergistic effect to greatly enhance glucose oxidation. Among them, the shape-controlled Cu/Au nanotubes prepared at 140 degrees C show the highest electrocatalytic activity for non-enzymatic glucose sensing in alkaline solution. In addition to high sensitivity and fast response, the Cu/Au nanotubes possess high selectivity against interferences from other potential interfering species and excellent reproducibility with long-term stability. By introducing gold into copper nanostructures at a low level of 3, 1 and 0.1 mol% relative to the initial copper precursor, a significant electrocatalytic enhancement of the resulting bimetallic Cu/Au nanostructures starts to occur at 1 mol%. Overall, the present fabrication of stable Cu/Au nanostructures offers a promising low-cost platform for sensitive, selective, reproducible and reusable electrochemical sensing of glucose. PMID- 26061697 TI - Culture and Cultural Competence in Nursing Education and Practice: The State of the Art. AB - PROBLEM: The concept of cultural competency has developed a substantial presence in nursing education and practice since first attracting widespread attention in the 1990s. While several theories and corresponding measures of cultural competency have been advanced and tried, much work remains, as many nursing professionals continue to call for greater evidence-based research and attention to patient perspectives and outcomes. METHODS: Using a method provided by Hawker et al. to appraise articles, this paper compares nine recent (2008-2013) studies (including two composite studies) related to cultural competency, undergraduate curricula, and teaching strategies in nursing to assess the state of the art in this important area of care. FINDINGS: The studies applied phenomenological, study abroad, online, and service learning strategies, four of which relied on some version of Campinha-Bacote's IAPCC(c) model. These studies reported a general improvement in competency among students, though generally only to a level of cultural awareness, and admitted being constrained by several common limitations. CONCLUSION: Improved results and more realistic expectations in this area may require a closer understanding of the nature of the "culture" that underlies cultural competence. Harkess Kaddoura. PMID- 26061698 TI - Dependence on Crystal Size of the Nanoscale Chemical Phase Distribution and Fracture in LixFePO4. AB - The performance of battery electrode materials is strongly affected by inefficiencies in utilization kinetics and cycle life as well as size effects. Observations of phase transformations in these materials with high chemical and spatial resolution can elucidate the relationship between chemical processes and mechanical degradation. Soft X-ray ptychographic microscopy combined with X-ray absorption spectroscopy and electron microscopy creates a powerful suite of tools that we use to assess the chemical and morphological changes in lithium iron phosphate (LiFePO4) micro- and nanocrystals that occur upon delithiation. All sizes of partly delithiated crystals were found to contain two phases with a complex correlation between crystallographic orientation and phase distribution. However, the lattice mismatch between LiFePO4 and FePO4 led to severe fracturing on microcrystals, whereas no mechanical damage was observed in nanoplates, indicating that mechanics are a principal driver in the outstanding electrode performance of LiFePO4 nanoparticles. These results demonstrate the importance of engineering the active electrode material in next generation electrical energy storage systems, which will achieve theoretical limits of energy density and extended stability. This work establishes soft X-ray ptychographic chemical imaging as an essential tool to build comprehensive relationships between mechanics and chemistry that guide this engineering design. PMID- 26061700 TI - Allocation Games: Addressing the Ill-Posed Nature of Allocation in Life-Cycle Inventories. AB - Allocation is required when a life cycle contains multi-functional processes. One approach to allocation is to partition the embodied resources in proportion to a criterion, such as product mass or cost. Many practitioners apply multiple partitioning criteria to avoid choosing one arbitrarily. However, life cycle results from different allocation methods frequently contradict each other, making it difficult or impossible for the practitioner to draw any meaningful conclusions from the study. Using the matrix notation for life-cycle inventory data, we show that an inventory that requires allocation leads to an ill-posed problem: an inventory based on allocation is one of an infinite number of inventories that are highly dependent upon allocation methods. This insight is applied to comparative life-cycle assessment (LCA), in which products with the same function but different life cycles are compared. Recently, there have been several studies that applied multiple allocation methods and found that different products were preferred under different methods. We develop the Comprehensive Allocation Investigation Strategy (CAIS) to examine any given inventory under all possible allocation decisions, enabling us to detect comparisons that are not robust to allocation, even when the comparison appears robust under conventional partitioning methods. While CAIS does not solve the ill-posed problem, it provides a systematic way to parametrize and examine the effects of partitioning allocation. The practical usefulness of this approach is demonstrated with two case studies. The first compares ethanol produced from corn stover hydrolysis, corn stover gasification, and corn grain fermentation. This comparison was not robust to allocation. The second case study compares 1,3-propanediol (PDO) produced from fossil fuels and from biomass, which was found to be a robust comparison. PMID- 26061701 TI - Outcomes of Renal Transplantation in HIV-1 Associated Nephropathy. AB - INTRODUCTION: Several studies have demonstrated that renal transplantation in HIV positive patients is both safe and effective. However, none of these studies have specifically examined outcomes in patients with HIV-associated nephropathy (HIVAN). METHODS: Medical records of all HIV-infected patients who underwent kidney transplantation at Johns Hopkins Hospital between September 2006 and January 2014 were reviewed. Data was collected to examine baseline characteristics and outcomes of transplant recipients with HIVAN defined pathologically as collapsing focal segmental glomerulosclerosis (FSGS) with tubulo-interstitial disease. RESULTS AND DISCUSSION: During the study period, a total of 16 patients with HIV infection underwent renal transplantation. Of those, 11 patients were identified to have biopsy-proven HIVAN as the primary cause of their end stage renal disease (ESRD) and were included in this study. They were predominantly African American males with a mean age of 47.6 years. Seven (64%) patients developed delayed graft function (DGF), and 6 (54%) patients required post-operative dialysis within one week of transplant. Graft survival rates at 1 and 3 years were 100% and 81%, respectively. Acute rejection rates at 1 and 3 years were 18% and 27%, respectively. During a mean follow up of 3.4 years, one patient died. CONCLUSIONS: Acute rejection rates in HIVAN patients in this study are higher than reported in the general ESRD population, which is similar to findings from prior studies of patients with HIV infection and ESRD of various causes. The high rejection rates appear to have no impact on short or intermediate term graft survival. PMID- 26061702 TI - Realization of Both High-Performance and Enhanced Durability of Fuel Cells: Pt Exoskeleton Structure Electrocatalysts. AB - Core-shell structure nanoparticles have been the subject of many studies over the past few years and continue to be studied as electrocatalysts for fuel cells. Therefore, many excellent core-shell catalysts have been fabricated, but few studies have reported the real application of these catalysts in a practical device actual application. In this paper, we demonstrate the use of platinum (Pt) exoskeleton structure nanoparticles as cathode catalysts with high stability and remarkable Pt mass activity and report the outstanding performance of these materials when used in membrane-electrode assemblies (MEAs) within a polymer electrolyte membrane fuel cell. The stability and degradation characteristics of these materials were also investigated in single cells in an accelerated degradation test using load cycling, which is similar to the drive cycle of a polymer electrolyte membrane fuel cell used in vehicles. The MEAs with Pt exoskeleton structure catalysts showed enhanced performance throughout the single cell test and exhibited improved degradation ability that differed from that of a commercial Pt/C catalyst. PMID- 26061703 TI - Influence of pH and Surface Chemistry on Poly(L-lysine) Adsorption onto Solid Supports Investigated by Quartz Crystal Microbalance with Dissipation Monitoring. AB - Poly(L-lysine) (PLL) adsorption onto various materials has been widely applied as a surface modification strategy and layer-by-layer fabrication method. Considering the role of electrostatic charges, a detailed understanding of the influence of solution pH on PLL adsorption process is important for optimization of PLL coating protocols. Herein, PLL adsorption onto different polar and hydrophilic substrates-silica, an amine-terminated self-assembled monolayer (SAM) on gold, and a carboxyl-terminated SAM on gold-across a range of pH conditions was investigated using the quartz crystal microbalance with dissipation. The adsorption kinetics consisted of an initial rapid phase, followed by a second phase where adsorption rate gradually decelerated. These features were interpreted by applying a mean-field kinetic model implying diffusion-limited adsorption in the first phase and reconfiguration of adsorbed PLL molecules in the second phase. The adsorption kinetics and uptake were found to be sensitive to the pH condition, surface chemistry, and flow rate. The strongest PLL adsorption occurred at pH 11 on all three surfaces while weak PLL adsorption generally occurred under acidic conditions. The surface morphology and roughness of adsorbed PLL layers were investigated using atomic force microscopy, and strong PLL adsorption is found to produce a uniform and smooth adlayer while weak adsorption formed a nonuniform and rough adlayer. PMID- 26061704 TI - Global Synthesis of Drought Effects on Food Legume Production. AB - Food legume crops play important roles in conservation farming systems and contribute to food security in the developing world. However, in many regions of the world, their production has been adversely affected by drought. Although water scarcity is a severe abiotic constraint of legume crops productivity, it remains unclear how the effects of drought co-vary with legume species, soil texture, agroclimatic region, and drought timing. To address these uncertainties, we collected literature data between 1980 and 2014 that reported monoculture legume yield responses to drought under field conditions, and analyzed this data set using meta-analysis techniques. Our results showed that the amount of water reduction was positively related with yield reduction, but the extent of the impact varied with legume species and the phenological state during which drought occurred. Overall, lentil (Lens culinaris), groundnut (Arachis hypogaea), and pigeon pea (Cajanus cajan) were found to experience lower drought-induced yield reduction compared to legumes such as cowpea (Vigna unguiculata) and green gram (Vigna radiate). Yield reduction was generally greater when legumes experienced drought during their reproductive stage compared to during their vegetative stage. Legumes grown in soil with medium texture also exhibited greater yield reduction compared to those planted on soil of either coarse or fine texture. In contrast, regions and their associated climatic factors did not significantly affect legume yield reduction. In the face of changing climate, our study provides useful information for agricultural planning and research directions for development of drought-resistant legume species to improve adaptation and resilience of agricultural systems in the drought-prone regions of the world. PMID- 26061705 TI - Population Fluctuation Promotes Cooperation in Networks. AB - We consider the problem of explaining the emergence and evolution of cooperation in dynamic network-structured populations. Building on seminal work by Poncela et al., which shows how cooperation (in one-shot prisoner's dilemma) is supported in growing populations by an evolutionary preferential attachment (EPA) model, we investigate the effect of fluctuations in the population size. We find that a fluctuating model - based on repeated population growth and truncation - is more robust than Poncela et al.'s in that cooperation flourishes for a wider variety of initial conditions. In terms of both the temptation to defect, and the types of strategies present in the founder network, the fluctuating population is found to lead more securely to cooperation. Further, we find that this model will also support the emergence of cooperation from pre-existing non-cooperative random networks. This model, like Poncela et al.'s, does not require agents to have memory, recognition of other agents, or other cognitive abilities, and so may suggest a more general explanation of the emergence of cooperation in early evolutionary transitions, than mechanisms such as kin selection, direct and indirect reciprocity. PMID- 26061706 TI - Seen and heard: towards child participation in dental research. AB - BACKGROUND: There has been an increasing emphasis in many countries worldwide to capture the views of children on health services and research. A previous systematic review found that most oral health research from 2000 to 2005 was conducted on children and highlighted the need for greater research with children. AIM: To describe the extent to which oral health research between 2006 and 2014 has been conducted with or on children. DESIGN: Systematic review. Electronic databases were searched for the literature on child dental health. Each identified paper was examined by two researchers and categorised based on the extent to which children were involved in the research, the type of study (evaluative or otherwise), the country of origin, and the clinical discipline. RESULTS: The search included 2950 papers after application of the exclusion criteria. Of these, 17.4% were with children, 18.3% involved the use of proxies (parents or clinician), and 64.2% were on children. CONCLUSIONS: The proportion of studies from 2006 to 2014 involving research with children has increased from 7.3% in 2000-2005. This systematic review provides evidence for movement towards children's involvement in dental research over the last 10 years. Future dental research must focus on incorporating children's perspectives into the evaluation of dental treatments to improve outcomes for children. PMID- 26061707 TI - Dielectric force microscopy: imaging charge carriers in nanomaterials without electrical contacts. AB - Nanomaterials are increasingly used in electronic, optoelectronic, bioelectronic, sensing, and energy nanodevices. Characterization of electrical properties at nanometer scales thus becomes not only a pursuit in basic science but also of widespread practical need. The conventional field-effect transistor (FET) approach involves making electrical contacts to individual nanomaterials. This approach faces serious challenges in routine characterization due to the small size and the intrinsic heterogeneity of nanomaterials, as well as the difficulties in forming Ohmic contact with nanomaterials. Since the charge carrier polarization in semiconducting and metallic materials dominates their dielectric response to external fields, detecting dielectric polarization is an alternative approach in probing the carrier properties and electrical conductivity in nanomaterials. This Account reviews the challenges in the electrical conductivity characterization of nanomaterials and demonstrates that dielectric force microscopy (DFM) is a powerful tool to address the challenges. DFM measures the dielectric polarization via its force interaction with charges on the DFM tip and thus eliminates the need to make electrical contacts with nanomaterials. Furthermore, DFM imaging provides nanometer-scaled spatial resolution. Single-walled carbon nanotubes (SWNTs) and ZnO nanowires are used as model systems. The transverse dielectric permittivity of SWNTs is quantitatively measured to be ~10, and the differences in longitudinal dielectric polarization are exploited to distinguish metallic SWNTs from semiconducting SWNTs. By application of a gate voltage at the DFM tip, the local carrier concentration underneath the tip can be accumulated or depleted, depending on charge carrier type and the density of states near the Fermi level. This effect is exploited to identify the conductivity type and carrier type in nanomaterials. By making comparison between DFM and FET measurements on the exact same SWNTs, it is found that the DFM gate modulation ratio, which is the ratio of DFM signal strengths at different gate voltage, is linearly proportional to the logarithm of FET device on/off ratio. A Drude-level model is established to explain the semilogarithmic correlation between DFM gate modulation ration and FET device on/off ratio and simulate the dependence of DFM force on charge carrier concentration and mobility. Future developments towards DFM imaging of charge carrier concentration or mobility in nanomaterials and nanodevices can thus be expected. PMID- 26061708 TI - rRNA synthesis inhibitor, CX-5461, activates ATM/ATR pathway in acute lymphoblastic leukemia, arrests cells in G2 phase and induces apoptosis. AB - Ribosome biogenesis is a fundamental cellular process and is elevated in cancer cells. As one of the most energy consuming cellular processes, it is highly regulated by signaling pathways in response to changing cellular conditions. Many of the regulators of this process are aberrantly activated in various cancers. Recently two novel rRNA synthesis inhibitors, CX-5461 and BMH-21, have been shown to selectively kill cancer cells while sparing normal cells. Here, we tested the effectiveness of pre-rRNA synthesis inhibitor CX-5461 on acute lymphoblastic leukemia cells with different cytogenetic abnormalities. Acute lymphoblastic leukemia cells are more sensitive to rRNA synthesis inhibition compared to normal bone marrow cells. CX-5461 treated cells undergo caspase-dependent apoptosis independent of their p53 status. More-over, CX5461, activates checkpoint kinases and arrests cells in G2 phase of cell cycle. Finally, overcoming this G2 arrest by inhibiting ATR kinase leads to robust cell killing. These results show that CX 5461 can be even more potent in combination with ATR inhibitors. PMID- 26061709 TI - Optimal adjuvant therapy for resected hepatocellular carcinoma: a systematic review with network meta-analysis. AB - OBJECTIVES: Major adjuvant therapies (ATs) for resected hepatocellular carcinoma (HCC) include chemotherapy, internal radiation therapy (IRT), interferon therapy (IFNT) and immunotherapy but the optimum regimen remains inconclusive. We aim to compare these therapies in terms of patient survival and recurrence rates. METHODS: We searched PubMed, EMBASE and Cochrane library databases for randomized trials comparing the above four therapies until 31 March 2014. We estimated the HRs for survival and ORs for overall recurrence among different therapies. Toxic effects were also evaluated. RESULTS: Fourteen eligible articles were included. IFNT improved 5-year survival greatly (HR 1.81, 95% CI 1.01-3.81, P = 0.034), whereas chemotherapy (HR 0.33, 95% CI 0.03-2.02), IRT (HR 0.31, 95% CI 0.02-3.33) and immunotherapy (HR 0.73, 95% CI 0.05-9.12) all provided a poorer survival outcome after 1-year. Similarly, for 5-year survival rates, although differing, IRT did not provide a significant improvement in survival (HR 1.38, 95% CI 0.34 5.19) compared with IFNT. Chemotherapy (HR 0.49, 95% CI 0.18-1.14) and immunotherapy (HR 0.56, 95% CI 0.17-1.59) did not appear to provide benefit over IFNT. Chemotherapy was ranked the worst in overall recurrence (OR 0.99, 95% CI 0.18-5.38) and most likely to cause toxic effects. CONCLUSIONS: IFNT was the most efficacious AT regimen both for short and long term survivals. Immunotherapy and IFNT were the most two effective in preventing overall relapse for resected HCC. PMID- 26061711 TI - Implications of stroke for caregiver outcomes: findings from the ASPIRE-S study. AB - BACKGROUND: Informal caregivers are vital to the long-term care and rehabilitation of stroke survivors worldwide. However, caregiving has been associated with negative psychological outcomes such as anxiety and depression, which leads to concerns about caregiver as well as stroke survivor well-being. Furthermore, caregivers may not receive the support and service provision they require from the hospitals and community. AIMS: This study examines caregiver psychological well-being and satisfaction with service provision in the context of stroke. METHODS: Caregiver data were collected as part of the ASPIRE-S study, a prospective study of secondary prevention and rehabilitation which assessed stroke patients and their carers at six-months post stroke. Carer assessment included measurement of demographics, satisfaction with care (UK Healthcare Commission National Patient Survey of Stroke Care), psychological distress (Hospital Anxiety and Depression Scale), and vulnerability (Vulnerable Elders Scale). Logistic regression analyses and chi-squared tests were performed using stata version 12. RESULTS: Analyses from 162 carers showed substantial levels of dissatisfaction (37.9%) with community and hospital services, as well as notable levels of anxiety (31.3%) and depressive symptoms (18.8%) among caregivers. Caregiver anxiety was predicted by stroke survivor anxiety (OR = 3.47, 95% CI 1.35-8.93), depression (OR = 5.17, 95% CI 1.83-14.58), and stroke survivor cognitive impairment (OR 2.35, 95% CI 1.00-5.31). Caregiver depression was predicted by stroke survivor anxiety (OR = 4.41, 95% CI 1.53-12.72) and stroke survivor depression (OR = 6.91, 95% CI 2.26-21.17). CONCLUSION: Findings indicate that caregiver and stroke survivor well-being are interdependent. Thus, early interventions, including increased training and support programs that include caregivers, are likely to reduce the risk of negative emotional outcomes. PMID- 26061710 TI - The neuroleptic drug pimozide inhibits stem-like cell maintenance and tumorigenicity in hepatocellular carcinoma. AB - Drug repurposing is currently an important approach for accelerating drug discovery and development for clinical use. Hepatocellular carcinoma (HCC) presents drug resistance to chemotherapy, and the prognosis is poor due to the existence of liver cancer stem-like cells. In this study, we investigated the effect of the neuroleptic agent pimozide to inhibit stem-like cell maintenance and tumorigenicity in HCC. Our results showed that pimozide functioned as an anti cancer drug in HCC cells or stem-like cells. Pimozide inhibited cell proliferation and sphere formation capacities in HCC cells by inducing G0/G1 phase cell cycle arrest, as well as inhibited HCC cell migration. Surprisingly, pimozide inhibited the maintenance and tumorigenicity of HCC stem-like cells, particularly the side population (SP) or CD133-positive cells, as evaluated by colony formation, sphere formation and transwell migration assays. Furthermore, pimozide was found to suppress STAT3 activity in HCC cells by attenuating STAT3 dependent luciferase activity and down-regulating the transcription levels of downstream genes of STAT3 signaling. Moreover, pimozide reversed the stem-like cell tumorigenic phenotypes induced by IL-6 treatment in HCC cells. Further, the antitumor effect of pimozide was also proved in the nude mice HCC xenograft model. In short, the anti-psychotic agent pimozide may act as a novel potential anti-tumor agent in treating advanced HCC. PMID- 26061713 TI - Relationship between inter-arm blood pressure differences and future cardiovascular events in coronary artery disease. AB - OBJECTIVE: Recent studies have shown that inter-arm blood pressure differences (IAD) may be a risk factor for cardiovascular events; however, none have addressed them in patients with coronary artery disease (CAD). METHODS: We measured blood pressure bilaterally with the ankle brachial index (ABI) in 657 patients with suspected CAD and assessed the presence of CAD by coronary angiography, and the severity of coronary atherosclerosis with the Gensini score. RESULTS: Mean IADs were significantly greater in risk factor matched patients with CAD than in those without it (P = 0.01), whereas Gensini scores were significantly greater in those with high IAD (>=10 mmHg) than in those with low IAD (P = 0.01) according to cross-sectional analysis. Patients with high IAD had a significantly greater probability of cardiovascular events than those in whom it was low (log-rank test, P < 0.01, mean follow-up range; 827.3 +/- 268.1 days). The presence of hypertension, ABI, usage of calcium channel blocker and high IAD were independent predictors of cardiovascular events according to longitudinal analysis (IAD; hazard ratio: 2.90, 95% confidence interval: 1.41-5.94, P < 0.01) in these patients. Patients with high IAD and peripheral artery disease had the highest Gensini scores according to cross-sectional analysis (P < 0.01) and highest probability of cardiovascular events according to longitudinal analysis (log-rank test, P < 0.001). CONCLUSION: IADs were increased in CAD patients and correlated with its severity. Greater than 10 mmHg of IAD was independently associated with future cardiovascular events. Assessing IAD by ABI measurement may facilitate risk stratification in CAD patients. PMID- 26061712 TI - Temporal and Spatial Variation in the Abundance of Total and Pathogenic Vibrio parahaemolyticus in Shellfish in China. AB - We investigated the abundance of total and pathogenic Vibrio parahaemolyticus in shellfish sampled from four provinces in China during May 2013 and March 2014 using the most probable number-polymerase chain reaction (MPN-PCR) method. Total V. parahaemolyticus was detected in 67.7% of 496 samples. A total of 38.1% and 10.1% of samples exceeded 1,000 MPN g(-1) and 10,000 MPN g(-1), respectively. V. parahaemolyticus densities followed a seasonal and geographical trend, with Guangxi and Sichuan shellfish possessing total V. parahaemolyticus levels that were 100-fold higher than those of the Liaoning and Shandong regions. Moreover, the levels of V. parahaemolyticus were at least 10-fold higher in the summer and autumn than in the cooler seasons. Pathogenic V. parahaemolyticus levels were generally lower than total V. parahaemolyticus levels by several log units and tended to be high in samples contaminated with high total V. parahaemolyticus levels. The aqua farms had a lower prevalence but higher abundance of total V. parahaemolyticus compared to retail markets. The catering markets showed the lowest levels of total V. parahaemolyticus, but 20.0% of samples exceeded 1,000 MPN g(-1). The levels of both total and pathogenic V. parahaemolyticus in oysters were higher than in clams. The log-transformed abundance of V. parahaemolyticus was significantly correlated with both water temperature and air temperature but not water salinity. These results provide baseline contamination data of V. parahaemolyticus in shellfish in China, which can be applied to local risk assessments to prioritize risk control to key sectors and evaluate the effectiveness of future control measures. PMID- 26061714 TI - Thermal breakage of a semiflexible polymer: breakage profile and rate. AB - Understanding fluctuation-induced breakages in polymers has important implications for basic and applied sciences. Here I present for the first time an analytical treatment of the thermal breakage problem of a semi-flexible polymer model that is asymptotically exact in the low temperature and high friction limits. Specifically, I provide analytical expressions for the breakage propensity and rate, and discuss the generalities of the results and their relevance to biopolymers. This work is fundamental to our understanding of the kinetics of living polymerisation. PMID- 26061715 TI - Loss of Drosophila Vps16A enhances autophagosome formation through reduced Tor activity. AB - The HOPS tethering complex facilitates autophagosome-lysosome fusion by binding to Syx17 (Syntaxin 17), the autophagosomal SNARE. Here we show that loss of the core HOPS complex subunit Vps16A enhances autophagosome formation and slows down Drosophila development. Mechanistically, Tor kinase is less active in Vps16A mutants likely due to impaired endocytic and biosynthetic transport to the lysosome, a site of its activation. Tor reactivation by overexpression of Rheb suppresses autophagosome formation and restores growth and developmental timing in these animals. Thus, Vps16A reduces autophagosome numbers both by indirectly restricting their formation rate and by directly promoting their clearance. In contrast, the loss of Syx17 blocks autophagic flux without affecting the induction step in Drosophila. PMID- 26061717 TI - Opioid-induced constipation. AB - Opioid-induced constipation (OIC) is a very troublesome, difficult to manage and a nearly universal complication of chronic opioid use to control pain associated with advanced illness. Some studies have reported that OIC is so intolerable in some patients that they skip their opioid medications and bear pain instead of OIC. Laxatives have commonly been used as a prophylaxis and treatment of OIC but they are frequently ineffective because the commonly available laxatives do not target the underlying mechanism of OIC, which is the blockade of peripheral mu receptors. Recently, there have been a number of advances in the treatment of OIC, which any physician involved with opioid-prescribing discipline should be aware of. This review will update the new options and strategies available for treating OIC along with the relevant clinical trials. Finally, this review also provides a recommendation on the preferred way to approach a patient with OIC in the modern era as well as highlight on the importance of doctor-patient communication in this setting. PMID- 26061718 TI - Electronic Reconstruction of alpha-Ag2WO4 Nanorods for Visible-Light Photocatalysis. AB - alpha-Ag2WO4 (AWO) has been studied extensively due to its H2 evolution and organic pollution degradation ability under the irradiation of UV light. However, the band gap of AWO is theoretically calculated to be 3.55 eV, resulting in its sluggish reaction to visible light. Herein, we demonstrated that, by using the electronic reconstruction of AWO nanorods upon a unique process of laser irradiation in liquid, these nanorods performed good visible-light photocatalytic organics degradation and H2 evolution. Using commercial AWO powders as the starting materials, we achieved the electronic reconstruction of AWO by a recrystallization of the starting powders upon laser irradiation in liquid and synthesized AWO nanorods. Due to the weak bond energy of AWO and the far from thermodynamic equilibrium process created by laser irradiation in liquid, abundant cluster distortions, especially [WO6] cluster distortions, are introduced into the crystal lattice, the defect density increases by a factor of 2.75, and uneven intermediate energy levels are inset into the band gap, resulting in a 0.44 eV decrease of the band gap, which modified the AWO itself by electronic reconstruction to be sensitive to visible light without the addition of others. Further, the first-principles calculation was carried out to clarify the electronic reconstruction of AWO, and the theoretical results confirmed the deduction based on the experimental measurements. PMID- 26061719 TI - Quantitative Analysis of Energy Transfer and Origin of Quenching in Er(3+)/Ho(3+) Codoped Germanosilicate Glasses. AB - The energy transfer mechanism between Ho(3+) and Er(3+) ions has been investigated in germanosilicate glass excited by 980 nm laser diode. A rate equation model was developed to demonstrate the energy transfer from Er(3+) to Ho(3+) ions, quantitatively. Energy transfer efficiency from the Er(3+):(4)I13/2 to the Ho(3+):(5)I7 level can reach as high as 75%. Such a high efficiency was attributed to the excellent matching of the host phonon energy with the energy gap between Er(3+):(4)I13/2 and Ho(3+):(5)I7 levels. In addition, the energy transfer microparameter (CDA) from Er(3+):(4)I13/2 to Ho(3+):(5)I7 level was estimated to (4.16 +/- 0.03) * 10(-40) cm(6).s(-1) via the host-assisted spectral overlap function, coinciding with the CDA (2,88 +/- 0.04) * 10(-40) cm(6).s(-1) from decay analysis of the Er(3+):(4)I13/2 level which also indicated hopping migration-assisted energy transfer. Furthermore, the concentration quenching of Ho(3+):(5)I7 -> (5)I8 transition was the dipole-dipole interaction in the diffusion-limited regime, and the quenching concentration of Ho(3+) reached 4.13 * 10(20) cm(-3). PMID- 26061720 TI - One-Step Purification of Human Skeletal Muscle Myoblasts and Subsequent Expansion Using Laminin-Coated Surface. AB - Skeletal myoblasts have been extensively used to study muscle growth and differentiation, and were recently tested for their application as cell therapy and as a gene delivery system to treat muscle and nonmuscle diseases. However, contamination of fibroblasts in isolated cells from skeletal muscle is one of the long-standing problems for routine expansion. This study aimed to establish a simple one-step process to purify myoblasts and maintain their purity during expansion. Mixed cells were preplated serially on laminin- and collagen type I coated surfaces in a different array for 5, 10, and 15 min. Immunocytochemical staining with antibodies specific to myoblasts was performed to evaluate myoblast attachment efficiency, purity, and yield. It was found that laminin-coated surface favors the attachment of myoblasts. Highest myoblast purity of 78.9% +/- 6.8% was achieved by 5 min of preplating only on the laminin-coated surface with a yield of 56.9% +/- 3.3%. Primary cells, isolated from skeletal muscle (n = 4), confirm the enhancement of purity through preplating on laminin-coated surface for 5 min. Subsequent expansion after preplating enhanced myoblast purity due to an increase in myoblast growth than fibroblasts. Myoblast purity of ~ 98% was achieved when another preplating was performed during passaging. In conclusion, myoblasts can be purified and efficiently expanded in one step by preplating on laminin-coated surface, which is a simple and robust technique. PMID- 26061721 TI - Disclination elastica model of loop collision and growth in confined nematic liquid crystals. AB - Theory and modeling are used to characterize disclination loop-loop interactions in nematic liquid crystals under capillary confinement with strong homeotropic anchoring. This defect process arises when a mesogen in the isotropic phase is quenched into the stable nematic state. The texture evolution starts with +1/2 disclination loops that merge into a single loop through a process that involves collision, pinching and relaxation. The process is characterized with a combined Rouse-Frank model that incorporates the tension and bending elasticity of disclinations and the rotational viscosity of nematics. The Frank model of disclinations follows the Euler elastica model, whose non-periodic solution, known as Poleni's curve, is shown to locally describe the loop-loop collision and to shed light on why loop-loop merging results in a disclination intersection angle of approximately 60 degrees . Additional Poleni invariants demonstrate how tension and bending pinch the two loops into a single +1/2 disclination ring. The Rouse model of disclination relaxation yields a Cahn-Hilliard equation whose time constant combines the confinement, tension/bending stiffness ratio and disclination diffusivity. Based on predictions made using this three stage process, a practical procedure is proposed to find viscoelastic parameters from defect geometry and defect dynamics. These findings contribute to the evolving understanding of textural transformations in nematic liquid crystals under confinement using the disclination elastica methodology. PMID- 26061722 TI - Visualizing Interactions Between HIV-1 Nef and Host Cellular Proteins Using Ground-State Depletion Microscopy. PMID- 26061723 TI - Prediction of cerebrospinal fluid parameters for tuberculous meningitis. AB - BACKGROUND: Tuberculous meningitis is the most lethal form of tuberculosis, but current diagnostic methods are inadequate. The measurement of cerebrospinal fluid parameters can provide early information for diagnosis. The present study focus on the validity of the cut-off value of cerebrospinal fluid parameters according to the Lancet consensus of scoring system for diagnosis of tuberculous meningitis. METHOD: A total of 100 confirmed patients were enrolled in this study. We evaluated significance of protein level (>1 g/l), chloride level (<120 mmol/l), glucose level (<2.2 mmol/l), cell counts (10-500 cells/MUl, lymphocytic pleocytosis (>50%), and neutrophil predominance (>50%) in early diagnosis of tuberculous meningitis. RESULT: The cerebrospinal fluid parameters were significantly different between the tuberculous meningitis group and the control group. The independent factors for diagnosis of tuberculous meningitis were protein level (>1 g/l), glucose level (<2.2 mmol/l), cell counts (10-500 cells/MUl and neutrophil predominance >50%). Neutrophil predominance (>50%) performed the best with the area under the curve of 89.7%. The sensitivity of protein level (>1 g/l), glucose level (<2.2 mmol/l), cell counts (10-500 cells/MUl) and neutrophil predominance (>50%) for diagnosis of tuberculous meningitis were 66%, 58%, 86%, and 54%, and the specificity were 84%, 98%, 32%, and 98%. There are 84% patients in tuberculous meningitis group at least having two positive parameters among the four independent parameters, while only 10% in control group. CONCLUSION: The cerebrospinal fluid parameters can help the clinicians to make a prompt diagnosis in the early stage of the disease. PMID- 26061724 TI - THE STRUCTURED CLINICAL INTERVIEW FOR COMPLICATED GRIEF: RELIABILITY, VALIDITY, AND EXPLORATORY FACTOR ANALYSIS. AB - BACKGROUND: Complicated grief (CG) has been recently included in the DSM-5, under the term "persistent complex bereavement disorder," as a condition requiring further study. To our knowledge, no psychometric data on any structured clinical interview for CG (SCI-CG) is available to date. In this manuscript, we introduce the SCI-CG, a 31-item "SCID-like" clinician-administered instrument to assess the presence of CG symptoms. METHODS: Participants were 281 treatment-seeking adults with CG (77.9% [n = 219] women, mean age = 52.4, standard deviation [SD] = 17.8) who were assessed with the SCI-CG and measures of depression, posttraumatic stress, anxiety, functional impairment. RESULTS: The SCI-CG exhibited satisfactory internal consistency (alpha = .78), good test-retest reliability (interclass correlation [ICC] 0.68, 95% CI [0.60-0.75]), and excellent interrater reliability (ICC = 0.95, 95% CI [0.89-0.98]). Exploratory factor analyses revealed that a five-factor structure, explaining 50.3% of the total variance, was the best fit for the data. CONCLUSIONS: The clinician-rated SCI-CG demonstrates good internal consistency, reliability, and convergent validity in treatment-seeking individuals with CG and therefore can be a useful tool to assess CG. Although diagnostic criteria for CG have yet to be adequately validated, the SCI-CG may facilitate this process. The SCI-CG can now be used as a validated instrument in research and clinical practice. PMID- 26061725 TI - Prenatal Testosterone Treatment Leads to Changes in the Morphology of KNDy Neurons, Their Inputs, and Projections to GnRH Cells in Female Sheep. AB - Prenatal testosterone (T)-treated ewes display a constellation of reproductive defects that closely mirror those seen in PCOS women, including altered hormonal feedback control of GnRH. Kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in steroid feedback control of GnRH secretion, and prenatal T treatment in sheep causes an imbalance of KNDy peptide expression within the ARC. In the present study, we tested the hypothesis that prenatal T exposure, in addition to altering KNDy peptides, leads to changes in the morphology and synaptic inputs of this population, kisspeptin cells of the preoptic area (POA), and GnRH cells. Prenatal T treatment significantly increased the size of KNDy cell somas, whereas POA kisspeptin, GnRH, agouti-related peptide, and proopiomelanocortin neurons were each unchanged in size. Prenatal T treatment also significantly reduced the total number of synaptic inputs onto KNDy neurons and POA kisspeptin neurons; for KNDy neurons, the decrease was partly due to a decrease in KNDy-KNDy synapses, whereas KNDy inputs to POA kisspeptin cells were unaltered. Finally, prenatal T reduced the total number of inputs to GnRH cells in both the POA and medial basal hypothalamus, and this change was in part due to a decreased number of inputs from KNDy neurons. The hypertrophy of KNDy cells in prenatal T sheep resembles that seen in ARC kisspeptin cells of postmenopausal women, and together with changes in their synaptic inputs and projections to GnRH neurons, may contribute to defects in steroidal control of GnRH observed in this animal model. PMID- 26061726 TI - Fish Oil-Rich Diet Promotes Hematopoiesis and Alters Hematopoietic Niche. AB - The self-renewal and differentiation of hematopoietic stem cells (HSCs) in bone marrow are essential to replenish all blood cell types, but how this process is influenced by diet remains largely unclear. Here we show that a diet rich in fish oils promotes self-renewal of HSCs and extramedullary hematopoiesis. Chronic intake of a fish oil-rich diet increases the abundance of HSCs, alters the hematopoietic microenvironment, and, intriguingly, induces the expression of matrix metalloproteinase 12 (MMP12) in the bone marrow. Pointing to a direct effect of fish oil on MMP12 expression, omega-3 polyunsaturated fatty acids induce the expression of MMP12 in a dose-dependent manner in bone marrow cells. Importantly, down-regulation of MMP12 activity using an MMP12-specific inhibitor attenuates diet-induced myelopoiesis in both bone marrow and spleen. Thus, a fish oil-rich diet promotes hematopoiesis in the bone marrow and spleen, in part via the activity of MMP12. Taken together, these data provide new insights into diet mediated regulation of hematopoiesis. PMID- 26061727 TI - Rapid Nongenomic Glucocorticoid Actions in Male Mouse Hypothalamic Neuroendocrine Cells Are Dependent on the Nuclear Glucocorticoid Receptor. AB - Corticosteroids act classically via cognate nuclear receptors to regulate gene transcription; however, increasing evidence supports rapid, nontranscriptional corticosteroid actions via activation of membrane receptors. Using whole-cell patch clamp recordings in hypothalamic slices from male mouse genetic models, we tested for nongenomic glucocorticoid actions at glutamate and gamma aminobutyric acid (GABA) synapses in hypothalamic neuroendocrine cells, and for their dependence on the nuclear glucocorticoid receptor (GR). In enhanced green fluorescent protein-expressing CRH neurons of the paraventricular nucleus (PVN) and in magnocellular neurons of the PVN and supraoptic nucleus (SON), dexamethasone activated postsynaptic membrane-associated receptors and G protein signaling to elicit a rapid suppression of excitatory postsynaptic inputs, which was blocked by genetic deletion of type I cannabinoid receptors and a type I cannabinoid receptor antagonist. In magnocellular neurons, dexamethasone also elicited a rapid nitric oxide-dependent increase in inhibitory postsynaptic inputs. These data indicate a rapid, synapse-specific glucocorticoid-induced retrograde endocannabinoid signaling at glutamate synapses and nitric oxide signaling at GABA synapses. Unexpectedly, the rapid glucocorticoid effects on both excitatory and inhibitory synaptic transmission were lost with conditional deletion of GR in the PVN and SON in slices from a single minded-1-cre-directed conditional GR knockout mouse. Thus, the nongenomic glucocorticoid actions at glutamate and GABA synapses on PVN and SON neuroendocrine cells are dependent on the nuclear GR. The nuclear GR, therefore, is responsible for transducing the rapid steroid response at the membrane, or is either a critical component in the signaling cascade or regulates a critical component of the signaling cascade of a distinct membrane GR. PMID- 26061728 TI - The Slothful Claw: Osteology and Taphonomy of Nothronychus mckinleyi and N. graffami (Dinosauria: Theropoda) and Anatomical Considerations for Derived Therizinosaurids. AB - Nothronychus was the first definitive therizinosaurian discovered in North America and currently represents the most specialized North American therizinosaurian genus. It is known from two species, No. mckinleyi from the Moreno Hill Formation (middle Turonian) in west-central New Mexico, and No. graffami from the Tropic Shale (early Turonian) in south-central Utah. Both species are represented by partial to nearly complete skeletons that have helped elucidate evolutionary trends in Therizinosauria. In spite of the biogeographical and evolutionary importance of these two taxa, neither has received a detailed description. Here, we present comprehensive descriptions of No. mckinleyi and No. graffami, the latter of which represents the most complete therizinosaurid skeleton known to date. We amend previous preliminary descriptions of No. mckinleyi and No. graffami based on these new data and modify previous character states based on an in-depth morphological analysis. Additionally, we review the depositional history of both specimens of Nothronychus and compare their taphonomic modes. We demonstrate that the species were not only separated geographically, but also temporally. Based on ammonoid biozones, the species appear to have been separated by at least 1.5 million years and up to 3 million years. We then discuss the impacts of diagenetic deformation on morphology and reevaluate potentially diagnostic characters in light of these new data. For example, the ulna of No. mckinleyi is curved whereas the ulna of No. graffami was considered straight, a character originally separating the two species. However, here we present the difference as much more likely related to diagenetic compression in No. graffami rather than as a true biologic difference. Finally, we include copies of three-dimensional surface scans of all major bones for both taxa for reference. PMID- 26061729 TI - Novel Synthesis, Coating, and Networking of Curved Copper Nanowires for Flexible Transparent Conductive Electrodes. AB - In this work, a whole manufacturing process of the curved copper nanowires (CCNs) based flexible transparent conductive electrode (FTCE) is reported with all solution processes, including synthesis, coating, and networking. The CCNs with high purity and good quality are designed and synthesized by a binary polyol coreduction method. In this reaction, volume ratio and reaction time are the significant factors for the successful synthesis. These nanowires have an average 50 nm in width and 25-40 MUm range in length with curved structure and high softness. Furthermore, a meniscus-dragging deposition (MDD) method is used to uniformly coat the well-dispersed CCNs on the glass or polyethylene terephthalate substrate with a simple process. The optoelectrical property of the CCNs thin films is precisely controlled by applying the MDD method. The FTCE is fabricated by networking of CCNs using solvent-dipped annealing method with vacuum-free, transfer-free, and low-temperature conditions. To remove the natural oxide layer, the CCNs thin films are reduced by glycerol or NaBH4 solution at low temperature. As a highly robust FTCE, the CCNs thin film exhibits excellent optoelectrical performance (T = 86.62%, R(s) = 99.14 Omega ?(-1)), flexibility, and durability (R/R(0) < 1.05 at 2000 bending, 5 mm of bending radius). PMID- 26061730 TI - New Insights into the Evolution of the Human Diet from Faecal Biomarker Analysis in Wild Chimpanzee and Gorilla Faeces. AB - Our understanding of early human diets is based on reconstructed biomechanics of hominin jaws, bone and teeth isotopic data, tooth wear patterns, lithic, taphonomic and zooarchaeological data, which do not provide information about the relative amounts of different types of foods that contributed most to early human diets. Faecal biomarkers are proving to be a valuable tool in identifying relative proportions of plant and animal tissues in Palaeolithic diets. A limiting factor in the application of the faecal biomarker approach is the striking absence of data related to the occurrence of faecal biomarkers in non human primate faeces. In this study we explored the nature and proportions of sterols and stanols excreted by our closest living relatives. This investigation reports the first faecal biomarker data for wild chimpanzee (Pan troglodytes) and mountain gorilla (Gorilla beringei). Our results suggest that the chemometric analysis of faecal biomarkers is a useful tool for distinguishing between NHP and human faecal matter, and hence, it could provide information for palaeodietary research and early human diets. PMID- 26061732 TI - Microsatellite Analysis of Museum Specimens Reveals Historical Differences in Genetic Diversity between Declining and More Stable Bombus Species. AB - Worldwide most pollinators, e.g. bumblebees, are undergoing global declines. Loss of genetic diversity can play an essential role in these observed declines. In this paper, we investigated the level of genetic diversity of seven declining Bombus species and four more stable species with the use of microsatellite loci. Hereto we genotyped a unique collection of museum specimens. Specimens were collected between 1918 and 1926, in 6 provinces of the Netherlands which allowed us to make interspecific comparisons of genetic diversity. For the stable species B. pascuorum, we also selected populations from two additional time periods: 1949 1955 and 1975-1990. The genetic diversity and population structure in B. pascuorum remained constant over the three time periods. However, populations of declining bumblebee species showed a significantly lower genetic diversity than co-occurring stable species before their major declines. This historical difference indicates that the repeatedly observed reduced genetic diversity in recent populations of declining bumblebee species is not caused solely by the decline itself. The historically low genetic diversity in the declined species may be due to the fact that these species were already rare, making them more vulnerable to the major drivers of bumblebee decline. PMID- 26061731 TI - Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays. AB - There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT) poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC). Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s) of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs). Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists. PMID- 26061733 TI - Higher Rate of Tuberculosis in Second Generation Migrants Compared to Native Residents in a Metropolitan Setting in Western Europe. AB - BACKGROUND: In Western Europe, migrants constitute an important risk group for tuberculosis, but little is known about successive generations of migrants. We aimed to characterize migration among tuberculosis cases in Berlin and to estimate annual rates of tuberculosis in two subsequent migrant generations. We hypothesized that second generation migrants born in Germany are at higher risk of tuberculosis compared to native (non-migrant) residents. METHODS: A prospective cross-sectional study was conducted. All tuberculosis cases reported to health authorities in Berlin between 11/2010 and 10/2011 were eligible. Interviews were conducted using a structured questionnaire including demographic data, migration history of patients and their parents, and language use. Tuberculosis rates were estimated using 2011 census data. RESULTS: Of 314 tuberculosis cases reported, 154 (49.0%) participated. Of these, 81 (52.6%) were first-, 14 (9.1%) were second generation migrants, and 59 (38.3%) were native residents. The tuberculosis rate per 100,000 individuals was 28.3 (95CI: 24.0 32.6) in first-, 10.2 (95%CI: 6.1-16.6) in second generation migrants, and 4.6 (95%CI: 3.7-5.6) in native residents. When combining information from the standard notification variables country of birth and citizenship, the sensitivity to detect second generation migration was 28.6%. CONCLUSIONS: There is a higher rate of tuberculosis among second generation migrants compared to native residents in Berlin. This may be explained by presumably frequent contact and transmission within migrant populations. Second generation migration is insufficiently captured by the surveillance variables country of birth and citizenship. Surveillance systems in Western Europe should allow for quantifying the tuberculosis burden in this important risk group. PMID- 26061734 TI - Severity of Scorpion Stings in the Western Brazilian Amazon: A Case-Control Study. AB - BACKGROUND: Scorpion stings are a major public health problem in Brazil, with an increasing number of registered cases every year. Affecting mostly vulnerable populations, the phenomenon is not well described and is considered a neglected disease. In Brazil, the use of anti-venom formulations is provided free of charge. The associate scorpion sting case is subject to compulsory reporting. This paper describes the epidemiology and identifies factors associated with severity of scorpions stings in the state of Amazonas, in the Western Brazilian Amazon. METHODOLOGY/PRINCIPAL FINDINGS: This study included all cases of scorpion stings in the state of Amazonas reported to the Brazilian Diseases Surveillance System from January 1, 2007 to December 31, 2014. A case-control study was conducted to identify factors associated with scorpions sting severity. A total of 2,120 cases were reported during this period. The mean incidence rate in the Amazonas was 7.6 per 100,000 inhabitants/year. Scorpion stings showed a large spatial distribution in the state and represent a potential occupational health problem for rural populations. There was a positive correlation between the absolute number of cases and the altimetric river levels in the Central (p<0.001; Rs = 0.479 linear) and Southwest (p = 0.032; linear Rs = 0.261) regions of the state. Cases were mostly classified as mild (68.6%), followed by moderate (26.8%), and severe (4.6%). The overall lethality rate was 0.3%. Lethality rate among children <=10 years was 1.3%. Age <10 years [OR = 2.58 (95%CI = 1.47-4.55; p = 0.001)], stings occurring in the rural area [OR = 1.97 (95%CI = 1.18-3.29; p = 0.033) and in the South region of the state [OR = 1.85 (95%CI = 1.17-2.93; p = 0.008)] were independently associated with the risk of developing severity. CONCLUSIONS/SIGNIFICANCE: Scorpion stings show an extensive distribution in the Western Brazilian Amazon threatening especially rural populations, children <=10 in particular. Thus, the mapping of scorpions fauna in different Amazon localities is essential and must be accompanied by the characterization of the main biological activities of the venoms. Urban and farming planning, in parallel with awareness of workers at risk for scorpion stings on the need for personal protective equipment use should be considered as public policies for preventing scorpionism. PMID- 26061737 TI - Three New Species of Deltoblastus Fay from the Permian of Timor. AB - Deltoblastus is a genus of Permian blastoid comprised of 15 species, each differing based on subtle thecal morphology differences. Three new species are introduced here, based on characteristics present which distinguish individuals from established morphotypes. In order to guarantee a more complete understanding of the genus, a complex character matrix containing all 15 named and three new species was created, defining all species based on the presence or absence of 30 unique traits. Differences in character compositions give evidence for unique thecal morphologies, supporting the three new species which are proposed. PMID- 26061735 TI - Between-Habitat Variation of Benthic Cover, Reef Fish Assemblage and Feeding Pressure on the Benthos at the Only Atoll in South Atlantic: Rocas Atoll, NE Brazil. AB - The Southwestern Atlantic harbors unique and relatively understudied reef systems, including the only atoll in South Atlantic: Rocas atoll. Located 230 km off the NE Brazilian coast, Rocas is formed by coralline red algae and vermetid mollusks, and is potentially one of the most "pristine" areas in Southwestern Atlantic. We provide the first comprehensive and integrative description of the fish and benthic communities inhabiting different shallow reef habitats of Rocas. We studied two contrasting tide pool habitats: open pools, which communicate with the open ocean even during low tides, thus more exposed to wave action; and closed pools, which remain isolated during low tide and are comparatively less exposed. Reef fish assemblages, benthic cover, algal turfs and fish feeding pressure on the benthos remarkably varied between open and closed pools. The planktivore Thalassoma noronhanum was the most abundant fish species in both habitats. In terms of biomass, the lemon shark Negaprion brevirostris and the omnivore Melichtys niger were dominant in open pools, while herbivorous fishes (mainly Acanthurus spp.) prevailed in closed pools. Overall benthic cover was dominated by algal turfs, composed of articulated calcareous algae in open pools and non-calcified algae in closed pools. Feeding pressure was dominated by acanthurids and was 10-fold lower in open pools than in closed pools. Besides different wave exposure conditions, such pattern could also be related to the presence of sharks in open pools, prompting herbivorous fish to feed more in closed pools. This might indirectly affect the structure of reef fish assemblages and benthic communities. The macroalgae Digenea simplex, which is uncommon in closed pools and abundant in the reef flat, was highly preferred in herbivory assays, indicating that herbivory by fishes might be shaping this distribution pattern. The variations in benthic and reef fish communities, and feeding pressure on the benthos between open and closed pools suggest that the dynamics in open pools is mostly driven by physical factors and the tolerance of organisms to harsh conditions, while in closed pools direct and indirect effects of species interactions also play an important role. Understanding the mechanisms shaping biological communities and how they scale-up to ecosystem functioning is particularly important on isolated near-pristine systems where natural processes can still be studied under limited human impact. PMID- 26061736 TI - Computational Paradigm to Elucidate the Effects of Arts-Based Approaches and Interventions: Individual and Collective Emerging Behaviors in Artwork Construction. AB - Art therapy, as well as other arts-based therapies and interventions, is used to reduce pain, stress, depression, breathlessness and other symptoms in a wide variety of serious and chronic diseases, such as cancer, Alzheimer and schizophrenia. Arts-based approaches are also known to contribute to one's well being and quality of life. However, much research is required, since the mechanisms by which these non-pharmacological treatments exert their therapeutic and psychosocial effects are not adequately understood. A typical clinical setting utilizing the arts consists of the creation work itself, such as the artwork, as well as the therapist and the patient, all of which constitute a rich and dynamic environment of occurrences. The underlying complex, simultaneous and interwoven processes of this setting are often considered intractable to human observers, and as a consequence are usually interpreted subjectively and described verbally, which affect their subsequent analyses and understanding. We introduce a computational research method for elucidating and analyzing emergent expressive and social behaviors, aiming to understand how arts-based approaches operate. Our methodology, which centers on the visual language of Statecharts and tools for its execution, enables rigorous qualitative and quantitative tracking, analysis and documentation of the underlying creation and interaction processes. Also, it enables one to carry out exploratory, hypotheses-generating and knowledge discovery investigations, which are empirical-based. Furthermore, we illustrate our method's use in a proof-of-principle study, applying it to a real world artwork investigation with human participants. We explore individual and collective emergent behaviors impacted by diverse drawing tasks, yielding significant gender and age hypotheses, which may account for variation factors in response to art use. We also discuss how to gear our research method to systematic and mechanistic investigations, as we wish to provide a broad empirical evidence for the uptake of arts-based approaches, also aiming to ameliorate their use in clinical settings. PMID- 26061738 TI - The Safety of Using Body-Transmit MRI in Patients with Implanted Deep Brain Stimulation Devices. AB - BACKGROUND: Deep brain stimulation (DBS) is an established treatment for patients with movement disorders. Patients receiving chronic DBS provide a unique opportunity to explore the underlying mechanisms of DBS using functional MRI. It has been shown that the main safety concern with MRI in these patients is heating at the electrode tips - which can be minimised with strict adherence to a supervised acquisition protocol using a head-transmit/receive coil at 1.5T. MRI using the body-transmit coil with a multi-channel receive head coil has a number of potential advantages including an improved signal-to-noise ratio. STUDY OUTLINE: We compared the safety of cranial MRI in an in vitro model of bilateral DBS using both head-transmit and body-transmit coils. We performed fibre-optic thermometry at a Medtronic ActivaPC device and Medtronic 3389 electrodes during turbo-spin echo (TSE) MRI using both coil arrangements at 1.5T and 3T, in addition to gradient-echo echo-planar fMRI exposure at 1.5T. Finally, we investigated the effect of transmit-coil choice on DBS stimulus delivery during MRI. RESULTS: Temperature increases were consistently largest at the electrode tips. Changing from head- to body-transmit coil significantly increased the electrode temperature elevation during TSE scans with scanner-reported head SAR 0.2W/kg from 0.45 degrees C to 0.79 degrees C (p<0.001) at 1.5T, and from 1.25 degrees C to 1.44 degrees C (p<0.001) at 3T. The position of the phantom relative to the body coil significantly impacted on electrode heating at 1.5T; however, the greatest heating observed in any position tested remained <1 degrees C at this field strength. CONCLUSIONS: We conclude that (1) with our specific hardware and SAR-limited protocol, body-transmit cranial MRI at 1.5T does not produce heating exceeding international guidelines, even in cases of poorly positioned patients, (2) cranial MRI at 3T can readily produce heating exceeding international guidelines, (3) patients with ActivaPC Medtronic systems are safe to be recruited to future fMRI experiments performed under the specific conditions defined by our protocol, with no likelihood of confound by inappropriate stimulus delivery. PMID- 26061740 TI - Severity scoring, outcome prediction and mortality endpoints in intensive care. PMID- 26061739 TI - Efficient Detection of Novel Nuclear Markers for Brassicaceae by Transcriptome Sequencing. AB - The lack of DNA sequence information for most non-model organisms impairs the design of primers that are universally applicable for the study of molecular polymorphisms in nuclear markers. Next-generation sequencing (NGS) techniques nowadays provide a powerful approach to overcome this limitation. We present a flexible and inexpensive method to identify large numbers of nuclear primer pairs that amplify in most Brassicaceae species. We first obtained and mapped NGS transcriptome sequencing reads from two of the distantly related Brassicaceae species, Cardamine hirsuta and Arabis alpina, onto the Arabidopsis thaliana reference genome, and then identified short conserved sequence motifs among the three species bioinformatically. From these, primer pairs to amplify coding regions (nuclear protein coding loci, NPCL) and exon-primed intron-crossing sequences (EPIC) were developed. We identified 2,334 universally applicable primer pairs, targeting 1,164 genes, which provide a large pool of markers as readily usable genomic resource that will help addressing novel questions in the Brassicaceae family. Testing a subset of the newly designed nuclear primer pairs revealed that a great majority yielded a single amplicon in all of the 30 investigated Brassicaceae taxa. Sequence analysis and phylogenetic reconstruction with a subset of these markers on different levels of phylogenetic divergence in the mustard family were compared with previous studies. The results corroborate the usefulness of the newly developed primer pairs, e.g., for phylogenetic analyses or population genetic studies. Thus, our method provides a cost effective approach for designing nuclear loci across a broad range of taxa and is compatible with current NGS technologies. PMID- 26061741 TI - Recent trends in children's exposure to second-hand smoke in England: cotinine evidence from the Health Survey for England. AB - AIMS: To examine changes in children's exposure to second-hand tobacco smoke in England since 1998. DESIGN: Repeated cross-sectional surveys of the general population in England. SETTING: The Health Survey for England. PARTICIPANTS: A total of 37 038 children participating in surveys from 1998 to 2012, 13 327 of whom were aged 4-15 years, had available cotinine and were confirmed non-smokers. MEASUREMENTS: The proportion of children with smoking parents; the proportion of children living in homes reported to be smoke-free; the proportion of children with undetectable concentrations of cotinine; linear and quadratic trend estimates of geometric mean cotinine across years. FINDINGS: By 2012, 87.3% of children lived in a home that was smoke-free {97.2% [95% confidence interval (CI) = 95.9-98.1] when parents were non-smokers, 61.3% (95% CI = 55.5-66.8) when one or both parents smoked}. A total of 68.6% (95% CI = 64.3-72.6%) of children had undetectable cotinine in 2012, up from 14.3% (95% CI = 12.7-16.0%) in 1998. There was a highly significant linear trend across years (with a small but significant quadratic term) to declining geometric mean cotinine in all children from 0.52 ng/ml (95% CI = 0.48-0.57) in 1998 to 0.11 ng/ml (95% CI = 0.10-0.12) in 2012. Children from routine/manual backgrounds were more exposed, but experienced similar gains across years to those from non-manual backgrounds. CONCLUSIONS: In England, children's exposure to second-hand smoke has declined by 79% since 1998, with continuing progress since smoke-free legislation in 2007. An emerging social norm in England has led to the adoption of smoke-free homes not only when parents are non-smokers, but also when they smoke. PMID- 26061742 TI - Origin of the low thermal isomerization rate of rhodopsin chromophore. AB - Low dark noise is a prerequisite for rod cells, which mediate our dim-light vision. The low dark noise is achieved by the extremely stable character of the rod visual pigment, rhodopsin, which evolved from less stable cone visual pigments. We have developed a biochemical method to quickly evaluate the thermal activation rate of visual pigments. Using an isomerization locked chromophore, we confirmed that thermal isomerization of the chromophore is the sole cause of thermal activation. Interestingly, we revealed an unexpected correlation between the thermal stability of the dark state and that of the active intermediate MetaII. Furthermore, we assessed key residues in rhodopsin and cone visual pigments by mutation analysis and identified two critical residues (E122 and I189) in the retinal binding pocket which account for the extremely low thermal activation rate of rhodopsin. PMID- 26061744 TI - Tin-Doped Inorganic Amorphous Films for Use as Transparent Monolithic Phosphors. AB - Although inorganic crystalline phosphors can exhibit high quantum efficiency, their use in phosphor films has been limited by a reliance on organic binders that have poor durability when exposed to high-power and/or high excitation energy light sources. To address this problem, Sn(2+)-doped transparent phosphate films measuring several micrometers in thickness have been successfully prepared through heat treatment and a subsequent single dip-coating process. The resulting monolithic inorganic amorphous film exhibited an internal quantum efficiency of over 60% and can potentially utilize transmitted light. Analysis of the film's emissivity revealed that its color can be tuned by changing the amount of Mn and Sn added to influence the energy transfer from Sn(2+) to Mn(2+). It is therefore concluded that amorphous films containing such emission centers can provide a novel and viable alternative to conventional amorphous films containing crystalline phosphors in light-emitting devices. PMID- 26061743 TI - Increased Functional Connectivity Between Subcortical and Cortical Resting-State Networks in Autism Spectrum Disorder. AB - IMPORTANCE: Individuals with autism spectrum disorder (ASD) exhibit severe difficulties in social interaction, motor coordination, behavioral flexibility, and atypical sensory processing, with considerable interindividual variability. This heterogeneous set of symptoms recently led to investigating the presence of abnormalities in the interaction across large-scale brain networks. To date, studies have focused either on constrained sets of brain regions or whole-brain analysis, rather than focusing on the interaction between brain networks. OBJECTIVES: To compare the intrinsic functional connectivity between brain networks in a large sample of individuals with ASD and typically developing control subjects and to estimate to what extent group differences would predict autistic traits and reflect different developmental trajectories. DESIGN, SETTING, AND PARTICIPANTS: We studied 166 male individuals (mean age, 17.6 years; age range, 7-50 years) diagnosed as having DSM-IV-TR autism or Asperger syndrome and 193 typical developing male individuals (mean age, 16.9 years; age range, 6.5 39.4 years) using resting-state functional magnetic resonance imaging (MRI). Participants were matched for age, IQ, head motion, and eye status (open or closed) in the MRI scanner. We analyzed data from the Autism Brain Imaging Data Exchange (ABIDE), an aggregated MRI data set from 17 centers, made public in August 2012. MAIN OUTCOMES AND MEASURES: We estimated correlations between time courses of brain networks extracted using a data-driven method (independent component analysis). Subsequently, we associated estimates of interaction strength between networks with age and autistic traits indexed by the Social Responsiveness Scale. RESULTS: Relative to typically developing control participants, individuals with ASD showed increased functional connectivity between primary sensory networks and subcortical networks (thalamus and basal ganglia) (all t >= 3.13, P < .001 corrected). The strength of such connections was associated with the severity of autistic traits in the ASD group (all r >= 0.21, P < .0067 corrected). In addition, subcortico-cortical interaction decreased with age in the entire sample (all r <= -0.09, P < .012 corrected), although this association was significant only in typically developing participants (all r <= -0.13, P < .009 corrected). CONCLUSIONS AND RELEVANCE: Our results showing ASD-related impairment in the interaction between primary sensory cortices and subcortical regions suggest that the sensory processes they subserve abnormally influence brain information processing in individuals with ASD. This might contribute to the occurrence of hyposensitivity or hypersensitivity and of difficulties in top-down regulation of behavior. PMID- 26061746 TI - Combination of body mass index and oxidized low density lipoprotein receptor 1 in prognosis prediction of patients with squamous non-small cell lung cancer. AB - Lung cancer, especially non-small cell lung cancer (NSCLC), represents enormous challenges in continuously achieving treatment improvements. Besides cancer, obesity is becoming ever more prevalent. Obesity is increasingly acknowledged as a major risk factor for several types of common cancers. Significant mechanisms overlap in the pathobiology of obesity and tumorigenesis. One of these mechanisms involves oxidized low density lipoprotein receptor 1 (OLR1), as a link between obesity and cancer. Additionally, body mass index (BMI) has been widely used in exploiting the role of obesity on a series of diseases, including cancer. Significantly, squamous NSCLC revealed to be divergent clinical and molecular phenotypes compared with non-squamous NSCLC. Consequently, OLR1 immunostaining score and BMI were assessed by Fisher's linear discriminant analysis to discriminate if progression-free survival (PFS) would exceed 2 years. In addition, the final model was utilized to calculate the discriminant score in each study participant. Finally, 131 patients with squamous NCSLC were eligible for analysis. And a prediction model was established for PFS based on these 2 markers and validated in a second set of squamous NCSLC patients. The model offers a novel tool for survival prediction and could establish a framework for future individualized therapy for patients with squamous NCSLC. PMID- 26061747 TI - Functional relevance of a six mesenchymal gene signature in epithelial mesenchymal transition (EMT) reversal by the triple angiokinase inhibitor, nintedanib (BIBF1120). AB - Epithelial-mesenchymal transition (EMT), a crucial mechanism in carcinoma progression, describes the process whereby epithelial cells lose their apico basal polarity and junctional complexes and acquire a mesenchymal-like morphology. Several markers are considered to be authentic indicators of an epithelial or mesenchymal status; however, there is currently no comprehensive or systematic method with which to determine their functional relevance. Previously, we identified a 33-gene EMT signature comprising 25 epithelial and 6 mesenchymal genes that best describe this concept of the EMT spectrum. Here, we designed small-scale siRNA screens targeting these six mesenchymal signature genes (CD99L2, EMP3, ITGA5, SYDE1, VIM, ZEB1) to explore their functional relevance and their roles during EMT reversal by nintedanib (BIBF1120) in a mesenchymal-like SKOV3 ovarian cancer cell line. We found that neither cell proliferation nor cytotoxicity was affected by silencing any of these genes. SKOV3 cells expressing siRNA against mesenchymal genes (ZEB1, EMP3, CD99L2, ITGA5, and SYDE1) showed enhanced colony compaction (reduced inter-nuclear distance). Inductions of E cadherin expression were only observed in SYDE1- and ZEB1-silenced SKOV3 cells. In addition, only SYDE1-silenced SKOV3 cells showed increased anoikis. Finally, we identified that SYDE1 and ZEB1 were down-regulated in nintedanib-treated SKOV3 cells and SYDE1- and ZEB1-silenced SKOV3 cells showed enhanced nintedanib-induced up-regulation of E-cadherin. Nintedanib-treated SKOV3 cells also showed colony compaction and decreases in EMT scores both in vitro and in vivo. We conclude that SYDE1 and ZEB1 are functionally relevant in EMT reversal. This study thus provides a proof-of-concept for the use of in vitro siRNA screening to explore the EMT-related functions of selected genes and their potential relevance in the discovery of EMT reversing drugs. PMID- 26061745 TI - The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice. AB - Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-alpha and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR. PMID- 26061749 TI - A Visible-Light-Induced alpha-H Chlorination of Alkylarenes with Inorganic Chloride under NanoAg@AgCl. AB - An efficient, photocatalytic chlorination of alkylarene alpha-H groups using NaCl/HCl as a chlorine source has been developed, which involves a radical mechanism under visible-light (including sunlight) conditions. A chlorine radical is proposed to be formed by an electron transfer from chloride ion to O2 in air through the bandgap hole of the semiconductor AgCl. The chlorination protocol is characterized by its use of natural sunlight or other visible light, mild conditions, cheap source of chlorine, green solvent, and high selectivity. The yield of benzylchloride is 95% with a toluene conversion as high as 40%, which rivals traditional chlorination methods. PMID- 26061748 TI - Identification of alsterpaullone as a novel small molecule inhibitor to target group 3 medulloblastoma. AB - Advances in the molecular biology of medulloblastoma revealed four genetically and clinically distinct subgroups. Group 3 medulloblastomas are characterized by frequent amplifications of the oncogene MYC, a high incidence of metastasis, and poor prognosis despite aggressive therapy. We investigated several potential small molecule inhibitors to target Group 3 medulloblastomas based on gene expression data using an in silico drug screen. The Connectivity Map (C-MAP) analysis identified piperlongumine as the top candidate drug for non-WNT medulloblastomas and the cyclin-dependent kinase (CDK) inhibitor alsterpaullone as the compound predicted to have specific antitumor activity against Group 3 medulloblastomas. To validate our findings we used these inhibitors against established Group 3 medulloblastoma cell lines. The C-MAP predicted drugs reduced cell proliferation in vitro and increased survival in Group 3 medulloblastoma xenografts. Alsterpaullone had the highest efficacy in Group 3 medulloblastoma cells. Genomic profiling of Group 3 medulloblastoma cells treated with alsterpaullone confirmed inhibition of cell cycle-related genes, and down regulation of MYC. Our results demonstrate the preclinical efficacy of using a targeted therapy approach for Group 3 medulloblastomas. Specifically, we provide rationale for advancing alsterpaullone as a targeted therapy in Group 3 medulloblastoma. PMID- 26061750 TI - Controlled assembly of magnetic nanoparticles on microbubbles for multimodal imaging. AB - Magnetic microbubbles (MMBs) consisting of microbubbles (MBs) and magnetic nanoparticles (MNPs) were synthesized for use as novel markers for improving multifunctional biomedical imaging. The MMBs were fabricated by assembling MNPs in different concentrations on the surfaces of MBs. The relationships between the structure, magnetic properties, stability of the MMBs, and their use in magnetic resonance/ultrasound (MR/US) dual imaging applications were determined. The MNPs used were NPs of 3-aminopropyltriethoxysilane (APTS)-functionalized superparamagnetic iron oxide gamma-Fe2O3 (SPIO). SPIO was assembled on the surfaces of polymer MBs using a "surface-coating" approach. An analysis of the underlying mechanism showed that the synergistic effects of covalent coupling, electrostatic adsorption, and aggregation of the MNPs allowed them to be unevenly assembled in large amounts on the surfaces of the MBs. With an increase in the MNP loading amount, the magnetic properties of the MMBs improved significantly; in this way, the shell structure and mechanical properties of the MMBs could be modified. For surface densities ranging from 2.45 * 10(-7) MUg per MMB to 8.45 * 10(-7) MUg per MMB, in vitro MR/US imaging experiments showed that, with an increase in the number of MNPs on the surfaces of the MBs, the MMBs exhibited better T2 MR imaging contrast, as well as an increase in the US contrast for longer durations. In vivo experiments also showed that, by optimizing the structure of the MMBs, enhanced MR/US dual-modality image signals could be obtained for mouse tumors. Therefore, by adjusting the shell composition of MBs through the assembly of MNPs in different concentrations, MMBs with good magnetic and acoustic properties for MR/US dual-modality imaging contrast agents could be obtained. PMID- 26061752 TI - The Trans-Pacific Partnership--Is It Bad for Your Health? PMID- 26061754 TI - Multiple Molecular Data Sets and the Classification of Adult Diffuse Gliomas. PMID- 26061753 TI - Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. AB - BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.). PMID- 26061755 TI - Factors associated with transmission of influenza-like illness in a cohort of households containing multiple children. AB - BACKGROUND: Household studies of influenza-like illness (ILI) afford opportunities to study determinants of respiratory virus transmission. OBJECTIVES: We examined predictors of ILI transmission within households containing at least two children. METHODS: A prospective cohort study recorded ILI symptoms daily for 2712 adult and child participants during the 1998 influenza season in Victoria, Australia. Logistic and Poisson regressions were used to explore predictors of household transmission of ILI and the secondary household attack proportion (SHAP). A date of illness onset during the influenza season was used as a proxy indicator of ILI associated with influenza infection (as opposed to other aetiological causes). RESULTS: A total of 1009 ILI episodes were reported by 781 of 2712 (29%) participants residing in 157 households. Transmission, defined as detection of ILI in one or more household members following identification of an index case, was observed in 206 of 705 (29%) household introductions. Transmission of ILI was significantly associated with the onset of ILI in the index case during the peak influenza season compared with the remainder of the observation period (37% versus 27%, odds ratio = 1.59, 95% CI 1.09, 2.31, P = 0.017). The SHAP was 0.12, higher if the index case was of secondary school age [incidence risk ratio (IRR) = 1.80, 95% CI 1.08, 2.98, P = 0.022]. CONCLUSIONS: Risk of household transmission of ILI was increased during the peak influenza season, indicating an increased burden of disease during the period of influenza circulation. In this cohort, secondary-school-aged children and adults were important transmitters of ILI. PMID- 26061756 TI - A-site-deficiency facilitated in situ growth of bimetallic Ni-Fe nano-alloys: a novel coking-tolerant fuel cell anode catalyst. AB - To date, most investigations of Ni-Fe bimetallic catalysts for solid oxide fuel cells (SOFCs) have focused on materials with micro-scale particle sizes, which severely restrict their catalytic activity. In this study, we fabricated a Ni- and/or Fe-doped A-site-deficient LaSrCrO3 perovskite (A-LSC) bimetallic anode material on which the in situ exsolution of uniformly dispersed nano Ni, Fe and Ni-Fe alloy with an average particle size of 25 to 30 nm was facilitated by the introduction of A-site deficiency under a reducing atmosphere. The dopants were shown to significantly enhance the electrical conductivity of the material by many orders of magnitude. Further characterization of the bimetallic material showed that the addition of Fe changed the reduction behavior and increased the amount of oxygen vacancies in the material. Fuel cell performance tests demonstrated that the prepared bimetallic anode catalyst with a highly catalytically active nano Ni-Fe alloy promoted the electrochemical performance in 5000 ppm H2S-syngas and improved the carbon deposition resistance compared to a monometallic anode catalyst. PMID- 26061757 TI - Deep intronic GPR143 mutation in a Japanese family with ocular albinism. AB - Deep intronic mutations are often ignored as possible causes of human disease. Using whole-exome sequencing, we analysed genomic DNAs of a Japanese family with two male siblings affected by ocular albinism and congenital nystagmus. Although mutations or copy number alterations of coding regions were not identified in candidate genes, the novel intronic mutation c.659-131 T > G within GPR143 intron 5 was identified as hemizygous in affected siblings and as heterozygous in the unaffected mother. This mutation was predicted to create a cryptic splice donor site within intron 5 and activate a cryptic acceptor site at 41nt upstream, causing the insertion into the coding sequence of an out-of-frame 41-bp pseudoexon with a premature stop codon in the aberrant transcript, which was confirmed by minigene experiments. This result expands the mutational spectrum of GPR143 and suggests the utility of next-generation sequencing integrated with in silico and experimental analyses for improving the molecular diagnosis of this disease. PMID- 26061758 TI - Noise assisted excitation energy transfer in a linear model of a selectivity filter backbone strand. AB - In this paper, we investigate the effect of noise and disorder on the efficiency of excitation energy transfer (EET) in a N = 5 sites linear chain with 'static' dipole-dipole couplings. In fact, here, the disordered chain is a toy model for one strand of the selectivity filter backbone in ion channels. It has recently been discussed that the presence of quantum coherence in the selectivity filter is possible and can play a role in mediating ion-conduction and ion-selectivity in the selectivity filter. The question is 'how a quantum coherence can be effective in such structures while the environment of the channel is dephasing (i.e. noisy)?' Basically, we expect that the presence of the noise should have a destructive effect in the quantum transport. In fact, we show that such expectation is valid for ordered chains. However, our results indicate that introducing the dephasing in the disordered chains leads to the weakening of the localization effects, arising from the multiple back-scatterings due to the randomness, and then increases the efficiency of quantum energy transfer. Thus, the presence of noise is crucial for the enhancement of EET efficiency in disordered chains. We also show that the contribution of both classical and quantum mechanical effects are required to improve the speed of energy transfer along the chain. Our analysis may help for better understanding of fast and efficient functioning of the selectivity filters in ion channels. PMID- 26061759 TI - Optic neuropathy, cardiomyopathy, cognitive disability in patients with a homozygous mutation in the nuclear MTO1 and a mitochondrial MT-TF variant. AB - We report on clinical, genetic and metabolic investigations in a family with optic neuropathy, non-progressive cardiomyopathy and cognitive disability. Ophthalmic investigations (slit lamp examination, funduscopy, OCT scan of the optic nerve, ERG and VEP) disclosed mild or no decreased visual acuity, but pale optic disc, loss of temporal optic fibers and decreased VEPs. Mitochondrial DNA and exome sequencing revealed a novel homozygous mutation in the nuclear MTO1 gene and the homoplasmic m.593T>G mutation in the mitochondrial MT-TF gene. Muscle biopsy analyses revealed decreased oxygraphic Vmax values for complexes I+III+IV, and severely decreased activities of the respiratory chain complexes (RCC) I, III and IV, while muscle histopathology was normal. Fibroblast analysis revealed decreased complex I and IV activity and assembly, while cybrid analysis revealed a partial complex I deficiency with normal assembly of the RCC. Thus, in patients with a moderate clinical presentation due to MTO1 mutations, the presence of an optic atrophy should be considered. The association with the mitochondrial mutation m.593T>G could act synergistically to worsen the complex I deficiency and modulate the MTO1-related disease. PMID- 26061760 TI - Hypoxia, Oxidative Stress and Fat. AB - Metabolic disturbances in white adipose tissue in obese individuals contribute to the pathogenesis of insulin resistance and the development of type 2 diabetes mellitus. Impaired insulin action in adipocytes is associated with elevated lipolysis and increased free fatty acids leading to ectopic fat deposition in liver and skeletal muscle. Chronic adipose tissue hypoxia has been suggested to be part of pathomechanisms causing dysfunction of adipocytes. Hypoxia can provoke oxidative stress in human and animal adipocytes and reduce the production of beneficial adipokines, such as adiponectin. However, time-dose responses to hypoxia relativize the effects of hypoxic stress. Long-term exposure of fat cells to hypoxia can lead to the production of beneficial substances such as leptin. Knowledge of time-dose responses of hypoxia on white adipose tissue and the time course of generation of oxidative stress in adipocytes is still scarce. This paper reviews the potential links between adipose tissue hypoxia, oxidative stress, mitochondrial dysfunction, and low-grade inflammation caused by adipocyte hypertrophy, macrophage infiltration and production of inflammatory mediators. PMID- 26061762 TI - The Influence of Carbohydrate Mouth Rinse on Self-Selected Intermittent Running Performance. AB - This study investigated the influence of mouth rinsing a carbohydrate solution on self-selected intermittent variable-speed running performance. Eleven male amateur soccer players completed a modified version of the Loughborough Intermittent Shuttle Test (LIST) on 2 occasions separated by 1 wk. The modified LIST allowed the self-selection of running speeds during Block 6 of the protocol (75-90 min). Players rinsed and expectorated 25 ml of noncaloric placebo (PLA) or 10% maltodextrin solution (CHO) for 10 s, routinely during Block 6 of the LIST. Self-selected speeds during the walk and cruise phases of the LIST were similar between trials. Jogging speed was significantly faster during the CHO (11.3 +/- 0.7 km . h(-1)) than during the PLA trial (10.5 +/- 1.3 km . h(-1)) (p = .010); 15-m sprint speeds were not different between trials (PLA: 2.69 +/- 0.18 s: CHO: 2.65 +/- 0.13 s) (F(2, 10), p = .157), but significant benefits were observed for sprint distance covered (p = .024). The threshold for the smallest worthwhile change in sprint performance was set at 0.2 s. Inferential statistical analysis showed the chance that CHO mouth rinse was beneficial, negligible, or detrimental to repeated sprint performance was 86%, 10%, and 4%, respectively. In conclusion, mouth rinsing and expectorating a 10% maltodextrin solution was associated with a significant increase in self-selected jogging speed. Repeated 15-m sprint performance was also 86% likely to benefit from routinely mouth rinsing a carbohydrate solution in comparison with a taste-matched placebo. PMID- 26061761 TI - CPSF30 at the Interface of Alternative Polyadenylation and Cellular Signaling in Plants. AB - Post-transcriptional processing, involving cleavage of precursor messenger RNA (pre mRNA), and further incorporation of poly(A) tail to the 3' end is a key step in the expression of genetic information. Alternative polyadenylation (APA) serves as an important check point for the regulation of gene expression. Recent studies have shown widespread prevalence of APA in diverse systems. A considerable amount of research has been done in characterizing different subunits of so-called Cleavage and Polyadenylation Specificity Factor (CPSF). In plants, CPSF30, an ortholog of the 30 kD subunit of mammalian CPSF is a key polyadenylation factor. CPSF30 in the model plant Arabidopsis thaliana was reported to possess unique biochemical properties. It was also demonstrated that poly(A) site choice in a vast majority of genes in Arabidopsis are CPSF30 dependent, suggesting a pivotal role of this gene in APA and subsequent regulation of gene expression. There are also indications of this gene being involved in oxidative stress and defense responses and in cellular signaling, suggesting a role of CPSF30 in connecting physiological processes and APA. This review will summarize the biochemical features of CPSF30, its role in regulating APA, and possible links with cellular signaling and stress response modules. PMID- 26061763 TI - Environmental Fate of Silver Nanoparticles in Boreal Lake Ecosystems. AB - Silver nanoparticles (AgNPs) are currently the most commonly used nanoparticles in consumer products, yet their environmental fate in natural waters is poorly understood. In the present study, we investigated the persistence, transformations and distribution of polyvinylpyrrolidone (PVP) and citrate (CT) coated AgNPs in boreal lake mesocosms dosed either with a 6-week chronic regimen or a one-time pulse treatment at environmentally relevant dosing levels. In the chronic treatments, total Ag (TAg) concentrations reached ~40% of target concentrations by the end of the experiment, and in the pulsed mesocosms, TAg dissipated slowly, with a half-life of ~20 days. Sediments and periphyton on the mesocosm walls were an important sink for Ag. We found little effect of AgNP loading and surface coating on the persistence of TAg. There were also no differences between treatments in the degree of agglomeration of AgNPs, as indicated by the accumulation and distribution of Ag in the particulate and colloidal fractions. The low ionic strength and relatively high dissolved organic carbon concentrations in the lake water likely contributed to the relative stability of AgNP in the water column. The low concentrations of dissolved Ag (<1 MUg L(-1)) in the size fraction <3 kDaA reflect the importance of natural ligands in controlling the concentrations of Ag released by dissolution of AgNPs. Overall, these data indicate that AgNPs are relatively stable in the tested lake environment and appear to result in quantities of highly toxic ionic Ag(+) that are below our limit of detection. PMID- 26061764 TI - Neurodegeneration: Aggregates feel the strain. PMID- 26061751 TI - Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. AB - BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.). PMID- 26061765 TI - A naturally occurring variant of the human prion protein completely prevents prion disease. AB - Mammalian prions, transmissible agents causing lethal neurodegenerative diseases, are composed of assemblies of misfolded cellular prion protein (PrP). A novel PrP variant, G127V, was under positive evolutionary selection during the epidemic of kuru--an acquired prion disease epidemic of the Fore population in Papua New Guinea--and appeared to provide strong protection against disease in the heterozygous state. Here we have investigated the protective role of this variant and its interaction with the common, worldwide M129V PrP polymorphism. V127 was seen exclusively on a M129 PRNP allele. We demonstrate that transgenic mice expressing both variant and wild-type human PrP are completely resistant to both kuru and classical Creutzfeldt-Jakob disease (CJD) prions (which are closely similar) but can be infected with variant CJD prions, a human prion strain resulting from exposure to bovine spongiform encephalopathy prions to which the Fore were not exposed. Notably, mice expressing only PrP V127 were completely resistant to all prion strains, demonstrating a different molecular mechanism to M129V, which provides its relative protection against classical CJD and kuru in the heterozygous state. Indeed, this single amino acid substitution (G->V) at a residue invariant in vertebrate evolution is as protective as deletion of the protein. Further study in transgenic mice expressing different ratios of variant and wild-type PrP indicates that not only is PrP V127 completely refractory to prion conversion but acts as a potent dose-dependent inhibitor of wild-type prion propagation. PMID- 26061768 TI - Retraction: HMGA2 functions as a competing endogenous RNA to promote lung cancer progression. PMID- 26061767 TI - Neurodegeneration: Evolved protection against human prions. PMID- 26061766 TI - alpha-Synuclein strains cause distinct synucleinopathies after local and systemic administration. AB - Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton alpha-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial alpha-synuclein (alpha-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal alpha-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of alpha-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that alpha-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined alpha-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that alpha-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that alpha-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct alpha-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes. PMID- 26061769 TI - Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria. AB - Gram-negative bacteria inhabit a broad range of ecological niches. For Escherichia coli, this includes river water as well as humans and animals, where it can be both a commensal and a pathogen. Intricate regulatory mechanisms ensure that bacteria have the right complement of beta-barrel outer membrane proteins (OMPs) to enable adaptation to a particular habitat. Yet no mechanism is known for replacing OMPs in the outer membrane, an issue that is further confounded by the lack of an energy source and the high stability and abundance of OMPs. Here we uncover the process underpinning OMP turnover in E. coli and show it to be passive and binary in nature, in which old OMPs are displaced to the poles of growing cells as new OMPs take their place. Using fluorescent colicins as OMP specific probes, in combination with ensemble and single-molecule fluorescence microscopy in vivo and in vitro, as well as molecular dynamics simulations, we established the mechanism for binary OMP partitioning. OMPs clustered to form ~0.5-MUm diameter islands, where their diffusion is restricted by promiscuous interactions with other OMPs. OMP islands were distributed throughout the cell and contained the Bam complex, which catalyses the insertion of OMPs in the outer membrane. However, OMP biogenesis occurred as a gradient that was highest at mid cell but largely absent at cell poles. The cumulative effect is to push old OMP islands towards the poles of growing cells, leading to a binary distribution when cells divide. Hence, the outer membrane of a Gram-negative bacterium is a spatially and temporally organized structure, and this organization lies at the heart of how OMPs are turned over in the membrane. PMID- 26061771 TI - Deployed Women Veterans: Important Culturally Sensitive Care. AB - PROBLEM: Today, with almost 23 million veterans in the nation, and currently only about 10 million, or less, of them seeking active services associated with the Veterans Administration (VA) health facilities, these men and women veterans will be seeking some, more, or even all of their health care over their life time in civilian-based facilities. METHODS: Pertinent literary sources were reviewed to gather applicable data about the problem. FINDINGS: Every patient that enters your health facility should be asked an essential assessment question: "Have you served in the military?" Importantly, to gain effective rapport when they present, civilian nurses will need to anticipate their health needs and provide culturally sensitive care. Specific issues of deployed women veterans are provided in a series of two articles. CONCLUSION: This article provides a snapshot of the uniquely entrenched military culture, as well as women service member experiences in wartime, including the Global War on Terror (Iraq and Afghanistan). The next article discusses the various healthcare differences (e.g., post-traumatic stress disorder and military sexual trauma), difficulties (e.g., reproductive, gynecologic, urinary, employment, homelessness issues), and gender disparities (varied treatment patterns) so the civilian nurse can better advocate for women veterans. PMID- 26061770 TI - Structural basis for retroviral integration into nucleosomes. AB - Retroviral integration is catalysed by a tetramer of integrase (IN) assembled on viral DNA ends in a stable complex, known as the intasome. How the intasome interfaces with chromosomal DNA, which exists in the form of nucleosomal arrays, is currently unknown. Here we show that the prototype foamy virus (PFV) intasome is proficient at stable capture of nucleosomes as targets for integration. Single particle cryo-electron microscopy reveals a multivalent intasome-nucleosome interface involving both gyres of nucleosomal DNA and one H2A-H2B heterodimer. While the histone octamer remains intact, the DNA is lifted from the surface of the H2A-H2B heterodimer to allow integration at strongly preferred superhelix location +/-3.5 positions. Amino acid substitutions disrupting these contacts impinge on the ability of the intasome to engage nucleosomes in vitro and redistribute viral integration sites on the genomic scale. Our findings elucidate the molecular basis for nucleosome capture by the viral DNA recombination machinery and the underlying nucleosome plasticity that allows integration. PMID- 26061772 TI - Long-term Survival After Pancreatic Cancer: Hope Has Arrived. PMID- 26061773 TI - Effects of NaCl concentration on anode microbes in microbial fuel cells. AB - Understanding of how operational parameters affect the composition of exoelectrogenic microbes is an important step in the development of efficient microbial fuel cells (MFCs). In the present study, single-chamber MFCs were inoculated with rice paddy-field soil and continuously supplied with an acetate medium containing different concentrations of NaCl (0-1.8 M). Polarization analyses showed that power output increased as the NaCl concentration increased to 0.1 M, while it was markedly diminished over 0.3 M. The increase in power output was associated with an increased abundance of anode microbes as assessed by protein assays. Notably, the power increase was also accompanied by an increase in the abundance ratio of Geobacter bacteria to total anode bacteria as assessed by pyrosequencing of 16S rRNA gene amplicons and specific quantitative PCR. Although most Geobacter species are known to exhibit high growth rates in freshwater media without NaCl, the present study shows that 0.1 M NaCl facilitates the growth of Geobacter in MFC anode biofilms. This result suggests that the optimum salt concentration in MFC is determined by the balance of two factors, namely, the solution conductivity and salt tolerance of exoelectrogens. PMID- 26061774 TI - Metabarcoding of the kombucha microbial community grown in different microenvironments. AB - Introducing of the DNA metabarcoding analysis of probiotic microbial communities allowed getting insight into their functioning and establishing a better control on safety and efficacy of the probiotic communities. In this work the kombucha poly-microbial probiotic community was analysed to study its flexibility under different growth conditions. Environmental DNA sequencing revealed a complex and flexible composition of the kombucha microbial culture (KMC) constituting more bacterial and fungal organisms in addition to those found by cultural method. The community comprised bacterial and yeast components including cultured and uncultivable microorganisms. Culturing the KMC under different conditions revealed the core part of the community which included acetobacteria of two genera Komagataeibacter (former Gluconacetobacter) and Gluconobacter, and representatives of several yeast genera among which Brettanomyces/Dekkera and Pichia (including former Issatchenkia) were dominant. Herbaspirillum spp. and Halomonas spp., which previously had not been described in KMC, were found to be minor but permanent members of the community. The community composition was dependent on the growth conditions. The bacterial component of KMC was relatively stable, but may include additional member-lactobacilli. The yeast species composition was significantly variable. High-throughput sequencing showed complexity and variability of KMC that may affect the quality of the probiotic drink. It was hypothesized that the kombucha core community might recruit some environmental bacteria, particularly lactobacilli, which potentially may contribute to the fermentative capacity of the probiotic drink. As many KMC associated microorganisms cannot be cultured out of the community, a robust control for community composition should be provided by using DNA metabarcoding. PMID- 26061775 TI - Developing a phenomenological model of the proton trajectory within a heterogeneous medium required for proton imaging. AB - To develop an accurate phenomenological model of the cubic spline path estimate of the proton path, accounting for the initial proton energy and water equivalent thickness (WET) traversed. Monte Carlo (MC) simulations were used to calculate the path of protons crossing various WET (10-30 cm) of different material (LN300, water and CB2-50% CaCO3) for a range of initial energies (180-330 MeV). For each MC trajectory, cubic spline trajectories (CST) were constructed based on the entrance and exit information of the protons and compared with the MC using the root mean square (RMS) metric. The CST path is dependent on the direction vector magnitudes (|P0,1|). First, |P0,1| is set to the proton path length (with factor Lambda(Norm)(0,1) = 1.0). Then, two optimal factor Lambda(0,1) are introduced in |P0,1|. The factors are varied to minimize the RMS difference with MC paths for every configuration. A set of Lambda(opt)(0,1) factors, function of WET/water equivalent path length (WEPL), that minimizes the RMS are presented. MTF analysis is then performed on proton radiographs of a line-pair phantom reconstructed using the CST trajectories. Lambda(opt)(0,1) was fitted to the WET/WEPL ratio using a quadratic function (Y = A + BX(2) where A = 1.01,0.99, B = 0.43,- 0.46 respectively for Lambda(opt)(0), Lambda(opt)(1)). The RMS deviation calculated along the path, between the CST and the MC, increases with the WET. The increase is larger when using Lambda(Norm)(0,1) than Lambda(opt)(0,1) (difference of 5.0% with WET/WEPL = 0.66). For 230/330 MeV protons, the MTF10% was found to increase by 40/16% respectively for a thin phantom (15 cm) when using the Lambda(opt)(0,1) model compared to the Lambda(Norm)(0,1) model. Calculation times for Lambda(opt)(0,1) are scaled down compared to MLP and RMS deviation are similar within standard deviation.B ased on the results of this study, using CST with the Lambda(opt)(0,1) factors reduces the RMS deviation and increases the spatial resolution when reconstructing proton trajectories. PMID- 26061777 TI - Effectiveness of different irrigation solutions on triple antibiotic paste removal from simulated immature root canal. AB - To evaluate the effectiveness of different irrigation solutions and ultrasonic activation of irrigation solutions on removal of triple antibiotic paste (TAP) from root canals of the simulated immature teeth. Fifty single-rooted teeth were used. TAP was placed into each root canal, and specimens were stored in distilled water for 4 weeks at 37 degrees C. After 4 weeks, the temporary coronal seal was removed and the samples were randomly divided into five groups as follows: (i) saline; (ii) ultrasonic activation of saline; (iii) NaOCl; (iv) ultrasonic activation of NaOCl; (v) chlorhexidine digluconate (CHX). The amount of remaining TAP on the canal walls was measured under stereomicroscope with 30* magnification. The data were analyzed using a one-way ANOVA and post-hoc Tukey test at a significance level of 0.05. There were statistically differences among CHX and ultrasonic activation of NaOCl and other groups (p < 0.05). There were no significant differences among the ultrasonic activation of saline, NaOCl, and saline groups (p > 0.05). Irrigation solutions and ultrasonic activation of the irrigation solutions could not completely remove the triple antibiotic paste from simulated immature root canals. Ultrasonic activation of the NaOCl gave the best and CHX was the worst results. PMID- 26061776 TI - Differential cell autonomous responses determine the outcome of coxsackievirus infections in murine pancreatic alpha and beta cells. AB - Type 1 diabetes (T1D) is an autoimmune disease caused by loss of pancreatic beta cells via apoptosis while neighboring alpha cells are preserved. Viral infections by coxsackieviruses (CVB) may contribute to trigger autoimmunity in T1D. Cellular permissiveness to viral infection is modulated by innate antiviral responses, which vary among different cell types. We presently describe that global gene expression is similar in cytokine-treated and virus-infected human islet cells, with up-regulation of gene networks involved in cell autonomous immune responses. Comparison between the responses of rat pancreatic alpha and beta cells to infection by CVB5 and 4 indicate that alpha cells trigger a more efficient antiviral response than beta cells, including higher basal and induced expression of STAT1-regulated genes, and are thus better able to clear viral infections than beta cells. These differences may explain why pancreatic beta cells, but not alpha cells, are targeted by an autoimmune response during T1D. PMID- 26061778 TI - Nanohole-Structured and Palladium-Embedded 3D Porous Graphene for Ultrahigh Hydrogen Storage and CO Oxidation Multifunctionalities. AB - Atomic-scale defects on carbon nanostructures have been considered as detrimental factors and critical problems to be eliminated in order to fully utilize their intrinsic material properties such as ultrahigh mechanical stiffness and electrical conductivity. However, defects that can be intentionally controlled through chemical and physical treatments are reasonably expected to bring benefits in various practical engineering applications such as desalination thin membranes, photochemical catalysts, and energy storage materials. Herein, we report a defect-engineered self-assembly procedure to produce a three dimensionally nanohole-structured and palladium-embedded porous graphene hetero nanostructure having ultrahigh hydrogen storage and CO oxidation multifunctionalities. Under multistep microwave reactions, agglomerated palladium nanoparticles having diameters of ~10 nm produce physical nanoholes in the basal plane structure of graphene sheets, while much smaller palladium nanoparticles are readily impregnated inside graphene layers and bonded on graphene surfaces. The present results show that the defect-engineered hetero-nanostructure has a ~5.4 wt % hydrogen storage capacity under 7.5 MPa and CO oxidation catalytic activity at 190 degrees C. The defect-laden graphene can be highly functionalized for multipurpose applications such as molecule absorption, electrochemical energy storage, and catalytic activity, resulting in a pathway to nanoengineering based on underlying atomic scale and physical defects. PMID- 26061780 TI - Direct Imaging of Nanoscale Conductance Evolution in Ion-Gel-Gated Oxide Transistors. AB - Electrostatic modification of functional materials by electrolytic gating has demonstrated a remarkably wide range of density modulation, a condition crucial for developing novel electronic phases in systems ranging from complex oxides to layered chalcogenides. Yet little is known microscopically when carriers are modulated in electrolyte-gated electric double-layer transistors (EDLTs) due to the technical challenge of imaging the buried electrolyte-semiconductor interface. Here, we demonstrate the real-space mapping of the channel conductance in ZnO EDLTs using a cryogenic microwave impedance microscope. A spin-coated ionic gel layer with typical thicknesses below 50 nm allows us to perform high resolution (on the order of 100 nm) subsurface imaging, while maintaining the capability of inducing the metal-insulator transition under a gate bias. The microwave images vividly show the spatial evolution of channel conductance and its local fluctuations through the transition as well as the uneven conductance distribution established by a large source-drain bias. The unique combination of ultrathin ion-gel gating and microwave imaging offers a new opportunity to study the local transport and mesoscopic electronic properties in EDLTs. PMID- 26061779 TI - Home pesticide exposures and risk of childhood leukemia: Findings from the childhood leukemia international consortium. AB - Some previous studies have suggested that home pesticide exposure before birth and during a child's early years may increase the risk of childhood leukemia. To further investigate this, we pooled individual level data from 12 case-control studies in the Childhood Leukemia International Consortium. Exposure data were harmonized into compatible formats. Pooled analyses were undertaken using multivariable unconditional logistic regression. The odds ratio (ORs) for acute lymphoblastic leukemia (ALL) associated with any pesticide exposure shortly before conception, during pregnancy and after birth were 1.39 (95% confidence interval [CI]: 1.25, 1.55) (using 2,785 cases and 3,635 controls), 1.43 (95% CI: 1.32, 1.54) (5,055 cases and 7,370 controls) and 1.36 (95% CI: 1.23, 1.51) (4,162 cases and 5,179 controls), respectively. Corresponding ORs for risk of acute myeloid leukemia (AML) were 1.49 (95% CI: 1.02, 2.16) (173 cases and 1,789 controls), 1.55 (95% CI: 1.21, 1.99) (344 cases and 4,666 controls) and 1.08 (95% CI: 0.76, 1.53) (198 cases and 2,655 controls), respectively. There was little difference by type of pesticide used. The relative similarity in ORs between leukemia types, time periods and pesticide types may be explained by similar exposure patterns and effects across the time periods in ALL and AML, participants' exposure to multiple pesticides, or recall bias. Although some recall bias is likely, until a better study design can be found to investigate the associations between home pesticide use and childhood leukemia in an equally large sample, it would appear prudent to limit the use of home pesticides before and during pregnancy, and during childhood. PMID- 26061782 TI - Meta-analysis of time-to-event data: a comparison of two-stage methods. AB - Meta-analysis is widely used to synthesise results from randomised trials. When the relevant trials collected time-to-event data, individual participant data are commonly sought from all trials. Meta-analyses of time-to-event data are typically performed using variants of the log-rank test, but modern statistical software allows for the use of maximum likelihood methods such as Cox proportional hazards models or interval-censored logistic regression. In this paper, the different approaches to the analysis of time-to-event data are examined and compared with show that log-rank test approaches are in fact first order approximations to the maximum likelihood methods and that some methods assume proportional hazards, whereas others assume proportional odds. A simulation study is performed to compare the different methods, which shows that log-rank test approaches give biased estimates when the underlying hazard ratio or odds ratio is far from unity. It also shows that proportional hazards methods give biased results when hazards are not proportional, and proportional odds methods give biased results when odds are not proportional. Maximum likelihood models should, therefore, be preferred to log-rank test based methods for the meta-analysis of time-to-event data and any such meta-analysis should investigate whether proportional hazards or proportional odds assumptions are valid. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061781 TI - Tonic nicotinic transmission enhances spinal GABAergic presynaptic release and the frequency of spontaneous network activity. AB - Synaptically driven spontaneous network activity (SNA) is observed in virtually all developing networks. Recurrently connected spinal circuits express SNA, which drives fetal movements during a period of development when GABA is depolarizing and excitatory. Blockade of nicotinic acetylcholine receptor (nAChR) activation impairs the expression of SNA and the development of the motor system. It is mechanistically unclear how nicotinic transmission influences SNA, and in this study we tested several mechanisms that could underlie the regulation of SNA by nAChRs. We find evidence that is consistent with our previous work suggesting that cholinergically driven Renshaw cells can initiate episodes of SNA. While Renshaw cells receive strong nicotinic synaptic input, we see very little evidence suggesting other spinal interneurons or motoneurons receive nicotinic input. Rather, we found that nAChR activation tonically enhanced evoked and spontaneous presynaptic release of GABA in the embryonic spinal cord. Enhanced spontaneous and/or evoked release could contribute to increased SNA frequency. Finally, our study suggests that blockade of nAChRs can reduce the frequency of SNA by reducing probability of GABAergic release. This result suggests that the baseline frequency of SNA is maintained through elevated GABA release driven by tonically active nAChRs. Nicotinic receptors regulate GABAergic transmission and SNA, which are critically important for the proper development of the embryonic network. Therefore, our results provide a better mechanistic framework for understanding the motor consequences of fetal nicotine exposure. PMID- 26061784 TI - Systematic literature searching in policy relevant, inter-disciplinary reviews: an example from culture and sport. AB - Within the systematic review process, the searching phase is critical to the final synthesis product, its use and value. Yet, relatively little is known about the utility of different search strategies for reviews of complex, inter disciplinary evidence. This article used a recently completed programme of work on cultural and sporting engagement to conduct an empirical evaluation of a comprehensive search strategy. Ten different types of search source were evaluated, according to three dimensions: (i) effectiveness in identifying relevant studies; (ii) efficiency in identifying studies; and (iii) adding value by locating studies that were not identified by any other sources. The study found that general bibliographic databases and specialist databases ranked the highest on all three dimensions. Overall, websites and journals were the next most valuable types of source. For reviewers, these findings highlight that general and specialist databases should remain a core component of the comprehensive search strategy, supplemented with other types of sources that can efficiently identify unique or grey literature. For policy makers and other research commissioners, this study highlights the value of methodological analysis for improving the understanding of, and practice in, policy relevant, inter-disciplinary systematic reviews. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061783 TI - Individual patient data meta-analysis of time-to-event outcomes: one-stage versus two-stage approaches for estimating the hazard ratio under a random effects model. AB - Meta-analyses of individual patient data (IPD) provide a strong and authoritative basis for evidence synthesis. IPD are particularly useful when the outcome of interest is the time to an event. Methodological developments now enable the meta analysis of time-to-event IPD using a single model, allowing treatment effect and across-trial heterogeneity parameters to be estimated simultaneously. This differs from the standard approaches used with aggregate data, and also predominantly with IPD. Facilitated by a simulation study, we investigate what these new 'one-stage' random-effects models offer over standard 'two-stage' approaches. We find that two-stage approaches represent a robust, reliable and easily implementable way to estimate treatment effects and account for heterogeneity. Nevertheless, one-stage models can be used to provide a deeper insight into the data. Software for fitting one-stage Cox models with random effects using Restricted Maximum Likelihood methodology is made available, and its use demonstrated on an IPD meta-analysis assessing post-operative radio therapy for patients with non-small cell lung cancer. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061785 TI - Conclusions from meta-analytic structural equation models generally do not change due to corrections for study artifacts. AB - Meta-analytic structural equations modeling is increasingly used in theory testing. There has been much debate when meta-analyzed correlation matrices are used in structural equations modeling on whether to use mean observed correlations (i.e., corrected only for sampling error) or correlations corrected for study artifacts such as unreliability in measures. This paper investigates whether the fit indices are affected by the corrections and if the stability of the paths (i.e., changes in significance, magnitude, and relative strengths or rank order) is affected by the corrections. Results suggest that substantive model conclusions are generally unaffected by study artifacts and related statistical corrections as long as the variables included in the path analyses had typical levels of reliability as found in the psychological literature. More specifically, all models examined exhibited similar model fit and pathway stability. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061786 TI - Pooling health-related quality of life outcomes in meta-analysis-a tutorial and review of methods for enhancing interpretability. AB - BACKGROUND: - Meta-analyses of health-related quality of life (HRQL) outcomes present difficulties in interpretation when studies use different instruments to measure the same construct. Presentation of results in standard deviation units (standardized mean difference) is widely used but is limited by vulnerability to differential variability in populations enrolled and interpretational challenges. OBJECTIVE: - The objective of this study is to identify and describe the available approaches for enhancing interpretability of meta-analyses involving HRQL outcomes. FINDINGS: - We identified 12 approaches in three categories: Summary estimates derived from the pooled standardized mean difference: conversion to units of the most familiar instrument or to risk difference or odds ratio. These approaches remain vulnerable to differential variability in populations. Summary estimates derived from the individual trial summary statistics: conversion to units of the most familiar instrument or to ratio of means. Both are appropriate complementary approaches to measures derived from converted probabilities. Summary estimates derived from the individual trial summary statistics and established minimally important differences for all instruments: presentation in minimally important difference units or conversion to risk difference or odds ratio. Risk differences are ideal for balancing desirable and undesirable consequences of alternative interventions. CONCLUSION: The use of these approaches may enhance the interpretability and the usefulness of systematic reviews involving HRQL outcomes. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26061787 TI - Review of Fleiss, statistical methods for rates and proportions. PMID- 26061788 TI - Spectroscopic and Molecular Docking Study of the Interaction of DNA with a Morpholinium Ionic Liquid. AB - The structural integrity of a nucleic acid under various conditions determines its utility in biocatalysis and biotechnology. Exploration of the ionic liquids (ILs) for extraction of DNA and other nucleic acid based applications requires an understanding of the nature of interaction between the IL and DNA. Considering these aspects, we have studied the interaction between calf-thymus DNA and a less toxic morpholinium IL, [Mor1,2][Br], employing fluorescence correlation spectroscopy (FCS), conventional steady state and time-resolved fluorescence, circular dichroism (CD) and molecular docking techniques. While the CD spectra indicate the stability of DNA and retention of its B-form in the presence of the morpholinium IL, the docking study reveals that [Mor1,2](+) binds to the minor groove of DNA with a binding energy of -4.57 kcal mol(-1). The groove binding of the cationic component of the IL is corroborated by the steady state fluorescence data, which indicated displacement of a known minor groove binder, DAPI, from its DNA-bound state on addition of [Mor1,2][Br]. The FCS measurements show that the hydrodynamic radius of DNA remains more or less constant in the presence of [Mor1,2][Br], thus suggesting that the structure of DNA is retained in the presence of the IL. DNA melting experiments show that the thermal stability of DNA is enhanced in the presence of morpholinium IL. PMID- 26061790 TI - Genetic variation of the weaning weight of beef cattle as a function of accumulated heat stress. AB - The objective of this study was to identify the genetic variation in the weaning weight (WW) of beef cattle as a function of heat stress. The WWs were recorded at approximately 205 days of age in three Brazilian beef cattle populations: Nelore (93,616), Brangus (18,906) and Tropical Composite (62,679). In view of the cumulative nature of WW, the effect of heat stress was considered as the accumulation of temperature and humidity index units (ACTHI) from the animal's birth to weaning. A reaction norm model was used to estimate the (co)variance components of WW across the ACTHI scale. The accumulation of THI units from birth to weaning negatively affected the WW. The definition of accumulated THI units as an environmental descriptor permitted to identify important genetic variation in the WW as a function of heat stress. As evidence of genotype by environment interaction, substantial heterogeneity was observed in the (co)variance components for WW across the environmental gradient. In this respect, the best animals in less stressful environments are not necessarily the best animals in more stressful environments. Furthermore, the response to selection for WW is expected to be lower in more stressful environments. PMID- 26061791 TI - How do you think she feels? Vulnerability in empathy and the role of attention in school-aged children born extremely preterm. AB - The aim of this study was to examine empathic competence in children born extremely preterm (EP, <28 weeks) given vulnerabilities in social relationships. Empathy in typically developing children is mediated by executive functions. Executive functioning is also impaired in preterm children. Of particular interest in this study are the attentional components of executive functioning as mediators of empathic development. Thirty-two 7-year-old EP children and 40 age matched term children participated in the Project K.I.D.S program and completed the Kids Empathy Development Scale (KEDS), Wechsler Intelligence Scale for Children (WISC-IV), and Test of Everyday Attention for Children (TEA-Ch). Children born extremely preterm exhibited poorer performance on all measures. The mediating role of attention in empathy competence was not supported by mediation modelling when FSIQ was controlled. As predicted, the EP group showed weaker empathic development relative to typically developing children. They also showed poorer attentional abilities. However, the effect of preterm birth on empathy was not mediated by executive-level attention. The cognitive mechanisms underpinning poor empathy competence in EP children remain unclear. Future research needs to examine the role of inhibition, social-emotional recognition, and regulation. PMID- 26061792 TI - Piezo-Electrochemical Energy Harvesting with Lithium-Intercalating Carbon Fibers. AB - The mechanical and electrochemical properties are coupled through a piezo electrochemical effect in Li-intercalated carbon fibers. It is demonstrated that this piezo-electrochemical effect makes it possible to harvest electrical energy from mechanical work. Continuous polyacrylonitrile-based carbon fibers that can work both as electrodes for Li-ion batteries and structural reinforcement for composites materials are used in this study. Applying a tensile force to carbon fiber bundles used as Li-intercalating electrodes results in a response of the electrode potential of a few millivolts which allows, at low current densities, lithiation at higher electrode potential than delithiation. More electrical energy is thereby released from the cell at discharge than provided at charge, harvesting energy from the mechanical work of the applied force. The measured harvested specific electrical power is in the order of 1 MUW/g for current densities in the order of 1 mA/g, but this has a potential of being increased significantly. PMID- 26061789 TI - Lysine Acetylation Activates Mitochondrial Aconitase in the Heart. AB - High-throughput proteomics studies have identified several thousand acetylation sites on more than 1000 proteins. Mitochondrial aconitase, the Krebs cycle enzyme that converts citrate to isocitrate, has been identified in many of these reports. Acetylated mitochondrial aconitase has also been identified as a target for sirtuin 3 (SIRT3)-catalyzed deacetylation. However, the functional significance of mitochondrial aconitase acetylation has not been determined. Using in vitro strategies, mass spectrometric analyses, and an in vivo mouse model of obesity, we found a significant acetylation-dependent activation of aconitase. Isolated heart mitochondria subjected to in vitro chemical acetylation with either acetic anhydride or acetyl-coenzyme A resulted in increased aconitase activity that was reversed with SIRT3 treatment. Quantitative mass spectrometry was used to measure acetylation at 21 lysine residues and revealed significant increases with both in vitro treatments. A high-fat diet (60% of kilocalories from fat) was used as an in vivo model and also showed significantly increased mitochondrial aconitase activity without changes in protein level. The high-fat diet also produced an increased level of aconitase acetylation at multiple sites as measured by the quantitative mass spectrometry assays. Treatment of isolated mitochondria from these mice with SIRT3 abolished the high-fat diet-induced activation of aconitase and reduced acetylation. Finally, kinetic analyses found that the increase in activity was a result of increased maximal velocity, and molecular modeling suggests the potential for acetylation at K144 to perturb the tertiary structure of the enzyme. The results of this study reveal a novel activation of mitochondrial aconitase by acetylation. PMID- 26061794 TI - Crucial Role of the Double Bond Isomerism in the Steroid B-Ring on the Membrane Properties of Sterols. Grazing Incidence X-Ray Diffraction and Brewster Angle Microscopy Studies. AB - Three cholesterol precursors-desmosterol, zymosterol, and lanosterol-were comprehensively characterized in monolayers formed at the air/water interface. The studies were based on registration of the surface pressure (pi)-area (A) isotherms complemented with in situ analysis performed with application of modern physicochemical techniques: grazing incidence X-ray diffraction (GIXD) and Brewster angle microscopy (BAM). In this approach we were interested in the correlation between molecular structures of the studied sterols found in the cholesterol biosynthetic pathway and their membrane properties. Our results revealed that only desmosterol behaves in Langmuir monolayers comparably to cholesterol, the molecules of which arrange in the monolayers into a hexagonal lattice, while the two remaining sterols possess extremely different properties. We found that molecules of both zymosterol and lanosterol are organized on the water surface in the two-dimensional oblique unit cells despite the fact that they are oriented perpendicular to the monolayer plane. The comparison of chemical structures of the investigated sterols leads to the conclusion that the only structural motive that can be responsible for such unusual behavior is the double bond in the B sterol ring, which is located in desmosterol in a different position from in the other two sterols. This issue, which was neglected in the scientific literature, seems to have crucial importance for sterol activity in biomembranes. We showed that this structural modification in sterol molecules is directly responsible for their adaptation to proper functioning in biomembranes. PMID- 26061795 TI - Reconstruction of facial nerve after radical parotidectomy. AB - CONCLUSION: Most patients benefitted from immediate facial nerve grafting after radical parotidectomy. Even weak movement is valuable and can be augmented with secondary static operations. Post-operative radiotherapy does not seem to affect the final outcome of facial function. OBJECTIVES: During radical parotidectomy, the sacrifice of the facial nerve results in severe disfigurement of the face. Data on the principles and outcome of facial nerve reconstruction and reanimation after radical parotidectomy are limited and no consensus exists on the best practice. METHOD: This study retrospectively reviewed all patients having undergone radical parotidectomy and immediate facial nerve reconstruction with a free, non-vascularized nerve graft at the Helsinki University Hospital, Helsinki, Finland during the years 1990-2010. There were 31 patients (18 male; mean age = 54.7 years; range = 30-82) and 23 of them had a sufficient follow-up time. RESULTS: Facial nerve function recovery was seen in 18 (78%) of the 23 patients with a minimum of 2-year follow-up and adequate reporting available. Only slight facial movement was observed in five (22%), moderate or good movement in nine (39%), and excellent movement in four (17%) patients. Twenty-two (74%) patients received post-operative radiotherapy and 16 (70%) of them had some recovery of facial nerve function. Nineteen (61%) patients needed secondary static reanimation of the face. PMID- 26061796 TI - Prevalence and Risk Factors of Violence by Psychiatric Acute Inpatients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Violence in acute psychiatric wards affects the safety of other patients and the effectiveness of treatment. However, there is a wide variation in reported rates of violence in acute psychiatric wards. OBJECTIVES: To use meta analysis to estimate the pooled rate of violence in published studies, and examine the characteristics of the participants, and aspects of the studies themselves that might explain the variation in the reported rates of violence (moderators). METHOD: Systematic meta-analysis of studies published between January 1995 and December 2014, which reported rates of violence in acute psychiatric wards of general or psychiatric hospitals in high-income countries. RESULTS: Of the 23,972 inpatients described in 35 studies, the pooled proportion of patients who committed at least one act of violence was 17% (95% confidence interval (CI) 14-20%). Studies with higher proportions of male patients, involuntary patients, patients with schizophrenia and patients with alcohol use disorder reported higher rates of inpatient violence. CONCLUSION: The findings of this study suggest that almost 1 in 5 patients admitted to acute psychiatric units may commit an act of violence. Factors associated with levels of violence in psychiatric units are similar to factors that are associated with violence among individual patients (male gender, diagnosis of schizophrenia, substance use and lifetime history of violence). PMID- 26061797 TI - Overcoming nutrient limitations for cell-based production of influenza vaccine. AB - Metabolic analysis for medium optimization represents a very useful strategy in the process development of production of vaccines in cells. During influenza vaccine production, viruses hijack host cells and take advantage of host's metabolism. As a consequence, the nutritional demand of host cells should undergo a profound change, and usually more nutrients such as glucose and amino acids should be consumed. As such, the maintaining media used in virus production processes often cannot provide sufficient nutrients, and novel methods are urged to be established to address this severe issue of nutritional limitation. A detailed study on impacts of influenza virus on cell death and metabolism, with a profound analysis of nutritional requirements during virus production process, followed by a rational medium optimization is expected to be the most straightfoward and effective strategy. This would ensure a balanced and adequate nutritional supply, which should minimize cell death and improve both cell specific virus yield and total influenza virus production. Such a metabolic analysis-based medium optimization would lay a solid foundation for the development of cell culture technology in influenza vaccine production. PMID- 26061798 TI - Differences in Response to Antiretroviral Therapy by Sex and Hepatitis C Infection Status. AB - Hepatitis C virus (HCV) co-infection and biological sex may each affect response to antiretroviral therapy (ART), yet no studies have examined HIV-associated outcomes by both HCV status and sex. We conducted a cohort study of HIV-infected adults initiating ART in Kaiser Permanente California during 1996-2011. We used piecewise linear regression to assess CD4 changes by sex and HCV status over 5 years. We used Cox regression to estimate hazard ratios (HR) by sex and HCV status for HIV RNA <500 copies/mL over 1 year, and for AIDS and death over the follow-up period. Among 12,865 subjects, there were 154 HIV/HCV-co-infected women, 1000 HIV/HCV-co-infected men, 1088 HIV-mono-infected women, and 10,623 HIV mono-infected men. CD4 increases were slower in the first year for HIV/HCV-co infected women (75 cells/MUL) and men (70 cells/MUL) compared with HIV-mono infected women (145 cells/MUL) and men (120 cells/MUL; p<0.001). After 5 years, women had higher CD4 than men in both HIV-mono-infected (598 vs. 562 cells/MUL, p=0.003) and HIV/HCV-co-infected individuals (567 vs. 509 cells/MUL, p=0.003). Regardless of sex, HIV/HCV co-infection was associated with 40% higher mortality [95% confidence interval (CI): 1.2-1.6] compared with HIV mono-infection, but was not associated with AIDS (HR 1.1, 95% CI: 0.9-1.3) or achieving HIV RNA <500 copies/mL (HR 1.0, 95% CI: 0.9-1.1). HIV/HCV-co-infected men and women have slower CD4 recovery after starting ART and have increased mortality compared with HIV-mono-infected men and women. HCV should be aggressively treated in HIV/HCV-co infected adults, regardless of sex. PMID- 26061799 TI - Energy Balance 4 Kids with Play: Results from a Two-Year Cluster-Randomized Trial. AB - BACKGROUND: Identifying sustainable approaches to improving the physical activity (PA) and nutrition environments in schools is an important public health goal. This study examined the impact of Energy Balance for Kids with Play (EB4K with Play), a school-based intervention developed by the Academy of Nutrition and Dietetics Foundation and Playworks, on students' PA, dietary habits and knowledge, and weight status over 2 years. METHODS: This cluster-randomized, controlled trial took place in four intervention and two control schools over 2 years (n=879; third- to fifth-grade students). PA (fourth and fifth grades only), dietary knowledge and behaviors, school policies, and BMI z-score were assessed at baseline (fall 2011), midpoint (spring 2012), and endpoint (fall 2012 for accelerometers; spring 2013 for all other outcomes). RESULTS: At endpoint, there were no group differences in change in PA or dietary behaviors, although BMI z score decreased overall by -0.07 (p=0.05). Students' dietary knowledge significantly increased, as did the amount of vegetables schools served. Post-hoc analyses stratified by grade revealed that, relative to control students, fourth grade intervention students reduced school-day sedentary time by 15 minutes (p=0.023) and third-grade intervention students reduced BMI z-score by -0.2 (0.05; p<0.05). There were no significant differences for older students. CONCLUSIONS: EB4K with Play, which leverages the existing infrastructure of two national programs, increases children's dietary knowledge and may improve weight status and decrease sedentary behaviors among younger children. Future iterations should examine programming specific for different age groups. PMID- 26061800 TI - Childhood maternal care is associated with DNA methylation of the genes for brain derived neurotrophic factor (BDNF) and oxytocin receptor (OXTR) in peripheral blood cells in adult men and women. AB - In adults, reporting low and high maternal care in childhood, we compared DNA methylation in two stress-associated genes (two target sequences in the oxytocin receptor gene, OXTR; one in the brain-derived neurotrophic factor gene, BDNF) in peripheral whole blood, in a cross-sectional study (University of Basel, Switzerland) during 2007-2008. We recruited 89 participants scoring < 27 (n = 47, 36 women) or > 33 (n = 42, 35 women) on the maternal care subscale of the Parental Bonding Instrument (PBI) at a previous assessment of a larger group (N = 709, range PBI maternal care = 0-36, age range = 19-66 years; median 24 years). 85 participants gave blood for DNA methylation analyses (Sequenom(R) EpiTYPER, San Diego, CA) and cell count (Sysmex PocH-100iTM, Kobe, Japan). Mixed model statistical analysis showed greater DNA methylation in the low versus high maternal care group, in the BDNF target sequence [Likelihood-Ratio (1) = 4.47; p = 0.035] and in one OXTR target sequence Likelihood-Ratio (1) = 4.33; p = 0.037], but not the second OXTR target sequence [Likelihood-Ratio (1) < 0.001; p = 0.995). Mediation analyses indicated that differential blood cell count did not explain associations between low maternal care and BDNF (estimate = -0.005, 95% CI = -0.025 to 0.015; p = 0.626) or OXTR DNA methylation (estimate = -0.015, 95% CI = -0.038 to 0.008; p = 0.192). Hence, low maternal care in childhood was associated with greater DNA methylation in an OXTR and a BDNF target sequence in blood cells in adulthood. Although the study has limitations (cross-sectional, a wide age range, only three target sequences in two genes studied, small effects, uncertain relevance of changes in blood cells to gene methylation in brain), the findings may indicate components of the epiphenotype from early life stress. PMID- 26061801 TI - Respiratory Tract Deposition of HFA-Beclomethasone and HFA-Fluticasone in Asthmatic Patients. AB - BACKGROUND: The asthmatic patient's respiratory tract deposition of HFA fluticasone (Flovent HFA(TM)) has not been established. There is a known large particle size difference with another commercial inhaled HFA steroid (QVAR(TM)). This study compared the 2D and 3D respiratory tract deposition of each inhaled steroid. METHODS: This study was an open label, crossover study in eight patients diagnosed with asthma. The regional respiratory and oropharyngeal deposition of the two steroids were compared and contrasted using planar and SPECT imaging following delivery of the (99m)Tc-radiolabeled drug in each product. The SPECT images were merged with computed tomography images to quantify regional deposition within the patients. RESULTS: Two-dimensional (2D) planar images indicated that 24% of the Flovent HFA dose and 55% of the QVAR dose deposited in the lungs. 2D oropharyngeal deposition indicated that 75% of the Flovent HFA dose was deposited in the oropharynx, while 42% of the QVAR dose deposited in the oropharynx. Three-dimensional (3D) SPECT data indicated that 22% of the Flovent HFA dose and 53% of the QVAR dose deposited in the lungs. 3D oropharyngeal and gut deposition indicated 78% of the Flovent HFA dose was deposited in the oropharynx, while 47% of the QVAR dose deposited in the oropharynx. The increased lung deposition and decreased oropharynx deposition for both 2D and 3D image data of QVAR were statistically different from Flovent HFA. CONCLUSIONS: QVAR exhibited a significant increase in lung delivery compared to Flovent HFA. Conversely, QVAR delivered a significantly lower dose to the oropharynx than Flovent HFA. The findings were presumed to be driven by the smaller particle size of QVAR (0.7 microns MMAD) compared with Flovent HFA (2.0 microns MMAD). PMID- 26061804 TI - Upregulation of ATG3 contributes to autophagy induced by the detachment of intestinal epithelial cells from the extracellular matrix, but promotes autophagy independent apoptosis of the attached cells. AB - Detachment of nonmalignant intestinal epithelial cells from the extracellular matrix (ECM) triggers their growth arrest and, ultimately, apoptosis. In contrast, colorectal cancer cells can grow without attachment to the ECM. This ability is critical for their malignant potential. We found previously that detachment-induced growth arrest of nonmalignant intestinal epithelial cells is driven by their detachment-triggered autophagy, and that RAS, a major oncogene, promotes growth of detached cells by blocking such autophagy. In an effort to identify the mechanisms of detachment-induced autophagy and growth arrest of nonmalignant cells we found here that detachment of these cells causes upregulation of ATG3 and that ATG3 upregulation contributes to autophagy and growth arrest of detached cells. We also observed that when ATG3 expression is artificially increased in the attached cells, ATG3 promotes neither autophagy nor growth arrest but triggers their apoptosis. ATG3 upregulation likely promotes autophagy of the detached but not that of the attached cells because detachment dependent autophagy requires other detachment-induced events, such as the upregulation of ATG7. We further observed that those few adherent cells that do not die by apoptosis induced by ATG3 become resistant to apoptosis caused by cell detachment, a property that is critical for the ability of normal epithelial cells to become malignant. We conclude that cell-ECM adhesion can switch ATG3 functions: when upregulated in detached cells in the context of other autophagy promoting events, ATG3 contributes to autophagy. However, when overexpressed in the adherent cells, in the circumstances not favoring autophagy, ATG3 triggers apoptosis. PMID- 26061805 TI - Chemosensitivity in Carcinoma Showing Thymus-Like Differentiation: A Case Report and Review of the Literature. AB - BACKGROUND: Carcinoma showing thymus-like differentiation (CASTLE) is an extremely rare malignant neoplasm of the thyroid that originates from ectopic thymic tissue. No sufficient evidence exists regarding the efficacy of chemotherapy for cases with distant metastases or advanced disease because of the rarity of the disease itself. PATIENT: We report a case of CASTLE with lung metastasis that showed good responses to first-line (cisplatin, doxorubicin, vincristine, and cyclophosphamide) and second-line (carboplatin and paclitaxel) chemotherapies. SUMMARY: This is the first case of CASTLE reported to show a good response to two serial chemotherapies. CONCLUSION: This case suggests that CASTLE is a chemosensitive tumor and that chemotherapy should be attempted in patients with advanced or metastatic CASTLE. PMID- 26061806 TI - Correlation between long-term outcome and steroid therapy in type 1 autoimmune pancreatitis: relapse, malignancy and side effect of steroid. AB - OBJECTIVES: Autoimmune pancreatitis (AIP) responds well to corticosteroid therapy (CST), and CST is essential to induce remission. However, the correlation between long-term outcome and CST has not been evaluated. We aimed to clarify the correlation between long-term outcome of AIP and CST. MATERIAL AND METHODS: We retrospectively evaluated relapse, risk of malignancy and side effects of CST by focusing on the correlation with CST in 84 patients with type 1 AIP. RESULTS: The incidence of relapse was 23.8%. The frequency of relapse after CST administration was significantly lower in patients taking CST for >6 months than in those who did not (22% versus 67%; p = 0.036). The incidence of malignancy was 10.7%. The standardized incidence ratio of malignancy was 2.14 [95% confidence interval 0.74 3.54]. There were no significant correlations between development of malignancy and CST. The incidences of total and serious side effects due to CST were 75% and 19.1%, respectively. Relapse was the only significant independent predictive risk factor for serious side effects in a multivariate analysis (odds ratio 4.065; 95% confidence interval 1.125-14.706; p = 0.032). The cumulative dose of corticosteroid was significantly higher in patients with serious side effects than in those without (12,645 mg versus 7322 mg; p = 0.041). CONCLUSIONS: CST reduces relapse of AIP. However, CST causes serious side effects, particularly in relapsing patients. Alternative maintenance therapy to prevent relapse is needed. PMID- 26061807 TI - Reflections: A Case for Intersectional Approaches in HIV Research. PMID- 26061808 TI - Fibrotic Effects of Arecoline N-Oxide in Oral Potentially Malignant Disorders. AB - The metabolites of environmental chemicals play key roles in carcinogenesis. Areca nut is strongly associated with the development of oral potentially malignant disorders (OPMD) or cancer. The main alkaloid in the areca nut is arecoline, which is highly cytotoxic and genotoxic. Arecoline N-oxide, a metabolite of areca nut alkaloids, which has been identified in animal urine, has been shown to induce mutagenicity in bacteria. In this study, it was found that its protein adduct could be detected in oral keratinocytes treated with areca nut extract. Increased collagen expression and severity of squamous hyperplasia were observed in arecoline N-oxide treated mice. In cultured oral fibroblasts, arecoline N-oxide showed stronger effects on the increase of fibrotic related genes including TGF-beta1, S100A4, MMP-9, IL-6, and fibronectin and a decrease of E-cadherin as compared with arecoline. Finally, arecoline N-oxide stimulation effectively increased the DNA damage marker, gamma-H2A.X, both in vitro and in vivo. Taken together, these results indicate that arecoline N-oxide shows a high potential for the induction of OPMD. PMID- 26061809 TI - Cytomorphology and immunohistochemistry of a recurrent clear cell odontogenic carcinoma with molecular analysis: A case report with review of literature. AB - Clear cell odontogenic carcinoma (CCOC) is a rare, odontogenic tumor of the jaws with mandibular involvement usually present in sixth decade of life with female preponderance. It is classified as a malignant tumor of odontogenic origin in 2005 by the World Health Organization because of its aggressive and destructive growth capacity and potential to metastasize. It needs to be distinguished from other primary and metastatic clear cell tumors of the oral and maxillofacial region. Recently, CCOCs have been noted to harbor a Ewing sarcoma breakpoint region 1 gene RNA-binding protein 1 (EWSR1) and activating transcription factor (ATF) gene translocation. To date, cytologic features of only one case have been reported in the literature. We report an additional case of 55-year-old woman with enlarging mass in the left mandible. This report describes cytologic and immunohistochemical features of CCOC with positive EWSR1 gene rearrangements by fluorescence in situ hybridization (FISH). As diagnosis of CCOC is challenging on fine-needle aspiration, immunohistochemistry and FISH analysis are very useful diagnostic tool in clear cell lesions of mandible. PMID- 26061810 TI - Dendrimer-Assisted Formation of Fe3O4/Au Nanocomposite Particles for Targeted Dual Mode CT/MR Imaging of Tumors. AB - A unique dendrimer-assisted approach is reported to create Fe3O4/Au nanocomposite particles (NCPs) for targeted dual mode computed tomography/magnetic resonance (CT/MR) imaging of tumors. In this approach, preformed Fe3O4 nanoparticles (NPs) are assembled with multilayers of poly(gamma-glutamic acid) (PGA)/poly(L lysine)/PGA/folic acid (FA)-modified dendrimer-entrapped gold nanoparticles via a layer-by-layer self-assembly technique. The interlayers are crosslinked via 1 ethyl-3-(3-dimethylaminopropyl)carbodiimide chemistry, the assembled Au core NPs are then used as seed particles for subsequent seed-mediated growth of Au shells via iterative Au salt reduction process, and subsequent acetylation of the remaining amines of dendrimers leads to the formation of Fe3O4/Au(n.)Ac-FA NCPs with a tunable molar ratio of Au/Fe3O4. It is shown that the Fe3O4/Au(n.)Ac-FA NCPs at an optimized Au/Fe3O4 molar ratio of 2.02 display a relatively high R2 relaxivity (92.67 * 10(-3) M(-1) s(-1)) and good X-ray attenuation property, and are cytocompatible and hemocompatible in the given concentration range. Importantly, with the FA-mediated targeting, the Fe3O4/Au(n.)Ac-FA NCPs are able to be specifically uptaken by cancer cells overexpressing FA receptors, and be used as an efficient nanoprobe for targeted dual mode CT/MR imaging of a xenografted tumor model. With the versatile dendrimer chemistry, the developed Fe3O4/Au NCPs may be differently functionalized, thereby providing a unique platform for diagnosis and therapy of different biological systems. PMID- 26061811 TI - Intraspecific trait variation across scales: implications for understanding global change responses. AB - Recognition of the importance of intraspecific variation in ecological processes has been growing, but empirical studies and models of global change have only begun to address this issue in detail. This review discusses sources and patterns of intraspecific trait variation and their consequences for understanding how ecological processes and patterns will respond to global change. We examine how current ecological models and theories incorporate intraspecific variation, review existing data sources that could help parameterize models that account for intraspecific variation in global change predictions, and discuss new data that may be needed. We provide guidelines on when it is most important to consider intraspecific variation, such as when trait variation is heritable or when nonlinear relationships are involved. We also highlight benefits and limitations of different model types and argue that many common modeling approaches such as matrix population models or global dynamic vegetation models can allow a stronger consideration of intraspecific trait variation if the necessary data are available. We recommend that existing data need to be made more accessible, though in some cases, new experiments are needed to disentangle causes of variation. PMID- 26061813 TI - High-Pressure Solvent Vapor Annealing with a Benign Solvent To Rapidly Enhance the Performance of Organic Photovoltaics. AB - A high-pressure solvent vapor annealing (HPSVA) treatment is suggested as an annealing process to rapidly achieve high-performance organic photovoltaics (OPVs); this process can be compatible with roll-to-roll processing methods and uses a benign solvent: acetone. Solvent vapor annealing can produce an advantageous vertical distribution in the active layer; however, conventional solvent vapor annealing is also time-consuming. To shorten the annealing time, high-pressure solvent vapor is exposed on the active layer of OPVs. Acetone is a nonsolvent for poly(3-hexylthiophene-2,5-diyl) (P3HT), but it can dissolve small amounts of 1-(3-methoxycarbonyl)-propyl-1,1-phenyl-(6,6)C61 (PCBM). Acetone vapor molecules can penetrate into the active layer under high vapor pressure conditions to alter the morphology. HPSVA induces a PCBM-rich phase near the cathode and facilitates the transport of free charge carriers to the electrode. Although P3HT is not soluble in acetone, locally rearranged P3HT crystallites are generated. The performance of OPV films was enhanced after HPSVA; the film treated at 30 kPa for 10 s showed optimum performance. Additionally, this HPSVA method could be adapted for mass production because the temporary exposure of films to high-pressure acetone vapor in ambient conditions also improved performance. PMID- 26061812 TI - Incomplete Restoration of Angiotensin II-Induced Renal Extracellular Matrix Deposition and Inflammation Despite Complete Functional Recovery in Rats. AB - Some diseases associated with a temporary deterioration in kidney function and/or development of proteinuria show an apparently complete functional remission once the initiating trigger is removed. While it was earlier thought that a transient impairment of kidney function is harmless, accumulating evidence now suggests that these patients are more prone to developing renal failure later in life. We therefore sought to investigate to what extent renal functional changes, inflammation and collagen deposition are reversible after cessation of disease induction, potentially explaining residual sensitivity to damage. Using a rat model of Angiotensin II (Ang II)-induced hypertensive renal disease we show the development of severe hypertension (212 +/- 10.43 vs. 146 +/- 1.4 mmHg, p<0.001) and proteinuria (51.4 +/- 6.3 vs. 14.7 +/- 2.0 mg/24h, p<0.01) with declined creatinine clearance (2.0 +/- 0.5 vs. 4.9 +/- 0.6 mL/min, p<0.001) to occur after 3 weeks of Ang II infusion. At the structural level, Ang II infusion resulted in interstitial inflammation (18.8 +/- 4.8 vs. 3.6 +/- 0.5 number of macrophages, p<0.001), renal interstitial collagen deposition and lymphangiogenesis (4.1 +/- 0.4 vs. 2.2 +/- 0.4 number of lymph vessels, p<0.01). Eight weeks after cessation of Ang II, all clinical parameters, pre-fibrotic changes such as myofibroblast transformation and increase in lymph vessel number (lymphangiogenesis) returned to control values. However, glomerular desmin expression, glomerular and periglomerular macrophages and interstitial collagens remained elevated. These dormant abnormalities indicate that after transient renal function decline, inflammation and collagen deposition may persist despite normalization of the initiating pathophysiological stimulus perhaps rendering the kidney more vulnerable to further damage. PMID- 26061814 TI - p53 attenuates AKT signaling by modulating membrane phospholipid composition. AB - The p53 tumor suppressor is the central component of a complex network of signaling pathways that protect organisms against the propagation of cells carrying oncogenic mutations. Here we report a previously unrecognized role of p53 in membrane phospholipids composition. By repressing the expression of stearoyl-CoA desaturase 1, SCD, the enzyme that converts saturated to mono unsaturated fatty acids, p53 causes a shift in the content of phospholipids with mono-unsaturated acyl chains towards more saturated phospholipid species, particularly of the phosphatidylinositol headgroup class. This shift affects levels of phosphatidylinositol phosphates, attenuates the oncogenic AKT pathway, and contributes to the p53-mediated control of cell survival. These findings expand the p53 network to phospholipid metabolism and uncover a new molecular pathway connecting p53 to AKT signaling. PMID- 26061815 TI - Anti-G-CSF treatment induces protective tumor immunity in mouse colon cancer by promoting protective NK cell, macrophage and T cell responses. AB - Granulocyte colony-stimulating factor (G-CSF) is a cytokine that is highly expressed in human and mouse colorectal cancers (CRC). We previously reported that G-CSF stimulated human CRC cell growth and migration, therefore in this study we sought to examine the therapeutic potential of anti-G-CSF treatment for CRC. G-CSF is known to mobilize neutrophils, however its impact on other immune cells has not been well examined. Here, we investigated the effects of therapeutic anti-G-CSF treatment on CRC growth and anti-tumor immune responses. C57BL/6 mice treated with azoxymethane/dextran sodium sulfate (AOM/DSS) to induce neoplasms were administered anti-G-CSF or isotype control antibodies three times a week for three weeks. Animals treated with anti-G-CSF antibodies had a marked decrease in neoplasm number and size compared to the isotype control group. Colon neutrophil and macrophage frequency were unchanged, but the number of macrophages producing IL-10 were decreased while IL-12 producing macrophages were increased. NK cells were substantially increased in colons of anti-G-CSF treated mice, along with IFNgamma producing CD4(+) and CD8(+) T cells. These studies are the first to indicate a crucial role for G-CSF inhibition in promoting protective anti-tumor immunity, and suggest that anti-G-CSF treatment is a potential therapeutic approach for CRC. PMID- 26061816 TI - Anti-cancer effect of snake venom toxin through down regulation of AP-1 mediated PRDX6 expression. AB - Snake venom toxin (SVT) from Vipera lebetina turanica contains a mixture of different enzymes and proteins. Peroxiredoxin 6 (PRDX6) is known to be a stimulator of lung cancer cell growth. PRDX6 is a member of peroxidases, and has calcium-independent phospholipase A2 (iPLA2) activities. PRDX6 has an AP-1 binding site in its promoter region of the gene. Since AP-1 is implicated in tumor growth and PRDX6 expression, in the present study, we investigated whether SVT inhibits PRDX6, thereby preventing human lung cancer cell growth (A549 and NCI-H460) through inactivation of AP-1. A docking model study and pull down assay showed that SVT completely fits on the basic leucine zipper (bZIP) region of c Fos of AP-1. SVT (0-10 MUg/ml) inhibited lung cancer cell growth in a concentration dependent manner through induction of apoptotic cell death accompanied by induction of cleaved caspase-3, -8, -9, Bax, p21 and p53, but decreased cIAP and Bcl2 expression via inactivation of AP-1. In an xenograft in vivo model, SVT (0.5 mg/kg and 1 mg/kg) also inhibited tumor growth accompanied with the reduction of PRDX6 expression, but increased expression of proapoptotic proteins. These data indicate that SVT inhibits tumor growth via inhibition of PRDX6 activity through interaction with its transcription factor AP-1. PMID- 26061817 TI - Continuous representation of tumor microvessel density and detection of angiogenic hotspots in histological whole-slide images. AB - Blood vessels in solid tumors are not randomly distributed, but are clustered in angiogenic hotspots. Tumor microvessel density (MVD) within these hotspots correlates with patient survival and is widely used both in diagnostic routine and in clinical trials. Still, these hotspots are usually subjectively defined. There is no unbiased, continuous and explicit representation of tumor vessel distribution in histological whole slide images. This shortcoming distorts angiogenesis measurements and may account for ambiguous results in the literature. In the present study, we describe and evaluate a new method that eliminates this bias and makes angiogenesis quantification more objective and more efficient. Our approach involves automatic slide scanning, automatic image analysis and spatial statistical analysis. By comparing a continuous MVD function of the actual sample to random point patterns, we introduce an objective criterion for hotspot detection: An angiogenic hotspot is defined as a clustering of blood vessels that is very unlikely to occur randomly. We evaluate the proposed method in N=11 images of human colorectal carcinoma samples and compare the results to a blinded human observer. For the first time, we demonstrate the existence of statistically significant hotspots in tumor images and provide a tool to accurately detect these hotspots. PMID- 26061818 TI - High PEEP levels are associated with overdistension and tidal recruitment/derecruitment in ARDS patients. AB - BACKGROUND: Positive end-expiratory pressure (PEEP) improves gas exchange and respiratory mechanics, and it may decrease tissue injury and inflammation. The mechanisms of this protective effect are not fully elucidated. Our aim was to determine the intrinsic effects of moderate and higher levels of PEEP on tidal recruitment/derecruitment, hyperinflation, and lung mechanics, in patients with acute respiratory distress syndrome (ARDS). METHODS: Nine patients with ARDS of mainly pulmonary origin were ventilated sequential and randomly using two levels of PEEP: 9 and 15 cmH2 O, and studied with dynamic computed tomography at a fix transversal lung region. Tidal recruitment/derecruitment and hyperinflation were determined as non-aerated tissue and hyperinflated tissue variation between inspiration and expiration, expressed as percentage of total weight. We also assessed the maximal amount of non-aerated and hyperinflated tissue weight. RESULTS: PEEP 15 cmH2 O was associated with decrease in non-aerated tissue in all the patients (P < 0.01). However, PEEP 15 cmH2 O did not decrease tidal recruitment/derecruitment compared to PEEP 9 cmH2 O (P = 1). In addition, PEEP 15 cmH2 O markedly increased maximal hyperinflation (P < 0.01) and tidal hyperinflation (P < 0.05). Lung compliance decreased with PEEP 15 cmH2 O (P < 0.001). CONCLUSION: In this series of patients with ARDS of mainly pulmonary origin, application of high levels of PEEP did not decrease tidal recruitment/derecruitment, but instead consistently increased tidal and maximal hyperinflation. PMID- 26061819 TI - Neurobiology of Sensory Overresponsivity in Youth With Autism Spectrum Disorders. AB - IMPORTANCE: More than half of youth with autism spectrum disorders (ASDs) have sensory overresponsivity (SOR), an extreme negative reaction to sensory stimuli. However, little is known about the neurobiological basis of SOR, and there are few effective treatments. Understanding whether SOR is due to an initial heightened sensory response or to deficits in regulating emotional reactions to stimuli has important implications for intervention. OBJECTIVE: To determine differences in brain responses, habituation, and connectivity during exposure to mildly aversive sensory stimuli in youth with ASDs and SOR compared with youth with ASDs without SOR and compared with typically developing control subjects. DESIGN, SETTING, AND PARTICIPANTS: Functional magnetic resonance imaging was used to examine brain responses and habituation to mildly aversive auditory and tactile stimuli in 19 high-functioning youths with ASDs and 19 age- and IQ matched, typically developing youths (age range, 9-17 years). Brain activity was related to parents' ratings of children's SOR symptoms. Functional connectivity between the amygdala and orbitofrontal cortex was compared between ASDs subgroups with and without SOR and typically developing controls without SOR. The study dates were March 2012 through February 2014. MAIN OUTCOMES AND MEASURES: Relative increases in blood oxygen level-dependent signal response across the whole brain and within the amygdala during exposure to sensory stimuli compared with fixation, as well as correlation between blood oxygen level-dependent signal change in the amygdala and orbitofrontal cortex. RESULTS: The mean age in both groups was 14 years and the majority in both groups (16 of 19 each) were male. Compared with neurotypical control participants, participants with ASDs displayed stronger activation in primary sensory cortices and the amygdala (P < .05, corrected). This activity was positively correlated with SOR symptoms after controlling for anxiety. The ASDs with SOR subgroup had decreased neural habituation to stimuli in sensory cortices and the amygdala compared with groups without SOR. Youth with ASDs without SOR showed a pattern of amygdala downregulation, with negative connectivity between the amygdala and orbitofrontal cortex (thresholded at z > 1.70, P < .05). CONCLUSIONS AND RELEVANCE: Results demonstrate that youth with ASDs and SOR show sensorilimbic hyperresponsivity to mildly aversive tactile and auditory stimuli, particularly to multiple modalities presented simultaneously, and show that this hyperresponsivity is due to failure to habituate. In addition, findings suggest that a subset of youth with ASDs can regulate their responses through prefrontal downregulation of amygdala activity. Implications for intervention include minimizing exposure to multiple sensory modalities and building coping strategies for regulating emotional response to stimuli. PMID- 26061821 TI - Change of Electronic Structures by Dopant-Induced Local Strain. AB - Ag-induced Si(111)-?3 x ?3 surfaces (?3-Ag) exhibit unusual electronic structures that cannot be explained by the conventional rigid band model and charge transfer model. The (?3-Ag surfaces feature a free-electron-like parabolic band, the S1 band, that selectively shifts downward upon the adsorption of noble metal or alkali metal adatoms. Furthermore, the downward shift of S1 is independent of the type of dopants, Au, Ag, and Na. According to charge transfer analysis, Au adatoms accumulate electrons from the substrate and become negatively charged, whereas Na adatoms become positively charged, which indicates that S1 should shift in the opposite direction for both the adatoms. Investigation of calculated structures, calculation of model structures, and tight-binding analysis disclose that the changes in the electronic structure are closely related to the average Ag-Ag distance in the substrate and have their origin in the local strain induced by dopants (adatoms). This explanation implies that the electronic structure is irrespective of the dopant characters itself and paves a new way for understanding the electronic structures associated with the presence of dopants. PMID- 26061822 TI - Habitat features and long-distance dispersal modify the use of social information by a long-distance migratory bird. AB - The processes by which individuals select breeding sites have important consequences for individual tness as well as population- and community-dynamics. Although there is increasing evidence that many animal species use information acquired from conspecics to assess the suitability of potential breeding sites, little is known about how the use of this social information is modified by biotic and abiotic conditions. We used an automated playback experiment to simulate two types of social information, post-breeding public information and pre-breeding location cues, to determine the relative importance of these cues for breeding site selection by a migratory songbird, the American redstart (Setophaga ruticilla). In addition, we used stable hydrogen isotopes to determine the dispersal status of individuals that responded to our experimental treatments and quantify whether long-distance dispersers use different social cues to select breeding sites compared to philopatric individuals. We found that points that received pre-breeding location cue treatments were signi cantly more likely to be settled by redstarts than control points that received no playback. However, we found no evidence the redstarts used post-breeding public information gathered during one season to select breeding sites the following year. Breeding site habitat structure was also a strong predictor of settlement probability, indicating that redstarts modi ed the use of social information based on habitat cues. Furthermore, stable hydrogen isotope signatures from individuals that responded to location cue treatments suggest that long-distance dispersers may rely more heavily on these cues than local recruits. Collectively, these results indicate that redstarts use multiple sources of information to select breeding sites, which could buffer individuals from selecting suboptimal sites when they breed in unfamiliar locations or when habitat quality becomes decoupled from social cues. PMID- 26061820 TI - DW-F5: A novel formulation against malignant melanoma from Wrightia tinctoria. AB - Wrightia tinctoria is a constituent of several ayurvedic preparations against skin disorders including psoriasis and herpes, though not yet has been explored for anticancer potential. Herein, for the first time, we report the significant anticancer properties of a semi-purified fraction, DW-F5, from the dichloromethane extract of W. tinctoria leaves against malignant melanoma. DW-F5 exhibited anti-melanoma activities, preventing metastasis and angiogenesis in NOD SCID mice, while being non-toxic in vivo. The major pathways in melanoma signaling mediated through BRAF, WNT/beta-catenin and Akt-NF-kappaB converging in MITF-M, the master regulator of melanomagenesis, were inhibited by DW-F5, leading to complete abolition of MITF-M. Purification of DW-F5 led to the isolation of two cytotoxic components, one being tryptanthrin and the other being an unidentified aliphatic fraction. The overall study predicts Wrightia tinctoria as a candidate plant to be further explored for anticancer properties and DW-F5 as a forthcoming drug formulation to be evaluated as a chemotherapeutic agent against malignant melanoma. PMID- 26061823 TI - A grey keratinous tarsal cyst with Gram+ cocci. PMID- 26061825 TI - Explanations for discordance of noncompaction in monozygotic twins. PMID- 26061826 TI - Universality of Viscosity Dependence of Translational Diffusion Coefficients of Carbon Monoxide, Diphenylacetylene, and Diphenylcyclopropenone in Ionic Liquids under Various Conditions. AB - Translational diffusion coefficients of diphenylcyclopropenone (DPCP), diphenylacetylene (DPA), and carbon monoxide (CO) in 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([BMIm][NTf2]) and 1-ethyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide ([EMIm][NTf2]) were determined by the transient grating (TG) spectroscopy under pressure from 0.1 to 200 MPa at 298 K and from 298 to 373 K under 0.1 MPa. Diffusion coefficients of these molecules at high temperatures in tributylmethylphosphonium bis(trifluoromethanesulfonyl)imide ([P4441][NTf2]), and tetraoctylphosphonium bis(trifluoromethanesulfonyl)imide ([P8888][NTf2]), and also in the mixtures of [BMIm][NTf2], N-methyl-N propylpiperidinium bis(trifluoromethanesulfonyl)imide ([Pp13][NTf2]), and trihexyltetradecylphosphonium bis(trifluoromethanesulfonyl)imide ([P66614][NTf2]) with ethanol or chloroform have been determined. Diffusion coefficients except in ILs of phosphonium cations were well scaled by the power law of T/eta, i.e., (T/eta)(P), where T and eta are the absolute temperature and the viscosity, irrespective of the solvent species, pressure and temperature, and the compositions of mixtures. The values of the exponent P were smaller for the smaller size of the molecules. On the other hand, the diffusion coefficients in ILs of phosphonium cations with longer alkyl chains were larger than the values expected from the correlation obtained by other ILs and conventional liquids. The deviation becomes larger with increasing the number of carbon atoms of alkyl chain of cation, and with decreasing the molecular size of diffusing molecules. The molecular size dependence of the diffusion coefficient was correlated by the ratio of the volume of the solute to that of the solvent as demonstrated by the preceding work (Kaintz et al., J. Phys. Chem. B 2013 , 117 , 11697 ). Diffusion coefficients have been well correlated with the power laws of both T/eta and the relative volume of the solute to the solvent. PMID- 26061824 TI - Genital Cytomegalovirus Replication Predicts Syphilis Acquisition among HIV-1 Infected Men Who Have Sex with Men. AB - OBJECTIVE: Sexually transmitted infections (STI) are common among HIV-infected men who have sex with men (MSM). While behavioral factors are important in STI acquisition, other biological factors such as immune modulation due to chronic viral infection may further predispose to STI acquisition. DESIGN: Post Hoc analysis including data collected over 12 months of follow-up from 131 HIV infected MSM receiving antiretroviral therapy and screened for incident bacterial STI every 3 months. METHODS: Genital secretions collected at baseline were used to measure herpesvirus replication and inflammatory cytokines. Baseline predictors of STI were determined using survival analysis of time to incident STI. RESULTS: All participants were seropositive for cytomegalovirus (CMV), and 52% had detectable genital CMV at baseline. Thirty-five individuals acquired STI during follow-up, sometimes with multiple pathogen (17 syphilis, 21 gonorrhea, 14 chlamydia). Syphilis acquisition was associated with genital CMV replication at baseline (19.1% CMV-shedders versus 4.8% non-shedders, p=0.03) and younger age (p=0.02). Lower seminal MCP-1 was associated with higher seminal CMV levels and with syphilis acquisition (p<0.01). For syphilis acquisition, in multivariable Cox-Proportional Hazard model adjusted hazard rates were 3.56 (95%CI:1.00-12.73) for baseline CMV replication and 2.50 (0.92-6.77) for younger age. CONCLUSIONS: This post hoc analysis suggest that CMV-associated decrease in seminal MCP-1 levels might predispose HIV-infected MSM to syphilis acquisition, but not other STI. Future studies should determine underlying mechanisms and if a causal association exists. PMID- 26061827 TI - Structural integrity of the ribonuclease H domain in HIV-1 reverse transcriptase. AB - The mature form of reverse transcriptase (RT) is a heterodimer comprising the intact 66-kDa subunit (p66) and a smaller 51-kDa subunit (p51) that is generated by removal of most of the RNase H (RNH) domain from a p66 subunit by proteolytic cleavage between residues 440 and 441. Viral infectivity is eliminated by mutations such as F440A and E438N in the proteolytic cleavage sequence, while normal processing and virus infectivity are restored by a compensatory mutation, T477A, that is located more than 10 A away from the processing site. The molecular basis for this compensatory effect has remained unclear. We therefore investigated structural characteristics of RNH mutants using computational and experimental approaches. Our Nuclear Magnetic Resonance and Differential Scanning Fluorimetry results show that both F440A and E438N mutations disrupt RNH folding. Addition of the T477A mutation restores correct folding of the RNH domain despite the presence of the F440A or E438N mutations. Molecular dynamics simulations suggest that the T477A mutation affects the processing site by altering relative orientations of secondary structure elements. Predictions of sequence tolerance suggest that phenylalanine and tyrosine are structurally preferred at residues 440 and 441, respectively, which are the P1 and P1' substrate residues known to require bulky side chains for substrate specificity. Interestingly, our study demonstrates that the processing site residues, which are critical for protease substrate specificity and must be exposed to the solvent for efficient processing, also function to maintain proper RNH folding in the p66/p51 heterodimer. PMID- 26061828 TI - A Comparative Study of Physiological Monitoring with a Wearable Opto-Electronic Patch Sensor (OEPS) for Motion Reduction. AB - This paper presents a comparative study in physiological monitoring between a wearable opto-electronic patch sensor (OEPS) comprising a three-axis Microelectromechanical systems (MEMs) accelerometer (3MA) and commercial devices. The study aims to effectively capture critical physiological parameters, for instance, oxygen saturation, heart rate, respiration rate and heart rate variability, as extracted from the pulsatile waveforms captured by OEPS against motion artefacts when using the commercial probe. The protocol involved 16 healthy subjects and was designed to test the features of OEPS, with emphasis on the effective reduction of motion artefacts through the utilization of a 3MA as a movement reference. The results show significant agreement between the heart rates from the reference measurements and the recovered signals. Significance of standard deviation and error of mean yield values of 2.27 and 0.65 beats per minute, respectively; and a high correlation (0.97) between the results of the commercial sensor and OEPS. T, Wilcoxon and Bland-Altman with 95% limit of agreement tests were also applied in the comparison of heart rates extracted from these sensors, yielding a mean difference (MD: 0.08). The outcome of the present work incites the prospects of OEPS on physiological monitoring during physical activities. PMID- 26061830 TI - Thermodynamic properties of liquid gallium from picosecond acoustic velocity measurements. AB - Due to discrepancies in the literature data the thermodynamic properties of liquid gallium are still in debate. Accurate measurements of adiabatic sound velocities as a function of pressure and temperature have been obtained by the combination of laser picosecond acoustics and surface imaging on sample loaded in diamond anvil cell. From these results the thermodynamic parameters of gallium have been extracted by a numerical procedure up to 10 GPa and 570 K. It is demonstrated that a Murnaghan equation of state accounts well for the whole data set since the isothermal bulk modulus BT has been shown to vary linearly with pressure in the whole temperature range. No evidence for a previously reported liquid-liquid transition has been found in the whole pressure and temperature range explored. PMID- 26061829 TI - Vertical Interface Induced Dielectric Relaxation in Nanocomposite (BaTiO3)1 x:(Sm2O3)x Thin Films. AB - Vertical interfaces in vertically aligned nanocomposite thin films have been approved to be an effective method to manipulate functionalities. However, several challenges with regard to the understanding on the physical process underlying the manipulation still remain. In this work, because of the ordered interfaces and large interfacial area, heteroepitaxial (BaTiO3)1-x:(Sm2O3)x thin films have been fabricated and used as a model system to investigate the relationship between vertical interfaces and dielectric properties. Due to a relatively large strain generated at the interfaces, vertical interfaces between BaTiO3 and Sm2O3 are revealed to become the sinks to attract oxygen vacancies. The movement of oxygen vacancies is confined at the interfaces and hampered by the misfit dislocations, which contributed to a relaxation behavior in (BaTiO3)1 x:(Sm2O3)x thin films. This work represents an approach to further understand that how interfaces influence on dielectric properties in oxide thin films. PMID- 26061831 TI - Competition Nutrition Practices of Elite Ultramarathon Runners. AB - Anecdotal claims have suggested that an increasing number of ultramarathoners purposely undertake chronic low-carbohydrate (CHO) ketogenic diets while training, and race with very low CHO intakes, as a way to maximize fat oxidation and improve performance. However, very little empirical evidence exists on specific fueling strategies that elite ultramarathoners undertake to maximize race performance. The study's purpose was to characterize race nutrition habits of elite ultramarathon runners. Three veteran male ultrarunners (M +/- SD; age 35 +/- 2 years; mass 59.5 +/- 1.7 kg; 16.7 +/- 2.5 hr 100-mi. best times) agreed to complete a competition- specific nutrition intake questionnaire for 100-mi. races. Verbal and visual instructions were used to instruct the athletes on portion sizes and confirm dietary intake. Throughout 2014, the athletes competed in 16 ultramarathons with a total of 8 wins, including the prestigious Western States Endurance Run 100-miler (14.9 hr). The average prerace breakfast contained 70 +/- 16 g CHO, 29 +/- 20 g protein, and 21 +/- 8 g fat. Athletes consumed an average of 1,162 +/- 250 g of CHO (71 +/- 20g/hr), with minor fat and protein intakes, resulting in caloric intakes totaling 5,530 +/- 1,673 kcals (333 +/- 105 kcals/hr) with 93% of calories coming from commercial products. Athletes also reported consuming 912 +/- 322 mg of caffeine and 6.9 +/- 2.4 g of sodium. Despite having limited professional nutritional input into their fueling approaches, all athletes practiced fueling strategies that maximize CHO intake and are congruent with contemporary evidence-based recommendations. PMID- 26061832 TI - From rhetoric to reality--community health workers in post-reform U.S. health care. PMID- 26061833 TI - Post-9/11 torture at CIA "black sites"--physicians and lawyers working together. PMID- 26061834 TI - Behavioral economics and physician compensation--promise and challenges. PMID- 26061835 TI - Early cardiopulmonary resuscitation in out-of-hospital cardiac arrest. AB - BACKGROUND: Three million people in Sweden are trained in cardiopulmonary resuscitation (CPR). Whether this training increases the frequency of bystander CPR or the survival rate among persons who have out-of-hospital cardiac arrests has been questioned. METHODS: We analyzed a total of 30,381 out-of-hospital cardiac arrests witnessed in Sweden from January 1, 1990, through December 31, 2011, to determine whether CPR was performed before the arrival of emergency medical services (EMS) and whether early CPR was correlated with survival. RESULTS: CPR was performed before the arrival of EMS in 15,512 cases (51.1%) and was not performed before the arrival of EMS in 14,869 cases (48.9%). The 30-day survival rate was 10.5% when CPR was performed before EMS arrival versus 4.0% when CPR was not performed before EMS arrival (P<0.001). When adjustment was made for a propensity score (which included the variables of age, sex, location of cardiac arrest, cause of cardiac arrest, initial cardiac rhythm, EMS response time, time from collapse to call for EMS, and year of event), CPR before the arrival of EMS was associated with an increased 30-day survival rate (odds ratio, 2.15; 95% confidence interval, 1.88 to 2.45). When the time to defibrillation in patients who were found to be in ventricular fibrillation was included in the propensity score, the results were similar. The positive correlation between early CPR and survival rate remained stable over the course of the study period. An association was also observed between the time from collapse to the start of CPR and the 30-day survival rate. CONCLUSIONS: CPR performed before EMS arrival was associated with a 30-day survival rate after an out-of-hospital cardiac arrest that was more than twice as high as that associated with no CPR before EMS arrival. (Funded by the Laerdal Foundation for Acute Medicine and others.). PMID- 26061836 TI - Mobile-phone dispatch of laypersons for CPR in out-of-hospital cardiac arrest. AB - BACKGROUND: Cardiopulmonary resuscitation (CPR) performed by bystanders is associated with increased survival rates among persons with out-of-hospital cardiac arrest. We investigated whether rates of bystander-initiated CPR could be increased with the use of a mobile-phone positioning system that could instantly locate mobile-phone users and dispatch lay volunteers who were trained in CPR to a patient nearby with out-of-hospital cardiac arrest. METHODS: We conducted a blinded, randomized, controlled trial in Stockholm from April 2012 through December 2013. A mobile-phone positioning system that was activated when ambulance, fire, and police services were dispatched was used to locate trained volunteers who were within 500 m of patients with out-of-hospital cardiac arrest; volunteers were then dispatched to the patients (the intervention group) or not dispatched to them (the control group). The primary outcome was bystander initiated CPR before the arrival of ambulance, fire, and police services. RESULTS: A total of 5989 lay volunteers who were trained in CPR were recruited initially, and overall 9828 were recruited during the study. The mobile-phone positioning system was activated in 667 out-of-hospital cardiac arrests: 46% (306 patients) in the intervention group and 54% (361 patients) in the control group. The rate of bystander-initiated CPR was 62% (188 of 305 patients) in the intervention group and 48% (172 of 360 patients) in the control group (absolute difference for intervention vs. control, 14 percentage points; 95% confidence interval, 6 to 21; P<0.001). CONCLUSIONS: A mobile-phone positioning system to dispatch lay volunteers who were trained in CPR was associated with significantly increased rates of bystander-initiated CPR among persons with out-of-hospital cardiac arrest. (Funded by the Swedish Heart-Lung Foundation and Stockholm County; ClinicalTrials.gov number, NCT01789554.). PMID- 26061837 TI - Efficacy of a sexual assault resistance program for university women. AB - BACKGROUND: Young women attending university are at substantial risk for being sexually assaulted, primarily by male acquaintances, but effective strategies to reduce this risk remain elusive. METHODS: We randomly assigned first-year female students at three universities in Canada to the Enhanced Assess, Acknowledge, Act Sexual Assault Resistance program (resistance group) or to a session providing access to brochures on sexual assault, as was common university practice (control group). The resistance program consists of four 3-hour units in which information is provided and skills are taught and practiced, with the goal of being able to assess risk from acquaintances, overcome emotional barriers in acknowledging danger, and engage in effective verbal and physical self-defense. The primary outcome was completed rape, as measured by the Sexual Experiences Survey-Short Form Victimization, during 1 year of follow-up. RESULTS: A total of 451 women were assigned to the resistance group and 442 women to the control group. Of the women assigned to the resistance group, 91% attended at least three of the four units. The 1-year risk of completed rape was significantly lower in the resistance group than in the control group (5.2% vs. 9.8%; relative risk reduction, 46.3% [95% confidence interval, 6.8 to 69.1]; P=0.02). The 1-year risk of attempted rape was also significantly lower in the resistance group (3.4% vs. 9.3%, P<0.001). CONCLUSIONS: A rigorously designed and executed sexual assault resistance program was successful in decreasing the occurrence of rape, attempted rape, and other forms of victimization among first-year university women. (Funded by the Canadian Institutes of Health Research and the University of Windsor; SARE ClinicalTrials.gov number, NCT01338428.). PMID- 26061838 TI - Images in clinical medicine. Preterm ovarian hyperstimulation. PMID- 26061839 TI - Case records of the Massachusetts General Hospital. Case 18-2015. A 41-year-old woman with decreased vision in the left eye and diplopia. PMID- 26061840 TI - Bystander-initiated CPR by design, not by chance. PMID- 26061841 TI - A comprehensive approach to sexual violence prevention. PMID- 26061842 TI - Expanding on exosomes and ectosomes in cancer. PMID- 26061843 TI - Endovascular therapy for ischemic stroke. PMID- 26061844 TI - Endovascular therapy for ischemic stroke. PMID- 26061845 TI - Endovascular therapy for ischemic stroke. PMID- 26061846 TI - Endovascular therapy for ischemic stroke. PMID- 26061847 TI - Endovascular therapy for ischemic stroke. PMID- 26061848 TI - Less-tight versus tight control of hypertension in pregnancy. PMID- 26061849 TI - Less-tight versus tight control of hypertension in pregnancy. PMID- 26061850 TI - Burden of Clostridium difficile infection in the United States. PMID- 26061851 TI - Burden of Clostridium difficile infection in the United States. PMID- 26061852 TI - Burden of Clostridium difficile infection in the United States. PMID- 26061853 TI - Compliance with results reporting at ClinicalTrials.gov. PMID- 26061854 TI - Compliance with results reporting at ClinicalTrials.gov. PMID- 26061855 TI - Sterile pyuria. PMID- 26061856 TI - Sterile pyuria. PMID- 26061857 TI - Sterile pyuria. PMID- 26061858 TI - Images in clinical medicine. Congenital adrenal hyperplasia. PMID- 26061859 TI - AM Last Page: a medical educator's guide to #MedEd. PMID- 26061860 TI - Recruiting primary care physicians to teach medical students in the ambulatory setting: a model of protected time, allocated money, and faculty development. AB - PROBLEM: Medical schools face barriers to recruiting physicians to teach in the ambulatory setting for many reasons, including time required to teach, loss of productivity when learners are present, and physicians' uncertainty about how to teach. APPROACH: In 2012, the primary care department of the University of Queensland-Ochsner Clinical School (UQ-OCS) implemented an innovative model for recruiting primary care physicians to teach students in their clinics. The model's three-pronged approach allows protected teaching time, allocates tuition money to reimburse physicians for teaching via educational value unit (EVU) tracking, and includes a faculty development program. OUTCOMES: In the first two years of EVU tracking (academic years 2012 and 2013), 5,530 EVUs were provided by 48 primary care faculty teaching 60 students at 11 sites. In academic year 2013, the first year in which tuition dollars were available to fund teaching by primary care faculty, over $120,000 in tuition money was transferred to the department to pay for EVUs. No faculty in 2012 or 2013 experienced a change in salary as a result of teaching activities. Faculty development workshops have been well attended. The general practice clerkship has been the top-rated third year clerkship by students for the first three years of clinical rotations at the UQ-OCS. NEXT STEPS: A qualitative study to describe the barriers to and solutions for recruiting physicians to teach students in ambulatory settings is planned. Other studies will evaluate the effectiveness of faculty development efforts and the impact of students' presence on patients' access to clinic appointments. PMID- 26061861 TI - The top-cited articles in medical education: a bibliometric analysis. AB - PURPOSE: To identify and examine the characteristics of the 50 top-cited articles in medical education. METHOD: Two searches were conducted in the Web of Knowledge database in March 2014: a search of medical education journals in the category "Education, Scientific Discipline" (List A) and a keyword search across all journals (List B). Articles identified were reviewed for citation count, country of origin, article type, journal, authors, and publication year. RESULTS: Both lists included 56 articles, not 50, because articles with the same absolute number of citations shared the same rank. The majority of List A articles were published in Academic Medicine (34; 60.7%) and Medical Education (16; 28.6%). In List B, 27 articles (48.2%) were published in medical education journals, 19 (33.9%) in general medicine and surgery journals, and 10 (17.9%) in higher education and educational psychology journals. Twenty-six articles were included in both lists, with different rankings. Reviews and articles constituted the majority of articles; there were only 8 research papers in List A and 13 in List B. Articles mainly originated from the United States, Canada, the Netherlands, and the United Kingdom. The majority were published from 1979 to 2007. There was no correlation between year and citation count. CONCLUSIONS: The finding that over half of List B articles were published in nonmedical education journals is consistent with medical education's integrated nature and subspecialty breadth. Twenty of these articles were among their respective non-medical-education journals' 50 top-cited papers, showing that medical education articles can compete with subject-based articles. PMID- 26061862 TI - A rational approach towards enhancing solar water splitting: a case study of Au RGO/N-RGO-TiO2. AB - A rational approach was employed to enhance the solar water splitting (SWS) efficiency by systematically combining various important factors that helps to increase the photocatalytic activity. The rational approach includes four important parameters, namely, charge generation through simulated sunlight absorption, charge separation and diffusion, charge utilization through redox reaction, and the electronic integration of all of the above three factors. The complexity of the TiO2 based catalyst and its SWS activity was increased systematically by adding reduced graphene oxide (RGO) or N-doped RGO and/or nanogold. Au-N-RGO-TiO2 shows the maximum apparent quantum yield (AQY) of 2.46% with a H2 yield (525 MUmol g(-1) h(-1)) from aqueous methanol, and overall water splitting activity (22 MUmol g(-1) h(-1); AQY = 0.1%) without any sacrificial agent under one sun conditions. This exercise helps to understand the factors which help to enhance the SWS activity. Activity enhancement was observed when there is synergy among the components, especially the simulated sunlight absorption (or one sun conditions), charge separation/conduction and charge utilization. Electronic integration among the components provides the synergy for efficient solar light harvesting. In our opinion, the above synergy helps to increase the overall utilization of charge carriers towards the higher activity. PMID- 26061863 TI - Nanomaterials in Biosolids Inhibit Nodulation, Shift Microbial Community Composition, and Result in Increased Metal Uptake Relative to Bulk/Dissolved Metals. AB - We examined the effects of amending soil with biosolids produced from a pilot scale wastewater treatment plant containing a mixture of metal-based engineered nanomaterials (ENMs) on the growth of Medicago truncatula, its symbiosis with Sinorhizobium meliloti, and on soil microbial community structure. Treatments consisted of soils amended with biosolids generated with (1) Ag, ZnO, and TiO2 ENMs introduced into the influent wastewater (ENM biosolids), (2) AgNO3, Zn(SO4)2, and micron-sized TiO2 (dissolved/bulk metal biosolids) introduced into the influent wastewater stream, or (3) no metal added to influent wastewater (control). Soils were amended with biosolids to simulate 20 years of metal loading, which resulted in nominal metal concentrations of 1450, 100, and 2400 mg kg(-1) of Zn, Ag, and Ti, respectively, in the dissolved/bulk and ENM treatments. Tissue Zn concentrations were significantly higher in the plants grown in the ENM treatment (182 mg kg(-1)) compared to those from the bulk treatment (103 mg kg( 1)). Large reductions in nodulation frequency, plant growth, and significant shifts in soil microbial community composition were found for the ENM treatment compared to the bulk/dissolved metal treatment. These results suggest differences in metal bioavailability and toxicity between ENMs and bulk/dissolved metals at concentrations relevant to regulatory limits. PMID- 26061864 TI - Inter-individual stereotypy of the Platynereis larval visual connectome. AB - Developmental programs have the fidelity to form neural circuits with the same structure and function among individuals of the same species. It is less well understood, however, to what extent entire neural circuits of different individuals are similar. Previously, we reported the neuronal connectome of the visual eye circuit from the head of a Platynereis dumerilii larva (Randel et al., 2014). We now report a full-body serial section transmission electron microscopy (ssTEM) dataset of another larva of the same age, for which we describe the connectome of the visual eyes and the larval eyespots. Anatomical comparisons and quantitative analyses of the two circuits reveal a high inter-individual stereotypy of the cell complement, neuronal projections, and synaptic connectivity, including the left-right asymmetry in the connectivity of some neurons. Our work shows the extent to which the eye circuitry in Platynereis larvae is hard-wired. PMID- 26061865 TI - Men's Sheds and the experience of depression in older Australian men. AB - BACKGROUND/AIM: Men's Sheds are community spaces where, usually, older men can socialise as they participate in a range of woodwork and other activities. There is currently little research evidence supporting the anecdotally reported mental health and wellbeing benefits of Men's Sheds. This research project investigated how older men with self-reported symptoms of depression experience their participation in Men's Sheds. METHODS: This study included in-depth interviews and administration of the Beck Depression Inventory-II with 12 men from 3 Men's Sheds, triangulated with observation of the different shed environments. Interviews explored how participation in the Men's Shed, living in a regional area, and retirement intersected with experiences of depression. Participants had either self-reported symptoms of depression or a diagnosis of depression. RESULTS: The findings from this study support the notion that participation at Men's Sheds decreases self-reported symptoms of depression. Beck Depression Inventory-II scores showed that most participants were currently experiencing minimal depression. The Men's Sheds environment promoted a sense of purpose through relationships and in the sharing of skills, new routines, motivation, and enjoyment for its members. The shed encouraged increased physical activity and use of cognitive skills. Finally, participants reported feelings of pride and achievement which had an impact on their sense of self-worth. CONCLUSION: Men's Sheds provide an opportunity to promote health and wellbeing among retired men. The shed's activity and social focus offers a way to help men rediscover purpose and self. Further research is required to measure symptoms of depression before and after participation in Men's Sheds. PMID- 26061866 TI - Brushes of semiflexible polymers in equilibrium and under flow in a super hydrophobic regime. AB - We performed molecular dynamics simulations to study the equilibrium and flow properties of a liquid in a nano-channel with confining surfaces coated with a layer of grafted semiflexible polymers. The coverage spans a wide range of grafting densities from essentially isolated chains to dense brushes. The end grafted polymers were described by a bead spring model with a harmonic potential to include the bond stiffness of the chains. We varied the rigidity of the chains, from fully flexible polymers to rigid rods, in which the configurational entropy of the chains is negligible. The brush-liquid interaction was tuned to obtain a super-hydrophobic channel, in which the liquid did not penetrate the polymer brush, giving rise to a Cassie-Baxter state. Equilibrium properties such as brush height and bending energy were measured, varying the grafting density and the stiffness of the polymers. We also studied the characteristics of the brush-liquid interface and the morphology of the polymer chains supporting the liquid for different bending rigidities. Non-equilibrium simulations were performed, moving the walls of the channel in opposite directions at constant speed, obtaining a Couette velocity profile in the bulk liquid. The molecular degrees of freedom of the polymers were studied as a function of the Weissenberg number. Also, the violation of the no-slip boundary condition and the slip properties were analyzed as a function of the shear rate, grafting density and bending stiffness. At high grafting densities, a finite slip length independent of the shear rate or bending constant was found, while at low grafting densities a very interesting non-monotonic dependence on the bending constant is observed. PMID- 26061867 TI - More Evidence That the Use of Venous Thromboembolism Rates as Hospital Quality Measures May Be Off the Mark. PMID- 26061868 TI - Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy. AB - The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies - the ketogenic diet with concurrent hyperbaric oxygen (KD+HBOT) and dietary ketone supplementation - could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies, we characterized the effects of high glucose (control), low glucose (LG), ketone supplementation (betaHB), hyperbaric oxygen (HBOT), or combination therapy (LG+betaHB+HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and betaHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers. PMID- 26061869 TI - Aligned-Braided Nanofibrillar Scaffold with Endothelial Cells Enhances Arteriogenesis. AB - The objective of this study was to enhance the angiogenic capacity of endothelial cells (ECs) using nanoscale signaling cues from aligned nanofibrillar scaffolds in the setting of tissue ischemia. Thread-like nanofibrillar scaffolds with porous structure were fabricated from aligned-braided membranes generated under shear from liquid crystal collagen solution. Human ECs showed greater outgrowth from aligned scaffolds than from nonpatterned scaffolds. Integrin alpha1 was in part responsible for the enhanced cellular outgrowth on aligned nanofibrillar scaffolds, as the effect was abrogated by integrin alpha1 inhibition. To test the efficacy of EC-seeded aligned nanofibrillar scaffolds in improving neovascularization in vivo, the ischemic limbs of mice were treated with EC seeded aligned nanofibrillar scaffold; EC-seeded nonpatterned scaffold; ECs in saline; aligned nanofibrillar scaffold alone; or no treatment. After 14 days, laser Doppler blood spectroscopy demonstrated significant improvement in blood perfusion recovery when treated with EC-seeded aligned nanofibrillar scaffolds, in comparison to ECs in saline or no treatment. In ischemic hindlimbs treated with scaffolds seeded with human ECs derived from induced pluripotent stem cells (iPSC-ECs), single-walled carbon nanotube (SWNT) fluorophores were systemically delivered to quantify microvascular density after 28 days. Near infrared-II (NIR II, 1000-1700 nm) imaging of SWNT fluorophores demonstrated that iPSC-EC-seeded aligned scaffolds group showed significantly higher microvascular density than the saline or cells groups. These data suggest that treatment with EC-seeded aligned nanofibrillar scaffolds improved blood perfusion and arteriogenesis, when compared to treatment with cells alone or scaffold alone, and have important implications in the design of therapeutic cell delivery strategies. PMID- 26061870 TI - Human Chromosome Y and Haplogroups; introducing YDHS Database. AB - BACKGROUND: As the high throughput sequencing efforts generate more biological information, scientists from different disciplines are interpreting the polymorphisms that make us unique. In addition, there is an increasing trend in general public to research their own genealogy, find distant relatives and to know more about their biological background. Commercial vendors are providing analyses of mitochondrial and Y-chromosomal markers for such purposes. Clearly, an easy-to-use free interface to the existing data on the identified variants would be in the interest of general public and professionals less familiar with the field. Here we introduce a novel metadatabase YDHS that aims to provide such an interface for Y-chromosomal DNA (Y-DNA) haplogroups and sequence variants. METHODS: The database uses ISOGG Y-DNA tree as the source of mutations and haplogroups and by using genomic positions of the mutations the database links them to genes and other biological entities. YDHS contains analysis tools for deeper Y-SNP analysis. RESULTS: YDHS addresses the shortage of Y-DNA related databases. We have tested our database using a set of different cases from literature ranging from infertility to autism. The database is at http://www.semanticgen.net/ydhs CONCLUSIONS: Y-chromosomal DNA (Y-DNA) haplogroups and sequence variants have not been in the scientific limelight, excluding certain specialized fields like forensics, mainly because there is not much freely available information or it is scattered in different sources. However, as we have demonstrated Y-SNPs do play a role in various cases on the haplogroup level and it is possible to create a free Y-DNA dedicated bioinformatics resource. PMID- 26061871 TI - Maximum flow approach to prioritize potential drug targets of Mycobacterium tuberculosis H37Rv from protein-protein interaction network. AB - BACKGROUND: In spite of the implementations of several strategies, tuberculosis (TB) is overwhelmingly a serious global public health problem causing millions of infections and deaths every year. This is mainly due to the emergence of drug resistance varieties of TB. The current treatment strategies for the drug resistance TB are of longer duration, more expensive and have side effects. This highlights the importance of identification and prioritization of targets for new drugs. This study has been carried out to prioritize potential drug targets of Mycobacterium tuberculosis H37Rv based on their flow to resistance genes. METHODS: The weighted proteome interaction network of the pathogen was constructed using a dataset from STRING database. Only a subset of the dataset with interactions that have a combined score value >=770 was considered. Maximum flow approach has been used to prioritize potential drug targets. The potential drug targets were obtained through comparative genome and network centrality analysis. The curated set of resistance genes was retrieved from literatures. Detail literature review and additional assessment of the method were also carried out for validation. RESULTS: A list of 537 proteins which are essential to the pathogen and non-homologous with human was obtained from the comparative genome analysis. Through network centrality measures, 131 of them were found within the close neighborhood of the centre of gravity of the proteome network. These proteins were further prioritized based on their maximum flow value to resistance genes and they are proposed as reliable drug targets of the pathogen. Proteins which interact with the host were also identified in order to understand the infection mechanism. CONCLUSION: Potential drug targets of Mycobacterium tuberculosis H37Rv were successfully prioritized based on their flow to resistance genes of existing drugs which is believed to increase the druggability of the targets since inhibition of a protein that has a maximum flow to resistance genes is more likely to disrupt the communication to these genes. Purposely selected literature review of the top 14 proteins showed that many of them in this list were proposed as drug targets of the pathogen. PMID- 26061872 TI - Fluorescent Silica Nanoparticles with Multivalent Inhibitory Effects towards Carbonic Anhydrases. AB - Invited for the cover of this issue are Jean-Yves Winum and co-workers at University of Montpellier (France) and University of Florence (Italy). The image depicts the multivalency approach applied to zinc metalloenzyme carbonic anhydrases. Read the full text of the article at 10.1002/chem.201501037. PMID- 26061873 TI - Editorial: Introducing Dr. Frank S. Prato. PMID- 26061874 TI - Blind intubation of anaesthetised children with supraglottic airway devices AmbuAura-i and Air-Q cannot be recommended: A randomised controlled trial. AB - BACKGROUND: Paediatric supraglottic airway devices AmbuAura-i and Air-Q were designed as conduits for tracheal intubation. Although fibreoptic-guided intubation has proved successful, blind intubation as a rescue technique has never been evaluated. OBJECTIVE: Evaluation of blind intubation through AmbuAura i and Air-Q. On the basis of fibreoptic view data, we hypothesised that the success rate with the AmbuAura-i would be higher than with the Air-Q. DESIGN: A randomised controlled trial. SETTING: University Childrens' Hospital; September 2012 to July 2014. PATIENTS: Eighty children, American Society of Anesthesiologists (ASA) class I to III, weight 5 to 50 kg. INTERVENTIONS: Tracheal intubation was performed through the randomised device with the tip of a fibrescope placed inside and proximal to the tip of the tracheal tube. This permitted sight of tube advancement, but without fibreoptic guidance (visualised blind intubation). MAIN OUTCOME MEASURES: Primary outcome was successfully visualised blind intubation; secondary outcomes included supraglottic airway device success, insertion times, airway leak pressure, fibreoptic view and adverse events. RESULTS: Personal data did not differ between groups. In contrast to our hypothesis, blind intubation was possible in 15% with the Air-Q and in 3% with the AmbuAura-i [95% confidence interval (95% CI) 6 to 31 vs. 0 to 13%; P = 0.057]. First attempt supraglottic airway device insertion success rates were 95% (Air-Q) and 100% (AmbuAura-i; 95% CI 83 to 99 vs. 91 to 100; P = 0.49). Median leak pressures were 18 cmH2O (Air-Q) and 17 cmH2O [AmbuAura-i; interquartile range (IQR) 14 to 18 vs. 14 to 19 cmH2O; P = 0.66]. Air-Q insertion was slower (27 vs. 19 s, P < 0.001). There was no difference in fibreoptic view, or adverse events (P > 0.05). In one child (Air-Q size 1.5, tube size 3.5), the tube dislocated during device removal. CONCLUSION: Ventilation with both devices is reliable, but success of blind intubation is unacceptably low and cannot be recommended for elective or rescue purposes. If intubation through a paediatric supraglottic airway device is desired, we suggest that fibreoptic guidance is used. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01692522. PMID- 26061875 TI - Salt Stress Effects on Secondary Metabolites of Cotton in Relation to Gene Expression Responsible for Aphid Development. AB - Many secondary metabolites have insecticidal efficacy against pests and may be affected by abiotic stress. However, little is known of how plants may respond to such stress as pertains the growth and development of pests. The objective of this study was to determine if and how salt stress on cotton plants affects the population dynamics of aphids. The NaCl treatment (50 mM, 100 mM, 150 mM and 200 mM) increased contents of gossypol in cotton by 26.8-51.4%, flavonoids by 22.5 37.6% and tannic by 15.1-24.3% at 7-28 d after salt stress. Compared with non stressed plants, the population of aphids on 150 and 200 mM NaCl stressed plants was reduced by 46.4 and 65.4% at 7d and by 97.3 and 100% at 14 days after infestation. Reductions in aphid population were possibly attributed to the elevated secondary metabolism under salt stress. A total of 796 clones for aphids transcriptome, 412 clones in the positive- library (TEST) and 384 clones in the reverse-library (Ck), were obtained from subtracted cDNA libraries and sequenced. Gene ontology (GO) functional classification and KEGG pathway analysis showed more genes related to fatty acid and lipid biosynthesis, and fewer genes related to carbohydrate metabolism, amino acid metabolism, energy metabolism and cell motility pathways in TEST than in Ck library, which might be the reason of aphids population reduction. A comparative analysis with qRT-PCR indicated high expression of transcripts CYP6A14, CYP6A13, CYP303A1, NADH dehydrogenase and fatty acid synthase in the TEST group. However, CYP307A1 and two ecdysone-induced protein genes were down regulated. The results indicate that genes of aphids related to growth and development can express at a higher level in reaction to the enhanced secondary metabolism in cotton under salinity stress. The expression of CYP307A1 was positively correlated with the population dynamics of aphids since it was involved in ecdysone synthesis. PMID- 26061876 TI - Changes in Sperm Motility and Capacitation Induce Chromosomal Aberration of the Bovine Embryo following Intracytoplasmic Sperm Injection. AB - Intracytoplasmic sperm injection (ICSI) has become the method of choice to treat human male infertility. One of the outstanding problems associated with this technique is our current lack of knowledge concerning the effect of sperm capacitation and motility upon the subsequent development of oocytes following ICSI. In the present study, we first examined the capacitation state of sperm exhibiting normal motility, along with sperm that had been activated, and examined the effect of reactive oxygen species (ROS) produced by these sperm types upon embryogenesis following bovine in vitro fertilization (IVF) and ICSI. Data showed that activated sperm reduced the chromosomal integrity of IVF/ICSI embryos at the blastocyst stage, while capacitated sperm produced ROS in capacitation media. Secondly, we treated sperm with carbonyl cyanide m chlorophenyl hydrazine (CCCP), a chemical known to uncouple cell respiration within the mitochondria, and investigated the effect of this treatment upon blastocyst formation and chromosomal integrity at the blastocyst stage. Activated sperm in which the mitochondria had been treated with CCCP reduced levels of chromosomal aberration at the blastocyst stage following ICSI, by reducing mitochondrial activity in activated sperm. In conclusion, these findings suggest that capacitated sperm exhibiting activated motility induced chromosomal aberration during development to the blastocyst stage following ICSI. The injection of sperm exhibiting normal motility, or activated sperm in which mitochondrial activity had been reduced, improved the quality of ICSI-derived embryos. Therefore, the selection of sperm exhibiting progressive motility may not always be better for early embryo development and fetal growth following human ICSI, and that the use of a bovine model may contribute to a deeper understanding of sperm selection for human ICSI embryo development. PMID- 26061877 TI - Why Social Pain Can Live on: Different Neural Mechanisms Are Associated with Reliving Social and Physical Pain. AB - Although social and physical pain recruit overlapping neural activity in regions associated with the affective component of pain, the two pains can diverge in their phenomenology. Most notably, feelings of social pain can be re-experienced or "relived," even when the painful episode has long passed, whereas feelings of physical pain cannot be easily relived once the painful episode subsides. Here, we observed that reliving social (vs. physical) pain led to greater self-reported re-experienced pain and greater activity in affective pain regions (dorsal anterior cingulate cortex and anterior insula). Moreover, the degree of relived pain correlated positively with affective pain system activity. In contrast, reliving physical (vs. social) pain led to greater activity in the sensory discriminative pain system (primary and secondary somatosensory cortex and posterior insula), which did not correlate with relived pain. Preferential engagement of these different pain mechanisms may reflect the use of different top-down neurocognitive pathways to elicit the pain. Social pain reliving recruited dorsomedial prefrontal cortex, often associated with mental state processing, which functionally correlated with affective pain system responses. In contrast, physical pain reliving recruited inferior frontal gyrus, known to be involved in body state processing, which functionally correlated with activation in the sensory pain system. These results update the physical-social pain overlap hypothesis: while overlapping mechanisms support live social and physical pain, distinct mechanisms guide internally-generated pain. PMID- 26061878 TI - Large Scale Bacterial Colony Screening of Diversified FRET Biosensors. AB - Biosensors based on Forster Resonance Energy Transfer (FRET) between fluorescent protein mutants have started to revolutionize physiology and biochemistry. However, many types of FRET biosensors show relatively small FRET changes, making measurements with these probes challenging when used under sub-optimal experimental conditions. Thus, a major effort in the field currently lies in designing new optimization strategies for these types of sensors. Here we describe procedures for optimizing FRET changes by large scale screening of mutant biosensor libraries in bacterial colonies. We describe optimization of biosensor expression, permeabilization of bacteria, software tools for analysis, and screening conditions. The procedures reported here may help in improving FRET changes in multiple suitable classes of biosensors. PMID- 26061880 TI - Rapid Morphological Change in the Masticatory Structures of an Important Ecosystem Service Provider. AB - Humans have altered the biotic and abiotic environmental conditions of most organisms. In some cases, such as intensive agriculture, an organism's entire ecosystem is converted to novel conditions. Thus, it is striking that some species continue to thrive under such conditions. The prairie deer mouse (Peromyscus maniculatus bairdii) is an example of such an organism, and so we sought to understand what role evolutionary adaptation played in the success of this species, with particular interest in adaptations to novel foods. In order to understand the evolutionary history of this species' masticatory structures, we examined the maxilla, zygomatic plate, and mandible of historic specimens collected prior to 1910 to specimens collected in 2012 and 2013. We found that mandibles, zygomatic plates, and maxilla have all changed significantly since 1910, and that morphological development has shifted significantly. We present compelling evidence that these differences are due to natural selection as a response to a novel and ubiquitous food source, waste grain (corn, Zea mays and soybean, Glycine max). PMID- 26061879 TI - Emotion Reactivity Is Increased 4-6 Weeks Postpartum in Healthy Women: A Longitudinal fMRI Study. AB - Marked endocrine alterations occur after delivery. Most women cope well with these changes, but the postpartum period is associated with an increased risk of depressive episodes. Previous studies of emotion processing have focused on maternal-infant bonding or postpartum depression (PPD), and longitudinal studies of the neural correlates of emotion processing throughout the postpartum period in healthy women are lacking. In this study, 13 women, without signs of post partum depression, underwent fMRI with an emotional face matching task and completed the MADRS-S, STAI-S, and EPDS within 48 h (early postpartum) and 4-6 weeks after delivery (late postpartum). Also, data from a previous study including 15 naturally cycling controls assessed in the luteal and follicular phase of the menstrual cycle was used. Women had lower reactivity in insula, middle frontal gyrus (MFG), and inferior frontal gyrus (IFG) in the early as compared to the late postpartum assessment. Insular reactivity was positively correlated with anxiety in the early postpartum period and with depressive symptoms late postpartum. Reactivity in insula and IFG were greater in postpartum women than in non-pregnant control subjects. Brain reactivity was not correlated with serum estradiol or progesterone levels. Increased reactivity in the insula, IFG, and MFG may reflect normal postpartum adaptation, but correlation with self rated symptoms of depression and anxiety in these otherwise healthy postpartum women, may also suggest that these changes place susceptible women at increased risk of PPD. These findings contribute to our understanding of the neurobiological aspects of the postpartum period, which might shed light on the mechanisms underlying affective puerperal disorders, such as PPD. PMID- 26061881 TI - The Search for Significance: A Few Peculiarities in the Distribution of P Values in Experimental Psychology Literature. AB - In this project I investigate the use and possible misuse of p values in papers published in five (high-ranked) journals in experimental psychology. I use a data set of over 135'000 p values from more than five thousand papers. I inspect (1) the way in which the p values are reported and (2) their distribution. The main findings are following: first, it appears that some authors choose the mode of reporting their results in an arbitrary way. Moreover, they often end up doing it in such a way that makes their findings seem more statistically significant than they really are (which is well known to improve the chances for publication). Specifically, they frequently report p values "just above" significance thresholds directly, whereas other values are reported by means of inequalities (e.g. "p<.1"), they round the p values down more eagerly than up and appear to choose between the significance thresholds and between one- and two-sided tests only after seeing the data. Further, about 9.2% of reported p values are inconsistent with their underlying statistics (e.g. F or t) and it appears that there are "too many" "just significant" values. One interpretation of this is that researchers tend to choose the model or include/discard observations to bring the p value to the right side of the threshold. PMID- 26061882 TI - Linear Dispersal of the Filth Fly Parasitoid Spalangia cameroni (Hymenoptera: Pteromalidae) and Parasitism of Hosts at Increasing Distances. AB - Release of parasitic wasps (Hymenoptera: Pteromalidae) as biological control agents for house flies and stable flies in livestock confinements has had variable success. In part, this may reflect a lack of knowledge regarding the optimal distance to be used between parasitoid release stations. In the current study, we assessed the effect of linear distance on host parasitism by the wasp Spalangia cameroni Perkins. In open fields at distances ranging from 1 m to 60 m from a central point, house fly puparia were placed in a mixture of pine shavings soiled with equine manure, urine, and alfalfa hay. Releases of S. cameroni then were made using a 5:1 host: parasitoid ratio. Host pupae were parasitized at all distances, with the highest rate of total parasitism (68.9%) recorded <= 5 m from the release site. Analyses of results using non-linear and linear models suggest that S. cameroni should be released in close proximity to host development areas. Additionally, releases may not be suitable in pasture situations where long distance flight is required for control. However, further testing is needed to examine the effect of density-dependent dispersal and diffusion of S. cameroni. PMID- 26061883 TI - Impaired Cellular Immunity in the Murine Neural Crest Conditional Deletion of Endothelin Receptor-B Model of Hirschsprung's Disease. AB - Hirschsprung's disease (HSCR) is characterized by aganglionosis from failure of neural crest cell (NCC) migration to the distal hindgut. Up to 40% of HSCR patients suffer Hirschsprung's-associated enterocolitis (HAEC), with an incidence that is unchanged from the pre-operative to the post-operative state. Recent reports indicate that signaling pathways involved in NCC migration may also be involved in the development of secondary lymphoid organs. We hypothesize that gastrointestinal (GI) mucosal immune defects occur in HSCR that may contribute to enterocolitis. EdnrB was deleted from the neural crest (EdnrBNCC-/-) resulting in mutants with defective NCC migration, distal colonic aganglionosis and the development of enterocolitis. The mucosal immune apparatus of these mice was interrogated at post-natal day (P) 21-24, prior to histological signs of enterocolitis. We found that EdnrBNCC-/- display lymphopenia of their Peyer's Patches, the major inductive site of GI mucosal immunity. EdnrBNCC-/- Peyer's Patches demonstrate decreased B-lymphocytes, specifically IgM+IgDhi (Mature) B lymphocytes, which are normally activated and produce IgA following antigen presentation. EdnrBNCC-/- animals demonstrate decreased small intestinal secretory IgA, but unchanged nasal and bronchial airway secretory IgA, indicating a gut-specific defect in IgA production or secretion. In the spleen, which is the primary source of IgA-producing Mature B-lymphocytes, EdnrBNCC-/- animals display decreased B-lymphocytes, but an increase in Mature B-lymphocytes. EdnrBNCC-/- spleens are also small and show altered architecture, with decreased red pulp and a paucity of B-lymphocytes in the germinal centers and marginal zone. Taken together, these findings suggest impaired GI mucosal immunity in EdnrBNCC-/- animals, with the spleen as a potential site of the defect. These findings build upon the growing body of literature that suggests that intestinal defects in HSCR are not restricted to the aganglionic colon but extend proximally, even into the ganglionated small intestine and immune cells. PMID- 26061884 TI - Landscape-Scale Controls on Aboveground Forest Carbon Stocks on the Osa Peninsula, Costa Rica. AB - Tropical forests store large amounts of carbon in tree biomass, although the environmental controls on forest carbon stocks remain poorly resolved. Emerging airborne remote sensing techniques offer a powerful approach to understand how aboveground carbon density (ACD) varies across tropical landscapes. In this study, we evaluate the accuracy of the Carnegie Airborne Observatory (CAO) Light Detection and Ranging (LiDAR) system to detect top-of-canopy tree height (TCH) and ACD across the Osa Peninsula, Costa Rica. LiDAR and field-estimated TCH and ACD were highly correlated across a wide range of forest ages and types. Top-of canopy height (TCH) reached 67 m, and ACD surpassed 225 Mg C ha-1, indicating both that airborne CAO LiDAR-based estimates of ACD are accurate in tall, high biomass forests and that the Osa Peninsula harbors some of the most carbon-rich forests in the Neotropics. We also examined the relative influence of lithologic, topoedaphic and climatic factors on regional patterns in ACD, which are known to influence ACD by regulating forest productivity and turnover. Analyses revealed a spatially nested set of factors controlling ACD patterns, with geologic variation explaining up to 16% of the mapped ACD variation at the regional scale, while local variation in topographic slope explained an additional 18%. Lithologic and topoedaphic factors also explained more ACD variation at 30-m than at 100-m spatial resolution, suggesting that environmental filtering depends on the spatial scale of terrain variation. Our result indicate that patterns in ACD are partially controlled by spatial variation in geologic history and geomorphic processes underpinning topographic diversity across landscapes. ACD also exhibited spatial autocorrelation, which may reflect biological processes that influence ACD, such as the assembly of species or phenotypes across the landscape, but additional research is needed to resolve how abiotic and biotic factors contribute to ACD variation across high biomass, high diversity tropical landscapes. PMID- 26061885 TI - Longitudinal Survey of Carotenoids in Human Milk from Urban Cohorts in China, Mexico, and the USA. AB - Emerging evidence indicates that carotenoids may have particular roles in infant nutrition and development, yet data on the profile and bioavailability of carotenoids from human milk remain sparse. Milk was longitudinally collected at 2, 4, 13, and 26 weeks postpartum from twenty mothers each in China, Mexico, and the USA in the Global Exploration of Human Milk Study (n = 60 donors, n = 240 samples). Maternal and neonatal plasma was analyzed for carotenoids from the USA cohort at 4 weeks postpartum. Carotenoids were analyzed by HPLC and total lipids by Creamatocrit. Across all countries and lactation stages, the top four carotenoids were lutein (median 114.4 nmol/L), beta-carotene (49.4 nmol/L), beta cryptoxanthin (33.8 nmol/L), and lycopene (33.7 nmol/L). Non-provitamin A carotenoids (nmol/L) and total lipids (g/L) decreased (p<0.05) with increasing lactation stage, except the provitamin A carotenoids alpha- and beta cryptoxanthin and beta-carotene did not significantly change (p>0.05) with lactation stage. Total carotenoid content and lutein content were greatest from China, yet lycopene was lowest from China (p<0.0001). Lutein, beta-cryptoxanthin, and beta-carotene, and lycopene concentrations in milk were significantly correlated to maternal plasma and neonatal plasma concentrations (p<0.05), with the exception that lycopene was not significantly associated between human milk and neonatal plasma (p>0.3). This enhanced understanding of neonatal exposure to carotenoids during development may help guide dietary recommendations and design of human milk mimetics. PMID- 26061886 TI - Runx3-regulated expression of two Ntrk3 transcript variants in dorsal root ganglion neurons. AB - Somatosensation is divided into proprioception and cutaneous sensation. Dorsal root ganglion (DRG) neurons project their fibers toward peripheral targets including muscles and skin, and centrally to the spinal cord. Proprioceptive DRG neurons transmit information from muscle spindles and Golgi tendon organs to the spinal cord. We previously showed that Runt-related transcription factor 3 (Runx3) is expressed in these neurons and their projections to the ventral spinal cord and muscle spindles are lost in Runx3-deficient (Runx3(-/-) ) mouse embryos. Although Runx3 is likely to contribute to the fate decision and projection of proprioceptive DRG neurons, the precise roles for Runx3 in these phenomena are unknown. To identify genes regulated by Runx3 in embryonic DRGs, we performed microarray analyses using cDNAs isolated from wild-type and Runx3(-/-) DRGs of embryonic day (E) 12.5 and selected two transcript variants of the tyrosine kinase receptor C (TrkC) gene. These variants, Ntrk3 variant 1 (Ntrk3-v1) and variant 2 (Ntrk3-v2), encode full-length and truncated receptors of neurotrophin 3, respectively. Using double in situ hybridization, we found that most of Ntrk3 v1 mRNA expression in E14.5 DRGs depended on Runx3 but that more than half of Ntrk3-v2 mRNA one were expressed in a Runx3-independent manner. Furthermore, our data revealed that the rate of Ntrk3-v1 and Ntrk3-v2 colocalization in DRGs changed from E14.5 to E18.5. Together, our data suggest that Runx3 may play a crucial role in the development of DRGs by regulating the expression of Ntrk3 variants and that DRG neurons expressing Ntrk3-v1 but not Ntrk3-v2 may differentiate into proprioceptive ones. PMID- 26061887 TI - Structural Approach to Bias in Meta-analyses. AB - Methods to calculate bias-adjusted estimates for meta-analyses are becoming more popular. The objective of this paper is to use the structural approach to bias and causal diagrams to show that (i) the current use of the bias-adjusted estimating tools may sometimes introduce bias rather than reduce it and (ii) the Cochrane collaboration risk of bias tool, which was designed for randomized studies, is also applicable to non-randomized studies with only minimal changes. Causal diagrams are used to illustrate each of the items in the current risk of bias tool and how they apply to both randomized and non-randomized studies. With the exception of confounding by indication, the structure of all potential biases present in non-randomized studies may also be present in randomized studies. In addition, causal diagrams demonstrate important limitations to the methods currently being developed to provide bias-adjusted estimates of individual studies in meta-analyses. Finally, causal diagrams can be helpful in deciding when it is appropriate to combine studies in a meta-analysis of non-randomized studies even though the studies may use different adjustment sets. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26061888 TI - Comparison of statistical inferences from the DerSimonian-Laird and alternative random-effects model meta-analyses - an empirical assessment of 920 Cochrane primary outcome meta-analyses. AB - In random-effects model meta-analysis, the conventional DerSimonian-Laird (DL) estimator typically underestimates the between-trial variance. Alternative variance estimators have been proposed to address this bias. This study aims to empirically compare statistical inferences from random-effects model meta analyses on the basis of the DL estimator and four alternative estimators, as well as distributional assumptions (normal distribution and t-distribution) about the pooled intervention effect. We evaluated the discrepancies of p-values, 95% confidence intervals (CIs) in statistically significant meta-analyses, and the degree (percentage) of statistical heterogeneity (e.g. I(2)) across 920 Cochrane primary outcome meta-analyses. In total, 414 of the 920 meta-analyses were statistically significant with the DL meta-analysis, and 506 were not. Compared with the DL estimator, the four alternative estimators yielded p-values and CIs that could be interpreted as discordant in up to 11.6% or 6% of the included meta analyses pending whether a normal distribution or a t-distribution of the intervention effect estimates were assumed. Large discrepancies were observed for the measures of degree of heterogeneity when comparing DL with each of the four alternative estimators. Estimating the degree (percentage) of heterogeneity on the basis of less biased between-trial variance estimators seems preferable to current practice. Disclosing inferential sensitivity of p-values and CIs may also be necessary when borderline significant results have substantial impact on the conclusion. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26061889 TI - On the moments of Cochran's Q statistic under the null hypothesis, with application to the meta-analysis of risk difference. AB - W. G. Cochran's Q statistic was introduced in 1937 to test for equality of means under heteroscedasticity. Today, the use of Q is widespread in tests for homogeneity of effects in meta-analysis, but often these effects (such as risk differences and odds ratios) are not normally distributed. It is common to assume that Q follows a chi-square distribution, but it has long been known that this asymptotic distribution for Q is not accurate for moderate sample sizes. In this paper, the effect and weight for an individual study may depend on two parameters: the effect and a nuisance parameter. We present expansions for the first two moments of Q without any normality assumptions. Our expansions will have wide applicability in testing for homogeneity in meta-analysis. As an important example, we present a homogeneity test when the effects are the differences of risks between treatment and control arms of the several studies-a test which is substantially more accurate than that currently used. In this situation, we approximate the distribution of Q with a gamma distribution. We provide the results of simulations to verify the accuracy of our proposal and an example of a meta-analysis of medical data. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26061890 TI - Multi-context versus context-specific qualitative evidence syntheses: combining the best of both. AB - There is an increasing interest in the conduct of qualitative evidence syntheses (QES), particularly in the field of health care. Approaches to QES vary in the way they conduct a search, a critical appraisal or the data-analysis. To date, the use of multi-context versus context-specific QES has not yet been fully considered. In a multi-context, QES exhaustive searches are used that retrieve studies from a broad variety of geographical, socio-cultural, political, historical, economical, health care, linguistic, or other context relevant to the review. Authors of a context-specific QES would generally have a particular end user in mind, therefore, using a selective search strategy with a focus on one particular context in order to provide lines of actions or theories that are sensitive to a local setting. We used the insights from a recently conducted, context-specific QES to map out potential strengths and weaknesses of these two approaches and make recommendations regarding the future conduct of QES. We propose two ways of combining the best of both: the production of umbrella reviews of context-specific syntheses and/or the trans-cultural modification and trans-contextual adaptation of findings from multi-context syntheses. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26061891 TI - Article Alerts: items from 2010, Part II. AB - The print component of this fourth 'Article Alerts' installment comprises 100 articles published in 2010. More than 2500 items have been added to the archive component since the preceding installment. Of these new archive items, more than 1500 were disseminated in 2009; the remainder, between 1994 and 1998, inclusive. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26061892 TI - Strong and Coherent Coupling of a Plasmonic Nanoparticle to a Subwavelength Fabry Perot Resonator. AB - A major aim in experimental nano- and quantum optics is observing and controlling the interaction between light and matter on a microscopic scale. Coupling molecules or atoms to optical microresonators is a prominent method to alter their optical properties such as luminescence spectra or lifetimes. Until today strong coupling of optical resonators to such objects has only been observed with atom-like systems in high quality resonators. We demonstrate first experiments revealing strong coupling between individual plasmonic gold nanorods (GNR) and a tunable low quality resonator by observing cavity-length-dependent nonlinear dephasing and spectral shifts indicating spectral anticrossing of the luminescent coupled system. These phenomena and experimental results can be described by a model of two coupled oscillators representing the plasmon resonance of the GNR and the optical fields of the resonator. The presented reproducible and accurately tunable resonator allows us to precisely control the optical properties of individual particles. PMID- 26061893 TI - The Use of Ozurdex (Dexamethasone Intravitreal Implant) During Anterior Segment Surgery in Patients with Chronic Recurrent Uveitis. AB - PURPOSE: To describe the outcomes of concurrent Ozurdex implantation during anterior segment surgery in patients with chronic recurrent uveitis. METHODS: Retrospective chart review. Data recorded from preoperative and 1-, 3-, and 6 month postoperative visits included visual acuity, intraocular pressure (IOP), medications, and clinical examination findings of inflammation. RESULTS: Twelve patients (12 eyes) with chronic, recurrent noninfectious uveitis undergoing cataract extraction (n=9) or intraocular lens (IOL) explantation (n=3) were included. Mean duration of follow-up after Ozurdex implantation was 12.9 months. There was a significant reduction (n=10, P=0.02) in the average number of inflammation recurrences 6 months before surgery compared to 6 months after surgery with Ozurdex in affected eyes. IOP remained stable in the postoperative period. One patient undergoing anterior chamber IOL (ACIOL) explantation experienced migration of Ozurdex into the anterior chamber resulting in corneal edema that resolved after 1 month. CONCLUSIONS: Ozurdex safely and effectively controlled postoperative inflammation in eyes with chronic recurrent uveitis when concurrently implanted during anterior segment surgery in our patients. Caution should be exercised in cases of IOL explantation, as Ozurdex use is now contraindicated in eyes with posterior capsule rupture and ACIOLs. PMID- 26061894 TI - Helicobacter pylori CheZ(HP) and ChePep form a novel chemotaxis-regulatory complex distinct from the core chemotaxis signaling proteins and the flagellar motor. AB - Chemotaxis is important for Helicobacter pylori to colonize the stomach. Like other bacteria, H. pylori uses chemoreceptors and conserved chemotaxis proteins to phosphorylate the flagellar rotational response regulator, CheY, and modulate the flagellar rotational direction. Phosphorylated CheY is returned to its non phosphorylated state by phosphatases such as CheZ. In previously studied cases, chemotaxis phosphatases localize to the cellular poles by interactions with either the CheA chemotaxis kinase or flagellar motor proteins. We report here that the H. pylori CheZ, CheZ(HP), localizes to the poles independently of the flagellar motor, CheA, and all typical chemotaxis proteins. Instead, CheZ(HP) localization depends on the chemotaxis regulatory protein ChePep, and reciprocally, ChePep requires CheZ(HP) for its polar localization. We furthermore show that these proteins interact directly. Functional domain mapping of CheZ(HP) determined the polar localization motif lies within the central domain of the protein and that the protein has regions outside of the active site that participate in chemotaxis. Our results suggest that CheZ(HP) and ChePep form a distinct complex. These results therefore suggest the intriguing idea that some phosphatases localize independently of the other chemotaxis and motility proteins, possibly to confer unique regulation on these proteins' activities. PMID- 26061895 TI - Long-term follow-up in patients treated with curative electrochemotherapy for cancer in the oral cavity and oropharynx. AB - CONCLUSION: ECT can be a safe curative mono modality treatment, especially in tongue cancer. The future role for ECT in head and neck cancer needs to be further investigated. INTRODUCTION: Electrochemotherapy (ECT) is a cancer treatment modality that uses electroporation to increase the intracellular accumulation of hydrophilic chemotherapeutic drugs, especially bleomycin. OBJECTIVES: To report the 5-year local tumor control, safety of treatment and survival after ECT, and the 1-year quality-of-life (QoL) data. MATERIALS AND METHODS: Nineteen patients with primary head and neck cancer were included and treated with ECT with curative intent. All except one patient had squamous cell carcinoma (SCC). Radiotherapy (RT) was performed in all patients with SCC and tumor infiltration >=5 mm. The EORTC H&N 35 questionnaire was used at baseline and 12 months after treatment. The Wilcoxon signed rank test and McNemar's test were used for paired data and Mann Whitney U-test and Fishers exact test were used for independent data (sub-group comparison). RESULTS: There were no local recurrences in the follow-up period. Thirteen patients were treated with adjuvant RT. The six patients that were treated with ECT alone were tumor-free and alive 5 years after treatment. There was one serious adverse event reported; aspiration after treatment of a tongue base tumor. The tumor-specific 5-year survival was 75%. The QoL outcome 1 year after ECT showed a significant increase in problems with senses (taste, smell), speech, mouth opening and xerostomia. The QoL outcome also showed worse outcome in the smoking patients regarding speech, in the patients receiving adjuvant RT regarding mouth dryness and swallowing and in the patients with non-tongue oral cavity cancer regarding need for painkillers. PMID- 26061896 TI - Early estimates of 2014/15 seasonal influenza vaccine effectiveness in preventing influenza-like illness in general practice using the screening method in France. AB - The ongoing influenza epidemic is characterized by intense activity with most influenza infections due to the A (H3N2) viruses. Using the screening method, mid season vaccine effectiveness (VE) in preventing influenza-like illness in primary care was estimated to 32% (95% CI; 23 to 40) among risk groups and was 11% (95% CI; -4 to 23) among the elderly (>= 65 y). The VE in >= 65 y was the lowest estimate regarding the 4 previous seasonal influenza epidemics. PMID- 26061897 TI - Antimicrobial Hyaluronic Acid/Poly(amidoamine) Dendrimer Multilayer on Poly(3 hydroxybutyrate-co-4-hydroxybutyrate) Prepared by a Layer-by-Layer Self-Assembly Method. AB - In this article, we prepared hyaluronic acid/poly(amidoamine) dendrimer (HA/PAMAM) multilayers on a poly(3-hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB 4HB)] substrate by a layer-by-layer self-assembly method for antimicrobial biomaterials. The results of zeta potential and quartz crystal microbalance with dissipation (QCM-D) showed that HA/PAMAM multilayers could be formed on the substrate layer by layer. We used QCM-D to show that both the HA outer layer and the PAMAM outer layer exhibited good protein-resistant activity to bovine serum albumin and bacterial antiadhesion activity to Escherichia coli. By a live/dead assay and the colony counting method, we found that the PAMAM outer layer could also exhibit bactericidal activity against E. coli, while the HA outer layer had no bactericidal activity. Both the bacterial antiadhesion activity and the bactericidal activity of the samples could be maintained even after storage in phosphate-buffered saline for up to 14 days. An in vitro MTT assay showed that the multilayers had no cytotoxicity to L929 cells, and HA molecules in the multilayers could improve the biocompatibility of the film. PMID- 26061898 TI - The Structure of an Oxalate Oxidoreductase Provides Insight into Microbial 2 Oxoacid Metabolism. AB - Thiamine pyrophosphate (TPP), a derivative of vitamin B1, is a versatile and ubiquitous cofactor. When coupled with [4Fe-4S] clusters in microbial 2 oxoacid:ferredoxin oxidoreductases (OFORs), TPP is involved in catalyzing low potential redox reactions that are important for the synthesis of key metabolites and the reduction of N2, H(+), and CO2. We have determined the high-resolution (2.27 A) crystal structure of the TPP-dependent oxalate oxidoreductase (OOR), an enzyme that allows microbes to grow on oxalate, a widely occurring dicarboxylic acid that is found in soil and freshwater and is responsible for kidney stone disease in humans. OOR catalyzes the anaerobic oxidation of oxalate, harvesting the low-potential electrons for use in anaerobic reduction and fixation of CO2. We compare the OOR structure to that of the only other structurally characterized OFOR family member, pyruvate:ferredoxin oxidoreductase. This side-by-side structural analysis highlights the key similarities and differences that are relevant for the chemistry of this entire class of TPP-utilizing enzymes. PMID- 26061899 TI - Risk Analysis for Unintentional Slide Deployment During Airline Operations. AB - We present a risk analysis undertaken to mitigate problems in relation to the unintended deployment of slides under normal operations within a commercial airline. This type of incident entails relevant costs for the airline industry. After assessing the likelihood and severity of its consequences, we conclude that such risks need to be managed. We then evaluate the effectiveness of various countermeasures, describing and justifying the chosen ones. We also discuss several issues faced when implementing and communicating the proposed measures, thus fully illustrating the risk analysis process. PMID- 26061900 TI - Endotoxin exposure and puberty in female rats: the role of nitric oxide and caspase-1 inhibition in neonates. AB - Bacterial toxins are widespread in the environment as well as in the digestive system of humans and animals. Toxin from Gram-negative bacteria (endotoxin or lipopolysaccharide; LPS) has a life-long programming effect on reproduction in rats, but the mediators have not been well-documented, so we investigated the effects of LPS on the timing of puberty in female rats. Because the levels of nitric oxide (NO) and interleukin 1beta (IL-1beta) increase following injection of LPS, we injected neonates (post-natal day (pnd) 7) with LPS, with or without NO or IL-1beta inhibitors. Half of the prepubescent (pnd 30) animals received an additional LPS injection. Vaginal opening, number of ovarian follicles, and serum anti-LPS antibodies were determined. A single LPS injection was sufficient to reduce the primordial follicle pool, but puberty was delayed when rats received 2 LPS injections (at pnd 7 and 30). NO or IL-1beta inhibitors improved both of these parameters, suggesting that the early detrimental effects of LPS on puberty and primordial follicle pool are mediated by NO and IL-1beta. PMID- 26061901 TI - Reconfigurable and tunable flat graphene photonic crystal circuits. AB - Photonic crystal waveguides and circuits are one of the basic modules for integrated photonic devices. They mainly rely on photonic bandgaps to achieve light confinement and manipulation. Herein, we propose a novel general principle or method to achieve reconfigurable and tunable flat graphene photonic crystals (FG-PCs) by selectively electrostatic gating a layer of graphene with periodic gold electrodes. The tunable flat photonic bandgap structure of the FG-PCs as a function of the Fermi level is investigated. Reconfigurable FG-PC defect waveguides and cavities created by external patterned-gate-voltage control are also proposed and discussed. The features of reconfigurable/tunable FG-PCs will add more flexibility and capabilities for the single chip integration of graphene based integrated photonic devices. PMID- 26061902 TI - Impact of the Outpatient Clinic Experience on Retention in Care: Perspectives of HIV-Infected Patients and Their Providers. PMID- 26061903 TI - Epidemiology and Microbiology of Secondary Peritonitis Caused by Viscus Perforation: A Single-Center Retrospective Study. AB - BACKGROUND: Complicated intra-abdominal infections are serious conditions that require urgent source control and antibiotic treatment. The purpose of this study was to evaluate the epidemiology and bacterial causation of such infections using blood and peritoneal cultures of Korean patients with peritonitis originating from viscus perforation. METHODS: The medical records of 419 consecutive patients who underwent emergency surgery because of bowel perforation from January 2007 to December 2011 were analyzed. Clinical characteristics, peri-operative conditions, perforation sites, and mortality data were obtained. Bacterial distributions and antibiotic resistance were evaluated using blood and peritoneal culture reports. RESULTS: The most common perforation site was the colon (165; 39.4%), and the overall mortality rate was 11.2%. Blood cultures were performed in 182 patients, and 20 patients (11.0%) had a positive culture. Blood culture positivity was significantly higher for colon perforations (17.7%) than perforations elsewhere (p=0.039). A peritoneal culture was performed for each of 210 patients (50.1%), and 145 of those patients (69.0%) had a positive culture. Enterococcus faecium (35.2%) was the most common gram-positive bacterium, and Escherichia coli was the most common gram-negative organism. There were 276 community-acquired infections (CAI) (65.9%) and 143 hospital-acquired infections (HAI) (34.1%). Escherichia coli producing extended-spectrum beta-lactamases were more common in the HAI than in the CAI group (p=0.016). CONCLUSIONS: The compositions and antibiotic resistances of micro-organisms found in this study are similar to those reported previously. A multicenter prospective study is needed of this disease state in South Korea. PMID- 26061904 TI - Combustion characteristics of paper and sewage sludge in a pilot-scale fluidized bed. AB - This study characterizes the combustion of paper and sewage sludge in a pilot scale fluidized bed. The highest temperature during combustion within the system was found at the surface of the fluidized bed. Paper sludge containing roughly 59.8% water was burned without auxiliary fuel, but auxiliary fuel was required to incinerate the sewage sludge, which contained about 79.3% water. The stability of operation was monitored based on the average pressure and the standard deviation of pressure fluctuations. The average pressure at the surface of the fluidized bed decreased as the sludge feed rate increased. However, the standard deviation of pressure fluctuations increased as the sludge feed rate increased. Finally, carbon monoxide (CO) emissions decreased as oxygen content increased in the flue gas, and nitrogen oxide (NOx) emissions were also tied with oxygen content. PMID- 26061905 TI - Structural Perturbations Present in the Folding Cores of Interleukin-33 and Interleukin-1beta Correlate to Differences in Their Function. AB - The interleukin-1 cytokines belong to the beta-trefoil fold family and play a key role in immune responses to infections and injury. We simulate the structure based models of two interleukin-1 cytokines, IL-33 and IL-1beta, and find that IL 33 has a lower barrier to folding than IL-1beta. We then design the folding motif (FM) of the beta-trefoil fold and identify structural deviations of IL-33 and IL 1beta from this FM. In previous work, we found that structural deviations from the FM that are large enough to lower folding free energy barriers were part of ligand binding sites. In contrast, we find that structural perturbations in IL-33 and IL-1beta which reduce the folding free energy barrier are located in the folding core and do not bind ligands. In both proteins, such core residues are interleaved with surface residues which are proximal to receptor binding sites. However, IL-33 has a lower folding barrier because its core perturbations are larger than those in IL-1beta. In order to understand the role of these core perturbations, we perform atomistic simulations of both proteins and find that the larger core perturbations may allow IL-33 to communicate signals differently across the protein. Integrating previous data, we also hypothesize that the larger IL-33 core perturbations may help accommodate its more charged binding site and may also aid in its inactivation by caspase-mediated cleavage. Together, our results suggest that protein folding landscapes are modulated not only by larger functional features such as binding sites but also by the details of protein function and fate. Furthermore, a comparative study of such landscapes may be a facile way to identify subtle differences in allosteric connectivity between two similar proteins. PMID- 26061906 TI - Ratio of total traction force to projected cell area is preserved in differentiating adipocytes. AB - During obesity development, preadipocytes proliferate and differentiate into new mature adipocytes, to increase the storage capacity of triglycerides. The morphology of the cells changes during differentiation from an elongated spindle shape preadipocyte into a rounded, differentiated adipocyte. That change allows efficient packing of spheroidal (triglyceride) lipid droplets in the cells, also reducing their ability to proliferate and migrate. The change in preadipocyte morphology is well known. However, little is known about the dynamic mechanical interactions of the cells with their microenvironment, and specifically the forces applied by the cells during and following differentiation. In this study, we evaluated changes in the morphology concurrently with the magnitude and location of forces applied by the cells onto a compliant gel-substrate. We found that the elongated preadipocytes applied forces concentrated at the poles of the cell, yet during differentiation the forces become more uniformly distributed around the cell and mostly at its perimeter. Furthermore, we observed that the total traction force per cell area is preserved, remaining essentially unchanged between preadipocytes and differentiated cells 3-14 days post-differentiation. At differentiation times longer than 8 days we also observed an increasing subset of cells that indent the gels, as opposed to merely applying horizontal traction forces. Our work provides insights into the dynamic mechanobiology of the adipogenesis process. PMID- 26061907 TI - Low Recurrence Rates in a Cohort of Differentiated Thyroid Carcinoma Patients: A Referral Center Experience. AB - BACKGROUND: Trends in the epidemiological profiles of differentiated thyroid cancer (DTC) have shifted the disease spectrum. This study aimed to evaluate the recurrence rates and identify factors related to persistent disease in a contemporary cohort of patients with DTC. METHODS: A cohort of DTC patients submitted to total thyroidectomy followed in a referral center were included in the study. "Disease free" was defined as no clinical, imaging, or biochemical evidence of tumors. "Recurrence" was defined as evidence of disease in a patient who had been previously classified as disease free. RESULTS: A total of 786 patients were included. The mean age at diagnosis was 45.8+/-15.1 years, 81.6% were female, and papillary thyroid cancer accounted for 86.6% of cases. The median tumor size was 2.0 cm, 28.5% had lymph node involvement, and 6.1% had distant metastases. Disease status after the initial therapy was available for 548 patients: 357 (65.1%) were disease free, and 191 (34.9%) had persistent disease (90 biochemical and 101 structural disease). In multivariate model analyses, the variables male sex, lateral lymph nodal involvement, distant metastasis, and 2009 ATA high-risk classification were independent prognostic factors for persist disease. After a four-year follow-up (two to eight years), 97.2% of the patients who had been classified as disease free remained in disease remission status. Of the 10 (2.8%) patients with recurrent disease, eight presented biochemical and two cervical structural disease. CONCLUSIONS: The majority of the DTC patients who were considered to be disease free after the initial treatment remained with this status at long-term follow-up. These data suggest that less intensive follow-up may apply for these patients. PMID- 26061909 TI - Could Insoles Offload Pressure? An Evaluation of the Effects of Arch-supported Functional Insoles on Plantar Pressure Distribution during Race Walking. AB - This study investigated the effectiveness of functional insoles on plantar pressure distribution during race walking so as to reduce the high plantar pressure and force on race walkers, who tend to suffer from overuse injury. A total of 20 male race walkers aged 21.19 +/- 3.66 years and with a mean height of 178.85 +/- 14.07 cm were recruited as participants. Each participant completed a race walking with functional or normal insoles. Plantar pressure insoles were used to collect vertical plantar pressure data. A two-way analysis of variance with a mixed design was used to determine the difference between the two conditions. Results showed that the use of functional insoles reduces the peak pressure and the impulse in the metatarsophalangeal joints and heels and thus suggest that functional insoles reduce the overuse injury risks of these parts. The first ground reaction force peak also decreased. This result suggested that functional insoles reduce the risks of foot and leg injuries. PMID- 26061908 TI - Macrophage autophagy protects against liver fibrosis in mice. AB - Autophagy is a lysosomal degradation pathway of cellular components that displays antiinflammatory properties in macrophages. Macrophages are critically involved in chronic liver injury by releasing mediators that promote hepatocyte apoptosis, contribute to inflammatory cell recruitment and activation of hepatic fibrogenic cells. Here, we investigated whether macrophage autophagy may protect against chronic liver injury. Experiments were performed in mice with mutations in the autophagy gene Atg5 in the myeloid lineage (Atg5(fl/fl) LysM-Cre mice, referred to as atg5(-/-)) and their wild-type (Atg5(fl/fl), referred to as WT) littermates. Liver fibrosis was induced by repeated intraperitoneal injection of carbon tetrachloride. In vitro studies were performed in cultures or co-cultures of peritoneal macrophages with hepatic myofibroblasts. As compared to WT littermates, atg5(-/-) mice exposed to chronic carbon tetrachloride administration displayed higher hepatic levels of IL1A and IL1B and enhanced inflammatory cell recruitment associated with exacerbated liver injury. In addition, atg5(-/-) mice were more susceptible to liver fibrosis, as shown by enhanced matrix and fibrogenic cell accumulation. Macrophages from atg5(-/-) mice secreted higher levels of reactive oxygen species (ROS)-induced IL1A and IL1B. Moreover, hepatic myofibroblasts exposed to the conditioned medium of macrophages from atg5(-/-) mice showed increased profibrogenic gene expression; this effect was blunted when neutralizing IL1A and IL1B in the conditioned medium of atg5(-/ ) macrophages. Finally, administration of recombinant IL1RN (interleukin 1 receptor antagonist) to carbon tetrachloride-exposed atg5(-/-) mice blunted liver injury and fibrosis, identifying IL1A/B as central mediators in the deleterious effects of macrophage autophagy invalidation. These results uncover macrophage autophagy as a novel antiinflammatory pathway regulating liver fibrosis. PMID- 26061910 TI - Effectiveness of drug treatment strategies to prevent asthma exacerbations and increase symptom-free days in asthmatic children: a network meta-analysis. AB - OBJECTIVE: To determine the effectiveness and safety of current maintenance therapies that include inhaled corticosteroids (ICS), long-acting beta-agonists (LABA) and/or leukotriene receptor antagonists (LTRAs) in preventing exacerbations and improving symptoms in pediatric asthma. METHODS: A systematic review with network meta-analysis was conducted after a comprehensive search for relevant studies in the PubMed, Cochrane Library, Embase and Clinical Trials databases, up to July 2014. Randomized clinical trials were selected comparing treatment strategies of the Global Initiative for Asthma guidelines. The full text randomized clinical trials compared maintenance treatments for asthma in children (<=18 years) of >=4 weeks duration, reporting exacerbations or symptom free days. The primary and secondary effectiveness outcomes were the rates of moderate/severe exacerbations and symptom-free days from baseline, respectively. Withdrawal rates were taken as the safety outcome. RESULTS: Included in the network meta-analysis was 35 trials, comprising 12,010 patients. For both primary and secondary outcomes, combined ICS and LABA was ranked first in effectiveness (OR 0.70, 95% CI: 0.52-0.97 and OR 1.23, 95% CI: 0.94-1.61, respectively, compared with low-dose ICS), but the result of secondary outcomes was statistically insignificant. Low-dose ICS, medium- or high-dose ICS and combined ICS and LTRA strategies were comparable in effectiveness. ICS monotherapies, and ICS + LABA and ICS + LTRA strategies were similarly safe. High-dose ICS had the highest rate of total withdrawals, but the difference was not significant. CONCLUSIONS: Combined ICS and LABA treatments were most effective in preventing exacerbations among pediatric asthma patients. Medium- or high-dose ICS, combined ICS and LTRAs, and low-dose ICS treatments seem to be equally effective. PMID- 26061911 TI - HIV Replication in LEGO Mosaic. PMID- 26061913 TI - PPARgamma Agonists Attenuate Palmitate-Induced ER Stress through Up-Regulation of SCD-1 in Macrophages. AB - BACKGROUND: Clinical trials have shown that treatment of patients with type 2 diabetes with pioglitazone, a peroxisome proliferator-activated receptor (PPAR)gamma agonist, reduces cardiovascular events. However, the effect of PPARgamma agonists on endoplasmic reticulum (ER) stress that plays an important role in the progression of atherosclerosis has not been determined. We sought to determine the effect of PPARgamma agonists on ER stress induced by palmitate, the most abundant saturated fatty acid in the serum. METHODS AND RESULTS: Protein expression of ER stress marker was evaluated by Western blot analysis and stearoyl-CoA desaturase1 (SCD-1) mRNA expression was evaluated by qRT-PCR. Macrophage apoptosis was detected by flowcytometry. Pioglitazone and rosiglitazone reduced palmitate-induced phosphorylation of PERK, a marker of ER stress, in RAW264.7, a murine macrophage cell line. Pioglitazone also suppressed palmitate-induced apoptosis in association with inhibition of CHOP expression, JNK phosphorylation and cleavage of caspase-3. These effects of pioglitazone were reversed by GW9662, a PPARgamma antagonist, indicating that PPARgamma is involved in this process. PPARgamma agonists increased expression of SCD-1 that introduces a double bond on the acyl chain of long-chain fatty acid. 4-(2-Chlorophenoxy)-N (3-(3-methylcarbamoyl)phenyl)piperidine-1-carboxamide, an inhibitor of SCD-1, abolished the anti-ER stress and anti-apoptotic effects of pioglitazone. These results suggest that PPARgamma agonists attenuate palmitate-induced ER stress and apoptosis through SCD-1 induction. Up-regulation of SCD-1 may contribute to the reduction of cardiovascular events by treatment with PPARgamma agonists. PMID- 26061915 TI - Mechanistic Insight into the Stability of HfO2 -Coated MoS2 Nanosheet Anodes for Sodium Ion Batteries. AB - It is demonstrated for the first time that surface passivation of 2D nanosheets of MoS2 by an ultrathin and uniform layer of HfO2 can significantly improve the cyclic performance of sodium ion batteries. After 50 charge/discharge cycles, bare MoS2 and HfO2 coated MoS2 electrodes deliver the specific capacity of 435 and 636 mAh g(-1) , respectively, at current density of 100 mA g(-1) . These results imply that batteries using HfO2 coated MoS2 anodes retain 91% of the initial capacity; in contrast, bare MoS2 anodes retain only 63%. Also, HfO2 coated MoS2 anodes show one of the highest reported capacity values for MoS2 . Cyclic voltammetry and X-ray photoelectron spectroscopy results suggest that HfO2 does not take part in electrochemical reaction. The mechanism of capacity retention with HfO2 coating is explained by ex situ transmission electron microscope imaging and electrical impedance spectroscopy. It is illustrated that HfO2 acts as a passivation layer at the anode/electrolyte interface and prevents structural degradation during charge/discharge process. Moreover, the amorphous nature of HfO2 allows facile diffusion of Na ions. These results clearly show the potential of HfO2 coated MoS2 anodes, which performance is significantly higher than previous reports where bulk MoS2 or composites of MoS2 with carbonaceous materials are used. PMID- 26061917 TI - In response to the letter by Carron et al. concerning the case report by Unterbuchner et al. PMID- 26061916 TI - Gold-Catalyzed Reactions via Cyclopropyl Gold Carbene-like Intermediates. AB - Cycloisomerizations of 1,n-enynes catalyzed by gold(I) proceed via electrophilic species with a highly distorted cyclopropyl gold(I) carbene-like structure, which can react with different nucleophiles to form a wide variety of products by attack at the cyclopropane or the carbene carbons. Particularly important are reactions in which the gold(I) carbene reacts with alkenes to form cyclopropanes either intra- or intermolecularly. In the absence of nucleophiles, 1,n-enynes lead to a variety of cycloisomerized products including those resulting from skeletal rearrangements. Reactions proceeding through cyclopropyl gold(I) carbene like intermediates are ideally suited for the bioinspired synthesis of terpenoid natural products by the selective activation of the alkyne in highly functionalized enynes or polyenynes. PMID- 26061918 TI - Newborn Screening in India. PMID- 26061919 TI - Necessity of Systematic HIV Disclosure in HIV-infected Families: Committed Communities Development Trusts Approach and Intervention. AB - Due to greater access to antiretroviral therapy, telling adolescents that they are HIV-infected and/or affected has become an integral and intricate part of the treatment protocol. Despite growing treatment resources from public and private sectors, there is a lack of systematic disclosure for children and adolescents affected and living with HIV/AIDS. Committed Communities Development Trust, a non government organization working with children and adults infected with and/or affected by HIV, conducted a mixed-methods, cross-sectional study with 33 families in their home-based care program to evaluate their current disclosure protocol. The findings indicate that these experiences implementing and fine tuning this protocol provide useful lessons for other Indian non-government organizations working with HIV-positive families. PMID- 26061914 TI - Risk factors for lung function decline in a large cohort of young cystic fibrosis patients. AB - OBJECTIVE: To identify novel risk factors and corroborate previously identified risk factors for mean annual decline in FEV1% predicted in a large, contemporary, United States cohort of young cystic fibrosis (CF) patients. METHODS: Retrospective observational study of participants in the EPIC Observational Study, who were Pseudomonas-negative and <=12 years of age at enrollment in 2004 2006. The associations between potential demographic, clinical, and environmental risk factors evaluated during the baseline year and subsequent mean annual decline in FEV1 percent predicted were evaluated using generalized estimating equations. RESULTS: The 946 participants in the current analysis were followed for a mean of 6.2 (SD 1.3) years. Mean annual decline in FEV1% predicted was 1.01% (95%CI 0.85-1.17%). Children with one or no F508del mutations had a significantly smaller annual decline in FEV1 compared to F508del homozygotes. In a multivariable model, risk factors during the baseline year associated with a larger subsequent mean annual lung function decline included female gender, frequent or productive cough, low BMI (<66th percentile, median in the cohort), >=1 pulmonary exacerbation, high FEV1 (>=115% predicted, in the top quartile), and respiratory culture positive for methicillin-sensitive Staphylococcus aureus, methicillin-resistant S. aureus, or Stenotrophomonas maltophilia. CONCLUSIONS: We have identified a range of risk factors for FEV1 decline in a large cohort of young, CF patients who were Pa negative at enrollment, including novel as well as previously identified characteristics. These results could inform the design of a clinical trial in which rate of FEV1 decline is the primary endpoint and identify high-risk groups that may benefit from closer monitoring. PMID- 26061920 TI - Nutritional Status and Induction Chemotherapy for Acute Lymphoblastic Leukemia. PMID- 26061921 TI - Vitamin B12 and Folic Acid: Significance in Human Health. PMID- 26061922 TI - Hand Washing Practices in Neonatal Intensive Care Units. PMID- 26061923 TI - Effect of Pre-treatment Nutritional Status, Folate and Vitamin B12 Levels on Induction Chemotherapy in Children with Acute Lymphoblastic Leukemia. AB - OBJECTIVE: To evaluate pre-treatment undernutrition, and folate and B12 deficiency in children with acute lymphoblastic leukemia, and their correlation with complications and outcome of induction chemotherapy. DESIGN: Observational study. SETTING: Tertiary care teaching hospital in Northern India. PARTICIPANTS: 50 children with acute lymphoblastic leukemia. PROCEDURE: Children were assessed for nutritional status (Weight for age Z-score, serum albumin, folate and B12) at presentation, and were followed-up during induction for bone marrow response, counts and outcome. Folate and B12 were repeated twice at monthly intervals after induction. Univariate and multivariate analyses were done to determine the association of nutritional parameters with the outcome variables. RESULTS: Baseline undernutrition was observed in 66%, hypo-albuminemia in 32.6%, folate deficiency in 41.3% and B12 deficiency in 36.9% of included children. Significant decline in folate levels was noted on serial assays during chemotherapy (P=0.001). Folate deficient children had higher risk for delayed marrow recovery and counts on day 14 (P=0.007 and P=0.001). Hypoalbuminemia (P=0.04), B12 deficiency (P=0.001) and folate (P=0.03) deficiency were associated with toxic deaths during induction. CONCLUSIONS: Baseline nutritional deficiencies negatively influence the outcome and occurrence of complications during induction chemotherapy in children with acute lymphoblastic leukemia. PMID- 26061924 TI - Human Surfactant Proteins A2 (SP-A2) and B (SP-B) Genes as Determinants of Respiratory Distress Syndrome. AB - OBJECTIVE: To study the relationship between SP-A2 and SP-B gene polymorphisms and respiratory distress syndrome in preterm neonates. DESIGN: Cross-sectional. SETTING: Neonatal intensive care unit and the Molecular Biology unit of the Chemical Pathology Department, Kasr Alainy hospital, Cairo University. PARTICIPANTS: Sixty-five preterm infants with respiratory distress syndrome and 50 controls. The genomic DNA was isolated using DNA extraction kits. SYBR Green based real-time PCR was used to determine the variant genotypes of SP-A2 c.751 G>A and SP-B c.8714 G>C single nucleotide polymorphisms. RESULTS: Homozygosity of SP-A (OR 46, 95% CI 14-151) and SP-B (OR 5.2, 95% CI 2.3-11.4) alleles increased the risk of respiratory distress syndrome. The logistic regression model showed that genotypes SP-A2 (OR 164) and SP-B (OR 18) were directly related to the occurrence of respiratory distress syndrome, whereas gestational age (OR 0.57) and 5-minute Apgar score (OR 0.19) were inversely related to its occurrence. CONCLUSIONS: There is a possible involvement of SP-A2 and SP-B genes polymorphisms in the genetic predisposition to respiratory distress syndrome. PMID- 26061925 TI - Factors Influencing Verbal Intelligence and Spoken Language in Children with Phenylketonuria. AB - OBJECTIVE: To determine verbal intelligence and spoken language of children with phenylketonuria and to study the effect of age at diagnosis and phenylalanine plasma level on these abilities. DESIGN: Cross-sectional. SETTING: Children with phenylketonuria were recruited from pediatric hospitals in 2012. Normal control subjects were recruited from kindergartens in Tehran. PARTICIPANTS: 30 phenylketonuria and 42 control subjects aged 4-6.5 years. Skills were compared between 3 phenylketonuria groups categorized by age at diagnosis/treatment, and between the phenylketonuria and control groups. MAIN OUTCOME MEASURES: Scores on Wechsler Preschool and Primary Scale of Intelligence for verbal and total intelligence, and Test of Language Development-Primary, third edition for spoken language, listening, speaking, semantics, syntax, and organization. RESULTS: The performance of control subjects was significantly better than that of early treated subjects for all composite quotients from Test of Language Development and verbal intelligence (P<0.001). Early-treated subjects scored significantly higher than the two groups of late-treated subjects for spoken language (P=0.01), speaking (P=0.04), syntax (P=0.02), and verbal intelligence (P=0.019). There was a negative correlation between phenylalanine level and verbal intelligence (r= 0.79) in early-treated subjects and between phenylalanine level and spoken language (r=-0.71), organization (r=-0.82) and semantics (r=-0.82) for late treated subjects diagnosed before the age one year. CONCLUSION: The study confirmed that diagnosis of newborns and control of blood phenylalanine concentration improves verbal intelligence and spoken language scores in phenylketonuria subjects. PMID- 26061926 TI - Health Related Quality of Life in Indian Children with Cystic Fibrosis. AB - OBJECTIVE: This study was devised to translate Cystic Fibrosis Questionnaire Revised to Hindi and administer it to Indian children and adolescents diagnosed with cystic fibrosis. DESIGN: Cross-sectional study. SETTING: This study was carried out in cystic fibrosis patients attending Pediatric Chest Clinic of a tertiary-care hospital in Northern India from July 2012 to December 2012. PARTICIPANTS: 45 children (6-13 years) and their parents, and 14 adolescents. Patients with unstable health in the past two weeks were excluded. INTERVENTION: Cystic Fibrosis Questionnaire- Revised translated in Hindi was administered. Clinical evaluation and scoring, throat swab cultures and spirometry were also done during the same visit. MAIN OUTCOME MEASURES: Health Related Quality of Life scores were the primary measures, and clinical scores, swab cultures and spirometry were secondary measures. RESULTS: Cronbachs alpha ranged from 0.020 0.863.The Factor analysis indicated that most test-items correlated more with competing scales than the intended scales. Convergence between self and proxy rating was found to be dependent on the domain. The Cystic Fibrosis Questionnaire Revised scores correlated well with clinical scores (r=0.65,P=0.011), Pseudomonas spp culture data and pulmonary function tests. There was an inverse relation between Health Related Quality of Life scores and age at diagnosis (r= 0.339, P=0.02). CONCLUSIONS: Hindi versions of Cystic Fibrosis Questionnaire- Revised: Child, Adolescent and Parents instruments will act as an important step towards data on Health Related Quality of Life of Indian patients with cystic fibrosis. PMID- 26061927 TI - Video Surveillance Audit of Hand-washing Practices in a Neonatal Intensive Care Unit. AB - OBJECTIVE: To audit hand-washing practices by video-surveillance. METHODS: Six main steps (step 2 to step 7) of World Health Organizations hand hygiene technique with soap and water were used for evaluation. Handwashing was categorized as excellent, acceptable and unacceptable. RESULTS: Of 1081 recordings, 403 (37.3%) were excellent, 521 (48.2%) were acceptable and 157 (14.5%) were unacceptable handwash. Unacceptable handwashing was more prevalent in the night in comparison to daytime (17.5% vs 12.5%). Thirteen people washed their face after washing their hands. CONCLUSIONS: Innovative interventions are required to improve handwashing during night shifts. PMID- 26061928 TI - Competency-based Medical Education, Entrustment and Assessment. AB - The realization that medical graduates are failing to serve the health needs of the society has compelled the medical educationists and regulatory authorities worldwide to review the medical training. A medical curriculum oriented towards developing the key competencies that enable a fresh graduate to be delivering socially responsive health care is seen as a promising step towards alleviating this problem. This calls for a departure from the traditional approach of organizing the curricular components around educational objectives, to a competency-based approach for planning the curriculum. The present article discusses the concept of competency-based medical education in Indian context, the steps in planning and implementing such a curriculum, and the key aspects of assessment for its effective implementation. PMID- 26061929 TI - Intermittent Short Course Rifapentine-Isoniazid Combination for Preventing Tuberculosis in Children: Evidence based Medicine Viewpoint. PMID- 26061933 TI - Congenital Cytomegalovirus Infection in Monozygotic Twins with Twin-to-twin Transfusion Syndrome. AB - BACKGROUND: Symptoms of congenital cytomegalovirus infection remains unclear. CASE CHARACTERISTICS: Extremely low birth weight twins with twin-to-twin transfusion syndrome were infected with cytomegalovirus congenitally. OBSERVATION: The donor showed neuronal impairment, whereas the recipient showed hepatic dysfunction. MESSAGE: Intrauterine hemodynamics may be important in pathophysiology of congenital cytomegalovirus infection. PMID- 26061932 TI - Childhood Hepatosplenic T-cell Lymphoma with Skin Involvement. AB - BACKGROUND: Hepatosplenic T-cell lymphoma is a rare malignancy in childhood. CASE CHARACTERISTICS: A 12-year-old boy who presented a pyrexia of unknown origin, multiple skin and lesions and marked hepatosplenomegaly. OBSERVATION: Bone marrow aspirate cytology showed no blast cells. Splenectomy was done, and spleen showed infiltration with atypical lymphoid cells positive for CD3, CD8 and T-cell restricted intracellular antigen. OUTCOME: The skin rash of patient subsided with chemotherapy. MESSAGE: Skin involvement may be an unusual clinical manifestation of hepatosplenic T-cell lymphoma. PMID- 26061934 TI - Personality Traits Influencing Effective Communication in Clinical Practice. PMID- 26061935 TI - Congenital Hypothyroidism Screening with Umbilical Cord Blood: Retrospective Analysis. AB - Incidence of congenital hypothyroidism varies across countries and different geographic regions. A retrospective analysis of cord blood thyroid stimulating hormone values, and their subsequent follow-up, was done in a tertiary-care center in Kerala, India. Congenital hypothyroidism was found at the rate of 1 in 244, which is higher than reported incidence from other centers. PMID- 26061936 TI - Iodine Status among School Children of remote Hilly regions of Nepal. AB - A cross-sectional study was conducted in remote hilly areas (Shree Antu and Ranke) of eastern Nepal to assess iodine status among school children aged 6-12 years. Urinary iodine excretion was estimated in 292 urine samples. The median urinary iodine excretion was 187.52 ug/L, and 33.6% children have insufficient urinary iodine excretion. PMID- 26061937 TI - Performance Appraisal of Anganwadi Workers. PMID- 26061938 TI - Tetrasomy X in a Child with Upper Limb Deformity. PMID- 26061939 TI - Aneurysm of Right Branch of Portal Vein in a Child. PMID- 26061940 TI - The False Positivity of Positron Emission Tomography Owing to Teething. PMID- 26061941 TI - What is Ideal Maintenance Intravenous Fluid in Children? PMID- 26061942 TI - Ideal Maintenance Intravenous Fluid in Children: Authors Reply. PMID- 26061943 TI - Recurrence of Kawasaki Disease: Look Before you Leap on the Bandwagon. PMID- 26061944 TI - Recurrence of Kawasaki Disease: Authors Reply. PMID- 26061945 TI - Guaranteeing the Volume Guarantee Ventilation. PMID- 26061946 TI - Meconium Periorchitis. PMID- 26061947 TI - Retina specific GCAPs in zebrafish acquire functional selectivity in Ca2+-sensing by myristoylation and Mg2+-binding. AB - Zebrafish photoreceptor cells express six guanylate cyclase-activating proteins (zGCAPs) that share a high degree of amino acid sequence homology, but differ in Ca(2+)-binding properties, Ca(2+)-sensitive target regulation and spatial temporal expression profiles. We here study a general problem in cellular Ca(2+) sensing, namely how similar Ca(2+)-binding proteins achieve functional selectivity to control finely adjusted cellular responses. We investigated two parameters of critical importance for the trigger and switch function of guanylate cyclase-activating proteins: the myristoylation status and the occupation of Ca(2+)-binding sites with Mg(2+). All zGCAPs can be myristoylated in living cells using click chemistry. Myristoylation does not facilitate membrane binding of zGCAPs, but it significantly modified the regulatory properties of zGCAP2 and zGCAP5. We further determined for all zGCAPs at least two binding sites exhibiting high affinities for Ca(2+) with KD values in the submicromolar range, whereas for other zGCAPs (except zGCAP3) the affinity of the third binding site was in the micromolar range. Mg(2+) either occupied the low affinity Ca(2+)-binding site or it shifted the affinities for Ca(2+)-binding. Hydrodynamic properties of zGCAPs are more influenced by Ca(2+) than by Mg(2+), although to a different extent for each zGCAP. Posttranslational modification and competing ion-binding can tailor the properties of similar Ca(2+)-sensors. PMID- 26061948 TI - Fluorescence imaging for a noninvasive in vivo toxicity-test using a transgenic silkworm expressing green fluorescent protein. AB - In drug development, the toxicity of candidate chemicals must be carefully examined in an animal model. Here we developed a live imaging technique using silkworms for a noninvasive toxicity test applicable for drug screening. Injection of carbon tetrachloride, a tissue-injuring chemical, into transgenic silkworms expressing green fluorescent protein (GFP) induced leakage of GFP from the tissues into the hemolymph. The leakage of GFP was suppressed by pre administration of either cimetidine, a cytochrome P450 inhibitor, or N-acetyl cysteine, a free-radical scavenger. The transgenic silkworm was made transparent by feeding a diet containing chemicals that inhibit uric acid deposition in the epithelial cells. In the transparent silkworms, GFP fluorescence in the fat body could be observed from outside the body. Injection of salicylic acid or iron sulfate, tissue-injuring chemicals, into the transparent silkworms decreased the fluorescence intensity of the GFP in the fat body. These findings suggest that the transparent GFP-expressing silkworm model is useful for evaluating the toxicity of chemicals that induce tissue injury. PMID- 26061951 TI - Moritz Kaposi. PMID- 26061952 TI - Jonathan Hutchinson--The Eponyms Physician. PMID- 26061953 TI - True Colors. PMID- 26061954 TI - Archeological Sites and Dermatologic Medications: More Similar Than One May Think. PMID- 26061955 TI - Hippocrates' Contributions to Dermatology Revealed. PMID- 26061956 TI - Missing Middle Initial in Author's Name. PMID- 26061957 TI - Incorrect Figure. PMID- 26061958 TI - Error in Byline. PMID- 26061959 TI - Error in Text. PMID- 26061960 TI - JAMA Dermatology Patient Page. Granuloma Annulare. PMID- 26061961 TI - Animal personality in a foundation species drives community divergence and collapse in the wild. AB - Despite thousands of papers on the topic, precious few of the studies on animal personality have considered the role of personality in shaping community-level processes. Here, we test the effect of individual variation on the long-term trajectories of biological communities, from initiation to their demise. The spider Anelosimus studiosus builds webs that serve as habitat for >50 species of spider, which together construct a species-rich silken reef. This species also exhibits a temporally consistent behavioural polymorphism where females exhibit either an aggressive or docile phenotype (personality). In this study, we established incipient colonies of either two docile or two aggressive females and then tracked community succession and persistence over 7 years in the field. In particular, we noted the community compositions associated with colony extinction/collapse events, which are common in this species. The community composition of webs founded by different phenotypes diverged rapidly in their early successional stages. However, this period of divergence was ephemeral and all communities eventually converged on a similar composition; communities founded by aggressive females merely took longer to reach it. This secondary stage of community convergence was itself short-lived and independent of founders' personality; all communities collapsed within a year of achieving it. Experimentally imposing this fatal climax composition on colonies caused 80% of communities to collapse within a year, suggesting that this climax composition actually causes the collapse of the community. Community collapse was characterized by a complete die-off of the foundation species and the dispersal of all other spiders. Thus, the behavioural traits of the founding, foundational individuals of these communities dictate their path of succession and longevity in the wild. PMID- 26061963 TI - Steinernema jeffreyense n. sp. (Rhabditida: Steinernematidae), a new entomopathogenic nematode from South Africa - ERRATUM. PMID- 26061965 TI - Bis(chalcogenones) as pincer ligands: isolation and Heck activity of the selone ligated unsymmetrical C,C,Se-Pd pincer complex. AB - The reaction of meta-phenylene-bis(1-methyl-1H-imidazole-2(3H)-selone) with [Pd2(MU-Cl)2(2-C6H4CH2NMe2)2] in dry benzene and glacial acetic acid resulted in the formation of an unsymmetrical 5,6-membered C,C,Se-Pd(II) pincer complex through C-H bond activation and extrusion of one selenium. This is the first example of a C,C,Se-Pd(II) complex wherein the central Pd(II) is simultaneously coordinated to a selone and an N-heterocyclic carbene. The chelated complex of the type [PdL2](2+)2[PF6](-) (L = bis(selone)) was isolated from the reaction of the bis(selone) with [PdCl2(PhCN)2] and NH4PF6. The unsymmetrical pincer complex was studied for Heck activity revealing its application as an acceptable catalyst in coupling of iodobenzene with acrylates and styrene. PMID- 26061962 TI - High-Throughput Sequencing Reveals Hypothalamic MicroRNAs as Novel Partners Involved in Timing the Rapid Development of Chicken (Gallus gallus) Gonads. AB - Onset of the rapid gonad growth is a milestone in sexual development that comprises many genes and regulatory factors. The observations in model organisms and mammals including humans have shown a potential link between miRNAs and development timing. To determine whether miRNAs play roles in this process in the chicken (Gallus gallus), the Solexa deep sequencing was performed to analyze the profiles of miRNA expression in the hypothalamus of hens from two different pubertal stages, before onset of the rapid gonad development (BO) and after onset of the rapid gonad development (AO). 374 conserved and 46 novel miRNAs were identified as hypothalamus-expressed miRNAs in the chicken. 144 conserved miRNAs were showed to be differentially expressed (reads > 10, P < 0.05) during the transition from BO to AO. Five differentially expressed miRNAs were validated by real-time quantitative RT-PCR (qRT-PCR) method. 2013 putative genes were predicted as the targets of the 15 most differentially expressed miRNAs (fold change > 4.0, P < 0.01). Of these genes, 7 putative circadian clock genes, Per2, Bmal1/2, Clock, Cry1/2, and Star were found to be targeted multiple times by the miRNAs. qRT-PCR revealed the basic transcription levels of these clock genes were much higher (P < 0.01) in AO than in BO. Further functional analysis suggested that these 15 miRNAs play important roles in transcriptional regulation and signal transduction pathways. The results provide new insights into miRNAs functions in timing the rapid development of chicken gonads. Considering the characteristics of miRNA functional conservation, the results will contribute to the research on puberty onset in humans. PMID- 26061966 TI - Converging evidence does not support GIT1 as an ADHD risk gene. AB - Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N = 19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N = 225), and (3) the Brain Imaging Genetics cohort (BIG, N = 1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences. (c) 2015 Wiley Periodicals, Inc. PMID- 26061967 TI - Structural characterization of AtmS13, a putative sugar aminotransferase involved in indolocarbazole AT2433 aminopentose biosynthesis. AB - AT2433 from Actinomadura melliaura is an indolocarbazole antitumor antibiotic structurally distinguished by its unique aminodideoxypentose-containing disaccharide moiety. The corresponding sugar nucleotide-based biosynthetic pathway for this unusual sugar derives from comparative genomics where AtmS13 has been suggested as the contributing sugar aminotransferase (SAT). Determination of the AtmS13 X-ray structure at 1.50-A resolution reveals it as a member of the aspartate aminotransferase fold type I (AAT-I). Structural comparisons of AtmS13 with homologous SATs that act upon similar substrates implicate potential active site residues that contribute to distinctions in sugar C5 (hexose vs. pentose) and/or sugar C2 (deoxy vs. hydroxyl) substrate specificity. PMID- 26061968 TI - New Variants of Tomato Thymidine Kinase 1 Selected for Increased Sensitivity of E. coli KY895 towards Azidothymidine. AB - Nucleoside analogues (NA) are prodrugs that are phosphorylated by deoxyribonucleoside kinases (dNKs) as the first step towards a compound toxic to the cell. During the last 20 years, research around dNKs has gone into new organisms other than mammals and viruses. Newly discovered dNKs have been tested as enzymes for suicide gene therapy. The tomato thymidine kinase 1 (ToTK1) is a dNK that has been selected for its in vitro kinetic properties and then successfully been tested in vivo for the treatment of malignant glioma. We present the selection of two improved variants of ToTK1 generated by random protein engineering for suicide gene therapy with the NA azidothymidine (AZT).We describe their selection, recombinant production and a subsequent kinetic and biochemical characterization. Their improved performance in killing of E. coli KY895 is accompanied by an increase in specificity for the NA AZT over the natural substrate thymidine as well as a decrease in inhibition by dTTP, the end product of the nucleoside salvage pathway for thymidine. The understanding of the enzymatic properties improving the variants efficacy is instrumental to further develop dNKs for use in suicide gene therapy. PMID- 26061970 TI - Special section: Selected papers from the Fifth International Workshop on Monte Carlo Techniques in Medical Physics. PMID- 26061971 TI - The SpeedCourt: Reliability, Usefulness, and Validity of a New Method to Determine Change-of-Direction Speed. AB - PURPOSE: To determine the reliability, usefulness, and validity of 3 different change-of-direction tests on a SpeedCourt (SC(CODT)) in team-sport players. METHODS: For reliability and usefulness, 30 players (16 female and 14 male; age 19 +/- 3 y, height 169 +/- 30 cm, body mass 70 +/- 11 kg) performed 3 SC(CODT)s differing in duration (7-45 s) on 3 occasions 1 wk apart. The total sprint times (TT) and time to change direction (TCD) were analyzed for each SC(CODT). For validity, 14 players performed the Illinois Agility Test (IAT) and 505 test on a separate occasion. RESULTS: TT for all SC(CODT)s is reliable (ICC > .79, CV < 5%), useful (TE < SWC0.5), and valid (IAT r > .71, P < .05; 505 test r > .54, P < .05). SC(CODT) variable TCD may be useful (TE = SWC0.5) but shows limited reliability with ICC >.65 and a CV >5%. CONCLUSIONS: All SC(CODT)s are reliable, useful, and valid to detect moderate performance changes regarding TT, with limited reliability for TCD. The quality of assessment improves when players are well familiarized with the SC(CODT). PMID- 26061969 TI - Constructing lncRNA functional similarity network based on lncRNA-disease associations and disease semantic similarity. AB - Increasing evidence has indicated that plenty of lncRNAs play important roles in many critical biological processes. Developing powerful computational models to construct lncRNA functional similarity network based on heterogeneous biological datasets is one of the most important and popular topics in the fields of both lncRNAs and complex diseases. Functional similarity network construction could benefit the model development for both lncRNA function inference and lncRNA disease association identification. However, little effort has been attempted to analysis and calculate lncRNA functional similarity on a large scale. In this study, based on the assumption that functionally similar lncRNAs tend to be associated with similar diseases, we developed two novel lncRNA functional similarity calculation models (LNCSIM). LNCSIM was evaluated by introducing similarity scores into the model of Laplacian Regularized Least Squares for LncRNA-Disease Association (LRLSLDA) for lncRNA-disease association prediction. As a result, new predictive models improved the performance of LRLSLDA in the leave-one-out cross validation of various known lncRNA-disease associations datasets. Furthermore, some of the predictive results for colorectal cancer and lung cancer were verified by independent biological experimental studies. It is anticipated that LNCSIM could be a useful and important biological tool for human disease diagnosis, treatment, and prevention. PMID- 26061972 TI - Working With Patients Living With Obesity in the Intensive Care Unit: A Study of Nurses' Experiences. AB - Increasing numbers of patients living with obesity (PLWO) are admitted to the intensive care unit (ICU). The goal of this qualitative study was to examine the experiences of ICU nurses who work with PLWO using the Othering framework developed by Canales in 2010. The first theme describes how PLWO become "Others" in the ICU. The second theme focuses on exclusionary Othering and how it manifests itself in the way PLWO are cared for and viewed. The third theme sheds light on inclusionary Othering in the form of strategies that are used by nurses to engage with PLWO. The last theme takes a closer look at the ICU environment and how resources impact the experiences of nurses working with PLWO. PMID- 26061973 TI - Bridging the transport pathway of charge carriers in a Ta3N5 nanotube array photoanode for solar water splitting. AB - This paper describes an approach to synthesize a tightly adhered Ta3N5 nanotube array (NTA) photoanode with enhanced electron conductivity between the Ta3N5 layer and the substrate via a two-step anodization method. The obtained tightly adhered Ta3N5 NTA photoanode exhibits excellent photoelectrochemical properties with an optimal photocurrent up to 5.3 mA cm(-2) at 1.6 V vs. the reversible hydrogen electrode. This approach provides an effective strategy to address the adhesion issue of one dimensional semiconductor photoanodes. PMID- 26061975 TI - Correction: CD4 and Viral Load Dynamics in Antiretroviral-Naive HIV-Infected Adults from Soweto, South Africa: A Prospective Cohort. PMID- 26061974 TI - Static and Dynamic Microscopy of the Chemical Stability and Aggregation State of Silver Nanowires in Components of Murine Pulmonary Surfactant. AB - The increase of production volumes of silver nanowires (AgNWs) and of consumer products incorporating them may lead to increased health risks from occupational and public exposures. There is currently limited information about the putative toxicity of AgNWs upon inhalation and incomplete understanding of the properties that control their bioreactivity. The lung lining fluid (LLF), which contains phospholipids and surfactant proteins, represents a first contact site with the respiratory system. In this work, the impact of dipalmitoylphosphatidylcholine (DPPC), Curosurf, and murine LLF on the stability of AgNWs was examined. Both the phospholipid and protein components of the LLF modified the dissolution kinetics of AgNWs, due to the formation of a lipid corona or aggregation of the AgNWs. Moreover, the hydrophilic proteins, but neither the hydrophobic surfactant proteins nor the phospholipids, induced agglomeration of the AgNWs. Finally, the generation of a secondary population of nanosilver was observed and attributed to the reduction of Ag(+) ions by the surface capping of the AgNWs. Our findings highlight that combinations of spatially resolved dynamic and static techniques are required to develop a holistic understanding of which parameters govern AgNW behavior at the point of exposure and to accurately predict their risks on human health and the environment. PMID- 26061976 TI - Emotion regulation of the affect-modulated startle reflex during different picture categories. AB - Previous studies on emotion regulation of the startle reflex found an increase in startle amplitude from down-, to non-, to up-regulation for pleasant and unpleasant stimuli. We wanted to clarify whether this regulation effect remains stable for different picture categories within pleasant and unpleasant picture sets. We assessed startle amplitude of 31 participants during down-, non-, or up regulation of feelings elicited by pleasant erotic and adventure and unpleasant victim and threat pictures. Startle amplitude was smaller during adventure and erotic compared to victim and threat pictures and increased from down-, to non-, to up-regulation independently of the picture category. Results indicate that the motivational priming effect on startle modulation elicited by different picture categories is independent of emotion regulation instructions. In addition, the emotion regulation effect is independent of motivational priming effects. PMID- 26061977 TI - Comparing the National Surgical Quality Improvement Program With the Nationwide Inpatient Sample Database. PMID- 26061978 TI - The Oligopoly of Academic Publishers in the Digital Era. AB - The consolidation of the scientific publishing industry has been the topic of much debate within and outside the scientific community, especially in relation to major publishers' high profit margins. However, the share of scientific output published in the journals of these major publishers, as well as its evolution over time and across various disciplines, has not yet been analyzed. This paper provides such analysis, based on 45 million documents indexed in the Web of Science over the period 1973-2013. It shows that in both natural and medical sciences (NMS) and social sciences and humanities (SSH), Reed-Elsevier, Wiley Blackwell, Springer, and Taylor & Francis increased their share of the published output, especially since the advent of the digital era (mid-1990s). Combined, the top five most prolific publishers account for more than 50% of all papers published in 2013. Disciplines of the social sciences have the highest level of concentration (70% of papers from the top five publishers), while the humanities have remained relatively independent (20% from top five publishers). NMS disciplines are in between, mainly because of the strength of their scientific societies, such as the ACS in chemistry or APS in physics. The paper also examines the migration of journals between small and big publishing houses and explores the effect of publisher change on citation impact. It concludes with a discussion on the economics of scholarly publishing. PMID- 26061979 TI - Enhanced Shubnikov-De Haas Oscillation in Nitrogen-Doped Graphene. AB - N-doped graphene displays many interesting properties compared with pristine graphene, which makes it a potential candidate in many applications. Here, we report that the Shubnikov-de Haas (SdH) oscillation effect in graphene can be enhanced by N-doping. We show that the amplitude of the SdH oscillation increases with N-doping and reaches around 5k Omega under a field of 14 T at 10 K for highly N-doped graphene, which is over 1 order of magnitude larger than the value found for pristine graphene devices with the same geometry. Moreover, in contrast to the well-established standard Lifshitz-Kosevich theory, the amplitude of the SdH oscillation decreases linearly with increasing temperature and persists up to a temperature of 150 K. Our results also show that the magnetoresistance (MR) in N-doped graphene increases with increasing temperature. Our results may be useful for the application of N-doped graphene in magnetic devices. PMID- 26061980 TI - Synthesis and application of boronic acid-functionalized magnetic adsorbent for sensitive analysis of salbutamol residues in pig tissues. AB - Salbutamol (SAL) is the most widely used beta2 -agonist drug for asthma and chronic obstructive pulmonary patients, but it is also often abused as feed additive. In recent years, the abuse of SAL has led to a large number of food safety incidents. Therefore, the monitoring of SAL residues in animal products is very important. A highly selective boronate affinity magnetic adsorbent was synthesized and developed for detection of trace levels of SAL residues in pig tissue samples. The obtained Fe3O4@SiO2@FPBA(4-formylphenylboronic acid) magnetic adsorbent showed good adsorption ability to catechol and SAL, and then it was successfully applied as special magnetic solid-phase phase extraction adsorbent coupled with high-performance liquid chromatography (HPLC) for simultaneous isolation and determination of cis-diol compounds. The binding capacity of catechol and SAL reached 96 and 50 umol/g, respectively. The method was successfully established for the detection of trace levels of SAL in pig tissue samples. The linear range extended from 0.32 to 800 ug/kg (R(2) = 0.9994). The limit of detection of SAL was 0.19 ug/kg. The recoveries were satisfactory (89.5 108.0%) at three spiked levels with RSD between 2.1 and 11.3%. These results indicated that the method has potential for enrichment and detection of trace levels of SAL residual in animal food products. PMID- 26061981 TI - Predicting changes in mandibular length and total anterior facial height using IGF-1, cervical stage, skeletal classification, and gender. AB - BACKGROUND: The purpose of this study was to predict the annual growth rate of the mandible and total anterior facial height using IGF-1 levels together with cervical stage, skeletal classification, and gender. METHODS: Twenty-five orthodontic patients (12 females and 13 males) had their cervical stages, blood spot IGF-1 levels, and cephalometric parameters measured at 1-year intervals. The number of years each patient was followed up varied between 1 and 5 years resulting in 43 12-month intervals collected from 77 observations. Descriptive, bivariate, and regression analyses were used to analyze this data. RESULTS: The linear regression model for predicting the annual mandibular growth rate was significant at p < 0.01 with an R-square value of 0.52. We found that the average IGF-1 level for the interval, the change in IGF-1 level, and the presence of a skeletal class III pattern were statistically significant predictors of mandibular growth. The regression model for predicting the annual change in anterior facial height was significant at p < 0.01 with an R-square value of 0.42. We found that the change in IGF-1 level was the only statistically significant predictor of this outcome. CONCLUSIONS: The proposed method which combines IGF-1 levels with information that is readily available to clinicians can be used to predict the timing and intensity of the growth spurt. These factors together explain more of the observed individual variation in growth rate than any of the factors used in isolation. PMID- 26061982 TI - Sagittal lip positions in different skeletal malocclusions: a cephalometric analysis. AB - BACKGROUND: The objectives of this paper are to (1) study use of soft tissue analyses advocated by Steiner, Ricketts, Burstone, Sushner and Holdway to develop soft tissue cephalometric norms as baseline data for sagittal lip position in Northeast Chinese adult population, (2) compare the sagittal lip positions in different skeletal malocclusions and (3) compare the sagittal lip positions in Northeast Chinese adults with other reported populations. METHODS: Lateral cephalometric radiographs of subjects were taken in natural head position. Radiographs were manually traced and five reference lines - Sushner, Steiner, Burstone, Holdway and Ricketts, were used. The linear distance between the tip of the lips and the five reference lines were measured. Statistical analysis was done using the Statistical Package for Social Sciences (SPSS) 21. Descriptive analysis was done for each variable for each subject. Coefficient of variation between lip positions as assessed by reference lines was determined. Post hoc Tukey's test was used for comparison of the mean cephalometric values of three skeletal malocclusions. The level of significance for the analysis was set at p < 0.05. RESULTS: The findings showed significant difference in the sagittal lip positions in different skeletal malocclusions. There was variation in consistent reference line in each skeletal malocclusion. The S2 line was the most consistent reference line in skeletal class I and class II group. The B line was the most consistent line in skeletal class III. In skeletal class II group, upper lips were the most protrusive and lower lips were retrusive than in skeletal class I and class III groups. In case of skeletal class III group, upper lips were retrusive and lower lips were more protrusive than in skeletal class I and class II groups. CONCLUSIONS: The sagittal lip positions were found to be associated with the skeletal malocclusion pattern. Northeast Chinese population has protrusive upper and lower lip in comparison to Caucasians. Each skeletal malocclusion group showed different preferable reference lines for analysis of sagittal lip position. PMID- 26061983 TI - Psychological impact of visible differences in patients with congenital craniofacial anomalies. AB - BACKGROUND: Patients with craniofacial anomalies often have appearance concerns and related social anxiety which can affect their quality of life. This study assessed the psychological impact of facial and dental appearance in patients with craniofacial anomalies in comparison to a general population control group. METHODS: The study involved 102 adult patients (51% male) with congenital craniofacial anomalies and 102 controls (49% male). Both groups completed the Nepali version of Derriford Appearance Scale (DAS) and the Psychological Impact of Dental Aesthetic Questionnaire (PIDAQ) in a clinical setting to assess appearance-related distress, avoidance, and anxiety. RESULTS: There was a significant difference between patients and controls on both PIDAQ (mean score for patients 33.25 +/- 9.45 while for controls 27.52 +/- 5.67, p < 0.001) and DAS59 scores (mean score for patients 159.16 +/- 31.54 while for controls 77.64 +/- 6.57, p < 0.001), indicating that patients experienced greater negative psychological impact of living with their appearance (PIDAQ) and more appearance related distress (DAS) than controls. DAS scores were not associated with gender. There was no association of the place of residence (rural vs. urban) with PIDAQ or DAS59 scores. CONCLUSIONS: There is a significant psychological impact of altered facial and dental appearance in patients with craniofacial anomalies compared to controls. There was no effect of locality (rural/urban) on the psychological impact of facial and dental appearance in patients. PMID- 26061984 TI - Association between tooth size and interarch relationships in children with operated complete unilateral cleft lip and palate. AB - BACKGROUND: To evaluate mesiodistal tooth width of patients with UCLP comparing tooth size in different Goslon Yardstick scores and between cleft and noncleft sides. METHODS: The Department of Orthodontics at Bauru Dental School and Hospital of Rehabilitation of Craniofacial Anomalies - University of Sao Paulo. Hundred forty-four pairs of dental casts of patients with UCLP. These dental casts were divided into 3 groups: group I (patients with Goslon rating of 1 and 2), group II (Goslon rating of 3) and group III (Goslon rating of 4 and 5). The control group consisted of 40 pairs of dental casts of noncleft Class I patients at the same age range. Mesiodistal width of maxillary permanent central incisors, lateral incisors and first molars were measured using a digital caliper. Intergroup comparisons were performed using ANOVA followed by Tukey tests. T tests were used to compare tooth size between cleft and noncleft sides (p <0.05). RESULTS: Differences for tooth size were observed between individuals with different Goslon Yardstik scores. Mesiodistal widths of maxillary central incisors in subjects of Group III were significantly smaller compared to Group I and to the control group. The lateral incisors at the cleft side were smaller than the antimere. CONCLUSIONS: Mesiodistal tooth size was smaller in poor Goslon yardstick scores. Cleft and noncleft sides demonstrated similar maxillary tooth size except for the lateral incisor. PMID- 26061985 TI - In vitro study of the potential protection of sound enamel against demineralization. AB - BACKGROUND: The objective of this study was to study the potential protection effect of different treatments against sound enamel demineralization around orthodontic brackets. METHODS: This is an in vitro randomized controlled study; artificial enamel demineralization of human premolars was created and compared with reference to control. The three materials used for enamel treatment were resin infiltrate (ICON), fluoridated varnish (Clinpro), and the self-etch primer system (Transbond Plus Self-Etch Primer). Fifty premolars divided equally into five groups were included in the study for quantitative surface micro-hardness assessment using a micro-hardness tester (MHT). Qualitative assessment of the enamel demineralization with a polarized light microscope (PLM) was also used. Enamel was demineralized by subjecting the specimens to cycling between artificial saliva solution and a demineralizing solution for 21 days. RESULTS: The mean Vickers hardness in kgf/mm(2) was as follows: intact enamel = 352.5 +/- 13.8, demineralized enamel = 301.6 +/- 34.0, enamel treated with Clinpro = 333.6 +/- 18.0, enamel treated with SEP = 370.7 +/- 38.8, and enamel treated with ICON = 380.5 +/- 53.8. CONCLUSIONS: ICON, Clinpro, and Transbond Plus Self-Etch Primer (TPSEP) increased enamel resistance to demineralization. Attempting to protect the enamel around the orthodontic brackets could be done by applying a preventive material before bonding, if not compromising the bond strength, the orthodontic brackets. PMID- 26061986 TI - An evaluation of two types of nickel-titanium wires in terms of micromorphology and nickel ions' release following oral environment exposure. AB - BACKGROUND: This study aimed to compare superelastic and heat-activated nickel titanium orthodontic wires' surface morphology and potential release of nickel ions following exposure to oral environment conditions. METHODS: Twenty-four 20 mm-length distal cuts of superelastic (NiTi Force I(r)) and 24 20-mm-length distal cuts of heat-activated (Therma-Ti Lite(r)) nickel-titanium wires (American Orthodontics, Sheboygan, WI, USA) were divided into two equal groups: 12 wire segments left unused and 12 segments passively exposed to oral environment for 1 month. Scanning electron microscopy and atomic force microscopy were used to analyze surface morphology of the wires which were then immersed in artificial saliva for 1 month to determine potential nickel ions' release by means of atomic absorption spectrophotometer. RESULTS: Heat-activated nickel-titanium (NiTi) wires were rougher than superelastic wires, and both types of wires released almost the same amount of Ni ions. After clinical exposure, more surface roughness was recorded for superelastic NiTi wires and heat-activated NiTi wires. However, retrieved superelastic NiTi wires released less Ni ions in artificial saliva after clinical exposure, and the same result was recorded regarding heat activated wires. CONCLUSIONS: Both types of NiTi wires were obviously affected by oral environment conditions; their surface roughness significantly increased while the amount of the released Ni ions significantly declined. PMID- 26061987 TI - The efficacy of maxillary protraction protocols with the micro-implant-assisted rapid palatal expander (MARPE) and the novel N2 mini-implant-a finite element study. AB - BACKGROUND: Maxillary protraction with the novel N2 mini-implant- and micro implant-assisted rapid palatal expander (MARPE) can potentially provide significant skeletal effects without surgery, even in older patients where conventional facemask therapy has limited skeletal effects. However, the skeletal effects of altering the location and direction of force from mini-implant assisted maxillary protraction have not been extensively analyzed. In this study, the application of the novel N2 mini-implant as an orthopedic anchorage device is explored in its ability to treat patients with class III malocclusions. METHODS: A 3D cranial mesh model with associated sutures was developed from CT images and Mimics modeling software. Utilizing ANSYS simulation software, protraction forces were applied at different locations and directions to simulate conventional facemask therapy and seven maxillary protraction protocols utilizing the novel N2 mini-implant. Stress distribution and displacement were analyzed. Video animations and superimpositions were created. RESULTS: By changing the vector of force and location of N2 mini-implant, the maxilla was displaced differentially. Varying degrees of forward, downward, and rotational movements were observed in each case. For brachyfacial patients, anterior micro-implant-supported protraction at -45 degrees or intermaxillary class III elastics at -45 degrees are recommended. For dolicofacial patients, either anterior micro-implants at -15 degrees or an intermaxillary spring at +30 degrees is recommended. For mesofacial patients with favorable vertical maxillary position, palatal micro implants at -30 degrees are recommended; anterior micro-implants at -30 degrees are preferred for shallow bites. For patients with a severe mid-facial deficiency, intermaxillary class III elastics at -30 degrees are most effective in promoting anterior growth of the maxilla. CONCLUSIONS: By varying the location of N2 mini-implants and vector of class III mechanics, clinicians can differentially alter the magnitude of forward, downward, and rotational movement of the maxilla. As a result, treatment protocol can be customized for each unique class III patient. PMID- 26061988 TI - Effect of non-surgical maxillary expansion on the nasal septum deviation: a systematic review. AB - Nasal breathing is a requirement for proper growth and development of the craniofacial complex. Inadequacy of the nasal airway from obstruction such as from nasal septal deviation (NSD) can affect craniofacial development. Further investigation of the possibility of rapid maxillary expansion (RME) correcting NSD would be valuable, considering the undesirable sequelae of NSD on nasal breathing, which can consequently affect craniofacial development. A systematic review of the effect of RME treatment on NSD was conducted. Electronic database searches were conducted until April 2015 using MEDLINE, EMBASE, Web of Science, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CCTR), Cochrane Methodology Register (CMR), Database of Abstracts of Reviews of Effects (DARE), American College of Physicians Journal Club (ACP Journal Club), Health Technology Assessments (HTA), and NHS Economic Evaluation Database (NHSEED). MeSH terms used in database searches were 'nasal septum,' 'palatal expansion,' and 'maxillary expansion,' 'orthodontic device,' and 'palatal expansion technique.' The methodological quality of studies was reviewed using methodological index for non-randomized studies (MINORS). Only two studies were finally selected and reviewed. Both studies had significant methodological limitations. One study reported a significant straightening of the nasal septum in the middle and the inferior third of nasal cavity from RME in children aged 5 to 9 years. The other study reported no positional change in the nasal septum from RME in adolescent orthodontic patients. Thus far, the limited available (moderate risk of bias) evidence suggests a potentially positive effect on the nasal septum asymmetry during childhood, but no significant change in adolescence from RME in patients with NSD. The clinical significance of reported changes could be considered questionable. PMID- 26061989 TI - Computational fluid dynamics analysis of the upper airway after rapid maxillary expansion: a case report. AB - BACKGROUND: Assessment of the upper airway volume, morphology, and mechanics is of great importance for the orthodontic patient. We hypothesize that upper airway dimensions have significant effects on the dynamics of the airway flow and that both the dimensions and mechanics of the upper airway are greatly affected by orthodontic and orthopedic procedures such as rapid maxillary expansion (RME). The aim of the current study was to assess the effect of RME on the airway flow rate and pattern by comparing the fluid dynamics results of pre- and post treatment finite element models. METHODS: Customized pre- and post-treatment computational fluid dynamics models of the patient's upper airway were built for comparison based on three-dimensional computed tomogram. The inhalation process was simulated using a constant volume flow rate for both models, and the wall was set to be rigid and stationary. Laminar and turbulent analyses were applied. RESULTS: Comparisons between before and after RME airway volume measurements showed that increases were only detected in nasal cavity volume, nasopharynx volume, and the most constricted area of the airway. Pressure, velocity, and turbulent kinetic energy decreased after dental expansion for laminar and turbulent flow. Turbulent flow shows relatively larger velocity and pressure than laminar flow. CONCLUSIONS: RME showed positive effects that may help understand the key reasons behind relieving the symptom of breathing disorders in this patient. Turbulence occurs at both nasal and oropharynx areas, and it showed relatively larger pressure and velocity compared to laminar flow. PMID- 26061990 TI - Three-dimensional assessment of teeth first-, second- and third-order position in Caucasian and African subjects with ideal occlusion. AB - BACKGROUND: The aim of this study was to provide an updated version of Andrews' seminal study by exploiting 3D software to analyse the tip, torque and in-out values of two groups of different racial and ethnic background. METHODS: The analysis was conducted on one Caucasian group (30 individuals) and one of African origin (29). All subjects were adult, in normal occlusion and had no previous history of orthodontic treatment. RhinocerosTM 3D modelling software was used to identify anatomical reference points, planes and axes and to make the appropriate measurements. RESULTS: Compared to Andrews' measurements, we found more positive coronal tip values in both African and Caucasian subjects, while the torque values we measured tended to be less negative in the posterior sectors than those reported by Andrews. We measured greater tip values in the lower jaw of Caucasian with respect to African subjects, particularly in the middle sectors. CONCLUSIONS: Race and ethnicity have a strong influence on values of tip, torque and in-out. This is translated as a more positive tip in Caucasian subjects and a more positive torque in those of African descent (greater proclination of the incisors). Finally, with respect to the values reported by Andrews, we found a tendency to more positive mean tip (except for at the upper second molars and lower incisors) and less negative torque in the posterior sectors. PMID- 26061992 TI - Natural Products Useful in Respiratory Disorders: Focus on Side-Effect Neutralizing Combinations. AB - This review summarizes literature related to medicinal plants reputed in traditional medical systems for treatment of asthma and coughs. The plants that are pharmacologically investigated for their effectiveness in such conditions, along with respective experimental protocol details, are also discussed. Some of plant origin compounds, which are considered useful as antitussive and antiasthmatic agents, are described as well. Chrysoeriol, a constituent of Aspalathus linearis (Fabaceae) was observed to be selective for relaxant effect in airways (through K+ channel activation), compared with other smooth muscles. We reported that Hypericum perforatum (Hyperieaceae), Andropogon muricatus (Poaceae), Juniper excelsa (Coniferae) and Nepeta cataria (Lamiaceae) exhibit bronchodilatory action, mediated through combination of Ca++ antagonist and phospohodiesrase inhibitory mechanisms, which scientifically explains their medicinal use in asthma. Hyocyamus niger (Solanaceae), Artemisia vulgaris (Compositae), Fumaria parviflora (Fumariaceae) and Terminalia bellerica (Combretaceae) caused bronchodilation via dual blockade of muscarinic receptors and Ca++ influx. Acorus calamus (Araceae), Carum roxburghianum (Apiaceae), Lens culinaris (Fabaceae) and Lepidium sativum (Cruciferae) mediate bronchodilatation through multiple pathways: anticholinergic and inhibition of Ca++ channels and PDE enzyme(s). In conclusion, this review presents an analysis of different novel combinations of pharmacological activities in medicinal plants with side effect neutralizing/synergistic potential, setting new trends in the therapeutic options for hyperactive respiratory disorders such as asthma and cough. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26061991 TI - Development of a standardized testing system for orthodontic sliding mechanics. AB - BACKGROUND: The primary objective of this study was to develop a computer controlled three-dimensional friction measuring system, the orthodontic friction simulator (OFS). A clinically-based in vitro experiment considering wet and dry friction for conventionally and self-ligated brackets is presented to elucidate debate surrounding sliding mechanics and illustrate capabilities of the OFS. METHODS: The OFS was designed and manufactured using sound engineering principles and with the primary concern of being able to measure all forces and moments generated during sliding mechanics. This required the implementation of a six axis load cell. A variety of translation and rotation stages were also incorporated to allow for precise positioning of the bracket relative to the archwire. Once designed and built, the OFS was then used to compare conventional and self-ligation methods in both the wet and dry state. Damon Q brackets and 0.018" * 0.025" stainless steel wires were used for all tests with a sample size of n = 65 for each ligation method. Archwires were pulled at a speed of 0.1 mm/s in 11 increments of 0.1 mm. At each increment, the bracket would be rotated 0.5 degrees resulting in a total archwire travel of 1.1 mm and a second-order bracket angle range of 0 degrees -5 degrees . A repeated measures ANOVA was conducted to determine if ligation method and/or addition of moisture effected resulting orthodontic loads. RESULTS: The developed equipment for studying orthodontic sliding mechanics was able to measure forces and moments in all three directions; a capability not previously realized in the literature. Additionally, it was found that passive ligation significantly reduced resistance to sliding, P <= 0.05, while the dry/wet state did not. CONCLUSIONS: The OFS certainly proved to be an adequate instrument for the scientific evaluation of orthodontic sliding mechanics. It is capable of measuring loads generated in all directions and is a fully automated apparatus allowing for simple and repeatable friction tests to be conducted. Furthermore, the addition of saliva was not found to significantly influence the loads generated during sliding mechanics regardless of ligation method. PMID- 26061993 TI - Apoptosis induced by farrerol in human gastric cancer SGC-7901 cells through the mitochondrial-mediated pathway. AB - Farrerol, a typical flavanone isolated from the Chinese medicinal plant Rhododendron dauricum L., has been found to show various biological activities. However, to the best of our knowledge, its inhibitory actions against cancer cells have not been reported as yet. Therefore, the present study aimed to investigate the cytotoxic and apoptotic effects of farrerol on human gastric cancer SGC-7901 cells. Farrerol showed a 50% inhibition of SGC-7901 cell growth at a concentration of 40.4 MUmol/l for 24 h according to MTT assays. The cell morphology results indicated that SGC-7901 cells treated with farrerol showed several features of apoptotic cell death, which was also confirmed by the Annexin V FITC/PI double-staining assay. Further studies showed that farrerol treatment induced the attenuation of mitochondrial membrane potential, accompanied by the release of Cyt-c and the activation of caspase-9 and caspase-3. Furthermore, farrerol decreased the gene expression of Bcl-2, whereas the gene expression level of Bax was found to increase after farrerol treatment. These combined results indicated that farrerol can induce apoptosis through a mitochondrial mediated pathway. PMID- 26061994 TI - An intron SNP rs807185 in ATG4A decreases the risk of lung cancer in a southwest Chinese population. AB - Autophagy acts as a double-edged sword in cancer. Over the years, there has been growing evidence of the involvement of autophagy-related genes (ATGs) in the etiology and progression of cancer. Importantly, lung cancer is one of the most common cancers and represents the leading cause of cancer-related mortality in developing countries. The genomic variant has emerged as an important factor in the risk of lung cancer. Here, we hypothesize that the intron single-nucleotide polymorphism (SNP) of rs807185 in ATG4A is associated with the risk of lung cancer. In this case-control study, we genotyped the SNP rs807185 with PCR restriction fragment length polymorphism. Our data suggest that the variant A allele frequency of rs807185 in controls is higher than that in cases (37.7 vs. 24.9%, P=0.006). The adjusted odds ratio is 1.989 (95% confidence interval 1.223 3.236). Compared with the wild T allele, the variant A allele of rs807185 in ATG4A is associated with a decreased risk of lung cancer (adjusted odds ratio=0.605, 95% confidence interval 0.456-0.803, P<0.001). Furthermore, stratified analysis in a recessive model suggests that the homozygous variant genotype (AA) of rs807185 could decrease the risk of lung cancer in smoking or nonsmoking groups. In conclusion, the variant of intron SNP rs807185 in ATG4A is associated significantly with a decreased risk of lung cancer in a southwest Chinese population. The results show that the variant rs807185 of ATG4A might be a protective factor for lung cancer. PMID- 26061995 TI - Synapse-dependent and independent mechanisms of thalamocortical axon branching are regulated by neuronal activity. AB - Axon branching and synapse formation are critical processes for establishing precise circuit connectivity. These processes are tightly regulated by neural activity, but the relationship between them remains largely unclear. We use organotypic coculture preparations to examine the role of synapse formation in the activity-dependent axon branching of thalamocortical (TC) projections. To visualize TC axons and their presynaptic sites, two plasmids encoding DsRed and EGFP-tagged synaptophysin (SYP-EGFP) were cotransfected into a small number of thalamic neurons. Time-lapse imaging of individual TC axons showed that most branches emerged from SYP-EGFP puncta, indicating that synapse formation precedes emergences of axonal branches. We also investigated the effects of neuronal activity on axon branching and synapse formation by manipulating spontaneous firing activity of thalamic cells. An inward rectifying potassium channel, Kir2.1, and a bacterial voltage-gated sodium channel, NaChBac, were used to suppress and promote firing activity, respectively. We found suppressing neural activity reduced both axon branching and synapse formation. In contrast, increasing neural activity promoted only axonal branch formation. Time-lapse imaging of NaChBac-expressing cells further revealed that new branches frequently appeared from the locations other than SYP-EGFP puncta, indicating that enhancing activity promotes axonal branch formation due to an increase of branch emergence at nonsynaptic sites. These results suggest that presynaptic locations are hotspots for branch emergence, and that frequent firing activity can shift branch emergence to a synapse-independent process. PMID- 26061996 TI - A New Synthetic Amphiploid (AADDAA) between Gossypium hirsutum and G. arboreum Lays the Foundation for Transferring Resistances to Verticillium and Drought. AB - Gossypium arboreum, a cultivated cotton species (2n = 26, AA) native to Asia, possesses invaluable characteristics unavailable in the tetraploid cultivated cotton gene pool, such as resistance to pests and diseases and tolerance to abiotic stresses. However, it is quite difficult to transfer favorable traits into Upland cotton through conventional methods due to the cross-incompatibility of G. hirsutum (2n = 52, AADD) and G. arboreum. Here, we improved an embryo rescue technique to overcome the cross-incompatibility between these two parents for transferring favorable genes from G. arboreum into G. hirsutum. Our results indicate that MSB2K supplemented with 0.5 mg l(-1) kinetin and 250 mg(-1) casein hydrolysate is an efficient initial medium for rescuing early (3 d after pollination) hybrid embryos. Eight putative hybrids were successfully obtained, which were further verified and characterized by cytology, molecular markers and morphological analysis. The putative hybrids were subsequently treated with different concentrations of colchicine solution to double their chromosomes. The results demonstrate that four putative hybrid plants were successfully chromosome doubled by treatment with 0.1% colchicine for 24 h and become amphiploid, which were confirmed by cytological observation, self-fertilization and backcrossing. Preliminary assessments of resistance at seedling stage indicate that the synthetic amphiploid showed highly resistant to Verticillium and drought. The synthetic amphiploid between G. hirsutum * G. arboreum would lay the foundation for developing G. arboreum-introgressed lines with the uniform genetic background of G. hirsutum acc TM-1, which would greatly enhance and simplify the mining, isolation, characterization, cloning and use of G. arboreum-specific desirable genes in future cotton breeding programs. PMID- 26061997 TI - The role of systematic reviews of qualitative evidence in evaluating interventions: a case study. AB - Systematic reviews of qualitative evidence have been widely used to provide information on the context and implementation of interventions, and their potential barriers and facilitators. However, such reviews face a number of methodological challenges, and there are ongoing debates as to how qualitative evidence can best be used to inform our understanding of interventions. In this paper, we use a case study of two systematic reviews of qualitative evidence on the prevention of skin cancer to explore these issues. We find that qualitative evidence not directly related to interventions is likely to be of value for such reviews, that it is often not possible to construct fully comprehensive search strategies, and that there are diminishing returns to the synthesis, in terms of added value or insight, from the inclusion of large numbers of primary studies. We conclude that there are a number of ways in which systematic reviews of qualitative evidence can be utilised in conjunction with evidence on intervention effectiveness, without compromising the rigour of the review process. In particular, the use of theory to inform frameworks for synthesis is a promising way to integrate a broader range of qualitative evidence. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26061998 TI - Performance of a proportion-based approach to meta-analytic moderator estimation: results from Monte Carlo simulations. AB - This research investigates the performance of a proportion-based approach to meta analytic moderator estimation through a series of Monte Carlo simulations. This approach is most useful when the moderating potential of a categorical variable has not been recognized in primary research and thus heterogeneous groups have been pooled together as a single sample. Alternative scenarios representing different distributions of group proportions are examined along with varying numbers of studies, subjects per study, and correlation combinations. Our results suggest that the approach is largely unbiased in its estimation of the magnitude of between-group differences and performs well with regard to statistical power and type I error. In particular, the average percentage bias of the estimated correlation for the reference group is positive and largely negligible, in the 0.5-1.8% range; the average percentage bias of the difference between correlations is also minimal, in the -0.1-1.2% range. Further analysis also suggests both biases decrease as the magnitude of the underlying difference increases, as the number of subjects in each simulated primary study increases, and as the number of simulated studies in each meta-analysis increases. The bias was most evident when the number of subjects and the number of studies were the smallest (80 and 36, respectively). A sensitivity analysis that examines its performance in scenarios down to 12 studies and 40 primary subjects is also included. This research is the first that thoroughly examines the adequacy of the proportion-based approach. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26061999 TI - Generalization of trim and fill for application in meta-regression. AB - Trim and fill is a popular method of accounting for publication bias in meta analysis. However, the use of trim and fill is limited to the setting in which all meta-analyzed studies represent a true common effect. In many practical settings, within-study effect estimates are a function of some covariate. Because methods of accounting for publication bias in meta-regression have received little attention, we propose here a generalization of trim and fill for application in meta-regression. The proposed algorithm preserves the computational features of trim and fill and adds only an assumption of symmetry in the hypothesized distribution of the measured covariate. By simulation, we evaluate properties (mean bias, root mean squared error, and coverage probability) of meta-regression parameter estimates and corresponding confidence intervals with application of the proposed algorithm in a range of scenarios, including violation of the aforementioned assumption of symmetry. We also evaluate the performance of common estimators of the number of suppressed studies. In general, we show that the proposed algorithm is successful in identifying suppression of studies and reducing the bias in regression parameters derived from the analysis of the augmented set of studies. We apply the proposed algorithm to an analysis of the effect of cognitive-behavioral therapy on the risk of recidivism. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062000 TI - Fast Waves at the Base of the Cochlea. AB - Georg von Bekesy observed that the onset times of responses to brief-duration stimuli vary as a function of distance from the stapes, with basal regions starting to move earlier than apical ones. He noticed that the speed of signal propagation along the cochlea is slow when compared with the speed of sound in water. Fast traveling waves have been recorded in the cochlea, but their existence is interpreted as the result of an experiment artifact. Accounts of the timing of vibration onsets at the base of the cochlea generally agree with Bekesy's results. Some authors, however, have argued that the measured delays are too short for consistency with Bekesy's theory. To investigate the speed of the traveling wave at the base of the cochlea, we analyzed basilar membrane (BM) responses to clicks recorded at several locations in the base of the chinchilla cochlea. The initial component of the BM response matches remarkably well the initial component of the stapes response, after a 4-MUs delay of the latter. A similar conclusion is reached by analyzing onset times of time-domain gain functions, which correspond to BM click responses normalized by middle-ear input. Our results suggest that BM responses to clicks arise from a combination of fast and slow traveling waves. PMID- 26062001 TI - Thrombospondin-1 and Pathogenesis of Age-Related Macular Degeneration. AB - The cardinal features of age-related macular degeneration (AMD) are the accumulation of subretinal debris, subretinal inflammation, neovascularization, and degeneration of the photoreceptors and retinal pigment epithelium (RPE). Thrombospondin-1 (TSP-1) is a major matricellular protein that is physiologically expressed in the RPE and choroid, but severely diminished in eyes with AMD. TSP-1 plays an important role in phagocytosis, potently inhibits neovascularization, and mediates immune suppression and immune privilege. The lack of TSP-1 could have a central role in the pathogenesis of AMD as it is implicated in the major pathways that seem to be deficient in the disease. We here give an overview of the major functions of TSP-1 and how it could intervene in AMD pathogenesis. PMID- 26062003 TI - Growth on glucose decreases cAMP-CRP activity while paradoxically increasing intracellular cAMP in the light-organ symbiont Vibrio fischeri. AB - Proteobacteria often co-ordinate responses to carbon sources using CRP and the second messenger cyclic 3', 5'-AMP (cAMP), which combine to control transcription of genes during growth on non-glucose substrates as part of the catabolite repression response. Here we show that cAMP-CRP is active and important in Vibrio fischeri during colonization of its host squid Euprymna scolopes. Moreover, consistent with a classical role in catabolite repression, a cAMP-CRP-dependent reporter showed lower activity in cells grown in media amended with glucose rather than glycerol. Surprisingly though, intracellular cAMP levels were higher in glucose-grown cells. Mutant analyses were consistent with predictions that CyaA was responsible for cAMP generation, that the EIIA(Glc) component of glucose transport could enhance cAMP production and that the phophodiesterases CpdA and CpdP consumed intracellular and extracellular cAMP respectively. However, the observation of lower cAMP levels in glycerol-grown cells seemed best explained by changes in cAMP export, via an unknown mechanism. Our data also indicated that cAMP-CRP activity decreased during growth on glucose independently of crp's native transcriptional regulation or cAMP levels. We speculate that some unknown mechanism, perhaps carbon-source-dependent post-translational modulation of CRP, may help control cAMP-CRP activity in V.fischeri. PMID- 26062002 TI - Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04 adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3 dose schedules in girls aged 9-14 years: Results to month 12 from a randomized trial. AB - This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV 6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9-14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV 6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV 6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49-1.91] for anti-HPV-16 and 4.52 [3.97-5.13] for anti-HPV-18; HPV 16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54-1.93] for anti-HPV-16 and 3.22 [2.82-3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8 fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9-14 years). PMID- 26062004 TI - Synthesizing a Healable Stretchable Transparent Conductor. AB - We report the first demonstration of a healable stretchable transparent electrode comprising a silver nanowire (AgNW) network and poly(3,4 ethylenedioxythiophene):polystyrenesulfonate (PEDOT) hybrid layer in the surface of a Diels-Alder elastomer substrate. The thin PEDOT layer solders the silver nanowires and confines the nanowire network in the substrate surface. The bonding between the nanowires and PEDOT is tuned via ethanol-water wetting, which allows for large-strain prestretching of the AgNW network. The composite electrode prepared via such a wetting and prestretching treatment has a figure-of-merit sheet resistance of 15 ohm/sq with 78% transmittance at 550 nm and can be stretched by 100% strain. Damages caused by razor blade cutting on the conductive surface could be healed, and the damaging-healing could be repeated for three times at the same location. The healed electrode exhibits similar resistance strain response as the fresh electrode because of the PEDOT layer being capable of circumventing broken nanowire sites. Fatigue-induced damages after 100 cycles of 60% strain can also be healed by simple heating. PMID- 26062006 TI - Geometrical and mechanical factors that influence slipped capital femoral epiphysis: a finite element study. AB - Slipped capital femoral epiphysis (SCFE) is an orthopedic pathology in which damage of the growth plate leads to the anterosuperior displacement of the femoral body in respect to the femoral head. Despite being a widely studied disease, its etiology is still unknown. This study was carried out to determine the influence of the physeal-diaphysis angle, body mass, the presence of the perichondrial ring, the type of physical activity, and physeal thickness on SCFE. For this purpose, a finite element analysis of the hip joint and the femur-physis interface was carried out. With the computational model, the Von Mises stresses along the growth plate were calculated and subsequently analyzed statistically to find their correlation with the studied factors. It was found that body mass, the type of physical activity, and the presence of the perichondrial ring had more statistical relevance for the physeal stresses than the physeal-diaphysis angle and the physeal thickness. Thus, our work suggests that changes in growth plate inclination and thickness do not influence the etiology of SCFE. PMID- 26062007 TI - Proceedings of the 14(th) Annual Meeting of the International Society for the Study of Women's Sexual Health, Austin, USA, February 19-22, 2015. PMID- 26062005 TI - Crystal Structure and Functional Analyses of the Lectin Domain of Glucosidase II: Insights into Oligomannose Recognition. AB - N-Glycans are modified as part of a quality control mechanism during glycoprotein folding in the endoplasmic reticulum (ER). Glucosidase II (GII) plays a critical role by generating monoglucosylated glycans that are recognized by lectin chaperones, calnexin and calreticulin. To understand how the hydrolytic activity of GIIalpha is enhanced by the mannose 6-phosphate receptor (MPR) homology domain (MRH domain) of its beta subunit, we now report a 1.6 A resolution crystal structure of the MRH domain of GIIbeta bound to mannose. A comparison of ligand bound and unbound structures reveals no major difference in their overall fold, but rather a repositioning of side chains throughout the binding pocket, including Y372. Mutation of Y372 inhibits GII activity, demonstrating an important role for Y372 in regulating GII activity. Comparison of the MRH domains of GIIbeta, MPRs, and the ER lectin OS-9 identified conserved residues that are critical for the structural integrity and architecture of the carbohydrate binding pocket. As shown by nuclear magnetic resonance spectroscopy, mutations of the primary binding pocket residues and adjacent W409, all of which inhibit the activity of GII both in vitro and in vivo, do not cause a significant change in the overall fold of the GIIbeta MRH domain but impact locally the stability of the binding pocket. W409 does not directly contact mannose; rather, its indole ring is stabilized by binding into a hydrophobic pocket of an adjacent crystallographic neighbor. This suggests that W409 interacts with a hydrophobic region of the GIIbeta or GIIalpha subunit to modulate its effect on GII activity. PMID- 26062008 TI - Accuracy Evaluation of Four Blood Glucose Monitoring Systems in Unaltered Blood Samples in the Low Glycemic Range and Blood Samples in the Concentration Range Defined by ISO 15197. AB - INTRODUCTION: Systems for self-monitoring of blood glucose (SMBG) are expected to be accurate enough to provide reliable measurement results. Especially in the low glycemic range, adequate therapeutic decisions based on reliable results can alleviate complications associated with hypoglycemia. MATERIALS AND METHODS: The accuracy of four SMBG systems (system 1 was the ACCU-CHEK((r)) Aviva [Roche Diagnostics GmbH, Mannheim, Germany], system 2 was the Contour((r)) XT [Bayer Consumer Care AG, Basel, Switzerland], system 3 was the GlucoCheck XL [aktivmed GmbH, Augsberg, Germany], and system 4 was the GlucoMen((r)) LX PLUS [A. Menarini Diagnostics S.r.l., Florence, Italy]) with three test-strip lots each was evaluated by calculating mean absolute relative differences (MARDs). Two datasets were evaluated: (1) 100 samples with blood glucose concentrations <70 mg/dL and (2) 100 samples distributed following International Organization for Standardization (ISO) standard 15197. Each sample was measured twice with each test-strip lot of each SMBG system. Comparison measurement results were obtained with a glucose oxidase method and a hexokinase method, both traceable according to ISO 17511. Analysis of variance of the MARD between the SMBG system and the comparison method was performed. RESULTS: MARD values ranged from 4.4% to 13.4% (<70 mg/dL) and 4.8% to 8.9% (ISO 15197-distributed) and differed significantly, with systems 1 and 2 showing lower MARDs than systems 3 and 4. MARD values deviated by up to 2.5% (corresponding to a relative deviation of approximately 40%) between the two comparison methods. CONCLUSIONS: The investigated SMBG systems showed a significant variation of accuracy (measured by MARD), especially with higher MARD values in the low glycemic range. The selected comparison method had an impact on the MARD and therefore on the apparent accuracy of the SMBG systems. Sufficient measurement accuracy in the low glycemic range is required to enable users to react adequately to hypoglycemia. PMID- 26062009 TI - Antioxidant activity of apple extract protects against rat tongue carcinogenesis induced by 4-nitroquinoline 1-oxide. AB - Several studies have shown that apple (Malus sp.) has many components able to exert chemopreventive activity. The aim of this study was to evaluate the chemopreventive potential of apple extract following medium-term oral carcinogenesis assay induced by 4-nitroquinoline 1-oxide (4NQO) by means of histopathological analysis and gene expression of antioxidant enzymes, such as CuZnSOD, MnSOD and catalase. A total of 30 male Wistar rats were distributed into five groups, as follows (n = 6 per group): Group 1 - negative control group (non treated group); Group 2 - received 4NQO during 8 weeks in drinking water and treated with apple extract by gavage between the 1st and 4th weeks daily (initiation phase); Group 3 - received 4NQO for 8 weeks in drinking water and treated with apple extract by gavage between the 5th and 8th weeks daily (promotion phase); Group 4 - received apple extract by gavage for eight consecutive weeks only; and Group 5 - received 4NQO for 8 weeks in drinking water daily. Histopathological analysis revealed that apple extract protect oral lesions induced by 4NQO at initiation or promotion phase. Higher gene expression of CuZnSOD and MnSOD enzymes were noticed in groups treated with apple extract as well. Taken together, our results demonstrate that the apple extract is able to modulate medium-term oral carcinogenesis assay as a result of antioxidant activity. PMID- 26062011 TI - Development of a platform for single cell genomics using convex lens-induced confinement. AB - We demonstrate a lab-on-a-chip that combines micro/nano-fabricated features with a Convex Lens-Induced Confinement (CLIC) device for the in situ analysis of single cells. A complete cycle of single cell analysis was achieved that includes: cell trapping, cell isolation, lysis, protein digestion, genomic DNA extraction and on-chip genomic DNA linearization. The ability to dynamically alter the flow-cell dimensions using the CLIC method was coupled with a flow control mechanism for achieving efficient cell trapping, buffer exchange, and loading of long DNA molecules into nanofluidic arrays. Finite element simulation of fluid flow gives rise to optimized design parameters for overcoming the high hydraulic resistance present in the micro/nano-confinement region. By tuning design parameters such as the pressure gradient and CLIC confinement, an efficient on-chip single cell analysis protocol can be obtained. We demonstrate that we can extract Mbp long genomic DNA molecules from a single human lybphoblastoid cell and stretch these molecules in the nanochannels for optical interrogation. PMID- 26062010 TI - Preliminary study of genotoxicity evaluation of orthodontic miniscrews on mucosa oral cells by the alkaline comet assay. AB - Miniscrew implants are widely used nowadays in orthodontic treatments due to their good results in clinical practice. However, data regarding the biocompatibility of commercially available orthodontic miniscrews and temporary devices are very scarce, and their role as genotoxicity inducers has been not previously evaluated with the alkaline comet assay. The aim of this study was to investigate the DNA damage in buccal cells of patients subjected to orthodontic treatments. The alkaline comet assay has been applied in oral mucosa cells from patients treated with conventional orthodontic treatment in comparison to patients treated additionally with miniscrews, non-treated volunteers (control) and smoking volunteers (positive control). The application of orthodontic appliances and miniscrews induced significant and similar (2-fold) increases of %DNA in tail in comparison to control group. Females experienced a significant increase in %DNA in all the treatments in comparison to the control group, whereas males showed significant damage only with the combined orthodontic and miniscrew treatment. In conclusion, conventional orthodontic appliances induced genotoxicity, and the incorporation of miniscrews assayed did not imply any additional increase of DNA damage. PMID- 26062012 TI - Dextran-coated superparamagnetic nanoparticles as potential cancer drug carriers in vivo. AB - Dextran-coated superparamagnetic iron oxide nanoparticles (DSPIONs) have gained considerable interest, because of their biocompatibility and biosafety in clinics. Doxorubicin (Dox), a widely used chemotherapeutic drug, always has limited applications in clinical therapy due to its serious side effects of dose limiting irreversible cardiotoxicity and myelo suppression. Herein, DSPIONs were synthesized and developed as magnetic carriers for doxorubicin. The Dox-DSPION conjugates were evaluated in the in vitro test of Dox release, which showed pH dependence with the highest release percentage of 50.3% at pH 5.0 and the lowest release percentage of 11.8% in a physiological environment. The cytotoxicity of DSPIONs and Dox-DSPIONs evaluated by the MTT assay indicated that DSPIONs had no cytotoxicity and the conjugates had significantly reduced the toxicity (IC50 = 1.36 MUg mL(-1)) compared to free Dox (IC50 = 0.533 MUg mL(-1)). Furthermore, confocal microscopic data of cell uptake suggest that less cytotoxicity of Dox DSPIONs may be attributed to the cellular internalization of the conjugates and sustainable release of Dox from the formulation in the cytoplasm. More importantly, the results from the rabbit VX2 liver tumor model test under an external magnetic field showed that the conjugates had approximately twice the anti-tumor activity and two and a half times the animal survival rate, respectively, compared to free Dox. Collectively, our data have demonstrated that Dox-DSPIONs have less toxicity with better antitumor effectiveness in in vitro and in vivo applications, suggesting that the conjugates have potential to be developed into chemo-therapeutic formulations. PMID- 26062014 TI - Expression Pattern and Localization Dynamics of Guanine Nucleotide Exchange Factor RIC8 during Mouse Oogenesis. AB - Targeting of G proteins to the cell cortex and their activation is one of the triggers of both asymmetric and symmetric cell division. Resistance to inhibitors of cholinesterase 8 (RIC8), a guanine nucleotide exchange factor, activates a certain subgroup of G protein alpha-subunits in a receptor independent manner. RIC8 controls the asymmetric cell division in Caenorhabditis elegans and Drosophila melanogaster, and symmetric cell division in cultured mammalian cells, where it regulates the mitotic spindle orientation. Although intensely studied in mitosis, the function of RIC8 in mammalian meiosis has remained unknown. Here we demonstrate that the expression and subcellular localization of RIC8 changes profoundly during mouse oogenesis. Immunofluorescence studies revealed that RIC8 expression is dependent on oocyte growth and cell cycle phase. During oocyte growth, RIC8 is abundantly present in cytoplasm of oocytes at primordial, primary and secondary preantral follicle stages. Later, upon oocyte maturation RIC8 also populates the germinal vesicle, its localization becomes cell cycle dependent, and it associates with chromatin and the meiotic spindle. After fertilization, RIC8 protein converges to the pronuclei and is also detectable at high levels in the nucleolus precursor bodies of both maternal and paternal pronucleus. During first cleavage of zygote RIC8 localizes in the mitotic spindle and cell cortex of forming blastomeres. In addition, we demonstrate that RIC8 co-localizes with its interaction partners Galphai1/2:GDP and LGN in meiotic/mitotic spindle, cell cortex and polar bodies of maturing oocytes and zygotes. Downregulation of Ric8 by siRNA leads to interferred translocation of Galphai1/2 to cortical region of maturing oocytes and reduction of its levels. RIC8 is also expressed at high level in female reproductive organs e.g. oviduct. Therefore we suggest a regulatory function for RIC8 in mammalian gametogenesis and fertility. PMID- 26062015 TI - The Association Between Subcutaneous Fat Density and the Propensity to Store Fat Viscerally. AB - BACKGROUND: Alterations in the cellular characteristics of subcutaneous adipose tissue (SAT) may reduce its ability to expand in times of caloric excess, increasing the propensity to store excess calories viscerally (visceral adipose tissue [VAT]). We hypothesized (1) that increased SAT density, an indirect marker of fat quality, would be associated with an increased VAT/SAT ratio and increased cardiovascular disease (CVD) risk and (2) that these associations would be independent of the absolute volume of SAT. METHODS: We investigated the association of SAT density with the VAT/SAT ratio and CVD risk in 3212 participants (48% women, mean age, 50.7 years) from the Framingham Heart Study. Adipose tissue depot density and volume were quantified by computed tomography; traditional CVD risk factors were quantified. RESULTS: Higher SAT density was correlated with a higher VAT/SAT ratio in men (r = 0.17; P < .0001) but not in women (r = 0.04; P >= .05). More adverse levels of CVD risk factors were observed in the high SAT density/high VAT/SAT ratio group than in the referent group (low density/low ratio). For example, women had an increased risk of diabetes (odds ratio [OR], 6.7; 95% confidence interval [CI], 2.6-17.6; P = .0001) and hypertension (OR, 1.6; 95% CI, 1.1-2.4; P = .009). Additional adjustment for SAT volume generally strengthened these associations (diabetes OR, 10.8; 95% CI, 4.1 29.0; hypertension OR, 2.5; 95% CI, 1.7-3.7; all P < .0001). These trends were similar but generally weaker in men. CONCLUSION: High fat density, an indirect marker of fat quality, is associated with the propensity to store fat viscerally vs subcutaneously and is jointly characterized by an increased burden of CVD risk factors. PMID- 26062016 TI - Increased Abdominal Adiposity in Adolescents and Young Adults With Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency. AB - CONTEXT: Childhood obesity rates in congenital adrenal hyperplasia (CAH) exceed the high rates seen in normal children, potentially increasing their risk of cardiovascular disease (CVD). Abdominal adiposity, in particular visceral adipose tissue (VAT), is strongly associated with metabolic syndrome and CVD. However, it remains unknown whether VAT is increased in CAH. OBJECTIVE: The objective of the study was to determine whether adolescents and young adults with classical CAH have more VAT and sc adipose tissue (SAT) than matched controls and whether VAT and SAT are associated with biomarkers of metabolic syndrome, inflammation, and hyperandrogenism in CAH. DESIGN/SETTING: This was a cross-sectional study at a tertiary center. PARTICIPANTS: CAH subjects (n = 28; 15.6 +/- 3.2 y; 15 females) were matched for age, sex, ethnicity, and body mass index to healthy controls (n = 28; 16.7 +/- 2.3 y; 15 females). MAIN OUTCOME MEASURES: VAT and SAT, using computed tomography imaging and serum biomarkers associated with CVD risk, were measured. Data are reported as mean +/- SD. RESULTS: Both VAT (43.8 +/- 45.5 cm(2)) and SAT (288.1 +/- 206.5 cm(2)) were higher in CAH subjects than controls (VAT 26.4 +/- 29.6 cm(2) and SAT 226.3 +/- 157.5 cm(2); both P < .001). The VAT to SAT ratio was also higher in CAH subjects (0.15 +/- 0.07) than controls (0.12 +/- 0.06; P < .05). Within CAH, measures of obesity (waist to height ratio, fat mass) and inflammation (plasminogen activator inhibitor-1, high-sensitivity C reactive protein, leptin) correlated strongly with VAT and SAT. In addition, homeostasis model assessment of insulin resistance, and low-density lipoprotein correlated with abdominal adiposity. There were no sex differences for VAT or SAT in CAH subjects. CONCLUSIONS: CAH adolescents and young adults have increased abdominal adiposity, with a higher proportion of proinflammatory VAT than SAT. An improved understanding of the mechanism of obesity in CAH may lead to targeted prevention and therapeutics in this high-risk population. PMID- 26062017 TI - IL13 activates autophagy to regulate secretion in airway epithelial cells. AB - Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent. PMID- 26062018 TI - Pathogenic Transdifferentiation of Th17 Cells Contribute to Perpetuation of Rheumatoid Arthritis during Anti-TNF Treatment. AB - T-helper cells producing interleukin (IL)-17A and IL-17F cytokines (Th17 cells) are considered the source of autoimmunity in rheumatoid arthritis (RA). In this study, we characterized specific pathogenic features of Th17 cells in RA. By using nano-string technology, we analyzed transcription of 419 genes in the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of 14 RA patients and 6 healthy controls and identified 109 genes discriminating Th17 cells of RA patients from the controls. Th17 cells of RA patients had an aggressive pathogenic profile and in addition to signature cytokines IL-17, IL-23 and IL-21, and transcriptional regulators RAR-related orphan receptor gamma of T cells (RORgammat) and Janus kinase 2 (JAK2), they produced high levels of IL-23R, C-C chemokine ligand type 20 (CCL20), granulocyte-monocyte colony-stimulating factor (GM-CSF ) and transcription factor Tbet required for synovial homing. We showed that Th17 cells are enriched with Helios-producing Foxp3- and IL2RA-deficient cells, indicating altered regulatory profile. The follicular T-helper (Tfh) cells presented a functional profile of adaptor molecules, transcriptional regulator Bcl-6 and B cell activating cytokines IL-21, IL-31 and leukemia inhibitory factor (LIF ). We observed that anti-tumor necrosis factor (TNF) treatment had a limited effect on the transcription signature of Th17 cells. Patients in remission retained the machinery of receptors (IL-23R and IL-1R1), proinflammatory cytokines (IL-17F, IL 23, IL-21 and TNF ) and adaptor molecules (C-X-C chemokine receptor 5 [CXCR5] and cytotoxic T-lymphocyte-associated protein 4 [CTLA-4]), essential for efficient transdifferentiation and accumulation of Th17 cells. This study convincingly shows that the peripheral blood CCR6(+)CXCR3(-) CD4(+) cells of RA patients harbor pathogenic subsets of Th17 and Tfh cells, which may transdifferentiate from Tregs and contribute to perpetuation of the disease. PMID- 26062019 TI - Humanin Derivatives Inhibit Necrotic Cell Death in Neurons. AB - Humanin and its derivatives are peptides known for their protective antiapoptotic effects against Alzheimer's disease. Herein, we identify a novel function of the humanin-derivative AGA(C8R)-HNG17 (namely, protection against cellular necrosis). Necrosis is one of the main modes of cell death, which was until recently considered an unmoderated process. However, recent findings suggest the opposite. We have found that AGA(C8R)-HNG17 confers protection against necrosis in the neuronal cell lines PC-12 and NSC-34, where necrosis is induced in a glucose-free medium by either chemohypoxia or by a shift from apoptosis to necrosis. Our studies in traumatic brain injury models in mice, where necrosis is the main mode of neuronal cell death, have shown that AGA(C8R)-HNG17 has a protective effect. This result is demonstrated by a decrease in a neuronal severity score and by a reduction in brain edema, as measured by magnetic resonance imaging (MRI). An insight into the peptide's antinecrotic mechanism was attained through measurements of cellular ATP levels in PC-12 cells under necrotic conditions, showing that the peptide mitigates a necrosis-associated decrease in ATP levels. Further, we demonstrate the peptide's direct enhancement of the activity of ATP synthase activity, isolated from rat-liver mitochondria, suggesting that AGA(C8R) HNG17 targets the mitochondria and regulates cellular ATP levels. Thus, AGA(C8R) HNG17 has potential use for the development of drug therapies for necrosis related diseases, for example, traumatic brain injury, stroke, myocardial infarction, and other conditions for which no efficient drug-based treatment is currently available. Finally, this study provides new insight into the mechanisms underlying the antinecrotic mode of action of AGA(C8R)-HNG17. PMID- 26062020 TI - Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver. AB - Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5 aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ~3- and 5-fold, and ALA and PBG concentrations were increased ~3- and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks. PMID- 26062022 TI - Re-Examining of Moffitt's Theory of Delinquency through Agent Based Modeling. AB - Moffitt's theory of delinquency suggests that at-risk youths can be divided into two groups, the adolescence- limited group and the life-course-persistent group, predetermined at a young age, and social interactions between these two groups become important during the adolescent years. We built an agent-based model based on the microscopic interactions Moffitt described: (i) a maturity gap that dictates (ii) the cost and reward of antisocial behavior, and (iii) agents imitating the antisocial behaviors of others more successful than themselves, to find indeed the two groups emerging in our simulations. Moreover, through an intervention simulation where we moved selected agents from one social network to another, we also found that the social network plays an important role in shaping the life course outcome. PMID- 26062024 TI - Accounting for Behavior in Treatment Effects: New Applications for Blind Trials. AB - The double-blind randomized controlled trial (DBRCT) is the gold standard of medical research. We show that DBRCTs fail to fully account for the efficacy of treatment if there are interactions between treatment and behavior, for example, if a treatment is more effective when patients change their exercise or diet. Since behavioral or placebo effects depend on patients' beliefs that they are receiving treatment, clinical trials with a single probability of treatment are poorly suited to estimate the additional treatment benefit that arises from such interactions. Here, we propose methods to identify interaction effects, and use those methods in a meta-analysis of data from blinded anti-depressant trials in which participant-level data was available. Out of six eligible studies, which included three for the selective serotonin re-uptake inhibitor paroxetine, and three for the tricyclic imipramine, three studies had a high (>65%) probability of treatment. We found strong evidence that treatment probability affected the behavior of trial participants, specifically the decision to drop out of a trial. In the case of paroxetine, but not imipramine, there was an interaction between treatment and behavioral changes that enhanced the effectiveness of the drug. These data show that standard blind trials can fail to account for the full value added when there are interactions between a treatment and behavior. We therefore suggest that a new trial design, two-by-two blind trials, will better account for treatment efficacy when interaction effects may be important. PMID- 26062023 TI - Efficacy of Non-Pharmacological Interventions to Prevent and Treat Delirium in Older Patients: A Systematic Overview. The SENATOR project ONTOP Series. AB - BACKGROUND: Non-pharmacological intervention (e.g. multidisciplinary interventions, music therapy, bright light therapy, educational interventions etc.) are alternative interventions that can be used in older subjects. There are plenty reviews of non-pharmacological interventions for the prevention and treatment of delirium in older patients and clinicians need a synthesized, methodologically sound document for their decision making. METHODS AND FINDINGS: We performed a systematic overview of systematic reviews (SRs) of comparative studies concerning non-pharmacological intervention to treat or prevent delirium in older patients. The PubMed, Cochrane Database of Systematic Reviews, EMBASE, CINHAL, and PsychINFO (April 28th, 2014) were searched for relevant articles. AMSTAR was used to assess the quality of the SRs. The GRADE approach was used to assess the quality of primary studies. The elements of the multicomponent interventions were identified and compared among different studies to explore the possibility of performing a meta-analysis. Risk ratios were estimated using a random-effects model. Twenty-four SRs with 31 primary studies satisfied the inclusion criteria. Based on the AMSTAR criteria twelve reviews resulted of moderate quality and three resulted of high quality. Overall, multicomponent non pharmacological interventions significantly reduced the incidence of delirium in surgical wards [2 randomized trials (RCTs): relative risk (RR) 0.71, 95% Confidence Interval (CI) 0.59 to 0.86, I2=0%; (GRADE evidence: moderate)] and in medical wards [2 CCTs: RR 0.65, 95%CI 0.49 to 0.86, I2=0%; (GRADE evidence: moderate)]. There is no evidence supporting the efficacy of non-pharmacological interventions to prevent delirium in low risk populations (i.e. low rate of delirium in the control group)[1 RCT: RR 1.75, 95%CI 0.50 to 6.10 (GRADE evidence: very low)]. For patients who have developed delirium, the available evidence does not support the efficacy of multicomponent non-pharmacological interventions to treat delirium. Among single component interventions only staff education, reorientation protocol (GRADE evidence: very low)] and Geriatric Risk Assessment MedGuide software [hazard ratio 0.42, 95%CI 0.35 to 0.52, (GRADE evidence: moderate)] resulted effective in preventing delirium. CONCLUSIONS: In older patients multi-component non-pharmacological interventions as well as some single-components intervention were effective in preventing delirium but not to treat delirium. PMID- 26062025 TI - Wasted Food: U.S. Consumers' Reported Awareness, Attitudes, and Behaviors. AB - The U.S. wastes 31 to 40% of its post-harvest food supply, with a substantial portion of this waste occurring at the consumer level. Globally, interventions to address wasted food have proliferated, but efforts are in their infancy in the U.S. To inform these efforts and provide baseline data to track change, we performed a survey of U.S. consumer awareness, attitudes and behaviors related to wasted food. The survey was administered online to members of a nationally representative panel (N=1010), and post-survey weights were applied. The survey found widespread (self-reported) awareness of wasted food as an issue, efforts to reduce it, and knowledge about how to do so, plus moderately frequent performance of waste-reducing behaviors. Three-quarters of respondents said they discard less food than the average American. The leading motivations for waste reduction were saving money and setting an example for children, with environmental concerns ranked last. The most common reasons given for discarding food were concern about foodborne illness and a desire to eat only the freshest food. In some cases there were modest differences based on age, parental status, and income, but no differences were found by race, education, rural/urban residence or other demographic factors. Respondents recommended ways retailers and restaurants could help reduce waste. This is the first nationally representative consumer survey focused on wasted food in the U.S. It provides insight into U.S. consumers' perceptions related to wasted food, and comparisons to existing literature. The findings suggest approaches including recognizing that many consumers perceive themselves as being already-knowledgeable and engaged, framing messages to focus on budgets, and modifying existing messages about food freshness and aesthetics. This research also suggests opportunities to shift retail and restaurant practice, and identifies critical research gaps. PMID- 26062026 TI - Intelligence and Disability Pension in Swedish Men and Women Followed from Childhood to Late Middle Age. AB - OBJECTIVE: To investigate the association between intelligence and disability pension due to mental, musculoskeletal, cardiovascular, and substance-use disorders among men and women, and to assess the role of childhood social factors and adulthood work characteristics. METHODS: Two random samples of men and women born 1948 and 1953 (n = 10 563 and 9 434), and tested for general intelligence at age 13, were followed in registers for disability pension until 2009. Physical and psychological strains in adulthood were assessed using job exposure matrices. Associations were examined using Cox proportional hazard regression models, with increases in rates reported as hazard ratios (HRs) with 95% confidence intervals (95%CI) per decrease in stanine intelligence. RESULTS: In both men and women increased risks were found for disability pension due to all causes, musculoskeletal disorder, mental disorder other than substance use, and cardiovascular disease as intelligence decreased. Increased risk was also found for substance use disorder in men. In multivariate models, HRs were attenuated after controlling for pre-school plans in adolescence, and low job control and high physical strain in adulthood. In the fully adjusted model, increased HRs remained for all causes (male HR 1.11, 95%CI 1.07-1.15, female HR 1.06, 95%CI 1.02-1.09) and musculoskeletal disorder (male HR 1.16, 95%CI 1.09-1.24, female HR 1.08, 95%CI 1.03-1.14) during 1986 to 2009. CONCLUSION: Relatively low childhood intelligence is associated with increased risk of disability pension due to musculoskeletal disorder in both men and women, even after adjustment for risk factors for disability pension measured over the life course. PMID- 26062027 TI - Effects of Decreased Occlusal Loading during Growth on the Mandibular Bone Characteristics. AB - BACKGROUND: Bone mass and mineralization are largely influenced by loading. The purpose of this study was to evaluate the reaction of the entire mandibular bone in response to decreased load during growth. It is hypothesized that decreased muscular loading will lead to bone changes as seen during disuse, i.e. loss of bone mass. METHODS AND FINDINGS: Ten 21-day-old Wistar strain male rats were divided into two groups (each n=5) and fed on either a hard- or soft-diet for 11 weeks. Micro-computed tomography was used for the investigation of bone mineralization, bone volume, bone volume fraction (BV/TV) and morphological analysis. Mandibular mineralization patterns were very consistent, showing a lower degree of mineralization in the ramus than in the corpus. In the soft-diet group, mineralization below the molars was significantly increased (p<0.05) compared to the hard diet group. Also, bone volume and BV/TV of the condyle and the masseter attachment were decreased in the soft-diet group (p<0.05). Morphological analysis showed inhibited growth of the ramus in the soft-diet group (p<0.05). CONCLUSION: Decreased loading by a soft diet causes significant changes in the mandible. However, these changes are very region-specific, probably depending on the alterations in the local loading regime. The results suggest that muscle activity during growth is very important for bone quality and morphology. PMID- 26062028 TI - Blood eosinophilia is associated with unfavorable hospitalization outcomes in children with bronchiolitis. AB - BACKGROUND: Bronchiolitis, the most common indication for hospitalization of young children, is associated with subsequent asthma. Blood eosinophilia is associated with increased severity of asthma, but it is unclear if eosinophilia is associated with severity of illness in bronchiolitis. We hypothesized that blood eosinophilia is associated with unfavorable short-term outcomes of bronchiolitis hospitalizations. METHODS: Data from initial bronchiolitis admissions to our institution between 2010 and 2013 were extracted using Population Explorer software (Explorys, Cleveland, OH). Children were categorized as "CBC-none" (no complete blood count [CBC] data during the first 7 days of hospitalization), EOS-positive (at least one CBC with >=300 eosinophils per microliter or >=3% of all leukocytes identified as eosinophils) or EOS-negative (at least one CBC and no eosinophilia). The association between hospitalization duration and maximum absolute eosinophil count (AEC) was analyzed using Spearman correlation. Variables independently associated with prolonged (>=72 hr) hospitalization were identified using stepwise multivariate logistic regression. RESULTS: In 1356 inpatients <24 months with bronchiolitis, median hospitalization duration was 2.46 days and 38.0% had prolonged hospitalization. CBC data were available in 32.4% of subjects: 20.7% were EOS-positive and 79.3% were EOS negative. Increased maximum AEC was significantly associated with longer duration of hospitalization. Prolonged hospitalization was independently associated with EOS-positive versus EOS-negative children (OR 1.88, 95%CI: 1.12-3.17, P = 0.020). Mechanical ventilation was most common in EOS-positive subjects (24.2% of cases), versus EOS-negative (7.2%) and CBC-none (0.7%) (P < 0.001). CONCLUSIONS: Blood eosinophilia is associated with unfavorable clinical outcomes in a large cohort of inpatients with bronchiolitis. PMID- 26062029 TI - Optomechanically induced transparency in the presence of an external time harmonic-driving force. AB - We propose a potentially valuable scheme to measure the properties of an external time-harmonic-driving force with frequency omega via investigating its interaction with the combination of a pump field and a probe field in a generic optomechanical system. We show that the spectra of both the cavity field and output field in the configuration of optomechanically induced transparency are greatly modified by such an external force, leading to many interesting linear and non-linear effects, such as the asymmetric structure of absorption in the frequency domain and the antisymmetry breaking of dispersion near omega = omegam. Furthermore, we find that our scheme can be used to measure the initial phase of the external force. More importantly, this setup may eliminate the negative impact of thermal noise on the measurement of the weak external force in virtue of the process of interference between the probe field and the external force. Finally, we show that our configuration can be employed to improve the measurement resolution of the radiation force produced by a weak ultrasonic wave. PMID- 26062031 TI - The Incidence of Audible Steam Pops Is Increased and Unpredictable With the ThermoCool(r) Surround Flow Catheter During Left Atrial Catheter Ablation: A Prospective Observational Study. AB - INTRODUCTION: Open irrigated radiofrequency (RF) ablation catheters with a porous tip (56 holes, TC-SF) permit delivering RF energy in a temperature-controlled mode without temperature rise. This prospective observational study investigated the association of different catheter parameters on the occurrence of audible steam pops during left atrial (LA) ablation. METHODS AND RESULTS: A total of 226 patients underwent TC-SF catheter ablation for atrial fibrillation. RF power delivery, impedance and catheter tip temperature were continually recorded throughout the ablation. Pulmonary vein isolation was performed with a maximum of 27 W and LA electrogram-guided or linear ablation with a maximum of 30 W. A total of 59 audible steam pops occurred, 2 of them resulting in pericardial tamponade. In the initial 89 patients, with an irrigation flow rate of 10 mL/min, 18 steam pops with one tamponade occurred in 12 (14%) patients. Subsequently, the irrigation flow rate was increased to 20 mL/min in the following 137 patients, resulting in the occurrence of 41 steam pops including one case of tamponade in a total of 30 (22%) patients. The maximal power was significantly higher in RF applications associated with a pop than those that did not. In only 12 (20%) steam pops, a significant impedance change occurred immediately before pop occurrence (4 [7%] impedance rise >10 ohm, 8 [13%] impedance drop >15 ohm). CONCLUSIONS: The TC-SF catheter does not provide sufficient feedback from the ablated tissue to prevent steam popping. PMID- 26062032 TI - Development of Chiral Spiro P-N-S Ligands for Iridium-Catalyzed Asymmetric Hydrogenation of beta-Alkyl-beta-Ketoesters. AB - The chiral tridentate spiro P-N-S ligands (SpiroSAP) were developed, and their iridium complexes were prepared. Introduction of a 1,3-dithiane moiety into the ligand resulted in a highly efficient chiral iridium catalyst for asymmetric hydrogenation of beta-alkyl-beta-ketoesters, producing chiral beta-alkyl-beta hydroxyesters with excellent enantioselectivities (95-99.9% ee) and turnover numbers of up to 355,000. PMID- 26062030 TI - Male- and Female-Biased Gene Expression of Olfactory-Related Genes in the Antennae of Asian Corn Borer, Ostrinia furnacalis (Guenee) (Lepidoptera: Crambidae). AB - The Asian corn borer (ACB), Ostrinia furnacalis (Guenee), is a destructive pest insect of cultivated corn crops, for which antennal-expressed receptors are important to detect olfactory cues for mate attraction and oviposition. Few olfactory related genes were reported in ACB, so we sequenced and characterized the transcriptome of male and female O. furnacalis antennae. Non-normalized male and female O. furnacalis antennal cDNA libraries were sequenced on the Illumina HiSeq 2000 and assembled into a reference transcriptome. Functional gene annotations identified putative olfactory-related genes; 56 odorant receptors (ORs), 23 odorant binding proteins (OBPs), and 10 CSPs. RNA-seq estimates of gene expression respectively showed up- and down-regulation of 79 and 30 genes in female compared to male antennae, which included up-regulation of 8 ORs and 1 PBP gene in male antennae as well as 3 ORs in female antennae. Quantitative real-time RT-PCR analyses validated strong male antennal-biased expression of OfurOR3, 4, 6, 7, 8, 11, 12, 13 and 14 transcripts, whereas OfurOR17 and 18 were specially expressed in female antennae. Sex-biases gene expression described here provides important insight in gene functionalization, and provides candidate genes putatively involved in environmental perception, host plant attraction, and mate recognition. PMID- 26062033 TI - Extracting entangled qubits from Majorana fermions in quantum dot chains through the measurement of parity. AB - We propose a scheme for extracting entangled charge qubits from quantum-dot chains that support zero-energy edge modes. The edge mode is composed of Majorana fermions localized at the ends of each chain. The qubit, logically encoded in double quantum dots, can be manipulated through tunneling and pairing interactions between them. The detailed form of the entangled state depends on both the parity measurement (an even or odd number) of the boundary-site electrons in each chain and the teleportation between the chains. The parity measurement is realized through the dispersive coupling of coherent-state microwave photons to the boundary sites, while the teleportation is performed via Bell measurements. Our scheme illustrates localizable entanglement in a fermionic system, which serves feasibly as a quantum repeater under realistic experimental conditions, as it allows for finite temperature effect and is robust against disorders, decoherence and quasi-particle poisoning. PMID- 26062034 TI - Posttraumatic Bilateral Abducens Nerve Palsy: Mechanism of Injury and Prognosis. PMID- 26062035 TI - A multiscale approach to simulating the conformational properties of unbound multi-C2H2 zinc finger proteins. AB - The conformational properties of unbound multi-Cys2 His2 (mC2H2) zinc finger proteins, in which zinc finger domains are connected by flexible linkers, are studied by a multiscale approach. Three methods on different length scales are utilized. First, atomic detail molecular dynamics simulations of one zinc finger and its adjacent flexible linker confirmed that the zinc finger is more rigid than the flexible linker. Second, the end-to-end distance distributions of mC2H2 zinc finger proteins are computed using an efficient atomistic pivoting algorithm, which only takes excluded volume interactions into consideration. The end-to-end distance distribution gradually changes its profile, from left-tailed to right-tailed, as the number of zinc fingers increases. This is explained by using a worm-like chain model. For proteins of a few zinc fingers, an effective bending constraint favors an extended conformation. Only for proteins containing more than nine zinc fingers, is a somewhat compacted conformation preferred. Third, a mesoscale model is modified to study both the local and the global conformational properties of multi-C2H2 zinc finger proteins. Simulations of the CCCTC-binding factor (CTCF), an important mC2H2 zinc finger protein for genome spatial organization, are presented. PMID- 26062036 TI - State-Issued Identification Cards Reveal Patterns in Adult Weight Status. AB - BACKGROUND: State-issued identification cards are a promising data source for neighborhood-level obesity estimates. METHODS: We used information from three million Oregon state-issued identification cards to compute age-adjusted estimates of average adult body mass index (BMI) for each census tract in the state. We used multivariate linear regression to identify associations between weight status and population characteristics, food access, commuting behavior, and geography. RESULTS: Together, home values, education, race, ethnicity, car commuting, and rural-urban commuting area (RUCA) explained 86% of the variation in BMI among tracts. BMI was lower in areas with higher home values and greater educational attainment, and higher in areas with more workers commuting by car. DISCUSSION: Our findings are consistent with other research on socioeconomic disparities in obesity. This demonstrates state-issued identification cards are a promising data source for BMI surveillance and may offer new insight into the association between weight status and economic and environmental factors. Public health agencies should explore options for developing their own obesity estimates from identification card data. PMID- 26062037 TI - Smoking Cessation among Low-Socioeconomic Status and Disadvantaged Population Groups: A Systematic Review of Research Output. AB - BACKGROUND: Smoking cessation research output should move beyond descriptive research of the health problem to testing interventions that can provide causal data and effective evidence-based solutions. This review examined the number and type of published smoking cessation studies conducted in low-socioeconomic status (low-SES) and disadvantaged population groups. METHODS: A systematic database search was conducted for two time periods: 2000-2004 (TP1) and 2008-2012 (TP2). Publications that examined smoking cessation in a low-SES or disadvantaged population were coded by: population of interest; study type (reviews, non-data based publications, data-based publications (descriptive, measurement and intervention research)); and country. Intervention studies were coded in accordance with the Cochrane Effective Practice and Organisation of Care data collection checklist and use of biochemical verification of self-reported abstinence was assessed. RESULTS: 278 citations were included. Research output (i.e., all study types) had increased from TP1 27% to TP2 73% (chi2=73.13, p<0.001), however, the proportion of data-based research had not significantly increased from TP1 and TP2: descriptive (TP1=23% vs. TP2=33%) or intervention (TP1=77% vs. TP2=67%). The proportion of intervention studies adopting biochemical verification of self-reported abstinence had significantly decreased from TP1 to TP2 with an increased reliance on self-reported abstinence (TP1=12% vs. TP2=36%). CONCLUSIONS: The current research output is not ideal or optimal to decrease smoking rates. Research institutions, scholars and funding organisations should take heed to review findings when developing future research and policy. PMID- 26062038 TI - What is the Relationship between Risky Outdoor Play and Health in Children? A Systematic Review. AB - Risky outdoor play has been associated with promoting children's health and development, but also with injury and death. Risky outdoor play has diminished over time, concurrent with increasing concerns regarding child safety and emphasis on injury prevention. We sought to conduct a systematic review to examine the relationship between risky outdoor play and health in children, in order to inform the debate regarding its benefits and harms. We identified and evaluated 21 relevant papers for quality using the GRADE framework. Included articles addressed the effect on health indicators and behaviours from three types of risky play, as well as risky play supportive environments. The systematic review revealed overall positive effects of risky outdoor play on a variety of health indicators and behaviours, most commonly physical activity, but also social health and behaviours, injuries, and aggression. The review indicated the need for additional "good quality" studies; however, we note that even in the face of the generally exclusionary systematic review process, our findings support the promotion of risky outdoor play for healthy child development. These positive results with the marked reduction in risky outdoor play opportunities in recent generations indicate the need to encourage action to support children's risky outdoor play opportunities. Policy and practice precedents and recommendations for action are discussed. PMID- 26062039 TI - What Is the Relationship between Outdoor Time and Physical Activity, Sedentary Behaviour, and Physical Fitness in Children? A Systematic Review. AB - The objective of this systematic review was to examine the relationship between outdoor time and: (1) physical activity, (2) cardiorespiratory fitness, (3) musculoskeletal fitness, (4) sedentary behaviour; or (5) motor skill development in children aged 3-12 years. We identified 28 relevant studies that were assessed for quality using the GRADE framework. The systematic review revealed overall positive effects of outdoor time on physical activity, sedentary behaviour, and cardiorespiratory fitness, although causality could not be assumed due to a lack of RCTs. Motor skill development was unrelated to outdoor time; however, this relationship was only examined in a single study of preschool children. No studies were found that examined associations between outdoor time and musculoskeletal fitness. PMID- 26062041 TI - Gelation-driven Dynamic Systemic Resolution: in situ Generation and Self Selection of an Organogelator. AB - An organogelator was produced and identified from a dynamic imine system, resolved and amplified by selective gelation. The formation of the organogel was monitored in situ by (1)H NMR, showing the existence of multiple reversible reactions operating simultaneously, and the redistribution of the involved species during gelation. The formed organogelator proved effective with a range of organic solvents, including DMSO, toluene, and longer, linear alcohols. PMID- 26062042 TI - Pacing Behavior and Tactical Positioning in 1500-m Short-Track Speed Skating. AB - PURPOSE: To gain more insight in pacing behavior and tactical positioning in 1500 m short-track speed skating, a sport in which several athletes directly compete in the same race. METHODS: Lap times and intermediate rankings of elite 1500-m short-track- skating competitors were collected over the season 2012-13 (N = 510, 85 races). Two statistical approaches were used to assess pacing behavior and tactical positioning. First, lap times were analyzed using a MANOVA, and for each lap differences between sex, race type, final rankings, and stage of competition were determined. Second, Kendall tau b correlations were used to assess relationships between intermediate and final rankings. In addition, intermediate rankings of the winner of each race were examined. RESULTS: In 1500 m (13.5 laps of 111.12 m), correlations between intermediate and final ranking gradually increased throughout the race (eg, lap 1, r = .05; lap 7, r = .26; lap 13, r = .85). Moreover, the percentage of race winners skating in the leading position was over 50% during the last 3 laps. Top finishers were faster than bottom-place finishers only during the last 5 laps, with on average 0.1- to 1.5-s faster lap times of the race winners compared with the others during the last 5 laps. CONCLUSIONS: Although a fast start led to faster finishing times, top finishers were faster than bottom-placed finishers only during the last 5 laps. Moreover, tactical positioning at 1 of the foremost positions during the latter phase of the race appeared to be a strong determinant of finishing position. PMID- 26062040 TI - Position Statement on Active Outdoor Play. AB - A diverse, cross-sectorial group of partners, stakeholders and researchers, collaborated to develop an evidence-informed Position Statement on active outdoor play for children aged 3-12 years. The Position Statement was created in response to practitioner, academic, legal, insurance and public debate, dialogue and disagreement on the relative benefits and harms of active (including risky) outdoor play. The Position Statement development process was informed by two systematic reviews, a critical appraisal of the current literature and existing position statements, engagement of research experts (N=9) and cross-sectorial individuals/organizations (N=17), and an extensive stakeholder consultation process (N=1908). More than 95% of the stakeholders consulted strongly agreed or somewhat agreed with the Position Statement; 14/17 participating individuals/organizations endorsed it; and over 1000 additional individuals and organizations requested their name be listed as a supporter. The final Position Statement on Active Outdoor Play states: "Access to active play in nature and outdoors--with its risks--is essential for healthy child development. We recommend increasing children's opportunities for self-directed play outdoors in all settings--at home, at school, in child care, the community and nature." The full Position Statement provides context for the statement, evidence supporting it, and a series of recommendations to increase active outdoor play opportunities to promote healthy child development. PMID- 26062043 TI - Association Between Sagittal Balance and Scoliosis in Patients with Parkinson Disease: A Cross-sectional Study. AB - OBJECTIVE: The aim of this study was to describe the association between scoliosis and sagittal balance parameters in Parkinson disease patients. DESIGN: This is a cross-sectional study. RESULTS: Fifty percent of the cohort presented a scoliosis larger than 11 degrees; 84% of the patients with scoliosis presented a thoracolumbar curve, 10% presented a thoracic one, and 6% presented a lumbar one. The group with scoliosis curves presented a lower spinosacral angle (111.6 [21.9] degrees vs. 121.7 [9.8] degrees, P < 0.05), whereas thoracic kyphosis, lumbar lordosis, and spinopelvic angle were similar. Pelvic incidence, pelvic tilt, and sacral slope were not statistically different. In the scoliosis group, the authors found negative correlations for lumbar lordosis/spinopelvic angle, sacral slope/spinosacral angle, and lumbar lordosis/pelvic tilt. Moreover, the sacral slope/pelvic tilt correlation was positive in patients without scoliosis and negative in others. The two groups did not present differences regarding age, years of disease, Hoehn-Yahr score, and Unified Parkinson Disease Rating Scale motor section. CONCLUSIONS: Pelvic parameters were similar in the two groups, whereas spinosacral angle was lower in patients with scoliosis. The prevalence of scoliosis in Parkinson disease was higher than what was previously described and the thoracolumbar spine was the mostly affected. PMID- 26062044 TI - Anti-inflammatory diterpene dimers from the root barks of Aphanamixis grandifolia. AB - A total of 14 new diterpene dimers, aphanamenes C-P ()1-14, with four known homologous compounds were isolated from the root barks of Aphanamixis grandifolia Bl. The structures of these compounds were elucidated by spectroscopic analyses, and their absolute configurations were determined using the CD exciton chirality method. In addition, all the compounds exhibited significant inhibition of lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophages, with IC50 values between 7.75 and 38.23 MUM. PMID- 26062045 TI - B-1 cells as a source of IgA. AB - Immunoglobulin A (IgA) is the most abundantly produced immunoglobulin found primarily on mucosal surfaces. The generation of IgA and its involvement in mucosal immune responses have been intensely studied over the past years. IgA can be generated in T cell-dependent and T cell-independent pathways, and it has an important impact on maintaining homeostasis within the mucosal immune system. There is good evidence that B-1 cells contribute substantially to the production of mucosal IgA and thus play an important role in regulating commensal microbiota. However, whether B-1 cells produce antigen-specific or only nonspecific IgA remains to be determined. This review will discuss what is currently known about IgA production by B-1 cells and the functional relevance of B-1 cell-derived IgA both in vitro and in vivo. PMID- 26062046 TI - Characteristics of 10-Year Survivors of Pancreatic Ductal Adenocarcinoma. AB - IMPORTANCE: To our knowledge, this study reports on the largest cohort of long term survivors (LTSs) (>=10 years) following a diagnosis of pancreatic ductal adenocarcinoma (PADC) and identifies the characteristics associated with LTS. OBJECTIVE: To determine patient, tumor, surgical, and sociodemographic characteristics associated with LTS. DESIGN, SETTING, AND PARTICIPANTS: A nationwide retrospective cohort study of patients with invasive PADC (International Classification of Diseases for Oncology, Third Edition codes 8140/3, 8500/3, 8021/3, and 8035/3) was conducted using data collected in the National Cancer Database (NCDB). A multivariable logistic regression model of factors significantly associated with LTS was developed and used to generate a nomogram predicting the likelihood of surviving at least 10 years from initial diagnosis. Data collected from more than 1500 academic centers and community hospitals in the United States and Puerto Rico were assessed. Patients included were those with histologically proven PADC who underwent pancreatic surgical resection aimed at removal of the primary tumor between January 1, 1998, and December 31, 2002 (n = 11,917). The initial cohort (n = 70,915) excluded noninvasive tumors or tumors with unknown histology (n = 11,696) and was limited to patients who underwent surgical resection (n = 47,302 excluded). Analysis was conducted from January 1, 1998, to December 31, 2011. EXPOSURES: Pancreatic ductal adenocarcinoma. MAIN OUTCOMES AND MEASURES: Long-term survival, defined as surviving at least 10 years from initial diagnosis. RESULTS: Of the 11,081 patients with complete survival information, 431 individuals (3.9%) were LTSs. Significant predictors of LTS included (determined using odds ratio [OR]; 95% CI), in order of importance, lymph node positivity ratio (0%: 4.6; 3.4-6.4), adjuvant chemotherapy (2.4; 2.0-3.0), pathologic T stage (T1: 3.1; 1.8-5.6), patient age (50-60 years: 3.4; 1.8-6.7), tumor grade (well differentiated: 2.2; 1.5-3.0), surgical margin (negative: 1.9; 1.4-2.6), pathologic M stage (M = X: 5.6; 2.1-22.8), tumor size (<2 cm: 1.7; 1.2-2.5), educational level (>86% high school graduates: 1.7; 1.2-2.4), and insurance status according to the patient's zip code (private: 2.0; 95% CI, 0.9-5.1). The model C index was 0.768. Based on our nomogram, patients with the most favorable characteristics had an 18.1% chance of LTS. Furthermore, survival curves demonstrated that the probability of dying following initial diagnosis of PADC reached a plateau of approximately 10% per year after 7 years of survival. CONCLUSIONS AND RELEVANCE: Although PADC remains a deadly disease, long-term survival is possible, even beyond the 10-year mark. Our adjusted analysis identified lymph node ratio, administration of adjuvant chemotherapy, and pathologic T stage as being the top 3 variables associated with LTS of PADC. In addition, our easy-to-use nomogram may be able to identify potential LTS among patients with resected PADC. PMID- 26062048 TI - I. Hodgkin lymphoma: special challenges and solutions. PMID- 26062049 TI - III. Current concepts in primary central nervous lymphoma. PMID- 26062050 TI - IV. Masses in the mediastinum: primary mediastinal lymphoma and intermediate types. PMID- 26062051 TI - V. Smoldering multiple myeloma. PMID- 26062052 TI - VI. FDG-PET as a biomarker in lymphoma: from qualitative to quantitative analysis. PMID- 26062053 TI - VII. Are lymphomas driven by epigenetic lesions? PMID- 26062054 TI - VIII. Treatment of chronic lymphocytic leukaemia, where are we heading? PMID- 26062055 TI - IX. Is it only about MYC? How to approach the diagnosis of diffuse large B-cell lymphomas. PMID- 26062056 TI - X. Challenges and future directions in peripheral T-cell lymphoma. PMID- 26062057 TI - XI. Management of paediatric and adult non-Hodgkin lymphoma: what lessons can each teach the other? AB - Is there anything that we can learn from each other regarding paediatric and adult non-Hodgkin Lymphoma (NHL) management? Do we treat the same patients? Are there differences in lymphoma biology in the different age groups? Are the procedures of decision making and the infrastructure comparable? Is the weighing of toxicity and outcome aspects in the benefit and risk assessments prior to treatment decisions comparable? Interestingly, the proportional distribution of the NHL subtypes and the spectrum of NHL occurring in children and adolescents differs significantly from that in adults. This observation might motivate biological studies aiming to elucidate the pathomechanisms of lymphomagenesis. Concerning NHL diagnosis and staging, the comparison of outcome data reported for paediatric and adult patient series is often impaired by the use of different staging systems. However, the impact of reference laboratories supporting correct subtyping and the advantages of population-based patient recruitment are experiences that might be transferable between paediatric and adult oncologists. Interestingly, the process of implementing new drugs into current treatment strategies and making these drugs available to patients varies substantially across patient's age groups. The far lower absolute number of patients, especially of relapsed patients, and the favorable outcome with current standard treatment may contribute to the marked differences in the kinetic of implementing new compounds comparing adult with paediatric NHL patients. Also, the basis for the conduction of cooperative clinical trials with pharmaceutical companies needs to be strengthened in paediatric clinical trial groups. In conclusion, both paediatric and adult oncologists benefit from the interdisciplinary discussion with each other, not only concerning results and experiences in clinical trials but also with respect to critical aspects of infrastructure. PMID- 26062058 TI - XII. Therapeutic exploitation of autologous T-cell activation in B-cell lymphoma. PMID- 26062059 TI - XIII. Molecular pathogenesis of transformed lymphomas. PMID- 26062060 TI - XIV. The pathology of transformation of indolent B cell lymphomas. PMID- 26062061 TI - XV. Clinical aspects of transformed lymphoma. PMID- 26062062 TI - XVI. Early stage Hodgkin lymphoma. PMID- 26062063 TI - XVII. Treatment of advanced-stage Hodgkin lymphoma. PMID- 26062064 TI - XVIII. Management of nodular lymphocyte predominant Hodgkin lymphoma. PMID- 26062065 TI - II. Challenges in the management of post-transplant lymphoproliferative disorder. PMID- 26062073 TI - Discovery of the K4 Structure Formed by a Triangular pi Radical Anion. AB - The K4 structure was theoretically predicted for trivalent chemical species, such as sp(2) carbon. However, since attempts to synthesize the K4 carbon have not succeeded, this allotrope has been regarded as a crystal form that might not exist in nature. In the present work, we carried out electrochemical crystallization of the radical anion salts of a triangular molecule, naphthalene diimide (NDI)-Delta, using various electrolytes. X-ray crystal analysis of the obtained crystals revealed the K4 structure, which was formed by the unique intermolecular pi overlap directed toward three directions from the triangular shape NDI-Delta radical anions. Electron paramagnetic resonance and static magnetic measurements confirmed the radical anion state of NDI-Delta and indicated an antiferromagnetic intermolecular interaction with the Weiss constant of theta = -10 K. The band structure calculation suggested characteristic features of the present material, such as a metallic ground state, Dirac cones, and flat bands. PMID- 26062074 TI - Combined endobronchial and esophageal endosonography for the diagnosis and staging of lung cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). PMID- 26062075 TI - Universal chiral-triggered magnetization switching in confined nanodots. AB - Spin orbit interactions are rapidly emerging as the key for enabling efficient current-controlled spintronic devices. Much work has focused on the role of spin orbit coupling at heavy metal/ferromagnet interfaces in generating current induced spin-orbit torques. However, the strong influence of the spin-orbit derived Dzyaloshinskii-Moriya interaction (DMI) on spin textures in these materials is now becoming apparent. Recent reports suggest DMI-stabilized homochiral domain walls (DWs) can be driven with high efficiency by spin torque from the spin Hall effect. However, the influence of the DMI on the current induced magnetization switching has not been explored nor is yet well-understood, due in part to the difficulty of disentangling spin torques and spin textures in nano-sized confined samples. Here we study the magnetization reversal of perpendicular magnetized ultrathin dots, and show that the switching mechanism is strongly influenced by the DMI, which promotes a universal chiral non-uniform reversal, even for small samples at the nanoscale. We show that ultrafast current induced and field-induced magnetization switching consists on local magnetization reversal with domain wall nucleation followed by its propagation along the sample. These findings, not seen in conventional materials, provide essential insights for understanding and exploiting chiral magnetism for emerging spintronics applications. PMID- 26062076 TI - 6-Acetoxy Cyperene, a Patchoulane-type Sesquiterpene Isolated from Cyperus rotundus Rhizomes Induces Caspase-dependent Apoptosis in Human Ovarian Cancer Cells. AB - Cyperus rotundus (Cyperaceae) has been widely used in traditional medicine for the treatment of various diseases, including cancer. Although an anti-tumour effect has been suggested for C. rotundus, the anti-tumour effects and underlying molecular mechanisms of its bioactive compounds are poorly understood. The n hexane fraction of an ethanol extract of C. rotundus rhizomes was found to inhibit cell growth in ovarian cancer (A2780, SKOV3 and OVCAR3) and endometrial cancer (Hec1A and Ishikawa) cells. Among the thirteen sesquiterpenes isolated from the n-hexane fraction, some patchoulane-type compounds, but not eudesmane type compounds, showed moderate cytotoxic activity in human ovarian cancer cells. In particular, the patchoulane sesquiterpene 6-acetoxy cyperene had the most potent cytotoxicity. In this regard, propidium iodide/Annexin V staining and terminal deoxynucleotidyl transferase dUTP (deoxynucleotide triphosphate) nick end labeling assay were performed to study cell cycle progression and apoptosis. 6-acetoxy cyperene induced apoptosis, as shown by the accumulation of sub-G1 and apoptotic cells. Furthermore, treatment with 6-acetoxy cyperene stimulated the activation of caspase-3, caspase-8 and caspase-9 and poly(ADP-ribose)polymerase in a dose-dependent manner. Pretreatment with caspase inhibitors neutralized the pro-apoptotic activity of 6-acetoxy cyperene. Taken together, these data suggest that 6-acetoxy cyperene, a patchoulane-type sesquiterpene isolated from C. rotundus rhizomes, is an anti-tumour compound that causes caspase-dependent apoptosis in ovarian cancer cells. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26062077 TI - Longitudinal Cerebral Fissure Anatomy Variations in Brachy-, Dolicho- and Mesaticephalic Dogs and Their Importance to Brain Surgery. AB - The study used a sample of 69 formalin-fixed brains from adult dog cadavers (n = 69) and aimed (1) to characterize the longitudinal cerebral fissure (LCF) anatomy in brachy-(B), dolicho-(D) and mesaticephalic-(M) dogs and their potential differences, and (2) to establish cranioencephalic relationships between the LCF and five classical craniometric points(cp): asterion(ast), bregma(b), stephanion(st), glabella(g), and pterion(pt). Anatomical records were collected using a digital caliper, and for statistical analysis P-values < 0.05 were considered significant. The LCF length can be ranked, in ascending order as B < D < M, and if used as a surgical corridor, the M group had the greatest surgical corridor area, and the D group the smallest. LCF morphology was uniform among the three groups exhibiting dilated anterior(AR) and posterior(PR) regions and narrow middle region, where the most marked differences were registered. The LCF AR is the ideal spot to begin brain surgery if the LCF is to be used as a surgical corridor in B and M, while the LCF PR should be considered in D. The five cp selected were quite useful to understand LCF anatomical morphology, its projections over the external skull surface, and to establish cranioencephalic relationships between the LCF and vault; allowing us to consider the vault anterior area in B, and in M, and the vault posterior area in D for craniotomy initial burr-hole placement. As for the distance from the cp projections in the brain surface to the LCF regions, major differences were registered by comparing the B group with the other two, and for both hemispheres. PMID- 26062078 TI - Neutrophil-to-lymphocyte ratio is not a predictor of liver histology in patients with nonalcoholic fatty liver disease. AB - OBJECTIVES: It has been reported that the neutrophil-to-lymphocyte ratio (NLR) can be measured relatively easily and can serve as a valuable index for much clinical pathology. The aim of this study was to investigate the association between NLR and hepatic histological findings in patients with nonalcoholic fatty liver disease (NAFLD). DESIGN AND METHODS: A total of 226 consecutive patients with biopsy-proven NAFLD [nonalcoholic steatohepatitis (NASH, n=105), borderline NASH (n=74), and simple steatosis (n=47)] were enrolled. NASH and fibrosis were diagnosed histologically using the NAFLD Clinical Research Network criteria. RESULTS: Significant differences were found in aspartate aminotransferase (P<0.001), alanine aminotransferase (P<0.001) levels, and white blood cell (P=0.007) and neutrophil counts (P=0.042) between the three groups of patients. In addition, significantly higher BMI (P=0.024), waist circumference (P=0.011), aspartate aminotransferase (P=0.003), alanine aminotransferase (P=0.005), insulin (P=0.008), and homeostasis model assessment-insulin resistance (P=0.009) levels were found in patients with fibrosis (n=133) in comparison with those without fibrosis (n=93). There was no correlation between NLR and glucose, homeostasis model assessment-insulin resistance, lipid parameters, and the NAFLD activity score. Analysis of the NLR in relation to histological findings also showed no association between these parameters. CONCLUSION: To the best of our knowledge, this is the largest study that has investigated these relationships in this clinically relevant condition. The findings of the present study show that NLR is not associated with the severity of hepatic inflammation or fibrosis and thus cannot be recommended as a surrogate marker of liver injury in patients with NAFLD. PMID- 26062079 TI - Nonalcoholic fatty liver disease and alteration in semen quality and reproductive hormones. AB - OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. Some reports have shown that NAFLD may cause multisystem damage, but its influence on male reproductive function has rarely been studied. AIM: To evaluate the influence of NAFLD on sperm quality and reproductive hormones in Chinese men. MATERIALS AND METHODS: A total of 102 NAFLD men and 94 healthy men without fatty liver (control) were enrolled in this study. All participants underwent a physical examination, and were subjected to lifestyle questionnaires and abdominal ultrasound examination. The semen quality (volume, concentration, motility, and morphology) and serum hormonal levels (testosterone, estradiol, follicle-stimulating hormone, inhibin B, sex hormone binding globulin, and luteinizing hormone) were examined and compared between the two groups. RESULTS: The levels of serum testosterone and sex hormone-binding globulin were significantly lower in the NAFLD patients compared with the control group. Sperm concentration (P=0.04), sperm count (P=0.01), and total motility (P=0.03) in the NAFLD patients were significantly decreased compared with the control group. However, no significant differences were observed in semen volume and morphology. Multivariate analysis showed that sperm concentration, sperm count, and motility were significantly associated with NAFLD and abstinence (P<0.05 or P<0.001). CONCLUSION: These results suggest that NAFLD could significantly affect sperm quality and reproductive hormones. PMID- 26062080 TI - Serological markers of autoimmunity in children with hepatitis A: relation to acute and fulminant presentation. AB - OBJECTIVES: Hepatitis A virus (HAV) infection tends to be a self-limiting disease without serious sequelae, but fulminant hepatitis, with a high mortality, develops in 0.1-0.2% of the cases. Sometimes, HAV infection precipitates autoimmune hepatitis (AIH). We aimed to assess the frequency and clinical significance of serologic markers of autoimmunity during hepatitis A infection with an acute or fulminant presentation compared with those in AIH. METHODS: The study included 126 children: 46 with HAV infection (33 with acute and 13 with fulminant presentation), 53 with AIH, and 27 healthy controls. In all, we measured autoantibodies titer (antinuclear antibody, antismooth muscle antibody, and liver kidney microsomal antibody-1) and serum gammaglobulins. RESULTS: Autoantibodies were detected in the majority of HAV (63.1%) and AIH (79.2%) groups, but in none of the controls. Gammaglobulins were significantly higher in the HAV group (1.93+/-0.57 g/dl) than in the controls (1.32+/-0.29 g/dl), but lower than that in the AIH group (2.93+/-1.2 g/dl) (P<0.0001 for all). In the HAV group, gammaglobulins were significantly higher in those with fulminant (2.21+/ 0.46 g/dl) than in those with acute presentation (1.82+/-0.57 g/dl) (P=0.019), but comparable with that in AIH (P=0.095). Gammaglobulins correlated significantly with disease severity in both HAV and AIH groups. CONCLUSION: Hypergammaglobulinemia and a high occurrence of autoantibodies are encountered in HAV infection. This may support the immunological basis of its pathogenesis. Moreover, the higher gammaglobulins in fulminant HAV, with an insignificant difference from that in AIH, suggest that a more aggressive immunological reaction is related to this presentation. PMID- 26062081 TI - Research Synthesis Methods special issue on network meta-analysis: introduction from the editors. PMID- 26062082 TI - Use of indirect comparison methods in systematic reviews: a survey of Cochrane review authors. AB - Because of insufficient evidence from direct comparison trials, the use of indirect or mixed treatment comparison methods has attracted growing interest recently. We investigated the views and knowledge of Cochrane systematic review authors regarding the use of indirect comparison and related methods in the evaluation of competing healthcare interventions. An online survey was sent to 84 authors of Cochrane systematic review reviews between January and March 2011. The response rate was 57%. Most respondents (87%) had heard of/had some knowledge of indirect comparison, and 23% actually used indirect comparison methods. Some were suspicious of the methods (9%). Most authors (89%) felt they needed more training, especially in assessing the validity of indirect evidence. Almost all felt that the validity of indirect comparison could potentially be influenced by a large number of effect modifiers. Many reviewers (76%) accepted that indirect evidence is needed as it may be the only source of information for relative effectiveness of competing interventions, provided that review authors and readers are conscious of its limitations. Time commitment and resources needed were identified as an important concern for Cochrane reviewers. In summary, there is an acceptance of the increasing demand for indirect comparison and related methods and an urgent need to develop structured guidance and training for its use and interpretation. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 26062083 TI - Indirect and mixed-treatment comparison, network, or multiple-treatments meta analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. AB - The ever increasing number of alternative treatment options and the plethora of clinical trials have put systematic reviews and meta-analysis under a new perspective by emphasizing the need to make inferences about competing treatments for the same condition. The statistical component in reviews that compare multiple interventions, network meta-analysis, is the next generation evidence synthesis toolkit which, when properly applied, can serve decision-making better than the established pairwise meta-analysis. The criticism and enthusiasm for network meta-analysis echo those that greeted the advent of simple meta-analysis. The main criticism is associated with the difficulty in evaluating the assumption underlying the statistical synthesis of direct and indirect evidence. In the present article, the assumption of the network meta-analysis are presented using various formulations, the statistical and nonstatistical methodological considerations are elucidated, and the progress achieved in this field is summarized. Throughout, focus is put on highlighting the analogy between the concerns and difficulties that the scientific community had some time ago when advancing from individual trials to their quantitative synthesis via meta analysis and those currently expressed about the transition from head-to-head meta-analyses to network meta-analysis. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062084 TI - Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. AB - Meta-analyses that simultaneously compare multiple treatments (usually referred to as network meta-analyses or mixed treatment comparisons) are becoming increasingly common. An important component of a network meta-analysis is an assessment of the extent to which different sources of evidence are compatible, both substantively and statistically. A simple indirect comparison may be confounded if the studies involving one of the treatments of interest are fundamentally different from the studies involving the other treatment of interest. Here, we discuss methods for addressing inconsistency of evidence from comparative studies of different treatments. We define and review basic concepts of heterogeneity and inconsistency, and attempt to introduce a distinction between 'loop inconsistency' and 'design inconsistency'. We then propose that the notion of design-by-treatment interaction provides a useful general framework for investigating inconsistency. In particular, using design-by-treatment interactions successfully addresses complications that arise from the presence of multi-arm trials in an evidence network. We show how the inconsistency model proposed by Lu and Ades is a restricted version of our full design-by-treatment interaction model and that there may be several distinct Lu-Ades models for any particular data set. We introduce novel graphical methods for depicting networks of evidence, clearly depicting multi-arm trials and illustrating where there is potential for inconsistency to arise. We apply various inconsistency models to data from trials of different comparisons among four smoking cessation interventions and show that models seeking to address loop inconsistency alone can run into problems. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062085 TI - Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. AB - Network meta-analysis (multiple treatments meta-analysis, mixed treatment comparisons) attempts to make the best use of a set of studies comparing more than two treatments. However, it is important to assess whether a body of evidence is consistent or inconsistent. Previous work on models for network meta analysis that allow for heterogeneity between studies has either been restricted to two-arm trials or followed a Bayesian framework. We propose two new frequentist ways to estimate consistency and inconsistency models by expressing them as multivariate random-effects meta-regressions, which can be implemented in some standard software packages. We illustrate the approach using the mvmeta package in Stata. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062086 TI - Selecting the best scale for measuring treatment effect in a network meta analysis: a case study in childhood nocturnal enuresis. AB - Dichotomous outcomes in pairwise meta-analysis are typically summarised using the odds ratio (OR), relative risk (RR) or risk difference (RD). The hazard ratio (HR) may also be used where events occur over time. Choice of scale is often determined by ease of interpretation or mathematical properties of a measure, as there is frequently insufficient power to compare goodness-of-fit across different scales. Network meta-analysis (NMA) combines evidence across a network of treatment comparisons. NMA allows the combination of a greater numbers of trials, so there is greater potential to use goodness-of-fit statistics to determine an appropriate scale on which the effects of treatments are additive. In this paper, we explore choice of scale in an NMA of childhood nocturnal enuresis for the outcome 'failure to achieve 14 days consecutive dry nights'. We compare OR, RR of both the harmful (RRH) and the beneficial (RRB) outcomes, RD and HR. Using a Bayesian framework, the posterior mean residual deviance and deviance information criterion are used to evaluate model fit and selection between the different summary effect measures. We use I(2) to examine within comparison heterogeneity for the pairwise analyses. The results suggest that the HR and RRB provide the best fit. We conclude that choice of scale should be based on physiological and epidemiological understanding of the disease process, together with an empirical assessment of model adequacy. HR should be given greater consideration where there is an underlying time-to-event process. We demonstrate how results can be transformed to an alternative scale to aid interpretability. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062087 TI - Accounting for correlation in network meta-analysis with multi-arm trials. AB - Multi-arm trials (trials with more than two arms) are particularly valuable forms of evidence for network meta-analysis (NMA). Trial results are available either as arm-level summaries, where effect measures are reported for each arm, or as contrast-level summaries, where the differences in effect between arms compare with the control arm chosen for the trial. We show that likelihood-based inference in both contrast-level and arm-level formats is identical if there are only two-arm trials, but that if there are multi-arm trials, results from the contrast-level format will be incorrect unless correlations are accounted for in the likelihood. We review Bayesian and frequentist software for NMA with multi arm trials that can account for this correlation and give an illustrative example of the difference in estimates that can be introduced if the correlations are not incorporated. We discuss methods of imputing correlations when they cannot be derived from the reported results and urge trialists to report the standard error for the control arm even if only contrast-level summaries are reported. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062088 TI - Using network meta-analysis to evaluate the existence of small-study effects in a network of interventions. AB - Suggested methods for exploring the presence of small-study effects in a meta analysis and the possibility of publication bias are associated with important limitations. When a meta-analysis comprises only a few studies, funnel plots are difficult to interpret, and regression-based approaches to test and account for small-study effects have low power. Assuming that the cause of funnel plot asymmetry is likely to affect an entire research field rather than only a particular comparison of interventions, we suggest that network meta-regression is employed to account for small-study effects in a set of related meta-analyses. We present several possible models for the direction and distribution of small study effects and we describe the methods by re-analysing two published networks. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062089 TI - Network meta-analysis of individual and aggregate level data. AB - Network meta-analysis is often performed with aggregate-level data (AgD). A challenge in using AgD is that the association between a patient-level covariate and treatment effects at the study level may not reflect the individual-level effect modification. In this paper, non-linear network meta-analysis models for combining individual patient data (IPD) and AgD are presented to reduce bias and uncertainty of direct and indirect treatment effects in the presence of heterogeneity. The first method uses the same model form for IPD and AgD. With the second method, the model for AgD is obtained by integrating an underlying IPD model over the joint within-study distribution of covariates, in line with the method by Jackson et al. for ecological inferences. With simulated examples, the models are illustrated. Having IPD for a subset of studies improves estimation of treatment effects in the presence of patient-level heterogeneity. Of the two proposed non-linear models for combining IPD and AgD, the second seems less affected by bias in situations with large treatment-by-patient-level-covariate interactions, probably at the cost of greater uncertainty. Additional studies are needed to better understand when one model is favorable over the other. For network meta-analysis, it is recommended to use IPD when available. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062090 TI - Plasticity in Vegetative Growth over Contrasted Growing Sites of an F1 Olive Tree Progeny during Its Juvenile Phase. AB - Climatic changes impact fruit tree growth and severely limit their production. Investigating the tree ability to cope with environmental variations is thus necessary to adapt breeding and management strategies in order to ensure sustainable production. In this study, we assessed the genetic parameters and genotype by environment interaction (GxE) during the early tree growth. One hundred and twenty olive seedlings derived from the cross 'Oliviere' x 'Arbequina' were examined across two sites with contrasted environments, accounting for ontogenetic trends over three years. Models including the year of growth, branching order, environment, genotype effects, and their interactions were built with variance function and covariance structure of residuals when necessary. After selection of a model, broad sense heritabilities were estimated. Despite strong environmental effect on most traits, no GxE was found. Moreover, the internal structure of traits co-variation was similar in both sites. Ontogenetic growth variation, related to (i) the overall tree form and (ii) the growth and branching habit at growth unit scale, was not altered by the environment. Finally, a moderate to strong genetic control was identified for traits at the whole tree scale and at internode scale. Among all studied traits, the maximal internode length exhibited the highest heritability (H2 = 0.74). Considering the determinant role of this trait in tree architecture and its stability across environments, this study consolidates its relevance for breeding. PMID- 26062091 TI - A New Spray Device to Deliver Topical Ocular Medication: Penetration of Fluorescein to the Anterior Segment. AB - PURPOSE: To measure the penetration of fluorescein into the anterior ocular compartments after exposure of the cornea to a mist of aerosol droplets. METHODS: This was an open-label proof-of-principle trial. Eighteen healthy volunteers were asked to participate. A conventional (50 MUL) drop of fluorescein solution (20 mg/mL) was administered to the right eye; an ocular mist (10 MUL) of the same solution was applied to the left eye. Autofluorescence (photons/s) was measured in the cornea, the anterior chamber (AC), and the lens before administration and at 1, 2, 5, 10, 20, 50, and 100 min thereafter. The area under the curve (AUC) was calculated. For the vitreous cavity, measurements were performed at baseline and after 100 min. RESULTS: All participants completed the study. AUC (mean+/-SD) for the cornea was (363+/-431)*10(4) photons after drop application and (154+/ 265)*10(4) photons after the mist (P=0.005). For the AC, these values were (6.9+/ 10.3)*10(4) and (2.9+/-5.4)*10(4) photons, respectively (P=0.14). Autofluorescence data obtained in the lens did not allow reliable AUC calculations. Autofluorescence in the vitreous at 100 min did not significantly exceed the level at baseline. CONCLUSION: It was demonstrated that fluorescein applied to the ocular surface with the spray device enters the AC. The total amount of fluorescein molecules reaching the ocular surface by the 2 methods of administration, however, is not equivalent. Therefore, no definitive conclusions on relative bioavailability can be drawn from this experiment. PMID- 26062092 TI - An Approach to Realizing Process Control for Underground Mining Operations of Mobile Machines. AB - The excavation and production in underground mines are complicated processes which consist of many different operations. The process of underground mining is considerably constrained by the geometry and geology of the mine. The various mining operations are normally performed in series at each working face. The delay of a single operation will lead to a domino effect, thus delay the starting time for the next process and the completion time of the entire process. This paper presents a new approach to the process control for underground mining operations, e.g. drilling, bolting, mucking. This approach can estimate the working time and its probability for each operation more efficiently and objectively by improving the existing PERT (Program Evaluation and Review Technique) and CPM (Critical Path Method). If the delay of the critical operation (which is on a critical path) inevitably affects the productivity of mined ore, the approach can rapidly assign mucking machines new jobs to increase this amount at a maximum level by using a new mucking algorithm under external constraints. PMID- 26062093 TI - Usefulness of measuring electrically evoked auditory brainstem responses in children with inner ear malformations during cochlear implantation. AB - CONCLUSIONS: EABR is a reliable and effective way of objectively confirming device function and implant-responsiveness of the peripheral auditory neurons up to the level of the brainstem in cases of inner ear malformation. OBJECTIVE: To investigate the usefulness of measuring the intra-operative electrically evoked compound action potential (ECAP) and electrically evoked auditory brainstem response (EABR) in patients with and without congenital inner ear anomalies during cochlear implantation. METHOD: Thirty-eight consecutive children (40 ears) aged 5 or younger with congenital profound hearing loss. Twenty-four (25 ears) lacked congenital inner ear anomalies. The 14 patients (15 ears) with a malformation had common cavities (four ears), incomplete partition type I (three ears), cochlea hypoplasia type III (three ears), enlarged vestibular aqueduct (four ears), and cochlear nerve canal stenosis (one ear). Main outcome measures are ECAP and EABR responses. RESULTS: Of the 25 ears lacking any malformation, 21, three, and one showed 'Good', 'Variable', and 'No' ECAP responses, respectively, and 24 and one showed 'Good' and 'Variable' intra-cochlear responses, respectively. Of the 15 ears with a malformation, two showed 'Good' ECAP responses, nine had 'Variable' ECAP responses, and four showed 'No' ECAP responses. Moreover, five showed 'Good' EABR responses and 10 showed 'Variable' EABR responses. PMID- 26062094 TI - Induction of a quorum sensing pathway by environmental signals enhances group A streptococcal resistance to lysozyme. AB - The human-restricted pathogen Streptococcus pyogenes (Group A Streptococcus, GAS) is responsible for wide-ranging pathologies at numerous sites in the body but has the proclivity to proliferate in individuals asymptomatically. The ability to survive in diverse tissues is undoubtedly benefited by sensory pathways that recognize environmental cues corresponding to stress and nutrient availability and thereby trigger adaptive responses. We investigated the impact that environmental signals contribute to cell-to-cell chemical communication [quorum sensing (QS)] by monitoring activity of the Rgg2/Rgg3 and SHP-pheromone system in GAS. We identified metal limitation and the alternate carbon source mannose as two environmental indicators likely to be encountered by GAS in the host that significantly induced the Rgg-SHP system. Disruption of the metal regulator MtsR partially accounted for the response to metal depletion, whereas ptsABCD was primarily responsible for QS induction due to mannose, but each sensory system induced Rgg-SHP signaling apparently by different mechanisms. Significantly, we found that induction of QS, regardless of the GAS serotype tested, led to enhanced resistance to the antimicrobial agent lysozyme. These results indicate the benefits for GAS to integrate environmental signals with intercellular communication pathways in protection from host defenses. PMID- 26062095 TI - Nutrition Policy Decreases Sugar-Sweetened Beverages in Municipal Parks: Lessons Learned From Carson, California. AB - In light of the childhood obesity epidemic, many cities are adopting healthy park vending policies, but the evidence on the effectiveness of these policies is scant. This study examines how implementation of a healthy vending policy in Carson, California, changes the types of beverages that are available in park vending machines. The study design is a pre-posttest with post-only comparison group. The main outcome is proportion of beverages in vending machines that is consistent with caloric and sugar content guidelines for children as defined by the Nutrition Environment Measures-Vending (NEMS-V) tool. This study finds that prior to implementation of the vending policy, 70% of the beverages did not meet NEMS-V guidelines, on average. After implementation of the vending policy, this number declined to 7%. This study suggests that healthy vending policies can have an impact on the types of beverages that are available in city parks. PMID- 26062096 TI - Out-of-School-Time Academic Programs to Improve School Achievement: A Community Guide Health Equity Systematic Review. AB - CONTEXT: Low-income and minority status in the United States are associated with poor educational outcomes, which, in turn, reduce the long-term health benefits of education. OBJECTIVE: This systematic review assessed the extent to which out of-school-time academic (OSTA) programs for at-risk students, most of whom are from low-income and racial/ethnic minority families, can improve academic achievement. Because most OSTA programs serve low-income and ethnic/racial minority students, programs may improve health equity. DESIGN: Methods of the Guide to Community Preventive Services were used. An existing systematic review assessing the effects of OSTA programs on academic outcomes (Lauer et al 2006; search period 1985-2003) was supplemented with a Community Guide update (search period 2003-2011). MAIN OUTCOME MEASURE: Standardized mean difference. RESULTS: Thirty-two studies from the existing review and 25 studies from the update were combined and stratified by program focus (ie, reading-focused, math-focused, general academic programs, and programs with minimal academic focus). Focused programs were more effective than general or minimal academic programs. Reading focused programs were effective only for students in grades K-3. There was insufficient evidence to determine effectiveness on behavioral outcomes and longer-term academic outcomes. CONCLUSIONS: OSTA programs, particularly focused programs, are effective in increasing academic achievement for at-risk students. Ongoing school and social environments that support learning and development may be essential to ensure the longer-term benefits of OSTA programs. PMID- 26062097 TI - Factors Associated With Provider Reporting of Child and Adolescent Vaccination History to Immunization Information Systems: Results From the National Immunization Survey, 2006-2012. AB - CONTEXT: Use of Immunization information systems (IISs) by providers can improve vaccination rates by identifying missed opportunities. However, provider reporting of children's vaccination histories to IISs remains suboptimal. OBJECTIVE: To assess factors associated with provider reporting to an IIS. DESIGN: Analysis of 2006-2012 National Immunization Survey (NIS) and NIS-Teen data. NIS and NIS-Teen are ongoing random-digit-dial telephone surveys of households with children and adolescents, respectively, followed by a mail survey to providers to obtain the patient's vaccination history. SETTING AND PARTICIPANTS: A total of 115 285 children aged 19 to 35 months and 83 612 adolescents aged 13 to 17 years and their immunization providers in the United States. MAIN OUTCOME MEASURES: The percentage of children and adolescents with 1 or more providers reporting to or obtaining vaccination information from their local IISs. Multivariable logistic regression was used to examine patient and provider factors associated with provider reporting to IISs and adjusted prevalence of children and adolescents with 1 or more providers reporting to IISs. RESULTS: In 2012, 79.4% of children and 77.4% of adolescents had 1 or more providers report any of their vaccination data to an IIS, and 41.9% of children and 51.5% of adolescents had providers who obtained any of their vaccination histories from an IIS. During 2006-2012, children and adolescents were more likely to have any of their vaccination data reported to an IIS if they received care from all public versus all private providers (children: 84.4% vs 69.6%, P < .0001; adolescents: 84.6% vs 66.4%, P < .0001), had 1 or more providers who ordered vaccines from a state or local health department (children: 76.7% vs 59.5%, P < .0001; adolescents: 77.0% vs 55.6%, P < .0001), or had 1 or more providers obtain vaccination information from the IIS (children: 86.1% vs 71.2%, P < .0001; adolescents: 83.7% vs 64.6%, P < .0001). CONCLUSIONS: Health department staff should target providers less likely to use IIS services, including private providers, and providers not ordering vaccines from health departments to ensure they use IIS services. PMID- 26062098 TI - Media Outlet and Consumer Reactions to Promotional Activities of the Choose Health LA Restaurants Program in Los Angeles County. AB - OBJECTIVE: This study sought to assess promotional activities undertaken to raise public awareness of the Choose Health LA Restaurants program in Los Angeles County, an environmental change strategy that recognizes restaurants for offering reduced-size and healthier menu options. DESIGN: We used multiple methods to assess public awareness of and reactions to the promotional activities, including an assessment of the reach of core promotional activities, a content analysis of earned media, and an Internet panel survey. SETTING: The study was conducted in Los Angeles County, home to more than 10 million residents. PARTICIPANTS: An online survey firm recruited participants for an Internet panel survey; to facilitate generalization of results to the county's population, statistical weights were applied to analyses of the survey data. INTERVENTION: Promotional activities to raise awareness of the program included community engagement, in store promotion, and a media campaign. MAIN OUTCOME MEASURES: Outcomes included media impressions, the number of people who reported seeing the Choose Health LA Restaurants logo, and a description of the themes present in earned media. RESULTS: Collectively, paid media outlets reported 335 587 229 total impressions. The Internet panel survey showed that 12% of people reported seeing the program logo. Common themes in earned media included the Choose Health LA Restaurants program aims to provide restaurant patrons with more choices, represents a new opportunity for restaurants and public health to work together, will benefit participating restaurants, and will positively impact health. CONCLUSIONS: Promotional activities for the Choose Health LA Restaurants program achieved modest reach and positive reactions from media outlets and consumers. The program strategy and lessons learned can help inform present and future efforts to combine environmental and individually focused strategies that target key influences of consumer food selection. PMID- 26062099 TI - Reproducibility and prognostic value of pattern of invasion scoring in low-stage oral squamous cell carcinoma. AB - AIMS: To evaluate and compare the prognostic value and reproducibility of different methods of pattern of invasion scoring in oral squamous cell carcinomas. The additional prognostic value to established histopathological prognostic factors was also analysed. METHODS AND RESULTS: The study group was confined to 211 previously untreated patients who underwent surgery for low-stage oral squamous cell carcinoma between 1997 and 2008. Median follow-up was 64 months (range 0-193 months). Pattern of invasion was scored using five previously described methods, at random and independently, by two observers. Pattern of invasion scoring showed moderate interobserver reproducibility (Cohen's kappa = 0.52-0.58). The predominant pattern of invasion and the summed predominant and worst pattern of invasion were independent prognosticators for locoregional recurrence-free survival (LRRFS) [hazard ratio (HR): 2.1, P = 0.033 and HR 2.2, P = 0.024, respectively] and disease-specific survival (DSS) (HR 2.3, P = 0.032 and HR 2.1, P = 0.044, respectively) in multivariate Cox regression analyses. The Harrell's C index for proven prognostic histopathological factors was 0.66 for LRRFS and 0.67 for DSS. This improved to 0.69 and 0.73 with the addition of pattern of invasion. CONCLUSIONS: Pattern of invasion is an independent prognostic factor in low-stage oral squamous cell carcinoma. However, it has a moderate reproducibility, and the contributory value next to other prognostic histopathological factors is minimal. PMID- 26062100 TI - Intratunical Injection of Genetically Modified Adipose Tissue-Derived Stem Cells with Human Interferon alpha-2b for Treatment of Erectile Dysfunction in a Rat Model of Tunica Albugineal Fibrosis. AB - INTRODUCTION: Peyronie's disease (PD) has frequently been associated with erectile dysfunction (ED) and may further compromise coitus. AIM: To investigate the efficacy of intratunical injection of genetically modified rat adipose tissue derived stem cells (ADSCs) expressing human interferon alpha-2b (ADSCs-IFN) in decreasing fibrosis and restoring erectile function in a rat model of tunica albugineal fibrosis (TAF). METHODS: A total of 36 Sprague-Dawley rats (12 weeks old; 300-350 g) were randomly divided in six equal groups: (i) sham group (50 MUL saline-injected into the tunica albuginea [TA]); (ii) TAF group (transforming growth factor [TGF]-beta1 [0.5 MUg/50 MUL] injected into the TA); (iii) TGF-beta1 plus 5 * 10(5) control ADSCs injected same day; (iv) TGF-beta1 plus 5 * 10(5) ADSCs-IFN injected same day; (v) TGF-beta1 plus 5 * 10(5) control ADSCs injected after 30 days; and (vi) TGF-beta1 plus 5 * 10(5) ADSCs-IFN injected after 30 days. Rat allogeneic ADSCs were harvested from inguinal fat tissue. MAIN OUTCOME MEASURES: Forty-five days following the TGF-beta1 injection, erectile function was assessed, and penile tissues were harvested for further evaluations. RESULTS: In the same-day injection groups, intratunical injection of ADSCs and ADSC-IFN improved erectile response observed upon stimulation of cavernous nerve compared with TAF group. Intratunical ADSC-IFN injection at day 30 improved erectile responses 3.1, 1.8, and 1.3 fold at voltages of 2.5, 5.0, and 7.0, respectively, when compared with TAF group. Furthermore, at voltages of 2.5 and 5.0, treatment on day 30 with ADSCs-IFN improved erectile responses 1.6- and 1.3-fold over treatment with ADSCs alone. Local injection of ADSCs or ADSCs-IFN reduced Peyronie's-like manifestations, and these effects might be associated with a decrease in the expression of tissue inhibitors of metalloproteinases. CONCLUSION: This study documents that transplantation of genetically modified ADSCs, with or without human IFN alpha-2b, attenuated Peyronie's-like changes and enhanced erectile function in a rat model of TAF. PMID- 26062101 TI - Redox Strategies for Crop Improvement. AB - SIGNIFICANCE: Recently, the agro-biotech industry has been driven by overcoming the limitations imposed by fluctuating environmental stress conditions on crop productivity. A common theme among (a)biotic stresses is the perturbation of the redox homeostasis. RECENT ADVANCES: As a strategy to engineer stress-tolerant crops, many approaches have been centered on restricting the negative impact of reactive oxygen species (ROS) accumulation. CRITICAL ISSUES: In this study, we discuss the scientific background of the existing redox-based strategies to improve crop performance and quality. In this respect, a special focus goes to summarizing the current patent landscape because this aspect is very often ignored, despite constituting the forefront of applied research. FUTURE DIRECTIONS: The current increased understanding of ROS acting as signaling molecules has opened new avenues to exploit redox biology for crop improvement required for sustainable food security. PMID- 26062102 TI - Postprandial or Fasting Hyperglycemia: Time to Move On? PMID- 26062103 TI - Commentary on Some Recent Theses Relevant to Combating Aging: June 2015. PMID- 26062104 TI - Tear-off patterning: a simple method for patterning nitrocellulose membranes to improve the performance of point-of-care diagnostic biosensors. AB - This article describes a new method, referred to as "tear-off patterning," for patterning nitrocellulose (NC) membranes in order to fabricate NC-based point-of care (POC) diagnostic devices. Paper-based microfluidic sensors usually employ hydrophobic barrier coatings such as paraffin wax on either paper or membranes. Herein, complex patterns were fabricated by stamping the target area with dimethyl sulfoxide before tearing off the stamped area. Fluid flow and morphological analyses were performed in order to characterize the patterned membranes. Furthermore, the myoglobin and creatine kinase-MB levels in human serum were measured simultaneously using a dual-fluidic-channel-patterned NC membrane in order to confirm the usefulness of the patterning method for fabricating POC biosensors. The proposed method for patterning NC membranes offers clear advantages, such as the ability to fabricate complex designs and patterns without a hydrophobic barrier after protein immobilization in a laboratory and in a simple, low-cost manner. We believe that this method can be used to develop various POC diagnostic biosensors at the research and development stage and can help improve the performance and features of POC diagnostic devices. PMID- 26062105 TI - In situ formation and photo patterning of emissive quantum dots in small organic molecules. AB - Nanostructured composites of inorganic and organic materials are attracting extensive interest for electronic and optoelectronic device applications. Here we report a novel method for the fabrication and patterning of metal selenide nanoparticles in organic semiconductor films that is compatible with solution processable large area device manufacturing. Our approach is based upon the controlled in situ decomposition of a cadmium selenide precursor complex in a film of the electron transporting material 1,3,5-tris(N-phenyl-benzimidazol-2-yl) benzene (TPBI) by thermal and optical methods. In particular, we show that the photoluminescence quantum yield (PLQY) of the thermally converted CdSe quantum dots (QDs) in the TPBI film is up to 15%. We also show that laser illumination can form the QDs from the precursor. This is an important result as it enables direct laser patterning (DLP) of the QDs. DLP was performed on these nanocomposites using a picosecond laser. Confocal microscopy shows the formation of emissive QDs after laser irradiation. The optical and structural properties of the QDs were also analysed by means of UV-Vis, PL spectroscopy and transmission electron microscopy (TEM). The results show that the QDs are well distributed across the film and their emission can be tuned over a wide range by varying the temperature or irradiated laser power on the blend films. Our findings provide a route to the low cost patterning of hybrid electroluminescent devices. PMID- 26062106 TI - Effects of metformin on the adrenal cortex of androgenized rats. AB - OBJECTIVE: To evaluate the sex steroid profile and histomorphometry of the adrenal cortical zones of androgenized rats (wistar) with polycystic ovary syndrome treated with metformin. STUDY DESIGN: Thirty animals were divided into three groups: GC (regular estrous cycle), GPE (permanent estrus), and GPEM (permanent estrus + metformin 28 mg/kg for 50 days). At the end of this period, blood was collected for hormone measurement. The width of the adrenal cortical zones and the nuclear volumes were analyzed by histomorphometry. The ANOVA test was used in the statistical analysis. RESULTS: The adrenal glands of the androgenized animals were larger and more intensely vascularized than those of the other groups. The concentration of androstenedione in GPE was higher than that in the other groups (0.4 +/- 0.1*>= 0.2 +/- 0.1 = 0.2 +/- 01, *p < 0.05). The width of the zona glomerulosa and of the zona reticularis and their nuclear volumes were greater in GPE compared to those of the other groups (GPE* > GPEM = GC, *p < 0.05). CONCLUSION: Metformin treatment may decrease the serum levels of androstenedione as well as the width and the nuclear volumes of the zona glomerulosa and of the zona reticularis in androgenized animals. PMID- 26062107 TI - Nesfatin-1 levels and metabolic markers in polycystic ovary syndrome. AB - Nesfatin-1 is a novel hormone synthesized in hypothalamus and several other specific organs to regulate eating habits, appetite and is thought to be related to ovarian functions. In our study, we aimed to evaluate the nesfatin-1 levels with other metabolic parameters in polycystic ovary syndrome (PCOS), a condition that is known to be related to both ovarian functions and obesity. Study subjects were chosen from the women attended to the Obstetrics and Gynecology Department of Istanbul Bilim University, Avrupa Florence Nightingale Hospital. Thirty-five healthy control subjects and 55 PCOS patients were included. Blood samples were obtained on the 3rd day of the menstrual cycle. Luteinizing hormone (LH), follicle stimulating hormone (FSH), free testosterone (FT), dehydroepiandrosterone sulfate (DHEA-S), insulin, fasting blood glucose (FBG), high density lipoprotein (HDL), low density lipoprotein (LDL), triglycerides (TG), sex hormone binding globulin (SHBG) levels were measured; homeostatic model assessment-insulin resistance (HOMA-IR) value was calculated. The nesfatin-1 levels were measured by competitive inhibition ELISA method. Due to our results, PCOS patients were having lower nesfatin-1 levels compared to the control group and this was not seemed to be related to body mass index (BMI) levels. This is an important result to be investigated in larger study groups and is related to other metabolic markers. PMID- 26062108 TI - Treatment of menopausal symptoms with three low-dose continuous sequential 17beta estradiol/progesterone parenteral monthly formulations using novel non-polymeric microsphere technology. AB - OBJECTIVE: To analyze the short-term efficacy and safety over menopausal symptoms of three low-dose continuous sequential 17beta-estradiol (E)/progesterone (P) parental monthly formulations using novel non-polymeric microspheres. METHODS: This was a multicenter, randomized, single blinded study in which peri- and postmenopausal women were assigned to receive a monthly intramuscular injection of 0.5 mg E + 15 mg P (Group A, n = 34), 1 mg E + 20 mg P (Group B, n = 24) or 1 mg E + 30 mg P (Group C, n = 26) for 6 months. Primary efficacy endpoints included mean change in the frequency and severity of hot flushes and the effect over urogenital atrophy symptoms at 3 and 6 months. Safety variables included changes in the rate of amenorrhea, endometrial thickness and histopathology, and local and systemic adverse events. RESULTS: Compared to baseline at month 6, the three treatment schemes significantly decreased the rate of urogenital atrophy symptoms and the frequency (mean number per day) and severity (mean number graded as moderate and severe per month) of hot flushes. No differences in studied efficacy parameters were observed between studied groups at baseline or at the end of the study. For all groups the most frequent adverse event was pain at the injection site; however they were all rated as mild. At the end of the study peri and postmenopausal women displayed no significant changes in endometrial thickness or histopathology in all treated groups. The rate of amenorrhea at the end of the study decreased for all studied groups yet was less evident among postmenopausal women as compared to perimenopausal ones. CONCLUSIONS: The three low-dose continuous sequential intramuscular monthly treatments of E/P using novel microsphere technology were effective at reducing menopausal symptoms at short-term with a low rate of adverse events. More long-term and comparative research is warranted to support our positive findings. PMID- 26062109 TI - Defining the Adipose Tissue Proteome of Dairy Cows to Reveal Biomarkers Related to Peripartum Insulin Resistance and Metabolic Status. AB - Adipose tissue is a central regulator of metabolism in dairy cows; however, little is known about the association between various proteins in adipose tissue and the metabolic status of peripartum cows. Therefore, the objectives were to (1) examine total protein expression in adipose tissue of dairy cows and (2) identify biomarkers in adipose that are linked to insulin resistance and to cows' metabolic status. Adipose tissue biopsies were obtained from eight multiparous cows at -17 and +4 days relative to parturition. Proteins were analyzed by intensity-based, label-free, quantitative shotgun proteomics (nanoLC-MS/MS). Cows were divided into groups with insulin-resistant (IR) and insulin-sensitive (IS) adipose according to protein kinase B phosphorylation following insulin stimulation. Cows with IR adipose lost more body weight postpartum compared with IS cows. Differential expression of 143 out of 586 proteins was detected in prepartum versus postpartum adipose. Comparing IR to IS adipose revealed differential expression of 18.9% of the proteins; those related to lipolysis (hormone-sensitive lipase, perilipin, monoglycerol lipase) were increased in IR adipose. In conclusion, we found novel biomarkers related to IR in adipose and to metabolic status that could be used to characterize high-yielding dairy cows that are better adapted to peripartum metabolic stress. PMID- 26062110 TI - Milestones and entrustable professional activities: The key to practically translating competencies for interprofessional education? AB - Competency-based education and practice have become foundational for developing interprofessional education (IPE) and interprofessional collaboration. There has been a plethora of competencies developed in these areas recently, both at individual institutions and nationally; however, their effective integration and thus potential has not been fully realized educationally. Milestones and entrustable professional activities (EPAs) are new concepts and assessment approaches from medical education that provide a way to functionally use and maximize competencies to ensure that competency is attained. They are applicable to learning activities both within the classroom and the clinic, as well as to lifelong learning. This paper defines and describes milestones and EPAs, considers the importance of their application to IPE, and summarizes a future research project that will identify EPAs for an IPE curriculum. PMID- 26062111 TI - Conservation of Forest Biodiversity: how sample size affects the estimation of genetic parameters. AB - Efficient designs are crucial for population genetic studies on forest species. In this study we employed individual based simulations aiming to evaluate what fraction of a population should be sampled to obtain confident estimations of allelic richness and of inbreeding coefficient in population genetic surveys. The simulations suggest that at least 10% of the total population has to be sampled to ensure reliable estimations of allelic richness and inbreeding coefficient. This approach will allow the confidence of the genetic parameters estimations of a larger number of populations, based on a minimal sample within each one. PMID- 26062112 TI - Coherent structures in wall-bounded turbulence. AB - The inherent difficulty of understanding turbulence has led to researchers attacking the topic in many different ways over the years of turbulence research. Some approaches have been more successful than others, but most only deal with part of the problem. One approach that has seen reasonable success (or at least popularity) is that of attempting to deconstruct the complex and disorganised turbulent flow field into to a set of motions that are in some way organised. These motions are generally called "coherent structures". There are several strands to this approach, from identifying the coherent structures within the flow, defining their characteristics, explaining how they are created, sustained and destroyed, to utilising their features to model the turbulent flow. This review considers research on coherent structures in wall-bounded turbulent flows: a class of flow which is extremely interesting to many scientists (mainly, but not exclusively, physicists and engineers) due to their prevalence in nature, industry and everyday life. This area has seen a lot of activity, particularly in recent years, much of which has been driven by advances in experimental and computational techniques. However, several ideas, developed many years ago based on flow visualisation and intuition, are still both informative and relevant. Indeed, much of the more recent research is firmly indebted to some of the early pioneers of the coherent structures approach. Therefore, in this review, selected historical research is discussed along with the more contemporary advances in an attempt to provide the reader with a good overview of how the field has developed and to highlight the perspicacity of some of the early researchers, as well as providing an overview of our current understanding of the role of coherent structures in wall-bounded turbulent flows. PMID- 26062113 TI - In vitro growth-inhibitory effect of Brazilian plants extracts against Paenibacillus larvae and toxicity in bees. AB - American foulbrood (AFB) is a serious worldwide spreading disease in bees caused by Paenibacillus larvae. Plants extracts are known to decrease or inhibit the growth of these bacteria. The purpose of this study was to evaluate the antimicrobial activity of Calendula. officinalis, Cariniana domestica, and Nasturtium officinale extracts against the P. larvae and to evaluate the toxicity of the extracts in bees. In vitro activity against P. larvae of the extracts was evaluated by micro dilution method and the minimal inhibitory concentrations (MICs) were also determined. The concentrations used in the toxicity test were established based on the MIC values and by the spraying application method. The P. larvae was susceptible to the evaluated crude extract of C. officinalis and N. officinale. To C. domestica, only the ethyl acetate (EtAc) fraction and n-butanol (BuOH) fractions had activity against P. larvae. Toxicity analysis in bees showed no toxicity for N. officinale crude extract and for C. domestica BuOH fraction during 15 days of treatment, however, some deaths of bees occurred during the first three days of treatment with C. officinalis and C. domestica EtAc fraction. The results with these species were firstly described and showed that N. officinale crude extract and C. domestica BuOH fraction both presented not toxic effects in the concentration tested by the spraying application method, and can be a useful alternative for treatment or prevention of AFB. PMID- 26062114 TI - Ecological strategies of Al-accumulating and non-accumulating functional groups from the cerrado sensu stricto. AB - The cerrado's flora comprises aluminum-(Al) accumulating and non-accumulating plants, which coexist on acidic and Al-rich soils with low fertility. Despite their existence, the ecological importance or biological strategies of these functional groups have been little explored. We evaluated the leaf flushing patterns of both groups throughout a year; leaf concentrations of N, P, K, Ca, Mg, S, Al, total flavonoids and polyphenols; as well as the specific leaf area (SLA) on young and mature leaves within and between the groups. In Al accumulating plants, leaf flushed throughout the year, mainly in May and September; for non-accumulating plants, leaf flushing peaked at the dry-wet seasons transition. However, these behaviors could not be associated with strategies for building up concentrations of defense compounds in leaves of any functional groups. Al-accumulating plants showed low leaf nutrient concentrations, while non-accumulating plants accumulated more macronutrients and produced leaves with high SLA since the juvenile leaf phase. This demonstrates that the increase in SLA is slower in Al-accumulating plants that are likely to achieve SLA values comparable to the rest of the plant community only in the wet season, when sunlight capture is important for the growth of new branches. PMID- 26062115 TI - Competition between rice (Oryza sativa L.) and (barnyardgrass (Echinochloa crus galli (L.) P. Beauv.) as affected by methanol foliar application. AB - Pot experiment was conducted in Iran, to evaluate the effect of methanol on competition between rice (Oryza sativa) and barnyardgrass (Echinochloa crus galli). The experiment was conducted as a randomized complete block design with a factorial treatment arrangement and three replicates. Factors were two aqueous methanol foliar applications (0, and 14% v/v) and five rice: barnyardgrass ratios (100:0, 75:25, 50:50, 25:6, and 0:100). Replacement series diagrams for aboveground dry weight illustrated that 'Shiroudi' was more competitive than barnyardgrass as averaged across methanol foliar applications. When methanol was not sprayed, the lines for 'Shiroudi' and barnyardgrass intersected at 75:25 rice: barnyardgrass ratio, but when methanol was sprayed at 14% v/v, the lines for 'Shiroudi' and barnyardgrass intersect at the left of the 75:25 rice: barnyardgrass mixture proportion. These indicate that methanol application reduced competitive ability of 'Shiroudi' against barnyardgrass for aboveground biomass accumulation. At the same time, Methanol foliar application significantly reduced the relative crowding coefficient of 'Shiroudi' while simultaneously it significantly increased the relative crowding coefficient of barnyard grass. This indicates that methanol foliar application reduced the competitive ability of 'Shiroudi' against barnyardgrass for shoot biomass accumulation. This experiment illustrated that foliar spray of aqueous methanol can not be recommended for rice under weedy conditions. PMID- 26062116 TI - Biostratigraphy and paleoecology of an unusual palynological record from the Aquidauana Formation, Late Pennsylvanian of Parana Basin. AB - The Aquidauana Formation is a Permo-Carboniferous sedimentary unit, widely stratigraphicaly distributed in the northwestern and northern portions of the Parana Basin. However, little paleontological data is available from this formation, preventing accurate biostratigraphic and paleoecological interpretations. An abundant, diversified and well preserved assemblage of palynomorphs was recognized from sampling conducted in an outcrop section in Cipolandia District of Aquidauana Municipality, state of Mato Grosso do Sul, Brazil. A total of 35 indigenous palynomorph taxa was recognized, comprising 6 species of spores (related to 5 genera), 28 species of pollen grains (14 genera) and 1 species of chlorophycean algae. Monosaccate pollen grains are exceptionally dominant, representing 90.38% of the association, particularly constituted by species of the genera Cannanoropollis (30.41% of the total assemblage), Potonieisporites (28.14%) and Plicatipollenites (19.52%). This quantitative overrepresentation is not usual from Gondwana deposits, revealing a particular plant dominance of Cordaitales in the terrestrial flora. These results are interpreted as an upland ecology characterized by plants with a moisture independent reproduction strategy, under a glacial climate influence. Certain species of pollen allow assignment of this assemblage to the Crucisaccites monoletus Zone (Late Pennsylvanian), which had been recognized only in the middle portion of the Itarare Group at the northeastern margin of the basin. PMID- 26062117 TI - Effects of cigarette smoke condensate on the production and characterization of exopolysaccharides by Bifidobacterium. AB - The aim of the study was to investigate the effect of cigarette smoke on the production and characterization of exopolysaccharides (EPSs) produced by Bifidobacterium. Cigarettes of Shanhua brand (nicotine: 1.1 mg, tar: 11 mg) were utilized to prepare a cigarette smoke condensate (CSC). The standard strain of Bifidobacterium animalis was cultured in MRS media under anaerobic addition of CSC. The results showed that CSC significantly decreased the growth of B. animalis as well as EPSs and acetic acid production. Furthermore, two EPSs fractions (Fr-I and Fr-II) were isolated and purified for chemical and molecular determination. By comparison with control, CSC was found to be of great impact on EPSs carbohydrate composition. The molecular weight mass of Fr-I changed from 3.33 * 10(5) g/mol (without CSC) to 2.99 * 10(5) (with CSC). In conclusion, in vitro studies revealed that CSC was directly able to affect the production of metabolites for B. animalis, which could be an essential factor in certain pathological disorders. PMID- 26062118 TI - Anatomy and fructan distribution in vegetative organs of Dimerostemma vestitum (Asteraceae) from the campos rupestres. AB - Among the compounds stored by plants, several functions are assigned to fructans, such as source of energy and protection against drought and extreme temperatures. In the present study we analyzed the anatomy and distribution of fructans in vegetative organs of Dimerostemma vestitum (Asteraceae), an endemic species from the Brazilian campos rupestres. D. vestitumhas amphistomatic and pubescent leaves, with both glandular and non-glandular trichomes. In the basal aerial stem the medulla has two types of parenchyma, which differ from the apical portion. The xylopodium has mixed anatomical origin. Interestingly, although inulin-type fructans with high degree of polymerization were found in all analyzed organs except the leaves, the highest amount and maximum degree of polymerization were detected in the xylopodium. Inulin sphero-crystals were visualized under polarized light in the medulla and in the vascular tissues mainly in the central region of the xylopodium, which has abundant xylem parenchyma. Secretory structures accumulating several compounds but not inulin were identified within all the vegetative organs. The presence of these compounds, in addition to inulin, might be related to the strategies of plants to survive adverse conditions in a semi-arid region, affected seasonally by water restriction and frequently by fire. PMID- 26062119 TI - Temporal dynamics of the response to Al stress in Eucalyptus grandis * Eucalyptus camaldulensis. AB - Lipid peroxidation and root elongation of Eucalyptus grandis * Eucalyptus camaldulensis were studied under stress conditions in response to aluminum (Al), a metal known to limit agricultural productivity in acidic soils primarily due to reduced root elongation. In Brazil, the Grancam 1277 hybrid (E. grandis * E. camaldulensis) has been planted in the "Cerrado", a region of the country with a wide occurrence of acidic soils. The present study demonstrated that the hybrid exhibited root growth reduction and increased levels of lipid peroxidation after 24h of treatment with 100 uM of Al, which was followed by a reduction in lipid peroxidation levels and the recovery of root elongation after 48 h of Al exposure, suggesting a rapid response to the early stressful conditions induced by Al. The understanding of the temporal dynamics of Al tolerance may be useful for selecting more tolerant genotypes and for identifying genes of interest for applications in bioengineering. PMID- 26062120 TI - Growth and reproduction of the mangrove crab Goniopsis cruentata (Latreille, 1803) (Crustacea: Decapoda: Grapsidae) in southeastern Brazil. AB - Goniopsis cruentata is a common semi-terrestrial crab in Brazilian mangroves and an important fishery resource for traditional communities in the northeastern Brazilian coast. Aiming to contribute to the knowledge about the species, this study evaluated the carapace width and weight growth curves, the relative growth of weight versus carapace width, and the temporal variation of gonadosomatic and hepatosomatic indices for the species. A total of 524 crabs were collected in a mangrove area of Ubatuba municipality, state of Sao Paulo. The growth-curves parameters and longevity (tmax) were estimated for males (CWinfinity=50.6 mm, WE=56.4 g, k=2.24, t0=0.003631502 year-1, tmax=1.3 years) and females (CWinfinity=50.7 mm, WEinfinity=58.8 g, k=2.50, t0=0.003247209 year-1, tmax=1.2 years). The age at onset of sexual maturity was 0.23 years for both genders. The weight-growth model was isometric for the immature developmental stages and allometric negative for adults. The species exhibited a continuous reproduction, with breeding peaks in spring and summer months. The weight dynamics of gonads and hepatopancreas were not clearly related. The growth and reproductive patterns indicated that Goniopsis cruentata has a life-history that prioritizes reproduction instead of survival. The species exhibited some of the highest growth rates and lowest longevity estimates reported for brachyuran species in Brazil. PMID- 26062121 TI - Antileishmanial activity of some Brazilian plants, with particular reference to Casearia sylvestris. AB - Leishmaniasis is a complex of diseases caused by Leishmania protozoa which treatment is restricted to a limited number of drugs that exhibit high toxicity, collateral effects and are often costly. There are a variety of tropical plants distributed in Brazil, and for many poor people the therapy for several diseases is based mainly on the use of traditional herbal remedies. In this work, the cytotoxic activity of 17 plant methanol extracts was evaluated on several Leishmania species and murine macrophages. Among them, the extract of Casearia sylvestris, Piptocarpha macropoda, Trembleya parviflora, Samanea tubulosa and Plectranthus neochilus showed a promissing leishmanicidal activity, exhibiting IC50 values below of 20 ug/mL against at least one species of Leishmania. Casearia sylvestris showed the most expressive activity against all promastigote forms of Leishmania species (IC50 values of 5.4 ug/mL, 5.0 ug/mL, 8.5 ug/mL and 7.7 ug/mL for L. amazonensis, L. braziliensis, L. chagasi and L. major, respectively), being more effective than the reference drug miltefosine. In spite of the cytotoxic effect on macrophages (CC50 value of 5.2 ug/mL), C. sylvestris exhibited a strong inhibition against intracellular amastigotes of L. braziliensis (IC50 value of 1.3 ug/mL). Further studies, including bio-guided fractionation will be conducted to identify the active compounds. PMID- 26062123 TI - Resolving the ambiguity in the relation between Stokes shift and Huang-Rhys parameter. AB - Electronic transitions in luminescent molecules or centers in crystals couple to vibrations. This results in broadening of absorption and emission bands, as well as in the occurence of a Stokes shift EStokes. In principle, one can derive from EStokes the Huang-Rhys parameter S, which describes the microscopic details of the vibrational coupling and can be related to the equilibrium position offset DeltaQe between the ground state and excited state. The commonly used textbook relations EStokes = (2S - 1)homega and EStokes = 2Shomega are only approximately valid. In this paper we investigate how EStokes is related to S, taking into account the effects of a finite temperature. We show that in different ranges of temperature, different approximate relations between EStokes and S are appropriate. Moreover, we demonstrate that the difference between the barycenters of absorption and emission bands can be used to determine S in an unambiguous way. The position of the barycenter is, contrary to the Stokes shift, unaffected by temperature. PMID- 26062122 TI - Isotopic niches of sympatric native and exotic fish species in a Neotropical floodplain. AB - This study investigated the isotopic niches of two fish species, one exotic and one native. It was hypothesized that these species would show little or no isotopic niche overlap. This hypothesis was tested with the isotopic niche concept and the trophic Layman's metrics. A considerable isotopic niche overlap was observed between the species, mainly for the exotic that showed the greater percentage of overlapping, indicating an interspecific competition for food resources. Layman's metrics also showed this species probably exploits a more specific array of food resources when compared with the native species. The native species probably has the ability to exploit a wider array of resources, highlighted by the higher values given for the Layman's metrics. The juveniles and adults of native species showed minor overlapping between the isotopic niches. This indicates that they have probably adopted different foraging strategies, minimizing intraspecific competition. Evidences that the exotic species explores a narrower range of resources and that the native species has a greater isotopic niche and possibly suffer less intraspecific competition, indicates that the native species can tolerate the presence of the exotic species and promote survival and maintenance of its population even under possible competition effects imposed by the exotic species. PMID- 26062125 TI - Diels-Alder Reactions of 1,2-Azaborines. AB - Diels-Alder reactions employing 1,2-azaborine heterocycles as 1,3-dienes are reported. Carbocyclic compounds with high stereochemical and functional complexity are produced, as exemplified by the straightforward two-step synthesis of an amino allyl boronic ester bearing four contiguous stereocenters as a single diastereomer. Whereas electron-deficient dienophiles undergo irreversible Diels Alder reactions, a reversible Diels-Alder reaction with the less electron deficient methyl acrylate is observed. Both the N and the B substituent of the 1,2-azaborine exert significant influence on the [4+2] cycloaddition reactivity as well as the aromatic character of the heterocycle. The experimentally determined thermodynamic parameters of the reversible Diels-Alder reaction between 1,2-azaborines and methyl acrylate correlate with aromaticity trends and place 1,2-azaborines approximately between furan and thiophene on the aromaticity scale. PMID- 26062124 TI - Two-Stage Priming of Allogeneic Natural Killer Cells for the Treatment of Patients with Acute Myeloid Leukemia: A Phase I Trial. AB - Human Natural Killer (NK) cells require at least two signals to trigger tumor cell lysis. Absence of ligands providing either signal 1 or 2 provides NK resistance. We manufactured a lysate of a tumour cell line which provides signal 1 to resting NK cells without signal 2. The tumor-primed NK cells (TpNK) lyse NK resistant Acute Myeloid Leukemia (AML) blasts expressing signal 2 ligands. We conducted a clinical trial to determine the toxicity of TpNK cell infusions from haploidentical donors. 15 patients with high risk AML were screened, 13 enrolled and 7 patients treated. The remaining 6 either failed to respond to re-induction chemotherapy or the donor refused to undergo peripheral blood apheresis. The conditioning consisted of fludarabine and total body irradiation. This was the first UK trial of a cell therapy regulated as a medicine. The complexity of Good Clinical Practice compliance was underestimated and led to failures requiring retrospective independent data review. The lessons learned are an important aspect of this report. There was no evidence of infusional toxicity. Profound myelosuppression was seen in the majority (median neutrophil recovery day 55). At six months follow-up, three patients treated in Complete Remission (CR) remained in remission, one patient infused in Partial Remission had achieved CR1, two had relapsed and one had died. One year post-treatment one patient remained in CR. Four patients remained in CR after treatment for longer than their most recent previous CR. During the 2 year follow-up six of seven patients died; median overall survival was 400 days post infusion (range 141-910). This is the first clinical trial of an NK therapy in the absence of IL-2 or other cytokine support. The HLA-mismatched NK cells survived and expanded in vivo without on-going host immunosuppression and appeared to exert an anti-leukemia effect in 4/7 patients treated. TRIAL REGISTRATION: ISRCTN trial registry ISRCTN11950134. PMID- 26062126 TI - A consensus guideline for antipsychotic drug use for dementia in care homes. Bridging the gap between scientific evidence and clinical practice. AB - BACKGROUND: To produce a practice guideline that includes a set of detailed consensus principles regarding the prescription of antipsychotics (APs) amongst people with dementia living in care homes. METHODS: We used a modified Delphi consensus procedure with three rounds, where we actively specified and optimized statements throughout the process, utilizing input from four focus groups, carried out in UK, Norway, and the Netherlands. This was done to identify relevant themes and a set of statement that experts agreed upon using the Research and Development/University of California at Los Angeles (RAND/UCLA) methodology. RESULTS: A total of 72 scientific and clinical experts and 14 consumer experts reached consensus upon 150 statements covering five themes: (1) General prescription stipulations, (2) assessments prior to prescription, (3) care and treatment plan, (4) discontinuation, and (5) long-term treatment. CONCLUSIONS: In this practice guideline, novel information was provided about detailed indication and thresholds of symptoms, risk factors, circumstances at which APs should be stopped or tapered, specific criteria for justifying long term treatment, involvement of the multidisciplinary team, and family caregiver in the process of prescription. The practice guideline is based on formal consensus of clinicians and consumer experts and provides clinicians relevant practical information that is lacking in current guidelines. PMID- 26062127 TI - Comparison of two different strategies for human monocyte subsets gating within the large-scale prospective CARE FOR HOMe Study. AB - Monocytes are heterogeneous cells consisting of (at least) three subsets: classical, intermediate, and nonclassical monocytes. Correct enumeration of cell counts necessitates well-defined gating strategies, which are essentially based upon CD14 and CD16 expression. For the delineation of intermediate from nonclassical monocytes, a "rectangular gating (RG) strategy" and a "trapezoid gating (TG) strategy" have been proposed. We compared the two gating strategies in a well-defined clinical cohort of patients with chronic kidney disease (CKD). Within the ongoing CARE FOR HOMe study, monocyte subsets were reanalyzed in 416 CKD patients, who were followed 3.6 +/- 1.6 years for the occurrence of a cardiovascular event. Gating was performed by either RG or TG. We analyzed the expression of surface markers, and compared the predictive role of cell counts of monocyte subsets, as defined by RG and TG, respectively. With both gating strategies, higher intermediate monocyte counts predicted the cardiovascular endpoint in Kaplan-Meier analyses (P < 0.001 with RG; P < 0.001 with TG). After correction for confounders, intermediate monocyte counts remained independent predictors in Cox-Regression analyses (HR = 1.013 [95% CI: 1.006-1.020; P < 0.001] with RG; HR = 1.015 [95% CI: 1.006-1.024; P = 0.001] with TG). NRI was 3.9% when reclassifying patients from quartiles of intermediate monocyte counts with RG strategy toward quartiles of intermediate monocytes counts with TG strategy. In expression analysis, those monocytes which are defined as intermediate monocytes by the RG strategy and as nonclassical monocytes by the TG strategy share characteristics of both subsets. In conclusion, intermediate monocytes were independent predictors of cardiovascular outcome irrespective of the applied gating strategy. Future studies should aim to identify markers that allow for an unequivocal definition of intermediate monocytes, which may further improve their power to predict cardiovascular events. PMID- 26062128 TI - Quantitative Structure-Antioxidant Activity Models of Isoflavonoids: A Theoretical Study. AB - Seventeen isoflavonoids from isoflavone, isoflavanone and isoflavan classes are selected from Dalbergia parviflora. The ChEMBL database is representative from these molecules, most of which result highly drug-like. Binary rules appear risky for the selection of compounds with high antioxidant capacity in complementary xanthine/xanthine oxidase, ORAC, and DPPH model assays. Isoflavonoid structure activity analysis shows the most important properties (log P, log D, pKa, QED, PSA, NH + OH ~ HBD, N + O ~ HBA). Some descriptors (PSA, HBD) are detected as more important than others (size measure Mw, HBA). Linear and nonlinear models of antioxidant potency are obtained. Weak nonlinear relationships appear between log P, etc. and antioxidant activity. The different capacity trends for the three complementary assays are explained. Isoflavonoids potency depends on the chemical form that determines their solubility. Results from isoflavonoids analysis will be useful for activity prediction of new sets of flavones and to design drugs with antioxidant capacity, which will prove beneficial for health with implications for antiageing therapy. PMID- 26062129 TI - From Pre-Clinical Studies to Clinical Trials: Generation of Novel Therapies for Pregnancy Complications. AB - Complications of pregnancy represent a significant disease burden, with both immediate and lasting consequences for mother and baby. Two key pregnancy complications, fetal growth restriction (FGR) and preeclampsia (PE), together affect around 10%-15% of all pregnancies worldwide. Despite this high incidence, there are currently no therapies available to treat these pregnancy disorders. Early delivery remains the only intervention to reduce the risk of severe maternal complications and/or stillbirth of the baby; however early delivery itself is associated with increased risk of neonatal mortality and morbidity. As such, there is a pressing need to develop new and effective treatments that can prevent or treat FGR and PE. Animal models have been essential in identifying and screening potential new therapies in this field. In this review, we address recent progress that has been made in developing therapeutic strategies for pregnancy disorders, some of which are now entering clinical trials. PMID- 26062130 TI - The Effect of Electrospun Gelatin Fibers Alignment on Schwann Cell and Axon Behavior and Organization in the Perspective of Artificial Nerve Design. AB - Electrospun fibrous substrates mimicking extracellular matrices can be prepared by electrospinning, yielding aligned fibrous matrices as internal fillers to manufacture artificial nerves. Gelatin aligned nano-fibers were prepared by electrospinning after tuning the collector rotation speed. The effect of alignment on cell adhesion and proliferation was tested in vitro using primary cultures, the Schwann cell line, RT4-D6P2T, and the sensory neuron-like cell line, 50B11. Cell adhesion and proliferation were assessed by quantifying at several time-points. Aligned nano-fibers reduced adhesion and proliferation rate compared with random fibers. Schwann cell morphology and organization were investigated by immunostaining of the cytoskeleton. Cells were elongated with their longitudinal body parallel to the aligned fibers. B5011 neuron-like cells were aligned and had parallel axon growth when cultured on the aligned gelatin fibers. The data show that the alignment of electrospun gelatin fibers can modulate Schwann cells and axon organization in vitro, suggesting that this substrate shows promise as an internal filler for the design of artificial nerves for peripheral nerve reconstruction. PMID- 26062131 TI - A Structural Overview of RNA-Dependent RNA Polymerases from the Flaviviridae Family. AB - RNA-dependent RNA polymerases (RdRPs) from the Flaviviridae family are representatives of viral polymerases that carry out RNA synthesis through a de novo initiation mechanism. They share a ~ 600-residue polymerase core that displays a canonical viral RdRP architecture resembling an encircled right hand with palm, fingers, and thumb domains surrounding the active site. Polymerase catalytic motifs A-E in the palm and motifs F/G in the fingers are shared by all viral RdRPs with sequence and/or structural conservations regardless of the mechanism of initiation. Different from RdRPs carrying out primer-dependent initiation, Flaviviridae and other de novo RdRPs utilize a priming element often integrated in the thumb domain to facilitate primer-independent initiation. Upon the transition to the elongation phase, this priming element needs to undergo currently unresolved conformational rearrangements to accommodate the growth of the template-product RNA duplex. In the genera of Flavivirus and Pestivirus, the polymerase module in the C-terminal part of the RdRP protein may be regulated in cis by the N-terminal region of the same polypeptide. Either being a methyltransferase in Flavivirus or a functionally unclarified module in Pestivirus, this region could play auxiliary roles for the canonical folding and/or the catalysis of the polymerase, through defined intra-molecular interactions. PMID- 26062134 TI - Political Imprisonment and Adult Functioning: A Life Event History Analysis of Palestinians. AB - Political imprisonment is a traumatic event, often accompanied by torture and deprivation. This study explores the association of political imprisonment between 1987 and 2011 with political, economic, community, psychological, physical, and family functioning in a population-based sample of Palestinian men ages 32-43 years (N = 884) derived from a dataset collected in 2011. Twenty-six percent (n = 233) had been politically imprisoned. Men imprisoned between 1987 and 2005 reported functioning as well as never-imprisoned men in most domains, suggesting that men imprisoned as youth have moved forward with their lives in ways similar to their nonimprisoned counterparts. In an exception to this pattern, men imprisoned during the Oslo Accords period (1994-1999) reported higher levels of trauma-related stress (B = 0.24, p = .027) compared to never imprisoned men. Men imprisoned since 2006 reported lower functioning in multiple domains: human insecurity (B = 0.33, p = .023), freedom of public expression (B = -0.48, p = .017), perceived government stability (B = -0.38, p = .009), feeling broken or destroyed (B = 0.59, p = .001), physical limitations (B = 0.55, p = .002), and community belonging (B = -0.33, p = .048). Findings pointed to the value of examining the effects of imprisonment on functioning in multiple domains. PMID- 26062133 TI - Characterization of a Bioflocculant (MBF-UFH) Produced by Bacillus sp. AEMREG7. AB - A bioflocculant named MBF-UFH produced by a Bacillus species isolated from sediment samples of Algoa Bay of the Eastern Cape Province of South Africa was characterized. The bacterial identification was through 16S rDNA sequencing; nucleotide sequences were deposited in GenBank as Bacillus sp. AEMREG7 with Accession Number KP659187. The production of the bioflocculant was observed to be closely associated with cell growth. The bioflocculant had the highest flocculating activity of 83.2% after 72 h of cultivation, and approximately 1.6 g of purified MBF-UFH was recovered from 1 L of fermentation broth. Its chemical analyses indicated that it is a glycoprotein composed of polysaccharide (76%) and protein (14%). Fourier transform infrared spectroscopy (FTIR) revealed that it consisted of hydroxyl, amide, carboxyl and methoxyl as the functional moieties. Scanning electron microscopy (SEM) revealed the amorphous structure of MBF-UFH and flocculated kaolin clay particles. The maximum flocculating activity of 92.6% against kaolin clay suspension was achieved at 0.3 mg/mL over pH ranges of 3-11 with the peak flocculating rate at pH 8 in the presence of MgCl2. The bioflocculant retained high flocculating activity of 90% after heating at 100 degrees C for 1 h. MBF-UFH appears to have immense potential as an alternative to conventional chemical flocculants. PMID- 26062135 TI - Emotional Activation and Habituation During Imaginal Exposure for PTSD Among Women With Borderline Personality Disorder. AB - The current study examined patterns and outcomes of emotional activation and habituation during imaginal exposure for posttraumatic stress disorder (PTSD). Participants were 16 women with borderline personality disorder (BPD), PTSD, and recent suicidal and/or self-injurious behavior who received imaginal exposure for PTSD concurrently with dialectical behavior therapy. The intensity of global distress and 6 specific emotions were assessed before and after imaginal exposure trials. Results indicated that significant within-session habituation (WSH) occurred for global distress (Hedge's g effect size = -2.52) and fear (g = 0.80), whereas significant between-session habituation (BSH) occurred for global distress (g = -2.18), fear (g = -1.89), guilt (g = -1.14), shame (g = -0.74), and disgust (g = -0.41). BSH significantly predicted PTSD diagnostic status at posttreatment, whereas activation and WSH were unrelated to outcome. Clients who remitted from PTSD showed significantly more BSH in global distress than nonremitters (eta(2) = .39). In addition, remitters reported reductions in sadness and anger across trials, whereas sadness and anger increased for those who did not remit (eta(2) = .54 and .40, respectively). Overall, BPD clients exhibited patterns of activation and habituation during imaginal exposure comparable to other client populations, and there was no evidence of persistent emotional engagement or habituation problems. PMID- 26062132 TI - Chemokine-Derived Peptides: Novel Antimicrobial and Antineoplasic Agents. AB - Chemokines are a burgeoning family of chemotactic cytokines displaying a broad array of functions such as regulation of homeostatic leukocyte traffic and development, as well as activating the innate immune system. Their role in controlling early and late inflammatory stages is now well recognized. An improper balance either in chemokine synthesis or chemokine receptor expression contributes to various pathological disorders making chemokines and their receptors a useful therapeutic target. Research in this area is progressing rapidly, and development of novel agents based on chemokine/ chemokine receptors antagonist functions are emerging as attractive alternative drugs. Some of these novel agents include generation of chemokine-derived peptides (CDP) with potential agonist and antagonist effects on inflammation, cancer and against bacterial infections. CDP have been generated mainly from N- and C-terminus chemokine sequences with subsequent modifications such as truncations or elongations. In this review, we present a glimpse of the different pharmacological actions reported for CDP and our current understanding regarding the potential use of CDP alone or as part of the novel therapies proposed in the treatment of microbial infections and cancer. PMID- 26062136 TI - Symptoms of Dissociation in a High-Risk Sample of Young Children Exposed to Interpersonal Trauma: Prevalence, Correlates, and Contributors. AB - Children who have experienced interpersonal trauma are at an increased risk of developing dissociation; however, little is known about the prevalence or correlates of dissociation in young children. The current study examined symptoms of dissociation in 140 children (mean age = 51.17 months, range = 36-72 months, SD = 10.31 months; 50.0% male; 45.7% Hispanic) who experienced trauma (e.g., witnessing domestic violence, experiencing abuse). Child dissociation and exposure to traumatic events were assessed using a clinician-administered interview with the biological mother (mean age = 32.02 years, SD = 6.13; 49.3% Hispanic; 25.5% married or cohabitating). Mothers completed measures of maternal dissociation, depression/anxiety, and child behavior problems. At least subclinical dissociation was present for 24.3% of children. Robust regression with least trimmed squares estimation showed that greater maternal dissociation was related to greater child dissociation, adjusting for child internalizing symptoms, number of traumas, and maternal depression/anxiety, B = 0.09, chi(2) = 10.47, p < .001, R(2) Delta = .04. Children who experienced direct victimization did not exhibit a significantly higher level of dissociation compared to children who experienced other traumas, F(1, 138) = 3.76, p = .054, eta(2) = .03. These findings highlight the need to assess dissociation in traumatized young children. PMID- 26062139 TI - Retroflexion-induced perforation during colonoscopy after polypectomy: a word of caution. PMID- 26062137 TI - A Defensin from the Model Beetle Tribolium castaneum Acts Synergistically with Telavancin and Daptomycin against Multidrug Resistant Staphylococcus aureus. AB - The red flour beetle Tribolium castaneum is a common insect pest and has been established as a model beetle to study insect development and immunity. This study demonstrates that defensin 1 from T. castaneum displays in vitro and in vivo antimicrobial activity against drug resistant Staphylococcus aureus strains. The minimum inhibitory concentration (MIC) of defensin 1 against 11 reference and clinical staphylococcal isolates was between 16-64 MUg/ml. The putative mode of action of the defensin peptide is disruption of the bacterial cell membrane. The antibacterial activity of defensin 1 was attenuated by salt concentrations of 1.56 mM and 25 mM for NaCl and CaCl2 respectively. Treatment of defensin 1 with the reducing agent dithiothreitol (DTT) at concentrations 1.56 to 3.13 mM abolished the antimicrobial activity of the peptide. In the presence of subinhibitory concentrations of antibiotics that also target the bacterial cell envelope such as telavancin and daptomycin, the MIC of the peptide was as low as 1 MUg/ml. Moreover, when tested against an S. aureus strain that was defective in D-alanylation of the cell wall, the MIC of the peptide was 0.5 MUg/ml. Defensin 1 exhibited no toxicity against human erythrocytes even at 400 MUg/ml. The in vivo activity of the peptide was validated in a Caenorhabditis elegans-MRSA liquid infection assay. These results suggest that defensin 1 behaves similarly to other cationic AMPs in its mode of action against S. aureus and that the activity of the peptide can be enhanced in combination with other antibiotics with similar modes of action or with compounds that have the ability to decrease D-alanylation of the bacterial cell wall. PMID- 26062140 TI - Gastrointestinal strongyloidiasis. PMID- 26062141 TI - Esophageal rupture caused by compressed nitrous oxide. PMID- 26062142 TI - Successful endoscopic treatment using biological fibrin glue (Tissucol) for an enterocutaneous fistula occurring after cephalic duodenopancreatectomy. PMID- 26062143 TI - Advanced rectal carcinoma caused by tumor cell implantation after curative endoscopic submucosal dissection of an intramucosal rectal carcinoma. PMID- 26062144 TI - Fluoroscopy-guided endoscopic recanalization of an obstructed gastroesophageal junction in a child. PMID- 26062145 TI - Diffuse gastric plasmacytoma involvement in multiple myeloma. PMID- 26062146 TI - A case of curatively resected gastric wall implantation of pancreatic cancer caused by endoscopic ultrasound-guided fine-needle aspiration. PMID- 26062147 TI - Enteroliths in a Kock continent ileostomy: case report and review of the literature. PMID- 26062148 TI - A novel method for endoscopic placement of a capsule endoscope with use of a transparent hood and real-time viewer. PMID- 26062149 TI - Double-balloon enteroscopy-assisted closure of perforated duodenal diverticulum using polyglycolic acid sheets. PMID- 26062150 TI - Placement of a novel fully covered metallic stent for refractory pancreatic duct stricture. PMID- 26062151 TI - Multistenting during balloon-assisted ERCP using small diameter plastic stents in patients with surgically altered upper gastrointestinal anatomy. PMID- 26062152 TI - Endoscopic resection of a duodenal web in an 11-month-old infant with multiple malformations. PMID- 26062153 TI - An unusual localized laterally spreading tumor. PMID- 26062154 TI - Bluish discoloration of the esophagus: cavernous hemangioma of the pharynx and larynx with esophageal involvement. PMID- 26062155 TI - Resection of a large ileal lipoma exhibiting ball-valve prolapse into the cecum with a "grasp-to-retract, ligate, unroof, and let-go" technique. PMID- 26062156 TI - A guidewire-assisted biopsy technique to assist advancement through a biliary stricture to perform selective mapping biopsy. PMID- 26062157 TI - The role of empiric embolization in diverticular bleeding. PMID- 26062158 TI - Dual esophageal and colon self-expanding metal stenting for colon cancer arising in esophageal interposition. PMID- 26062159 TI - Fat accumulation in enterocytes: a key to the diagnosis of abetalipoproteinemia or homozygous hypobetalipoproteinemia. PMID- 26062160 TI - Umbelliferone Improves an Impaired Glucose and Lipid Metabolism in High-Fat Diet/Streptozotocin-Induced Type 2 Diabetic Rats. AB - Umbelliferone (UMB) is a natural product that has several pharmacological effects including antihyperglycemic activity in diabetic rats. Thus, the objective of this study was to investigate the effect of UMB on insulin resistance and on the regulation of glucose and lipid metabolism in type 2 diabetic rats. Type 2 diabetes was induced in rats by feeding a high-fat diet (45 kcal% fat) and a single dose of streptozotocin injection. After 8 weeks of treatment, UMB significantly reduced the elevated blood glucose levels and insulin resistance and increased the liver glycogen and serum adiponectin. Moreover, the serum lipid and the storages of triglyceride and non-esterified fatty acid in liver tissue were reduced. From histological examination, the lipid droplets in liver tissue were clearly decreased, and the fat cell size in the fat tissue was smaller in diabetic rats treated with UMB. Interestingly, UMB increased fat cell adiponectin, plasma membrane glucose transporter 4 (GLUT4) and peroxisome proliferator-activated receptor gamma (PPARgamma), and liver PPARalpha protein expressions. Our findings demonstrate that UMB improves glucose and lipid metabolism in type 2 diabetes by stimulating the insulin secretion and the related mechanisms via stimulating expression of adiponectin, GLUT4, PPARgamma, and PPARalpha-protein expressions. Copyright (c) 2015 John Wiley & Sons, Ltd. PMID- 26062161 TI - Does emotional intelligence change during medical school gross anatomy course? Correlations with students' performance and team cohesion. AB - Emotional intelligence (EI) has been associated with increased academic achievement, but its impact on medical education is relatively unexplored. This study sought to evaluate change in EI, performance outcomes, and team cohesion within a team-based medical school anatomy course. Forty-two medical students completed a pre-course and post-course Schutte Self-Report Emotional Intelligence Test (SSEIT). Individual EI scores were then compared with composite course performance grade and team cohesion survey results. Mean pre-course EI score was 140.3 out of a possible 160. During the course, mean individual EI scores did not change significantly (P = 0.17) and no correlation between EI scores and academic performance was noted (P = 0.31). In addition, EI did not correlate with team cohesion (P = 0.16). While business has found significant utility for EI in increasing performance and productivity, its role in medical education is still uncertain. PMID- 26062162 TI - Costing program implementation using systematic reviews: interventions for the prevention of adolescent depression. AB - Systematic reviews can provide up-to-date syntheses of reliable evidence on "what works" to help policymakers, practitioners, and people who use services make well informed decisions about social and behavioral interventions. However, systematic reviews of social and behavioral interventions do not typically include evidence on resource use and costs, critical dimensions for decision makers to consider when faced with limited resources and constrained budgets. This paper builds on existing recommendations for including evidence for resource use and costs in systematic reviews by illustrating the development and use of an instrument to code resource use and cost data from an existing systematic review on the effects of adolescent depression prevention programs and applying that instrument to 46 studies included in that review. We demonstrate that resource use and cost data are relatively sparsely reported for treatment conditions in reports of included studies and even more so for comparison conditions, although the reporting of the most important cost drivers is reasonably frequent for treatment conditions. To allow for better integration of resource use and cost data into systematic reviews, future studies that aim to inform decision making should report more detail about program resource use and costs required for implementation, perhaps using the template provided in this paper. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062163 TI - Handsearching did not yield additional unique FDG-PET diagnostic test accuracy studies compared with electronic searches: a preliminary investigation. AB - We explored the value of handsearching to identify diagnostic test accuracy (DTA) studies to inform systematic reviews of DTA. Handsearching was conducted alongside a systematic review of the DTA of 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) for colorectal cancer. Ten journals, identified by frequency analysis of studies from six imaging reviews, were handsearched for reports of DTA studies. The numbers of studies identified by handsearching and by database searching were compared. A total of 573 journal issues from ten journals were handsearched in 185 h. A total of 936 potential reports of DTA studies were identified: 25 were relevant to the FDG PET-CT review. 7/25 FDG PET-CT papers had not been identified by database searches. No papers met the systematic review inclusion criteria. The FDG-PET systematic review included 30 papers, from 24 different journals. Handsearching two of those journals identified 211 potential reports of DTA studies for all topics and 18 for FDG PET-CT. Handsearching identified previously unseen papers but did not yield unique relevant DTA studies for the specific review. DTA imaging studies are widely distributed, and it may be more efficient to choose journals to handsearch after the identification of some relevant studies. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062164 TI - GOSH - a graphical display of study heterogeneity. AB - Estimates from individual studies included in a meta-analysis often are not in agreement, giving rise to statistical heterogeneity. In such cases, exploration of the causes of heterogeneity can advance knowledge by formulating novel hypotheses. We present a new method for visualizing between-study heterogeneity using combinatorial meta-analysis. The method is based on performing separate meta-analyses on all possible subsets of studies in a meta-analysis. We use the summary effect sizes and other statistics produced by the all-subsets meta analyses to generate graphs that can be used to investigate heterogeneity, identify influential studies, and explore subgroup effects. This graphical approach complements alternative graphical explorations of data. We apply the method to numerous biomedical examples, to allow readers to develop intuition on the interpretation of the all-subsets graphical display. The proposed graphical approach may be useful for exploratory data analysis in systematic reviews. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062165 TI - A standardized mean difference effect size for single case designs. AB - Single case designs are a set of research methods for evaluating treatment effects by assigning different treatments to the same individual and measuring outcomes over time and are used across fields such as behavior analysis, clinical psychology, special education, and medicine. Emerging standards for single case designs have focused attention on the need for effect sizes for summarizing and meta-analyzing findings from the designs; although many effect size measures have been proposed, there is little consensus regarding their use. This article proposes a new effect size measure for single case research that is directly comparable with the standardized mean difference (Cohen's d) often used in between-subjects designs. Techniques are provided for estimating the new effect size, as well as its variance, from balanced or unbalanced treatment reversal designs. The proposed estimation methods are further evaluated using a simulation study and then demonstrated in two applications. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062166 TI - Semiparametric hazard function estimation in meta-analysis for time to event data. AB - Meta-analyses have been widely used to combine information from survival data using estimated parameters in, for example, a Cox model. A number of approaches dealing with study level random effects have been developed. However, there are far fewer meta-analysis approaches for estimating survival or hazard functions. Typical approaches are based on the cumulative survival function using the generalized estimating equation. We propose an alternative approach following Efron's discrete logistic regression (Efron, 1988), but using generalized linear mixed models. We show that spline functions can be used in fitting the models to obtain smoothed estimates for hazard functions. The models also allow a semi parametric structure to include factors such as random study effects and treatment groups. This approach models the hazard function based on which the survival function can be estimated too. We also propose a Bayesian bootstrap approach for statistical inference for both hazard and survival functions. This approach was applied to two meta-analysis data sets as examples to illustrate its use. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062167 TI - Retrieving treatment and control proportions from incomplete summary data in meta analysis. AB - One of the vexing problems often encountered when combining the results of independent studies in a meta-analysis is that the data provided in individual studies are incomplete. Some studies may provide only a risk difference and others only an odds ratio. Of course, if the proportions for treatment and control are reported, then the meta-analyst can carry out a variety of analyses, such as fixed or random effect estimates. Excluding studies with incomplete data carries a risk and should be avoided if it is possible to retrieve the original proportions. Inclusion criteria in some meta-analyses may require that studies contain full data. This requirement can be relaxed if the original data can be retrieved. Copyright (c) 2012 John Wiley & Sons, Ltd. PMID- 26062168 TI - Linear inference for mixed treatment comparison meta-analysis: a two-stage approach. PMID- 26062172 TI - Complications in CT-Guided, Semi-Automatic Coaxial Core Biopsy of Potentially Malignant Pulmonary Lesions. AB - PURPOSE: Histological verification of pulmonary lesions is important to ensure correct treatment. Computed tomographic (CT) transthoracic core biopsy is a well established procedure for this. Comparison of available studies is difficult though, as technical and patient characteristics vary. Using a standardized biopsy technique, we evaluated our results for CT-guided coaxial core biopsy in a semi-automatic technique. MATERIALS AND METHODS: Within 2 years, 664 consecutive transpulmonary biopsies were analyzed retrospectively. All interventions were performed using a 17/18G semi-automatic core biopsy system (4 to 8 specimens). The incidence of complications and technical and patient-dependent risk factors were evaluated. RESULTS: Comparing the histology with the final diagnosis, the sensitivity was 96.3%, and the specificity was 100%. 24 procedures were not diagnostic. In all others immunohistological staining was possible. The main complication was pneumothorax (PT, 21.7%), with chest tube insertion in 6% of the procedures (n = 40). Bleeding without therapeutic consequences was seen in 43 patients. There was no patient mortality. The rate of PT with chest tube insertion was 9.6% in emphysema patients and 2.8% without emphysema (p = 0.001). Smokers with emphysema had a 5 times higher risk of developing PT (p = 0.001). Correlation of tumor size or biopsy angle and the risk of PT was not significant. The risk of developing a PT was associated with an increasing intrapulmonary depth of the lesion (p = 0.001). CONCLUSION: CT-guided, semiautomatic coaxial core biopsy of the lung is a safe diagnostic procedure. The rate of major complications is low, and the sensitivity and specificity of the procedure are high. Smokers with emphysema are at a significantly higher risk of developing pneumothorax and should be monitored accordingly. KEY POINTS: Using an 18G core biopsy system with 6 specimens will allow immunohistological staining with high sensitivity and specificity. Smokers with emphysema are at a significantly higher risk of developing a pneumothorax. PMID- 26062170 TI - Lipid Nanoparticles for Ocular Gene Delivery. AB - Lipids contain hydrocarbons and are the building blocks of cells. Lipids can naturally form themselves into nano-films and nano-structures, micelles, reverse micelles, and liposomes. Micelles or reverse micelles are monolayer structures, whereas liposomes are bilayer structures. Liposomes have been recognized as carriers for drug delivery. Solid lipid nanoparticles and lipoplex (liposome polycation-DNA complex), also called lipid nanoparticles, are currently used to deliver drugs and genes to ocular tissues. A solid lipid nanoparticle (SLN) is typically spherical, and possesses a solid lipid core matrix that can solubilize lipophilic molecules. The lipid nanoparticle, called the liposome protamine/DNA lipoplex (LPD), is electrostatically assembled from cationic liposomes and an anionic protamine-DNA complex. The LPD nanoparticles contain a highly condensed DNA core surrounded by lipid bilayers. SLNs are extensively used to deliver drugs to the cornea. LPD nanoparticles are used to target the retina. Age-related macular degeneration, retinitis pigmentosa, and diabetic retinopathy are the most common retinal diseases in humans. There have also been promising results achieved recently with LPD nanoparticles to deliver functional genes and micro RNA to treat retinal diseases. Here, we review recent advances in ocular drug and gene delivery employing lipid nanoparticles. PMID- 26062169 TI - Fear and the Defense Cascade: Clinical Implications and Management. AB - Evolution has endowed all humans with a continuum of innate, hard-wired, automatically activated defense behaviors, termed the defense cascade. Arousal is the first step in activating the defense cascade; flight or fight is an active defense response for dealing with threat; freezing is a flight-or-fight response put on hold; tonic immobility and collapsed immobility are responses of last resort to inescapable threat, when active defense responses have failed; and quiescent immobility is a state of quiescence that promotes rest and healing. Each of these defense reactions has a distinctive neural pattern mediated by a common neural pathway: activation and inhibition of particular functional components in the amygdala, hypothalamus, periaqueductal gray, and sympathetic and vagal nuclei. Unlike animals, which generally are able to restore their standard mode of functioning once the danger is past, humans often are not, and they may find themselves locked into the same, recurring pattern of response tied in with the original danger or trauma. Understanding the signature patterns of these innate responses--the particular components that combine to yield the given pattern of defense-is important for developing treatment interventions. Effective interventions aim to activate or deactivate one or more components of the signature neural pattern, thereby producing a shift in the neural pattern and, with it, in mind-body state. The process of shifting the neural pattern is the necessary first step in unlocking the patient's trauma response, in breaking the cycle of suffering, and in helping the patient to adapt to, and overcome, past trauma. PMID- 26062173 TI - Role of Experience, Leadership and Individual Protection in the Cath Lab--A Multicenter Questionnaire and Workshop on Radiation Safety. AB - PURPOSE: Radiation exposure in invasive cardiology remains considerable. We evaluated the acceptance of radiation protective devices and the role of operator experience, team leadership, and technical equipment in radiation safety efforts in the clinical routine. MATERIALS AND METHODS: Cardiologists (115 from 27 centers) answered a questionnaire and documented radiation parameters for 10 coronary angiographies (CA), before and 3.1 months after a 90-min. mini-course in radiation-reducing techniques. RESULTS: Mini-course participants achieved significant median decreases in patient dose area products (DAP: from 26.6 to 13.0 Gy * cm(2)), number of radiographic frames (-29%) and runs (-8%), radiographic DAP/frame (-2%), fluoroscopic DAP/s (-39%), and fluoroscopy time ( 16%). Multilevel analysis revealed lower DAPs with decreasing body mass index ( 1.4 Gy * cm(2) per kg/m(2)), age (-1.2 Gy * cm(2)/decade), female sex (-5.9 Gy * cm(2)), participation of the team leader (-9.4 Gy * cm(2)), the mini-course itself (-16.1 Gy * cm(2)), experience (-0.7 Gy * cm(2)/1000 CAs throughout the interventionalist's professional life), and use of older catheterization systems (-6.6 Gy * cm(2)). Lead protection included apron (100%), glass sheet (95%), lengthwise (94%) and crosswise (69%) undercouch sheet, collar (89%), glasses (28%), cover around the patients' thighs (19%), foot switch shield (7%), gloves (3%), and cap (1%). CONCLUSION: Radiation-protection devices are employed less than optimally in the clinical routine. Cardiologists with a great variety of interventional experience profited from our radiation safety workshop - to an even greater extent if the interventional team leader also participated. KEY POINTS: Radiation protection devices are employed less than optimally in invasive cardiology. The presented radiation-safety mini-course was highly efficient. Cardiologists at all levels of experience profited from the mini-course - considerably more so if the team leader also took part. Interventional experience was less relevant for radiation reduction. Consequently both fellows and trainers should be encouraged to practice autonomy in radiation safety. PMID- 26062174 TI - Lung Volume Reduction in Pulmonary Emphysema from the Radiologist's Perspective. AB - Pulmonary emphysema causes decrease in lung function due to irreversible dilatation of intrapulmonary air spaces, which is linked to high morbidity and mortality. Lung volume reduction (LVR) is an invasive therapeutical option for pulmonary emphysema in order to improve ventilation mechanics. LVR can be carried out by lung resection surgery or different minimally invasive endoscopical procedures. All LVR-options require mandatory preinterventional evaluation to detect hyperinflated dysfunctional lung areas as target structures for treatment. Quantitative computed tomography can determine the volume percentage of emphysematous lung and its topographical distribution based on the lung's radiodensity. Modern techniques allow for lobebased quantification that facilitates treatment planning. Clinical tests still play the most important role in post-interventional therapy monitoring, but CT is crucial in the detection of postoperative complications and foreshadows the method's high potential in sophisticated experimental studies. Within the last ten years, LVR with endobronchial valves has become an extensively researched minimally-invasive treatment option. However, this therapy is considerably complicated by the frequent occurrence of functional interlobar shunts. The presence of "collateral ventilation" has to be ruled out prior to valve implantations, as the presence of these extraanatomical connections between different lobes may jeopardize the success of therapy. Recent experimental studies evaluated the automatic detection of incomplete lobar fissures from CT scans, because they are considered to be a predictor for the existence of shunts. To date, these methods are yet to show acceptable results. KEY POINTS: Today, surgical and various minimal invasive methods of lung volume reduction are in use. Radiological and nuclear medical examinations are helpful in the evaluation of an appropriate lung area. Imaging can detect periinterventional complications. Reduction of lung volume has not yet been conclusively proven to be effective and is a therapeutical option with little scientific evidence. PMID- 26062175 TI - [Clinical manifestation of a uterus unicornis with rudimentary noncommunicating horn in a 13-year-old girl]. PMID- 26062176 TI - [Hyperdense pulmonary sign - pulmonary embolism detection in native multislice spiral CT imaging of the thorax]. PMID- 26062177 TI - [Acute gastric volvulus after mesenteric colectomy as a rare cause of acute abdomen in adults]. PMID- 26062178 TI - [Multiple enlarged metabolically active lymph nodes in 18F-FDG PET/CT after anti CTLA-4 antibody therapy in metastatic melanoma - disease progression or immunologically induced side effect?]. PMID- 26062179 TI - Effectiveness of Corticosteroid Injections in the Treatment of Plantar Fasciitis. AB - CLINICAL SCENARIO: For active individuals, plantar fasciitis (PF) is one of the most clinically diagnosed causes of heel pain. When conservative treatment fails, one of the next most commonly used treatments includes corticosteroid injections. Although PF has been identified as a degenerative condition, rather than inflammatory, corticosteroid injection is still commonly prescribed. However, the literature has not been examined to determine the effect of corticosteroid injection on PF. Focused Clinical Question: Are corticosteroid injections more effective than other interventions (placebo, platelet-rich plasma, and tenoxicam injections) in the short- and long-term treatment of PF? Summary of Key Findings: Corticosteroid injections are not more effective in the long-term treatment of PF pain than other treatments (platelet-rich plasma, tenoxicam). Clinical Bottom Line: The level 2 and 3 evidence shows that corticosteroids are more effective than placebo injections but are no more effective than tenoxicam injections and perhaps less effective than platelet-rich plasma treatment. STRENGTH OF RECOMMENDATION: Level 2 and 3 evidence suggests that corticosteroid injections are not more effective in the long-term treatment of PF than platelet-rich plasma or tenoxicam. PMID- 26062180 TI - [Efficacy of acupuncture intervention on urinary retention after spinal anesthesia]. AB - OBJECTIVE: To observe the acupuncture effect on urinary retention after spinal anesthesia. METHODS: One hundred and fifty-four patients with spinal anesthesia were randomized into an observation group (80 cases) and a control group (74 cases). In the observation group, the electroacupuncture was applied to bilateral Fushe (SP 13) and Shuidao (ST 28); 2 Hz/50 Hz, retaining for 30 min. One treatment was required. In the control group, no any intervention was applied after operation. The incidence of the postoperative urinary retention, the time of the first automatic micturition since 30 min after spinal anesthesia, the volume of the first micturition, the postoperative urine condition, the lower abdominal distention, incomplete urination and the others were observed. RESULTS: The incidence of urinary retention in the observation group was lower than that in the control group; the first automatic micturition in 30 min after spinal anesthesia was earlier than that in the control group; the comfortable urination rate was higher than that in the control group; the incidence of incomplete urination and lower abdominal distention were lower than those in the control group. The differences were significant in comparison of the two groups (all P<0.05). CONCLUSION: Acupuncture apparently shortens the time of first automatic micturition after spinal anesthesia and promotes the recovery of bladder urinary reflection. This therapy acts on promoting urination and reducing postoperative urinary retention. PMID- 26062181 TI - [Acupuncture at tendons node combined with movement for 30 cases of post-stroke spastic paralysis in lower limbs]. PMID- 26062182 TI - [Clinical observation on delayed encephalopathy after carbon monoxide poisoning treated with acupuncture to restore consciousness combined with hyperbaric oxygen treatment]. AB - OBJECTIVE: To compare the efficacy differences on delayed encephalopathy after carbon monoxide poisoning (DEACMP) between acupuncture to restore consciousness combined with hyperbaric oxygen treatment and simple hyperbaric oxygen treatment. METHODS: Forty-one patients with DEACMP were randomly divided into an observation group (21 cases) and a control group (20 cases). In the observation group, acupuncture was applied at Neiguan (PC 6), Shuigou (GV 26), Baihui (GV 20), Sishencong (EX-HN 1), Fengchi (GB 20), Hegu (LI 4), Sanyinjiao (SP 6) and Taichong (LR 3), and hyperbaric oxygen treatment was given as well. In the control group, simple hyperbaric oxygen treatment was used. The treatment was adopted once every day, and continuous 5 days' treatment made one session in the two groups. There were two days at the interval between two sessions and 6 sessions in the two groups. The changes of scores of mini mental state examination (MMSE) and Barthel index (BI) for activity of daily life and routine electroencephalogram (EEG) before and after treatment were compared. RESULTS: After treatment, the scores of MMSE and BI and EEG were all improved compared with those before treatment (all P<0.01). The raise of the scores of MMSE and BI in the observation group was more obvious than that in the control group (both P<0.05) and the improvement of EEG abnormal condition in the observation group was also superior to that in the control group after treatment (P<0.05). CONCLUSION: Acupuncture to restore consciousness combined with hyperbaric oxygen could obviously improve the cognitive function, activity of daily life and changes of EEG, and it is better than simple hyperbaric oxygen treatment. PMID- 26062183 TI - [Impacts on adductor muscle tension in children of spasmodic cerebral palsy treated with acupuncture at the three-spasm-needle therapy]. AB - OBJECTIVE: To explore the effective therapeutic method for reducing adductor muscle tension in the children of spasmodic cerebral palsy. METHODS: One hundred and forty cases of spasmodic cerebral palsy met the inclusive criteria were randomized into an observation group and a control group, 70 cases in each one. In the control group, the conventional physical therapies (Bobath therapy and lower extremities therapy) and scalp acupuncture (seven-intelligent needles, motor area, sensory area, foot-motor-sensory area and balance area) were adopted. In the observation group, on the basis of the treatment as the control group, the three-spasm-needle therapy was applied to Jiejian, Xuehaishang and Houxuehai. The physical therapies were given once every day, acupuncture was given once every two days, the treatment of 20 days made one session. There were 15 to 20 days at the interval among the sessions and 3 sessions were required totally. Separately before and after treatment, the modified Ashworth scale was used to evaluate the adductor muscle tension, and measure the adductor muscle angle, and D and E regions of gross motor function measure (GMFM-88) were adopted for clinical efficacy evaluation. RESULTS: After treatment, the scores of the adductor muscle tension were decreased to different extends in the two groups (both P<0.01), the adductor muscle angle was increased as compared with that before treatment (both P<0.01) and the scores of D and F regions in GMFM-88 were all improved (all P<0.01). The efficacy in the observation group was more significant than that in the control group (all P<0.01). CONCLUSION: The three-spasm-needle therapy effectively reduces adductor muscle tension and improves the range of motion in hip joint, independent walking, running and jumping abilities in the children of spasmodic cerebral palsy. PMID- 26062184 TI - [Hiccup after stroke treated with acupuncture at Yongquan (KI 1)]. PMID- 26062185 TI - [Acupuncture at the sensitive point for 60 cases of occipital neuralgia]. PMID- 26062186 TI - [Effect of acupuncture and moxibustion on depressive states of stroke patients' spouses]. AB - OBJECTIVE: To verify the clinical efficacy of acupuncture and moxibustion on depressive states of stroke patients' spouses. METHODS: Forty-four subjects who were stroke patients' spouses and according with inclusive criteria with mild or moderate depressive states were randomly divided into an acupuncture-moxibustion group and a blank control group, 22 cases in each group. In the acupuncture moxibustion group, acupuncture was applied at Baihui (GV 20), Shenting (GV 24), Sishencong (EX-HN 1), Hegu (LI 4), Zusanli (ST 36) and Taichong (LR 3), and suspended moxibustion was used at Shenque (CV 8), Guanyuan (CV 4) and Zhongwan (CV 12). The treatment was given twice a week for continuous 8 weeks. In the blank control group, neither acupuncture nor moxibustion treatment was given, and the patients were only treated with health and psychological guidance. Before treatment and after 8-week treatment, scores of self-rating depression scale (SDS) and numbers of insomnia severity grade were observed. RESULTS: In the two groups, the scores of SDS were both reduced than those before treatment (both P<0.05), and the decrease in the acupuncture-moxibustion group was more obvious (P<0.05). After treatment, the number of insomnia severity grade in the acupuncture-moxibustion group was improved than that before treatment (P<0.001), and the improvement was evidently superior to that in the blank control group (P<0.05). The numbers of insomnia severity grade of the blank control group before and after treatment had no statistic significance (P>0.05). CONCLUSION: The acupuncture and moxibustion intervention plan has clinical treatment significance on the improvement of mild and moderate depressive states for the stroke patients' primary caregivers who are the patients' spouses. PMID- 26062187 TI - [Primary hypertension treated with acupuncture combined with auricular point sticking: a randomized controlled trial]. AB - OBJECTIVE: To compare the differences of clinical effects on primary hypertension between acupuncture combined with auricular point sticking and western medicine. METHODS: Ninety patients with primary hypertension were randomly divided into a medication group and a combination group, 45 cases in each group. In the medication group, captopril tablets were treated with oral administration, 12.5 mg each time, twice a day; in the combination group, acupuncture and auricular point sticking were used, and acupuncture was applied at Renying (ST 9), Fengchi (GB 20) and Baihui (GV 20), while auricular point sticking was adopted at Shenmen (TF4), Xin (CO15), Jiangyagou and Jiaogan (AH6a), once a day for continuous 4 weeks. After treatment, the changes of 24 h ambulatory blood pressure, angiotensin II (Ang II) level, creatinine level and syndrome scores were observed and the clinical efficacy was assessed in the two groups. RESULTS: After 4 weeks' treatment, the 24 h ambulatory blood pressure was both improved compared with that before treatment in the two groups (P<0.01, P<0.05). The reducing of 24 h ambulatory blood pressure in the combination group was superior to that in the medication group (P<0.05). There were reducing tendencies about coefficients of variation (CVs) of the two groups, and in the combination group, the CVs of 24 h ambulatory blood pressure and systolic pressure acquired more obvious reducing range compared with the medication group (both P<0.05). Serum Ang II level and plasma creatinine level of the patients in the two groups after treatment were both decreased (both P<0.05) and the reducing of Ang II level and creatinine level of the combination group was more obvious than that of the medication group (both P<0.05). The syndrome scores of the two groups after treatment were both remarkably decreased (both P<0.05), and the reducing of the syndrome scores of the combination group was more marked than that of the medication group (P<0.05). The total effective rate of the combination group was 95.6% (43/45), which was superior to 71.1% (32/45) of the medication group (P<0.05). CONCLUSION: Acupuncture combined with auricular point sticking for primary hypertension has reliable effect. It is better than captopril for the improvement of 24 h ambulatory blood pressure, AngII level and creatinine level, and can improve dizzy, palpitation and other clinical symptoms. PMID- 26062188 TI - [Floating acupuncture combined with jaw movement and TDP for 15 cases of temporomandibular joint disorder]. PMID- 26062189 TI - [Impacts of the injection with flurphen mixture at Shenshu (BL 23) on hemodynamics and analgesia in patients with extracorporeal shock wave lithotripsy]. AB - OBJECTIVE: To compare the differences in pain reaction, hemodynamics and clinical efficacy between extracorporeal shock wave lithotripsy (ESWL) after injection with flurphen mixture (mixture of droperidol and fentanyl citrate) at Shenshu (BL 23) and simple ESWL in the patients. METHODS: Sixty-four cases of urinary calculi with ESWL were randomized into an observation group and a control group, 32 cases in each one. In the observation group, 15 to 20 min before ESWL, flurphen mixture (droperidol injection 1.25 mg and fentanyl citrate injection 0.05 mg were diluted to 6 mL with 0.9% sodium chloride solution 4.5 mL) was injected at bilateral Shenshu (BL 23). In the control group, no any adjuvant therapy and medication were used before ESWL. The changes in blood pressure and heart rate, visual analogue scale (VAS) score, lithotripsy frequency till calculi complete removal and the rate of calculi complete removal after the first lithotripsy were observed in the two groups. RESULTS: In the control group, blood pressure and heart rate were higher during lithotripsy than those before lithotripsy (both P<0.05). In the observation group, the differences in blood pressure and heart rate were not significant statistically as compared with those before lithotripsy (both P>0.05). The blood pressure and heart rate during lithotripsy in the observation group were apparently lower than those in the control group (both P<0.05). VAS scores during lithotripsy in the observation group were lower apparently than those in the control group (both P<0.05). The lithotripsy frequency in the observation group was less than that in the control group. The rate of calculi complete removal in 1 week after the first lithotripsy in the observation group was higher than that in the control group [75.0% (24/32) vs 50.0% (16/32), P<0.05]. CONCLUSION: The flurphen mixture at Shenshu (BL 23) significantly alleviates pain reaction in patients undergoing ESWL, avoids the fluctuation of hemodynamics and improves the clinical effect of lithotripsy. PMID- 26062190 TI - [Clinical observation of auricular point sticking combined with western medicine for preventing and treating postoperative complications of external excision and internal ligation on mixed hemorrhoid]. AB - OBJECTIVE: To explore the effect of auricular point sticking before operation for postoperative complications of external excision and internal ligation on mixed hemorrhoid. METHODS: Eighty patients with mixed hemorrhoid were randomly divided into an observation group and a control group, 40 cases in each group. In the control group, paracetamol and dihydrocodeine tartrate tablets were applied with oral administration 1 h after operation, 510 mg each time, twice a day; at the same time, diosmin tablets were treated with oral administration, 0.9 g each time, twice a day. Three days' treatments were required successively. In the observation group, auricular point sticking was used before operation based on the treatment in the control group. The auricular points of Shen (Co10), Pangguang (CO9), Shenmen (TF4), Pizhixia (AT4), Jiaogan (AH6a) and Gangmen (HX5) were selected. The patients were asked to press the points 3-6 times per day, 3-5 min each time, 3 days' treatment in total. The scores of the postoperative complications in the 1st and the 2nd days were compared between the two groups such as pain, edema, hematochezia, retention of urine, etc. RESULTS: After operation, the scores of pain, edema, hematochezia, retention of urine in the 2nd day were all decreased obviously than those in the 1st day in the two groups (all P<0.05); and the scores of pain, edema, hematochezia, retention of urine in the 1st and the 2nd days of the observation group were lower than those in the control group (all P<0.05). CONCLUSION: Auricular point sticking before operation combined with conventional western medicine with oral administration for preventing and treating postoperative complications of external excision and internal ligation on mixed hemorrhoid achieves positive and reliable efficacy. PMID- 26062191 TI - [Acupuncture on the corresponding acupoints on meridians of the same name for 66 cases of joint sprain]. PMID- 26062192 TI - [Preventive effect on menstrual migraine treated with subgaleal acupoint injection with metoclopramide]. AB - OBJECTIVE: To observe the differences in clinical effect on menstrual migraine between subgaleal acupoint injection with metoclopramide and oral administration of medication. METHODS: Sixty-four patients of menstrual migraine were randomized into a subgaleal acupoint injection group and a medication group, 32 cases in each one. In the subgaleal acupoint injection group, the acupoint injection started 10 days before menstruation. Eight acupoints on the head were selected and injected alternatively in two groups, once every 2 days, 4 treatments made one session and 3 sessions (3 menstrual cycles) were required. In the medication group, flunarizine was applied with oral administration, 2.5 mg each time, once every night. The duration of treatment was 3 months. The analgesic effect, frequency and time of pain attack were observed in 3 and 6 months after treatment in the two groups. RESULTS: After treatment, VAS scores were lower than those before treatment in the two groups (P<0.01, P<0.05), the attack frequency and pain time were all reduced as compared with those before treatment (all P<0.01). After treatment, VAS score, the frequency and time of pain attack in the subgaleal acupoint injection group were improved significantly as compared with the medication group (all P<0.01). CONCLUSION: The subgaleal acupoint injection with metoclopramide achieves the superior preventive effect in clinical treatment of menstrual migraine as compared with flunarizine. PMID- 26062193 TI - [Discussions on "Problems in theories of different schools of acupuncture and moxibustion"]. PMID- 26062194 TI - [Case of dupuytren's contracture]. PMID- 26062195 TI - [Acupuncture therapy for regaining consciousness in terms of acupoint location, needle insertion and needle manipulation]. AB - Acupuncture therapy for regaining consciousness activates soreness, numbness, distention, heaviness, radiating and moving, electric shock and ant climbing sensations at the specific acupoints in the stroke patients. Radiating and moving sensations are the summary of needling sensations such as soreness, numbness and twitching presenting during lifting and thrusting manipulation. These sensations are the essential factors of the therapeutic effect of regaining consciousness. Radiating sensation refers to the conduction along meridians and radiation of soreness and numbness. Moving sensation refers to the local muscular twitching at acupoints and the involuntary movement of limbs, joints and the distal. Acupuncture at the specific acupoints achieves radiating and moving sensations for promoting the circulation in meridians, regulating qi and mind and balancing yin and yang in stroke patients. This therapy was introduced in the paper in view of acupoint location, needle insertion and manipulation. PMID- 26062196 TI - [Blood-pricking combined with moxibustion on positive reaction point for 35 cases of greater occipital neuralgia]. PMID- 26062197 TI - [Research and thinking on needling sensation of acupoint Huantiao (GB 30)]. AB - Taken Huantiao (GB 30) as breakthrough point, acupuncture manipulations of generating various needling sensations by different physicians are sorted. Types of acupoint needling sensations and conducting directions after acupuncture and all kinds of factors that affect needling sensations are analyzed from new perspectives. It is considered that attention should be paid to acupoint location, postures of patients, manipulation methods, types of needling sensations, transmission lines and duration time of needling sensations, etc. PMID- 26062198 TI - [Effects of moxibustion with seed-sized moxa cone on apoptosis of myocardial cells after sport fatigue in mice]. AB - OBJECTIVE: To observe the effects of moxibustion on factors related with apoptosis of myocardial cells after sports fatigue in mice as well as the relationship among histone acetyltransferases p300 (p300), CREB binding protein (CBP) and cell apoptosis to discuss the role of p300 and CBP in moxibustion against apoptosis of myocardial cells. METHODS: Sixty clean-grade male Kunming mice were randomly divided into a control group, a sport group and a moxibustion group, 20 cases in each one. Mice in all group received identical feeding environment. Mice in the control group did not received sport nor moxibustion; mice in the sport group and moxibustion group received non-weight swimming training which lasted from 30 min per day to 90 min per day gradually for 21 days; 1 h after swimming training, mice in the moxibustion group received moxibustion with seed-sized moxa cone at "Zusanli" (ST 36) and "Guanyuan" (CV 4), 5 cones at each acupoint, once a day for 21 days. 24 h after the final swimming training, cardiac muscle tissue was collected to test factor associated suicide (Fas), B cell lymphoma/lewkmia-2 (Bcl-2) by immunohistochemical method and expression of p300 and CBP. RESULTS: Compared with the control group, the apoptosis rate of myocardial cells in the sport group was significantly increased (P<0.01), and apoptosis body with dense distribution and deep coloring can be seen in the field of microscope; the expression of Fas protein was significantly increased (P<0.01), and expression of Bcl-2, p300 and CBP was reduced (all P<0.01). The equally distributed apoptosis body with slight coloring was seen in the moxibustion group. Compared with the sport group, the apoptosis rate of myocardial cells in the moxibustion group was significantly reduced (P<0.05); the expression of Fas protein was significantly reduced (P<0.05), and expression of Bcl-2, p300 and CBP was increased (all P<0.05). CONCLUSION: Moxibustion could promote the expression of p300 and CBP in myocardial cells after sports fatigue in mice to inhibit the starting of apoptotic process, therefore reducing the apoptosis of myocardial cells after heavy exercise and protecting heart function. PMID- 26062199 TI - [Effects of acupuncture and moxibustion on serum contents of hematopoietic growth factor in mice with marrow inhibition]. AB - OBJECTIVE: To observe serum contents of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) in mice with marrow inhibition before and after acupuncture and moxibustion treatment, so as to discuss the molecular biological mechanisms of acupuncture and moxibustion on improving marrow inhibition and increasing white cells after chemotherapy. METHODS: Eighty clean-grade male Kunming mice were selected and randomly divided into a normal group, a model group, an acupuncture group and a moxibustion group according to the weight, 20 cases in each one. Mice in the model group, acupuncture group and moxibustion group were injected with cyclophosphamide (CTX) to establish mice models of marrow inhibition, while mice in the normal group received intraperitoneal injection of 0.9% NaCl. Four hours after model establishment, mice in the acupuncture group and moxibustion group were treated with acupuncture or moxibustion at "Dazhui" (GV 14), "Geshu" (BL 17), "Shenshu" (BL 23) and "Zusanli" (ST 36), respectively. Mice in the normal group and model group were immobilized without any treatment. All the treatment was given once a day for consecutive 5 days. Mice blood samples were collected from caudal vein. With manual examination, the white blood cells in peripheral blood were measured on each day from model establishment to end of treatment. Enzyme linked immunosorbent assay (ELISA) method was used to measure the serum contents of GM CSF and G-CSF 3 days and 5 days after treatment. RESULTS: Compared with the normal group, the white cells in the model group were all reduced at each time point (all P<0.05), and the serum contents of GM-CSF and G-CSF were significantly reduced (all P<0.05). Three days after treatment, compared with the model group, the white cells in the acupuncture group and moxibustion group were increased, and the difference in acupuncture group was significant (P<0.05); the serum contents of GM-CSF and G-CSF were significantly lifted (P<0.05). Four days after treatment, compared with the model group, the white cells in the acupuncture group and moxibustion group were increased (both P<0.05). Five days after treatment, compared with the model group, the white cells in the acupuncture group and moxibustion group were increased and close to the normal level; the serum contents of GM-CSF and G-CSF were significantly lifted (all P<0.05). CONCLUSION: Through increasing serum contents of GM-CSF and G-CSF in CTX mice, acupuncture and moxibustion could prompt maturation and proliferation of myeloid hematopoietic cells, which is benefit to the reconstruction of hematopoietic function and relieve the marrow inhibition caused by CTX, and thus lift peripheral white blood cells. PMID- 26062200 TI - [Multiple functions of transcutaneous electrical acupoint stimulation in peri anesthesia period]. AB - Through literature retrieval, the effects of transcutaneous electrical acupoint stimulation (TEAS) in peri-anesthesia period are summarized. It is found out that TEAS can reduce anesthetics consumption, relieve stress reaction of surgery, stabilize patients' hemodynamics, reduce surgical complication and improve immune function and quality of recovery; besides, it has protective function on heart, brain, liver, stomach, intestines and so on. However, except certain analgesic effect, the sham TEAS and transcutaneous electrial nerve stimulation do not have other functions of TEAS. The acupoint selection and stimulation parameter of TEAS in assisting anesthesia are still needed be improved and united. PMID- 26062201 TI - [Intersive moxibustion at Guanyuan (CV 4) and Mingmen (GV 4) for 56 cases of intractable insomnia]. PMID- 26062202 TI - [Guasha combined with bleeding therapy for mild hypertension]. AB - OBJECTIVE: To observe the immediate antihypertensive effect of guasha combined with bleeding therapy for mild (grade I) hypertension. METHODS: Thirty patients with mild (grade I) hypertension and 30 cases with normal blood pressure were compared. Areas and acupoints in governor vessel, meridian of foot-taiyang, meridian of hand-yangming and meridian of foot-yangming were scraped for 3 times, which was followed by bleeding therapy. The blood pressures after each guasha and bleeding therapy were recorded as well as the skin temperature in Dazhui (GV 14) after each guasha. The treatment was given once a week and totally 4 treatments were given. RESULTS: There were significant antihypertensive effects after the first guasha, the second guasha and the third guasha and bleeding therapy (all P<0.01), in which guasha combined with bleeding therapy had the most significant antihypertensive effect (P<0.01). The skin temperature in Dazhui (GV 14) was obviously increased after three times of guasha (all P<0.01). CONCLUSION: Guasha or combined with bleeding therapy has better antihypertensive effect for mild hypertension, which is likely to be related with warming stimulation on meridians and acupoints. PMID- 26062203 TI - [Case of tremor syndrome]. PMID- 26062204 TI - [Diagnosis and treatment characteristics of head-wind sha in She medicine]. AB - The diagnosis and treatment characteristics of head-wind sha in She medicine were analyzed and summarized. By visiting She-nationality villages and towns in Zhejiang province and Fujian province and interviewing hundreds of doctors of She medicine, the sha diagnosis, sha differentiation, experience and theory of treatment were arranged, and a comprehensive summary on theory and application of head-wind sha in She medicine such as pathogeny, name of disease, mechanism, diagnosis, differential diagnosis and treatment was made. It is believed that the methods of diagnosis and treatment in She medicine for head-wind sha could effectively enhance curative effect, safety and patients' quality of life, and the further research should be carried out. PMID- 26062205 TI - [Case of motor nerve injury after herpes zoster]. PMID- 26062206 TI - [Professor LAI Xinsheng's treatment experience of infertility by Tongyuan needling technique]. AB - Professor LAI Xinsheng's treatment experience of infertility mainly by Tongyuan needling technique for both females and males is summarized. Tongyuan needling technique is a treatment method of leading qi to its primordial location mainly through viscera back-shu points that can dredge the governor vessel and tonify the spirit and conception vessel points in abdomen and abdominal front-mu points, and according to state of illness acupoints for opening the 4 gates or five shu points are combined; reinforcing and reducing manipulations of acupuncture are applied for reference. With the method of listing cases, professor LAI Xinsheng's Tongyuan needling technique is detailedly introduced in different aspects, such as the treatment of polycystic ovary syndrome infertility and male infertility and improving the success rate of test-tube baby, and the manipulation of Tongyuan needling technique is summarized, indicating that Tongyuan needling technique is worth vigorously prompting in clinical treatment of infertility. PMID- 26062207 TI - [Artificial cycle therapy of acupuncture and moxibustion for irregular menstruation]. AB - Through the discussion on TCM physiological characters of females in follicular, ovulatory, luteal and menstrual phases and treatment principles, the clinical application of artificial cycle therapy of acupuncture and moxibustion was introduced for irregular menstruation and the typical cases were attached. It is suggested that the menstrual cycle follows the growth-consumption rule of yin, yang, qi and blood. The corresponding treatment principles should be applied in accordance with the change rule of menstrual cycle. Hence, it is worth to adopt the artificial cycle therapy of acupuncture and moxibustion for irregular menstruation in clinical application. PMID- 26062208 TI - [Case of ulcerative colitis]. PMID- 26062209 TI - [Analysis on literature regarding acupuncture-moxibustion with high impact factor journal of SCI during the recent 5 years]. AB - The status of acupuncture-moxibustion is more and more recognized by mainstream medicine in the world in recent years, and literature regarding acupuncture moxibustion with high impact factor (IF) published in the worldwide mainstream medicine journals is also gradually growing by years. To understand the situation of related literature, literature regarding acupuncture-moxibustion with IF of more than 10 in Science Citation Index (SCI) during the recent 5 years was retrieved. The number, the types, the diseases involved, the publishing states of the acquired articles and the source, the citation, the IF of the publishing journals were analyzed and summarized. Additionally, some of the research foci, the new research tendencies and the deficiencies of research were discussed. The thoughts and suggestions are expected to be provided for further research of acupuncture. PMID- 26062210 TI - [The theorotical basis for chronic fatigue syndrome from bladder meridian of foot taiyang]. AB - The bladder meridian of foot-taiyang is considered as key of six meridians and the yang of the yang, which is the pivot of transportation for qi and blood in the meridians and zang-fu. The running route and treatment characteristic of bladder meridian is closely related with chronic fatigue syndrome (CFS). The bladder meridian belongs to brain and connects with governor vessel, which has a close relationship with zang-fu function, quality of sleep and fatigue. Besides, the running route of bladder meridian is highly consistent with the surface projections of important anatomical structures such as muscle, nerve and sympathetic trunk, etc. Therefore, regulating the meridian-qi of bladder meridian can harmonize five-zang and calm the mind, but also effectively relieve physical and mental fatigue in CFS. PMID- 26062211 TI - [Comments on "Acupuncture for chronic knee pain: a randomized clinical trial" from Journal of the American Medical Association]. AB - The development of TCM acupuncture represents a internationalized and modern trend. A recent study with the title of "Acupuncture for chronic knee pain: a randomized clinical trial" published in Journal of the American Medical Association on October 1st, 2014, which raised doubts on acupuncture efficacy as well as traditional manipulation and acupoint theory, makes some negative impact and challenges on the development of acupuncture. From the view of future development of acupuncture, the potential influence of this research on acupuncture development is proposed, and by combining acupuncture theory, some discussions and doubts on the research design and outcome explanations are made. Additionally, enlightenments of this research on further clinical research are summarized. PMID- 26062212 TI - [Academic thoughts on Practice of acupuncture and moxibustion written by CHEN Jingwen, the acupuncture master in the Republic of China]. AB - Through the collection of Practice of acupuncture and moxibustion written by CHEN Jingwen, the acupuncture master in the Republic of China, the academic characteristics on acupuncture and moxibusiton were analyzed. The literature comparison method was adopted to compare the works of LUO Zhaoju, ZENG Tianzhi and LI Wenxian, etc. at the same period. It was discovered that CHEN Jingwen was the medical master who systematicly brought up the theory of acupoint properties earlier in the modern times. Classifying drugs based on acupoints was his academic feature. Additionally, the compatibility therapy of Chinese medicine was introduced to explain the essential ideas on the acupoints combination. The treatment was determined on the basis of zangxiang theory and the reinforcing and reducing therapy of acupuncture was emphasized in the determination of treatment and prescription. CHEN Jingwen's theory of acupoint property had been stressed and spread among the medical scholars in the Republic of China and he had made the beneficial exploration for the development of modern acupuncture and moxibustion therapy. PMID- 26062214 TI - [Collections of the Kyo-u Library]. PMID- 26062213 TI - [Mechanism progress on enteric nervous system of acupuncture for slow transit constipation]. AB - In recent years, according to the etiology and pathology researches of slow transit constipation (STC) STC is considered as a kind of "enteric neuropathy", indicating it is a kind of disease caused by abnormity of the enteric nervous system (ENS). Through reviewing the mechanism of acupuncture to regulate STC, it is found out that there is a close relationship between acupuncture regulating STC and ENS. Through various channels including ganglion cells, nerve plexus, neurotransmitter and TRPV1 (the primary sensory neurons receptor of the ENS) of the ENS, acupuncture is likely to make comprehensive adjustment on STC. PMID- 26062215 TI - [Seishu Hanaoka and anaesthesia]. PMID- 26062216 TI - [I. The past and present of Doshomachi]. PMID- 26062217 TI - [II. Medicine in early modern Osaka]. PMID- 26062218 TI - [III. Medicine blending Chinese and Dutch styles]. PMID- 26062219 TI - [Deep brain stimulation and "translational revolution": the central role of clinicians]. PMID- 26062220 TI - [Deep brain stimulation: past, present time and future]. AB - Recently awarded by the prestigious Lasker Foundation, high-frequency deep brain stimulation (DBS) has been used for the first time in 1987 in tremor and in 1993 in Parkinson's disease (PD) by the Grenoble group. So far, over 100 000 patients have been operated on worldwide. In PD, DBS induces an almost complete abatement of tremor, motor fluctuations and dyskinesias along with a reduction in levodopa dose. Although its mechanism of action is not fully understood, DBS would inhibit or modulate the expression of abnormal neuronal networks associated with given symptoms. It is therefore expected that DBS will extend to other severe neurological and psychiatric disorders. Furthermore, technological advances of the procedure are ongoing to optimize final outcomes. PMID- 26062221 TI - [Deep brain stimulation for movement disorders: indications, results and complications]. AB - Movement disorders such as Parkinson's disease (PD), essential tremor (ET) and dystonia can benefit from deep brain stimulation (DBS). DBS is considered when symptoms are disabling despite optimal medical therapy. Contraindications include dementia, uncontrolled psychiatric disease and/or comorbid conditions with potential for evolution. Targets are the subthalamic nucleus for PD, the ventral intermediate nucleus for ET and the globus pallidus internus for dystonia. The beneficial effet of DBS has been well documented for symptom control. Optimal target localization of the electrodes reduces the occurrence of side-effects. Stimulation-induced adverse effects can usually be abolished by turning the stimulation off, changing the active contact or other stimulation parameters. PMID- 26062222 TI - [Trajectory of a patient with deep brain stimulation (DBS)]. AB - An eligibility assessment for deep brain stimulation is performed in order to select patients who are likely to benefit from it. Parkinson's patients have to stop dopaminergic drugs the day before surgery. During the operation, the patient must remain awake for recording of neuronal activity and for test stimulations to optimize the position of the electrodes. Postoperatively, the stimulation is increased progressively in parallel with a decrease of dopaminergic treatments. After about ten days, the patient can return to home and controls continue as an outpatient. Three months postoperatively, a complete testing of the neurostimulator is performed and at the one year follow-up visit, the effectiveness of the DBS is assessed. PMID- 26062223 TI - [Operative and perioperative aspects of deep brain stimulation]. AB - Deep brain stimulation (DBS) requires the surgical implantation of a system including brain electrodes and impulsion generator(s). The nuclei targeted by the stereotaxic implantation methodology have to be visualized at best by high resolution imaging. The surgical procedure for implanting the electrodes is performed if possible under local anaesthesia to make electro-physiological measurements and to test intra-operatively the effect of the stimulation, in order to optimize the position of the definitive electrode. In a second step, the impulsion generator(s) are implanted under general anaesthesia. DBS for movement disorders has a very good efficacy and a low albeit non-zero risk of serious complications. Complications related to the material are the most common. PMID- 26062224 TI - [Deep brain stimulation: new targets and new indications]. AB - It is thanks to great advances in the field of neuroscience, which allowed identifying dysfunctions in neural networks as the cause of many psychiatric and neurological diseases, that the number of indications for deep brain stimulation (DBS) has quickly expanded. Although the precise mechanism of action of DBS is unknown, this method probably works by influencing the neural pathways through stimulation of deep targeted brain nuclei which behave as "hubs" in these complex networks. Currently, there is growing interest on DBS' potential benefit, especially in the psychiatric field. This review intends to tackle the current and future psychiatric and neurological indications of DBS. PMID- 26062225 TI - [Non-invasive brain stimulation for Parkinson's disease]. AB - Parkinson's disease (PD) is a major socio-economic burden increasing with the aging population. In advanced PD, the emergence of symptoms refractory to conventional therapy poses a therapeutic challenge. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in non-invasive brain stimulation (NIBS) as an alternative therapeutic tool. NIBS could offer an alternative approach for patients at risk who are excluded from surgery and/or to treat refractory symptoms. The treatment of the freezing of gait, a major cause of disability and falls in PD patients, could be enhanced by transcranial direct current stimulation (tDCS). A therapeutic study is currently performed at the Department of Neurology at the CHUV. PMID- 26062226 TI - [Shining light on translational research in deep brain stimulation]. AB - For the last decade, optogenetics has revolutionised the neurosciences by enabling an unprecedented characterisation of the circuits involved in brain diseases, in particular addiction, depression, and obsessive compulsive disorders (OCD) and other anxiety disorders. Recently, the technique has also been used to propose blueprints for novel treatments of these diseases. For many reasons, optogenetics cannot be applied to humans applications anytime soon; we therefore argue that an intermediate step would be novel deep brain stimulation (DBS) protocols that emulate successful optogenetic "treatments" in animal models. Here we provide a roadmap of a translational path to rational, optogenetically inspired DBS protocols to refine existing approaches and expand it to novel indications. PMID- 26062227 TI - [Will your doctor hide the truth?]. PMID- 26062228 TI - [Promised doctor!]. PMID- 26062229 TI - [Wiskott-Aldrich syndrome: a new advance in gene therapy]. PMID- 26062230 TI - [Drug headache: impact of a brief intervention in primary care medicine]. PMID- 26062232 TI - [Electronic patient record: the competition begins]. PMID- 26062231 TI - [Syphilis and its treatment in Germany in the early sixteenth century]. PMID- 26062234 TI - [Excellence, the great conformism]. PMID- 26062233 TI - [HUG: less nosocomial transmission of influenza]. PMID- 26062235 TI - The importance of healthcare planning. PMID- 26062236 TI - HLA testing for coeliac disease in Ireland? PMID- 26062237 TI - The prevalence of cardiovascular risk factors in obese children. AB - Childhood Obesity poses a public health problem in Ireland. Complications associated include metabolic disease and cardiovascular disease risk. Our aim was to determine the prevalence of cardiovascular risk factors in a cohort of obese Irish children. Assessments were performed on obese children attending weight management clinic. Pedometers and self report physical activity questionnaires were administered to each participant to determine physical activity levels. Fifty-nine children (21 prepubertal and 38 pubertal/post-pubertal) were metabolically profiled. Mean +/- SD of z scores for BMI, Waist Circumference and Body Fat % were +3.29 +/- 0.48, +3.98 +/- 0.73 and +2.75 +/- 0.50 respectively. 43% (n = 9) prepubertal and 68% (n = 26) pubertal/postpubertal children had at least one other cardiovascular risk factor in addition to obesity. Increased moderate-vigorous physical activity levels correlated with reduced incidence of cardiovascular risk factors. There is a significant prevalence of cardiovascular risk factors among obese pre-pubertal children and pubertal/post-pubertal adolescents attending an Irish obesity clinic. PMID- 26062239 TI - Immediate care training in Ireland, 2002-2013: a potential link between high uptake rates and effect. AB - Recent data suggest GPs contribute to successful resuscitation of cardiac arrests in the community. This paper examines uptake of Immediate Care training by GPs over a 12 year period. Data was collated on all courses and attenders (2002 2013). 244 cardiac, trauma and paediatric courses were held with 4247 attendances by 2069 individuals, including 1790 (86.5%) doctors. Of these 1648 (92.1% of all doctors) were GPs or GP registrars who generated 3585 days of attendance (84.4% of the total); 1270 attended more than one course. Between 2006 and 2013, an average of 219 (range 186-261) GPs/GP registrars attended at least one course each year, representing around 8% of all GPs in Ireland. A subset of these GPs has been shown to have a significant success rate in cardiac arrest care; there may be links between uptake of training and the clinical effectiveness of care provided. PMID- 26062238 TI - Treatment outcome for adolescents abusing alcohol and cannabis: how many 'reliably improve'? AB - Alcohol and cannabis are the primary substances contributing to referrals of adolescents to substance abuse treatment services. Their outcome has not been examined in Ireland. A three month follow-up was conducted in an outpatient adolescent treatment program. We followed up 35 high risk users of alcohol and 55 high risk users of cannabis. Although the high risk drinkers achieved a significant reduction in median number of days drinking (p = 0.004), only four (11 %) were abstinent at follow up. A further five (14%) achieved a reliable reduction in days of drinking. The high risk cannabis users demonstrated a significant drop in median days of use (p < 0.001), although only six (11%) were abstinent at follow up. A further 20 (36%) achieved a reliable reduction in days of use. Calculation of reliable change allows examination of outcomes which fall short of the elusive goal of abstinence. PMID- 26062240 TI - A review of bed utilisation in the west of Ireland. AB - To ensure efficient use of Irish acute hospitals, the study aimed to assess the appropriateness of admission and days of care. The Appropriateness Evaluation Protocol (AEP) was applied to a stratified random sample of 286 medical and surgical, elective and non-elective patients from four acute hospitals in the west of Ireland. A total of 23 patients (8%) were inappropriately admitted. Of these 15 (65%) could have been avoided. Of the 34 elective/booked admissions, seven (21%) were inappropriate in terms of location of surgery criteria. Over three quarters of elective patients (77%) were admitted one or more days prior to surgery which was not justified for 13 (57%) of these patients. Over a quarter of days of care (n = 73, 26%) were inappropriate. Evidence of discharge planning was found for 48% of patients. The study provides a benchmark to monitor progress. Existing policies and programmes should be implemented and monitored. PMID- 26062241 TI - Transurethral resection of the prostate--"now and then". AB - The number of transurethral resections of the prostate (TURP) performed each year is decreasing. The aim of this study was to assess a cohort of patients undergoing TURP and compare this to one twenty years earlier in terms of procedure, complications and outcomes. A retrospective comparative analysis of one hundred consecutive TURPs performed in 2010 was compared to one hundred cases performed in 1990. Fifty-five (55%) had a urinary catheter (UC) in situ pre operatively in 2010 compared to 22 (22%) in 1990. The length of catheterisation time was significantly longer in 2010 compared with 1990 (average 65 days vs 20 days). Infective complications occurred in six (6%) patients in 2010 and three (3%) in the 1990 cohort. Patients who had UCs in situ preoperatively for longer periods had a higher rate of infective complications and more serious complications. This highlights the importance of early specialist referral for patients diaqnosed with urinary retention. PMID- 26062242 TI - Follow up of infants born to women with hepatitis B in the National Maternity Hospital. AB - Infants born to women with hepatitis B virus (HBV) are at risk of vertical transmission. This risk is significantly reduced with correct post-natal treatment After initial perinatal management and neonatal treatment, these infants receive subsequent follow up HBV immunisations at two, four and six months. These infants then require post vaccination serological testing. This review was conducted to determine the number of infants born to mothers with HBV in the National Maternity Hospital who had appropriate post vaccination serological testing. There were seventy-eight HBV infections identified antenatally in the years 2010 and 2011 resulting in seventy live born infants at our institution. Thirteen (18.6%) infants had evidence of post vaccination serological testing. This is below international rates of follow up. There is an urgent need for a centralised national programme to ensure adequate follow up and management of all infants born to women with HBV in Ireland. PMID- 26062243 TI - Accidental ingestion of magnetic spheres in children. AB - Magnetic foreign body ingestion can have a very serious sequale if multiple or combined with another metal object inside the abdomen. We report 2 cases of ingestion of rare-earth magnets with a very different consequences. This adds to the world's literature on this topic. PMID- 26062244 TI - An unusual cause for massive inflation. AB - Chagas disease is a rare condition but with an increasing incidence. Megacolon is a known sequelae. Surgical management remains the only disease modifying treatment option; with variable long-term success. We highlight an interesting case to emphasize attention to this rare condition as a differential diagnosis in any patient presenting with massive intestinal dilatation. PMID- 26062245 TI - Oxytocin is unequally distributed in a bag of normal saline--true or false? AB - Oxytocin infusion used in labour can sometimes be left hung on the stand for many hours. There has been no study to determine if oxytocin is equally distributed throughout the infusion bag and if the distribution stays the same with time. We postulated that there may be settling of the molecules such that oxytocin concentrates at the bottom of the infusion bag. Eight infusion bags were prepared by mixing 10 IU of oxytocin in 1 litre of normal saline. The infusion bags were hung on infusion stands for 8 hours after which 10 samples of 100 mls of the solution from each bag were taken in different containers and the concentration of oxytocin calculated using oxytocin specific Enzyme Immunoassay (EIA) in the different samples. No statistically significant correlation between the oxytocin concentration and the sample number was observed (p-value = 0.738). There was no obvious relationship between oxytocin concentration and the sample number in each bag. There was no evidence to suggest that a linear oxytocin concentration gradient develops in a bag of normal saline over an 8-hour period. In fact the distribution appears to be random and unequal. PMID- 26062246 TI - Post operative complications in a dedicated elective orthopaedic hospital: transfers requiring specialist critical care support. AB - We aim to report our experience with out of hospital transfers for postoperative complications in a stand-alone elective orthopaedic hospital. We aim to describe the cohort of patients transferred, the rate of transfer and assess the risk factors for transfer. Patients were identified who were transferred out of the hospital to another acute hospital for management of non-routine medical problems. Patient data was collected relating to age, BMI, ASA, type of surgery, nature of the complication, timing and the outcome of transfer. In 2012, 2,853 inpatient surgical procedures were carried out, 51 patients (1.8%) developed a postoperative complication that required out of hospital transfer. Mean age of patients transferred was 67 (12-86) years, mean age of the overall case mix 58 years (0-96) (p = 0.01). 37.7% of the overall case mix of surgeries was made up of primary hip and knee arthroplasty procedures, these patients made up 63.7% of patients transferred out (p = 0.001). Mean BMI recorded was 31.7 (22-48) compared to the mean BMI of the total arthroplasty case mix of 28.8 (20-44) (p = 0.02). 59% of all patients at our institution were ASA category II or III. 76% of patients transferred were ASA category II or III (p = 0.005). We can conclude that patients requiring transfer are typically older. Arthroplasty patients are more likely to require transfer than patients undergoing other orthopaedic procedures. Among the arthroplasty cohort transferred patients will typically have a higher BMI than average. Patients with ASA category II or III make up nearly three quarters of those patients transferred. The mean age of patients transferred is typically older by 9 years. PMID- 26062247 TI - Back pain following a lumbar puncture--what's unusual about that? PMID- 26062248 TI - Another case of Lemierre's syndrome. PMID- 26062249 TI - Genetic tales. PMID- 26062250 TI - Strategies to address poor influenza vaccine compliance in healthcare workers. PMID- 26062251 TI - Aidan Halligan (Trinity College Dublin, 1984). PMID- 26062252 TI - Dental caries in children and the level of repeat general anaesthetics for dental extractions. A national disgrace. PMID- 26062253 TI - Essentials of medical history-taking in dental patients. AB - The starting point in the assessment and management of any patient is dependent on good history-taking. The main parts of the history-taking process well known to practitioners are the presenting complaint, the history of the presenting complaint and the current and past medical history. This paper concentrates on those aspects of the process that are particularly important to dental practitioners. Clinical Relevance: The cornerstone of safe and effective patient management lies with the history. This paper describes various aspects of history taking and highlights important areas. PMID- 26062254 TI - The Francis Report--implications for the regulator. AB - The professional regulators were identified in the Francis Report as having a central role in maintaining fundamental standards of care. This paper describes the key themes in the Report and the importance of regulatory powers to ensure that the serious failings in patient care highlighted by the Mid-Staffs Inquiry cannot be repeated. The central role of the GDC Standards in the profession's response to the Francis Report is stressed. Clinical Relevance: The importance of our professional regulator in ensuring adherence to fundamental standards of care is a central tenet of clinical dentistry. PMID- 26062255 TI - The Francis Report--implications for oral care of the elderly. AB - Oral health is an essential, yet often neglected, aspect of care in the elderly population. A mouth free of pain and disease which is functional, comfortable and aesthetic improves quality of life. Following the shocking reports of patient neglect and abuse published in the Francis Report, the dental profession must acknowledge that there are longstanding deficiencies in the provision of oral healthcare for the elderly, whether residing in care homes, hospitals or at home with support. It must be a universal goal to improve the care provision for this population through developing a greater understanding and overcoming the multi factorial barriers to care. This article will highlight the key features of the Francis Report and its significance in the context of oral healthcare provision for the elderly. Clinical Relevance: To provide insight into the oral healthcare needs of the growing elderly population and the necessity of dealing with the current limitations in service provision. PMID- 26062256 TI - The Francis Report--dento-legal implications. AB - This article explores the potential implications of the Francis Report for members of the dental team from a dento-legal perspective. It looks at the broad recommendations in light of the existing ethical environment in which dental registrants work and asks what is new and what the recommendations will actually mean for dental professionals in practical terms. Clinical Relevance: The fundamental recommendations of the Francis Report, namely, that those who provide care should put patients' interests first and be open about outcomes and performance, are not new concepts. A breach of these ethically based expectations may, however, create grounds for legal proceedings, which is clearly a significant point for all members of the dental team. It is therefore important to be aware of what is expected of those providing clinical care. PMID- 26062257 TI - Rehabilitation of oncology patients with hard palate defects. Part 1: The surgical planning phase. AB - This article is the first in a series of three papers that will discuss the conventional non-implant retained prosthodontic rehabilitation of oncology patients with surgically acquired hard palate defects. In this first paper, the dental challenges posed by the oncology patients will briefly be discussed. The interface between the specialist restorative dentist and the maxillofacial surgeon when planning the conventional dental rehabilitation of an oncology patient with a hard palate defect will be discussed in detail. Clinical Relevance: To highlight the importance of the restorative dentistry/surgical interface when planning a treatment for a patient requiring a maxillectomy and conventional obturation. PMID- 26062258 TI - Pain paper 2b: classification of orofacial pain and an update on assessment and diagnosis. AB - The classification of chronic orofacial pain remains a contentious area. However, more recently, with the clarification of pain mechanisms and improved understanding of the underlying neurophysiology and modulation factors, there is more clarity of the possible division of pain conditions. Interestingly, the pathophysiology provides a basis for classification that has more clinical relevance. The principles of assessing and managing patients with pain have modified significantly, in line with recent improved understanding of the affective and emotional components in pain behaviour and suffering. Clinical Relevance: This paper aims to provide the dental and medical teams with a review of the classification of trigeminal pain with an overview of how to assess and diagnose patients with trigeminal pain. PMID- 26062259 TI - Assessment and management of halitosis. AB - Halitosis is an unpleasant condition that may be the origin of concern not only for a possible health condition but also for frequent psychological alterations which may lead to social and personal isolation. The most frequent sources of halitosis that exist in the oral cavity include bacterial reservoirs such as the dorsum of the tongue, saliva and periodontal pockets. Volatile sulphur compounds (VSCs) are the prominent elements of oral malodour. Genuine halitosis and pseudo halitosis should be in the treatment realm of dental practitioners. Clinical Relevance: Halitosis can be a symptom of underlying systemic disease, therefore the exact diagnosis and its source (oral or non-oral) is important in the proper approach to its management. PMID- 26062260 TI - Mouth cancer for clinicians. Part 2: Epidemiology. AB - A MEDLINE search early in 2015 revealed more than 250,000 papers on head and neck cancer; over 100,000 on oral cancer; and over 60,000 on mouth cancer. Not all publications contain robust evidence. We endeavour to encapsulate the most important of the latest information and advances now employed in practice, in a form comprehensible to healthcare workers, patients and their carers. This series offers the primary care dental team, in particular, an overview of the aetiopathogenesis, prevention, diagnosis and multidisciplinary care of mouth cancer, the functional and psychosocial implications, and minimization of the impact on the quality of life of patient and family. Clinical Relevance: This article offers the dental team an overview of the changing epidemiology of, and increases in mouth cancer. PMID- 26062261 TI - Fibre-reinforced composite (FRC) bridge--a minimally destructive approach. AB - Replacing missing teeth is an integral part of the clinical services of the dental practitioner. The fibre-reinforced composite (FRC) bridge is a relatively new method for replacing missing teeth. This article will explain and discuss this alternative treatment option. Practical instructions on how to construct a FRC bridge will be given, by means of a clinical case. Different technique options will be illustrated to provide the reader with a good understanding of the most practical way to use the FRC strips. The fibre-reinforced composite provides a non-destructive, aesthetically pleasing and cost-effective way to restore missing teeth. Clinical Relevance: Minimally invasive options should always be considered and destruction of healthy enamel and dentine during the preparation phase of a replacement treatment should be avoided as much as possible. PMID- 26062262 TI - Osteochondroma of the mandibular condyle: an unusual case of dentofacial asymmetry. AB - An osteochondroma of the mandibular condyle is a rare tumour of the maxillofacial region that could first present to the general dental practitioner. This case report describes an osteochondroma of the posterio-medial mandibular condyle presenting with marked facial asymmetry and trismus over a six- month period. Appropriate referral and investigation enabled successful removal of the tumour, recontouring of the condyle and an uncomplicated, positive outcome for our patient. Clinical Relevance: Temporomandibular joint disorders can be a cause of dento-facial asymmetry. Pathology of the temporomandibular joint should be considered in the differential diagnosis when such a patient presents. PMID- 26062263 TI - A clinical guide to needle desensitization for the paediatric patient. AB - Needle phobia is a common problem encountered by dental practitioners and it can pose a challenge, especially in the paediatric patient. Needle desensitization can be used for patients who have needle fear or phobia and help them overcome this by repeated, non-threatening and controlled contacts. This paper will describe an accepted technique of needle desensitization and work through the steps required to achieve a successful outcome of local anaesthesia being delivered in a calm, safe and controlled manner. Clinical Relevance: Needle desensitization is an effective technique which can be used to enable a needle phobic patient to receive a dental injection. PMID- 26062264 TI - Maintenance periodontal therapy after systemic antibiotic and regenerative therapy of generalized aggressive periodontitis. A case report with 10-year follow-up. AB - Aggressive periodontitis (AgP) is an inflammatory disease characterized by rapid attachment loss and bone destruction. This case report presents the 10-year results in a subject with generalized AgP treated by a regenerative periodontal therapeutic approach and the adjunctive use of antibiotics, following a systematic maintenance periodontal therapy. The use of enamel matrix derivatives (EMD) and adjunctive antibiotic therapy to treat AgP yielded improvements in clinical parameters and radiographic bony fill. This combined therapeutic approach following a systematic supportive periodontal therapy supports the long term maintenance of teeth with previous advanced periodontal defects, demonstrating successful stability after 10-years follow-up. Clinical Relevance: The combined treatment protocol using EMD plus adjunctive antibiotic therapy, associated with a systematic supportive periodontal therapy, benefits the long term maintenance of teeth with previous advanced periodontal defects in subjects presenting AgP, supporting this approach as an alternative in the treatment of AgP. PMID- 26062265 TI - Clinical challenges Q&A. 10. Dental appearance. PMID- 26062267 TI - Peanut allergy--is it time to change infant feeding practice? PMID- 26062266 TI - Technique tips--The removal of a primary tooth anterior abutment root to salvage a fixed prosthesis. PMID- 26062268 TI - GPs have key role in early diagnosis of endometriosis. AB - Endometriosis is defined as the presence of endometrial-like tissue outside the uterus. Deposits are commonly distributed on the ovaries, uterosacral ligaments, pouch of Douglas, rectum and sigmoid colon, bladder and ureter. Endometriosis is common, affecting 10% of the female adult population and up to 50% of women with infertility. Risk factors include early menarche, late menopause, delayed childbearing, vaginal outflow obstruction and a first-degree relative affected. Women commonly present to their GP with pelvic pain, painful intercourse or subfertility. Classically the pain starts several days before the period which is extremely painful. After the period, symptoms tend to improve until mid-cycle when the pattern repeats again. Patients also complain of fatigue. Abdominal palpation, bimanual and speculum examination are important to identify signs of endometriosis, but also to exclude alternative diagnoses such as fibroid uterus, infection or pregnancy. However, a normal examination does not exclude a diagnosis of endometriosis. Serum CA125 can be raised in endometriosis but is not specific or sensitive for the condition and is therefore not recommended as a screening test. A normal pelvic ultrasound scan does not exclude a diagnosis of endometriosis. The gold standard investigation for endometriosis is laparoscopy and biopsy with histological confirmation. Referral should be considered if pain is not controlled with simple analgesia or the diagnosis is suspected in a woman who is actively trying to conceive. Early referral should be considered in women with abnormal examination findings, or an abnormal ultrasound result. PMID- 26062269 TI - Be vigilant for perinatal mental health problems. AB - The postnatal period appears to be associated with higher rates of adjustment disorder, generalised anxiety disorder, and depression. Women who have a history of serious mental illness are at higher risk of developing a postpartum relapse, even if they have been well during pregnancy. Psychiatric causes of maternal death are more common than some direct causes of death. UK rates increased from 13/100,000 in 2006-2008 to 16/100,000 in 2010-2012, higher than, for example, mortality caused by haemorrhage or anaesthetic complications of childbirth. Postnatal depression is more severe than baby blues, follows a chronic course and may relapse outside the perinatal period. Although 13% of patients already have depression in pregnancy, the majority tend to be diagnosed after delivery; up to 19% from childbirth to three months postpartum. NICE recommends using the Two Question Depression Screen and the Generalized Anxiety Disorder scale from the booking visit through to one year postpartum. A positive response to depression or anxiety questions warrants a full assessment using either PHQ-9 or the Edinburgh Postnatal Depression Scale. Bipolar disorder may present as a first depressive episode in pregnancy or the postnatal period. In the postpartum period women have a high risk of severe relapse. Postpartum psychosis has a sudden and dramatic presentation with delusions, mania, severe depression, or mixed episodes with wide fluctuations of symptoms and severe mood swings. PMID- 26062271 TI - Pruritus. PMID- 26062270 TI - Improving detection and management of drug allergy. AB - Suspected adverse drug reactions may be subdivided on the basis of mechanism e.g. immunological (requiring sensitisation by previous exposure) versus nonimmunological; timing (e.g. immediate or delayed), or whether the phenomenon is dose dependent or not. In the NICE guideline the main approach is to classify the event according to whether it: is immediate (within an hour of drug administration) or delayed (hours or days); affects a single or multiple systems; is clinically severe/life threatening or not. An immediate, immunologically mediated, multisystem, life-threatening reaction would for example include anaphylaxis (type 1 or typically IgE- mediated hypersensitivity) especially if the clinical features (e.g. bronchospasm, hypotension) are suggestive. Serum mast cell tryptase should be tested ideally within two hours and certainly before four hours post reaction. Detailed investigation of suspected cases in a specialist clinic is ideally delayed for 4-6 weeks after the event. Adverse drug reactions need to be meticulously recorded and the patient fully informed. Documentation should include: date of reaction; drug name (chemical and generic); route of administration; time interval between first dose and event; and nature and severity of symptoms. Written guidance should be provided on which other chemically related drugs also need to be avoided. Specialist referral is indicated for: suspected anaphylaxis; severe/life- threatening episodes e.g. Stevens-Johnson syndrome; severe NSAID reactions with ongoing need for NSAID therapy; suspected penicillin allergy (if alternative antibiotics are not available); and problems related to general and local anaesthesia. PMID- 26062273 TI - All doctors should have their own GP. PMID- 26062272 TI - Obstetric mutilations. 1915. PMID- 26062274 TI - An action list for the new CDO. PMID- 26062275 TI - Ebola: a very dangerous viral haemorrhagic fever. AB - Ebola is a highly dangerous infectious disease seen mainly in West Africa or travellers from there. All healthcare workers should check the recent travel history of their patients and follow formal guidance issued. Clinical Relevance: This article discusses the relevance of the Ebola virus in dentistry. PMID- 26062276 TI - Vacuum-formed retainers: an overview. AB - The need for long-term retention following orthodontic treatment is now considered essential to prevent post-orthodontic treatment relapse. The vacuum formed retainer (VFR) has gained popularity in recent times. This paper describes briefly the characteristics of VFRs and summarizes the evidence in relation to their effectiveness. Clinical Relevance: VFRs are now widely used after orthodontic treatment and it is important that clinicians adopt an evidenced based approach to their use. PMID- 26062277 TI - Functional crown lengthening surgery in the aesthetic zone; periodontic and prosthodontic considerations. AB - Crown lengthening surgery aims to increase the amount of supragingival tooth tissue by resection of the soft and/or hard tissues to enable otherwise unrestorable teeth to be restored by increasing the retention and resistance forms of the teeth. Restoration of the worn dentition may require significant prosthodontic knowledge and skill. A prosthodontist should be involved from the beginning of the management of the patient. A number of key stages should be considered for correct management. Although the periodontist may guide the prosthodontist with regards to what may or may not be possible surgically, the overall treatment plan should be prosthodontically driven. Clinical Relevance: Toothwear of the anterior dentition provides a unique challenge to restore not only function but also to manage the aesthetic demands of the patient. To ensure that the correct outcome is reached, clinicians should be familiar with the normal anatomical proportions and relationships to enable planning and treatment to take place. PMID- 26062278 TI - Challenges in treating traumatically intruded and ankylosed permanent incisors: a case report with a multidisciplinary approach. AB - This report discusses the challenges, complications and management of traumatic intrusion injuries affecting the permanent dentition. A case is described where trimming of the incisal edge of a severely intruded and ankylosed upper lateral incisor resulted in an unexpected re-eruption of the tooth. It is suggested that the vibrations from drilling may have disrupted the ankylosis, initiating spontaneous re-eruption and this approach could provide a minimally invasive and conservative pathway to treating ankylosed teeth. Clinical Relevance: To date no effective treatment has been described to reverse the development of replacement root resorption leading to the loss of the affected tooth. The hypothesis proposed here suggests that mechanical vibrations, if strong enough, may disturb the ankylosis and allow re-eruption of the intruded tooth. PMID- 26062279 TI - Prosthetic rehabilitation of the gagging patient using acrylic training plates. AB - Patients with a hyper-responsive gag reflex pose dentists with a challenging problem. The gag reflex of some patients may be so severe that patients (and operating clinician) may favour extraction of any painful, infected teeth as opposed to more lengthy and complicated procedures such as root canal therapy. However, consistently adopting this approach may render the gagging patient completely edentulous. Such patients may then present to the dental surgeon requesting tooth replacement with some form of denture. This in itself can be a challenging task given the difficulties one may experience whilst taking impressions in this cohort of patients. This article will discuss the prosthetic management of the maxillary arch in edentulous patients with a severe gag reflex. There will be particular emphasis on the aetiology and physiology of the gag reflex, impression-taking techniques to allow the construction of an acrylic training plate (as an interim measure), principles of training plate design and construction of the definitive removable denture. Clinical Relevance: Removable training plates can be used as an interim measure to desensitize edentulous gagging patients before providing them with a definitive removable denture. PMID- 26062280 TI - The use of the operating microscope in general dental practice. Part 2: If you can see it, you can treat it! AB - The use of magnification by dental clinicians when carrying out examinations and treatments is becoming more commonplace. The best instrument for this purpose is the operating microscope which has been shown to enhance quality, longevity and outcome of clinical work as well as facilitating better ergonomics for both the dentist and dental nurse. This paper, the second of two, explores the potential uses for the operating microscope in general dental as well as specialist practice (such as endodontics) and discusses how the interested clinician can use such equipment in a practical manner. Clinical Relevance: The operating microscope enhances the dental surgeon's vision so improving treatment outcomes not only in specialist fields, such as endodontics, but also in many of the disciplines which general dental practice encompasses. PMID- 26062281 TI - The role of dental implants in the management of dento-alveolar trauma. Part 2. AB - Patients who suffer dento-alveolar trauma present a unique challenge for the dentist. There are numerous options to consider when attempting to restore the dentition. This article reviews the role of dental implants and how thorough planning and execution of such treatment could result in an optimal outcome. Clinical Relevance: Knowledge of the role of dental implants and factors imperative for a successful treatment outcome will assist the clinician in achieving optimal restorative results. PMID- 26062282 TI - Patient assessment: preparing for a predictable aesthetic outcome. AB - The flux of patients seeking to make changes to the appearance of their smile zone appears to be on a pathway of continual increase. This is possibly due to an increase in awareness towards oral health, and perhaps social, peer and media pressures, respectively. Cohorts of dental practitioners have thus responded to the latter demands by attending a plethora of educational courses, often focusing on either restorative techniques or other disciplines, notably orthodontics and clear aligners in particular. Consequently, treatment planning and thus treatment provision may carry the risk of being biased or indeed 'outcome driven' whereby the skills and knowledge of any clinician towards a particular faculty may significantly influence the ultimate treatment plan, with the unfortunate tendency sometimes to overlook the role of the interdisciplinary approach of concomitant restorative and contemporary techniques. The role of orthodontics to facilitate the provision of such treatment, along with predictable enamel bonding, has the distinct advantage of providing an acceptable aesthetic result with minimal biological intervention. However, to achieve an optimal result in such cases requires meticulous treatment planning and patient selection to avoid pitfalls with regards to long-term stability and function. This article suggests a standardized approach to patient assessment, with an interdisciplinary perspective in mind. Clinical Relevance: With the growth of patient demand for improving the appearance of the smile, a meticulous assessment protocol is required along with effective interdisciplinary communication. This enables a comprehensive treatment plan to be developed with the correct priorities. PMID- 26062283 TI - Articaine hydrochloride: is it the solution? AB - In recent times there has been raised interest regarding the use of articaine hydrochloride as a dental local anaesthetic solution. The use of articaine hydrochloride as a dental local anaesthetic agent has been reported to be safe and effective. Paraesthesia is a rare but unwanted adverse effect attributed to the use of this local anaesthetic in dentistry, particularly following the administration of a nerve block injection. There is no evidence to support the opinion that the use of articaine carries a greater associated risk of paraesthesia than with the use of any other local anaesthetic. Clinical Relevance: The aim of this article is to review the relative merits of articaine hydrochloride against its documented potential drawbacks. The article will also aim to update readers on the use of articaine hydrochloride for local analgesia in dentistry, including the pharmacology, efficacy and safety concerns (including the risks of nerve paraesthesia) commonly associated with the administration of this agent. PMID- 26062284 TI - Clinical challenges Q&A. 7. Rough mouth. PMID- 26062285 TI - Technique tips--distraction anaesthesia: applying the gate control theory in delivering painless anaesthesia. PMID- 26062287 TI - Factors for sustainability of evidence-based practice innovations: Part I. PMID- 26062286 TI - Theory development and application emphasized in current issue. PMID- 26062288 TI - Intervention mapping protocol for developing a theory-based diabetes self management education program. AB - Development of behavior theory-based health promotion programs is encouraged with the paradigm shift from contents to behavior outcomes. This article describes the development process of the diabetes self-management program for older Koreans (DSME-OK) using intervention mapping (IM) protocol. The IM protocol includes needs assessment, defining goals and objectives, identifying theory and determinants, developing a matrix to form change objectives, selecting strategies and methods, structuring the program, and planning for evaluation and pilot testing. The DSME-OK adopted seven behavior objectives developed by the American Association of Diabetes Educators as behavioral outcomes. The program applied an information-motivation-behavioral skills model, and interventions were targeted to 3 determinants to change health behaviors. Specific methods were selected to achieve each objective guided by IM protocol. As the final step, program evaluation was planned including a pilot test. The DSME-OK was structured as the 3 determinants of the IMB model were intervened to achieve behavior objectives in each session. The program has 12 weekly 90-min sessions tailored for older adults. Using the IM protocol in developing a theory-based self-management program was beneficial in terms of providing a systematic guide to developing theory-based and behavior outcome-focused health education programs. PMID- 26062289 TI - Self-concepts of exercise in frail older adults with heart failure: a literature review. AB - The co-occurrence of frailty and heart failure (HF) in older adults (65 years or older) can adversely affect the ability to engage in self-care management behaviors, which may alter self-concepts and decrease quality of life. Little is known about how frailty and HF influence older adults' self-concepts or how these self-concepts affect exercise behaviors. Therefore, the aims of this literature review were to identify the self-concepts of older frail adults with HF and to identify how these self-concepts affect their exercise behaviors. Guided by the schema model of self-concept, publications before April 2013 that examined the impact of the self-concepts of older adults with HF and/or frailty on exercise behavior were reviewed. As a result, 6 articles were included. Three of the 6 articles focused on frailty, and 3 of the 6 articles focused on HF. However, no study was found that specifically examined the self-concepts of frail older adults with HF. The self-concepts of older adults with HF and/or frailty are multifaceted and include both cognitive resources (facilitating exercise) and cognitive liabilities (hindering exercise). Studies are needed to determine how the co-occurrence of frailty and HF impact self-concepts and exercise behaviors in older adults. PMID- 26062290 TI - The meaning of family nursing intervention: what do acute care nurses think? AB - Understanding the concept of family nursing intervention from the perspective of practicing nurses is essential for implementing a family-centered approach in the acute care context. Data from this qualitative study were analyzed using a colloquial concept analysis method derived from Rodgers' evolutionary theory. Five main attributes of family nursing interventions were identified. Family nursing interventions were viewed as a time-limited, collaborative process, initiated and/or facilitated by nurses and directed at either the individual or the family to solve problems. The antecedents of family nursing interventions were "family assessment," "the presence of a family-related problem," "willingness to participate (provider and family)" and a "supportive organizational structure." The most common consequences (outcomes) were identified as positive (good) or negative (bad) individual or family-related out comes following a family nursing intervention. The analysis suggests that family nursing interventions are essential but variable in nature within nursing practice. In addition, the analysis implies a need for further inquiry in diverse settings to define the concept and test relationships between the antecedents and outcomes to advance nurses' translational knowledge of culturally appropriate family nursing interventions. PMID- 26062291 TI - Motherhood: a discrepancy theory. AB - Motherhood is a highly anticipated and positive event for most women. Society has constructed many ideal images of motherhood, giving women standards to live up to, and many times setting them up for disappointment. When this disappointment occurs, an emotional reaction follows, which may be fear, guilt, or shame. However, some women are able to experience this mismatch between an ideal and actual self and adapt with minimal emotional reaction. There was not a nursing theory that described this phenomenon. "Self-Discrepancy: A Theory Relating Self and Affect" (Higgins, 1987), from the psychology discipline provided concepts and definitions that could be used to derive a nursing theory. The derivation resulted in a testable mid-range theory that could have a significant impact on nursing interventions for postpartum mood disorders. PMID- 26062292 TI - How to accommodate women with mobility limitations in biological studies. AB - People with disabilities should be routinely included in research studies if there is no specific reason for their exclusion. Regardless, they may be inadvertently excluded because of the procedures of the study. By conducting a community-based biological study with women aging with mobility limitations, these authors gained further understanding of their accommodation needs during research participation. The women aging with mobility limitations offered specific physical, cultural, or environmental needs that could have influenced the methods, procedures, and possible outcomes involved when conducting a biological study with this community living population. The authors and participants identified methodological challenges for women with mobility impairments within three key areas: recruitment procedures, laboratory procedures, and community-based data collection. The authors propose possible solutions to these identified challenges. It is our hope that this will begin a larger dialogue on how to routinely accommodate people with disabilities in biological research studies. PMID- 26062293 TI - Metabolomics-based promising candidate biomarkers and pathways in Alzheimer's disease. AB - Pathologically, loss of synapses and neurons, extracellular senile plaques and intracellular neurofibrillary tangles (NFTs) are observed in the brains of patients with Alzheimer's disease (AD). These features are associated with changes Abeta (amyloid beta) 40, Abeta42, total tau and phosphorylated tau (p tau), which are as definitely biomarkers for severe AD state. However, biomarkers for effectively diagnosing AD in the pre-clinical state for directing therapeutic strategies are lacking. Metabolic profiling as a powerful tool to identify new biomarkers is receiving increasing attention in AD. This review will focus on metabolomics-based detection of promising candidate biomarkers and pathways in AD to facilitate the discovery of new medicines and disease pathways. PMID- 26062294 TI - Identification, synthesis and characterization of new impurities in tenofovir. AB - A detailed impurity study was conducted on tenofovir, (R)-({[1-(6-amino-9H-purin 9-yl)propan-2-yl]oxy}methyl)phosphonic acid (1), which is the key starting material of manufacturing the active pharmaceutical ingredient (API) tenofovir disoproxil fumarate (2) based on a recently reported procedure. The major impurities generated in the production of tenofovir (1) have been synthesized, characterized and confirmed. The possible formation mechanisms of these impurities were elucidated herein, which would help to understand the process. In addition, this work will also improve the quality control during manufacturing tenofovir and tenofovir disoproxil fumarate (2). PMID- 26062295 TI - Strategic development of a multivariate calibration model for the uniformity testing of tablets by transmission NIR analysis. AB - The use of transmission near infrared spectroscopy (TNIRS) is of particular interest in the pharmaceutical industry. This is because TNIRS does not require sample preparation and can analyze several tens of tablet samples in an hour. It has the capability to measure all relevant information from a tablet, while still on the production line. However, TNIRS has a narrow spectrum range and overtone vibrations often overlap. To perform content uniformity testing in tablets by TNIRS, various properties in the tableting process need to be analyzed by a multivariate prediction model, such as a Partial Least Square Regression modeling. One issue is that typical approaches require several hundred reference samples to act as the basis of the method rather than a strategically designed method. This means that many batches are needed to prepare the reference samples; this requires time and is not cost effective. Our group investigated the concentration dependence of the calibration model with a strategic design. Consequently, we developed a more effective approach to the TNIRS calibration model than the existing methodology. PMID- 26062296 TI - Effect of gamma-cyclodextrin as a lyoprotectant for freeze-dried actinidin. AB - Actinidin (ATD) is a cysteine protease found in kiwifruit. It is used to tenderize meat and to enhance the digestion of proteins in the small intestine. However, ATD is unstable during freeze-drying, which alters its bioactivity. It is well known that sugars have the ability to protect proteins from the stress of freeze-drying. In this study, we investigated the protective effect of various saccharides on the stability of ATD during freeze-drying. The ATD activities of the samples containing gamma-cyclodextrin (CyD) showed only a small decrease, and compared with trehalose and sucrose, gamma-CyD was a more effective stabilizer for ATD. Secondary structural changes in freeze-dried ATD were observed by circular dichroism spectroscopy and compared with the changes in stabilized samples. There was a close relationship between the alpha-helix content and the stabilization. The sugars stabilized the protein by suppressing the changes in the alpha-helix. Fourier transform infrared spectroscopy measurement showed that the amide I band of ATD with gamma-CyD was shifted to a lower wavenumber compared with other sugars. Therefore, stronger hydrogen bonds may be formed between ATD and gamma-CyD than between ATD and other sugars. The suppression of changes in the protein secondary structure accompanying the formation of hydrogen bonding between the protein and the sugar also contributed to the protective effect of the sugars. PMID- 26062297 TI - Mechanical and adhesive properties of cellulosic film coats containing polymeric additives. AB - The effects of some polymeric additives, i.e. corn starch (CS) and magnesium stearate (MS), on mechanical properties (tensile strength, modulus of elasticity, and elongation at break) and adhesive toughness of hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) film coats were investigated. The free and in situ films containing 10 and 20% additives by weight of polymer were prepared by spray method. The mechanical properties of both HPMC and EC free films decreased as the concentration of additives was increased because of the lower stiffening effect brought about by hydrodynamic or reinforcing effect. However, adhesive toughness of in situ films was found to increase for HPMC whereas that of EC films decreased with the increasing concentration of polymeric additives. Such contradictory results between these two film forming polymers may be attributed to the net result of the opposite effects between interference of film-tablet interfacial bonds and the reduction of mechanical properties. The former seemed to be preferential in the case of EC films, while the latter predominated for HPMC films. Such conclusions were supported by the FTIR results, in which the polymer-additive interaction was found for EC. Increase in concentration of polymeric additives resulted in the decrease in mechanical properties of free films whereas the adhesive toughness of in situ films may be influenced by either the interference of film-tablet interfacial bonds or the significant reduction of mechanical properties. PMID- 26062298 TI - A pharmacokinetic/pharmacodynamic analysis of a standard voriconazole regimen in different CYP2C19 genotypes by Monte Carlo simulation. AB - OBJECTIVES: The objective of this study was to evaluate the standard voriconazole dosage regimen (maintenance dose was 200 mg bid orally) against Aspergillus infections in different CYP2C19 genotypes from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. METHOD: Monte Carlo simulation (MCS) was applied to simulate 5,000 patients by integrating published pharmacokinetic (PK) parameters, variability of PK parameters on CYP2C19 genotypes and microbiological data. RESULTS: The standard dosage regimen for poor metabolizers (PM) with Aspergillus infections was effective except A. versicolor, for heterozygous extensive metabolizers (HEM), Aspergillus fumigatus, A. terreus and A. nidulans infections could be treated effectively with the standard dosage regimen; for extensive metabolizers (EM), the standard voriconazole dosage regimen failed to achieve the best outcome for the six Aspergillus spp. Increasing dose (e.g. 300 mg bid) or even changing the antifungal drug was needed for EM and most HEM patients with Aspergillus infection. CONCLUSION: Instead of using a standard dosage regimen for all patients, the voriconazole dosage regimen needs to be optimized for patients with different CYP2C19 genotypes. PMID- 26062299 TI - Long noncoding RNA HIF1A-AS1A reduces apoptosis of vascular smooth muscle cells: implications for the pathogenesis of thoracoabdominal aorta aneurysm. AB - Long non-coding RNAs (IncRNAs) play important roles in various biological processes, such as transcriptional regulation, cell growth and tumorigenesis. However, little is known about the role of IncRNA HIF 1 alpha-antisense RNA 1 (HIF1a-AS1) in regulating the proliferation and apoptosis of vascular smooth muscle cells (VSMCs) and the expression of HIF1a-AS1 in serum of thoracoabdominal aortic aneurysm (TAAA) patients. The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining. Expression of genes and proteins were analyzed by real-time PCR and western blotting, respectively. Cells were transfected with siRNAs as a gene silencing method. In serum of TAAA patients, the expression of HIF1a-AS1 was significantly increased (superior to 6-fold) compared to the normal control. Moreover, Palmitic acid (PA) induced cell apoptosis in VSMCs in a time- and dose-dependent manner, and the proportion of the apoptotic cells had gained as compared to untreatment group. PA also induced up-regulation expression of HIF1a-AS1. We also found that transfection of cells with HIF1a-AS1 siRNA decreased the expression of caspase-3 and caspase-8 and increased the expression of Bcl2, and protected PA-induced cell apoptosis in VSMCs. HIF1a-AS1 was overexpressed in the TAAA and the interaction between HIF1a-AS1 and apoptotic proteins plays a key role in the proliferation and apoptosis of VSMCs in vitro, which may contribute to the pathogenesis of TAAA. PMID- 26062300 TI - Changes of glucocorticoid receptor isoforms expression in acute lymphoblastic leukemia correlate with glucocorticoid resistance. AB - Alternative splicing of the glucocorticoid receptor (GR) gene results in several GR isoforms, we examined their expression (GRalpha, GRbeta, GRgamma and GR-P) by real-time RT-PCR in glucocorticoid (GC) sensitive (CEM-C7), GC resistant (CEM-C1) cells and adult acute lymphoblastic leukemia (ALL) patients, to determine the association of GR isoform expression profiles and GC resistance in adult ALL patients. With GC treatment, GR levels in C1 cells showed no obvious changes. In C7 cells, the mRNA levels of GRalpha, GRbeta and GRgamma first increased and then decreased, whereas GR-P mRNA had a continued rising trend. C7 cells had a higher GRalpha/GRgamma, lower GRalpha/GR-P and GRgamma/GR-P ratios than C1 cells (P < 0.01). In adult ALL patients, GRgamma mRNA varied in different ALL stages (complete remission CR 15.82 vs. relapsed 8.21 vs. initial 1.93 P < 0.05). It also did in the ratios between GR isoforms that GRalpha/GRgamma and GRalpha/GR-P in initial patients were higher than relapsed and CR (P < 0.05), while GRgamma/GR P in CR was higher than initial and relapsed patients (P < 0.05). GR-P mRNA in T ALL patients was much higher than that in B-ALL patients (P < 0.05). Peripheral blood hemoglobin (HB) was positively correlated with GRalpha mRNA and GR-P mRNA (P < 0.05), while white blood cells (WBC) negatively correlated with GRgamma mRNA (P < 0.05). The present study demonstrates that GR autoinduction is more important to GC sensitivity than its basal level expression. GC sensitivity is also significantly correlated with GRalpha mRNA and mildly associated with GRbeta mRNA expression. Both GRgamma mRNA and the ratios between GR isoforms (GRalpha/GRgamma, GRalpha/GR-P and GRgamma/GR-P) are correlated with ALL stages. The changes of mRNA expression levels of GRalpha, GR-P and GRgamma may provide valuable information for GC resistance. Peripheral blood HB and WBC affect GR isoform expression. PMID- 26062301 TI - The synergistic killing of AML cells co-cultured with HS-5 bone marrow stromal cells by As2O3 and the PI3K/Akt signaling pathway inhibitor LY294002. AB - We aimed to investigate whether a combination of resistance to arsenic trioxide (As2O3) and the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway inhibitor LY294002 can inhibit the proliferation of AML cells in the bone marrow microenvironment. Three AML cell lines were grown with HS-5 human bone marrow stromal cells in adherent co-cultures. The inhibitory effects of As2O3 alone or in combination with LY294002 on the proliferation of these co-cultured AML cells were observed. The PI3K/Akt signaling pathway was detected by Western Blot in co cultured AML cells cultured alone or treated with As2O3 alone or in combination with LY294002. Our results demonstrate that AML cells adhered to stroma exhibited significantly reduced sensitivity to As2O3. The resistance can be partially abolished by inhibiting the PI3K/Akt pathway. The administration of As2O3 in combination with a PI3K/Akt signaling pathway inhibitor may be expected to become a new approach to the treatment of AML. PMID- 26062302 TI - Anti-diabetic effect of 2,5-dimethoxy(4-methoxyphenyl)benzamide. AB - This study was undertaken to identify new anti-diabetic substances, and we successfully identified the new potent anti-diabetic agent 2,5-dimethoxy(4 methoxyphenyl)benzamide (DMPB). The glucose uptake of C2C12 muscle cells more than doubled following treatment with 50 MUM DMPB. This compound also enhanced the expressions of pAMPK, pACC, and pAKT, which are target proteins for glucose uptake improvement in C2C12 cells. Moreover, DMPB increased the transcriptional activity of the peroxisome proliferator-activated receptor in HEK 293 kidney cells. These results suggest that DMPB has potential as an anti-diabetic substance. PMID- 26062303 TI - Piroxicam inhibits herpes simplex virus type 1 infection in vitro. AB - Piroxicam is a potent, nonsteroidal, anti-inflammatory agent (NSAID) which also exhibits antipyretic activity. The antiviral effect of piroxicam against herpes simplex virus type 1 (HSV-1) was examined in vitro on RC-37 monkey kidney cells using a plaque reduction assay. Piroxicam was dissolved in ethanol or dimethylsulfoxide (DMSO) and the 50% inhibitory concentration (IC50) was determined at 4 MUg/ml and 75 MUg/ml, respectively. The IC50 for the standard antiherpetic drug acyclovir was determined at 1.6 MUM. At non-cytotoxic concentrations of these piroxicam solutions, plaque formation was significantly reduced by 62.4% for ethanolic piroxicam and 72.8% for piroxicam in DMSO. The mode of antiviral action of these drugs was assessed by time-on-addition assays. No antiviral effect was observed when cells were incubated with piroxicam prior to infection with HSV-1 or when HSV-1 infected cells were treated with dissolved piroxicam. Herpesvirus infection was, however, significantly inhibited when HSV-1 was incubated with piroxicam prior to the infection of cells. These results indicate that piroxicam affected the virus before adsorption, but not after penetration into the host cell, suggesting that piroxicam exerts a direct antiviral effect on HSV-1. Free herpesvirus was sensitive to piroxicam in a concentration-dependent manner and the inhibition of HSV-1 appears to occur before entering the cell but not after penetration of the virus into the cell. Considering the lipophilic nature of piroxicam, which enables it to penetrate the skin, it might be suitable for topical treatment of herpetic infections. PMID- 26062304 TI - Isolation of three dibenzocyclooctadiene lignans from in vitro cultures of Schisandra chinensis (Turcz.) Baill.--the first report. AB - Three dibenzocyclooctadiene lignans: deoxyschizandrin (1), gomisin A (2) and schizandrin (3) were isolated from biomass extracts of Schisandra chinensis (Turcz.) Baill. shoot-differentiating callus cultures. The mentioned lignans were not isolated earlier from in vitro cultures of this plant species. This is the first report concerning on isolation of dibenzocyclooctadiene lignans from in vitro cultures of Schisandra chinensis. PMID- 26062305 TI - Bioconversion of ginsenoside Rd to ginsenoside M1 by snailase hydrolysis and its enhancement effect on insulin secretion in vitro. AB - In the present work, we report efficient production of ginsenoside M1 (G-M1) from ginsenoside Rd (G-Rd) by snailase hydrolysis using response surface methodology (RSM). During investigation of the hydrolysis of ginsenoside Rd by various glycoside hydrolases, snailase showed a strong ability to transform G-Rd into G M1 with 100% conversion. RSM was used to optimize the effects of the reaction temperature, enzyme load, and reaction time on the conversion process. Validation of the RSM model was verified by the good agreement between the experimental and the predicted values of G-M1 conversion yield. The optimum preparation conditions were as follows: temperature of 41.0 degrees C; enzyme load of 17.5%; reaction time of 18 h. The determined method may be highly applicable for the enzymatic preparation of G-M1 for medicinal purpose. Furthermore, the effect of G-M1 on insulin secretion in MIN6 pancreatic beta-cells was investigated. PMID- 26062306 TI - A new cyclic bisdesmoside from Actinostemma lobatum Maxim. AB - A new cyclic bisdesmoside treterpene saponin, lobatoside N (1), together with four known triterpenoids, was isolated from the herb of Actinostemma lobatum Maxim. Structures were established by means of extensive spectral data analysis. Furthermore, the cytotoxic activities of the identified compounds were evaluated using HCT-116, HT-29, MCF-7 and A549 human cancer cell lines. As a result, compounds 1-5 showed significant cytotoxicities in a dose-dependent manner against the cell lines tested. Especially, compound 5 exhibited stronger activities, with IC50 value of 0.88 MUM and 0.98 MUM, than that of the positive control drug (Cis-platinum) against HT-29 and A549 cell lines. PMID- 26062307 TI - Wide cleft between theory and practice: medical students' perception of their education in patient and medication safety. AB - In medicine today, future doctors are expected to ensure patient safety. Yet medical students often feel uncertain if they can meet these high expectations. This study aims to quantify the perceptions of medical students regarding the actual quality of their education in the fields of patient safety and, in particular, medication safety. A questionnaire was designed and distributed to about 100 upper-level medical students. The students had to respond to 12 questions regarding the following categories: 1) familiarity with patient safety and/or medication safety; 2) personal experience in high-risk clinical situations; and 3) perceived relevance of knowledge in the area of patient and medication Safety for clinical practice. Of the respondents 42.1% and 36.8% had delved into the topic patient safety and medication safety, respectively. In clinical practice 88.2% of respondents had experienced a high-risk situation for patients. Regarding patient safety and medication safety, respectively, 82.9% and 85.3% of the respondents found these topics to be particularly relevant to their clinical practice. This study has shown that there is a measurable discrepancy between the students' perceived quality of their medical education and their feelings that they are well prepared to cope with severe clinical challenges. PMID- 26062308 TI - Overview of perioperative topics. PMID- 26062309 TI - Impact of information technology on preoperative scheduling systems: a pilot study modeling scheduling systems in the preoperative clinic. AB - BACKGROUND: Scheduling systems that consider volume and patient acuity are crucial to maximize the use of resources during preoperative assessments. Identifying patients with specific needs and developing resource-efficient pathways to address these needs is essential to achieve a high-value framework. At our facility, we triage patients for assessment by phone or in-person visit. Significant variation in lengths of visits results in longer waiting times and inefficient scheduling of clinical and space resources. Developing a schedule that included appointments of shorter and longer lengths based on patient triage factors could optimize resource use. METHODOLOGY: We utilized a survey methodology to determine clinical and non-clinical factors that clinicians identified as important determinants of visit length. RESULTS: Within the system based issues, incomplete information given to the patient during the surgical office visit and the need for additional phone calls to outside medical facilities for information gathering afforded the longest mean appointment time lengths. Within patient-based issues, new clinical findings discovered during the visit and patients who lacked social support demonstrated the longest mean appointment times. CONCLUSIONS: Both clinical and non-clinical issues contribute to visit length; a proper understanding of both can assist in developing evidence based scheduling that maximizes value for both the patient and the system, as well as optimizing patient experience and outcomes. PMID- 26062310 TI - The use of emergency manuals in perioperative crisis management: a cautious approach. AB - When an unexpected perioperative crisis arises, simulation studies have suggested that the use of an emergency manual (EM) may offset the large cognitive load involved in crisis management, facilitating the efficient performance of key steps in treatment. However, little is known about how well EMs will translate into actual practice and what is required to use them optimally. While EMs are a promising tool in the management of perioperative critical events, more research is needed to define best practices and their limitations. In the interim, cautious use of these cognitive aids is recommended, especially when the diagnosis is not straightforward, falls "in between" sections of the EM, or falls outside of the EM itself. Further research should focus on the efficacy of EMs as measured by the percentage of critical steps correctly performed by their users in scenarios that do not closely mirror one of the listed EM scenarios from the beginning or as the situation evolves. PMID- 26062311 TI - A systematic guide for peer reviewers for a medical journal. AB - Performing a peer review of an article under consideration for publication requires not only an understanding of the subject matter, but also a systematic approach that includes screening for conflicts of interest; determining whether the manuscript is within or outside the reviewer's area of expertise; properly classifying the manuscript; and writing a detailed, organized review. Although some journals may provide guidelines for the reviewers, the guidelines usually are not detailed and do not take into consideration the variability in reviewer experience. This article is meant to serve as a guideline for peer reviewers and provide concrete information on how to write a comprehensive, unbiased review that will serve both the author and the journal well. PMID- 26062312 TI - Concepts in creating an evidence-based anesthetic protocol for robot-assisted laparoscopic pelvic surgery. AB - BACKGROUND: Robotic-assisted surgery has increased in popularity in recent years. Benefits have been observed for both the patient and hospital system as the technology shifts surgery from the open to the laparoscopic arena. Some of the advantages of robotic-assisted surgery include increased patient satisfaction along with shorter hospital stays, decreased risk of infection, and improved postsurgical cosmetic outcomes. METHODS: We developed an evidence-based protocol for the anesthetic management of the preoperative, intraoperative, and postoperative phases of patient care based on the review of primary literature and consensus from surgeons and anesthesiologists at our institution. RESULTS: Robotic-assisted surgery creates a unique set of anesthetic considerations to ensure patient safety. Anesthetic considerations include the physiological changes associated with steep Trendelenburg patient positioning, pneumoperitoneum, fluid management, management of pressure points, and spatial restrictions imposed by the robot relative to the conventional anesthetic area. CONCLUSION: A perioperative protocol can help ensure optimal clinical care, patient safety, and better patient and provider satisfaction with the utilization of robotic surgery. PMID- 26062313 TI - Effective strategies in improving operating room case delays and cancellations at an academic medical center. AB - BACKGROUND: Traditionally, the operating room (OR) in an academic medical center has faced numerous challenges to effective clinical productivity, including additional missions of teaching and research. Level 1 trauma poses more challenges related to the need for additional specialized personnel in anesthesia, surgery, and nursing. The present investigation explores lessons learned in efficiency, teamwork, and data evaluation at a level 1 academic teaching facility. METHODS: The months of July 2012, July 2013, and July 2014 were selected for this study. Multiple strategies were implemented through the Operating Room Committee during this time in an effort to reduce the number of OR delays and cancellations. RESULTS: Case cancellations decreased significantly over the three-year period, while delays remained relatively stable. In July 2012, 15.0% of cases were cancelled and 10.2% were delayed. Cancellations decreased to 6.3% in 2013 and to 5.9% in 2014. The total number of cases completed per month increased each year throughout the study, from 577 in 2012 to 649 in 2013 to 842 in 2014. CONCLUSION: These results are remarkable in comparison to the greater-than 20% cancellation rate recorded in 2005 when the current OR leadership team first assessed OR efficiency. An increase in the number of cases completed per month likely can be attributed to a reduction in the number of case cancellations. Increased efficiency allows for more operations to be performed, leading to increased profitability and an increased ability of hospitals to continue caring for patients. We advocate the implementation of a comprehensive multidisciplinary strategy for sustained improvement in OR efficiency and utilization. PMID- 26062314 TI - Qualitative analysis of barriers to efficient operating room turnovers in a tertiary care academic medical center. AB - BACKGROUND: The operating room (OR) turnover is a critical period in patient care and OR management. Turnover time (TOT) is a traditional quantitative measure of OR efficiency but is lacking when used to describe the TOT process. METHODS: Frontline staff members involved with OR turnover were interviewed regarding turnover duties, barriers to performing these duties, ways to facilitate these duties, and satisfaction with the turnover process. A grounded theory approach was used to identify common themes, which were then tabulated. RESULTS: Interviews were completed for 38 frontline staff, including anesthesiologists, surgeons, nurses, and OR assistants. We identified the following common themes among barriers to successful OR turnover: communications, patient transport, preoperative preparations, staffing, workflow, and workload. CONCLUSIONS: Interview data of OR staff can supplement quantitative efficiency measures and identify areas of opportunity in OR management and patient safety. PMID- 26062315 TI - Perceptions of communication in the operating room: a pilot survey study. AB - BACKGROUND: An operating room (OR) environment is challenging and complicated. At any given time, several vital tasks are being performed by skilled individuals, including physicians, nurses, and ancillary staff. There is a potential for multifactorial mistakes; many arise because of communication issues. METHODS: To evaluate the current state of perceptions of interdisciplinary communication in an OR setting, a survey was developed and administered to four academic residency training departments of anesthesiology in a single U.S. state. RESULTS: The results of this survey show that perceived poor communication within the OR leads to a lack of emphasis on a multidisciplinary approach to patient care in the OR. CONCLUSIONS: Survey data can be used internally to identify shortcomings in communication at a facility, to stress the importance of communication, and to serve as a powerful education tool to potentially improve patient care. Through this type of survey, which emphasizes communication in the OR, stakeholders can work more effectively to improve patient care and decrease adverse outcomes in the hospital environment. PMID- 26062316 TI - Medication errors in anesthesia. AB - Medication errors represent one of the most common causes of morbidity and mortality in hospitalized patients. Anesthesia has specific medication-related risks; providers must administer many potent intravenous medications quickly, often with minimal to no supervision. Well-described reasons for medication administration errors in anesthesia include medication ampoules with similar appearance and packaging, clinician inattention, ineffective communication, fatigue, and haste. Technologies that are used widely in other parts of the hospital, such as barcoding, are a challenge to implement in anesthesia, and systemic approaches, including color-coding of syringe labels and barcoding technology of syringes, have been evaluated with mixed results. Emphasis should be placed on implementing forcing functions when possible, utilizing technology, standardization, and education about the need for awareness in specific situations. More studies need to be done to define the epidemiology of medication errors in anesthesia, and more importantly, to assess interventions for preventing them. PMID- 26062317 TI - A procedural sedation quality improvement audit form tool for interventional radiology. AB - As the number of interventional radiology (IR) procedures performed in the United States increases, so does the need for procedural sedation (PS) performed outside the operating room. PS is not without risk, and without the use of proper guidelines and adequate training, adverse outcomes can occur. Improved oversight and evaluation of PS practice are necessary. This concept paper presents a method to incorporate a quality improvement tool in the IR suite that can be implemented at any healthcare center. This tool was created by radiologists, anesthesiologists, and nurses performing PS and evaluates preprocedural, intraprocedural, and postprocedural steps related to effectiveness of sedation, safety practices, and communication. It was implemented in the IR suite at a large tertiary care hospital. The goal of this study is to show that the tool is practical and easily implementable in any tertiary center and can be used as a quality measure to assess outcomes of PS. PMID- 26062318 TI - Novel improvements in perioperative sterility. AB - Operative sterility is a critical factor with regard to infection in the postoperative period. In recent years, techniques and devices have been developed to reduce the potential for exposure to pathogens. This brief review details the SteriCup, a unique product that has the potential to reduce the risk of healthcare-acquired infections. The SteriCup provides a designated sterile area to store suction catheters and removed endotracheal tubes and allows for their simple and safe disposal. Devices such as the SteriCup have the potential to improve operating room systems and minimize potential for operative infection. PMID- 26062319 TI - A primer for billing in interventional pain management. AB - The surge of interest in pain from many types of physicians over the past few decades has resulted in a specialty with unique challenges. In response to the growth in pain medicine, pain fellowships have emerged to appropriately diagnose and to treat a wide variety of pain conditions. Despite improvements and standardization among pain fellowships, education in the basics of billing and coding is typically limited. Though courses on proper billing practices exist within the specialty of pain medicine, many new practitioners are challenged by clinical responsibilities with limited training with regards to billing and coding of pain services. Inaccurate billing and coding can result in financial issues and legal ramifications. ICD-10, which is expected later this year, will present additional challenges to effective billing and coding. In summary, there are frequent changes to the rules and regulations governing pain management that can significantly impact practice management. Strong consideration should be made by stakeholders in any pain practitioner to attend regular educational meetings and take steps necessary for continued compliance, efficiency, quality, and profitability. A basic primer on concepts related to billing and code terminology, therefore, is presented for clinicians. PMID- 26062320 TI - ACA to be repealed under proposed budget plan; lawmakers attempt to prepare for Supreme Court rulings on health subsidies. PMID- 26062321 TI - Communicative management in ambulance services: a study of interaction between station managers and paramedics working in frontline units. AB - This article, the second in a series of three, presents a study of professional communication between ambulance station managers and paramedics. The study used observation and field memos from 20 ambulance stations as a basis for understanding real-life communication in this area of medical practice. The results showed that the unpredictable nature of ambulance work made it difficult for managers and employees to find time for extensive communication, and that the lack of face-to-face contact often led to misunderstanding and poor dialogue. Furthermore, the paramedics expressed health perspectives and norms of patient treatment that conflicted with economic-administrative frameworks expressed on management levels. PMID- 26062322 TI - The intent to commit fraud: what triggers a fraud and abuse audit? PMID- 26062323 TI - ACOs in real life: a reflection on the Medicare Shared Savings Program. AB - The Medicare Shared Savings Program introduced Accountable Care Organizations (ACOs) as one potential method for meeting the often-cited triple aim of better individual care, improved population health, and lower cost. Built on concepts originating from HMOs and then Medicare Advantage plans, ACOs provide incentives based on total cost of care rather than any individual provider's cost. Early quality and cost results are mixed, and, more importantly, so is physician response. The ACO program still has potential to be a bright spot for the future of healthcare, but until there is widespread physician engagement, achieving the triple aim is likely to remain elusive. PMID- 26062324 TI - Effective writing that attracts patients. AB - Doctors today not only must communicate verbally, they must also realize that the written word is important to their ability to connect with the patients that they already have and also to attract new patients. Doctors will be expected to write blogs, to create content for their Web sites, to write articles for local publications, and even to learn to express themselves in 140 characters or less (i.e., Twitter). This article presents 10 rules for selecting the right words to enhance your communication with existing patients and potentially to attract new patients to your practice. PMID- 26062325 TI - Assignment of benefits; plan limits for 2015; target date funds and longevity annuities. PMID- 26062326 TI - Bring 'em on: key issues in merging medical practices. AB - More and more physicians are exploring strategic mergers to form larger group practices. A merger of medical practices will bring significant and long-term benefits to physicians. However, the challenges and barriers to creating a large medical group are substantial. This article will illustrate the benefits and challenges that should be considered when forming and operating large single specialty group practices as well as outline the process of merging and integrating medical practices. PMID- 26062327 TI - A case study of quality improvement methods for complex adaptive systems applied to an academic hepatology program. AB - Although demands for greater access to hepatology services that are less costly and achieve better outcomes have led to numerous quality improvement initiatives, traditional quality management methods may be inappropriate for hepatology. We empirically tested a model for conducting quality improvement in an academic hepatology program using methods developed to analyze and improve complex adaptive systems. We achieved a 25% increase in volume using 15% more clinical sessions with no change in staff or faculty FTEs, generating a positive margin of 50%. Wait times for next available appointments were reduced from five months to two weeks; unscheduled appointment slots dropped from 7% to less than 1%; "no show" rates dropped to less than 10%; Press-Ganey scores increased to the 100th percentile. We conclude that framing hepatology as a complex adaptive system may improve our understanding of the complex, interdependent actions required to improve quality of care, patient satisfaction, and cost-effectiveness. PMID- 26062328 TI - Understanding medical practice team roles. AB - Do you believe that the roles your employees play on your medical practice team are identical to their job titles or job descriptions? Do you believe that team roles are determined by personality type? This article suggests that a more effective way to build and manage your medical practice team is to define team roles through employee behaviors. It provides 10 rules of behavioral team roles that can help practice managers to select and build high-performing teams, build more productive team relationships, improve the employee recruitment process, build greater team trust and understanding; and increase their own effectiveness. This article describes in detail Belbin's highly regarded and widely used team role theory and summarizes four additional behavioral team role theories and systems. It offers lessons learned when applying team role theory to practice. Finally, this article offers an easy-to-implement method for assessing current team roles. It provides a simple four-question checklist that will help practice managers balance an imbalanced medical practice team. PMID- 26062329 TI - Worrier or warrior? Taking control of your investment plan. AB - The current economic and investment environment may seem different from before, but historically there has been uncertainty in most, if not all, time periods. The basis for selecting investments should be the needs, temperament, and available resources of each individual or family. Experience has taught that the most appropriate investment for one person often is far less suited for someone else. Advice given in the media or from other investors unfamiliar with your particular situation adds to the confusion. In this article, we discuss choosing the most appropriate investments for your specific situation and how the process can be made easier by carefully considering, and answering, six questions. PMID- 26062330 TI - "How can we help you?": Kinder, gentler collections. PMID- 26062331 TI - Seven reasons you are losing patients to the competition. AB - Patients who choose elective procedures such as laser treatments, plastic surgery, Botox, fillers, bioidentical hormone therapy, or alternative medicine will leave your practice if their experience is anything less than favorable. This is true even if they get the results they were seeking. It is up to the office manager to create the right environment and engagement from the staff to ensure sustainability. This article offers seven reasons practices lose patients to the competition, and what to do to course-correct. PMID- 26062332 TI - Oh, the places you may go--just follow Dr. Seuss. AB - All physicians have mentors, role models, and even historical figures in medicine to whom they turn for advice on everything from treating their patients to running their practices. To be sure, many physicians have learned valuable lessons from Osler, Halstead, Fleming, Pasteur, and a long list of former professors, supervisors, and practice partners. In this article, however, we suggest that modern physicians can turn to a most unlikely source of wisdom and knowledge. We would like to put the spotlight on another doctor--Dr. Seuss. It may be hard to believe, but modern physicians can learn much about the care of patients and the business of running their practices from the very same books they are reading with their children and grandchildren. The idea that well trained and sophisticated physicians can learn from Dr. Seuss is not as far fetched as it may seem initially. PMID- 26062333 TI - Undocumented and uninsured: aftereffects of the Patient Protection and Affordable Care Act. AB - Although with the implementation of the Patient Protection and Affordable Care Act millions of previously uninsured American residents will gain access to healthcare coverage, millions more will remain uninsured due to the lack of mandatory state Medicaid expansion as well as mandates that forbid undocumented immigrants and legal residents of less than five years from purchasing insurance through the newly available market exchange. With limited options for healthcare coverage due to employment and lack of citizen status, undocumented immigrants rely heavily on funds provided by both Emergency Medicaid and Disproportionate Share Hospital programs. Through reevaluation of current funding, mandates forbidding access to market exchanges, and plans to further enable access to affordable health coverage, states have the unique opportunity to both aid their residents and relieve the financial burden on healthcare facilities and Emergency Medicaid funds. PMID- 26062334 TI - Bundled payment and enhanced recovery after surgery. AB - Medicare's fee-for-service (FFS) payment model may contribute to unsustainable spending growth. Payers are turning to alternative payment methods. The leading alternative payment model to the FFS problem is bundled payment. The Centers for Medicare & Medicaid Services (CMS) is taking another step to improve healthcare quality at lower cost. The CMS's Center for Medicare and Medicaid Innovation developed four models of bundled payments and 48 discrete clinical condition episodes. Many surgical care procedures are included in the 48 different clinical condition episodes. PMID- 26062335 TI - Negotiation best practices: what a healthcare professional needs to know today. AB - This article reviews negotiation best practices while highlighting some of the factors that confound or enhance the ability to negotiate. Healthcare professionals will benefit by obtaining a set of practices that they can consistently apply to obtain more value from negotiation. In today's turbulent healthcare market, more relationships are governed by and through negotiated agreements, so it is imperative that healthcare professionals develop and sharpen their negotiating acumen. PMID- 26062336 TI - Business entity selection: why it matters to healthcare practitioners--part I- Conceptual framework, sole proprietorships, and partnerships. AB - The Bureau of Labor statistics indicates only a 50% four-year survivability rate among businesses classified as "education and health services." Gaining knowledge of IRS business entities can result in cost savings, operational efficiency, reduced liability, and enhanced sustainability. Each entity has unique disadvan- tages, depending on size, diversity of ownership, desire to expand, and profitability. Business structures should be compatible with the organizational mission or vision statement, services and products, and professional codes of ethics. Healthcare reform will require greater business acumen. We have an ethical duty to disseminate and acquire the knowledge to properly establish and manage healthcare practices to ensure sustainable services that protect and serve the community. PMID- 26062337 TI - Your shopping list--or don't buy groceries when you're hungry. AB - When exploring major investments at your medical practice, you will improve your chances for getting your money's worth by taking the time to create a request for proposal (RFP). Large, complex organizations go through a meticulous process to create RFPs. Yours doesn't need to be terribly complex, but you should include seven components to ensure clear understanding between you and your vendor. Make sure you get input from stakeholders in your organization most affected by the proposed purchase. Make RFPs part of the routine in your practice when purchasing equipment or services from any major vendor. PMID- 26062338 TI - [Harvesting microalgae via flocculation: a review]. AB - Microalgae have been identified as promising candidates for biorefinery of value added molecules. The valuable products from microalgae include polyunsaturated fatty acids and pigments, clean and sustainable energy (e.g. biodiesel). Nevertheless, high cost for microalgae biomass harvesting has restricted the industrial application of microalgae. Flocculation, compared with other microalgae harvesting methods, has distinguished itself as a promising method with low cost and easy operation. Here, we reviewed the methods of microalgae harvesting using flocculation, including chemical flocculation, physical flocculation and biological flocculation, and the progress and prospect in bio flocculation are especially focused. Harvesting microalgae via bio-flocculation, especially using bio-flocculant and microalgal strains that is self-flocculated, is one of the eco-friendly, cost-effective and efficient microalgae harvesting methods. PMID- 26062339 TI - [Advances in poly (N-isopropylacrylamide) based platforms for cell culture]. AB - Poly (N-isopropylacrylamide) (PNIPAAm), a temperature-responsive polymer, can be potentially applied to replace enzymes or cell scrapers to recover attached cells. Taking full advantage of this unique function of PNIPAAm, cells can be protected from enzymatic hydrolysis and mechanical treatment, thereby to provide ideal seed cells with high quality for biomedical fields. In this review we describe the method to facilitate cell effective adhesion and rapid detachment on thermoresponsive two dimensional surfaces, including selecting special substrate, introducing hydrophilic group, adjusting reactant ratio, controlling polymer thickness/density, providing appropriate external force, so as to effectively improve adherent cell adaptability to thermoresponsive surfaces, depress the risk of bacterial contamination and reduce the effect of low-temperature treatment on the cells. The three dimensional cell culture systems involved in temperature sensitive microcarriers, scaffolds and gels were briefly discussed. The application based on the platforms for cell culture was also presented. PMID- 26062340 TI - [Development of an interferon-gamma ELISPOT for bovine tuberculosis]. AB - We established an ELISPOT for bovine interferon-gamma (BoIFN-gamma), and applied it in the diagnosis of bovine tuberculosis (bTB). Monoclonal antibodies that can bind with native BoIFN-gamma were screened as the coating antibody and detecting antibody. After optimization of detecting conditions including coating antibody concentration, cell number, and detecting antibody concentration, the ELISPOT assay was established. Peripheral mononuclear cells (PBMCs) isolated from 30 cows were co-cultured with PPD, and detected with the ELISPOT assay. The optimal conditions of ELISPOT assay were 2.5 MUg/mL coating antibody 2G5, 2.5 x 10(5) cells/well, and 1 MUg/mL detecting antibody Bio-5E11. In these 30 cows tested both with the ELISPOT assay and the BOVIGAM kit, 11 cows were proved to be positive in ELISOPT assay with the sensitivity of 78.6%, and 12 cows were proved to be negative in ELISOPT assay with the specificity of 75%. The ELISPOT assay for BoIFN-gamma could be used to detect bTB efficiently and it might be an alternative method for the diagnosis of bTB. PMID- 26062341 TI - [Effects on the expression of lipopolysaccharide-induced inflammatory cytokines mediated by bovine bactericidal/permeability-increasing protein]. AB - Bactericidal/permeability-increasing protein (BPI) can bind to and specifically neutralize lipopolysaccharide (LPS) from the outer membrane of Gram-negative bacteria. In order to evaluate potent LPS-neutralizing activity of bovine BPI, the full-length coding sequence (1 449bp) or 714 bp N-terminal coding sequence (BPI714) of bovine BPI was transfected into mHEK293 cells and the expression of LPS-induced inflammatory cytokines was studied. First, we constructed the lentiviral expression vectors and generated mHEK293 cells stably expressing recombinant bovine BPI or BPI714. Then, we detected the expression of IL-8, IL 1beta, TNF-alpha, NF-kappaB-1 and NF-kappaB-2 genes by real-time PCR at 0, 1, 3, 6, 12, 24, 36 and 48 h post of LPS induction in cells with or without recombinant bovine BPI or BPI714 ectopic expression, respectively. In response to LPS, the robust abundance of inflammatory cytokines including IL-8, IL-1beta, TNF-alpha and NF-kappaB-2 was observed in wild type mHEK293 cells at eachtime point. On the contrary, mRNA abundance of IL-8, TNF-alpha and NF-kappaB-2 in transfected mHEK293 cells showed no significant changes at each indicated time point. Our results demonstrated that recombinant bovine full length BPI or BPI714 down regulated the expression of inflammatory cytokines and revealed that either of bovine BPI or BPI714 was able to inhibit the immune respond stimulated by LPS. This study provides evidence for further investigating the mechanisms and application of BPI/LPS-neutralizing activity and also documents a reliable approach for analysis of the efficacy of antibacterial proteins. PMID- 26062342 TI - [Production of coenzyme Q10 by metabolically engineered Escherichia coli]. AB - Coenzyme Q10 (CoQ10) is a lipophilic antioxidant that improves human immunity, delays senility and enhances the vitality of the human body and has wide applications in pharmaceutical and cosmetic industries. Microbial fermentation is a sustainable way to produce CoQ10, and attracts increased interest. In this work, the native CoQ8 synthetic pathway of Escherichia coli was replaced by the CoQ10 synthetic pathway through integrating decaprenyl diphosphate synthase gene (dps) from Rhodobacter sphaeroides into chromosome of E. coli ATCC 8739, followed by deletion of the native octaprenyl diphosphate synthase gene (ispB). The resulting strain GD-14 produced 0.68 mg/L CoQ10 with a yield of 0.54 mg/g DCW. Modulation of dxs and idi genes of the MEP pathway and ubiCA genes in combination led to 2.46-fold increase of CoQ10 production (from 0.54 to 1.87 mg/g DCW). Recruiting glucose facilitator protein of Zymomonas mobilis to replace the native phosphoenolpyruvate: carbohydrate phosphotransferase systems (PTS) further led to a 16% increase of CoQ10 yield. Finally, fed-batch fermentation of the best strain GD-51 was performed, which produced 433 mg/L CoQ10 with a yield of 11.7 mg/g DCW. To the best of our knowledge, this was the highest CoQ10 titer and yield obtained for engineered E. coli. PMID- 26062343 TI - [High throughput screening of active and stereoselective carbonyl reductases]. AB - In this study, a fast carbonyl reductases colorimetric screening method for discovering stereoselective carbonyl reductases was established by combining the reverse alcohol oxidation with the azoreductase-catalyzed reduction of azo dye. When azo dye (Orange I , 4-(4-hydroxy-1-naphthylazo) benzenesulfonic acid) and azoreductase (AzoB) were added into the reaction system of alcohol oxidation catalyzed by carbonyl reductase, the produced NAD(P)H served as electron donor for the azoreductase to reduce the azo dye, resulting the color fade. Hence, the carbonyl reductases can be screened by the obvious color change. When chiral alcohol was used as the substrate, the activity and stereoselectivity of carbonyl reductases can be screened at the same time. PMID- 26062344 TI - [Improvement of acetic acid tolerance and fermentation performance of industrial Saccharomyces cerevisiae by overexpression of flocculent gene FLO1 and FLO1c]. AB - Flocculent gene FLO1 and its truncated form FLO1c with complete deletion of repeat unit C were expressed in a non-flocculent industrial strain Saccharomyces cerevisiae CE6 to generate recombinant flocculent strains 6-AF1 and 6-AF1c respectively. Both strains of 6-AF1 and 6-AF1c displayed strong flocculation and better cell growth than the control strain CE6-V carrying the empty vector under acetic acid stress. Moreover, the flocculent strains converted glucose to ethanol at much higher rates than the control strain CE6-V under acetic acid stress. In the presence of 0.6% (V/V) acetic acid, the average ethanol production rates of 6 AF1 and 6-AF1c were 1.56 and 1.62 times of that of strain CE6-V, while the ethanol production rates of 6-AF1 and 6-AF1c were 1.21 and 1.78 times of that of strain CE6-V under 1.0% acetic acid stress. Results in this study indicate that acetic acid tolerance and fermentation performance of industrial S. cerevisiae under acetic acid stress can be improved largely by flocculation endowed by expression of flocculent genes, especially FLO1c. PMID- 26062345 TI - [Net energy analysis for annual 200 000 ton cassava ethanol production at Guangxi COFCO]. AB - Guangxi COFCO innovates its annual 200 000 ton cassava ethanol production in recent years. To evaluate the energy input/output of the production process, we used the domestic life cycle model. The calculation results show that the net energy value was 9.56 MJ/L ethanol. Energy input for ethanol production was 51.3% of the total. 61.5% of energy input for ethanol production was used for steam input in ethanol distillation. Energy produced from by-product was 5.03 MJ/L ethanol. Hence, efficient use of raw materials is an important measure to improve the energy efficiency in Guangxi COFCO and energy compensation from byproducts has key impact on the net energy saving. PMID- 26062346 TI - [A novel flat plate photobioreactor for microalgae cultivation]. AB - Flashing light effect on microalgae could significantly improve the light efficiency and biomass productivity of microalgae. In this paper, the baffles were introduced into the traditional flat plate photobioreactor so as to enhance the flashing light effect of microalgae. Making Chlorella sp. as the model microalgae, the effect of light intensity and inlet velocity on the biomass concentration of Chlorella sp. and light efficiency were evaluated. The results showed that, when the inlet velocity was 0.16 m/s, with the increase of light intensity, the cell dry weight of Chlorella sp. increased and light efficiency decreased. With increasing the inlet velocity, the cell dry weight of Chlorella sp. and light efficiency both increased under the condition of 500 MUmol/(m2 x s) light intensity. The cell dry weight of Chlorella sp. cultivated in the novel flat plate photobioreactor was 39.23% higher than that of the traditional one, which showed that the flashing light effect of microalgae could be improved in the flat plate photobioreactor with inclined baffles built-in. PMID- 26062347 TI - [Construction of PPENK-MIDGE-NLS gene vector and the expression in rat]. AB - Increasing the production and secretion of endogenous opioid peptide by immune cell can significantly induce myocardial protective effects against ischemia reperfusion injury. Gene therapy is promising to increase endogenous enkephalin (ENK). However, classical viral and plasmid vectors for gene delivery are hampered by immunogenicity, gene recombination, oncogene activation, the production of antibacterial antibody and changes in physiological gene expression. Minimalistic immunologically defined gene expression (MIDGE) can overcome all the deficients of viral and plasmid vectors. The exon of rat's preproenkephalin (PPENK) gene was amplified by PCR and the fragments were cloned into pEGFP-N1 plasmids. The recombined plasmids were digested with enzymes to obtain a linear vector contained promoter, preproenkephalin gene, RNA stable sequences and oligodesoxy nucleotides (ODNs) added to both ends of the gene vector to protect gene vector from exonuclease degradation. A nuclear localization sequence (NLS) was attached to an ODN to ensure the effective transport to the nucleus and transgene expression. Flow cytometry, laser confocal microscopy and Western blotting demonstrated that PPENK-MIDGE-NLS can transfect leukocyte of rat in vivo, increase the expression of proenkephalin (PENK) in tissue, and the transfection efficiency depends on gene vector's dosage. These results indicate that PPENK-MIDGE-NLS could be an innovative method to protect and treatment of myocardial ischemia-reperfusion injury. PMID- 26062348 TI - [Virtual screening and molecular simulations of antisense peptides targeting MT1 MMP]. AB - Membrane type-1 matrix metalloproteinase (MT1-MMP or MMP14) plays the pivotal role in tumor development and metastasis, so it is a promising drug target in malignancy. To acquire MT1-MMP specific binding peptides, we first analyzed MMPs sequences to find the divergent and specific sequence of MT1-MMP by bioinformatics approach, then set the specific sequence as the sense peptide target and designed antisense peptide library. Finally, by means of molecular docking, molecular dynamics simulation and in vitro cell assays, we screened the antisense peptide library against MT1-MMP and further studied the obtained specific peptides. Here, we identified the divergent and specific sequence of AYIREGHE (Named MT1-loop) located in MT1-MMP loop by multiple sequence alignment and established the antisense peptides library with capacity of 1 536 sequences. After two rounds of virtual screening, we obtained five antisense peptides with Rerankscores in the top for further screening. They all interacted with MT1-MMP, and docked well at the active site composed of MT1-loop sequence. Analysis of the affinities of these five antisense peptides to other MMPs (MMP1-3, MMP7-13, MMP14 HPX, MMP16) revealed that the peptide FVTFPYIR was more specific to MT1-MMP. Molecular dynamics simulation showed that the peptide FVTFPYIR might affect the stability of MT1-MMP and thus have effects on its activities. Meanwhile, the peptide FVTFPYIR could specifically inhibit the growth of MG63 and MDA-MB-231 tumor cells both of which expressed MT1-MMP. The work provides a new insight and way for the development of antitumor lead peptides targeting MT1-MMP. PMID- 26062349 TI - [Reconstitution of polyunsaturated fatty acid synthesis enzymes in mammalian cells to convert LA to DHA]. AB - DHA (22:6n-3) is a Omega-3 polyunsaturated fatty acid with 22 carbon atoms and 6 double bonds, which has important biological functions in human body. Human and other mammals synthesize only limited amounts of DHA, more requirements must be satisfied from food resources. However, the natural resources of DHA (Mainly deep sea fish and other marine products) are prone to depletion. New resources development is still insufficient to satisfy the growing market demand. Previous studies have revealed that the mammals can increase the synthesis of DHA and other long-chain polyunsaturated fatty acids after transgenic procedures. In this study, mammalian cells were transfected with Delta6, Delta5 desaturase, Delta6, Delta5 elongase, Delta15 desaturase (Isolated from nematode Caenorhabditis elegans) and Delta4 desaturase (Isolated from Euglena gracilis), simultaneously. Results show that the expression or overexpression of these 6 enzymes is capable of conversion of the o-6 linoleic acid (LA, 18:2n-6) in DHA (22:6n-3). DHA content has increased from 16.74% in the control group to 25.3% in the experimental group. The strategy and related technology in our research provided important data for future production the valuable DHA (22:6n-3) by using genetically modified animals. PMID- 26062350 TI - [Development and application of morphological analysis method in Aspergillus niger fermentation]. AB - Filamentous fungi are widely used in industrial fermentation. Particular fungal morphology acts as a critical index for a successful fermentation. To break the bottleneck of morphological analysis, we have developed a reliable method for fungal morphological analysis. By this method, we can prepare hundreds of pellet samples simultaneously and obtain quantitative morphological information at large scale quickly. This method can largely increase the accuracy and reliability of morphological analysis result. Based on that, the studies of Aspergillus niger morphology under different oxygen supply conditions and shear rate conditions were carried out. As a result, the morphological responding patterns of A. niger morphology to these conditions were quantitatively demonstrated, which laid a solid foundation for the further scale-up. PMID- 26062351 TI - Nurses' role in preventing cancer. PMID- 26062352 TI - Time to pay more than lip service to gender safety. PMID- 26062353 TI - A nurse's legacy of excellence. PMID- 26062354 TI - The President comments. PMID- 26062355 TI - Pay a major issue for aged-care workers. PMID- 26062356 TI - Rising public sector cancer costs. PMID- 26062357 TI - Survival rates vary. PMID- 26062358 TI - Achieving 'gold standards' across DHBs. PMID- 26062359 TI - Ten per cent of nurses leave after first year. PMID- 26062360 TI - Opioid collaborative targets safe use of medication. PMID- 26062361 TI - Balancing profits with public good. PMID- 26062362 TI - A nurse shares her cancer journey. PMID- 26062363 TI - NP practice makes cancer nurse think more broadly. PMID- 26062364 TI - Understanding a little known form of cancer. PMID- 26062365 TI - One nurse's struggle with NETs. PMID- 26062366 TI - What's best for the breast? PMID- 26062367 TI - Effective communication eases grief. PMID- 26062369 TI - Empowering the family to care. PMID- 26062368 TI - Healing family rifts. PMID- 26062370 TI - Implementing care capacity demand management. PMID- 26062371 TI - It's time for workers to take heart. PMID- 26062372 TI - Leaving a 'tough' job. PMID- 26062373 TI - DHBs: a staffing story with a happy ending! PMID- 26062374 TI - Finding new ways to settle disputes. PMID- 26062375 TI - Urging action, promoting calm. ANA and affiliated organizations work to respond effectively to Ebola. PMID- 26062376 TI - ANA and nurses come together to move the needle on this critical issue. PMID- 26062377 TI - The innovative edge. Nurses work to reduce readmissions, improve at-home Alzheimer's care. PMID- 26062378 TI - What we measure, we can improve. PMID- 26062379 TI - Nurse-led initiatives improve patient outcomes. PMID- 26062380 TI - NYU: scholarships support underrepresented nursing students. PMID- 26062381 TI - Spurring conversations between health care professionals and patients. PMID- 26062382 TI - Roll up your sleeves, wash your hands and other precautionary advice. PMID- 26062383 TI - The quality question: pearls for practice. PMID- 26062384 TI - Meet Phillip Bautista. PMID- 26062386 TI - What the ACA means for nursing a year after open enrollment. PMID- 26062385 TI - Driven to improve nurse satisfaction, quality, compassion toward colleagues. PMID- 26062387 TI - Wave of newly insured individuals escalates the need for services and payment. PMID- 26062388 TI - WHO Expert Committee on Drug Dependence. Thirty-sixth report. AB - This report presents the recommendations of the thirty-sixth WHO Expert Committee on Drug Dependence (ECDD). The ECDD is responsible for the assessment of therapeutic usefulness, the liability to abuse and dependence and the public health and social harm of each substance under review. After receiving the advice from the Expert Committee to schedule or to amend the scheduling status of a substance, the Director-General of WHO will as appropriate, communicate the recommendations to the United Nations. The report summarizes the review of 26 substances and the Committee's recommendations for scheduling under the international drug control conventions. The report also contains updates from international bodies concerned with controlled substances, a summary of the follow-up on recommendations made at the previous Committee meeting and a summary of the discussion on improving data collection and evidence for prioritization and substance evaluation, in particular for new psychoactive substances. Issues identified for consideration at future Expert Committee meetings are also listed. PMID- 26062389 TI - [Leber's hereditary optic neuropathy: the problems and future challenges]. PMID- 26062390 TI - [Designation criteria for Leber's hereditary optic neuropathy]. AB - Designation criteria for Leber's hereditary optic neuropathy (LHON) have been established by a working group for retino-choroidal and optic atrophy funded by the Ministry of Health, Labor, and Welfare (MHLW) of Japan in collaboration with the Japanese Neuro-ophthalmology Society. The criteria are composed of three major symptoms and three ancillary test findings. According to the number and the combination of these symptoms and findings, subjects are classified into definite, probable, and possible LHON cases and asymptomatic carriers. The major symptoms include bilateral involvement with a time-lag, a papillomacular bundle atrophy, both characteristic optic disc findings at the acute phase. In the ancillary testings, mitochondrial DNA mutations specific for LHON are detailed with a table listing the mutation loci being attached. To enhance readers' understanding of description of the major symptoms and ancillary test findings, explanatory remarks on 11 parameters are supplemented. The establishment of the criteria facilitates epidemiological survey of LHON by MHLW and contributes to improvement of welfare for patients with LHON in Japan. PMID- 26062391 TI - [Incidence of endogenous intraocular inflammation patients who visited Nippon Medical School Hospital during the 8 years from 2004 to 2012]. AB - PURPOSE: To report the clinical statistical analysis of patients with endogenous intraocular inflammation who visited Nippon Medical School Hospital during the 8 years from 2004 to 2012. SUBJECTS AND METHODS: This retrospective study involved 759 new patients with endogenous intraocular inflammation who visited Nippon Medical School Hospital during the 8 years from April 2004 to April 2012. RESULTS: The subjects comprised 357 men and 402 women. The ratio of men to women was 1 : 1.1. The age averaged 50.8 +/- 16.6 years. Definitive diagnosis was made in 464 cases (61.1%). The most frequent clinical entity was sarcoidosis, followed by scleritis, Vogt-Koyanagi-Harada disease, herpetic iridocyclitis without acute retinal necrosis, acute anterior uveitis associated with human leukocyte antigen (HLA) -B27 and Behcet's disease. Anterior uveitis was the most frequent compared with intermediate, posterior, and pan-uveitis. The incidence of secondary glaucoma was 28.6%, and steroid responder was 28.6%. CONCLUSION: Sarcoidosis, scleritis and Vogt-Koyanagi-Harada disease were frequent intraocular inflammations in ophthalmologic patients at Nippon Medical School Hospital. PMID- 26062392 TI - [Two cases of Vogt-Koyanagi-Harada disease presenting shallow anterior chamber]. AB - PURPOSE: We report two cases of Vogt-Koyanagi-Harada disease (VKH) in which shallow anterior chambers were improved after steroid pulse therapy. CASE: The patients were women aged 65 and 72. They had headaches, decreased visual acuity and shallow anterior chamber in both eyes. There was no inflammation in the anterior chamber. Ultrasound biomicroscopy (UBM) showed ciliary edema, ciliochoroidal detachment, and angle closure. One case showed high intraocular pressure (IOP), and a diagnosis of acute primary angle closure was made. Although cataract surgery was performed in the left eye, postoperative optical coherence tomography (OCT) revealed serous retinal detachment in both eyes. The shallow anterior chamber and UBM findings were improved and serous retinal detachment disappeared after steroid pulse therapy in both cases. CONCLUSION: VKH may cause shallow anterior chamber and angle closure. The inflammatory changes of VKH in the anterior segment, i. e. ciliary edema and ciliochoroidal detachment, may exacerbate the shallow anterior chambers and narrow angles and result in an acute increase in IOP in eyes with short axial length. VKH associated with shallow anterior chamber may be misdiagnosed as acute primary angle closure. For differential diagnosis, examinations of the ocular fundus including OCT are useful. PMID- 26062394 TI - A renaissance in biomedical innovation: global villages raise effective therapies. PMID- 26062393 TI - Effect of squalane on mebendazole-loaded Compritol(r) nanoparticles. AB - The objective of this study is to develop nanostructured lipid formulations of Compritol for the delivery of mebendazole. The formulations were prepared with Compritol 888 ATO, squalane, and Pluronic F68. Nine batches with different amounts of modifier, squalane, and drug were prepared. The formulations were characterized by evaluating particle size, morphology, and zeta potential. The thermal properties of the formulations were analyzed by differential scanning calorimetry (DSC). The encapsulation efficiency of each formulation and the drug release rates from each formulation were quantified by UPLC. The particles were spherical and had median particle sizes between 300 and 600 nm (50th percentile). A linear relationship was observed between Compritol/squalane composition and the melting point of the mixture. The DSC scans of the formulations revealed some recrystallization of the drug from the formulations, and the amount of recrystallization correlated with the amount of squalane in the formulation. Approximately, 70% efficiency of encapsulation was observed in the formulations with 30% (w/w) squalane, and these formulations also had faster dissolution rates compared to the other formulations. Overall, the formulations with 30% squalane are the preferred formulation for future testing. PMID- 26062395 TI - CETSA: a target engagement assay with potential to transform drug discovery. PMID- 26062396 TI - Rational drug design, synthesis and biological evaluation of dihydrofolate reductase inhibitors as antituberculosis agents. AB - BACKGROUND: A series of 2,4-diamino-s-triazines was designed, with potential for activity against Mycobacterium tuberculosis (Mtb) dihydrofolate reductase enzyme, on the basis of virtual screening results and structure-based drug design. RESULTS: The compounds were evaluated against Mtb (H37Rv) and their cytotoxicity was assessed using VERO cell lines. Of particular note, two compounds were found to have the most promising antituberculosis activity (6b minimum inhibitory concentration: 1.76 MUM and 6i minimum inhibitory concentration: 1.57 MUM) along with low cytotoxicity (CC50: >300 MUM). The enzyme assay results of these two indicated significant inhibition of Mtb dihydrofolate reductase along with selectivity. Selected derivatives were tested against dormant tubercle bacilli in vivo and ex vivo indicating potential inhibition. CONCLUSION: This study provides promising antituberculosis dihydrofolate reductase inhibitors that can act as potential leads for further development. PMID- 26062398 TI - Modifying peptides to enhance permeability. AB - Recently, peptides have been validated to address intracellular targets and/or to be orally bioavailable. This review describes some of these scaffolds, offers insight in new cyclization methodologies thought to be beneficial to enhance permeability, and highlights modification on peptides thought to improve oral bioavailability. In this context, side chains and back-bone derivatization beneficial to encourage cellular uptake are presented. In addition, new methodologies supporting the assessment of permeability are discussed. PMID- 26062397 TI - SecA: a potential antimicrobial target. AB - There is a consensus in the medical profession of the pressing need for novel antimicrobial agents due to issues related to drug resistance. In practice, solutions to this problem to a large degree lie with the identification of new and vital targets in bacteria and subsequently designing their inhibitors. We consider SecA a very promising antimicrobial target. In this review, we compile and analyze information available on SecA to show that inhibition of SecA has a multitude of consequences. Furthermore, we discuss issues critical to the design and evaluation of SecA inhibitors. PMID- 26062401 TI - Interactions of HIV-1 proteins as targets for developing anti-HIV-1 peptides. AB - Protein-protein interactions (PPI) are essential in every step of the HIV replication cycle. Mapping the interactions between viral and host proteins is a fundamental target for the design and development of new therapeutics. In this review, we focus on rational development of anti-HIV-1 peptides based on mapping viral-host and viral-viral protein interactions all across the HIV-1 replication cycle. We also discuss the mechanism of action, specificity and stability of these peptides, which are designed to inhibit PPI. Some of these peptides are excellent tools to study the mechanisms of PPI in HIV-1 replication cycle and for the development of anti-HIV-1 drug leads that modulate PPI. PMID- 26062399 TI - Highly resistant HIV-1 proteases and strategies for their inhibition. AB - The virally encoded protease is an important drug target for AIDS therapy. Despite the potency of the current drugs, infections with resistant viral strains limit the long-term effectiveness of therapy. Highly resistant variants of HIV protease from clinical isolates have different combinations of about 20 mutations and several orders of magnitude worse binding affinity for clinical inhibitors. Strategies are being explored to inhibit these highly resistant mutants. The existing inhibitors can be modified by introducing groups with the potential to form new interactions with conserved protease residues, and the flexible flaps. Alternative strategies are discussed, including designing inhibitors to bind to the open conformation of the protease dimer, and inhibition of the protease catalyzed processing of the Gag-Pol precursor. PMID- 26062402 TI - Recent progress in natural products as DPP-4 inhibitors. AB - Diabetes mellitus is a chronic disease affecting patients' daily life and increasing patients' risk of other complication. Dipeptidyl peptidase-4 (DPP-4) is a serine aminopeptidase, which is one of the validated targets for Type 2 diabetes therapy due to its regulatory effect of incretin hormone. Seven DPP-4 inhibitors are commercially available nowadays on the market as Type 2 diabetes drugs. They are all chemically synthesized compounds with good therapeutic effects, but long-term safety remains unknown. On the other hand, nature provides a rich source for search of desired safe and effective medications; and actually more than half of the drugs on market are natural product related. Therefore, a systematic search for new DPP-4 inhibitors from nature sources seems to be of great utility for developing novel antidiabetic drugs. This review summarized recent progress of DPP-4 inhibitors from natural products, revealed that both pure natural products and the crude extracts of herbs or the hydrolyzates of proteins are active as DPP-4 inhibitors. Therefore, both could be served as useful clues for developing next generation of antidiabetes medicines via inhibiting DPP-4 activity. PMID- 26062400 TI - Rho kinase as a target for cerebral vascular disorders. AB - The development of novel pharmaceutical treatments for disorders of the cerebral vasculature is a serious unmet medical need. These vascular disorders are typified by a disruption in the delicate Rho signaling equilibrium within the blood vessel wall. In particular, Rho kinase overactivation in the smooth muscle and endothelial layers of the vessel wall results in cytoskeletal modifications that lead to reduced vascular integrity and abnormal vascular growth. Rho kinase is thus a promising target for the treatment of cerebral vascular disorders. Indeed, preclinical studies indicate that Rho kinase inhibition may reduce the formation/growth/rupture of both intracranial aneurysms and cerebral cavernous malformations. PMID- 26062403 TI - Interface Energetics and Charge Carrier Density Amplification by Sn-Doping in LaAlO3/SrTiO3 Heterostructure. AB - Tailoring the two-dimensional electron gas (2DEG) at the n-type (TiO2)(0)/(LaO)(+1) interface between the polar LaAlO3 (LAO) and nonpolar SrTiO3 (STO) insulators can potentially provide desired functionalities for next generation low-dimensional nanoelectronic devices. Here, we propose a new approach to tune the electronic and magnetic properties in the n-type LAO/STO heterostructure (HS) system via electron doping. In this work, we modeled four types of layer doped LAO/STO HS systems with Sn dopants at different cation sites and studied their electronic structures and interface energetics by using first principles electronic structure calculations. We identified the thermodynamic stability conditions for each of the four proposed doped configurations with respect to the undoped LAO/STO interface. We further found that the Sn-doped LAO/STO HS system with Sn at Al site (Sn@Al) is energetically most favorable with respect to decohesion, thereby strengthening the interface, while the doped HS system with Sn at La site (Sn@La) exhibits the lowest interfacial cohesion. Moreover, our results indicate that all the Sn-doped LAO/STO HS systems exhibit the n-type conductivity with the typical 2DEG characteristics except the Sn@La doped HS system, which shows p-type conductivity. In the Sn@Al doped HS model, the Sn dopant exists as a Sn(4+) ion and introduces one additional electron into the HS system, leading to a higher charge carrier density and larger magnetic moment than that of all the other doped HS systems. An enhanced charge confinement of the 2DEG along the c-axis is also found in the Sn@Al doped HS system. We hence suggest that Sn@Al doping can be an effective way to enhance the electrical conduction and magnetic moment of the 2DEG in LAO/STO HS systems in an energetically favorable manner. PMID- 26062404 TI - Older people with incurable cancer: Existential meaning-making from a life-span perspective. AB - OBJECTIVE: An increasing number of older people in Western countries are living with incurable cancer, receiving palliative care from specialized healthcare contexts. The aim of our article was to understand how they experience the existential meaning-making function in daily living from a life-span perspective. METHOD: Some 21 participants (12 men and 9 women), aged 70-88, were interviewed in a semistructured framework. They were recruited from somatic hospitals in southeastern Norway. We applied the model of selective optimization with compensation (SOC) from life-span developmental psychology in a deductive manner to explore the participants' life-oriented adaptive strategies. A meaning component was added to the SOC model. RESULTS: The participants experienced the existential meaning-making function on two levels. On a superordinate level, it was an important component for interpreting and coordinating the adaptive strategies of SOC for reaching the most important goals in daily living. The existential meaning-making framework provided for a comprehensive understanding of resilience, allowing for both restoration and growth components to be identified. The second level was related to strategy, in that the existential meaning-making function was involved in a complex interaction with behavioral resources and resilience, leading to continuation of goals and more realistic goal adjustments. A few experienced existential meaning-making dysfunction. SIGNIFICANCE OF RESULTS: The modified SOC model was seen as applicable for palliative care in specialized healthcare contexts. Employing the existential meaning-making framework with its complementary understanding of resilience as growth potential to the SOC model's restoration potential can help older people to identify how they make meaning and how this influences their adaptation process to being incurably sick. PMID- 26062405 TI - The Absence of Fever or Leukocytosis Does Not Exclude Infection Following Cranioplasty. AB - BACKGROUND: Cranioplasty encompasses various cranial reconstruction techniques that are used following craniectomy due to stroke or trauma. Despite classical infectious signs, symptoms, and radiologic findings, however, the diagnosis of infection following cranioplasty can be elusive, with the potential to result in definitive treatment delay. We sought to determine if fever or leukocytosis at presentation were indicative of infection, as well as to identify any factors that may limit its applicability. METHODS: Following institutional review board approval, a retrospective cohort of 239 patients who underwent cranioplasty following craniectomy for stroke or trauma was established from 2001-2011 at a single center (Massachusetts General Hospital). Analysis was then focused on those who developed a surgical site infection, as defined by either frank intra operative purulence or positive intra-operative cultures, and subsequently underwent operative management. RESULTS: In 27 total cases of surgical site infection, only two had a fever and four had leukocytosis at presentation. This yielded a false-negative rate for fever of 92.6% and for leukocytosis of 85.2%. In regard to infectious etiology, 22 (81.5%) cases generated positive intra operative cultures, with Propionibacterium acnes being the most common organism isolated. Median interval to infection was 99 days from initial cranioplasty to time of infectious presentation, and average follow-up was 3.4 years. CONCLUSIONS: The utilization of fever and elevated white blood cell count in the diagnosis of post-cranioplasty infection is associated with a high false-negative rate, making the absence of these features insufficient to exclude the diagnosis of infection. PMID- 26062406 TI - Association between history of psychosis and cardiovascular disease in bipolar disorder. AB - OBJECTIVES: To determine whether clinical features of bipolar disorder, such as history of psychosis, and cardiovascular disease (CVD) risk factors contribute to a higher risk of CVD among patients with bipolar disorder. METHODS: This cross sectional study included a sample of 988 patients with bipolar I or bipolar II disorder or schizoaffective bipolar type confirmed by the Structured Clinical Interview for DSM-IV-TR disorders (SCID). Medical comorbidity burden was quantified utilizing the Cumulative Illness Severity Rating Scale (CIRS). This 13 item organ-based scale includes cardiac disease severity quantification. Confirmed by medical record review, patients who scored 1 (current mild or past significant problem) or higher in the cardiac item were compared by logistic regression to patients who scored 0 (no impairment), adjusting for CVD risk factors that were selected using a backwards stepwise approach or were obtained from the literature. RESULTS: In a multivariate model, age [odds ratio (OR) = 3.03, 95% confidence interval (CI): 1.66-5.54, p < 0.0001], hypertension (OR = 2.43, 95% CI: 1.69-3.55, p < 0.0001), and history of psychosis (OR = 1.48, 95% CI: 1.03-2.13, p = 0.03) were associated with CVD. When CVD risk factors from the literature were added to the analysis, age (OR = 3.19, 95% CI: 1.67-6.10, p = 0.0005) and hypertension (OR = 2.46, 95% CI: 1.61-3.76, p < 0.01) remained significant, with psychosis being at the trend level (OR = 1.43, 95% CI: 0.96 2.13, p = 0.08). CONCLUSIONS: The phenotype of psychotic bipolar disorder may reflect higher illness severity with associated cardiac comorbidity. Further studies are encouraged to clarify the effect of the disease burden (i.e., depression), lifestyle, and treatment interventions (i.e., atypical antipsychotics) on this risk association. PMID- 26062407 TI - Trends in perinatal deaths from 2010 to 2013 in the Guatemalan Western Highlands. AB - BACKGROUND: While progress has been made in reducing neonatal mortality in Guatemala, stillbirth and maternal mortality rates remain high, especially among the indigenous populations, which have among the highest adverse pregnancy related mortality rates in Guatemala. METHODS: We conducted a prospective study in the Western Highlands of Guatemala from 2010 through 2013, enrolling women during pregnancy with follow-up through 42-days postpartum. All pregnant women were identified and enrolled by study staff in the clusters in the Chimaltenango region for which we had 4 years of data. Enrolment usually occurred during the antenatal period; women were also visited following delivery and 42-days postpartum to collect outcomes. Measures of antenatal and delivery care were also obtained. RESULTS: Approximately four thousand women were enrolled annually (3,869 in 2010 to 4,570 in 2013). The stillbirth rate decreased significantly, from 22.0 per 1000 births (95% CI 16.6, 29.0) in 2010 to 16.7 (95% CI 13.5, 20.6) in 2013 (p-value 0.0223). The perinatal mortality rate decreased from 43.9 per 1,000 births (95% CI 36.0, 53.6) to 31.6 (95% CI 27.2, 36.7) (p-value 0.0003). The 28-day neonatal mortality rate decreased from 28.9 per 1000 live births (95% CI 25.2, 33.2) to 21.7 (95% CI 17.5, 26.9), p-value 0.0004. The maternal mortality rate was 134 per 100,000 in 2010 vs. 113 per 100,000 in 2013. Over the same period, hospital birth rates increased from 30.0 to 50.3%. CONCLUSIONS: In a relatively short time period, significant improvements in neonatal, fetal and perinatal mortality were noted in an area of Guatemala with a history of poor pregnancy outcomes. These changes were temporally related to major increases in hospital-based delivery with skilled birth attendants, as well as improvements in the quality of delivery care, neonatal care, and prenatal care. PMID- 26062408 TI - Progress towards Millennium Development Goals 4 & 5: strengthening human resources for maternal, newborn and child health. PMID- 26062409 TI - [Effect of beta2GPI immunization on mouse T helper cell subset differentiation]. AB - OBJECTIVE: To explore the mechanism of beta2 glycoprotein I (beta2GPI)-caused T helper cell subset differentiation and anti-beta2GPI antibody (abeta2GPI Ab) production in mice. METHODS: The healthy BALB/c mice were randomly divided into two groups: normal saline (NS) group and beta2GPI group. The mice were immunized i.v. with either human beta2GPI or equal amount of NS for a total of two or four times at 2-week intervals. The titer of abeta2GPI Ab in mice serum was evaluated by indirect ELISA. The expressions of GATA binding protein 3 (GATA3), interleukin 4 (IL-4), T-box expressed in T cells (T-bet), interferon-gamma (IFN-gamma) and Foxp3 mRNAs in mouse splenic cells were detected by real-time quantitative PCR (qRT-PCR), and the percentage of GATA3+ or Foxp3+ cells in lymphocytes of mouse spleen was detected by flow cytometry. RESULTS: The high titer (1:100,000) of abeta2GPI Ab was detected in mouse serum following the two times of immunization with beta2GPI. The expressions of Th2 specific markers GATA3 and IL-4 mRNAs and the percentage of GATA3+ cells in lymphocytes were higher than those of NS treated group. After four times of immunization with beta2GPI, the titer of abeta2GPI Ab in mouse serum was elevated to a higher level (>1:100,000). The expressions of GATA3, Th1 specific markers T-bet and IFN-gamma, and regulatory T cell (Treg) specific marker Foxp3 mRNAs in mouse spleen cells, but no significant change was found in IL-4 mRNA expression. Furthermore, the percentage of GATA3+ cells in mouse spleen increased, while the percentage of Foxp3+ cells decreased. CONCLUSION: beta2GPI immunization could induce Th2 cell bias polarization and Th1 cell and Treg suppression in mice, which might contribute to the production of abeta2GPI Ab. PMID- 26062410 TI - [Chemerin induces insulin resistance in C2C12 cells through nuclear factor-kappaB pathway-mediated inflammatory reaction]. AB - OBJECTIVE: To explore the insulin resistance-inducing effect of chemerin on murine C2C12 myoblasts and the underlying molecular mechanism. METHODS: Following 24-hour treatment with various concentrations of chemerin (0, 10, 100) ng/mL and 30-minute insulin stimulation in C2C12 cells, the glucose uptake was evaluated using a fluorescence microplate reader. ELISA was used to detect the levels of interleukin-6 (IL-6), IL-8 and tumor necrosis factor alpha (TNF-alpha) in culture fluid. In addition, the expression of nuclear factor kappaB (NF-kappaB) was determined by Western blotting. The underlying mechanism involved in chemerin induced insulin resistance was evaluated with the precondition of NF-kappaB blocker pyrrolidine dithiocarbamate (PDTC). RESULTS: Chemerin inhibited the glucose uptake of C2C12 cells in a dose-dependent manner, concomitant with the increases of IL-6, IL-8, TNF-alpha levels. Furthermore, chemerin stimulation improved the expression of NF-kappaB. However, pretreatment with NF-kappaB blocker PDTC significantly abated the inhibitory effect of chemerin on glucose uptake, and also obviously decreased the levels of IL-6, IL-8 and TNF-alpha induced by chemerin. CONCLUSION: Chemerin might induce insulin resistance in C2C12 cells through NF-kappaB pathway-mediated inflammatory reaction. PMID- 26062411 TI - [Pneumococcal HSP40 induces the immune response in mouse macrophages via p38MAPK and JNK signaling pathways]. AB - OBJECTIVE: To investigate the mechanism of immune response in mouse macrophage induced by Pneumococcal heat shock protein 40 (HSP40). METHODS: After recombinant HSP40 (rHSP40) underwent expression detection and purification, lipopolysaccharide (LPS) was removed from it. Then rHSP40 was used to stimulate bone marrow derived macrophages (BMDMs) derived from C57BL/6 wild-type mice. The mRNA levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL 1beta, IL-23p19, IL-12p40, IL-12p35 and IL-10 in BMDMs were determined by reverse transcription PCR; the expressions of TNF-alpha, IL-6 and IL-12p40 were measured by ELISA. After stimulated by rHSP40, the levels of TNF-alpha and IL-6 expressed by wide-type, TLR2-/- and TLR4-/- BMDMs were detected by ELISA. The effects of the pretreatment of mitogen-activated protein kinases (MAPK) inhibitors on the secretion of TNF-alpha and IL-6 induced by rHSP40 were also evaluated by ELISA in BMDMs. The phosphorylation levels of p38MAPK and c-Jun N-terminal kinase (JNK) were determined by Western blotting. RESULTS: The rHSP40 protein reached a purity of more than 90%. It significantly enhanced the phosphorylation levels of p38MAPK and JNK as well as the expressions of TNF-alpha and IL-6. The p38MAPK and JNK inhibitors significantly suppressed the expressions of TNF-alpha and IL-6. The expressions of TNF-alpha and IL-6 in TLR4-/- BMDMs significantly decreased compared with wide-type BMDMs. CONCLUSION: HSP40-induced immune response of mouse macrophages is regulated by p38MAPK and JNK signaling pathways, and this induction process depends on TLR4. PMID- 26062412 TI - [miR-141-3p regulates the expression of androgen receptor by targeting its 3'UTR in prostate cancer LNCaP cells]. AB - OBJECTIVE: To detect the target degradation of miR-141-3p on androgen receptor (AR) gene in LNCaP cells and demonstrate whether AR gene is a target of miR-141 3p. METHODS: After prostate cancer cell line LNCaP was transfected with miR-141 3p mimics, expression levels of AR mRNA and protein in the LNCaP cells were detected by reverse transcription PCR and Western blotting, respectively. The 3'untranslated regions (3'UTR) of AR mRNA containing the binding site of miR-141 3p was amplified by PCR and inserted into pmiR-report vector (a 3'downstream luciferase reporter gene). The product was termed pmiR-AR-3'UTR. Double luciferase reporter system was employed to verify the potential target effect of miR-141-3p on pmiR-AR-3'UTR. RESULTS: Transfection of miR-141-3p mimics decreased both mRNA and protein expression levels of AR in LNCaP cells. Compared with control group, miR-141-3p transfection significantly inhibited the activity of luciferase of pmiR-AR-3'UTR. CONCLUSION: AR is a direct target gene of miR-141 3p. PMID- 26062413 TI - [Enhanced expression of Toll-like receptor 3 in the basilar arteries and hippocampus of subarachnoid hemorrhage rats]. AB - OBJECTIVE: To observe the dynamic expression and significance of Toll-like receptor 3 (TLR3) in subarachnoid hemorrhage (SAH) model. METHODS: SAH model was established using blood injection into the prechiasmatic cistern. Sixty SD rats were randomly divided into sham group and SAH groups (including SAH 1-, 3-, 7-day groups), each with 15 rats. The operation steps were the same in groups except the sham group that was injected with normal saline instead. At different time points after modeling, the basilar arteries and brain were obtained. The mRNA and protein expression of TLR3 was detected using reverse transcription PCR, Western blotting and immunohistochemistry, respectively. Meanwhile, the distribution of TLR3 was analyzed using the immunofluorescence double labeling technique. RESULTS: The mRNA and protein expression of TLR3 was weak in sham group and highly expressed in SAH groups, and the highest expression were found in SAH 3 day group. Immunohistochemistry showed that TLR3 was highly expressed in vascular endothelial and hippocampal neurons. The sham group showed a weak TLR3 expression in the cytoplasm, while the SHA group showed the strongly expressed TLR3 mainly in the nucleus and cytoplasm. The result of immunofluorescence double labeling also suggested TLR3 was co-localization with CD34 in the endothelial cells. CONCLUSION: The TLR3 expression was enhanced in the basilar arteries and hippocampus when the rats suffered from SAH, which suggested TLR3 might play a certain role in the pathogenesis of SAH. PMID- 26062415 TI - [Phenotypic changes and apoptosis of Jurkat cells induced by over-expression of C Src kinase-binding protein]. AB - OBJECTIVE: To explore the effects of up-regulated expression of C-Src kinase binding protein (CBP) on biological functions and cell ultrastructure in Jurkat cells. METHODS: We constructed the CBP-EGFP viral vector and established a stably transfected Jurkat cell line with it. Cell growing status was observed under a light microscope. The transfection efficiency and the location of CBP were examined with confocal microscopy. The complexity of cell organelles was observed by electron microscopy. Apoptotic cells were detected by flow cytometry. The expressions of C-Src kinase (CSK) and Vav oncoprotein in CBP signaling pathway were measured by real-time quantitative PCR (qRT-PCR). RESULTS: We found more pyknotic cells and less homogeneity in the transfected Jurkat cells under light microscope. Confocal microscopy revealed that cell transfection efficiency was up to 100% and CBP was located on the cell membrane. Moreover, there were more complex organelles in CBP-EGFP transfected Jurkat cells with a lot of mitochondrions and the lysosome-like clumps accumulation. Detection of apoptosis showed that CBP-EGFP transfected Jurkat cells had more necrotic cells compared with the negative group. Finally, qRT-PCR indicated the expression of CSK increased and Vav decreased in the CBP-EGFP transfected group. CONCLUSION: Up regulated expression of CBP in Jurkat cells could reduce cell homogeneity and promote cell apoptosis. PMID- 26062414 TI - [Triplet anti-tumor therapy based on thymosin alpha-1 attenuates incidence of hepatoma and serum alpha-fetoprotein level in rat hepatoma model]. AB - OBJECTIVE: To explore the impact of triple anti-tumor therapy based on thymosin alpha1 (Talpha1) combined with Huaier granule(HG) and sirolimus on the level of serum alpha-fetoprotein (AFP) in rat models of liver cancer. METHODS: Ninety Sprague-Dawley rats were randomly divided into triple anti-tumor therapy group, Talpha1 group, HG group, sirolimus group, positive control and blank control groups, with 15 rats in each group. Except the blank control group, the rats in the other groups were induced using diethylnitrosamine (DEN) to establish liver cancer models. After DEN treatment, the triple therapy group underwent 0.8 mg/kg Talpha1 subcutaneous injection (from once a day for two weeks to twice a week since the third week), 0.35 g/kg HG gavage (three times a day) and 1 mg/kg sirolimus gavage (once a day). The dose of the rest single drug groups were the same with that of the triple therapy group. The positive control and blank control groups were not treated with the drugs. The treatment lasted 20 weeks. Then, the behavior of the rats were observed at the different time points, and the level of serum AFP in the rats were detected at 6, 16, 18, 20 weeks, respectively. RESULTS: The typical symptoms of liver cancer were seen in the DEN induced rats at 16 weeks. Since the tenth week, 6 rats died one after another. Pathological section of rat liver tissue suggested that the rat models were established successfully. According to the incidence rate of liver cancer and the survival rate at 20 weeks, the triple anti-tumor therapy was significantly superior to the single drug treatments. In addition, the triple anti-tumor therapy significantly reduced the level of serum AFP in the rats. CONCLUSION: The triple anti-tumor therapy can significantly prolong the survival time of rats with liver cancer, decrease the cancer incidence rate and the level of serum AFP. PMID- 26062416 TI - [AG490 inhibits the proliferation of human medullary thyroid carcinoma TT cells and increases their radiosensitivity]. AB - OBJECTIVE: To investigate the effects of AG490 on the proliferation, apoptosis and radiosensitivity of human medullary thyroid carcinoma TT cells. METHODS: Human medullary thyroid carcinoma TT cells were treated with different concentrations of AG490 (0, 25, 50, 100 MUmol/L). Cell proliferation and apoptosis were detected by MTT and flow cytometry, respectively. Radiosensitivity was detected by clone formation assay. The expressions of Janus kinase 2 (JAK2), phosphated signal transducer and activator of transcription 3 (p-STAT3), Bcl-2 and Bax were evaluated by Western blotting. RESULTS: Compared with the control group, the proliferation of thyroid TT cells in 25, 50, 100 MUmol/L AG490 treated groups significantly decreased in a time- and concentration-dependent manner, and the apoptosis rate of TT cells gradually increased along with the increased of the concentrations of AG490. There was a significant decrease in cell survival fraction and radiobiological parameters (SF2, D0, Dq and N), while the sensitivity enhancement ratio (SER D0, SERDq) showed a significant increase in 50 MUmol/L AG490 treated group compared with the control group. Western blotting showed that the expressions of JAK2, p-STAT3 and Bcl-2 were gradually reduced, while the expression of Bax was raised with the increasing concentration of AG490. CONCLUSION: AG490 can inhibit the proliferation, increase the apoptosis rate and enhance the radiosensitivity of human medullary thyroid carcinoma TT cells in vitro. PMID- 26062417 TI - [Over-expression of cannabinoid receptor 2 induces the apoptosis of cervical carcinoma Caski cells]. AB - OBJECTIVE: To construct a eukaryotic expression vector containing human cannabinoid receptor 2 (hCB2R) gene and investigate its expression, location and the influence on the apoptosis of cervical cancer Caski cells. METHODS: The eukaryotic expression vector GV230-hCB2R was constructed and identified by double enzyme digestion and DNA sequencing analysis. Then it was transfected into HEK293 cells and Caski cells by Lipofectamine(TM) 2000. The expression and cellular localization of hCB2R protein were detected by Western blotting and immunofluorescent cytochemistry combined with laser scanning confocal microscopy, the apoptosis rate was tested by flow cytometry. The mRNA and protein expressions of hCB2R, Bcl-2, Bax and Bad were examined by real-time fluorescent quantitative PCR (qRT-PCR) and Western blotting, respectively. RESULTS: The gene fragment of 1128 bp was obtained by double enzyme digestion, it had 99% homology with human hCB2R gene nucleic acid sequence reported (NM_001841.2). After transfected into HEK293 cells, hCB2R protein, with the relative molecular mass (Mr) being 40 000, was expressed in both cytoplasm and cellular membrane. The over-expression of hCB2R promoted apoptosis of Caski cells via up-regulating the Bax, Bad expressions and down-regulating the Bcl-2 expression. CONCLUSION: The up regulated expression of hCB2R could induce cell apoptosis by enhancing the expressions of Bax, Bad and suppressing the expression of Bcl-2 in Caski cells. PMID- 26062418 TI - [The expression of retrogene Nanogp8 is related to the biological characteristics of human SGC-7901 gastric cancer cells]. AB - OBJECTIVES: To explore the effects of NANOGP8 on proliferation, apoptosis, cell cycle, invasion and migration of human SGC-7901 gastric cancer cells. METHODS: Eukaryotic expression vector pEGFP-N1-NANOGP8 and recombinant plasmid shRNA NANOGP8 were constructed and confirmed by enzyme digestion and sequencing analysis. Then, vector pEGFP-N1-NANOGP8 and recombinant plasmid shRNA-NANOGP8 were transfected into SGC-7901 cells via liposome. The expression of NANOGP8 mRNA and protein were tested by fluorescence microscopy, reverse transcription PCR and Western blotting, respectively. The proliferation of SGC-7901 cells was detected by CCK-8 assay. The apoptosis and cell cycle were examined by flow cytometry. TranswellTM assay proved the changes in the invasion and migration abilities of SGC-7901 cells. RESULTS: The recombinant plasmids pEGEP-N1-NANOGP8 and pshRNA NANOGP8 were constructed successfully and transfected into gastric cancer cells. pEGEP-N1-NANOGP8 transfection group showed high expression of NANOGP8, conversely, pshRNA-NANOGP8 transfection group showed low expression of NANOGP8. High expression of NANOGP8 significantly promoted the proliferation of tumor cells, arrested cells cycle in the S phase, decreased apoptotic cells and increased cell invasion and migration obviously. While the low expression group presented with inhibited cell proliferation, cell-cycle arrest in the G0/G1 phase, promoted cell apoptosis and inhibited migration and invasion. CONCLUSION: The transcription and expression of retrogene NANOGP8 has a close relationship with the proliferation, cycle, apoptosis, migration and invasion of SGC-7901 gastric cancer cells. PMID- 26062419 TI - [The expression of AQP9 in HepG2 cells affects cell biological behaviors and sensitivity to As2O3]. AB - OBJECTIVE: To investigate the effect of aquaporin 9 (AQP9) expression level on the apoptosis and biological behaviors of HepG2 cells induced by arsenic trioxide (As2O3). METHODS: The effects of different concentration As2O3 on the cell proliferation were measured by MTT assay, and IC50 was calculated. The recombinant plasmids pEGFP-N1-AQP9 and pshRNA-AQP9 were transfected into HepG2 cells. The expression of AQP9 mRNA and protein were detected by reverse transcription PCR and Western blotting, respectively. Then As2O3 was added to plasmid-transfected cells and untreated HepG2 cells. Cell proliferation was detected by MTT assay, cell cycle and apoptosis rate were determined by flow cytometry, and cell invasion and migration ability were examined by Transwell(TM) (Boyden Chamber) assay. The activity of caspase-3 was detected by microplate reader. RESULTS: The recombinant plasmids remarkably influenced the expression of AQP9. Compared with the group treated with As2O3 alone (control group), the cell proliferation, invasion and migration of HepG2 cells transfected with pEGFP-N1 AQP9 were attenuated significantly, while the cells transfected with pshRNA-AQP9 increased. The increasing population of apoptotic cells, augmented caspase 3 activity and highest percentage of cells stagnating at G0/G1 phase were observed in HepG2 cells transfected with pEGFP-N1-AQP9 as compared with the control HepG2 cells; in contrast, the HepG2 cells transfected with pshRNA-AQP9 presented with lower caspase 3 activity and stronger invasion and migration ability than the control HepG2 cells did. CONCLUSION: The alterations in the expression of AQP9 could affect the biological behaviors of HepG2 cells, but also their sensitivity to As2O3. PMID- 26062420 TI - [Testosterone suppresses oxidized low-density lipoprotein-induced vascular smooth muscle cell phenotypic transition and proliferation]. AB - OBJECTIVE: To investigate the inhibitory effect of testosterone on oxidized low density lipoproteins (ox-LDL)-stimulated phenotypic transition and proliferation of vascular smooth muscle cells (VSMCs) in vitro, and explore its possible mechanisms. METHODS: Rat VSMCs were cultured using serum starvation method to make cell synchronization. Cells in vitro were divided into control group, ox-LDL group (treated with 50 MUg/mL ox-LDL), FBS group (treated with 100 mL/L fetal bovine serum), and testosterone groups (treated respectively with 5*10(-8) and 5*10(-7) mol/L testosterone for 12 hours, followed by incubation with 50 MUg/mL ox-LDL). The effect of testosterone on the ox-LDL-induced proliferation of VSMCs was explored by WST-1 assay. The cell cycle distribution was determined using flow cytometry. Western blotting was used to detect the expressions of mitofusin 2 (Mfn2), phosphorylated extracellular signal-regulated kinase 1/2 (p-ERK1/2), proliferating cell nuclear antigen (PCNA), alpha-smooth muscle actin (alpha-SMA) and osteopontin (OPN). RESULTS: Compared with control group, the proliferation of VSMCs was promoted by ox-LDL, the number of VSMCs decreased in G0/G1 phase and increased in S phase significantly, the expression levels of Mfn2 and alpha-SMA were significant reduced, and the expression levels of p-ERK1/2, PCNA and OPN were significant raised in ox-LDL group. Compared with ox-LDL group, testosterone showed stronger inhibitory effect on the proliferation of VSMCs induced by ox LDL, arrested most of the cells in the G0/G1 phase, ascended significantly the expression levels of Mfn2 and alpha-SMA, and descended significantly the expression levels of p-ERK1/2, PCNA and OPN in the two testosterone groups in a slight dose-dependent manner. CONCLUSION: Testosterone can inhibit phenotypic transition and proliferation of VSMCs induced by ox-LDL in vitro, which may be related to the up-regulated expression of Mfn2 and the suppression on ERK1/2 pathway. PMID- 26062421 TI - [The increased level of IL-17 in stomach and up-regulated splenic Th17 cell frequency and IL-17 mRNA level in rats infected with Helicobacter pylori]. AB - OBJECTIVE: To investigate the variation of Th17 cell frequency and IL-17 level in rats infected with Helicobacter pylori (Hp). METHODS: A total of 30 rats were used to be infected with Hp by intragastric administration of bacterial suspension. Every 10 rats were sacrificed after 3, 6 and 9 weeks, respectively. The gastric tissues of rats were pathologically examined by HE staining. The level of IL-17 in the gastric tissues of rats was detected by ELISA. The flow cytometry was performed to determine Th17 cell frequency and reverse transcription PCR was to detect the level of IL-17 mRNA in single-cell suspensions of rat spleen. RESULTS: Hp infection induced the obvious pathological changes in the rat gastric mucosa. The level of IL-17 in the gastric tissues increased with the prolonging of the Hp infection. Both Th17 cell frequency and IL-17 mRNA level in rat spleen cells infected with Hp at 3, 6 and 9 weeks were significantly higher than those in control rats, and they were significantly different when compared among different time points. CONCLUSION: Hp infection could induce the damage of rat gastric mucosa and increase IL-17 level in the stomach. Furthermore, Hp infection could up-regulate the Th17 cell frequency and IL-17 mRNA level in rat spleen cells. PMID- 26062422 TI - [Nuclear protein 1 knockdown inhibits proliferation and migration of HepG2 cells]. AB - OBJECTIVE: To observe the expression of nuclear protein 1 (Nupr1), a stress related nuclear protein, in a panel of human hepatocellular carcinoma cell lines, and its effects on the proliferation and migration of hepatocellular carcinoma cells by RNA interference-mediated knockdown. METHODS: Real-time quantitative PCR was employed to detect Nupr1 mRNA levels in hepatocellular carcinoma cell lines, including BEL-7402, QSG-7703, SMMC-7721 and HepG2. After Nupr1 expression was knocked down by RNA interference, cell proliferation was monitored by MTT assay and colony formation in plate. Cell cycle was analyzed by flow cytometry and cell migration was assayed by TranswellTM assay. RESULTS: Higher expression of Nupr1 was detected in HepG2 as compared with the other cell lines. Nupr1 expression in HepG2 cells were efficiently knocked down by two short hairpin RNAs (shRNAs), with inhibitory rates being 72.25% and 84.25%, respectively. HepG2 cells with Nupr1 knockdown displayed lower rate of proliferation, G1 arrest, and significantly decreased abilities of cell migration and colony formation. Western blotting showed that Nupr1 knockdown increased the expressions of p21 and p27, two negative regulators of cell cycle. CONCLUSION: Knockdown of Nupr1 inhibited the proliferation and migration of HepG2 hepatocellular carcinoma cells. PMID- 26062423 TI - [Spermidine enhances osteogenic differentiation and inhibits adipogenic differentiation of bone marrow-derived mesenchymal stem cells from ovariectomized mice]. AB - OBJECTIVE: To investigate the effects of spermidine (SPD) on the differentiation ability of bone marrow-derived mesenchymal stem cells (BMMSCs) from estrogen deficient mouse models. METHODS: Female C57/BL6J mice were randomly divided into sham group and ovariectomized (OVX) group. Two months after modeling, BMMSCs of sham and OVX mice were harvested and cultured, and then Western blotting was used to detect the expressions of alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), peroxisome proliferator activated receptor gamma (PPARgamma) and lipoprtein lipase (LPL). Mineralized nodules and lipid droplet formation ability of the BMMSCs from sham and OVX mice were evaluated and compared by alizarin red staining and oil red O staining, respectively. After BMMSCs from the OVX mice were cultured in osteogenesis-induced medium and adipogenesis-induced medium supplemented with SPD, their osteogenic and adipogenic differentiation capacities were evaluated by Western blotting and reverse transcription PCR to detect the expressions of Runx2, ALP, PPARgamma and LPL, and the mineralized nodules and lipid droplet formation ability were examined by alizarin red staining and oil red O staining, respectively. RESULTS: BMMSCs from OVX mice showed lower ability of osteogenic differentiation and higher ability of adipogenic differentiation compared to the ones from sham mice. SPD strengthened the ability of osteogenic differentiation and depressed the ability of adipogenic differentiation of BMMSCs from OVX mice compared with the BMMSCs without SPD intervention. CONCLUSION: SPD enhances osteogenic differentiation and inhibits adipogenic differentiation of BMMSCs from OVX mice. PMID- 26062424 TI - [Ginkgo biloba extract enhances the immune function of spleen and thymus in SD rats]. AB - OBJECTIVE: To study the effect of Ginkgo biloba extract (GBE) on the immune function of spleen and thymus in SD rats. METHODS: Forty SD rats were randomly divided into four groups (10 rats each group). Three experimental groups were given GBE daily by gavage in doses of 40, 120, 360 mg/(kg.d), respectively. Animals in the control group were fed the same amount of PBS. After 28 days, the rats were sacrificed by chloral hydrate anesthesia. The spleen and thymus were harvested to determine the organ index first. MTT assay was used to detect the concanavalin A (ConA)-induced splenic lymphocyte proliferation and transformation. Neutral red assay was performed to measure the rat peritoneal macrophage phagocytosis. The ultrastructural changes of spleen and thymus were observed under scanning electron microscope. RESULTS: Administration of GBE in the rats increased the mass indexes of rat thymus and spleen, dose-dependently elevated the lymphocyte proliferative responses and enhanced the peritoneal macrophage phagocytosis. In experimental groups, the numbers of mature spleen and thymus lymphocytes were significantly raised in comparison with the control rats. CONCLUSION: GBE plays a regulatory role in immune function of the rat by increasing the mass of immune organs, increasing the number of mature T lymphocytes as well as their proliferative responses, and enhancing the phagocytic capacity of peritoneal macrophages. PMID- 26062425 TI - [Up-regulation of TIM-3 on CD4+ tumor infiltrating lymphocytes predicts poor prognosis in human non-small-cell lung cancer]. AB - OBJECTIVE: To characterize the expression of negative costimulatory molecule, T cell immunoglobulin and mucin-domain-containing molecules 3 (TIM-3), on tumor infiltrating lymphocytes (TILs) in human non-small-cell lung cancer (NSCLC) and explore the clinical significance of the expression. METHODS: A total of 56 human lung cancer tissue specimens were obtained from pathologically confirmed and newly diagnosed NSCLC patients. Infiltrating lymphocytes from both tumor tissues and adjacent normal lung tissues were analyzed for TIM-3 expression by immunofluorescence staining and flow cytometry. Correlation analysis was performed between TIM-3 expression on TILs and the prognosis of the patients. RESULTS: The expression of TIM-3 on CD4+ TILs in tumor tissues [(28.64+/-10.46)%] was significantly higher than that on CD4+ T cells in adjacent normal tissues [(13.32+/-6.95)%]. Similarly, the expression of TIM-3 on CD8+ TILs in tumor tissues [(30.77+/-15.58)%] was up-regulated as compared with that on CD8+ T cells in adjacent normal tissues [(12.98+/-8.19)%]. Moreover, majority of the TIM-3 positive TILs from both adjacent normal tissues and tumor lung tissues were positive for another negative costimulatory molecule, programmed death 1 (PD-1). Importantly, TIM-3 expression on CD4+ TILs was correlated with poor prognosis of the patients. CONCLUSION: TIM-3, as a key negative regulator in the anti-tumor immunity, contributes to the tumor immune evasion. It has an adverse influence on the prognosis of NSCLC patients. PMID- 26062426 TI - [IL-23 promotes invasion of esophageal squamous cell carcinoma cells by activating DLL4/Notch1 signaling pathway]. AB - OBJECTIVE: To investigate the role of interlukin-23 (IL-23) in the invasion of human esophageal squamous cell carcinoma (ESCC) cells and the related mechanism. METHODS: IL-23 expression in tumor and adjacent tissues from 10 ESCC patients were detected by immunohistochemistry. Real-time fluorescent PCR was used to examine the expressions of Notch1 and Foxn4 mRNAs in different concentration IL 23-treated TE-1 cells. After Notch pathway was blocked with gamma-secretase inhibitor DAPT, expressions of Notch intracellular domain (NICD), Delta-like 4 (DLL4), hairy enhancer of split 1 (Hes1), matrix metalloproteinase 9 (MMP-9) in IL-23-treated TE-1 cells were measured by Western blotting. And the migration of IL-23-treated TE-1 cells was studied by TranswellTM migration assay. RESULTS: Compared with adjacent tissues, IL-23 was highly expressed in ESCC tissues. IL-23 treatment up-regulated significantly the expressions of NICD, DLL4, Hes1 and MMP 9 in TE-1 cells. The blockade of Notch1 pathway inhibited the expressions induced by IL-23. Migration assay revealed that IL-23 treatment significantly enhanced the migration of TE-1 cells. CONCLUSION: IL-23 could promote migration of human ESCC cells by activating DLL4/Notch1 signaling pathway. PMID- 26062427 TI - [High-resolution melting technology for detecting genetic polymorphisms of IL 1beta and IL-1Ra in patients with coronary artery disease]. AB - OBJECTIVE: To develop a method of high-resolution melting curve analysis (HRM) for investigating the association of single nucleotide polymorphisms (SNPs) of IL 1beta and IL-1Ra genes with susceptibility to coronary heart disease (CHD) and serological indexes in CHD. METHODS: PCR-HRM assays were established for detecting four SNPs (IL-1B-511C>T, IL-1B-31C>T, IL-1B+3954C>T and IL-1RNT>C) in 260 patients with CHD and 274 healthy controls. A case-control study was performed for analyzing the relationships of the four SNPs with CHD risk and serological indexes. RESULTS: No significant statistical difference was observed between the four SNPs and the susceptibility to CHD, however, the result of gender stratification showed that there was the statistical differences in the male IL-1B-31C>T and the female IL-1B+3954C>T allele frequencies (P=0.039, 0.032, respectively). The result of haplotype analysis of the four SNPs showed that haplotype of IL-1B-511T/IL-1B-31C/IL-1B+3954C/IL-1RN T (TCCT) had a significant correlation with obviously increased CHD risk, but without statistical difference (OR=1.217, 95%CI: 0.950-1.559, P=0.123), while those of CTCC and TTCT had significant correlations with decreased CHD risk (OR=0.612, 95%CI: 0.376-0.994, P=0.046; OR=0.365, 95%CI: 0.154-0.862, P=0.017). No association was found between the four SNPs and the serological indexes in CHD subjects. CONCLUSION: The developed PCR-HRM detection assays based on HRM technology has been verified by direct sequencing and clinical specimen detection to be a rapid and homogeneous detection method for genotyping of the four SNPs. The SNPs of IL-1B-31C>T, IL 1B+3954C>T and the haplotypes of CTCC and TTCT are associated with the susceptibility to CHD in Chinese Han population of Lanzhou region. PMID- 26062428 TI - [Phenotypic and functional features of NK and NKT cells in chronic hepatitis B]. AB - OBJECTIVE: To detect the ratio of natural killer (NK)/natural killer T (NKT) cells in peripheral blood, the levels of NKG2D/NKG2A, interferon gamma (IFN gamma) and tumor necrosis factor alpha (TNF-alpha) in patients with chronic hepatitis B (CHB). METHODS: Peripheral blood mononuclear cells (PBMCs) were harvested from CHB patients. The ratio of NK/NKT cells in PBMCs and the levels of NKG2D and NKG2A were detected by flow cytometry. The expressions of intracellular IFN-gamma and TNF-alpha were analyzed by flow cytometry after the treatment with phorbol 12-myristate 13-acetate (PMA), brefeldin A (BFA) or ionomycin in vitro. The comparison between two groups was performed by independent sample t-test. The relationship of each index to hepatitis B virus load and serum alanine aminotransferase was analyzed by Pearson correlation analysis. RESULTS: Compared with healthy controls, CHB patients presented with significantly decreased peripheral blood NK/NKT cell ratio and significantly elevated proportions of NKG2A+ NK and NKG2A+NKT cells, and after the treatment with PMA/BFA/ionomycin, IFN-gamma+ NK and IFN-gamma+ NKT cells were significantly reduced in CHB patients. CONCLUSION: NK and NKT cells showed a reduced ratio, disordered receptor expressions and decreased cytokine secretion capacity in CHB patients. PMID- 26062429 TI - [Preparation of monoclonal antibody against bovine phosphoenolpyruvate carboxykinase]. AB - OBJECTIVE: To prepare the monoclonal antibody against bovine phosphoenolpyruvate carboxykinase (PEPCK) and characterize its biological functions. METHODS: The recombinant plasmid containing PEPCK gene was constructed and used to transfect Escherichia coli. After expression induction in E.coli, the recombinant protein PEPCK was purified and used to immunize BALB/c mice. After the spleen B cells in the immunized mice were fused with murine myeloma cells, the positive clones were identified and selected by indirect ELISA for titer determination. PEPCK mAb produced by the positive hybridoma cells was enriched and its biological functions were examined by Western blotting, immunohistochemistry and immunoprecipitation. RESULTS: One hybridoma cell line steadily secreting PEPCK mAb was successfully generated, namely 3D36H. Western blotting, immunohistochemistry and immunoprecipitation showed that the PEPCK mAb was able to specifically bind to bovine PEPCK protein. CONCLUSION: The bovine PEPCK mAb was prepared successfully and had a good ability and specificity. PMID- 26062430 TI - [Screening of anti-human death receptor 5 antibody from a large natural phage antibody library]. AB - OBJECTIVE: To clone anti-human death receptor 5 (DR5) single-chain variable fragments (scFvs) from a large natural phage antibody library and identify the antigen-binding activity. METHODS: Phage antibodies against human DR5 were screened from a large natural phage antibody library constructed in our laboratory by four rounds of panning process using eukaryotically expressed DR5 Fc protein. The antigen-binding activity of the obtained scFvs was determined by immunocytochemistry and ELISA, and then the scFVs were analyzed by DNA fingerprinting and sequence analysis. RESULTS: After 4 rounds of panning, we obtained 26 positive clones with specific binding ability to DR5 protein. DNA fingerprinting and sequence analysis showed that there were four different variable fragments that were derived from different gene families. Soluble scFv fragments were prepared and then confirmed to bind specifically to DR5 protein in SW480 cells by immunocytochemistry. CONCLUSION: Specific anti-human DR5 scFvs has been obtained from a large phage antibody library. PMID- 26062431 TI - Mothers and offspring: The rabbit as a model system in the study of mammalian maternal behavior and sibling interactions. AB - This article is part of a Special Issue "Parental Care". Jay Rosenblatt effectively promoted research on rabbit maternal behavior through his interaction with colleagues in Mexico. Here we review the activities of pregnant and lactating rabbits (Oryctolagus cuniculus), their neuro-hormonal regulation, and the synchronization of behavior between mother and kits. Changing concentrations of estradiol, progesterone, and prolactin throughout gestation regulate nest building (digging, straw-carrying, fur-pulling) and prime the mother's brain to respond to the newborn. Nursing is the only mother-young contact throughout lactation. It happens once/day, inside the nest, with ca. 24h periodicity, and lasts around 3min. Periodicity and duration of nursing depend on a threshold of suckling as procedures reducing the amount of nipple stimulation interfere with the temporal aspects of nursing, though not with the doe's maternal motivation. Synchronization between mother and kits, critical for nursing, relies on: a) the production of pheromonal cues which guide the young to the mother's nipples for suckling; b) an endogenous circadian rhythm of anticipatory activity in the young, present since birth. Milk intake entrains the kits' locomotor behavior, corticosterone secretion, and the activity of several brain structures. Sibling interactions within the huddle, largely determined by body mass at birth, are important for: a) maintaining body temperature; b) ensuring normal neuromotor and social development. Suckling maintains nursing behavior past the period of abundant milk production but abrupt and efficient weaning occurs in concurrently pregnant-lactating does by unknown factors. CONCLUSION: female rabbits have evolved a reproductive strategy largely dissociating maternal care from maternal presence, whose multifactorial regulation warrants future investigations. PMID- 26062433 TI - Vibrational spectroscopy and theory of Fe2(+)(CH4)(n) (n = 1-3). AB - Vibrational spectra are measured for Fe2(+)(CH4)n (n = 1-3) in the C-H stretching region (2650-3100 cm(-1)) using photofragment spectroscopy, by monitoring the loss of CH4. All of the spectra exhibit an intense peak corresponding to the symmetric C-H stretch around 2800 cm(-1). The presence of a single peak suggests a nearly equivalent interaction between the iron dimer and the methane ligands. The peak becomes slightly blue shifted as the number of methane ligands increases. Density functional theory calculations, B3LYP and BPW91, are used to identify possible structures and predict the spectra. Results suggest that the methane(s) bind in a terminal configuration and the complexes are in the octet spin state. PMID- 26062434 TI - Syphacia (Syphacia) maxomyos sp. n. (Nematoda: Oxyuridae) from Maxomys spp. (Rodentia: Muridae) from Sulawesi and Sumatra, Indonesia. AB - The present report describes Syphacia (Syphacia) maxomyos sp. n. (Nematoda: Oxyuridae) from two species of spiny rats, Maxomys musschenbroekii from Sulawesi and M. whiteheadi from Sumatra. It is characterized by a cephalic plate extending laterally with dorsoventral constriction and stumpy eggs with an operculum rim reaching pole. It is readily distinguishable by the former feature from all of hitherto known representatives of this genus in Indonesia, but it resembles parasites in Murini and Hydromyni rodents in continental Asia and Sahul. This is the first Syphacia species distributed in both the Sunda Shelf and Sulawesi with the exception of Syphacia muris, a cosmopolitan pinworm found in rodents of the of genus Rattus. It is surmised that S. maxomyos is specific to Maxomys and that it was introduced to Sulawesi by dispersal of some Maxomys from the Sunda Shelf. PMID- 26062432 TI - Neural mechanisms of mother-infant bonding and pair bonding: Similarities, differences, and broader implications. AB - This article is part of a Special Issue "Parental Care". Mother-infant bonding is a characteristic of virtually all mammals. The maternal neural system may have provided the scaffold upon which other types of social bonds in mammals have been built. For example, most mammals exhibit a polygamous mating system, but monogamy and pair bonding between mating partners occur in ~5% of mammalian species. In mammals, it is plausible that the neural mechanisms that promote mother-infant bonding have been modified by natural selection to establish the capacity to develop a selective bond with a mate during the evolution of monogamous mating strategies. Here we compare the details of the neural mechanisms that promote mother-infant bonding in rats and other mammals with those that underpin pair bond formation in the monogamous prairie vole. Although details remain to be resolved, remarkable similarities and a few differences between the mechanisms underlying these two types of bond formation are revealed. For example, amygdala and nucleus accumbens-ventral pallidum (NA-VP) circuits are involved in both types of bond formation, and dopamine and oxytocin actions within NA appear to promote the synaptic plasticity that allows either infant or mating partner stimuli to persistently activate NA-VP attraction circuits, leading to an enduring social attraction and bonding. Further, although the medial preoptic area is essential for maternal behavior, its role in pair bonding remains to be determined. Our review concludes by examining the broader implications of this comparative analysis, and evidence is provided that the maternal care system may have also provided the basic neural foundation for other types of strong social relationships, beyond pair bonding, in mammals, including humans. PMID- 26062435 TI - Ligand-binding characteristics of feline insulin-binding immunoglobulin G. AB - Polyclonal immunoglobulin (Ig) G autoantibodies against insulin have been identified in sera of healthy cats. We purified and fractionated insulin-binding IgGs from cat sera by affinity chromatography and analyzed affinity of insulin binding IgGs for insulin and their epitopes. Following the passing of fraction A, which did not bind to insulin, insulin-binding IgGs were eluted into two fractions, B and C, by affinity chromatography using a column fixed with bovine insulin. Dissociation constant (KD) values between insulin-binding IgGs and insulin, determined by surface plasmon resonance analysis (BiacoreTMsystem), were 1.64e(-4) M for fraction B (low affinity IgGs) and 2e(-5) M for fraction C (high affinity IgGs). Epitope analysis was conducted using 16 peptide fragments synthesized in concord with the amino acid sequence of feline insulin by an enzyme-linked immunosorbent assay. Fractions B and C showed higher absorbance (affinity) of the peptide fragment of 10 amino acid residues at the carboxyl terminal of the B chain (peptide No. 19), followed by peptide fragments of 6 to 15 amino acid residues of the B chain (peptide No. 8). Fraction C showed a higher absorbance to 7 to 16 amino acid residues of the B chain (peptide No. 5) compared with the absorbance of fraction B. Polyclonal insulin-binding IgGs may form a macromolecule complex with insulin through the multiple affinity sites of IgG molecules. Feline insulin-binding IgGs are multifocal and may be composed of multiple IgG components and insulin. PMID- 26062436 TI - Antibody responses after vaccination against equine influenza in the Republic of Korea in 2013. AB - In this study, antibody responses after equine influenza vaccination were investigated among 1,098 horses in Korea using the hemagglutination inhibition (HI) assay. The equine influenza viruses, A/equine/South Africa/4/03 (H3N8) and A/equine/Wildeshausen/1/08 (H3N8), were used as antigens in the HI assay. The mean seropositive rates were 91.7% (geometric mean antibody levels (GMT), 56.8) and 93.6% (GMT, 105.2) for A/equine/South Africa/4/03 and A/equine/Wildeshausen/1/08, respectively. Yearlings and two-year-olds in training exhibited lower positive rates (68.1% (GMT, 14) and 61.7% (GMT, 11.9), respectively, with different antigens) than average. Horses two years old or younger may require more attention in vaccination against equine influenza according to the vaccination regime, because they could be a target of the equine influenza virus. PMID- 26062437 TI - Edoxaban versus placebo, aspirin, or aspirin plus clopidogrel for stroke prevention in atrial fibrillation. An indirect comparison analysis. AB - As non-valvular atrial fibrillation (AF) brings a risk of stroke, oral anticoagulants (OAC) are recommended. In 'real world' clinical practice, many patients (who may be, or perceived to be, intolerant of OACs) are either untreated or are treated with anti-platelet agents. We hypothesised that edoxaban has a better net clinical benefit (NCB, balancing the reduction in stroke risk vs increased risk of haemorrhage) than no treatment or anti-platelet agents. We performed a network meta-analysis of published data from 24 studies of 203,394 AF patients to indirectly compare edoxaban with aspirin alone, aspirin plus clopidogrel, and placebo. Edoxaban 30 mg once daily significantly reduced the risk of all stroke, ischaemic stroke and mortality compared to placebo and aspirin. Compared to aspirin plus clopidogrel, there was a lower risk of intra cranial haemorrhage (ICH). Edoxaban 60 mg once-daily had a reduced risk of any stroke and systemic embolism compared to placebo, aspirin, and aspirin plus clopidogrel. Mortality rates for both edoxaban doses were estimated to be lower compared to any anti-platelet, and significantly lower compared to placebo. With overall reduced risk of ischemic stroke and ICH, both edoxaban doses bring a NCB of mean (SD) 1.68 (0.15) saved events per 100 patients per year compared to anti platelet drugs in a clinical trial population. The NCB was demonstrated to be lower, at 0.77 (0.12) events saved (p< 0.01) when modeled to data from a 'real world' cohort of AF patients. In conclusion, edoxaban is likely to provide even better protection from stroke and ICH than placebo, aspirin alone, or aspirin plus clopidogrel in both clinical trial populations and unselected community populations. Both edoxaban doses would also bring a positive NCB compared to anti platelet drugs or placebo/non-treatment based on 'real world' data. PMID- 26062438 TI - Three-Dimensional NiMoO4 Nanosheets Supported on a Carbon Fibers@Pre-Treated Ni Foam (CF@PNF) Substrate as Advanced Electrodes for Asymmetric Supercapacitors. AB - Herein, we report a nanoarchitectured nickel molybdate/carbon fibers@pre-treated Ni foam (NiMoO4 /CF@PNF) electrode for supercapacitors. The synthesis of NiMoO4 /CF@PNF mainly consists of a direct chemical vapor deposition (CVD) growth of dense carbon fibers (CFs) onto pre-treated Ni foam (PNF) as the substrate, followed by in situ growth of NiMoO4 nanosheets (NSs) on the CF@PNF substrate by means of a hydrothermal process. The NiMoO4 /CF@PNF electrode exhibits a high areal capacitance (5.14 F cm(-2) at 4 mA cm(-2) ) and excellent cycling stability (97 % capacitance retention after 2000 cycles at 10 mA cm(-2) ). Furthermore, we have successfully assembled NiMoO4 NSs//activated carbon (AC) asymmetric supercapacitors, which can achieve an energy density of 45.6 Wh kg(-1) at 674 W kg(-1) , and excellent stability with 93 % capacitance retention after 2000 cycles at 5 mA cm(-2) . These superior properties hold great promise for energy storage applications. PMID- 26062439 TI - Rapid plant evolution in the presence of an introduced species alters community composition. AB - Because introduced species may strongly interact with native species and thus affect their fitness, it is important to examine how these interactions can cascade to have ecological and evolutionary consequences for whole communities. Here, we examine the interactions among introduced Rocky Mountain elk, Cervus canadensis nelsoni, a common native plant, Solidago velutina, and the diverse plant-associated community of arthropods. While introduced species are recognized as one of the biggest threats to native ecosystems, relatively few studies have investigated an evolutionary mechanism by which introduced species alter native communities. Here, we use a common garden design that addresses and supports two hypotheses. First, native S. velutina has rapidly evolved in the presence of introduced elk. We found that plants originating from sites with introduced elk flowered nearly 3 weeks before plants originating from sites without elk. Second, evolution of S. velutina results in a change to the plant-associated arthropod community. We found that plants originating from sites with introduced elk supported an arthropod community that had ~35 % fewer total individuals and a different species composition. Our results show that the impacts of introduced species can have both ecological and evolutionary consequences for strongly interacting species that subsequently cascade to affect a much larger community. Such evolutionary consequences are likely to be long-term and difficult to remediate. PMID- 26062440 TI - A test of energetic trade-offs between growth and immune function in watersnakes. AB - Energy budgets explain how organisms allocate energetic intake to accomplish essential processes. A likely life history trade-off occurs between growth and immune response in juvenile organisms, where growth is important to avoid predation or obtain larger prey and immune response is essential to survival in the presence of environmental pathogens. We examined the innate (wound healing) and adaptive (lymphoid tissue, thymus and spleen) components of immune response along with growth in two populations of the diamond-backed watersnake Nerodia rhombifer raised in a common environment. We found that neonate snakes born to females from populations characterized by different predator and prey environments did not differ in energetic intake, but snakes from the population containing large prey grew significantly faster than those from a population containing small prey. Thymus mass, when corrected for body mass, was larger in snakes from the small prey population than in snakes from the large prey population. Additionally, the snakes from the population containing small prey healed significantly faster than those from the population containing large prey. Thus, we detected a negative correlation between growth (over a 4-month period) and wound healing across populations that is suggestive of an energetic trade-off between growth and immune response. The differences observed in growth and immune response among these two populations appear to suggest different energy allocation strategies to maximize fitness in response to differing conditions experienced by snakes in the two populations. PMID- 26062441 TI - Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer. AB - Reprogramming metabolism of tumor cells is a hallmark of cancer. Lactate dehydrogenase A (LDHA) is frequently overexpressed in tumor cells. Previous studies has shown higher levels of LDHA is related with colorectal cancer (CRC), but its role in tumor maintenance and underlying molecular mechanisms has not been established. Here, we investigated miRNAs-induced changes in LDHA expression. We reported that colorectal cancer express higher levels of LDHA compared with adjacent normal tissue. Knockdown of LDHA resulted in decreased lactate and ATP production, and glucose uptake. Colorectal cancer cells with knockdown of LDHA had much slower growth rate than control cells. Furthermore, we found that miR-34a, miR-34c, miR-369-3p, miR-374a, and miR-4524a/b target LDHA and regulate glycolysis in cancer cells. There is a negative correlation between these miRNAs and LDHA expression in colorectal cancer tissues. More importantly, we identified a genetic loci newly associated with increased colorectal cancer progression, rs18407893 at 11p15.4 (in 3'-UTR of LDHA), which maps to the seed sequence recognized by miR-374a. Cancer cells overexpressed miR-374a has decreased levels of LDHA compared with miR-374a-MUT (rs18407893 at 11p15.4). Taken together, these novel findings provide more therapeutic approaches to the Warburg effect and therapeutic targets of cancer energy metabolism. PMID- 26062442 TI - miR-181c associates with tumor relapse of high grade osteosarcoma. AB - High-grade osteosarcoma (OS) is characterized by low incidence, high aggressiveness and moderate 5-years survival rate after aggressive poly chemotherapy and surgery. Here we used miRNA profiling as a tool to possibly predict and monitor OS's development and therapeutic outcome. First, we evaluated the altered expression of selected miRNAs from a case of Giant Cell Tumor (GCT) apparently evolved into an OS. We found that most of modulated miRs were associated with pathways of bone resorption and osteogenesis. miRNA expression also revealed that GCT and OS were distinct tumors. Second, we validated the observed miRNA profile in two independent casuistries of ten GCT (not evolved into malignant tumors) and sixteen OS patients. Interestingly, we found that miR 181c and other three miRNAs identified in the first step of the study were also consistently de-regulated in all OS patients. Ectopic expression of miR-181c reduced cell viability and enhanced chemotherapeutic-induced cell death of U2OS and SAOS2 cells. These findings indicate that: i) miRNAs aberrantly modulated in GCT could be predictive of its development into OS and ii) miRNAs expression could be useful to monitor the OS therapeutic outcome. PMID- 26062443 TI - Genomic characterization of a large panel of patient-derived hepatocellular carcinoma xenograft tumor models for preclinical development. AB - Lack of clinically relevant tumor models dramatically hampers development of effective therapies for hepatocellular carcinoma (HCC). Establishment of patient derived xenograft (PDX) models that faithfully recapitulate the genetic and phenotypic features of HCC becomes important. In this study, we first established a cohort of 65 stable PDX models of HCC from corresponding Chinese patients. Then we showed that the histology and gene expression patterns of PDX models were highly consistent between xenografts and case-matched original tumors. Genetic alterations, including mutations and DNA copy number alterations (CNAs), of the xenografts correlated well with the published data of HCC patient specimens. Furthermore, differential responses to sorafenib, the standard-of-care agent, in randomly chosen xenografts were unveiled. Finally, in the models expressing high levels of FGFR1 gene according to the genomic data, FGFR1 inhibitor lenvatinib showed greater efficacy than sorafenib. Taken together, our data indicate that PDX models resemble histopathological and genomic characteristics of clinical HCC tumors, as well as recapitulate the differential responses of HCC patients to the standard-of-care treatment. Overall, this large collection of PDX models becomes a clinically relevant platform for drug screening, biomarker discovery and translational research in preclinical setting. PMID- 26062444 TI - Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma. AB - The chromatin-modifying enzyme lysine-specific demethylase 1, KDM1A/LSD1 is involved in maintaining the undifferentiated, malignant phenotype of neuroblastoma cells and its overexpression correlated with aggressive disease, poor differentiation and infaust outcome. Here, we show that LSD1 physically binds MYCN both in vitro and in vivo and that such an interaction requires the MYCN BoxIII. We found that LSD1 co-localizes with MYCN on promoter regions of CDKN1A/p21 and Clusterin (CLU) suppressor genes and cooperates with MYCN to repress the expression of these genes. KDM1A needs to engage with MYCN in order to associate with the CDKN1A and CLU promoters. The expression of CLU and CDKN1A can be restored in MYCN-amplified cells by pharmacological inhibition of LSD1 activity or knockdown of its expression. Combined pharmacological inhibition of MYCN and LSD1 through the use of small molecule inhibitors synergistically reduces MYCN-amplified Neuroblastoma cell viability in vitro. These findings demonstrate that LSD1 is a critical co-factor of the MYCN repressive function, and suggest that combination of LSD1 and MYCN inhibitors may have strong therapeutic relevance to counteract MYCN-driven oncogenesis. PMID- 26062446 TI - Mesoscale modeling of phase transition dynamics of thermoresponsive polymers. AB - We present a non-isothermal mesoscopic model for investigation of the phase transition dynamics of thermoresponsive polymers. Since this model conserves energy in the simulations, it is able to correctly capture not only the transient behavior of polymer precipitation from solvent, but also the energy variation associated with the phase transition process. Simulations provide dynamic details of the thermally induced phase transition and confirm two different mechanisms dominating the phase transition dynamics. A shift of endothermic peak with concentration is observed and the underlying mechanism is explored. PMID- 26062447 TI - Last Laughs: Gallows Humor and Medical Education. AB - This paper argues that "backstage" gallows humor among clinical mentors not only affects medical students' perceptions of what it means to be a doctor but is also symptomatic and indicative of a much larger problem in medicine-namely, the failure to attend fully to the complexity and profundity of the lived experiences of illness, suffering, and death. Reorienting the discourse surrounding gallows humor away from whether or in what context it is acceptable and toward the reasons why doctors feel the need to use such humor in the first place addresses this issue in a more illuminating way. PMID- 26062445 TI - Discovery of new small molecules inhibiting 67 kDa laminin receptor interaction with laminin and cancer cell invasion. AB - The 67 kDa laminin receptor (67LR) is a non-integrin receptor for laminin (LM) that derives from a 37 kDa precursor (37LRP). 67LR expression is increased in neoplastic cells and correlates with an enhanced invasive and metastatic potential. We used structure-based virtual screening (SB-VS) to search for 67LR inhibitory small molecules, by focusing on a 37LRP sequence, the peptide G, able to specifically bind LM. Forty-six compounds were identified and tested on HEK 293 cells transfected with 37LRP/67LR (LR-293 cells). One compound, NSC47924, selectively inhibited LR-293 cell adhesion to LM with IC50 and Ki values of 19.35 and 2.45 MUmol/L. NSC47924 engaged residues W176 and L173 of peptide G, critical for specific LM binding. Indeed, NSC47924 inhibited in vitro binding of recombinant 37LRP to both LM and its YIGSR fragment. NSC47924 also impaired LR 293 cell migration to LM and cell invasion. A subsequent hierarchical similarity search with NSC47924 led to the identification of additional four compounds inhibiting LR-293 cell binding to LM: NSC47923, NSC48478, NSC48861, and NSC48869, with IC50 values of 1.99, 1.76, 3.4, and 4.0 MUmol/L, respectively, and able to block in vitro cancer cell invasion. These compounds are promising scaffolds for future drug design and discovery efforts in cancer progression. PMID- 26062449 TI - [Medical examination: Preparation for ENT specialisation : Part 19]. PMID- 26062448 TI - [Interpretation of ultrasound findings in otorhinolaryngology. Salivary glands, paraganglioma, angioma, esophagus, hypopharynx, extra cranial vessels and temporomandibular joint]. AB - The second part of this continuing medical education article focuses on sonographic assessment of the salivary glands, cervical paraganglioma, angioma, esophagus, extra cranial blood vessels and the temporomandibular joint. The currently available minimally invasive therapeutic options (e. g. sialendoscopy, lithotripsy, therapeutic duct lavage and extracapsular dissection) for salivary gland disease presuppose a precise imaging modality. Modern ultrasound is able to meet this challenge, making additional imaging a rare necessity. Regions of the neck with a difficult topography (esophagus and hypopharynx) can often be successfully portrayed sonographically. Furthermore, ultrasound enables functional evaluation of swallowing in the cervical parts of the esophagus in dysphagia patients. In addition to the branchial cleft anomalies and lymph nodes discussed in part 1, paraganglioma, angiomatosis and neurogenic tumors are important differential diagnoses of solid lesions of the neck. Finally, venous and arterial alterations of the extracranial vessels of the neck relevant to clinical routine are depicted, as are pathological conditions of the temporomandibular joint relevant to the otorhinolaryngologist. PMID- 26062450 TI - [Auditory processing and perception disorders (APPD): summary and updated overview]. AB - The APD guideline of 2009 was supplemented by the statements listed here. The addition is based on current knowledge and findings. Otherwise, the Guideline 2009 remains valid. Here, a summary of the updated APD guideline is given, thus proving an overview of the definition of APD, diagnosis, differential diagnosis and recommended for APD management. PMID- 26062451 TI - The structure of the folded domain from the signature multifunctional protein ICP27 from herpes simplex virus-1 reveals an intertwined dimer. AB - Herpesviruses cause life-long infections by evading the host immune system and establishing latent infections. All mammalian herpesviruses express an essential multifunctional protein that is typified by ICP27 encoded by Herpes Simplex Virus 1. The only region that is conserved among the diverse members of the ICP27 family is a predicted globular domain that has been termed the ICP27 homology domain. Here we present the first crystal structure of the ICP27 homology domain, solved to 1.9 A resolution. The protein is a homo-dimer, adopting a novel intertwined fold with one CHCC zinc-binding site per monomer. The dimerization, which was independently confirmed by SEC-MALS and AUC, is stabilized by an extensive network of intermolecular contacts, and a domain-swap involving the two N-terminal helices and C-terminal tails. Each monomer contains a lid motif that can clamp the C-terminal tail of its dimeric binding partner against its globular core, without forming any distinct secondary structure elements. The binding interface was probed with point mutations, none of which had a noticeable effect on dimer formation; however deletion of the C-terminal tail region prevented dimer formation in vivo. The structure provides a template for future biochemical studies and modelling of ICP27 homologs from other herpesviruses. PMID- 26062453 TI - RESEARCHERS, RELIGION AND CHILDLESSNESS. AB - This study analysed childlessness and religion among female research scientists in the Austrian context. The aim of the study was to investigate the role of religion in intended childlessness and realized childlessness. The analysis was based on a representative sample of Austrian women aged 25-45 (N=2623), with a specific sample of female research scientists aged 25-45 (N=186), carried out in the framework of the Generations and Gender Survey conducted in 2008/09. The results indicate that religious affiliation and self-assessed religiosity are strongly related to fertility. Multivariate analyses reveal that education has no explanatory power in terms of explaining intended childlessness, once religious affiliation and self-assessed religiosity are taken into consideration. PMID- 26062452 TI - ePathOptimize: A Combinatorial Approach for Transcriptional Balancing of Metabolic Pathways. AB - The ability to fine tune gene expression has created the field of metabolic pathway optimization and balancing where a variety of factors affecting flux balance are carefully modulated to improve product titers, yields, and productivity. Using a library of isopropyl beta-D-1-thiogalactopyranoside (IPTG) inducible mutant T7 promoters of varied strength a combinatorial method was developed for transcriptional balancing of the violacein pathway. Violacein biosynthesis involves a complex five-gene pathway that is an excellent model for exploratory metabolic engineering efforts into pathway regulation and control due to many colorful intermediates and side products allowing for easy analysis and strain comparison. Upon screening approximately 4% of the total initial library, several high-titer mutants were discovered that resulted in up to a 63-fold improvement over the control strain. With further fermentation optimization, titers were improved to 1829 +/- 46 mg/L; a 2.6-fold improvement in titer and a 30-fold improvement in productivity from previous literature reports. PMID- 26062454 TI - Erratum to: Catching the Invisible: Mesial Temporal Source Contribution to Simultaneous EEG and SEEG Recordings. PMID- 26062455 TI - MicroRNA-196a post-transcriptionally upregulates the UBE2C proto-oncogene and promotes cell proliferation in breast cancer. AB - Accumulating evidence has shown that miR-196a plays an important role in tumorigenesis and tumor progression in various types of cancer. miRNA profiling studies have suggested that miR-196a is highly overexpressed in breast cancer. However, the functional mechanism of miR-196a in breast cancer remains unclear. In the present study, we first showed that the expression of miR-196a was significantly upregulated in human breast cancer samples and breast cancer cell lines. Using a loss-of-function approach, we showed that the downregulation of miR-196a inhibited the proliferation of breast cancer cells in vitro and in vivo. Ubiquitin-conjugating enzyme E2C (UBE2C) gene as a cellular proto-oncogene, which was overexpressed and positively correlated with miR-196a expression in breast cancer tissues, was identified as a direct target of miR-196a. Moreover, in order to investigate whether miR-196a regulated cell growth in breast cancer cells by targeting UBE2C, rescue studies were performed in breast cancer cells. The restoration of UBE2C by transfecting UBE2C cDNA in anti-miR-196a-transfected breast cancer cells rescued the suppression of cell proliferation. In conclusion, the present study showed that miR-196a promoted cell proliferation by targeting UBE2C in breast cancer. Thus, miR-196a may be a potential oncogene in breast cancer and a promising therapeutic target in breast cancer treatment. PMID- 26062456 TI - Genotoxic and hematological parameters in Colossoma macropomum (Pisces, Serrasalmidae) as biomarkers for environmental impact assessment in a protected area in northeastern Brazil. AB - Genotoxic and hematological parameters in tambaqui (Colossoma macropomum), a native freshwater fish, were used as biomarkers to assess exposure to environmental stressors within the Maracana Protected Area of Maranhao State, Brazil. Fish were sampled at two sites-Serena Lagoon (control) and Ambude River on four occasions (dry and rainy season), and biometric data (length and weight) recorded and blood collected from all fish for analysis. Erythrocyte indices-mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration-were calculated. Blood samples were stained with Giemsa and acridine orange, and microscopically examined for micronuclei and morphological nuclear abnormalities. Micronuclei were observed in fish from both sites, although the frequency was significantly higher in fish from the Ambude River and morphological nuclear abnormalities were only observed in fish from the Ambude River. More morphological nuclear abnormalities and a larger number of micronuclei were observed in erythrocytes stained with acridine orange compared with those stained with Giemsa. On average, erythrocyte indices were lower in fish from the Ambude River than from the Serena Lagoon. The results confirm that genotoxic and hematological parameters in C. macropomum can be used as indicators of environmental health and could be valuable tools for monitoring environmental conditions within protected areas. PMID- 26062457 TI - Heavy metal contamination in sediments of an artificial reservoir impacted by long-term mining activity in the Almaden mercury district (Spain). AB - Sediments from the Castilseras reservoir, located downstream on the Valdeazogues River in the Almaden mercury district, were collected to assess the potential contamination status related to metals(oids) associated with river sediment inputs from several decommissioned mines. Metals(oids) concentrations in the reservoir sediments were investigated using different physical and chemical techniques. The results were analyzed by principal component analysis (PCA) to explain the correlations between the sets of variables. The degree of contamination was evaluated using the enrichment factor (EF) and the geoaccumulation index (Igeo). PCA revealed that the silty fraction is the main metals(oids) carrier in the sediments. Among the potentially harmful elements, there is a group (Al, Cr, Cu, Fe, Mn, Ni, and Zn) that cannot be strictly correlated to the mining activity since their concentrations depend on the lithological and edaphological characteristics of the materials. In contrast, As, Co, Hg, Pb, and S showed significant enrichment and contamination, thus suggesting relevant contributions from the decommissioned mines through fluvial sediment inputs. As far as Hg and S are concerned, the high enrichment levels pose a question concerning the potential environmental risk of transfer of the organic forms of Hg (mainly methylmercury) from the bottom sediments to the aquatic food chain. PMID- 26062459 TI - Economic growth, combustible renewables and waste consumption, and CO2 emissions in North Africa. AB - This paper uses panel cointegration techniques and Granger causality tests to examine the dynamic causal link between per capita real gross domestic product (GDP), combustible renewables and waste (CRW) consumption, and CO2 emissions for a panel of five North African countries during the period 1971-2008. Granger causality test results suggest short- and long-run unidirectional causalities running from CO2 emissions and CRW consumption to real GDP and a short-run unidirectional causality running from CRW to CO2 emissions. The results from panel long-run fully modified ordinary least squares (FMOLS) and dynamic ordinary least squares (DOLS) estimates show that CO2 emissions and CRW consumption have a positive and statistically significant impact on GDP. Our policy recommendations are that these countries should use more CRW because this increases their output, reduces their energy dependency on fossil energy, and may decrease their CO2 emissions. PMID- 26062458 TI - Multi-element atmospheric deposition in Macedonia studied by the moss biomonitoring technique. AB - Moss biomonitoring technique using moss species Homolothecium lutescens (Hedw.) Robins and Hypnum cupressiforme (Hedw.) was applied to air pollution studies in the Republic of Macedonia. The study was performed in the framework of the International Cooperative Programme on Effects of Air Pollution on Natural Vegetation and Crops under the auspices of the United Nations Economic Commission for Europe (UNECE) Convention on Long-Range Transboundary Air Pollution (LRTAP). The presence of 47 elements was determined by instrumental epithermal neutron activation analysis, atomic absorption spectrometry and atomic emission spectrometry with inductively coupled plasma. Normality of the datasets of elements was investigated, and Box-Cox transformation was used in order to achieve normal distributions of the data. Different pollution sources were identified and characterized using principal component analysis (PCA). Distribution maps were prepared to point out the regions most affected by pollution and to relate this to the known sources of contamination. The cities of Veles, Skopje, Tetovo, Radovis and Kavadarci were determined to experience particular environmental stress. Moreover, three reactivated lead-zinc mines were also shown to contribute to a high content of lead and zinc in the eastern part of the country. However, a comparison with the previous moss survey conducted in 2005 showed a decreasing trend of pollution elements that are usually associated with emission from industrial activities. PMID- 26062460 TI - Assessment of bioaerosol contamination (bacteria and fungi) in the largest urban wastewater treatment plant in the Middle East. AB - Bioaerosol concentration was measured in wastewater treatment units in south of Tehran, the largest wastewater treatment plant in the Middle East. Active sampling was carried out around four operational units and a point as background. The results showed that the aeration tank with an average of 1016 CFU/m(3) in winter and 1973 CFU/m(3) in summer had the greatest effect on emission of bacterial bioaerosols. In addition, primary treatment had the highest impact on fungal emission. Among the bacteria, Micrococcus spp. showed the widest emission in the winter, and Bacillus spp. was dominant in summer. Furthermore, fungi such as Penicillium spp. and Cladosporium spp. were the dominant types in the seasons. Overall, significant relationship was observed between meteorological parameters and the concentration of bacterial and fungal aerosols. PMID- 26062461 TI - Heavy metal content in vegetables and fruits cultivated in Baia Mare mining area (Romania) and health risk assessment. AB - Information about heavy metal concentrations in food products and their dietary intake are essential for assessing the health risk of local inhabitants. The main purposes of the present study were (1) to investigate the concentrations of Zn, Cu, Pb, and Cd in several vegetables and fruits cultivated in Baia Mare mining area (Romania); (2) to assess the human health risk associated with the ingestion of contaminated vegetables and fruits by calculating the daily intake rate (DIR) and the target hazard quotient (THQ); and (3) to establish some recommendations on human diet in order to assure an improvement in food safety. The concentration order of heavy metals in the analyzed vegetable and fruit samples was Zn > Cu > Pb > Cd. The results showed the heavy metals are more likely to accumulate in vegetables (10.8-630.6 mg/kg dw for Zn, 1.4-196.6 mg/kg dw for Cu, 0.2-155.7 mg/kg dw for Pb, and 0.03-6.61 mg/kg dw for Cd) than in fruits (4.9-55.9 mg/kg dw for Zn, 1.9-24.7 mg/kg dw for Cu, 0.04-8.82 mg/kg dw for Pb, and 0.01-0.81 mg/kg dw for Cd). Parsley, kohlrabi, and lettuce proved to be high heavy metal accumulators. By calculating DIR and THQ, the data indicated that consumption of parsley, kohlrabi, and lettuce from the area on a regular basis may pose high potential health risks to local inhabitants, especially in the area located close to non-ferrous metallurgical plants (Romplumb SA and Cuprom SA) and close to Tautii de Sus tailings ponds. The DIR for Zn (85.3-231.6 MUg/day kg body weight) and Cu (25.0-44.6 MUg/day kg body weight) were higher in rural areas, while for Pb (0.6-3.1 MUg/day kg body weight) and Cd (0.22-0.82 MUg/day kg body weight), the DIR were higher in urban areas, close to the non-ferrous metallurgical plants SC Romplumb SA and SC Cuprom SA. The THQ for Zn, Cu, Pb, and Cd was higher than 5 for <1, <1, 12, and 6% of samples which indicates that those consumers may experience major health risks. PMID- 26062462 TI - Use of dispersant in mudflat oil-contaminated sediment: behavior and effects of dispersed oil on micro- and macrobenthos. AB - The present study aimed to examine whether the use of dispersant would be suitable for favoring the hydrocarbon degradation in coastal marine sediments without impacting negatively micro- and macrobenthic organisms. Mudflat sediments, maintained during 286 days in mesocosms designed to simulate natural conditions, were contaminated or not with Ural blend crude oil (REBCO) and treated or not with third-generation dispersant (Finasol OSR52). While the dispersant did not lead to an increase of hydrocarbon biodegradation, its use enables an attenuation of more than 55 % of the sediment concentration of total petroleum hydrocarbons (TPH). Canonical correspondence analysis (CCA) correlating T-RFLP patterns with the hydrocarbon content and bacterial abundance indicated weak differences between the different treatments except for the mesocosm treated with oil and dispersant for which a higher bacterial biomass was observed. The use of the dispersant did not significantly decrease the macrobenthic species richness or macroorganisms' densities in uncontaminated or contaminated conditions. However, even if the structure of the macrobenthic communities was not affected, when used in combination with oil, biological sediment reworking coefficient was negatively impacted. Although the use of the dispersant may be worth considering in order to accelerate the attenuation of hydrocarbon contaminated mudflat sediments, long-term effects on functional aspects of the benthic system such as bioturbation and bacterial activity should be carefully studied before. PMID- 26062463 TI - Cytochrome c adducts with PCB quinoid metabolites. AB - Polychlorinated biphenyls (PCBs) are a group of 209 individual congeners widely used as industrial chemicals. PCBs are found as by-products in dye and paint manufacture and are legacy, ubiquitous, and persistent as human and environmental contaminants. PCBs with fewer chlorine atoms may be metabolized to hydroxy- and dihydroxy-metabolites and further oxidized to quinoid metabolites both in vitro and in vivo. Specifically, quinoid metabolites may form adducts on nucleophilic sites within cells. We hypothesized that the PCB-quinones covalently bind to cytochrome c and, thereby, cause defects in the function of cytochrome c. In this study, synthetic PCB quinones, 2-(4'-chlorophenyl)-1,4-benzoquinone (PCB3-pQ), 4 4'-chlorophenyl)-1,2-benzoquinone (PCB3-oQ), 2-(3', 5'-dichlorophenyl)-1,4 benzoquinone, 2-(3',4', 5'-trichlorophenyl)-1,4-benzoquinone, and 2-(4' chlorophenyl)-3,6-dichloro-1,4-benzoquinone, were incubated with cytochrome c, and adducts were detected by liquid chromatography-mass spectrometry (LC-MS) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI TOF). Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) was employed to separate the adducted proteins, while trypsin digestion and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were applied to identify the amino acid binding sites on cytochrome c. Conformation change of cytochrome c after binding with PCB3-pQ was investigated by SYBYL-X simulation and cytochrome c function was examined. We found that more than one molecule of PCB-quinone may bind to one molecule of cytochrome c. Lysine and glutamic acid were identified as the predominant binding sites. Software simulation showed conformation changes of adducted cytochrome c. Additionally, cross-linking of cytochrome c was observed on the SDS-PAGE gel. Cytochrome c was found to lose its function as electron acceptor after incubation with PCB quinones. These data provide evidence that the covalent binding of PCB quinone metabolites to cytochrome c may be included among the toxic effects of PCBs. PMID- 26062464 TI - Static magnetic field exposure-induced oxidative response and caspase-independent apoptosis in rat liver: effect of selenium and vitamin E supplementations. AB - In the present study, we investigated the implication of oxidative stress and apoptosis under static magnetic field (SMF) in the brain and liver. Moreover, we estimated the protective role of selenium and vitamin E in rat tissues against disorders induced by SMF. Exposure of rats to SMF (128 mT, 1 h/day during five consecutive days) increased the activity of catalase (CAT) (+24 %) in the liver but not in the brain. By contrast, the same treatment failed to alter malondialdehyde (MDA) concentration in the brain and liver. Exposure to SMF also induced hepatocyte apoptosis through a caspase-independent pathway involving mitochondrial apoptosis-inducing factor (AIF) but not in the brain. Selenium and vitamin E supplementations to SMF-exposed rats restored liver CAT activity but failed to minimize liver apoptosis. PMID- 26062465 TI - Microscopic biomineralization processes and Zn bioavailability: a synchrotron based investigation of Pistacia lentiscus L. roots. AB - Plants growing on polluted soils need to control the bioavailability of pollutants to reduce their toxicity. This study aims to reveal processes occurring at the soil-root interface of Pistacia lentiscus L. growing on the highly Zn-contaminated tailings of Campo Pisano mine (SW Sardinia, Italy), in order to shed light on possible mechanisms allowing for plant adaptation. The study combines conventional X-ray diffraction (XRD) and scanning electron microscopy (SEM) with advanced synchrotron-based techniques, micro-X-ray fluorescence mapping (MU-XRF) and X-ray absorption spectroscopy (XAS). Data analysis elucidates a mechanism used by P. lentiscus L. as response to high Zn concentration in soil. In particular, P. lentiscus roots take up Al, Si and Zn from the rhizosphere minerals in order to build biomineralizations that are part of survival strategy of the species, leading to formation of a Si-Al biomineralization coating the root epidermis. XAS analysis rules out Zn binding to organic molecules and indicates that Zn coordinates Si atoms stored in root epidermis leading to the precipitation of an amorphous Zn-silicate. These findings represent a step forward in understanding biological mechanisms and the resulting behaviour of minor and trace elements during plant-soil interaction and will have significant implications for development of phytoremediation techniques. PMID- 26062466 TI - Characterization of particulate matter concentrations and bioaerosol on each floor at a building in Seoul, Korea. AB - Particulate matter (PM) in buildings are mostly sourced from the transport of outdoor particles through a heating, ventilation, and air conditioning (HVAC) system and generation of particle within the building itself. We investigated the concentrations and characteristic of indoor and outdoor particles and airborne bacteria concentrations across four floors of a building located in a high traffic area. In all the floors we studied (first, second, fifth, and eighth), the average concentrations of particles less than 10 MUm (PM10) in winter for were higher than those in summer. On average, a seasonal variation in the PM10 level was found for the first, fifth, and eighth floors, such that higher values occurred in the winter season, compared to the summer season. In addition, in winter, the indoor concentrations of PM10 on the first, fifth, and eighth floors were higher than those of the outdoor PM10. The maximum level of airborne bacteria concentration was found in a fifth floor office, which held a private academy school consisting of many students. Results indicated that the airborne bacteria remained at their highest concentration throughout the weekday period and varied by students' activity. The correlation coefficient (R (2)) and slope of linear approximation for the concentrations of particulate matter were used to evaluate the relationship between the indoor and outdoor particulate matter. These results can be used to predict both the indoor particle levels and the risk of personal exposure to airborne bacteria. PMID- 26062467 TI - Electrokinetic remediation of manganese and ammonia nitrogen from electrolytic manganese residue. AB - Electrolytic manganese residue (EMR) is a solid waste found in filters after sulphuric acid leaching of manganese carbonate ore, which mainly contains manganese and ammonia nitrogen and seriously damages the ecological environment. This work demonstrated the use of electrokinetic (EK) remediation to remove ammonia nitrogen and manganese from EMR. The transport behavior of manganese and ammonia nitrogen from EMR during electrokinetics, Mn fractionation before and after EK treatment, the relationship between Mn fractionation and transport behavior, as well as the effects of electrolyte and pretreatment solutions on removal efficiency and energy consumption were investigated. The results indicated that the use of H2SO4 and Na2SO4 as electrolytes and pretreatment of EMR with citric acid and KCl can reduce energy consumption, and the removal efficiencies of manganese and ammonia nitrogen were 27.5 and 94.1 %, respectively. In these systems, electromigration and electroosmosis were the main mechanisms of manganese and ammonia nitrogen transport. Moreover, ammonia nitrogen in EMR reached the regulated level, and the concentration of manganese in EMR could be reduced from 455 to 37 mg/L. In general, the electrokinetic remediation of EMR is a promising technology in the future. PMID- 26062468 TI - Pb(II), Cr(VI) and atrazine sorption behavior on sludge-derived biochar: role of humic acids. AB - Pyrolyzing municipal wastewater treatment sludge into biochar can be a promising sludge disposal approach, especially as the produced sludge-derived biochar (SDBC) is found to be an excellent sorbent for heavy metals and atrazine. The aim of this study was to investigate how and why the coexisting humic acids influence the sorption capacity, kinetic, and binding of these contaminants on SDBC surface. Results showed humic acids enhanced Pb(II)/Cr(VI) sorption binding, and increased the corresponding Pb(II) Langmuir sorption capacity at pH 5.0 from 197 to 233 MUmol g(-1), and from 688 to 738 MUmol g(-1) for Cr(VI) at pH 2.0. It can be mainly attributed to the sorbed humic acids, whose active functional groups can offer the additional sites to form stronger inner-sphere complexes with Pb(2+), and supply more reducing agent to facilitate the transformation of Cr(VI) to Cr(III). However, humic acids reduced the atrazine adsorption Freundlich constant from 1.085 to 0.616 MUmol g(-1). The pore blockage, confirmed by the decreased BET-specific surface area, as well as the more hydrophilic surface with more sorbed water molecules may be the main reasons for that suppression. Therefore, the coexisting humic acids may affect heavy metal stabilization or pesticide immobilization during SDBC application to contaminated water or soils, and its role thus should be considered especially when organic residues are also added significantly to increase the humic acid content there. PMID- 26062470 TI - Assessment of pollution and identification of sources of heavy metals in the sediments of Changshou Lake in a branch of the Three Gorges Reservoir. AB - To assess the heavy metal pollution in Changshou Lake, sediments were collected from nine sites at three periods (dry, normal, and wet) in 2013. The Hg, As, Cr, Cd, Pb, Cu, and Zn levels were then determined. The index of geoaccumulation (I geo) and the sediment pollution index (SPI) were applied to the sediment assessment, and Pearson's correlation analysis and factor analysis (FA) were performed to identify common pollution sources in the basin. The results showed that heavy metals presented significant spatial variations with Cr, Cd, Pb, Cu, Zn, Hg, and As concentrations of 29.66~42.58, 0.62~0.91, 24.91~37.96, 21.18~74.91, 41.65~86.86, 0.079~0.152, and 20.17~36.88 mg kg(-1), respectively, and no obvious variations were found among the different periods. The average contents of the metals followed the order Zn > Cu > Cr > Pb > As > Cd > Hg, which showed a high pollution in the sediments collected from open water and at the river mouth. The assessment results indicated that toxic heavy metals presented obvious pollution with I Hg of 0.64~1.36 (moderately polluted), I Cd of 1.66~2.22 (moderately to heavily polluted), and I As of 1.21~2.07 (moderately to heavily polluted). The heavy metal pollution states followed the order Cd > As > Hg > Cu > Pb > Zn > Cr, and the SPI showed that the sediment collected from open water area was more polluted than those obtained from the tributaries and the river mouth. Cr, Cd, Hg, Pb, Cu, As, and Zn were mainly attributed to sediment weathering with Hg, Pb, and Cu and partially due to domestic sewage from the upper reaches. These results indicate that the more attention should be paid to the inner loads of sediment in order to achieve improvements in reservoir water quality after the control of external pollution. PMID- 26062469 TI - Laboratory calibration and field testing of the Chemcatcher-Metal for trace levels of rare earth elements in estuarine waters. AB - Little knowledge is available about water concentrations of rare earth elements (REEs) in the marine environment. The direct measurement of REEs in coastal waters is a challenging task due to their ultra-low concentrations as well as the high salt content in the water samples. To quantify these elements at environmental concentrations (pg L(-1) to low ng L(-1)) in coastal waters, current analytical techniques are generally expensive and time consuming, and require complex chemical preconcentration procedures. Therefore, an integrative passive sampler was tested as a more economic alternative sampling approach for REE analysis. We used a Chemcatcher-Metal passive sampler consisting of a 3M Empore Chelating Disk as the receiving phase, as well as a cellulose acetate membrane as the diffusion-limiting layer. The effect of water turbulence and temperature on the uptake rates of REEs was analyzed during 14-day calibration experiments by a flow-through exposure tank system. The sampling rates were in the range of 0.42 mL h(-1) (13 degrees C; 0.25 m s(-1)) to 4.01 mL h(-1) (13 degrees C; 1 m s(-1)). Similar results were obtained for the different REEs under investigation. The water turbulence was the most important influence on uptake. The uptake rates were appropriate to ascertain time-weighted average concentrations of REEs during a field experiment in the Elbe Estuary near Cuxhaven Harbor (exposure time 4 weeks). REE concentrations were determined to be in the range 0.2 to 13.8 ng L(-1), where the highest concentrations were found for neodymium and samarium. In comparison, most of the spot samples measured along the Chemcatcher samples had REE concentrations below the limit of detection, in particular due to necessary dilution to minimize the analytical problems that arise with the high salt content in marine water samples. This study was among the first efforts to measure REE levels in the field using a passive sampling approach. Our results suggest that passive samplers could be an effective tool to monitor ultra-trace concentrations of REEs in coastal waters with high salt content. PMID- 26062471 TI - Huachansu mediates cell death in non-Hodgkin's lymphoma by induction of caspase-3 and inhibition of MAP kinase. AB - Huachansu (HCS), a hot water extract of the skin glands of Bufo gargarizans (B. melanostictus), has been used extensively in the treatment of various solid tumors in Asia, particularly in China. However, its effect on the growth of malignancies of hematopoietic origin, particularly lymphomas, is limited. Here we investigated the antiproliferative effect and molecular mechanisms of HCS using non-Hodgkin's lymphoma (NHL) Raji, Ramos, and Namalwa cells and the mantle cell lymphoma cells SP53. HCS inhibited proliferation in these cell lines with an IC50 ranging from 3.1 to 25 ul/ml. At a concentration of 25 ul/ml, HCS triggered a sub G1 arrest in Ramos cells and induced early to late apoptotic cell death. Cleaved caspase-3 was formed in a concentration-dependent manner in Ramos cells following treatment with HCS for 24 h. Intriguingly, when the Ramos cells were treated with the caspase inhibitor ZDEVD, the apoptotic activity of HCS was partially blocked. Furthermore, HCS also blocked the expression of survivin and pRB proteins in a concentration-dependent manner in Ramos cells. Mechanistically, HCS downregulated both the MAPK gene and proteins in Ramos cells. Collectively, our data suggest that HCS is effective in inducing cell death and apoptosis, in part, by activating caspase-3 activity and suppressing MAP kinase in NHL cells. PMID- 26062472 TI - Undue burdens. PMID- 26062473 TI - Sex and the law. PMID- 26062474 TI - Tough targets. PMID- 26062475 TI - Funders must encourage scientists to share. PMID- 26062487 TI - African academics challenge homophobic laws. PMID- 26062488 TI - Injectable brain implant spies on individual neurons. PMID- 26062489 TI - Start-ups fight for a place in Boston's biotech hub. PMID- 26062490 TI - South Korean MERS outbreak spotlights lack of research. PMID- 26062492 TI - Clarifications. PMID- 26062491 TI - DNA deluge reveals Bronze Age secrets. PMID- 26062493 TI - The military-bioscience complex. PMID- 26062494 TI - The rise of Africa's super vegetables. PMID- 26062495 TI - Nuclear physics: pull together for fusion. PMID- 26062496 TI - Reproducibility: use mouse biobanks or lose them. PMID- 26062499 TI - Animal research: share surplus animal tissue. PMID- 26062500 TI - Environment: phosphate mining risks atoll culture. PMID- 26062501 TI - Workforce: the joys of research in retirement. PMID- 26062502 TI - Policy: climate advisers must be astute. PMID- 26062503 TI - Malaria: a master lock for deadly parasites. PMID- 26062504 TI - Nanophotonics: bright future for hyperbolic chips. PMID- 26062505 TI - Climate science: timing is everything during deglaciations. PMID- 26062506 TI - Human evolution: ancient DNA steps into the language debate. PMID- 26062508 TI - Small particles dominate Saturn's Phoebe ring to surprisingly large distances. AB - Saturn's faint outermost ring, discovered in 2009 (ref. 1), is probably formed by particles ejected from the distant moon Phoebe. The ring was detected between distances of 128 and 207 Saturn radii (RS = 60,330 kilometres) from the planet, with a full vertical extent of 40RS, making it well over ten times larger than Saturn's hitherto largest known ring, the E ring. The total radial extent of the Phoebe ring could not, however, be determined at that time, nor could particle sizes be significantly constrained. Here we report infrared imaging of the entire ring, which extends from 100RS out to a surprisingly distant 270RS. We model the orbital dynamics of ring particles launched from Phoebe, and construct theoretical power-law profiles of the particle size distribution. We find that very steep profiles fit the data best, and that elevated grain temperatures, arising because of the radiative inefficiency of the smallest grains, probably contribute to the steepness. By converting our constraint on particle sizes into a form that is independent of the uncertain size distribution, we determine that particles with radii greater than ten centimetres, whose orbits do not decay appreciably inward over 4.5 billion years, contribute at most about ten per cent to the cross-sectional area of the ring's dusty component. PMID- 26062509 TI - Small-scale dynamo magnetism as the driver for heating the solar atmosphere. AB - The long-standing problem of how the solar atmosphere is heated has been addressed by many theoretical studies, which have stressed the relevance of two specific mechanisms, involving magnetic reconnection and waves, as well as the necessity of treating the chromosphere and corona together. But a fully consistent model has not yet been constructed and debate continues, in particular about the possibility of coronal plasma being heated by energetic phenomena observed in the chromosphere. Here we report modelling of the heating of the quiet Sun, in which magnetic fields are generated by a subphotospheric fluid dynamo intrinsically connected to granulation. We find that the fields expand into the chromosphere, where plasma is heated at the rate required to match observations (4,500 watts per square metre) by small-scale eruptions that release magnetic energy and drive sonic motions. Some energetic eruptions can even reach heights of 10 million metres above the surface of the Sun, thereby affecting the very low corona. Extending the model by also taking into account the vertical weak network magnetic field allows for the existence of a mechanism able to heat the corona above, while leaving unchanged the physics of chromospheric eruptions. Such a mechanism rests on the eventual dissipation of Alfven waves generated inside the chromosphere and that carry upwards the required energy flux of 300 watts per square metre. The model shows a topologically complex magnetic field of 160 gauss on the Sun's surface, agreeing with inferences obtained from spectropolarimetric observations, chromospheric features (contributing only weakly to the coronal heating) that can be identified with observed spicules and blinkers, and vortices that may be possibly associated with observed solar tornadoes. PMID- 26062507 TI - Population genomics of Bronze Age Eurasia. AB - The Bronze Age of Eurasia (around 3000-1000 BC) was a period of major cultural changes. However, there is debate about whether these changes resulted from the circulation of ideas or from human migrations, potentially also facilitating the spread of languages and certain phenotypic traits. We investigated this by using new, improved methods to sequence low-coverage genomes from 101 ancient humans from across Eurasia. We show that the Bronze Age was a highly dynamic period involving large-scale population migrations and replacements, responsible for shaping major parts of present-day demographic structure in both Europe and Asia. Our findings are consistent with the hypothesized spread of Indo-European languages during the Early Bronze Age. We also demonstrate that light skin pigmentation in Europeans was already present at high frequency in the Bronze Age, but not lactose tolerance, indicating a more recent onset of positive selection on lactose tolerance than previously thought. PMID- 26062510 TI - Visible-frequency hyperbolic metasurface. AB - Metamaterials are artificial optical media composed of sub-wavelength metallic and dielectric building blocks that feature optical phenomena not present in naturally occurring materials. Although they can serve as the basis for unique optical devices that mould the flow of light in unconventional ways, three dimensional metamaterials suffer from extreme propagation losses. Two-dimensional metamaterials (metasurfaces) such as hyperbolic metasurfaces for propagating surface plasmon polaritons have the potential to alleviate this problem. Because the surface plasmon polaritons are guided at a metal-dielectric interface (rather than passing through metallic components), these hyperbolic metasurfaces have been predicted to suffer much lower propagation loss while still exhibiting optical phenomena akin to those in three-dimensional metamaterials. Moreover, because of their planar nature, these devices enable the construction of integrated metamaterial circuits as well as easy coupling with other optoelectronic elements. Here we report the experimental realization of a visible frequency hyperbolic metasurface using single-crystal silver nanostructures defined by lithographic and etching techniques. The resulting devices display the characteristic properties of metamaterials, such as negative refraction and diffraction-free propagation, with device performance greatly exceeding those of previous demonstrations. Moreover, hyperbolic metasurfaces exhibit strong, dispersion-dependent spin-orbit coupling, enabling polarization- and wavelength dependent routeing of surface plasmon polaritons and two-dimensional chiral optical components. These results open the door to realizing integrated optical meta-circuits, with wide-ranging applications in areas from imaging and sensing to quantum optics and quantum information science. PMID- 26062512 TI - Experimental constraints on the electrical anisotropy of the lithosphere asthenosphere system. AB - The relative motion of lithospheric plates and underlying mantle produces localized deformation near the lithosphere-asthenosphere boundary. The transition from rheologically stronger lithosphere to weaker asthenosphere may result from a small amount of melt or water in the asthenosphere, reducing viscosity. Either possibility may explain the seismic and electrical anomalies that extend to a depth of about 200 kilometres. However, the effect of melt on the physical properties of deformed materials at upper-mantle conditions remains poorly constrained. Here we present electrical anisotropy measurements at high temperatures and quasi-hydrostatic pressures of about three gigapascals on previously deformed olivine aggregates and sheared partially molten rocks. For all samples, electrical conductivity is highest when parallel to the direction of prior deformation. The conductivity of highly sheared olivine samples is ten times greater in the shear direction than for undeformed samples. At temperatures above 900 degrees Celsius, a deformed solid matrix with nearly isotropic melt distribution has an electrical anisotropy factor less than five. To obtain higher electrical anisotropy (up to a factor of 100), we propose an experimentally based model in which layers of sheared olivine are alternated with layers of sheared olivine plus MORB or of pure melt. Conductivities are up to 100 times greater in the shear direction than when perpendicular to the shear direction and reproduce stress-driven alignment of the melt. Our experimental results and the model reproduce mantle conductivity-depth profiles for melt-bearing geological contexts. The field data are best fitted by an electrically anisotropic asthenosphere overlain by an isotropic, high-conductivity lowermost lithosphere. The high conductivity could arise from partial melting associated with localized deformation resulting from differential plate velocities relative to the mantle, with subsequent upward melt percolation from the asthenosphere. PMID- 26062511 TI - Bipolar seesaw control on last interglacial sea level. AB - Our current understanding of ocean-atmosphere-cryosphere interactions at ice-age terminations relies largely on assessments of the most recent (last) glacial interglacial transition, Termination I (T-I). But the extent to which T-I is representative of previous terminations remains unclear. Testing the consistency of termination processes requires comparison of time series of critical climate parameters with detailed absolute and relative age control. However, such age control has been lacking for even the penultimate glacial termination (T-II), which culminated in a sea-level highstand during the last interglacial period that was several metres above present. Here we show that Heinrich Stadial 11 (HS11), a prominent North Atlantic cold episode, occurred between 135 +/- 1 and 130 +/- 2 thousand years ago and was linked with rapid sea-level rise during T II. Our conclusions are based on new and existing data for T-II and the last interglacial that we collate onto a single, radiometrically constrained chronology. The HS11 cold episode punctuated T-II and coincided directly with a major deglacial meltwater pulse, which predominantly entered the North Atlantic Ocean and accounted for about 70 per cent of the glacial-interglacial sea-level rise. We conclude that, possibly in response to stronger insolation and CO2 forcing earlier in T-II, the relationship between climate and ice-volume changes differed fundamentally from that of T-I. In T-I, the major sea-level rise clearly post-dates Heinrich Stadial 1. We also find that HS11 coincided with sustained Antarctic warming, probably through a bipolar seesaw temperature response, and propose that this heat gain at high southern latitudes promoted Antarctic ice sheet melting that fuelled the last interglacial sea-level peak. PMID- 26062514 TI - Antiinflammatory and Analgesic Activities of Ethanol Extract and Isolated Compounds from Millettia pulchra. AB - The plant Millettia pulchra was commonly used in folk medicine for the management of inflammation. However, there was no scientific rationale for these effects and the mechanism of action remained incompletely understood. The present study was designed to investigate the antiinflammatory and analgesic activities of an ethanol extract of the stem of M. pulchra (EMP) in vivo, and to explore the antiinflammatory activity of compounds isolated from EMP in vitro. We found that EMP reduced xylene-induced ear edema and relieved both acetic acid-induced pain and pain in the hot plate test. Additionally, a significant decrease in nitric oxide (NO) production was observed in cells treated with the isolated compounds. Lanceolatin B, which showed the greatest inhibition of NO synthesis among the compounds tested, also reduced levels of interleukin-1 beta (IL-1beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nuclear factor-kappa B (NF-kappaB), and phosphorylation inhibitory kappa B alpha (p-IkappaBalpha) in a dose-dependent manner. These findings provide convincing evidence that EMP and the individual isolated compounds possess significant antiinflammatory and analgesic activities. PMID- 26062516 TI - Holokinetic centromeres and efficient telomere healing enable rapid karyotype evolution. AB - Species with holocentric chromosomes are often characterized by a rapid karyotype evolution. In contrast to species with monocentric chromosomes where acentric fragments are lost during cell division, breakage of holocentric chromosomes creates fragments with normal centromere activity. To decipher the mechanism that allows holocentric species an accelerated karyotype evolution via chromosome breakage, we analyzed the chromosome complements of irradiated Luzula elegans plants. The resulting chromosomal fragments and rearranged chromosomes revealed holocentromere-typical CENH3 and histone H2AThr120ph signals as well as the same mitotic mobility like unfragmented chromosomes. Newly synthesized telomeres at break points become detectable 3 weeks after irradiation. The presence of active telomerase suggests a telomerase-based mechanism of chromosome healing. A successful transmission of holocentric chromosome fragments across different generations was found for most offspring of irradiated plants. Hence, a combination of holokinetic centromere activity and the fast formation of new telomeres at break points enables holocentric species a rapid karyotype evolution involving chromosome fissions and rearrangements. PMID- 26062518 TI - Family history and ethnicity influencing clinical presentation of type 1 diabetes in childhood. AB - BACKGROUND: A different clinical presentation of type 1 diabetes (T1DM) could be supposed in children belonging to different ethnicities, with or without family history of autoimmunity. OBJECTIVE: This study investigates the effect of ethnicity and family history of T1DM on clinical characteristics at presentation in a group of T1DM children. METHODS: One hundred ninety-six T1DM children <18 years, consecutively diagnosed during the years 2011-2014, were studied including 91 % of Caucasians of Italian ancestry and 9 % of non-Caucasian origin. RESULTS: Children with 1st or 2nd degree relatives affected by T1DM were younger at disease onset (p = 0.005) and showed lower HbA1C levels (p = 0.002), and higher IAA levels (p = 0.01). Non-Caucasian children were younger at disease onset (p = 0.029), and showed more severe hyperglycemia (p = 0.008) and ketoacidosis (pH p < 0.001). HbA1C levels were negatively related to positive family history of T1DM (p = 0.01), fasting C-peptide levels (p = 0.003), IAA levels (p = 0.03), and IA-2 levels (p = 0.003). The level of pH was positively influenced by fasting C peptide (p = 0.004), and negatively impacted by C-reactive protein (p = 0.01) and non-Caucasian ethnicity (p = 0.03). CONCLUSION: The milder metabolic decompensation in children with a positive family history of T1DM is probably explained by the awareness of the families in terms of early symptoms of T1DM, while the younger age at onset and the higher levels of autoantibodies may suggest a stronger genetic susceptibility, associated with a more aggressive autoimmune process. The younger age in non-Caucasian children is probably explained by the higher genetic susceptibility in subjects belonging to ethnic groups with a low T1DM incidence. Social aspects and poor living conditions probably predominate in determining the increased severity of metabolic decompensation at onset in children from non-Caucasian ethnicities. PMID- 26062517 TI - Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. AB - INTRODUCTION: Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65-75 % of cases), maternal uniparental disomy 15 (20-30 % of cases), and imprinting defect (1-3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS. METHODS: An extensive review of the literature was performed and interpreted within the context of clinical practice and frequently asked questions from referring physicians and families to include the current status of the cause and diagnosis of the clinical, genetics and endocrine findings in PWS. CONCLUSIONS: Updated information regarding the early diagnosis and management of individuals with Prader-Willi syndrome is important for all physicians and will be helpful in anticipating and managing or modifying complications associated with this rare obesity-related disorder. PMID- 26062519 TI - Serum concentrations of HGF and IL-8 in patients with active Graves' orbitopathy before and after methylprednisolone therapy. AB - INTRODUCTION: Graves' disease is the most common cause of hyperthyroidism, and orbitopathy is the most frequent extrathyroidal manifestation of Graves' disease. The aims of this study were as follows: (1) to evaluate the serum concentration of HGF and IL-8 in the blood of newly diagnosed Graves' disease patients with the first episode of active GO and healthy controls; (2) to estimate the influence of the thyroid function (euthyreosis vs. hyperthyreosis) on HGF and IL-8 blood levels in patients with active GO; (3) to evaluate the influence of intravenous (i.v.) methylprednisolone (MP) pulse therapy and additional oral MP treatment on HGF and IL-8 blood levels in patients with active GO. PATIENTS AND METHODS: Thirty-nine Graves' disease patients with the first episode of clinically active GO (Group A) were enrolled in the study. To estimate the influence of the thyroid function on serum concentrations of the studied proangiogenic factors, Group A was divided into Group A I (n = 18) in euthyroid and Group A II (n = 21) in hyperthyroid stage of Graves' disease in moderate-to-severe stage of GO. The control group consisted of 20 healthy volunteers age- and sex-matched to the GO group. Concentrations of the studied proangiogenic factors in serum samples were measured by an enzyme-linked immunosorbent assay before (Group A) and after (Group A1) intensive pulse i.v.MP treatment and 1 month after the end of additional oral MP treatment (Group A2). RESULTS: We found a significant increase in serum concentrations of studied factors in the GO group before immunosuppressive therapy when compared with the control group and decrease after i.v.MP treatment. One month after the end of additional oral MP treatment (Group A2), serum concentrations of HGF and IL-8 still decreased and no significant difference was observed in HGF and IL-8 concentrations when compared with the control group. We did not find the difference in serum concentration of the studied proangiogenic factors between patients in euthyroid and hyperthyroid stage of Graves' disease before MP therapy. CONCLUSIONS: Serum HGF and IL-8 concentrations are elevated in Graves' disease patients with active Graves' orbitopathy as compared to the healthy control group. Successful management of active Graves' orbitopathy with glucocorticoids is associated with a decrease in HGF and IL-8 serum concentrations. PMID- 26062520 TI - Growth hormone insensitivity: diagnostic and therapeutic approaches. AB - INTRODUCTION: Growth hormone resistance defines several genetic (primary) and acquired (secondary) pathologies that result in completely or partially interrupted activity of growth hormone. An archetypal disease of this group is the Laron-type dwarfism caused by mutations in growth hormone receptors. The diagnosis is based on high basal levels of growth hormone, low insulin like growth factor-I (IGF-1) level, unresponsiveness to IGF generation test and genetic testing. Recombinant IGF-1 preparations are used in the treatment CONCLUSION: In this article, clinical characteristics, diagnosis and therapeutic approaches of the genetic and other diseases leading to growth hormone insensitivity are reviewed. PMID- 26062521 TI - Artesunate protects pancreatic beta cells against cytokine-induced damage via SIRT1 inhibiting NF-kappaB activation. AB - AIM: Artesunate (ART) has been known as the most effective and safe reagents to treat malaria for many years. In this study, we explored whether ART could protect pancreatic beta-cell against cytokine-induced damage. MATERIALS AND METHODS: The production of nitrite (NO) was detected with the Griess Assay Kit. SIRT1 and inducible nitric oxide synthase (iNOS) expression were determined with Western blot. The transcriptional activity of NF-kappaB was evaluated by luciferase reporter assay. The expression of Sirt1 was silenced by RNA interference. Glucose-stimulated insulin secretion (GSIS) and potassium stimulated insulin secretion (KSIS) assays were performed to measure the effect of ART on pancreatic beta-cells' function. The effect of ART on beta-cells apoptosis was evaluated by using Hochest/PI staining and TUNEL assay. RESULTS: ART enhanced GSIS (KSIS) and reduced apoptosis of pancreatic beta-cells induced by IL-1beta. Further study showed that ART inhibited IL-1beta-induced increase of NF-kappaB activity, iNOS expression, and NO production. Moreover, ART up regulated SIRT1 expression in INS-1 cells and islets exposed to IL-1beta. Inhibition of SIRT1 expression could partially abolished the inhibitory effect of ART on NF-kappaB activity in IL-1beta-treated beta-cells. More importantly, the protective effect of ART on cytokine-induced damage was reversed by silencing SIRT1 expression. CONCLUSIONS: ART can elicit a protective effect on beta-cells exposed to IL-1beta by stimulating SIRT1 expression, which resulted in the decrease of NF-kappaB activity, iNOS expression, and NO production. Hence, ART might be an effective drug for diabetes. PMID- 26062522 TI - Potential impact of maternal vitamin D status on obstetric well-being. AB - Despite its discovery 100 years ago, vitamin D (VD) has emerged as one of the most controversial nutrients and prohormones of the 21st century. In the past few years, a growing interest in VD has been observed in the biomedical literature due to evidences demonstrating a relevant relationship not only between regulation of calcium and phosphorus homeostasis, but also multiple disease states and low VD status in the population. Indeed, several studies carried out to decipher its role in the body in almost every cell, tissue, and different organs. Recent findings suggested a significant implication of VD in different physiologic processes , such as vascular health, immune function, metabolism, and placental function. In the attempt to focus the attention on effect of VD on female reproductive health, there has been a paucity of data from randomized controlled trials to establish clear beneficial. Human and animal data suggest that low VD status is associated with impaired fertility, endometriosis, and polycystic ovary syndrome. Findings from observational studies show higher rates of preeclampsia, gestational diabetes, preterm birth, and bacterial vaginosis in women with low VD levels. By recent evidences, this review explored the association between maternal VD status and selected effects on maternal, perinatal, and infant health, and the impact of VD supplementation during pregnancy on obstetric well-being. PMID- 26062523 TI - IRX2-mediated upregulation of MMP-9 and VEGF in a PI3K/AKT-dependent manner. AB - Osteosarcoma (OS) is the most frequent type of primitive malignant bone tumor with a poor prognosis due to distant metastasis. Our previous studies have demonstrated that IRX2 is overexpressed and is important in cell proliferation and invasion. However, the molecular mechanisms underlying the IRX2-dependent regulation of OS progression remains to be elucidated. In the present study, the effects of IRX2 on the upregulation of MMP2 and VEGF in OS were determined by western blotting, and the underlying molecular mechanisms were elucidated. These findings provided data suggesting that IRX2 modulates the expression levels of MMP2 and VEGF in an AKT-dependent manner. The overexpression of IRX2 promoted the activation of PI3K/Akt and increased the proliferation and invasiveness of the OS cell lines as shown by CCK8 and invasion assays. Notably, interruption of the AKT pathway by treatment with LY294002, a specific PI3K inhibitor, attenuated IRX2 induced cell proliferation and invasive ability, and the upregulation of MMP2 and VEGF. The results of the present study suggested that inhibition of the IRX2 mediated AKT signaling pathway may be a suitable therapeutic target for the treatment of OS. PMID- 26062524 TI - Delayed-onset heparin-induced thrombocytopenia without thrombosis in a patient receiving postoperative thromboprophylaxis with rivaroxaban. PMID- 26062525 TI - CyberKnife stereotactic radiotherapy for isolated recurrence in the prostatic bed. AB - PURPOSE: To report a clinical experience of stereotactic body radiation therapy (SBRT) for isolated recurrence in the prostatic bed from prostate cancer. MATERIALS AND METHODS: Between November 2011 and November 2013, 16 patients were treated with SBRT for a macroscopic isolated recurrence of prostate cancer in the prostatic bed. All patients were initially treated with radical prostatectomy, and half of them also received radiotherapy. Two schedules of SBRT were used: 30 Gy in 5 fractions in previously irradiated patients, 35 Gy in five fractions in radiotherapy-naive patients. RESULTS: At a median follow-up of 10 months (range 2 21 months), a significant biochemical response was found in all but one patient. At imaging evaluation, no local progression was noted: 10 patients showed partial response while four stable disease. At the moment of analysis, all 16 patients were alive. Seven of them experienced distant relapse, while nine maintained biochemical control, with no further therapy. Median time to relapse was 9.3 months (range 3-15.2 months). The treatment was well tolerated: One patient experienced G2 acute genitourinary and gastrointestinal toxicity. CONCLUSIONS: Our experience shows that SBRT with CyberKnife for isolated nodal relapse is a safe and well-tolerated treatment. PMID- 26062527 TI - A novel nanoporous Fe-doped lithium manganese phosphate material with superior long-term cycling stability for lithium-ion batteries. AB - Here, we prepared LiMn0.8Fe0.2PO4 microspheres with an open three-dimensional nanoporous structure by a facile ion-exchange solvothermal method. The micro/nano structured material exhibits an ultralong cycle life, and retains a reversible capacity of 105 mA h g(-1) after 1000 cycles at 5 C, corresponding to the capacity retention of 94.0% and only 0.0068 mA h g(-1) loss per cycle. PMID- 26062526 TI - Treatment of Primary Progressive Aphasia. AB - OPINION STATEMENT: Primary progressive aphasia (PPA) is a neurodegenerative disease that primarily affects language functions and often begins in the fifth or sixth decade of life. The devastating effects on work and home life call for the investigation of treatment alternatives. In this paper, we present a review of the literature on treatment approaches for this neurodegenerative disease. We also present new data from two intervention studies we have conducted, a behavioral one and a neuromodulatory one using transcranial direct current stimulation (tDCS) combined with written production intervention. We show that speech-language intervention improves language outcomes in individuals with PPA, and especially in the short term, tDCS augments generalization and maintenance of positive language outcomes. We also outline current issues and challenges in intervention approaches in PPA. PMID- 26062528 TI - Perceived Stress and Professional Quality of Life in Neonatal Intensive Care Unit Nurses in Gujarat, India. AB - OBJECTIVE: To study the levels of perceived stress in Neonatal Intensive Care Unit (NICU) nurses and its association with professional quality of life domains viz. compassion satisfaction, burnout and secondary trauma. METHODS: In this multicenter, cross sectional study, data was collected by surveying 129 nurses from nine NICUs across six cities of Gujarat, India using demographic questionnaire, Perceived Stress Scale (PSS14) and Professional Quality of Life Scale (ProQOL5) during July to September 2013. Descriptive statistics, correlation coefficient and multiple regression were used for analysis. RESULTS: The mean (SD) age of participants was 28.37 (8.20) y. Most were single, satisfied with salary benefits and reported 'good' to 'excellent' relationships at work. The mean (SD) duration of duty hours was 8.12 (0.76) h and 43.6% were attending to more than 4 patients/shift. The mean (SD) perceived stress level was 22.19 (7.17) [Range: 3 to 39]. High compassion satisfaction, high burnout, and high secondary traumatic stress were reported by 25 (19.4%), 30 (23.3%) and 30 (23.3%) nurses respectively. PSS14 was negatively correlated with compassion satisfaction (r = -0.28) and positively correlated with burnout (r = 0.43) and secondary traumatic stress (r = 0.24). CONCLUSIONS: Most of the nurses (91, 70.5%) were identified as perceiving moderate to high stress. Professional quality of life domains correlated with perceived stress. There is further need to study domains influencing NICU nurses' professional QOL. Identifying stress and QOL issues in NICU nurses can help formulate relevant policies. PMID- 26062529 TI - Decolorization of acid and basic dyes: understanding the metabolic degradation and cell-induced adsorption/precipitation by Escherichia coli. AB - Escherichia coli strain DH5alpha was successfully employed in the decolorization of commercial anthraquinone and azo dyes, belonging to the general classes of acid or basic dyes. The bacteria showed an aptitude to survive at different pH values on any dye solution tested, and a rapid decolorization was obtained under aerobic conditions for the whole collection of dyes. A deep investigation about the mode of action of E. coli was carried out to demonstrate that dye decolorization mainly occurred via three different pathways, specifically bacterial induced precipitation, cell wall adsorption, and metabolism, whose weight was correlated with the chemical nature of the dye. In the case of basic azo dyes, an unexpected fast decolorization was observed after just 2-h postinoculation under aerobic conditions, suggesting that metabolism was the main mechanism involved in basic azo dye degradation, as unequivocally demonstrated by mass spectrometric analysis. The reductive cleavage of the azo group by E. coli on basic azo dyes was also further demonstrated by the inhibition of decolorization occurring when glucose was added to the dye solution. Moreover, no residual toxicity was found in the E. coli-treated basic azo dye solutions by performing Daphnia magna acute toxicity assays. The results of the present study demonstrated that E. coli can be simply exploited for its natural metabolic pathways, without applying any recombinant technology. The high versatility and adaptability of this bacterium could encourage its involvement in industrial bioremediation of textile and leather dyeing wastewaters. PMID- 26062530 TI - Response of rhizosphere microbial community structure and diversity to heavy metal co-pollution in arable soil. AB - Due to the emerging environmental issues related to heavy metals, concern about the soil quality of farming lands near manufacturing district is increasing. Investigating the function of soil microorganisms exposed to long-term heavy metal contamination is meaningful and important for agricultural soil utilization. This article studied the potential influence of several heavy metals on microbial biomass, activity, abundance, and community composition in arable soil near industrial estate in Zhuzhou, Hunan province, China. The results showed that soil organic contents (SOC) were significantly positive correlated with heavy metals, whereas dehydrogenase activity (DHA) was greatly depressed by the heavy metal stress. Negative correlation was found between heavy metals and basal soil respiration (BSR), and no correlation was found between heavy metals and microbial biomass content (MBC). The quantitative PCR (QPCR) and polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) analysis could suggest that heavy metal pollution has significantly decreased abundance of bacteria and fungi and also changed their community structure. The results could contribute to evaluate heavy metal pollution level in soil. By combining different environmental parameters, it would promote the better understanding of heavy metal effect on the size, structure, and activity of microbial community in arable soil. PMID- 26062531 TI - A novel chimeric flagellum fused with the multi-epitope vaccine CTB-UE prevents Helicobacter pylori-induced gastric cancer in a BALB/c mouse model. AB - Helicobacter pylori (H. pylori) infection causes peptic ulcers, gastric adenocarcinoma, and mucosa-associated lymphoid tissue (MALT) lymphoma. The eradication of H. pylori might be an effective means of preventing gastric cancer. A dual-antigen epitope and dual-adjuvant vaccine called CTB-UE-CF (CCF) was constructed by combining a multi-epitope vaccine CTB-UE with a novel chimeric flagellum (CF) to simultaneously activate Toll-like receptor (TLR) 5-agonist activity and preserve the immunogenicity of H. pylori flagellum FlaA. The evaluation of efficacy to reduce H. pylori colonization was performed using BALB/c mice by oral immunization with a triple dose of this vaccine strain. Two weeks after the last immunization, mice were sacrificed to determine specific antibody levels and proinflammatory cytokine production. To determine the presence of H. pylori, we detected the number of H. pylori by real-time quantitative PCR (qPCR) and measured the urease activity in the gastric tissue. The results showed that the immunogenicity and mucosal immune responses of CCF performed significantly better than those of CTB-UE. This dual-antigen epitope and dual-adjuvant system might greatly contribute to the development of a safe and efficient therapeutic vaccine for humans against H. pylori infection. PMID- 26062532 TI - Transcriptome analysis of acetic-acid-treated yeast cells identifies a large set of genes whose overexpression or deletion enhances acetic acid tolerance. AB - Acetic acid inhibits the metabolic activities of Saccharomyces cerevisiae. Therefore, a better understanding of how S. cerevisiae cells acquire the tolerance to acetic acid is of importance to develop robust yeast strains to be used in industry. To do this, we examined the transcriptional changes that occur at 12 h post-exposure to acetic acid, revealing that 56 and 58 genes were upregulated and downregulated, respectively. Functional categorization of them revealed that 22 protein synthesis genes and 14 stress response genes constituted the largest portion of the upregulated and downregulated genes, respectively. To evaluate the association of the regulated genes with acetic acid tolerance, 3 upregulated genes (DBP2, ASC1, and GND1) were selected among 34 non-protein synthesis genes, and 54 viable mutants individually deleted for the downregulated genes were retrieved from the non-essential haploid deletion library. Strains overexpressing ASC1 and GND1 displayed enhanced tolerance to acetic acid, whereas a strain overexpressing DBP2 was sensitive. Fifty of 54 deletion mutants displayed enhanced acetic acid tolerance. Three chosen deletion mutants (hsps82Delta, ato2Delta, and ssa3Delta) were also tolerant to benzoic acid but not propionic and sorbic acids. Moreover, all those five (two overexpressing and three deleted) strains were more efficient in proton efflux and lower in membrane permeability and internal hydrogen peroxide content than controls. Individually or in combination, those physiological changes are likely to contribute at least in part to enhanced acetic acid tolerance. Overall, information of our transcriptional profile was very useful to identify molecular factors associated with acetic acid tolerance. PMID- 26062533 TI - Conditions for supplemental biogenic substrates to enhance activated sludge degradation of xenobiotic. AB - The effects of biogenic presence on the degradation of xenobiotic organics by natural microbial populations have been reported as either advantageous or disadvantageous. The inconsistency of the reports implies there could be a turning point from disadvantageous to advantageous outcomes so that conditions may exist that could bring an optimum advantage. This study tested the supplementations of varying concentrations of sucrose and peptone, separately and combined, to acclimated activated sludge degradation of xenobiotic 2,4-D, while other operational and microbiological conditions were held constant. Our test results showed that biogenic may indeed enhance or slow down xenobiotic degradation rates. The highest enhancements exist at concentrations of 50 and 80 mg/L, respectively, for sucrose and peptone when supplemented separately, and 20 mg/L sucrose and 40 mg/L peptone combined. Conditions for advantageous biogenic supplementation were identified for activated sludge degradation of a xenobiotic; specifically, the highest degradation rate enhancements occurred when biogenic supplementation was approximately 0.5 to 0.7 the concentration of 2,4-D base on chemical oxygen demand (COD), which brought a biomass yield of approximately double that yielded by 2,4-D. Kinetics analyses provided clues for the possible causes of advantageous and disadvantageous effects due to biogenic supplementation. PMID- 26062534 TI - Improving heterologous polyketide production in Escherichia coli by transporter engineering. AB - Expelling heterologous compounds out of hosts by transporters is a potential strategy to enhance product titers in microbial cell factories. In this work, to increase heterologous polyketide 6-deoxyerythronolide B (6dEB, erythromycin precursor) production, tripartite multidrug efflux pumps MacAB-TolC, AcrAB-TolC, MdtEF-TolC, and MexAB-OprM were modulated in a 6dEB production strain. Compared with the control, overexpression of a single component of efflux pumps (except oprM) repressed 6dEB production, but modulation of two components MacA and MacB or the complete pumps MacAB-TolC and MdtEF-TolC significantly improved 6dEB titer by 100 +/- 11, 118 +/- 54, and 98 +/- 12 %, respectively. In addition, to avoid the challenging fine-tuning components of pumps, the transcriptional regulators of efflux pumps were modulated to improve the 6dEB production. Overexpression of RpoH (activator of MdtEF-TolC) and EvgA (activator of EmrKY-TolC and AcrAD-TolC) strongly increased 6dEB titer by 152 +/- 54 and 142 +/- 85 %, respectively. This is the first report of transporter engineering for improving heterologous polyketide production in Escherichia coli. Our results provide an effective strategy for improving the yield of the heterologous products in chassis cell. PMID- 26062535 TI - Expression of CotA laccase in Pichia pastoris and its electrocatalytic sensing application for hydrogen peroxide. AB - The CotA laccase from Bacillus subtilis WD23 was successfully overexpressed in Pichia pastoris, and the production level reached 891.2 U/L. The recombinant CotA laccase was purified to homogeneity. The optimal enzymatic activity was found at pH 4.6, 6.6, and 6.8 for 2, 2'-azino-bis (3-ethylbenzothiazoline-6-sulfonate) (ABTS), 4-hydroxy-3, 5-dimethoxybenzaldehyde azine (SGZ), and 2, 6 dimethoxyphenol (2, 6-DMP) oxidation, respectively. The maximal enzyme activity was observed at 80 degrees C with SGZ as a substrate. The kinetic constant K m values for ABTS, SGZ, and 2, 6-DMP were 162 +/- 20, 24 +/- 2, and 166 +/- 18 MUM, respectively, with corresponding k cat values of 15 +/- 1.0, 7.6 +/- 1.5, and 0.87 +/- 0.1 s(-1). Remarkably, the laccase activity increased to 561.9 % of its initial activity at pH 9.0 after 7 days of incubation and the half-life of laccase inactivation was approximately 3 h at 80 degrees C, which indicated that the recombinant CotA was a highly thermo-alkali-stable laccase. Bioelectrocatalytic reduction of H2O2 by the CotA laccase was detected when the recombinant CotA was adsorbed on pyrogenation graphite electrodes. Based on the bioelectrocatalytic reduction, a mediator-free amperometric biosensor for hydrogen peroxide was designed. The linear range of the H2O2 biosensor was from 0.05 to 4.75 mM, with a detection limit of 3.1 MUM. The amperometric biosensor for H2O2 by CotA-modified electrode is a novel application for CotA laccase. PMID- 26062536 TI - Experimental application of Lactobacillus fermentum CCM 7421 in combination with chlorophyllin in dogs. AB - Chlorophyll belongs in a larger class of phytochemical plant pigments currently receiving more attention as a physiologically active dietary component. Although most research has focused on its biological activities such as its antioxidant, antimutagenic, anti-inflammatory or apoptotic effects in humans or rodents, there is limited knowledge at this time about the combinative possibilities of chlorophyll with probiotic bacteria. Our aim was to test the growth characteristics of canine-derived probiotic strain Lactobacillus fermentum CCM 7421 in the presence of different concentrations of chlorophyllin in vitro. Antimicrobial activity of chlorophyllin against canine indicator bacteria was also detected. In the in vivo study, chlorophyllin, L. fermentum CCM 7421 and the combination of both additives on faecal microbiota, faecal organic acid concentrations, haematological and immunological parameters in dogs were tested. Forty dogs were divided into 4 treatment groups; control (C); receiving chlorophyllin (60 mg/day/dog, CH group); L. fermentum CCM 7421 (10(8) CFU/day/dog, LF group); and both additives (CH + LF group), 10 dogs in each group. The experiment lasted for 28 days with a 14-day treatment period (sample collection at days 0, 7, 14 and 28). Results showed no growth inhibition of strain CCM 7421 by 0.05-0.25 % of chlorophyllin in broth after 24 h. Reduced growth of staphylococci, Listeria monocytogenes and Citrobacter freundii was observed at 1 % chlorophyllin (P < 0.05). In dogs, lower coliform bacteria numbers and higher concentration of propionic acid in faeces of the CH group during the treatment compared to baseline were detected (P < 0.01). Phagocytic activity of leukocytes was stimulated in all three treated groups of dogs (P < 0.05). PMID- 26062537 TI - Cost effectiveness of lanthanum carbonate in chronic kidney disease patients in Spain before and during dialysis. AB - AIMS: In Spain, the first line treatment of hyperphosphatemia in Chronic Kidney Disease (CKD) consists of calcium-based phosphate binders (CB). However, their use is associated with vascular calcification and an increased mortality risk. The aim of this study was to assess the incremental cost-effectiveness of second line Lanthanum Carbonate (LC) treatment in patients not responding to CB (calcium carbonate and calcium acetate). MATERIAL AND METHODS: A lifetime Markov model was developed considering three health states (predialysis, dialysis and death). Transitions between states and efficacy data were obtained from randomized clinical trials and the European Dialysis and Transplant Association Annual report. Mortality rate was adjusted with the relative risk related to serum phosphorus levels. According to the Spanish healthcare system perspective, only medical direct costs were considered. Dialysis costs (2013 prices in Euros) were obtained from diagnosis-related groups. Drug costs were derived from ex-factory prices, adjusted with 7.5% mandatory rebate. Quality of life estimates were based on a published systematic review. Costs and benefits were discounted at 3%. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: At the end of simulation, costs per patient with LC therapy were 1,169 and 5,044 with CB alone. 4.653 Quality Adjusted Life Years (QALYs) were gained per patient treated with LC, and 4.579 QALYs with CB. CB therapy is dominated by the LC strategy (i.e. lower costs, higher QALYs). Assuming a 30,000/QALY threshold, LC was dominant in 100% of PSA simulations. CONCLUSIONS: LC is a cost-effective second line treatment of hyperphosphatemia in CKD patients irrespective of dialysis status in Spain. PMID- 26062538 TI - Paying for the quantity and quality of hospital care: the foundations and evolution of payment policy in England. AB - Prospective payment arrangements are now the main form of hospital funding in most developed countries. An essential component of such arrangements is the classification system used to differentiate patients according to their expected resource requirements. In this article we describe the evolution and structure of Healthcare Resource Groups (HRGs) in England and the way in which costs are calculated for patients allocated to each HRG. We then describe how payments are made, how policy has evolved to incentivise improvements in quality, and how prospective payment is being applied outside hospital settings. PMID- 26062539 TI - Room-temperature acetylene hydration by a Hg(II)-laced metal-organic framework. AB - Thiol (-SH) groups within a Zr(IV)-based metal-organic framework (MOF) anchor Hg(II) atoms; oxidation by H2O2 then leads to acidic sulfonate functions for catalyzing acetylene hydration at room temperature. PMID- 26062540 TI - Maintenance therapy with toceranib following doxorubicin-based chemotherapy for canine splenic hemangiosarcoma. AB - BACKGROUND: Spenic hemangiosarcoma (HSA) in dogs treated with surgery alone is associated with short survival times, and the addition of doxorubicin (DOX) chemotherapy only modestly improves outcome. The purpose of this study was to evaluate the impact of toceranib administration on progression free survival in dogs with stage I or II HSA following splenectomy and single agent DOX chemotherapy. We hypothesized that dogs with splenic HSA treated with adjuvant DOX followed by toceranib would have prolonged disease-free interval (DFI) and overall survival time (OS) when compared to historical dogs treated with DOX based chemotherapy alone. RESULTS: Dogs with stage I or II splenic HSA were administered 5 cycles of single-agent DOX every 2 weeks beginning within 14 days of splenectomy. Dogs were restaged 2 weeks after completing DOX, and those without evidence of metastatic disease began toceranib therapy at 3.25 mg/kg every other day. Forty-three dogs were enrolled in this clinical trial. Seven dogs had evidence of metastatic disease either before or at re-staging, and an additional 3 dogs were found to have metastatic disease within 1 week of toceranib administration. Therefore 31 dogs went on to receive toceranib following completion of doxorubicin treatment. Twenty-five dogs that received toceranib developed metastatic disease. The median disease free interval for all dogs enrolled in this study (n = 43) was 138 days, and the median disease free interval for those dogs that went on to receive toceranib (n = 31) was 161 days. The median survival time for all dogs enrolled in this study was 169 days, and the median survival time for those dogs that went on to receive toceranib was 172 days. CONCLUSIONS: The use of toceranib following DOX chemotherapy does not improve either disease free interval or overall survival in dogs with stage I or II HSA. PMID- 26062541 TI - High mobility group box 1 levels in large vessel vasculitis are not associated with disease activity but are influenced by age and statins. AB - INTRODUCTION: Takayasu arteritis (TA) and giant cell arteritis (GCA) are large vessel vasculitides (LVV) that usually present as granulomatous inflammation in arterial walls. High mobility group box 1 (HMGB1) is a nuclear protein that acts as an alarmin when released by dying or activated cells. This study aims to evaluate whether serum HMGB1 can be used as a biomarker in LVV. METHODS: Twenty nine consecutive TA patients with 29 healthy controls (HC) were evaluated in a cross-sectional study. Eighteen consecutive GCA patients with 16 HC were evaluated at the onset of disease and some of them during follow-up. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay. RESULTS: In GCA patients at disease onset mean serum HMGB1 levels did not differ from HC (5.74 +/ 4.19 ng/ml vs. 4.17 +/- 3.14 ng/ml; p = 0.230). No differences in HMGB1 levels were found between GCA patients with and without polymyalgia rheumatica (p = 0.167), ischemic manifestations (p = 0.873), systemic manifestations (p = 0.474) or relapsing disease (p = 0.608). During follow-up, no significant fluctuations on serum HMGB1 levels were observed from baseline to 3 months (n = 13) (p = 0.075), 12 months (n = 6) (p = 0.093) and at the first relapse (n = 4) (p = 0.202). Serum HMGB1 levels did not differ between TA patients and HC [1.19 (0.45 2.10) ng/ml vs. 1.46 (0.89-3.34) ng/ml; p = 0.181] and no difference was found between TA patients with active disease and in remission [1.31 (0.63-2.16) ng/ml vs. 0.75 (0.39-2.05) ng/ml; p = 0.281]. HMGB1 levels were significantly lower in 16 TA patients on statins compared with 13 patients without statins [0.59 (0.29 1.46) ng/ml vs. 1.93 (0.88-3.34) ng/ml; p = 0.019]. Age was independently associated with higher HMGB1 levels regardless of LVV or control status. CONCLUSIONS: Patients with TA and GCA present similar serum HMGB1 levels compared with HC. Serum HMGB1 is not useful to discriminate between active disease and remission. In TA, use of statins was associated with lower HMGB1 levels. HMGB1 is not a biomarker for LVV. PMID- 26062542 TI - Combinatorial optimization of synthetic operons for the microbial production of p coumaryl alcohol with Escherichia coli. AB - BACKGROUND: Microbes are extensively engineered to produce compounds of biotechnological or pharmaceutical interest. However, functional integration of synthetic pathways into the respective host cell metabolism and optimization of heterologous gene expression for achieving high product titers is still a challenging task. In this manuscript, we describe the optimization of a tetracistronic operon for the microbial production of the plant-derived phenylpropanoid p-coumaryl alcohol in Escherichia coli. RESULTS: Basis for the construction of a p-coumaryl alcohol producing strain was the development of Operon-PLICing as method for the rapid combinatorial assembly of synthetic operons. This method is based on the chemical cleavage reaction of phosphorothioate bonds in an iodine/ethanol solution to generate complementary, single-stranded overhangs and subsequent hybridization of multiple DNA-fragments. Furthermore, during the assembly of these DNA-fragments, Operon-PLICing offers the opportunity for balancing gene expression of all pathway genes on the level of translation for maximizing product titers by varying the spacing between the Shine-Dalgarno sequence and START codon. With Operon-PLICing, 81 different clones, each one carrying a different p-coumaryl alcohol operon, were individually constructed and screened for p-coumaryl alcohol formation within a few days. The absolute product titer of the best five variants ranged from 48 to 52 mg/L p-coumaryl alcohol without any further optimization of growth and production conditions. CONCLUSIONS: Operon-PLICing is sequence-independent and thus does not require any specific recognition or target sequences for enzymatic activities since all hybridization sites can be arbitrarily selected. In fact, after PCR-amplification, no endonucleases or ligases, frequently used in other methods, are needed. The modularity, simplicity and robustness of Operon-PLICing would be perfectly suited for an automation of cloning in the microtiter plate format. PMID- 26062543 TI - Did Bartonella henselae contribute to the deaths of two veterinarians? AB - Bartonella henselae, a flea-transmitted bacterium, causes chronic, zoonotic, blood stream infections in immunocompetent and immunocompromised patients throughout the world. As an intra-erythrocytic and endotheliotropic bacterium, B. henselae causes a spectrum of symptomatology ranging from asymptomatic bacteremia to fever, endocarditis and death. Veterinary workers are at occupational risk for acquiring bartonellosis. As an emerging, and incompletely understood, stealth bacterial pathogen, B. henselae may or may not have been responsible for the deaths of two veterinarians; however, recent evidence indicates that this genus is of much greater medical importance than is currently appreciated by the majority of the biomedical community. PMID- 26062545 TI - A prospective survey of critical care procedures performed by physicians in helicopter emergency medical service: is clinical exposure enough to stay proficient? AB - BACKGROUND: Physicians in prehospital care must be proficient in critical care procedures. Procedure proficiency requires a combination of training, experience and continuous clinical exposure. Most physicians in helicopter emergency medical service (HEMS) in Norway are well-trained and experienced anaesthesiologists, but we know little about their exposure to critical care procedures in the prehospital arena. This knowledge is required to plan clinical training and in hospital practice to maintain core competences for a HEMS physician. METHODS: We collected survey data on critical care procedures performed by physicians at three HEMS bases in Norway for a one-year period. To correct for differences in duty time between physicians, the expected number of procedures performed in a full time engagement at each HEMS base was calculated. Data was analysed using descriptive statistics and expected procedure volume at each base was compared using one-way between group analysis of variance. RESULTS: We received data from 82.7 % of the duty hours in the study period. Physicians at Oslo University Hospital HEMS had the highest volume of procedures in most categories and were expected to perform a majority of the procedures at least once a year. There were significant differences in procedure volume between the bases in 25 procedures. CONCLUSIONS: Physicians in Norwegian HEMS perform critical care procedures with variable frequencies. The low procedure volume in some cases and variance between bases indicate the need for a tailored procedure maintenance training and relevant in-hospital clinical practice. PMID- 26062544 TI - Hepato-protective effect of rutin via IL-6/STAT3 pathway in CCl4-induced hepatotoxicity in rats. AB - BACKGROUND: Carbon tetrachloride (CCl4) induces hepatotoxicity in animal models, including the increased blood flow and cytokine accumulation that are characteristic of tissue inflammation. The present study investigates the hepato protective effect of rutin on CCl4-induced hepatotoxicity in rats. RESULTS: Forty male Wistar rats were divided into four groups. Group I (control group) received 1 mL/kg of dimethyl sulfoxide intragastrically and 3 mL/kg olive oil intraperitoneally twice a week for 4 weeks. Group II received 70 mg/kg rutin intragastrically. Groups III and IV received CCl4 (3 mL/kg, 30 % in olive oil) intraperitoneally twice a week for 4 weeks. Group IV received 70 mg/kg rutin intragastrically after 48 h of CCl4 treatment. Liver enzyme levels were determined in all studied groups. Expression of the following genes were monitored with real-time PCR: interleukin-6 (IL-6), dual-specificity protein kinase 5 (MEK5), Fas-associated death domain protein (FADD), epidermal growth factor (EGF), signal transducer and activator of transcription 3 (STAT3), Janus kinase (JAK), B-cell lymphoma 2 (Bcl2) and B-cell lymphoma-extra-large (Bcl-XL). The CCl4 groups showed significant increases in biochemical markers of hepatotoxicity and up-regulation of expression levels of IL-6, Bcl-XL, MEK5, FADD, EGF, STAT3 and JAK compared with the control group. However, CCl4 administration resulted in significant down-regulation of Bcl2 expression compared with the control group. Interestingly, rutin supplementation completely reversed the biochemical markers of hepatotoxicity and the gene expression alterations induced by CCl4. CONCLUSION: CCl4 administration causes alteration in expression of IL-6/STAT3 pathway genes, resulting in hepatotoxicity. Rutin protects against CCl4-induced hepatotoxicity by reversing these expression changes. PMID- 26062546 TI - Novel antiviral activity of mung bean sprouts against respiratory syncytial virus and herpes simplex virus -1: an in vitro study on virally infected Vero and MRC-5 cell lines. AB - BACKGROUND: New sources for discovering novel antiviral agents are desperately needed. The current antiviral products are both expensive and not very effective. METHODS: The antiviral activity of methanol extract of mung bean sprouts (MBS), compared to Ribavarin and Acyclovir, on respiratory syncytial virus (RSV) and Herpes Simplex virus -1 (HSV-1) was investigated using cytotoxicity, virus yield reduction, virucidal activity, and prophylactic activity assays on Vero and MRC-5 cell lines. Moreover, the level of antiviral cytokines, IFNbeta, TNFalpha, IL-1, and IL-6 was assessed in MBS-treated, virally infected, virally infected MBS treated, and control groups of MRC-5 cells using ELISA. RESULTS: MBS extract showed reduction factors (RF) 2.2 * 10 and 0.5 * 10(2) for RSV and HSV-1, respectively. The 2 h incubation virucidal and prophylactic selectivity indices (SI) of MBS on RSV were 14.18 and 12.82 versus Ribavarin SI of 23.39 and 21.95, respectively, and on HSV-1, SI were 18.23 and 10.9 versus Acyclovir, 22.56 and 15.04, respectively. All SI values were >10 indicating that MBS has a good direct antiviral and prophylactic activities on both RSV and HSV-1. Moreover, interestingly, MBS extract induced vigorously IFNbeta, TNFalpha, IL-1, and IL-6 cytokines in MRC-5 infected-treated group far more than other groups (P < 0.05) and induced TNFalpha and IL-6 in treated group more than infected group (P < 0.05). CONCLUSIONS: MBS extract has potent antiviral and to a lesser extent, prophylactic activities against both RSV and HSV-1, and in case of HSV-1, these activities were comparable to Acyclovir. Part of the underlying mechanism(s) of these activities is attributed to MBS potential to remarkably induce antiviral cytokines in human cells. Hence, we infer that MBS methanol extract could be used as such or as purified active component in protecting and treating RSV and HSV-1 infections. More studies are needed to pinpoint the exact active components responsible for the MBS antiviral activities. PMID- 26062547 TI - Role of viscogens on the macromolecular assemblies of fibrinogen at liquid/air and solid/air interfaces. AB - In this study, an attempt has been made to understand the organization and association of fibrinogen (Fg) in solvent environment induced by viscogens such as 1-ethyl 3-methyl imidazolium ethyl sulfate (IL-emes), Ficoll, and Trehalose. The author observed that Fg in IL-emes adsorbed on solid surface shows higher beta-sheet conformation. Shear viscosity measured using quartz crystal microbalance, for Fg in IL-emes was highest with a corresponding higher adsorbed mass 3.26 MUg/cm(2). Associated assemblies of the protein at the liquid/air interface were monitored with changes in surface tension and were used to calculate work of adhesion. Changes in work of adhesion were used as a tool to measure the adsorption of Fg to solid surfaces in presence of viscogens and highest adsorption was observed for hydrophilic surfaces. Scanning electron microscopy images show Fg in trehalose forms elongated bead like structures implying organization of the protein at the interface. Crowding in the solvent environment induced by viscogens can slow down organization of Fg, leading to macromolecular assemblies near the interface. PMID- 26062548 TI - A composite genome approach to identify phylogenetically informative data from next-generation sequencing. AB - BACKGROUND: Improvements in sequencing technology now allow easy acquisition of large datasets; however, analyzing these data for phylogenetics can be challenging. We have developed a novel method to rapidly obtain homologous genomic data for phylogenetics directly from next-generation sequencing reads without the use of a reference genome. This software, called SISRS, avoids the time consuming steps of de novo whole genome assembly, multiple genome alignment, and annotation. RESULTS: For simulations SISRS is able to identify large numbers of loci containing variable sites with phylogenetic signal. For genomic data from apes, SISRS identified thousands of variable sites, from which we produced an accurate phylogeny. Finally, we used SISRS to identify phylogenetic markers that we used to estimate the phylogeny of placental mammals. We recovered eight phylogenies that resolved the basal relationships among mammals using datasets with different levels of missing data. The three alternate resolutions of the basal relationships are consistent with the major hypotheses for the relationships among mammals, all of which have been supported previously by different molecular datasets. CONCLUSIONS: SISRS has the potential to transform phylogenetic research. This method eliminates the need for expensive marker development in many studies by using whole genome shotgun sequence data directly. SISRS is open source and freely available at https://github.com/rachelss/SISRS/releases. PMID- 26062550 TI - Manchester expands seven day general practice to three million people. PMID- 26062549 TI - Dynamic expressions of monocyte chemo attractant protein-1 and CC chamomile receptor 2 after balloon injury and their effects in intimal proliferation. AB - OBJECTIVE: The dynamic expressions of monocyte chemo attractant protein-1 (MCP-1) and CC chamomile receptor 2 (CCR2) after balloon injury and their effects in intimal proliferation were discussed. In this study, the expression of MCP-1 and its receptor during the intimal proliferation in rat artery after balloon injury were studied. METHODS: Using the model of balloon injury of rats' arteries, the changes of intimal proliferation were observed with optical microscopy and the expressions of MCP-1 and CCR2 at different times were examined with the methods of RT-PCR and immunohistochemistry. The expressions of MCP-1 and CCR2 in the arterial tissues were detected using reverse transcription polymerase chain reaction (RT-PCR) and analyzed by semi-quantitative method. RESULTS: The expressions of MCP-1 and CCR2 mRNA began to gradually increase after balloon injury. The MCP-1 reached to the peak on the first day, but decreased gradually later on. Expressions of CCR2 mRNA began to increase on the first day and reached to the peak on the 7th day, but then started to decrease gradually until 28th day when we can still detect it. The expressions of MCP-1 proteins began to increase gradually after balloon injury and were obviously detected in the VSMC on the 4th and 7th day, until 14th day when we can still detect it clearly in the proliferating intima. CONCLUSION: The dynamic expressions of MCP-1, MCP-1 proteins and CCR2 mRNA after balloon injury were shown to play an important role in intimal proliferation. PMID- 26062551 TI - Vitamin D Promotes Odontogenic Differentiation of Human Dental Pulp Cells via ERK Activation. AB - The active metabolite of vitamin D such as 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3) is a well-known key regulatory factor in bone metabolism. However, little is known about the potential of vitamin D as an odontogenic inducer in human dental pulp cells (HDPCs) in vitro. The purpose of this study was to evaluate the effect of vitamin D3 metabolite, 1alpha,25(OH)2D3, on odontoblastic differentiation in HDPCs. HDPCs extracted from maxillary supernumerary incisors and third molars were directly cultured with 1alpha,25(OH)2D3 in the absence of differentiation-inducing factors. Treatment of HDPCs with 1alpha,25(OH)2D3 at a concentration of 10 nM or 100 nM significantly upregulated the expression of dentin sialophosphoprotein (DSPP) and dentin matrix protein1 (DMP1), the odontogenesis-related genes. Also, 1alpha,25(OH)2D3 enhanced the alkaline phosphatase (ALP) activity and mineralization in HDPCs. In addition, 1alpha,25(OH)2D3 induced activation of extracellular signal-regulated kinases (ERKs), whereas the ERK inhibitor U0126 ameliorated the upregulation of DSPP and DMP1 and reduced the mineralization enhanced by 1alpha,25(OH)2D3. These results demonstrated that 1alpha,25(OH)2D3 promoted odontoblastic differentiation of HDPCs via modulating ERK activation. PMID- 26062552 TI - Identification of Protein Markers Specific for Papillary Renal Cell Carcinoma Using Imaging Mass Spectrometry. AB - Since the emergence of proteomics methods, many proteins specific for renal cell carcinoma (RCC) have been identified. Despite their usefulness for the specific diagnosis of RCC, such proteins do not provide spatial information on the diseased tissue. Therefore, the identification of cancer-specific proteins that include information on their specific location is needed. Recently, matrix assisted laser desorption ionization (MALDI) mass spectrometry (MS) based imaging mass spectrometry (IMS) has emerged as a new tool for the analysis of spatial distribution as well as identification of either proteins or small molecules in tissues. In this report, surgical tissue sections of papillary RCC were analyzed using MALDI-IMS. Statistical analysis revealed several discriminative cancer specific m/z-species between normal and diseased tissues. Among these m/z species, two particular proteins, S100A11 and ferritin light chain, which are specific for papillary RCC cancer regions, were successfully identified using LC MS/MS following protein extraction from independent RCC samples. The expressions of S100A11 and ferritin light chain were further validated by immunohistochemistry of human tissues and tissue microarrays (TMAs) of RCC. In conclusion, MALDI-IMS followed by LC-MS/MS analysis in human tissue identified that S100A11 and ferritin light chain are differentially expressed proteins in papillary RCC cancer regions. PMID- 26062553 TI - Quercetin Enhances Cisplatin Sensitivity of Human Osteosarcoma Cells by Modulating microRNA-217-KRAS Axis. AB - Quercetin can suppress osteosarcoma cell growth and metastasis. However, other effects of quercetin on osteosarcoma remain largely unknown. This research aims to evaluate the effects of quercetin in combination with cisplatin as treatment for osteosarcoma and investigate its regulatory mechanism. Cell viability and apoptosis in 143B cell line were determined after treatment with quercetin and/or cisplatin. RT-PCR and Western blot analysis were performed to determine the RNA or protein expression levels. Moreover, transwell assay was used to evaluate metastasis. Furthermore, rescue experiments were performed to investigate the potential regulatory mechanism of the treatment. Results showed that quercetin with concentration that was equal to or greater than 10 MUM inhibited 143B proliferation, while 5 MUM quercetin enhanced the cisplatin sensitivity of 143B cells. Expression of miR-217 was upregulated after quercetin and/or cisplatin treatment, while its target KRAS was downregulated both at mRNA and protein levels. MiR-217 knockdown led to the loss of enhanced cisplatin sensitivity while miR-217 overexpression showed the opposite effects, indicating that quercetin regulated cisplatin sensitivity by modulating the miR-217-KRAS axis. In conclusion, 5 MUM quercetin enhanced the cisplatin sensitivity by modulating the miR-217-KRAS axis. This finding suggests that quercetin may be administered with cisplatin to improve the treatment for osteosarcoma. PMID- 26062555 TI - Traditional healing practices originating in Aruba, Bonaire, and Curacao: A review of the literature on psychiatry and Brua. AB - Brua is an Afro-Caribbean religion and healing tradition from the southern part of the former Netherlands Antilles. Like other Caribbean healing traditions, it plays a significant role in shaping how individuals experience and express disorders which Western health professionals consider to require psychiatric care. Because little has been published on Brua, and because patients from Aruba, Bonaire, and Curacao are often reluctant to discuss their commitment to this tradition, they are often misdiagnosed and either over- or undertreated by biomedically trained health professionals. The present paper provides a review of the literature on Brua and its relation to psychiatry. A systematic search was carried out in PubMed, the Ovid database, Google Scholar, and the historical literature. Our search yielded 35 texts on Brua, including three peer-reviewed scientific papers and eight academic theses. From those texts Brua emerges as a holistic patchwork of creolized beliefs and practices which are considered to be both cause and remedy for a wide variety of ailments. Despite the fact that tension between the Brua discourse and Western-oriented psychiatric practice is significant, adherence to Brua does not seem to cause much patient delay in help seeking. However, belief in Brua as a possible source of mental and physical complaints, as well as patients' frequent recourse to Brua practices, including the use of hallucinogens, may affect the diagnosis and treatment of mental disorders. PMID- 26062554 TI - Enhanced Healing of Rat Calvarial Bone Defects with Hypoxic Conditioned Medium from Mesenchymal Stem Cells through Increased Endogenous Stem Cell Migration via Regulation of ICAM-1 Targeted-microRNA-221. AB - The use of conditioned medium from mesenchymal stem cells may be a feasible approach for regeneration of bone defects through secretion of various components of mesenchymal stem cells such as cytokines, chemokines, and growth factors. Mesenchymal stem cells secrete and accumulate multiple factors in conditioned medium under specific physiological conditions. In this study, we investigated whether the conditioned medium collected under hypoxic condition could effectively influence bone regeneration through enhanced migration and adhesion of endogenous mesenchymal stem cells. Cell migration and adhesion abilities were increased through overexpression of intercellular adhesion molecule-1 in hypoxic conditioned medium treated group. Intercellular adhesion molecule-1 was upregulated by microRNA-221 in mesenchymal stem cells because microRNAs are key regulators of various biological functions via gene expression. To investigate the effects in vivo, evaluation of bone regeneration by computed tomography and histological assays revealed that osteogenesis was enhanced in the hypoxic conditioned medium group relative to the other groups. These results suggest that behavioral changes of endogenous mesenchymal stem cells through microRNA-221 targeted-intercellular adhesion molecule-1 expression under hypoxic conditions may be a potential treatment for patients with bone defects. PMID- 26062556 TI - Live birth after autograft of ovarian tissue cryopreserved during childhood. AB - Ovarian insufficiency is a major long-term adverse event, following the administration of a myeloablative conditioning regimen, and occurring in >80% of children and adolescents receiving such treatment for malignant or non-malignant disease. Cryopreservation of ovarian tissue is currently offered to preserve the fertility of these young patients. At least 35 live births have been reported after transplantation of cryopreserved ovarian tissue in adult patients, but the procedure remains unproven for ovarian tissue harvested at a prepubertal or pubertal age. We report here the first live birth after autograft of cryopreserved ovarian tissue in a woman with primary ovarian failure after a myeloablative conditioning regimen as part of a hematopoietic stem cell transplantation performed for homozygous sickle-cell anemia at age 14 years. This first report of successful fertility restoration after the graft of ovarian tissue cryopreserved before menarche offers reassuring evidence for the feasibility of the procedure when performed during childhood. PMID- 26062557 TI - Metformin's Intrinsic Blood-to-Plasma Partition Ratio (B/P): Reconciling the Perceived High In Vivo B/P > 10 with the In Vitro Equilibrium Value of Unity. AB - Blood cells are considered an important distributional compartment for metformin based on the high blood-to-plasma partition ratio (B/P) in humans (>10 at Cmin). However, literature reports of metformin's intrinsic in vitro B/P values are lacking. At present, the extent and rate of metformin cellular partitioning was determined in incubations of fresh human and rat blood with [(14)C]metformin for up to 1 week at concentrations spanning steady-state plasma Cmin, Cmax, and a concentration associated with lactic acidosis. The results showed that metformin's intrinsic equilibrium B/P was ~0.8-1.4 in blood, which is <10% of the reported clinical value. Kinetics of metformin partitioning into human blood cells and repartitioning back into plasma were slow (repartitioning half-life ~32 39 hours). These data, along with in vivo rapid and efficient renal clearance of plasma metformin (plasma renal extraction ratio ~90%-100%), explain why the clinical terminal half-life of metformin in plasma (6 hours) is 3- to 4-fold shorter than the half-life in whole blood (18 hours) and erythrocytes (23 hours). The rate constant for metformin repartitioning from blood cells to plasma (~0.02 h(-1)) is far slower than the clinical renal elimination rate constant (0.3 h( 1)). Blood distributional rate constants were incorporated into a metformin physiologically-based pharmacokinetic model, which predicted the differential elimination half-life in plasma and blood. The present study demonstrates that the extent of cellular drug partitioning in blood observed in a dynamic in vivo system may be very different from the static in vitro values when repartitioning from blood cells is far slower than clearance of drug in plasma. PMID- 26062558 TI - An In Vivo Method to Identify microRNA Targets Not Predicted by Computation Algorithms: p21 Targeting by miR-92a in Cancer. AB - microRNA (miRNA) dysregulation is involved in the development and progression of various human cancers, including hepatocellular carcinoma (HCC). However, how to identify the miRNAs targeting specific mRNA in cells is a significant challenge because of the interaction complexity and the limited knowledge of rules governing these processes. Some miRNAs are not predictable by current computer algorithms available. Here, using p21 mRNA as target, we established a new method, called miRNA in vivo precipitation (miRIP), to identify which kind of miRNAs can actually bind to the specific mRNA in cells. Several unpredictable miRNAs that bound p21 mRNA in HepG2 and PC-3 cells were identified by the miRIP method. Among these miRNAs identified by miRIP, miR-92a was found and confirmed to interact robustly with p21 mRNA, both in HepG2 and PC-3 cells. miR-92a was found to be remarkably increased in HCC tissues, and higher expression of miR-92a significantly correlated with lower expression of p21, which is related to poor survival of HCC patients. Moreover, inhibition of miR-92a could significantly suppress HCC growth in vitro and in vivo by upregulating p21. Together, miR-92a, which is identified by miRIP, is functionally shown to be associated with HCC growth as an oncogenic miRNA by inhibiting expression of targeting gene p21. In addition, several unpredictable miRNAs that target STAT3 mRNA were also identified by the miRIP method in HepG2 cells. Our results demonstrated that the miRIP approach can effectively identify the unpredictable but intracellular existing miRNAs that target specific mRNA in vivo. PMID- 26062559 TI - Outbreak of invasive pneumococcal disease at a Belfast shipyard in men exposed to welding fumes, Northern Ireland, April-May 2015: preliminary report. AB - We report an outbreak of four confirmed cases of invasive pneumococcal disease (IPD) in individuals occupationally exposed to welding fumes, at a Belfast shipyard (Northern Ireland). All cases were hospitalised. A high-risk sub-group of 679 workers has been targeted for antibiotic prophylaxis and pneumococcal vaccination. Physicians and public health institutions outside Northern Ireland should be alert to individuals presenting with pneumonia or IPD and recent links to the shipyard, to facilitate early assessment and treatment. PMID- 26062560 TI - A prolonged outbreak of invasive meningococcal disease in an extended Irish Traveller family across three Health Service Executive (HSE) areas in Ireland, 2010 to 2013. AB - Between March 2010 and November 2013 eight laboratory-confirmed cases of serogroup B, invasive meningococcal disease (IMD) were identified in an extended Irish Traveller family across three Health Service Executive (HSE) areas of Ireland. Cases were aged between 5 and 46 months, and were either a cousin or sibling of another case. All eight cases survived. Chemoprophylaxis was given to relevant nuclear family members and close contacts on each occasion, but failed to prevent further cases. Neisseria meningitidis isolates from six cases were highly related, belonging to the ST-41/44 clonal complex, and shared the porA designation 7-2,4. In November 2013, the outbreak control team recommended that directly observed ciprofloxacin chemoprophylaxis be administered simultaneously to the extended family, and that the four component meningococcal B (4CMenB) vaccine be administered to family members aged 2 months to 23 years inclusive and relevant close contacts of the eighth case. Subsequently these recommendations were implemented at three regional clinics. Additionally pharyngeal swabs (n=112) were collected to assess carriage rates of N. meningitidis in this extended family. Pharyngeal carriage of N. meningitidis was detected in 15 (13%) family members. From the epidemiological investigation and carriage study overcrowding was the most likely risk factor identified in this outbreak. To date, the combination of directly observed ciprofloxacin chemoprophylaxis and use of 4CMenB vaccine have controlled the outbreak with no further cases diagnosed. PMID- 26062561 TI - Genomic analyses of Francisella tularensis strains confirm disease transmission from drinking water sources, Turkey, 2008, 2009 and 2012. AB - Waterborne epidemics of tularaemia caused by Francisella tularensis are increasingly reported in Turkey. We have used whole genome sequencing to investigate if F. tularensis isolated from patients could be traced back to drinking water sources. Tonsil swabs from 33 patients diagnosed with oropharyngeal tularaemia in three outbreaks and 140 water specimens were analysed. F. tularensis subsp. holarctica was confirmed by microagglutination and PCR in 12 patients and five water specimens. Genomic analysis of three pairs of patient and water isolates from outbreaks in Sivas, Corum, and Kocaeli showed the isolates to belong to two new clusters of the F. tularensis B.12 genetic clade. The clusters were defined by 19 and 15 single nucleotide polymorphisms (SNPs) in a multiple alignment based on 507 F. tularensis genomes. One synonymous SNP was chosen as a new canonical SNP (canSNP) for each cluster for future use in diagnostic assays. No SNP was identified between the genomes from the patient water pair of isolates from Kocaeli, one SNP between the pair of isolates from Sivas, whereas the pair from Corum differed at seven SNPs. These results illustrate the power of whole genome sequencing for tracing F. tularensis patient isolates back to their environmental source. PMID- 26062562 TI - WHO member states adopt global action plan on antimicrobial resistance. PMID- 26062564 TI - Authors' correction for Euro Surveill. 2015;20(20). PMID- 26062563 TI - Erratum for Euro Surveill. 2015;20(19). PMID- 26062566 TI - Effect of ibandronate on bending strength and toughness of rodent cortical bone: Possible implications for fracture prevention. AB - OBJECTIVES: There remains conflicting evidence regarding cortical bone strength following bisphosphonate therapy. As part of a study to assess the effects of bisphosphonate treatment on the healing of rat tibial fractures, the mechanical properties and radiological density of the uninjured contralateral tibia was assessed. METHODS: Skeletally mature aged rats were used. A total of 14 rats received 1ug/kg ibandronate (iban) daily and 17 rats received 1 ml 0.9% sodium chloride (control) daily. Stress at failure and toughness of the tibial diaphysis were calculated following four-point bending tests. RESULTS: Uninjured cortical bone in the iban group had a significantly greater mean (standard deviation (sd)), p < 0.001, stress at failure of 219.2 MPa (sd 45.99) compared with the control group (169.46 MPa (sd 43.32)) following only nine weeks of therapy. Despite this, the cortical bone toughness and work to failure was similar. There was no significant difference in radiological density or physical dimensions of the cortical bone. CONCLUSIONS: Iban therapy increases the stress at failure of uninjured cortical bone. This has relevance when normalising the strength of repair in a limb when comparing it with the unfractured limb. However, the 20% increase in stress at failure with iban therapy needs to be interpreted with caution as there was no corresponding increase in toughness or work to failure. Further research is required in this area, especially with the increasing clinical burden of low-energy diaphyseal femoral fractures following prolonged use of bisphosphonates. Cite this article: Bone Joint Res 2015;4:99-104. PMID- 26062567 TI - Sarcocystis calchasi encephalitis in a rock pigeon. AB - A rock pigeon (Columba livia) caught in Akihabara, Tokyo, showed neurological symptoms, such as head tilt and circling. Pathological examinations revealed abundant Sarcocystic cysts in the skeletal muscle and myocardium with mild myositis, and numerous schizonts and sarcocysts with severe multifocal granulomatous T-lymphocytic infiltration in the central nervous system. A Sarcocystis calchasi-specific gene was detected in the muscle and brain. This case indicates S. calchasi was distributed in Japan and caused severe encephalitis to rock pigeons. PMID- 26062568 TI - Acquired Fanconi syndrome in a dog exposed to jerky treats in Japan. AB - A 6-year-old spayed female Jack Russell Terrier presented with a 1-month history of lethargy, anorexia, vomiting and weight loss. The dog was fed beef and chicken jerky treats daily in addition to a commercial diet. Laboratory tests revealed azotemia, hypokalemia, hyperchloremia, metabolic acidosis and glucosuria with normoglycemia. Urine amino acid analysis showed significant amino acid loss into the urine. Thus, Fanconi syndrome was diagnosed, and based on the case history and extensive diagnostic testing, excessive consumption of jerky treats was strongly suspected as the cause. Glucosuria resolved 7 days after the withdrawal of jerky treats and fluid therapy. Aminoaciduria was substantially, but not completely, improved 3 months after diagnosis. Mild azotemia remained, suggesting chronic renal disease. To the best of our knowledge, this is the first reported case of Fanconi syndrome following the consumption of jerky treats in Japan. PMID- 26062569 TI - The therapeutic effects of SET/I2PP2A inhibitors on canine melanoma. AB - Canine melanoma is one of the most important diseases in small animal medicine. Protein phosphatase 2A (PP2A), a well conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. SET/I2PP2A is an endogenous inhibitor for PP2A, which directly binds to PP2A and suppresses its phosphatase activity. Elevated SET protein levels have been reported to exacerbate human tumor progression. The role of SET in canine melanoma, however, has not been understood. Here, we investigated the potential therapeutic role for SET inhibitors in canine melanoma. The expression of SET protein was observed in 6 canine melanoma cell lines. We used CMeC-1 cells (primary origin) and CMeC-2 cells (metastatic origin) to generate cell lines stably expressing SET-targeting shRNAs. Knockdown of SET expression in CMeC-2, but not in CMeC-1, leads to decreased cell proliferation, invasion and colony formation. Phosphorylation level of p70 S6 kinase was decreased by SET knockdown in CMeC-2, suggesting the involvement of mTOR (mammalian target of rapamycin)/p70 S6 kinase signaling. The SET inhibitors, OP449 and FTY720, more effectively killed CMeC-2 than CMeC-1. We observed PP2A activation in CMeC-2 treated with OP449 and FTY720. These results demonstrated the potential therapeutic application of SET inhibitors for canine melanoma. PMID- 26062570 TI - Contextual socioeconomic factors associated with childhood mortality in Nigeria: a multilevel analysis. AB - BACKGROUND: Childhood mortality is a well-known public health issue, particularly in the low and middle income countries. The overarching aim of this study was to examine whether neighbourhood socioeconomic disadvantage is associated with childhood mortality beyond individual-level measures of socioeconomic status in Nigeria. METHODS: Multilevel logistic regression models were applied to data on 31 482 under-five children whether alive or dead (level 1) nested within 896 neighbourhoods (level 2) from the 37 states in Nigeria (level 3) using the most recent 2013 Nigeria Demographic and Health Survey (DHS). RESULTS: More than 1 of every 10 children studied had died before reaching the age of 5 years (130/1000 live births). The following factors independently increased the odds of childhood mortality: male sex, mother's age at 15-24 years, uneducated mother or low maternal education attainment, decreasing household wealth index at individual level (level 1), residing in rural area and neighbourhoods with high poverty rate at level 2. There were significant neighbourhoods and states clustering in childhood mortality in Nigeria. CONCLUSIONS: The study provides evidence that individual-level and neighbourhood-level socioeconomic conditions are important correlates of childhood mortality in Nigeria. The findings of this study also highlight the need to implement public health prevention strategies at the individual level, as well as at the area/neighbourhood level. These strategies include the establishment of an effective publicly funded healthcare system, as well as health education and poverty alleviation programmes. PMID- 26062571 TI - Fibronectin extradomain A: balancing atherosclerotic plaque burden and stability. PMID- 26062572 TI - Stereotactic Radiosurgery for Metastases in Eloquent Central Brain Locations. AB - BACKGROUND: To examine stereotactic radiosurgery (SRS) following whole brain radiotherapy for metastases in eloquent, central brain locations: brainstem, thalamus, and basal ganglia. METHODS: We conducted a retrospective review of patients with metastases in eloquent, central brain locations who were treated with SRS between January 2000 and April 2012. All patients had whole brain radiotherapy. Patients eligible for SRS had one to three brain metastases, metastasis size <=4 cm, and Karnofsky performance status >=70. Local progression free survival and overall survival were calculated using the Kaplan-Meier method. RESULTS: For 24 patients, the median age was 50 years (range, 36-73). Metastases by location were: 11 brainstem, 9 thalamus, and 5 basal ganglia. The median metastasis size was 15 mm (range, 2-33) and the median SRS dose prescription was 15 Gy (range, 12-24). The median local progression-free survival was 13.7 months and median overall survival was 16.4 months. Compared with a cohort of 188 patients with noneloquent brain metastases receiving a median dose of 24 Gy, overall survival of 10.8 months was not significantly different (p=0.16). The only symptomatic complication was grade 2 headache in 8.3%. Asymptomatic adverse radiologic events were radionecrosis in two (8.3%), peritumoural edema in four (16.7%), and hemorrhage in one patient (4.2%). CONCLUSIONS: Lower SRS marginal doses do not appear to compromise survival in patients with eloquently located brain metastases compared with higher doses for other brain metastases, with minimal symptomatic complications. PMID- 26062573 TI - Knowledge of advance directive and perceptions of end-of-life care in Chinese American elders: The role of acculturation. AB - OBJECTIVE: This study aimed to describe knowledge of an advance directive (AD) and preferences regarding end-of-life (EoL) care communication, decision making, and designation of surrogates in Chinese-American elders and to examine the role of acculturation variables in AD awareness. METHOD: Survey data were collected through face-to-face interviews on a sample of 385 Chinese-American elders aged 55 or above living in the Phoenix metropolitan area. The choice of language (Mandarin, Cantonese, or English) and place of interview (senior apartments, Chinese senior centers, or homes) was at the respondent's preference. Hierarchical logistic regression analysis was employed to examine the influence of acculturation variables on AD awareness. RESULTS: Some 21% of participants had heard about ADs, and only 10% had completed one. Elders with higher acculturation levels (OR = 1.04, p < 0.10) and those residing more than 20 years in the United States (OR = 6.87, p < 0.01) were more likely to be aware of ADs after controlling for the effects of demographics, health, and experiences of EoL care. The majority preferred physicians to initiate AD discussions (84.9%) and identified burdens on families as the most important factor in making EoL decisions (89.3%). About 55.1 % considered daughters as the preferred healthcare surrogate. SIGNIFICANCE OF RESULTS: Acculturation levels influence awareness of an AD, and family values are crucial in EoL care decision making. Cultural factors should be considered in designing and delivering appropriate programs to promote knowledge of EoL care among Chinese-American elders and their families. PMID- 26062574 TI - Whole-grain foods and chronic disease: evidence from epidemiological and intervention studies. AB - Cereal-based foods are key components of the diet and they dominate most food based dietary recommendations in order to achieve targets for intake of carbohydrate, protein and dietary fibre. Processing (milling) of grains to produce refined grain products removes key nutrients and phytochemicals from the flour and although in some countries nutrients may be replaced with mandatory fortification, overall this refinement reduces their potential nutritional quality. There is increasing evidence from both observational and intervention studies that increased intake of less-refined, whole-grain (WG) foods has positive health benefits. The highest WG consumers are consistently shown to have lower risk of developing CVD, type 2 diabetes and some cancers. WG consumers may also have better digestive health and are likely to have lower BMI and gain less weight over time. The bulk of the evidence for the benefits of WG comes from observational studies, but evidence of benefit in intervention studies and potential mechanisms of action is increasing. Overall this evidence supports the promotion of WG foods over refined grain foods in the diet, but this would require adoption of standard definitions of 'whole grain' and 'whole-grain foods' which will enable innovation by food manufacturers, provide clarity for the consumer and encourage the implementation of food-based dietary recommendations and public health strategies. PMID- 26062577 TI - beta-elemene enhances both radiosensitivity and chemosensitivity of glioblastoma cells through the inhibition of the ATM signaling pathway. AB - Glioblastoma multiforme (GBM), a tumor associated with poor prognosis, is known to be resistant to radiotherapy and alkylating agents such as temozolomide (TMZ). beta-elemene, a monomer found in Chinese traditional herbs extracted from Curcuma wenyujin, is currently being used as an antitumor drug for different types of tumors including GBM. In the present study, we investigated the roles of beta elemene in the radiosensitivity and chemosensitivity of GBM cells. Human GBM cell lines U87-MG, T98G, U251, LN229 and rat C6 cells were treated with beta-elemene combined with radiation or TMZ. We used MTT and colony forming assays to evaluate the proliferation and survival of the cells, and the comet assay to observe DNA damage. Expression of proteins was analyzed by immunoblotting. In the present study, we found that beta-elemene inhibited the proliferation and survival of different GBM cell lines when combined with radiotherapy or TMZ via inhibition of DNA damage repair. Treatment of GBM cells with beta-elemene decreased the phosphorylation of ataxia telangiectasia mutated (ATM), AKT and ERK following radiotherapy or chemotherapy. These results revealed that beta-elemene could significantly increase the radiosensitivity and chemosensitivity of GBM. beta elemene may be used as a potential drug in combination with the radiotherapy and chemotherapy of GBM. PMID- 26062575 TI - Cerebral Toxocariasis: Silent Progression to Neurodegenerative Disorders? AB - Toxocara canis and T. cati are highly prevalent nematode infections of the intestines of dogs and cats. In paratenic hosts, larvae do not mature in the intestine but instead migrate through the somatic tissues and organs of the body. The presence of these migrating larvae can contribute to pathology. Toxocara larvae can invade the brains of humans, and while case descriptions of cerebral toxocariasis are historically rare, improved diagnosis and greater awareness have contributed to increased detection. Despite this, cerebral or neurological toxocariasis (NT) remains a poorly understood phenomenon. Furthermore, our understanding of cognitive deficits due to toxocariasis in human populations remains particularly deficient. Recent data describe an enhanced expression of biomarkers associated with brain injury, such as GFAP, AbetaPP, transforming growth factor beta1 (TGF-beta1), NF-L, S100B, tTG, and p-tau, in mice receiving even low doses of Toxocara ova. Finally, this review outlines a hypothesis to explore the relationship between the presence of T. canis larvae in the brain and the progression of Alzheimer's disease (AD) due to enhanced AD-associated neurodegenerative biomarker expression. PMID- 26062578 TI - Expression of HAX-1 in colorectal cancer and its role in cancer cell growth. AB - Colorectal cancer (CRC) is one of the most common types of cancer worldwide. Hematopoietic cell-specific protein 1-associated protein X-1 (HAX-1) has been found to be involved in several types of cancer. However, the role of HAX-1 in CRC remains to be elucidated. The aim of the present study was to investigate whether the expression of HAX-1 is associated with the progression of CRC, and to determine the effects of HAX-1 on the apoptosis and proliferation of CRC cells. Tumor tissues and adjacent noncancerous tissues were collected from 60 patients with CRC, following the provision of informed consent. The expression levels of HAX-1 and the association with clinical and pathological characteristics were then analyzed. The expression levels of HAX-1 were significantly higher in the cancerous tissues from the patients with CRC, particularly in tissues of an advanced stage of cancer. In addition, HAX-1 expression was associated with malignant progression and poor prognosis. Furthermore, SW480 CRC cells, overexpressing HAX-1, exhibited increased resistance to camptothecin in vitro, and promoted proliferation in vitro and in vivo. By contrast, HAX-1 knockdown significantly decreased the proliferation. In addition, the expression levels of ki-67 and phosphorylated-akt were inhibited following HAX-1 knockdown. In conclusion, the expression levels of HAX-1 were increased in cancerous tissue from patients with CRC, and were associated with progression of the disease. These results suggested that HAX-1 may contribute to chemotherapy resistance and malignant progression in CRC. PMID- 26062579 TI - Prolonged Antegrade Cerebral Perfusion via Right Axillary Artery (>=60 min) Does Not Affect Early Outcomes in a Repair of Type A Acute Aortic Dissection. AB - PURPOSE: We aim to investigate whether the duration of antegrade cerebral perfusion (ACP) via right axillary artery with an 8-mm prosthetic graft affects early outcomes in a repair of type A acute aortic dissection (AAD). METHODS: Over the 24 months from April 2010, a repair of AAD under ACP via the right axillary artery and mild hypothermic circulatory arrest (rectum temperature, 28-30 degrees C) was performed in 34 patients. Mean age was 64.5 +/- 13.7 years of age.Preoperative shock status was in three due to cardiac tamponade. Organ malperfusion occurred in 11 patients preoperatively. Mean follow-up period was 9.6 +/- 8.4 months and follow-up rate was 100%. RESULTS: Hospital mortality rate was 8.8%. No newly required hemodialysis and new onset of temporary or permanent neurologic deficits were present in survivors.There were no statistically significant differences of mortality rate, new onset of permanent or temporary neurologic deficits and distal organ dysfunction between ACP duration <60 min and >=60 min. The 12-month survival was 84.4% +/- 6.4%. And, freedom from aorta related events at 12 and 18 months were 100% +/- 0.0% and 88.9% +/- 10.5%, respectively. CONCLUSIONS: The duration of ACP via right axillary artery does not affect early outcomes following a repair of AAD. PMID- 26062580 TI - Selection of prosthetic valve and evidence--need for the development of Japan's own guidelines. AB - PURPOSE: In 2014, the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines were largely revised with regard to the selection of prosthetic valves. (1) A mechanical prosthesis is reasonable for aortic valve replacement (AVR) or mitral valve replacement (MVR) in patients less than 60 years of age, (2) A bioprosthesis is reasonable in patients more than 70 years of age, and (3) Either a bioprosthetic or mechanical valve is reasonable in patients between 60 and 70 years of age.Japan faces the unprecedented population aging, and moreover, the average life expectancy is longer among the Japanese than the Westerners. In Japan, whether this choice is appropriate seems questionable. METHODS: This time, with the revision of the AHA/ACC guidelines, it might be necessary to take into consideration the average life expectancy of Japanese people and revise the Japanese guidelines accordingly. RESULTS: We should consider whether 60-70 years should be set as a gray zone regarding the age criteria for choosing biological valves, or if the age should be set higher relative to that specified in the western guidelines, given the longer Japanese life expectancy. CONCLUSION: We believe that the development of unique, Japanese guidelines for the selection of prosthetic valves will allow us to provide appropriate selection and treatment for each patient. PMID- 26062581 TI - [Recent Developments in the Field of Material Perception: Why is Shitsukan Important?]. AB - Shitsukan (material perception) is a cognitive function to infer the material and surface conditions of objects based on sensory information. We can obtain biologically important information on objects through Shitsukan. Shitsukan is also closely associated with preference and emotion toward objects. To understand the mechanisms of Shitsukan, understanding the physical properties of the objects, sensory features generated from the objects, and neural processing in the brain are all important, and interdisciplinary collaborations across engineering science, psychophysics, and brain science is critically important. PMID- 26062582 TI - [Visual Recognition of the Shitsukan, or Material Properties, of Objects]. AB - Natural objects, such as animals, flowers, and wood, as well as artificial objects, such as Japanese lacquerware, glass, and metal coins, have their own shape and surface appearances. Although object shapes play important roles in visual object recognition, the material properties or Shitsukan of objects are relevant for the recognition of visual objects. In this review, we introduce recent advances in the understanding of the neural basis of the cognition of Shitsukan. First, we introduce the results of single-neuron recording studies that examined neuronal activity in the inferior temporal cortex of macaque monkeys in response to the presentation of two-dimensional and three-dimensional shapes. Next, we introduce the studies of neuronal response property to the Shitsukan of objects, such as color, texture, glossiness, and the combinations of these features. Then, we discuss how the selective responses to Shitsukan are constructed by hierarchical processing in the ventral visual cortical pathway, which consists of V1, V2, and V4. Finally, we discuss the encoding of Shitsukan information in the inferior temporal cortex. PMID- 26062583 TI - [Neural Representation of Sound Texture in the Auditory Cortex]. AB - Natural sounds have a variety of sound spectra, which produce the so-called textures of sounds. These sound textures are extracted and perceived through interactions of the auditory, emotional, and cognitive systems in our brain. Recent studies have investigated how our brain handles musical sound textures, such as consonant and dissonant chords, or major and minor scales. Accumulating evidence indicates that the mammal auditory system has adapted to extract the harmonic structure of sounds and that this adaptation plays crucial roles in the perception of the consonance of two-tone chords. In addintion, functional magnetic resonance imaging studies have shown that major and minor scales activate not only the auditory system but also the emotional and cognitive systems. Our study revealed that phase synchrony within the auditory cortex of rodents represents the tonality of three-tone chords in a band-specific manner, and these findings support the hypothesis that the auditory system interact with the emotional and/or cognitive systems. Thus, the neural bases for the perception of sound textures are widely distributed within our brain, and these evolution of these neural systems significantly affects the establishment of musical grammar. PMID- 26062584 TI - [Human Brain Representations of Haptic and Visual Textures]. AB - We present a literature review of functional brain imaging studies of haptic and visual texture perception, and highlight our ongoing functional magnetic resonance imaging (fMRI) experiment of the crossmodal links between vision and touch. In the fMRI experiment, the subjects viewed or touched a piece of wool or denim cloth. A multivoxel pattern analysis of whole-brain fMRI activity revealed the crossmodal nature of natural texture perception. Visual texture representations were found in the somatosensory and association cortices as well as the visual cortex, while haptic texture representations were found in the visual cortex and association cortices as well as the somatosensory cortex. Furthermore, shared visuo-haptic representations were found in the parietal association, somatosensory, and visual cortices. These results that suggested the crossmodal transfer of texture information across functionally segregated sensory and associative brain regions are discussed in relation to previous findings on texture perception and aesthetic texture or shitsukan. PMID- 26062585 TI - [Visual Texture Agnosia in Humans]. AB - Visual object recognition requires the processing of both geometric and surface properties. Patients with occipital lesions may have visual agnosia, which is impairment in the recognition and identification of visually presented objects primarily through their geometric features. An analogous condition involving the failure to recognize an object by its texture may exist, which can be called visual texture agnosia. Here we present two cases with visual texture agnosia. Case 1 had left homonymous hemianopia and right upper quadrantanopia, along with achromatopsia, prosopagnosia, and texture agnosia, because of damage to his left ventromedial occipitotemporal cortex and right lateral occipito-temporo-parietal cortex due to multiple cerebral embolisms. Although he showed difficulty matching and naming textures of real materials, he could readily name visually presented objects by their contours. Case 2 had right lower quadrantanopia, along with impairment in stereopsis and recognition of texture in 2D images, because of subcortical hemorrhage in the left occipitotemporal region. He failed to recognize shapes based on texture information, whereas shape recognition based on contours was well preserved. Our findings, along with those of three reported cases with texture agnosia, indicate that there are separate channels for processing texture, color, and geometric features, and that the regions around the left collateral sulcus are crucial for texture processing. PMID- 26062586 TI - [The Contribution of the Orbitofrontal Cortex to the Preference for Visual Stimuli]. AB - Both humans and animals like to watch neutral and biologically insignificant visual stimuli. Behavioral studies have revealed that animals more frequently select stimuli with symmetrical and regular patterns and short movies compared to stimuli with unsymmetrical and irregular patterns and photographs. Preferred visual stimuli can serve as rewards for animals performing behavioral tasks. Preferences for visual stimuli are determined by the magnitude of the pleasant feelings that are experienced when the stimuli are seen. The orbitofrontal cortex is known to participate in the detection and prediction of reward, the estimation of the value of the stimuli as a reward, and positive emotion. Human neuroimaging studies and animal neurophysiological studies have shown that the magnitude of orbitofrontal responses to the presentation of neutral visual stimuli correlates with the strength of the preference for the stimuli in the behavioral studies. These results suggest that the magnitude of orbitofrontal responses to the visual stimuli correlates with the strength of the pleasant feelings that are produced by the stimuli and that the orbitofrontal cortex plays an important role in the judgment of the preference for visual stimuli. PMID- 26062576 TI - Global Epidemiology of Campylobacter Infection. AB - Campylobacter jejuni infection is one of the most widespread infectious diseases of the last century. The incidence and prevalence of campylobacteriosis have increased in both developed and developing countries over the last 10 years. The dramatic increase in North America, Europe, and Australia is alarming, and data from parts of Africa, Asia, and the Middle East indicate that campylobacteriosis is endemic in these areas, especially in children. In addition to C. jejuni, there is increasing recognition of the clinical importance of emerging Campylobacter species, including Campylobacter concisus and Campylobacter ureolyticus. Poultry is a major reservoir and source of transmission of campylobacteriosis to humans. Other risk factors include consumption of animal products and water, contact with animals, and international travel. Strategic implementation of multifaceted biocontrol measures to reduce the transmission of this group of pathogens is paramount for public health. Overall, campylobacteriosis is still one of the most important infectious diseases that is likely to challenge global health in the years to come. This review provides a comprehensive overview of the global epidemiology, transmission, and clinical relevance of Campylobacter infection. PMID- 26062587 TI - [Diabetes and Dementia]. AB - An aging global population is driving the current epidemic of dementia and type 2 diabetes mellitus. Diabetes is a known risk factor for the development of vascular dementia, Alzheimer's disease, and mild cognitive impairment. Good control of diabetes may improve cognitive decline and prevent Alzheimer's disease. Mild cognitive impairment with type 2 diabetes (DM-MCI) often presents as a decline in attention, psychomotor speed, executive function, and memory. The Montreal Cognitive Assessment (MoCA) is one of the best screening tools for detecting DM-MCI. We found that 72% of the patients admitted to educational hospitalization for type 2 diabetes could also be categorized into groups with frontal lobe dysfunction, delayed recall, and a mixed-type group. Anti-diabetic drugs and insulin may protect and improve cognitive dysfunction in Alzheimer's disease and DM-MCI, but more studies are needed to verify this claim. Diabetes mellitus may be linked not only to Alzheimer's disease but also to other neurodegenerative diseases, such as Parkinson's, Huntington's and frontotemporal lobe dementia. PMID- 26062588 TI - [Roles of Aquaporins in Brain Disorders]. AB - Aquaporin (AQP) is a water channel protein that is expressed in the cell membranes. AQPs are related to several kinds of human diseases such as cataract. In the mammalian central nervous system (CNS), AQP4 is specifically expressed in the astrocyte membranes lining the perivascular and periventricular structures. AQP4 plays a role in the development of brain edema associated with certain brain disorders. Neuromyelitis optica (NMO) is a demyelinating disorder, and patients with NMO develop autoimmune antibodies against AQP4 in their serum. Therefore, AQP4 is involved in NMO pathogenesis. A new concept referred to as "glymphatic pathway" has been recently proposed to explain the lymphatic system in the CNS. Dysfunction of the "glymphatic pathway" may cause several neurodegenerative diseases and mood disorders. Importantly, AQP4 may play a role in the "glymphatic pathway". Further investigation of AQP4 in CNS disorders is necessary, and a new drug against AQP4 is expected. PMID- 26062589 TI - [Treatment and Pathomechanism of Citrin Deficiency]. AB - Citrin, encoded by SLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, a small number of adults with citrin deficiency develop adult-onset type II citrullinemia (CTLN2), which causes hyperammonemic encephalopathy leading to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. Hepatic glycolysis is coupled with hepatic lipogenesis via the NADH shuttles composed of the malate aspartate shuttle and malate-citrate shuttle. Citrin deficiency is expected to impair glycolysis and lipogenesis in hepatocytes. We noticed that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. We extended this therapy for CTLN2 and found that an MCT supplementation therapy under a low-carbohydrate formula prevented the relapse of hyperammonemic encephalopathy, normalized the liver dysfunction (including the Fisher ratio), and gradually improved the level of plasma citrulline and fatty liver. An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to improvement of the cytosolic NAD+/NADH ratio via the malate-citrate shuttle. MCT supplementation could be a promising therapy for citrin deficiency. PMID- 26062590 TI - [Adjunctive Therapy with Levetiracetam for Elderly Japanese with Partial Epilepsy: Effectiveness of Levetiracetam in Seizure Management of Epilepsy Patients with Advanced-age Onset in a Practical Setting]. AB - This prospective, nationwide, specified drug use-results survey investigated the effects of levetiracetam (LEV) in elderly individuals with partial-onset seizures of advanced-age onset in a practical setting. Participants comprised LEV-naive patients with onset of focal epilepsy at >=50 years old and management by at least one antiepileptic drug. Efficacy measures were the physician-rated global improvement scale (GIS), and proportions of patients showing 50% and 100% seizure reduction by comparing seizure frequency during the 4-week pre-treatment period and the last 4 weeks of the 25-week treatment period. Adverse drug reactions (ADRs) and retention rate were also evaluated. Data for safety, GIS evaluation, and seizure frequency analyses were available from 105, 78, and 76, respectively, of 116 enrolled patients, 83 (71.55%) of whom were enrolled by neurosurgeons. Improvement rate (improved or markedly improved) as determined by GIS was 98.72% (77/78). Seventy-four (97.37%) and 64 patients (84.21%) showed 50% and 100% seizure reduction, respectively. Incidence of ADRs was 12.38%, including one serious ADR (mania). LEV retention rate remained high at the end of the 25-week treatment period (96.00%). LEV appears efficacious and well-tolerated in elderly patients with focal epilepsy. Including LEV in the treatment regimen may allow elderly patients to achieve freedom from seizures. PMID- 26062591 TI - [A Case of Corticobasal Syndrome Complicated with Hypopituitarism and Hashimoto's Disease]. AB - We report the case of an individual with corticobasal syndrome (CBS), hypopituitarism due to a post-traumatic leptomeningeal cyst, and Hashimoto's disease. A 71-year-old woman was admitted to our hospital because of cognitive dysfunction and bradykinesia. Following a primary diagnosis of hypopituitarism and hypothyroidism, she was given hormone replacement therapy, and her clinical symptoms appeared to improve. However, some cognitive impairment and extrapyramidal symptoms remained. The results of careful neurological examinations, as well as magnetic resonance, single-photon emission computed tomography, and positron emission tomography images, suggested a diagnosis of CBS CBD (corticobasal degeneration). Because parkinsonism and cognitive impairment can be caused by endocrinopathy, it was initially difficult to reach the complete diagnosis that included CBS. Thus, it is important to understand that complicated neurological presentations can be caused by several different disorders. PMID- 26062592 TI - [Rare Case of Wall-Eyed Bilateral Internuclear Ophthalmoplegia in Unilateral Pontine Infarction]. PMID- 26062593 TI - Protective effect of vitamin E on methyl methanesulfonate-induced teratozoospermia in adult Sprague-Dawley rats. AB - The protective effect of vitamin E (VE, alpha-tocopherol) on methyl methanesulfonate (MMS)-induced teratozoospermia was investigated in adult rats. Rats (n=6 per group) were divided into three groups: i) Control group, treated with distilled water from days 1 to 5; ii) the MMS group, treated with MMS at a dose of 40 mg.kg(-1) from days 1-5; or iii) the VE+MMS group, treated with MMS at a dose of 40 mg.kg(-1) from days 1-5, followed by VE at a dose of 150 mg.kg(-1) from day 6 for 6 weeks. Sperm count, motility and morphology were examined following treatment with VE. The serum testosterone level and antioxidant enzyme activity were measured, and the localization of Vasa, promyelocytic leukemia zinc finger protein (Plzf) and synaptonemal complex protein 3 (Scp3) were also examined. MMS treatment decreased sperm count and motility, and the levels of immunoreactive serum testosterone and endogenous antioxidants. In addition, MMS increased the percentage of abnormal sperm and the levels of free radicals. After MMS and VE treatment, sperm count and motility were significantly higher in rats from the VE+MMS group than in the MMS group. In addition, the serum testosterone concentration, as well as the levels of Vasa and free radicals and the percentage of abnormal sperm, decreased. The results indicated that VE has protective effects against MMS-induced teratozoospermia in adult rats. PMID- 26062594 TI - Risks and benefits of trial participation: A qualitative study of participants' perspectives in Russia. AB - BACKGROUND: The Russian Federation is one of the emerging clinical trial regions where the numbers of international clinical trials have been significantly rising over the course of recent years. PURPOSE: Our aims were to describe and explain risk-benefit calculus by clinical trial participants in Russia and to analyse the significance of the results for the ethical regulation of globalizing clinical trials. METHODS: In-depth semi-structured interviews were conducted with 21 individuals participating in trials for cardiovascular disease. Analysis was based on the inductive constant comparative method. RESULTS: Interviewed participants perceived multiple benefits in trial enrolment including regular check-ups, provision and explanation of individual test results, the opportunity to ask investigators for advice and the provision of treatment recommendations for those with limited access to a physician outside of the trial. Participants tried to manage risks of trial enrolment by paying attention to how they felt and reporting changes to investigators. Regular monitoring, the opportunity to drop out of the trial and health insurance provision in case of adverse events were viewed as further minimizing individual risks. Importantly, interviewed trial participants did not assess the risks and benefits of a single trial independently of wider social situation or particularities of their own health condition. Value of trial enrolment benefits for participants was enhanced by the healthcare system that was viewed as being unresponsive to the needs of people with cardiovascular disease. Therefore, in their risk-benefit assessment, participants weighed enrolment risks against the risks of dealing with their fragile health without continuous contact with a medical professional. LIMITATIONS: A relatively small number of interviews was conducted, only participants of cardiovascular disease trials were interviewed and the extent to which the described perspectives are generalizable is not established. CONCLUSION: The risk-benefit assessment as performed by most interviewed trial participants involved multiple components, including the ones unrelated to the trial itself, and was largely context-dependent. Perspectives of research participants can enrich frameworks for the evaluation of trial risks and benefits. PMID- 26062595 TI - Post hoc subgroups in clinical trials: Anathema or analytics? AB - BACKGROUND: There is currently much interest in generating more individualized estimates of treatment effects. However, traditional statistical methods are not well suited to this task. Post hoc subgroup analyses of clinical trials are fraught with methodological problems. We suggest that the alternative research paradigm of predictive analytics, widely used in many business contexts, can be adapted to help. METHODS: We compare the statistical and analytics perspectives and suggest that predictive modeling should often replace subgroup analysis. We then introduce a new approach, cadit modeling, that can be useful to identify and test individualized causal effects. RESULTS: The cadit technique is particularly useful in the context of selecting from among a large number of potential predictors. We describe a new variable-selection algorithm that has been applied in conjunction with cadit. The cadit approach is illustrated through a reanalysis of data from the Randomized Aldactone Evaluation Study trial, which studied the efficacy of spironolactone in heart-failure patients. The trial was successful, but a serious adverse effect (hyperkalemia) was subsequently discovered. Our reanalysis suggests that it may be possible to predict the degree of hyperkalemia based on a logistic model and to identify a subgroup in which the effect is negligible. CONCLUSION: Cadit modeling is a promising alternative to subgroup analyses. Cadit regression is relatively straightforward to implement, generates results that are easy to present and explain, and can mesh straightforwardly with many variable-selection algorithms. PMID- 26062596 TI - University of Pennsylvania 7th annual conference on statistical issues in clinical trials: Current issues regarding the use of biomarkers and surrogate endpoints in clinical trials (morning panel discussion). PMID- 26062597 TI - Sleep monitoring of a six-day microcycle in strength and high-intensity training. AB - This study examined the effect of microcycles in eccentric strength and high intensity interval training (HIT) on sleep parameters and subjective ratings. Forty-two well-trained athletes (mean age 23.2 +/- 2.4 years) were either assigned to the strength (n = 21; mean age 23.6 +/- 2.1 years) or HIT (n = 21; mean age 22.8 +/- 2.6 years) protocol. Sleep monitoring was conducted with multi sensor actigraphy (SenseWear ArmbandTM, Bodymedia, Pittsburg, PA, USA) and sleep log for 14 days. After a five-day baseline phase, participants completed either eccentric accented strength or high-intensity interval training for six days, with two training sessions per day. This training phase was divided into two halves (part 1 and 2) for statistical analyses. A three-day post phase concluded the monitoring. The Recovery-Stress Questionnaire for Athletes was applied at baseline, end of part 2, and at the last post-day. Mood ratings were decreased during training, but returned to baseline values afterwards in both groups. Sleep parameters in the strength group remained constant over the entire process. The HIT group showed trends of unfavourable sleep during the training phase (e.g., objective sleep efficiency at part 2: mean = 83.6 +/- 7.8%, F3,60 = 2.57, P = 0.06, [Formula: see text] = 0.114) and subjective improvements during the post phase for awakenings (F3,60 = 2.96, P = 0.04, [Formula: see text] = 0.129) and restfulness of sleep (F3,60 = 9.21, P < 0.001, [Formula: see text] = 0.315). Thus, the HIT protocol seems to increase higher recovery demands than strength training, and sufficient sleep time should be emphasised and monitored. PMID- 26062598 TI - Bone mineralisation of weaned piglets fed a diet free of inorganic phosphorus and supplemented with phytase, as assessed by dual-energy X-ray absorptiometry. AB - Sixteen female piglets (58 d of age, 16.8 +/- 0.8 kg body weight [BW]) were assigned to two groups (n = 8) and received until day 100 of age (50.3 +/- 1.2 kg BW) ad libitum either a diet with a standard (diet C) or low (diet L) total phosphorus (P) content (5.38 and 4.23 g/kg, respectively). Diet C was supplemented with mineral P (1.15 g/kg) and did not contain microbial phytase. Diet L did not contain any inorganic P but 750 FTU/kg of microbial phytase. Despite these treatments, both diets were composed with the same ingredients. Body mineralisation of each gilt was assessed by determining the bone mineral content (BMC), area bone mineral density (BMD) by the dual-energy X-ray absorptiometry (DXA) at days 58, 72, 86 and 100 of age. Feeding diet L caused a higher P digestibility (p = 0.008) measured from days 72 to 86 of age and at 100 days of age a higher BMC and BMD (p <= 0.01). Furthermore, the gilts of group L deposited more minerals in the body than control pigs (by 2.4 g/d, p = 0.008). It was found that BMD and BMC were positively correlated with body lean mass and digestible P intake. The results indicated that, even for very young pigs, the addition of microbial phytase instead of inorganic P increases the amount of digestible P covering the requirements of piglets for proper bone mineralisation. Furthermore, it was proved that the DXA method can be successfully applied to measure body fat and lean mass contents as well as bone mineralisation of growing pigs using the same animals. PMID- 26062599 TI - Pro-inflammatory cytokines reduce human TAFI expression via tristetraprolin mediated mRNA destabilisation and decreased binding of HuR. AB - Thrombin activatable fibrinolysis inhibitor (TAFI) is the zymogen form of a basic carboxypeptidase (TAFIa) with both anti-fibrinolytic and anti-inflammatory properties. The role of TAFI in inflammatory disease is multifaceted and involves modulation both of specific inflammatory mediators as well as of the behaviour of inflammatory cells. Moreover, as suggested by in vitro studies, inflammatory mediators are capable of regulating the expression of CPB2, the gene encoding TAFI. In this study we addressed the hypothesis that decreased TAFI levels observed in inflammation are due to post-transcriptional mechanisms. Treatment of human HepG2 cells with pro-inflammatory cytokines TNFalpha, IL-6 in combination with IL-1beta, or with bacterial lipopolysaccharide (LPS) decreased TAFI protein levels by approximately two-fold over 24 to 48 hours of treatment. Conversely, treatment of HepG2 cells with the anti-inflammatory cytokine IL-10 increased TAFI protein levels by two-fold at both time points. We found that the mechanistic basis for this modulation of TAFI levels involves binding of tristetraprolin (TTP) to the CPB2 3'-UTR, which mediates CPB2 mRNA destabilisation. In this report we also identified that HuR, another ARE-binding protein but one that stabilises transcripts, is capable of binding the CBP2 3'UTR. We found that pro inflammatory mediators reduce the occupancy of HuR on the CPB2 3'-UTR and that the mutation of the TTP binding site in this context abolishes this effect, although TTP and HuR appear to contact discrete binding sites. Interestingly, all of the mediators tested appear to increase TAFI protein expression in THP-1 macrophages, likewise through effects on CPB2 mRNA stability. PMID- 26062600 TI - Regulation of the cystic fibrosis transmembrane conductance regulator anion channel by tyrosine phosphorylation. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) channel is activated by PKA phosphorylation of a regulatory domain that interacts dynamically with multiple CFTR domains and with other proteins. The large number of consensus sequences for phosphorylation by PKA has naturally focused most attention on regulation by this kinase. We report here that human CFTR is also phosphorylated by the tyrosine kinases p60c-Src (proto-oncogene tyrosine-protein kinase) and the proline-rich tyrosine kinase 2 (Pyk2), and they can also cause robust activation of quiescent CFTR channels. In excised patch-clamp experiments, CFTR activity during exposure to Src or Pyk2 reached ~80% of that stimulated by PKA. Exposure to PKA after Src or Pyk2 caused a further increase to the level induced by PKA alone, implying a common limiting step. Channels became spontaneously active when v-Src or the catalytic domain of Pyk2 was coexpressed with CFTR and were further stimulated by the tyrosine phosphatase inhibitor dephostatin. Exogenous Src also activated 15SA-CFTR, a variant that lacks 15 potential PKA sites and has little response to PKA. PKA-independent activation by tyrosine phosphorylation has implications for the mechanism of regulation by the R domain and for the physiologic functions of CFTR. PMID- 26062601 TI - New aminopeptidase from "microbial dark matter" archaeon. AB - Marine sediments host a large population of diverse, heterotrophic, uncultured microorganisms with unknown physiologies that control carbon flow through organic matter decomposition. Recently, single-cell genomics uncovered new key players in these processes, such as the miscellaneous crenarchaeotal group. These widespread archaea encode putative intra- and extracellular proteases for the degradation of detrital proteins present in sediments. Here, we show that one of these enzymes is a self-compartmentalizing tetrameric aminopeptidase with a preference for cysteine and hydrophobic residues at the N terminus of the hydrolyzed peptide. The ability to perform detailed characterizations of enzymes from native subsurface microorganisms, without requiring that those organisms first be grown in pure culture, holds great promise for understanding key carbon transformations in the environment as well as identifying new enzymes for biomedical and biotechnological applications. PMID- 26062603 TI - Estrogen preserves Fas ligand levels by inhibiting microRNA-181a in bone marrow derived mesenchymal stem cells to maintain bone remodeling balance. AB - Estrogen protects bone loss by promoting Fas ligand (FasL) transcription in osteoclasts and osteoblasts to induce apoptosis of osteoclasts. Bone marrow derived mesenchymal stem cells (BMMSCs) express FasL protein, which is necessary for BMMSCs to induce T-cell apoptosis in cell therapy. However, the physiologic function of FasL in BMMSCs is unknown. In this study, using an in vitro coculture system and an in vivo BMMSC transplantation assay, we found that BMMSCs potently induced apoptosis of osteoclasts through the FasL/Fas pathway. Estrogen was necessary for this process as a promoter of FasL protein accumulation in BMMSCs. Furthermore, estrogen elevated FasL protein accumulation, not by increasing FasL gene transcription, but through microRNA-mediated posttranscriptional regulation. In brief, estrogen down-regulated expression of miR-181a, a negative modulator of FasL targeting the 3'-UTR of FasL mRNA. Estrogen deficiency resulted in excessive miR-181a, which decreased FasL protein levels to suppress BMMSC-induced osteoclast apoptosis. Furthermore, knockdown of miR-181a recovered the BMMSC defect to induce osteoclast apoptosis during estrogen deficiency. Taken together, our results showed that estrogen preserves FasL protein accumulation by inhibiting miR-181a expression in BMMSCs to maintain bone remodeling balance, suggesting a novel mechanism by which estrogen preserves bone mass. PMID- 26062602 TI - Systemic gene delivery following intravenous administration of AAV9 to fetal and neonatal mice and late-gestation nonhuman primates. AB - Several acute monogenic diseases affect multiple body systems, causing death in childhood. The development of novel therapies for such conditions is challenging. However, improvements in gene delivery technology mean that gene therapy has the potential to treat such disorders. We evaluated the ability of the AAV9 vector to mediate systemic gene delivery after intravenous administration to perinatal mice and late-gestation nonhuman primates (NHPs). Titer-matched single-stranded (ss) and self-complementary (sc) AAV9 carrying the green fluorescent protein (GFP) reporter gene were intravenously administered to fetal and neonatal mice, with noninjected age-matched mice used as the control. Extensive GFP expression was observed in organs throughout the body, with the epithelial and muscle cells being particularly well transduced. ssAAV9 carrying the WPRE sequence mediated significantly more gene expression than its sc counterpart, which lacked the woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) sequence. To examine a realistic scale-up to larger models or potentially patients for such an approach, AAV9 was intravenously administered to late-gestation NHPs by using a clinically relevant protocol. Widespread systemic gene expression was measured throughout the body, with cellular tropisms similar to those observed in the mouse studies and no observable adverse events. This study confirms that AAV9 can safely mediate systemic gene delivery in small and large animal models and supports its potential use in clinical systemic gene therapy protocols. PMID- 26062605 TI - Expression of RCK2 MAPKAP (MAPK-activated protein kinase) rescues yeast cells sensitivity to osmotic stress. AB - BACKGROUND: Saccharomyces cerevisiae is the micro-organism of choice for the conversion of fermentable sugars during beverage or bioethanol fermentations. These fermentations are characterised by high osmotic stress on a yeast cell, with selected brewing fermentations beginning at 20-25% fermentable sugars and bioethanol fermentations at 13% fermentable sugars. RESULTS: RCK2 encodes for a MAPKAP (MAPK-activated protein kinase) enzyme and was identified on a locus by QTL analysis in yeast cells under osmotic stress, RCK2 expression was placed under a tetracycline regulatable vector and rescued glucose, sorbitol or glycerol induced osmotic stress in an rck2 null strain. A strain overexpressing RCK2 had significantly faster fermentation rates when compared with the empty vector control strain. CONCLUSIONS: Presence of RCK2 increased rates of glucose utilisation (~40 g glucose in first 8 h) during a 15% glucose fermentation and concurrent production of ethanol when compared with empty vector controls. Tolerance to osmotic stress using the tetracycline regulatable vectors could be turned off with the addition of tetracycline returning a rck2 null strain back to osmotic sensitivity. PMID- 26062604 TI - "Down syndrome: an insight of the disease". AB - Down syndrome (DS) is one of the commonest disorders with huge medical and social cost. DS is associated with number of phenotypes including congenital heart defects, leukemia, Alzeihmer's disease, Hirschsprung disease etc. DS individuals are affected by these phenotypes to a variable extent thus understanding the cause of this variation is a key challenge. In the present review article, we emphasize an overview of DS, DS-associated phenotypes diagnosis and management of the disease. The genes or miRNA involved in Down syndrome associated Alzheimer's disease, congenital heart defects (AVSD), leukemia including AMKL and ALL, hypertension and Hirschprung disease are discussed in this article. Moreover, we have also reviewed various prenatal diagnostic method from karyotyping to rapid molecular methods - MLPA, FISH, QF-PCR, PSQ, NGS and noninvasive prenatal diagnosis in detail. PMID- 26062606 TI - Vector sequence contamination of the Plasmodium vivax sequence database in PlasmoDB and In silico correction of 26 parasite sequences. AB - We found a 47 aa protein sequence that occurs 17 times in the Plasmodium vivax nucleotide database published on PlasmoDB. Coding sequence analysis showed multiple restriction enzyme sites within the 141 bp nucleotide sequence, and a His6 tag attached to the 3' end, suggesting cloning vector origins. Sequences with vector contamination were submitted to NCBI, and BLASTN was used to cross examine whole-genome shotgun contigs (WGS) from four recently deposited P. vivax whole genome sequencing projects. There are at least 26 genes listed in the PlasmoDB database that incorporate this cloning vector sequence into their predicted provisional protein products. PMID- 26062607 TI - Chest pain in the emergency department: risk stratification with Manchester triage system and HEART score. AB - BACKGROUND: Fast and accurate chest pain risk stratification in the emergency department (ED) is critical. The HEART score predicts the short-term incidence of major adverse cardiac events (MACE) in this population, dividing it in three risk categories. We aimed to describe the population with chest pain, to characterize the subgroup of patients with acute coronary syndrome (ACS) and to assess the prognostic value of Manchester triage system and of HEART score. METHODS: Retrospective observational study including patients admitted to the ED of a tertiary hospital with chest pain as the presenting symptom. The primary outcome was a composite of all-cause mortality, myocardial infarction or unscheduled revascularization at 6 weeks. RESULTS: We enrolled 233 patients (age 58 +/- 19; 55.4 % males). The most common final diagnosis was non-specific chest pain (n = 86, 36.9 %), followed by ACS (n = 22, 9.4 %). Male gender, smoking and chronic kidney disease were associated with higher risk of ACS. According to Manchester triage system, chest pain patients stratified with red or orange priority had a higher incidence of ACS (16.5 % vs. 3.8 %, p = 0.006). The application of HEART score showed that most patients were in low risk category (56.3 %). The six-week incidence of MACE in each category was 2 %, 15.6 % and 76.9 % (p < 0.001). HEART score accurately predicted the short-term incidence of MACE in chest pain patients (c-statistic 0.880; 95 % CI, 0.807-0.950, p < 0.001). CONCLUSIONS: Chest pain patients have very different levels of severity and the discriminatory power of Manchester triage system should be used in the assessment of this population. The HEART score seems to be an effective tool for risk stratification in the ED. PMID- 26062608 TI - Using clinical supervision to improve the quality and safety of patient care: a response to Berwick and Francis. AB - BACKGROUND: After widely publicised investigations into excess patient deaths at Mid Staffordshire hospital the UK government commissioned reports from Robert Francis QC and Professor Don Berwick. Among their recommendations to improve the quality and safety of patient care were lifelong learning, professional support and 'just culture'. Clinical supervision is in an excellent position to support these activities but opportunities are in danger of being squeezed out by regulatory and managerial demands. Doctors who have completed their training are responsible for complex professional judgements for which narrative supervision is particularly helpful. With reference to the literature and my own practice I propose that all practicing clinicians should have regular clinical supervision. DISCUSSION: Clinical supervision has patient-safety and the quality of patient care as its primary purposes. After training is completed, doctors may practice for the rest of their career without any clinical supervision, the implication being that the difficulties dealt with in clinical supervision are no longer difficulties, or are better dealt with some other way. Clinical supervision is sufficiently flexible to be adapted to the needs of experienced clinicians as its forms can be varied, though its functions remain focused on patient safety, good quality clinical care and professional wellbeing. The evidence linking clinical supervision to the quality and safety of patient care reveals that supervision is most effective when its educational and supportive functions are separated from its managerial and evaluative functions. Among supervision's different forms, narrative-based-supervision is particularly useful as it has been developed for clinicians who have completed their training. It provides ways to explore the complexity of clinical judgements and encourages doctors to question one another's authority in a supportive culture. To be successful, supervision should also be professionally led and learner centred rather than externally imposed and centred on institutions. I propose that regular clinical supervision should be a professional requirement if the quality and safety aspirations of Francis and Berwick are to be met. PMID- 26062609 TI - Identification of four novel group-specific bluetongue virus NS3 protein B-cell epitopes. AB - BACKGROUND: The non-structural protein 3 (NS3) of bluetongue virus (BTV) is the second smaller non-structural protein produced in host cells, playing an important role in BTV trafficking and release. RESULTS: In this study, we generated five BTV NS3-reactive monoclonal antibodies (mAbs), named 3D8, 2G9, 1B5, 4H8, and 2B12. A panel of overlapping NS3-derived peptides representing the entirety of the BTV15 NS3 protein was screened to identify linear peptide epitopes recognized by each mAb. Based on the initial screen, a series of progressively truncated peptides were produced to identify the minimal linear peptide sequence required to maintain mAb binding. We found that mAb 3D8 reacted with the motif (36)PPRYA(40), 2G9 reacted with the motif (82)AEAFRDDVRLRQIK(95), 1B5 reacted with the motif (205)YNDAVRMSF(213), 2B12 and 4H8 reacted with the motif (204)SYNDAVRMSF(213). Sequence alignments demonstrated that these linear epitopes are highly conserved among all BTV serotypes, consistent with the observation that each mAb was able to recognize cells infected with BTV1-24 serotypes tested and each identified B cell epitope was able to be recognized by BTV-infect sheep serum. CONCLUSION: This collection of mAbs along with defined linear epitopes may provide useful reagents for investigations of NS3 protein function and the development of BTV group-specific diagnostics. PMID- 26062610 TI - Maternal and newborn outcomes in Pakistan compared to other low and middle income countries in the Global Network's Maternal Newborn Health Registry: an active, community-based, pregnancy surveillance mechanism. AB - BACKGROUND: Despite global improvements in maternal and newborn health (MNH), maternal, fetal and newborn mortality rates in Pakistan remain stagnant. Using data from the Global Network's Maternal Newborn Health Registry (MNHR) the objective of this study is to compare the rates of maternal mortality, stillbirth and newborn mortality and levels of putative risk factors between the Pakistani site and those in other countries. METHODS: Using data collected through a multi site, prospective, ongoing, active surveillance system to track pregnancies and births in communities in discrete geographical areas in seven sites across six countries including Pakistan, India, Kenya, Zambia, Guatemala and Argentina from 2010 to 2013, the study compared MNH outcomes and risk factors. The MNHR captures more than 60,000 deliveries annually across all sites with over 10,000 of them in Thatta, Pakistan. RESULTS: The Pakistan site had a maternal mortality ratio almost three times that of the other sites (313/100,000 vs 116/100,000). Stillbirth (56.5 vs 22.9/1000 births), neonatal mortality (50.0 vs 20.7/1000 livebirths) and perinatal mortality rates (95.2/1000 vs 39.0/1000 births) in Thatta, Pakistan were more than twice those of the other sites. The Pakistani site is the only one in the Global Network where maternal mortality increased (from 231/100,000 to 353/100,000) over the study period and fetal and neonatal outcomes remained stagnant. The Pakistan site lags behind other sites in maternal education, high parity, and appropriate antenatal and postnatal care. However, facility delivery and skilled birth attendance rates were less prominently different between the Pakistani site and other sites, with the exception of India. The difference in the fetal and neonatal outcomes between the Pakistani site and the other sites was most pronounced amongst normal birth weight babies. CONCLUSIONS: The increase in maternal mortality and the stagnation of fetal and neonatal outcomes from 2010 to 2013 indicates that current levels of antenatal and newborn care interventions in Thatta, Pakistan are insufficient to protect against poor maternal and neonatal outcomes. Delivery care in the Pakistani site, while appearing quantitatively equivalent to the care in sites in Africa, is less effective in saving the lives of women and their newborns. By the metrics available from this study, the quality of obstetric and neonatal care in the site in Pakistan is poor. TRIAL REGISTRATION: The study is registered at clinicaltrials.gov [NCT01073475]. PMID- 26062611 TI - Beware of Data Gaps in Home Care Research: The Streetlight Effect and Its Implications for Policy Making on Long-Term Services and Supports. AB - Policy initiatives increasingly seek greater use of home- and community-based services for older persons and those with chronic care needs, yet large gaps persist in our knowledge of home care, an indispensable component of long-term services and supports. Unrecognized data gaps, including the scope of home care provided by private hire and nonmedical providers, can distort knowledge and poorly inform long-term services and supports policy. The purpose of this article is to examine these gaps by describing the universe of formal home care services and provider types in relationship to major national sources. Findings reveal four distinct home care sectors and that the majority of formal home care is provided in the sectors that are understudied. We discuss the policy implications of data gaps and conclude with recommendations on where to expand and refine home care research. PMID- 26062612 TI - Organization of Hospital Nursing, Provision of Nursing Care, and Patient Experiences With Care in Europe. AB - This study integrates previously isolated findings of nursing outcomes research into an explanatory framework in which care left undone and nurse education levels are of key importance. A moderated mediation analysis of survey data from 11,549 patients and 10,733 nurses in 217 hospitals in eight European countries shows that patient care experience is better in hospitals with better nurse staffing and a more favorable work environment in which less clinical care is left undone. Clinical care left undone is a mediator in this relationship. Clinical care is left undone less frequently in hospitals with better nurse staffing and more favorable nurse work environments, and in which nurses work less overtime and are more experienced. Higher proportions of nurses with a bachelor's degree reduce the effect of worse nurse staffing on more clinical care left undone. PMID- 26062613 TI - Projecting Primary Care Use in the Medicaid Expansion Population: Evidence for Providers and Policy Makers. AB - Millions of low-income adults are beginning to gain Medicaid coverage under the Affordable Care Act. To forecast the resulting need for primary care providers, we estimate the effect of Medicaid take-up on visits to office-based primary care providers, including clinics. We estimate that adults with Medicaid coverage at any point in the year have an average of 1.32 visits per year to primary care providers, 0.48 more visits than low-income adults without Medicaid. Consequently, we project a need for 2,113 additional primary care providers (range: 1,130-3,138) if all states expand Medicaid. Our estimates are somewhat lower than several recent forecasts, which may not have controlled adequately for selection bias, and which used non-representative samples for forecasting. Our findings shed light on disparities in access to care, particularly in counties with relatively few primary care providers per capita. Efforts to expand access to primary care should focus on where providers practice, rather than simply training more providers. PMID- 26062614 TI - The prognostic role of HER2 expression in ductal breast carcinoma in situ (DCIS); a population-based cohort study. AB - BACKGROUND: HER2 is a well-established prognostic and predictive factor in invasive breast cancer. The role of HER2 in ductal breast carcinoma in situ (DCIS) is debated and recent data have suggested that HER2 is mainly related to in situ recurrences. Our aim was to study HER2 as a prognostic factor in a large population based cohort of DCIS with long-term follow-up. METHODS: All 458 patients diagnosed with a primary DCIS 1986-2004 in two Swedish counties were included. Silver-enhanced in situ hybridisation (SISH) was used for detection of HER2 gene amplification and protein expression was assessed by immunohistochemistry (IHC) in tissue microarrays. HER2 positivity was defined as amplified HER2 gene and/or HER2 3+ by IHC. HER2 status in relation to new ipsilateral events (IBE) and Invasive Breast Cancer Recurrences, local or distant (IBCR) was assessed by Kaplan-Meier survival analyses and Cox proportional hazards regression models. RESULTS: Primary DCIS was screening-detected in 75.5% of cases. Breast conserving surgery (BCS) was performed in 78.6% of whom 44.0% received postoperative radiotherapy. No patients received adjuvant endocrine- or chemotherapy. The majority of DCIS could be HER2 classified (N=420 (91.7%)); 132 HER2 positive (31%) and 288 HER2 negative (69%)). HER2 positivity was related to large tumor size (P=0.002), high grade (P<0.001) and ER- and PR negativity (P<0.001 for both). During follow-up (mean 184 months), 106 IBCRs and 105 IBEs were identified among all 458 cases corresponding to 54 in situ and 51 invasive recurrences. Eighteen women died from breast cancer and another 114 had died from other causes. The risk of IBCR was statistically significantly lower subsequent to a HER2 positive DCIS compared to a HER2 negative DCIS, (Log-Rank P=0.03, (HR) 0.60 (95% CI 0.38-0.94)). Remarkably, the curves did not separate until after 10 years. In ER-stratified analyses, HER2 positive DCIS was associated with lower risk of IBCR among women with ER negative DCIS (Log-Rank P=0.003), but not for women with ER positive DCIS. CONCLUSIONS: Improved prognostic tools for DCIS patients are warranted to tailor adjuvant therapy. Here, we demonstrate that HER2 positive disease in the primary DCIS is associated with lower risk of recurrent invasive breast cancer. PMID- 26062615 TI - Validating reference microRNAs for normalizing qRT-PCR data in bovine oocytes and preimplantation embryos. AB - BACKGROUND: MicroRNAs (miRNAs) are small noncoding RNAs that act as post transcriptional regulators of gene targets. Accurate quantification of miRNA expression using validated internal controls should aid in the understanding of their role in epigenetic modification of genome function. To date, most studies that have examined miRNA expression levels have used the global mean expression of all expressed genes or the expression of reference mRNAs or nuclear RNAs for normalization. RESULTS: We analyzed the suitability of a number of miRNAs as potential expression normalizers in bovine oocytes and early embryos, and porcine oocytes. The stages examined were bovine oocytes at the germinal vesicle (GV) and metaphase II stages, bovine zygotes, 2, 4 and 8 cell embryos, morulae and blastocysts, as well as porcine cumulus oocyte complexes, GV, metaphase I and II oocytes. qRT-PCR was performed to quantify expression of miR-93, miR-103, miR 26a, miR-191, miR-23b, Let-7a and U6 for bovine samples and miR-21, miR-26a, miR 93, miR-103, miR-148a, miR-182 and miR-191 for porcine oocytes. The average starting material for each sample was determined using specific standard curves for each primer set. Subsequently, geNorm and BestKeeper software were used to identify a set of stably expressed miRNAs. Stepwise removal to determine the optimum number of reference miRNAs identified miR-93 and miR-103 as the most stably expressed in bovine samples and miR-26a, miR-191 and miR-93 in porcine samples. CONCLUSIONS: The combination of miR-93 and miR-103 is optimal for normalizing miRNA expression for qPCR experiments on bovine oocytes and preimplantation embryos; the preferred combination for porcine oocytes is miR 26a, miR-191 and miR-93. PMID- 26062616 TI - Computational modeling of peripheral pain: a commentary. AB - This commentary is intended to find possible explanations for the low impact of computational modeling on pain research. We discuss the main strategies that have been used in building computational models for the study of pain. The analysis suggests that traditional models lack biological plausibility at some levels, they do not provide clinically relevant results, and they cannot capture the stochastic character of neural dynamics. On this basis, we provide some suggestions that may be useful in building computational models of pain with a wider range of applications. PMID- 26062617 TI - [New Indings in Methotrexate Pharmacology - Diagnostic Possibilities and Impact on Clinical Care]. AB - Methotrexate is an anti-cancer drug used to treat several malignancies including pediatric acute lymphoblastic leukemia and choriocarcinoma. Despite recent advances in cancer chemotherapy, it remains a mainstay of therapy since its discovery in the early second half of the previous century. Moreover, low-dose methotrexate is a gold standard antirheumatic drug in the treatment of rheumatoid arthritis, psoriasis, systemic scleroderma and other autoimmune disorders. Side effects of methotrexate treatment are well known and described; however, their occurrence may often be unpredictable due to lack of specific biomarkers of toxicity. Methotrexate plasma levels are routinely monitored by therapeutic drug monitoring, nevertheless, occurrence and concentrations of its metabolites are not measured. During methotrexate treatment 7- hydroxymethotrexate and 2,4- diamino- N10- mehylpteroic acid appear in plasma. The latter can further be hydroxylated and glucuronidated resulting in five possible extracellular methotrexate metabolites. In addition, methotrexate is intracellularly converted to its active polyglutamylated forms. Therapeutic efficacy is dependent on formation of methotrexate polyglutamates as it keeps intracellular pool of the drug and enhances its affinity towards various target enzymes. In this study, we describe pharmacokinetic and pharmacodynamic characteristics of methotrexate metabolites. We also review methotrexate blood brain barrier transport to cerebrospinal fluid regarding its use in the prevention of leukemic central nervous system involvement and management of methotrexate toxicity with the use of carboxypeptidase- G2. Finally, we discuss laboratory methods for monitoring methotrexate metabolites and benefits of simultaneous determination of methotrexate and metabolites as possible biomarkers of therapeutic efficacy and clinical toxicity. PMID- 26062618 TI - [Early Integration of Palliative Care into Standard Oncology Care - Benefits, Limitations, Barriers and Types of Palliative Care]. AB - Patients with advanced cancer experience a significant number of physical symptoms and psychological distress, which worsen their quality of life (QOL). Palliative care is oriented to prevent and relieve suffering and promote QOL of patients with advanced cancer. In oncology, the role of palliative care is traditionally perceived to be the treatment after the antineoplastic therapy is finished. A concept of early integration of palliative care into standard oncology practice has been recently introduced. There is a lot of data supporting this concept of parallel application of both oncology care and palliative care. Early palliative care has been shown to provide benefits in QOL, mood, symptoms, health care utilization and survival. In this review, we summarize published data about benefits and difficulties of early palliative care. We also discuss the model of general and specialized palliative care integrated into oncological practice, their differences and consequences. PMID- 26062619 TI - [Anxio-depressive Syndrome - Biopsychosocial Model of Supportive Care]. AB - BACKGROUND: Acute stress in patients experiencing cancer diagnosis and the post traumatic stress disorder in cancer survivors results in impaired overall quality of life mainly due to associated psychological and physical alterations, including anxiety, depression, sleep disturbances, cognitive dysfunctions, fatigue, pain, cachexia and others. Recent studies revealed a new insight into molecular mechanisms contributing to the development of cancer-related co morbidities. It has been shown that adverse psychosomatic reactions including cancer depression to emotional cancer distress result from neuroendocrinne dysfunctions, disruption of the hypothalamus- pituitary-adrenal axis and sympathetic nervous system, serotonin-dopamine interactions and circadian sleep- wake rhythm disruption. AIM: The aim of the present study was to evaluate clinical studies oriented toward elucidation of the hypothesis that cancer related anxio- depressive syndrome is the major disorder leading to the development of accompanying psychosomatic disruptions. MATERIAL AND METHODS: The data of the biopsychosocial approach in the treatment of cancer presented in the current literature were collecting using appropriate electronic databases and were elaborated in the form of meta-analysis of 24 selected publications. RESULTS: According to relevant clinical studies, psychosocial interventions and psychopharmacological treatment has been shown to reduce cancer symptomatology and to improve the ability of patients to cope with the disease. Thus, one of the key pillars of supportive care in oncology is stress reduction. Cognitive- behavioral interventions and group psychosocial therapies have shown to reduce stress from the diagnosis and treatment, to palliate depression and to help in restoring the circadian rhythm. Psychopharamacological interventions are the most useful approaches in the reduction of stress-induced cancer comorbidities. In the presented study, a plausible role of stress reduction in the protection of cancer patients from posttraumatic and anxio- depressive syndrome, physical and psychical suffering, from decrease of patients quality of life, ability to cope with the disease and cooperate in cancer treatment has been analyzed. CONCLUSION: Implementation of the biopsychosocial model of cancer care needs further cooperation between behavioral scientists and clinical oncologists attempted to elucidate further possibilities of psychosocial and pharmacological interventions leading to the regulation of stress-induced alterations of the neurotransmitter system and neuroendocrinne dysfunctions reduction of cancer-related co morbidities and improvement of patients survival time. PMID- 26062620 TI - [Tumour Hypoxia - Molecular Mechanisms and Clinical Relevance]. AB - Oxygen is absolutely essential for correct functioning of living organisms and alterations in its concentration lead to serious consequences. In tumor tissues, oxygen plays an important role in energy production and modulation of red- ox balance. Insufficient oxygen supply within tissues results in hypoxia that is a characteristic feature of the tumor microenvironment. Hypoxia- inducible transcriptional factor represents a key executor of a cellular and molecular response to hypoxia and can activate the expression of more than hundred genes involved in various essential cellular processes. From the clinical point of view, phenotypic alterations caused by hypoxia are serious. Tumor hypoxia has been associated with resistance to therapy, disease progression and recurrence as well as increased mortality. Therefore, intratumoral hypoxia represents a clinically relevant problem, and its detection within tumors is very important for patient stratification for a suitable treatment. Currently available strategies directed towards the detection of hypoxic regions within tumor tissue suffer from numerous limitations e. g. invasiveness, inaccessibility of tumor tissue, low sensibility, inaccurate interpretation etc. On the other hand, the use of an intrinsic endogenous hypoxic marker, which can be detected through immunohistochemistry, is relatively simple, routinely available, and reproducible and can be performed on both prospective and retrospective samples. These include carbonic anhydrase IX (CA IX), one of the most strongly hypoxia-induced proteins and a prominent indicator of chronic hypoxia. Moreover, hypoxia-induced proteins (including CA IX) are also potential targets of anticancer therapy, and their practical application is a subject of intense research. PMID- 26062621 TI - Effect of Fractionated Irradiation on the Hippocampus in an Experimental Model. AB - BACKGROUND: Ionizing radiation induces altered brain tissue homeostasis and can lead to morphological and functional deficits. The aim of the present study was to investigate the short-term and long-term effect of ionizing radiation on cell population resides adult rat hippocampus. MATERIALS AND METHODS: Adult male Wistar rats received whole- brain irradiation with fractionated doses of gamma rays (a total dose of 20 Gy) and were investigated 30 and 100 days later. A combination of Fluoro-Jade C histochemistry for visualization of degenerating neurons, immunohistochemistry for detection of astrocytes and confocal microscopy were used to quantify the neurodegenerative changes in the hippocampal dentate gyrus and CA1 subfield. RESULTS: A significant increase of Fluoro-Jade C labelled neurons was seen in both of investigated areas through the whole experiment, predominantly 30 days after irradiation. Non- significant decrease of GFAP- immunoreactive astrocytes was found in the hippocampal dentate gyrus and CA1 subfield until 100 days after irradiation. CONCLUSION: Our recent results showed that radiation response of cell types resides the adult hippocampus may play contributory role in the development of adverse radiation-induced late effects. PMID- 26062622 TI - [Long Term Monitoring of Nutritional, Clinical Status and Quality of Life in Head and Neck Cancer Patients]. AB - BACKGROUND: Malnutrition in head and neck cancer (HNC) patients decreases survival, quality of life (QOL) and oncological outcomes. The aim of the prospective three-year study was to compare QOL, clinical symptoms and variables (complications, survival and mortality rates in HNC patients). PATIENTS AND METHODS: A total of 726 patients aged 55 to 72 years with treatable HNC were included from January 2004 to December 2009; these patients were randomized to either group with PEG and enteral nutrition and nonPEG group with nutritional counselling according to nutritional care. We used EORTC questionnaires QOL C-30 and Head and neck module (HN-35) for measuring of QOL. The following variables due to expectable influence on QOL (demographic data, oncological data, nutritional screening, Clinical symptom score, Karnofsky performance status score, Charlson comorbidity index) were included. Monitoring was done five times in three years. RESULTS: In the first six months, we found decrease of weight and body mass index (BMI). After this critical time point and finish of oncological treatment, a marked difference in the development of patients treated with PEG. Negative factors influencing patients survival, QOL, clinical status were males aged > 63 years, hypopharyngeal cancer (stage III- IV), smoking, weight loss > 10%, BMI < 21 and disallowance of PEG. CONCLUSIONS: QOL is an essential factor for cancer patients. Our study showed that nutritional intervention with early enteral nutrition may improve QOL and survival in HNC patients. The PEG group better tolerated oncological treatment, had lower incidence of complications, shorter time to re-entry of permanent increase in weight, lower rate of rehospitalization and its shorter length. We found QOL questionnaires to be very important for better understanding and communication and a key instrument for improving solution of patients difficulties during their therapy in multidisciplinary approach. PMID- 26062623 TI - A Very Rare Case - Hairy Cell Leukemia in Patient with Sarcoidosis. AB - Although the coexistence of hairy cell leukemia with sarcoidosis has been reported in a few cases in the literature, in our case the patient had been diagnosed and followed about 10 years with sarcoidosis and massive splenomegaly. It has been demonstrated that T helper 1 cells exist in organs influenced by sarcoidosis. These cells produce IL-2 and IFN-gamma and induce a nonspecific inflammatory response and granuloma formation. Also these cytokines may play a role in the development of hairy cell leukemia.Key words: hairy cell leukemia - sarcoidosis - massive splenomegaly. PMID- 26062624 TI - Shifting management of a community volunteer system for improved child health outcomes: results from an operations research study in Burundi. AB - BACKGROUND: Community-based strategies that foster frequent contact between caregivers of children under five and provide credible sources of health information are essential to improve child survival. Care Groups are a community based implementation strategy for the delivery of social and behavior change interventions. This study assessed if supervision of Care Group activities by Ministry of Health (MOH) personnel could achieve the same child health outcomes as supervision provided by specialized non-governmental organization (NGO) staff. METHODS: The study was a pretest-posttest quasi-experimental design implemented in Burundi. A total of 45 MOH-led Care Groups with 478 Care Group Volunteers (CGVs) were established in the intervention area; and 50 NGO-led Care Groups with 509 CGVs were formed in the comparison area. Data were collected from 593 and 700 mothers of children 0-23 months at baseline and endline, respectively. Pearson's chi-squared test and difference-in-difference analysis assessed changes in 40 child health and nutrition outcomes. A qualitative process evaluation was also conducted midway through the study. RESULTS: The MOH-led Care Group model performed at least as well as the NGO-led model in achieving specific child health and nutrition outcomes. Mothers of children 0-23 months in the intervention and comparison sites reported similar levels of knowledge and practices for 38 of 40 dependent variables measured in the study, and these results remained unchanged after accounting for differences in the indicator values at baseline. Process monitoring data confirmed that the MOH-led Care Group model and the NGO-led Care Group model were implemented with similar intervention strength. CONCLUSIONS: The study demonstrated that behavior change interventions traditionally led by NGOs can be implemented through the existing MOH systems and achieve similar results, thereby increasing the potential for sustainable child health outcomes. Future research on the MOH-led Care Group model is required to systematically document all inputs and monetary costs borne by the MOH to implement the model. PMID- 26062625 TI - The preclinical stage of spinocerebellar ataxias. AB - The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of degenerative diseases of the cerebellum and connected regions. The discovery of various SCA genes and the subsequent possibility of predictive testing currently allow a genetic diagnosis to be established years or even decades before the actual appearance of ataxia symptoms. A growing body of evidence, however, indicates that this preclinical stage is subject to the earliest pathophysiologic changes. This review article comprehensively summarizes the studies conducted in preclinical carriers of a mutation in one of the SCA genes. From these data, it can indeed be concluded that the preclinical phase in SCA is already characterized by detectable central and peripheral nervous system changes, which are reflected by subtle abnormalities during a careful clinical examination, changes in structural and functional brain imaging, abnormal neurophysiologic measurements, and/or altered motor learning paradigms. As these may be compensated for a long time, ataxia symptoms probably only appear after a certain threshold of dysfunction or degeneration has been exceeded. Detailed knowledge of this disease stage is of particular relevance for a better understanding of the pathogenesis of SCAs, will allow us to determine the optimal point in time for interventions in future therapeutic trials, and points to objective, valid biomarkers to assess disease progression. Further studies will benefit from a consensus-based definition of the preclinical stage, from using one and the same validated ataxia rating scale with one fixed cutoff value, and from applying similar mathematical models to calculate time to predicted disease onset. PMID- 26062628 TI - Network signatures of age-related cognitive decline. PMID- 26062626 TI - Age-specific penetrance of LRRK2 G2019S in the Michael J. Fox Ashkenazi Jewish LRRK2 Consortium. AB - OBJECTIVE: Estimates of the penetrance of LRRK2 G2019S vary widely (24%-100%), reflective of differences in ascertainment, age, sex, ethnic group, and genetic and environmental modifiers. METHODS: The kin-cohort method was used to predict penetrance in 2,270 relatives of 474 Ashkenazi Jewish (AJ) Parkinson disease (PD) probands in the Michael J. Fox LRRK2 AJ Consortium in New York and Tel Aviv, Israel. Patients with PD were genotyped for the LRRK2 G2019S mutation and at least 7 founder GBA mutations. GBA mutation carriers were excluded. A validated family history interview, including age at onset of PD and current age or age at death for each first-degree relative, was administered. Neurologic examination and LRRK2 genotype of relatives were included when available. RESULTS: Risk of PD in relatives predicted to carry an LRRK2 G2019S mutation was 0.26 (95% confidence interval [CI] 0.18-0.36) to age 80 years, and was almost 3-fold higher than in relatives predicted to be noncarriers (hazard ratio [HR] 2.89, 95% CI 1.73-4.55, p < 0.001). The risk among predicted G2019S carrier male relatives (0.22, 95% CI 0.10-0.37) was similar to predicted carrier female relatives (0.29, 95% CI 0.18 0.40; HR male to female: 0.74, 95% CI 0.27-1.63, p = 0.44). In contrast, predicted noncarrier male relatives had a higher risk (0.15, 95% CI 0.11-0.20) than predicted noncarrier female relatives (0.07, 95% CI 0.04-0.10; HR male to female: 2.40, 95% CI 1.50-4.15, p < 0.001). CONCLUSION: Penetrance of LRRK2 G2019S in AJ is only 26% and lower than reported in other ethnic groups. Further study of the genetic and environmental risk factors that influence G2019S penetrance is warranted. PMID- 26062627 TI - Cognitive activity relates to cognitive performance but not to Alzheimer disease biomarkers. AB - OBJECTIVE: We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer disease biomarkers. METHODS: In a cross-sectional study, we evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with mean age of 74 +/- 6 years. Using backward elimination general linear models, we tested the hypotheses that greater cognitive or physical activity would be associated with lower Pittsburgh compound B-PET retention, greater (18)F-fluorodeoxyglucose-PET metabolism, and larger hippocampal volume, as well as better cognitive performance on neuropsychological testing. RESULTS: Linear regression demonstrated that history of greater cognitive activity was correlated with greater estimated IQ and education, as well as better neuropsychological testing performance. Self-reported recent physical activity was related to objective exercise monitoring. However, contrary to hypotheses, we did not find evidence of an association of Pittsburgh compound B retention, (18)F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, or with current physical activity. CONCLUSIONS: We conclude that a history of lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain beta-amyloid burden, brain glucose metabolism, or hippocampal volume. PMID- 26062629 TI - Clinical effect of white matter network disruption related to amyloid and small vessel disease. AB - BACKGROUND: We tested our hypothesis that the white matter network might mediate the effect of amyloid and small vessel disease (SVD) on cortical thickness and/or cognition. METHODS: We prospectively recruited 232 patients with cognitive impairment. Amyloid was assessed using Pittsburgh compound B-PET. SVD was quantified as white matter hyperintensity volume and lacune number. The regional white matter network connectivity was measured as regional nodal efficiency by applying graph theoretical analysis to diffusion tensor imaging data. We measured cortical thickness and performed neuropsychological tests. RESULTS: SVD burden was associated with decreased nodal efficiency in the bilateral frontal, lateral temporal, lateral parietal, and occipital regions. Path analyses showed that the frontal nodal efficiency mediated the effect of SVD on the frontal atrophy and frontal-executive dysfunction. The temporoparietal nodal efficiency mediated the effect of SVD on the temporoparietal atrophy and memory dysfunction. However, Pittsburgh compound B retention ratio affected cortical atrophy and cognitive impairment without being mediated by nodal efficiency. CONCLUSIONS: We suggest that a disrupted white matter network mediates the effect of SVD, but not amyloid, on specific patterns of cortical atrophy and/or cognitive impairment. Therefore, our findings provide insight to better understand how amyloid and SVD burden can give rise to brain atrophy or cognitive impairment in specific patterns. PMID- 26062630 TI - Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. AB - OBJECTIVE: Diverse autolysosomal proteins were quantified in neurally derived blood exosomes from patients with Alzheimer disease (AD) and controls to investigate disordered neuronal autophagy. METHODS: Blood exosomes obtained once from patients with AD (n = 26) or frontotemporal dementia (n = 16), other patients with AD (n = 20) both when cognitively normal and 1 to 10 years later when diagnosed, and case controls were enriched for neural sources by anti-human L1CAM antibody immunoabsorption. Extracted exosomal proteins were quantified by ELISAs and normalized with the CD81 exosomal marker. RESULTS: Mean exosomal levels of cathepsin D, lysosome-associated membrane protein 1 (LAMP-1), and ubiquitinylated proteins were significantly higher and of heat-shock protein 70 significantly lower for AD than controls in cross-sectional studies (p <= 0.0005). Levels of cathepsin D, LAMP-1, and ubiquitinylated protein also were significantly higher for patients with AD than for patients with frontotemporal dementia (p <= 0.006). Step-wise discriminant modeling of the protein levels correctly classified 100% of patients with AD. Exosomal levels of all proteins were similarly significantly different from those of matched controls in 20 patients 1 to 10 years before and at diagnosis of AD (p <= 0.0003). CONCLUSIONS: Levels of autolysosomal proteins in neurally derived blood exosomes distinguish patients with AD from case controls and appear to reflect the pathology of AD up to 10 years before clinical onset. These preliminary results confirm in living patients with AD the early appearance of neuronal lysosomal dysfunction and suggest that these proteins may be useful biomarkers in large prospective studies. PMID- 26062631 TI - Differential localization of ion transporters suggests distinct cellular mechanisms for calcification and photosynthesis between two coral species. AB - Ion transport is fundamental for multiple physiological processes, including but not limited to pH regulation, calcification, and photosynthesis. Here, we investigated ion-transporting processes in tissues from the corals Acropora yongei and Stylophora pistillata, representatives of the complex and robust clades that diverged over 250 million years ago. Antibodies against complex IV revealed that mitochondria, an essential source of ATP for energetically costly ion transporters, were abundant throughout the tissues of A. yongei. Additionally, transmission electron microscopy revealed septate junctions in all cell layers of A. yongei, as previously reported for S. pistillata, as well as evidence for transcellular vesicular transport in calicoblastic cells. Antibodies against the alpha subunit of Na(+)/K(+)-ATPase (NKA) and plasma membrane Ca(2+) ATPase (PMCA) immunolabeled cells in the calicoblastic epithelium of both species, suggesting conserved roles in calcification. However, NKA was abundant in the apical membrane of the oral epithelium in A. yongei but not S. pistillata, while PMCA was abundant in the gastroderm of S. pistillata but not A. yongei. These differences indicate that these two coral species utilize distinct pathways to deliver ions to the sites of calcification and photosynthesis. Finally, antibodies against mammalian sodium bicarbonate cotransporters (NBC; SLC4 family) resulted in strong immunostaining in the apical membrane of oral epithelial cells and in calicoblastic cells in A. yongei, a pattern identical to NKA. Characterization of ion transport mechanisms is an essential step toward understanding the cellular mechanisms of coral physiology and will help predict how different coral species respond to environmental stress. PMID- 26062633 TI - Effects of cold water immersion and active recovery on hemodynamics and recovery of muscle strength following resistance exercise. AB - Cold water immersion (CWI) and active recovery (ACT) are frequently used as postexercise recovery strategies. However, the physiological effects of CWI and ACT after resistance exercise are not well characterized. We examined the effects of CWI and ACT on cardiac output (Q), muscle oxygenation (SmO2), blood volume (tHb), muscle temperature (Tmuscle), and isometric strength after resistance exercise. On separate days, 10 men performed resistance exercise, followed by 10 min CWI at 10 degrees C or 10 min ACT (low-intensity cycling). Q (7.9 +/- 2.7 l) and Tmuscle (2.2 +/- 0.8 degrees C) increased, whereas SmO2 (-21.5 +/- 8.8%) and tHb (-10.1 +/- 7.7 MUM) decreased after exercise (P < 0.05). During CWI, Q (-1.1 +/- 0.7 l) and Tmuscle (-6.6 +/- 5.3 degrees C) decreased, while tHb (121 +/- 77 MUM) increased (P < 0.05). In the hour after CWI, Q and Tmuscle remained low, while tHb also decreased (P < 0.05). By contrast, during ACT, Q (3.9 +/- 2.3 l), Tmuscle (2.2 +/- 0.5 degrees C), SmO2 (17.1 +/- 5.7%), and tHb (91 +/- 66 MUM) all increased (P < 0.05). In the hour after ACT, Tmuscle, and tHb remained high (P < 0.05). Peak isometric strength during 10-s maximum voluntary contractions (MVCs) did not change significantly after CWI, whereas it decreased after ACT ( 30 to -45 Nm; P < 0.05). Muscle deoxygenation time during MVCs increased after ACT (P < 0.05), but not after CWI. Muscle reoxygenation time after MVCs tended to increase after CWI (P = 0.052). These findings suggest first that hemodynamics and muscle temperature after resistance exercise are dependent on ambient temperature and metabolic demands with skeletal muscle, and second, that recovery of strength after resistance exercise is independent of changes in hemodynamics and muscle temperature. PMID- 26062632 TI - Orexin-A enhances feeding in male rats by activating hindbrain catecholamine neurons. AB - Both lateral hypothalamic orexinergic neurons and hindbrain catecholaminergic neurons contribute to control of feeding behavior. Orexin fibers and terminals are present in close proximity to hindbrain catecholaminergic neurons, and fourth ventricular (4V) orexin injections that increase food intake also increase c-Fos expression in hindbrain catecholamine neurons, suggesting that orexin neurons may stimulate feeding by activating catecholamine neurons. Here we examine that hypothesis in more detail. We found that 4V injection of orexin-A (0.5 nmol/rat) produced widespread activation of c-Fos in hindbrain catecholamine cell groups. In the A1 and C1 cell groups in the ventrolateral medulla, where most c-Fos positive neurons were also dopamine beta hydroxylase (DBH) positive, direct injections of a lower dose (67 pmol/200 nl) of orexin-A also increased food intake in intact rats. Then, with the use of the retrogradely transported immunotoxin, anti-DBH conjugated to saporin (DSAP), which targets and destroys DBH-expressing catecholamine neurons, we examined the hypothesis that catecholamine neurons are required for orexin-induced feeding. Rats given paraventricular hypothalamic injections of DSAP, or unconjugated saporin (SAP) as control, were implanted with 4V or lateral ventricular (LV) cannulas and tested for feeding in response to ventricular injection of orexin-A (0.5 nmol/rat). Both LV and 4V orexin-A stimulated feeding in SAP controls, but DSAP abolished these responses. These results reveal for the first time that catecholamine neurons are required for feeding induced by injection of orexin-A into either LV or 4V. PMID- 26062634 TI - Enhanced insulin signaling in human skeletal muscle and adipose tissue following gastric bypass surgery. AB - Roux-en-Y gastric bypass (RYGB) leads to increased peripheral insulin sensitivity. The aim of this study was to investigate the effect of RYGB on expression and regulation of proteins involved in regulation of peripheral glucose metabolism. Skeletal muscle and adipose tissue biopsies from glucose tolerant and type 2 diabetic subjects at fasting and during a hyperinsulinemic euglycemic clamp before as well as 1 wk and 3 and 12 mo after RYGB were analyzed for relevant insulin effector proteins/signaling components. Improvement in peripheral insulin sensitivity mainly occurred at 12 mo postsurgery when major weight loss was evident and occurred concomitantly with alterations in plasma adiponectin and in protein expression/signaling in peripheral tissues. In skeletal muscle, protein expression of GLUT4, phosphorylated levels of TBC1D4, as well as insulin-induced changes in phosphorylation of Akt and glycogen synthase activity were enhanced 12 mo postsurgery. In adipose tissue, protein expression of GLUT4, Akt2, TBC1D4, and acetyl-CoA carboxylase (ACC), phosphorylated levels of AMP-activated protein kinase and ACC, as well as insulin-induced changes in phosphorylation of Akt and TBC1D4, were enhanced 12 mo postsurgery. Adipose tissue from glucose-tolerant subjects was the most responsive to RYGB compared with type 2 diabetic patients, whereas changes in skeletal muscle were largely similar in these two groups. In conclusion, an improved molecular insulin sensitive phenotype of skeletal muscle and adipose tissue appears to contribute to the improved whole body insulin action following a substantial weight loss after RYGB. PMID- 26062636 TI - Estradiol augments while progesterone inhibits arginine transport in human endothelial cells through modulation of cationic amino acid transporter-1. AB - Decreased generation of nitric oxide (NO) by endothelial NO synthase (eNOS) characterizes endothelial dysfunction (ECD). Delivery of arginine to eNOS by cationic amino acid transporter-1 (CAT-1) was shown to modulate eNOS activity. We found in female rats, but not in males, that CAT-1 activity is preserved with age and in chronic renal failure, two experimental models of ECD. In contrast, during pregnancy CAT-1 is inhibited. We hypothesize that female sex hormones regulate arginine transport. Arginine uptake in human umbilical vein endothelial cells (HUVEC) was determined following incubation with either 17beta-estradiol (E2) or progesterone. Exposure to E2 (50 and 100 nM) for 30 min resulted in a significant increase in arginine transport and reduction in phosphorylated CAT-1 (the inactive form) protein content. This was coupled with a decrease in phosphorylated MAPK/extracellular signal-regulated kinase (ERK) 1/2. Progesterone (1 and 100 pM for 30 min) attenuated arginine uptake and increased phosphorylated CAT-1, phosphorylated protein kinase Calpha (PKCalpha), and phosphorylated ERK1/2 protein content. GO-6976 (PKCalpha inhibitor) prevented the progesterone-induced decrease in arginine transport. Coincubation with both progesterone and estrogen for 30 min resulted in attenuated arginine transport. While estradiol increases arginine transport and CAT-1 activity through modulation of constitutive signaling transduction pathways involving ERK, progesterone inhibits arginine transport and CAT-1 via both PKCalpha and ERK1/2 phosphorylation, an effect that predominates over estradiol. PMID- 26062637 TI - Ultrasonography of adnexal causes of acute pelvic pain in pre-menopausal non pregnant women. AB - Acute-onset pelvic pain is an extremely common symptom in premenopausal women presenting to the emergency department. After excluding pregnancy in reproductive age women, ultrasonography plays a major role in the prompt and accurate diagnosis of adnexal causes of acute pelvic pain, such as hemorrhagic ovarian cysts, endometriosis, ovarian torsion, and tubo-ovarian abscess. Its availability, relatively low cost, and lack of ionizing radiation make ultrasonography an ideal imaging modality in women of reproductive age. The primary goal of imaging in these patients is to distinguish between adnexal causes of acute pelvic pain that may be managed conservatively or medically, and those requiring emergency/urgent surgical or percutaneous intervention. PMID- 26062635 TI - Autonomic and inflammatory consequences of posttraumatic stress disorder and the link to cardiovascular disease. AB - Stress- and anxiety-related disorders are on the rise in both military and general populations. Over the next decade, it is predicted that treatment of these conditions, in particular, posttraumatic stress disorder (PTSD), along with its associated long-term comorbidities, will challenge the health care system. Multiple organ systems are adversely affected by PTSD, and PTSD is linked to cancer, arthritis, digestive disease, and cardiovascular disease. Evidence for a strong link between PTSD and cardiovascular disease is compelling, and this review describes current clinical data linking PTSD to cardiovascular disease, via inflammation, autonomic dysfunction, and the renin-angiotensin system. Recent clinical and preclinical evidence regarding the role of the renin-angiotensin system in the extinction of fear memory and relevance in PTSD-related immune and autonomic dysfunction is also addressed. PMID- 26062638 TI - Characteristics of breast cancer detected by supplementary screening ultrasonography. PMID- 26062639 TI - Elucidating low-frequency vibrational dynamics in calcite and water with time resolved third-harmonic generation spectroscopy. AB - Low-frequency vibrations are foundational for material properties including thermal conductivity and chemical reactivity. To resolve the intrinsic molecular conformational dynamics in condensed phase, we implement time-resolved third harmonic generation (TRTHG) spectroscopy to unravel collective skeletal motions in calcite, water, and aqueous salt solution in situ. The lifetime of three Raman active modes in polycrystalline calcite at 155, 282 and 703 cm(-1) is found to be ca. 1.6 ps, 1.3 ps and 250 fs, respectively. The lifetime difference is due to crystallographic defects and anharmonic effects. By incorporating a home-built wire-guided liquid jet, we apply TRTHG to investigate pure water and ZnCl2 aqueous solution, revealing ultrafast dynamics of water intermolecular stretching and librational bands below 500 cm(-1) and a characteristic 280 cm(-1) vibrational mode in the ZnCl4(H2O)2(2-) complex. TRTHG proves to be a compact and versatile technique that directly uses the 800 nm fundamental laser pulse output to capture ultrafast low-frequency vibrational motion snapshots in condensed phase materials including the omnipresent water, which provides the important time dimension to spectral characterization of molecular structure-function relationships. PMID- 26062640 TI - Interface Coupling in Twisted Multilayer Graphene by Resonant Raman Spectroscopy of Layer Breathing Modes. AB - Raman spectroscopy is the prime nondestructive characterization tool for graphene and related layered materials. The shear (C) and layer breathing modes (LBMs) are due to relative motions of the planes, either perpendicular or parallel to their normal. This allows one to directly probe the interlayer interactions in multilayer samples. Graphene and other two-dimensional (2d) crystals can be combined to form various hybrids and heterostructures, creating materials on demand with properties determined by the interlayer interaction. This is the case even for a single material, where multilayer stacks with different relative orientations have different optical and electronic properties. In twisted multilayer graphene there is a significant enhancement of the C modes due to resonance with new optically allowed electronic transitions, determined by the relative orientation of the layers. Here we show that this applies also to the LBMs, which can be now directly measured at room temperature. We find that twisting has a small effect on LBMs, quite different from the case of the C modes. This implies that the periodicity mismatch between two twisted layers mostly affects shear interactions. Our work shows that ultralow-frequency Raman spectroscopy is an ideal tool to uncover the interface coupling of 2d hybrids and heterostructures. PMID- 26062641 TI - Structure and Stability of Fish Oil Organogels Prepared with Sunflower Wax and Monoglyceride. AB - The aims of this study were to develop fish oil (FO) organogels with sunflower wax (SW) and monoglyceride (MG), and compare them with a commercial margarine (CM). The organogels were stored at 4 and 20 degrees C for 90 days and their storage stability was investigated. The color values, oil binding capacity, crystal formation time, solid fat content, thermal properties and crystal structures of the organogels were measured. During storage, their textural properties and peroxide values were monitored. The melting temperature of the MG organogels was found similar to that of the CM sample. Otherwise, the melting points of the MG gels were lower than those of the SW gels. Crystal morphology of the CM sample was found similar to MG gels by X-ray measurements. The firmness values of the SW organogels were higher than those of the MG gels. The peroxide values of all gels were within the legal limits. PMID- 26062642 TI - Determination of Other Related Carotenoids Substances in Astaxanthin Crystals Extracted from Adonis amurensis. AB - Astaxanthin is a kind of important carotenoids with powerful antioxidation capacity and other health functions. Extracting from Adonis amurensis is a promising way to obtain natural astaxanthin. However, how to ensure the high purity and to investigate related substances in astaxanthin crystals are necessary issues. In this study, to identify possible impurities, astaxanthin crystal was first extracted from Adonis amurensis, then purified by saponification and separation. The concentration of total carotenoids in purified astaxanthin crystals was as high as 97% by weight when analyzed by UV-visible absorption spectra. After identified with TLC, HPLC and MS, besides free astaxanthin as main ingredient in the crystals, there existed four other unknown related substances, which were further investigated by HPLC/ESI/MS with the positive ion mode combining with other auxiliary reference data obtained in stress tests, at last it was confirmed that four related carotenoids substances were three structural isomers of semi-astacene and adonirubin. PMID- 26062644 TI - Influenza case definitions - optimising sensitivity and specificity. PMID- 26062643 TI - Motor performance and correlates of mental health in children who are deaf or hard of hearing. AB - AIM: This cross-sectional study investigates the relationship between motor performance and mental health in a representative population of children with hearing impairment. METHOD: Ninety-three pupils (45 males, 48 females) aged 6 years to 16 years (mean 11 y 3 mo, SD 2 y 9 mo) with hearing impairment of at least 40 dB and a Nonverbal IQ greater than 70 were assessed for motor performance with the Zurich Neuromotor Assessment (ZNA) and for mental health with the parent version of the Strengths and Difficulties Questionnaire (SDQ). RESULTS: Children with hearing impairment had lower motor performance scores in all four ZNA subscales compared with ZNA norms (z-scores -1.42 to -2.67). After controlling for Nonverbal IQ, ZNA pure motor performance correlated negatively with the SDQ total difficulties score. Pure motor, pegboard, and dynamic balance subscales correlated negatively with peer-relationship problems. Dynamic balance correlated negatively with emotional problems. Performance in pure motor and dynamic balance skills correlated negatively with age. Except for static balance, no correlation was found between motor performance and the degree of hearing impairment. INTERPRETATION: Results confirm that a high percentage of children with hearing impairment have poor motor performance. These problems are associated with difficulties in social relationships. Early recognition of these problems may lead to interventions to assist children with hearing impairment with their peer relationships. PMID- 26062645 TI - Performance of case definitions for influenza surveillance. AB - Influenza-like illness (ILI) case definitions, such as those from the European Centre for Disease Control and Prevention, World Health Organization (WHO) and United States Centers for Disease Control and Prevention, are commonly used for influenza surveillance. We assessed how various case definitions performed during the initial wave of influenza A(H1N1) pdm09 infections in Singapore on a cohort of 727 patients with two to three blood samples and whose symptoms were reviewed fortnightly from June to October 2009. Using seroconversion (>= 4-fold rise) to A/California/7/2009 (H1N1), we identified 36 presumptive influenza A(H1N1)pdm09 episodes and 664 episodes unrelated to influenza A(H1N1)pdm09. Cough, fever and headache occurred more commonly in presumptive influenza A(H1N1)pdm09. Although the sensitivity was low (36%), the recently revised WHO ILI case definition gave a higher positive predictive value (42%) and positive likelihood ratio (13.3) than the other case definitions. Results including only episodes with primary care consultations were similar. Individuals who worked or had episodes with fever, cough or sore throat were more likely to consult a physician, while episodes with Saturday onset were less likely, with some consultations skipped or postponed. Our analysis supports the use of the revised WHO ILI case definition, which includes only cough in the presence of fever defined as body temperature >= 38 degrees C for influenza surveillance. PMID- 26062646 TI - Hepatitis C virus infection among pregnant women in Slovenia: study on 31,849 samples obtained in four screening rounds during 1999, 2003, 2009 and 2013. AB - The majority of people infected with hepatitis C virus (HCV) are unaware of their infection. Assessment of the prevalence of HCV infection in the general population and in key populations at increased risk is needed for evidence-based testing policies. Our objectives were to estimate the prevalence of antibodies to HCV (anti-HCV), the prevalence of HCV viraemia (HCV RNA), and to describe HCV genotype distribution among pregnant women in Slovenia. Unlinked anonymous testing was performed on residual sera obtained from 31,849 pregnant women for routine syphilis screening during 1999, 2003, 2009, and 2013. Anti-HCV reactive specimens were tested for HCV RNA and HCV genotypes were determined. Annual prevalence of anti-HCV ranged between 0.09% (95% confidence interval (CI): 0.03 0.18) in 2009 and 0.21% (95% CI: 0.12-0.34) in 2003 and HCV RNA positivity between 0.06% (95% CI: 0.02-0.14) in 2009 and 0.14% (95% CI: 0.07-0.25) in 2003. We observed no statistically significant differences in anti-HCV or HCV RNA prevalence between age groups (<20, 20-29 and >=30 years) in any year and no trend in time. Of 29 HCV active infections, 19 were with genotype 1 and 10 with genotype 3. HCV infection among pregnant women was rare suggesting a low burden in the Slovenian general population. Antenatal screening for HCV in Slovenia could not be recommended. PMID- 26062647 TI - ECDC publishes new interactive online tool: West Nile fever maps for 2015. PMID- 26062650 TI - Emergence of a Novel Binary Toxin-Positive Strain of Clostridium difficile Associated With Severe Diarrhea That Was Not Ribotype 027 and 078 in China. PMID- 26062651 TI - Purine analogue ENERGI-F706 induces apoptosis of 786-O renal carcinoma cells via 5'-adenosine monophosphate-activated protein kinase activation. AB - Purine compounds are known to activate 5'-adenosine monophosphate-activated protein kinase (AMPK), which has important roles in treatments for renal cell carcinoma. The present study was aimed to investigate the effects of the purine analogue ENERGI-F706 on the human renal carcinoma cell line 786-O and the underlying mechanisms. The results revealed that ENERGI-F706 (0.2-0.6 mg/ml) significantly decreased the cell viability to up to 36.4+/-2.4% of that of the control. Compared to 786-O cells, ENERGI-F706 exerted less suppressive effects on the viability of the human non-tumorigenic renal cell line HK-2. Flow cytometric analysis showed that ENERGI-F706 contributed to cell cycle arrest at S-phase and triggered apoptosis of 786-O cells. Immunoblot analysis revealed that anti apoptotic B-cell lymphoma 2 (Bcl-2) levels were reduced and pro-apoptotic Bcl-2 associated X protein levels were diminished. In addition, activation of caspase 9, caspase-3 and poly(adenosine diphosphate ribose) polymerase (PARP) was promoted in 786-O cells in response to ENERGI-F706. Effects of ENERGI-F706 on AMPK cascades were investigated and the results showed that ENERGI-F706 enhanced phosphorylation of AMPKalpha (T172) and p53 (S15), a downstream target of AMPK. In addition, the AMPK activation, p53 (S15) phosphorylation, reduction of Bcl-2, cleavage of caspase-3 and PARP as well as suppressed cell viability induced by ENERGI-F706 were reversed in the presence of AMPK inhibitor compound C (dorsomorphin). In conclusion, the findings of the present study revealed that ENERGI-F706 significantly suppressed the viability of 786-O cells via induction of cell cycle arrest and apoptosis, attributing to AMPK and p53 activation and subsequent cell cycle regulatory and apoptotic signaling. It was therefore indicated that ENERGI-F706 may be suitable for the treatment of renal cell carcinoma. PMID- 26062652 TI - Implications of skeletal muscle loss for public health nutrition messages: a brief report. AB - Age-related skeletal muscle loss, sarcopenia, cachexia and wider malnutrition (under nutrition) are complex in aetiology with interaction of clinical, social and economic factors. Weight loss and loss of skeletal muscle mass in older people are associated with increased morbidity and mortality with implications for increasing health and social care costs. There is insufficient evidence to identify the ideal treatment options. However, preventing weight loss and loss of skeletal muscle in older age will be keys to reducing morbidity and mortality. This will require all those coming into contact with older people to identify and address weight loss early, including through diet, improving physical activity and increasing social interaction. Public health messages on diet should, in the main, continue to focus on older people achieving current UK dietary recommendations for their age as visually depicted in the eatwell plate together with associated messages regarding dietary supplements where appropriate. PMID- 26062654 TI - 111In-cetuximab as a diagnostic agent by accessible epidermal growth factor (EGF) receptor targeting in human metastatic colorectal carcinoma. AB - Colorectal adenocarcinoma is a common cause death cancer in the whole world. The aim of this study is to define the 111In-cetuximab as a diagnosis tracer of human colorectal adenocarcinoma. In this research, cell uptake, nano-SPECT/CT scintigraphy, autoradiography, biodistribution and immunohitochemical staining of EGF receptor were included. HCT-116 and HT-29 cell expressed a relatively high and moderate level of EGF receptor, respectively. The nano-SPECT/CT image of 111In-cetuximab showed tumor radiation uptake of subcutaneous HCT-116 xenograft tumor was higher than SW-620. Autoradiography image also showed that tumor of HCT 116 had high 111In-cetuximab uptake. Mice that bearing CT-26 in situ xenograft colorectal tumors showed similar high uptake in vivo and ex vivo through nano SPECT/CT imaging at 72 hours. Metastatic HCT-116/Luc tumors demonstrated the highest uptake at 72 hours after the injection of 111In-cetuximab. Relatively, results of 111In-DTPA showed that metabolism through urinary system, especially in the kidney. The quantitative analysis of biodistribution showed count value of metastatic HCT-116/Luc tumors that treated with 111In-cetuximab had a significant difference (P < 0.05) compared with that treated with 111In-DTPA after injection 72 hours. Result of immunohistologic staining of EGF receptor also showed high EGF receptor expression and uptake in metastatic colorectal tumors. In summary, we suggested that 111In-cetuximab will be a potential tool for detecting EGF receptor expression in human metastatic colorectal carcinoma. PMID- 26062653 TI - Dual regulation by microRNA-200b-3p and microRNA-200b-5p in the inhibition of epithelial-to-mesenchymal transition in triple-negative breast cancer. AB - Epithelial to mesenchymal transition (EMT) involves loss of an epithelial phenotype and activation of a mesenchymal one. Enhanced expression of genes associated with a mesenchymal transition includes ZEB1/2, TWIST, and FOXC1. miRNAs are known regulators of gene expression and altered miRNA expression is known to enhance EMT in breast cancer. Here we demonstrate that the tumor suppressive miRNA family, miR-200, is not expressed in triple negative breast cancer (TNBC) cell lines and that miR-200b-3p over-expression represses EMT, which is evident through decreased migration and increased CDH1 expression. Despite the loss of migratory capacity following re-expression of miR-200b-3p, no subsequent loss of the conventional miR-200 family targets and EMT markers ZEB1/2 was observed. Next generation RNA-sequencing analysis showed that enhanced expression of pri-miR-200b lead to ectopic expression of both miR-200b-3p and miR 200b-5p with multiple isomiRs expressed for each of these miRNAs. Furthermore, miR-200b-5p was expressed in the receptor positive, epithelial breast cancer cell lines but not in the TNBC (mesenchymal) cell lines. In addition, a compensatory mechanism for miR-200b-3p/200b-5p targeting, where both miRNAs target the RHOGDI pathway leading to non-canonical repression of EMT, was demonstrated. Collectively, these data are the first to demonstrate dual targeting by miR-200b 3p and miR-200b-5p and a previously undescribed role for microRNA processing and strand expression in EMT and TNBC, the most aggressive breast cancer subtype. PMID- 26062655 TI - Maintaining human fetal pancreatic stellate cell function and proliferation require beta1 integrin and collagen I matrix interactions. AB - Pancreatic stellate cells (PaSCs) are cells that are located around the acinar, ductal, and vasculature tissue of the rodent and human pancreas, and are responsible for regulating extracellular matrix (ECM) turnover and maintaining the architecture of pancreatic tissue. This study examines the contributions of integrin receptor signaling in human PaSC function and survival. Human PaSCs were isolated from pancreata collected during the 2nd trimester of pregnancy and identified by expression of stellate cell markers, ECM proteins and associated growth factors. Multiple integrins are found in isolated human PaSCs, with high levels of beta1, alpha3 and alpha5. Cell adhesion and migration assays demonstrated that human PaSCs favour collagen I matrix, which enhanced PaSC proliferation and increased TGFbeta1, CTGF and alpha3beta1 integrin. Significant activation of FAK/ERK and AKT signaling pathways, and up-regulation of cyclin D1 protein levels, were observed within PaSCs cultured on collagen I matrix. Blocking beta1 integrin significantly decreased PaSC adhesion, migration and proliferation, further complementing the aforementioned findings. This study demonstrates that interaction of beta1 integrin with collagen I is required for the proliferation and function of human fetal PaSCs, which may contribute to the biomedical engineering of the ECM microenvironment needed for the efficient regulation of pancreatic development. PMID- 26062656 TI - Reversing stem cell aging. PMID- 26062657 TI - The effectiveness of caregiver social support is associated with cancer survivors' memories of stem cell transplantation: A linguistic analysis of survivor narratives. AB - OBJECTIVE: People who undergo hematopoietic stem cell transplantation are highly dependent on their caregiver during their lengthy treatment and recovery. The effectiveness of their caregiver's social support can profoundly affect their day to-day treatment experiences and, in turn, how they recall those experiences and are affected by them long after the treatment ends. METHOD: Our participants were 182 men and women who had undergone a transplant within the previous 9 months to 3 years. They completed baseline measures (including a measure of caregiver social support effectiveness) and then completed three writing assignments describing their transplant experiences. Linguistic analyses were conducted to investigate their use of words indicating negative emotions, cognitive processing (insight and causation), and practical problems with money and insurance. Theory based hypotheses predicted associations between specific functional types of caregiver support (emotional, informational, and instrumental) and these word categories. RESULTS: As hypothesized, the effectiveness of different functional types of support from a caregiver were uniquely associated with theoretically relevant categories of word use. Structural equation models indicated that more effective caregiver emotional support predicted lower use of negative emotion words; more effective caregiver informational support predicted lower use of causation words; and more effective caregiver instrumental support predicted lower use of words related to money and insurance. SIGNIFICANCE OF RESULTS: Our findings provide insights to guide research on the mechanisms through which caregiver support influences patient outcomes after stem cell transplantation. For instance, research suggests that these kinds of effects could have implications for survivors' current self-concept, psychosocial functioning, and meaning-making. PMID- 26062658 TI - Lifetime trauma victimization and PTSD in relation to psychopathy and antisocial personality disorder in a sample of incarcerated women and men. AB - PURPOSE: Antisocial personality disorder (ASPD) and psychopathy are similar, but distinct, psychiatric conditions that are common in male and female inmates; a segment of the population with high rates of trauma exposure. It is unclear whether specific types of lifetime trauma are associated with ASPD and psychopathy in incarcerated women and men. Furthermore, the unique roles of post traumatic stress disorder (PTSD) symptom severity and trauma victimization in antisocial personality disturbance are not well-understood. The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: This study investigated associations between trauma variables (different kinds of traumatic experiences and PTSD) and antisocial personality variables (ASPD and psychopathy) in a sample of incarcerated women and men who participated in a randomized clinical trial for major depressive disorder. In total, 88 incarcerated men and women were assessed for ASPD diagnosis, psychopathy severity, PTSD symptom severity, and history of physical, sexual, and crime-related trauma. Regression analyses predicted ASPD or psychopathy from trauma variables, controlling for gender. FINDINGS: Physical trauma was the only form of trauma that was significantly related to psychopathy. Physical trauma and crime-related trauma were associated with ASPD. PTSD symptom severity was not associated with psychopathy or ASPD. ORIGINALITY/VALUE: There are associations between some kinds of lifetime trauma exposure and current ASPD/psychopathy in the target sample, but these associations do not appear to be mediated through current PTSD symptoms. PMID- 26062659 TI - Alcohol-related risk and harm amongst young offenders aged 11-17. AB - PURPOSE: The purpose of this paper is to examine the prevalence of alcohol use disorders (AUDs) amongst young people in the criminal justice system (CJS) in the North East of England and to compare the ability of the Alcohol Use Disorders Identification Test (AUDIT) to the Youth Justice Board ASSET tool in identifying alcohol-related need in Youth Offending Team (YOT) clients. DESIGN/METHODOLOGY/APPROACH: A validated screening tool (AUDIT) was used to identify alcohol-related health risk or harm. Findings from AUDIT were compared with those of the standard criminogenic risk screening tool used in CJS (ASSET). An anonymous cross-sectional questionnaire was administered during a one-month period in 2008. The questionnaires were completed by 11-17-year-old offenders who were in contact with three YOTs, one Youth Offending Institution and one Secure Training Estate. FINDINGS: In total, 429 questionnaires were completed out of a possible 639 (67 per cent). The majority (81 per cent) of the young offenders were identified as experiencing alcohol-related health risk or harm and 77 per cent scored within a possibly alcohol-dependent range. In total, 77 (30 per cent) of young people completing both assessments were identified as having an AUD by AUDIT but not identified as needing alcohol-related treatment using ASSET. RESEARCH LIMITATIONS/IMPLICATIONS: This research was confined to one geographical area of England, however, the results show that even in this area of high drinking by young people the levels of AUDs amongst young people in the CJS are very high. Social implications - There are major social implications to this research. It is imperative for changes to be made to the care pathways in place in the UK for young people coming through the CJS with alcohol-related issues. ORIGINALITY/VALUE: This paper adds to the evidence base by using well-validated tools to measure alcohol use amongst young people in the CJS in the UK. PMID- 26062660 TI - Expert views of peer-based interventions for prisoner health. AB - PURPOSE: Formalised support services for prisoners that rely on peer methods of delivery show promising health and social outcomes but there is also conjecture that negative effects, both at an individual and organisational level, can occur. The paper aims to discuss these issues. DESIGN/METHODOLOGY/APPROACH: Individuals with recognised professional expertise from various sectors (including ex prisoners) were invited to contribute to an expert symposium to share their perceptions of the positive and negative effects of peer interventions in prison. Discussions and debate were audio recorded with the consent of all delegates and verbatim transcripts were analysed using framework analysis. FINDINGS: According to the participants, peer interventions in the prison setting created both positive and negative impacts. It was clear from the evidence gathered that peer interventions in prisons can impact positively on health outcomes, but these effects were perceived to be more well-defined for peer deliverers. The notion that peer deliverers can be subjected to "burnout" suggests that supervisory processes for peer workers need to be considered carefully in order to avoid the intervention from being counter-productive. Organisationally, one of the salient issues was the adverse effects that peer interventions cause to the security of the prison. ORIGINALITY/VALUE: To the authors' knowledge, this is the first time an expert symposium has been conducted to specifically examine peer interventions in prison and to consider the effects, both positive and negative, of such schemes. PMID- 26062661 TI - Criminal social identity and suicide ideation among Pakistani young prisoners. AB - PURPOSE: Suicidal behaviour is a common in prisoners, yet little is known about the factors that may protect against thoughts of ending one's life. The purpose of this paper is to specify and test a structural model to examine the relationship between three criminal social identity (CSI) dimensions (in-group affect, in-group ties, and cognitive centrality) and suicide ideation while controlling for period of confinement, age, criminal friends, and offense type (violent vs non-violent). DESIGN/METHODOLOGY/APPROACH: Participants were 415 male juvenile offenders incarcerated in prisons in Khyber Pakhtunkhwa Pakistan. A structural model was specified and tested using Mplus to examine the relationships between the three factors of CSI and suicidal thoughts, while controlling for age, offender type, period of confinement, and substance dependence. FINDINGS: The model provided an adequate fit for the data, explaining 22 per cent of variance in suicidal thoughts. In-group affect (the level of personal bonding with other criminals) was found to exert a strong protective effect against suicide ideation. ORIGINALITY/VALUE: The research contributes important information on suicide ideation in Pakistan, an Islamic country in which suicide is considered a sin and subsequently a criminal offence. Results indicate that Juvenile offenders' sense of shared identity may help to prevent the development of thoughts of death by suicide. Consequently, separating and isolating young prisoners may be ill advised. PMID- 26062662 TI - Influence of offence type and prior imprisonment on risk of death following release from prison: a whole-population linked data study. AB - PURPOSE: The purpose of this paper is to examine the influence of offence type, prior imprisonment and various socio-demographic characteristics on mortality at 28 and 365 days following prison release. DESIGN/METHODOLOGY/APPROACH: Using whole-population linked, routinely collected administrative state-based imprisonment and mortality data, the authors conducted a retrospective study of 12,677 offenders released from Western Australian prisons in the period 1994 2003. Cox proportional hazards regression was used to examine the association between mortality at 28 and 365 days post-release and offence type, prior imprisonment, and a range of socio-demographic characteristics (age, gender, social disadvantage and Indigenous status). FINDINGS: Overall, 135 (1.1 per cent) died during the 365 days follow-up period, of these, 17.8 per cent (n=24) died within the first 28 days (four weeks) of their index release. Ex-prisoners who had committed drug-related offences had significantly higher risk of 28-day post release mortality (HR=28.4; 95 per cent CI: 1.3-615.3, p=0.033), than those who had committed violent (non-sexual) offences. A significant association was also found between the number of previous incarcerations and post-release mortality at 28 days post-release, with three prior prison terms carrying the highest mortality risk (HR=73.8; 95 per cent CI: 1.8-3,092.5, p=0.024). No association between mortality and either offence type or prior imprisonment was seen at 365 days post-release. ORIGINALITY/VALUE: Post-release mortality at 28 days was significantly associated with offence type (with drug-related offences carrying the greatest risk) and with prior imprisonment, but associations did not persist to 365 days after release. Targeting of short-term transitional programmes to reduce preventable deaths after return to the community could be tailored to these high-risk ex-prisoners. PMID- 26062663 TI - En face Doppler total retinal blood flow measurement with 70 kHz spectral optical coherence tomography. AB - An automated algorithm was developed for total retinal blood flow (TRBF) using 70 kHz spectral optical coherence tomography (OCT). The OCT was calibrated for the transformation from Doppler shift to speed based on a flow phantom. The TRBF scan pattern contained five repeated volume scans (2 x 2 mm) obtained in 3 s and centered on central retinal vessels in the optic disc. The TRBF was calculated using an en face Doppler technique. For each retinal vein, blood flow was measured at an optimal plane where the calculated flow was maximized. The TRBF was calculated by summing flow in all veins. The algorithm tracked vascular branching so that either root or branch veins are summed, but never both. The TRBF in five repeated volumes were averaged to reduce variation due to cardiac cycle pulsation. Finally, the TRBF was corrected for eye length variation. Twelve healthy eyes and 12 glaucomatous eyes were enrolled to test the algorithm. The TRBF was 45.4 +/- 6.7 MUl/min for healthy control and 34.7 +/- 7.6 MUl/min for glaucomatous participants (p-value = 0.01). The intravisit repeatability was 8.6% for healthy controls and 8.4% for glaucoma participants. The proposed automated method provided repeatable TRBF measurement. PMID- 26062665 TI - [Picture in clinical hematology]. PMID- 26062664 TI - MicroRNA-153 is a prognostic marker and inhibits cell migration and invasion by targeting SNAI1 in human pancreatic ductal adenocarcinoma. AB - Human pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with early metastasis, which leads to poor prognosis for patients. Mounting evidence suggests that microRNAs (miRNAs) act as critical factors for tumor recurrence and metastasis. miR-153 has been suggested as a novel tumor-associated miRNA, which is involved in tumor metastasis. However, the clinical significance of miR-153 and its role in PDAC remains to be investigated. The aim of the present study was to investigate the expression levels of miR-153 using RT-qPCR in human PDAC cell lines and tissues. A clinical association analysis was performed to investigate the clinical significance of miR-153. The results showed that, the relative expression of miR-153 in PDAC cells was obviously decreased as compared to that in the normal human pancreatic duct epithelial cell line. The mean expression of miR-153 in PDAC tissues was significantly reduced as compared to that in the normal pancreatic tissues. The clinical analysis revealed that a low expression of miR-153 was closely associated with poor prognostic features and shorter long term survival of PDAC patients. Furthermore, univariate and multivariate Cox regression analyses showed that miR-153 was an independent prognostic factor for predicting survival in PDAC patients. In vitro studies demonstrated that the upregulation of miR-153 inhibited migration and invasion in MIAPaCa-2 cells. By contrast, the downregulation of miR-153 increased the number of migrated and invaded AsPC-1 cells. miR-153 inversely regulated SNAI1 abundance in MIAPaCa-2 cells. Notably, SNAI1 was identified as a direct target of miR-153 in PDAC. Furthermore, an inverse correlation between miR-153 and SNAI1 expression was observed in PDAC tissues. In conclusion, the results showed miR-153 is an independent prognostic marker for predicting survival in PDAC patients and inhibits cell migration and invasion by targeting SNAI1. PMID- 26062666 TI - Unrelated cord blood transplantation vs. related transplantation with HLA 1 antigen mismatch in the GVH direction. AB - The donor selection superiority of HLA 1-antigen mismatched related donor versus unrelated cord blood (UCB) is an important issue for patients without an HLA matched related or unrelated donor. Using Japanese registry data, we analyzed patients with leukemia and myelodysplastic syndrome who received transplantation using UCB or from a related donor with 1-antigen mismatch in the graft-versus host (GVH) direction (RD/1AG-MM-GVH). Compared to the UCB group, neutrophil engraftment was significantly faster, and the incidences of acute and chronic GVHD were significantly higher in the RD/1AG-MM-GVH group. As a result, there was no significant difference in overall survival between transplantation using the RD/1AG-MM-GVH and UCB. However, the HLA-B-antigen mismatched group showed significantly inferior overall survival. The RD/1AG-MM-GVH group using anti thymocyte globulin (ATG) showed neutrophil engraftment comparable to that of the non-ATG group and a GVHD incidence similar to that of the UCB group, which resulted in a better overall survival rate in the ATG than in the UCB group. In particular, the adverse effects of HLA-B mismatch were not observed in the ATG group. RD/1AGMM-GVH transplantation using ATG could potentially improve outcomes, and a prospective study of RD/1AGMM-GVH transplantation using low-dose ATG is currently ongoing. PMID- 26062667 TI - Role of endothelial antigen ESAM in activated hematopoietic stem cells. AB - Through their differentiation and self-renewal capabilities, hematopoietic stem cells (HSCs) supply the vast amounts of blood cells needed throughout life. The use of surface markers to purify HSCs has been promoted. After bone marrow injury, however, HSCs are activated, and the expression pattern of HSC-related antigens changes dramatically. Endothelial cell-selective adhesion molecule (ESAM), an immunoglobulin superfamily protein, was originally identified as an endothelium-specific molecule. We recently reported ESAM as a new HSC marker. In the present study, we demonstrate the monitoring of ESAM levels to provide a useful indicator of HSC activation. Expression levels of ESAM clearly mirrored shifts in HSC status between quiescence and activation, and the shifts were more prominent than those of other HSC-related antigens. ESAMHi HSCs were active in the cell cycle while maintaining a high capacity for long-term reconstitution. More than 80% of ESAMHi HSCs were located near endothelium in the bone marrow after 5-FU treatment. Furthermore, ESAM is functionally important for HSCs to re establish homeostatic hematopoiesis. Our data demonstrate ESAM expression levels to be useful for monitoring HSC status, tracing the proliferation of HSCs in vivo and understanding the molecular events underlying HSC activation. PMID- 26062668 TI - Pharmacokinetics of 8 mg/kg anti-human T-lymphocyte rabbit immunoglobulin conditioning for hematopoietic stem cell transplantation in Japanese patients. AB - Anti-human T-lymphocyte immunoglobulin, rabbit (ATG, Zetbulin((r)) intravenous infusion liquid), is an immunosuppressive agent that is indicated for aplastic anemia in Japan. The "prevention of graft-versus-host disease (GVHD) for allogeneic hematopoietic stem cell transplantation in adults" indication has been added to ATG in 32 countries worldwide, but has not yet been approved for GVHD prevention in Japan. The pharmacokinetics of ATG in Japanese people has not yet been assessed. In this study, to assess ATG pharmacokinetics, ATG (2 mg/kg/day from day-4 to day-1) as a pretransplant treatment was administered to six patients who had received transplantation of HLA-haploidentical stem cells. The ATG concentration was measured using an ELISA kit for rabbit IgG. The serum ATG concentration increased with administration for 4 consecutive days, peaking at a concentration of 66.0 MUg/ml (+/-8.8 SD). Subsequently, it gradually decreased with an elimination half-life of 21.9 days (+/-20.4 SD) but was still detectable in serum even a few weeks after allogeneic hematopoietic stem cell transplantation. We found the pharmacokinetics of ATG in this study to be comparable to those described in previous reports from Europe. PMID- 26062669 TI - Incidental detection of congenital Robertsonian translocation at diagnosis of Philadelphia chromosome-positive acute lymphocytic leukemia. AB - A man in his early forties who had undergone 3 years of unsuccessful treatment for infertility due to oligospermia and asthenospermia developed fever and bone pain in December 20XX. He was subsequently diagnosed with acute lymphocytic leukemia. Conventional cytogenetic analysis revealed Robertsonian translocation (RT) with der(13;14)(q10;q10) in addition to the Philadelphia (Ph) chromosome. Dasatinib and prednisolone induced complete remission (CR) with disappearance of the Ph chromosome. However, RT persisted despite achieving CR. We speculate that RT is possibly congenital in our present case and might also have been responsible for the aforementioned infertility. Hematologists should be aware of the possibility that congenital chromosomal disorders might be found incidentally through diagnostic chromosome analysis for leukemia. PMID- 26062670 TI - Chronic GVHD complicated with polymyositis and cardiomyopathy after myeloablative hematopoietic stem cell transplantation. AB - A 50-year-old woman presented with leukocytosis, anemia, and thrombocytopenia in June 2013. She was diagnosed with de novo acute myeloid leukemia with the t(16;21)(q24;q22) translocation. She received an allogeneic hematopoietic stem cell transplant from an HLA-DRB1 locus-mismatched unrelated donor in June 2014. The myeloablative preparative regimen consisted of cyclophosphamide at 60 mg/kg for 2 days and total body irradiation at 12 Gy. On Day 55, she was treated with prednisolone at 20 mg/day for acute GVHD (Grade III; Skin Stage 2, Gut Stage 2, Liver Stage 0) and gradually improved. She had fever, myalgia in the upper limbs, and asymptomatic sinus tachycardia on Day 145. Laboratory tests showed elevated CK, CKMB, aldolase, and troponin I. Electromyographic examination revealed myopathic abnormalities compatible with the diagnosis of myositis. Electrocardiography showed tachycardia and anteroseptal ST elevation, and echocardiography showed hypokinesia of the left interventricular septal wall without evidence of infection or leukemia relapse. She was immediately treated with 40 mg/day prednisolone after the diagnosis of polymyositis and cardiomyopathy, associated with chronic GVHD. The polymyositis and cardiomyopathy improved promptly after the administration of prednisolone and the patient remains in remission with a current maintenance program of prednisolone at 5 mg/day. PMID- 26062671 TI - Severe fever with thrombocytopenia syndrome mimicking intravascular lymphoma. AB - A 63-year-old woman was admitted to our hospital, because of a high fever and general malaise which had persisted for several days. Laboratory findings showed leucopenia, thrombocytopenia, and abnormal liver functions. A bone marrow smear revealed hemophagocytosis. Since a diagnosis of intravascular large B cell lymphoma was strongly suspected, a random skin biopsy was performed but revealed no evidence of malignant lymphoma. She was treated with steroids, blood product transfusions, and antibiotics, and then gradually recovered. The severe fever with thrombocytopenia syndrome (SFTS) viral genome was detected in her serum obtained in the acute phase. Therefore, the final diagnosis was SFTS, which is among the major causes of hemophagocytic syndrome. PMID- 26062672 TI - Development of acquired hemophilia A during treatment of multiple myeloma with lenalidomide. AB - We describe a 67-year-old female demonstrating symptomatic multiple myeloma (MM) with anemia and bone lesions initially diagnosed in 2009. Although a partial response was achieved after bortezomib and dexamethasone treatment, MM recurred in 2012. Therefore, treatment with lenalidomide, cyclophosphamide, and dexamethasone was commenced. Coagulation tests conducted prior to the chemotherapy were normal. Lenalidomide was discontinued after 10 days due to exacerbation of renal dysfunction. Simultaneously, activated partial thromboplastin time (APTT) was prolonged to 89.5 seconds. The mixing test showed an inhibitor pattern, with factor VIII at 2% and factor VIII inhibitor at 4.85 BU/ml. A diagnosis of acquired hemophilia A was made, and treatment with prednisolone was started, after which APTT improved to 36.4 seconds and factor VIII inhibitor decreased to 1.09 BU/ml. The factor VIII inhibitor level again increased concomitantly with restarting lenalidomide, which was, therefore, discontinued, while immunosuppressive therapy was administered with the addition of cyclophosphamide. Factor VIII inhibitor gradually disappeared from the patient's blood over the next four months. To the best of our knowledge, this is the first description of lenalidomide as a possible cause of acquired hemophilia A. Our experience indicates that we need to pay attention to acquired hemophilia A after initiating lenalidomide therapy in patients with hematologic malignancies. PMID- 26062673 TI - Young adult onset systemic Epstein-Barr virus-positive T-cell lymphoproliferative disorders of childhood. AB - A 20-year-old woman had a fever, pancytopenia, and liver failure, and was suspected to be suffering from chronic active Epstein-Barr virus (EBV) infection, based on the detection of high EBV-DNA and EBV antibody titers at another hospital. At our institution one month later, clinical manifestations had diminished, and antibody titers had decreased but remained elevated relative to normal levels. Four days later, the patient required hospitalization due to fever, liver damage, and cervical lymphadenopathy. Bone marrow examination and lymph node biopsy results showed EBV-positive cytotoxic T-cells that were predominantly CD4-positive. The disease followed a fulminant course and the patient died of multiple organ failure on hospitalization day 11. Because complicated chromosomal aberrations and T-cell receptor gene rearrangements were identified, we diagnosed her as having systemic EBV-positive T-cell lymphoproliferative disorder of childhood. This disease type includes a lymphoproliferative disorder that is associated with chronic active EBV infection. However, it is clinically different from the type following acute EBV infection. We consider distinguishing between these two types to be important for selecting an early diagnostic procedure and the optimal therapy. PMID- 26062674 TI - Development of CMV retinitis in an antigenemia-negative infant after cord blood transplantation. AB - A five-month-old male infant with familial hemophagocytic lymphohistiocytosis underwent cord blood transplantation using reduced-intensity conditioning. Methylprednisolone (mPSL) pulse administration was performed for marked pulmonary edema during the early phase of transplantation, followed by GVHD treatment with mPSL until day 100. CMV antigenemia was detected on days 27 and 55, but serum became negative with 2- to 3-week ganciclovir (GCV) treatment on both occasions. On day 120, ophthalmological findings included multiple bilateral white spots and a positive PCR study using anterior chamber fluid confirmed the diagnosis of CMV retinitis affecting both eyes, although CMV antigenemia was negative. Re treatment with GCV had a minimal effect on the ophthalmological findings, while foscarnet administration markedly improved the retinitis and decreased the CMV DNA level. Considering that a substantial proportion of patients develop CMV retinitis even when CMV antigenemia is not present, routine monitoring involving ophthalmological examinations should be conducted for hematopoietic transplant patients, especially infants, who cannot complain of ocular symptoms. PMID- 26062675 TI - Successful switching from eltrombopag to romiplostim in a pediatric patient with refractory chronic ITP. AB - Herein, we report a successful treatment experience with romiplostim in a child with immune thrombocytopenia (ITP) refractory to eltrombopag. A 9-year-old female developed chronic ITP, which was refractory to standard treatments, including intravenous immunoglobulin, cepharanthine and splenectomy, and she thus became dependent on prednisolone (PSL). At age 12 years, eltrombopag was started, but failed to increase her platelet count. Another thrombopoietin receptor agonist (TPO-RA), romiplostim, possibly having a different mechanism of action, was then administered. Platelet counts increased and PSL could thus be terminated. Our case suggests TPO-RA alteration to potentially be effective for chronic refractory ITP. PMID- 26062680 TI - Carbon quantum dot/CuSx nanocomposites towards highly efficient lubrication and metal wear repair. AB - Mechanical wear accounts for one third of present global energy consumption. However, it still lacks an efficient lubricant to simultaneously achieve a highly efficient lubrication and metal wear repair. Herein, we report that carbon quantum dots (CQDs)/CuSx nanocomposites show enhanced lubrication and metal wear surface repair abilities when used as additives. The highly efficient lubrication and metal wear repair properties should be attributed to the combination of the multi-layer graphite structure of CQDs and the high chemical activity of CuSx nanoparticles. PMID- 26062682 TI - Photon harvesting, coloring and polarizing in photovoltaic cell integrated color filters: efficient energy routing strategies for power-saving displays. AB - We describe the integral electro-optical strategies that combine the functionalities of photovoltaic (PV) electricity generation and color filtering as well as polarizing to realize more efficient energy routing in display technology. Unlike the conventional pigment-based filters and polarizers, which absorb substantial amounts of unwanted spectral components and dissipate them in the form of heat, we propose converting the energy of those photons into electricity by constructing PV cell-integrated color filters based on a selectively transmitting aluminum (Al) rear electrode perforated with nanoholes (NHs). Combining with a dielectric-metal-dielectric (DMD) front electrode, the devices were optimized to enable efficient cavity-enhanced photon recycling in the PV functional layers. We perform a comprehensive theoretical and numerical analysis to explore the extraordinary optical transmission (EOT) through the Al NHs and identify basic design rules for achieving structural coloring or polarizing in our PV color filters. We show that the addition of thin photoactive polymer layers on the symmetrically configured Al NH electrode narrows the bandwidth of the EOT-assisted high-pass light filtering due to the strongly damped anti-symmetric coupling of the surface modes excited on the front and rear surface of the Al NHs, which facilitates the whole visible coloring with relatively high purity for the devices. By engineering the cut-off characteristics of the plasmonic waveguide mode supported by the circular or ellipsoidal Al NHs, beyond the photon recycling capacity, PV color filters and PV polarizing color filters that allow polarization-insensitive and strong polarization-anisotropic color filtering were demonstrated. The findings presented here may shed some light on expanding the utilization of PV electricity generation across new-generation energy-saving electrical display devices. PMID- 26062681 TI - Genomic expression profiling and bioinformatics analysis of pancreatic cancer. AB - Pancreatic cancer is a polygenic disease and the fourth leading cause of cancer associated mortality worldwide; however, the tumorigenesis of pancreatic cancer remains poorly understood. Research at a molecular level, which includes the exploration of biomarkers for early diagnosis and specific targets for therapy, may effectively aid in the diagnosis of pancreatic cancer in its early stages and in the development of targeted molecular-biological approaches for treatment, thus improving prognosis. By conducting expression profiling in para-carcinoma, carcinoma and relapse of human pancreatic tissues, 319 genes or transcripts with differential expression levels >3-fold between these tissue types were identified. Further analysis with Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes demonstrated that the translation, nucleus assembly processes and molecular functions associated with vitamin B6 and pyridoxal phosphate binding in pancreatic carcinoma were abnormal. Pancreatic cancer was additionally identified to be closely associated with certain autoimmune diseases, including type I diabetes mellitus and systemic lupus erythematosus. PMID- 26062683 TI - Accelerated extracellular matrix turnover during exacerbations of COPD. AB - BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) contribute significantly to disease progression. However, the effect on tissue structure and turnover is not well described. There is an urgent clinical need for biomarkers of disease activity associated with disease progression. Extracellular matrix (ECM) turnover reflects activity in tissues and consequently assessment of ECM turnover may serve as biomarkers of disease activity. We hypothesized that the turnover of lung ECM proteins were altered during exacerbations of COPD. METHODS: 69 patients with COPD hospitalised for an exacerbation were recruited at admission and returned for a 4 weeks follow-up. Competitive ELISAs measuring circulating protein fragments in serum or plasma assessed the formation and degradation of collagen types III (Pro-C3 and C3M, respectively), IV (P4NP 7S and C4M, respectively), and VI (Pro-C6 and C6M, respectively), and degradation of elastin (ELM7 and EL-NE) and versican (VCANM). RESULTS: Circulating levels of C3M, C4M, C6M, ELM7, and EL-NE were elevated during an exacerbation of COPD as compared to follow-up (all P <0.0001), while VCANM levels were decreased (P <0.0001). Pro-C6 levels were decreased and P4NP 7S levels were elevated during exacerbation (P <0.0001). Pro-C3 levels were unchanged. At time of exacerbation, degradation/formation ratios were increased for collagen types III and VI and decreased for collagen type IV. CONCLUSIONS: Exacerbations of COPD resulted in elevated levels of circulating fragments of structural proteins, which may serve as markers of disease activity. This suggests that patients with COPD have accelerated ECM turnover during exacerbations which may be related to disease progression. PMID- 26062684 TI - Serological and molecular diagnostic surveys combined with examining hematological profiles suggests increased levels of infection and hematological response of cattle to babesiosis infections compared to native buffaloes in Egypt. AB - BACKGROUND: Babesiosis threatens the development of the cattle and buffaloes industries in Egypt and improved control is needed. The main objectives of this study are surveying the presence of bovine babesiosis in distinct selected bovine and buffalo populations in Egypt using novel molecular and previously validated serological methods, while also comparing the occurrence of hematological alterations among Babesia infected cattle and buffalos. METHODS: A total of 253 and 81 blood samples from apparently healthy cattle and buffaloes, respectively, were randomly collected from diverse locations in Egypt. All samples were tested for Babesia bovis and B. bigemina infection using blood film examination, competitive ELISA (cELISA) and PCR. Novel semi-nested and nested PCR assays for the detection of B. bovis and B. bigemina respectively, were developed and used to analyze DNA extracted from bovine and buffalo samples. Hematological profiles were studied using a hematological analyzer. RESULTS: Blood films examination revealed 13.8% and 7.4% Babesia infection rates in cattle and buffaloes, respectively. However, in cattle, the cELISA detected 32.8%, 21.3% and 10.7% infection rates with B. bigemina, B. bovis and mixed infection, respectively. In addition, cELISA identified 22.2%, 22.2% and 6.2% infection rates with B. bigemina, B. bovis and mixed infection, respectively in buffaloes. The semi nested PCR assay showed that 15% of the tested samples were positive for B. bovis in cattle, but just 3% in buffaloes. Infections with B. bigemina were also found in cattle (32.4%), but not in buffaloes upon nested PCR analysis. Sequencing analysis confirmed the identity of the PCR amplicons and showed that Egyptian genotypes of B. bigemina and B. bovis highly resemble sequences previously deposited in GenBank. Hemograms performed on the sampled animals revealed macrocytic hypochromic anemia associated with reduced platelet counts in infected cattle with babesiosis. In addition, marked increases in total leukocyte and granulocytic counts and decreases in lymphocytic counts were found in infected cattle. In contrast, no such hematological anomalies were found in presumably Babesia-infected buffaloes. CONCLUSIONS: Frequent occurrence of babesiosis among apparently healthy bovines in Egypt, suggests the need for appropriately designed prevalence studies in this country. Infected bovine, but not buffalo, populations often present hematological disorders compatible with intravascular hemolysis and thrombocytopenia. PMID- 26062685 TI - Human megakaryocytes confer tissue factor to a subset of shed platelets to stimulate thrombin generation. AB - Tissue factor (TF), the main activator of the blood coagulation cascade, has been shown to be expressed by platelets. Despite the evidence that both megakaryocytes and platelets express TF mRNA, and that platelets can make de novo protein synthesis, the main mechanism thought to be responsible for the presence of TF within platelets is through the uptake of TF positive microparticles. In this study we assessed 1) whether human megakaryocytes synthesise TF and transfer it to platelets and 2) the contribution of platelet-TF to the platelet hemostatic capacity. In order to avoid the cross-talk with circulating microparticles, we took advantage from an in vitro cultured megakaryoblastic cell line (Meg-01) able to differentiate into megakaryocytes releasing platelet-like particles. We show that functionally active TF is expressed in human megakaryoblasts, increased in megakaryocytes, and is transferred to a subset of shed platelets where it contributes to clot formation. These data were all confirmed in human CD34pos derived megakaryocytes and in their released platelets. The effect of TF silencing in Meg-megakaryoblasts resulted in a significant reduction of TF expression in these cells and also in Meg-megakaryocytes and Meg-platelets. Moreover, the contribution of platelet-TF to the platelet hemostatic capacity was highlighted by the significant delay in the kinetic of thrombin formation observed in platelets released by TF-silenced megakaryocytes. These findings provide evidences that TF is an endogenously synthesised protein that characterises megakaryocyte maturation and that it is transferred to a subset of newly-released platelets where it is functionally active and able to trigger thrombin generation. PMID- 26062686 TI - Effects of elastic seats on seated body apparent mass responses to vertical whole body vibration. AB - Apparent mass (AM) responses of the body seated with and without a back support on three different elastic seats (flat and contoured polyurethane foam (PUF) and air cushion) and a rigid seat were measured under three levels of vertical vibration (overall rms acceleration: 0.25, 0.50 and 0.75 m/s(2)) in the 0.5 to 20 Hz range. A pressure-sensing system was used to capture biodynamic force at the occupant-seat interface. The results revealed strong effects of visco-elastic and vibration transmissibility characteristics of seats on AM. The response magnitudes with the relatively stiff air seat were generally higher than those with the PUF seats except at low frequencies. The peak magnitude decreased when sitting condition was changed from no back support to a vertical support; the reduction however was more pronounced with the air seat. Further, a relatively higher frequency shift was evident with soft seat compared with stiff elastic seat with increasing excitation. PRACTITIONER SUMMARY: The effects of visco elastic properties of the body-seat interface on the apparent mass responses of the seated body are measured under vertical vibration. The results show considerable effects of the coupling stiffness on the seated body apparent mass, apart from those of excitation magnitude and back support. PMID- 26062687 TI - [Hyperkalemia : what can we expect from new potassium-lowering drugs?]. AB - Hyperkalemia is a common clinical problem. While several options are available to treat acute hyperkalemia, there are few options for long-term treatment. The use of oral potassium binders might be such an option. Sodium zirconium cyclosilicate and patiromer are two new oral potassium binders awaiting approval. The efficacy of these novel potassium-lowering agents were tested in several phase 3 short term studies published in late 2014. PMID- 26062688 TI - Palladium-Catalyzed Domino Addition and Cyclization of Arylboronic Acids with 3 Hydroxyprop-1-yn-1-yl Phosphonates Leading to 1,2-Oxaphospholenes. AB - A novel and efficient palladium-catalyzed domino addition-cyclization of a wide range of arylboronic acids with various 3-hydroxyprop-1-yn-1-yl phosphonates has been developed, affording a convenient and powerful tool for the preparation of valuable 1,2-oxaphospholenes with mild reaction conditions, broad substrate applicability, and good to excellent yields. Mechanistic studies revealed that the reaction might involve Michael addition and nucleophilic substitution. PMID- 26062689 TI - A randomized controlled trial on the effects of goal-directed therapy on the inflammatory response open abdominal aortic aneurysm repair. AB - INTRODUCTION: Goal-directed therapy (GDT) has been shown in numerous studies to decrease perioperative morbidity and mortality. The mechanism of benefit of GDT, however, has not been clearly elucidated. Targeted resuscitation of the vascular endothelium with GDT might alter the postoperative inflammatory response and be responsible for the decreased complications with this therapy. METHODS: This trial was registered at ClinicalTrials.gov as NCT01681251. Forty patients undergoing elective open repair of their abdominal aortic aneurysm, 18 years of age and older, were randomized to an interventional arm with GDT targeting stroke volume variation with an arterial pulse contour cardiac output monitor, or control, where fluid therapy was administered at the discretion of the attending anesthesiologist. We measured levels of several inflammatory cytokines (C reactive protein, Pentraxin 3, suppressor of tumorgenicity--2, interleukin-1 receptor antagonist, and tumor necrosis factor receptor-III) preoperatively and at several postoperative time points to determine if there was a difference in inflammatory response. We also assessed each group for a composite of postoperative complications. RESULTS: Twenty patients were randomized to GDT and twenty were randomized to control. Length of stay was not different between groups. Intervention patients received less crystalloid and more colloid. At the end of the study, intervention patients had a higher cardiac index (3.4 +/- 0.5 vs. 2.5 +/- 0.7 l/minute per m(2), p < 0.01) and stroke volume index (50.1 +/- 7.4 vs. 38.1 +/- 9.8 ml/m(2), p < 0.01) than controls. There were significantly fewer complications in the intervention than control group (28 vs. 12, p = 0.02). The length of hospital and ICU stay did not differ between groups. There was no difference in the levels of inflammatory cytokines between groups. CONCLUSIONS: Despite being associated with fewer complications and improved hemodynamics, there was no difference in the inflammatory response of patients treated with GDT. This suggests that the clinical benefit of GDT occurs in spite of a similar inflammatory burden. Further work needs to be performed to delineate the mechanism of benefit of GDT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01681251 . Registered 18 May 2011. PMID- 26062691 TI - Challenges and opportunities associated with neglected tropical disease and water, sanitation and hygiene intersectoral integration programs. AB - BACKGROUND: Recent research has suggested that water, sanitation, and hygiene (WASH) interventions, in addition to mass drug administration (MDA), are necessary for controlling and eliminating many neglected tropical diseases (NTDs). OBJECTIVES: This study investigated the integration of NTD and WASH programming in order to identify barriers to widespread integration and make recommendations about ideal conditions and best practices critical to future integrated programs. METHODS: Twenty-four in-depth, semi-structured interviews were conducted with key stakeholders in the global NTD and WASH sectors to identify barriers and ideal conditions in programmatic integration. RESULTS: The most frequently mentioned barriers to WASH and NTD integration included: 1) differing programmatic objectives in the two sectors, including different indicators and metrics; 2) a disproportionate focus on mass drug administration; 3) differences in the scale of funding; 4) siloed funding; and 5) a lack of coordination and information sharing between the two sectors. Participants also conveyed that a more holistic approach was needed if future integration efforts are to be scaled-up. The most commonly mentioned requisite conditions included: 1) education and advocacy; 2) development of joint indicators; 3) increased involvement at the ministerial level; 4) integrated strategy development; 5) creating task forces or committed partnerships; and 6) improved donor support. CONCLUSIONS: Public health practitioners planning to integrate NTD and WASH programs can apply these results to create conditions for more effective programs and mitigate barriers to success. Donor agencies should consider funding more integration efforts to further test the proof of principle, and additional support from national and local governments is recommended if integration efforts are to succeed. Intersectoral efforts that include the development of shared indicators and objectives are needed to foster conditions conducive to expanding effective integration programs. PMID- 26062690 TI - Identification of the notothenioid sister lineage illuminates the biogeographic history of an Antarctic adaptive radiation. AB - BACKGROUND: Antarctic notothenioids are an impressive adaptive radiation. While they share recent common ancestry with several species-depauperate lineages that exhibit a relictual distribution in areas peripheral to the Southern Ocean, an understanding of their evolutionary origins and biogeographic history is limited as the sister lineage of notothenioids remains unidentified. The phylogenetic placement of notothenioids among major lineages of perciform fishes, which include sculpins, rockfishes, sticklebacks, eelpouts, scorpionfishes, perches, groupers and soapfishes, remains unresolved. We investigate the phylogenetic position of notothenioids using DNA sequences of 10 protein coding nuclear genes sampled from more than 650 percomorph species. The biogeographic history of notothenioids is reconstructed using a maximum likelihood method that integrates phylogenetic relationships, estimated divergence times, geographic distributions and paleogeographic history. RESULTS: Percophis brasiliensis is resolved, with strong node support, as the notothenioid sister lineage. The species is endemic to the subtropical and temperate Atlantic coast of southern South America. Biogeographic reconstructions imply the initial diversification of notothenioids involved the western portion of the East Gondwanan Weddellian Province. The geographic disjunctions among the major lineages of notothenioids show biogeographic and temporal correspondence with the fragmentation of East Gondwana. CONCLUSIONS: The phylogenetic resolution of Percophis requires a change in the classification of percomorph fishes and provides evidence for a western Weddellian origin of notothenioids. The biogeographic reconstruction highlights the importance of the geographic and climatic isolation of Antarctica in driving the radiation of cold-adapted notothenioids. PMID- 26062692 TI - Osteoarticular complications of brucellosis: The diagnostic value and importance of detection matrix metalloproteinases. AB - OBJECTIVES: Matrix metalloproteinases (MMPs) has been implicated in the pathogenesis of infective, cancer and autoimmune diseases. In this study, we investigated the serum level of MMPs and its clinical importance in human brucellosis. PATIENTS AND METHODS: This study included 60 brucellosis patients treated at the Clinic for Infectious Diseases, Clinical Centre, University of Sarajevo. Matrix metalloproteinases serum levels were quantified by ELISA. RESULTS: The investigation involved three groups: 30 patients with complications, 30 patients without complications of brucellosis and 30 healthy control examinees. The complications of human brucellosis varied but osteoarticular involvement dominated (n=21/30; 70%). Matrix metalloproteinases serum levels in the patients with complications were highest. The serum level of MMP-1 in patients with complications was the highest at 9.45; in patients without complications it was 3.78 and in the control examinees it was lowest at 3.62 (p=0.001). The serum level of MMP-9 in patients with complications was the highest at 105.66; in patients without complications 64.67, and in the control examinees it was lowest at 37.32 (p=0.001). The serum level of MMP-13 in patients with complications was highest at 138.86; in patients without complications at 64.85; and in the control examinees it was the lowest at 29.55 (p=0.001). Pearson's coefficient showed a statistically significant positive correlation between levels of tested matrix metalloproteinases and development complications in human brucellosis (p=0.001). CONCLUSION: This study showed the diagnostic value and importance of detection of matrix metalloproteinases in human brucellosis. MMPs are a useful serum biomarker for assessment of disease activity. PMID- 26062693 TI - Methicillin-resistant Staphylococcus aureus in North-east Croatia. AB - OBJECTIVE: The aim of this 5-year study was to determine the frequency and antibiotic susceptibility of methicillin-resistant Staphylococcus aureus (MRSA) related infections at Osijek Clinical Hospital. MATERIALS AND METHODS: A total of 1987 staphylococci-infected clinical isolates were collected and analysed at the Microbiology Department of the Public Health Institute of Osijek-Baranja County. RESULTS: Between 2008 and 2012, the average rate of MRSA-related infections in staphylococci-infected patients was 27.4%. The proportion of MRSA-related infections on all Staphylococcus aureus (S. aureus) isolates from clinical specimens showed a decreasing trend, from 32.6% in 2008 to 25.5% in 2012. MRSA related infections were mostly detected in wound swabs (50.6%) and aspirates (28.8%) of patients hospitalized in the surgical (49.8%) and intensive care units (27.9%). MRSA-related infection showed an increase compared to S. aureus infections in samples of wounds and aspirates in 2011 and 2012 (57.9%/34.9% and 35.2%/16.3%, respectively). The majority of strains of MRSA-related infections were resistant to several antibiotics, including erythromycin and clindamycin, where susceptibility were less than 10%. All MRSA isolates were susceptible to vancomycin, teicoplanin and linezolid. Therefore, antibiotic therapies for MRSA infections include vancomycin, teicoplanin and linezolid, but microbiological diagnostics need to be performed in order to know when the use of glycopeptides and oxazolidinones is indicated. CONCLUSION: Our results suggest that appropriate prevention measures, combined with the more rational use of antibiotics are crucial to reduce the spread of MRSA-related infection in healthcare settings. Further monitoring is necessary of the incidence and antibiotic susceptibility of MRSA-related infections in our community. PMID- 26062694 TI - National survey of pain clinics in Croatia: Organization and services. AB - OBJECTIVE: To analyze organization and therapeutic procedures administered in tertiary outpatient pain clinics in Croatia. METHODS: Data about organization of pain clinics, its personnel, equipment, continuing medical education, therapeutic procedures, research activities and relations with pharmaceutical industry were collected using questionnaires. RESULTS: Twenty-two Croatian pain clinics were included in the study. Most of the pain clinics employ exclusively anesthesiologists and nurses. The most frequently prescribed therapeutic procedures in pain clinics were pharmacotherapy, transcutaneous electrical nerve stimulation, acupuncture and trigger point injections. Almost all pain clinics provide educational material for patients. Most of the pain clinics have regular interactions with pharmaceutical companies. Prescribing decisions were based mostly on information from scientific meetings, research articles and consultations with colleagues. Information sources which are considered to be the gold standard--the systematic reviews of The Cochrane Collaboration--were used less frequently (n=12; 57%) than advertising materials from pharmaceutical companies (n=16; 76%). Few physicians and other pain clinics staff had scientific degrees or academic titles or were involved in a research project. CONCLUSION: The national study about pain clinics in Croatia pointed out that there is room for improvement of their organization and services. Pain clinics should employ health-care professionals with diverse backgrounds. They should offer treatments backed by the highest-level of scientific evidence. Since pain is a major public health issue, pain clinic staff should engage more in research to contribute to the growing field of pain research, to enhance capacities for pain research in Croatia, to incorporate scientific evidence into their daily decision-making and to enable evidence-based practice. PMID- 26062695 TI - Morphological and morphometric analysis of the shape, position, number and size of mental foramen on human mandibles. AB - OBJECTIVE: To provide anatomical information on the position, morphological variations and incidence of mental foramen (MF) and accessory mental foramen (AMF) as they are important for dental surgeons, anesthetists in nerve block and surgical procedures, to avoid injury to the neurovascular bundle in the mental foramen area. METHODS: Our study was conducted on 150 adult dry human mandibles from the osteological collection of the Department of Anatomy of the Faculty of Medicine, University of Sarajevo. The location and shape of the MF and the presence of the AMF were studied by visual examination. The size and position of the MF were measured using a digital vernier caliper. SPSS, version 17 software was used for the statistical analysis. RESULTS: Bilateral mental foramina were presented in all 150 mandibles. In the majority of mandibles, the MF was located between the first and second premolar (20.3%) or on the level of the root of the second premolar (60.3%), midway between the inferior margin and the alveolar margin of the mandible. Most of the mental foramina were oval in shape (83.3%). An AMF was present in four mandibles (2.7%) on the right side. CONCLUSION: This study may be a very useful new supplement to data on variations in the incidence, position, shape and size of mental and accessory mental foramina, which may help surgeons, anaesthetists, neurosurgeons and dentists in carrying out surgical procedures successfully. PMID- 26062696 TI - Tumor marker CA 15-3 in breast cancer patients. AB - OBJECTIVE: The aim of this study was to determine whether there is a correlation between the serum concentration of the tumor marker CA 15-3 and breast cancer, which has not been proven by the existence of regional and distant metastases, and breast cancer with the presence of regional and distant metastases. PATIENTS AND METHODS: The study was a retrospective-prospective study, and was conducted on 100 women aged 40-70 years of age in the period of January 2007 until June 2011, in whom, after surgery, breast cancer was histologically verified, where before the surgery serum tumor marker CA 15-3 levels were established. The serum tumor marker CA 15-3 concentrations are determined in all patients after radiological diagnosis of suspected breast cancer (radiological findings concluded as BI RADS 4 and 5). The study excluded patients with liver cirrhosis, liver cancer and lung cancer. The study group consisted of patients with metastatic breast cancer, and the control group of patients with breast cancer comprised those shown to be without verified metastatic disease. To calculate the correlation, Spearman's correlation coefficient was used. A difference in p values of less than 0.05 (p<0.05) was considered statistically significant. RESULTS: The serum tumor marker CA 15-3 was elevated in all patients with proven remote or clubbing metastasis in 35.5% of patients with metastasis spreading to regional lymph nodes. CONCLUSION: There is a significant correlation between serum concentrations of the tumor marker CA 15-3 and the presence of metastasis, and serum concentrations of tumor markers and the dissemination of the underlying disease. PMID- 26062697 TI - Understanding wider environmental influences on mentoring: Towards an ecological model of mentoring in academic medicine. AB - Mentoring is a complex developmental relationship that contributes to individual growth and career advancement in different areas of human activity, including academic medicine. This article describes a broader environmental milieux in which mentoring occurs and considers the ways in which the environmental factors may affect the process and outcomes of mentoring. An ecological model of mentoring is proposed that takes into account various factors broadly operating at three contextual levels. The first is societal or "macro" level, which implies cultural, economic, and political factors. The second is institutional or "meso" level, consisting of a) system-related factors such as field and discipline characteristics, and government policies, and b) organization-related factors such as mentoring climate, reward structure, and work design. The third contextual level relates to intrapersonal and interpersonal characteristics of mentor-mentee dyads. If mentoring dyad is viewed as the focal point, societal and institutional levels may be labeled as "external", and personal level as "internal". The conceptual diversity and methodological challenges in the study of mentoring need to be acknowledged, but should not be an excuse to leave the external contextual elements out of the researchers' horizon, as they inevitably shape and modify the mentoring relationships. CONCLUSION: Model presented in this article offers a holistic view of mentoring in academic medicine that may help one comprehend and appreciate the complexity of influences on mentoring, and inform the future research agenda on this important topic. PMID- 26062698 TI - Cochrane and its prospects in Bosnia and Herzegovina: Relying on Cochrane Croatia. AB - In this article we describe Cochrane and its products: Cochrane systematic reviews (CSRs) and other Cochrane evidence. Cochrane is a unique, international, non-profit organisation that offers health care providers, health care consumers and other decision makers unbiased and highly reliable information on health, which is pivotal for conscientious and responsible decision making in overall healthcare. Cochrane offers the highest ranked evidence in Evidence Based Medicine (EBM)--systematic reviews. Currently, CSRs are freely available in BH, and therefore, they ought to be widely used, and understood. We will present the new Cochrane Strategy to 2020, which was the main topic of the 6th Croatian Cochrane Symposium (CroCoS), as well as explore prospects for spreading Cochrane activities to Bosnia and Herzegovina (BH), through collaboration with Cochrane Croatia. BH has no officially organized Cochrane activity, as yet. We hope that this article will raise awareness about Cochrane in BH, help promote its activities, and deepen the existing collaboration with Cochrane Croatia. There are already some changes being introduced concerning Cochrane--at least, in one half, the Federation of BH (FBH). Two documents symbolising official recognition of policy changes towards Cochrane have recently been published in the Official Gazette of FBH. CONCLUSION: Since founding a BH Cochrane Branch would be costly and difficult to achieve in a complicated environment, such as the one we have, BH could use the good will, experience, knowledge, and translated educational, training and web materials of Cochrane Croatia, particularly given the language similarities, to promote evidence based medicine in BH. PMID- 26062699 TI - Postgraduate studies (1978-1985) at the Medical Faculty of the University of Tuzla, Tuzla, Bosnia and Herzegovina. AB - The Postgraduate studies (PS) at the Medical Faculty (MF) of the University of Tuzla (UT) were founded with the aim of training future staff of the MF in scientific research work. The course lasted four semesters. Up to 1986, classes were attended by five generations or 141 postgraduate students, and 57 of them received their Master's degree (MSc's). Classes were held every week on Fridays and Saturdays. One part of the classes was taught at the MF in Szeged (Hungary). Besides teachers from the UT, classes were also taught by teachers from other universities from the former Yugoslavia and abroad. The most important textbooks were: Cell and Molecular Biology by de Robertisa, Mathematics and statistics for use in pharmacy, biology, and chemistry by Saunders & Fleming, and Kako se pisu saopstenja o medicinskim istrazivanjima (How to write reports of medical research) by Rajko Igic. Searching the index base Pub Med at the end of 2014, by the surnames and initials of the names of the 57 masters, we found that they had published 14 articles before completing their MSc's and 821 articles after completing their Master of Science. Later, 35 masters received PhDs and were appointed assistant professors, and later they were also appointed to higher ranks. CONCLUSION: Looking at the results of the PS, MF of the UT in the above mentioned period, it can be said that the PS was the place where the formation began of the future scientific and teaching staff of the MF in Tuzla. PMID- 26062700 TI - Cross-cultural common denominators of the mentoring in biomedicine. PMID- 26062701 TI - Mentoring in academic medicine: A challenging yet rewarding endeavour. PMID- 26062702 TI - Mentoring--hard and underappreciated but rewarding. PMID- 26062703 TI - When to start with science teaching in academic medicine? PMID- 26062704 TI - Overcoming the impeding influences of institutional and social factors in the mentoring process. PMID- 26062705 TI - Expression profiling of white sponge nevus by RNA sequencing revealed pathological pathways. AB - BACKGROUND: White sponge nevus (WSN) is a rare periodontal hereditary disease. To date, almost all WSN studies have focused on case reports or mutation reports. Thus, the mechanism behind WSN is still unclear. We investigated the pathogenesis of WSN using expression profiling. METHODS: Sequence analysis of samples from a WSN Chinese family revealed a mutation (332 T > C) in the KRT13 gene that resulted in the amino acid change Leu111Pro. The pathological pathway behind the WSN expression profile was investigated by RNA sequencing (RNA-seq). RESULTS: Construction of a heatmap revealed 24 activated genes and 57 reduced genes in the WSN patients. The ribosome structure was damaged in the WSN patients. Moreover, the translation rate was limited in the WSN patients, whereas ubiquitin-mediated proteolysis was enhanced. CONCLUSIONS: Our results suggest that the abnormal degradation of the KRT13 protein in WSN patients may be associated with keratin 7 (KRT7) and an abnormal ubiquitination process. PMID- 26062715 TI - [In Process Citation]. PMID- 26062714 TI - Data quality monitoring and performance metrics of a prospective, population based observational study of maternal and newborn health in low resource settings. AB - BACKGROUND: To describe quantitative data quality monitoring and performance metrics adopted by the Global Network's (GN) Maternal Newborn Health Registry (MNHR), a maternal and perinatal population-based registry (MPPBR) based in low and middle income countries (LMICs). METHODS: Ongoing prospective, population based data on all pregnancy outcomes within defined geographical locations participating in the GN have been collected since 2008. Data quality metrics were defined and are implemented at the cluster, site and the central level to ensure data quality. Quantitative performance metrics are described for data collected between 2010 and 2013. RESULTS: Delivery outcome rates over 95% illustrate that all sites are successful in following patients from pregnancy through delivery. Examples of specific performance metric reports illustrate how both the metrics and reporting process are used to identify cluster-level and site-level quality issues and illustrate how those metrics track over time. Other summary reports (e.g. the increasing proportion of measured birth weight compared to estimated and missing birth weight) illustrate how a site has improved quality over time. CONCLUSION: High quality MPPBRs such as the MNHR provide key information on pregnancy outcomes to local and international health officials where civil registration systems are lacking. The MNHR has measures in place to monitor data collection procedures and improve the quality of data collected. Sites have increasingly achieved acceptable values of performance metrics over time, indicating improvements in data quality, but the quality control program must continue to evolve to optimize the use of the MNHR to assess the impact of community interventions in research protocols in pregnancy and perinatal health. TRIAL REGISTRATION NUMBER: NCT01073475. PMID- 26062716 TI - [Manifestation of bilateral choroidal osteoma in childhood. Progressive myopia due to staphyloma posticum]. AB - BACKGROUND: Case report of a 6-year-old boy with bilateral choroidal osteoma. CASE REPORT: The patient was followed up for the next 6 years and during this period bilateral tumor progression was observed. In one eye a staphyloma posticum developed in the area of the osteoma which led to secondary anisometric myopia. CONCLUSION: If undetected, this rare complication can lead to anisometric amblyopia; therefore, repeated cycloplegic refractometry is advisable in children with choroidal osteoma. PMID- 26062717 TI - [Ocriplasmin as a treatment option for symptomatic vitreomacular traction with and without macular hole. First clinical experiences]. AB - PURPOSE: To evaluate the resolution rate in patients with symptomatic vitreomacular traction (<= 1500 MUm) with or without macular holes (<= 400 MUm) after therapy with intravitreal ocriplasmin (Jetrea(r)) injection in a clinical setting. METHODS: Until now we have prospectively examined 21 eyes of 21 consecutive patients with symptomatic vitreomacular traction with or without macular holes who underwent intravitreal operative injection of 0.1 ml ocriplasmin. The best corrected visual acuity and high-resolution optical coherence tomography (SD-OCT) ultrastructural parameters were measured before injection and again 1, 3 and 4 months after treatment. The numbers of resolved vitreomacular traction and closed macular holes were documented. RESULTS: Vitreomacular traction was resolved in 15 out of 21 (71 %) eyes. Of the five eyes which initially presented with vitreomacular traction with macular holes, all showed resolution of vitreomacular traction but only two of the macular holes were closed. The average best corrected visual acuity was 0.38 logMAR (+/- 0.23) at baseline and 0.43 logMAR (+/- 0.28), 0.38 logMAR (+/- 0.27) and 0.36 logMAR (+/- 0.24) 1, 3 and 4 months after injection, respectively. The average foveal thickness was 355.95 MUm (+/- 114.53 MUm) at baseline, reducing to 304.61 MUm (+/ 100.91 MUm), 308.00 MUm (+/-76.17 MUm) and 277.50 MUm (+/- 26.24 MUm) after 1, 3 and 4 months, respectively. CONCLUSION: In this ongoing study there was a high percentage of resolution of vitreomacular traction (71 %) 1 month after intravitreal operative injection of Jetrea(r) and closure of two out of five macular holes. This was further associated with stabilization of visual acuity and reduction of foveal thickness. Further investigations are necessary to document the effectiveness of the pharmacological vitreolysis in a clinical setting. PMID- 26062718 TI - Antidepressant-like activity of Tagetes lucida Cav. is mediated by 5-HT(1A) and 5 HT(2A) receptors. AB - It has been demonstrated that the aqueous extract of Tagetes lucida Cav. shows an antidepressant-like effect on the forced swimming test (FST) in rats. The aim of this study was to analyze the participation of the serotoninergic system in the antidepressant-like effect of the aqueous extract of T. lucida. Different doses of the extract of T. lucida were administered at 72, 48, 24, 18 and 1 h before FST. The animals were pretreated with a 5-HT1A receptor antagonist (WAY-100635, 0.5 mg/kg), a 5-HT2A receptor antagonist (ketanserin, 5 mg/kg), a beta noradrenergic receptor antagonist (propranolol, 200 mg/kg), and with a alpha2 noradrenergic receptor antagonist (yohimbine, 1 mg/kg) alone or combined with the extract and pretreated with a serotonin synthesis inhibitor (PCPA) before treatment with 8-OH-DPAT + the extract of T. lucida. In addition, suboptimal doses of the 5-HT1A agonist (8-OH-DPAT) + non-effective dose of extract was analyzed in the FST. To determine the presence of flavonoids, the aqueous extract of T. lucida (20 ul, 4 mg/ml) was injected in HPLC; however, a quercetin concentration of 7.72 mg/g of extract weight was detected. A suboptimal dose of 8 OH-DPAT + extract of T. lucida decreased immobility and increased swimming and climbing. An antidepressant-like effect with the aqueous extract of T. lucida at doses of 100 and 200 mg/kg was observed on the FST with decreased immobility behavior and increased swimming; however, this effect was blocked by WAY-100635, ketanserin and PCPA but not by yohimbine and propranolol, suggesting that the extract of T. lucida could be modulating the release/reuptake of serotonin. PMID- 26062719 TI - Prenatal diagnosis of Abernethy malformation by three-dimensional ultrasonography. PMID- 26062722 TI - Investigation of the vertical electrical transport in a-Si:H/nc-Si:H superlattice thin films. AB - Tuning the size of silicon nano-crystallites (Si-ncs) has been realized simply by controlling the thickness of the nc-Si:H sub-layer (tnc) in the a-Si:H/nc-Si:H superlattice thin films grown by low temperature plasma processing in PE-CVD. The vertical electrical transport phenomena accomplished in superlattice films have been investigated in order to identify their effective utilization in practical device configuration. The reduced size of the Si-ncs at thinner tnc and the associated band gap widening due to quantum confinement effects generates the Coulomb potential barrier at the a-Si/nc-Si interface which in turn obstructs the transport of charge carriers to the allowed energy states in Si-ncs, leading to the Poole-Frenkel tunneling as the prevailing charge transport mechanism in force. The advantages of the conduction process governed by the Poole-Frenkel mechanism are two-fold. The lower barrier height caused by the a-Si:H sub-layer in the superlattice than the silicon oxide sub-layer in conventional structures enhances the conduction current. Moreover, increasing trapped charges in the a Si:H sub-layer can arbitrarily increase the current conduction. Accordingly, a Si:H/nc-Si:H superlattice structures could provide superior electrical transport in stacked layer devices e.g., multi-junction all silicon solar cells. PMID- 26062720 TI - Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase. AB - Nitric oxide generated by bacterial nitric oxide synthase (NOS) increases the susceptibility of Gram-positive pathogens Staphylococcus aureus and Bacillus anthracis to oxidative stress, including antibiotic-induced oxidative stress. Not surprisingly, NOS inhibitors also improve the effectiveness of antimicrobials. Development of potent and selective bacterial NOS inhibitors is complicated by the high active site sequence and structural conservation shared with the mammalian NOS isoforms. To exploit bacterial NOS for the development of new therapeutics, recognition of alternative NOS surfaces and pharmacophores suitable for drug binding is required. Here, we report on a wide number of inhibitor-bound bacterial NOS crystal structures to identify several compounds that interact with surfaces unique to the bacterial NOS. Although binding studies indicate that these inhibitors weakly interact with the NOS active site, many of the inhibitors reported here provide a revised structural framework for the development of new antimicrobials that target bacterial NOS. In addition, mutagenesis studies reveal several key residues that unlock access to bacterial NOS surfaces that could provide the selectivity required to develop potent bacterial NOS inhibitors. PMID- 26062721 TI - Prevalent high-risk HPV infection and vaginal microbiota in Nigerian women. AB - In this study, we evaluated the association between high-risk human papillomavirus (hrHPV) and the vaginal microbiome. Participants were recruited in Nigeria between April and August 2012. Vaginal bacterial composition was characterized by deep sequencing of barcoded 16S rRNA gene fragments (V4) on Illumina MiSeq and HPV was identified using the Roche Linear Array(r) HPV genotyping test. We used exact logistic regression models to evaluate the association between community state types (CSTs) of vaginal microbiota and hrHPV infection, weighted UniFrac distances to compare the vaginal microbiota of individuals with prevalent hrHPV to those without prevalent hrHPV infection, and the Linear Discriminant Analysis effect size (LEfSe) algorithm to characterize bacteria associated with prevalent hrHPV infection. We observed four CSTs: CST IV B with a low relative abundance of Lactobacillus spp. in 50% of participants; CST III (dominated by L. iners) in 39.2%; CST I (dominated by L. crispatus) in 7.9%; and CST VI (dominated by proteobacteria) in 2.9% of participants. LEfSe analysis suggested an association between prevalent hrHPV infection and a decreased abundance of Lactobacillus sp. with increased abundance of anaerobes particularly of the genera Prevotella and Leptotrichia in HIV-negative women (P < 0.05). These results are hypothesis generating and further studies are required. PMID- 26062723 TI - Serological and molecular analysis of feline vector-borne anaplasmosis and ehrlichiosis using species-specific peptides and PCR. AB - BACKGROUND: With the exception of Bartonella spp. or Cytauxzoon felis, feline vector-borne pathogens (FVBP) have been less frequently studied in North America and are generally under-appreciated as a clinical entity in cats, as compared to dogs or people. This study investigated selected FVBP seroreactivity and PCR prevalence in cats using archived samples. METHODS: Feline blood samples submitted to the Vector Borne Diseases Diagnostic Laboratory (VBDDL) at North Carolina State University College of Veterinary Medicine (NCSU-CVM) between 2008 and 2013 were tested using serological assays and PCR. An experimental SNAP(r) Multi-Analyte Assay (SNAP(r) M-A) (IDEXX Laboratories, Inc. Westbrook, Maine, USA) was used to screen all sera for antibodies to Anaplasma and Ehrlichia genus peptides and A. phagocytophilum, A. platys, B. burgdorferi, E. canis, E. chaffeensis, and E. ewingii species-specific peptides. PCR assays were used to amplify Anaplasma or Ehrlichia DNA from extracted ethylenediaminetetraacetic acid (EDTA)-anti-coagulated blood samples. Amplicons were sequenced to identify species. RESULTS: Overall, 7.8% (56/715) of cats were FVBP seroreactive and 3.2% (13/406) contained Anaplasma or Ehrlichia DNA. Serologically, B. burgdorferi (5.5%) was the most prevalent FVBP followed by A. phagocytophilum (1.8%). Ehrlichia spp. antibodies were found in 0.14% (12/715) of cats with species specific seroreactivity to E. canis (n = 5), E. ewingii (n = 2) and E. chaffeensis (n = 1). Of seropositive cats, 16% (9/56) were exposed to more than one FVBP, all of which were exposed to B. burgdorferi and either A. phagocytophilum (n = 7) or E. ewingii (n = 2). Based upon PCR and DNA sequencing, 4, 3, 3, 2, and 1 cat were infected with A. phagocytophilum, A. platys, E. ewingii, E. chaffeensis and E. canis, respectively. CONCLUSIONS: Cats are exposed to and can be infected with vector-borne pathogens that commonly infect dogs and humans. To our knowledge, this study provides the first evidence for E. chaffeensis and E. ewingii infection in naturally-exposed cats in North America. Results from this study support the need for regional, serological and molecular FVBP prevalence studies, the need to further optimize serodiagnostic and PCR testing for cats, and the need for prospective studies to better characterize clinicopathological disease manifestations in cats infected with FVBP. PMID- 26062724 TI - Bottom-Up Synthesis of Necklace-Like Graphene Nanoribbons. AB - Graphene nanoribbons (GNRs) with an unprecedented "necklace-like" structure were synthesized through a bottom-up chemical approach, based on the oxidative cyclodehydrogenation of tailor-made polyphenylene precursors. A polycyclic aromatic hydrocarbon consisting of 84 sp(2) carbons (C84) was also synthesized and characterized as a model compound. Characterizations by a combination of MALDI-TOF MS and FTIR, Raman, and UV/Vis absorption spectroscopy validated the formation of the necklace-like GNRs. The absorption spectrum and DFT calculations revealed a bandgap of approximately 1.4 eV for this novel GNR system, which has not been attained with other GNR structures, enabling further fine-tuning of GNR bandgaps by structural modulation. PMID- 26062725 TI - Construction of porous cationic frameworks by crosslinking polyhedral oligomeric silsesquioxane units with N-heterocyclic linkers. AB - In fields of materials science and chemistry, ionic-type porous materials attract increasing attention due to significant ion-exchanging capacity for accessing diversified applications. Facing the fact that porous cationic materials with robust and stable frameworks are very rare, novel tactics that can create new type members are highly desired. Here we report the first family of polyhedral oligomeric silsesquioxane (POSS) based porous cationic frameworks (PCIF-n) with enriched poly(ionic liquid)-like cationic structures, tunable mesoporosities, high surface areas (up to 1,025 m(2) g(-1)) and large pore volumes (up to 0.90 cm(3) g(-1)). Our strategy is designing the new rigid POSS unit of octakis(chloromethyl)silsesquioxane and reacting it with the rigid N-heterocyclic cross-linkers (typically 4,4'-bipyridine) for preparing the desired porous cationic frameworks. The PCIF-n materials possess large surface area, hydrophobic and special anion-exchanging property, and thus are used as the supports for loading guest species PMo10V2O40(5-); the resultant hybrid behaves as an efficient heterogeneous catalyst for aerobic oxidation of benzene and H2O2 mediated oxidation of cyclohexane. PMID- 26062726 TI - Erratum to: Persistent complete remission of acute leukemic-phase CCR4-positive gamma-delta peripheral T-cell lymphoma by autologous stem cell transplantation with mogamulizumab. PMID- 26062728 TI - Butorphanol, a synthetic opioid, sensitizes ABCB1-mediated multidrug resistance via inhibition of the efflux function of ABCB1 in leukemia cells. AB - Multidrug resistance (MDR) remains a formidable challenge in the use of chemotherapy and represents a powerful obstacle to the treatment of leukemia. ATP binding cassette subfamily B member 1 (ABCB1) is a recognized factor which causes MDR and is closely related to poor outcome and relapse in leukemia. Ongoing research concerning the strategy for inhibiting the abnormally high activity of the ABCB1 transporter is critically needed. In the present study, we sought to elucidate the interaction between ABCB1 transporter and butorphanol. Our results showed that butorphanol significantly antagonized ABCB1-mediated drug efflux and increased the intracellular drug concentration by inhibiting the transport activity of ABCB1 in leukemia cells. Mechanistic investigations demonstrated that butorphanol did not alter the protein expression or localization of ABCB1 in HL60/VCR and K562/ADR cells. Furthermore, homology modeling indicated that butorphanol could fit into the large drug-binding cavity of ABCB1 and form a binding conformation. In conclusion, butorphanol reversed the ABCB1-mediated MDR in leukemia cells by directly suppressing the efflux activity of ABCB1. PMID- 26062727 TI - Physical activity restriction in age-related eye disease: a cross-sectional study exploring fear of falling as a potential mediator. AB - BACKGROUND: Fear of falling (FoF) is predictive of decreased physical activity. This study sought to determine if FoF mediates the relationship between decreased vision and physical activity restriction in individuals with glaucoma and age related macular degeneration (AMD). METHODS: Accelerometers were used to measure physical activity over 1 week in 59 control, 83 glaucoma, and 58 AMD subjects. Subjects completed the University of Illinois at Chicago Fear of Falling Questionnaire, and the extent of FoF was estimated using Rasch analysis. In negative binomial models adjusting for demographic, health, and social factors, FoF was investigated as a potential mediator between the severity of visual field (VF) loss (in glaucoma patients) or the severity of contrast sensitivity (CS) loss (in AMD patients) and decreased engagement in physical activity, defined as minutes spent in moderate-to-vigorous physical activity (MVPA) per day. RESULTS: In multivariate negative binomial regression models, 5-decibels worse VF mean deviation was associated with 26 % less engagement in MVPA [rate ratio (RR) = 0.74, p < 0.01] amongst glaucoma subjects. When FoF was added to the model, the RR increased from 0.74 to 0.78, and VF loss severity remained associated with less MVPA at a statistically significant level (p < 0.01). Likewise, 0.1 log units worse CS was associated with 11 % less daily MVPA (RR = 0.89, p < 0.01) amongst AMD subjects. When FoF was added to the model, the RR increased from 0.89 to 1.02, and CS loss was no longer associated with MVPA at a statistically significant level (p = 0.53). CONCLUSIONS: FoF may mediate the relationship between vision loss and physical activity restriction amongst patients with AMD. Future work should determine optimal strategies for reducing FoF in individuals with vision loss in order to prevent the deleterious effects of physical activity restriction. PMID- 26062729 TI - 'Trust my doctor, trust my pancreas': trust as an emergent quality of social practice. AB - BACKGROUND: Growing attention is being paid to the importance of trust, and its corollaries such as mistrust and distrust, in health service and the central place they have in assessments of quality of care. Although initially focussing on doctor-patient relationships, more recent literature has broadened its remit to include trust held in more abstract entities, such as organisations and institutions. There has consequently been growing interest to develop rigorous and universal measures of trust. METHODS: Drawing on illustrative ethnographic material from observational research in a UK diabetes clinic, this paper supports an approach that foregrounds social practice and resists conceiving trust as solely a psychological state that can be divorced from its context. Beyond exploring the less-than-conscious nature of trust, the interpretations attend to the extent to which trust practices are distributed across a range of actors. RESULTS: Data from clinical encounters reveal the extent to which matters of trust can emerge from the relationships between people, and sometimes people and things, as a result of a wide range of pragmatic concerns, and hence can usefully be conceived of as an extended property of a situation rather than a person. Trust is rarely explicitly articulated, but remains a subtle feature of experience that is frequently ineffable. CONCLUSIONS: A practice approach highlights some of the problems with adopting a general psychological or intellectualist conception of trust. In particular, assuming it is a sufficiently stable internal state that can be stored or measured not only transforms a diffuse and often ephemeral quality into a durable thing, but ultimately presents it as a generic state that has meaning independent of the specific relationships and context that achieve it. Emphasising the context-specific nature of trust practices does not dismiss the potential of matters of trust, when they emerge, to be transposed to other contexts. But it does highlight how, on each occasion, trust as a relational quality is ways 'done' or 'achieved' anew. PMID- 26062731 TI - The impact of repeated autologous infusion of haematopoietic stem cells in patients with liver insufficiency. AB - INTRODUCTION: The worldwide shortage of donor livers has prompted the search for alternative cell therapies. Previous data from our laboratory proved a supportive role for stem cell therapy in the treatment of end-stage liver disease patients. Therefore; this study was conducted to assess the clinical and biochemical effects of repeated stem cell infusion. METHODS: Ninety patients with liver cirrhosis were randomized to receive either one session treatment (G-I) or two sessions 4 months apart (G-II) of autologous haematopoietic stem cells (HSCs) transplantation and a control group (G-III) who received regular liver treatment. G-CSF was administered to transplanted patients before infusion; HSCs were isolated from 400 cc bone marrow (BM) aspirate. CD34+/CD133+ cells were purified: 50 % of the cells were infused locally in the portal vein on the same day and the other 50 % were differentiated to MSC and infused systemically in a peripheral vein (one session treatment G-I). In G-II, the same process was repeated after 4 months from the first treatment (two session's treatment G-II). Liver function was monitored for 12 months after stem cell therapy (SCT). RESULTS: Statistically significant improvement was reported in the transplanted patients (G-1) as regards the mean serum albumin, bilirubin and INR levels which started to improve after 2 weeks of treatment and continued to improve till the 6(th) month in the single infusion group. The two sessions infused group (G-II) showed sustained response which continued throughout the all follow-up period (12 month). By the end of the study, 36.7 % of the patients in G-I and 66.7 % in G-II showed improvement in the degree of ascites compared to the control group (G-III). We also reported an improvement in the hepatic functional reserve as assessed by the Child-Pugh and MELD score. Safety of the procedure was evidenced by the low incidence of complications encountered. CONCLUSION: In patients with end-stage liver disease, the repeated infusion with combined routes portal and peripheral veins has a beneficial effect on liver functions with minimal adverse events and more lasting clinical efficacy after repeated HSCs infusion. PMID- 26062732 TI - Factors associated with use and non-use of the Fecal Immunochemical Test (FIT) kit for Colorectal Cancer Screening in Response to a 2012 outreach screening program: a survey study. AB - BACKGROUND: The one-sample fecal immunochemical test (FIT) is gaining popularity for colorectal cancer (CRC) screening of average-risk people. However, uptake and annual use remain suboptimal. METHODS: In 2013, we mailed questionnaires to three groups of nonHispanic White, Black, and Latino Kaiser Permanente Northern California (KPNC) members ages 52-76 who received FIT kits in 2010-2012: Continuers did the FIT all 3 years; Converts in 2012, but not 2010 or 2011; and Nonusers in none of the 3 years. The questionnaires covered social influences, perceived CRC risk, reasons for using (Continuers, Converts) or avoiding using (Nonusers) the FIT, and recommendations for improving the kit. RESULTS: Continuers (n = 607, response rate 67.5%), Converts (n = 317, response rate 35.6%), and Nonusers (n = 215, response rate 21.1%) did not differ in perceived risk or family history of CRC, but Nonusers were less likely than Continuers and Converts to know someone who had polyps or CRC. Continuers, Converts, and Nonusers did not differ in social network encouragement of CRC screening, but did differ in believing that it was very important that they be screened (88.3%, 68.4%, 47.7%) and that their medical team thought it very important that they be screened (88.6%, 79.9%, 53.9%). Approximately half of Continuers and Converts completed the FIT to please their doctor. Converts were less likely than Continuers to use the FIT to "make sure they were OK" (53.7% vs. 72.6%) or "protect their health" (46.1% vs. 76.4%). Nearly half of Converts completed the FIT out of guilt. Approximately half of FIT kit users suggested adding a disposable glove, extra paper, and wider-mouth tube to the kit. Nonusers' reasons for not using the FIT included discomfort, disgust, or embarrassment (59.6%); thinking it unnecessary (32.9%); fatalism/fear (15.5%); and thinking it too difficult to use (14.5%), but <10% did not want CRC screening at all. CONCLUSIONS: Nonusers and irregular users of the FIT are less intrinsically motivated to get CRC screening than long-term users and more averse to preparing their stool sample. Changes to the FIT kit to address discomfort and difficulty factors might improve uptake and continued use. PMID- 26062733 TI - The Eucalyptus terpene synthase gene family. AB - BACKGROUND: Terpenoids are abundant in the foliage of Eucalyptus, providing the characteristic smell as well as being valuable economically and influencing ecological interactions. Quantitative and qualitative inter- and intra- specific variation of terpenes is common in eucalypts. RESULTS: The genome sequences of Eucalyptus grandis and E. globulus were mined for terpene synthase genes (TPS) and compared to other plant species. We investigated the relative expression of TPS in seven plant tissues and functionally characterized five TPS genes from E. grandis. Compared to other sequenced plant genomes, Eucalyptus grandis has the largest number of putative functional TPS genes of any sequenced plant. We discovered 113 and 106 putative functional TPS genes in E. grandis and E. globulus, respectively. All but one TPS from E. grandis were expressed in at least one of seven plant tissues examined. Genomic clusters of up to 20 genes were identified. Many TPS are expressed in tissues other than leaves which invites a re-evaluation of the function of terpenes in Eucalyptus. CONCLUSIONS: Our data indicate that terpenes in Eucalyptus may play a wider role in biotic and abiotic interactions than previously thought. Tissue specific expression is common and the possibility of stress induction needs further investigation. Phylogenetic comparison of the two investigated Eucalyptus species gives insight about recent evolution of different clades within the TPS gene family. While the majority of TPS genes occur in orthologous pairs some clades show evidence of recent gene duplication, as well as loss of function. PMID- 26062734 TI - Dynamics and Diagnostic Relevance of Kynurenine Serum Level after Kidney Transplantation. AB - BACKGROUND: Inflammatory events after kidney transplantation (Tx) may lead to activation of the tryptophane-catabolizing enzyme indoleamine 2,3-dioxygenase followed by the formation of kynurenine (KYN). Post-transplant KYN serum levels in kidney allograft recipients were analyzed for their diagnostic value. MATERIAL AND METHODS: This was a retrospective analysis of KYN levels (normal value: 2.7+/ 0.6 nmol/ml) measured in 4083 blood samples collected from 355 kidney graft recipients in connection with uncomplicated courses, acute rejections (ARs), infections, and type of immunosuppression. We performed descriptive data analysis and analysis of variance. RESULTS: In 212 recipients with immediately functioning grafts, the KYN levels dropped from pre-Tx 13.3+/-5.9 nmol/ml to nearly normal values at day 5 (5.8+/-3.0 nmol/ml). In patients with delayed graft function, the KYN reduction started only after the last hemodialysis treatment. With respect to ARs in recipients with creatinine values <300 umol/l pre-AR, the increase of KYN levels depended on the severity of ARs (steroid-sensitive ARs: from 4.5+/-1.4 to 6.0+/-6.1 nmol/ml; steroid-resistant ARs: from 6.1+/-3.1 to 12.9+/-7.1 nmol/ml; vascular rejections: from 5.8+/-3.0 to 16.9+/-9.1 nmol/ml). In patients with creatinine values >=300 umol/l pre-AR, a further increase of the KYN level (from 10.1 to 13.2 nmol/ml) was only observed in severe, steroid-resistant ARs. With respect to infections evaluated, the KYN levels before diagnosis/start of treatment were 5.7+/-3.4 nmol/ml in asymptomatic CMV infections, 7.5+/-4.4 nmol/ml in CMV diseases, 8.3+/-3.3 nmol/ml in pneumonia, and 10.4+/-6.5 nmol/ml in bacterial sepsis. CONCLUSIONS: Serum KYN seems to be a reliable diagnostic tool for the assessment of post-transplant inflammatory complications, already in an early stage, and for monitoring the efficacy of therapeutic interventions. Prospective studies are recommended. PMID- 26062735 TI - Psychosocial support and resilience building among health workers in Sierra Leone: interrelations between coping skills, stress levels, and interpersonal relationships. AB - BACKGROUND: In low- and middle-income countries, a shortage of properly trained, supervised, motivated and equitably distributed health workers often hinder the delivery of lifesaving interventions. Various health workforce bottlenecks can be addressed by tackling well-being and interpersonal relationships of health workers with their colleagues and clients. This paper uses data from the Helping Health Workers Cope (HHWC) project in a rural district of Sierra Leone to achieve three objectives. First, we describe the effect of counseling and psychosocial training on coping skills, stress levels, and provider-provider and provider client relationships. Second, we examine whether a change in coping skills is associated with a change in relationships. Finally, we qualitatively identify key ways through which the uptake of coping skills is linked to a change in relationships. METHODS: The HHWC project was implemented from February 2012 to June 2013 in Kono district in the Eastern province of Sierra Leone, with the neighboring district of Tonkolili selected as the control site. The evaluation followed a mixed-methods approach, which included a quantitative survey, in-depth interviews and focus group discussions with health workers and clients. Mean values of the variables of interest were compared across sub-populations, and correlation analyses were performed between changes in coping skills, stress levels, and changes in relationships. RESULTS: Overall, the results demonstrate that the HHWC intervention had a positive effect on coping skills, stress levels and provider-provider and provider-client relationships. Furthermore, associations were observed between changes in coping skills and changes in relationships as well as changes in stress management skills and changes in relationships. CONCLUSIONS: Psychosocial education can have major impacts on health worker well-being and the quality of health care delivery. Integrating psychosocial counseling and training interventions into health worker pre-service and in-service curricula would allow the positive effects of the HHWC intervention to be scaled up across Sierra Leone and beyond. A roll out of the HHWC approach alongside health system strengthening initiatives could have major implications for improving health and chances of survival. PMID- 26062736 TI - Electromagnetic exploration of the oceanic mantle. AB - Electromagnetic exploration is a geophysical method for examining the Earth's interior through observations of natural or artificial electromagnetic field fluctuations. The method has been in practice for more than 70 years, and 40 years ago it was first applied to ocean areas. During the past few decades, there has been noticeable progress in the methods of instrumentation, data acquisition (observation), data processing and inversion. Due to this progress, applications of this method to oceanic regions have revealed electrical features of the oceanic upper mantle down to depths of several hundred kilometers for different geologic and tectonic environments such as areas around mid-oceanic ridges, areas around hot-spot volcanoes, subduction zones, and normal ocean areas between mid oceanic ridges and subduction zones. All these results estimate the distribution of the electrical conductivity in the oceanic mantle, which is key for understanding the dynamics and evolution of the Earth together with different physical properties obtained through other geophysical methods such as seismological techniques. PMID- 26062737 TI - Laser-driven electron beam and radiation sources for basic, medical and industrial sciences. AB - To date active research on laser-driven plasma-based accelerators have achieved great progress on production of high-energy, high-quality electron and photon beams in a compact scale. Such laser plasma accelerators have been envisaged bringing a wide range of applications in basic, medical and industrial sciences. Here inheriting the groundbreaker's review article on "Laser Acceleration and its future" [Toshiki Tajima, (2010)],(1)) we would like to review recent progress of producing such electron beams due to relativistic laser-plasma interactions followed by laser wakefield acceleration and lead to the scaling formulas that are useful to design laser plasma accelerators with controllability of beam energy and charge. Lastly specific examples of such laser-driven electron/photon beam sources are illustrated. PMID- 26062738 TI - Precision synthesis, structure and function of helical polymers. AB - Helical structures are chiral, which means that if we can synthesize a polymer having a stable one-handed helicity, the polymer is optically active. In 1979, we succeeded in the synthesis of a one-handed helical polymer from an optically inactive achiral monomer, triphenylmethyl methacrylate (TrMA). This is the first example of the asymmetric synthesis of an optically active one-handed helical polymer. The polymer (PTrMA) exhibited an unexpected high chiral recognition ability and afforded a practically useful chiral stationary phase (CSP) for high performance liquid chromatography (HPLC) by coating it on silica gel. In addition, we also succeeded in the development of very useful CSPs for HPLC using the phenylcarbamate derivatives of polysaccharides, cellulose and amylose. These CSPs can efficiently resolve a broad range of chiral compounds, and have been used all over the world for separating and analyzing chiral compounds. PMID- 26062739 TI - Characteristics of the 2011 Tohoku Tsunami and introduction of two level tsunamis for tsunami disaster mitigation. AB - Characteristics of the 2011 Tohoku Tsunami have been revealed by collaborative tsunami surveys extensively performed under the coordination of the Joint Tsunami Survey Group. The complex behaviors of the mega-tsunami were characterized by the unprecedented scale and the low occurrence frequency. The limitation and the performance of tsunami countermeasures were described on the basis of tsunami surveys, laboratory experiments and numerical analyses. These findings contributed to the introduction of two-level tsunami hazards to establish a new strategy for tsunami disaster mitigation, combining structure-based flood protection designed by the Level-1 tsunami and non-structure-based damage reduction planned by the Level-2 tsunami. PMID- 26062740 TI - Fistulotomy or fistulectomy and primary sphincteroplasty for anal fistula (FIPS): a systematic review. AB - There is still no clear consensus about surgical treatment of anal fistulas. Fistulotomy or fistulectomy and primary sphincter reconstruction is still regarded with skepticism. The aim of this systematic review was to evaluate the evidence in the literature supporting the use of this technique in the treatment of complex anal fistulas. MEDLINE, EMBASE and Cochrane Library databases were searched for the period between 1985 and 2015. The studies selected were peer reviewed articles, with no limitations concerning the study cohort size, length of the follow-up or language. Technical notes, commentaries, letters and meeting abstracts were excluded. The major endpoints were the technique adopted, clinical efficacy, changes at anorectal manometry and assessment of quality of life after the procedure. Fourteen reports (666 patients) satisfied the inclusion criteria. The quality of the studies was low. Some differences about the surgical technique emerged; however, after a weighted average duration of follow-up of 28.9 months, the overall success rate was 93.2 %, with a low morbidity rate. The overall postoperative worsening continence rate was 12.4 % (mainly post-defecation soiling). In almost all cases, the anorectal manometry parameters remained unchanged. The quality of life, when evaluated, improved significantly. Fistulotomy or fistulectomy and primary sphincteroplasty could be a therapeutic option for complex anal fistula. Success rates were very high and the risk of postoperative fecal incontinence was lower than after simple fistulotomy. Well designed trials are needed to support the inclusion of this technique in a treatment algorithm for the management of complex anal fistulas. PMID- 26062741 TI - Combined social cognitive and neurocognitive rehabilitation strategies in schizophrenia: neuropsychological and psychopathological influences on Theory of Mind improvement. AB - BACKGROUND: Neurocognitive and social cognitive impairments represent important treatment targets in schizophrenia, as they are significant predictors of functional outcome. Different rehabilitative interventions have recently been developed, addressing both cognitive and psychosocial domains. Although promising, results are still heterogeneous and predictors of treatment outcome are not yet identified. In this study we evaluated the efficacy of two newly developed social cognitive interventions, respectively based on the use of videotaped material and comic strips, combined with domain-specific Cognitive Remediation Therapy (CRT). We also analysed possible predictors of training outcome, including basal neurocognitive performance, the degree of cognitive improvement after CRT and psychopathological variables. METHOD: Seventy-five patients with schizophrenia treated with CRT, were randomly assigned to: social cognitive training (SCT) group, Theory of Mind Intervention (ToMI) group, and active control group (ACG). RESULTS: ANOVAs showed that SCT and ToMI groups improved significantly in ToM measures, whereas the ACG did not. We reported no influences of neuropsychological measures and improvement after CRT on changes in ToM. Both paranoid and non-paranoid subjects improved significantly after ToMI and SCT, without differences between groups, despite the better performance in basal ToM found among paranoid patients. In the ACG only non-paranoid patients showed an improvement in non-verbal ToM. CONCLUSION: Results showed that both ToMI and SCT are effective in improving ToM in schizophrenia with no influence of neuropsychological domains. Our data also suggest that paranoid symptoms may discriminate between different types of ToM difficulties in schizophrenia. PMID- 26062742 TI - Human anti-CAIX antibodies mediate immune cell inhibition of renal cell carcinoma in vitro and in a humanized mouse model in vivo. AB - BACKGROUND: Carbonic anhydrase (CA) IX is a surface-expressed protein that is upregulated by the hypoxia inducible factor (HIF) and represents a prototypic tumor-associated antigen that is overexpressed on renal cell carcinoma (RCC). Therapeutic approaches targeting CAIX have focused on the development of CAIX inhibitors and specific immunotherapies including monoclonal antibodies (mAbs). However, current in vivo mouse models used to characterize the anti-tumor properties of fully human anti-CAIX mAbs have significant limitations since the role of human effector cells in tumor cell killing in vivo is not directly evaluated. METHODS: The role of human anti-CAIX mAbs on CAIX(+) RCC tumor cell killing by immunocytes or complement was tested in vitro by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cellular phagocytosis (ADCP) as well as on CAIX(+) RCC cellular motility, wound healing, migration and proliferation. The in vivo therapeutic activity mediated by anti-CAIX mAbs was determined by using a novel orthotopic RCC xenograft humanized animal model and analyzed by histology and FACS staining. RESULTS: Our studies demonstrate the capacity of human anti-CAIX mAbs that inhibit CA enzymatic activity to result in immune-mediated killing of RCC, including nature killer (NK) cell-mediated ADCC, CDC, and macrophage mediated ADCP. The killing activity correlated positively with the level of CAIX expression on RCC tumor cell lines. In addition, Fc engineering of anti-CAIX mAbs was shown to enhance the ADCC activity against RCC. We also demonstrate that these anti-CAIX mAbs inhibit migration of RCC cells in vitro. Finally, through the implementation of a novel orthotopic RCC model utilizing allogeneic human peripheral blood mononuclear cells in NOD/SCID/IL2Rgamma(-/-) mice, we show that anti-CAIX mAbs are capable of mediating human immune response in vivo including tumor infiltration of NK cells and activation of T cells, resulting in inhibition of CAIX(+) tumor growth. CONCLUSIONS: Our findings demonstrate that these novel human anti-CAIX mAbs have therapeutic potential in the unmet medical need of targeted killing of HIF-driven CAIX(+)RCC. The orthotopic tumor xenografted humanized mouse provides an improved model to evaluate the in vivo anti-tumor capabilities of fully human mAbs for RCC therapy. PMID- 26062743 TI - Up-regulation of IL-12 expression in patients with chronic hepatitis B is mediated by the PI3K/Akt pathway. AB - Hepatitis B virus (HBV) replicates noncytopathically in hepatocytes, but HBV or proteins encoded by HBV genome could induce cytokines, chemokines expression by hepatocytes.IL-12 is a typical proinflammatory cytokine that plays a critical role in host defense against pathogens, including the HBV. However, the role of IL-12 in chronic hepatitis B (CHB) remains unclear. The aims of this study were to detect the expression of IL-12 in CHB patients and explore the molecular mechanism of HBV-induced IL-12 expression. The results showed that serum levels and hepatic expression of IL-12 were significantly upregulated in CHB patients. HBx protein increased IL-12 expression in a dose-dependent manner. Furthermore, inhibition of PI3K/Akt significantly decreased the HBx-induced IL-12 expression and Akt activation. Taken together, these results indicate that the molecular mechanism of HBV-induced IL-12 expression involves activation of the PI3K/Akt pathway by HBx, leading to transactivation of the IL-12 p35 and p40 promoters. PMID- 26062744 TI - Tuberothalamic infarction causing a central Horner syndrome with contralateral ataxia and paraphasia. PMID- 26062746 TI - Debates on Genetically Modified Crops in the Context of Sustainable Development. AB - The paper discusses conflicts in perceptions of GM crops illustrating the complexities of GM debates and applications of the concept of sustainable development. The concept consists of three discourses that both opponents and supporters of GM crops refer to in their analyses: environmentalism, social and economic development and the two sub-issues of sustainable development biodiversity loss and food security. This creates a unique situation when both proponents and opponents of GM food use the same framework of sustainable development to support their arguments and do not reach a common ground. This will be illustrated by a review of the arguments brought by these two groups. PMID- 26062745 TI - The IDA/IDA-LIKE and PIP/PIP-LIKE gene families in Arabidopsis: phylogenetic relationship, expression patterns, and transcriptional effect of the PIPL3 peptide. AB - Peptide ligands play crucial roles in the life cycle of plants by modulating the innate immunity against pathogens and regulating growth and developmental processes. One well-studied example is INFLORESCENCE DEFICIENT IN ABSCISSION (IDA), which controls floral organ abscission and lateral root emergence in Arabidopsis thaliana. IDA belongs to a family of five additional IDA-LIKE (IDL) members that have all been suggested to be involved in regulation of Arabidopsis development. Here we present three novel members of the IDL subfamily and show that two of them are strongly and rapidly induced by different biotic and abiotic stresses. Furthermore, we provide data that the recently identified PAMP-INDUCED SECRETED PEPTIDE (PIP) and PIP-LIKE (PIPL) peptides, which show similarity to the IDL and C-TERMINALLY ENCODED PEPTIDE (CEP) peptides, are not only involved in innate immune response in Arabidopsis but are also induced by abiotic stress. Expression patterns of the IDA/IDL and PIP/PIPL genes were analysed using in silico data, qRT-PCR and GUS promoter lines. Transcriptomic responses to PIPL3 peptide treatment suggested a role in regulation of biotic stress responses and cell wall modification. PMID- 26062747 TI - Facing up to Complexity: Implications for Our Social Experiments. AB - Biological systems are highly complex, and for this reason there is a considerable degree of uncertainty as to the consequences of making significant interventions into their workings. Since a number of new technologies are already impinging on living systems, including our bodies, many of us have become participants in large-scale "social experiments". I will discuss biological complexity and its relevance to the technologies that brought us BSE/vCJD and the controversy over GM foods. Then I will consider some of the complexities of our social dynamics, and argue for making a shift from using the precautionary principle to employing the approach of evaluating the introduction of new technologies by conceiving of them as social experiments. PMID- 26062748 TI - RapGene: a fast and accurate strategy for synthetic gene assembly in Escherichia coli. AB - The ability to assemble DNA sequences de novo through efficient and powerful DNA fabrication methods is one of the foundational technologies of synthetic biology. Gene synthesis, in particular, has been considered the main driver for the emergence of this new scientific discipline. Here we describe RapGene, a rapid gene assembly technique which was successfully tested for the synthesis and cloning of both prokaryotic and eukaryotic genes through a ligation independent approach. The method developed in this study is a complete bacterial gene synthesis platform for the quick, accurate and cost effective fabrication and cloning of gene-length sequences that employ the widely used host Escherichia coli. PMID- 26062750 TI - Benefits and risks of contralateral prophylactic mastectomy in women undergoing treatment for sporadic unilateral breast cancer: a decision analysis. AB - The rate of contralateral prophylactic mastectomy (CPM) is rising rapidly, despite limited evidence about the procedure's relative benefits and harms. The objective of this study is to examine the impact of CPM on life expectancy (LE) and quality-adjusted life expectancy (QALE) in women with sporadic unilateral breast cancer. A Markov model was developed to compare 18 hypothetical cohorts of 45-year-old women with newly diagnosed unilateral, sporadic breast cancer treated with or without CPM. The probability of developing distant metastases by American Joint Committee on Cancer stage and molecular subtype was derived from British Columbia Cancer Agency data. Additional model parameters were identified from the medical literature. Sensitivity analyses were performed to examine the impact of plausible variations in key model parameters on results. CPM improved LE in all cohorts (range 0.06-0.54 years). Stage had more effect on LE than subtype (stage I mean, 0.44 years, stage III mean, 0.11 years). However, after adjusting for quality-of-life, No CPM was favored in all cohorts. Univariate sensitivity analysis demonstrated that the most influential model parameter was the post-CPM health state utility. The preferred strategy shifted from No CPM to CPM when the post-CPM utility exceeded 0.83 (base case value 0.81). PSA indicated that LE gains and QALE decreases were stable in all cohorts. The primary determinant of survival after unilateral breast cancer is stage at diagnosis. Our results suggest that routine CPM would not improve quality-adjusted survival for the majority of women with unilateral sporadic breast cancer. PMID- 26062749 TI - Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes. AB - We evaluated suggested metastasis-related microRNAs (miRNAs) for their associations with disease-free survival (DFS) and overall survival (OS) of triple negative breast cancer (TNBC). In a cohort of 456 TNBC cases, we systematically evaluated 57 previously reported metastasis-related miRNAs in tumor tissue using the NanoString nCounter assay. Cox regression was applied to evaluate miRNA expression in association with DFS and OS. In vitro assays using the TNBC cell line MDA-MB-231 were also conducted to validate epidemiological study findings. During a median follow-up of 5.3 years, 112 deaths and 97 recurrences were documented. High levels of miR-374b-5p, miR-218-5p, or miR-126-3p, or low levels of miR-27b-3p were independently associated with a favorable TNBC outcome (P < 0.01 for all). A composite score based on the levels of these four miRNAs was associated with DFS, with hazard ratios (95 % confidence interval) of 0.70 (0.43 1.15), 0.51 (0.29-0.90), and 0.18 (0.09-0.37) for the second, third, and fourth compared to the lowest quartile. Incorporating the miRNA score with known TNBC outcome predictors, i.e., age at diagnosis, tumor stage, and basal-like subtype, increased the C-index for predicting DFS from 0.68 to 0.74. Additionally, miR-126 3p was correlated with basal-like breast cancer, and miR-374b-5p modified the therapeutic effects of 5-Fluorouracil and Cyclophosphamide treatments in basal like breast cancer patients. Restoring miR-126-3p, miR-218-5p, or miR-374b-5p, or inhibiting miR-27b-3p in MDA-MB-231 cells reduced cell proliferation. miR-374b-5p suppressed cell invasion and miR-218-5p inhibited colonization. This study provides strong evidence that the expression levels of miR-374b-5p, miR-27b-3p, miR-126-3p, and miR-218-5p in tumor tissues predict TNBC outcomes. PMID- 26062751 TI - Inhibition of SDF-1/CXCR4-induced epithelial-mesenchymal transition by kisspeptin 10. AB - Recently we have shown that breast cancer cell invasion was dramatically increased when co-cultured with MG63 cells. In addition we have generated mesenchymal transformed MCF-7 breast cancer cells (MCF-7-EMT), showing significantly increased invasion in contrast to wild type MCF-7 cells (MCF-7 WT). In this study we have analyzed whether stromal derived factor-1 (SDF-1) is responsible for MCF-7 and T-47-D breast cancer cell invasion and epithelial mesenchymal-transition (EMT). In addition we have analyzed whether kisspeptin-10 (KP-10) treatment affects SDF-1-induced invasion and EMT. Invasion was quantified by assessment of MCF-7 and T-47-D breast cancer cell migration rate through an artificial basement membrane in a modified Boyden chamber during co-culture with MG63 cells or after treatment with SDF-1alpha, SDF-1beta or the combination of both isoforms. Induction of EMT was verified by analysis of protein expression of epithelial marker E-cadherin (CDH1) and mesenchymal markers N-cadherin (CDH2) and Vimentin (VIM). The role of SDF-1 for invasion and induction of EMT in breast cancer cells was analyzed by blocking SDF-1 secretion during co-culture with MG63 cells. In addition effects of KP-10 treatment on SDF-1-induced invasion and EMT were analyzed. Breast cancer cell invasion was significantly increased when co cultured with MG63 cells. During co-culture SDF-1 protein expression of MG63 cells was significantly induced. The increased breast cancer cell invasion could be blocked by anti-SDF-1 antibodies. Treatment of breast cancer cells in monoculture (without MG63) with SDF-1alpha, SDF-1beta or the combination of both isoforms resulted in a significant escalation of breast cancer cell invasion and induction of EMT. Protein expression of mesenchymal markers CDH2 and VIM was clearly elevated, whereas protein expression of epithelial marker CDH1 was clearly decreased. The SDF-1-induced increase of cell invasion was significantly reduced after treatment with KP-10. In addition, induction of EMT was inhibited. Furthermore, protein expression of the binding site of SDF-1, CXC-motive chemokine receptor 4 (CXCR-4), was reduced by KP-10. Treatment of MCF-7-EMT cells with KP-10 resulted in a significant drop of cell invasion and CXCR-4 protein expression. Our findings suggest that SDF-1 plays a major role in breast cancer invasion and EMT. SDF-1-induced invasion and EMT can be inhibited by KP-10 treatment by down-regulating CXCR-4 expression. PMID- 26062752 TI - A new measure of home care patients' dignity at the end of life: The Palliative Patients' Dignity Scale (PPDS). AB - OBJECTIVE: This study aimed to develop a new and brief instrument to be employed in dignity measurement, one based on the perceptions of patients, relatives, and professionals about dignity. METHOD: Surveys of patients receiving palliative care, family caregivers, and palliative care professionals were first carried out (sample 1). In the second step, palliative care patients were surveyed with a pilot questionnaire (sample 2). Finally, a survey design was used to assess patients admitted into a home care unit (sample 3). Sample 1 included 78 subjects, including patients, family caregivers, and professionals. Some 20 additional palliative patients participated in sample 2. Finally, 70 more patients admitted to a home care unit participated were surveyed (sample 3). Together with the Palliative Patients' Dignity Scale (PPDS), our survey included other measures of dignity, anxiety, depression, resilient coping, quality of life, spirituality, and social support. RESULTS: After analyzing data from steps 1 and 2, an eight-item questionnaire was presented for validation. The new scale showed appropriate factorial validity (chi2(19) = 21.43, p = 0.31, CFI = 0.99, GFI = 0.92, SRMR = 0.07, and RMSEA = 0.04), reliability (internal consistency estimations of 0.75 and higher), criterial validity (significant correlations with the hypothesized related variables), and a cutoff criteria of 50 on the overall scale. SIGNIFICANCE OF RESULTS: The new PPDS has appropriate psychometric properties that, together with its briefness, encourages its applicability for dignity assessment at the end of life. PMID- 26062753 TI - Pythium rishiriense sp. nov. from water and P. alternatum sp. nov. from soil, two new species from Japan. AB - In an investigation of Pythium species in natural ecosystems of Rishiri Island in Northern Japan, two new species, Pythium rishiriense and P. alternatum, were identified based on morphological and molecular analyses. Pythium rishiriense differed morphologically from other Pythium species by its characteristic oogonial formation which occasionally arranged in chains. Pythium alternatum differed morphologically from other Pythium species by its distinguishing sexual organs where oogonia occasionally arranged alternately with antheridia in chains. Pythium rishiriense is a fast growing, high-temperature loving species, while P. alternatum is a slow growing species. Phylogenetic analyses based on the internal transcribed spacer region and cytochrome c oxidase 1 gene sequences showed that these two species are clearly separate from morphologically similar species. PMID- 26062754 TI - Treprostinil indirectly regulates endothelial colony forming cell angiogenic properties by increasing VEGF-A produced by mesenchymal stem cells. AB - Pulmonary vasodilators and prostacyclin therapy in particular, have markedly improved the outcome of patients with pulmonary hypertension (PH). Endothelial dysfunction is a key feature of PH, and we previously reported that treprostinil therapy increases number and proliferative potential of endothelial colony forming cells (ECFC) isolated from PH patients' blood. In the present study, the objective was to determine how treprostinil contributes to the proangiogenic functions of ECFC. We examined the effect of treprostinil on ECFC obtained from cord blood in terms of colony numbers, proliferative and clonogenic properties in vitro, as well as in vivo vasculogenic properties. Surprisingly, treprostinil inhibited viability of cultured ECFC but did not modify their clonogenic properties or the endothelial differentiation potential from cord blood stem cells. Treprostinil treatment significantly increased the vessel-forming ability of ECFC combined with mesenchymal stem cells (MSC) in Matrigel implanted in nude mice. In vitro, ECFC proliferation was stimulated by conditioned media from treprostinil-pretreated MSC, and this effect was inhibited either by the use of VEGF-A blocking antibodies or siRNA VEGF-A in MSC. Silencing VEGF-A gene in MSC also blocked the pro-angiogenic effect of treprostinil in vivo. In conclusion, increased VEGF-A produced by MSC can account for the increased vessel formation observed during treprostinil treatment. The clinical relevance of these data was confirmed by the high level of VEGF-A detected in plasma from patients with paediatric PH who had been treated with treprostinil. Moreover, our results suggest that VEGF-A level in patients could be a surrogate biomarker of treprostinil efficacy. PMID- 26062755 TI - MDM2 beyond cancer: podoptosis, development, inflammation, and tissue regeneration. AB - Murine double minute (MDM)-2 is an intracellular molecule with diverse biological functions. It was first described to limit p53-mediated cell cycle arrest and apoptosis, hence, gain of function mutations are associated with malignancies. This generated a rationale for MDM2 being a potential therapeutic target in cancer therapy. Meanwhile, several additional functions and pathogenic roles of MDM2 have been identified that either enforce therapeutic MDM2 blockade or raise caution about potential side effects. MDM2 is also required for organ development and tissue homeostasis because unopposed p53 activation leads to p53 overactivation-dependent cell death, referred to as podoptosis. Podoptosis is caspase-independent and, therefore, different from apoptosis. The mitogenic role of MDM2 is also needed for wound healing upon tissue injury, while MDM2 inhibition impairs re-epithelialization upon epithelial damage. In addition, MDM2 has p53-independent transcription factor-like effects in nuclear factor-kappa beta (NFkappaB) activation. Therefore, MDM2 promotes tissue inflammation and MDM2 inhibition has potent anti-inflammatory effects in tissue injury. Here we review the biology of MDM2 in the context of tissue development, homeostasis, and injury and discuss how the divergent roles of MDM2 could be used for certain therapeutic purposes. MDM2 blockade had mostly anti-inflammatory and anti-mitotic effects that can be of additive therapeutic efficacy in inflammatory and hyperproliferative disorders such as certain cancers or lymphoproliferative autoimmunity, such as systemic lupus erythematosus or crescentic glomerulonephritis. PMID- 26062757 TI - Health reform law is the "new reality," says Obama. PMID- 26062756 TI - Are mast cells implicated in asphyxia? AB - In a previous immunohistochemical (IHC) study, we documented the reaction of lung tissue vessels to hypoxia through the immunodetection of HIF1-alpha protein, a key regulator of cellular response to hypoxic conditions. Findings showing that asphyxia deaths are associated with an increase in the number of mast cell (MC) derived tryptase enzymes in the blood suggests that HIF1-alpha production may be correlated with MC activation in hypoxic conditions. This hypothesis prompted us to investigate the possible role of pulmonary MC in acute asphyxia deaths. Lung of 47 medico-legal autopsy cases (35 asphyxia/hypoxia deaths, 11 controls, and 1 anaphylactic death) were processed by IHC analysis using anti-CD117 (c-Kit) antibody to investigate peri-airway and peri-vascular MC together with their counts and features. Results showed a significant increase in peri-vascular c kit(+) MC in some asphyxia deaths, such as hanging, strangulation, and aspiration deaths. A strong activation of MC in peri-airway and peri-vascular areas was also observed in lung samples from the anaphylaxis case, which was used as a positive control. Our study points to the potential role of MC in hypoxia and suggests that an evaluation of MC in the lungs may be a useful parameter when forensic pathologists are required to make a differential diagnosis between acute asphyxia deaths and other kinds of death. PMID- 26062758 TI - Cost-benefit analysis: newborn screening for inborn errors of metabolism in Lebanon. AB - OBJECTIVES: Few countries in the Middle East-North Africa region have adopted national newborn screening for inborn errors of metabolism by tandem mass spectrometry (MS/MS). We aimed to evaluate the cost-benefit of newborn screening for such disorders in Lebanon, as a model for other developing countries in the region. METHODS: Average costs of expected care for inborn errors of metabolism cases as a group, between ages 0 and 18, early and late diagnosed, were calculated from 2007 to 2013. The monetary value of early detection using MS/MS was compared with that of clinical "late detection", including cost of diagnosis and hospitalizations. RESULTS: During this period, 126000 newborns were screened. Incidence of detected cases was 1/1482, which can be explained by high consanguinity rates in Lebanon. A reduction by half of direct cost of care, reaching on average 31,631 USD per detected case was shown. This difference more than covers the expense of starting a newborn screening programme. CONCLUSION: Although this model does not take into consideration the indirect benefits of the better quality of life of those screened early, it can be argued that direct and indirect costs saved through early detection of these disorders are important enough to justify universal publicly-funded screening, especially in developing countries with high consanguinity rates, as shown through this data from Lebanon. PMID- 26062759 TI - Cadmium-induced autophagy is mediated by oxidative signaling in PC-12 cells and is associated with cytoprotection. AB - Oxidative stress induced by cadmium (Cd) is a common phenomenon that has been observed in numerous studies. However, the underlying mechanism remains unknown. Recently, exposure of PC-12 cells to Cd has been shown to activate autophagy, which acts as a temporary survival pathway under stressful conditions by delaying the occurrence of apoptosis. The present study investigated the impact of oxidative stress on Cd-induced autophagy in PC-12 cells. The results demonstrated that Cd-induced autophagy (following treatment with Cd for 4 h), increased the levels of intracellular reactive oxygen species (ROS), decreased the mitochondrial membrane potential and resulted in apoptosis. A treatment with chloroquine (CQ; an autophagic inhibitor) sensitized the PC-12 cells to Cd, due to the increased production of ROS, which was associated with the incapacity to reduce mitochondrial and cell death. N-acetyl-L-cysteine, an antioxidant agent, decreased Cd-induced autophagy and reduced intracellular ROS levels, but enhanced CQ-induced apoptotic cell death. These findings indicate that moderate levels of ROS are essential in the regulation of Cd-induced autophagy, which subsequently enhances cell survival. Thus, the results of the present study provide an insight for future investigation of Cd-induced neurotoxicity. PMID- 26062760 TI - Breast-lesion Segmentation Combining B-Mode and Elastography Ultrasound. AB - Breast ultrasound (BUS) imaging has become a crucial modality, especially for providing a complementary view when other modalities (i.e., mammography) are not conclusive in the task of assessing lesions. The specificity in cancer detection using BUS imaging is low. These false-positive findings often lead to an increase of unnecessary biopsies. In addition, increasing sensitivity is also challenging given that the presence of artifacts in the B-mode ultrasound (US) images can interfere with lesion detection. To deal with these problems and improve diagnosis accuracy, ultrasound elastography was introduced. This paper validates a novel lesion segmentation framework that takes intensity (B-mode) and strain information into account using a Markov Random Field (MRF) and a Maximum a Posteriori (MAP) approach, by applying it to clinical data. A total of 33 images from two different hospitals are used, composed of 14 cancerous and 19 benign lesions. Results show that combining both the B-mode and strain data in a unique framework improves segmentation results for cancerous lesions (Dice Similarity Coefficient of 0.49 using B-mode, while including strain data reaches 0.70), which are difficult images where the lesions appear with blurred and not well defined boundaries. PMID- 26062761 TI - Methylene Blue inhibits the inflammatory process of the acetic acid-induced colitis in the rat colonic mucosa. AB - Inflammatory bowel disease is a serious health problem. Although it has been widely investigated, treatment of inflammatory bowel diseases currently remains as a challenging clinical problem. Over production of nitric oxide has been demonstrated to cause tissue damage and inflammation. In this study, the effect of methylene blue (MB), a well-known inhibitor of nitric oxide synthesis, was investigated in acetic acid (AA)-induced colitis model in Sprague-Dawley rats. Eighty male rats randomized into 4 groups (control, control MB, colitis, colitis + MB). AA was applied to groups 3 and 4. MB was added into group 2 and 4. Three days later, animals were sacrificed and 8 cm distal colonic segment resected and the specimens are examined using macroscopical, histological, and biochemical methods. The results of the macroscopic and microscopic examination showed that in group 4 the mucosal damage and inflammation score significantly lower than group 3. Increased intestinal permeability in acetic acid-administered group was significantly reversed by MB application. Myeloperoxidase activity and malondialdehyde levels increased significantly, while superoxide dismutase and catalase activities were suppressed after AA-administration. These biochemical parameters were reversed in MB-treated group. Administration of acetic acid resulted in increased levels of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, total nitrite/nitrate levels and nitric oxide synthase activity. These biochemical alterations were significantly reversed by MB application also. In conclusion, our results indicate that MB decreases the level of nitric oxide and decreases inflammation in acetic acid-induced colitis. PMID- 26062762 TI - Association between daily glucose fluctuation and coronary plaque properties in patients receiving adequate lipid-lowering therapy assessed by continuous glucose monitoring and optical coherence tomography. AB - BACKGROUND: Glucose fluctuation has been recognized as a residual risk apart from dyslipidemia for the development of coronary artery disease (CAD). This study aimed to investigate the association between glucose fluctuation and coronary plaque morphology in CAD patients. METHODS: This prospective study enrolled 72 consecutive CAD patients receiving adequate lipid-lowering therapy. They were divided into 3 tertiles according to the mean amplitude of glycemic excursions (MAGE), which represents glucose fluctuation, measured by continuous glucose monitoring (tertile 1; < 49.1, tertile 2; 49.1 ~ 85.3, tertile 3; >85.3). Morphological feature of plaques were evaluated by optical coherence tomography. Lipid index (LI) (mean lipid arc * length), fibrous cap thickness (FCT), and the prevalence of thin-cap fibroatheroma (TCFA) were assessed in both culprit and non culprit lesions. RESULTS: In total, 166 lesions were evaluated. LI was stepwisely increased according to the tertile of MAGE (1958 +/- 974 [tertile 1] vs. 2653 +/- 1400 [tertile 2] vs. 4362 +/- 1858 [tertile 3], p < 0.001), whereas FCT was the thinnest in the tertile 3 (157.3 +/- 73.0 MUm vs. 104.0 +/- 64.1 MUm vs. 83.1 +/- 34.7 MUm, p < 0.001, respectively). The tertile 3 had the highest prevalence of TCFA. Multiple linear regression analysis showed that MAGE had the strongest effect on LI and FCT (standardized coefficient beta = 0.527 and -0.392, respectively, both P < 0.001). Multiple logistic analysis identified MAGE as the only independent predictor of the presence of TCFA (odds ratio 1.034; P < 0.001). CONCLUSIONS: Glucose fluctuation and hypoglycemia may impact the formation of lipid-rich plaques and thinning of fibrous cap in CAD patients with lipid lowering therapy. PMID- 26062763 TI - Evaluation of the toxicity and repellence of an organic fatty acids mixture (C8910) against insecticide susceptible and resistant strains of the major malaria vector Anopheles funestus Giles (Diptera: Culicidae). AB - BACKGROUND: Malaria vector control relies principally on the use of insecticides, especially pyrethroids. Because of the increasing occurrence of insecticide resistance in target vector populations, the development of new insecticides, particularly those with novel modes of action, is particularly important, especially in terms of managing insecticide resistance. The C8910 formulation is a patented mixture of compounds comprising straight-chain octanoic, nonanoic and decanoic saturated fatty acids. This compound has demonstrated toxic and repellent effects against several arthropod species. The aims of this study were to measure the insecticidal effects of C8910 against an insecticide susceptible (FANG) and a pyrethroid resistant (FUMOZ-R) laboratory strain of An. funestus as well as against wild-caught An. funestus material from Zambia (ZamF), and to investigate the repellent effects of two formulations of C8910 against these strains. METHODS: Toxicity against adult females was assessed using a range of concentrations based on the CDC bottle bioassay method and repellence of three different C8910 formulations was assessed using standard choice-chamber bioassays. RESULTS: C8910 proved equally toxic to adult females of the FUMOZ-R and FANG laboratory strains, as well as to adult females of the wild-caught (ZamF) sample. None of the C8910 formulations tested gave any conclusive indication of repellence against any of the strains. CONCLUSION: C8910 is equally effective as an adulticide against pyrethroid resistant and insecticide susceptible An. funestus. However, the formulations tested did not show any consistent repellence against laboratory reared and wild-caught female samples of this species. Nevertheless, C8910 shows potential as an adulticide that can be used for malaria vector control, particularly in those instances where insecticide resistance management is required. PMID- 26062764 TI - Resistive switching in metallic Ag2S memristors due to a local overheating induced phase transition. AB - Resistive switchings in nanometer-scale metallic junctions formed between an inert metallic tip and an Ag film covered by a thin Ag2S layer are investigated as a function of temperature at different biasing conditions. The observed switching threshold voltages along with the ON and OFF state resistances are quantitatively understood by taking the local overheating of the junction volume and the resulting structural phase transition of the Ag2S matrix into account. Our results demonstrate that the essential characteristics of the resistive switching in Ag2S based nanojunctions can be routinely optimized by suitable sample preparation and biasing schemes. PMID- 26062765 TI - Cadmium body burden of the Swiss population. AB - Urinary cadmium (Cd) excretion was measured within a representative Swiss collective. With a median of 0.23 ug/24 h (n = 1409) and the 95th percentile at 0.81 ug/24 h, no increased health risk for the general non-exposed population was identified. The independent variables Age, BMI and Smoking habit had a significant effect on urinary Cd excretion. No association was found with the region of residence and sex. A subsample comparison between 24-h and spot urines of the same subjects (n = 90) did not reveal an evident concentration difference for both creatinine-adjusted sample types. Dependencies on age and gender were observed for creatinine, which consequently impacts on the creatinine normalisation of urine samples. PMID- 26062766 TI - Clinicopathological Manifestations of Ichthyosiform Mycosis Fungoides. PMID- 26062767 TI - Coxsackievirus B3 infection reduces female mouse fertility. AB - Previously we demonstrated coxsackievirus B3 (CVB3) infection during early gestation as a cause of pregnancy loss. Here, we investigated the impacts of CVB3 infection on female mouse fertility. Coxsackievirus-adenovirus receptor (CAR) expression and CVB3 replication in the ovary were evaluated by immunohistochemistry or reverse transcription-polymerase chain reaction (RT-PCR). CAR was highly expressed in granulosa cells (GCs) and CVB3 replicated in the ovary. Histological analysis showed a significant increase in the number of atretic follicles in the ovaries of CVB3-infected mice (CVBM). Estrous cycle evaluation demonstrated that a higher number of CVBM were in proestrus compared to mock mice (CVBM vs. mock; 61.5%, 28.5%, respectively). Estradiol concentration in GC culture supernatant and serum were measured by an enzyme-linked immunosorbent assay. Baseline and stimulated levels of estradiol in GC were decreased in CVBM, consistent with significantly reduced serum levels in these animals. In addition, aromatase transcript levels in GCs from CVBM were also decreased by 40% relative to the mock. Bone mineral density evaluated by micro computed tomography was significantly decreased in the CVBM. Moreover, the fertility rate was also significantly decreased for the CVBM compared to the mock (CVBM vs. mock; 20%, 94.7%, respectively). This study suggests that CVB3 infection could interfere with reproduction by disturbing ovarian function and cyclic changes of the uterus. PMID- 26062768 TI - Novel phenotype in beagle dogs characterized by skin response to compound 48/80 focusing on skin mast cell degranulation. AB - Beagle dogs have long been employed in toxicology studies and as skin disease models. Compared with other experimental animal species, they are known to be susceptible to skin responses, such as rashes, from exposure to various chemical compounds. Here, a unique dog phenotype was identified that showed no skin response to compound 48/80, a mast cell degranulating agent. Although the skin responses to intradermal injection of polyoxyethylene castor oil derivative (HCO 60, a nonionic detergent), histamine dihydrochloride, concanavalin A (IgE receptor-mediated stimuli), or calcium ionophore A23187 were comparable in wild type (WT) dogs and these nonresponder (NR) dogs, only the response to compound 48/80 was entirely absent from NR dogs. The skin mast cell density and histamine content per mast cell were histologically comparable between WT and NR dogs. By checking for skin responses to compound 48/80, NR dogs were found to exist at the proportion of 17-20% among four animal breeders. From retrospective analysis of in-house breeding histories, the NR phenotype appears to conform to the Mendelian pattern of recessive inheritance. The standard skin response in WT dogs developed at 2-4 months of age. In conclusion, this unique phenotype, typified by insensitivity in the compound 48/80-induced degranulation pathway in mast cells, has been widely retained by recessive inheritance in beagle dogs among general experimental animal breeders. The knowledge concerning this phenotype could lead to better utilization of dogs in studies and aid in model development. PMID- 26062769 TI - Structure, Crystallographic Sites, and Tunable Luminescence Properties of Eu(2+) and Ce(3+)/Li(+)-Activated Ca1.65Sr0.35SiO4 Phosphors. AB - Eu(2+) and Ce(3+)/Li(+) singly doped and Eu(2+)/Ce(3+)/Li(+)-codoped Ca1.65Sr0.35SiO4 phosphors have been synthesized by a solid-state reaction method. The crystal structure was determined by Rietveld refinement to verify the formation of the alphaL'-Ca2SiO4 phase with the Sr addition into Ca2SiO4, and the preferred crystallographic positions of the Eu(2+) and Ce(3+)/Li(+) ions in Ca1.65Sr0.35SiO4 were analyzed based on a comparison of the unit-cell volumes and the designed chemical compositions of undoped isostructural compounds Ca(2 x)Sr(x)SiO4 (x = 0.25, 0.35, 0.45, 0.55 and 0.65). Ce(3+)/Li(+) singly activated Ca1.65Sr0.35SiO4 phosphors exhibit strong absorption in the range of 250-450 nm and a blue emission peak centered at about 465 nm. When Eu(2+) ions are codoped, the emission colors of Ca1.65Sr0.35SiO4:Ce(3+)/Li(+),Eu(2+) phosphors under the irradiation of 365 nm can be finely tuned from blue to green through the energy transfer from Ce(3+) to Eu(2+). The involved energy-transfer process between Ce(3+) and Eu(2+) and the corresponding mechanism are discussed in detail. The reported Ca1.65Sr0.35SiO4:Ce(3+)/Li(+),Eu(2+) phosphor might be a candidate for color-tunable blue-green components in the fabrication of near-ultraviolet-pumped white-light-emitting diodes (WLEDs). PMID- 26062770 TI - Probing the tunable surface chemistry of graphene oxide. AB - The determination of oxygen content, hydrophobicity and reduction efficiency of graphene oxide (GO) are difficult tasks because of its heterogeneous structure. Herein, we describe a novel approach for the detailed understanding of the surface chemistry of GO by studying the interactions between [Ru(bpy)3](2+) and GO. PMID- 26062771 TI - Convergent weaponry in a biological arms race. AB - Bacterial surface proteins covalently attach to host cells via a mechanism that is also used by immune system proteins that help eliminate invading pathogens. PMID- 26062772 TI - Molecular mechanisms underlying the emergence of bacterial pathogens: an ecological perspective. AB - The rapid emergence of new bacterial diseases negatively affects both human health and agricultural productivity. Although the molecular mechanisms underlying these disease emergences are shared between human- and plant pathogenic bacteria, not much effort has been made to date to understand disease emergences caused by plant-pathogenic bacteria. In particular, there is a paucity of information in the literature on the role of environmental habitats in which plant-pathogenic bacteria evolve and on the stress factors to which these microbes are unceasingly exposed. In this microreview, we focus on three molecular mechanisms underlying pathogenicity in bacteria, namely mutations, genomic rearrangements and the acquisition of new DNA sequences through horizontal gene transfer (HGT). We briefly discuss the role of these mechanisms in bacterial disease emergence and elucidate how the environment can influence the occurrence and regulation of these molecular mechanisms by directly impacting disease emergence. The understanding of such molecular evolutionary mechanisms and their environmental drivers will represent an important step towards predicting bacterial disease emergence and developing sustainable management strategies for crops. PMID- 26062774 TI - Mismatch repair deficiency predicts benefit of anti-PD-1 therapy. PMID- 26062773 TI - Clopidogrel significantly lowers the development of atherosclerosis in ApoE deficient mice in vivo. AB - The anti-platelet drug clopidogrel has been shown to modulate adhesion molecule and cytokine expression, both playing an important role in the pathogenesis of atherosclerosis. The aim of this study was to investigate the impact of clopidogrel on the development and progression of atherosclerosis. ApoE(-/-) mice fed an atherogenic diet (cholesterol: 1 %) for 6 months received a daily dose of clopidogrel (1 mg/kg) by i.p. injection. Anti-platelet treatment was started immediately in one experimental group, and in another group clopidogrel was started 2 month after beginning of the atherogenic diet. Blood was analysed at days 30, 60 and 120 to monitor the lipid profile. After 6 months the aortic arch and brachiocephalic artery were analysed by Sudan IV staining for plaque size and by morphometry for luminal occlusion. Serum levels of various adhesion molecules were investigated by ELISA and the cellular infiltrate was analysed by immunofluorescence. After daily treatment with 1 mg/kg clopidogrel mice showed a significant reduction of atherosclerotic lesions in the thoracic aorta and within cross sections of the aortic arch [plaque formation 55.2 % (clopidogrel/start) vs. 76.5 % (untreated control) n = 8, P < 0.05]. After treatment with clopidogrel P-/E-selectin levels and cytokine levels of MCP-1 and PDGFbeta were significantly reduced as compared to controls. The cellular infiltrate showed significantly reduced macrophage and T-cell infiltration in clopidogrel-treated animals. These results show that clopidogrel can effectively delay the development and progression of 'de-novo' atherosclerosis. However, once atherosclerotic lesions were already present, anti-platelet treatment alone did not result in reverse remodelling of these lesions. PMID- 26062775 TI - Combination immunotherapy breakthrough for melanoma. PMID- 26062776 TI - Nivolumab for squamous-cell non-small-cell lung cancer. PMID- 26062777 TI - Palbociclib for hormone receptor-positive breast cancer. PMID- 26062778 TI - 2015 ASCO Annual Meeting. PMID- 26062779 TI - Synthesis, Properties, and Packing Structures of Corannulene-Based pi-Systems Containing Heptagons. AB - Introduction of heptagons into hexagonal carbon lattices can generate negatively curved polycyclic aromatic hydrocarbons, which are of significant interest in the field of exotic molecular nanocarbons. We have successfully synthesized and characterized corannulene-based pi-systems containing heptagons (4 and 5) as new negatively curved polycyclic aromatic hydrocarbons as well as possible intermediates in the synthesis of warped nanographene 1. The formation of 4 and 5 represents the first example for which a heptagon is formed under Scholl reaction conditions before all hexagons are formed. Even more interestingly, we discovered that the mode and degree of solid-phase intermolecular pi-pi interaction can be altered significantly by the degree of ring closure. PMID- 26062782 TI - Vibronic bandshape of the absorption spectra of dibenzoylmethanatoboron difluoride derivatives: analysis based on ab initio calculations. AB - The nature of absorption bandshapes of dibenzoylmethanatoboron difluoride (DBMBF2) dye substituted in ortho-, meta-, and para-positions of the phenyl ring is investigated using DFT and TDDFT with the range-separated hybrid CAM-B3LYP functional and the 6-311G(d,p) basis set. The solvent effects are taken into account within the polarized continuum model. The vibronic bandshape is simulated using a time-dependent linear coupling model with a vertical gradient approach through an original code. For flexible chromophores, the spectra of individual conformers are summed up with Boltzmann factors. It is shown that the long wavelength absorption bandshape of DBMBF2 derivatives is determined by three factors: the relative statistical weights of conformers with different electronic absorption patterns, the relative position and intensity of the second low-energy electronic transition, and the vibronic structure of individual electronic peaks. The latter is governed by the relationship between the hard vibrational modes, which contribute to vibronic progression, and soft modes, which provide broadening of the peaks. The simulated spectra of the dyes in the study are generally consistent with the available experimental data and explain the observed spectral features. PMID- 26062780 TI - Overexpression of delta-catenin is associated with a malignant phenotype and poor prognosis in colorectal cancer. AB - Little is known regarding the expression or clinical significance of delta catenin, a member of the catenin family, in colorectal cancer (CRC). The present study examined the expression of delta-catenin using immunohistochemistry in 110 cases of CRC, including 70 cases with complete follow-up records and 40 cases with paired lymph node metastases. In addition, delta-catenin mRNA and protein expression were compared in 30 pairs of matched CRC and normal colorectal tissues by reverse transcription quantitative polymerase chain reaction and western blot analysis. delta-Catenin was weakly expressed or absent in the cytoplasm of normal intestinal epithelial cells, whereas positive delta-catenin expression localized to the cytoplasm was observed in CRC cells. The rate of positive delta-catenin expression in CRC (68.18%; 75/110) was significantly higher than that in normal colorectal tissues (36.7%; 11/30; P<0.001). In addition, delta-catenin mRNA and protein expression were significantly increased in CRC tissues compared to those in their matched normal tissues (all P<0.05). The expression of delta-catenin in stage III-IV CRC was higher than that in stage I-II CRC, and the expression of delta-catenin in the tumors of patients with lymph node metastases was higher than that in patients without lymph node metastases. Kaplan-Meier survival curves demonstrated that the survival time of patients with positive delta-catenin expression was shorter than that of patients with negative delta-catenin expression (P=0.005). Furthermore, Cox multivariate analysis indicated that the tumor, nodes and metastasis stage (P=0.02) and positive delta-catenin expression (P=0.033) were independent prognostic factors in CRC. The present study therefore indicated that delta-catenin may be a suitable independent prognostic factor for CRC. PMID- 26062783 TI - Heterogeneous distribution of plankton within the mixed layer and its implications for bloom formation in tropical seas. AB - Intensive sampling at the coastal waters of the central Red Sea during a period of thermal stratification, prior to the main seasonal bloom during winter, showed that vertical patches of prokaryotes and microplankton developed and persisted for several days within the apparently density uniform upper layer. These vertical structures were most likely the result of in situ growth and mortality (e.g., grazing) rather than physical or behavioural aggregation. Simulating a mixing event by adding nutrient-rich deep water abruptly triggered dense phytoplankton blooms in the nutrient-poor environment of the upper layer. These findings suggest that vertical structures within the mixed layer provide critical seeding stocks that can rapidly exploit nutrient influx during mixing, leading to winter bloom formation. PMID- 26062784 TI - Nanoscale opening fabrication on Si (111) surface from SiO2 barrier for vertical growth of III-V nanowire arrays. AB - We reported here a selectively additive process to fabricate nanoscale openings of an Si (111) surface from an SiO2 barrier layer. Such nanoscale openings are made for the growth of vertical III-V nanowires. The Si (111) surface protected by a patterned SiNx layer was thermally oxidized, which resulted in a selectively added SiO2 barrier layer. After removing the SiNx, nanoscale openings of the Si (111) surface were exposed for the nanowire growth. Arrays with patterned nanoholes of varied diameters from 60 nm to 334 nm have been used for position controlled catalyst-free growth of vertical InAs nanowire arrays by metal-organic chemical vapor deposition. Correlations between the nanohole diameter and the diameter, length and growth yield of as-fabricated nanowire arrays have been investigated, showing a repeatable stability. This technique offers an alternative approach for the fabrication of novel III-V nanowire devices using vertical array configuration. A lateral thermal oxidation effect led to a smaller size of the Si opening than that of the SiNx protection nanoislands; therefore, the technique also offers a controllable way to produce nanoholes with an ultra small diameter. PMID- 26062785 TI - Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis. AB - Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), N-methyl-D-aspartate (NMDA) antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: (1) placebo vs 10 mg of memantine or (2) placebo vs 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices, and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age dependent and most evident in older CPD patients, whereas those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients. PMID- 26062786 TI - Disrupted-in-Schizophrenia-1 Attenuates Amyloid-beta Generation and Cognitive Deficits in APP/PS1 Transgenic Mice by Reduction of beta-Site APP-Cleaving Enzyme 1 Levels. AB - Disrupted-in-Schizophrenia-1 (DISC1) is a genetic risk factor for a wide range of major mental disorders, including schizophrenia, major depression, and bipolar disorders. Recent reports suggest a potential role of DISC1 in the pathogenesis of Alzheimer's disease (AD), by referring to an interaction between DISC1 and amyloid precursor protein (APP), and to an association of a single-nucleotide polymorphism in a DISC1 intron and late onset of AD. However, the function of DISC1 in AD remains unknown. In this study, decreased levels of DISC1 were observed in the cortex and hippocampus of 8-month-old APP/PS1 transgenic mice, an animal model of AD. Overexpression of DISC1 reduced, whereas knockdown of DISC1 increased protein levels, but not mRNA levels of beta-site APP-Cleaving Enzyme 1 (BACE1), a key enzyme in amyloid-beta (Abeta) generation. Reduction of BACE1 protein levels by overexpression of DISC1 was accompanied by an accelerating decline rate of BACE1, and was blocked by the lysosomal inhibitor chloroquine, rather than proteasome inhibitor MG-132. Moreover, overexpression of DISC1 in the hippocampus with an adeno-associated virus reduced the levels of BACE1, soluble Abeta40/42, amyloid plaque density, and rescued cognitive deficits of APP/PS1 transgenic mice. These results indicate that DISC1 attenuates Abeta generation and cognitive deficits of APP/PS1 transgenic mice through promoting lysosomal degradation of BACE1. Our findings provide new insights into the role of DISC1 in AD pathogenesis and link a potential function of DISC1 to the psychiatric symptoms of AD. PMID- 26062787 TI - Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit. AB - Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders. PMID- 26062788 TI - Contextual Information Drives the Reconsolidation-Dependent Updating of Retrieved Fear Memories. AB - Stored memories enter a temporary state of vulnerability following retrieval known as 'reconsolidation', a process that can allow memories to be modified to incorporate new information. Although reconsolidation has become an attractive target for treatment of memories related to traumatic past experiences, we still do not know what new information triggers the updating of retrieved memories. Here, we used biochemical markers of synaptic plasticity in combination with a novel behavioral procedure to determine what was learned during memory reconsolidation under normal retrieval conditions. We eliminated new information during retrieval by manipulating animals' training experience and measured changes in proteasome activity and GluR2 expression in the amygdala, two established markers of fear memory lability and reconsolidation. We found that eliminating new contextual information during the retrieval of memories for predictable and unpredictable fear associations prevented changes in proteasome activity and glutamate receptor expression in the amygdala, indicating that this new information drives the reconsolidation of both predictable and unpredictable fear associations on retrieval. Consistent with this, eliminating new contextual information prior to retrieval prevented the memory-impairing effects of protein synthesis inhibitors following retrieval. These results indicate that under normal conditions, reconsolidation updates memories by incorporating new contextual information into the memory trace. Collectively, these results suggest that controlling contextual information present during retrieval may be a useful strategy for improving reconsolidation-based treatments of traumatic memories associated with anxiety disorders such as post-traumatic stress disorder. PMID- 26062789 TI - Development of new methods for determining the heparanase enzymatic activity. AB - INTRODUCTION: Heparanase is a mammalian endo-beta-glucuronidase. Notwithstanding its importance in various pathological and non-pathological events few straightforward methods for heparanase enzymatic activity has been stated. The aim of this study was to develop two heparanase activity assays to cover a whole range of applications. First, a fast and easy method based on commercial homogenous substrate, fondaparinux, was described. The other method is a quantitative assay based on biotinylated heparan sulfate that uses an easier technique to immobilize the substrate in a 96-well plate. METHODS: 1): The heparanase recombinant enzyme and fondaparinux were incubated overnight. After incubation, a fluorescent redox marker, resazurin, was added. The reduction of resazurin depends on the amount of glucuronic acid released by heparanase digestion. Fluorescence measurements were done using excitation and emission wavelengths of 560 nm and 590 nm, respectively. METHODS: 2): The 96-well plate was incubated with protamine sulfate. Subsequently, biotinylated heparan sulfate was immobilized. The enzymatic assay was performed using chimeric recombinant heparanase at different concentrations. In sequence, the immobilized biotinylated heparan sulfate that was not digested by recombinant heparanase was bound to streptavidin conjugated with europium. Fluorescence was measured using a time resolved fluorometer. CONCLUSION: Both methods have high sensitivity and can be used to detect heparanase activity. Fondaparinux assay is a quick and easy method for screening of heparanase inhibitors using recombinant enzyme or bacterial crude extract. Biotinylated heparan sulfate assay can be used for quantitative analysis in biological samples and protamine sulfate showed been capable to immobilized heparan sulfate. PMID- 26062791 TI - Establishment of a Maternal Newborn Health Registry in the Belgaum District of Karnataka, India. AB - BACKGROUND: Pregnancy-related vital registration is important to inform policy to reduce maternal, fetal and newborn mortality, yet few systems for capturing accurate data are available in low-middle income countries where the majority of the mortality occurs. Furthermore, methods to effectively implement high-quality registration systems have not been described. The goal of creating the registry described in this paper was to inform public health policy makers about pregnancy outcomes in our district so that appropriate interventions to improve these outcomes could be undertaken and to position the district to be a leader in pregnancy-related public health research. METHODS: We created a prospective maternal and newborn health registry in Belgaum, Karnataka State, India. To initiate this registry, we worked with the Ministry of Health to first establish estimated birth rates and define the catchment areas of the clusters, working within the existing health system and primary health centers. We also undertook household surveys to identify women likely to become pregnant. We then implemented monitoring measures to ensure high quality and completeness of the maternal newborn health registry. All pregnant women in the catchment area were identified, consented and enrolled during pregnancy, with follow-up visits to ascertain pregnancy outcomes and mother/infant status at 42-days postpartum. RESULTS: From 2008 through 2014, we demonstrated continued improvements in both the coverage for enrollment and accuracy of reporting pregnancy outcomes within the defined catchment area in Belgaum, India. Nearly 100% of women enrolled had follow-up at birth and 99% had 42-day follow-up. Furthermore, we facilitated earlier enrollment of women during pregnancy while achieving more timely follow up and decreased time of reporting from the date of the pregnancy event. CONCLUSIONS: We created a pregnancy-related registry which includes demographic data, risk factors, and outcomes allowing for high rates of ascertainment and follow-up while working within the existing health system. Understanding the elements of the system used to create the registry is important to improve the quality of the results. Tracking of pregnancies and their outcomes is an important step toward reducing maternal and perinatal mortality. PMID- 26062792 TI - The Development of a Humanitarian Health Ethics Analysis Tool. AB - Introduction Health care workers (HCWs) who participate in humanitarian aid work experience a range of ethical challenges in providing care and assistance to communities affected by war, disaster, or extreme poverty. Although there is increasing discussion of ethics in humanitarian health care practice and policy, there are very few resources available for humanitarian workers seeking ethical guidance in the field. To address this knowledge gap, a Humanitarian Health Ethics Analysis Tool (HHEAT) was developed and tested as an action-oriented resource to support humanitarian workers in ethical decision making. While ethical analysis tools increasingly have become prevalent in a variety of practice contexts over the past two decades, very few of these tools have undergone a process of empirical validation to assess their usefulness for practitioners. METHODS: A qualitative study consisting of a series of six case analysis sessions with 16 humanitarian HCWs was conducted to evaluate and refine the HHEAT. RESULTS: Participant feedback inspired the creation of a simplified and shortened version of the tool and prompted the development of an accompanying handbook. CONCLUSION: The study generated preliminary insight into the ethical deliberation processes of humanitarian health workers and highlighted different types of ethics support that humanitarian workers might find helpful in supporting the decision-making process. PMID- 26062790 TI - Stroke with atrial fibrillation or atrial flutter: a descriptive population-based study from the Brest stroke registry. AB - BACKGROUND: In the 1990s, epidemiological studies estimated the prevalence of stroke caused by atrial fibrillation (AF) at about 15 %. Given the aging population, there is a rise in the number of AF patients. AF prevention guidelines based on clinical practice and the literature have been published and updated since 2001. Implementation seems to have an impact on the prescription of vitamin K antagonist (VKA). During the last 20 years, few population-based studies have focused on the prevalence of atrial arrhythmia (AA) in patients with stroke. The objective of the present prospective study, using data from 2008, was to evaluate the prevalence of AA (atrial fibrillation/flutter) in patients with stroke and the impact of implementing AF guidelines. METHODS: The prevalence of AA was studied in patients diagnosed with stroke from January 1 to December 31, 2008 in the population-based Stroke Registry of Brest, France (total population, 363,760 according to the 2008 census, with 295,553 aged 15 years or older). Guidelines implementation was assessed in terms of antithrombotic therapy (VKA, antiplatelet agent, none), and the CHADS2 (Congestive heart failure, Hypertension, Age > 75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack). RESULTS: 851 cases of stroke were identified. The prevalence of AA was 31.7 % (n = 264), and increased with age from < 20 % in patients aged 45 to 54 years to nearly 50 % in patients >= 85 years. In patients with AA, 231 strokes were ischemic, 28 hemorrhagic and 5 undetermined. At time of stroke, AA was known in 207 patients (78.4 %). 54 of the 152 patients with CHADS2 score >= 2 (35.5 %) were treated with VKA; this proportion decreased with age: 50 % between 50 and 74 years, 43.8 % between 75 and 84 years, and 25 % at 85 years and older. CONCLUSION: The prevalence of AA in the population-based Brest Stroke Registry in 2008 was higher than that reported by studies conducted 20 years ago. Despite publication of AF prevention guidelines, VKA prescription and use in elderly patients were significantly low. PMID- 26062793 TI - Chrysin inhibits diabetic renal tubulointerstitial fibrosis through blocking epithelial to mesenchymal transition. AB - Renal fibrosis is a crucial event in the pathogenesis of diabetic nephropathy (DN). The process known as epithelial to mesenchymal transition (EMT) contributes to the accumulation of matrix proteins in kidneys, in which renal tubular epithelial cells play an important role in progressive renal fibrosis. The current study investigated that chrysin (5,7-dihydroxyflavone) present in bee propolis and herbs, inhibited renal tubular EMT and tubulointerstitial fibrosis due to chronic hyperglycemia. Human renal proximal tubular epithelial cells (RPTEC) were incubated in media containing 5.5 mM glucose, 27.5 mM mannitol (as an osmotic control), or 33 mM glucose (HG) in the absence and presence of 1-20 MUM chrysin for 72 h. Chrysin significantly inhibited high glucose-induced renal EMT through blocking expression of the mesenchymal markers vimentin, alpha-smooth muscle actin, and fibroblast-specific protein-1 in RPTEC and db/db mice. Chrysin reversed the HG-induced down-regulation of the epithelial marker E-cadherin and the HG-enhanced N-cadherin induction in RPTEC. In addition, chrysin inhibited the production of collagen IV in tubular cells and the deposition of collagen fibers in mouse kidneys. Furthermore, chrysin blocked tubular cell migration concurrent with decreasing matrix metalloproteinase-2 activity, indicating epithelial cell derangement and tubular basement membrane disruption. Chrysin restored the induction of the tight junction proteins Zona occludens protein-1 (ZO-1) and occludin downregulated in diabetic mice. Chrysin inhibited renal tubular EMT mediated tubulointerstitial fibrosis caused by chronic hyperglycemia. Therefore, chrysin may be a potent renoprotective agent for the treatment of renal fibrosis associated DN. KEY MESSAGES: * Glucose increases renal tubular epithelial induction of vimentin, alpha-SMA and FSP-1. * Glucose enhances renal EMT by blocking tubular epithelial E-cadherin expression. * Chrysin inhibits tubular EMT mediated tubulointerstitial fibrosis in mouse kidneys. * Chrysin restores renal tubular induction of ZO-1 and occludin downregulated in diabetic mice. * Chrysin blocks glucose-induced renal tubular cell migration with reducing MMP-2 activity. PMID- 26062794 TI - LapOntoSPM: an ontology for laparoscopic surgeries and its application to surgical phase recognition. AB - PURPOSE: The rise of intraoperative information threatens to outpace our abilities to process it. Context-aware systems, filtering information to automatically adapt to the current needs of the surgeon, are necessary to fully profit from computerized surgery. To attain context awareness, representation of medical knowledge is crucial. However, most existing systems do not represent knowledge in a reusable way, hindering also reuse of data. Our purpose is therefore to make our computational models of medical knowledge sharable, extensible and interoperational with established knowledge representations in the form of the LapOntoSPM ontology. To show its usefulness, we apply it to situation interpretation, i.e., the recognition of surgical phases based on surgical activities. METHODS: Considering best practices in ontology engineering and building on our ontology for laparoscopy, we formalized the workflow of laparoscopic adrenalectomies, cholecystectomies and pancreatic resections in the framework of OntoSPM, a new standard for surgical process models. Furthermore, we provide a rule-based situation interpretation algorithm based on SQWRL to recognize surgical phases using the ontology. RESULTS: The system was evaluated on ground-truth data from 19 manually annotated surgeries. The aim was to show that the phase recognition capabilities are equal to a specialized solution. The recognition rates of the new system were equal to the specialized one. However, the time needed to interpret a situation rose from 0.5 to 1.8 s on average which is still viable for practical application. CONCLUSION: We successfully integrated medical knowledge for laparoscopic surgeries into OntoSPM, facilitating knowledge and data sharing. This is especially important for reproducibility of results and unbiased comparison of recognition algorithms. The associated recognition algorithm was adapted to the new representation without any loss of classification power. The work is an important step to standardized knowledge and data representation in the field on context awareness and thus toward unified benchmark data sets. PMID- 26062795 TI - Computation of the change in length of a braided device when deployed in realistic vessel models. AB - PURPOSE: An important issue in the deployment of braided stents, such as flow diverters, is the change in length, also known as foreshortening, underwent by the device when is released from the catheter into a blood vessel. The position of the distal end is controlled by the interventionist, but knowing a priori the position of the proximal end of the device is not trivial. In this work, we assess and validate a novel computer method to predict the length that a braided stent will adopt inside a silicon model of an anatomically accurate vessel. METHODS: Three-dimensional rotational angiography images of aneurysmatic patients were used to generate surface models of the vessels (3D meshes) and then create accurate silicon models from them. A braided stent was deployed into each silicon model to measure its length. The same stents deployed on the silicon models were virtually deployed on the 3D meshes using the method being evaluated. RESULTS: The method was applied to five stent placements on three different silicon models. The length adopted by the real braided device in the silicon models varies between 15 and 30% from the stent length specified by the manufacturer. The final length predicted by the method was within the estimated error of the measured real stent length. CONCLUSIONS: The method provides, in a few seconds, the length of a braided stent deployed inside a vessel, showing an accurate estimation of the final length for the cases studied. This technique could provide useful information for planning the intervention and improve endovascular treatment of intracranial aneurysms in the future. PMID- 26062796 TI - Which quality of life measures fit your relative effectiveness assessment? AB - BACKGROUND: Health-related quality of life (HRQoL) is an important endpoint of many healthcare interventions. This study develops guidance on how to select appropriate HRQoL measures for inclusion in a clinical trial, given the purposes of the HRQoL measurement. METHODS: The guidance is based on a systematic literature review, discussions with members of the European Network for Health Technology Assessment (EUnetHTA) and two rounds of public consultation. RESULTS: A set of twelve recommendations was developed, addressing the requirements for HRQoL data for relative effectiveness assessment, for cost-utility analyses and for informing clinical decision making. Recommendations relate to the choice of the type of measure as well as to aspects such as measurement frequency, target population and presentation. CONCLUSIONS: The purpose and context of HRQoL measurement is crucial for the relevance of the data obtained with a specific HRQoL measure. It is recommended to always include a generic HRQoL instrument in clinical trials to cover a wide range of possible future uses of the HRQoL data. PMID- 26062797 TI - Visfatin promotes osteosarcoma cell migration and invasion via induction of epithelial-mesenchymal transition. AB - Visfatin is considered to be a biomarker in various types of cancers. However, no evidence has been reported for the direct effect of visfatin on osteosarcoma cell metastasis. The aims of the present study were to investigate the influence of visfatin on the migration and invasion of osteosarcoma cells and clarify the underlying mechanism. The expression levels of epithelial-mesenchymal transition (EMT) markers, as well as the transcriptional factor Snail-1, were first detected at both the protein and mRNA levels in U2OS osteosarcoma cells after stimulation of visfatin. Then the expression of NF-kappaB (p65) was detected by western blot analysis, and siRNA of Snail-1 and inhibitor of NF-kappaB were used to investigate the effect of visfatin. Finally, migration and invasion of the cells were detected respectively by scratch wound healing and transwell assays. Visfatin downregulated E-cadherin and upregulated N-cadherin in concentration- and time-dependent manners at the protein and mRNA levels. The expression of Snail-1 was also upregulated. Moreover, visfatin also promoted the nuclear translocation of the NF-kappaB pathway. Administration of siRNA of Snail-1 and the inhibitor BAY11-7082 validated the roles of Snail-1 and NF-kappaB in the visfatin-induced regulation of EMT markers. Migration and invasion of U2OS osteosarcoma cells were promoted following the application of visfatin. These results demonstrated that visfatin enhances the migration and invasion of osteosarcoma cells via the NF-kappaB/Snail-1/EMT pathway. PMID- 26062798 TI - Ginsenoside Rb1 inhibits matrix metalloproteinase 13 through down-regulating Notch signaling pathway in osteoarthritis. AB - Mounting evidence suggests that an excess of matrix metalloproteinase-13 (MMP-13) plays an important role in the breakdown of extracellular matrix in osteoarthritis (OA). Here, the effects of ginsenoside Rb1 (GRb1) on the expression of MMP-13 in IL-1beta-induced SW 1353 chondrosarcoma cells and an experimental rat model of OA induced by anterior cruciate ligament transection (ACLT) were investigated. SW1353 chondrosarcoma cells were pretreated with or without GRb1 and Notch signaling pathway inhibitor, DAPT, then were stimulated with IL-1beta. In rats, experimental OA was induced by ACLT. These rats then received intra-articular injections of vehicle, an inhibitor of gamma-secretase, DAPT, and/or GRb1. Expression of MMP-13, collagen type II (CII), Notch1, and jagged 1 (JAG1) were verified by western blotting and immunohistochemistry. In addition, levels of MMP-13 mRNA were detected using quantitative real-time PCR. In histological analyses, treatment with DAPT reduced the number of cartilage lesions present and the expressions of MMP-13, CII, Notch1, and JAG1. In addition, treatment with GRb1 was associated with lower levels of Notch1 and JAG1 in both IL-1beta-induced SW1353 chondrosarcoma cells and in the rat OA model. Furthermore, the suppressive effect of GRb1 on MMP-13 was greater than that exhibited by the signaling pathway inhibitor. In conclusion, GRb1 inhibits MMP-13 through down-regulating Notch signaling pathway in OA. PMID- 26062799 TI - The liver X receptor agonist TO901317 protects mice against cisplatin-induced kidney injury. AB - Liver X receptors are in the nuclear receptor superfamily and are contained in the regulation of lipid and cholesterol metabolism. Besides, liver X receptors are considered crucial regulators of the inflammatory response and innate immunity. The current study evaluates the in vivo effects that the synthetic liver X receptor agonist TO901317 protects against cisplatin-induced kidney injury in mice. Mice received cisplatin administration through a single intraperitoneal injection (20 mg/kg in saline). And then the mice were treated with the TO901317 by daily gavage (10 mg/kg/day) 12 h postcisplatin administration, and cisplatin nephrotoxicity was evaluated. At 72 h after cisplatin treatment, elevated plasma urea and creatinine levels (P < 0.05) were evidenced which indicates the renal dysfunction of the vehicle-treated mice, consistent with tubular necrosis, protein cast, dilation of renal tubules, and desquamation of epithelial cells in renal tubules. In contrast, the severity of renal dysfunction and histological damage was reduced in TO901317 treated mice (P < 0.05). In accordance, circulating tumor necrosis factor alpha levels, renal tumor necrosis factor alpha, p47(phox), gp91(phox), and protein expression levels and COX-2 mRNA, renal monocyte chemoattractant protein 1, VACAM-1 mRNA and intercellular adhesion molecule-1 contents, and renal prostaglandin E2 amounts, were higher in samples from cisplatin-treated mice in comparison with controls (P < 0.05) but attenuated in the TO901317 treatment group (P < 0.05). Taken together, treatment with the liver X receptor agonist TO901317 ameliorated the inflammatory response and oxidative stress in cisplatin-induced kidney injury in mice. PMID- 26062800 TI - Immunohistochemical Predictors of Bone Metastases in Breast Cancer Patients. AB - Bones are the most common metastatic site of relapse in breast cancer patients and the prediction of bone metastases (BM) risk might prompt developing preventive and therapeutic strategies. The aim of the study was to correlate immunohistochemical (IHC) expression of selected proteins in primary breast cancer with the occurrence of BM. We analyzed expression of proteins potentially associated with BM in primary tumors of 184 patients with metastatic breast cancer (113 with- and 71 without BM). Expression of estrogen receptor (ER) in primary tumor was more common in patients with- compared to those without BM (74 vs. 45 % respectively, p = 0.0001), whereas in this subset less common was expression of parathyroid hormone related protein receptor type 1 (16 vs. 34 %, respectively, p = 0.007) and cytoplasmic expression of osteopontin (OPNcyt; 1.9 vs. 14 %, respectively, p = 0.002). The relationship between expression of ER and OPNcyt and the occurrence of BM was confirmed in the multivariate analysis. The ER-positive/OPNcyt negative phenotype was significantly more common in patients with- compared to those without BM (75 and 25 %, p < 0.0001, respectively; HR 1.79, p = 0.013). Luminal A (43 vs. 23 % respectively, p = 0.009) and luminal B/HER2-positive (16 vs. 4.9 % respectively, p = 0.032) subtypes were more common in patients with- compared to those without BM, whereas triple negative breast cancer subtype was less common (16 vs. 38 %, p = 0.002). PMID- 26062801 TI - Eating and drinking interventions for people at risk of lacking decision-making capacity: who decides and how? AB - BACKGROUND: Some people with progressive neurological diseases find they need additional support with eating and drinking at mealtimes, and may require artificial nutrition and hydration. Decisions concerning artificial nutrition and hydration at the end of life are ethically complex, particularly if the individual lacks decision-making capacity. Decisions may concern issues of life and death: weighing the potential for increasing morbidity and prolonging suffering, with potentially shortening life. When individuals lack decision making capacity, the standard processes of obtaining informed consent for medical interventions are disrupted. Increasingly multi-professional groups are being utilised to make difficult ethical decisions within healthcare. This paper reports upon a service evaluation which examined decision-making within a UK hospital Feeding Issues Multi-Professional Team. METHODS: A three month observation of a hospital-based multi-professional team concerning feeding issues, and a one year examination of their records. The key research questions are: a) How are decisions made concerning artificial nutrition for individuals at risk of lacking decision-making capacity? b) What are the key decision-making factors that are balanced? c) Who is involved in the decision-making process? RESULTS: Decision-making was not a singular decision, but rather involved many different steps. Discussions involving relatives and other clinicians, often took place outside of meetings. Topics of discussion varied but the outcome relied upon balancing the information along four interdependent axes: (1) Risks, burdens and benefits; (2) Treatment goals; (3) Normative ethical values; (4) Interested parties. CONCLUSIONS: Decision-making was a dynamic ongoing process with many people involved. The multiple points of decision-making, and the number of people involved with the decision-making process, mean the question of 'who decides' cannot be fully answered. There is a potential for anonymity of multiple decision makers to arise. Decisions in real world clinical practice may not fit precisely into a model of decision-making. The findings from this service evaluation illustrate that within multi-professional team decision-making; decisions may contain elements of both substituted and supported decision-making, and may be better represented as existing upon a continuum. PMID- 26062802 TI - Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists. AB - Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) alpha/beta were tested in vitro. Compound 26 had an IC50 value of 6.4 uM against LXRalpha and an IC50 value of 5.6 uM against LXRbeta. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRalpha/beta antagonists. PMID- 26062803 TI - A Preliminary Investigation of Normal Pancreas and Acute Pancreatitis Elasticity Using Virtual Touch Tissue Quantification (VTQ) Imaging. AB - BACKGROUND: The aim of this study was to prospectively evaluate the use of elastometry in healthy volunteers and patients with acute pancreatitis using virtual touch tissue quantification (VTQ) imaging technology performed on the pancreas. MATERIAL AND METHODS: We enrolled 210 healthy volunteers and 44 acute pancreatitis patients in the study between March 2012 and June 2013. Healthy subjects were divided into 3 groups: young (18-30 years), middle-aged (30-50 years), and elderly (>50 years). VTQ was performed on the pancreatic head and body regions to obtain shear wave velocity (SWV) measurements, which were used to evaluate the elasticity values of tissues. RESULTS: The pancreatic head SWV value in the whole healthy group was 1.18+/-0.23 m/s, and that in the pancreatic body was 1.21+/-0.20 m/s. In patients with acute pancreatitis, the mean SWV measurements at the head were 1.18+/-0.20 m/s, compared to 1.25+/-0.19 m/s in the pancreatic body. There was no statistically significant difference between whole healthy volunteers and the acute pancreatitis group. CONCLUSIONS: VTQ is a new method that shows promise for the quantification of pancreatic elasticity, but further studies are warranted. PMID- 26062804 TI - Chronic inflammatory pain upregulates expression of P2Y2 receptor in small diameter sensory neurons. AB - Roles of ionotropic purinergic (P2X) receptors in chronic pain have been intensively investigated. However, the contribution of metabotropic purinergic (P2Y) receptors to pathological pain is controversial. In the present study, using single cell RT-PCR (reverse transcription-polymerase chain reaction) and single cell nested-PCR techniques, we examined the expression of P2X(2), P2X(3), P2Y(1) and P2Y(2) mRNA transcripts in retrogradely labeled cutaneous sensory neurons from mouse lumber dorsal root ganglia (DRGs) following peripheral inflammation. The percentage of cutaneous sensory neurons expressing P2Y(2) mRNA transcripts increased after complete Freund's adjuvant (CFA) treatment. Particularly, the P2Y(2) mRNA transcripts were more frequently detected in small diameter cutaneous neurons from CFA-treated mice than those from control mice. Coexpression of P2Y(2) and P2X (P2X(2) or P2X(3)) mRNAs was more frequently observed in cutaneous sensory neurons from CFA-treated mice relative to controls. Pain behavioral tests showed that the blockade of P2Y receptors by suramin attenuated mechanical allodynia evoked either by CFA or uridine triphosphate (UTP), an endogenous P2Y(2) and P2Y(4) agonist. These results suggest that chronic inflammatory pain enhances expression of P2Y(2) receptor in peripheral sensory neurons that innervate the injured tissue and the activation of P2Y receptors contributes to mechanical allodynia following inflammation. PMID- 26062805 TI - Peer-driven quality improvement among health workers and traditional birth attendants in Sierra Leone: linkages between providers' organizational skills and relationships. AB - BACKGROUND: Sierra Leone has among the poorest maternal and child health indicators in the world and investments in public health have been predominately to increase demand for services, with fewer initiatives targeting supply side factors that influence health workers' work environment. This paper uses data from the Quality Circles project in a rural district of Sierra Leone to achieve three objectives. First, we examine the effect of the intervention on organizational skills and relationships among coworkers as well as between health workers and traditional birth attendants. Second, we examine whether changes in organizational skills are associated with changes in relationships among and between formal and informal health providers and between health providers and clients. Third, we aim to further understand these changes through the perspectives of health workers and traditional birth attendants. METHODS: The Quality Circles project was implemented in Kailahun District in the Eastern province of Sierra Leone from August 2011 to June 2013, with adjacent Tonkolili District serving as the control site. Using a mixed-methods approach, the evaluation included a quantitative survey, in-depth interviews and focus group discussions with health workers and traditional birth attendants. Mean values of the variables of interest were compared across sub-populations, and correlation analyses were performed between changes in organizational skills and changes in relationships. RESULTS: The results demonstrate that the Quality Circles intervention had positive effects on organizational skills and relationships. Furthermore, improvements in all organizational skill variables - problem solving, strategizing and negotiation skills - were strongly associated with a change in the overall relationship variable. CONCLUSIONS: The Quality Circles approach has the potential to support health workers to improve their organizational skills and relationships, which in turn can contribute to improving the interpersonal dimensions of the quality of care in low-resource contexts. This method brings together peers in a structured process for constructive group work and individual skill development, which are important in low-resource contexts where active participation and resourcefulness of health workers can also contribute to better health service delivery. PMID- 26062806 TI - Ex vivo manipulation of bone marrow cells to rescue uremia-induced dysfunction for autologous therapy. AB - Uremic toxins are known to affect the regenerative properties of tissue-resident and circulating stem cells and thus appear to be a limiting factor for autologous stem cell-based approaches for treating chronic kidney disease. The recent article by van Koppen and colleagues in Stem Cell Research & Therapy provides evidence that an ex vivo short-term pre-treatment with statins reverts the dysfunction of bone marrow stem cells isolated from rats with renal impairment. Indeed, statin pre-treated cells improved renal function in a model of established chronic kidney disease. Our commentary discusses the potential of this approach in the context of autologous cell therapy and the available knowledge on the mechanisms involved in uremia-induced stem cell dysfunction. PMID- 26062808 TI - A comprehensive assessment of the malaria microscopy system of Aceh, Indonesia, in preparation for malaria elimination. AB - BACKGROUND: The Health Office of Aceh aims to eliminate malaria from Aceh Province, Indonesia by 2015. Malaria was formerly common in Aceh (population 4.5 million), but has declined dramatically in recent years consequent to post tsunami control efforts. Successful elimination will depend upon rapid and accurate diagnosis and case follow-up at community level. A prerequisite to this is widespread coverage of high quality malaria diagnosis. This study describes the results of a comprehensive assessment of the malaria diagnostic capacity in Aceh as the province moves towards malaria elimination. METHODS: The study was conducted in 23 districts in Aceh from October 2010 to July 2011. Six types of questionnaires were used to collect data on competency of microscopists and laboratory capacity. Standardized slides were used to evaluate the proficiency of all microscopists. In addition, site visits to 17 primary health centres (PHC) assessed diagnostic practice and logistics capacity. RESULTS: Five hundred and seventy four malaria microscopists have been officially registered and assigned to duty in the 23 districts in Aceh Province. They work in 345 laboratories, predominantly in PHCs (69 %) and hospitals (25 %). Three laboratories were evaluated as adequate for all 30 elements, while 29 laboratories were adequate for less than five of 30 elements. Standardized proficiency tests showed that 413 microscopists were at basic (in training) level, with 10 advanced and 9 reference level. No microscopist achieved expert level. Neither the province nor any of Aceh's districts has a standardized inventory and logistics database for malaria diagnostics, nor did any of the surveyed laboratories operate a quality assurance programme for either microscopy or rapid diagnostic tests. CONCLUSIONS: The study highlights the importance of careful assessment of diagnostic capacity when embarking upon a large-scale malaria elimination programme. Aceh's laboratories have minimal infrastructure with nearly all microscopists still in training. On the positive side, a large workforce of microscopists has been assigned to laboratories with the needed equipment. Aceh will need to embark on a large-scale comprehensive quality assurance scheme if it is to achieve malaria elimination. PMID- 26062809 TI - CMRegNet-An interspecies reference database for corynebacterial and mycobacterial regulatory networks. AB - BACKGROUND: Organisms utilize a multitude of mechanisms for responding to changing environmental conditions, maintaining their functional homeostasis and to overcome stress situations. One of the most important mechanisms is transcriptional gene regulation. In-depth study of the transcriptional gene regulatory network can lead to various practical applications, creating a greater understanding of how organisms control their cellular behavior. DESCRIPTION: In this work, we present a new database, CMRegNet for the gene regulatory networks of Corynebacterium glutamicum ATCC 13032 and Mycobacterium tuberculosis H37Rv. We furthermore transferred the known networks of these model organisms to 18 other non-model but phylogenetically close species (target organisms) of the CMNR group. In comparison to other network transfers, for the first time we utilized two model organisms resulting into a more diverse and complete network of the target organisms. CONCLUSION: CMRegNet provides easy access to a total of 3,103 known regulations in C. glutamicum ATCC 13032 and M. tuberculosis H37Rv and to 38,940 evolutionary conserved interactions for 18 non-model species of the CMNR group. This makes CMRegNet to date the most comprehensive database of regulatory interactions of CMNR bacteria. The content of CMRegNet is publicly available online via a web interface found at http://lgcm.icb.ufmg.br/cmregnet . PMID- 26062810 TI - Relationship between sentinel lymph nodes and postoperative tangential fields in early breast cancer, evaluated using SPECT/CT. AB - Single-photon emission computed tomography/computed tomography (SPECT/CT) demonstrates the precise location of the sentinel lymph nodes (SLNs) in patients with breast cancer. We evaluated the relationship between SLNs and postoperative tangential fields by using SPECT/CT images. Subjects included 72 patients with early breast cancer who underwent SPECT/CT of the SLNs and received whole-breast irradiation with tangential fields after partial mastectomy. The SLN locations evaluated by using SPECT/CT images were entered into the treatment-planning CT image with a 5-mm-diameter sphere. A 15-mm-diameter sphere including the 5-mm treatment margin around the SLNs was defined as PTV-SLN. The PTV-SLN doses with tangential irradiation were evaluated and expressed as the percentage of the prescribed dose. In 69 patients, SLNs were detected by using SPECT/CT; 68 SLNs were located at axillary lymph node Level I, and one was located at Level II. A total of 62 SLNs (90%) were determined to be located inside the tangential fields on the digitally reconstructed radiography (DRR) images. The median doses of SLN center, mean PTV-SLN dose, and PTV-SLN D95 (the minimum dose delivered to 95% of the volume) were 94.1% (range, 15.3-101.9%), 93.7% (range, 29.3-104.0%) and 84.8% (range, 6.8-99.8%). The D95 for the SLNs with treatment margins were <=90% of the prescribed doses in more than half of the cases. Modification of the individual treatment fields seemed to be necessary to ensure coverage of the SLNs in whole breast irradiation. PMID- 26062811 TI - Filling the gap in central shielding: three-dimensional analysis of the EQD2 dose in radiotherapy for cervical cancer with the central shielding technique. AB - This study aimed to provide accurate dose distribution profiles of radiotherapy for cervical cancer when treated with the central shielding technique by analysing the composite 3D EQD2 dose distribution of external beam radiotherapy (EBRT) plus intracavitary brachytherapy (ICBT). On a phantom, four patterns of the combinations of whole pelvis irradiation (WP) (4 fields), pelvis irradiation with central shielding technique (CS) [anterior-posterior/posterior-anterior (AP PA fields), shielding width of 3 or 4 cm] and ICBT using Point-A prescription were created: 30 Gy/15 fractions + 20 Gy/10 fractions + 24 Gy/4 fractions [Plan (30 + 20 + 24)], 40 Gy/20 fractions + 10 Gy/5 fractions + 18 Gy/3 fractions [Plan (40 + 10 + 18)], 40 Gy/20 fractions + 10 Gy/5 fractions + 24 Gy/4 fractions [Plan (40 + 10 + 24)] and 45 Gy/25 fractions + 0 Gy + 28 Gy/4 fractions [Plan (45 + 0 + 28)]. The composite EQD2 dose distributions of the complete treatment were analysed. The Point-A dose of Plan (30 + 20 + 24), Plan (40 + 10 + 18), Plan (40 + 10 + 24) and Plan (45 + 0 + 28) were 78.0 Gy (CS 3 cm)/71.8 Gy (CS 4 cm), 72.1 Gy (CS 3 cm)/69.0 Gy (CS 4 cm), 80.1 Gy (CS 3 cm)/77.0 Gy (CS 4 cm) and 84.1 Gy, whereas it has been previously reported to be 62 Gy, 64 Gy, 72 Gy and 84 Gy, respectively. For all the treatment plans with CS, equivalent or wider coverage of 60 Gy (EQD2) was achieved in the right-left direction, while coverage in the anterior-posterior direction decreased in plans with CS. There were no irregularly 'cold' regions around the central target. The use of CS in radiotherapy for cervical cancer resulted in tumor coverage in the lateral direction with doses higher than the previously reported Point-A doses. PMID- 26062812 TI - Retrospective identification of a previously undetected clinical case of OXA-48 producing K. pneumoniae and E. coli: the importance of adequate detection guidelines. AB - INTRODUCTION: The laboratory detection of OXA-48-carbapenemase-producing Enterobacteriaceae is difficult, as minimum inhibition concentrations for carbapenems are often below the clinical breakpoint. In 2011, the Dutch national guideline for the detection of highly resistant micro-organisms was issued, which includes recommendations on the use of carbapenem screening breakpoints for the detection of carbapenemase-producing Enterobacteriaceae. MATERIALS AND METHODS: During a validation study of the Check-MDR CT103 microarray (Check-Points, Wageningen, The Netherlands) in 2013, an OXA-48-like carbapenemase gen was identified in two isolates that were previously obtained from a patient with non Hodgkin lymphoma in 2007. Whole-genome sequencing (WGS) and subsequent BLAST Ringe Image Generator (BRIG) analysis were performed to establish the presence of OXA-48 carbapenemase encoding plasmids and their similarity. RESULTS: This case report describes the first documented OXA-48-producing Klebsiella pneumonia (ST648) and Escherichia coli (ST866) in the Netherlands. A similar IncL/M plasmid was identified in both strains, suggesting within-patient horizontal transfer. CONCLUSION: This case illustrates that OXA-48-carbapenemase-producing Enterobacteriaceae can be unnoticed without adequate laboratory detection procedures. Our observation stresses the importance of uniform and adequate laboratory methods for the timely and accurate detection of important antimicrobial resistance. PMID- 26062814 TI - Single breath-hold 3D measurement of left atrial volume using compressed sensing cardiovascular magnetic resonance and a non-model-based reconstruction approach. AB - BACKGROUND: Left atrial (LA) dilatation is associated with a large variety of cardiac diseases. Current cardiovascular magnetic resonance (CMR) strategies to measure LA volumes are based on multi-breath-hold multi-slice acquisitions, which are time-consuming and susceptible to misregistration. AIM: To develop a time efficient single breath-hold 3D CMR acquisition and reconstruction method to precisely measure LA volumes and function. METHODS: A highly accelerated compressed-sensing multi-slice cine sequence (CS-cineCMR) was combined with a non model-based 3D reconstruction method to measure LA volumes with high temporal and spatial resolution during a single breath-hold. This approach was validated in LA phantoms of different shapes and applied in 3 patients. In addition, the influence of slice orientations on accuracy was evaluated in the LA phantoms for the new approach in comparison with a conventional model-based biplane area length reconstruction. As a reference in patients, a self-navigated high resolution whole-heart 3D dataset (3D-HR-CMR) was acquired during mid-diastole to yield accurate LA volumes. RESULTS: Phantom studies. LA volumes were accurately measured by CS-cineCMR with a mean difference of -4.73 +/- 1.75 ml (-8.67 +/- 3.54%, r2 = 0.94). For the new method the calculated volumes were not significantly different when different orientations of the CS-cineCMR slices were applied to cover the LA phantoms. Long-axis "aligned" vs "not aligned" with the phantom long-axis yielded similar differences vs the reference volume (-4.87 +/- 1.73 ml vs. -4.45 +/- 1.97 ml, p = 0.67) and short-axis "perpendicular" vs. "not perpendicular" with the LA long-axis (-4.72 +/- 1.66 ml vs. -4.75 +/- 2.13 ml; p = 0.98). The conventional bi-plane area-length method was susceptible for slice orientations (p = 0.0085 for the interaction of "slice orientation" and "reconstruction technique", 2-way ANOVA for repeated measures). To use the 3D-HR CMR as the reference for LA volumes in patients, it was validated in the LA phantoms (mean difference: -1.37 +/- 1.35 ml, -2.38 +/- 2.44%, r2 = 0.97). Patient study: The CS-cineCMR LA volumes of the mid-diastolic frame matched closely with the reference LA volume (measured by 3D-HR-CMR) with a difference of -2.66 +/- 6.5 ml (3.0% underestimation; true LA volumes: 63 ml, 62 ml, and 395 ml). Finally, a high intra- and inter-observer agreement for maximal and minimal LA volume measurement is also shown. CONCLUSIONS: The proposed method combines a highly accelerated single-breathhold compressed-sensing multi-slice CMR technique with a non-model-based 3D reconstruction to accurately and reproducibly measure LA volumes and function. PMID- 26062815 TI - Screw sense alone can govern enantioselective extension of a helical peptide by kinetic resolution of a racemic amino acid. AB - Helical peptides built principally from the achiral quaternary amino acid Aib but with an induced preferred screw-sense exhibit enantioselectivity in their chain extension reactions when presented with a racemic tertiary amino acid. This is the first demonstration that secondary structure alone, in the absence of local chiral residues, can direct the enantioselectivity of peptide coupling. PMID- 26062813 TI - Targeting phosphatidylinositol-3-kinase pathway for the treatment of Philadelphia negative myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPN) are a diverse group of chronic hematological disorders that involve unregulated clonal proliferation of white blood cells. Sevearl of them are associated with mutations in receptor tyrosine kinases or cytokine receptor associated tyrosine kinases rendering them independent of cytokine-mediated regulation. Classically they have been broadly divided into BCR ABL1 fusion + ve (Ph + ve) or -ve (Ph-ve) MPNs. Identification of BCR-ABL1 tyrosine kinase as a driver of chronic myeloid leukemia (CML) and successful application of small molecule inhibitors of the tyrosine kinases in the clinic have triggered the search for kinase dependent pathways in other Ph-ve MPNs. In the past few years, identification of mutations in JAK2 associated with a majority of MPNs raised the hopes for similar success with specific targeting of JAK2. However, targeting JAK2 kinase activity has met with limited success. Subsequently, mutations in genes other than JAK2 have been identified. These mutations specifically associate with certain MPNs and can drive cytokine independent growth. Therefore, targeting alternate molecules and pathways may be more successful in management of MPNs. Among other pathways, phosphatidylinositol -3 kinase (PI3K) has emerged as a promising target as different cell surface receptor induced signaling pathways converge on the PI3K signaling axis to regulate cell metabolism, growth, proliferation, and survival. Herein, we will review the clinically relevant inhibitors of the PI3K pathway that have been evaluated or hold promise for the treatment of Ph-ve MPNs. PMID- 26062816 TI - Quantification and assessment of heat and cold waves in Novi Sad, Northern Serbia. AB - Physiologically equivalent temperature (PET) has been applied to the analysis of heat and cold waves and human thermal conditions in Novi Sad, Serbia. A series of daily minimum and maximum air temperature, relative humidity, wind, and cloud cover was used to calculate PET for the investigated period 1949-2012. The heat and cold wave analysis was carried out on days with PET values exceeding defined thresholds. Additionally, the acclimatization approach was introduced to evaluate human adaptation to interannual thermal perception. Trend analysis has revealed the presence of increasing trend in summer PET anomalies, number of days above defined threshold, number of heat waves, and average duration of heat waves per year since 1981. Moreover, winter PET anomaly as well as the number of days below certain threshold and number of cold waves per year until 1980 was decreasing, but the decrease was not statistically significant. The highest number of heat waves during summer was registered in the last two decades, but also in the first decade of the investigated period. On the other hand, the number of cold waves during six decades is quite similar and the differences are very small. PMID- 26062817 TI - Relationship between physical attributes and heat stress in dairy cattle from different genetic groups. AB - Dairy cattle raised under harsh conditions have to adapt and prevent heat stress. The aim of this study was to evaluate physical characteristics and their association with heat tolerance in different genetic groups of dairy cattle. Thickness of the skin and coat, length and number of hairs, body measurements, as well as physiological parameters and body temperatures by infrared thermography were determined in 19 Holstein and 19 Girolando (1/2 and 3/4 Holstein) cows. The Holstein cattle were less tolerant to heat stress than Girolando (GH50 and GH75 Holstein), because of the difficulty in dissipating heat due to the larger body size, as well as thicker and longer hairs. The correlations between physical characteristics, physiological parameters, and thermographic measurements prove to be inconsistent among genetic groups and therefore are not predictive of heat tolerance, while the regressions of morphometric characteristics on physiological and thermographic measures were not significant. Thus, the physical characteristics were not good predictors of physiological indices and thermographic temperature and so should not be used. PMID- 26062818 TI - Dual-template docking oriented molecular imprinting: a facile strategy for highly efficient imprinting within mesoporous materials. AB - We present a new strategy, called dual-template docking oriented molecular imprinting (DTD-OMI), for facile and highly efficient imprinting within mesoporous materials. As compared with bulk imprinting, which is a widely used strategy, DTD-OMI did not require additional steps, but provided significantly improved imprinting efficiency and binding properties. PMID- 26062819 TI - The Canadian National EMS Research Agenda: Impact and Feasibility of Implementation of Previously Generated Recommendations. AB - BACKGROUND: A recent mixed-methods study on the state of emergency medical services (EMS) research in Canada led to the generation of nineteen actionable recommendations. As part of the dissemination plan, a survey was distributed to EMS stakeholders to determine the anticipated impact and feasibility of implementing these recommendations in Canadian systems. METHODS: An online survey explored both the implementation impact and feasibility for each recommendation using a five-point scale. The sample consisted of participants from the Canadian National EMS Research Agenda study (published in 2013) and additional EMS research stakeholders identified through snowball sampling. Responses were analysed descriptively using median and plotted on a matrix. Participants reported any planned or ongoing initiatives related to the recommendations, and required or anticipated resources. Free text responses were analysed with simple content analysis, collated by recommendation. RESULTS: The survey was sent to 131 people, 94 (71.8%) of whom responded: 30 EMS managers/regulators (31.9%), 22 researchers (23.4%), 15 physicians (16.0%), 13 educators (13.8%), and 5 EMS providers (5.3%). Two recommendations (11%) had a median impact score of 4 (of 5) and feasibility score of 4 (of 5). Eight recommendations (42%) had an impact score of 5, with a feasibility score of 3. Nine recommendations (47%) had an impact score of 4 and a feasibility score of 3. CONCLUSIONS: For most recommendations, participants scored the anticipated impact higher than the feasibility to implement. Ongoing or planned initiatives exist pertaining to all recommendations except one. All of the recommendations will require additional resources to implement. PMID- 26062821 TI - Targeting HCC Therapy: On or Off ToPiX? PMID- 26062820 TI - Role of Environmental Factors in the Development of Pediatric Eosinophilic Esophagitis. AB - BACKGROUND: Despite accumulating data on the pathogenesis of eosinophilic esophagitis, not much is known about risk factors for the development of the disease. The role of factors such as smoking, breastfeeding, early antibiotic exposure and other factors that have been associated with other allergic diseases has not been well studied in children with eosinophilic esophagitis. AIM: To explore the role of environmental and medication exposures in the development of pediatric eosinophilic esophagitis. METHODS: We conducted a cross-sectional case control study, utilizing a parent and child questionnaire and medical chart review. Urine cotinine levels, measured by high-performance liquid chromatography, were obtained as objective evidence for smoking exposure. RESULTS: One hundred and two children with eosinophilic esophagitis and 167 controls were recruited. The controls were mainly diagnosed with functional gastrointestinal disorders (33%) and gastroesophageal reflux disease (29%). Food allergy, specifically for peanuts and tree nuts, and allergy to pollen, tree, and grass were significantly higher among eosinophilic esophagitis children. Smoking exposure, both primary and secondary, was not associated with pediatric eosinophilic esophagitis when compared to controls (odds ratio 0.96, 95% confidence interval 0.58-1.59). Furthermore, early smoking exposure in the first year of life was higher among controls. Common accepted risk factors for allergy and atopy, such as breastfeeding practices, antibiotics exposure, animals' exposure, and others, were not found to be associated with eosinophilic esophagitis in our study. CONCLUSION: Common risk factors in other allergic and atopic conditions were not found to be associated with eosinophilic esophagitis. PMID- 26062822 TI - The "OPTI-CLOT" trial. A randomised controlled trial on periOperative PharmacokineTIc-guided dosing of CLOTting factor concentrate in haemophilia A. AB - Haemophilia A is an X-linked inherited, rare bleeding disorder, caused by a deficiency of coagulation factor VIII (FVIII). Previous studies in prophylactic dosing have demonstrated that FVIII consumption can be significantly reduced by individualising dosing based on combined analysis of individual pharmacokinetic (PK) profiling and population PK data (Bayesian analysis). So far, no studies have been performed that address perioperative concentrate consumption using iterative PK-guided dosing based on a PK population model. The "OPTI-CLOT" trial is an open-label, prospective, multicentre randomised controlled superiority trial (RCT), aiming to detect a 25 % difference in perioperative FVIII concentrate consumption with iterative Bayesian PK-guided dosing in comparison to the standard dosing procedure. Sixty haemophilia A patients >= 12 years of age, with FVIII plasma levels <= 0.05 IUml(-1) will be included requiring FVIII replacement therapy administered either by continuous or bolus infusion for an elective, low or medium risk surgical procedure. The proposed study aims to investigate a novel perioperative iterative PK-guided dosing strategy, based on a recently constructed perioperative PK population model. This model will potentially decrease underdosing and overdosing of clotting factor concentrate and is expected to overall reduce FVIII consumption by minimally 25 %. Moreover, participating hospitals will gain experience with PK-guided dosing, facilitating future implementation of this intervention which is expected to optimise current care and reduce costs of treatment. PMID- 26062824 TI - Environmental factors in the development of narcolepsy with cataplexy. A case control study. AB - INTRODUCTION: Epidemiological studies suggest the importance of environmental factors in the etiology of narcolepsy-cataplexy in genetically predisposed subjects. AIM: To assess the role of environmental factors in the development of narcolepsy-cataplexy, using a case-control design with control subjects being matched for ethnicity and age. PATIENTS AND METHODS: All patients were recruited through two outpatient clinics at the community of Madrid, ant the diagnosis of narcolepsy fulfilled the criteria of the International Classification on Sleep Disorders-2005. A questionnaire, including 54 environmental psychological stressor life events and 42 infectious diseases items, was administered to 54 patients. We specifically assessed the stressful factors and infectious diseases that occurred in the year preceding the onset of the first symptom of narcolepsy (excessive daytime sleepiness and/or cataplexy). The same questionnaire was administered to 84 control subjects recruited from non-related family members of the same community. RESULTS: Fifty four patients (55.6% males) answered the questionnaire, The mean age at onset of the first symptom was 21.6 +/- 9.3 years, and the mean age at diagnosis was 36.5 +/- 12.4 years. The main finding in narcoleptic patients as compared to control subjects was major changes in the 'number of arguments with partner, family, or friends' (odds ratio: 5.2; 95% confidence interval: 1.8-14.5). This can be interpreted as having a protective function and it suggests that psychological mechanisms are present since the beginning of the disease. As for the infectious factors, chickenpox was the most frequently reported. No significant differences were found in terms of total numbers of stress-related and infectious factors between cases and controls. CONCLUSION: Prospective studies regarding the interaction between environmental and genetic factors are warranted. PMID- 26062823 TI - STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion. AB - BACKGROUND: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options. To our knowledge, this case represents the first report of clinical response to targeted therapy in a tumor harboring a DCTN1-ALK fusion protein. METHODS: Hybridization capture of 315 cancer-related genes plus introns from 28 genes often rearranged or altered in cancer was applied to >50 ng of DNA extracted from this sample and sequenced to high, uniform coverage. Therapy was given in the context of a phase I clinical trial ClinicalTrials.gov Identifier: ( NCT01548144 ). RESULTS: Immunostains showed diffuse positivity for ALK1 expression and comprehensive genomic profiling identified an in frame DCTN1-ALK gene fusion. The diagnosis of STUMP was revised to that of an IMT with myxoid features. The patient was enrolled in a clinical trial and treated with an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib/Xalkori(r)) and a multikinase VEGF inhibitor (pazopanib/Votrient(r)). The patient experienced an ongoing partial response (6+ months) by response evaluation criteria in solid tumors (RECIST) 1.1 criteria. CONCLUSIONS: For myxoid tumors of the gynecologic tract, comprehensive genomic profiling can identify clinical relevant genomic alterations that both direct treatment targeted therapy and help discriminate between similar diagnostic entities. PMID- 26062825 TI - [Prevalence, type of epilepsy and use of antiepileptic drugs in primary care]. AB - INTRODUCTION: Epilepsy is a disease with great social and economic impact. The prevalence should be used as the most important basis for planning the secondary and tertiary prevention. AIMS: To identify patients with a diagnosis of epilepsy in a primary care center and determine the prevalence, demographic characteristics, type of epileptic syndrome and the use of antiepileptic drugs. PATIENTS AND METHODS: Retrospective cross-sectional descriptive study. Included 196 patients with a diagnosis of epilepsy belonging to a primary care center and review the medical history, studying socio-demographic variables and clinical pharmacological. RESULTS: The prevalence of epilepsy: 8.4/1000 inhabitants. Mean age: 50.3 years. Sex: 52.6% men. SCOPE: 79.6% urban. Family history of epilepsy: 14.8%. Type of epilepsy: symptomatic focal stroke (14.3%), idiopathic generalized (13.8%), focal cryptogenic (8.7%), not classified (31.1%). Average age at the beginning of seizures: 31.6 years. Neurological and/or psychiatric comorbidity: 62.8%. Last follow-up: 18.9% without antiepileptic treatment, 56.6% monotherapy and 24.5% polytherapy. Seizure-free: 76.5%. Drugs most frequently prescribed: valproic acid, carbamazepine, phenytoin, lamotrigine, levetiracetam. 78.6% without side effects. Exitus: 4.1%. CONCLUSIONS: The prevalence of patients with epilepsy was 8.4/1000 inhabitants, most frequent etiology the symptomatic focal stroke. More than half of patients suffered neurological and/or psychiatric comorbidity. At the end of follow-up the great majority were seizure-free without adverse effects of the antiepileptic drug treatment. PMID- 26062826 TI - [Email in a dedicated headache clinic: experience gained over a five-year period]. AB - INTRODUCTION: The use of email can facilitate communication between the different levels of an organisation. Our primary care physicians have had an email service in the dedicated headache clinic (DHC) since November 2009, and our aim is therefore to analyse the use of email over that five-year period. PATIENTS AND METHODS: Data concerning the emails sent up until October 2014 were collected prospectively. The questions were classified as need for referral to the DHC (group 1), progress made by the cases seen in the DHC (group 2), training in headaches (group 3) or the treatment of the headaches suffered by primary care physicians themselves as patients (group 4). RESULTS: A total of 274 email messages were analysed. Monthly consultations have increased (from 1.5 per month during the first year to 7.5 per month during the fifth). Findings showed that 10.2% of the email messages came from rural health centres and 89.8% were sent from urban health centres. Replies were sent within 2 +/- 2.8 days (range: 0-24 days). Altogether 130 consultations were classified as belonging to group 1 (47.4%), in which referral through the normal channel was recommended in 60 cases (46.2%), via the preferential channel in 47 (36.2%) and non-referral was suggested in 23 cases (17.6%). Group 2 included 125 emails (45.7%) and in 80 cases there was no need to make a new appointment or to bring forward the existing one (64%). Thirteen visits (4.7%) were classified into group 3 and six (2.2%) in group 4. CONCLUSIONS: Our primary care physicians are using the email of the DHC on an increasingly more frequent basis. Its use makes it possible to detect patients whose appointment -whether the first or a follow-up- needs to be brought forward, as well as allowing issues to be solved without the need for referral. It is effective for the treatment of physicians who themselves have headaches and as a tool for continuing education. PMID- 26062827 TI - [Stimulation of the centromedian nucleus in refractory epilepsy associated to ring chromosome 20]. AB - INTRODUCTION: Ring chromosome 20 syndrome is a rare genetic disorder, with a late diagnosis. CASE REPORT: A 43-year-old woman who had had refractory epilepsy since the age of six years, for which she was treated with deep brain stimulation of the centromedian nucleus, and also a ring chromosome 20. CONCLUSIONS: From the findings of the study it can be concluded that deep brain stimulation of the centromedian nucleus is ineffective in patients with ring chromosome, but note must be taken of the importance of genetic characterisation for the management of refractory epilepsy. PMID- 26062828 TI - [Proposal for a neuropsychological cognitive evaluation battery for detecting and distinguishing between mild cognitive impairment and dementias]. AB - The early and etiological diagnosis of dementia syndrome in the clinical practice remains the neuropsychological assessment through the study of the cognitive profile of the patient and the qualitative and quantitative analysis of the functions, both impaired and preserved. In this article, we describe a neuropsychological battery of cognitive evaluation to detect mild cognitive impairment in any of its clinical forms and dementia; as well as discriminate between the main profiles of dementia syndrome, based on its topographic and etiological classification (frontotemporal, temporoparietal, subcortical, cortico subcortical and multifocal). This battery is implemented in the neuropsychological assessment specialized surgery from Navarra Hospital Center Neurology Service. Not only the tests that form the assessment protocol are presented, but also the theoretical models that are considered more appropriate for their interpretation. PMID- 26062829 TI - [MicroRNAs and their neuroimmunoregulator mechanisms in multiple sclerosis. Development of biomarkers for diagnosis]. AB - INTRODUCTION: MicroRNAs (miRNAs) are molecules that in the last decade have gained increased attention a key mediator of the process of gene silencing in mammals. Deregulation of miRNAs is linked to illnesses such as cancer, and autoimmunity. Different reports claim for these molecules pivotal roles in both neuronal and immune processes, as well as in prediction of diseases affecting both systems. Multiple sclerosis (MS) is an example of an illness affecting myelin of axons, caused by autoimmune deregulation. AIM: To show the close relationship of the functions of miRNAs and their deregulation processes related to the immune and brain mechanisms in MS. In addition, we illustrate the use of miRNAs a potential noninvasive diagnostics for the assessment of the health status of a patient with MS. DEVELOPMENT: In the scientific literature, there has been a widely identified role of miRNAs as modulators. However, little is known about the role that these molecules perform together with glial cells in neuronal plasticity and de/re- myelination processes. In spite of the acknowledged role played by miRNAs in all function, little has been investigated on their potential. An overview is presented here in the research, development and implementation o diagnostic techniques relating miRNA and MS. CONCLUSIONS: There is strong evidence of the role of miRNA and homeostatic processes of brain's white matter in MS. In a field study to exploit and can aid in early diagnosis and also in the development of therapies based on the use of miRNAs. PMID- 26062830 TI - [Anastomosis of the vertebrobasilar carotid system. Persistent hypoglossal artery]. PMID- 26062831 TI - [Treatment strategy for Fabry's disease following a stroke]. PMID- 26062832 TI - [Treatment strategy for Fabry's disease following a stroke. Reply]. PMID- 26062834 TI - William John Adie (1886-1935). PMID- 26062835 TI - Jozsef von Lenhossek (1818-1888). PMID- 26062836 TI - An intraosseous epidermal cyst developing in a metacarpal bone after K-wire fixation: a case report. AB - Intraosseous epidermal cysts (IECs) are rare benign lesions caused by the proliferation of epidermal cells within the bone. The pathogenesis of IEC remains unclear; however, trauma-triggered infiltration of the bone by epidermal elements has been suggested. Here, we present a case of an IEC in the metacarpal bone of the little finger associated with K-wire fixation for treatment of a fifth metacarpal fracture. PMID- 26062838 TI - Analysis of polyunsaturated fatty acids and the omega-6 inflammatory pathway in hepatic ischemia/re-perfusion injury. AB - The aim of the present study was to assess omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) in liver tissue and evaluate changes in the n 6-associated inflammatory pathway following liver ischemia/re-perfusion (IR) injury. Male Wistar rats which were allowed free access to standard rat chow were included in the study. Blood vessels supplying the median and left lateral hepatic lobes were occluded with an arterial clamp for 60 min, followed by 60 min of re-perfusion. Levels of arachidonic acid (AA, C20:4n-6), dihomo-gamma linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) in liver tissue were determined by an optimized multiple reaction monitoring method using ultra fast-liquid chromatography coupled with tandem mass spectrometry. Phospholipase A2 (PLA2), cyclooxygenase (COX) and prostaglandin E2 (PGE2) were measured in tissue samples to evaluate changes in the n-6 inflammatory pathway. Total histopathological score of cellular damage were significantly increased following hepatic IR injury. n-3 and n-6 PUFA levels were significantly increased in post-ischemic liver tissue compared to those in non-ischemic controls. No significant difference was observed in the AA/DHA and AA/EPA ratio in post-ischemic liver tissues compared with that in the control. Tissue activity of PLA2 and COX as well as PGE2 levels were significantly increased in post-ischemic liver tissues compared to those in non-ischemic controls. The results of the present study suggested that increased hydrolysis of fatty acids via PLA2 triggers the activity of COX and leads to increased PGE2 levels. Future studies evaluating agents which block the formation of eicosanoids derived from n-6 PUFAs may facilitate the development and application of treatment strategies in liver injury following IR. PMID- 26062839 TI - Alcohol Consumption and Periodontitis: Quantification of Periodontal Pathogens and Cytokines. AB - BACKGROUND: There are few studies on periodontal status related to microbiologic and immunologic profiles among individuals not or occasionally using alcohol and those with alcohol dependence. The aim of this study is to determine the effect of alcohol consumption on the levels of subgingival periodontal pathogens and proinflammatory cytokines (interleukin [IL]-1beta and tumor necrosis factor [TNF] alpha) in the gingival fluid among individuals with and without periodontitis. METHODS: This observational analytic study includes 88 volunteers allocated in four groups (n = 22): individuals with alcohol dependence and periodontitis (ADP), individuals with alcohol dependence and without periodontitis (ADNP), individuals not or occasionally using alcohol with periodontitis (NAP), and individuals not or occasionally using alcohol without periodontitis (NANP). Levels of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Prevotella intermedia, Eikenella corrodens, and Fusobacterium nucleatum were determined by real-time polymerase chain reaction on the basis of the subgingival biofilm, and IL-1beta and TNF-alpha were quantified by enzyme-linked immunosorbent assay in gingival fluid samples. RESULTS: Individuals with alcohol dependence showed worse periodontal status and higher levels of P. intermedia, E. corrodens, F. nucleatum, and IL-1beta than non-users. No significant correlations between TNF-alpha and bacterial levels were observed. However, in the ADP group, higher levels of E. corrodens were correlated with higher levels of IL-1beta. CONCLUSION: A negative influence of alcohol consumption was observed on clinical and microbiologic periodontal parameters, as well as a slight influence on immunologic parameters, signaling the need for additional studies. PMID- 26062840 TI - Associations Between Sex Hormone Levels and Periodontitis in Men: Results From NHANES III. AB - BACKGROUND: Sex hormones are linked to inflammation and bone turnover. The goal of this study is to explore the association between sex hormone levels and periodontitis in men using data from the third National Health and Nutrition Examination Survey (NHANES III). METHODS: Data from 755 men (aged >= 30 years), including serum levels of testosterone, estradiol, sex hormone binding globulin, and androstenediol glucuronide, were analyzed. Calculated bioavailable testosterone (CBT) and estradiol-to-testosterone ratio were calculated. Periodontitis was defined using the latest classification of extent and severity of periodontitis for NHANES data (>= 2 interproximal sites with >= 3 mm attachment loss, >= 2 interproximal sites with probing depth [PD] >= 4 mm not on the same tooth, or one site with PD >= 5 mm). Sex hormones were evaluated as categorized and continuous variables. Correlations between the presence and severity of periodontitis and levels of sex hormones were determined and expressed as odds ratios (ORs). RESULTS: When adjusted for confounding factors, high total testosterone (TT) and CBT levels correlated with both the prevalence (OR [95% confidence interval (CI)], 2.1 [1 to 4.5] and 3.9 [1 to 14.8], respectively) and severity (OR [95% CI], 2.1 [1 to 4.3] and 3.4 [1.2 to 9.8]) of periodontitis. When continuous variables were used, the ORs (95% CIs) for presence and severity of periodontitis were 1.4 (0.6 to 3.3) and 1.5 (0.6 to 3.6) for TT and 1.3 (0.9 to 1.9) and 1.3 (0.9 to 1.8) for CBT, respectively. CONCLUSIONS: These findings are consistent with the existence of an association of periodontitis with sex hormone levels, especially testosterone, in men. PMID- 26062841 TI - Adjuvant Therapy With Sodium Alendronate for the Treatment of Experimental Periodontitis in Rats. AB - BACKGROUND: This study assesses the effects of topical sodium alendronate (SA) as an adjuvant to the mechanical treatment of ligature-induced periodontitis in rats. METHODS: Ninety animals were subjected to the induction of periodontitis via the installation of a ligature around the mandibular left first molar. After 7 days, the ligature was removed, and the animals were distributed into the following groups: 1) NT group (n = 30), no treatment; 2) SRP group (n = 30), scaling and root planing (SRP) and local irrigation with physiologic saline solution; and 3) SRP/SA group (n = 30), SRP and local irrigation with SA (10(-5) M). Ten animals from each group were euthanized at 7, 15, and 30 days after treatment. Histologic and histometric analyses were performed in the furcation region. The percentage of bone in the furcation (PBF) was measured. Immunohistochemical analyses for detecting the receptor activator of nuclear factor-kappaB ligand (RANKL), osteoprotegerin (OPG), tartrate-resistant acid phosphatase (TRAP), and activated caspase-3 were performed at the furcation region. RESULTS: Compared with the other groups, the SRP/SA group showed less local inflammation and better tissue reparation during the entire experiment. There was more PBF in the SRP/SA group than in the other groups at days 7 and 15. Stronger OPG immunolabeling and weaker RANKL immunolabeling were observed in the SRP/SA group at 15 and 30 days. There were fewer TRAP-positive cells in the SRP/SA group than in the NT group at all of the time points. There was no difference in the number of activated caspase-3-positive osteocytes among groups and time points. CONCLUSION: It can be concluded that topical use of SA as an adjuvant to SRP is effective in the treatment of experimental periodontitis. PMID- 26062842 TI - Prescription for a pharmacyte. AB - The efficient homing capacity of T cells may be used to deliver cell-associated, drug-laden nanoparticles to lymphoma cells that are resident in lymph nodes, increasing drug efficacy compared with drug encapsulated in free nanoparticles or free drug (Huang et al., this issue). PMID- 26062843 TI - Understanding disease pleiotropy: From puzzle to solution. AB - The total amount of functional mutant protein produced by cells underpins disease pleiotropy in the ciliopathies. PMID- 26062844 TI - From passengers to co-pilots: Patient roles expand. AB - The premier position of medical research on the U.S. national policy agenda offers an unprecedented opportunity to advance the science of patient input and marks a turning point in the evolution of patient engagement. PMID- 26062845 TI - Genetic variants associated with autoimmunity drive NFkappaB signaling and responses to inflammatory stimuli. AB - The transcription factor nuclear factor kappaB (NFkappaB) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFkappaB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFkappaB. We report that MS-associated variants proximal to NFkappaB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFkappaB signaling after tumor necrosis factor-alpha (TNFalpha) stimulation. Both variants result in increased degradation of inhibitor of NFkappaB alpha (IkappaBalpha), a negative regulator of NFkappaB, and nuclear translocation of p65 NFkappaB. The variant proximal to NFkappaB1 controls signaling responses by altering the expression of NFkappaB itself, with the GG risk genotype expressing 20-fold more p50 NFkappaB and diminished expression of the negative regulators of the NFkappaB pathway: TNFalpha-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (CIAP1). Finally, naive CD4 T cells from patients with MS express enhanced activation of p65 NFkappaB. These results demonstrate that genetic variants associated with risk of developing MS alter NFkappaB signaling pathways, resulting in enhanced NFkappaB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFkappaB signaling may identify individuals amenable to NFkappaB or cytokine blockade. PMID- 26062846 TI - Active targeting of chemotherapy to disseminated tumors using nanoparticle carrying T cells. AB - Tumor cells disseminate into compartments that are poorly accessible from circulation, which necessitates high doses of systemic chemotherapy. However, the effectiveness of many drugs, such as the potent topoisomerase I poison SN-38, is hampered by poor pharmacokinetics. To deliver SN-38 to lymphoma tumors in vivo, we took advantage of the fact that healthy lymphocytes can be programmed to phenocopy the biodistribution of the tumor cells. In a murine model of disseminated lymphoma, we expanded autologous polyclonal T cells ex vivo under conditions that retained homing receptors mirroring lymphoma cells, and functionalized these T cells to carry SN-38-loaded nanocapsules on their surfaces. Nanocapsule-functionalized T cells were resistant to SN-38 but mediated efficient killing of lymphoma cells in vitro. Upon adoptive transfer into tumor bearing mice, these T cells served as active vectors to deliver the chemotherapeutic into tumor-bearing lymphoid organs. Cell-mediated delivery concentrated SN-38 in lymph nodes at levels 90-fold greater than free drug systemically administered at 10-fold higher doses. The live T cell delivery approach reduced tumor burden significantly after 2 weeks of treatment and enhanced survival under conditions where free SN-38 and SN-38-loaded nanocapsules alone were ineffective. These results suggest that tissue-homing lymphocytes can serve as specific targeting agents to deliver nanoparticles into sites difficult to access from the circulation, and thus improve the therapeutic index of chemotherapeutic drugs with unfavorable pharmacokinetics. PMID- 26062847 TI - MK2 inhibitory peptide delivered in nanopolyplexes prevents vascular graft intimal hyperplasia. AB - Autologous vein grafts are commonly used for coronary and peripheral artery bypass but have a high incidence of intimal hyperplasia (IH) and failure. We present a nanopolyplex (NP) approach that efficiently delivers a mitogen activated protein kinase (MAPK)-activated protein (MAPKAP) kinase 2 inhibitory peptide (MK2i) to graft tissue to improve long-term patency by inhibiting pathways that initiate IH. In vitro testing in human vascular smooth muscle cells revealed that formulation into MK2i-NPs increased cell internalization, endosomal escape, and intracellular half-life of MK2i. This efficient delivery mechanism enabled MK2i-NPs to sustain potent inhibition of inflammatory cytokine production and migration in vascular cells. In intact human saphenous vein, MK2i-NPs blocked inflammatory and migratory signaling, as confirmed by reduced phosphorylation of the posttranscriptional gene regulator heterogeneous nuclear ribonucleoprotein A0, the transcription factor cAMP (adenosine 3',5'-monophosphate) element-binding protein, and the chaperone heat shock protein 27. The molecular effects of MK2i NPs caused functional inhibition of IH in human saphenous vein cultured ex vivo. In a rabbit vein transplant model, a 30-min intraoperative graft treatment with MK2i-NPs significantly reduced in vivo IH 28 days posttransplant compared with untreated or free MK2i-treated grafts. The decrease in IH in MK2i-NP-treated grafts in the rabbit model also corresponded with decreased cellular proliferation and maintenance of the vascular wall smooth muscle cells in a more contractile phenotype. These data indicate that nanoformulated MK2 inhibitors are a promising strategy for preventing graft failure. PMID- 26062850 TI - Copper-catalysed ring-opening trifluoromethylation of cyclopropanols. AB - A copper-catalysed ring-opening trifluoromethylation reaction of cyclopropanols has been developed. Various beta-trifluoromethyl ketones are obtained in good to excellent yields under mild reaction conditions. The present method also exhibits good functional-group compatibility. The mechanism of this new ring-opening trifluoromethylation reaction was investigated by radical trapping reactions. PMID- 26062849 TI - Basal exon skipping and genetic pleiotropy: A predictive model of disease pathogenesis. AB - Genetic pleiotropy, the phenomenon by which mutations in the same gene result in markedly different disease phenotypes, has proven difficult to explain with traditional models of disease pathogenesis. We have developed a model of pleiotropic disease that explains, through the process of basal exon skipping, how different mutations in the same gene can differentially affect protein production, with the total amount of protein produced correlating with disease severity. Mutations in the centrosomal protein of 290 kDa (CEP290) gene are associated with a spectrum of phenotypically distinct human diseases (the ciliopathies). Molecular biologic examination of CEP290 transcript and protein expression in cells from patients carrying CEP290 mutations, measured by quantitative polymerase chain reaction and Western blotting, correlated with disease severity and corroborated our model. We show that basal exon skipping may be the mechanism underlying the disease pleiotropy caused by CEP290 mutations. Applying our model to a different disease gene, CC2D2A (coiled-coil and C2 domains-containing protein 2A), we found that the same correlations held true. Our model explains the phenotypic diversity of two different inherited ciliopathies and may establish a new model for the pathogenesis of other pleiotropic human diseases. PMID- 26062852 TI - High INR on warfarin. PMID- 26062848 TI - Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia. AB - FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations resulting in constitutive kinase activity are common in acute myeloid leukemia (AML) and carry a poor prognosis. Several agents targeting FLT3 have been developed, but their limited clinical activity suggests that the inhibition of other factors contributing to the malignant phenotype is required. We examined gene expression data sets as well as primary specimens and found that the expression of GLI2, a major effector of the Hedgehog (Hh) signaling pathway, was increased in FLT3-ITD compared to wild-type FLT3 AML. To examine the functional role of the Hh pathway, we studied mice in which Flt3-ITD expression results in an indolent myeloproliferative state and found that constitutive Hh signaling accelerated the development of AML by enhancing signal transducer and activator of transcription 5 (STAT5) signaling and the proliferation of bone marrow myeloid progenitors. Furthermore, combined FLT3 and Hh pathway inhibition limited leukemic growth in vitro and in vivo, and this approach may serve as a therapeutic strategy for FLT3-ITD AML. PMID- 26062851 TI - Estimation of biological half-life of urinary cadmium in inhabitants after cessation of environmental cadmium pollution using a mixed linear model. AB - We investigated the biological half-life of urinary cadmium concentration (U-Cd) based on a 22-year follow-up study after cessation of environmental Cd pollution. Spot urine samples were obtained from the inhabitants (32 men and 36 women) in the target area in 1986, 1991, 1999, 2003 and 2008. These inhabitants were divided into higher or lower baseline U-Cd group by the cut-off of 5 MUg l(-1) or 5 MUg g(-1) creatinine. Biological half-life of U-Cd was estimated using a linear mixed model adjusted for the baseline age. In the higher baseline U-Cd groups, the estimated half-life and 95% confidence intervals were 12.4 years (9.3-18.8 years) and 11.4 years (9.3-14.6 years) for unadjusted U-Cd in men and women, respectively. For creatinine-adjusted U-Cd, they were 16.0 years (13.0-20.7 years) and 20.4 years (16.6-26.2 years) in men and women, respectively. In the lower baseline U-Cd groups, biological half-life for unadjusted U-Cd in men was solely significant (23.4 years) and longer than the corresponding half-life in the higher baseline U-Cd group. The biological half-lives of U-Cd obtained in this study were identical with the values for U-Cd or total body burden determined by a different method. PMID- 26062853 TI - Effects of initial periodontal therapy on interleukin-1beta level in gingival crevicular fluid and clinical periodontal parameters. AB - Inflammatory cytokines may have important roles in periodontitis. We assessed the effects of initial periodontal therapy on clinical periodontal parameters and interleukin-1beta (IL-1beta) level in gingival crevicular fluid (GCF) from chronic periodontitis (CP) patients. After initial screening, baseline periodontal parameters such as probing pocket depth (PPD) and bleeding on probing (BOP) were measured. GCF samples were collected from 13 shallow (<=3 mm) and deep (>=5 mm) PPD sites from 13 CP patients, and GCF volume and IL-1beta concentration were determined at baseline (before scaling and root planning) and at 2 and 4 months after initial therapy. Baseline BOP rate, GCF volume, and IL-1beta level were significantly higher at deep PPD sites than at shallow PPD sites. Significant improvements in PPD and BOP were observed at 2 and 4 months after periodontal initial therapy in deep PPD sites only. In contrast, GCF volume and IL-1beta concentration were lower at 2 and 4 months after initial therapy at all sites. These results suggest that GCF volume and IL-1beta level in samples reflect disease severity and that these variables are better than PPD and BOP as markers of gingival inflammation. PMID- 26062854 TI - Frequency of root resorption following trauma to permanent teeth. AB - This retrospective study evaluated the frequency of development of root resorption in dental trauma cases involving supporting tissue. For 249 traumatized teeth of 125 patients aged between 7 and 51 years, we collected data on the gender and age of the patient, the teeth involved, the type of trauma, and the period between dental injury and initial examination. Radiographic parameters examined in relation to root resorption included the presence of inflammatory external root resorption, internal root resorption, replacement resorption, and canal calcification. Data were analyzed by chi-squared test, Fisher's exact test, and mult iple logistic regression (P < 0.05). The results indicated that there was a significant relationship between the period from the date of injury until initial examination and the occurrence of inflammatory external resorption (P = 0.0199), as well as the type of injury (P = 0.0406). Furthermore, external resorption was most frequently associated with intrusive luxation (92.8%), followed by avulsion (89.0%), lateral luxation (80.2%), and extrusive luxation (77.4%). Among the types of dental injury, replacement resorption was observed more frequently in cases of avulsion (87.2%). The only factor that was significantly associated with this type of resorption was the type of injury (P < 0.0001). Root resorption is observed more frequently and its risk of development is higher in cases of severe trauma, especially avulsion and intrusive luxation. PMID- 26062855 TI - Comparative study of radiopacity of resin-based and glass ionomer-based bulk-fill restoratives using digital radiography. AB - This study investigated the radiopacity values of glass ionomer- and resin-based bulk-fill restoratives of different thicknesses using digital radiography. Two glass ionomer-based and three resin-based bulk-fill restoratives, and a conventional composite were studied. Five disc-shaped specimens were prepared from each of these materials at three different thicknesses; specimens of enamel and dentin with the same thicknesses were also prepared. Materials were placed over a complementary metal oxide-semiconductor sensor together with the tooth specimen and an aluminum step-wedge, and then exposed using a dental X-ray unit. The images were analyzed using a software program to measure the mean gray values (MGVs), which were converted to equivalent aluminum thicknesses. Two-way ANOVA was used to investigate the significance of differences among the groups. The GCP Glass Fill specimens showed the lowest radiopacity values, and the Quixfil specimens had the highest values. All materials had higher radiopacity values than enamel and dentin, except for GCP Glass Fill, which had a radiopacity similar to that of enamel. The resin-based bulk-fill restoratives had significantly higher radiopacity values than glass ionomer-based restoratives. All of the tested materials showed radiopacity values higher than that of dentin, as recommended by the ISO. PMID- 26062856 TI - Impact of the severity of chronic periodontal disease on quality of life. AB - We examined the impact of the severity of periodontal disease on quality of life in adults with chronic periodontitis. One hundred patients (age, 30-58 years) who were assisted at the Basic Health Care Unit in the city of Passo Fundo, RS, Brazil underwent clinical examination of all standing teeth, including gingival bleeding on probing, probing depth, and clinical attachment level, and were divided into those with mild/moderate (n = 49; group G1) and severe (n = 51; group G2) chronic periodontitis. The participants were then interviewed, using a structured questionnaire. The Brazilian Oral Health Impact Profile (OHIP-14Br) questionnaire was used to assess oral health-related quality of life. Associations were investigated, and those with a P value of less than 0.2 were tested using multiple logistic regression models. Those with a P value of 0.05 or less were considered significant. There was a significant association between G2 and education level (P = 0.00051). OHIP-14Br score was higher for G2 (24.1) than for G1 (18.2) (P = 0.0455). Severe chronic periodontitis was associated with low education level (<=8 years) (odds ratio [OR], 3.0; 95% confidence interval [CI], 1.2-7.3) and pronunciation difficulties (OR, 3.1; 95% CI, 1.0-9.3). In conclusion, periodontal disease severity was inversely associated with quality of life among Brazilian adults. PMID- 26062857 TI - Maxillary sinus perforation by orthodontic anchor screws. AB - To facilitate safe placement of orthodontic anchor screws (miniscrews), we investigated the frequency of maxillary sinus perforation after screw placement and the effect of sinus perforation on screw stability. Maxillary sinus perforations involving 82 miniscrews (diameter, 1.6 mm; length, 8 mm) were evaluated using cone-beam computed tomography. All miniscrews were placed in maxillary alveolar bone between the second premolar and first molar for anchorage for anterior retraction in patients undergoing first premolar extraction. The placement torque and screw mobility of each implant were determined using a torque tester and a Periotest device, and variability in these values in relation to sinus perforation was evaluated. Eight of the 82 miniscrews perforated the maxillary sinus. There was no case of sinusitis in patients with miniscrew perforation and no significant difference in screw mobility or placement torque between perforating and non-perforating miniscrews. The sinus floor was significantly thinner in perforated cases than in non-perforated cases. A sinus floor thickness of 6.0 mm or more is recommended in order to avoid miniscrew perforation of the maxillary sinus. PMID- 26062858 TI - Three-year clinical evaluation of posterior composite restorations placed with a single-step self-etch adhesive. AB - In this clinical study, we evaluated the 3-year clinical performance of a resin composite containing a surface-prereacted glass ionomer (S-PRG) filler (Beautifil II; Shofu Inc., Kyoto, Japan) placed with a single-step self-etch adhesive (BeautiBond; Shofu Inc.) in posterior restorations. Using modified US Public Health Service criteria, two experienced investigators performed clinical evaluations at the baseline, 6 months, 18 months, and 3 years. Color match, marginal adaptation, anatomical form, surface roughness, marginal discoloration, postoperative sensitivity, and secondary caries were evaluated. After 3 years, 26 patients attended the recall and 31 restorations were evaluated. No postoperative sensitivity or secondary caries was observed at any time point, and no restorations failed during the follow-up period. However, surface roughness, marginal adaptation, and marginal discoloration showed deterioration after 3 years. In conclusion, although some clinical changes were observed, resin composite containing S-PRG filler placed with self-etch adhesive exhibited acceptable clinical behavior in posterior restorations. PMID- 26062859 TI - Evaluation of hearing deficit in patients with oral submucous fibrosis. AB - Oral submucous fibrosis (OSMF) is a well recognized premalignant condition predominantly affecting the oral cavity, but sometimes extending to the pharynx, esophagus or even the larynx. OSMF may lead to stiffness of the oral cavity, resulting in trismus and inability to eat, difficulty with speech or swallowing, pain in the throat and ears, and a relative loss of auditory acuity. To evaluate the hearing deficit in patients with OSMF, we examined a study group comprising 40 patients, and also 10 age- and sex-matched healthy subjects as controls. All of the subjects were evaluated for hearing loss by pure tone audiometry. The OSMF group showed a significant degree of hearing loss relative to the control group. OSMF in advanced stages was significantly associated with mild conductive hearing loss (P < 0.01). The present study revealed a significant association between OSMF and hearing deficit. Involvement of the palatal muscles with OSMF may decrease the patency of the Eustachian tube, leading to conductive hearing loss. Therefore, all patients with OSMF should be evaluated for hearing deficit and advised about appropriate treatment. PMID- 26062860 TI - GLUT-1 immunoexpression in oral epithelial dysplasia, oral squamous cell carcinoma, and verrucous carcinoma. AB - Glucose transporters, such as GLUT-1, mediate the important mechanisms involved in cellular glucose influx, allowing cells to proliferate and survive. The significance of GLUT-1 expression in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) has been less explored, and no study has investigated it in relation to verrucous carcinoma (VC). We evaluated 30 cases each of OED, OSCC, and VC, graded further on the basis of their differentiation, immunohistochemically for GLUT-1 expression, along with 10 specimens of normal oral mucosa (NOM) as controls. In OSCC, GLUT-1 expression increased with the degree of dysplasia and increasing grade (P < 0.001). The expression in VC was predominantly membranous and intense, resembling well differentiated OSCC. This increase of GLUT-1 expression in OSCC along with the degree of dysplasia and the histologic grade reflects the expanding glycolytic response to hypoxia. This is the first study to have revealed prominent GLUT-1 expression in VC, highlighting its inherent metabolic capacity. PMID- 26062861 TI - Dental caries experience among indigenous children and adolescents. AB - Investigations into the oral health status of indigenous populations are scarce. The aim of this study was to evaluate caries experience and associated factors among 342 indigenous children and adolescents aged 5-15 years of the Xukuru community in the municipality of Pesqueira, Brazil. A cross-sectional census study was carried out using the criteria of the World Health Organization to determine caries experience. Examinations were performed by two calibrated dentists and a questionnaire was administered to parents/caregivers addressing socio-demographic data, diet and oral hygiene habits. Logistic regression analysis were performed, with dmft and DMFT as the dependent variables (P < 0.05). Caries experience (dmft/DMFT) was high in both the primary and permanent dentition (75.6% and 62.9%, respectively). Mean dmft and DMFT indices were 3.11 and 2.21, respectively. Caries experience in the primary dentition was associated with children residing in villages far from urban areas (P = 0.016), while caries in the permanent dentition was associated with older children (P < 0.001) and with children from villages at an intermediate distance and far from urban areas (P < 0.001). The indigenous subjects exhibited a high degree of caries experience, which was associated with age and group of villages. Public policies are needed to improve the oral health status of this population. PMID- 26062862 TI - Effects of parathyroid hormone dosage and schedule on bone regeneration. AB - This study investigated the effects of administration of parathyroid hormone (PTH) at different dosages and schedules on bone regeneration in critical-size bone defects in rat calvariae. After calvarial defects had been prepared in 50 rats, they were divided into five treatment groups: 15 ug/kg PTH daily (PTH-15), 35 ug/kg PTH three times per week (PTH-35), 105 ug/kg once per week (PTH-105-1), 105 ug/kg three times per week (PTH-105-3), and controls given vehicle alone. Bone regeneration was evaluated radiographically using micro-computed tomography (micro-CT) or histologically. The amount of newly generated bone in the calvarial defects was found to be significantly greater in the PTH groups than in the control group, and did not differ significantly among the PTH-15, PTH-35, and PTH 105-1 groups, whereas the PTH-105-3 group showed a significantly greater degree of new bone formation than the other PTH groups. It appeared that a higher dose of PTH stimulated a greater degree of bone regeneration in this experimental setting. The present results also suggest that the total dose of PTH administered is significantly related to the amount of bone regenerated within a defined period, indicating that less frequent administration of PTH might be a feasible protocol for bone regeneration therapy. PMID- 26062863 TI - Effects of critical thermal cycling on the flexural strength of resin composites. AB - We compared flexural strength (FS) in four resin composites before and after three protocols for thermal cycling aging. Four resin composites were evaluated: Enamel Plus Hri, Gradia Direct Posterior, Grandioso, and Grandioso Flow. Sixty specimens (2 * 2 * 25 mm) were fabricated using a split metallic mold and light cured for 30 s. The specimens were then randomly divided into four groups and tested using one of the following thermal cycling procedures: (1) storage in deionized water for 24 h (control group), (2) 15,000 cycles, 3) 30,000 cycles, and 4) 45,000 cycles. Each thermal cycling procedure was conducted between 5 degrees C and 55 degrees C, with a dwell time of 30 s. All specimens were subjected to a three-point bending test, to determine FS (0.5 mm/min). "Material" and "thermal aging" were significantly associated with FS (P < 0.001). A statistically significant interaction between the two factors was also detected (P < 0.001). In the non-aged groups, nanohybrid composites had the highest FS. FS significantly decreased after thermal cycling protocols in all composites tested. Gradia composite exhibited decrease in FS only after 45,000 cycles. In contrast, FS significantly decreased in the Grandioso Flow composite at 15,000 cycles. The trend in the decrease varied among composites, and the decrement in FS was not proportional to baseline values. PMID- 26062864 TI - Comparative evaluation of pro-inflammatory cytokine levels in pulpotomized primary molars. AB - The present in vivo study was performed to investigate the levels of the pro inflammatory cytokines, interleukin (IL)-1alpha, IL-6, and IL-8, in primary molars for which pulpotomy was clinically indicated, and to evaluate the success rates of three different pulpotomy agents employed for cariously (CExp) or mechanically exposed (MExp) primary molars. Forty-seven primary molars were classified as MExp or CExp according to the type of pulpal exposure. Pulp tissue was harvested and analyzed using enzyme-linked immunosorbent assay (ELISA). Subsequently, three pulpotomy agents-calcium hydroxide (CH), mineral trioxide aggregate (MTA), and formocresol (FC)-were applied randomly, and the outcome was observed radiographically for 18 months. Levels of IL-6 and IL-8 were significantly higher in CExp pulp than in MExp pulp (P < 0.05). In the CH pulpotomy group, MExp teeth showed a higher success rate than CExp teeth. There was no significant difference in success rate between MExp and CExp teeth in both the FC and MTA groups. The levels of IL-6 and IL-8 have the potential to become indicators of pulp status and can be monitored by researchers to make the prognosis of vital pulp therapies less uncertain. As MTA and FC yielded higher rates of success than CH in CExp teeth, the choice of pulpotomy agent appears to be important in this context. PMID- 26062865 TI - Evaluation of genial tubercle anatomy using cone beam computed tomography. AB - The purpose of this study was to characterize the anatomy of the genial tubercle using cone beam computed tomography (CBCT). The morphology and detailed anatomy of the genial tubercle were assessed retrospectively in 201 patients (101 females, 100 males) using CBCT images. The parameters examined were the height (GH) and width (GW) of the genial tubercle, the distance from the lower incisors to the superior border of the tubercle (I-SGT), the distance from the inferior margin of the tubercle to the inferior margin of the mandible (IGM-IBM), and the anterior mandible thickness (AMT). Statistical analysis was performed to assess relationships among these parameters, gender, and orthodontic malocclusion (P < 0.05). The values obtained were GH 7.3-8.7 mm, GW 7.9-9.2 mm, I-SGT 7.1-9.1 mm, IGM-IBM 8.3-10.1 mm, and AMT 14.0-16.2 mm. GH, GW, and I-SGT showed no significant differences between genders (P > 0.05). However, IGM-IBM was larger for class III than for class I and class II male patients, and larger than for class I female patients. AMT in class III patients was greater than in class I and II patients (P < 0.05). The use of CBCT, which employs less radiation, is important for dental professionals, especially those performing surgery for obstructive sleep apnea (OSA), in order to avoid possible surgical complications. PMID- 26062866 TI - Developmental disturbance of a mandibular central incisor following trauma to the primary predecessor. AB - When a primary tooth sustains a traumatic injury, development of the permanent tooth can be disturbed, leading to various malformations. This case report details the 7-year follow-up of a developmental anomaly of a central mandibular incisor in a 10-year-old Japanese girl with a history of dental trauma that had occurred at age 4. The trauma had resulted in unusual crown dilaceration in the permanent successor, which exhibited a discoloured and abnormal crown morphology. Radiographic examination revealed crown dilaceration of the tooth, which had a curved root canal. PMID- 26062867 TI - Chromium Dermatitis in a Metal Worker Due to Leather Gloves and Alkaline Coolant. PMID- 26062868 TI - Push-Pull Type Oligo(N-annulated perylene)quinodimethanes: Chain Length and Solvent-Dependent Ground States and Physical Properties. AB - Research on stable open-shell singlet diradicaloids recently became a hot topic because of their unique optical, electronic, and magnetic properties and promising applications in materials science. So far, most reported singlet diradicaloid molecules have a symmetric structure, while asymmetric diradicaloids with an additional contribution of a dipolar zwitterionic form to the ground state were rarely studied. In this Article, a series of new push-pull type oligo(N-annulated perylene)quinodimethanes were synthesized. Their chain length and solvent-dependent ground states and physical properties were systematically investigated by various experimental methods such as steady-state and transient absorption, two-photon absorption, X-ray crystallographic analysis, electron spin resonance, superconducting quantum interference device, Raman spectroscopy, and electrochemistry. It was found that with extension of the chain length, the diradical character increases while the contribution of the zwitterionic form to the ground state becomes smaller. Because of the intramolecular charge transfer character, the physical properties of this push-pull system showed solvent dependence. In addition, density functional theory calculations on the diradical character and Hirshfeld charge were conducted to understand the chain length and solvent dependence of both symmetric and asymmetric systems. Our studies provided a comprehensive understanding on the fundamental structure- and environment property relationships in the new asymmetric diradicaloid systems. PMID- 26062869 TI - The theoretical model of the school-based prevention programme Unplugged. AB - Unplugged is a school-based prevention programme designed and tested in the EU Dap trial. The programme consists of 12 units delivered by class teachers to adolescents 12-14 years old. It is a strongly interactive programme including a training of personal and social skills with a specific focus on normative beliefs. The aim of this work is to define the theoretical model of the program, the contribution of the theories to the units, and the targeted mediators. The programme integrates several theories: Social Learning, Social Norms, Health Belief, theory of Reasoned Action-Attitude, and Problem Behaviour theory. Every theory contributes to the development of the units' contents, with specific weights. Knowledge, risk perception, attitudes towards drugs, normative beliefs, critical and creative thinking, relationship skills, communication skills, assertiveness, refusal skills, ability to manage emotions and to cope with stress, empathy, problem solving and decision making skills are the targeted mediators of the program. PMID- 26062871 TI - How many segments are necessary to characterize delayed colonic transit time? AB - BACKGROUND AND AIMS: Measuring colonic transit time with radiopaque markers is simple, inexpensive, and very useful in constipated patients. Yet, the algorithm used to identify colonic segments is subjective, rather than founded on prior experimentation. The aim of the present study is to describe a rational way to determine the colonic partition in the measurement of colonic transit time. METHODS: Colonic transit time was measured in seven segments: ascending colon, hepatic flexure, right and left transverse colon, splenic flexure, descending colon, and rectosigmoid in 852 patients with functional bowel and anorectal disorders. An unsupervised algorithm for modeling Gaussian mixtures served to estimate the number of subgroups from this oversegmented colonic transit time. After that, we performed a k-means clustering that separated the observations into homogenous groups of patients according to their oversegmented colonic transit time. RESULTS: The Gaussian mixture followed by the k-means clustering defined 4 populations of patients: "normal and fast transit" (n = 548) and three groups of patients with delayed colonic transit time "right delay" (n = 82) in which transit is delayed in the right part of the colon, "left delay" (n = 87) with transit delayed in the left part of colon and "outlet constipation" (n = 135) for patients with transit delayed in the terminal intestine. Only 3.7 % of patients were "erroneously" classified in the 4 groups recognized by clustering. CONCLUSIONS: This unsupervised analysis of segmental colonic transit time shows that the classical division of the colon and the rectum into three segments is sufficient to characterize delayed segmental colonic transit time. PMID- 26062874 TI - Emotional Distress, Alcohol Use, and Bidirectional Partner Violence Among Lesbian Women. AB - This study examined the relationship between emotional distress (defined as depression, brooding, and negative affect), alcohol outcomes, and bidirectional intimate partner violence among lesbian women. Results lend support to the self medication hypothesis, which predicts that lesbian women who experience more emotional distress are more likely to drink to cope, and in turn report more alcohol use, problem drinking, and alcohol-related problems. These alcohol outcomes were, in turn, associated with bidirectional partner violence (BPV). These results offer preliminary evidence that, similar to findings for heterosexual women, emotional distress, alcohol use, and particularly, alcohol related problems are risk factors for BPV among lesbian women. PMID- 26062875 TI - Effects of p67phox on the mitochondrial oxidative state in the kidney of Dahl salt-sensitive rats: optical fluorescence 3-D cryoimaging. AB - The goal of the present study was to quantify and correlate the contribution of the cytosolic p67(phox) subunit of NADPH oxidase 2 to mitochondrial oxidative stress in the kidneys of the Dahl salt-sensitive (SS) hypertensive rat. Whole kidney redox states were uniquely assessed using a custom-designed optical fluorescence three-dimensional cryoimager to acquire multichannel signals of the intrinsic fluorophores NADH and FAD. SS rats were compared with SS rats in which the cytosolic subunit p67(phox) was rendered functionally inactive by zinc finger nuclease mutation of the gene (SS(p67phox)-null rats). Kidneys of SS rats fed a 0.4% NaCl diet exhibited significantly (P = 0.023) lower tissue redox ratio (NADH/FAD; 1.42 +/- 0.06, n = 5) than SS(p67phox)-null rats (1.64 +/- 0.07, n = 5), indicating reduced levels of mitochondrial electron transport chain metabolic activity and enhanced oxidative stress in SS rats. When fed a 4.0% salt diet for 21 days, both strains exhibited significantly lower tissue redox ratios (P < 0.001; SS rats: 1.03 +/- 0.05, n = 9, vs. SS(p67phox)-null rats: 1.46 +/- 0.04, n = 7) than when fed a 0.4% salt, but the ratio was still significantly higher in SS(p67phox) rats at the same salt level as SS rats. These results are consistent with results from previous studies that found elevated medullary interstitial fluid concentrations of superoxide and H2O2 in the medulla of SS rats. We conclude that the p67(phox) subunit of NADPH oxidase 2 plays an important role in the excess production of ROS from mitochondria in the renal medulla of the SS rat. PMID- 26062876 TI - Isolation and perfusion of rat inner medullary vasa recta. AB - Outer medullary isolated descending vasa recta have proven to be experimentally tractable, and consequently much has been learned about outer medullary vasa recta endothelial transport, pericyte contractile mechanisms, and tubulovascular interactions. In contrast, inner medullary vasa recta have never been isolated from any species, and therefore isolated vasa recta function has never been subjected to in vitro quantitative evaluation. As we teased out inner medullary thin limbs of Henle's loops from the Munich-Wistar rat, we found that vasa recta could be isolated using similar protocols. We isolated ~30 inner medullary vasa recta from 23 adult male Munich-Wistar rats and prepared them for brightfield or electron microscopy, gene expression analysis by RT-PCR, or isolated tubule microperfusion. Morphological characteristics include branching and nonbranching segments exhibiting a thin endothelium, axial surface filaments radiating outward giving vessels a hairy appearance, and attached interstitial cells. Electron microscopy shows multiple cells, tight junctions, and either continuous or fenestrated endothelia. Isolated vasa recta express genes encoding the urea transporter UT-B and/or the fenestral protein PV-1, genes expressed in descending or ascending vasa recta, respectively. The transepithelial NaCl permeability (383.3 +/- 60.0 * 10(-5) cm/s, mean +/- SE, n = 4) was determined in isolated perfused vasa recta. Future quantitative analyses of isolated inner medullary vasa recta should provide structural and functional details important for more fully understanding fluid and solute flows through the inner medulla and their associated regulatory pathways. PMID- 26062878 TI - Estradiol regulates AQP2 expression in the collecting duct: a novel inhibitory role for estrogen receptor alpha. AB - While there is evidence that sex hormones influence multiple systems involved in salt and water homeostasis, the question of whether sex hormones regulate aquaporin-2 (AQP2) and thus water handling by the collecting duct has been largely ignored. Accordingly, the present study investigated AQP2 expression, localization and renal water handling in intact and ovariectomized (OVX) female rats, with and without estradiol or progesterone replacement. OVX resulted in a significant increase in urine osmolality and increase in p256-AQP2 in the renal cortex at 7 days post-OVX, as well as induced body weight changes. Relative to OVX alone, estradiol repletion produced a significant increase in urine output, normalized urinary osmolality and reduced both total AQP2 (protein and mRNA) and p256-AQP2 expression, whereas progesterone repletion had little effect. Direct effects of estradiol on AQP2 mRNA and protein levels were further tested in vitro using the mpkCCD principal cell line. Estradiol treatment of mpkCCD cells reduced AQP2 at both the mRNA and protein level in the absence of deamino-8-d-AVP (dDAVP) and significantly blunted the dDAVP-induced increase in AQP2 at the protein level only. We determined that mpkCCD and native mouse collecting ducts express both estrogen receptor (ER)alpha and ERbeta and that female mice lacking ERalpha displayed significant increases in AQP2 protein compared with wild-type littermates, implicating ERalpha in mediating the inhibitory effect of estradiol on AQP2 expression. These findings suggest that changes in estradiol levels, such as during menopause or following reproductive surgeries, may contribute to dysregulation of water homeostasis in women. PMID- 26062877 TI - Cells of renin lineage are adult pluripotent progenitors in experimental glomerular disease. AB - Modified vascular smooth muscle cells of the kidney afferent arterioles have recently been shown to serve as progenitors for glomerular epithelial cells in response to glomerular injury. To determine whether such cells of renin lineage (CoRL) serve as progenitors for other cells in kidney disease characterized by both glomerular and tubulointerstitial injury, permanent genetic cell fate mapping of adult CoRL using Ren1cCreER * Rs-tdTomato-R reporter mice was performed. TdTomato-labeled CoRL were almost completely restricted to the juxtaglomerular compartment in healthy kidneys. Following 2 wk of antibody mediated focal segmental glomerulosclerosis (FSGS) or 16 wk of 5/6 nephrectomy induced chronic kidney diseases, tdTomato-mapped CoRL were identified in both interstitial and glomerular compartments. In the interstitium, PDGFbeta receptor (R)-expressing cells significantly increased, and a portion of these expressed tdTomato. This was accompanied by a decrease in native pericyte number, but an increase in the number of tdTomato cells that coexpressed the pericyte markers PDGFbeta-R and NG2. These cells surrounded vessels and coexpressed the pericyte markers CD73 and CD146, but not the endothelial marker ERG. Within glomeruli of reporter mice with the 5/6 nephrectomy model, a subset of labeled CoRL migrated to the glomerular tuft and coexpressed podocin and synaptopodin. By contrast, labeled CoRL were not detected in glomerular or interstitial compartments following uninephrectomy. These observations indicate that in addition to supplying new adult podocytes to glomeruli, CoRL have the capacity to become new adult pericytes in the setting of interstitial disease. We conclude that CoRL have the potential to function as progenitors for multiple adult cell types in kidney disease. PMID- 26062879 TI - Limited use for dual treatment with boosted protease inhibitors plus lamivudine in first-line antiretroviral therapy. PMID- 26062882 TI - Tribute to Jean-Michel Mestdagh. PMID- 26062883 TI - Autobiography of Jean-Michel Mestdagh. PMID- 26062880 TI - Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. AB - BACKGROUND: Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. METHODS: In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged >=18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per MUL or >100 cells per MUL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. FINDINGS: Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86.6%) of 127 patients in the triple treatment group responded to treatment versus 108 (87.8%) of 123 in the dual treatment group (difference -1.2% [95% CI -9.6 to 7.3]; p=0.92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0.515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0.223). INTERPRETATION: Dual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment. FUNDING: AbbVie and Red Tematica Cooperativa de Investigacion en Sida. PMID- 26062885 TI - Publications of Jean-Michel Mestdagh. PMID- 26062888 TI - Integrated analysis of differentially expressed mRNAs and miRNAs between hepatocellular carcinoma and their matched adjacent normal liver tissues. AB - Hepatocellular carcinoma has a high mortality rate, thus, there is a need for improvement of prognosis of such patients. The aim of the present study was to identify differentially expressed mRNAs and miRNAs between hepatocellular carcinoma tissues and their matched adjacent normal liver tissues, and to carry out a bioinformatics analysis. Agilent 8x60K microarray technology was used to detect the changes of mRNA and miRNA expression between hepatocellular carcinoma tissues and their matched adjacent normal liver tissues. To select differentially expressed mRNAs and miRNAs, gene ontology (GO) and pathway analysis were performed using bioinformatics methods. qPCR was used to verify the microarray data. As a result, 924 mRNAs and 21 miRNAs exhibited a higher expression in the hepatocellular carcinoma tissue than their matched adjacent normal liver tissue. In comparison with the adjacent normal tissue, the carcinoma tissue showed a downregulated expression of 1,770 mRNAs and 12 miRNAs. The GO and pathway analysis showed that these RNAs were involved in the transcription process, REDOX, signal transduction, ion transport, immune response, cell adhesion and binding functions. A total of 572 target genes of 14 miRNAs were identified, most of which were involved in tumors. The results of qPCR were in concordance with the microarray results. In summary, the differentially expressed mRNAs and miRNAs that include signal transduction, immune response and many other key links may provide novel targets for early diagnosis and therapy of hepatocellular carcinoma. PMID- 26062889 TI - Theoretical survey of the ligand tunability of poly(azolyl)borates. AB - Using density functional calculations, we have systematically investigated a series of homoleptic poly(azolyl)borate ligands, which display unusual steadily declining bond strengths accompanied by bond contractions when the azolyl groups are sequentially substituted to the parent BH4(-). As ligands, their effects on the coordinated metal ions (Cu(i) and Mo(0)) are quantitatively represented by two ligand tunability descriptors: the vibration frequency (nuCO) of the CO groups complexed to the metal ions and the charge of the metal-(CO)x moiety, between which a good linear correlation exists. For the same number of azolyl substitutions, the boundary of ligand tunability is always marked by the pyrazolyl and tetrazolyl groups at the two ends, which feature the lowest and the highest nitrogen content in the azolyl ring, respectively. With the increase of the azolyl substitution number in the borate ligands, the nuCO range expands, indicating a higher tunability of the ligands. The type of metal ion and the charge they carry play minor roles in influencing the ligand tunability. PMID- 26062886 TI - Accessible Synthetic Probes for Staining Actin inside Platelets and Megakaryocytes by Employing Lifeact Peptide. AB - Lifeact is a 17-residue peptide that can be employed in cell microscopy as a probe for F-actin when fused to fluorescent proteins, but therefore is not suitable for all cell types. We have conjugated fluorescently labelled Lifeact to three different cell-penetrating systems (a myristoylated carrier (myr), the pH low insertion peptide (pHLIP) and the cationic peptide TAT) as a strategy to deliver Lifeact into cells and developed new tools for actin staining with improved synthetic accessibility and low toxicity, focusing on their suitability in platelets and megakaryocytes. Using confocal microscopy, we characterised the cell distribution of the new hybrids in fixed cells, and found that both myr- and pHLIP-Lifeact conjugates provide efficient actin staining upon cleavage of Lifeact from the carriers, without affecting cell spreading. This new approach could facilitate the design of new tools for actin visualisation. PMID- 26062881 TI - Dual treatment with atazanavir-ritonavir plus lamivudine versus triple treatment with atazanavir-ritonavir plus two nucleos(t)ides in virologically stable patients with HIV-1 (SALT): 48 week results from a randomised, open-label, non inferiority trial. AB - BACKGROUND: Problems associated with lifelong antiretroviral therapy, such as need for strict adherence, drug-related toxic effects, difficulties with treatment schedules, and cost, mean that simplification strategies should be sought. We aimed to explore the efficacy and safety of dual treatment with atazanavir-ritonavir plus lamivudine as an option to switch to from standard combination antiretroviral therapy in patients with an HIV-1 infection who are virologically suppressed. METHODS: In this randomised, open-label, non inferiority trial, we recruited patients aged 18 years and older with chronic HIV 1 infection and no previous treatment failure or resistance, and with HIV-1 RNA of less than 50 copies per mL for at least 6 months, negative hepatitis B virus surface antigen, and good general health, from 30 hospitals in Spain. Exclusion criteria were switch in antiretroviral therapy during the previous 4 months, previous virological failure, pregnancy or breastfeeding, Gilbert's syndrome, use of contraindicated drugs, grade 4 laboratory abnormalities, and previous intolerance to any of the study drugs. We randomly assigned patients (1:1; stratified by active hepatitis C virus infection and previous treatment; computer generated random number sequence) to dual treatment with oral atazanavir (300 mg once daily) and ritonavir (100 mg once daily) plus lamivudine (300 mg once daily) or triple treatment with oral atazanavir (300 mg once daily) and ritonavir (100 mg once daily) plus two nucleos(t)ide reverse transcriptase inhibitors at the discretion of the investigators. The primary endpoint was virological response, defined as HIV-1 RNA of less than 50 copies per mL at week 48, in the per protocol population, with a non-inferiority margin of 12%. We included patients who received at least one dose of the study drug in the safety analysis. This study is registered at ClinicalTrials.gov, number NCT01307488. FINDINGS: Between Sept 29, 2011, and May 2, 2013, we randomly assigned 286 patients (143 [50%] to each group). At week 48 in the per-protocol population, 112 (84%) of 133 patients had virological response in the dual-treatment group versus 105 (78%) of 135 in the triple-treatment group (difference 6% [95% CI -5 to 16%), showing non inferiority at the prespecified level. 14 (5%) patients developed severe adverse events (dual treatment six [4%]; triple treatment eight [6%]), none of which we deemed related to the study drug. Grade 3-4 adverse events were similar between groups (dual treatment 77 [55%] of 140; triple treatment 78 [55%] of 141). Treatment discontinuations were less frequent in the dual-treatment group (three [2%]) than in the triple-treatment group (ten [7%]; p=0.047). INTERPRETATION: In our trial, dual treatment was effective, safe, and non-inferior to triple treatment in patients with an HIV-1 infection who are virologically suppressed who switch antiretroviral therapy because of toxic effects, intolerance, or simplification. This combination has the potential to suppress some of the long term toxic effects associated with nucleos(t)ide reverse transcriptase inhibitors, preserve future treatment options, and reduce the cost of antiretroviral therapy. FUNDING: Bristol Myers-Squibb and Fundacion SEIMC-GESIDA. PMID- 26062896 TI - UV photodecomposition of zinc acetate for the growth of ZnO nanowires. AB - The thermal annealing of zinc precursors to form suitable seed layers for the growth of ZnO nanowires is common. However, the process is relatively long and involves high temperatures which limit substrate choice. In this study the use of a low temperature, ultra-violet (UV) exposure is demonstrated for photodecomposition of zinc acetate precursors to form suitable seed layers. Comparisons are made between ZnO nanowire growth performed on seed layers produced through thermal annealing and exposure to UV. The dependence of growth density and nanowire diameter on UV exposure time is investigated. Growth quality is confirmed with energy dispersive x-ray (EDX) and x-ray diffraction analyses. The chemical composition of the exposed layers is investigated with EDX and x-ray photoelectron spectroscopy (XPS). Atomic force microscopy (AFM) is utilized to investigate morphological changes with respect to UV exposure. The diameter and density of the resultant growth was found to be strongly dependent on the UV exposure time. UV exposure times of only 25-30 s led to maximum density of growth and minimum diameter, significantly faster than thermal annealing. EDX, XPS and AFM analyses of the seed layers confirmed decomposition of the zinc precursor and morphological changes which influenced the growth. PMID- 26062895 TI - The p53 binding protein PDCD5 is not rate-limiting in DNA damage induced cell death. AB - The tumour suppressor p53 is an important mediator of cell cycle arrest and apoptosis in response to DNA damage, acting mainly by transcriptional regulation of specific target genes. The exact details how p53 modulates this decision on a molecular basis is still incompletely understood. One mechanism of regulation is acetylation of p53 on lysine K120 by the histone-acetyltransferase Tip60, resulting in preferential transcription of proapoptotic target genes. PDCD5, a protein with reported pro-apoptotic function, has recently been identified as regulator of Tip60-dependent p53-acetylation. In an effort to clarify the role of PDCD5 upon DNA damage, we generated cell lines in which PDCD5 expression was conditionally ablated by shRNAs and investigated their response to genotoxic stress. Surprisingly, we failed to note a rate-limiting role of PDCD5 in the DNA damage response. PDCD5 was dispensable for DNA damage induced apoptosis and cell cycle arrest and we observed no significant changes in p53 target gene transcription. While we were able to confirm interaction of PDCD5 with p53, we failed to do so for Tip60. Altogether, our results suggest a role of PDCD5 in the regulation of p53 function but unrelated to cell cycle arrest or apoptosis, at least in the cell types investigated. PMID- 26062897 TI - Metastasis: An influential delivery. PMID- 26062898 TI - Direct Mitsunobu monoesterification of N-protected tobramycin competes with intramolecular pyrrolidine formation in ester prodrug synthesis. AB - Unlike the related aminoglycoside neomycin B, N-protected tobramycin can be selectively esterified at its sole, primary hydroxyl group under Mitsunobu conditions. However, depending on the reaction conditions, the reaction can take a different course with intramolecular cyclization of an N-Boc amine leading to formation of an unusual tobramycin pyrrolidine derivative as the major reaction product. PMID- 26062900 TI - Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): modifying serotonin's downstream effects on glutamate and GABA (gamma amino butyric acid) release. AB - Vortioxetine is an antidepressant with multiple pharmacologic modes of action at targets where serotonin neurons connect with other neurons. These actions modify the release of both glutamate and GABA (gamma amino butyric acid) within various brain circuits. PMID- 26062899 TI - Lost to follow-up among pregnant women in a multi-site community based maternal and newborn health registry: a prospective study. AB - BACKGROUND: It is important when conducting epidemiologic studies to closely monitor lost to follow up (LTFU) rates. A high LTFU rate may lead to incomplete study results which in turn can introduce bias to the trial or study, threatening the validity of the findings. There is scarce information on LTFU in prospective community-based perinatal epidemiological studies. This paper reports the rates of LTFU, describes socio-demographic characteristics, and pregnancy/delivery outcomes of mothers LTFU in a large community-based pregnancy registry study. METHODS: Data were from a prospective, population-based observational study of the Global Network for Women's and Children's Health Research Maternal Newborn Health Registry (MNHR). This is a multi-centre, international study in which pregnant women were enrolled in mid-pregnancy, followed through parturition and 42 days post-delivery. Risk for LTFU was calculated within a 95%CI. RESULTS: A total of 282,626 subjects were enrolled in this study, of which 4,893 were lost to follow-up. Overall, there was a 1.7% LTFU to follow up rate. Factors associated with a higher LTFU included mothers who did not know their last menstrual period (RR 2.2, 95% CI 1.1, 4.4), maternal age of < 20 years (RR 1.2, 95% CI 1.1, 1.3), women with no formal education (RR 1.2, 95% CI 1.1, 1.4), and attending a government clinic for antenatal care (RR 2.0, 95% CI 1.4, 2.8). Post natal factors associated with a higher LTFU rate included a newborn with feeding problems (RR 1.6, 94% CI 1.2, 2.2). CONCLUSIONS: The LTFU rate in this community based registry was low (1.7%). Maternal age, maternal level of education, pregnancy status at enrollment and using a government facility for ANC are factors associated with being LTFU. Strategies to ensure representation and high retention in community studies are important to informing progress toward public health goals. TRIAL REGISTRATION: Registration at the Clinicaltrials.gov (ID# NCT01073475). PMID- 26062901 TI - ? PMID- 26062903 TI - Antibiotic use for Vibrio infections: important insights from surveillance data. AB - BACKGROUND: There is a paucity of data on the in vivo efficacy of antibiotics for lethal Vibrio species. Analyses of long-term surveillance datasets may provide insights into use of antibiotics to decrease mortality. METHODS: The United States Centers for Disease Control and Prevention (CDC) Cholera and Other Vibrio Illness Surveillance (COVIS) dataset from 1990 to 2010, with 8056 records, was analysed to ascertain trends in antibiotics use and mortality. RESULTS: Two thirds of patients (5243) were prescribed antibiotics - quinolones (56.1 %), cephalosporins (24.1 %), tetracyclines (23.5 %), and penicillins (15.4 %). Considering all Vibrio species, the only class of antibiotic associated with reduced odds of mortality was quinolone (odds ratio 0.56, 95 % CI 0.46-0.67). Patients with V. vulnificus treated according to CDC recommendations had lower mortality (quinolone alone: 16.7 %, 95 % CI 10.2-26.1; tetracycline plus cephalosporin: 21.7 %, 16.8-27.5; no antibiotic: 51.1 %, 45.6-56.7; each p < 0.001). Cephalosporin alone was associated with higher mortality (36.8 %, 28.2 46.3). For V. cholerae non-O1, non-O139, mortality rates were lower for quinolone (0 %, 0-2.0) or tetracycline (4.3 %, 1.2-14.5) compared to no antibiotic (9.3 %, 6.4-13.3). For all Vibrio species, mortality rates increased with number of antibiotics in the treatment regimen (p < 0.001). Treatment regimens that included quinolone were associated with lower mortality rates regardless of the number of antibiotics used. The main clinical syndromes of patients with V. vulnificus infection were septicaemia (53.1 %) and wound infections (30.6 %). Mortality among V. vulnificus patients with septicaemia was significantly higher than for other clinical syndromes (p < 0.001). In a multivariate regression model, mortality in cases with V. vulnificus was associated with presence of pre existing conditions (ORs ranged from 4.52 to 10.30), septicaemia (OR 2.64, 95 % CI 1.92-3.63) and no antibiotic treatment (OR 7.89, 95 % CI 3.94-15.80). CONCLUSION: In view of the lack of randomized control trials, surveillance data may inform treatment decisions for potentially lethal Vibriosis. Considering all Vibrio species, use of quinolones is associated with lower mortality and penicillin alone is not particularly effective. For the most lethal species, V. vulnificus, treatment that includes either quinolone or tetracycline is associated with lower mortality than cephalosporin alone. We recommend treating patients who present with a clinical syndrome suggestive of V. vulnificus infection with a treatment regimen that includes a quinolone. PMID- 26062904 TI - Evaluation of patient involvement in a health technology assessment. AB - OBJECTIVES: We sought to evaluate patient involvement (consultation and direct participation) in the assessment of alternative measures to restraint and seclusion among adults in short-term hospital wards (in psychiatry) and long-term care facilities for the elderly. METHODS: We conducted individual semi-structured interviews with thirteen stakeholders: caregivers, healthcare managers, patient representatives, health technology assessment (HTA) unit members, researchers, and members of the local HTA scientific committee. Data were collected until saturation. We carried out content analysis of two HTA reports and four other documents that were produced in relation with this HTA. We also used field notes taken during formal meetings and informal discussions with stakeholders. We performed thematic analysis based on a framework for assessing patient involvement in HTA. We then triangulated data. RESULTS: For the majority of interviewees, patient consultation enriched the content of the HTA report and its recommendations. This also made it possible to suggest other alternatives that could reduce the use of restraint and seclusion and helped confirm some views and comments from healthcare professionals consulted in this HTA. The direct participation of patient representatives enabled rephrasing of some findings so as to bring the patient perspective to the HTA report. CONCLUSIONS: Patient consultation was seen as having directly influenced the content of the HTA report while direct participation made it possible to rephrase some findings. This is one of few studies to assess the impact of patient involvement in HTA and more such studies are needed to identify the best ways to improve the input of such involvement. PMID- 26062902 TI - The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. AB - The end of twentieth century has introduced some changes into T helper (Th) cells division. The identification of the new subpopulation of T helper cells producing IL-17 modified model of Th1-Th2 paradigm and it was named Th17. High abilities to stimulate acute and chronic inflammation made these cells ideal candidate for crucial player in development of autoimmune disorders. Numerous publications based on animal and human models confirmed their pivotal role in pathogenesis of human systemic and organ-specific autoimmune diseases. These findings made Th17 cells and pathways regulating their development and function a good target for therapy. Therapies based on inhibition of Th17-dependent pathways are associated with clinical benefits, but on the other hand are frequently inducing adverse effects. In this review, we attempt to summarize researches focused on the importance of Th17 cells in development of human autoimmune diseases as well as effectiveness of targeting IL-17 and its pathways in pre-clinical and clinical studies. PMID- 26062905 TI - Atrophy of the Cerebellar Vermis in Essential Tremor: Segmental Volumetric MRI Analysis. AB - Postmortem studies of essential tremor (ET) have demonstrated the presence of degenerative changes in the cerebellum, and imaging studies have examined related structural changes in the brain. However, their results have not been completely consistent and the number of imaging studies has been limited. We aimed to study cerebellar involvement in ET using MRI segmental volumetric analysis. In addition, a unique feature of this study was that we stratified ET patients into subtypes based on the clinical presence of cerebellar signs and compared their MRI findings. Thirty-nine ET patients and 36 normal healthy controls, matched for age and sex, were enrolled. Cerebellar signs in ET patients were assessed using the clinical tremor rating scale and International Cooperative Ataxia Rating Scale. ET patients were divided into two groups: patients with cerebellar signs (cerebellar-ET) and those without (classic-ET). MRI volumetry was performed using CIVET pipeline software. Data on whole and segmented cerebellar volumes were analyzed using SPSS. While there was a trend for whole cerebellar volume to decrease from controls to classic-ET to cerebellar-ET, this trend was not significant. The volume of several contiguous segments of the cerebellar vermis was reduced in ET patients versus controls. Furthermore, these vermis volumes were reduced in the cerebellar-ET group versus the classic-ET group. The volume of several adjacent segments of the cerebellar vermis was reduced in ET. This effect was more evident in ET patients with clinical signs of cerebellar dysfunction. The presence of tissue atrophy suggests that ET might be a neurodegenerative disease. PMID- 26062906 TI - N-Linked Glycosylation at an Appropriate Position in the Pre-S2 Domain Is Critical for Cellular and Humoral Immunity against Middle HBV Surface Antigen. AB - Infection with hepatitis B virus (HBV) remains a worldwide health problem, and DNA-based vaccines against HBV have been tested for therapeutic applications. HBV possesses three envelope lipoproteins that are translated from a single reading frame: large, middle, and small HBV surface antigens. Among these envelope proteins, the middle HBV surface antigen (MHBs) contains a constitutive N-linked glycosylation site at position 4 (Asn4) in the amino-terminal portion (MQWNSTTFHQ) of pre-S2 domain. Asn4 (shown in bold) is essential for secretion of viral particles and conserved among all serotypes of HBV, but its influence on the immunogenicity of MHBs remains unknown. Here, we constructed four MHBs genes carrying mutations, underlined, in the amino-terminal portion of pre-S2 domain. One mutant protein contains Q at position 4 (MQWQSTTFHQ). In addition, each of three mutant MHBs proteins contains a N-linked glycosylation site (N-X-S/T), relocated to position 5 (MQWQNTTFHQ), 6 (MQWQSNTSHQ) or 7 (MQWQSTNFTQ) in pre-S2 domain. The expression and immunogenic properties of mutant DNA vaccines were examined in 293T human renal epithelial cells and in BALB/c mice, respectively. We showed that Asn4 was critical for secretion and immunogenicity of MHBs. Moreover, the MHBs protein that carries a N-linked glycosylation site at position 5 or 7 retained the properties similar to wild-type MHBs. In contrast, the secretion-defective mutant protein carrying Asn at position 6 induced only marginal humoral and cellular immune responses in mice, despite the N-linked glycosylation. In conclusion, N-linked glycosylation at an appropriate position in pre-S2 domain is an essential requirement for DNA vaccine expressing MHBs. PMID- 26062907 TI - Sustainability of evidence-based healthcare: research agenda, methodological advances, and infrastructure support. AB - BACKGROUND: Little is known about how well or under what conditions health innovations are sustained and their gains maintained once they are put into practice. Implementation science typically focuses on uptake by early adopters of one healthcare innovation at a time. The later-stage challenges of scaling up and sustaining evidence-supported interventions receive too little attention. This project identifies the challenges associated with sustainability research and generates recommendations for accelerating and strengthening this work. METHODS: A multi-method, multi-stage approach, was used: (1) identifying and recruiting experts in sustainability as participants, (2) conducting research on sustainability using concept mapping, (3) action planning during an intensive working conference of sustainability experts to expand the concept mapping quantitative results, and (4) consolidating results into a set of recommendations for research, methodological advances, and infrastructure building to advance understanding of sustainability. Participants comprised researchers, funders, and leaders in health, mental health, and public health with shared interest in the sustainability of evidence-based health care. RESULTS: Prompted to identify important issues for sustainability research, participants generated 91 distinct statements, for which a concept mapping process produced 11 conceptually distinct clusters. During the conference, participants built upon the concept mapping clusters to generate recommendations for sustainability research. The recommendations fell into three domains: (1) pursue high priority research questions as a unified agenda on sustainability; (2) advance methods for sustainability research; (3) advance infrastructure to support sustainability research. CONCLUSIONS: Implementation science needs to pursue later-stage translation research questions required for population impact. Priorities include conceptual consistency and operational clarity for measuring sustainability, developing evidence about the value of sustaining interventions over time, identifying correlates of sustainability along with strategies for sustaining evidence-supported interventions, advancing the theoretical base and research designs for sustainability research, and advancing the workforce capacity, research culture, and funding mechanisms for this important work. PMID- 26062909 TI - Information-Theoretic Considerations Concerning the Origin of Life. AB - Research investigating the origins of life usually either focuses on exploring possible life-bearing chemistries in the pre-biotic Earth, or else on synthetic approaches. Comparatively little work has explored fundamental issues concerning the spontaneous emergence of life using only concepts (such as information and evolution) that are divorced from any particular chemistry. Here, I advocate studying the probability of spontaneous molecular self-replication as a function of the information contained in the replicator, and the environmental conditions that might enable this emergence. I show (under certain simplifying assumptions) that the probability to discover a self-replicator by chance depends exponentially on the relative rate of formation of the monomers. If the rate at which monomers are formed is somewhat similar to the rate at which they would occur in a self-replicating polymer, the likelihood to discover such a replicator by chance is increased by many orders of magnitude. I document such an increase in searches for a self-replicator within the digital life system avida. PMID- 26062908 TI - Independent genomewide screens identify the tumor suppressor VTRNA2-1 as a human epiallele responsive to periconceptional environment. AB - BACKGROUND: Interindividual epigenetic variation that occurs systemically must be established prior to gastrulation in the very early embryo and, because it is systemic, can be assessed in easily biopsiable tissues. We employ two independent genome-wide approaches to search for such variants. RESULTS: First, we screen for metastable epialleles by performing genomewide bisulfite sequencing in peripheral blood lymphocyte (PBL) and hair follicle DNA from two Caucasian adults. Second, we conduct a genomewide screen for genomic regions at which PBL DNA methylation is affected by season of conception in rural Gambia. Remarkably, both approaches identify the genomically imprinted VTRNA2-1 as a top environmentally responsive epiallele. We demonstrate systemic and stochastic interindividual variation in DNA methylation at the VTRNA2-1 differentially methylated region in healthy Caucasian and Asian adults and show, in rural Gambians, that periconceptional environment affects offspring VTRNA2-1 epigenotype, which is stable over at least 10 years. This unbiased screen also identifies over 100 additional candidate metastable epialleles, and shows that these are associated with cis genomic features including transposable elements. CONCLUSIONS: The non-coding VTRNA2-1 transcript (also called nc886) is a putative tumor suppressor and modulator of innate immunity. Thus, these data indicating environmentally induced loss of imprinting at VTRNA2-1 constitute a plausible causal pathway linking early embryonic environment, epigenetic alteration, and human disease. More broadly, the list of candidate metastable epialleles provides a resource for future studies of epigenetic variation and human disease. PMID- 26062910 TI - Male engagement as a strategy to improve utilization and community-based delivery of maternal, newborn and child health services: evidence from an intervention in Odisha, India. AB - BACKGROUND: In response to persistently poor levels of maternal, newborn and child health (MNCH) in rural India, the National Rural Health Mission (NRHM) was launched to support the provision of accessible, affordable and quality health care in deprived and underserved communities. The Accredited Social Health Activists (ASHAs), local women, are trained as health promoters to generate demand for, and facilitate access to MNCH care in their communities. While they are also expected to provide husbands of expectant women with information on MNCH care and family planning, their reach to the husbands is limited. The aim of this study is to describe the influence of a male engagement project on the utilization and community-based delivery of MNCH care in a rural district of the country. METHODS: We used qualitative data from the evaluation of a project which recruited and trained male Community Health Workers (CHWs) known as Male Health Activists (MHAs) to complement the work of ASHAs and target outreach to men. This paper uses data from in-depth interviews (IDIs) with ASHAs (n=11), Anganwadi Workers (AWWs) (n=4) and Auxiliary Nurse Midwives (ANMs) (n=2); with women who had delivered at home, community health center or district hospital in the few months preceding the date of the interview (n=11); and with husbands of these women (n=7). RESULTS: Participants' responses are broadly organized around the facilitation of ASHAs' work by MHAs, and male engagement activities undertaken by MHAs. More specifically, the narratives reflected gender-based divisions of work and space in three core areas of delivery and use of MNCH services: escorting women to health centers for facility-based deliveries; mobilizing women and children to attend Village Health and Nutrition Days and Immunization Days; and raising awareness among men on MNCH and family planning. CONCLUSION: This study sheds light on male engagement as a strategy to improve the delivery, access and uptake of maternal, newborn and child health in the context of prevailing gender norms and gendered roles in rural India. Ultimately, it unveils the complementarity of male and female CHWs in the community-based delivery of, and increased demand for, MNCH services. PMID- 26062911 TI - Electroencephalography and Brain MRI Patterns in Encephalopathy. AB - INTRODUCTION: Using electroencephalography (EEG) and histology in patients with diffuse encephalopathy, Gloor et al reported that paroxysmal synchronous discharges (PSDs) on EEG required combined cortical gray (CG) and "subcortical" gray (SCG) matter pathology, while polymorphic delta activity (PDA) occurred in patients with white matter pathology. In patients with encephalopathy, we compared EEG findings and magnetic resonance imaging (MRI) to determine if MRI reflected similar pathological EEG correlations. METHODS: Retrospective case control study of 52 cases with EEG evidence of encephalopathy and 50 controls without evidence of encephalopathy. Review of clinical, EEG and MRI data acquired within 4 days of each other. RESULTS: The most common EEG finding in encephalopathy was background slowing, in 96.1%. We found PSDs in 0% of cases with the combination of CG and SCG abnormalities. Although 13.5% (n=7) had PSDs on EEG; 3 of these had CG and 4 had SCG abnormalities. A total of 73.1% (38/52) had white matter abnormalities-of these 28.9% (11/38) had PDA. CONCLUSION: PSDs were found with either CG or "SCG" MRI abnormalities and did not require a combination of the two. In agreement with Gloor et al, PDA occurred with white matter MRI abnormalities in the absence of gray matter abnormalities. PMID- 26062912 TI - Satisfaction of clients with the services of an outpatient pharmacy at a university hospital in northwestern Ethiopia: a cross-sectional study. AB - BACKGROUND: Evaluation of patient/client satisfaction with pharmacy services as a crucial part of the health services through appropriate studies is important. This will help identify specific areas of the service which need improvement in realizing high quality pharmacy services in general and enhance the positive changes in the current pharmaceutical services provision in Ethiopia. The current study aimed at assessing the level of client satisfaction with the services of the outpatient pharmacy of Gondar University Referral Hospital (GURH) in northwestern Ethiopia. METHODS: An institution-based cross-sectional study was conducted involving 400 clients who had prescriptions/orders filled at the outpatient pharmacy of the hospital during the period of 5th to 25th of November 2013. The data on the level of satisfaction of clients with the services of the outpatient pharmacy in the hospital was collected using a structured interview guide adopted from an instrument translated into Amharic and validated. The data collected was entered into and analyzed using Statistical Packages for Social Sciences (SPSS) version 16. RESULTS: The overall mean score the respondents gave to satisfaction with the pharmaceutical services was 2.48 out of a maximum of 5.00 score. The mean scores for all the individual parameters rated were less than 3.00. Maximum mean scores were given for parameters asking about the promptness of prescription medication service (2.99), and professionalism of the pharmacy staff (2.96) with the lowest being scored for information given to clients about the storage of medication (1.25), and explanations of possible side effects (1.27). Clients who were served free of fee recorded significantly higher level of satisfaction than those who paid. Higher levels of satisfaction were also reported among illiterates, older adults and those with no job compared to those with higher education, merchants and government employees. CONCLUSIONS: This study showed that the overall mean satisfaction level of clients of the outpatient pharmacy was low and it differed among different socio-demographic characteristics. Further research in to the reasons behind the low satisfaction should be done to provide appropriate solutions to improve the service. PMID- 26062914 TI - Rivaroxaban in the Prevention of Stroke and Systemic Embolism in Patients with Non-Valvular Atrial Fibrillation: Clinical Implications of the ROCKET AF Trial and Its Subanalyses. AB - Atrial fibrillation (AF) is an increasingly common cause of stroke and systemic embolism. While warfarin has been the mainstay of stroke prevention in patients with AF, newer novel oral anticoagulant medications are now available. Rivaroxaban, a direct factor Xa inhibitor with a rapid onset and offset after oral administration, offers potential advantages over warfarin, predominantly due to its predictable pharmacokinetics across wide patient populations. It requires no coagulation monitoring, and only two different doses are needed (20 mg daily for patients with normal renal function and 15 mg daily in those with reduced renal function). A large randomized trial (ROCKET AF) has shown non-inferiority to warfarin for preventing stroke or systemic embolism in the per-protocol population and superiority to warfarin in the on-treatment safety population. Several subanalyses confirm that the treatment effect of rivaroxaban is consistent across different patient subgroups, including those with reduced renal function. The tolerability of rivaroxaban appears similar to that of warfarin, with comparable overall bleeding rates in clinical trials. In ROCKET AF, significantly lower rates of fatal and intracranial bleeding were seen with rivaroxaban, while lower rates of gastrointestinal bleeding were seen with warfarin. Important contraindications to rivaroxaban include valvular AF, the presence of a prosthetic valve (mechanical or bioprosthetic) or valve repair, the need for concurrent dual antiplatelet therapy, and creatinine clearance <30 ml/min. Once-daily dosing and the lack of coagulation monitoring may increase utilization and adherence compared with warfarin, potentially decreasing the large burden of care associated with stroke secondary to AF. Overall, rivaroxaban offers a useful alternative to warfarin for stroke prevention in patients with AF. PMID- 26062913 TI - Investigating the contribution of IL-17A and IL-17F to the host response during Escherichia coli mastitis. AB - Mastitis remains a major disease of cattle with a strong impact on the dairy industry. There is a growing interest in understanding how cell mediated immunity contributes to the defence of the mammary gland against invading mastitis causing bacteria. Cytokines belonging to the IL-17 family, and the cells that produce them, have been described as important modulators of the innate immunity, in particular that of epithelial cells. We report here that expression of IL-17A and IL-17F genes, encoding two members of the IL-17 family, are induced in udder tissues of cows experimentally infected with Escherichia coli. The impact of IL 17A on the innate response of bovine mammary epithelial cells was investigated using a newly isolated cell line, the PS cell line. We first showed that PS cells, similar to primary bovine mammary epithelial cells, were able to respond to agonists of TLR2 and to LPS, provided CD14 was added to the culture medium. We then showed that secretion of CXCL8 and transcription of innate immunity related genes by PS cells were increased by IL-17A, in particular when these cells were stimulated with live E. coli bacteria. Together with data from the literature, these results support the hypothesis that IL-17A and IL-17 F could play an important role in mediating of host-pathogen interactions during mastitis. PMID- 26062915 TI - Hypercholesterolemia and Hypertension: Two Sides of the Same Coin. AB - The aim of this review article is to summarize the current knowledge about mechanisms that connect blood pressure regulation and hypercholesterolemia, the mutual interaction between hypertension and hypercholesterolemia, and their influence on atherosclerosis development. Our research shows that at least one third of the population of Western Europe has hypertension and hypercholesterolemia. Several biohumoral mechanisms could explain the relationship between hypertension and hypercholesterolemia and the association between these risk factors and accelerated atherosclerosis. The most investigated mechanisms are the renin-angiotensin-aldosterone system, oxidative stress, endothelial dysfunction, and increased production of endothelin-1. Arterial hypertension is frequently observed in combination with hypercholesterolemia, and this is related to accelerated atherosclerosis. Understanding the mechanisms behind this relationship could help explain the benefits of therapy that simultaneously reduce blood pressure and cholesterol levels. PMID- 26062916 TI - Caffeine and 3-km cycling performance: Effects of mouth rinsing, genotype, and time of day. AB - We assessed the efficacy of caffeine mouth rinsing on 3-km cycling performance and determined whether caffeine mouth rinsing affects performance gains influenced by the CYP1A2 polymorphism. Thirty-eight recreational cyclists completed four simulated 3-km time trials (TT). Subjects ingested either 6 mg/kg BW of caffeine or placebo 1 h prior to each TT. Additionally, 25 mL of 1.14% caffeine or placebo solution were mouth rinsed before each TT. The treatments were Placebo, caffeine Ingestion, caffeine Rinse and Ingestion+Rinse. Subjects were genotyped and classified as AA homozygotes or AC heterozygotes for the rs762551 polymorphism of the CYP1A2 gene involved in caffeine metabolism. Magnitude-based inferences were used to evaluate treatment differences in mean power output based on a predetermined meaningful treatment effect of 1.0%. AC heterozygotes (4.1%) and AA homozygotes (3.4%) benefited from Ingestion+Rinse, but only AC performed better with Ingestion (6.0%). Additionally, Rinse and Ingestion+Rinse elicited better performance relative to Placebo among subjects that performed prior to 10:00 h (Early) compared with after 10:00 h (Late). The present study provides additional evidence of genotype and time of day factors that affect the ergogenic value of caffeine intake that may allow for more personalized caffeine intake strategies to maximize performance. PMID- 26062917 TI - Giant cell tumor of the clavicle: report of a case in a rare location with consideration of surgical method. AB - BACKGROUND: Most bone tumors that occur in the clavicle are malignant. A few giant cell tumors (GCTs) of the clavicle have been reported; however, the most appropriate operative method for this tumor has never been discussed. CASE PRESENTATION: A 54-year-old man noticed enlargement of the proximal aspect of the right clavicle. A plain X-ray revealed lytic change and ballooning of the proximal end of the right clavicle. The tumor was isointense on T1-weighted magnetic resonance images and showed a mixture of low- and high-intensity areas on T2-weighted images without extension to the surrounding soft tissues. Bone scintigraphy showed strong accumulation (normal/tumor ratio, 2.31), and positron emission tomography revealed strong uptake of fluorine-18-2-fluoro-2-deoxy-d glucose (SUVmax, 6.0) in the proximal part of the right clavicle. Because we could not completely exclude malignancy, an open biopsy was performed. Pathologically, the tumor comprised mononuclear stromal cells and multinuclear giant cells, resulting in a diagnosis of a GCT of the bone. Although curettage may be considered for such lesions (Campanacci grade II), we chose resection to minimize the chance of recurrence. The tumor was resected en-bloc with the proximal half of the clavicle. No postoperative shoulder disproportion was observed, and full range of motion of the right shoulder was maintained. The patient was satisfied with the surgical outcome (Musculoskeletal Tumor Society score of 96 %). He returned to his original job as a land and house investigator without any signs of recurrence for 1 year after surgery. CONCLUSIONS: Although GCT of the bone rarely occurs in the clavicle, the typical X-ray findings demonstrated in the present case are helpful for a correct diagnosis. Although en bloc resection without reconstruction is appropriate for GCTs in expendable bones, there has been much discussion about shoulder function after total claviculectomy. Considering the importance of the function of the clavicle, which is to support the scapula through the acromioclavicular joint, we preserved the muscle attachments of the deltoid, trapezius, and pectoralis major. Because both the oncological and functional outcomes were satisfactory, we recommend preservation of as much of the clavicle as possible in patients with clavicular bone tumors. PMID- 26062919 TI - Soluble Expression of (+)-gamma-Lactamase in Bacillus subtilis for the Enantioselective Preparation of Abacavir Precursor. AB - Chiral Vince lactam (gamma-lactam) is an important precursor of many carbocyclic nucleoside analogues and pharmaceuticals. Here, a (+)-gamma-lactamase encoding gene delm from Delftia sp. CGMCC 5755 was identified through genome hunting. To achieve its soluble and functional expression, Escherichia coli and Bacillus subtilis expression systems were introduced. Compared with E. coli system, recombinant (+)-gamma-lactamase showed improved protein solubility and catalytic activity in B. subtilis 168. Reaction conditions for enantioselective resolution of gamma-lactam were optimized to be at 30 degrees C, pH 9.0, and 300 rpm when employing the recombinant B. subtilis 168/pMA5-delm whole cells. Kinetic analysis showed that the apparent V max and K m were 0.595 mmol/(min . gDCW) and 378 mmol/L, respectively. No obvious substrate inhibition was observed. In a 500-mL reaction system, enantioselective resolution of 100 g/L gamma-lactam was achieved with 10 g/L dry cells, resulting in 55.2 % conversion and 99 % ee of (-)-gamma lactam. All above suggested that recombinant B. subtilis 168/pMA5-delm could potentially be applied in the preparation of optically pure (-)-gamma-lactam. PMID- 26062918 TI - Population structure of mitochondrial genomes in Saccharomyces cerevisiae. AB - BACKGROUND: Rigorous study of mitochondrial functions and cell biology in the budding yeast, Saccharomyces cerevisiae has advanced our understanding of mitochondrial genetics. This yeast is now a powerful model for population genetics, owing to large genetic diversity and highly structured populations among wild isolates. Comparative mitochondrial genomic analyses between yeast species have revealed broad evolutionary changes in genome organization and architecture. A fine-scale view of recent evolutionary changes within S. cerevisiae has not been possible due to low numbers of complete mitochondrial sequences. RESULTS: To address challenges of sequencing AT-rich and repetitive mitochondrial DNAs (mtDNAs), we sequenced two divergent S. cerevisiae mtDNAs using a single-molecule sequencing platform (PacBio RS). Using de novo assemblies, we generated highly accurate complete mtDNA sequences. These mtDNA sequences were compared with 98 additional mtDNA sequences gathered from various published collections. Phylogenies based on mitochondrial coding sequences and intron profiles revealed that intraspecific diversity in mitochondrial genomes generally recapitulated the population structure of nuclear genomes. Analysis of intergenic sequence indicated a recent expansion of mobile elements in certain populations. Additionally, our analyses revealed that certain populations lacked introns previously believed conserved throughout the species, as well as the presence of introns never before reported in S. cerevisiae. CONCLUSIONS: Our results revealed that the extensive variation in S. cerevisiae mtDNAs is often population specific, thus offering a window into the recent evolutionary processes shaping these genomes. In addition, we offer an effective strategy for sequencing these challenging AT-rich mitochondrial genomes for small scale projects. PMID- 26062920 TI - Concurrence of Anaerobic Ammonium Oxidation and Organotrophic Denitrification in Presence of p-Cresol. AB - This study was carried out to evaluate the capacity of anaerobic granular sludge for oxidizing ammonium and p-cresol with nitrate as terminal electron acceptor. Kinetics for the anaerobic oxidation of ammonium and p-cresol is described in this paper. The phenolic compound was very efficiently consumed, achieving 65 % of mineralization. Ammonium and nitrate were also consumed at 83 and 92 %, respectively, being the main product N2. Anaerobic ammonium oxidation was promoted owing to accumulation of nitrite, and it allowed the synergy of anaerobic ammonium oxidation and organotrophic denitrification for the simultaneous removal of ammonium, nitrate, and p-cresol. A carbonaceous intermediate partially identified was transiently accumulated, and it transitorily truncated the respiratory process of denitrification. These experimental results might be considered for defining strategies in order to remove nitrate, ammonium, and phenolic compounds from wastewaters. PMID- 26062921 TI - Shifts in Microbial Community and Its Correlation with Degradative Efficiency in a Wastewater Treatment Plant. AB - A wastewater treatment plant controls the level of pollution reaching the environment. Yet, despite being the most common aerobic route for treatment of wastewater, the activated sludge process is not utilized to its full potential. This is mainly due to the lack of knowledge base correlating the microbial community in the activated sludge to its degradative performance. In this study, the activated biomass at the treatment site was monitored for five consecutive months. Even though operational parameters were kept constant, the microbial community was observed to change after 3 months. This shift was seen to correlate with 25 % loss of degradative efficiency. Target oxygenases were monitored at two time points, and results indicated that the dominating pathway operating in the common effluent treatment plant (CETP) is the degradation of chlorinated aromatics. This study demonstrates the change in degradative efficiency in a CETP with the change in microbial community and analyzes the parameters influencing the microbial community of activated sludge. PMID- 26062922 TI - Influence of external magnetic field and magnetic-site dilution on the magnetic dynamics of a one-dimensional Tb(III)-radical complex. AB - A new Tb(III)-radical chain complex was synthesized and characterized, which exhibited two separate relaxation processes. The influence of external magnetic field and magnetic-site dilution on the magnetic dynamics of a one-dimensional Tb(III)-radical complex was studied. PMID- 26062923 TI - Unplanned oncology admissions within 14 days of non-surgical discharge: a retrospective study. AB - AIM: The aim of this study was to identify the incidence, causes, risk factors and interventions for cancer patients requiring unplanned admissions within 14 days of discharge at a large metropolitan private hospital without a co-located emergency department. METHODS: Retrospective data were collected on cancer patients who had an unplanned admission within 14 days of discharge during the period December 1, 2011 and May 31, 2012. Data were collected from the inpatient bed administration database and medical record review. Variables collected included demographics, cancer diagnosis, reasons for admission, interventions, and length of stay. RESULTS: A total of 133 oncology patients required 206 unplanned admissions (UPAs). The most common cancer diagnoses associated with unplanned readmission were upper gastrointestinal (25.4%), colorectal (19.6%), gynaecological (18.8%) and breast (13.8%) cancers. The symptoms most commonly associated with unplanned re-admission were pain (16%); infection not associated with neutropaenia (15.5%); fever and febrile neutropaenia (14.6%); nausea, vomiting and dehydration (13.6%); dyspnoea (8.3%) and altered neurological status (7.8%). The median length of stay (LOS) was 6 days. Length of stay during UPA was decreased for patients with a partner and for those who had a palliative care consult. The need for psychological supports was related to a longer LOS during UPA. CONCLUSION: Cancer patients are at a significant risk of requiring unscheduled care and admission. Strategies and services to limit the burden on patients and the health care system should be reviewed to minimise the incidence of unplanned admission. PMID- 26062924 TI - The association between the strength of the working alliance and sharing concerns by advanced cancer patients: a pilot study. AB - OBJECTIVES: A strong therapeutic alliance between cancer patients and medical staff is associated with treatment adherence, better health outcomes, and an emotional acceptance of a terminal illness. Given its significant role, the current study investigated the association between the working alliance and sharing concerns by advanced cancer patients. METHODS: Advanced cancer patients completed the Working Alliance Inventory-Short Revised and a checklist of topics in which they rated their degree of concern about the topics and the degree of sharing them with their physician/nurse. RESULTS: Fifty-two patients completed the study. The working alliance was found to be strong with respect to treating physicians and nurses. The four topics that concerned patients the most were family coping with their illness (81%), fear of future suffering (71%), symptom control (67%), and the oncological treatment (65%). Patients with a strong working alliance with their physician shared to a higher extent the personal and main concern regarding their family's coping, and a significant correlation was found between them (r = 0.53, p < .01). In addition, sharing fears of future suffering was also correlated with a strong working alliance with the physician (r = 0.28, p < .05). A strong working alliance with the nurse was correlated with discussing symptoms control (r = 0.30, p < .05). CONCLUSION: These findings provide preliminary support for an association between the strength of the working alliance and the type of concerns that advanced cancer patients choose to discuss with their medical staff and highlight the importance of follow-up studies to further explore this association. PMID- 26062926 TI - Chemoenzymatic one-pot synthesis in an aqueous medium: combination of metal catalysed allylic alcohol isomerisation-asymmetric bioamination. AB - The ruthenium-catalysed isomerisation of allylic alcohols was coupled, for the first time, with asymmetric bioamination in a one-pot process in an aqueous medium. In the cases involving prochiral ketones, the omega-TA exhibited excellent enantioselectivity, identical to that observed in the single step. As a result, amines were obtained from allylic alcohols with high overall yields and excellent enantiomeric excesses. PMID- 26062927 TI - Management of Discharged Emergency Department Patients with a Primary Diagnosis of Hypertension: A Multicentre Study. AB - Introduction Many patients are seen in the emergency department (ED) for hypertension, and the numbers will likely increase in the future. Given limited evidence to guide the management of such patients, the practice of one's peers provides a de facto standard. METHODS: A survey was distributed to emergency physicians during academic rounds at three community and four tertiary EDs. The primary outcome measure was the proportion of participants who had a blood pressure (BP) threshold at which they would offer a new antihypertensive prescription to patients they were sending home from the ED. Secondary outcomes included patient- and provider-level factors associated with initiating an antihypertensive based on clinical vignettes of a 69-year-old man with two levels of hypertension (160/100 vs 200/110 mm Hg), as well as the recommended number of days after which to follow up with a primary care provider following ED discharge. RESULTS: All 81 surveys were completed (100%). Half (51.9%; 95% CI 40.5-63.1) of participants indicated that they had a systolic BP threshold for initiating an antihypertensive, and 55.6% (95% CI 44.1-66.6) had a diastolic threshold: mean systolic threshold was 199 mm Hg (SD 19) while diastolic was 111 mm Hg (SD 8). A higher BP (OR 12.9; 95% CI 7.5-22.2) and more patient comorbidities (OR 3.0; 95% CI 2.1-4.3) were associated with offering an antihypertensive prescription, while physician years of practice, certification type, and hospital type were not. Participants recommended follow-up care within a median 7.0 and 3.0 days for the patient with lower and higher BP levels, respectively. CONCLUSIONS: Half of surveyed emergency physicians report having a BP threshold to start an antihypertensive; BP levels and number of patient comorbidities were associated with a modification of the decision, while physician characteristics were not. Most physicians recommended follow-up care within seven days of ED discharge. PMID- 26062925 TI - Effects of enhanced caregiver training program on cancer caregiver's self efficacy, preparedness, and psychological well-being. AB - PURPOSE: We examined the effects of an enhanced informal caregiver training (Enhanced-CT) protocol in cancer symptom and caregiver stress management to caregivers of hospitalized cancer patients. METHODS: We recruited adult patients in oncology units and their informal caregivers. We utilized a two-armed, randomized controlled trial design with data collected at baseline, post training, and at 2 and 4 weeks after hospital discharge. Primary outcomes were self-efficacy for managing patients' cancer symptoms and caregiver stress and preparedness for caregiving. Secondary outcomes were caregiver depression, anxiety, and burden. The education comparison (EDUC) group received information about community resources. We used general linear models to test for differences in the Enhanced-CT relative to the EDUC group. RESULTS: We consented and randomized 138 dyads: Enhanced-CT = 68 and EDUC = 70. The Enhanced-CT group had a greater increase in caregiver self-efficacy for cancer symptom management and stress management and preparation for caregiving at the post-training assessment compared to the EDUC group but not at 2- and 4-week post-discharge assessments. There were no intervention group differences in depression, anxiety, and burden. CONCLUSION: An Enhanced-CT protocol resulted in short-term improvements in self efficacy for managing patients' cancer symptoms and caregiver stress and preparedness for caregiving but not in caregivers' psychological well-being. The lack of sustained effects may be related to the single-dose nature of our intervention and the changing needs of informal caregivers after hospital discharge. PMID- 26062928 TI - Phase II study of saracatinib (AZD0530) in patients with previously treated metastatic colorectal cancer. AB - BACKGROUND: Src has a critical role in tumor cell migration and invasion. Increased Src activity has been shown to correlate with disease progression and poor prognosis, suggesting Src could serve as a therapeutic target for kinase inhibition. Saracatinib (AZD0530) is a novel selective oral Src kinase inhibitor. METHODS: Metastatic colorectal cancer patients who had received one prior treatment and had measurable disease were enrolled in this phase 2 study. Saracatinib was administered at 175 mg by mouth daily for 28 day cycles until dose-limiting toxicity or progression as determined by staging every 2 cycles. The primary endpoint was improvement in 4 month progression-free survival. Design of Thall, Simon, and Estey was used to monitor proportion of patients that were progression free at 4 months. The trial was opened with plan to enroll maximum of 35 patients, with futility assessment every 10 patients. RESULTS: A total of 10 patients were enrolled between January and November 2007. Further enrollment was stopped due to futility. Median progression-free survival was 7.9 weeks, with all 10 patients showing disease progression following radiographic imaging. Median overall survival was 13.5 months. All patients were deceased by time of analysis. Observed adverse events were notable for a higher than expected number of patients with grade 3 hypophosphatemia (n = 5). CONCLUSION: Saracatinib is a novel oral Src kinase inhibitor that was well tolerated but failed to meet its primary endpoint of improvement in 4 month progression-free survival as a single agent in previously treated metastatic colorectal cancer patients. PMID- 26062929 TI - The influence of low-grade inflammation on platelets in patients with stable coronary artery disease. AB - Inflammation is likely to be involved in all stages of atherosclerosis. Numerous inflammatory biomarkers are currently being studied, and even subtle increases in inflammatory biomarkers have been associated with increased risk of cardiovascular events in patients with coronary artery disease (CAD). Low-grade inflammation may influence both platelet production and platelet activation potentially leading to enhanced platelet aggregation. Thrombopoietin is considered the primary regulator of platelet production, but it likely acts in conjunction with numerous cytokines, of which many have altered levels in CAD. Previous studies have shown that high-sensitive C-reactive protein (CRP) independently predicts increased platelet aggregation in stable CAD patients. Increased levels of CRP, fibrinogen, interleukin-6, stromal cell-derived factor 1, CXC motif ligand 16, macrophage migration inhibitory factor, RANTES, calprotectin, and copeptin have been associated with increased risk of cardiovascular events in CAD patients. Additionally, some of these inflammatory markers have been associated with enhanced platelet activation and aggregation. However, CRP and other inflammatory markers provide only limited additional predictive value to classical risk factors such as smoking, blood pressure, and cholesterol levels. Existing data do not clarify whether inflammation simply accompanies CAD and increased production and aggregation of platelets, or whether a causal relationship exists. In this review, we provide a comprehensive overview of inflammatory markers in stable CAD with particular emphasis on platelet production, activation, and aggregation in CAD patients. PMID- 26062930 TI - Resilience and well-being amongst seafarers: cross-sectional study of crew across 51 ships. AB - OBJECTIVES: Duration at sea was investigated as a potential chronic stressor amongst seafarers in addition to the mediating roles of previous seafaring experience and hardiness between duration and stress. METHODS: In a cross sectional design, questionnaires were emailed to 53 tanker vessels in an international shipping company with questions relating to duration at sea, perceived stress, personality hardiness and work characteristics. The sample comprised 387 seafarers (98% male) including ratings, crew, officers, engineers, and catering staff that had been on board their ship between 0 and 24 weeks. RESULTS: Duration at sea was unrelated to self-reported perceived stress, even after controlling for previous seafaring experience and hardiness. Additional regression analyses demonstrated that self-reported higher levels of resilience, longer seafaring experience and greater instrumental work support were significantly associated with lower levels of self-reported stress at sea. CONCLUSIONS: These results imply that at least for the first 24 weeks at sea, exposure to the seafaring environment did not act as a chronic stressor. The confined environment of a ship presents particular opportunities to introduce resilience and work support programmes to help seafarers manage and reduce stress, and to enhance their well-being at sea. PMID- 26062931 TI - Histological Validation of measurement of diffuse interstitial myocardial fibrosis by myocardial extravascular volume fraction from Modified Look-Locker imaging (MOLLI) T1 mapping at 3 T. AB - BACKGROUND: Gadolinium (Gd) Extracellular volume fraction (ECV) by Cardiovascular Magnetic Resonance (CMR) has been proposed as a non-invasive method for assessment of diffuse myocardial fibrosis. Yet only few studies used 3 T CMR to measure ECV, and the accuracy of ECV measurements at 3 T has not been established. Therefore the aims of the present study were to validate measurement of ECV by MOLLI T1 mapping by 3 T CMR against fibrosis measured by histopathology. We also evaluated the recently proposed hypothesis that native-T1 mapping without contrast injection would be sufficient to detect fibrosis. METHODS: 31 patients (age = 58 +/- 17 years, 77% men) with either severe aortic stenosis (n = 12) severe aortic regurgitation (n = 9) or severe mitral regurgitation (n = 10), all free of coronary artery disease, underwent 3 T-CMR with late gadolinium enhancement (LGE) and pre- and post-contrast MOLLI T1 mapping and ECV computation, prior to valve surgery. LV biopsies were performed at the time of surgery, a median 13 [1-30] days later, and stained with picrosirius red. Pre-, and post-contrast T1 values, ECV, and amount of LGE were compared against magnitude of fibrosis by histopathology by Pearson correlation coefficients. RESULTS: The average amount of interstitial fibrosis by picrosirius red staining in biopsy samples was 6.1 +/- 4.3%. ECV computed from pre-post contrast MOLLI T1 time changes was 28.9 +/- 5.5%, and correlated (r = 0.78, p < 0.001) strongly with the magnitude of histological fibrosis. By opposition, neither amount of LGE (r = 0.17, p = 0.36) nor native pre-contrast myocardial T1 time (r = -0.18, p = 0.32) correlated with fibrosis by histopathology. CONCLUSIONS: ECV determined by 3 T CMR T1 MOLLI images closely correlates with histologically determined diffuse interstitial fibrosis, providing a non-invasive estimation for quantification of interstitial fibrosis in patients with valve diseases. By opposition, neither non-contrast T1 times nor the amount of LGE were indicative of the magnitude of diffuse interstitial fibrosis measured by histopathology. PMID- 26062932 TI - Investigation into the interchangeability of generic formulations using immunosuppressants and a broad selection of medicines. AB - PURPOSE: To date, the interchangeability of generic drugs has only been investigated for a limited number of medicines. The objective of this study was to investigate generic-generic drug interchangeability in a large subset of generic formulations in order to cover a broad spectrum of drugs. METHODS: Orally administered drugs for investigation in this study were selected using strict, predefined criteria, with the purpose to avoid bias. This selection procedure yielded atorvastatin, bicalutamide, naratriptan, olanzapine, perindopril, and venlafaxine. Further, ciclosporin, tacrolimus, and mycophenolate mofetil were investigated as test immunosuppressants. Adjusted indirect comparisons were conducted between generic drugs containing the same active substance, and the 90% confidence interval (CI) for AUC and Cmax was calculated. RESULTS: In total, 120 bioequivalence studies were identified in the Dutch medicine regulatory agency's database, allowing 292 indirect comparisons between generic drugs. The indirect comparison results indicated that in the vast majority of cases, i.e., 80.5%, the 90% CIs for both AUCt and Cmax fell within the bioequivalence criteria (in 90.1 and 87.0% for AUCt and Cmax, respectively). In 1% of the 292 indirect comparison for AUCt and 3% for Cmax, a wider range of 75-133% (or 80-125%) was exceeded. CONCLUSIONS: Overall, our study suggests that exposure-related risks associated with the exchange of different generic drugs in clinical practice are not increased to a relevant extent compared to the situation in which a generic is exchanged with the innovator. PMID- 26062933 TI - Biodistribution of the 18F-FPPRGD2 PET radiopharmaceutical in cancer patients: an atlas of SUV measurements. AB - PURPOSE: The aim of this study was to investigate the biodistribution of 2 fluoropropionyl-labeled PEGylated dimeric arginine-glycine-aspartic acid (RGD) peptide (PEG3-E[c{RGDyk}]2) ((18)F-FPPRGD2) in cancer patients and to compare its uptake in malignant lesions with (18)F-FDG uptake. METHODS: A total of 35 patients (11 men, 24 women, mean age 52.1 +/- 10.8 years) were enrolled prospectively and had (18)F-FPPRGD2 PET/CT prior to treatment. Maximum standardized uptake values (SUVmax) and mean SUV (SUVmean) were measured in 23 normal tissues in each patient, as well as in known or suspected cancer lesions. Differences between (18)F-FPPRGD2 uptake and (18)F-FDG uptake were also evaluated in 28 of the 35 patients. RESULTS: Areas of high (18)F-FPPRGD2 accumulation (SUVmax range 8.9 - 94.4, SUVmean range 7.1 - 64.4) included the bladder and kidneys. Moderate uptake (SUVmax range 2.1 - 6.3, SUVmean range 1.1 - 4.5) was found in the choroid plexus, salivary glands, thyroid, liver, spleen, pancreas, small bowel and skeleton. Compared with (18)F-FDG, (18)F-FPPRGD2 showed higher tumor-to-background ratio in brain lesions (13.4 +/- 8.5 vs. 1.1 +/- 0.5, P < 0.001), but no significant difference in body lesions (3.2 +/- 1.9 vs. 4.4 +/- 4.2, P = 0.10). There was no significant correlation between the uptake values (SUVmax and SUVmean) for (18)F FPPRGD2 and those for (18)F-FDG. CONCLUSION: The biodistribution of (18)F-FPPRGD2 in cancer patients is similar to that of other RGD dimer peptides and it is suitable for clinical use. The lack of significant correlation between (18)F-FPPRGD2 and (18)F-FDG uptake confirms that the information provided by each PET tracer is different. PMID- 26062934 TI - A dynamic intracellular distribution of Vangl2 accompanies cell polarization during zebrafish gastrulation. AB - During vertebrate gastrulation, convergence and extension movements elongate embryonic tissues anteroposteriorly and narrow them mediolaterally. Planar cell polarity (PCP) signaling is essential for mediolateral cell elongation underlying these movements, but how this polarity arises is poorly understood. We analyzed the elongation, orientation and migration behaviors of lateral mesodermal cells undergoing convergence and extension movements in wild-type zebrafish embryos and mutants for the Wnt/PCP core component Vangl2 (Trilobite). We demonstrate that Vangl2 function is required at the time when cells transition to a highly elongated and mediolaterally aligned body. vangl2 mutant cells fail to undergo this transition and to migrate along a straight path with high net speed towards the dorsal midline. Instead, vangl2 mutant cells exhibit an anterior/animal pole bias in cell body alignment and movement direction, suggesting that PCP signaling promotes effective dorsal migration in part by suppressing anterior/animalward cell polarity and movement. Endogenous Vangl2 protein accumulates at the plasma membrane of mesenchymal converging cells at the time its function is required for mediolaterally polarized cell behavior. Heterochronic cell transplantations demonstrated that Vangl2 cell membrane accumulation is stage dependent and regulated by both intrinsic factors and an extracellular signal, which is distinct from PCP signaling or other gastrulation regulators, including BMP and Nodals. Moreover, mosaic expression of fusion proteins revealed enrichment of Vangl2 at the anterior cell edges of highly mediolaterally elongated cells. These results demonstrate that the dynamic Vangl2 intracellular distribution is coordinated with and necessary for the changes in convergence and extension cell behaviors during gastrulation. PMID- 26062935 TI - Distinct developmental genetic mechanisms underlie convergently evolved tooth gain in sticklebacks. AB - Teeth are a classic model system of organogenesis, as repeated and reciprocal epithelial and mesenchymal interactions pattern placode formation and outgrowth. Less is known about the developmental and genetic bases of tooth formation and replacement in polyphyodonts, which are vertebrates with continual tooth replacement. Here, we leverage natural variation in the threespine stickleback fish Gasterosteus aculeatus to investigate the genetic basis of tooth development and replacement. We find that two derived freshwater stickleback populations have both convergently evolved more ventral pharyngeal teeth through heritable genetic changes. In both populations, evolved tooth gain manifests late in development. Using pulse-chase vital dye labeling to mark newly forming teeth in adult fish, we find that both high-toothed freshwater populations have accelerated tooth replacement rates relative to low-toothed ancestral marine fish. Despite the similar evolved phenotype of more teeth and an accelerated adult replacement rate, the timing of tooth number divergence and the spatial patterns of newly formed adult teeth are different in the two populations, suggesting distinct developmental mechanisms. Using genome-wide linkage mapping in marine-freshwater F2 genetic crosses, we find that the genetic basis of evolved tooth gain in the two freshwater populations is largely distinct. Together, our results support a model whereby increased tooth number and an accelerated tooth replacement rate have evolved convergently in two independently derived freshwater stickleback populations using largely distinct developmental and genetic mechanisms. PMID- 26062936 TI - MicroRNAs are essential for differentiation of the retinal pigmented epithelium and maturation of adjacent photoreceptors. AB - Dysfunction of the retinal pigmented epithelium (RPE) results in degeneration of photoreceptors and vision loss and is correlated with common blinding disorders in humans. Although many protein-coding genes are known to be expressed in RPE and are important for its development and maintenance, virtually nothing is known about the in vivo roles of non-coding transcripts. The expression patterns of microRNAs (miRNAs) have been analyzed in a variety of ocular tissues, and a few were implicated to play role in RPE based on studies in cell lines. Here, through RPE-specific conditional mutagenesis of Dicer1 or Dgcr8 in mice, the importance of miRNAs for RPE differentiation was uncovered. miRNAs were found to be dispensable for maintaining RPE fate and survival, and yet they are essential for the acquisition of important RPE properties such as the expression of genes involved in the visual cycle pathway, pigmentation and cell adhesion. Importantly, miRNAs of the RPE are required for maturation of adjacent photoreceptors, specifically for the morphogenesis of the outer segments. The alterations in the miRNA and mRNA profiles in the Dicer1-deficient RPE point to a key role of miR-204 in regulation of the RPE differentiation program in vivo and uncover the importance of additional novel RPE miRNAs. This study reveals the combined regulatory activity of miRNAs that is required for RPE differentiation and for the development of the adjacent neuroretina. PMID- 26062937 TI - The intracellular domains of Notch1 and Notch2 are functionally equivalent during development and carcinogenesis. AB - Although Notch1 and Notch2 are closely related paralogs and function through the same canonical signaling pathway, they contribute to different outcomes in some cell and disease contexts. To understand the basis for these differences, we examined in detail mice in which the Notch intracellular domains (N1ICD and N2ICD) were swapped. Our data indicate that strength (defined here as the ultimate number of intracellular domain molecules reaching the nucleus, integrating ligand-mediated release and nuclear translocation) and duration (half life of NICD-RBPjk-MAML-DNA complexes, integrating cooperativity and stability dependent on shared sequence elements) are the factors that underlie many of the differences between Notch1 and Notch2 in all the contexts we examined, including T-cell development, skin differentiation and carcinogenesis, the inner ear, the lung and the retina. We were able to show that phenotypes in the heart, endothelium, and marginal zone B cells are attributed to haploinsufficiency but not to intracellular domain composition. Tissue-specific differences in NICD stability were most likely caused by alternative scissile bond choices by tissue specific gamma-secretase complexes following the intracellular domain swap. Reinterpretation of clinical findings based on our analyses suggests that differences in outcome segregating with Notch1 or Notch2 are likely to reflect outcomes dependent on the overall strength of Notch signals. PMID- 26062938 TI - JNK signalling is necessary for a Wnt- and stem cell-dependent regeneration programme. AB - Regeneration involves the integration of new and old tissues in the context of an adult life history. It is clear that the core conserved signalling pathways that orchestrate development also play central roles in regeneration, and further study of conserved signalling pathways is required. Here we have studied the role of the conserved JNK signalling cascade during planarian regeneration. Abrogation of JNK signalling by RNAi or pharmacological inhibition blocks posterior regeneration and animals fail to express posterior markers. While the early injury-induced expression of polarity markers is unaffected, the later stem cell dependent phase of posterior Wnt expression is not established. This defect can be rescued by overactivation of the Hh or Wnt signalling pathway to promote posterior Wnt activity. Together, our data suggest that JNK signalling is required to establish stem cell-dependent Wnt expression after posterior injury. Given that Jun is known to be required in vertebrates for the expression of Wnt and Wnt target genes, we propose that this interaction may be conserved and is an instructive part of planarian posterior regeneration. PMID- 26062939 TI - Wnt signaling and tbx16 form a bistable switch to commit bipotential progenitors to mesoderm. AB - Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2. We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cell-autonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16, which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial high-Wnt environment. PMID- 26062942 TI - Reducing radiation exposure in children with febrile neutropenia: can pulmonary MRI replace CT? PMID- 26062941 TI - Nanoparticle-mediated RNA interference of angiotensinogen decreases blood pressure and improves myocardial remodeling in spontaneously hypertensive rats. AB - Angiotensinogen (AGT) has been shown to have a role in cardiac hypertrophy, while depletion of the AGT gene in spontaneously hypertensive rats (SHR) has not been investigated. The present study investigated the effect of AGT knockdown on cardiac hypertrophy in SHR. For this, small hairpin (sh)RNAs were intravenously injected into SHRs, using a nanoparticle-mediated transfection system. The experimental rats were divided into the following groups: a) Blank control with water treatment only, b) negative control with biscarbamate-crosslinked Gal polyethylene glycol polyethylenimine nanoparticles (GPE)/negative shRNA, c) AGT RNA interference (RNAi) group with GPE/AGT-shRNA, and 4) normotensive control using Wistar-Kyoto rats (WKY) with water treatment. Three and five days following the first injection, the levels of hepatic AGT mRNA and AGT protein as well as plasma levels of AGT were markedly decreased in the AGT-RNAi group (P<0.05). Furthermore, a significant decrease in systolic blood pressure (SBP), left ventricular weight to body weight ratio and heart weight to body weight ratio were observed in the AGT-RNAi group compared with those in the control groups. The depletion of AGT in SHR led to a reduction in SBP by 30+/-4 mmHg, which was retained for >10 days. Cardiac hypertrophy was also significantly improved in AGT knockdown rats. In conclusion, the present study showed that AGT-silencing had a significant inhibitory effect on hypertension and hypertensive-induced cardiac hypertrophy in SHRs. PMID- 26062940 TI - Musculoskeletal integration at the wrist underlies the modular development of limb tendons. AB - The long tendons of the limb extend from muscles that reside in the zeugopod (arm/leg) to their skeletal insertions in the autopod (paw). How these connections are established along the length of the limb remains unknown. Here, we show that mouse limb tendons are formed in modular units that combine to form a functional contiguous structure; in muscle-less limbs, tendons develop in the autopod but do not extend into the zeugopod, and in the absence of limb cartilage the zeugopod segments of tendons develop despite the absence of tendons in the autopod. Analyses of cell lineage and proliferation indicate that distinct mechanisms govern the growth of autopod and zeugopod tendon segments. To elucidate the integration of these autopod and zeugopod developmental programs, we re-examined early tendon development. At E12.5, muscles extend across the full length of a very short zeugopod and connect through short anlagen of tendon progenitors at the presumptive wrist to their respective autopod tendon segment, thereby initiating musculoskeletal integration. Zeugopod tendon segments are subsequently generated by proximal elongation of the wrist tendon anlagen, in parallel with skeletal growth, underscoring the dependence of zeugopod tendon development on muscles for tendon anchoring. Moreover, a subset of extensor tendons initially form as fused structures due to initial attachment of their respective wrist tendon anlage to multiple muscles. Subsequent individuation of these tendons depends on muscle activity. These results establish an integrated model for limb tendon development that provides a framework for future analyses of tendon and musculoskeletal phenotypes. PMID- 26062944 TI - Membranous glomerulonephritis as a novel paraneoplastic syndrome in a young man with chronic myeloid leukemia. PMID- 26062943 TI - Ibrutinib, idelalisib and obinutuzumab for the treatment of patients with chronic lymphocytic leukemia: three new arrows aiming at the target. AB - Over the last 20 years there have been sustained and dramatic improvements in the therapy of chronic lymphocytic leukemia (CLL). Until 1990, therapy for CLL was based on alkylating agents, chlorambucil and cyclophosphamide, which did not impact meaningfully on overall survival. The more recent therapeutic regimens, built on combination chemoimmunotherapy, achieve complete responses in 40-50% of cases. However, these regimens are limited in their applicability mostly to the treatment of younger and physically fit patients due to their associated toxicity. Furthermore, since disease progression and drug resistance are considered inevitable, CLL remains incurable. Fortunately, significant progress in the understanding of CLL biology has enabled the development of new molecular drugs targeting the B-cell receptor signaling pathway, such as ibrutinib and idelalisib, which have shown impressive results in patients with relapsed/refractory disease or with TP53 mutation/deletion. Furthermore, obinutuzumab, a type II anti-CD20 antibody, which results in direct cell death and antibody-dependent cell-mediated cytotoxicity, also has proven efficacy when used in combination with chlorambucil in previously untreated and unfit patients. All these three new drugs have recently received FDA approval for the treatment of CLL. This review focuses on the role of ibrutinib, idelalisib and obinutuzumab in therapy of CLL. PMID- 26062945 TI - [Sleep disorders in neurological diseases]. AB - Sleep disorders can be diagnosed in approximately 15 % of the population and have been shown to increase with age. The relationship between sleep disorders and neurological disorders, however, is still insufficiently considered in the clinical practice. Sleep disorders can be an early symptom of the disease, such as the presence of rapid eye movement (REM) sleep behavior disorder (RBD) as an early indicator of neurodegeneration. Sleep disorders have also been shown to be a main symptom of various neurological syndromes, such as in restless legs syndrome (RLS), periodic limb movement disorder (PLMD) and narcolepsy. The international classification of sleep disorders 2nd edition (ICSD 2) describes the main diagnoses, insomnia, circadian rhythm sleep disorders, sleep-related breathing disorders and hypersomnia but all of these can also appear as symptoms in various neurological diseases. Parasomnias are largely considered a differential diagnosis to nocturnal epilepsy. In this review, the main sleep disorders are described with a particular focus on how they relate to neurological diseases; in particular, how they influence disease-related symptoms and how they affect the course of the disease. PMID- 26062946 TI - Correction: enantioselective synthesis of chiral heterocycles containing both chroman and pyrazolone derivatives catalysed by a chiral squaramide. PMID- 26062947 TI - A case of kaposiform hemangioendothelioma at the sigmoid colon. AB - We report a case of kaposiform hemangioendothelioma (KHE) occurring at the sigmoid colon in an 8-year-old male. He had experienced lower abdominal pain and fever for several days. Contrast-enhanced CT images revealed a well-enhanced mass involving several large and small cystic parts with thin, enhanced walls at the sigmoid colon. The diagnosis was made histopathologically after surgical resection; the cystic parts corresponded to dilated lymphatic vessels. KHE is a rare, locally aggressive, vascular tumor that usually occurs in the soft tissues of the extremities. However, a case occurring in the bowel is extremely rare, and usually appears as bowel wall thickening. This is a unique case of KHE appearing as a mass-shaped hypervascular lesion in the bowel. Dilated lymphatic vessels in KHE may appear as a cystic part of the lesion. PMID- 26062948 TI - A suitable method to detect potential fraud of bringing Malayan box turtle (Cuora amboinensis) meat into the food chain. AB - Malayan box turtle (Cuora amboinensis) has been a wildlife-protected vulnerable turtle species in Malaysia since 2005. However, because of its purported usage in traditional medicine, tonic foods and feeds, clandestine black market trade is rampant. Several polymerase chain reaction (PCR) assays for the taxonomic detection and classification of turtle species have been proposed. These assays are based on long-length target amplicons which are assumed to break down under compromised states and, hence, might not be suitable for the forensic tracing and tracking of turtle trafficking. For the first time this paper develops a very short-amplicon-length PCR assay (120 bp) for the detection of Malayan box turtle meat in raw, processed and mixed matrices, and experimental evidence is produced that such an assay is not only more stable and reliable but also more sensitive than those previously published. We checked the assay specificity against 20 different species and no cross-species detection was observed. The possibility of any false-negative detection was eliminated by a universal endogenous control for eukaryotes. The assay detection limit was 0.0001 ng of box turtle DNA from pure meat and 0.01% turtle meat in binary and ternary admixtures and commercial meatballs. Superior target stability and sensitivity under extreme treatments of boiling, autoclaving and microwave cooking suggested that this newly developed assay would be suitable for any forensic and/or archaeological identification of Malayan box turtle species, even in severely degraded specimens. Further, in silico studies indicated that the assay has the potential to be used as a universal probe for the detection of nine Cuora species, all of which are critically endangered. PMID- 26062949 TI - Time-Course Changes of Cardiac-Specific Inflammation in a Patient With Left Ventricular Calcified Amorphous Tumor. PMID- 26062950 TI - Therapeutic Ultrasound Promotes Reperfusion and Angiogenesis in a Rat Model of Peripheral Arterial Disease. AB - BACKGROUND: Shock wave therapy (SWT) is an acoustic technology clinically used for the non-invasive treatment of ischemic heart disease (IHD). Therapeutic ultrasound (TUS) has more recently been developed for the same indication, although its effects on reperfusion and angiogenesis have yet to be directly compared to those of SWT. METHODS AND RESULTS: TUS and SWT acoustic parameters were matched, and their ability to promote angiogenesis and reperfusion in a rat hindlimb ischemia model was compared. After left femoral artery excision, 3 weekly TUS, SWT or sham treatments (n=10 rats each) of the left hindlimb were performed for 2 weeks. Laser Doppler perfusion imaging demonstrated improved perfusion with TUS (66+/-4% L:R hindlimb perfusion, mean+/-SEM, P=0.02), but not with SWT (59+/-4%, P=0.13) compared with sham (50+/-4%). Immunohistochemistry of CD31 demonstrated increased microvascular density with TUS (222.6 vessels/high power field, P=0.001) and SWT (216.9, P=0.01) compared to sham-treated rats (196.0). Tissue vascular endothelial growth factor mRNA levels were elevated in the left hindlimb of TUS-, but not SWT- or sham-treated rats. CONCLUSIONS: Direct comparison demonstrates that TUS is more effective than SWT at promoting reperfusion, whereas both therapies promote angiogenesis in ischemic gastrocnemius muscle. These results suggest that TUS may be more effective than SWT for the treatment of IHD and peripheral arterial disease. PMID- 26062953 TI - Physical inactivity and obesity is not a myth: Dr. Steven Blair comments on Dr. Aseem Malhotra's editorial. PMID- 26062954 TI - Watch and learn: educational videos at your finger tips. PMID- 26062952 TI - MiRNA-based therapeutic intervention of cancer. AB - MicroRNAs (miRNAs) are important modulators of eukaryotic gene expression. By targeting protein coding transcripts, miRNAs influence the cellular transcriptome and proteome, thus helping to determine cell fate. MiRNAs have emerged as crucial molecules in cancer research, in which recent studies have linked erratic expression of miRNAs to carcinogenesis and have provided solid evidence for their potential in cancer therapy. This review briefly summarises the recent knowledge on the involvement of miRNAs in tumourigenesis and reviews current studies on the therapeutic strategies and advances in the delivery of miRNAs. PMID- 26062955 TI - Ultrasound-guided hip joint injections are more accurate than landmark-guided injections: a systematic review and meta-analysis. AB - AIM: To compare the accuracy of ultrasound (US)-guided versus landmark-guided hip joint injections. METHODS: PubMed, Medline and Cochrane libraries were searched up to 31 July 2014. Two independent authors selected studies assessing accuracy of intra-articular hip injections based on predetermined inclusion and exclusion criteria. Selected papers were then evaluated for quality and a meta-analysis of accuracy was performed using random effects models. RESULTS: 4 US-guided (136 hip injections) and 5 landmark-guided (295 hip injections) studies were reviewed. The weighted means for US-guided and landmark-guided hip injection accuracies were 100% (95% CI 98% to 100%) and 72% (95% CI 56% to 85%), respectively. US-guided hip injection accuracy was significantly higher than landmark-guided accuracy (p<0.0001). SUMMARY: This is the first systematic review and meta-analysis of the accuracy of US-guided versus landmark-guided hip joint injections that has revealed that US-guided injections are significantly more accurate than those that are landmark guided. Future studies should compare US with fluoroscopic guided hip joint injections for accuracy, efficacy, safety profile, cost effectiveness and patient satisfaction. PMID- 26062956 TI - After revision anterior cruciate ligament reconstruction, who returns to sport? A systematic review and meta-analysis. AB - BACKGROUND: Return to sport and to pre-injury level represents an important outcome after both primary and revision anterior cruciate ligament (ACL) reconstructions. PURPOSE: The aim of the present meta-analysis was to determine the return to sport rate after revision ACL reconstruction. MATERIAL AND METHODS: A systematic search was performed of the MEDLINE, Embase and the Cochrane Central Register of Controlled Trials Databases. All the studies that reported return to sport, return to pre-injury sport level and return to high level/competitive sport was considered for the meta-analysis. The overall pooled mean of post operative knee laxity and pooled rate of positive pivot-shift and objective International Knee Documentation Committee (IKDC) categories was calculated as well. RESULTS: Overall, 472 abstracts were identified and screened for inclusion and only 16 studies reported the rate of return to any level of sport activity at the final follow-up of 4.7 years (range 1.0-13.2 years), showing a pooled rate of 85.3% (CI 79.7 to 90.2). The return to pre-injury sport level was achieved in 53.4% (CI 37.8 to 68.7) of cases. Normal or quasi-normal objective IKDC, less than 5 mm of side-to-side difference at arthrometric evaluations and grade I-II pivot-shift test were reported in 84%, 88% and 93% patients, respectively. CONCLUSIONS: In spite of almost 8 patients out of 10 returning to sport after revision ACL reconstruction and showing good stability, only half of the patients returned to the same pre-injury sport level. PMID- 26062957 TI - Misrepresentation of carbohydrate for exercise: 'It is time to bust the myth of physical inactivity and obesity: you cannot outrun a bad diet'. PMID- 26062958 TI - Increased Prevalence of Advanced Liver Fibrosis in Patients with Psoriasis: A Cross-sectional Analysis from the Rotterdam Study. AB - Prevalence of non-alcoholic fatty liver disease is increased in patients with psoriasis. However, it is not known how liver fibrosis correlates with psoriasis. This study investigated the association between psoriasis and liver fibrosis compared with participants without psoriasis within the population-based Rotterdam Study. All participants were screened for liver fibrosis using transient elastography. Liver stiffness > 9.5 kPa suggested advanced liver fibrosis. Psoriasis was identified using a validated algorithm. A total of 1,535 participants were included (mean age +/- standard deviation 70.5 +/- 7.9 years; 50.8% female; median body mass index 26.4 kg/m2 (interquartile range 24.2-28.9)) of whom 74 (4.7%) had psoriasis. Prevalence of advanced liver fibrosis was 8.1% in psoriasis patients compared with 3.6% in the reference group (p = 0.05). The risk of advanced liver fibrosis in psoriasis patients remained comparable after adjustment for demographics, lifestyle characteristics and laboratory findings (odds ratio 2.57 (95% confidence interval 1.00-6.63). This study suggests that elderly people with psoriasis are twice as likely to have advanced liver fibrosis irrespective of common risk factors. PMID- 26062959 TI - Imidazolium Cations with Exceptional Alkaline Stability: A Systematic Study of Structure-Stability Relationships. AB - Highly base-stable cationic moieties are a critical component of anion exchange membranes (AEMs) in alkaline fuel cells (AFCs); however, the commonly employed organic cations have limited alkaline stability. To address this problem, we synthesized and characterized the stability of a series of imidazolium cations in 1, 2, or 5 M KOH/CD3OH at 80 degrees C, systematically evaluating the impact of substitution on chemical stability. The substituent identity at each position of the imidazolium ring has a dramatic effect on the overall cation stability. We report imidazolium cations that have the highest alkaline stabilities reported to date, >99% cation remaining after 30 days in 5 M KOH/CD3OH at 80 degrees C. PMID- 26062960 TI - Facile and efficient exfoliation of inorganic layered materials using liquid alkali metal alloys. AB - A facile and efficient exfoliation process has been reported to produce single- and few-layer nanosheets of MoS2, WS2 and BN using liquid alloys of alkali metals at room temperature. The colloidal dispersions of MoS2 and WS2 layers were highly stable over several months, which allowed us to easily prepare films of MoS2 and WS2 by vacuum filtration or spraying. PMID- 26062962 TI - [Age(ing) and participative neighbourhood development. Obstacles and perspectives for social sustainability]. AB - Ageing urban societies face the challenge of enabling a "good" life for older people in their neighbourhood areas. This article focuses on potential obstacles and required preconditions for processes of neighbourhood development, based on results from the research and development project "Quality of life of older people in their neighbourhood" (LiW). Preconditions and obstacles include political and organizational requirements, differing understandings of participation of local experts, as well as the organization of the process and the access to the process. Furthermore, problems and social conflicts, which have to be dealt with on the local level, are examined. An example for such conflicts are statements of group-focused enmity. The paper aims to point out the significials of such processes as well as potential barriers and limits in order to inform academics as well as practitioners and to contribute to the sustainable integration of participative neighbourhood development. PMID- 26062963 TI - Prescription errors in geriatric patients can be avoided by means of a computerized physician order entry (CPOE). AB - BACKGROUND: The implementation of a computerized physician order entry (CPOE) can help reduce prescription errors in clinical practice. OBJECTIVE: The aim of this study was to evaluate the effects of a CPOE for geriatric patients with the two most common conditions for drug-induced iatrogenic diseases, dysphagia and renal failure. SUBJECTS AND METHODS: A retrospective analysis of actual drug prescriptions versus CPOE recommendations in the geriatric department of the St. Marien Hospital in Cologne, Germany was carried out. Actual drug prescriptions were collected for 26 patients with dysphagia (15 female, 11 male, average age 82.3 +/- 8.0 years) and 35 patients with renal failure (23 female, 12 male, average age 80.5 +/- 6.7 years) which were compared with recommended prescriptions by means of a CPOE and discrepancies were statistically analyzed. RESULTS: Prescription errors for at least 1 drug were detected in 46 % of patients with renal failure and the administration of at least 1 drug with inadequate crushing was observed in 77 % of dysphagia patients. CONCLUSION: Prescription errors appear to be frequent to highly frequent in the medical routine even in a highly specialized geriatric setting. Inaccuracies might be reduced by the implementation of a CPOE and even more if coupled to a decision support system. Drug-drug or drug-disease interactions, which are particularly high risks in patients with multimorbidities, multidrug therapy, renal failure or malnutrition, might be kept under control through careful verification of medication indications, organ function status as well as drug administration and preparation in cases of tube feeding. PMID- 26062966 TI - The serologic decoy receptor 3 (DcR3) levels are associated with slower disease progression in HIV-1/AIDS patients. AB - BACKGROUND/PURPOSE: The decoy receptor 3 (DcR3) is a member of the tumor necrosis factor receptor (TNFR) super-family. It counteracts the biological effects of Fas ligands and inhibits apoptosis. The goals of this study were to understand the associations between serologic DcR3 (sDcR3) levels and different human immunodeficiency virus type 1 (HIV-1) subtypes, as well as the AIDS disease progression. METHODS: Serum samples from 61 HIV/AIDS patients, who had been followed up every 6 months for 3 years, were collected. sDcR3 levels were quantified using an enzyme immunoassay (EIA). RESULTS: The sDcR3 levels in patients with HIV-1 subtype B were significantly higher than those in patients infected with subtype CRF01_AE (p < 0.001). In addition, multivariable linear mixed model analysis demonstrated that HIV-1 subtype B and slow disease progression were associated with higher levels of sDcR3, adjusting for potential predictors (p = 0.0008 and 0.0455, respectively). CONCLUSION: HIV-1-infected cells may gain a survival advantage by activating DcR3, which prevents infected cell detection by the host immune system. These data indicate that the sDcR3 level is a biomarker for AIDS disease progression. PMID- 26062967 TI - Initiating long-acting injectable antipsychotics during acute admission for patients with schizophrenia--A 3-year follow-up. AB - BACKGROUND/PURPOSE: The debate on whether long-acting injectable antipsychotic (LAIA) medication is superior to oral medication, in preventing rehospitalization of patients with schizophrenia, remains inconclusive. We compared rehospitalization rates over 3 years following discharge from an acute admission, in which patients either began using LAIAs regularly for the first time, or continued to use oral antipsychotics. METHODS: A retrospective observational study of 92 inpatients with schizophrenia from a university-based medical center during 2004-2008. The primary outcome measure is the rehospitalization rates between groups, as estimated by Kaplan-Meier survival analysis. RESULTS: Eighteen of 47 (38.3%) LAIA patients, and 16 of 45 (35.6%) oral medication patients were rehospitalized (average time to rehospitalization, 378 +/- 262 vs. 378 +/- 340 days; p = 0.997). The estimated cumulative rates of rehospitalization were similar between groups. The overall odds comparing the LAIA to the oral medication group were 1.085 +/- 0.373 (95% confidence interval: 0.553-2.13, p = 0.813). Compared to the oral medication group, the LAIA group had fewer coded with sufficient previous treatment response (32% vs. 69%, p < 0.001), more poorly compliant (91% vs. 56%, p < 0.001), and a slightly longer length of stay at index admission (32.7 +/- 11.3vs. 27.6 +/- 12.1, p = 0.04). CONCLUSION: Initiating LAIAs during admission for an acute psychotic episode, to a group of patients with an inadequate previous treatment response and poorer compliance, might keep their rehospitalization rates to the level of their oral antipsychotic medication treated counterparts. PMID- 26062968 TI - Missing link in community psychiatry: When a patient with schizophrenia was expelled from her home. AB - Treatment and disposition of homeless patients with schizophrenia represent a great challenge in clinical practice. We report a case of this special population, and discuss the development of homelessness, the difficulty in disposition, their utilization of health services, and possible applications of mandatory community treatment in this group of patients. A 51-year-old homeless female was brought to an emergency department for left femur fracture caused by an assault. She was diagnosed with schizophrenia about 20 years ago but received little help from mental health services over the decades. During hospitalization, her psychotic symptoms were only partially responsive to treatment. Her family refused to handle caretaking duties. The social welfare system was mobilized for long-term disposition. Homeless patients with schizophrenia are characterized by family disruption, poor adherence to health care, and multiple emergency visits and hospitalization. We hope this article can provide information about the current mental health policy to medical personnel. It is possible that earlier intervention and better outcome can be achieved by utilizing mandatory community treatment in the future, as well as preventing patients with schizophrenia from losing shelters. PMID- 26062969 TI - Family carers' experiences of the Admiral Nursing Service: a quantitative analysis of carer feedback. AB - OBJECTIVES: Family carers of people with dementia often experience difficulty in accessing information, services and adequate support. Admiral Nurses, registered nurses specialising in dementia, provide holistic and person-centred support to families living with dementia. This study assessed the effectiveness of the Admiral Nurses' approach from the perspective of family carers who had accessed their service. METHOD: A questionnaire was developed with input from family carers and Admiral Nurses and questions were based around the Admiral Nursing Standards. 685 questionnaires were sent out in total to carers in receipt of care from three different regions in England. RESULTS: 207 questionnaires (30.2% response rate) were analysed. Admiral Nurses' knowledge and skills and their interventions were found helpful by 81.5% and 82.6% of respondents, respectively (mean values). Respondents also rated them effective in developing rapport (96.5%, mean value) and recognising and supporting the needs of the dyad (85.8%, mean value). More varied views were expressed in relation to activities and stimulation for the person with dementia, and to advice around medications and their effects, with around a third (n = 57, 31% and n = 63, 33.9%, respectively) of respondents finding Admiral Nurses not helpful, whilst 24.6% (n = 46) thought so in relation to care coordination. A higher number of contacts with Admiral Nurses (5+) and carer gender (female) were significant predictors of carers' satisfaction. CONCLUSION: Whilst some aspects of supporting carers are performed less well from the carers' perspective, overall family carers in receipt of Admiral Nursing support perceived their family-centred approach as helpful/effective. PMID- 26062971 TI - Anatomy classes, but not as we know them. PMID- 26062970 TI - Combined creatinine velocity and nadir creatinine: A reliable predictor of renal outcome in neonatally diagnosed posterior urethral valves. AB - INTRODUCTION: Nadir creatinine (lowest creatinine during the first year following diagnosis) is a recognised indicator of future chronic renal impairment (CRI) in posterior urethral valve (PUV) patients. We recently described "creatinine velocity" (Cvel), the rate of change of creatinine following initial bladder drainage, as a new early predictor of CRI in neonatally diagnosed PUV. Rising Cvel (>3 MUmol/L/day) is associated with increased risk of CRI. OBJECTIVE: We studied these two prognostic indicators in combination, as a test for future CRI in neonatally diagnosed PUV patients. STUDY DESIGN: Medical records for patients treated by endoscopic valve ablation at our institution between 1993 and 2004 were reviewed. Simple linear regression was used to calculate Cvel. Creatinine velocity and nadir creatinine were considered predictive of future CRI if they were greater than 3 MUmol/L/day or greater than 75 MUmol/L (0.85 mg/dL), respectively. Chronic renal insufficiency was defined as CKD2 or higher. Outcomes in test groups were analysed by Fisher exact test. Statistical significance was defined as p < 0.05. RESULTS: Sixty-two patients were treated within the first 30 days of life and had sufficient data to calculate both Cvel and nadir creatinine. Mean follow-up was 9.4 years. Patients were grouped as having both risk factors (Group A), one risk factor (Group B), or neither risk factor (Group C). All four (100%) patients from Group A developed CRI, compared with 11 of 17 (64.7%) patients from Group B and three of 41 (7.3%) patients from Group C (p <= 0.0005). As a diagnostic test for future CRI, "presence of at least one risk factor" had a specificity of 86.4%, sensitivity of 83.3%, positive predictive value of 71.4%, and negative predictive value of 92.7%. Additional prognostic information was obtained by assigning a score from 1 to 3 for each prognostic indicator (Table). The sum of these scores gave a PUV Risk Score. No patient with a PUV Risk Score of 2 developed CRI, while all patients with a Score of 6 developed CRI. Incidence of CRI in patients with PUV Risk Scores of 3, 4, and 5 was 8.3%, 50%, and 63.6%, respectively (p <= 0.0005). CONCLUSION: Considered together, these prognostic indicators provide a powerful test for future CRI. Presence of at least one of these risk factors should be considered "at risk for CRI". Patients with neither risk factor are unlikely to develop CRI. Calculation of the PUV Risk Score provides an even more accurate prognosis. PMID- 26062972 TI - Optimizing the Photocontrol of bZIP Coiled Coils with Azobenzene Crosslinkers: Role of the Crosslinking Site. AB - DNA binding by bZIP-type coiled-coil proteins can be inhibited by dominant negative versions of the proteins in which the N-terminal basic region is replaced by an acidic extension. Photocontrol of bZIP function can be achieved by introducing intramolecular azobenzene-based crosslinkers into dominant negatives. We show that the largest degree of photocontrol is achieved when the crosslinker is introduced into the zipper region of the dominant negative between Cys residues placed at f sites in the heptad segment showing the highest intrinsic helical propensity. The overall affinity of the dominant negative can then be tuned by varying the length of the acidic extension. PMID- 26062973 TI - Safety of Prolonged Use of Trophic Feeds in the Critically Ill Patient: It Depends on the Nutrition Risk of the Patient! PMID- 26062974 TI - Human FMO2-based microbial whole-cell catalysts for drug metabolite synthesis. AB - BACKGROUND: Getting access to authentic human drug metabolites is an important issue during the drug discovery and development process. Employing recombinant microorganisms as whole-cell biocatalysts constitutes an elegant alternative to organic synthesis to produce these compounds. The present work aimed for the generation of an efficient whole-cell catalyst based on the flavin monooxygenase isoform 2 (FMO2), which is part of the human phase I metabolism. RESULTS: We show for the first time the functional expression of human FMO2 in E. coli. Truncations of the C-terminal membrane anchor region did not result in soluble FMO2 protein, but had a significant effect on levels of recombinant protein. The FMO2 biocatalysts were employed for substrate screening purposes, revealing trifluoperazine and propranolol as FMO2 substrates. Biomass cultivation on the 100 L scale afforded active catalyst for biotransformations on preparative scale. The whole-cell conversion of trifluoperazine resulted in perfectly selective oxidation to 48 mg (46% yield) of the corresponding N (1)-oxide with a purity >98%. CONCLUSIONS: The generated FMO2 whole-cell catalysts are not only useful as screening tool for human metabolites of drug molecules but more importantly also for their chemo- and regioselective preparation on the multi-milligram scale. PMID- 26062975 TI - Design and evaluation of a recombinant multi-epitope antigen for serodiagnosis of Toxoplasma gondii infection in humans. AB - BACKGROUND: Serological investigation remains the primary approach to achieve satisfactory results in Toxoplasma gondii identification. However, the accuracy of the native antigen used in the current diagnostic kits has proven to be insufficient as well as difficult to standardize, so significant efforts have been made to find alternative reagents as capture antigens. Consequently, multi epitope peptides are promising diagnostic markers, with the potential for improving the accuracy of diagnostic kits. In this study, we described a simple, inexpensive and improved strategy to acquire such diagnostic markers. The study was aimed at producing novel synthetic protein consisting of multiple immunodominant epitopes of several T. gondii antigens. FINDINGS: To accomplish our goals, a single synthetic gene of approximately 456 bp, which encodes potential epitopes of T. gondii antigens, was successfully constructed using gene assembly PCR. The constructed gene was cloned into a pET32a expression vector and transformed into BL21 E. coli. The entire protein was successfully expressed and purified. Subsequently, the preliminary diagnostic performance of expressed protein was evaluated by developing IgG enzyme-linked immunosorbent assay (ELISA) and Western blot analysis using human sera. The results showed 100 % sensitivity and specificity. CONCLUSION: A purified protein expressing multi-immunodominant epitopes of T. gondii was generated. Further studies are required to evaluate the immunogenicity in animal models and to verify the immuno-reactivity of USM.TOXO1 as a diagnostic antigen. PMID- 26062976 TI - Stuck in the Heart: Embolized Strut Fracture of IVC Filter. PMID- 26062977 TI - Inhibitory effects of forkhead box L1 gene on osteosarcoma growth through the induction of cell cycle arrest and apoptosis. AB - Forkhead box L1 (FOXL1), which is considered a novel candidate tumor suppressor, inhibits proliferation and invasion in certain types of cancer. However, the regulation and function of FOXL1 in osteosarcoma remains unclear. The expression of FOXL1 gene in osteosarcoma tissues and cell lines was examined using RT-PCR, immunohistochemistry and western blot analysis. pcDNA-FOXL1 carrying full-length FOXL1 cDNA was constructed to upregulate the level of FOXL1 expression in osteosarcoma cell lines. The proliferation, cell cycle and apoptosis of osteosarcoma cells in vitro or in vivo were examined following transfection with pcDNA-FOXL1. In addition, the expression of p21, p27, cytochrome c and caspase-3, which may be involved in the regulation of the cell cycle and apoptosis was examined using western blot analysis. The results showed that FOXL1 expression was downregulated in osteosarcoma tissues and cell lines. Loss or downregulation of FOXL1 was associated with poor prognosis. Ectopic FOXL1 expression inhibited cell proliferation in vitro and in vivo. The ectopic FOXL1 expression increased the expression of p21 and p27, which induced G1 arrest in the U-2 OS cells. In addition, the ectopic FOXL1 expression induced cytochrome c release between mitochondria and cytoplasm, which disrupted the mitochondrial transmembrane potential and triggered intrinsic pathway apoptosis. In conclusion, the downregulation of FOXL1 expression was associated with osteosarcoma cell growth. Restoration of FOXL1 gene expression by gene therapy may have a therapeutic potential for patients with osteosarcoma. PMID- 26062979 TI - Dramatic reduction in hepatitis B through school-based immunization without a routine infant program in a low endemicity region. AB - BACKGROUND: Hepatitis B (HB) prevention in the low-endemicity province of Quebec Canada, (population: ~8.2 million; birth cohort ~85,000/year), includes two decades of pre-adolescent school-based immunization, as well as catch-up immunization for those born since 1983 and pre-natal maternal HBsAg screening. To estimate the potential added benefit of routine infant HB immunization, notifiable disease reports were analyzed (1990-2013). Clinical and demographic information about cases was retrieved from standard questionnaires used by local public health units to investigate HB cases. METHODS: The Quebec provincial registry of notifiable diseases was used to identify confirmed HB cases reported between 1990 and 2013. Clinical and demographic information on cases was retrieved from the standard questionnaires used by local public health units to investigate reported HB cases. RESULTS: Between 1990-2013, acute-HB incidence per 100,000 population decreased by 97 % from 6.5 to 0.2. Compared to 1990, incidence fell from 0.6 to zero since 2010 among children <=9 years of age (yoa), from 3.2 to zero since 2007 in those 10-19 yoa, and from 15 to zero in 2013 among adults 20-29 yoa, previously the age group of highest incidence (all p < 0.0001). During the same period, the newly-reported chronic HB rate per 100,000 decreased by 66 % from 17.7 to 6.1 (p < 0.0001), with a reduction of 92 % (2.4 to 0.2;p < 0.001) in children <=9 yoa and 83 % (7.2 to 1.2;p = 0.003) in those 10-19 yoa. The incidence of unspecified HB cases did not decrease significantly overall (5.9 vs. 5.4; p = 0.24), in children <= 9 yoa (0.3 vs. 0.2;p = 0.70) or 10-19 yoa (1.6 vs. 1.5;p = 0.45). Overall, 91 % of cases <=19 yoa were immigrants likely infected before arrival in Canada. Among those <=9 yoa, there were 9 acute-HB case reports between 2005 and 2013, of whom 8 were not preventable by infant immunization. CONCLUSIONS: Two decades of school-based immunization coupled with prenatal screening achieved striking reduction in disease burden in the low-endemicity province of Quebec, Canada. The oldest cohorts targeted by catch-up campaigns are now beyond the average age at childbirth so that neo-natal transmission and the potential incremental benefit of infant immunization will likely further diminish. PMID- 26062980 TI - Gaucher Disease-Induced Pluripotent Stem Cells Display Decreased Erythroid Potential and Aberrant Myelopoiesis. AB - Gaucher disease (GD) is the most common lysosomal storage disease resulting from mutations in the lysosomal enzyme glucocerebrosidase (GCase). The hematopoietic abnormalities in GD include the presence of characteristic Gaucher macrophages that infiltrate patient tissues and cytopenias. At present, it is not clear whether these cytopenias are secondary to the pathological activity of Gaucher cells or a direct effect of GCase deficiency on hematopoietic development. To address this question, we differentiated induced pluripotent stem cells (iPSCs) derived from patients with types 1, 2, and 3 GD to CD34(+)/CD45(+)/CD43(+)/CD143(+) hematopoietic progenitor cells (HPCs) and examined their developmental potential. The formation of GD-HPCs was unaffected. However, these progenitors demonstrated a skewed lineage commitment, with increased myeloid differentiation and decreased erythroid differentiation and maturation. Interestingly, myeloid colony-formation assays revealed that GD-HPCs, but not control-HPCs, gave rise to adherent, macrophage-like cells, another indication of abnormal myelopoiesis. The extent of these hematologic abnormalities correlated with the severity of the GCase mutations. All the phenotypic abnormalities of GD-HPCs observed were reversed by incubation with recombinant GCase, indicating that these developmental defects were caused by the mutated GCase. Our results show that GCase deficiency directly impairs hematopoietic development. Additionally, our results suggest that aberrant myelopoiesis might contribute to the pathological properties of Gaucher macrophages, which are central to GD manifestations. The hematopoietic developmental defects we observed reflect hematologic abnormalities in patients with GD, demonstrating the utility of GD-iPSCs for modeling this disease. PMID- 26062981 TI - Efficient Gene Editing in Pluripotent Stem Cells by Bacterial Injection of Transcription Activator-Like Effector Nuclease Proteins. AB - The type III secretion system (T3SS) of Pseudomonas aeruginosa is a powerful tool for direct protein delivery into mammalian cells and has successfully been used to deliver various exogenous proteins into mammalian cells. In the present study, transcription activator-like effector nuclease (TALEN) proteins have been efficiently delivered using the P. aeruginosa T3SS into mouse embryonic stem cells (mESCs), human ESCs (hESCs), and human induced pluripotent stem cells (hiPSCs) for genome editing. This bacterial delivery system offers an alternative method of TALEN delivery that is highly efficient in cleavage of the chromosomal target and presumably safer by avoiding plasmid DNA introduction. We combined the method of bacterial T3SS-mediated TALEN protein injection and transfection of an oligonucleotide template to effectively generate precise genetic modifications in the stem cells. Initially, we efficiently edited a single-base in the gfp gene of a mESC line to silence green fluorescent protein (GFP) production. The resulting GFP-negative mESC was cloned from a single cell and subsequently mutated back to a GFP-positive mESC line. Using the same approach, the gfp gene was also effectively knocked out in hESCs. In addition, a defined single-base edition was effectively introduced into the X-chromosome-linked HPRT1 gene in hiPSCs, generating an in vitro model of Lesch-Nyhan syndrome. T3SS-mediated TALEN protein delivery provides a highly efficient alternative for introducing precise gene editing within pluripotent stem cells for the purpose of disease genotype phenotype relationship studies and cellular replacement therapies. PMID- 26062982 TI - Concise Review: Manufacturing of Pancreatic Endoderm Cells for Clinical Trials in Type 1 Diabetes. AB - The cellular component of ViaCyte's VC-01 combination product for type 1 diabetes, pancreatic endoderm cells (PEC-01) derived from CyT49 human embryonic stem cells, matures after transplantation and functions to regulate blood glucose in rodent models. The aims in manufacturing PEC-01 at scale are to generate a consistent and robust transplantable population that functions reliably and safely in vivo. ViaCyte has integrated multiple bioprocessing strategies to enable a tightly controlled PEC-01 manufacturing process for clinical entry. PMID- 26062983 TI - Lysine-specific demethylase 1 promotes the stemness and chemoresistance of Lgr5+ liver cancer initiating cells by suppressing negative regulators of beta-catenin signaling. PMID- 26062984 TI - Alternation of aromatic-nonaromatic rings in belt-like structures. The behavior of [6.8](3)cyclacene in magnetic fields. AB - [6.8]3Cyclacene is an interesting belt-like structure displaying aromatic-non aromatic alternation, which is useful to gain an understanding of the intramolecular and intermolecular interactions between the anisotropic cones in the magnetic behavior of such rings. From the analysis of certain components in an induced magnetic field and (13)C-NMR shielding under its own principal axis system (PAS), the individual and overall magnetic behavior of each respective aromatic and non-aromatic fragments can be clearly described. Interestingly, the magnetic response of [6.8]3cyclacene suggests a characteristic behavior given by its confinement into a belt-like structure. PMID- 26062985 TI - Selective etching of focused gallium ion beam implanted regions from silicon as a nanofabrication method. AB - A focused ion beam (FIB) is otherwise an efficient tool for nanofabrication of silicon structures but it suffers from the poor thermal stability of the milled surfaces caused by segregation of implanted gallium leading to severe surface roughening upon already slight annealing. In this paper we show that selective etching with KOH:H2O2 solutions removes the surface layer with high gallium concentration while blocking etching of the surrounding silicon and silicon below the implanted region. This remedies many of the issues associated with gallium FIB nanofabrication of silicon. After the gallium removal sub-nm surface roughness is retained even during annealing. As the etching step is self-limited to a depth of 25-30 nm for 30 keV ions, it is well suited for defining nanoscale features. In what is essentially a reversal of gallium resistless lithography, local implanted areas can be prepared and then subsequently etched away. Nanopore arrays and sub-100 nm trenches can be prepared this way. When protective oxide masks such as Al2O3 grown with atomic layer deposition are used together with FIB milling and KOH:H2O2 etching, ion-induced amorphization can be confined to sidewalls of milled trenches. PMID- 26062986 TI - Modes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): actions at serotonin receptors may enhance downstream release of four pro-cognitive neurotransmitters. AB - Vortioxetine is an antidepressant with multiple pharmacologic modes of action that enhance release of dopamine, norepinephrine, acetylcholine, and histamine. PMID- 26062988 TI - Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression. AB - AIMS: Activated mast cells have been identified in the intima and perivascular tissue of human atherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruitment during atherosclerotic plaque progression. METHODS AND RESULTS: Systemic IgE-mediated mast cell activation in apoE(-/-)MUMT mice resulted in an increase in atherosclerotic lesion size as compared to control mice, and interestingly, the number of neutrophils was highly increased in these lesions. In addition, peritoneal mast cell activation led to a massive neutrophil influx into the peritoneal cavity in C57Bl6 mice, whereas neutrophil numbers in mast cell deficient Kit(W(-sh)/W(-sh)) mice were not affected. Within the newly recruited neutrophil population, increased levels of CXCR2(+) and CXCR4(+) neutrophils were observed after mast cell activation. Indeed, mast cells were seen to contain and release CXCL1 and CXCL12, the ligands for CXCR2 and CXCR4. Intriguingly, peritoneal mast cell activation in combination with anti-CXCR2 receptor antagonist resulted in decreased neutrophil recruitment, thus establishing a prominent role for the CXCL1/CXCR2 axis in mast cell-mediated neutrophil recruitment. CONCLUSIONS: Our data suggest that chemokines, and in particular CXCL1, released from activated mast cells induce neutrophil recruitment to the site of inflammation, thereby aggravating the ongoing inflammatory response and thus affecting plaque progression and destabilization. PMID- 26062987 TI - T-cell mediated anti-tumor immunity after photodynamic therapy: why does it not always work and how can we improve it? AB - Photodynamic therapy (PDT) uses the combination of non-toxic photosensitizers and harmless light to generate reactive oxygen species that destroy tumors by a combination of direct tumor cell killing, vascular shutdown, and activation of the immune system. It has been shown in some animal models that mice that have been cured of cancer by PDT, may exhibit resistance to rechallenge. The cured mice can also possess tumor specific T-cells that recognize defined tumor antigens, destroy tumor cells in vitro, and can be adoptively transferred to protect naive mice from cancer. However, these beneficial outcomes are the exception rather than the rule. The reasons for this lack of consistency lie in the ability of many tumors to suppress the host immune system and to actively evade immune attack. The presence of an appropriate tumor rejection antigen in the particular tumor cell line is a requisite for T-cell mediated immunity. Regulatory T-cells (CD25+, Foxp3+) are potent inhibitors of anti-tumor immunity, and their removal by low dose cyclophosphamide can potentiate the PDT-induced immune response. Treatments that stimulate dendritic cells (DC) such as CpG oligonucleotide can overcome tumor-induced DC dysfunction and improve PDT outcome. Epigenetic reversal agents can increase tumor expression of MHC class I and also simultaneously increase expression of tumor antigens. A few clinical reports have shown that anti-tumor immunity can be generated by PDT in patients, and it is hoped that these combination approaches may increase tumor cures in patients. PMID- 26062989 TI - Angiopoietin-2 blocking antibodies reduce early atherosclerotic plaque development in mice. AB - OBJECTIVE: Angiopoietin-2 (Ang-2) blocking agents are currently undergoing clinical trials for use in cancer treatment. Ang-2 has also been associated with rupture-prone atherosclerotic plaques in humans, suggesting a role for Ang-2 in plaque stability. Despite the availability of Ang-2 blocking agents, their clinical use is still lacking. Our aim was to establish if Ang-2 has a role in atheroma development and in the transition of subclinical to clinically relevant atherosclerosis. We investigated the effect of antibody-mediated Ang-2 blockage on atherogenesis after in a mouse model of atherosclerosis. METHODS: Hypercholesterolemic (low-density lipoprotein receptor(-/-) apolipoprotein B(100/100)) mice were subjected to high-cholesterol diet for eight weeks, one group with and one group without Ang-2 blocking antibody treatment during weeks 4 8.To enhance plaque development, a peri-adventitial collar was placed around the carotid arteries at the start of antibody treatment. Aortic root, carotid arteries and brachiocephalic arteries were analyzed to evaluate the effect of Ang 2 blockage on atherosclerotic plaque size and stable plaque characteristics. RESULTS: Anti-Ang-2 treatment reduced the size of fatty streaks in the brachiocephalic artery (-72%, p < 0.05). In addition, antibody-mediated Ang-2 blockage reduced plasma triglycerides (-27%, p < 0.05). In contrast, Ang-2 blockage did not have any effect on the size or composition (collagen content, macrophage percentage, adventitial microvessel density) of pre-existing plaques in the aortic root or collar-induced plaques in the carotid artery. CONCLUSIONS: Ang-2 blockage was beneficial as it decreased fatty streak formation and plasma triglyceride levels, but had no adverse effect on pre-existing atherosclerosis in hypercholesterolemic mice. PMID- 26062990 TI - Egg consumption and coronary artery calcification in asymptomatic men and women. AB - OBJECTIVE: The association of egg consumption with subclinical coronary atherosclerosis remains unknown. Our aim was to examine the association between egg consumption and prevalence of coronary artery calcium (CAC). METHODS: Cross sectional study of 23,417 asymptomatic adult men and women without a history of cardiovascular disease (CVD) or hypercholesterolemia, who underwent a health screening examination including cardiac computed tomography for CAC scoring and completed a validated food frequency questionnaire at the Kangbuk Samsung Hospital Total Healthcare Centers, South Korea (March 2011-April 2013). RESULTS: The prevalence of detectable CAC (CAC score > 0) was 11.2%. In multivariable adjusted models, CAC score ratio (95% confidence interval [CI]) comparing participants eating >= 7 eggs/wk to those eating < 1 egg/wk was 1.80 (1.14-2.83; P for trend = 0.003). The multivariable CAC score ratio (95% CI) associated with an increase in consumption of 1 egg/day was 1.54 (1.11-2.14). The positive association seemed to be more pronounced among participants with low vegetable intake (P for interaction = 0.02) and those with high BMI (P for interaction = 0.05). The association was attenuated and no longer significant after further adjustment for dietary cholesterol. CONCLUSION: Egg consumption was associated with an increased prevalence of subclinical coronary atherosclerosis and with a greater degree of coronary calcification in asymptomatic Korean adults, which may be mediated by dietary cholesterol. The association was particularly pronounced among individuals with low vegetable intake and those with high BMI. PMID- 26062991 TI - Txnip ablation reduces vascular smooth muscle cell inflammation and ameliorates atherosclerosis in apolipoprotein E knockout mice. AB - OBJECTIVE: Inflammation of vascular smooth muscle cells (VSMC) is intimately linked to atherosclerosis and other vascular inflammatory disease. Thioredoxin interacting protein (Txnip) is a key regulator of cellular sulfhydryl redox and a mediator of inflammasome activation. The goals of the present study were to examine the impact of Txnip ablation on inflammatory response to oxidative stress in VSMC and to determine the effect of Txnip ablation on atherosclerosis in vivo. METHODS AND RESULTS: Using cultured VSMC, we showed that ablation of Txnip reduced cellular oxidative stress and increased protection from oxidative stress when challenged with oxidized phospholipids and hydrogen peroxide. Correspondingly, expression of inflammatory markers and adhesion molecules were diminished in both VSMC and macrophages from Txnip knockout mice. The blunted inflammatory response was associated with a decrease in NF-KB nuclear translocation. Loss of Txnip in VSMC also led to a dramatic reduction in macrophage adhesion to VSMC. In vivo data from Txnip-ApoE double knockout mice showed that Txnip ablation led to 49% reduction in atherosclerotic lesion in the aortic root and 71% reduction in the abdominal aorta, compared to control ApoE knockout mice. CONCLUSION: Our data show that Txnip plays an important role in oxidative inflammatory response and atherosclerotic lesion development in mice. The atheroprotective effect of Txnip ablation implicates that modulation of Txnip expression may serve as a potential target for intervention of atherosclerosis and inflammatory vascular disease. PMID- 26062992 TI - Risk factors for maternal death and trends in maternal mortality in low- and middle-income countries: a prospective longitudinal cohort analysis. AB - BACKGROUND: Because large, prospective, population-based data sets describing maternal outcomes are typically not available in low- and middle-income countries, it is difficult to monitor maternal mortality rates over time and to identify factors associated with maternal mortality. Early identification of risk factors is essential to develop comprehensive intervention strategies preventing pregnancy-related complications. Our objective was to describe maternal mortality rates in a large, multi-country dataset and to determine maternal, pregnancy related, delivery and postpartum characteristics that are associated with maternal mortality. METHODS: We collected data describing all pregnancies from 2010 to 2013 among women enrolled in the multi-national Global Network for Women's and Children's Health Research Maternal and Neonatal Health Registry (MNHR). We reported the proportion of mothers who died per pregnancy and the maternal mortality ratio (MMR). Generalized linear models were used to evaluate the relationship of potential medical and social factors and maternal mortality and to develop point and interval estimates of relative risk associated with these factors. Generalized estimating equations were used to account for the correlation of outcomes within cluster to develop appropriate confidence intervals. RESULTS: We recorded 277,736 pregnancies and 402 maternal deaths for an MMR of 153/100,000 live births. We observed an improvement in the total MMR from 166 in 2010 to 126 in 2013. The MMR in Latin American sites (91) was lower than the MMR in Asian (178) and African sites (125). When adjusted for study site and the other variables, no formal education (RR 3.2 [1.5, 6.9]), primary education only (RR 3.4 [1.6, 7.5]), secondary education only (RR 2.5 [1.1, 5.7]), lack of antenatal care (RR 1.8 [1.2, 2.5]), caesarean section delivery (RR 1.9 [1.3, 2.8]), hemorrhage (RR 3.3 [2.2, 5.1]), and hypertensive disorders (RR 7.4 [5.2, 10.4]) were associated with higher risks of death. CONCLUSIONS: The MNHR identified preventable causes of maternal mortality in diverse settings in low- and middle-income countries. The MNHR can be used to monitor public health strategies and determine their association with reducing maternal mortality. TRIAL REGISTRATION: clinicaltrials.gov NCT01073475. PMID- 26062993 TI - A host-microbiome interaction mediates the opposing effects of omega-6 and omega 3 fatty acids on metabolic endotoxemia. AB - Metabolic endotoxemia, commonly derived from gut dysbiosis, is a primary cause of chronic low grade inflammation that underlies many chronic diseases. Here we show that mice fed a diet high in omega-6 fatty acids exhibit higher levels of metabolic endotoxemia and systemic low-grade inflammation, while transgenic conversion of tissue omega-6 to omega-3 fatty acids dramatically reduces endotoxemic and inflammatory status. These opposing effects of tissue omega-6 and omega-3 fatty acids can be eliminated by antibiotic treatment and animal co housing, suggesting the involvement of the gut microbiota. Analysis of gut microbiota and fecal transfer revealed that elevated tissue omega-3 fatty acids enhance intestinal production and secretion of intestinal alkaline phosphatase (IAP), which induces changes in the gut bacteria composition resulting in decreased lipopolysaccharide production and gut permeability, and ultimately, reduced metabolic endotoxemia and inflammation. Our findings uncover an interaction between host tissue fatty acid composition and gut microbiota as a novel mechanism for the anti-inflammatory effect of omega-3 fatty acids. Given the excess of omega-6 and deficiency of omega-3 in the modern Western diet, the differential effects of tissue omega-6 and omega-3 fatty acids on gut microbiota and metabolic endotoxemia provide insight into the etiology and management of today's health epidemics. PMID- 26062994 TI - Fostering diffusion of scientific contents of National Society Cardiovascular Journals: The new ESC search engine. AB - European Society of Cardiology (ESC) National Society Cardiovascular Journals (NSCJs) are high-quality biomedical journals focused on cardiovascular diseases. The Editors' Network of the ESC devises editorial initiatives aimed at improving the scientific quality and diffusion of NSCJ. In this article we will discuss on the importance of the Internet, electronic editions and open access strategies on scientific publishing. Finally, we will propose a new editorial initiative based on a novel electronic tool on the ESC web-page that may further help to increase the dissemination of contents and visibility of NSCJs. PMID- 26062995 TI - Polyfunctional, Pathogenic CD161+ Th17 Lineage Cells Are Resistant to Regulatory T Cell-Mediated Suppression in the Context of Autoimmunity. AB - In autoimmune diseases such as rheumatoid arthritis (RA), regulatory T cells (Tregs) fail to constrain autoimmune inflammation; however, the reasons for this are unclear. We investigated T cell regulation in the RA joint. Tregs from RA synovial fluid suppressed autologous responder T cells; however, when compared with Tregs from healthy control peripheral blood, they were significantly less suppressive. Despite their reduced suppressive activity, Tregs in the RA joint were highly proliferative and expressed FOXP3, CD39, and CTLA-4, which are markers of functional Tregs. This suggested that the reduced suppression is due to resistance of RA synovial fluid responder T cells to Treg inhibition. CD161(+) Th17 lineage cells were significantly enriched in the RA joint; we therefore investigated their relative susceptibility to Treg-mediated suppression. Peripheral blood CD161(+) Th cells from healthy controls were significantly more resistant to Treg-mediated suppression, when compared with CD161(-) Th cells, and this was mediated through a STAT3-dependant mechanism. Furthermore, depletion of CD161(+) Th cells from the responder T cell population in RA synovial fluid restored Treg-mediated suppression. In addition, CD161(+) Th cells exhibited pathogenic features, including polyfunctional proinflammatory cytokine production, an ability to activate synovial fibroblasts, and to survive and persist in the inflamed and hypoxic joint. Because CD161(+) Th cells are known to be enriched at sites of autoinflammation, our finding that they are highly proinflammatory and resistant to Treg-mediated suppression suggests an important pathogenic role in RA and other autoimmune diseases. PMID- 26062996 TI - Nonclassical MHC-Restricted Invariant Valpha6 T Cells Are Critical for Efficient Early Innate Antiviral Immunity in the Amphibian Xenopus laevis. AB - Nonclassical MHC class Ib-restricted invariant T (iT) cell subsets are attracting interest because of their potential to regulate immune responses against various pathogens. The biological relevance and evolutionary conservation of iT cells have recently been strengthened by the identification of iT cells (invariant Valpha6 [iValpha6]) restricted by the nonclassical MHC class Ib molecule XNC10 in the amphibian Xenopus laevis. These iValpha6 T cells are functionally similar to mammalian CD1d-restricted invariant NKT cells. Using the amphibian pathogen frog virus 3 (FV3) in combination with XNC10 tetramers and RNA interference loss of function by transgenesis, we show that XNC10-restricted iValpha6 T cells are critical for early antiviral immunity in adult X. laevis. Within hours following i.p. FV3 infection, iValpha6 T cells were specifically recruited from the spleen into the peritoneum. XNC10 deficiency and concomitant lack of iValpha6 T cells resulted in less effective antiviral and macrophage antimicrobial responses, which led to impaired viral clearance, increased viral dissemination, and more pronounced FV3-induced kidney damage. Together, these findings imply that X. laevis XNC10-restricted iValpha6 T cells play important roles in the early anti FV3 response and that, as has been suggested for mammalian invariant NKT cells, they may serve as immune regulators polarizing macrophage effector functions toward more effective antiviral states. PMID- 26062997 TI - Evaluating the Role of HLA-DM in MHC Class II-Peptide Association Reactions. AB - Ag presentation by MHC class II (MHC II) molecules to CD4(+) T cells plays a key role in the regulation of the adaptive immune response. Loading of antigenic peptides onto MHC II is catalyzed by HLA-DM (DM), a nonclassical MHC II molecule. The mechanism of DM-facilitated peptide loading is an outstanding problem in the field of Ag presentation. In this study, we systemically explored possible kinetic mechanisms for DM-catalyzed peptide association by measuring real-time peptide association kinetics using fluorescence polarization assays and comparing the experimental data with numerically modeled peptide association reactions. We found that DM does not facilitate peptide association by stabilizing peptide-free MHC II against aggregation. Moreover, DM does not promote transition of an inactive peptide-averse conformation of MHC II to an active peptide-receptive conformation. Instead, DM forms an intermediate with MHC II that binds peptide with faster kinetics than MHC II in the absence of DM. In the absence of peptides, interaction of MHC II with DM leads to inactivation and formation of a peptide-averse form. This study provides novel insights into how DM efficiently catalyzes peptide loading during Ag presentation. PMID- 26062998 TI - Eos Is Redundant for Regulatory T Cell Function but Plays an Important Role in IL 2 and Th17 Production by CD4+ Conventional T Cells. AB - Eos belongs to the Ikaros family of transcription factors. It was reported to be a regulatory T cell (Treg) signature gene, to play a critical role in Treg suppressor functions, and to maintain Treg stability. We used mice with a global deficiency in Eos to re-examine the role of Eos expression in both Tregs and conventional T cells (Tconvs). Tregs from Eos-deficient (Eos(-/-)) mice developed normally, displayed a normal Treg phenotype, and exhibited normal suppressor function in vitro. Eos(-/-) Tregs were as effective as Tregs from wild-type (WT) mice in suppressing inflammation in a model of inflammatory bowel disease. Bone marrow (BM) from Eos(-/-) mice was as effective as that from WT mice in controlling T cell activation when used to reconstitute immunodeficient mice in the presence of scurfy fetal liver cells. Surprisingly, Eos was expressed in activated Tconvs and was required for IL-2 production, CD25 expression, and proliferation in vitro by CD4(+) Tconvs. Eos(-/-) mice developed more severe experimental autoimmune encephalomyelitis than WT mice, displayed increased numbers of effector T cells in the periphery and CNS, and amplified IL-17 production. In conclusion, our studies are not consistent with a role for Eos in Treg development and function but demonstrate that Eos plays an important role in the activation and differentiation of Tconvs. PMID- 26062999 TI - Cutting Edge: Dual Function of PPARgamma in CD11c+ Cells Ensures Immune Tolerance in the Airways. AB - The respiratory tract maintains immune homeostasis despite constant provocation by environmental Ags. Failure to induce tolerogenic responses to allergens incites allergic inflammation. Despite the understanding that APCs have a crucial role in maintaining immune tolerance, the underlying mechanisms are poorly understood. Using mice with a conditional deletion of peroxisome proliferator activated receptor gamma (PPARgamma) in CD11c(+) cells, we show that PPARgamma performs two critical functions in CD11c(+) cells to induce tolerance, thereby preserving immune homeostasis. First, PPARgamma was crucial for the induction of retinaldehyde dehydrogenase (aldh1a2) selectively in CD103(+) dendritic cells, which we recently showed promotes Foxp3 expression in naive CD4(+) T cells. Second, in all CD11c(+) cells, PPARgamma was required to suppress expression of the Th17-skewing cytokines IL-6 and IL-23p19. Also, lack of PPARgamma in CD11c(+) cells induced p38 MAPK activity, which was recently linked to Th17 development. Thus, PPARgamma favors immune tolerance by promoting regulatory T cell generation and blocking Th17 differentiation. PMID- 26063001 TI - Diagnostic colposcopic accuracy by the gynocular and a stationary colposcope. AB - OBJECTIVES: The aim of this study was to evaluate the diagnostic accuracy of sensitivity and specificity of cervical lesions by the low-cost, portable Gynocular colposcope and a stationary colposcope, in women referred for colposcopy with abnormal cervical cytology. METHODS: A randomized cross-over clinical trial for evaluating the diagnostic accuracy in detecting cervical lesions by the Gynocular and a stationary colposcope. The Swede score systematic colposcopy system was used for evaluation of colposcopic abnormalities. Directed punch biopsy and excisional cone biopsy were used as the "gold-standard" by histologically confirmed high grade cervical lesions CIN2+ (CIN2, CIN3, CIN3+). In total, 123 women referred for colposcopy due to abnormal cervical cytology were recruited at the Department of Obstetrics and Gynecology, Danderyd Hospital, Stockholm, Sweden. The percentage agreement and the kappa statistic were calculated for Swede score by the Gynocular and a stationary colposcope. Swede scores were compared with the results from directed punch biopsy and excisional cone biopsy. RESULTS: The Gynocular and the stationary colposcope had a high agreement of Swede scores with a Kappa statistic of 0.947, p < .0001. Punch biopsy diagnosed CIN2+ (CIN2, CIN3, and invasive cancer) in 44 (35.7 percent) women while cytology detected CIN2+ in 34 (27.6 percent) women. There were no significant differences of the sensitivity and specificity for different Swede scores by the Gynocular or a stationary colposcope in detecting CIN 2+. CONCLUSIONS: There were no significant differences in sensitivity or specificity in detecting cervical lesions by the Gynocular or stationary colposcope. The Gynocular is as accurate in diagnosing cervical lesions as a stationary colposcope. PMID- 26063002 TI - Use of a Hand Sanitizing Wipe for Reducing Risk of Viral Illness in the Home. AB - This study determined whether a hand sanitizing wipe can reduce virus transmission in households, and could reduce the probability of infection by rhinovirus and rotavirus. Bacteriophage MS-2 (a marker virus) was used to assess viral transmission in five households having at least two children of ages 2-18. Hands of one female adult were inoculated with ~10(8) PFU MS-2 bacteriophages in each home, and after 8 h, hands of all family members and select fomites were sampled to determine baseline contamination without intervention. This sequence was repeated with the intervention, where all family members were instructed to use a quaternary ammonium compound-based sanitizing wipe at least once per day. A significant reduction of virus after the intervention occurred on inoculated hands (95.3%; p = 0.0039), all fomites combined (74.5%; p < 0.005), and non inoculated hands and fomites combined (73.5%; p < 0.005). However, viral reduction on non-inoculated hands was not significant, likely due to small sample size. Using rhinovirus and rotavirus as models it was estimated that infection risk was reduced by ~30 to 89% with the use of sanitizing wipes once per day depending on the starting concentration of these viruses on hands of susceptible individuals. Therefore, using a hand sanitizing wipe can significantly reduce viral transmission and risk of illness in homes. Previous studies have shown other hand hygiene interventions, such as alcohol-based hand sanitizers, are even more effective for reducing risk of illness in homes; however the sanitizing wipe used in this study is appropriate to use for microbial reduction. PMID- 26063000 TI - Functional Heterogeneity and Antimycobacterial Effects of Mouse Mucosal Associated Invariant T Cells Specific for Riboflavin Metabolites. AB - Mucosal-associated invariant T (MAIT) cells have a semi-invariant TCR Valpha chain, and their optimal development is dependent upon commensal flora and expression of the nonpolymorphic MHC class I-like molecule MR1. MAIT cells are activated in an MR1-restricted manner by diverse strains of bacteria and yeast, suggesting a widely shared Ag. Recently, human and mouse MR1 were found to bind bacterial riboflavin metabolites (ribityllumazine [RL] Ags) capable of activating MAIT cells. In this study, we used MR1/RL tetramers to study MR1 dependency, subset heterogeneity, and protective effector functions important for tuberculosis immunity. Although tetramer(+) cells were detected in both MR1(+/+) and MR1(-/-) TCR Valpha19i-transgenic (Tg) mice, MR1 expression resulted in significantly increased tetramer(+) cells coexpressing TCR Vbeta6/8, NK1.1, CD44, and CD69 that displayed more robust in vitro responses to IL-12 plus IL-18 and RL Ag, indicating that MR1 is necessary for the optimal development of the classic murine MAIT cell memory/effector subset. In addition, tetramer(+) MAIT cells expressing CD4, CD8, or neither developing in MR1(+/+) Valpha19i-Tg mice had disparate cytokine profiles in response to RL Ag. Therefore, murine MAIT cells are considerably more heterogeneous than previously thought. Most notably, after mycobacterial pulmonary infection, heterogeneous subsets of tetramer(+) Valpha19i Tg MAIT cells expressing CXCR3 and alpha4beta1 were recruited into the lungs and afforded early protection. In addition, Valpha19iCalpha(-/-)MR(+/+) mice were significantly better protected than were Valpha19iCalpha(-/-)MR1(-/-), wild-type, and MR1(-/-) non-Tg mice. Overall, we demonstrate considerable functional diversity of MAIT cell responses, as well as that MR1-restricted MAIT cells are important for tuberculosis protective immunity. PMID- 26063003 TI - Hemispheric Differences in Leukoaraiosis in Patients with Carotid Artery Stenosis: A Systematic Review. AB - PURPOSE: Despite the prevalence of leukoaraiosis in neuroimaging and its link to dementia, stroke, and death, the exact pathogenesis is still unclear. While some have postulated a link between carotid artery disease and leukoaraiosis, the exact relationship between the two common clinical findings is unknown. To determine the link between carotid disease and leukoaraiosis, we performed a systematic review of interhemispheric differences in white matter disease in patients with carotid artery disease. METHODS: We performed a comprehensive literature search in multiple electronic databases evaluating the association of carotid artery and white matter disease using both subjective and volumetric assessment of white matter burden. The included studies examined patients with at least 30 % carotid artery stenosis for white matter burden both ipsilateral and contralateral to the site of carotid artery disease. RESULTS: Of the 2920 manuscripts screened, five were included in the systematic review. One study used a volumetric analysis of the white matter burden and the others used various subjective methods. Four studies found no statistically significant relationship between carotid artery disease and ipsilateral white matter burden and one study found a significantly higher amount of white matter disease ipsilateral to carotid artery stenosis. CONCLUSIONS: The mixed results in degree of hemispheric leukoaraiosis in patients with carotid artery disease indicate that no definite relationship can be established based on the existing literature. Given the complex nature of carotid artery disease, including increased risk with certain plaque components, the exact relationship requires further investigation with more rigorous research design. PMID- 26063006 TI - Purity Determination of Acetaldehyde in an Acetaldehyde Certified Reference Material. AB - Acetaldehyde is regulated as a toxic substance in various fields, and the method for monitoring or analysis of acetaldehyde is important. However, handling is difficult because of the high reactivity and low boiling point of acetaldehyde. Therefore, a reference material for high purity acetaldehyde with high accuracy was not available. Although the measuring method of acetaldehyde as a reagent is published in the Japanese Industrial Standard (JIS) where the specification of acetaldehyde purity is more than 80%, the analytical method described in JIS is not enough for an accuracy purity determination method. In this research, the high precision purity determination method for development of a certified reference material (CRM) of acetaldehyde was examined. By controlling the volatility and reactivity of acetaldehyde, we established the purity determination method of acetaldehyde with a relative standard uncertainty of less than 0.3%. Furthermore, this method was applied to develop a high purity acetaldehyde CRM with an expanded uncertainty of 0.005 kg kg(-1) (k = 2). PMID- 26063004 TI - MRI of the Fetal Brain. AB - The purpose of this article is to provide an overview of the possibilities for fetal magnetic resonance imaging (MRI) in the evaluation of the fetal brain. For brain pathologies, fetal MRI is usually performed when an abnormality is detected by previous prenatal ultrasound, and is, therefore, an important adjunct to ultrasound. The most commonly suspected brain pathologies referred to fetal MRI for further evaluation are ventriculomegaly, missing corpus callosum, and abnormalities of the posterior fossa. We will briefly discuss the most common indications for fetal brain MRI, as well as recent advances. PMID- 26063007 TI - A G-quadruplex-based Label-free Fluorometric Aptasensor for Adenosine Triphosphate Detection. AB - A G-quadruplex-based, label-free fluorescence assay was demonstrated for the detection of adenosine triphosphate (ATP). A double-stranded DNA (dsDNA), hybridized by ATP-aptamer and its complementary sequence, was employed as a substrate for ATP binding. SYBR Green I (SG I) was a fluorescent probe and exonuclease III (Exo III) was a nuclease to digest the dsDNA. Consequently, in the absence of ATP, the dsDNA was inset with SG I and was digested by Exo III, resulting in a low background signal. In the presence of ATP, the aptamer in dsDNA folded into a G-quadruplex structure that resisted the digestion of Exo III. SG I was inserted into the structure, showing high fluorescence. Owing to a decrease of the background noise, a high signal-to-noise ratio could be obtained. This sensor can detect ATP with a concentration ranging from 50 MUM to 5 mM, and possesses a capacity for the sensitive determination of other targets. PMID- 26063008 TI - Sensitive and Specific Neutrophil Gelatinase-associated Lipocalin Detection by Solid-phase Proximity Ligation Assay. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is a candidate diagnostic biomarker for acute kidney injury (AKI). Since there is no specific treatment to reverse AKI, a good biomarker such as NGAL can increase the performance of clinical care. Therefore, a timely, specific and sensitive assay for detecting NGAL is critical for clinical determination. In this study, we established a solid-phase proximity ligation assay for the detection of NGAL using polyclonal antibodies conjugated with a pair of oligonucleotides. The data are read out as the Ct value via quantitative real-time polymerase chain reaction (qPCR). Our results demonstrate that this new assay performs with good specificity and sensitivity for detection of NGAL spiked in buffer or serum, which indicates that the solid-phase proximity ligation technique is a promising tool for diagnostics in clinical decisions. PMID- 26063009 TI - Photoluminescent Detection of Nitrite with Carbon Nanodots Prepared by Microwave assisted Synthesis. AB - A photoluminescent detection method for nitrite with high selectivity and sensitivity using carbon nanodots (CNDs) is demonstrated. The selectivity of nitrite is accomplished by a highly specific diazotization reaction between nitrite and p-phenylenediamine (p-PDA). In the presence of nitrite, p-PDA easily reacts to form the diazonium cation in the acidic aqueous solution. By alkalization of the reaction mixture, diazonium cation of p-PDA was converted to an aryl radical to form aggregated CNDs, which causes the change in the photoluminescent intensity of CNDs. In the present method, nitrite can be selectively detected down to 1 MUM over several anions, such as nitrate, perchlorate, sulfate, fluoride, chloride, and bromide at mM levels. PMID- 26063010 TI - Fluorescence Enhancement of Nanoraspberry Hot-spot Source Composed of Gold Nanoparticles and Aniline Oligomers. AB - In this study, we examined raspberry-shaped organic/inorganic hybrid structure for potential development of a nanoantenna system capable of detecting and labeling biomolecules. The structure is characterized by a high density of gold nanoparticles (AuNPs) separated by closely packed aniline oligomers that serve as a linkage between adjacent particles. In particular, the structure was based on repeated sequences of AuNP-aniline oligomer-AuNP in a three-dimensional arrangement, which enabled the creation of optical hot spots that can hold multiple molecules. We examine the expression of such features by focusing on the structure and characteristics of the hybrid. We demonstrate that these optical hot spots enhance the dye fluorescence without quenching. As a result, we were able to create a nanoantenna structure enabling the efficient use of light. PMID- 26063011 TI - Thermal-induced Immuno-nephelometry Using Gold Nanoparticles Conjugated with a Thermoresponsive Polymer for the Detection of Avidin. AB - Thermoresponsive immunonephelometry was achieved with biotinylated poly(acrylate) and thermoresponsive gold nanocomposites composed of 13-nm gold nanoparticles and thermoresponsive polymers containing triethylenetetramine and biotin groups. The avidin-biotin interaction was used to model an immunoreaction in order to demonstrate thermoresponsive immunonephelometry. In the absence of avidin, positively charged gold nanocomposites electrostatically interacted with biotinylated poly(acrylate) to form binary complexes, in which the charges canceled each other out. The charge cancelation resulted in the binary complexes precipitating when the solution was heated above the phase-transition temperature. However, adding avidin formed ternary sandwich complexes through the avidin-biotin interaction. The ternary complexes remained sufficiently soluble above the phase-transition temperature because of the spatial isolation of the positive and negative charges. The transmittance of the solution containing the thermoresponsive gold nanocomposites and biotinylated poly(acrylate) at 37 degrees C increased as the avidin concentration increased. A sigmoidal profile was observed from 10(-6.5) to 10(-5.5) mol/L. The concentration of avidin spiked in bovine serum was determined by our method. PMID- 26063012 TI - Deviation from Normal Boltzmann Distribution of High-lying Energy Levels of Iron Atom Excited by Okamoto-cavity Microwave-induced Plasmas Using Pure Nitrogen and Nitrogen-Oxygen Gases. AB - This paper describes several interesting excitation phenomena occurring in a microwave-induced plasma (MIP) excited with Okamoto-cavity, especially when a small amount of oxygen was mixed with nitrogen matrix in the composition of the plasma gas. An ion-to-atom ratio of iron, which was estimated from the intensity ratio of ion to atomic lines having almost the same excitation energy, was reduced by adding oxygen gas to the nitrogen MIP, eventually contributing to an enhancement in the emission intensities of the atomic lines. Furthermore, Boltzmann plots for iron atomic lines were observed in a wide range of the excitation energy from 3.4 to 6.9 eV, indicating that plots of the atomic lines having lower excitation energies (3.4 to 4.8 eV) were well fitted on a straight line while those having more than 5.5 eV deviated upwards from the linear relationship. This overpopulation would result from any other excitation process in addition to the thermal excitation that principally determines the Boltzmann distribution. A Penning-type collision with excited species of nitrogen molecules probably explains this additional excitation mechanism, in which the resulting iron ions recombine with captured electrons, followed by cascade de-excitations between closely-spaced excited levels just below the ionization limit. As a result, these high-lying levels might be more populated than the low-lying levels of iron atom. The ionization of iron would be caused less actively in the nitrogen-oxygen plasma than in a pure nitrogen plasma, because excited species of nitrogen molecule, which can provide the ionization energy in a collision with iron atom, are consumed through collisions with oxygen molecules to cause their dissociation. It was also observed that the overpopulation occurred to a lesser extent when oxygen gas was added to the nitrogen plasma. The reason for this was also attributed to decreased number density of the excited nitrogen species due to collisions with oxygen molecule. PMID- 26063013 TI - MALDI MS-based Composition Analysis of the Polymerization Reaction of Toluene Diisocyanate (TDI) and Ethylene Glycol (EG). AB - This study describes an MS-based analysis method for monitoring changes in polymer composition during the polyaddition polymerization reaction of toluene diisocyanate (TDI) and ethylene glycol (EG). The polymerization was monitored as a function of reaction time using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS). The resulting series of polymer adducts terminated with various end-functional groups were precisely identified and the relative compositions of those series were estimated. A new MALDI MS data interpretation method was developed, consisting of a peak-resolving algorithm for overlapping peaks in MALDI MS spectra, a retrosynthetic analysis for the generation of reduced unit mass peaks, and a Gaussian fit-based selection of the most prominent polymer series among the reconstructed unit mass peaks. This method of data interpretation avoids errors originating from side reactions due to the presence of trace water in the reaction mixture or MALDI analysis. Quantitative changes in the relative compositions of the resulting polymer products were monitored as a function of reaction time. These results demonstrate that the mass data interpretation method described herein can be a powerful tool for estimating quantitative changes in the compositions of polymer products arising during a polymerization reaction. PMID- 26063014 TI - Reversed Phase Column HPLC-ICP-MS Conditions for Arsenic Speciation Analysis of Rice Flour. AB - New measurement conditions for arsenic speciation analysis of rice flour were developed using HPLC-ICP-MS equipped with a reversed phase ODS column. Eight arsenic species, namely, arsenite [As(III)], arsenate [As(V)], monomethylarsonic acid (MMAA), dimethylarsinic acid (DMAA), trimethylarsine oxide (TMAO), tetramethylarsonium (TeMA), arsenobetaine (AsB) and arsenocholine (AsC), were separated and determined under the proposed conditions. In particular, As(III) and MMAA and DMAA and AsB were completely separated using a newly proposed eluent containing ammonium dihydrogen phosphate. Importantly, the sensitivity changes, in particular those of As(V) and As(III) caused by coexisting elements and by complex matrix composition, which had been problematical in previously reported methods, were eliminated. The new eluent can be applied to C8, C18 and C30 ODS columns with the same effectiveness and with excellent repeatability. The proposed analytical method was successfully applied to extracts of rice flour certified reference materials. PMID- 26063015 TI - A Miniaturized Stepwise Injection Spectrophotometric Analyzer. AB - A novel micro-stepwise injection analyzer (MUSWIA) has been developed for the automation and miniaturization of spectrophotometric analysis. The main unit of this device is a mixing chamber (MC) connected to the atmosphere. This part of the MUSWIA provides rapid and effective homogenization of the reaction mixture components and completion of the reaction by means of gas bubbling. The MUSWIA contained a rectangular labyrinth channel designed in way allowing one to eliminate bubbles by moving a solution from the MC to an optical channel. The light-emitting diode (LED) was used as a light emitter and the analytical signal was measured by a portable spectrophotometer. Fluid movement was attained via the use of a computer-controlled syringe pump. The MUSWIA was successfully used for the spectrophotometric determination of cysteine in biologically active supplements and fodder by using 18-molybdo-2-phosphate heteropoly anion (18-MPA) as the reagent. PMID- 26063016 TI - A Comprehensive Method for Quality Evaluation of Houttuyniae Herba by a Single Standard to Determine Multi-components, Fingerprint and HPTLC Method. AB - A method of quality evaluation by a single standard to determine multi-components (SSDMC), fingerprint and high-performance thin layer-chromatography (HPTLC) was developed for traditional Chinese medicine (TCM), and validated with dry Houttuyniae Herba (HH). In quantitative analysis, an SSDMC method involving nine components has been established with the desirable linearity (r(2) >= 0.9998), precision (RSD < 2.7%), accuracy (97.4 - 103.1%) and ruggedness. Compared with the results obtained using the external standard method (ESM), this alternative SSDMC method was found to have no statistically significant differences. In fingerprint analysis, nine of fourteen peaks were identified. Simultaneously, 15 HH samples from different origins were classified by similarity analysis and hierarchical clustering analysis (HCA). Additionally, the HPTLC method with three flavonoid markers was firstly established. The combination of SSDMC with the fingerprint and HPTLC method has been verified in the quality control of HH both quantitatively and qualitatively, and will provide a new quality evaluation pattern for TCMs. PMID- 26063017 TI - Novel Method for the Analysis of Ribonuclease Based on Fluorescence Recovery of a Cationic Aluminum Phthalocyanine-RNA Association Complex as a Red-emitting Fluorogenic Substrate. AB - The conventional spectrophotometric method that is often applied to determine ribonuclease (RNase) has disadvantages that include cumbersome manipulation, time consuming processing and a lack of linear range. We had found that a low concentration of RNA could induce cationic aluminum phthalocyanine (tetra(trimethylammonio)aluminum phthalocyanine (TTMAAlPc)), which emitted strong red fluorescence to aggregate in neutral media, resulting in an almost complete quenching of fluorescence from the cationic aluminum phthalocyanine. The RNA is degraded through hydrolysis by RNase, which destroys the induced aggregation of TTMAAlPc on RNA and releases free TTMAAlPc, leading to a significant fluorescence recovery of the reaction system. Based on this new finding, a method to detect RNase by enhanced fluorescence was established using the TTMAAlPc-RNA association complex as a new fluorogenic substrate of RNase. The optimal conditions were determined, and the interfering foreign substances were investigated. Under optimal conditions, the linear range was 0.05 - 50 MUg/L, and the detection limit was 0.02 MUg/L. This method was applied for the analysis of ribonuclease in urine specimens from normal adults, and the results were consistent with those determined by conventional spectrophotometric methods. The developed method is easy to operate and highly sensitive, and has a wide linear range, thus solving issues with conventional methods. This study applied, for the first time, cationic phthalocyanine as a fluorescent probe in the detection of nuclease, which provides new applications of phthalocyanine as a fluorescent probe emitting at the red wavelength region. PMID- 26063018 TI - Kinetic Spectrophotometric Determination of Trace Cadmium in Environmental Fresh Water with 5,10,15,20-Tetraphenyl-21H,23H-porphinetetrasulfonic Acid. AB - Cadmium-catalyzed complexation of zinc with 5,10,15,20-tetraphenyl-21H,23H porphinetetrasulfonic acid (TPPS) was monitored spectrophotometrically. A kinetic parameter for the determination was obtained under kinetic consideration. Absorbance of zinc-TPPS at a fixed reaction time was proportional to the concentration of cadmium at pH 8 and 25 degrees C. Tolerable concentration of interfering ions were 200, 200, 2000, 50, 500 and 1 MUg L(-1) for Mg(II), Al(III), Ca(II), Fe(III), Zn(II) and Hg(II), respectively, in the determination of 20 MUg L(-1) of cadmium, indicating Ca(II) and Mg(II) interferes with the analysis of natural fresh water. Such interference became tolerable at 5 mg L(-1) by the addition of an excess Ca(II) (50 mg L(-1)) in the reacting solution of sample and cadmium standards. A calibration curve of Cd(II) was linear up to 100 MUg L(-1) with a detection limit of 2 MUg L(-1). The reliability of the proposed method was confirmed by the recovery test of cadmium spiked into tap, river and reservoir water samples. PMID- 26063019 TI - External and Intraparticle Diffusion of Coumarin 102 with Surfactant in the ODS silica Gel/water System by Single Microparticle Injection and Confocal Fluorescence Microspectroscopy. AB - The release mechanism of coumarin 102 from a single ODS-silica gel microparticle into the water phase in the presence of Triton X-100 was investigated by confocal fluorescence microspectroscopy combined with the single microparticle injection technique. The release rate significantly depended on the Triton X-100 concentration in the water phase and was not limited by diffusion in the pores of the microparticle. The release rate constant was inversely proportional to the microparticle radius squared, indicating that the rate-determining step is the external diffusion between the microparticle and the water phase. PMID- 26063020 TI - Complementary Use of LC-ICP-MS and LC-ESI-Q-TOF-MS for Selenium Speciation. AB - We demonstrated the complementary use of inductively coupled plasma-mass spectrometry (ICP-MS) and electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-Q-TOF-MS) for the analysis of Se-containing compounds, such as selenate, selenomethionine (SeMet), and trimethylselenonium ion (TMSe), found in biological samples. The sensitivity of ESI-Q-TOF-MS for Se-containing compounds was strongly dependent on the chemical species. ICP-MS exhibited higher sensitivity than ESI-Q-TOF-MS, and had no species dependency. On the other hand, ESI-Q-TOF-MS enabled easy and robust identification of Se-containing compounds. PMID- 26063022 TI - Adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma. PMID- 26063023 TI - Adjuvant chemotherapy after liver transplantation for hepatocellular carcinoma: a systematic review and a meta-analysis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide and liver transplantation (LT) is considered as the best therapeutic option for patients with HCC combined with cirrhosis. However, tumor recurrence after LT for HCC remains the major obstacle for long-term survival. The present study was to evaluate the efficacy and necessity of adjuvant chemotherapy in patients with HCC who had undergone LT. DATA SOURCES: Several databases were searched to identify comparative studies fulfilling the predefined selection criteria before October 2014. Suitable studies were chosen and data extracted for meta-analysis. Three authors independently evaluated the bias of each study according to the Cochrane Handbook for Systematic Review of Intervention. Stata 12 was used for statistical analysis. Hazard ratio (HR) was considered as a summary statistic for overall survival, disease-free survival and recurrence rate. RESULTS: Three prospective studies and 5 retrospective studies including 360 patients (166 in the adjuvant chemotherapy group, and 194 in the control group) were included. Compared with the control group, post-LT adjuvant chemotherapy conferred significant benefit for overall survival (HR: 0.34; 95% CI: 0.22-0.52; P=0.000). Meanwhile, the results showed an improvement for disease free survival on favoring adjuvant chemotherapy (HR: 0.87; 95% CI: 0.78-0.95; P=0.004). However, no significant difference in HCC recurrence rate was observed between the two groups (HR: 1.26; 95% CI: 0.40-4.00; P=0.696). Descriptions of adverse events were of anecdotal nature and did not allow meta-analytic calculations. CONCLUSIONS: Adjuvant chemotherapy after LT for HCC can significantly prolong patient's survival and delay the recurrence of HCC. For advanced HCC with poor differentiation, patients may perhaps benefit from the early implantation of adjuvant chemotherapy after LT. PMID- 26063024 TI - Early markers of reperfusion injury after liver transplantation: association with primary dysfunction. AB - BACKGROUND: In patients with end-stage liver disease, liver transplantation is the only available curative treatment. Although the outcome and quality of life in the patients have improved over the past decades, primary dys- or nonfunction (PDF/PNF) can occur. Early detection of PDF and PNF is crucial and could lead to individual therapies. This study was designed to identify early markers of reperfusion injury and PDF in liver biopsies taken during the first hour after reperfusion. METHODS: Biopsies from donor livers were prospectively taken as a routine during the first hour after reperfusion. Recipient data, transaminases and outcome were routinely monitored. In total, 10 biopsy specimens taken from patients with 90-day mortality and PDF, and patients with long-term survival but without PDF were used for DNA microarrays. Markers that were significantly up- or down-regulated in the microarray were verified using quantitative real-time PCR. RESULTS: Age, indications and labMELD score were similar in both groups. Peak transaminases during the first week after transplantation were significantly different in the two groups. In total, 20 differentially regulated markers that correlated to PDF were identified using microarray analysis and verified with quantitative real-time PCR. CONCLUSIONS: The markers identified in this study could predict PDF at a very early time point and might point to interventions that ameliorate reperfusion injury and thus prevent PDF. Identification of patients and organs at risk might lead to individualized therapies and could ultimately improve outcome. PMID- 26063025 TI - Self-management and self-efficacy status in liver recipients. AB - BACKGROUND: Liver transplantation (LT) is a viable treatment for patients with end-stage chronic liver diseases. The main aim of LT is to prolong life and improve life quality. However, although survival after LT continues to improve, some aspects of recipient's health-related quality of life such as self management and self-efficacy have been largely ignored. METHODS: A total of 124 LT recipients were included in this study. Questionnaires for general health status information and a "Self-Management Questionnaire for Liver Transplantation Recipients" modified from the Chinese version of "Chronic Disease Self-Management Program Questionnaire Code Book" were used in the survey. Data were collected by self-administered questionnaires. RESULTS: The overall status of self-management in LT recipients was not optimistic. The major variables affecting the self management of LT recipients were marital status, educational level and employment. The overall status of self-efficacy in LT recipients was around the medium-level. Postoperative time and self-assessment of overall health status were found as the factors impacting on self-efficacy. CONCLUSIONS: The self management behavior of LT recipients needs to be improved. The health care professionals need to offer targeted health education to individual patients, help them to establish healthy lifestyle, enhance physical activity and improve self-efficacy. The development of the multilevel and multifaceted social support system will greatly facilitate the self-management in LT patients. PMID- 26063026 TI - Splenic artery trunk embolization reduces the surgical risk of liver transplantation. AB - BACKGROUND: Portal hypertension is one of the most important clinical conditions that cause intraoperative intensive hemorrhage in cirrhotic patients undergoing liver transplantation. Pre-transplant portal decompression may reduce the intraoperative bleeding during liver transplantation. METHODS: Splenic artery trunk embolization (SATE) was performed one month prior to liver transplantation. Platelet count, prealbumin, international normalized ratio, and blood flow in the portal vein and hepatic artery were monitored before and one month after SATE. The measurements above were collected on admission and before surgery in the non SATE patients, who served as controls. We also recorded the intraoperative blood loss, operating time, required transfusion, post-transplant ascites, and complications within three months after operation in all patients. RESULTS: SATE significantly reduced portal venous blood flow, increased hepatic arterial blood flow, normalized platelet count, and improved prealbumin and international normalized ratio in the patients before liver transplantation. Compared to the non-SATE patients, the pre-transplant SATE significantly decreased the operating time, intraoperative bleeding, post-transplant ascites and severe surgical complications. CONCLUSION: Pre-transplant SATE decreases portal pressure, improves liver function reserve, and reduces the surgical risk of liver transplantation effectively in patients with severe portal hypertension. PMID- 26063027 TI - Patterns of cancer recurrence in localized resected hepatocellular carcinoma. AB - BACKGROUND: Tumor resection in non-metastatic hepatocellular carcinoma (HCC) patients with adequate liver reserve offers a potential cure, but has a high 5 year recurrence rate. We analyzed the patterns of cancer relapse after partial hepatectomy to guide post-operative management. METHODS: A total of 144 HCC patients (1996-2011) after partial hepatectomy were reviewed. Statistical correlations were determined using univariate and partition analyses. RESULTS: A median follow-up of 20 months showed recurrence in 71 (49%) patients, and the median time to recurrence was 11.9 months. Vascular invasion (P<0.01) and number of lesions (P<0.01) predicted for recurrence. Histologic grade was not correlated with recurrence. Twenty-two (31%) patients developed both surgical margin (SM) and concurrent intrahepatic recurrences, and 28 (40%) had non-SM intrahepatic recurrences with no other signs of recurrence. On partition analysis, the risk of marginal recurrence in patients with SM <1 mm and SM >=1 mm was 35% and 13.5% respectively. Approximately 57% of patients with intrahepatic recurrence had recurrence <=2.5 cm from SM. CONCLUSIONS: Intrahepatic recurrence after partial hepatectomy is common and is significantly associated with vascular invasion and tumor stage. About 57% of patients with intrahepatic relapse had a recurrence close (<=2.5 cm) to the SM. Additionally, patients with SM <1 mm have a higher recurrence rate and may benefit from adjuvant local therapy. PMID- 26063028 TI - Esophagogastric devascularization without splenectomy in portal hypertension: safe and effective? AB - BACKGROUND: Esophagogastric variceal hemorrhage is a life-threatening complication of portal hypertension. In this study, we compared the therapeutic effect of a novel surgical procedure, esophagogastric devascularization without splenectomy (EDWS), with the widely used modified esophagogastric devascularization (MED) with splenectomy for the treatment of portal hypertension. METHODS: Fifty-five patients with portal hypertension were included in this retrospective study. Among them, 27 patients underwent EDWS, and the other 28 patients underwent MED. Patients' characteristics, perioperative parameters and long-term follow-up were analyzed. RESULTS: The portal venous pressure was decreased by 20% postoperatively in both groups. The morbidity rate of portal venous system thrombosis in the EDWS group was significantly lower than that in the MED group (P=0.032). The 1- and 3-year recurrence rates of esophagogastric variceal hemorrhage were 0% and 4.5% in the EDWS group, and 0% and 8.7% in the MED group, respectively (P=0.631). CONCLUSIONS: EDWS is a safe and effective treatment for esophagogastric varices secondary to portal hypertension in selected patients. Patients treated with EDWS had a lower complication rate of portal venous system thrombosis compared with those treated with conventional MED. PMID- 26063029 TI - Genotype 3 is the predominant hepatitis C genotype in a multi-ethnic Asian population in Malaysia. AB - BACKGROUND: Genotypes of hepatitis C virus (HCV) are distributed differently across the world. There is a paucity of such data in a multi-ethnic Asian population like Malaysia. The objectives of this study were to determine the distribution of HCV genotypes between major ethnic groups and to ascertain their association with basic demographic variables like age and gender. METHODS: This was a cross-sectional prospective study conducted from September 2007 to September 2013. Consecutive patients who were detected to have anti-HCV antibodies in the University of Malaya Medical Centre were included and tested for the presence of HCV RNA using Roche Cobas Amplicor Analyzer and HCV genotype using Roche single Linear Array HCV Genotyping strip. RESULTS: Five hundred and ninety-six subjects were found to have positive anti-HCV antibodies during this period of time. However, only 396 (66.4%) were HCV RNA positive and included in the final analysis. Our results showed that HCV genotype 3 was the predominant genotype with overall frequency of 61.9% followed by genotypes 1 (35.9%), 2 (1.8%) and 6 (0.5%). There was a slightly higher prevalence of HCV genotype 3 among the Malays when compared to the Chinese (P=0.043). No other statistical significant differences were observed in the distribution of HCV genotypes among the major ethnic groups. There was also no association between the predominant genotypes and basic demographic variables. CONCLUSIONS: In a multi-ethnic Asian society in Malaysia, genotype 3 is the predominant genotype among all the major ethnic groups with genotype 1 as the second commonest genotype. Both genotypes 2 and 6 are uncommon. Neither genotype 4 nor 5 was detected. There is no identification of HCV genotype according to ethnic origin, age and gender. PMID- 26063030 TI - High frequency of thrombocytopenia in patients with acute-on-chronic liver failure treated with linezolid. AB - BACKGROUND: Linezolid is an effective antibiotic reagent for Gram-positive bacterial infection; its most common side effect is thrombocytopenia. However, the incidence of thrombocytopenia in patients with acute-on-chronic liver failure (ACLF) who underwent linezolid therapy was unclear. The present study was to evaluate the incidence of thrombocytopenia in ACLF and non-ACLF patients treated with linezolid and the risk factors of thrombocytopenia in these patients. METHODS: Thirty-five patients with ACLF who had been subjected to intravenous administration of 600 mg linezolid every 12 hours for more than 7 days were categorized as a ACLF treatment (ACLF-T) group, 72 patients without ACLF treated with the same dosage of linezolid were recruited as a non-ACLF treatment (NACLF T) group, and 70 patients with ACLF without linezolid treatment served as an ACLF control (ACLF-C) group. The incidences of thrombocytopenia in different groups were compared at day 14. Risk factors were investigated using logistic regression analysis. RESULTS: The incidence of thrombocytopenia at day 14 was significantly higher in the ACLF-T group than in the ACLF-C group (20/35 vs 24/70, P=0.025) and in the NACLF-T group (20/35 vs 9/72, P<0.001). Multivariate analysis showed that the ratio of platelet count (day 7/day 0)<1 (OR=10.021; P=0.012) and the baseline platelet count (OR=0.985; P=0.036) were independent risk factors of thrombocytopenia at day 14 of linezolid therapy. CONCLUSIONS: The benefits of linezolid treatment should outweigh the risk of thrombocytopenia in patients with ACLF. Moreover, it is necessary to closely monitor the platelet count during linezolid therapy especially in the patients with decreased platelet count at day 7 of linezolid therapy. PMID- 26063031 TI - Fast magnetic reconstruction of the portal vein with allogeneic blood vessels in canines. AB - BACKGROUND: The resection and reconstruction of large vessels, including the portal vein, are frequently needed in tumor resection. Warm ischemia before reconstruction might have deleterious effects on the function of some vital organs and therefore, how to reconstruct the vessels quickly after resection is extremely important. The present study was to introduce a new type of magnetic compression anastomosis (MCA) device to establish a quick non-suture anastomosis of the portal vein after resection in canines. METHODS: The new MCA device consists of a pair of titanium alloy and neodymium-ferrum-boron magnet (Ti-NdFeB) composite rings. The NdFeB magnetic ring as a core of the device was hermetically sealed inside the biomedical titanium alloy case. Twelve canines were divided into two groups: a MCA group in which the end-to-end anastomoses was made with a new device after resection in the portal vein and a traditional manual suture (TMS) group consisted of 6 canines. The anastomosis time, anastomotic patency and quality were investigated at week 24 postoperatively. RESULTS: The portal vein was reconstructed successfully in all of the animals and they all survived. The duration of portal vein anastomosis was significantly shorter in the MCA group than in the TMS group (8.16+/-1.25 vs 36.24+/-2.17 min, P<0.05). Portography and ultrasound showed that the blood flow was normal without angiostenosis or thrombosis in all of the canines. Hematoxylin-eosin staining and electron microscope scanning showed in contrast to the TMS group, MCA anastomotic intimal was much smoother with more regularly arranged endothelial cells at week 24 postoperatively. CONCLUSIONS: The Ti-NdFeB composite MCA device was applicable in reconstruction of large vessels after resection. This device was easy to use and the anastomosis was functionally better than the traditional sutured anastomosis. PMID- 26063032 TI - Histological examination of frozen sections for patients with acute cholecystitis during cholecystectomy. AB - BACKGROUND: Unexpected gallbladder cancer may present with acute cholecystitis like manifestations. Some authors recommended that frozen section analysis should be performed during laparoscopic cholecystectomy for all cases of acute cholecystitis. Others advocate selective use of frozen section analysis based on gross examination of the specimen by the surgeon. The aim of the present study was to evaluate whether surgeons could effectively identify suspected gallbladder with macroscopic examination alone. If not, is routine frozen section analysis worth advocating? METHODS: A total of 1162 patients with acute cholecystitis who had undergone simple cholecystectomy in our hospital from February 2009 to February 2014 were enrolled in the study. The data of patients with acute cholecystitis especially those with concurrent gallbladder cancer in terms of clinical characteristics, operative records, frozen section diagnosis and histopathology reports were analyzed. RESULTS: Thirteen patients with acute cholecystitis were found to have concurrent gallbladder cancer, with an incidence of 1.1% in acute cholecystitis. Forty patients with acute cholecystitis were suspected to have gallbladder cancer by macroscopic examination and specimens were taken for frozen section analysis. Six patients with gallbladder cancer were correctly identified by macroscopic examination alone but 7 patients with gallbladder cancer missed, including 3 patients with advanced cancer (2 T3 and 1 T2). Meanwhile, in 6 gallbladder cancer specimens sent for frozen section analysis, 3 early gallbladder cancers (2 Tis and 1 T1a) were missed by frozen section analysis. However, the remaining 3 patients with advanced gallbladder cancers (2 T3 and 1 T2) were correctly diagnosed. CONCLUSIONS: The incidence of comorbidity of gallbladder cancer and acute cholecystitis is higher than that of non-acute cholecystitis. The accurate diagnosis of gallbladder cancer by surgeons is poor and frozen section analysis is necessary. PMID- 26063033 TI - Endoscopic ultrasound-guided fine-needle aspiration cytology in pancreaticobiliary carcinomas: diagnostic efficacy of cell-block immunocytochemistry. AB - BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration cytology was demonstrated to be a useful tool for the diagnosis and staging of pancreaticobiliary neoplastic lesions. Nonetheless, the diagnostic value of this procedure may be limited by low cellularity of the specimen, contamination of intestinal cells and unfeasibility of ancillary immunocytochemical procedures. The present study was to evaluate its usefulness in the diagnosis of neoplastic lesions. METHODS: A series of 46 pancreaticobiliary carcinomas with available cell block preparations was submitted to immunocytochemistry against cytokeratins, carcinoembryonic antigen, E-cadherin, CD10 and p53. The sensitivity, specificity, positive and negative predictive values of the cytological smear in the discrimination of malignant lesions were calculated and compared with those of cell block preparation with the immunocytochemical stains against p53 and CD10. RESULTS: According to our findings, the use of cell block preparations together with immunostains against p53 and CD10 allowed to discriminate malignant versus benign specimens with higher sensitivity than the only cytological examination. In detail, CD10 immunostaining was of significant help for the discrimination between cytological contaminants, such as benign gastrointestinal cells, and the neoplastic elements of pancreaticobiliary well differentiated adenocarcinomas. Also, intense nuclear immunoreactivity for p53 was encountered in about 2/3 of the cases and identified pancreatic malignancy with high sensitivity. CONCLUSIONS: We suggest that immunocytochemistry against both CD10 and p53 could be applied case by case, mainly to differentiate gastrointestinal and pancreatic benign cellular contaminants showing hyperplasia or reactive changes from differentiated pancreaticobiliary adenocarcinomas. PMID- 26063034 TI - Omental flaps reduces complications after pancreaticoduodenectomy. AB - BACKGROUND: Major complications after pancreaticoduodenectomy are usually caused by a leaking pancreaticojejunal anastomosis. Omental flaps around various anastomoses were used to prevent the formation of fistula. METHODS: We reviewed 147 patients who had undergone pancreaticoduodenectomy between March 2006 and March 2012. The patients were divided into 2 groups according to the application of omental flaps around various anastomoses: group A (101 patients) who underwent omental wrapping procedure; group B (46 patients) who did not undergo the omental wrapping procedure. Perioperative data of the two groups were reviewed to assess the effectiveness of omental flap procedure in the prevention of pancreatic fistula and other complications. RESULTS: No differences were observed in the clinical characteristics between the 2 groups. The incidences of pancreatic fistula (4.0% vs 17.4%), post-pancreatectomy hemorrhage (0 vs 6.5%), biliary fistula (1.0% vs 13.0%), and delayed gastric emptying (4.0% vs 17.4%) were significantly less frequent in group A. The overall morbidity (18.8% vs 47.8%) and hospital stay (8.3 vs 9.6 days) were also significantly lower in group A than in group B. CONCLUSIONS: Omental flaps around various anastomoses after pancreaticoduodenectomy can reduce the incidences of pancreatic fistula, biliary fistula, post-pancreatectomy hemorrhage and delayed gastric emptying. This procedure is simple and effective to reduce the overall morbidity after pancreaticoduodenectomy. PMID- 26063035 TI - Combined right hemicolectomy and pancreaticoduodenectomy for locally advanced right hemicolon cancer. AB - Extracolonic invasion of the duodenum and/or pancreatic head rarely occurs in patients with right hemicolon cancer. However, when necessary, combined radical operation is a challenge to the surgeon. We reported 7 patients with locally advanced right hemicolon cancer who underwent combined right hemicolectomy (RH) and pancreaticoduodenectomy (PD) due to direct involvement of the duodenum or pancreatic head. This study included four males and three females with a mean age of 66.9+/-5.9 years. Computed tomography (CT) scans revealed right hemicolon cancer with duodenal invasion (5 patients) and pancreatic invasion (2). The mean operation time was 410+/-64 minutes and the estimated blood loss was 514+/-157 mL. After the operation, the mean postoperative hospital stay was 22.1+/-7.2 days. Five patients had postoperative complications. The mean follow-up time was 16.4+/-5.9 months. During this period, three patients died from tumor recurrence, one from postoperative complications, one from pulmonary disease, and two survived until the last scheduled follow-up. Five patients survived more than one year. Combined RH and PD for locally advanced right hemicolon cancer can be performed safely, thus providing a long-term survival rate in selected patients in a high-volume center. PMID- 26063036 TI - miR-215 overexpression distinguishes ampullary carcinomas from pancreatic carcinomas. AB - Distinguishing ampullary carcinoma from pancreatic carcinoma is important because of their different prognoses. microRNAs are differentially expressed according to the tissue of origin. However, there is rare research on the differential diagnosis between the two types of cancers by microRNA in periampullary cancers. The present study was undertaken to compare microRNA profiles between ampullary and pancreatic carcinomas using microarrays. miR-215 was most significantly overexpressed in ampullary carcinomas; whereas the expressions of miR-134 and miR 214 were significantly lower in ampullary carcinomas than in pancreatic carcinomas. When these discriminatory microRNAs were applied to liver metastases, they were correctly predicted for the tissue of origin. Although this study is limited by small sample size, striking difference in microRNA expression and concordant expression of discriminating microRNAs in primary tumors and metastases suggest that these novel discriminatory microRNAs warrant future validation. PMID- 26063037 TI - Comment on "p38 MAPK inhibition alleviates experimental acute pancreatitis in mice". PMID- 26063038 TI - Potential therapeutic benefits stemming from the thermal nature of irreversible electroporation of solid cancers. PMID- 26063039 TI - Daily Movements and Microhabitat Selection of Hantavirus Reservoirs and Other Sigmodontinae Rodent Species that Inhabit a Protected Natural Area of Argentina. AB - Abundance, distribution, movement patterns, and habitat selection of a reservoir species influence the dispersal of zoonotic pathogens, and hence, the risk for humans. Movements and microhabitat use of rodent species, and their potential role in the transmission of hantavirus were studied in Otamendi Natural Reserve, Buenos Aires, Argentina. Movement estimators and qualitative characteristics of rodent paths were determined by means of a spool and line device method. Sampling was conducted during November and December 2011, and March, April, June, October, and December 2012. Forty-six Oxymycterus rufus, 41 Akodon azarae, 10 Scapteromys aquaticus and 5 Oligoryzomys flavescens were captured. Movement patterns and distances varied according to sex, habitat type, reproductive season, and body size among species. O. flavescens, reservoir of the etiologic agent of hantavirus pulmonary syndrome in the region, moved short distances, had the most linear paths and did not share paths with other species. A. azarae had an intermediate linearity index, its movements were longer in the highland grassland than in the lowland marsh and the salty grassland, and larger individuals traveled longer distances. O. rufus had the most tortuous paths and the males moved more during the non-breeding season. S. aquaticus movements were associated with habitat type with longer distances traveled in the lowland marsh than in the salty grassland. Hantavirus antibodies were detected in 20% of A. azarae and were not detected in any other species. Seropositive individuals were captured during the breeding season and 85% of them were males. A. azarae moved randomly and shared paths with all the other species, which could promote hantavirus spillover events. PMID- 26063040 TI - Applying One Health to the Study of Animal-Assisted Interventions. AB - The use of animal-assisted interventions in therapeutic programs is a growing phenomenon. Animal-assisted interventions (AAIs) involve a variety of species (dogs, cats, horses, domesticated birds, etc.) in primary health care. Despite their increasing application in a wide range of therapeutic services, the empirical evidence base of AAIs is limited. The authors of this paper propose that the public health framework of One Health can be adapted to advance AAI research. One Health's perspective on the environment is primarily ecological. The environmental impact on the human-animal interactions within AAIs, however, incorporates social, cultural, political, and economic factors. The environment has received minimal attention in AAI research. The authors discuss how this framework has been used in their prior AAI research and work with Indigenous people. Applying this framework to AAIs may guide future AAI research. PMID- 26063041 TI - The Effect of Environmental Temperature on Hendra Virus Survival. PMID- 26063042 TI - Adverse childhood experiences are associated with spontaneous preterm birth: a case-control study. AB - BACKGROUND: More than 1 in 10 infants are born prematurely worldwide, making preterm birth the leading cause of neonatal mortality and morbidity. Chronic maternal stress is increasingly recognized as one of the contributing risk factors for preterm birth, yet its specific role remains largely unknown. Examining the exposure to stressors over a mother's life course might provide more perspective on the role of maternal stress in preterm birth. Our aim was therefore to retrospectively explore the associations between chronic, lifelong stressors and protective factors and spontaneous preterm birth. METHODS: This study was part of a large case-control study based in Edmonton, Canada, examining gene-environment interactions and preterm birth. Cases were mothers with a spontaneous singleton preterm birth (<37 weeks) without preterm premature rupture of membranes. Controls were mothers with an uncomplicated singleton term birth without a history of preterm birth. Sociodemographic and medical data were collected. A postpartum telephone questionnaire was administered to assess stressors across the lifespan. Both individual and contextual variables that could influence stress response systems were examined. Overall, 622 women were included, of which 223 subjects - 75 cases and 148 controls - completed the stress questionnaire. Univariate and multivariate logistic regression analyses were performed. RESULTS: Multivariate analysis showed that exposure to two or more adverse childhood experiences (ACEs) was associated with a two-fold risk of preterm birth, regardless of maternal age, smoking status, educational status, and history of miscarriage (adjusted OR, 2.09; 95 % CI, 1.10-3.98; P = 0.024). The adjusted odds ratio for the ACE score was 1.18 (95 % CI, 0.99-1.40), suggesting that for every increase in childhood adverse event endorsed, the risk of preterm birth increased by 18 %. Lifetime physical and emotional abuse was also associated with spontaneous preterm birth in our study population (adjusted OR, 1.30; 95 % CI, 1.02-1.65; P = 0.033). CONCLUSIONS: A strong relationship between ACEs and preterm birth was observed. It has been shown that two or more ACEs have a notable two-fold increase in the risk of spontaneous preterm birth. These data demonstrate that stressors throughout life can have a significant effect on pregnancy outcomes such as preterm birth. PMID- 26063043 TI - Strengthening human resources for health systems resilience to care for mothers and children. PMID- 26063044 TI - Bacterial determinants of importance in the virulence of Gallibacterium anatis in poultry. AB - Gallibacterium anatis, a member of the Pasteurellaceae family, constitute a part of the normal micro-flora of the upper respiratory tract and the lower genital tract in chickens. However, increasing evidence indicate that G. anatis is also associated with a wide range of pathological changes, particularly in the reproductive organs, which leads to decreased egg production, lowered animal welfare and increased mortality. As a recently defined opportunistic pathogen limited focus has been placed on the pathogenesis and putative virulence factors permitting G. anatis to cause disease. One of the most studied virulence determinants is a large RTX-like toxin (GtxA), which has been demonstrated to induce a strong leukotoxic effect on avian macrophages. A number of fimbria of different sizes and shapes has been described. Particularly fimbriae belonging to the F17-like family appears to be common in a diverse selection of G. anatis strains. Mutants lacking the FlfA fimbria were severely attenuated in experimentally infected chickens. Additional characteristics including the ability to express capsular material possibly involved in serum resistance; secretion of metalloproteases capable of degrading immunoglobulins, and hemagglutinins, which may promote biofilm formation are all factors likely linked to the virulence of G. anatis. A major advantage for the study of how G. anatis interact with its host is the ability to perform biologically relevant experimental infections where natural routes of exposure allows reproduction of lesions observed during spontaneous infections. This review summarizes the current understanding of the G. anatis pathogenesis and discusses the contribution of the established and putative virulence factors described for this bacterium to date. PMID- 26063045 TI - In Vitro and In Vivo Efficacy of Self-Assembling RGD Peptide Amphiphiles for Targeted Delivery of Paclitaxel. AB - PURPOSE: The objective of this work was to compare the efficacy of self assembling cyclic and linear RGD peptide amphiphiles as carriers for delivering paclitaxel to alphavbeta3 integrin overexpressing tumors. METHODS: Linear (C18 ADA5-RGD) and cyclic (C18-ADA5-cRGDfK) peptide amphiphiles were synthesized and characterized for CMC, aggregation number and micelle stability using fluorescence spectroscopy methods. Size and morphology of micelles was studied using TEM. Fluorescence polarization and confocal microscopy assays were established to compare binding and internalization of micelles. The targeting efficacy was studied in A2058 cells using cytotoxicity assay as well as in vivo in melanoma xenograft mouse model. RESULTS: The linear and cyclic RGD amphiphiles exhibited CMC of 25 and 8 MUM, respectively, formed nano-sized spherical micelles and showed competitive binding to alphavbeta3 integrin protein. FITC-loaded RGD micelles rapidly internalized into A2058 melanoma cells. Paclitaxel-loaded RGD micelles exhibited higher cytotoxicity compared with free drug in A2058 cells in vitro as well as in vivo. CONCLUSION: Cyclic RGD micelles exhibited better targeting efficacy but were less effective compared to linear RGD micelles as drug delivery vehicle due to lower drug solubilization capacity and lesser kinetic stability. Results from the study proved the effectiveness of self assembling low molecular weight RGD amphiphiles as carriers for targeted delivery of paclitaxel. PMID- 26063046 TI - Salt formation during freeze-drying--an approach to enhance indomethacin dissolution. AB - PURPOSE: (i) Prepare a freeze-dried injectable indomethacin (IMC) dosage form. (ii) Convert IMC to its tris salt during freeze-drying so as to facilitate rapid dissolution (reconstitution). (iii) Modulate salt crystallinity by annealing the frozen solution. METHODS: Aqueous IMC solutions buffered with tris were freeze dried, with or without annealing the frozen solutions. The lyophiles were characterized by X-ray diffractometry, differential scanning calorimetry and infra-red spectroscopy and also subjected to water sorption and dissolution studies. RESULTS: Based on IR spectroscopy, the final lyophile was confirmed to contain the IMC tris salt. In the absence of annealing, the lyophile was X-ray amorphous with a glass transition temperature of 19 degrees C. Annealing the frozen solutions caused a substantial increase in lyophile crystallinity. Interestingly, both the amorphous and partially crystalline lyophiles dissolved "instantaneously" and completely in the dissolution medium. In contrast, the crystalline IMC as well as its physical mixture with tris exhibited much slower dissolution with ~ 50% drug dissolved in 30 min. CONCLUSION: In situ IMC tris salt formation resulted in an elegant lyophile with a very short reconstitution time. Tris served two roles - as a buffer in the prelyophilization solution and as the counterion for the salt in the final lyophile. This approach for solubility enhancement could be extended to other acidic drugs wherein salt formation was observed during freeze-drying. PMID- 26063047 TI - Changed Plasma Levels of Zinc and Copper to Zinc Ratio and Their Possible Associations with Parent- and Teacher-Rated Symptoms in Children with Attention Deficit Hyperactivity Disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is associated with alterations in the metabolism of some trace elements which may participate in the pathogenesis of this disorder. The aims of the present study were to investigate the trace element status (copper (Cu), zinc (Zn), copper to zinc ratio (Cu/Zn ratio), selenium (Se), and lead (Pb)) of ADHD children and compare them with the control group. Associations between examined elements and ratings of ADHD symptoms were also assessed. Fifty-eight ADHD children and 50 healthy children (aged 6-14 years) were included in the study. The concentrations of Cu, Zn, and Se in the plasma and Pb in the whole blood were measured by atomic absorption spectrometry. We found lower Zn level (p = 0.0005) and higher Cu/Zn ratio (p = 0.015) in ADHD children when compared with the control group. Copper levels in ADHD children were higher than those in the control group, but not significantly (p > 0.05). No significant differences in levels of Se and Pb between both groups were found. Zinc levels correlated with parent-rated score for inattention (r = -0.231, p = 0.029) as well as with teacher-rated score for inattention (r = -0.328, p = 0.014). Cu/Zn ratio correlated with teacher-rated score for inattention (r = 0.298, p = 0.015). Significant associations of Se and Pb with parent- and teacher rated symptoms were not observed. The results of this study indicate that there are alterations in plasma levels of Cu and Zn as well as significant relationships to symptoms of ADHD. PMID- 26063048 TI - Case report and operative management of gallbladder herniation. AB - BACKGROUND: Incarcerated abdominal wall hernias may contain a variety of contents, but very rarely contains the gallbladder. This rare diagnosis is often not considered and, when diagnosed, has a different management approach. The experience of the small number of case reports have yet to be collected and summarised. CASE PRESENTATION: We report a presentation and management of an 85 year old Caucasian female with a gallbladder hernia into a parastomal defect, and outline the operative management. CONCLUSION: Incarcerated gallbladder hernia is an extremely unusual condition, best diagnosed by CT scan. Management should involve operative reduction, cholecystectomy and consideration of repair of the defect. PMID- 26063049 TI - Ticagrelor: Pharmacokinetic, Pharmacodynamic and Pharmacogenetic Profile: An Update. AB - Despite advancements in treatments for acute coronary syndromes over the last 10 years, they continue to be life-threatening disorders. Currently, the standard of treatment includes dual antiplatelet therapy consisting of aspirin plus a P2Y12 receptor antagonist. The thienopyridine class of P2Y12 receptor antagonists, clopidogrel and prasugrel, have demonstrated efficacy. However, their use is associated with several limitations, including the need for metabolic activation and irreversible P2Y12 receptor binding causing prolonged recovery of platelet function. In addition, response to clopidogrel is variable and efficacy is reduced in patients with certain genotypes. Although prasugrel is a more consistent inhibitor of platelet aggregation than clopidogrel, it is associated with an increased risk of life-threatening and fatal bleeding. Ticagrelor is an oral antiplatelet agent of the cyclopentyltriazolopyrimidine class and also acts through the P2Y12 receptor. In contrast to clopidogrel and prasugrel, ticagrelor does not require metabolic activation and binds rapidly and reversibly to the P2Y12 receptor. In light of new data, this review provides an update on the pharmacokinetic, pharmacodynamic and pharmacogenetic profiles of ticagrelor in different study populations. Recent studies report that no dose adjustment for ticagrelor is required on the basis of age, gender, ethnicity, severe renal impairment or mild hepatic impairment. The non-P2Y12 actions of ticagrelor are reviewed, showing indirect positive effects on cellular adenosine concentration and biological activity, by inhibition of equilibrative nucleoside transporter-1 independently of the P2Y12 receptor. CYP2C19 and ABCB1 genotypes do not appear to influence ticagrelor pharmacodynamics. A summary of drug interactions is also presented. PMID- 26063050 TI - Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design. AB - BACKGROUND AND OBJECTIVE: The use of an opportunistic (also called scavenged) sampling strategy in a prospective pharmacokinetic study combined with population pharmacokinetic modelling has been proposed as an alternative strategy to conventional methods for accomplishing pharmacokinetic studies in neonates. However, the reliability of this approach in this particular paediatric population has not been evaluated. The objective of the present study was to evaluate the performance of an opportunistic sampling strategy for a population pharmacokinetic estimation, as well as dose prediction, and compare this strategy with a predetermined pharmacokinetic sampling approach. METHODS: Three population pharmacokinetic models were derived for ciprofloxacin from opportunistic blood samples (SC model), predetermined (i.e. scheduled) samples (TR model) and all samples (full model used to previously characterize ciprofloxacin pharmacokinetics), using NONMEM software. The predictive performance of developed models was evaluated in an independent group of patients. RESULTS: Pharmacokinetic data from 60 newborns were obtained with a total of 430 samples available for analysis; 265 collected at predetermined times and 165 that were scavenged from those obtained as part of clinical care. All datasets were fit using a two-compartment model with first-order elimination. The SC model could identify the most significant covariates and provided reasonable estimates of population pharmacokinetic parameters (clearance and steady-state volume of distribution) compared with the TR and full models. Their predictive performances were further confirmed in an external validation by Bayesian estimation, and showed similar results. Monte Carlo simulation based on area under the concentration-time curve from zero to 24 h (AUC24)/minimum inhibitory concentration (MIC) using either the SC or the TR model gave similar dose prediction for ciprofloxacin. CONCLUSION: Blood samples scavenged in the course of caring for neonates can be used to estimate ciprofloxacin pharmacokinetic parameters and therapeutic dose requirements. PMID- 26063051 TI - Pharmacokinetics-Based Approaches for Bioequivalence Evaluation of Topical Dermatological Drug Products. AB - The pharmacokinetic approach has accelerated the development of high-quality generic medicines with extraordinary cost savings, transforming the pharmaceutical industry and healthcare system in the USA. While this is true for systemically absorbed drug products, the availability of generic versions of topical dermatological products remains constrained due to the limited methods accepted for bioequivalence evaluation of these products. The current review explores the possibility of developing appropriate bioequivalence approaches based on pharmacokinetic principles for topical dermatological products. This review focuses on the strengths and limitations of the three most promising pharmacokinetics-based methods to evaluate the performance and bioequivalence of topical dermatological products, which include in vivo skin stripping, in vivo microdialysis, and in vitro permeation testing (IVPT) with excised human skin. It is hoped that recent advances in pharmaceutical and regulatory science will facilitate the development of robust bioequivalence approaches for these dosage forms, enable more efficient methodologies to compare the performance of new drug products in certain pre-approval or post-approval change situations, and promote the availability of high-quality generic versions of topical dermatological products. PMID- 26063052 TI - Aeromonas punctata derived depolymerase improves susceptibility of Klebsiella pneumoniae biofilm to gentamicin. AB - BACKGROUND: To overcome antibiotic resistance in biofilms, enzymes aimed at biofilm dispersal are under investigation. In the present study, applicability of an Aeromonas punctata derived depolymerase capable of degrading the capsular polysaccharide (CPS) of Klebsiella pneumoniae, in disrupting its biofilm and increasing gentamicin efficacy against biofilm was investigated. RESULTS: Intact biofilm of K. pneumoniae was recalcitrant to gentamicin due to lack of antibiotic penetration. On the other hand, gentamicin could not act on disrupted biofilm cells due to their presence in clusters. However, when depolymerase (20 units/ml) was used in combination with gentamicin (10 MUg/ml), dispersal of CPS matrix by enzyme facilitated gentamicin penetration across biofilm. This resulted in significant reduction (p < 0.05) in bacterial count in intact and disrupted biofilms. Reduction in CPS after treatment with depolymerase was confirmed by confocal microscopy and enzyme linked lectinosorbent assay. Furthermore, to substantiate our study, the efficacy of bacterial depolymerase was compared with a phage borne depolymerase possessing similar application against K. pneumoniae. Although both were used at same concentration i.e. 20 units/ml, but a higher efficacy of bacterial depolymerase particularly against older biofilms was visibly clear over its phage counterpart. This could be explained due to high substrate affinity (indicated by Km value) and high turnover number (indicated by Kcat value) of the bacterial depolymerase (Km = 89.88 MUM, Kcat = 285 s(-1)) over the phage derived one (Km = 150 MUM, Kcat = 107 s(-1)). CONCLUSION: Overall the study indicated that, the A. punctata derived depolymerase possesses antibiofilm potential and improves gentamicin efficacy against K. pneumoniae. Moreover, it can serve as a potential substitute to phage borne depolymerases for treating biofilms formed by K. pneumoniae. PMID- 26063053 TI - Dietary supplementation with omega-3 fatty acid attenuates 5-fluorouracil induced mucositis in mice. AB - BACKGROUND: Studies showed the positive effects of omega-3 fatty acid (n-3 FA) for the treatment of inflammatory bowel disease as it alleviated the symptoms and promoted better mucosal integrity. The objective of this study was to determine whether a diet with the addition of n-3 FA helps control the inflammation observed in 5-fluorouracil (5-FU) induced mucositis. METHODS: BALB/c mice were randomly divided into four groups as follows: 1: control (CTL), fed a standard chow diet; 2: CTL + n-3 FA - n-3 FA, fed a diet with n-3; 3: mucositis (MUC), fed a standard chow diet and subjected to mucositis; and 4: MUC+ n-3 FA, fed a diet with n-3 FA and subjected to mucositis. On the 8th day, the animals of the MUC and MUC + n-3 FA groups received an intraperitoneal injection of 300 mg/kg 5-FU for mucositis induction. After 24 h or 72 h, all mice were euthanized and evaluated for intestinal permeability, bacterial translocation, intestinal histology and apoptosis. RESULTS: Mice that received the diet with n-3 FA and a 5 FU injection showed less weight loss compared to the animals of the MUC group (p < 0.005). Decreased intestinal permeability and bacterial translocation were also observed in animals fed n-3 FA, and these mice underwent mucositis compared to the MUC group (p < 0.005). These data were associated with mucosal integrity and a reduced number of apoptotic cells in the ileum mucosa compared to the mice that received the control diet and 5-FU injection. CONCLUSION: Together, these results show that omega-3 fatty acid decreases the mucosal damage caused by 5-FU-induced mucositis. PMID- 26063054 TI - Spinal pain--good sleep matters: a secondary analysis of a randomized controlled trial. AB - PURPOSE: The estimated prevalence of poor sleep in patients with non-specific chronic low back pain is estimated to 64% in the adult population. The annual cost for musculoskeletal pain and reported poor sleep is estimated to be billions of dollars annually in the US. The aim of this cohort study with one-year follow up was to explore the role of impaired sleep with daytime consequence on the prognosis of non-specific neck and/or back pain. METHODS: Secondary analysis of a randomized controlled trial, including 409 patients. RESULTS: Patients with good sleep at baseline were more likely to experience a minimal clinically important difference in pain [OR 2.03 (95% CI 1.22-3.38)] and disability [OR 1.85 (95% CI 1.04-3.30)] compared to patients with impaired sleep at one-year follow-up. CONCLUSION: Patients with non-specific neck and/or back pain and self-reported good sleep are more likely to experience a minimal clinically important difference in pain and disability compared to patients with impaired sleep with daytime consequence. PMID- 26063055 TI - A multicentre retrospective review of muscle necrosis of the leg following spinal surgery with motor evoked potential monitoring: a cause for concern? AB - PURPOSE: There are very few reported cases of compartment syndrome of the leg following spinal surgery via a posterior approach. An association between compartment syndrome and muscle over-activity via nerve stimulation during evoked potential monitoring was first suggested in 2003. No further reports have suggested this link. We present a multicentre retrospective review of a series of five patients who developed compartment syndrome of the leg following spinal surgery via a posterior approach, whilst un-paralysed and with combined sensory (SSEP)/motor evoked potential (MEP) monitoring with an aim of highlighting this possible causative factor. METHODS: All data were collected contemporaneously and retrospective analysis was performed. We then arranged for a multidisciplinary review of the cases including surgeons, anaesthetists, radiologists, neurophysiologists and theatre and ward nursing staff. Finally, the literature was reviewed. RESULTS: All patients were operated on by three different surgeons, on different operating tables/mattresses in the prone position. The common factors were un-paralysed patients having motor/sensory monitoring, mechanical calf pumps and total intravenous anaesthesia. Three patients underwent surgical decompression of their compartments and two were treated expectantly. Three patients had confirmed intra-compartmental changes on MRI consistent with compartment syndrome and one had intra-compartmental pressure monitoring which confirmed the diagnosis. CONCLUSIONS: Previous cases in the literature have related to mal-positioning on the Jackson table or use of the knee-chest position for surgery. This was not the case for our patients; therefore, we suspect an association between overactive muscle stimulation and muscle necrosis. Further experimental studies investigating this link are required. PMID- 26063056 TI - National Survey of Emergency Physicians to Define Functional Decline in Elderly Patients with Minor Trauma. AB - BACKGROUND: There are a number of screening tools to predict return to the emergency department (ED) in elderly trauma patients, but none exist to specifically screen for functional decline after a minor injury. The objective of this study was to identify outcome measures for a possible future clinical decision rule to be used in the ED to identify previously independent patients at high risk of functional decline at six months post minor injury. METHODS: After a rigorous development process, a survey instrument was administered to a random sample of 178 emergency physicians using the Dillman's Tailored Design Method. RESULTS: Of 156 eligible surveys, we received 81 completed surveys (response rate 51.9%). Considering all 14 activities of daily living (ADL) items, 90% of physicians deemed a minimal clinically important difference (MCID) in function to be at least three points on the 28-point Older Americans Resources and Services (OARS) ADL Scale as clinically significant. A tool with a sensitivity of 93% to detect patients at risk of functional decline at six months post injury would meet or exceed the sensitivity deemed to be required by 90% of physicians. The majority of emergency physicians do not assess elderly injured patients for the majority of the tasks. CONCLUSIONS: A drop of three points on the 28-point OARS ADL Scale would be deemed clinically important by the vast majority of emergency physicians. Further, a sensitivity of 93% for a clinical decision tool would satisfy the MCID requirements of the vast majority of emergency physicians. There appears to be a gap between physician knowledge and actual practice. We intend to use these findings in the development of a clinical decision rule to identify high-risk elderly trauma patients. PMID- 26063057 TI - Evaluation of a Rheumatology Transition Clinic. AB - BACKGROUND: An adolescent with a chronic condition must prepare for transition from the pediatric to the adult health care system. Ideally, transition is a purposeful and coordinated process between the two systems. We sought to evaluate a pediatric rheumatology transition clinic from the perspective of the young adults who attended the clinic. METHODS: Young adults who attended the IWK Health Centre Pediatric Rheumatology Transition Clinic in Halifax, Nova Scotia, Canada were asked to complete a mail questionnaire. In this clinic an adult rheumatologist joins the pediatric team for the patient's visit. Subjects rated satisfaction with the clinic and how completely a number of items were addressed (e.g. knowledge about disease, self-management, adolescent issues) on a 10 cm visual analog scale (higher scores reflecting more favourable assessment). Compliance with follow-up post-transfer to adult care was assessed by self-report and a chart review. Data were summarized descriptively. RESULTS: The response rate was 34% (51/151). The mean age of respondents was 22 years with the majority diagnosed with juvenile idiopathic arthritis. Most patients were transferred to adult care between the ages of 17 and 20 years. The mean overall satisfaction score with the transition clinic was 7.3 +/- 2.6. There was significant variability regarding how well individual transition-related items were perceived to have been addressed, with an overall mean of 6.1 +/- 3.2. Items which received a majority of scores of > 7 included learning about side effects of medications, learning to live with their disease, confidence in disease management, and control of disease at transfer. Items rated as <5 by a third of respondents included addressing teen issues (smoking, alcohol, sexual health) and learning about new developments related to their condition. 74% of patients reported regular appointments with adult rheumatology. CONCLUSIONS: Most young adults reported overall satisfaction with the transition clinic, however their perception of how adequately various transition issues were addressed was quite variable. It appears that there were some perceived deficits in the care that was provided in all areas, but possibly more so in counselling around general adolescent issues. There was a high rate of follow-up after transfer to the local adult clinic. PMID- 26063059 TI - Complications and mortality following surgery for oral cavity cancer: analysis of 408 cases. AB - OBJECTIVES: To analyze the postoperative complications and mortality for oral cavity cancers, their time course, and to identify modifiable risk factors associated with their occurrence. STUDY DESIGN: Retrospective cohort study. METHODS: Patients undergoing surgery for oral cavity cancer were identified in the American College of Surgeons National Surgical Quality Improvement Program Participant Use Data File (2005-2010). Overall and disease-specific complication and mortality data were analyzed using chi-square and multivariate regression analysis. RESULTS: There were 408 cases identified. The overall 30-day complication and mortality rates were 20.3% and 1.0%, respectively. The most common adverse events were reoperation (9.6%), infectious (6.6%), and respiratory (5.1%) complications. Twenty patients (4.9%) experienced postdischarge complications. Fifty-two percent of postdischarge wound dehiscences and 67% of postdischarge surgical-site infections occurred by postdischarge day 7, and 91% of all postdischarge complications occurred by postdischarge day 14. Smoking was independently associated with respiratory (odds ratio [OR] 3.59, P = .008) and surgical site complications (OR 5.13, P =.004). Neck dissection was independently associated with respiratory (OR 6.17, P = .001), surgical site (OR 6.30, P = .003), and infectious (OR 3.83, P = .003) complications. CONCLUSION: Current smokers and those undergoing neck dissection are at high risk of postoperative complications after oral cavity cancer surgery. Less than 5% of patients experienced postdischarge complications, nearly all of which occurred by postdischarge day 14. Most early postdischarge complications occurred at the surgical site. In order to mitigate postdischarge complications and their sequelae, early clinical follow-up should be sought for high-risk patients. LEVEL OF EVIDENCE: 4. PMID- 26063058 TI - SUMOylation and Ubiquitylation Circuitry Controls Pregnane X Receptor Biology in Hepatocytes. AB - Several nuclear receptor (NR) superfamily members are known to be the molecular target of either the small ubiquitin-related modifier (SUMO) or ubiquitin signaling pathways. However, little is currently known regarding how these two post-translational modifications interact to control NR biology. We show that SUMO and ubiquitin circuitry coordinately modifies the pregnane X receptor (PXR, NR1I2) to play a key role in regulating PXR protein stability, transactivation capacity, and transcriptional repression. The SUMOylation and ubiquitylation of PXR is increased in a ligand- and tumor necrosis factor alpha -: dependent manner in hepatocytes. The SUMO-E3 ligase enzymes protein inhibitor of activated signal transducer and activator of transcription-1 (STAT1) STAT-1 (PIAS1) and protein inhibitor of activated STAT Y (PIASy) drive high levels of PXR SUMOylation. Expression of protein inhibitor of activated stat 1 selectively increases SUMO(3)ylation as well as PXR-mediated induction of cytochrome P450, family 3, subfamily A and the xenobiotic response. The PIASy-mediated SUMO(1)ylation imparts a transcriptionally repressive function by ameliorating interaction of PXR with coactivator protein peroxisome proliferator-activated receptor gamma coactivator-1-alpha. The SUMO modification of PXR is effectively antagonized by the SUMO protease sentrin protease (SENP) 2, whereas SENP3 and SENP6 proteases are highly active in the removal of SUMO2/3 chains. The PIASy-mediated SUMO(1)ylation of PXR inhibits ubiquitin-mediated degradation of this important liver-enriched NR by the 26S proteasome. Our data reveal a working model that delineates the interactive role that these two post-translational modifications play in reconciling PXR-mediated gene activation of the xenobiotic response versus transcriptional repression of the proinflammatory response in hepatocytes. Taken together, our data reveal that the SUMOylation and ubiquitylation of the PXR interface in a fundamental manner directs its biologic function in the liver in response to xenobiotic or inflammatory stress. PMID- 26063060 TI - Identifying and managing risk factors for salt-affected soils: a case study in a semi-arid region in China. AB - Soil salinization and desalinization are complex processes caused by natural conditions and human-induced risk factors. Conventional salinity risk identification and management methods have limitations in spatial data analysis and often provide an inadequate description of the problem. The objectives of this study were to identify controllable risk factors, to provide response measures, and to design management strategies for salt-affected soils. We proposed to integrate spatial autoregressive (SAR) model, multi-attribute decision making (MADM), and analytic hierarchy process (AHP) for these purposes. Our proposed method was demonstrated through a case study of managing soil salinization in a semi-arid region in China. The results clearly indicated that the SAR model is superior to the OLS model in terms of risk factor identification. These factors include groundwater salinity, paddy area, corn area, aquaculture (i.e., ponds and lakes) area, distance to drainage ditches and irrigation channels, organic fertilizer input, and cropping index, among which the factors related to human land use activities are dominant risk factors that drive the soil salinization processes. We also showed that ecological irrigation and sustainable land use are acceptable strategies for soil salinity management. PMID- 26063061 TI - The relationship between exercise intensity, cerebral oxygenation and cognitive performance in young adults. AB - PURPOSE: To assess the relationship between exercise intensity, cerebral HbO2 and cognitive performance (Executive and non-Executive) in young adults. METHODS: We measured reaction time (RT) and accuracy, during a computerized Stroop task, in 19 young adults (7 males and 12 females). Their mean +/- SD age, height, body mass and body mass index (BMI) were 24 +/- 4 years, 1.67 +/- 0.07 m, 72 +/- 14 kg and 25 +/- 3 kg m(-2), respectively. Each subject performed the Stroop task at rest and during cycling at exercise of low intensity [40% of peak power output (PPO)], moderate intensity (60% of PPO) and high intensity (85% of PPO). Cerebral oxygenation was monitored during the resting and exercise conditions over the prefrontal cortex (PFC) using near-infrared spectroscopy (NIRS). RESULTS: High intensity exercise slowed RT in both the Naming (p = 0.04) and the Executive condition (p = 0.04). The analysis also revealed that high-intensity exercise was associated with a decreased accuracy when compared to low-intensity exercise (p = 0.021). Neuroimaging results confirm a decrease of cerebral oxygenation during high-intensity exercise in comparison to low- (p = 0.004) and moderate-intensity exercise (p = 0.003). Correlations revealed that a lower cerebral HbO2 in the prefrontal cortex was associated with slower RT in the Executive condition only (p = 0.04, g = -0.72). CONCLUSION: Results of the present study suggest that low to moderate exercise intensity does not alter Executive functioning, but that exercise impairs cognitive functions (Executive and non-Executive) when the physical workload becomes heavy. The cerebral HbO2 correlation suggests that a lower availability of HbO2 was associated with slower RT in the Executive condition only. PMID- 26063062 TI - Choline and Betaine Intakes Are Not Associated with Cardiovascular Disease Mortality Risk in Japanese Men and Women. AB - BACKGROUND: Dietary intakes of betaine and choline may reduce the risk of cardiovascular disease; however, epidemiologic evidence is limited. Seafood is a rich source of betaine and is a popular traditional food in Japan. OBJECTIVE: We examined the associations of betaine and choline intakes with cardiovascular disease mortality in a population-based cohort study in Japan. METHODS: Study subjects were 13,355 male and 15,724 female residents of Takayama City, Japan, who were aged >=35 y and enrolled in 1992. Their diets were assessed by a validated food frequency questionnaire. Deaths from coronary heart disease and stroke were identified from death certificates over 16 y. Multivariable-adjusted HRs were computed by using Cox regression models. RESULTS: During follow-up, we documented 308 deaths from coronary heart disease and 676 deaths from stroke (393 from ischemic and 153 from hemorrhagic strokes). Compared with the lowest quartile, the second, third, and highest quartiles of betaine intake were significantly associated with a decreased risk of mortality from coronary heart disease in men after controlling for covariates. The HRs were 0.58 (95% CI: 0.36, 0.93), 0.62 (95% CI: 0.39, 0.998), and 0.60 (95% CI: 0.37, 0.97), respectively. The trend was not statistically significant (P = 0.08). There was no significant association between betaine intake and the risk of mortality from ischemic stroke. In women, betaine intake was unrelated risk of mortality from coronary heart disease and stroke (P = 0.32 and 0.73, respectively, for interaction by sex). There was no significant association between choline intake and cardiovascular disease mortality risk in men or women. CONCLUSION: Overall, we found no clear evidence of significant associations between choline and betaine intakes and cardiovascular disease mortality risk in Japanese men and women. PMID- 26063063 TI - Nondietary Gut Materials Interfere with the Determination of Dietary Fiber Digestibility in Growing Pigs When Using the Prosky Method. AB - BACKGROUND: Reported negative ileal and total tract dietary fiber (DF) digestibility values are physiologically untenable and suggest the presence of nondietary material in the gut contents that interferes with the DF determination. OBJECTIVE: The objective of this study was to demonstrate the importance of interfering material (IM) when the Prosky method was used to determine DF digestibility. METHODS: Fourteen pigs (41.6 +/- 3.0 kg) were surgically implanted with ileal T-cannulas. A semisynthetic fiber-free diet and 2 semisynthetic diets containing kiwifruit as the sole fiber source [25 or 50 g fiber/kg dry matter (DM)] were prepared. Titanium dioxide was used as an indigestible marker. Pigs were fed the kiwifruit-containing diets (n=7 per diet) for 44 d, followed by the fiber-free diet (n=14) for 7 d. Ileal digesta and feces were collected over 3 d, starting on days 42 and 49. The flow of IM and the soluble, insoluble, and total DF digestibility were determined. RESULTS: Considerable amounts of IM were present when the Prosky method was applied to ileal digesta (12 g/kg DM intake) and feces (28 g/kg DM intake) collected from pigs fed the fiber-free diet after adaptation to the diet containing 50 g/kg DM of fiber. The pigs adapted to the highest fiber concentration had 0.9- and 0.7 fold greater ileal and fecal IM flows than their counterparts adapted to the lowest concentration. In the ileal digesta, crude mucin was the main IM source in the soluble DF fraction (66%). In the ileal digesta and feces, microbial cells were the main IM source in the insoluble DF fraction. The determined ileal soluble DF and total tract insoluble DF digestibilities increased by 44-54% and 78% respectively after correction for IM (P < 0.001). CONCLUSIONS: Large amounts of IM are present in ileal digesta and feces of pigs when fiber is determined with the Prosky method, leading to a marked underestimation. PMID- 26063064 TI - Twenty Years of the Dietary Supplement Health and Education Act--How Should Dietary Supplements Be Regulated? AB - The Dietary Supplement Health and Education Act (DSHEA) of 1994 defines the FDA's statutory authority to regulate dietary supplement products in the United States. The dietary supplement industry has rapidly expanded since 1994, presenting an obvious need for "DSHEA 2.0." Current regulations surrounding dietary supplements have been increasingly and reasonably scrutinized, given their widespread use by over one-half of the US population as well as highly publicized safety concerns over the past 20 y. As the market continues to expand and evolve, so too must the laws that protect consumers from potential harm and misleading communication. This article is meant to begin a scientific dialogue on how regulations may be improved to provide both ease of access and safer products to the consumer by focusing on 4 topics: premarket approval, label claims, current Good Manufacturing Practices, and adverse event reporting. PMID- 26063065 TI - A Combination of Single-Nucleotide Polymorphisms Is Associated with Interindividual Variability in Dietary beta-Carotene Bioavailability in Healthy Men. AB - BACKGROUND: The bioavailability of beta-carotene, the main dietary provitamin A carotenoid, varies among individuals. It is not known whether this variability can affect long-term beta-carotene, and hence vitamin A, status. OBJECTIVES: We hypothesized that variations in genes involved in beta-carotene absorption and postprandial metabolism could at least partially explain the high interindividual variability in beta-carotene bioavailability. Thus, the main objectives of this study were to identify associated single-nucleotide polymorphisms (SNPs), and to estimate whether populations with different allele frequencies at these SNPs could have different abilities to absorb provitamin A carotenoids. METHODS: In this single-group design, 33 healthy, nonobese adult men were genotyped with the use of whole-genome microarrays. After an overnight fast, they consumed a test meal containing 100 g tomato puree providing 0.4 mg beta-carotene. The postprandial plasma chylomicron beta-carotene concentration was then measured at regular time intervals over 8 h. Partial least squares (PLS) regression was used to identify the best combination of SNPs in or near candidate genes (54 genes representing 2172 SNPs) that was associated with the postprandial chylomicron beta-carotene response (incremental beta-carotene area-under-the-curve concentration over 8 h in chylomicrons). RESULTS: The postprandial chylomicron beta-carotene response was highly variable (CV = 105%) and was positively correlated with the fasting plasma beta-carotene concentration (r = 0.78; P < 0.0001). A significant (P = 6.54 * 10(-3)) multivalidated PLS regression model, which included 25 SNPs in 12 genes, explained 69% of the variance in the postprandial chylomicron beta-carotene response, i.e., beta-carotene bioavailability. CONCLUSIONS: Interindividual variability in beta-carotene bioavailability appears to be partially modulated by a combination of SNPs in 12 genes. This variability likely affects the long-term blood beta-carotene status. A theoretic calculation of beta-carotene bioavailability in 4 populations of the international HapMap project suggests that populations with different allele frequencies in these SNPs might exhibit a different ability to absorb dietary beta-carotene. This trial was registered at clinicaltrials.gov as NCT02100774. PMID- 26063066 TI - Provision of 10-40 g/d Lipid-Based Nutrient Supplements from 6 to 18 Months of Age Does Not Prevent Linear Growth Faltering in Malawi. AB - BACKGROUND: Complementing infant diets with lipid-based nutrient supplements (LNSs) has been suggested to improve growth and reduce morbidity, but the daily quantity and the milk content of LNSs affect their cost. OBJECTIVE: We tested the hypotheses that the change in mean length-for-age z score (LAZ) for infants provided with 10-40 g LNSs/d from ages 6 to 18 mo would be greater than that for infants receiving no dietary intervention at the same age and that provision of LNSs that did not contain milk would be as good as milk-containing LNSs in promoting linear growth. METHODS: We enrolled in a randomized single-blind trial 6-mo-old infants who were allocated to 1 of 6 groups to receive 10, 20, or 40 g LNSs/d containing milk powder; 20 or 40 g milk-free LNSs/d; or no supplement until 18 mo of age. The primary outcome was change in LAZ. RESULTS: Of the 1932 enrolled infants, 78 (4.0%) died and 319 (16.5%) dropped out during the trial. The overall reported supplement consumption was 71.6% of days, with no difference between the groups (P = 0.26). The overall mean +/- SD length and LAZ changes were 13.0 +/- 2.1 cm and -0.45 +/- 0.77 z score units, respectively, which did not differ between the groups (P = 0.66 for length and P = 0.74 for LAZ). The difference in mean LAZ change in the no-milk LNS group compared with the milk LNS group was -0.02 (95% CI: -0.10, 0.06; P = 0.72). CONCLUSION: Our results do not support the hypothesis that LNS supplementation during infancy and childhood promotes length gain or prevents stunting between 6 and 18 mo of age in Malawi. This trial was registered at clinicaltrials.gov as NCT00945698. PMID- 26063067 TI - Pregnant Canadian Women Achieve Recommended Intakes of One-Carbon Nutrients through Prenatal Supplementation but the Supplement Composition, Including Choline, Requires Reconsideration. AB - BACKGROUND: Folate, vitamin B-6, vitamin B-12, and choline are involved in one carbon metabolism and play critical roles in pregnancy including prevention of birth defects and promotion of neurodevelopment. However, excessive intakes may adversely affect disease susceptibility in offspring. Intakes of these nutrients during pregnancy are not well characterized. OBJECTIVE: Our aim was to determine dietary and supplemental intakes and major dietary sources of one-carbon nutrients during pregnancy. METHODS: In pregnant women (n = 368) at <=16 wk postconception, supplement use >30 d before pregnancy was assessed by maternal recall and supplement and dietary intakes in early (0-16 wk) and late pregnancy (23-37 wk) were assessed by food-frequency questionnaire. RESULTS: Preconception, 60.1% (95% CI: 55.8, 64.3) of women used B vitamin-containing supplements. This increased to 92.8% (95% CI: 89.6, 95.2) in early and 89.0% (95% CI: 85.0, 92.3) in late pregnancy. Median supplemental folic acid, vitamin B-12, and vitamin B-6 were 1000 MUg/d, 2.6 MUg/d, and 1.9 mg/d, respectively. Forty-one percent and 50% of women had dietary intakes of folate and vitamin B-6 less than the estimated average requirement (520 mg/d dietary folate equivalents and 1.6 mg/d, respectively). Eight-seven percent of women had choline intakes less than the Adequate Intake (450 mg/d). Dietary intakes did not change appreciably during pregnancy. Fruits and vegetables and fortified foods contributed ~57% to total dietary folate intake. Fruits and vegetables contributed ~32% to total dietary vitamin B-6 intake and dairy and egg products contributed ~37% to total dietary vitamin B-12 intake. CONCLUSIONS: Vitamin supplements were an important source of one-carbon nutrients during pregnancy in our sample. Without supplements, many women would not have consumed quantities of folate and vitamin B-6 consistent with recommendations. Given the importance of choline in pregnancy, further research to consider inclusion in prenatal supplements is warranted. This trial was registered at clinicaltrials.gov as NCT02244684. PMID- 26063068 TI - Prenatal Iron Supplementation Reduces Maternal Anemia, Iron Deficiency, and Iron Deficiency Anemia in a Randomized Clinical Trial in Rural China, but Iron Deficiency Remains Widespread in Mothers and Neonates. AB - BACKGROUND: Previous trials of prenatal iron supplementation had limited measures of maternal or neonatal iron status. OBJECTIVE: The purpose was to assess effects of prenatal iron-folate supplementation on maternal and neonatal iron status. METHODS: Enrollment occurred June 2009 through December 2011 in Hebei, China. Women with uncomplicated singleton pregnancies at <=20 wk gestation, aged >=18 y, and with hemoglobin >=100 g/L were randomly assigned 1:1 to receive daily iron (300 mg ferrous sulfate) or placebo + 0.40 mg folate from enrollment to birth. Iron status was assessed in maternal venous blood (at enrollment and at or near term) and cord blood. Primary outcomes were as follows: 1) maternal iron deficiency (ID) defined in 2 ways as serum ferritin (SF) <15 MUg/L and body iron (BI) <0 mg/kg; 2) maternal ID anemia [ID + anemia (IDA); hemoglobin <110 g/L]; and 3) neonatal ID (cord blood ferritin <75 MUg/L or zinc protoporphyrin/heme >118 MUmol/mol). RESULTS: A total of 2371 women were randomly assigned, with outcomes for 1632 women or neonates (809 placebo/folate, 823 iron/folate; 1579 mother-newborn pairs, 37 mothers, 16 neonates). Most infants (97%) were born at term. At or near term, maternal hemoglobin was significantly higher (+5.56 g/L) for iron vs. placebo groups. Anemia risk was reduced (RR: 0.53; 95% CI: 0.43, 0.66), as were risks of ID (RR: 0.74; 95% CI: 0.69, 0.79 by SF; RR: 0.65; 95% CI: 0.59, 0.71 by BI) and IDA (RR: 0.49; 95% CI: 0.38, 0.62 by SF; RR: 0.51; 95% CI: 0.40, 0.65 by BI). Most women still had ID (66.8% by SF, 54.7% by BI). Adverse effects, all minor, were similar by group. There were no differences in cord blood iron measures; >45% of neonates in each group had ID. However, dose response analyses showed higher cord SF with more maternal iron capsules reported being consumed (beta per 10 capsules = 2.60, P < 0.05). CONCLUSIONS: Prenatal iron supplementation reduced anemia, ID, and IDA in pregnant women in rural China, but most women and >45% of neonates had ID, regardless of supplementation. This trial was registered at clinicaltrials.gov as NCT02221752. PMID- 26063069 TI - Targeted Beverage Taxes Influence Food and Beverage Purchases among Households with Preschool Children. AB - BACKGROUND: How beverage taxes might influence purchases of foods and beverages among households with preschool children is unclear. Thus, we examined the relation between beverage taxes and food and beverage purchases among US households with a child 2-5 y of age. OBJECTIVES: We examined how a potential tax on sugar-sweetened beverages (SSBs), or SSBs and >1% fat and/or high-sugar milk, would influence household food and beverage purchases among US households with a preschool child. We aimed to identify the lowest tax rate associated with meaningful changes in purchases. METHODS: We used household food and beverage purchase data from households with a single child who participated in the 2009 2012 Nielsen Homescan Panel. A 2-part, multilevel panel model was used to examine the relation between beverage prices and food and beverage purchases. Logistic regression was used in the first part of the model to estimate the probability of a food/beverage being purchased, whereas the second part of the model used log linear regression to estimate predicted changes in purchases among reporting households. Estimates from both parts were combined, and bootstrapping was performed to obtain corrected SEs. In separate models, prices of SSBs, or SSBs and >1% and/or high-sugar milk, were perturbed by +10%, +15%, and +20%. Predicted changes in food and beverage purchases were compared across models. RESULTS: Price increases of 10%, 15%, and 20% on SSBs were associated with fewer purchases of juice drinks, whereas price increases of 10%, 15%, and 20% simulated on both SSBs plus >1% fat and/or high-sugar milk (combined tax) were associated with fewer kilocalories purchased from >1% fat, low-sugar milk, and meat, poultry, fish, and mixed meat dishes. CONCLUSIONS: Our study provides further evidence that a tax on beverages high in sugar and/or fat may be associated with favorable changes in beverage purchases among US households with a preschool child. PMID- 26063071 TI - The shading sign: is it exclusive of endometriomas? AB - OBJECTIVES: To investigate if the shading sign is an exclusive MRI feature of endometriomas or endometrioid tumors, and to analyze its different patterns. METHODS: Three hundred and fourty six women with adnexal masses who underwent 1.5/3-T MRI were included in this retrospective, board-approved study. The shading sign was found in 56 patients, but five cases were excluded due to lack of imaging follow-up or histological correlation. The final sample included 51 women. The type of tumor and the pattern of shading were recorded for each case. RESULTS: Thirty endometriomas and five endometrioid carcinomas were found. The remaining 16 cases corresponded to other benign and malignant tumors. The overall sensitivity, specificity, positive predictive value, and negative predictive value were 73%, 93%, 59%, and 96%, respectively. Restricting the analysis to cystic lesions without solid or fat component, sensitivity, specificity, positive predictive value, and negative predictive value were 73%, 96%, 94%, and 80%. Five shading patterns were identified: layering (15.7%), liquid-liquid level (11.8%), homogenous (45.1%), heterogeneous (11.8%), and focal/multifocal shading within a complex mass (19.6%). No significant correlation was found between these patterns and the type of tumor. CONCLUSIONS: The shading sign is not exclusive of endometriomas or endometrioid tumors. Homogenous shading was the most prevalent pattern in endometriomas and half of the cases with focal/multifocal shading within a complex mass were endometrioid carcinomas. PMID- 26063072 TI - Imaging of body packing: errors and medico-legal issues. AB - Body packing is the ingestion or insertion in the human body of packed illicit substances. Over the last 20 years, drug smuggling has increased global and new means of transport of narcotics have emerged. Among these, the most frequent one is the gastrointestinal tract: from mouth to anus, vagina, and ears. Cocaine is one of the most traded drugs, followed by heroin. Condoms, latex gloves, and balloons are typically used as drug packets for retention in the body. There are different radiologic modalities to detect illicit drugs in body packing: Plain radiography, computed tomography (CT), ultrasound, and magnetic resonance. Current protocols recommend the use of radiography to confirm packet retention and, in case of doubt, the use of abdominal CT scan with reduced mAs. In case of packet rupture, catastrophic effects can occur. Management of patients carrying packets of drugs is a recurrent medico-legal problem. To improve diagnostic accuracy and prevent hazardous complications, radiologists and emergency physicians should be familiar with radiologic features of body packing. The radiologist plays both a social and a medico-legal role in their assessment, and it should not be limited only to the identification of the packages but must also provide accurate information about their number and their exact location. In this review, we focus on diagnostic errors and medico-legal issues related to the radiological assessment of body packers. PMID- 26063073 TI - Diagnostic accuracy study of a factor VIII ELISA for detection of factor VIII antibodies in congenital and acquired haemophilia A. AB - Antibody formation to factor VIII (FVIII) remains the greatest clinical and diagnostic challenge to the haemophilia-treating physician. Current guidance for testing for inhibitory FVIII antibodies (inhibitors) recommends the functional Nijmegen-Bethesda assay (NBA). A FVIII ELISA offers a complementary, immunological approach for FVIII antibody testing. It was the aim of this study to retrospectively evaluate the performance of a FVIII ELISA (index) for detection of FVIII antibodies, compared with the NBA (reference). All samples sent for routine FVIII antibody testing at two haemophilia Comprehensive Care Centres, were tested in parallel using the NBA and a solid-phase, indirect FVIII ELISA kit (Immucor). A total of 497 samples from 239 patients (severe haemophilia A=140, non-severe haemophilia A=85, acquired haemophilia A=14) were available for analysis. Sixty-three samples tested positive by the NBA (prevalence 12.7%, 95% confidence interval [CI], 9.9-15.9 %), with a median inhibitor titre of 1.2 BU/ml (range 0.7-978.0). The FVIII ELISA demonstrated a specificity of 94.0% (95%CI, 91.3-96.0), sensitivity of 77.8% (95%CI, 65.5-87.3), negative predictive value of 96.7% (95%CI, 94.5-98.2), positive predictive value 65.3% (95%CI, 53.5-76.0), negative likelihood ratio 0.2 (95%CI, 0.1-0.4), positive likelihood ratio 13.0 (95%CI, 8.7-19.3) and a diagnostic odds ratio of 54.9 (95%CI, 27.0-112.0). Strong positive correlation (r=0.77, p<0.001) was seen between the results of the NBA (log adjusted) and FVIII ELISA optical density. In conclusion, FVIII ELISA offers a simple, specific, surveillance method enabling batch testing of non-urgent samples for the presence of FVIII antibodies. PMID- 26063070 TI - Membrane Protein Structure, Function, and Dynamics: a Perspective from Experiments and Theory. AB - Membrane proteins mediate processes that are fundamental for the flourishing of biological cells. Membrane-embedded transporters move ions and larger solutes across membranes; receptors mediate communication between the cell and its environment and membrane-embedded enzymes catalyze chemical reactions. Understanding these mechanisms of action requires knowledge of how the proteins couple to their fluid, hydrated lipid membrane environment. We present here current studies in computational and experimental membrane protein biophysics, and show how they address outstanding challenges in understanding the complex environmental effects on the structure, function, and dynamics of membrane proteins. PMID- 26063074 TI - Knockdown of SUMO-activating enzyme subunit 2 (SAE2) suppresses cancer malignancy and enhances chemotherapy sensitivity in small cell lung cancer. AB - BACKGROUND: SUMO-activating enzyme subunit 2 (SAE2) is the sole E1-activating enzyme required for numerous important protein SUMOylation, abnormal of which is associated with carcinogenesis. SAE2 inactivation was recently reported to be a therapeutic strategy in cancers with Myc overexpression. However, the roles of SAE2 in small cell lung cancer (SCLC) are largely unknown. METHODS: Stably SAE2 knockdown in H446 cells were established with a lentiviral system. Cell viability, cell cycle, and apoptosis were analyzed using MTT assay and flow cytometric assay. Expression of SAE2 mRNA and protein were detected by qPCR, western blotting, and immunohistochemical staining. Cell invasion and migration assay were determined by transwell chamber assay. H446 cells with or without SAE2 knockdown, nude mice models were established to observe tumorigenesis. RESULTS: SAE2 was highly expressed in SCLC and significantly correlated with tumorigenesis in vivo. Cancer cells with RNAi-mediated reduction of SAE2 expression exhibited growth retardation and apoptosis increasing. Furthermore, down-regulation of SAE2 expression inhibited migration and invasion, simultaneously increased the sensitivity of H446 to etoposide and cisplatin. CONCLUSIONS: SAE2 plays an important role in tumor growth, metastasis, and chemotherapy sensitivity of H446 and is a potential clinical biomarker and therapeutic target in SCLC with high c Myc expression. PMID- 26063075 TI - [Image-guided pain therapy. Sympathicolysis]. AB - BACKGROUND: In the autonomic nerve system most sympathetic neurons synapse peripherally in the ganglia of the sympathetic trunk. A reduction in sympathicotonia by partial elimination of these ganglia is a therapeutic approach that has been used for more than 100 years. In the early 1920s the first attempts at percutaneous sympathicolysis (SL) were carried out. Nowadays, minimally invasive image-guided SL has become an integral part of interventional radiology. Established indications for SL are hyperhidrosis, critical limb ischemia and the complex regional pain syndrome. METHODS: The standard imaging guidance modality in SL is computed tomography (CT) which allows the exact placement of the puncture needle in the target area under visualization of the surrounding structures. Ethanol is normally used for chemical lysis, which predominantly eliminates the unmyelinated autonomic axons. In order to visualize the distribution of the ethanol during application, iodine-containing contrast medium is added. RESULTS: The sympathetic nervous system (SNS) controls sweat secretion via the efferent neurons; therefore, effective therapy of idiopathic palmar, axillary and plantar hyperhidrosis can be achieved when SL is performed at the corresponding level of the sympathetic trunk. Furthermore, due to the vasomotor innervation of most blood vessels, by reduction of the sympathicotonus an atony of the smooth muscles and therefore vasodilatation occurs, which is used as a palliative therapeutic option in patients with critical limb ischemia. By elimination of the afferent sensory fibers this also results in pain relief. This principle is also used in the SL therapy of the complex regional pain syndrome. CONCLUSION: After the introduction of CT guidance, major complications have become rare events. In addition to the usual risks of percutaneous interventions there are, however, a number of specific complications, such as syncope caused by irritation of cardiac sympathetic nerves in thoracic SL and ureteral injury in lumbar SL. PMID- 26063076 TI - [Drug therapy in interventional radiology]. AB - In the context of pre-interventional drug therapy, a premedication is given to patients who are known to have an allergy to contrast media, have renal impairment or hyperthyroidism. An already existing anticoagulation therapy, in anticipation of the planned intervention, must be reviewed and changed or even suspended as required. For peri-interventional drug therapy it is important to consider how strenuous the procedure will be as well as the general condition of the patient. Further discussion with anesthetists may be required for the planning of pain therapy or sedation during the procedure. These factors help to ensure maximum patient comfort as well as the success of the intervention. Post interventional anticoagulation therapy, usually started peri-interventionally, plays an important role in minimizing the risk of acute thrombosis as well as in maintaining long-term functioning of the implanted material. The form of the anticoagulation therapy is set according to the type of intervention. PMID- 26063078 TI - Thuja orientalis reduces airway inflammation in ovalbumin-induced allergic asthma. AB - Thuja orientalis (TO) may be used as a herbal remedy for the treatment of numerous inflammatory diseases. In the present study, the effects of TO were evaluated on airway inflammation in ovalbumin (OVA)-induced allergic asthma and RAW264.7 murine macrophage cells. The effects of TO on the production of proinflammatory mediators, were determined in RAW264.7 cells that had been stimulated with lipopolysaccharide (LPS). Furthermore, an in vivo experiment was performed on mice that were sensitized to OVA and then received an OVA airway challenge. TO was administered by daily oral gavage at a dose of 30 mg/kg, 21-23 days after the initial OVA sensitization. TO was shown to reduce nitric oxide production and reduce the relative mRNA expression levels of inducible nitric oxide synthase (iNOS), interleukin (IL)-6, cyclooxygenase-2, matrix metalloproteinase (MMP)-9, and tumor necrosis factor-alpha in RAW264.7 cells stimulated with LPS. In addition, TO markedly decreased the inflammatory cell counts in bronchial alveolar lavage fluid, reduced the levels of IL-4, IL-5, IL 13, eotaxin and immunoglobulin E, and reduced airway hyperresponsivenes, in the OVA sensitized mice. Furthermore, TO attenuated airway inflammation and mucus hypersecretion, induced by the OVA challenge of the lung tissue. TO also reduced the expression of iNOS and MMP-9 in lung tissue. In conclusion, TO exerted anti inflammatory effects in an OVA-induced allergic asthma model, and in LPS stimulated RAW264.7 cells. These results suggest that TO may be a useful therapeutic agent for the treatment of inflammatory diseases, including allergic asthma. PMID- 26063079 TI - Reduction of the Incidence of Delayed Gastric Emptying in Side-to-Side Gastrojejunostomy in Subtotal Stomach-Preserving Pancreaticoduodenectomy. AB - BACKGROUND: One of the most common morbidities of pancreaticoduodenectomies is delayed gastric emptying (DGE). The recent advent of subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) attempts to lessen this troublesome complication; however, the incidence of DGE still remains to be 4.5-20%. This study aims to evaluate whether the incidence of DGE can be reduced by the side-to-side gastric greater curvature-to-jejunal anastomosis in comparison with the gastric stump-to jejunal end-to-side anastomosis in SSPPD. METHODS: Between October 2007 and September 2012, a total of 160 consecutive patients who had undergone SSPPD were analyzed retrospectively. In the first period (October 2007-March 2010), gastrojejunostomy was performed with end-to-side anastomosis in 80 patients (SSPPD-ETS group). In the second period (April 2010-September 2012), gastrojejunostomy was performed with the greater curvature side-to-jejunal side anastomosis in 80 patients (SSPPD-STS group). The postoperative data were collected prospectively in a database and reviewed retrospectively. RESULTS: The incidence of DGE was 21.3% in the SSPPD-ETS group and 2.5% in the SSPPD-STS group (P = 0.0002). According to the classification of the International Study Group of Pancreatic Surgery (ISGPS), the incidence of DGE of grades A, B, and C were 5, 5, and 7 in the SSPPD-ETS group and 0, 2, and 0 in the SSPPD-STS group, respectively. The overall morbidity and postoperative hospital stay of the two groups were not significantly different. CONCLUSIONS: The greater curvature side to-side anastomosis of gastrojejunostomy is associated with a reduced incidence of DGE after SSPPD. PMID- 26063081 TI - Factors Associated with Word Memory Test Performance in Persons with Medically Documented Traumatic Brain Injury. AB - OBJECTIVES: (1) To examine the rate of poor performance validity in a large, multicenter, prospectively accrued cohort of community dwelling persons with medically documented traumatic brain injury (TBI), (2) to identify factors associated with Word Memory Test (WMT) performance in persons with TBI. METHOD: This was a prospective cohort, observational study of 491 persons with medically documented TBI. Participants were administered a battery of cognitive tests, questionnaires on emotional distress and post-concussive symptoms, and a performance validity test (WMT). Additional data were collected by interview and review of medical records. RESULTS: One hundred and seventeen participants showed poor performance validity using the standard cutoff. Variable cluster analysis was conducted as a data reduction strategy. Findings revealed that the 10 cognitive tests and questionnaires could be summarized as 4 indices of emotional distress, speed of cognitive processing, verbal memory, and verbal fluency. Regression models revealed that verbal memory, emotional distress, age, and injury severity (time to follow commands) made unique contribution to prediction of poor performance validity. CONCLUSIONS: Poor performance validity was common in a research sample of persons with medically documented TBI who were not evaluated in conjunction with litigation, compensation claims, or current report of symptoms. Poor performance validity was associated with poor performance on cognitive tests, greater emotional distress, lower injury severity, and greater age. Many participants expected to have residual deficits based on initial injury severity showed poor performance validity. PMID- 26063082 TI - Impact of Demographic Changes on the Natural Course, Features and Prognosis of Critical Limb Ischemia. PMID- 26063080 TI - Defining Post Hepatectomy Liver Insufficiency: Where do We stand? AB - BACKGROUND: Post-hepatectomy liver failure (PHLF) is a major source of morbidity and mortality in patients undergoing liver resection. The aim of this review is to summarize the recent literature available on PHLF including its definition, predictive factors, preoperative risk assessment, severity grading, preventative measures, and management strategies. METHODS: A systematic literature search was carried out with the search engines PubMed, Medline, and Cochrane Database using the keywords related to "liver failure", "posthepatectomy", and "hepatic resection". RESULTS: Liver resection is a curative treatment of liver tumors. However, it leads to concurrent death and regeneration of the remaining hepatocytes. Factors related to the patient, liver parenchyma and the extent of surgery can inhibit regeneration leading to PHLF. CONCLUSION: Given its resistance to treatment and the high postoperative mortality associated with PHLF, great effort has been put in to both accurately identify patients at high risk and to develop strategies that can help prevent its occurrence. PMID- 26063083 TI - How Should We Evaluate the Activity of Myocardial Inflammation and Guide Corticosteroid Treatment in Patients With Cardiac Sarcoidosis? PMID- 26063085 TI - Australian vaccine preventable disease epidemiological review series: measles 2000-2011. AB - BACKGROUND: Since the introduction of measles vaccine to the vaccination schedule, the burden of measles has substantially fallen in Australia. Despite this, a number of recent measles outbreaks have occurred. The aim of this study was to examine the burden of measles in Australia using notification, hospitalisation and mortality data with the objectives of setting a baseline for comparison prior to the introduction of the combined measles-mumps-rubella varicella vaccine. METHODS: Data were obtained from the Australian National Notifiable Diseases Surveillance System, the National Hospital Morbidity Database and the National Mortality Database to obtain notification, hospitalisation and death data, respectively from 2000 to 2011. Rates were calculated and compared over time by age group and jurisdiction. RESULTS: Since 1993, measles notifications have fallen considerably in Australia. However, between 2000 and 2011, measles notification rates and hospitalisation rates fluctuated. Between 2000 and 2011, there were 990 measles notifications in Australia. The average annual notification rate was 0.4 per 100,000 population. Children aged 0-4 years were the most susceptible group, particularly infants less than 1 year of age (average annual rate, 1.6 per 100,000 population). High incidence was also observed in adolescents (average annual rate, 0.7 per 100,000 population) and young adults (average annual rate, 0.8 per 100,000 population). Jurisdictional variation occurred with differing patterns of notifications and hospitalisations. CONCLUSIONS: Although a marked reduction in measles notifications and hospitalisations has occurred in the past decade, susceptible individuals should be vaccinated to prevent outbreaks and to maintain a low incidence of measles and Australia's elimination status. PMID- 26063084 TI - Rhodiola rosea suppresses thymus T-lymphocyte apoptosis by downregulating tumor necrosis factor-alpha-induced protein 8-like-2 in septic rats. AB - In recent years, several studies have shown that Rhodiola rosea can enhance cellular immunity and humoral immune function in mice, and thus, it has become a research hotspot. However, its underlying mechanism of action has remained elusive. The present study investigated whether Rhodiola rosea was able to downregulate the expression of tumor necrosis factor-alpha-inducible protein 8 like 2 (TIPE2), thereby inhibiting the expression of apoptotic genes, attenuating T-lymphocyte apoptosis and improving immunity in septic mice. A mouse model of caecal ligation and puncture (CLP)-induced sepsis was established, and animals in the treatment group were pre-treated with an intraperitoneal injection of Rhodiola rosea extract, while animals in the control group and sham-operated group were injected with an equivalent amount of normal saline. TIPE2, B-cell lymphoma 2 (Bcl-2), Fas and Fas ligand (FasL) mRNA and protein levels in thymic T cells were determined using reverse transcription quantitative polymerase chain reaction and western blot analysis, respectively. Furthermore, the thymus T lymphocyte apoptosis rate, thymus T-lymphocyte count and thymus T-lymphocyte sub sets were assessed using flow cytometry. Levels of T-helper cell type 1 (Th1) cytokines [Interleukin (IL)-2, IL-12 and interferon (IFN)-gamma] and Th2 cytokines (IL-4 and IL-10) were determined using ELISA. The results showed that, compared to that in the CLP group, the expression of TIPE2, Fas and FasL in the treatment group was significantly decreased, while the expression of Bcl-2 was increased (P<0.05). The thymus lymphocyte count in the CLP group was significantly higher compared with that in the treatment group (P<0.05). Furthermore, the apoptotic rate of thymus T-lymphocytes in the treatment group was significantly lower than that in the CLP group (P<0.05). In addition, treatment with Rhodiola rosea rescued decreased in the counts of the CD3(+) T and CD4(+) T sub-sets of thymus T lymphocytes in the CLP group (P<0.05), while not affecting the increased levels of Th2 cytokines (IL-4 and IL-10) in the CLP group compared with those in the control groups. In addition, the Th1 cytokines (IL-12, IL-2 and IFN-gamma) were significantly increased (P<0.05) in the CLP group, and treatment with Rhodiola rosea led to further increases. The thymus index of septic mice treated with Rhodiola rosea as well as their survival rate were improved as compared with those in the CLP group. These findings suggested that Rhodiola rosea has protective effects against sepsis by decreasing apoptosis, increasing Th1 cytokines and enhancing the host's immunity via the regulation of TIPE2 expression. PMID- 26063086 TI - Australian vaccine preventable disease epidemiological review series: mumps 2008 2012. AB - In 2007, Australia recorded the highest notification rate (2.8 per 100,000) for mumps since it became notifiable, with outbreaks in Western Australia and the Northern Territory. Of particular concern was the number of cases seen in vaccinated individuals. The aim of this study was to review subsequent epidemiological data. Notification, hospitalisation and mortality data from the National Notifiable Diseases Surveillance System, the National Hospital Morbidity Database and Australian Bureau of Statistics (ABS) respectively, from 2008 to 2012 for notifications and 2008 to 2011 for hospitalisations and deaths, were analysed by age, year and jurisdiction. ABS population data were used to calculate rates. National mumps notification rates decreased from 1.3 per 100,000 in 2008 to 0.4 per 100,000 in 2010, but then increased to 0.9 per 100,000 in 2012, predominantly due to increased notifications in New South Wales (1.4 per 100,000). Hospitalisation rates remained stable at 0.4 per 100,000 over the 2008 2011 period. The median age of notified cases was 30 years and for hospitalisations, 27 years. The highest rate of notifications and hospitalisations was in the 25-34 years age group. Completeness of vaccination status ranged from 16% to 39%. The increasing trend in mumps notifications needs to be closely monitored. Improved data quality, in particular on vaccination status, is needed to inform the monitoring of vaccine effectiveness. In March 2014 the World Health Organization certified that Australia had achieved measles elimination. Greater availability of case history (vaccination status and place of acquisition) and genotyping data would facilitate an assessment of Australia's progress in relation to mumps elimination. PMID- 26063087 TI - Australian Gonococcal Surveillance Programme annual report, 2013. AB - The Australian Gonococcal Surveillance Programme has continuously monitored antimicrobial resistance in clinical isolates of Neisseria gonorrhoeae from all states and territories since 1981. In 2013, 4,897 clinical isolates of gonococci from public and private sector sources were tested for in vitro antimicrobial susceptibility by standardised methods. Decreased susceptibility to ceftriaxone (MIC value 0.06-0.125 mg/L) was found nationally in 8.8% of isolates, double that reported in 2012 (4.4%). The highest proportions were reported from New South Wales and Victoria (both states reporting 11.8%), with a high proportion of strains also reported from Tasmania but a low number of isolates were tested. In addition, there was a multi-drug-resistant strain of N. gonorrhoeae isolated from a traveller to Australia, with a ceftraixone MIC value of 0.5 mgL-the highest ever reported in Australia. These antimicrobial resistance data from Australia in 2013 are cause for considerable concern. With the exception of remote Northern Territory where penicillin resistance rates remain low (1.3%) the proportion of strains resistant to penicillin remained high in all jurisdictions ranging from 15.6% in the Australian Capital Territory to 44.1% in Victoria. Quinolone resistance ranged from 16% in the Australian Capital Territory to 46% in Victoria. Azithromycin susceptibility testing was performed in all jurisdictions and resistance ranged from 0.3% in the Northern Territory to 5.7% in Queensland. High level resistance to azithromycin (MIC value was > 256 mg/L) was reported for the first time in Australia, in 4 strains: 2 each from Queensland and Victoria. Azithromycin resistant gonococci were not detected in the Australian Capital Territory, Tasmania or from the remote Northern Territory. Nationally, all isolates remained susceptible to spectinomycin. PMID- 26063088 TI - National trachoma surveillance annual report, 2012. AB - Australia remains the only developed country to have endemic levels of trachoma (a prevalence of 5% or greater among children) in some regions. Endemic trachoma in Australia is found predominantly in remote and very remote Aboriginal communities. The Australian Government funds a National Trachoma Surveillance and Reporting Unit to collate, analyse and report trachoma prevalence data and document trachoma control strategies in Australia through an annual surveillance report. This report presents data collected in 2012. Data are collected from Aboriginal and Torres Strait communities designated as at-risk for endemic trachoma in the Northern Territory, Queensland, South Australia and Western Australia. The World Health Organization grading criteria were used to diagnose cases of trachoma in Aboriginal children with jurisdictions focusing screening activities on the 5-9 years age group; however, some children in the 1-4 and 10 14 years age groups were also screened. The prevalence of trachoma within a community was used to guide treatment strategies as a public health response. Aboriginal adults aged 40 years or older were screened for trichiasis. Community screening coverage of the designated at-risk communities was 96%. Screening coverage of the estimated population of children aged 5-9 years and adults aged 40 years or older in at-risk communities was 71% and 31%, respectively. Trachoma prevalence among children aged 5-9 years who were screened was 4%. Of communities screened, 63% were found to have no cases of active trachoma and 25% were found to have endemic levels of trachoma. Treatment was required in 87 at-risk communities screened. Treatment coverage of active cases and their contacts varied from 79%-97% between jurisdictions. Trichiasis prevalence was 2% within the screened communities. PMID- 26063089 TI - National Notifiable Diseases Surveillance System, 1 October to 31 December 2014. PMID- 26063090 TI - Australian childhood immunisation coverage, 1 January to 31 March cohort, assessed as at 30 June 2014. PMID- 26063091 TI - Australian childhood immunisation coverage, April to June cohort, assessed as at 30 September 2014. PMID- 26063092 TI - Australian Sentinel Practices Research Network, 1 October to 31 December 2013. PMID- 26063093 TI - Invasive pneumococcal disease surveillance Australia, 1 July to 30 September 2014. PMID- 26063094 TI - Australian vaccine preventable disease epidemiological review series: rubella 2008-2012. AB - INTRODUCTION: Since the introduction of universal rubella vaccination in 1989, the incidence of rubella and congenital rubella syndrome (CRS) in Australia has declined significantly. Worldwide, there has been a focus on elimination, with the region of the Americas declaring rubella elimination in 2011. This study aims to review Australian rubella epidemiology for the 2008-2012 period, in the context of historical and international trends. METHODS: Notification, hospitalisation and mortality data were sourced from the National Notifiable Diseases Surveillance System, the National Hospital Morbidity Database and the Australian Bureau of Statistics (ABS). Data analysis focused on 2008-2012 for notifications and 2008-2011 for hospitalisations and deaths. ABS population data were used to calculate rates. RESULTS: The average annual rubella notification rate in Australia from 2008-2012 was 0.18 per 100,000 and the average annual hospitalisation rate was 0.03 per 100,000 from 2008-2011. One case of CRS was notified in 2012 and 1 hospitalisation with a principal diagnosis of CRS was recorded in 2008. The median age of rubella notifications was 29 years and 37% of notifications were for infections acquired overseas. DISCUSSION: Rubella continues to be well controlled in Australia and CRS is rare. The low incidence and increasing proportion of imported cases and other evidence suggest that elimination has been achieved; however, for formal verification of rubella elimination the expansion of genotypic surveillance will be required. Ongoing rubella control needs to focus on improved surveillance, maintenance of high levels of vaccine coverage, vaccination of at-risk populations in Australia, and regional and global efforts towards rubella elimination. PMID- 26063095 TI - A field study of household attack rates and the effectiveness of macrolide antibiotics in reducing household transmission of pertussis. AB - Bordetella pertussis (whooping cough) is an endemic, highly contagious bacterial respiratory infection, which is notifiable to Australian state and territory health departments. Between 2008 and 2011 there was a substantial outbreak in New South Wales with an initial increase in cases occurring in North Coast New South Wales from late 2007. During September and October 2011 the North Coast Public Health Unit conducted a household study of secondary attack rates to assess the effectiveness of pertussis vaccination as well as the timely use of antibiotics in preventing household transmission. At the time the study was commenced, notified cases included a large proportion of individuals with a documented history of vaccination against pertussis. We found lower attack rates amongst vaccinated compared with non-vaccinated subjects in all age groups, with the exception of the 5-11 years age group, who were also primarily responsible for the introduction of pertussis into the household. There was an increased risk of pertussis transmission from the household first primary case to contacts when antibiotic treatment was commenced later than 7 days after the onset of symptoms compared with within 7 days. This protective effect of timely antibiotic treatment in relation to transmission highlights the need to control for antibiotic treatment in field studies of pertussis. The benefits of timely diagnosis and use of antibiotics in preventing household transmission underscore the importance of early presentation and diagnosis of pertussis cases, particularly in households with susceptible occupants. PMID- 26063096 TI - Norovirus genotype diversity associated with gastroenteritis outbreaks in Victoria in 2013. AB - The noroviruses are now considered a leading cause of outbreaks of non-bacterial gastroenteritis worldwide. Vaccine strategies against norovirus are currently under consideration but depend on a detailed knowledge of the capsid genotypes. This study examined the incidence of norovirus outbreaks in Victoria over 1 year (2013) and documented the genotypes occurring in the different outbreak settings (healthcare and non-healthcare) and age groups. It was found that 63.1% of gastroenteritis outbreaks were associated with norovirus, thereby showing norovirus to be the major viral cause of illness in gastroenteritis outbreaks. Sixteen capsid genotypes were identified and included GI.2, GI.3, GI.4, GI.6, GI.7, GI.8, GI.9, GII.1, GII.2, GII.3, GII.4, GII.5, GII.6, GII.7, GII.13 and an as yet unclassified GII genotype. All genotypes found in the study, with the exception of GI.9, were detected in the elderly, indicating prior exposure to a norovirus genotype did not appear to confer long term immunity in many cases. The incidence of genotypes GII.1, GII.4 and GII.7 was linked with setting and age. As setting and age were correlated it was not possible to determine which variable was critical with the exception of GII.7, which appeared to be linked to age. The findings indicate that norovirus vaccine strategies should encompass a broad range of genotypes and, as setting or age may be important in determining genotype incidence, this should be taken into account as well. PMID- 26063097 TI - Review of 2005 Public Health Laboratory Network Neisseria gonorrhoeae nucleic acid amplification tests guidelines. AB - At the request of the Public Health Laboratory Network (PHLN), the National Neisseria Network (NNN) met to discuss the 2009 PHLN Neisseria gonorrhoeae nucleic acid amplification test (NAAT) guidelines and the need for supplementary testing. A central point of discussion at this NNN meeting, which took place in May 2013, was the potential for N. gonorrhoeae supplementary testing to lead to false-negative results. Data were presented at the meeting that questioned the sensitivity of commonly used in-house supplementary methods as compared with later generation commercial NAAT systems. It was the opinion of the NNN that supplementary testing remains best practice, but that caution should be used when reporting negative results. The NNN recommends that urogenital samples providing a positive result in a screening method and a negative result by a supplemental method should not be reported as negative for N. gonorrhoeae without an appropriate explanatory comment indicating that gonococcal infection cannot be excluded. PMID- 26063098 TI - Australia's notifiable disease status, 2012: Annual report of the National Notifiable Diseases Surveillance System. AB - In 2012, 65 diseases and conditions were nationally notifiable in Australia. States and territories reported a total of 243,822 notifications of communicable diseases to the National Notifiable Diseases Surveillance System, an increase of 2% on the number of notifications in 2011. In 2012, the most frequently notified diseases were sexually transmissible infections (99,250 notifications, 40.7% of total notifications), vaccine preventable diseases (85,810 notifications, 35.2% of total notifications), and gastrointestinal diseases (31,155 notifications, 12.8% of total notifications). There were 16,846 notifications of bloodborne diseases; 8,305 notifications of vector-borne diseases; 1,924 notifications of other bacterial infections; 578 notifications of zoonoses; and 5 notifications of quarantinable diseases. PMID- 26063099 TI - Designed filamentous cell penetrating peptides: probing supramolecular structure dependent membrane activity and transfection efficiency. AB - In this work, we will demonstrate a simple yet powerful strategy to assemble single-chain cationic peptides into macromolecular filamentous nanostructures with dramatically improved membrane activity, stability and transfection efficiency. PMID- 26063100 TI - Copper-Free Postsynthetic Labeling of Nucleic Acids by Means of Bioorthogonal Reactions. AB - Postsynthetic modification of nucleic acids has the advantage that the chemical development of only a few building blocks is necessary, each bearing a chosen reactive functional group that is applicable to its reactive counterpart for a variety of different labeling types. The reactive group is either linked to phosphoramidites for chemical synthesis on solid phase or attached to nucleoside triphosphates for application in primer extension experiments and PCR. Chemoselectivity is required for this strategy, together with bioorthogonality to perform these labelings in living cells or even organisms. Currently, the copper free reactions include strain-promoted 1,3-dipolar cycloadditions, "photoclick" reactions, Diels-Alder reactions with inverse electron demand, and nucleophilic additions. The majority of these modification strategies show good to excellent reaction kinetics, an important prerequisite for labeling inside cells and in vivo in order to keep the concentrations of the reacting partners as low as possible. PMID- 26063102 TI - International Journal of Surgery. Editor's perspectives--June 2015. PMID- 26063101 TI - Bacterial imaging and photodynamic inactivation using zinc(II)-dipicolylamine BODIPY conjugates. AB - Targeted imaging and antimicrobial photodynamic inactivation (PDI) are emerging methods for detecting and eradicating pathogenic microorganisms. This study describes two structurally related optical probes that are conjugates of a zinc(II)-dipicolylamine targeting unit and a BODIPY chromophore. One probe is a microbial targeted fluorescent imaging agent, mSeek, and the other is an oxygen photosensitizing analogue, mDestroy. The conjugates exhibited high fluorescence quantum yield and singlet oxygen production, respectively. Fluorescence imaging and detection studies examined four bacterial strains: E. coli, S. aureus, K. pneumonia, and B. thuringiensis vegetative cells and purified spores. The fluorescent probe, mSeek, is not phototoxic and enabled detection of all tested bacteria at concentrations of ~100 CFU mL(-1) for B. thuringiensis spores, ~1000 CFU mL(-1) for S. aureus and ~10,000 CFU mL(-1) for E. coli. The photosensitizer analogue, mDestroy, inactivated 99-99.99% of bacterial samples and selectively killed bacterial cells in the presence of mammalian cells. However, mDestroy was ineffective against B. thuringiensis spores. Together, the results demonstrate a new two-probe strategy to optimize PDI of bacterial infection/contamination. PMID- 26063103 TI - Conditions that induce biofilm production by Ornithobacterium rhinotracheale. AB - Ornithobacterium rhinotracheale (ORT) is a Gram-negative bacillus that causes respiratory disease in birds, and directly affects the poultry industry. The mechanisms behind these infections are not completely known. Currently, its capacity to form biofilms on inert surfaces has been reported; however, the conditions for biofilm development have not been described yet. The present work was aimed at identifying the conditions that enhance in vitro biofilm formation and development by ORT. For this, serovars A-E were analysed to assess their ability to induce biofilm development on 96-well flat-bottom polystyrene microtitre plates under diverse conditions: temperature, incubation time, and CO2 concentration. The results obtained showed not only that all serovars have the ability to produce in vitro biofilms, but also that the optimal conditions for biofilm density were 40 degrees C after 72 h at an elevated CO2 concentration. In conclusion, ORT biofilm formation depends on the environmental conditions and may contribute to the persistence of this microorganism. PMID- 26063104 TI - Diaphragmatic herniation due to massive hepatomegaly in a patient with pulmonary arterial hypertension. PMID- 26063105 TI - Acute calcific periarthiritis of the knee presenting with calcification within the lateral collateral ligament. AB - A 71-year-old woman was admitted with acute swelling of the right knee, pain on the lateral aspect and restricted movement. There was no instability or locking. She had no history of trauma and was generally in good health. Plain radiographs demonstrated a calcific opacity adjacent to the lateral femoral condyle. This was shown to be within the lateral collateral ligament (LCL) at ultrasound and MRI. A diagnosis of acute calcific periarthritis (ACP) was made. The patient's symptoms resolved within a few weeks with simple analgaesia. ACP presenting with calcification within the LCL is rare. It is important to recognise the clinical and imaging findings of this condition as it may mimic other more serious pathologies such as infection and gout. This may result in unnecessary investigations, misdiagnoses and incorrect treatments. PMID- 26063106 TI - Bronchial-oesophageal fistula: a rare initial presentation of squamous cell carcinoma of the lung. AB - A 61-year-old Caucasian man with hypertension and hepatitis C presented to the emergency department with 7 days of productive cough and low-grade fevers despite outpatient therapy with oral azithromycin. On initial evaluation, he was lethargic with peripheral cyanosis and oxygen saturation in the low 70 s on room air, necessitating endotracheal intubation. Chest imaging revealed diffuse bilateral infiltrates compatible with the diagnosis of acute respiratory distress syndrome. Patient subsequently developed profound hypoxaemia and on day 2 of admission, veno-veno extracorporeal membrane oxygenation (ECMO) was initiated. Bronchoscopy revealed a necrotic ulcer on the posterior wall of the left mainstem bronchus, compatible with a bronchial-oesophageal fistula, which was later confirmed by endoscopy, and stented. Histology revealed poorly differentiated squamous cell carcinoma of the lung. Despite stenting of the fistula and ECMO support, the patient expired 5 days after admission. PMID- 26063107 TI - Group B streptococcal neonatal parotitis. AB - Acute neonatal parotitis (ANP) is a rare condition, characterised by parotid swelling and other local inflammatory signs. The most common pathogen is Staphylococcus aureus, but other organisms can be implicated. We describe the case of a 13-day-old term newborn, previously healthy, with late-onset group B Streptococcus (GBS) bacteraemia with ANP, who presented with irritability, reduced feeding and tender swelling of the right parotid. Laboratory evaluation showed neutrophilia, elevated C reactive protein and procalcitonin, with normal serum amylase concentration. Ultrasound findings were suggestive of acute parotitis. Empiric antibiotic therapy was immediately started and adjusted when culture results became available. The newborn was discharged after 10 days, with clinical improvement within the first 72 h. Although S. aureus is the most common pathogen implicated in ANP, GBS should be included in the differential diagnosis. PMID- 26063108 TI - Just another abdominal pain? Psoas abscess-like metastasis in large cell lung cancer with adrenal insufficiency. AB - The authors report the case of a 69-year-old man with chronic obstructive pulmonary disease and previous pulmonary tuberculosis, who presented to the emergency department with abdominal and low back pain, anorexia and weight loss, rapidly evolving into shock. An initial CT scan revealed pulmonary condensation with associated cavitation and an iliopsoas mass suggestive of a psoas abscess. He was admitted in an intensive care unit unit; after a careful examination and laboratory assessment, the aetiology was yet undisclosed. MRI showed multiple retroperitoneal lymphadenopathies, bulky nodular adrenal lesions and bilateral iliac lytic lesions. Hypocortisolism was detected and treated with steroids. A CT guided biopsy to the psoas mass and lytic lesions identified infiltration of non small lung carcinoma. The patient died within days. Psoas metastases and adrenal insufficiency as initial manifestations of malignancy are rare and can be misdiagnosed, particularly in the absence of a known primary tumour. PMID- 26063109 TI - Brachial artery pseudoaneurysm arising from the stump of a ligated arteriovenous fistula. AB - An 85-year-old man presented to A&E department with a bleeding, pulsatile mass within the left antecubital fossa. He reported a 3-month history of an increasing, painless swelling. He had a history of end-stage renal failure secondary to antiglomerular basement membrane disease. 14 years prior, he had a left brachiocephalic fistula created, which was ligated shortly after its creation due to Steal syndrome. Examination revealed a 10*15*10 cm pulsatile, non tender mass with overlying ulceration in the left antecubital fossa. Arterial duplex demonstrated a pseudoaneurysm arising from the left distal brachial artery with a 9 mm neck. The patient underwent surgical exploration and repair. At surgery, a large brachial artery pseudoaneurysm at the site of the previous fistula ligation was found. The overlying ulcerated skin and pseudoaneurysm were excised en mass, and the arterial defect repaired by transection and end-to-end anastomosis. This is the first reported case of a brachial artery pseudoaneurysm occurring following arteriovenous fistula ligation. PMID- 26063110 TI - Immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a severe opportunistic infection of the central nervous system. A 52-year-old man with HIV infection, recently started on antiretroviral therapy, presented with symptoms of mental cloudiness, blurry vision and ataxia. MRI of the brain showed nodular perivascular space enhancement with surrounding vasogenic oedema and midline shift. A lumbar puncture revealed non-inflammatory cerebrospinal fluid and was positive for JC virus. As the patient developed worsening symptoms in the setting of initiation of antiretroviral therapy with immune recovery, a diagnosis of JC virus-associated immune reconstitution inflammatory syndrome (IRIS) was made. With recent literature on the use of CCR5 antagonist maraviroc in PML, our patient was started on maraviroc and noted to have improvement in PML IRIS. This is the first case of an HIV-positive patient successfully treated for PML IRIS with maraviroc, as verified by our literature review; also, our case has clinical implications in improving outcome in PML IRIS. PMID- 26063111 TI - A rare case of intranasal vascular leiomyoma. AB - Vascular leiomyoma (VL) is a solitary and rare form of leiomyoma that usually occurs in the skin or subcutaneous tissue of the lower extremities. Intranasal VL is extremely rare, probably due to the lack of smooth muscle in the nasal cavity. In this study, we report a case of a 70-year-old woman with VL of the inferior nasal turbinate. An endoscopic examination revealed a pinkish globular mass at the inferior turbinate. A preoperative CT scan exhibited a highly enhanced mass originating from the inferior turbinate, and haemangioma was suspected. The patient underwent complete excision of the mass endoscopically, and the histopathological report indicated that the mass was a VL. The tumour was determined to be negative for progesterone and estrogen receptors by immunohistochemical staining. The postoperative period was uneventful. There was no local recurrence during the 12-month follow-up period. PMID- 26063112 TI - Parapelvic solitary neurofibroma of the kidney. AB - A middle-aged man presented with intermittent gross haematuria and dull aching left flank pain for 1 month. He was a chronic smoker for 15 years. Contrast enhanced CT scan of the abdomen detected a 4.5*3.0*2.5 cm, heterogeneous and poorly contrast-enhancing mass in the left renal sinus and upper ureteric region causing narrowing of the pelviureteric junction and upper ureter. Considering it to be a transitional cell carcinoma of upper urinary tract, the patient underwent laparoscopic radical nephroureterectomy. Histopathology revealed the mass to be a neurofibroma in the renal sinus extending around the upper ureter. PMID- 26063114 TI - Margaret McCartney: Trust the patient. PMID- 26063113 TI - Impact of primary tumor volume and location on the prognosis of patients with locally recurrent nasopharyngeal carcinoma. AB - INTRODUCTION: The properties of a tumor itself were considered the main factors determining the survival of patients with locally recurrent nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT). However, recurrent tumors were mainly evaluated by using the American Joint Committee on Cancer staging system, which was modeled on primary tumors and did not incorporate the tumor volume. This study aimed to investigate the prognostic values of the primary tumor location and tumor volume, and to determine whether evaluating these parameters could improve the current staging system. METHODS: Magnetic resonance (MR) images for 229 patients with locally recurrent NPC who underwent IMRT were analyzed retrospectively. RESULTS: The skull base, parapharyngeal space, and intracranial cavity were the most common sites of tumors. There was a difference in the survival between patients with T1 and T2 diseases (77.6% vs. 50.0%, P<0.01) and those with T3 and T4 diseases (33.0% vs. 18.0%, P=0.04) but no difference between patients with T2 and T3 diseases (50.0% vs. 33.0%, P=0.18). Patients with a tumor volume<=38 cm3 had a significantly higher survival rate compared with those with a tumor volume>38 cm3 (48.7% vs. 15.2%, P<0.01). CONCLUSIONS: A new staging system has been proposed, with T3 tumors being down-staged to T2 and with the tumor volume being incorporated into the staging, which may lead to an improved evaluation of these tumors. This new system can be used to guide the treatment strategy for different risk groups of recurrent NPC. PMID- 26063115 TI - Molecular dynamic study of the mechanical properties of two-dimensional titanium carbides Ti(n+1)C(n) (MXenes). AB - Two-dimensional materials beyond graphene are attracting much attention. Recently discovered 2D carbides and nitrides (MXenes) have shown very attractive electrical and electrochemical properties, but their mechanical properties have not been characterized yet. There are neither experimental measurements reported in the literature nor predictions of strength or fracture modes for single-layer MXenes. The mechanical properties of two-dimensional titanium carbides were investigated in this study using classical molecular dynamics. Young's modulus was calculated from the linear part of strain-stress curves obtained under tensile deformation of the samples. Strain-rate effects were observed for all Tin+1Cn samples. From the radial distribution function, it is found that the structure of the simulated samples is preserved during the deformation process. Calculated values of the elastic constants are in good agreement with published DFT data. PMID- 26063117 TI - Effects of social mobility from childhood to adolescence on BMI. AB - OBJECTIVE: Little is known about the contribution of childhood socio-economic position (SEP) and social mobility to weight change. The present study evaluated the effect of family SEP during the pre-school years and social mobility on BMI between birth and adolescence. DESIGN: Longitudinal. The SEP of each child's family was classified according to an asset-based wealth index as low, medium or high. Four different categories of childhood-adolescence SEP groups were created in order to examine social mobility: low-medium/high, medium-medium, medium-high and high-high/medium. For each of these categories, BMI was tracked from birth to adolescence. Linear mixed-effects models were used to analyse the data. SETTING: Cuiaba-MT, Brazil. SUBJECTS: A population-based cohort of children born between 1994 and 1999 was assessed between 1999 and 2000, and again between 2009 and 2011. RESULTS: A total of 1716 adolescents were followed from childhood to adolescence (71.4 % of baseline). The prevalence of overweight/obesity was 20.4 % in childhood and 27.7 % in adolescence. A higher SEP in childhood was associated with a greater prevalence of overweight in adolescence. Expressive upward social mobility occurred, mainly in the lowest SEP group. There was a greater rate of change in BMI between birth and adolescence among children with a higher SEP in childhood and children who remained in the higher SEP from childhood to adolescence. CONCLUSION: Individuals from a higher SEP in childhood and those who remained in the higher social classes showed greater rate of change in BMI. Thus, initial SEP was the major determinant of changes in BMI. PMID- 26063118 TI - Prediction of hip joint load and translation using musculoskeletal modelling with force-dependent kinematics and experimental validation. AB - Musculoskeletal lower limb models are widely used to predict the resultant contact force in the hip joint as a non-invasive alternative to instrumented implants. Previous musculoskeletal models based on rigid body assumptions treated the hip joint as an ideal sphere with only three rotational degrees of freedom. An musculoskeletal model that considered force-dependent kinematics with three additional translational degrees of freedom was developed and validated in this study by comparing it with a previous experimental measurement. A 32-mm femoral head against a polyethylene cup was considered in the musculoskeletal model for calculating the contact forces. The changes in the main modelling parameters were found to have little influence on the hip joint forces (relative deviation of peak value < 10 BW%, mean trial deviation < 20 BW%). The centre of the hip joint translation was more sensitive to the changes in the main modelling parameters, especially muscle recruitment type (relative deviation of peak value < 20%, mean trial deviation < 0.02 mm). The predicted hip contact forces showed consistent profiles, compared with the experimental measurements, except in the lateral medial direction. The ratio-average analysis, based on the Bland-Altman's plots, showed better limits of agreement in climbing stairs (mean limits of agreement: 2.0 to 6.3 in walking, mean limits of agreement: -0.5 to 3.1 in climbing stairs). Better agreement of the predicted hip contact forces was also found during the stance phase. The force-dependent kinematics approach underestimated the maximum hip contact force by a mean value of 6.68 +/- 1.75% BW compared with the experimental measurements. The predicted maximum translations of the hip joint centres were 0.125 +/- 0.03 mm in level walking and 0.123 +/- 0.005 mm in climbing stairs. PMID- 26063116 TI - 3-(2-Bromoethyl)-indole inhibits the growth of cancer cells and NF-kappaB activation. AB - Indole-3-carbinol (I3C) and diindolylmethane (DIM), found in cruciferous vegetables, have chemopreventive and anticancer properties. In the present study, 14 substituted indoles were tested for activity against SW480 colon cancer cells. Among these, 3-(2-bromoethyl)-indole, named BEI-9, showed the greatest inhibition. The effects of BEI-9 on cancer cells were analyzed by MTS and CellTiter-Glo assays for effects on cell viability, by microscopy for phenotypic changes, by scratch wound assays for effects on migration, by flow cytometry for changes in the cell cycle, by immunoblotting for cyclin D and A to assess effects on cell cycle regulation, and by NF-kappaB reporter assays for effects on basal and drug-induced NF-kappaB activation. BEI-9 inhibited the growth of SW480 and HCT116 colon cancer cells at concentrations of 12.5 and 5 uM, respectively. BEI-9 also inhibited cell motility as determined with scratch wound assays, and reduced the levels of cyclin D1 and A. Furthermore, in reporter cells, BEI-9 (0.8 uM) inhibited basal and induced NF-kappaB activation and increased cell death when combined with the cytokine TNFalpha or the drug camptothecin (CPT), both of which activate NF-kappaB. Preliminary experiments to identify a safe dose range for immunodeficient mice showed that BEI-9, administered intraperitoneally, was tolerable at doses below 10 mg/kg. Thus, BEI-9 and other indole derivatives may be useful in chemoprevention or as chemosensitizers. Since NF-kappaB activation is implicated in carcinogenesis and in reducing sensitivity to anticancer drugs, BEI-9 should be investigated in combination with drugs such as CPT, which activate NF-kappaB. PMID- 26063119 TI - Electrophysiological and behavioral characterization of bioactive compounds of the Thymus vulgaris, Cymbopogon winterianus, Cuminum cyminum and Cinnamomum zeylanicum essential oils against Anopheles gambiae and prospects for their use as bednet treatments. AB - BACKGROUND: Laboratory and field studies showed that repellent, irritant and toxic actions of common public health insecticides reduce human-vector contact and thereby interrupt disease transmission. One of the more effective strategies to reduce disease risk involves the use of long-lasting treated bednets. However, development of insecticide resistance in mosquito populations makes it imperative to find alternatives to these insecticides. Our previous study identified four essential oils as alternatives to pyrethroids: Thymus vulgaris, Cymbopogon winterianus, Cuminum cyminum, Cinnamomum zeylanicum. The objectives of this study were to identify active compounds of these essential oils, to characterize their biological activity, and to examine their potential as a treatment for bednets. METHODS: We evaluated the electrophysiological, behavioural (repellency, irritancy) and toxic effects of the major compounds of these oils against Anopheles gambiae strain 'Kisumu'. RESULTS: Aldehydes elicited the strongest responses and monoterpenes the weakest responses in electroantennogram (EAG) trials. However, EAG responses did not correlate consistently with results of behavioral assays. In behavioral and toxicity studies, several of the single compounds did exhibit repellency, irritancy or toxicity in An. gambiae; however, the activity of essential oils did not always correlate with activity expected from the major components. On the contrary, the biological activity of essential oils appeared complex, suggesting interactions between individual compounds and the insect under study. Data also indicated that the three effects appeared independent, suggesting that repellency mechanism(s) may differ from mechanisms of irritancy and toxicity. CONCLUSIONS: Based on the bioassays reported here, some of the compounds merit consideration as alternative bednet treatments. PMID- 26063120 TI - Integrated platform with a combination of online digestion and (18)O labeling for proteome quantification via an immobilized trypsin microreactor. AB - A novel automated integrated platform for quantitative proteome analysis was established with a combination of online digestion of proteins and in situ(18)O labeling by an immobilized enzyme reactor (IMER); digests were captured and desalted by a C18 trap column, and peptides were analyzed by nanoRPLC-ESI-MS/MS. Bovine serum albumin (BSA) was used to evaluate the performance of the developed platform. Compared with traditional offline methods, not only the digestion and labeling time was shortened from 36 h to just 1 h, but also the labeling efficiency was improved from 95% to 99%. Furthermore, the back-exchange from (18)O to (16)O could also be efficiently avoided by the use of IMER. The platform was further evaluated by the quantitative analysis of 100 ng (18)O and (16)O online labeled yeast sample with a mixing ratio of 1 : 1, and the results showed significantly improved sensitivity and reproducibility, as well as improved quantitative accuracy than offline method. With these advantages, the integrated platform was finally applied to the quantitative profiling of 100 ng proteins extracted from two mouse hepatocarcinoma ascites syngeneic cell lines with high and low lymph node metastases rates, and ten differentially expressed proteins were successfully found, most of which were related to tumorigenesis and tumor metastasis. All these results demonstrate that the developed integrated platform can provide a new way for high efficiency (18)O labeling and the quantitative analysis of trace amounts of sample with high accuracy and high reproducibility. PMID- 26063122 TI - Erratum to: Detoxifying Escherichia coli for endotoxin-free production of recombinant proteins. PMID- 26063123 TI - Strain-controlled critical temperature in REBa2Cu3Oy-coated conductors. AB - Recently, we succeeded in detwinning REBa2Cu3O7 (RE123, RE = rare-earth elements) coated conductors by annealing under an external uniaxial strain. Using the untwinned RE123 tapes, the uniaxial-strain dependencies of the critical temperature Tc along the a and b crystal axes were investigated over a wide strain region from compression to tension. We found that the strain dependencies of Tc for the a and b axes obey a power law but exhibit opposite slopes. In particular, the maximum value of Tc is obtained when the CuO2 plane becomes a square, and its lattice constant is close to 0.385 nm. It is suggested that a tetragonal structure with a ~ 0.385 nm is the optimum condition for a high critical temperature in high-Tc cuprates. PMID- 26063124 TI - The correlations among bond ionicity, lattice energy and microwave dielectric properties of (Nd(1-x)La(x))NbO4 ceramics. AB - (Nd1-xLax)NbO4 ceramics were prepared via a conventional solid-state reaction route and the correlations among bond ionicity, lattice energy, phase stability and microwave dielectric properties were investigated. The diffraction patterns showed that the (Nd1-xLax)NbO4 ceramics possessed a monoclinic fergusonite structure. The chemical bond ionicity, bond covalency and lattice energy were calculated using the empirical method. The phase structure stability varied with the lattice energy which resulted due to the substitution content of La(3+) ions. With the increase of La(3+) ion contents, the decrease of Nd/La-O bond ionicity was observed, which could be attributed to the electric polarization. epsilonr has a close relationship with the Nd/La-O bond covalency. The increase of the Q * f values and tauf values could be attributed to the change in the lattice energy. The microwave dielectric properties of (Nd1-xLax)NbO4 ceramics with a monoclinic fergusonite structure were strongly dependent on the chemical bond ionicity, bond covalency and lattice energy. PMID- 26063125 TI - Neonatal mortality and coverage of essential newborn interventions 2010 - 2013: a prospective, population-based study from low-middle income countries. AB - BACKGROUND: Approximately 3 million neonatal deaths occur each year worldwide. Simple interventions have been tested and found to be effective in reducing the neonatal mortality. In order to effectively implement public health interventions, it is important to know the rates of neonatal mortality and understand the contributing risk factors. Hence, this prospective, population based, observational study was carried out to inform these needs. METHODS: The Global Network's Maternal Newborn Health Registry was initiated in the seven sites in 2008. Registry administrators (RAs) attempt to identify and enroll all eligible women by 20 weeks gestation and collect basic health data, and outcomes after delivery and at 6 weeks post-partum. All study data were collected, reviewed, and edited by staff at each study site. The study was reviewed and approved by each sites' ethics review committee. RESULTS: Overall, the 7-day neonatal mortality rate (NMR) was 20.6 per 1000 live births and the 28-day NMR was 25.7 per 1000 live births. Higher neonatal mortality was associated with maternal age > 35 and <20 years relative to women 20-35 years of age. Preterm births were at increased risk of both early and 28-day neonatal mortality (RR 8.1, 95% CI 7.5-8.8 and 7.5, 95% CI 6.9-8.1) compared to term as were those with low birth weight (<2500g). Neonatal resuscitation rates were 4.8% for hospital deliveries compared to 0.9% for home births. In the hospital, 26.5% of deliveries were by cesarean section with an overall cesarean section rate of 12.5%. Neonatal mortality rates were highest in the Pakistan site and lowest in Argentina. CONCLUSIONS: Using prospectively collected data with high follow up rates (99%), we documented characteristics associated with neonatal mortality. Low birth weight and prematurity are among the strongest predictors of neonatal mortality. Other risk factors for neonatal deaths included male gender, multiple gestation and major congenital anomalies. Breech presentation/transverse lie, and no antenatal care were also significant risk factors for neonatal death. Coverage of interventions varied by setting of delivery, with the overall population rate of most evidence-based interventions low. This study informs about risk factors for neonatal mortality which can serve to design strategies/interventions to reduce risk of neonatal mortality. TRIAL REGISTRATION: The trial is registered at clinicaltrials.gov. ClinicalTrial.gov TRIAL REGISTRATION: NCT01073475. PMID- 26063126 TI - Origins and processes of groundwater salinization in the urban coastal aquifers of Recife (Pernambuco, Brazil): A multi-isotope approach. AB - In the coastal multilayer aquifer system of a highly urbanized southern city (Recife, Brazil), where groundwaters are affected by salinization, a multi isotope approach (Sr, B, O, H) was used to investigate the sources and processes of salinization. The high diversity of the geological bodies, built since the Atlantic opening during the Cretaceous, highly constrains the heterogeneity of the groundwater chemistry, e.g. Sr isotope ratios, and needs to be integrated to explain the salinization processes and groundwater pathways. A paleoseawater intrusion, most probably the 120 kyB.P. Pleistocene marine transgression, and cationic exchange are clearly evidenced in the most salinized parts of the Cabo and Beberibe aquifers. All (87)Sr/(86)Sr values are above the past and present day seawater signatures, meaning that the Sr isotopic signature is altered due to additional Sr inputs from dilution with different freshwaters, and water-rock interactions. Only the Cabo aquifer presents a well-delimitated area of Na-HCO3 water typical of a freshening process. The two deep aquifers also display a broad range of B concentrations and B isotope ratios with values among the highest known to date (63-68.50/00). This suggests multiple sources and processes affecting B behavior, among which mixing with saline water, B sorption on clays and mixing with wastewater. The highly fractionated B isotopic values were explained by infiltration of relatively salty water with B interacting with clays, pointing out the major role played by (palaeo)-channels for the deep Beberibe aquifer recharge. Based on an increase of salinity at the end of the dry season, a present-day seawater intrusion is identified in the surficial Boa Viagem aquifer. Our conceptual model presents a comprehensive understanding of the major groundwater salinization pathways and processes, and should be of benefit for other southern Atlantic coastal aquifers to better address groundwater management issues. PMID- 26063127 TI - Y-junction carbon nanocoils: synthesis by chemical vapor deposition and formation mechanism. AB - Y-junction carbon nanocoils (Y-CNCs) were synthesized by thermal chemical vapor deposition using Ni catalyst prepared by spray-coating method. According to the emerging morphologies of Y-CNCs, several growth models were advanced to elucidate their formation mechanisms. Regarding the Y-CNCs without metal catalyst in the Y junctions, fusing of contiguous CNCs and a tip-growth mechanism are considered to be responsible for their formation. However, as for the Y-CNCs with catalyst presence in the Y-junctions, the formation can be ascribed to nanoscale soldering/welding and bottom-growth mechanism. It is found that increasing spray coating time for catalyst preparation generates agglomerated larger nanoparticles strongly adhering to the substrate, resulting in bottom-growth of CNCs and appearance of the metal catalyst in the Y-junctions. In the contrary case, CNCs catalyzed by isolated smaller nanoparticles develop Y-junctions with an absence of metal catalyst by virtue of weaker adhesion of catalyst with the substrate and tip-growth of CNCs. PMID- 26063128 TI - Integrating ethics in health technology assessment: many ways to Rome. AB - OBJECTIVES: The aim of this study was to identify and discuss appropriate approaches to integrate ethical inquiry in health technology assessment (HTA). METHODS: The key question is how ethics can be integrated in HTA. This is addressed in two steps: by investigating what it means to integrate ethics in HTA, and by assessing how suitable the various methods in ethics are to be integrated in HTA according to these meanings of integration. RESULTS: In the first step, we found that integrating ethics can mean that ethics is (a) subsumed under or (b) combined with other parts of the HTA process; that it can be (c) coordinated with other parts; or that (d) ethics actively interacts and changes other parts of the HTA process. For the second step, we found that the various methods in ethics have different merits with respect to the four conceptions of integration in HTA. CONCLUSIONS: Traditional approaches in moral philosophy tend to be most suited to be subsumed or combined, while processual approaches being close to the HTA or implementation process appear to be most suited to coordinated and interactive types of integration. The article provides a guide for choosing the ethics approach that appears most appropriate for the goals and process of a particular HTA. PMID- 26063129 TI - Airway neurofibroma. PMID- 26063148 TI - [Physiological and pharmacological actions involved in the pharyngeal and laryngeal sensation?]. PMID- 26063147 TI - [Mild head injury in children and adults: Diagnostic challenges in the emergency department]. AB - Mild head injuries are one of the most frequent reasons for attending emergency departments and are particularly challenging in different ways. While clinically important injuries are infrequent, delayed or missed injuries may lead to fatal consequences. The initial mostly inconspicuous appearance may not reflect the degree of intracranial injury and computed tomography (CT) is necessary to rule out covert injuries. Furthermore, infants and young children with a lack of or rudimentary cognitive and language development are challenging, especially for those examiners not familiar with pediatric care. Established check lists of clinical risk factors for children and adults regarding traumatic brain injuries allow specific and rational decision-making for cranial CT imaging. Clinically important intracranial injuries can be reliably detected and unnecessary radiation exposure avoided at the same time. PMID- 26063149 TI - [Frontiers in molecular therapy for aspiration pneumonia: from pharyngeal sensory receptor to lymphangiogenic factors?]. PMID- 26063150 TI - [A remedy for dry mouth using taste stimulation?]. PMID- 26063151 TI - [Targeting PP2A inhibitors as a novel anti-cancer strategy?]. PMID- 26063152 TI - [Current status and future prospects of Muse cell research?]. PMID- 26063153 TI - [Measurement method of vagal afferent and efferent activity]. PMID- 26063154 TI - [For the realization of the medicine capital Toyama flapping in the world?]. PMID- 26063155 TI - [Discovery and development of alectinib hydrochloride (ALECENSAR capsule 20 mg and 40 mg)?]. PMID- 26063156 TI - [Astrovascular interaction]. PMID- 26063157 TI - [Corticosteroid sensitivity in intractable respiratory disease]. PMID- 26063158 TI - [Clinical research topics on the Umami taste sensitivity test for a taste diagnosis?]. PMID- 26063159 TI - Treatment expectations of men with ED and their female partners: an exploratory qualitative study based on grounded theory. AB - Erectile dysfunction (ED) can impair the quality of life and the relationship. An early treatment is necessary to avoid the development of comorbid complaints. To arise the help-seeking behavior and to improve the treatment of affected men, it is necessary to be aware of the treatment expectations. The objective of this study was to investigate the treatment expectations of men with ED and their female partners. This is an explorative qualitative study using semistructured telephone interviews with 12 men with ED and their female partners. Interviews were tape-recorded, transcribed and analyzed on the basis of the grounded theory. We could identify various treatment expectations, which could be differentiated into expectations according to the conditions (for example, low costs and an early access), the handling of the practitioner (for example, showing interest and taking the patient seriously or incorporate the female partner), the treatment itself (for example, clearing the causes and helpful medication) and the treatment outcome (for example, having no ED and more sexual desire). Considering the identified expectations could increase treatment motivation and compliance. We derive five theses from our data, how to implement our findings. PMID- 26063160 TI - Surgical anatomy of the pudendal nerve and its branches in South Africans. AB - Dissection of the pudendal nerve (PN) and its branches in 71 cadavers revealed anatomic variations not previously described. Knowledge of this variation is necessary to prevent nerve injury resulting in sexual of sensory dysfunction. Because descriptions vary, this study re-evaluated the anatomy of the PN as implicated in perineal procedures in South Africans. The course of the PN from the gluteal region into the perineum was dissected in an adult sample of both sexes and of African and European ancestry. Distances between PN and branches to applicable landmarks were measured. Basic descriptive statistics and comparisons were carried out between groups. In 5/13 African females, the inferior rectal nerve (IRN) entered the gluteal region separately and in 12/13 cases it passed medial to the ischial spine with the PN. The dorsal nerve of the clitoris or penis (DNC/DNP) was closer to the bony frame in those of European ancestry. The IRN branches were more superficial in females, but deeper in males of European ancestry. In African females, a PN block and Richter stitch should be placed more medial. Outside-in transobturator tape procedures might endanger the DNC/DNP in obese individuals. In females of European ancestry the IRN branches are compromised during ischioanal abscess drainage. In males of European ancestry, the dorsal penile nerve block might be less effective. Predictions should be verified clinically. PMID- 26063162 TI - Experimental Investigation of Pressure Applied on the Lower Leg by Elastic Compression Bandage. AB - Compression therapy with stockings or bandages is the most common treatment for venous or lymphatic disorders. The objective of this study was to investigate the influence of bandage mechanical properties, application technique and subject morphology on the interface pressure, which is the key of this treatment. Bandage stretch and interface pressure measurements (between the bandage and the leg) were performed on 30 healthy subjects (15 men and 15 women) at two different heights on the lower leg and in two positions (supine and standing). Two bandages were applied with two application techniques by a single operator. The statistical analysis of the results revealed: no significant difference in pressure between men and women, except for the pressure variation between supine and standing positions; a very strong correlation between pressure and bandage mechanical properties (p < 0.00001) and between pressure and bandage overlapping (p < 0.00001); a significant pressure increase from supine to standing positions (p < 0.0001). Also, it showed that pressure tended to decrease when leg circumference increased. Overall, pressure applied by elastic compression bandages varies with subject morphology, bandage mechanical properties and application technique. A better knowledge of the impact of these parameters on the applied pressure may lead to a more effective treatment. PMID- 26063161 TI - A Mobile Health Intervention Supporting Heart Failure Patients and Their Informal Caregivers: A Randomized Comparative Effectiveness Trial. AB - BACKGROUND: Mobile health (mHealth) interventions may improve heart failure (HF) self-care, but standard models do not address informal caregivers' needs for information about the patient's status or how the caregiver can help. OBJECTIVE: We evaluated mHealth support for caregivers of HF patients over and above the impact of a standard mHealth approach. METHODS: We identified 331 HF patients from Department of Veterans Affairs outpatient clinics. All patients identified a "CarePartner" outside their household. Patients randomized to "standard mHealth" (n=165) received 12 months of weekly interactive voice response (IVR) calls including questions about their health and self-management. Based on patients' responses, they received tailored self-management advice, and their clinical team received structured fax alerts regarding serious health concerns. Patients randomized to "mHealth+CP" (n=166) received an identical intervention, but with automated emails sent to their CarePartner after each IVR call, including feedback about the patient's status and suggestions for how the CarePartner could support disease care. Self-care and symptoms were measured via 6- and 12-month telephone surveys with a research associate. Self-care and symptom data also were collected through the weekly IVR assessments. RESULTS: Participants were on average 67.8 years of age, 99% were male (329/331), 77% where white (255/331), and 59% were married (195/331). During 15,709 call-weeks of attempted IVR assessments, patients completed 90% of their calls with no difference in completion rates between arms. At both endpoints, composite quality of life scores were similar across arms. However, more mHealth+CP patients reported taking medications as prescribed at 6 months (8.8% more, 95% CI 1.2-16.5, P=.02) and 12 months (13.8% more, CI 3.7-23.8, P<.01), and 10.2% more mHealth+CP patients reported talking with their CarePartner at least twice per week at the 6 month follow-up (P=.048). mHealth+CP patients were less likely to report negative emotions during those interactions at both endpoints (both P<.05), were consistently more likely to report taking medications as prescribed during weekly IVR assessments, and also were less likely to report breathing problems or weight gains (all P<.05). Among patients with more depressive symptoms at enrollment, those randomized to mHealth+CP were more likely than standard mHealth patients to report excellent or very good general health during weekly IVR calls. CONCLUSIONS: Compared to a relatively intensive model of IVR monitoring, self management assistance, and clinician alerts, a model including automated feedback to an informal caregiver outside the household improved HF patients' medication adherence and caregiver communication. mHealth+CP may also decrease patients' risk of HF exacerbations related to shortness of breath and sudden weight gains. mHealth+CP may improve quality of life among patients with greater depressive symptoms. Weekly health and self-care monitoring via mHealth tools may identify intervention effects in mHealth trials that go undetected using typical, infrequent retrospective surveys. TRIAL REGISTRATION: ClinicalTrials.gov NCT00555360; https://clinicaltrials.gov/ct2/show/NCT00555360 (Archived by WebCite at http://www.webcitation.org/6Z4Tsk78B). PMID- 26063164 TI - Protective effect of cytotoxic T lymphocytes targeting HTLV-1 bZIP factor. AB - Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and inflammatory diseases in a small percentage of infected individuals. Host immune responses, in particular cytotoxic T lymphocytes (CTLs), influence the proliferation and survival of ATL cells and HTLV-1-infected cells. We generated recombinant vaccinia viruses (rVVs) expressing HTLV-1 basic leucine zipper (bZIP) factor (HBZ) or Tax to study the immunogenic potential of these viral proteins. Vaccination with rVV expressing Tax or HBZ induced specific T cell responses, although multiple boosters were needed for HBZ. HBZ-stimulated T cells killed HBZ peptide-pulsed T cells and CD4(+) T cells from HBZ transgenic (HBZ-Tg) mice. The anti-lymphoma effect of the CTLs targeting HBZ was tested in mice inoculated with a lymphoma cell line derived from an HBZ-Tg mouse. Transfer of splenocytes from HBZ-immunized mice increased the survival of the lymphoma cell-inoculated mice, suggesting that the anti-HBZ CTLs have a protective effect. The rVV could also induce specific T-cell responses to HBZ and Tax in HTLV-1 infected rhesus monkeys. On the basis of the results of rVV-vaccinated mice and macaques, we identified a candidate peptide (HBZ157-176) for vaccine development. Dendritic cells pulsed with this peptide could generate HBZ-specific CTLs from human CD8(+) T cells. This study demonstrates that HBZ could be a target for immunotherapy of patients with ATL. PMID- 26063163 TI - Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. AB - The paucity of regulatory T cells (Tregs) limits clinical translation to control aberrant immune reactions including graft-versus-host disease (GVHD). Recent studies showed that the agonistic antibody to DR3 (alphaDR3) expanded CD4(+)FoxP3(+) Tregs in vivo. We investigated whether treating donor mice with a single dose of alphaDR3 could alleviate acute GVHD in a MHC-mismatched bone marrow transplantation model. alphaDR3 induced selective proliferation of functional Tregs. CD4(+) T cells isolated from alphaDR3-treated mice contained higher numbers of Tregs and were less proliferative to allogeneic stimuli. In vivo GVHD studies confirmed that Tregs from alphaDR3-treated donors expanded robustly and higher frequencies of Tregs within donor CD4(+) T cells were maintained, resulting in improved survival. Conventional T cells derived from alphaDR3-treated donors showed reduced activation and proliferation. Serum levels of proinflammatory cytokines (IFNgamma, IL-1beta, and TNFalpha) and infiltration of donor T cells into GVHD target tissues (gastrointestinal tract and liver) were decreased. T cells from alphaDR3-treated donors retained graft-vs-tumor (GVT) effects. In conclusion, a single dose of alphaDR3 alleviates acute GVHD while preserving GVT effects by selectively expanding and maintaining donor Tregs. This novel strategy will facilitate the clinical application of Treg-based therapies. PMID- 26063165 TI - New role for the (pro)renin receptor in T-cell development. AB - The (pro)renin receptor (PRR) was originally thought to be important for regulating blood pressure via the renin-angiotensin system. However, it is now emerging that PRR has instead a generic role in cellular development. Here, we have specifically deleted PRR from T cells. T-cell-specific PRR-knockout mice had a significant decrease in thymic cellularity, corresponding with a 100-fold decrease in the number of CD4(+) and CD8(+) thymocytes, and a large increase in double-negative (DN) precursors. Gene expression analysis on sorted DN3 thymocytes indicated that PRR-deficient thymocytes have perturbations in key cellular pathways essential at the DN3 stage, including transcription and translation. Further characterization of DN T-cell progenitors leads us to propose that PRR deletion affects thymocyte survival and development at multiple stages; from DN3 through to DN4, double-positive, and single-positive CD4 and CD8. Our study thus identifies a new role for PRR in T-cell development. PMID- 26063167 TI - Insulin analogues as a new example of interference in insulin assays. PMID- 26063166 TI - The Global Network Maternal Newborn Health Registry: a multi-national, community based registry of pregnancy outcomes. AB - BACKGROUND: The Global Network for Women's and Children's Health Research (Global Network) supports and conducts clinical trials in resource-limited countries by pairing foreign and U.S. investigators, with the goal of evaluating low-cost, sustainable interventions to improve the health of women and children. Accurate reporting of births, stillbirths, neonatal deaths, maternal mortality, and measures of obstetric and neonatal care is critical to efforts to discover strategies for improving pregnancy outcomes in resource-limited settings. Because most of the sites in the Global Network have weak registration within their health care systems, the Global Network developed the Maternal Newborn Health Registry (MNHR), a prospective, population-based registry of pregnancies at the Global Network sites to provide precise data on health outcomes and measures of care. METHODS: Pregnant women are enrolled in the MNHR if they reside in or receive healthcare in designated groups of communities within sites in the Global Network. For each woman, demographic, health characteristics and major outcomes of pregnancy are recorded. Data are recorded at enrollment, the time of delivery and at 42 days postpartum. RESULTS: From 2010 through 2013 Global Network sites were located in Argentina, Guatemala, Belgaum and Nagpur, India, Pakistan, Kenya, and Zambia. During this period, 283,496 pregnant women were enrolled in the MNHR; this number represented 98.8% of all eligible women. Delivery data were collected for 98.8% of women and 42-day follow-up data for 98.4% of those enrolled. In this supplement, there are a series of manuscripts that use data gathered through the MNHR to report outcomes of these pregnancies. CONCLUSIONS: Developing public policy and improving public health in countries with poor perinatal outcomes is, in part, dependent upon understanding the outcome of every pregnancy. Because the worst pregnancy outcomes typically occur in countries with limited health registration systems and vital records, alternative registration systems may prove to be highly valuable in providing data. The MNHR, an international, multicenter, population-based registry, assesses pregnancy outcomes over time in support of efforts to develop improved perinatal healthcare in resource-limited areas. PMID- 26063169 TI - Health-related quality of life in a sample of Australian adolescents: gender and age comparison. AB - PURPOSE: The primary purpose of this study was to profile the health-related quality of life (HRQoL) in a sample of secondary school-aged children in Australia. The secondary purpose was to contribute to the international literature on the HRQoL of adolescents using the KIDSCREEN instrument. METHODS: The KIDSCREEN-27 Questionnaire was completed by 1111 adolescents aged between 11 and 17 from six Australian secondary schools. MANCOVA analysis was employed to examine age and gender differences. RESULTS: Over 70 % of participants reported high levels of HRQoL across all five dimensions. Age patterns were identified with younger adolescents reporting greater HRQoL than older adolescents. Similarly, gender differences were noted with male adolescents reporting higher scores than female adolescents on three out of five dimensions of HRQoL. CONCLUSIONS: This is the first study to measure HRQoL in Australian adolescents using the KIDSCREEN instrument. Consistent with previous research, gender and age differences were found across most dimensions of HRQoL. These results highlight the importance of comprehensively measuring the HRQoL in adolescents to capture developmental shifts and to inform preventative and supportive programs as needed. PMID- 26063168 TI - Frailty and the prediction of dependence and mortality in low- and middle-income countries: a 10/66 population-based cohort study. AB - BACKGROUND: In countries with high incomes, frailty indicators predict adverse outcomes in older people, despite a lack of consensus on definition or measurement. We tested the predictive validity of physical and multidimensional frailty phenotypes in settings in Latin America, India, and China. METHODS: Population-based cohort studies were conducted in catchment area sites in Cuba, Dominican Republic, Venezuela, Mexico, Peru, India, and China. Seven frailty indicators, namely gait speed, self-reported exhaustion, weight loss, low energy expenditure, undernutrition, cognitive, and sensory impairment were assessed to estimate frailty phenotypes. Mortality and onset of dependence were ascertained after a median of 3.9 years. RESULTS: Overall, 13,924 older people were assessed at baseline, with 47,438 person-years follow-up for mortality and 30,689 for dependence. Both frailty phenotypes predicted the onset of dependence and mortality, even adjusting for chronic diseases and disability, with little heterogeneity of effect among sites. However, population attributable fractions (PAF) summarising etiologic force were highest for the aggregate effect of the individual indicators, as opposed to either the number of indicators or the dichotomised frailty phenotypes. The aggregate of all seven indicators provided the best overall prediction (weighted mean PAF 41.8 % for dependence and 38.3 % for mortality). While weight loss, underactivity, slow walking speed, and cognitive impairment predicted both outcomes, whereas undernutrition predicted only mortality and sensory impairment only dependence. Exhaustion predicted neither outcome. CONCLUSIONS: Simply assessed frailty indicators identify older people at risk of dependence and mortality, beyond information provided by chronic disease diagnoses and disability. Frailty is likely to be multidimensional. A better understanding of the construct and pathways to adverse outcomes could inform multidimensional assessment and intervention to prevent or manage dependence in frail older people, with potential to add life to years, and years to life. PMID- 26063170 TI - Examining differential responses of youth with and without autism on a measure of everyday activity performance. AB - PURPOSE: This study further investigated items with differential item function (DIF) in the Social/Cognitive domain of a measure of everyday activity performance, the Pediatric Evaluation of Disability Inventory-Computer Adapted Test version for Autism "PEDI-CAT (ASD)," to understand possible sources of response variation in a heterogeneous sample of youth with autism compared to the national standardization sample. METHODS: Cross-sectional design. A convenience sample of parents who identified they had a child between 3 and 21 years (M = 11.9 years, SD = 4.67 years) with autism (n = 365) completed an online survey that included the PEDI-CAT (ASD) and descriptive measures. For 28 items previously identified as having DIF, the PEDI-CAT (ASD) expected item score curves for the autism sample were compared to the original PEDI-CAT standardization sample. The weighted area between expected score curves (wABC) was also calculated; values >0.24 indicate significant DIF. RESULTS: All items had wABC that exceeded the criterion. Compared with peers without disabilities at the same ability level, 11 items were significantly more difficult for the youth with autism and 16 items were significantly easier. One item demonstrated non uniform DIF. CONCLUSION: Differential responses could indicate that: (1) children with autism have a different developmental pattern of skill acquisition for everyday activities in the Social/Cognitive domain, or (2) parents of children with autism utilize a unique appraisal process when assessing their children's functional performance of everyday activities. Further research is required to better understand the factors leading to differential responses on the targeted items. The study illustrates the value of in-depth analysis of DIF to gain insight into the impact of a clinical condition on functional performance. PMID- 26063171 TI - Proposing a re-adapted successful aging model addressing chronic diseases in low- and middle-income countries. AB - PURPOSE: Global aging is a phenomenon experienced throughout the world. Research demonstrates an increased incidence of chronic diseases due to global aging in low- and middle-income countries. Before addressing chronic diseases, a platform for change must be created. METHODS: A basic review was conducted on successful aging, adaptations to Rowe and Kahn's model of successful aging, and environmental challenges in low- and middle-income countries. RESULTS: The successful aging model by Rowe and Kahn includes trajectories based on various biological and environmental components and determines how lifetime experiences contribute to adverse health effects, such as chronic diseases, in aging populations. This model was primarily designed for high-income populations and may not be transferable to populations in low- and middle-income countries. Suggested changes to the current model have been made and include optimal health activities and access to health care, but have not considered environmental contaminants or hazards. A re-adapted model should be encompassing and consider the environment as well as successful aging elements, optimal aging activities, and access to health care. CONCLUSION: The overall goal of this commentary is to theoretically propose a novel successful aging model that may be used to target chronic diseases in aging populations in low- and middle-income countries. This model can then be used as a theoretical foundation for health promotion and disease prevention. PMID- 26063172 TI - Osteopathology in the Equine Distal Phalanx Associated With the Development and Progression of Laminitis. AB - Although the equine distal phalanx and hoof lamellae are biomechanically and physiologically integrated, bony changes in the distal phalanx are poorly described in laminitis. The aims of this study were (1) to establish a laminitis grading scheme that can be applied to the wide spectrum of lesions seen in naturally occurring cases and (2) to measure and describe changes in the distal phalanx associated with laminitis using micro-computed tomography (micro-CT) and histology. Thirty-six laminitic and normal feet from 15 performance and nonperformance horses were evaluated. A laminitis grading scheme based on radiographic, gross, histopathologic, and temporal parameters was developed. Laminitis severity grades generated by this scheme correlated well with clinical severity and coincided with decreased distal phalanx bone volume and density as measured by micro-CT. Laminitic hoof wall changes included progressive ventral rotation and distal displacement of the distal phalanx with increased thickness of the stratum internum-corium tissues with lamellar wedge formation. Histologically, there was epidermal lamellar necrosis with basement membrane separation and dysplastic regeneration, including acanthosis and hyperkeratosis, corresponding to the lamellar wedge. The changes detected by micro-CT corresponded to microscopic findings in the bone, including osteoclastic osteolysis of trabecular and osteonal bone with medullary inflammation and fibrosis. Bone changes were identified in horses with mild/early stages of laminitis as well as severe/chronic stages. The authors conclude that distal phalangeal pathology is a quantifiable and significant component of laminitis pathology and may have important implications for early detection or therapeutic intervention of equine laminitis. PMID- 26063173 TI - Animal Models of Osteoarthritis: Comparisons and Key Considerations. AB - Osteoarthritis (OA) is unquestionably one of the most important chronic health issues in humans, affecting millions of individuals and costing billions of dollars annually. Despite widespread awareness of this disease and its devastating impact, the pathogenesis of early OA is not completely understood, hampering the development of effective tools for early diagnosis and disease modifying therapeutics. Most human tissue available for study is obtained at the time of joint replacement, when OA lesions are end stage and little can be concluded about the factors that played a role in disease development. To overcome this limitation, over the past 50 years, numerous induced and spontaneous animal models have been utilized to study disease onset and progression, as well as to test novel therapeutic interventions. Reflecting the heterogeneity of OA itself, no single "gold standard" animal model for OA exists; thus, a challenge for researchers lies in selecting the most appropriate model to answer a particular scientific question of interest. This review provides general considerations for model selection, as well as important features of species such as mouse, rat, guinea pig, sheep, goat, and horse, which researchers should be mindful of when choosing the "best" animal model for their intended purpose. Special consideration is given to key variations in pathology among species as well as recommended guidelines for reporting the histologic features of each model. PMID- 26063174 TI - Mouse Models of Rheumatoid Arthritis. AB - Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder characterized by synovitis that leads to cartilage and bone erosion by invading fibrovascular tissue. Mouse models of RA recapitulate many features of the human disease. Despite the availability of medicines that are highly effective in many patient populations, autoimmune diseases (including RA) remain an area of active biomedical research, and consequently mouse models of RA are still extensively used for mechanistic studies and validation of therapeutic targets. This review aims to integrate morphologic features with model biology and cover the key characteristics of the most commonly used induced and spontaneous mouse models of RA. Induced models emphasized in this review include collagen-induced arthritis and antibody-induced arthritis. Collagen-induced arthritis is an example of an active immunization strategy, whereas antibody- induced arthritis models, such as collagen antibody-induced arthritis and K/BxN antibody transfer arthritis, represent examples of passive immunization strategies. The coverage of spontaneous models in this review is focused on the TNFDelta (ARE) mouse, in which arthritis results from overexpression of TNF-alpha, a master proinflammatory cytokine that drives disease in many patients. PMID- 26063175 TI - Regularity of follow-up, glycemic burden, and risk of microvascular complications in patients with type 2 diabetes: a 9-year follow-up study : Reply to Dr. Tasci et al. PMID- 26063176 TI - Glycemic control and the risk of microvascular complications in people with diabetes mellitus. PMID- 26063177 TI - A Daytime Fast Track Improves Throughput in a Single Physician Coverage Emergency Department. AB - OBJECTIVES: Fast tracks are one approach to reduce emergency department (ED) crowding. No studies have assessed the use of fast tracks in smaller hospitals with single physician coverage. Our study objective was to determine if implementation of an ED fast track in a single physician coverage setting would improve wait times for low-acuity patients without negatively impacting those of higher acuity. METHODS: A daytime fast track opened in 2010 at Strathroy Middlesex General Hospital, a southwestern Ontario community hospital. Before and after intervention groups comprised of ED visits in 2009 and 2011 were compared. Pooled comparison of all Canadian Triage and Acuity Scale (CTAS) patients in each period, and between subgroups CTAS 2-5 comparisons were performed for: wait time (WT), length of stay (LOS), WTs that met national CTAS time guidelines (MNCTG), and proportion of patients that left without being seen (LWBS). RESULTS: WT and LOS were six minutes (88 min to 82 min, p=0.002) and 15 minutes (158 min to 143 min, p<0.001) lower, respectively, in the post-intervention period. Subgroup analysis showed CTAS 4 had the most pre- to post-intervention decrease in WT, of 13 minutes (98 min to 85 min, p<0.001). There was statistical improvement in MNCTG in the post-intervention period. No differences were found in outcome measures for higher-acuity patients or LWBS rates. CONCLUSIONS: Implementation of a fast track in a medium-volume community hospital with single physician coverage can improve patient throughput by decreasing WT and LOS without negatively impacting high-acuity patients. This may be clinically relevant, particularly for hospital administrators, given the improvement in meeting national WT standards we found post-intervention. PMID- 26063179 TI - Treatment by a nurse practitioner in primary care improves the severity and impact of urinary incontinence in women. An observational study. AB - BACKGROUND: Urinary Incontinence (UI) is a common problem in women. The management of UI in primary care is time consuming and suboptimal. Shift of incontinence-care from General Practitioners (GP's) to a nurse practitioner maybe improves the quality of care. The purpose of this observational (pre/post) study is to determine the effectiveness of introducing a nurse practitioner in UI care and to explore women's reasons for not completing treatment. METHODS: Sixteen trained nurse practitioners treated female patients with UI. All patients were examined and referred by the GP to the nurse practitioner working in the same practice. At baseline the severity of the UI (Sandvik-score), the impact on the quality of life (IIQ) and the impressed severity (PGIS) was measured and repeated after three months Differences were tested by the paired t and the NcNemar test. Reasons for not completing treatment were documented by the nurse practitioner and differences between the group that completed treatment and the drop-out group were tested. RESULTS: We included 103 women, mean age 55 years (SD 12.6). The Sandvik severity categories improved significantly (P < 0.001), as did the impact on daily life (2.54 points, P = 0.012). Among the IIQ score the impact on daily activities increased 0.73 points (P = 0.032), on social functioning 0.60 points (P = 0.030) and on emotional well-being 0.63 points (P = 0.031). The PGIS-score improved in 41.3% of the patients. The most important reasons for not completing the treatment were lack of improvement of the UI and difficulties in performing the exercises. Women who withdraw from guidance by the nurse practitioner perceived more impact on daily life (P = 0.036), in particular on the scores for social functioning (P = 0.015) and emotional well-being (P = 0.015). CONCLUSION: Treatment by a trained nurse practitioner seems positively affects the severity of the UI and the impact on the quality of life. Women who did not complete treatment suffer from more impact on quality of life, experience not enough improvement and mention difficulties in performing exercises. PMID- 26063180 TI - The impact of free trial acceptance on demand for alternative nicotine products: evidence from experimental auctions. AB - OBJECTIVES: This study explored the relationship between product trials and consumer demand for alternative nicotine products (ANP). METHODS: An experimental auction was conducted with 258 adult smokers, wherein participants were randomly assigned to one of four experimental conditions. The participants received the opportunity to try, but did not have to accept, one of three relatively novel ST products (i.e., snus, dissolvable tobacco, or medicinal nicotine), or they were placed into a control group (i.e., no trial). All the participants then bid on all three of these products, as well as on cigarettes. We assessed interest in using ANP based on both trial of the product and bids placed for the products in the experimental auction. RESULTS: Fewer smokers were willing to try snus (44%) than dissolvable tobacco (64%) or medicine nicotine (68%). For snus, we find modest evidence suggesting that willingness to try is associated with greater demand for the product. For dissolvable tobacco or medicinal nicotine, we find no evidence that those who accept the product trial have higher demand for the product. CONCLUSIONS: Free trials of a novel ANP were not strongly associated with product demand, as assessed by willingness to pay. Given the debate over the potential for ANP to reduce the harm from smoking, these results are important in understanding the impact of free trial offers on adoption of ST product as a strategy to reduce harm from tobacco use. PMID- 26063178 TI - SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9-Rad1-Hus1 checkpoint clamp. AB - BACKGROUND: SIRT6, a member of the NAD(+)-dependent histone/protein deacetylase family, regulates genomic stability, metabolism, and lifespan. MYH glycosylase and APE1 are two base excision repair (BER) enzymes involved in mutation avoidance from oxidative DNA damage. Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp promotes cell cycle checkpoint signaling and DNA repair. BER is coordinated with the checkpoint machinery and requires chromatin remodeling for efficient repair. SIRT6 is involved in DNA double-strand break repair and has been implicated in BER. Here we investigate the direct physical and functional interactions between SIRT6 and BER enzymes. RESULTS: We show that SIRT6 interacts with and stimulates MYH glycosylase and APE1. In addition, SIRT6 interacts with the 9-1-1 checkpoint clamp. These interactions are enhanced following oxidative stress. The interdomain connector of MYH is important for interactions with SIRT6, APE1, and 9-1-1. Mutagenesis studies indicate that SIRT6, APE1, and Hus1 bind overlapping but different sequence motifs on MYH. However, there is no competition of APE1, Hus1, or SIRT6 binding to MYH. Rather, one MYH partner enhances the association of the other two partners to MYH. Moreover, APE1 and Hus1 act together to stabilize the MYH/SIRT6 complex. Within human cells, MYH and SIRT6 are efficiently recruited to confined oxidative DNA damage sites within transcriptionally active chromatin, but not within repressive chromatin. In addition, Myh foci induced by oxidative stress and Sirt6 depletion are frequently localized on mouse telomeres. CONCLUSIONS: Although SIRT6, APE1, and 9-1-1 bind to the interdomain connector of MYH, they do not compete for MYH association. Our findings indicate that SIRT6 forms a complex with MYH, APE1, and 9-1-1 to maintain genomic and telomeric integrity in mammalian cells. PMID- 26063188 TI - Erratum to: Thermodynamic Prediction of Glycine Polymerization as a Function of Temperature and pH Consistent with Experimentally Obtained Results. PMID- 26063186 TI - Anti-Citrullinated Protein Antibodies Induce Macrophage Subset Disequilibrium in RA Patients. AB - We used samples from rheumatoid arthritis (RA) patients to examine whether Anti citrullinated protein antibodies (ACPAs) alter macrophage subset distribution and promote RA development. Macrophage subset distributions and interferon regulatory factor 4 (IRF4) and IRF5 expressions were analyzed. ACPAs were purified by affinity column. After RA and osteoarthritis (OA) patients' macrophages were cocultured with ACPAs, macrophage subsets and IRF4 and IRF5 expressions were measured. Small interfering RNAs (siRNAs) were transfected into ACPA-activated cells to suppress IRF4 or IRF5. Fluorescence-activated cell sorting (FACS), Western blot, and immunohistochemistry were performed. Macrophage subset disequilibrium occurred in RA patient synovial fluids. IRF4 and IRF5 were all expressed in the synovial fluid and synovium. ACPAs (40 IU/ml) could induce macrophages to polarize to M1 subsets, and the percentage of increased M1/M2 ratio of RA patients was higher than that of the OA patients. ACPAs also induce IRF4 and IRF5 protein expressions. IRF5 siRNA transfection impaired ACPA activity significantly. We demonstrated that macrophage subset disequilibrium occurred in RA patients. ACPAs induced IRF5 activity and led to M1 macrophage polarization. PMID- 26063187 TI - Ox-LDL Upregulates IL-6 Expression by Enhancing NF-kappaB in an IGF2-Dependent Manner in THP-1 Macrophages. AB - Interleukin 6 (IL-6) is a pro-inflammatory cytokine that is well established as a vital factor in determining the risk of coronary heart disease and pathogenesis of atherosclerosis. Moreover, accumulating evidences have shown that oxidized low density lipoprotein (ox-LDL) can promote IL-6 expression in macrophages. Nevertheless, the underlying mechanism of how ox-LDL upregulates IL-6 expression remains largely unexplained. We found that the expression of insulin-like growth factor 2 (IGF2), nuclear factor kappa B (NF-kappaB), and IL-6 was upregulated at both the messenger RNA (mRNA) and protein levels in a dose-dependent manner when treated with 0, 25, 50, or 100 MUg/mL of ox-LDL for 48 h in THP-1 macrophages. Moreover, overexpression of IGF2 significantly upregulated NF-kappaB and IL-6 expressions in THP-1 macrophages. However, the upregulation of NF-kappaB and IL-6 expressions induced by ox-LDL were significantly abolished by IGF2 small interfering RNA (siRNA) in THP-1 macrophages. Further studies indicated the upregulation of IL-6 induced by ox-LDL could be abolished when treated with NF kappaB siRNA in THP-1 macrophages. Ox-LDL might upregulate IL-6 in the cell and its secretion via enhancing NF-kappaB in an IGF2-dependent manner in THP-1 macrophages. PMID- 26063189 TI - Micromorphology, histochemistry and ultrastructure of the foliar trichomes of Withania somnifera (L.) Dunal (Solanaceae). AB - MAIN CONCLUSION: The leaves of Withania somnifera contained four morphologically distinct trichome types: glandular capitate, non-glandular dendritic (branched), non-glandular bicellular and non-glandular multicellular trichomes. Major phytochemical compounds present within glandular and non-glandular trichomes were alkaloids and phenolic compounds. The aim of this study was to characterize the micromorphology of the foliar trichomes of Withania somnifera as well as to elucidate the location and composition of the secretory products. Trichome density and length was also determined in three developmental stages of the leaves. Light microscopy and scanning electron microscopy showed the presence of four morphologically distinct trichome types: glandular capitate, non-glandular dendritic, non-glandular bicellular and non-glandular multicellular. The dendritic trichomes exhibited cuticular warts which are involved in the "Lotus Effect". Glandular capitate and non-glandular dendritic trichomes were aggregated on the mid-vein of young and mature leaves, possibly to protect underlying vasculature. Histochemical staining also revealed the presence of two major classes of phytochemical compounds that are of medicinal importance, i.e. alkaloids and phenolic compounds. These compounds are used to treat a wide variety of ailments and also act as chemical deterrents in plants. The results of this study explain possible roles of four morphologically distinct trichome types based on their morphology, foliar distribution and content. PMID- 26063190 TI - Headache prevalence following recovery from TTP and aHUS. AB - Thrombotic thrombocytopenia purpura (TTP) and atypical hemolytic uremic syndromes (aHUS) are distinct clinical disorders characterized by hemolytic anemia, thrombocytopenia, microthrombi, and end organ damage. TTP is characterized by a low ADAMTS13 activity level at diagnosis of <10 % ADAMTS13 activity, while aHUS is characterized as having >10 % ADAMTS13 activity. Despite clinical remission, survivors of thrombotic microangiopathy suffer significant comorbidity and decreased quality of life (QOL) than their healthy counterparts. The reason for this is unclear. Is it a lingering effect from their initial acute episode or ongoing subclinical injury/inflammation despite clinical remission? Common clinical complaints validated in practice include increased depression, deficits in memory, concentration, mood, and mental endurance. We suspect headaches may be an important clinical tool toward understanding patient morbidity and decreased QOL. To date, no studies report headache frequency or severity in this population. To answer this question, adult patients >3 months since their last acute episode of TTP or aHUS were approached to take a Headache Impact Test (HIT 6) survey. Between June 1, 2013 and May 30, 2014, 31 patients in remission (21 patients with prior TTP and 10 patients with prior aHUS) completed the HIT-6 survey. The survey scores were then compared to the HIT-6 normative population data established by Qualitymetric incorporated. Overall, TTP patients had a significantly higher average HIT-6 score of 59.9 compared to an average HIT-6 score of 51 seen in sex-matched controls (SD 9.6, p value 0.002). No significant difference was seen in the HIT-6 scores of aHUS patients. Of TTP patients studied, approximately 57 % (12/21) had three or more episodes and were >24 months since the last episode. The average time since last acute episode in TTP patients was 37.5 months. There was no significant correlation between TTP survivor HIT-6 scores and the number of prior episodes (1, 2, or >3) or timing from the last episode (3-6, 7-12, 13-24, or >24 months). About 19/21 (90 %) patients, who are TTP survivors, also had a normal ADAMTS13 activity level (>10 %) on the day of the survey. Our study suggests that headaches have significant impact on TTP survivors and should be followed in the clinical setting to prevent undue patient morbidity. Larger studies are needed to understand how headaches impact long-term survival and risk of relapse. PMID- 26063192 TI - Evidence-based reflection on the value of FDG-PET for interim and end-of treatment response assessment in diffuse large B-cell lymphoma. PMID- 26063191 TI - Factors associated with hematopoietic cell transplantation (HCT) among patients in a population-based study of myelodysplastic syndrome (MDS) in Minnesota. AB - Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective erythropoiesis, and an increased risk of developing acute myeloid leukemia. Treatment planning for patients with MDS is a complex process, and we sought to better characterize hematopoietic cell transplantation (HCT) outcomes and the factors that play into decision-making regarding referral of adults with MDS for definitive therapy with HCT. Patients enrolled in a population-based study of MDS between April 2010 and January 2013 who underwent HCT within the first year after enrollment were included in this analysis. Age- and risk-matched MDS patient controls also enrolled during that time period were used as a comparison. Survival was significantly better in the HCT group (48 vs. 21 %, log-rank p value 0.009). Non-HCT patients were more likely to have comorbidities, and HCT patients were more likely to have a college degree and an income >$80,000. All three of these variables were independently associated with HCT, but none impacted survival. Patients with MDS in our study who underwent HCT had better survival than a comparable group of patients who did not undergo HCT. With refined treatment techniques, more patients may be able to be considered for this therapy. More work needs to be done to determine why education and income appear to impact the decision to pursue HCT, but these factors may impact referral to an academic center where aggressive therapy like HCT is more likely to be considered. PMID- 26063193 TI - International survey on periextubation practices in extremely preterm infants. AB - OBJECTIVE: To determine periextubation practices in extremely preterm infants (<28 weeks gestation). DESIGN: A survey consisting of 13 questions related to weaning from mechanical ventilation, assessment of extubation readiness and postextubation respiratory support was developed and sent to clinical directors of level III NICUs in Australia, Canada, Ireland, New Zealand and USA. A descriptive analysis of the results was performed. RESULTS: 112/162 (69%) units responded; 36% reported having a guideline (31%) or written protocol (5%) for ventilator weaning. Extubation readiness was assessed based on ventilatory settings (98%), blood gases (92%) and the presence of clinical stability (86%). Only 54% ensured that infants received caffeine <=24 h prior to extubation. 16% of units systematically extubated infants on the premise that they passed a Spontaneous Breathing Test with a duration ranging from 3 min (25%) to more than 10 min (35%). Nasal continuous positive airway pressure was the most common type of respiratory support used (84%) followed by nasal intermittent positive pressure ventilation (55%) and high-flow nasal cannula (33%). Reintubation was mainly based on clinical judgement of the responsible physician (88%). There was a lack of consensus on the time frame for definition of extubation failure (EF), the majority proposing a period between 24 and 72 h; 43% believed that EF is an independent risk factor for increased mortality and morbidity. CONCLUSIONS: Periextubation practices vary considerably; decisions are frequently physician dependent and not evidence based. The definition of EF is variable and well defined criteria for reintubation are rarely used. High-quality trials are required to inform guidelines and standardise periextubation practices. PMID- 26063195 TI - Childhood scurvy: an unusual cause of refusal to walk in a child. AB - Scurvy, or vitamin C deficiency, is rarely presented to a rheumatology clinic. It can mimic several rheumatologic disorders. Although uncommon, it may present as pseudovasculitis or chronic arthritis. Scurvy still exists today within certain populations, particularly in patients with neurodevelopmental disabilities, psychiatric illness or unusual dietary habits.Scurvy presentation to the rheumatologist varies from aches and mild pains to excruciating bone pain or arthritis. Musculoskeletal and mucocutaneous features of scurvy are often what prompts referrals to pediatric rheumatology clinics. Unless health care providers inquire about nutritional habits and keep in mind the risk of nutritional deficiency, it will be easy to miss the diagnosis of scurvy. Rarity of occurrence as compared to other nutritional deficiencies, combined with a lack of understanding about modern-day risk factors for nutritional deficiency, frequently leads to delayed recognition of vitamin C deficiency. We report a case of scurvy in a mentally handicapped Saudi child, who presented with new onset inability to walk with diffuse swelling and pain in the left leg. Skin examination revealed extensive ecchymoses, hyperkeratosis and follicular purpura with corkscrew hairs, in addition to gingival swelling with bleeding. Clinical diagnosis of scurvy was rendered and confirmed by low serum vitamin C level. The patient did extremely well with proper nutritional support and vitamin C supplementation. It has been noticed lately that there is increased awareness about scurvy in rheumatology literature. A high index of suspicion, together with taking a thorough history and physical examination, is required for diagnosis of scurvy in patient who presents with musculoskeletal symptoms. Nutritional deficiency should also be considered by the rheumatologist formulating differential diagnosis for musculoskeletal or mucocutaneous complaints in children, particularly those at risk. PMID- 26063196 TI - B regulatory cells are increased in hypercholesterolaemic mice and protect from lesion development via IL-10. AB - Whilst innate B1-B cells are atheroprotective, adaptive B2-B cells are considered pro-atherogenic. Different subsets of B regulatory cells (B(reg)) have been described. In experimental arthritis and lupus-like disease, B(reg) are contained within the CD21(hi)CD23(hi)CD24(hi) B cell pool. The existence and role of B(reg) in vascular disease is not known. We sought to investigate the existence, identity and location of B(reg) in vascular disease. The representation of B2-B cell subsets in the spleens and lymph nodes (LNs) of Apolipoprotein E(-/-) (ApoE( /-)) mice compared to controls was characterised by flow cytometry. Additionally, we utilised a model of neointima formation based on the placement of a perivascular collar around the carotid artery in ApoE(-/-) mice to ascertain whether B cells and B cell subsets confer protection against lesion development. Adoptive transfer of B cells was performed from wild type or genetically modified mice. We showed that CD21(hi)CD23(hi)CD24(hi) B cells are unexpectedly increased in the draining LNs of ApoE(-/-) mice. Adoptive transfer of LN-derived B2-B cells or purified CD21(hi)CD23(hi)CD24(hi) B cells to syngeneic mice reduced lesion size and inflammation without changing serum cholesterol levels. Follicular B2-B cells did not confer protection. IL-10 blockade or transfer of IL10-deficient B cells prevented LN-derived B cell-mediated protection. This is the first identification of a specific LN-derived B2-B(reg) subset that confers IL-10 mediated protection from neointima formation. This may open the way for immune modulatory approaches in cardiovascular disease. PMID- 26063194 TI - New horizons for newborn brain protection: enhancing endogenous neuroprotection. AB - Intrapartum-related events are the third leading cause of childhood mortality worldwide and result in one million neurodisabled survivors each year. Infants exposed to a perinatal insult typically present with neonatal encephalopathy (NE). The contribution of pure hypoxia-ischaemia (HI) to NE has been debated; over the last decade, the sensitising effect of inflammation in the aetiology of NE and neurodisability is recognised. Therapeutic hypothermia is standard care for NE in high-income countries; however, its benefit in encephalopathic babies with sepsis or in those born following chorioamnionitis is unclear. It is now recognised that the phases of brain injury extend into a tertiary phase, which lasts for weeks to years after the initial insult and opens up new possibilities for therapy.There has been a recent focus on understanding endogenous neuroprotection and how to boost it or to supplement its effectors therapeutically once damage to the brain has occurred as in NE. In this review, we focus on strategies that can augment the body's own endogenous neuroprotection. We discuss in particular remote ischaemic postconditioning whereby endogenous brain tolerance can be activated through hypoxia/reperfusion stimuli started immediately after the index hypoxic-ischaemic insult. Therapeutic hypothermia, melatonin, erythropoietin and cannabinoids are examples of ways we can supplement the endogenous response to HI to obtain its full neuroprotective potential. Achieving the correct balance of interventions at the correct time in relation to the nature and stage of injury will be a significant challenge in the next decade. PMID- 26063198 TI - Enhanced endoplasmic reticulum stress in bone marrow angiogenic progenitor cells in a mouse model of long-term experimental type 2 diabetes. AB - AIMS/HYPOTHESIS: Bone marrow-derived circulating angiogenic cells (CACs) play an important role in vascular repair. In diabetes, compromised functioning of the CACs contributes to the development of diabetic retinopathy; however, the underlying mechanisms are poorly understood. We examined whether endoplasmic reticulum (ER) stress, which has recently been linked to endothelial injury, is involved in diabetic angiogenic dysfunction. METHODS: Flow cytometric analysis was used to quantify bone marrow-derived progenitors (Lin(-)/c-Kit(+)/Sca 1(+)/CD34(+)) and blood-derived CACs (Sca-1(+)/CD34(+)) in 15-month-old Lepr (db) (db/db) mice and in their littermate control (db/+) mice used as a model of type 2 diabetes. Markers of ER stress in diabetic (db/db) and non-diabetic (db/+) bone marrow-derived early outgrowth cells (EOCs) and retinal vascular density were measured. RESULTS: The numbers of bone-marrow progenitors and CACs were significantly reduced in db/db mice. Vascular density was markedly decreased in the retinas of db/db mice, and this was accompanied by vascular beading. Microglial activation was enhanced, as was the production of hypoxia inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF). The production of ER stress markers (glucose-regulated protein-78 [GRP-78], phosphorylated inositol-requiring enzyme-1alpha [p-IRE-1alpha], phosphorylated eukaryotic translation initiation factor-2alpha [p-eIF2alpha], activating transcription factor-4 [ATF4], C/EBP homologous protein [CHOP] and spliced X-box binding protein-1 [XBP1s]) was significantly increased in bone marrow-derived EOCs from db/db mice. In addition, mouse EOCs cultured in high-glucose conditions demonstrated higher levels of ER stress, reduced colony formation, impaired migration and increased apoptosis, all of which were largely prevented by the chemical chaperone 4-phenylbutyrate. CONCLUSIONS/INTERPRETATION: Taken together, our results indicate that diabetes increases ER stress in bone marrow angiogenic progenitor cells. Thus, targeting ER stress may offer a new approach to improving angiogenic progenitor cell function and promoting vascular repair in diabetes. PMID- 26063197 TI - MicroRNA-26a inhibits TGF-beta-induced extracellular matrix protein expression in podocytes by targeting CTGF and is downregulated in diabetic nephropathy. AB - AIMS/HYPOTHESIS: The accumulation of extracellular matrix (ECM) is a characteristic of diabetic nephropathy, and is partially caused by profibrotic proteins TGF-beta and connective tissue growth factor (CTGF). We aimed to identify microRNAs (miRNAs) targeting CTGF on podocytes in diabetic nephropathy. METHODS: We investigated miRNAs targeting CTGF on podocytes with miRNA array analysis and identified a candidate miRNA, miR-26a. Using overexpression and silencing of miR-26a in cultured podocytes, we examined changes of ECM and its host genes. We further investigated glomerular miR-26a expression in humans and in mouse models of diabetic nephropathy. RESULTS: miR-26a, which was downregulated by TGF-beta1, was expressed in glomerular cells including podocytes and in tubules by in situ hybridisation. Glomerular miR-26a expression was downregulated by 70% in streptozotocin-induced diabetic mice. Transfection of miR 26a mimics in cultured human podocytes decreased the CTGF protein level by 50%, and directly inhibited CTGF expression in podocytes, as demonstrated by a reporter assay with the 3'-untranslated region of the CTGF gene. This effect was abolished by a mutant plasmid. miR-26a mimics also inhibited TGF-beta1-induced collagen expression, SMAD-binding activity and expression of its host genes CTDSP2 and CTDSPL. Knockdown of CTDSP2 and CTDSPL increased collagen expression in TGF-beta-stimulated podocytes, suggesting that host genes also regulate TGF beta/SMAD signalling. Finally, we observed a positive correlation between microdissected glomerular miR-26a expression levels and estimated GFR in patients with diabetic nephropathy. CONCLUSIONS/INTERPRETATION: The downregulation of miR 26a is involved in the progression of diabetic nephropathy both in humans and in mice through enhanced TGF-beta/CTGF signalling. PMID- 26063200 TI - Blockade of vascular endothelial growth factor-A/receptor 2 exhibits a protective effect on angiotensin-II stimulated podocytes. AB - Vascular endothelial growth factor (VEGF) and Angiotensin II (Ang-II) are important in glomerulosclerosis, which is one of the main causes of chronic kidney disease. Previous studies have demonstrated that angiotensin type 1 receptor blocker (ARB) can inhibit the synthesis of VEGF mediated by Ang-II and can effectively treat diabetic nephropathy. In the present study, the expression of VEGF and its receptors (VEGFR1/VEGFR2) was examined in Ang-II stimulated podocytes, which were treated with SU5416, a specific VEGFR2 inhibitor. The protein expression of synaptopodin, VEGFR1/2, phosphorylated VEGFR2 and extracellular signal-regulated kinases (ERK) was assessed by western blot analysis. The mRNA expression of transforming growth factor (TGF)-beta1 was examined by reverse transcription-quantitative polymerase chain reaction. It was observed that Ang-II increased the expression of VEGF-A and VEGFR2. Simultaneously, the increased expression of phosphorylated (p-)VEGFR2 and p-ERK induced by Ang-II was downregulated by SU5416. SU5416 can decrease the expression of synaptopodin and increase the expression of TGF-beta1 induced by Ang-II as well as ARB treatment. The expression of VEGFR1 remained unchanged by either Ang II or SU5416 treatment. However, the normal podocytes administered SU5416 alone showed low levels of synaptopodin and high expression of TGF-beta1 compared with the control. In conclusion, VEGF-A/VEGFR2 may be essential for podocytes in a normal state. It is suggested that blockade of VEGF-A/VEGFR2 may exhibit a protective effect on Ang-II stimulated podocytes. PMID- 26063201 TI - Sutton's Law: Keep Going Where The Money Is. PMID- 26063202 TI - China upgrades surveillance and control measures of Middle East respiratory syndrome (MERS). AB - Three years after the identification of Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia, the first case of MERS in China was reported on May 29, 2015. Although the Chinese government issued the MERS Prevention and Control Plan in 2013, a novel edition was released on June 5, 2015 to better cope with the current epidemic situation. The revised Plan refines the descriptions in case-finding and establishment of case-monitoring systems. In addition, tougher regulations on close contacts of confirmed patients and suspected cases are introduced in this new Plan. It is expected these countermeasures will play a greater role in surveilling and controlling MERS in China. PMID- 26063203 TI - Ginsenoside Rg1 reduces aldosterone-induced autophagy via the AMPK/mTOR pathway in NRK-52E cells. AB - Aldosterone is a steroid hormone secreted from the adrenal cortex, which regulates blood pressure. Higher concentrations of aldosterone can cause several diseases, including hypertension, diabetic nephropathy and chronic kidney disease. Previous reports have demonstrated that aldosterone has a pathogenic role in renal injury via reactive oxygen species (ROS), which involves the regulation of autophagy. However, whether aldosterone can induce autophagy in renal tubular cells remains to be elucidated. In the present study, elevated autophagy was observed in rat renal tubular NRK-52E cells exposed to aldosterone, which was demonstrated by the increased number of autophagosomes, conversion of LC3-I to LC3-II and the expression of Beclin-1. The enhanced autophagy was accompanied by increased production of intracellular ROS, which was reversed by N acetylcysteine, a specific inhibitor of ROS signaling. Furthermore, treatment with ginsenoside Rg1 reduced the aldosterone-induced autophagy and production of ROS, possibly through reducing the phosphorylation of AMPK and preserving mTOR activity. These findings demonstrated that aldosterone promoted ROS generation and increased autophagy in the NRK-52E cells. Ginsenoside Rg1 effectively relieved aldosterone-induced oxidative stress and abnormal autophagy, suggesting that Rg1 may be used as a potential therapeutic drug to inhibit the renal injury, which is induced by aldosterone. PMID- 26063205 TI - Direct Chemical Activation of a Rationally Engineered Signaling Enzyme. AB - Few chemical strategies for activating enzymes have been developed. Here we show that a biarsenical compound (FlAsH) can directly activate a rationally engineered protein tyrosine phosphatase (Shp2 PTP) by disrupting autoinhibitory interactions between Shp2's N-terminal SH2 domain and its PTP domain. We found that introducing a tricysteine motif at a loop of Shp2's N-SH2 domain confers affinity for FlAsH; binding of FlAsH to the cysteine-enriched loop relieves Shp2's inhibitory interdomain interaction and substantially increases the enzyme's PTP activity. Activation of engineered Shp2 is substrate independent and is observed in the contexts of both purified enzyme and complex proteomes. A chemical means for activating Shp2 could be useful for investigating its roles in signaling and oncogenesis, and the loop-targeting strategy described herein could provide a blueprint for the development of target-specific activators of other autoinhibited enzymes. PMID- 26063204 TI - MicroRNA-29b attenuates non-small cell lung cancer metastasis by targeting matrix metalloproteinase 2 and PTEN. AB - BACKGROUND: Our pilot study using miRNA PCR array found that miRNA-29b (miR-29b) is differentially expressed in primary cultured CD133-positive A549 cells compared with CD133-negative A549 cells. METHODS: Ten human non-small cell lung cancer (NSCLC) cell lines and samples from thirty patients with NSCLC were analyzed for the expression of miR-29b by quantitative RT-PCR. Bioinformatics analysis combined with tumor metastasis PCR array showed the potential target genes for miR-29b. miR-29b lentivirus and inhibitors were transfected into NSCLC cells to investigate its role on regulating cell proliferation which was measured by CCK-8 assay in vitro and nude mice xenograft tumor assay in vivo. Cell motility ability was evaluated by transwell assay. The target genes of miR-29b were determined by luciferase assay, quantitative RT-PCR and western blot. RESULTS: Bioinformatics analysis combined with tumor metastasis PCR array showed that matrix metalloproteinase 2 (MMP2) and PTEN could be important target genes of miR-29b. The expression of miR-29b was down regulated in NSCLC tissues compared to the normal tissues. Clinicopathological analysis demonstrated that miR-29b had significant negative correlation with lymphatic metastasis. The gain of-function studies revealed that ectopic expression of miR-29b decreased cell proliferation, migration and invasion abilities of NSCLC cells. In contrasts, loss-of-function studies showed that inhibition of miR-29b promoted cell proliferation, migration and invasion of NSCLC cells in vitro. Nude mice xenograft tumor assay confirmed that miR-29b inhibited lung cancer growth in vivo. High-invasion (A549-H) and low-invasion (A549-L) NSCLC cell sublines from A549 cells were created by using the repeated transwell assay aimed to confirm the effect of miR-29b on migration and invasion of NSCLC. Furthermore, the dual luciferase reporter assay demonstrated that miR-29b inhibited the expression of the luciferase gene containing the 3'-UTRs of MMP2 and PTEN mRNA. Western blotting and quantitative RT-PCR indicated that miR-29b down-regulated the expression of MMP2 at the protein and mRNA levels. CONCLUSION: Taken together, our results demonstrate that miR-29b serves as a tumor metastasis suppressor, which suppresses NSCLC cell metastasis by directly inhibiting MMP2 expression. The results show that miR-29b may be a novel therapeutic candidate target to slow NSCLC metastasis. PMID- 26063206 TI - Knowledge of human social and behavioral factors essential for the success of community malaria control intervention programs: The case of Lomahasha in Swaziland. AB - BACKGROUND: Although malaria control programs have made rapid progress recently, they neglect important social and behavioral factors associated with the disease. Social, political, and cultural factors are involved in malaria control, and individuals in a community may be comfortable in behaving in ways that, to an outsider, may seem contrary to commonly held perceptions. Malaria control efforts can no longer afford to overlook the multidimensional human contexts that create and support varying notions of malaria and its prevention, treatment, and control. This study aimed to assess the knowledge and perceptions of malaria issues in the community, and to identify practices that support or hinder the progress of malaria control programs. METHODS: A triangulation study involving individual interviews, focus group discussions, and observatory analysis between 2003 and 2010 at Lomahasha, a malarious community on the eastern border of Swaziland and Mozambique, was conducted. RESULTS: Results indicated that a high knowledge level and good perception of the disease were observed in the age group of < 40 years, contrary to those in higher age groups, among the Lomahasha community members. However, behavior of certain community groups includes practices that are not supportive of the national control program's aspirations, such as delay in seeking medical attention, staying outdoors until late, maintaining stagnant water in roadside excavations, and seeking medical assistance from wrong sources. Malpractices are more commonly observed among men, boys, and those who drink alcohol. CONCLUSION: This study suggests a thorough community diagnosis before all intervention programs for malaria control are instituted. PMID- 26063207 TI - Brain Delivery of Chemotherapeutics in Brain Cancer. AB - Treatment of brain tumour is a major challenge. This is mainly because of the limited bioavailability of chemotherapeutics in the brain. The major hurdle for brain availability of anticancer agents is the blood brain barrier (BBB). BBB is supposed to protect the brain and maintain homeostasis. It allows vital nutrient for normal brain function and effluxes out foreign toxic substance. Advance in knowledge of bidirectional movement across BBB has allowed development of strategies to enhance brain availability of chemotherapeutics for management of brain tumour. In this review we have focussed on various approaches adopted for enhancing delivery of anticancer agents. We have given a critical analysis of the approaches for further research. PMID- 26063208 TI - Photochemical upconversion and triplet annihilation limit from a boron dipyrromethene emitter. AB - Non-coherent sensitized red-to-green upconversion has been achieved utilizing platinum(II) tetraphenyltetrabenzoporphyrin (PtTPTBP) as the triplet sensitizer and a nearly quantitatively fluorescent meso-(2,6-dichloropyridyl)-substituted boron dipyrromethene (Cl2PyBODIPY) chromophore (Phi = 0.99 in toluene) as the energy acceptor/annihilator in deoxygenated toluene. Dynamic Stern-Volmer analysis revealed that PtTPTBP phosphorescence as quenched by Cl2PyBODIPY occurs with a KSV of 108,000 M(-1), yielding a triplet-triplet energy transfer rate constant of 2.3 * 10(9) M(-1) s(-1). Using a non-coherent red light-emitting diode excitation source centered at 626 nm, the incident power dependence responsible for generating singlet BODIPY fluorescence in the green was shown to traverse quadratic to linear regimes, the latter being achieved near 60 mW cm( 2). These data were consistent with a photochemical upconversion mechanism being responsible for generating singlet fluorescence from the Cl2PyBODIPY chromophores through sensitized triplet-triplet annihilation (TTA). Integrated delayed fluorescence transients were utilized to reveal the TTA efficiency for the Cl2PyBODIPY chromophore and saturated near 46%, representing the lower limit for the TTA process. Kinetic modelling of the delayed fluorescence transient produced from 1.5 mJ laser pulses (lambdaex = 615 nm) revealed a maximum limiting TTA efficiency of 64% for this upconverting composition, implying that this is indeed an extremely relevant acceptor/annihilator composition for photochemical upconversion. PMID- 26063209 TI - Caring for people with severe myalgic encephalomyelitis: An interpretative phenomenological analysis of parents' experiences. AB - Experiences of parents who care for sons or daughters with severe myalgic encephalomyelitis are rarely discussed within the literature. Narratives of parent-carers in Lost Voices from a Hidden Illness were analyzed using interpretative phenomenological analysis. This study aimed to give voices to those who care for individuals with myalgic encephalomyelitis and are often stigmatized and inform future research supporting parent-carers. Results included themes of identity change, guilt, feeling like outsiders, uncertainty, changing perceptions of time, coping mechanisms, and improvement/symptom management. Findings could inform the development of carer-focused interventions and provide vital information to health professionals about parent-carers' lived experience. PMID- 26063210 TI - Recent anxiety symptoms and drug use associated with sexually transmitted infection diagnosis among an online US sample of men who have sex with men. AB - The extent to which mental health problems, including current anxiety and depressive symptoms, may co-occur, or are associated, with the acquisition of sexually transmitted infections other than HIV remains largely unexplored among men who have sex with men. In a cross-sectional survey of 8,381 US men who have sex with men recruited from a sexual networking website, 15 percent reported a past 60-day sexually transmitted infection diagnosis. Among HIV-negative men, increased odds of reporting a sexually transmitted infection were associated with current anxiety symptoms and past 60-day drug use. Findings underscore the need to better understand causal pathways among anxiety, drug use, and sexually transmitted infection acquisition and transmission among men who have sex with men. PMID- 26063211 TI - Who does not get screened? A simple model of the complex relationships in mammogram non-attendance. AB - With increasing mammogram rates, identifying attributes of non-attending women entails going beyond differences in demographic groups to reveal complex interactions among personality attributes. In this study, we analyzed survey data from 474 women aged 41 years and older using decision trees. By incorporating personality, religiousness, and age, we were able to correctly classify 42.9 percent of non-attenders compared to 4.4 percent with logistic regression analysis. Our findings suggest that incorporating personality and religiousness attributes may increase non-attender identification. Furthermore, the simple profile generated by decision trees provides a clear map useful for intervention planning. PMID- 26063212 TI - Nintedanib: A Review of Its Use in Patients with Idiopathic Pulmonary Fibrosis. AB - Nintedanib (Ofev((r))) inhibits receptor tyrosine kinases implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This article reviews the efficacy and tolerability of oral nintedanib in the treatment of IPF, as well as summarizing its pharmacological properties. In the randomized, double-blind, multinational, 12-month INPULSIS-1 and -2 trials in patients with IPF, nintedanib significantly reduced the decline in forced vital capacity versus placebo, indicating a slowing of disease progression. The time to first acute exacerbation was significantly increased with nintedanib in INPULSIS-2, but not in INPULSIS-1, and significantly less deterioration in health-related quality of life was seen with nintedanib in INPULSIS-2, but not in INPULSIS-1. Nintedanib had an acceptable tolerability profile in patients with IPF; gastrointestinal adverse events (diarrhoea, nausea, vomiting) were reported most commonly. In conclusion, nintedanib is an important new option for the treatment of IPF. PMID- 26063213 TI - Dexmedetomidine: A Review of Its Use for Sedation in the Intensive Care Setting. AB - Dexmedetomidine (Dexdor((r))) is a highly selective alpha2-adrenoceptor agonist. It has sedative, analgesic and opioid-sparing effects and is suitable for short- and longer-term sedation in an intensive care setting. In the randomized, double blind, multicentre MIDEX and PRODEX trials, longer-term sedation with dexmedetomidine was noninferior to midazolam and propofol in terms of time spent at the target sedation range, as well as being associated with a shorter time to extubation than midazolam or propofol, and a shorter duration of mechanical ventilation than midazolam. Patients receiving dexmedetomidine were also easier to rouse, more co-operative and better able to communicate than patients receiving midazolam or propofol. Dexmedetomidine had beneficial effects on delirium in some randomized, controlled trials (e.g. patients receiving dexmedetomidine were less likely to experience delirium than patients receiving midazolam, propofol or remifentanil and had more delirium- and coma-free days than patients receiving lorazepam). Intravenous dexmedetomidine had an acceptable tolerability profile; hypotension, hypertension and bradycardia were the most commonly reported adverse reactions. In conclusion, dexmedetomidine is an important option for sedation in the intensive care setting. PMID- 26063214 TI - TLR3 gene polymorphisms in cancer: a systematic review and meta-analysis. AB - INTRODUCTION: Recent studies examining the association of Toll-like receptor 3 (TLR3) gene polymorphisms with the risk of developing various types of cancer have reported conflicting results. Clarifying this association could advance our knowledge of the influence of TLR3 single nucleotide polymorphisms (SNPs) on cancer risk. METHODS: We systematically reviewed studies that focused on a collection of 12 SNPs located in the TLR3 gene and the details by which these SNPs influenced cancer risk. Additionally, 14 case-control studies comprising a total of 7997 cases of cancer and 8699 controls were included in a meta-analysis of 4 highly studied SNPs (rs3775290, rs3775291, rs3775292, and rs5743312). RESULTS: The variant TLR3 genotype rs5743312 (C9948T, intron 3, C>T) was significantly associated with an increased cancer risk as compared with the wild type allele (odds ratio [OR]=1.11, 95% confidence interval [CI]=1.00-1.24, P=0.047). No such association was observed with other TLR3 SNPs. In the stratified analysis, the rs3775290 (C13766T, C>T) variant genotype was found to be significantly associated with an increased cancer risk in Asian populations. Additionally, the rs3775291 (G13909A, G>A) variant genotype was significantly associated with an increased cancer risk in Asians, subgroup with hospital-based controls, and subgroup with a small sample size. CONCLUSION: After data integration, our findings suggest that the TLR3 rs5743312 polymorphism may contribute to an increased cancer risk. PMID- 26063215 TI - Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. AB - OBJECTIVE: To study the association between benzodiazepine prescribing patterns including dose, type, and dosing schedule and the risk of death from drug overdose among US veterans receiving opioid analgesics. DESIGN: Case-cohort study. SETTING: Veterans Health Administration (VHA), 2004-09. PARTICIPANTS: US veterans, primarily male, who received opioid analgesics in 2004-09. All veterans who died from a drug overdose (n=2400) while receiving opioid analgesics and a random sample of veterans (n=420,386) who received VHA medical services and opioid analgesics. MAIN OUTCOME MEASURE: Death from drug overdose, defined as any intentional, unintentional, or indeterminate death from poisoning caused by any drug, determined by information on cause of death from the National Death Index. RESULTS: During the study period 27% (n=112,069) of veterans who received opioid analgesics also received benzodiazepines. About half of the deaths from drug overdose (n=1185) occurred when veterans were concurrently prescribed benzodiazepines and opioids. Risk of death from drug overdose increased with history of benzodiazepine prescription: adjusted hazard ratios were 2.33 (95% confidence interval 2.05 to 2.64) for former prescriptions versus no prescription and 3.86 (3.49 to 4.26) for current prescriptions versus no prescription. Risk of death from drug overdose increased as daily benzodiazepine dose increased. Compared with clonazepam, temazepam was associated with a decreased risk of death from drug overdose (0.63, 0.48 to 0.82). Benzodiazepine dosing schedule was not associated with risk of death from drug overdose. CONCLUSIONS: Among veterans receiving opioid analgesics, receipt of benzodiazepines was associated with an increased risk of death from drug overdose in a dose-response fashion. PMID- 26063217 TI - NMR study of Ba8Cu5Si(x)Ge(41-x) clathrate semiconductors. AB - We have performed (63)Cu, (65)Cu, and (137)Ba NMR on Ba8Cu5SixGe41-x, a series of intermetallic clathrates known for their potential as thermoelectric materials, in order to investigate the electronic behavior of the samples. The spectra and spin-lattice relaxation times were measured at 77 K and 290 K for the entire composition range 0 <= x <= 41. Magnetic and quadrupole shifts and relaxation rates of the Cu NMR data were extracted, and thereby carrier-induced metallic contributions identified. The observed shifts change in a nonlinear way with increasing Si substitution: from x = 0 to about 20 the shifts are essentially constant, while approaching x = 41 they increase rapidly. At the same time, Ba NMR data indicate greater Ba-site participation in the conduction band in Ba8Cu5Si41 than in Ba8Cu5Ge41. The results indicate surprisingly little change in electronic features vs. Si content for most of the composition range, while Ba8Cu5Si41 exhibits enhanced hybridization and a more metallic framework than Ba8Cu5Ge41. PMID- 26063216 TI - Impregnating hessian strips with the volatile pyrethroid transfluthrin prevents outdoor exposure to vectors of malaria and lymphatic filariasis in urban Dar es Salaam, Tanzania. AB - BACKGROUND: Semi-field trials using laboratory-reared Anopheles arabiensis have shown that, delivering the volatile pyrethroid transfluthrin by absorption into hessian strips, consistently provided > 99% human protective efficacy against bites for 6 months without retreating. Here the impact of this approach upon human exposure to wild populations of vectors for both malaria and filariasis under full field conditions is assessed for the first time. METHODS: Transfluthrin-treated and untreated strips were placed around human volunteers conducting human landing catch in an outdoor environment in urban Dar es Salaam, where much human exposure to malaria and filariasis transmission occurs outdoors. The experiment was replicated 9 times at 16 outdoor catching stations in 4 distinct locations over 72 working nights between May and August 2012. RESULTS: Overall, the treated hessian strips conferred 99% protection against An. gambiae (1 bite versus 159) and 92% protection against Culex spp. (1478 bites versus 18,602). No decline in efficacy over the course of the study could be detected for the very sparse populations of An. gambiae (P = 0.32) and only a slow efficacy decline was observed for Culex spp. (P < 0.001), with protection remaining satisfactory over 3 months after strip treatment. Diversion of mosquitoes to unprotected humans in nearby houses was neither detected for An. gambiae (P = 0.152) nor for Culex spp. (Relative rate, [95% CI] = 1.03, [0.95, 1.11], P = 0.499). CONCLUSION: While this study raises more questions than it answers, the presented evidence of high protection over long periods suggest this technology may have potential for preventing outdoor transmission of malaria, lymphatic filariasis and other vector-borne pathogens. PMID- 26063218 TI - Effect by custom-made foot orthoses with added support under the first metatarso phalangeal joint in hallux limitus patients: Improving on first metatarso phalangeal joint extension. AB - BACKGROUND: Hallux limitus is one of the most common disorders affecting foot biomechanics. Custom-made foot orthoses can improve the function of the first metatarso-phalangeal joint. OBJECTIVES: The objective underlying this study was to test whether custom-made foot orthoses increased the range of mobility of metatarso-phalangeal joint in patients with hallux limitus. STUDY DESIGN: Randomized, double-blinded, and clinical trial. METHODS: The study consisted of 20 participants (40 feet) diagnosed with hallux limitus. A control group and an experimental group both wore the same custom-made foot orthoses and, in the experimental group, a support element under the first metatarso-phalangeal joint was added to the orthoses. Two measurements were made with both groups: the relaxed position of the first metatarso-phalangeal joint and the maximum extension of the hallux. These measurements were made before first placing the foot orthoses and 6 months after application of the treatment. RESULTS: In the experimental group, the results showed an improvement of 4.5 degrees in the relaxed position and 22.2 degrees in the maximum extension being statistically significant (p < 0.001) for both measurements. CONCLUSION: Custom-made foot orthoses with added support under the first metatarso-phalangeal joint were proved to be an effective treatment to restore functionality of this joint in hallux limitus patients. CLINICAL RELEVANCE: Limitation of hallux movement in the joints propulsive phase of gait negatively affects the biomechanics of the lower extremity, causing changes in the rest of the joins. The use of foot orthoses designed in this study restores range of motion of the first metatarso-phalangeal joint. PMID- 26063219 TI - Toward a systematic approach to assessment and care planning in palliative care: A practical review of clinical tools. AB - OBJECTIVE: Ensuring a consistent and systematic approach to the delivery of care for people with advanced disease is a priority for palliative care services worldwide. Many clinical tools are available to aid in this process; however, they are often used sporadically, and implementation of a routine set of clinical tools to guide care planning in the specialist palliative care sector in Australia has not been achieved. This study sought to recommend key clinical tools that may assist with the assessment and care planning of specialist palliative care provision for patients and family caregivers admitted to specialist palliative care settings (home, hospital, and hospice). METHOD: A mixed-methods sequential approach over four phases was employed, involving: (1) a palliative care sector survey, (2) a systematic literature review, (3) an appraisal of identified clinical tools, and (4) a focus group with an expert panel who critiqued and endorsed a final suite of clinical tools recommended for specialist palliative care. RESULTS: Twelve tools with practical relevance were recommended for use across settings of care. SIGNIFICANCE OF RESULTS: Palliative services should review current practices and seek to implement this recommended suite of tools to enhance assessment and guide care delivery across care settings. Subsequent evaluation should also occur. PMID- 26063220 TI - Morphological study of mechanoreceptors in collateral ligaments of the ankle joint. AB - BACKGROUND: The aim of this study was to analyze the pattern and types of sensory nerve endings in ankle collateral ligaments using histological techniques, in order to observe the morphology and distribution of mechanoreceptors in the collateral ligaments of cadaver ankle joint, and to provide the morphological evidence for the role of the ligament in joint sensory function. METHODS: Twelve lateral collateral ligaments including anterior talofibular ligament (ATFL; n = 6), posterior talofibular ligament (PTFL; n = 6), and calcaneofibular ligament (CFL; n = 6) were harvested from six fresh frozen cadavers. The ligaments were embedded in paraffin, sectioned at 4 MUm, and then stained using a modified gold chloride staining methods. The collateral ligament was divided into three segments: proximal, middle, and distal segments. Fifty-four ATFL slides, 90 PTFL slides, and 108 CFL slides were analyzed. Mechanoreceptors were classified based on Freemen and Wyke's classification. Mechanoreceptor distribution was analyzed statistically. One-way ANOVA (postHoc LSD) was used for statistical analysis. RESULTS: All the four typical types of nerve endings (the Ruffini corpuscles, Pacinian corpuscles, Golgi tendon organs, and free nerve endings) were identified in these ligaments. Pacinian corpuscles were the predominant in all four complexes. More mechanoreceptors were found in synovial membrane near both ends of the ligaments attached to the bone. No statistical differences were found in the amount of mechanoreceptors among distal, middle, and proximal parts of the ligaments. CONCLUSIONS: The four typical types of mechanoreceptors were all identified in the collateral ligaments of the human ankle. Pacinian corpuscles were the predominant in all four complexes. This indicates that the main function of ankle collateral ligaments is to sense joint speeds in motions. PMID- 26063221 TI - miR-183 regulates biological behavior in papillary thyroid carcinoma by targeting the programmed cell death 4. AB - Numerous studies have demonstrated that microRNAs (miRNAs) play vital roles in papillary thyroid carcinoma (PTC). The aim of the present study was to examine the expression levels of miR-183 in PTC and investigate whether its potential roles involved targeting the programmed cell death 4 (PDCD4). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to examine the expression levels of miR-183 in 38 PTC specimens and 4 PTC cell lines. MTT, colony formation, wound-healing and Transwell invasion assays, and flow cytometry were conducted to explore the potential functions of miR-183 in human TPC1 papillary thyroid carcinoma cells. The dual-luciferase reporter assay was performed to validate whether PDCD4 was a direct target of miR-183. The effects of modulating miR-183 on endogenous levels of PDCD4 were subsequently confirmed via RT-qPCR and western blotting. Functional assays were used to indicate the roles of endogenous PDCD4 in TPC1. The results showed the miR-183 expression levels were significantly upregulated in PTC specimens and cell lines (P<0.05). Overexpression of miR-183 in TPC1 promoted cell proliferation, migration, invasion and decreased apoptosis. The dual-luciferase reporter assay confirmed that PDCD4 was a direct target of miR-183. RT-qPCR and western blotting showed that miR-183 negatively regulated PDCD4 protein expression but had no impact on mRNA expression of PDCD4. Knockdown of PDCD4 expression in TPC1 cells significantly enhanced cell proliferation, migration, invasion and inhibited apoptosis. The results of the present study suggested that miR-183 acts as a papillary thyroid carcinoma oncogene through the negative regulation of PDCD4 protein expression at the post-transcriptional levels. Therefore, targeting miR 183 provides a novel strategy for the diagnosis and treatment of patients with PTC. PMID- 26063222 TI - High Anti-Dengue Virus Activity of the OAS Gene Family Is Associated With Increased Severity of Dengue. AB - Dengue is a mosquito-borne viral disease that afflicts millions of individuals worldwide every year. Infection by any of the 4 dengue virus (DENV) serotypes can result in a spectrum of disease severity. We investigated the impact of variants of interferon-regulated innate immunity genes with a potent antiviral effect on the outcome of DENV infection. We compared the effect of OAS gene family variants on 2 DENV serotypes in cell culture. While both OAS1-p42 and p46 showed antiviral activity against DENV-2, only OAS1-p42 presented anti-DENV-1 activity. Conversely, whereas both OAS3_S381 and R381 variants were able to block DENV-1 infection, the anti-DENV-2 activity observed for OAS3_S381 was largely lost for the R381 variant. By means of an allelic association study of a cohort of 740 patients with dengue, we found a protective effect of OAS3_R381 against shock (odds ratio [OR], 0.37; P < .001). This effect was due to DENV-2 infections (OR, 0.13; P = .007) but was absent for DENV-1, in accordance with the serotype dependent OAS3 activity found in the functional study. Severe dengue has long been associated with a cytokine storm of unclear origin. This work identifies an early innate immunity process that could lead to the immune overreaction observed in severe dengue and could be triggered by a specific host genotype-pathogen genotype interaction. PMID- 26063223 TI - Considerations in the Use of Nonhuman Primate Models of Ebola Virus and Marburg Virus Infection. AB - The filoviruses, Ebola virus and Marburg virus, are zoonotic pathogens that cause severe hemorrhagic fever in humans and nonhuman primates (NHPs), with case fatality rates ranging from 23% to 90%. The current outbreak of Ebola virus infection in West Africa, with >26 000 cases, demonstrates the long underestimated public health danger that filoviruses pose as natural human pathogens. Currently, there are no vaccines or treatments licensed for human use. Licensure of any medical countermeasure may require demonstration of efficacy in the gold standard cynomolgus or rhesus macaque models of filovirus infection. Substantial progress has been made over the last decade in characterizing the filovirus NHP models. However, there is considerable debate over a variety of experimental conditions, including differences among filovirus isolates used, routes and doses of exposure, and euthanasia criteria, all of which may contribute to variability of results among different laboratories. As an example of the importance of understanding these differences, recent data with Ebola virus shows that an addition of a single uridine residue in the glycoprotein gene at the editing site attenuates the virus. Here, we draw on decades of experience working with filovirus-infected NHPs to provide a perspective on the importance of various experimental conditions. PMID- 26063224 TI - Preclinical Development of Inactivated Rabies Virus-Based Polyvalent Vaccine Against Rabies and Filoviruses. AB - We previously described the generation of a novel Ebola virus (EBOV) vaccine based on inactivated rabies virus (RABV) containing EBOV glycoprotein (GP) incorporated in the RABV virion. Our results demonstrated safety, immunogenicity, and protective efficacy in mice and nonhuman primates (NHPs). Protection against viral challenge depended largely on the quality of the humoral immune response against EBOV GP.Here we present the extension and improvement of this vaccine by increasing the amount of GP incorporation into virions via GP codon-optimization as well as the addition of Sudan virus (SUDV) and Marburg virus (MARV) GP containing virions. Immunogenicity studies in mice indicate similar immune responses for both SUDV GP and MARV GP compared to EBOV GP. Immunizing mice with multiple antigens resulted in immune responses similar to immunization with a single antigen. Moreover, immunization of NHP with the new inactivated RABV EBOV vaccine resulted in high titer neutralizing antibody levels and 100% protection against lethal EBOV challenge when applied with adjuvant.Our results indicate that an inactivated polyvalent vaccine against RABV filoviruses is achievable. Finally, the novel vaccines are produced on approved VERO cells and a clinical grade RABV/EBOV vaccine for human trials has been produced. PMID- 26063229 TI - Impact of an energy-conserving strategy on succinate production under weak acidic and anaerobic conditions in Enterobacter aerogenes. AB - BACKGROUND: Succinate is an important C4 building block chemical, and its production via fermentative processes in bacteria has many practical applications in the biotechnology field. One of the major goals of optimizing the bacterium based succinate production process is to lower the culture pH from the current neutral conditions, as this would reduce total production costs. In our previous studies, we selected Enterobacter aerogenes, a rapid glucose assimilator at pH 5.0, in order to construct a metabolically engineered strain that could produce succinate under weakly acidic conditions. This engineered strain produced succinate from glucose with a 72.7% (g/g) yield at pH 5.7, with a volumetric productivity of 0.23 g/L/h. Although this demonstrates proof-of-concept that bacterium-based succinate fermentation can be improved under weakly acidic conditions, several parameters still required further optimization. RESULTS: In this study, we genetically modified an E. aerogenes strain previously developed in our laboratory in order to increase the production of ATP during succinate synthesis, as we inferred that this would positively impact succinate biosynthesis. This led to the development of the ES08DeltaptsG strain, which contains the following modifications: chromosomally expressed Actinobacillus succinogenes phosphoenolpyruvate carboxykinase, enhanced fumarate reductase, inactivated pyruvate formate lyase, pyruvate oxidase, and glucose phosphotransferase permease (enzyme IIBC(Glc)). This strain produced 55.4 g/L succinate from glucose, with 1.8 g/L acetate as the major byproduct at pH 5.7 and anaerobic conditions. The succinate yield and volumetric productivity of this strain were 86.8% and 0.92 g/L/h, respectively. CONCLUSIONS: Focusing on increasing net ATP production during succinate synthesis leads to increased succinate yield and volumetric productivity in E. aerogenes. We propose that the metabolically engineered E. aerogenes ES08DeltaptsG strain, which effectively produces succinate under weakly acidic and anaerobic conditions, has potential utility for economical succinate production. PMID- 26063230 TI - Development of an internationally agreed minimal dataset for juvenile dermatomyositis (JDM) for clinical and research use. AB - BACKGROUND: Juvenile dermatomyositis (JDM) is a rare autoimmune inflammatory disorder associated with significant morbidity and mortality. International collaboration is necessary to better understand the pathogenesis of the disease, response to treatment and long-term outcome. To aid international collaboration, it is essential to have a core set of data that all researchers and clinicians collect in a standardised way for clinical purposes and for research. This should include demographic details, diagnostic data and measures of disease activity, investigations and treatment. Variables in existing clinical registries have been compared to produce a provisional data set for JDM. We now aim to develop this into a consensus-approved minimum core dataset, tested in a wider setting, with the objective of achieving international agreement. METHODS/DESIGN: A two-stage bespoke Delphi-process will engage the opinion of a large number of key stakeholders through Email distribution via established international paediatric rheumatology and myositis organisations. This, together with a formalised patient/parent participation process will help inform a consensus meeting of international experts that will utilise a nominal group technique (NGT). The resulting proposed minimal dataset will be tested for feasibility within existing database infrastructures. The developed minimal dataset will be sent to all internationally representative collaborators for final comment. The participants of the expert consensus group will be asked to draw together these comments, ratify and 'sign off' the final minimal dataset. DISCUSSION: An internationally agreed minimal dataset has the potential to significantly enhance collaboration, allow effective communication between groups, provide a minimal standard of care and enable analysis of the largest possible number of JDM patients to provide a greater understanding of this disease. The final approved minimum core dataset could be rapidly incorporated into national and international collaborative efforts, including existing prospective databases, and be available for use in randomised controlled trials and for treatment/protocol comparisons in cohort studies. PMID- 26063231 TI - Mesenchymal stem cells for therapeutic applications in pulmonary medicine. AB - INTRODUCTION: Mesenchymal stem cells (MSCs) of different biological sources are in Phase 1 clinical trials and are being considered for Phase 2 therapy of lung disorders, and lung (progenitor) cells derived from pluripotent stem cells (SCs) are under development in preclinical animal models. SOURCES OF DATA: PubMed.gov and ClinicalTrials.gov. AREAS OF AGREEMENT: There is consensus about the therapeutic potential of transplanted SCs, mainly MSCs, primarily involves paracrine 'bystander' effects that confer protection of the epithelial and endothelial linings of the lung caused by inflammation and/or fibrosis and lead to increased survival in animal models. Clinical trials of Phase 1 indicate safety and suggest that the efficacy of SC therapy in patients with various lung diseases will require a higher dosage than previously evaluated. AREAS OF CONTROVERSY: A growing interest in the re-epithelialization and re endothelialization of damaged lung tissue involves the putative pulmonary differentiation of exogenous MSCs. Currently, it is not clear whether or not the observed regeneration of distal airways/vasculature is derived from lung-resident and/or transplanted SCs. GROWING POINTS: Important topics under investigation include optimization of the cell source with a decrease in cell population heterogeneity characterized by defined markers, route of delivery for effective treatment, potential dose and therapeutic protocol of SC application, development of quantitative assays and biomarkers of lung disease and repair, and the potential use of tissue engineered lung. AREAS TIMELY FOR DEVELOPING RESEARCH: Ability of MSCs to differentiate into epithelial cells of the lung, use of autologous induced pluripotent SCs (iPSCs) derived from the patients, complete biochemical characterization of the secretome of SCs used for therapy, and the incorporation of simultaneous and/or subsequent treatment with drugs which also aid in lung repair and regeneration. CAUTIONARY NOTE: Although safety of MSC based cell therapy was proved in Phase 1, efficacy, long-term survival and preservation of lung respiratory function need to be further evaluated, cautioning against hastily translating SCs therapy from animal models of lung injury to clinical trials of patients with lung disorders. PMID- 26063232 TI - Local and systemic effect of transfection-reagent formulated DNA vectors on equine melanoma. AB - BACKGROUND: Equine melanoma has a high incidence in grey horses. Xenogenic DNA vaccination may represent a promising therapeutic approach against equine melanoma as it successfully induced an immunological response in other species suffering from melanoma and in healthy horses. In a clinical study, twenty-seven, grey, melanoma-bearing, horses were assigned to three groups (n = 9) and vaccinated on days 1, 22, and 78 with DNA vectors encoding for equine (eq) IL-12 and IL-18 alone or in combination with either human glycoprotein (hgp) 100 or human tyrosinase (htyr). Horses were vaccinated intramuscularly, and one selected melanoma was locally treated by intradermal peritumoral injection. Prior to each injection and on day 120, the sizes of up to nine melanoma lesions per horse were measured by caliper and ultrasound. Specific serum antibodies against hgp100 and htyr were measured using cell based flow-cytometric assays. An Analysis of Variance (ANOVA) for repeated measurements was performed to identify statistically significant influences on the relative tumor volume. For post-hoc testing a Tukey-Kramer Multiple-Comparison Test was performed to compare the relative volumes on the different examination days. An ANOVA for repeated measurements was performed to analyse changes in body temperature over time. A one-way ANOVA was used to evaluate differences in body temperature between the groups. A p-value < 0.05 was considered significant for all statistical tests applied. RESULTS: In all groups, the relative tumor volume decreased significantly to 79.1 +/- 26.91% by day 120 (p < 0.0001, Tukey-Kramer Multiple Comparison Test). Affiliation to treatment group, local treatment and examination modality had no significant influence on the results (ANOVA for repeated measurements). Neither a cellular nor a humoral immune response directed against htyr or hgp100 was detected. Horses had an increased body temperature on the day after vaccination. CONCLUSIONS: This is the first clinical report on a systemic effect against equine melanoma following treatment with DNA vectors encoding eqIL12 and eqIL18 and formulated with a transfection reagent. Addition of DNA vectors encoding hgp100 respectively htyr did not potentiate this effect. PMID- 26063235 TI - Truck Drivers' Experiences and Perspectives Regarding Factors Influencing Traffic Accidents: A Qualitative Study. AB - Traffic accidents are a major public health problem, leading to death and disability. Although pertinent studies have been conducted, little data are available in Iran. This study explored the experiences of truck drivers and their perspectives regarding factors contributing to traffic accidents. Eighteen truck drivers, purposively sampled, participated in semi-structured interviews. Data were analyzed using qualitative content analysis. A main theme, lack of ability to control stress, emerged as a factor influencing the incidence of traffic accidents. This main theme was found to have three subthemes: poor organization of the job, lack of workplace facilities and proper equipment, and unsupportive environment. Although several factors were found to contribute to traffic accidents, their effects were not independent, and all were considered significant. Identifying factors that contribute to traffic accidents requires a systematic and holistic approach. Findings could be used by the transportation industry and community health centers to prevent traffic accidents. PMID- 26063234 TI - Curcumin as a double-edged sword for stem cells: dose, time and cell type specific responses to curcumin. AB - BACKGROUND: The beneficial effects of curcumin which includes its antioxidant, anti-inflammatory and cancer chemo-preventive properties have been identified. Little information is available regarding the optimal dose and treatment periods of curcumin on the proliferation rate of different sources of stem cells. METHODS: In this study, the effect of various concentrations of curcumin on the survival and proliferation of two types of outstanding stem cells which includes bone marrow stem cells (BMSCs) and adult rat neural stem/progenitor cells (NS/PCs) at different time points was investigated. BMSCs were isolated from bilateral femora and tibias of adult Wistar rats. NS/PCs were obtained from subventricular zone of adult Wistar rat brain. The curcumin (0.1, 0.5, 1, 5 and 10 MUM/L) was added into a culture medium for 48 or 72 h. Fluorescent density of 5-bromo-2'-deoxyuridine (Brdu)-positive cells was considered as proliferation index. In addition, cell viability was assessed by MTT assay. RESULTS: Treatment of BMSCs with curcumin after 48 h, increased cell survival and proliferation in a dose-dependent manner. However, it had no effect on NSCs proliferation except a toxic effect in the concentration of 10 MUM of curcumin. After a 72 h treatment period, BMSCs and NS/PCs survived and proliferated with low doses of curcumin. However, high doses of curcumin administered for 72 h showed toxic effects on both stem cells. CONCLUSIONS: These findings suggest that curcumin survival and proliferative effects depend on its concentration, treatment period and the type of stem cells. Appropriate application of these results may be helpful in the outcome of combination therapy of stem cells and curcumin. PMID- 26063236 TI - Monoclonal Antibody-Defined Specific C Epitope of Brucella O-Polysaccharide Revisited. AB - The C epitope of Brucella O-polysaccharide (O-PS) has so far lacked definitive structural identity. Revised structures for this antigen revealed a unique capping perosamine tetrasaccharide consisting of a sequence of 1,2:1,3:1,2 interresidue linkages. Here, using synthetic oligosaccharide glycoconjugates, the alpha-1,3 linkage of the O-PS is shown to be an integral structural requirement of this epitope. Although A-dominant strains possess only one or two copies of the capping tetrasaccharide, this creates a unique pentasaccharide antigenic determinant with the linkage sequence 1,2:1,3:1,2:1,2 that is always present in major pathogenic Brucella species. PMID- 26063233 TI - Analyzing dendritic spine pathology in Alzheimer's disease: problems and opportunities. AB - Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer's disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer's disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer's disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer's disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer's disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder. PMID- 26063237 TI - New Approaches for Immunization and Therapy against Human Metapneumovirus. AB - Human metapneumovirus (HMPV) is a paramyxovirus discovered in 2001 in the Netherlands. Studies have identified HMPV as an important causative agent of acute respiratory disease in infants, the elderly, and immunocompromised individuals. Clinical signs of infection range from mild upper respiratory illness to more serious lower respiratory illness, including bronchiolitis and pneumonia. There are currently no licensed therapeutics or vaccines against HMPV. However, several research groups have tested vaccine candidates and monoclonal antibodies in various animal models. Several of these approaches have shown promise in animal models. This minireview summarizes the current therapies used to treat HMPV infection as well as different approaches for immunization. PMID- 26063240 TI - Correction. AB - In the article by Dunoyer et al. (2002), Figures 2, 3 and 6 contain northern or western blot images comprising spliced lanes that were not indicated in the original Figures, and in agreement with the editors, we have decided to replace these figures with updated versions in which the spliced lanes are now clearly indicated by white vertical bars. While correcting these figures, it was found that one panel of Figure 2c was also incorrect and this has been replaced with the correct panel. The corresponding figure legends have also been modified to acknowledge these changes. PMID- 26063238 TI - Early Defensive Mechanisms against Human Papillomavirus Infection. AB - Cervical cancer is the fourth most common cancer in women and is almost exclusively caused by human papillomavirus (HPV) infection. HPV is also frequently associated with other cancers arising from mucosal epithelium, including anal and oropharyngeal cancers, which are becoming more common in both men and women. Viral persistence and progression through precancerous lesion stages are prerequisites for HPV-associated cancer and reflect the inability of cell-mediated immune mechanisms to clear infections and eliminate abnormal cells in some individuals. Cell-mediated immune responses are initiated by innate pathogen sensing and subsequent secretion of soluble immune mediators and amplified by the recruitment and activation of effector T lymphocytes. This review discusses early defensive mechanisms of innate responders to natural HPV infection, their influence on response polarization, and the underappreciated role of keratinocytes in this process. PMID- 26063241 TI - Centrifugal opening of dura for total extirpation of large convexity meningiomas: modifying the "classic" technique to prevent injury to the adjacent brain and veins. AB - BACKGROUND: Traditionally, the dura is opened along the margin of a convexity meningioma, jeopardizing the adjacent herniating brain and compressed veins in case of large meningioma. In this work, we describe a technique to open the dura centrifugally over convexity meningiomas. METHODS: Fifteen cases of large convexity meningiomas were operated on using the new technique. In our technique, the involved dura over large convexity meningiomas was opened in a centrifugal manner just short of the tumor-brain interface. The tumor was decompressed while preserving the arachnoid. The involved dura, along with the cuff of adjoining normal dura, was cut after tumor excision. RESULTS: Gross total excision could be achieved in all cases without any added deficits. There was arachnoid breach in three patients with insignificant venous injury in one. The preoperative symptoms improved in all. CONCLUSIONS: In this technique, the dura provides a natural barrier to protect the adjacent compressed brain and veins, thus avoiding handling the compressed adjacent neurovascular structures during surgery for large convexity meningioma without compromising the extent of resection. PMID- 26063239 TI - Substantial reprogramming of the Eutrema salsugineum (Thellungiella salsuginea) transcriptome in response to UV and silver nitrate challenge. AB - BACKGROUND: Cruciferous plants synthesize a large variety of tryptophan-derived phytoalexins in response to pathogen infection, UV irradiation, or high dosages of heavy metals. The major phytoalexins of Eutrema salsugineum (Thellungiella salsuginea), which has recently been established as an extremophile model plant, are probably derivatives of indole glucosinolates, in contrast to Arabidopsis, which synthesizes characteristic camalexin from the glucosinolate precursor indole-3-acetaldoxime. RESULTS: The transcriptional response of E. salsugineum to UV irradiation and AgNO3 was monitored by RNAseq and microarray analysis. Most transcripts (respectively 70% and 78%) were significantly differentially regulated and a large overlap between the two treatments was observed (54% of total). While core genes of the biosynthesis of aliphatic glucosinolates were repressed, tryptophan and indole glucosinolate biosynthetic genes, as well as defence-related WRKY transcription factors, were consistently upregulated. The putative Eutrema WRKY33 ortholog was functionally tested and shown to complement camalexin deficiency in Atwrky33 mutant. CONCLUSIONS: In E. salsugineum, UV irradiation or heavy metal application resulted in substantial transcriptional reprogramming. Consistently induced genes of indole glucosinolate biosynthesis and modification will serve as candidate genes for the biosynthesis of Eutrema specific phytoalexins. PMID- 26063242 TI - Overexpression of p53 predicts colorectal neoplasia risk in patients with inflammatory bowel disease and mucosa changes indefinite for dysplasia. AB - BACKGROUND AND AIMS: We previously demonstrated a significant colorectal neoplasia risk in inflammatory bowel disease (IBD) patients with mucosal changes indefinite for dysplasia (IND) and the potential diagnostic utility of p53 and cytokeratin 7 immunohistochemistry in IBD-associated neoplasia. The primary aim of this exploratory study was to determine the predictive value of the two markers for neoplasia risk in the IBD-IND population. METHODS: We identified 44 eligible cases with IBD and IND in colon biopsy from our pathology database. We semi-quantified the expression of p53 and cytokeratin 7 in the colon biopsies by immunohistochemistry and correlated their expression, demographic information, and clinical features with colorectal neoplasia outcome. RESULTS: The mean age of the cohort was 46.6 +/- 15.1 years, with 25 (56.8%) being male. The median follow up was 101 months (range: 6-247) after IND diagnosis. Among these 44 patients, 11 (25%) progressed to neoplasia (low-grade dysplasia = 6; high-grade dysplasia = 2; cancer 3) at a median follow-up of 66 months (range: 19-145). Univariate analysis demonstrated that age and p53 overexpression were associated with progression to neoplasia. CONCLUSIONS: Twenty-five percent of patients with IBD and IND developed colorectal dysplasia or cancer. Overexpression of p53 and age are associated with neoplastic progression. PMID- 26063244 TI - Implementing transition: Ready Steady Go. AB - There is good evidence that morbidity and mortality increase for young persons (YP) following the move from paediatric to adult services. Studies show that effective transition between paediatric and adult care improves long-term outcomes. Many of the issues faced by young people across subspecialties with a long-term condition are generic. This article sets out some of the obstacles that have delayed the implementation of effective transition. It reports on a successful generic transition programme 'Ready Steady Go' that has been implemented within a large National Health Service teaching hospital in the UK, with secondary and tertiary paediatric services, where it is now established as part of routine care. PMID- 26063243 TI - The effect of pre-existing mental health comorbidities on the stage at diagnosis and timeliness of care of solid tumor malignances in a Veterans Affairs (VA) medical center. AB - There are limited data on the impact of mental health comorbidities (MHC) on stage at diagnosis and timeliness of cancer care. Axis I MHC affect approximately 30% of Veterans receiving care within the Veterans Affairs (VA) system. The purpose of this study was to compare stage at diagnosis and timeliness of care of solid tumor malignancies among Veterans with and without MHC. We performed a retrospective analysis of 408 charts of Veterans with colorectal, urothelial, and head/neck cancer diagnosed and treated at VA Connecticut Health Care System (VACHS) between 2008 and 2011. We collected demographic data, stage at diagnosis, medical and mental health co-morbidities, treatments received, key time intervals, and number of appointments missed. The study was powered to assess for stage migration of 15-20% from Stage I/II to Stage III/IV. There was no significant change in stage distribution for patients with and without MHC in the entire study group (p = 0.9442) and in each individual tumor type. There were no significant differences in the time intervals from onset of symptoms to initiation of treatment between patients with and without MHC (p = 0.1135, 0.2042 and 0.2352, respectively). We conclude that at VACHS, stage at diagnosis for patients with colorectal, urothelial and head and neck cancers did not differ significantly between patients with and without MHC. Patients with MHC did not experience significant delays in care. Our study indicates that in a medical system in which mental health is integrated into routine care, patients with Axis I MHC do not experience delays in cancer care. PMID- 26063245 TI - High-level expression of a novel liver-targeting fusion interferon with preferred Escherichia coli codon preference and its anti-hepatitis B virus activity in vivo. AB - BACKGROUND: In our previous study, a novel liver-targeting fusion interferon (IFN CSP) combining IFN alpha2b with plasmodium region I peptide was successfully constructed. IFN-CSP has significant inhibition effects on HBV-DNA replication in HepG2.2.15 cells. The aim of the present investigation was focused on how to produce high levels of recombinant IFN-CSP and its in vivo anti-hepatitis B virus (HBV) activity. METHODS: A modified DNA fragment encoding IFN-CSP was synthesized according to Escherichia coli (E. coli) preferred codon usage and transformed into E. coli BL21 (DE3) for protein expression. The induction conditions were systematically examined by combining one-factor experiments with an orthogonal test (L(9)(3)(4)). The antigenicity of the purified protein was characterized by western blot analysis. The in vivo tissue distribution were assayed and compared with native IFN alpha2b. HBV-transgenic mice were used as in vivo model to evaluate the anti-HBV effect of the recombinant IFN-CSP. RESULTS: The results showed that the E. coli expression system was very efficient to produce target protein. CONCLUSION: Our current research demonstrates for the first time that IFN-CSP gene can be expressed at high levels in E. coli through codon and expression conditions optimization. The purified recombinant IFN-CSP showed liver targeting potentiality and anti-HBV activity in vivo. The present study further supported the application of IFN-CSP in liver-targeting anti-HBV medicines. PMID- 26063246 TI - Management of hypogonadism: is there a role for salivary testosterone. PMID- 26063248 TI - X-ray spectroscopy characterization of azobenzene-functionalized triazatriangulenium adlayers on Au(111) surfaces. AB - Triazatriangulenium (TATA) platform molecules allow the preparation of functionalized surfaces with well-defined lateral spacings of freestanding functional groups. Using scanning tunneling microscopy, synchrotron-based X-ray photoelectron spectroscopy, near edge X-ray absorption fine structure spectroscopy and complementary density functional theory calculations the chemical composition and orientational order of adlayers of functionalized azobenzene containing TATA platform molecules were characterized. According to these studies the molecules are chemically intact on the surface after self assembly from solution and exhibit a well-defined adsorption geometry where the azobenzene units are oriented almost perpendicular to the surface. PMID- 26063247 TI - Developmental pluripotency-associated 4: a novel predictor for prognosis and a potential therapeutic target for colon cancer. AB - BACKGROUNDS: Developmental pluripotency-associated 4 (Dppa4) gene plays an important role in self-renewal and pluripotency sustainability in embryonic stem cells. It is re-expressed in several malignant tumors and is identified as a new pluripotency-related oncogene. The present study investigates the expression and clinical significance of Dppa4 in colon cancer. METHODS: Real-time polymerase chain reaction and Western blotting were used to evaluate Dppa4 mRNA and protein expression in 39 pairs of fresh-frozzen colon cancer samples, which were compared with adjacent normal mucosa. The Dppa4 protein was evaluated by immunohistochemical techniques using colon tissue microarrays (TMA). The sample included 185 cancer specimens and corresponding normal colorectal mucosa. The effect of Dppa4 knockdown on colorectal cancer cell proliferation was investigated using Cell Counting Kit-8 (CCK8) assays and colony-formation assays. RESULTS: Both the mRNA and protein level expression of Dppa4 gene was found to be upregulated in colon cancer tissues. Furthermore, the upregulated expression of Dppa4 was significantly correlated with the results of American Joint Committee on Cancer (AJCC) stage (P = 0.01), invasion depth (P = 0.028), nodal involvement (P = 0.012), distant metastasis (P = 0.003), and differentiation (P = 0.002). Dppa4 was also shown to be an independent prognostic indicator of disease-free survival (HR 6.118, 95 % CI 3.004-12.462) and overall survival (HR 6.348, 95 % CI 2.875-14.014) for patients with colon cancer. Knockdown of Dppa4 expression inhibited the proliferation of colorectal cancer cell lines through G1/S transition regulation. CONCLUSION: The results indicate that Dppa4 might play an important role in colon cancer progression and function as a novel prognostic indicator and a potential therapeutic target. PMID- 26063249 TI - Risk assessment of hazardous substances revisited. PMID- 26063250 TI - Towards communication requirements in the operating room and clinic IT. AB - Today, connecting medical devices to the hospital network becomes a priority for many hospitals. User and operator requirements for communication must be considered in order to develop an adequate interoperable integration approach. This paper conducts a requirement study using questionnaires and working groups investigating 16 clinical communication requirements for connecting medical devices with each other and with clinical IT systems. Six German Hospitals order the communication requirements by their clinical relevance and categorize those into four main clusters. Communication requirements regarding accurate data transfer and processing for patients and devices have top priority, while communication requirements regarding remote manipulation of medical devices have low rank. Connecting medical devices to clinical IT systems improves clinical documentation and with it patient care processes. PMID- 26063251 TI - Semantic retrieval and navigation in clinical document collections. AB - Patients with chronic diseases undergo numerous in- and outpatient treatment periods, and therefore many documents accumulate in their electronic records. We report on an on-going project focussing on the semantic enrichment of medical texts, in order to support recall-oriented navigation across a patient's complete documentation. A document pool of 1,696 de-identified discharge summaries was used for prototyping. A natural language processing toolset for document annotation (based on the text-mining framework UIMA) and indexing (Solr) was used to support a browser-based platform for document import, search and navigation. The integrated search engine combines free text and concept-based querying, supported by dynamically generated facets (diagnoses, procedures, medications, lab values, and body parts). The prototype demonstrates the feasibility of semantic document enrichment within document collections of a single patient. Originally conceived as an add-on for the clinical workplace, this technology could also be adapted to support personalised health record platforms, as well as cross-patient search for cohort building and other secondary use scenarios. PMID- 26063252 TI - Standardized quality assurance forms for organ transplantations with multilingual support, open access and UMLS coding. AB - Quality assurance (QA) is a key factor to evaluate success of organ transplantations. In Germany QA documentation is progressively developed and enforced by law. Our objective is to share QA models from Germany in a standardized format within a form repository for world-wide reuse and exchange. Original QA forms were converted into standardized study forms according to the Operational Data Model (ODM) and shared for open access in an international forms repository. Form elements were translated into English and semantically enriched with Concept Unique Identifiers from the Unified Medical Language System (UMLS) based on medical expert decision. All forms are available on the web as multilingual ODM documents. UMLS concept coverage analysis indicates 92% coverage with few but critically important definition gaps. New content and infrastructure for harmonized documentation forms is provided in the domain of organ transplantations enabling world-wide reuse and exchange. PMID- 26063253 TI - Standardized mappings--a framework to combine different semantic mappers into a standardized web-API. AB - BACKGROUND: Automatic coding of medical terms is an important, but highly complicated and laborious task. OBJECTIVES: To compare and evaluate different strategies a framework with a standardized web-interface was created. Two UMLS mapping strategies are compared to demonstrate the interface. METHODS: The framework is a Java Spring application running on a Tomcat application server. It accepts different parameters and returns results in JSON format. To demonstrate the framework, a list of medical data items was mapped by two different methods: similarity search in a large table of terminology codes versus search in a manually curated repository. These mappings were reviewed by a specialist. RESULTS: The evaluation shows that the framework is flexible (due to standardized interfaces like HTTP and JSON), performant and reliable. Accuracy of automatically assigned codes is limited (up to 40%). CONCLUSION: Combining different semantic mappers into a standardized Web-API is feasible. This framework can be easily enhanced due to its modular design. PMID- 26063254 TI - Standardized data sharing in a paediatric oncology research network--a proof-of concept study. AB - Data that has been collected in the course of clinical trials are potentially valuable for additional scientific research questions in so called secondary use scenarios. This is of particular importance in rare disease areas like paediatric oncology. If data from several research projects need to be connected, so called Core Datasets can be used to define which information needs to be extracted from every involved source system. In this work, the utility of the Clinical Data Interchange Standards Consortium (CDISC) Operational Data Model (ODM) as a format for Core Datasets was evaluated and a web tool was developed which received Source ODM XML files and--via Extensible Stylesheet Language Transformation (XSLT)--generated standardized Core Dataset ODM XML files. Using this tool, data from different source systems were extracted and pooled for joined analysis in a proof-of-concept study, facilitating both, basic syntactic and semantic interoperability. PMID- 26063255 TI - Development of text mining based classification of written communication within a telemedical collaborative network. AB - Chronic diseases like Heart Failure are widespread in the ageing population. Affected patients can be treated with the aid of a disease management program, including a telemedical collaborative network. Evaluation of a currently used system has shown that the information of the textual communication is of pivotal importance for the collaboration in the network. Thus, the challenge is to make this unstructured information useable, potentially leading to a better understanding of the collaboration so as to optimize the processes. This paper presents the setup of an analysis pipeline for processing textual information automatically, and, how this pipeline can be utilized to train a model that is able to automatically classify the written messages into a set of meaningful task and status categories. PMID- 26063256 TI - Citizens' visions on active assisted living. AB - People aged 65 years and older are the fastest growing section of the population in many countries. Great hopes are projected on technology to support solutions for many of the challenges arising from this trend, thus making our lives more independent, more efficient and safer with a higher quality of life. But, as research and innovation ventures are often closely linked to the market, their focus may lead to biased planning in research and development as well as in policy-making with severe social and economic consequences. Thus the main research question concerned desirable settings of ageing in the future from different perspectives. The participatory foresight study CIVISTI-AAL cross linked knowledge of lay persons, experts and stakeholders to include a wide variety of perspectives and values into productive long-term planning of research and development. Results include citizens' visions for autonomous living in 2050, implicitly and explicitly containing basic needs towards technological, social and organizational development as well as recommendations for implementation. Conclusions suggest that personalized health and living environments play an important part in the lay persons' view of aging in the future, but only if technologies support social and organizational innovations and yet do not neglect the importance of social affiliation and inclusion. PMID- 26063257 TI - A personalized feedback system for supporting behavior change for patients after an acute myocardial infarction. AB - Cardiovascular diseases belong to the most common causes of death. Telehealth applications can help to improve therapy and support behavior change. It was the objective of the present work to construct and evaluate within a trial (25 patients) an automated feedback system for a telehealth application to support behavior change. We used a rule-based approach and constructed 26 rules in 9 categories. Rule design and implementation followed the principles of the Austrian Medical Product Law, resulting in an automated rule-based feedback system. Evaluations show high user satisfaction with 80% of all users perceiving the system as useful. PMID- 26063258 TI - Textual analysis of collaboration notes of the telemedical heart failure network HerzMobil Tirol. AB - Management of heart failure is usually multidisciplinary and collaboration between stakeholders in a dedicated HI network like the HerzMobil Tirol can be supported by a mHealth-based telemedicine approach. The aim is to gain insights through textual analysis of collaboration notes that might trigger further developments and improvements of the HI network. A reusable pipeline for textual analysis of unstructured textual notes was implemented using the open source analytics software KNIME. After preprocessing, a keyword analysis was performed resulting in a classification of all notes in predefined categories. RESULTS: Medical and organizational issues dominate the communication with health status and therapy aspects as well as clinical treatment, discharge letter and home visits. Beside aspects of data transmission and mobile phone, technological issues are minor topics during the collaboration. It is possible to gain new insights with respect to technology like additional control Apps for mobile phone settings and to the HI network like clinical experts and technical help desk involvement. PMID- 26063259 TI - Semi-automated evaluation of biomedical ontologies for the biobanking domain based on competency questions. AB - BACKGROUND: Biosample collections and biobank information systems have become a key enabler for medical research. Therefore it is important to identify potentially relevant ontologies to semantically enrich information related to the biobanking domain. OBJECTIVES: We present a three-stage semi-automated evaluation approach which allows identifying relevant ontologies for the biobanking domain based on competency questions. METHODS: After identifying candidate biobanking ontologies (Stage 1) and competency questions (Stage 2), a six-step lexical evaluation approach, which assesses the coverage of concepts, properties or instances defined by competency questions is suggested and described (Stage 3). RESULTS: We were able to perform a proof-of-concept evaluation of the OMIABIS ontology using our proposed three-stage approach together with a sample competency question. CONCLUSION: Our evaluation approach allows a swift evaluation of candidate ontology entities based on a search for higher hierarchy key terms that exist in comprehensive medical vocabularies in order to state the usability of specific ontologies for the biobanking domain. PMID- 26063260 TI - Development of the Austrian Nursing Minimum Data Set (NMDS-AT): the third Delphi Round, a quantitative online survey. AB - BACKGROUND: A Nursing Minimum Data Set (NMDS) aims at systematically describing nursing care in terms of patient problems, nursing activities, and patient outcomes. In an earlier Delphi study, 56 data elements were proposed to be included in an Austrian Nursing Minimum Data Set (NMDS-AT). OBJECTIVES: To identify the most important data elements of this list, and to identify appropriate coding systems. METHODS: Online Delphi-based survey with 88 experts. RESULTS: 43 data elements were rated as relevant for an NMDS-AT (strong agreement of more than half of the experts): nine data elements concerning the institution, patient demographics, and medical condition; 18 data elements concerning patient problems by using nursing diagnosis; seven data elements concerning nursing outcomes, and nine data elements concerning nursing interventions. As classification systems, national classification systems were proposed besides ICNP, NNN, and nursing-sensitive indicators. CONCLUSION: The resulting proposal for an NMDS-AT will now be tested with routine data. PMID- 26063261 TI - Evaluation of a clinical decision support rule-set for medication adjustments in mHealth-based heart failure management. AB - Decision-support based medication adjustment in heart failure management. Prospective analysis of clinical decision support in fifteen patients that collected vital parameters and medication intake up to one year within a clinical trial. Correlation of event episodes and medication adjustments with respect to applied rule-sets and medication classes. 713 events were grouped to 195 event episodes. Physicians performed 86 medication adjustments. 30 of them were triggered by event episodes. 35% of all performed medication adjustments occurred between event episodes. 20% of all episodes triggered a medication adjustment. 15% of all episodes triggered the expected medication adjustment. Correlation between episodes and medication adjustment was low. Further analysis needs to be done, to evaluate reasons for low correlation and how the rule-set should be adapted to increase reliability. PMID- 26063262 TI - Web-based multi-site feasibility questionnaire tool. AB - The design of clinical trial (CT) study protocols, currently supported by clinicians, is often a slow and cumbersome process. The Electronic Health Records for Clinical Research (EHR4CR) project supports the design of study protocols through a multi-site patient count cohort system. However, there is still a need to improve the process step in which the clinicians are involved. This research aims to enhance the EHR4CR platform with a tool to support the contact of CT sponsors with clinical investigators to obtain their input regarding feasibility data for the CT protocol design. From a list of requirements, a technical architecture that responds to the needs of feasibility assessments was modelled. With this architecture as a basis, a system that allows users to generate, send, fill out and visualise results of feasibility questionnaires across clinical sites was developed and integrated within the EHR4CR platform. The resulting system improves the current methods by providing direct contact to clinical investigators, facilitating the creation and answer of feasibility questionnaires for CTs. PMID- 26063263 TI - Towards sustainable data management in professional biobanking. AB - BACKGROUND: Professional biobanks become increasingly important for fostering personalized medicine. While setting up and operating a high-quality collection of biomaterial specimens, biobank managers must face several challenges concerning quality management. OBJECTIVES: Designing and implementing a data management, which ensures patient's privacy and simultaneously provides researchers with all relevant patient information, is particularly demanding. The requirements of all involved stakeholders must be considered without impairing the biobank's efficiency. METHODS: To link biomaterial samples to medical data documented in different contexts, an asymmetric encryption scheme with pseudonymization for existing clinical identifiers was implemented. RESULTS: The presented pseudonymization scheme allows establishing a comprehensive flow for pseudonymized data for biomaterial samples. CONCLUSION: Most of the content stored in clinical databases, except for personally identifying data, can be evaluated, combined with individually documented medical data and associated this to a biomaterial sample without revealing personally identifying data. PMID- 26063264 TI - Development of a virtual lab for practical eLearning in eHealth. AB - In recent years an ongoing development in educational offers for professionals working in the field of eHealth has been observed. This education is increasingly offered in the form of eLearning courses. Furthermore, it can be seen that simulations are a valuable part to support the knowledge transfer. Based on the knowledge profiles defined for eHealth courses a virtual lab should be developed. For this purpose, a subset of skills and a use case is determined. After searching and evaluating appropriate simulating and testing tools six tools were chosen to implement the use case practically. Within an UML use case diagram the interaction between the tools and the user is represented. Initially tests have shown good results of the tools' feasibility. After an extensive testing phase the tools should be integrated in the eHealth eLearning courses. PMID- 26063265 TI - Assistive technologies along supply chains in health care and in the social services sector. AB - Health care systems in Austria and Slovenia are currently facing challenges due to scarce resources and demographic change which can be seen especially along the supply chains. The main objective of this paper is to present an option to improve the use of assistive technologies. An extensive literature research for the theoretic part as well as a qualitative survey for the empiric part focusing on short-term care were carried out. Results show that there is a lack of information and training on assistive technologies. As a consequence, their full potential cannot be exploited. Therefore a guideline for nursing consultations was developed. To conclude, both the literature research and the qualitative survey show that assistive technologies have high potentials to improve the supply chains in the health care and social services sector, but there is a lot of information and training on them needed. PMID- 26063266 TI - AAL robotics: state of the field and challenges. AB - The field of "AAL Robotics", combining AAL and robotics as disciplines, has not yet been precisely defined and does not present accepted structures and concepts that would allow to communicate unequivocally its methods, projects, and approaches. The paper presents a method of defining and categorizing AAL robots and presents the resulting classes of robots with regard to the activities they assist. The classification is useful in that it is able to cover the breadth of the field, but a more fine-grained description of functionalities will be needed in further research to establish the potential of robots to assist independent living of older adults. PMID- 26063267 TI - AAL service development loom--from the idea to a marketable business model. AB - The Ambient Assisted Living (AAL) market is still in an early stage of development. Previous approaches of comprehensive AAL services are mostly supply side driven and focused on hardware and software. Usually this type of AAL solutions does not lead to a sustainable success on the market. Research and development increasingly focuses on demand and customer requirements in addition to the social and legal framework. The question is: How can a systematic performance measurement strategy along a service development process support the market-ready design of a concrete business model for AAL service? Within the EU funded research project DALIA (Assistant for Daily Life Activities at Home) an iterative service development process uses an adapted Osterwalder business model canvas. The application of a performance measurement index (PMI) to support the process has been developed and tested. Development of an iterative service development model using a supporting PMI. The PMI framework is developed throughout the engineering of a virtual assistant (AVATAR) as a modular interface to connect informal carers with necessary and useful services. Future research should seek to ensure that the PMI enables meaningful transparency regarding targeting (e.g. innovative AAL service), design (e.g. functional hybrid AAL service) and implementation (e.g. marketable AAL support services). To this end, a further reference to further testing practices is required. The aim must be to develop a weighted PMI in the context of further research, which supports both the service engineering and the subsequent service management process. PMID- 26063268 TI - Quality of assistive technologies in the home care for elderly. AB - Due to demographic changes, the number of elderly people who are in need of care is increasing. Assistive technologies make it possible for many elderly people to remain home despite their health conditions, which many prefer. Quality is an essential element of nursing care, and the elderly are becoming increasingly aware of this and are beginning to make high demands. The aims of this paper, which is based on a master's thesis, were to identify quality criteria in the field of assistive technologies and to present indicators for measuring quality. An extensive literature research was conducted for the theoretical part, and the empirical part employed a qualitative survey. The results show that the elderly's contentment and quality of life are the decisive factors for quality. A catalogue of quality indicators was developed by merging the results from literature with those from the expert consultation. To conclude, further research in this context, based on the results of this paper, is needed, in order to support the increasing use of assistive technologies. PMID- 26063269 TI - Telemonitoring and medical care supporting of patients with chronic respiratory diseases. AB - Experts refer to innovative telemonitoring technologies to deal with chronic respiratory diseases, especially the chronic obstructive pulmonary disease - COPD. In chronic respiratory diseases, sudden acute exacerbations may occur that can be life-threatening in some cases. Telemonitoring solutions help to detect the beginning of an impaired medical condition and can induce an adequate countermeasure in time. As soon as individually determined parameters are passed, appropriate warning signs can be transmitted. As part of a project, a new monitoring device for the detection of COPD-typical parameters has been utilized and optimized. Furthermore, an innovative 3D-Video-System was used to enable the implementation of physical exercises in the domestic environment. The systems assists the patient during the entire training unit and creates a feedback based on the quality of his or her exercises. PMID- 26063270 TI - Development of a generic monitoring application by the example of coronary artery disease. AB - The demographic change, the social structure and the development of new and complex therapies for diseases are responsible for a permanent rise of health expenditure. To guarantee affordable health care, AAL (Ambient Assisted Living) is one possibility. Our objective is to show that it is possible to create remote support for caregivers by physicians even with widely available and versatile hardware. A single board computer currently only equipped with 6 different sensors to measure blood pressure, glucose level, pulse, oxygen saturation, temperature and ECG is used as a showcase for patients with e.g. coronary artery disease. We created a user-friendly local application that collects and stores all data and transmits them to a remote server as soon as an Internet connection becomes available. Additionally, a web-application gives access to remote physicians and nurses to support caregivers and patients. Patients keep the overview of their vital signs, caregivers, nurses and physician can be alerted on demand or check the patient's data anytime to give advice. We conclude, that projects like this are showcases for the usage of technology that can foster AAL due to the focus on widely available and cheap, versatile equipment. PMID- 26063271 TI - Supporting prolonged COPD monitoring using an application for mobile devices. AB - COPD (chronic obstructive pulmonary disease) is the most frequent form of chronic respiratory disease. During the progress of this disease, phases of aggravation of pulmonary function (exacerbations) can occur, which reduce the quality of life. Clinical experience shows that single investigations are insufficient. Therefore a prolonged monitoring is required to recognize an exacerbation early. This home monitoring will involve a quick respiratory test and a related application for Android, iOS and Windows phones. This rapid test transmits the relevant pulmonary parameters, converted in an Extensible Markup Language file to the smartphone. The application will analyze the incoming data to evaluate the current health status of the patient. Additionally the data will be transferred to the virtual control point (server) and stored in a database. If critical values are detected, the server will send a notification to prior defined relatives and doctors. A connection to a Hospital Information System will be possible through an included Health Level 7 interface. This offers an improved site-independent patient care. The project is planned to be in development until 2016. PMID- 26063272 TI - EMPOWER--pathways for supporting the self-management of diabetes patients. AB - Diabetes is a serious world-wide medical challenge and there is a recognised need for improved diabetes care outcomes. This paper describes results of the EMPOWER project, to foster the self-management of diabetes patients by integration of existing and new services offered to patients after having been diagnosed with diabetes. The Self-Management Pathway described in this paper helps patients in the specification of personalized activities based on medical recommendations and personal goals, as well as self-monitoring of the results. The whole process is supported by innovative ICT services that motivate patients to change their lifestyle and adhere to defined medication and activity plans. We describe the approach and present the findings of the validation phase in Germany and Turkey. PMID- 26063273 TI - Architecture for an advanced biomedical collaboration domain for the European paediatric cancer research community (ABCD-4-E). AB - Today, progress in biomedical research often depends on large, interdisciplinary research projects and tailored information and communication technology (ICT) support. In the context of the European Network for Cancer Research in Children and Adolescents (ENCCA) project the exchange of data between data source (Source Domain) and data consumer (Consumer Domain) systems in a distributed computing environment needs to be facilitated. This work presents the requirements and the corresponding solution architecture of the Advanced Biomedical Collaboration Domain for Europe (ABCD-4-E). The proposed concept utilises public as well as private cloud systems, the Integrating the Healthcare Enterprise (IHE) framework and web-based applications to provide the core capabilities in accordance with privacy and security needs. The utility of crucial parts of the concept was evaluated by prototypic implementation. A discussion of the design indicates that the requirements of ENCCA are fully met. A whole system demonstration is currently being prepared to verify that ABCD-4-E has the potential to evolve into a domain-bridging collaboration platform in the future. PMID- 26063274 TI - Managing integrated oncology treatment in virtual networks. AB - Interdisciplinary and intersectoral coordinated healthcare management based on Clinical Practice Guidelines is essential to achieve high quality in oncological networks. The objective of our research project is to create a cookbook, which can be used by oncological networks as a template. The cookbook is based on guideline-compliant care processes. To develop these care processes, the three S3 guidelines breast, colon and prostate carcinoma have been formalized. The thus obtained platform-independent process fragments were transformed into an underlying metamodel, which is based on HL7 and can be used for modeling clinical pathways. Additional, qualitative guided interviews were chosen to capitalize on the experts' (e.g. chief residents, resident specialists) wide knowledge and experience in oncological health care management. One of these use cases (tumor board scheduling) is developed for a healthcare management platform which is linked to a national electronic case record. The projected result of our approach is a cookbook which shows, how the treatment can be controlled by interdisciplinary and intersectoral care processes in an oncological network. PMID- 26063275 TI - Development and evaluation of a web-based application for digital findings and documentation in physiotherapy education. AB - Findings in physiotherapy have standardized approaches in treatment, but there is also a significant margin of differences in how to implement these standards. Clinical decisions require experience and continuous learning processes to consolidate personal values and opinions and studies suggest that lecturers can influence students positively. Recently, the study course of Physiotherapy at the University of Applied Science in Graz has offered a paper based finding document. This document supported decisions through the adaption of the clinical reasoning process. The document was the starting point for our learning application called "EasyAssess", a Java based web-application for a digital findings documentation. A central point of our work was to ensure efficiency, effectiveness and usability of the web-application through usability tests utilized by both students and lecturers. Results show that our application fulfills the previously defined requirements and can be efficiently used in daily routine largely because of its simple user interface and its modest design. Due to the close cooperation with the study course Physiotherapy, the application has incorporated the various needs of the target audiences and confirmed the usefulness of our application. PMID- 26063276 TI - Implementation and validation of a conceptual benchmarking framework for patient blood management. AB - BACKGROUND: Public health authorities and healthcare professionals are obliged to ensure high quality health service. Because of the high variability of the utilisation of blood and blood components, benchmarking is indicated in transfusion medicine. OBJECTIVES: Implementation and validation of a benchmarking framework for Patient Blood Management (PBM) based on the report from the second Austrian Benchmark trial. METHODS: Core modules for automatic report generation have been implemented with KNIME (Konstanz Information Miner) and validated by comparing the output with the results of the second Austrian benchmark trial. RESULTS: Delta analysis shows a deviation <0.1% for 95% (max. 1.4%). CONCLUSION: The framework provides a reliable tool for PBM benchmarking. The next step is technical integration with hospital information systems. PMID- 26063277 TI - Evaluation of the Styrian personal eXray-record. AB - The European PALANTE project aims to improve patient empowerment. The Austrian contribution to the PALANTE objectives is the personal, electronic Xray-Record "eRontgenpass", which has been available to the public since October 2014. The eXray-Record is integrated into the patient portal of the Styrian Hospital Cooperation KAGes and can accesses data of recent radiological examinations which were carried out in KAGes hospitals. The main goal is to provide necessary information on the personal radiological exposure to allow for informed decisions of patients, when discussing diagnostic alternatives with health care providers. This paper describes the multi-step process of setting up an evaluation for these goals which can be adapted to other online portals for accessing medical data. Pre-tests showed that the integration of the evaluation process from the beginning of the project has led to a more concise evaluation method which is still able to produce relevant data for assessing the project objectives. This emphasizes the necessity of an integrated evaluation process from the beginning of portal development in contrast to an evaluation task at the end of the development. PMID- 26063278 TI - The emergency data set for the German Electronic Health Card--which benefits can be expected? AB - BACKGROUND: In order to improve access to pre-existing patient information in case of emergency, the German Electronic Health Card (EHC) is supposed to hold emergency data. As a basis, the German Medical Association developed an emergency data set, which provides the possibility to store information on prior diagnoses, medications, allergies and other emergency-relevant information. OBJECTIVES: One main objective of the study is to evaluate the usefulness of the emergency data in specific emergency situations. METHODS: Within a two-phase exploratory study, a total of 64 paper-based emergency data sets were completed by primary care physicians, and then were evaluated by clinicians, emergency physicians, and paramedics. RESULTS: Clinicians, emergency physicians as well as paramedics rated the emergency data set in more than 70% of the reviewed cases as very useful or useful. The greatest benefit was attributed to the information on diagnoses and medication. CONCLUSION: The implementation of an emergency data on the EHC has the potential to improve safety, quality and efficiency of emergency care. PMID- 26063279 TI - Prefetching of medical imaging data across XDS affinity domains. AB - Prior studies as well as medical imaging data are crucial for a radiologist to diagnose a patient. In this paper the radiological workflow is analyzed from a patient's perspective in order to gain knowledge on how possible existing prefetching strategies still can be applied in connection with a standardized distributed health information system conforming to architectures defined by IHE and ELGA. As a result an adaption to such architectures is proposed and further evaluated in a testing environment. Although the approach presented works in terms of prefetching relevant prior studies together with medical imaging data, additional research has to be carried out on how to apply intelligent search strategies in order to narrow retrieved results concerning their possible utilization for a specific diagnosis. PMID- 26063280 TI - An approach for software-driven and standard-based support of cross-enterprise tumor boards. AB - INTRODUCTION: For tumor boards, the networking of different medical disciplines' expertise continues to gain importance. However, interdisciplinary tumor boards spread across several institutions are rarely supported by information technology tools today. The aim of this paper is to point out an approach for a tumor board management system prototype. METHODS: For analyzing the requirements, an incremental process was used. The requirements were surveyed using Informal Conversational Interview and documented with Use Case Diagrams defined by the Unified Modeling Language (UML). Analyses of current EHR standards were conducted to evaluate technical requirements. RESULT: Functional and technical requirements of clinical conference applications were evaluated and documented. In several steps, workflows were derived and application mockups were created. CONCLUSION: Although there is a vast amount of common understanding concerning how clinical conferences should be conducted and how their workflows should be structured, these are hardly standardized, neither on a functional nor on a technical level. This results in drawbacks for participants and patients. Using modern EHR technologies based on profiles such as IHE Cross Enterprise document sharing (XDS), these deficits could be overcome. PMID- 26063281 TI - Towards lifetime electronic health record implementation. AB - Integrated care concepts can help to diminish demographic challenges. Hereof, the use of eHealth, esp. overarching electronic health records, is recognized as an efficient approach. The article aims at rigorously defining the concept of lifetime electronic health records (LEHRs) and the identification of core factors that need to be fulfilled in order to implement such. A literature review was conducted. Existing definitions were identified and relevant factors were categorized. The derived assessment categories are demonstrated by a case study on Germany. Seven dimensions to differentiate types of electronic health records were found. The analysis revealed, that culture, regulation, informational self determination, incentives, compliance, ICT infrastructure and standards are important preconditions to successfully implement LEHRs. The article paves the way for LEHR implementation and therewith for integrated care. Besides the expected benefits of LEHRs, there are a number of ethical, legal and social concerns, which need to be balanced. PMID- 26063282 TI - Governance guidelines for digital healthcare ecosystems. AB - Advanced Information and Communication Technologies (ICT) solutions are the key instrument to enable modern integrated care. They are not limited the traditional boundaries. Moreover, their aim is to provide medical care at the right point, in the right manner, at the right time without technological, institutional boundaries or integration issues, esp. for comorbidity treatment cases. Open digital ecosystems enabled by eHealth platforms can help to create a prospering eHealth environment. However, the creation of digital ecosystems in the health care domain is an ambitious task. The conditions how an open system can be achieved are often consented in complex projects, but they are not often scientific questioned. Conducting an action design research process, the paper contributes 13 guidelines for implementing eHealth platforms by reflection of the work in an EU-funded infrastructure project, which can be used as input for further research to provide generic guidelines for eHealth ecosystem projects. PMID- 26063290 TI - Associations Between Exposure to and Expression of Negative Opinions About Human Papillomavirus Vaccines on Social Media: An Observational Study. AB - BACKGROUND: Groups and individuals that seek to negatively influence public opinion about the safety and value of vaccination are active in online and social media and may influence decision making within some communities. OBJECTIVE: We sought to measure whether exposure to negative opinions about human papillomavirus (HPV) vaccines in Twitter communities is associated with the subsequent expression of negative opinions by explicitly measuring potential information exposure over the social structure of Twitter communities. METHODS: We hypothesized that prior exposure to opinions rejecting the safety or value of HPV vaccines would be associated with an increased risk of posting similar opinions and tested this hypothesis by analyzing temporal sequences of messages posted on Twitter (tweets). The study design was a retrospective analysis of tweets related to HPV vaccines and the social connections between users. Between October 2013 and April 2014, we collected 83,551 English-language tweets that included terms related to HPV vaccines and the 957,865 social connections among 30,621 users posting or reposting the tweets. Tweets were classified as expressing negative or neutral/positive opinions using a machine learning classifier previously trained on a manually labeled sample. RESULTS: During the 6 month period, 25.13% (20,994/83,551) of tweets were classified as negative; among the 30,621 users that tweeted about HPV vaccines, 9046 (29.54%) were exposed to a majority of negative tweets. The likelihood of a user posting a negative tweet after exposure to a majority of negative opinions was 37.78% (2780/7361) compared to 10.92% (1234/11,296) for users who were exposed to a majority of positive and neutral tweets corresponding to a relative risk of 3.46 (95% CI 3.25-3.67, P<.001). CONCLUSIONS: The heterogeneous community structure on Twitter appears to skew the information to which users are exposed in relation to HPV vaccines. We found that among users that tweeted about HPV vaccines, those who were more often exposed to negative opinions were more likely to subsequently post negative opinions. Although this research may be useful for identifying individuals and groups currently at risk of disproportionate exposure to misinformation about HPV vaccines, there is a clear need for studies capable of determining the factors that affect the formation and adoption of beliefs about public health interventions. PMID- 26063291 TI - Rates and determinants of early initiation of breastfeeding and exclusive breast feeding at 42 days postnatal in six low and middle-income countries: A prospective cohort study. AB - BACKGROUND: Early initiation of breastfeeding after birth and exclusive breastfeeding through six months of age confers many health benefits for infants; both are crucial high impact, low-cost interventions. However, determining accurate global rates of these crucial activities has been challenging. We use population-based data to describe: (1) rates of early initiation of breastfeeding (defined as within 1 hour of birth) and of exclusive breastfeeding at 42 days post-partum; and (2) factors associated with failure to initiate early breastfeeding and exclusive breastfeeding at 42 days post-partum. METHODS: Prospectively collected data from women and their live-born infants enrolled in the Global Network's Maternal and Newborn Health Registry between January 1, 2010 December 31, 2013 included women-infant dyads in 106 geographic areas (clusters) at 7 research sites in 6 countries (Kenya, Zambia, India [2 sites], Pakistan, Argentina and Guatemala). Rates and risk factors for failure to initiate early breastfeeding were investigated for the entire cohort and rates and risk factors for failure to maintain exclusive breastfeeding was assessed in a sub-sample studied at 42 days post-partum. RESULT: A total of 255,495 live-born women-infant dyads were included in the study. Rates and determinants for the exclusive breastfeeding sub-study at 42 days post-partum were assessed from among a sub sample of 105,563 subjects. Although there was heterogeneity by site, and early initiation of breastfeeding after delivery was high, the Pakistan site had the lowest rates of early initiation of breastfeeding. The Pakistan site also had the highest rate of lack of exclusive breastfeeding at 42 days post-partum. Across all regions, factors associated with failure to initiate early breastfeeding included nulliparity, caesarean section, low birth weight, resuscitation with bag and mask, and failure to place baby on the mother's chest after delivery. Factors associated with failure to achieve exclusive breastfeeding at 42 days varied across the sites. The only factor significant in all sites was multiple gestation. CONCLUSIONS: In this large, prospective, population-based, observational study, rates of both early initiation of breastfeeding and exclusive breastfeeding at 42 days post-partum were high, except in Pakistan. Factors associated with these key breastfeeding indicators should assist with more effective strategies to scale-up these crucial public health interventions. TRIAL REGISTRATION: Registration at the Clinicaltrials.gov website (ID# NCT01073475). PMID- 26063292 TI - Stillbirth rates in low-middle income countries 2010 - 2013: a population-based, multi-country study from the Global Network. AB - BACKGROUND: Stillbirth rates remain nearly ten times higher in low-middle income countries (LMIC) than high income countries. In LMIC, where nearly 98% of stillbirths worldwide occur, few population-based studies have documented characteristics or care for mothers with stillbirths. Non-macerated stillbirths, those occurring around delivery, are generally considered preventable with appropriate obstetric care. METHODS: We undertook a prospective, population-based observational study of all pregnant women in defined geographic areas across 7 sites in low-resource settings (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). Staff collected demographic and health care characteristics with outcomes obtained at delivery. RESULTS: From 2010 through 2013, 269,614 enrolled women had 272,089 births, including 7,865 stillbirths. The overall stillbirth rate was 28.9/1000 births, ranging from 13.6/1000 births in Argentina to 56.5/1000 births in Pakistan. Stillbirth rates were stable or declined in 6 of the 7 sites from 2010-2013, only increasing in Pakistan. Less educated, older and women with less access to antenatal care were at increased risk of stillbirth. Furthermore, women not delivered by a skilled attendant were more likely to have a stillbirth (RR 2.8, 95% CI 2.2, 3.5). Compared to live births, stillbirths were more likely to be preterm (RR 12.4, 95% CI 11.2, 13.6). Infants with major congenital anomalies were at increased risk of stillbirth (RR 9.1, 95% CI 7.3, 11.4), as were multiple gestations (RR 2.8, 95% CI 2.4, 3.2) and breech (RR 3.0, 95% CI 2.6, 3.5). Altogether, 67.4% of the stillbirths were non-macerated. 7.6% of women with stillbirths had cesarean sections, with obstructed labor the primary indication (36.9%). CONCLUSIONS: Stillbirth rates were high, but with reductions in most sites during the study period. Disadvantaged women, those with less antenatal care and those delivered without a skilled birth attendant were at increased risk of delivering a stillbirth. More than two-thirds of all stillbirths were non-macerated, suggesting potentially preventable stillbirth. Additionally, 8% of women with stillbirths were delivered by cesarean section. The relatively high rate of cesarean section among those with stillbirths suggested that this care was too late or not of quality to prevent the stillbirth; however, further research is needed to evaluate the quality of obstetric care, including cesarean section, on stillbirth in these low resource settings. STUDY REGISTRATION: Clinicaltrials.gov (ID# NCT01073475). PMID- 26063293 TI - Downregulation of Annexin A1 by short hairpin RNA inhibits the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells. AB - Annexin A1 (ANX A1) is essential in cell differentiation and proliferation. However, the role of ANX A1 in bone marrow-derived mesenchymal stem cell (BM-MSC) osteogenic differentiation and proliferation remains unclear. To investigate whether endogenous ANX A1 influences BM-MSC proliferation and osteogenic differentiation, a stable ANX A1-knockdown cell line was generated using short hairpin RNA (shRNA). The proliferation rate of BM-MSCs was analyzed by 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay. Additionally, BM-MSCs were differentiated into osteoblasts and subsequently used to isolate total proteins to analyze the expression of ANX A1. Cell differentiation was assayed using Alizarin red S staining. The results revealed that the knockdown of ANX A1 in BM-MSCs exerts no apparent effect on the proliferation rate under normal conditions, however, following exposure to an osteogenic medium, downregulation of ANX A1 protected cells from the effect of osteogenic medium-induced inhibition of cell proliferation. Silencing ANX A1 with shRNA significantly inhibited the phosphorylation of extracellular signal regulated kinase 1/2 and the expression of differentiation-associated genes (including runt-related transcription factor 2, osteopontin and osteocalcin) during osteogenesis and resulted in reduced differentiation of BM-MSCs. The results indicate the potential role of ANX A1 in the regulation of BM-MSC proliferation and osteogenic differentiation. PMID- 26063294 TI - Uncoupling between core genome and virulome in extraintestinal pathogenic Escherichia coli. AB - Extraintestinal pathogenic Escherichia coli (ExPEC) are among the most frequently isolated bacterial pathogens in hospitals. They are considered opportunistic pathogens and are found mostly in urinary and bloodstream infections. They are genetically diverse, and many studies have sought associations between genotypes or virulence genes and infection site, severity, or outcome, with varied, often contradictory, results. To understand these difficulties, we have analyzed the diversity patterns in the core genomes and virulomes of more than 500 ExPEC isolates from 5 different collections. The core genome was analyzed using a multilocus sequence type-based single-nucleotide polymorphism (SNP) pyrosequencing approach, while the virulence gene content (the virulome) was studied by polymerase chain reaction detection of 25 representative genes. SNP typing showed a similar population structure in the different collections: half of the isolates belong to a few sequence types (5 to 8), while the other half is composed of a large diversity of sequence types that are found once or twice. Sampling analysis by rarefaction plots of SNP profiles showed saturation curves indicative of a limited diversity. Contrary to this, the virulome shows an extremely high diversity, with almost as many gene profiles as isolates, and linear, nonsaturating, rarefaction plots, even within sequence types. These data show that genetic exchange rates are very heterogeneous along the chromosome, being much higher in the virulome fraction of the genome than in the core genome. PMID- 26063295 TI - Management of Simultaneous Symptomatic Bilateral Carotid Stenosis. PMID- 26063296 TI - Qualitative visual trichotomous assessment improves the value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in predicting the prognosis of diffuse large B-cell lymphoma. AB - INTRODUCTION: Fluorine-18 fluorodeoxyglucose (18 F-FDG) positron emission tomography/computed tomography (PET/CT) is a powerful tool for monitoring the response of diffuse large B-cell lymphoma (DLBCL) to therapy, but the criteria to interpret PET/CT results remain under debate. We investigated the value of post treatment PET/CT in predicting the prognosis of DLBCL patients when interpreted according to qualitative visual trichotomous assessment (QVTA) criteria compared with the Deauville criteria. METHODS: In this retrospective study, final PET/CT scans of DLBCL patients treated with rituximab-based regimens between October 2005 and November 2010 were interpreted using the Deauville and QVTA criteria. Survival curves were estimated using Kaplan-Meier analysis and compared using the log-rank test. RESULTS: A total of 253 patients were enrolled. The interpretation according to the Deauville criteria revealed that 181 patients had negative PET/CT scan results and 72 had positive results. The 3 year overall survival (OS) rate was significantly higher in patients with negative scan results than in those with positive results (91.6% vs. 57.5%, P<0.001). The 72 patients with positive scan results according to the Deauville criteria were divided into two groups by the interpretation according to the QVTA criteria: 29 had indeterminate results, and 43 had positive results. The 3 year OS rate was significantly higher in patients with indeterminate scan results than in those with positive results (91.2% vs. 33.5%, P<0.001) but was similar between patients with negative and indeterminate scan results (91.6% vs. 91.2%, P=0.921). CONCLUSIONS: Compared with the Deauville criteria, using the QVTA criteria for interpreting post-treatment PET/CT scans of DLBCL patients is likely to reduce the number of false positive results. The QVTA criteria are feasible for therapeutic outcome evaluation and can be used to guide risk-adapted therapy. PMID- 26063297 TI - Acanthocercodes n. g. (Monogenoidea: Diplectanidae) for species parasitising threadfins (Perciformes: Polynemidae), with description of Acanthocercodes bullardi n. sp. from the Atlantic threadfin Polydactylus octonemus (Girard) and reassignment of three species of Diplectanum Monticelli, 1903 from the Indo Pacific Ocean. AB - Acanthocercodes n. g. (Diplectanidae) is proposed for Acanthocercodes bullardi n. sp. and three previously described species of Diplectanum all parasites of the gill lamellae of threadfins (Perciformes: Polynemidae). The new genus is characterised by species having peduncular spines composed of an anteriorly directed point and a flattened base from which an anterior root arises. Members of the genus lack auxiliary spinous or sucker-like structures in the haptor. Acanthocercodes bullardi n. sp. is described from the Atlantic threadfin, Polydactylus octonemus (Girard), in the Gulf of Mexico off Louisiana, USA. Diplectanum polynemus Tripathi, 1957 is redescribed and transferred to Acanthocercodes as A. polynemus (Tripathi, 1957) n. comb. based on specimens collected from the fourfinger threadfin, Eleutheronema tetradactylum (Shaw), from the mouth of the River Adelaide, Northern Territory, Australia. Diplectanum spinosum (Maillard & Vala, 1980) (=Pseudodiplectanum spinosum Maillard & Vala, 1980) and Diplectanum megacirrus (Maillard & Vala, 1980) (=Pseudodiplectanum megacirrus Maillard & Vala, 1980) from the lesser African threadfin, Galeoides decadactylus (Bloch), are transferred to Acanthocercodes as A. spinosum (Maillard & Vala, 1980) n. comb. and A. megacirrus (Maillard & Vala, 1980) n. comb., respectively. PMID- 26063298 TI - New tentacled leech Ceratobdella quadricornuta n. g., n. sp. (Hirudinida: Piscicolidae) parasitic on the starry skate Raja georgiana Norman from the Scotia Sea, Antarctica. AB - A new fish leech Ceratobdella quadricornuta n. g., n. sp. (Hirudinida: Piscicolidae), a parasite of the Antarctic skate Raja georgiana Norman (Rajiformes: Rajidae) collected between the Falkland Islands and South Georgia Island in the Scotia Sea, is described and compared with related genera. Ceratobdella quadricornuta is characterised by an uncommon appearance of its anterior sucker bearing four well-developed tentacles and a unique combination of features of the reproductive and digestive systems: crop and intestine equally developed, posterior crop caeca separated; accessory glands, conductive tissue and external copulatory area lacking; common part of ejaculatory ducts (common atrium) voluminous and muscular, male copulatory bursa short, small ovisacs opening into female copulatory bursa (vagina). PMID- 26063299 TI - Molecular evidence for the existence of species complexes within Macvicaria Gibson & Bray, 1982 (Digenea: Opecoelidae) in the western Mediterranean, with descriptions of two new species. AB - Morphological and molecular characterisation of specimens of Macvicaria spp. (Digenea: Opecoelidae) from five species of Mediterranean sparids (Teleostei: Sparidae) sampled in the Bizerte Lagoon and the Bay of Bizerte (Tunisia) revealed the presence of two species complexes designated as "obovata" and "crassigula" groups. Detailed comparative morphological and phylogenetic analyses revealed that two of the specimen sets, one from each complex, represent species new to science. M. maamouriae n. sp. from Sparus aurata L. and Lithognathus mormyrus (L.) appeared genetically similar to M. obovata (Molin, 1859) but differs in having a much larger ventral sucker relative to body width, a cirrus-sac extending dorsally to the posterior margin of the ventral sucker or more posterior, vitelline fields comprising distinctly more abundant vitelline follicles, reaching the level of the pharynx both ventrally and dorsally and confluent dorsally in the forebody, and an ovary contiguous with the anterior testis. Macvicaria bartolii n. sp. from Diplodus annularis (L.) and Spondyliosoma cantharus (L.) belongs to the "crassigula" group and is characterised by having almost exclusively dorsal vitelline follicles forming two non-confluent fields in the forebody. Additional morphological data are provided for Macvicaria dubia (Stossich, 1905), a poorly known parasite of Oblada melanura (L.). Morphological descriptions are associated with ITS1-5.8S-ITS2 and 28S rDNA sequences for the three Mediterranean species of Macvicaria Gibson & Bray, 1982. The results of our study suggest that further exploration of the species diversity within this genus should be based on both morphological and molecular data. PMID- 26063300 TI - A species pair of Bivesicula Yamaguti, 1934 (Trematoda: Bivesiculidae) in unrelated Great Barrier Reef fishes: implications for the basis of speciation in coral reef fish trematodes. AB - Combined morphological and molecular analysis shows that a species of Bivesicula Yamaguti, 1934 from four species of Apogonidae Gunther [Nectamia fusca (Quoy & Gaimard), Ostorhinchus angustatus (Smith & Radcliffe), O. cookii (Macleay) and Taeniamia fucata (Cantor)] on the Great Barrier Reef is morphologically similar to, but clearly distinct from B. unexpecta Cribb, Bray & Barker, 1994 which infects a sympatric pomacentrid, Acanthochromis polyacanthus (Bleeker). Bivesicula neglecta n. sp. is proposed for the form from apogonids. Novel ITS2 rDNA sequences generated for the two species differ at just one consistent base position, implying that the two species are closely related. The combination of their close relationship, high but distinct specificity and co-occurrence suggests that speciation was driven by a recent host switching event enabled by similar dietary ecomorphology. PMID- 26063301 TI - Two new feather mites of the genus Calcealges Gaud, 1952 (Acari: Trouessartiidae) from antbirds (Passeriformes: Thamnophilidae) in Brazil. AB - Two new feather mites of the genus Calcealges Gaud, 1952 (Acari: Trouessartiidae) are described from antbirds (Passeriformes: Thamnophilidae) in Brazil: Calcealges formicivorae n. sp. from Formicivora grisea (Boddaert) and C. stymphalornithi n. sp. from Stymphalornis acutirostris Bornschein, Reinert & Teixeira. Calcealges formicivorae n. sp. differs from C. trinidadensis Orwig by having, in both sexes, the inner margin of the humeral shields deeply incised and, in females, setae d2 reaching only to the level of trochanters III. Calcealges stymphalornithi n. sp. differs from C. novimundus Orwig, 1968 by having in both sexes the posterolateral areas of the prodorsal shield with longitudinal and oblique striae; males also have the central area of hysteronotal shield without ornamentation and relatively shorter setae d2. PMID- 26063302 TI - Two new species of Haliotrema Johnston & Tiegs, 1922 (Monogenea: Dactylogyridae) from Acanthurus nigrofuscus (Forsskal) and A. triostegus (Linnaeus) (Teleostei: Acanthuridae) in the South China Sea. AB - Haliotrema nanhaiense n. sp. and Haliotrema triostegum n. sp. are described respectively from the gills of Acanthurus nigrofuscus (Forsskal) and Acanthurus triostegus (Linnaeus) in the South China Sea. Haliotrema nanhaiense n. sp. differs from other existing congeneric species by its male copulatory complex, comprising a C-shaped copulatory tube, a saucer-shaped base and a sickle-shaped accessory piece. Haliotrema triostegum n. sp. can be differentiated from all other members of Haliotrema by having a unique copulatory complex, a cup-shaped base, inverted L-shaped copulatory tube with a small sclerotised piece arising from its distal portion, and a large accessory piece from the proximal portion of copulatory tube. PMID- 26063303 TI - Description of Diorchis thracica n. sp. (Cestoda, Hymenolepididae) from the ruddy shelduck Tadorna ferruginea (Pallas) (Anseriformes, Anatidae) in Bulgaria. AB - Diorchis thracica n. sp. (Cestoda, Cyclophyllidea, Hymenolepididae) is described from the ruddy shelduck Tadorna ferruginea (Pallas) (Aves, Anseriformes, Anatidae), collected in the vicinities of Radnevo, Stara Zagora Region, Bulgaria. The new species is differentiated from other members of Diorchis Clerc, 1903 by possessing rostellar hooks with length of 36 um, a thick-walled cirrus-sac with strong longitudinal muscular fibres in its middle part and a copulatory vagina with two sphincters. Main morphological criteria for distinguishing species of the genus Diorchis are discussed. PMID- 26063304 TI - Sarcocystis clethrionomyelaphis Matuschka, 1986 (Apicomplexa: Sarcocystidae) infecting the large oriental vole Eothenomys miletus (Thomas) (Cricetidae: Microtinae) and its phylogenetic relationships with other species of Sarcocystis Lankester, 1882. AB - Sarcocystis clethrionomyelaphis Matuschka, 1986 was first identified in skeletal muscles of 47 (75.8%) of 62 large oriental voles Eothenomys miletus (Thomas) captured between March 2012 and May 2014 in Anning Prefecture of Yunnan Province (China). Sarcocyst walls were thick and possessed villous protrusions measuring 3.5-5.5 MUm in length. Beauty rat snakes Elaphe taeniura (Cope) fed sarcocysts of the species shed sporulated oocysts measuring 13-18*9-13 (16*12) MUm with a prepatent period of 16 to 17 days. Phylogenetic analysis based on 18S rRNA gene sequences revealed a close relationship between S. clethrionomyelaphis and other colubrid-transmitted species of Sarcocystis Lankester, 1882. This is the first report identifying S. clethrionomyelaphis from its natural intermediate host. PMID- 26063305 TI - Structure-activity relationship of hybrids of Cinchona alkaloids and bile acids with in vitro antiplasmodial and antitrypanosomal activities. AB - In this work, a series of hybrid compounds were tested as antiparasitic substances. These hybrids were prepared from bile acids and a series of antiparasitic Cinchona alkaloids by the formation of a covalent C-C bond via a decarboxylative Barton-Zard reaction between the two entities. The bile acids showed only weak antiparasitic properties, but all the hybrids exhibited high in vitro activities (IC50: 0.48-5.39 MUM) against Trypanosoma brucei. These hybrids were more active than their respective parent alkaloids (up to a 135 fold increase in activity), and displayed good selectivity indices. Aditionally, all these compounds inhibited the in vitro growth of a chloroquine-sensitive strain of Plasmodium falciparum (3D7: IC50: 36.1 nM to 8.72 MUM), and the most active hybrids had IC50s comparable to that of artemisinin (IC50: 36 nM). Some structure activity relationships among the group of 48 hybrids are discussed. The increase in antiparasitic activity may be explained by an improvement in bioavailability, since the more lipophilic derivatives showed the lowest IC50s. PMID- 26063306 TI - Isolation and characterization of a novel marine Bacteroidetes as Algitalea ulvae gen. nov., sp. nov., isolated from the green alga Ulva pertusa. AB - A polyphasic taxonomic investigation was performed on a bacterial strain, 38-Ka 2(T), which was isolated from the green alga Ulva pertusa Kjellman (Chlorophyta) in Hokkaido, Japan. The bacterial cells were observed to be golden-yellow coloured, Gram-negative, strictly aerobic, non-spore-forming, non-motile and rod shaped. Phylogenetic analyses based on the 16S rRNA gene sequence indicated that the new strain is a member of the family Flavobacteriaceae within the phylum Bacteroidetes and that it shows high sequence similarity (94.8 %) to Aquimarina addita JC2680(T). The genomic DNA G+C content of strain 38-Ka-2(T) was determined to be 36 mol%; MK-6 was identified as the major menaquinone; and the presence of iso-C15:0, C18:0 and iso-C17:0 3-OH as the major (>10 %) cellular fatty acids. The polar lipid profile was found to consist of phosphatidylethanolamine, an unidentified glycolipid and two unidentified lipids. From the distinct phylogenetic position and combination of genotypic and phenotypic characteristics, strain 38-Ka-2(T) is considered to represent a novel genus for which the name Algitalea ulvae gen. nov., sp. nov. is proposed. The type strain of A. ulvae is 38-Ka-2(T) (=KCTC 32994(T) = NBRC 110017(T)). PMID- 26063308 TI - Dietary food groups intake and cooking methods associations with pancreatic cancer: a case-control study. AB - BACKGROUND: The role of dietary habits in the etiology of pancreatic cancer (PC) has not yet been well elucidated. AIM: The aim of the present study was to examine the association of the frequency of different food groups' intake and their cooking methods with PC risk based on a well-designed case-control study. METHODS: A case-control study including 307 PC patients and 322 controls referred to four tertiary endosonography centers was conducted from January 2011 to January 2014 to compare the frequency intake of different food items and their cooking methods between cases and controls. RESULTS: After adjustment for gender, age, body mass index, years of education, diabetes and alcohol history, smoking status, and opium use, a significant direct relationship was observed between PC risk and intake frequency (time/week) of bread (OR = 1.50; 95 % CI 1.05-2.13; p value 0.024), rice (OR = 2.10; 95 % CI 1.15-3.82; p for trend 0.034), and red meat (OR = 2.25; 95 % CI 1.22-4.14; p for trend 0.033) (time/day), when comparing the highest category of intake frequency with the lowest, while increasing frequency of fish consumption was associated with a lower risk of PC (OR = 0.93; 95 % CI0.59-1.47; p for trend 0.009). Increasing consumption of barbecuing red meat and deep fried vegetables was associated with 67 % and 70 % increased risk of PC (p-value 0.025 and 0.006, respectively). CONCLUSION: Our results indicate that increased frequency of intake of bread, rice, and red meat (especially barbecued) and deep fried vegetables can aggregate PC risk, while increased frequency of fish consumption can protect against PC. However, more studies are still needed. PMID- 26063311 TI - Selective reporting in trials of high risk cardiovascular devices: cross sectional comparison between premarket approval summaries and published reports. AB - OBJECTIVE: To investigate characteristics of clinical trials and results on safety and effectiveness reported in US Food and Drug Administration (FDA) documents for recently approved high risk cardiovascular devices compared with the characteristics and results reported in peer reviewed publications. DESIGN: A search of the publicly available FDA database was performed for all cardiovascular devices that received premarket approval from 1 January 2000 to 31 December 2010. For each study listed in the premarket approval documents, a Medline search was conducted to obtain the corresponding publication. MAIN OUTCOME MEASURES: Clinical trial characteristics, primary endpoints, and safety and efficacy results in the FDA documents and corresponding publications. RESULTS: 106 cardiovascular devices received premarket approval from 1 January 2000 to 31 December 2010. FDA premarket approval documents for these devices contained 177 studies, of which 86 (49%) had been published by 1 January 2013. These 86 publications corresponded to 60 distinct devices. The mean time from FDA approval to publication in a peer reviewed journal was 6.5 months (range -4.8-7.5 years). In 22 (26%) of the 86 compared studies the number of participants enrolled in the study differed in the FDA summary and the corresponding publications. Of 152 primary endpoints identified in the FDA documents, in the corresponding publications three (2%) were labeled as secondary, 43 (28%) were unlabeled, and 15 (10%) were not found. Among the primary results, 69 (45%) were identical, 35 (23%) were similar, 17 (11%) were substantially different, and 31 (20%) could not be compared. CONCLUSIONS: Many clinical trials for high risk cardiovascular devices approved by the FDA remain unpublished. Even when trials are published, the study population, primary endpoints, and results can differ substantially from data submitted to the FDA. PMID- 26063312 TI - Interprofessional sepsis education module: a pilot study. AB - Although there is an increasing emphasis on interprofessional collaboration for safer health care systems, there remains a paucity of opportunities for postgraduate trainees to engage in formal interprofessional education (IPE). Current opportunities for interprofessional learning, such as simulation sessions, typically do not provide true IPE because they often utilize actors or confederates as support staff, making residents the only stakeholders in the education experience. Here, we describe a flexible educational module designed to provide genuine IPE for physicians, nurses, and respiratory therapists. We outline how simulation, feedback, and group discussions can be used to teach interprofessional team communication, collaboration, and crew resource management skills-while, at the same time, also teaching a highly relevant medical topic (sepsis management) and thus resulting in learner engagement and motivation. PMID- 26063313 TI - Anti-tumor peptide AP25 decreases cyclin D1 expression and inhibits MGC-803 proliferation via phospho-extracellular signal-regulated kinase-, Src-, c-Jun N terminal kinase- and phosphoinositide 3-kinase-associated pathways. AB - The anti-tumor peptide AP25 is a prototype integrin antagonist, which exhibits anti-angiogenic and anti-tumor activity. The molecular mechanisms by which AP25 inhibits the growth of the MGC-803 gastric carcinoma cell line were investigated in the present study. K-ras specific RNA interference by lentiviral infection was successfully induced in MGC-803 cells [MGC-803 short hairpin (sh)RNA group] and the expression levels of K-ras, phosphorylated extracellular signal-regulated kinase (p-ERK) and cyclin D1 were observed to be markedly decreased. By contrast, AP25 caused cell cycle arrest of intact MGC-803 cells and decreased p-ERK and cyclin D1 expression levels. Of note, 0.4-3.2 uM AP25 no longer inhibited MGC-803 shRNA growth, indicating that AP25, at such concentrations, exerts its effect mainly through the Ras/Raf/mitogen-activated protein kinase kinase/ERK pathway, whereas at 25 uM, AP25 was able to inhibit MGC-803 shRNA growth. Chemical inhibitors of Src, c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K) were used to confirm that 25 uM AP25 inhibited growth of cells in the MGC 803 shRNA group and activated intracellular signaling pathways with Src, JNK and PI3K as key enzymes. In conclusion, the present study revealed the signal transduction pathways activated by AP25 at low (0.4-3.2 uM) or high (25 uM) concentrations. It also confirmed that integrins, when interacting with the freely moving ligand AP25 instead of immobilized extracellular matrix glycoproteins, are able to initiate cell signaling via similar pathways as in the latter case but with a reversed effect, to inhibit cell growth. PMID- 26063314 TI - Transdifferentiation of erythroblasts to megakaryocytes using FLI1 and ERG transcription factors. AB - Platelet transfusion has been widely used to prevent and treat life-threatening thrombocytopenia; however, preparation of a unit of concentrated platelet for transfusion requires at least 4-6 units of whole blood. At present, a platelet unit from a single donor can be prepared using apheresis, but lack of donors is still a major problem. Several approaches to produce platelets from other sources, such as haematopoietic stem cells and pluripotent stem cells, have been attempted but the system is extremely complicated, time-consuming and expensive. We now report a novel and simpler technology to obtain platelets using transdifferentiation of human bone marrow erythroblasts to megakaryocytes with overexpression of the FLI1 and ERG genes. The obtained transdifferentiated erythroblasts (both from CD71+ and GPA+ erythroblast subpopulations) exhibit typical features of megakaryocytes including morphology, expression of specific genes (cMPL and TUBB1) and a marker protein (CD41). They also have the ability to generate megakaryocytic CFU in culture and produce functional platelets, which aggregate with normal human platelets to form a normal-looking clot. Overexpression of FLI1 and ERG genes is sufficient to transdifferentiate erythroblasts to megakaryocytes that can produce functional platelets. PMID- 26063315 TI - microRNA regulation of the embryonic hypoxic response in Caenorhabditis elegans. AB - Layered strategies to combat hypoxia provide flexibility in dynamic oxygen environments. Here we show that multiple miRNAs are required for hypoxic survival responses during C. elegans embryogenesis. Certain miRNAs promote while others antagonize the hypoxic survival response. We found that expression of the mir-35 family is regulated by hypoxia in a HIF-1-independent manner and loss of mir-35 41 weakens hypoxic survival mechanisms in embryos. In addition, correct regulation of the RNA binding protein, SUP-26, a mir-35 family target, is needed for survival in chronic hypoxia. The identification of the full mRNA target repertoire of these miRNAs will reveal the miRNA-regulated network of hypoxic survival mechanisms in C. elegans. PMID- 26063317 TI - Clinical trials of integrative medicine for rheumatoid arthritis: Issues and recommendations. AB - Controlled clinical trials of integrative therapies available to patients with rheumatoid arthritis (RA) improved dramatically in the past 20 years, largely because of the growing need and the methodologies improvement. Tripterygium wilfordii Hook. F., a typical example of popular use herb, has been extensively studied in trials. However, clear and convincing evidence of integrative therapy, effectiveness and safety, remains insufficient to make decision. Many research efforts are hampered by standing problems with 'syndrome' recruitment failure. In addition, the outcome multiplicity induces the findings inefficiency to generalize to RA patients at large. Development of validated syndrome outcomes and methodologies has also been critical. Current efforts to enhance the understanding of integrative treatment options for patients with RA include the development of drug-specific rather than disease-specific strategies, studies in predictive biomarkers, and development of peer-review trial protocol for regular clinical trials. PMID- 26063316 TI - Professional mathematicians differ from controls in their spatial-numerical associations. AB - While mathematically impaired individuals have been shown to have deficits in all kinds of basic numerical representations, among them spatial-numerical associations, little is known about individuals with exceptionally high math expertise. They might have a more abstract magnitude representation or more flexible spatial associations, so that no automatic left/small and right/large spatial-numerical association is elicited. To pursue this question, we examined the Spatial Numerical Association of Response Codes (SNARC) effect in professional mathematicians which was compared to two control groups: Professionals who use advanced math in their work but are not mathematicians (mostly engineers), and matched controls. Contrarily to both control groups, Mathematicians did not reveal a SNARC effect. The group differences could not be accounted for by differences in mean response speed, response variance or intelligence or a general tendency not to show spatial-numerical associations. We propose that professional mathematicians possess more abstract and/or spatially very flexible numerical representations and therefore do not exhibit or do have a largely reduced default left-to-right spatial-numerical orientation as indexed by the SNARC effect, but we also discuss other possible accounts. We argue that this comparison with professional mathematicians also tells us about the nature of spatial-numerical associations in persons with much less mathematical expertise or knowledge. PMID- 26063318 TI - Effect of Shenzhu Guanxin Recipe () on patients with angina pectoris after percutaneous coronary intervention: A prospective, randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy and safety of a combination therapy using Chinese medicine (CM) Shenzhu Guanxin Recipe (, SGR) and standard Western medicine treatment (SWMT) in patients with angina pectoris after percutaneous coronary intervention (PCI). METHODS: Double-blind randomized controlled trial was used in this experimental procedure. One hundred and eighty-seven patients with coronary heart disease receiving SWMT after PCI were randomly assigned to the treatment (SGR) and control (placebo) groups. Outcome measures including angina pectoris score (APS), CM symptom score, and Seattle Angina Questionnaire (SAQ) score were evaluated in 1, 2, 3 and 12 months, and the death rate, restenosis and other emergency treatments were observed. The mixed-effects models were employed for the data analysis. RESULTS: In the treatment group, a larger within-treatment effect size (d=1.74) was found, with a 76.7% reduction in APS from pretreatment to 12-month follow-up assessment compared with the control group (d=0.83, 53.8% symptom reduction); betweentreatment (BT) effect size was d=0.66. CM symptom scores included an 18.3% reduction in the treatment group (d=0.46), and a 16.1% decrease in the control group (d=0.31); d=0.62 for BT effect size. In regard to scores of SAQ, the BT effect size of cognition level of disease was larger in the treatment group (d=0.63), followed by the level of body limitation of activity (d=0.62), condition of angina pectoris attacks (d=0.55), satisfaction level of treatments (d=0.31), and steady state of angina pectoris (d=0.30). Two cardiovascular related deaths and one incidental death were recorded in the control and treatment groups, respectively. No significant difference in any cardiovascular event (including death toll, frequency of cardiovascular hospitalization or emergency room visits) was found between the two groups. CONCLUSION: The combination therapy of SGR and SWMT is effective and safe in patients with angina pectoris after PCI when compared with SWMT alone. PMID- 26063319 TI - Efficacy of electroacupuncture in the treatment of functional constipation: A randomized controlled pilot trial. AB - OBJECTIVE: To evaluate the efficacy and safety of electroacupuncture at Tianshu (ST25) for patients with functional constipation (FC). METHODS: Ninety-six patients with FC were randomized to receive deep needling on bilateral ST25 (group A, 48 cases) or shallow needling on bilateral ST25 (group B, 48 cases) with electroacupuncture once daily for 4 weeks. The proportion of patients with four or more complete spontaneous bowel movements (CSBMs) per week, and scores of constipation symptoms and satisfaction with treatment were compared between two groups. Safety was also assessed. RESULTS: The proportion of patients with four or more CSBMs per week was 52.1% in group A, significantly higher than 25.0% in group B during the 4-week treatment (P<0.05). The constipation symptom score of patients were significantly improved in group A as compared with group B at week 2-4 (P<0.05). Patients in group A were more satisfied with their treatment compared with those in group B at week 1-4 (P<0.05). Five patients in group A felt significant pain and discomfort. No other adverse reaction was observed in both groups. CONCLUSION: Using electroacupuncture at ST25 to treat patients with FC is effectively, and deep needling had more stable effect than shallow needling. PMID- 26063321 TI - A microscopic Gibbs field model for the macroscopic yielding behaviour of a viscoplastic fluid. AB - We present a Gibbs random field model for the microscopic interactions in a viscoplastic fluid. The model has only two parameters which are sufficient to describe the internal energy of the material in the absence of external stress and a third parameter for a constant externally applied stress. The energy function is derived from the Gibbs potential in terms of the external stress and internal energy. The resulting Gibbs distribution, over a configuration space of microscopic interactions, can mimic experimentally observed macroscopic behavioural phenomena that depend on the externally applied stress. A simulation algorithm that can be used to approximate samples from the Gibbs distribution is given and it is used to gain several insights about the model. Corresponding to weak interactions between the microscopic solid units, our model reveals a smooth solid-fluid transition which is fully reversible upon increasing/decreasing external stresses. If the interaction between neighbouring microscopic constituents exceeds a critical threshold the solid-fluid transition becomes abrupt and a hysteresis of the deformation states is observed even at the asymptotic limit of steady forcing. Quite remarkably, in spite of the limited number of parameters involved, the predictions of our model are in a good qualitative agreement with macro rheological experimental results on the solid fluid transition in various yield stress materials subjected to an external stress. PMID- 26063320 TI - Comparative assessment of transmission-blocking vaccine candidates against Plasmodium falciparum. AB - Malaria transmission-blocking vaccines (TBVs) target the development of Plasmodium parasites within the mosquito, with the aim of preventing malaria transmission from one infected individual to another. Different vaccine platforms, mainly protein-in-adjuvant formulations delivering the leading candidate antigens, have been developed independently and have reported varied transmission-blocking activities (TBA). Here, recombinant chimpanzee adenovirus 63, ChAd63, and modified vaccinia virus Ankara, MVA, expressing AgAPN1, Pfs230-C, Pfs25, and Pfs48/45 were generated. Antibody responses primed individually against all antigens by ChAd63 immunization in BALB/c mice were boosted by the administration of MVA expressing the same antigen. These antibodies exhibited a hierarchy of inhibitory activity against the NF54 laboratory strain of P. falciparum in Anopheles stephensi mosquitoes using the standard membrane feeding assay (SMFA), with anti-Pfs230-C and anti-Pfs25 antibodies giving complete blockade. The observed rank order of inhibition was replicated against P. falciparum African field isolates in A. gambiae in direct membrane feeding assays (DMFA). TBA achieved was IgG concentration dependent. This study provides the first head-to-head comparative analysis of leading antigens using two different parasite sources in two different vector species, and can be used to guide selection of TBVs for future clinical development using the viral-vectored delivery platform. PMID- 26063322 TI - Dimensions of Maternal Parenting and Infants' Autonomic Functioning Interactively Predict Early Internalizing Behavior Problems. AB - Developmental pathways to childhood internalizing behavior problems are complex, with both environmental and child-level factors contributing to their emergence. The authors use data from a prospective longitudinal study (n = 206) to examine the associations between dimensions of caregiving experiences in the first year of life and anxious/depressed and withdrawn behaviors in early childhood. Additionally, the authors examine the extent to which these associations were moderated by infants' autonomic functioning in the first year of life indexed using measures of respiratory sinus arrhythmia (RSA) and heart period (HP). Findings suggest that higher levels of maternal sensitivity in infancy are associated with fewer anxious/depressed and withdrawn behaviors at age 3 years. Negative intrusiveness was found to be positively associated with children's anxious/depressed behaviors but not withdrawn behaviors. Further, moderation analyses suggested that the link between negative intrusive parenting during infancy and subsequent anxious/depressed behaviors is exacerbated for infants with average or low baseline HP and that positive engaging parenting during infancy was negatively related to withdrawn behaviors for infants demonstrating average to high levels baseline HP. Interestingly, RSA was not found to moderate the associations between parenting in infancy and later internalizing behavior problems suggesting that, during infancy, overall autonomic functioning may have greater implications for the development of internalizing behaviors than do parasympathetic influences alone. Implications of these findings and future directions for research are discussed. PMID- 26063323 TI - Norcantharidin combined with EGFR-TKIs overcomes HGF-induced resistance to EGFR TKIs in EGFR mutant lung cancer cells via inhibition of Met/PI3k/Akt pathway. AB - PURPOSE: Hepatocyte growth factor (HGF) induces resistance to reversible and irreversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR TKI) in EGFR mutant lung cancer cells by activating Met and the downstream phosphoinositide 3-kinase (PI3K)/Akt pathway. Moreover, continuous exposure to HGF accelerates the emergence of EGFR-TKI-resistant clones. We examined whether norcantharidin (NCTD), a demethylated analog of cantharidin, could reverse HGF induced resistance to EGFR-TKIs in mutant lung cancer cells PC-9 and HCC827. METHODS: MTT assay was used to evaluate cell proliferation of NCTD on PC-9 and HCC827 cells in vitro. Western blotting assays were used to determine the expression of EGFR, p-EGFR (Thr 669), MET, p-MET, AKT, p-AKT (Ser473), PI3kp85, or p-PI3k p85. HGF concentrations were measured by ELISA. HGF-producing cells and PC-9/HGF were established by recombinant adenovirus vectors Ad-GFP-HGF. Xenograft model in SCID mice was used to test the regressive effect of tumor growth on PC-9 cells in vivo. RESULTS: NCTD could reverse resistance to EGFR-TKIs induced by exogenous and endogenous HGF in EGFR mutant lung cancer cells via inhibiting the Met/PI3K/Akt pathway. These results suggested that NCTD may be a promising candidate for developing preventive agents against EGFR-TKIs acquired resistance in NSCLC. In the in vivo model, NCTD plus gefitinib resulted in marked regression of tumor growth associated with inhibition of Akt phosphorylation in cancer cells. CONCLUSIONS: NCTD may be a promising candidate for developing preventive agents against EGFR-TKIs acquired resistance in NSCLC. PMID- 26063324 TI - Epidemiology of coinfection with soil transmitted helminths and Plasmodium falciparum among school children in Bumula District in western Kenya. AB - BACKGROUND: Many school children living in Africa are infected with plasmodia and helminth species and are consequently at risk of coinfection. However, the epidemiology of such coinfection and the implications of coinfection for children's health remain poorly understood. This study describes the epidemiology of Ascaris lumbricoides-Plasmodium and hookworm-Plasmodium coinfection among school children living in western Kenya and investigates the associated risk factors. METHODS: As part of a randomized trial, a baseline cross-sectional survey was conducted among school children aged 5-18 years in 23 schools in Bumula District. Single stool samples were collected to screen for helminth infections using the Kato-Katz technique and malaria parasitaemia was determined from a finger prick blood sample. Demographic and anthropometric data were also collected. RESULTS: Overall, 46.4% of the children were infected with Plasmodium falciparum while 27.6% of the children were infected with at least one soil transmitted helminth (STH) species, with hookworm being the most common (16.8%) followed by A. lumbricoides (15.3%). Overall 14.3% of the children had STH Plasmodium coinfection, with hookworm-Plasmodium (9.0%) coinfection being the most common. Geographical variation in the prevalence of coinfection occurred between schools. In multivariable logistic regression analysis, hookworm was positively associated with P. falciparum infection. In stratified analysis, hookworm infection was associated with increased odds of P. falciparum infection among both boys (P < 0.001) and girls (P = 0.01), whereas there was no association between A. lumbricoides and P. falciparum. CONCLUSION: These findings demonstrate STH infections are still prevalent, despite the ongoing national deworming programme in Kenya, and that malaria parasitaemia is widespread, such that coinfection occurs among a proportion of children. A subsequent trial will allow us to investigate the implications of coinfection for the risk of clinical malaria. PMID- 26063325 TI - Comparison of two different folic acid doses with methotrexate--a randomized controlled trial (FOLVARI Study). AB - INTRODUCTION: There is reasonable evidence that folic acid 5-10 mg per week leads to reduction in methotrexate (MTX) toxicity in rheumatoid arthritis (RA). However, this is based on studies conducted with lower MTX dosage than used currently. It is unclear whether higher doses of folic acid may be better in reducing toxicity. METHODS: This was a double-blind randomized controlled trial of 24 weeks duration. To be eligible, patients should have rheumatoid arthritis (1987 American College of Rheumatology criteria), be 18-75 years of age, not be on MTX and have active disease as defined by 'Modified Disease Activity Score using three variables' (DAS28(3)) > 3.2. MTX was started at 10 mg/week and escalated to 25 mg/week by 12 weeks. Folic acid was given at a dose of 10 mg (FA10) or 30 mg per week (FA30). Co-primary endpoints were incidence of toxicity (undesirable symptoms and laboratory abnormalities) and change in disease activity by 24 weeks. Intention-to-treat and per-protocol analyses were performed. RESULTS: Among 100 patients enrolled, 51 and 49 were randomized to FA10 and FA30 respectively. By 24 weeks, there were 6 patient withdrawals in either group and mean(+/-SD) dose of MTX was 22.8 +/- 4.4 and 21.4 +/- 4.6 mg per week (p = 0.1). Frequency of patients with undesirable symptoms was non significantly lower by 7.4% (95% confidence interval -27.4 to 12.7%) in FA10 compared to FA30. There was also no difference in frequency of transaminitis (>Upper limit of normal (ULN)) (42.6, 45.7%, p = 0.7) or transminitis as per primary endpoint (>2xULN) (10.6, 8.7%, p = 1.0) or cytopenias (4.3, 4.3%, p = 0.9). There was no difference in the primary end-point of occurrence of any adverse effect (symptom or laboratory) in FA10 and FA30 (46.8, 54.3%, p = 0.5). At 24 weeks, DAS28(3) declined in both groups by a similar extent (-1.1 +/- 1.0, 1.3 +/- 1.0, p = 0.2) and 'European League Against Rheumatism' good or moderate response occurred in 56.9 and 67.4% (p = 0.3). CONCLUSIONS: Even with the high doses of MTX used in current practice, there was no additional benefit (or harm) of a higher dose of folic acid (30 mg/week) over a usual dose (10 mg/week). TRIAL REGISTRATION: Clinicaltrials.gov NCT01583959 Registered 15 March 2012. PMID- 26063326 TI - Prediction of complex human diseases from pathway-focused candidate markers by joint estimation of marker effects: case of chronic fatigue syndrome. AB - BACKGROUND: The current practice of using only a few strongly associated genetic markers in regression models results in generally low power in prediction or accounting for heritability of complex human traits. PURPOSE: We illustrate here a Bayesian joint estimation of single nucleotide polymorphism (SNP) effects principle to improve prediction of phenotype status from pathway-focused sets of SNPs. Chronic fatigue syndrome (CFS), a complex disease of unknown etiology with no laboratory methods for diagnosis, was chosen to demonstrate the power of this Bayesian method. For CFS, such a genetic predictive model in combination with clinical evidence might lead to an earlier diagnosis than one based solely on clinical findings. METHODS: One of our goals is to model disease status using Bayesian statistics which perform variable selection and parameter estimation simultaneously and which can induce the sparseness and smoothness of the SNP effects. Smoothness of the SNP effects is obtained by explicit modeling of the covariance structure of the SNP effects. RESULTS: The Bayesian model achieved perfect goodness of fit when tested within the sampled data. Tenfold cross validation resulted in 80% accuracy, one of the best so far for CFS in comparison to previous prediction models. Model reduction aspects were investigated in a computationally feasible manner. Additionally, genetic variation estimates provided by the model identified specific genetic markers for their biological role in the disease pathophysiology. CONCLUSIONS: This proof-of-principle study provides a powerful approach combining Bayesian methods, SNPs representing multiple pathways and rigorous case ascertainment for accurate genetic risk prediction modeling of complex diseases like CFS and other chronic diseases. PMID- 26063327 TI - Comparison of content of FDA letters not approving applications for new drugs and associated public announcements from sponsors: cross sectional study. AB - OBJECTIVES: To describe the content of non-public complete response letters issued by the US Food and Drug Administration (FDA) when they do not approve marketing applications from sponsors (drug companies) and to compare them with the content any subsequent press releases issued by those sponsors DESIGN: Cross sectional study. DATA SOURCES: All applications for which FDA's Center for Drug Evaluation and Research initially issued complete response letters (n=61) from 11 August 2008 to 27 June 2013. Complete response letters and press releases were divided into discrete statements related to seven domains and 64 subdomains and assessed to determine whether they matched. RESULTS: 48% (29) of complete response letters cited deficiencies in both the safety and efficacy domains, and only 13% cited neither safety nor efficacy deficiencies. No press release was issued for 18% (11) of complete response letters, and 21% (13) of press releases did not match any statements from the letters. Press release statements matched 93 of the 687 statements (14%), including 16% (30/191) of efficacy and 15% (22/150) of safety statements. Of 32 complete response letters that called for a new clinical trial for safety or efficacy, 59% (19) had matching press release statements. Seven complete response letters reported higher mortality rates in treated participants; only one associated press release mentioned this fact. CONCLUSIONS: FDA generally issued complete response letters to sponsors for multiple substantive reasons, most commonly related to safety and/or efficacy deficiencies. In many cases, press releases were not issued in response to those letters and, when they were, omitted most of the statements in the complete response letters. Press releases are incomplete substitutes for the detailed information contained in complete response letters. PMID- 26063329 TI - Synthesis of nanocrystals of Zr-based metal-organic frameworks with csq-net: significant enhancement in the degradation of a nerve agent simulant. AB - The synthesis of nano-sized particles of NU-1000 (length from 75 nm to 1200 nm) and PCN-222/MOF-545 (length from 350 nm to 900 nm) is reported. The catalytic hydrolysis of methyl paraoxon was investigated as a function of NU-1000 crystallite size and a significant enhancement in the rate was observed for the nano-sized crystals compared to microcrystals. PMID- 26063328 TI - Comprehensive analysis of Panax ginseng root transcriptomes. AB - BACKGROUND: Korean ginseng (Panax ginseng C.A. Meyer) is a highly effective medicinal plant containing ginsenosides with various pharmacological activities, whose roots are produced commercially for crude drugs. RESULTS: Here, we used the Illumina platform to generate over 232 million RNA sequencing reads from four root samples, including whole roots from one-year-old plants and three types of root tissue from six-year-old plants (i.e., main root bodies, rhizomes, and lateral roots). Through de novo assembly and reference-assisted selection, we obtained a non-redundant unigene set consisting of 55,949 transcripts with an average length of 1,250 bp. Among transcripts in the unigene set, 94 % were functionally annotated via similarity searches against protein databases. Approximately 28.6 % of the transcripts represent novel gene sequences that have not previously been reported for P. ginseng. Digital expression profiling revealed 364 genes showing differential expression patterns among the four root samples. Additionally, 32 were uniquely expressed in one-year-old roots, while seven were uniquely expressed in six-year-old root tissues. We identified 38 transcripts encoding enzymes involved in ginsenoside biosynthesis pathways and 189 encoding UDP-glycosyltransferases. CONCLUSION: Our analysis provides new insights into the role of the root transcriptome in development and secondary metabolite biosynthesis in P. ginseng. PMID- 26063330 TI - Fully-automated, high-throughput micro-computed tomography analysis of body composition enables therapeutic efficacy monitoring in preclinical models. AB - BACKGROUND: The ability to non-invasively measure body composition in mouse models of obesity and obesity-related disorders is essential for elucidating mechanisms of metabolic regulation and monitoring the effects of novel treatments. These studies aimed to develop a fully automated, high-throughput micro-computed tomography (micro-CT)-based image analysis technique for longitudinal quantitation of adipose, non-adipose and lean tissue as well as bone and demonstrate utility for assessing the effects of two distinct treatments. METHODS: An initial validation study was performed in diet-induced obesity (DIO) and control mice on a vivaCT 75 micro-CT system. Subsequently, four groups of DIO mice were imaged pre- and post-treatment with an experimental agonistic antibody specific for anti-fibroblast growth factor receptor 1 (anti-FGFR1, R1MAb1), control immunoglobulin G antibody, a known anorectic antiobesity drug (rimonabant, SR141716), or solvent control. The body composition analysis technique was then ported to a faster micro-CT system (CT120) to markedly increase throughput as well as to evaluate the use of micro-CT image intensity for hepatic lipid content in DIO and control mice. Ex vivo chemical analysis and colorimetric analysis of the liver triglycerides were performed as the standard metrics for correlation with body composition and hepatic lipid status, respectively. RESULTS: Micro-CT-based body composition measures correlate with ex vivo chemical analysis metrics and enable distinction between DIO and control mice. R1MAb1 and rimonabant have differing effects on body composition as assessed by micro-CT. High-throughput body composition imaging is possible using a modified CT120 system. Micro-CT also provides a non-invasive assessment of hepatic lipid content. CONCLUSIONS: This work describes, validates and demonstrates utility of a fully automated image analysis technique to quantify in vivo micro-CT-derived measures of adipose, non-adipose and lean tissue, as well as bone. These body composition metrics highly correlate with standard ex vivo chemical analysis and enable longitudinal evaluation of body composition and therapeutic efficacy monitoring. PMID- 26063332 TI - Pain management experience at a central Taiwan medical center. AB - Pain management is typically more developed in western countries compared to Asia. From the accreditation standard of the Joint Commission International (JCI), there is a broad scope for pain management. In 2008, our medical center established the pain management policy, and the goal is to be a pain-free medical facility. The Framework of Pain Management Policy including: 1. the rights of patients and family members 2. Employee education 3. Assessment of pain (screening, evaluating, monitoring) 4. Patient care of pain. After implementation of pain management program, the compliance of pain assessment, the analysis of pain score before and after pain management and the analysis of Pain Management Index (PMI), all showed improvement in pain management program. The consumption of opioids usage steadily increased from 2010 to 2014. The success of our pain management program implementation could be attributed to the clear pain management policy, the firm support of higher leadership, the cooperation of IT department, and the quality control. PMID- 26063331 TI - The intake of high-fat diets induces the acquisition of brown adipocyte gene expression features in white adipose tissue. AB - BACKGROUND/OBJECTIVE: White-to-brown adipose tissue remodeling (browning) in response to different stimuli constitutes an active research area for obesity treatment. The emergence in traditional white adipose tissue (WAT) depots of multilocular adipocytes that express uncoupling protein 1 (UCP1) and resemble brown adipocytes, the so called 'brite' adipocytes, could contribute to increased energy expenditure. In rodents, obesogenic stimuli such as the intake of hyperlipidic diets can increase brown adipose tissue (BAT) thermogenic capacity and contribute to maintaining body weight. The aim of this study was to investigate the potential of two different hyperlipidic diets, a commercial high fat (HF) diet and a highly palatable cafeteria (CAF) diet, to induce WAT browning. METHODS: We analyzed gene expression of a wide number of brown/brite adipocyte markers in different WAT depots, in BAT and in peripheral blood mononuclear cells (PBMCs) increasingly being used in nutrition studies as a potential source of biomarkers of physiological effects. We also performed morphological analysis of adipose tissue. RESULTS: Both HF diets studied were able to increase the expression of the markers studied in WAT in a depot-specific manner, as well as in BAT; some of these changes were also reflected in PBMCs. This increased browning capacity was translated into the appearance of UCP1- and CIDE-A (cell death-inducing DFFA-like effector A)-positive brite adipocytes in retroperitoneal WAT. Administration of the CAF diet, associated with higher adiposity, produced the strongest impact on the parameters studied while its withdrawal restored basal conditions. CONCLUSIONS: Acquisition of brown adipocyte features in WAT could evidence an adaptation to try to counteract increased adiposity due to the intake of HF diets. Additionally, PBMCs could constitute an interesting easily obtainable material to assess the effect of nutritional interventions on browning capacity. PMID- 26063333 TI - Undertreatment of caner pain. AB - Pain is a burdensome symptom that can commonly exist chronically along the cancer trajectory. Uncontrolled pain will impact on cancer patients' quality of life, even further negatively affect cancer survivors' employment. Based on systemic reviews of studies for past 10 years, the paper reported that although there is enormous advancement on the knowledge of cancer pain and pain management, studies still documented undertreatment of cancer pain globally. Additionally, pain distress a significant portion of cancer survivors. The pain in cancer survivors distinct from the pain related with cancer, instead emphasize on pain related with cancer treatment, such as neuropathic pain, muscular syndrome. Evidence based pain management with common pain problems in cancer survivors is lacking. Further studies are needed to understand the pain in cancer survivors and to develop effective strategies in helping cancer survivors to manage their pain. PMID- 26063335 TI - Gap Between Evidence and Patient Access: Policy Implications for Bariatric and Metabolic Surgery in the Treatment of Obesity and its Complications. AB - Despite consistently supportive evidence of clinical effectiveness and economic advantages compared with currently available non-surgical obesity treatments, patient access to bariatric and metabolic surgery (BMS) is impeded. To address this gap and better understand the relationship between value and access, the objectives of this study were twofold: (i) identify the multidimensional barriers to adoption of BMS created by clinical guidelines, public policies, and health technology assessments; and, most importantly, (ii) develop recommendations for stakeholders to improve patient access to BMS. Updated public policies focused on treatment and clinical guidelines that reflect the demonstrated advantages of BMS, patient education on safety and effectiveness, updated reimbursement policies, and additional data on long-term BMS effectiveness are needed to improve patient access. PMID- 26063334 TI - Scale-up bioprocess development for production of the antibiotic valinomycin in Escherichia coli based on consistent fed-batch cultivations. AB - BACKGROUND: Heterologous production of natural products in Escherichia coli has emerged as an attractive strategy to obtain molecules of interest. Although technically feasible most of them are still constrained to laboratory scale production. Therefore, it is necessary to develop reasonable scale-up strategies for bioprocesses aiming at the overproduction of targeted natural products under industrial scale conditions. To this end, we used the production of the antibiotic valinomycin in E. coli as a model system for scalable bioprocess development based on consistent fed-batch cultivations. RESULTS: In this work, the glucose limited fed-batch strategy based on pure mineral salt medium was used throughout all scales for valinomycin production. The optimal glucose feed rate was initially detected by the use of a biocatalytically controlled glucose release (EnBase(r) technology) in parallel cultivations in 24-well plates with continuous monitoring of pH and dissolved oxygen. These results were confirmed in shake flasks, where the accumulation of valinomycin was highest when the specific growth rate decreased below 0.1 h(-1). This correlation was also observed for high cell density fed-batch cultivations in a lab-scale bioreactor. The bioreactor fermentation produced valinomycin with titers of more than 2 mg L(-1) based on the feeding of a concentrated glucose solution. Valinomycin production was not affected by oscillating conditions (i.e. glucose and oxygen) in a scale down two-compartment reactor, which could mimic similar situations in industrial bioreactors, suggesting that the process is very robust and a scaling of the process to a larger industrial scale appears a realistic scenario. CONCLUSIONS: Valinomycin production was scaled up from mL volumes to 10 L with consistent use of the fed-batch technology. This work presents a robust and reliable approach for scalable bioprocess development and represents an example for the consistent development of a process for a heterologously expressed natural product towards the industrial scale. PMID- 26063336 TI - The effect of patent foramen ovale closure in patients with platypnea-orthodeoxia syndrome. AB - BACKGROUND: Platypnea-orthodeoxia syndrome is a rare condition characterized by hypoxemia in the upright position that is improved in the supine position. Although several etiologies of platypnea-orthodeoxia exist, it is frequently associated with right-to-left shunting of blood at the cardiac or pulmonary level, usually via a patent foramen ovale (PFO). The aim of this study was to evaluate the incidence of platypnea-orthodeoxia syndrome in a select patient population with right-to-left shunting and to describe the outcomes after PFO closure. METHODS: Patients with platypnea-orthodeoxia were prospectively identified from a population of patients who had a PFO and were referred to UCLA from 2001 to 2012. Those patients who elected to have their PFO closed were assessed for the severity of their symptoms and interval SaO2 changes. The changes in SaO2 before and after closure were compared in the supine and upright position. Patients were classified depending on the result of PFO closure as having "improved SaO2 " or "no change." RESULTS: Of 683 patients with PFO associated conditions, 17 (2.5%) had platypnea-orthodeoxia and elected to close their PFO. The results in 11 of 17 patients (64.8%) were classified as having "improved SaO2 "; they experienced improvement or complete resolution of their dyspnea and hypoxemia (improved SaO2 from baseline 5.2 +/- 4.7% when recumbent and 15.6 +/- 3.0% when upright, P = 0.03 and P < 0.0001, respectively). Patients with no change after PFO closure predominantly had a pulmonary etiology for their hypoxia, with elevated mean pulmonary pressures measured before closure (51.4 +/ 16.8 mmHg, P = 0.06). CONCLUSION: PFO closure may resolve symptomatic postural dyspnea and hypoxemia and is an effective method for treating platypnea orthodeoxia, but is not effective when the primary etiology of the hypoxemia is due to a pulmonary cause. PMID- 26063337 TI - Sero-prevalence and risk factors associated with African swine fever on pig farms in southwest Nigeria. AB - BACKGROUND: African swine fever (ASF) is one of the major setbacks to development of the pig industry in Nigeria. It is enzootic in southwest Nigeria. We determined the sero-prevalence and factors associated with ASF among-herd seropositivity in 144 pig farms in six States from southwest Nigeria during the dry and rainy seasons using indirect Enzyme Linked Immunosorbent Assay (ELISA) for ASF IgG antibodies. An interviewer-administered questionnaire was used to collect information on demography, environmental and management factors. We performed descriptive statistics, and univariate and multivariable analyses to determine the among-herd sero-prevalence of ASF and its associated factors. RESULTS: The overall herd sero-prevalence of ASF was 28% (95% Confidence interval (95% CI) 21-36); it was significantly higher (P <0.05) in the dry season (54%; 95% CI 37-70) than the rainy season (18%; 95% CI 11-27). In the univariate analysis, having a quarantine/ isolation unit within 100 m radius of a regular pig pen (OR = 3.3; 95% CI 1.3-8.9), external source of replacement stock (OR = 3.2; 95% CI 1.3-8.3) and dry season (OR = 5.3; 95% CI 2.2-12.7) were risk factors for ASF among-herd seropositivity. In the multivariable logistic regression, there was interaction between season and herd size. Our final model included season, source of replacement stock, herd size and interaction between herd size and season. Herds with an external source of replacement always had higher ASF sero-prevalence compared with herds with an internal source. The herd size effect varied between seasons. CONCLUSIONS: The ASF herd level sero-prevalence in southwest Nigeria was higher in pig herds with an external source of replacement stock and in the dry season. The effect of season of the year the samples were taken on ASF seropositivity was modified by herd size. We encourage strict compliance with biosecurity measures, especially using an internal source of replacement stock and measures that minimize movement on pig farms in southwest Nigeria, in order to enhance ASF free farms. PMID- 26063338 TI - Association between the emotional status of family caregivers and length of stay in a palliative care unit: A retrospective study. AB - OBJECTIVE: Several factors associated with referral time to hospice and/or palliative care services have been identified, but there is no literature on the association between these services and the emotional status of the family caregivers (FCs). This article is intended to address that issue. METHOD: A semistructured interview was employed to collect data for a retrospective cohort study. The primary FCs of terminally ill cancer patients were interviewed at the time of the patient's referral to the palliative care unit. Interview data were combined with patients' medical record data for our analysis. The emotional status of the FCs was categorized into one of three groups according to their responses to the anticipated death of their family member: acceptance, anxious/depressed, and denial/angry. A Cox proportional hazard model was used to examine and identify the factors related to the length of stay (LOS) in the palliative care unit. RESULTS: A total of 198 patient-FC pairs were identified. The median LOS was 18 days. A multivariate analysis with adjustment for potential variables revealed significant differences in LOS according to cancer type and time since cancer diagnosis. The denial/angry FC category was independently associated with a shorter LOS (vs. acceptance, adjusted hazard ratio (aHR) 2.11; 95% confidence interval (CI), 1.11-4.03). SIGNIFICANCE OF RESULTS: We found that terminally ill cancer patients who were referred late had FCs who were in denial or were angry about the anticipated death of their loved one. The emotional status of FCs should be considered when patients with terminal cancer are referred to palliative care. PMID- 26063339 TI - Photoredox catalysis under shear using thin film vortex microfluidics. AB - A microfluidic vortex fluidic device (VFD) operating in either confined or continuous mode is effective in high yielding photoredox reactions involving Rose Bengal, with short reaction times. This processing can be translated to multi components reactions, also with significantly reduced processing times relative to batch processing and channel microfluidic processing, with comparable or improved yields. PMID- 26063340 TI - P2Y2 nucleotide receptor-mediated extracellular signal-regulated kinases and protein kinase C activation induces the invasion of highly metastatic breast cancer cells. AB - Tumor metastasis is considered the main cause of mortality in cancer patients, thus it is important to investigate the differences between high- and low metastatic cancer cells. Our previous study showed that the highly metastatic breast cancer cell line MDA-MB-231 released higher levels of ATP and exhibited higher P2Y2R activity compared with the low-metastatic breast cancer cell line MCF-7. In addition, P2Y2R activation by ATP released from MDA-MB-231 cells induced hypoxia-inducible factor-1alpha expression, lysyl oxidase secretion and collagen crosslinking, generating a receptive microenvironment for pre-metastatic niche formation. Thus, in the present study, we investigated which P2Y2R-related signaling pathways are involved in the invasion of breast cancer cells. The highly metastatic breast cancer cells MDA-MB-231 and SK-BR-3 showed higher invasion than MCF-7 and T47D cells at a basal level, which was abolished through P2Y2R knockdown or in the presence of apyrase, an enzyme that hydrolyzes extracellular nucleotides. MDA-MB-231 cells also showed high levels of mesenchymal markers, such as Snail, Vimentin and N-cadherin, but not the epithelial marker E-cadherin and this expression was inhibited through ATP degradation or P2Y2R knockdown. Moreover, SK-BR-3 and MDA-MB231 cells exhibited higher ERK and PKC phosphorylation levels than T47D and MCF-7 cells and upregulated phospho-ERK and -PKC levels in MDA-MB-231 cells were significantly downregulated by apyrase or P2Y2R knockdown. Specific inhibitors of ERK, PKC and PLC markedly reduced the invasion and levels of mesenchymal marker expression in MDA-MB-231 cells. These results suggest that over-activated ERK and PKC pathways are involved in the P2Y2R-mediated invasion of breast cancer cells. PMID- 26063341 TI - Erratum to: Comparative quantitative study of 'signature' pathological lesions in the hippocampus and adjacent gyri of 12 neurodegenerative disorders. PMID- 26063342 TI - Court orders on procreation. AB - OBJECTIVE: The aim of this study is to empirically evaluate judgments entered from 1913 to 2013 in the matters of compulsory sterilization. METHODS: Holdings and dispositions at the U.S. Appellate and Supreme courts are randomly located in LexisNexis using Shepard's symbols. Continuous variables are processed with the Mantel-Haenszel method. Court orders are used as units of analysis. RESULTS: The majority of cases (56.4 %) concern minors at a mean age of 11.7 years. Forty-four (80 %) petitions are filed by the parents or guardians; 11 (20 %) are parens patriae. Petitions for female sterilization are denied in 56.4 % cases under the Federal Laws (2 U.S.C. 431; 28 U.S.C; 29 U.S.C; 42 U.S.C; 424 U.S.), Procedural due process clause of the 14th Amendment, statutes, and common law precedents. Petitions for female sterilization are granted in 36.4 % cases under the statutory penal codes, the Law of the land, precedents, and the dicta. No significant associations are found between the parity and degree of mental impairment (r = 0.342). Substantial correlations are met between the gender, degree of impairment (r (2) = 0.724), and dispositions (r (2) = 802). The mean age of women is 20.78 years; the mean age of men is 30.25 years. Correlations fail to establish reasoning between the age of the subjects and the entered judgments (r (2) = 0. 356). CONCLUSIONS: (1) The female/male ratio (8:1) and age gap of the respondents indicate on a disproportionate impact of the statutes. (2) The procedure of sterilization in itself is incommensurate with equality, as the volume of surgery is uneven in males and females. (3) The case law is instructive with respect to which arguments have not been advanced. (4) Lastly, due to the etiological intricacy of mental impairment, with genetic transmission strikingly different in men and women, expert-witnesses ought to act in a medical vacuum because there is no mathematical certainty as to the transmission mode of the traits in question (exon and intron mutations, triplet repeat disorders, histone disorders, autosomal-dominant or autosomal-recessive transmission, sex chromosome linkage, polygenomic imprinting, and organic reasons). PMID- 26063343 TI - A Web-Based Tool for Patient Triage in Emergency Department Settings: Validation Using the Emergency Severity Index. AB - BACKGROUND: We evaluated the concordance between triage scores generated by a novel Internet clinical decision support tool, Clinical GPS (cGPS) (Lumiata Inc, San Mateo, CA), and the Emergency Severity Index (ESI), a well-established and clinically validated patient severity scale in use today. Although the ESI and cGPS use different underlying algorithms to calculate patient severity, both utilize a five-point integer scale with level 1 representing the highest severity. OBJECTIVE: The objective of this study was to compare cGPS results with an established gold standard in emergency triage. METHODS: We conducted a blinded trial comparing triage scores from the ESI: A Triage Tool for Emergency Department Care, Version 4, Implementation Handbook to those generated by cGPS from the text of 73 sample case vignettes. A weighted, quadratic kappa statistic was used to assess agreement between cGPS derived severity scores and those published in the ESI handbook for all 73 cases. Weighted kappa concordance was defined a priori as almost perfect (kappa > 0.8), substantial (0.6 < kappa < 0.8), moderate (0.4 < kappa < 0.6), fair (0.2 < kappa< 0.4), or slight (kappa < 0.2). RESULTS: Of the 73 case vignettes, the cGPS severity score matched the ESI handbook score in 95% of cases (69/73 cases), in addition, the weighted, quadratic kappa statistic showed almost perfect agreement (kappa = 0.93, 95% CI 0.854-0.996). In the subanalysis of 41 case vignettes assigned ESI scores of level 1 or 2, the cGPS and ESI severity scores matched in 95% of cases (39/41 cases). CONCLUSIONS: These results indicate that the cGPS is a reliable indicator of triage severity, based on its comparison to a standardized index, the ESI. Future studies are needed to determine whether the cGPS can accurately assess the triage of patients in real clinical environments. PMID- 26063345 TI - Simvastatin inhibits ischemia/reperfusion injury-induced apoptosis of retinal cells via downregulation of the tumor necrosis factor-alpha/nuclear factor-kappaB pathway. AB - Simvastatin, which is widely used in the prevention and treatment of hyperlipidemia-associated diseases, has been reported to enhance the survival of retinal ganglion cells (RGCs) in a model of retinal ischemia/reperfusion (IR) injury. However, the underlying mechanism of the anti-apoptotic effects of simvastatin on the retina have yet to be elucidated. In the present study, rats were treated with simvastatin or saline for 7 days prior to IR via ligation of the right cephalic artery. The results showed that simvastatin prevented the apoptosis of RGCs and cells in the inner nuclear layer. Furthermore, simvastatin regulated the expression of apoptosis-associated proteins. The expression levels of the anti-apoptotic protein B-cell lymphoma-2 were upregulated 4 and 24 h after IR in the simvastatin/IR group compared to those in the saline/IR group. Conversely, the levels of pro-apoptotic protein Bax were downregulated in the simvastatin/IR group compared to those in the saline/IR group. Furthermore, the results of the present study showed for the first time, to the best of our knowledge, that simvastatin decreased IR injury-induced tumor necrosis factor alpha (TNF-alpha) and nuclear factor-kappaB (NF-kappaB) expression in the retina. These findings strongly suggested that simvastatin inhibits apoptosis following IR-induced retinal injury by inhibition of the TNF-alpha/NF-kappaB pathway. The present study also provided a rationale for developing therapeutic methods to treat IR-induced retinal injury in the clinic. PMID- 26063347 TI - Transport of photogenerated charges and photoelectric properties in two types of heterostructures with different ZnO microstructures. AB - ZnO films with several microstructures including nanoparticles, nanowire arrays, nanorod arrays and nanotube arrays were prepared using different methods. In2O3 and/or Cu4Bi4S9 were deposited onto each nanostructured ZnO film, and two types of heterostructures (ZnO/Cu4Bi4S9 and ZnO/In2O3/Cu4Bi4S9) as well as solid state dye-sensitized solar cells were fabricated. The signals of steady state and electric field-induced surface photovoltage spectroscopy indicate that all of ZnO/In2O3/Cu4Bi4S9 heterostructures exhibit higher photovoltaic response than the relative ZnO/Cu4Bi4S9. The same type of heterostructure with different ZnO films presents various photovoltaic properties. Transient surface photovoltage spectroscopy can contribute to study the separation and transport mechanism of photogenerated charges. Here, ZnO nanotubes/Cu4Bi4S9 and ZnO nanotubes/In2O3/Cu4Bi4S9 cells exhibit the best performances with the highest efficiencies of 6.2% and 6.8%, respectively. The internal relations of photoelectric properties to some factors, such as film thickness, surface area, microstructure, double energy level matchings, etc. were discussed in detail. Qualitative and quantitative analysis further verified the comprehensive effect and the difference of factors. The exploration to understand the transport mechanism of light-induced charges in composite films will promote the nanocrystal application in solid state solar cells and photovoltaic community. PMID- 26063346 TI - Postpartum contraceptive use and unmet need for family planning in five low income countries. AB - BACKGROUND: During the post-partum period, most women wish to delay or prevent future pregnancies. Despite this, the unmet need for family planning up to a year after delivery is higher than at any other time. This study aims to assess fertility intention, contraceptive usage and unmet need for family planning amongst women who are six weeks postpartum, as well as to identify those at greatest risk of having an unmet need for family planning during this period. METHODS: Using the NICHD Global Network for Women's and Children's Health Research's multi-site, prospective, ongoing, active surveillance system to track pregnancies and births in 100 rural geographic clusters in 5 countries (India, Pakistan, Zambia, Kenya and Guatemala), we assessed fertility intention and contraceptive usage at day 42 post-partum. RESULTS: We gathered data on 36,687 women in the post-partum period. Less than 5% of these women wished to have another pregnancy within the year. Despite this, rates of modern contraceptive usage varied widely and unmet need ranged from 25% to 96%. Even amongst users of modern contraceptives, the uptake of the most effective long-acting reversible contraceptives (intrauterine devices) was low. Women of age less than 20 years, parity of two or less, limited education and those who deliver at home were at highest risk for having unmet need. CONCLUSIONS: Six weeks postpartum, almost all women wish to delay or prevent a future pregnancy. Even in sites where early contraceptive adoption is common, there is substantial unmet need for family planning. This is consistently highest amongst women below the age of 20 years. Interventions aimed at increasing the adoption of effective contraceptive methods are urgently needed in the majority of sites in order to reduce unmet need and to improve both maternal and infant outcomes, especially amongst young women. STUDY REGISTRATION: Clinicaltrials.gov (ID# NCT01073475). PMID- 26063348 TI - Prognostic and Mechanistic Factors Characterizing Seizure-Associated Crossed Cerebellar Diaschisis. AB - BACKGROUND: Crossed cerebellar diaschisis is a rare finding of hemispheric cerebellar depression following contralateral cerebral injury, hypothesized to result from excessive neuronal excitatory synaptic activity along cortico-pontine cerebellar pathways. The phenomenon is typically observed following ischemic stroke, but has also been characterized during seizure activity--in particular, status epilepticus (SE). Neurological outcome has varied widely in published reports, with some patients achieving full neurologic recovery, while others experience persistent disability. METHODS: Case report and literature review. RESULTS: We present a 54-year-old man found unresponsive with a right hemispheric syndrome several days after discharge following amygdalohippocampectomy for refractory right temporal lobe epilepsy. Prolonged electroencephalogram demonstrated one subclinical right frontal seizure, along with right frontal periodic lateralized epileptiform discharges, presumed to be associated with SE preceding his admission. Initial MRI demonstrated restricted diffusion on diffusion weighted imaging in the right cerebral hemisphere, ipsilateral thalamus, and contralateral cerebellum. A head CT one week later showed diffuse sulcal effacement with loss of gray-white differentiation in the right frontal and insular regions with low attenuation changes of right thalamus. An MRI showed worsened diffusion restriction, despite a corresponding increase in perfusion. The patient remained paretic at discharge and follow-up. Follow-up MRI at 2 months demonstrated pronounced right cerebral and left cerebellar atrophy, loss of gray matter in much of the right cerebrum, and scattered areas of T2 hyperintensity, consistent with permanent right fronto-temporal neuronal loss. CONCLUSIONS: Collectively, these observations indicate that imaging findings of persistent cerebral restricted diffusion and cytotoxic edema in the subacute post ictal period may predict irreversible neuronal injury and poor long-term outcome even when accompanied by evidence of cortical hyperperfusion and recovery of second- and third-order neurons along the involved circuit. PMID- 26063349 TI - Concerning ionizing radiation-induced cancer from internally deposited radionuclides. AB - PURPOSE: A comparative evaluation was conducted of ionizing radiation-induced cancer from internally deposited radionuclides. MATERIALS AND METHODS: Data were evaluated for humans for (226)Ra, and for laboratory animal studies for alpha emitters (228)Ra, (226)Ra, (224)Ra, (238)Pu, (239)Pu, (228)Th, (252)Cf, (249)Cf, and (241)Am, and for beta-emitters (90)Sr, (90)Y, (91)Y, and (144)Ce. Intake routes included ingestion, inhalation, and injection. RESULTS: Cancer risk associated with protracted ionizing radiation exposure is a non-linear function of lifetime average dose rate to the affected tissues. The lifetime effects are best described by three-dimensional average-dose-rate/time/response surfaces that compete with other causes of death during an individual's lifetime. At the higher average dose rates the principal deleterious effects are those associated with radiation-induced injury, while at intermediate average dose rates radiation induced cancer predominates. CONCLUSIONS: The cumulative radiation dose is neither an accurate nor an appropriate measure of cancer risk associated with protracted ionizing radiation exposure. At low average dose rates the long latency time required for radiation-induced cancer may exceed the natural lifespan yielding a lifespan virtual threshold for radiation-induced cancer for cumulative doses below about 5-10 Sv for bone, bone marrow and lungs. PMID- 26063350 TI - Adverse maternal and perinatal outcomes in adolescent pregnancies: The Global Network's Maternal Newborn Health Registry study. AB - BACKGROUND: Adolescent girls between 15 and 19 years give birth to around 16 million babies each year, around 11% of births worldwide. We sought to determine whether adolescent mothers are at higher risk of maternal and perinatal adverse outcomes compared with mothers aged 20-24 years in a prospective, population based observational study of newborn outcomes in low resource settings. METHODS: We undertook a prospective, population-based multi-country research study of all pregnant women in defined geographic areas across 7 sites in six low-middle income countries (Kenya, Zambia, India, Pakistan, Guatemala and Argentina). The study population for this analysis was restricted to women aged 24 years or less, who gave birth to infants of at least 20 weeks' gestation and 500g or more. We compared adverse pregnancy maternal and perinatal outcomes among pregnant adolescents 15-19 years, <15 years, and adults 20-24 years. RESULTS: A total of 269,273 women were enrolled from January 2010 to December 2013. Of all pregnancies 11.9% (32,097/269,273) were in adolescents 15-19 years, while 0.14% (370/269,273) occurred among girls <15 years. Pregnancy among adolescents 15-19 years ranged from 2% in Pakistan to 26% in Argentina, and adolescent pregnancies <15 year were only observed in sub-Saharan Africa and Latin America. Compared to adults, adolescents did not show increased risk of maternal adverse outcomes. Risks of preterm birth and LBW were significantly higher among both early and older adolescents, with the highest risks observed in the <15 years group. Neonatal and perinatal mortality followed a similar trend in sub-Saharan Africa and Latin America, with the highest risk in early adolescents, although the differences in this age group were not significant. However, in South Asia the risks of neonatal and perinatal death were not different among adolescents 15-19 years compared to adults. CONCLUSIONS: This study suggests that pregnancy among adolescents is not associated with worse maternal outcomes, but is associated with worse perinatal outcomes, particularly in younger adolescents. However, this may not be the case in regions like South Asia where there are decreasing rates of adolescent pregnancies, concentrated among older adolescents. The increased risks observed among adolescents seems more likely to be associated with biological immaturity, than with socio-economic factors, inadequate antenatal or delivery care. TRIAL REGISTRATION NUMBER: NCT01073475. PMID- 26063351 TI - Changing trends in the incidence (1999-2011) and mortality (1983-2013) of cervical cancer in the Republic of Korea. AB - Cervical cancer is a well-known preventable cancer worldwide. Many countries including Korea have pursued the positive endpoint of a reduction in mortality from cervical cancer. Our aim is to examine changing trends in cervical cancer incidence and mortality after the implementation of a national preventive effort in Korea. Cervical cancer incidence data from 1999 to 2011 and mortality data from 1983 to 2013 were collected from the Korean Statistical Information Service. Yearly age-standardized rates (ASR) per 100,000 were compared using two standards: the 2005 Korean population and the world standard population, based on Segi's world standard for incidence and the World Health Organization for mortality. In Korea, the age-standardized incidence of cervical cancer per 100,000 persons declined from 17.2 in 2000 to 11.8 in 2011. However, the group aged 25 to 29 showed a higher rate in 2011 (ASR, 6.5) than in 2000 (ASR, 3.6). The age-standardized mortality rate per 100,000 persons dropped from 2.81 in 2000 to 1.95 in 2013. In the worldwide comparison, the incidence rates remained close to the average incidence estimate of more developed regions (ASR, 9.9). The decreasing mortality trend in Korea approached the lower rate observed in Australia (ASR, 1.4) in 2010. Although the incidence rate of cervical cancer is continuously declining in Korea, it is still high relative to other countries. Moreover, incidence and mortality rates in females aged 30 years or under have recently increased. It is necessary to develop effective policy to reduce both incidence and mortality, particularly in younger age groups. PMID- 26063352 TI - Epidemiological evidence in law: a comment on Supreme Court Decision 2011Da22092, South Korea. AB - This paper offers a commentary on three aspects of the Supreme Court's recent decision (2011Da22092). First, contrary to the Court's finding, this paper argues that epidemiological evidence can be used to estimate the probability that a given risk factor caused a disease in an individual plaintiff. Second, the distinction between specific and non-specific diseases, upon which the Court relies, is shown to be without scientific basis. Third, this commentary points out that the Court's finding concerning defect of expression effectively enables tobacco companies to profit from the efforts of epidemiologists and others involved in public health to raise awareness of the dangers of smoking. PMID- 26063353 TI - Identification of Aspergillus nomius in Bees Visiting Brazil Nut Flowers. AB - We designed a primer pair (BtubNomF/BtubNomR) specifically for amplifying Aspergillus nomius DNA. In vitro assays confirmed BtubNomF/BtubNomR specificity, corroborating its usefulness in detecting and identifying A. nomius. We then investigated the occurrence of A. nomius in floral visitors of Bertholletia excelsa trees by means of PCR, and A. nomius was detected in the following bees: Xylocopa frontalis, Bombus transversalis, Centris denudans, C. ferruginea, and Epicharis flava. The presence of A. nomius in bees visiting Brazil nuts opens up new avenues for obtaining novel insights into the process whereby Brazil nuts are contaminated by aflatoxin-producing fungi. PMID- 26063354 TI - Prospective Randomized Study of Sarpogrelate Versus Clopidogrel-based Dual Antiplatelet Therapies in Patients Undergoing Femoropopliteal Arterial Endovascular Interventions: Preliminary Results. AB - BACKGROUND: Sarpogrelate is a selective 5-hydroxytryptamine (5-HT) receptor subtype 2A antagonist which blocks 5-HT induced platelet aggregation and proliferation of vascular smooth muscle cells. We compared the efficacy of sarpogrelate-based dual antiplatelet therapies for the prevention of restenosis and target lesion revascularization (TLR) rates comparing with that of clopidogrel after percutaneous endovascular interventions (EVIs) of femoropopliteal (FP) arterial lesions. METHODS: This prospective, multicenter, randomized clinical trial recruited a total of 120 patients with successful EVI of FP lesions at seven centers across China between January 2011 and June 2012. Patients were randomized to receive either sarpogrelate (100 mg trice daily for 6 months, n = 63) or clopidogrel (75 mg once daily for 6 months, n = 57). All patients also received oral aspirin (100 mg once daily for 12 months). Clinical follow-up was conducted up to 12 months postprocedure. RESULTS: There was no significant difference between the two groups in basic demographic data. The restenosis rate was higher in the clopidogrel group (22.80%) than in sarpogrelate group (17.50%), but there was no significant difference between these two groups (P = 0.465). The TLR rate, ipsilateral amputation rate, mortality in all-cause and bleeding rate were also similar in the two groups (P > 0.05). CONCLUSIONS: Aspirin plus sarpogrelate is a comparable antithrombotic regimen to aspirin plus clopidogrel after EVI of FP arterial lesions. Dual antiplatelet therapies might play an important role in preventing restenosis after successful EVI of FP lesions. PMID- 26063355 TI - Clustering of Risk Behaviors and their Social Determinants among Primary School Learners in Beijing, China: A Cross-sectional Study. AB - BACKGROUND: Studies in developed countries reveal that poor lifestyle choices triggering diseases typically cluster among children. However, there is insufficient evidence on the clustering of risk behaviors among children in developing countries. This study aimed to determine the clustering of risk behaviors and their social determinants among 4 th -and 5 th -grade learners in Beijing, China. METHODS: The sample comprised of 967 learners from six primary schools enrolled migrant and resident learners by two-stage stratified cluster sampling. Prevalence denoted the risk behaviors and their clustering. A log linear model was used to explore the clustering patterns. Ordinal logistic regression determined the influence of demographic characteristics, school environment, and family context on behavioral clustering. RESULTS: The prevalence of none, one, two, and three or more risk factors was 61.2%, 20.0%, 10.8%, and 8.1% for infectious diseases and 46.0%, 30.6%, 15.4%, and 8.0% for chronic diseases, respectively. Some behaviors appeared dependent and were more likely to be observed together. The three most influential factors for infectious diseases were school type (odds ratio [OR] =4.47, 95% confidence interval [CI] 3.00-6.66), school located in an inner suburb (OR = 0.27, 95% CI 0.18-0.38), and gender (OR = 0.56, 95% CI 0.42-0.74). Regarding risk behaviors for chronic diseases, clustering was not associated with household registration status and number of appliances, but was significantly associated with school type (OR = 5.36, 95% CI 3.72-7.73), school located in an inner suburb (OR = 0.59, 95% CI 0.43-0.81), and gender (OR = 0.61, 95% CI 0.47-0.78). School environment variables were the most significant contributor to the number of risk behaviors. CONCLUSIONS: The characteristics of schools enrolling migrants and residents influenced the number of risk behaviors. Therefore, improved school conditions and integrated behavioral interventions are particularly recommended for health promotion. PMID- 26063356 TI - Value of the Ratio of Occluder Versus Atrial Septal Length for Predicting Arrhythmia Occurrence after Transcatheter Closure in Children with Ostium Secundum Atrial Septal Defect. AB - BACKGROUND: Transcatheter occlusion has been applied to treat ostium secundum atrial septal defect (OS ASD) since 1997. During the clinical practice, several postoperative complications including arrhythmia have been reported. This study aimed to evaluate the value of the ratio of atrial septal occluder (ASO) versus atrial septal length (ASL) for predicting arrhythmia occurrence after transcatheter closure in children with OS ASD. METHODS: Six hundred and fifty-one children diagnosed with OS ASD underwent occlusion procedures after completing routine examinations. The onsets and types of arrhythmia both during and after the occlusion procedures were monitored. Treatments were given based on the individual types of arrhythmia. The binary logistic regression analysis and receiver-operating characteristic (ROC) curve were used in the analysis of value of the ratio of ASO/ASL for predicting postoperative arrhythmia occurrence. RESULTS: Transcather occlusions were conducted in 651 children, among whom 7 children had different types and degrees of arrhythmia, with an incidence of 1.1%. The types of arrhythmia included sinus bradycardia, atrial premature beats, bundle branch block, and different degrees of atrioventricular block. Normal electrocardiograph findings were resumed in these 7 patients following active therapies such as corticoids, nutrition, and surgeries. The binary logistic regression and ROC analysis suggested that the ratio of ASO/ASL exhibited an intermediate predictive value for predicting arrhythmia occurrence after occlusion procedures. A cut-off value of 0.576 in the ratio provided a sensitivity of 87.5% and a specificity of 76.2% with an area under the ROC curve of 0.791 (95% confidence intervals, 0.655-0.926; P < 0.05) in predicting arrhythmia occurrence after the closure procedures. CONCLUSIONS: The ratio of ASO/ASL might be a useful index for predicting arrhythmia occurrence after closure procedures in children with OS ASD. PMID- 26063357 TI - Cross-sectional Anatomy of Ilium for Guiding Acetabular Component Placement Using High Hip Center Technique in Asian Population. AB - BACKGROUND: Many clinical studies have been published involving the use of a high hip center (HHC), achieved good follow-up. However, there is a little anatomic guidance in the literature regarding the amount of bone stock available for initial implant coverage in this area of the ilium. The purpose of this study was to evaluate the thickness and width of the human ilium and related acetabular cup coverage for guiding acetabular component placement in HHC. METHODS: A total of 120 normal hips in 60 cases of adult patients from lower extremities computer tomographic angiography Digital Imaging and Communications in Medicine data were chosen for the study. After importing the data to the mimics software, we chose the cross sections every 5-mm increments from the rotational center of the hip to the cephalic of the ilium according the body sagittal axis, then we measured the thickness and width of the ilium for each cross section in axial plane, calculated the cup coverage at each chosen section. RESULTS: At the acetabular dome, the mean thickness and width of the ilium were 49.71 +/- 4.88 mm and 38.92 +/- 3.67 mm, respectively, whereas at 1 cm above the dome, decreased to 41.35 +/- 5.13 and 31.13 +/- 3.37 respectively, and 2 cm above the dome, decreased to 31.25 +/- 4.04 and 26.65 +/- 3.43, respectively. Acetabular cup averaged coverage for 40-, 50-, and 60-mm hemispheric shells, was 100%, 89%, and 44% at the acetabular dome, 100%, 43.7%, and 27.5% for 1 cm above the dome, and 37.5%, 21.9%, and 14.2% for 2 cm above the dome. CONCLUSIONS: HHC reconstructions within 1 cm above the acetabular dome will be an acceptable and smaller diameter prosthesis would be better. PMID- 26063358 TI - Expression of Nitric Oxide Synthase Isoenzyme in Lung Tissue of Smokers with and without Chronic Obstructive Pulmonary Disease. AB - BACKGROUND: It has been demonstrated that only 10%-20% cigarette smokers finally suffer chronic obstructive pulmonary disease (COPD). The underlying mechanism of development remains uncertain so far. Nitric oxide (NO) has been found to be closely associated with the pathogenesis of COPD, the alteration of NO synthase (NOS) expression need to be revealed. The study aimed to investigate the alterations of NOS isoforms expressions between smokers with and without COPD, which might be helpful for identifying the susceptibility of smokers developing into COPD. METHODS: Peripheral lung tissues were obtained from 10 nonsmoker control subjects, 15 non-COPD smokers, and 15 smokers with COPD. Neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS) mRNA and protein levels were measured in each sample by using real-time polymerase chain reaction and Western blotting. RESULTS: INOS mRNA was significantly increased in patients with COPD compared with nonsmokers and smokers with normal lung function (P < 0.001, P = 0.001, respectively). iNOS protein was also higher in COPD patients than nonsmokers and smokers with normal lung function (P < 0.01 and P = 0.01, respectively). However, expressions of nNOS and eNOS did not differ among nonsmokers, smokers with and without COPD. Furthermore, there was a negative correlation between iNOS protein level and lung function parameters forced expiratory volume in 1 s (FEV1) (% predicted) (r = -0.549, P = 0.001) and FEV1/forced vital capacity (%, r = -0.535, P = 0.001). CONCLUSIONS: The expression of iNOS significantly increased in smokers with COPD compared with that in nonsmokers or smokers without COPD. The results suggest that iNOS might be involved in the pathogenesis of COPD, and may be a potential marker to identify the smokers who have more liability to suffer COPD. PMID- 26063359 TI - Intracytoplasmic Sperm Injection Fertilization Rate Does Not Depend on the Proportion of Round-headed Sperm, Small-acrosomal Sperm, or Morphologically Normal Sperm in Patients with Partial Globozoospermia. AB - BACKGROUND: Generally, intracytoplasmic sperm injection (ICSI) may be the preferable method to treat partial globozoospermia, but whether there exist some correlations between ICSI fertilization rate and the proportion of round-headed sperm or morphologically normal sperm remains open. This study was to explore the correlation between ICSI fertilization rate and the sperm morphology in patients with partial globozoospermia. METHODS: Thirty-four patients diagnosed with partial globozoospermia accepted the following assisted fertilization treatments 2 cases accepted in-vitro fertilization (IVF) alone, 26 cases accepted ICSI alone, and 6 accepted split IVF/ICSI. Detailed morphological characteristics were described using Diff-Quik rapid staining. Sixty cases accepting IVF or ICSI treatment in our reproductive center were considered as the control group after being matched by relevant criteria. Fertilization rate, embryo quality, embryo implantation rate and clinical pregnancy rate were calculated. RESULTS: Besides very high proportion of round-headed sperm, partial globozoospermia also showed very high proportion of small-acrosomal sperm and very low proportion of morphologically normal sperm. Fertilization rate of IVF (IVF alone plus split IVF) was very low in partial globozoospermia (25.4% +/- 17.4%), but ICSI (ICSI alone plus split ICSI) achieved satisfying fertilization rate compared with the control group (66.2% +/- 22.5% vs. 68.8% +/- 29.4%, P > 0.05). In patients with partial globozoospermia, there were no correlations between ICSI fertilization rate and the proportion of round-headed sperm, small-acrosomal sperm, or morphologically normal sperm. CONCLUSIONS: There was high proportion of small acrosomal sperm in partial globozoospermia. For patients with partial globozoospermia, ICSI is more preferable than IVF. ICSI fertilization rate does not depend on the proportion of round-headed sperm, small-acrosomal sperm, or morphologically normal sperm. PMID- 26063360 TI - Mini-percutaneous Nephrolithotomy Under Total Ultrasonography in Patients Aged Less Than 3 Years: A Single-center Initial Experience from China. AB - BACKGROUND: Urolithiasis in pediatric population is a serious problem with the incidence increased these years. In the management of larger stones (diameters >2 cm), percutaneous nephrolithotomy (PCNL) is considered to be the gold standard. This study aimed to investigate the efficacy and safety of mini-PCNL under total ultrasonography in patients aged <3 years. METHODS: We reviewed 68 patients (80 renal units) aged <3 years between August 2006 and December 2014 in Peking University People's Hospital and Beijing Tsinghua Changung Hospital, including 36 renal units with a single stone, 6 with staghorn stones, 14 with upper ureteral stones, and 24 with multiple stones. The mean age of the patients was 24.2 months (range 6-36 months), and the mean maximum stone diameter was 19.2 mm (range 10-35 mm). The puncture site selection and tract dilation were guided by Doppler ultrasonography solely. All procedures were performed using 12-16 Fr tracts. Stones were fragmented using pneumatic lithotripsy and a holmium laser with an 8/9.8 Fr rigid ureteroscope. RESULTS: Fifty-six patients with unilateral stones underwent a single session procedure, and 12 patients with bilateral stones underwent two procedures. The mean time to establish access was 2.8 min (range 1.8-5.0 min), the mean operative time was 36.5 min (range 20-88 min), the mean decrease in hemoglobin concentration was 8.9 g/L (2-15 g/L), and the stone-free rate (SFR) at hospital discharge was 94.0%. The mean postoperative hospital stay was 7.1 days (range 3-13 days). Postprocedure complications included fever (>38.5 degrees C) in five patients and reactive pleural effusion in one patient. Blood loss requiring transfusion, sepsis, adjacent organ injury, and kidney loss were not observed. CONCLUSIONS: This study indicated that ultrasound-guided mini-PCNL is feasible and safe in patients aged <3 years, without major complications or radiation exposure. PMID- 26063361 TI - Wall Imaging for Unilateral Intracranial Vertebral Artery Hypoplasia with Three dimensional High-isotropic Resolution Magnetic Resonance Images. AB - BACKGROUND: There are few studies for evaluating wall characteristics of intracranial vertebral artery hypoplasia (VAH). The aim of this study was to determine wall characteristics of VAH with three-dimensional volumetric isotropic turbo spin echo acquisition (3D VISTA) images and differentiate between acquired atherosclerotic stenosis and VAH. METHODS: Thirty patients with suspicious VAH by luminograms were retrospectively enrolled between January 2014 and February 2015. The patients were classified as "acquired atherosclerotic stenosis" or "VAH" based on 3D VISTA images. The wall characteristics of VAH were assessed to determine the presence of atherosclerotic lesions, and the patients were classified into two subgroups (VAH with atherosclerosis and VAH with normal wall). Wall characteristics of basilar arteries and vertebral arteries were also assessed. The clinical and wall characteristics were compared between the two groups. RESULTS: Five of 30 patients with suspicious VAH were finally diagnosed as acquired atherosclerotic stenosis by 3D VISTA images. 25 patients were finally diagnosed as VAH including 16 (64.00%) patients with atherosclerosis and 9 (36.00%) patients with normal wall. In the 16 patients with atherosclerosis, plaque was found in 9 patients, slight wall thickening in 6 patients, and thrombus and wall thickening in 1 patient. Compared with VAH patients with normal wall, VAH patients with atherosclerosis showed atherosclerotic basilar arteries and dominant vertebral arteries more frequently (P = 0.000). CONCLUSIONS: Three dimensional VISTA images enable differentiation between the acquired atherosclerotic stenosis and VAH. VAH was also prone to atherosclerotic processes. PMID- 26063362 TI - A Retrospective Study of Pulmonary Actinomycosis in a Single Institution in China. AB - BACKGROUND: Actinomycosis is a rare indolent infectious disease caused by Actinomyces. Although pulmonary actinomycosis is thought to be more prevalent in developing countries, data from developing countries are scanty. This study was to reveal the current situation of pulmonary actinomycosis in developing countries and the difference from that in developed countries. METHODS: Patients fulfilling the inclusion criteria for pulmonary actinomycosis from Peking Union Medical College Hospital in China between January 2003 and December 2014 were retrospectively analyzed. Baseline characteristics, clinical symptoms, underlying diseases, diagnostic methods, pulmonary function test results, chest computed tomography (CT) tests, fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) tests, initial diagnosis, treatment and prognosis were retrieved from medical records and analyzed. RESULTS: Twenty-six patients were included in this study (mean age 52.0 + 13.1 years). The ratio of male to female was 1.17:1. Most common clinical symptoms were cough (15/26), sputum (12/26) and hemoptysis (12/26). Chest CT findings presented as masses (13/26), nodules (10/26) and infiltrates (3/26). FDG-PET had an increased standardized uptake value and 4/6 patients were misdiagnosed as malignancy. Many kinds of antibiotics were used in the treatment of pulmonary actonomycosis and all got favorable results. Five patients receiving complete resection of the lesion were cured without postoperative use of antibiotic. CONCLUSIONS: Pulmonary actinomycosis is a rare disease even in developing countries, and both misdiagnosis and missed diagnosis are common. FDG-PET seems useless in the differential diagnosis, and complete resection of the pulmonary lesion without postoperative antibiotic therapy might be enough to achieve cure. PMID- 26063363 TI - Prediction of Cerebral Hyperperfusion Syndrome with Velocity Blood Pressure Index. AB - BACKGROUND: Cerebral hyperperfusion syndrome is an important complication of carotid endarterectomy (CEA). An >100% increase in middle cerebral artery velocity (MCAV) after CEA is used to predict the cerebral hyperperfusion syndrome (CHS) development, but the accuracy is limited. The increase in blood pressure (BP) after surgery is a risk factor of CHS, but no study uses it to predict CHS. This study was to create a more precise parameter for prediction of CHS by combined the increase of MCAV and BP after CEA. METHODS: Systolic MCAV measured by transcranial Doppler and systematic BP were recorded preoperatively; 30 min postoperatively. The new parameter velocity BP index (VBI) was calculated from the postoperative increase ratios of MCAV and BP. The prediction powers of VBI and the increase ratio of MCAV (velocity ratio [VR]) were compared for predicting CHS occurrence. RESULTS: Totally, 6/185 cases suffered CHS. The best-fit cut-off point of 2.0 for VBI was identified, which had 83.3% sensitivity, 98.3% specificity, 62.5% positive predictive value and 99.4% negative predictive value for CHS development. This result is significantly better than VR (33.3%, 97.2%, 28.6% and 97.8%). The area under the curve (AUC) of receiver operating characteristic: AUC(VBI) = 0.981, 95% confidence interval [CI] 0.949-0.995; AUC(VR) = 0.935, 95% CI 0.890-0.966, P = 0.02. CONCLUSIONS: The new parameter VBI can more accurately predict patients at risk of CHS after CEA. This observation needs to be validated by larger studies. PMID- 26063364 TI - Gene Expression Profile of Persistent Postoperative Hypertension Patients with Aldosterone-producing Adenomas. AB - BACKGROUND: Hypertension often persists after adrenalectomy for primary aldosteronism (PA). Many studies have analyzed the outcomes of adrenalectomy for aldosterone-producing adenomas (APA) to identify predictive factors for persistent hypertension. However, differentially expressed genes in persistent postoperative hypertension remain unknown. Our aim was to describe gene expression profile of persistent postoperative hypertension patients with APA. METHODS: In this study, we described and compared gene expression profiles in persistent postoperative hypertension and postoperative normotension in Chinese patients with APA using microarray analysis. Confirmation was performed with quantitative real time-polymerase chain reaction analysis. Bioinformatic analysis (gene ontology analysis, pathway analysis and network analysis) was used for further research. RESULTS: Microarray analysis identified a total of 99 differentially expressed genes, including 18 up-regulated and 81 down-regulated genes. Among the dysregulated genes were fat atypical cadherin 1 as well as fatty acid binding protein 4 and other genes that have not been previously studied in persistent postoperative hypertension with APA. Bioinformatics analysis indicated that differentially expressed genes were associated with lipid metabolic process, metal ion binding, and cell differentiation. Pathway analysis determined that five pathways corresponded to the dysregulated transcripts. The mRNAs-ncRNAs co expression network was composed of 49 network nodes and 72 connections between 18 coding genes and 31 noncoding genes. CONCLUSIONS: This study revealed differentially expressed genes in persistent postoperative hypertension with APA and provided a resource of candidate genes for exploration of possible drug targets and prognostic markers. PMID- 26063365 TI - Differences in Liver Injury and Trophoblastic Mitochondrial Damage in Different Preeclampsia-like Mouse Models. AB - BACKGROUND: Preeclampsia is a multifactorial disease during pregnancy. Dysregulated lipid metabolism may be related to some preeclampsia. We investigated the relationship between triglycerides (TGs) and liver injury in different preeclampsia-like mouse models and their potential common pathways. METHODS: Preeclampsia-like models (Nw-nitro-L-arginine-methyl ester [L-NAME], lipopolysaccharide [LPS], apolipoprotein C-III [Apo] transgnic mice + L-NAME, beta2 glycoprotein I [betaGPI]) were used in four experimental groups: L-NAME (LN), LPS, Apo-LN and betaGPI, respectively, and controls received saline (LN-C, LPS-C, Apo-C, betaGPI-C). The first three models were established in preimplantation (PI), early-, mid- and late-gestation (EG, MG and LG). betaGPI and controls were injected before implantation. Mean arterial pressure (MAP), 24 hour urine protein, placental and fetal weight, serum TGs, total cholesterol (TC) and pathologic liver and trophocyte changes were assessed. RESULTS: MAP and proteinuria were significantly increased in the experimental groups. Placenta and fetal weight in PI, EP and MP subgroups were significantly lower than LP. Serum TGs significantly increased in most groups but controls. TC was not different between experimental and control groups. Spotty hepatic cell necrosis was observed in PI, EG, MG in LN, Apo-LN and betaGPI, but no morphologic changes were observed in the LPS group. Similar trophoblastic mitochondrial damage was observed in every experimental group. CONCLUSIONS: Earlier preeclampsia onset causes a higher MAP and urine protein level, and more severe placental and fetal damage. Preeclampsia-like models generated by varied means lead to different changes in lipid metabolism and associated with liver injury. Trophoblastic mitochondrial damage may be the common terminal pathway in different preeclampsia like models. PMID- 26063366 TI - An Appreciation for the Rabbit Ladderlike Modeling of Radiation-induced Lung Injury with High-energy X-Ray. AB - BACKGROUND: To evaluate the utility of rabbit ladderlike model of radiation induced lung injury (RILI) for the future investigation of computed tomography perfusion. METHODS: A total of 72 New Zealand rabbits were randomly divided into two groups: 36 rabbits in the test group were administered 25 Gy of single fractionated radiation to the whole lung of unilateral lung; 36 rabbits in the control group were sham-radiated. All rabbits were subsequently sacrificed at 1, 6, 12, 24, 48, 72 h, and 1, 2, 4, 8,1 6, 24 weeks after radiation, and then six specimens were extracted from the upper, middle and lower fields of the bilateral lungs. The pathological changes in these specimens were observed with light and electron microscopy; the expression of tumor necrosis factor-alpha (TNF-a) and transforming growth factor-beta1 (TGF-beta1) in local lung tissue was detected by immunohistochemistry. RESULTS: (1) Radiation-induced lung injury occurred in all rabbits in the test group. (2) Expression of TNF-a and TGF-beta1 at 1 h and 48 h after radiation, demonstrated a statistically significant difference between the test and control groups (each P < 0.05). (3) Evaluation by light microscopy demonstrated statistically significant differences between the two groups in the following parameters (each P < 0.05): thickness of alveolar wall, density of pulmonary interstitium area (1 h after radiation), number of fibroblasts and fibrocytes in interstitium (24 h after radiation). The test group metrics also correlated well with the time of postradiation. (4) Evaluation by electron microscopy demonstrated statistically significant differences in the relative amounts of collagen fibers at various time points postradiation in the test group (P < 0.005), with no significant differences in the control group (P > 0.05). At greater than 48 h postradiation the relative amount of collagen fibers in the test groups significantly differ from the control groups (each P < 0.05), correlating well with the time postradiation (r = 0.99318). CONCLUSIONS: A consistent and reliable rabbit model of RILI can be generated in gradient using 25 Gy of high-energy X-ray, which can simulate the development and evolution of RILI. PMID- 26063367 TI - Comparison of Cerebral Metabolism between Pig Ventricular Fibrillation and Asphyxial Cardiac Arrest Models. AB - BACKGROUND: Morbidity and mortality after resuscitation largely depend on the recovery of brain function. Ventricular fibrillation cardiac arrest (VFCA) and asphyxial cardiac arrest (ACA) are the two most prevalent causes of sudden cardiac death. Up to now, most studies have focused on VFCA. However, results from the two models have been largely variable. So, it is necessary to characterize the features of postresuscitation cerebral metabolism of both models. METHODS: Forty-four Wuzhishan miniature inbred pigs were randomly divided into three groups: 18 for VFCA group, ACA group, respectively, and other 8 for sham-operated group (SHAM). VFCA was induced by programmed electric stimulation, and ACA was induced by endotracheal tube clamping. After 8 min without treatment, standard cardiopulmonary resuscitation (CPR) was initiated. Following neurological deficit scores (NDS) were evaluated at 24 h after achievement of spontaneous circulation, cerebral metabolism showed as the maximum standardized uptake value (SUVmax) was measured by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Levels of serum markers of brain injury, neuron specific enolase (NSE), and S100beta were quantified with an enzyme-linked immunosorbent assay. RESULTS: Compared with VFCA group, fewer ACA animals achieved restoration of spontaneous circulation (61.1% vs. 94.4%, P < 0.01) and survived 24-h after resuscitation (38.9% vs. 77.8%, P < 0.01) with worse neurological outcome (NDS: 244.3 +/- 15.3 vs. 168.8 +/- 9.71, P < 0.01). The CPR duration of ACA group was longer than that of VFCA group (8.1 +/- 1.2 min vs. 4.5 +/- 1.1 min, P < 0.01). Cerebral energy metabolism showed as SUVmax in ACA was lower than in VFCA (P < 0.05 or P < 0.01). Higher serum biomarkers of brain damage (NSE, S100beta) were found in ACA than VFCA after resuscitation (P < 0.01). CONCLUSIONS: Compared with VFCA, ACA causes more severe cerebral metabolism injuries with less successful resuscitation and worse neurological outcome. PMID- 26063368 TI - Effect of Oenanthe Javanica Extract on Antioxidant Enzyme in the Rat Liver. AB - BACKGROUND: Oenanthe javanica (O. javanica) has been known to have high antioxidant properties via scavenging reactive oxygen species. We examined the effect of O. javanica extract (OJE) on antioxidant enzymes in the rat liver. METHODS: We examined the effect of the OJE on copper, zinc-superoxide dismutase (SOD1), manganese superoxide dismutase (SOD2), catalase (CAT), and glutathione peroxidase (GPx) in the rat liver using immunohistochemistry and western blot analysis. Sprague-Dawley rats were randomly assigned to three groups; (1) normal diet fed group (normal-group), (2) diet containing ascorbic acid (AA)-fed group (AA-group) as a positive control, (3) diet containing OJE-fed group (OJE-group). RESULTS: In this study, no histopathological finding in the rat liver was found in all the experimental groups. Numbers of SOD1, SOD2, CAT, and GPx immunoreactive cells and their protein levels were significantly increased in the AA-fed group compared with those in the normal-group. On the other hand, in the OJE-group, numbers of SOD1, SOD2, CAT, and GPx immunoreactive cells in the liver were significantly increased by about 190%, 478%, 685%, and 346%, respectively, compared with those in the AA-group. In addition, protein levels of SOD1, SOD2, CAT, and GPx in the OJE-group were also significantly much higher than those in the AA-group. CONCLUSION: OJE significantly increased expressions of SOD1 and SOD2, CAT, and GPx in the liver cells of the rat, and these suggests that significant enhancements of endogenous enzymatic antioxidants by OJE might be a legitimate strategy for decreasing oxidative stresses in the liver. PMID- 26063369 TI - Biomechanical and Macroscopic Evaluations of the Effects of 5-Fluorouracil on Partially Divided Flexor Tendon Injuries in Rabbits. AB - BACKGROUND: The main goals of flexor tendon surgery are to restore digital motion by providing tendon healing and to preserve tendon gliding. Our purpose was to investigate the effects of 5-fluorouracil (5-FU) on tendon adhesions in partially divided profundus flexor tendons (flexor digitorum profundus [FDPs]) following surgical repair and in partially divided FDPs without surgical repair, and to compare the results of the repair versus the nonrepair of zone two injuries via macroscopic and biomechanical evaluations of tendon adhesions. METHODS: We used 32 adult male European rabbits (Oryctolagus cunniculus) weighing from 2.5 to 3.5 kg. The study was performed on the deep flexor tendons of the second and third digits of the right hind paws of the rabbits; thus, a total of 64 tendons were examined in this study. RESULTS: Based on the results achieved in our experimental study, the load (N) significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared with subgroup 2a in which tendons were surgically repaired and treated with 5-FU. CONCLUSIONS: The load (N) significantly increased in subgroup 1a in which the tendons were surgically repaired and were not treated with 5-FU compared to subgroup 2a in which the tendons were surgically repaired and treated with 5-FU. Therefore, these results revealed a decrease in adhesion formation in the subgroup that was treated with 5-FU due to increased resistance to tendon adhesions during their excursion through the tendon sheath, which in this case required greater traction force. PMID- 26063370 TI - Testin on Atherosclerosis in Rabbits. AB - BACKGROUND: The expression of TES, a novel tumor suppressor gene, is found to be down-regulated in the left anterior descending aorta of patients with coronary artery disease (CAD) compared with non-CAD subjects. This study aimed to investigate the expression of TES during the development of atherosclerosis in rabbits. METHODS: Thirty-two New Zealand rabbits were randomly divided into a normal diet (ND) and high-fat diet (HFD) groups. Body weight and serum lipid levels were measured at 0, 4, and 12 weeks after diet treatment. The degree of atherosclerosis in thoracic aortas was analyzed by histological examinations. The expression of Testin in the tissue samples was inspected via immunohistochemical and immunofluorescence confocal microscopy. Real time-polymerase chain reaction and Western blot analysis were performed to evaluate the expression of TES/Testin at mRNA and protein levels in the aortic tissues. RESULTS: After 12 weeks postenrollment, rabbits in HFD group had a higher level of serum lipids and atherosclerotic plaque compared to ND group (P < 0.05). Testin expression was detected at high levels in the endothelium and a weak expression on the subendothelium area. The expression of TES mRNA was markedly reduced by 10-fold in the aortic tissues in the HFD group compared with the ND group (P = 0.015), and the protein level was also significantly decreased in the HFD group (P < 0.05). CONCLUSIONS: Reduced TES/Testin expression is associated with the development of atherosclerosis, implicating a potentially important role in the pathogenesis of atherosclerosis. PMID- 26063371 TI - C-reactive Protein -717A>G and -286C>T>A Gene Polymorphism and Ischemic Stroke. AB - BACKGROUND: Inflammation plays a pivotal role in the formation and progression of ischemic stroke. Recently, more and more epidemiological studies have focused on the association between C-reactive protein (CRP) -717A > G and -286C > T > A genetic polymorphisms and ischemic stroke. However, the findings of these researches are not conclusive. METHODS: We performed a meta-analysis to determine whether these two polymorphisms are associated with the risk of ischemic stroke. Eligible studies were identified from the database of PubMed, Medline, Embase, Web of Science, CNKI, Weipu, and Wanfang. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) to assess the strength of the association. RESULTS: Four articles were included in our study, including 1926 cases and 2678 controls for -717A > G polymorphism, 652 cases and 1103 controls for -286C > T > A polymorphism. The results of meta-analysis showed that single nucleotide polymorphism (SNP) -717A > G was not significantly associated with the risk of ischemic stroke (GG vs. AA, OR = 1.12, 95% CI = 0.83-1.50, P = 0.207; GG + GA vs. AA, OR = 1.04, 95% CI = 0.93-1.17, P = 0.533; GG vs. GA + AA, OR = 1.10, 95% CI = 0.82-1.47, P = 0.220). Meta-analysis of SNP - 286C > T > A also demonstrated no statistical evidence of a significant association with the risk of ischemic stroke (AA vs. CC, OR = 0.86, 95% CI = 0.59-1.25, P = 0.348; AA vs. CC, OR = 0.92, 95% CI = 0.80-1.06, P = 0.609; AA vs. CC, OR = 0.89, 95% CI = 0.62-1.30, P = 0.374). CONCLUSIONS: This meta-analysis demonstrated little evidence to support a role of CRP gene -717A > G, -286C > T > A polymorphisms in ischemic stroke predisposition. However, to draw comprehensive and more reliable conclusions, further larger studies are needed to validate the association between CRP gene polymorphisms and ischemic stroke in various ethnic groups. PMID- 26063373 TI - Early Hypothermia for Refractory Status Epilepticus. PMID- 26063372 TI - Sirtuins Function as the Modulators in Aging-related Diseases in Common or Respectively. PMID- 26063374 TI - Distance, Depth and Puncture Angle for Cisterna Magna in Chinese Adults as Read from Magnetic Resonance Imaging. PMID- 26063375 TI - Sonographic Features and Diagnostic Analysis of Benign Chronic Inflammatory Breast Lesions in Nonlactating Women. PMID- 26063376 TI - Diagnosis and Management of 60 Children with Congenital Vascular Rings: A 10-year Experience. PMID- 26063377 TI - Hepatotoxicity Associated with a Short Course of Rosuvastatin. PMID- 26063378 TI - Noninvasive Measurement of Coronary Fractional Flow Reserve: An Under-exploiting Newland. PMID- 26063379 TI - Xanthogranulomatous Cholecystitis and Misdiagnosis Analysis. PMID- 26063380 TI - Left Circumflex Artery as a Terminal Extension of Right Coronary Artery. PMID- 26063381 TI - Letter Concerning: "Genotyping for Kidd, Kell, Duffy, Scianna, and RHCE Blood Group Antigens Polymorphisms in Jiangsu Chinese Han". PMID- 26063382 TI - Associations between hepatitis B virus basal core promoter/pre-core region mutations and the risk of acute-on-chronic liver failure: a meta-analysis. AB - BACKGROUND: Several studies have suggested a relationship between hepatitis B virus (HBV) basal core promoter/pre-core mutations and HBV-induced acute-on chronic liver failure (ACLF). Therefore, we evaluated this potential relationship using a meta-analysis. METHODS: Chinese or English studies from 1966 to January 31, 2014 were included in the analysis. A random or fixed-effects model was used to merge the odds ratios (ORs). RESULTS: We identified 31 case-control studies containing a total population of 1995 ACLF and 3822 chronic hepatitis B (CHB) patients. Several mutations were significantly correlated with ACLF: T1753V (1.889, 95 % confidence interval (CI) [1.357-2.631]), A1762T (2.696 [2.265 3.207]), G1764A (3.005 [2.077-4.347]), A1762T/G1764A (2.379 [1.519-3.727]), C1766T (1.849 [1.403-2.437]), T1768A (2.440 [1.405-3.494]), A1846T (3.163 [2.157 4.639]), G1896A (2.181 [1.800-2.642]), G1899A (3.569 [2.906-4.385]) and G1896A/A1762T/G1764A (1.575 [1.172-2.116]). Additionally, HBeAg-negative status was also statistically significant for the progression to ACLF (OR = 2.813, 95 % CI = 2.240-3.533, p < 0.001). However, there was no association between ACLF development and HBV genotype. CONCLUSIONS: The HBV basal core promoter/pre-core mutations T1753V, A1762T, G1764A, C1766T, T1768A, A1846T, G1896A and G1899A, and an HBeAg-negative status correlate with an increased risk of HBV-ACLF. PMID- 26063383 TI - Bioresorbable Vascular Scaffold Implantation for Successful Treatment of a Symptomatic Coronary Lesion in a 17-Year-Old Boy After Kawasaki Disease. AB - Coronary stenting is considered a promising treatment option for patients with coronary artery lesions caused by Kawasaki disease (KD). Here, we report the case of an adolescent with KD who successfully underwent implantation of a fully bioresorbable vascular scaffold (BVS) in a Kawasaki-related, highly obstructed coronary artery. Control coronary angiography 6 months later showed a remaining good result without restenosis or development of aneurysm. Cardial MRI and clinical follow-up revealed stable results at 6 and 18 months without any signs of ischemia. To our knowledge, this is the first report of a successful implantation of a fully bioresorbable vascular scaffold in a young adult with the history of KD. The case illustrates the feasibility and safety of BVS implantation for the treatment of KD. It remains to be confirmed by further studies, if this approach by this novel material might be a therapeutic alternative to coronary bypass grafting or other coronary interventions. PMID- 26063384 TI - The immunocheckpoints in modern oncology: the next 15 years. AB - The notion that the immune system can act as a key factor in controlling cancer cell proliferation and thus its stimulation may be an important resource for cancer therapy has long been known. Tumors can elude the immune system by deploying proteins that shut down the immune response by binding to specific surface receptors on immune cells. Several promising strategies have been designed to overcome cancer cells' ability to suppress the immune surveillance. Immune checkpoint molecules that block cytotoxic T-lymphocyte associated antigen 4 (ipilimumab) or the programmed death-1/programmed death-ligand 1 axis (i.e., nivolumab and pembrolizumab) promote antitumor immunity, reactivating T-cell proliferation and activity. This efficient strategy currently represents one of the major oncological breakthroughs, with impressive clinically durable responses observed in cancer patients, particularly in melanoma, renal cell carcinoma, NSCLC and more recently in bladder cancer patients. Fifteen years ago, we replaced the IL-2 and INF-alpha for molecular targeted therapies. Today, we believe that immune therapy will represent the future, perhaps as part of a combination of different therapeutic strategies that act synergistically in each tumor and individual patient. PMID- 26063385 TI - Fecal microbiota transplantation for Clostridium difficile infection: back to the future. AB - INTRODUCTION: Clostridium difficile infection (CDI) is a leading cause of diarrhea in the industrialized world. The estimated costs of this infection are impressive: over 3.2 billion dollars annually in the US. The introduction of fecal microbiota transplantation (FMT) to clinical practice can be considered a Copernican Revolution. The rationale of this approach consists of correcting the imbalance of the organisms dwelling in the gut by reintroducing a normal flora. AREAS COVERED: This review focuses on the indication for FMT in CDI; it examines in-depth the most relevant aspects of the techniques used, and the safety and efficacy of this new 'old' therapy. EXPERT OPINION: Authoritative guidelines about the management of CDI strongly recommend FMT for multiple recurrent episodes of infection by C. difficile unresponsive to repeated antibiotic treatment. The cure rates are about 90%, with no serious adverse events having been reported. The main concerns are the long-term outcomes, lack of a standardized procedure for the delivery of donor material, and a cultural barrier to the transplantation of fecal microbiota. A promising solution to some of these problems could be the use of a more acceptable administration route of fecal material, namely, oral capsules. PMID- 26063386 TI - Metreleptin and generalized lipodystrophy and evolving therapeutic perspectives. AB - INTRODUCTION: Metreleptin was recently approved by the Food and Drug Administration for the treatment of generalized lipodystrophy, a condition characterized by leptin deficiency. Its efficacy as hormone replacement therapy suggests broader applications in diseases also characterized by leptin abnormalities, such as familial partial lipodystrophy (FPLD), non-alcoholic fatty liver disease (NAFLD), and common obesity. Metreleptin, in conjunction with other pharmacologic interventions, has the potential to address one of the most widespread epidemics of our time, obesity. AREAS COVERED: This review covers the physiology of leptin, the pharmacologic properties of recombinant methionyl human leptin (R-metHu-Leptin, metreleptin), evidence for metreleptin's efficacy in the treatment of generalized lipodystrophy from both completed and ongoing clinical trials, safety concerns, and future directions in metreleptin research. EXPERT OPINION: Metreleptin's approval for generalized lipodystrophy is the first step in defining and expanding its role to other metabolic diseases. Clinical trials are underway to delineate its efficacy in FPLD, human immunodeficiency virus/highly active anti-retroviral therapy-associated acquired lipodystrophy (HAL), and NAFLD. Additionally, there is growing data that support a therapeutic role in obesity. One of the barriers to development, however, is metreleptin's safety and immunogenicity. Further advances in biologic compatibility are required before metreleptin can be approved for additional indications. PMID- 26063388 TI - Counseling at a Seizure Clinic Does Not Ensure Disclosure to the Transportation Registry. AB - BACKGROUND: The effectiveness of current self-reporting driving laws for medically-unfit potential seizure patients is unknown in Canada. We designed a prospective cohort study of patients' self-reporting practices to the local Transportation Registry (TR) and their driving behaviors following detailed counselling at a seizure clinic in a discretionary physician-reporting jurisdiction. METHODS: Medically unfit drivers, referred to our seizure clinic, who had a valid driver's permit at the time of their episode of impaired consciousness were included. Patients' self-reporting and driving behaviours were assessed using a standardized interview prior to a neurologist's counseling and later at a follow-up visit. RESULTS: Sixty three patients were included; 77% were diagnosed as having had a seizure at the time of their referral. Prior to their seizure clinic visit, 3/63 (5%) had been counseled to self-report to the TR by a non-neurologist physician, and none had done so. Following a neurologist's documented counseling 34/63 (54%) had self-reported themselves at the follow-up seizure clinic visit, and 53/63 (84%) were not driving. CONCLUSION: This prospective study design is the first in North America to examine self-reporting rates for unfit drivers with a seizure disorder. Our findings suggest that self reporting laws do not ensure high rates of self-reporting behaviors even when patients seen at a seizure clinic are appropriately counseled of their legal obligations. The rate of driving cessation appears greater than the rate of self reporting to the TR among counseled patients. PMID- 26063389 TI - The Chromatin Remodeler SPLAYED Negatively Regulates SNC1-Mediated Immunity. AB - SNC1 (SUPPRESSOR OF NPR1, CONSTITUTIVE 1) is one of a suite of intracellular Arabidopsis NOD-like receptor (NLR) proteins which, upon activation, result in the induction of defense responses. However, the molecular mechanisms underlying NLR activation and the subsequent provocation of immune responses are only partially characterized. To identify negative regulators of NLR-mediated immunity, a forward genetic screen was undertaken to search for enhancers of the dwarf, autoimmune gain-of-function snc1 mutant. To avoid lethality resulting from severe dwarfism, the screen was conducted using mos4 (modifier of snc1, 4) snc1 plants, which display wild-type-like morphology and resistance. M2 progeny were screened for mutant, snc1-enhancing (muse) mutants displaying a reversion to snc1 like phenotypes. The muse9 mos4 snc1 triple mutant was found to exhibit dwarf morphology, elevated expression of the pPR2-GUS defense marker reporter gene and enhanced resistance to the oomycete pathogen Hyaloperonospora arabidopsidis Noco2. Via map-based cloning and Illumina sequencing, it was determined that the muse9 mutation is in the gene encoding the SWI/SNF chromatin remodeler SYD (SPLAYED), and was thus renamed syd-10. The syd-10 single mutant has no observable alteration from wild-type-like resistance, although the syd-4 T-DNA insertion allele displays enhanced resistance to the bacterial pathogen Pseudomonas syringae pv. maculicola ES4326. Transcription of SNC1 is increased in both syd-4 and syd-10. These data suggest that SYD plays a subtle, specific role in the regulation of SNC1 expression and SNC1-mediated immunity. SYD may work with other proteins at the chromatin level to repress SNC1 transcription; such regulation is important for fine-tuning the expression of NLR-encoding genes to prevent unpropitious autoimmunity. PMID- 26063390 TI - Quantitative RT-PCR Platform to Measure Transcript Levels of C and N Metabolism Related Genes in Durum Wheat: Transcript Profiles in Elevated [CO2] and High Temperature at Different Levels of N Supply. AB - Only limited public transcriptomics resources are available for durum wheat and its responses to environmental changes. We developed a quantitative reverse transcription-PCR (qRT-PCR) platform for analysing the expression of primary C and N metabolism genes in durum wheat in leaves (125 genes) and roots (38 genes), based on available bread wheat genes and the identification of orthologs of known genes in other species. We also assessed the expression stability of seven reference genes for qRT-PCR under varying environments. We therefore present a functional qRT-PCR platform for gene expression analysis in durum wheat, and suggest using the ADP-ribosylation factor as a reference gene for qRT-PCR normalization. We investigated the effects of elevated [CO(2)] and temperature at two levels of N supply on C and N metabolism by combining gene expression analysis, using our qRT-PCR platform, with biochemical and physiological parameters in durum wheat grown in field chambers. Elevated CO(2) down-regulated the photosynthetic capacity and led to the loss of N compounds, including Rubisco; this effect was exacerbated at low N. Mechanistically, the reduction in photosynthesis and N levels could be associated with a decreased transcription of the genes involved in photosynthesis and N assimilation. High temperatures increased stomatal conductance, and thus did not inhibit photosynthesis, even though Rubisco protein and activity, soluble protein, leaf N, and gene expression for C fixation and N assimilation were down-regulated. Under a future scenario of climate change, the extent to which C fixation capacity and N assimilation are down-regulated will depend upon the N supply. PMID- 26063391 TI - Chlamydomonas Flavodiiron Proteins Facilitate Acclimation to Anoxia During Sulfur Deprivation. AB - The flavodiiron proteins (FDPs) are involved in the detoxification of oxidative compounds, such as nitric oxide (NO) or O(2) in Archaea and Bacteria. In cyanobacteria, the FDPs Flv1 and Flv3 are essential in the light-dependent reduction of O(2) downstream of PSI. Phylogenetic analysis revealed that two genes (flvA and flvB) in the genome of Chlamydomonas reinhardtii show high homology to flv1 and flv3 genes of the cyanobacterium Synechocystis sp. PCC 6803. The physiological role of these FDPs in eukaryotic green algae is not known, but it is of a special interest since these phototrophic organisms perform oxygenic photosynthesis similar to higher plants, which do not possess FDP homologs. We have analyzed the levels of flvA and flvB transcripts in C. reinhardtii cells under various environmental conditions and showed that these genes are highly expressed under ambient CO(2) levels and during the early phase of acclimation to sulfur deprivation, just before the onset of anaerobiosis and the induction of efficient H(2) photoproduction. Importantly, the increase in transcript levels of the flvA and flvB genes was also corroborated by protein levels. These results strongly suggest the involvement of FLVA and FLVB proteins in alternative electron transport. PMID- 26063392 TI - Sucrose Transporter AtSUC9 Mediated by a Low Sucrose Level is Involved in Arabidopsis Abiotic Stress Resistance by Regulating Sucrose Distribution and ABA Accumulation. AB - Sucrose (Suc) transporters (SUCs or SUTs) are important regulators in plant growth and stress tolerance. However, the mechanism of SUCs in plant abiotic stress resistance remains to be dietermined. Here, we found that AtSUC9 expression was induced by abiotic stress, including salt, osmotic and cold stress conditions. Disruption of AtSUC9 led to sensitive responses to abiotic stress during seed germination and seedling growth. Further analyses indicated that the sensitivity phenotype of Atsuc9 mutants resulted from higher Suc content in shoots and lower Suc content in roots, as compared with that in wild-type (WT) plants. In addition, we found that the expression of AtSUC9 is induced in particular by low levels of exogenous and endogenous Suc, and deletion of AtSUC9 affected the expression of the low Suc level-responsive genes. AtSUC9 also showed an obvious response to treatments with low concentrations of exogenous Suc during seed germination, seedling growth and Suc distribution, and Atsuc9 mutants hardly grew in abiotic stress treatments without exogenous Suc. Moreover, our results illustrated not only that deletion of AtSUC9 blocks abiotic stress-inducible ABA accumulation but also that Atsuc9 mutants had a lower content of endogenous ABA in stress conditions than in normal conditions. Deletion of AtSUC9 also inhibited the expression of many ABA-inducible genes (SnRk2.2/3/6, ABF2/3/4, ABI1/3/4, RD29A, KIN1 and KIN2). These results indicate that AtSUC9 is induced in particular by low Suc levels then mediates the balance of Suc distribution and promotes ABA accumulation to enhance Arabidopsis abiotic stress resistance. PMID- 26063393 TI - Essential Role of Acyl-ACP Synthetase in Acclimation of the Cyanobacterium Synechococcus elongatus Strain PCC 7942 to High-Light Conditions. AB - Most organisms capable of oxygenic photosynthesis have an aas gene encoding an acyl-acyl carrier protein synthetase (Aas), which activates free fatty acids (FFAs) via esterification to acyl carrier protein. Cyanobacterial aas mutants are often used for studies aimed at photosynthetic production of biofuels because the mutation leads to intracellular accumulation of FFAs and their secretion into the external medium, but the physiological significance of the production of FFAs and their recycling involving Aas has remained unclear. Using an aas-deficient mutant of Synechococcus elongatus strain PCC 7942, we show here that remodeling of membrane lipids is activated by high-intensity light and that the recycling of FFAs is essential for acclimation to high-light conditions. Unlike wild-type cells, the mutant cells could not increase their growth rate as the light intensity was increased from 50 to 400 umol photons m(-2) s(-1), and the high light-grown mutant cells accumulated FFAs and the lysolipids derived from all the four major classes of membrane lipids, revealing high-light-induced lipid deacylation. The high-light-grown mutant cells showed much lower PSII activity and Chl contents as compared with the wild-type cells or low-light-grown mutant cells. The loss of Aas accelerated photodamage of PSII but did not affect the repair process of PSII, indicating that PSII is destabilized in the mutant. Thus, Aas is essential for acclimation of the cyanobacterium to high-light conditions. The relevance of the present finding s to biofuel production using cyanobacteria is discussed. PMID- 26063394 TI - Dynamics of the Light-Dependent Transition of Plant Peroxisomes. AB - Peroxisomes are present in almost all plant cells. These organelles are involved in various metabolic processes, such as lipid catabolism and photorespiration. A notable feature of plant peroxisomes is their flexible adaptive responses to environmental conditions such as light. When plants shift from heterotrophic to autotrophic growth during the post-germinative stage, peroxisomes undergo a dynamic response, i.e. enzymes involved in lipid catabolism are replaced with photorespiratory enzymes. Although the detailed molecular mechanisms underlying the functional transition of peroxisomes have previously been unclear, recent analyses at the cellular level have enabled this detailed machinery to be characterized. During the functional transition, obsolete enzymes are degraded inside peroxisomes by Lon protease, while newly synthesized enzymes are transported into peroxisomes. In parallel, mature and oxidized peroxisomes are eliminated via autophagy; this functional transition occurs in an efficient manner. Moreover, it has become clear that quality control mechanisms are important for the peroxisomal response to environmental stimuli. In this review, we highlight recent advances in elucidating the molecular mechanisms required for the regulation of peroxisomal roles in response to changes in environmental conditions. PMID- 26063395 TI - Development and Application of a High-Resolution Imaging Mass Spectrometer for the Study of Plant Tissues. AB - Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) or imaging mass spectrometry (imaging MS) has been a powerful tool to map the spatial distribution of molecules on the surface of biological materials. This technique has frequently been applied to animal tissue slices for the purpose of mapping proteins, peptides, lipids, sugars or small metabolites to find disease-specific biomarkers or to study drug metabolism. Recently, it has also been applied to intact plant tissues or thin slices thereof using commercial mass spectrometers. The present work is concerned with the refinement of MALDI/laser desorption/ionization (LDI)-Fourier transform ion cyclotron resonance (FTICR)-MS incorporating certain specific features namely, ultra-high mass resolution (>100,000), ultra-high molecular mass accuracy (<1 p.p.m.) and high spatial resolution (<10 um) for imaging MS of plant tissues. Employing an in house built mass spectrometer, the imaging MS analysis of intact Arabidopsis thaliana tissues, namely etiolated seedlings and roots of seedlings, glued to a small transparent ITO (indium tin oxide)-coated conductive glass was performed. A matrix substance was applied to the vacuum-dried intact tissues by sublimation prior to the imaging MS analysis. The images of various small metabolites representing their two-dimensional distribution on the dried intact tissues were obtained with or without different matrix substances. The effects of MALDI matrices on the ionization of small metabolites during imaging MS acquisition are discussed. PMID- 26063396 TI - Erratum to: Inferior vena cava filters: current best practices. PMID- 26063397 TI - Opinion Paper: Modular Drug Delivery Systems for Personalized Oral Dosage Forms. PMID- 26063398 TI - Opinion Paper: Nanotechnology: A Successful Approach to Improve Oral Bioavailability of Phytochemicals. PMID- 26063399 TI - Patients' perception and satisfaction on quality of laboratory malaria diagnostic service in Amhara Regional State, North West Ethiopia. AB - BACKGROUND: The most effective strategies in the fight against malaria are to correctly diagnose and timely treat the illness. A diagnosis based on clinical symptoms alone is subjected to misuse of anti-malarial drugs, increased costs to the health services, patient dissatisfaction and also contributes to an increase in non-malaria morbidity and mortality. Among others, inappropriate perception and inadequate satisfaction of patients are significant challenges reported to affect the quality of laboratory malaria diagnostic services. METHODS: A facility based, cross-sectional study was conducted from November to December 2013 among 300 patients. Their level of satisfaction was measured using both pre-tested structured and open ended questionnaires. A 5-point Likert scales and their weighted average were used to categorize satisfaction level of the patients. Data were entered in Epi-Info version 3.5.3 and analysed using SPSS version 20. Chi square test was used to see the association between the outcome variable and independent and the strength of the association was identified using odds ratio in the binary logistic regression. In addition the open ended questionnaire findings were coded and analysed thematically. RESULTS: Over half (52.6%) of the patients were satisfied with the malaria diagnostic service with a 98.7% response rate. The majority (89.3%) of patients perceived they were well diagnosed in facing fever upon giving blood for laboratory malaria diagnosis within 30 min waiting time in most (62.5%) of the patients. Ethnicity, residence, knowing malaria diagnosis after consulting clinician, and time period to receive malaria result were the independent predictors for patient satisfaction (p<0.05). The open ended questionnaire responses also revealed providing precise laboratory result timely, availability of the right treatment, presence of health professionals performing the laboratory test upon request in the health facility were among the major enabling factors for patients' satisfaction. CONCLUSION: The observed level of satisfaction in the current study though encouraging when compared with some previous studies conducted in eastern Ethiopia on general laboratory services, still it requires scale-up in the enhancement of malaria laboratory diagnostic service in the fight against malaria. PMID- 26063400 TI - Impacts of (14)C discharges from a nuclear fuel reprocessing plant on surrounding vegetation: Comparison between grass field measurements and TOCATTA-chi and SSPAM(14)C model computations. AB - This article compares and discusses the ability of two different models to reproduce the observed temporal variability in grass (14)C activity in the vicinity of AREVA-NC La Hague nuclear fuel reprocessing plant in France. These two models are the TOCATTA-chi model, which is specifically designed for modelling transfer of (14)C (and tritium) in the terrestrial environment over short to medium timescales (days to years), and SSPAM(14)C, which has been developed to model the transfer of (14)C in the soil-plant-atmosphere with consideration over both short and long timescales (days to thousands of years). The main goal of this article is to discuss the strengths and weaknesses of the models studied, and to investigate if modelling could be improved through consideration of a much higher level of detail of plant physiology and/or higher number of plant compartments. These models have been applied here to the La Hague field data as it represents a medium term data set with both short term variation and a sizeable time series of measurements against which to compare the models. The two models have different objectives in terms of the timescales they are intended to be applied over, and thus incorporate biological processes, such as photosynthesis and plant growth, at different levels of complexity. It was found that the inclusion of seasonal dynamics in the models improved predictions of the specific activity in grass for such a source term of atmospheric (14)C. PMID- 26063401 TI - Distal Biceps Tendon Ruptures: An Epidemiological Analysis Using a Large Population Database. AB - BACKGROUND: The incidence of distal biceps tendon ruptures was studied more than 10 years ago in a small patient cohort. Recent diagnostic advancements have improved the ability to detect this rare injury. HYPOTHESIS: The incidence of distal biceps tendon ruptures will be significantly greater than previously reported. STUDY DESIGN: Descriptive epidemiologic study. METHODS: A query of the PearlDiver Technologies national database containing public and private insurance patients was used to estimate the national incidence of distal biceps tendon ruptures in the United States. A retrospective chart review of our local population identified demographic groups and risk factors that increased likelihood of injury. RESULTS: The estimated national incidence of distal biceps tendon rupture was 2.55 per 100,000 patient-years. The local incidence was 5.35 per 100,000 patient-years. The mean and median ages of patients in our regional cohort were 46.3 and 46 years, respectively. Males composed the majority of the injured population (national 95%, regional 96%). Smoking and elevated body mass index were found to be associated with increased likelihood of injury, while diabetes mellitus showed no association. CONCLUSION: The incidence of distal biceps tendon ruptures in this study was higher than previously reported. PMID- 26063402 TI - A Biomechanical Comparison of an Open Repair and 3 Minimally Invasive Percutaneous Achilles Tendon Repair Techniques During a Simulated, Progressive Rehabilitation Protocol. AB - BACKGROUND: While the nonoperative management of Achilles tendon ruptures is a viable option, surgical repair is preferred in healthy and active populations. Recently, minimally invasive percutaneous repair methods with assistive devices have been developed. HYPOTHESIS/PURPOSE: The purpose of this study was to biomechanically analyze 3 commercially available, minimally invasive percutaneous techniques compared with an open Achilles repair during a simulated, progressive rehabilitation program. It was hypothesized that no significant biomechanical differences would exist between repair techniques. STUDY DESIGN: Controlled laboratory study. METHODS: A simulated, midsubstance Achilles rupture was created 6 cm proximal to the calcaneal insertion in 33 fresh-frozen cadaveric ankles. Specimens were then randomly allocated to 1 of 4 different Achilles repair techniques: (1) open repair, (2) the Achillon Achilles Tendon Suture System, (3) the PARS Achilles Jig System, or (4) an Achilles Midsubstance SpeedBridge Repair variation. Repairs were subjected to a cyclic loading protocol representative of progressive postoperative rehabilitation: 250 cycles at 1 Hz for each loading range: 20-100 N, 20-200 N, 20-300 N, and 20-400 N. RESULTS: The open repair technique demonstrated significantly less elongation (5.2 +/- 1.1 mm) when compared with all minimally invasive percutaneous repair methods after 250 cycles (P < .05). No significant differences were observed after 250 cycles between the Achillon, PARS, or SpeedBridge repairs, with mean displacements of 9.9 +/- 2.2 mm, 12.2 +/- 4.4 mm, and 10.0 +/- 3.9 mm, respectively. When examined over smaller cyclic intervals, the majority of elongation, regardless of repair, occurred within the first 10 cycles. Within the first 10 cycles, open repairs achieved 71.2% of the total elongation observed after 250 cycles. Corresponding values for the Achillon, PARS, and SpeedBridge repairs were 81.8%, 77.9%, and 69.0%, respectively. No significant differences were observed in the total number of cycles to failure between minimally invasive percutaneous repairs and open repairs. Minor differences in the mechanism of failure were noted; however, the majority of all repairs failed at the suture-tendon interface. CONCLUSION: Minimally invasive percutaneous repair techniques demonstrated a susceptibility to significant early repair elongation when compared with open repairs. However, the ultimate strengths of repairs (cycles to failure) were comparable across all techniques. CLINICAL RELEVANCE: The reduced early elongation of open repairs suggests that patients treated with this technique may be able to progress through an earlier and/or more aggressive postoperative rehabilitation protocol with a lower risk of early irrevocable repair elongation or gapping about the repair site. However, in cases where cosmesis or wound-healing complications are of significant concern, minimally invasive percutaneous techniques provide a biomechanically reasonable alternative based on their repair strengths (cycles to failure). These repairs may need to be protected longer postoperatively to allow for biological healing and avoid early repair elongation and potential gapping between the healing tendon ends. PMID- 26063403 TI - Diurnal questing behavior of Amblyomma mixtum (Acari: Ixodidae). AB - The diurnal questing behavior of Amblyomma mixtum Koch was monitored in the laboratory while held on a 12:12 diurnal cycle, and outdoors, using actographic chambers to determine the daily incidences of questing for a host. Nymphs and adults increased their questing activity during the morning. Adult activity peaked in the morning and continued until afternoon, whereas nymphal activity peaked in the afternoon. Nymphs and adults returned to the bottom of the chambers at night. The questing pattern for nymphs held outdoors was similar to that observed indoors. Both nymphs and adults had a higher average questing height when held at 95% RH than at 56% RH. The increase in average questing height was found to be due to fewer ticks questing-and for adults, a decrease in the mean questing height-at lower RH. PMID- 26063404 TI - Regulation of three isoforms of SOD gene by environmental stresses in citrus red mite, Panonychus citri. AB - Superoxide dismutase (SOD) is a family of enzymes with multiple isoforms that possess antioxidative abilities in response to environmental stresses. Panonychus citri is one of the most important pest mites and has a global distribution. In this study, three distinct isoforms of SOD were cloned from P. citri and identified as cytoplasmic Cu-ZnSOD (PcSOD1), extracellular Cu-ZnSOD (PcSOD2), and mitochondrial MnSOD (PcSOD3). mRNA expression level analysis showed that all three isoforms were up-regulated significantly after exposure to the acaricide abamectin and to UV-B ultraviolet irradiation. In particular, PcSOD3 was up regulated under almost all environmental stresses tested. The fold change of PcSOD3 expression was significantly higher than those of the two Cu-ZnSOD isoforms. Taken together, the results indicate that abamectin and UV-B can induce transcripts of all three SOD isoforms in P. citri. Furthermore, PcSOD3 seems to play a more important role in P. citri tolerance to oxidative stress. PMID- 26063405 TI - Lack of acquired resistance in dogs to successive infestations of Rhipicephalus sanguineus ticks from Brazil and Argentina. AB - Comparative studies between brown dog tick Rhipicephalus sanguineus populations from Brazil (Jaboticabal, Sao Paulo) and Argentina (Rafaela, Santa Fe) showed significant biological, morphological and genetic differences between them. This work aimed to study, in a comparative way, the acquisition of resistance in domestic dogs to R. sanguineus from Jaboticabal and Rafaela, after successive and controlled infestations. Ticks were kept in a BOD incubator under controlled conditions (27 degrees C, 80 % relative humidity, 12-h photoperiod). Ten dogs, Dachshund breed, males and females, 6 months old, short- or long-haired, without prior contact with ticks, were used as hosts. They were distributed into two experimental groups composed of five animals each: G1 infested with ten adult couples of R. sanguineus (Jaboticabal) per animal, and G2 infested with ten adult couples of R. sanguineus (Rafaela) per animal. Ticks' biological parameters and titration of antibodies from the dogs' sera by ELISA test were used for comparison between the strains. Results of the biological parameters showed that the dogs did not acquire immunity to either of the R. sanguineus strains after repeated infestations. The ELISA test showed low antibody titers in sera of dogs from G2, in successive infestations, and higher antibody responses post second and third infestations in G1. It also demonstrated cross-reactivity between sera of dogs infested with R. sanguineus (Jaboticabal) and antigens from R. sanguineus (Rafaela) and vice versa. We conclude that Dachshund dogs did not develop resistance against neither Jaboticabal nor Rafaela strains of R. sanguineus. PMID- 26063407 TI - Transcatheter arterial chemoembolization combined with CT-guided percutaneous thermal ablation versus hepatectomy in the treatment of hepatocellular carcinoma. AB - INTRODUCTION: Transcatheter arterial chemoembolization (TACE) plus thermal ablation has been widely used recently in the treatment of hepatocellular carcinoma (HCC). In this study, we aimed to compare results of the combination of TACE and percutaneous thermal ablation with those of hepatectomy in patients with HCC. METHODS: The clinical data of 137 HCC patients who sequentially received TACE and computed tomography (CT)-guided percutaneous thermal ablation as an initial curative treatment (combination group) and 148 matched HCC patients who received hepatectomy (surgery group) between 2004 and 2011 were collected and analyzed. After TACE, multiphase contrast-enhanced CT was performed to identify the total number of tumors as well as lipiodol deposition in the liver. Survival was calculated by using the Kaplan-Meier method and compared by using the log rank test. The prognostic factors were assessed with multivariate Cox proportional hazards regression analysis. RESULTS: Of all 285 patients, 225 (79.0%) had cancerous lesions<=5 cm in diameter. In preoperative contrast enhanced CT or magnetic resonance imaging, the number of tumors was 1-4 for each patient. The 1-, 3-, and 5-year overall survival rates were 95, 74%, and 67% in the combination group and 88, 66, and 47% in the surgery group, respectively (P=0.004); the corresponding recurrence-free survival rates for the two groups were 92, 69, and 61% and 75, 58, and 44%, respectively (P=0.001). In the multivariate analysis, treatment allocation was an independent prognostic factor for survival. Only 60 patients in the combination group had sufficient imaging data, and 135 new lesions with lipiodol deposition were diagnosed as malignancies in 22 of 60 patients, whereas 20 new lesions were found in 11 of 148 patients in the surgery group. CONCLUSION: The combination of TACE and CT-guided percutaneous thermal ablation for HCC improves survival of HCC patients compared with hepatectomy. PMID- 26063408 TI - Bisphenol A affects placental layers morphology and angiogenesis during early pregnancy phase in mice. AB - Bisphenol A (BPA) is a widespread endocrine disrupter mainly used in food contact plastics. Much evidence supports the adverse effects of BPA, particularly on susceptible groups such as pregnant women. The present study considered placental development - relevant for pregnancy outcomes and fetal nutrition/programming - as a potential target of BPA. Pregnant CD-1 mice were administered per os with vehicle, 0.5 (BPA05) or 50 mg kg(-1) (BPA50) body weight day(-1) of BPA, from gestational day (GD) 1 to GD11. At GD12, BPA50 induced significant degeneration and necrosis of giant cells, increased vacuolization in the junctional zone in the absence of glycogen accumulation and reduction of the spongiotrophoblast layer. In addition, BPA05 induced glycogen depletion as well as significant nuclear accumulation of beta-catenin in trophoblasts of labyrinthine and spongiotrophoblast layers, supporting the activation of the Wnt/beta-catenin pathway. Transcriptomic analysis indicated that BPA05 promoted and BPA50 inhibited blood vessel development and branching; morphologically, maternal vessels were narrower in BPA05 placentas, whereas embryonic and maternal vessels were irregularly dilated in the labyrinth of BPA50 placentas. Quantitative polymerase chain reaction evidenced an estrogen receptor beta induction by BPA50, which did not correspond to downstream genes activation; indeed, the transcription factor binding sites analysis supported the AhR/Arnt complex as regulator of BPA50-modulated genes. Conversely, Creb appeared as the main transcription factor regulating BPA05-modulated genes. Embryonic structures (head, forelimb) showed divergent perturbations upon BPA05 or BPA50 exposure, potentially related to unbalanced embryonic nutrition and/or to modulation of genes involved in embryo development. Our findings support placenta as an important target of BPA, even at environmentally relevant dose levels. PMID- 26063409 TI - Preoperative platelet/lymphocyte ratio is a superior prognostic factor compared to other systemic inflammatory response markers in ovarian cancer patients. AB - The aim of the present study was to determine the most meaningful preoperative prognostic factor of cancer-related death in ovarian cancer patients by comparing potentially prognostic systemic inflammatory response (SIR) markers. The levels of fibrinogen, albumin, C-reactive protein (CRP), and serum cancer antigen-125 (CA-125) and the neutrophil/lymphocyte ratio (NLR) and platelet/lymphocyte ratio (PLR) were evaluated in 190 ovarian cancer patients to identify predictors of overall survival (OS) and progression-free survival (PFS) using univariate and multivariate analyses. Patients with a PLR >203 had a shorter PFS and OS than the patients in PLR <=203 group (11 vs. 24 months and 28 vs. 64 months). Univariate analyses revealed that tumor stage, postoperative residual tumor mass, ascites, and the levels of all SIR markers were associated with PFS and OS. Multivariate analysis revealed that PLR was independently associated with PFS (hazard ratio [HR] 1.852, 95% confidence interval [CI] 1.271-2.697, P = 0.001) and OS (HR 2.158, 95%CI 1.468-3.171, P < 0.001), as well as tumor stage and postoperative residual tumor mass. In contrast, fibrinogen remained significant only for PFS (HR 1.724, 95%CI 1.197-2.482, P = 0.003). Patients with a PLR >203 were more prone to have advanced tumor stage (P = 0.002), postoperative residual tumor mass >2 cm (P = 0.032), malignant ascites (P < 0.001), and all the other elevated SIR markers (P < 0.001). Preoperative PLR is superior to other SIR markers (CA-125, NLR, fibrinogen, CRP, and albumin) as a predictor of survival in ovarian cancer patients. PMID- 26063411 TI - Clinical and radiologic outcomes associated with the use of dynamic locking screws (DLS) in distal tibia fractures. AB - BACKGROUND: The locked screw plate construct is often cited as being too rigid and prolonging healing in patients with metaphyseal fractures. The newly introduced dynamic locking screws (DLS) allow 0.2 mm of axial motion, which should optimize healing near the near cortex. The purpose of this study was to analyze the clinical results of dynamic locking screws in distal tibia fractures. METHODS: Data were acquired retrospectively. Only distal meta-diaphyseal tibia fractures treated with minimally invasive plate osteosynthesis and DLS were evaluated. Cortical and locking head screws were used for distal plate fixation to minimize soft tissue irritation over the medial malleolus, and DLS were used in the proximal plate fixation. Clinical and radiographic data were evaluated after 6 weeks, 3 months, 6 months and 1 year until fracture union. RESULTS: Twenty-two patients were treated with minimally invasive plate osteosynthesis and DLS. Six patients could not be evaluated because they returned to a foreign residence after the procedure. Fourteen fractures healed after a mean of 3.1 months. Two fractures with insufficient reduction showed delayed union and healed after 9 and 9.5 months, respectively. The callus index peaked at 6 months. CONCLUSIONS: Dynamic fracture fixation might be a promising concept to reduce the frequency of metaphyseal non-unions in distal tibia fractures. But nevertheless, the dynamic construct cannot compensate for insufficient reduction. PMID- 26063412 TI - Children are not young adults: a call for standardized guidelines for dealing with pediatric patients in the emergency department of Canadian community hospitals. PMID- 26063410 TI - Shogaol overcomes TRAIL resistance in colon cancer cells via inhibiting of survivin. AB - In this study, we showed the ability of representative shogaol, which as a major component of ginger, to overcome TRAIL resistance by increasing apoptosis in colon cancer cells. Shogaol increased death receptor 5 (DR5) levels. Furthermore, shogaol decreased the expression level of antiapoptotic proteins (survivin and Bcl-2) and increased pro-apoptotic protein, Bax. Shogaol treatment induced apoptosis and a robust reduction in the levels of the antiapoptotic protein survivin but did not affect the levels of many other apoptosis regulators. Moreover, knockdown of survivin sensitized colon cancer cells to resistant of TRAIL-induced apoptosis. Therefore, we showed the functions of shogaol as a sensitizing agent to induce cell death of TRAIL-resistant colon cancer cells. This study gives rise to the possibility of applying shogaol as an antitumor agent that can be used for the purpose of combination treatment with TRAIL in TRAIL-resistant colon tumor therapy. PMID- 26063413 TI - microRNA-513c suppresses the proliferation of human glioblastoma cells by repressing low-density lipoprotein receptor-related protein 6. AB - Aberrant activation of the Wnt/beta-catenin signaling pathway is frequently observed in glioblastoma (GBM) cells. Therefore, it was hypothesized that low density lipoprotein receptor-related protein 6 (LRP6) may be involved in activating the Wnt/beta-catenin pathway in the progression of GBM. The present study reported that the expression of microRNA (miR)-513c was markedly downregulated in GBM cells and GBM tissues compared with that in normal human astrocytes and normal brain tissues. Previous studies have demonstrated that miR 513c is critical in a variety of biological processes in various human cancer cells. The role of this miR in GBM cells was therefore investigated in the present study. Ectopic expression of miR-513c reduced the proliferation and anchorage-independent growth of GBM cells, whereas inhibition of miR-513c promoted this effect. Bioinformatic analysis further identified LRP6, a putative tumor suppressor, as a potential target of miR-513c. Luciferase reporter assays revealed that miR-513c directly bound to the 3'-untranslated region of LRP6 mRNA and repressed the expression at the transcriptional as well as the translational level. In functional assays, miR-513c suppressed GBM cell proliferation, which was reversed by an inhibitor of miR-513c. In conclusion, the present study provided compelling evidence that miR-513c functions as a tumor suppressor miRNA, which may be important in the inhibition of cell proliferation in GBM. In addition, the tumor suppressive effects were mediated predominantly through the direct suppression of the expression of LRP6. PMID- 26063414 TI - Cleaved high-molecular-weight kininogen inhibits neointima formation following vascular injury. AB - Cleaved high-molecular-weight kininogen (HKa) or its peptide domain 5 (D5) alone exert anti-adhesive properties in vitro related to impeding integrin-mediated cellular interactions. However, the anti-adhesive effects of HKa in vivo remain elusive. In this study, we investigated the effects of HKa on leukocyte recruitment and neointima formation following wire-induced injury of the femoral artery in C57BL/6 mice. Local application of HKa significantly reduced the accumulation of monocytes and also reduced neointimal lesion size 14 days after injury. Moreover, C57BL/6 mice transplanted with bone marrow from transgenic mice expressing enhanced green fluorescence protein (eGFP) showed a significantly reduced accumulation of eGFP+-cells at the arterial injury site and decreased neointimal lesion size after local application of HKa or the polypeptide D5 alone. A differentiation of accumulating eGFP+-cells into highly specific smooth muscle cells (SMC) was not detected in any group. In contrast, application of HKa significantly reduced the proliferation of locally derived neointimal cells. In vitro, HKa and D5 potently inhibited the adhesion of SMC to vitronectin, thus impairing their proliferation, migration, and survival rates. In conclusion, application of HKa or D5 decreases the inflammatory response to vascular injury and exerts direct effects on SMC by impeding the binding of integrins to extracellular matrix components. Therefore, HKa and D5 may hold promise as novel therapeutic substances to prevent neointima formation. PMID- 26063415 TI - Proliferation rate and breast cancer subtype, but not ALDH1 expression, predict pathological response to neoadjuvant chemotherapy in locally advanced breast cancer. AB - For locally advanced breast cancer, pathological complete response (pCR) following neoadjuvant chemotherapy (NACT) is associated with good disease-free survival. In several studies, response to chemotherapy according to various parameters has shown strong inter-individual variability. We investigated whether different prognostic factors, including ALDH1 expression, might predict response to NACT in female patients with locally advanced breast carcinoma. ER, PR, Her2/neu, Ki-67 and ALDH1 immunohistochemistry were performed on the initial biopsy and subsequent resection specimens. Residual tumour burden was calculated in post NACT resection specimens using residual cancer burden (RCB) protocol. Of our cohort of 66 patients, 24 (36 %) achieved pCR. Triple negative phenotype and high Ki-67 proliferative index (>40 %) were significantly associated with good response to NACT. ALDH1 expression in tumour epithelial (20 %) or stromal (44 %) cells did not correlate with tumour grade, molecular subtype, proliferative index or NACT response. However, epithelial and stromal ALDH1 expression was significantly increased in residual tumour after NACT. In conclusion, triple negative phenotype and high proliferative index, but not ALDH1 expression, are predictive of good pathological response to NACT. Increased ALDH1 expression following NACT might be associated with a higher probability of recurrent disease. PMID- 26063416 TI - PROX1 is involved in progression of rectal neuroendocrine tumors, NETs. AB - PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little is known about the molecular pathogenesis of rectal NETs or their metastasis propensity. The objectives were to find out whether PROX1 plays a role in progression of rectal NETs and whether it has value as prognostic marker. In grading of rectal NETs, we applied the WHO 2010 classification. We carried out immunohistochemical staining of PROX1 on 72 primary tumors and six metastases and evaluated nuclear positivity in each tumor. Correlation between PROX1 expression, metastasis and patient survival was then assessed. Annexin A1, a downstream target of PROX1, was immunohistochemically assessed in 18 tumors. PROX1 protein was detected in about half of the tumors, with stronger expression in metastasized cases. PROX1 expression correlated with tumor metastasis and patient prognosis. Annexin A1 was negative in most of the high-grade tumors correlating strongly with grade and metastatic potential. Our results indicate that immunohistochemical detection of PROX1 correlates with a more malignant phenotype in rectal NETs. High PROX1 expression was associated with increased metastatic potential and poor patient survival but not as strongly as grade by the WHO 2010 classification. PROX1 may be involved in progression of rectal NETs as a part of the Wnt pathway. PMID- 26063417 TI - Differential Impact of In Vivo CD8+ T Lymphocyte Depletion in Controller versus Progressor Simian Immunodeficiency Virus-Infected Macaques. AB - Numerous studies have demonstrated that CD8(+) T lymphocytes suppress virus replication during human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection. However, the mechanisms underlying this activity of T cells remain incompletely understood. Here, we conducted CD8(+) T lymphocyte depletion in 15 rhesus macaques (RMs) infected intravenously (i.v.) with SIVmac239. At day 70 postinfection, the animals (10 progressors with high viremia and 5 controllers with low viremia) were CD8 depleted by i.v. administration of the antibody M-T807R1. As expected, CD8 depletion resulted in increased virus replication, more prominently in controllers than progressors, which correlated inversely with predepletion viremia. Of note, the feature of CD8(+) T lymphocyte predepletion that correlated best with the increase in viremia postdepletion was the level of CD8(+) T-bet(+) lymphocytes. We next found that CD8 depletion resulted in a homogenous increase of SIV RNA in superficial and mesenteric lymph nodes, spleen, and the gastrointestinal tract of both controllers and progressors. Interestingly, the level of SIV DNA increased postdepletion in both CD4(+) central memory T lymphocytes (TCM) and CD4(+) effector memory T lymphocytes (TEM) in progressor RMs but decreased in the CD4(+) TCM of 4 out of 5 controllers. Finally, we found that CD8 depletion is associated with a greater increase in CD4(+) T lymphocyte activation (measured by Ki-67 expression) in controllers than in progressors. Overall, these data reveal a differential impact of CD8(+) T lymphocyte depletion between controller and progressor SIV-infected RMs, emphasizing the complexity of the in vivo antiviral role of CD8(+) T lymphocytes. IMPORTANCE: In this study, we further dissect the impact of CD8(+) T lymphocytes on HIV/SIV replication during SIV infection. CD8(+) T lymphocyte depletion leads to a relatively homogenous increase in viral replication in peripheral blood and tissues. CD8(+) T lymphocyte depletion resulted in a more prominent increase in viral loads and CD4(+) T lymphocyte activation in controllers than in progressors. Interestingly, we found T-bet expression on CD8(+) T lymphocytes to be the best predictor of viral load increase following depletion. The levels of SIV DNA increase postdepletion in both CD4(+) TCM and TEM in progressor RMs but decrease in the CD4(+) TCM of controllers. The findings described in this study provide key insights into the differential functions of CD8(+) T lymphocytes in controller and progressor RMs. PMID- 26063418 TI - The Canonical Immediate Early 3 Gene Product pIE611 of Mouse Cytomegalovirus Is Dispensable for Viral Replication but Mediates Transcriptional and Posttranscriptional Regulation of Viral Gene Products. AB - Transcription of mouse cytomegalovirus (MCMV) immediate early ie1 and ie3 is controlled by the major immediate early promoter/enhancer (MIEP) and requires differential splicing. Based on complete loss of genome replication of an MCMV mutant carrying a deletion of the ie3-specific exon 5, the multifunctional IE3 protein (611 amino acids; pIE611) is considered essential for viral replication. Our analysis of ie3 transcription resulted in the identification of novel ie3 isoforms derived from alternatively spliced ie3 transcripts. Construction of an IE3-hemagglutinin (IE3-HA) virus by insertion of an in-frame HA epitope sequence allowed detection of the IE3 isoforms in infected cells, verifying that the newly identified transcripts code for proteins. This prompted the construction of an MCMV mutant lacking ie611 but retaining the coding capacity for the newly identified isoforms ie453 and ie310. Using Deltaie611 MCMV, we demonstrated the dispensability of the canonical ie3 gene product pIE611 for viral replication. To determine the role of pIE611 for viral gene expression during MCMV infection in an unbiased global approach, we used label-free quantitative mass spectrometry to delineate pIE611-dependent changes of the MCMV proteome. Interestingly, further analysis revealed transcriptional as well as posttranscriptional regulation of MCMV gene products by pIE611. IMPORTANCE: Cytomegaloviruses are pathogenic betaherpesviruses persisting in a lifelong latency from which reactivation can occur under conditions of immunosuppression, immunoimmaturity, or inflammation. The switch from latency to reactivation requires expression of immediate early genes. Therefore, understanding of immediate early gene regulation might add insights into viral pathogenesis. The mouse cytomegalovirus (MCMV) immediate early 3 protein (611 amino acids; pIE611) is considered essential for viral replication. The identification of novel protein isoforms derived from alternatively spliced ie3 transcripts prompted the construction of an MCMV mutant lacking ie611 but retaining the coding capacity for the newly identified isoforms ie453 and ie310. Using Deltaie611 MCMV, we demonstrated the dispensability of the canonical ie3 gene product pIE611 for viral replication and delineated pIE611 dependent changes of the MCMV proteome. Our findings have fundamental implications for the interpretation of earlier studies on pIE3 functions and highlight the complex orchestration of MCMV gene regulation. PMID- 26063419 TI - Epidemiology, Evolution, and Recent Outbreaks of Avian Influenza Virus in China. AB - Novel reassortants of H7N9, H10N8, and H5N6 avian influenza viruses (AIVs) are currently circulating in China's poultry flocks, occasionally infecting humans and other mammals. Combined with the sometimes enzootic H5N1 and H9N2 strains, this cauldron of genetically diverse AIVs pose significant risks to public health. Here, we review the epidemiology, evolution, and recent outbreaks of AIVs in China, discuss reasons behind the recent increase in the emergence of novel AIVs, and identify warning signs which may point to the emergence of a potentially virulent and highly transmissible AIV to humans. This review will be useful to authorities who consider options for the detection and control of AIV transmission in animals and humans, with the goal of preventing future epidemics and pandemics. PMID- 26063420 TI - Marine Snails and Slugs: a Great Place To Look for Antiviral Drugs. AB - Molluscs, comprising one of the most successful phyla, lack clear evidence of adaptive immunity and yet thrive in the oceans, which are rich in viruses. There are thought to be nearly 120,000 species of Mollusca, most living in marine habitats. Despite the extraordinary abundance of viruses in oceans, molluscs often have very long life spans (10 to 100 years). Thus, their innate immunity must be highly effective at countering viral infections. Antiviral compounds are a crucial component of molluscan defenses against viruses and have diverse mechanisms of action against a wide variety of viruses, including many that are human pathogens. Antiviral compounds found in abalone, oyster, mussels, and other cultured molluscs are available in large supply, providing good opportunities for future research and development. However, most members of the phylum Mollusca have not been examined for the presence of antiviral compounds. The enormous diversity and adaptations of molluscs imply a potential source of novel antiviral compounds for future drug discovery. PMID- 26063421 TI - Identification of Owl Monkey CD4 Receptors Broadly Compatible with Early-Stage HIV-1 Isolates. AB - Most HIV-1 variants isolated from early-stage human infections do not use nonhuman primate versions of the CD4 receptor for cellular entry, or they do so poorly. We and others have previously shown that CD4 has experienced strong natural selection over the course of primate speciation, but it is unclear whether this selection has influenced the functional characteristics of CD4 as an HIV-1 receptor. Surprisingly, we find that selection on CD4 has been most intense in the New World monkeys, animals that have never been found to harbor lentiviruses related to HIV-1. Based on this, we sampled CD4 genetic diversity within populations of individuals from seven different species, including five species of New World monkeys. We found that some, but not all, CD4 alleles found in Spix's owl monkeys (Aotus vociferans) encode functional receptors for early stage human HIV-1 isolates representing all of the major group M clades (A, B, C, and D). However, only some isolates of HIV-1 subtype C can use the CD4 receptor encoded by permissive Spix's owl monkey alleles. We characterized the prevalence of functional CD4 alleles in a colony of captive Spix's owl monkeys and found that 88% of surveyed individuals are homozygous for permissive CD4 alleles, which encode an asparagine at position 39 of the receptor. We found that the CD4 receptors encoded by two other species of owl monkeys (Aotus azarae and Aotus nancymaae) also serve as functional entry receptors for early-stage isolates of HIV-1. IMPORTANCE: Nonhuman primates, particularly macaques, are used for preclinical evaluation of HIV-1 vaccine candidates. However, a significant limitation of the macaque model is the fact that most circulating HIV-1 variants cannot use the macaque CD4 receptor to enter cells and have to be adapted to these species. This is particularly true for viral variants from early stages of infection, which represent the most relevant vaccine targets. In this study, we found that some individuals from captive owl monkey populations harbor CD4 alleles that are compatible with a broad collection of HIV-1 isolates, including those isolated from early in infection in highly affected populations and representing diverse subtypes. PMID- 26063422 TI - Context-Dependent Cleavage of the Capsid Protein by the West Nile Virus Protease Modulates the Efficiency of Virus Assembly. AB - The molecular mechanisms that define the specificity of flavivirus RNA encapsulation are poorly understood. Virions composed of the structural proteins of one flavivirus and the genomic RNA of a heterologous strain can be assembled and have been developed as live attenuated vaccine candidates for several flaviviruses. In this study, we discovered that not all combinations of flavivirus components are possible. While a West Nile virus (WNV) subgenomic RNA could readily be packaged by structural proteins of the DENV2 strain 16681, production of infectious virions with DENV2 strain New Guinea C (NGC) structural proteins was not possible, despite the very high amino acid identity between these viruses. Mutagenesis studies identified a single residue (position 101) of the DENV capsid (C) protein as the determinant for heterologous virus production. C101 is located at the P1' position of the NS2B/3 protease cleavage site at the carboxy terminus of the C protein. WNV NS2B/3 cleavage of the DENV structural polyprotein was possible when a threonine (Thr101 in strain 16681) but not a serine (Ser101 in strain NGC) occupied the P1' position, a finding not predicted by in vitro protease specificity studies. Critically, both serine and threonine were tolerated at the P1' position of WNV capsid. More extensive mutagenesis revealed the importance of flanking residues within the polyprotein in defining the cleavage specificity of the WNV protease. A more detailed understanding of the context dependence of viral protease specificity may aid the development of new protease inhibitors and provide insight into associated patterns of drug resistance. IMPORTANCE: West Nile virus (WNV) and dengue virus (DENV) are mosquito-borne flaviviruses that cause considerable morbidity and mortality in humans. No specific antiflavivirus therapeutics are available for treatment of infection. Proteolytic processing of the flavivirus polyprotein is an essential step in the replication cycle and is an attractive target for antiviral development. The design of protease inhibitors has been informed by insights into the molecular details of the interactions of proteases and their substrates. In this article, studies of the processing of WNV and DENV capsid proteins by the WNV protease identified an unexpected contribution of the sequence surrounding critical residues within the cleavage site on protease specificity. This demonstration of context-dependent protease cleavage has implications for the design of chimeric flaviviruses, new therapeutics, and the interpretation of flavivirus protease substrate specificity studies. PMID- 26063423 TI - Characterization of Ribosomal Frameshifting in Theiler's Murine Encephalomyelitis Virus. AB - Theiler's murine encephalomyelitis virus (TMEV) is a member of the genus Cardiovirus in the Picornaviridae, a family of positive-sense single-stranded RNA viruses. Previously, we demonstrated that in the related cardiovirus, Encephalomyocarditis virus, a programmed-1 ribosomal frameshift (1 PRF) occurs at a conserved G_GUU_UUU sequence within the 2B-encoding region of the polyprotein open reading frame (ORF). Here we show that-1 PRF occurs at a similar site during translation of the TMEV genome. In addition, we demonstrate that a predicted 3= RNA stem-loop structure at a noncanonical spacing downstream of the shift site is required for efficient frameshifting in TMEV and that frameshifting also requires virus infection. Mutating the G_GUU_UUU shift site to inhibit frameshifting results in an attenuated virus with reduced growth kinetics and a small-plaque phenotype. Frameshifting in the virus context was found to be extremely efficient at 74 to 82%, which, to our knowledge, is the highest frameshifting efficiency recorded to date for any virus. We propose that highly efficient-1 PRF in TMEV provides a mechanism to escape the confines of equimolar expression normally inherent in the single-polyprotein expression strategy of picornaviruses. PMID- 26063424 TI - African Swine Fever Virus Georgia 2007 with a Deletion of Virulence-Associated Gene 9GL (B119L), when Administered at Low Doses, Leads to Virus Attenuation in Swine and Induces an Effective Protection against Homologous Challenge. AB - African swine fever virus (ASFV) is the etiological agent of an often lethal disease of domestic pigs. Disease control strategies have been hampered by the unavailability of vaccines against ASFV. Since its introduction in the Republic of Georgia, a highly virulent virus, ASFV Georgia 2007 (ASFV-G), has caused an epizootic that spread rapidly into Eastern European countries. Currently no vaccines are available or under development to control ASFV-G. In the past, genetically modified ASFVs harboring deletions of virulence-associated genes have proven attenuated in swine, inducing protective immunity against challenge with homologous parental viruses. Deletion of the gene 9GL (open reading frame [ORF] B119L) in highly virulent ASFV Malawi-Lil-20/1 produced an attenuated phenotype even when administered to pigs at 10(6) 50% hemadsorption doses (HAD50). Here we report the construction of a genetically modified ASFV-G strain (ASFV-G Delta9GLv) harboring a deletion of the 9GL (B119L) gene. Like Malawi-Lil-20/1 Delta9GL, ASFV-G-Delta9GL showed limited replication in primary swine macrophages. However, intramuscular inoculation of swine with 10(4) HAD50 of ASFV G-Delta9GL produced a virulent phenotype that, unlike Malawi-Lil-20/1-Delta9GL, induced a lethal disease in swine like parental ASFV-G. Interestingly, lower doses (10(2) to 10(3) HAD50) of ASFV-G-Delta9GL did not induce a virulent phenotype in swine and when challenged protected pigs against disease. A dose of 10(2) HAD50 of ASFV-G-Delta9GLv conferred partial protection when pigs were challenged at either 21 or 28 days postinfection (dpi). An ASFV-G-Delta9GL HAD50 of 10(3) conferred partial and complete protection at 21 and 28 dpi, respectively. The information provided here adds to our recent report on the first attempts toward experimental vaccines against ASFV-G. IMPORTANCE: The main problem for controlling ASF is the lack of vaccines. Studies on ASFV virulence lead to the production of genetically modified attenuated viruses that induce protection in pigs but only against homologous virus challenges. Here we produced a recombinant ASFV lacking virulence-associated gene 9GL in an attempt to produce a vaccine against virulent ASFV-G, a highly virulent virus isolate detected in the Caucasus region in 2007 and now spreading though the Caucasus region and Eastern Europe. Deletion of 9GL, unlike with other ASFV isolates, did not attenuate completely ASFV-G. However, when delivered once at low dosages, recombinant ASFV-G-Delta9GL induces protection in swine against parental ASFV-G. The protection against ASFV-G is highly effective after 28 days postvaccination, whereas at 21 days postvaccination, animals survived the lethal challenge but showed signs of ASF. Here we report the design and development of an experimental vaccine that induces protection against virulent ASFV-G. PMID- 26063425 TI - Restriction of HIV-1 Requires the N-Terminal Region of MxB as a Capsid-Binding Motif but Not as a Nuclear Localization Signal. AB - The interferon alpha (IFN-alpha)-inducible restriction factor MxB blocks HIV-1 infection after reverse transcription but prior to integration. Fate-of-capsid experiments have correlated the ability of MxB to block HIV-1 infection with stabilization of viral cores during infection. We previously demonstrated that HIV-1 restriction by MxB requires capsid binding and oligomerization. Deletion and gain-of-function experiments have mapped the HIV-1 restriction ability of MxB to its N-terminal 25 amino acids. This report reveals that the N-terminal 25 amino acids of MxB exhibit two separate functions: (i) the ability of MxB to bind to HIV-1 capsid and (ii) the nuclear localization signal of MxB, which is important for the ability of MxB to shuttle into the nucleus. To understand whether MxB restriction of HIV-1 requires capsid binding and/or nuclear localization, we genetically separated these two functions and evaluated their contributions to restriction. Our experiments demonstrated that the (11)RRR(13) motif is important for the ability of MxB to bind capsid and to restrict HIV-1 infection. These experiments suggested that capsid binding is necessary for the ability of MxB to block HIV-1 infection. Separately from the capsid binding function of MxB, we found that residues (20)KY(21) regulate the ability of the N terminal 25 amino acids of MxB to function as a nuclear localization signal; however, the ability of the N-terminal 25 amino acids to function as a nuclear localization signal was not required for restriction. IMPORTANCE: MxB/Mx2 blocks HIV-1 infection in cells from the immune system. MxB blocks infection by preventing the uncoating process of HIV-1. The ability of MxB to block HIV-1 infection requires that MxB binds to the HIV-1 core by using its N-terminal domain. The present study shows that MxB uses residues (11)RRR(13) to bind to the HIV-1 core during infection and that these residues are required for the ability of MxB to block HIV-1 infection. We also found that residues (20)KY(21) constitute a nuclear localization signal that is not required for the ability of MxB to block HIV-1 infection. PMID- 26063426 TI - SIRT1 Suppresses Human T-Cell Leukemia Virus Type 1 Transcription. AB - Human T-cell leukemia virus type 1 (HTLV-1)-associated diseases are poorly treatable, and HTLV-1 vaccines are not available. High proviral load is one major risk factor for disease development. HTLV-1 encodes Tax oncoprotein, which activates transcription from viral long terminal repeats (LTR) and various types of cellular promoters. Counteracting Tax function might have prophylactic and therapeutic benefits. In this work, we report on the suppression of Tax activation of HTLV-1 LTR by SIRT1 deacetylase. The transcriptional activity of Tax on the LTR was largely ablated when SIRT1 was overexpressed, but Tax activation of NF-kappaB was unaffected. On the contrary, the activation of the LTR by Tax was boosted when SIRT1 was depleted. Treatment of cells with resveratrol shunted Tax activity in a SIRT1-dependent manner. The activation of SIRT1 in HTLV-1-transformed T cells by resveratrol potently inhibited HTLV-1 proviral transcription and Tax expression, whereas compromising SIRT1 by specific inhibitors augmented HTLV-1 mRNA expression. The administration of resveratrol also decreased the production of cell-free HTLV-1 virions from MT2 cells and the transmission of HTLV-1 from MT2 cells to uninfected Jurkat cells in coculture. SIRT1 associated with Tax in HTLV-1-transformed T cells. Treatment with resveratrol prevented the interaction of Tax with CREB and the recruitment of CREB, CRTC1, and p300 to Tax-responsive elements in the LTR. Our work demonstrates the negative regulatory function of SIRT1 in Tax activation of HTLV 1 transcription. Small-molecule activators of SIRT1 such as resveratrol might be considered new prophylactic and therapeutic agents in HTLV-1-associated diseases. IMPORTANCE: Human T-cell leukemia virus type 1 (HTLV-1) causes a highly lethal blood cancer or a chronic debilitating disease of the spinal cord. Treatments are unsatisfactory, and vaccines are not available. Disease progression is associated with robust expression of HTLV-1 genes. Suppressing HTLV-1 gene expression might have preventive and therapeutic benefits. It is therefore critical that host factors controlling HTLV-1 gene expression be identified and characterized. This work reveals a new host factor that suppresses HTLV-1 gene expression and a natural compound that activates this suppression. Our findings not only provide new knowledge of the host control of HTLV-1 gene expression but also suggest a new strategy of using natural compounds for prevention and treatment of HTLV-1 associated diseases. PMID- 26063427 TI - Rotavirus NSP3 Is a Translational Surrogate of the Poly(A) Binding Protein Poly(A) Complex. AB - Through its interaction with the 5' translation initiation factor eIF4G, poly(A) binding protein (PABP) facilitates the translation of 5'-capped and 3'-poly(A) tailed mRNAs. Rotavirus mRNAs are capped but not polyadenylated, instead terminating in a 3' GACC motif that is recognized by the viral protein NSP3, which competes with PABP for eIF4G binding. Upon rotavirus infection, viral, GACC tailed mRNAs are efficiently translated, while host poly(A)-tailed mRNA translation is, in contrast, severely impaired. To explore the roles of NSP3 in these two opposing events, the translational capabilities of three capped mRNAs, distinguished by either a GACC, a poly(A), or a non-GACC and nonpoly(A) 3' end, have been monitored after electroporation of cells expressing all rotavirus proteins (infected cells) or only NSP3 (stably or transiently transfected cells). In infected cells, we found that the magnitudes of translation induction (GACC tailed mRNA) and translation reduction [poly(A)-tailed mRNA] both depended on the rotavirus strain used but that translation reduction not genetically linked to NSP3. In transfected cells, even a small amount of NSP3 was sufficient to dramatically enhance GACC-tailed mRNA translation and, surprisingly, to slightly favor the translation of both poly(A)- and nonpoly(A)-tailed mRNAs, likely by stabilizing the eIF4E-eIF4G interaction. These data suggest that NSP3 is a translational surrogate of the PABP-poly(A) complex; therefore, it cannot by itself be responsible for inhibiting the translation of host poly(A)-tailed mRNAs upon rotavirus infection. IMPORTANCE: To control host cell physiology and to circumvent innate immunity, many viruses have evolved powerful mechanisms aimed at inhibiting host mRNA translation while stimulating translation of their own mRNAs. How rotavirus tackles this challenge is still a matter of debate. Using rotavirus-infected cells, we show that the magnitude of cellular poly(A) mRNA translation differs with respect to rotavirus strains but is not genetically linked to NSP3. Using cells expressing rotavirus NSP3, we show that NSP3 alone not only dramatically enhances rotavirus-like mRNA translation but also enhances poly(A) mRNA translation rather than inhibiting it, likely by stabilizing the eIF4E-eIF4G complex. Thus, the inhibition of cellular polyadenylated mRNA translation during rotavirus infection cannot be attributed solely to NSP3 and is more likely the result of global competition between viral and host mRNAs for the cellular translation machinery. PMID- 26063428 TI - Infection Patterns Induced in Naive Adult Woodchucks by Virions of Woodchuck Hepatitis Virus Collected during either the Acute or Chronic Phase of Infection. AB - The infectivity of hepadnavirus virions produced during either acute or chronic stages of infection was compared by testing the ability of the virions of woodchuck hepatitis virus (WHV) to induce productive acute infection in naive adult woodchucks. Serum WHV collected during acute infection was compared to virions harvested from WHV-infected woodchucks during either (i) early chronic infection, when WHV-induced hepatocellular carcinoma (HCC) was not yet developed, or (ii) late chronic infection, when established HCC was terminal. All tested types of WHV inoculum were related, because they were collected from woodchucks that originally were infected with standardized WHV7 inoculum. Despite the individual differences between animals, the kinetics of accumulation of serum relaxed circular DNA of WHV demonstrated that the virions produced during early or late chronic infection are fully capable of inducing productive acute infection with long-lasting high viremia. These findings were further supported by the analysis of such intrahepatic markers of WHV infection as replicative intermediate DNA, covalently closed circular DNA, pregenomic RNA, and the percentage of WHV core antigen-positive hepatocytes measured at several time points over the course of 17.5 weeks after the inoculation. In addition, the observed relationship between the production of antibodies against WHV surface antigens and parameters of WHV infection appears to be complex. Taken together, the generated data suggest that in vivo hepadnavirus virions produced during different phases of chronic infection did not demonstrate any considerable deficiencies in infectivity compared to that of virions generated during the acute phase of infection. IMPORTANCE: The generated data suggest that infectivity of virions produced during the early or late stages of chronic hepadnavirus infection is not compromised. Our novel results provided several lines of further evidence supporting the idea that during the state of chronic infection in vivo, the limitations of hepadnavirus cell-to-cell spread/superinfection (observed recently in the woodchuck model) are not due to the diminished infectivity of the virions circulating in the blood and likely are (i) related to the properties of hepatocytes (i.e., their capacity to support hepadnavirus infection/replication) and (ii) influenced by the immune system. The obtained results further extend the understanding of the mechanisms regulating the persistence of hepadnavirus infection. Follow-up studies that will further investigate hepadnavirus cell-to cell spread as a potential regulator of the chronic state of the infection are warranted. PMID- 26063429 TI - Characterization of a Novel Megabirnavirus from Sclerotinia sclerotiorum Reveals Horizontal Gene Transfer from Single-Stranded RNA Virus to Double-Stranded RNA Virus. AB - Mycoviruses have been detected in all major groups of filamentous fungi, and their study represents an important branch of virology. Here, we characterized a novel double-stranded RNA (dsRNA) mycovirus, Sclerotinia sclerotiorum megabirnavirus 1 (SsMBV1), in an apparently hypovirulent strain (SX466) of Sclerotinia sclerotiorum. Two similarly sized dsRNA segments (L1- and L2-dsRNA), the genome of SsMBV1, are packaged in rigid spherical particles purified from strain SX466. The full-length cDNA sequence of L1-dsRNA/SsMBV1 comprises two large open reading frames (ORF1 and ORF2), which encode a putative coat protein and an RNA-dependent RNA polymerase (RdRp), respectively. Phylogenetic analysis of the RdRp domain clearly indicates that SsMBV1 is related to Rosellinia necatrix megabirnavirus 1 (RnMBV1). L2-dsRNA/SsMBV1 comprises two nonoverlapping ORFs (ORFA and ORFB) encoding two hypothetical proteins with unknown functions. The 5'-terminal regions of L1- and L2-dsRNA/SsMBV1 share strictly conserved sequences and form stable stem-loop structures. Although L2-dsRNA/SsMBV1 is dispensable for replication, genome packaging, and pathogenicity of SsMBV1, it enhances transcript accumulation of L1-dsRNA/SsMBV1 and stability of virus-like particles (VLPs). Interestingly, a conserved papain-like protease domain similar to a multifunctional protein (p29) of Cryphonectria hypovirus 1 was detected in the ORFA-encoded protein of L2-dsRNA/SsMBV1. Phylogenetic analysis based on the protease domain suggests that horizontal gene transfer may have occurred from a single-stranded RNA (ssRNA) virus (hypovirus) to a dsRNA virus, SsMBV1. Our results reveal that SsMBV1 has a slight impact on the fundamental biological characteristics of its host regardless of the presence or absence of L2 dsRNA/SsMBV1. IMPORTANCE: Mycoviruses are widespread in all major fungal groups, and they possess diverse genomes of mostly ssRNA and dsRNA and, recently, circular ssDNA. Here, we have characterized a novel dsRNA virus (Sclerotinia sclerotiorum megabirnavirus 1 [SsMBV1]) that was isolated from an apparently hypovirulent strain, SX466, of Sclerotinia sclerotiorum. Although SsMBV1 is phylogenetically related to RnMBV1, SsMBV1 is markedly distinct from other reported megabirnaviruses with two features of VLPs and conserved domains. Our results convincingly showed that SsMBV1 is viable in the absence of L2 dsRNA/SsMBV1 (a potential large satellite-like RNA or genuine genomic virus component). More interestingly, we detected a conserved papain-like protease domain that commonly exists in ssRNA viruses, including members of the families Potyviridae and Hypoviridae. Phylogenetic analysis based on the protease domain suggests that horizontal gene transfer might have occurred from an ssRNA virus to a dsRNA virus, which may provide new insights into the evolutionary history of dsRNA and ssRNA viruses. PMID- 26063430 TI - Lower Respiratory Tract Infection of the Ferret by 2009 H1N1 Pandemic Influenza A Virus Triggers Biphasic, Systemic, and Local Recruitment of Neutrophils. AB - Infection of the lower respiratory tract by influenza A viruses results in increases in inflammation and immune cell infiltration in the lung. The dynamic relationships among the lung microenvironments, the lung, and systemic host responses during infection remain poorly understood. Here we used extensive systematic histological analysis coupled with live imaging to gain access to these relationships in ferrets infected with the 2009 H1N1 pandemic influenza A virus (H1N1pdm virus). Neutrophil levels rose in the lungs of H1N1pdm virus infected ferrets 6 h postinfection and became concentrated at areas of the H1N1pdm virus-infected bronchiolar epithelium by 1 day postinfection (dpi). In addition, neutrophil levels were increased throughout the alveolar spaces during the first 3 dpi and returned to baseline by 6 dpi. Histochemical staining revealed that neutrophil infiltration in the lungs occurred in two waves, at 1 and 3 dpi, and gene expression within microenvironments suggested two types of neutrophils. Specifically, CCL3 levels, but not CXCL8/interleukin 8 (IL-8) levels, were higher within discrete lung microenvironments and coincided with increased infiltration of neutrophils into the lung. We used live imaging of ferrets to monitor host responses within the lung over time with [(18)F]fluorodeoxyglucose (FDG). Sites in the H1N1pdm virus-infected ferret lung with high FDG uptake had high levels of proliferative epithelium. In summary, neutrophils invaded the H1N1pdm virus-infected ferret lung globally and focally at sites of infection. Increased neutrophil levels in microenvironments did not correlate with increased FDG uptake; hence, FDG uptake may reflect prior infection and inflammation of lungs that have experienced damage, as evidenced by bronchial regeneration of tissues in the lungs at sites with high FDG levels. IMPORTANCE: Severe influenza disease is characterized by an acute infection of the lower airways that may progress rapidly to organ failure and death. Well developed animal models that mimic human disease are essential to understanding the complex relationships of the microenvironment, organ, and system in controlling virus replication, inflammation, and disease progression. Employing the ferret model of H1N1pdm virus infection, we used live imaging and comprehensive histological analyses to address specific hypotheses regarding spatial and temporal relationships that occur during the progression of infection and inflammation. We show the general invasion of neutrophils at the organ level (lung) but also a distinct pattern of localized accumulation within the microenvironment at the site of infection. Moreover, we show that these responses were biphasic within the lung. Finally, live imaging revealed an early and sustained host metabolic response at sites of infection that may reflect damage and repair of tissues in the lungs. PMID- 26063432 TI - Two Mutations Were Critical for Bat-to-Human Transmission of Middle East Respiratory Syndrome Coronavirus. AB - To understand how Middle East respiratory syndrome coronavirus (MERS-CoV) transmitted from bats to humans, we compared the virus surface spikes of MERS-CoV and a related bat coronavirus, HKU4. Although HKU4 spike cannot mediate viral entry into human cells, two mutations enabled it to do so by allowing it to be activated by human proteases. These mutations are present in MERS-CoV spike, explaining why MERS-CoV infects human cells. These mutations therefore played critical roles in the bat-to-human transmission of MERS-CoV, either directly or through intermediate hosts. PMID- 26063431 TI - Lung CD8+ T Cell Impairment Occurs during Human Metapneumovirus Infection despite Virus-Like Particle Induction of Functional CD8+ T Cells. AB - Human metapneumovirus (HMPV) is a major cause of respiratory disease in infants, the elderly, and immunocompromised individuals worldwide. There is currently no licensed HMPV vaccine. Virus-like particles (VLPs) are an attractive vaccine candidate because they are noninfectious and elicit a neutralizing antibody response. However, studies show that serum neutralizing antibodies are insufficient for complete protection against reinfection and that adaptive T cell immunity is important for viral clearance. HMPV and other respiratory viruses induce lung CD8(+) T cell (TCD8) impairment, mediated by programmed death 1 (PD 1). In this study, we generated HMPV VLPs by expressing the fusion and matrix proteins in mammalian cells and tested whether VLP immunization induces functional HMPV-specific TCD8 responses in mice. C57BL/6 mice vaccinated twice with VLPs and subsequently challenged with HMPV were protected from lung viral replication for at least 20 weeks postimmunization. A single VLP dose elicited F- and M-specific lung TCD8s with higher function and lower expression of PD-1 and other inhibitory receptors than TCD8s from HMPV-infected mice. However, after HMPV challenge, lung TCD8s from VLP-vaccinated mice exhibited inhibitory receptor expression and functional impairment similar to those of mice experiencing secondary infection. HMPV challenge of VLP-immunized MUMT mice also elicited a large percentage of impaired lung TCD8s, similar to mice experiencing secondary infection. Together, these results indicate that VLPs are a promising vaccine candidate but do not prevent lung TCD8 impairment upon HMPV challenge. IMPORTANCE: Human metapneumovirus (HMPV) is a leading cause of acute respiratory disease for which there is no licensed vaccine. Virus-like particles (VLPs) are an attractive vaccine candidate and induce antibodies, but T cell responses are less defined. Moreover, HMPV and other respiratory viruses induce lung CD8(+) T cell (TCD8) impairment mediated by programmed death 1 (PD-1). In this study, HMPV VLPs containing viral fusion and matrix proteins elicited epitope-specific TCD8s that were functional with low PD-1 expression. Two VLP doses conferred sterilizing immunity in C57BL/6 mice and facilitated HMPV clearance in antibody deficient MUMT mice without enhancing lung pathology. However, regardless of whether responding lung TCD8s had previously encountered HMPV antigens in the context of VLPs or virus, similar proportions were impaired and expressed comparable levels of PD-1 upon viral challenge. These results suggest that VLPs are a promising vaccine candidate but do not prevent lung TCD8 impairment upon HMPV challenge. PMID- 26063433 TI - VP2 Exchange and NS3/NS3a Deletion in African Horse Sickness Virus (AHSV) in Development of Disabled Infectious Single Animal Vaccine Candidates for AHSV. AB - African horse sickness virus (AHSV) is a virus species in the genus Orbivirus of the family Reoviridae. There are nine serotypes of AHSV showing different levels of cross neutralization. AHSV is transmitted by species of Culicoides biting midges and causes African horse sickness (AHS) in equids, with a mortality rate of up to 95% in naive horses. AHS has become a serious threat for countries outside Africa, since endemic Culicoides species in moderate climates appear to be competent vectors for the related bluetongue virus (BTV). To control AHS, live attenuated vaccines (LAVs) are used in Africa. We used reverse genetics to generate "synthetic" reassortants of AHSV for all nine serotypes by exchange of genome segment 2 (Seg-2). This segment encodes VP2, which is the serotype determining protein and the dominant target for neutralizing antibodies. Single Seg-2 AHSV reassortants showed similar cytopathogenic effects in mammalian cells but displayed different growth kinetics. Reverse genetics for AHSV was also used to study Seg-10 expressing NS3/NS3a proteins. We demonstrated that NS3/NS3a proteins are not essential for AHSV replication in vitro. NS3/NS3a of AHSV is, however, involved in the cytopathogenic effect in mammalian cells and is very important for virus release from cultured insect cells in particular. Similar to the concept of the bluetongue disabled infectious single animal (BT DISA) vaccine platform, an AHS DISA vaccine platform lacking NS3/NS3a expression was developed. Using exchange of genome segment 2 encoding VP2 protein (Seg-2[VP2]), we will be able to develop AHS DISA vaccine candidates for all current AHSV serotypes. IMPORTANCE: African horse sickness virus is transmitted by species of Culicoides biting midges and causes African horse sickness in equids, with a mortality rate of up to 95% in naive horses. African horse sickness has become a serious threat for countries outside Africa, since endemic Culicoides species in moderate climates are supposed to be competent vectors. By using reverse genetics, viruses of all nine serotypes were constructed by the exchange of Seg-2 expressing the serotype-determining VP2 protein. Furthermore, we demonstrated that the nonstructural protein NS3/NS3a is not essential for virus replication in vitro. However, the potential spread of the virus by biting midges is supposed to be blocked, since the in vitro release of the virus was strongly reduced due to this deletion. VP2 exchange and NS3/NS3a deletion in African horse sickness virus were combined in the concept of a disabled infectious single animal vaccine for all nine serotypes. PMID- 26063434 TI - Human Papillomavirus Infectious Entry and Trafficking Is a Rapid Process. AB - Previous studies have indicated that human papillomavirus (HPV) infectious entry is slow, requiring many hours after initial infection for the virus to gain entry into the nucleus. However, intracellular transport pathways typically are very rapid, and in the context of a natural HPV infection in a wounded epithelium, such slow intracellular transport would seem to be at odds with a normal viral infection. Using synchronized cell populations, we show that HPV trafficking can be a rapid process. In cells that are infected in the late S-early G2/M phase of the cell cycle, HPV16 pseudovirion (PsV) reporter DNA gene expression is detectable by 8 h postinfection. Likewise, reporter DNA can be visualized within the nucleus in conjunction with PML nuclear bodies 1 h to 2 h postinfection in cells that are infected with PsVs just prior to mitotic entry. This demonstrates that endosomal trafficking of HPV is rapid, with mitosis being the main restriction on nuclear entry. IMPORTANCE: HPV infectious entry appears to be slow and requires mitosis to occur before the incoming viral DNA can access the nucleus. In this study, we show that HPV trafficking in the cell actually is very rapid. This demonstrates that in the context of a normal virus infection, the cell cycle state will have a major influence on the time it takes for an incoming virus to enter the nucleus and initiate viral gene expression. PMID- 26063435 TI - Novel Receptor Specificity of Avian Gammacoronaviruses That Cause Enteritis. AB - Viruses exploit molecules on the target membrane as receptors for attachment and entry into host cells. Thus, receptor expression patterns can define viral tissue tropism and might to some extent predict the susceptibility of a host to a particular virus. Previously, others and we have shown that respiratory pathogens of the genus Gammacoronavirus, including chicken infectious bronchitis virus (IBV), require specific alpha2,3-linked sialylated glycans for attachment and entry. Here, we studied determinants of binding of enterotropic avian gammacoronaviruses, including turkey coronavirus (TCoV), guineafowl coronavirus (GfCoV), and quail coronavirus (QCoV), which are evolutionarily distant from respiratory avian coronaviruses based on the viral attachment protein spike (S1). We profiled the binding of recombinantly expressed S1 proteins of TCoV, GfCoV, and QCoV to tissues of their respective hosts. Protein histochemistry showed that the tissue binding specificity of S1 proteins of turkey, quail, and guineafowl CoVs was limited to intestinal tissues of each particular host, in accordance with the reported pathogenicity of these viruses in vivo. Glycan array analyses revealed that, in contrast to the S1 protein of IBV, S1 proteins of enteric gammacoronaviruses recognize a unique set of nonsialylated type 2 poly-N-acetyl lactosamines. Lectin histochemistry as well as tissue binding patterns of TCoV S1 further indicated that these complex N-glycans are prominently expressed on the intestinal tract of various avian species. In conclusion, our data demonstrate not only that enteric gammacoronaviruses recognize a novel glycan receptor but also that enterotropism may be correlated with the high specificity of spike proteins for such glycans expressed in the intestines of the avian host. IMPORTANCE: Avian coronaviruses are economically important viruses for the poultry industry. While infectious bronchitis virus (IBV), a respiratory pathogen of chickens, is rather well known, other viruses of the genus Gammacoronavirus, including those causing enteric disease, are hardly studied. In turkey, guineafowl, and quail, coronaviruses have been reported to be the major causative agent of enteric diseases. Specifically, turkey coronavirus outbreaks have been reported in North America, Europe, and Australia for several decades. Recently, a gammacoronavirus was isolated from guineafowl with fulminating disease. To date, it is not clear why these avian coronaviruses are enteropathogenic, whereas other closely related avian coronaviruses like IBV cause respiratory disease. A comprehensive understanding of the tropism and pathogenicity of these viruses explained by their receptor specificity and receptor expression on tissues was therefore needed. Here, we identify a novel glycan receptor for enteric avian coronaviruses, which will further support the development of vaccines. PMID- 26063436 TI - Characterization of Two Human Monoclonal Antibodies Neutralizing Influenza A H7N9 Viruses. AB - H7N9 was a cause of significant global health concern due to its severe infection and approximately 35% mortality in humans. By screening a Fab antibody phage library derived from patients who recovered from H7N9 infections, we characterized two human monoclonal antibodies (HuMAbs), HNIgGD5 and HNIgGH8. The epitope of these two antibodies was dependent on two residues in the receptor binding site at positions V186 and L226 of the hemagglutinin glycoprotein. Both antibodies possessed high neutralizing activity. PMID- 26063437 TI - Identification of the Conformational transition pathway in PIP2 Opening Kir Channels. AB - The gating of Kir channels depends critically on phosphatidylinositol 4,5 bisphosphate (PIP2), but the detailed mechanism by which PIP2 regulates Kir channels remains obscure. Here, we performed a series of Targeted molecular dynamics simulations on the full-length Kir2.1 channel and, for the first time, were able to achieve the transition from the closed to the open state. Our data show that with the upward motion of the cytoplasmic domain (CTD) the structure of the C-Linker changes from a loop to a helix. The twisting of the C-linker triggers the rotation of the CTD, which induces a small downward movement of the CTD and an upward motion of the slide helix toward the membrane that pulls the inner helix gate open. At the same time, the rotation of the CTD breaks the interaction between the CD- and G-loops thus releasing the G-loop. The G-loop then bounces away from the CD-loop, which leads to the opening of the G-loop gate and the full opening of the pore. We identified a series of interaction networks, between the N-terminus, CD loop, C linker and G loop one by one, which exquisitely regulates the global conformational changes during the opening of Kir channels by PIP2. PMID- 26063438 TI - Cognitive impairment and associated loss in brain white microstructure in aircrew members exposed to engine oil fumes. AB - Cabin air in airplanes can be contaminated with engine oil contaminants. These contaminations may contain organophosphates (OPs) which are known neurotoxins to brain white matter. However, it is currently unknown if brain white matter in aircrew is affected. We investigated whether we could objectify cognitive complaints in aircrew and whether we could find a neurobiological substrate for their complaints. After medical ethical approval from the local institutional review board, informed consent was obtained from 12 aircrew (2 females, on average aged 44.4 years, 8,130 flying hours) with cognitive complaints and 11 well matched control subjects (2 females, 43.4 years, 233 flying hours). Depressive symptoms and self-reported cognitive symptoms were assessed, in addition to a neuropsychological test battery. State of the art Magnetic Resonance Imaging (MRI) techniques were administered that assess structural and functional changes, with a focus on white matter integrity. In aircrew we found significantly more self-reported cognitive complaints and depressive symptoms, and a higher number of tests scored in the impaired range compared to the control group. We observed small clusters in the brain in which white matter microstructure was affected. Also, we observed higher cerebral perfusion values in the left occipital cortex, and reduced brain activation on a functional MRI executive function task. The extent of cognitive impairment was strongly associated with white matter integrity, but extent of estimated number of flight hours was not associated with cognitive impairment nor with reductions in white matter microstructure. Defects in brain white matter microstructure and cerebral perfusion are potential neurobiological substrates for cognitive impairments and mood deficits reported in aircrew. PMID- 26063439 TI - Prenatal Programming of Postnatal Susceptibility to Memory Impairments: A Developmental Double Jeopardy. AB - In the study reported here, we examined the effects of fetal exposure to a synthetic stress hormone (synthetic glucocorticoids) on children's susceptibility to postnatal sociodemographic adversity. We recruited children who were born healthy and at term. Twenty-six had been treated with steroid hormones (glucocorticoids) during the prenatal period, and 85 had not. Only children exposed to both prenatal stress hormones and postnatal sociodemographic adversity showed impaired performance on standardized tests of memory function. The association was specific to long-term memory. General intellectual functioning and expressive language were not affected by fetal glucocorticoid exposure. Results were independent of maternal intelligence and maternal depression at the time of the study. These findings are consistent with a vulnerability-stress model: Prenatal exposure to synthetic stress hormones is associated with increased susceptibility to subsequent adversity, with consequences for cognitive functioning that persist 6 to 10 years after birth. PMID- 26063440 TI - Using Nonnaive Participants Can Reduce Effect Sizes. AB - Although researchers often assume their participants are naive to experimental materials, this is not always the case. We investigated how prior exposure to a task affects subsequent experimental results. Participants in this study completed the same set of 12 experimental tasks at two points in time, first as a part of the Many Labs replication project and again a few days, a week, or a month later. Effect sizes were markedly lower in the second wave than in the first. The reduction was most pronounced when participants were assigned to a different condition in the second wave. We discuss the methodological implications of these findings. PMID- 26063441 TI - Determinants of Propranolol's Selective Effect on Loss Aversion. AB - Research on emotion and decision making has suggested that arousal mediates risky decisions, but several distinct and often confounded processes drive such choices. We used econometric modeling to separate and quantify the unique contributions of loss aversion, risk attitudes, and choice consistency to risky decision making. We administered the beta-blocker propranolol in a double-blind, placebo-controlled within-subjects study, targeting the neurohormonal basis of physiological arousal. Matching our intervention's pharmacological specificity with a quantitative model delineating decision-making components allowed us to identify the causal relationships between arousal and decision making that do and do not exist. Propranolol selectively reduced loss aversion in a baseline- and dose-dependent manner (i.e., as a function of initial loss aversion and body mass index), and did not affect risk attitudes or choice consistency. These findings provide evidence for a specific, modulatory, and causal relationship between precise components of emotion and risky decision making. PMID- 26063443 TI - Oil diffusivity through fat crystal networks. AB - Oil migration in chocolate and chocolate-based confections leads to undesirable visual and textural changes. Establishing ways to slow this unavoidable process would increase shelf life and reduce consumer rejection. Diffusion is most often credited as the main pathway by which oil migration occurs. Here, we use fluorescence recovery after photobleaching (FRAP) to explore the diffusion coefficients of vegetable and mineral oil through fat crystal networks at different solid fat contents (SFC). Differences in compatibility between the fat and oil lead to unique primary crystal clusters, yet those variations do not affect diffusion at low SFCs. Trends deviate at higher SFCs, which we ascribe to the influence of the differing crystal cluster structures. We relate our results to the strong and weak-link rheological regimes of fat crystal networks. Finally, we connect the results to relationships developed for polymer gel systems. PMID- 26063442 TI - Seasonal gene expression kinetics between diapause phases in Drosophila virilis group species and overwintering differences between diapausing and non-diapausing females. AB - Most northern insect species experience a period of developmental arrest, diapause, which enables them to survive over the winter and postpone reproduction until favorable conditions. We studied the timing of reproductive diapause and its long-term effects on the cold tolerance of Drosophila montana, D. littoralis and D. ezoana females in seasonally varying environmental conditions. At the same time we traced expression levels of 219 genes in D. montana using a custom-made microarray. We show that the seasonal switch to reproductive diapause occurs over a short time period, and that overwintering in reproductive diapause has long lasting effects on cold tolerance. Some genes, such as Hsc70, Jon25Bi and period, were upregulated throughout the diapause, while others, including regucalcin, couch potato and Thor, were upregulated only at its specific phases. Some of the expression patterns induced during the sensitive stage, when the females either enter diapause or not, remained induced regardless of the later conditions. qPCR analyses confirmed the findings of the microarray analysis in D. montana and revealed similar gene expression changes in D. littoralis and D. ezoana. The present study helps to achieve a better understanding of the genetic regulation of diapause and of the plasticity of seasonal responses in general. PMID- 26063444 TI - Paenibacillus enshidis sp. nov., Isolated from the Nodules of Robinia pseudoacacia L. AB - A Gram-positive, motile, endospore-forming, rod-shaped bacterium, designated RP 207(T), was isolated from the nodules of Robinia pseudoacacia L. plants planted in Enshi District, Hubei, PR China. Phylogenetic analyses based on the 16S rRNA gene sequence showed that the novel strain was affiliated to the genus Paenibacillus, with its closest relatives being Paenibacillus xylanilyticus XIL14(T) (95.6%), Paenibacillus peoriae DSM8320(T) (95.3%) and Paenibacillus polymyxa DSM 36(T) (95.3%). The DNA G+C content was 47.0 mol%. DNA-DNA hybridization value between strain RP-207(T) and P. xylanilyticus XIL14(T) was 40.1%. The diamino acid found in the cell wall peptidoglycan was meso diaminopimelic. The major polar lipids were phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, an unidentified amino phospholipid and an unknown phospholipid. The predominant menaquinone was menaquinone-7 (MK-7), and the major fatty acid was anteiso-C15:0 and C16:0. On the basis of its physiological and biochemical characteristics and the level of DNA-DNA hybridization, strain RP-207(T) is considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus enshidis sp. nov. is proposed. The type strain is RP-207(T) (=CCTCC AB 2013275(T) = KCTC 33519(T)). PMID- 26063445 TI - Sequence Analysis of lip R: A Good Method for Molecular Epidemiology of Clinical Isolates of Mycobacterium tuberculosis. AB - Advances in DNA sequencing have greatly enhanced the molecular epidemiology studies. In order to assess evolutionary and phylogenetic relation of Mycobacterium tuberculosis isolates several gene targets were evaluated. In this study, appropriate fragments of 5 highly variable genes (rpsL, mprA, lipR, katG, and fgd1 genes) were sequenced. The sequence data were analyzed with neighbor joining method using mega and Geneious software. The phylogenetic trees analyzes revealed that the discriminatory power of lipR is much stronger than that observed in the other genes. lipR could distinguish between more clinical isolates. Therefore, lipR is a promising target for sequence analyzes of M. tuberculosis. PMID- 26063446 TI - Model invariance across genders of the Broad Autism Phenotype Questionnaire. AB - ASD is one of the most heritable neuropsychiatric disorders, though comprehensive genetic liability remains elusive. To facilitate genetic research, researchers employ the concept of the broad autism phenotype (BAP), a milder presentation of traits in undiagnosed relatives. Research suggests that the BAP Questionnaire (BAPQ) demonstrates psychometric properties superior to other self-report measures. To examine evidence regarding validity of the BAPQ, the current study used confirmatory factor analysis to test the assumption of model invariance across genders. Results of the current study upheld model invariance at each level of parameter constraint; however, model fit indices suggested limited goodness-of-fit between the proposed model and the sample. Exploratory analyses investigated alternate factor structure models but ultimately supported the proposed three-factor structure model. PMID- 26063447 TI - Investigating visual-tactile interactions over time and space in adults with autism. AB - It has been suggested that the sensory symptoms which affect many people with autism spectrum conditions (ASC) may be related to alterations in multisensory processing. Typically, the likelihood of interactions between the senses increases when information is temporally and spatially coincident. We explored visual-tactile interactions in adults with ASC for the first time in two experiments using low-level stimuli. Both participants with ASC and matched neurotypical controls only produced crossmodal interactions to near simultaneous stimuli, suggesting that temporal modulation is unaffected in the adult population. We also provide preliminary evidence that visual-tactile interactions may occur over greater spatial distances in participants with ASC, which merits further exploration. PMID- 26063448 TI - Corrigendum to: Incremental prognostic utility of coronary CT angiography for asymptomatic patients based upon extent and severity of coronary artery calcium: results from the COronary CT Angiography EvaluatioN For Clinical Outcomes InteRnationalMulticenter (CONFIRM) Study. [Eur Heart J (2015) 36 (8): 501-508; doi:10.1093/eurheartj/ehu358]. PMID- 26063449 TI - Edoxaban and amiodarone: interactions on multiple levels. PMID- 26063450 TI - Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. AB - Type 2 diabetes mellitus (T2DM) is characterized by multiple pathophysiologic abnormalities. With time, multiple glucose-lowering medications are commonly required to reduce and maintain plasma glucose concentrations within the normal range. Type 2 diabetes mellitus individuals also are at a very high risk for microvascular complications and the incidence of heart attack and stroke is increased two- to three-fold compared with non-diabetic individuals. Therefore, when selecting medications to normalize glucose levels in T2DM patients, it is important that the agent not aggravate, and ideally even improve, cardiovascular risk factors (CVRFs) and reduce cardiovascular morbidity and mortality. In this review, we examine the effect of oral (metformin, sulfonylureas, meglitinides, thiazolidinediones, DPP4 inhibitors, SGLT2 inhibitors, and alpha-glucosidase inhibitors) and injectable (glucagon-like peptide-1 receptor agonists and insulin) glucose-lowering drugs on established CVRFs and long-term studies of cardiovascular outcomes. Firm evidence that in T2DM cardiovascular disease can be reversed or prevented by improving glycaemic control is still incomplete and must await large, long-term clinical trials in patients at low risk using modern treatment strategies, i.e., drug combinations designed to maximize HbA1c reduction while minimizing hypoglycaemia and excessive weight gain. PMID- 26063451 TI - Regular assembly of cage siloxanes by hydrogen bonding of dimethylsilanol groups. AB - A new class of ordered silica-based materials has been prepared by hydrogen bond directed assembly of cage siloxanes modified with dimethylsilanol groups, providing a soft-chemical approach to crystalline silica materials with molecularly designed architectures. PMID- 26063452 TI - Analgesic efficacy of two interscalene blocks and one cervical epidural block in arthroscopic rotator cuff repair. AB - PURPOSE: Despite its effectiveness in other surgeries, studies on continuous epidural block in upper-extremity surgery are rare because of technical difficulties and potential complications. This study compared postoperative analgesic efficacy and safety of ultrasound-guided continuous interscalene brachial plexus block (UCISB) and fluoroscopy-guided targeted continuous cervical epidural block (FCCEB) in arthroscopic rotator cuff repair (ARCR). METHODS: Seventy-five patients were randomly and equally assigned to groups FCCEB (0.2%), UCISB75 (0.75%), and UCISB20 (0.2%) according to the initial ropivacaine dose (8 ml). The background infusion (0.2% ropivacaine at 5 ml/h), bolus (3 ml of 0.2% ropivacaine), and lockout time (20 min) were consistent. Respiratory effects [respiratory discomfort (modified Borg scale), ventilatory function, and hemidiaphragmatic excursion (ultrasound)], analgesic quality [pain severity at rest and motion attempt (VAS-R and -M), number of boluses, analgesic supplements, and sleep disturbance], neurologic effects, procedural discomfort, satisfaction, and adverse effects were evaluated preprocedurally and up to 72 h postoperatively. RESULTS: FCCEB caused less respiratory depression and sensorimotor block, but had less analgesic efficacy than UCISBs (P < 0.05). FCCEB caused nausea, vomiting, and dizziness more frequently (P < 0.05) and had lower patient satisfaction than UCISBs (P < 0.05). UCISB75 can cause severe respiratory distress in patients with lung disorders. Other variables were not significantly different between the groups. CONCLUSIONS: UCISB20 may provide superior postoperative analgesia and is the most recommendable postoperative analgesic method in ARCR. LEVEL OF EVIDENCE: Randomized controlled trials, Therapeutic study, Level I. PMID- 26063453 TI - Modified minimally invasive transforaminal lumbar interbody fusion using a trans multifidus approach: a safe and effective alternative to open-TLIF. AB - BACKGROUND: Application of minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) is limited by long fluoroscopy time and a steep learning curve. Herein, MI-TLIF was modified using a trans-multifidus approach, assisted by microscope, termed MMI-TLIF, and the clinical outcomes of MMI-TLIF and open-TLIF were compared. METHODS: Forty-nine patients treated with MMI-TLIF were matched with 49 subjects who underwent open-TLIF. Patients were assessed using the North American Spine Society Score (NASS), Oswestry Disability Index (ODI), Short Form 36 (SF-36), and Visual Analogue Score (VAS) before surgery and during follow-up (6 months and 2 years). The four-type Bridwell anterior fusion grading system was used to evaluate fusion rates at 2 years. RESULTS: The median fluoroscopic time did not differ significantly between the MMI-TLIF and open-TLIF groups. MMI-TLIF surgery took significantly longer than open-TLIF (91.3 vs. 82.5 min; P < 0.05). Meanwhile, MMI-TLIF patients lost significantly less blood than open-TLIF patients (75.3 vs. 215.2 ml; P < 0.05), and MMI-TLIF patients were hospitalized for less long than open-TLIF patients (3.7 vs. 6.9 days; P < 0.05) and reported less pain, faster ambulation, and lower morphine intake than open-TLIF patients (all P < 0.05). The NASS, ODI, VAS, and SF-36 scores were significantly improved 6 months and 2 years postsurgery in both groups, compared with preoperative values, and similar values were obtained for both groups. Finally, fusion rates were similar in MMI-TLIF and open-TLIF patients. CONCLUSIONS: Overall, these findings strongly suggest the superiority of MMI-TLIF to open-TLIF. Therefore, MMI-TLIF could be a safe and effective alternative to MI-TLIF and open-TLIF. PMID- 26063454 TI - Attainment and characteristics of clinical remission according to the new ACR EULAR criteria in abatacept-treated patients with early rheumatoid arthritis: new analyses from the Abatacept study to Gauge Remission and joint damage progression in methotrexate (MTX)-naive patients with Early Erosive rheumatoid arthritis (AGREE). AB - INTRODUCTION: This study evaluated various remission criteria in abatacept plus methotrexate (MTX)-treated patients with early rheumatoid arthritis (RA). We aimed to investigate the time to, and sustainability of, remission, and to evaluate the relationship between remission, function and structure. METHODS: Post hoc analyses were performed from the 12-month, double-blind period of the Abatacept study to Gauge Remission and joint damage progression in methotrexate (MTX)-naive patients with Early Erosive rheumatoid arthritis (AGREE) in patients with early RA (<=2 years) and poor prognostic factors, comparing abatacept plus MTX (n = 210) versus MTX alone (n = 209). RESULTS: At month 12, Disease Activity Score 28, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index and Boolean remission rates were, for abatacept plus MTX versus MTX alone: 47.6 % versus 27.3 %, 33.3 % versus 12.4 %, 34.3 % versus 16.3 %, and 23.8 % versus 5.7 %, respectively. Cumulative probability demonstrated higher proportions achieving first remission and first sustained remission for abatacept plus MTX versus MTX alone (e.g., 23.3 % [95 % confidence interval (CI): 17.6, 29.1] vs 12.9 % [8.4, 17.5] for first SDAI remission over 0-6 months). For patients in SDAI remission at month 3, mean Health Assessment Questionnaire Disability Index at month 12 was 0.20 versus 0.50 for abatacept plus MTX versus MTX alone. Mean changes in radiographic score from baseline to month 12 were minimal for patients in SDAI remission at month 3 in both groups, while less structural damage progression was seen, 0.75 versus 1.35, respectively, for abatacept plus MTX versus MTX alone for patients with moderate/high disease activity at month 3 (adjusted mean treatment difference: -0.60 [95 % CI: -1.11, 0.09; P < 0.05]). CONCLUSIONS: High proportions of abatacept plus MTX-treated patients achieved stringent remission criteria. Remission was associated with long-term functional benefit; dissociation was seen between clinical and structural outcomes for abatacept. These findings highlight the impact of reaching stringent remission targets early, on physical function and structural damage, in MTX-naive biologic-treated patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00122382. Registered 19 July 2005. PMID- 26063455 TI - Molecular evolution and expression profile of the chemerine encoding gene RARRES2 in baboon and chimpanzee. AB - BACKGROUND: Chemerin, encoded by the retinoic acid receptor responder 2 (RARRES2) gene is an adipocytesecreted protein with autocrine/paracrine functions in adipose tissue, metabolism and inflammation with a recently described function in vascular tone regulation, liver, steatosis, etc. This molecule is believed to represent a critical endocrine signal linking obesity to diabetes. There are no data available regarding evolution of RARRES2 in non-human primates and great apes. Expression profile and orthology in RARRES2 genes are unknown aspects in the biology of this multigene family in primates. Thus; we attempt to describe expression profile and phylogenetic relationship as complementary knowledge in the function of this gene in primates. To do that, we performed A RT-PCR from different tissues obtained during necropsies. Also we tested the hypotheses of positive evolution, purifying selection, and neutrality. And finally a phylogenetic analysis was made between primates RARRES2 protein. RESULTS: RARRES2 transcripts were present in liver, lung, adipose tissue, ovary, pancreas, heart, hypothalamus and pituitary tissues. Expression in kidney and leukocytes were not detectable in either species. It was determined that the studied genes are orthologous. CONCLUSIONS: RARRES2 evolution fits the hypothesis of purifying selection. Expression profiles of the RARRES2 gene are similar in baboons and chimpanzees and are also phylogenetically related. PMID- 26063456 TI - An inflection point for country health data. PMID- 26063457 TI - Using clinical parameters to guide fluid therapy in high-risk thoracic surgery. A retrospective, observational study. AB - BACKGROUND: Despite extensive research, the debate continues as to the optimal way of guiding intraoperative and postoperative fluid therapy. In 2009 we changed our institutional guideline for perioperative fluid therapy in patients undergoing extrapleural pneumonectomy (EPP) and implemented the use of central venous oxygen saturation and intended low urine output to guide therapy in the early postoperative period. Here we evaluate the consequences of our changes. METHODS: Retrospective, observational study of 30 consecutive patients undergoing EPP; 18 who had surgery before and 12 who had surgery after the changes. Data were collected from patient files and from institutional databases. Outcome measures included: Volumes of administered fluids, fluid balances, length of stays and postoperative complications. Dichotomous variables were compared with Fisher's exact test, whereas continuous variables were compared with Student's unpaired t-test or the Wilcoxon Two-Sample Test depending on the distribution of data. RESULTS: The applied changes significantly reduced the volumes of administered fluids, both in the intraoperative (p = 0.01) and the postoperative period (p = 0.04), without increasing the incidence of postoperative complications. Mean length of stay in the intensive care unit (LOSI) was reduced from three to one day (p = 0.04) after the changes. CONCLUSION: The use of clinical parameters to balance fluid restriction and a sufficient circulation in patients undergoing EPP was associated with a reduction in mean LOSI without increasing the incidence of postoperative complications. Due to methodological limitations these results are only hypothesis generating. PMID- 26063458 TI - Plasma diacylglycerol composition is a biomarker of metabolic syndrome onset in rhesus monkeys. AB - Metabolic syndrome is linked with obesity and is often first identified clinically by elevated BMI and elevated levels of fasting blood glucose that are generally secondary to insulin resistance. Using the highly translatable rhesus monkey (Macaca mulatta) model, we asked if metabolic syndrome risk could be identified earlier. The study involved 16 overweight but healthy, euglycemic monkeys, one-half of which spontaneously developed metabolic syndrome over the course of 2 years while the other half remained healthy. We conducted a series of biometric and plasma measures focusing on adiposity, lipid metabolism, and adipose tissue-derived hormones, which led to a diagnosis of metabolic syndrome in the insulin-resistant animals. Plasma fatty acid composition was determined by gas chromatography for cholesteryl ester, FFA, diacylglycerol (DAG), phospholipid, and triacylglycerol lipid classes; plasma lipoprotein profiles were generated by NMR; and circulating levels of adipose-derived signaling peptides were determined by ELISA. We identified biomarker models including a DAG model, two lipoprotein models, and a multiterm model that includes the adipose-derived peptide adiponectin. Correlations among circulating lipids and lipoproteins revealed shifts in lipid metabolism during disease development. We propose that lipid profiling may be valuable for early metabolic syndrome detection in a clinical setting. PMID- 26063459 TI - Scap and the intestinal epithelial stem cell niche: new insights from lipid biology. PMID- 26063460 TI - Ganglioside accumulation in activated glia in the developing brain: comparison between WT and GalNAcT KO mice. AB - Our previous studies have shown accumulation of GM2 ganglioside during ethanol induced neurodegeneration in the developing brain, and GM2 elevation has also been reported in other brain injuries and neurodegenerative diseases. Using GM2/GD2 synthase KO mice lacking GM2/GD2 and downstream gangliosides, the current study explored the significance of GM2 elevation in WT mice. Immunohistochemical studies indicated that ethanol-induced acute neurodegeneration in postnatal day 7 (P7) WT mice was associated with GM2 accumulation in the late endosomes/lysosomes of both phagocytic microglia and increased glial fibrillary acidic protein (GFAP) positive astrocytes. However, in KO mice, although ethanol induced robust neurodegeneration and accumulation of GD3 and GM3 in the late endosomes/lysosomes of phagocytic microglia, it did not increase the number of GFAP-positive astrocytes, and the accumulation of GD3/GM3 in astrocytes was minimal. Not only ethanol, but also DMSO, induced GM2 elevation in activated microglia and astrocytes along with neurodegeneration in P7 WT mice, while lipopolysaccharide, which did not induce significant neurodegeneration, caused GM2 accumulation mainly in lysosomes of activated astrocytes. Thus, GM2 elevation is associated with activation of microglia and astrocytes in the injured developing brain, and GM2, GD2, or other downstream gangliosides may regulate astroglial responses in ethanol-induced neurodegeneration. PMID- 26063462 TI - Paid for by the NHS, treated privately. PMID- 26063461 TI - Long-chain n-3 PUFAs from fish oil enhance resting state brain glucose utilization and reduce anxiety in an adult nonhuman primate, the grey mouse lemur. AB - Decreased brain content of DHA, the most abundant long-chain n-3 polyunsaturated fatty acid (n-3 LCPUFA) in the brain, is accompanied by severe neurosensorial impairments linked to impaired neurotransmission and impaired brain glucose utilization. In the present study, we hypothesized that increasing n-3 LCPUFA intake at an early age may help to prevent or correct the glucose hypometabolism observed during aging and age-related cognitive decline. The effects of 12 months' supplementation with n-3 LCPUFA on brain glucose utilization assessed by positron emission tomography was tested in young adult mouse lemurs (Microcebus murinus). Cognitive function was tested in parallel in the same animals. Lemurs supplemented with n-3 LCPUFA had higher brain glucose uptake and cerebral metabolic rate of glucose compared with controls in all brain regions. The n-3 LCPUFA-supplemented animals also had higher exploratory activity in an open-field task and lower evidence of anxiety in the Barnes maze. Our results demonstrate for the first time in a nonhuman primate that n-3 LCPUFA supplementation increases brain glucose uptake and metabolism and concomitantly reduces anxiety. PMID- 26063463 TI - Atrial fibrillation: an inherited cardiovascular disease--a commentary on genetics of atrial fibrillation: from families to genomes. PMID- 26063464 TI - Genetic analysis of common variants in the HDAC2 gene with schizophrenia susceptibility in Han Chinese. AB - Schizophrenia (SCZ) is a complex psychiatric disorder that is strongly influenced by a genetic component. Recent studies suggested that histone deacetylases (HDACs) might increase the expression of several key genes in the brain and may also be associated with susceptibility to SCZ. Among human HDACs, HDAC2 is a critical modulator of gene regulation. Here, we designed a two-stage case-control study to thoroughly examine the association between the HDAC2 gene and SCZ. A total of 19 common single-nucleotide polymorphisms (SNPs) in the region of the HDAC2 gene were analyzed in the test group of 1430 patients and 2862 matched healthy controls. A comparison of the genotype and allele frequencies of the SNPs between cases and controls revealed that three SNPs, rs13212283, rs6568819 and rs9488289, were nominally associated with SCZ. However, we failed to observe any association between these SNPs and SCZ in the validation group consisting of 896 cases and 1815 matched healthy controls. Furthermore, haplotypic analysis also confirmed the negative results. Our results provide preliminary evidence that HDAC2 may not confer susceptibility to SCZ in Han Chinese. Additional genetic studies from a large population are required to obtain more conclusive results. PMID- 26063465 TI - Genotype-phenotype relationship in Japanese patients with congenital central hypoventilation syndrome. AB - Examine the genotype-phenotype relationship in Japanese congenital central hypoventilation syndrome (CCHS) patients and estimate the incidence of CCHS in Japan. Subjects were 92 Japanese patients with PHOX2B mutations; 19 cases carried 25 polyalanine repeat expansion mutations (PARMs); 67 cases carried 26 or more PARMs; and 6 had non-PARMs (NPARMs). We collected clinical data in all patients and estimated the development or intelligent quotients only in the patients carrying 25 PARM. The estimated incidence of CCHS was greater than one case per 148 000 births. Polyhydramnios was observed in three cases. Twelve infants exhibited depressed respiration at birth. In 19 cases carrying 25 PARM, the male to-female ratio was ~3, no cases had Hirschsprung disease; 7 cases (37%) developed hypoventilation after the neonatal period, and 8 cases (42%) had mental retardation. In other 73 cases carrying 26 or more PARMs or NPARMs, male-to female ratio was equal; patients frequently complicated with Hirschsprung disease and constipation, and all patients presented with hypoventilation in the neonatal period. Clinical symptoms were severe in most patients carrying long PARMs and NPARMs. In 25 PARM, additional genetic and/or epigenetic factors were required for CCHS development and male sex is likely a predisposing factor. The patients carrying 25 PARM frequently had mental retardation likely because they were not able to receive appropriate ventilation support following a definitive diagnosis owing to subtle and or irregular hypoventilation. Molecular diagnosis provides a definitive diagnosis and enables to receive appropriate ventilator support. PMID- 26063467 TI - Lived-through past, experienced present, anticipated future: Understanding "existential loss" in the context of life-limiting illness. AB - OBJECTIVE: Motor Neurone Disease (MND) is a rare, devastating neurodegenerative disease of middle/later life, usually presenting in the sixth and seventh decades (McDermot & Shaw, 2008). People have to wait many months to receive a diagnosis of MND (Donaghy et al., 2008), and during this period they have already experienced the degenerative nature that characterizes MND (Bolmsjo, 2001). However, information on the meaning of life with MND through time is limited. The aim of the present research was to answer the research question "What does it mean to be a person living through the illness trajectory of MND?" and to research the phenomenon of existence when given a diagnosis of MND and in the context of receiving healthcare. METHOD: Hermeneutic phenomenology, inspired by the philosophers Heidegger and Gadamer, informed the methodological approach employed, which asked people to tell their story from when they first thought something untoward was happening to them. The hermeneutic analysis involved a five-stage process in order to understand (interpret) the lifeworld 1 of four people diagnosed with MND, and a lifeworld perspective helped to make sense of the meaning of existence when given a terminal diagnosis of MND. RESULTS: The concept of "existential loss" identified in relation to MND was the loss of past ways of being-in-the-world, and the loss of embodiment, spatiality, and the future. SIGNIFICANCE OF RESULTS: The concept of existential loss requires closer attention by healthcare professionals from the time of diagnosis and on through the illness trajectory. The study findings are conceptualized into a framework, which when used as a clinical tool may prompt healthcare professionals to focus on their patients' existential loss and existential concerns. This research adds to the existing literature calling for a lifeworld approach to healthcare. PMID- 26063466 TI - Production of beta-ionone by combined expression of carotenogenic and plant CCD1 genes in Saccharomyces cerevisiae. AB - BACKGROUND: Apocarotenoids, like the C13-norisoprenoids, are natural compounds that contribute to the flavor and/or aroma of flowers and foods. They are produced in aromatic plants-like raspberries and roses-by the enzymatic cleavage of carotenes. Due to their pleasant aroma and flavour, apocarotenoids have high commercial value for the cosmetic and food industry, but currently their production is mainly assured by chemical synthesis. In the present study, a Saccharomyces cerevisiae strain that synthesizes the apocarotenoid beta-ionone was constructed by combining integrative vectors and high copy number episomal vectors, in an engineered strain that accumulates FPP. RESULTS: Integration of an extra copy of the geranylgeranyl diphosphate synthase gene (BTS1), together with the carotenogenic genes crtYB and crtI from the ascomycete Xanthophyllomyces dendrorhous, resulted in carotenoid producing cells. The additional integration of the carotenoid cleavage dioxygenase gene from the plant Petunia hybrida (PhCCD1) let to the production of low amounts of beta-ionone (0.073 +/- 0.01 mg/g DCW) and changed the color of the strain from orange to yellow. The expression of the crtYB gene from a high copy number plasmid in this former strain increased beta-ionone concentration fivefold (0.34 +/- 0.06 mg/g DCW). Additionally, the episomal expression of crtYB together with the PhCCD1 gene in the same vector resulted in a final 8.5-fold increase of beta-ionone concentration (0.63 +/- 0.02 mg/g DCW). Batch fermentations with this strain resulted in a final specific concentration of 1 mg/g DCW at 50 h, which represents a 15-fold increase. CONCLUSIONS: An efficient beta-ionone producing yeast platform was constructed by combining integrative and episomal constructs. By combined expression of the genes BTS1, the carotenogenic crtYB, crtI genes and the plant PhCCD1 gene-the highest beta-ionone concentration reported to date by a cell factory was achieved. This microbial cell factory represents a starting point for flavor production by a sustainable and efficient process that could replace current methods. PMID- 26063468 TI - Effects of D-Pinitol on Insulin Resistance through the PI3K/Akt Signaling Pathway in Type 2 Diabetes Mellitus Rats. AB - D-pinitol, a compound isolated from Pinaceae and Leguminosae plants, has been reported to possess insulin-like properties. Although the hypoglycemic activity of D-pinitol was recognized in recent years, the molecular mechanism of D-pinitol in the treatment of diabetes mellitus remains unclear. In this investigation, a model of type 2 diabetes mellitus (T2DM) with insulin resistance was established by feeding a high-fat diet (HFD) and injecting streptozocin (STZ) to Sprague Dawley (SD) rats, targeting the exploration of more details of the mechanism in the therapy of T2DM. D-pinitol was administrated to the diabetic rats as two doses [30, 60 mg/(kg.body weight.day)]. The level of fasting blood glucose (FBG) was decreased 12.63% in the high-dosage group, and the ability of oral glucose tolerance was improved in D-pinitol-treated groups. The biochemical indices revealed that D-pinitol had a positive effect on hypoglycemic activity. Western boltting suggested that D-pinitol could promote the expression of the phosphatidylinositol-3-kinase (PI3K) p85, PI3Kp110, as well as the downstream target protein kinase B/Akt (at Ser473). Besides, D-pinitol inhibited the expression of glycogen synthesis kinase-3beta (GSK-3beta) protein and regulated the expression of glycogen synthesis (GS) protein and then accelerated the glycogen synthesis. Above all, D-pinitol played a positive role in regulating insulin-mediated glucose uptake in the liver through translocation and activation of the PI3K/Akt signaling pathway in T2DM rats. PMID- 26063469 TI - Detection of Mycobacterium avium subspecies in the gut associated lymphoid tissue of slaughtered rabbits. AB - BACKGROUND: Rabbits are susceptible to infection by different species of the genus Mycobacterium. Particularly, development of specific lesions and isolation of Mycobacterium avium subsp. avium and Mycobacterium avium subsp. paratuberculosis, both subspecies of the M. avium complex, has been reported in wildlife conditions. Although, rabbit meat production worldwide is 200 million tons per year, microbiological data on this source of meat is lacking and more specifically reports of mycobacterial presence in industrially reared rabbit for human consumption have not been published. To this end, we sought mycobacteria by microbiological and histopathological methods paying special attention to Mycobacterium avium subsp. paratuberculosis in rabbits from commercial rabbitries from the North East of Spain. RESULTS: M. avium subsp. paratuberculosis was not detected either by culture or PCR. However, Mycobacterium avium subsp. avium was detected in 15.15% (10/66) and Mycobacterium avium subsp. hominissuis was detected in 1.51% (1/66) of gut associated lymphoid tissue of sampled animals by PCR, whereas caecal contents were negative. 9% (6/66) of the animals presented gross lesions suggestive of lymphoid activation, 6% (4/66) presented granulomatous lesions and 3% (2/66) contained acid fast bacilli. Mycobacterial isolation from samples was not achieved, although colonies of Thermoactinomycetes sp. were identified by 16s rRNA sequencing in 6% (4/66) of sampled animals. CONCLUSIONS: Apparently healthy farmed rabbits that go to slaughter may carry M. avium subspecies in gut associated lymphoid tissue. PMID- 26063470 TI - The Optimal Load for Maximal Power Production During Lower-Body Resistance Exercises: A Meta-Analysis. AB - BACKGROUND: The development of muscular power is often a key focus of sports performance enhancement programs. OBJECTIVE: The purpose of this meta-analysis was to examine the effect of load on peak power during the squat, jump squat, power clean, and hang power clean, thus integrating the findings of various studies to provide the strength and conditioning professional with more reliable evidence upon which to base their program design. METHODS: A search of electronic databases [MEDLINE (SPORTDiscus), PubMed, Google Scholar, and Web of Science] was conducted to identify all publications up to 30 June 2014. Hedges' g (95% confidence interval) was estimated using a weighted random-effect model. A total of 27 studies with 468 subjects and 5766 effect sizes met the inclusion criterion and were included in the statistical analyses. Load in each study was labeled as one of three intensity zones: Zone 1 represented an average intensity ranging from 0 to 30% of one repetition maximum (1RM); Zone 2 between 30 and 70% of 1RM; and Zone 3 >=70% of 1RM. RESULTS: These results showed different optimal loads for each exercise examined. Moderate loads (from >30 to <70% of 1RM) appear to provide the optimal load for power production in the squat exercise. Lighter loads (<=30% of 1RM) showed the highest peak power production in the jump squat. Heavier loads (>=70% of 1RM) resulted in greater peak power production in the power clean and hang power clean. CONCLUSION: Our meta-analysis of results from the published literature provides evidence for exercise-specific optimal loads for power production. PMID- 26063471 TI - Photoinduced cytotoxicity of a photochromic diarylethene via caspase cascade activation. AB - The photo-generated closed-ring isomer of bis(5-methyl-2 phenylthiazoyl)perfluorocyclopentene shows cytotoxicity to Madin-Darby canine kidney (MDCK) cells through a caspase cascade and induces apoptosis of cells. PMID- 26063473 TI - Transitioning health systems for multimorbidity. PMID- 26063474 TI - Development of a Culturally Appropriate Bilingual Electronic App About Hepatitis B for Indigenous Australians: Towards Shared Understandings. AB - BACKGROUND: Hepatitis B is endemic in Indigenous communities in Northern Australia; however, there is a lack of culturally appropriate educational tools. Health care workers and educators in this setting have voiced a desire for visual, interactive tools in local languages. Mobile phones are increasingly used and available in remote Indigenous communities. In this context, we identified the need for a tablet-based health education app about hepatitis B, developed in partnership with an Australian remote Indigenous community. OBJECTIVE: To develop a culturally appropriate bilingual app about hepatitis B for Indigenous Australians in Arnhem Land using a participatory action research (PAR) framework. METHODS: This project was a partnership between the Menzies School of Health Research, Miwatj Aboriginal Health Corporation, Royal Darwin Hospital Liver Clinic, and Dreamedia Darwin. We have previously published a qualitative study that identified major knowledge gaps about hepatitis B in this community, and suggested that a tablet-based app would be an appropriate and popular tool to improve this knowledge. The process of developing the app was based on PAR principles, particularly ongoing consultation, evaluation, and discussion with the community throughout each iterative cycle. Stages included development of the storyboard, the translation process (forward translation and backtranslation), prelaunch community review, launch and initial community evaluation, and finally, wider launch and evaluation at a viral hepatitis conference. RESULTS: We produced an app called "Hep B Story" for use with iPad, iPhone, Android tablets, and mobile phones or personal computers. The app is culturally appropriate, audiovisual, interactive, and users can choose either English or Yolnu Matha (the most common language in East Arnhem Land) as their preferred language. The initial evaluation demonstrated a statistically significant improvement in Hep B related knowledge for 2 of 3 questions (P=.01 and .02, respectively) and overwhelmingly positive opinion regarding acceptability and ease of use (median rating of 5, on a 5-point Likert-type scale when users were asked if they would recommend the app to others). CONCLUSIONS: We describe the process of development of a bilingual hepatitis B-specific app for Indigenous Australians, using a PAR framework. The approach was found to be successful with positive evaluations. PMID- 26063475 TI - Correspondence between pigmented lesions identified by melanoma patients trained to perform partner-assisted skin self-examination and dermatological examination. AB - BACKGROUND: Skin self-examination (SSE) training interventions can increase understanding of melanoma early detection criteria and promote SSE. However, there remains a need to evaluate whether intervention participants can apply such early detection skills to accurately identify concerning, or potentially malignant, pigmented lesions during full body SSE. METHODS: We assessed SSE accuracy using data from a randomized control trial of a SSE skills training intervention designed to promote partner-assisted SSE among melanoma patients. In the trial, patient-partner pairs were administered the training intervention and performed monthly SSE to identify, evaluate, and track concerning pigmented skin lesions. Patients received a total body skin examination by a dermatologist approximately 4-months postintervention. SSE accuracy was assessed as the correspondence between the specific concerning pigmented lesions identified by 274 study pairs during SSE with those identified during dermatological examination. We also examined whether lesions that were biopsied during the study were identified prior to biopsy during SSE. RESULTS: Approximately three in four of the concerning lesions identified by pairs during SSE were also identified during the dermatological exam. There were 81 biopsies performed during the study and pairs had identified 73% of the corresponding lesions during SSE. Of the five melanoma detected, three were identified during SSE. CONCLUSION: Melanoma patients and partner taught to do SSE using an evidence-based program developed a high degree of correspondence with the study dermatologist in identifying concerning lesions. IMPACT: This study provides novel evidence that supports the accuracy of full-body SSE for the patient identification of concerning lesions. PMID- 26063476 TI - Use of common analgesics is not associated with ovarian cancer survival. AB - BACKGROUND: Use of analgesics has been associated with lower risk of ovarian cancer, but, to date, very few studies have explored the association between analgesics and ovarian cancer survival. METHODS: We examined the relationship between self-reported prediagnostic use of aspirin, ibuprofen, and acetaminophen and overall survival (OS), progression-free survival (PFS), ascites at the time of primary treatment, and persistence of disease after primary treatment among 699 women diagnosed with epithelial ovarian carcinoma. The associations between use of these medications and OS and PFS were estimated using Cox proportional hazards models. We utilized unconditional logistic regression models to estimate associations between medication use and presence of ascites and persistence of disease. RESULTS: Prediagnostic intake of aspirin, both low-dose and regular dose, ibuprofen, and acetaminophen was not associated with any of the outcomes of interest. CONCLUSIONS: Our results indicate a lack of association between prediagnostic intake of selected analgesics and OS, PFS, presence of ascites at the time of primary treatment, and persistence of disease after primary treatment. IMPACT: Prediagnostic intake of analgesics may not be associated with ovarian cancer outcomes. PMID- 26063477 TI - Contribution of the neighborhood environment and obesity to breast cancer survival: the California Breast Cancer Survivorship Consortium. AB - Little is known about neighborhood attributes that may influence opportunities for healthy eating and physical activity in relation to breast cancer mortality. We used data from the California Breast Cancer Survivorship Consortium and the California Neighborhoods Data System (CNDS) to examine the neighborhood environment, body mass index, and mortality after breast cancer. We studied 8,995 African American, Asian American, Latina, and non-Latina white women with breast cancer. Residential addresses were linked to the CNDS to characterize neighborhoods. We used multinomial logistic regression to evaluate the associations between neighborhood factors and obesity and Cox proportional hazards regression to examine associations between neighborhood factors and mortality. For Latinas, obesity was associated with more neighborhood crowding [quartile 4 (Q4) vs. Q1: OR, 3.24; 95% confidence interval (CI), 1.50-7.00]; breast cancer-specific mortality was inversely associated with neighborhood businesses (Q4 vs. Q1: HR, 0.46; 95% CI, 0.25-0.85) and positively associated with multifamily housing (Q3 vs. Q1: HR, 1.98; 95% CI, 1.20-3.26). For non-Latina whites, lower neighborhood socioeconomic status (SES) was associated with obesity [quintile 1 (Q1) vs. Q5: OR, 2.52; 95% CI, 1.31-4.84], breast cancer-specific (Q1 vs. Q5: HR, 2.75; 95% CI, 1.47-5.12), and all-cause (Q1 vs. Q5: HR, 1.75; 95% CI, 1.17-2.62) mortality. For Asian Americans, no associations were seen. For African Americans, lower neighborhood SES was associated with lower mortality in a nonlinear fashion. Attributes of the neighborhood environment were associated with obesity and mortality following breast cancer diagnosis, but these associations differed across racial/ethnic groups. PMID- 26063478 TI - Caffeine, coffee, and tea intake and urinary estrogens and estrogen metabolites in premenopausal women. AB - BACKGROUND: Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones. METHODS: High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses' Health Study II with mid-luteal phase urine samples and caffeine, coffee, and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways, and ratios by intake categories, and P values for tests of linear trend. RESULTS: Compared with women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16alpha-hydroxyestrone (28% difference; Ptrend = 0.01) and 16-epiestriol (13% difference; Ptrend = 0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (Ptrend = 0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, >=4 cups/day vs. <=6 cups/week; Ptrend = 0.001) and 2-hydroxyestrone (52% difference; Ptrend = 0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (>=2 cups/day vs. <=1-3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; Ptrend = 0.01) and 17-epiestriol (48% difference; Ptrend = 0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend = 0.01). CONCLUSION: Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women. IMPACT: Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism. PMID- 26063480 TI - Organization and logistics of drug-induced sleep endoscopy in a training hospital. AB - Drug-induced sleep endoscopy (DISE) is a rapidly growing method to evaluate airway collapse in patients receiving non-CPAP therapies for sleep-disordered breathing (SDB). The growing number of DISEs has consequences for the organization of clinical protocols. In this paper we present our recent experiences with DISE, performed by an ENT resident, with sedation given by a nurse anesthetist, in an outpatient endoscopy setting, while the staff member/sleep surgeon discusses the findings and the recommended treatment proposal on the same day. PMID- 26063479 TI - Oral contraceptive use and colorectal cancer in the Nurses' Health Study I and II. AB - BACKGROUND: It remains unclear if oral contraceptive (OC) use is associated with the incidence of colorectal cancer. Few studies have examined this association by duration of OC use, time since last OC use, and different cancer subsites. METHODS: Among 88,691 participants of the Nurses' Health Study I (NHSI) and 93,080 participants of the Nurses' Health Study II (NHSII), we assessed OC use every 2 years between 1976 and 2010 and categorized it as ever use, duration of use, and time since last use. We included incident colorectal cancer cases through 2010 (NHSI: age at diagnosis = 36-88, N = 1,764; NHSII: age at diagnosis = 33-64, N = 206). Multivariable hazard ratios and 95% confidence intervals were estimated using Cox proportional hazards regression models. RESULTS: Ever OC use was not associated with colorectal cancer in NHSI [1.01 (0.91, 1.12)] nor NHSII [1.03 (0.69, 1.53)]. In NHSII, when compared with never-users, longer durations (5+ years) of OC use were inversely associated with the risk of colon cancers (Ptrend = 0.02) but the number of endpoints was limited. No other colorectal cancer subsites were associated with OC durations or times since last OC use in either cohort. CONCLUSIONS: In two large prospective cohorts, we found little evidence that OC use may be protective for colorectal cancer, except potentially with longer durations of use among younger women. IMPACT: Our results do not support the previous initial studies that reported an inverse association of recent OC use with colorectal cancer but instead support newer, larger studies demonstrating no such association. PMID- 26063481 TI - Lapatinib sensitizes quiescent MDA-MB-231 breast cancer cells to doxorubicin by inhibiting the expression of multidrug resistance-associated protein-1. AB - The quiescent state plays an important role in tumor recurrence because it protects cancer cells from chemotherapy. Previously, we optimized tumorsphere cultures for in vitro screening methods for targeting quiescent cell population since the majority of cells in tumorspheres are quiescent. In this study, we analyzed efficacies of current chemotherapeutics in tumorsphere assays to seek better strategies for eradicating quiescent cell population. Tumorspheres generated from MDA-MB-231 cells exhibited accumulations of cells in the G0/G1 phase as compared with cells in monolayer culture, suggesting that sphere formation contributes to an increase of quiescent cells. As a result of a decreased doxorubicin uptake, MDA-MB-231 tumorspheres exhibited chemoresistance to both doxorubicin and paclitaxel. Since we found that the enhanced EGFR signaling is characteristics of MDA-MB-231 tumorspheres, the combination effects of chemotherapy with lapatinib, a dual ErbB1/ErbB2 inhibitor, were accessed in tumorsphere assays. Western blot analysis revealed that lapatinib inhibited the phosphorylation of EGFR, AKT and p38 in doxorubicin-treated tumorspheres. The inhibition of EGFR signaling by the treatment with lapatinib suppressed the expression of multidrug resistance-associated protein-1 (MRP-1), leading to increased cytotoxicity of doxorubicin to tumorspheres. Furthermore, blockade of the PI3K/AKT and p38 MAPK signaling pathways resulted in a remarkable decrease in the expression of MRP-1 in doxorubicin-treated tumorspheres. These results demonstrate that lapatinib sensitizes quiescent MDA-MB-231 breast cancer cells to doxorubicin by inhibiting doxorubicin-induced MRP-1 expression via PI3K/AKT and p38 MAPK signaling pathways. Thus, this study suggests that treatment with lapatinib in combination with anti-mitotic drugs maybe a useful approach to improve clinical response by eradicating the quiescent cancer cell population. PMID- 26063482 TI - Heterobimetallic complexes with redox-active mesoionic carbenes as metalloligands: electrochemical properties, electronic structures and catalysis. AB - A mesoionic carbene with a ferrocene backbone is used as a metalloligand to generate the first example of their Fe-Au heterobimetallic complexes. The details of geometric and electronic structures in different redox states and preliminary catalytic results are presented. PMID- 26063484 TI - MicroRNA-26a/b directly regulate La-related protein 1 and inhibit cancer cell invasion in prostate cancer. AB - Our past studies of microRNA (miRNA) expression signatures of cancers including prostate cancer (PCa) revealed that microRNA-26a and microRNA-26b (miR-26a and miR-26b) were significantly downregulated in cancer tissues. In the present study, we found that restoration of miR-26a or miR-26b significantly inhibited PCa cell invasion. Gene expression data and in silico analysis showed that the gene encoding La-related protein 1 (LARP1) was a putative candidate of miR-26a and miR-26b regulation. Moreover, luciferase reporter assays revealed that LARP1 was a direct target of both miR-26a and miR-26b. Overexpression of LARP1 was observed in PCa clinical specimens and knockdown of LARP1 inhibited cancer cell migration. Therefore, LARP1 acted as an oncogene in PCa cells. Moreover, 'ribosome', 'RNA transport' and 'mTOR signaling pathway' were identified as LARP1 regulated pathways. Our present data suggested that loss of tumor-suppressive miR 26a and miR-26b enhanced cancer cell invasion in PCa through direct regulation of oncogenic LARP1. Elucidation of the molecular networks regulated by tumor suppressive miRNAs will provide insights into the molecular mechanisms of PCa oncogenesis and metastasis. PMID- 26063483 TI - A prospective observational description of frequency and timing of antenatal care attendance and coverage of selected interventions from sites in Argentina, Guatemala, India, Kenya, Pakistan and Zambia. AB - BACKGROUND: The Global Network for Women's and Children's Health Research is one of the largest international networks for testing and generating evidence-based recommendations for improvement of maternal-child health in resource-limited settings. Since 2009, Global Network sites in six low and middle-income countries have collected information on antenatal care practices, which are important as indicators of care and have implications for programs to improve maternal and child health. We sought to: (1) describe the quantity of antenatal care attendance over a four-year period; and (2) explore the quality of coverage for selected preventative, screening, and birth preparedness components. METHODS: The Maternal Newborn Health Registry (MNHR) is a prospective, population-based birth and pregnancy outcomes registry in Global Network sites, including: Argentina, Guatemala, India (Belgaum and Nagpur), Kenya, Pakistan, and Zambia. MNHR data from these sites were prospectively collected from January 1, 2010 - December 31, 2013 and analyzed for indicators related to quantity and patterns of ANC and coverage of key elements of recommended focused antenatal care. Descriptive statistics were generated overall by global region (Africa, Asia, and Latin America), and for each individual site. RESULTS: Overall, 96% of women reported at least one antenatal care visit. Indian sites demonstrated the highest percentage of women who initiated antenatal care during the first trimester. Women from the Latin American and Indian sites reported the highest number of at least 4 visits. Overall, 88% of women received tetanus toxoid. Only about half of all women reported having been screened for syphilis (49%) or anemia (50%). Rates of HIV testing were above 95% in the Argentina, African, and Indian sites. The Pakistan site demonstrated relatively high rates for birth preparation, but for most other preventative and screening interventions, posted lower coverage rates as compared to other Global Network sites. CONCLUSIONS: Results from our large, prospective, population-based observational study contribute important insight into regional and site-specific patterns for antenatal care access and coverage. Our findings indicate a quality and coverage gap in antenatal care services, particularly in regards to syphilis and hemoglobin screening. We have identified site-specific gaps in access to, and delivery of, antenatal care services that can be targeted for improvement in future research and implementation efforts. TRIAL REGISTRATION: Registration at Clinicaltrials.gov (ID# NCT01073475). PMID- 26063486 TI - Late presentation of encapsulating peritoneal sclerosis following renal transplantation and the potential under-reporting of the incidence and prevalence of encapsulating peritoneal sclerosis. AB - Encapsulating peritoneal sclerosis is an infrequent but potentially devastating complication of peritoneal dialysis. The reported incidence and prevalence of encapsulating peritoneal sclerosis vary markedly between countries. Currently, peritoneal dialysis vintage remains the major risk factor for encapsulating peritoneal sclerosis, and dialysis vintage differs between countries due to the relative competing risks of transplantation, availability of haemodialysis and peritonitis. However, the diagnosis of encapsulating peritoneal sclerosis is often only established when patients have transferred modality to transplantation or haemodialysis. Switching treatment modality may potentially lead to an under reporting of encapsulating peritoneal sclerosis, as many countries which collect data on dialysis patients in national registries often have separate registries for dialysis and transplant patients, and this may potentially lead to under reporting of encapsulating peritoneal sclerosis in patients presenting after renal transplantation. Secondly, the question arises as to how long former peritoneal dialysis patients should be followed before a diagnosis of encapsulating peritoneal sclerosis can be confidently excluded. To highlight this point, we present four cases that developed symptomatic encapsulating peritoneal sclerosis more than 5 years, and in once case more than 10 years after the discontinuation of peritoneal dialysis. Delayed or late presentation may not only delay the diagnosis, but also risk surgical interventions by non-specialists. A more robust system is required to record cases of encapsulating peritoneal sclerosis to determine the incidence and prevalence, and so provide accurate information to both patients and clinicians as to the risks of long-term peritoneal dialysis therapy. PMID- 26063487 TI - Improved genetic counseling in Alport syndrome by new variants of COL4A5 gene. AB - There are current requirements of using genetic databases for offering a better genetic assistance to patients of some syndromes, especially those with X-linked heredity patterns (like Alport Syndrome) for the high probability of having descendants affected by the disease. We describe the first reported case of COL4A5 gene missense c.1499 G>T mutation in a 16-year-old girl confirmed to be affected by Alport Syndrome after genetic counseling. Next Generation Sequencing procedures let discover this mutation and offer an accurate clinical treatment to this patient. Current scientific understanding of genetic syndromes suggests the high importance of updated databases and the inclusion of Variant of Unknown Significance related to clinical cases. All of this updating could enable patients to have a better opportunity of diagnosis and having genetic and clinical counseling. This event is even more important in women planning to start a family to have correct genetic counseling regarding the risk posed to offspring, and allowing the decision to undergo prenatal testing. PMID- 26063488 TI - Fibrillary glomerulonephritis: An apparent familial form? AB - Fibrillary glomerulonephritis is a rare cause of glomerulonephritis characterized by non-amyloid fibrillary deposits of unknown aetiology. It is generally considered idiopathic but may be associated with secondary causes such as monoclonal gammopathy, hepatitis B and C infections, autoimmune diseases and malignancies. We report two Australian families with apparent familial fibrillary glomerulonephritis inherited in an autosomal dominant pattern, and postulate the existence of a primary familial entity. Family 1 consists of an affected father and daughter; the daughter progressed to end-stage renal failure within 18 months of diagnosis, despite immunosuppressive therapy. The father, however, remains stable at 10 months follow up. Family 2 comprises an affected mother and son; the mother commenced haemodialysis 5 years after diagnosis and subsequently underwent successful renal transplantation. The son is presently stable at last follow-up after 5 years. A further review of the second family history reveals a third family member (maternal father) dying of 'Bright's disease'. We describe their histopathology, clinical progression and treatment outcomes, and provide a review of the current understanding of this heterogeneous condition that is associated with poor renal outcomes. PMID- 26063489 TI - Giant kidneys. PMID- 26063490 TI - Influenza vaccination and anti-neutrophil cytoplasmic antibody-associated vasculitis. PMID- 26063472 TI - Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990 2013: a systematic analysis for the Global Burden of Disease Study 2013. AB - BACKGROUND: Up-to-date evidence about levels and trends in disease and injury incidence, prevalence, and years lived with disability (YLDs) is an essential input into global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013), we estimated these quantities for acute and chronic diseases and injuries for 188 countries between 1990 and 2013. METHODS: Estimates were calculated for disease and injury incidence, prevalence, and YLDs using GBD 2010 methods with some important refinements. Results for incidence of acute disorders and prevalence of chronic disorders are new additions to the analysis. Key improvements include expansion to the cause and sequelae list, updated systematic reviews, use of detailed injury codes, improvements to the Bayesian meta-regression method (DisMod-MR), and use of severity splits for various causes. An index of data representativeness, showing data availability, was calculated for each cause and impairment during three periods globally and at the country level for 2013. In total, 35 620 distinct sources of data were used and documented to calculated estimates for 301 diseases and injuries and 2337 sequelae. The comorbidity simulation provides estimates for the number of sequelae, concurrently, by individuals by country, year, age, and sex. Disability weights were updated with the addition of new population-based survey data from four countries. FINDINGS: Disease and injury were highly prevalent; only a small fraction of individuals had no sequelae. Comorbidity rose substantially with age and in absolute terms from 1990 to 2013. Incidence of acute sequelae were predominantly infectious diseases and short-term injuries, with over 2 billion cases of upper respiratory infections and diarrhoeal disease episodes in 2013, with the notable exception of tooth pain due to permanent caries with more than 200 million incident cases in 2013. Conversely, leading chronic sequelae were largely attributable to non-communicable diseases, with prevalence estimates for asymptomatic permanent caries and tension-type headache of 2.4 billion and 1.6 billion, respectively. The distribution of the number of sequelae in populations varied widely across regions, with an expected relation between age and disease prevalence. YLDs for both sexes increased from 537.6 million in 1990 to 764.8 million in 2013 due to population growth and ageing, whereas the age-standardised rate decreased little from 114.87 per 1000 people to 110.31 per 1000 people between 1990 and 2013. Leading causes of YLDs included low back pain and major depressive disorder among the top ten causes of YLDs in every country. YLD rates per person, by major cause groups, indicated the main drivers of increases were due to musculoskeletal, mental, and substance use disorders, neurological disorders, and chronic respiratory diseases; however HIV/AIDS was a notable driver of increasing YLDs in sub-Saharan Africa. Also, the proportion of disability-adjusted life years due to YLDs increased globally from 21.1% in 1990 to 31.2% in 2013. INTERPRETATION: Ageing of the world's population is leading to a substantial increase in the numbers of individuals with sequelae of diseases and injuries. Rates of YLDs are declining much more slowly than mortality rates. The non-fatal dimensions of disease and injury will require more and more attention from health systems. The transition to non-fatal outcomes as the dominant source of burden of disease is occurring rapidly outside of sub-Saharan Africa. Our results can guide future health initiatives through examination of epidemiological trends and a better understanding of variation across countries. FUNDING: Bill & Melinda Gates Foundation. PMID- 26063491 TI - Sulfadiazine-induced crystal nephropathy: a new 'old' problem. PMID- 26063493 TI - Assessment of students' satisfaction with a student-led team-based learning course. AB - PURPOSE: To date, no studies in the literature have examined student delivery of team-based learning (TBL) modules in the classroom. We aimed to assess student perceptions of a student-led TBL elective. METHODS: Third-year pharmacy students were assigned topics in teams and developed learning objectives, a 15-minute mini lecture, and a TBL application exercise and presented them to student colleagues. Students completed a survey upon completion of the course and participated in a focus group discussion to share their views on learning. RESULTS: The majority of students (n=23/30) agreed that creating TBL modules enhanced their understanding of concepts, improved their self-directed learning skills (n=26/30), and improved their comprehension of TBL pedagogy (n=27/30). However, 60% disagreed with incorporating student-generated TBL modules into core curricular classes. Focus group data identified student-perceived barriers to success in the elective, in particular the development of TBL application exercises. CONCLUSION: This study provides evidence that students positively perceived student-led TBL as encouraging proactive learning from peer-to-peer teaching. PMID- 26063492 TI - A prospective population-based study of maternal, fetal, and neonatal outcomes in the setting of prolonged labor, obstructed labor and failure to progress in low- and middle-income countries. AB - BACKGROUND: This population-based study sought to quantify maternal, fetal, and neonatal morbidity and mortality in low- and middle-income countries associated with obstructed labor, prolonged labor and failure to progress (OL/PL/FTP). METHODS: A prospective, population-based observational study of pregnancy outcomes was performed at seven sites in Argentina, Guatemala, India (2 sites, Belgaum and Nagpur), Kenya, Pakistan and Zambia. Women were enrolled in pregnancy and delivery and 6-week follow-up obtained to evaluate rates of OL/PL/FTP and outcomes resulting from OL/PL/FTP, including: maternal and delivery characteristics, maternal and neonatal morbidity and mortality and stillbirth. RESULTS: Between 2010 and 2013, 266,723 of 267,270 records (99.8%) included data on OL/PL/FTP with an overall rate of 110.4/1000 deliveries that ranged from 41.6 in Zambia to 200.1 in Pakistan. OL/PL/FTP was more common in women aged <20, nulliparous women, more educated women, women with infants >3500g, and women with a BMI >25 (RR 1.4, 95% CI 1.3 - 1.5), with the suggestion of OL/PL/FTP being less common in preterm deliveries. Protective characteristics included parity of >=3, having an infant <1500g, and having a BMI <18. Women with OL/PL/FTP were more likely to die within 42 days (RR 1.9, 95% CI 1.4 - 2.4), be infected (RR 1.8, 95% CI 1.5 - 2.2), and have hemorrhage antepartum (RR 2.8, 95% CI 2.1 - 3.7) or postpartum (RR 2.4, 95% CI 1.8 - 3.3). They were also more likely to have a stillbirth (RR 1.6, 95% CI 1.3 - 1.9), a neonatal demise at < 28 days (RR 1.9, 95% CI 1.6 - 2.1), or a neonatal infection (RR 1.2, 95% CI 1.1 - 1.3). As compared to operative vaginal delivery and cesarean section (CS), women experiencing OL/PL/FTP who gave birth vaginally were more likely to become infected, to have an infected neonate, to hemorrhage in the antepartum and postpartum period, and to die, have a stillbirth, or have a neonatal demise. Women with OL/PL/FTP were far more likely to deliver in a facility and be attended by a physician or other skilled provider than women without this diagnosis. CONCLUSIONS: Women with OL/PL/FTP in the communities studied were more likely to be primiparous, younger than age 20, overweight, and of higher education, with an infant with birthweight of >3500g. Women with this diagnosis were more likely to experience a maternal, fetal, or neonatal death, antepartum and postpartum hemorrhage, and maternal and neonatal infection. They were also more likely to deliver in a facility with a skilled provider. CS may decrease the risk of poor outcomes (as in the case of antepartum hemorrhage), but unassisted vaginal delivery exacerbates all of the maternal, fetal, and neonatal outcomes evaluated in the setting of OL/PL/FTP. PMID- 26063494 TI - Increased High-Sensitivity Troponin-T Levels Are Associated with Mortality After Ischemic Stroke. AB - Biomarkers for diagnosis, treatment, and outcome prediction after stroke are lacking. Therefore, we aimed to evaluate the association between increased serum troponin, stroke severity, and mortality. Unselected patients with acute ischemic stroke assessed for troponin levels were included over the span of 1 year. Risk factor profile, stroke etiology, stroke severity, and mortality during acute admission were recorded. The study included 212 patients, and 35 had increased troponin levels. Elevated troponin levels were associated with older age (82.1 +/ 10.7 vs. 72.2 +/- 12.6, p < 0.001), poor kidney function (calculated GFR 58.7 +/ 29.8 vs. 82.7 +/- 28.4, p < 0.001), and known ischemic heart disease (51.4% vs. 33.9%, p = 0.049). Patients with increased troponin had increased stroke severity on admission (National Institutes of Health Stroke Scale (NIHSS) 16.0 +/- 9.4 vs. 10.4 +/- 8.0, p < 0.001). This association remained significant after multivariate analysis but was nonlinear. Mortality rates were significantly higher in patients with increased troponin (37.1 vs. 5.6%, p < 0.001). On multivariate analysis, elevated troponin (odds ratio [OR] 22.57, 95% CI 4.4 116.6), absence of ischemic heart disease (OR 10.3, 95% CI 1.8-57.6), and admission NIHSS score (OR 1.59 for every 5 points, 95% CI 1.1-2.4) were associated with mortality. This study indicates that elevated troponin is an independent marker for severe deficits on presentation and for mortality in stroke patients. PMID- 26063495 TI - Identification and pathogenicity of a variant porcine epidemic diarrhea virus field strain with reduced virulence. AB - BACKGROUND: Since 2010, a variant Porcine epidemic diarrhea virus (PEDV), which causes an acute, highly contagious, and devastating viral enteric disease with a high mortality rate in suckling pigs, broke out in China and spread rapidly to neighboring countries, even to the North America. This virus gradually became the main subtype of PEDV worldwide. However, there were no reports of mild pathogenicity of a variant porcine epidemic diarrhea virus in China. FINDINGS: In 2013, a PEDV-positive sample from a sow with very mild clinical sign was used to inoculate in Vero cells to isolate the virus. This PEDV field strain, designated FL2013 strain, was successfully propagated and genetically characterized. The phylogenetic trees based upon either the complete genome or S gene showed that the FL2013 strain belongs to the genogroup G2b. The S gene of FL2013 has a 7-aa deletion (FEKVHVQ) in the C-terminus comparison with the other G2 PEDV sequences. Further comparative pathology study indicated that the FL2013 strain had reduced virulence to newborn piglets. CONCLUSIONS: A novel variant PEDV strain FL2013 with reduced virulence, as determined by the pathological study, was identified from east China. This strain is closely related to the genogroup-2 PEDV strains prevalent in the U.S. and China currently, but had a short deletion at the 3'-end of the spike gene. PMID- 26063496 TI - Paediatric cyclical Cushing's disease due to corticotroph cell hyperplasia. AB - BACKGROUND: Cushing's disease is very rare in the paediatric population. Although uncommon, corticotroph hyperplasia causing Cushing's syndrome has been described in the adult population, but appears to be extremely rare in children. Likewise, cyclical cortisol hypersecretion, while accounting for 15 % of adult cases of Cushing's disease, has only rarely been described in the paediatric population. Here, we describe a very rare case of a 13-year old boy with cyclical cortisol hypersecretion secondary to corticotroph cell hyperplasia. CASE PRESENTATION: The case is that of a 13-year old boy, presenting with a long history of symptoms and signs suggestive of hypercortisolism, who was found to have cyclical ACTH dependent hypercortisolism following dynamic pituitary testing and serial late night salivary cortisol measurements. The patient underwent endoscopic transsphenoidal resection of the pituitary. Early surgical remission was confirmed by undetectable post-operative morning plasma cortisol levels. Histology and immunocytochemistry of the resected pituitary tissue showed extensive corticotroph cell hyperplasia. CONCLUSION: This report describes a rare case of cyclical Cushing's disease secondary to corticotroph hyperplasia in a paediatric patient. This highlights the challenging and varied nature of Cushing's disease and its diagnosis, and the need to keep a differential diagnosis in mind during the diagnostic process. PMID- 26063497 TI - Six years of experience in entomological surveillance of indoor residual spraying against malaria transmission in Benin: lessons learned, challenges and outlooks. AB - BACKGROUND: From 2008 to 2013, a prevention intervention against malaria based on indoor residual spraying (IRS) was implemented in Benin. From 2008 to 2012, Ficam M((r)), a bendiocarb-containing product was used for house spraying, in association with pirimiphos methyl EC (Actellic EC) in 2013. This operation aimed to strengthen the effectiveness of treated nets so as to expedite the achievement of Millennium Development Goals (MDGs): the reduction of morbidity and mortality due to malaria by 75 % from 2000 to 2015. METHODS: Monitoring and evaluation (M&E) was implemented in order to evaluate the impact of IRS intervention on malaria transmission. Anopheles gambiae s.l. populations were sampled by human landing catch. In addition, window exit traps and pyrethrum spray catches were performed to assess exophagic behaviour of Anopheles vectors the main malaria vector in the treated areas. The residual activity of insecticide in the treated walls was also assessed using WHO bioassay test. RESULTS: The purpose of this project was to draw attention to new challenges and future prospects for the success of IRS in Benin. The main strength of the intervention was a large-scale operation in which more than 80 % of the houses were treated due to the strong adhesion of population. In addition, a significant reduction of the EIR in areas under IRS were observed. However, there were many challenges including the high cost of IRS implementation and the identification of suitable areas to implement IRS. This was because of the low and short residual effect of the insecticides recommended for IRS and the management strategy for vector resistance to insecticides. This indicated that challenges are accompanied by suggested solutions. For the cost of IRS to be accessible to states, then local organizations need to be created in partnership with the National Malaria Control Programme (NMCP) in order to ensure relevant planning and implementation of IRS. CONCLUSION: As an anticipatory measure against vector resistance, this paper proposes various methods, such as periodic IRS based on a combination of two or three insecticides of different classes used in rotation every two or three years. PMID- 26063498 TI - Action of Nanoparticles on Platelet Activation and Plasmatic Coagulation. AB - Nanomaterials can get into the blood circulation after injection or by release from implants but also by permeation of the epithelium after oral, respiratory or dermal exposure. Once in the blood, they can affect hemostasis, which is usually not intended. This review addresses effects of biological particles and engineered nanomaterials on hemostasis. The role of platelets and coagulation in normal clotting and the interaction with the immune system are described. Methods to identify effects of nanomaterials on clotting and results from in vitro and in vivo studies are summarized and the role of particle size and surface properties discussed. The literature overview showed that mainly pro-coagulative effects of nanomaterials have been described. In vitro studies suggested stronger effects of smaller than of larger NPs on coagulation and a greater importance of material than of surface charge. For instance, carbon nanotubes, polystyrene particles, and dendrimers inferred with clotting independent from their surface charge. Coating of particles with polyethylene glycol was able to prevent interaction with clotting by some particles, while it had no effect on others and the more recently developed bio-inspired surfaces might help to design coatings for more biocompatible particles. The mainly pro-coagulative action of nanoparticles could present a particular risk for individuals affected by common diseases such as diabetes, cancer, and cardiovascular diseases. Under standardized conditions, in vitro assays using human blood appear to be a suitable tool to study mechanisms of interference with hemostasis and to optimize hemocompatibility of nanomaterials. PMID- 26063499 TI - Lipoic acid decreases Mcl-1, Bcl-xL and up regulates Bim on ovarian carcinoma cells leading to cell death. AB - BACKGROUND: Ovarian carcinoma is the leading cause of death from gynecological cancer because there is risk of chemoresistance. As previously demonstrated in our laboratory, Alpha-lipoic acid (LA), a co-factor for metabolic enzymes, suppresses the tumor growth. In this study, we have researched the mechanisms that are responsible for the activity of LA. METHODS: We have studied the mechanisms of LA in two ovarian cancer cell lines, a cisplatin sensitive one, IGROV1 and its resistant counterpart, IGROV1-R10. These cells have been exposed to lipoic acid at various concentrations. Cell proliferation, cell cycle repartition and nuclear staining with DAPI were recorded. Western blot analyses were performed to detect various proteins implied in apoptotic cell death pathways. To investigate the formation of ROS, the oxidation of CM-DCFH2-DA were also determined. FINDINGS: LA suppressed growth proliferation and induced apoptosis in both ovarian cell lines. Moreover, LA provoked a down regulation of two anti-apoptotic proteins, Mcl-1 and Bcl-xL protein and a strong induction of the BH3-only protein Bim. Furthermore, LA induced ROS generation which could be involved in the CHOP induction which is known to activate the Bim translation. CONCLUSIONS: Our results reveal novel actions of LA which could explain the anti tumoral effects of the LA. Therefore, LA seems to be a promising compound for ovarian cancer treatment. PMID- 26063500 TI - Poly(ethylene glycol)-poly(lactic-co-glycolic acid) core-shell microspheres with enhanced controllability of drug encapsulation and release rate. AB - Poly(lactic-co-glycolic acid) (PLGA) microspheres have been widely used as drug carriers for minimally invasive, local, and sustained drug delivery. However, their use is often plagued by limited controllability of encapsulation efficiency, initial burst, and release rate of drug molecules, which cause unsatisfactory outcomes and several side effects including inflammation. This study presents a new strategy of tuning the encapsulation efficiency and the release rate of protein drugs from a PLGA microsphere by filling the hollow core of the microsphere with poly(ethylene glycol) (PEG) hydrogels of varying cross linking density. The PEG gel cores were prepared by inducing in situ cross linking reactions of PEG monoacrylate solution within the PLGA microspheres. The resulting PEG-PLGA core-shell microspheres exhibited (1) increased encapsulation efficiency, (2) decreased initial burst, and (3) a more sustained release of protein drugs, as the cross-linking density of the PEG gel core was increased. In addition, implantation of PEG-PLGA core-shell microspheres encapsulated with vascular endothelial growth factor (VEGF) onto a chicken chorioallantoic membrane resulted in a significant increase in the number of new blood vessels at an implantation site, while minimizing inflammation. Overall, this strategy of introducing PEG gel into PLGA microspheres will be highly useful in tuning release rates and ultimately in improving the therapeutic efficacy of a wide array of protein drugs. PMID- 26063502 TI - Myoclonus in Exertional Rhabdomyolysis Without Renal Failure. PMID- 26063501 TI - The dynamin inhibitor dynasore inhibits bone resorption by rapidly disrupting actin rings of osteoclasts. AB - The cytoskeletal organization of osteoclasts is required for bone resorption. Binding of dynamin with guanosine triphosphate (GTP) was previously suggested to be required for the organization of the actin cytoskeleton. However, the role of the GTPase activity of dynamin in the organization of the actin cytoskeleton as well as in the bone-resorbing activity of osteoclasts remains unclear. This study investigated the effects of dynasore, an inhibitor of the GTPase activity of dynamin, on the bone-resorbing activity of and actin ring formation in mouse osteoclasts in vitro and in vivo. Dynasore inhibited the formation of resorption pits in osteoclast cultures by suppressing actin ring formation and rapidly disrupting actin rings in osteoclasts. A time-lapse image analysis showed that dynasore shrank actin rings in osteoclasts within 30 min. The intraperitoneal administration of dynasore inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced trabecular bone loss in mouse femurs. These in vitro and in vivo results suggest that the GTPase activity of dynamin is critical for the bone-resorbing activity of osteoclasts and that dynasore is a seed for the development of novel anti-resorbing agents. PMID- 26063503 TI - A Randomized Study of the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of Clopidogrel in Three Different CYP2C19 Genotype Groups of Healthy Japanese Subjects. AB - AIM: We investigated the safety of 600/150 mg regimen of clopidogrel and the pharmacodynamics and pharmacokinetics of both 300/75 mg regimen and 600/150 mg regimen of clopidogrel in 72 Japanese subjects. METHODS: A randomized study was conducted in healthy Japanese male subjects. Eligible subjects were stratified by dose regimen (300 mg loading dose of clopidogrel on day 1 followed by a 75 mg maintenance dose from days 2 to 7 or a 600 mg loading dose of clopidogrel on day 1 followed by a 150 mg maintenance dose from days 2 to 7) and CYP2C19 metabolizer group [extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs)]. Platelet aggregation and platelet reactivity were evaluated by measuring the maximum platelet aggregation intensity (MAI) induced by 5 and 20 MUM ADP, phosphorylation of vasodilator-stimulated phosphoprotein (VASP), and P2Y12 reaction units (PRU) using the VerifyNow system, respectively. We also measured the plasma concentrations of clopidogrel and its active metabolite H4. RESULTS: No treatment emergent adverse events in the 300/75 mg and 600/150 mg regimen were observed in EMs, IMs, and PMs. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP in the 300/75 mg and 600/150 mg clopidogrel regimens, and MAI (%) in IM group was equipotent to EM irrespective of the clopidogrel dosage. The double dose regimen decreased MAI in the PM group as equipotent to the IM group receiving the standard dose regimen without the extension of bleeding time. No clear relationship of exposure to clopidogrel and CYP2C19 function was observed, whereas active metabolite H4 exposure was likely to be related to CYP2C19 function. CONCLUSION: Clopidogrel in the 600/150 mg regimen was well tolerated. All CYP metabolizer groups exhibited a lower MAI (%) induced by ADP and anti-platelet activities analyzed by VASP and VerifyNow test in the 300/75 mg and 600/150 mg regimens in healthy Japanese subjects. PMID- 26063504 TI - Non-HDL-C Levels and the Criteria in Japanese Children. PMID- 26063505 TI - Analysis of Loss-of-Function Mutants in Aspartate Kinase and Homoserine Dehydrogenase Genes Points to Complexity in the Regulation of Aspartate-Derived Amino Acid Contents. AB - Biosynthesis of aspartate (Asp)-derived amino acids lysine (Lys), methionine (Met), threonine (Thr), and isoleucine involves monofunctional Asp kinases (AKs) and dual-functional Asp kinase-homoserine dehydrogenases (AK-HSDHs). Four-week old loss-of-function Arabidopsis (Arabidopsis thaliana) mutants in the AK-HSDH2 gene had increased amounts of Asp and Asp-derived amino acids, especially Thr, in leaves. To explore mechanisms behind this phenotype, we obtained single mutants for other AK and AK-HSDH genes, generated double mutants from ak-hsdh2 and ak mutants, and performed free and protein-bound amino acid profiling, transcript abundance, and activity assays. The increases of Asp, Lys, and Met in ak-hsdh2 were also observed in ak1-1, ak2-1, ak3-1, and ak-hsdh1-1. However, the Thr increase in ak-hsdh2 was observed in ak-hsdh1-1 but not in ak1-1, ak2-1, or ak3 1. Activity assays showed that AK2 and AK-HSDH1 are the major contributors to overall AK and HSDH activities, respectively. Pairwise correlation analysis revealed positive correlations between the amount of AK transcripts and Lys sensitive AK activity and between the amount of AK-HSDH transcripts and both Thr sensitive AK activity and total HSDH activity. In addition, the ratio of total AK activity to total HSDH activity negatively correlates with the ratio of Lys to the total amount of Met, Thr, and isoleucine. These data led to the hypothesis that the balance between Lys-sensitive AKs and Thr-sensitive AK-HSDHs is important for maintaining the amounts and ratios of Asp-derived amino acids. PMID- 26063506 TI - FOREVER YOUNG FLOWER Negatively Regulates Ethylene Response DNA-Binding Factors by Activating an Ethylene-Responsive Factor to Control Arabidopsis Floral Organ Senescence and Abscission. AB - In this study of Arabidopsis (Arabidopsis thaliana), we investigated the relationship between FOREVER YOUNG FLOWER (FYF) and Ethylene Response DNA-binding Factors (EDFs) and functionally analyzed a key FYF target, an Ethylene-Responsive Factor (ERF), that controls flower senescence/abscission. Ectopic expression of EDF1/2/3/4 caused promotion of flower senescence/abscission and the activation of the senescence-associated genes. The presence of a repressor domain in EDFs and the enhancement of the promotion of senescence/abscission in EDF1/2/3/4+SRDX (converting EDFs to strong repressors by fusion with the ERF-associated amphiphilic repression motif repression domain SRDX) transgenic plants suggested that EDFs act as repressors. The significant reduction of beta-glucuronidase (GUS) expression by 35S:FYF in EDF1/2/3/4:GUS plants indicates that EDF1/2/3/4 functions downstream of FYF in regulating flower senescence/abscission. In this study, we also characterized an ERF gene, FOREVER YOUNG FLOWER UP-REGULATING FACTOR1 (FUF1), which is up-regulated by FYF during flower development. Ectopic expression of FUF1 caused similar delayed flower senescence/abscission as seen in 35S:FYF plants. This phenotype was correlated with deficient abscission zone formation, ethylene insensitivity, and down-regulation of EDF1/2/3/4 and abscission-associated genes in 35S:FUF1 flowers. In contrast, significant promotion of flower senescence/abscission and up-regulation of EDF1/2/3/4 were observed in 35S:FUF1+SRDX transgenic dominant-negative plants, in which FUF1 is converted to a potent repressor by fusion to an SRDX-suppressing motif. Thus, FUF1 acts as an activator in suppressing EDF1/2/3/4 function and senescence/abscission of the flowers. Our results reveal that FYF regulates flower senescence/abscission by negatively regulating EDF1/2/3/4, which is the downstream gene in the ethylene response, by activating FUF1 in Arabidopsis. PMID- 26063507 TI - Aerobic training decreases bronchial hyperresponsiveness and systemic inflammation in patients with moderate or severe asthma: a randomised controlled trial. AB - BACKGROUND: The benefits of aerobic training for the main features of asthma, such as bronchial hyperresponsiveness (BHR) and inflammation, are poorly understood. We investigated the effects of aerobic training on BHR (primary outcome), serum inflammatory cytokines (secondary outcome), clinical control and asthma quality of life (Asthma Quality of Life Questionnaire (AQLQ)) (tertiary outcomes). METHODS: Fifty-eight patients were randomly assigned to either the control group (CG) or the aerobic training group (TG). Patients in the CG (educational programme+breathing exercises (sham)) and the TG (same as the CG+aerobic training) were followed for 3 months. BHR, serum cytokine, clinical control, AQLQ, induced sputum and fractional exhaled nitric oxide (FeNO) were evaluated before and after the intervention. RESULTS: After 12 weeks, 43 patients (21 CG/22 TG) completed the study and were analysed. The TG improved in BHR by 1 doubling dose (dd) (95% CI 0.3 to 1.7 dd), and they experienced reduced interleukin 6 (IL-6) and monocyte chemoattractant protein 1 (MCP-1) and improved AQLQ and asthma exacerbation (p<0.05). No effects were seen for IL-5, IL-8, IL 10, sputum cellularity, FeNO or Asthma Control Questionnaire 7 (ACQ-7; p>0.05). A within-group difference was found in the ACQ-6 for patients with non-well controlled asthma and in sputum eosinophil and FeNO in patients in the TG who had worse airway inflammation. CONCLUSIONS: Aerobic training reduced BHR and serum proinflammatory cytokines and improved quality of life and asthma exacerbation in patients with moderate or severe asthma. These results suggest that adding exercise as an adjunct therapy to pharmacological treatment could improve the main features of asthma. TRIAL REGISTRATION NUMBER: NCT02033122. PMID- 26063508 TI - Double-blind randomised controlled trial of vitamin D3 supplementation for the prevention of acute respiratory infection in older adults and their carers (ViDiFlu). AB - RATIONALE: Low-dose vitamin D supplementation is already recommended in older adults for prevention of fractures and falls, but clinical trials investigating whether higher doses could provide additional protection against acute respiratory infection (ARI) are lacking. OBJECTIVE: To conduct a clinical trial of high-dose versus low-dose vitamin D3 supplementation for ARI prevention in residents of sheltered-accommodation housing blocks ('schemes') and their carers in London, UK. MEASUREMENTS AND METHODS: Fifty-four schemes (137 individual participants) were allocated to the active intervention (vitamin D3 2.4 mg once every 2 months +10 MUg daily for residents, 3 mg once every 2 months for carers), and 54 schemes with 103 participants were allocated to control (placebo once every 2 months +vitamin D3 10 MUg daily for residents, placebo once every 2 months for carers) for 1 year. Primary outcome was time to first ARI; secondary outcomes included time to first upper/lower respiratory infection (URI/LRI, analysed separately), and symptom duration. MAIN RESULTS: Inadequate vitamin D status was common at baseline: 220/240 (92%) participants had serum 25(OH)D concentration <75 nmol/L. The active intervention did not influence time to first ARI (adjusted HR (aHR) 1.18, 95% CI 0.80 to 1.74, p=0.42). When URI and LRI were analysed separately, allocation to the active intervention was associated with increased risk of URI (aHR 1.48, 95% CI 1.02 to 2.16, p=0.039) and increased duration of URI symptoms (median 7.0 vs 5.0 days for active vs control, adjusted ratio of geometric means 1.34, 95% CI 1.09 to 1.65, p=0.005), but not with altered risk or duration of LRI. CONCLUSIONS: Addition of intermittent bolus-dose vitamin D3 supplementation to a daily low-dose regimen did not influence risk of ARI in older adults and their carers, but was associated with increased risk and duration of URI. TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT01069874. PMID- 26063509 TI - Behaviour of NBD-head group labelled phosphatidylethanolamines in POPC bilayers: a molecular dynamics study. AB - A complete homologous series of fluorescent phosphatidylethanolamines (diCnPE), labelled at the head group with a 7-nitrobenz-2-oxa-1,3-diazo-4-yl(NBD) fluorophore and inserted in 1-palmitoyl, 2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers, was studied using atomistic molecular dynamics simulations. The longer-chained derivatives of NBD-diCnPE, with n = 14, 16, and 18, are commercially available, and widely used as fluorescent membrane probes. Properties such as location of atomic groups and acyl chain order parameters of both POPC and NBD-diCnPE, fluorophore orientation and hydrogen bonding, membrane electrostatic potential and lateral diffusion were calculated for all derivatives in the series. Most of these probes induce local disordering of POPC acyl chains, which is on the whole counterbalanced by ordering resulting from binding of sodium ions to lipid carbonyl/glycerol oxygen atoms. An exception is found for NBD-diC16PE, which displays optimal matching with POPC acyl chain length and induces a slight local ordering of phospholipid acyl chains. Compared to previously studied fatty amines, acyl chain-labelled phosphatidylcholines, and sterols bearing the same fluorescent tag, the chromophore in NBD-diCnPE locates in a similar region of the membrane (near the glycerol backbone/carbonyl region) but adopts a different orientation (with the NO2 group facing the interior of the bilayer). This modification leads to an inverted orientation of the P-N axis in the labelled lipid, which affects the interface properties, such as the membrane electrostatic potential and hydrogen bonding to lipid head group atoms. The implications of this study for the interpretation of the photophysical properties of NBD-diCnPE (complex fluorescence emission kinetics, differences with other NBD lipid probes) are discussed. PMID- 26063510 TI - IMMEDIATE MENTAL CONSEQUENCES OF THE GREAT EAST JAPAN EARTHQUAKE AND FUKUSHIMA NUCLEAR POWER PLANT ACCIDENT ON MOTHERS EXPERIENCING MISCARRIAGE, ABORTION, AND STILLBIRTH: THE FUKUSHIMA HEALTH MANAGEMENT SURVEY. AB - BACKGROUND: The Fukushima Pregnancy and Birth Survey was launched to monitor pregnant mothers' health after the Great East Japan Earthquake and Fukushima Daiichi Nuclear Power Plant (NPP) accident. Several lines of investigations have indicated that a disaster impacts maternal mental health with childbirth. However, there is no research regarding mental health of mothers with fetal loss after a disaster. In this report, we focus on those women immediately after the Great East Japan Earthquake and Fukushima NPP accident and discuss their support needs. MATERIALS AND METHODS: Data regarding 61 miscarriages, 5 abortions, and 22 stillbirths were analyzed among the women who were pregnant at the time of the accident in the present study. We used a two-item case-finding instrument for depression screening, and compared the childbirth group with the fetal loss groups. We also analyzed mothers' opinions written as free-form text. RESULTS: Among the three fetal loss groups, the proportion of positive depression screens was significantly higher in the miscarriage and stillbirth group than in the childbirth group. Mothers' opinions were grouped into six categories, with pregnancy-related items being most common, especially in the miscarriage and stillbirth groups. CONCLUSION: A higher proportion of Fukushima mothers with fetal loss, especially those with miscarriage and stillbirth, had depressive symptoms compared to those who experienced childbirth. Health care providers need to pay close attention to this vulnerable group and respond to their concerns regarding the effects on their fertility. PMID- 26063511 TI - MECHANISTIC INSIGHTS OF CORONARY VASOSPASM AND NEW THERAPEUTIC APPROACHES. PMID- 26063512 TI - LONG-TERM FOLLOW-UP OF FREE VASCULARIZED FIBULAR HEAD GRAFT FOR RECONSTRUCTION OF THE PROXIMAL HUMERUS AFTER WIDE RESECTION FOR BONE SARCOMA. AB - PURPOSE: This study investigated the shape of bone grafts and associations with upper limb function over the long term after free vascularized fibular head graft (FVFHG) for reconstruction of the proximal humerus after wide resection for bone sarcoma. METHODS: Patients comprised 3 women who had undergone FVFHG at least 5 years previously. Age at surgery was 12 years in 2 cases and 76 years in one. The mean follow-up periods were 10 years 4 months. Evaluated parameters comprised: 1) graft hypertrophy, and 2) shape of the fibular head as changes in shape of the bone graft; and 3) ISOLS score, and 4) DASH score as indicators of upper limb function. RESULTS: Rates of graft hypertrophy of the fibular shaft were -14%, 17%, and -20%, respectively, with transverse diameter decreasing in all cases. In terms of changes in shape of the grafted fibular head, transverse diameter had diminished in 2 patients (-5 mm and -2 mm), and the head had been completely resorbed in the remaining patient. Both patients in whom the fibular head remained were young, and both had good ISOLS scores >80% and good DASH scores of 5.0 and 8.3. The patient in whom the fibular head had been resorbed was elderly, with ISOLS and DASH scores of 73.3% and 34.2, respectively; comparatively poor compared with the other two. A comparison of ISOLS and DASH scores before and after fibular head resorption, however, showed no deterioration in either score. CONCLUSIONS: Long-term follow-up of humerus reconstruction by FVFHG showed no deterioration in upper limb function despite the risk of fibular head resorption. FVFHG of the proximal humerus is a reconstruction technique that can provide good long-term upper limb function. PMID- 26063513 TI - Zingiber mioga (Thunb.) Roscoe attenuates allergic asthma induced by ovalbumin challenge. AB - Zingiber mioga (Thunb.) Roscoe (ZM) is a traditional medicine, used to treat inflammatory diseases. The present study aimed to evaluate the inhibitory effects of ZM on the inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophage cells and in a mouse model of ovalbumin (OVA)-induced allergic asthma. Mice received OVA sensitization on day 0 and 14, and were challenged with OVA between days 21 and 23. ZM was administered to the mice at a dose of 30 mg/kg, 1 h prior to OVA challenge. In LPS-stimulated RAW264.7 cells, ZM significantly decreased nitric oxide (NO) and tumor necrosis factor (TNF) alpha production in a concentration-dependent manner, and mRNA expression of inducible NO synthase (iNOS), TNF-alpha and matrix metalloproteinase (MMP)-9 was reduced. In addition, treatment with ZM decreased the inflammatory cell count in bronchoalveolar lavage fluid from the mice, and reduced the expression of interleukin (IL)-4, IL-5, IL-13, eotaxin and immunoglobulin E. ZM also reduced airway hyperresponsiveness in OVA-challenged mice, and attenuated the infiltration of inflammatory cells and mucus production in the airways, with a decrease in the expression of iNOS and MMP-9 in lung tissue. In conclusion, the results of the present study indicate that ZM effectively inhibits inflammatory responses. Therefore, it may be that ZM has potential as a therapeutic agent for use in inflammatory diseases. PMID- 26063514 TI - Evaluation of low-cost materials for sorption of hydrophobic organic pollutants in stormwater. AB - Conventional stormwater treatment techniques such as sedimentation and filtration are inefficient for removing the dissolved and colloidal phases of hydrophobic organic compounds (HOCs) present in stormwater. Adsorption could be a promising technique for removing colloidal and dissolved pollutants. Five low-cost sorbent materials were investigated in this project, including two minerals - vermiculite and perlite - and three waste products - two pine barks and a sawdust - as potential adsorbents for removal of polycyclic aromatic hydrocarbons (PAHs), alkylphenols and phthalates; HOCs commonly found in stormwater. Adsorption capacity and kinetics were studied through batch adsorption tests using synthetic stormwater spiked with a mixture of HOCs. Vermiculite and perlite exhibited insignificant removal of the organic contaminants. The three wood-based materials retained >80% of the initial HOC concentration (10-300 MUg/L). The two barks exhibited slightly higher adsorption capacities of HOCs than the sawdust. For all compounds tested, maximum adsorption onto the wood-based media was reached in <10 min. The highest adsorption capacity was found for PAHs (up to 45 MUg/g), followed by alkylphenols and phthalates. No correlation was found between adsorption capacity and physical-chemical parameters such as solubility and partition coefficients (log K(ow)). Agreement between empirical data and the pseudo-second order kinetic model suggest chemisorption of HOCs onto a monolayer on wood-based media. This could lead to early saturation of the materials and should be investigated in future studies through repeated adsorption of HOCs, for example in column studies. PMID- 26063515 TI - Mixotrophic cultivation of a microalga Scenedesmus obliquus in municipal wastewater supplemented with food wastewater and flue gas CO2 for biomass production. AB - The biomass and lipid/carbohydrate production by a green microalga Scenedesmus obliquus under mixotrophic condition using food wastewater and flue gas CO2 with municipal wastewater was investigated. Different dilution ratios (0.5-2%) of municipal wastewater with food wastewater were evaluated in the presence of 5, 10 and 14.1% CO2. The food wastewater (0.5-1%) with 10-14.1% CO2 supported the highest growth (0.42-0.44 g L(-1)), nutrient removal (21-22 mg TN L(-1)), lipid productivity (10-11 mg L(-1)day(-1)) and carbohydrate productivity (13-16 mg L( 1)day(-1)) by S. obliquus after 6 days of cultivation. Food wastewater increased the palmitic and oleic acid contents up to 8 and 6%, respectively. Thus, application of food wastewater and flue gas CO2 can be employed for enhancement of growth, lipid/carbohydrate productivity and wastewater treatment efficiency of S. obliquus under mixotrophic condition, which can lead to development of a cost effective strategy for microalgal biomass production. PMID- 26063516 TI - A tool to assess potential for alien plant establishment and expansion under climate change. AB - Predicting the influence of climate change on the potential distribution of naturalised alien plant species is an important and challenging task. While prioritisation of management actions for alien plants under current climatic conditions has been widely adopted, very few systems explicitly incorporate the potential of future changes in climate conditions to influence the distribution of alien plant species. Here, we develop an Australia-wide screening tool to assess the potential of naturalised alien plants to establish and spread under both current and future climatic conditions. The screening tool developed uses five spatially explicit criteria to establish the likelihood of alien plant population establishment and expansion under baseline climate conditions and future climates for the decades 2035 and 2065. Alien plants are then given a threat rating according to current and future threat to enable natural resource managers to focus on those species that pose the largest potential threat now and in the future. To demonstrate the screening tool, we present results for a representative sample of approximately 10% (n = 292) of Australia's known, naturalised alien plant species. Overall, most alien plant species showed decreases in area of habitat suitability under future conditions compared to current conditions and therefore the threat rating of most alien plant species declined between current and future conditions. Use of the screening tool is intended to assist natural resource managers in assessing the threat of alien plant establishment and spread under current and future conditions and thus prioritise detailed weed risk assessments for those species that pose the greatest threat. The screening tool is associated with a searchable database for all 292 alien plant species across a range of spatial scales, available through an interactive web-based portal at http://weedfutures.net/. PMID- 26063517 TI - Comparison between rice husk ash grown in different regions for stabilizing fly ash from a solid waste incinerator. AB - The Stabilization of heavy metals from municipal solid waste incineration (MSWI) fly ash by rice husk ash (RHA) is under intense study as an effective strategy to recover and reuse industrial and agricultural waste together. We compare the metal entrapment performances of RHA from different Asian rice sources - namely from Japonica rice grown in Italy and Indica rice grown in India - Physicochemical and morphological characterization of the final stabilized material show that the same thermal treatment may result in marked structural differences in the silica contained in the two RHA. Remarkably, one of them displays a crystalline silica content, although obtained by a thermal treatment below 800 degrees C. We also find that the presence of an alkali metal ion (potassium) in the rice husk plays a crucial role in the attainment of the final silica phase. These physicochemical differences are mirrored by different stabilization yields by the two RHA. PMID- 26063518 TI - The bone marrow metastasis niche in retinoblastoma. AB - BACKGROUND: Retinoblastoma (Rb) is a progressive cancer which mainly occurs in children, and which is caused by different genetic or epigenetic alterations that lead to inactivation of both alleles of the RB1 gene. Hereditary and non hereditary forms of Rb do exist, and the hereditary form is associated with an increased risk of secondary malignancies. Metastasis to distant organs is a critical feature of many tumors, and may be caused by various molecular alterations at different stages. Recognition of these alterations and, thus, insight into the processes underlying the development of metastases may result in novel preventive as well as effective targeted treatment options. Rb is associated with metastases to various organs and tissues, including the bone marrow (BM). METHODS: Here, we provide an overview of mutations and other molecular changes known to be involved in Rb development and metastasis to the BM. This overview is based on a literature search ranging from 1990 to 2015. CONCLUSIONS: The various BM metastasis-related molecular changes identified to date may be instrumental for a better diagnosis, prognosis and classification of Rb patients, as well as for the development of novel comprehensive (targeted) therapies. PMID- 26063521 TI - [Big data in medicine and healthcare]. AB - Healthcare is one of the business fields with the highest Big Data potential. According to the prevailing definition, Big Data refers to the fact that data today is often too large and heterogeneous and changes too quickly to be stored, processed, and transformed into value by previous technologies. The technological trends drive Big Data: business processes are more and more executed electronically, consumers produce more and more data themselves - e.g. in social networks - and finally ever increasing digitalization. Currently, several new trends towards new data sources and innovative data analysis appear in medicine and healthcare. From the research perspective, omics-research is one clear Big Data topic. In practice, the electronic health records, free open data and the "quantified self" offer new perspectives for data analytics. Regarding analytics, significant advances have been made in the information extraction from text data, which unlocks a lot of data from clinical documentation for analytics purposes. At the same time, medicine and healthcare is lagging behind in the adoption of Big Data approaches. This can be traced to particular problems regarding data complexity and organizational, legal, and ethical challenges. The growing uptake of Big Data in general and first best-practice examples in medicine and healthcare in particular, indicate that innovative solutions will be coming. This paper gives an overview of the potentials of Big Data in medicine and healthcare. PMID- 26063522 TI - [Health care research: potential beneficiary of big data]. AB - Health care research focuses on the description and analysis of the health care system and its requirements. Research-derived innovations are the subject of trials and evaluation of the transfer to daily routine. For this purpose health care research has developed a broad theory-based spectrum of methods. On the other hand, the concept of big data is an new informatics-driven approach to large data sets independent of content. With its technical vocabulary the concept of big data does not easily fit into traditional health care research. Central tasks of health care research such as the generation of theories, norm-oriented evaluations or proof of causality can neither be supported nor replaced by big data. However, the concept of big data has the potential to support health care research, with traditional tasks such as data linkage, analysis of health care paths, quick access to up-to-date data on the distribution and acceptance of health care services, as well as prediction and the generation of hypotheses. The prerequisite for all this is a trust-based linkage of different medical and nonmedical data sources on the basis of the legal regulation of data access and data protection. PMID- 26063523 TI - [Linkage of large secondary and registry data sources with data of cohort studies : usage of a dual potential]. AB - Cohort studies provide the best evidence of all epidemiological observational studies for the identification of causal relationships between risk factors and diseases. However, this design may lead to drawbacks that may affect the validity and reliability of the results. This follows in particular from systematic errors, such as selection bias or recall bias. One possibility to avoid or counteract some of these drawbacks is to link primary data from cohort studies with secondary and register data. The linkage of these data may also be used for mutual validations. Data that were previously linked with primary data within the context of cohort studies in Germany were obtained from statutory health insurances and pensions as well as data from the Federal Employment Agency and cancer registries. All these data have two features in common: First, they all cover detailed information about a large population and over a long period of time. Second, all sources are in principle able to provide data on an individual level such that an individual data linkage, e.g. with primary data, is possible. However, use and linkage of each of these data sources are restricted by several limitations. These have to be accounted for as well as numerous legal restrictions that exist in Germany to especially prevent the misuse of social data. PMID- 26063524 TI - Gene polymorphisms as risk factors for predicting the cardiovascular manifestations in Marfan syndrome. Role of folic acid metabolism enzyme gene polymorphisms in Marfan syndrome. AB - Folic acid metabolism enzyme polymorphisms are believed to be responsible for the elevation of homocysteine (HCY) concentration in the blood plasma, correlating with the pathogenesis of aortic aneurysms and aortic dissection. We studied 71 Marfan patients divided into groups based on the severity of cardiovascular involvement: no intervention required (n=27, Group A); mild involvement requiring intervention (n=17, Group B); severe involvement (n=27, Group C) subdivided into aortic dilatation (n=14, Group C1) and aortic dissection (n=13, Group C2), as well as 117 control subjects. We evaluated HCY, folate, vitamin B12 and the polymorphisms of methylenetetrahydrofolate reductase (MTHFR;c.665C>T and c.1286A>C), methionine synthase (MTR;c.2756A>G) and methionine synthase reductase (MTRR;c.66A>G). Multiple comparisons showed significantly higher levels of HCY in Group C2 compared to Groups A, B, C1 and control group (p<0.0001, p<0.0001, p=0.001 and p=0.003, respectively). Folate was lower in Group C2 than in Groups A, B, C1 and control subjects (p<0.0001, p=0.02, p<0.0001 and p<0.0001, respectively). Group C2 had the highest prevalence of homozygotes for all four gene polymorphisms. Multivariate logistic regression analysis revealed that HCY plasma level was an independent risk factor for severe cardiovascular involvement (Group C; odds ratio [OR] 1.85, 95% confidence interval [CI] 1.28-2.67, p=0.001) as well as for aortic dissection (Group C2; OR 2.49, 95%CI 1.30-4.78, p=0.006). In conclusion, severe cardiovascular involvement in Marfan patients, and especially aortic dissection, is associated with higher HCY plasma levels and prevalence of homozygous genotypes of folic acid metabolism enzymes than mild or no cardiovascular involvement. These results suggest that impaired folic acid metabolism has an important role in the development and remodelling of the extracellular matrix of the aorta. PMID- 26063525 TI - Oscillating epidemics in a dynamic network model: stochastic and mean-field analysis. AB - An adaptive network model using SIS epidemic propagation with link-type-dependent link activation and deletion is considered. Bifurcation analysis of the pairwise ODE approximation and the network-based stochastic simulation is carried out, showing that three typical behaviours may occur; namely, oscillations can be observed besides disease-free or endemic steady states. The oscillatory behaviour in the stochastic simulations is studied using Fourier analysis, as well as through analysing the exact master equations of the stochastic model. By going beyond simply comparing simulation results to mean-field models, our approach yields deeper insights into the observed phenomena and help better understand and map out the limitations of mean-field models. PMID- 26063526 TI - On the establishment, persistence, and inevitable extinction of populations. AB - Comprehensive models of stochastic, clonally reproducing populations are defined in terms of general branching processes, allowing birth during maternal life, as for higher organisms, or by splitting, as in cell division. The populations are assumed to start small, by mutation or immigration, reproduce supercritically while smaller than the habitat carrying capacity but subcritically above it. Such populations establish themselves with a probability wellknown from branching process theory. Once established, they grow up to a band around the carrying capacity in a time that is logarithmic in the latter, assumed large. There they prevail during a time period whose duration is exponential in the carrying capacity. Even populations whose life style is sustainble in the sense that the habitat carrying capacity is not eroded but remains the same, ultimately enter an extinction phase, which again lasts for a time logarithmic in the carrying capacity. However, if the habitat can carry a population which is large, say millions of individuals, and it manages to avoid early extinction, time in generations to extinction will be exorbitantly long, and during it, population composition over ages, types, lineage etc. will have time to stabilise. This paper aims at an exhaustive description of the life cycle of such populations, from inception to extinction, extending and overviewing earlier results. We shall also say some words on persistence times of populations with smaller carrying capacities and short life cycles, where the population may indeed be in danger in spite of not eroding its environment. PMID- 26063527 TI - A nonlocal and periodic reaction-diffusion-advection model of a single phytoplankton species. AB - In this article, we are concerned with a nonlocal reaction-diffusion-advection model which describes the evolution of a single phytoplankton species in a eutrophic vertical water column where the species relies solely on light for its metabolism. The new feature of our modeling equation lies in that the incident light intensity and the death rate are assumed to be time periodic with a common period. We first establish a threshold type result on the global dynamics of this model in terms of the basic reproduction number R0. Then we derive various characterizations of R0 with respect to the vertical turbulent diffusion rate, the sinking or buoyant rate and the water column depth, respectively, which in turn give rather precise conditions to determine whether the phytoplankton persist or become extinct. Our theoretical results not only extend the existing ones for the time-independent case, but also reveal new interesting effects of the modeling parameters and the time-periodic heterogeneous environment on persistence and extinction of the phytoplankton species, and thereby suggest important implications for phytoplankton growth control. PMID- 26063529 TI - Anthelmintic activity of ginger, curcumin, and praziquentel against Raillietina cesticillus (in vitro and in vivo). AB - This work evaluates the anthelminitic activity of ginger and curcumin on the cestode Raillietina cesticillus. Live parasites were collected from intestine of naturally infected chickens in PBS 0.9 % and then incubated at 37 degrees C in media containing ginger extract at three different concentrations (125, 250, and 500 mg); every concentration was dissolved in 10 ml media. The curcumin extract was used at three different concentrations (250, 500, and 1000 mg); each was dissolved in 10 ml media. Praziquantel at a concentration of 600 mg was added to 10 ml media. A control one without extract was reported. Regression of worms increased gradually in all concentrations. At 500 mg ginger (50 +/- 0 %), worms were regressed at 48 h post-exposure (h.p.e.). Also (50 +/- 1.8 %), worms were regressed at 1000 mg curcumin at the same time. On the other hand, praziquantel showed the highest regression (65 +/- 2.3 %). The extract efficacy was exhibit as concentration-time-dependent mainly at higher concentrations used after 48 h. In vivo effects of ginger and curcumin were lower than those in vitro. PMID- 26063531 TI - Distribution and diversity of Nosema bombi (Microsporidia: Nosematidae) in the natural populations of bumblebees (Bombus spp.) from West Siberia. AB - Nosema bombi is an obligate intracellular parasite of bumblebees (Hymenoptera, Bombus spp.), which has significant negative effect on individual bumblebees, colony fitness, and development. Recently, several new genetic variants of N. bombi without a defined taxonomic status were identified in natural bumblebee populations from Russia, China, and several European countries, as well as N. ceranae, originally isolated from honey bees, was described in bumblebee species. Thus, it is required to investigate more Nosema variability in bumblebee populations for identifying new genetic Nosema variants. In our study, we used several methods such as total DNA isolation, polymerase chain reaction (PCR) amplification, cloning, sequencing, and comparative and phylogenetic analysis to investigate a prevalence of N. bombi and its diversity in the natural populations of bumblebees across West Siberia. DNA was extracted from intestinal bumblebee tissues. Identification of the parasite was conducted, using PCR with primers specific for the ribosomal RNA gene cluster and methionine aminopeptidase 2 gene of N. bombi followed by sequencing. Seven hundred twenty-seven individual bumblebees belonging to 16 species were tested; 64 specimens revealed presence of the parasite. Prevalence of Nosema bombi infection was different in each region and varied from 4 to 20 %. No infection was found in Bombus agrorum (n = 194) and Bombus equestris (n = 132), both common bumblebees in West Siberia. Three different genetic variants of the same species, N. bombi, were identified. The first variant belonged to N. bombi (AY008373) identified by Fies et al. (J Apicult Res 40:91-96, 2001), second (N. bombi WS2) was identical to the West Siberian variant identified by Szentgyorgyi et al. (Polish Journal of Ecology 59:599-610, 2011), and the last variant, N. bombi WS3, was new. The results led us to suggest that the prevalence of the N. bombi is related to the population structure of bumblebees and distribution of the particular genetic variants of N. bombi. PMID- 26063530 TI - Green-synthesized silver nanoparticles as a novel control tool against dengue virus (DEN-2) and its primary vector Aedes aegypti. AB - Dengue is an arthropod-borne viral infection mainly vectored through the bite of Aedes mosquitoes. Recently, its transmission has strongly increased in urban and semi-urban areas of tropical and sub-tropical regions worldwide, becoming a major international public health concern. There is no specific treatment for dengue. Its prevention and control solely depends on effective vector control measures. In this study, we proposed the green-synthesis of silver nanoparticles (AgNP) as a novel and effective tool against the dengue serotype DEN-2 and its major vector Aedes aegypti. AgNP were synthesized using the Moringa oleifera seed extract as reducing and stabilizing agent. AgNP were characterized using a variety of biophysical methods including UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD), and sorted for size categories. AgNP showed in vitro antiviral activity against DEN-2 infecting vero cells. Viral titer was 7 log10 TCID50/ml in control (AgNP-free), while it dropped to 3.2 log10 TCID50/ml after a single treatment with 20 MUl/ml of AgNP. After 6 h, DEN-2 yield was 5.8 log10 PFU/ml in the control, while it was 1.4 log10 PFU/ml post-treatment with AgNP (20 MUl/ml). AgNP were highly effective against the dengue vector A. aegypti, with LC50 values ranging from 10.24 ppm (I instar larvae) to 21.17 ppm (pupae). Overall, this research highlighted the concrete potential of green synthesized AgNP in the fight against dengue and its primary vector A. aegypti. Further research on structure-activity relationships of AgNP against other dengue serotypes is urgently required. PMID- 26063532 TI - The surface topography of Callorhynchocotyle callorhynchi (Manter, 1955) (Monogenea: Hexabothriidae), a parasite of the holocephalan fish Callorhinchus capensis. AB - A scanning electron microscopical study, incorporating some transmission electron microscopical observations, was undertaken on the surface topography of the gill parasite Callorhynchocotyle callorhynchi (Manter, 1955) (Monogenea: Hexabothriidae) from the Cape elephant fish Callorhinchus capensis (Holocephali) off the western coast of South Africa. The study revealed the presence of several new characteristics for this species. These include the presence of regularly distributed, knob-shaped projections on the surface of the haptor, haptoral appendix and sucker peduncles measuring 0.2 MUm and in concentrations of approximately 100 per 10 MUm(2) and the existence of a ridge which bisects each sucker lumen, forming two different loculi. We also report, for the first time for any monogenean, the presence of 'true spines'; these occur on the luminal surface of the haptoral suckers and have all of the characteristics of the tegumental spines of digeneans, i.e. they are situated within the distal syncytial tegumental cytoplasm, rest on the basal plasma membrane, have a uniform structure and are covered apically by the tegumental surface plasma membrane. These spines are simple, straight and single-pointed. Under the scanning electron microscopy (SEM), within an area of 20 MUm in diameter, 23 such spines were counted, but their concentration and arrangement varies in different regions of the sucker. At their base, they measure about 1.5 MUm in width and reach approximately 2 MUm in height above the general level of the tegument, but transmission electron microscopy (TEM) measurements of an entire spine indicate that they may reach 3 MUm in total length. The presence of spines, possessing similar morphological characteristics in both basal polyopisthocotylean monogeneans and digeneans, represents another characteristic which may prove useful in understanding the evolutionary relationships within the Neodermata. PMID- 26063534 TI - Clinical Tools to Assess and Monitor Spondyloarthritis. AB - Assessment and monitoring is important in diseases affecting multiple sites and organs, such as axial spondyloarthritis (axSpA) that may have several signs and symptoms, and for which several treatments are available. Instruments for assessment and monitoring should be appropriately validated, and it should be feasible to use them in clinical practice as well as in clinical trials. The Assessment in SpondyloArthritis International Society (ASAS) has developed core sets of domains of disease and instruments to measure these domains, and recommends only the most important domains being measured with the best available methods. This article describes the ASAS core sets, as well as a few recent developments in the field of assessment, to be applied in clinical practice and research studies. PMID- 26063533 TI - Religious Influence on Older Americans' Sexual Lives: A Nationally-Representative Profile. AB - This study investigated the relationship between religious influence and sexual expression in older Americans, with specific attention to gender. Using the National Social Life, Health, and Aging Project, a nationally-representative survey of older adults, we created a composite measure of religious influence on sexual expression using Latent Class Analysis. We found more variability within denominations than between in terms of membership in the high-influence class; this indicated that religious influence on sexual expression was diverse within faiths. We show that religious influence was associated with higher self-reported satisfaction with frequency of sex, as well as higher physical and emotional satisfaction with sex, but only for men. Men were also significantly more likely than women to report that they would only have sex with a person they love. These results persisted in the presence of controls for demographic characteristics, religious affiliation, church attendance, intrinsic religiosity, political ideology, and functional health. PMID- 26063535 TI - Correction Approach for Delta Function Convolution Model Fitting of Fluorescence Decay Data in the Case of a Monoexponential Reference Fluorophore. AB - A correction is proposed to the Delta function convolution method (DFCM) for fitting a multiexponential decay model to time-resolved fluorescence decay data using a monoexponential reference fluorophore. A theoretical analysis of the discretised DFCM multiexponential decay function shows the presence an extra exponential decay term with the same lifetime as the reference fluorophore that we denote as the residual reference component. This extra decay component arises as a result of the discretised convolution of one of the two terms in the modified model function required by the DFCM. The effect of the residual reference component becomes more pronounced when the fluorescence lifetime of the reference is longer than all of the individual components of the specimen under inspection and when the temporal sampling interval is not negligible compared to the quantity (tauR (-1) - tau(-1))(-1), where tauR and tau are the fluorescence lifetimes of the reference and the specimen respectively. It is shown that the unwanted residual reference component results in systematic errors when fitting simulated data and that these errors are not present when the proposed correction is applied. The correction is also verified using real data obtained from experiment. PMID- 26063536 TI - Use of a Latent Topic Model for Characteristic Extraction from Health Checkup Questionnaire Data. AB - OBJECTIVES: When patients complete questionnaires during health checkups, many of their responses are subjective, making topic extraction difficult. Therefore, the purpose of this study was to develop a model capable of extracting appropriate topics from subjective data in questionnaires conducted during health checkups. METHODS: We employed a latent topic model to group the lifestyle habits of the study participants and represented their responses to items on health checkup questionnaires as a probability model. For the probability model, we used latent Dirichlet allocation to extract 30 topics from the questionnaires. According to the model parameters, a total of 4381 study participants were then divided into groups based on these topics. Results from laboratory tests, including blood glucose level, triglycerides, and estimated glomerular filtration rate, were compared between each group, and these results were then compared with those obtained by hierarchical clustering. RESULTS: If a significant (p < 0.05) difference was observed in any of the laboratory measurements between groups, it was considered to indicate a questionnaire response pattern corresponding to the value of the test result. A comparison between the latent topic model and hierarchical clustering grouping revealed that, in the latent topic model method, a small group of participants who reported having subjective signs of urinary disorder were allocated to a single group. CONCLUSIONS: The latent topic model is useful for extracting characteristics from a small number of groups from questionnaires with a large number of items. These results show that, in addition to chief complaints and history of past illness, questionnaire data obtained during medical checkups can serve as useful judgment criteria for assessing the conditions of patients. PMID- 26063538 TI - Governance and Regional Variation of Homicide Rates: Evidence From Cross-National Data. AB - Criminological theories of cross-national studies of homicide have underestimated the effects of quality governance of liberal democracy and region. Data sets from several sources are combined and a comprehensive model of homicide is proposed. Results of the spatial regression model, which controls for the effect of spatial autocorrelation, show that quality governance, human development, economic inequality, and ethnic heterogeneity are statistically significant in predicting homicide. In addition, regions of Latin America and non-Muslim Sub-Saharan Africa have significantly higher rates of homicides ceteris paribus while the effects of East Asian countries and Islamic societies are not statistically significant. These findings are consistent with the expectation of the new modernization and regional theories. PMID- 26063537 TI - Transient silencing of the KASII genes is feasible in Nicotiana benthamiana for metabolic engineering of wax ester composition. AB - The beta-ketoacyl-ACP synthase II (KASII) is an enzyme in fatty acid biosynthesis, catalyzing the elongation of 16:0-acyl carrier protein (ACP) to 18:0-ACP in plastids. Mutations in KASII genes in higher plants can lead to lethality, which makes it difficult to utilize the gene for lipid metabolic engineering. We demonstrated previously that transient expression of plastid directed fatty acyl reductases and wax ester synthases could result in different compositions of wax esters. We hypothesized that changing the ratio between C16 (palmitoyl-compounds) and C18 (stearoyl-compounds) in the plastidic acyl-ACP pool by inhibition of KASII expression would change the yield and composition of wax esters via substrate preference of the introduced enzymes. Here, we report that transient inhibition of KASII expression by three different RNAi constructs in leaves of N. benthamiana results in almost complete inhibition of KASII expression. The transient RNAi approach led to a shift of carbon flux from a pool of C18 fatty acids to C16, which significantly increased wax ester production in AtFAR6-containing combinations. The results demonstrate that transient inhibition of KASII in vegetative tissues of higher plants enables metabolic studies towards industrial production of lipids such as wax esters with specific quality and composition. PMID- 26063539 TI - What Makes Them More Vulnerable Than Others? Obesity, Negative Emotions, and Peer Bullying Victimization. AB - Negative impacts resulting from peer bullying victimization include psychological stress, emotional and academic maladjustment, decreased self-esteem, relational problems with peers, and may also lead to suicidal ideation and behavior. Therefore, efforts have been concentrated toward identifying characteristics of victims and perpetrators of bullying to allocate resources for preventive strategies. The current study adds to this ongoing research by using a nationally representative sample of adolescents to identify health-related correlates (obesity and negative emotions) of students vulnerable to peer bullying victimization, as well as exploring individual and school-related characteristics. Findings suggest that negative emotions are related to peer bully victimization, but a relationship between obesity and victimization is not clear. In addition, students attending schools with bullying prevention programs were more likely to report physical victimization. Discussion is offered regarding these findings and suggestions for future research in this area. PMID- 26063540 TI - Defining Probability in Sex Offender Risk Assessment. AB - There is ongoing debate and confusion over using actuarial scales to predict individuals' risk of sexual recidivism. Much of the debate comes from not distinguishing Frequentist from Bayesian definitions of probability. Much of the confusion comes from applying Frequentist probability to individuals' risk. By definition, only Bayesian probability can be applied to the single case. The Bayesian concept of probability resolves most of the confusion and much of the debate in sex offender risk assessment. Although Bayesian probability is well accepted in risk assessment generally, it has not been widely used to assess the risk of sex offenders. I review the two concepts of probability and show how the Bayesian view alone provides a coherent scheme to conceptualize individuals' risk of sexual recidivism. PMID- 26063541 TI - Offspring-Perpetrated Familicide: Examining Family Homicides Involving Parents as Victims. AB - The majority of studies examining familicide involve the male head of the family killing his wife or intimate partner and children. Little research exists on familicide cases involving children killing one or both parents plus other family members (siblings, grandparents, etc.). This study used the National Incident Based Reporting System, which currently contains arrest data for about 25% of the U.S. population, to examine familicide incidents perpetrated by adult and juvenile offenders over the 20-year period from 1991 to 2010. Fourteen cases of familicide involving two different family victim types were identified. None of these cases involved multiple offenders. Frequencies reported include victim, offender, and incident characteristics. The typical familicide offender was a White male approximately 26 years of age. Firearms predominated as murder weapons in these incidents; however, when a biological mother was one of the victims, offenders used more diverse methods. Only one case of familicide involved a female offender. Newspapers were searched to supplement available case information. Findings from this study were similar to cases identified by Liem and Reichelmann as "extended parricide cases" in their familicide study using Supplementary Homicide Report data. Study limitations, implications, and directions for future research are discussed. PMID- 26063542 TI - An Evaluation of the Impact of Goal Setting and Cell Phone Calls on Juvenile Rearrests. AB - Using a sample of 256 juvenile offenders who were randomly assigned to treatment or control groups, this study evaluates a cognitive-behavioral program that combines cognitive training, goal setting, and a phone-coach follow-up. The training involved six classroom sessions where participants received instruction and help in creating individualized goals. After attending the classes, participants received automated phone calls twice a day for up to a year. During the year following the program, the treatment and control groups were not significantly different in whether or not they were rearrested or in total rearrests. However, the total number of calls received had a significant negative association with whether or not they were rearrested for a felony and with the total number of felony rearrests. PMID- 26063543 TI - Longitudinal Relation Between General Well-Being and Self-Esteem. AB - This study investigated the longitudinal relation between general well-being and self-esteem of male adolescents with severe psychiatric disorders. Moreover, the transition out of secure residential care was studied. Adolescents ( N = 172) were assessed three times with 6 months between each assessment. The sample comprised adolescents who were admitted throughout the entire study ( n = 116) and who had been discharged at 6/12 months follow-up ( n = 56). General well being and self-esteem were stable concepts over time. The relation between general well-being and self-esteem differed for both groups. Among the admitted group general well-being positively predicted self-esteem and self-esteem negatively predicted general well-being from Time 2 to Time 3. Among the discharged adolescents, self-esteem at Time 1 positively predicted general well being at Time 2 and general well-being at Time 2 positively predicted self-esteem at Time 3. Changing social contexts, as well as problems experienced during the transition out of secure care, might affect this relationship. PMID- 26063544 TI - Extending Recidivism Monitoring for Drug Courts: Methods Issues and Policy Implications. AB - A wealth of research has been amassed documenting the effectiveness of drug treatment courts in addressing the needs of substance-abusing individuals involved with the criminal justice system. However, there is a relative dearth of research that examines the long-term impact of these programs on recidivism rates for both drug treatment court graduates and those unsuccessfully discharged from the program. In this study, we examine which demographic and programmatic/legal factors influence program disposition and recidivism rates of participants (both graduates and those unsuccessfully discharged) across the 5 years following their discharge from a drug treatment court program located in a suburban city in the Midwest. The study sample consists of 249 (N = 249) male participants who have been out of the program for more than 5 years. Results from the univariate and multivariate analyses are provided, as well as policy implications, directions for future research, and study limitations. PMID- 26063545 TI - The Impact of Individual and Institutional Factors on Turnover Intent Among Taiwanese Correctional Staff. AB - The existing literature on turnover intent among correctional staff conducted in Western societies focuses on the impact of individual-level factors; the possible effects of institutional contexts have been largely overlooked. Moreover, the relationships of various multidimensional conceptualizations of both job satisfaction and organizational commitment to turnover intent are still largely unknown. Using data collected by a self-reported survey of 676 custody staff employed in 22 Taiwanese correctional facilities during April of 2011, the present study expands upon theoretical models developed in Western societies and examines the effects of both individual and institutional factors on turnover intent simultaneously. Results from the use of the hierarchical linear modeling (HLM) statistical method indicate that, at the individual-level, supervisory versus non-supervisory status, job stress, job dangerousness, job satisfaction, and organizational commitment consistently produce a significant association with turnover intent after controlling for personal characteristics. Specifically, three distinct forms of organizational commitment demonstrated an inverse impact on turnover intent. Among institutional-level variables, custody staff who came from a larger facility reported higher likelihood of thinking about quitting their job. PMID- 26063546 TI - Friendship Group Composition and Juvenile Institutional Misconduct. AB - The present study examines both the patterns of friendship networks and how these network characteristics relate to the risk factors of institutional misconduct for incarcerated youth. Using friendship networks collected from males incarcerated with California's Division of Juvenile Justice (DJJ), latent profile analysis was utilized to create homogeneous groups of friendship patterns based on alter attributes and network structure. The incarcerated youth provided 144 egocentric networks reporting 558 social network relationships. Latent profile analysis identified three network profiles: expected group (67%), new breed group (20%), and model citizen group (13%). The three network profiles were integrated into a multiple group analysis framework to examine the relative influence of individual-level risk factors on their rate of institutional misconduct. The analysis finds variation in predictors of institutional misconduct across profile types. These findings suggest that the close friendships of incarcerated youth are patterned across the individual characteristics of the youth's friends and that the friendship network can act as a moderator for individual risk factors for institutional misconduct. PMID- 26063547 TI - A nationwide survey concerning practices in pessary use for pelvic organ prolapse in The Netherlands: identifying needs for further research. AB - INTRODUCTION AND HYPOTHESIS: To identify practice variation in management of patients with a vaginal pessary for pelvic organ prolapse (POP). METHODS: A nationwide survey was sent to all Dutch gynecologists with a special interest in urogynecology. RESULTS: The response rate was 59 %. Of the respondents, 13 % had a written protocol for pessary treatment in their department. Pessary treatment was proposed by 69 % of respondents as a treatment option. Counseling about side effects varied. All respondents provided information concerning the possibility of serious vaginal discharge. Concerning this side effect, 15 % of the respondents stated that it occurs in 5 - 20 % of patients, 27 % that it occurs in 20 - 40 % of patients, and 57 % that it occurs in more than 40 % of patients. Another item concerned counseling for the likelihood of vaginal blood loss. All respondents provided information concerning the possibility of vaginal blood loss. Concerning this side effect, 53 % of the respondents stated that it occurs in 5 - 20 % of patients, 33 % that it occurs in 20 - 40 %, and 14 % that it occurs in more than 40 % of patients. Follow-up after initial placement was done by 69 % of the respondents at 2 - 6 weeks, by 2 % at 8 weeks, and by 29 % at 12 weeks or more. Most (98 %) of the respondents extended the interval between visits when the patient had no complaints, and 96 % of the respondents reported that they routinely instruct patients about self-management. CONCLUSIONS: Pessaries are suggested as a treatment option by a majority of gynecologists, but practice varies widely. We consider that the variation in practice is due to a lack of available protocols and lack of evidence. PMID- 26063548 TI - Holmium laser excision for urinary mesh erosion: a minimally invasive treatment with favorable long-term results. AB - INTRODUCTION AND HYPOTHESIS: Mesh erosion into the urinary tract following surgery for stress urinary incontinence is a potentially serious complication. Traditional open resection is complicated and potentially morbid. Therefore, we sought to evaluate the long-term patient outcomes following transurethral endoscopic excision using the holmium laser (TEEH). METHODS: A retrospective series of ten patients who had undergone TEEH at our institution between May 2011 and July 2014 were identified. Nine had a prior urethral sling placed, and one had suture erosion following a Marshall-Marchetti-Krantz procedure. Outcomes assessed included resolution of symptoms, successful treatment of exposed mesh on repeat cystoscopy, and recurrence of stress urinary incontinence. Patients were followed up through office examination, cystoscopy and/or through written or telephone correspondence. RESULTS: The median age of the patients at the time of surgery was 58 years (IQR 54 - 66 years). The median time from anti-incontinence surgery to onset of symptoms was 12 months (IQR 1 - 72 months). Patients with mesh erosion most commonly presented with irritative voiding symptoms (60%). The median follow-up was 27 months (IQR 14 - 32 months) with 80% of patients reporting symptomatic improvement. Eight patients underwent follow-up cystoscopy with anatomic success (resolution of erosion on cystoscopy) after one procedure in five patients (63%). The anatomic success rate was higher for bladder erosions than for urethral erosions (80% vs. 33%). Notably, three patients experienced recurrent stress urinary incontinence following TEEH, with one patient undergoing repeat anti-incontinence surgery. CONCLUSIONS: TEEH is a viable, minimally invasive option for management of urinary mesh erosions. Notably, there is a risk of recurrent stress urinary incontinence following laser mesh excision. PMID- 26063549 TI - Introduction to the Conference: Innovations in the Prevention and Management of Early Childhood Caries. PMID- 26063550 TI - Prevalence and Measurement of Dental Caries in Young Children. AB - PURPOSE: Dental caries in preschool children was historically considered to have a unique and more intense pattern of decay and was known by a variety of terms. In 1999, the term early childhood caries (ECC), along with a classification system, was proposed to facilitate epidemiologic research of dental caries in young children. The purpose of this study was to assess the impact of those early childhood caries recommendations on the prevalence and measurement of caries in preschool children. METHODS: A systematic search of the MEDLINE database was performed. Key search words included: ECC, dental decay, dental caries, carious dentin, baby bottle tooth decay, nursing caries, maxillary anterior caries, and labial caries. English language studies and studies on more than 100 children younger than six years old were eligible for selection. National Health and Nutrition Examination Survey data collected from 1988 to 1994, 1999 to 2004, and 2011 to 2012 were used to assess ECC prevalence using different operational definitions. RESULTS: There were 87 articles selected for this review. The term ECC was used in 55 percent of the selected articles as the primary outcome measure. The majority of studies used a cross-section study design, but diagnostic criteria varied greatly. Caries experience in young children may be shifting away from majority of untreated surfaces to a majority of restored surfaces. Little difference was observed by dental surface type in the distribution of decayed and filled surfaces in primary teeth. CONCLUSIONS: Although the term early childhood caries is widely used, varied use of diagnostic criteria and operational definitions continue to limit comparability across studies. Emerging changes in the proportion of decayed and filled surfaces in the United States also raises questions regarding the ECC case definition limiting our ability to understand the epidemiology of dental caries in preschool children. PMID- 26063551 TI - The Clinical, Environmental, and Behavioral Factors That Foster Early Childhood Caries: Evidence for Caries Risk Assessment. AB - Caries risk assessment, an essential component of targeted health care delivery for young children, is of paramount importance in the current environment of increasing health care costs and resource constraints. The purpose of this manuscript was to review recent best available evidence behind the factors that influence caries risk assessment and the validity of strategies to assess the caries risk of young children. Moderate to weak evidence supports the following recommendations: (1) Children should have a caries risk assessment done in their first year (or as soon as their first tooth erupts) as part of their overall health assessment, and this should be reassessed periodically over time. (2) Multiple clinical, environmental, and behavioral factors should be considered when assessing caries risk in young children, including factors associated with the primary caregiver. (3) The use of structured forms, although most may not yet be validated, may aid in systematic assessment of multiple caries risk factors and in objective record-keeping. (4) Children from low socioeconomic status groups should be considered at increased risk when developing community preventive programs. PMID- 26063553 TI - Evidence of Effectiveness of Current Therapies to Prevent and Treat Early Childhood Caries. AB - PURPOSE: The purpose of this paper was to systematically review the quality of evidence related to self-applied and professionally applied fluorides, antimicrobial agents, fissure sealants, temporary restorations, and restorative care for the prevention and management of early childhood caries (ECC). METHODS: Relevant papers were selected after an electronic search for literature published in English between 2000 and April 2014. From 877 reports, 33 were included for full review. The quality of evidence was expressed according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. RESULTS: There was moderate and limited quality of evidence in support of fluoride toothpaste and fluoride varnish for ECC prevention, while the evidence for fluoride tablets/drops was insufficient. The support for the use of silver diamine fluoride, xylitol, chlorhexidine varnish/gel, povidone iodine, probiotic bacteria, and remineralizing agents (casein phosphopeptide-amorphous calcium phosphate) was insufficient. There was also insufficient quality of evidence for the use of sealants, temporary restorations, and traditional restorative care to reduce incidence of ECC. CONCLUSION: The results reinforce the need for high quality clinical research and point out the knowledge gaps to be addressed in future studies. PMID- 26063554 TI - Motivational Interviewing for Parent-child Health Interventions: A Systematic Review and Meta-Analysis. AB - PURPOSE: Motivational interviewing (MI) is a patient-centered approach focusing on building intrinsic motivation for change. This paper presents a meta-analysis of parent-involved MI to improve pediatric health behavior and health outcomes. METHODS: Study inclusion criteria: (1) examined modifiable pediatric health behaviors (< 18 years old); (2) used MI or motivational enhancement; (3) conducted a randomized controlled trial with a comparison group (non-MI control or active treatment group); (4) conducted the intervention with only a parent or both a parent and child; and (5) were written in English. Twenty-five studies (with 5,130 participants) were included and independently rated. Weighted mean effect sizes, using random-effects assumptions, were calculated. RESULTS: Relative to comparison groups, MI was associated with significant improvements in health behaviors (e.g., oral health, diet, physical activity, reduced screen time, smoking cessation, reduced second hand smoke) and reduction in body mass index. Results suggest that MI may also outperform comparison groups in terms of dental caries, but more studies are needed. MI interventions were more successful at improving diets for Caucasians and when the intervention included more MI components. CONCLUSIONS: Our findings provide support for providing motivational interviewing to parents and children to improve pediatric health behaviors. PMID- 26063552 TI - Effect of Antimicrobial Interventions on the Oral Microbiota Associated with Early Childhood Caries. AB - PURPOSE: The purposes of this systematic literature review were to identify research-based evidence for an effect of antimicrobial therapeutic approaches on the cariogenic microbiota and early childhood caries (ECC) outcomes; and to review methods used to perform microbial assessments in clinical studies of ECC. METHODS: Multiple databases were searched; only clinical cohort studies and randomized controlled trials published from 1998 to 2014 were selected. A total of 471 titles and abstracts were identified; 114 studies met the inclusion criteria for a full review, from which 41 studies were included in the meta analyses. RESULTS: In most of the reviewed studies, moderate reductions in cariogenic bacterial levels, mainly in mutans streptococci (MS), were demonstrated following the use of antimicrobial agents, but bacterial regrowth occurred and new carious lesions developed once the treatment had ceased, particularly in high-risk children. Relatively consistent findings suggested that anti-cariogenic microbial interventions in mothers significantly reduced MS acquisition by children. However, studies of the long-term benefits of ECC prevention are lacking. CONCLUSION: Based on the meta-analyses, antimicrobial interventions and treatments show temporary reductions in MS colonization levels. However, there is insufficient evidence to indicate that the approaches used produced sustainable effects on cariogenic microbial colonization or ECC reduction and prevention. PMID- 26063555 TI - Integrating Oral Health Into Overall Health Care to Prevent Early Childhood Caries: Need, Evidence, and Solutions. AB - Medicaid data shows that few one- to two-year-olds receive a preventive dental visit, indicating our limited success implementing the existing policy paradigm of dental home establishment by 12 months of age. Few pediatricians refer children for early dental care, few dentists are comfortable seeing children younger than two-years-old, fewer still provide restorative care, and many dentists do not accept Medicaid insurance. These realities mandate new strategies to meet the needs of children and families and effectively tackle early childhood caries (ECC). Primary care medical providers have frequent contact with families, providing opportunities to incorporate oral health promotion and prevention in non-dental settings. Components of such an approach include: screening; risk assessment; oral health counseling; fluoride varnish application; successful referral for children needing intense intervention; policy support; and financial incentives to sustain change. Current research indicates that oral health counseling, particularly motivational interviewing, and fluoride varnish applied in the non-dental setting positively affect patient outcomes. Cost savings may only be realized if ECC prevention programs use: support professionals; integrative disease management; and innovative insurance structures. The purpose of this paper was to examine the evidence for the effectiveness of the provision of oral health preventive services in the primary care setting. PMID- 26063556 TI - The Indian Health Service Early Childhood Caries Collaborative: A Five-year Summary. AB - PURPOSE: The purpose of this study was to assess a national initiative's effect on prevalence of early childhood caries and untreated decay in zero- to five-year old Indian/Alaska Native preschool children. METHODS: The Indian Health Service (IHS) conducted a five-year Early Childhood Caries Collaborative from October 1, 2009 to September 30, 2014. The program used educational materials and routine communication with the 322 IHS and United States tribal dental programs, with an emphasis on early access to care, dental sealanth, fluoride varnish, and interim therapeutic restorations (ITRs). Prevalence and untreated decay data were obtained through the nationwide oral health survey (2010 and 2014). Data were also collected on access to care, sealants, fluoride, and ITRs. RESULTS: The number of zero- to five-year-olds with a dental visit increased seven percent: dental sealants placed increased 65 percent; and fluoride varnish applications increased 161.2 percent. Between 2010 and 2014, the percentage of one- to two year-olds with decay experience and untreated decay declined, but the difference was not statistically significant. CONCLUSIONS: Early childhood caries prevention strategies, such as early access to dental care, sealants, fluoride varnish, and interim therapeutic restorations, demonstrated some initial improvement in the oral health status of zero- to five-year-old Indian/Alaska Native children. PMID- 26063557 TI - Chronic Disease Management Strategies of Early Childhood Caries: Support from the Medical and Dental Literature. AB - An Institute of Medicine report places chronic disease management (CDM) as an intervention on a treatment spectrum between prevention and acute care. CDM commonly focuses on conditions in which patient self-care efforts are significant. Framing early childhood caries (ECC) as such a chronic condition invites dentistry to reconsider its approach to caries management and shift gears from a strictly surgical approach to one that also incorporates a medical approach. This paper's purpose was to explore the definition of and concepts inherent in CDM. An explanatory model is introduced to describe the multiple factors that influence ECC-CDM strategies. Reviewed literature suggests that early evidence from ECC-CDM interventions, along with results of pediatric asthma and diabetes CDM, supports CDM of ECC as a valid approach that is independent of both prevention and repair. Early results of ECC-CDM endeavors have demonstrated a reduction in rates of new cavitation, dental pain, and referral to the operating room compared to baseline rates. ECC-CDM strategies hold strong promise to curtail caries activity while complementing dental repair when needed, thereby reducing disease progression and cavity recurrence. Institutionalizing ECC-CDM will both require and benefit from evolving health care delivery and financing systems that reward positive health outcomes. PMID- 26063558 TI - Business Barriers and Opportunities for Transforming to Preventive Care to Treat Early Childhood Caries. AB - Primary, secondary, and tertiary preventive dental services have the potential for achieving the triple aim of better health outcomes for populations, better patient experience of care, and lower per capita costs. Yet, maximization of preventive services has not occurred in dental practice nor been promoted by dental plans. While the lack of such things as diagnostic codes, caries classification systems, and validated risk assessment tools are barriers to increasing preventive care, they may not be the primary barriers that need to be addressed. The purpose of this paper was to focus on three issues: (1) the dental care business model based on a value proposition of surgical care rather than preventive care; (2) the benefit plan design that undervalues or does not cover effective primary, secondary, and tertiary preventive services; and (3) the current financial crisis in health care. It is the business model of dental practice and the benefit design of payers that are the biggest barriers that will have to change to transform dental care into a more effective and efficient means of achieving and maintaining health. PMID- 26063559 TI - Progress in Early Childhood Caries and Opportunities in Research, Policy, and Clinical Management. AB - The 2014 Early Childhood Caries Conference encompassed evidence-based reviews on the state of the science regarding early childhood carries (ECC) epidemiology, etiology, prevention, and disease management. The purpose of this paper was to discuss the work presented at the conference and identify opportunities in research, policy, and clinical management that may improve early childhood caries outcomes and lower costs of care. While great progress has been made since the 1997 ECC Conference, there remains a paucity of high-quality evidence from randomized controlled trials on what are the most effective means to prevent and manage ECC. Analyses of studies indicate that some approaches, such as chlorhexidine, iodine, and remineralizing agents, have not shown consistent findings in preventing ECC. However, evidence exists to yield recommendations in some areas. There are useful risk assessment indicators to identify preschool children at risk for caries. Fluoridated toothpaste and fluoride varnish currently are the most effective chemotherapeutic strategies to prevent ECC. Motivational interviewing, a form of patient-centered counseling, is effective for motivating oral health behaviors and shows promise for reducing caries. Additionally, evidence is emerging that shows the value of chronic disease management approaches and integrating ECC oral health care within medical care settings. Recommendations for future directions in ECC research and policy were also key outcomes of the conference. PMID- 26063560 TI - Perfusion imaging and coronary anatomy. PMID- 26063561 TI - Hypertension and mortality in the Golestan Cohort Study: A prospective study of 50 000 adults in Iran. AB - High blood pressure has been the second most important determinant of disease burden in Iran since the 1990s. Despite well-recognized evidence on the association of high blood pressure and mortality in other countries, this relationship has not been fully investigated in the demographic setting of Iran. The current study is the first large-scale longitudinal study of this association in Iran. Briefly, 50 045 subjects between 40 and 75 years of age have been recruited and followed. Blood pressure measurements were carried out at baseline. Causes of death were reported and verified by verbal autopsy throughout the follow-up period. The outcomes of interest were all-cause deaths and deaths due to ischemic heart disease (IHD) or stroke. Cox proportional hazards regression models were used to estimate hazard ratios (HRs). A total of 46 674 subjects free from cardiovascular disease at baseline were analyzed. Absolute mortality rates increased along with increasing systolic or diastolic blood pressure above 120 and 80 mm Hg, respectively. Adjusted HRs (95% confidence intervals) for each 20 mm Hg increase in systolic blood pressure in all age groups were 1.18 (1.13-1.23) for all-cause mortality, 1.21 (1.13-1.31) for deaths due to IHD and 1.50 (1.39 1.63) for deaths due to stroke. Unadjusted and adjusted HRs were higher in younger subjects and decreased with increasing age of the participants. High blood pressure is a serious threat to the health of Iranians. The entire health care system of Iran should be involved in a comprehensive action plan for controlling blood pressure. PMID- 26063562 TI - The vascular health status of a population of adult Canadian Indigenous peoples from British Columbia. AB - Indigenous populations currently experience greater cardiovascular disease burdens. However, subclinical vascular structure and function among these populations is not well known. This investigation evaluated vascular structure and function among Canadian Indigenous populations. Blood pressure, body composition, pulse-wave velocity (PWV), baroreceptor sensitivity (BRS), arterial compliance and intima-media thickness (IMT) were measured. Vascular measures were evaluated across sexes and age groups. Vascular assessments were conducted among 55 Indigenous adults (38+/-18 years, 29 Female), including both First Nations (N=36) and Metis (N=19) individuals. Some differences in vascular measures were found between males and females, respectively (spectral BRS: 9.6+/-6.8 ms mm Hg( 1) vs 16.9+/-10.0 ms mm Hg(-1), P=0.01; small arterial compliance: 8.9+/-3.7 ml mm Hg(-1) * 100 vs 6.4+/-2.3 ml mm Hg(-1) * 100, P=0.004), with similar measures of overall IMT (0.61+/-0.14 mm vs 0.57+/-0.08 mm, P=0.19) and central PWV (5.7+/ 2.5 m s(-1) vs 5.1+/-2.3 m s(-1), P=0.58). Greater IMT, and lower BRS and arterial compliance were identified among older adults. This relatively healthy population demonstrated healthy vascular measures, with poorer measures among older individuals. PMID- 26063563 TI - Leisure time computer use and adolescent bone health--findings from the Tromso Study, Fit Futures: a cross-sectional study. AB - OBJECTIVES: Low levels of physical activity may have considerable negative effects on bone health in adolescence, and increasing screen time in place of sporting activity during growth is worrying. This study explored the associations between self-reported screen time at weekends and bone mineral density (BMD). DESIGN: In 2010/2011, 1038 (93%) of the region's first-year upper-secondary school students (15-18 years) attended the Tromso Study, Fit Futures 1 (FF1). A follow-up survey (FF2) took place in 2012/2013. BMD at total hip, femoral neck and total body was measured as g/cm(2) by dual X-ray absorptiometry (GE Lunar prodigy). Lifestyle variables were self-reported, including questions on hours per day spent in front of television/computer during weekends and hours spent on leisure time physical activities. Complete data sets for 388/312 girls and 359/231 boys at FF1/FF2, respectively, were used in analyses. Sex stratified multiple regression analyses were performed. RESULTS: Many adolescents balanced 2 4 h screen time with moderate or high physical activity levels. Screen time was positively related to body mass index (BMI) in boys (p=0.002), who spent more time in front of the computer than girls did (p<0.001). In boys, screen time was adversely associated with BMDFF1 at all sites, and these associations remained robust to adjustments for age, puberty, height, BMI, physical activity, vitamin D levels, smoking, alcohol, calcium and carbonated drink consumption (p<0.05). Screen time was also negatively associated with total hip BMD(FF2) (p=0.031). In contrast, girls who spent 4-6 h in front of the computer had higher BMD than the reference (<2 h). CONCLUSIONS: In Norwegian boys, time spent on screen-based sedentary activity was negatively associated with BMD levels; this relationship persisted 2 years later. Such negative associations were not present among girls. Whether this surprising result is explained by biological differences remains unclear. PMID- 26063564 TI - Change in quality of life in patients with acromegaly after treatment with octreotide LAR: first application of AcroQoL in Korea. AB - OBJECTIVES: This study was designed to investigate changes in health-related quality of life (HRQoL) of patients with acromegaly in Korea after medical treatment with octreotide LAR using the validated Korean version of the acromegaly quality of life questionnaire (AcroQoL). DESIGN: A prospective, open label, single-arm study. SETTING: 11 tertiary centres in Korea. PARTICIPANTS: 58 Korean patients (aged 21-72 years) who were newly diagnosed with acromegaly between 2009 and 2012 were prescribed octreotide LAR 20 mg at the time of enrolment. During 24 weeks of observation, AcroQoL survey questionnaires and measurement of growth hormone insulin-like growth factor 1(GH/IGF-I) were performed at baseline, week 12 and week 24. MAIN OUTCOME MEASURES: We assessed the HRQoL of Korean patients with acromegaly after medical treatment with octreotide LAR using the validated Korean version of the AcroQoL questionnaire. RESULTS: Patients had a mean age of 47.2 years (29 males), and GH and IGF-I significantly decreased during the first 12 weeks (GH: 4.8 vs 1.9 MUg/L, p<0.001; IGF-I: 497 vs 265 MUg/L, p<0.001), but showed insignificant change at week 24 (GH: 2.3 MUg/L; IGF-I: 294 MUg/L). Only AcroQoL scores for the psychological appearance subdomain showed a significant increase during the entire 24 weeks (p<0.05). The change in the psychological appearance subdomain of AcroQoL scores demonstrated a significant but weak negative correlation with change in IGF-I levels (r=-0.282, p=0.039). When patients were divided into two groups according to their disease activity at week 24 (controlled vs uncontrolled), there was no difference in AcroQoL scores, but the psychological appearance subdomain of the two groups appeared to change differently over the entire 24-week period (p=0.047). CONCLUSIONS: Medical treatment with octreotide LAR in patients with acromegaly has a limited contribution to HRQoL as assessed by the AcroQoL. PMID- 26063565 TI - How do GPs in Switzerland perceive their patients' satisfaction and expectations? An observational study. AB - OBJECTIVES: To assess doctors' perceptions of their patients' satisfaction and expectations in primary care. STUDY DESIGN: Cross-sectional study using questionnaires completed by general practitioners (GPs) and their patients. SETTING: Primary care practices in Geneva, Switzerland. PARTICIPANTS: 23 GPs from a random list of 75 GPs practising in the canton of Geneva (participation rate 31%), who each recruited between 50 and 100 consecutive patients coming to the practice for a scheduled medical consultation, leading to a total of 1637 patients (participation rate: 97%, women: 63%, mean age: 54 years). Patient exclusion criteria were: new patients, those consulting in an emergency situation or suffering from disorders affecting their ability to consent, and those who did not speak French. MAIN OUTCOME MEASURES: Patients satisfaction with and expectations from the care they received in this practice; GPs perceptions of their patient's satisfaction and expectations. RESULTS: GPs underestimated all patient satisfaction items (p<0.001 for all items) whereas they overestimated their expectations, except for equipment (laboratory and X-ray) and some accessibility items. In a multivariate analysis to assess which GP factors were associated with correct assessment of their patients' views, only GPs' certification status was a significant factor. CONCLUSIONS: GPs tend to underestimate patients' satisfaction but overestimate their expectations in primary care. These findings may help GPs to understand patients' views in order to adequately meet their expectations and concerns. PMID- 26063566 TI - Effects of number and gender of offspring on quality of life among older adults: evidence from the Korean Longitudinal Study of Aging, 2006-2012. AB - OBJECTIVES: We examined correlations between number and gender of offspring and health-related quality of life (HRQoL) and quality of life (QoL) in older adults. SETTING: We used data from the 2006-2012 data sets of the Korean Longitudinal Study of Aging. PARTICIPANTS: There were 10,242, 8680, 7907 and 7480 participants in 2006, 2008, 2010 and 2012, respectively. INTERVENTIONS: Number and gender of offspring. PRIMARY AND SECONDARY OUTCOME MEASURES: We measured participants' QoL and HRQoL using a visual analogue scale developed by the Korea Labour Institute and which is similar to the EQ-VAS, a European measure. RESULTS: We estimated the HRQoL and QoL of individuals with offspring. Estimates for the HRQoL and QoL of parents with no offspring were -7.762 and -9.384, respectively (both p<0.0001) versus parents with two offspring. For parents with five or more offspring, the estimates for the HRQoL and QoL were -1.529 and 0.885, respectively (p<0.001 and p<0.017, respectively) compared with parents with two offspring. For fathers with no offspring compared with fathers with two offspring, the estimates for the HRQoL and QoL were -6.143 and -7.492, respectively (both p<0.0001). CONCLUSIONS: These results suggest that number of offspring is associated with both HRQoL and QoL. Those with no offspring showed the lowest HRQoL and QoL. Although having five or more children had positive associations with QoL, it had negative associations with HRQoL. Public health services for those with poor quality of life should provide effective support programmes and services based on these findings. PMID- 26063567 TI - Magnetoencephalography to investigate central perception of exercise-induced breathlessness in people with chronic lung disease: a feasibility pilot. AB - OBJECTIVES: Neuroimaging in chronic breathlessness is challenging. The study objective was to test the feasibility of magnetoencephalography (MEG) for functional neuroimaging of people with chronic breathlessness. DESIGN: Feasibility pilot study. SETTING: Respiratory clinic out-patients. PARTICIPANTS: 8 patients (mean age=62; (range 47-83); 4 men) with chronic non-malignant lung disease; modified MRC breathlessness score >= (median mMRC=4), intensity of exercise-induced breathlessness >3/10; no contraindication to MRI scanning. METHODS AND MEASURES: 4 MEG scans were conducted for each participant: (1) at rest (5 mins), (2) postseated leg exercise-induced breathlessness during recovery (10 mins). Recovery scans (2) were conducted with/without facial airflow in random order; both scans were repeated 1 h later. Participants rated breathlessness intensity (0-10 Numerical Rating Scale (NRS)) at baseline, maximal exertion and every minute during recovery, and rated acceptability of study procedures at the end of the study (0-10 NRS). A structural MRI scan was conducted for MEG coregistration and source-space analyses. Rest data were compared with data from healthy volunteers (N=6; 5 men; mean age=30.7 years +/- 3.9 years). RESULTS: Exercises and MEG scanning were acceptable to all participants; 7/8 completed the MRI scans. Maximum breathlessness intensity was induced by 5 min' exercise. The same level was induced for repeat scans (median=8; IQR=7-8). All recovered to baseline by 10 min. Time-frequency profiles of data from the first and last 3 min were analysed in MEG source space based on breathlessness location estimates. Source localisation was performed, but anatomical source inference was limited to the level of the lobe. Differences in areas of activity were seen: during recovery scans; with and without airflow; and between participants/normal volunteers at rest. CONCLUSIONS: MEG is a feasible method to investigate exercise-induced breathlessness in people breathless with chronic lung disease, and able to identify neural activity related to changes in breathlessness. PMID- 26063568 TI - Developments in the invasive diagnostic-therapeutic cascade of women and men with acute coronary syndromes from 2005 to 2011: a nationwide cohort study. AB - OBJECTIVES: To investigate for trends in sex-related differences in the invasive diagnostic-therapeutic cascade in a population of patients with acute coronary syndromes (ACS). DESIGN: A nationwide cohort study. SETTING: Administrative and clinical registries covering all hospitalisations, invasive cardiac procedures and deaths in the Danish population of 5.6 million inhabitants. PARTICIPANTS: We included 52,565 patients aged 30-90 years who were hospitalised with a first ACS from January 2005 to November 2011. Follow-up was 60 days from the day of index admission. MAIN OUTCOME MEASURES: Diagnostic coronary angiography, percutaneous coronary intervention or coronary artery bypass within 60 days of index admission. RESULTS: Women constituted 36%, were older, had more comorbidity and were less likely to be admitted to a hospital with cardiac catheterisation facilities than men. Mortality rates were similar for both sexes. Diagnostic coronary angiography was performed less frequently on women compared with men, both within 1 day (31% vs 42%; p<0.001) and within 60 days (67% vs 80%; p<0.001), yielding adjusted female-male HRs of 0.83 (0.79-0.87) and 0.86 (0.84-0.89), respectively.Among the 39,677 patients undergoing coronary angiography, non obstructive coronary artery disease was more frequent among women than men (22% vs 9%; p<0.001). Women were less likely to undergo percutaneous coronary intervention (58% vs 72%; p<0.001) and coronary artery bypass (6% vs 11%, p<0.001) within 60 days than men, yielding adjusted HRs of 0.96 (0.92-0.99) and 0.81 (0.74-0.89), respectively. The sex-related differences were not attenuated over time for any of the invasive cardiac procedures (p values for trend >0.05). CONCLUSIONS: In this nationwide study, men were more likely to undergo an invasive approach than women when hospitalised with a first ACS--a difference persisting from 2005 to 2011. Future studies should focus on the potential mechanisms behind this differential treatment. PMID- 26063569 TI - The impact of time-window bias on the assessment of the long-term effect of medication adherence: the case of secondary prevention after myocardial infarction. AB - OBJECTIVES: Time-window bias was described in case-control studies and led to a biased estimate of drug effect. No studies have measured the impact of this bias on the assessment of the effect of medication adherence on health outcomes. Our goals were to estimate the association between adherence to drug therapies after myocardial infarction (MI) and the incidence of a new MI, and to quantify the error that would have been produced by a time-window bias. SETTING: This is a population-based study. Data were obtained from the Regional Health Information Systems of the Lazio Region in Central Italy (around 5 million inhabitants). PARTICIPANTS: Patients discharged after MI in 2006-2007 were enrolled in the cohort and followed through 2009. OUTCOME MEASURE: The study outcome was reinfarction: either mortality, or hospital admission for MI, whichever occurred first. DESIGN: A nested case-control study was performed. Controls were selected using both time-dependent and time-independent sampling. Adherence to antiplatelets, beta-blockers, ACE inhibitors/angiotensin receptor blockers (ACEI/ARBs) and statins was calculated using the proportion of days covered (PDC). RESULTS: A total of 6880 patients were enrolled in the cohort. Using time dependent sampling, a protective effect was detected for all study drugs. Conversely, using time-independent sampling, the beneficial effect was attenuated, as in the case of antiplatelet agents and statins, or completely masked, as in the case of ACEI/ARBs and beta-blockers. For ACEI/ARBs, the time dependent approach produced ORs of 0.83 (95% CI 0.57 to 1.21) and 0.72 (0.55 to 0.95), respectively, for '0.5 < PDC <= 0.75' and 'PDC>0.75' versus '0 <= PDC <= 0.5'. Using the time-independent approach, the ORs were 0.96 (0.65 to 1.43) and 1.00 (0.76 to 1.33), respectively. CONCLUSIONS: A time-independent definition of a time-dependent exposure introduces a bias when the length of follow-up varies with the outcome. The persistence of time-related biases in peer-reviewed papers strongly suggests the need for increased awareness of this methodological pitfall. PMID- 26063570 TI - Establishing integrated rural-urban cohorts to assess air pollution-related health effects in pregnant women, children and adults in Southern India: an overview of objectives, design and methods in the Tamil Nadu Air Pollution and Health Effects (TAPHE) study. AB - INTRODUCTION: In rapidly developing countries such as India, the ubiquity of air pollution sources in urban and rural communities often results in ambient and household exposures significantly in excess of health-based air quality guidelines. Few efforts, however, have been directed at establishing quantitative exposure-response relationships in such settings. We describe study protocols for The Tamil Nadu Air Pollution and Health Effects (TAPHE) study, which aims to examine the association between fine particulate matter (PM2.5) exposures and select maternal, child and adult health outcomes in integrated rural-urban cohorts. METHODS AND ANALYSES: The TAPHE study is organised into five component studies with participants drawn from a pregnant mother-child cohort and an adult cohort (n=1200 participants in each cohort). Exposures are assessed through serial measurements of 24-48 h PM2.5 area concentrations in household microenvironments together with ambient measurements and time-activity recalls, allowing exposure reconstructions. Generalised additive models will be developed to examine the association between PM2.5 exposures, maternal (birth weight), child (acute respiratory infections) and adult (chronic respiratory symptoms and lung function) health outcomes while adjusting for multiple covariates. In addition, exposure models are being developed to predict PM2.5 exposures in relation to household and community level variables as well as to explore inter relationships between household concentrations of PM2.5 and air toxics. Finally, a bio-repository of peripheral and cord blood samples is being created to explore the role of gene-environment interactions in follow-up studies. ETHICS AND DISSEMINATION: The study protocols have been approved by the Institutional Ethics Committee of Sri Ramachandra University, the host institution for the investigators in this study. Study results will be widely disseminated through peer-reviewed publications and scientific presentations. In addition, policy relevant recommendations are also being planned to inform ongoing national air quality action plans concerning ambient and household air pollution. PMID- 26063571 TI - Human telomerase: biogenesis, trafficking, recruitment, and activation. AB - Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species. PMID- 26063572 TI - The SLC36 transporter Pathetic is required for extreme dendrite growth in Drosophila sensory neurons. AB - Dendrites exhibit enormous diversity in form and can differ in size by several orders of magnitude even in a single animal. However, whether neurons with large dendrite arbors have specialized mechanisms to support their growth demands is unknown. To address this question, we conducted a genetic screen for mutations that differentially affected growth in neurons with different-sized dendrite arbors. From this screen, we identified a mutant that selectively affects dendrite growth in neurons with large dendrite arbors without affecting dendrite growth in neurons with small dendrite arbors or the animal overall. This mutant disrupts a putative amino acid transporter, Pathetic (Path), that localizes to the cell surface and endolysosomal compartments in neurons. Although Path is broadly expressed in neurons and nonneuronal cells, mutation of path impinges on nutrient responses and protein homeostasis specifically in neurons with large dendrite arbors but not in other cells. Altogether, our results demonstrate that specialized molecular mechanisms exist to support growth demands in neurons with large dendrite arbors and define Path as a founding member of this growth program. PMID- 26063573 TI - Sex comb on midleg (Scm) is a functional link between PcG-repressive complexes in Drosophila. AB - The Polycomb group (PcG) proteins are key regulators of development in Drosophila and are strongly implicated in human health and disease. How PcG complexes form repressive chromatin domains remains unclear. Using cross-linked affinity purifications of BioTAP-Polycomb (Pc) or BioTAP-Enhancer of zeste [E(z)], we captured all PcG-repressive complex 1 (PRC1) or PRC2 core components and Sex comb on midleg (Scm) as the only protein strongly enriched with both complexes. Although previously not linked to PRC2, we confirmed direct binding of Scm and PRC2 using recombinant protein expression and colocalization of Scm with PRC1, PRC2, and H3K27me3 in embryos and cultured cells using ChIP-seq (chromatin immunoprecipitation [ChIP] combined with deep sequencing). Furthermore, we found that RNAi knockdown of Scm and overexpression of the dominant-negative Scm-SAM (sterile alpha motif) domain both affected the binding pattern of E(z) on polytene chromosomes. Aberrant localization of the Scm-SAM domain in long contiguous regions on polytene chromosomes revealed its independent ability to spread on chromatin, consistent with its previously described ability to oligomerize in vitro. Pull-downs of BioTAP-Scm captured PRC1 and PRC2 and additional repressive complexes, including PhoRC, LINT, and CtBP. We propose that Scm is a key mediator connecting PRC1, PRC2, and transcriptional silencing. Combined with previous structural and genetic analyses, our results strongly suggest that Scm coordinates PcG complexes and polymerizes to produce broad domains of PcG silencing. PMID- 26063574 TI - Minishelterins separate telomere length regulation and end protection in fission yeast. AB - The conserved shelterin complex is critical for chromosome capping and maintaining telomere length homeostasis. In fission yeast, shelterin is comprised of five proteins. Taz1, Rap1, and Poz1 function as negative regulators of telomere elongation, whereas Pot1 and Tpz1 are critical for end capping and telomerase recruitment. How the five proteins work together to safeguard chromosome ends and promote telomere length homeostasis is a matter of great interest. Using a combination of deletions, fusions, and tethers, we define key elements of shelterin important for telomere length regulation. Surprisingly, deletion of the entire Rap1 and Poz1 proteins does not impair telomere length regulation as long as a static bridge is provided between Taz1 and Tpz1. Cells harboring minishelterin display wild-type telomere length and intact subtelomeric silencing. However, protection against end fusions in G1 is compromised in the absence of Rap1. Our data reveal a remarkable plasticity in shelterin architecture and separate functions in length regulation and end protection. PMID- 26063575 TI - A cell cycle-controlled redox switch regulates the topoisomerase IV activity. AB - Topoisomerase IV (topo IV), an essential factor during chromosome segregation, resolves the catenated chromosomes at the end of each replication cycle. How the decatenating activity of the topo IV is regulated during the early stages of the chromosome cycle despite being in continuous association with the chromosome remains poorly understood. Here we report a novel cell cycle-regulated protein in Caulobacter crescentus, NstA (negative switch for topo IV decatenation activity), that inhibits the decatenation activity of the topo IV during early stages of the cell cycle. We demonstrate that in C. crescentus, NstA acts by binding to the ParC DNA-binding subunit of topo IV. Most importantly, we uncover a dynamic oscillation of the intracellular redox state during the cell cycle, which correlates with and controls NstA activity. Thus, we propose that predetermined dynamic intracellular redox fluctuations may act as a global regulatory switch to control cellular development and cell cycle progression and may help retain pathogens in a suitable cell cycle state when encountering redox stress from the host immune response. PMID- 26063577 TI - Corrigendum: Oxygen-sensing PHDs regulate bone homeostasis through the modulation of osteoprotegerin. PMID- 26063578 TI - Equal in the presence of death? PMID- 26063576 TI - Mechanism of regulation of 'chromosome kissing' induced by Fob1 and its physiological significance. AB - Protein-mediated "chromosome kissing" between two DNA sites in trans (or in cis) is known to facilitate three-dimensional control of gene expression and DNA replication. However, the mechanisms of regulation of the long-range interactions are unknown. Here, we show that the replication terminator protein Fob1 of Saccharomyces cerevisiae promoted chromosome kissing that initiated rDNA recombination and controlled the replicative life span (RLS). Oligomerization of Fob1 caused synaptic (kissing) interactions between pairs of terminator (Ter) sites that initiated recombination in rDNA. Fob1 oligomerization and Ter-Ter kissing were regulated by intramolecular inhibitory interactions between the C terminal domain (C-Fob1) and the N-terminal domain (N-Fob1). Phosphomimetic substitutions of specific residues of C-Fob1 counteracted the inhibitory interaction. A mutation in either N-Fob1 that blocked Fob1 oligomerization or C Fob1 that blocked its phosphorylation antagonized chromosome kissing and recombination and enhanced the RLS. The results provide novel insights into a mechanism of regulation of Fob1-mediated chromosome kissing. PMID- 26063579 TI - 'Ethical responsibility' or 'a whole can of worms': differences in opinion on incidental finding review and disclosure in neuroimaging research from focus group discussions with participants, parents, IRB members, investigators, physicians and community members. AB - PURPOSE: To identify the specific needs, preferences and expectations of the stakeholders impacted by returning neuroimaging incidental findings to research participants. METHODS: Six key stakeholder groups were identified to participate in focus group discussions at our active neuroimaging research facility: Participants, Parents of child participants, Investigators, Institutional Review Board (IRB) Members, Physicians and Community Members. A total of 151 subjects attended these discussions. Transcripts were analysed using principles of Grounded Theory and group consensus coding. RESULTS: A series of similar and divergent themes were identified across our subject groups. Similarities included beliefs that it is ethical for researchers to disclose incidental findings as it grants certain health and emotional benefits to participants. All stakeholders also recognised the potential psychological and financial risks to disclosure. Divergent perspectives elucidated consistent differences between our 'Participant' subjects (Participants, Parents, Community Members) and our 'Professional' subjects (IRB Members, Investigators and Physicians). Key differences included (1) what results should be reported, (2) participants' autonomous right to research information and (3) the perception of the risk benefit ratio in managing results. CONCLUSIONS: Understanding the perceived impact on all stakeholders involved in the process of disclosing incidental findings is necessary to determine appropriate research management policy. Our data further demonstrate the challenge of this task as different stakeholders evaluate the balance between risk and benefit related to their unique positions in this process. These findings offer some of the first qualitative insight into the expectations of the diverse stakeholders affected by incidental finding disclosure. PMID- 26063580 TI - Experts call for tobacco industry to pay for smoking cessation work. PMID- 26063581 TI - Characterization of Diterpenes from Euphorbia prolifera and Their Antifungal Activities against Phytopathogenic Fungi. AB - Euphorbia prolifera is a poisonous plant belonging to the Euphorbiaceae family. In this survey on plant secondary metabolites to obtain bioactive substances for the development of new antifungal agents for agriculture, the chemical constituents of the plant E. prolifera were investigated. This procedure led to the isolation of six new and two known diterpenes. Their structures, including absolute configurations, were elucidated on the basis of extensive NMR spectroscopic data analyses and time-dependent density functional theory ECD calculations. Biological screenings revealed that these diterpenes possessed antifungal activities against three phytopathogenic fungi. The results of the phytochemical investigation further revealed the chemical components of the poisonous plant E. prolifera, and biological screenings implied the extract or bioactive diterpenes from this plant may be regarded as candidate agents of antifungal agrochemicals for crop protection products. PMID- 26063582 TI - Pilot Study of Serum MicroRNA-21 as a Diagnostic and Prognostic Biomarker in Egyptian Breast Cancer Patients. AB - BACKGROUND: MicroRNAs are small RNA molecules that bind to complementary sequences of target messenger RNAs and down-regulate their translation to protein or degrade them. MicroRNAs play critical roles in many different cellular processes. Hence, aberrant microRNA expression is common in a variety of disorders, including cancer. PATIENTS AND METHODS: In this work, we quantified serum microRNA-21 (miR-21) expression levels in 30 breast cancer patients, 30 cancer-free individuals with risk factors for developing breast cancer, and another 30 controls without risk factors, in order to test the role of miR-21 as a possible diagnostic and prognostic biomarker in breast cancer. RESULTS: Our results indicated that miR-21 expression was elevated in asymptomatic high-risk individuals (2.98-fold) compared with healthy non-risk controls (p < 0.001), and was increased in almost all sera of cancer patients (12.72-fold) compared with healthy controls (p < 0.001). Higher levels of serum miR-21 were also correlated with tumors of higher grades, more nodal involvement, distal metastasis and advanced clinical stages (p < 0.01). Furthermore, over-expression levels declined towards normal after surgical tumor resection (p < 0.001). CONCLUSION: In conclusion, our findings demonstrate that serum miR-21 expression profile may serve as a potential non-invasive diagnostic and prognostic biomarker for breast cancer. PMID- 26063583 TI - Let-7c is a Candidate Biomarker for Cervical Intraepithelial Lesions: A Pilot Study. AB - BACKGROUND: Numerous studies have been performed to discover predictive/prognostic biomarkers for human papillomavirus (HPV) infection and cervical cancer development. More recently, microRNAs were suggested as possible biomarkers of HPV-associated cancers and our aim was to characterize the expression of let-7c in exfoliated cervical cells from women with cervical intraepithelial lesions. METHODS: Let-7c expression was evaluated by quantitative reverse transcription-polymerase chain reaction in 73 women with normal or cervical intraepithelial lesions: normal epithelium with (n = 17) and without (n = 21) HPV infection; low-grade squamous intraepithelial lesions (n = 14); and high-grade squamous intraepithelial lesions (n = 21). RESULTS: Data showed a trend to down-regulation in women with low-grade squamous intraepithelial lesions (2(-DeltaDeltaCt) = 0.38, p = 0.06) and a significant decreased expression of let 7c in women with low-grade squamous intraepithelial lesions (2(-DeltaDeltaCt) = 0.21; p = 0.004). The combined analysis of all cervical intraepithelial lesions revealed a down-regulation of let-7c expression (2(-DeltaDeltaCt) = 0.27; p = 0.011). CONCLUSION: Our results showed that let-7c expression is significantly changed in the different cervical intraepithelial lesions and its levels should be further investigated as a possible biomarker for cervical intraepithelial lesions using exfoliated cervical cells as the sample source. PMID- 26063584 TI - Terrestrial gamma radiation baseline mapping using ultra low density sampling methods. AB - Baseline terrestrial gamma radiation maps are indispensable for providing basic reference information that may be used in assessing the impact of a radiation related incident, performing epidemiological studies, remediating land contaminated with radioactive materials, assessment of land use applications and resource prospectivity. For a large land mass, such as Queensland, Australia (over 1.7 million km(2)), it is prohibitively expensive and practically difficult to undertake detailed in-situ radiometric surveys of this scale. It is proposed that an existing, ultra-low density sampling program already undertaken for the purpose of a nationwide soil survey project be utilised to develop a baseline terrestrial gamma radiation map. Geoelement data derived from the National Geochemistry Survey of Australia (NGSA) was used to construct a baseline terrestrial gamma air kerma rate map, delineated by major drainage catchments, for Queensland. Three drainage catchments (sampled at the catchment outlet) spanning low, medium and high radioelement concentrations were selected for validation of the methodology using radiometric techniques including in-situ measurements and soil sampling for high resolution gamma spectrometry, and comparative non-radiometric analysis. A Queensland mean terrestrial air kerma rate, as calculated from the NGSA outlet sediment uranium, thorium and potassium concentrations, of 49 +/- 69 nGy h(-1) (n = 311, 3sigma 99% confidence level) is proposed as being suitable for use as a generic terrestrial air kerma rate background range. Validation results indicate that catchment outlet measurements are representative of the range of results obtained across the catchment and that the NGSA geoelement data is suitable for calculation and mapping of terrestrial air kerma rate. PMID- 26063585 TI - High IGF2 expression is associated with poor clinical outcome in human ovarian cancer. AB - Ovarian cancer is one of the most common types of cancer in females and is the leading cause of death among gynaecological cancers in women worldwide. In the present study, we identified insulin-like growth factor 2 (IGF2) as a differentially expressed gene between cancerous and non-cancerous ovarian tissues. IGF2 was frequently increased in the human ovarian cancers when compared to the frequency in the non-cancerous ovarian tissues both at the mRNA (30/35) and protein level (61/72). The mean level of IGF2 in the tumor tissues was markedly higher than that in the non-cancerous tissues (nearly 3-fold change) (P=0.000). There was a significant correlation of IGF2 expression with histological grade (P=0.047). Kaplan-Meier analysis indicated that the ovarian cancer patients with high IGF2 expression showed a poorer prognosis both in regards to overall survival (OS) and progression-free survival (PFS) (n=1,648, P=0.000). Further analysis revealed that high expression of IGF2 was an unfavorable factor for the prognosis of the ovarian cancer patients at clinical stage I + II, stage III, histological grade 2, grade 3 or those treated with chemotherapy containing platin and Taxol. Our data provide evidence that IGF2 expression is frequently increased in ovarian cancer tissues, and high expression of IGF2 may be a significant prognostic factor for poor survival in ovarian cancer patients. PMID- 26063587 TI - Paternalism and factitious disorder: medical treatment in illness deception. AB - The primary aims are to consider whether a range of paternalistic medical interventions can be justified in the treatment of factitious disorder (FD) and to show that the particularities of FD and its management make it an ideal phenomenon to highlight the difficulties of balancing respect for self determination, responsibility and duty of care in psychiatry. FD is usually classified as a mental disorder involving deliberate and hidden feigning or inducement of illness, in order to achieve patient status. Both the nature of the disorder and the approach to treatment are controversial and under-researched. It is argued that FD should be classified as a mental disorder; may well expose the patient to extreme risk; can warrant paternalistic interventions, in order to fulfil duty of care. Moreover, treatment of FD is inherently paternalistic and therefore raises interesting questions about justifications and type of paternalistic interventions in psychiatry both for FD and in general. A brief account of key questions concerning psychiatry and paternalism is followed by some case histories of FD, the clinical dilemmas posed and the question of how this disorder might warrant paternalistic interventions. In order to answer this question, two things are considered: the legitimacy and character of FD as a mental disorder; possible frameworks for and types of paternalistic interventions. To conclude, it is argued that there are no compelling reasons for rejecting the use of paternalistic interventions for FD, but that further investigation of FD and type and frameworks for psychiatric paternalism, in relation to FD and other mental disorders, are urgently needed. PMID- 26063586 TI - Institutional deliveries and perinatal and neonatal mortality in Southern and Central India. AB - BACKGROUND: Skilled birth attendance and institutional delivery have been advocated for reducing maternal, perinatal and neonatal mortality (PMR and NMR). India has successfully implemented various strategies to promote skilled attendance and incentivize institutional deliveries in the last 5 years. OBJECTIVES: The study evaluates the trends in institutional delivery, PMR, NMR, and their risk factors in two Eunice Kennedy Shriver NICHD Global Network for Women's and Children's Health Research sites, in Belgaum and Nagpur, India, between January 2010 and December 2013. DESIGN/METHODS: Descriptive data stratified by level of delivery care and key risk factors were analyzed for 36 geographic clusters providing 48 months of data from a prospective, population based surveillance system that registers all pregnant permanent residents in the study area, and their pregnancy outcomes irrespective of where they deliver. Log binomial models with generalized estimating equations to control for correlation of clustered observations were used to test the trends significance RESULTS: 64,803 deliveries were recorded in Belgaum and 39,081 in Nagpur. Institutional deliveries increased from 92.6% to 96.1% in Belgaum and from 89.5% to 98.6% in Nagpur (both p<0.0001); hospital rates increased from 63.4% to 71.0% (p=0.002) and from 63.1% to 72.0% (p<0.0001), respectively. PMR declined from 41.3 to 34.6 (p=0.008) deaths per 1,000 births in Belgaum and from 47.4 to 40.8 (p=0.09) in Nagpur. Stillbirths also declined, from 22.5 to 16.3 per 1,000 births in Belgaum and from 29.3 to 21.1 in Nagpur (both p=0.002). NMR remained unchanged. CONCLUSIONS: Significant increases in institutional deliveries, particularly in hospitals, were accompanied by reductions in stillbirths and PMR, but not by NMR. PMID- 26063588 TI - An exploratory trial of parental advice for increasing vegetable acceptance in infancy. AB - Research suggests that repeatedly offering infants a variety of vegetables during weaning increases vegetable intake and liking. The effect may extend to novel foods. The present study aimed to investigate the impact of advising parents to introduce a variety of single vegetables as first foods on infants' subsequent acceptance of a novel vegetable. Mothers of 4- to 6-month-old infants in the UK, Greece and Portugal were randomised to either an intervention group (n 75), who received guidance on introducing five vegetables (one per d) as first foods repeated over 15 d, or a control group (n 71) who received country-specific 'usual care'. Infant's consumption (g) and liking (maternal and researcher rated) of an unfamiliar vegetable were assessed 1 month post-intervention. Primary analyses were conducted for the full sample with secondary analyses conducted separately by country. No significant effect of the intervention was found for vegetable intake in the three countries combined. However, sub-group analyses showed that UK intervention infants consumed significantly more novel vegetable than control infants (32.8 (SD 23.6) v. 16.5 (sd 12.1) g; P =0.003). UK mothers and researchers rated infants' vegetable liking higher in the intervention than in control condition. In Portugal and Greece, there was no significant intervention effect on infants' vegetable intake or liking. The differing outcome between countries possibly reflects cultural variations in existing weaning practices. However, the UK results suggest in countries where vegetables are not common first foods, advice on introducing a variety of vegetables early in weaning may be beneficial for increasing vegetable acceptance. PMID- 26063589 TI - Interaction of Vaccination and Reduction of Antibiotic Use Drives Unexpected Increase of Pneumococcal Meningitis. AB - Antibiotic-use policies may affect pneumococcal conjugate-vaccine effectiveness. The reported increase of pneumococcal meningitis from 2001 to 2009 in France, where a national campaign to reduce antibiotic use was implemented in parallel to the introduction of the 7-valent conjugate vaccine, provides unique data to assess these effects. We constructed a mechanistic pneumococcal transmission model and used likelihood to assess the ability of competing hypotheses to explain that increase. We find that a model integrating a fitness cost of penicillin resistance successfully explains the overall and age-stratified pattern of serotype replacement. By simulating counterfactual scenarios of public health interventions in France, we propose that this fitness cost caused a gradual and pernicious interaction between the two interventions by increasing the spread of nonvaccine, penicillin-susceptible strains. More generally, our results indicate that reductions of antibiotic use may counteract the benefits of conjugate vaccines introduced into countries with low vaccine-serotype coverages and high-resistance frequencies. Our findings highlight the key role of antibiotic use in vaccine-induced serotype replacement and suggest the need for more integrated approaches to control pneumococcal infections. PMID- 26063590 TI - Plasma Homocysteine Levels Predict the Risk of Acute Cerebral Infarction in Patients with Carotid Artery Lesions. AB - This study examined the association between elevated plasma homocysteine (Hcy) levels and the risk of acute cerebral infarction in patients with carotid artery lesions. A total of 78 patients were divided into two groups, the high Hcy group (n = 38; Hcy levels >15 umol/L) and the low Hcy group (n = 40; Hcy levels <=15 umol/L). High-resolution B-mode ultrasounds were performed to assess intima media thickness (IMT), infarcts, plaques, and stenosis in the extracranial carotid artery of these patients. All patients underwent 3 T MR scanners to evaluate cerebral artery stenosis in the intracranial cerebral artery. The plasma Hcy levels did not show any statistically significant differences when comparisons were based on gender, age, blood pressure, diabetes, hyperlipidemia, and systolic and diastolic pressures. Importantly, the incidence of carotid plaque and severe stenosis of intracranial and extracranial artery were significantly higher in the high Hcy group compared to the low Hcy group. Pearson's test indicated that plasma Hcy levels positively correlated with IMT, total number of plaques and unstable plaques. Overall, the elevated plasma Hcy levels correlated with increased frequency of carotid plaque formation, extra- and intracranial arterial stenosis, and the degree of stenosis. In conclusion, we find a significant correlation between elevated plasma Hcy levels and the increased incidence of acute cerebral infarction in patients with carotid artery lesions. PMID- 26063591 TI - Protection of the Crayfish Mechanoreceptor Neuron and Glial Cells from Photooxidative Injury by Modulators of Diverse Signal Transduction Pathways. AB - Oxidative stress is the reason of diverse neuropathological processes. Photodynamic therapy (PDT), an effective inducer of oxidative stress, is used for cancer treatment, including brain tumors. We studied the role of various signaling pathways in photodynamic injury and protection of single neurons and satellite glial cells in the isolated crayfish mechanoreceptor. It was photosensitized with alumophthalocyanine Photosens in the presence of inhibitors or activators of various signaling proteins. PDT eliminated neuronal activity and killed neurons and glial cells. Inhibitory analysis showed the involvement of protein kinases Akt, glycogen synthase kinase-3beta (GSK-3beta), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinases 1 and 2 (MEK1/2), calmodulin, calmodulin-dependent kinase II (CaMKII), adenylate cyclase, and nuclear factor NF-kappaB in PDT-induced necrosis of neurons. Nitric oxide (NO) and glial cell-derived neurotrophic factor (GDNF) reduced neuronal necrosis. In glial cells, protein kinases Akt, calmodulin, and CaMKII; protein kinases C and G, adenylate cyclase, and p38; and nuclear transcription factor NF-kappaB also mediated PDT-induced necrosis. In contrast, NO and neurotrophic factors nerve growth factor (NGF) and GDNF demonstrated anti-necrotic activity. Phospholipase Cgamma, protein kinase C, GSK-3beta, mTOR, NF-kappaB, mitochondrial permeability transition pores, and NO synthase mediated PDT-induced apoptosis of glial cells, whereas protein kinase A, tyrosine phosphatases, and neurotrophic factors NGF, GDNF, and neurturin were involved in protecting glial cells from photoinduced apoptosis. Signaling pathways that control cell survival and death differed in neurons and glia. Inhibitors or activators of some signaling pathways may be used as potential protectors of neurons and glia from photooxidative stress and following death. PMID- 26063592 TI - Melatonin Ameliorates Arsenite-Induced Neurotoxicity: Involvement of Autophagy and Mitochondria. AB - In the present study, the neuroprotective effect of melatonin on arsenite-induced neurotoxicity was investigated in rat primary cultured cortical neurons. Incubation of melatonin prevented arsenite-induced neuronal cell loss in a concentration-dependent manner. Furthermore, melatonin significantly attenuated arsenite-induced elevation in microtubule-associated protein light chain 3 (LC3) II levels, a biomarker of autophagy. Our fluorescent staining assay showed that melatonin decreased arsenite-induced elevation of co-localized fluorescent puncta of monodansylcadaverine (a specific marker of autophagic vacuoles) and lysotracker red (a specific marker of lysosomes), indicating that melatonin is capable of inhibiting arsenite-induced autophagy and autolysosome formation. Because 3-methyladenine (an autophagic inhibitor) attenuated the arsenite-reduced alpha-synuclein levels (a protein essential for the neurite outgrowth and synaptic plasticity), melatonin via inhibiting autophagy attenuated the arsenite reduced alpha-synuclein levels. At the same time, melatonin ameliorated the arsenite-induced reduction in growth associated protein 43 (a hallmark protein of neurite outgrowth) and discontinuous neurites of rat primary cultured cortical neurons. In addition, melatonin was found to prevent arsenite-induced decreases in cytochrome c oxidase levels (a biomarker of mitochondrial mass) and elevation in co-localized fluorescent puncta of autolysosomes and cytochrome c oxidase. Moreover, melatonin prevented arsenite-induced reduction in peroxisome proliferator-activated receptor gamma co-activator 1 alpha, a transcriptional co activator of mitochondrial biosynthesis. Taken together, melatonin may exert its neuroprotective action via inhibiting arsenite-induced autophagy and enhancing mitochondrial biogenesis and thus restoring alpha-synuclein levels, neuronal integrity, and mitochondrial mass in rat primary cultured cortical neurons. PMID- 26063594 TI - Chimeric Self-assembling Nanofiber Containing Bone Marrow Homing Peptide's Motif Induces Motor Neuron Recovery in Animal Model of Chronic Spinal Cord Injury; an In Vitro and In Vivo Investigation. AB - To date, spinal cord injury (SCI) has remained an incurable disaster. The use of self-assembling peptide nanofiber containing bioactive motifs such as bone marrow homing peptide (BMHP1) as an injectable scaffold in spinal cord regeneration has been suggested. Human endometrial-derived stromal cells (hEnSCs) have been approved by the FDA for clinical application. In this regard, we were interested in investigating the role of BMHP1 in hEnSCs' neural differentiation in vitro and evaluating the supportive effects of this scaffold in rat model of chronic SCI. 1,1-Diphenyl-2-picryl-hydrazyl (DPPH), lactate dehydrogenase (LDH) release, 3 (4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay, real-time PCR, and immunocyotochemistry (ICC) were performed as a biocompatibility and neural differentiation evaluations on neuron-like hEnSC-derived cells encapsulated into nanofiber. Nanofiber was implanted into rats and followed by behavioral test, Nissl, luxol fast blue (LFB) staining and immunohistostaining (IHC). Results indicated that cell membrane of neuroblastoma cells were more sensitive than hEnSCs to concentration of proton and cell proliferation decreased with increase of concentration. This effect might be related to oxygen tension and elastic modules of scaffold. -BMHP1 nanofiber induced neural differentiation in hEnSC and decreased GFAP gene and protein as a marker of reactive astrocytes in vitro and in vivo. A reason for this finding might be related to the role of spacer number in induction of mechano-transduction signals. The presented study revealed the chimeric BMHP1 nanofiber induced higher axon regeneration and myelniation around the cavity and motor neuron function was encouraged to improve with less inflammatory response following SCI in rats. These effects were possibly due to nanostructured topography and mechano-transduction signals derived from hydrogel at low concentration. PMID- 26063593 TI - Manganese-Enhanced Magnetic Resonance Imaging Reflects Brain Pathology During Progressive HIV-1 Infection of Humanized Mice. AB - Progressive human immunodeficiency viral (HIV) infection commonly leads to a constellation of cognitive, motor, and behavioral impairments. These are collectively termed HIV-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) reduces HAND severity, it does not affect disease prevalence. Despite decades of research, there remain no biomarkers for HAND and all potential comorbid conditions must first be excluded for a diagnosis to be made. To this end, we now report that manganese (Mn(2+))-enhanced magnetic resonance imaging (MEMRI) can reflect brain region-specific HIV-1-induced neuropathology in chronically virus-infected NOD/scid-IL-2Rgammac(null) humanized mice. MEMRI diagnostics mirrors the abilities of Mn(2+) to enter and accumulate in affected neurons during disease. T1 relaxivity and its weighted signal intensity are proportional to Mn(2+) activities in neurons. In 16-week virus infected humanized mice, altered MEMRI signal enhancement was easily observed in affected brain regions. These included, but were not limited to, the hippocampus, amygdala, thalamus, globus pallidus, caudoputamen, substantia nigra, and cerebellum. MEMRI signal was coordinated with levels of HIV-1 infection, neuroinflammation (astro- and micro-gliosis), and neuronal injury. MEMRI accurately demonstrates the complexities of HIV-1-associated neuropathology in rodents that reflects, in measure, the clinical manifestations of neuroAIDS as it is seen in a human host. PMID- 26063595 TI - Elevated IL-6 and TNF-alpha Levels in Cerebrospinal Fluid of Subarachnoid Hemorrhage Patients. AB - The present study investigated the correlation between interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) levels in cerebrospinal fluid (CSF) and subarachnoid hemorrhage (SAH) progression. A meta-analysis was further conducted from pooled data to analyze the clinical value of IL-6 and TNF-alpha in SAH diagnosis. In our case-control study, a total of 57 SAH patients were assigned to two groups, CVS group (n = 27) and non-CVS group (n = 30), based on the presence of cerebral vasospasm (CVS). In addition, 65 healthy subjects were enrolled as controls. IL-6 and TNF-alpha levels in CSF were measured in all the study subjects by enzyme-linked immunosorbent assay (ELISA). For meta-analysis, an exhaustive literature search was conducted to identify relevant published articles and strict inclusion and exclusion criteria were applied to select studies for the present meta-analysis. Data extracted from these studies was analyzed using STATA 12.0 software. IL-6 and TNF-alpha levels in CSF of SAH patients were markedly higher than those of healthy controls (all P < 0.001). Further, CVS patients showed elevated IL-6 and TNF-alpha levels in CSF compared to non-CVS patients (all P < 0.001). The increase in IL-6 and TNF-alpha levels in CSF correlated with the increasing disease severity, based on Hunt-Hess grade, in SAH patients (all P < 0.05). Our meta-analysis also confirmed that IL-6 and TNF alpha CSF levels were markedly higher in SAH patients compared to healthy controls (all P < 0.001). Ethnicity-stratified analysis showed that both IL-6 and TNF-alpha CSF levels were elevated in Asian SAH patients, compared to their healthy counterparts (all P < 0.05). The TNF-alpha CSF levels were significantly higher in Caucasian SAH patients (P < 0.001), but the IL-6 CSF levels showed no such differences compared to the healthy controls (P = 0.219). Subgroup analysis based on the presence of CVS showed that both IL-6 and TNF-alpha CSF levels were markedly higher in CVS patients than those in non-CVS patients (all P < 0.05). Our results provide strong evidence that IL-6 and TNF-alpha CSF levels are elevated in SAH patients and may participate in SAH development. Thus, these two cytokines could be important biomarkers for early diagnosis and disease monitoring in SAH patients. PMID- 26063596 TI - Early results after modular non-cemented reverse total shoulder arthroplasty: a prospective single-centre study of 38 consecutive cases. AB - BACKGROUND: This study evaluated the outcome of a third generation modular non cemented reverse total shoulder arthroplasty (RTSA) in incongruent glenohumeral degeneration with severe rotator cuff deficiency. MATERIALS AND METHODS: Thirty eight consecutive RTSA with a mean age of 72 years (range 58-89 years) were prospectively enrolled. Mean follow-up was 24 months (range 21-29 months). Pain and standardized clinical functional scores were monitored. Radiographic and MRI findings have been scored and correlated to clinical outcome and complication rate. RESULTS: Preoperative pain decreased significantly from VAS 8 to 2 at 24 months postop., as ROM improved significantly, by at least doubling preoperative values of elevation, abduction, and external rotation. Nevertheless, internal rotation languished. The preoperative median constant was 18 points and 70 points 24 months postop. (p < 0.001). Initial median DASH was 95 vs. 50 2 years after surgery (p < 0.001). Median prospective ASES was 23 (IQR 8-33) vs. 70 points (p < 0.001) at final follow-up. Each outcome measurement improved significantly at 6, 12, and 24 months follow-up. There was no significant correlation between pre operative radiographic findings of osseous and/or soft-tissue degeneration and short-term clinical outcome and/or complication rate (13 %). At final follow-up, 54 % showed radiographic signs of inferior scapular notching. There was no revision and/or loosening observed. CONCLUSION: RSTA with this modular system results in significant pain relief and improvement of functional clinical outcomes. However, longevity of the device is currently unknown. PMID- 26063597 TI - The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications. AB - INTRODUCTION: Prolactin (PRL) signaling has emerged as a relevant target in breast and prostate cancers. This has encouraged various laboratories to develop compounds targeting the PRL receptor (PRLR). As the latter is widely distributed, it is timely to address whether other conditions could also benefit from such inhibitors. AREAS COVERED: The authors briefly overview the two classes of PRLR blockers, which involve: i) PRL-core based analogs that have been validated as competitive antagonists in various preclinical models, and ii) anti-PRLR neutralizing antibodies that are currently in clinical Phase I for advanced breast and prostate cancers. The main purpose of this review is to discuss the multiple organs/diseases that may be considered as potential targets/indications for such inhibitors. This is done in light of reports suggesting that PRLR expression/signaling is increased in disease, and/or that systemic or locally elevated PRL levels correlate with (or promote) organ pathogenesis. EXPERT OPINION: The two immediate challenges in the field are i) to provide the scientific community with potent anti-prolactin receptor antibodies to map prolactin receptor expression in target organs, and ii) to take advantage of the availability of functionally validated PRLR blockers to establish the relevance of these potential indications in humans. PMID- 26063600 TI - Ru-Catalyzed Regioselective CH-Hydroarylation of Alkynes with Benzylthioethers Using Sulfur as Directing Group. AB - Benzylthioethers react with internal alkynes in the presence of catalytic amounts of [Ru(cymene)Cl2]2 to give the corresponding ortho-alkenylated species, using sulfur as the sole directing group. The reaction is regiospecific, tolerates different substituents at both the sulfur and the aryl ring, and proceeds very efficiently with a large variety of electron-rich alkynes. PMID- 26063598 TI - Subcellular localization of grapevine red blotch-associated virus ORFs V2 and V3. AB - Grapevine red blotch-associated virus is a recently discovered plant monopartite gemini-like virus found in North American grapevines. Leaf discoloration and a decrease in fruit quality are associated with its infection. Two of its six open reading frames (ORFs), V2 and V3, are of unknown function and share no obvious homology with plant or viral genes. Transient expression of these ORFs in fusion with the green fluorescent protein demonstrated that the V2 protein localizes in the nucleoplasm, Cajal bodies, and cytoplasm; and the V3 protein localizes in various unidentified subnuclear bodies. Additionally, the V2 protein is redirected to the nucleolus upon co-expression with the nucleolus and Cajal body associated protein Fib2. PMID- 26063599 TI - Transposon-mediated death of an ancestral A-23-like allele: evolution of TCR positioning motifs in the HLA-A lineage. AB - HLA-A alleles are characterized by tandem arginine and histidine/arginine motifs (i.e., R65 and H151R motifs) present on the alpha1- and alpha2-helix, respectively. In crystallographic structures, alpha/beta T-cell receptors (TCR) contact both motifs and appear to be geometrically positioned for alloreactivity. Herein, bioinformatics of "dual-motif" MHC A-like alleles were investigated across phylogeny. While A-like alleles with the R65 motif are widespread, the H151R motif has segregated out of most species. Surprisingly, an uncharacterized orf in tarsiers (Loc-103275158) encodes R151 within a truncated A-23-like gene, which is in frame with short footprints of Tc5 and Tigger transposons (TE); the extant tarsier A-23 allele is totally missing exon-3 and part of exon-4; together, suggesting TE-mediated inactivation of an intact/ancestral A-23 allele. Since the only other (non-human) dual-motif A-like alleles are in gorilla, chimpanzee, and the Florida manatee, we speculate that dual-motif A alleles first emerged in the Afrotherian lineage and reappeared during the evolution of higher primates. PMID- 26063601 TI - Mesoporous ZnCo2O4 nanoflakes grown on nickel foam as electrodes for high performance supercapacitors. AB - ZnCo2O4 nanoflakes, as electrodes for supercapacitors, are grown on a cellular nickel foam using a cost-effective hydrothermal procedure. The mesoporous ZnCo2O4 nanoflakes have large electroactive surface areas with strong adhesion to the Ni foam, allowing fast ion and electron transport. The nanoarchitecture electrodes deliver an excellent specific capacitance of 1220 F g(-1) at a current density of 2 A g(-1) in a 2 M KOH aqueous solution and a long-term cyclic stability of 94.2% capacitance retention after 5000 cycles. The fabrication strategy is facile, cost effective, and can offer great promise for large-scale supercapacitor applications. PMID- 26063602 TI - Ethanol-related alterations in gene expression patterns in the developing murine hippocampus. AB - It is well known that consuming alcohol prior to and during pregnancy can cause harm to the developing fetus. Fetal alcohol spectrum disorder is a term commonly used to describe a range of disabilities that may arise from prenatal alcohol exposure such as fetal alcohol syndrome, partial fetal alcohol syndrome, alcohol related neurodevelopmental disorders, and alcohol-related birth defects. Here, we report that maternal binge alcohol consumption alters several important genes that are involved in nervous system development in the mouse hippocampus at embryonic day 18. Microarray analysis revealed that Nova1, Ntng1, Gal, Neurog2, Neurod2, and Fezf2 gene expressions are altered in the fetal hippocampus. Pathway analysis also revealed the association of the calcium signaling pathway in addition to other pathways with the differentially expressed genes during early brain development. Alteration of such important genes and dynamics of the signaling pathways may cause neurodevelopmental disorders. Our findings offer insight into the molecular mechanism involved in neurodevelopmental disorders associated with alcohol-related defects. PMID- 26063603 TI - Alteration of sperm protein profile induced by cigarette smoking. AB - Cigarette smoking is associated with lower semen quality, but how cigarette smoking changes the semen quality remains unclear. The aim of this study was to screen the differentially expressed proteins in the sperm of mice with daily exposure to cigarette smoke. The 2D gel electrophoresis (2DE) and mass spectrometry (MS) analyses results showed that the mouse sperm protein profile was altered by cigarette smoking. And 22 of the most abundant proteins that correspond to differentially expressed spots in 2DE gels of the sperm samples were identified. These proteins were classified into different groups based on their functions, such as energy metabolism, reproduction, and structural molecules. Furthermore, the 2DE and MS results of five proteins (Aldoa, ATP5a1, Gpx4, Cs, and Spatc1) were validated by western blot analysis and reverse transcriptase-polymerase chain reaction. Results showed that except Spatc1 the other four proteins showed statistically significant different protein levels between the smoking group and the control group (P < 0.05). The expressions of three genes (Aldoa, Gpx4, and Spatc1) were significantly different (P < 0.05) at transcription level between the smoking group and the control group. In addition, five proteins (Aldoa, ATP5a1, Spatc1, Cs, and Gpx4) in human sperm samples from 30 male smokers and 30 non-smokers were detected by western blot analysis. Two proteins (Aldoa and Cs) that are associated with energy production were found to be significantly altered, suggesting that these proteins may be potential diagnostic markers for evaluation of smoking risk in sperm. Further study of these proteins may provide insight into the pathogenic mechanisms underlying infertility in smoking persons. PMID- 26063604 TI - A Meta-Synthesis of Qualitative Findings About Dance/Movement Therapy for Individuals With Trauma. AB - The therapeutic potential of using dance/movement therapy is being increasingly recognized. Preliminary interdisciplinary research findings suggest engaging the body in trauma treatment might reduce the length of treatment by addressing the connections among thoughts, feelings, neurobiology, and somatic responses in the survivor. Unfortunately, empirical research investigating its effectiveness as a psychotherapeutic intervention has been limited due to the lack of a clear manual for mental health care practitioners. The present study aims to synthesize findings from the existing qualitative literature in a qualitative meta synthesis. Our findings will contribute to the development of a body-oriented intervention for mental health care practitioners to use for trauma. PMID- 26063605 TI - Women's Experiences of Publicly Funded Non-Invasive Prenatal Testing in Ontario, Canada: Considerations for Health Technology Policy-Making. AB - Non-invasive prenatal testing (NIPT) via fetal DNA in maternal blood has been publicly funded in Ontario, Canada, for high-risk women since 2014. We solicited women's experiences and values related to this new health technology to describe how this test is currently being used in Ontario and to provide information about patient priorities to inform future policy decisions about the use of NIPT. Guided by constructivist grounded theory methodology, we interviewed 38 women who had diverse personal experiences with NIPT. Participants' accounts of their values for decision making about NIPT heavily relied on three mutually modulating factors: timing, accuracy, and risk. The values expressed by women conflict with the way that publicly funded NIPT has typically been implemented in Ontario. We offer recommendations for how NIPT might be integrated into prenatal care pathways in a way more consistent with women's values. PMID- 26063606 TI - Acting Independently While Living Alone: The Strategies and Struggles of Cancer Patients. AB - Cancer patients who live alone place specific importance on acting independently during treatment. We want to describe what it means to act independently and which strategies patients use to continue to act independently. We used a qualitative design, based on grounded theory. We interviewed 32 patients, 17 of them a second time. Patients who live alone defined acting independently in two different ways: It meant not only doing things alone but also using the help of others in a controlled way. These two meanings lead to two types of strategies. As treatment evolves, patients needed to change their preferred type of strategies to continue acting independently. Succeeding to change led to a feeling of mastery and success. However, failing to change led to struggling, whereby patients' needs became invisible. Health care providers should anticipate patients' inability to change strategies during cancer treatment, thereby preventing the patient's struggle from only becoming visible during crisis. PMID- 26063607 TI - Methodological and Epistemological Considerations in Utilizing Qualitative Inquiry to Develop Interventions. AB - The purpose of this article is to discuss methodological and epistemological considerations involved in using qualitative inquiry to develop interventions. These considerations included (a) using diverse methodological approaches and (b) epistemological considerations such as generalization, de-contextualization, and subjective reality. Diverse methodological approaches have the potential to inform different stages of intervention development. Using the development of a psychosocial hope intervention for advanced cancer patients as an example, the authors utilized a thematic study to assess current theories/frameworks and interventions. However, to understand the processes that the intervention needed to target to affect change, grounded theory was used. Epistemological considerations provided a framework to understand and, further, critique the intervention. Using diverse qualitative methodological approaches and examining epistemological considerations were useful in developing an intervention that appears to foster hope in patients with advanced cancer. PMID- 26063608 TI - A study of pyrazines in cigarettes and how additives might be used to enhance tobacco addiction. AB - BACKGROUND: Nicotine is known as the drug that is responsible for the addicted behaviour of tobacco users, but it has poor reinforcing effects when administered alone. Tobacco product design features enhance abuse liability by (A) optimising the dynamic delivery of nicotine to central nervous system receptors, and affecting smokers' withdrawal symptoms, mood and behaviour; and (B) effecting conditioned learning, through sensory cues, including aroma, touch and visual stimulation, to create perceptions of pending nicotine reward. This study examines the use of additives called 'pyrazines', which may enhance abuse potential, their introduction in 'lights' and subsequently in the highly market successful Marlboro Lights (Gold) cigarettes and eventually many major brands. METHODS: We conducted internal tobacco industry research using online databases in conjunction with published scientific literature research, based on an iterative feedback process. RESULTS: Tobacco manufacturers developed the use of a range of compounds, including pyrazines, in order to enhance 'light' cigarette products' acceptance and sales. Pyrazines with chemosensory and pharmacological effects were incorporated in the first 'full-flavour, low-tar' product achieving high market success. Such additives may enhance dependence by helping to optimise nicotine delivery and dosing and through cueing and learned behaviour. CONCLUSIONS: Cigarette additives and ingredients with chemosensory effects that promote addiction by acting synergistically with nicotine, increasing product appeal, easing smoking initiation, discouraging cessation or promoting relapse should be regulated by the US Food and Drug Administration. Current models of tobacco abuse liability could be revised to include more explicit roles with regard to non-nicotine constituents that enhance abuse potential. PMID- 26063609 TI - Malfunction of spermatogenesis in experimental ischemic mice. AB - An experimental ischemia (EI)-induced mouse model was used to analyze pathological and biochemical alterations in testes. Initial morphological changes were observed in Sertoli cells of EI testes at the light microscopic level. Examination of the ultrastructure using transmission electron microscopy confirmed that Sertoli cells were partially detached from the basement membrane of the seminiferous epithelium and that the cell membranes of adjacent Sertoli cells were not joined. The functional integrity of the blood-testis barrier (BTB) was assessed using the lanthanum tracer technique. Lanthanum had penetrated into the spaces between adjacent Sertoli cells in the adluminal compartment up to the lumen of the seminiferous epithelium in EI testes. Proteome analysis showed that the expression of heat shock protein (HSP) 70 was significantly upregulated in EI testes. Western blot analysis confirmed that the expression of HSP70 increased in a time-dependent manner after the EI procedure. HSP70 immunostaining was observed in spermatocytes and in round and elongated spermatids in EI testes. Our results suggest that a change in the junctions between adjacent Sertoli cells on the basal compartment is involved in the BTB disruption in EI testes. Therefore, male infertility caused by the BTB disruption could be associated with heat stress induced by ischemia. PMID- 26063610 TI - RNAi-mediated knockdown of INHBB increases apoptosis and inhibits steroidogenesis in mouse granulosa cells. AB - Inhibins are members of the TGFbeta superfamily and act as suppressors of follicle stimulating hormone (FSH) secretion from pituitary glands via a negative feedback mechanism to regulate folliculogenesis. In this study, the INHBB gene was knocked down by three RNAi-Ready pSIREN-RetroQ-ZsGreen vector- mediated recombinant plasmids to explore the effects of INHBB silencing on granulosa cell (GC) cell cycle, apoptosis and steroid production in vitro. Quantitative real time polymerase chain reaction, Western blot, flow cytometry and ELISA were performed to evaluate the role of INHBB in the mouse GC cell cycle, apoptosis and steroid production in vitro. The results showed that the relative mRNA and protein expression of INHBB in mouse GCs can be significantly reduced by RNAi with pshRNA-B1, pshRNA-B2 and pshRNA-B3 plasmids, with pshRNA-B3 having the best knockdown efficiency. Downregulation of the expression of INHBB significantly arrests cells in the G1 phase of the cell cycle and increases the apoptosis rate in GCs. This was further confirmed by downregulation of the protein expressions of Cyclin D1, Cyclin E and Bcl2, while the protein expression of Bax was upregulated. In addition, specific downregulation of INHBB markedly decreased the concentration of estradiol and progesterone, which was further validated by the decrease in the mRNA levels of CYP19A1 and CYP11A1. These findings suggest that inhibin betaB is important in the regulation of apoptosis and cell cycle progression in granulosa cells. Furthermore, the inhibin betaB subunit has a role in the regulation of steroid hormone biosynthesis. Evidence is accumulating to support the concept that inhibin betaB is physiologically essential for early folliculogenesis in the mouse. PMID- 26063611 TI - Single-session attention bias modification and error-related brain activity. AB - An attentional bias to threat has been implicated in the etiology and maintenance of anxiety disorders. Recently, attention bias modification (ABM) has been shown to reduce threat biases and decrease anxiety. However, it is unclear whether ABM modifies neural activity linked to anxiety and risk. The current study examined the relationship between ABM and the error-related negativity (ERN), a putative biomarker of risk for anxiety disorders, and the relationship between the ERN and ABM-based changes in attention to threat. Fifty-nine participants completed a single-session of ABM and a flanker task to elicit the ERN--in counterbalanced order (i.e., ABM-before vs. ABM-after the ERN was measured). Results indicated that the ERN was smaller (i.e., less negative) among individuals who completed ABM-before relative to those who completed ABM-after. Furthermore, greater attentional disengagement from negative stimuli during ABM was associated with a smaller ERN among ABM-before and ABM-after participants. The present study suggests a direct relationship between the malleability of negative attention bias and the ERN. Explanations are provided for how ABM may contribute to reductions in the ERN. Overall, the present study indicates that a single-session of ABM may be related to a decrease in neural activity linked to anxiety and risk. PMID- 26063613 TI - Next-generation transcriptome analysis in transgenic birch overexpressing and suppressing APETALA1 sheds lights in reproduction development and diterpenoid biosynthesis. AB - KEY MESSAGE: Overexpression of BpAP1 could cause early flowering in birch. BpAP1 affected the expression of many flowering-related unigenes and diterpenoid biosynthesis in transgenic birch, and BpPI was a putative target gene of BpAP1. APETALA1 (AP1) is an MADS-box transcription factor that is involved in the flowering process in plants and has been a focus of genetic studies examining flower development. Here, we carried out transcriptome analysis of birch (Betula platyphylla Suk.), including BpAP1 overexpression lines, BpAP1 suppression lines, and non-transgenic line (NT). Compared with NT, we detected 8302 and 7813 differentially expressed unigenes in 35S::BpAP1 and 35S::BpAP1RNAi transgenic lines, respectively. Overexpression and suppression of BpAP1 in birch affected diterpenoid biosynthesis and altered expression of many flowering-related unigenes. Moreover, combining information from the RNA-seq database and the birch genome, we predicted downstream target genes of BpAP1. Among the 166 putative target genes of BpAP1, there was a positive correlation between BpAP1 and BpPI. These results provide references for further examining the relationship between BpAP1 and its target genes, and reveal that BpAP1 functions as a transcription regulator in birch. PMID- 26063614 TI - Protein-protein and DNA-protein interactions mediate induction of defense genes by fruit extract of Azadirachta indica A. Juss. in Solanum lycopersicum L. AB - KEY MESSAGE: The present work demonstrates that induction of defense-related genes in tomato by neem extract was mediated by protein-protein and DNA-protein interactions. The induction of elicitor-mediated defense responses in plants is known, but the molecular mechanisms underlying its induction are not well studied. In the present study, third node leaf from the base of aseptically raised tomato plants was treated with aqueous fruit extracts of Azadirachta indica A. Juss. (neem). Samples were collected from the treated node at 24-h intervals for up to 96 h and analyzed for the gene expression of phenylalanine ammonia lyase (PAL), Peroxidase (POX) and Polyphenol Oxidase (PPO), beta-actin (standard). Samples were collected from elicitor-induced node at 5-min interval up to 70 min for analysis of protein-protein and DNA-protein interactions. The results demonstrated the induction of expression of PAL, POX and PPO due to the treatment whereas no change was observed in the expression of beta-actin. There was disappearance of lower molecular weight proteins which cross-linked with other proteins to form complexes. MALDI-TOF MS analysis revealed the interaction of mitogen-activated protein kinases (MAPK). The analysis of proteins interacted with DNA after induction by neem extract indicated the involvement of WRKY transcriptional factors. Neem-elicited defense responses could possibly due to interaction of proteins with other proteins and transcription factors with DNA which might be crucial in enhancing the expression of defense-related genes (PAL, POX and PPO). PMID- 26063616 TI - Generic, phenomenological, on-the-fly renormalized repulsion model for self limited organization of terminal supraparticle assemblies. AB - Self-limited, or terminal, supraparticles have long received great interest because of their abundance in biological systems (DNA bundles and virus capsids) and their potential use in a host of applications ranging from photonics and catalysis to encapsulation for drug delivery. Moreover, soft, uniform colloidal aggregates are a promising candidate for quasicrystal and other hierarchical assemblies. In this work, we present a generic coarse-grained model that captures the formation of self-limited assemblies observed in various soft-matter systems including nanoparticles, colloids, and polyelectrolytes. Using molecular dynamics simulations, we demonstrate that the assembly process is self-limited when the repulsion between the particles is renormalized to balance their attraction during aggregation. The uniform finite-sized aggregates are further shown to be thermodynamically stable and tunable with a single dimensionless parameter. We find large aggregates self-organize internally into a core-shell morphology and exhibit anomalous uniformity when the constituent nanoparticles have a polydisperse size distribution. PMID- 26063615 TI - A key role for PTP1B in dendritic cell maturation, migration, and T cell activation. AB - Dendritic cells (DC) are the major antigen-presenting cells bridging innate and adaptive immunity, a function they perform by converting quiescent DC to active, mature DC with the capacity to activate naive T cells. They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues. Here, we demonstrate that myeloid cell-specific genetic deletion of PTP1B (LysM PTP1B) leads to defects in lipopolysaccharide-driven bone marrow-derived DC (BMDC) activation associated with increased levels of phosphorylated Stat3. We show that myeloid cell-specific PTP1B deletion also causes decreased migratory capacity of epidermal DC, as well as reduced CCR7 expression and chemotaxis to CCL19 by BMDC. PTP1B deficiency in BMDC also impairs their migration in vivo. Further, immature LysM PTP1B BMDC display fewer podosomes, increased levels of phosphorylated Src at tyrosine 527, and loss of Src localization to podosome puncta. In co-culture with T cells, LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC. Finally, LysM PTP1B BMDC fail to present antigen to T cells as efficiently as control BMDC. These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation. PMID- 26063617 TI - TLR4 has a TP53-dependent dual role in regulating breast cancer cell growth. AB - Breast cancer is a leading cause of cancer-related death, and it is important to understand pathways that drive the disease to devise effective therapeutic strategies. Our results show that Toll-like receptor 4 (TLR4) drives breast cancer cell growth differentially based on the presence of TP53, a tumor suppressor. TP53 is mutationally inactivated in most types of cancer and is mutated in 30-50% of diagnosed breast tumors. We demonstrate that TLR4 activation inhibits growth of TP53 wild-type cells, but promotes growth of TP53 mutant breast cancer cells by regulating proliferation. This differential effect is mediated by changes in tumor cell cytokine secretion. Whereas TLR4 activation in TP53 mutant breast cancer cells increases secretion of progrowth cytokines, TLR4 activation in TP53 wild-type breast cancer cells increases type I IFN (IFN-gamma) secretion, which is both necessary and sufficient for mediating TLR4-induced growth inhibition. This study identifies a novel dichotomous role for TLR4 as a growth regulator and a modulator of tumor microenvironment in breast tumors. These results have translational relevance, demonstrating that TP53 mutant breast tumor growth can be suppressed by pharmacologic TLR4 inhibition, whereas TLR4 inhibitors may in fact promote growth of TP53 wild-type tumors. Furthermore, using data generated by The Cancer Genome Atlas consortium, we demonstrate that the effect of TP53 mutational status on TLR4 activity may extend to ovarian, colon, and lung cancers, among others, suggesting that the viability of TLR4 as a therapeutic target depends on TP53 status in many different tumor types. PMID- 26063618 TI - Association between STAT3 polymorphisms and cancer risk: a meta-analysis. AB - Five polymorphisms, rs2293152, rs4796793, rs12949918, rs6503695, rs744166, in the STAT3 gene have been implicated in susceptibility to cancer, but the results were inconclusive. The aim of this meta-analysis is to investigate the association between the five polymorphisms and cancer risk. All eligible case-control studies published up to March 2015 were identified by searching PubMed, Web of Science, Wanfang, VIP, and CNKI. Effect sizes of odds ratio (OR) and 95 % confidence interval (95 % CI) were calculated by using a fixed- or random-effect model. A total of 15 articles were included. Overall, a significantly decreased risk was found for rs12949918 polymorphism (dominant model: OR = 0.83, 95 % CI: 0.75-0.91, recessive model: OR = 0.77, 95 % CI: 0.68-0.87, TC vs. TT: OR = 0.87, 95 % CI: 0.79-0.96, CC vs. TT: OR = 0.71, 95 % CI: 0.62-0.81), and for rs744166 polymorphism (recessive model: OR = 0.75, 95 % CI: 0.58-0.98; GG vs. AA: OR = 0.68, 95 % CI: 0.51-0.90), while there was no significant association for other three polymorphisms under all genetic models. In subgroup analysis by ethnicity, for rs12949918 polymorphism, similar results were detected among Caucasians, similarly, a significant decreased risk was observed in Asians under dominant and CC vs. TT model; for rs2293152 polymorphism, significant association was detected among Asians under recessive model. This meta-analysis suggests that the STAT3 rs12949918 and rs744166 polymorphisms, but not other three polymorphisms, may be an important protective factor for cancer. PMID- 26063619 TI - Multiple-site genetic modifications in Escherichia coli using lambda-Red recombination and I-SceI cleavage. AB - OBJECTIVES: Genetic modifications to bacterial chromosomes are important for research; recently we reported a two-plasmid system for single locus modification in Escherichia coli and an improved method for simultaneous multiple-loci modification is needed. RESULTS: An intermediate bacterial strain was generated with different resistance marker genes flanked by I-SceI recognition sites at multiple target loci. Then a donor plasmid carrying several alleles with desired modifications was transformed into the intermediate strain together with a bifunctional helper plasmid encoding lambda-Red recombinase and I-SceI endonuclease. I-SceI would induce double-strand breaks (DSBs) in the chromosome and lambda-Red would induce recombination between chromosome DSBs and allele fragments from the donor plasmid, resulting in genomic modifications. CONCLUSIONS: This method has been used to successfully perform three different loci modifications simultaneously. PMID- 26063620 TI - (-)-Epicatechin-3-gallate (a polyphenol from green tea) potentiates doxorubicin induced apoptosis in H9C2 cardiomyocytes. AB - OBJECTIVE: The effect of epicatechin-3-gallate (ECG), a polyphenol that is present in green tea, on doxorubicin (DOX) cytotoxicity in H9C2 cardiomyocytes and its underlying mechanisms were investigated. RESULTS: Pretreatment with ECG (20 and 30 MUM) significantly increased DOX-induced apoptosis to 16-18% in H9C2 cardiomyocytes. The Bax/Bcl-2 ratio increased significantly after 1 h pretreatment with ECG. ECG also enhanced the phosphorylation of AMP-activated protein kinase (AMPK) which was induced by DOX in a dose-dependent manner. CONCLUSION: Pretreatment with ECG sensitized H9C2 cells to DOX-mediated apoptosis through modulation of proteins involved in apoptosis and AMPK. PMID- 26063621 TI - A MALDI-MS-based quantitative targeted glycomics (MALDI-QTaG) for total N-glycan analysis. AB - OBJECTIVES: To develop a sensitive and quantitative method for monitoring the abnormal glycosylation of clinical and biopharmaceutical products. RESULTS: MALDI MS-based quantitative targeted glycomics (MALDI-QTaG) was proposed for sensitive and quantitative analysis of total N-glycans. The derivatization reactions (i.e., amidation of sialic acid and incorporation of a positive charge moiety into the reducing end) dramatically increased the linearity (R(2) > 0.99) and sensitivity (limit of detection is 0.5 pmol/glycoprotein) relative to underivatized glycans. In addition, the analytical strategy was chromatographic purification-free and non-laborious process accessible to the high-throughput analyses. We used MALDI QTaG to analyze the N-glycans of alpha-fetoprotein (AFP) purified from normal cord blood and HCC cell line (Huh7 cells). The total percentages of core fucosylated AFP N-glycans from Huh7 cells and normal cord blood were 98 and 18%, respectively. CONCLUSIONS: This MALDI-MS-based glycomics technology has wide applications in many clinical and bioengineering fields requiring sensitive, quantitative and fast N-glycosylation validation. PMID- 26063622 TI - Aeration strategy for biofilm cultivation of the microalga Scenedesmus dimorphus. AB - OBJECTIVE: Biofilm cultivation of microalgae may be useful for biofuel production. However, many aspects for this cultivation method have not been well assessed. Accordingly, aeration strategy for biofilm cultivation of Scenedesmus dimorphus has been explored. RESULTS: Biomass, lipid and triacylglycerol (TAG) productivity in increased S. dimorphus as the CO2 concentration increased within 0.038-0.5% and kept constant with further increases. The biomass, lipid and TAG productivity increased with the speed increasing and an obvious threshold point was observed at 6.6 ml(-2) min(-1). The lipid and TAG content was unaffected by the aeration rate. CONCLUSIONS: Both the CO2 concentration as well as aeration speed affected the growth of S. dimorphus in biofilm cultivation. The optimized aeration strategy for biofilm cultivation was continuous air flow enriched with 1% CO2 (v/v) at 6.6 ml(-2) min(-1). PMID- 26063623 TI - Two-step biocatalytic process using lipase and whole cell catalysts for biodiesel production from unrefined jatropha oil. AB - OBJECTIVE: To avoid lipase deactivation by methanol in the enzymatic transesterification process, a two-step biocatalytic process for biodiesel production from unrefined jatropha oil was developed. RESULTS: Unrefined jatropha oil was first hydrolyzed to free fatty acids (FFAs) by the commercial enzyme Candida rugosa lipase. The maximum yield achieved of FFAs 90.3% at 40 degrees C, water/oil ratio 0.75:1 (v/v), lipase content 2% (w/w) after 8 h reaction. After hydrolysis, the FFAs were separated and converted to biodiesel by using Rhizopus oryzae IFO4697 cells immobilized within biomass support particles as a whole-cell biocatalyst. Molecular sieves (3 A) were added to the esterification reaction mixture to remove the byproduct water. The maximum fatty acid methyl ester yield reached 88.6% at 35 degrees C, molar ratio of methanol to FFAs 1.2:1, molecular sieves (3 A) content 60% (w/w) after 42 h. In addition, both C. rugosa lipase and R. oryzae whole cell catalyst in the process showed excellent reusability, retaining 89 and 79% yields, respectively, even after six batches of reactions. CONCLUSION: This novel process, combining the advantages of enzyme and whole cell catalysts, saved the consumption of commercial enzyme and avoid enzyme deactivation by methanol. PMID- 26063624 TI - Identification and spectroscopic characterization of neurosporene. AB - OBJECTIVES: Neurosporene is a carotene and an intermediate in the synthesis of lycopene from phytoene. Its content in carotenogenic organisms is very low; hence, the complete assignments of its spectroscopic data, including NMR, are insufficient. RESULTS: A purple bacterium of Rhodobacter sphaeroides G1C mutant had only one carotenoid. This carotenoid was extracted and purified using silica gel, DEAE-Toyopearl and C18-HPLC columns. It was identified using its absorption spectra, mass spectra, and (1)H- and (13)C-NMR spectra, including two-dimensional spectral analyses. CONCLUSION: The major carotenoid in the Rhodobacter sphaeroides G1C mutant was identified as neurosporene (7,8-dihydro-psi,psi carotene) using spectroscopic measurements, including complete assignments of its (1)H- and (13)C-NMR spectral data. PMID- 26063625 TI - Optimizing Patient Population for MP-MRI and Fusion Biopsy for Prostate Cancer Detection. AB - The diagnosis and treatment of prostate cancer continue to evolve with advances in science and technology. The utilization of multiparametric MRI (mp-MRI) to identify lesions in the prostate has given clinicians the ability to visualize malignancy in the prostate with greater confidence. With this new ability came the advancement of fusion biopsy platforms, which allow for direct targeting of these lesions. As with any new technology in medicine, the proper use of these modalities and how they fit into current clinical practice need to be addressed. This review summarizes the current knowledge on how to best optimize which men undergo mp-MRI and fusion biopsies both in the screening and treatment settings. PMID- 26063626 TI - Highly sensitive DNA methylation analysis at CpG resolution by surface-enhanced Raman scattering via ligase chain reaction. AB - Sensitive and accurate DNA methylation analysis at CpG resolution was demonstrated using surface-enhanced Raman scattering (SERS) via ligase chain reaction (LCR). The method was sensitive to 10% changes in methylation and the accuracy of methylation estimates in cells and serum DNA validated with sequencing. The LCR/SERS approach may have broad applications as an alternative (epi)genetic detection method. PMID- 26063627 TI - Jackpot Structural Features: Rollover Effect and Goal-Gradient Effect in EGM Gambling. AB - Relatively little research has been undertaken on the influence of jackpot structural features on electronic gaming machine (EGM) gambling behavior. This study considered two common features of EGM jackpots: progressive (i.e., the jackpot incrementally growing in value as players make additional bets), and deterministic (i.e., a guaranteed jackpot after a fixed number of bets, which is determined in advance and at random). Their joint influences on player betting behavior and the moderating role of jackpot size were investigated in a crossed design experiment. Using real money, players gambled on a computer simulated EGM with real jackpot prizes of either $500 (i.e., small jackpot) or $25,000 (i.e., large jackpot). The results revealed three important findings. Firstly, players placed the largest bets (20.3 % higher than the average) on large jackpot EGMs that were represented to be deterministic and non-progressive. This finding was supportive of a hypothesized 'goal-gradient effect', whereby players might have felt subjectively close to an inevitable payoff for a high-value prize. Secondly, large jackpots that were non-deterministic and progressive also promoted high bet sizes (17.8 % higher than the average), resembling the 'rollover effect' demonstrated in lottery betting, whereby players might imagine that their large bets could be later recouped through a big win. Lastly, neither the hypothesized goal-gradient effect nor the rollover effect was evident among players betting on small jackpot machines. These findings suggest that certain high-value jackpot configurations may have intensifying effects on player behavior. PMID- 26063628 TI - Youden's Index and the Likelihood Ratio Positive in Diagnostic Testing. AB - We refer to a recent letter to the editor by Hughes and show that, despite existing similarities between Youden's index and the log-likelihood ratio positive, important differences between these two measures remain to exist which can play an important difference in clinical practice. PMID- 26063629 TI - Room Temperature, Hybrid Sodium-Based Flow Batteries with Multi-Electron Transfer Redox Reactions. AB - We introduce a new concept of hybrid Na-based flow batteries (HNFBs) with a molten Na alloy anode in conjunction with a flowing catholyte separated by a solid Na-ion exchange membrane for grid-scale energy storage. Such HNFBs can operate at ambient temperature, allow catholytes to have multiple electron transfer redox reactions per active ion, offer wide selection of catholyte chemistries with multiple active ions to couple with the highly negative Na alloy anode, and enable the use of both aqueous and non-aqueous catholytes. Further, the molten Na alloy anode permits the decoupled design of power and energy since a large volume of the molten Na alloy can be used with a limited ion-exchange membrane size. In this proof-of-concept study, the feasibility of multi-electron transfer redox reactions per active ion and multiple active ions for catholytes has been demonstrated. The critical barriers to mature this new HNFBs have also been explored. PMID- 26063630 TI - Prostaglandin E2 excitatory effects on rat urinary bladder: a comparison between the beta-adrenoceptor modulation of non-voiding activity in vivo and micro contractile activity in vitro. AB - Prostaglandin E2 (PGE2) is well known to modulate urinary bladder functions, but it is also thought to be involved in the pathophysiology of lower urinary tract dysfunctions, since high levels of PGE2 have been found in overactive bladder (OAB) patients. beta-Adrenoceptors are major players in detrusor muscle relaxation, and the selective beta3-adrenoceptor (AR) agonist mirabegron was recently approved for the treatment of overactive bladder (OAB). beta Adrenoceptor modulation of PGE2 excitatory effects on bladder detrusor muscle was investigated by i.v. mirabegron after intravesical PGE2 infusion in conscious rats. Non-voiding activity (NVA) was assessed under isovolumetric conditions. In addition, mirabegron and isoprenaline (0.01-10 MUM) were studied on PGE2 increased micro-contractile activity during isometric tension recordings of intact isolated bladder muscle strips. Our investigations showed that PGE2 dramatically increased NVA in vivo and spontaneous micro-contractions in vitro. In vivo administration of mirabegron (0.1, 0.3 and 3 mg/kg) reduced PGE2 augmented NVA in dose-dependent manner, while the PGE2-increased micro contractions in isolated bladder strips were poorly inhibited. Isoprenaline inhibited PGE2-augmented micro-contractions in a concentration-dependent manner and had a higher potency compared to mirabegron. The apparent pKB of 7.25 for metoprolol at the isoprenaline concentration-response curve for PGE2-augmented micro-contractions suggests a beta1-AR-mediated. PMID- 26063631 TI - Xenia Forsselliana 2014. PMID- 26063632 TI - Population-based analysis of the impact and generalizability of the NSABP-B24 study on endocrine therapy for patients with ductal carcinoma in situ of the breast. AB - BACKGROUND: In 1999, the National Surgical Adjuvant Breast and Bowel Project (NSABP)-B24 trial demonstrated that tamoxifen reduced relapse risk in women with ductal carcinoma in situ (DCIS) treated with breast-conserving surgery (BCS) and radiotherapy (RT). In 2002, Allred's subgroup analysis showed that tamoxifen mainly benefitted estrogen receptor (ER)-positive disease. This study evaluates the impact and generalizability of these trial findings at the population level. PATIENTS AND METHODS: From 1989 to 2009, 2061 women with DCIS underwent BCS + RT in British Columbia. The following cohorts were analyzed: (1) pre-NSABP-B24 era (1989-1998, N = 417); (2) post-NSABP-B24 era (2000-2009, N = 1548). Cohort 2 was further divided into pre- and post-Allred eras. RESULTS: Endocrine therapy (ET) was used in 404/2061 (20%) patients. Median age of patients treated with compared with without ET, was 53 versus 57 years, (P < 0.0005). One of 417 (0.2%) versus 399/1548 (26%) patients took ET before versus after NSABP-B24. Among the post Allred era cohort treated with ET (N = 227), tumors were ER-positive in 65%, ER negative in 1%, and ER-unknown in 33%; whereas of those treated without ET (N = 801), ER was positive in 43%, negative in 15%, and unknown in 42% (P < 0.0005). On multivariable analysis of the post-NSABP-B24 era, ET was associated with improved event-free survival (EFS) (hazard ratio 0.6; P = 0.02); 5-year EFS were 96.9% with ET versus 94.5% without ET. CONCLUSIONS: ET use in DCIS patients treated with BCS + RT increased significantly after the NSABP-B24 study. ER+ disease and younger age were associated with increased ET use. ET was associated with improved EFS, confirming the generalizability of trial data at a population level. PMID- 26063634 TI - St Gallen International Expert Consensus on the primary therapy of early breast cancer: an invaluable tool for physicians and scientists. PMID- 26063633 TI - Pazopanib in pretreated advanced neuroendocrine tumors: a phase II, open-label trial of the Spanish Task Force Group for Neuroendocrine Tumors (GETNE). AB - BACKGROUND: The management of advanced neuroendocrine tumors (NETs) has recently changed. We assessed the activity of pazopanib after failure of other systemic treatments in advanced NETs. METHODS: This was a multicenter, open-label, phase II study evaluating pazopanib as a single agent in advanced NETs (PAZONET study). The clinical benefit rate (CBR) at 6 months was the primary end point. Translational correlation of radiological response and progression-free survival (PFS) with circulating and tissue biomarkers was also evaluated. RESULTS: A total of 44 patients were enrolled. Twenty-five patients (59.5%) were progression-free at 6 months (4 partial responses, 21 stable diseases) with a median PFS of 9.5 months [95% confidence interval (CI) 4.8-14.1]. The CBR varied according to prior therapy received, with 73%, 60% and 25% in patients treated with prior multitarget inhibitors, prior mTOR inhibitors and both agents, respectively. A nonsignificant increase in PFS was observed in patients presenting lower baseline circulating tumor cell (CTC) counts (9.1 versus 5.8 months; P = 0.22) and in those with decreased levels of soluble-vascular endothelial growth factor receptor-2 (sVEGFR-2) (12.6 versus 9.1 months; P = 0.067). A trend toward reduced survival was documented in patients with VEGFR3 rs307821 and rs307826 missense polymorphisms [hazard ratio (HR): 12.3; 95% CI 1.09-139.2; P = 0.042 and HR: 6.9; 95% CI 0.96-49.9; P = 0.055, respectively]. CONCLUSIONS: Pazopanib showed clinical activity in patients with advanced NETs regardless of previous treatments. Additionally, CTCs, soluble-s VEFGR-2 and VEGFR3 gene polymorphisms constitute potential biomarkers for selecting patients for pazopanib (NCT01280201). CLINICAL TRIAL NUMBER: NCT01280201. PMID- 26063635 TI - Targeting the folate receptor: diagnostic and therapeutic approaches to personalize cancer treatments. AB - BACKGROUND: In cancer therapy, molecularly targeted agents have the potential to maximize antitumor efficacy while minimizing treatment-related toxicity. However, these agents may only be effective in specific tumor subtypes with defined genomic profiles. This emphasizes the importance of developing personalized cancer therapeutic strategies (i.e. through the use of companion diagnostic tests) to appropriately select and treat patients who are likely to benefit from specific targeted therapies, thus leading to improvements in clinical and safety outcomes. A potential biological target is the folate receptor (FR), which has been shown to be overexpressed on the surface of many cancers, including tumors of the lungs and ovaries. DESIGN: We carried out a literature search to identify how the FR can be a potential target for selected tumors, and how the FR expression can be exploited by targeted therapies. RESULTS: The two main therapeutic strategies for targeting the FR are based on the use of: (i) an anti FR antibody (e.g. farletuzumab) and (ii) folate conjugates of folate-targeted chemotherapies and companion radiodiagnostic imaging agents (e.g. vintafolide and (99m)technetium-etarfolatide). Both of these strategies are being assessed in phase III trials. CONCLUSIONS: The important role that the FR plays in cancer development and progression has led to the development of FR-targeted therapeutic approaches. To date, the promising data observed in phase II clinical trials have not been confirmed in phase III studies. Accordingly, there is a need for further research in the refinement of patient selection and identification of new therapeutic combinations. In particular, the development of these targeted therapies requires reliable methods to be developed to detect FR-positive tumors in order to help select patients who may benefit from treatment. PMID- 26063636 TI - Longer self-reported sleep duration is associated with decreased performance on the montreal cognitive assessment in older adults. AB - BACKGROUND: Previous studies investigating the relationship between sleep duration and cognitive function in older adults have suggested that longer sleep durations are associated with decreased cognitive performance. AIM: The intent of this study is to determine if performance on the Montreal Cognitive Assessment (MoCA) and the Mini Mental State Exam (MMSE) is associated with self-reported sleep duration in older adults. METHODS: Data from 189 cognitively normal older adults aged 75 and older (mean age 89.29 +/- 7.62) and free of severe depression were used for this analysis. Individuals were grouped based on their self reported hours of sleep (short duration = <7, normal duration = 7, >9, and long duration = >=9). The Kruskal-Wallis test was used to discern group differences on the MoCA scores, while multinomial logistic regression was used to assess the association between MoCA and MMSE scores and sleep group. RESULTS: The long duration group had significantly lower MoCA scores than the normal duration group (p = 0.02). The short duration group was not significantly different from the normal duration group (p = 0.33). Individuals in the short duration group were more likely to have higher MoCA scores than those in long duration group after adjusting for age, gender, and presence of depressive symptoms [OR 0.86, 95 % CI (0.76, 0.98), p = 0.02]. CONCLUSION: The results of this study suggest that in a group of non-demented, very old subjects, self-reported sleep duration of nine or more hours is associated with decreased cognitive performance on the MoCA in older adults, even after accounting for age, gender, and presence of depressive symptoms. PMID- 26063637 TI - Self-reported hearing is associated with time spent out-of-home and withdrawal from leisure activities in older community-dwelling adults. AB - BACKGROUND: Hearing difficulties are prevalent among older people and can lead to difficulties in social interaction. These difficulties may increase the tendency to remain at home and withdraw from leisure activities. AIMS: To investigate whether self-reported hearing problems are associated with time spent out-of-home and withdrawal from a leisure activity among older persons. METHODS: Cross sectional and longitudinal data on 75- to 90-year-old community-dwelling men and women (n = 767) was used. Self-reports of hearing, diseases, and difficulty walking 2 km were obtained via home interviews at baseline, and withdrawal from a leisure activity via 1- and 2-year follow-up telephone interviews. Time spent out of-home was obtained from a subsample (n = 532) via seven-day diaries at baseline. RESULTS: Hearing problems were associated with time spent out-of-home (p = 0.025) and withdrawal from a leisure activity (p = 0.025) among persons reporting no walking difficulty, but not among those reporting walking difficulty (p = 0.269 and 0.396, respectively). Among the former, persons with major hearing problems spent significantly less time out-of-home (estimated marginal mean 161 min, 95 % CI 122-212) than those with good hearing (242, 95 % CI 218-270). Persons with major hearing problems also had 3.0 times higher odds (95 % CI 1.3 7.1) for withdrawal from a leisure activity than persons with good hearing during the two-year follow-up. DISCUSSION AND CONCLUSIONS: Among older adults without walking difficulty, hearing problems may reduce time spent out-of-home and increase the likelihood for withdrawal from a leisure activity. Decreased leisure and out-of-home activity may have negative effects on older persons' social, mental and physical functioning. PMID- 26063638 TI - Development of a combined database for meta-epidemiological research. PMID- 26063639 TI - Myeloid Sarcoma Masquerading as Granulation Tissue: A Diagnostic Pitfall. AB - Myeloid sarcoma is an uncommon neoplasm, comprising an extramedullary tumorous proliferation of immature myeloid cells. Its rarity and tendency for diverse clinical presentation contribute to difficulty in timely diagnosis. This report describes a case of a painful back lump in an elderly Chinese male, which was initially diagnosed as a carbuncle. Histology on the saucerization specimen was reported as inflamed granulation tissue. Failure of expected wound healing prompted surgical debridement; microscopic examination on the subsequent specimen revealed an immature myeloid population with an increased MIB-1 proliferative index, highlighted by myeloperoxidase, lysozyme, CD117, and CD43 immunoreactivity, in keeping with myeloid sarcoma. Despite aggressive management, the patient eventually died. This report draws attention to potential pitfalls in the pathological diagnosis of this uncommon tumor and briefly summarizes its salient features. PMID- 26063640 TI - An enhanced ascorbate peroxidase 2/antibody-binding domain fusion protein (APEX2 ABD) as a recombinant target-specific signal amplifier. AB - A recombinant target-specific signal amplifier was constructed by genetically fusing the enhanced ascorbate peroxidase 2 (APEX2) and an antibody-binding domain (ABD). The fusion protein APEX2-ABD possessed the peroxidase activity and the antibody-binding capability simultaneously and replaced the conventional HRP conjugated secondary antibodies in a TSA assay for amplifying fluorescence signals. PMID- 26063642 TI - Correction. PMID- 26063643 TI - Women are four times less likely to have curative surgery if breast cancer is diagnosed as emergency rather than urgent GP referral. PMID- 26063641 TI - Effect of adenosine and adenosine receptor antagonist on Muller cell potassium channel in Rat chronic ocular hypertension models. AB - Muller cells are principal glial cells in rat retina and have attracted much attention in glaucoma studies. However, it is not clear whether adenosine and adenosine receptor (AR) antagonists play any roles in the regulation of potassium channels in Muller cells and subsequently in the promotion of glutamine synthetase (GS) and L-Glutamate/L-Aspartate Transporter (GLAST) functions. We found that chronic ocular hypertension (COH) in rat down-regulated Muller cells Kir2.1, Kir4.1, TASK-1, GS and GLAST expressions and attenuated the peak of inward potassium current. Retinal ganglion cells (RGC) count was lower in the COH rats than that in the sham operation animals. Intravitreal injection of selective A2A AR antagonist SCH442416 up-regulated Muller cell Kir4.1, TASK-1, GS and GLAST expressions and enhanced inward potassium currents compared with those in the COH rats with vehicle control. Meanwhile, the RGC count was higher following intravitreal injection of SCH442416 in the COH rats than that after vehicle injection. The fact that PKA inhibitor H-89 blocked these SCH442416 effects suggested that the PKA signaling pathway was involved in the observed ocular responses following the intravitreal SCH442416 injection. PMID- 26063644 TI - Expression of serum miR-200a, miR-200b, and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features. AB - BACKGROUND: MicroRNAs (miRs) have been implicated in the etiology of various human cancers. The aim of this study was to investigate the association of the expression of three members--miR 200a, miR 200b, and miR 200c belonging to the miR-200 family with clinicopathological characteristics and their impact on the progression of epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Total RNA from serum was isolated by Trizol method, polyadenylated, and reverse transcribed into cDNA. Expression levels of miR-200a, miR-200b, and miR-200c were detected by using miRNA qRT-PCR. We measured miR expression in 70 serum samples of EOC patients with matched controls using U6 snRNA as a reference. Levels of miR expression was compared with distinct clinicopathological features. RESULTS: Expression of miR-200a was found to be greater than six-fold (p = 0.01), miR-200b and miR-200c greater than three-fold (p = 0.01) in comparison with matched normal controls. Association of miRNA expression with clinicopathological factors and progression was statistically evaluated. The expression levels of miR-200a and miR-200c were found to be significantly associated with disease progression (p = 0.04 and p < 0.001, respectively). miR-200a overexpression was found be associated with tumor histology and stage. Patients with lymph node metastasis showed significant elevation of miR-200c (p = 0.006). The AUC in ROC curve also indicated that serum levels of miR-200a and miR-200c might be worthwhile as a diagnostic tool in the near future. CONCLUSION: Our findings suggest that miR 200a, miR-200b, and miR-200c overexpressions are associated with the aggressive tumor progression and be recognized as reliable markers to predict the prognosis and survival in EOC patients. PMID- 26063645 TI - Prognosis of small cell lung cancer patients with diabetes treated with metformin. AB - BACKGROUNDS: It has been reported that metformin has an anticancer impact in various solid tumors, but its role in small cell lung cancer (SCLC) remains unclear. This study aimed to investigate the effect of metformin on survival in diabetic SCLC patients. METHODS: A total of 79 SCLC patients with diabetes treated in our hospital between 2000 and 2010 were enrolled. The clinicopathological data and survival time were collected and evaluated. Univariate and multivariate analyses were used to investigate the association between metformin use and the survival of SCLC. RESULTS: Among the 79 diabetic patients, 36 patients took metformin. The median OS and DFS were significantly better in the metformin group compared to non-metformin group (OS 18.0 vs 11.5 months, p < 0.001; DFS 10.8 vs 6.5 months, p < 0.001). Multivariate Cox analysis indicated that metformin use was an independent prognostic factor for long-term outcome (HR = 0.549, 95 % CI 0.198-0.978, p = 0.001). CONCLUSIONS: The prognosis of SCLC patients with diabetes treated with metformin was improved, which might be considered a potential useful anticancer drug in treating SCLC patients. PMID- 26063646 TI - Non-surgical periodontal therapy supplemented with systemically administered azithromycin: a systematic review of RCTs. AB - BACKGROUND: Azithromycin may be an alternative adjunctive systemic antibiotic in non-surgical periodontal therapy. OBJECTIVE: This study aims to identify randomized controlled trials evaluating non-surgical periodontal treatment of chronic and/or aggressive periodontitis supplemented with systemically administered azithromycin. MATERIALS AND METHODS: A systematic literature search was performed for publications published by 31 March 2014 using electronic databases and hand search. Randomized controlled trials published in English or German language, with a follow-up >=6 months were included. From 231 titles identified, nine publications were eligible for inclusion. RESULTS: Among the studies included, showing some risk of bias, seven reported on patients with chronic periodontitis and two with aggressive periodontitis. Minor adverse events were described in five studies. A synthesis of results using a vote counting method was applied. Significant (p < 0.05) beneficial effects of azithromycin were shown in six studies for probing depth changes and in five studies for clinical attachment level changes. CONCLUSION: In contrast to aggressive periodontitis patients, data from this analysis indicate a potential benefit of systemic azithromycin as adjunctive to non-surgical periodontal therapy in chronic periodontitis patients. CLINICAL RELEVANCE: When contraindications for the standard antibiotics are present, azithromycin (AZM) may be considered as alternative systemically administered antibiotic drug in selected cases of chronic periodontitis. PMID- 26063648 TI - Web 2.0 and academic debate: Social media challenges traditions in scientific publishing. PMID- 26063647 TI - Biodegradation of roxarsone by a bacterial community of underground water and its toxic impact. AB - Roxarsone is included in chicken food as anticoccidial and mainly excreted unchanged in faeces. Microorganisms biotransform roxarsone into toxic compounds that leach and contaminate underground waters used for human consumption. This study evaluated roxarsone biotransformation by underground water microorganisms and the toxicity of the resulting compounds. Underground water from an agricultural field was used to prepare microcosms, containing 0.05 mM roxarsone, and cultured under aerobic or anaerobic conditions. Bacterial communities of microcosms were characterized by PCR-DGGE. Roxarsone degradation was measured by HPLC/HG/AAS. Toxicity was evaluated using HUVEC cells and the Toxi-ChromoTest kit. Roxarsone degradation analysis, after 15 days, showed that microcosms of underground water with nutrients degraded 90 and 83.3% of roxarsone under anaerobic and aerobic conditions, respectively. Microcosms without nutrients degraded 50 and 33.1% under anaerobic and aerobic conditions, respectively. Microcosms including nutrients showed more roxarsone conversion into toxic inorganic arsenic species. DGGE analyses showed the presence of Proteobacteria, Firmicutes, Actinobacteria, Planctomycetes and Spirochaetes. Toxicity assays showed that roxarsone biotransformation by underground water microorganisms in all microcosms generated degradation products toxic for eukaryotic and prokaryotic cells. Furthermore, toxicity increased when roxarsone leached though a soil column and was further transformed by the bacterial community present in underground water. Therefore, using underground water from areas where roxarsone containing manure is used as fertilizer might be a health risk. PMID- 26063649 TI - Levelling the lingo playing field. PMID- 26063650 TI - Probing the ligand recognition and discrimination environment of the globin coupled oxygen sensor protein YddV by FTIR and time-resolved step-scan FTIR spectroscopy. AB - YddV is a newly discovered signal transducer heme protein that recognizes O2 and CO. Structural differences in the ligand-bound heme complex in YddV reflect variations in catalytic regulation by O2 and CO. Time-resolved step-scan (TRS(2)) FTIR studies of the wild type and of the important in oxygen recognition and stability of the heme Fe(II)-O2 complex L65M, L65T, Y43A, Y43F and Y43W mutants were performed to determine the site-specific protein dynamics following carbon monoxide (CO) photodissociation. These mutations were designed to perturb the electrostatic field near the iron-bound gaseous ligand (CO) and also to allow us to investigate the communication pathway between the distal residues of the protein and heme. TRS(2)-FTIR spectra of YddV-heme-CO show that the heme propionates are in protonated and deprotonated states. Moreover, the rate of decay of the vibrations of amide I is on a time scale that coincides with the rate of rebinding of CO, which suggests that there is coupling between ligation dynamics in the distal heme environment and (i) relaxation of the protein backbone and (ii) the environment sensed by the heme propionates. The fast recombination rates in L65M, L65T and Y43W imply a significant role of L65 and Y43 in controlling the ligand dynamics. The implications of these results with respect to the role of the heme propionates and the charged or proton-donating residues in the distal pocket, which are crucial for stabilizing bound gaseous ligands, are discussed. PMID- 26063651 TI - BitMapper: an efficient all-mapper based on bit-vector computing. AB - BACKGROUND: As the next-generation sequencing (NGS) technologies producing hundreds of millions of reads every day, a tremendous computational challenge is to map NGS reads to a given reference genome efficiently. However, existing methods of all-mappers, which aim at finding all mapping locations of each read, are very time consuming. The majority of existing all-mappers consist of 2 main parts, filtration and verification. This work significantly reduces verification time, which is the dominant part of the running time. RESULTS: An efficient all mapper, BitMapper, is developed based on a new vectorized bit-vector algorithm, which simultaneously calculates the edit distance of one read to multiple locations in a given reference genome. Experimental results on both simulated and real data sets show that BitMapper is from several times to an order of magnitude faster than the current state-of-the-art all-mappers, while achieving higher sensitivity, i.e., better quality solutions. CONCLUSIONS: We present BitMapper, which is designed to return all mapping locations of raw reads containing indels as well as mismatches. BitMapper is implemented in C under a GPL license. Binaries are freely available at http://home.ustc.edu.cn/%7Echhy. PMID- 26063652 TI - Restorative Proctocolectomy for Ulcerative Colitis in 1985-2009. AB - BACKGROUND AND AIMS: Restorative proctocolectomy is the most common operation in patients with ulcerative colitis. The aim was to evaluate long-term changes in our operative treatment and early and late complications related to restorative proctocolectomy. MATERIAL AND METHODS: The study comprised 352 (149 females) patients over 18 years of age with ulcerative colitis who underwent restorative proctocolectomy in 1985-2009 median follow-up time of 5 years. RESULTS: The indication for surgery was active chronic colitis in 168 (47.7%), acute colitis in 159 (45.2%), and cancer or dysplasia in 25 (7.1%) patients. Ileal pouch-anal anastomosis was performed using hand-sewn anastomosis with mucosectomy in 283 patients and stapled anastomosis in 69. A shift from hand-sewn to stapler ileal pouch-anal anastomosis took place in 2005. Covering ileostomy was carried out in 133 (37.8%) patients. There were 82 (23.3%) J-pouch-related complications. The operative mortality was 0.3%. There were significantly fewer leakages and early re-operations when covering ileostomy was used than when it was omitted: 6.0% versus 16.4% (p = 0.004), 4.5% versus 11.9% (p = 0.02), respectively. There were more strictures in hand-sewn than in stapled ileal pouch-anal anastomoses (17.6% vs. 0%, p = 0.001). Pouchitis occurred at least once in 134 (38.1%) patients. CONCLUSION: The ileal pouch-anal anastomosis technique used in restorative proctocolectomy had changed over the past years from hand-sewn to stapled anastomosis. Covering ileostomy seemed to protect against major complications. Pouchitis was the most common late complication. PMID- 26063653 TI - Time discounting and time preference in animals: A critical review. AB - Animals are an important model for studies of impulsivity and self-control. Many studies have made use of the intertemporal choice task, which pits small rewards available sooner against larger rewards available later (typically several seconds), repeated over many trials. Preference for the sooner reward is often taken to indicate impulsivity and/or a failure of self-control. This review shows that very little evidence supports this assumption; on the contrary, ostensible discounting behavior may reflect a boundedly rational but not necessarily impulsive reward-maximizing strategy. Specifically, animals may discount weakly, or even adopt a long-term rate-maximizing strategy, but fail to fully incorporate postreward delays into their choices. This failure may reflect learning biases. Consequently, tasks that measure animal discounting may greatly overestimate the true discounting and may be confounded by processes unrelated to time preferences. If so, animals may be much more patient than is widely believed; human and animal intertemporal choices may reflect unrelated mental operations; and the shared hyperbolic shape of the human and animal discount curves, which is used to justify cross-species comparisons, may be coincidental. The discussion concludes with a consideration of alternative ways to measure self-control in animals. PMID- 26063654 TI - Toward the concept of "standardized" international prescriptions. PMID- 26063655 TI - Intratumoral metabolic heterogeneity predicts invasive components in breast ductal carcinoma in situ. AB - OBJECTIVES: This study investigated whether texture-based imaging parameters could identify invasive components of ductal carcinoma in situ (DCIS). METHODS: We enrolled 65 biopsy-confirmed DCIS patients (62 unilateral, 3 bilateral) who underwent (18) F-FDG PET, diffusion-weighted imaging (DWI), or breast-specific gamma imaging (BSGI). We measured SUV max and intratumoral metabolic heterogeneity by the area under the curve (AUC) of cumulative SUV histograms (CSH) on PET, tumour-to-normal ratio (TNR) and coefficient of variation (COV) as an index of heterogeneity on BSGI, minimum ADC (ADC min ) and ADC difference (ADC diff ) as an index of heterogeneity on DWI. After surgery, final pathology was categorized as pure-DCIS (DCIS-P), DCIS with microinvasion (DCIS-MI), or invasive ductal carcinoma (IDC). Clinicopathologic features of DCIS were correlated with final classification. RESULTS: Final pathology confirmed 44 DCIS-P, 14 DCIS-MI, and 10 IDC. The invasive component of DCIS was significantly correlated with higher SUV max (p = 0.017) and lower AUC-CSH (p < 0.001) on PET, higher TNR (p = 0.008) and COV (p = 0.035) on BSGI, lower ADC min (p = 0.016) and higher ADC diff (p = 0.009) on DWI, and larger pathologic size (p = 0.018). On multiple regression analysis, AUC-CSH was the only significant predictor of invasive components (p = 0.044). CONCLUSIONS: The intratumoral metabolic heterogeneity of (18) F-FDG PET was the most important predictor of invasive components of DCIS. KEY POINTS: * Preoperative identification of invasion in DCIS is important for axillary nodal management * Higher SUV max and lower AUC-CSH from FDG PET may indicate invasive components of DCIS * Higher TNR and COV from BSGI may indicate invasive components of DCIS * Lower ADC min and higher ADC diff from DWI may indicate invasive components of DCIS * AUC-CSH, an index of metabolic heterogeneity, is an independent predictor for invasive components. PMID- 26063656 TI - The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy. PMID- 26063657 TI - Reply: The p.Ser107Leu in BICD2 is a mutation 'hot spot' causing distal spinal muscular atrophy. PMID- 26063658 TI - Heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease. AB - Cerebral small vessel disease represents a heterogeneous group of disorders leading to stroke and cognitive impairment. While most small vessel diseases appear sporadic and related to age and hypertension, several early-onset monogenic forms have also been reported. However, only a minority of patients with familial small vessel disease carry mutations in one of known small vessel disease genes. We used whole exome sequencing to identify candidate genes in an autosomal dominant small vessel disease family in which known small vessel disease genes had been excluded, and subsequently screened all candidate genes in 201 unrelated probands with a familial small vessel disease of unknown aetiology, using high throughput multiplex polymerase chain reaction and next generation sequencing. A heterozygous HTRA1 variant (R166L), absent from 1000 Genomes and Exome Variant Server databases and predicted to be deleterious by in silico tools, was identified in all affected members of the index family. Ten probands of 201 additional unrelated and affected probands (4.97%) harboured a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (P = 4.2 * 10(-6); odds ratio = 15.4; 95% confidence interval = 4.9-45.5), strongly suggesting causality. Seven of these variants were located within or close to the HTRA1 protease domain, three were in the N terminal domain of unknown function and one in the C-terminal PDZ domain. In vitro activity analysis of HTRA1 mutants demonstrated a loss of function effect. Clinical features of this autosomal dominant small vessel disease differ from those of CARASIL and CADASIL by a later age of onset and the absence of the typical extraneurological features of CARASIL. They are similar to those of sporadic small vessel disease, except for their familial nature. Our data demonstrate that heterozygous HTRA1 mutations are an important cause of familial small vessel disease, and that screening of HTRA1 should be considered in all patients with a hereditary small vessel disease of unknown aetiology. PMID- 26063659 TI - An Unusual Role for doublesex in Sex Determination in the Dipteran Sciara. AB - The gene doublesex, which is placed at the bottom of the sex-determination gene cascade, plays the ultimate discriminatory role for sex determination in insects. In all insects where this gene has been characterized, the dsx premessenger RNA (pre-mRNA) follows a sex-specific splicing pattern, producing male- and female specific mRNAs encoding the male-DSXM and female-DSXF proteins, which determine male and female development, respectively. This article reports the isolation and characterization of the gene doublesex of dipteran Sciara insects. The Sciara doublesex gene is constitutively transcribed during development and adult life of males and females. Sciara had no sex-specific doublesex mRNAs but the same transcripts, produced by alternative splicing of its primary transcript, were present in both sexes, although their relative abundance is sex specific. However, only the female DSXF protein, but not the male DSXM protein, was produced at similar amounts in both sexes. An analysis of the expression of female and male Sciara DSX proteins in Drosophila showed that these proteins conserved female and male function, respectively, on the control of Drosophila yolk-protein genes. The molecular evolution of gene doublesex of all insects where this gene has been characterized revealed that Sciara doublesex displays a considerable degree of divergence in its molecular organization and its splicing pattern with respect to the rest of dipterans as suggested by its basal position within the doublesex phylogeny. It is suggested that the doublesex gene is involved in Sciara sex determination although it appears not to play the discriminatory role performed in other insects. PMID- 26063660 TI - Stable Patterns of CENH3 Occupancy Through Maize Lineages Containing Genetically Similar Centromeres. AB - While the approximate chromosomal position of centromeres has been identified in many species, little is known about the dynamics and diversity of centromere positions within species. Multiple lines of evidence indicate that DNA sequence has little or no impact in specifying centromeres in maize and in most multicellular organisms. Given that epigenetically defined boundaries are expected to be dynamic, we hypothesized that centromere positions would change rapidly over time, which would result in a diversity of centromere positions in isolated populations. To test this hypothesis, we used CENP-A/cenH3 (CENH3 in maize) chromatin immunoprecipitation to define centromeres in breeding pedigrees that included the B73 inbred as a common parent. While we found a diversity of CENH3 profiles for centromeres with divergent sequences that were not inherited from B73, the CENH3 profiles from centromeres that were inherited from B73 were indistinguishable from each other. We propose that specific genetic elements in centromeric regions favor or inhibit CENH3 accumulation, leading to reproducible patterns of CENH3 occupancy. These data also indicate that dramatic shifts in centromere position normally originate from accumulated or large-scale genetic changes rather than from epigenetic positional drift. PMID- 26063661 TI - Selective Advantages of a Parasexual Cycle for the Yeast Candida albicans. AB - The yeast Candida albicans can mate. However, in the natural environment mating may generate progeny (fusants) fitter than clonal lineages too rarely to render mating biologically significant: C. albicans has never been observed to mate in its natural environment, the human host, and the population structure of the species is largely clonal. It seems incapable of meiosis, and most isolates are diploid and carry both mating-type-like (MTL) locus alleles, preventing mating. Only chromosome loss or localized loss of heterozygosity can generate mating competent cells, and recombination of parental alleles is limited. To determine if mating is a biologically significant process, we investigated if mating is under selection. The ratio of nonsynonymous to synonymous mutations in mating genes and the frequency of mutations abolishing mating indicated that mating is under selection. The MTL locus is located on chromosome 5, and when we induced chromosome 5 loss in 10 clinical isolates, most of the resulting MTL-homozygotes could mate with each other, producing fusants. In laboratory culture, a novel environment favoring novel genotypes, some fusants grew faster than their parents, in which loss of heterozygosity had reduced growth rates, and also faster than their MTL-heterozygous ancestors-albeit often only after serial propagation. In a small number of experiments in which co-inoculation of an oral colonization model with MTL-homozygotes yielded small numbers of fusants, their numbers declined over time relative to those of the parents. Overall, our results indicate that mating generates genotypes superior to existing MTL-heterozygotes often enough to be under selection. PMID- 26063663 TI - The Neurotoxic Effect of 13,19-Didesmethyl and 13-Desmethyl Spirolide C Phycotoxins Is Mainly Mediated by Nicotinic Rather Than Muscarinic Acetylcholine Receptors. AB - Spirolides are a large family of lipophilic marine toxins produced by dinoflagellates that have been detected in contaminated shellfish. Among them, 13,19-didesmethyl and 13-desmethyl spirolide C phycotoxins are widely distributed and their mode of action needs to be clearly defined. In order to further characterize the pharmacological profiles of these phycotoxins on various nicotinic acetylcholine receptor (nAChR) subtypes and to examine whether they act on muscarinic receptors (mAChRs), functional electrophysiological studies and competition binding experiments have been performed. While 13-desmethyl spirolide C interacted efficiently with sub-nanomolar affinities and low selectivity with muscular and neuronal nAChRs, 13,19-didesmethyl spirolide C was more selective of muscular and homopentameric alpha7 receptors and recognized only weakly neuronal heteropentameric receptors, especially the alpha4beta2 subtype. Thus, the presence of an additional methyl group on the tetrahydropyran ring significantly modified the pharmacological profile of 13-desmethyl spirolide C by notably increasing its affinity on certain neuronal nAChRs. Structural explanations of this selectivity difference are proposed, based on molecular docking experiments modeling different spirolide-receptor complexes. In addition, the 2 spirolides interacted only with low micromolar affinities with the 5 mAChRs, highlighting that the toxicity of the spirolide C analogs is mainly due to their high inhibition potency on various peripheral and central nAChRs and not to their low ability to interact with mAChR subtypes. PMID- 26063662 TI - Mutation of ATF6 causes autosomal recessive achromatopsia. AB - Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1-q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans. PMID- 26063666 TI - What Is the Role of the Adipocyte Mineralocorticoid Receptor in the Metabolic Syndrome? PMID- 26063667 TI - Urinary Proteome and Systolic Blood Pressure as Predictors of 5-Year Cardiovascular and Cardiac Outcomes in a General Population. AB - In a previous cross-sectional study, we identified a multidimensional urinary classifier (HF1), which was associated with left ventricular dysfunction. We investigated whether HF1 predicts cardiovascular end points over and beyond traditional risk factors. In 791 randomly recruited Flemish (mean age, 51.2 years; 50.6% women), we quantified HF1 by capillary electrophoresis coupled with mass spectrometry. In addition, we measured cardiovascular risk factors. HF1 averaged -0.97 U (range, -3.26 to 2.60). Over 6.1 years (median), 35 participants died and 63, 45, and 22 experienced fatal or nonfatal cardiovascular, cardiac, or coronary events, respectively. The incidence of fatal combined with nonfatal cardiovascular and cardiac end points, standardized for sex and age, increased across thirds of the HF1 distribution (P<=0.014), whereas trends for all-cause mortality and coronary events were nonsignificant (P>=0.10). The multivariable adjusted hazard ratios (+1-SD) were 1.30 (95% confidence interval, 1.03-1.65; P=0.029) and 1.39 (1.06-1.84; P=0.018) for cardiovascular and cardiac events in relation to HF1. For systolic pressure, the corresponding estimates were 0.97 (0.74-1.28; P=0.85) and 0.93 (0.67-1.29; P=0.66), respectively. The HF1 upper thresholds optimized by maximizing Younden's index were -0.50 and -0.36 U for cardiovascular and cardiac end points, respectively. Prognostic accuracy significantly (P<=0.006) improved by adding HF1 to Cox models already including the other baseline predictors. Sensitivity analyses, from which we excluded 71 participants with previous cardiovascular disease, were confirmatory. In conclusion, over a 6-year period, the urinary proteome, but not systolic pressure, predicted cardiovascular and cardiac disease. PMID- 26063668 TI - Change in Intra-Abdominal Fat Predicts the Risk of Hypertension in Japanese Americans. AB - In Japanese Americans, intra-abdominal fat area measured by computed tomography is positively associated with the prevalence and incidence of hypertension. Evidence in other populations suggests that other fat areas may be protective. We sought to determine whether a change in specific fat depots predicts the development of hypertension. We prospectively followed up 286 subjects (mean age, 49.5 years; 50.4% men) from the Japanese American Community Diabetes Study for 10 years. At baseline, subjects did not have hypertension (defined as blood pressure >=140/90 mm Hg) and were not taking blood pressure or glucose-lowering medications. Mid-thigh subcutaneous fat area, abdominal subcutaneous fat area, and intra-abdominal fat area were directly measured by computed tomography at baseline and 5 years. Logistic regression was used to estimate odds of incident hypertension over 10 years in relation to a 5-year change in fat area. The relative odds of developing hypertension for a 5-year increase in intra-abdominal fat was 1.74 (95% confidence interval, 1.28-2.37), after adjusting for age, sex, body mass index, baseline intra-abdominal fat, alcohol use, smoking status, and weekly exercise energy expenditure. This relationship remained significant when adjusted for baseline fasting insulin and 2-hour glucose levels or for diabetes mellitus and pre-diabetes mellitus classification. There were no significant associations between baseline and change in thigh or abdominal subcutaneous fat areas and incident hypertension. In conclusion, in this cohort of Japanese Americans, the risk of developing hypertension is related to the accumulation of intra-abdominal fat rather than the accrual of subcutaneous fat in either the thigh or the abdominal areas. PMID- 26063671 TI - Correction. PMID- 26063670 TI - Correction. PMID- 26063669 TI - B-Type Natriuretic Peptide Deletion Leads to Progressive Hypertension, Associated Organ Damage, and Reduced Survival: Novel Model for Human Hypertension. AB - Altered myocardial structure and function, secondary to chronically elevated blood pressure, are leading causes of heart failure and death. B-type natriuretic peptide (BNP), a guanylyl cyclase A agonist, is a cardiac hormone integral to cardiovascular regulation. Studies have demonstrated a causal relationship between reduced production or impaired BNP release and the development of human hypertension. However, the consequences of BNP insufficiency on blood pressure and hypertension-associated complications remain poorly understood. Therefore, the goal of this study was to create and characterize a novel model of BNP deficiency to investigate the effects of BNP absence on cardiac and renal structure, function, and survival. Genetic BNP deletion was generated in Dahl salt-sensitive rats. Compared with age-matched controls, BNP knockout rats demonstrated adult-onset hypertension. Increased left ventricular mass with hypertrophy and substantially augmented hypertrophy signaling pathway genes, developed in young adult knockout rats, which preceded hypertension. Prolonged hypertension led to increased cardiac stiffness, cardiac fibrosis, and thrombi formation. Significant elongation of the QT interval was detected at 9 months in knockout rats. Progressive nephropathy was also noted with proteinuria, fibrosis, and glomerular alterations in BNP knockout rats. End-organ damage contributed to a significant decline in overall survival. Systemic BNP overexpression reversed the phenotype of genetic BNP deletion. Our results demonstrate the critical role of BNP defect in the development of systemic hypertension and associated end organ damage in adulthood. PMID- 26063672 TI - Correction. PMID- 26063673 TI - Challenges in the Diagnosis and Management of Inflammatory Bowel Disease in the Elderly. AB - OPINION STATEMENT: Among inflammatory bowel disease (IBD) patients, 4-12 % is diagnosed after the age of 60. Both the rates of elderly and IBD are increasing worldwide. In older patients, the diagnosis of Crohn's disease (CD) and ulcerative colitis (UC) is made more difficult due to polypharmacy and multimorbidity along with disease processes that mimic IBD. The clinical presentation in older-onset IBD differs from younger patients, and there is minimal disease progression over time. The management of the older IBD patient involves a combination of medical and surgical strategies. Few treatment efficacy studies exist in elderly IBD as most authors have focused on the adverse events related to therapy. A vast number of incident CD and UC cases in elderly have been treated with 5-aminosalicylic acid agents and do not require the use of immune modifying agents or biologics. Many other older IBD patients are prescribed long-term corticosteroids despite guidelines recommending more effective and safer maintenance therapy regimens. Serious infections, malignancy, and drug interactions are the most concerning complications of medical therapy. There are particularly important health care maintenance issues in older IBD patients including vaccinations, colorectal cancer screening, and bone loss prevention. PMID- 26063675 TI - Bangladesh. PMID- 26063674 TI - Latinas' Mammography Intention Following a Home-Based Promotores-Led Intervention. AB - Despite increases in mammography rates among Latinas, screening rates remain lower than in non-Latina Whites and Latinas typically present with breast cancer at a later stage. Trained lay community workers (promotores) have been successfully used to increase screening mammography intention in Latinas. Little is known, however, about the potential mechanisms of these interventions, such as increased breast cancer knowledge (knowledge) and social interactions concerning mammography practices (social engagement). This prospective pre-post study examined this gap in the literature by (1) documenting changes in knowledge and social engagement after receipt of a promotores-based intervention; and (2) establishing if post-intervention knowledge and social engagement predicted mammography intention, after adjusting for socio-demographic and lifetime mammography history. There were significant increases in knowledge and social engagement about mammography. Finally, post-intervention social engagement was a significant predictor of mammography intention. Future promotores-based interventions should focus on enhancing social engagement to improve mammography intention and use. PMID- 26063676 TI - Novel nitrogen doped graphene sponge with ultrahigh capacitive deionization performance. AB - As water shortage has become a serious global problem, capacitive deionization (CDI) with high energy efficiency and low cost, is considered as a promising desalination technique to solve this problem. To date, CDI electrodes are mainly made up of porous carbon materials. However, the electrosorption performance obtained by now still cannot meet the demand of practical application. Therefore, a rationally designed structure of electrode materials has been an urgent need for CDI application. Here, a novel nitrogen-doped graphene sponge (NGS), with high specific surface area and rationally designed structure was fabricated, and used as CDI electrodes for the first time. The results show that NGS exhibits an ultrahigh electrosorption capacity of 21.0 mg g(-1) in ~ 500 mg L(-1) NaCl solution, and to our knowledge, it is the highest value reported for carbon electrodes in similar experimental conditions by now. NGS in this work is expected to be a promising candidate as CDI electrode material. PMID- 26063677 TI - New onset executive function difficulties at menopause: a possible role for lisdexamfetamine. AB - RATIONALE: Reports of cognitive decline, particularly in the domains of executive functions (EFs), are common among menopausal women. OBJECTIVE: This study aims to determine the impact of the psychostimulant lisdexamfetamine (LDX) on subjective and objective cognitive function among menopausal women who report new-onset EF complaints. METHODS: Thirty-two healthy perimenopausal and early postmenopausal women experiencing mid-life-onset executive function difficulties as measured using the Brown Attention Deficit Disorder Scale (BADDS) were administered LDX 40 60 mg/day for 4 weeks in this double-blind, placebo-controlled, cross-over study. Diagnosis of lifetime ADHD was exclusionary. BADDS total and subscale scores and performance on verbal memory and working memory tasks were outcomes of interest. RESULTS: Analyses revealed a significant effect of LDX treatment over placebo for total BADDS scores (p = 0.0001) and for four out of the five BADDS subscales (all p < 0.004). LDX treatment also resulted in significant improvement in delayed paragraph recall (p = 0.018), but there was no significant effect of treatment on other cognitive measures. Systolic blood pressure (p = 0.017) and heart rate increased significantly (p = 0.006) when women were on LDX but remained, on average, within the normal range. CONCLUSIONS: LDX 40-60 mg/day was well tolerated and improved the subjective measures of executive function as well as objective measures of delayed verbal recall in this sample of healthy menopausal women. PMID- 26063679 TI - Suicide Response Guidelines for Residency Trainees: A Novel Postvention Response for the Care and Teaching of Psychiatry Residents who Encounter Suicide in Their Patients. AB - Suicide is an event that is almost universally encountered by psychiatrists and psychiatry residents. Because psychiatric patients are at a higher risk for completing suicide than patients of other specialties, psychiatry residents are at risk for experiencing the suicide of a patient during their training. A review of the literature shows that there is continually growing research into the negative emotional effects of patient suicides on psychiatry residents and the need for clear response protocols when a suicide occurs, also known as postvention protocols. However, there are no Graduate Medical Education requirements to specifically train psychiatry residents about this, even with a well-voiced desire by residents to receive this training. In the National Capitol Consortium Psychiatry Residency, encounters with patient suicides by residents in a time of war led us to a place in which interventions were designed and instituted to care for the caregiver, in this case focusing on psychiatry trainees. Our process and product, described here, offers an example of a systematic postvention response. It addresses aspects of what is known in the research base, combined with acknowledgement of the human response and the institutional need for a consistent and objective response. PMID- 26063680 TI - The Suicide Prevention, Depression Awareness, and Clinical Engagement Program for Faculty and Residents at the University of California, Davis Health System. AB - OBJECTIVE: The authors replicated a program developed by UC San Diego, identified medical staff at risk for depression and suicide using a confidential online survey, and studied aspects of that program for 1 year. METHODS: The authors used a 35-item, online assessment of stress and depression depression developed and licensed by the American Foundation for Suicide Prevention that aims to identify and suicide risk and facilitate access to mental health services. RESULTS: During 2013/2014, all 1864 UC Davis residents/fellows and faculty physicians received an invitation to take the survey and 158 responded (8% response rate). Most respondents were classified at either moderate (86 [59%]) or high risk for depression or suicide (54 [37%]). Seventeen individuals (11%) were referred for further evaluation or mental health treatment. Ten respondents consented to participate in the follow-up portion of the program. Five of the six who completed follow-up surveys reported symptom improvement and indicated the program should continue. CONCLUSIONS: This program has led to continued funding and a plan to repeat the Wellness Survey annually. Medical staff will be regularly reminded of its existence through educational interventions, as the institutional and professional culture gradually changes to promptly recognize and seek help for physicians' psychological distress. PMID- 26063678 TI - Dissociable effects of mGluR5 allosteric modulation on distinct forms of impulsivity in rats: interaction with NMDA receptor antagonism. AB - RATIONALE: Impaired N-methyl-D-aspartate (NMDA) receptor signalling underlies several psychiatric disorders that express high levels of impulsivity. Although synergistic interactions exist between NMDA receptors and metabotropic glutamate receptor 5 (mGluR5), the significance of this interaction for impulsivity is unknown. OBJECTIVE: This study aims to investigate the effects of negative and positive allosteric mGluR5 modulation (NAM/PAM) on trait impulsivity and impulsivity evoked by NMDA receptor antagonism in rats. METHODS: Motor and choice impulsivity were assessed using the five-choice serial reaction time task (5 CSRTT) and delayed-discounting task (DDT), respectively. The effects of RO4917523 and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (NAMs) and ADX47273 (PAM) were investigated in non-impulsive rats and in trait high- and low impulsive rats. The effects of these compounds on impulsivity induced by NMDA receptor antagonism (MK801) in the 5-CSRTT were also investigated. RESULTS: RO4917523 (0.1-1 mg/kg) decreased premature responding and increased omissions but had no effect on locomotor activity up to 0.1 mg/kg. MTEP significantly increased omissions, decreased accuracy and slowed responding but had no effect on premature responding. ADX47273 decreased premature responding at doses that had no effect on locomotor activity. MK801 increased premature responding and impaired attentional accuracy; these deficits were dose dependently rescued by ADX47273 pre-treatment. Allosteric modulation of mGluR5 had no significant effect on choice impulsivity, nor did it modulate general task performance. CONCLUSIONS: These findings demonstrate that mGluR5 allosteric modulation selectively dissociates motor and choice impulsivity. We further show that mGluR5 PAMs may have therapeutic utility in selectively targeting specific aspects of impulsivity and executive dysfunction. PMID- 26063681 TI - A Model of Regulatory Alignment to Enhance the Long-Term Care Survey Process in a Veterans Health Care Network. AB - Regulatory oversight aims to promote quality of care in US nursing homes. A survey of long-term care (LTC) inspection practices in a Veterans Administration network in 2006 revealed great variability in monitoring and reporting processes, with opportunities for improvement. Modern organization theory and the PARIHS Implementation Framework provide a model for process improvement to enhance oversight for LTC facilities. Over a 3-year time frame, 6 facility inspection teams utilized a modified Delphi approach to arrive at and adopt a standardized structured inspection process. In the 2 districts where 10 facility contracts were terminated for quality deficits identified as a result of process improvement, Star Ratings of approved facilities improved (3.2 to 3.3). The 10 facilities terminated had a mean rating of 1.2 (0.48) (t = 3.87, P < .01). Standardization of a structured LTC inspection process enhances organizational oversight and may contribute to improved quality of care. PMID- 26063682 TI - Adiponectin exacerbates collagen-induced arthritis via enhancing Th17 response and prompting RANKL expression. AB - We previously reported adiponectin (AD) is highly expressed in the inflamed synovial joint tissue and correlates closely with progressive bone erosion in Rheumatoid arthritis (RA) patients. Here, we investigate the role of adiponectin in regulating Th17 response and the expression of receptor activator of nuclear factor-kappaB ligand (RANKL) in mice with CIA mice by intraarticularly injection of adiponectin into knee joints on day 17, day 20 and day 23 post first collagen immunization. The increased adiponectin expression was found in inflamed joint tissue of collagen-induced arthritis (CIA) mice. Adiponectin injection resulted in an earlier onset of arthritis, an aggravated arthritic progression, more severe synovial hyperplasia, bone erosion and osteoporosis in CIA mice. CD4(+)IL 17(+) Th17 cells, IL-17 mRNA and RANKL mRNA expression were markedly increased in the joint tissue of adiponectin treated CIA mice. Moreover, adiponectin treatment markedly enhanced Th17 cell generation from naive CD4(+) T cells in vitro, which accompanied by the high expression of Th17 transcription factor ROR-gammat, and Th17 cytokine genes included IL-22 and IL-23. This study reveals a novel effect of adiponectin in exacerbating CIA progression by enhancing Th17 cell response and RANKL expression. PMID- 26063683 TI - Effects and mechanisms of kerosene use-related toxicity. AB - Kerosene is a heterogeneous hydrocarbon substance that continues to find many uses worldwide due to its economic viability and ease of availability. In spite of kerosene's many uses, it is known to cause harm to various body organs and systems. Major affected body organs/systems are the pulmonary system, central nervous system, cardiovascular system, the skin, immune system and liver. This review discusses the various kerosene-mediated adverse health effects and possible mechanisms by which kerosene is likely to inflict such effects. These mechanisms are quite varied and include induction of inflammation, loss of effectiveness of pulmonary surfactants, hypoxia, production of highly reactive oxidative metabolites, extraction of endogenous epidermal and membrane lipids, necrosis, hormonal and enzymatic levels changes, and immunosuppression. Understanding of the above will allow for proper relevant policy formulation and targeted kerosene-mediated morbidity and mortality preventive and management initiatives. PMID- 26063685 TI - Time to consider the risks of caesarean delivery for long term child health. PMID- 26063686 TI - Incidence of and predictors for appropriate implantable cardioverter defibrillator therapy in patients with a secondary preventive implantable cardioverter-defibrillator indication. AB - AIMS: Incidence of implantable cardioverter-defibrillator (ICD) therapy in secondary prevention has been assessed in randomized trials and registries. However, results are considerably limited by short follow-up and hazy definition of treated arrhythmias. This study aimed to determine appropriate ICD therapy and to define predictors based on registry patients followed for up to 20 years. METHODS AND RESULTS: All patients with a secondary prevention indication and ischaemic or dilated cardiomyopathy were identified. Arrhythmic endpoints were appropriate ICD therapies for any ventricular tachycardia (VT) >175 b.p.m. and appropriate ICD therapies in the ventricular fibrillation (VF) zone of >220 b.p.m. (potentially life-threatening). Predictors were determined by analysing 19 baseline characteristics. We included 357 patients, age 65 +/- 11 years, predominantly male (89%) with ischaemic cardiomyopathy (83%). During follow-up of 82 +/- 53 months, 156 (44%) patients died and 208 received any form of ICD therapies (59%), 71 of them (34%) in the VF zone. Forty-four patients (28%) died without experiencing any form of appropriate ICD therapy. Cumulative incidence of any form of ICD therapy at 10 years was 65%. Predictors for any form of ICD therapy were implantation for VT and age [VT: hazard ratio (HR) 1.45, 95% confidence interval (95% CI) 1.05-2.01, P = 0.03; age (per year): HR 1.02, 95% CI 1.01-1.04, P = 0.001]. For therapy in the VF zone, univariate analysis determined male gender (29 vs. 5%, P = 0.01) as predictor. CONCLUSION: The rate of appropriate ICD therapies in secondary prevention is high. No useful predictors for them, especially not for life-threatening arrhythmias could be identified. PMID- 26063687 TI - Experience with erlotinib in the treatment of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths. In the last decade, the epidermal growth factor receptor (EGFR) signalling pathway has emerged as one of the most important molecular aberrations, representing an attractive therapeutic target in NSCLC. Drugs interfering with the tyrosine kinase domain of the EGFR (EGFR TKIs), such as erlotinib and gefitinib, have demonstrated efficacy in patients with advanced NSCLC irrespective of therapy line and particularly in patients harbouring activating mutations in the EGFR gene (EGFR(mut+)). Results of large phase III randomized trials clearly established that EGFR TKIs are superior to chemotherapy as frontline treatment in patients with EGFR(mut+), whereas in the EGFR wild-type (EGFR(WT)) or EGFR unknown population, platinum-based chemotherapy remains the standard of care, with no consistent benefit produced by the addition of EGFR TKI. In pretreated NSCLC, EGFR TKIs are considered more effective than standard monotherapy with cytotoxics in the presence of classical EGFR mutations, whereas in the EGFR(WT) population, a similar efficacy to docetaxel or pemetrexed in terms of survival has been demonstrated. Unfortunately, patients who initially responded to EGFR TKIs invariably develop acquired resistance. For such patients there is an urgent need for more effective strategies able to delay or possibly overcome resistance. In the present review we analysed the available data on erlotinib in the treatment of advanced NSCLC. PMID- 26063688 TI - A multicentre randomised controlled trial and economic evaluation of continuous positive airway pressure for the treatment of obstructive sleep apnoea syndrome in older people: PREDICT. AB - BACKGROUND: The therapeutic and economic benefits of continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnoea syndrome (OSAS) have been established in middle-aged people. In older people there is a lack of evidence. OBJECTIVE: To determine the clinical efficacy of CPAP in older people with OSAS and to establish its cost-effectiveness. DESIGN: A randomised, parallel, investigator-blinded multicentre trial with within-trial and model based cost-effectiveness analysis. METHODS: Two hundred and seventy-eight patients, aged >= 65 years with newly diagnosed OSAS [defined as oxygen desaturation index at >= 4% desaturation threshold level for > 7.5 events/hour and Epworth Sleepiness Scale (ESS) score of >= 9] recruited from 14 hospital based sleep services across the UK. INTERVENTIONS: CPAP with best supportive care (BSC) or BSC alone. Autotitrating CPAP was initiated using standard clinical practice. BSC was structured advice on minimising sleepiness. COPRIMARY OUTCOMES: Subjective sleepiness at 3 months, as measured by the ESS (ESS mean score: months 3 and 4) and cost-effectiveness over 12 months, as measured in quality-adjusted life-years (QALYs) calculated using the European Quality of Life-5 Dimensions (EQ 5D) and health-care resource use, information on which was collected monthly from patient diaries. SECONDARY OUTCOMES: Subjective sleepiness at 12 months (ESS mean score: months 10, 11 and 12) and objective sleepiness, disease-specific and generic quality of life, mood, functionality, nocturia, mobility, accidents, cognitive function, cardiovascular risk factors and events at 3 and 12 months. RESULTS: Two hundred and seventy-eight patients were randomised to CPAP (n = 140) or BSC (n = 138) over 27 months and 231 (83%) patients completed the trial. Baseline ESS score was similar in both groups [mean (standard deviation; SD) CPAP 11.5 (3.3), BSC 11.4 (4.2)]; groups were well balanced for other characteristics. The mean (SD) in ESS score at 3 months was -3.8 (0.4) in the CPAP group and -1.6 (0.3) in the BSC group. The adjusted treatment effect of CPAP compared with BSC was -2.1 points [95% confidence interval (CI) -3.0 to -1.3 points; p < 0.001]. At 12 months the effect was -2.0 points (95% CI -2.8 to -1.2 points; p < 0.001). The effect was greater in patients with increased CPAP use or higher baseline ESS score. The number of QALYs calculated using the EQ-5D was marginally (0.005) higher with CPAP than with BSC (95% CI -0.034 to 0.044). The average cost per patient was L1363 (95% CI L1121 to L1606) for those allocated to CPAP and L1389 (95% CI L1116 to L1662) for those allocated to BSC. On average, costs were lower in the CPAP group (mean -L35; 95% CI -L390 to L321). The probability that CPAP was cost-effective at thresholds conventionally used by the NHS (L20,000 per QALY gained) was 0.61. QALYs calculated using the Short Form questionnaire-6 Dimensions were 0.018 higher in the CPAP group (95% CI 0.003 to 0.034 QALYs) and the probability that CPAP was cost-effective was 0.96. CPAP decreased objective sleepiness (p = 0.02), increased mobility (p = 0.03) and reduced total and low density lipoprotein cholesterol (p = 0.05, p = 0.04, respectively) at 3 months but not at 12 months. In the BSC group, there was a fall in systolic blood pressure of 3.7 mmHg at 12 months, which was not seen in the CPAP group (p = 0.04). Mood, functionality, nocturia, accidents, cognitive function and cardiovascular events were unchanged. There were no medically significant harms attributable to CPAP. CONCLUSION: In older people with OSAS, CPAP reduces sleepiness and is marginally more cost-effective than BSC over 12 months. Further work is required in the identification of potential biomarkers of sleepiness and those patients at increased risk of cognitive impairment. Early detection of which could be used to inform the clinician when in the disease cycle treatment is needed to avert central nervous system sequelae and to assist patients decision-making regarding treatment and compliance. Treatment adherence is also a challenge in clinical trials generally, and adherence to CPAP therapy in particular is a recognised concern in both research studies and clinical practice. Suggested research priorities would include a focus on optimisation of CPAP delivery or support and embracing the technological advances currently available. Finally, the improvements in quality of life in trials do not appear to reflect the dramatic changes noted in clinical practice. There should be a greater focus on patient centred outcomes which would better capture the symptomatic improvement with CPAP treatment and translate these improvements into outcomes which could be used in health economic analysis. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90464927. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 40. See the NIHR Journals Library website for further project information. PMID- 26063689 TI - Retinoid X receptor: the forgotten partner in regulating lipid metabolism? PMID- 26063690 TI - Dietary protein and kidney function: when higher glomerular filtration rate is desirable. PMID- 26063691 TI - Interaction of omega-3 fatty acids with B vitamins in slowing the progression of brain atrophy: identifying the elderly at risk. PMID- 26063692 TI - Is the association between alcohol use and coronary artery disease causal? Evidence from a long-term twin study. PMID- 26063693 TI - Dietary Approaches to Stop Hypertension diet retains effectiveness to reduce blood pressure when lean pork is substituted for chicken and fish as the predominant source of protein. AB - BACKGROUND: Hypertension is a major, modifiable risk factor for cardiovascular and kidney disease and premature mortality that is improved by the DASH (Dietary Approaches to Stop Hypertension) diet. The DASH diet emphasizes increased consumption of fruit and vegetables, whole grains, low-fat dairy, nuts, and poultry and fish and reduced intakes of fats, red meats (including pork), sodium, and added sugars. OBJECTIVE: We sought to evaluate whether the consumption of lean pork compared with the consumption of chicken and fish as the predominant protein source in a DASH-style diet affected blood pressure (BP) control in men and women with elevated BP. DESIGN: In a randomized crossover study, 13 women and 6 men [mean +/- SEM age: 61 +/- 2 y; BMI (in kg/m2): 31.2 +/- 1.4] with elevated BP [systolic blood pressure (SBP)/diastolic blood pressure (DBP): 130 +/- 2/85 +/ 2 mm Hg] consumed a DASH-style diet for two 6-wk controlled dietary interventions (with a 4-wk diet washout between interventions) with either lean pork [DASH diet with pork (DASH-P)] or chicken and fish [DASH diet with chicken and fish (DASH-CF), the control diet] as the major protein source (55% of total protein intake). SBP and DBP were measured manually and with a 24-h BP monitoring system on 3 d before and 3 d at the end of each diet intervention. RESULTS: Preintervention manual BP (DASH-P: 130/84 +/- 2/1 mm Hg; DASH-CF: 129/84 +/- 2/1 mg Hg) and postintervention manual BP (DASH-P: 122/79 +/- 2/1 mm Hg; DASH-CF: 123/78 +/- 3/1) were not different between the DASH-P and DASH-CF. Consumption of these DASH-style diets for 6 wk reduced all measures of BP (P < 0.05) with no differences in responses between the DASH-CF and DASH-P. CONCLUSION: The results indicate that adults with elevated BP may effectively incorporate lean pork into a DASH-style diet for BP reduction. PMID- 26063694 TI - Comparative intention-to-treat analysis of the video-assisted thoracoscopic surgery approach to pulmonary segmentectomy for lung carcinoma?. AB - OBJECTIVES: To compare the video-assisted thoracoscopic surgery (VATS) with the open thoracotomy access to pulmonary segmentectomy by the clinical outcomes and long-term survival in lung carcinoma. METHODS: Non-randomized comparative intention-to-treat study of prospective institutional registry data and survival data of 100 consecutive patients undergoing segmentectomy. RESULTS: Within one decade (2002-12), 100 patients with proven or highly suspected lung carcinoma underwent 100 anatomical sub-lobar pulmonary resections (52 typical and 20 atypical segmentectomies, 28 split-lobe procedures). Fifty-six patients were operated by VATS and 44 by thoracotomy access. Comparison of demographic, medical, oncological and surgical baseline data did not provide evidence for differences between the VATS and thoracotomy groups. The surgery time for the VATS group was 225 +/- 62 min and 195 +/- 57 min for the thoracotomy group (P = 0.014). Postoperative hospitalization was 9 days for the VATS group and 12 days for the thoracotomy group (P = 0.034). Postoperative morbidity was 35.7% for the VATS group and 50% for the thoracotomy group (P = 0.161). Both groups had no 30 day mortality. Conversion to thoracotomy occurred in 30.4% of the VATS group. Conversion was more frequent in patients with male gender, critical and prohibitive lung function, tumours with diameters exceeding 3 cm and atypical segmentectomies. The fractions of the pathological Union international contre le cancer (UICC) stages I, II and III were 74.4, 11.6 and 14% in the VATS group, and 70, 20 and 10% in the thoracotomy group (P = 0.445), respectively. Five-year overall survival was 86% in the VATS group and 69.9% in the thoracotomy group (P = 0.047), and 5-year recurrence-free survival was 58.5 and 48.6% (P = 0.480), respectively. CONCLUSIONS: Compared with thoracotomy access, the VATS approach to segmentectomy was associated with less postoperative morbidity and a 25% decrease in median hospital stay, despite a conversion rate of 30% due to the inclusion of atypical segmentectomies, higher tumour stages and patients with critical function for single lung ventilation. Five-year survival estimates suggested a small but significant overall survival benefit and a 10% difference of recurrence free survival in favour of VATS. Although not fully conclusive, long-term results indicate that the thoracoscopic access to segmentectomy is probably not inferior to the thoracotomy approach. Confirmation by a larger number of risk-adjusted outcome data is required. PMID- 26063696 TI - Neurointerventional participation in craniopagus separation. AB - Craniopagus-type conjoined twins (joined at the head) are exceedingly rare. Separation of craniopagus conjoined twins is a challenging task mainly owing to complex vascular anatomy and limited experience with this disorder. Modern neuroimaging techniques including digital subtraction angiography can be used to preoperatively assess the cerebral vascular system. These techniques can also provide the raw data to fabricate three-dimensional true-scale models. We report a case in which endovascular techniques have been used in the separation of craniopagus conjoined twins. To our knowledge there are no reports of successful incorporation of neurointerventional methods in the disconnection of shared venous channels. PMID- 26063698 TI - A balancing act: Clozapine adjustment in smokers. PMID- 26063697 TI - Percutaneous transluminal angioplasty and stenting for severe stenosis of the intracranial extradural internal carotid artery causing transient ischemic attack or minor stroke. AB - The purpose of this study is to assess the technical feasibility and clinical efficacy of percutaneous transluminal angioplasty and stenting (PTAS) for symptomatic stenosis of the intracranial extradural (petrous and cavernous) internal carotid artery (ICA).Review of medical records identified 26 consecutive patients who underwent PTAS using a balloon-expandable coronary stent (n = 15, 57.7%) or a Wingspan self-expandable stent (n = 11, 42.3%) for treatment of severe stenosis (>70%) involving the intracranial extradural ICA. The inclusion criteria were transient ischemic attack with an ABCD(2) score of >=3 (n = 12, 46.2%) or minor stroke with an NIHSS score of <=4 (n = 14, 53.8%). Technical success rates, complications, and angiographic and clinical outcomes were analyzed retrospectively.PTAS was technically successful in all patients. The mean stenosis ratio decreased from 77.1% to 10.0% immediately after PTAS. The overall incidence of procedural complications was 23.1%, and the postoperative permanent morbidity/mortality rate was 7.7%. A total of 22 patients were tracked over an average period of 29.9 months. During the observation period, 20 patients (90.9%) had no further cerebrovascular events and stroke recurrence occurred in two patients (9.1%), resulting in an annual stroke risk of 3.7%. Two cases (11.1%) of significant in-stent restenosis (>50%) were found on follow-up angiography (n = 18).PTAS for severe stenosis (>70%) involving the intracranial extradural ICA showed a good technical feasibility and favorable clinical outcome in patients with transient ischemic attack or minor stroke. PMID- 26063695 TI - Physiologic imaging in acute stroke: Patient selection. AB - Treatment of acute stroke is changing, as endovascular intervention becomes an important adjunct to tissue plasminogen activator. An increasing number of sophisticated physiologic imaging techniques have unique advantages and applications in the evaluation, diagnosis, and treatment-decision making of acute ischemic stroke. In this review, we first highlight the strengths, weaknesses, and possible indications for various stroke imaging techniques. How acute imaging findings in each modality have been used to predict functional outcome is discussed. Furthermore, there is an increasing emphasis on using these state-of the-art imaging modalities to offer maximal patient benefit through IV therapy, endovascular thrombolytics, and clot retrieval. We review the burgeoning literature in the determination of stroke treatment based on acute, physiologic imaging findings. PMID- 26063699 TI - Cost and effects of a universal parenting programme delivered to parents of preschoolers. AB - BACKGROUND: Parenting programmes are effective in improving child behaviour and parental well-being, but long follow-up studies of universally offered programmes are scarce. METHODS: A cluster randomized controlled trial was conducted to assess the costs and effects of Triple P levels 2-3 on child externalizing behaviours and parental mental health. The programme was offered universally to parents of preschoolers (self-selection allowed). Preschools were randomized to Triple P or a waitlist control. Health outcomes were reduction in externalizing behaviours measured on the Eyberg Child Behaviour Inventory-22 and improvement in parental mental health measured on the Depression Anxiety Stress Scales collected at baseline, 6-, 12- and 18-month follow-up. Child outcomes were based on 355 children aged 3-5 years (child sample) and parental outcomes on 759 parents (parental sample) with baseline data. Costs were collected from a municipality perspective, including 312 children and 488 parents with baseline data in the intervention preschools. RESULTS: Sixty-seven (29%) parents attended the intervention. Triple P showed no significant improvement in child externalizing behaviours or parental mental health at either of the follow-up points. Triple P had an average yearly total cost of 3007 Swedish Krona (SEK) (?323) per child or 1922 SEK (?207) per parent. Running Triple P cost 227 SEK (?24) per child or 145 SEK (?16) per parent yearly. CONCLUSION: Offering low intensity levels of Triple P with 29% attendance may not be a reasonable use of public resources, as no evidence of improvement in child externalizing behaviours or parental mental health was found. PMID- 26063700 TI - Assessment of exposure to cadmium, lead, manganese, and nickel in workers from foundries. AB - OBJECTIVES: In this study, biological exposure indicators were used to assess the exposure of workers to cadmium (Cd), lead (Pb), manganese (Mn), and nickel (Ni) in nonferrous metal smelters. METHODS: A total of 273 male participants (178 exposed and 95 nonexposed control group), working in nonferrous metal foundries located in southern Brazil, were evaluated based on biological indicators, environmental levels, and different types of work performed by the participants. Blood Pb (BPb), urinary Cd (UCd), urinary Mn (UMn), and urinary Ni (UNi) levels were quantified by graphite furnace atomic absorption spectrometry with Zeeman background correction. RESULTS: Significant differences between the exposed and nonexposed groups were observed for all of the analyzed elements. The average levels of BPb were higher than the recommended occupational exposure level. Relatively low concentrations were found for UCd, UMn, and UNi. CONCLUSIONS: Although metal production is an important segment of the Brazilian economy, information related to employee health in this sector is scarce. The environmental levels are determinant in occupational exposure in foundries. In companies where air levels of Pb, Cd, and Mn were above the established limits, the different types of activity did not represent an important influence on the biological levels found among workers. In situations with low air levels of these metals, the workers from the "melting" sector were actually more vulnerable. PMID- 26063701 TI - Jocelyn Cornwell: Innovative, sociable would-be foodie. PMID- 26063702 TI - Albinism in Africa: a medical and social emergency. PMID- 26063703 TI - The Fundamental Rule and Fundamental Value of Psychoanalysis. PMID- 26063704 TI - beta3-Adrenoceptor activation relieves oxidative inhibition of the cardiac Na+-K+ pump in hyperglycemia induced by insulin receptor blockade. AB - Dysregulated nitric oxide (NO)- and superoxide (O2 (.-))-dependent signaling contributes to the pathobiology of diabetes-induced cardiovascular complications. We examined if stimulation of beta3-adrenergic receptors (beta3-ARs), coupled to endothelial NO synthase (eNOS) activation, relieves oxidative inhibition of eNOS and the Na(+)-K(+) pump induced by hyperglycemia. Hyperglycemia was established in male New Zealand White rabbits by infusion of the insulin receptor antagonist S961 for 7 days. Hyperglycemia increased tissue and blood indexes of oxidative stress. It induced glutathionylation of the Na(+)-K(+) pump beta1-subunit in cardiac myocytes, an oxidative modification causing pump inhibition, and reduced the electrogenic pump current in voltage-clamped myocytes. Hyperglycemia also increased glutathionylation of eNOS, which causes its uncoupling, and increased coimmunoprecipitation of cytosolic p47(phox) and membranous p22(phox) NADPH oxidase subunits, consistent with NADPH oxidase activation. Blocking translocation of p47(phox) to p22(phox) with the gp91ds-tat peptide in cardiac myocytes ex vivo abolished the hyperglycemia-induced increase in glutathionylation of the Na(+)-K(+) pump beta1-subunit and decrease in pump current. In vivo treatment with the beta3-AR agonist CL316243 for 3 days eliminated the increase in indexes of oxidative stress, decreased coimmunoprecipitation of p22(phox) with p47(phox), abolished the hyperglycemia induced increase in glutathionylation of eNOS and the Na(+)-K(+) pump beta1 subunit, and abolished the decrease in pump current. CL316243 also increased coimmunoprecipitation of glutaredoxin-1 with the Na(+)-K(+) pump beta1-subunit, which may reflect facilitation of deglutathionylation. In vivo beta3-AR activation relieves oxidative inhibition of key cardiac myocyte proteins in hyperglycemia and may be effective in targeting the deleterious cardiac effects of diabetes. PMID- 26063706 TI - Drought responses of two gymnosperm species with contrasting stomatal regulation strategies under elevated [CO2] and temperature. AB - Future climate regimes characterized by rising [CO2], rising temperatures and associated droughts may differentially affect tree growth and physiology. However, the interactive effects of these three factors are complex because elevated [CO2] and elevated temperature may generate differential physiological responses during drought. To date, the interactive effects of elevated [CO2] and elevated temperature on drought-induced tree mortality remain poorly understood in gymnosperm species that differ in stomatal regulation strategies. Water relations and carbon dynamics were examined in two species with contrasting stomatal regulation strategies: Pinus radiata D. Don (relatively isohydric gymnosperm; regulating stomata to maintain leaf water potential above critical thresholds) and Callitris rhomboidea R. Br (relatively anisohydric gymnosperm; allowing leaf water potential to decline as the soil dries), to assess response to drought as a function of [CO2] and temperature. Both species were grown in two [CO2] (C(a) (ambient, 400 MUl l(-1)) and C(e) (elevated, 640 MUl l(-1))) and two temperature (T(a) (ambient) and T(e) (ambient +4 degrees C)) treatments in a sun lit glasshouse under well-watered conditions. Drought plants were then exposed to a progressive drought until mortality. Prior to mortality, extensive xylem cavitation occurred in both species, but significant depletion of non-structural carbohydrates was not observed in either species. Te resulted in faster mortality in P. radiata, but it did not modify the time-to-mortality in C. rhomboidea. C(e) did not delay the time-to-mortality in either species under drought or T(e) treatments. In summary, elevated temperature (+4 degrees C) had greater influence than elevated [CO2] (+240 MUl l(-1)) on drought responses of the two studied gymnosperm species, while stomatal regulation strategies did not generally affect the relative contributions of hydraulic failure and carbohydrate depletion to mortality under severe drought. PMID- 26063705 TI - Effect of denervation on the regulation of mitochondrial transcription factor A expression in skeletal muscle. AB - The purpose of this study was to determine how the expression of mitochondrial transcription factor A (Tfam), a protein that governs mitochondrial DNA (mtDNA) transcription and replication, is regulated during a state of reduced organelle content imposed by muscle disuse. We measured Tfam expression at 8 h, 16 h, 24 h, 3 days, or 7 days following denervation and hypothesized that decreases in Tfam expression would precede mitochondrial loss. Muscle mass was lowered by 13% and 38% at 3 and 7 days postdenervation, while cytochrome c oxidase activity fell by 33% and 39% at the same time points. Tfam promoter activation in vivo was reduced by 30-65% between 8 h and 3 days of denervation, while Tfam transcript half-life was increased following 8-24 h of denervation. Protein expression of RNA-binding proteins that promote mRNA degradation (CUG repeat-binding protein and K homology splicing regulator protein) was elevated at 3 and 7 days of denervation. Tfam localization within subsarcolemmal mitochondria was reduced after 3 and 7 days of denervation and was associated with suppression of the cytochrome c oxidase type I transcript at 3 days, indicating that denervation impairs both mitochondrial Tfam import and mtDNA transcription during an early period following denervation. These data suggest that putative signals downregulate Tfam transcription during the earliest stages following denervation but are counteracted by increases in Tfam mRNA stability. Import of Tfam into the mitochondrion seems to be the most critical point of regulation of this protein during the early onset of denervation, an impairment of which is coincident with the loss of mitochondria during muscle disuse. PMID- 26063707 TI - Development of flower buds in the Japanese pear (Pyrus pyrifolia) from late autumn to early spring. AB - We periodically investigated the lateral flower bud morphology of 1-year shoots of 'Kosui' pears (Pyrus pyrifolia Nakai) in terms of dormancy progression, using magnetic resonance imaging. The size of flower buds did not change significantly during endodormancy, but rapid enlargement took place at the end of the ecodormancy stage. To gain insight into the physiological status during this period, we analyzed gene expression related to cell cycle-, cell expansion- and water channel-related genes, namely cyclin (CYC), expansin (EXPA), tonoplast intrinsic proteins (TIP) and plasma membrane intrinsic proteins (PIP). Constant but low expression of pear cyclin genes (PpCYCD3s) was observed in the transition phase from endodormancy to ecodormancy. The expression levels of PpCYCD3s were consistent with few changes in flower bud size, but up-regulated before the sprouting stage. In contrast, the expression of pear expansin and water channel related genes (PpEXPA2, PpPIP2A, PpPIP2B, PpIdeltaTIP1A and PpIdeltaTIP1B) were low until onset of the rapid enlargement stage of flower buds. However, expression of these genes rapidly increased during sprouting along with a gradual increase of free water content in the floral primordia of buds. Taken together, these results suggest that flower bud size tends to stay constant until the endodormancy phase transition. Rapid enlargement of flower buds observed in March is partly due to the enhancement of the cell cycle. Then, sprouting takes place concomitant with the increase in cell expansion and free water movement. PMID- 26063708 TI - Patterns of drought-induced embolism formation and spread in living walnut saplings visualized using X-ray microtomography. AB - Embolism formation and spread are dependent on conduit structure and xylem network connectivity. Detailed spatial analysis has been limited due to a lack of non-destructive methods to visualize these processes in living plants. We used synchrotron X-ray computed tomography (microCT) to visualize these processes in vivo for Juglans microcarpa Berl. saplings subjected to drought, and also evaluated embolism repair capability after re-watering. Cavitation was not detected in vivo until stem water potentials (Psi(stem)) reached -2.2 MPa, and loss of stem hydraulic conductivity as derived from microCT images predicted that 50% of conductivity was lost at Psi(stem) of ~ -3.5 MPa; xylem vulnerability as determined with the centrifuge method was comparable only in the range of Psi(stem) from -2.5 to -3.5 MPa. MicroCT images showed that cavitation appeared initially in isolated vessels not connected to other air-filled conduits. Once embolized vessels were present, multiple vessels in close proximity cavitated, and 3-D analysis along the stem axis revealed some connections between cavitated vessels. A tomography-derived automated xylem network analysis found that only 36% of vessels had one or more connections to other vessels. Cavitation susceptibility was related to vessel diameter, with large diameter vessels (>40 MUm, mean diameter 25-30 MUm) cavitating mainly under moderate stress (Psi(stem) > -3 MPa) and small diameter vessels (<30 MUm) under severe stress. After re watering there was no evidence for short or longer term vessel refilling over 2 weeks despite a rapid recovery of plant water status. The low embolism susceptibility in 1-year-old J. microcarpa may aid sapling survival during establishment. PMID- 26063709 TI - A state-space modeling approach to estimating canopy conductance and associated uncertainties from sap flux density data. AB - Uncertainties in ecophysiological responses to environment, such as the impact of atmospheric and soil moisture conditions on plant water regulation, limit our ability to estimate key inputs for ecosystem models. Advanced statistical frameworks provide coherent methodologies for relating observed data, such as stem sap flux density, to unobserved processes, such as canopy conductance and transpiration. To address this need, we developed a hierarchical Bayesian State Space Canopy Conductance (StaCC) model linking canopy conductance and transpiration to tree sap flux density from a 4-year experiment in the North Carolina Piedmont, USA. Our model builds on existing ecophysiological knowledge, but explicitly incorporates uncertainty in canopy conductance, internal tree hydraulics and observation error to improve estimation of canopy conductance responses to atmospheric drought (i.e., vapor pressure deficit), soil drought (i.e., soil moisture) and above canopy light. Our statistical framework not only predicted sap flux observations well, but it also allowed us to simultaneously gap-fill missing data as we made inference on canopy processes, marking a substantial advance over traditional methods. The predicted and observed sap flux data were highly correlated (mean sensor-level Pearson correlation coefficient = 0.88). Variations in canopy conductance and transpiration associated with environmental variation across days to years were many times greater than the variation associated with model uncertainties. Because some variables, such as vapor pressure deficit and soil moisture, were correlated at the scale of days to weeks, canopy conductance responses to individual environmental variables were difficult to interpret in isolation. Still, our results highlight the importance of accounting for uncertainty in models of ecophysiological and ecosystem function where the process of interest, canopy conductance in this case, is not observed directly. The StaCC modeling framework provides a statistically coherent approach to estimating canopy conductance and transpiration and propagating estimation uncertainty into ecosystem models, paving the way for improved prediction of water and carbon uptake responses to environmental change. PMID- 26063710 TI - Selective clinical trial reporting: betraying trial participants, harming patients. PMID- 26063711 TI - Postoperative trans women in sexual health clinics: managing common problems after vaginoplasty. PMID- 26063712 TI - Construct Validity of the Social Provisions Scale: A Bifactor Exploratory Structural Equation Modeling Approach. AB - Extant theory posits well-differentiated dimensions of perceived social support as measured using the Social Provisions Scale (SPS). However, evidence is inconsistent with this multidimensionality perspective, with SPS factor correlations near unity and higher between-factor than within-factor item correlations. This article reports on research investigating the internal structure, gender invariance, and predictive validity of SPS scores. The analyses are conducted in a novel bifactor exploratory structural equation modeling (ESEM) framework, which is designed to account for presumed psychometric multidimensionality in SPS items due to (a) their fallibility as pure indicators of the constructs they are purported to measure and (b) the coexistence of general and specific factors. Based on 376 item responses, evidence was obtained for a bifactor-ESEM representation of the SPS data. In addition, support was found for the invariance of item thresholds and the latent mean invariance of six of the seven SPS factors in the retained solution. Only mean levels of Social Integration were found to differ by gender, with men scoring higher than women. Finally, evidence was obtained for the predictive validity of SPS scores with respect to loneliness and psychological well-being. Quite apart from yielding evidence validating the SPS, this research demonstrates the utility of bifactor ESEM for psychological assessment. PMID- 26063713 TI - Editorial Commentary: The Detection of and Response to a Foodborne Disease Outbreak: A Cautionary Tale. PMID- 26063714 TI - Editorial Commentary: Linezolid vs Daptomycin for Vancomycin-Resistant Enterococci: The Evidence Gap Between Trials and Clinical Experience. PMID- 26063715 TI - Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients. AB - BACKGROUND: Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are becoming increasingly common. Linezolid and daptomycin are the primary treatment options for VRE-BSI, but optimal treatment is unclear. METHODS: This was a national retrospective cohort study comparing linezolid and daptomycin for the treatment of VRE-BSI among Veterans Affairs Medical Center patients admitted during 2004-2013. The primary outcome was treatment failure, defined as a composite of (1) 30-day all-cause mortality; (2) microbiologic failure; and (3) 60-day VRE-BSI recurrence. Poisson regression was conducted to determine if antimicrobial treatment was independently associated with clinical outcomes. RESULTS: A total of 644 patients were included (linezolid, n = 319; daptomycin, n = 325). Overall, treatment failure was 60.9% (n = 392/644), and 30-day all-cause mortality was 38.2% (n = 246/644). Linezolid was associated with a significantly higher risk of treatment failure compared with daptomycin (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.13-1.67; P = .001). After adjusting for confounding factors in Poisson regression, the relationship between linezolid use and treatment failure persisted (adjusted RR, 1.15; 95% CI, 1.02-1.30; P = .026). Linezolid was also associated with higher 30-day mortality (42.9% vs 33.5%; RR, 1.17; 95% CI, 1.04-1.32; P = .014) and microbiologic failure rates (RR, 1.10; 95% CI, 1.02-1.18; P = .011). No difference in 60-day VRE-BSI recurrence was observed between treatment groups. CONCLUSIONS: Treatment with linezolid for VRE-BSI resulted in significantly higher treatment failure in comparison to daptomycin. Linezolid treatment was also associated with greater 30-day all-cause mortality and microbiologic failure in this cohort. PMID- 26063716 TI - Second-line Antiretroviral Treatment in Resource-Limited Settings: Abandon Lopinavir/Ritonavir Monotherapy or Search for New Candidates? PMID- 26063717 TI - Editorial Commentary: Fosfomycin: The Current Status of the Drug. PMID- 26063718 TI - Start Smart With Antimicrobial Stewardship. PMID- 26063719 TI - Discordant Syphilis Immunoassays in Pregnancy: Perinatal Outcomes and Implications for Clinical Management. AB - BACKGROUND: The reverse sequence algorithm is often used for prenatal syphilis screening by high-volume laboratories, beginning with a treponemal test such as the chemiluminescence immunoassay (CIA), followed by testing of CIA-positive (CIA(+)) specimens with the rapid plasma reagin test (RPR). The clinical significance of discordant serology (CIA(+)/RPR(-)) for maternal and neonatal outcomes is unknown. METHODS: From August 2007 to August 2010, all pregnant women at Kaiser Permanente Northern California with discordant treponemal serology underwent reflexive testing with Treponema pallidum particle agglutination assay (TP-PA) and were categorized as "TP-PA confirmed" (CIA(+)/RPR(-)/TP-PA(+)) or "isolated CIA positive" (CIA(+)/RPR(-)/TP-PA(-)). Demographic variables and clinical data were abstracted from the medical record and compared by TP-PA status. RESULTS: Of 194 pregnant women, 156 (80%) were CIA(+)/RPR(-)/TP-PA(-) and 38 (20%) were CIA(+)/RPR(-)/TP-PA(+). Among the 77 (49%) CIA(+)/RPR(-)/TP-PA(-) women who were retested, 53% became CIA(-). CIA(+)/RPR(-)/TP-PA(+) (n = 38) women were more likely to be older, have a prior history of sexually transmitted infections, and receive treatment for syphilis during pregnancy than women who were CIA(+)/RPR(-)/TP-PA(-) (all P < .005). Most pregnancies (189/194 [97.5%]) resulted in a live birth; there was no difference in birth outcomes according to TP-PA status and no stillbirths attributable to syphilis. CONCLUSIONS: Most pregnant women with discordant serology were CIA(+)/RPR(-)/TP-PA(-); more than half who were retested became CIA(-). CIA(+)/RPR(-)/TP-PA(-) serology in pregnancy is likely to be falsely positive. Reflexive testing of discordant specimens with TP-PA is important to stratify risk given the likelihood of false positive results in this population. PMID- 26063721 TI - Establishment and Replenishment of the Viral Reservoir in Perinatally HIV-1 infected Children Initiating Very Early Antiretroviral Therapy. AB - BACKGROUND: Combination antiretroviral therapy (cART) generally suppresses the replication of the human immunodeficiency virus type 1 (HIV-1) but does not cure the infection, because proviruses persist in stable latent reservoirs. It has been proposed that low-level proviral reservoirs might predict longer virologic control after discontinuation of treatment. Our objective was to evaluate the impact of very early initiation of cART and temporary treatment interruption on the size of the latent HIV-1 reservoir in vertically infected children. METHODS: This retrospective study included 23 perinatally HIV-1-infected children who initiated very early treatment within 12 weeks after birth (n = 14), or early treatment between week 12 and 1 year (n = 9). We measured the proviral reservoir (CD4(+) T-cell-associated HIV-1 DNA) in blood samples collected beyond the first year of sustained virologic suppression. RESULTS: There is a strong positive correlation between the time to initiation of cART and the size of the proviral reservoir. Children who initiated cART within the first 12 weeks of life showed a proviral reservoir 6-fold smaller than children initiating cART beyond this time (P < .01). Rapid virologic control after initiation of cART also limits the size of the viral reservoir. However, patients who underwent transient treatment interruptions showed a dramatic increase in the size of the viral reservoir after discontinuation. CONCLUSIONS: Initiation of cART during the first 12 weeks of life in perinatally HIV-1-infected children limits the size of the viral reservoir. Treatment interruptions should be undertaken with caution, as they might lead to fast and irreversible replenishment of the viral reservoir. PMID- 26063720 TI - Sustained Domestic Vector Exposure Is Associated With Increased Chagas Cardiomyopathy Risk but Decreased Parasitemia and Congenital Transmission Risk Among Young Women in Bolivia. AB - BACKGROUND: We studied women and their infants to evaluate risk factors for congenital transmission and cardiomyopathy in Trypanosoma cruzi-infected women. METHODS: Women provided data and blood for serology and quantitative polymerase chain reaction (PCR). Infants of infected women had blood tested at 0 and 1 month by microscopy, PCR and immunoblot, and serology at 6 and 9 months. Women underwent electrocardiography (ECG). RESULTS: Of 1696 women, 456 (26.9%) were infected; 31 (6.8%) transmitted T. cruzi to their infants. Women who transmitted had higher parasite loads than those who did not (median, 62.0 [interquartile range {IQR}, 25.8-204.8] vs 0.05 [IQR, 0-29.6]; P < .0001). Transmission was higher in twin than in singleton births (27.3% vs 6.4%; P = .04). Women who had not lived in infested houses transmitted more frequently (9.7% vs 4.6%; P = .04), were more likely to have positive results by PCR (65.5% vs 33.9%; P < .001), and had higher parasite loads than those who had lived in infested houses (median, 25.8 [IQR, 0-64.1] vs 0 [IQR, 0-12.3]; P < .001). Of 302 infected women, 28 (9.3%) had ECG abnormalities consistent with Chagas cardiomyopathy; risk was higher for older women (odds ratio [OR], 1.06 [95% confidence interval {CI}, 1.01 1.12] per year) and those with vector exposure (OR, 3.7 [95% CI, 1.4-10.2]). We observed a strong dose-response relationship between ECG abnormalities and reported years of living in an infested house. CONCLUSIONS: We hypothesize that repeated vector-borne infection sustains antigen exposure and the consequent inflammatory response at a higher chronic level, increasing cardiac morbidity, but possibly enabling exposed women to control parasitemia in the face of pregnancy-induced Th2 polarization. PMID- 26063722 TI - Partial Failure of Milk Pasteurization as a Risk for the Transmission of Campylobacter From Cattle to Humans. AB - BACKGROUND: Cattle are the second most common source of human campylobacteriosis. However, routes to account for this scale of transmission have not been identified. In contrast to chicken, red meat is not heavily contaminated at point of sale. Although effective pasteurization prevents milk-borne infection, apparently sporadic infections may include undetected outbreaks from raw or perhaps incompletely pasteurized milk. METHODS: A rise in Campylobacter gastroenteritis in an isolated population was investigated using whole-genome sequencing (WGS), an epidemiological study, and environmental investigations. RESULTS: A single strain was identified in 20 cases, clearly distinguishable from other local strains and a reference population by WGS. A case-case analysis showed association of infection with the outbreak strain and milk from a single dairy (odds ratio, 8; Fisher exact test P value = .023). Despite temperature records indicating effective pasteurization, mechanical faults likely to lead to incomplete pasteurization of part of the milk were identified by further testing and examination of internal components of dairy equipment. CONCLUSIONS: Here, milk distribution concentrated on a small area, including school-aged children with low background incidence of campylobacteriosis, facilitated outbreak identification. Low-level contamination of widely distributed milk would not produce as detectable an outbreak signal. Such hidden outbreaks may contribute to the substantial burden of apparently sporadic Campylobacter from cattle where transmission routes are not certain. The effective discrimination of outbreak isolates from a reference population using WGS shows that integrating these data and approaches into surveillance could support the detection as well as investigation of such outbreaks. PMID- 26063723 TI - Fosfomycin for Treatment of Prostatitis: New Tricks for Old Dogs. AB - Treatment options for prostatitis caused by multidrug-resistant gram-negative bacilli are limited. We report two cases cured with oral fosfomycin and provide a pharmacokinetic analysis of fosfomycin predose concentrations during treatment. PMID- 26063724 TI - Dyspnea and Risk of Death in Ebola Infected Patients: Is Lung Really Involved? PMID- 26063725 TI - Aberrant TET1 Methylation Closely Associated with CpG Island Methylator Phenotype in Colorectal Cancer. AB - Inactivation of methylcytosine dioxygenase, ten-eleven translocation (TET) is known to be associated with aberrant DNA methylation in cancers. Tumors with a CpG island methylator phenotype (CIMP), a distinct subgroup with extensive DNA methylation, show characteristic features in the case of colorectal cancer. The relationship between TET inactivation and CIMP in colorectal cancers is not well understood. The expression level of TET family genes was compared between CIMP positive (CIMP-P) and CIMP-negative (CIMP-N) colorectal cancers. Furthermore, DNA methylation profiling, including assessment of the TET1 gene, was assessed in colorectal cancers, as well as colon polyps. The TET1 was silenced by DNA methylation in a subset of colorectal cancers as well as cell lines, expression of which was reactivated by demethylating agent. TET1 methylation was more frequent in CIMP-P (23/55, 42%) than CIMP-N (2/113, 2%, P < 0.0001) colorectal cancers. This trend was also observed in colon polyps (CIMP-P, 16/40, 40%; CIMP N, 2/24, 8%; P = 0.002), suggesting that TET1 methylation is an early event in CIMP tumorigenesis. TET1 methylation was significantly associated with BRAF mutation but not with hMLH1 methylation in the CIMP-P colorectal cancers. Colorectal cancers with TET1 methylation have a significantly greater number of DNA methylated genes and less pathological metastasis compared to those without TET1 methylation (P = 0.007 and 0.045, respectively). Our data suggest that TET1 methylation may contribute to the establishment of a unique pathway in respect to CIMP-mediated tumorigenesis, which may be incidental to hMLH1 methylation. In addition, our findings provide evidence that TET1 methylation may be a good biomarker for the prediction of metastasis in colorectal cancer. PMID- 26063726 TI - Psychological flexibility in migraine: A study of pain acceptance and values based action. AB - BACKGROUND: Studies of musculoskeletal pain patients confirm that acceptance of pain and values-based action are strong predictors of pain-related disability and that interventions fostering "psychological flexibility" confer positive outcomes. However, data on these processes in migraine remain limited. This cross sectional study examined relations between components of psychological flexibility and headache among treatment-seeking migraineurs. METHODS: A total of 103 adults (M age = 41.5 (11.9) years; 88.2% female) with ICHD-confirmed migraine (71.8% episodic, 28.2% chronic) across three clinics completed measures of psychological flexibility and headache-related disability. Hierarchical regressions quantified relations between acceptance/values-based action and headache variables after first controlling for pain severity and gender. RESULTS: Acceptance of pain and values-based action accounted for 10% of unique variance in headache severity (DeltaR(2) p = 0.006) and up to 20% in headache-related disability (DeltaR(2) ps = 0.02 and < 0.001) but were weakly related to headache frequency. Psychological flexibility was more strongly associated with MIDAS measured disability than was headache severity or headache frequency. Significant effects were typically of medium-to-large size and driven primarily by values based action. CONCLUSIONS: Paralleling results from the broader chronic pain literature, pain acceptance and values-based action play significant roles in headache pain and disability. Further study of interventions targeting these processes may enhance existing treatments. PMID- 26063727 TI - Reviving old antibiotics. AB - In the face of increasing antimicrobial resistance and the paucity of new antimicrobial agents it has become clear that new antimicrobial strategies are urgently needed. One of these is to revisit old antibiotics to ensure that they are used correctly and to their full potential, as well as to determine whether one or several of them can help alleviate the pressure on more recent agents. Strategies are urgently needed to 're-develop' these drugs using modern standards, integrating new knowledge into regulatory frameworks and communicating the knowledge from the research bench to the bedside. Without a systematic approach to re-developing these old drugs and rigorously testing them according to today's standards, there is a significant risk of doing harm to patients and further increasing multidrug resistance. This paper describes factors to be considered and outlines steps and actions needed to re-develop old antibiotics so that they can be used effectively for the treatment of infections. PMID- 26063728 TI - Connexin43 phosphorylation by PKC and MAPK signals VEGF-mediated gap junction internalization. AB - Gap junctions (GJs) exhibit a complex modus of assembly and degradation to maintain balanced intercellular communication (GJIC). Several growth factors, including vascular endothelial growth factor (VEGF), have been reported to disrupt cell-cell junctions and abolish GJIC. VEGF directly stimulates VEGF receptor tyrosine kinases on endothelial cell surfaces. Exposing primary porcine pulmonary artery endothelial cells (PAECs) to VEGF for 15 min resulted in a rapid and almost complete loss of connexin43 (Cx43) GJs at cell-cell appositions and a concomitant increase in cytoplasmic, vesicular Cx43. After prolonged incubation periods (60 min), Cx43 GJs reformed and intracellular Cx43 were restored to levels observed before treatment. GJ internalization correlated with efficient inhibition of GJIC, up to 2.8-fold increased phosphorylation of Cx43 serine residues 255, 262, 279/282, and 368, and appeared to be clathrin driven. Phosphorylation of serines 255, 262, and 279/282 was mediated by MAPK, whereas serine 368 phosphorylation was mediated by PKC. Pharmacological inhibition of both signaling pathways significantly reduced Cx43 phosphorylation and GJ internalization. Together, our results indicate that growth factors such as VEGF activate a hierarchical kinase program--including PKC and MAPK--that induces GJ internalization via phosphorylation of well-known regulatory amino acid residues located in the Cx43 C-terminal tail. PMID- 26063729 TI - HJURP is involved in the expansion of centromeric chromatin. AB - The CENP-A-specific chaperone HJURP mediates CENP-A deposition at centromeres. The N-terminal region of HJURP is responsible for binding to soluble CENP-A. However, it is unclear whether other regions of HJURP have additional functions for centromere formation and maintenance. In this study, we generated chicken DT40 knockout cell lines and gene replacement constructs for HJURP to assess the additional functions of HJURP in vivo. Our analysis revealed that the middle region of HJURP associates with the Mis18 complex protein M18BP1/KNL2 and that the HJURP-M18BP1 association is required for HJURP function. In addition, on the basis of the analysis of artificial centromeres induced by ectopic HJURP localization, we demonstrate that HJURP exhibits a centromere expansion activity that is separable from its CENP-A-binding activity. We also observed centromere expansion surrounding natural centromeres after HJURP overexpression. We propose that this centromere expansion activity reflects the functional properties of HJURP, which uses this activity to contribute to the plastic establishment of a centromeric chromatin structure. PMID- 26063730 TI - Cross-talk between androgen receptor/filamin A and TrkA regulates neurite outgrowth in PC12 cells. AB - Steroids and growth factors control neuronal development through their receptors under physiological and pathological conditions. We show that PC12 cells harbor endogenous androgen receptor (AR), whose inhibition or silencing strongly interferes with neuritogenesis stimulated by the nonaromatizable synthetic androgen R1881 or NGF. This implies a role for AR not only in androgen signaling, but also in NGF signaling. In turn, a pharmacological TrkA inhibitor interferes with NGF- or androgen-induced neuritogenesis. In addition, androgen or NGF triggers AR association with TrkA, TrkA interaction with PI3-K delta, and downstream activation of PI3-K delta and Rac in PC12 cells. Once associated with AR, filamin A (FlnA) contributes to androgen or NGF neuritogenesis, likely through its interaction with signaling effectors, such as Rac. This study thus identifies a previously unrecognized reciprocal cross-talk between AR and TrkA, which is controlled by beta1 integrin. The contribution of FlnA/AR complex and PI3-K delta to neuronal differentiation by androgens and NGF is also novel. This is the first description of AR function in PC12 cells. PMID- 26063731 TI - Androgen receptor modulates Foxp3 expression in CD4+CD25+Foxp3+ regulatory T cells. AB - CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells are able to inhibit proliferation and cytokine production in effector T-cells and play a major role in immune responses and prevention of autoimmune disease. A master regulator of Treg cell development and function is the transcription factor Foxp3. Several cytokines, such as TGF-beta and IL-2, are known to regulate Foxp3 expression as well as methylation of the Foxp3 locus. We demonstrated previously that testosterone treatment induces a strong increase in the Treg cell population both in vivo and in vitro. Therefore we sought to investigate the direct effect of androgens on expression and regulation of Foxp3. We show a significant androgen-dependent increase of Foxp3 expression in human T-cells from women in the ovulatory phase of the menstrual cycle but not from men and identify a functional androgen response element within the Foxp3 locus. Binding of androgen receptor leads to changes in the acetylation status of histone H4, whereas methylation of defined CpG regions in the Foxp3 gene is unaffected. Our results provide novel evidence for a modulatory role of androgens in the differentiation of Treg cells. PMID- 26063732 TI - DRC3 connects the N-DRC to dynein g to regulate flagellar waveform. AB - The nexin-dynein regulatory complex (N-DRC), which is a major hub for the control of flagellar motility, contains at least 11 different subunits. A major challenge is to determine the location and function of each of these subunits within the N DRC. We characterized a Chlamydomonas mutant defective in the N-DRC subunit DRC3. Of the known N-DRC subunits, the drc3 mutant is missing only DRC3. Like other N DRC mutants, the drc3 mutant has a defect in flagellar motility. However, in contrast to other mutations affecting the N-DRC, drc3 does not suppress flagellar paralysis caused by loss of radial spokes. Cryo-electron tomography revealed that the drc3 mutant lacks a portion of the N-DRC linker domain, including the L1 protrusion, part of the distal lobe, and the connection between these two structures, thus localizing DRC3 to this part of the N-DRC. This and additional considerations enable us to assign DRC3 to the L1 protrusion. Because the L1 protrusion is the only non-dynein structure in contact with the dynein g motor domain in wild-type axonemes and this is the only N-DRC-dynein connection missing in the drc3 mutant, we conclude that DRC3 interacts with dynein g to regulate flagellar waveform. PMID- 26063733 TI - A novel function of the monomeric CCTepsilon subunit connects the serum response factor pathway to chaperone-mediated actin folding. AB - Correct protein folding is fundamental for maintaining protein homeostasis and avoiding the formation of potentially cytotoxic protein aggregates. Although some proteins appear to fold unaided, actin requires assistance from the oligomeric molecular chaperone CCT. Here we report an additional connection between CCT and actin by identifying one of the CCT subunits, CCTepsilon, as a component of the myocardin-related cotranscription factor-A (MRTF-A)/serum response factor (SRF) pathway. The SRF pathway registers changes in G-actin levels, leading to the transcriptional up-regulation of a large number of genes after actin polymerization. These genes encode numerous actin-binding proteins as well as actin. We show that depletion of the CCTepsilon subunit by siRNA enhances SRF signaling in cultured mammalian cells by an actin assembly-independent mechanism. Overexpression of CCTepsilon in its monomeric form revealed that CCTepsilon binds via its substrate-binding domain to the C-terminal region of MRTF-A and that CCTepsilon is able to alter the nuclear accumulation of MRTF-A after stimulation by serum addition. Given that the levels of monomeric CCTepsilon conversely reflect the levels of CCT oligomer, our results suggest that CCTepsilon provides a connection between the actin-folding capacity of the cell and actin expression. PMID- 26063734 TI - A complex of ZO-1 and the BAR-domain protein TOCA-1 regulates actin assembly at the tight junction. AB - Assembly and sealing of the tight junction barrier are critically dependent on the perijunctional actin cytoskeleton, yet little is known about physical and functional links between barrier-forming proteins and actin. Here we identify a novel functional complex of the junction scaffolding protein ZO-1 and the F-BAR domain protein TOCA-1. Using MDCK epithelial cells, we show that an alternative splice of TOCA-1 adds a PDZ-binding motif, which binds ZO-1, targeting TOCA-1 to barrier contacts. This isoform of TOCA-1 recruits the actin nucleation-promoting factor N-WASP to tight junctions. CRISPR-Cas9-mediated knockout of TOCA-1 results in increased paracellular flux and delayed recovery in a calcium switch assay. Knockout of TOCA-1 does not alter FRAP kinetics of GFP ZO-1 or occludin, but longer term (12 h) time-lapse microscopy reveals strikingly decreased tight junction membrane contact dynamics in knockout cells compared with controls. Reexpression of TOCA-1 with, but not without, the PDZ-binding motif rescues both altered flux and membrane contact dynamics. Ultrastructural analysis shows actin accumulation at the adherens junction in TOCA-1-knockout cells but unaltered freeze-fracture fibril morphology. Identification of the ZO-1/TOCA-1 complex provides novel insights into the underappreciated dependence of the barrier on the dynamic nature of cell-to-cell contacts and perijunctional actin. PMID- 26063735 TI - The p53 family member p73 modulates the proproliferative role of IGFBP3 in short children born small for gestational age. AB - The regulation of insulin-like growth factor-binding protein 3 (IGFBP3) gene expression is complex, because it can be induced by agents that both stimulate and inhibit the proliferation. The principal aim of this study was to investigate whether p73, a member of the p53 gene family, has a role in the regulation of the IGFBP3 expression and whether this regulation occurs in a context of cell survival or death. We demonstrate that IGFBP3 is a direct TAp73alpha (the p73 isoform that contains the trans-activation domain) target gene and activates the expression of IGFBP3 in actively proliferating cells. As IGFBP3 plays a key role in regulating the growth hormone/insulin-like growth factor type 1 (GH/IGF1) axis, whose alterations in gene expression appear to have a role in the growth failure of children born small for gestational age (SGA), we measured the mRNA expression levels of p73 and IGFBP3 in a group of SGA children. We found that mRNA expression levels of p73 and IGFBP3 are significantly lower in SGA children compared with controls and, in particular, p73 mRNA expression is significantly lower in SGA children with respect to height. Our results shed light on the intricate GH/IGF pathway, suggesting p73 as a good biomarker of the clinical risk for SGA children to remain short in adulthood. PMID- 26063736 TI - The landscape of antisense gene expression in human cancers. AB - High-throughput RNA sequencing has revealed more pervasive transcription of the human genome than previously anticipated. However, the extent of natural antisense transcripts' (NATs) expression, their regulation of cognate sense genes, and the role of NATs in cancer remain poorly understood. Here, we use strand-specific paired-end RNA sequencing (ssRNA-seq) data from 376 cancer samples covering nine tissue types to comprehensively characterize the landscape of antisense expression. We found consistent antisense expression in at least 38% of annotated transcripts, which in general is positively correlated with sense gene expression. Investigation of sense/antisense pair expressions across tissue types revealed lineage-specific, ubiquitous and cancer-specific antisense loci transcription. Comparisons between tumor and normal samples identified both concordant (same direction) and discordant (opposite direction) sense/antisense expression patterns. Finally, we provide OncoNAT, a catalog of cancer-related genes with significant antisense transcription, which will enable future investigations of sense/antisense regulation in cancer. Using OncoNAT we identified several functional NATs, including NKX2-1-AS1 that regulates the NKX2 1 oncogene and cell proliferation in lung cancer cells. Overall, this study provides a comprehensive account of NATs and supports a role for NATs' regulation of tumor suppressors and oncogenes in cancer biology. PMID- 26063737 TI - Using genome-wide measures of coancestry to maintain diversity and fitness in endangered and domestic pig populations. AB - Conservation and breeding programs aim at maintaining the most diversity, thereby avoiding deleterious effects of inbreeding while maintaining enough variation from which traits of interest can be selected. Theoretically, the most diversity is maintained using optimal contributions based on many markers to calculate coancestries, but this can decrease fitness by maintaining linked deleterious variants. The heterogeneous patterns of coancestry displayed in pigs make them an excellent model to test these predictions. We propose methods to measure coancestry and fitness from resequencing data and use them in population management. We analyzed the resequencing data of Sus cebifrons, a highly endangered porcine species from the Philippines, and genotype data from the Pietrain domestic breed. By analyzing the demographic history of Sus cebifrons, we inferred two past bottlenecks that resulted in some inbreeding load. In Pietrain, we analyzed signatures of selection possibly associated with commercial traits. We also simulated the management of each population to assess the performance of different optimal contribution methods to maintain diversity, fitness, and selection signatures. Maximum genetic diversity was maintained using marker-by-marker coancestry, and least using genealogical coancestry. Using a measure of coancestry based on shared segments of the genome achieved the best results in terms of diversity and fitness. However, this segment-based management eliminated signatures of selection. We demonstrate that maintaining both diversity and fitness depends on the genomic distribution of deleterious variants, which is shaped by demographic and selection histories. Our findings show the importance of genomic and next-generation sequencing information in the optimal design of breeding or conservation programs. PMID- 26063738 TI - Sequence determinants of improved CRISPR sgRNA design. AB - The CRISPR/Cas9 system has revolutionized mammalian somatic cell genetics. Genome wide functional screens using CRISPR/Cas9-mediated knockout or dCas9 fusion mediated inhibition/activation (CRISPRi/a) are powerful techniques for discovering phenotype-associated gene function. We systematically assessed the DNA sequence features that contribute to single guide RNA (sgRNA) efficiency in CRISPR-based screens. Leveraging the information from multiple designs, we derived a new sequence model for predicting sgRNA efficiency in CRISPR/Cas9 knockout experiments. Our model confirmed known features and suggested new features including a preference for cytosine at the cleavage site. The model was experimentally validated for sgRNA-mediated mutation rate and protein knockout efficiency. Tested on independent data sets, the model achieved significant results in both positive and negative selection conditions and outperformed existing models. We also found that the sequence preference for CRISPRi/a is substantially different from that for CRISPR/Cas9 knockout and propose a new model for predicting sgRNA efficiency in CRISPRi/a experiments. These results facilitate the genome-wide design of improved sgRNA for both knockout and CRISPRi/a studies. PMID- 26063739 TI - Determinants of nucleosome positioning and their influence on plant gene expression. AB - Nucleosome positioning influences the access of transcription factors (TFs) to their binding sites and gene expression. Studies in plant, animal, and fungal models demonstrate similar nucleosome positioning patterns along genes and correlations between occupancy and expression. However, the relationships among nucleosome positioning, cis-regulatory element accessibility, and gene expression in plants remain undefined. Here we showed that plant nucleosome depletion occurs on specific 6-mer motifs and this sequence-specific nucleosome depletion is predictive of expression levels. Nucleosome-depleted regions in Arabidopsis thaliana tend to have higher G/C content, unlike yeast, and are centered on specific G/C-rich 6-mers, suggesting that intrinsic sequence properties, such as G/C content, cannot fully explain plant nucleosome positioning. These 6-mer motif sites showed higher DNase I hypersensitivity and are flanked by strongly phased nucleosomes, consistent with known TF binding sites. Intriguingly, this 6-mer specific nucleosome depletion pattern occurs not only in promoter but also in genic regions and is significantly correlated with higher gene expression level, a phenomenon also found in rice but not in yeast. Among the 6-mer motifs enriched in genes responsive to treatment with the defense hormone jasmonate, there are no significant changes in nucleosome occupancy, suggesting that these sites are potentially preconditioned to enable rapid response without changing chromatin state significantly. Our study provides a global assessment of the joint contribution of nucleosome occupancy and motif sequences that are likely cis elements to the control of gene expression in plants. Our findings pave the way for further understanding the impact of chromatin state on plant transcriptional regulatory circuits. PMID- 26063740 TI - Follow-up of 316 molecularly defined pediatric long-QT syndrome patients: clinical course, treatments, and side effects. AB - BACKGROUND: Inherited long-QT syndrome (LQTS) is associated with risk of sudden death. We assessed the clinical course and the fulfillment of current treatment strategies in molecularly defined pediatric LQTS type 1 and (LQT1) and type 2 (LQT2) patients. METHODS AND RESULTS: Follow-up data covering a mean of 12 years were collected for 316 genotyped LQT1 and LQT2 patients aged 0 to 18 years. No arrhythmic deaths occurred during the follow-up. Finnish KCNQ1 and KCNH2 founder mutations were associated with fewer cardiac events than other KCNQ1 and KCNH2 mutations (hazard ratio [HR], 0.33; P=0.03 and HR, 0.16; P=0.01, respectively). QTc interval >=500 ms increased the risk of cardiac events compared with QTc <470 ms (HR, 3.32; P=0.001). Treatment with beta-blocker medication was associated with reduced risk of first cardiac event (HR, 0.23; P=0.001). Noncompliant LQT2 patients were more often symptomatic than compliant LQT2 patients (18% and 0%, respectively; P=0.03). Treatment with implantable cardioverter defibrillator was rare (3%) and resulted in reinterventions in 44% of cases. CONCLUSIONS: Severe cardiac events are uncommon in molecularly defined and appropriately treated pediatric LQTS mutation carriers. beta-Blocker medication reduces the risk of cardiac events and is generally well tolerated in this age group of LQTS patients. PMID- 26063741 TI - Safety of oral dofetilide for rhythm control of atrial fibrillation and atrial flutter. AB - BACKGROUND: Although dofetilide is widely used in the United States for rhythm control of atrial fibrillation, there is limited postapproval safety data in the atrial fibrillation population despite its known risk of Torsade de pointes (TdP). METHODS AND RESULTS: We conducted a retrospective chart review of a cohort of 1404 patients initially loaded on dofetilide for atrial fibrillation suppression at the Cleveland Clinic from 2008 to 2012 to evaluate the incidence and risk factors for in-hospital adverse events and the long-term safety of continued use. Of the 17 patients with TdP during loading (1.2%), 10 had a cardiac arrest requiring resuscitation (1 death), 5 had syncope/presyncope, and 2 were asymptomatic. Dofetilide loading was stopped for 105 patients (7.5%) because of QTc prolongation or TdP. Variables correlated with TdP were (1) female sex, 2) 500-MUg dose, (3) reduced ejection fraction, and (4) increase in QTc from baseline. One-year all-cause mortality was higher in patients who continued dofetilide compared with those who discontinued use (hazard ratio, 2.48; 95% confidence interval, 1.08-5.71; P=0.03). Those patients who had a TdP event had higher one-year all-cause mortality than those who did not (17.6% versus 3% at 1 year; P<0.001). CONCLUSIONS: Dofetilide loading has a low but finite risk of TdP and other adverse events that warrant the current Food and Drug Administration mandated practice of inpatient monitoring during drug loading. In this cohort, all-cause mortality was higher at 1 year in those patients continued on dofetilide and in those patients who experienced TdP while loading. PMID- 26063742 TI - Suppression of Reserve MCM Complexes Chemosensitizes to Gemcitabine and 5 Fluorouracil. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer and is very difficult to treat with conventional chemotherapeutic regimens. Gemcitabine and 5-fluorouracil are used in the management of PDAC and act by indirectly blocking replicative forks. However, these drugs are not highly effective at suppressing disease progression, indicating a need for the development of innovative therapeutic approaches. Recent studies indicate that suppression of the MCM helicase may provide a novel means to sensitize cancer cells to chemotherapeutic agents that inhibit replicative fork progression. Mammalian cells assemble more MCM complexes on DNA than are required to start S phase. The excess MCM complexes function as backup initiation sites under conditions of replicative stress. The current study provides definitive evidence that cosuppression of the excess/backup MCM complexes sensitizes PDAC tumor lines to both gemcitabine and 5-FU, leading to increased loss of proliferative capacity compared with drugs alone. This occurs because reduced MCM levels prevent efficient recovery of DNA replication in tumor cells exposed to drug. PDAC tumor cells are more sensitive to MCM loss in the presence of gemcitabine than are nontumor, immortalized epithelial cells. Similarly, colon tumor cells are rendered less viable when cosuppression of MCM complexes occurs during exposure to the crosslinking agent oxaliplatin or topoisomerase inhibitor etoposide. IMPLICATIONS: These studies demonstrate that suppressing the backup complement of MCM complexes provides an effective sensitizing approach with the potential to increase the therapeutic index of drugs used in the clinical management of PDAC and other cancers. PMID- 26063743 TI - Echocardiographic and Hemodynamic Predictors of Survival in Precapillary Pulmonary Hypertension: Seven-Year Follow-Up. AB - BACKGROUND: In this study, we looked at the prognostic value of echocardiographic and hemodynamic measures in a large cohort of patients with precapillary pulmonary hypertension before and after initiation of treatment. METHODS AND RESULTS: Data were collected prospectively in a cohort of consecutive patients with precapillary pulmonary hypertension referred between 2002 and 2011. A range of clinical and echocardiographic variables were collected and stored on a database to assess predictors of survival. Invasive hemodynamic data including pulmonary artery pressure, pulmonary vascular resistance, capillary wedge pressure, and cardiac index were also obtained at baseline in all patients. Outcome was defined as mortality because of cardiovascular-related death. The study cohort comprised 777 patients (514 women) with precapillary pulmonary hypertension. A total of 195 (25%) died. In multivariable analysis, moderate or severe tricuspid regurgitation (hazard ratio [HR], 26.537; 95% confidence interval, 11.536-61.044; P<0.001), right ventricular myocardial performance index (HR, 3.421; 95% confidence interval, 1.777-6.584; P<0.001), and the presence of pericardial effusion (HR, 1.38; 95% confidence interval, 1.023-1.862; P=0.035) were independent predictors of mortality. High pulmonary vascular resistance and right atrial pressure by invasive hemodynamic measurements were independent predictors of mortality (HR, 1.084; 95% confidence interval, 1.041-1.130, and 1.079, respectively; 95% confidence interval, 1.049-1.111; P<0.001 for both), whereas patients with a higher cardiac index had better survival overall (HR, 0.384; 95% confidence interval, 0.307-0.481; P<0.001). CONCLUSIONS: Right ventricular dysfunction, moderate-severe tricuspid regurgitation, low cardiac index, and raised right atrial pressure were associated with poor survival for both pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertensive disease patients. The severity of tricuspid regurgitation, myocardial performance index, presence of pericardial effusion, pulmonary vascular resistance, cardiac index, and right atrial pressure may be used to stratify risk of death. PMID- 26063744 TI - Expert guided natural language processing using one-class classification. AB - INTRODUCTION: Automatically identifying specific phenotypes in free-text clinical notes is critically important for the reuse of clinical data. In this study, the authors combine expert-guided feature (text) selection with one-class classification for text processing. OBJECTIVES: To compare the performance of one class classification to traditional binary classification; to evaluate the utility of feature selection based on expert-selected salient text (snippets); and to determine the robustness of these models with respects to irrelevant surrounding text. METHODS: The authors trained one-class support vector machines (1C-SVMs) and two-class SVMs (2C-SVMs) to identify notes discussing breast cancer. Manually annotated visit summary notes (88 positive and 88 negative for breast cancer) were used to compare the performance of models trained on whole notes labeled as positive or negative to models trained on expert-selected text sections (snippets) relevant to breast cancer status. Model performance was evaluated using a 70:30 split for 20 iterations and on a realistic dataset of 10 000 records with a breast cancer prevalence of 1.4%. RESULTS: When tested on a balanced experimental dataset, 1C-SVMs trained on snippets had comparable results to 2C-SVMs trained on whole notes (F = 0.92 for both approaches). When evaluated on a realistic imbalanced dataset, 1C-SVMs had a considerably superior performance (F = 0.61 vs. F = 0.17 for the best performing model) attributable mainly to improved precision (p = .88 vs. p = .09 for the best performing model). CONCLUSIONS: 1C-SVMs trained on expert-selected relevant text sections perform better than 2C-SVMs classifiers trained on either snippets or whole notes when applied to realistically imbalanced data with low prevalence of the positive class. PMID- 26063745 TI - Domain adaptation for semantic role labeling of clinical text. AB - OBJECTIVE: Semantic role labeling (SRL), which extracts a shallow semantic relation representation from different surface textual forms of free text sentences, is important for understanding natural language. Few studies in SRL have been conducted in the medical domain, primarily due to lack of annotated clinical SRL corpora, which are time-consuming and costly to build. The goal of this study is to investigate domain adaptation techniques for clinical SRL leveraging resources built from newswire and biomedical literature to improve performance and save annotation costs. MATERIALS AND METHODS: Multisource Integrated Platform for Answering Clinical Questions (MiPACQ), a manually annotated SRL clinical corpus, was used as the target domain dataset. PropBank and NomBank from newswire and BioProp from biomedical literature were used as source domain datasets. Three state-of-the-art domain adaptation algorithms were employed: instance pruning, transfer self-training, and feature augmentation. The SRL performance using different domain adaptation algorithms was evaluated by using 10-fold cross-validation on the MiPACQ corpus. Learning curves for the different methods were generated to assess the effect of sample size. RESULTS AND CONCLUSION: When all three source domain corpora were used, the feature augmentation algorithm achieved statistically significant higher F-measure (83.18%), compared to the baseline with MiPACQ dataset alone (F-measure, 81.53%), indicating that domain adaptation algorithms may improve SRL performance on clinical text. To achieve a comparable performance to the baseline method that used 90% of MiPACQ training samples, the feature augmentation algorithm required <50% of training samples in MiPACQ, demonstrating that annotation costs of clinical SRL can be reduced significantly by leveraging existing SRL resources from other domains. PMID- 26063746 TI - Innovating to enhance clinical data management using non-commercial and open source solutions across a multi-center network supporting inpatient pediatric care and research in Kenya. AB - OBJECTIVE: To share approaches and innovations adopted to deliver a relatively inexpensive clinical data management (CDM) framework within a low-income setting that aims to deliver quality pediatric data useful for supporting research, strengthening the information culture and informing improvement efforts in local clinical practice. MATERIALS AND METHODS: The authors implemented a CDM framework to support a Clinical Information Network (CIN) using Research Electronic Data Capture (REDCap), a noncommercial software solution designed for rapid development and deployment of electronic data capture tools. It was used for collection of standardized data from case records of multiple hospitals' pediatric wards. R, an open-source statistical language, was used for data quality enhancement, analysis, and report generation for the hospitals. RESULTS: In the first year of CIN, the authors have developed innovative solutions to support the implementation of a secure, rapid pediatric data collection system spanning 14 hospital sites with stringent data quality checks. Data have been collated on over 37 000 admission episodes, with considerable improvement in clinical documentation of admissions observed. Using meta-programming techniques in R, coupled with branching logic, randomization, data lookup, and Application Programming Interface (API) features offered by REDCap, CDM tasks were configured and automated to ensure quality data was delivered for clinical improvement and research use. CONCLUSION: A low-cost clinically focused but geographically dispersed quality CDM (Clinical Data Management) in a long-term, multi-site, and real world context can be achieved and sustained and challenges can be overcome through thoughtful design and implementation of open-source tools for handling data and supporting research. PMID- 26063747 TI - Back to Gondwanaland: can ancient vicariance explain (some) Indian Ocean disjunct plant distributions? AB - Oceans, or other wide expanses of inhospitable environment, interrupt present day distributions of many plant groups. Using molecular dating techniques, generally incorporating fossil evidence, we can estimate when such distributions originated. Numerous dating analyses have recently precipitated a paradigm shift in the general explanations for the phenomenon, away from older geological causes, such as continental drift, in favour of more recent, long-distance dispersal (LDD). For example, the 'Gondwanan vicariance' scenario has been dismissed in various studies of Indian Ocean disjunct distributions. We used the gentian tribe Exaceae to reassess this scenario using molecular dating with minimum (fossil), maximum (geological), secondary (from wider analyses) and hypothesis-driven age constraints. Our results indicate that ancient vicariance cannot be ruled out as an explanation for the early origins of Exaceae across Africa, Madagascar and the Indian subcontinent unless a strong assumption is made about the maximum age of Gentianales. However, both the Gondwanan scenario and the available evidence suggest that there were also several, more recent, intercontinental dispersals during the diversification of the group. PMID- 26063748 TI - The importance of mammalian torpor for survival in a post-fire landscape. AB - Wildfires have increased in frequency and intensity worldwide with climate change as a main driving factor. While a number of studies have focused on population changes in regard to fires, there are essentially no quantitative data on behavioural and physiological adjustments that are vital for the persistence of individuals during and after fires. Here we show that brown antechinus, a small insectivorous marsupial mammal, (i) endured a prescribed fire in situ, (ii) remained in their scorched home range despite unburned areas nearby, and (iii) substantially increased post-fire torpor use and thus reduced foraging requirements and exposure to predators. Hence, torpor is a physiological adaptation that, although not quantified in this context previously, appears to play a key role in post-fire survival for this and other heterothermic species. PMID- 26063749 TI - A model for the origin of group reproduction during the evolutionary transition to multicellularity. AB - During the evolution of multicellular organisms, the unit of selection and adaptation, the individual, changes from the single cell to the multicellular group. To become individuals, groups must evolve a group life cycle in which groups reproduce other groups. Investigations into the origin of group reproduction have faced a chicken-and-egg problem: traits related to reproduction at the group level often appear both to be a result of and a prerequisite for natural selection at the group level. With a focus on volvocine algae, we model the basic elements of the cell cycle and show how group reproduction can emerge through the coevolution of a life-history trait with a trait underpinning cell cycle change. Our model explains how events in the cell cycle become reordered to create a group life cycle through continuous change in the cell cycle trait, but only if the cell cycle trait can coevolve with the life-history trait. Explaining the origin of group reproduction helps us understand one of life's most familiar, yet fundamental, aspects-its hierarchical structure. PMID- 26063750 TI - Negative frequency-dependent selection is intensified at higher population densities in protist populations. AB - Natural populations of free-living protists often exhibit high-levels of intraspecific diversity, yet this is puzzling as classic evolutionary theory predicts dominance by genotypes with high fitness, particularly in large populations where selection is efficient. Here, we test whether negative frequency-dependent selection (NFDS) plays a role in the maintenance of diversity in the marine flagellate Oxyrrhis marina using competition experiments between multiple pairs of strains. We observed strain-specific responses to frequency and density, but an overall signature of NFDS that was intensified at higher population densities. Because our strains were not selected a priori on the basis of particular traits expected to exhibit NFDS, these data represent a relatively unbiased estimate of the role for NFDS in maintaining diversity in protist populations. These findings could help to explain how bloom-forming plankton, which periodically achieve exceptionally high population densities, maintain substantial intraspecific diversity. PMID- 26063751 TI - Downsizing a giant: re-evaluating Dreadnoughtus body mass. AB - Estimates of body mass often represent the founding assumption on which biomechanical and macroevolutionary hypotheses are based. Recently, a scaling equation was applied to a newly discovered titanosaurian sauropod dinosaur (Dreadnoughtus), yielding a 59 300 kg body mass estimate for this animal. Herein, we use a modelling approach to examine the plausibility of this mass estimate for Dreadnoughtus. We find that 59 300 kg for Dreadnoughtus is highly implausible and demonstrate that masses above 40 000 kg require high body densities and expansions of soft tissue volume outside the skeleton several times greater than found in living quadrupedal mammals. Similar results from a small sample of other archosaurs suggests that lower-end mass estimates derived from scaling equations are most plausible for Dreadnoughtus, based on existing volumetric and density data from extant animals. Although volumetric models appear to more tightly constrain dinosaur body mass, there remains a clear need to further support these models with more exhaustive data from living animals. The relative and absolute discrepancies in mass predictions between volumetric models and scaling equations also indicate a need to systematically compare predictions across a wide size and taxonomic range to better inform studies of dinosaur body size. PMID- 26063752 TI - Geographical ancestry of Lake Malawi's cichlid fish diversity. AB - The Lake Malawi haplochromine cichlid flock is one of the largest vertebrate adaptive radiations. The geographical source of the radiation has been assumed to be rivers to the south and east of Lake Malawi, where extant representatives of the flock are now present. Here, we provide mitochondrial DNA evidence suggesting the sister taxon to the Lake Malawi radiation is within the Great Ruaha river in Tanzania, north of Lake Malawi. Estimates of the time of divergence between the Lake Malawi flock and this riverine sister taxon range from 2.13 to 6.76 Ma, prior to origins of the current radiation 1.20-4.06 Ma. These results are congruent with evaluations of 2-3.75 Ma fossil material that suggest past faunal connections between Lake Malawi and the Ruaha. We propose that ancestors of the Malawi radiation became isolated within the catchment during Pliocene rifting that formed both Lake Malawi and the Kipengere/Livingstone mountain range, before colonizing rivers to the south and east of the lake region and radiating within the lake basin. Identification of this sister taxon allows tests of whether standing genetic diversity has predisposed Lake Malawi cichlids to rapid speciation and adaptive radiation. PMID- 26063753 TI - Drivers of extinction: the case of Azorean beetles. AB - Oceanic islands host a disproportionately high fraction of endangered or recently extinct endemic species. We report on species extinctions among endemic Azorean beetles following 97% habitat loss since AD 1440. We infer extinctions from historical and contemporary records and examine the influence of three predictors: geographical range, habitat specialization and body size. Of 55 endemic beetle species investigated (out of 63), seven can be considered extinct. Single-island endemics (SIEs) were more prone to extinction than multi-island endemics. Within SIEs restricted to native habitat, larger species were more extinction-prone. We thus show a hierarchical path to extinction in Azorean beetles: species with small geographical range face extinction first, with the larger bodied ones being the most threatened. Our study provides a clear warning of the impact of habitat loss on island endemic biotas. PMID- 26063754 TI - Social synchronization of circadian rhythmicity in female mice depends on the number of cohabiting animals. AB - Communal animals often engage in group activities that require temporal synchrony among its members, including synchrony on the circadian timescale. The principles and conditions that foster such collective synchronization are not understood, but existing literature hints that the number of interacting individuals may be a critical factor. We tested this by recording individual circadian body temperature rhythms of female house mice housed singly, in twos (pairs), or in groups of five (quintets) in constant darkness; determining the daily phases of the circadian peak for each animal; and then calculating the cycle-to-cycle phase relationship between cohabiting animals over time. Significant temporal coherence was observed in quintets: the proportion of quintets (4/7), but not pairs (2/8), that became synchronized was greater than could be achieved by the complete simulated reassortment of all individuals. We speculate that the social coupling of individual circadian clocks of group members may be adaptive under certain conditions, and we propose that optimal group sizes in nature may depend not only on species-specific energetics, spatial behaviour and natural history but also on the mathematics of synchronizing assemblies of weakly coupled animal oscillators. PMID- 26063756 TI - Patterns of Recovery Following Sport-Related Concussion in Children and Adolescents. AB - Time to symptom resolution, return to school, and return to play after a sport related concussion in children and adolescents (8-17 years of age) was examined using a retrospective cohort design. A total of 198 patients aged 8 to 17 years were included, with a mean age of 13.5 years (SD = 2.2). Patients aged 8 to 12 years were symptom-free in a median of 12.0 (range 1-60) days whereas 13- to 17 year olds were symptom-free in a median of 14.0 (range 1-300) days (P = .04). Patients aged 8 to 12 years returned to learn in a median of 4.0 (range 0-30) days compared with 2.5 (range 0-55.0) days in 13- to 17-year-olds (P = .86). Patients aged 8 to 12 years returned to play in a median of 14.0 (range 4-75) days compared with a median of 19.5 (range 5-75) days in 13- to 17-year-olds (P = .06). These results indicate that children and adolescents generally take 2 to 4 weeks to recover from a sport-related concussion. PMID- 26063755 TI - The value of models in informing resource allocation in colorectal cancer screening: the case of The Netherlands. AB - In May 2011, the Dutch government decided to implement a national programme for colorectal cancer (CRC) screening using biennial faecal immunochemical test screening between ages 55 and 75. Decision modelling played an important role in informing this decision, as well as in the planning and implementation of the programme afterwards. In this overview, we illustrate the value of models in informing resource allocation in CRC screening using the role that decision modelling has played in the Dutch CRC screening programme as an example. PMID- 26063757 TI - Familial Risk in Low-Income Children With Chronic Illness Exposed to Passive Smoke. AB - BACKGROUND: This study highlights the family characteristics of a child living in a state of triple risk: chronically ill, exposed to passive smoke, and residing in a low-income household. METHODS: Head Start families were divided into 4 groups based on passive smoke exposure and child chronic illness status. Analyses of covariance controlling for parent education, parent employment, marital status, and residence were conducted to identify group differences in the Family Map risk areas. RESULTS: Families of chronically ill, passive smoke-exposed children demonstrated the highest levels of risks across a range of areas including: meeting basic needs, family conflict, parenting stress, and parental depression and anxiety. CONCLUSIONS: Children living in poverty with a chronic illness who are exposed to smoke are likely to face many challenges in addition to their illness. Healthcare professionals can identify family risks and provide targeted educate and support to potentially reduce risk factors for children. PMID- 26063758 TI - A Case of Postinfectious Protein S Deficiency Masquerading as Henoch-Schonlein Purpura. PMID- 26063759 TI - Validation of a Five-Item Parent Questionnaire to Screen Preschool Children for Reading Problems. PMID- 26063760 TI - Regulation of a strong F9 cryptic 5'ss by intrinsic elements and by combination of tailored U1snRNAs with antisense oligonucleotides. AB - Mutations affecting specific splicing regulatory elements offer suitable models to better understand their interplay and to devise therapeutic strategies. Here we characterize a meaningful splicing model in which numerous Hemophilia B causing mutations, either missense or at the donor splice site (5'ss) of coagulation F9 exon 2, promote aberrant splicing by inducing the usage of a strong exonic cryptic 5'ss. Splicing assays with natural and artificial F9 variants indicated that the cryptic 5'ss is regulated, among a network of regulatory elements, by an exonic splicing silencer (ESS). This finding and the comparative analysis of the F9 sequence across species showing that the cryptic 5'ss is always paralleled by the conserved ESS support a compensatory mechanism aimed at minimizing unproductive splicing. To recover splicing we tested antisense oligoribonucleotides masking the cryptic 5'ss, which were effective on exonic changes but promoted exon 2 skipping in the presence of mutations at the authentic 5'ss. On the other hand, we observed a very poor correction effect by small nuclear RNA U1 (U1snRNA) variants with increased or perfect complementarity to the defective 5'ss, a strategy previously exploited to rescue splicing. Noticeably, the combination of the mutant-specific U1snRNAs with antisense oligonucleotides produced appreciable amounts of correctly spliced transcripts (from 0 to 20-40%) from several mutants of the exon 2 5'ss. Based on the evidence of an altered interplay among ESS, cryptic and the authentic 5'ss as a disease causing mechanism, we provide novel experimental insights into the combinatorial correction activity of antisense molecules and compensatory U1snRNAs. PMID- 26063761 TI - Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington's disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. AB - Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by motor and cognitive impairments, involving striatum, cortex and hippocampus. Synaptic and memory dysfunction in HD mouse models have been related to low levels of brain-derived neurotrophic factor (BDNF) and imbalance between TrkB and p75(NTR) receptors. In addition, astrocyte over-activation has also been suggested to contribute to HD cognitive deficits. Fingolimod (FTY720), a modulator of sphingosine-1 phosphate (S1P) receptors, has been shown to increase BDNF levels and to reduce astrogliosis, proving its potential to regulate trophic support and inflammatory response. In this view, we have investigated whether FTY720 improves synaptic plasticity and memory in the R6/1 mouse model of HD, through regulation of BDNF signaling and astroglial reactivity. Chronic administration of FTY720 from pre-symptomatic stages ameliorated long-term memory deficits and dendritic spine loss in CA1 hippocampal neurons from R6/1 mice. Furthermore, FTY720 delivery prevented astrogliosis and over-activation of nuclear factor kappa beta (NF-kappaB) signaling in the R6/1 hippocampus, reducing tumor necrosis factor alpha (TNFalpha) and induced nitric oxide synthase (iNOS) levels. TNFalpha decrease correlated with the normalization of p75(NTR) expression in the hippocampus of FTY720-treated R6/1 mice, thus preventing p75(NTR)/TrkB imbalance. In addition, FTY720 increased cAMP levels and promoted phosphorylation of CREB and RhoA in the hippocampus of R6/1 mice, further supporting its role in the enhancement of synaptic plasticity. Our findings provide new insights into the mechanism of action of FTY720 and reveal a novel therapeutic strategy to treat memory deficits in HD. PMID- 26063762 TI - Randomized Trial of the Effect of Pharmacist Prescribing on Improving Blood Pressure in the Community: The Alberta Clinical Trial in Optimizing Hypertension (RxACTION). AB - BACKGROUND: Hypertension control rates remain suboptimal. Pharmacists' scope of practice is evolving, and their position in the community may be ideal for improving hypertension care. We aimed to study the impact of pharmacist prescribing on blood pressure (BP) control in community-dwelling patients. METHODS AND RESULTS: We designed a patient-level, randomized, controlled trial, enrolling adults with above-target BP (as defined by Canadian guidelines) through community pharmacies, hospitals, or primary care teams in 23 communities in Alberta. Intervention group patients received an assessment of BP and cardiovascular risk, education on hypertension, prescribing of antihypertensive medications, laboratory monitoring, and monthly follow-up visits for 6 months (all by their pharmacist). Control group patients received a wallet card for BP recording, written hypertension information, and usual care from their pharmacist and physician. Primary outcome was the change in systolic BP at 6 months. A total of 248 patients (mean age, 64 years; 49% male) were enrolled. Baseline mean+/-SD systolic/diastolic BP was 150+/-14/84+/-11 mm Hg. The intervention group had a mean+/-SE reduction in systolic BP at 6 months of 18.3+/-1.2 compared with 11.8+/ 1.9 mm Hg in the control group, an adjusted difference of 6.6+/-1.9 mm Hg (P=0.0006). The adjusted odds of patients achieving BP targets was 2.32 (95% confidence interval, 1.17-4.15 in favor of the intervention). CONCLUSIONS: Pharmacist prescribing for patients with hypertension resulted in a clinically important and statistically significant reduction in BP. Policy makers should consider an expanded role for pharmacists, including prescribing, to address the burden of hypertension. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00878566. PMID- 26063763 TI - Community Pharmacy and Blood Pressure Control. PMID- 26063765 TI - Efficacy and Tolerability of a GD2-Directed Trifunctional Bispecific Antibody in a Preclinical Model: Subcutaneous Administration Is Superior to Intravenous Delivery. AB - Trifunctional bispecific antibodies (trAb) are novel anticancer drugs that recruit and activate different types of immune effector cells at the targeted tumor. Thus, tumor cells are effectively eliminated and a long-lasting tumor specific T-cell memory is induced. The trAb Ektomab is directed against human CD3 on T cells and the tumor-associated ganglioside GD2, which is an attractive target for immunotherapy of melanoma in humans. To optimize clinical applicability, we studied different application routes with respect to therapeutic efficacy and tolerability by using the surrogate trAb Surek (anti-GD2 * anti-murine CD3) and a murine melanoma engineered to express GD2. We show that subcutaneous injection of the trAb is superior to the intravenous delivery pathway, which is the standard application route for therapeutic antibodies. Despite lower plasma levels after subcutaneous administration, the same tumor protective potential was observed in vivo compared with intravenous administration of Surek. However, subcutaneously delivered Surek showed better tolerability. This could be explained by a continuous release of the antibody leading to constant plasma levels and a delayed induction of proinflammatory cytokines. Importantly, the induction of counter-regulatory mechanisms was reduced after subcutaneous application. These findings are relevant for the clinical application of trifunctional bispecific antibodies and, possibly, also other immunoglobulin constructs. Mol Cancer Ther; 14(8); 1877-83. (c)2015 AACR. PMID- 26063764 TI - Pilot Trial of Selecting Molecularly Guided Therapy for Patients with Non-V600 BRAF-Mutant Metastatic Melanoma: Experience of the SU2C/MRA Melanoma Dream Team. AB - Targeted therapies and immunotherapies have led to significant improvements in the treatment of advanced cancers, including metastatic melanoma. However, new strategies are desperately needed to overcome therapeutic resistance to these agents, as well as to identify effective treatment approaches for cancer patients that fall outside major targetable mutational subtypes (e.g., non-V600 BRAF melanoma). One such strategy is to extend the paradigm of individually tailored, molecularly targeted therapy into a broader spectrum of melanoma patients, particularly those bearing tumors without commonly recognized therapeutic targets, as well as having failed or were ineligible for immunotherapy. In this nontreatment pilot study, next-generation sequencing (NGS) technologies were utilized, including whole genome and whole transcriptome sequencing, to identify molecular aberrations in patients with non-V600 BRAF metastatic melanoma. This information was then rationally matched to an appropriate clinical treatment from a defined pharmacopeia. Five patients with advanced non-V600 BRAF metastatic melanoma were enrolled. We demonstrated successful performance of the following during a clinically relevant time period: patient tumor biopsy, quality DNA/RNA extraction, DNA/RNA-based sequencing for gene expression analysis, analysis utilizing a series of data integration methodologies, report generation, and tumor board review with formulated treatment plan. Streamlining measures were conducted based on the experiences of enrolling, collecting specimens, and analyzing the molecular signatures of patients. We demonstrated the feasibility of using NGS to identify molecular aberrations and generate an individualized treatment plan in this patient population. A randomized treatment study utilizing lessons learned from the conduct of this pilot study is currently underway. PMID- 26063766 TI - Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin. AB - Glucosylceramide synthase (GCS) overexpression is associated with multidrug resistance in several human cancers. GCS blockade, which overcomes multidrug resistance by downregulating P-glycoprotein (P-gp), has not been tested in head and neck cancer (HNC). This study investigates whether GCS is targetable in HNC by assessing whether GCS inhibition sensitizes HNC to cisplatin. The effect of genetic or pharmacologic GCS inhibition (using GCS siRNA/shRNA or d,l-threo-PPMP, respectively) on cisplatin sensitivity was assessed in several human HNC cells and acquired cisplatin-resistant HNC cells by measuring cell viability, cell cycle, death, mRNA and protein expression, ceramide production, and in preclinical tumor xenograft mouse models. GCS and P-gp expression were significantly associated with cisplatin resistance in several HNC cell lines (P = 0.007). Both were significantly increased in HN9-cisR cells, which display acquired cisplatin resistance (P < 0.001). Genetic or pharmacologic inhibition of GCS induced accumulation of increased ceramide levels. GCS inhibition increased cisplatin-induced cell death in HNC cells via P-gp downregulation and proapoptotic protein activation, which were abrogated by siPUMA transfection. Genetic and pharmacologic GCS inhibition sensitized resistant HNC cells to cisplatin in vitro and in vivo. GCS and P-gp overexpression is associated with acquired cisplatin resistance, suggesting a role for these molecules as therapeutic targets for HNC. Genetic or pharmacologic GCS blockade may have therapeutic benefit in cisplatin-resistant HNC. PMID- 26063767 TI - Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism. AB - Because radiotherapy significantly increases median survival in patients with glioblastoma, the modulation of radiation resistance is of significant interest. High glycolytic states of tumor cells are known to correlate strongly with radioresistance; thus, the concept of metabolic targeting needs to be investigated in combination with radiotherapy. Metabolically, the elevated glycolysis in glioblastoma cells was observed postradiotherapy together with upregulated hypoxia-inducible factor (HIF)-1alpha and its target pyruvate dehydrogenase kinase 1 (PDK1). Dichloroacetate, a PDK inhibitor currently being used to treat lactic acidosis, can modify tumor metabolism by activating mitochondrial activity to force glycolytic tumor cells into oxidative phosphorylation. Dichloroacetate alone demonstrated modest antitumor effects in both in vitro and in vivo models of glioblastoma and has the ability to reverse the radiotherapy-induced glycolytic shift when given in combination. In vitro, an enhanced inhibition of clonogenicity of a panel of glioblastoma cells was observed when dichloroacetate was combined with radiotherapy. Further mechanistic investigation revealed that dichloroacetate sensitized glioblastoma cells to radiotherapy by inducing the cell-cycle arrest at the G2-M phase, reducing mitochondrial reserve capacity, and increasing the oxidative stress as well as DNA damage in glioblastoma cells together with radiotherapy. In vivo, the combinatorial treatment of dichloroacetate and radiotherapy improved the survival of orthotopic glioblastoma-bearing mice. In conclusion, this study provides the proof of concept that dichloroacetate can effectively sensitize glioblastoma cells to radiotherapy by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of dichloroacetate and radiotherapy in clinical trials. PMID- 26063768 TI - The association between marine n-3 polyunsaturated fatty acid levels and survival after renal transplantation. AB - BACKGROUND AND OBJECTIVES: Several studies have reported beneficial cardiovascular effects of marine n-3 polyunsaturated fatty acids. To date, no large studies have investigated the potential benefits of marine n-3 polyunsaturated fatty acids in recipients of renal transplants. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this observational cohort study of 1990 Norwegian recipients of renal transplants transplanted between 1999 and 2011, associations between marine n-3 polyunsaturated fatty acid levels and mortality were investigated by stratified analysis and multivariable Cox proportional hazard regression analysis adjusting for traditional and transplant-specific mortality risk factors. Marine n-3 polyunsaturated fatty acid levels in plasma phospholipids were measured by gas chromatography in a stable phase 10 weeks after transplantation. RESULTS: There were 406 deaths (20.4%) during a median follow-up period of 6.8 years. Mortality rates were lower in patients with high marine n-3 polyunsaturated fatty acid levels (>=7.95 weight percentage) compared with low levels (<7.95 weight percentage) for all age categories (pooled mortality rate ratio estimate, 0.69; 95% confidence interval, 0.57 to 0.85). When divided into quartiles according to marine n-3 polyunsaturated fatty acid levels, patients in the upper quartile compared with the lower quartile had a 56% lower risk of death (adjusted hazard ratio, 0.44; 95% confidence interval, 0.26 to 0.75) using multivariable Cox proportional hazard regression analysis. There was a lower hazard ratio for death from cardiovascular disease with high levels of marine n-3 polyunsaturated fatty acid and a lower hazard ratio for death from infectious disease with high levels of the marine n-3 polyunsaturated fatty acid eicosapentaenoic acid, whereas there was no association between total or individual marine n-3 polyunsaturated fatty acid levels and cancer mortality. CONCLUSIONS: Higher plasma phospholipid marine n-3 polyunsaturated fatty acid levels were independently associated with better patient survival. PMID- 26063769 TI - Task-dependent modification of leg motor neuron synaptic input underlying changes in walking direction and walking speed. AB - Animals modify their behavior constantly to perform adequately in their environment. In terrestrial locomotion many forms of adaptation exist. Two tasks are changes of walking direction and walking speed. We investigated these two changes in motor output in the stick insect Cuniculina impigra to see how they are brought about at the level of leg motor neurons. We used a semi-intact preparation in which we can record intracellularly from leg motor neurons during walking. In this single-leg preparation the middle leg of the animal steps in a vertical plane on a treadwheel. Stimulation of either abdomen or head reliably elicits fictive forward or backward motor activity, respectively, in the fixed and otherwise deafferented thorax-coxa joint. With a change of walking direction only thorax-coxa-joint motor neurons protractor and retractor changed their activity. The protractor switched from swing activity during forward to stance activity during backward walking, and the retractor from stance to swing. This phase switch was due to corresponding change of phasic synaptic inputs from inhibitory to excitatory and vice versa at specific phases of the step cycle. In addition to phasic synaptic input a tonic depolarization of the motor neurons was present. Analysis of changes in stepping velocity during stance showed only a significant correlation to flexor motor neuron activity, but not to that of retractor and depressor motor neurons during forward walking. These results show that different tasks in the stick insect walking system are generated by altering synaptic inputs to specific leg joint motor neurons only. PMID- 26063770 TI - Linking express saccade occurance to stimulus properties and sensorimotor integration in the superior colliculus. AB - Express saccades represent the fastest possible eye movements to visual targets with reaction times that approach minimum sensory-motor conduction delays. Previous work in monkeys has identified two specific neural signals in the superior colliculus (SC: a midbrain sensorimotor integration structure involved in gaze control) that are required to execute express saccades: 1) previsual activity consisting of a low-frequency increase in action potentials in sensory motor neurons immediately before the arrival of a visual response; and 2) a transient visual-sensory response consisting of a high-frequency burst of action potentials in visually responsive neurons resulting from the appearance of a visual target stimulus. To better understand how these two neural signals interact to produce express saccades, we manipulated the arrival time and magnitude of visual responses in the SC by altering target luminance and we examined the corresponding influences on SC activity and express saccade generation. We recorded from saccade neurons with visual-, motor-, and previsual related activity in the SC of monkeys performing the gap saccade task while target luminance was systematically varied between 0.001 and 42.5 cd/m(2) against a black background (~0.0001 cd/m(2)). Our results demonstrated that 1) express saccade latencies were linked directly to the arrival time in the SC of visual responses produced by abruptly appearing visual stimuli; 2) express saccades were generated toward both dim and bright targets whenever sufficient previsual activity was present; and 3) target luminance altered the likelihood of producing an express saccade. When an express saccade was generated, visuomotor neurons increased their activity immediately before the arrival of the visual response in the SC and saccade initiation. Furthermore, the visual and motor responses of visuomotor neurons merged into a single burst of action potentials, while the visual response of visual-only neurons was unaffected. A linear combination model was used to test which SC signals best predicted the likelihood of producing an express saccade. In addition to visual response magnitude and previsual activity of saccade neurons, the model identified presaccadic activity (activity occurring during the 30-ms epoch immediately before saccade initiation) as a third important signal for predicting express saccades. We conclude that express saccades can be predicted by visual, previsual, and presaccadic signals recorded from visuomotor neurons in the intermediate layers of the SC. PMID- 26063771 TI - Enhanced astroglial GABA uptake attenuates tonic GABAA inhibition of the presympathetic hypothalamic paraventricular nucleus neurons in heart failure. AB - gamma-Aminobutyric acid (GABA) generates persistent tonic inhibitory currents (Itonic) and conventional inhibitory postsynaptic currents in the hypothalamic paraventricular nucleus (PVN) via activation of GABAA receptors (GABAARs). We investigated the pathophysiological significance of astroglial GABA uptake in the regulation of Itonic in the PVN neurons projecting to the rostral ventrolateral medulla (PVN-RVLM). The Itonic of PVN-RVLM neurons were significantly reduced in heart failure (HF) compared with sham-operated (SHAM) rats. Reduced Itonic sensitivity to THIP argued for the decreased function of GABAAR delta subunits in HF, whereas similar Itonic sensitivity to benzodiazepines argued against the difference of gamma2 subunit-containing GABAARs in SHAM and HF rats. HF Itonic attenuation was reversed by a nonselective GABA transporter (GAT) blocker (nipecotic acid, NPA) and a GAT-3 selective blocker, but not by a GAT-1 blocker, suggesting that astroglial GABA clearance increased in HF. Similar and minimal Itonic responses to bestrophin-1 blockade in SHAM and HF neurons further argued against a role for astroglial GABA release in HF Itonic attenuation. Finally, the NPA-induced inhibition of spontaneous firing was greater in HF than in SHAM PVN RVLM neurons, whereas diazepam induced less inhibition of spontaneous firing in HF than in SHAM neurons. Overall, our results showed that combined with reduced GABAARs function, the enhanced astroglial GABA uptake-induced attenuation of Itonic in HF PVN-RVLM neurons explains the deficit in tonic GABAergic inhibition and increased sympathetic outflow from the PVN during heart failure. PMID- 26063772 TI - Dynamic sound localization in cats. AB - Sound localization in cats and humans relies on head-centered acoustic cues. Studies have shown that humans are able to localize sounds during rapid head movements that are directed toward the target or other objects of interest. We studied whether cats are able to utilize similar dynamic acoustic cues to localize acoustic targets delivered during rapid eye-head gaze shifts. We trained cats with visual-auditory two-step tasks in which we presented a brief sound burst during saccadic eye-head gaze shifts toward a prior visual target. No consistent or significant differences in accuracy or precision were found between this dynamic task (2-step saccade) and the comparable static task (single saccade when the head is stable) in either horizontal or vertical direction. Cats appear to be able to process dynamic auditory cues and execute complex motor adjustments to accurately localize auditory targets during rapid eye-head gaze shifts. PMID- 26063773 TI - Prediction strength modulates responses in human area CA1 to sequence violations. AB - Emerging human, animal, and computational evidence suggest that, within the hippocampus, stored memories are compared with current sensory input to compute novelty, i.e., detecting when inputs deviate from expectations. Hippocampal subfield CA1 is thought to detect mismatches between past and present, and detected novelty is thought to modulate encoding processes, providing a mechanism for gating the entry of information into memory. Using high-resolution functional MRI, we examined human hippocampal subfield and medial temporal lobe cortical activation during prediction violations within a sequence of events unfolding over time. Subjects encountered sequences of four visual stimuli that were then reencountered in the same temporal order (Repeat) or a rearranged order (Violation). Prediction strength was manipulated by varying whether the sequence was initially presented once (Weak) or thrice (Strong) prior to the critical Repeat or Violation sequence. Analyses of blood oxygen level-dependent signals revealed that task-responsive voxels in anatomically defined CA1, CA23/dentate gyrus, and perirhinal cortex were more active when expectations were violated than when confirmed. Additionally, stronger prediction violations elicited greater activity than weaker violations in CA1, and CA1 contained the greatest proportion of voxels displaying this prediction violation pattern relative to other medial temporal lobe regions. Finally, a memory test with a separate group of subjects showed that subsequent recognition memory was superior for items that had appeared in prediction violation trials than in prediction confirmation trials. These findings indicate that CA1 responds to temporal order prediction violations, and that this response is modulated by prediction strength. PMID- 26063774 TI - Spatial specificity and inheritance of adaptation in human visual cortex. AB - Adaptation at early stages of sensory processing can be propagated to downstream areas. Such inherited adaptation is a potential confound for functional magnetic resonance imaging (fMRI) techniques that use selectivity of adaptation to infer neuronal selectivity. However, the relative contributions of inherited and intrinsic adaptation at higher cortical stages, and the impact of inherited adaptation on downstream processing, remain unclear. Using fMRI, we investigated how adaptation to visual motion direction and orientation influences visually evoked responses in human V1 and extrastriate visual areas. To dissociate inherited from intrinsic adaptation, we quantified the spatial specificity of adaptation for each visual area as a measure of the receptive field sizes of the area where adaptation originated, predicting that adaptation originating in V1 should be more spatially specific than adaptation intrinsic to extrastriate visual cortex. In most extrastriate visual areas, the spatial specificity of adaptation did not differ from that in V1, suggesting that adaptation originated in V1. Only in one extrastriate area-MT-was the spatial specificity of direction selective adaptation significantly broader than in V1, consistent with a combination of inherited V1 adaptation and intrinsic MT adaptation. Moreover, inherited adaptation effects could be both facilitatory and suppressive. These results suggest that adaptation at early visual processing stages can have widespread and profound effects on responses in extrastriate visual areas, placing important constraints on the use of fMRI adaptation techniques, while also demonstrating a general experimental strategy for systematically dissociating inherited from intrinsic adaptation by fMRI. PMID- 26063775 TI - The effect of crossed reflex responses on dynamic stability during locomotion. AB - In recent studies, we demonstrated that a neural pathway within the human spinal cord allows direct communication between muscles located in the opposing limb. Short-latency crossed responses (SLCRs) are elicited in the contralateral triceps surae at an onset of 40-69 ms following electrical stimulation of the ipsilateral tibial nerve (iTN). The SLCRs are significantly affected by lesions of the central nervous system where the patients are unable to attain normal walking symmetry. The aim of this study was to elucidate the functionality of SLCRs by investigating their effects on the center of pressure (CoP) and pressure distribution. SLCRs were elicited by iTN stimulation at the end of the ipsilateral swing phase while the participants (n = 8) walked on a treadmill. CoP location and pressure distribution on the sole of the contralateral foot were recorded using instrumented insoles inserted bilaterally in the participant's shoes. The SLCR induced a significant displacement of the CoP toward the medial and anterior direction, associated with a significant increase in pressure at the level of the first metatarsal head. The SLCR contributed to dynamic stability, accelerating the propulsion phase of the contralateral leg and thus preparing for a faster step in the event that the ipsilateral leg is not able to support body weight. The results presented here provide new insight into the functionality of SLCRs, introducing the perspective that training these reflexes, as shown successfully for other reflex pathways, would increase dynamic stability in patients with impaired locomotion. PMID- 26063776 TI - A neuro-computational model of economic decisions. AB - Neuronal recordings and lesion studies indicate that key aspects of economic decisions take place in the orbitofrontal cortex (OFC). Previous work identified in this area three groups of neurons encoding the offer value, the chosen value, and the identity of the chosen good. An important and open question is whether and how decisions could emerge from a neural circuit formed by these three populations. Here we adapted a biophysically realistic neural network previously proposed for perceptual decisions (Wang XJ. Neuron 36: 955-968, 2002; Wong KF, Wang XJ. J Neurosci 26: 1314-1328, 2006). The domain of economic decisions is significantly broader than that for which the model was originally designed, yet the model performed remarkably well. The input and output nodes of the network were naturally mapped onto two groups of cells in OFC. Surprisingly, the activity of interneurons in the network closely resembled that of the third group of cells, namely, chosen value cells. The model reproduced several phenomena related to the neuronal origins of choice variability. It also generated testable predictions on the excitatory/inhibitory nature of different neuronal populations and on their connectivity. Some aspects of the empirical data were not reproduced, but simple extensions of the model could overcome these limitations. These results render a biologically credible model for the neuronal mechanisms of economic decisions. They demonstrate that choices could emerge from the activity of cells in the OFC, suggesting that chosen value cells directly participate in the decision process. Importantly, Wang's model provides a platform to investigate the implications of neuroscience results for economic theory. PMID- 26063777 TI - Cross-species comparison of anticipatory and stimulus-driven neck muscle activity well before saccadic gaze shifts in humans and nonhuman primates. AB - Recent studies have described a phenomenon wherein the onset of a peripheral visual stimulus elicits short-latency (<100 ms) stimulus-locked recruitment (SLR) of neck muscles in nonhuman primates (NHPs), well before any saccadic gaze shift. The SLR is thought to arise from visual responses within the intermediate layers of the superior colliculus (SCi), hence neck muscle recordings may reflect presaccadic activity within the SCi, even in humans. We obtained bilateral intramuscular recordings from splenius capitis (SPL, an ipsilateral head-turning muscle) from 28 human subjects performing leftward or rightward visually guided eye-head gaze shifts. Evidence of an SLR was obtained in 16/55 (29%) of samples; we also observed examples where the SLR was present only unilaterally. We compared these human results with those recorded from a sample of eight NHPs from which recordings of both SPL and deeper suboccipital muscles were available. Using the same criteria, evidence of an SLR was obtained in 8/14 (57%) of SPL recordings, but in 26/29 (90%) of recordings from suboccipital muscles. Thus, both species-specific and muscle-specific factors contribute to the low SLR prevalence in human SPL. Regardless of the presence of the SLR, neck muscle activity in both human SPL and in NHPs became predictive of the reaction time of the ensuing saccade gaze shift ~70 ms after target appearance; such pregaze recruitment likely reflects developing SCi activity, even if the tectoreticulospinal pathway does not reliably relay visually related activity to SPL in humans. PMID- 26063778 TI - Abnormal tuning of saccade-related cells in pontine reticular formation of strabismic monkeys. AB - Strabismus is a common disorder, characterized by a chronic misalignment of the eyes and numerous visual and oculomotor abnormalities. For example, saccades are often highly disconjugate. For humans with pattern strabismus, the horizontal and vertical disconjugacies vary with eye position. In monkeys, manipulations that disturb binocular vision during the first several weeks of life result in a chronic strabismus with characteristics that closely match those in human patients. Early onset strabismus is associated with altered binocular sensitivity of neurons in visual cortex. Here we test the hypothesis that brain stem circuits specific to saccadic eye movements are abnormal. We targeted the pontine paramedian reticular formation, a structure that directly projects to the ipsilateral abducens nucleus. In normal animals, neurons in this structure are characterized by a high-frequency burst of spikes associated with ipsiversive saccades. We recorded single-unit activity from 84 neurons from four monkeys (two normal, one exotrope, and one esotrope), while they made saccades to a visual target on a tangent screen. All 24 neurons recorded from the normal animals had preferred directions within 30 degrees of pure horizontal. For the strabismic animals, the distribution of preferred directions was normal on one side of the brain, but highly variable on the other. In fact, 12/60 neurons recorded from the strabismic animals preferred vertical saccades. Many also had unusually weak or strong bursts. These data suggest that the loss of corresponding binocular vision during infancy impairs the development of normal tuning characteristics for saccade-related neurons in brain stem. PMID- 26063779 TI - Impaired cerebral autoregulation and brain injury in newborns with hypoxic ischemic encephalopathy treated with hypothermia. AB - Impaired cerebral autoregulation may contribute to secondary injury in newborns with hypoxic-ischemic encephalopathy (HIE). Continuous, noninvasive assessment of cerebral pressure autoregulation can be achieved with bedside near-infrared spectroscopy (NIRS) and systemic mean arterial blood pressure (MAP) monitoring. This study aimed to evaluate whether impaired cerebral autoregulation measured by NIRS-MAP monitoring during therapeutic hypothermia and rewarming relates to outcome in 36 newborns with HIE. Spectral coherence analysis between NIRS and MAP was used to quantify changes in the duration [pressure passivity index (PPI)] and magnitude (gain) of cerebral autoregulatory impairment. Higher PPI in both cerebral hemispheres and gain in the right hemisphere were associated with neonatal adverse outcomes [death or detectable brain injury by magnetic resonance imaging (MRI), P < 0.001]. NIRS-MAP monitoring of cerebral autoregulation can provide an ongoing physiological biomarker that may help direct care in perinatal brain injury. PMID- 26063780 TI - Hypothalamic gonadotropin-releasing hormone (GnRH) receptor neurons fire in synchrony with the female reproductive cycle. AB - Gonadotropin-releasing hormone (GnRH) controls mammalian reproduction via the hypothalamic-pituitary-gonadal (hpg) axis, acting on gonadotrope cells in the pituitary gland that express the GnRH receptor (GnRHR). Cells expressing the GnRHR have also been identified in the brain. However, the mechanism by which GnRH acts on these potential target cells remains poorly understood due to the difficulty of visualizing and identifying living GnRHR neurons in the central nervous system. We have developed a mouse strain in which GnRHR neurons express a fluorescent marker, enabling the reliable identification of these cells independent of the hormonal status of the animal. In this study, we analyze the GnRHR neurons of the periventricular hypothalamic nucleus in acute brain slices prepared from adult female mice. Strikingly, we find that the action potential firing pattern of these neurons alternates in synchrony with the estrous cycle, with pronounced burst firing during the preovulatory period. We demonstrate that GnRH stimulation is sufficient to trigger the conversion from tonic to burst firing in GnRHR neurons. Furthermore, we show that this switch in the firing pattern is reversed by a potent GnRHR antagonist. These data suggest that endogenous GnRH acts on GnRHR neurons and triggers burst firing in these cells during late proestrus and estrus. Our data have important clinical implications in that they indicate a novel mode of action for GnRHR agonists and antagonists in neurons of the central nervous system that are not part of the classical hpg axis. PMID- 26063781 TI - Formation of a long-term memory for visuomotor adaptation following only a few trials of practice. AB - The term savings refers to faster motor adaptation upon reexposure to a previously experienced perturbation, a phenomenon thought to reflect the existence of a long-term motor memory. It is commonly assumed that sustained practice during the first perturbation exposure is necessary to create this memory. Here we sought to test this assumption by determining the minimum amount of experience necessary during initial adaptation to a visuomotor rotation to bring about savings the following day. Four groups of human subjects experienced 2, 5, 10, or 40 trials of a counterclockwise 30 degrees cursor rotation during reaching movements on one day and were retested the following day to assay for savings. Groups that experienced five trials or more of adaptation on day 1 showed clear savings on day 2. Subjects in all groups learned significantly more from the first rotation trial on day 2 than on day 1, but this learning rate advantage was maintained only in groups that had reached asymptote during the initial exposure. Additional experiments revealed that savings occurred when the magnitude, but not the direction, of the rotation differed across exposures, and when a 5-min break, rather than an overnight one, separated the first and second exposure. The overall pattern of savings we observe across conditions can be explained as rapid retrieval of the state of learning attained during the first exposure rather than as modulation of sensitivity to error. We conclude that a long-term memory for compensating for a perturbation can be rapidly acquired and rapidly retrieved. PMID- 26063782 TI - Inhibitory input to the direction-selective ganglion cell is saturated at low contrast. AB - Direction-selective ganglion cells (DSGCs) respond selectively to motion toward a "preferred" direction, but much less to motion toward the opposite "null" direction. Directional signals in the DSGC depend on GABAergic inhibition and are observed over a wide range of speeds, which precludes motion detection based on a fixed temporal correlation. A voltage-clamp analysis, using narrow bar stimuli similar in width to the receptive field center, demonstrated that inhibition to DSGCs saturates rapidly above a threshold contrast. However, for wide bar stimuli that activate both the center and surround, inhibition depends more linearly on contrast. Excitation for both wide and narrow bars was also more linear. We propose that positive feedback, likely within the starburst amacrine cell or its network, produces steep saturation of inhibition at relatively low contrast. This mechanism renders GABA release essentially contrast and speed invariant, which enhances directional signals for small objects and thereby increases the signal to-noise ratio for direction-selective signals in the spike train over a wide range of stimulus conditions. The steep saturation of inhibition confers to a neuron immunity to noise in its spike train, because when inhibition is strong no spikes are initiated. PMID- 26063784 TI - Cortical specificity in neurovascular coupling. AB - Despite mounting contrary evidence, the metabolic hypothesis is viewed as the predominant theory underlying neurovascular coupling, or the link between neural activity and cerebral blood flow. In a recent study, Huo et al. (Huo BX, Smith JB, Drew PJ. J Neurosci 34: 10975-10981, 2014) combined multimodal imaging and electrophysiology in experiments using awake, voluntarily moving mice to explore whether neurovascular coupling is uniform throughout the cortex. Whereas their results can be viewed as demonstrating that neural activity and blood flow are uncoupled in the frontal cortex during movement, the importance of this study is the elucidation that the metabolic hypothesis may not be the principle facilitator of neurovascular coupling in some regions of the cortex. PMID- 26063783 TI - Understanding the mechanisms through which spatial attention acts on nociception. AB - Previous studies have shown that spatial attention can influence the magnitude of brain responses to nociceptive inputs. In their recent article (Franz M, Nickel MM, Ritter A, Miltner WH, Weiss T. J Neurophysiol 113: 2760-2768, 2015), Franz and colleagues expand this observation by showing that spatial attention is further able to modify the chronometry of nociceptive processing by modulating the latency and temporal jitter of the recorded responses. The mechanisms through which attention could possibly modulate nociceptive processing are discussed here, with a particular focus on novel findings and future perspectives. PMID- 26063785 TI - Cell dialysis by sharp electrodes can cause nonphysiological changes in neuron properties. AB - We recorded from lobster and leech neurons with two sharp electrodes filled with solutions often used with these preparations (lobster: 0.6 M K2SO4 or 2.5 M KAc; leech: 4 M KAc), with solutions approximately matching neuron cytoplasm ion concentrations, and with 6.5 M KAc (lobster, leech) and 0.6 M KAc (lobster). We measured membrane potential, input resistance, and transient and sustained depolarization-activated outward current amplitudes in leech and these neuron properties and hyperpolarization-activated current time constant in lobster, every 10 min for 60 min after electrode penetration. Neuron properties varied with electrode fill. For fills with molarities >=2.5 M, neuron properties also varied strongly with time after electrode penetration. Depending on the property being examined, these variations could be large. In leech, cell size also increased with noncytoplasmic fills. The changes in neuron properties could be due to the ions being injected from the electrodes during current injection. We tested this possibility in lobster with the 2.5 M KAc electrode fill by making measurements only 10 and 60 min after penetration. Neuron properties still changed, although the changes were less extreme. Making measurements every 2 min showed that the time-dependent variations in neuron properties occurred in concert with each other. Neuron property changes with high molarity electrode fill solutions were great enough to decrease neuron firing strongly. An experiment with (14)C-glucose electrode fill confirmed earlier work showing substantial leak from sharp electrodes. Sharp electrode work should thus be performed with cytoplasm-matched electrode fills. PMID- 26063787 TI - Icodextrin reduces insulin resistance in non-diabetic patients undergoing automated peritoneal dialysis: results of a randomized controlled trial (STARCH). AB - BACKGROUND: Insulin resistance is a common risk factor in chronic kidney disease patients contributing to the high cardiovascular burden, even in the absence of diabetes. Glucose-based peritoneal dialysis (PD) solutions are thought to intensify insulin resistance due to the continuous glucose absorption from the peritoneal cavity. The aim of our study was to analyse the effect of the substitution of glucose for icodextrin on insulin resistance in non-diabetic PD patients in a multicentric randomized clinical trial. METHODS: This was a multicenter, open-label study with balanced randomization (1:1) and two parallel groups. Inclusion criteria were non-diabetic adult patients on automated peritoneal dialysis (APD) for at least 3 months on therapy prior to randomization. Patients assigned to the intervention group were treated with 2L of icodextrin 7.5%, and the control group with glucose 2.5% during the long dwell and, at night in the cycler, with a prescription of standard glucose-based PD solution only in both groups. The primary end-point was the change in insulin resistance measured by homeostatic model assessment (HOMA) index at 90 days. RESULTS: Sixty patients were included in the intervention (n = 33) or the control (n = 27) groups. There was no difference between groups at baseline. After adjustment for pre-intervention HOMA index levels, the group treated with icodextrin had the lower post-intervention levels at 90 days in both intention to treat [1.49 (95% CI: 1.23-1.74) versus 1.89 (95% CI: 1.62-2.17)], (F = 4.643, P = 0.03, partial eta(2) = 0.078); and the treated analysis [1.47 (95% CI: 1.01-1.84) versus 2.18 (95% CI: 1.81-2.55)], (F = 7.488, P = 0.01, partial eta(2) = 0.195). CONCLUSIONS: The substitution of glucose for icodextrin for the long dwell improved insulin resistance measured by HOMA index in non-diabetic APD patients. PMID- 26063788 TI - A 6-Week School Curriculum Improves Boys' Attitudes and Behaviors Related to Gender-Based Violence in Kenya. AB - This study investigated the effects of a gender-based violence (GBV) educational curriculum on improving male attitudes toward women and increasing the likelihood of intervention if witnessing GBV, among adolescent boys in Nairobi, Kenya. In total, 1,543 adolescents participated in this comparison intervention study: 1,250 boys received six 2-hr sessions of the "Your Moment of Truth" (YMOT) intervention, and 293 boys comprised the standard of care (SOC) group. Data on attitudes toward women were collected anonymously at baseline and 9 months after intervention. At follow-up, boys were also asked whether they encountered situations involving GBV and whether they successfully intervened. Compared with baseline, YMOT participants had significantly higher positive attitudes toward women at follow-up, whereas scores for SOC participants declined. At follow-up, the percentage of boys who witnessed GBV was similar for the two groups, except for physical threats, where the intervention group reported witnessing more episodes. The percentage of boys in the intervention group who successfully intervened when witnessing violence was 78% for verbal harassment, 75% for physical threat, and 74% for physical or sexual assault. The percentage of boys in the SOC group who successfully intervened was 38% for verbal harassment, 33% for physical threat, and 26% for physical or sexual assault. Results from the logistic regression demonstrate that more positive attitudes toward women predicted whether boys in the intervention group would intervene successfully when witnessing violence. This standardized 6-week GBV training program is highly effective in improving attitudes toward women and increasing the likelihood of successful intervention when witnessing GBV. PMID- 26063786 TI - Systems-level quantification of division timing reveals a common genetic architecture controlling asynchrony and fate asymmetry. AB - Coordination of cell division timing is crucial for proper cell fate specification and tissue growth. However, the differential regulation of cell division timing across or within cell types during metazoan development remains poorly understood. To elucidate the systems-level genetic architecture coordinating division timing, we performed a high-content screening for genes whose depletion produced a significant reduction in the asynchrony of division between sister cells (ADS) compared to that of wild-type during Caenorhabditis elegans embryogenesis. We quantified division timing using 3D time-lapse imaging followed by computer-aided lineage analysis. A total of 822 genes were selected for perturbation based on their conservation and known roles in development. Surprisingly, we find that cell fate determinants are not only essential for establishing fate asymmetry, but also are imperative for setting the ADS regardless of cellular context, indicating a common genetic architecture used by both cellular processes. The fate determinants demonstrate either coupled or separate regulation between the two processes. The temporal coordination appears to facilitate cell migration during fate specification or tissue growth. Our quantitative dataset with cellular resolution provides a resource for future analyses of the genetic control of spatial and temporal coordination during metazoan development. PMID- 26063789 TI - Characterizing Drug-Facilitated Sexual Assault Subtypes and Treatment Engagement of Victims at a Hospital-Based Rape Treatment Center. AB - Variation among existing studies in labeling, defining, identifying, and subtyping cases of suspected drug-facilitated sexual assault (DFSA) poses challenges to integrating research findings for public health purposes. This descriptive study addressed methodological issues of nomenclature and DFSA operational definitions to improve case identification and was designed to distinguish assault subtypes. We studied a 2-year ethnically diverse cohort of 390 patients who presented acutely to an urban rape treatment center (RTC). We abstracted data from RTC medical and mental health records via chart review. Assault incidence rates; engagement into medical, forensic, and mental health services; injury sustained; and weapon use were calculated separately for assault subtypes and compared. DFSA accounted for over half of the total sexual assault (SA) cases. Involuntary DFSA (in which an incapacitating substance was administered to victims without their knowledge or against their will) increased from 25% to 33% of cases over the 2-year period. DFSA victims presented sooner, and more often attended medical follow-up and psychotherapy than non-DFSA victims. Incidence rates indicated increasing risk for young males. These findings indicate that DFSA continues to be a growing and complex phenomenon and suggest that DFSA victims have greater service needs. The field would benefit from innovations to address symptomatology arising from this novel type of trauma and the unique risks and needs of male victims, as well as underscoring the ongoing need for DFSA-specific prevention efforts for both victims and perpetrators. PMID- 26063790 TI - Does Polyvictimization Affect Incarcerated and Non-Incarcerated Adult Women Differently? An Exploration Into Internalizing Problems. AB - In this study, we used data from life histories of 424 non-incarcerated ( n = 266) and incarcerated ( n = 158) women to examine the extent to which women are exposed to multiple forms of victimization, including child abuse, intimate partner violence, sexual assault, and traumatic life events. We assessed the effects of polyvictimization (e.g., multiple victimizations) on women's health related outcomes (e.g., attempted suicide, drug and alcohol problems) as well as whether the prevalence rates and effects of victimization were significantly different between the subsamples of women. Results indicate that incarcerated women experience significantly more victimization than non-incarcerated women, and while polyvictimization was associated with a higher likelihood of alcohol problems, drug problems, and attempted suicide among non-incarcerated women, it was only marginally associated with an increased likelihood of alcohol problems among incarcerated women. Finally, low levels of polyvictimization affected alcohol and drug problems among incarcerated and non-incarcerated women differently. PMID- 26063791 TI - Identification of a Novel Proto-oncogenic Network in Head and Neck Squamous Cell Carcinoma. AB - BACKGROUND: The developmental transcription factor Grainyhead-like 3 (GRHL3) plays a critical tumor suppressor role in the mammalian epidermis through direct regulation of PTEN and the PI3K/AKT/mTOR signaling pathway. GRHL3 is highly expressed in all tissues derived from the surface ectoderm, including the oral cavity, raising a question about its potential role in suppression of head and neck squamous cell carcinoma (HNSCC). METHODS: We explored the tumor suppressor role of Grhl3 in HNSCC using a conditional knockout (Grhl3 (?/-) /K14Cre (+) ) mouse line (n = 26) exposed to an oral chemical carcinogen. We defined the proto oncogenic pathway activated in the HNSCC derived from these mice and assessed it in primary human HNSCC samples, normal oral epithelial cell lines carrying shRNA to GRHL3, and human HNSCC cell lines. Data were analyzed with two-sided chi square and Student's t tests. RESULTS: Deletion of Grhl3 in oral epithelium in mice did not perturb PTEN/PI3K/AKT/mTOR signaling, but instead evoked loss of GSK3B expression, resulting in stabilization and accumulation of c-MYC and aggressive HNSCC. This molecular signature was also evident in a subset of primary human HNSCC and HNSCC cell lines. Loss of Gsk3b in mice, independent of Grhl3, predisposed to chemical-induced HNSCC. Restoration of GSK3B expression blocked proliferation of normal oral epithelial cell lines carrying shRNA to GRHL3 (cell no., Day 8: Scramble ctl, 616+/-21.8 x 10(3) vs GRHL3-kd, 1194+/-44 X 10(3), P < .001; GRHL3-kd vs GRHL3-kd + GSK3B, 800+/-98.84 X 10(3), P = .003) and human HNSCC cells. CONCLUSIONS: We defined a novel molecular signature in mammalian HNSCC, suggesting new treatment strategies targeting the GRHL3/GSK3B/c MYC proto-oncogenic network. PMID- 26063792 TI - Immune Regulation by Self-Recognition: Novel Possibilities for Anticancer Immunotherapy. AB - Circulating T cells that specifically target normal self-proteins expressed by regulatory immune cells were first described in patients with cancer, but can also be detected in healthy individuals. The adaptive immune system is distinguished for its ability to differentiate between self-antigens and foreign antigens. Thus, it was remarkable to discover T cells that apparently lacked tolerance to important self-proteins, eg, IDO, PD-L1, and FoxP3, expressed in regulatory immune cells. The ability of self-reactive T cells to react to and eliminate regulatory immune cells can influence general immune reactions. This suggests that they may be involved in immune homeostasis. It is here proposed that these T cells should be termed antiregulatory T cells (anti-Tregs). The role of anti-Tregs in immune-regulatory networks may be diverse. For example, pro inflammatory self-reactive T cells that react to regulatory immune cells may enhance local inflammation and inhibit local immune suppression. Further exploration is warranted to investigate their potential role under different malignant conditions and the therapeutic possibilities they possess. Utilizing anti-Tregs for anticancer immunotherapy implies the direct targeting of cancer cells in addition to regulatory immune cells. Anti-Tregs provide the immune system with yet another level of immune regulation and contradict the notion that immune cells involved in the adjustment of immune responses only act as suppressor cells. PMID- 26063793 TI - Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases. AB - BACKGROUND: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported. METHODS: Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9-12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided. RESULTS: Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm(2), 95% CI = 149 to 365 vessels/mm(2); bevacizumab group mean = 327 vessels/mm(2), 95% CI = 140 to 514 vessels/mm(2), P = .78). CONCLUSION: We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases. PMID- 26063795 TI - Successful treatment of a giant pediatric fusiform basilar trunk aneurysm with surpass flow diverter. AB - Fusiform aneurysms present a unique challenge to traditional microsurgical and endovascular treatment because of the lack of a discernible neck and the involvement of parent vessel. Flow diversion has increasingly become the treatment of choice for fusiform aneurysms in the anterior circulation, but its results in the posterior circulation are variable. We report successful treatment of a giant fusiform upper basilar trunk aneurysm with the Surpass flow diverter in an adolescent, and discuss the potential advantages of this emerging technology in the treatment of fusiform posterior circulation aneurysms. PMID- 26063794 TI - Estrogen Receptor Status and the Future Burden of Invasive and In Situ Breast Cancers in the United States. AB - BACKGROUND: No study has predicted the future incidence rate and annual burden (number) of new cases in the United States of invasive and in situ female breast cancers stratified by the estrogen receptor (ER) status. METHODS: We constructed forecasts for women age 30 to 84 years in 2011 through 2030 using cancer incidence data from the Surveillance, Epidemiology, and End Results Program, novel age-period-cohort forecasting models, and population projections from the US Census Bureau. RESULTS: The total number of new tumors (invasive plus in situ) is expected to rise from 283 000 in 2011 to 441 000 in 2030 (plausible range 353 500 to 466 700 cases). The proportion of all new case patients age 70 to 84 years is expected to increase from 24.3% to 34.8%, while the proportion ages 50 to 69 years is expected to decrease from 54.7% to 43.6%. The proportion of ER-positive invasive cancers is expected to remain nearly the same at 62.6%, whereas the proportion of ER-positive in situ cancers is expected to increase from 19.1% to 28.9%. The proportion of ER-negative cancers (invasive and in situ) is expected to decrease from 16.8% to 8.6%. CONCLUSIONS: Breast cancer overall will rise in the United States through 2030, especially for ER-positive in situ tumors among women age 70 to 84 years. In contrast, ER-negative invasive and in situ tumors will fall, for reasons that are not fully understood. These results highlight a need to optimize case management among older women, characterize the natural history of in situ cancers, and identify those factors responsible for declining ER-negative incidence. PMID- 26063796 TI - Ignoring floor and ceiling effects may underestimate the effect of carotid artery stenting on cognitive performance. AB - INTRODUCTION: Data on neuropsychological outcome after carotid artery stenting (CAS) remain inconsistent, furthermore cognitive outcome seems to be unpredictable in the individual case. Previous studies reporting improvement or decline might be due to ceiling and floor effects of the applied cognitive tests. We applied cognitive testing before and after CAS, avoiding the pitfall of ceiling and floor effects. METHODS: In our prospective database, we identified 72 patients free of clinical stroke with >=70% carotid artery stenosis, who were treated with CAS. They were administered a neurocognitive test battery before and 3 months after CAS to compare cognitive performance before and after CAS. To avoid ceiling and floor effects of test performances, we additionally analysed subgroups of patients without baseline floor and ceiling cognitive performance. RESULTS: Pre-interventional to post-interventional cognitive performance improved significantly in the subtests measuring verbal episodic memory; deterioration was observed in spatial memory. The subgroups of patients without baseline floor and ceiling cognitive performance improved in measures of global cognition, verbal episodic memory (patients with left-sided CAS) and divided attention (patients with right-sided CAS); we observed no significant effects in the other domains. CONCLUSIONS: Ignoring floor and ceiling effects may underestimate the impact of CAS on cognitive performance. PMID- 26063797 TI - A novel route of revascularization in basilar artery occlusion and review of the literature. AB - Ischemia of the basilar artery is one of the most devastating types of arterial occlusive disease. Despite treatment of basilar artery occlusions (BAO) with intravenous tissue plasminogen activator, antiplatelet agents, intra-arterial therapy or a combination, fatality rates remain high. Aggressive recanalization with mechanical thrombectomy is therefore often necessary to preserve life. When direct access to the basilar trunk is not possible, exploration of chronically occluded vessels through collaterals with angioplasty and stenting creates access for manual aspiration. We describe the first report of retrograde vertebral artery (VA) revascularization using thyrocervical collaterals for anterograde mechanical aspiration of a BAO followed by stenting of the chronically occluded VA origin. Our novel retrograde-anterograde approach resulted in resolution of the patient's clinical stroke syndrome. PMID- 26063798 TI - Supersaturation-limited and Unlimited Phase Transitions Compete to Produce the Pathway Complexity in Amyloid Fibrillation. AB - Although amyloid fibrils and amorphous aggregates are two types of aggregates formed by denatured proteins, their relationship currently remains unclear. We used beta2-microglobulin (beta2m), a protein responsible for dialysis-related amyloidosis, to clarify the mechanism by which proteins form either amyloid fibrils or amorphous aggregates. When ultrasonication was used to accelerate the spontaneous fibrillation of beta2m at pH 2.0, the effects observed depended on ultrasonic power; although stronger ultrasonic power effectively accelerated fibrillation, excessively strong ultrasonic power decreased the amount of fibrils formed, as monitored by thioflavin T fluorescence. An analysis of the products formed indicated that excessively strong ultrasonic power generated fibrillar aggregates that retained beta-structures but without high efficiency as seeds. On the other hand, when the spontaneous fibrillation of beta2m was induced at higher concentrations of NaCl at pH 2.0 with stirring, amorphous aggregates became more dominant than amyloid fibrils. These apparent complexities in fibrillation were explained comprehensively by a competitive mechanism in which supersaturation limited reactions competed with supersaturation-unlimited reactions. We link the kinetics of protein aggregation and a conformational phase diagram, in which supersaturation played important roles. PMID- 26063799 TI - Selective Sensitization of Zinc Finger Protein Oxidation by Reactive Oxygen Species through Arsenic Binding. AB - Cysteine oxidation induced by reactive oxygen species (ROS) on redox-sensitive targets such as zinc finger proteins plays a critical role in redox signaling and subsequent biological outcomes. We found that arsenic exposure led to oxidation of certain zinc finger proteins based on arsenic interaction with zinc finger motifs. Analysis of zinc finger proteins isolated from arsenic-exposed cells and zinc finger peptides by mass spectrometry demonstrated preferential oxidation of C3H1 and C4 zinc finger configurations. C2H2 zinc finger proteins that do not bind arsenic were not oxidized by arsenic-generated ROS in the cellular environment. The findings suggest that selectivity in arsenic binding to zinc fingers with three or more cysteines defines the target proteins for oxidation by ROS. This represents a novel mechanism of selective protein oxidation and demonstrates how an environmental factor may sensitize certain target proteins for oxidation, thus altering the oxidation profile and redox regulation. PMID- 26063800 TI - Promoters of Human Cosmc and T-synthase Genes Are Similar in Structure, Yet Different in Epigenetic Regulation. AB - The T-synthase (core 1 beta3-galactosyltransferase) and its molecular chaperone Cosmc regulate the biosynthesis of mucin type O-glycans on glycoproteins, and evidence suggests that both T-synthase and Cosmc are transcriptionally suppressed in several human diseases, although the transcriptional regulation of these two genes is not understood. Here, we characterized the promoters essential for human Cosmc and T-synthase transcription. The upstream regions of the genes lack a conventional TATA box but contain CpG islands, cCpG-I and cCpG-II for Cosmc and tCpG for T-synthase. Using luciferase reporter assays, site-directed mutagenesis, ChIP assays, and mithramycin A treatment, we identified the core promoters within cCpG-II and tCpG, which contain two binding sites for Kruppel-like transcription factors, including SP1/SP3, respectively. Methylome analysis of Tn4 B cells, which harbor a silenced Cosmc, confirmed the hypermethylation of the Cosmc core promoter but not for T-synthase. These results demonstrate that Cosmc and T synthase are transcriptionally regulated at a basal level by the specificity protein/Kruppel-like transcription factor family of members, which explains their ubiquitous and coordinated expression, and also indicate that they are differentially epigenetically regulated beyond X chromosome imprinting. These results are important in understanding the regulation of these genes that have roles in human diseases, such as IgA nephropathy and cancer. PMID- 26063801 TI - Repression of the Low Affinity Iron Transporter Gene FET4: A NOVEL MECHANISM AGAINST CADMIUM TOXICITY ORCHESTRATED BY YAP1 VIA ROX1. AB - Cadmium is a well known mutagenic metal that can enter cells via nonspecific metal transporters, causing several cellular damages and eventually leading to death. In the yeast Saccharomyces cerevisiae, the transcription factor Yap1 plays a key role in the regulation of several genes involved in metal stress response. We have previously shown that Yap1 represses the expression of FET4, a gene encoding a low affinity iron transporter able to transport metals other than iron. Here, we have studied the relevance of this repression in cell tolerance to cadmium. Our results indicate that genomic deletion of Yap1 increases FET4 transcript and protein levels. In addition, the cadmium toxicity exhibited by this strain is completely reversed by co-deletion of FET4 gene. These data correlate well with the increased intracellular levels of cadmium observed in the mutant yap1. Rox1, a well known aerobic repressor of hypoxic genes, conveys the Yap1-mediated repression of FET4. We further show that, in a scenario where the activity of Yap1 or Rox1 is compromised, cells activate post-transcriptional mechanisms, involving the exoribonuclease Xrn1, to compensate the derepression of FET4. Our data thus reveal a novel protection mechanism against cadmium toxicity mediated by Yap1 that relies on the aerobic repression of FET4 and results in the impairment of cadmium uptake. PMID- 26063802 TI - Tryptophan Scanning Mutagenesis Identifies the Molecular Determinants of Distinct Barttin Functions. AB - CLC-K chloride channels are expressed in the kidney and in the inner ear and require the accessory subunit barttin for proper function and membrane insertion. Barttin exerts multiple functions on CLC-proteins: it modifies protein stability and intracellular trafficking as well as channel activity, ion conduction, and gating. So far, the molecular determinants of these distinct barttin functions have remained elusive. Here we performed serial perturbation mutagenesis to identify the sequence determinants of barttin function. Barttin consists of two transmembrane helices followed by a long intracellular carboxyl terminus, and earlier work demonstrated that the transmembrane core of barttin suffices for most effects on the alpha-subunit. We individually substituted every amino acid of the predicted transmembrane core (amino acids 9-26 and 35-55) with tryptophan, co-expressed mutant barttin with hClC-Ka or V166E rClC-K1, and characterized CLC K/barttin channels by patch clamp techniques, biochemistry, and confocal microscopy. The majority of mutations left the chaperone function of barttin, i.e. the effects on endoplasmic reticulum exit and surface membrane insertion, unaffected. In contrast, tryptophan insertion at multiple positions resulted in impaired activity of hClC-Ka/barttin and changes in gating of V166E rClC K1/barttin. These results demonstrate that mutations in a cluster of hydrophobic residues within transmembrane domain 1 affect barttin-CLC-K interaction and impair gating modification by the accessory subunit. Whereas tight interaction is necessary for functional modification, even impaired association of barttin and CLC-K suffices for normal intracellular trafficking. Our findings allow definition of a likely interaction surface and clarify the mechanisms underlying CLC-K channel modification by barttin. PMID- 26063803 TI - YbiB from Escherichia coli, the Defining Member of the Novel TrpD2 Family of Prokaryotic DNA-binding Proteins. AB - We present the crystal structure and biochemical characterization of Escherichia coli YbiB, a member of the hitherto uncharacterized TrpD2 protein family. Our results demonstrate that the functional diversity of proteins with a common fold can be far greater than predictable by computational annotation. The TrpD2 proteins show high structural homology to anthranilate phosphoribosyltransferase (TrpD) and nucleoside phosphorylase class II enzymes but bind with high affinity (KD = 10-100 nM) to nucleic acids without detectable sequence specificity. The difference in affinity between single- and double-stranded DNA is minor. Results suggest that multiple YbiB molecules bind to one longer DNA molecule in a cooperative manner. The YbiB protein is a homodimer that, therefore, has two electropositive DNA binding grooves. But due to negative cooperativity within the dimer, only one groove binds DNA in in vitro experiments. A monomerized variant remains able to bind DNA with similar affinity, but the negative cooperative effect is eliminated. The ybiB gene forms an operon with the DNA helicase gene dinG and is under LexA control, being induced by DNA-damaging agents. Thus, speculatively, the TrpD2 proteins may be part of the LexA-controlled SOS response in bacteria. PMID- 26063804 TI - Apoptosis-inducing Factor (AIF) and Its Family Member Protein, AMID, Are Rotenone sensitive NADH:Ubiquinone Oxidoreductases (NDH-2). AB - Apoptosis-inducing factor (AIF) and AMID (AIF-homologous mitochondrion-associated inducer of death) are flavoproteins. Although AIF was originally discovered as a caspase-independent cell death effector, bioenergetic roles of AIF, particularly relating to complex I functions, have since emerged. However, the role of AIF in mitochondrial respiration and redox metabolism has remained unknown. Here, we investigated the redox properties of human AIF and AMID by comparing them with yeast Ndi1, a type 2 NADH:ubiquinone oxidoreductase (NDH-2) regarded as alternative complex I. Isolated AIF and AMID containing naturally incorporated FAD displayed no NADH oxidase activities. However, after reconstituting isolated AIF or AMID into bacterial or mitochondrial membranes, N-terminally tagged AIF and AMID displayed substantial NADH:O2 activities and supported NADH-linked proton pumping activities in the host membranes almost as efficiently as Ndi1. NADH:ubiquinone-1 activities in the reconstituted membranes were highly sensitive to 2-n-heptyl-4-hydroxyquinoline-N-oxide (IC50 = ~1 MUm), a quinone-binding inhibitor. Overexpressing N-terminally tagged AIF and AMID enhanced the growth of a double knock-out Escherichia coli strain lacking complex I and NDH-2. In contrast, C-terminally tagged AIF and NADH-binding site mutants of N-terminally tagged AIF and AMID failed to show both NADH:O2 activity and the growth-enhancing effect. The disease mutant AIFDeltaR201 showed decreased NADH:O2 activity and growth-enhancing effect. Furthermore, we surprisingly found that the redox activities of N-terminally tagged AIF and AMID were sensitive to rotenone, a well known complex I inhibitor. We propose that AIF and AMID are previously unidentified mammalian NDH-2 enzymes, whose bioenergetic function could be supplemental NADH oxidation in cells. PMID- 26063805 TI - The Levels of a Universally Conserved tRNA Modification Regulate Cell Growth. AB - N(6)-Threonylcarbamoyl-adenosine (t(6)A) is a universal modification occurring at position 37 in nearly all tRNAs that decode A-starting codons, including the eukaryotic initiator tRNA (tRNAi (Met)). Yeast lacking central components of the t(6)A synthesis machinery, such as Tcs3p (Kae1p) or Tcs5p (Bud32p), show slow growth phenotypes. In the present work, we show that loss of the Drosophila tcs3 homolog also leads to a severe reduction in size and demonstrate, for the first time in a non-microbe, that Tcs3 is required for t(6)A synthesis. In Drosophila and in mammals, tRNAi (Met) is a limiting factor for cell and animal growth. We report that the t(6)A-modified form of tRNAi (Met) is the actual limiting factor. We show that changing the proportion of t(6)A-modified tRNAi (Met), by expression of an un-modifiable tRNAi (Met) or changing the levels of Tcs3, regulate target of rapamycin (TOR) kinase activity and influences cell and animal growth in vivo. These findings reveal an unprecedented relationship between the translation machinery and TOR, where translation efficiency, limited by the availability of t(6)A-modified tRNA, determines growth potential in eukaryotic cells. PMID- 26063806 TI - Redox-dependent Ligand Switching in a Sensory Heme-binding GAF Domain of the Cyanobacterium Nostoc sp. PCC7120. AB - The genome of the cyanobacterium Nostoc sp. PCC7120 carries three genes (all4978, all7016, and alr7522) encoding putative heme-binding GAF (cGMP-specific phosphodiesterases, adenylyl cyclases, and FhlA) proteins that were annotated as transcriptional regulators. They are composed of an N-terminal cofactor domain and a C-terminal helix-turn-helix motif. All4978 showed the highest affinity for protoheme binding. The heme binding capability of All7016 was moderate, and Alr7522 did not bind heme at all. The "as isolated" form of All4978, identified by Soret band (lambdamax = 427 nm), was assigned by electronic absorption, EPR, and resonance Raman spectroscopy as a hexa-coordinated low spin Fe(III) heme with a distal cysteine ligand (absorption of delta-band around 360 nm). The protoheme cofactor is noncovalently incorporated. Reduction of the heme could be accomplished by chemically using sodium dithionite and electrospectrochemically; this latter method yielded remarkably low midpoint potentials of -445 and -453 mV (following Soret and alpha-band absorption changes, respectively). The reduced form of the heme (Fe(II) state) binds both NO and CO. Cysteine coordination of the as isolated Fe(III) protein is unambiguous, but interestingly, the reduced heme instead displays spectral features indicative of histidine coordination. Cys His ligand switches have been reported as putative signaling mechanisms in other heme-binding proteins; however, these novel cyanobacterial proteins are the first where such a ligand-switch mechanism has been observed in a GAF domain. DNA binding of the helix-turn-helix domain was investigated using a DNA sequence motif from its own promoter region. Formation of a protein-DNA complex preferentially formed in ferric state of the protein. PMID- 26063807 TI - Molecular Determinants of Calpain-dependent Cleavage of Junctophilin-2 Protein in Cardiomyocytes. AB - Junctophilin-2 (JP2), a membrane-binding protein that provides a structural bridge between the plasmalemma and sarcoplasmic reticulum, is essential for precise Ca(2+)-induced Ca(2+) release during excitation-contraction coupling in cardiomyocytes. In animal and human failing hearts, expression of JP2 is decreased markedly, but the molecular mechanisms underlying JP2 down-regulation remain incompletely defined. In mouse hearts, ischemia/reperfusion injury resulted in acute JP2 down-regulation, which was attenuated by pretreatment with the calpain inhibitor MDL-28170 or by transgenic overexpression of calpastatin, an endogenous calpain inhibitor. Using a combination of computational analysis to predict calpain cleavage sites and in vitro calpain proteolysis reactions, we identified four putative calpain cleavage sites within JP2 with three N-terminal and one C-terminal cleavage sites. Mutagenesis defined the C-terminal region of JP2 as the predominant calpain cleavage site. Exogenous expression of putative JP2 cleavage fragments was not sufficient to rescue Ca(2+) handling in JP2 deficient cardiomyocytes, indicating that cleaved JP2 is non-functional for normal Ca(2+)-induced Ca(2+) release. These data provide new molecular insights into the posttranslational regulatory mechanisms of JP2 in cardiac diseases. PMID- 26063808 TI - Determinants of Cation Permeation and Drug Sensitivity in Predicted Transmembrane Helix 9 and Adjoining Exofacial Re-entrant Loop 5 of Na+/H+ Exchanger NHE1. AB - Mammalian Na(+)/H(+) exchangers (NHEs) regulate numerous physiological processes and are involved in the pathogenesis of several diseases, including tissue ischemia and reperfusion injuries, cardiac hypertrophy and failure, and cancer progression. Hence, NHEs are being targeted for pharmaceutical-based clinical therapies, but pertinent information regarding the structural elements involved in cation translocation and drug binding remains incomplete. Molecular manipulations of the prototypical NHE1 isoform have implicated several predicted membrane-spanning (M) helices, most notably M4, M9, and M11, as important determinants of cation permeation and drug sensitivity. Here, we have used substituted-cysteine accessibility mutagenesis and thiol-modifying methanethiosulfonate (MTS) reagents to further probe the involvement of evolutionarily conserved sites within M9 (residues 342-363) and the adjacent exofacial re-entrant loop 5 between M9 and M10 (EL5; residues 364-415) of a cysteine-less variant of rat NHE1 on its kinetic and pharmacological properties. MTS treatment significantly reduced the activity of mutants containing substitutions within M9 (H353C, S355C, and G356C) and EL5 (G403C and S405C). In the absence of MTS, mutants S355C, G403C, and S405C showed modest to significant decreases in their apparent affinities for Na(+) o and/or H(+) i. In addition, mutations Y370C and E395C within EL5, whereas failing to confer sensitivity to MTS, nevertheless, reduced the affinity for Na(+) o, but not for H(+) i. The Y370C mutant also exhibited higher affinity for ethylisopropylamiloride, a competitive antagonist of Na(+) o transport. Collectively, these results further implicate helix M9 and EL5 of NHE1 as important elements involved in cation transport and inhibitor sensitivity, which may inform rational drug design. PMID- 26063810 TI - Correction. Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study. PMID- 26063809 TI - In the idiopathic inflammatory myopathies (IIM), do reactive oxygen species (ROS) contribute to muscle weakness? AB - The idiopathic inflammatory myopathies (IIMs) are a group of rare autoimmune disorders, collectively known as myositis. Affected patients present with proximal muscle weakness, which usually improves following treatment with immunosuppressants, but often incompletely so, thus many patients remain weak. IIMs are characterised histologically by inflammatory cell infiltrates into skeletal muscle and overexpression of major histocompatibility complex I on muscle cell surfaces. Although inflammatory cell infiltrates represent a major feature of myositis there is growing evidence that muscle weakness correlates only poorly with the degree of cellular infiltration, while weakness may in fact precede such infiltrations. The mechanisms underpinning such non-immune cell mediated weakness in IIM are poorly understood. Activation of the endoplasmic reticulum stress pathways appears to be a potential contributor. Data from non muscle cells indicate that endoplasmic reticulum stress results in altered redox homeostasis capable of causing oxidative damage. In myopathological situations other than IIM, as seen in ageing and sepsis, evidence supports an important role for reactive oxygen species (ROS). Modified ROS generation is associated with mitochondrial dysfunction, depressed force generation and activation of muscle catabolic and autophagy pathways. Despite the growing evidence demonstrating a key role for ROS in skeletal muscle dysfunction in myopathologies other than IIM, no research has yet investigated the role of modified generation of ROS in inducing the weakness characteristic of IIM. This article reviews current knowledge regarding muscle weakness in the absence of immune cells in IIM, and provides a background to the potential role of modified ROS generation as a mechanism of muscle dysfunction. The authors suggest that ROS-mediated mechanisms are potentially involved in non-immune cell mediated weakness seen in IIM and outline how these mechanisms might be investigated in this context. This appears a timely strategy, given recent developments in targeted therapies which specifically modify ROS generation. PMID- 26063812 TI - Introductory paragraph. PMID- 26063811 TI - The R3 receptor-like protein tyrosine phosphatase subfamily inhibits insulin signalling by dephosphorylating the insulin receptor at specific sites. AB - The autophosphorylation of specific tyrosine residues occurs in the cytoplasmic region of the insulin receptor (IR) upon insulin binding, and this in turn initiates signal transduction. The R3 subfamily (Ptprb, Ptprh, Ptprj and Ptpro) of receptor-like protein tyrosine phosphatases (RPTPs) is characterized by an extracellular region with 6-17 fibronectin type III-like repeats and a cytoplasmic region with a single phosphatase domain. We herein identified the IR as a substrate for R3 RPTPs by using the substrate-trapping mutants of R3 RPTPs. The co-expression of R3 RPTPs with the IR in HEK293T cells suppressed insulin induced tyrosine phosphorylation of the IR. In vitro assays using synthetic phosphopeptides revealed that R3 RPTPs preferentially dephosphorylated a particular phosphorylation site of the IR: Y960 in the juxtamembrane region and Y1146 in the activation loop. Among four R3 members, only Ptprj was co-expressed with the IR in major insulin target tissues, such as the skeletal muscle, liver and adipose tissue. Importantly, the activation of IR and Akt by insulin was enhanced, and glucose and insulin tolerance was improved in Ptprj-deficient mice. These results demonstrated Ptprj as a physiological enzyme that attenuates insulin signalling in vivo, and indicate that an inhibitor of Ptprj may be an insulin-sensitizing agent. PMID- 26063813 TI - Evaluation of antinuclear antibody (ANA) in ANA-associated connective tissue diseases. PMID- 26063814 TI - Hybrid organic-inorganic porous semiconductor transducer for multi-parameters sensing. AB - Porous silicon (PSi) non-symmetric multi-layers are modified by organic molecular beam deposition of an organic semiconductor, namely the N,N'-1H,1H perfluorobutyldicyanoperylene-carboxydi-imide (PDIF-CN2). Joule evaporation of PDIF-CN2 into the PSi sponge-like matrix not only improves but also adds transducing skills, making this solid-state device a dual signal sensor for chemical monitoring. PDIF-CN2 modified PSi optical microcavities show an increase of about five orders of magnitude in electric current with respect to the same bare device. This feature can be used to sense volatile substances. PDIF-CN2 also improves chemical resistance of PSi against alkaline and acid corrosion. PMID- 26063815 TI - Properties of neuronal facilitation that improve target tracking in natural pursuit simulations. AB - Although flying insects have limited visual acuity (approx. 1 degrees ) and relatively small brains, many species pursue tiny targets against cluttered backgrounds with high success. Our previous computational model, inspired by electrophysiological recordings from insect 'small target motion detector' (STMD) neurons, did not account for several key properties described from the biological system. These include the recent observations of response 'facilitation' (a slow build-up of response to targets that move on long, continuous trajectories) and 'selective attention', a competitive mechanism that selects one target from alternatives. Here, we present an elaborated STMD-inspired model, implemented in a closed loop target-tracking system that uses an active saccadic gaze fixation strategy inspired by insect pursuit. We test this system against heavily cluttered natural scenes. Inclusion of facilitation not only substantially improves success for even short-duration pursuits, but it also enhances the ability to 'attend' to one target in the presence of distracters. Our model predicts optimal facilitation parameters that are static in space and dynamic in time, changing with respect to the amount of background clutter and the intended purpose of the pursuit. Our results provide insights into insect neurophysiology and show the potential of this algorithm for implementation in artificial visual systems and robotic applications. PMID- 26063816 TI - The emergence of cooperation from a single mutant during microbial life cycles. AB - Cooperative behaviour is widespread in nature, even though cooperating individuals always run the risk of being exploited by free-riders. Population structure effectively promotes cooperation given that a threshold in the level of cooperation was already reached. However, the question how cooperation can emerge from a single mutant, which cannot rely on a benefit provided by other cooperators, is still puzzling. Here, we investigate this question for a well defined but generic situation based on typical life cycles of microbial populations where individuals regularly form new colonies followed by growth phases. We analyse two evolutionary mechanisms favouring cooperative behaviour and study their strength depending on the inoculation size and the length of a life cycle. In particular, we find that population bottlenecks followed by exponential growth phases strongly increase the survival and fixation probabilities of a single cooperator in a free-riding population. PMID- 26063817 TI - Unrelated toxin-antitoxin systems cooperate to induce persistence. AB - Persisters are drug-tolerant bacteria that account for the majority of bacterial infections. They are not mutants, rather, they are slow-growing cells in an otherwise normally growing population. It is known that the frequency of persisters in a population is correlated with the number of toxin-antitoxin systems in the organism. Our previous work provided a mechanistic link between the two by showing how multiple toxin-antitoxin systems, which are present in nearly all bacteria, can cooperate to induce bistable toxin concentrations that result in a heterogeneous population of slow- and fast-growing cells. As such, the slow-growing persisters are a bet-hedging subpopulation maintained under normal conditions. For technical reasons, the model assumed that the kinetic parameters of the various toxin-antitoxin systems in the cell are identical, but experimental data indicate that they differ, sometimes dramatically. Thus, a critical question remains: whether toxin-antitoxin systems from the diverse families, often found together in a cell, with significantly different kinetics, can cooperate in a similar manner. Here, we characterize the interaction of toxin antitoxin systems from many families that are unrelated and kinetically diverse, and identify the essential determinant for their cooperation. The generic architecture of toxin-antitoxin systems provides the potential for bistability, and our results show that even when they do not exhibit bistability alone, unrelated systems can be coupled by the growth rate to create a strongly bistable, hysteretic switch between normal (fast-growing) and persistent (slow growing) states. Different combinations of kinetic parameters can produce similar toxic switching thresholds, and the proximity of the thresholds is the primary determinant of bistability. Stochastic fluctuations can spontaneously switch all of the toxin-antitoxin systems in a cell at once. The spontaneous switch creates a heterogeneous population of growing and non-growing cells, typical of persisters, that exist under normal conditions, rather than only as an induced response. The frequency of persisters in the population can be tuned for a particular environmental niche by mixing and matching unrelated systems via mutation, horizontal gene transfer and selection. PMID- 26063818 TI - Mechanics regulates ATP-stimulated collective calcium response in fibroblast cells. AB - Cells constantly sense their chemical and mechanical environments. We study the effect of mechanics on the ATP-induced collective calcium response of fibroblast cells in experiments that mimic various tissue environments. We find that closely packed two-dimensional cell cultures on a soft polyacrylamide gel (Young's modulus E = 690 Pa) contain more cells exhibiting calcium oscillations than cultures on a rigid substrate (E = 36 000 Pa). Calcium responses of cells on soft substrates show a slower decay of calcium level relative to those on rigid substrates. Actin enhancement and disruption experiments for the cell cultures allow us to conclude that actin filaments determine the collective Ca(2+) oscillatory behaviour in the culture. Inhibition of gap junctions results in a decrease of the oscillation period and reduced correlation of calcium responses, which suggests additional complexity of signalling upon cell-cell contact. Moreover, the frequency of calcium oscillations is independent of the rigidity of the substrate but depends on ATP concentration. We compare our results with those from similar experiments on individual cells. Overall, our observations show that collective chemical signalling in cell cultures via calcium depends critically on the mechanical environment. PMID- 26063819 TI - Three-dimensional imaging of human stem cells using soft X-ray tomography. AB - Three-dimensional imaging of human stem cells using transmission soft X-ray tomography (SXT) is presented for the first time. Major organelle types--nuclei, nucleoli, mitochondria, lysosomes and vesicles--were discriminated at approximately 50 nm spatial resolution without the use of contrast agents, on the basis of measured linear X-ray absorption coefficients and comparison of the size and shape of structures to transmission electron microscopy (TEM) images. In addition, SXT was used to visualize the distribution of a cell surface protein using gold-labelled antibody staining. We present the strengths of SXT, which include excellent spatial resolution (intermediate between that of TEM and light microscopy), the lack of the requirement for fixative or contrast agent that might perturb cellular morphology or produce imaging artefacts, and the ability to produce three-dimensional images of cells without microtome sectioning. Possible applications to studying the differentiation of human stem cells are discussed. PMID- 26063820 TI - Modelling group navigation: transitive social structures improve navigational performance. AB - Collective navigation demands that group members reach consensus on which path to follow, a task that might become more challenging when the group's members have different social connections. Group decision-making mechanisms have been studied successfully in the past using individual-based modelling, although many of these studies have neglected the role of social connections between the group's interacting members. Nevertheless, empirical studies have demonstrated that individual recognition, previous shared experiences and inter-individual familiarity can influence the cohesion and the dynamics of the group as well as the relative spatial positions of specific individuals within it. Here, we use models of collective motion to study the impact of social relationships on group navigation by introducing social network structures into a model of collective motion. Our results show that groups consisting of equally informed individuals achieve the highest level of accuracy when they are hierarchically organized with the minimum number of preferred connections per individual. We also observe that the navigational accuracy of a group will depend strongly on detailed aspects of its social organization. More specifically, group navigation does not only depend on the underlying social relationships, but also on how much weight leading individuals put on following others. Also, we show that groups with certain social structures can compensate better for an increased level of navigational error. The results have broader implications for studies on collective navigation and motion because they show that only by considering a group's social system can we fully elucidate the dynamics and advantages of joint movements. PMID- 26063821 TI - The role of heterogeneity in contact timing and duration in network models of influenza spread in schools. AB - Influenza poses a significant health threat to children, and schools may play a critical role in community outbreaks. Mathematical outbreak models require assumptions about contact rates and patterns among students, but the level of temporal granularity required to produce reliable results is unclear. We collected objective contact data from students aged 5-14 at an elementary school and middle school in the state of Utah, USA, and paired those data with a novel, data-based model of influenza transmission in schools. Our simulations produced within-school transmission averages consistent with published estimates. We compared simulated outbreaks over the full resolution dynamic network with simulations on networks with averaged representations of contact timing and duration. For both schools, averaging the timing of contacts over one or two school days caused average outbreak sizes to increase by 1-8%. Averaging both contact timing and pairwise contact durations caused average outbreak sizes to increase by 10% at the middle school and 72% at the elementary school. Averaging contact durations separately across within-class and between-class contacts reduced the increase for the elementary school to 5%. Thus, the effect of ignoring details about contact timing and duration in school contact networks on outbreak size modelling can vary across different schools. PMID- 26063822 TI - Tensor methods for parameter estimation and bifurcation analysis of stochastic reaction networks. AB - Stochastic modelling of gene regulatory networks provides an indispensable tool for understanding how random events at the molecular level influence cellular functions. A common challenge of stochastic models is to calibrate a large number of model parameters against the experimental data. Another difficulty is to study how the behaviour of a stochastic model depends on its parameters, i.e. whether a change in model parameters can lead to a significant qualitative change in model behaviour (bifurcation). In this paper, tensor-structured parametric analysis (TPA) is developed to address these computational challenges. It is based on recently proposed low-parametric tensor-structured representations of classical matrices and vectors. This approach enables simultaneous computation of the model properties for all parameter values within a parameter space. The TPA is illustrated by studying the parameter estimation, robustness, sensitivity and bifurcation structure in stochastic models of biochemical networks. A Matlab implementation of the TPA is available at http://www.stobifan.org. PMID- 26063823 TI - Hiding the squid: patterns in artificial cephalopod skin. AB - Cephalopods employ their chromomorphic skins for rapid and versatile active camouflage and signalling effects. This is achieved using dense networks of pigmented, muscle-driven chromatophore cells which are neurally stimulated to actuate and affect local skin colouring. This allows cephalopods to adopt numerous dynamic and complex skin patterns, most commonly used to blend into the environment or to communicate with other animals. Our ultimate goal is to create an artificial skin that can mimic such pattern generation techniques, and that could produce a host of novel and compliant devices such as cloaking suits and dynamic illuminated clothing. This paper presents the design, mathematical modelling and analysis of a dynamic biomimetic pattern generation system using bioinspired artificial chromatophores. The artificial skin is made from electroactive dielectric elastomer: a soft, planar-actuating smart material that we show can be effective at mimicking the actuation of biological chromatophores. The proposed system achieves dynamic pattern generation by imposing simple local rules into the artificial chromatophore cells so that they can sense their surroundings in order to manipulate their actuation. By modelling sets of artificial chromatophores in linear arrays of cells, we explore the capability of the system to generate a variety of dynamic pattern types. We show that it is possible to mimic patterning seen in cephalopods, such as the passing cloud display, and other complex dynamic patterning. PMID- 26063824 TI - Resonance of human brain under head acceleration. AB - Although safety standards have reduced fatal head trauma due to single severe head impacts, mild trauma from repeated head exposures may carry risks of long term chronic changes in the brain's function and structure. To study the physical sensitivities of the brain to mild head impacts, we developed the first dynamic model of the skull-brain based on in vivo MRI data. We showed that the motion of the brain can be described by a rigid-body with constrained kinematics. We further demonstrated that skull-brain dynamics can be approximated by an under damped system with a low-frequency resonance at around 15 Hz. Furthermore, from our previous field measurements, we found that head motions in a variety of activities, including contact sports, show a primary frequency of less than 20 Hz. This implies that typical head exposures may drive the brain dangerously close to its mechanical resonance and lead to amplified brain-skull relative motions. Our results suggest a possible cause for mild brain trauma, which could occur due to repetitive low-acceleration head oscillations in a variety of recreational and occupational activities. PMID- 26063825 TI - Simplified mechanistic models of gene regulation for analysis and design. AB - Simplified mechanistic models of gene regulation are fundamental to systems biology and essential for synthetic biology. However, conventional simplified models typically have outputs that are not directly measurable and are based on assumptions that do not often hold under experimental conditions. To resolve these issues, we propose a 'model reduction' methodology and simplified kinetic models of total mRNA and total protein concentration, which link measurements, models and biochemical mechanisms. The proposed approach is based on assumptions that hold generally and include typical cases in systems and synthetic biology where conventional models do not hold. We use novel assumptions regarding the 'speed of reactions', which are required for the methodology to be consistent with experimental data. We also apply the methodology to propose simplified models of gene regulation in the presence of multiple protein binding sites, providing both biological insights and an illustration of the generality of the methodology. Lastly, we show that modelling total protein concentration allows us to address key questions on gene regulation, such as efficiency, burden, competition and modularity. PMID- 26063826 TI - Contaminant adhesion (aerial/ground biofouling) on the skin of a gecko. AB - In this study, we have investigated the micro- and nano-structuring and contaminant adhesional forces of the outer skin layer of the ground dwelling gecko--Lucasium steindachneri. The lizard's skin displayed a high density of hairs with lengths up to 4 MUm which were spherically capped with a radius of curvature typically less than 30 nm. The adhesion of artificial hydrophilic (silica) and hydrophobic (C18) spherical particles and natural pollen grains were measured by atomic force microscopy and demonstrated extremely low values comparable to those recorded on superhydrophobic insects. The lizard scales which exhibited a three-tier hierarchical architecture demonstrated higher adhesion than the trough regions between scales. The two-tier roughness of the troughs comprising folding of the skin (wrinkling) limits the number of contacting hairs with particles of the dimensions used in our study. The gecko skin architecture on both the dorsal and trough regions demonstrates an optimized topography for minimizing solid-solid and solid-liquid particle contact area, as well as facilitating a variety of particulate removal mechanisms including water-assisted processes. These contrasting skin topographies may also be optimized for other functions such as increased structural integrity, levels of wear protection and flexibility of skin for movement and growth. While single hair adhesion is low, contributions of many thousands of individual hairs (especially on the abdominal scale surface and if deformation occurs) may potentially aid in providing additional adhesional capabilities (sticking ability) for some gecko species when interacting with environmental substrates such as rocks, foliage and even man made structuring. PMID- 26063827 TI - Understanding Zipf's law of word frequencies through sample-space collapse in sentence formation. AB - The formation of sentences is a highly structured and history-dependent process. The probability of using a specific word in a sentence strongly depends on the 'history' of word usage earlier in that sentence. We study a simple history dependent model of text generation assuming that the sample-space of word usage reduces along sentence formation, on average. We first show that the model explains the approximate Zipf law found in word frequencies as a direct consequence of sample-space reduction. We then empirically quantify the amount of sample-space reduction in the sentences of 10 famous English books, by analysis of corresponding word-transition tables that capture which words can follow any given word in a text. We find a highly nested structure in these transition tables and show that this 'nestedness' is tightly related to the power law exponents of the observed word frequency distributions. With the proposed model, it is possible to understand that the nestedness of a text can be the origin of the actual scaling exponent and that deviations from the exact Zipf law can be understood by variations of the degree of nestedness on a book-by-book basis. On a theoretical level, we are able to show that in the case of weak nesting, Zipf's law breaks down in a fast transition. Unlike previous attempts to understand Zipf's law in language the sample-space reducing model is not based on assumptions of multiplicative, preferential or self-organized critical mechanisms behind language formation, but simply uses the empirically quantifiable parameter 'nestedness' to understand the statistics of word frequencies. PMID- 26063828 TI - An in silico study on the role of smooth muscle cell migration in neointimal formation after coronary stenting. AB - Excessive migration and proliferation of smooth muscle cells (SMCs) has been observed as a major factor contributing to the development of in-stent restenosis after coronary stenting. Building upon the results from in vivo experiments, we formulated a hypothesis that the speed of the initial tissue re-growth response is determined by the early migration of SMCs from the injured intima. To test this hypothesis, a cellular Potts model of the stented artery is developed where stent struts were deployed at different depths into the tissue. An extreme scenario with a ruptured internal elastic lamina was also considered to study the role of severe injury in tissue re-growth. Based on the outcomes, we hypothesize that a deeper stent deployment results in on average larger fenestrae in the elastic lamina, allowing easier migration of SMCs into the lumen. The data also suggest that growth of the neointimal lesions owing to SMC proliferation is strongly dependent on the initial number of migrated cells, which form an initial condition for the later phase of the vascular repair. This mechanism could explain the in vivo observation that the initial rate of neointima formation and injury score are strongly correlated. PMID- 26063829 TI - Warburg Micro syndrome is caused by RAB18 deficiency or dysregulation. AB - RAB18, RAB3GAP1, RAB3GAP2 and TBC1D20 are each mutated in Warburg Micro syndrome, a rare autosomal recessive multisystem disorder. RAB3GAP1 and RAB3GAP2 form a binary 'RAB3GAP' complex that functions as a guanine-nucleotide exchange factor (GEF) for RAB18, whereas TBC1D20 shows modest RAB18 GTPase-activating (GAP) activity in vitro. Here, we show that in the absence of functional RAB3GAP or TBC1D20, the level, localization and dynamics of cellular RAB18 is altered. In cell lines where TBC1D20 is absent from the endoplasmic reticulum (ER), RAB18 becomes more stably ER-associated and less cytosolic than in control cells. These data suggest that RAB18 is a physiological substrate of TBC1D20 and contribute to a model in which a Rab-GAP can be essential for the activity of a target Rab. Together with previous reports, this indicates that Warburg Micro syndrome can be caused directly by loss of RAB18, or indirectly through loss of RAB18 regulators RAB3GAP or TBC1D20. PMID- 26063830 TI - Three-Dimensional Analysis of Long-Term Midface Volume Change After Vertical Vector Deep-Plane Rhytidectomy. AB - BACKGROUND: Facial aging is a complicated process that includes volume loss and soft tissue descent. This study provides quantitative 3-dimensional (3D) data on the long-term effect of vertical vector deep-plane rhytidectomy on restoring volume to the midface. OBJECTIVE: To determine if primary vertical vector deep plane rhytidectomy resulted in long-term volume change in the midface. METHODS: We performed a prospective study on patients undergoing primary vertical vector deep-plane rhytidectomy to quantitate 3D volume changes in the midface. Quantitative analysis of volume changes was made using the Vectra 3D imaging software (Canfield Scientific, Inc, Fairfield, New Jersey) at a minimum follow-up of 1 year. RESULTS: Forty-three patients (86 hemifaces) were analyzed. The average volume gained in each hemi-midface after vertical vector deep-plane rhytidectomy was 3.2 mL. CONCLUSIONS: Vertical vector deep-plane rhytidectomy provides significant long-term augmentation of volume in the midface. These quantitative data demonstrate that some midface volume loss is related to gravitational descent of the cheek fat compartments and that vertical vector deep plane rhytidectomy may obviate the need for other volumization procedures such as autologous fat grafting in selected cases. LEVEL OF EVIDENCE: 4 Therapeutic. PMID- 26063831 TI - Response to "Comments on 'The Role of Gravity in Periorbital and Midfacial Aging'". PMID- 26063832 TI - Commentary on: Assessing Demographic Differences in Patient-Perceived Improvement in Facial Appearance and Quality of Life Following Rhinoplasty. PMID- 26063833 TI - Human Adipose Tissue-Derived Stromal/Stem Cells Promote Migration and Early Metastasis of Head and Neck Cancer Xenografts. AB - BACKGROUND: Fat grafting has become popular for repair of postsurgical/postradiation defects after head/neck cancers resection. Fat graft supplementation with adipose tissue-derived stromal/stem cells (ASCs) is proposed to improve graft viability/efficacy, although the impact of ASCs on head/neck cancer cells is unknown. OBJECTIVES: To determine whether ASCs affect growth, migration, and metastasis of human head/neck cancer. METHODS: Human Cal-27 and SCC-4 head/neck cancer cells were co-cultured human ASCs, or treated with ASC conditioned medium (CM), and cancer cell growth/migration was assessed by MTT, cell count, and scratch/wound healing assays in vitro. Co-injection of 3 * 10(6) Cal-27/green fluorescent protein (GFP) cells and ASCs into the flank of NUDE mice assessed ASC effect on tumor growth/morphology. Quantitation of human chromosome 17 DNA in mouse organs assessed ASC effects on micrometastasis. Primary tumors were evaluated for markers of epithelial-to-mesenchymal transition, matrix metalloproteinases, and angiogenesis by immunohistochemistry. RESULTS: Co-culture of Cal-27 or SCC-4 cells with ASCs from 2 different donors or ASC CM had no effect on cell growth in vitro. However, ASC CM stimulated Cal-27 and SCC-4 migration. Co-injection of ASCs from 2 different donors with Cal-27 cells did not affect tumor volume at 6 weeks, but increased Cal-27 micrometastasis to the brain. Evaluation of tumors sections from 1 ASC donor co-injection revealed that ASCs were viable and well integrated with Cal-27/GFP cells. These tumors exhibited increased MMP2, MMP9, IL-8, and microvessel density. CONCLUSIONS: Human ASCs did not alter growth of human head/neck cancer cells or tumor xenografts, but stimulated migration and early micrometastasis to mouse brain. PMID- 26063834 TI - Patient Satisfaction After Rhinoplasty: A Social Media Analysis. AB - BACKGROUND: Compared to other cosmetic procedures, rhinoplasty has a relatively low patient satisfaction rate, due to the difficulty of the procedure, and potentially unrealistic patient expectations. Understanding the reasons behind patient dissatisfaction is key to improving outcomes. Previous authors have done surgeon-initiated surveys, expert ratings, and morphologic measurements, to measure rhinoplasty success. No study has analyzed online reviews by patients to identify reasons for dissatisfaction with rhinoplasty. OBJECTIVES: The goal of this study was to analyze satisfaction patterns in rhinoplasty using online reviews. METHODS: All primary rhinoplasty reviews on RealSelf (Seattle, WA), a social media website for patients undergoing cosmetic surgery, were reviewed. The researchers recorded patient gender, whether they were satisfied, and the reasons for satisfaction or dissatisfaction. Male and female patients were compared, using chi-squared analysis. RESULTS: There were 2326 reviews for primary rhinoplasty (2032 females, 294 males). The overall satisfaction rate was 83.6%. Significantly more females than males were satisfied (87.6% vs 56.1%, P < .001). Among males, the most common reasons for dissatisfaction were residual dorsal hump, under-rotated tip, and a nose that was too small. Among females, the most common reasons for dissatisfaction were residual dorsal hump, under-rotated tip, and bulbous tip. Among dissatisfied patients, females were significantly more likely than males to precisely verbalize the morphologic or functional reason for their dissatisfaction. CONCLUSIONS: We found that males had lower satisfaction with rhinoplasty, and were more vague when expressing reasons for dissatisfaction, than females. Social media provides a novel way to understand reasons for patient dissatisfaction after cosmetic surgery. PMID- 26063835 TI - Thoughts on "commentary on labia minora reduction techniques: a comprehensive literature review". PMID- 26063836 TI - Report of Allergic Reaction After Application of Botulinum Toxin. AB - Botulinum toxin is a widely used treatment with satisfactory results, and it is relatively safe in the doses used for cosmetic procedures. The authors report a case of allergic reaction to Chinese botulinum toxin serotype A (CBTX-A). Although this is a rare adverse event, it is nonetheless clinically relevant to healthcare professionals. A 44-year-old woman presented to the authors' hospital complaining of dynamic wrinkles. CBTX-A was used to treat her. Minutes after application, she developed urticarial plaques proximal to the injection site. The patient had an allergic reaction, as documented by a positive skin test, which was controlled by the administration of antihistamines and systemic corticosteroids. This report is intended to guide healthcare professionals faced with this type of adverse event regarding how to proceed without hindering the delivery and effectiveness of the treatment. When performed by a qualified health professional, this treatment brings excellent results in the vast majority of cases. LEVEL OF EVIDENCE: 5 Risk. PMID- 26063837 TI - Assessing Demographic Differences in Patient-Perceived Improvement in Facial Appearance and Quality of Life Following Rhinoplasty. AB - BACKGROUND: As rhinoplasty patient demographics evolve, surgeons must consider the impact of demographics on patient satisfaction. OBJECTIVES: The objective of this study was to identify independent demographic predictors of differences in satisfaction with appearance and quality of life following rhinoplasty utilizing the FACE-Q patient-reported outcome instrument. METHODS: Patients presenting for rhinoplasty completed the following FACE-Q scales: Satisfaction with Facial Appearance, Satisfaction with Nose, Social Function, and Psychological Well being. Higher FACE-Q scores indicate greater satisfaction with appearance or superior quality of life. Pre- and post-treatment scores were compared in the context of patient demographics. RESULTS: The scales were completed by 59 patients. Women demonstrated statistically significant improvements in Satisfaction with Facial Appearance and quality of life while men only experienced significant improvement in Satisfaction with Facial appearance. Caucasians demonstrated statistically significant improvement in Satisfaction with Facial Appearance and quality of life while non-Caucasians did not. Patients younger than 35 years old were more likely to experience enhanced Satisfaction with Facial Appearance and quality of life compared with patients older than 35 years old. Patients with income >=$100,000 were more likely to experience significant increases in Satisfaction with Facial Appearance and quality of life than patients with incomes <$100,000. CONCLUSIONS: In an objective study using a validated patient-reported outcome instrument, the authors were able to quantify differences in the clinically meaningful change in perception of appearance and quality of life that rhinoplasty patients gain based on demographic variables. The authors also demonstrated that these variables are potential predictors of differences in satisfaction. PMID- 26063838 TI - Comments on "The Role of Gravity in Periorbital and Midfacial Aging". PMID- 26063839 TI - oposSOM: R-package for high-dimensional portraying of genome-wide expression landscapes on bioconductor. AB - MOTIVATION: Comprehensive analysis of genome-wide molecular data challenges bioinformatics methodology in terms of intuitive visualization with single-sample resolution, biomarker selection, functional information mining and highly granular stratification of sample classes. oposSOM combines those functionalities making use of a comprehensive analysis and visualization strategy based on self organizing maps (SOM) machine learning which we call 'high-dimensional data portraying'. The method was successfully applied in a series of studies using mostly transcriptome data but also data of other OMICs realms. AVAILABILITY AND IMPLEMENTATION: oposSOM is now publicly available as Bioconductor R package. CONTACT: wirth@izbi.uni-leipzig.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26063840 TI - EXIMS: an improved data analysis pipeline based on a new peak picking method for EXploring Imaging Mass Spectrometry data. AB - MOTIVATION: Matrix Assisted Laser Desorption Ionization-Imaging Mass Spectrometry (MALDI-IMS) in 'omics' data acquisition generates detailed information about the spatial distribution of molecules in a given biological sample. Various data processing methods have been developed for exploring the resultant high volume data. However, most of these methods process data in the spectral domain and do not make the most of the important spatial information available through this technology. Therefore, we propose a novel streamlined data analysis pipeline specifically developed for MALDI-IMS data utilizing significant spatial information for identifying hidden significant molecular distribution patterns in these complex datasets. METHODS: The proposed unsupervised algorithm uses Sliding Window Normalization (SWN) and a new spatial distribution based peak picking method developed based on Gray level Co-Occurrence (GCO) matrices followed by clustering of biomolecules. We also use gist descriptors and an improved version of GCO matrices to extract features from molecular images and minimum medoid distance to automatically estimate the number of possible groups. RESULTS: We evaluated our algorithm using a new MALDI-IMS metabolomics dataset of a plant (Eucalypt) leaf. The algorithm revealed hidden significant molecular distribution patterns in the dataset, which the current Component Analysis and Segmentation Map based approaches failed to extract. We further demonstrate the performance of our peak picking method over other traditional approaches by using a publicly available MALDI-IMS proteomics dataset of a rat brain. Although SWN did not show any significant improvement as compared with using no normalization, the visual assessment showed an improvement as compared to using the median normalization. AVAILABILITY AND IMPLEMENTATION: The source code and sample data are freely available at http://exims.sourceforge.net/. CONTACT: awgcdw@student.unimelb.edu.au or chalini_w@live.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 26063841 TI - Choice mechanisms for past, temporally extended outcomes. AB - Accurate retrospection is critical in many decision scenarios ranging from investment banking to hedonic psychology. A notoriously difficult case is to integrate previously perceived values over the duration of an experience. Failure in retrospective evaluation leads to suboptimal outcome when previous experiences are under consideration for revisit. A biologically plausible mechanism underlying evaluation of temporally extended outcomes is leaky integration of evidence. The leaky integrator favours positive temporal contrasts, in turn leading to undue emphasis on recency. To investigate choice mechanisms underlying suboptimal outcome based on retrospective evaluation, we used computational and behavioural techniques to model choice between perceived extended outcomes with different temporal profiles. Second-price auctions served to establish the perceived values of virtual coins offered sequentially to humans in a rapid monetary gambling task. Results show that lesser-valued options involving successive growth were systematically preferred to better options with declining temporal profiles. The disadvantageous inclination towards persistent growth was mitigated in some individuals in whom a longer time constant of the leaky integrator resulted in fewer violations of dominance. These results demonstrate how focusing on immediate gains is less beneficial than considering longer perspectives. PMID- 26063842 TI - Bone strain magnitude is correlated with bone strain rate in tetrapods: implications for models of mechanotransduction. AB - Hypotheses suggest that structural integrity of vertebrate bones is maintained by controlling bone strain magnitude via adaptive modelling in response to mechanical stimuli. Increased tissue-level strain magnitude and rate have both been identified as potent stimuli leading to increased bone formation. Mechanotransduction models hypothesize that osteocytes sense bone deformation by detecting fluid flow-induced drag in the bone's lacunar-canalicular porosity. This model suggests that the osteocyte's intracellular response depends on fluid flow rate, a product of bone strain rate and gradient, but does not provide a mechanism for detection of strain magnitude. Such a mechanism is necessary for bone modelling to adapt to loads, because strain magnitude is an important determinant of skeletal fracture. Using strain gauge data from the limb bones of amphibians, reptiles, birds and mammals, we identified strong correlations between strain rate and magnitude across clades employing diverse locomotor styles and degrees of rhythmicity. The breadth of our sample suggests that this pattern is likely to be a common feature of tetrapod bone loading. Moreover, finding that bone strain magnitude is encoded in strain rate at the tissue level is consistent with the hypothesis that it might be encoded in fluid-flow rate at the cellular level, facilitating bone adaptation via mechanotransduction. PMID- 26063843 TI - More, smaller bacteria in response to ocean's warming? AB - Heterotrophic bacteria play a major role in organic matter cycling in the ocean. Although the high abundances and relatively fast growth rates of coastal surface bacterioplankton make them suitable sentinels of global change, past analyses have largely overlooked this functional group. Here, time series analysis of a decade of monthly observations in temperate Atlantic coastal waters revealed strong seasonal patterns in the abundance, size and biomass of the ubiquitous flow-cytometric groups of low (LNA) and high nucleic acid (HNA) content bacteria. Over this relatively short period, we also found that bacterioplankton cells were significantly smaller, a trend that is consistent with the hypothesized temperature-driven decrease in body size. Although decadal cell shrinking was observed for both groups, it was only LNA cells that were strongly coherent, with ecological theories linking temperature, abundance and individual size on both the seasonal and interannual scale. We explain this finding because, relative to their HNA counterparts, marine LNA bacteria are less diverse, dominated by members of the SAR11 clade. Temperature manipulation experiments in 2012 confirmed a direct effect of warming on bacterial size. Concurrent with rising temperatures in spring, significant decadal trends of increasing standing stocks (3% per year) accompanied by decreasing mean cell size (-1% per year) suggest a major shift in community structure, with a larger contribution of LNA bacteria to total biomass. The increasing prevalence of these typically oligotrophic taxa may severely impact marine food webs and carbon fluxes by an overall decrease in the efficiency of the biological pump. PMID- 26063844 TI - Exploring macroevolution using modern and fossil data. AB - Macroevolution, encompassing the deep-time patterns of the origins of modern biodiversity, has been discussed in many contexts. Non-Darwinian models such as macromutations have been proposed as a means of bridging seemingly large gaps in knowledge, or as a means to explain the origin of exquisitely adapted body plans. However, such gaps can be spanned by new fossil finds, and complex, integrated organisms can be shown to have evolved piecemeal. For example, the fossil record between dinosaurs and Archaeopteryx has now filled up with astonishing fossil intermediates that show how the unique plexus of avian adaptations emerged step by step over 60 Myr. New numerical approaches to morphometrics and phylogenetic comparative methods allow palaeontologists and biologists to work together on deep-time questions of evolution, to explore how diversity, morphology and function have changed through time. Patterns are more complex than sometimes expected, with frequent decoupling of species diversity and morphological diversity, pointing to the need for some new generalizations about the processes that lie behind such patterns. PMID- 26063845 TI - Ants adjust their pheromone deposition to a changing environment and their probability of making errors. AB - Animals must contend with an ever-changing environment. Social animals, especially eusocial insects such as ants and bees, rely heavily on communication for their success. However, in a changing environment, communicated information can become rapidly outdated. This is a particular problem for pheromone trail using ants, as once deposited pheromones cannot be removed. Here, we study the response of ant foragers to an environmental change. Ants were trained to one feeder location, and the feeder was then moved to a different location. We found that ants responded to an environmental change by strongly upregulating pheromone deposition immediately after experiencing the change. This may help maintain the colony's foraging flexibility, and allow multiple food locations to be exploited simultaneously. Our treatment also caused uncertainty in the foragers, by making their memories less reliable. Ants which had made an error but eventually found the food source upregulated pheromone deposition when returning to the nest. Intriguingly, ants on their way towards the food source downregulated pheromone deposition if they were going to make an error. This may suggest that individual ants can measure the reliability of their own memories and respond appropriately. PMID- 26063846 TI - Social genetic and social environment effects on parental and helper care in a cooperatively breeding bird. AB - Phenotypes expressed in a social context are not only a function of the individual, but can also be shaped by the phenotypes of social partners. These social effects may play a major role in the evolution of cooperative breeding if social partners differ in the quality of care they provide and if individual carers adjust their effort in relation to that of other carers. When applying social effects models to wild study systems, it is also important to explore sources of individual plasticity that could masquerade as social effects. We studied offspring provisioning rates of parents and helpers in a wild population of long-tailed tits Aegithalos caudatus using a quantitative genetic framework to identify these social effects and partition them into genetic, permanent environment and current environment components. Controlling for other effects, individuals were consistent in their provisioning effort at a given nest, but adjusted their effort based on who was in their social group, indicating the presence of social effects. However, these social effects differed between years and social contexts, indicating a current environment effect, rather than indicating a genetic or permanent environment effect. While this study reveals the importance of examining environmental and genetic sources of social effects, the framework we present is entirely general, enabling a greater understanding of potentially important social effects within any ecological population. PMID- 26063848 TI - A novel spatio-temporal scale based on ocean currents unravels environmental drivers of reproductive timing in a marine predator. AB - Life-history strategies have evolved in response to predictable patterns of environmental features. In practice, linking life-history strategies and changes in environmental conditions requires comparable space-time scales between both processes, a difficult match in most marine system studies. We propose a novel spatio-temporal and dynamic scale to explore marine productivity patterns probably driving reproductive timing in the inshore little penguin (Eudyptula minor), based on monthly data on ocean circulation in the Southern Ocean, Australia. In contrast to what occurred when considering any other fixed scales, little penguin's highly variable laying date always occurred within the annual peak of ocean productivity that emerged from our newly defined dynamic scale. Additionally, local sea surface temperature seems to have triggered the onset of reproduction, acting as an environmental cue informing on marine productivity patterns at our dynamic scale. Chlorophyll-a patterns extracted from this scale revealed that environment factors in marine ecosystems affecting breeding decisions are related to a much wider region than foraging areas that are commonly used in current studies investigating the link between animals' life history and their environment. We suggest that marine productivity patterns may be more predictable than previously thought when environmental and biological data are examined at appropriate scales. PMID- 26063847 TI - Condition-dependent reproductive effort in frogs infected by a widespread pathogen. AB - To minimize the negative effects of an infection on fitness, hosts can respond adaptively by altering their reproductive effort or by adjusting their timing of reproduction. We studied effects of the pathogenic fungus Batrachochytrium dendrobatidis on the probability of calling in a stream-breeding rainforest frog (Litoria rheocola). In uninfected frogs, calling probability was relatively constant across seasons and body conditions, but in infected frogs, calling probability differed among seasons (lowest in winter, highest in summer) and was strongly and positively related to body condition. Infected frogs in poor condition were up to 40% less likely to call than uninfected frogs, whereas infected frogs in good condition were up to 30% more likely to call than uninfected frogs. Our results suggest that frogs employed a pre-existing, plastic, life-history strategy in response to infection, which may have complex evolutionary implications. If infected males in good condition reproduce at rates equal to or greater than those of uninfected males, selection on factors affecting disease susceptibility may be minimal. However, because reproductive effort in infected males is positively related to body condition, there may be selection on mechanisms that limit the negative effects of infections on hosts. PMID- 26063849 TI - Thirty-year recovery of mollusc communities after nuclear experimentations on Fangataufa atoll (Tuamotu, French Polynesia). AB - A 30-year study of temporal changes in gastropod community structure on the reefs of a Pacific Ocean atoll (Fangataufa, Tuamotu Archipelago) subjected to atmospheric nuclear tests during the 1960s offered the opportunity for an otherwise impossible field experiment that could help ecologists understand mollusc primary succession. Reef molluscs were partly or entirely wiped out by the heat of the nuclear tests and the reefs were recolonized by ocean larvae. On all reefs, community composition before the tests was very different from what it evolved to afterwards. A new method of analysis was developed to study the temporal variation in community composition before versus after the tests (temporal beta diversity). Analyses showed that community compositions diverged through time among the reefs. Only some species can survive the harsh conditions of supralittoral zones, so the same species recolonized them; environmental filtering controlled the development of the new communities. In the reef flat and edge zones, differences in community composition seem to be the result of neutral stochastic colonization by larvae coming from the open ocean. All reefs developed a community composition quite different from that before the nuclear tests. PMID- 26063850 TI - Evidence for aggressive mimicry in an adult brood parasitic bird, and generalized defences in its host. AB - Mimicry of a harmless model (aggressive mimicry) is used by egg, chick and fledgling brood parasites that resemble the host's own eggs, chicks and fledglings. However, aggressive mimicry may also evolve in adult brood parasites, to avoid attack from hosts and/or manipulate their perception of parasitism risk. We tested the hypothesis that female cuckoo finches (Anomalospiza imberbis) are aggressive mimics of female Euplectes weavers, such as the harmless, abundant and sympatric southern red bishop (Euplectes orix). We show that female cuckoo finch plumage colour and pattern more closely resembled those of Euplectes weavers (putative models) than Vidua finches (closest relatives); that their tawny flanked prinia (Prinia subflava) hosts were equally aggressive towards female cuckoo finches and southern red bishops, and more aggressive to both than to their male counterparts; and that prinias were equally likely to reject an egg after seeing a female cuckoo finch or bishop, and more likely to do so than after seeing a male bishop near their nest. This is, to our knowledge, the first quantitative evidence for aggressive mimicry in an adult bird, and suggests that host-parasite coevolution can select for aggressive mimicry by avian brood parasites, and counter-defences by hosts, at all stages of the reproductive cycle. PMID- 26063851 TI - An Investigation into Laboratory Misidentification of a Bloodstream Klebsiella variicola Infection. PMID- 26063852 TI - Antibody and Viral Nucleic Acid Testing of Serum and Cerebrospinal Fluid for Diagnosis of Eastern Equine Encephalitis. AB - Eastern equine encephalitis diagnostic serum antibody can appear 6 days after the onset of symptoms, and its numbers can increase 4-fold in 4 days, arguing for early and frequent serum testing. In populations where cerebrospinal fluid viral nucleic acid testing sensitivity and specificity remain undetermined, cerebrospinal antibody testing should also be performed. PMID- 26063854 TI - Brown-Pigmented Mycobacterium mageritense as a Cause of Prosthetic Valve Endocarditis and Bloodstream Infection. AB - Mycobacterium spp. are a rare cause of endocarditis. Herein, we describe a case of Mycobacterium mageritense prosthetic valve endocarditis. This organism produced an unusual brown pigment on solid media. Cultures of valve tissue for acid-fast bacilli might be considered in some cases of apparently culture negative prosthetic valve endocarditis. PMID- 26063853 TI - Molecular Types of Methicillin-Resistant Staphylococcus aureus and Methicillin Sensitive S. aureus Strains Causing Skin and Soft Tissue Infections and Nasal Colonization, Identified in Community Health Centers in New York City. AB - In November 2011, The Rockefeller University Center for Clinical and Translational Science (CCTS), the Laboratory of Microbiology and Infectious Diseases, and Clinical Directors Network (CDN) launched a research and learning collaborative project with six community health centers in the New York City metropolitan area to determine the nature (clonal type) of community-acquired Staphylococcus aureus strains causing skin and soft tissue infections (SSTIs). Between November 2011 and March 2013, wound and nasal samples from 129 patients with active SSTIs suspicious for S. aureus were collected and characterized by molecular typing techniques. In 63 of 129 patients, the skin wounds were infected by S. aureus: methicillin-resistant S. aureus (MRSA) was recovered from 39 wounds and methicillin-sensitive S. aureus (MSSA) was recovered from 24. Most-46 of the 63-wound isolates belonged to the CC8/Panton-Valentine leukocidin-positive (PVL(+)) group of S. aureus clone USA300: 34 of these strains were MRSA and 12 were MSSA. Of the 63 patients with S. aureus infections, 30 were also colonized by S. aureus in the nares: 16 of the colonizing isolates were MRSA, and 14 were MSSA, and the majority of the colonizing isolates belonged to the USA300 clonal group. In most cases (70%), the colonizing isolate belonged to the same clonal type as the strain involved with the infection. In three of the patients, the identity of invasive and colonizing MRSA isolates was further documented by whole genome sequencing. PMID- 26063855 TI - Evaluation of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Nontuberculous Mycobacteria from Clinical Isolates. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for the identification of nontuberculous mycobacterial (NTM) isolates was evaluated in this study. Overall, 125 NTM isolates were analyzed by MALDI-TOF and GenoType CM/AS. Identification by 16S rRNA/hsp65 sequencing was considered the gold standard. Agreements between MALDI-TOF and GenoType CM/AS with the reference method were, respectively, 94.4% and 84.0%. In 17 cases (13.6%), results provided by GenoType and MALDI-TOF were discordant; however, the reference method agreed with MALDI-TOF in 16/17 cases (94.1%; P = 0.002). PMID- 26063856 TI - Identification of Highly Pathogenic Microorganisms by Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry: Results of an Interlaboratory Ring Trial. AB - In the case of a release of highly pathogenic bacteria (HPB), there is an urgent need for rapid, accurate, and reliable diagnostics. MALDI-TOF mass spectrometry is a rapid, accurate, and relatively inexpensive technique that is becoming increasingly important in microbiological diagnostics to complement classical microbiology, PCR, and genotyping of HPB. In the present study, the results of a joint exercise with 11 partner institutions from nine European countries are presented. In this exercise, 10 distinct microbial samples, among them five HPB, Bacillus anthracis, Brucella canis, Burkholderia mallei, Burkholderia pseudomallei, and Yersinia pestis, were characterized under blinded conditions. Microbial strains were inactivated by high-dose gamma irradiation before shipment. Preparatory investigations ensured that this type of inactivation induced only subtle spectral changes with negligible influence on the quality of the diagnosis. Furthermore, pilot tests on nonpathogenic strains were systematically conducted to ensure the suitability of sample preparation and to optimize and standardize the workflow for microbial identification. The analysis of the microbial mass spectra was carried out by the individual laboratories on the basis of spectral libraries available on site. All mass spectra were also tested against an in-house HPB library at the Robert Koch Institute (RKI). The averaged identification accuracy was 77% in the first case and improved to >93% when the spectral diagnoses were obtained on the basis of the RKI library. The compilation of complete and comprehensive databases with spectra from a broad strain collection is therefore considered of paramount importance for accurate microbial identification. PMID- 26063857 TI - Cytomegalovirus Infection Management in Allogeneic Stem Cell Transplant Recipients: a National Survey in Spain. AB - This study gathered information about current practices of cytomegalovirus (CMV) infection management in allogeneic stem cell transplant recipients at Spanish centers. A wide variety of preemptive antiviral therapy strategies for CMV infection guided by real-time PCR assays was found, yet the incidence of CMV disease was low (<3%). PMID- 26063858 TI - Performance of a New Rapid Immunoassay Test Kit for Point-of-Care Diagnosis of Significant Bacteriuria. AB - Urinary tract infections (UTIs) are frequently encountered in clinical practice and most commonly caused by Escherichia coli and other Gram-negative uropathogens. We tested RapidBac, a rapid immunoassay for bacteriuria developed by Silver Lake Research Corporation (SLRC), compared with standard bacterial culture using 966 clean-catch urine specimens submitted to a clinical microbiology laboratory in an urban academic medical center. RapidBac was performed in accordance with instructions, providing a positive or negative result in 20 min. RapidBac identified as positive 245/285 (sensitivity 86%) samples with significant bacteriuria, defined as the presence of a Gram-negative uropathogen or Staphylococcus saprophyticus at >=10(3) CFU/ml. The sensitivities for Gram-negative bacteriuria at >=10(4) CFU/ml and >=10(5) CFU/ml were 96% and 99%, respectively. The specificity of the test, detecting the absence of significant bacteriuria, was 94%. The sensitivity and specificity of RapidBac were similar on samples from inpatient and outpatient settings, from male and female patients, and across age groups from 18 to 89 years old, although specificity was higher in men (100%) compared with that in women (92%). The RapidBac test for bacteriuria may be effective as an aid in the point-of-care diagnosis of UTIs especially in emergency and primary care settings. PMID- 26063859 TI - Development and Evaluation of an Enterovirus D68 Real-Time Reverse Transcriptase PCR Assay. AB - We have developed and evaluated a real-time reverse transcriptase PCR (RT-PCR) assay for the detection of human enterovirus D68 (EV-D68) in clinical specimens. This assay was developed in response to the unprecedented 2014 nationwide EV-D68 outbreak in the United States associated with severe respiratory illness. As part of our evaluation of the outbreak, we sequenced and published the genome sequence of the EV-D68 virus circulating in St. Louis, MO. This sequence, along with other GenBank sequences from past EV-D68 occurrences, was used to computationally select a region of EV-D68 appropriate for targeting in a strain-specific RT-PCR assay. The RT-PCR assay amplifies a segment of the VP1 gene, with an analytic limit of detection of 4 copies per reaction, and it was more sensitive than commercially available assays that detect enteroviruses and rhinoviruses without distinguishing between the two, including three multiplex respiratory panels approved for clinical use by the FDA. The assay did not detect any other enteroviruses or rhinoviruses tested and did detect divergent strains of EV-D68, including the first EV-D68 strain (Fermon) identified in California in 1962. This assay should be useful for identifying and studying current and future outbreaks of EV-D68 viruses. PMID- 26063860 TI - Reducing Unnecessary and Duplicate Ordering for Ovum and Parasite Examinations and Clostridium difficile PCR in Immunocompromised Patients by Using an Alert at the Time of Request in the Order Management System. AB - We implemented hospital information system (HIS) alerts to deter unnecessary test orders for ovum and parasite (O&P) exams and Clostridium difficile PCR. The HIS alerts decreased noncompliant O&P orders (orders after >72 h of hospitalization) from 49.8% to 30.9%, an overall decrease of 19%, and reduced noncompliant C. difficile PCR orders (orders <7 days after a previous positive result) from 30.6% to 19.2%, an overall decrease of 31.9%. PMID- 26063861 TI - Comparison of Three Different FDA-Approved Plasma HIV-1 RNA Assay Platforms Confirms the Virologic Failure Endpoint of 200 Copies per Milliliter Despite Improved Assay Sensitivity. AB - Discrepancies between HIV-1 RNA results assayed by different FDA-approved platforms have been reported. Plasma samples collected from 332 randomly selected clinical trial participants during the second year of antiretroviral treatment were assayed with three FDA-approved platforms: UltraSensitive Roche Amplicor Monitor, v1.5 (Monitor), the Abbott RealTime HIV-1 test on the m2000 system (Abbott), and the Roche TaqMan HIV-1 test, v2.0 (TaqMan). Samples from 61 additional participants with confirmed HIV-1 RNA levels of >50 copies/ml during trial follow-up were also included. Endpoints were HIV-1 RNA quantification of <=50 copies/ml versus >50 copies/ml at an individual-sample level (primary) and determination of confirmed virologic failure (VF) from longitudinal samples. A total of 389 participants had results obtained from all assays on at least one sample (median = 6). Proportions of results of >50 copies/ml were 19% (Monitor), 22% (TaqMan), and 25% (Abbott). Despite indication of strong agreement (Cohen's kappa, 0.76 to 0.82), Abbott was more likely to detect HIV-1 RNA levels of >50 copies/ml than Monitor (matched-pair odds ratio [mOR] = 4.2; modified Obuchowski P < 0.001) and TaqMan (mOR = 2.1; P < 0.001); TaqMan was more likely than Monitor (mOR = 2.6; P < 0.001). Despite strong agreement in classifying VF across assay comparisons (kappa, 0.75 to 0.92), at a 50-copies/ml threshold, differences in the probability of VF classification (in the same direction as primary) were apparent (all McNemar's P < 0.007). At a 200-copies/ml VF threshold, no differences between assays were apparent (all P > 0.13). Despite strong agreement among assays, significant differences were observed with respect to detecting HIV 1 RNA levels of >50 copies/ml and identifying VF at the 50-copies/ml threshold. This has important implications for the definition of VF in clinical trials and clinical practice. PMID- 26063862 TI - Transmitted Extended-Spectrum Extensively Drug-Resistant Tuberculosis in Beijing, China, with Discordant Whole-Genome Sequencing Analysis Results. AB - Drug resistance to tuberculosis remains a major public health threat. Here, we report two cases of extended-spectrum extensively drug-resistant (XXDR) tuberculosis showing resistance to most first- and second-line agents. The results of a correlation of whole-genome sequencing (WGS) and phenotypic testing were discordant, suggesting that overreliance on WGS may miss clinically relevant resistance in extensively drug-resistant disease. PMID- 26063863 TI - Overdiagnosis of Urinary Tract Infection and Underdiagnosis of Sexually Transmitted Infection in Adult Women Presenting to an Emergency Department. AB - Urinary tract infections (UTIs) and sexually transmitted infections (STIs) are commonly diagnosed in emergency departments (EDs). Distinguishing between these syndromes can be challenging because of overlapping symptomatology and because both are associated with abnormalities on urinalysis (UA). We conducted a 2-month observational cohort study to determine the accuracy of clinical diagnoses of UTI and STI in adult women presenting with genitourinary (GU) symptoms or diagnosed with GU infections at an urban academic ED. For all urine specimens, UA, culture, and nucleic acid amplification testing for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis were performed. Of 264 women studied, providers diagnosed 175 (66%) with UTIs, 100 (57%) of whom were treated without performing a urine culture during routine care. Combining routine care and study performed urine cultures, only 84 (48%) of these women had a positive urine culture. Sixty (23%) of the 264 women studied had one or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI within 7 days of the ED visit. Fourteen (64%) of these 22 women were diagnosed with a UTI instead of an STI. Ninety-two percent of the women studied had an abnormal UA finding (greater than-trace leukocyte esterase level, positive nitrite test result, or pyuria). The positive and negative predictive values of an abnormal UA finding were 41 and 76%, respectively. In this population, empirical therapy for UTI without urine culture testing and overdiagnosis of UTI were common and associated with unnecessary antibiotic exposure and missed STI diagnoses. Abnormal UA findings were common and not predictive of positive urine cultures. PMID- 26063864 TI - Candida quercitrusa Candidemia in a 6-Year-Old Child. AB - We present the first case of candidemia due to Candida quercitrusa in a pediatric patient. The identification of the isolate was protracted and ultimately dependent upon sequence analysis of the internal transcribed spacer region. To further define the antifungal susceptibility characteristics of this species, we performed antifungal susceptibility testing of clinical and type strains. In light of the antifungal susceptibility testing results, we caution against the use of fluconazole for treating C. quercitrusa infections. PMID- 26063866 TI - Airborne Transmission of a Novel Tembusu Virus in Ducks. AB - The routes of transmission of a newly emerged Tembusu virus (TMUV, Flavivirus) in ducks in China remain unclear. Our epidemiological data show that TMUV is spread in winter, when mosquitos are inactive, which suggests that nonvector transmission routes are involved in the spread of TMUV. Furthermore, in vivo studies indicate that TMUV can be transmitted efficiently among ducks by both direct contact and aerosol transmission. This finding has important implications for the control of infection with this novel TMUV in the field. PMID- 26063865 TI - Accuracy of Lipoarabinomannan and Xpert MTB/RIF Testing in Cerebrospinal Fluid To Diagnose Tuberculous Meningitis in an Autopsy Cohort of HIV-Infected Adults. AB - Point-of-care tests for tuberculous meningitis (TBM) are needed. We studied the diagnostic accuracy of the lipoarabinomannan (LAM) lateral flow assay (LFA), LAM enzyme-linked immunosorbent assay (ELISA), and Xpert MTB/RIF in cerebrospinal fluid (CSF) in an autopsy cohort of Ugandan HIV-infected adults. We obtained written informed consent postmortem from the next of kin. A complete autopsy was done and CSF obtained. We performed LAM LFA (on unprepared and supernatant CSF after heating and spinning), LAM ELISA, and Xpert MTB/RIF on the CSF samples. Accuracy parameters were calculated for histopathological TBM and also for the composite standard, including Xpert MTB/RIF-positive cases. We tested CSF of 91 patients. LAM LFA had a sensitivity of 75% for definite histopathological TBM, ELISA a sensitivity of 43%, and Xpert MTB/RIF a sensitivity of 100% and specificities of 87%, 91%, and 87%, respectively. LAM LFA had a sensitivity of 50% for definite and probable histopathological TBM, ELISA a sensitivity of 38%, and Xpert MTB/RIF a sensitivity of 86% and specificities of 70%, 91%, and 87%, respectively. LAM LFA had a sensitivity of 68% for the composite standard and ELISA a sensitivity of 48% and specificities of 78% and 98%, respectively. The rapid diagnostic tests detected TBM in 22% to 78% of patients not on anti-TB treatment. Point-of-care tests have high accuracy in diagnosis of TBM in deceased HIV-infected adults. LAM LFA in CSF is a useful additional diagnostic tool. PMID- 26063867 TI - Bartonella quintana Aortitis in a Man with AIDS, Diagnosed by Needle Biopsy and 16S rRNA Gene Amplification. AB - A man with newly diagnosed AIDS presented with months of back pain and fever. Computed tomography (CT) results demonstrated aortitis with periaortic tissue thickening. DNA amplification of biopsy tissue revealed Bartonella quintana, and Bartonella serologies were subsequently noted to be positive. The patient improved with prolonged doxycycline and rifabutin treatment. This case illustrates how molecular techniques are increasingly important in diagnosing Bartonella infections. PMID- 26063868 TI - Effects of Endocrine-Disrupting Chemicals on the Ovary. AB - Endocrine-disrupting chemicals (EDCs) are found abundantly in the environment, resulting in daily human exposure. This is of concern because many EDCs are known to target the female reproductive system and, more specifically, the ovary. In the female, the ovary is the key organ responsible for reproductive and endocrine functions. Exposure to EDCs is known to cause many reproductive health problems such as infertility, premature ovarian failure, and abnormal sex steroid hormone levels. Some EDCs and their effects on adult ovarian function have been studied extensively over the years, whereas the effects of others remain unclear. This review covers what is currently known about the effects of selected EDCs (bisphenol A, methoxychlor, 2,3,7,8-tetrachlorodibenzo-p-dioxin, phthalates, and genistein) on the adult ovary and the mechanisms by which they act upon the ovary, focusing primarily on their effects on folliculogenesis and steroidogenesis. Furthermore, this review discusses future directions needed to better understand the effects of EDCs, including the need to examine the effects of multiple and more consistent doses and to study different mechanisms of action. PMID- 26063869 TI - Reduced Gene Dosage of Tfap2c Impairs Trophoblast Lineage Differentiation and Alters Maternal Blood Spaces in the Mouse Placenta. AB - Tfap2c is required for placental development and trophoblast stem cell maintenance. Deletion of Tfap2c results in early embryonic loss because of failure in placental development. We evaluated the effect of reduced Tfap2c expression on fetal outcome and placental development. Sixty percent of the heterozygous mice were lost directly after birth. Labyrinthine differentiation was impaired, as indicated by enhanced proliferation and inclusions of cobblestone-shaped cell clusters characterized by expression of Tfap2c and glycogen stores. Moreover, expression of marker genes such as Cdx2, Eomes, Gata3, and Ascl2 are decreased in the spongiotrophoblast and indicate a lowered stem cell potential. On Day 18.5 postcoitum, the labyrinth layer of Tfap2c(+/-) placentas exhibited massive hemorrhages in the maternal blood spaces; these hemorrhages might have contributed to the significantly reduced number of live born pups. These morphological alterations were accompanied by a shift toward sinusoidal trophoblast giant cells as the cell subpopulation lining the maternal sinusoids and toward reduction in expression of the prolactin gene family member Prl2c2, a finding characteristic of the spiral arteries lining trophoblast cells. The trophoblast stem cells heterozygous for Tfap2c exhibited a reduction in the expression level of stem cell markers and in their proliferation and differentiation capacity but did not exhibit changes in marker genes of the trophoblast giant cell lineage. Taken together, these findings indicate that a reduction in the gene dosage of placental Tfap2c leads to morphological changes in the labyrinth at midgestation and in the maternal blood spaces during late pregnancy. PMID- 26063870 TI - Follicle-Stimulating Hormone Increases Gap Junctional Communication Between Somatic and Germ-Line Follicular Compartments During Murine Oogenesis. AB - Germ cells develop in intimate contact and communication with somatic cells of the gonad. In female mammals, oocyte development depends crucially on gap junctions that couple it to the surrounding somatic granulosa cells of the follicle, yet the mechanisms that regulate this essential intercellular communication remain incompletely understood. Follicle-stimulating hormone (FSH) drives the terminal stage of follicular development. We found that FSH increases the steady-state levels of mRNAs encoding the principal connexins that constitute gap junctions and cadherins that mediate cell attachment. This increase occurs both in granulosa cells, which express the FSH-receptor, and in oocytes, which do not. FSH also increased the number of transzonal projections that provide the sites of granulosa cell-oocyte contact. Consistent with increased connexin expression, FSH increased gap junctional communication between granulosa cells and between the oocyte and granulosa cells, and it accelerated oocyte development. These results demonstrate that FSH regulates communication between the female germ cell and its somatic microenvironment. We propose that FSH regulated gap junctional communication ensures that differentiation processes occurring in distinct cellular compartments within the follicle are precisely coordinated to ensure production of a fertilizable egg. PMID- 26063871 TI - The Inhibitory Effects of RFamide-Related Peptide 3 on Luteinizing Hormone Release Involves an Estradiol-Dependent Manner in Prepubertal but Not in Adult Female Mice. AB - The mammalian gonadotropin-inhibitory hormone (GnIH) ortholog, RFamide-related peptide (RFRP), is considered to act on gonadotropin-releasing hormone (GnRH) neurons and the pituitary to inhibit gonadotropin synthesis and release. However, there is little evidence documenting whether RFamide-related peptide 3 (RFRP-3) plays a primary role in inhibition of the hypothalamo-pituitary-gonadal (HPG) axis prior to the onset of puberty. The present study aimed to understand the functional significance of the neuropeptide on pubertal development. The developmental changes in reproductive-related gene expression at the mRNA level were investigated in the hypothalamus of female mice. The results indicated that RFRP-3 may be an endogenous inhibitory factor for the activation of the HPG axis prior to the onset of puberty. In addition, centrally administered RFRP-3 significantly suppressed plasma luteinizing hormone (LH) levels in prepubertal female mice. Surprisingly, centrally administered RFRP-3 had no effects on plasma LH levels in ovariectomized (OVX) prepubescent female mice. In contrast, RFRP-3 also inhibited plasma LH levels in OVX prepubescent female mice that were treated with 17beta-estradiol replacement. Our study also examined the effects of RFRP-3 on plasma LH release in adult female mice that were ovariectomized at dioestrus, with or without estradiol (E2). Our results showed that the inhibitory effects of RFRP-3 were independent of E2 status. Quantitative real-time PCR and immunohistochemistry analyses showed that RFRP-3 inhibited GnRH expression at both the mRNA and protein levels in the hypothalamus. These data demonstrated that RFRP-3 could effectively suppress pituitary LH release, via the inhibition of GnRH transcription and translation in prepubescent female mice, which is associated with estrogen signaling pathway and developmental stages. PMID- 26063872 TI - Store-Operated Ca2+ Entry Sustains the Fertilization Ca2+ Signal in Pig Eggs. AB - The role of store-operated Ca(2+) entry (SOCE) in the maintenance of sperm induced Ca(2+) oscillations was investigated in porcine eggs. We found that 10 MUM gadolinium (Gd(3+)), which is known to inhibit SOCE, blocked Ca(2+) entry that was triggered by thapsigargin-induced store depletion and also caused an abrupt cessation of the fertilization Ca(2+) signal. In a similar manner 3,5 bis(trifluoromethyl)pyrazole 2 (20 MUM), and tetrapandin-2 (10 MUM), potent SOCE inhibitors, also blocked thapsigargin-stimulated Ca(2+) entry and disrupted the Ca(2+) oscillations after sperm-egg fusion. The downregulation of Stim1 or Orai1 in the eggs did not alter the Ca(2+) content of the intracellular stores, whereas co-overexpression of these proteins led to the generation of irregular Ca(2+) transients after fertilization that stopped prematurely. We also found that thapsigargin completely emptied the endoplasmic reticulum, and that the series of Ca(2+) transients stopped abruptly after the addition of thapsigargin to the fertilized eggs, indicating that the proper reloading of the intracellular stores is a prerequisite for the maintenance of the Ca(2+) oscillations. These data strengthen our previous findings that in porcine eggs SOCE is a major signaling cascade that is responsible for sustaining the repetitive Ca(2+) signal at fertilization. PMID- 26063873 TI - Production of Interspecific Germline Chimeras via Embryo Replacement. AB - In avian species, primordial germ cells (PGCs) use the vascular system to reach their destination, the genital ridge. Because of this unique migratory route of avian germ cells, germline chimera production can be achieved via germ cell transfer into a blood vessel. This study was performed to establish an alternative germ cell-transfer system for producing germline chimeras by replacing an original host embryo with a donor embryo, while retaining the host extraembryonic tissue and yolk, before circulation. First, to test the migratory capacity of PGCs after embryo replacement, Korean Oge (KO) chick embryos were used to replace GFP transgenic chick embryos. Four days after replacement, GFP positive cells were detected in the replaced KO embryonic gonads, and genomic DNA PCR analysis with the embryonic gonads demonstrated the presence of the GFP transgene. To produce an interspecific germline chimera, the original chick embryo proper was replaced with a quail embryo onto the chick yolk. To detect the gonadal PGCs in the 5.5-day-old embryonic gonads, immunohistochemistry was performed with monoclonal antibodies specific to either quail or chick PGCs, i.e., QCR1 and anti-stage-specific embryonic antigen-1 (SSEA-1), respectively. Both the QCR1-positive and SSEA-1-positive cells were detected in the gonads of replaced quail embryos. Forty percent of the PGC population in the quail embryos was occupied by chick extraembryonically derived PGCs. In conclusion, replacement of an embryo onto the host yolk before circulation can be applied to produce interspecies germline chimeras, and this germ cell-transfer technology is potentially applicable for reproduction of wild or endangered bird species. PMID- 26063875 TI - Neoadjuvant Model in Cancer Treatment: From Clinical Opportunity to Health-Care Utility. AB - In the last few decades, research has demonstrated that cancer can be treated and cured if diagnosed at very early stage and a proper therapeutic strategy is adopted. Recent omics-based approaches have unveiled the molecular mechanisms of cancer tumorigenesis and have aided in identifying next-generation molecular markers for early diagnosis, prognosis, and targeted therapy. New tests based on genomic profiling, circulating tumor cells, or mutation profiling are appraised for purpose by Health Technology Assessment. The potential clinical utility of these tests lies on their ability to discriminate between patients who will benefit to a greater or lesser extent from a therapeutic intervention. Assessment of new technologies for the management of cancer could be of interest to other countries given the potentially high impact that they can have on the quality and cost of health care services. PMID- 26063874 TI - Cell Type-Specific Sexual Dimorphism in Rat Pituitary Gene Expression During Maturation. AB - The most obvious functional differences between mammalian males and females are related to the control of reproductive physiology and include patterns of GnRH and gonadotropin release, the timing of puberty, sexual and social behavior, and the regulation of food intake and body weight. Using the rat as the best-studied mammalian model for maturation, we examined the expression of major anterior pituitary genes in five secretory cell types of developing males and females. Corticotrophs show comparable Pomc profiles in both sexes, with the highest expression occurring during the infantile period. Somatotrophs and lactotrophs also exhibit no difference in Gh1 and Prl profiles during embryonic to juvenile age but show the amplification of Prl expression in females and Gh1 expression in males during peripubertal and postpubertal ages. Gonadotrophs exhibit highly synchronized Lhb, Fshb, Cga, and Gnrhr expression in both sexes, but the peak of expression occurs during the infantile period in females and at the end of the juvenile period in males. Thyrotrophs also show different developmental Tshb profiles, which are synchronized with the expression of gonadotroph genes in males but not in females. These results indicate the lack of influence of sex on Pomc expression and the presence of two patterns of sexual dimorphism in the expression of other pituitary genes: a time shift in the peak expression during postnatal development, most likely reflecting the perinatal sex-specific brain differentiation, and modulation of the amplitude of expression during late development, which is secondary to the establishment of the hypothalamic pituitary-gonadal and -thyroid axes. PMID- 26063876 TI - Primary Systemic Treatment in the Management of Operable Breast Cancer: Best Surgical Approach for Diagnosis, Biological Evaluation, and Research. AB - Despite the ever-changing breast surgeon's technical role, the surgeon forms an indispensible link between imaging, diagnostics, pathology, and the medical oncologist. Biomarkers of prognosis, prediction of response, and resistance to treatments, including imaging, tissue and circulating markers apply to the primary diagnostic and treatment settings as well as scenarios which include disease recurrence, both in the early and advanced settings. Whether it is via the diagnostic clinic referred by the primary care physician or via a breast screening service, primary early breast cancer is referred for initial treatment and/or diagnosis and currently remains the domain of the surgical oncologist. The surgeon is privileged by this unique "window of opportunity" to consider the biological aspects of the diagnosis and guide the patient appropriately toward initial therapy, only one of which is primary surgery. Options of neoadjuvant endocrine, cytotoxic, or targeted therapy as either standard of care or else in the clinical trial context should be considered to optimize treatment in all patients. PMID- 26063877 TI - Optimizing Radiation Treatment Decisions for Patients Who Receive Neoadjuvant Chemotherapy. AB - The indications for postoperative radiotherapy after surgery following neoadjuvant systemic therapy for breast cancer are reviewed and the controversial issues summarized. Current standards and areas of future development are delineated. The need of collecting data on radiotherapy characteristics and results, according to different clinical and biological parameters, in the framework of perspective clinical studies, is underlined. PMID- 26063878 TI - Surgical Considerations After Neoadjuvant Chemotherapy: Breast Conservation Therapy. AB - The increasing use of chemotherapy before surgery has affected a number of local regional treatment decisions including surgical and radiation management of the breast, management of axillary lymph nodes, and the indications for postmastectomy radiation. In this monograph, we will focus on surgical and radiation management as components of breast conservation therapy. The early randomized trials that compared neoadjuvant to adjuvant chemotherapy in breast cancer demonstrated that rates of breast conservation can be increased when chemotherapy is sequenced first. This was a direct consequence of high response rates seen with neoadjuvant treatment, which permitted downstaging of a large primary tumor to a volume that permitted breast-conserving surgery. Some initial studies found higher rates of breast recurrences with this approach but over time, with improved multidisciplinary coordination and proper patient selection, rates of breast recurrences have improved to the excellent levels achieved when surgery is performed first. New clinical trials are also ongoing to define the role of sentinel lymph node surgery and regional lymph node radiation. PMID- 26063879 TI - Magnetic Resonance Imaging, Digital Mammography, and Sonography: Tumor Characteristics and Tumor Biology in Primary Setting. AB - The use of imaging in the arena of primary treatment for breast cancer is gaining importance as a technique for assessing response to chemotherapy as well as assessing the underlying tumor biology. Both mammography and ultrasound have traditionally been used, in addition to clinical evaluation, to evaluate response to treatment although they have shed little light on the underlying biological processes. Functional magnetic resonance imaging techniques have the ability to assess response to treatments in addition to providing valuable information on changes in tumor perfusion, vascular permeability, oxygenation, cellularity, proliferation, and metabolism both at baseline and after treatment. This noninvasive method of evaluating cellular function is of importance both as endpoints for clinical trials and to our understanding of the biological mechanisms of cancer. PMID- 26063880 TI - RECIST for Response (Clinical and Imaging) in Neoadjuvant Clinical Trials in Operable Breast Cancer. AB - Although approximately 70% of breast cancer patients demonstrate a clinical response on neoadjuvant systemic therapy on physical examination or on anatomic radiographic imaging, only 3%-40% achieve a pathologic complete response (pCR). Magnetic resonance imaging (MRI) is superior to physical examination, ultrasound, and mammography in response evaluation during neoadjuvant systemic therapy. The accuracy of breast MRI to predict pCR has a moderate sensitivity, but high specificity. The accuracy of anatomic imaging to assess residual disease and predict pCR depended on anatomic radiographic imaging cancer subtypes. Response monitoring using breast is accurate in triple-negative or HER2-positive tumors. It was inaccurate in estrogen receptor-positive/HER2-negative subtype. Another approach currently under investigation is dynamic contrast-enhanced MRI and diffusion weighted-imaging, (18)F-fluorodeoxyglucose positron emission tomography, fluorodeoxyglucose positron emission tomography/computed tomography. PMID- 26063881 TI - Early Surrogate Markers of Treatment Activity: Where Are We Now? AB - The assessment of new therapies in the adjuvant setting in early breast cancer requires large numbers of patients and many years of follow-up for results to be presented. Therefore, the neoadjuvant study setting, which allows for early prediction of treatment response in smaller patient sets, has become increasingly popular. Ki67 is the most commonly used and extensively studied intermediate biomarker of treatment activity and residual risk in neoadjuvant trials on endocrine therapy, new biological therapies, and chemotherapy. It is increasingly being used as a primary endpoint for new therapies particularly those added to endocrine therapy. The PeriOperative Endocrine Therapy for Individualizing Care (POETIC) trial, including more than 4000 postmenopausal, estrogen receptor (ER) positive patients randomly assigned to receive 2 weeks of presurgical treatment with an aromatase inhibitor or no further treatment, is the largest window-of opportunity trial conducted and is assessing the clinical utility of on-treatment Ki67 as a predictor of long-term outcome. For generalizability, Ki67 measurements in the POETIC and other trials need to use standard methodology. The International Working Group on Ki67 in Breast Cancer is conducting a series of studies to bring this to reality. PMID- 26063882 TI - Comprehensive Review on the Surrogate Endpoints of Efficacy Proposed or Hypothesized in the Scientific Community Today. AB - An intermediate endpoint is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest. A suitable intermediate endpoint in neoadjuvant trials of specific breast cancer subtypes is pathological complete response (pCR) rate, defined as no invasive (+/-noninvasive) residual cancer in breast and nodes at surgery. On the basis of available evidence, Food and Drug Administration the US allowed to use of pCR as a surrogate endpoint for accelerated approval process. However, surrogacy to long-term outcome remains an unresolved issue. Literature data provide indications that triple-negative, HER2 positive, and high-grade hormone receptor-positive breast cancer subtypes achieved the highest pCR rate; the prognostic impact of pCR on survival is established only for these aggressive subtypes. In the German experience, early response after two to four cycles of neoadjuvant treatment strongly correlated with both pCR rate and long-term outcome. Therefore, early response may be considered a predictive marker for pCR and used for driving clinical trial design. PMID- 26063883 TI - Neoadjuvant Treatment Approach: The Rosetta Stone for Breast Cancer? AB - Breast cancer represents a heterogeneous group of diseases with varied biological features, behavior, and response to therapy; thus, management of breast cancer relies on the availability of robust predictive and prognostic factors to support therapy decision-making. Traditionally, neoadjuvant treatment for breast cancer was preserved for locally advanced, converting an inoperable to a surgical resectable cancer. Neoadjuvant trials, additionally, offer: 1) the opportunity to evaluate new treatment options in a faster way and with fewer patients than large adjuvant trials; 2) to identify and validate the prognostic and predictive value of a marker with its association with clinical outcome in relation to the administered treatment. In this setting, thanks to new, affordable technologies which help to detail the molecular profiles of tumors, new trial designs based on new target therapies, like window-of-opportunity, are also suggested, as they represent the chance to identify tumor sensitivity or to overcome tumor resistance to the treatment used, based on its interaction with tumor biology in early tumor stages. However, clinicians and researchers should pay particular attention: In this setting, the safety of patients is paramount, given the exposure of potentially curable patients to investigational agents with limited safety experience, the definition of the study population and the study design, such as adaptive strategies, should limit patient exposure to ineffective agents, and intensify safety monitoring in the course of the treatment. Here, issues related to outcome determination in breast cancer, including some critical points of view, are presented. PMID- 26063884 TI - Neoadjuvant Chemotherapy: What Are the Benefits for the Patient and for the Investigator? AB - Neoadjuvant chemotherapy has several appealing potential benefits compared with classic adjuvant chemotherapy. Of these, the only proven benefit is to facilitate the surgical approach, either by converting an inoperable cancer to one that is operable, or by converting a patient who is felt to be a candidate for mastectomy to one who might be treated successfully with breast conserving therapy. Randomized trials comparing neoadjuvant chemotherapy with postoperative chemotherapy have failed to demonstrate prolongation of overall survival. The benefits of monitoring apparent response during neoadjuvant chemotherapy have not been proven. Conduct of phase II drug development trials in the neoadjuvant setting may be advantageous compared with performing such trials in the metastatic setting. However, such trials raise concerns that are not unavoidable but need to be addressed. PMID- 26063886 TI - The Perfect Pathology Report After Neoadjuvant Therapy. AB - Neoadjuvant therapy is increasingly being used in the management of breast cancer patients and, since comprehensive specimen handling and precise histological reporting is essential to assess the degree of response to therapy, histopathologists are acknowledged to play a key role in this multidisciplinary setting. However, as a matter of fact, only minimal guidelines for specimen handling are on record. This means that in every day routine practice it is not uncommon for oncologists to deal with pathology reports where important parameters are missing (such as formal comments about therapy response). According to the latest American Joint Committee on Cancer (AJCC) staging classification, posttreatment size of residual disease (ypT) should be estimated based on the best combination of imaging, gross and microscopic histological findings. Therefore, pathologists should ideally be provided with clinical and radiological information before proceeding with careful grossing. During the cut up, large sections or extensive mapping of samples submitted to microscopic evaluation should be carried out to reconstruct the disease extent: this is particularly crucial when the lesion is unapparent both at imaging and at macroscopic observation. Histopathological reports cannot preclude from mandatory information about the presence of residual invasive carcinoma, such as histotyping, staging (ypTNM), reevaluation of prognostic and predictive factors, and categorization of degree of response according to dedicated classification systems (performed by comparing pretreatment biopsies with surgical specimens). In this review we will analyze the critical issues in such an assessment and we will provide a pragmatic approach with the intent to aim at the "perfect" pathology report. PMID- 26063887 TI - Neoadjuvant Model for Testing Emerging Targeted Therapies in Breast Cancer. AB - Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that will potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need smaller sample sizes and are less expensive, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Recently the US Food and Drug Administration has released a draft Guidance to Industry, outlining a pathway to accelerated approval for neoadjuvant breast cancer therapies using pCR. The association between pCR and outcome is clear for chemotherapy in triple negative breast cancer and for HER2-targeted agents in HER2-positive disease, but might not hold true for other tumor subtypes such as luminal cancers. Since pCR is rarely achieved with either chemotherapy or endocrine therapy in hormone receptor-positive breast cancer, in this setting we need to identify different intermediate endpoints, which might be translational endpoints within "window-of opportunity," "residual disease," and "genome forward" trials. Prospective validation of effective noninvasive techniques for monitoring of residual disease burden could enhance the ability to identify promising targeted therapies in the neoadjuvant setting. PMID- 26063885 TI - Multiparametric and Multimodality Functional Radiological Imaging for Breast Cancer Diagnosis and Early Treatment Response Assessment. AB - Breast cancer is the second leading cause of cancer death among US women, and the chance of a woman developing breast cancer sometime during her lifetime is one in eight. Early detection and diagnosis to allow appropriate locoregional and systemic treatment are key to improve the odds of surviving its diagnosis. Emerging data also suggest that different breast cancer subtypes (phenotypes) may respond differently to available adjuvant therapies. There is a growing understanding that not all patients benefit equally from systemic therapies, and therapeutic approaches are being increasingly personalized based on predictive biomarkers of clinical benefit. Optimal use of established and novel radiological imaging methods, such as magnetic resonance imaging and positron emission tomography, which have different biophysical mechanisms can simultaneously identify key functional parameters. These methods provide unique multiparametric radiological signatures of breast cancer, that will improve the accuracy of early diagnosis, help select appropriate therapies for early stage disease, and allow early assessment of therapeutic benefit. PMID- 26063888 TI - IBC as a Rapidly Spreading Systemic Disease: Clinical and Targeted Approaches Using the Neoadjuvant Model. AB - Inflammatory breast cancer (IBC) is a rare and aggressive form of invasive breast cancer accounting for 2.5% of all breast cancer cases. It is characterized by rapid progression, younger age of onset as compared with other cancers, local and distant metastases, and lower overall survival. The multidisciplinary management of IBC includes neoadjuvant systemic chemotherapy, surgery, radiotherapy, and hormonal therapy in hormone receptor-positive disease. Pathological complete response represents an important prognostic factor suggesting IBC as the ideal in vivo model for therapeutic development. Molecular subtyping demonstrated higher frequency of basal-like an HER2 disease in IBC compared with non-IBC indicating the areas of novel therapeutic interventions. The prospective testing of HER2 targeted therapies (eg, trastuzumab and lapatinib) demonstrated the validity of this concept and the potential to change the outcome of this aggressive disease. PMID- 26063889 TI - Circulating Biomarkers for Prediction of Treatment Response. AB - For cancer management, predicting and monitoring response to treatment and disease progression longitudinally is crucial due to changes in tumor biology and therapy responsiveness over time. However, solid tumors are usually sampled only at time of initial diagnosis, as obtaining tissue biopsies is an invasive procedures with associated risks. Thus, there is a pressing need for approaches able to serially detect function-related reliable biomarkers reflecting treatment response and/or disease progression through easy noninvasive procedures, amenable for longitudinal analysis of tumor molecular features. Recent evidences indicate that blood and other body fluids could replace invasive surgical biopsies and represent a "liquid biopsy" containing cells and nucleic acids released by primary and metastatic lesions, reflecting their biological features and allowing identification of clinically useful biomarkers and treatment-induced cancer adaption processes. The development of new and highly sensitive technologies that allow to detect and characterize circulating tumor cells, to identify cell-free nucleic acids (circulating tumor-associated microRNAs and cancer-specific mutations in circulating DNA) and to measure their eventual dynamic changes represents therefore a major achievement for disease monitoring. However, notwithstanding preliminary findings support the prognostic and/or predictive role of this new generation of biomarkers, there are a number of technical and biological caveats that still require additional studies to demonstrate and validate their clinical utility. A unique opportunity to rapidly assess the contribution of circulating tumor cells and cell-free nucleic acids to patient management and to personalized medicine could derive by their combined consideration in the neoadjuvant setting. PMID- 26063891 TI - Chemotherapy and Cognitive Function in Breast Cancer Patients: The So-Called Chemo Brain. AB - Self-perceived problems of cognitive functioning after treatment for early-stage breast cancer have the potential to substantially affect the lives of patients. In the past two decades, neuropsychological studies have accumulated evidence of corresponding cognitive deficits that have mostly been attributed to neurotoxic effects of chemotherapy. Nevertheless, observations of impaired cognitive functioning already before the start of adjuvant or neoadjuvant chemotherapy question the singular role of chemotherapy for the causation of these deficits. The divergence between mostly subtle neuropsychological deficits and often dramatic subjective cognitive complaints as well as the lack of association between both in the majority of studies present an unsolved puzzle. Recent investigations that include brain imaging have begun to yield tentative answers in this regard. The present review aims at briefly summarizing and integrating the current evidence from clinical studies for purposes of patient counseling. PMID- 26063890 TI - Effect of Primary Letrozole Treatment on Tumor Expression of mTOR and HIF-1alpha and Relation to Clinical Response. AB - INTRODUCTION: Recently the combination of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the aromatase inhibitor exemestane has been shown to double the progression-free survival rate in advanced breast cancer. However, the effect of the interrelated pathways of hypoxia-inducible factor-1alpha (HIF 1alpha) and mTOR signaling, both of which are associated with a more aggressive breast cancer phenotype and endocrine resistance, on response in the neoadjuvant setting is unknown. We, therefore, have investigated the influence of these pathways with the aim of better defining those patients most likely to benefit from an endocrine-based therapy associated with/without mTOR inhibitors. PATIENTS AND METHODS: A total of 107 women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to 6 months of primary letrozole (2.5 mg/daily) (LET) or LET plus oral "metronomic" cyclophosphamide (50mg/daily) (LET CYC). Phospo-mTOR and HIF-1alpha were evaluated in tumor specimens collected before and after treatment using a tissue microarray format. RESULTS: LET-based therapy induced a downregulation of phospho-mTOR and HIF-1alpha expression (P = .0001 and P < .004, respectively). The reduction of HIF-1alpha expression observed was positively correlated with phospho-mTOR reduction (P < .03); however, no treatment interaction between the two proteins was detected. HIF 1alpha expression was significantly modulated by the treatment (P < .004) with a reduction both in the LET arm (45%, n = 36/80) (P = .05) and LET-CYC arm (55%, n = 44/80) (P = .04). HIF-1alpha reduction showed a relationship with clinical response confined in LET arm only (P < .03). CONCLUSIONS: In this neoadjuvant population, LET was able to modulate the phospho-mTOR and HIF-1alpha pathways and may define a subpopulation of nonresponders who may be most likely to benefit from mTOR inhibitors. PMID- 26063892 TI - High-Dose Chemotherapy With Autologous Hematopoietic Stem Cell Transplantation for High-Risk Primary Breast Cancer. AB - BACKGROUND: The efficacy of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation for breast cancer (BC) has been an area of intense controversy among the medical oncology community. Over the last decade, due to the presentation of negative results from early randomized studies, this approach has not longer been considered an option by the vast majority of medical oncologists. This article is aimed to clarify what happened and where we are now in this not exhausted field. METHODS: We critically revised the published literature regarding HDC in the setting of high-risk BC, including a recent meta-analysis using individual patient data from 15 randomized studies. RESULTS: A significant benefit by HDC in recurrence-free survival has been clearly documented in unselected patient populations. In HER2-negative population, particularly in the triple-negative disease, a positive effect of intensified therapy in overall survival is biologically plausible and supported by clinical evidence. Over the years HDC with support of adequate number of stem cells has become a safe treatment modality. CONCLUSIONS: The administration of higher doses of chemotherapy with stem cell support may still represent a therapeutic option (and not a recommendation) in selected BC patients. This approach should be investigated further. PMID- 26063893 TI - RNA Disruption and Drug Response in Breast Cancer Primary Systemic Therapy. AB - BACKGROUND: As there is now evidence that switching clinical nonresponders early in primary systemic therapy to alternate treatment regimens can enhance survival in some breast cancer patients, the need for a robust intermediate endpoint that can guide treatment response across all tumor subtypes is urgent. Recently, chemotherapy drugs have been shown to induce a decrease in RNA quality in tumor cells from breast cancer biopsies in some patients at midtherapy, and that this has been associated with subsequent achievement of pathological complete response (pCR). The decrease in RNA quality has been shown to be associated with RNA disruption; aberrant RNA bands visualized by RNA electrophoresis have been associated with subsequent tumor cell death. The objectives of these studies are to show that a new assay based on induction of RNA disruption in tumor cells by chemotherapy can stratify at midtherapy, pCR responders from non-pCR responders irrespective of clinical response and to present early evidence that clinically useful RNA disruption can be detected as early as 14 days after initiation of treatment. METHODS: RNA disruption in tumor cells was quantified by analysis of the RNA electrophoresis banding pattern and expressed as an RNA disruption index (RDI). To develop the RNA disruption assay (RDA), RDI was correlated with clinical outcome (pCR) from the NCIC-CTG MA.22 breast cancer clinical trial (ClinicalTrials.gov NCT00066443). RDA Zones were established by stratifying patients using RDI values into Zone 1, Zone 2, and Zone 3. Zone 3 included seven out of eight pCR responders, whereas Zone 1 contained no pCR responders. An intermediate zone (Zone 2) was established which contained one pCR. Subsequently, to determine early drug response, RNA disruption was examined by RDI after 14 days exposure to trastuzumab, zoledronic acid, or letrozole + cyclophosphamide +/ sorafenib therapy. RESULTS: In MA.22, RDA stratified 23 of 85 patients in Zone 1 as pCR nonresponders, 24 patients in Zone 2, an intermediate zone, and 38 patients in Zone 3, pCR responders and non-pCR patients who share RDI comparable to those achieving pCR. In the early response studies, after 14 days exposure to chemotherapy, some RNA disruption as measured by RDI elevation could be detected in 3/12 trastuzumab, 7/15 zoledronic acid, 5/29 letrozole + cyclophosphamide, and 5/23 letrozole + cyclophosphamide + sorafenib patients. CONCLUSIONS: RDA is a novel intermediate endpoint that has promise for clinical utility for breast cancers early in response-guided primary systemic therapy. PMID- 26063894 TI - Neoadjuvant Window Studies of Metformin and Biomarker Development for Drugs Targeting Cancer Metabolism. AB - There has been growing interest in the potential of the altered metabolic state typical of cancer cells as a drug target. The antidiabetes drug, metformin, is now under intense investigation as a safe method to modify cancer metabolism. Several studies have used window of opportunity in breast cancer patients before neoadjuvant chemotherapy to correlate gene expression analysis, metabolomics, immunohistochemical markers, and metabolic serum markers with those likely to benefit. We review the role metabolite measurement, functional imaging and gene sequencing analysis play in elucidating the effects of metabolically targeted drugs in cancer treatment and determining patient selection. PMID- 26063895 TI - Radiotherapy Issues After Neoadjuvant Chemotherapy. AB - Radiotherapy (RT) is standard following neoadjuvant chemotherapy (NCT) and breast conserving surgery. NCT leads to pathologic down-staging, allowing some patients to undergo breast-conserving therapy (BCT) instead of mastectomy. BCT can also be considered in select stage III patients who respond well to NCT. Clearly-negative surgical margins should be obtained in all patients undergoing BCT. RT is used selectively following NCT and mastectomy. Indications for RT have not been fully established; retrospective data and results from National Surgical Adjuvant Breast and Bowel Project B-18 and B-27 currently form the basis for recommending RT. Patients with locally advanced breast cancer should receive postmastectomy RT (PMRT). Patients with residual nodal involvement require PMRT. Stage I-II patients with a pathologic complete response do not require PMRT. Patients without residual nodal involvement, but with residual breast involvement represent an intermediate-risk group. NCT also provides down-staging in the axilla. The role of axillary RT in the setting of NCT is under investigation in ongoing randomized trials. PMID- 26063897 TI - Erratum. Cancer Survival: An Overview of Measures, Uses, and Interpretation. PMID- 26063898 TI - Erratum. Clinical Practice Guidelines on the Use of Integrative Therapies as Supportive Care in Patients Treated for Breast Cancer. PMID- 26063896 TI - International Expert Consensus on Primary Systemic Therapy in the Management of Early Breast Cancer: Highlights of the Fifth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, Cremona, Italy (2013). AB - Expert consensus-based recommendations regarding key issues in the use of primary (or neoadjuvant) systemic treatment (PST) in patients with early breast cancer are a valuable resource for practising oncologists. PST remains a valuable therapeutic approach for the assessment of biological antitumor activity and clinical efficacy of new treatments in clinical trials. Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need fewer patients and are less expensive than adjuvant trial, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Although pCR is an early clinical endpoint, its role as a surrogate for long-term outcomes is the key issue. New and better predictors of treatment efficacy are needed to improve treatment and outcomes. After PST, accurate management of post-treatment residual disease is mandatory. The surgery of the sentinel lymph-node could be an acceptable option to spare the axillary dissection in case of clinical negativity (N0) of the axilla at the diagnosis and/or after PST. No data exists yet to support the modulation of the extent of locoregional radiation therapy on the basis of the response attained after PST although trials are underway. PMID- 26063902 TI - Myosin II and dynamin control actin rings to mediate fission during activity dependent bulk endocytosis. PMID- 26063903 TI - Insights into social perception in autism. PMID- 26063905 TI - Loss of the neuron-specific F-box protein FBXO41 models an ataxia-like phenotype in mice with neuronal migration defects and degeneration in the cerebellum. AB - The cerebellum is crucial for sensorimotor coordination. The cerebellar architecture not only requires proper development but also long-term integrity to ensure accurate functioning. Developmental defects such as impaired neuronal migration or neurodegeneration are thus detrimental to the cerebellum and can result in movement disorders including ataxias. In this study, we identify FBXO41 as a novel CNS-specific F-box protein that localizes to the centrosome and the cytoplasm of neurons and demonstrate that cytoplasmic FBXO41 promotes neuronal migration. Interestingly, deletion of the FBXO41 gene results in a severely ataxic gait in mice, which show delayed neuronal migration of granule neurons in the developing cerebellum in addition to deformities and degeneration of the mature cerebellum. We show that FBXO41 is a critical factor, not only for neuronal migration in the cerebellum, but also for its long-term integrity. PMID- 26063904 TI - Disease mechanisms and therapeutic approaches in spinal muscular atrophy. AB - Motor neuron diseases are neurological disorders characterized primarily by the degeneration of spinal motor neurons, skeletal muscle atrophy, and debilitating and often fatal motor dysfunction. Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease of high incidence and severity and the most common genetic cause of infant mortality. SMA is caused by homozygous mutations in the survival motor neuron 1 (SMN1) gene and retention of at least one copy of the hypomorphic gene paralog SMN2. Early studies established a loss-of-function disease mechanism involving ubiquitous SMN deficiency and suggested SMN upregulation as a possible therapeutic approach. In recent years, greater knowledge of the central role of SMN in RNA processing combined with deep characterization of animal models of SMA has significantly advanced our understanding of the cellular and molecular basis of the disease. SMA is emerging as an RNA disease not limited to motor neurons, but one that involves dysfunction of motor circuits that comprise multiple neuronal subpopulations and possibly other cell types. Advances in SMA research have also led to the development of several potential therapeutics shown to be effective in animal models of SMA that are now in clinical trials. These agents offer unprecedented promise for the treatment of this still incurable neurodegenerative disease. PMID- 26063906 TI - Molecular mechanisms controlling the migration of striatal interneurons. AB - In the developing telencephalon, the medial ganglionic eminence (MGE) generates many cortical and virtually all striatal interneurons. While the molecular mechanisms controlling the migration of interneurons to the cortex have been extensively studied, very little is known about the nature of the signals that guide interneurons to the striatum. Here we report that the allocation of MGE derived interneurons in the developing striatum of the mouse relies on a combination of chemoattractive and chemorepulsive activities. Specifically, interneurons migrate toward the striatum in response to Nrg1/ErbB4 chemoattraction, and avoid migrating into the adjacent cortical territories by a repulsive activity mediated by EphB/ephrinB signaling. Our results also suggest that the responsiveness of MGE-derived striatal interneurons to these cues is at least in part controlled by the postmitotic activity of the transcription factor Nkx2-1. This study therefore reveals parallel mechanisms for the migration of MGE derived interneurons to the striatum and the cerebral cortex. PMID- 26063908 TI - Disrupting the supplementary motor area makes physical effort appear less effortful. AB - The perception of physical effort is relatively unaffected by the suppression of sensory afferences, indicating that this function relies mostly on the processing of the central motor command. Neural signals in the supplementary motor area (SMA) correlate with the intensity of effort, suggesting that the motor signal involved in effort perception could originate from this area, but experimental evidence supporting this view is still lacking. Here, we tested this hypothesis by disrupting neural activity in SMA, in primary motor cortex (M1), or in a control site by means of continuous theta-burst transcranial magnetic stimulation, while measuring effort perception during grip forces of different intensities. After each grip force exertion, participants had the opportunity to either accept or refuse to replicate the same effort for varying amounts of reward. In addition to the subjective rating of perceived exertion, effort perception was estimated on the basis of the acceptance rate, the effort replication accuracy, the influence of the effort exerted in trial t on trial t+1, and pupil dilation. We found that disruption of SMA activity, but not of M1, led to a consistent decrease in effort perception, whatever the measure used to assess it. Accordingly, we modeled effort perception in a structural equation model and found that only SMA disruption led to a significant alteration of effort perception. These findings indicate that effort perception relies on the processing of a signal originating from motor-related neural circuits upstream of M1 and that SMA is a key node of this network. PMID- 26063907 TI - Linkage analysis in a Dutch population isolate shows no major gene for left handedness or atypical language lateralization. AB - Cerebral dominance of language function and hand preference are suggested to be heritable traits with possible shared genetic background. However, joined genetic studies of these traits have never been conducted. We performed a genetic linkage study in 37 multigenerational human pedigrees of both sexes (consisting of 355 subjects) enriched with left-handedness in which we also measured language lateralization. Hand preference was measured with the Edinburgh Handedness Inventory, and language lateralization was measured with functional transcranial Doppler during language production. The estimated heritability of left-handedness and language lateralization in these pedigrees is 0.24 and 0.31, respectively. A parametric major gene model was tested for left-handedness. Nonparametric analyses were performed for left-handedness, atypical lateralization, and degree of language lateralization. We did not observe genome-wide evidence for linkage in the parametric or nonparametric analyses for any of the phenotypes tested. However, multiple regions showed suggestive evidence of linkage. The parametric model showed suggestive linkage for left-handedness in the 22q13 region [heterogeneity logarithm of odds (HLOD) = 2.18]. Nonparametric multipoint analysis of left-handedness showed suggestive linkage in the same region [logarithm of odds (LOD) = 2.80]. Atypical language lateralization showed suggestive linkage in the 7q34 region (LODMax = 2.35). For strength of language lateralization, we observed suggestive linkage in the 6p22 (LODMax = 2.54), 7q32 (LODMax = 1.93), and 9q33 (LODMax = 2.10) regions. We did not observe any overlap of suggestive genetic signal between handedness and the extent of language lateralization. The absence of significant linkage argues against the presence of a major gene coding for both traits; rather, our results are suggestive of these traits being two independent polygenic complex traits. PMID- 26063909 TI - Copula regression analysis of simultaneously recorded frontal eye field and inferotemporal spiking activity during object-based working memory. AB - Inferotemporal (IT) neurons are known to exhibit persistent, stimulus-selective activity during the delay period of object-based working memory tasks. Frontal eye field (FEF) neurons show robust, spatially selective delay period activity during memory-guided saccade tasks. We present a copula regression paradigm to examine neural interaction of these two types of signals between areas IT and FEF of the monkey during a working memory task. This paradigm is based on copula models that can account for both marginal distribution over spiking activity of individual neurons within each area and joint distribution over ensemble activity of neurons between areas. Considering the popular GLMs as marginal models, we developed a general and flexible likelihood framework that uses the copula to integrate separate GLMs into a joint regression analysis. Such joint analysis essentially leads to a multivariate analog of the marginal GLM theory and hence efficient model estimation. In addition, we show that Granger causality between spike trains can be readily assessed via the likelihood ratio statistic. The performance of this method is validated by extensive simulations, and compared favorably to the widely used GLMs. When applied to spiking activity of simultaneously recorded FEF and IT neurons during working memory task, we observed significant Granger causality influence from FEF to IT, but not in the opposite direction, suggesting the role of the FEF in the selection and retention of visual information during working memory. The copula model has the potential to provide unique neurophysiological insights about network properties of the brain. PMID- 26063910 TI - Respiratory modulation of spontaneous subthreshold synaptic activity in olfactory bulb granule cells recorded in awake, head-fixed mice. AB - Although the firing patterns of principal neurons in the olfactory bulb are known to be modulated strongly by respiration even under basal conditions, less is known about whether inhibitory local circuit activity in the olfactory bulb (OB) is modulated phasically. The diverse phase preferences of principal neurons in the OB and olfactory cortex that innervate granule cells (GCs) may interfere and prevent robust respiratory coupling, as suggested by recent findings. Using whole cell recording, we examined the spontaneous, subthreshold membrane potential of GCs in the OBs of awake head-fixed mice. We found that, during periods of basal respiration, the synaptic input to GCs was strongly phase modulated, leading to a phase preference in the average, cycle-normalized membrane potential. Subthreshold phase tuning was heterogeneous in both mitral and tufted cells (MTCs) and GCs but relatively constant within each GC during periods of increased respiratory frequency. The timing of individual EPSPs in GC recordings also was phase modulated with the phase preference imparted by large-amplitude EPSPs, with fast kinetics often matching the phase tuning of the average membrane potential. These results suggest that activity in a subset of excitatory afferents to GCs, presumably including cortical feedback projections and other sources of large amplitude unitary EPSPs, function to provide a timing signal linked to respiration. The phase preference we find in the membrane potential may provide a mechanism to dynamically modulate recurrent and lateral dendrodendritic inhibition of MTCs and to selective engage a subpopulation of interneurons based on the alignment of their phase tuning relative to sensory-driven MTC discharges. PMID- 26063911 TI - Time-varying effective connectivity during visual object naming as a function of semantic demands. AB - Accumulating evidence suggests that visual object understanding involves a rapid feedforward sweep, after which subsequent recurrent interactions are necessary. The extent to which recurrence plays a critical role in object processing remains to be determined. Recent studies have demonstrated that recurrent processing is modulated by increasing semantic demands. Differentially from previous studies, we used dynamic causal modeling to model neural activity recorded with magnetoencephalography while 14 healthy humans named two sets of visual objects that differed in the degree of semantic accessing demands, operationalized in terms of the values of basic psycholinguistic variables associated with the presented objects (age of acquisition, frequency, and familiarity). This approach allowed us to estimate the directionality of the causal interactions among brain regions and their associated connectivity strengths. Furthermore, to understand the dynamic nature of connectivity (i.e., the chronnectome; Calhoun et al., 2014) we explored the time-dependent changes of effective connectivity during a period (200-400 ms) where adding semantic-feature information improves modeling and classifying visual objects, at 50 ms increments. First, we observed a graded involvement of backward connections, that became active beyond 200 ms. Second, we found that semantic demands caused a suppressive effect in the backward connection from inferior frontal cortex (IFC) to occipitotemporal cortex over time. These results complement those from previous studies underscoring the role of IFC as a common source of top-down modulation, which drives recurrent interactions with more posterior regions during visual object recognition. Crucially, our study revealed the inhibitory modulation of this interaction in situations that place greater demands on the conceptual system. PMID- 26063912 TI - Motion makes sense: an adaptive motor-sensory strategy underlies the perception of object location in rats. AB - Tactile perception is obtained by coordinated motor-sensory processes. We studied the processes underlying the perception of object location in freely moving rats. We trained rats to identify the relative location of two vertical poles placed in front of them and measured at high resolution the motor and sensory variables (19 and 2 variables, respectively) associated with this whiskers-based perceptual process. We found that the rats developed stereotypic head and whisker movements to solve this task, in a manner that can be described by several distinct behavioral phases. During two of these phases, the rats' whiskers coded object position by first temporal and then angular coding schemes. We then introduced wind (in two opposite directions) and remeasured their perceptual performance and motor-sensory variables. Our rats continued to perceive object location in a consistent manner under wind perturbations while maintaining all behavioral phases and relatively constant sensory coding. Constant sensory coding was achieved by keeping one group of motor variables (the "controlled variables") constant, despite the perturbing wind, at the cost of strongly modulating another group of motor variables (the "modulated variables"). The controlled variables included coding-relevant variables, such as head azimuth and whisker velocity. These results indicate that consistent perception of location in the rat is obtained actively, via a selective control of perception-relevant motor variables. PMID- 26063913 TI - Vision loss shifts the balance of feedforward and intracortical circuits in opposite directions in mouse primary auditory and visual cortices. AB - Loss of a sensory modality leads to widespread changes in synaptic function across sensory cortices, which are thought to be the basis for cross-modal adaptation. Previous studies suggest that experience-dependent cross-modal regulation of the spared sensory cortices may be mediated by changes in cortical circuits. Here, we report that loss of vision, in the form of dark exposure (DE) for 1 week, produces laminar-specific changes in excitatory and inhibitory circuits in the primary auditory cortex (A1) of adult mice to promote feedforward (FF) processing and also strengthens intracortical inputs to primary visual cortex (V1). Specifically, DE potentiated FF excitatory synapses from layer 4 (L4) to L2/3 in A1 and recurrent excitatory inputs in A1-L4 in parallel with a reduction in the strength of lateral intracortical excitatory inputs to A1-L2/3. This suggests a shift in processing in favor of FF information at the expense of intracortical processing. Vision loss also strengthened inhibitory synaptic function in L4 and L2/3 of A1, but via laminar specific mechanisms. In A1-L4, DE specifically potentiated the evoked synaptic transmission from parvalbumin positive inhibitory interneurons to principal neurons without changes in spontaneous miniature IPSCs (mIPSCs). In contrast, DE specifically increased the frequency of mIPSCs in A1-L2/3. In V1, FF excitatory inputs were unaltered by DE, whereas lateral intracortical connections in L2/3 were strengthened, suggesting a shift toward intracortical processing. Our results suggest that loss of vision produces distinct circuit changes in the spared and deprived sensory cortices to shift between FF and intracortical processing to allow adaptation. PMID- 26063914 TI - Generalization in category learning: the roles of representational and decisional uncertainty. AB - Effective generalization in a multiple-category situation involves both assessing potential membership in individual categories and resolving conflict between categories while implementing a decision bound. We separated generalization from decision bound implementation using an information integration task in which category exemplars varied over two incommensurable feature dimensions. Human subjects first learned to categorize stimuli within limited training regions, and then, during fMRI scanning, they also categorized transfer stimuli from new regions of perceptual space. Transfer stimuli differed both in distance from the training region prototype and distance from the decision bound, allowing us to independently assess neural systems sensitive to each. Across all stimulus regions, categorization was associated with activity in the extrastriate visual cortex, basal ganglia, and the bilateral intraparietal sulcus. Categorizing stimuli near the decision bound was associated with recruitment of the frontoinsular cortex and medial frontal cortex, regions often associated with conflict and which commonly coactivate within the salience network. Generalization was measured in terms of greater distance from the decision bound and greater distance from the category prototype (average training region stimulus). Distance from the decision bound was associated with activity in the superior parietal lobe, lingual gyri, and anterior hippocampus, whereas distance from the prototype was associated with left intraparietal sulcus activity. The results are interpreted as supporting the existence of different uncertainty resolution mechanisms for uncertainty about category membership (representational uncertainty) and uncertainty about decision bound (decisional uncertainty). PMID- 26063915 TI - Endogenous sequential cortical activity evoked by visual stimuli. AB - Although the functional properties of individual neurons in primary visual cortex have been studied intensely, little is known about how neuronal groups could encode changing visual stimuli using temporal activity patterns. To explore this, we used in vivo two-photon calcium imaging to record the activity of neuronal populations in primary visual cortex of awake mice in the presence and absence of visual stimulation. Multidimensional analysis of the network activity allowed us to identify neuronal ensembles defined as groups of cells firing in synchrony. These synchronous groups of neurons were themselves activated in sequential temporal patterns, which repeated at much higher proportions than chance and were triggered by specific visual stimuli such as natural visual scenes. Interestingly, sequential patterns were also present in recordings of spontaneous activity without any sensory stimulation and were accompanied by precise firing sequences at the single-cell level. Moreover, intrinsic dynamics could be used to predict the occurrence of future neuronal ensembles. Our data demonstrate that visual stimuli recruit similar sequential patterns to the ones observed spontaneously, consistent with the hypothesis that already existing Hebbian cell assemblies firing in predefined temporal sequences could be the microcircuit substrate that encodes visual percepts changing in time. PMID- 26063916 TI - Potent KCNQ2/3-specific channel activator suppresses in vivo epileptic activity and prevents the development of tinnitus. AB - Voltage-gated Kv7 (KCNQ) channels are voltage-dependent potassium channels that are activated at resting membrane potentials and therefore provide a powerful brake on neuronal excitability. Genetic or experience-dependent reduction of KCNQ2/3 channel activity is linked with disorders that are characterized by neuronal hyperexcitability, such as epilepsy and tinnitus. Retigabine, a small molecule that activates KCNQ2-5 channels by shifting their voltage-dependent opening to more negative voltages, is an US Food and Drug Administration (FDA) approved anti-epileptic drug. However, recently identified side effects have limited its clinical use. As a result, the development of improved KCNQ2/3 channel activators is crucial for the treatment of hyperexcitability-related disorders. By incorporating a fluorine substituent in the 3-position of the tri aminophenyl ring of retigabine, we synthesized a small-molecule activator (SF0034) with novel properties. Heterologous expression of KCNQ2/3 channels in HEK293T cells showed that SF0034 was five times more potent than retigabine at shifting the voltage dependence of KCNQ2/3 channels to more negative voltages. Moreover, unlike retigabine, SF0034 did not shift the voltage dependence of either KCNQ4 or KCNQ5 homomeric channels. Conditional deletion of Kcnq2 from cerebral cortical pyramidal neurons showed that SF0034 requires the expression of KCNQ2/3 channels for reducing the excitability of CA1 hippocampal neurons. Behavioral studies demonstrated that SF0034 was a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 provides, not only a powerful tool for investigating ion channel properties, but, most importantly, it provides a clinical candidate for treating epilepsy and preventing tinnitus. PMID- 26063917 TI - mTORC2/rictor signaling disrupts dopamine-dependent behaviors via defects in striatal dopamine neurotransmission. AB - Disrupted neuronal protein kinase B (Akt) signaling has been associated with dopamine (DA)-related neuropsychiatric disorders, including schizophrenia, a devastating mental illness. We hypothesize that proper DA neurotransmission is therefore dependent upon intact neuronal Akt function. Akt is activated by phosphorylation of two key residues: Thr308 and Ser473. Blunted Akt phosphorylation at Ser473 (pAkt-473) has been observed in lymphocytes and postmortem brains of schizophrenia patients, and psychosis-prone normal individuals. Mammalian target of rapamycin (mTOR) complex 2 (mTORC2) is a multiprotein complex that is responsible for phosphorylation of Akt at Ser473 (pAkt-473). We demonstrate that mice with disrupted mTORC2 signaling in brain exhibit altered striatal DA-dependent behaviors, such as increased basal locomotion, stereotypic counts, and exaggerated response to the psychomotor effects of amphetamine (AMPH). Combining in vivo and ex vivo pharmacological, electrophysiological, and biochemical techniques, we demonstrate that the changes in striatal DA neurotransmission and associated behaviors are caused, at least in part, by elevated D2 DA receptor (D2R) expression and upregulated ERK1/2 activation. Haloperidol, a typical antipsychotic and D2R blocker, reduced AMPH hypersensitivity and elevated pERK1/2 to the levels of control animals. By viral gene delivery, we downregulated mTORC2 solely in the dorsal striatum of adult wild-type mice, demonstrating that striatal mTORC2 regulates AMPH-stimulated behaviors. Our findings implicate mTORC2 signaling as a novel pathway regulating striatal DA tone and D2R signaling. PMID- 26063918 TI - Mechanisms of mouse neural precursor expansion after neonatal hypoxia-ischemia. AB - Neonatal hypoxia-ischemia (H-I) is the leading cause of brain damage resulting from birth complications. Studies in neonatal rats have shown that H-I acutely expands the numbers of neural precursors (NPs) within the subventricular zone (SVZ). The aim of these studies was to establish which NPs expand after H-I and to determine how leukemia inhibitory factor (LIF) insufficiency affects their response. During recovery from H-I, the number of Ki67(+) cells in the medial SVZ of the injured hemisphere increased. Similarly, the number and size of primary neurospheres produced from the injured SVZ increased approximately twofold versus controls, and, upon differentiation, more than twice as many neurospheres from the damaged brain were tripotential, suggesting an increase in neural stem cells (NSCs). However, multimarker flow cytometry for CD133/LeX/NG2/CD140a combined with EdU incorporation revealed that NSC frequency diminished after H-I, whereas that of two multipotential progenitors and three unique glial-restricted precursors expanded, attributable to changes in their proliferation. By quantitative PCR, interleukin-6, LIF, and CNTF mRNA increased but with significantly different time courses, with LIF expression correlating best with NP expansion. Therefore, we evaluated the NP response to H-I in LIF haplodeficient mice. Flow cytometry revealed that one subset of multipotential and bipotential intermediate progenitors did not increase after H-I, whereas another subset was amplified. Altogether, our studies demonstrate that neonatal H I alters the composition of the SVZ and that LIF is a key regulator for a subset of intermediate progenitors that expand during acute recovery from neonatal H-I. PMID- 26063919 TI - Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus. AB - We identified a family in which a translocation between chromosomes X and 14 was associated with cognitive impairment and a complex genetic disorder termed "Genetic Epilepsy and Febrile Seizures Plus" (GEFS(+)). We demonstrate that the breakpoint on the X chromosome disrupted a gene that encodes an auxiliary protein of voltage-gated Na(+) channels, fibroblast growth factor 13 (Fgf13). Female mice in which one Fgf13 allele was deleted exhibited hyperthermia-induced seizures and epilepsy. Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of hippocampus. Electrophysiological recordings revealed decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons of Fgf13 mutants. We speculate that reduced expression of Fgf13 impairs excitability of inhibitory interneurons, resulting in enhanced excitability within local circuits of hippocampus and the clinical phenotype of epilepsy. These findings reveal a novel cause of this syndrome and underscore the powerful role of FGF13 in control of neuronal excitability. PMID- 26063920 TI - Spinocerebellar ataxia type 6 protein aggregates cause deficits in motor learning and cerebellar plasticity. AB - Spinocerebellar ataxia type 6 (SCA6) is linked to poly-glutamine (polyQ) within the C terminus (CT) of the pore-forming subunits of P/Q-type Ca(2+) channels (Cav2.1) and is characterized by CT protein aggregates found in cerebellar Purkinje cells (PCs). One hypothesis regarding SCA6 disease is that a CT fragment of the Cav2.1 channel, which is detected specifically in cytosolic and nuclear fractions in SCA6 patients, is associated with the SCA6 pathogenesis. To test this hypothesis, we expressed P/Q-type channel protein fragments from two different human CT splice variants, as predicted from SCA6 patients, in PCs of mice using viral and transgenic approaches. These splice variants represent a short (CT-short without polyQs) and a long (CT-long with 27 polyQs) CT fragment. Our results show that the different splice variants of the CTs differentially distribute within PCs, i.e., the short CTs reveal predominantly nuclear inclusions, whereas the long CTs prominently reveal both nuclear and cytoplasmic aggregates. Postnatal expression of CTs in PCs in mice reveals that only CT-long causes SCA6-like symptoms, i.e., deficits in eyeblink conditioning (EBC), ataxia, and PC degeneration. The physiological phenotypes associated specifically with the long CT fragment can be explained by an impairment of LTD and LTP at the parallel fiber-to-PC synapse and alteration in spontaneous PC activity. Thus, our results suggest that the polyQ carrying the CT fragment of the P/Q-type channel is sufficient to cause SCA6 pathogenesis in mice and identifies EBC as a new diagnostic strategy to evaluate Ca(2+) channel-mediated human diseases. PMID- 26063921 TI - Differential patterns of amygdala and ventral striatum activation predict gender specific changes in sexual risk behavior. AB - Although the initiation of sexual behavior is common among adolescents and young adults, some individuals express this behavior in a manner that significantly increases their risk for negative outcomes including sexually transmitted infections. Based on accumulating evidence, we have hypothesized that increased sexual risk behavior reflects, in part, an imbalance between neural circuits mediating approach and avoidance in particular as manifest by relatively increased ventral striatum (VS) activity and relatively decreased amygdala activity. Here, we test our hypothesis using data from seventy 18- to 22-year-old university students participating in the Duke Neurogenetics Study. We found a significant three-way interaction between amygdala activation, VS activation, and gender predicting changes in the number of sexual partners over time. Although relatively increased VS activation predicted greater increases in sexual partners for both men and women, the effect in men was contingent on the presence of relatively decreased amygdala activation and the effect in women was contingent on the presence of relatively increased amygdala activation. These findings suggest unique gender differences in how complex interactions between neural circuit function contributing to approach and avoidance may be expressed as sexual risk behavior in young adults. As such, our findings have the potential to inform the development of novel, gender-specific strategies that may be more effective at curtailing sexual risk behavior. PMID- 26063922 TI - Neural activity selects myosin IIB and VI with a specific time window in distinct dynamin isoform-mediated synaptic vesicle reuse pathways. AB - Presynaptic nerve terminals must maintain stable neurotransmissions via synaptic vesicle (SV) resupply despite encountering wide fluctuations in the number and frequency of incoming action potentials (APs). However, the molecular mechanism linking variation in neural activity to SV resupply is unknown. Myosins II and VI are actin-based cytoskeletal motors that drive dendritic actin dynamics and membrane transport, respectively, at brain synapses. Here we combined genetic knockdown or molecular dysfunction and direct physiological measurement of fast synaptic transmission from paired rat superior cervical ganglion neurons in culture to show that myosins IIB and VI work individually in SV reuse pathways, having distinct dependency and time constants with physiological AP frequency. Myosin VI resupplied the readily releasable pool (RRP) with slow kinetics independently of firing rates but acted quickly within 50 ms after AP. Under high frequency AP firing, myosin IIB resupplied the RRP with fast kinetics in a slower time window of 200 ms. Knockdown of both myosin and dynamin isoforms by mixed siRNA microinjection revealed that myosin IIB-mediated SV resupply follows amphiphysin/dynamin-1-mediated endocytosis, while myosin VI-mediated SV resupply follows dynamin-3-mediated endocytosis. Collectively, our findings show how distinct myosin isoforms work as vesicle motors in appropriate SV reuse pathways associated with specific firing patterns. PMID- 26063923 TI - Computational modeling of resting-state activity demonstrates markers of normalcy in children with prenatal or perinatal stroke. AB - Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere "take over" their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children. PMID- 26063924 TI - The phase difference between neural drives to antagonist muscles in essential tremor is associated with the relative strength of supraspinal and afferent input. AB - The pathophysiology of essential tremor (ET), the most common movement disorder, is not fully understood. We investigated which factors determine the variability in the phase difference between neural drives to antagonist muscles, a long standing observation yet unexplained. We used a computational model to simulate the effects of different levels of voluntary and tremulous synaptic input to antagonistic motoneuron pools on the tremor. We compared these simulations to data from 11 human ET patients. In both analyses, the neural drive to muscle was represented as the pooled spike trains of several motor units, which provides an accurate representation of the common synaptic input to motoneurons. The simulations showed that, for each voluntary input level, the phase difference between neural drives to antagonist muscles is determined by the relative strength of the supraspinal tremor input to the motoneuron pools. In addition, when the supraspinal tremor input to one muscle was weak or absent, Ia afferents provided significant common tremor input due to passive stretch. The simulations predicted that without a voluntary drive (rest tremor) the neural drives would be more likely in phase, while a concurrent voluntary input (postural tremor) would lead more frequently to an out-of-phase pattern. The experimental results matched these predictions, showing a significant change in phase difference between postural and rest tremor. They also indicated that the common tremor input is always shared by the antagonistic motoneuron pools, in agreement with the simulations. Our results highlight that the interplay between supraspinal input and spinal afferents is relevant for tremor generation. PMID- 26063925 TI - Reduction of empathy for pain by placebo analgesia suggests functional equivalence of empathy and first-hand emotion experience. AB - Previous research in social neuroscience has consistently shown that empathy for pain recruits brain areas that are also activated during the first-hand experience of pain. This has been interpreted as evidence that empathy relies upon neural processes similar to those underpinning the first-hand experience of emotions. However, whether such overlapping neural activations imply that equivalent neural functions are engaged by empathy and direct emotion experiences remains to be demonstrated. We induced placebo analgesia, a phenomenon specifically modulating the first-hand experience of pain, to test whether this also reduces empathy for pain. Subjective and neural measures of pain and empathy for pain were collected using self-report and event-related potentials (ERPs) while participants underwent painful electrical stimulation or witnessed that another person was undergoing such stimulation. Self-report showed decreased empathy during placebo analgesia, and this was mirrored by reduced amplitudes of the pain-related P2, an ERP component indexing neural computations related to the affective-motivational component of pain. Moreover, these effects were specific for pain, as self-report and ERP measures of control conditions unrelated to pain were not affected by placebo analgesia. Together, the present results suggest that empathy seems to rely on neural processes that are (partially) functionally equivalent to those engaged by first-hand emotion experiences. Moreover, they imply that analgesics may have the unwanted side effect of reducing empathic resonance and concern for others. PMID- 26063928 TI - Impact of collaterals on the efficacy and safety of endovascular treatment in acute ischaemic stroke: a systematic review and meta-analysis. AB - OBJECTIVE: We aimed to investigate the role of pretreatment collateral status in predicting the efficacy and safety of endovascular treatment (EVT) in acute ischaemic stroke due to cervical and/or cerebral arterial occlusions. METHODS: Relevant full-text articles published since 1 January 2000, investigating correlations between collateral status and any efficacy or safety outcome in patients undergoing EVT in cohort or case-control studies, or randomised clinical trials, were retrieved by PubMed and manual search. Two authors extracted data from eligible studies and assessed study quality. Risk ratios (RR) were pooled for good versus poor collaterals for outcomes based on a random-effects model. Sensitivity and subgroup analyses were conducted. RESULTS: In total, 35 (3542 participants) and 23 (2652 participants) studies were included in qualitative review and quantitative meta-analysis, respectively. Overall, good pretreatment collaterals increased the rate of favourable functional outcome at 3 months (RR=1.98, 95% CI 1.64 to 2.38; p<0.001), and reduced the risks of periprocedural symptomatic intracranial haemorrhage (RR=0.59, 95% CI 0.43 to 0.81; p=0.001) and 3-month mortality (RR=0.49, 95% CI 0.38 to 0.63; p<0.001), as compared with poor collaterals, in patients with acute ischaemic stroke under EVT. No individual study could alter the estimate of overall effect of collateral status, but there were moderate to significant heterogeneities between subgroups of studies with different modes of EVT, different arterial occlusions and different collateral grading methods. CONCLUSIONS: Good pretreatment collateral status is associated with higher rates of favourable functional outcome, and lower rates of symptomatic intracranial haemorrhage and mortality, in patients with acute ischaemic stroke receiving endovascular therapies. PMID- 26063926 TI - Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c Fos activation in a DNA methylation-dependent manner. AB - Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway. PMID- 26063927 TI - The role of G-protein receptor 84 in experimental neuropathic pain. AB - G-protein receptor 84 (GPR84) is an orphan receptor that is induced markedly in monocytes/macrophages and microglia during inflammation, but its pathophysiological function is unknown. Here, we investigate the role of GPR84 in a murine model of traumatic nerve injury. Naive GPR84 knock-out (KO) mice exhibited normal behavioral responses to acute noxious stimuli, but subsequent to partial sciatic nerve ligation (PNL), KOs did not develop mechanical or thermal hypersensitivity, in contrast to wild-type (WT) littermates. Nerve injury increased ionized calcium binding adapter molecule 1 (Iba1) and phosphorylated p38 MAPK immunoreactivity in the dorsal horn and Iba1 and cluster of differentiation 45 expression in the sciatic nerve, with no difference between genotypes. PCR array analysis revealed that Gpr84 expression was upregulated in the spinal cord and sciatic nerve of WT mice. In addition, the expression of arginase-1, a marker for anti-inflammatory macrophages, was upregulated in KO sciatic nerve. Based on this evidence, we investigated whether peripheral macrophages behave differently in the absence of GPR84. We found that lipopolysaccharide-stimulated KO macrophages exhibited attenuated expression of several proinflammatory mediators, including IL-1beta, IL-6, and TNF-alpha. Forskolin-stimulated KO macrophages also showed greater cAMP induction, a second messenger associated with immunosuppression. In summary, our results demonstrate that GPR84 is a proinflammatory receptor that contributes to nociceptive signaling via the modulation of macrophages, whereas in its absence the response of these cells to an inflammatory insult is impaired. PMID- 26063929 TI - Predictive value of transcranial evoked potentials during mechanical endovascular therapy for acute ischaemic stroke: a feasibility study. AB - BACKGROUND AND PURPOSE: Mechanical endovascular therapy (MET) is a promising adjuvant or stand-alone therapy for acute ischaemic stroke caused by occlusion of a large vessel. Real-time monitoring of recanalisation success with regard to functional outcome is usually not possible because these procedures are mainly performed under general anaesthesia. We present a novel application for evoked potential monitoring for real-time evaluation of reperfusion success with respect to functional outcome during MET for acute ischaemic stroke. METHODS: Prospective observational study from March 2012 to April 2013 of patients presenting with acute ischaemic stroke who were eligible for MET. Transcranial motor evoked potentials (MEPs) and somatosensory evoked potentials (SSEPs) were measured bilaterally during MET throughout the intervention. The electrophysiological data of the contralateral side served as control. Neurological outcome was assessed by the modified Rankin Scale and National Institutes of Health Stroke Scale at 0, 7 and 90 days following intervention. RESULTS: 20 patients were examined. MEPs and SSEPs were technically successful in 19 (95%) and 9 (45%) cases, respectively. Successful reperfusion was achieved in 16 cases. Functional recovery was observed in 14 patients. MEPs and SSEPs recovery status was a better predictor of functional recovery than successful reperfusion with a positive predictive value of 92%, 83% and 75% for MEPs, SSEPs and reperfusion, respectively. CONCLUSIONS: MEPs and SSEPs are safe and feasible methods of real-time monitoring of reperfusion success with respect to functional outcome during MET for acute ischaemic stroke. PMID- 26063930 TI - Clinicoradiological comparisons between vascular parkinsonism and Parkinson's disease. PMID- 26063931 TI - Is it necessary to split nitrogen fertilization for winter wheat? On-farm research on Luvisols in South-West Germany. AB - Mineral nitrogen (N) fertilization in cereals is commonly split into three or four applications. In order to simplify N fertilization, a single N application either broadcast or placed on the soil surface was compared to conventionally split fertilization for winter wheat (Triticum aestivum L.). The 4-year experiment (2007-2010) was performed using a participatory approach on farmers' fields on deep loamy soils (Luvisols) in South-West Germany. Grain yield and crude protein contents differed only slightly or not at all between treatments including different N fertilizer types (calcium ammonium nitrate, urea ammonium nitrate solution, urea) and application techniques (broadcast, placed). Furthermore, no differences were found for the yield components ears/m2 and thousand grain weight. Inorganic N in the soil profile after harvest was generally below 40 kg N/ha and did not differ between treatments. In the area where N was placed, mineral N was depleted during the vegetation period. At the experimental sites a single N application in the period between tillering and stem elongation was sufficient to achieve high yield and quality of winter wheat without increased risk of nitrate leaching. This finding was independent of the method of application or the type of fertilizer. PMID- 26063932 TI - Alternative Synthesis and Structures of C-monoacetylenic Phosphaalkenes. AB - An alternative synthesis of C-monoacetylenic phosphaalkenes trans Mes*P=C(Me)(C=CR) (Mes* = 2, 4, 6-tBu3Ph, R = Ph, SiMe3) from C bromophosphaalkenes cis-Mes*P=C(Me)Br using standard Sonogashira coupling conditions is described. Crystallographic studies confirm cis-trans isomerization of the P=C double bond during Pd-catalyzed cross coupling, leading exclusively to trans-acetylenic phosphaalkenes. Crystallographic studies of all synthesized compounds reveal the extend of pi-conjugation over the acetylene and P=C pi systems. PMID- 26063933 TI - Challenges and Opportunities for Customizing Polyhydroxyalkanoates. AB - Polyhydroxyalkanoates (PHAs) as an alternative to synthetic plastics have been gaining increasing attention. Being natural in their origin, PHAs are completely biodegradable and eco-friendly. However, consistent efforts to exploit this biopolymer over the last few decades have not been able to pull PHAs out of their nascent stage, inspite of being the favorite of the commercial world. The major limitations are: (1) the high production cost, which is due to the high cost of the feed and (2) poor thermal and mechanical properties of polyhydroxybutyrate (PHB), the most commonly produced PHAs. PHAs have the physicochemical properties which are quite comparable to petroleum based plastics, but PHB being homopolymers are quite brittle, less elastic and have thermal properties which are not suitable for processing them into sturdy products. These properties, including melting point (Tm), glass transition temperature (Tg), elastic modulus, tensile strength, elongation etc. can be improved by varying the monomeric composition and molecular weight. These enhanced characteristics can be achieved by modifications in the types of substrates, feeding strategies, culture conditions and/or genetic manipulations. PMID- 26063934 TI - Genome Wide Analysis for Searching Novel Markers to Rapidly Identify Clostridium Strains. AB - Microbial classification is based largely on the 16S rRNA (rrs) gene sequence, which is conserved throughout the prokaryotic domain. The Ribosomal Database Project (RDP) has become a reference point for almost all practical purposes. The use of this gene is limited by the fact that it can be used to identify only to the extent to what has been known and is available in the RDP. In order to identify an organism whose rrs is not present in the RDP database, we need to generate novel markers to place the unknown on the evolutionary map. Here, sequenced genomes of 27 Clostridium strains belonging to 9 species have been used to identify two sets of genes: (1) common to most of the species, and (2) unique to a species. Combinations of genes (recN, dnaJ, secA, mutS, and/or grpE) and their unique restriction endonuclease digestion (AluI, BfaI and/or Tru9I) patterns have been established to rapidly identify Clostridium species. This strategy for identifying novel markers can be extended to all other organisms and diagnostic applications. PMID- 26063935 TI - Enhancing Degradation of Low Density Polyethylene Films by Curvularia lunata SG1 Using Particle Swarm Optimization Strategy. AB - ABSTRACT: In the present study, artificial neural network (ANN) modelling coupled with particle swarm optimization (PSO) algorithm was used to optimize the process variables for enhanced low density polyethylene (LDPE) degradation by Curvularia lunata SG1. In the non-linear ANN model, temperature, pH, contact time and agitation were used as input variables and polyethylene bio-degradation as the output variable. Further, on application of PSO to the ANN model, the optimum values of the process parameters were as follows: pH = 7.6, temperature = 37.97 degrees C, agitation rate = 190.48 rpm and incubation time = 261.95 days. A comparison between the model results and experimental data gave a high correlation coefficient ([Formula: see text]). Significant enhancement of LDPE bio-degradation using C. lunata SG1by about 48 % was achieved under optimum conditions. Thus, the novelty of the work lies in the application of combination of ANN-PSO as optimization strategy to enhance the bio-degradation of LDPE. PMID- 26063936 TI - Diversity of the Intestinal Bacteria of Cattle Fed on Diets with Different Doses of Gelatinized Starch-Urea. AB - Gelatinized starch-urea (Starea, SU) is an effective and economical source of urea for ruminants. Here we assessed the influence of dietary supplementation with gelatinized starch-urea on the diversity of intestinal bacteria in finishing cattle. Fifty steers were randomly allotted to five treatments with diets supplemented with different doses of Starea [0 % (SU0), 8 % (SU8), 16 % (SU16), 24 % (SU24), and 32 % (SU32) of urea-N in total nitrogen]. Denaturing gradient gel electrophoresis (DGGE) of 16S rRNA genes was used to examine the effect of dietary supplementation of Starea on intestinal bacterial flora. Shannon-Weaver and Simpson diversity indices consistently showed the lowest bacterial diversity in the SU0 treatment. Increasing doses of Starea increased the diversity up to SU24 after which, diversity decreased. Cluster analysis of 16S rRNA gene DGGE profiles indicates that the intestinal bacterial communities associated with cattle that were not supplemented with Starea in feed differed in composition and structure from those supplemented with Starea. The amount of Starea supplemented in cattle diets influenced the abundance of several key species affiliated with Lachnospiraceae, Ruminococcaceae, Peptostreptococcaceae, Comamonadaceae and Moraxellaceae. These results suggest that Starea influences the composition and structure of intestinal bacteria which may play a role in promoting ruminant health and production performance. PMID- 26063937 TI - Effect of Direct-Current Electric Field on Enzymatic Activity and the Concentration of Laccase. AB - This work investigates the effect of direct-current electric field on the extracellular enzymatic activity, concentration and other experimental parameters of laccase from Trametes versicolor. The results showed that laccase could significantly contribute to the change of pH at the end of graphite electrode. In addition, it increased the electrical conductivity of the water. In the experiment, the optimum pH and catalytic pH range for laccase activity were 3.0 and pH 2.5-4.0. The application of 6 V direct current showed significant effects on the laccase enzyme activity. The activity of laccase was enhanced in the anodic region, but at the same time was strongly inhibited at the cathode. The electric charge characteristics of laccase were changed when exposed to electric field, and some laccases molecules moved to the anode, which produced a slight migration phenomenon. This study is the basis of combination of laccase and electrical technology, at the same time, providing a new direction of enhancing laccase activity. Compared to immobilization, using electric field is simple, no chemical additives, and great potential. PMID- 26063938 TI - Mapping of the Interaction Between Agrobacterium tumefaciens and Vanda Kasem's Delight Orchid Protocorm-Like Bodies. AB - Physical contact between A. tumefaciens and the target plant cell walls is essential to transfer and integrate the transgene to introduce a novel trait. Chemotaxis response and attachment of Agrobacterium towards Vanda Kasem's Delight (VKD) protocorm-like bodies (PLBs) were studied to analyse the interaction between Agrobacterium and PLB during the transformation event. The study shows that initially A. tumefaciens reversibly attached to PLB surface via polar and lateral mode of adherence followed by the irreversible attachment which involved the production of cellulosic fibril by A. tumefaciens. Cellulosic fibril allows formation of biofilm at the tip of trichome. Contrarily, attachment mutant Escherichia coli strain DH5alpha was significantly deficient in the attachment process. Spectrophotometric GUS assay showed the mean value of attachment by A. tumefaciens was 8.72 % compared to the negative control E. coli strain DH5alpha that produced 0.16 %. A. tumefaciens swarmed with sharper and brighter edge when severe wounding was applied to the PLBs producing the highest swarming ratio of 1.46 demonstrating the positive effect of the plant exudates on bacterial movement. The study shows that VKD's PLBs are the suitable explants for Agrobacterium-mediated transformation since the bacteria expressed higher competency rate. PMID- 26063939 TI - Fermentative Production of Pyranone Derivate I from Marine Vibrio sp. SKMARSP9: Isolation, Characterization and Bioactivity Evaluation. AB - Pyranone derivative I was isolated from fermented broth of isolated marine bacterial strain Vibrio sp. SKMARSP9. The compound I was characterized, and evaluated for its antimicrobial properties. The isolated strain was identified based on 16S rRNA based phylogenetic analysis. The molecular analysis data suggested that this strain is closely related to Vibrio ruber, Vibrio sp. MSSRF10 and Vibrio rhizosphaerae. The best fermentative growth of this isolate was achieved under halophilic conditions and grew efficiently at 30 degrees C in the presence of 12 % NaCl. The compound I production by this strain is associated with growth. The unpurified extract is hydrophobic in nature, and released only during late growth phase. The extract was purified and characterized by spectral data using NMR, DEPT, and ESI-MS. The purity of I was 97 % which was confirmed by HPLC. The pyranone derivative I exhibited >50 % antioxidant activity and broad spectrum antimicrobial properties against gram negative and gram positive strains. Molecular docking analysis revealed that this pyranone derivative I may be a potential candidate at pharmaceutical sector. PMID- 26063940 TI - Copper(II) Complexes with N,O-Donor Ligands and Ofloxacin Drug as Antibacterial, DNA Interacting, Cytotoxic and SOD Mimic Agent. AB - ABSTRACT: The N,O-donor bidentate ligands (L (1) -L (7) ) derived from the reaction between chalcones and pyridinium salt of 2-acetyl furan were synthesized and characterized by IR and NMR spectroscopic techniques. Their complexes [1-7] of Cu(II) were synthesized and characterized by elemental analysis, magnetic measurements, TG analyses, IR and mass spectroscopy. Synthesized complexes were carried out for their biological elucidation using different biological experiments like minimum inhibitory concentration, DNA binding and cleavage study, cytotoxicity, and antiradical activity. Efficient cleavage of pUC19 DNA was observed for all the test complexes than the reference drug. GRAPHICAL ABSTRACT: Increase in DNA chain length and hence the relative viscosity as the complexes binds to DNA via intercalative mode and involves a strong stacking interaction between an aromatic chromophore and the DNA base pair. PMID- 26063941 TI - Functional Identification of OphR, an IclR Family Transcriptional Regulator Involved in the Regulation of the Phthalate Catabolic Operon in Rhodococcus sp. Strain DK17. AB - A putative gene for a transcriptional regulator (ophR) was detected near each copy of the duplicated phthalate-degrading operon of Rhodococcus sp. DK17. Sequence analysis and molecular modeling indicate that OphR belongs to the IclR family of transcriptional regulators and possesses the N-terminal DNA-binding and C-terminal effector-binding domains. DNA-binding assays demonstrate that OphR regulates the phthalate operon by binding to the ophA1-ophR intergenic region. PMID- 26063942 TI - Molecular Epidemiology of Nontyphoidal Salmonella in Poultry and Poultry Products in India: Implications for Human Health. AB - Human infections with non-typhoidal Salmonella (NTS) serovars are increasingly becoming a threat to human health globally. While all motile Salmonellae have zoonotic potential, Salmonella Enteritidis and Salmonella Typhimurium are most commonly associated with human disease, for which poultry are a major source. Despite the increasing number of human NTS infections, the epidemiology of NTS in poultry in India has not been fully understood. Hence, as a first step, we carried out epidemiological analysis to establish the incidence of NTS in poultry to evaluate the risk to human health. A total of 1215 samples (including poultry meat, tissues, egg and environmental samples) were collected from 154 commercial layer farms from southern India and screened for NTS. Following identification by cultural and biochemical methods, Salmonella isolates were further characterized by multiplex PCR, allele-specific PCR, enterobacterial repetitive intergenic consensus (ERIC) PCR and pulse field gel electrophoresis (PFGE). In the present study, 21/1215 (1.73 %) samples tested positive for NTS. We found 12/392 (3.06 %) of tissue samples, 7/460 (1.52 %) of poultry products, and 2/363 (0.55 %) of environmental samples tested positive for NTS. All the Salmonella isolates were resistant to oxytetracycline, which is routinely used as poultry feed additive. The multiplex PCR results allowed 16/21 isolates to be classified as S. Typhimurium, and five isolates as S. Enteritidis. Of the five S. Enteritidis isolates, four were identified as group D Salmonella by allele-specific PCR. All of the isolates produced different banding patterns in ERIC PCR. Of the thirteen macro restriction profiles (MRPs) obtained by PFGE, MRP 6 was predominant which included 6 (21 %) isolates. In conclusion, the findings of the study revealed higher incidence of contamination of NTS Salmonella in poultry tissue and animal protein sources used for poultry. The results of the study warrants further investigation on different type of animal feed sources, food market chains, processing plants, live bird markets etc., to evaluate the risk factors, transmission and effective control measures of human Salmonella infection from poultry products. PMID- 26063943 TI - Promising Biological Indicator of Heavy Metal Pollution: Bioluminescent Bacterial Strains Isolated and Characterized from Marine Niches of Goa, India. AB - In present study, several marine water samples collected from the North Goa Beaches, India for isolation of luminescent bacterial species. Isolates obtained labelled as DP1-5 and AB1-6. Molecular characterization including identification of a microbial culture using 16S rRNA gene based molecular technique and phylogenetic analysis confirmed that DP3 & AB1 isolates were Vibrio harveyi. All of the isolates demonstrated multiple metal resistances in terms of growth, with altered luminescence with variable metal concentration. Present investigations were an attempt towards exploring and reporting an updated diversity of bioluminescent bacterial species from various sites around the Goa, India which would be explored in future for constructing luminescence based biosensor for efficiently monitoring the level of hazardous metals in the environment. PMID- 26063944 TI - In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study. AB - The diseases caused by dermatophytes are common among several other infections which cause serious threat to human health. It is evident that enzyme squalene epoxidase is responsible for prolonged dermatophyte infection and it is appealing to note that this enzyme is also responsible for fatty acid synthesis in these groups of fungi. In the present study, terbinafine drug which targets enzyme squalene epoxidase has been explored to design its various novel analogues. The present study suggests that many more prominent drug analogues could be constituted which may be crucial towards designing new drug candidates. In the present study, we have designed a series of such analogues viz. [(2E)-6,6 dimethylhept-2-en-4-yn-1-yl](methyl)(naphthalen-1-ylmethyl)amine, N-[8-({[(2E) 6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]-2 (sulfoamino) acetamide, {[4-(dihydroxyamino)-8-({[(2E)-6,6-dimethylhept-2-en-4-yn 1-yl](methyl)amino}methyl)naphthalen-1-yl]sulfanyl}methanol and (R)-{[4 ({[(2E,6R)-6,7-dimethyloct-2-en-4-yn-1-yl](methyl)amino}methyl)-5 [(hydroxysulfamoyl)amino]naphthalen-1-yl]amino}sulfinic acid. Moreover, further by molecular docking approach the binding between enzyme and designed analogues was further analysed. The present preliminary report suggested a considerably good docking interaction score of -338.75 kcal/mol between terbinafine and squalene epoxidase from Trichophyton rubrum. This preliminary study implies that few designed candidate ligands can be effectual towards the activity of this enzyme and can play crucial role in pathogenesis control of T. rubrum. PMID- 26063945 TI - Ethics in Science. AB - Ethics are a set of moral principles and values a civilized society follows. Doing science with principles of ethics is the bedrock of scientific activity. The society trusts that the results and the projected outcome of any scientific activity is based on an honest and conscientious attempt by the scientific community. However, during the last few decades, there has been an explosion of knowledge and the advent of digital age. We can access the publications of competitors with just a "click". The evaluation parameters have evolved a lot and are based on impact factors, h-index and citations. There is a general feeling that the scientific community is under a lot of pressure for fulfilling the criteria for upward growth and even retention of the positions held. The noble profession of scientific research and academics has been marred by the temptation to falsify and fabricate data, plagiarism and other unethical practices. Broadly speaking, the breach of ethics involves: plagiarism, falsification of data, redundant (duplicate) publication, drawing far-fetched conclusions without hard data, for early publicity, gift authorship (receiving as well as giving), not giving sufficient attention and consideration to scholars and post-docs as per the norms, self promotion at the cost of team-members, treating colleagues (overall all juniors) in a feudal way and Machiavellianism (cunningness and duplicity in general conduct and push to positions of power and pelf). Misconduct in Indian academics and science is also under a lot of focus. It is important and urgent that science, engineering, and health departments and institutions in our country have in place systems for education and training in pursuit of science with ethics by sound and professional courses in Responsible Conduct of Research. All research and academic institution must have the Office of Ethics for information, guidelines, training and professional oversight of conduct of research with the ethos and ethics of research. PMID- 26063946 TI - Anti-chlamydial IgG Neutralizing Ability in Nonzoonotic Atypical Community Acquired Respiratory Tract Infections. AB - Chlamydophila pneumoniae is a pathogenic agent, involved in various types of infection. This study has evaluated the ability of IgG antibodies in outpatient, with acute respiratory tract infections from C. pneumoniae, to neutralize in vitro purified elementary bodies of this bacterium, revealing a good neutralizing performance of IgG antibodies. PMID- 26063947 TI - A Unifying Model for Capture-Recapture and Distance Sampling Surveys of Wildlife Populations. AB - A fundamental problem in wildlife ecology and management is estimation of population size or density. The two dominant methods in this area are capture recapture (CR) and distance sampling (DS), each with its own largely separate literature. We develop a class of models that synthesizes them. It accommodates a spectrum of models ranging from nonspatial CR models (with no information on animal locations) through to DS and mark-recapture distance sampling (MRDS) models, in which animal locations are observed without error. Between these lie spatially explicit capture-recapture (SECR) models that include only capture locations, and a variety of models with less location data than are typical of DS surveys but more than are normally used on SECR surveys. In addition to unifying CR and DS models, the class provides a means of improving inference from SECR models by adding supplementary location data, and a means of incorporating measurement error into DS and MRDS models. We illustrate their utility by comparing inference on acoustic surveys of gibbons and frogs using only capture locations, using estimated angles (gibbons) and combinations of received signal strength and time-of-arrival data (frogs), and on a visual MRDS survey of whales, comparing estimates with exact and estimated distances. Supplementary materials for this article are available online. PMID- 26063949 TI - Monocyte Proteomics Reveals Involvement of Phosphorylated HSP27 in the Pathogenesis of Osteoporosis. AB - Peripheral monocytes, precursors of osteoclasts, have emerged as important candidates for identifying proteins relevant to osteoporosis, a condition characterized by low Bone Mineral Density (BMD) and increased susceptibility for fractures. We employed 4-plex iTRAQ (isobaric tags for relative and absolute quantification) coupled with LC-MS/MS (liquid chromatography coupled with tandem mass spectrometry) to identify differentially expressed monocyte proteins from premenopausal and postmenopausal women with low versus high BMD. Of 1801 proteins identified, 45 were differentially abundant in low versus high BMD, with heat shock protein 27 (HSP27) distinctly upregulated in low BMD condition in both premenopausal and postmenopausal categories. Validation in individual samples (n = 80) using intracellular ELISA confirmed that total HSP27 (tHSP27) as well as phosphorylated HSP27 (pHSP27) was elevated in low BMD condition in both categories (P < 0.05). Further, using transwell assays, pHSP27, when placed in the upper chamber, could increase monocyte migration (P < 0.0001) and this was additive in combination with RANKL (receptor activator of NFkB ligand) placed in the lower chamber (P = 0.05). Effect of pHSP27 in monocyte migration towards bone milieu can result in increased osteoclast formation and thus contribute to pathogenesis of osteoporosis. Overall, this study reveals for the first time a novel link between monocyte HSP27 and BMD. PMID- 26063948 TI - Effect of Extended-Release Niacin/Laropiprant Combination on Plasma Adiponectin and Insulin Resistance in Chinese Patients with Dyslipidaemia. AB - OBJECTIVES: This study examined whether the increase of adiponectin associated with extended-release (ER) niacin/laropiprant combination attenuates the adverse effect of niacin on glucose and insulin resistance in Hong Kong Chinese patients with dyslipidaemia. METHODS: Patients (N = 121) were treated with ER niacin/laropiprant 1 g/20 mg for 4 weeks and then the dose was doubled for an additional 8 weeks. Measurements of fasting lipids, glucose, insulin, and adiponectin were performed at baseline and during the study. RESULTS: There were significant (P < 0.001) increases in glucose (9.4 +/- 13.1%), insulin (70.2 +/- 91.0%), HOMA-IR (87.8 +/- 103.9%), and adiponectin (169.3 +/- 111.6%). The increase in adiponectin was significantly associated with increase in glucose (r = 0.221, P < 0.05), insulin (r = 0.184, P < 0.05), and HOMA-IR (r = 0.237, P < 0.01) and the association remained significant after adjustment for changes in body weight or body fat mass. CONCLUSION: Treatment with ER niacin/laropiprant led to a significant increase in adiponectin levels but worsening of glucose levels and insulin resistance, and the increase in adiponectin and insulin resistance were correlated suggesting the increase in adiponectin did not ameliorate the deterioration in insulin resistance. Clinical trial is registered with number on WHO-ICTRP: ChiCTR-ONC-10001038. PMID- 26063950 TI - Vitamin D Is a Good Marker for Disease Activity of Rheumatoid Arthritis Disease. AB - AIM: This study was conducted to find out the optimal vitamin D cutoff point in predicting activity of RA disease. MATERIALS AND METHODS: One hundred and two rheumatoid arthritis Saudi patients of both genders were recruited in this study. Vitamin D as 25-hydroxy-vitamin D [25(OH)D] was measured and serum level less than 20 ng/mL defined as deficient patient. Disease activity was measured based on the disease activity score index of a 28-joint count (DAS28) using serum erythrocyte sedimentation rate levels. Receiver operating characteristic (ROC) curves were used to determine the optimal vitamin D cutoff points for identifying disease activity. RESULTS: It has been observed that vitamin D levels were lower (P < 0.05) in patients with high disease activity. A significant inverse correlation between serum 25(OH)D levels and DAS28 (r = -0.277, P = 0.014) was shown. ROC curves results showed that vitamin D less than 12.3 ng/mL predicted high disease activity, and vitamin D more than 17.9 ng/mL predicted low disease activity, with good sensitivity and accuracy results regarding vitamin D. CONCLUSION: Study results concluded that vitamin D is a good predictor of RA disease activity in Saudi patients. PMID- 26063951 TI - Frequency of Surgery in Black Patients with Malignant Pleural Mesothelioma. AB - INTRODUCTION: Malignant Pleural Mesothelioma (MPM) is a rare disease, even less frequently described in minority patients. We used a large population-based dataset to study the role of race in MPM presentation, treatment, and survival. METHODS: All cases of pathologically proven MPM were identified in the Surveillance, Epidemiology, and End Results (SEER) database. Age, sex, diagnosis year, stage, cancer-directed surgery, radiation, and vital status were analyzed according to self-reported race (black or white). RESULTS: There were 13,046 white and 688 black MPM patients (incidence: 1.1 per 100,000 whites; 0.5 per 100,000 blacks; age-adjusted, p = 0.01). Black patients were more likely to be female, younger, and with advanced stage and less likely to undergo cancer directed surgery than whites, after adjustment by stage. On multivariable analysis, younger age and having surgery were associated with longer survival for both cohorts; female gender (HR 0.82 (0.77-0.88)) and early stage at diagnosis (HR 0.83 (0.76-0.90)) were predictive of longer survival in white, but not in black, patients. CONCLUSIONS: Surgery was associated with improved survival for both black and white MPM patients. However, black patients were less likely to undergo cancer-directed surgery. Increased surgical intervention in MPM black patients with early stage disease may improve their survival. PMID- 26063953 TI - Overexpression of Growth-Related Oncogene-beta Is Associated with Tumorigenesis, Metastasis, and Poor Prognosis in Ovarian Cancer. AB - BACKGROUND: Growth-related oncogene- (GRO-) beta is a member of the CXC chemokine family, which may mediate various functions, such as attracting neutrophils to sites of inflammation, regulating angiogenesis, and participating in tumorigenesis and progression. However, the expression of GRO-beta in ovarian cancer and its relationship to the clinical characteristics of this disease remain poorly understood. METHODS: In this study, immunohistochemical analysis using tissue microarray (TMA) was employed to evaluate the expression of GRO-beta in ovarian cancer and to contrast expression with normal ovarian epithelial cells and oviduct epithelial cells. Next, we observed the correlation between GRO-beta expression and clinicopathological features of ovarian cancer as well as patient outcome. RESULTS: High GRO-beta cytoplasmic expression was observed in 55.15% of patients with ovarian cancer, which was related to lymph node or other metastases (P < 0.001), ascites (P = 0.027), and International Federation of Obstetricians and Gynaecologists (FIGO) stage (P = 0.032). Kaplan-Meier survival and Cox regression analysis revealed that high GRO-beta expression (P = 0.002) and high CA19-9 level (P = 0.003) were independent prognostic indicators of poor outcome in ovarian cancer. CONCLUSIONS: Overall, high GRO-beta expression correlates with poor prognosis and contributes to ovarian cancer tumorigenesis and metastasis. PMID- 26063952 TI - The Role of Power Doppler Ultrasonography as Disease Activity Marker in Rheumatoid Arthritis. AB - Structural damage in rheumatoid arthritis (RA) occurs early if inflammation is not treated promptly. Treatment targeted to reduce inflammation, in particular, that of synovial inflammation in the joints (synovitis), has been recommended as standard treat-to-target recommendations by rheumatologists. The goal is to achieve disease remission (i.e., no disease activity). Several accepted remission criteria have not always equated to the complete absence of true inflammation. Over the last decade, musculoskeletal ultrasonography has been demonstrated to detect subclinical synovitis not appreciated by routine clinical or laboratory assessments, with the Power Doppler modality allowing clinicians to more readily appreciate true inflammation. Thus, targeting therapy to Power Doppler activity may provide superior outcomes compared with treating to clinical targets alone, making it an attractive marker of disease activity in RA. However, more validation on its true benefits such as its benefits to patients in regard to patient related outcomes and issues with standardized training in acquisition and interpretation of power Doppler findings are required. PMID- 26063954 TI - The Value of Circulating Nogo-B for Evaluating Hepatic Functional Reserve in Patients with Cirrhosis. AB - OBJECTIVE: To examine Nogo-B in liver tissues and plasma of patients with liver cirrhosis and associate them with various clinical parameters. MATERIALS AND METHODS: Nogo-B protein expression was examined by immunohistochemistry in 24 human fibrotic/cirrhotic liver specimens and 10 healthy controls. We determined plasma Nogo-B levels by enzyme-linked immunosorbent assay in 301 patients with liver cirrhosis and 153 healthy controls, and then analyzed various clinical parameters. RESULTS: Nogo-B was mainly expressed in nonparenchymal cells in the liver and was marked increased in liver with significant fibrosis/cirrhosis compared to controls. Moreover, Metavir F4 showed a higher level of expression than F2. Plasma Nogo-B levels were significantly higher in cirrhotic patients than in healthy controls and were the highest in Child-Pugh class C patients. Plasma Nogo-B levels were positively correlated with Child-Pugh scores. However, there was no relationship between plasma Nogo-B levels and etiology of liver diseases, ALT, AST, platelet counts, and the severity of esophagogastric varices. CONCLUSIONS: Nogo-B is mainly expressed in hepatic nonparenchymal cells and is present in plasma. Abnormally high plasma levels of Nogo-B are associated with hepatic cirrhosis and Child-Pugh score, but not correlated with the grade of liver inflammation or portal hypertension. Plasma Nogo-B may be a novel surrogate marker to reflect liver function reserve. PMID- 26063955 TI - Dynamic Changes, Cut-Off Points, Sensitivity, and Specificity of Laboratory Data to Differentiate Macrophage Activation Syndrome from Active Disease. AB - PURPOSE: To compare the laboratory data and changes in these data between patients with MAS and patients with flare-up of the autoimmune diseases. METHODS: In a prospective study, the static laboratory data and dynamic changes in the selected data in 17 consecutive patients with MAS and 53 patients with active disease of SJIA, PJIA, Kawasaki disease, and SLE were compared. The ROC curve analysis was used to evaluate cut-off points, sensitivity, and specificity of the static and dynamic laboratory data to differentiate between MAS and active disease. RESULTS: In the MAS group, the mean CRP3, ALT, AST, total bilirubin, ferritin, LDH, PT, PTT, and INR were significantly higher and the mean WBC2, PMN2, Lymph2, Hgb1, 2, 3, ESR2, serum albumin, and sodium were significantly lower than in control group. Some of the important cut-off points were PLT2 < 209000/microliter, AST > 38.5, ALT > 38, WBC < 8200 * 103/UL, ferritin > 5277 ng/mL. CONCLUSION: The dynamic changes in some laboratory data, especially PLT, can differentiate between MAS and active disease. The changes in WBC, PMN, and ESR and the levels of the liver enzymes may also be helpful in the early differentiation. Very high levels of ferritin may also help the diagnosis along with other clinical and laboratory signs. PMID- 26063956 TI - Circulating MicroRNA-21 Is a Potential Diagnostic Biomarker in Gastric Cancer. AB - MicroRNA-21 was upexpressed in gastric cancer (GC) indicating that it is a potential diagnostic biomarker for GC. In this study, 50 GC patients and 50 healthy controls were recruited. miR-21 levels in serum and peripheral blood mononuclear cells (PBMCs) were quantified using quantitative real-time PCR. CA199, and CEA were measured using electrochemiluminescence assay. The sensitivity and specificity of circulating miR-21, CA199 and CEA in GC diagnosis, the correlation of circulating miR-21 to clinicopathological features, and the diagnostic value of miR-21 in different GC stages were determined. The levels of miR-21 in both serum and PBMCs increased significantly in GC patients comparing to healthy controls; however, no correlation was observed between circulating miR 21 level and clinicopathological features. The sensitivity and specificity of miR 21 in serum and PBMCs, and CA199 and CEA in GC diagnosis were 88.4%, 79.6%, 81.3%, 73.4%, 60.5%, 55.9%, and 68.6%, 59.3%, respectively. The positive prediction rates of circulating miR-21 in GC stages I to IV were all around 90%, while those of CA199 and CEA were around or less than 50%. Our data suggest circulating miR-21 (both in serum and in PBMCs) can serve as a good biomarker for GC and could be used in diagnosis of early (stage I) and late GC (stage IV). PMID- 26063957 TI - Prognostic Value of MicroRNA-182 in Cancers: A Meta-Analysis. AB - OBJECTIVE: MicroRNA-182 (miR-182) exhibits altered expression in various cancers. The aim of this study was to investigate the predictive value of miR-182 expression for cancer patient survival. METHODS: Eligible studies were identified through multiple search strategies, and the hazard ratios (HRs) for patient outcomes were extracted and estimated. A meta-analysis was performed to evaluate the prognostic value of miR-182. RESULTS: In total, 14 studies were included. A high miR-182 expression level predicted a worse outcome with a pooled HR of 2.18 (95% CI: 1.53-3.11) in ten studies related to overall survival (OS), especially in Chinese populations. The results of seven studies evaluating disease-free survival/relapse-free survival/recurrence-free interval/disease-specific survival (DFS/RFS/RFI/DSS) produced a pooled HR of 1.77 (95% CI: 0.91-3.43), which was not statistically significant; however, the trend was positive. When disregarding the DSS from one study, the expression of miR-182 was significantly correlated with DFS/RFS/RFI (pooled HR = 2.52, 95% CI: 1.67-3.79). CONCLUSIONS: High miR-182 expression is associated with poor OS and DFS/RFS/RFI in some types of cancers, and miR-182 may be a useful prognostic biomarker for predicting cancer prognosis. However, given the current insufficient relevant data, further clinical studies are needed. PMID- 26063958 TI - Serum Enzyme Profiles Differentiate Five Types of Muscular Dystrophy. AB - BACKGROUND: Differentiation among types of muscular dystrophy (MD) has remained challenging. In this retrospective study, we sought to develop a methodology for differentiation of MD types using analysis of serum enzyme profiles. METHODS: The serum levels of enzymes from 232 patients, including 120 with DMD, 36 with BMD, 36 with FSHD, 46 with LGMD, and 11 with EDMD, were evaluated. RESULTS: The characteristic profiles of serum enzymes facilitated differentiation of these five types of MD. DMD was characterized by simultaneous elevation of ALT, AST, LDH, and ALP; BMD and LGMD were characterized by elevation of ALT, AST, and LDH; and FSHD and EDMD were characterized by a lack of abnormal serum enzyme levels. We further developed discriminant functions to distinguish BMD and LGMD. For LGMD, LGMD2B patients had significantly higher ALP levels than non-LGMD2B patients (98 +/- 59 U/L versus 45 +/- 9 U/L, resp., p < 0.05). CONCLUSIONS: Our approach enabled the determination of MD subtypes using serum enzyme profiles prior to genetic testing, which will increase the chance a mutation will be found in the first gene analyzed. PMID- 26063959 TI - Ventilatory Efficiency in Children and Adolescents: A Systematic Review. AB - INTRODUCTION: The index of ventilatory efficiency (VE/VCO2) obtained by the progressive exercise test has been considered the gold standard in the prognosis of adults with heart failure, but few studies have evaluated this approach in children. OBJECTIVE: To verify the scientific evidence about the VE/VCO2 in pediatric and adolescents patients. METHODS: A systematic literature review was carried out using the key words VE/VCO2, children, and adolescents using the PEDro and PubMed/MedLine databases. Clinical trials published from 1987 to 2014, including children, adolescents, and young adults up to 25 years, addressing the VE/VCO2 index as a method of evaluation, monitoring, and prognosis were considered. RESULTS: Initially, 95 articles were found; 12 were excluded as the title/abstract did not contain the VE/VCO2 index or because they included patients greater than 25 years of age. From the remaining 83, 58 were repeated between the databases. The final sample consisted of 32 studies including healthy children and children with respiratory and other diseases. CONCLUSION: There are few studies involving cardiorespiratory assessment by ventilatory efficiency. The studies highlight the fact that high VE/VCO2 values are associated with a worse prognosis of patients due to the relationship with the decrease in pulmonary perfusion and cardiac output. PMID- 26063960 TI - Expression of Spindle and Kinetochore-Associated Protein 1 Is Associated with Poor Prognosis in Papillary Thyroid Carcinoma. AB - AIM: Spindle and kinetochore-associated protein 1 (SKA1) is one subtype of SKA, whose protein can make spindle microtubules attach steadily to the kinetochore in the middle of mitosis. At present, there are fewer researches on the relationship between SKA1 expression and tumor development. METHODS: In this study, immunohistochemical analysis was used to determine the expression of SKA1 in papillary thyroid carcinoma (PTC) and adjacent tissues. We used quantitative real time polymerase chain reaction (qRT-PCR) and Western blot analysis to further verify the results. RESULTS: We found that SKA1 expression was significantly higher in PTC tissues than normal adjacent tissues (P < 0.05). There existed a significant correlation among a higher SKA1 expression, including lymphoid node (P = 0.005), clinical stage (P = 0.015), and extrathyroid invasion (P = 0.004). Survival analysis showed high SKA1 expression in PTC patients more likely to relapse after surgery. CONCLUSION: High SKA1 expression is predictive of poor prognosis of PTC, implying that SKA1 may be a promising new target for targeted therapies for PTC. PMID- 26063961 TI - Elevated ZNF703 Protein Expression Is an Independent Unfavorable Prognostic Factor for Survival of the Patients with Head and Neck Squamous Cell Carcinoma. AB - AIM: Data from The Cancer Genome Atlas (TCGA) show that the ZNF703 gene amplifies and overexpresses in head and neck squamous cell carcinomas (HNSCC). However, the clinical relevance of this observation in HNSCC is unclear. The purpose of this study was to clarify the expression of ZNF703 protein and its prognostic effect on HNSCC. METHODS: Two hundred ten HNSCC patients from Sun Yat-Sen University Cancer Center with complete survival follow-up were included in this study. Tumor samples from primary sites were collected. The expression of the ZNF703 protein was tested by immunohistochemistry (IHC). RESULTS: The high expression of ZNF703 in HNSCC tumor tissues was significantly higher than that of the matched noncancerous tissues (48.6% versus 11.6%, P < 0.001). ZNF703 overexpression was correlated with tumor position (laryngeal carcinoma) and recurrence (all P < 0.05). Multivariate analysis revealed that ZNF703 protein overexpression was an independent prognostic factor (P = 0.022, hazard ratio = 1.635, 95% CI 1.073 2.493) in HNSCC patients. CONCLUSION: ZNF703 overexpression is associated with adverse prognosis in HNSCC, which might be a novel biomarker of HNSCC. PMID- 26063962 TI - Association between Programmed Cell Death 6 Interacting Protein Insertion/Deletion Polymorphism and the Risk of Breast Cancer in a Sample of Iranian Population. AB - It has been suggested that genetic factors contribute to patients' vulnerability to breast cancer (BC). The programmed cell death 6 interacting protein (PDCD6IP) encodes for a protein that is known to bind to the products of the PDCD6 gene, which is involved in the apoptosis pathway. The aim of this case-control study is to investigate the relationship between the PDCD6IP 15 bp insertion/deletion (I/D) polymorphism (rs28381975) and BC risk in an Iranian population. A total of 491 females, including 266 BC patients and 225 control subjects without cancer, were enrolled into the study. Our findings revealed that the PDCD6IP 15 bp I/D polymorphism decreased the risk of BC in codominant (OR = 0.44, 95% CI = 0.31 0.65, p < 0.0001, I/D versus DD; OR = 0.39, 95% CI = 0.17-0.88, p = 0.030, I/I versus DD) and dominant (OR = 0.44, 95% CI = 0.30-0.63, p < 0.0001, D/I + I/I versus D/D) tested inheritance models. Also, the PDCD6IP I allele significantly decreased the risk of BC (OR = 0.59, 95% CI = 0.45-0.78, p < 0.001) compared to the D allele. PMID- 26063963 TI - Stress Assignment Errors in Surface Dyslexia: Evidence from Two Italian Patients with a Selective Deficit of the Orthographic Input Lexicon. AB - Surface dyslexia designates a selective impairment in reading irregular words, with spared ability to read regular and novel words, following a cerebral damage usually located in the left dominant hemisphere. In Italian language, which is regular at the segmental level, surface dyslexia is characterized by stress assignment errors. Here we report on two cases of Italian surface dyslexic patients who produced stress assignment errors, mainly in reading irregular words. In reading nonwords they usually applied the regular stress pattern. Both patients were also impaired in lexical decision and in semantic discrimination tasks when the processing of homophones was required. Our patients' performance relied almost exclusively on the phonological coding of the stimulus, revealing a deficit in accessing the orthographical input lexicon. In addition, one patient showed a cerebral lesion limited to the right thalamus, providing evidence of a possible role of the right hemisphere in the reading process. PMID- 26063964 TI - The Classical Pathways of Occipital Lobe Epileptic Propagation Revised in the Light of White Matter Dissection. AB - The clinical evidences of variable epileptic propagation in occipital lobe epilepsy (OLE) have been demonstrated by several studies. However the exact localization of the epileptic focus sometimes represents a problem because of the rapid propagation to frontal, parietal, or temporal regions. Each white matter pathway close to the supposed initial focus can lead the propagation towards a specific direction, explaining the variable semiology of these rare epilepsy syndromes. Some new insights in occipital white matter anatomy are herein described by means of white matter dissection and compared to the classical epileptic patterns, mostly based on the central position of the primary visual cortex. The dissections showed a complex white matter architecture composed by vertical and longitudinal bundles, which are closely interconnected and segregated and are able to support specific high order functions with parallel bidirectional propagation of the electric signal. The same sublobar lesions may hyperactivate different white matter bundles reemphasizing the importance of the ictal semiology as a specific clinical demonstration of the subcortical networks recruited. Merging semiology, white matter anatomy, and electrophysiology may lead us to a better understanding of these complex syndromes and tailored therapeutic options based on individual white matter connectivity. PMID- 26063965 TI - Hyperthermia-Induced Febrile Seizures Have Moderate and Transient Effects on Spatial Learning in Immature Rats. AB - The aim of this study was to characterize a novel animal model hyperthermia induced febrile seizure and to investigate the impacts of repetitive febrile seizures on spatial learning and memory performances in immature rats. Methods. Rats were subjected to hyperthermia exposure one, two, or three times in 10-day intervals during 30 min in a water bath warmed at 45-50 degrees C and their behaviour was monitored. Morris water maze spatial learning and memory were examined for control and treated groups. Results showed that rats subjected to 30 minute hyperthermia hot water developed rapidly myoclonic jerks and then generalized seizures. After a single hyperthermia exposure, the time for generalised tonic-clonic seizures appearance was 16.08 +/- 0.60 min and it decreased gradually with repetitive exposure to reach 12.46 +/- 0.39 min by the third exposure. Febrile seizures altered the spatial learning and memory abilities in Morris water maze and increased the time spent to attain the platform after one or two exposures, while after a third exposure rats exhibited the same latency compared to controls. Similar results were obtained in probe test where rats, subjected to hyperthermia for one or two episodes, spent less time in the target quadrant compared to corresponding controls. Further, when platform was moved from northwest to southwest quadrant, memory transfer test indicated that after one or two hyperthermia exposures cognitive performances were slightly altered, while after a third exposure the latency to escape increased significantly compared to untreated group. It was concluded that 30 min of hyperthermia hot water was sufficient to induce febrile seizures in immature rats and an increase of susceptibility was observed with repetitive hyperthermia exposure. Hyperthermia treatment impaired cognitive performances but the effects were mostly transient and moderate. PMID- 26063966 TI - Coexistence of Gait Disturbances and Chorea in Experimental Huntington's Disease. AB - Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an expanded CAG repeat. The clinical features are progressive motor dysfunction, cognitive deterioration, and psychiatric disturbances. Unpredictable choreic movements, among the most characteristic hallmarks, may contribute to gait disturbances and loss of balance in HD individuals. In this study, we aimed to investigate and characterize the gait abnormalities and choreic movements in a transgenic rat model of HD (tgHD). TgHD presents typical neuropathological, neurophysiological, and behavioral aspects mimicking some of the key features of human HD and is the only described experimental model for HD that exhibits choreiform movements. We used the Catwalk, with emphasis on static and dynamic gait parameters, to test the hypothesis that at symptomatic age (9 months) the dynamic measures of gait in HD are altered and coexist with choreiform movements. Our results showed that the dynamic parameters seem to be more affected than static parameters at this age in tgHD rats. The number of steps and step cycles and swing speed of the paws were increased in tgHD rat in comparison to wild-type controls. Our study demonstrates that gait abnormalities coexist with chorea rather than being caused by it. These symptoms may originate from distinct networks in the basal ganglia and downstream connections. PMID- 26063967 TI - Porphyromonas gingivalis Periodontal Infection and Its Putative Links with Alzheimer's Disease. AB - Periodontal disease (PD) and Alzheimer's disease (AD) are inflammatory conditions affecting the global adult population. In the pathogenesis of PD, subgingival complex bacterial biofilm induces inflammation that leads to connective tissue degradation and alveolar bone resorption around the teeth. In health, junctional epithelium seals the gingiva to the tooth enamel, thus preventing bacteria from entering the gingivae. Chronic PD involves major pathogens (Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia) which have an immune armoury that can circumvent host's immune surveillance to create and maintain an inflammatory mediator rich and toxic environment to grow and survive. The neurodegenerative condition, AD, is characterised by poor memory and specific hallmark proteins; periodontal pathogens are increasingly being linked with this dementing condition. It is therefore becoming important to understand associations of periodontitis with relevance to late-onset AD. The aim of this review is to discuss the relevance of finding the keystone periodontal pathogen P. gingivalis in AD brains and its plausible contribution to the aetiological hypothesis of this dementing condition. PMID- 26063968 TI - Increased Migratory and Activation Cell Markers of Peripheral Blood Lymphocytes in an Experimental Model of Nephrotic Syndrome. AB - The present study aimed to evaluate the expression of CD80 and CD18 in subpopulations of peripheral blood leukocytes and oxidative kidney damage in rats with nephrotic syndrome (NS) induced by doxorubicin (Dox) in comparison to control animals at different time points. Male adult Wistar rats were submitted to 24-hour urine and blood collection for biochemical and immunological analysis at 7, 14, 21, and 28 days after Dox injection. After euthanasia, the kidneys were removed for histological analysis and the evaluation of oxidative stress. The phenotypic characterization of leukocytes was performed using flow cytometry. Dox injected animals exhibited increased CD18 expression in cytotoxic T lymphocytes, NK cells, and monocytes and high CD80 expression in monocytes. Kidney oxidative damage was positively correlated with CD80 expression in monocytes and serum levels of creatinine. These results suggest that phagocytic and cytotoxic cells are preferentially recruited to the tissue injury site, which may contribute to kidney dysfunction in this animal model of NS. The blockade of integrin and costimulatory molecules may provide new therapeutic opportunities for NS. PMID- 26063969 TI - Systemic Lupus Erythematosus with and without Anti-dsDNA Antibodies: Analysis from a Large Monocentric Cohort. AB - OBJECTIVES: The anti-dsDNA antibodies are a marker for Systemic Lupus Erythematosus (SLE) and 70-98% of patients test positive. We evaluated the demographic, clinical, laboratory, and therapeutical features of a monocentric SLE cohort according to the anti-dsDNA status. METHODS: We identified three groups: anti-dsDNA + (persistent positivity); anti-dsDNA +/- (initial positivity and subsequent negativity during disease course); anti-dsDNA - (persistent negativity). Disease activity was assessed by the European Consensus Lupus Activity Measurement (ECLAM). RESULTS: We evaluated 393 patients (anti-dsDNA +: 62.3%; anti-dsDNA +/-: 13.3%; anti-dsDNA -: 24.4%). The renal involvement was significantly more frequent in anti-dsDNA + (30.2%), compared with anti-dsDNA +/- and anti-dsDNA - (21.1% and 18.7%, resp.; P = 0.001). Serositis resulted significantly more frequent in anti-dsDNA - (82.3%) compared to anti-dsDNA + and anti-dsDNA +/- (20.8% and 13.4%, resp.; P < 0.0001). The reduction of C4 serum levels was identified significantly more frequently in anti-dsDNA + and anti dsDNA +/- (40.0% and 44.2%, resp.) compared with anti-dsDNA - (21.8%, P = 0.005). We did not identify significant differences in the mean ECLAM values before and after modification of anti-dsDNA status (P = 0.7). CONCLUSION: Anti-dsDNA status influences the clinical and immunological features of SLE patients. Nonetheless, it does not appear to affect disease activity. PMID- 26063970 TI - Effects of Intravenous Injection of Porphyromonas gingivalis on Rabbit Inflammatory Immune Response and Atherosclerosis. AB - The effects of intravenous injection of Porphyromonas gingivalis (Pg) on rabbit inflammatory immune response and atherosclerosis were evaluated by establishing a microamount Pg bacteremia model combined with high-fat diet. Twenty-four New Zealand rabbits were randomly divided into Groups A-D (n = 6). After 14 weeks, levels of inflammatory factors (C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1)) in peripheral blood were detected by ELISA. The aorta was subjected to HE staining. Local aortic expressions of toll-like receptor-2 (TLR-2), TLR-4, TNF alpha, CRP, IL-6, matrix metallopeptidase-9, and MCP-1 were detected by real-time PCR, and those of nuclear factor-kappaB (NF-kappaB) p65, phospho-p38 mitogen activated protein kinase (MAPK), and phospho-c-Jun N-terminal kinase (JNK) proteins were detected by Western blot. Intravenous injection of Pg to the bloodstream alone induced atherosclerotic changes and significantly increased systemic and local aortic expressions of inflammatory factors, NF-kappaB p65, phospho-p38-MAPK, and JNK, especially in Group D. Injection of microamount Pg induced inflammatory immune response and accelerated atherosclerosis, in which the NF-kappaB p65, p38-MAPK, and JNK signaling pathways played important roles. Intravenous injection of Pg is not the same as Pg from human periodontitis entering the blood stream. Therefore, our results cannot be extrapolated to human periodontitis. PMID- 26063971 TI - Monocytic Tissue Transglutaminase in a Rat Model for Reversible Acute Rejection and Chronic Renal Allograft Injury. AB - Acute rejection is a major risk factor for chronic allograft injury (CAI). Blood leukocytes interacting with allograft endothelial cells during acute rejection were suggested to contribute to the still enigmatic pathogenesis of CAI. We hypothesize that tissue transglutaminase (Tgm2), a multifunctional protein and established marker of M2 macrophages, is involved in acute and chronic graft rejection. We focus on leukocytes accumulating in blood vessels of rat renal allografts (Fischer-344 to Lewis), an established model for reversible acute rejection and CAI. Monocytes in graft blood vessels overexpress Tgm2 when acute rejection peaks on day 9 after transplantation. Concomitantly, caspase-3 is activated, suggesting that Tgm2 expression is linked to apoptosis. After resolution of acute rejection on day 42, leukocytic Tgm2 levels are lower and activated caspase-3 does not differ among isografts and allografts. Cystamine was applied for 4 weeks after transplantation to inhibit extracellular transglutaminase activity, which did, however, not reduce CAI in the long run. In conclusion, this is the first report on Tgm2 expression by monocytes in vivo. Tgm2 may be involved in leukocytic apoptosis and thus in reversion of acute rejection. However, our data do not support a role of extracellular transglutaminase activity as a factor triggering CAI during self-limiting acute rejection. PMID- 26063972 TI - Oxygenator Is the Main Responsible for Leukocyte Activation in Experimental Model of Extracorporeal Circulation: A Cautionary Tale. AB - In order to assess mechanisms underlying inflammatory activation during extracorporeal circulation (ECC), several small animal models of ECC have been proposed recently. The majority of them are based on home-made, nonstandardized, and hardly reproducible oxygenators. The present study has generated fundamental information on the role of oxygenator of ECC in activating inflammatory signaling pathways on leukocytes, leading to systemic inflammatory response, and organ dysfunction. The present results suggest that experimental animal models of ECC used in translational research on inflammatory response should be based on standardized, reproducible oxygenators with clinical characteristics. PMID- 26063973 TI - The In Vivo Granulopoietic Response to Dexamethasone Injection Is Abolished in Perforin-Deficient Mutant Mice and Corrected by Lymphocyte Transfer from Nonsensitized Wild-Type Donors. AB - Exogenously administered glucocorticoids enhance eosinophil and neutrophil granulocyte production from murine bone-marrow. A hematological response dependent on endogenous glucocorticoids underlies bone-marrow eosinophilia induced by trauma or allergic sensitization/challenge. We detected a defect in granulopoiesis in nonsensitized, perforin-deficient mice. In steady-state conditions, perforin- (Pfp-) deficient mice showed significantly decreased bone marrow and blood eosinophil and neutrophil counts, and colony formation in response to GM-CSF, relative to wild-type controls of comparable age and/or weight. By contrast, peripheral blood or spleen total cell and lymphocyte numbers were not affected by perforin deficiency. Dexamethasone enhanced colony formation by GM-CSF-stimulated progenitors from wild-type controls, but not Pfp mice. Dexamethasone injection increased bone-marrow eosinophil and neutrophil counts in wild-type controls, but not Pfp mice. Because perforin is expressed in effector lymphocytes, we examined whether this defect would be corrected by transferring wild-type lymphocytes into perforin-deficient recipients. Short-term reconstitution of the response to dexamethasone was separately achieved for eosinophils and neutrophils by transfer of distinct populations of splenic lymphocytes from nonsensitized wild-type donors. Transfer of the same amount of splenic lymphocytes from perforin-deficient donors was ineffective. This demonstrates that the perforin-dependent, granulopoietic response to dexamethasone can be restored by transfer of innate lymphocyte subpopulations. PMID- 26063974 TI - Notch Signaling Pathway Was Involved in Regulating Programmed Cell Death 1 Expression during Sepsis-Induced Immunosuppression. AB - Programmed cell death 1 (PD-1) plays an important pathologic role in sepsis induced immunosuppression. However, whether PD-1 overexpression occurs early during septic shock is unknown and its regulation mechanism is also unknown. Our study investigated the expressions of PD-1/programmed death-ligand 1 (PD-L1) on immune cells in peripheral blood from the early-stage septic shock patients. We found that both PD-1 and PD-L1 showed increased expressions on the CD4(+) T cells and monocytes. It indicated that PD-1 expression might be an early biomarker to assess illness severity and predict the prognosis of septic shock. Then, we further investigated the mechanism underlying the regulation of PD-1 expression. Our data showed that Notch signaling pathway was activated in both septic shock patients and lipopolysaccharide- (LPS-) tolerant THP1 cells and both interleukin 10 (IL-10) and PD-1 were increased in the THP1 cells. Inhibition of Notch signaling by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenyl glycinet-butyl ester (DAPT) induced significantly decreased expressions of PD-1 and IL-10 in the LPS-tolerant cell model. Our work suggested that Notch signaling pathway was involved in the regulation of PD-1 expression. PMID- 26063975 TI - Bromoenol Lactone, an Inhibitor of Calcium-Independent Phospholipase A2, Suppresses Carrageenan-Induced Prostaglandin Production and Hyperalgesia in Rat Hind Paw. AB - Prostaglandin (PG) E2 and PGI2 are essential to hyperalgesia in inflammatory tissues. These prostaglandins are produced from arachidonic acid, which is cleaved from membrane phospholipids by the action of phospholipase A2 (PLA2). Which isozyme of PLA2 is responsible for the cleavage of arachidonic acid and the production of prostaglandins essential to inflammation-induced hyperalgesia is not clear. In this study, we examined the effects of two PLA2 isozyme-specific inhibitors on carrageenan-induced production of PGE2 and PGI2 in rat hind paw and behavioral nociceptive response to radiant heat. Local administration of bromoenol lactone (BEL), an inhibitor of calcium-independent PLA2 (iPLA2), significantly reduced carrageenan-induced elevation of prostaglandins in the inflamed foot pad 3 h after injection. It also ameliorated the hyperalgesic response between 1 h and 3 h after carrageenan injection. On the other hand, AACOCF3, an inhibitor of cytosolic PLA2, suppressed neither prostaglandin production nor the hyperalgesic response. BEL did not suppress the mRNA levels of iPLA2 beta, iPLA2 gamma, cyclooxygenase-2, microsomal prostaglandin E synthase, prostaglandin I synthase, or proinflammatory cytokines in the inflamed foot pad, indicating that BEL did not suppress inflammation itself. These results suggest that iPLA2 is involved in the production of prostaglandins and hyperalgesia at the inflammatory loci. PMID- 26063977 TI - Antioxidative Strategy for Inflammatory Diseases. PMID- 26063976 TI - Matching Diabetes and Alcoholism: Oxidative Stress, Inflammation, and Neurogenesis Are Commonly Involved. AB - Diabetes and alcohol misuse are two of the major challenges in health systems worldwide. These two diseases finally affect several organs and systems including the central nervous system. Hippocampus is one of the most relevant structures due to neurogenesis and memory-related processing among other functions. The present review focuses on the common profile of diabetes and ethanol exposure in terms of oxidative stress and proinflammatory and prosurvival recruiting transcription factors affecting hippocampal neurogenesis. Some aspects around antioxidant strategies are also included. As a global conclusion, the present review points out some common hits on both diseases giving support to the relations between alcohol intake and diabetes. PMID- 26063978 TI - Atorvastatin Improves Inflammatory Response in Atherosclerosis by Upregulating the Expression of GARP. AB - Regulatory T cells play an important role in the progression of atherosclerosis. GARP is a newly biological membrane molecule existed on activated Tregs, which is related to the release of TGF-beta. The antiatherosclerosis effects of statins partly depend on their multiple immune modulatory potencies. In this paper, we present that atorvastatin could upregulate the expression of GARP and TGF-beta in CD4+ T cells and increase the numbers of CD4+LAP+ and CD4+Foxp3+ regulatory T cells in ApoE-/- mice. Also, we indicate that atorvastatin promotes the aggregation of GARP+ and Foxp3+ cells and secretory of the TGF-beta1 in atherosclerotic plaques. Furthermore, we prove that atorvastatin could delay the procession of atherosclerosis and improve the stability of atherosclerotic plaques. Interestingly, we report that inhibition of GARP distinctly inhibits the anti-inflammatory effects of atorvastatin. We conclude that atorvastatin improves the inflammatory response in atherosclerosis partly by upregulating the expression of GARP on regulatory T cells. PMID- 26063979 TI - The Effect of Cyclooxygenase Inhibition on Tendon-Bone Healing in an In Vitro Coculture Model. AB - The effects of cyclooxygenase (COX) inhibition following the reconstruction of the anterior cruciate ligament remain unclear. We examined the effects of selective COX-2 and nonselective COX inhibition on bone-tendon integration in an in vitro model. We measured the dose-dependent effects of ibuprofen and parecoxib on the viability of lipopolysaccharide- (LPS-) stimulated and unstimulated mouse MC3T3-E1 and 3T3 cells, the influence on gene expression at the osteoblast, interface, and fibroblast regions measured by quantitative PCR, and cellular outgrowth assessed on histological sections. Ibuprofen led to a dose-dependent suppression of MC3T3 cell viability, while parecoxib reduced the viability of 3T3 cultures. Exposure to ibuprofen significantly suppressed expression of Alpl (P < 0.01), Bglap (P < 0.001), and Runx2 (P < 0.01), and although parecoxib reduced expression of Alpl (P < 0.001), Fmod (P < 0.001), and Runx2 (P < 0.01), the expression of Bglap was increased (P < 0.01). Microscopic analysis showed a reduction in cellular outgrowth in LPS-stimulated cultures following exposure to ibuprofen and parecoxib. Nonselective COX inhibition and the specific inhibition of COX-2 led to region-specific reductions in markers of calcification and cell viability. We suggest further in vitro and in vivo studies examining the biologic and biomechanical effects of selective and nonselective COX inhibition. PMID- 26063980 TI - Microcystins Induces Vascular Inflammation in Human Umbilical Vein Endothelial Cells via Activation of NF-kappaB. AB - Microcystins (MCs) produced by toxic cyanobacteria cause serious water pollution and public health hazard to humans and animals. However, direct molecular mechanisms of MC-LR in vascular endothelial cells (ECs) have not been understood yet. In this study, we investigated whether MC-LR induces vascular inflammatory process in cultured human umbilical vein endothelial cells (HUVECs). Our data demonstrated that MC-LR decreased HUVECs proliferation and tube formation and enhanced apoptosis. MC-LR also induced intracellular reactive oxygen species formation (ROS) in HUVECs. The MC-LR directly stimulated phosphorylation of NF kappaB. Furthermore, MC-LR also increased cell adhesion molecules (ICAM-1 and VCAM-1) expression in HUVECs. Taken together, the present data suggested that MC LR induced vascular inflammatory process, which may be closely related to the oxidative stress, NF-kappaB activation, and cell adhesion molecules expression in HUVECs. Our findings may highlight that MC-LR causes potential damage to blood vessels. PMID- 26063981 TI - Inflammation Biomarkers of Advanced Disease in Nongingival Tissues of Chronic Periodontitis Patients. AB - Chronic periodontitis is a multifactorial inflammatory disease that affects supporting structures of the teeth. Although the gingival response is largely described, little is known about the immune changes in the alveolar bone and neighboring tissues that could indicate periodontal disease (PD) activity. Then, in this study we identified the ongoing inflammatory changes and novel biomarkers for periodontitis in the tissues directly affected by the destructive disease in PD patients. Samples were collected by osteotomy in 17 control subjects during extraction of third molars and 18 patients with advanced PD, in which alveoloplasty was necessary after extraction of teeth with previous extensive periodontal damage. Patients presented mononuclear cells infiltration in the connective tissue next to the bone and higher fibrosis area, along with increased accumulation of IL-17(+) and TRAP(+) cells. The levels of TNF-alpha and MMP-2 mRNA were also elevated compared to controls and a positive and significant correlation was observed between TNF-alpha and MMP-2 mRNA expression, considering all samples evaluated. In conclusion, nongingival tissues neighboring large periodontal pockets present inflammatory markers that could predict ongoing bone resorption and disease spreading. Therefore, we suggested that the detailed evaluation of these regions could be of great importance to the assessment of disease progression. PMID- 26063983 TI - Prevalence of bovine fasciolosis based on faecal examination and abattoir survey in Karnataka. AB - The prevalence of fasciolosis was evaluated in bovines based on coprological examination and postmortem liver examination of slaughtered cattle and buffaloes. The faecal examination of 130 cattle and 135 buffaloes revealed a prevalence of 9.9 % in cattle and 13.3 % in buffaloes respectively. The examination of livers from cattle and buffaloes (155 each) slaughtered at the KMPMCL abattoir revealed the prevalence of fasciolosis was 20.6 % in cattle and 22.5 % in buffaloes. The results were statistically significant in faecal examination and not significant in liver examination from cattle and buffaloes respectively. PMID- 26063984 TI - Prevalence of intestinal parasites in a population in Eghbalieh city from Qazvin Province, Iran. AB - Intestinal parasitic infections are endemic worldwide and have been described as constituting the greatest single worldwide cause of illness and disease. The prevalence of Intestinal parasitic infections was estimated to be 5.92 %. Entamoeba coli was the most common parasite followed by Giardia lamblia and Blastocystis hominis. About 5.15 % of samples contained a single parasite and 0.76 % contained multiple parasites. In this study, the prevalence of intestinal parasites especially helminthic infections was low. The study aimed to estimate prevalence of intestinal parasites in Eghbalieh city from Qazvin Province, Iran. PMID- 26063982 TI - Lysosome and Cytoskeleton Pathways Are Robustly Enriched in the Blood of Septic Patients: A Meta-Analysis of Transcriptomic Data. AB - BACKGROUND: Sepsis is a leading cause of mortality in intensive care units worldwide. A better understanding of the blood systems response to sepsis should expedite the identification of biomarkers for early diagnosis and therapeutic interventions. METHODS: We analyzed microarray studies whose data is available from the GEO repository and which were performed on the whole blood of septic patients and normal controls. RESULTS: We identified 6 cohorts consisting of 450 individuals (sepsis = 323, control = 127) providing genome-wide messenger RNA (mRNA) expression data. Through meta-analysis we found the "Lysosome" and "Cytoskeleton" pathways were upregulated in human sepsis patients relative to controls, in addition to previously known signaling pathways (including MAPK, TLR). The key regulatory genes in the "Lysosome" pathway include lysosomal acid hydrolases (e.g., protease cathepsin A, D) as well as the major (LAMP1, 2) and minor (SORT1, LAPTM4B) membrane proteins. In contrast, pathways related to "Ribosome", "Spliceosome" and "Cell adhesion molecules" were found to be downregulated, along with known pathways for immune dysfunction. Overall, our study revealed distinct mRNA activation profiles and protein-protein interaction networks in blood of human sepsis. CONCLUSIONS: Our findings suggest that aberrant mRNA expression in the lysosome and cytoskeleton pathways may play a pivotal role in the molecular pathobiology of human sepsis. PMID- 26063985 TI - Prevalence of ectoparasites in carp fry and fingerlings of Rajshahi district, Bangladesh. AB - The Study has been carried out to find out the prevalence of ectoparasites of carp fry and fingerlings during June 2010 to May 2011 from Rajshahi district, Bangladesh. Four groups of ectoparasites viz. myxozoan, ciliophoran, monogenean and crustacean were recorded from 560 species of endemic and exotic carps collected from Rajshahi District, Bangladesh. The highest ectoparasitic prevalence (37.5 %) has been recorded for ciliophoran group in winter and the lowest prevalence in crustacean (5 %) in summer. However, no crustacean was recorded in Rainy season (June-September). The seasonal highest ectoparasitic prevalence (25 %) was recorded during the winter season (October to January) while the lowest prevalence (11 %) in rainy season (June-September). The study shows that the carp fry and fingerlings are most susceptible to ectoparasites in winter. PMID- 26063986 TI - Studying the correlations among hematological and serum biochemical constituents in cattle theileriosis. AB - The present study was undertaken to investigate the influence of tropical theileriosis on serum constituents, erythrocytes and platelets pictures and to study the correlation between the studied parameters. A total number of 26 cows were subjected to study. Out of them 16 cows were suffered from theileria infection. Comparing theileria infected group with the control group revealed significant decreases in total RBCS counts (p < 0.01), haemoglobin concentration (p < 0.01), packed cell volume (PCV) (p < 0.01), platelets count (PLT) (p < 0.01), plateletcrit (PCT) (p < 0.01), significant decreases in serum total proteins (p < 0.01), albumin (p < 0.01), calcium (p < 0.01), and phosphorus (p < 0.01) levels, and significant increases in serum blood urea nitrogen (BUN) (p < 0.05) and creatinine (p < 0.05) levels, and in serum aspartate aminotransferase (p < 0.01) and gamma glutamyl transferase (GGT) (p < 0.01) activities. Correlations between serum biochemical parameters revealed significant positive correlations between total proteins and albumin (r = 0.598*), A/G ratio and albumin (r = 0.860**), calcium and albumin (r = 0.729*), calcium and A/G ratio (r = 0.752*), GGT and BUN (r = 0.539*), and significant negative correlations between A/G ratio and globulins (r = -0.809**) and between glucose and albumin (r = -0.614*). Erythrocytes count showed a significant negative correlation with mean corpuscular volume (MCV) (r = -0.966**) and red blood cells distribution width (RDW) (r = -0.909**). MCV showed a significant positive correlation with RDW (r = 0.860*) and PCV (r = 0.781*). RDW was positively correlated with PCV (r = 0.966**). PLT count showed a significant positive correlation with mean platelet volume (MPV) (r = 0.992**), platelets distribution width (PDW) (r = 0.956**) and PCT (r = 0.994**). Furthermore, MPV showed a significant positive correlation with PDW (r = 0.940**) and a negative correlation with PCT (r = 0.974**). PDW was negatively correlated with PCT (r = -0.974**). It could be concluded that theileria infection in cattle resulted in anaemia, thrombocytopenia, hypoproteinaemia, hypoalbuminaemia and hypophosphataemia, in addition to hepatic and kidney dysfunction. PMID- 26063987 TI - Occurrence of Linguatula serrata nymphs in cattle slaughtered in Tabriz, Iran. AB - The Linguatula serrata is a tongue-shaped parasite that infects carnivores or insectivorous reptile as final and herbivores as intermediate host. The aim of this study was to evaluate the prevalence of nymphal stages of L. serrata in mesenteric nodes (MLN) and mediastinal lymph nodes of cattle slaughtered in Tabriz slaughterhouse, North West of Iran. Mesenteric and mediastinal lymph nodes of 640 cattle of different sex and age were inspected. A digestion method was applied for investigation of samples revealing an infection prevalence of 18.9 %. The MLNs in 97 cattle out of 640 (15.1 %) and the mediastinal lymph nodes in 47 cattle out of 640 (7.3 %) were infected by L. serrata nymphs. The results showed infection rate of mesenteric lymph nodes higher than mediastinal mesenteric lymph nodes (P < 0.05). The infection rate increased with age (P < 0.05). Although a significant difference seen in the infection rate between male and female but it was not significant at the same age groups of male and female (P > 0.05). In addition, there was a significant difference in the infection rate of different seasons (P < 0.05). Linguatulosis occurs as an endemic zoonosis in the northwest of Iran and has an active transmission life cycle. PMID- 26063988 TI - Record of gut associated nemathelminth in the giant African snail Achatina fulica (Bowdich) from Bangalore, India. AB - Prevalence of nematodes in Achatina fulica (Bowdich) sample collected from two different sites within Bangalore University Jnana Bharathi Campus viz., Dhanavanthari vana and Botany Department garden was 84 and 100 % respectively. However, the identity of the nemathelminth could not be established to the species level as it did not respond to the clearing agent and its genital organs were not located which is key character for taxonomic identification. Also, no Cercariae were recorded in the samples, perhaps the snail sample was non endemic for parasitic population. Helminthological prospection with regard to the giant African snail from the region has not been performed till date. The present work is a preliminary study in that direction intended to determine the nemathelminth fauna associated with A. fulica populations in Bangalore region laying emphasis on further studies to be undertaken in this regard. PMID- 26063989 TI - Pathomorphological alterations associated with chicken coccidiosis in Jammu division of India. AB - Pathomorphological alterations of chicken coccidiosis in Jammu division were undertaken in both organized and backyard chickens during the year 2010-2011. A total 240 intestines were examined from both organized farms and backyard chickens for histopathological studies. Out of 240 samples processed, 48 samples were found to be positive for coccidiosis with a prevalence of 20 %. Coccidiosis was initially diagnosed on the basis of faecal examination and confirmed by the presence of sporulated oocysts and pathomorphological alterations in intestines. Eimeria species were identified by morphometry. Five Eimeria species identified were Eimeria tenella, E. necatrix, E. maxima, E. acervulina and E. mitis. Histopathological lesions revealed loss of epithelial tissue, congestion of blood vessels which indicate disruption followed by haemorrhage, severe muscular oedema and necrosis of submucosa of intestine and caecum. There was loss of intestinal villi, disruption of caecal mucosa and clusters of oocysts seen. There was massive infiltration by heterophils and mononuclear cells. Several merozoites, schizonts and microgametes were found in the epithelial cells. PMID- 26063990 TI - Occurrence of Setaria labiatopapillosa in peritoneal cavity of a crossbred cattle. AB - The current study reports the occurrence of Setaria labiatopapillosa, a filarid worm, during post mortem examination in the peritoneal cavity of an adult female cross-bred cattle died due to foreign body syndrome from Ludhiana district, Punjab. The worms were cleared in lactophenol after collection and mounted in glycerol for identification. The worms were 90-95 mm in length, milky white, tapering, long with spirally coiled hind ends. The anterior end of the mounted parasite revealed peribuccal chitinous rings with lateral epaulette like structures in the head region. The posterior end of the female revealed thin, cone shaped, two lateral appendages and terminating into a prominent rosette like structure carrying a number of differently sized spikes. PMID- 26063991 TI - Correlation between some hematological parameters, acute phase proteins and serum immunoglobulins in experimental caprine besnoitiosis. AB - The present study was undertaken to investigate correlation between some hematological parameters, acute phase proteins and immunoglobulins in the experimentally infected goats with Besnoitia caprae from the time of infection till 360 days post infection (DPI). Six male goats, approximately 12-16 months old, were inoculated subcutaneously with approximately 1.3 * 10(8) bradyzoites of B. caprae and blood samples were collected at weekly intervals from the jugular vein of the goats. Total leukocyte count and differential leukocyte counts were determined. Acute phase proteins (APPs) including serum amyloid A (SAA), haptoglobin (Hp), fibrinogen and ceruloplasmin were undertaken at weekly intervals. We evaluated an enzyme-linked immunosorbent assay (ELISA) (using a somatic antigen of bradyzoite) to detect anti-B. caprae antibodies in caprine sera. Cysts were present in the skin biopsies of the distal parts of the leg of the infected goats from 28 DPI. From 30 to 360 DPI, results showed that the APPs concentrations including SAA, Hp, fibrinogen and ceruloplasmin were enhanced in the serum of infected goats. However, there were some variation in hematological parameters; the differences were not significant with those of the normal values. Some variations were seen in the levels of specific antibodies against this parasite and they had correlation with some hematological parameters and acute phase proteins. PMID- 26063992 TI - In vitro protoscolicidal effects of fungal chitosan isolated from Penicillium waksmanii and Penicillium citrinum. AB - Hydatidosis is caused by a tapeworm which infects humans by the larval stage. In humans, the disease is so serious that it requires surgery for treatment. Documents show that there have been many efforts in finding new scolicidal agents for reducing the rate of the infection. The objective of this study was determination of the scolicidal effect of two fungal chitosan types, produced from Penicillium spp. and commercially chitosan (CC) on Echinococcus granulosus protoscolex. Protoscolices were aseptically aspirated from sheep livers hydatid cysts. Four concentrations (50, 100, 200, 400 MUg/ml) of each type of prepared chitosan were used for 10, 30, 60 and 180 min. Viability of protoscolices was detected by 0.1 % eosin staining. Fungal chitosan which was the most bioactive type with higher degree of deacetylation showed stronger scolicidal activity in vitro (P < 0.05). Fungal chitosan could be recommended, as good as CC for hydatid cysts control and is a noble alternative for synthetic and chemical scolicidal. PMID- 26063993 TI - First report of Cobboldia elephantis (Cobbold, 1866) larvae in a free ranging wild elephant from Andhra Pradesh, India. AB - Larvae of Cobboldia elephantis have been reported from the stomach of a free ranging wild elephant (Elephas maximus) while conducting post mortem examination at Palamner forest range, Chittoor district of Andhra Pradesh state, India. This is the first report of C. elephantis in free ranging wild elephant in Andhra Pradesh state, India. PMID- 26063994 TI - Treatment of mange infection in a weaner flock of sheep with ivermectin at sheep breeding farm Hardishiva of Kashmir valley. AB - An outbreak of Sarcoptes scabiei mange occured in a weaner flock that comprised of 74 animals including 31 male and 43 female at sheep breeding farm Hardishiva of Kashmir valley. All the animals in the flock were affected. Animals were very weak and emaciated skin lesions were confined to the lips, nostrils, ears, face, and were characterized by pruritus, erythema, papule formation, alopecia and scab formation. Microscopic examination of skin scraping revealed S. scabiei mange infestation. The affected animals were treated with ivermectin at 1 ml/50 kg b.wt. S/C, as single dose along with supportive therapy. 7th day post treatment scrapping examinations revealed absence of mites or their eggs in these scrapings. PMID- 26063995 TI - Comparative efficacy of different in vitro cultivation media for Trypanosoma evansi isolated from different mammalian hosts inhabiting different geographical areas of India. AB - The present study was undertaken to establish an optimal medium for primary culture initiation and maintenance of T. evansi isolated from different mammalian hosts of diverse geographical regions of India viz. donkey/1 (Hardoi, Uttar Pradesh), donkey/2 (Junagarh, Gujarat), pony/1 (Hisar, Haryana), camel/1 (Bikaner, Rajasthan) which represented isolates 1, 2, 3 and 4, respectively. Primary cultures were initiated with all four isolates in five different in vitro cultivation media with seeding density of 1 * 10(6) trypanosomes/ml. The parasites of all four isolates could remain viable only for 48 h in medium E (Alsever's solution) and for 72 h in medium A, C and D. Parasites reached to a maximum density (2.5-3.75 * 10(6)/ml) within 24 h and thereafter, a sharp decline (0.5-0.75 * 10(6)/ml) in the next 72 h was observed in 1, 2 and 3 isolates cultured in medium B. In isolate 4, parasite counts got more than doubled in 24 h and then decreased gradually up to sixth day post initiation of cultivation which thereafter increased gradually up to 34 days and a constant parasite number of 10(5)/ml could be achieved for 90 days in medium B. During this prolonged culture the trypanosomes retained their long slender morphology and infectivity to mice. PMID- 26063996 TI - Prevalence of gastrointestinal helminth parasites of equids from organized farms of Mumbai and Pune. AB - A total of 1,304 faecal samples of different species of equids were examined for presence of helminthic eggs from five different centres in Mumbai and Pune regions of Maharashtra state from October 2011 to June 2012. Overall prevalence of helminthic infestation was found to be 20.63 % with higher rate of occurrence in monsoon (31.29 %) followed by winter (20.40 %) and summer (14.23 %). Four species of nematodes viz. strongyles (10.81 %), Strongyloides westeri (13.19 %), Parascaris equorum (0.23 %) and Dictyocaulus arnfieldi (0.23 %); two species of trematodes viz. amphistomes (1.38 %) and Schistosoma indicum (0.31 %) and only one species of cestode viz. Anoplocephala spp. (0.07 %) were encountered in the study. Coproculture studies revealed that Strongylus vulgaris was predominant species (36.87 %) among strongyles followed by cyathostomes. Amongst equids, mules had the lowest prevalence of 14.80 % followed by ponies (20.61 %) horses (38.79) and donkeys (51.90 %). PMID- 26063997 TI - An alternative method for producing Toxocara canis second stage larvae from a paratenic host (pigeon) for mRNA extraction purpose. AB - Toxocara canis is a prevalent zoonotic parasite which can cause serious disease in puppies and humans. Excretory-secretory and coating antigens of the second stage larvae (L2) are the best targets for performing immunodiagnostic and also immunoprophylactic tests. Various hatching methods have been described to bring out L2 from the resistant infective egg shell; but these methods are difficult to do and have had different results when performed by different practitioners. In this study, second stage larvae were obtained from the viscera of pigeons (a paratenic host) which were infected with infective eggs. Infective Toxocara canis eggs were given to ten pigeons and live larvae were recovered from their excised livers and lungs by using the Baermann's apparatus in the next days. Two in vitro methods for larvae hatching were also performed including a so-called physiological hatching method according to Ponce-Macotela et al. (J Parasitol 175:382-385, 2010), and a mechanical hatching method according to Alcantara-Neves and Santos (J Exp Parasitol 119:349-351, 2008) and their results were compared with the in-vivo method. Results show that averagely 36.2 % of fed larvae recovered from livers and 0.15 % from lungs. Average larvae recovery in the first day after infection (24.2 %) was significantly lower than subsequent days (39 %). Maximum larvae recovered in day 3 (55 %). In-vitro methods we carried out did not have acceptable results and only a few larvae did hatch using these methods. PMID- 26063998 TI - Clinical and cytological characteristics and prognostic implications on sheep and goat Theileria infection in north of Iran. AB - The present research was carried out during 3 months from early June through late August, in northern zones of Iran. In addition, the present study was performed on 300 sheep and goats, in which 50 specimens were isolated based on clinical signs, blood smears and lymph node puncture. The results indicated clinical signs of theileriosis in sheep (with more prominent signs) and goats were diagnosable. The reliable clinical signs in sheep and goats included fever, tachycardia, cough, increased respiratory rate, mucosal pallor, anorexia, ruminal hypomotility and lymph node enlargement. Furthermore, the frequency of cough, abnormal pulmonary sounds, anorexia and ruminal hypomotility were significantly more in sheep than goats (P < 0.05). PMID- 26063999 TI - Temporal variation of the cestode, Cotugnia cuneata (Meggit, 1924) in their host, domestic pigeons, Columba livia domestica (Gmelin, 1789). AB - A study of the temporal variation of Cotugnia cuneata, on a monthly basis, was carried out from January 2008 to December 2010. The study revealed a similarity in the percentage prevalence and mean intensity of infection with higher values in the beginning of the year that gradually declined towards the middle and rose to moderate values towards the end of the year. The periodicity clearly shows a correlation with the seasonal changes throughout the year and provides important insights to the survival strategies of the parasite as well as its life-cycle. PMID- 26064000 TI - Anthelmintic efficacy of aqueous extract of Butea monosperma (Lam.) Kuntze against Haemonchus contortus of sheep and goats. AB - Infection with Haemonchus contortus is one of the most important economic problems in small ruminants worldwide. Resistance development by parasites, drug residues in meat, toxicity, non-availability and high cost limit the usefulness of currently used synthetic drugs. Therefore, the present study was undertaken to evaluate in vitro anthelmintic efficacy of aqueous extract of seeds of Butea monosperma (Lam.) Kuntze against H. contortus. Phytochemical analysis of extract showed high concentration of phenolic (11.93 +/- 0.64 mg of GAE/g of extract), flavonoids (238.17 +/- 19.14 mg of quercetin/g extract) and tannin (10.80 +/- 0.70 mg of GAE/g of extract) content. The observations revealed that parasites were sluggish and movement was little at 4 h post exposure of 25, 50 mg/ml and very sluggish in 100 mg/ml concentration. The extract showed complete mortality of the adult H. contortus worms at the concentrations of 100 mg/ml at the time exposure of 6 h and with the concentration of 50 mg/ml at the post exposure of 8 h. At 25 mg/ml concentration 50 % mortality was recorded at 6 h and complete at 8 h post exposure. The LC50 at 6 and 8 h were 45.20 and 17.50 mg/ml respectively. Levamisole at concentration of 0.5 mg/ml caused 50 % mortality at 2 h post exposure and full mortality at 4 h post exposure. These cidal effects may be due to presence of high phenolic, flavonoids and tannin content in the extract. The results confirm the aqueous extract of B. monosperma (Lam.) Kuntze on adult H. contortus worms. PMID- 26064001 TI - Occurrence of cymothoid isopod from Miri, East Malaysian marine fishes. AB - To identify the isopod parasite, which has been recorded from Miri, East Malaysian marine fishes. During the present study, four cymothoid isopods are reported three genera, including Cymothoa eremita, Lobothorax typus, Nerocila longispina and Nerocila loveni. Nerocila longispina and N. loveni are also previously reported from Malaysia and two additional cymothoids C. eremita and L. typus are reported for the first record of Miri coast, East Malaysia. New hosts were identified for N. loveni on Chirocentrus dorab for the first time in the world fauna. The Parasitological indexes were calculated. The site of attachment of the parasites on their hosts was also observed. These parasites can cause the damage in gill, eye and internal organ including swim bladder. Marine fish parasitology is a rapidly developing field of aquatic science. PMID- 26064002 TI - Molecular cloning and characterization of arginine kinase gene of Toxocara canis. AB - Toxocara canis is an important gastrointestinal nematode of dogs and also a causative agent of visceral larva migrans in humans. Arginine kinase (AK) gene is one of the important biomolecule of phosphagen kinase of T. canis which is emerging as an exciting novel diagnostic target in toxocarosis. The present study was carried out to clone and characterize AK gene of T. canis for future utilization as a diagnostic molecule. Total RNA was extracted from intact adult worms and reverse transcription was done with oligo dT primers to obtain complementary DNA (cDNA). Polymerase chain reaction (PCR) was carried out using cDNA as template with specific primers which amplified a product of 1,202 bp. The amplicon was cloned into pDrive cloning vector and clone was confirmed by colony PCR and restriction endonuclease analysis. Sequence analysis of the gene showed 99.8 and 77.9 % homology with the published AK gene of T. canis (EF015466.1) and Ascaris suum respectively. Structural analysis shown that the mature AK protein consist of 400 amino acids with a molecular wt of 45360.73 Da. Further expression studies are required for producing the recombinant protein for its evaluation in the diagnosis of T. canis infection in humans as well as in adult dogs. PMID- 26064003 TI - Haematological and biochemical changes in experimental Trypanosoma evansi infection in rabbits. AB - New Zealand white rabbits (N = 4) were challenged with the local strain of Trypanosoma evansi. Each rabbit was infected with 5 * 10(5) trypanosomes subcutaneously. The infection was characterized by intermittent pyrexia, undulating parasitaemia, anorexia and emaciation. The infected rabbits were examined daily for development of clinical signs and infection status by wet blood-films made from the ear veins. Thick and thin blood smears were also examined daily until the end of the experiment for description of blood cells. Differential leukocyte count (DLC) was also done. The parasite was observed in the blood during the acute phase only. Leukocytosis in the acute phase followed by leukopenia during the chronic phase was recognized. Haematological studies revealed reduced TEC, Hb and PCV. The main changes in the erythrocytes were macrocytes, hypochromic cells, Howell-Jolly bodies, target cells, stomatocytes and burr cells. Serum chemistry revealed hypoproteinemia, hypocholesterolaemia, hypoglycemia, hyperbilirubinemia, elevated creatinine, BUN, increased AST and ALT. PMID- 26064004 TI - Canine visceral leishmaniasis: seroprevalence survey of asymptomatic dogs in an endemic area of northwestern Iran. AB - Canine visceral leishmaniasis is a major public health problem that is endemic in tropical and sub tropical countries and is fatal in humans and dogs. In addition to symptomatic dogs, asymptomatic ones seem as source of Leishmania infantum infection. Thus surveillance and control programs of reservoir hosts are essential. This study aimed to evaluate the sero-prevalence of visceral leishmaniasis in asymptomatic domestic dogs from in an endemic area of north west, Iran. A cross sectional study was carried out in Meshkin-Shahr district during 2011-2012. Blood samples collected from 508 asymptomatic domestic dogs were tested by direct agglutination test. In this study 508 dogs (397 males and 111 females, mean age, 3.24 years) from western and eastern parts of the Meshkin Shahr were examined. A total of 508 dogs examined 119 dogs (23.4 %) had antibodies (titers of >=1:320) against L. infantum. Statistically significance was occurred between male (25.4 %) and female (16.2) sero-prevalence (P = 0.042). No statistically significance was observed between age groups (P = 0.22). Compared with previous studies it seems to increase sero-prevalence of visceral leishmaniasis in dogs in the studied areas caused by ecological changes. High proportion of asymptomatic but seropositive dogs emphasizes the importance of dogs without clinical signs in the epidemiology of zoonotic leishmaniasis. Thus, the necessity of using serological tests in asymptomatic dogs is recommended for disease control strategy. PMID- 26064005 TI - Eight known species of Aphelenchoides nematodes with description of a new species from Manipur, India. AB - Study of Aphelenchoides nematodes from different localities of Manipur were conducted for their documentation. During the study eight known and a new species were identified. Aphelenchoides aerialis sp. nov. differed from all other species of Aphelenchoides in having a tail without bifurcation and strong ventral mucro with single ventrosublateral caudal papillae in male. The known species along with the new species are described in the present study. PMID- 26064006 TI - Importance of cystic echinococcosis in slaughtered herbivores from Iran. AB - Cystic echinococcosis (CE) or hydatidosis is well-known as one of the zoonotic diseases in world-wide including Iran. Hydatidosis was considered as a disease that causes severe reduction in meat wool and milk in livestock animals which all of them indicating its importance. Thus, present study was designed to evaluated prevalence of CE in slaughtered animals from Delfan region in Lorestan province of Iran. The samples 6,885 animals were considered based on type of species in a slaughter from Lorestan province. The study performed from 3 April 2009 to 3 April 2012 and inspection carried out from 4,101 cattle, 2,150 sheep and 634 goat. The liver and lungs examined based on CE and showed the highest prevalence in cattle (25.7 %) and the lowest 3.8 % in goat, likewise, CE was more in the lung than to liver. There was significant difference between species of animals and infected organ (P < 0.001). The highest prevalence was seen in winter (32.8 % for cattle, 8.1 % for goat) while, it was 15.7 % for sheep in summer (P = 0.04). Overall these data indicate the necessity of disease control strategy for reduction of CE. PMID- 26064007 TI - Prevalence of canine trypanosomiasis in certain areas of Andhra Pradesh. AB - A total of 937 dogs were screened for Trypanosoma evansi infection by wet blood film, blood smear staining techniques and micro haematocrit centrifugation technique (MHCT). In the present study, 2.28 % of male dogs and 2.40 % of female dogs were found positive by MHCT method. The findings indicated that there was no effect of T. evansi infection on sex of dogs. Higher prevalence of T. evansi infection was observed in Mongrel than in Pomeranian, Cross breeds, German Shepherd, Doberman and Labrador breeds. Age wise prevalence of T. evansi infection in dogs revealed that younger ones, below the 2 years age group recorded the highest prevalence than the above the 2 years age group dogs. PMID- 26064008 TI - Experimental Neospora caninum infection in domestic bird's embryonated eggs. AB - To date, there are no reports regarding comparison between different bird species in Neospora. caninum infection. In the present study 70 embryonated eggs from quail, partridge, broiler and egg laying chickens were divided into 7 groups equally. Six groups in each species were inoculated with different dilutions (10, 10(2), 10(3), 10(4), 10(5), and 10(6)) of tachyzoites/embryonated egg in the chorioallantoic membrane and the seventh group was considered as control. The mortality rates and clinical signs were studied. All the egg laying chickens and some of the broiler chickens and quails showed neurologic signs like. The results revealed that the mortality rate was dose dependent in broiler chicken embryonated eggs. But mortality rate was dose independent in egg laying chickens and quail. Partridge revealed 100 % mortality rate in all doses. The LD50 in broiler chicken embryonated was 10(2.3). In conclusion, LD50 in the broiler chickens is the lowest between different animal models which shows that the broiler chicken embryonated egg is the best animal model for experimental inducing of neosporosis. Partridge is the most susceptible bird to N. caninum infection. These results reinforce that there is genetic susceptibility to N. caninum in chickens like mice and provide new insights to reach an inexpensive and available animal model for N. caninum infection. PMID- 26064009 TI - Hematological parameters associated with parasitism in pike, Esox lucius caught from Anzali wetland. AB - This study involved 120 pike, Esox lucius, captured from Anzali wetland. Parasite fauna were identified in captured fish. Also, changes of haematological parameters were compared both infected and uninfected fish. Parasitological inspections revealed the following infestations: Skin: Lernea cyprinacea, Argulus foliaceus (Crustacean) and Tricodina sp. (Ciliatea). Gill: Dactylogyrus sp. (Digenea) and Tetraonchus monenteron (Monogenea). Eye: Diplostomum spathaceum (Digenea). Gut: Eustrongylides exises, Rhipdocotyle illense, Raphidascaris acus (Nematode), Corynosoma Strumosum (Acanthocephala). Most prevalence and intensity were related to Eustrongylides exises and Rhipdocotyle illense. Following haematological parameters were evaluated: haematocrit, haemoglobin concentration, erythrocyte and leukocyte counts, mean cell volume (MCV), mean cell haemoglobin, mean cell haemoglobin concentration lymphocytes, monocytes and eosinophils. Significant difference was found for MCV between infected and uninfected fish. PMID- 26064010 TI - Detection of Theileria annulata in blood samples of native cattle by PCR and smear method in Southeast of Iran. AB - Theileria annulata, a protozoan parasite of cattle is causes tropical theileriosis. Polymerase chain reaction (PCR) was used to assess the presence and the frequency of T. annulata infection in blood samples obtained from carrier cattle in Kerman, Southeast of Iran. Blood samples were collected in citrate solution from 150 native cattle with mean age of 1 year which selected randomly. Primarily, a thin layer smear was prepared from their ear sublime vein blood and was fixed with methanol and stained with Giemsa dye. Blood smears were examined for the presence of parasites, and blood samples were analyzed by PCR. Piroplasmic forms of T. annulata were seen in 16 of 150 (10.66 %) by examination the blood smears with light microscope, whereas 68 of 150 (45.33 %) cattle were positive by PCR method. All animals that were positive by blood smears were also positive by PCR. Difference between these methods was significant (P < 0.05). Our results demonstrate that this PCR assay in diagnosing T. annulata parasites in carrier cattle is more sensitive than method of smear preparation and can be used in epidemiological studies. PMID- 26064011 TI - Toxoplasma gondii: sexual transmission in mice. AB - This study was performed to evaluate sexual transmission of Toxoplasma gondii in mice. RH strain tachyzoites were intraperitoneally inoculated into 10 Balb/C male mice and after 48 h, their semen were collected from epididymis and examined by giemsa staining and PCR. Twenty Balb/C female mice mated with four infected male mice four times and any mating time was 48 h whilst 20 female control mice mated with four uninfected male mice for 8 days. Female mate choice was assessed using a three-chambered cage. Four female mice were placed in a central chamber and in one side of it, two infected male mice were kept and in other side, two naive male mice were placed. Due each quarter, every of the female movement was reported and then the female was replaced to middle chamber. Besides on the detection of DNA and whole parasite in semen, no abortion and death was seen in female mice. Pregnancy was seen only 4 out of 20 female mice which mated with infected males while 17 pregnancies were seen from 20 control female mice (P value = 0.0001). No statistical significant was seen in female mate choice between naive male (45 movement) and infected male (36 movement). This study showed that toxoplasmosis could not transmit to female mice and their offspring due to mating and the parasite had not effect on female mate choice. It seems that infected male mice cannot entirely mate with females due to reduction of male weapon and body size, physiological vigor and energy. PMID- 26064012 TI - Survey on anthelmintic resistance to gastrointestinal nematodes in unorganized goat farms of Tamil Nadu. AB - One of the major problems in small ruminant farms is emergence of anthelmintic resistance (AR) to commonly used dewormers. This study investigated AR to gastrointestinal nematodes affecting goats in 27 unorganized farms in three different agro-climatic zones (Cauvery delta zone, high altitude zone and high rainfall zone) of Tamil Nadu, India. Two anthelmintics viz., albendazole (AZ) and levamisole (LEV) were used in this study as per the dose recommended by the manufacturer. Status of AR was detected by using the faecal egg count reduction test. Results revealed the presence of high level of resistance to both AZ and LEV. In the high rainfall and high altitude zones, all the farm flocks were found to be resistant to LEV. In the Cauvery delta zone, 13 farm flocks were resistant and four farm flocks showed suspect resistance to AZ. Fifteen farm flocks showed resistance and two showed suspect resistance to LEV. Further, morphological characterization of the infective larvae derived from faecal cultures indicated that by far the most predominant gastrointestinal nematode species found in goats was Haemonchus contortus. PMID- 26064013 TI - Microfilariae recurrence in graded murrah buffalo treated with repeated doses of ivermectin. AB - Filariosis is one of the common parasitic diseases of animals and man caused by a small group of filarid nematodes throughout the world. This disease is highly prevalent in hot and humid arenas of India especially hilly parts of Tarai region of Uttar Pradesh and coastal areas of Andhra Pradesh, (Kumar et al. 2005). Microfilariosis is manifested by pyerxia, loss of appetite, reduced milk yield, weakness, edema of dependent parts. Macrofilaricidal and micerfilaricidal are the most effective drugs to get rid of the larvae and adult worm burden. Ivermectin 200 MUg/kg body wt subcutaneous route is used as a curative drug in present clinical case and animal was responded well with the treatment. After 2 months the animal brought with same symptoms which were reported earlier. Wet blood film examination revealed recurrence of microfilariae in the peripheral blood circulation. PMID- 26064014 TI - Babesia bigemina infection in a 14-day old Jersey crossbred calf: a case report. AB - Babesia bigemina infection was diagnosed in a 14-day old Jersey female calf. The infected calf showed clinical symptoms of high fever, increased respiratory rate, pale conjunctival mucous membrane and haemoglobinuria. Blood smears were prepared and subjected for Giemsas staining method. Microscopic examination of the stained blood smear confirmed the characteristic intra-erythrocytic B. bigemina organisms. PMID- 26064015 TI - An epidemiological survey on intestinal helminths of stray dogs in Mashhad, North east of Iran. AB - This research was conducted to determine the prevalence of gastrointestinal helminths in stray dogs in the northeast of Iran, with special attention to those parasites that can be transmitted to human. In this experiment, a total of 72 adult and 18 juvenile stray dogs were collected and necropsied for the presence of helminth parasites from October 2011 to August 2012. The overall prevalence of gastrointestinal helminths was 86 % (95 % CI: 79.2-92.8 %). The observed helminths of the gastrointestinal tract were listed as follows: Toxocara canis (29 %), Toxascaris leonina (7 %), Ancylostoma caninum (2 %), Taenia hydatigena (43 %), Dipylidium caninum (39 %), Echinococcus granulosus (38 %), Mesocestoides lineatus (16 %), Taenia multiceps (11 %), Taenia ovis (3 %). There were no significant differences for the prevalence of gastrointestinal helminths between female (83.6 %) and male (89.7 %) and between young (89 %) and adult (72.2 %) animals. However, the prevalence of E. granulosus, T. hydatigena and D. caninum showed an increasing trend with increasing host age, significantly. Based on our data, it is important to point out the presence of zoonotic agents, namely E. granulosus and T. canis in stray dogs in the investigated area. Due to its impact on public health, appropriate control measures should be taken and it is recommended to determine the most appropriate preventive methods. PMID- 26064016 TI - Prevalence and histopathological finding of thin-walled and thick-walled Sarcocysts in slaughtered cattle of Karaj abattoir, Iran. AB - Sarcocystosis is a zoonotic disease caused by Sarcocystis spp. with obligatory two host life cycle generally alternating between an herbivorous intermediate host and a carnivorous definitive host. Some species of this coccidian parasite can cause considerable morbidity and mortality in cattle. The present study was set to investigate the prevalence of Sarcocystis spp. and type of cyst wall in slaughtered cattle of Karaj abattoir, Iran. For this purpose 125 cattle (88 males and 37 females) were investigated for the presence of macroscopic and microscopic Sarcocystis cysts in muscular tissues. No macroscopic Sarcocystis cysts were found in any of the samples. In light microscopy, 121 out of 125 cattle (96.8 %) had thin-walled cysts of Sarcocystis cruzi, while 43 out of them (34.4 %) had thick-walled Sarcocystis cyst. In this survey, the most infected tissue was esophagus and heart and the less was diaphragm. Thin-walled cysts (S. cruzi) mostly found in heart and skeletal muscle showed the less. However, thick-walled cyst (S. hominis or S. hirsuta) mostly were detected in diaphragm, heart muscle showed no thick-walled cyst. No significant relation was observed between age and sex and the rate of infection. The results showed that Sarcocystis cyst is prevalent in cattle in the North part of Iran and the evaluation of infection potential can be useful when considering control programs. PMID- 26064017 TI - A study on rate of infestation to Sarcocystis cysts in supplied raw hamburgers. AB - This study was carried on for determination of presence of Sarcocystis cysts in raw hamburgers in Tabriz North West of Iran. Ninety-six samples of industrial (70 % meat content) and traditional (30 % meat content) hamburgers (80 samples industrial and 16 samples traditional) were obtained from retail fast food stores. The samples were examined by gross examination, and microscopic examination methods consist impression smear and peptic digestion. Macroscopic cysts did not observed in any of the samples in gross examination. Microscopic study showed that from 96 samples 54 (56.25 %) samples were infected by at least one bradyzoites of Sarcocystis. From 54 infected samples, 45 industrial hamburgers and nine traditional hamburgers samples were infected. Statistical analysis showed that there was not significant differences between industrial and traditional hamburgers in infection to Sarcocystis. Infestation of hamburgers to Sarcocystis in summer was higher than other seasons but this difference was not significant. In Iran, beef meat is used for preparation of 70 % of hamburger and infestation of cattle to sarcocystosis was reported in many investigations in Iran. With regard to the high prevalence of Sarcocystis infection in meat products such as hamburgers in this study, it is strongly recommended to avoid eating raw or under-cooked hamburgers or keep them at freezing temperature for at least 3-5 days. PMID- 26064018 TI - Clinical and morphopathological characteristics of an enzootic occurrence of acute coenurosis (Coenurus cerebralis) in a sheep herd. AB - In this study, 30 sheep from a flock suddenly showed acute neurological symptoms associated with more than 30 % mortality. At necropsy, thickening associated with congestion and turbidity of meningeal membranes particularly on cerebellum, focal to multifocal necrotic areas and whitish spots measuring 1 to 3 cm in diameter were observed in the cortex of cerebrum and cerebellum. Grossly, numerous white tracts were also observed in the myocardium. Histopathologically, the cross sections of coenurus larvae associated with necrotic suppurative meningoencephalitis were observed. Multiple necrotic areas were also observed in the gray matter of cerebellum due to migration of the larvae with an extensive infiltration of eosinophils and neutrophils. In the heart, multifocal granulomatous myocarditis was diagnosed. No growth was seen in bacterial cultures of the brain and heart. Also, no bacteria were seen in these tissues stained with Ziehl-Neelsen and Brown-Brenn Gram stain. On basis of gross and histopathologic lesions, acute coenurosis was diagnosed. Unlike chronic coenurosis, acute form of the disease rarely reported in sheep. PMID- 26064019 TI - Toxocariasis presenting as eosinophilic ascites in a post-partum female. AB - Toxocariasis remains a problem throughout the world, and the overall prevalence is estimated to be 2.8 % within the United States. The clinical spectrum of toxocariasis in humans varies from asymptomatic infection to severe organ injury, and is determined by parasitic load, sites of larval migration from the gut, and the host's inflammatory response. We present a case of eosinophilic ascites with diarrhea in a post-partum woman attributed to toxocariasis. To our knowledge, this is the first reported case of toxocara infection presenting in the post partum period. PMID- 26064020 TI - Population dynamics of cestode, Circumonchobothrium shindei (Cestoda: Pseudophyllidea Carus, 1863) in the freshwater eel, Mastacembelus armatus Lacepede, 1800 from River Godavari, Rajahmundry. AB - The freshwater eel, Mastacembelus armatus Lacepede, 1800 is often found infected with adults and larval plerocercoids of the cestode, Circumonchobothrium shindei. The population dynamics of C. shindei was studied in the freshwater eel, M. armatus during September 2005 to August 2007 from Godavari River, Rajahmundry. A total of 494 eels were examined; 184 (37.24 %) were infected with this cestode. Infection intensity ranged from 1 to 13 for C. shindei and their plerocercoids. C. shindei occupy the position of secondary species in community structure of metazoan parasites of M. armatus, with mean intensity, mean abundance and index of infection (2.5 +/- 1.22; 1.1 +/- 1.45 and 0.57 respectively). The present investigation deals with monthly population dynamics of C. shindei in M. armatus which summarizes percentage of prevalence, intensity, abundance and index of infection. Medium sized fish depicted more infection with this cestode and female fish illustrates comparatively higher infection rate than male fish. PMID- 26064022 TI - Toxicity of Millettia ferruginea darasana (family: Fabaceae) against the larvae and adult ticks of Amblyomma variegatum Fabricius a three-host tick in cattle. AB - The in vitro toxicity of Millettia ferruginea darasana (family: Fabaceae) was tested against the larvae adult male and female of a three-host tick, Amblyomma variegatum Fabricius (family: Ixodidae or hard tick), known as 'tropical bont tick' parasitic mainly to cattle found in Ethiopia and other equatorial Africa. The 20, 40, 60, 80 and 100 % concentrations of the seed oil extracted with petroleum ether were found to kill all (100 % mortality) larvae after 12, 9, 6, 3 and 1.5 h respectively. The results summarized in the Table 1 was found to be statistically significant at the probability level of p = 0.05. The 100 % concentration of the oil caused 100 % mortality of adult male, adult female and fully engorged female tick after 5, 7 and 12 h respectively. The root and root bark showed less toxicity. The leaves did not show any toxicity. [Table: see text]. PMID- 26064021 TI - Immune responses against rHaa86 in cross-bred cattle. AB - Tick vaccines are important component of integrated pest management for sustainable control of tick and tick born diseases. Immune responses against rHaa86 (homologue of Bm86) recombinant Hyalomma tick antigen were determined in experimental crossbred calves. The humoral antibody responses of the calves were measured against rHaa86 in an optimized ELISA format. The expression of the interferon gamma (IFN-gamma), was also evaluated in the culture supernatant of blood culture from blood samples of the experimental calves. The expression patterns were studied after stimulating the blood cells in vitro with rHaa86 antigen and subsequently optical density was measured against IFN-gamma. The results were expressed as stimulation indices. All the rHaa86 immunized animal showed strong humoral antibody response just after 1st vaccination and reach to pick after 2nd booster and thereafter maintained up to days 120 from post primary immunization. The humoral antibody response was dominated by IgG1 against IgG2 throughout the period of antibody monitoring. The standard graph of bovine recombinant IFN-gamma was plotted which showed a significant difference in SI and OD value up to 200 pg/ml. The lowest detectable value of IFN-gamma was 20 pg/ml and SI at this level is 1.16 which is greater than maximum SI calculated from individual calf. The IFN-gamma response never reached at significant level and the IgG1 response was dominated over IgG2 response throughout the period of experiment. Since IgG2 and IFN-gamma are interlinked, the present study established the Th2 response as a possible mode of mechanism of conferring antibody mediated protection against challenged ticks. PMID- 26064023 TI - Notoedres cati in cats and its management. AB - Notoedres cati was observed in two domestic cats. Cats exhibited crust formation, hyperkeratosis, alopecia and intense pruritus. Distribution of lesions observed at the ear margins, face, and legs. Owners also had intense pruritus over the hands, small erythematic crusted papules on the wrists and both the legs. Laboratory examination of skin scrapings from the cat revealed the presence of ova, adult mites of N. cati. The infected cats were treated with weekly twice oral administration of ivermectin at 200 MUg/kg body weight, oral administration of 2 ml of multi-vitamin and mineral syrup daily. Improvement was noticed by complete clinical recovery along with absence of mites in skin scrapings, after completion of four doses of oral ivermectin along with supportive therapy. PMID- 26064024 TI - Seroprevalence of Toxoplasma gondii antibodies of stray cats in Garmsar, Iran. AB - Toxoplasmosis is a zoonotic parasitic disease caused by protozoan, Toxoplasma gondii. The infection may be serious if is transmitted to the fetus during pregnancy. The infection in non-exposure mothers leads to abortion, congenital disorders and blindness. Infections of human are common and are usually asymptomatic but it is so dangerous in immunosuppressed and HIV positive patients. The Aim of this study was to determine the seroprevalence of Toxoplasma IgG antibodies in cats of Garmsar. From December 2007 to August 2008, blood samples of 107 stray cats were collected and analyzed for T. gondii IgG antibody using ELISA method (Toxoplasma IgG antibodies kit, Trinity Biotech Co., USA). RESULTS: 32 samples were male and 75 were female. 64.48 % (69 samples) were positive and 35.51 % (38 samples) were negative. There was no statistically significant difference between male and female. The seropositivity rate of T. gondii increased with age (p < 0.05). There was no statistically significant difference between various regions of the city. The results of recent study showed the high seroprevalence of toxoplasmosis in Garmsar rather than other countries. According to high seroprevalence of Toxoplasma IgG antibodies in cats, Performing a screening test and determination IgG antibodies titer in high risk population (young girls, pregnant women) is recommended. PMID- 26064025 TI - Seroprevalence of anti-Toxoplasma gondii antibodies in cattle and pigs in Ibadan, Nigeria. AB - Toxoplasmosis is an important food borne parasitic zoonoses. However, data on Toxoplasma gondii infection in domestic animals mostly used for human consumption in Nigeria are scarce. We thus conducted a survey on the seroprevalence of T. gondii infection in a representative sample of cattle and pigs in farms and the abattoirs between June and December 2012. Sera from 210 cattle (both sexes) and 302 pigs (both sexes), were examined for T. gondii specific IgG antibodies by indirect Enzyme linked immunosorbent assay (ELISA). The seroprevalences determined were 13.91 % in cattle and 29.14 % in pigs. The antibody levels ranged from 0.499 to 2.103 in cattle, and 0.544 to 3.020 in pigs. The prevalence of IgG anti-T. gondii antibodies was positively correlated with the age. The seroprevalences (26.23 %) and (36.54 %) for adult cattle and pigs respectively, were higher compared to younger groups. However the difference was not significant (P > 0.05) in cattle but significant (P < 0.05) in pigs. In Nigeria, exposure to raw or undercooked foods is a risk factor for T. gondii infection. Knowledge of the prevalence of toxoplasmosis will help to target prevention efforts. PMID- 26064026 TI - Epidemiological study of gastrointestinal helminths of equines in Damot-Gale district, Wolaita zone, Ethiopia. AB - The prevalence of equines helminthosis studied from November 2011 to May 2012 in two agroecological zones Damot-Gale district, Wolaita zone, Southern Ethiopia. The objective of the study was to estimate the prevalence, and to see the distribution of internal helminth parasites of equines. A total of 500 faecal samples collected for coprological examination of gastrointestinal helminth ova. From each species of studied animals 200 positive faecal samples were pooled and cultured, and then the larvae recovered and identified. The coprological examination revealed 100 % Strongyle, 16.6 % Fasciola species, 10.2 % Parascaris equorum, 2.1 % Oxyuris equi, 1.1 % Strongyloides westeri, and 0.7 % Gastrodiscus species in donkeys. The coproscopic examination of horse faeces revealed prevalence of 100 % Strongyle, 17.5 % Fasciola species, 5.5 % Parascaris equorum, 1.4 % Oxyuris equi, 0.5 % Strongyloides westeri. A statistically significant variations in the prevalence of equines helminthes were not observed among putative risk factors (P > 0.05), except in the case of Parascaris equorum and Fasciola species, in which statistical significant variations were observed with age and purpose of the animal, respectively (P < 0.05). The average egg per gram of faeces in this study was 689.8, with a range of 100-1,600 eggs per gram of faeces. Statistically significant variations in mean eggs per gram of faeces were observed in all the considered putative risk factors (P < 0.05), except in the case of sexes. The coproculture performed on 200 pooled faecal samples revealed that Cyathostome species, Strongyius vulgaris, Trichostrongylus axei, Triodontophorus species, Strongylus equinus, Strongylus edentatus and Oesophagodontus robustus were the major helminth parasites of equines in Damot Gale district, Wolaita. PMID- 26064027 TI - Hymenolepiosis in a group of albino rats (Rattus albus): a study. AB - A study was carried out on adult albino Wistar laboratory rats to know the incidence of hymenolepiosis, a zoonotic disease which were brought for experiment purpose. Faecal samples of 95 rats examined for parasitic infection by simple floatation technique in which 32 were positive (33.68 %) for hymenolepiosis. Identification of species of Hymenolepis was done based on morphology of egg. The highest prevalence of Hymenolepis diminuta (23.15 %) was recorded followed by Hymenolepis nana (10.52 %). Heavy infection with Hymenolepis in rats draws attention in view of public health importance in contact persons. PMID- 26064028 TI - Larval cyathostominosis in a working donkey. AB - Parasitic infections are one of the most common factors that threaten the health and working performance of donkeys. One of the life threatening parasites is the small strongyles that encyst or burrow into the large intestine and their larvae can initiate severe damage in the lining of the intestine. A 6 years old female donkey with clinical signs of diarrhea and emaciation was necropsied and gross examination of gastro-intestinal tract revealed thin-walled, hyperemic and hemorrhagic cecum. Multifocal petechial hemorrhages were particularly prominent in the submucosa of cecum. Parasitological examination revealed two cyathostomin species included Cylicocyclus elongatus and Cyathostomum pathratum. At microscopic examination, cross sections of cyathostomins larvae associated with parasitic granuloma were observed in the submucosa of cecum. The lesions were associated with non-suppurative enteritis with infiltration of eosinophils, plasma cells, lymphocytes and macrophages in the intestinal mucosa, submucosa and lamina propria. PMID- 26064029 TI - First isolation and establishment of in vitro culture of Theileria lestoquardi from a naturally infected cow. AB - Theileria infected cell line was isolated from the prescapular lymph node of an adult crossbred cow. Molecular study confirmed this cell line of bovine lymphocyte has been transformed by the Theileria lestoquardi. This strain of T. lestoquardi designated Ka-6 and sheep were inoculated with this strain didn't show any clinical signs of theileriosis which shows the significance of this cell line to develop a tissue-culture vaccine against malignant ovine theileriosis. Contrary to accepted belief that the T. lestoquardi not capable of causing disease in cattle, the present study describes the first isolation and establishment of in vitro culture of T. lestoquardi-infected cell line from a naturally infected cow with typical singes of acute theileriosis. PMID- 26064030 TI - Isolated musculoskeletal hydatid disease: diagnosis on fine needle aspiration and cell block. AB - Hydatidosis is a zoonotic infection caused by Echinococcus granulosus. The most common sites of involvement are liver and lungs. Isolated musculoskeletal hydatidosis in absence of visceral involvement is rare and it mimics bone or soft tissue neoplasm. Fine needle aspiration cytology and cell block aids in diagnosis in such unusual location. Here we present one such rare case of isolated musculoskeletal hydatidosis diagnosed on fine needle aspiration cytology and cell block which was mimicking as fibrous dysplasia on radiology. PMID- 26064031 TI - A rare clinical presentation of transplacental transmission and subsequent abortion by Babesia (Theileria) equi in a mare. AB - The present article deals with the rare presentation of transplacental transmission and subsequent abortion by Babesia (Theileria) equi. A pregnant mare was brought with the history of fever and inappetence. Per rectal examination revealed absence of fremitus of the foetus. The foetus was removed using foetotomy. Blood smear examination of the dam and contact smear of the aborted foetus revealed characteristic Maltese cross appearance of B. equi. The possible routes of transmission of parasite, its pathogenesis and future strategies are described in the present article. PMID- 26064032 TI - A case report of typical leishmaniasis in dog. AB - Leishmania spp. are vector-borne flagellates transferred by sand flies. They cause cutaneous, mucocutaneous and visceral infections in mammals, especially in humans and dogs. A mature male boxer with ulcerative nodules around his eyes and snout was referred to Small Animal Hospital, Faculty of Veterinary Medicine, University of Tehran. Multiple cutaneous lesions were seen in physical examination. Mild leukocytosis, neutrophilia, left shift, lymphopenia, and thrombocytopenia were reported by the laboratory. Diagnosis was confirmed by the observation of amastigotes in blood samples and inside tissue macrophages. The infection was treated using pentavalent antimonial drug for four weeks. PMID- 26064033 TI - Entomological indicators during transmission season of dengue in Silvassa (India). AB - The entomological surveillance was conducted in urban, semi-urban/slum, industrial and residential areas during main transmission period from June to November 2012. In residential sites house index was 41.7-35.0, breteau index 71.7 136.7 and container index 11.6-20.2. During transmission period all the values ware much higher than the threshold level. The causes of high values of entomological indicator appeared to be rapid industrialization, unawareness of the conditions or factors that can exacerbate mosquito breeding, water storage habits in community and un-implementation of health related legislation. PMID- 26064034 TI - Congenital malaria in a neonate: case report with a comprehensive review on differential diagnosis, treatment and prevention in Indian perspective. AB - Although malaria in pregnancy, lactation and congenital malaria can be a disease burden in the endemic zones of Africa and Indian sub-continent, it is still epidemiologically less investigated in India. As it may lead to considerable maternal and perinatal morbidity and mortality, awareness and timely intervention is necessary for desirable outcome and prevention of the condition. Very few reports of congenital malaria are available in the literature from an endemic country like India. Herein we describe a case of congenital malaria from north India in a 21-day neonate. Clinical presentation of this condition in the neonate may offer a considerable diagnostic challenge, and differentiation from vector borne malaria in infants may be important from the management point of view. Hence a review of the differential diagnosis, management and prevention of congenital malaria has been attempted in the Indian perspective. PMID- 26064035 TI - Human dirofilariasis: an emerging zoonosis in India. AB - Human dirofilariasis is an uncommon zoonotic infection having a widespread geographical distribution. World over 800 cases of Dirofilaria are on record with highest numbers from Italy, Sri Lanka and republics of the ex-Soviet Union. Dirofilaria repens belongs to the subgenus Nochtiella and is the most common species identified in India. Topographically, the orbital/periorbital regions are the most common regions involved by Dirofilaria. We present a brief review of cases from India including two received in our own institute. This review focuses on the epidemiology of the disease including its geographical distribution and the probable causation of the recent increase in its incidence in Indian subcontinent. PMID- 26064036 TI - Coagulant Recovery from Water Treatment Residuals: A Review of Applicable Technologies. AB - Conventional water treatment consumes large quantities of coagulant and produces even greater volumes of sludge. Coagulant recovery (CR) presents an opportunity to reduce both the sludge quantities and the costs they incur, by regenerating and purifying coagulant before reuse. Recovery and purification must satisfy stringent potable regulations for harmful contaminants, while remaining competitive with commercial coagulants. These challenges have restricted uptake and lead research towards lower-gain, lower-risk alternatives. This review documents the context in which CR must be considered, before comparing the relative efficacies and bottlenecks of potential technologies, expediting identification of the major knowledge gaps and future research requirements. PMID- 26064037 TI - Synthesis, spectroscopic, and cellular properties of alpha-pegylated cis-A2B2- and A3B-types ZnPcs. AB - A series of pegylated cis-A2B2- or A3B-type ZnPcs, substituted on the alpha positions with tri(ethylene glycol) and hydroxyl groups, were synthesized from a new bis-phthalonitrile. A clamshell-type bis-phthalocyanine was also obtained as a byproduct. The hydroxyl group of one ZnPc was alkylated with 3 dimethylaminopropyl chloride to afford a pegylated ZnPc functionalized with an amine group. All mononuclear ZnPcs were soluble in polar organic solvents, showed intense Q absorptions in DMF, and had fluorescence quantum yields in the range 0.10-0.23. The clamshell-type bis-phthalocyanine adopts mainly open shell conformations in DMF, and closed clamshell conformations in chloroform. All ZnPcs were highly phototoxic to human carcinoma HEp2 cells, particularly the amino-ZnPc mainly protonated under physiological conditions, which showed the highest phototoxicity (IC50 = 0.5 MUM at 1.5 J/cm2) and dark cytotoxicity (IC50 = 22 MUM), in part due to its high cellular uptake. The ZnPcs localized in multiple organelles, including mitochondria, lysosomes, Golgi and ER. PMID- 26064038 TI - Influence of Flue Gas Desulfurization Gypsum Amendments on Heavy Metal Distribution in Reclaimed Sodic Soils. AB - Although flue gas desulfurization (FGD) gypsum has become an effective soil amendment for sodic soil reclamation, it carries extra heavy metal contamination into the soil environment. The fate of heavy metals introduced by FGD gypsum in sodic or saline-alkali soils is still unclear. This work aims to investigate the effects of FGD gypsum addition on the heavy metal distributions in a sodic soil. Original soil samples were collected from typical sodic land in north China. Soil column leaching tests were conducted to investigate the influence of FGD gypsum addition on the soil properties, especially on distribution profiles of the heavy metals (Pb, Cd, Cr, As, and Hg) in the soil layers. Results showed that pH, electrical conductivity, and exchangeable sodium percentage in amended soils were significantly reduced from 10.2 to 8.46, 1.8 to 0.2 dS/m, and 18.14% to 1.28%, respectively. As and Hg concentrations in the soils were found to be positively correlated with FGD gypsum added. The amount of Hg in the leachate was positively correlated with FGD gypsum application ratio, whereas a negative correlation was observed between the Pb concentration in the leachate and the FGD gypsum ratio. Results revealed that heavy metal concentrations in soils complied well with Environmental Quality Standard for Soils in China (GB15618-1995). This work helps to understand the fate of FGD gypsum-introduced heavy metals in sodic soils and provides a baseline for further environmental risk assessment associated with applying FGD gypsum for sodic soil remediation. PMID- 26064039 TI - Atmospheric Emissions from Forest Biomass Residues to Energy Supply Chain: A Case Study in Portugal. AB - During the past decades, pressures on global environment and energy security have led to an increasing demand on renewable energy sources and diversification of the world's energy supply. The Portuguese energy strategy considers the use of Forest Biomass Residues (FBR) to energy as being essential to accomplish the goals established in the National Energy Strategy for 2020. However, despite the advantages pointing to FBR to the energy supply chain, few studies have evaluated the potential impacts on air quality. In this context, a case study was selected to estimate the atmospheric emissions of the FBR to the energy supply chain in Portugal. Results revealed that production, harvesting, and energy conversion processes are the main culprits for the biomass energy supply chain emissions (with a contribution higher than 90%), while the transport processes have a minor importance for all the pollutants. Compared with the coal-fired plants, the FBR combustion produces lower greenhouses emissions, on a mass basis of fuel consumed; the same is true for NOX and SO2 emissions. PMID- 26064040 TI - Powerful Tukey's One Degree-of-Freedom Test for Detecting Gene-Gene and Gene Environment Interactions. AB - Genome-wide association studies (GWASs) have identified thousands of single nucleotide polymorphisms (SNPs) robustly associated with hundreds of complex human diseases including cancers. However, the large number of GWAS-identified genetic loci only explains a small proportion of the disease heritability. This "missing heritability" problem has been partly attributed to the yet-to-be identified gene-gene (G * G) and gene-environment (G * E) interactions. In spite of the important roles of G * G and G * E interactions in understanding disease mechanisms and filling in the missing heritability, straightforward GWAS scanning for such interactions has very limited statistical power, leading to few successes. Here we propose a two-step statistical approach to test G * G/G * E interactions: the first step is to perform principal component analysis (PCA) on the multiple SNPs within a gene region, and the second step is to perform Tukey's one degree-of-freedom (1-df) test on the leading PCs. We derive a score test that is computationally fast and numerically stable for the proposed Tukey's 1-df interaction test. Using extensive simulations we show that the proposed approach, which combines the two parsimonious models, namely, the PCA and Tukey's 1-df form of interaction, outperforms other state-of-the-art methods. We also demonstrate the utility and efficiency gains of the proposed method with applications to testing G * G interactions for Crohn's disease using the Wellcome Trust Case Control Consortium (WTCCC) GWAS data and testing G * E interaction using data from a case-control study of pancreatic cancer. PMID- 26064041 TI - Pre- and in-therapy predictive score models of adult OSAS patients with poor adherence pattern on nCPAP therapy. AB - OBJECTIVES: To identify patterns of adherence to nasal continuous positive airway pressure (nCPAP) use in the first 3 months of therapy among newly diagnosed adult patients with obstructive sleep apnea/hypopnea syndrome (OSAS) and their predictors. To develop pretherapy and in-therapy scores to predict adherence pattern. METHODS: Newly diagnosed adult OSAS patients were consecutively recruited from March to August 2013. Baseline clinical information and measures such as Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), Zung's Self Rating Depression Scale (SDS), and The Pittsburgh Sleep Quality Index (PSQI) at baseline and at the end of 3rd-week therapy were collected. Twelve weeks' adherence data were collected from the nCPAP memory card, and K-means cluster analysis was used to explore adherence patterns. Predictive scores were developed from the coefficients of cumulative logit models of adherence patterns using variables available at baseline and after 3 weeks of therapy. Performance of the score was validated using 500 bootstrap resamples. RESULTS: Seventy six patients completed a 12-week follow-up. Three patterns were revealed. Patients were identified as developing an adherence pattern that was poor (n=14, mean +/- SD, 2.3+/-0.9 hours per night), moderate (n=19, 5.3+/-0.6 hours per night), or good (n=43, 6.8+/-0.3 hours per night). Cumulative logit regression models (good -> moderate -> poor) revealed independent baseline predictors to be ESS (per unit increase) (OR [95% CI], 0.763 [0.651, 0.893]), SDS (1.461 [1.238, 1.724]), and PSQI (2.261 [1.427, 3.584]); and 3-week therapy predictors to be ESS (0.554 [0.331, 0.926]), PSQI (2.548 [1.454, 4.465]), and the changes (3rd week-baseline data) in ESS (0.459 [0.243, 0.868]), FSS (3.556 [1.788, 7.070]), and PSQI (2.937 [1.273, 6.773]). Two predictive score formulas for poor adherence were developed. The area under the curve (AUC) of the receiver operating characteristics (ROC) curves for baseline and 3-week formulas were 0.989 and 0.999, respectively. Bootstrap analysis indicated positive predictive values of baseline and 3-week predictive scores in our patient population of 0.82 (95% CI [0.82, 0.83]) and 0.94 (95% CI [0.93, 0.94]), respectively. CONCLUSION: A high level of prediction of poor adherence pattern is possible both before and at the first 3 weeks of therapy. The predictive scores should be further evaluated for external validity. PMID- 26064042 TI - Uncontrolled hypertension and orthostatic hypotension in relation to standing balance in elderly hypertensive patients. AB - OBJECTIVE: To investigate the associations among uncontrolled hypertension, orthostatic hypotension (OH), and standing balance impairment in the elderly hypertensive patients referred to comprehensive geriatric assessment (CGA). METHODS: In a cross-sectional study, a total of 176 elderly hypertensive patients who underwent CGA were divided into OH group (n=36) and non-OH group (n=140) according to blood pressure measurement in the supine position, after immediate standing up, and after 1 minute and 3 minutes of standing position. Uncontrolled hypertension was defined as blood pressure of >=140/90 mmHg if accompanied by diabetes mellitus (DM) or chronic kidney disease (CKD), or >=150/90 mmHg if no DM and no CKD. Standing balance, including immediate standing balance and prolonged standing balance, was assessed in side-by-side and tandem stance. RESULTS: Neither uncontrolled hypertension nor OH was associated with prolonged standing balance impairment in elderly hypertensive patients (P>0.05). Blood pressure decrease after postural change was significantly associated with immediate standing balance impairment in side-by-side and tandem stance (P<0.05). Patients with OH were at greater risk of immediate standing balance impairment in both side-by-side and tandem stance than those without OH (odds ratio [OR] 3.44, 95% confidence interval [CI] 1.26-9.33, P<0.05; OR 3.14, 95% CI 1.14-8.64, P<0.01). Furthermore, uncontrolled hypertension was associated with immediate standing balance impairment in side-by-side stance (OR 2.96, 95% CI 1.31-6.68, P<0.05). CONCLUSION: Uncontrolled hypertension, OH, and blood pressure decrease after postural change were associated with immediate standing balance impairment, and therefore, a better understanding of the underlying associations might have major clinical value. PMID- 26064043 TI - Oral treatment with herbal formula B401 alleviates penile toxicity in aging mice with manganism. AB - The present study aims to elucidate the roles of nitric oxide synthase activity, oxidative stress, inflammation, and apoptosis in penile toxicity of aging mice associated with excess manganese (Mn) treatment and to investigate the effect of oral treatment with the herbal formula B401 in this respect. ICR strain mice were divided into two groups: the vehicle (sham group) and the B401 (50 mg/kg) group. The mice were orally treated for 5 days; then a high single dose of MnCl2 (100 mg/kg) was given by intraperitoneal injection to the mice. One day after MnCl2 treatment, corpora cavernosal tissues of both Mn-treated mice and their controls were simultaneously sampled to examine their immunohistochemical staining and Western blot analysis. Nitric oxide (NO) production, levels of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS), expression levels of factors governing angiogenesis (vascular endothelial growth factor), oxidative stress (catalase, superoxide dismutase 2,4-hydroxynonenal), inflammation (tumor necrosis factor alpha), apoptosis (B-cell lymphoma 2 [Bcl-2], Bcl-2-associated X protein [Bax], cleaved poly(adenosine diphosphate-ribose) polymerase [c-PARP], cytochrome C, caspase-12, and caspase-3) were evaluated in penile corpus cavernosum of the mice. We found that penile toxicity in the mice was enhanced under excess Mn treatment through reduction of NOS activity and increase in oxidative stress, inflammation, and apoptosis in the penile cavernous tissue. Furthermore, the penile toxicity in mice with manganism was alleviated by oral B401 treatment through enhancement of both nitric oxide synthesis and angiogenesis, with simultaneous reduction of oxidative stress, inflammation, and apoptosis in penile corpus cavernosum. We suggest that the herbal formula B401 may serve as a potential dietotherapeutic supplement for penile toxicity or dysfunction in aging males. PMID- 26064044 TI - Acute vasoreactivity test results in severe pulmonary hypertension patients with chronic obstructive pulmonary disease: our experience with 29 cases. AB - AIM: The aim of the current study is to evaluate acute vasoreactivity test (AVT) results in severe pulmonary hypertension patients with chronic obstructive pulmonary disease and to compare the demographical, clinical, and laboratory variables in positive and negative cases. METHODS: This retrospective, clinical study was performed on 29 cases in the departments of cardiology and chest diseases of our tertiary care center. AVT was positive in 12 (41.4%) cases and negative in 17 (58.6%) cases. Demographical variables, cardiopulmonary indicators, and laboratory findings were compared in these two subgroups. RESULTS: The mean age was 62.3+/-7.8 years for AVT negative group, while it was 64.8+/-7.3 years in AVT positive group (P=0.38). Except for the changes in systolic, diastolic, and mean pulmonary arterial pressures before and after iloprost administration, there were no statistically significant differences regarding any of the parameters under investigation in both groups. CONCLUSION: Despite the high rate of positivity for AVT in severe pulmonary hypertension patients with chronic obstructive pulmonary disease, none of the variables under investigation displayed a noteworthy difference between AVT negative and positive groups. Identification of factors likely to influence AVT results is important for establishment of appropriate treatment protocols especially for AVT negative cases. PMID- 26064045 TI - Evaluation of the COPD Assessment Test and GOLD patient types: a cross-sectional analysis. AB - BACKGROUND: The COPD Assessment Test (CAT) has been recently developed to quantify COPD impact in routine practice. However, no relationship with other measures in the Global Initiative for Obstructive Lung Disease (GOLD) strategy has been evaluated. The present study aimed to evaluate the relationship of the CAT with other GOLD multidimensional axes, patient types, and the number of comorbidities. METHODS: This was a cross-sectional analysis of the Clinical presentation, diagnosis, and course of chronic obstructive pulmonary disease (On Sint) study. The CAT score was administered to all participants at the inclusion visit. A GOLD 2011 strategy consisting of modified Medical Research Council scale (MRC) scores was devised to study the relationship between the CAT, and GOLD 2011 axes and patient types. The relationship with comorbidities was assessed using the Charlson comorbidity index, grouped as zero, one to two, and three or more. RESULTS: The CAT questionnaire was completed by 1,212 patients with COPD. The CAT maintained a relationship with all the three axes, with a ceiling effect for dyspnea and no distinction between mild and moderate functional impairment. The CAT score increased across GOLD 2011 patient types A-D, with similar scores for types B and C. Within each GOLD 2011 patient type, there was a considerably wide distribution of CAT values. CONCLUSION: Our study indicates a correlation between CAT and the GOLD 2011 classification axes as well as the number of comorbidities. The CAT score can help clinicians, as a complementary tool to evaluate patients with COPD within the different GOLD patient types. PMID- 26064047 TI - Being parents with epilepsy: thoughts on its consequences and difficulties affecting their children. AB - OBJECTIVE: Parents with epilepsy can be concerned about the consequences of epilepsy affecting their children. The aim of this paper is to describe aspects of what it means being a parent having epilepsy, focusing the parents' perspectives and their thoughts on having children. METHODS: Fourteen adults aged 18-35 years with epilepsy and subjective memory decline took part in focus-group interviews. The interviews were conducted according to a semi-structured guideline. Material containing aspects of parenthood was extracted from the original interviews and a secondary analysis was done according to a content analysis guideline. Interviews with two parents for the Swedish book Leva med epilepsi [To live with epilepsy] by AM Landtblom (Stockholm: Bilda ide; 2009) were analyzed according to the same method. RESULTS: Four themes emerged: (1) a persistent feeling of insecurity, since a seizure can occur at any time and the child could be hurt; (2) a feeling of inadequacy - of not being able to take full responsibility for one's child; (3) acknowledgment that one's children are forced to take more responsibility than other children do; and (4) a feeling of guilt - of not being able to fulfill one's expectations of being the parent one would like to be. CONCLUSION: The parents with epilepsy are deeply concerned about how epilepsy affects the lives of their children. These parents are always aware that a seizure may occur and reflect on how this can affect their child. They try to foresee possible dangerous situations and prevent them. These parents were sad that they could not always take full responsibility for their child and could not live up to their own expectations of parenthood. Supportive programs may be of importance since fear for the safety of the child increases the psychosocial burden of epilepsy. There were also a few parents who did not acknowledge the safety issue of their child - the authors believe that it is important to identify these parents and provide extra information and support to them. PMID- 26064046 TI - Connectivity pattern differences bilaterally in the cerebellum posterior lobe in healthy subjects after normal sleep and sleep deprivation: a resting-state functional MRI study. AB - OBJECTIVE: The aim of this study was to use functional magnetic resonance imaging (fMRI) technique to explore the resting-state functional connectivity (rsFC) differences of the bilaterial cerebellum posterior lobe (CPL) after normal sleep (NS) and after sleep deprivation (SD). METHODS: A total of 16 healthy subjects (eight males, eight females) underwent an fMRI scan twice at random: once following NS and the other following 24 hours' SD, with an interval of 1 month between the two scans. The fMRI scanning included resting state and acupuncture stimulation. The special activated regions located during the acupuncture stimulation were selected as regions of interest for rsFC analysis. RESULTS: Bilateral CPLs were positively activated by acupuncture stimulation. In the NS group, the left CPL showed rsFC with the bilateral CPL, bilateral frontal lobe (BFL), left precuneus and right inferior parietal lobule, while the right CPL showed rsFC with the bilateral temporal lobe, right cerebellum anterior lobe, right CPL, left frontal lobe, left anterior cingulate, right posterior cingulate, and bilateral inferior parietal lobule. In the SD group, the left CPL showed rsFC with the left posterior cingulate gyrus bilateral CPL, left precuneus, left precentral gyrus, BFL, and the left parietal lobe, while the right CPL showed rsFC with bilateral cerebellum anterior lobe, bilateral CPL, left frontal lobe and left temporal lobe. Compared with the NS group, the left CPL had increased rsFC in the SD group with the right inferior frontal gyrus, right fusiform gyrus, right cingulate gyrus, right thalamus, and bilateral precuneus, and decreased rsFC with the BFL, while the right CPL had increased rsFC with the left superior frontal gyrus and decreased rsFC with the left precentral gyrus, right superior temporal gyrus, and the BFL. CONCLUSION: Bilateral CPL are possibly involved in acupuncture stimulation in different manners, and the right CPL showed more rsFC impairment. PMID- 26064048 TI - Efficacy and safety of aripiprazole once-monthly in obese and nonobese patients with schizophrenia: a post hoc analysis. AB - PURPOSE: To assess the efficacy and safety of aripiprazole once-monthly 400 mg (AOM 400), an extended-release injectable suspension of aripiprazole, in obese and nonobese patients. PATIENTS AND METHODS: This post hoc analysis of a 38-week randomized, double-blind, active-controlled, noninferiority study (NCT00706654) compared the clinical profile of AOM 400 in obese (body mass index [BMI] >=30 kg/m(2)) and nonobese (BMI <30 kg/m(2)) patients with schizophrenia for >=3 years. Patients were randomized 2:2:1 to AOM 400, oral aripiprazole 10-30 mg/d, or aripiprazole once-monthly 50 mg (AOM 50 mg) (subtherapeutic dose). Within obese and nonobese patient subgroups, treatment-group differences in Kaplan-Meier estimated relapse rates at week 26 (z-test) and in observed rates of impending relapse through week 38 (chi-square test) were analyzed. Treatment-emergent adverse events (TEAEs) (>10% in any treatment group) were summarized. RESULTS: At baseline of the randomized phase, obesity rates were similar among patients randomized to AOM 400 (n=95/265, 36%), oral aripiprazole (n=95/266, 36%), and AOM 50 mg (n=43/131, 33%). In both obese and nonobese patients, relapse rates through week 38 for patients randomized to AOM 400 (obese, 7.4%; nonobese, 8.8%) were similar to those in patients on oral aripiprazole (obese, 8.4%; nonobese, 7.6%), whereas relapse rates were significantly lower with AOM 400 versus AOM 50 mg (obese, 27.9% [P=0.0012]; nonobese, 19.3% [P=0.0153]). The most common TEAEs with AOM 400 in obese and nonobese patients were insomnia (12.6% and 11.2%), headache (12.6% and 8.2%), injection site pain (11.6% and 5.3%), akathisia (10.5% and 10.6%), upper respiratory tract infection (10.5% and 4.7%), weight increase (10.5% and 8.2%), and weight decrease (6.3% and 11.8%). Within the AOM 400 group, 7.6% of patients who were nonobese at baseline became obese, and 17.9% of obese patients became nonobese during randomized treatment. CONCLUSION: The clinical profile of AOM 400 was similar in obese and nonobese patients. PMID- 26064049 TI - Comparison of paroxetine and agomelatine in depressed type 2 diabetes mellitus patients: a double-blind, randomized, clinical trial. AB - BACKGROUND: Comorbid depression/anxiety in type 2 diabetes mellitus (DM) patients is highly prevalent, affecting both diabetes control and quality of life. However, the best treating method for depression/anxiety in type 2 DM patients is still unclear. This study was conducted to compare the efficacy of paroxetine and agomelatine on depression/anxiety and metabolic control of type 2 DM patients. METHODS: A total of 116 depressed, type 2 DM patients were recruited for 12 weeks treatment. Patients were randomly assigned to receive either paroxetine or agomelatine. Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale were used to assess depression and anxiety, respectively. Hemoglobin A1c, fasting plasma glucose, and body mass index were assessed at baseline and at the end of the trial. RESULTS: At the end of the trial, there were 34 (60.7%) responders and 22 (39.3%) remissions in paroxetine group; and 38 (63.3%) responders and 26 (43.3%) remissions in agomelatine group. Compared to paroxetine group, lower depression scores were observed in agomelatine group. Fasting plasma glucose and body mass index were not significantly different after 12 weeks treatment between the two groups, but agomelatine group had a significantly lower final hemoglobin A1c level compared to paroxetine group. The two antidepressants had comparable acceptability. CONCLUSION: These results showed that compared to paroxetine, agomelatine might have some advantages in treating symptoms of depression/anxiety and glycemic control in depressed type 2 DM patients. The clinical applicability of agomelatine shows greater promise and should be explored further. Limited by the relatively small samples, future studies are needed to verify and support our findings. PMID- 26064051 TI - Ranitidine reduced levodopa-induced dyskinesia by remodeling neurochemical changes in hemiparkinsonian model of rats. AB - BACKGROUND: Levodopa (l-dopa) remains the best drug in the treatment of Parkinson's disease (PD). Unfortunately, long-term l-dopa caused motor complications, one of which is l-dopa-induced dyskinesia (LID). The precise mechanisms of LID are not fully understood. We have previously reported that ranitidine could reduce LID by inhibiting the activity of protein kinase A pathway in a rat model of PD. It is demonstrated that neurotransmitters such as gamma-aminobutyric-acid (GABA) and glutamate (Glu) are also involved in the expression of LID. But whether ranitidine could reduce LID by remodeling the neurochemical changes is unknown. METHODS: In the present study, we produced PD rats by injection of 6-hydroxydopamine. Then PD rats were treated with vehicle, l dopa (6 mg/kg, plus benserazide 12 mg/kg, intraperitoneal [ip]) or l-dopa (6 mg/kg, plus benserazide 12 mg/kg, ip) plus ranitidine (10 mg/kg, oral). Abnormal voluntary movements were adopted to measure the antidyskinetic effect of ranitidine in PD rats. Rotarod tests were used to observe whether ranitidine treatment affects the antiparkinsonian effect of l-dopa. In vivo microdialysis was used to measure nigral GABA and striatal Glu in PD rats. RESULTS: We found that ranitidine pretreatment reduced abnormal voluntary movements in l-dopa primed PD rats without affecting the antiparkinsonian effect of l-dopa. In parallel with behavioral improvement, ranitidine pretreatment reduced protein kinase A activity and suppressed the surge of nigral GABA and striatal Glu. CONCLUSION: These data indicated that ranitidine could reduce LID by modeling neurochemical changes induced by l-dopa, suggesting a novel mechanism of ranitidine in the treatment of LID. PMID- 26064052 TI - Attitudes and beliefs of patients with chronic depression toward antidepressants and depression. AB - BACKGROUND: Many patients have erroneous views with regard to depression and its management, and it was noted that these attitudes and beliefs significantly affected their adherence rates. OBJECTIVES: The primary aim of this study was to determine the attitudes and beliefs of patients with depression toward depression and antidepressants. A secondary aim was to assess the influence of ethnicity on patients' attitudes and beliefs. PATIENTS AND METHODS: The study involved patients with chronic depression being followed up at an outpatient clinic at a government-run hospital in Malaysia. Patients' attitudes and beliefs were assessed using the Antidepressant Compliance Questionnaire. RESULTS: A total of 104 patients of Malay, Chinese, and Indian ethnic groups met the selection criteria. Chinese patients had significantly negative attitudes and beliefs toward depression and antidepressants compared to Malays and Indians (b=-8.96, t 103=-3.22; P<0.05). Component analysis revealed that 59% of patients believed that antidepressants can cause a person to have less control over their thoughts and feelings, while 67% believed that antidepressants could alter one's personality; 60% believed it was okay to take fewer tablets on days when they felt better, while 66% believed that antidepressants helped solve their emotional problems and helped them worry less. CONCLUSION: Patients had an overall positive view as to the benefits of antidepressants, but the majority had incorrect views as to the acceptable dosing of antidepressants and had concerns about the safety of the medication. Assessing patients' attitudes and beliefs, as well as the impact of their respective cultures, can be used in tailoring psychoeducation sessions accordingly. PMID- 26064050 TI - Brain in flames - animal models of psychosis: utility and limitations. AB - The neurodevelopmental hypothesis of schizophrenia posits that schizophrenia is a psychopathological condition resulting from aberrations in neurodevelopmental processes caused by a combination of environmental and genetic factors which proceed long before the onset of clinical symptoms. Many studies discuss an immunological component in the onset and progression of schizophrenia. We here review studies utilizing animal models of schizophrenia with manipulations of genetic, pharmacologic, and immunological origin. We focus on the immunological component to bridge the studies in terms of evaluation and treatment options of negative, positive, and cognitive symptoms. Throughout the review we link certain aspects of each model to the situation in human schizophrenic patients. In conclusion we suggest a combination of existing models to better represent the human situation. Moreover, we emphasize that animal models represent defined single or multiple symptoms or hallmarks of a given disease. PMID- 26064053 TI - A 6-year open-label study of the efficacy and safety of olanzapine long-acting injection in patients with schizophrenia: a post hoc analysis based on the European label recommendation. AB - PURPOSE: To assess the long-term efficacy and safety of olanzapine long-acting injection (LAI) in the treatment of schizophrenia, focusing on clinical trial data consistent with the approved indication and dosing recommendations in the European label and which forms the basis for treatment decisions made by clinicians in daily clinical practice. PATIENTS AND METHODS: This was a post hoc analysis of a 6-year open-label study of olanzapine LAI in patients (male or female, 18-75 years old) with schizophrenia entering this study following feeder studies of olanzapine LAI. Patients were flexibly dosed (45-405 mg, 2- to 4-week intervals), but those receiving oral olanzapine supplementation whose total olanzapine dose was >20 mg/day equivalent were excluded from this post hoc analysis. RESULTS: Data from 669 patients were analyzed (44.5% completed). Positive and Negative Syndrome Scale total scores did not change significantly from baseline to endpoint; Clinical Global Impression-Severity scores improved significantly. Mean weight change was +2.19 kg (P<0.001), with 40.8% of patients experiencing >=7% weight gain. There were 24 occurrences of post-injection delirium/sedation syndrome (PDSS). CONCLUSION: Olanzapine LAI appeared to be effective in the long-term maintenance of schizophrenia, and the safety profile was consistent with that of oral olanzapine, except for injection-related events and PDSS events. PMID- 26064054 TI - Profile of guanfacine extended release and its potential in the treatment of attention-deficit hyperactivity disorder. AB - The alpha2-adrenergic receptor agonist guanfacine, in its extended-release formulation (GXR), is the most recent nonstimulant medication approved in several countries for the treatment of attention-deficit hyperactivity disorder (ADHD) as monotherapy and as adjunctive pharmacotherapy to stimulants in children and adolescents. The present paper aims to review comprehensively and critically the pharmacodynamic and pharmacokinetic characteristics and the published evidence on the efficacy and safety profile of GXR in the treatment of ADHD. A comprehensive search of relevant databases (PubMed, Embase, and PsycInfo) was conducted to identify studies published in peer-reviewed journals until January 15, 2015. Though the precise mechanism of action of guanfacine in the treatment of ADHD is not fully understood, it is thought to act directly by enhancing noradrenaline functioning via alpha2A-adrenoceptors in the prefrontal cortex. Weight-adjusted doses should be used, with a dosing regime on a milligram per kilogram basis, starting at doses in the range 0.05-0.08 mg/kg/day, up to 0.12 mg/kg/day. As evidenced in short-term randomized controlled trials and in long-term open-label extension studies, GXR has been shown to be effective as monotherapy in the treatment of ADHD. Furthermore, GXR has also been found to be effective as adjunctive therapy to stimulant medications in patients with suboptimal responses to stimulants. Many of the adverse reactions associated with GXR, particularly sedation-related effects, were dose-related, transient, mild to moderate in severity, and did not interfere with attention or overall efficacy. There are no reports of serious cardiovascular adverse events associated with GXR alone or in combination with psychostimulants. PMID- 26064055 TI - Predictors of quality of life among individuals with schizophrenia. AB - PURPOSE: The study reported here aimed to evaluate both biological and psychosocial factors as predictors for quality of life as well as to examine the associations between the factors and quality of life in individuals with schizophrenia. METHODS: Eighty individuals with schizophrenia were recruited to the study. The Thai version of the World Health Organization Quality of Life-BREF was utilized to measure the quality of life. The five Marder subscales of the Positive and Negative Syndrome Scale were applied. Other tools for measurement included the Calgary Depression Scale for Schizophrenia and six social support deficits (SSDs). Pearson/Spearman correlation coefficients and the independent t test were used for the statistical analysis to determine the associations of variables and the overall quality of life and the four domain scores. A multiple linear regression analysis of the overall quality of life and four domain scores was applied to determine their predictors. RESULTS: The Positive and Negative Syndrome Scale total score, positive symptoms, negative symptoms, disorganized thought, and anxiety/depression showed a significant correlation with the overall quality of life and most of the four domain scores. Depression, SSDs, and adverse drug events showed a significant correlation with a poorer overall quality of life. The multiple linear regression model revealed that negative symptoms, depression, and seeing a relative less often than once per week were predictors for the overall quality of life (adjusted R (2)=0.472). Negative symptoms were also found to be the main factors predicting a decrease in the four domains of quality of life - physical health, psychological, social relationships, and environment. CONCLUSION: Negative symptoms, depression, and poor contact with relatives were the foremost predictors of poor quality of life in individuals with schizophrenia. Positive symptoms, negative symptoms, disorganized thought, anxiety/depression, SSDs, and adverse events were also found to be correlated with quality of life. PMID- 26064056 TI - Two cases of Paget's disease of scrotum in biological brothers. AB - This article reports two cases of scrotum Paget's disease in two biological brothers who were admitted and treated in our hospital in 2013. They are very rare cases. The present article discusses the potential management of Paget's disease and the importance of long-term follow-up. PMID- 26064057 TI - Current and emerging strategies in the management of venous thromboembolism: benefit-risk assessment of dabigatran. AB - Venous thromboembolism (VTE) is a disease state that carries significant morbidity and mortality, and is a known cause of preventable death in hospitalized and orthopedic surgical patients. There are many identifiable risk factors for VTE, yet up to half of VTE incident cases have no identifiable risk factor and carry a high likelihood of recurrence, which may warrant extended therapy. For many years, parenteral unfractionated heparin, low-molecular weight heparin, fondaparinux, and oral vitamin K antagonists (VKAs) have been the standard of care in VTE management. However, limitations in current drug therapy options have led to suboptimal treatment, so there has been a need for rapid onset, fixed-dosing novel oral anticoagulants in both VTE treatment and prophylaxis. Oral VKAs have historically been challenging to use in clinical practice, with their narrow therapeutic range, unpredictable dose responsiveness, and many drug-drug and drug-food interactions. As such, there has also been a need for novel anticoagulant therapies with fewer limitations, which has recently been met. Dabigatran etexilate is a fixed-dose oral direct thrombin inhibitor available for use in acute and extended treatment of VTE, as well as prophylaxis in high-risk orthopedic surgical patients. In this review, the risks and overall benefits of dabigatran in VTE management are addressed, with special emphasis on clinical trial data and their application to general clinical practice and special patient populations. Current and emerging therapies in the management of VTE and monitoring of dabigatran anticoagulant-effect reversal are also discussed. PMID- 26064058 TI - Knowledge and attitude toward interdisciplinary team working among obstetricians and gynecologists in teaching hospitals in South East Nigeria. AB - BACKGROUND: Interdisciplinary team working could facilitate the efficient provision and coordination of increasingly diverse health services, thereby improving the quality of patient care. The purpose of this study was to describe knowledge of interdisciplinary team working among obstetricians and gynecologists in two teaching hospitals in South East Nigeria and to determine their attitude toward an interdisciplinary collaborative approach to patient care in these institutions. METHODS: This was a questionnaire-based cross-sectional study. Data analysis involved descriptive statistics and was carried out using Statistical Package for the Social Sciences software version 17.0 for Windows. RESULTS: In total, 116 doctors participated in the study. The mean age of the respondents was 31.9+/-7.0 (range 22-51) years. Approximately 74% of respondents were aware of the concept of interdisciplinary team working. Approximately 15% of respondents who were aware of the concept of interdisciplinary team working had very good knowledge of it; 52% had good knowledge and 33% had poor knowledge. Twenty-nine percent of knowledgeable respondents reported ever receiving formal teaching/training on interdisciplinary team working in the course of their professional development. About 78% of those aware of team working believed that interdisciplinary teams would be useful in obstetrics and gynecology practice in Nigeria, with 89% stating that it would be very useful. Approximately 77% of those aware of team working would support establishment and implementation of interdisciplinary teams at their centers. CONCLUSION: There was a high degree of knowledge of the concept and a positive attitude toward interdisciplinary team working among obstetricians and gynecologists in the study centers. This suggests that the attitude of physicians may not be an impediment to implementation of a collaborative interdisciplinary approach to clinical care in the study centers. PMID- 26064059 TI - Clinical and pathological analysis of 116 cases of adult adrenal cortical adenoma and literature review. AB - BACKGROUND: The aim of this study is to investigate origin, gross features, microscopic features, immunohistochemical properties, and differential diagnosis of adrenal cortical adenoma (ACA) in patients >=20 years old. METHODS: The clinicopathological features of 116 cases of ACA and the immunohistochemical features of 50 cases of ACA were evaluated, and the relevant literature was reviewed. RESULTS: In our cohort, 76.72% (89/116) of the cases were functional, and 27 cases had non-functional, benign adrenal adenomas. ACA presented as an island tumor with an envelope, and the mean tumor size was 3.6 cm (range 1-5 cm), with a mean tumor weight of 9.28 g (range 5-113 g). The shape of the tumor cells was consistent, and mitosis was rarely observed. Forty of the 46 patients with cortisol-secreting ACA had tumors containing granule cells. Primary aldosteronism was observed in 43 cases. Thirty-eight cases had endoscopically visible tumors, with clear cells and lipid-rich cytoplasm arranged in irregular patches or strips. Cortisol-producing ACAs were associated with atrophy of the non-tumorous cortex. Adrenocortical adenomas displayed positive immunohistochemical staining for MELAN-A, Syn (46 of 50 cases of ACA), NSE (44 of 50 cases of ACA), Vim (42 of 50 cases of ACA) and Ki-67 <5% (24 of 50 cases of ACA; the remaining 26 cases were negative for Ki-67). CONCLUSION: Prediction of endocrine syndrome in functional ACA was possible based on its structure and morphologic features, which could prevent an unanticipated postoperative crisis. However, a clinical study is needed to validate these findings. PMID- 26064060 TI - The clinical significances of the abnormal expressions of Piwil1 and Piwil2 in colonic adenoma and adenocarcinoma. AB - OBJECTIVE: The objective of the present investigation was to study the clinical significances of the abnormal expressions of Piwil1 and Piwil2 protein in colonic adenoma and adenocarcinoma. METHODS: This study had applied immunohistochemical method to detect 45 cases of tissues adjacent to carcinoma (distance to cancerous tissue was above 5 cm), 41 cases of colonic adenoma and 92 cases of colon cancer tissues, and their Piwil1 and Piwil2 protein expression levels. ANALYSIS: The correlation of both expression and its relationship with clinicopathological features of colon cancer was analyzed. RESULTS: Positive expression rates of Piwil1 in tissues adjacent to carcinoma, colonic adenoma, and colon cancer were 11.1% (5/45), 53.7% (22/41), and 80.4% (74/92), respectively; the expression rates increased, and the comparisons between each two groups were statistically significant (P<0.05). In each group, the positive expression rates of Piwil2 were 24.4% (11/45 cases), 75.6% (31/41 cases), and 92.4% (85/92 cases); expression rates increased, and the comparisons between each two groups were statistically significant (P<0.05). Piwil1 expression and the correlation of the degree of differentiation, TNM stage, and lymph node metastasis were statistically significant (P<0.05). Piwil2 expression and the correlation of the degree of differentiation, tumor node metastasis (TNM) stage, and lymph node metastasis had no statistical significance (P>0.05). In colon cancer tissue, Piwil1 and Piwil2 expressions were positively correlated (r=0.262, P<0.05). CONCLUSION: The results showed that the abnormal expression of Piwil1 and Piwil2 might play an important role in the process of colon cancer development. PMID- 26064061 TI - Hyperthermia combined with 5-fluorouracil promoted apoptosis and enhanced thermotolerance in human gastric cancer cell line SGC-7901. AB - This study was designed to investigate the proliferation inhibition and apoptosis promoting effect under hyperthermia and chemotherapy treatment, at cellular level. Human gastric cancer cell line SGC-7901 was cultivated with 5-fluorouracil at different temperatures. Cell proliferation and apoptosis were determined, and expression of Bcl-2 and HSP70 was measured at different treatments. Cell survival rates and inhibition rates in chemotherapy group, thermotherapy group, and thermo chemotherapy group were drastically lower than the control group (P<0.05). For tumor cells in the thermo-chemotherapy group, survival rates and inhibition rates at three different temperatures were all significantly lower than those in chemotherapy group and thermotherapy group (P<0.05). 5-Fluorouracil induced apoptosis of SGC-7901 cells with a strong temperature dependence, which increased gradually with increase in temperature. At 37 degrees C and 43 degrees C there were significant differences between the thermotherapy group and chemotherapy group and between the thermo-chemotherapy group and thermotherapy group (P<0.01). The expression of Bcl-2 was downregulated and HSP70 was upregulated, with increase in temperature in all groups. Cell apoptosis was not significant at 46 degrees C (P>0.05), which was probably due to thermotolerance caused by HSP70 accumulation. These results suggested that hyperthermia combined with 5 fluorouracil had a synergistic effect in promoting apoptosis and enhancing thermotolerance in gastric cancer cell line SGC-7901. PMID- 26064062 TI - Adherence to statin treatment following a myocardial infarction: an Italian population-based survey. AB - BACKGROUND: Statins are standard therapies after myocardial infarction (MI) in the general population. In the current study, we assessed adherence to statin treatment by patients after an MI in Italy, and estimated the effect of in hospital statin therapy on persistence in treatment during a 2-year follow-up. PATIENTS AND METHODS: This was a retrospective cohort observation study of patients who experienced their MI between January 1, 2004 and December 31, 2005. Patients to enroll were identified by a diagnosis of MI at discharge from hospital. Previous drug therapies and hospital admissions for cardiovascular reasons in the 12 months before hospitalization for MI, statin treatment and lipid levels during hospitalization, indication for statin treatment at hospital discharge, and adherence to statin treatment in the following 24 months using an integrated analysis of administrative databases and hospital case records were evaluated. Also, factors associated either positively or negatively with consistent acute and long-term use of this efficacy-proven therapy were evaluated. RESULTS: We identified 3,369 patients: 28.5% of patients had not been consistently treated with statins during their hospital stay for MI, and 36.2% of patients did not receive a statin prescription at hospital discharge. Of the 2,629 patients persistent with treatment during the follow-up, only 1,431 had an adherence to statins >80%. Either during the hospitalization or during the follow up, the use of statins was negatively associated with older age and the presence of diabetes and chronic kidney disease. Lipid levels were significantly higher in treated than in untreated patients, but did not contribute to adherence to treatment. An important factor in long-term adherence to statin treatment was a statin prescription at the time of hospital discharge. CONCLUSION: Since the statin undertreatment rate in routine care is still high, physicians need to increase the awareness of patients regarding the implications of discontinuation and/or underuse of their medications and encourage higher adherence. PMID- 26064063 TI - Dystrophic epidermolysis bullosa: a review. AB - Dystrophic epidermolysis bullosa is a rare inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. The deficiency and/or dysfunction of type VII collagen leads to subepidermal blistering immediately below the lamina densa, resulting in mucocutaneous fragility and disease complications such as intractable ulcers, extensive scarring, malnutrition, and malignancy. The disease is usually diagnosed by immunofluorescence mapping and/or transmission electron microscopy and subsequently subclassified into one of 14 subtypes. This review provides practical knowledge on the disease, including new therapeutic strategies. PMID- 26064064 TI - Tapentadol prolonged release for patients with multiple myeloma suffering from moderate-to-severe cancer pain due to bone disease. AB - CONTEXT: Myeloma bone disease (MBD) is a devastating complication of multiple myeloma that leads to severe pain. OBJECTIVES: The aim of this study was to evaluate the efficacy and tolerability of tapentadol prolonged release (PR) in the management of patients with MBD suffering from moderate-to-severe cancer pain. METHODS: A 12-week prospective study was carried out in 25 opioid-naive MBD patients. Patients initially received twice-daily doses of tapentadol PR 50 mg. Doses were then managed to maintain adequate relief or dose-limiting toxicity. The following parameters were recorded at weekly intervals for 4 weeks, and then at weeks 8 and 12: pain, opioid-related adverse effects, use of other analgesics, DN4 (Douleur Neuropathique 4) score. Quality of life (SF-36 [36-item short-form health survey]) was measured at baseline and at final evaluation. RESULTS: Of 25 patients, 22 completed the study. Pain intensity significantly decreased from baseline to all the week intervals (P<0.01). Quality of life significantly improved with respect to all SF-36 subscale parameters (P<0.01), and so did both the physical and mental status (P<0.01). Tapentadol PR significantly reduced DN4 mean value (P<0.01) and the number of patients with neuropathic component (DN4 >=4) (P<0.01). After 8 weeks of treatment, all patients were negative for the DN4 score. Tapentadol PR was well tolerated, and the use of other analgesics was reduced during the study period. CONCLUSION: Tapentadol PR started in doses of 100 mg/day was effective and well tolerated in opioid-naive MBD patients with moderate-to-severe pain. Tapentadol PR can be considered a first-choice opioid in cancer patients suffering from mixed pain with a neuropathic component. PMID- 26064065 TI - Can intractable discogenic back pain be managed by low-level laser therapy without recourse to operative intervention? AB - OBJECTIVE: The aim of the study reported here was to investigate the possible clinical role of low-level laser therapy (LLLT) in discogenic back pain patients who failed to respond to a conventional physical therapy program to avoid recourse to operative intervention. METHODS: The paper reports on the long-term mean 5-year prospective follow-up of a patient cohort of 50 unselected patients visiting our tertiary referral pain center for discogenic back pain who had had a single-level lesion documented by magnetic resonance imaging followed by subsequent discography to confirm the affected disc being the pain generator. All of the patients who entered the study had failed response to a combination of nonsteroidal anti-inflammatory agents and had had not less than 3 months of conventional physical therapy. LLLT, at a wavelength of 810 nm wavelength emitted from a GaAIAs semiconductor laser device with 5.4 J per point and a power density of 20 mW/cm(2), was employed. The treatment regimen consisted of three sessions of treatment per week for 12 consecutive weeks. RESULTS: All but one patient had significant improvement in their Oswestry Disability Index score, from a mean of 50% score to a mean of 10% score, at the end of treatment at 12 weeks. In addition, surprisingly, the improvement was found maintained at follow-up assessments 1 year and 5 years later. The one patient among the 50 patients who failed to respond eventually required surgery, while the others did not require surgery. CONCLUSION: We conclude that LLLT is a viable option in the conservative treatment of discogenic back pain, with a positive clinical result of more than 90% efficacy, not only in the short-term but also in the long-term, with lasting benefits. PMID- 26064066 TI - Short and Long-term Effects of rTMS Treatment on Alzheimer's Disease at Different Stages: A Pilot Study. AB - Repetitive transcranial magnetic stimulation (rTMS) uses a magnetic coil to induce an electric field in brain tissue. As a pilot study, we investigated the effect of rTMS treatment on 10 volunteers with Alzheimer's disease (AD) in a two stage study. The first stage consisted of a double-blind crossover study with real and sham treatments. Each treatment block consisted of 13 sessions over 4 weeks. During each session, 2000 TMS pulses at 90%-100% of resting motor threshold were applied to dorsolateral prefrontal cortex bilaterally, and the patients were kept cognitively active by object/action naming during the treatment. The second stage was an open-label study, in which the same treatments were performed in 2-week blocks (10 sessions) approximately every 3 months as follow-up treatments on six of the volunteers, who completed the first stage of the study. Primary outcome measures were the Montreal Cognitive Assessment (MOCA) and the Alzheimer's Disease Assessment Scale-cognitive subscale. The secondary outcome measures were the Revised Memory and Behavior Checklist as well as our team's custom-designed cognitive assessments. The results showed a noticeably stronger improvement on all assessments during the real treatment as compared to the sham treatment. The changes in MOCA scores as well as our designed cognitive assessment were found to be statistically significant, with particularly strong results in the six volunteers who were in the early stages of the disease. The long-term trends observed in the second stage of the study also showed generally less decline than would be expected for their condition. It appears that rTMS can be an effective tool for improving the cognitive abilities of patients with early to moderate stages of AD. However, the positive effects of rTMS may persist for only up to a few weeks. Specific skills being practiced during rTMS treatment may retain their improvement for longer periods. PMID- 26064067 TI - Development and psychometric testing of a breast cancer patient-profiling questionnaire. AB - INTRODUCTION: The advent of "personalized medicine" has been driven by technological advances in genomics. Concentration at the subcellular level of a patient's cancer cells has meant inevitably that the "person" has been overlooked. For this reason, we think there is an urgent need to develop a truly personalized approach focusing on each patient as an individual, assessing his/her unique mental dimensions and tailoring interventions to his/her individual needs and preferences. The aim of this study was to develop and test the psychometric properties of the ALGA-Breast Cancer (ALGA-BC), a new multidimensional questionnaire that assesses the breast cancer patient's physical and mental characteristics in order to provide physicians, prior to the consultation, with a patient's profile that is supposed to facilitate subsequent communication, interaction, and information delivery between the doctor and the patient. METHODS: The specific validation processes used were: content and face validity, construct validity using factor analysis, reliability and internal consistency using test-retest reliability, and Cronbach's alpha correlation coefficient. The exploratory analysis included 100 primary breast cancer patients and 730 healthy subjects. RESULTS: The exploratory factor analysis revealed eight key factors: global self-rated health, perceived physical health, anxiety, self efficacy, cognitive closure, memory, body image, and sexual life. Test-retest reliability and internal consistency were good. Comparing patients with a sample of healthy subjects, we also observed a general ability of the ALGA-BC questionnaire to discriminate between the two. CONCLUSION: The ALGA-BC questionnaire with 29 items is a valid instrument with which to obtain a patient's profile that is supposed to help physicians achieve meaningful personalized care which supplements biological and genetic analyses. PMID- 26064069 TI - Environmental and host-related determinants of tuberculosis in Metema district, north-west Ethiopia. AB - BACKGROUND: Each year, one third of the world's population is estimated to be infected with tuberculosis (TB). Globally in 2011, there were an estimated 8.7 million TB cases that resulted in 1.4 million deaths. In Ethiopia, TB is the leading cause of morbidity and the third most common cause of hospital admission. The aim of this study is to assess environmental and host-related determinants of TB in Metema district, north-west Ethiopia. METHODS: A community-based unmatched case-control study was conducted from March 12 to April 5, 2013. The study population included 655 subjects (218 cases and 437 controls in a ratio of 1:2). Cases were TB patients selected from a total of 475 cases registered and treated from March 2012 to February 2013 at the Metema District Hospital DOTS (direct observation therapy, short-course) clinic and selected randomly using a lottery method. Controls were people who had had no productive cough for at least 2 weeks previously and were selected from the community. RESULTS: A total of 655 respondents (218 cases and 437 controls) participated in the study. In multivariate analysis, being illiterate (adjusted odds ratio [AOR] 3.65, 95% confidence interval [CI] 2.31-5.76), households containing more than four family members (AOR 3.09, 95% CI 2.07-4.61), living space <4 m(2) per person (AOR 3.11, 95% CI 2.09-4.63), a nonseparated kitchen (AOR 3.27, 95% CI 1.99-5.35), history of contact with a TB patient (AOR 2.05, 95% CI 1.35-3.12), a house with no ceiling (AOR 1.46, 95% CI 1.07-2.21), and absence of windows (AOR 4.42, 95% CI 2.46-7.95) were independently associated with the development of TB. CONCLUSION: This study identified that the number of family members in the household, educational status, room space per person, history of contact with a TB patient, availability and number of windows, location of kitchen facilities within the house, and whether or not the house had a ceiling were independently associated with contracting TB. Every community should construct houses with the kitchen separated from the main living room, and include a ceiling and more than one window. Cigarette smoking should be avoided since this also contributed to the risk of transmission of TB. Further research focusing on coinfection with human immunodeficiency virus, helminth burden, and malnutrition is important for the control and prevention of TB. PMID- 26064068 TI - The impact of mindfulness-based interventions on symptom burden, positive psychological outcomes, and biomarkers in cancer patients. AB - Research on the use of mindfulness-based stress reduction and related mindfulness based interventions (MBIs) in cancer care has proliferated over the past decade. MBIs have aimed to facilitate physical and emotional adjustment to life with cancer through the cultivation and practice of mindfulness (ie, purposeful, nonjudgmental, moment-to-moment awareness). This descriptive review highlights three categories of outcomes that have been evaluated in MBI research with cancer patients - namely, symptom reduction, positive psychological growth, and biological outcomes. We also examine the clinical relevance of each targeted outcome, while describing recently published original studies to highlight novel applications of MBIs tailored to individuals with cancer. Accumulating evidence suggests that participation in a MBI contributes to reductions in psychological distress, sleep disturbance, and fatigue, and promotes personal growth in areas such as quality of life and spirituality. MBIs may also influence markers of immune function, hypothalamic-pituitary-adrenal axis regulation, and autonomic nervous system activity, though it remains unclear whether these biological changes translate to clinically important health benefits. We conclude by discussing methodological limitations of the extant literature, and implications of matching MBIs to the needs and preferences of cancer patients. Overall, the growing popularity of MBIs in cancer care must be balanced against scientific evidence for their impact on specific clinical outcomes. PMID- 26064070 TI - Antifungal agent utilization evaluation in hospitalized neutropenic cancer patients at a large teaching hospital. AB - To evaluate pattern of using of three antifungal drugs: fluconazole, amphotericin B and voriconazole, at the hematology-oncology and bone marrow transplant wards of one large teaching hospital. In a prospective cross-sectional study, we evaluated the appropriateness of using antifungal drugs in patients, using Infectious Disease Society of America (IDSA) and National Comprehensive Cancer Network (NCCN) guidelines. All the data were recorded daily by a pharmacist in a form designed by a clinical pharmacist and infectious diseases specialist, for antifungals usage, administration, and monitoring. During the study, 116 patients were enrolled. Indications of prescribing amphotericin B, fluconazole, and voriconazole were appropriate according to guidelines in 83.4%, 80.6%, and 76.9% respectively. The duration of treatments were appropriate according to guidelines in 75%, 64.5%, and 71.1% respectively. The dose of voriconazole was appropriate according to guidelines in 46.2% of patients. None of the patients received salt loading before administration of amphotericin B. The most considerable problems with the mentioned antifungals were about the indications and duration of treatment. In addition, prehydration for amphotericin B and dosage of voriconazole were not completely compatible with the mentioned guidelines. A suitable combination of controlling the use of antifungals and educational programs could be essential for improving the general process of using antifungal drugs at our hospital. PMID- 26064071 TI - Do loss to follow-up and death rates from ART care vary across primary health care facilities and hospitals in south Ethiopia? A retrospective follow-up study. AB - BACKGROUND: Decentralization and task shifting has significantly improved access to antiretroviral therapy (ART). Many studies conducted to determine the attrition rate in Ethiopia have not compared attrition rates between hospitals and health centers in a relatively recent cohort of patients. This study compared death and loss to follow-up (LTFU) rates among ART patients in hospitals and health centers in south Ethiopia. METHODS: Data routinely collected from patients aged older than 15 years who started ART between July 2011 and August 2012 in 20 selected health facilities (12 being hospitals) were analyzed. The outcomes of interest were LTFU and death. The data were entered, cleaned, and analyzed using Statistical Package for the Social Sciences version 20.0 and Stata version 12.0. Competing-risk regression models were used. RESULTS: The service years of the facilities were similar (median 8 and 7.5 for hospitals and health centers, respectively). The mean patient age was 33.7+/-9.6 years. The median baseline CD4 count was 179 (interquartile range 93-263) cells/mm(3). A total of 2,356 person years of observation were made with a median follow-up duration of 28 (interquartile range 22-31) months; 24.6% were either dead or LTFU, resulting in a retention rate of 75.4%. The death rates were 3.0 and 1.5 and the LTFU rate were 9.0 and 10.9 per 100 person-years of observation in health centers and hospitals, respectively. The competing-risk regression model showed that the gap between testing and initiation of ART, body mass index, World Health Organization clinical stage, isoniazid prophylaxis, age, facility type, and educational status were independently associated with LTFU. Moreover, baseline tuberculous disease, poor functional status, and follow-up at a health center were associated with an elevated probability of death. CONCLUSION: We observed a higher death rate and a lower LTFU rate in health centers than in hospitals. Most of the associated variables were also previously documented. Higher LTFU was noticed for patients with a smaller gap between testing and initiation of treatment. PMID- 26064073 TI - Calciphylaxis in a patient affected by rheumatoid arthritis, chronic renal failure, and hyperparathyroidism: a case report. AB - Calciphylaxis, or calcific uremic arteriolopathy, is the tissue and vascular calcification that occurs mainly in chronic kidney disease. However, it can be secondary to parathyroid dysfunction and it has been described in rheumatic patients. We present a case of calciphylaxis in a woman with inactive rheumatoid arthritis, acute renal failure, and hyperparathyroidism. PMID- 26064074 TI - Incidental retinal vascular occlusions on hydroxychloroquine screening in patients with systemic lupus erythematosus. AB - OBJECTIVE: The proportion of patients with systemic lupus erythematosus (SLE) who manifest retinal involvement increases many fold in patients with active systemic disease. The objective of this report is to stress upon the significance of comprehensive ophthalmic assessment of all SLE patients to prevent and manage blinding ocular manifestations of the disease. METHODS: Retrospective case review. RESULTS: Incidental retinal vascular complications seen in patients undergoing baseline hydroxychloroquine screening. CONCLUSION: The purpose of comprehensive ophthalmic screening in SLE patients is twofold. It will aid in the diagnosis and treatment of blinding ocular complications of the disease and monitor hydroxychloroquine macular toxicity. PMID- 26064072 TI - Clinical utility of exemestane in the treatment of breast cancer. AB - Breast cancer is the most prevalent cancer in women, causing a significant mortality worldwide. Different endocrine strategies are available for the treatment of hormone-sensitive breast cancer, including antiestrogen tamoxifen and fulvestrant, as well as third-generation aromatase inhibitors (AIs), such as letrozole, anastrozole, and exemestane. In this review, we will focus on exemestane, its clinical use, and its side effects. Exemestane is a steroidal third-generation AI now used in all treatment settings for breast cancer. In the metastatic disease, it has been extensively investigated as the first-, second-, and further-line treatment and it is now registered for the treatment of postmenopausal women with advanced estrogen-receptor-positive breast cancer whose disease has progressed following antiestrogen therapy. A potential lack of cross resistance with nonsteroidal AIs has been described, giving additional therapeutic opportunities in sequences of endocrine agents. Exemestane is also approved for the adjuvant treatment of postmenopausal early breast cancer, either as upfront monotherapy for 5 years, as a switch following 2-3 years of tamoxifen, or as extended therapy beyond 5 years of adjuvant treatment. New promising data also showed a beneficial effect in young premenopausal early breast cancer patients, when administered together with ovarian suppression. Interesting results have also emerged when exemestane has been investigated as neodjuvant treatment as well as preventive agent in healthy women at high risk for breast cancer. Exemestane is generally well tolerated, with a side effect profile similar to that of other AIs, including menopausal symptoms, arthralgia, and bone loss. In conclusion, exemestane can be considered an effective and well-tolerated endocrine treatment option for all stages of breast cancer. PMID- 26064075 TI - Effect of Habitual Khat Chewing on Glycemic Control, Body Mass Index, and Age at Diagnosis of Diabetes in Patients with Type 2 Diabetes Mellitus in Yemen. AB - Khat chewing is common in Yemen. We conducted this study to see if it affected diabetes control in patients with type 2 diabetes mellitus (DM). We studied 1540 patients with type 2 DM attending an endocrinology clinic in Sana'a, Yemen, of which 997 were khat chewers (KC) and 543 were non-khat chewers (NKC). The patients answered a questionnaire regarding khat chewing. Hemoglobin A1c (HbA1c) and body mass index (BMI) were measured. KC had a higher mean HbA1c of 9.8 (95% confidence interval (95% CI) 9.6-10) than the NKC, with a mean of 9.1 (95% CI 8.9 9.4) (adjusted odds ratios (AOR) 1.74, P < 0.001) after multivariate regression analysis. KC also had a lower mean BMI, 26.9 (95% CI 26.6-27.2), than the NKC, mean BMI 27.6 (95% CI 27.1-28) (P < 0.01). The mean age at diagnosis of DM among the KC group was 43.3 (10.1) and among the NKC group was 45.9 (11.8) (AOR 1.4 P < 0.008) after multivariate regression analysis. KC patients had a higher mean HbA1c, a lower BMI, and a younger age at diagnosis of type 2 DM when compared with NKC. PMID- 26064076 TI - Internal medicine residents' perspectives and practice about do not resuscitate orders: survey analysis in the western region of Saudi Arabia. AB - BACKGROUND: The purpose of this study was to analyze the perceptions and practices of internal medicine residents in the western region of Saudi Arabia regarding the implementation of do not resuscitate (DNR) orders to improve future training practices among physicians. METHODS: Medical residents involved in training programs in the western region of Saudi Arabia, including Jeddah, Makah, Medinah, and Taif, were invited to participate in a cross-sectional, anonymous, online survey regarding DNR orders. The 16-question survey was distributed to residents in all training programs in the region using surveymonkey.com, and the results were collected and tabulated. RESULTS: Of 364 residents, 157 completed the questionnaire, resulting in a 43% response rate. The study showed that most (66%) internal medicine residents in the western region of Saudi Arabia participate in DNR discussions with patients and family or surrogate decision makers. In addition, 43% were observed by faculty members, and half of them (51.9%) reported feeling comfortable during these discussions. Furthermore, most residents believed that additional educational programs would enhance their competence in addressing issues related to DNR discussions. CONCLUSION: This study highlights the need for a structured curriculum to teach skills relating to end-of-life issues such as DNR orders to residents in the Saudi Arabian medical system. The majority of residents surveyed believe they would benefit from additional training in DNR discussions. Therefore, an evidence-based curriculum providing instruction for improving discussions regarding DNR orders would improve physician confidence and effectiveness in caring for critically ill patients. PMID- 26064077 TI - The Use of Radiation Therapy in Well-Differentiated Soft Tissue Sarcoma of the Extremities: An NCDB Review. AB - Objective. This study investigated patterns of utilization of radiation therapy (RT) and correlated this with overall survival by assessing patients with well differentiated soft tissue sarcoma of the extremity (STS-E) in the National Cancer Database (NCDB). Methods. All patients diagnosed with well-differentiated STS-E between 1998 and 2006 were identified in the NCDB. Patients were stratified by use of surgery alone versus use of adjuvant RT after surgery and analyzed using multivariate analysis, Kaplan-Meier analysis, and propensity matching. Results. 2113 patients with well-differentiated STS-E were identified in the NCDB for inclusion with a mean follow-up time of 74 months. 69% of patients were treated with surgery alone, while 26% were treated with surgery followed by adjuvant RT. Patients undergoing amputation were less likely to receive adjuvant RT. There was no difference in overall survival between patients with well differentiated STS treated with surgery alone and those patients who received adjuvant RT. Conclusions. In the United States, adjuvant RT is being utilized in a quarter of patients being treated for well-differentiated STS-E. While the use of adjuvant RT may be viewed as a means to facilitate limb salvage, this large national database review confirms no survival benefit, regardless of tumor size or margin status. PMID- 26064078 TI - Medication Exposures and Subsequent Development of Ewing Sarcoma: A Review of FDA Adverse Event Reports. AB - Background. Ewing sarcoma family of tumors (ESFT) are rare but deadly cancers of unknown etiology. Few risk factors have been identified. This study was undertaken to ascertain any possible association between exposure to therapeutic drugs and ESFT. Methods. This is a retrospective, descriptive study. A query of the FDA Adverse Event Reporting System (FAERS) was conducted for all reports of ESFT, January 1, 1998, through December 31, 2013. Report narratives were individually reviewed for patient characteristics, underlying conditions and drug exposures. Results. Over 16 years, 134 ESFT reports were identified, including 25 cases of ESFT following therapeutic drugs and biologics including immunosuppressive agents and hormones. Many cases were confounded by concomitant medications and other therapies. Conclusions. This study provides a closer look at medication use and underlying disorders in patients who later developed ESFT. While this study was not designed to demonstrate any clear causative association between ESFT and prior use of a single product or drug class, many drugs were used to treat immune-related disease and growth or hormonal disturbances. Further studies may be warranted to better understand possible immune or neuroendocrine abnormalities or exposure to specific classes of drugs that may predispose to the later development of ESFT. PMID- 26064079 TI - Metaphors in search of a target: the curious case of epigenetics. AB - Carrying out research in genetics and genomics and communicating about them would not be possible without metaphors such as "information," "code," "letter" or "book." Genetic and genomic metaphors have remained relatively stable for a long time but are now beginning to shift in the context of synthetic biology and epigenetics. This article charts the emergence of metaphors in the context of epigenetics, first through collecting some examples of metaphors in scientific and popular writing and second through a systematic analysis of metaphors used in two UK broadsheets. Findings show that while source domains for metaphors can be identified, such as our knowledge of electrical switches or of bookmarks, it is difficult to pinpoint target domains for such metaphors. This may be indicative both of struggles over what epigenetics means for scientists (natural and social) and of difficulties associated with talking about this, as yet, young field in the popular press. PMID- 26064080 TI - Observations on the expression of human papillomavirus major capsid protein in HeLa cells. AB - BACKGROUND: The goal of this study was to identify the nature of the inclusion bodies that have been found in HeLa cells (cervical cancer immortal cell line) by electron microscope and to determine whether the major capsid protein (L1) of human papillomavirus (HPV) can be expressed in HPV-positive uterine cervix cancer cells. METHODS: HPV L1 protein expression in HeLa cells was detected with anti HPV L1 multivalent mice monoclonal antibody and rabbit polyclonal anti-HPV L1 antibody by ELISA, light microscope immunohistochemistry, electron microscope immunocytochemistry and Western blotting assays. Reverse transcriptional PCR (RT PCR) was performed to detect the transcription of L1 mRNA in HeLa cells. The immortalized human keratinocyte HeCat was used as the negative control. RESULTS: HPV L1 proteins reacted positively in the lysate of HeLa cells by ELISA assays. HRP labeled light microscope immunohistochemistry assay showed that there was a strong HPV L1 positive reaction in HeLa cells. Under the electron microscope, irregular shaped inclusion bodies, assembled by many small and uniform granules, had been observed in the cytoplasm of some HeLa cells. These granules could be labeled by the colloidal gold carried by HPV L1 antibody. The Western blotting assay showed that there was a L1 reaction strap at 80-85 kDa in the HeLa cell lysates, hence demonstrating the existence of HPV18 L1 in HeLa cells. RT-PCR assay showed that the L1 mRNA was transcribed in HeLa cells. CONCLUSIONS: The inclusion bodies found in the cytoplasm of HeLa cells are composed of HPV18 L1 protein. Since HeLa cell line is a type of cervical cancer cells, this implies that HeLa cells have the ability to express HPV L1 proteins. PMID- 26064081 TI - T helper cell mediated-tolerance towards fetal allograft in successful pregnancy. AB - Trophoblast HLA-C antigens from paternal origins, which liken the trophoblast to a semiallograft, could be presented by the maternal APCs to the specific maternal CD4+ T helper cells, which could release various cytokines in response to these alloantigens. On the basis of the cytokines produced, these cells can be classified in Th1, Th2 and Th17 cells. Th1 and Th17 cells, known to be responsible for acute allograft rejection, could be involved in miscarriage and Th2 cells together with regulatory CD4+ T cells, known to be involved in allograft tolerance, could be responsible, at least in part, for the success of pregnancy. In this review we focus the role effector CD4+ T cells Th1, Th2 and Th17 cells on the fetal allograft tolerance. PMID- 26064082 TI - gems: An R Package for Simulating from Disease Progression Models. AB - Mathematical models of disease progression predict disease outcomes and are useful epidemiological tools for planners and evaluators of health interventions. The ?? package gems is a tool that simulates disease progression in patients and predicts the effect of different interventions on patient outcome. Disease progression is represented by a series of events (e.g., diagnosis, treatment and death), displayed in a directed acyclic graph. The vertices correspond to disease states and the directed edges represent events. The package gems allows simulations based on a generalized multistate model that can be described by a directed acyclic graph with continuous transition-specific hazard functions. The user can specify an arbitrary hazard function and its parameters. The model includes parameter uncertainty, does not need to be a Markov model, and may take the history of previous events into account. Applications are not limited to the medical field and extend to other areas where multistate simulation is of interest. We provide a technical explanation of the multistate models used by gems, explain the functions of gems and their arguments, and show a sample application. PMID- 26064083 TI - Corrosion Performance of Fe-Cr-Ni Alloys in Artificial Saliva and Mouthwash Solution. AB - Several austenitic stainless steels suitable for high temperature applications because of their high corrosion resistance and excellent mechanical properties were investigated as biomaterials for dental use. The steels were evaluated by electrochemical techniques such as potentiodynamic polarization curves, cyclic polarization curves, measurements of open circuit potential, and linear polarization resistance. The performance of steels was evaluated in two types of environments: artificial saliva and mouthwash solution at 37 degrees C for 48 hours. In order to compare the behavior of steels, titanium a material commonly used in dental applications was also tested in the same conditions. Results show that tested steels have characteristics that may make them attractive as biomaterials for dental applications. Contents of Cr, Ni, and other minor alloying elements (Mo, Ti, and Nb) determine the performance of stainless steels. In artificial saliva steels show a corrosion rate of the same order of magnitude as titanium and in mouthwash have greater corrosion resistance than titanium. PMID- 26064085 TI - An Improved Quantum-Behaved Particle Swarm Optimization Algorithm with Elitist Breeding for Unconstrained Optimization. AB - An improved quantum-behaved particle swarm optimization with elitist breeding (EB QPSO) for unconstrained optimization is presented and empirically studied in this paper. In EB-QPSO, the novel elitist breeding strategy acts on the elitists of the swarm to escape from the likely local optima and guide the swarm to perform more efficient search. During the iterative optimization process of EB-QPSO, when criteria met, the personal best of each particle and the global best of the swarm are used to generate new diverse individuals through the transposon operators. The new generated individuals with better fitness are selected to be the new personal best particles and global best particle to guide the swarm for further solution exploration. A comprehensive simulation study is conducted on a set of twelve benchmark functions. Compared with five state-of-the-art quantum-behaved particle swarm optimization algorithms, the proposed EB-QPSO performs more competitively in all of the benchmark functions in terms of better global search capability and faster convergence rate. PMID- 26064084 TI - The Role of PPAR Gamma in Systemic Sclerosis. AB - Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARgamma ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPARgamma function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-beta/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARgamma as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis. PMID- 26064087 TI - Site-Specific Immunomodulator: A Novel Treatment for Crohn's Disease. AB - We investigated the mechanism of action, safety, and efficacy of the Site Specific Immunomodulator (SSI) QBECO, a novel immunotherapy for Crohn's disease (CD). Using human monocytic THP-1 cells, we demonstrate that SSI QBECO (derived from the common colon bacteria E. coli) activates macrophages to an M1 phenotype (associated with enhanced capacity to eliminate bacteria and activate innate immune responses). We assessed SSI QBECO in a compassionate use protocol of ten adult patients with active CD. Patients with moderate to severe clinical symptoms receiving conventional CD treatments and/or complementary therapies were included, except patients receiving anti-TNF medications. SSI QBECO was self administered subcutaneously every second day, for a minimum of 2.5 months and a maximum of 11 months. All 10 patients reported improvement of symptoms while on the SSI QBECO treatment. Seven patients reported full resolution of clinical symptoms during a course of SSI QBECO of at least three months. Three patients have experienced ongoing sustained clinical remission after discontinuing all medications, including SSI treatment. The longest case of clinical remission is still ongoing (>4 years). No serious severe adverse clinical events were reported. Collectively, we conclude that treatment with the immunoactive SSI QBECO was well tolerated and effective for treatment of Crohn's disease in this case series. PMID- 26064086 TI - Current Review of Genetically Modified Lactic Acid Bacteria for the Prevention and Treatment of Colitis Using Murine Models. AB - Inflammatory Bowel Diseases (IBD) are disorders of the gastrointestinal tract characterized by recurrent inflammation that requires lifelong treatments. Probiotic microorganisms appear as an alternative for these patients; however, probiotic characteristics are strain dependent and each probiotic needs to be tested to understand the underlining mechanisms involved in their beneficial properties. Genetic modification of lactic acid bacteria (LAB) was also described as a tool for new IBD treatments. The first part of this review shows different genetically modified LAB (GM-LAB) described for IBD treatment since 2000. Then, the two principally studied strategies are discussed (i) GM-LAB producing antioxidant enzymes and (ii) GM-LAB producing the anti-inflammatory cytokine IL 10. Different delivery systems, including protein delivery and DNA delivery, will also be discussed. Studies show the efficacy of GM-LAB (using different expression systems) for the prevention and treatment of IBD, highlighting the importance of the bacterial strain selection (with anti-inflammatory innate properties) as a promising alternative. These microorganisms could be used in the near future for the development of therapeutic products with anti-inflammatory properties that can improve the quality of life of IBD patients. PMID- 26064088 TI - A Longitudinal Computed Tomography Imaging in the Diagnosis of Gallbladder Cancer. AB - Background/Aim. To assess whether the diagnostic power of longitudinal multiplanar reformat (MPR) images is superior to that of conventional horizontal images for gallbladder cancer (GBC). Methods. Between 2006 and 2010, a total of 54 consecutive patients with preoperatively diagnosed gallbladder neoplasms located in gallbladder bed were analyzed. These patients underwent cholecystectomy with resection of the adjacent liver parenchyma. The patients were divided into the GBC group (n = 30) and the benign group (n = 24). MPR images obtained by preoperative multidetector row CT (MDCT) were assessed. Results. Mucosal line was more significantly disrupted in GBC group than that in benign group (93% [28/30 patients] versus 13% [3/24], p < 0.001). Maximum (9.3 [4.2-24.8] versus 7.0 mm [2.4-22.6], p = 0.29) and minimum (1.2 [1.0-2.4] versus 1.3 mm [1.0-2.6], p = 0.23) wall thicknesses on a single MPR plane did not differ significantly; however, the wall thickness ratio (max/min) differed significantly (6.8 [1.92-14.0] versus 5.83 [2.3-8.69], p = 0.04). Partial liver enhancement adjacent to tumor on longitudinal images was more common in GBC (40.0% [12/30 patients] versus 12.5% [3/24], p = 0.03). Mucosal line disruption was the most reliable independent predictor of diagnosis (odds ratio, 8.5; 95% CI, 5.99-28.1, p < 0.001). Conclusion. Longitudinal MPR images are more useful than horizontal images for the diagnosis of GBC. PMID- 26064089 TI - The Emerging Adult with Inflammatory Bowel Disease: Challenges and Recommendations for the Adult Gastroenterologist. AB - Incidence of pediatric inflammatory bowel disease (IBD) is rising. Adult gastroenterologists are seeing increasing numbers of young adults with IBD, a subpopulation with unique needs and challenges that can impair their readiness to thrive in an adult healthcare system. Most adult gastroenterologists might not have the training or resources to address these needs. "Emerging adulthood" is a useful developmental lens through which this group can be studied. With complex disease phenotype and specific concerns of medication side effects and reproductive health, compounded by challenges of geographical and social flux and lack of adequate health insurance, emerging adults with IBD (EAI) are at risk of disrupted care with lack of continuity. Lessons learned from structured healthcare transition process from pediatric to adult services can be applied towards challenges in ongoing care of this population in the adult healthcare system. This paper provides an overview of the challenges in caring for the post transition EAI from the perspective of adult gastroenterologists and offers a checklist of provider and patient skills that enable effective care. This paper discusses the system-based challenges in care provision and search for meaningful patient-oriented outcomes and presents a conceptual model of determinants of continuity of care in this unique population. PMID- 26064091 TI - German Bowel Cancer Center: An Attempt to Improve Treatment Quality. AB - Background. Colorectal cancer remains the second most common cause of death from malignancies, but treatment results show high diversity. Certified bowel cancer centres (BCC) are the basis of a German project for improvement of treatment. The aim of this study was to analyze if certification would enhance short-term outcome in rectal cancer surgery. Material and Methods. This quality assurance study included 8197 patients with rectal cancer treated between 1 January 2008 and 31 December 2010. We compared cohorts treated in certified and noncertified hospitals regarding preoperative variables and perioperative outcomes. Outcomes were verified by matched-pair analysis. Results. Patients of noncertified hospitals had higher ASA-scores, higher prevalence of risk factors, more distant metastases, lower tumour localization, lower frequency of pelvic MRI, and higher frequencies of missing values and undetermined TNM classifications (significant differences only). Outcome analysis revealed more general complications in certified hospitals (20.3% versus 17.4%, p = 0.03). Both cohorts did not differ significantly in percentage of R0-resections, intraoperative complications, anastomotic leakage, in-hospital death, and abdominal wall dehiscence. Conclusions. The concept of BCC is a step towards improving the structural and procedural quality. This is a good basis for improving outcome quality but cannot replace it. For a primary surgical disease like rectal cancer a specific, surgery targeted program is still needed. PMID- 26064092 TI - Comparison of Three Methods Used in the Diagnosis of Extraesophageal Reflux in Children with Chronic Otitis Media with Effusion. AB - Objectives. Detection of extraesophageal reflux (EER) in children with chronic otitis media with effusion (OME) using three different diagnostic methods. Methods. Children between 1 and 7 years with OME who underwent adenoidectomy and myringotomy with insertion of a ventilation tube were included in this prospective study. EER was detected using three methods: oropharyngeal pH was monitored for 24 hours using the Restech system; detection of pepsin in middle ear fluid obtained during myringotomy was done using Peptest, and detection of pepsin in an adenoid specimen was done immunohistochemically. Results. Altogether 21 children were included in the study. Pathological oropharyngeal pH was confirmed in 13/21 (61.9%) children. Pepsin in the middle ear fluid was present in 5/21 (23.8%) children; these 5 patients were diagnosed with the most severe EER established through monitoring of oropharyngeal pH. No specimen of adenoids tested was positive for pepsin upon immunohistochemical examination. Conclusions. Diagnosis of EER in patients with OME using Restech is sensitive but less specific when compared to the detection of pepsin in middle ear fluid using Peptest. Pepsin in the middle ear was consistently present in patients with RYAN score above 200, and these patients in particular could potentially profit from antireflux therapy. PMID- 26064090 TI - Long Noncoding RNAs in Digestive System Malignancies: A Novel Class of Cancer Biomarkers and Therapeutic Targets? AB - High throughput methodologies have revealed the existence of an unexpectedly large number of long noncoding RNAs (lncRNAs). The unconventional role of lncRNAs in gene expression regulation and their broad implication in oncogenic and tumor suppressive pathways have introduced lncRNAs as novel biological tumor markers. The most prominent example of lncRNAs application in routine clinical practice is PCA3, a FDA-approved biomarker for prostate cancer. Regarding digestive system malignancies, the oncogenic HOTAIR is one of the most widely studied lncRNAs in the preclinical level and has already been identified as a potent prognostic marker for major malignancies of the gastrointestinal tract. Here, we provide an overview of recent findings regarding the emerging role of lncRNAs not only as key regulators of cancer initiation and progression in colon, stomach, pancreatic, liver, and esophageal cancers, but also as reliable tumor markers and therapeutic tools. lncRNAs can be easily, rapidly, and cost-effectively determined in tissues, serum, and gastric juice, making them highly versatile analytes. Taking also into consideration the largely unmet clinical need for early diagnosis and more accurate prognostic/predictive markers for gastrointestinal cancer patients, we comment upon the perspectives of lncRNAs as efficient molecular tools that could aid in the clinical management. PMID- 26064093 TI - Diagnostic Value of Semiquantitative Analysis of Dynamic Susceptibility Contrast Magnetic Resonance Imaging with GD-EOB-DTPA in Focal Liver Lesions Characterization: A Feasibility Study. AB - Purpose. To assess the diagnostic accuracy of dynamic susceptibility contrast enhanced magnetic resonance imaging (DSCE-MRI) in differentiation between benign and malignant liver lesions by assessment of tumoral perfusion parameters. Methods Materials. Seventy-three patients with known focal liver lesions, including 45 benign (16 FNH, 27 angiomas, and 2 abscesses) and 28 malignant ones (17 metastases, 9 HCCs, and 2 cholangiocarcinoma) underwent 1.5 T MRI upper abdominal study, with standard protocol that included dynamic contrast-enhanced sequences. On dedicated workstation, time-intensity curves were determined and the following perfusion parameters were calculated: relative arterial, venous and late enhancement (RAE, RVE, RLE), maximum enhancement (ME), relative enhancement (RE), and time to peak (TTP). Results. All diagnoses were established either by histopathology or imaging follow-up. Perfusion mean values calculated in benign lesions were RAE 33.8%, RVE 66.03%, RLE 80.63%, ME 776.00%, MRE 86.27%, and TTP 146.95 sec. Corresponding perfusion values calculated in malignant lesions were RAE 22.47%, RVE 40.54%, RLE 47.52%, ME 448.78%, MRE 49.85%, and TTP 183.79 sec. Statistical difference (p < 0.05) was achieved in all the perfusion parameters calculated, obtaining different cluster of perfusion kinetics between benign and malignant lesions. Conclusions. DSCE-MRI depicts kinetic differences in perfusion parameters among the different common liver lesions, related to tumour supply and microvascular characteristics. PMID- 26064094 TI - Novel Molecular Targets in Malignant Diseases of Digestive System 2014. PMID- 26064095 TI - Combination of Triple Therapy and Chronic PPI Use May Decrease Risk of Colonic Adenomatous Polyps in Helicobacter pylori Infection. AB - Aim. The aim of the paper is to determine association between H. pylori and colonic adenomatous polyps and to explore whether treatment or chronic PPI use can mitigate this risk. Methods. This case-control study included 943 patients who had H. pylori testing and underwent colonoscopy. Presence of polyps was the outcome of interest, whereas age, sex, race, H. pylori infection, triple therapy, and chronic PPI use were independent variables. Multivariate regression analysis was used to calculate odds ratios at 95% confidence intervals. This study was approved by the New York Medical College Institutional Review Board. Results. H. pylori was associated with increased odds of colonic adenomatous polyps (adjusted OR 1.43, 95% CI 1.04-1.77), with stronger association among patients older than 50 (OR 1.65, 95% CI 1.18-2.33). Triple therapy (OR 0.69, 95% CI 0.44-1.07) or chronic PPI use (OR 0.69, 95% CI 0.43-1.09) decreased odds of polyp formation. Analysis revealed a statistically significant reduction in patients who received both triple therapy and chronic PPI, lowering the odds by 60% (adjusted OR 0.43, 95% CI 0.27-0.67). Conclusion. There is increased risk of colonic adenomatous polyps among H. pylori-infected patients. Triple therapy or chronic PPI use may mitigate this risk, with further reduction when these two interventions are combined. PMID- 26064096 TI - Primary Antimicrobial Susceptibility Changes in Children with Helicobacter pylori Infection over 13 Years in Northern Italy. AB - The eradication therapy of Helicobacter pylori (H. pylori) infection is still a challenge for gastroenterologists. One of the main causes of failure in H. pylori eradication is the antibiotic resistance mainly to clarithromycin. Culture from biopsies is maybe the most used method among the antimicrobial susceptibility techniques. In this study, we compared the antimicrobial susceptibility changes in children with H. pylori infection over 13 years and we confirmed that clarithromycin resistance has been increased (16% versus 26%) though with no statistically signficant value. Therefore, clarithromycin should not be used in empiric treatment of H. pylori eradication therapy in children, but its use should be limited only to children with known antimicrobial susceptibility. On the other hand, metronidazole resistance has decreased over this time period in statistically significant manner (56% versus 33%, p = 0.014). Furthermore, ampicillin resistance has been confirmed to be very rare (3% versus 0%) in children with H. pylori infection. In conclusion, in H. pylori infection, if we do not know the antibiotic susceptibility of patients, we should recommend an eradication therapy based on the local distribution of antibiotic resistance rates trying to limit the therapeutic failures. PMID- 26064098 TI - Standard Triple Therapy versus Sequential Therapy in Helicobacter pylori Eradication: A Double-Blind, Randomized, and Controlled Trial. AB - Aim. To compare 10-day standard triple therapy versus sequential therapy as first line treatment in patients infected with H. pylori. Methods. One hundred H. pylori positive patients (diagnosed by rapid urease test and histology), with average age of 47.2, M/F = 28/72, were randomized to receive either standard triple treatment (TT) as follows: lansoprazole 30 mg, clarithromycin 500 mg, and amoxicillin 1 g, b.i.d. for ten days, or sequential treatment (ST) as follows: lansoprazole 30 mg, amoxicillin and placebo 1.0 g b.i.d for the first five days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and tinidazole 500 mg b.i.d, for the remaining five days. Eradication rates were determined 60 days after treatment by urease, histology, or (13)C-urea breath test. Results. In intention to treat (ITT) analysis, the rate of H. pylori eradication in the TT and ST groups was the same for both regimens as follows: 86% (43/50), 95% CI 93,3 to 73.4%. In Per protocol (PP) analysis, the rate of H. pylori eradication in the TT and ST groups was 87.8% (43/49), 95% CI 94,5 to 75.3% and 89.6% (43/48), 95% CI 95,8 to 77.3%, respectively. Conclusions. In Brazil, standard triple therapy is as equally effective as sequential therapy in eradicating Helicobacter pylori patients. This study was registered under Clinical Trials with number ISRCTN62400496. PMID- 26064097 TI - Assessing of Celiac Disease and Nonceliac Gluten Sensitivity. AB - The publication of papers on the topic of gluten related disorders has substantially increased over the last few years. This has motivated healthcare professionals to pay attention not only to celiac disease and wheat allergy but also to a condition termed nonceliac gluten sensitivity (NCGS). Until now this condition has been diagnosed clinically on the basis of exclusion criteria and clinical response to gluten withdrawal. In addition, recent research in this field has shown that other food components distinct from gluten are implicated in NCGS cases, thereby changing our general understanding of NCGS diagnosis in either individuals on gluten containing diets or those already following a gluten free diet with no proper diagnostic work-up of celiac disease. With this in mind, the assessment of NCGS will require extensive knowledge of celiac disease manifestations and the laboratory tests commonly performed during diagnosis of celiac disease. PMID- 26064099 TI - Clinicopathological Characteristics of Serrated Polyposis Syndrome in Korea: Single Center Experience. AB - Background/Aim. Serrated polyposis syndrome (SPS) is a rare condition characterized by multiple serrated polyps throughout the colon and rectum. The aim of this study was to evaluate the clinicopathological characteristics of SPS in Koreans. Methods. This retrospective analysis of prospectively collected data was performed using information from the endoscopy, clinical records, and pathology database system of Uijeongbu St. Mary's Hospital. Consecutive patients satisfying the updated 2010 World Health Organization criteria for SPS between June 2011 and May 2014 were enrolled. Results. Of the 17,552 patients who underwent colonoscopies during the study period, 11 (0.06%) met the criteria for SPS. The mean age of these patients was 55.6 years. Ten patients (91%) were males. None had a family history of CRC or a first-degree relative with SPS. Seven patients (64%) had synchronous advanced adenoma. One patient had coexistence of SPS with CRC that was diagnosed at the initial colonoscopy. Five patients (45%) had more than 30 serrated polyps. One of the patients underwent surgery and 10 underwent endoscopic resection. Conclusion. The prevalence of SPS in this study cohort was comparable to that in Western populations. Considering the high risk of CRC, correct diagnosis and careful follow-up for SPS are necessary. PMID- 26064100 TI - Transitioning the Adolescent with IBD from Pediatric to Adult Care: A Review of the Literature. AB - The incidence of inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), has increased in pediatric populations over the last decade. Patients diagnosed during childhood often survive well into adulthood, and therefore their healthcare requires transfer to an adult gastroenterologist, usually at age 18 years. Transition has been defined in the literature as the "purposeful planned movement of adolescents and young adults with chronic conditions from child-centered to adult-oriented health care systems" (Blum et al., 1993). The purpose of this review is to establish the current state of knowledge regarding the transition from pediatric to adult care in IBD. This review highlights that developmentally appropriate transitional care is now recognized as a healthcare priority and thoughtful targeted intervention is needed. PMID- 26064101 TI - Starch Origin and Thermal Processing Affect Starch Digestion in a Minipig Model of Pancreatic Exocrine Insufficiency. AB - Although steatorrhea is the most obvious symptom of pancreatic exocrine insufficiency (PEI), enzymatic digestion of protein and starch is also impaired. Low praecaecal digestibility of starch causes a forced microbial fermentation accounting for energy losses and meteorism. To optimise dietetic measures, knowledge of praecaecal digestibility of starch is needed but such information from PEI patients is rare. Minipigs fitted with an ileocaecal fistula with (n = 3) or without (n = 3) pancreatic duct ligation (PL) were used to estimate the rate of praecaecal disappearance (pcD) of starch. Different botanical sources of starch (rice, amaranth, potato, and pea) were fed either raw or cooked. In the controls (C), there was an almost complete pcD (>92%) except for potato starch (61.5%) which was significantly lower. In PL pcD of raw starch was significantly lower for all sources of starch except for amaranth (87.9%). Thermal processing increased pcD in PL, reaching values of C for starch from rice, potato, and pea. This study clearly underlines the need for precise specification of starch used for patients with specific dietetic needs like PEI. Data should be generated in suitable animal models or patients as tests in healthy individuals would not have given similar conclusions. PMID- 26064102 TI - Hypomagnesemia Induced by Long-Term Treatment with Proton-Pump Inhibitors. AB - In 2006, hypomagnesemia was first described as a complication of proton-pump inhibitors. To address this issue, we systematically reviewed the literature. Hypomagnesemia, mostly associated with hypocalcemic hypoparathyroidism and hypokalemia, was reported in 64 individuals on long-term proton-pump inhibitors. Hypomagnesemia recurred following replacement of one proton-pump inhibitor with another but not with a histamine type-2 receptor antagonist. The association between proton-pump inhibitors and magnesium metabolism was addressed in 14 case control, cross-sectional studies. An association was found in 11 of them: 6 reports found that the use of proton-pump inhibitors is associated per se with a tendency towards hypomagnesemia, 2 found that this tendency is more pronounced in patients concurrently treated with diuretics, carboplatin, or cisplatin, and 2 found a relevant tendency to hypomagnesemia in patients with poor renal function. Finally, findings likely reflecting decreased intestinal magnesium uptake were observed on treatment with proton-pump inhibitors. Three studies did not disclose any relationship between magnesium metabolism and treatment with histamine type-2 receptor antagonists. In conclusion, proton-pump inhibitors may cause hypomagnesemia. In these cases, switching to a histamine type-2 receptor antagonist is advised. PMID- 26064103 TI - Anti-Inflammatory Effects of Heparin and Its Derivatives: A Systematic Review. AB - Background. Heparin, used clinically as an anticoagulant, also has anti inflammatory properties. The purpose of this systematic review was to provide a comprehensive review regarding the efficacy and safety of heparin and its derivatives as anti-inflammatory agents. Methods. We searched the following databases up to March 2012: Pub Med, Scopus, Web of Science, Ovid, Elsevier, and Google Scholar using combination of Mesh terms. Randomized Clinical Trials (RCTs) and trials with quasi-experimental design in clinical setting published in English were included. Quality assessments of RCTs were performed using Jadad score and Consolidated Standards of Reporting Trials (CONSORT) checklist. Results. A total of 280 relevant studies were reviewed and 57 studies met the inclusion criteria. Among them 48 studies were RCTs. About 65% of articles had score of 3 and higher according to Jadad score. Twelve studies had a quality score > 40% according to CONSORT items. Asthma (n = 7), inflammatory bowel disease (n = 5), cardiopulmonary bypass (n = 8), and cataract surgery (n = 6) were the most studied disease condition. Forty studies use unfractionated heparin (UFH) for intervention; the remaining studies use low molecular weight heparin (LMWH). Conclusion. Despite the conflicting results, heparin seems to be a safe and effective anti-inflammatory agent; although it is shown that heparin can decrease the level of inflammatory biomarkers and improves patient conditions, still more data from larger rigorously designed studies are needed to support use of heparin as an anti-inflammatory agent in clinical setting. However, because of the association between inflammation, atherogenesis, thrombogenesis, and cell proliferation, heparin and related compounds with pleiotropic effects may have greater therapeutic efficacy than compounds acting against a single target. PMID- 26064104 TI - Antileishmanial Effect of 5,3'-Hydroxy-7,4'-dimethoxyflavanone of Picramnia gracilis Tul. (Picramniaceae) Fruit: In Vitro and In Vivo Studies. AB - Species of Picramnia genus are used in folk medicine to treat or prevent skin disorders, but only few species have been studied for biological activity and chemical composition. P. gracilis Tul. is a native species from Central and South America and although its fruits are edible, phytochemical analysis or medicinal uses of this species are not known. In the search of candidates to antileishmanial drugs, this work aimed to evaluate the antileishmanial activity of P. gracilis Tul. in in vitro and in vivo studies. Only ethanolic extract of fruits showed leishmanicidal activity. The majoritarian metabolite was 5,3' hydroxy-7,4'-dimethoxyflavanone ether that exhibited high activity against L. (V.) panamensis (EC50 17.0 + 2.8 mg/mL, 53.7 MUM) and low toxicity on mammalian U 937 cells, with an index of selectivity >11.8. In vivo studies showed that the flavanone administered in solution (2 mg/kg/day) or cream (2%) induces clinical improvement and no toxicity in hamsters with CL. In conclusion, this is the first report about isolation of 5,3'-hydroxy-7,4'-dimethoxyflavanone of P. gracilis Tul. The leishmanicidal activity attributed to this flavanone is also reported for the first time. Finally, the in vitro and in vivo leishmanicidal activity reported here for 5,3'-hydroxy-7,4'-dimethoxyflavanone offers a greater prospect towards antileishmanial drug discovery and development. PMID- 26064105 TI - Postoperative Residual Neuromuscular Paralysis at an Australian Tertiary Children's Hospital. AB - Purpose. Residual neuromuscular blockade (RNMB) is known to be a significant but frequently overlooked complication after the use of neuromuscular blocking agents (NMBA). Aim of this prospective audit was to investigate the incidence and severity of RNMB at our Australian tertiary pediatric center. Methods. All children receiving NMBA during anesthesia were included over a 5-week period at the end of 2011 (Mondays to Fridays; 8 a.m.-6 p.m.). At the end of surgery, directly prior to tracheal extubation, the train-of-four (TOF) ratio was assessed quantitatively. Data related to patient postoperative outcome was collected in the postoperative acute care unit. Results. Data of 64 patients were analyzed. Neostigmine was given in 34 cases and sugammadex in 1 patient. The incidence of RNMB was 28.1% overall (without reversal: 19.4%; after neostigmine: 37.5%; n.s.). Severe RNMB (TOF ratio < 0.7) was found in 6.5% after both no reversal and neostigmine, respectively. Complications in the postoperative acute care unit were infrequent, with no differences between reversal and no reversal groups. Conclusions. In this audit, RNMB was frequently observed, particularly in cases where patients were reversed with neostigmine. These findings underline the well known problems associated with the use of NMBA that are not fully reversed. PMID- 26064106 TI - Cognitive Function and Salivary DHEA Levels in Physically Active Elderly African American Women. AB - Serum and plasma dehydroepiandrosterone sulfate (DHEAS) concentration has been associated with several health parameters associated with aging including cognitive function, bone mineral density, and muscular strength. However, the effectiveness of salivary DHEA for the prediction of cognitive function, bone mineral density, and muscular strength in older adults is currently unknown. Thirty elderly African American females provided early morning salivary samples and DHEA levels were determined using a commercially available immunoassay. Participants completed testing for psychomotor and executive function via Trail Making Tests (TMT) A and B, respectively. Bone ultrasound attenuation (BUA) was used to bone density and an isometric mid-thigh pull (IMTP) was used to determine isometric strength. Age significantly correlated with time on TMT A (r=0.328) and B (r=0.615) but was not related to DHEA, BUA, or IMTP outcomes. Elevated DHEA was associated with longer time to completion for TMT A (chi (2) = 5.14) but not to TMT B. DHEA levels were not associated with BUA or IMTP outcomes. While elevated levels of DHEA were correlated with impaired psychomotor function, salivary DHEA is not associated with executive function, bone mineral density, or isometric strength in elderly African American women. PMID- 26064107 TI - Noninvasive Assessment of Fibrosis in Patients with Nonalcoholic Fatty Liver Disease. AB - Nonalcoholic fatty liver disease (NAFLD) is prevalent in 20-25% of the general population and is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia. Histologically, NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. As NASH develops in only 10-15% of patients with NAFLD, it is not practical to biopsy all patients who present with NAFLD. Noninvasive fibrosis tests have been extensively developed recently and offer alternatives for staging fibrosis. Despite their increasing use, such tests cannot adequately differentiate simple steatosis from NASH. At present, such tests can be used as first line tests to rule out patients without advanced fibrosis and thus prevent unnecessary secondary care referrals in a significant number of patients. In this review we present the evidence for the use of noninvasive fibrosis tests in patients with NAFLD. PMID- 26064108 TI - Effect of Orexin-A on Cortisol Secretion in H295R Cells via p70S6K/4EBP1 Signaling Pathway. AB - Orexin-A is a neuropeptide that orchestrates diverse central and peripheral processes. It is now clear that orexin system plays a central role in the regulation of endocrine, paracrine, and neurocrine. It is involved in the regulation of growth hormone, adrenocorticotropic hormone, thyroid, mineralocorticoid, and cortisol secretion. These hormones may also serve as a kind of signal linking energy balance regulation, reproduction, stress response, and cardiovascular regulation. Many studies have demonstrated the ability of orexin-A to regulate adrenocortical cells through the MAPK (mitogen-activated protein kinases) pathway. The aim of our study is to investigate the effect of orexin-A on cortisol secretion via the protein 70 ribosomal protein S6 kinase-1 (p70S6K) and eukaryotic translation initiation factor 4E binding proteins (4EBP1) signaling pathway in adrenocortical cells. We reported the first evidence that orexin-A stimulated p70S6K and 4EBP1 in human H295R adrenocortical cells in a concentration and time-dependent manner. 10(-6) M orexin-A treatment for 1 hour was the most potent. Our results also indicated that p70S6K and 4EBP1 kinases participated in controlling cortisol secretion via OX1 receptor in H295R cells, which implied important role of p70S6K and 4EBP1 kinases in regulating adrenal function induced by orexin-A. PMID- 26064109 TI - Incidental Adrenal Nodules and Masses: The Imaging Approach. AB - Adrenal nodules are detected with increasing frequency. The National Institute of Health (NIH), American College of Radiology (ACR), and the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons (AACE/AAES) have produced guidelines for the management of incidental adrenal nodules. This review provides a summary of the consensus radiologic approach to these nodules. PMID- 26064111 TI - Long-Term Effect of Surgery in Graves' Disease: 20 Years Experience in a Single Institution. AB - The present study compared the long-term outcome of subtotal thyroidectomy (ST) to that of total thyroidectomy (TT) in Graves' disease (GD). Patients with GD requiring surgery were divided between two groups: ST and TT. Postoperative thyroid function (PoTF) changes, including hypothyroidism, euthyroidism, and hyperthyroidism, and surgical complications were analyzed 3 months and 2 years after surgery. During the study period, 350 GD patients underwent surgery, of whom 254 underwent ST and 96 underwent TT. In the ST group, the rates of hypothyroidism, euthyroidism, and hyperthyroidism were 92.5%, 6.7%, and 0.4%, respectively, after 3 months, and 86.1%, 8.6%, and 5.3%, respectively, after 2 years. No difference in the rate of surgical complication was observed between the ST and TT groups (p = 0.089). Most of the ST patients showed hypothyroidism after surgery, and euthyroidism was rare. The long-term outcome of ST included noticeable PoTF changes and recurrence of GD. These results suggest that TT should be considered as a treatment option in GD requiring surgery. PMID- 26064110 TI - Differential Role of Leptin and Adiponectin in Cardiovascular System. AB - Leptin and adiponectin are differentially expressed adipokines in obesity and cardiovascular diseases. Leptin levels are directly associated with adipose tissue mass, while adiponectin levels are downregulated in obesity. Although significantly produced by adipocytes, leptin is also produced by vascular smooth muscle cells and cardiomyocytes. Plasma leptin concentrations are elevated in cases of cardiovascular diseases, such as hypertension, congestive heart failure, and myocardial infarction. As for the event of left ventricular hypertrophy, researchers have been stirring controversy about the role of leptin in this form of cardiac remodeling. In this review, we discuss how leptin has been shown to play an antihypertrophic role in the development of left ventricular hypertrophy through in vitro experiments, population-based cross-sectional studies, and longitudinal cohort studies. Conversely, we also examine how leptin may actually promote left ventricular hypertrophy using in vitro analysis and human-based univariate and multiple linear stepwise regression analysis. On the other hand, as opposed to leptin's generally detrimental effects on the cardiovascular system, adiponectin is a cardioprotective hormone that reduces left ventricular and vascular hypertrophy, oxidative stress, and inflammation. In this review, we also highlight adiponectin signaling and its protective actions on the cardiovascular system. PMID- 26064112 TI - C/EBPbeta Isoforms Expression in the Rat Brain during the Estrous Cycle. AB - The CCAAT/enhancer-binding protein beta (C/EBPbeta) is a transcription factor expressed in different areas of the brain that regulates the expression of several genes involved in cell differentiation and proliferation. This protein has three isoforms (LAP1, LAP2, and LIP) with different transcription activation potential. The role of female sex hormones in the expression pattern of C/EBPbeta isoforms in the rat brain has not yet been described. In this study we demonstrate by western blot that the expression of the three C/EBPbeta isoforms changes in different brain areas during the estrous cycle. In the cerebellum, LAP2 content diminished on diestrus and proestrus and LIP content diminished on proestrus and estrus days. In the prefrontal cortex, LIP content was higher on proestrus and estrus days. In the hippocampus, LAP isoforms presented a switch on diestrus day, since LAP1 content was the highest while that of LAP2 was the lowest. The LAP2 isoform was the most abundant one in all the three brain areas. The LAP/LIP ratio changed throughout the cycle and was tissue specific. These results suggest that C/EBPbeta isoforms expression changes in a tissue-specific manner in the rat brain due to the changes in sex steroid hormone levels presented during the estrous cycle. PMID- 26064113 TI - A 2-Week Course of Enteral Treatment with a Very Low-Calorie Protein-Based Formula for the Management of Severe Obesity. AB - Background. Multiple weight loss failures among obese patients suggest the design of new therapeutic strategies. We investigated the role of 2-week course of enteral treatment with a very low-calorie protein-based formula in the management of severe obesity. Methods. We evaluated the feasibility, safety, and efficacy of 2-week continuous administration of a protein-based formula (1.2 g/kg of ideal body weight/day) by nasogastric tube in severely obese adults (body mass index (BMI) >= 40 kg/m(2)). Results. In total, 364 patients (59% women; BMI = 46.6 +/- 7.2 kg/m(2)) were recruited. The intervention was discontinued within 48 hours in 26 patients, due to nasogastric tube intolerance. No serious adverse events occurred. During the first and the second week, 65% and 80% patients, respectively, reported no side effects. All biochemical safety parameters were affected by the intervention, particularly uric acid (+45%) and aminotransferases (+48%). In the other cases the change was negligible. We observed significant weight loss (5.7 +/- 2.3%) and improvement in blood pressure and glucose and lipid metabolism parameters (P < 0.001). Conclusions. A 2-week course of enteral treatment with a very low-calorie protein-based formula appeared a feasible, likely safe, and efficacious therapeutic option to be considered for inclusion into a composite weight loss program for the management of severe obesity. This trial is registered with ClinicalTrials.gov Identifier: NCT01965990. PMID- 26064114 TI - Gender-Specific Differences in Clinical Profile and Biochemical Parameters in Patients with Cushing's Disease: A Single Center Experience. AB - Cushing's disease (CD) is remarkably prevalent among females; however, more severe clinical presentation and adverse outcomes have been found in males. The purpose of this study was to investigate the overall clinical profile and biochemical parameters in patients with CD to identify the gender differences. Here we describe our series of CD patients referred to our medical center during 2012-2013. Among 73 cases, females presented a marked preponderance compared to males. Males had significantly higher ACTH, BMI, HbA1c, systolic blood pressure, and hemoglobin than females. For the first time, the incidence of fatty liver and hepatic function was also shown to be elevated in males. Multiple linear regression analysis was performed to further investigate the correlation of risk factors with hypokalemia, HbA1c, and systolic blood pressure. Gender and serum cortisol were associated with hypokalemia. Age, gender, and serum cortisol were significantly associated with HbA1c. Additionally, only gender was significantly associated with systolic blood pressure. Regarding clinical presentation, purple striae seemed to occur more frequently in males than in females. Thus, more severe clinical presentation, biochemical parameters, and complications were found in males than in females. Clinical professionals should pay more attention to the diagnosis and management of males with CD. PMID- 26064115 TI - The Lipid Parameters and Lipoprotein(a) Excess in Hashimoto Thyroiditis. AB - Objective. The risk of atherosclerotic heart disease is increased in autoimmune thyroiditis, although the reason is not clear. Lipoprotein(a) (Lp(a)) excess has been identified as a powerful predictor of premature atherosclerotic vascular diseases. The aim of this study is to investigate the relationship between Lp(a) levels and thyroid hormones in Hashimoto patients. Method. 154 premenopausal female Hashimoto patients (48 patients with overthypothyroid (OH), 50 patients with subclinical hypothyroid (SH), and 56 patients with euthyroid Hashimoto to (EH)) were enrolled in this study. The control group consists of 50 age matched volunteers. In every group, thyroid function tests and lipid parameters with Lp(a) were measured. Lp(a) excess was defined as Lp(a) > 30 mg/dL. Results. Total C, LDL-C, TG, and Lp(a) levels were increased in Hashimoto group. Total-C, LDL-C, and TG levels were higher in SH group than in the control group. Total-C and LDL C levels were also higher in EH group compared to controls. Lp(a) levels were similar in SH and EH groups with controls. However, excess Lp(a) was more common in subclinical hypothyroid and euthyroid Hashimoto group than in the control group. Conclusion. The Total-C and LDL-C levels and excess Lp(a) were higher even in euthyroid Hashimoto patients. Thyroid autoimmunity may have some effect on Lp(a) and lipid metabolism. PMID- 26064116 TI - Comparison of Enoxaparin and Warfarin for Secondary Prevention of Cancer Associated Stroke. AB - Background. The aim of this study was to determine which anticoagulant is superior for secondary prevention of cancer-associated stroke, using changes in D dimer levels as a biomarker for recurrent thromboembolic events. Methods. We conducted a retrospective, single center observational study including patients with cancer-associated stroke who were treated with either enoxaparin or warfarin. Blood samples for measuring the initial and follow-up D-dimer levels were collected at admission and a median of 8 days after admission, respectively. Multiple logistic regression analysis was conducted to evaluate the factors that influenced D-dimer levels after treatment. Results. Although the initial D-dimer levels did not differ between the two groups, the follow-up levels were dramatically decreased in patients treated with enoxaparin, while they did not change with use of warfarin (3.88 MUg/mL versus 17.42 MUg/mL, p = 0.026). On multiple logistic regression analysis, use of warfarin (OR 12.95; p = 0.001) and the presence of systemic metastasis (OR 18.73; p = 0.017) were independently associated with elevated D-dimer levels (>=10 MUg/mL) after treatment. Conclusion. In cancer-associated stroke patients, treatment with enoxaparin may be more effective than treatment with warfarin for lowering the D-dimer levels. Future prospective studies are warranted to show that enoxaparin is better than warfarin for secondary prevention in cancer-associated stroke. PMID- 26064117 TI - Do Diametric Measurements Provide Sufficient and Reliable Tumor Assessment? An Evaluation of Diametric, Areametric, and Volumetric Variability of Lung Lesion Measurements on Computerized Tomography Scans. AB - Diametric analysis is the standard approach utilized for tumor measurement on medical imaging. However, the availability of newer more sophisticated techniques may prove advantageous. An evaluation of diameter, area, and volume was performed on 64 different lung lesions by three trained users. These calculations were obtained using a free DICOM viewer and standardized measuring procedures. Measurement variability was then studied using relative standard deviation (RSD) and intraclass correlation. Volumetric measurements were shown to be more precise than diametric. With minimal RSD and variance between different users, volumetric analysis was demonstrated as a reliable measurement technique. Additionally, the diameters were used to calculate an estimated area and volume; thereafter the estimated area and volume were compared against the actual measured values. The results in this study showed independence of the estimated and actual values. Estimated area deviated an average of 43.5% from the actual measured, and volume deviated 88.03%. The range of this variance was widely scattered and without trend. These results suggest that diametric measurements cannot be reliably correlated to actual tumor size. Access to appropriate software capable of producing volume measurements has improved drastically and shows great potential in the clinical assessment of tumors. Its applicability merits further consideration. PMID- 26064119 TI - Computer-Guided Implant Surgery in Fresh Extraction Sockets and Immediate Loading of a Full Arch Restoration: A 2-Year Follow-Up Study of 14 Consecutively Treated Patients. AB - Statement of Problem. Low scientific evidence is identified in the literature for combining implant placement in fresh extraction sockets with immediate function. Moreover, the few studies available on immediate implants in postextraction sites supporting immediate full-arch rehabilitation clearly lack comprehensive protocols. Purpose. The purpose of this study is to report outcomes of a comprehensive protocol using CAD-CAM technology for surgical planning and fabrication of a surgical template and to demonstrate that immediate function can be easily performed with immediate implants in postextraction sites supporting full-arch rehabilitation. Material and Methods. 14 subjects were consecutively rehabilitated (13 maxillae and 1 mandible) with 99 implants supporting full-arch fixed prostheses followed between 6 and 24 months (mean of 16 months). Outcome measures were prosthesis and implant success, biologic and prosthetic complications, pain, oedema evaluation, and radiographic marginal bone levels at surgery and then at 6, 12, 18, and 24 months. Data were analyzed with descriptive statistics. Results. The overall cumulative implant survival rate at mean follow up time of 16 months was 97.97%. The average marginal bone loss was 0,9 mm. Conclusions. Within the limitations of this study, the results validate this treatment modality for full-arch rehabilitations with predictable outcomes and high survival rate after 2 years. PMID- 26064118 TI - Viral Etiology of Chronic Obstructive Pulmonary Disease Exacerbations during the A/H1N1pdm09 Pandemic and Postpandemic Period. AB - Viral infections are one of the main causes of acute exacerbations of chronic obstructive pulmonary disease (AE-COPD). Emergence of A/H1N1pdm influenza virus in the 2009 pandemic changed the viral etiology of exacerbations that were reported before the pandemic. The aim of this study was to describe the etiology of respiratory viruses in 195 Spanish patients affected by AE-COPD from the pandemic until the 2011-12 influenza epidemic. During the study period (2009 2012), respiratory viruses were identified in 48.7% of samples, and the proportion of viral detections in AE-COPD was higher in patients aged 30-64 years than >=65 years. Influenza A viruses were the pathogens most often detected during the pandemic and the following two influenza epidemics in contradistinction to human rhino/enteroviruses that were the main viruses causing AE-COPD before the pandemic. The probability of influenza virus detection was 2.78-fold higher in patients who are 30-64 years old than those >=65. Most respiratory samples were obtained during the pandemic, but the influenza detection rate was higher during the 2011-12 epidemic. There is a need for more accurate AE-COPD diagnosis, emphasizing the role of respiratory viruses. Furthermore, diagnosis requires increased attention to patient age and the characteristics of each influenza epidemic. PMID- 26064120 TI - Electrochemical Deposition and Dissolution of Thallium from Sulfate Solutions. AB - The electrochemical behavior of thallium was studied on glassy carbon electrodes in sulfate solutions. Cyclic voltammetry was used to study the kinetics of the electrode processes and to determine the nature of the limiting step of the cathodic reduction of thallium ions. According to the dependence of current on stirring rate and scan rate, this process is diffusion limited. Chronocoulometry showed that the electrodeposition can be performed with a current efficiency of up to 96% in the absence of oxygen. PMID- 26064121 TI - Development of HPLC Protocol and Simultaneous Quantification of Four Free Flavonoids from Dracocephalum heterophyllum Benth. AB - Quantification of the four flavonoids, namely, luteolin, kaempferol, diosmetin, and chrysosplenetin, has been performed for the first time in 80% ethanolic extract of Dracocephalum heterophyllum B. through HPLC coupled to UV detector after optimization of extracting solvent and chromatographic conditions. Total flavonoids quantified were 0.324 mg/mL of the extract. HPLC analysis delivered contents of the luteolin, kaempferol, diosmetin, and chrysosplenetin as 0.08%, 0.14%, 0.28%, and 0.79% of the dried extract, respectively. LOD (%) values calculated were 0.04, 0.03, 0.03, and 0.08 and LOQ (%) values were 0.08, 0.12, 0.11, and 0.28 for luteolin, kaempferol, diosmetin, and chrysosplenetin, respectively. The recovery percentages for these flavonoids were within the acceptable range of 95% to 105%. Standard deviation and %RSD were calculated for each target analytes individually in extract for determining the reproducibility and accuracy of the method. In no case the %RSD was higher than 1 taking retention time as a factor while in the case of area under the curve maximum %RSD was noted in the case of diosmetin as 2.85. From our literature review regarding the plant species under study, it appears that these flavonoids have not been quantified before and are reported for the first time in this paper. PMID- 26064122 TI - Production of Sterilizing Agents from Calendula officinalis Extracts Optimized by Response Surface Methodology. AB - The aim of this study was to produce hand sterilizing liquid and wet wipes with the extracts of Calendula officinalis. Since this plant has well known antimicrobial activity due to its phytochemical constituents, the increase in the extraction yield was chosen as the principle part of the production process. To achieve the maximum yield, parameters of solid-to-liquid ratio, extraction temperature, and time were studied. The optimum conditions were determined by response surface methodology as 41 degrees C, 7 h, and 3.3 g/200 mL for temperature, time, and solid-to-liquid ratio, respectively. The yield achieved at those conditions was found to be 90 percent. The highest amounts of flavonoids were detected at optimum, whereas the highest triterpene and saponin constituents were determined at different design points. The microbial efficiencies of extracts were determined by the inhibition of the growth of selected microorganisms. Different dilution rates and interaction times were used as parameters of inhibition. Not any of the constituent but symbiotic relation in between reached the highest inhibition of 90 percent. The pH values of the extracts were 5.1 to 5.4. As a result, the extraction of Calendula officinalis at the optimum conditions can be used effectively in the production of wet wipes and hand sterilizing liquid. PMID- 26064123 TI - Viral Agents of Diarrhea in Young Children in Two Primary Health Centers in Edo State, Nigeria. AB - Enteric viruses have been shown to be responsible for diarrhea among children during their early childhood. This study was carried out to determine the prevalence of rotavirus, adenovirus, and norovirus infection in young children with diarrhea in two primary health centers in Edo State, Nigeria. A total of 223 stool specimens were collected from children aged 0-36 months with clinical signs of diarrhea and 59 apparently healthy age-matched children as control. These specimens were investigated for three viral agents using immunochromatographic technique (ICT). The overall results showed that at least one viral agent was detected in 95/223 (42.6%) of the children with diarrhea while the control had none. The prevalence of rotavirus was 28.3%, adenovirus 19.3%, and norovirus 3.6%. There was a significant association between age group and infection (P < 0.0001). Seasonal pattern of enteric viruses was not statistically significant (P = 0.17). The overall coinfection rate was 7.6% and rotavirus-adenovirus coinfection had the highest with 5.4%. Rotavirus was the most prevalent viral agent. Coinfections are not uncommon among the population studied. The most commonly associated clinical symptom of viral diarrhea in this study was vomiting. Viral diagnostic tests are advocated for primary health care facilities in this locality. PMID- 26064124 TI - Evaluation of Ovarian Reserve with Anti-Mullerian Hormone in Familial Mediterranean Fever. AB - Objective. To investigate ovarian reserves in attack-free familial Mediterranean fever (AF-FMF) patients at the reproductive age by anti-Mullerian hormone (AMH), antral follicle count (AFC), ovarian volume, and hormonal parameters. Methods. Thirty-three AF-FMF patients aging 18-45 years and 34 healthy women were enrolled and FSH, LH, E2, PRL, and AMH levels were measured in the morning blood samples at 2nd-4th days of menstruation by ELISA. Concomitant pelvic ultrasonography was performed to calculate AFC and ovarian volumes. Results. In FMF patient group, median AMH levels were statistically significantly lower in the M69V mutation positive group than in the negative ones (P = 0.018). There was no statistically significant difference in median AMH levels between E148Q mutation positive patients and the negative ones (P = 0.920). There was also no statistically significant difference in median AMH levels between M680I mutation positive patients and the negative ones (P = 0.868). No statistically significant difference was observed in median AMH levels between patients who had at least one mutation and those with no mutations (P = 0.868). We realized that there was no difference in comparisons between ovarian volumes, number of follicles, and AMH levels ovarian reserves when compared with FMF patients and healthy individuals. Conclusions. Ovarian reserves of FMF pateints were similar to those of healthy subjects according to AMH. However, AMH levels were lower in FMF patients with M694V mutation. PMID- 26064125 TI - Macrophage Activation Syndrome as Onset of Systemic Lupus Erythematosus: A Case Report and a Review of the Literature. AB - Macrophage activation syndrome (MAS) is a potentially fatal condition. It belongs to the hemophagocytic lymphohistiocytosis group of diseases. In adults, MAS is rarely associated with systemic lupus erythematosus, but it also arises as complication of several systemic autoimmune disorders, like ankylosing spondylitis, rheumatoid arthritis, and adult-onset Still's disease. Several treatment options for MAS have been reported in the literature, including a therapeutic regimen of etoposide, dexamethasone, and cyclosporine. Here we report a case of 42-year-old woman in whom MAS occurred as onset of systemic lupus erythematosus. PMID- 26064126 TI - Recurrent Syncope Associated with Lung Cancer. AB - Syncope is an important problem in clinical practice with many possible causes that might be misdiagnosed. We present an unusual case of syncope, which has a normal chest X-ray. Exercise EKG and coronary angioplasty results confirmed the existence of serious coronary heart disease. The patient was treated with coronary stent transplantation. However, scope occurred again and the elevated tumor makers cytokeratin-19-fragment and neuron-specific enolase revealed the bronchogenic carcinoma, which was confirmed by enhanced CT examination. The treatment of carcinoma by chemotherapy was indeed sufficient for prompt elimination of the syncope symptoms. PMID- 26064127 TI - Spontaneous Bacterial Peritonitis and Henoch-Schonlein Purpura in a Patient with Liver Cirrhosis. AB - Henoch-Schonlein purpura (HSP) is a small vessel systemic vasculitis, predominantly affecting children, characterized by a tetrad of manifestations, specifically palpable purpura, arthralgia, abdominal pain, and renal disease. HSP in the adult population is rare, and no case has been described of HSP in liver cirrhosis with spontaneous bacterial peritonitis (SBP). We present the case of a 58-year-old male with liver cirrhosis, who was subsequently diagnosed with SBP and later HSP. In this patient, the diagnosis of HSP was demonstrated clinically by his palpable purpura, diarrhea, hematuria, and abdominal pain and confirmed pathologically by his renal and skin biopsies demonstrating leukocytoclastic vasculitis and IgA complexes. We believe that this is an example of altered IgA processing in cirrhosis leading to the development of IgA immune complexes and ultimately HSP. The patient additionally had SBP, which may have increased his risk for developing HSP given antigen processing by mucosa-associated lymphoid tissues leading to immune complex deposition, which may not have been effectively cleared in the context of his liver disease. The patient unfortunately died of gastrointestinal hemorrhage, which is unclear to be due to his underlying cirrhosis or a gastrointestinal manifestation of HSP itself. PMID- 26064128 TI - Rare Case of Aspergillus ochraceus Osteomyelitis of Calcaneus Bone in a Patient with Diabetic Foot Ulcers. AB - Diabetes is the most common metabolic disease in humans. One of the major complications of the disease is foot ulcer that is prone to infection. The most common causes of infection which have been reported in these patients are bacteria and fungi such as Candida, Aspergillus, and Rhizopus species. We report one such rare case with calcaneal osteomyelitis caused by Aspergillus ochraceus in a patient with diabetic foot osteomyelitis. The case was a 68-year-old male with a history of type II diabetes for 2 years. The patient had two ulcers on the right heel bones for the past 6 months with no significant improvement. One of the most important predisposing factors to infectious diseases, especially opportunistic fungal infection, is diabetes mellitus. Aspergillus species can involve bony tissue through vascular system, direct infection, and trauma. Proper and early diagnosis and treatment of diabetic foot infection can reduce or prevent complications, such as osteomyelitis and amputation. The annual examination of feet for skin and nail lesion, sensation, anatomical changes, and vascular circulation can be useful for prevention and control of infection. PMID- 26064129 TI - A Case of Diverticular Perforation in a Young Patient with Rheumatoid Arthritis on Methotrexate. AB - Background. Disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX), are associated with gastrointestinal toxicity. MTX inhibits dihydrofolate reductase, but it is unclear if polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene predict toxicity. Case. We describe a 33-year-old male with polyarticular rheumatoid arthritis who developed sigmoid diverticular perforation while receiving methotrexate, folic acid, prednisone, and naproxen. He tested heterozygous for the C677T allele MTHFR gene. Discussion. Rheumatoid arthritis and its treatments are associated with increased risk of gastrointestinal disease. In one study, perforation was highest among individuals with concomitant exposure to NSAIDs, nonbiologic DMARDs, and glucocorticoids. Multiple mutations of the MTHFR gene have been identified, but their association with MTX toxicity is unclear. This case adds to a growing body of literature that could help inform the treatment of others in the future. PMID- 26064130 TI - A Rare Reason for Pelvic Pain in Pregnancy: Infectious Sacroiliitis. AB - Introduction. Although the incidence of pregnancy-associated sacroiliitis is low, it is associated with significant morbidity and mortality. Timely diagnosis of the disease is confusing due to its nonspecific clinical features. Case. A 28 year-old woman at 34 weeks of gestation with severe pain in her right buttock radiating down the backside of the right thigh was admitted to our hospital. White blood cell (WBC) count and C-reactive protein (CRP) were elevated. The pelvic magnetic resonance imaging (MRI) scan revealed right sacroiliitis. Conclusion. Infectious sacroiliitis should be considered as a differential diagnosis even in low-risk women who present with debilitating pelvic pain in pregnancy and medical treatment should not be delayed. PMID- 26064131 TI - A Rare Cutaneous Adnexal Tumor: Malignant Proliferating Trichilemmal Tumor. AB - Proliferating trichilemmal tumors (PTTs) are neoplasms derived from the outer root sheath of the hair follicle. These tumors, which commonly affect the scalp of elderly women, rarely demonstrate malignant transformation. Although invasion of the tumors into neighboring tissues and being accompanied with anaplasia and necrosis are accepted as findings of malignancy, histological features may not always be sufficient to identify these tumors. The clinical behavior of the tumor may be incompatible with its histological characteristics. Squamous-cell carcinoma should certainly be considered in differential diagnosis because of its similarity in morphological appearance with PTT. Immunostaining for CD34, P53, and Ki-67 is a useful adjuvant diagnostic method that can be used in differential diagnosis aside from morphological findings. In this study, we aimed to present the case of a 52-year-old female patient with clinicopathological features. We reported a low-grade malignant proliferating trichilemmal tumor in this patient and detected no relapse or metastasis in a 24-month period of follow-up. PMID- 26064132 TI - Autologous Fat Grafting in the Treatment of Painful Postsurgical Scar of the Oral Mucosa. AB - Background. Persistent pain as a consequence of surgical treatment has been reported for several common surgical procedures and represents a clinical problem of great magnitude. Material and Methods. We describe the case of a 47-year-old female who presented a retractile scar that adhered to deep planes at the upper right of the vestibule due to surgical removal of maxillary exostosis, which determined important pain symptoms extending till the right shoulder during both chewing and rest. We subsequently treated her with autologous fat grafting according to Coleman's technique. Results. Clinical assessments were performed at 5 and 14 days, 1, 3, and 6 months, and 1 year after surgical procedure. We observed a progressive release of scar retraction together with an important improvement of pain symptoms. Conclusion. The case described widens the possible application of autologous fat grafting on a new anatomical site as buccal vestibule and in one specific clinical setting confirming its promising biological effects. PMID- 26064133 TI - Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18)(q21;q21), and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature. AB - Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin's lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL) has rarely been reported. Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18)(q21;q21). The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45. Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma. PMID- 26064135 TI - Stem Cells and Cardiac Repair. PMID- 26064134 TI - MicroRNA Regulation of Brain Tumour Initiating Cells in Central Nervous System Tumours. AB - CNS tumours occur in both pediatric and adult patients and many of these tumours are associated with poor clinical outcome. Due to a paradigm shift in thinking for the last several years, these tumours are now considered to originate from a small population of stem-like cells within the bulk tumour tissue. These cells, termed as brain tumour initiating cells (BTICs), are perceived to be regulated by microRNAs at the posttranscriptional/translational levels. Proliferation, stemness, differentiation, invasion, angiogenesis, metastasis, apoptosis, and cell cycle constitute some of the significant processes modulated by microRNAs in cancer initiation and progression. Characterization and functional studies on oncogenic or tumour suppressive microRNAs are made possible because of developments in sequencing and microarray techniques. In the current review, we bring recent knowledge of the role of microRNAs in BTIC formation and therapy. Special attention is paid to two highly aggressive and well-characterized brain tumours: gliomas and medulloblastoma. As microRNA seems to be altered in the pathogenesis of many human diseases, "microRNA therapy" may now have potential to improve outcomes for brain tumour patients. In this rapidly evolving field, further understanding of miRNA biology and its contribution towards cancer can be mined for new therapeutic tools. PMID- 26064136 TI - Hedgehog and Resident Vascular Stem Cell Fate. AB - The Hedgehog pathway is a pivotal morphogenic driver during embryonic development and a key regulator of adult stem cell self-renewal. The discovery of resident multipotent vascular stem cells and adventitial progenitors within the vessel wall has transformed our understanding of the origin of medial and neointimal vascular smooth muscle cells (SMCs) during vessel repair in response to injury, lesion formation, and overall disease progression. This review highlights the importance of components of the Hh and Notch signalling pathways within the medial and adventitial regions of adult vessels, their recapitulation following vascular injury and disease progression, and their putative role in the maintenance and differentiation of resident vascular stem cells to vascular lineages from discrete niches within the vessel wall. PMID- 26064137 TI - What Makes Umbilical Cord Tissue-Derived Mesenchymal Stromal Cells Superior Immunomodulators When Compared to Bone Marrow Derived Mesenchymal Stromal Cells? AB - MSCs derived from the umbilical cord tissue, termed UCX, were investigated for their immunomodulatory properties and compared to bone marrow-derived MSCs (BM MSCs), the gold-standard in immunotherapy. Immunogenicity and immunosuppression were assessed by mixed lymphocyte reactions, suppression of lymphocyte proliferation and induction of regulatory T cells. Results showed that UCX were less immunogenic and showed higher immunosuppression activity than BM-MSCs. Further, UCX did not need prior activation or priming to exert their immunomodulatory effects. This was further corroborated in vivo in a model of acute inflammation. To elucidate the potency differences observed between UCX and BM-MSCs, gene expression related to immune modulation was analysed in both cell types. Several gene expression profile differences were found between UCX and BM MSCs, namely decreased expression of HLA-DRA, HO-1, IGFBP1, 4 and 6, ILR1, IL6R and PTGES and increased expression of CD200, CD273, CD274, IL1B, IL-8, LIF and TGFB2. The latter were confirmed at the protein expression level. Overall, these results show that UCX seem to be naturally more potent immunosuppressors and less immunogenic than BM-MSCs. We propose that these differences may be due to increased levels of immunomodulatory surface proteins such as CD200, CD273, CD274 and cytokines such as IL1beta, IL-8, LIF and TGFbeta2. PMID- 26064138 TI - Neural Progenitor Cells Derived from Human Embryonic Stem Cells as an Origin of Dopaminergic Neurons. AB - Human embryonic stem cells (hESCs) are able to proliferate in vitro indefinitely without losing their ability to differentiate into multiple cell types upon exposure to appropriate signals. Particularly, the ability of hESCs to differentiate into neuronal subtypes is fundamental to develop cell-based therapies for several neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In this study, we differentiated hESCs to dopaminergic neurons via an intermediate stage, neural progenitor cells (NPCs). hESCs were induced to neural progenitor cells by Dorsomorphin, a small molecule that inhibits BMP signalling. The resulting neural progenitor cells exhibited neural bipolarity with high expression of neural progenitor genes and possessed multipotential differentiation ability. CBF1 and bFGF responsiveness of these hES-NP cells suggested their similarity to embryonic neural progenitor cells. A substantial number of dopaminergic neurons were derived from hES-NP cells upon supplementation of FGF8 and SHH, key dopaminergic neuron inducers. Importantly, multiple markers of midbrain neurons were detected, including NURR1, PITX3, and EN1, suggesting that hESC-derived dopaminergic neurons attained the midbrain identity. Altogether, this work underscored the generation of neural progenitor cells that retain the properties of embryonic neural progenitor cells. These cells will serve as an unlimited source for the derivation of dopaminergic neurons, which might be applicable for treating patients with Parkinson's disease. PMID- 26064139 TI - Occurring of In Vitro Functional Vasculogenic Pericytes from Human Circulating Early Endothelial Precursor Cell Culture. AB - Pericytes are periendothelial cells of the microcirculation which contribute to tissue homeostasis and hemostasis by regulating microvascular morphogenesis and stability. Because of their multipotential ex vivo differentiation capabilities, pericytes are becoming very interesting in regenerative medicine field. Several studies address this issue by attempting to isolate pericyte/mesenchymal-like cells from peripheral blood; however the origin of these cells and their culture conditions are still debated. Here we showed that early Endothelial Progenitor Cells (EPCs) expressing CD45+/CD146+/CD31+ can be a source of cells with pericyte/mesenchymal phenotype and function, identified as human Progenitor Perivascular Cells (hPPCs). We provided evidence that hPPCs have an immunophenotype consistent with Mesenchymal Stem Cells (MSCs) from human adipose tissue (hASCs) and fetal membranes of term placenta (FM-hMSCs). In addition, hPPCs can be subcultured and exhibit expression of pluripotent genes (OCT-4, KLF 4, and NANOG) as well as a remarkable vasculogenic potential. Our findings could be helpful to develop innovative cell-based therapies for future clinical applications with distinct therapeutic purposes. PMID- 26064140 TI - Phenotypic Detection of Genitourinary Candidiasis among Sexually Transmitted Disease Clinic Attendees in Ladoke Akintola University Teaching Hospital, Osogbo, Nigeria. AB - The management of genitourinary candidiasis (GC) is fraught with challenges, especially, in an era of increasing antifungal resistance. This descriptive cross sectional study conducted between May 2013 and January 2014 determined the prevalence and characteristics of GC and the species of Candida among 369 attendees of a Sexually Transmitted Disease (STD) clinic of Ladoke Akintola University Teaching Hospital, Osogbo, Nigeria. Appropriate urogenital specimen collected from each attendee was examined by microscopy and culture for Candida, with preliminary species identification by CHROMAgar Candida and confirmation by Analytical Profile Index (API) 20C AUX. The age range of attendees was 1-80 years, mean age was 36.32 +/- 11.34 years, and male to female ratio was 1 to 3. The prevalence of genitourinary candidiasis was 47.4%, with 4.9% in males and 42.5% in females (p < 0.0001). The age groups 31-45 and 16-30 have the highest prevalence of 23.3% and 16.8%, respectively. The species of Candida recovered include Candida glabrata 46.9%, Candida albicans 33.7%, Candida dubliniensis 9.7%, Candida tropicalis 5.7%, Candida krusei 1.7%, Candida lusitaniae 1.7%, and Candida utilis 0.6%. This study reported non-C. albicans Candida, especially C. glabrata, as the most frequently isolated species in GC, contrary to previous studies in this environment and elsewhere. PMID- 26064142 TI - Successful desensitization in a boy with severe cow's milk allergy by a combination therapy using omalizumab and rush oral immunotherapy. AB - BACKGROUND: Rush oral immunotherapy (OIT) combined with omalizumab (OMB) has been reported to be an effective and safe treatment for severe milk allergies. However, no report has described long-term follow-up observations after OMB discontinuation. The purpose of this case report was to evaluate the safety and efficacy of rush OIT in combination with OMB during a long period of treatment. CASE PRESENTATION: A 5-year-old boy presented with a past history of two severe episodes of anaphylaxis (at the age of 2 and 3 years) after consuming small amounts of cow's milk (CM). Before the OIT, the total immunoglobulin E (IgE) level was 654 IU/mL, and specific-IgE (sIgE) levels for CM, casein, and beta lactoglobulin were 77.0 kUA/L, 86.2 kUA/L and 12.0 kUA/L, respectively. The skin prick test (SPT) for CM showed a wheal (diameter, 20 mm) and erythema (diameter, 50 mm). In the open food challenge, he reacted to a 0.2 mL ingestion of CM and presented with dyspnea and laryngospasms, and he was then administrated 150 mg OMB every 2 weeks for 8 weeks. In the 9th week, he was admitted to hospital for the rush phase of the OIT. Once he was able ingest a dose of 200 mL CM without having an adverse reaction, he was discharged and allowed to continue a daily dose of 200 mL CM at home. During this phase, the sIgE levels were elevated, but the end-point titration values from the SPT gradually decreased, and the SPT was negative after 1 year of OMB treatment. Five months after discontinuation of OMB, the daily CM ingestion was ceased for a 2-week period, followed by an oral food challenge (OFC) that was negative. The patient experienced only five mild adverse events during the course of rush OIT, even after the discontinuation of OMB and his quality of life improved dramatically afterwards. CONCLUSIONS: The combination therapy of rush OIT and OMB successfully maintained desensitization to CM in a boy with severe allergies. We propose that a negative SPT may be useful to guide discontinuation of OMB in such patients. PMID- 26064141 TI - Prevalence of Upper Extremity Musculoskeletal Disorders in Dentists: Symptoms and Risk Factors. AB - AIM: The purpose of the present research was to examine the factors that lead to musculoskeletal disorders in dentists by assessing their posture using RULA method. MATERIALS AND METHODS: In this cross-sectional study, 130 dentists (84 male and 46 female) participated. The posture of the subjects during their normal workload was recorded by using the RULA method, and the range of musculoskeletal pains by using the Nordic Musculoskeletal Questionnaire (NMQ), and individual and professional data was assessed by a demographics questionnaire. All tests were performed at the P < 0.05 level. RESULTS: Assessment of the physical status of the subjects showed that 82.8% of subjects were at high risk of musculoskeletal disorders. The majority of musculoskeletal pains were in the neck (55.9%) and the shoulder (43.8%). Moreover, 68.9% of the subjects had experienced pain at least once over the last year. Significant relationships were observed between musculoskeletal pain and daily work hours (P = 0.07) and number of patients (P = 0.02), but the pain was not significantly associated with BMI and experience. CONCLUSION: The present findings showed that unsuitable posture of dentists during work has a considerable effect on musculoskeletal disorders. Therefore, further investigation is required to avoid the detrimental effects of wrong posture. PMID- 26064143 TI - Prevalence of Lumbar Disc Herniation in Adolescent Males in Seoul, Korea: Prevalence of Adolescent LDH in Seoul, Korea. AB - OBJECTIVE: The authors surveyed the prevalence and the clinical character of lumbar disc herniation (LDH) in Korean male adolescents, and the usefulness of current conscription criteria. METHODS: The data of 39,673 nineteen-year-old males that underwent a conscription examination at the Seoul Regional Korean Military Manpower Administration (MMA) from October 2010 to May 2011 were investigated. For those diagnosed as having lumbar disc herniation, prevalences, subject characteristics, herniation severities, levels of herniation, and modified Korean Oswestry low back pain disability scores by MMA physical grade were evaluated. The analysis was performed using medical certificates, medical records, medical images, and electromyographic and radiologic findings. RESULTS: The prevalence of adolescent LDH was 0.60%(237 of the 39,673 study subjects), and the prevalence of serious adolescent LDH with thecal sac compression or significant discogenic spinal stenosis was 0.28%(110 of the 39,673 study subjects). Of the 237 adolescent LDH cases, 105 (44.3%) were of single level LDH and 132 (55.7%) were of multiple level LDH, and the L4-5 level was the most severely and frequently affected. Oswestry back pain disability scores increased with herniation severity (p<0.01), and were well correlated with MMA grade. CONCLUSIONS: In this large cohort of 19-year-old Korean males, the prevalence of adolescent LDH was 0.60% and the prevalence of serious adolescent LDH, which requires management, was relatively high at 0.28%. MMA physical grade was confirmed to be a useful measure of the disability caused by LDH. PMID- 26064144 TI - Diagnostic Value of Biopsy Techniques in Lumbar Spondylodiscitis: Percutaneous Needle Biopsy and Open Biopsy. AB - OBJECTIVE: The objective of this study was to evaluate and compare the diagnostic value of the open biopsy technique and the percutaneous biopsy techniques in lumbar spondylodiscitis. METHODS: Between January 2004 and December 2009, we retrospectively reviewed the medical records of 57 patients with infectious lumbar spondylodiscitis. The etiologic diagnosis of the infectious spondylodiscitis was obtained by two methods. Of 57 cases, twenty-seven patients underwent open biopsy and thirty patients underwent percutaneous needle biopsy including computed tomography (CT) - guided and fluoroscopy-guided needle aspiration. All biopsies were performed by experienced two neurosurgeons and one interventional radiologist. RESULTS: Of the 57 cases radiologically consistent with spinal infection, 29 (50.9%) biopsy specimens resulted in positive cultures and 28 (49.1%) returned negative cultures. According to the type of biopsy techniques, the culture-positive rate was higher (p=0.005) in the open biopsy group than the percutaneous needle biopsy group. 19 (70.4%) of 27 biopsy specimens were positive in the open biopsy group, and 10 (33.3%) of 30 biopsy specimens were positive in the percutaneous needle biopsy group. Furthermore, the open biopsy showed higher positive culture rate than the percutaneous needle biopsy in cases with administration of empirical antibiotics although there was no statistically significant (p=0.137). CONCLUSIONS: Open biopsy should be considered for administration of organism-specific antibiotics for the successful treatment when percutaneous needle yield negative result. Furthermore, empirical antibiotics should be delayed until results of cultures unless the patient is severely septic, critically ill, neutropenic or neurologically compromised. PMID- 26064145 TI - Spontaneous Spinal Epidural Hematoma: A Retrospective Study on Prognostic Factors and Review of the Literature. AB - OBJECTIVES: The spontaneous spinal epidural hematoma (SSEH) is a rare clinical entity. Patients typically present with sudden onset back pain followed by neurological deficits. METHODS: Diagnosis of SSEH is usually made with MRI and standard treatment is surgical evacuation. In 1996, Groen published the most comprehensive review on the SSEH in which he analyzed 333 cases. We review 104 cases of SSEH presented in the English literature since the last major review and add three of our own cases, for a total of 107 cases. RESULTS: Our patients presented with back pain and neurologic deficits. Two made excellent functional recovery with prompt surgical decompression while one continued to have significant deficits despite evacuation. Better postoperative outcome was associated with less initial neurological dysfunction, shorter time to operation from symptom onset and male patients. CONCLUSION: We discuss the etiology of SSEH and report current trends in diagnosis, treatment, and outcome. PMID- 26064146 TI - Differentiation between Tuberculous Spondylitis and Pyogenic Spondylitis on MR Imaging. AB - OBJECTIVE: The objective of this study was to compare the magnetic resonance (MR) imaging of tuberculous spondylitis with pyogenic spondylitis. METHODS: MR images of the spines of 41 patients with infectious spondylitis at our institution over 8-years of period were retrospectively reviewed. Eighteen patients with infective spondylitis were excluded because their results on the marrow biopsy and culture were negative. MR imaging findings in 6 patients with tuberculous spondylitis (3 male, 3 female) were compared with those of 17 patients (10 male, 7 female) with pyogenic spondylitis. RESULTS: Two MR imaging findings were statiscally significant in differentiating the tuberculous spondylitis from pyogenic spondylitis: a well defined paraspinal abnormal signal and a thin and smooth abscess wall. There were no significant differences in the following MR imaging findings: paraspinal abscess or intraosseous abscess, subligamentous spread to three or more vertebra, involvement of multiple vertebra, hyperintense signal on T2-weighted images, heterogenous low signal on T1-weighted images, involvement of posterior element, epidural extension, involvement of intervertebral disk, disk space narrowing, rim enhancement of the abscess, skip lesion, and endplate destruction. CONCLUSION: MR imaging is an appropriate modality for differentiation of tuberculous spondylitis from pyogenic spondylitis. PMID- 26064147 TI - Tuberculous Abscess of the Psoas Muscle in a Patient with Acute Lumbar Burst Fracture: A Missed Diagnosis. AB - The authors present a rare case of tuberculous spondylitis and a large abscess in the left psoas muscle that occurred after spinal surgery for an acute traumatic burst fracture of the L2 vertebral body. We retrospectively reviewed the patient's first magnetic resonance imaging (MRI) we found that some unusual findings, indicative of psoas abscess had been overlooked. As a result, diagnosis and treatment of tuberculous psoas abscess and spondylitis were considerably delayed. Despite the critical condition of patients in a similar emergency, surgeons should always pay close attention to the radiological findings and clinical symptoms of the patient before considering a surgical intervention or biopsy. PMID- 26064148 TI - Combined Anterior Approach with Transcorporeal Herniotomy for a Huge Migrated Cervical Disc Herniation. AB - The report describes the herniation of a huge migrated cervical disc, which was treated by a combined anterior approach. A 50-year-old man presented with radiculopathy and myelopathy. Radiological images revealed the herniation of a huge disc which had migrated superiorly from the C6-7 disc to the C5-6 disc. We tried to combine an anterior cervical discectomy and fusion (ACDF) and transcorporeal herniotomy to avoid corpectomy. Postoperatively, successful clinical and radiological results were obtained. It is therefore possible to remove a huge migrated herniated cervical disc completely by a combined ACDF and trancorporeal approach without corpectomy. PMID- 26064149 TI - Long-term Sequela of Intradural Extramedullary Tuberculoma in the Thoracic Dorsal Spinal Cord: Case Report and Review of the Literature. AB - A 45-year old man, who had tuberculosis five years ago presented with paresthesia, decreased proprioception, and gait disturbance in the lower extremity which were aggravated for a month. Magnetic resonance imaging revealed the T3-7 intradural extramedullary fibrotic mass with dark signal intensity on T2 weighted images. The yellowish material in the thick fibrous mass was confirmed as caseous necrosis. Two days after the operation, the symptoms improved. Although quite rare, intradural extramedullary tuberculoma should be considered as a chronic sequel of the previous medical history of pulmonary tuberculosis or tuberculous meningitis. PMID- 26064150 TI - Propriospinal Myoclonus Induced by a Herniated Lumbar Intervertebral Disc at a Young Age: A Case Report. AB - The cause of propriospinal myoclonus (PSM) is idiopathic. Cervical trauma, ischemic myelopathy secondary to a spinal dural arteriovenous fistula, syringomyelia, Lyme neuroborreliosis, human immunodeficiency virus central nervous system infection, and cervical disc herniation can be the cause of PSM, but lumbar herniated intervertebral disc (HIVD) induced PSM has not been reported. We describe a patient who presented with PSM induced by HIVD and was treated with an epidural steroid injection using a transforaminal approach. PMID- 26064151 TI - Surgery for Recurrent Lumbar Disc Herniation During Pregnancy: A Case Report. AB - A few cases of lumbar disc herniation (LDH) that have been treated by surgery during pregnancy have been reported in the literature. However, symptomatic recurrent LDH during pregnancy has been rarely reported. A 32-year-old parous woman presented with lumbago and severe right leg pain at 20 weeks' gestation. Eleven years prior to admission, she had undergone an open discectomy for right sided LDH at the L4-5 level. Magnetic resonance imaging (MRI) showed a recurrent disc herniation that affected the nerve root at the right L4-5 level. The radiating pain did not respond to conservative treat-ment. Revision surgery was performed under general anesthesia and in the left lateral position to avoid fetal stress and aortocaval compression, and the ruptured disc particle was completely removed. Postoperatively, the radiating pain was completely relieved. She delivered a full-term healthy girl (birth weight, 3.39 kg) at 40 weeks' gestation by normal vaginal delivery. We report the rare case of a 32-year-old parous woman with recurrent LDH that was successfully treated by revision surgery. In recurrent LDH patients with incapacitating pain who do not respond to opioid injections, surgical treat-ment could lead to a satisfactory outcome maintaining pregnancy. PMID- 26064152 TI - Complementary and Alternative Therapies for Functional Gastrointestinal Diseases. PMID- 26064153 TI - Is Skin-Touch Sham Needle Not Placebo? A Double-Blind Crossover Study on Pain Alleviation. AB - It remains an open question whether placebo/sham acupuncture, in which the needle tip presses the skin, can be used as a placebo device for research on pain. We compare the analgesic effect of the skin-touch placebo needle with that of the no touch placebo needle, in which the needle tip does not touch the skin, in a double-blind crossover manner including no-treatment control in 23 healthy volunteers. The subjects received painful electrical stimulation in the forearm before and during needle retention to the LI 4 acupoint and after the removal of the needle and rated pain intensity using a visual analogue scale. We found no significant difference in analgesic effects among the skin-touch placebo needle, no-touch placebo needle, and no-treatment control at every point before, during, and after the treatments (p > 0.05). The results indicate that the skin-touch placebo needle can be used as a placebo device in clinical studies on pain. PMID- 26064154 TI - Jingtong Granule: A Chinese Patent Medicine for Cervical Radiculopathy. AB - Objective. This paper systematically assessed the efficacy and safety of Jingtong granule (JG) for cervical radiculopathy (CR). Methods. Randomized controlled trials comparing JG with no intervention, placebo, or conventional therapies were retrieved. The trials testing JG combined with conventional therapies versus conventional therapies were also enrolled. Study selection, methodological assessment, data extraction, and analysis were conducted in accordance with the Cochrane standards. The strength of evidence was evaluated according to GRADE approach. Results. Three trials with 400 participants were included. Methodological quality was evaluated as generally low. One study found that JG showed significant difference on decreasing pain scores compared with placebo. Meta-analysis indicated that JG plus conventional analgesic exhibited a significant immediate effect on the pain scores (WMD = 1.63; 95% CI: 1.29 to 1.98; P < 0.00001). Additionally, JG combined with analgesic presented beneficial immediate effect on neck disability index. However, the treatment effects of JG demonstrated in the trials were not large, and the safety of JG was unproven. Finally the evidence level was evaluated to be low. Conclusions. Our results indicated that JG showed some potential benefits for CR. Nevertheless, treatment effects are uncertain due to both the methodological concerns and the very modest reported improvements. PMID- 26064155 TI - Ameliorating Effect of Transcutaneous Electroacupuncture on Impaired Gastric Accommodation in Patients with Postprandial Distress Syndrome-Predominant Functional Dyspepsia: A Pilot Study. AB - Patients with functional dyspepsia (FD) have both reduced gastric accommodation and impaired gastric motility that are difficult to treat. The aim of this study was to investigate the therapeutic potential of transcutaneous electroacupuncture (TEA) for both of these disorders in FD patients. Acute experiments were performed in FD patients to study the effect of TEA and sham-TEA on gastric accommodation assessed by a nutrient drink test and gastric motility assessed by the measurement of the electrogastrogram (EGG). TEA or sham-TEA was performed via cutaneous electrodes at acupoints ST36 and PC6 or sham-points nonacupoints. It was found that (1) gastric accommodation (maximum tolerable volume) was reduced in FD patients compared with the controls (P < 0.03). TEA improved gastric accommodation in FD patients (P < 0.02). (2) Acute TEA significantly increased the percentage and power of normal gastric slow waves in the fed state assessed in the FD patients by the EGG in comparison with sham-TEA. (3) TEA increased vagal activity assessed by the spectral analysis of the heart rate variability in the fed state in FD patients. It was concluded that needleless method of transcutaneous electroacupuncture may have a therapeutic potential for treating both impaired gastric accommodation and impaired gastric motility in patients with FD. PMID- 26064156 TI - Efficacy of Acupuncture in Itch: A Systematic Review and Meta-Analysis of Clinical Randomized Controlled Trials. AB - Background. Itch (pruritus) is a sensitive state that provokes the desire to scratch. It is not only a common symptom of skin diseases but it also occurs in some systemic diseases. Clinical studies on the efficacy of the acupuncture therapy in alleviating itch are increasing, while systematic reviews assessing the efficacy of acupuncture therapy are still lacking. Objective. This systematic review aims to assess the effectiveness of acupuncture therapy for itch. Materials and Methods. A comprehensive literature search of eight databases was performed up to June 2014, and randomized controlled trials which compared acupuncture therapy and placebo acupuncture or no treatment group were identified. Accordingly, a meta-analysis was conducted. Results. This review included three articles of randomized controlled trials (RCTs) from a total of 2530 articles. The results of Meta-analysis showed that acupuncture therapy was effective to alleviate itch compared with placebo acupuncture and no treatment group. Conclusion. Based on the findings of this systematic review, we cautiously suggest that acupuncture therapy could improve the clinical efficacy of itch. However, this conclusion needs more studies on various ethnic samples to confirm our final conclusion. PMID- 26064158 TI - Effects of Jae-Seng Acupuncture Treatment on the Improvement of Nasolabial Folds and Eye Wrinkles. AB - The microneedle therapy system (MTS), a mechanical method involving making minute multiple holes in the skin, reportedly improves skin condition, such as by reducing flushing and melanin. A newly attempted bloodletting therapy, Jae-Seng Acupuncture, has several advantages over traditional mechanical punching methods because it allows the practitioner to regulate the depth and direction of needle stimulations and to choose whether to stimulate the muscle layers. This study was conducted to determine the efficacy of Jae-Seng Acupuncture in the treatment of nasolabial folds and eye wrinkles. The nasolabial folds and eye wrinkles of 107 patients ranging in age from their 20s to their 70s were subjected to DermaVision, a digital skin image analyzer, before the treatment and one to six months after treatment. Additionally, stimulation of the meridians, such as Taeyang, Tongjaryo, Chongmyong, Sungup, Sabaek, Yonghyang, Chichang, Taeyong, was performed to improve the function of the stomach, large intestine. Analyses of the images indicate that Jae-Seng Acupuncture improved nasolabial folds and eye wrinkles, suggesting that this technique is a safe and effective method for the improvement of facial skin conditions. PMID- 26064157 TI - Complementary and Alternative Therapies for Autism Spectrum Disorder. AB - Background. Complementary and alternative medicine (CAM) represents a popular therapeutic option for patients with autism spectrum disorder (ASD). Unfortunately, there is a paucity of data regarding the efficacy of CAM in ASD. The aim of the present systematic review is to investigate trials of CAM in ASD. Material and Methods. We searched the following databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, CINAHL, Psychology and Behavioral Sciences Collection, Agricola, and Food Science Source. Results. Our literature search identified 2687 clinical publications. After the title/abstract screening, 139 publications were obtained for detailed evaluation. After detailed evaluation 67 studies were included, from hand search of references we retrieved 13 additional studies for a total of 80. Conclusion. There is no conclusive evidence supporting the efficacy of CAM therapies in ASD. Promising results are reported for music therapy, sensory integration therapy, acupuncture, and massage. PMID- 26064159 TI - Antioxidant, Antibacterial, Cytotoxic, and Anti-Inflammatory Potential of the Leaves of Solanum lycocarpum A. St. Hil. (Solanaceae). AB - Ethanol extract and fractions obtained from leaves of Solanum lycocarpum were examined in order to determine their phenolic composition, antioxidant, antibacterial, anti-inflammatory, and cytotoxic potential. High performance liquid chromatography coupled with DAD analysis indicated that the flavonoids apigenin and kaempferol were the main phenolic compounds present in dichloromethane and ethyl acetate fractions, respectively. The antioxidant activity was significantly more pronounced for dichloromethane, ethyl acetate, and hydroethanol fractions than that of the commercial antioxidant 2,6-di-tert butyl-4-methylphenol. The hexane and dichloromethane fractions were more active against the tested bacteria. The hydroethanol fraction exhibited significant anti inflammatory activity at the dose of 75 and 150 mg/kg in the later phase of inflammation. However, the antiedematogenic effect of the higher dose of the ethyl acetate fraction (150 mg/kg) was more pronounced. The ethyl acetate fraction also presented a less cytotoxic effect than the ethanol extract and other fractions. These activities found in S. lycocarpum leaves can be attributed, at least in part, to the presence of phenolic constituents such as flavonoids. This work provided the knowledge of phenolic composition in the extract and fractions and the antioxidant, antibacterial, anti-inflammatory, and cytotoxic activities of leaves of S. lycocarpum. PMID- 26064160 TI - Ethanol Extract of Perilla frutescens Suppresses Allergen-Specific Th2 Responses and Alleviates Airway Inflammation and Hyperreactivity in Ovalbumin-Sensitized Murine Model of Asthma. AB - This study was to investigate the effects of different fractions of Perilla frutescens (Pf) leaves extracted by water or ethanol on asthma. BALB/c mice sensitized intraperitoneally and challenged with ovalbumin (OVA) were divided into six groups. Each group of mice was tube-feeding with 0 (control), 80 MUg (PfWL), or 320 MUg (PfWH) water extracts or 80 MUg (PfEL) or 320 MUg (PfEH) ethanol extracts of perilla leaves daily for 3 weeks. A negative control group (PBS) was neither sensitized nor treated with Pf. The effects of perilla leave extracts on allergic immune response were evaluated. The results showed that OVA specific IL-5 and IL-13 secretions from OVA-stimulated splenocytes were significantly suppressed in the ethanol extract groups PfEL and PfEH. Serum level of anti-OVA IgE tended to be lower in the PfEH group. The inflammatory mediators, such as eotaxin and histamine, and total cells, particularly eosinophils in bronchoalveolar lavage fluid (BALF), were also decreased in the PfEL and the PfEH groups. Therefore, the PfEL and the PfEH groups had significantly lower methacholine-induced hyperresponsiveness (AHR). In conclusion, ethanol extracts, rather than water extract, of perilla leaves could significantly suppress Th2 responses and airway inflammation in allergic murine model of asthma. PMID- 26064161 TI - Xuebijing Injection Promotes M2 Polarization of Macrophages and Improves Survival Rate in Septic Mice. AB - Xuebijing (XBJ) injection, a concoction of several Chinese herbs, has been widely used as an immunomodulator for the treatment of severe sepsis in China. However, the precise mechanisms responsible for its efficacy have not been fully elucidated. In our study, we determined the flow cytometry markers (F4/80, CD11c, and CD206), the levels of secreted cytokines (TNF-alpha, IL-6, and IL-10), and the expression of specific proteins of M2 (Ym1, Fizz1, and Arg1) to assess macrophage polarization. Treatment with XBJ lowered M1 associated cytokine levels and increased the level of M2 associated cytokine level. The percentage of M2 phenotype cells of XBJ group was much higher than that of the control group. Expressions of phosphorylated Janus kinase 1 (JAK1) and signal transducer and activator of transcription 6 (STAT6) were markedly enhanced after the administration of XBJ; on the other hand, the M2 associated cytokines and proteins were decreased following treatment with JAK1 or STAT6 inhibitor. In addition, the treatment of XBJ significantly improved the survival rate of septic mice. These studies demonstrate that XBJ can markedly promote M2 polarization and improve the survival rate of septic mice, thereby contributing to therapeutic effect in the treatment of septic complications. PMID- 26064162 TI - A New Strategy Using Rikkunshito to Treat Anorexia and Gastrointestinal Dysfunction. AB - Because the clinical condition of gastrointestinal dysfunction, including functional dyspepsia, involves tangled combinations of pathologies, there are some cases of insufficient curative efficacy. Thus, traditional herbal medicines (Kampo medicines) uniquely developed in Japan are thought to contribute to medical treatment for upper gastrointestinal symptoms. Rikkunshito is a Kampo medicine often used to treat dyspeptic symptoms. Over the past few years, several studies have investigated the efficacy of rikkunshito for dysmotility, for example, upper abdominal complaints, in animals and humans. Rikkunshito ameliorated the decrease in gastric motility and anorexia in cisplatin-treated rats, stress-loaded mice, and selective serotonin reuptake inhibitor-treated rats by enhancing plasma ghrelin levels via serotonin2B/2C receptor antagonism. In addition, rikkunshito ameliorated the decrease in food intake in aged mice and stress-loaded decreased gastric motility via enhanced ghrelin receptor signaling. Several clinical studies revealed that rikkunshito was effective in ameliorating upper gastrointestinal symptoms, including dyspepsia, epigastric pain, and postprandial fullness. In this review, we discuss these studies and propose additional evidence-based research that may promote the clinical use of Kampo medicines, particularly rikkunshito, for treating anorexia and gastrointestinal dysfunction. PMID- 26064163 TI - Complementary and Alternative Therapies for Chronic Constipation. AB - Chronic constipation, an ancient disease, is prevalent, and costly in the general population. Complementary and alternative therapies are frequently used for constipation. This review introduces various methods of complementary and alternative therapies, including acupuncture, moxibustion, massage, and herbal medicine. Efficacy, safety, influence factors, sham control design, and mechanisms of these therapies are discussed and evaluated. Acupuncture or electroacupuncture was found to be most commonly used for constipation among these complementary and alternative therapies, followed by herbal medicine. Although only a small number of clinical studies are flawless, our review of the literature seems to suggest that acupuncture or electroacupuncture and herbal medicine are effective in treating constipation, whereas findings on massage and moxibustion are inconclusive. More well-designed clinical trials are needed to improve and prove the efficacy of the complementary and alternative therapies for constipation; mechanistic studies that would lead to wide spread use and improvement of the methods are also discussed in this review. PMID- 26064164 TI - Irritable Bowel Syndrome: Yoga as Remedial Therapy. AB - Irritable bowel syndrome (IBS) is a group of symptoms manifesting as a functional gastrointestinal (GI) disorder in which patients experience abdominal pain, discomfort, and bloating that is often relieved with defecation. IBS is often associated with a host of secondary comorbidities such as anxiety, depression, headaches, and fatigue. In this review, we examined the basic principles of Pancha Kosha (five sheaths of human existence) concept from an Indian scripture Taittiriya Upanishad and the pathophysiology of a disease from the Yoga approach, Yoga Vasistha's Adhi (originated from mind) and Vyadhi (ailment/disease) concept. An analogy between the age old, the most profound concept of Adhi-Vyadhi, and modern scientific stress-induced dysregulation of brain-gut axis, as it relates to IBS that could pave way for impacting IBS, is emphasized. Based on these perspectives, a plausible Yoga module as a remedial therapy is provided to better manage the primary and secondary symptoms of IBS. PMID- 26064165 TI - Myelinated Afferents Are Involved in Pathology of the Spontaneous Electrical Activity and Mechanical Hyperalgesia of Myofascial Trigger Spots in Rats. AB - Myofascial trigger points (MTrPs) are common causes for chronic pain. Myelinated afferents were considered to be related with muscular pain, and our clinical researches indicated they might participate in the pathology of MTrPs. Here, we applied myofascial trigger spots (MTrSs, equal to MTrPs in human) of rats to further investigate role of myelinated afferents. Modified pyridine-silver staining revealed more nerve endings at MTrSs than non-MTrSs (P < 0.01), and immunohistochemistry with Neurofilament 200 indicated more myelinated afferents existed in MTrSs (P < 0.01). Spontaneous electrical activity (SEA) recordings at MTrSs showed that specific block of myelinated afferents in sciatic nerve with tetrodotoxin (TTX) led to significantly decreased SEA (P < 0.05). Behavioral assessment showed that mechanical pain thresholds (MPTs) of MTrSs were lower than those of non-MTrSs (P < 0.01). Block of myelinated afferents by intramuscular TTX injection increased MPTs of MTrSs significantly (P < 0.01), while MPTs of non MTrSs first decreased (P < 0.05) and then increased (P > 0.05). 30 min after the injection, MPTs at MTrSs were significantly lower than those of non-MTrSs (P < 0.01). Therefore, we concluded that proliferated myelinated afferents existed at MTrSs, which were closely related to pathology of SEA and mechanical hyperalgesia of MTrSs. PMID- 26064166 TI - The Effects of Acupuncture at Real or Sham Acupoints on the Intrinsic Brain Activity in Mild Cognitive Impairment Patients. AB - Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network in mild cognitive impairment (MCI) and Alzheimer's disease (AD) patients. Acupuncture at different acupoints could exert different modulatory effects on the brain network. However, whether acupuncture at real or sham acupoints can produce different effects on the brain network in MCI or AD patients remains unclear. Using resting-state fMRI, we reported that acupuncture at Taixi (KI3) induced amplitude of low-frequency fluctuation (ALFF) change of different brain regions in MCI patients from those shown in the healthy controls. In MCI patients, acupuncture at KI3 increased or decreased ALFF in the different regions from those activated by acupuncture in the healthy controls. Acupuncture at the sham acupoint in MCI patients activated the different brain regions from those in healthy controls. Therefore, we concluded that acupuncture displays more significant effect on neuronal activities of the above brain regions in MCI patients than that in healthy controls. Acupuncture at KI3 exhibits different effects on the neuronal activities of the brain regions from acupuncture at sham acupoint, although the difference is only shown at several regions due to the close distance between the above points. PMID- 26064168 TI - A Pilot Study: Warm Stimulation on Guangming (GB37) to Relief Asthenopia. AB - Infrared thermometry was performed in 15 female asthenopia patients (average +/- SD: 54.88 +/- 7.30 years) prior to, during, and after stimulation using electrothermal Bian-stone at the Guangming (GB37) acupoints. The results of this controlled pilot study (control points at the Yongquan (KI1) and Tianshu (ST25) points) showed significant (P <= 0.05) increases in eyes' temperature. At the same time, no changes were found at the control points. Furthermore, after warm stimulation on Guangming (GB37) acupoints, the clinical symptoms were getting better than the control points. The symptoms' score was decreased significantly too (P <= 0.05). It was demonstrated that there is some relationship between Guangming (GB37) point and eyes, and warm stimulation on Guangming (GB37) could relief uncomfortable of asthenopia. PMID- 26064167 TI - Inhibition of Tumor Growth and Immunomodulatory Effects of Flavonoids and Scutebarbatines of Scutellaria barbata D. Don in Lewis-Bearing C57BL/6 Mice. AB - Immunomodulatory effect has been found to be an important therapeutic measure for immune responses against cancer. In this study, we evaluated the inhibition of Scutellaria barbata D. Don (SB), an anti-inflammatory and an antitumor Chinese herb, including flavonoids and scutebarbatines on tumor growth and its immunomodulatory effects in vivo. HPLC and LC/MS/MS methods were conducted for the analysis of flavonoids and scutebarbatines in SB. Lewis-bearing C57BL/6 mice model was established and tumor volume was evaluated by high frequency color ultrasound experiment. ELISA and western blot analysis were performed for the determination of immunomodulatory factors. SB treatment at the dose of 10, 6.67, and 3.33 g crude drug/kg/d significantly inhibited tumor growth of Lewis-bearing C57BL/6 mice with the inhibition rates of 44.41 +/- 5.44%, 33.56 +/- 4.85%, and 27.57 +/- 4.96%, respectively. More importantly, the spleen and thymus indexes were increased remarkably by SB treatment. SB could decrease IL-17, IL-10, FOXP3, TGF-beta1, RORgammat, and IL-6 levels whereas it could increase remarkably IL-2 and IFN-gamma levels. Our results demonstrated that SB could inhibit tumor growth in vivo through regulating immune function in tumor-bearing mice and suggested that the immunomodulatory function of SB had a potential therapeutic effect in lung cancer. PMID- 26064169 TI - The Effectiveness of Electroacupuncture for Functional Constipation: A Randomized, Controlled, Clinical Trial. AB - Background. Electroacupuncture (EA) has been reported to treat functional constipation (FC). The aim of this study was to investigate the efficacy and safety of EA with different needle insertion method for FC. Methods. Sixty-seven participants were randomly assigned to control (EA with shallow puncture) and EA (with deep puncture) groups. Every patient received 5 treatments per week in the first two weeks, then 3 treatments per week during the following six weeks. Complete spontaneous bowel movements (CSBM), spontaneous bowel movements (SBM), Bristol stool scores (BSS), and Patient Assessment of Constipation Quality of Life (PAC-QOL) were assessed. Results. Both shallow and deep EA significantly increased CSBM frequency compared to the baseline. CSBM was increased from 0.50 +/- 0.59/wk to 2.00 +/- 1.67/wk with deep EA and from 0.48 +/- 0.59/wk to 1.33 +/ 1.09/wk with shallow EA (P < 0.05, resp.). Similar finding was noted in SBM. Deep EA was more potent than shallow EA (P < 0.05) during the treatment period. No difference was found on BSS and PAC-QOL between two groups. Conclusion. It is effective and safe with EA to treat FC. Studies with large sample size and long term observation are needed for further investigation. PMID- 26064170 TI - Curcumin Pharmacokinetic and Pharmacodynamic Evidences in Streptozotocin-Diabetic Rats Support the Antidiabetic Activity to Be via Metabolite(s). AB - This study measures the curcumin concentration in rat plasma by liquid chromatography and investigates the changes in the glucose tolerance and insulin sensitivity of streptozotocin-diabetic rats treated with curcumin-enriched yoghurt. The analytical method for curcumin detection was linear from 10 to 500 ng/mL. The C max? and the time to reach C max? (t max?) of curcumin in plasma were 3.14 +/- 0.9 MUg/mL and 5 minutes (10 mg/kg, i.v.) and 0.06 +/- 0.01 MUg/mL and 14 minutes (500 mg/kg, p.o.). The elimination half-time was 8.64 +/- 2.31 (i.v.) and 32.70 +/- 12.92 (p.o.) minutes. The oral bioavailability was about 0.47%. Changes in the glucose tolerance and insulin sensitivity were investigated in four groups: normal and diabetic rats treated with yoghurt (NYOG and DYOG, resp.) and treated with 90 mg/kg/day curcumin incorporated in yoghurt (NC90 and DC90, resp.). After 15 days of treatment, the glucose tolerance and the insulin sensitivity were significantly improved in DC90 rats in comparison with DYOG, which can be associated with an increase in the AKT phosphorylation levels and GLUT4 translocation in skeletal muscles. These findings can explain, at least in part, the benefits of curcumin-enriched yoghurt to diabetes and substantiate evidences for the curcumin metabolite(s) as being responsible for the antidiabetic activity. PMID- 26064171 TI - Therapeutic Effects of Oligonol, Acupuncture, and Quantum Light Therapy in Chronic Nonbacterial Prostatitis. AB - This research aimed to compare anti-inflammatory effects of oligonol, acupuncture, and quantum light therapy in rat models of estrogen-induced prostatitis. Adult male Wistar albino rats were grouped as follows: Group I, control (n = 10); Group II, chronic prostatitis (n = 10); Group III, oligonol (n = 10); Group IV, acupuncture (n = 10); Group V, quantum (n = 10); Group VI, oligonol plus quantum (n = 10); Group VII, acupuncture plus oligonol (n = 10); Group VIII, quantum plus acupuncture (n = 10); and Group IX, acupuncture plus quantum plus oligonol (n = 10). Chronic prostatitis (CP) was induced by the administration of 17-beta-estradiol (E2) and dihydrotestosterone (DHT). Oligonol was given for 6 weeks at a dose of 60 mg/day. Acupuncture needles were inserted at CV 3/4 and bilaterally B 32/35 points with 1-hour manual stimulation. Quantum therapy was administered in 5-minute sessions three times weekly for 6 weeks. Lateral lobes of prostates were dissected for histopathologic evaluation. Although all of the treatment modalities tested in this study showed anti inflammatory effects in the treatment of CP in male rats, a synergistic effect was observed for oligonol plus quantum light combination. Monotherapy with oligonol showed a superior anti-inflammatory efficacy as compared to quantum light and acupuncture monotherapies. PMID- 26064172 TI - Trigger Point Dry Needling and Proprioceptive Exercises for the Management of Chronic Ankle Instability: A Randomized Clinical Trial. AB - Objective. To compare the effects of combined trigger point dry needling (TrP-DN) and proprioceptive/strengthening exercises to proprioceptive/strengthening exercises on pain and function in ankle instability. Methods. Twenty-seven (44% female, mean age: 33 +/- 3 years) individuals with unilateral ankle instability were randomly assigned to an experimental group who received proprioceptive/strengthening exercises combined with TrP-DN into the lateral peroneus muscle and a comparison group receiving the same proprioceptive/strengthening exercise program alone. Outcome included function assessed with the Foot and Ankle Ability Measure (FAAM) and ankle pain intensity assessed with a numerical pain rate scale (NPRS). They were captured at baseline and 1-month follow-up after the intervention. Results. The ANOVAs found significant Group * Time Interactions for both subscales of the FAAM (ADL: F = 8.211; P = 0.008; SPORTS: F = 13.943; P < 0.001) and for pain (F = 44.420; P < 0.001): patients receiving TrP-DN plus proprioceptive/strengthening exercises experienced greater improvements in function and pain than those receiving the exercise program alone. Between-groups effect sizes were large in all outcomes (SMD > 2.1) in favor of the TrP-DN group. Conclusions. This study provides evidence that the inclusion of TrP-DN within the lateral peroneus muscle into a proprioceptive/strengthening exercise program resulted in better outcomes in pain and function 1 month after the therapy in ankle instability. PMID- 26064173 TI - Antiperoxidative Activity of Tetracarpidium conophorum Leaf Extract in Reproductive Organs of Male Rats. AB - Tetracarpidium conophorum (Mull. Arg.) Hutch. & Dalz is one of the many medicinal plants used in folklore as male fertility enhancers. This research was aimed at evaluating the anti-peroxidative activity of the leaves of this plant by determining their capacity to reduce malondialdehyde (MDA) level in reproductive organs and accessory glands of rats. Adult male rats were administered orally with the aqueous leaf extract from T. conophorum at 50, 500 and 1000 mg/kg body weight for 21 consecutive days while clomiphene citrate (1.04 mg/kg body weight), a fertility drug was used as standard. The results of the study indicated that there was increase in relative organ weight, body weight, mean total food and water consumed by the treated groups. Testicular MDA level was highly significantly different from that of the control (p < 0.0001) although a tentatively decreased MDA level was observed. However, MDA levels in the reproductive accessory glands, epididymis, seminal vesicle and prostate gland were insignificantly (p < 0.05) lower than those of controls. The highest percentage decrease of MDA level (66.35, 42.68, 62.50 and 63.36%) was observed at the highest concentration of the extract (1000 mg/kg) in the testis, epididymis, seminal vesicle and prostate gland respectively. These values were two-fold greater than the values obtained for the standard drug. Interestingly, the treatment of rats with the extract significantly increased the activities of superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), glutathione-S transferase (GST) and the levels of GSH, vitamin C and total protein. Collectively, the results suggest that the extract from T. conophorum leaves had greater capacity to reduce lipid peroxidation in reproductive organs and accessory glands and thus, this plant may be useful in the treatment/management of reproductive cellular damage involving reactive oxygen species. PMID- 26064174 TI - Efficacy and Cost Effectiveness of the Acupuncture Treatment Using a New Skin Stimulus Tool Called M-Test Which Is a Measure Based on Symptoms Accompanied with Body Movements: A Pragmatic RCT Targeting Hemodialysis Patients. AB - M-Test can simultaneously reduce hemodialysis patients' diverse symptoms. Its diagnosis and treatment are based on simple movements that can be performed by anyone and allow determining which meridians have problems by analyzing symptoms accompanied with movement. It also enables to conduct a safe and effective treatment with use of microcorn which is a noninvasive treatment tool. This time we conducted microcorn intervention on hemodialysis patients based on diagnosis of M-Test. As a result, almost all of the dialysis patients' complaints have been relieved while the score of HR-QOL increased. According to our calculation of cost effectiveness, it confirmed that it is very cost-effective. PMID- 26064175 TI - The Lyophilization Process Maintains the Chemical and Biological Characteristics of Royal Jelly. AB - The alternative use of natural products, like royal jelly (RJ), may be an important tool for the treatment of infections caused by antibiotic-resistant bacteria. RJ presents a large number of bioactive substances, including antimicrobial compounds. In this study, we carried out the chemical characterization of fresh and lyophilized RJ and investigated their antibacterial effects with the purpose of evaluating if the lyophilization process maintains the chemical and antibacterial properties of RJ. Furthermore, we evaluated the antibacterial efficacy of the main fatty acid found in RJ, the 10-hydroxy-2 decenoic acid (10H2DA). Chromatographic profile of the RJ samples showed similar fingerprints and the presence of 10H2DA in both samples. Furthermore, fresh and lyophilized RJ were effective against all bacteria evaluated; that is, the lyophilization process maintains the antibacterial activity of RJ and the chemical field of 10H2DA. The fatty acid 10H2DA exhibited a good antibacterial activity against Streptococcus pneumoniae. Therefore, it may be used as an alternative and complementary treatment for infections caused by antibiotic resistant S. pneumoniae. PMID- 26064176 TI - Downregulation of Spinal G Protein-Coupled Kinase 2 Abolished the Antiallodynic Effect of Electroacupuncture. AB - Acupuncture or electroacupuncture (EA) has been demonstrated to have a powerful antihypernociceptive effect on inflammatory pain. The attenuation of G protein coupled receptor kinase 2 (GRK2) in spinal cord and peripheral nociceptor has been widely acknowledged to promote the transition from acute to chronic pain and to facilitate the nociceptive progress. This study was designed to investigate the possible role of spinal GRK2 in EA antiallodynic in a rat model with complete Freund's adjuvant (CFA) induced inflammatory pain. EA was applied to ST36 ("Zusanli") and BL60 ("Kunlun") one day after CFA injection. Single EA treatment at day 1 after CFA injection remarkably alleviated CFA induced mechanical allodynia two hours after EA. Repeated EA displayed significant antiallodynic effect from 2nd EA treatment and a persistent effect was observed during the rest of treatments. However, downregulation of spinal GRK2 by intrathecal exposure of GRK2 antisense 30 mins after EA treatment completely eliminated both the transient and persistent antiallodynic effect by EA treatment. These pieces of data demonstrated that the spinal GRK2 played an important role in EA antiallodynia on inflammatory pain. PMID- 26064177 TI - Laughter and Stress Relief in Cancer Patients: A Pilot Study. AB - The purpose of this study was to examine the effect of a therapeutic laughter program and the number of program sessions on anxiety, depression, and stress in breast cancer patients. A randomized controlled trial was conducted involving 31 patients who received four sessions of therapeutic laughter program comprised and 29 who were assigned to the no-program control group. Scores for anxiety, depression, and stress were measured using an 11-point numerical rating scale. While no change was detected in the control group, the program group reported reductions of 1.94, 1.84, and 2.06 points for anxiety, depression, and stress, respectively (p < 0.01, p < 0.01, and p < 0.01). Scores decreased significantly after the first therapeutic laughter session (p < 0.05, p < 0.01, and p < 0.01). As the therapeutic laughter program was effective after only a single session in reducing anxiety, depression, and stress in breast cancer patients, it could be recommended as a first-line complementary/alternative therapy. PMID- 26064178 TI - Efficacy of Adaptive Biofeedback Training in Treating Constipation-Related Symptoms. AB - Biofeedback therapy is a well-known and effective therapeutic treatment for constipation. A previous study suggested that adaptive biofeedback (ABF) training was more effective than traditional (fixed training parameters) biofeedback training. The aim of this study was to verify the effectiveness of ABF in relieving constipation-related symptoms. We noticed that in traditional biofeedback training, a patient usually receives the training twice per week. The long training sessions usually led to poor compliance. This study proposes an intensive biofeedback therapy and compares intensive therapy with nonintensive therapy in patients with constipation-related symptoms. Methods. 63 patients with constipation-related symptoms were treated with ABF between 2012 and 2013. These patients were further divided into the intensive therapy and nonintensive therapy groups. Results. A total of 63 patients were enrolled in the study, including 24 in the nonintensive therapy group and 39 in the intensive therapy group. 100% (N = 21) of constipation patients achieved the primary efficacy endpoint (>=3 bowel movements/week). There was significant improvement in constipation-related symptoms after adaptive biofeedback. The intensive biofeedback therapy did not show better performance compared to nonintensive biofeedback therapy. Conclusions. This investigation provides support for the efficacy of biofeedback for constipation-related symptoms. The efficacy of intensive therapy is similar to nonintensive therapy. PMID- 26064180 TI - Inflamed macrophage microvesicles induce insulin resistance in human adipocytes. AB - BACKGROUND: Cytokines secreted by adipose tissue macrophages (ATMs) significantly alter adipocyte function, inducing inflammatory responses and decreasing insulin sensitivity. However, little relevant information is available regarding the role of microvesicles (MVs) derived from ATMs in macrophage-adipocyte crosstalk. METHODS: MVs were generated by stimulation of M1 or M2 phenotype THP-1 macrophages and incubated with human primary mature adipocytes and differentiated adipocytes. Subsequently, insulin-stimulated phosphorylation of Akt (pAkt) and glucose uptake were determined. Glucose transporter 4 (GLUT4) translocation and nuclear translocation of nuclear factor (NF)-kappa B were also analyzed in treated adipocytes. RESULTS: M1 macrophage-derived MVs (M1 MVs) significantly reduced protein abundance of insulin-induced Akt phosphorylation in human primary mature adipocytes and differentiated adipocytes, when compared with the same concentration of M2 macrophage-derived MVs (M2 MVs). In contrast to M2 MVs, which enhanced the insulin-induced glucose uptake measured by 2-NBDG, M1 MVs decreased this effect in treated adipocytes. M1 MVs treatment also brought about a significant increase in the nuclear translocation of nuclear factor (NF)-kappa B, coupled with a decrease in pAkt level and GLUT4 translocation compared with M2 MVs-treated adipocytes. These effects were reversed by BAY 11-7085, a NF- kappa B specific inhibitor. CONCLUSIONS: MVs derived from proinflammatory (M1) macrophages may, at least in part, contribute to the pathogenesis of obesity induced insulin resistance, reducing insulin signal transduction and decreasing glucose uptake in human adipocytes, through NF-kappa B activation. Therefore, these MVs may be potential therapy candidates for the management of type 2 diabetes mellitus. PMID- 26064179 TI - A novel anti-inflammatory natural product from Sphaeranthus indicus inhibits expression of VCAM1 and ICAM1, and slows atherosclerosis progression independent of lipid changes. AB - A large body of evidence suggests that atherosclerosis is an inflammatory disease, in which cytokines and growth factors play a major role in disease progression. The methanolic extracts of Sphaeranthus indicus as well as its active ingredient, 7-hydroxy frullanoide (7-HF), are shown to suppress LPS induced cytokine production from mononuclear cells, and inhibit the expression of VCAM1, ICAM1 and E-selectin by TNF-alpha- stimulated HUVECs in a concentration dependent manner. We tested the hypothesis that the inhibition of cytokines and adhesion molecules should attenuate the progression of atherosclerosis, independent of changes in the lipid profile. Studies were carried out in two animal models: a high fat-fed LDLr(-/-) mouse and a high fat-fed hyperlipidemic hamster. Methanolic extract of S. indicus was dosed to hyperlipidemic LDLr(-/-) at 100 and 300 mg (equivalent to 20 and 60 mg 7-HF)/kg body weight/ day for 8 weeks, and plasma lipids as well as aortic lesion area were quantitated. Hyperlipidemic hamsters were treated with one dose of 200 mg/kg/day. S. indicus extract treatment did not alter the lipid profile in both animal models, but reduced aortic lesion area in LDLr(-/-) mice and hyperlipidemic hamsters by 22 % and 45 %, respectively. Fenofibrate, included as a reference agent, decreased aortic lesions by 26 % in LDLr (-/-) mice and 84 % in hyperlipidemic hamsters, respectively, which was driven by massive reductions in proatherogenic lipoproteins. The lipid-independent anti-atherosclerotic activity of S. indicus was associated with the reductions in the circulating levels of MCP-1, TNF-alpha, and IL-6 via phosphorylation and degradation of IkB-alpha that prevents translocation of NF-kB in the nucleus to induce proinflammatory cytokines. Our findings demonstrate that anti-inflammatory agents that lower pro-inflammatory proteins inhibit the progression of atherosclerosis. The methanolic extract of S. inducus, currently being used to treat psoriasis, offer promise to benefit individuals who have high circulating pro-inflammatory cytokines, and predisposed to coronary artery disease. PMID- 26064181 TI - A 2D Markerless Gait Analysis Methodology: Validation on Healthy Subjects. AB - A 2D markerless technique is proposed to perform lower limb sagittal plane kinematic analysis using a single video camera. A subject-specific, multisegmental model of the lower limb was calibrated with the subject in an upright standing position. Ankle socks and underwear garments were used to track the feet and pelvis segments, whereas shank and thigh segments were tracked by means of reference points identified on the model. The method was validated against a marker based clinical gait model. The accuracy of the spatiotemporal parameters estimation was found suitable for clinical use (errors between 1% and 3% of the corresponding true values). Comparison analysis of the kinematics patterns obtained with the two systems revealed high correlation for all the joints (0.82 < R(2) < 0.99). Differences between the joint kinematics estimates ranged from 3.9 deg to 6.1 deg for the hip, from 2.7 deg to 4.4 deg for the knee, and from 3.0 deg to 4.7 deg for the ankle. The proposed technique allows a quantitative assessment of the lower limb motion in the sagittal plane, simplifying the experimental setup and reducing the cost with respect to traditional marker based gait analysis protocols. PMID- 26064182 TI - The Multivariate Largest Lyapunov Exponent as an Age-Related Metric of Quiet Standing Balance. AB - The largest Lyapunov exponent has been researched as a metric of the balance ability during human quiet standing. However, the sensitivity and accuracy of this measurement method are not good enough for clinical use. The present research proposes a metric of the human body's standing balance ability based on the multivariate largest Lyapunov exponent which can quantify the human standing balance. The dynamic multivariate time series of ankle, knee, and hip were measured by multiple electrical goniometers. Thirty-six normal people of different ages participated in the test. With acquired data, the multivariate largest Lyapunov exponent was calculated. Finally, the results of the proposed approach were analysed and compared with the traditional method, for which the largest Lyapunov exponent and power spectral density from the centre of pressure were also calculated. The following conclusions can be obtained. The multivariate largest Lyapunov exponent has a higher degree of differentiation in differentiating balance in eyes-closed conditions. The MLLE value reflects the overall coordination between multisegment movements. Individuals of different ages can be distinguished by their MLLE values. The standing stability of human is reduced with the increment of age. PMID- 26064183 TI - The Parametric Model of the Human Mandible Coronoid Process Created by Method of Anatomical Features. AB - Geometrically accurate and anatomically correct 3D models of the human bones are of great importance for medical research and practice in orthopedics and surgery. These geometrical models can be created by the use of techniques which can be based on input geometrical data acquired from volumetric methods of scanning (e.g., Computed Tomography (CT)) or on the 2D images (e.g., X-ray). Geometrical models of human bones created in such way can be applied for education of medical practitioners, preoperative planning, etc. In cases when geometrical data about the human bone is incomplete (e.g., fractures), it may be necessary to create its complete geometrical model. The possible solution for this problem is the application of parametric models. The geometry of these models can be changed and adapted to the specific patient based on the values of parameters acquired from medical images (e.g., X-ray). In this paper, Method of Anatomical Features (MAF) which enables creation of geometrically precise and anatomically accurate geometrical models of the human bones is implemented for the creation of the parametric model of the Human Mandible Coronoid Process (HMCP). The obtained results about geometrical accuracy of the model are quite satisfactory, as it is stated by the medical practitioners and confirmed in the literature. PMID- 26064184 TI - Structural, Dynamical, and Energetical Consequences of Rett Syndrome Mutation R133C in MeCP2. AB - Rett Syndrome (RTT) is a progressive neurodevelopmental disease affecting females. RTT is caused by mutations in the MECP2 gene and various amino acid substitutions have been identified clinically in different domains of the multifunctional MeCP2 protein encoded by this gene. The R133C variant in the methylated-CpG-binding domain (MBD) of MeCP2 is the second most common disease causing mutation in the MBD. Comparative molecular dynamics simulations of R133C mutant and wild-type MBD have been performed to understand the impact of the mutation on structure, dynamics, and interactions of the protein and subsequently understand the disease mechanism. Two salt bridges within the protein and two critical hydrogen bonds between the protein and DNA are lost upon the R133C mutation. The mutation was found to weaken the interaction with DNA and also cause loss of helicity within the 141-144 region. The structural, dynamical, and energetical consequences of R133C mutation were investigated in detail at the atomic resolution. Several important implications of this have been shown regarding protein stability and hydration dynamics as well as its interaction with DNA. The results are in agreement with previous experimental studies and further provide atomic level understanding of the molecular origin of RTT associated with R133C variant. PMID- 26064185 TI - Segmentation of Bone with Region Based Active Contour Model in PD Weighted MR Images of Shoulder. AB - Proton density (PD) weighted MR images present inhomogeneity problem, low signal to noise ratio (SNR) and cannot define bone borders clearly. Segmentation of PD weighted images is hampered with these properties of PD weighted images which even limit the visual inspection. The purpose of this study is to determine the effectiveness of segmentation of humeral head from axial PD MR images with active contour without edge (ACWE) model. We included 219 images from our original data set. We extended the use of speckle reducing anisotropic diffusion (SRAD) in PD MR images by estimation of standard deviation of noise (SDN) from ROI. To overcome the problem of initialization of the initial contour of these region based methods, the location of the initial contour was automatically determined with use of circular Hough transform. For comparison, signed pressure force (SPF), fuzzy C-means, and Gaussian mixture models were applied and segmentation results of all four methods were also compared with the manual segmentation results of an expert. Experimental results on our own database show promising results. This is the first study in the literature to segment normal and pathological humeral heads from PD weighted MR images. PMID- 26064186 TI - Solitary scalp metastasis - a rare presentation of hepatocellular carcinoma. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is among the commonest cancers in the world. Metastasis is one of the most significant factors affecting prognosis. Common sites of extrahepatic metastases include lungs, regional lymph nodes and less commonly bone. CASE PRESENTATION: A 56-year-old male presented with a painless occipital scalp lump of three months duration, with recent rapid enlargement. His skull x-ray showed a lytic lesion over occipital bone and the contrast CT scan of the brain showed a scalp mass with destruction of the adjacent skull. Core biopsy of the lesion revealed a metastatic deposit from a hepatocellular carcinoma. CONCLUSION: Primary presentation with skeletal metastases are rare in HCC with only a few reported cases. Here we report a case of HCC presenting as a solitary scalp lump. PMID- 26064187 TI - Novel enaminone derived from thieno [2,3-b] thiene: Synthesis, x-ray crystal structure, HOMO, LUMO, NBO analyses and biological activity. AB - BACKGROUND: Due to their structural and therapeutic diversity, thienothiophene derivatives have attracted much synthetic interest because of their reactivity and biological activity. The thieno [2,3-b] thiophene moiety has been used in the design of a novel pharmaceutical therapies. Additionally, its enaminones derivatives are versatile synthons and have a lot of synthetic applications such as N-heterocycles, wide variety of naturally occurring alkaloids and pharmaceutical drugs. RESULTS: Synthesis of (2E,2'E)-1,1'-(3,4-diphenylthieno [2,3-b] thiophene-2,5-diyl) bis (3-(dimethylamino) prop-2-en-1-one) 5 was reported. The structure of compound 5 was deduced by spectroscopic techniques. The compound was crystallizes in the monoclinic system with space group P-1 with cell coordinates a=9.9685 (8) A, b=10.1382 (8) A, c=13.3220 (11) A, alpha=101.018 (2) degrees , beta=94.480 (2) degrees , gamma=107.207 (1) degrees , V=1249.3 (1) A3, and Z=2. In the crystal molecules are packed in chains formed via weak intermolecular C21-H21A... O1, C22-H22A...O2 and C27-H27A...O2 hydrogen bondings. Theoretical quantum chemical calculations have been performed on the studied compound using the DFT B3LYP/6-311G (d, p) method. The geometric parameters of the optimized structure are in good agreement with the experimental data obtained from our reported X-ray structure. The two benzene rings and the two side chains are not coplanar with the fused thiophene rings. The electronic spectra of the studied compound have been calculated using the TD-DFT method at the same level of theory. The transition bands at 352.9 nm (f=0.5549) and 332.1 nm (f=0.2190) are due to the H-1 -> L (72%) and H -> L + 1 (82%) excitations respectively. The NBO calculations were performed to predict the natural atomic charges at the different atomic sites and to study the different intramolecular charge transfer (ICT) interactions occurring in the studied system. It is found that the O and N atoms have the highest negative charge densities while the S-atoms are the most electropositive. These results give idea about how our molecule could react with the receptor active sites. Compound 5 was evaluated against ant-microbial activity. CONCLUSIONS: Synthesis, molecular structure and spectroscopic invesitgation of (2E,2'E)-1,1'-(3,4-diphenylthieno [2,3-b] thiophene-2,5-diyl) bis (3- (dimethylamino) prop-2-en-1-one) 5 was studied. Graphical AbstractMolecular structure investigation of novel enaminone derived from thieno [2,3-b] thiene. PMID- 26064188 TI - Synthesis, anticholinesterase and antioxidant potentials of ketoesters derivatives of succinimides: a possible role in the management of Alzheimer's. AB - BACKGROUND: Based on the pharmacological potency and structural features of succinimides, this study was designed to synthesize new ketoesters derivatives of succinimides. Furthermore, the synthesized compounds were evaluated for their possible anticholinesterase and antioxidant potentials. The compounds were synthesized by organocatalytic Michael additions of alpha-ketoesters to N-aryl maleimides. Acetyl and butyrylcholinesterase inhibitory activities were determined using Ellman's spectrophotometric assay. The antioxidant activity was performed with DPPH and ABTS free radicals scavenging assay. RESULTS: The Michael additions of alpha-ketoesters to maleimides was promoted by 8-hydroxyquinoline. The organocatalyst (8-hydroxyquinoline, 20 mol %) produced the compounds in relatively shorter time (20-24 h) and with excellent isolated yields (84-98 %). The synthesized compounds (1-4) showed outstanding acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potentials, i.e., 98.75 and 90.00 % respectively for compound 2, with IC50 < 0.1 MUg/mL. Additionally, compounds 1-4 revealed moderate antioxidant activity at different concentrations. In DPPH free radical scavenging assay, compound 1 showed dominant result with 72.41 +/- 0.45, 52.49 +/- 0.78 and 35.60 +/- 0.75 % inhibition at concentrations of 1000, 500 and 250 MUg/mL respectively, IC50 value of 440 MUg/mL. However, the free radical scavenging was better when used ABTS free radicals. In ABTS free radicals scavenging assay compound 1 exhibited 88.51 +/- 0.62 % inhibition at highest tested concentration i.e., 1000 MUg/mL. CONCLUSIONS: Herein, we have synthesized four ketoesters derivatives of succinimides in a single step reaction and high yields. As a highlight, we have showed a first report on the anticholinesterase and antioxidant potentials of succinimides. All the compounds showed overwhelming enzyme inhibitions and moderate antioxidant potentials. Graphical AbstractGraphical representation of synthesis, anticholinesterase and antioxidant potentials of ketoester derivatives of succinimides. PMID- 26064189 TI - The effect of age on muscle characteristics of the abductor hallucis in people with hallux valgus: a cross-sectional observational study. AB - BACKGROUND: The abductor hallucis muscle plays an important role in maintaining alignment of the first metatarsophalangeal joint. The aims of this study were (1) to determine differences in abductor hallucis muscle characteristics in people with hallux valgus between three age groups (20-44 years, 45-64 years, and 65+ years); and (2) to determine the association between age and abductor hallucis size and quality. METHODS: Characteristics of the abductor hallucis muscle were measured in 96 feet with hallux valgus using musculoskeletal ultrasound. Muscle characteristics included width, thickness, cross-sectional area and echo intensity. A one-way ANCOVA was conducted to compare the mean muscle characteristic values between the three age groups while adjusting for hallux valgus severity as a covariate. A Bonferroni post-hoc was used to adjust for multiple testing (p < 0.0167). Spearman's rho correlation coefficient was used to determine the association between age and the abductor hallucis muscle parameters. RESULTS: There was a significant difference in dorso-plantar thickness (p = 0.003) and cross-sectional area (p = 0.008) between the three age groups. The Bonferroni post hoc analysis revealed a significant difference in mean thickness and mean cross-sectional area between the 20-44 age group (p = 0.003) and the 65+ age group (p = 0.006). No significant differences were noted between the three age groups for medio-lateral width (p > 0.05) or echo-intensity (p > 0.05). Increasing age was significantly associated with a reduction in dorso plantar thickness (r = -0.27, p = 0.008) and cross-sectional area (r = -0.24, p = 0.019) but with small effect sizes. There was no significant correlation between age and medio-lateral width (r = -0.51, p = 0.142) or echo intensity (r =0.138, p =0.179). CONCLUSION: Increasing age is associated with a greater reduction in size of the abductor hallucis muscle in people with hallux valgus. People over the age of 65 years old with hallux valgus display a significant reduction in abductor hallucis muscle size compared to those aged less than 45 years old. This is consistent with age-related changes to skeletal muscle. PMID- 26064190 TI - Diabetic foot: prevalence, knowledge, and foot self-care practices among diabetic patients in Dar es Salaam, Tanzania - a cross-sectional study. AB - BACKGROUND: At the time of diagnosis, more than 10 % of people with type 2 diabetes mellitus have one or two risk factors for a foot ulceration and a lifetime risk of 15 %. Diabetic foot ulcers can be prevented through well coordinated foot care services. The objective of this study was to determine knowledge of foot care and reported practice of foot self-care among diabetic patients with the aim of identifying and addressing barriers to preventing amputations among diabetic patients. METHODS: Patients were randomly selected from all public diabetic clinics in Dar es Salaam. A questionnaire containing knowledge and foot care practice questions was administered to all study participants. A detailed foot examination was performed on all patients, with the results categorized according to the International Diabetes Federation foot risk categories. Statistics were performed using SPSS version 14. RESULTS: Of 404 patients included in this study, 15 % had foot ulcers, 44 % had peripheral neuropathy, and 15 % had peripheral vascular disease. In multivariate analysis, peripheral neuropathy and insulin treatment were significantly associated with presence of foot ulcer. The mean knowledge score was 11.2 +/- 6.4 out of a total possible score of 23. Low mean scores were associated with lack of formal education (8.3 +/- 6.1), diabetes duration of < 5 years (10.2 +/- 6.7) and not receiving advice on foot care (8.0 +/- 6.1). Among the 404 patients, 48 % had received advice on foot care, and 27.5 % had their feet examined by a doctor at least once since their initial diagnosis. Foot self-care was significantly higher in patients who had received advice on foot care and in those whose feet had been examined by a doctor at least once. CONCLUSIONS: The prevalence of diabetic foot is high among patients attending public clinics in Dar es Salaam. There is an urgent need to establish coordinated foot care services within the diabetic clinic to identify feet at risk, institute early management, and provide continuous foot care education to patients and health care providers. PMID- 26064191 TI - A multi-label approach to target prediction taking ligand promiscuity into account. AB - BACKGROUND: According to Cobanoglu et al., it is now widely acknowledged that the single target paradigm (one protein/target, one disease, one drug) that has been the dominant premise in drug development in the recent past is untenable. More often than not, a drug-like compound (ligand) can be promiscuous - it can interact with more than one target protein. In recent years, in in silico target prediction methods the promiscuity issue has generally been approached computationally in three main ways: ligand-based methods; target-protein-based methods; and integrative schemes. In this study we confine attention to ligand based target prediction machine learning approaches, commonly referred to as target-fishing. The target-fishing approaches that are currently ubiquitous in cheminformatics literature can be essentially viewed as single-label multi classification schemes; these approaches inherently bank on the single target paradigm assumption that a ligand can zero in on one single target. In order to address the ligand promiscuity issue, one might be able to cast target-fishing as a multi-label multi-class classification problem. For illustrative and comparison purposes, single-label and multi-label Naive Bayes classification models (denoted here by SMM and MMM, respectively) for target-fishing were implemented. The models were constructed and tested on 65,587 compounds/ligands and 308 targets retrieved from the ChEMBL17 database. RESULTS: On classifying 3,332 test multi label (promiscuous) compounds, SMM and MMM performed differently. At the 0.05 significance level, a Wilcoxon signed rank test performed on the paired target predictions yielded by SMM and MMM for the test ligands gave a p-value < 5.1 * 10(-94) and test statistics value of 6.8 * 10(5), in favour of MMM. The two models performed differently when tested on four datasets comprising single-label (non-promiscuous) compounds; McNemar's test yielded chi (2) values of 15.657, 16.500 and 16.405 (with corresponding p-values of 7.594 * 10(-05), 4.865 * 10( 05) and 5.115 * 10(-05)), respectively, for three test sets, in favour of MMM. The models performed similarly on the fourth set. CONCLUSIONS: The target prediction results obtained in this study indicate that multi-label multi-class approaches are more apt than the ubiquitous single-label multi-class schemes when it comes to the application of ligand-based classifiers to target-fishing. PMID- 26064192 TI - Peripheral and central effects of gamma-secretase inhibition by semagacestat in Alzheimer's disease. AB - INTRODUCTION: The negative efficacy study examining the gamma-secretase inhibitor semagacestat in mild to moderate Alzheimer's disease (AD) included a number of biomarkers of the disease as well as safety outcomes. We analyzed these data to explore relationships between drug exposure and pharmacodynamic effects and to examine the correlations among outcome measures. METHODS: The study was a multicenter, randomized, placebo-controlled trial of two dose regimens of semagacestat and a placebo administered for 18 months to individuals with mild to moderate AD. Changes in measures of central and peripheral drug activity were compared between the three treatment groups using one-way analysis of variance. The relationship between changes in each of the outcome measures and measures of drug exposure and peripheral pharmacodynamic effect were assessed using Spearman's correlation coefficient. RESULTS: Assignment to the active treatment arms was associated with reduction in plasma amyloid-beta (Abeta) peptides, increase in ventricular volume, decrease in cerebrospinal fluid phosphorylated tau (p-tau) and several other laboratory measures and adverse event categories. Within the active arms, exposure to drug, as indicated by area under the concentration curve (AUC) of blood concentration, was associated with reduction in plasma Abeta peptides and a subset of laboratory changes and adverse event rates. Ventricular volume increase, right hippocampal volume loss and gastrointestinal symptoms were related to change in plasma Abeta peptide but not AUC, supporting a link to inhibition of gamma-secretase cleavage of the amyloid precursor protein. Cognitive decline correlated with ventricular expansion and reduction in p-tau. CONCLUSION: These findings may inform future studies of drugs targeting secretases involved in Abeta generation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00594568. Registered 11 January 2008. PMID- 26064193 TI - Deformability-based circulating tumor cell separation with conical-shaped microfilters: Concept, optimization, and design criteria. AB - Circulating tumor cells (CTCs) separation technology has made positive impacts on cancer science in many aspects. The ability of detecting and separating CTCs can play a key role in early cancer detection and treatment. In recent years, there has been growing interest in using deformability-based CTC separation microfilters due to their simplicity and low cost. Most of the previous studies in this area are mainly based on experimental work. Although experimental research provides useful insights in designing CTC separation devices, there is still a lack of design guidelines based on fundamental understandings of the cell separation process in the filters. While experimental efforts face challenges, especially microfabrication difficulties, we adopt numerical simulation here to study conical-shaped microfilters using deformability difference between CTCs and blood cells for the separation process. We use the liquid drop model for modeling a CTC passing through such microfilters. The accuracy of the model in predicting the pressure signature of the system is validated by comparing it with previous experiments. Pressure-deformability analysis of the cell going through the channel is then carried out in detail in order to better understand how a CTC behaves throughout the filtration process. Different system design criteria such as system throughput and unclogging of the system are discussed. Specifically, pressure behavior under different system throughput is analyzed. Regarding the unclogging issue, we define pressure ratio as a key parameter representing the ability to overcome clogging in such CTC separation devices and investigate the effect of conical angle on the optimum pressure ratio. Finally, the effect of unclogging applied pressure on the system performance is examined. Our study provides detailed understandings of the cell separation process and its characteristics, which can be used for developing more efficient CTC separation devices. PMID- 26064194 TI - Jamming and unjamming transition of oil-in-water emulsions under continuous temperature change. AB - To analyze the jamming and unjamming transition of oil-in-water emulsions under continuous temperature change, we simulated an emulsion system whose critical volume fraction was 0.3, which was validated with experimental results under oscillatory shear stress. In addition, we calculated the elastic modulus using the phase lag between strain and stress. Through heating and cooling, the emulsion experienced unjamming and jamming. A phenomenon-which is when the elastic modulus does not reach the expected value at the isothermal system occurred when the emulsion system was cooled. We determined that this phenomenon was caused by the frequency being faster than the relaxation of the deformed droplets. We justified the relation between the frequency and relaxation by simulating the frequency dependency of the difference between the elastic modulus when cooled and the expected value at the same temperature. PMID- 26064195 TI - Flow characterization of electroconvective micromixer with a nanoporous polymer membrane in-situ fabricated using a laser polymerization technique. AB - Electroconvection is known to cause strong convective mixing in a microchannel near a nanoporous membrane or a nanochannel in contact with an electrolyte solution due to the external electric field. This study addresses micromixer behavior subject to electroconvection occurring near a nanoporous membrane in situ fabricated by a laser polymerization technique on a microfluidic chip. We found that the micromixer behavior can be categorized into three regimes. Briefly, the weak electroconvection regime is characterized by weak mixing performance at a low applied voltage and KCl concentration, whereas the strong electroconvection regime has a high mixing performance when the applied voltage and KCl concentration are moderately high. Finally, the incomplete electroconvection regime has an incomplete electric double-layer overlap in the nanopores of the membrane when the electrolyte concentration is very high. The mixing index reached 0.92 in the strong electroconvection regime. The detailed fabrication methods for the micromixer and characterization results are discussed in this paper. PMID- 26064196 TI - Prognostic value of cancer stem cell marker CD133 in ovarian cancer: a meta analysis. AB - OBJECTIVE: To investigate the association between CD133 expression and prognosis and clinicopathological features of ovarian cancer. METHODS: The electronic and manual searches were performed through the database of PubMed Chinese Wanfang databases (up to September 15, 2014) was performed using the following keywords ovarian cancer, CD133, AC133, prominin-1. Meta-analysis was performed by using Review Manager 5.2 and the outcomes included the overall survival and various clinicopathological features. RESULTS: A total of 1051 ovarian cancer patients from 8 studies were included. Meta-analysis showed that overexpression of CD133 was highly correlated with reduced 2-year overall survival (OR = 1.67, 95% CI: 1.06-2.63, P = 0.03, fixed-effect). With respect to clinicopathological features, CD133 level was positively correlated with tumor stage (OR = 0.26, 95% CI: 0.12 0.58, P = 0.001 random-effect). But not correlated with patients' age (OR = 1.12, 95% CI: 0.68-1.86, P = 0.65 fixed-effect), tumor grade (OR = 1.20, 95% CI: 0.06 1.62, P = 0.17 random-effect), histological type (OR = 1.10, 95% CI: 0.82-1.47, P = 0.54 fixed-effect) and response to treatment (OR = 0.84, 95% CI: 0.61-1.16, P = 0.29 fixed-effect). CONCLUSION: On the basis of current retrospective evidence, the present meta-analysis indicated that high level of CD133 expression trends to correlate with a worse prognosis in patients with ovarian cancer. PMID- 26064197 TI - Role of Rho kinase signal pathway in inflammatory bowel disease. AB - Inflammatory Bowel Disease (IBD) is nonspecific inflammation in the intestinal track, including Ulcerative Colitis (UC) and Crohn's disease (CD). The incidence of IBD has increased significantly, with its numerous rising up to five million globally, more than 1,700,000 in China. Pathological character of IBD is the inflammation of intestinal mucosa and intestinal fibrosis. Although the pathogenesis of the disease has not yet been fully clarified, some evidence suggests that excessive intestinal inflammation reaction, intestinal barrier impairment and abnormal immune response can initiate IBD. As research continues, some of them have provided new insights toward understanding of Rho kinase signal pathway function at the occurrence and development of IBD. This review aims to summarize the general principles of Rho kinase signal pathway in the pathological procedure of IBD. PMID- 26064198 TI - Prognostic significance of the neutrophil to lymphocyte ratio in patients with non-small cell lung cancer: a systemic review and meta-analysis. AB - Neutrophil to Lymphocyte Ratio (NLR) was recently demonstrated as a useful index in predicting the prognosis of Non-Small Cell Lung Cancer (NSCLC). Thus, a meta analysis was performed to demonstrate the relationship between NLR and overall survival (OS), progress-free survival (PFS) or disease free survival (DFS) in patients with NSCLC. We searched for relevant literatures in PubMed, EMBASE and Cochrane library and pooled the eligible studies and synthesized hazard ratios (HRs) using Stata 12.0. Final analysis of NSCLC patients from 12 eligible studies was performed. Combined HR suggested that high NLR had an unfavorable effect on patients' OS (n=1700 in 11 studies; HR= 1.43, 95% CI: 1.25-1.64; I^2=80.2%, P<0.01) and PFS (n=664 in 5 studies, HR=1.37, 95% CI: 1.07-1.74; I^2=70.8%, P=0.004). Subgroup analysis based on cutoff shown that, compared with other subgroups, the subgroup with a cutoff of 5 had a significantly poorer survival (HR=1.87, 95% CI 1.49-2.34) with less heterogeneity (I^2=21.3%, P=0.28). However, subgroup analysis based on treatment method indicated that the "surgery" subgroup seemed to have not a significant impact on survival (HR=1.32, 95% CI 0.99-1.77; I^2=80.0%, P=0.063) compared with the chemotherapy subgroup (HR=1.61, 95% CI 1.24 2.10; I^2=82.6%, P<0.01). Additionally, combined odds ratio (OR) suggested high NLR was associated inversely with response to treatment (n = 276 in 2 studies; OR = 1.73, 95% CI: 1.04-2.88; I^2=0%, P=0.40). This study suggests high NLR (especially with a cutoff of 5) seems to be associated with a worse prognosis in patients with NSCLC as well as a worse response to treatments. PMID- 26064199 TI - Association between CTLA-4 exon-1 +49A/G polymorphism and asthma: an updated meta analysis. AB - The results of studies on association between CTLA-4 exon-1 +49A/G (rs231775) polymorphism and susceptibility to asthma are controversial. To derive a more precise estimation of the relationship between the CTLA-4 exon-1 +49A/G polymorphism and asthma, a meta-analysis of 15 published case-control studies was performed. 15 studies meeting our inclusion criteria comprising 4006 asthma cases and 3729 controls were included. The effect summary odds ratio (OR) and 95% confidence intervals were obtained. Publication bias was tested by funnel plot, Egger's test and heterogeneity was assessed. The combined results showed that there were significant differences in genotype distribution between asthma cases and control on the basis of all studies, GG + GA versus AA (OR = 0.76, 95% CI: 0.62-0.93; P = 0.008). When stratifying for the race, the phenomenon was found that asthma cases had a significantly higher frequency of GG/GA versus AA (OR = 0.71; 95% CI: 0.51-0.99; P = 0.04) than control in Caucasian. Stratifying subjects by age indicated an association between CTLA-4 +49 GG + GA genotype and asthma in children (OR = 0.75; 95% CI: 0.62-0.90; P = 0.002), but no association in adults (OR = 0.93; 95% CI: 0.76-1.14; P = 0.48). Furthermore, significant association was observed in atopic asthma under the fixed-effects model (GG + GA vs. AA: P = 0.03, OR = 0.81, 95% CI = 0.67-0.98, P heterogeneity = 0.22). Our meta-analysis results suggest that CTLA-4 exon-1 +49A/G polymorphism might be a risk factor for asthma susceptibility, at least in Caucasian, children, and patients with atopy status. PMID- 26064200 TI - Clinical analysis of pulmonary cryptococcosis in non-HIV patients in south China. AB - AIMS: The aim of this study was to investigate the clinical characteristics of pulmonary cryptococcosis occurring in non-HIV patients, and to develop early diagnosis of pulmonary cryptococcosis in immunocompetent cases as well. METHODS: We retrospectively reviewed the clinical data of 41 non-HIV infected patients with pulmonary cryptococcosis who were admitted to the First Affiliated Hospital of Wenzhou Medical University from January 2006 to April 2014. RESULTS: The study included a total of 41 patients (23 males and 18 females) with mean age of 47 years. 12.19% of patients had a history of direct exposure to pigeon droppings; 31.70% of the patients' working or living environments were potentially contaminated by fungal spores. Almost one-third of the patients involved into the study were asymptomatic. The most common clinical manifestations were cough, expectoration and hemoptysis. The most common radiological manifestation was single node or mass in lung, which was described as untypical. Of all cases, 11 patients were diagnosed by CT-guided percutaneous cutting needle biopsy (PCNB), 5 patients were diagnosed by operation, and Crytococcus spore was found in 7 patients' cerebrospinal fluid. 8 patients' blood Cryptococcus Neoformans capsular polysaccharide antigens latex agglutination tests were positive. 36 patients received antifungal therapy. 5 patients underwent surgical resection. During 6 to 24 months follow-up, 40 cases showed total recovery and 1 cases showed improvement. CONCLUSIONS: Pulmonary cryptococcosis in non-HIV subjects might be related to fungus-contaminated environmental exposure. The great variations and protean manifestations of its clinical features often lead to misdiagnosis. Recognition and invasive examination of non-HIV infected patients' pulmonary cryptococcosis in the early stage may help with improvement of its diagnosis and prognosis. PMID- 26064201 TI - The TP53 codon 72 Pro/Pro genotype may be associated with an increased lung cancer risk in North China: an updated meta-analysis. AB - BACKGROUND: The polymorphism of TP53 codon 72, a transversion of G to C (Arg to Pro), has been demonstrated to be associated with the risk for lung cancer. However, individual studies conducted in Chinese have provided conflicting and inconclusive findings. Thus, we performed a meta-analysis by pooling all currently available case-control studies to estimate the effect of TP53 codon 72 Arg/Pro polymorphism on the development of lung cancer in the Chinese population. MATERIAL/METHODS: Related studies were identified from PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biology Medicine (CBM) till 10 October 2014. Pooled ORs and 95% CIs were used to assess the strength of the associations. RESULTS: A total of 12 case-control studies including 3681 lung cancer cases and 4358 controls were involved in this meta-analysis. Overall, no significant association was found between TP53 codon 72 variation and lung cancer risk when all studies in the Chinese population pooled into this meta-analysis. However, in the subgroup analysis by geographical locations, significantly increased risk was found in the population from North China under all genetic models (Allele model, OR=1.22, 95% CI: 1.04-1.43; Dominant model, OR=1.13, 95% CI: 1.01-1.25; Recessive model, OR=1.41, 95% CI: 1.07-1.87; Homozygous model, OR=1.47, 95% CI: 1.09-1.99; Heterozygous model, OR=1.40, 95% CI: 1.04-1.89). CONCLUSIONS: This meta-analysis provides the evidence that TP53 codon 72 polymorphism may contribute to the lung cancer development in North China and studies with large sample size and gene gene (gene-environment) interactions are warranted to verify this finding. PMID- 26064202 TI - Application of bone marrow mesenchymal stem cells to the treatment of osteonecrosis of the femoral head. AB - Osteonecrosis of the femoral head (ONFH) is a type of common and refractory disease in the orthopedic clinic that is primarily caused by a partial obstruction of the blood supply to the femoral head, resulting in a series of pathological processes. Mesenchymal stem cells (MSCs) comprise a mixture of various stem cells in myeloid tissue with multipotential differentiation capacity. They can differentiate into bone cells under specific conditions and can be used to treat ONFH through cell transplantation. This review summarizes research on MSCs in the field of ONFH in recent years, reveals the inner characteristics of MSCs, describes their potential to treat osteonecrosis disease, and analyzes the existing challenges of using MSCs in clinical applications. PMID- 26064203 TI - FoxM1: a novel tumor biomarker of lung cancer. AB - FoxM1 is a member of the Forkhead box (Fox) family of transcription factors, which is expressed in actively dividing cells and is critical for cell cycle progression. Increased expression of FoxM1 was found in many tumors including non small cell lung cancer (NSCLC). A more recent study showed FoxM1 is associated with poor prognosis of NSCLC patients through promoting tumor metastasis; elucidated FoxM1 could exert a direct effect on the prognosis of NSCLCs patients. In this review, we summarize the role FoxM1 in lung cancer in the hope of providing insights into the utility of FoxM1 as a novel biomarker of lung cancer. PMID- 26064204 TI - Attenuation of EGFL7 inhibits human laryngocarcinoma cells growth and invasion. AB - AIM: To investigate its effect on the proliferation and invasion of laryngeal carcinoma and understand the potential underlying mechanisms to provide new targets for the diagnosis and treatment of recurrent laryngeal cancer metastasis. METHODS: We constructed a lentiviral vector expressing EGFL7 specific shRNA, and introduced it in EGFL7 functions were attenuated by a lentiviral vector harboring shRNA targeting at EGFL7 in laryngeal carcinoma cell line Hep-2. Prolifereation and invasion assays were carried out in vitro. And in vivo tumor burden assay was done in nude mice. RESULTS: The expression of EGFL7 was knocked-down by 80% in hep-2 cells transfected by the lentiviral EGFL7 shRNA vector and EGFL7 gene expression was detected by realtime PCR and Western blotting analysis respectively. The flow cytometric analysis showed that arrested the cell cycle in G1 phase, In tumor burden assay, to parental And vector control cells, the survival rates Of nude mice in EGFL7 shRNA group dropped down from the first day after implantation as indicated by MTT assay (P < 0.05). The formation and growth rate of xenograft tumor in mice transfected with siRNA against Bmi-1 slowed down significantly. CONCLUSION: Attenuation of EGFL7 function significantly suppresses tumor growth and induces apoptosis, both in vitro and in vivo. EGFL7 may be play a key role in invasion and metastasis of Laryngeal squamous cell carcinoma (LSCC), thus would to be a new target for gene therapy in LSCC. PMID- 26064205 TI - Efficacy and safety of secukinumab in the treatment of moderate to severe plaque psoriasis: a meta-analysis of randomized controlled trials. AB - Psoriasis is a chronic inflammatory skin disease with high rate of recurrence. New anti-interleukin-17 (IL-17) and anti-IL17RA biologics are in Phase 3 clinical trials and may prove to be more effective than existing biologic drugs. Now we perform a meta-analysis on efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis. In this meta-analysis, data analysis was performed with the Cochrane Collaboration's RevMan 5.0 software. Eight randomized controlled trials (RCTs) with a total of 3,213 psoriasis cases were included in the meta-analysis. Co-primary endpoints (week 12) were >= 75%/90% improvement in psoriasis area and a score of 0 (clear) or 1 (almost clear) on a 5-point Investigator's Global Assessment scale (IGA mod 2011 0/1) versus placebo [1]. The overall efficacy in the meta-analysis was as follows: PASI 75: for secukinumab 150 mg versus placebo, fixed-effects OR = 49.25, 95% CI: 33.67-72.06, Z = 20.07, P < 0.00001; PASI 90: for secukinumab 150 mg versus placebo, fixed-effects OR = 44.92, 95% CI: 24.72-81.62, Z = 12.49, P < 0.00001; IGA mod 2011 0/1: for secukinumab 150 mg versus placebo, random-effects OR = 22.25, 95% CI: 7.63-64.84, Z = 5.68, P < 0.00001; Compared with placebo, there were no significant adverse effects in the secukinumab groups, demonstrating safety in the treatment of moderate to severe plaque psoriasis. The proportion of patients who achieved 75%, 90% and IGA mod 2011 0/1 reductions respectively was significant in the secukinumab groups, demonstrating a rapid clinical improvement accompanied by a favorable short-term safety profile. PMID- 26064206 TI - Association between ORMDL3 polymorphism and susceptibility to asthma: a meta analysis. AB - The aim of this study was to determine whether orosomucoid1- like 3 (ORMDL3) single nucleotide polymorphisms rs7216389, rs11650680, rs12603332 are associated with susceptibility to asthma. We performed a meta-analysis by searching PubMed, EMBASE, Elsevier and Wanfang Databases. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of associations. We examined the association between the three SNPs and asthma risk in four genetic models (TT + TC vs. CC, TC vs. CC, TT vs. CC, TT vs. TC + CC). Thirteen published case control studies involving 6462 cases and 7357 controls were included. Our meta analysis indicated that rs7216389 was significantly associated with increased asthma risk in overall population. Subgroup analysis by age indicated significant association between the rs7216389 and asthma in children. Moreover, ORMDL3 rs11650680 was significantly associated with decreased asthma risk in dominant model (TT + TC vs. CC), and rs12603332 was significantly associated with decreased asthma risk in 3 models (TT + TC vs. CC, TC vs. CC and TT vs. CC). To Conclude, ORMDL3 rs7216389 polymorphism is associated with susceptibility to asthma. Children with variant T allele (TT or TC) and adults with TT homozygote in rs7216389 are at high risks to suffer from asthma. However, people with T allele in rs11650680 or rs12603332 are protected from asthma. PMID- 26064207 TI - Correlation of increased plasma osteoprotegerin and cardiovascular risk factors in patients with adult growth hormone deficiency. AB - Adult growth hormone deficiency (AGHD) is correlated to many adverse effects on metabolism and increases cardiovascular risk. 40 patients with AGHD and 40 healthy subjects were included. Anthropometric parameters such as body mass index, waist circumference, and waist-hip ratio were measured. Meanwhile, plasma levels of total cholesterol, triglyceride, high sensitivity C-relative protein, interleukin-6 and OPG were determined. Homeostasis model assessments for insulin resistance (HOMA-IR) and beta-cell function (HOMA-beta) were calculated using homeostasis model. Plasma OPG concentrations of AGHD patients were significantly higher than those in healthy subjects (131.82 +/- 45.04 versus 81.02 +/- 45.04, P < 0.01). Plasma OPG levels were positively correlated with age, body mass index, waist circumference, hip circumference, waist-hip ratio, fasting insulin, total cholesterol, triglyceride, high sensitivity C-relative protein and interleukin-6 (P < 0.05), but negatively correlated with high-density lipoprotein cholesterol (P < 0.05). Multiple linear stepwise regression analysis demonstrated that body mass index, triglyceride, and interleukin-6 were independently related to plasma OPG levels (P < 0.05). The levels of plasma OPG were increased in AGHD patients and were closely correlated with glycolipid metabolism and chronic inflammation. OPG might play an important role in the occurrence and development of cardiovascular diseases in AGHD patients. PMID- 26064208 TI - CT features and common causes of arc of Riolan expansion: an analysis with 64 detector-row computed tomographic angiography. AB - OBJECTIVE: To study the manifestations of arc of Riolan expansion (ARE) using multi-detector computed tomography angiography (MDCTA). MATERIALS AND METHODS: The manifestations and clinical data of 626 consecutive mesentery CTA images were retrospectively analyzed. The 47 cases with ARE and 47 patients without expansion were involved. The average diameter of arc of Riolan was measured. Two radiologists after reaching consensus analyzed the shapes of mesenteric artery, CT findings and the occurrence and causes of ARE. RESULTS: The mean diameter of arc of Riolan was 1.2 mm, 4.6 mm, 2.5 mm, 2.3 mm, 1.9 mm, 2.5 mm, and 2.0 mm at baseline and following obstruction of superior mesenteric artery (SMA), stenosis of SMA, obstruction of inferior mesenteric artery (IMA), stenosis of IMA, colon cancer, and active ulcerative colitis, respectively. The expansion of arc of Riolan was the most significant following obstruction of SMA. The diameters of arc of Riolan were significantly different between the upward flow group and the downward or the two-way flow groups, and between the colon tumor group and the active ulcerative colitis group. CT findings such as bowel wall thickening, contrast enhancement, intestinal obstruction, marginal artery expansion, lymph node enlargement varied and were help to identify the cause of ARE. CONCLUSIONS: ARE often suggests the occurrence of obstructed intestinal feeding artery or intestinal lesions. MDCTA can clearly display the situation of arc of Riolan and collateral circulation, and together with CT symptoms, can guide the selection of diagnosis and treatment schemes in clinic. PMID- 26064209 TI - Research of osteoblastic induced rat bone marrow mesenchymal stem cells cultured on beta-TCP/PLLA porous scaffold. AB - BACKGROUND: Ceramic and polymer composite scaffolds are widely used in tissue engineering for bone tissue regeneration. Composite of beta-tricalcium phosphate (beta-TCP) and poly L-lactic acid (PLLA), due to its biocompatibility and biodegradability, is widely used in bioengineering. However, optimal ratio, porosity and pore size of this kind of scaffolds were not very clear yet. MATERIALS AND METHODS: We cultured osteoblastic induced rMSCs on beta-TCP/PLLA scaffolds to investigate the optimum construction, which owned better properties for supporting cells growth, proliferation and differentiation. A total of 24 mice were divided into three groups: rMSCs + beta-TCP/PLLA, osteoblastic rMSCs + beta-TCP/PLLA and beta-TCP/PLLA without cells. 8 rude mice were implanted with rMSCs + beta-TCP/PLLA in the left thighs and beta-TCP/PLLA without cells in the right thighs. 8 rude mice were implanted with osteoblastic rMSCs + beta-TCP/PLLA in the left thighs and the same treatments in the right thighs as the above. After 8 and 12 weeks, the mice were sacrificed and implants with the surrounding tissues were harvested together. Paraffin sections were got and HE stain and Masson-Goldner stain were employed to observe the ectopic bone formation. RESULTS: The scaffolds of beta-TCP/PLLA = 2:1 significantly increased osteocalcin production of the cells. In addition, scaffolds with NaCl = 70 wt%, pore size 200~450 MUm showed better compatibility to these seeding cells. A significantly larger area of bone formation in the osteoblastic rMSCs and beta-TCP/PLLA composite than that in rMSCs/scaffold and in the scaffold without cells in vivo. CONCLUSION: compounds of osteoblastic induced rMSCs and the scaffold with beta TCP/PLLA = 2:1, NaCl = 70 wt%, pore size = 200-450 MUm had good properties as a kind of bone substitute. PMID- 26064210 TI - SHIP2 on pI3K/Akt pathway in palmitic acid stimulated islet beta cell. AB - This study is to investigate the influence of SHIP2 on palmitic acid stimulated islet beta cell and insulin secretion, as well as its role in pI3K/Akt pathway. We defined four groups: control, acid group, acid + NC siRNA group and acid + siRNA transfection group. The control was neither treated by palmitic acid nor transfection. The acid group was subjected to palmitic acid incubation. The acid + NC siRNA group was transiently transfected by NC siRNA, then was stimulated by palmitic acid. The acid + siRNA group was transiently transfected by siRNA, then was stimulated by palmitic acid. Cell proliferation and apoptosis were measured by MTT and flow cytometry. Immunocytochemistry, Western Blot and QPCR were designed to detect the expression of SHIP2, Akt, p-Akt protein and mRNA. Insulin secretion was tested by radioimmunoassay. The apoptosis rate in the acid + siRNA group was non-significantly lower than the acid group and the acid + NC siRNA group (P > 0.05). The expression levels of Akt phosphorylation in the acid + siRNA group was significantly higher than in the acid + NC siRNA group and the acid group (P < 0.05). And under 22.4 mmol/L glucose KRB, insulin secretion in the acid + siRNA group was significantly more than the acid + NC siRNA group and the acid group (P < 0.05). SHIP2 silencing probably stimulates insulin secretion, which may be associated with the enhanced proliferation in the pI3K/Akt pathway. PMID- 26064211 TI - Resveratrol alleviates nerve injury after cerebral ischemia and reperfusion in mice by inhibiting inflammation and apoptosis. AB - The role of resveratrol in cerebral ischemia/reperfusion injury is not well understood. The aim of this study was to investigate whether resveratrol modulates inflammation and oxidative stress in cerebral ischemia/reperfusion injury in mice. Rats were subjected to 2 h of transient middle cerebral artery occlusion (MCAO), followed by 24 h of reperfusion. Rats were randomly exposed to sham operation group, MCAO group and MCAO+ resveratrol group. The results demonstrated that compared to I/R, resveratrol reduced cerebral infarction area, brain water content, neuronal apoptosis, myeloperoxidase (MPO) levels, and cerebral TNF-alpha production. Our results suggested that resveratrol has protective effects against cerebral I/R injury in rats, which may be attributed to attenuating inflammation and apoptosis induced by cerebral ischemia reperfusion. PMID- 26064212 TI - Effect of mir-16 on proliferation and apoptosis in human A549 lung adenocarcinoma cells. AB - OBJECTIVE: To investigate the expression of mir-16 in lung adenocarcinoma cancer line and to observe the effect of mir-16 on the biological behaviors of human lung adenocarcinoma cancer A549 cell. Methods the expression of mir-16 in A549 cells was examined by quantitative real-time (qRT)-PCR. mir-16 minics was chemically synthesized and transfected into A549 cells by Lipofectamine 2000. The cell cycle and apoptosis changes were assayed by flow cytometry, the cell proliferation was measured by MTS assay. The wild-type and mutant wip1 3'-UTR luciferase reporter rectors were constructed. The relative activity of renila luciferase was detected to confirm the binding site of mir-16 on wip1 mRNA. Results, the expression of mir-16 is reduced in A549 cell compared with the normal bronchial epithelial cell. Transfection of mir-16 minics significantly suppressed the luciferase reporter containing wild type not mutant wip1 3'-UTR. Furthermore enforced expression of mir-16 lead to reduced A549 cell proliferation and promote apoptosis. Conclusion Therapeutic strategies to resume miRNA-16 expression may be benefit to patients with NSCLC in the feature. PMID- 26064213 TI - In vitro visualization of human endodontic structures using different endoscope systems. AB - Different endoscope optics for the visualization of interradicular structures were evaluated as a diagnostic tool. A sample of 20 extracted human lower molar teeth was used. Only teeth with fully formed apices were included. All samples were evaluated with three different endoscopic procedures: pulp endoscopy (PE), canal entrance endoscopy (CEE) and root canal endoscopy (RCE). All pulp chambers could be observed using PE (100%), however, only 41 of 60 (68.3%) canals were observed. With CEE, all entrances could be observed, and the middle third of the canals could be visualized in 85% of the canals. The semiflexible endoscope for RCE allowed successful observation of 91.6% of the middle third of the canals. The application of the endoscope may be useful in the identification of root canals even under difficult visual work field conditions. The combined use of a set of various optics might enable the operator to enhance the quality of non surgical endodontic procedures. PMID- 26064214 TI - Correlation between smoking history and molecular pathways in sporadic colorectal cancer: a meta-analysis. AB - BACKGROUND: Epidemiological studies have shown that smoking increases the risk for colorectal cancer (CRC). Evidence of the guiding significance of smoking history for molecular classification and molecular targeted anti-tumor therapy is not well established. AIMS: To provide indirectly evidence, we conducted a systematic meta-analysis of association between smoking history and different molecular classification. METHODS: We searched in multiple databases up to January 2014, and identified 27 eligible studies. All studies were divided into seven groups based on different molecular alteration categories, which are MSI, CIMP, and three molecular pathway-associated gene alterations (APC, KRAS, P53, BRAF mutation, and APC methylation). Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were calculated to evaluate the association. RESULTS: Smoking showed a significantly positive correlation with P53 mutation (exons 4 to 8), BRAF (codon 600) mutation, MSI positivity, and CIMP positivity, with ORs of 1.25 (95% CI: 1.07-1.45), 1.41 (95% CI: 1.18-1.68), 1.28 (95% CI: 1.12-1.47), and 1.23 (95% CI: 1.01-1.50), respectively. However, smoking was not positively correlated with APC (mutation cluster region) and KRAS (codons 12 and 13) mutation in sporadic CRC patients. CONCLUSIONS: These findings suggested smoking history occurred with P53 mutation, BRAF mutation, MSI positivity, and CIMP positivity in sporadic CRCs; and could guide those specifically therapeutic designs when molecular classification with genetic test was infeasible. More associated studies should be conducted for strengthening and renewing the current result. PMID- 26064215 TI - Effects of PDTC on NF-kappaB expression and apoptosis in rats with severe acute pancreatitis-associated lung injury. AB - We investigated the effects of pyrrolidine dithiocarbamate (PDTC) on intrapulmonary expression of nuclear factor-kappaB (NF-kappaB), and apoptosis in rats with severe acute pancreatitis (SAP). We induced SAP, then used immunohistochemistry, TUNEL staining, quantitative PCR assays and western blotting to examine PDTC effects. Treatment with PDTC resulted in interstitial edema and widening of the basement membrane, with swollen mitochondria and aggregation of nuclear chromatin. Expression of NF-kappaB, Fas, Bcl-2 and TNF alpha in lung tissues of SAP rats was increased, with NF-kappaB, Fas and TNF alpha levels maximal after 6 h. PDTC appeared to ameliorate pathological changes, with low levels of NF-kappaB, Fas, TNF-alpha, and Caspase-3 mRNA observed and a lower apoptosis index compared with that seen in SAP rats. Expression of NF kappaB could be involved in lung tissue apoptosis during SAP. We postulate that PDTC inhibits the activation of NF-kappaB and apoptosis, effectively alleviating the severity of lung injury. PMID- 26064216 TI - Elevated glycated hemoglobin levels may increase the risk of atrial fibrillation in patients with diabetes mellitus. AB - BACKGROUND: As the most common cardiac arrhythmia, atrial fibrillation (AF) is always accompanied with various complications if without detection and treatment timely. Blood-based pleiotropic molecule biomarkers have now been popularly applied in clinical detection. We hence performed this meta-analysis to evaluate the correlation of serum glycated hemoglobin (HbA1c) levels with the risk of AF in patients with diabetes mellitus (DM). METHODS: Covering myriads of computerized databases, we identified potential relevant studies for statistical analysis. We used a standard reporting form to extract data from each included study. Newcastle-Ottawa Scale (NOS) criteria was used for methodological quality assessment. Statistical analyses were conducted with the STATA statistical software. RESULTS: Six cohort studies in full text fulfilled our inclusion criteria, and following overestimation indicated that serum levels of HbA1c in DM patients with AF was higher than that in DM patients without AF (SMD = 0.67, 95% CI: 0.39-0.94, P < 0.001). Subgroup analyses by sample size and detection method implicated that elevated serum HbA1c levels exhibited significant correlations with an increased risk of AF in DM patients in the large-size subgroup (n >= 200), the small-size subgroup (n < 200), the high performance liquid chromatography (HPLC) subgroup and the non-HPLC subgroup (Large-size: SMD = 0.70, 95% CI: 0.38-1.03, P < 0.001; Small-size: SMD = 0.64, 95% CI: 0.09-1.19, P = 0.023; HPLC: SMD = 0.81, 95% CI: 0.49-1.12, P < 0.001; Non-HPLC: SMD = 0.36, 95% CI: 0.04-0.68, P = 0.029; respectively). CONCLUSION: Elevated serum HbA1c levels may be associated with an increased risk of AF in DM patients, possibly reflecting that serum HbA1c level might be a potential biomarker in the prediction of AF in DM patients. PMID- 26064217 TI - Prognostic significance of matrix metalloproteinase 7 immunohistochemical expression in colorectal cancer: a meta-analysis. AB - Matrix metalloproteinase 7 (MMP-7) was speculated to have a key role in the development and progression of human cancer. Considerable studies investigated the relationship between its expression and survival in colorectal cancer (CRC), but inconsistent results were obtained. The clinical significance of MMP-7 overexpression in CRC remains controversial. Therefore, in this article, we conducted a meta-analysis to analyze the prognostic value of MMP-7 in CRC. We searched studies in PubMed, Medline, and Web of Science databases until August 2014 to find relevant studies. A total of six high-quality studies met the inclusion criteria and 1631 patients were included in our study. Combined hazard ratios (HRs) suggested that MMP-7 overexpression had an unfavorable impact on overall survival (HR = 1.83, 95% CI: 1.24-2.71). Subgroup and sensitivity analyses further validated the role of MMP-7 as a predictor for prognosis. In conclusion, MMP-7 overexpression detected by immunohistochemistry indicated worse prognosis in CRC and may help to guide clinical therapy. PMID- 26064218 TI - Immunohistochemical and genetic markers to distinguish hemangiopericytoma and meningioma. AB - Hemangiopericytoma (HPC) and meningioma, for their morphology immunohistochemical markers similarity, were usually confused especially before surgery. This study aimed to develop a panel of biomarkers to differentiate HPC from meningioma. Real time PCR and immunohistochemical staining were employed to determine the levels of p53, bcl-2, c-myc, vimentin, CD34, FVIIIa, MGMT and reticular fiber in 15 meningiomas, HPCs and their normal controls. We found that, in the mRNA expression level, both Bcl-2 and c-myc were high in HPC and meningiomas, but bcl 2 was higher in HPC than in meningiomas, c-myc was lower in HPC than in meningiomas. In protein expression level, reticular fibers were around most HPC tumor cells but observed null in meningiomas; CD34 and FVIIIa were both found positive in HPCs but negative in meningiomas; MGMT was weak focal in HPC but strong diffuse in meningiomas. In conclusion, bcl-2, c-myc, and MGMT could be employed as the new panels of biomarkers for distinguishing HPC from meningiomas. PMID- 26064219 TI - Association between glutathione S-transferases M1 and T1 gene polymorphisms and esophageal cancer prognosi. AB - OBJECTIVE: To investigate the independent factors affecting the prognosis of patients after resection of esophageal cancer, and to inquire into the relationship between GSTM1, GSTT1 gene polymorphisms and esophageal cancer prognosis. METHODS: The clinical data of 273 patients with esophageal cancer were retrospectively analyzed. The patients were followed-up after their surgery, and the gene polymorphisms of GSTM1 and GSTT1 in each individual were detected by polymerase chain reaction (PCR). The clinical features along with the gene polymorphisms of GSTM1 and GSTT1 associated with the prognosis of patients were analyzed by using the method of univariate analysis and Cox proportional hazard model. The cumulative survival rate was estimated by Kaplan-Meier methods, and the survival curves were compared by using the log-rank test. RESULTS: The overall cumulative survival rate of first year, third year and fifth year is 94.6%, 58.5% and 17.8%, respectively. The median survival time (MST) is 38.7 months. The results of univariate analysis showed that: infiltration depth, length of tumor, the number of lymph node metastasis, the region of lymph node metastasis and the genetic polymorphism of GSTM1 and GSTT1 gene loci were associated with the survival of postoperative patients. Cox multivariate analysis further indicated that the length of tumor, the number of lymph node metastasis and the combined genotype (1) [GSTM1 (+/+) or (+/-) & GSTT1 (-/-)] were the independent prognostic factors. The length of tumor, the number of lymph node metastasis were the risk factors for the prognosis, and the combined genotype (1) had protective effect on survival when compared with reference [GSTM1 (+/+) or (+/-) & GSTT1 (+/+) or (+/-)]. CONCLUSION: The length of tumor, the number of lymph node metastasis were confirmed as the independent prognostic factors of esophageal carcinoma, and the null genotypes for GSTT1 (-/-) might be a protective factor for survival and GSTM1 (-/-) might be a potential negative prognostic factor in patients with esophageal cancer. PMID- 26064220 TI - Effects of hyperbaric oxygen on glucose-regulated protein 78 and c-Jun N-terminal kinase expression after spinal cord injury in rats. AB - Spinal cord injury (SCI) is not only devastating but also represents a public health burden for society. Endoplasmic reticulum stress (ERS) is implicated in secondary injury following damage to the SC. Hyperbaric oxygen (HBO) treatment can improve the recovery of motor function after SCI, but the effect of HBO on the ERS response is unknown. This study tested the hypothesis that HBO treatment protects against secondary SCI by inhibiting the ERS response via regulation of glucose-regulated protein (GRP) 78 and c-Jun N-terminal kinase (JNK) expression. Rats were randomly assigned to sham, SCI, and SCI + HBO groups and the extent of neuronal damage and neurological recovery were evaluated 1, 3, 7, and 14 days after surgery. GRP78 and JNK expression was evaluated by immunohistochemical, western blot, and real-time reverse transcription-polymerase chain reaction analyses, while caspase-3 activation was evaluated by enzyme-linked immunosorbent assay. SCI resulted in an upregulation in GRP78 and JNK expression compared to sham-operated animals. HBO treatment increased GRP78 level, but decreased that of JNK and suppressed caspase-3 activation as well as neuronal damage relative to the SCI group. In addition, hind limb motor function was improved by HBO treatment. HBO treatment reduces SCI-induced neuronal death and promotes the recovery of neurological function recovery by inhibiting the ERS response via modulation of GRP78 and JNK expression levels. PMID- 26064221 TI - Balanced oxidative status by nesfatin-1 in intestinal ischemia-reperfusion. AB - OBJECTIVE: Ischemia causes reversible or irreversible cell or tissue damage and reperfusion can exaggerate cellular damage. Microvascular dysfunction is induced and causes enhanced fluid filtration in capillaries. At the acute phase of reperfusion more oxygen radicals are activated. Nesfatin-1 protects brain against oxidative damage and heart against ischemia/reperfusion damage. In our study, we aimed to investigate the acute effect of chronic peripheral nesfatin-1 administration in intestinal ischemia/reperfusion created rats. METHOD: Two months-old, 28 Wistar Albino male rats, weighing an average of 200-250 g, were used and randomly divided into four experimental groups (n=7) as; Laparotomy, Ischemia/Reperfusion, Nesfatin-1+Laparotomy, Nesfatin-1+Ischemia/Reperfusion. Serum levels of total oxidant status (TOS) and total antioxidant status (TAS) were determined by colorimetric measurement method. The plasma levels of endotelin-1 and endothelial nitric oxide syntheses (eNOS) were analyzed by rat ELISA assay kits. RESULTS: Plasma levels of endothelin-1 significantly increased, plasma level of eNOS, serum levels of TOS and TAS significantly decreased in nesfatin-1 applied groups. Additionally, The oxidative stress index (OSI) parameters decreased significantly in three groups compared to laparotomy. CONCLUSION: Chronic peripheral nesfatin-1 administration can decrease eNOS level and OSI at the acute phase of ischemia/reperfusion. We suppose that it can be protective for ischemia/reperfusion injury by balancing oxidant capacity. On the other hand, this effect of nesfatin-1 is not related with micro-circular compensation and increases anti-oxidant capacity. PMID- 26064222 TI - Analysis of the vacuum phenomenon in plain hip radiographs in children. AB - OBJECTIVES: To find the accurate incidence of the vacuum phenomenon in the hip and the best projection position for producing the vacuum phenomenon in plain hip radiographs in children. METHODS: All pediatric anteroposterior (AP)-view and frog-leg-position plain hip joint radiographs obtained in our hospital between January 2003 and March 2013 were examined. The subjects' ages ranged between 0 and 14 years (mean, 4.2 years). All of the plain radiographs showing crescent-, linear-, and irregular-shaped lucencies between the femoral head and acetabulum were included in the present study. RESULTS: A total of 16,749 cases, including 12,422 cases (5,912 boys and 6,510 girls) with only AP-view plain radiographs and 4,327 cases (1,537 boys and 2,790 girls) with both AP-view and frog-leg-position plain radiographs that were assessed in our hospital between January 2003 and March 2013, were examined. None of the AP-view plain hip radiographs exhibited the vacuum phenomenon. Vacuum phenomenon of the hips was found in only 258 cases (321 hips) in the frog-leg-position plain radiographs of 4,327 cases, resulting in a constituent ratio of 5.96% (258/4327). A total of 1,738 normal children were assessed in the 4,327 frog-leg-position radiographs, and 150 cases of the vacuum phenomenon were found in the normal children; thus, the incidence of the vacuum phenomenon in normal children was 8.63% (150/1,738). In 2,360 children with developmental dysplasia of the hip (DDH) who were assessed in the 4,327 frog-leg position radiographs, 98 cases of vacuum phenomenon were found, yielding an incidence of 4.15% in children with DDH (98/2,360). Thus, the 258 cases with vacuum phenomenon included 150 normal hips (58.14%), 98 cases with DDH (37.98%), 5 cases with Legg-Calve-Perthes disease (1.94%), and 1 case each of solitary eosinophilic granuloma in the left ischium (0.39%), polyostotic fibrous dysplasia of the left and right proximal femurs (0.39%), 1 case of hereditary multiple exostoses (0.39%), 1 case of congenital coxa vara (0.39%), and 1 fracture of the femoral neck after surgery (0.39%). The 321 hips in the 258 cases were classified as complete (121 hips, 37.69%) or partial (200 hips, 62.31%) types according to the proportion of the lucency area in the hip joints and as linear (159 hips, 49.53%), crescent (151 hips, 47.04%), or irregular (11 hips, 3.43%) lucencies according to the shape of the lucency area in the hips. CONCLUSIONS: The vacuum phenomenon of the hip in children is found in frog-leg-position plain radiographs. It is easier to find the vacuum phenomenon in normal hips compared to cases with DDH. Frog-leg-position plain radiographs provide a better projection position for obtaining the vacuum phenomenon of the hip in children compared to AP-view plain radiographs. PMID- 26064223 TI - A case of annular pancreas accompanied with intraductal papillary mucinous neoplasm-case report. AB - OBJECTIVES: Annular pancreas is a rare congenital anomaly characterized by pancreatic tissues wrapping completely or incompletely around the descending duodenum. In most patients with annular pancreas, onset occurs in early childhood. Adults with annular pancreas are prone to duodenal ulcers and pancreatitis. Intraductal papillary mucinous neoplasm (IPMN) is a type of papillary mucinous secretory epithelial tumor, which originates in the main pancreatic duct and/or branch duct. We report a case of annular pancreas accompanied with intraductal papillary mucinous neoplasm. METHODS: A 52-year-old male patient hospitalized due to recurrent upper abdominal pain for one and a half years was enrolled in this study. RESULTS: One case of annular pancreas accompanied with intraductal papillary mucinous neoplasm which manifested as recurrent chronic pancreatitis was found. After pancreaticoduodenectomy, the patient died from uncontrollable gastrointestinal bleeding. CONCLUSIONS: To the best of our knowledge, this is the first case in China and the second case worldwide of annular pancreas accompanied with IPMN in English literature. PMID- 26064224 TI - Parathyroid hormone plus alendronate in osteoporosis: a meta-analysis of randomized controlled trials. AB - BACKGROUND: Parathyroid hormone (PTH) increases both bone formation (BMD) and bone resorption, whereas alendronate reduces bone resorption. It is possible that the combination therapy of PTH with alendronate will enhance their effects on BMD. Therefore, we conducted this meta-analysis to evaluate the efficacy of the combination therapy of PTH with alendronate in the treatment of patients with osteoporosis. METHODS: A comprehensive literature search of PubMed, Embase, and Web of Science was conducted to identify relative studies. Eligible studies were randomized controlled trials (RCT), which assessed the efficacy of combination therapy in patients with osteoporosis. The outcomes included the mean percent increases in BMD of lumbar spine, femoral neck, total hip, and distal radius. Weighted mean difference (WMD) with 95% confidence intervals (CIs) were calculated using of random-effects or fixed-effects model, depending on the heterogeneity between the included studies. RESULTS: Six RCTs with a total number of 833 patients were included in this meta-analysis. The pooled estimates showed that, the combination therapy of PTH with alendronate resulted in a higher mean percent change of increased BMD in distal radius (WMD = 2.45, 95% CI: 1.58, 3.31; P = 0.000), but not in lumbar spine (WMD = -0.83, 95% CI: -3.48, 1.81; P = 0.538), femoral neck (WMD = -0.99, 95% CI: -2.04, 0.07; P = 0.068), and total hip (WMD = -0.06, 95% CI: -0.93, 0.81; P = 0.892). The subgroup analysis based on the dosage and schedule of PTH, study duration, gender of patients, and anabolic agents, were conducted. And results revealed that among the patients in the combination therapy group, greater increases in the spine BMD were observed when the PTH was administered with a dosage of 20 MUg (WMD = 2.33, 95% CI: 1.24, 3.43; P = 0.000), or the treatment duration lasted more than 12 months (WMD = 2.23, 95% CI: 1.00, 3.47; P = 0.000), or the combination therapy was used in osteoporosis women (WMD = 1.58, 95% CI: 0.63, 2.53; P = 0.001). However, the combination of PTH of 40 MUg with alendronate produced a decrease in the BMD at spine (WMD = 4.56, 95% CI: -7.56, -1.56; P = 0.003) and femoral neck (WMD = -5.82, 95% CI: 9.91, -1.72; P = 0.005). CONCLUSION: Our findings indicated that the addition of alendronate to PTH in the treatment of osteoporosis, reduced the ability of PTH therapy to increase the BMD at the lumbar spine, femoral neck, and total hip. PMID- 26064225 TI - Temporal and spatial changes in VEGF, alphaA- and alphaB-crystallin expression in a mouse model of oxygen-induced retinopathy. AB - OBJECTIVE: Retinal neovascularization is an iconic change in retinopathies. Vascular Endothelial Growth Factor (VEGF) and alpha-crystallins have been identified to mediate the pathogenesis of retinopathy. However, the special and temporal changes in their expression associated with retinal neovascularization have not yet been determined. Therefore, we examined the expression and distribution of VEGF, alphaA- and alphaB-crystallins in the retina using a mouse model of oxygen-induced retinopathy (OIR). METHODS: 90 C57/BL mice were randomly divided into the OIR and control groups. The OIR group at postnatal day 7 (P7) were kept at high oxidation state (75 +/- 5%) for 5 days before returned to normal environment. Retinal tissue was cut into sections. Oxygen induced retinal neovascularization and vascular structural changes were evaluated using retinal fluorescein angiography. The number of endothelial cell nuclei breaking through the retinal internal limiting membrane was counted after H&E staining. The mRNA expression levels of VEGF, alphaA- and alphaB-crystallins in the mouse retina were determined using real-time RT-PCR. The distribution of alphaA- and alphaB crystallins in the retina was detected by fluorescent immunohistochemistry staining. RESULTS: Oxygen induction triggered new blood vessel formation in the retina and impaired the structure of the retinal vascular network. The number of endothelial cell nuclei breaking through the retinal internal limiting membrane was significantly increased in the OIR group compared to the control group at P13, P17 and P21 (P < 0.01), reaching the peak on P17. The expression levels of VEGF, alphaA- and alphaB-crystalllins were also significantly different between the OIR and control groups. VEGF expression was highest on P15, alphaA-crystallin expression was highest on P17, whereas alphaB-crystallin expression kept increasing during the time frame of our study. Both alphaA- and alphaB crystallins were expressed in the ganglion cell layer and the inner nuclear cell layer. While alphaA- and alphaB-crystallins were only located on the cell membrane in the outer ganglion cell layer, they were observed both on the cell membrane and in the cytoplasm in the inner layer of cells. CONCLUSION: Using our mouse model of oxygen-induced retinopathy, we showed that the expression patterns of VEGF, alphaA- and alphaB-crystallins during retinal neovascularization in both spatially and temporally manners, providing significant insights into the molecular mechanisms of retinopathy and the associated neovascularization. PMID- 26064226 TI - Treatment for displacement of PAAG mixture after injection augmentation mammoplasty. AB - BACKGROUND: The incidence of serious complications after augmentation mammaplasty with injection of polyacrylamide hydrogel (PAAG) was high. OBJECTIVE: To design a new method for healing of the cavities and cysts after augmentation mammaplasty. METHODS: 102 patients in whom PAAG exceeded the breast and spread to the thoracic abdominal walls were enrolled and divided into two groups. RESULTS: The flowing masses of different sizes exceeded the breast and spread to the thoracic abdominal walls, and a large number of PAAG showed flowing degenerative mixture in the tissues and were invaded by many inflammatory cells. PAAG deposited extensively in the breast tissues, armpits and space of the thoracic-abdominal wall, and the breast was connected with the abdominal wall through the fistula of different sizes. At 2 weeks, the percentages of decrease in drainage volume and in lesion lacuna size of the thoracic-abdominal wall (82% and 80%, respectively) in patients receiving the multiple incisions combined with radical therapy were significantly different from those who did not receive the multiple incisions (46% and 45%) (Both P<0.01). At 4 weeks, in some of the patients receiving the multiple incisions combined with radical therapy, the lacuna of the thoracic abdominal wall disappeared completely, and the lesions with flowing masses had been cleared. CONCLUSIONS: The new method of subareolar incision combined with surgery for inferior segment of mass to clean the mixture and thoroughly eliminate the lacuna of the thoracic-abdominal wall as well as suture to close the intramammary fistula can improve the treatment efficacy. PMID- 26064227 TI - Study on the function and mechanism of atorvastatin in regulating leukemic cell apoptosis by the PI3K/Akt pathway. AB - OBJECTIVE: To investigate the effects of atorvastatin on the proliferation and apoptosis of leukemic cell lines (Jurkat, K562 and HL-60), and expore the function of TLR4/MYD88/NF-kappaB and PI3K/AKT signal pathway in this process. METHODS: Cells in logarithmic growth phase were divided into negative control group and experimental group (cells were treated with atorvastatin with intervention concentrations of 1, 5 and 10 MUmol/L respectively) and cultured for 24 hours. Changes in apoptosis and cell cycle of leukemic cells were detected utilizing the Flow Cytometry. Changes in the expression of TLR4/MYD88/NF-kappaB and PI3K/AKT signal pathway related genes were detected utilizing Real-time PCR and Western Blot method. RESULTS: Atorvastatin inhibit proliferation and induce apoptosis in K562, HL-60 and Jurkat cells in a dose-dependent manner. K562, HL-60 and Jurkat cells in G0/G1 phase increased and that in S phase decreased after being treated with atorvastatin for 24 hours compared with that in control group, suggesting that the atorvastatin can retard the three cells in the G0/G1 phase. The study find that the basal expressions of TLR4, MYD88 and NF-kappaB gene in K562, HL-60 and Jurkat cells are obviously down-regulated in a dose-dependent manner after being treated with atorvastatin with different concentrations. This down-regulation action of atorvastatin to the expression of the TLR4, MYD88 and NF-kappaB gene becomes more obvious with the increase of the drug level. In addition, the PI3K, AKT and their phosphorylation levels in the above cells down regulate obviously in a dose-dependent manner after being treated with atorvastatin. This down-regulation action of atorvastatin to the PI3K, AKT and their phosphorylation levels become more obvious with the increase of the drug level. CONCLUSIONS: Atorvastatin can inhibit proliferation and induce apoptosis in leukemia cells, which may be associated with the regulation of atorvastatin to the TLR4/MYD88/PI3K/AKT/NF-kappaB signaling pathway. PMID- 26064228 TI - Study of ascending aortic elasticity in the Chinese population with a high risk of aortic diseases. AB - PURPOSE: To analyze aortic elastic properties (AEP) characteristics, dissection and elastic data of ascending aorta (AA) in the population with a high risk of aortic diseases. METHODS: Forty five patients with artery diseases undergoing aortic digital subtraction angiography (DSA) were enrolled in this study. The maximal, minimal diameter and changes in diameter of ascending and descending aorta were measured, and the aortic stiffness index (ASI) and aortic distensibility (AD) were calculated. RESULTS: The mean changes in diameter were (2.34 +/- 0.95), (1.6 +/- 0.71), (1.65 +/- 0.68) and (0.99 +/- 0.28) mm. The ASI of D1-D4 aorta was (9.67 +/- 5.02), (15.54 +/- 7.85), (13.78 +/- 6.45) and (15.53 +/- 4.74). AD (mmHg(-1)) * 10(-3) of D1-D4 aorta was (2.76 +/- 1.65), (1.76 +/- 1.15), (1.94 +/- 1.23) and (1.33 +/- 0.40). The ratio of diameter difference/minimal diameter was (7.18 +/- 3.21), (4.6 +/- 2.3), (4.96 +/- 2.22) and (3.86 +/- 1.16). The tapered angle of D2-D3 aorta was (2.47 +/- 1.80) degrees . The maximal and minimal diameters of D1 aorta significantly differed between male and female subjects. CONCLUSION: DSA and artery pressure accurately measure the changes in diameter and artery pressure of aorta along with single beat. Aortic ASI and AD could be accurately calculated to precisely analyze AEP. Over aging and arteriosclerosis development, D2 aorta is the most vulnerable to elasticity attenuation, whereas D1 aorta is the least vulnerable part with certain elasticity. PMID- 26064229 TI - Application of ultrasound imaging of upper lip orbicularis oris muscle. AB - In this study, we aim to understand the morphology and structure of upper lip orbicularis oris muscle, and to provide clinical evidence for evaluating the effect of repair operation in cleft lip. Subjects included 106 healthy people and 36 postoperative patients of unilateral cleft lip. The upper lip orbicularis oris muscle was scanned using ultrasound in natural closure and pout states. Our results showed that the hierarchical structure of upper lip tissue was demonstrated clearly in ultrasonic images. After reconstruction of unilateral cleft lip, the left and right philtrum columns were still obviously asymmetric, their radian displayed clearly and showed better continuity. In the place of cleft lip side equivalent to philtrum columns, orbicularis oris muscle showed discontinuity and unclear hierarchical structure, which was replaced by hyperechoic scar tissue. The superficial layer would become thicker when pouting. In reconstructed unilateral cleft lip, the superficial layer was thinner than that of healthy controls. In normal upper lip orbicularis oris muscle, the superficial layer thickness was no less than 2.89 mm in philtrum dimple and no less than 3.92 mm in philtrum column, and the deep layer thickness was no less the 1.12 mm. Otherwise, the layer thickness less than above reference values may be considered as diagnostic criteria for dysplasia of upper lip orbicularis oris muscle. In conclusions, ultrasound imaging is able to clearly show the hierarchical structure of upper lip orbicularis oris muscle, and will be beneficial in guiding the upper lip repair and reconstruction surgery. PMID- 26064230 TI - Oxidative damage of DNA induced by X-irradiation decreases the uterine endometrial receptivity which involves mitochondrial and lysosomal dysfunction. AB - X irradiation may lead to female infertility and the mechanism is still not clear. After X irradiation exposure, significantly morphological changes and functional decline in endometrial epithelial cells were observed. The mitochondrial and lysosomal dysfunction and oxidative DNA damage were noticed after X irradiation. In addition, pretreatment with NAC, NH4Cl or Pep A reduced the X irradiation induced damages. These studies demonstrate that the oxidative DNA damage which involved dysfunctional lysosomal and mitochondrial contribute to X irradiation-induced impaired receptive state of uterine endometrium and proper protective reagents can be helpful in improving endometrial function. PMID- 26064231 TI - Effect of Ipr1 on expression levels of immune genes related to macrophage anti infection of mycobacterium tuberculosis. AB - BACKGROUND: Intracellular pathogen resistance 1 (Ipr1) has been found in macrophages and plays a pivotal role in fighting against Mycobacterium tuberculosis (Mtb) infection. This study is designed to evaluate the effect of Iprl on the expression of macrophage genes related to the anti-infection of Mtb. Design or methods: In the experimental and control groups, the macrophages were infected with Mycobacterium H37Ra, and then the related immune genes between two groups were detected using microarray assay. Real-time quantitative PCR was applied to detect the differences in the expression of three up-regulated genes detected by microarray assay and to verify the reliability of microarray assay. RESULTS: The expression of Iprl up-regulated 11 genes related to macrophage anti immunity involved TLRs signaling pathway including TLR2 and TLR4, Irak1, Traf7, Ifngr1 and Tnfrsfla. No significant difference was found in terms of the molecular expression involved in regulation of the adaptive immune response, such as IL-1 and IL-12. The results of real-time PCR were consistent with the findings of microarray assay. CONCLUSIONS: The expression of Iprl gene probably promotes macrophage activity and enhances the ability of macrophages to fight against Mtb infection. The underlying mechanism may be achieved by up-regulating the expression levels of innate immunity genes, especially TLR2/TLR4 and signal transduction molecules, which is determined using microarray assay. All these findings offer the basis for subsequent study of the mechanisms of Ipr1 gene in host innate immunity against Mtb infection. PMID- 26064232 TI - Bufalin promotes apoptosis of gastric cancer by down-regulation of miR-298 targeting bax. AB - Bufalin is used to treat many patients with solid malignant tumors clinically. Bufalin could induce gastric cancer cell apoptosis via BAX. microRNA (miRNA) plays important roles in gene regulation. However, miRNA involving in bufalin inducing apoptosis of gastric cancer cells remains to futher research. To study the regulatory role of miRNA in bufalin induced cancer cell apoptosis. Firstly, we verifed that bufalin could induce gastric cancer cell apoptosis by inducing BAX expression. miR-298 was predicted as a regulator of BAX and further study verified Bax was a target gene of miR-298 by luciferase reporter assay. miR-298 could down-regulate BAX on mRNA and protein level in gastric cancer cells. miR 298 promoted cell proliferation and inhibited apoptosis of gastric cancer cells. It was also found that bufalin inhibited cell proliferation and promoted cell apoptosis by down-regualtion of miR-298. In summary, bufalin-associated miR-298 may indirectly be involved in cell proliferation and apoptosis by targeting BAX, pointing to use as a potential molecular target in gastric cancer therapy. PMID- 26064233 TI - Association between PON1 L55M polymorphism and ischemic stroke: a systematic review and meta-analysis. AB - OBJECTIVE: The present study aims to evaluate the relation between PON1 L55M polymorphism and ischemic stroke by a meta-analysis method. METHODS: English and Chinese databases were retrieved to find qualified studies; a random or fixed effects model was used to merge the odds ratio (OR); Q test was used to assess the heterogeneity among studies, and Egger's test and funnel plot were used for the assessment of publication bias. RESULTS: 14 studies were included in the meta analysis; in total populations, there was no association between PON1 gene L55M polymorphism and ischemic stroke in additive, dominant, and recessive model, respectively. Furthermore, we did not found associations between L55M and ischemic stroke in Asian or Caucasian population. CONCLUSION: Available evidences suggested that L55M polymorphism had no effect on the risk of ischemic stroke. However, this conclusion needs further validation by larger sample and well designed studies. PMID- 26064234 TI - Enterobacter cloacae infection after anterior cervical decompression and fusion: case study and literature review. AB - Wound infection after anterior cervical decompression and fusion can lead to disastrous consequences despite a low incidence rate. Although Gram-positive bacteria such as Staphylococcus aureus are the most common pathogenic bacteria, some rare bacteria such as conditional pathogenic bacteria may also result in such a condition. To the best of our knowledge, E. cloacae-caused acute infection after anterior cervical decompression and fusion has not been reported. Here, we report an E. cloacae-caused acute infection after anterior vertical decompression and fusion. This infection was eventually controlled by virtue of an early diagnosis and the correspondingly-adopted anti-infection, internal fixation removal, and drainage treatments. Exploring the reasons underlying acute infection after anterior cervical decompression and fusion caused by rare bacteria, particularly E. cloacae, by analyzing this case was the basic therapeutic principle in this study. We believe that the therapeutic principle for E. cloacae-caused wound infection after anterior cervical internal fixation is basically consistent with that for other bacterium-caused wound infections after spinal internal fixation. Sufficient drainage, the adoption of sensitive antibacterials, and internal fixation removal as early as possible when necessary are the essential measures in infection control. PMID- 26064235 TI - Chrysophanol affords neuroprotection against microglial activation and free radical-mediated oxidative damage in BV2 murine microglia. AB - In this study, chrysophanol, isolated from a marine fungus, was examined for its protective effects against inflammatory responses and oxidative stress in BV2 microglia. Chrysophanol was studied to assess its capabilities of protecting against lipopolysaccharide (LPS)-induced inflammatory responses in BV2 cells. It was found that chrysophanol reduced the level of nitric oxide (NO) and prostaglandin-E2 (PGE2) production by diminishing reducing the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2). Assessment of the inhibitory activities of chrysophanol on the generation of pro-inflammatory cytokines was also performed. Furthermore, Chrysophanol treatment significantly reduced intracellular reactive oxygen species (ROS)-mediated cell damage and inhibited DNA oxidation in BV2 cells. Moreover, antioxidative mechanisms by of chrysophanol were evaluated investigated by measuring the expression levels of antioxidative enzymes such superoxide dismutase (SOD) and glutathione (GSH). Therefore, results suggested that chrysophanol has potential antioxidant and anti inflammatory activities in microglia and further might be a useful therapeutic agent for the treatment of neurodegenerative diseases. PMID- 26064236 TI - Immunostimulatory activities of dendritic cells loaded with adenovirus vector carrying HBcAg/HBsAg. AB - OBJECTIVE: This study is to investigate the immunostimulatory activities of dendritic cells (DCs) transfected with HBcAg and/or HBsAg recombinant adenovirus (rAd). METHODS: DCs were transfected with rAd (DC/Ad-C+Ad-S, DC/Ad-C, and DC/Ad S), or pulsed with HBcAg antigen (DC/HBcAg). Flow cytometry was used to detect the phenotype of DCs and the cytokine production of T lymphocytes. Mice were vaccinated with DCs transfected with rAd or pulsed with antigen, and DNA vaccine. Mixed lymphocyte reaction (MLR) was used to evaluate the T-cell stimulatory capacity, and HBcAg-specific cytotoxic T lymphocyte (CTL) activity was assessed. RESULTS: Phenotypic analysis showed that DCs transfected with rAd or pulsed with HBcAg antigen exhibited mature phenotypes. MLR indicated no significant differences in stimulating T-cell proliferation between the DC/rAd and DC/HBcAg groups. When mixed with DCs, Th and Tc cells mainly secreted IFN-gamma, indicating type I immune responses. In vaccinated mice, DCs transduced with rAd and pulsed with HBcAg induced significantly more IFN-gamma secretion from Th cells, compared with DNA vaccine, indicating stronger Th1 response. Moreover, DCs transduced with rAd stimulated Tc cells to produce more IFN-gamma, indicating stronger Tc1 response. In vaccinated mice, HBcAg-specific CTL activities were decreased in the following order: the DC/Ad-C+Ad-S, DC/Ad-C, DC/Ad-S, DC/HBcAg, and DNA vaccine groups. CONCLUSION: DCs transfected with rAd induce stronger Th1/Tc1 (type I) cell immune responses and specific CTL response than HBcAg pulsed DCs or DNA vaccine. Our findings suggest that DCs transfected with rAd C/rAd-S might provide an effective approach in the treatment of persistent hepatitis B virus infection. PMID- 26064238 TI - NUDT11 rs5945572 polymorphism and prostate cancer risk: a meta-analysis. AB - The association between the NUDT10 rs5945572 polymorphism and prostate cancer (PCa) was not clear. We thus conducted a meta-analysis to assess the association between NUDT10 rs5945572 polymorphism and PCa risk. A literature search was carried out using PUBMED, EMBASE, and Cochrane Library Central database before Dec 2014. The strength of the associations between the NUDT10 rs5945572 polymorphism and PCa risk was measured by odds ratios (OR) with 95% confidence intervals (CI). The random-effects model was used. NUDT10 rs5945572 polymorphism was significantly associated with PCa risk (OR = 1.22, 95% CI 1.19-1.26, P < 0.001, I(2) = 0%, Figure 2). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 1.25, 95% CI 1.00-1.57, P = 0.05, I(2) = 0%), and Asians (OR = 1.23, 95% CI 1.19-1.28, P < 0.001, I(2) = 0%), and Africans (OR = 1.22, 95% CI 1.03-1.45, P = 0.02, I(2) = 48%). In conclusion, this meta-analysis found a significant association between NUDT10 rs5945572 polymorphism and prostate cancer. PMID- 26064237 TI - Endothelin-A receptor antagonists in prostate cancer treatment-a meta-analysis. AB - Prostate cancer remains the second leading cause of cancer death in men due to inefficiency of androgen deprivation therapy or androgen blockade. Endothelins (ETs) and the two endothelin receptor family members A and B (ETA and ETB) are known to play important roles in the progression of many malignancies, including prostate cancer. However, phase III clinical studies did not reach a unanimous conclusion regarding ETA receptor antagonists in prostate cancer treatment. Here, we provide a meta-analysis of clinical studies using ETA receptor antagonists to treat prostate cancer, especially the hormone refractory prostate cancer (HRPC). Data were extracted from nine studies that used Zibotentan or Atrasentan, two selective ETA receptor antagonists, to treat prostate cancer and meet the selection criteria. The results indicated that the overall survival (OS) and the progression-free survival (PFS) of patients treated with Zibotentan did not show significant difference with the patients treated with placebo (pooled hazard ratio (HR) for OS, 0.86, 95% CI 0.70-1.06; pooled HR for PFS, 0.98, 95% CI 0.91 1.06). No statistically significant difference was detected either as to the OS and PFS of patients between the Atrasentan treated group and the group treated with placebo (pooled HR for OS, 0.99, 95% CI 0.90-1.08; pooled HR for PFS, 0.94, 95% CI 0.86-1.02). Notably, the level of prostate-specific antigen (PSA) and the incidence of bone pain were significantly lower in the Atrasentan treated patients compared to the controls (pooled HR for time of PSA progression, 0.87, 95% CI 0.78-0.97; and pooled relative risk (RR) for bone pain, 0.68, 95% CI 0.48 0.97). In addition, increasing of PSA and bone alkaline phosphatase (BALP) were significantly delayed with Atrasentan treatment (P<0.05). Together, these data suggest that Atrasentan has an effect on cancer-related bone pain and skeletal events in patients with prostate cancer. PMID- 26064239 TI - MiR-374a promotes the proliferation of human osteosarcoma by downregulating FOXO1 expression. AB - MiRNAs play crucial roles in development of cancer. However, the underlying mechanisms of miRNAs in osteosarcoma (OS) are poorly understood. In the present study, we reported that the expression of miR-374a was markedly upregulated in OS tissues and OS cells compared with the matched adjacent normal tissues and human osteoclast h-FOB cell lines. Overexpression of miR-374a promoted the proliferation and anchorage-independent growth of OS cells, whereas inhibition of miR-374a showed opposite effect. Furthermore, we identified that FOXO1 is the functional target of miR-374a. MiR-374a-induced proliferation was correlated with FOXO1, upregulating of the cell cycle regulator cyclin D1 and downregulating of cyclin-dependent kinase inhibitors p27. In functional assays, FOXO1 downregulation is required for miR-374a-induced OS cell proliferation. In sum, our data provide compelling evidence that a novel mechanism of FOXO1 suppression mediated by miR-374a in OS. PMID- 26064240 TI - MiR-592 inhibited cell proliferation of human colorectal cancer cells by suppressing of CCND3 expression. AB - Accumulating evidence shows that microRNA (miRNA) is frequently associated with multiple kinds of human cancers, including colorectal cancer (CRC). Previous studies have shown that miR-592 play critical roles in cancer cell biological processes. However, the function of miR-592 in CRC remains largely unknown. In the present study, we investigated the miR-592's role in cell proliferation of colorectal cancer. MiR-592 expression was markedly down-regulated in CRC tissues and CRC cells. Overexpression of miR-592 reduced the proliferation and anchorage independent growth of CRC cells. Furthermore, bioinformatics analysis further revealed CCND3, a putative tumor promoter, was found to be a potential target of miR-592 in CRC. The dual-luciferase reporter gene assay results showed that CCND3 was a direct target of miR-592. Ectopic expression of miR-592 led to down regulation of CCND3 protein, which resulted in the down-regulation of phosphorylated retinoblastoma (p-Rb). In functional assays, CCND3-silenced in miR 592-in-transfected SW48 cells have positive effect to suppress cell proliferation, suggesting that direct CCND3 suppression is required for miR-592 induced cell proliferation of CRC. We conclude that miR-592 can regulate CCND3 and function as a tumor suppressor in CRC. Therefore, miR-592 represents a potential anti-onco-miR and serves as a useful therapeutic agent for miRNA-based CRC therapy. PMID- 26064241 TI - Biodegradation and biocompatibility of a degradable chitosan vascular prosthesis. AB - An instrument made by ourselves was used to fabricate biodegradable chitosan heparin artificial vascular prosthesis with small internal diameter (2 mm) and different crosslinking degree from biodegradable chitosan, chitosan derivates and heparin. In vivo and in vitro degradation studies, inflammatory analysis and electron microscope scanning of this artificial vascular prosthesis were performed. It was observed that 50% of the prosthesis decomposed in vivo and was replaced by natural tissues. The degradation process of the chitosan-heparin artificial vascular prosthesis of small diameter could be controlled by changing the crosslinking degree. This kind of artificial vascular prosthesis shows good biocompatibility that can be controllability designed to achieve desirable in vascular replacement application. PMID- 26064242 TI - Negative pressure wound therapy accelerates rats diabetic wound by promoting agenesis. AB - Negative Pressure Wound Therapy (NPWT) has become widely adopted to several wound treatment over the last 15 years, including diabetic foot ulcer (DFU). Much of the existing evidence supports that NPWT increase in blood flow, reduce in edema, decrease bacterial proliferation and accelerate granulation-tissue formation. However, the accurate mechanism is not clear till now. The aim of the present study was to further elucidate the effects of NPWT on angiogenesis of diabetic wound model. As result, our data showed: 1) NPWT promoted the wound healing and blood perfusion on both diabetic and normal wound compared with control, 2) The NPWT increased wound vessel density, and the wound treated with NPWT showed well developed and more functional vessels at day 7 post operation compared with control 3) NPWT up regulated the expression of VEGF at day 3 and Ang1 at day 7 on RNA and protein level. 4) Ang2 was up regulated in diabetic rats but NPWT attenuated this affection. Our data indicated that NPWT increased vessel density and promoted the maturation of neovascular over the potential mechanism of up regulated VEGF and Ang1 and down regulated of Ang2. PMID- 26064243 TI - Neuroprotective effect of ginseng against spinal cord injury induced oxidative stress and inflammatory responses. AB - The pathophysiological effects of spinal cord injury (SCI) occur as a result of oxidative stress and inflammatory mechanisms. In the present study we analyzed the protective role of ginseng on spinal injury in wistar rats. To evaluate the redox status, we investigated various parameters including estimation of reactive oxygen species, lipid peroxidation content, protein carbonyl and sulphydryl content, myeloperoxidase activity, antioxidant status (superoxide dismutase, catalase, glutathione peroxidase, glutathione-s-transferase). Expression of antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) was determined through immunoblot. Inflammatory study was performed by evaluating the expression of nuclear factor-kappaB, cycloxygenase-2 by western blot analysis. Further the pro-inflammatory cytokines were determined through ELISA (IL-6, TNF-alpha, IL-1beta). We observed a significant enhancement in oxidative stress and inflammatory markers in rats with SCI injury. Ginseng treatment significantly down regulated the oxidative stress by enhancing the antioxidant status in SCI rats. Significant inhibition of inflammation was observed through down regulation of inflammatory proteins and pro-inflammatory cytokines. Thus our findings show that Ginseng significantly ameliorated spinal cord injury in wistar rats by modulating oxidative stress and inflammation. PMID- 26064245 TI - Cardiac output measurement using a modified carbon dioxide Fick method: comparison analysis with pulmonary artery catheter method and pulse induced contour cardiac output method. AB - OBJECTIVES: In the present study, cardiac output in mechanically ventilated patients were determined using three methods including modified CO2-Fick (mCO2F), pulmonary artery catheter (PAC), and pulse induced contour cardiac output (PiCCO) methods and the results were compared to assess the effectiveness of mCO2F method in measuring the cardiac output. METHOD: Mechanically ventilated and hemodynamically unstable patients (n=39) were sedated and intubated with Swan Ganz or PiCCO arterial catheters. At the beginning of the experiment and at 4 h after the experiment, the CO2 concentration in expiratory air was measured through a CO2 monitor and it was used further in the cardiac output calculation using mCO2F method. The cardiac output was also determined using PAC and PiCCO methods. RESULTS: The cardiac output determined by PAC and mCO2F method was not significantly (P>0.05) different [5.53+/-2.85 L.min(-1) (PAC) and 5.96+/-2.92 L.min(-1) (mCO2F)] at the beginning of the experiment and [6.22+/-2.7 L.min(-1) (PAC) and 6.36+/-2.35 L.min(-1) (mCO2F)] at 4 h after the experiment; however, they were highly correlated (r=0.939 and 0.908, P<0.001). The cardiac output determined by PiCCO and mCO2F method was also not significantly (P>0.05) different [6.05+/-2.49 L.min(-1) (PiCCO) and 5.44+/-1.64 L.min(-1) (mCO2F)] at the beginning of the experiment, and [6.17+/-2.04 L.min(-1) (PiCCO) and 5.70+/ 1.72 L.min(-1) (mCO2F)] at 4 h after the experiment; however, they were highly correlated (r=0.776 and 0.832, P<0.001). CONCLUSION: The mCO2F method could accurately measure the cardiac output in mechanically ventilated patients without using any expensive equipment's and invasive procedures. PMID- 26064246 TI - A novel green synthesis of silver nanoparticles using soluble starch and its antibacterial activity. AB - A green method of Silver nanoparticles (AgNPs) preparation has been established. This method depends on reduction of silver nitrate with soluble starch. The formation of AgNPs was observed by the color change from colorless to dark brown through the starch addition into silver nitrate solution. It was observed that use of starch makes convenient method for the synthesis of silver nanoparticles and can reduce silver ions into the produced silver nanoparticles within one hour of reaction time without using any harsh conditions. The prepared silver nanoparticles were characterized by using UV-visible spectroscopy and evaluated for its antimicrobial activity. The synthesized green AgNPs showed a potential antibacterial activity that was stronger against Gram positive pathogenic bacteria (Staphylococus aureus and Streptococus pyogenes) than against Gram negative pathogenic bacteria (Salmonella typhi, Shigellasonnei and Pseudomonas aeruginosa). Inhibition zones diameter of antibacterial activity depends upon nanoparticles concentration as AgNPs exhibited greater inhibition zone for S.aureus (16.4 mm) followed by P. aeruginosa and S. pyogenes while the least activity was observed for S. typhi (10.4 mm) at 40 MUl/ disc. These results suggested that AgNPs can be used as an effective antiseptic agents in medical fields and process of synthesis creates new opportunities in process development for the synthesis of safe and eco-friendly AgNPs. PMID- 26064244 TI - Effect of ginkgolide B on brain metabolism and tissue oxygenation in severe haemorrhagic stroke. AB - Ginkgolide B, a diterpene, is an herbal constituent isolated from the leaves of Ginkgo biloba tree. The present study demonstrates the effect of ginkgolide B in osmotherapy on brain metabolism and tissue oxygenation. Multimodality monitoring including intracranial pressure (ICP), cerebral perfusion pressure (CPP), partial pressure of brain tissue oxygen (PbtO2), lactate/pyruvate ratio (LPR) and microdialysis were employed to study the effect of ginkgolide B osmotherapy. The results demonstrated that administration of 15% solution of ginkgolide B to the comatose patients with raised ICP (> 20 mm Hg) and resistant to standard therapy led to a significant decrease in ICP. The cerebral microdialysis was used to compare mean arterial blood pressure (MAP), ICP, CPP, PbtO2, brain lactate, pyruvate and glucose level after hourly intervals starting 3 h before and up to 4 h after hyperosmolar therapy. There was a decrease in ICP in 45 min from 23 +/- 14 mm Hg (P < 0.001) to 18 +/- 24 mm Hg and increase in CPP after 1 h of gingkolide B infusion from 74 +/- 18 to 85 +/- 22 mm Hg (P < 0.002). However there was no significant effect on MAP but PbtO2 was maintained in the range of 22-26. The peak lactate/pyruvate ratio was recorded at the time of initiation of osmotherapy (44 +/- 20) with an 18% decrease over 2 h following gingkolide B therapy. Also the brain glucose remained unaffected. PMID- 26064247 TI - GFA Taq I polymorphism and cleft lip with or without cleft palate (CL/P) risk. AB - The transforming growth factor alpha (TGFA) Taq I polymorphism has been indicated to be correlated with cleft lip with or without cleft palate (CL/P) susceptibility, but study results are still debatable. Thus, a meta-analysis was conducted. We conducted a comprehensive search of Embase, Ovid, Web of Science, the Cochrane database, PubMed, the Chinese Biomedical Literature Database (CBM disc, 1979-2014), the database of National Knowledge Infrastructure (CNKI, 1979 2014) and the full paper database of Chinese Science and Technology of Chongqing (VIP, 1989-2014) to identify suitable studies. There were 18 studies suitable for this meta-analysis, involving a total of 3135 cases and 3575 controls. Significantly increased CL/P risk was observed (OR = 1.49; 95% CI 1.17-1.89; P = 0.001). In subgroup analyses stratified by ethnicity, there was evidence in the Caucasian population for an association between this polymorphism and CL/P risk (OR = 1.52; 95% CI 1.14-2.02; P = 0.004). However, no significant association was found between this his polymorphism and CL/P risk in African and Hispanic populations. According to a specific CL/P type, increased clip lip and palate risk and clip palate risk were found (OR = 1.38; 95% CI 1.10-1.73; P = 0.005; OR = 1.29; 95% CI 1.01-1.66; P = 0.042). In conclusion, the present meta-analysis found that the TGFA Taq I polymorphism may be associated with CL/P susceptibility. PMID- 26064248 TI - Five-year follow-up after conversion from calcineurin inhibitor to sirolimus based treatment in kidney transplant patients with chronic allograft nephropathy. AB - Chronic allograft nephropathy (CAN) is a major cause of graft loss in long-term kidney transplant recipients. To identify the safety and efficacy of conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) in patients with CAN, we investigated 92 biopsy demonstrated CAN patients during a 5-year follow-up.45 patients were converted to sirolimus treatment (SRL group) and remaining 47 patients continued CNI immunosuppression (CNI group). Renal function, proteinuria, hepatic function, lipid level and blood routine examination were observed for 60 months in each group. During the period of conversion, serum creatinine was superior in SRL group to CNI group. It dropped significantly from (174.0 +/- 62.8) umol/L to (150.7 +/- 83.4) umol/L in SRL group whereas increased to (200.9 +/- 73.5) umol/L in CNI group (P < 0.05). However, SRL group showed increased proteinuria, triglycerides and decreased Plt (P < 0.05). We also found those patients in SRL group with a good baseline of renal function (serum creatinine < 200 umol/L or proteinuria < 800 mg/day at conversion) would ameliorate the impaired renal function from CAN at 60 months. In conclusion, it is safe and effective to convert from CNI to SRL for patients with CAN in our long-term observation. Early conversion is associated with an improvement of renal function. PMID- 26064249 TI - Longitudinal analysis of meta-analysis literatures in the database of ISI Web of Science. AB - The meta-analysis is regarded as an important evidence for making scientific decision. The database of ISI Web of Science collected a great number of high quality literatures including meta-analysis literatures. However, it is significant to understand the general characteristics of meta-analysis literatures to outline the perspective of meta-analysis. In this present study, we summarized and clarified some features on these literatures in the database of ISI Web of Science. We retrieved the meta-analysis literatures in the database of ISI Web of Science including SCI-E, SSCI, A&HCI, CPCI-S, CPCI-SSH, CCR-E, and IC. The annual growth rate, literature category, language, funding, index citation, agencies and countries/territories of the meta-analysis literatures were analyzed, respectively. A total of 95,719 records, which account for 0.38% (99% CI: 0.38%-0.39%) of all literatures, were found in the database. From 1997 to 2012, the annual growth rate of meta-analysis literatures was 18.18%. The literatures involved in many categories, languages, fundings, citations, publication agencies, and countries/territories. Interestingly, the index citation frequencies of the meta-analysis were significantly higher than that of other type literatures such as multi-centre study, randomize controlled trial, cohort study, case control study, and cases report (P<0.0001). The increasing numbers, intensively global influence and high citations revealed that the meta analysis has been becoming more and more prominent in recent years. In future, in order to promote the validity of meta-analysis, the CONSORT and PRISMA standard should be continuously popularized in the field of evidence-based medicine. PMID- 26064250 TI - STAT4 polymorphisms and diabetes risk: a meta-analysis with 18931 patients and 23833 controls. AB - Some studies were conducted to investigate the association between signal transducer and activator of transcription 4 (STAT4) polymorphisms and diabetes risk. However, the results were inconsistent. We thus did a meta-analysis. We searched the articles in the PubMed, Embase and CNKI databases (the last search updated on November 2014). Pooled odds ratios (OR) with 95% confidence intervals (CI) were derived from random-effects models or fixed-effects models. Ten case control studies with 18931 cases and 23833 controls were included in this study. STAT4 rs7574865 polymorphism was significantly associated with diabetes risk (OR = 1.28; 95% CI 1.16-1.42; P < 0.00001). This polymorphism also increased type 1 diabetes risk significantly (OR = 1.27; 95% CI 1.15-1.41; P < 0.00001). In the subgroup analysis by ethnicity, a significant association was found among Asians (OR = 1.33; 95% CI 1.04-1.71; P = 0.02) and Caucasians (OR = 1.24; 95% CI 1.12 1.38; P < 0.0001). In the subgroup analysis by age, both children (OR = 1.28; 95% CI 1.12-1.45; P = 0.0002) and adults (OR = 1.27; 95% CI 1.13-1.42; P < 0.0001) with this polymorphism showed increased diabetes risk. Other STAT4 polymorphisms were not investigated in this meta-analysis due to insufficient data. This meta analysis indicated that STAT4 rs7574865 polymorphism was associated with diabetes risk. PMID- 26064251 TI - Impact of sleeve gastrectomy verses sleeve gastrectomy plus side-to-side jejunoileal anastomosis on weight loss and metabolic control in an obese rat model. AB - AIM: To study the impact of sleeve gastrectomy plus side-to-side jejunoileal anastomosis on weight loss and the remission of type 2 diabetes mellitus. METHODS: Thirty-three 7 weeks old male Zucker diabetic fatty rats were randomized into three groups: sleeve gastrectomy plus side-to-side jejunoileal anastomosis (JI-SG group), sleeve gastrectomy (SG group), sham surgery (Control group). RESULTS: The weight of rats in JI-SG group and SG group was significantly lower than control group at 2 weeks postoperatively, and body weight in JI-SG group was lower than SG group since 4 week postoperatively. The blood Glucose was significantly improved for both JI-SG group and SG group, and increased in Control group at 2 weeks after surgery. The serum ghrelin level of rats in JI-SG, SG group was significantly decreased, but without difference between two groups; compared with that preoperatively, the GLP-1 level of rats in JI-SG group was significantly higher at 12 weeks postoperatively; SG group and SO group had no difference in the GLP-1. The serum insulin level in rats was also decreased in JI SG group and SG group at 6 weeks postoperatively, and plasma insulin level in JI SG group was significantly lower than those in the SG group at 12 weeks postoperatively. CONCLUSIONS: JI-SG is superior to SG as the treatment of type 2 diabetes mellitus and weight control in obese diabetic rodents. PMID- 26064252 TI - Unilateral posterior vertebral column resection for severe thoracolumbar kyphotic deformity caused by old compressive vertebrae fracture: a technical improvement. AB - Severe thoracolumbar kyphotic deformity caused by old compressive vertebrae fracture remains a big challenge for spine surgeons. When symptoms related to significant deformities cannot be adequately managed conservatively, posterior vertebral column resection (PVCR) is required, but with long operating time and severe blood loss. We develop a UPVCR technique, which is done through a unilateral approach instead of a bilateral approach, vertebral body resection advancing to cross the midline in an abrasive way from an extreme oblique orientation enable the resection of most contralateral vertebral body. In the present study, the effects of UPVCR for severe thoracolumbar kyphotic deformity were investigated. We did find that satisfactory correction of sagittal deformity, functional improvement and pain relief can be achieved by UPVCR, and it has the advantage of shortening surgery time, reducing blood loss and incidence of nerve root impingement over PVCR. PMID- 26064253 TI - Effects and mechanisms of icariin on atherosclerosis. AB - PURPOSE: Icariin, a flavonoid isolated from the traditional Chinese herbal medicine Epimedium brevicornum Maxim, has been shown to process anti inflammatory, antioxidative actions and anti-atherosclerosis activity in vivo and in vitro. The purpose of this study was to investigate the effects and mechanisms of icariin on atherosclerosis by human umbilical vein endothelial cells (HUVECs). METHODS: The effects of icariin on the activity of HUVECs induced by oxidized low density lipoprotein (ox-LDL) were detected by MTT assay. Then we studied the effects of icariin on the adhesion of monocyte with HUVECs induced by ox-LDL. The secretion of E-selectin, intercellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1) by HUVECs were measured by enzyme-linked immunosorbent assay (ELISA) method. Finally the mRNA levels of ICAM-1, VCAM-1, E selectin of HUVECs were analyzed by real time RT-PCR. RESULTS: MTT result indicated that icariin (10, 20, 40 MUmol/L) could inhibit HUVECs injury induced by ox-LDL in a concentration-dependent manner (P < 0.05). The adhesion of monocyte with HUVECs induced by ox-LDL was inhibited by icariin in a concentration-dependent manner (P < 0.05). The levels of ICAM-1, VCAM-1, E selectin of icariin groups were significantly decreased in a concentration dependent manner compared with ox-LDL-simulated group (P < 0.05). The mRNA expressions of ICAM-1, VCAM-1, E-selectin of icariin groups were also downregulated significantly compared with ox-LDL-simulated group (P < 0.05). CONCLUSIONS: Icariin can prevent atherosclerotic lesion. Its mechanism may be that it can defend against the oxidation damage to HUVECs, inhibit the adhesion of monocyte to HUVECs, and reduce the secretion and expression of adhesion molecules including ICAM-1, VCAM-1, E-selectin. PMID- 26064254 TI - CYP1A1 genetic polymorphisms and uterine leiomyoma risk: a meta-analysis. AB - BACKGROUND: Some studies assessed the association between CYP1A1 MspI and Ile462Val polymorphisms and uterine leiomyoma (UL) risk. However, the results were controversial. We did this meta-analysis to determine the association between CYP1A1 MspI and Ile462Val polymorphisms and UL risk. MATERIALS AND METHODS: We searched databases containing PubMed, Springer Link, EMBASE, Chinese National Knowledge Infrastructure (CNKI) up to 11 October 2014. Pooled ORs and 95% CIs were used to assess the strength of the associations. RESULTS: In total, 9 case-control studies with 2157 UL cases and 2197 healthy controls were included in this meta-analysis. CYP1A1 Ile462Val polymorphism was significantly associated with UL risk (OR = 2.29, 95% CI 1.75-2.99, P < 0.00001). In the subgroup analysis by race, significantly increased risks were found in the Asians (OR = 2.76, 95% CI 1.86-4.09, P < 0.00001) and Caucasians (OR = 1.87, 95% CI 1.30-2.68, P = 0.0007). However, MspI polymorphism was not significantly associated with UL risk (OR = 1.15, 95% CI 0.90-1.47, P = 0.27). In the subgroup analysis by race, no significant association was found in the Asians (OR = 1.15, 95% CI 0.86-1.54, P = 0.35). CONCLUSION: In summary, the results of the meta-analysis suggested that CYP1A1 Ile462Val polymorphism was significantly associated with UL risk. PMID- 26064255 TI - CD44 family proteins in gastric cancer: a meta-analysis and narrative review. AB - With a meta-analysis and narrative review, we evaluated the clinical and prognostic role of all CD44 family proteins in gastric cancer (GC). Literatures published up to August 2014 were searched on PubMed. Among the 37 eligible studies (6606 patients), 34 were included in meta-analysis, and 10 were subjected to narrative review. With meta-analysis, standard CD44 (CD44s) was demonstrated to predict reduced overall survival (OS) (HR = 1.93, 95% CI: 1.58-2.34, PHR = 0.0222) and disease free survival (HR = 3.13, 95% CI: 1.02-9.68, PHR = 0.0469), advanced N-stage (RR = 1.12, 95% CI: 1.04-1.21, PRR = 0.0019), and distant metastasis (RR = 2.14, 95% CI: 1.46-3.14, PRR < 0.0001) of GC. CD44 variant 6 (CD44v6) in GC might influence OS (5 studies; HR = 1.27, 95% CI: 0.75-2.14, PHR = 0.3783; 4 studies; HR = 1.52, 95% CI: 1.09-2.14, PHR = 0.0139), while significantly associated with N-stage (RR = 1.23, 95% CI: 1.03-1.48, PRR = 0.0240), M-stage (RR = 2.54, 95% CI: 1.08-6.00, PRR = 0.0333), TNM-stage (RR = 1.72, 95% CI: 1.18-2.50, PRR = 0.0045), Lauren type (RR = 0.67, 95% CI: 0.50 0.91, PRR = 0.0106), lymphatic invasion (RR = 1.13, 95% CI: 1.04-1.23, PRR = 0.0057), and liver metastasis (RR = 3.20, 95% CI: 1.94-5.27, PRR < 0.0001) of the disease. Moreover, a narrative review was performed for CD44 isoforms, such as v3, v5, v7, v8-10, and v9, in GC. In conclusion, CD44s and CD44v6 as evaluated by immunohistochemistry, respectively, predicts the prognosis and disease severity of GC. PMID- 26064256 TI - A noncytolytic antibody-like extendin-4-IgG4 fusion protein as a long-acting potential anti-diabetic agent. AB - BACKGROUND: GLP-1 and its analogs have a variety of anti-diabetic effects. However, short half-life and rapid degraded by DPP-IV limits the therapeutic potential of the native GLP-1. So, many DPP-IV-resistant and long-acting GLP-1 analogs were developed. In this study, an antibody-like extendin-4-IgG4 fusion protein was developed. METHODS: The gamma4 constant region contains two amino acid substitutions relative to native gamma4 (S228P and L235E) lead to affinity for FcgammaRI to be low and stability of the IgG4 molecular. The fusion protein was expressed in CHO cells and assembled into an immunoglobulin-like structure with molecular weight of approximately 130 kDa. RESULTS: The Exendin-4-IgG4 fusion protein was found to affinity bind GLP-1R in vitro. In vivo when compared the potency and duration of glucose-lowering effects in diabetic (db/db) mice at the same dose, exendin-4 resulted in a glucose-lowering effect that persisted only for 6 hours, but the extendin-4-IgG4 fusion protein for more than 168 hours. Injecting subcutaneously with a high dose of the fusion protein led normal BALB/c mice to the lower blood glucose level but did not cause serious hypoglycemia. Especially, the half-life time of the fusion protein in cynomolgus monkeys was about 180 hours, almost the longest half-life time among the developed GPL-1 analogues, which suggested a longer half-life time in human. CONCLUSIONS: The intact antibody-like fusion protein has more advantages than the Fc fusion protein including the intent of prolonging the half-life. These results also suggested the fusion protein was a safe and long-acting potential anti-diabetic agent. PMID- 26064257 TI - Interaction network analysis of differentially expressed genes and screening of cancer marker in the urine of patients with invasive bladder cancer. AB - OBJECTIVE: To detect the expression profile of bladder cancer and to delineate the interaction network of these genes in invasive bladder cancer. METHODS: A total of 126 differentially expressed genes were identified, and input into STRING online database to delineate interaction network. The network data were screened with central nodes. The expression of genes with the most evident change in the exfoliated cells of urine was detected. RNA markers with over-expression in stage Ta tumor and/or T1 to T4 tumors but low expression in blood or inflammatory cells were characterized. RESULTS: On the basis of assay of 21,639 whole-genome oligonucleotide microarray, a total of 126 differentially expressed genes were identified, of which 69 had up-regulated expression and 57 had down regulated expression. STRING screening showed there were interactions among 103 genes in the bladder cancer which formed a complex network. A total of 23 central nodes were screened with Cytoscape and are involved in multiple signaling pathways related to tumorigenesis. The test specificity was 80% for the 30 control patients with urinary tract infections. The combination of BLCA-4 and HOXA13 could distinguish between low and high grade tumors, with specificity and sensitivity of 80%. CONCLUSION: The interaction network of differentially expressed genes, especially the central nodes of this network, can provide evidence for the early diagnosis and molecular targeted therapy of invasive bladder cancer, and combined detection of IGF-1, hTERT, BLCA-4 and HOXA13 genes is helpful to evaluate BTCC at different stages. PMID- 26064258 TI - Novel autosomal recessive gene mutations in aquaporin-2 in two Chinese congenital nephrogenic diabetes insipidus pedigrees. AB - Recent evidence has linked novel mutations in the arginine vasopressin receptor 2 gene (AVPR2) and aquaporin-2 gene (AQP2) present in Southeast Asian populations to congenital nephrogenic diabetes insipidus (NDI). To investigate mutations in 2 distinct Chinese pedigrees with NDI patients, clinical data, laboratory findings, and genomic DNA sequences from peripheral blood leukocytes were analyzed in two 5.5- and 8-year-old boys (proband 1 and 2, respectively) and their first-degree relatives. Water intake, urinary volume, body weight and medication use were recorded. Mutations in coding regions and intron-exon borders of both AQP2 and AVPR2 gene were sequenced. Three mutations in AQP2 were detected, including previously reported heterozygous frameshift mutation (c.127_128delCA, p.Gln43Aspfs *63) inherited from the mother, a novel frameshift mutation (c.501_502insC, p.Val168Argfs *30, inherited from the father) in proband 1 and a novel missense mutation (c. 643G>A, p. G215S), inherited from both parents in proband 2. In family 2 both parents and one sister were heterozygous carriers of the novel missense mutation. Neither pedigree exhibited mutation in the AVPR2 gene. The patient with truncated AQP2 may present with much more severe NDI manifestations. Identification of these novel AQP2 gene mutations expands the AQP2 genotypic spectrum and may contribute to etiological diagnosis and genetic counseling. PMID- 26064259 TI - Effect of simvastatin on mitochondrial enzyme activities, ghrelin, hypoxia inducible factor 1alpha in hepatic tissue during early phase of sepsis. AB - We aimed to investigate the effects of prior treatment of simvastatin on mitochondrial enzyme, ghrelin, and hypoxia-inducible factor 1 alpha (HIF-1 alpha) on hepatic tissue in rats treated with Lipopolysaccharides (LPS) during the early phase of sepsis. Rats were divided into four groups: control, LPS (20 mg/kg, i.p.), Simvastatin (20 mg/kg, p.o.), and LPS + Simvastatin group. We measured citrate synthase, complex I, II, I-III, II-III enzymes activities, serum and tissue levels of TNF-alpha, IL-10 using ELISA. Liver sections underwent histopathologic examination and TNF-alpha, IL-10, HIF-1alpha and ghrelin immunoreactivity were examined using immunohistochemistry methods. There were no differences in all groups for mitochondrial enzyme activities. In terms of both ELISA and immunohistochemistry findings; the levels of serum and tissue TNF-alpha and IL-10 were higher in the experimental groups than controls (P < 0.05). In the LPS group, the hepatocyte cell membrane and sinusoid structure were damaged. In the Simvastatin +LPS group, hepatocytes and sinusoidal cord structure were partially improved. For HIF-1alpha, in all experimental groups immunoreactivity was increased (P < 0.05). In the Simvastatin group, Ghrelin levels were increased in comparison with the other groups (P < 0.01). Ghrelin levels were greatly decreased in LPS (P < 0.05). We observed that the degree of hepatocellular degeneration was partially reduced depending on the dosage and duration of prior simvastatin treatment with LPS, probably due to alterations of Ghrelin and HIF 1alpha levels. PMID- 26064260 TI - A study of the fluorescence characteristics of common cariogenic microorganisms. AB - OBJECTIVE: To explore the fluorescence characteristics of common cariogenic bacteria: Streptococcus mutans, S. sanguis, Actinomyces viscosus, Prevotella intermedia, Lactobacillus acidophilus, and Candida albicans. METHODS: The bacteria were cultured on brain heart infusion (BHI) agar and BHI blood agar, and bacterial colonies were collected for further amplification in liquid medium. Bacterial suspensions in physiological saline were equally divided into three parts for bacteria counting, fluorescence spectrometry detection, and fluorescence microscope examination. RESULTS: The optimal excitation wavelength of the bacteria was 350 nm; their characteristic fluorescence peak position was at 436 +/- 4 nm. There was a significant linear correlation between fluorescence intensity and bacterial concentration. The mean optical density (MOD) of S. mutans and L. acidophilus cultivated in BHI blood was significantly higher than that cultivated in BHI agar (110 +/- 10 vs. 57 +/- 20; 94 +/- 16 vs. 31 +/- 12, respectively, P < 0.05). The MOD of S. sanguis, A. viscosus, and P. intermedia cultivated in BHI blood agar was higher than that cultivated in BHI agar (37 +/- 12 vs. 36 +/- 11; 43 +/- 17 vs. 38 +/- 6; 86 +/- 21 vs. 72 +/- 8, respectively, P > 0.05); the opposite was observed for C. albicans. CONCLUSION: At 350 nm excitation wavelength, 436 +/- 4 nm is an indicator for detecting six cariogenic bacteria. The fluorescence energy, Q, is a valuable index reflecting bacterial concentration under fluorescence spectrometry detection. Exogenous fluorescence groups have greater influence on fluorescence intensity and little influence on fluorescence peak position detection. PMID- 26064261 TI - MTHFR gene C677T polymorphism and type 2 diabetic nephropathy in Asian populations: a meta-analysis. AB - BACKGROUND: Many studies have suggested a correlation between the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and diabetic nephropathy (DN), but their results are inconclusive. METHODS: To confirm this correlation, we performed a meta-analysis of 15 studies. The dichotomous data are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: The results of this study suggested that the MTHFR 677 T allele was more likely to increase the risk of DN in Asian (OR = 1.466, 95% CI = 1.143-1.880, P = 0.003), West Asian (OR = 1.750, 95% CI = 1.150-2.664, P = 0.009), and Chinese populations (OR = 2.162, 95% CI = 1.719-2.719, P = 0.001), but not in East Asian or Japanese populations. The carriers of the MTHFR 677 T allele were associated with progression of DN in the "5-10 year duration" group, but not in the "> 10 year duration" group (OR = 2.187, 95% CI = 1.787-2.677, P = 0.001). CONCLUSION: Development of DN is associated with MTHFR C677T polymorphisms in Asian populations, especially in early type 2 diabetes. PMID- 26064262 TI - The association between deficient manganese levels and breast cancer: a meta analysis. AB - There are conflicting reports on the correlation between manganese (Mn) levels and breast cancer. The purpose of the present study is to clarify the association between Mn levels and breast cancer using a meta-analysis approach. We searched articles indexed in Pubmed and the Chinese Journal Full-text Database (CJFD) published as of August 2014 that met our predefined criteria. Eleven eligible studies involving 1302 subjects were identified. Overall, pooled analysis indicated that subjects with breast cancer had lower Mn levels than the healthy controls (SMD = -1.51, 95% CI = [-2.47, -0.56]). Further subgroup analysis found a similar pattern in China (SMD = -1.32, 95% CI = [-2.33, -0.32]) and Korea (SMD = -4.08, 95% CI = [-4.63, -3.54]), but not in Turkey (SMD = -0.96, 95% CI = [ 3.19, 1.27]). Further subgroup analysis also found a similar pattern in different sample specimens (serum: SMD = -1.24, 95% CI = [-2.31, -0.16]; hair: SMD = -1.99, 95% CI = [-3.91, -0.06]) and different types of Mn measurement (inductively coupled plasma-atomic absorption spectrometry (ICP-AAS): SMD = -1.14, 95% CI = [ 2.24, -0.04]; graphite furnace atomic absorption spectroscopy (GFAAS): SMD = 1.94, 95% CI = [-2.38, -1.49]; inductively coupled plasma-atomic emission spectrometry (ICP-AES): SMD = -3.77, 95% CI = [-4.70, -2.85]). No evidence of publication bias was observed. In conclusion, this meta-analysis supports a significant association between deficient Mn levels and breast cancer. However, the subgroup analysis found that there was contradiction regarding races and geography, like China and Turkey. Thus this finding needs further confirmation by trans-regional multicenter, long-term observation in a cohort design to obtain better understanding of causal relationships between Mn levels and breast cancer, through measuring Mn at baseline to investigate whether the highest Mn category versus lowest was associated with breast cancer risk. PMID- 26064263 TI - Evaluation of azithromycin induced cardiotoxicity in rats. AB - Although there are possible cardiovascular adverse effects associated with the azithromycin treatment according to some case reports and cohort studies, there is no experimental study evaluating cardiotoxicity in repeated pharmacological doses of this drug. In our study, 15 mg/kg and 30 mg/kg azithromycin were orally administered to rats for 14 days to evaluate the cardiotoxicity of this drug. ECGs of the azithromycin-treated and control animals were recorded. Blood samples were assayed to determine LDH and CK-MB levels. Additionally, CAT, SOD, GSH and MDA levels of heart tissues were measured. According to our ECG recordings, decreased heart rate, prolonged PR and QT intervals, QRS complex and T wave abnormalities were observed in 30 mg/kg azithromycin-administered group significantly when compared with control group. Plasma CK-MB and LDH levels were increased in 30 mg/kg azithromycin-administered group significantly when compared to the control group. In heart tissues, CAT, SOD and GSH levels were decreased while MDA levels were increased in both azithromycin-administered groups significantly when compared with the control group. In conclusion, our findings supported the possible cardiotoxicity risk with azithromycin treatment and also, oxidative stress, which was induced by azithromycin in our study, was thought to be occurred secondary to cardiac toxicity of the drug. PMID- 26064264 TI - The C8092A polymorphism in the ERCC1 gene and breast carcinoma risk: a meta analysis of case-control studies. AB - The C8092A polymorphism in the ERCC1 (excision repair cross-complementation group 1) gene was shown to be associated with breast carcinoma risk. However, the results of different studies remain controversial. A meta-analysis including 3,308 cases and 3,242 controls from eight studies was performed to explore the association between the C8092A polymorphism in the ERCC1 gene and breast cancer risk. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by the random effects model. No significant association was detected in an allelic genetic model (OR: 1.081, 95% CI: 0.994 1.175, P=0.068, Pheterogeneity=0.331), a homozygote model (OR: 1.213, 95% CI: 0.926-1.589, P=0.160, Pheterogeneity=0.071), a heterozygote model (OR: 1.061, 95% CI: 0.958-1.176, P=0.256, Pheterogeneity=0.950), a dominant genetic model (OR: 1.082, 95% CI: 0.981-1.193, P=0.113, Pheterogeneity=0.816) and a recessive genetic model (OR: 1.181, 95% CI: 0.904-1.543, P=0.223, Pheterogeneity=0.060) between the C8092A polymorphism in the ERCC1 gene and breast tumor. A significant relationship between the C8092A polymorphism in the ERCC1 gene and breast tumor in Caucasian group was found in a homozygote genetic model (OR: 1.353, 95% CI: 1.009-1.815, P=0.044, Pheterogeneity=0.516) and a recessive genetic model (OR: 1.339, 95% CI: 1.004-1.785, P=0.047, Pheterogeneity=0.532). Individuals with the C8092A polymorphism in the ERCC1 gene have a higher risk of breast cancer in Caucasians, but not for Asians. PMID- 26064265 TI - Analysis of plasma MicroRNAs to identifying early diagnostic molecule for gastric cancer. AB - Gastric cancer (GC) remains the second leading cause of cancer-related death worldwide. Owing to the lack of early diagnostic techniques, GC is often diagnosed at advanced stage and that leading to low survival rate. Growing evidences have been suggesting that circulating microRNAs play an important role in earlier diagnostic of disease. In the present study, we analyze the circulating miRNAs expression in plasma of volunteers with/without GC aiming to identifying early diagnostic biomarkers. Plasma samples were collected form 6 volunteers including 3 early patients with GC and 3 healthy adults. And then miRNAs microarrays were performed to detect the expression profile of miRNAs in these plasma samples. For further validate the results from miRNAs microarray, qRT-PCR was performed. Finally, target genes of miRNAs were predicted by bioinformatic means. Compared to control plasma, 11 up-regulated and 13 down regulated miRNAs were detected in the plasma from earlier patients with GC (fold change >= 2, P < 0.05). Then, 5 differential expression miRNAs (miR-223, miR-19b 2*, miR-194*, miR-141, miR-1233) were chose to confirm by qRT-PCR. The result is nearly consistent with previous data from miRNAs microarray. Finally, 53 target genes of the 5 miRNAs are predicted by bioinformatics. These differential expression miRNAs may be used as biomarker candidates for minimally invasive diagnosis of early patients with GC in the future. PMID- 26064266 TI - Expression of lncRNA-CCAT1, E-cadherin and N-cadherin in colorectal cancer and its clinical significance. AB - OBJECTIVE: To explore the expression and clinical significance of IncRNA-CCAT and EMT related molecule E-cadherin and N-cadherin in colorectal cancer. METHODS: The expression of IncRNA-CCAT1, E-cadherin and N-cadherin in 37 colorectal cancer tissue and para-carcinoma tissue was detected using qRT-PCR method, and the correlation of expression level with clinical and pathological features was studied. RESULTS: The expression of IncRNA-CCAT1 in tumor tissue was significantly higher than that in normal para-carcinoma tissue (P < 0.001), and the expression level of CCAT1was significantly correlated with local infiltration depth (P < 0.001), tumor staging (P < 0.001), vascular invasion (P < 0.001) and CA19-9 level (P < 0.001); but not related with age, gender, location of tumor, tumor differentiation level, size of primary lesion and level of CEA (P > 0.05). The expression of E-cadherin in tumor tissues was significantly lower than in normal para-carcinoma tissues (P < 0.001), and the expression of N-cadherin was significantly higher than that in normal para-carcinoma tissues. The decrease in expression of E-cadherin and increase in expression of N-cadherin were significantly correlated with local infiltration depth (P < 0.001), tumor staging (P < 0.001), vascular invasion (P < 0.001), tumor differentiation level (P < 0.001) and CA19-9 level (P < 0.001), however not related with age, gender, tumor location, size of primary lesion and CEA level (P > 0.05). CONCLUSION: CCAT1 plays an important role in the genesis, development, invasion and metastasis; it mediates the EMT process of colorectal cancer; and it's expected to be a new marker and treatment target in colorectal diagnosis and treatment. PMID- 26064267 TI - Compatibility of Astragalus and Salvia extract inhibits myocardial fibrosis and ventricular remodeling by regulation of protein kinase D1 protein. AB - AIMS: This study is to determine the effect of astragalus and salvia extract on the alteration of myocardium in a rat model of myocardial infarction. METHODS: A total of 40 male Sprague-Dawley rats were randomly divided into the sham-operated group, the control group, the Astragalus group, the Salvia group, and the compatibility of Astragalus and Salvia and group. The cardiac functions were determined at 8 weeks after treatment. Hematoxylin-eosin staining was performed to observe the morphology and arrangement of cardiomyocytes. Masson's trichrome staining was performed to investigate the distribution of myocardial interstitial collagen. Immunohistochemical staining was performed to determine the expression ofprotein kinase D1 in myocardial tissues. RESULTS: In the sham-operated group, the Astragalus group, the Salvia group, and the compatibility of Astragalus and Salvia group, the left ventricular systolic pressure and the maximum rate of left ventricular pressure were significantly increased while the left ventricular end diastolic pressure were significantly decreased when compared with those in the control group (P < 0.05). Normal morphology and arrangement of cardiomyocytes were maintained in the compatibility of Astragalus and Salvia group. Contents of collagen fibers in myocardial tissues were decreased in the compatibility of Astragalus and Salvia group (P < 0.05). Expression levels of protein kinase D1 were significantly decreased in cardiomyocytes of the compatibility of Astragalus and Salvia group. CONCLUSIONS: Compatibility of Astragalus and Salvia extract may inhibit myocardial fibrosis and ventricular remodeling by regulation of protein kinase D1 protein in a rat model of myocardial infarction. PMID- 26064268 TI - +Gz-induced post-cholecystectomy syndrome in rabbit model by using a telemetric method. AB - Aviation-related mechanism may exist in the post-cholecystectomy syndrome (PCS) of aircrew patients. The aim of this study was to test this hypothesis on vivo rabbit model and to explore the mechanism by using a novel telemetric method. We constructed a bile duct-to-intestinal bridge bypass on 30 rabbits, with a telemetry implant attached to the Oddi's sphincter. Then a telemetric recording system was used to record the biliary pressure fluctuation through the subcutaneous bridge and the changes of electromyography of the Oddi's sphincter under different +Gz acceleration. Self-control comparison was made before and after cholecystectomy. The fully implantable device was very well accepted by rabbits and the data could reflect the real experimental environment simultaneously. Biliary pressure in common bile duct increased accordingly with +Gz acceleration increased, but bile secretion didn't change. Although +Gz acceleration could increase the frequency of burst of spike potentials in the Oddi's sphincter, the frequency didn't change with the +Gz acceleration increased, and the spike activity didn't change obviously before cholecystectomy. After cholecystectomy, the biliary pressure in common bile duct remained high in 12 rabbits (40%) under +Gz exposure, and the pressure value didn't change as the +Gz acceleration increased. The long-time changes in electromyography of the Oddi's sphincter were observed in the same 12 rabbits, with symptoms of PCS developed in 9 of them. +Gz exposure is an important external factor leading to the biliary physiology disorder, and it may induce PCS in some aircrew patients with individual susceptibility, which means gallbladder maybe a dominant factor in regulating the biliary physiology in theses aircrew patients. PMID- 26064269 TI - Histone deacetylase 10 suppresses proliferation and invasion by inhibiting the phosphorylation of beta-catenin and serves as an independent prognostic factor for human clear cell renal cell carcinoma. AB - OBJECTIVE: Histone deacetylase (HDAC) is a tumor suppressor gene in various carcinomas; however, the effect of HDAC10 on human renal cell carcinoma (RCC) remains unknown. In the current study we analyzed the expression and function of HDAC10 in human clear cell RCC. METHODS: RCC tissues from 145 patients who underwent radical nephrectomies were evaluated. HDAC10 protein and mRNA expression was examined by immunohistochemistry and quantitative RT-PCR, respectively. HDAC10 expression was increased by stable transfection with a vector containing full-length cDNA of HDAC10, and HDAC10 expression was decreased by siRNA in two RCC cell lines. Proliferation analysis of RCC cells in vitro was investigated using the WST-1 assay, and the invasion assay was performed using a 24-well Transwell chamber. The phosphorylation of beta-catenin induced by HDAC10 was evaluated by Western blot. RESULTS: HDAC10 expression in RCC tissues was significantly down-regulated compared to normal kidney tissues. Moreover, the low level of HDAC10 expression was uniformly associated with advanced clinical stage, larger tumor diameter, higher pathologic grade, and metastatic RCC. In addition, decreased expression of HDAC10 significantly prompted the proliferation and invasion of RCC cells in vitro. Although HDAC10 did not regulate the expression of beta-catenin, HDAC10 suppressed the phosphorylation of beta-catenin in RCC cells. CONCLUSIONS: HDAC10 expression is suppressed in human clear cell RCC and is involved in development and metastasis of RCC. The findings herein suggest that HDAC10 is an independent predictive factor for RCC prognosis, and restoring HDAC10 expression may be a new therapeutic strategy for advanced RCC. PMID- 26064270 TI - Differential peroxisome proliferator activated receptors activity in a rodent model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder that is characterized by the irreversible loss of corticospinal neurons and motor neurons. Recent studies has demonstrated an anti-inflammatory activity for the Peroxisome Proliferator-Activated Receptor (PPARs) agonists, which in ALS have been able to decrease the production of proinflammatory genes, including cytokines and chemokines. The comprehension of the molecular mechanisms that are responsible for their neuroprotective activity of PPARs could possibly lead to identify new targets for unprecedented therapeutic approaches. Using a PPRE-Luc; hSOD1-G93AALS transgenic mice we investigated the PPAR transcriptional activity over the course of ALS pathogenesis. The analysis of the enzymatic activity of luciferase in the spinal cord and the brain areas of PPRE-Luc; hSOD1-G93A mice showed an abrupt increase of PPAR activity at the end stage of the disease in the spinal cord, which was not shared by the peripheral organs. Furthermore, it was not dependent on the metabolic modifications induced from the starvation that the animals experienced during the last days of their life when they are almost completely paralyzed. Analysis of the nuclear translocation of PPARalpha, PPARbeta/delta and PPARgamma in the spinal cord of hSOD1-G93A mice with an ELISA based Transcription Factor Assay showed that the overall nuclear presence of the different isoforms of PPARs did not change during the course of the disease. Our results indicate that the increase in PPAR activity at the end stage of the disease could represent a compensatory mechanism aimed at counteracting the intense neurodegenerative process which takes place at this time. PMID- 26064271 TI - Association between cytotoxic T-lymphocyte antigen-4 +49A/G polymorphism and colorectal cancer risk: a meta-analysis. AB - The Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) gene has been implicated in the development of colorectal cancer (CRC). However, the results are inconsistent. In this study, we performed a meta-analysis to assess the associations between the CTLA-4 +49A/G polymorphism and risk of CRC. Relevant studies were identified using PubMed, Web of Science, CNKI and WanFang databases up to November 10, 2014. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association using the fixed or random effect model. A total of 8 case-control studies, including 1180 cases and 2110 controls, were included. Overall, a significant association between the CTLA-4 +49A/G polymorphism and CRC risk was found (dominant model: OR=1.63, 95% CI: 1.09-2.43; AG vs. AA: OR=1.69, 95% CI: 1.15-2.48). In the subgroup analysis by ethnicity, we observed a significant association in Asian descent (dominant model: OR=2.42, 95% CI: 1.40 4.16; AG vs. AA: OR=2.39, 95% CI: 1.52-3.76), but not among Europeans; when stratified by source of control, no significant association was detected in both population-based and hospital-based populations. This meta-analysis demonstrated that the CTLA-4 +49A/G polymorphism significantly increases the risk of CRC, especially for Asians. PMID- 26064272 TI - Association of CRR9 locus with elevated risk of squamous cell carcinoma and basal cell carcinoma. AB - BACKGROUND: Published studies have generated inconsistent results related to the contribution of CRR9 rs401681 C allele to the risk of developing non-melanoma skin cancer (NMSC), and it is the inconsistency that promoted us to undertake a meta-analysis to identify the degree of impact the C allele has on NMSC. METHOD: The PubMed, Science Direct, Embase and Cochrane Library were thoroughly searched from the start of November 2013 to the end of April 2014 by using CRR9, polymorphism, skin cancer and their synonyms. Based on a total of 44,036 subjects, we calculated ORs and 95% CIs to measure the influence of the C allele on NMSC predisposition. RESULTS: Overall, individuals carrying the risk C allele at rs401681 had 1.16 times (OR = 1.16, 95% CI: 1.10-1.21, heterogeneity: P = 0.298 and I2 = 0.166, Figure 2) greater risk of NMSC compared to the common T allele. In the further stratified analyses, we found a significant association between the C allele and BCC, Icelanders, and non-Icelanders. CONCLUSION: The results of this meta-analysis suggest that the C allele at rs401681 is likely to modify the genetic predisposition to NMSC. PMID- 26064273 TI - Carriage of NBN polymorphisms and acute leukemia risk. AB - BACKGROUND: Recent reports revealed a significant association of NBN polymorphisms with risk of acute leukemia among Chinese, but not among Europeans. The objective of this study was to obtain a more precise measure of acute leukemia risk associated with NBN rs1805794, rs2735383, rs709816 polymorphisms. METHODS: Using PubMed, Embase, ISI Web of Science, and the Cochrane Library databases, we undertook a systematic literature search up to September 1, 2014. Eligible studies were singled out from 31 possibly related publications by two investigators. Based on the extracted NBN genotypes, we calculated pooled odds ratios (ORs) and 95% confidence intervals (95% CI) by use of the random effects model proposed by DerSimonian and Laird. RESULTS: We finally derived 3,065 subjects for meta-analysis of rs1805794, and found that carriage of the CC genotype was associated with approximately 1.70-fold increased risk of acute leukemia (OR 1.66, 95% CI 1.17-2.36; OR 1.77, 95% CI 1.23-2.54). A 25% higher risk was also identified among the individuals with the C allele (OR 1.25, 95% CI 1.03-1.51). Among 1,553 subjects for rs2735383, no significant association was indicated in the investigated comparison models. Nor did the analysis of 1,485 samples for rs709816 suggest any noteworthy connection. CONCLUSIONS: Carriage of rs1805794 polymorphism in the NBN gene may be associated with the occurrence of acute leukemia. New clinical studies are needed to identify the genetic associations and thus facilitates an increased understanding of the molecular mechanisms of this malignancy. PMID- 26064274 TI - Rare blood donors screening by multiplex PCR methods in Chinese Zhuang and Dong population and pedigree analysis. AB - There are little data available regarding the frequencies of the blood group antigens other than ABO and RhD in the Chinese Zhuang and Dong population. Knowledge of the antigen frequencies is important to assess risk of antibody formation and to guide the probability of finding antigen-negative donor blood, which is especially useful when blood is required for a patient who has multiple red cell alloantibodies. The aim of this study is sought to massively screen for rare blood donors with antigen-negative (e.g. Fy (a-), s-, k-, Di (b-) and Js (b )) in an ethnic Zhuang and Dong population of China, for providing precious rare blood type materials which can be used to improve the capability of compatible infusion and reduce the transfusion reactions. Finally, inheritance of the Fy (a ), s-, k-, Di (b-) and Js (b-) phenotypes was investigated by pedigree analysis. We screened for Fy (a-), s-, k-, Di (b-) and Js (b-) phenotypes in blood donors by multiplex polymerase chain reaction. The rare phenotypes Fy (a-), s-, k-, Di (b-) and Js (b-) were verified by flow cytometry and sequencing analysis. The results indicated that there are five Fy (a-), three s (-), two Di (b-) in 4490 Zhuang random samples and three Fy (a-) in 1927 Dong random samples. In conclusion, this study is the first small step to create a rare donor data bank for Chinese Zhuang and Dong population and to prepare antigen negative compatible blood to patients with multiple alloantibodies. PMID- 26064275 TI - Prevalence of risk factors for diabetic foot complications in a Chinese tertiary hospital. AB - AIMS: To determine the prevalency of risk factors for diabetic foot complications in diabetic patients free of active ulceration in a hospital setting and to investigate the knowledge of foot care of the patients. METHODS: A retrospective study was conducted on a cohort of 296 patients with diabetes hospitalized in a tertiary hospital. A convenience sampling was adopted to recruit subjects during 2012/2013. All completed an interviewer-administered questionnaire and underwent medical assessment including foot examination and assessment of presence of peripheral sensory neuropathy (PSN) and peripheral arterial disease (PVD). The patients were assigned to a foot risk category which was developed by the International Working Group on the Diabetic Foot (IWGDF). RESULTS: 296 inpatients were evaluated. Foot deformity was noticed in 124 patients (42%), hallux valgus was the most prevalent abnormality, found in 65% of patients. Prevalency of neuropathy hypertension, nephropathy and retinopathy were 66.2%, 57.1%, 48.3% and 44.9% respectively. 37 (12.5%) patients had a history of ulceration (n = 33) and/or toe amputation (n = 4). According to the classification system of the IWGDF, 35.1% of patients were considered as having low-risk by the modified IWGDF classification (group 0), and 49% of the study population were at high risk for pedal ulceration (group 2 and 3). There was a clear trend between the increasing severity of the staging and HbA1c, duration of diabetes, prevalence of hypertension, nephropathy and retinopathy and absent of physical activity. The mean knowledge score of foot care was 21.21+/-3.84. CONCLUSION: The risk factors for foot ulceration and lack of fool care knowledge was rather common in a hospital-based diabetic population, emphasizing the importance of implementing simple and affordable screening tools and methods to identify high-risk patients and providing foot care education for them. PMID- 26064276 TI - Study on the molecular regulatory mechanism of MicroRNA-195 in the invasion and metastasis of colorectal carcinoma. AB - OBJECTIVE: This study aims to identify the target gene of hsa-miR-195 and to research the molecular mechanism of hsa-miR-195 which is through its target genes in the colorectal cancer invasion and metastasis. METHODS: We used biological informatics (RNAhybrid and Target Scan analysis database) to predict the target genes of hsa-miR-195. Collected colon cancer tissues from clinical colorectal cancer patients by surgical removal of the carcinoma and control tissues, and researched the expression of Bcl-2 in tissues by immunohistochemical. Next, Real time PCR was used to research the expression of hsa-miR-195 in Caco-2 and NCM460 cell line. hsa -miR-195 Mimics was transient transfered to Caco-2 cells, western blot was used to analysis the expression changes of Bcl-2. To analysis the possibility that hsa-miR-195 can affect the invasive ability of tumor cells by Bcl-2, we transferred hsa-miR-195 Mimics and Bcl-2 expression plasmid, and used the cell invasion experiment to discusses hsa-miR-195 effect on the ability of tumor cell invasion. RESULTS: the immunohistochemical results showed that, the semi-quantitative parameters for the Bcl-2: control by 0.89 +/- 0.51, 6 colon cancer by 31 +/- 0.79. The expression of has-miR-195 in Caco-2 is 0.39 +/- 1.5 while the value in control is2.01 +/- 0.2, **P < 0.01. CONCLUSION: In colorectal cancer, has-miR-195 can promote cell apoptosis and inhibit the invasion and metastasis by inhibiting the expression of Bcl-2. PMID- 26064277 TI - MiR-615 inhibited cell proliferation and cell cycle of human breast cancer cells by suppressing of AKT2 expression. AB - MicroRNAs (miRNAs) have emerged as important regulators that potentially play critical roles in various biological processes. Previous studies have shown that miR-615 regulates proliferation and apoptosis in many types of cancers. The biological function of this microRNA in breast cancer remains largely unexplored. In the present study, we found that miR-615 expression was markedly downregulated in breast cancer tissues and breast cancer cells. The enforced expression of miR 615 was able to inhibite the proliferation and anchorage-independent growth of breast cancer cells, while miR-615-in showed the opposite effect. Bioinformatics analysis further revealed AKT2, a putative tumor promoter as a potential target of miR-615. Ectopic expression of miR-615 led to downregulation of AKT2 protein, which resulted in the upregulation of p27 and p21 and the downregulation of cyclin D1. In sum, these results suggest that miR-615 represents a potential anti onco-miR and participates in breast cancer carcinogenesis by suppressing AKT2 expression. PMID- 26064278 TI - Upregulation of Tim-3 on CD4(+) T cells is associated with Th1/Th2 imbalance in patients with allergic asthma. AB - T cell Ig and mucin domain-containing molecule-3 (Tim-3) is a negative regulator preferentially expressed on Th1 cells. Allergic asthma is a clinical syndrome well characterized by Th1/Th2 imbalance. To investigate the role of Tim-3 in the pathogenesis of asthma and its relationship with Th1/Th2 imbalance, a total of 40 patients with allergic asthma and 40 healthy controls were enrolled. Expression of Tim-3 and Th1/Th2 imbalance as well as the relationship between them was analyzed by flow cytometry and real-time PCR. Peripheral blood mononuclear cells (PBMCs) were cultured in vitro and anti-Tim-3 was used to block Tim-3 signaling; Th1/Th2 cytokines in the culture supernatant were detected by enzyme linked immunosorbent assay (ELISA). CD4(+) T cells and B cells were sorted and co cultured in vitro, and anti-Tim-3 was used to block Tim-3 signaling; Total IgG/IgE in the culture supernatant was detected by ELISA. The mRNA level of T-bet and IFN-gamma were significantly decreased in allergic asthma patients, while GATA-3 and IL-4 were significantly increased. Expression of Tim-3 on CD4(+) T cells was much higher in allergic asthma patients and it was negatively correlated with T-bet/GATA-3 ratio or IFN-gamma/IL-4 ratio. Blocking of Tim-3 significantly increased Th1 cytokines (TNF-alpha and IFN-gamma) and decreased Th2 cytokines (IL-4, IL-5, IL-13) in the culture supernatant of PBMCs. Blocking of Tim-3 dramatically reduced the production of IgG and IgE in the co-culture supernatant of CD4(+) T cells and B cells. In conclusion, Tim-3 was up-regulated in allergic asthma patients and related with the Th1/Th2 imbalance. Blocking of Tim-3 may be of therapeutic benefit by enhancing the Th1 cytokines response, down regulating the Th2 cytokines response, and reducing IgG/IgE production. PMID- 26064279 TI - Association between Fas/FasL polymorphism and susceptibility to leukemia: a meta analysis. AB - The polymorphisms in Fas/FasL system were proposed to be associated with susceptibility to leukemia, but recent studies reported controversial findings. Hence, we performed a meta-analysis to assess the association between Fas gene polymorphisms and susceptibility to leukemia. We carried out a literature search in PubMed, Embase, Web of Science and CNKI databases for studies on the associations between Fas/FasL gene polymorphisms and susceptibility to leukemia. The associations were assessed by odds ratio (OR) together with its 95% confidence intervals (CIs). 7 literatures and 14 studies with a total of 8787 subjects were eventually included into our meta-analysis. Overall, there was no association between Fas/FasL polymorphisms and susceptibility to leukemia. In subgroup analysis by ethnicity, there was also no association between Fas/FasL polymorphisms and susceptibility to leukemia in Asians and Caucasians. In addition, there was also a significant association between Fas-1377G/A polymorphism and susceptibility to leukemia in ALL patients, the A allele seemed to be a protective factor in ALL risk. In summary, more studies with large sample size are needed to provide further evidence for association between Fas/FasL polymorphisms and susceptibility to leukemia. PMID- 26064280 TI - Ischemic preconditioning potentiates the protective effect of mesenchymal stem cells on endotoxin-induced acute lung injury in mice through secretion of exosome. AB - OBJECTIVE: To explore the effect of bone marrow mesenchymal stem cells (MSCs) on endotoxin-induced acute lung injury in mice and verify the role of exosome. METHODS: Exosome was isolated from the culture supernatant of MSC. For ischemic preconditioning, MSCs were subjected to anoxia for 0 min (MSCs group), 30 min (MSCs(IPC-30) group), 60 min (MSCs(IPC-60) group) and 90 min (MSCs(IPC 90) group), and then used to treat endotoxin-injured mice. The exosome from the optimal group was used to treat endotoxin-injured mice. In addition, the exosome from the optimal group was also used to treat the endotoxin-stimulated RAW 264.7 cells for 6 h and 12 h. RESULTS: CD63 positive exosome were acquired through ExoQuick kits. Administration of MSCs, MSCs(IPC-30), MSCs(IPC-60) and MSCs(IPC 90) could reduce the level of white blood cells (WBC) and neutrophils into the bronchoalveolar lavage (BAL) fluid of endotoxin-injured mice, and the MSCIPC-60 group had the greatest reduction, which reduced WBC by 57% and neutrophils by 55%. Administration of MSCs(IPC-60) exosome could also reduce the level of WBC, neutrophils, MIP-2 and penetration protein into the BAL fluid of endotoxin injured mice, which had the same effect as MSCs(IPC-60) and showed a dose dependent, compared to MSCs exosome. In addition, MSCs(IPC-60) exosome were used to treat endotoxin-stimulated RAW 264.7 cells, and the level of TNFalpha at 6 h and 12 h was significantly reduced, while the level of IL-10 at 12 h increased. CONCLUSION: Ischemic preconditioning for 60 min can potentiates the protective effect of MSC on endotoxin-induced Acute Lung Injury through the secretion of Exosome. PMID- 26064281 TI - Ethyl acetate extracts of Fructus Ligustri Lucide induce cell apoptosis in human neuroglioma cell. AB - OBJECTIVE: Previous studies have shown that Fructus Ligustri Lucide (FLL) can be used to improve the tumor cells sensitivity to chemotherapeutics and promote cell death. However, the mechanism by which FLL mediate this effect is unclear. In the present study, ethyl acetate extracts of FLL induced cell apoptosis in human neuroglioma cell was investigated. METHODS: The cell viability was detected by the CCK8 assay. The cell apoptosis was assessed by annexin V-PI double-labeling staining and hoechst 33342 staining. The protein expression of cell cycle regulators and tumor suppressors were analyzed by western blotting. RESULTS: Treatment of human neuroglioma cell with FLL induced cell death in a dose-and time-dependent manner by using CCK8 assay. Consistent with the CCK8 assay, the flow cytometry results showed that the proportion of the early and terminal phase of apoptosis cells had gained after FLL treatment as compared to untreatment group. Moreover, human neuroglioma cells were exposed to the ethyl acetate extracts of FLL for 48 h, which resulted in an accumulation of cells in G2/Mphase. Apoptotic bodies were clearly observed in human neuroglioma cells that had been treated with FLL for 48 h and then stained with Hochest 33342. The expression of Cyclin B1, CDC2 and cdc25C were downregulated upon FLL treatment in human neuroglioma cells. The expression level of Cyclin B1, CDC2 and cdc25C was negatively correlated with the time of treatment by FLL. In contrast, p53, p21 and p16 were obviously upregulated by FLL treatment in a time-dependent manner. CONCLUSIONS: These results confirmed that FLL could induce apoptosis in human neuroglioma cells, the underlying molecular mechanisms, at least partially, through activation p21/p53 and suppression CDC2/cdc25C signaling in vitro. PMID- 26064282 TI - Clinical efficacy and prognosis factors of open calcaneal fracture: a retrospective study. AB - BACKGROUND: Treatment of open calcaneal fractures remains to be a challenge for orthopaedic surgeons. The aim of this study is to assess factors affecting the treatment results of open calcaneal fractures. METHODS: A total of 98 patients who have 101 open calcaneal fractures were recruited in our hospital, they were all treated with a standard protocol based on the appearance of the traumatic wound. Data on mechanism of injury, location and size of wound, classification, fixation methods and subsequent soft-tissue complications were collected and evaluated. AOFAS Ankle-Hindfoot Survey and physical examinations were performed to access outcomes. RESULTS: No statistical difference was found in complication and AOFAS score in open calcaneal fractures treated with different fixation, and no statistical difference was found in AOFAS between gustilo I and II type open calcaneal fractures (P > 0.05). There was significant difference between gustilo I and III type or gustilo II and III type fractures (P < 0.05). The more serious soft tissue injury of open calcaneal fracture lead to the worse outcome and higher incidence of complications obtained. CONCLUSION: Open calcaneal fractures have a high propensity for soft-tissue complications no matter which fixation method was chose. There was no significant difference between patients who had been treated with different fixations in complication rates. Soft-tissue injury played an important role in outcomes of open calcaneal fractures. Deep infections and osteomyelitis were rare by means of emergency debridement and following repeated debridement. PMID- 26064283 TI - Astragalus polysaccharide suppresses excessive collagen accumulation in a murine model of bleomycin-induced scleroderma. AB - Systemic scleroderma is an autoimmune disease characterized by fibrotic changes in skin and other organs involving excessive collagen deposition. The transforming growth factor-beta (TGF-beta) signaling pathway plays a key role in the fibrotic process in systemic scleroderma (SSc). Astragalus polysaccharides (APS) isolated from one of the Chinese herbs, Astragalus mongholicus, are known to have a variety of immunomodulatory activities. The present study aimed to investigate the effect of APS on TGF-beta signaling and its potential mechanism using a murine model of bleomycin-induced scleroderma. Scleroderma was induced in C3H/He N mice by subcutaneous bleomycin injections daily for 21 days. Skin samples were obtained 7, 14, and 21 days and TGF-beta1, Smad2, Smad3 mRNA expression was observed by real time PCR. The hydroxyproline content which consistent with the collagen content in skin samples from the BLM-injected group was significantly higher than the PBS group, and corresponded with dermal thickening at the injection site. In contrast, mice treated with APS after initiating BLM injection showed obviously lesser collagen content. Increased TGF beta1, Smad2, Smad3 mRNA expression were also observed in the BLM group. TGF beta1, Smad2, Smad3 expression was significantly lesser for the APS group than for the BLM group. In contrast, TGF-beta1 mRNA expression was remarkably inhibited by APS. These results suggest that APS treatment may inhibit TGF-beta1 production, and thus could be a potential drug for managing fibrotic disorders such as SSc. PMID- 26064284 TI - Efficacy of zoledronic acid in treatment of osteoporosis in men and women-a meta analysis. AB - BACKGROUND: Osteoporosis is a significant cause of morbidity and mortality in the elderly and an important public health issue. Bisphosphonates are the primary treatment options for osteoporosis. The oral administration of bisphosphonates may result in poor patient compliance and thence reduced treatment efficacy. Intravenously administered bisphosphonates may therefore show better treatment efficacy. We have carried out a meta-analysis to evaluate the efficacy of zoledronic acid treatment for osteoporosis in both men and women with either vertebral or non-vertebral fracture. MATERIAL AND METHODS: Randomized controlled trials with zoledronic acid treatment for osteoporosis were retrieved from PubMed, EMBASE and clinicaltrials.gov. The risk ratio with 95% confidence interval (RR, 95% CI) was calculated to evaluate the effect of zoledronic acid treatment on incidence of fracture. Data on changes in bone mineral density (BMD) following zoledronic acid (ZOL) treatment was also extracted. STATA software was used for all the statistical analyses. RESULTS: Significant reduction in the incidence of both vertebral and nonvertebral fracture was observed following ZOL treatment, as seen from the values for RR with 95% CI (RR 0.24 and 95% CI 0.15 to 0.40 for vertebral fractures; RR 0.76 and 95% CI 0.67 to 0.86 for nonvertebral fractures). BMD was also seen to be increased after ZOL treatment. CONCLUSION: Ourmeta-analysis showed that zoledronic acid was effective in reducing the incidence of vertebral fractures as well as nonvertebral fractures, including hip fractures. Significant increase in bone mineral density (BMD) was also observed in patients administered ZOL as compared to placebo. PMID- 26064285 TI - CCDC26 rs4295627 polymorphism and glioma risk: a meta-analysis. AB - Several studies have examined the association of CCDC26 rs4295627 polymorphism and glioma risk. However, the results were conflicting. Thus, a meta-analysis was conducted. We searched for relevant studies up to Dec 2014 in both English and Chinese through the PubMed/MEDLINE, EMBASE, the China National Knowledge Infrastructure (CNKI) platforms, WanFang and VIP database. Overall, 14 studies with 17419 cases and 28465 controls were selected for final meta-analysis. CCDC26 rs4295627 polymorphism was significantly associated with an increased risk of glioma (OR = 1.25, 95% CI 1.15-1.36, P < 0.00001). Interestingly, CCDC26 rs4295627 polymorphism might decrease the risk of glioma in Asians (OR = 0.92, 95% CI 0.82-1.03, P = 0.15). However, Caucasians with CCDC26 rs4295627 polymorphism showed an increased risk of glioma (OR = 1.33, 95% CI 1.25-1.46, P < 0.00001). Subgroup analysis was performed by histology. Significant associations were observed among astrocytoma patients (OR = 1.31, 95% CI 1.17-1.47, P < 0.00001) and oligodendroglioma patients (OR = 1.79, 95% CI 1.47-2.17, P < 0.00001). No significant association was found between this polymorphism and glioblastoma risk (OR = 0.11, 95% CI 0.92-1.33, P = 0.28). This meta-analysis suggested that CCDC26 rs4295627 polymorphism was a risk factor for glioma. PMID- 26064286 TI - Platelet function parameters in management of hepatic hydatid disease: a case controlled study. AB - AIM: To evaluate platelet function in patients with a history of surgical treatment for hepatic hydatid disease (HD). METHODS: This retrospective case controlled study was performed in a state hospital in Turkey from January 2009 to November 2013. The patients were divided into two groups: those evaluated in the preoperative period (Group 1) and those evaluated in the postoperative period (Group 2). The patient groups were compared with a control group (Group 3). All three groups were evaluated using laboratory records from day 1 of the preoperative period and day 30 of the postoperative period. The haematocrit level (HTC), platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and percentage of eosinophils (EOS) were compared among the groups. RESULTS: Fifty-three patients who had undergone surgical treatment of hepatic HD and 55 healthy controls were included in the study. The mean follow-up time for all patients was 45 (14-70) months. The patients comprised 33 (62%) females and 20 (38%) males. The control group comprised 37 (67%) females and 18 (33%) males. The median age of the patients was 48 (19-78) years, while that of the control group was 42 (16-64) years. No significant differences in the HTC, PLT, or EOS were present among the groups. The MPV and PDW indicated that platelet function was significantly different between Group 1 and Groups 2 and 3. Additionally, nine patients had undergone previous surgical treatment for HD. In a separate long-term follow-up, these patients exhibited no statistically significant differences in MPV or PDW between the preoperative and postoperative periods. CONCLUSIONS: MPV and PDW can be used in the initial follow-up of patients with hepatic HD, but have limited use in long-term follow-up. PMID- 26064287 TI - BAFF level increased in patients with autoimmune hemolytic anemia. AB - INTRODUCTION: BAFF (B-cell activating factor of the TNF family), an important regulator of B-cell, has been observed to be over-expressed in a variety of autoimmune diseases. Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disease occurred when antibodies directed against autologous red blood cells. We assessed serum levels of BAFF in AIHA patients with different serological characteristics. METHODS: Serum BAFF levels were measured in 44 AIHA patients with different direct antiglobulin test (DAT) results and 25 healthy controls. The correlation of BAFF expression with DAT results and serological characteristics was assessed. RESULTS: Serum levels of BAFF in AIHA patients were significantly higher than in healthy subjects (AIHA: 1382.7 +/- 1412.8 pg/ml, healthy control: 725.0 +/- 415.7 pg/ml, P = 0.0057). Serum BAFF levels were significantly higher in patients with IgG(+)C3(+) or IgG(+) than healthy controls (DAT: negative) (P = 0.012, 0.004, respectively). No significant correlations were presented between serum BAFF levels and four serological parameters: hemoglobine, percentage of reticulocyte, total serum bilirubin, and lactate dehydrogenase. CONCLUSIONS: AIHA patients present higher serum BAFF levels than healthy controls, especially for those of IgG(+)C3(+) DAT result. This might lead to a new approach of AIHA treatment. PMID- 26064288 TI - Effects of different anesthesia methods on cognitive dysfunction after hip replacement operation in elder patients. AB - There are many risk factors for the cause of postoperative cognitive dysfunction (POCD), however, the anesthesia selection always trigger controversy for the POCD occurrence. This study aims to explore the relationship between the anesthesia and the occurrence of POCD in elder patients, and also investigate the mechanism of the POCD. One hundred elder patients with hip replacement were included in this study, which were divided into general anesthesia (GA) and epidural analgesia (EA) group. Minimum mental state examination (MMSE) method was employed to assess the nervous and mental function (POCD) in both analgesia group patients. Abeta and tau protein levels in blood were detected by using the ELISA assay. The correlation between MMSE in POCD patients and Abeta or tau was analyzed by employing the Spearman rank correlation method. The results indicated that epidural analgesia decreases the MMSE scoring compared to general analgesia (P < 0.05). General analgesia enhanced the Abeta and tau level compared to epidural analgesia (P < 0.05). Abeta and tau level were increased in the patients with POCD. The POCD occurrence rate in GA group was significantly higher compared to EA group (P < 0.05). MMSE scores of POCD patients positively correlated with Abeta or tau level (P < 0.05). In conclusion, the epidural analgesia method was better than general analgesia method for the hip replacement in elder patients. The mechanism of the POCD may be caused by the enhancement of Abeta and Tau protein. PMID- 26064289 TI - Osteopontin can decrease the cartilage cellular inflammatory reaction induced by LPS. AB - OBJECTIVE: This study aims to explore the effect of osteopontin on the inflammatory reaction of cartilage cells stimulated by LPS and its possible signal pathway. METHODS: The inflammatory reaction of cartilage cells was induced by LPS, and then the cells were treated with OPN and PD98059 respectively. The expression of TNF-alpha, IL-1beta and ERK1/2 were detected by ELISA or Western blotting methods. RESULTS: Osteopontin could decrease the cartilage cellular inflammatory reaction induced by LPS with dose dependent, while PD98059 could reverse the inhibition of osteopontin. CONCLUSION: Osteopontin could decrease the cartilage cellular inflammatory reaction induced by LPS, which may be associated with the ERK1/2 signal pathway. PMID- 26064290 TI - CLPTM1L polymorphism and lung cancer risk. AB - The association of Cleft Lip and Palate Transmembrane Protein 1 (CLPTM1L) rs31489 polymorphism with risk of lung cancer has been evaluated in many studies; however, the results from these studies are controversial. Thus, further analysis on association between CLPTM1L rs31489 polymorphism and risk of lung cancer is needed among a larger study population. A literature search in PubMed, Embase, Web of Science, Science Direct, SpringerLink, EBSCO, Wanfang, and Chinese National Knowledge Infrastructure (CNKI) databases was carried out to identify studies investigating the association between lung cancer risk and CLPTM1L rs31489 polymorphism. The strength of the association between CLPTM1L rs31489 polymorphism and lung cancer risk was estimated by calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs). In the overall analysis, there was significant association between CLPTM1L rs31489 polymorphism and lung cancer risk under an allele model (OR = 1.12; 95% CI, 1.06-1.18; P < 0.00001; I(2) = 57%). Subgroup analysis by ethnicity was performed. Stratified analysis by ethnicity showed that a statistically increased cancer risk was found in the Caucasian population (OR = 1.15; 95% CI, 1.10-1.21; P < 0.00001; I(2) = 22%), but there was no significant association between lung cancer risk and CLPTM1L rs31489 polymorphism in the Asian population (OR = 1.03; 95% CI, 0.97-1.08; P = 0.37; I(2) = 15%). In conclusion, this meta-analysis demonstrates that CLPTM1L rs31489 polymorphism significantly modified the risk of lung cancer. PMID- 26064291 TI - Changes of serum TNF-alpha, IL-5 and IgE levels in the patients of mycoplasma pneumonia infection with or without bronchial asthma. AB - OBJECTIVE: This study aimed to investigate the changes of serum levels of TNF alpha, IL-5 and IgE in mycoplasma pneumonia (MP) infection patients with or without bronchial asthma and explore its clinical importance. METHODS: ELISA and Western blot assay were performed to detect the serum levels of TNF-alpha, IL-5 and IgE in 35 healthy subjects, 45 patients with MP infection and 40 bronchial asthma patients with MP infection. RESULTS: The serum levels of TNF-alpha, IL-5 and IgE in MP infection patients and asthma patients with MP infection were significantly higher than those in healthy subjects (P<0.01). Moreover, the serum levels of TNF-alpha, IL-5 and IgE in asthma patients with MP infection was markedly higher than those in MP infection patients (P<0.05). Correlation analysis showed serum TNF-alpha was positively associated with serum IL-5 (r=0.9636, P<0.01), serum TNF-alpha positively related to IgE (r=0.9841, P<0.01) and serum IgE positively relevant with serum IL-5 (r=0.9572, P<0.01) in asthma patients with MP infection. CONCLUSION: Our findings indicate that serum levels of TNF-alpha, IL-5 and IgE may play important roles in the pathogenesis of MP infection, especially in asthma patients. PMID- 26064292 TI - Special needle over cannula for postoperative analgesia in geriatric lower extremity joint arthroplasty. AB - OBJECTIVE: To investigate superiorities of a special needle-over-cannula adopting different location methods for continuous femoral nerve block (CFNB) for geriatric lower extremity joint arthroplasty. METHODS: 60 elderly patients intending to receive scheduled knee or hip replacement surgery were recruited and divided into 3 groups randomly. Group 1 (n=20) adopted fascial pop for continuous femoral nerve block and postoperative analgesia with indwelling cannula. Group 2 (n=20) adopted location guided by B ultrasound, and Group 3 (n=20) adopted fascial pop combined with B ultrasound. RESULTS: There was significant difference in the performing time of cannula indwelling on average between each two groups (P<0.01). There was no significant difference among three groups about visual analogue scale (VAS) score, Ramsay sedation score (RSS), incidence of nausea and vomit, or patient's satisfaction at 6, 12, 24 and 48 h. Infection at the puncture site, toxic reaction of local anesthetics and respiratory depression were absent during the cannula indwelling. All the patients did not receive any other analgesic, and the indwelling time of external cannula was 45.3 hours on average. There was only one patient in group 2 who felt mild pains in front of the thigh after removing the indwelling cannula. No stolidity or other abnormal symptom was found among the remaining patients. CONCLUSIONS: Shorter indwelling cannula time and higher success rate of single attempt placement suggest that fascial pop combined ultrasound guidance is worth for clinical recommendation. PMID- 26064293 TI - Management for the anterior combined with posterior urethral stricture: a 9-year single centre experience. AB - OBJECTIVE: Therapy for anterior combined with posterior urethral stricture is difficult and controversial. This study aims to introduce a standard process for managing anterior combined with posterior urethral stricture. PATIENTS AND METHODS: 19 patients with anterior combined with posterior urethral stricture were treated following our standard process. Average (range) age was 52 (21-72) years old. In this standard process, anterior urethral stricture should be treated first. Endoscopic surgery is applied for anterior urethra stricture as a priority as long as obliteration does not occur, and operation for posterior urethral stricture can be conducted in the same stage. Otherwise, an open reconstructive urethroplasty for anterior urethral is needed; while in this condition, the unobliterated posterior urethra can also be treated with endoscopic surgery in the same stage; however, if posterior urethra obliteration exists, then open reconstructive urethroplasty for posterior urethral stricture should be applied 2-3 months later. RESULTS: The median (range) follow-up time was 25.8 (3-56) months. All 19 patients were normal in urethrography after 1 month of the surgery. 4 patients (21.1%) recurred urethral stricture during follow-up, and the locations of recurred stricture were bulbomembranous urethra (2 cases), bulbar urethra (1 case) and bladder neck (1 case). 3 of them restored to health through urethral dilation, yet 1 underwent a second operation. 2 patients (10.5%) complaint of dripping urination. No one had painful erection, stress urinary incontinence or other complications. CONCLUSIONS: The management for anterior combined with posterior urethral stricture following our standard process is effective and safe. PMID- 26064294 TI - Association between vitamin E and non-alcoholic steatohepatitis: a meta-analysis. AB - Non-alcoholic fatty liver disease (NAFLD) generally has a relatively favorable clinical course; however, non-alcoholic steatohepatitis (NASH) was much more frequently progresses to cirrhosis and hepatocellular carcinoma. We performed a systematic review and meta-analysis of clinical trials to examine the effects of vitamin E supplementation in improving liver histology in NASH. We performed a comprehensive search of the PubMed, Embase and Cochrane databases through October 2014. Weighted mean differences (WMDs) and their respective 95% confidence intervals (CIs) were calculated to assess the efficacy of vitamin E in improving liver histological scores by using fixed effects or random effects. Standard methods were performed to explore statistical heterogeneity and publication bias. Compared with controls, vitamin E supplementation significantly improved all histological parameters, including steatosis (WMD = -0.62, 95% CI: -0.95, -0.77, P = 0.0002), hepatocyte ballooning (WMD = -0.30, 95% CI: -0.56, -0.04, P = 0.03), lobular inflammation (WMD = -0.39, 95% CI: -0.67, -0.11, P = 0.007) and fibrosis (WMD = -0.39, 95% CI: -0.72, -0.06, P = 0.02). Our analysis also indicated the absence of publication bias between NASH and Vitamin E intake. This meta-analysis indicates that vitamin E supplementation had a significant and positive effect in the improvement of steatosis, ballooning degeneration, lobular inflammation and fibrosis in patients with NASH. PMID- 26064295 TI - Cyclooxygenase-2 polymorphisms and bladder cancer risk: a meta-analysis based on case-control studies. AB - The current meta-analysis incorporating 15 case-control studies involving 4,138 cases and 4,269 controls was performed on the basis of a systematical search in electronic databases for a more precise estimation on the associations of three common polymorphisms -765 G>C (rs20417), -1195G>A (rs689466) and +8473 C>T (rs5275) in Cyclooxygenase-2 (Cox-2) gene with the susceptibility to bladder cancer. The results showed that there was a significant association between rs5275 polymorphism and bladder cancer risk (C vs. T; OR=0.84; CC vs. TT: OR=0.76), especially among Chinese (CC vs. TC+TT: OR=0.48) and American (C vs. T; OR=0.83; TC vs. TT: OR=0.73; CC+TC vs. TT: OR=0.73). and the rs20417 polymorphism was significantly associated with an increased risk of bladder cancer among Chinese (C vs. G: OR=1.46; GC vs. GG: OR=1.49; CC+GC vs. GG: OR=1.51) and Indian (GC vs. GG: OR=1.63; CC+GC vs. GG: OR=1.46), but a reduced risk among American (C vs. G: OR=0.81; GC vs. GG: OR=0.76; CC+GC vs. GG: OR=0.76). Additionally, we found that the rs689466 polymorphism was associated with a decreased risk of bladder cancer in Indian (GA vs. GG: OR=0.68; AA vs. GG: OR=0.39).The present meta-analysis suggests that Cox-2 rs5275 polymorphism may contribute to the risk of bladder cancer, particularly among Chinese and American. The rs20417 polymorphism may play a protective role in the development of bladder cancer in Indian and Chinese but act as a risk factor among American, while the rs689466 polymorphism was more likely to be associated with a decreased risk of bladder cancer in Indian. PMID- 26064296 TI - An overview of neuro-oncology research and practice in Iran, three years with the NOSC initiative. AB - Research and practice of neuro-oncology compiles clinical neuroscience expertise from neurosurgery, radiation oncology, neuroradiology, medical oncology, neuropathology and related disciplines to optimize planning and therapy in central nervous system malignancies. Such an interdisciplinary context prompted health-care providers from all related disciplines to establish the Neuro Oncology Scientific Club (NOSC) in Iran and let it flourish since 3 years ago. With the advent of advanced technologies and through continued share of experience, NOSC members have tried to provide more integrated diagnoses and therapeutic care to brain tumor patients across the country. NOSC activities revolve around some key tenets including dissemination of education and updates, facilitation of institutional collaborations; data registry and patients' awareness. By virtue of recent insights on molecular characterization of brain tumors such as codeletion of chromosomes 1p and 19q in anaplastic gliomas and O6 methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma, a range of translational research is being followed within NOSC. The most recent NOSC meeting which was held in Tehran, recapitulated main advances and dealt with the current debates on functional neurosurgery, biological markers and neuroimaging, risk prediction models in high grade gliomas and clinical issues in pediatric neuro-oncology. This article gives an overview of current hotspots in neuro-oncology research and practice which are pursued within NOSC. PMID- 26064297 TI - Association of microstructural and mechanical properties of cancellous bone and their fracture risk assessment tool scores. AB - This study is to investigate the association between fracture probabilities determined by using the fracture risk assessment tool (FRAX) and the microstructure and mechanical properties of femoral bone trabecula in osteoporosis (OP) and osteoarthritis (OA) patients with hip replacements. By using FRAX, we evaluated fracture risks of the 102 patients with bone replacements. Using micro CT scanning, we obtained the analysis parameters of microstructural properties of cancellous bone. Through morphometric observations, fatigue tests and compression tests, we obtained parameters of mechanical properties of cancellous bones. Relevant Pearson analysis was performed to investigate the association between the fracture probability and the microstructure and mechanical properties of femoral bone trabecula in patients. Fifteen risk factors in FRAX were compared between OP and OA patients. FRAX hip fracture risk score and major osteoporotic in OP and OA patients were significantly different. FRAX was associated with tissue bone mineral density and volumetric bone mineral density. Our study suggests that the probabilities of major osteoporotic and hip fracture using FRAX is associated with bone mass but not with micro bone quality. PMID- 26064298 TI - Effects of Foxp3 gene modified dendritic cells on mouse corneal allograft rejection. AB - OBJECTIVE: To investigate the effect of Foxp3 gene modified dendritic cells (Foxp3 + DC) on allogeneic T cells proliferation and to study the effect of Foxp3 + DC on corneal allograft rejection. METHODS: Lentivirus-Foxp3 was transfected into DC2.4 cells, as Foxp3 + DC cells. 42 BALB/c mice were randomly divided into: Group A (n = 6), normal group; Group B (n = 12), Group C (n = 12) and Group D (n = 12), allograft groups, were treated with normal saline, DC2.4, Foxp3 + DC by intraperitoneal injection, respectively. RESULTS: Compared with the control group, Foxp3 protein in the Foxp3 + DC cells increased significantly (P < 0.05); the expressions of CD80 and CD86 immunophenotypes of Foxp3 + DC cells decreased significantly (P < 0.05); IL-12 secretion reduced (P < 0.05), but IL-10 secretion was promoted (P < 0.05). The average transplant survival time in Group B was (14.833 +/- 1.472) d, and Group C and Group D led to a statistically significant prolongation of transplant survival to (17.667 +/- 1.366, 23.000 +/- 2.000) d (P < 0.05) respectively. 14 d after transplantation, as compared with Group C and D, the expressions of IFN-gamma in grafts markedly increased in Group B. 14 d after transplantation, as compared with Group B, the expressions of Foxp3 mRNA, IDO mRNA in grafts decreased remarkably in Group C and D (P < 0.05); as compared with Group C, the expressions of Foxp3 mRNA, IDO mRNA in grafts decreased remarkably in Group D (P < 0.05). CONCLUSION: Foxp3 + DC cells reduce the expression of costimulatory factors, reduce the secretion of IL-12, promote IL-10 production and inhibit the stimulation of alloreactive T cell proliferation response capacity. Foxp3 + DC cells play important roles in inhibiting corneal allograft immune response and prolonging graft survival time. PMID- 26064299 TI - Conventional MRI techniques combined with MR sialography on T2-3D-DRIVE in Sjogren syndrome. AB - AIM: To investigate the value of conventional MRI techniques combined with MR sialography on T2-3D-DRIVE in the diagnosis of Sjogren syndrome (SS). METHODS: 107 patients were divided into SS group and non-SS group. Conventional MRI techniques, such as T1WI, T2WI, and STIR images were used for changes of fat signal in the parotid gland, while the MR sialography were used for ducts dilation of the parotid gland. RESULTS: Among 93 SS patients, MRI identified abnormal fat deposit in the parotid glands in 86 patients. The fat signal based on MRI images showed 7 patients were in stage 0, 28 in stage 1, 14 in stage 2, 32 in stage 3 and 12 in stage 4. T2-3D-DRIVEMR MR sialography identified peripheral ducts dilation in 86 patients. The duct dilation based on MR sialography showed 7 patients in stage 0, 14 patients in stage 1, 44 patients in stage 2, 26 patients in stage 3, and 2 patients in stage 4. On MRI and MR sialography, both had a positive diagnostic rate of 92.5%. When MRI and MR sialography techniques were used together, the positive diagnostic rate increased to 96.8%. However, Kappa test showed that the MRI fat signal staging and MR sialogrpahy duct dilation staging had statistical difference (Kappa = 0.241, P = 0.000). CONCLUSION: T2-3D DRIVE MR sialography detects peripheral ducts dilation in parotid glands with unmatched spatial resolution, also MRI fat suppression techniques detect diffusive fat deposit in parotid glands with high accuracy. Combining two techniques will provide optimal diagnosis workup for SS. PMID- 26064300 TI - Analysis of correlative risk factors for C5 palsy after anterior cervical decompression and fusion. AB - BACKGROUND: It has been reported that C5 palsy is a potential complication of both anterior and posterior cervical spine surgery, although several mechanisms of C5 palsy following posterior cervical surgery have been proposed, few reports about correlative risk factors have been elaborated on C5 palsy after anterior cervical decompression and fusion (ACDF). OBJECTIVE: The purpose of this study was to investigate the correlative risk factors of C5 palsy after anterior cervical decompression and fusion. METHODS: This is a retrospective study. A total of 161 patients (108 males and 53 females) who underwent ACDF between 2007 and 2012 were included in this study. C5 palsy is characterized by deltoid and/or biceps brachii weakness. The patients were divided into two groups: one that had experienced C5 palsy (group A) and the other one had not (group B). In both groups, the age, gender, duration of disease, diagnosis, No. of surgical levels, cervical curvature correction, occupying rate of spinal canal at C4/5, diameter of the C4/5 foramen, intervertebral height variation, decompression width and preoperative high-signal intensity zone (HIZ) of spinal cord in T2-weighted MRI at C4/5 were measured and evaluated. The risk factors of C5 palsy were detected with logistic regression analysis. RESULTS: There were no significant differences in age, gender, duration of disease, diagnosis, No. of surgical levels, rate of spinal canal at C4/5 and HIZ of spinal cord in T2-weighted MRI at C4/5. Cervical curvature correction, diameter of the C4/5 foramen, intervertebral height variation and decompression width had significant differences between the two groups (P<0.05). Logistic regression analysis revealed that cervical curvature, diameter of the C4/5 foramen, intervertebral height and decompression width were the pivotal risk factors for the incidence of C5 palsy. CONCLUSION: For patients with ACDF, greater cervical curvature correction, narrow diameter of the C4/5 foramen, improper intervertebral height variation and larger decompression width were the correlative risk factors for C5 palsy after ACDF. PMID- 26064301 TI - Association of beta2-microglobulin with the prognosis of non-Hodgkin's lymphoma: a meta analysis. AB - OBJECTIVE: The influence of beta2-microglobulin (beta2-MG) on the prognosis of non-Hodgkin's lymphoma (NHL) remains controversial. This study performed meta analyses to evaluate the prognostic value of beta2-MG on the overall survival (OS) of NHL. METHODS: Through a search of relevant literature in PubMed, EMbase, Science Direct, OVID and Wanfang databases from 1980-2013, the hazard ratios (HRs) of OS between the normal beta2-MG group and the increased beta2-MG group were retrieved, and the results were combined using a fixed effect model and a random effect model. Subgroup analyses were performed based on univariate and multivariate analysis results, and sensitivity analyses were performed to estimate the changes of the combined HRs. In addition, funnel plots and fail-safe numbers were used to estimate publication bias. RESULTS: A total of 17 qualified publications were included, with a cumulative total of 2,479 cases. The result of heterogeneity examination showed that there was heterogeneity among all studies (P < 0.001, I(2) = 87%). In the random effect model, the combined HR was 2.71 (95% confidence interval [CI]: 1.91-3.85). The result of the total effect examination was statistically significant (Z = 5.59, P < 0.001). CONCLUSION: The increased beta2-MG level was an independent risk factor for the prognosis of NHL. PMID- 26064302 TI - Sodium butyrate protects the intestinal barrier function in peritonitic mice. AB - OBJECTIVE: Peritonitis is a commonly seen disease with high morbidity and mortality. It is prevalently considered that the impaired intestinal barrier during peritonitis is the access point of gut microbes into the blood system, and acts as the engine of the following systemic infection. In our previous study, we found that Sodium Butyrate (NaB) was protective on intestinal barrier function. In this study, we aim to evaluate the effects of NaB on overwhelming infection animal models of peritonitis. METHODS: Mouse cecal ligation and puncture (CLP) model was used to study the effects of NaB on the intestinal barrier. Experimental animals were fed of NaB by gavage. Post-CLP mortality, gut permeability and intestinal histological alterations were studied. RESULTS: Gastrointestinal NaB pharmacodynamics profiles after medication were studied. Measurements of NaB concentration in chyme showed significantly higher intestinal concentration of NaB in the NaB treated group than that of the control group. CLP induced mortality was significantly decreased by oral NaB treatments. Gut permeability was largely increased after CLP, which was partially prevented by NaB feeding. Histological study showed that intestinal, especially ileal injury following peritonitis was substantially alleviated by NaB treatments. Moreover, tissue regeneration was also prompted by NaB. CONCLUSION: NaB has a potential protective effect on intestinal barrier function in peritonitis. PMID- 26064303 TI - IFN-gamma +874 T/A polymorphisms contributes to cervical cancer susceptibility: a meta-analysis. AB - Interferon gamma (IFN-gamma) is a potent proinflammatory cytokine which plays an important role in the antiviral, antiproliferative, and antitumor activities. So our meta-analysis was conducted to evaluate the correlations between common genetic polymorphisms in the IFN-gamma gene and susceptibility to cervical cancer. The +874 polymorphism in IFN gene region reportedly affects cancer risk. In order to derive a more precise estimation of the association, eight clinical case-control studies met all the inclusion criteria and were included in this meta-analysis. A total of 2,375 cancer cases and 2,106 controls were involved in this meta-analysis. Overall, no significant association was detected in allelic model (A allele vs. T allele OR=0.97, 95% CI, 0.73~1.28), homozygote comparison (AA vs. TT OR=1.12, 95% CI, 0.68~1.85), heterozygote comparison (AT vs. TT OR=1.43, 95% CI, 0.97~1.61), dominant model (AA+AT vs. TT OR=1.19, 95% CI, 0.87~1.63), nor recessive model (AA vs. AT+TT OR=0.95, 95% CI, 0.64~1.40). Subgroup analysis based on ethnicity, genotyping method, and Hardy-Weinberg equilibrium status. Ethnicity suggested that genetic polymorphisms in the IFN gamma gene were closely correlated with increased cervical cancer risk among Asians (allele model: OR=1.11, 95% CI=0.61~2.02, P<0.001; recessive model: OR=0.98, 95% CI=0.36~2.96, P<0.001; homozygous model: OR=1.43, 95% CI=0.56~3.65, P=0.001; respectively), but not among Mixed (all P>0.05). In conclusion, the current meta-analysis supported that IFN-gamma genetic polymorphism may contribute to cervical cancer susceptibility, and further well-designed studies with large sample size are warranted to validate our conclusion. PMID- 26064304 TI - Effect of different 1, 25-(OH)2D3 doses on high mobility group box1 and toll-like receptors 4 expression in lung tissue of asthmatic mice. AB - We established a mouse model of asthmatic airway remodeling. To investigate the effects of different doses of 1,2 5-(OH)2D3 on airway remodeling, expression of high mobility group box 1 (HMGB1) and Toll-like receptors 4 (TLR4) in asthmatic mice. The female mice (BALB/c) groups consisted of a control group, asthma group and 1,2 5-(OH)2D3 low, middle, high dose group. Each group contained 10 mice. An asthmatic mice model was induced by ovalbumin. The control group and asthma group used physiological saline instead. 1,2 5-(OH)2D3 low, middle and high dose group was given different doses of 1,2 5-(OH)2D3 respectively. Changes in mice airway structure were observed by hematoxylin-eosin (H&E). The expression of HMGB1 and TLR4 in molecular lever were monitored by RT-PCR. We used immunohistochemistry to test HMGB1 and TLR4 protein levels. Obvious changes were noted in the airway of OVA-induced asthma mice compared with the control group by HE. These changes were less pronounced in mice receiving the low and middle doses of 1,2 5-(OH)2D3, but were more pronounced in mice receiving the highest dose of 1,2 5-(OH)2D3. Immunohistochemistry showed that expression of HMGB1 and TLR4 in the asthma group was higher than the control group. And low and middle dose group was decreased compared with asthma group, while higher than the control group; high dose group had an increased expression compared with the asthma group. From RT-PCR we got the same results as immunohistochemistry. In the asthmatic airway remodeling animal model, the appropriate amount of 1,2 5-(OH)2D3 reduced airway remodeling in asthmatic mice, and decreased the expression of HMGB1 and TLR4 in the asthmatic mice. However, over dose might play detrimental effect. PMID- 26064305 TI - Tetrandrine down-regulates expression of miRNA-155 to inhibit signal-induced NF kappaB activation in a rat model of diabetes mellitus. AB - AIMS: This study is to investigate expression of miRNA-155 and the related signaling pathway in a rat model of diabetes mellitus (DM). METHODS: Thirty-six SD rats were divided into control, DM, and tetrandrine groups. A rat model of DM was constructed by tail vein injection with alloxan. Levels of related cytokines in serum samples were detected. The mRNA levels of IkappaBalpha and TNF-alpha in pancreatic islet tissues were detected by real-time PCR. Protein expression of IkappaBalpha and TNF-alpha was detected by western blotting. Expression of miRNA 155 in pancreatic islet tissues and serum samples was detected by real-time PCR. RESULTS: Compared with those in the control and the tetrandrine groups, activities of methane dicarboxylic aldehyde and reactive oxygen species in serum samples and pancreatic islet mitochondria tissues in the DM group were increased (P < 0.05), while activity of superoxide dismutase in the DM group was decreased (P < 0.05). Activities of haemoglobin A1c and glucose in serum samples in the DM group were increased, while insulin in the DM group was decreased (P < 0.05). The mRNA and protein levels of IkappaBalpha in pancreatic islet tissues in the DM group were decreased (P < 0.05), while the mRNA and protein levels of TNF-alpha in the DM group were increased (P < 0.05). Expression of miRNA-155 in pancreatic islet tissues and serum samples in the DM group was increased (P < 0.05). CONCLUSION: Tetrandrine prevented injury in rat pancreatic islet caused by alloxan, which was related with decreased oxidative stress, down-regulated miRNA 155 and decreased TNF-alpha in the NF-kappaB signaling pathway. These results indicate that tetrandrine plays an important role in DM by regulating expression of miRNA-155. PMID- 26064306 TI - Antidepression medication improves quality of life in elderly patients with benign prostatic hyperplasia and depression. AB - We aim to explore the influence of an antidepression medication on symptom scores and quality of life in elderly patients with benign prostatic hyperplasia accompanied by depression. We conducted a randomized controlled clinical trial which included 94 elderly patients with benign prostatic hyperplasia accompanied by depression in Xuan Wu Hospital and Beijing Boai Hospital during August 2008 to May 2012. The study was designed to compare outcomes related to patient quality of life (QoL). The patients were randomly assigned to one of two groups, consisting of a control group (n = 47) and a therapy group (n = 47), and were followed up for 3 months. The pre-treatment and post-treatment changes among patients in the two groups were compared using their respective IPSS symptom scores, HAM-D scores, and scores on the Short Form 36 Health Survey. Following treatment, the patient IPSS symptom scores in the therapy group were significantly lower than those in the control group (10.74 +/- 4.72 vs. 16.42 +/- 8.09, respectively; t = 4.157, P < 0.05). Additionally, each measured dimension of QoL was significantly higher in the therapy group [total score (69.12 +/- 3.92) vs. (61.30 +/- 3.51), P < 0.05]. The results show antidepression medication can improve the symptoms and quality of life among elderly patients with benign prostatic hyperplasia accompanied by depression. Our findings suggest that an antidepression medication should be included when treating elderly patients with benign prostatic hyperplasia. PMID- 26064307 TI - Risk stratification and prognostic value of grace and timi risk scores for female patients with non-st segment elevation acute coronary syndrome. AB - AIM: To investigate the value of Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) risk scores for risk stratification and prognosis in female patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS). METHODS: Non-elderly (<65 years) and elderly (>=65 years) female patients with NSTE-ACS (totally 869 cases) were enrolled in this study. The patients were further divided into low, intermediate and high risk groups according to their GRACE and TIMI scores. Patients were followed up for 1 year to record the mortality and incidence of major adverse cardiac events (MACE). Differences in mortality and MACE incidence between the two scoring systems were compared by the area under the ROC curve. RESULTS: The area under ROC curve corresponding to the mortality and MACE incidence in any period by the GRACE scoring system was significantly larger than the TIMI scoring system in the elderly patients (P<0.05). Mortality and MACE incidence increased in parallel with the scores. Risk ratio values of Cox regression analysis based on GRACE and TIMI scores were greater than 1 (P<0.001). CONCLUSION: Both GRACE and TIMI were adoptable in clinical risk stratification and prognosis of female patients with NSTE-ACS at different age groups. GRACE showed better accuracy than the TIMI scores. PMID- 26064308 TI - Assessment of total cardiac repolarization's spatial distribution among patients with aortic sclerosis. AB - OBJECTIVE: To measure the Tp-e value, which shows the spatial distribution of cardiac repolarization and is defined as a possible predictor for ventricular arrhythmia among patients with aortic sclerosis (AS), and to compare this parameter's length to QTc length within the same population. METHOD: 60 patients that have been diagnosed with AS have been prospectively included in this study. RESULTS: 60 AS and 64 control patients were evaluated as part of the study. The median age, prevalence for hypertension and diabetes, baseline medications and laboratory results of the groups were similar. The Electrocardiographic QT length of both groups were found similar. In the AS group Tp-e tangent and Tp-e tail values were more longer than control group (P < 0.001). Tp-e tangent index and Tp e tail index values were also statistically higher among AS patients when compared to the control group. (P < 0.001). CONCLUSION: Our study showed that Tp e durations had increased in AS patients with no structural coronary heart disease. AS causes local degeneration on the aortic root and also has a negative effect on the total cardiac spatial repolarization. PMID- 26064309 TI - Early diagnosis, treatment and prognosis of epilepsy with continuous spikes and waves during slow sleep. AB - The study is to investigate the importance of early diagnosis and treatment to the prognosis of epilepsy with continuous spikes and waves during slow sleep (CSWS). A total of 8 cases of CSWS children were followed up for 6 months to 4 years. Retrospective analysis of the clinical and electroencephalographic (EEG) characteristics, treatment and prognosis was performed in these 8 cases. Of the 8 cases of CSWS patients, 5 were males and 3 were females. Epilepsy onset ages were from 3 years and 1 month to 10 years and 6 months. Five cases of the patients were with brain lesions while the other 3 cases appeared normally by imaging detection. After treatment with valproic acid, clonazepam, lamotrigine and hormone for 3 months, clinical symptoms and EEG were improved significantly in 7 cases. Two cases relapsed at 6 months after comprehensive treatment. For atypical early performance of CSWS, early diagnosis and regular treatment could improve the condition of children with seizures and effectively inhibit the epileptic activity with good prognosis. PMID- 26064310 TI - Novel cyclotides from Hedyotis diffusa induce apoptosis and inhibit proliferation and migration of prostate cancer cells. AB - BACKGROUND: Hedyotis diffusa is a well-known herb in traditional Chinese Medicine (TCM) which is used to treat various cancers including prostate cancer. Recently, lots of cyclotides possessing anti-cancer activities were found in Hedyotis family plants, suggesting that H.diffusa may also contain these bioactive ingredients. Cyclotides are heat-stable macrocyclic peptides from plants that display a wide range of biological activities. Currently, over 250 cyclotides have been discovered. OBJECTIVE: This study tried to isolate novel cyclotides from H.diffusa and further investigate their anti-cancer activities for the prostate cancer cells in vitro and in vivo. METHODS: The novel cyclotides from H.diffusa were isolated and purified by High-performance liquid chromatography (HPLC), amino acid sequences in their primary structure were confirmed using Edman degradation and gene cloning. Colorimetric cell viability assay (CCK8 assay), wound healing assay and human prostate cancer xenograft were used to analyze their anti-prostate cancer activity in vitro and in vivo. RESULTS: Three novel cyclotides, termed as Diffusa cyclotide 1 to 3 (DC1-3) from the leaves and root of H.diffusa, were isolated firstly based on my knowledge. Using Edman degradation sequencing and gene cloning, we confirmed their amino acid sequence and obtained precursors of these peptides. By CCK8 assay, all present cyclotides showed potent cytotoxicity against all three prostate cancer cell lines, especially for DC3. In migration assay and wound healing assay, DC3 inhibited the cell migration and invasion Of LNCap cells. By model of prostate xenograft, DC3 could significantly inhibit development of the tumor in weight and size compared to the placebo. CONCLUSION: The novel cyclotides extracted from H.Diffusa have anti-cancer effects, and they are potential bioactive ingredients in H.diffusa. PMID- 26064311 TI - Peroxisome proliferator-activated receptor-gamma (PPARgamma) Pro12Ala polymorphism and colorectal cancer (CRC) risk. AB - BACKGROUND: The association between the peroxisome proliferator-activated receptor-gamma (PPARgamma) Pro12Ala polymorphism and colorectal cancer (CRC) risk was inconclusive. We conducted a meta-analysis to evaluate the association between PPARgamma Pro12Ala polymorphism and CRC risk. MATERIAL AND METHOD: We searched Pubmed, EMBASE, and China National Knowledge Infrastructure databases. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: A total of 17 case-control studies with 12635 and 15803 controls were included in this meta-analysis. Overall, PPARgamma Pro12Ala polymorphism was associated with CRC risk (OR = 0.84, 95% CI 0.75-0.94, P = 0.003, I(2) = 35%). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 0.85, 95% CI 0.75-0.96, P = 0.007, I(2) = 38%) but not among Asians (OR = 0.76, 95% CI 0.51-1.12, P = 0.17, I(2) = 28%). In the subgroup analysis by CRC site, a significant association was found among colon cancer (OR = 0.81, 95% CI 0.66-0.98, P = 0.03, I(2) = 16%) but not among rectal cancer (OR = 0.83, 95% CI 0.57-1.21, P = 0.34, I(2) = 63%). The sensitivity analysis did not influence the result by omitting low-quality studies (OR = 0.76, 95% CI 0.63-0.93, P = 0.006, I(2) = 51%). CONCLUSIONS: In conclusion, this meta-analysis suggested that PPARgamma Pro12Ala polymorphism was significant associated with CRC risk. PMID- 26064312 TI - Down-regulation of microRNA-26b rescued hypoxia-induced apoptosis in cultured neonatal rat cardiac myocytes by regulating PTEN. AB - BACKGROUND: Cardiomyocyte hypoxia causes cardiac hypertrophy and other major myocardial injuries. We investigated the molecular mechanism of microRNA-26b (miR 26b) in regulating hypoxia-induced apoptosis in rat neonatal cardiomyocytes. METHODS: Neonatal rat cardiomyocytes was prepared in vitro and hypoxia was induced. Apoptotic cardiomyocytes were examined by TUNEL staining and the expression of miR-26b were monitored by qRT-PCR. The effect of mir-26b downregulation on hypoxia-induced apoptosis, or expression of PTEN in cardiomyocytes was monitored. PTEN was knocked down in cardiomyocytes by siRNA to further investigate its association with miR-26b. RESULTS: Hypoxia induced severe apoptosis and upregulated miR-26b in neonatal rat cardiomyocytes in vitro. Down regulation of miR-26b markedly ameliorated hypoxia-induced apoptosis and up regulated PTEN. Luciferase reporter assay confirmed PTEN was directly targeted by miR-26b, and knocking down PTEN reduced cytotoxicity induced by miR-26b upregulation. CONCLUSION: Downregulation of miR-26b protected cardiomyocytes from hypoxia-induced apoptosis, and the protective effect was very likely to be associated with PTEN regulation. PMID- 26064313 TI - Effects of minocycline-HCl paste root conditioning on periodontal surgery: in vitro and in vivo studies. AB - OBJECTIVES: This study was aimed to investigate effects of 2% minocycline-HCl paste root conditioning on periodontal surgery. MATERIALS AND METHODS: In vitro, cementum slices affected by periodontitis were randomly conditioned with 2% minocycline-HCl paste, 2% minocycline-HCl liquid, and 0.9% saline. NIH3T3 cells were cultured and attached to the each slide, and the viability and proliferation of cells were observed; In vivo, 21 deep periodontal pockets were treated by periodontal surgery, and the exposed root surfaces were randomly conditioned with 2% minocycline-HCl paste or 0.9% saline. The periodontal parameters were measured at baseline, after 3 and 6 months of periodontal surgery. RESULTS: In vitro, NIH3T3 cell showed better viability and proliferation at 3, 5, and 7 day in groups conditioned with minocycline-HCl than the group conditioned with 0.9% saline (at 3 day (P < 0.05); at 7 day (P < 0.01)) Minimal differences were found between minocycline-HCl paste and liquid groups; In vivo, 3 months after periodontal surgery, the greater CAL reduction was found in the minocycline-HCl treated group than in the control group (P < 0.05). The similar results were found for both CAL and PD (P < 0.05; P < 0.05) between two groups at 6 months after surgery. PI and SBI variations showed no statistical differences between two groups after periodontal surgery. CONCLUSION: Our results suggested that root conditioning with minocycline-HCl paste during periodontal surgery improve the periodontal healing, which may be associated with the promotion of the periodontal cell attachment and growth onto the root surfaces. PMID- 26064314 TI - MEK1 expression and its relationship with clinical pathological features in hepatocellular carcinoma. AB - BACKGROUND: MEK1 is overexpressed in various human carcinomas, but the role of MEK1 is not well unknown in hepatocellular carcinoma (HCC). In the present study, we aimed to explore MEK1 expression of in HCC tissues, and to evaluate its relationship with clinical pathological features. METHODS: Expressions of MEK1 were detected by western blot assay, real-time quantitative PCR and immunohistochemical (IHC) staining in 30 HCC tissues and their adjacent normal tissues. Pearson Chi-square test was used to analyze the relationship between MEK1 expression and clinical pathological features. The survival curve was drawn by Kaplan-Meier method, and survival was analyzed by Lon-rank test. RESULTS: The expression of MEK1 mRNA in HCC tissues was significantly higher than that in adjacent normal tissues and so was the expression of MEK1 protein. In the 30 specimens, 70% was with Tumor/Normal ratio > 2, 10% with Tumor/Normal ratio < 1 and 20% with 1 < Tumor/Normal ratio < 2. The mean survival time in high MEK1 expression group was significantly lower than that in low MEK1 expression group (Log-rank value = 11.946, P < 0.01). CONCLUSION: MEK1 expressions in HCC tissues were significantly higher than that in adjacent normal tissues, which indicated that MEK1 was involved in the genesis and development of HCC. Moreover, it was closely related to the postoperative survival time of patients with HCC. PMID- 26064315 TI - Neuroprotective effect of lentivirus mediated VEGF on rat model with cerebral ischemic injury. AB - This study aimed to investigate the neuroprotective effect and its mechanism of lentivirus mediated VEGF on rat model with cerebral ischemic injury. 45 rats with cerebral ischemic injury constructed by the suture method were randomly divided into sham group, model group, vector group and VEGF group. The packaged vector lentivirus and lentivirus carrying VEGF gene were injected into the lateral ventricular of rats in vector group and VEGF group respectively. The equal volume of PBS buffer was injected in sham group and model group respectively. The expression of VEGF and protein in brain tissue were detected by real-time fluorescence quantitative PCR and Western blot. The change of brain tissue vascular density was analyzed by immunohistochemistry. The brain infarction area and the degree of nervous functional defect of the rats were analyzed. VEGF mRNA and protein levels were significantly higher in brain tissue of rats in VEGF group than those in model group and vector group (P < 0.05). The brain tissue vascular density increased significantly in VEGF group (P < 0.05). Compared with sham group, the infarction area of brain tissue and the degree of nervous functional defect increased significantly in model group, vector group and VEGF group, but the VEGF group was significantly lower than those in model group and vector group (P < 0.05). In conclusion, the overexpression of VEGF in cerebral ischemia injury contributed to the angiogenesis in brain tissues, reduced the brain injury caused by cerebral ischemia and protected brain neuronal function. PMID- 26064316 TI - Protection by LPS-induced inhibitory CD11b(+) cells on corneal allograft. AB - OBJECTIVE: It is widely reported that CD11b(+)Gr1+ myeloid-derived suppressor cells can cause allograft tolerance in mice and human, however, little is known on the therapy role in chronic transplantation rejection. In this paper, their role in corneal transplantation was studied for the first time. METHOD: Inhibitory CD11b(+) cells were obtained by murine LPS-induced septic model. Phenotype, endocytosis, antigen presenting ability, and T cell suppression assays were performed by flow cytometry analysis. The suppressive ability in vivo was analyzed by targeting allogeneic corneal transplantation. RESULTS: LPS was intraperitoneally injected into C57BL/6 mice, the percentage of CD11b(+) Gr1+ cells was increased in mice spleen, blood, and bone marrow, respectively. Compared with control mice, Ly6C, TLR2, and MHC-11 expression were higher in LPS treated mice. CD11b(+) Gr1+ cells could inhibit allogenic corneal reaction in vivo after adoptive transfer, in consistent with an observation of inhibition effect on the antigen presenting cells (APCs) and CD4+ T cells proliferation in vitro. CONCLUSION: CD11b(+) cells induced by LPS could function as inhibitory APCs, suppress CD4+ T cells proliferation and improve corneal allograft survival. Predictly, its application for cells transfer therapy in clinic in the further. PMID- 26064317 TI - Different expressions of TLRs and related factors in peripheral blood of preterm infants. AB - OBJECTIVE: TLR insufficiency increases newborn's susceptibility to infectious disease. METHODS: The peripheral blood of four premature births has been collected weekly from the 28(th) gestational week (GW) until maturity at 36(th) GW. Microarray assays were used to derive dynamic follow-up data of TLR1-10 and other TLR signaling pathway associated factor changes. RESULTS: The follow-up results showed that the transcription level of TLR1 increased at the 36(th), TLR 3 decreased at the 33(rd) and TLR7 increased at the 34(th) GW significantly, whereas NFkB and its activator TBK1 were highest transcribed in the 28(th) and 32(nd) GW. Low TLR4 transcription in addition to late MD-2 maturation (33(rd) GW) indicated a lack of defense mechanisms against bacterial infections in preterm births particular in the first weeks after birth. Late transcriptional enhancements of TLR1 and MYD88 (35(th) week) as well as beta 2 microglobulin (35(th) GW) also indicated a weak immune system in the early maturation stages. CONCLUSION: The transcription levels of TLR1, 3, 7 and the signaling pathway associated cofactors were different transcribed during the 28(th) and 36(th) GWs of the premature newborns. In the early stage after preterm birth, beside peak transcriptions of NFkB and TBK1, the immune system is not fully developed and maturation takes place mainly between the 33th and 35(th) GW. PMID- 26064318 TI - The variance of peripheral blood lymphocyte subsets of streptozotocin-induced diabetic mice after bone marrow transplantation. AB - Type 1 diabetes (T1D) results from the host immune disorder, which elicits the selective destruction of insulin-producing s in the pancreatic islets. Bone marrow transplantation (BMT) has been reported to treat T1D in numerous studies, and has been proved to be effective in treating T1D based on immune ablation and regeneration. In this study, we aimed to evaluate the curative effect of syngeneic bone marrow transplantation (syn-BMT) and to analyze peripheral blood lymphocyte phenotypes of streptozotocin (STZ)-induced diabetic mice after syn BMT, and further to reveal possible mechanisms of syn-BMT involved in normalization of blood glucose. After multiple injections of low-dose STZ, most male C57BL/6J inbred mice got hyperglycemia, and then underwent syn-BMT. Fasting blood glucose was detected every 10 days after syn-BMT. The hemocytes count was evaluated every 3 days after syn-BMT in mice. Before syn-BMT, and on days 30, 60, and 90 after syn-BMT, we examined proportion of peripheral blood T lymphocytes, CD19(+) B lymphocytes, and NK cells by flow cytometry. Our data showed that hyperglycemia could be reversed and normal blood glucose level could be maintained in the whole observation period after syn-BMT. The peripheral blood elevated CD4(+)/CD8(+) T lymphocyte ratio, CD19(+) B lymphocyte proportion and NK cell proportion in diabetic mice significantly decreased after syn-BMT. This study indicated that syn-BMT could reverse hyperglycemia and revealed immune ablation and immune system regeneration might be a possible mechanism of syn-BMT involved in normalization of blood glucose. PMID- 26064319 TI - Human cord blood mononuclear cell transplantation for the treatment of premature ovarian failure in nude mice. AB - OBJECTIVE: This study explored the potential of human cord blood mononuclear cell (HCMNC) transplantation as a treatment for premature ovarian failure (POF) in a nude mouse model. METHODS: Female nude mice were randomly divided into three groups; a normal control group (n = 35), a POF group (POF plus vehicle, n = 35) and a POF plus cell transplantation group (HCMNCs were implanted into the ovaries, n = 35). HCMNCs were isolated by Ficoll density gradient centrifugation and labeled with BrdU. Four weeks after transplantation, the nude mice were sacrificed to determine serum levels of E2, FSH and LH as indicators of ovarian function, and the ovaries were examined both histologically and immunochemically. RESULTS: The transplanted HCMNCs survived in the transplantation group and were detected by BrdU. In the transplantation group, serum levels of E2 significantly increased while serum levels of FSH and LH significantly decreased compared to the POF control group. Additionally, the transplantation group had a recovery in follicle number. CONCLUSION: HCMNCs can be successfully transplanted into the ovaries of nude mice and can improve ovarian function in POF. PMID- 26064320 TI - The energy loss may predict rupture risks of anterior communicating aneurysms: a preliminary result. AB - Anterior communicating artery (ACoA) aneurysms are well documented to have a higher rupture risk compared with aneurysms at other locations. However, the risk predicting factors for these aneurysms still remain unclear due to the complex arteries geometries and flow patterns involved. The authors introduce a comprehensive method to quantitatively illustrate the development of ACoA aneurysms using a computational fluid dynamics (CFD) approach. Seven ACoA aneurysms, which included 2 ruptured and 5 unruptured aneurysms, were employed. Patient-specific whole anterior circulation geometries were segmented to simulate the real circumstances in vivo. The energy losses (EL) and flow architectures of these 7 aneurysms were evaluated using an algorithm modality. Overall, the 2 ruptured aneurysms, along with 1 unruptured aneurysm that was defined as highly likely to rupture due to ACoA location and a bleb sitting at the top of the dome, had a significantly larger EL and more complex and unstable flow architecture than the others. Two aneurysms had a negative value of EL indicating that the geometries with aneurysms of the anterior communicating complex (ACC) had a smaller loss of energy than the geometries without aneurysms. Despite a small sample size resulting in a low statistical significance, EL may serve as a development predictor of ACoA aneurysms. PMID- 26064321 TI - Lack of association between CD14-159 C/T polymorphism and acute pancreatitis: a meta-analysis. AB - The CD14-159 C/T polymorphism has been implicated in susceptibility to acute pancreatitis (AP), but the results were inconclusive. The present meta-analysis aimed to explore the correlation between CD14-159 C/T polymorphism and AP risk. All eligible case-control studies published up to November 10th, 2014 were identified by searching PubMed, Web of Science, CNKI, and WanFang databases. Two reviewers independently identified the literature according to inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.2 and Stata 12.0 software. A total of five studies comprising 1211 cases and 932 controls were included. Overall, no significant association between CD14-159 C/T polymorphism and AP risk was found under all four genetic models [CT + TT vs CC: OR = 1.09, 95% CI (0.91, 1.31); TT vs CT + CC: OR = 1.04, 95% CI (0.83, 1.29); CT vs CC: OR = 1.08, 95% CI (0.89, 1.32); TT vs CC: OR = 1.15, 95% CI (0.88, 1.49)]; In stratification analysis by disease severity, we also failed to detect any association between CD14-159C/T polymorphism and the risk of mild AP (MAP) or severe AP (SAP); In subgroup analysis by ethnicity, similar results were observed in Asian and European populations. This meta-analysis suggested that the CD14 159C/T polymorphism is not associated with the susceptibility of acute pancreatitis. PMID- 26064322 TI - Low expression of microRNA-143 is related to degenerative scoliosis possibly by regulation of cyclooxygenase-2 expression. AB - AIMS: This study is to determine if expression level of microRNA-143 (miR-143) and cyclooxygenase-2 (COX-2) are related to the occurrence and development of degenerative scoliosis. METHODS: A total of 30 patients with degenerative scoliosis, 30 patients with adolescent idiopathic scoliosis were enrolled in this study. For control, 30 patients with spinal burst fractures were also enrolled in this study. Real-time PCR and western blotting was performed to measure the expression levels of COX-2 in intervertebral disc tissues, peripheral blood and cerebrospinal. Expression levels of miR-143 in intervertebral disc tissues, peripheral blood and cerebrospinal were detected by real-time PCR. RESULTS: The expression levels of COX-2 were increased in intervertebral disc tissues, peripheral blood and cerebrospinal of patients with degenerative scoliosis when compared with those of patients with adolescent idiopathic scoliosis and spinal burst fractures (P < 0.05). However, the expression levels of miR-143 were decreased in intervertebral disc tissues, peripheral blood and cerebrospinal of patients with degenerative scoliosis when compared with those of patients with adolescent idiopathic scoliosis and spinal burst fractures (P < 0.05). CONCLUSIONS: COX-2 is highly expressed whereas miR-143 is lowly expressed in patients with degenerative scoliosis. Decreased expression of miR-143 may be related to the aggravation of degenerative scoliosis by regulation of COX-2. PMID- 26064323 TI - Preoperative CRP levels is not predictive early renal dysfunction after coronary artery bypass surgery. AB - BACKGROUND: The aim of this retrospective study is to determine the correlation between preoperative CRP levels and the early renal dysfunction after cardiac surgery. METHODS: From January 2012 to December 2013, values for preoperative CRP were available for 546 unselected patients undergoing cardiac operations. CRP was used to divide this cohort in two groups: a normal CRP levels group (Group I) of 432 patients with CRP of less than 0.5 mg/dL, and a high CRP levels group (group II) of 114 patients with a CRP of 0.5 mg/dL or more. RESULTS: Median CRP preoperative values were significantly different in the group II (2.49+/-1.03 mg/dL) than in the group I (0.32+/-0.14 mg/dL; P < 0.0001). Median CRP postoperative values were significantly different in the group I (17.62+/-2.99) than in the group II (23.13+/-3.01; P < 0.0001). Preoperative levels of serum blood urea nitrogen (BUN), creatinine and CrCl were not significantly different between group I and group II. Postoperative levels of BUN, Cr and CrCl between the two groups were not significantly different. CONCLUSIONS: The early Cr and CrCl levels after surgery are not significantly different in group I and group II. The early renal function after CABG is not correlated with the preoperative CRP levels. PMID- 26064324 TI - Melanocortin-4 receptor expression in autonomic circuitry involved in gastric function. AB - Several studies have shown that CNS provides the regulation of gastric functions. Recent evidence indicated that the activation of melanocortin 4 receptors (MC4R) in brain nuclei played an important role in modulating gastric activity. This study was designed to assess whether MC4R signaling existed in autonomic circuitry modulated the activity of stomach by a virally mediated transsynaptic tracing study. Pseudorabies virus (PRV)-614 was injected into the ventral stomach wall in adult male MC4R-green fluorescent protein (GFP) transgenic mice (n = 5). After a survival time of 5 days, the mice were assigned to humanely sacrifice, and spinal cords and caudal brainstem were removed and sectioned, and processed for PRV-614 visualization. Neurons involved in the efferent control of the stomach were identified following visualization of PRV-614 retrograde tracing. The neurochemical phenotype of MC4R-GFP-positive neurons was identified using fluorescence immunocytochemical labeling. PRV-614/MC4R-GFP dual labeled neurons were detected in spinal IML and the dorsal motor nucleus of the vagus nerve (DMV). Our findings support the hypothesis that MC4R signaling in autonomic circuitry may participate in the modulation of gastric activity by the melanocortinergic-sympathetic pathway or melanocortinergic-parasympathetic pathway. PMID- 26064325 TI - FOXP3(+)Treg/Th17 cell imbalance in lung tissues of mice with asthma. AB - Immunocyte imbalances, particularly of Th1 and Th2 type helper T (Th) cells, have been implicated in the pathogenesis of chronic inflammatory diseases like asthma. Recent studies have suggested an important role for the balance between Th17 cells and FOXP3(+) regulatory T cells (Treg). However, whether this balance is important in asthma remains unknown. This study sought to detect the populations of T cell subtypes (Th1, Th2, FOXP3(+) Treg, Th17) in lung tissue of a mouse model of asthma to understand the significance of immunocyte balances in the disease. An asthma model was generated by sensitizing ten pathogen-free BALB/c mice using a standard ovalbumin challenge; ten other mice were challenged with PBS to serve as a control group. Total white cells and differential cell counts were determined in bronchoalveolar lavage fluid, and percentages of T cell subtypes were determined using flow cytometry. The severity of inflammation in lung tissue was evaluated in tissue sections, and airway hyperresponsiveness was assessed by unrestrained plethysmography. In mice with asthma, compared to those in the control group, total white cell, eosinophil, monocyte, and lymphocyte cell counts were higher, and lung inflammation and airway hyperresponsiveness were more severe (P<0.05), indicating that the model of asthma was successfully generated. Further, mice with asthma had higher percentages of Th2 and Th17 cells and lower percentages of Th1 and Foxp3(+) Treg cells in lung tissue (P<0.05). Consequently, the ratios of Th1/Th2 cells and FOXP3(+)Treg/Th17 cells were higher in the asthma group (P<0.05). Thus, in addition to the imbalance of Th1/Th2 cells, an imbalance of FOXP3(+)Treg/Th17 cells may play an important role in the pathogenesis of asthma. PMID- 26064326 TI - Histological grade of hepatocellular carcinoma predicted by quantitative diffusion-weighted imaging. AB - OBJECTIVE: This study is to evaluate the application of diffusion-weighted imaging (DWI) in determining the histological grade of hepatocellular carcinoma (HCC). METHODS: Totally, 27 HCC patients who received DWI examination before surgical resection were included in this study. Relationships of apparent diffusion coefficient (ADC) and signal intensity (SI) with the histological grade of HCC were analyzed. RESULTS: These 27 HCC patients could be classified into 6 well, 10 moderately, and 11 poorly differentiated HCCs. The overall ADC value for all HCC cases was (1.28 +/- 0.19) * 10(-3) mm(2)/s. The ADC value for poorly differentiated HCCs was (1.16 +/- 0.16) * 10(-3) mm(2)/s, significantly lower than the well [(1.43 +/- 0.09) * 10(-3) mm(2)/s] and moderately [(1.34 +/- 0.19) * 10(-3) mm(2)/s] differentiated HCCs. There was no significant difference in ADC between the well and moderately differentiated HCCs. The overall SI value for all the HCC cases was 75.66 +/- 32.94. The mean SI value for the moderately differentiated HCC cases was 54.37 +/- 28.37, significantly lower than the well (90.78 +/- 27.49) and poorly (86.77 +/- 31.51) differentiated HCCs. No significant difference in SI was observed between the well and poorly differentiated HCCs. Additionally, there was a significant negative correlation between the ADC value and the histological grade of HCC. CONCLUSION: The ADC value based on DWI is useful in determining the histological grade of HCC, while the SI value provides limited contribution to HCC histological grade evaluation. PMID- 26064327 TI - Inhibition of mouse B16 melanoma by sodium butyrate correlated to tumor associated macrophages differentiation suppression. AB - OBJECTIVE: As one member of the histone deacetylase inhibitor (HDACi) family, Sodium butyrate (NaB) was found out that could be used as a differentiation inducer of much cancer cell. But its effects on tumor microenvironment cells are not well recognized. The goal of this research is to investigate the effect of NaB on B16 melanoma and analysis its relevant mechanism. METHODS: We observed the effect of sodium butyrate on B16 melanoma in vivo and in vitro. MTT method was performed to detect cell apoptosis rate after treatment. Tumor associated macrophage infiltration condition was detected by flow cytometry. Western blotting and immunohistochemical method were used to detect the expression of tumor associated macrophage cytokines. RESULTS: A certain concentration of sodium butyrate could effectively inhibit B16 melanoma growth in vivo and in vitro, and this inhibition effects related to the suppression of tumor associated macrophage differentiation. At the same time we observed the relevant macrophage factors were down-regulated compared to the control. CONCLUSION: Sodium butyrate could effectively inhibit B16 melanoma growth through suppressing tumor associated macrophage proliferation and reduce relevant pro-tumor macrophage factors expression, which may help to promote the clinical study of melanoma epigenetic therapy. PMID- 26064328 TI - Hepatitis B virus infection in hepatocellular carcinoma tissues upregulates expression of DNA methyltransferases. AB - PURPOSE: Our previous research identified that Hepatitis B virus (HBV) infection results in the increased methylation of p16; however, the mechanism(s) of the methylation changes observed following HBV infection are yet to be deduced. DNA methylation is governed by the interaction of DNA methyltransferases (DNMT). To investigate the expression of DNMT in cancerous tissue, cirrhotic tissues and non cancerous tissue, we examined the relationship between HBV infection and DNMT expression. METHODS: We compared the mRNA expression levels of the four DNMTs in cancerous, cirrhotic and matched non-cancerous tissues of HCC with HBV infection by real-time PCR. RESULTS: The results showed that compared with the level in the corresponding non-cancerous liver tissues, the levels of DNMT1, DNMT3A and DNMT3B were elevated in 54.5%, 68.2% and 38.6% of cancerous tissues and 31.4%, 40% and 25.8% of cirrhotic tissues, respectively. The average mRNA expression for DNMT2 in cancerous and cirrhotic tissues of HCC was not significantly different from that in the corresponding non-cancerous liver tissues. In HBV-associated tissue samples, both the average level and the elevated frequency of DNMT1, DNMT3A and DNMT3B mRNA expression were significantly higher than in non-HBV-associated cirrhotic and cancerous tissues; even in non-cancerous tissues, the mRNA levels of DNMT1 and DNMT3A in HBV-associated samples were significantly higher than in the non-HBV-associated samples. Correlations analysis demonstrated a significant association between HBV infection and the overexpression of DNMTs and p16 methylation. CONCLUSIONS: The results of our current study suggest that persistent HBV infection can stimulate the overexpression of DNMTs, particularly DNMT1, DNMT3A and DNMT3B, which may result in the hyper-methylation/inactivation of p16, thus indirectly regulating the progression of hepatocellular carcinogenesis. PMID- 26064329 TI - Down-regulation of dual-specificity phosphatase 5 predicts poor prognosis of patients with prostate cancer. AB - Dual-specificity phosphatase 5 (DUSP5), which specifically inactivates the extracellular signal-regulated kinase (ERK) 1/2 within the mitogen-activated protein kinase (MAPK) signaling, has recently been considered to be a tumor suppressor. However, its role in prostate cancer is still elusive. In this study, we performed immunohistochemistry analysis on human tissue microarray (TMA) to detect the DUSP5 protein expression pattern. The results indicated that DUSP5 was down-regulated in the human prostate cancer relative to the adjacent benign tissues (IRS: PCa = 4.29 +/- 1.72 versus Benign = 4.89 +/- 1.58, P = 0.04). In addition, when we linked the DUSP5 protein levels to the clinicopathological features of the patients, we found that the downregulation of DUSP5 was significantly associated with advanced pathological stage (P = 0.004) and high Gleason score (P = 0.009). Moreover, we attempted to validate these findings and investigate the prognostic value of DUSP5 in a publicly available microarray based Taylor Dataset. Statistic analysis demonstrated that the downregulation of DUSP5 was closely correlated with high Gleason score (P = 0.011), positive metastasis (P < 0.001) and biochemical recurrence (BCR) (P = 0.016). More importantly, Kaplan-Meier analysis revealed that significant differences between patients with high and low DUSP5 expression level in regard to the BCR-free survival of overall (P = 0.009), non-metastatic (P = 0.006) and patients with Gleason score 7 (P = 0.044). Multivariate analysis by Cox regression indicated that DUSP5 could be an independent predictor for the risk of BCR (HR: 0.41, 95% CI: 0.2-0.82; P = 0.012). In summary, our findings disclose that DUSP5 may be an important tumor suppressor that inhibits the progression of PCa. The downregulation of DUSP5 may accurately predict poor prognosis in PCa patients. PMID- 26064330 TI - Relation of stem cell markers ALDH1 and CD44 with clinicopathological factors in urothelial carcinomas of urinary bladder. AB - Molecular studies are ongoing in regards to superficial urothelial carcinoma of the bladder (UCB) either to define targeted therapy or to better select aggressive therapy candidates and also to delineate the outcome of the disease. In this study, we aimed to present the impact of ALDH1 and CD44 as stem cell markers in tumorigenesis and their prognostic value in urothelial carcinoma. We investigated ALDH1 and CD44 immunohistochemically in paraffin-embedded material of 125 non-muscle-invasive (NMI) cases in 163 UCB patients. In the NMI-UCB subgroup, we found ALDH1 to be significantly correlated with all poor prognostic factors, including high stage (>=pT2), high grade, recurrence and progression development and poor survey (P=0.001) in contrast to CD44 expression (P>0.05). Although ALDH1 expression had a good correlation with a poor clinical course of UCB, it could be used as a molecular marker to determine the best treatment strategy and could contribute to the development of targeted therapies. PMID- 26064331 TI - A proteomic study of the differential protein expression in MDBK cells after bovine herpesvirus type 1 infection (BHV-1) strain treatment. AB - Different BHV-1 strains, such as the virulent IBRV LN01/08 strains and the attenuated vaccine strain IBRV LNM, produces different clinical immune responses; however, the study of the differential protein expression in Madin-Darby bovine kidney (MDBK) cells after BHV-1-infection still remains unclear. Here, we applied a comparative proteomic strategy, based on 2D and MALDI-TOF/MS platforms, to examine the differential expression of proteins in MDBK cells that were treated and not treated with virulent IBRV LN01/08 and attenuated IBRV LNM strains. A total of eight differential proteins, including pyruvate kinase, heat shock protein (HSP) 90 (HSP90AA1 and HSP90AB1), annexin A, albumin (ALB), scinderin (SCIN), tubulin (alpha 1a) and vimentin (VIM), were identified. Among these proteins, pyruvate kinase, and HSP90 (HSP90AB1), tubulin and vimentin were identified in the virulent IBRV LN01/08 strain group, but were not identified in the attenuated IBRV LNM group. These results play an important role in tumor formation and development, cell migration, tumor cell line apoptosis, cell invasion and viral infection. The HSP90 (HSP90AA1) protein was identified in the control group and the attenuated IBRV LNM-infected group. Most studies have shown that HSP90 proteins were more of a cancer gene target, and inhibiting its function would result to oncogene degradation during cancer treatment. On the other hand, ALB is associated to cell differentiation, apoptosis, necrosis, cell death, viral infection, autophagy, interstitial tissue inflammation, and cell survival. These results provide a theoretical basis for the systematic understanding of BHV-1-infection mechanisms and BHV-1-induced immune responses. PMID- 26064332 TI - Clinical and pathological characteristics of adrenal lymphangioma treated by laparoscopy via a retroperitoneal approach: experience and analysis of 7 cases. AB - To describe the clinical and pathological characteristics of adrenal lymphangioma (AL) and share our experiences of the treatment of AL with retroperitoneal laparoscopic surgery. All patients pathologically diagnosed with AL were examined. The clinical and pathological characteristics, process of diagnosis, and preparation and treatment of all patients, especially patients treated with laparoscopic surgery, were summarized and retrospectively analyzed. From January 2008 to May 2014, 8 patients underwent adrenalectomies and were diagnosed with AL in our hospital. The median age was 45.5 years. All of these patients experienced a smooth adrenalectomy: 7 performed by laparoscopy via a retroperitoneal approach and 1 performed by open surgery. Five were female and the other 3 were male. These patients had unilateral adrenal lesions. Four were located on the right which to be same as the contralateral. In addition, 1 specimen was assayed by immunohistochemistry (IHC), which revealed positive results for CD31, CD34, Factor VIII-related antigen and D2-40, and negative results for cytokeratin AE1/AE3. During a brief follow up, all patients exhibited favorable results without discomfort. AL is a benign lesion with mild bio-behavior and patients are generally asymptomatic. The use of computerized tomography (CT) combined with enhanced CT has a superior advantage in diagnosis. Laparoscopic adrenalectomies that are performed via a retroperitoneal approach would be a very safe and efficient choice for AL treatment. D2-40 can be considered as a specific IHC marker in the pathological diagnosis of AL. However, pheochromocytoma and adrenal tuberculosis should be ruled out before and during the operation. PMID- 26064333 TI - ATRA and Genistein synergistically inhibit the metastatic potential of human lung adenocarcinoma cells. AB - OBJECTIVE: This study was to investigate the effects of all-trans retinoic acid (ATRA) in combination with Genistein on the proliferation, expression of apoptosis related proteins and adhesion molecules (MUC1 and ICAM-1) and invasiveness of A549 cells, aiming to investigate whether combined therapy of ATRA and Genistein is superior to monotherapy in suppressing metastasis of lung cancer cells. METHODS: ATRA, Genistein and both were used to treat human lung adenocarcinoma cells (A549 cells). Immunohistochemistry was done for MUC1 expression, flow cytometry for ICAM-1 expression, fluorescence quantitative PCR for MUC1 expression and Western blot assay for the expressions of cell cycle related proteins (CDK4, Rb and p-ERK1/2) and apoptosis related proteins (Bax and Bcl-2). Cells were seeded into Matrigel pre-coated Transwell chambers, and the migrating cells were counted. RESULTS: Combined treatment with ATRA and Genistein was able to reduce the expressions of Bcl-2, MUC1 and ICAM-1 and exerted synergistic effects to inhibit the invasion of A549 cells. CONCLUSION: ATRA and Genistein may synergistically inhibit MUC1 and ICAM-1 expressions and affect the expressions of cell cycle related proteins (CDK4, Rb and p-ERK1/2) and apoptosis related proteins (Bax and Bcl-2), inhibit the metastatic potential of lung cancer A549 cells. PMID- 26064334 TI - The impact of hemoglobin level and transfusion on the outcomes of chemotherapy in gastric cancer patients. AB - OBJECTIVE: To examine the impact of hemoglobin levels in predicting outcomes and evaluate whether transfusion could improve the outcomes of chemotherapy on gastric cancer patients. METHODS: A total 310 patients were divided into two groups: high Hb group (Hb >90 g/L) and low Hb group (Hb <90 g/L). A portion of patients in low Hb group received transfusion. The effect of hemoglobin level on the chemotherapy outcomes was determined according to the comparison between patients with high hemoglobin and patients with low hemoglobin without transfusion. The effect of transfusion on the chemotherapy outcomes was evaluated by comparing the two low groups (with and without transfusion). RESULTS: A total of 310 patients were within the study criteria. Among them, 27.7% patients in high Hb group, 44.5% patients in low Hb without transfusion and 27.7% patients in low Hb with transfusion were followed up. The 5-years survival rates of high Hb group, low Hb group without transfusion and with transfusion were respectively 29%, 10% and 8%. The survival rate of patients in Hb group without transfusion was higher. The chemotherapy rates of patients in high Hb group, low Hb without transfusion group and with transfusion group were respectively 32.56%, 42.03% and 18.6%. CONCLUSION: Low nadir Hb (<90 g/L) during chemotherapy had an effect on the survival and chemotherapy response rate. The chemotherapy outcomes could not be improved through increasing Hb level by red blood cell (RBC) transfusion. PMID- 26064335 TI - Predictive model of portal venous system thrombosis in cirrhotic portal hypertensive patients after splenectomy. AB - OBJECTIVE: This study is to investigate the risk factors of portal venous system thrombosis (PVT) in patients with cirrhotic portal hypertension after splenectomy and to establish a Logistic regression prediction model. METHODS: A total of 119 patients with cirrhotic portal hypertension were enrolled. Their clinical data was retrospectively analyzed. They were divided into PVT group (n = 18) and non PVT group (n = 101). One-way analysis and multivariate Logistic regression analysis were performed to analyze the independent risk factors of PVT. Logistic regression prediction model was established. The receiver operating characteristic curve was generated and correlation analysis was conducted. RESULTS: Platelet count (PLT), mean platelet volume (MPV) and D-Dimer were independent risk factors affecting PVT. Anticoagulation therapy (UAT) and usage of reducing portal pressure therapy (URPT) were independent protective factors of PVT. Logistic regression prediction model was expressed as Logit P = -9.165 + 0.664 * PLT (* 10(11)/L) + 0.413 * MPV (fL) + 0.662 * D-Dimer (mg/L) -1.674 * UAT (Yes = 1, No = 0) -1.518 * URPT (Yes = 1, No = 0). And, the cut-off value of Logit P was -1.14. The area under the receiver operating characteristic curve and the accuracy were 0.865 and 84.03%. The cut-off value of PLT, MPV and D-Dimer were 4.42 * 10(11)/L, 13.30 fL and 2.55 mg/L, respectively. MPV and D-Dimer were positively correlated. CONCLUSION: PLT, MPV and D-Dimer are independent risk factors while UAT and URPT are independent protective factors of PVT. Logistic regression prediction model can predict PVT with a high sensitivity, specificity and accuracy. It provides theoretical foundation and cut-off value for predicting PVT after splenectomy. PMID- 26064336 TI - Improved nephrostomy tube can reduce percutaneous nephrolithotomy postoperative bleeding. AB - Renal hemorrhage is one of the most common and worrisome complications of post percutaneous nephrolithotomy (PCNL). This study aimed at evaluating the safety, effectiveness of utilization of the absorbable hemostatic gauze cover renal tract for hemorrhage of post-PCNL. The prospective study including 188 patients with upper urinary tract calculi was carried out in the department of Urology at Linyi People's Hospital from November 2011 to September 2013. All patients underwent PCNL procedures and they were divided into two groups randomly before the procedure. Group A (n=91) was indwelled a 16F catheter as nephrostomy tube at the end of the surgery, Group B (n=97) was indwelled a 14F catheter covered with absorbable hemostatic gauze for hemostasis. Blood loss was estimated based on the mass of hemoglobin in the draining liquid and urine during postoperative duration by HiCN method. The average blood loss was 25.76+/-23.99 g for Group A, and 14.25+/-6.87 g for Group B, respectively, with statistical difference by comparison (P<0.05). The delta hemoglobin was 16.24+/-10.98 mmol/L for Group A, and 10.71+/-5.57 mmol/L for Group B, respectively, also with statistical difference by comparison (P<0.05). Nephrostomy channel applications of absorbable hemostatic gauze after PCNL can significantly reduce postoperative bleeding. Utilizing the absorbable hemostatic gauze for post-PCNL hemorrhage is safe, effective and feasible. PMID- 26064337 TI - Reference values of T lymphocyte subsets among health adults in Inner Mongolia Region. AB - Estimation of T-lymphocyte subsets continues to be an important aspect for monitoring HIV disease progression and response to antiretroviral therapy. Most of the diagnostic laboratories often rely on studies from western for CD4+T lymphocyte reference values, which could, often be unreliable for usage in local settings. To establish the normal reference values of T lymphocyte subsets from healthy people of Inner Mongolia Autonomous Region, flow cytometry was performed to determine the reference ranges for lymphocyte subsets (CD3 and CD4 cells) in 400 healthy multiracial adult population from 12 League Cities in Inner Mongolia Region, China. The basic information including age, gender, nationality and history was collected. There were significant differences in the absolute counting, percentage of CD3+T lymphocytes, and CD4+T lymphocyte percentage counting among different age groups. There were significant differences in CD3+, CD4+T lymphocyte percentage in the groups with different genders. There were significant differences in CD3+T lymphocyte percentage count, absolute count of CD4+T lymphocytes and CD4+T lymphocyte percentage counting in the group with ages of 16-20. There were dramatic differences in CD3+T lymphocyte percentage count and CD4+T lymphocyte percentage counting in the group with ages of 31-40. There were significant differences in CD4+T lymphocyte percentage counting. By this study, age, gender and ethnic specific lymphocyte subset reference ranges have been locally established in Inner Mongolia Autonomous Region. PMID- 26064338 TI - 23-gauge vitrectomy and silicone oil tamponade with and without phacoemulsification in rhegmatogenous retinal detachment. AB - The aim of this study is to assess clinical outcomes of 23-gauge vitrectomy and silicone oil (SO) tamponade combined with and without phacoemulsification (PE) in rhegmatogenous retinal detachment (RRD). The study included forty eyes of 40 patients that underwent 23-gauge vitrectomy and SO tamponade combined with and without PE. Twenty eyes of 20 cases, of whom underwent 23-gauge vitrectomy and SO tamponade combined with PE were allocated to the group 1. Likewise, 20 eyes of 20 cases that underwent 23-gauge vitrectomy and SO tamponade alone were allocated to the group 2. Best corrected visual acuity (BCVA) between two groups was compared. There was no significant difference in BCVA between the two groups during the 6 months (P = 0.3). Recurrent retinal detachments were observed in 2 cases (10%) in both groups. There was no statistically significant difference between two groups as a point of recurrent retinal detachments (P = 1). We have found higher rates of post-vitrectomy cataract progression (45%) in the eyes with RRD who underwent 23-gauge vitrectomy and SO tamponade. Combined vitrectomy and PE is safe and effective for the patients with RRD. PMID- 26064339 TI - Radiation dose is associated with prognosis of small cell lung cancer with superior vena cava syndrome. AB - Approximately 10% of small cell lung cancer (SCLC) cases develop superior vena cava syndrome (SVCS). Many SCLC patients with SVCS have relatively limited disease, requiring curative rather than palliative treatment. Besides chemotherapy, radiotherapy is important for treating SCLC with SVCS. We retrospectively evaluated the influence of radiotherapy dose on the prognosis of 57 patients with SCLC with SVCS treated with concurrent chemoradiotherapy. The mean biological equivalent radiation dose was 71.5 Gy. We administered etoposide/cisplatin as sequential and concurrent chemotherapy. All patients received at least one cycle of concurrent chemotherapy. All patients had partial or complete response; SVCS-associated symptoms were reduced in 87.7% (50/57) of patients within 3-10 days after treatment. Radiation dose did not affect 2-year local control (74.2% vs. 80.8%). Patients who received high-dose radiation had a lower 2-year overall survival rate than those who received low-dose radiation (11.6 vs. 33%; P = 0.024). The high dose group median survival was 15.0 months (95% confidence interval [CI]: 11.2-19.0) compared with 18.7 months (95% CI: 13.9 23.6) in the low dose group. Grade 3/4 neutropenia occurred in 22/26 high dose patients (84.6%) and 21/31 low dose patients (67.7%). In the high dose group, 30.8% of patients had grade 3/4 esophagitis compared with 19.4% of low dose patients. Only 29.0% of low dose patients received < 4 cycles of chemotherapy in the first 12 weeks after treatment began compared with 46.2% of high dose patients. Concurrent chemoradiotherapy is a tolerable modality for treating stage IIIA/IIIB SCLC with SVCS. Moderate-dose radiotherapy is preferable. PMID- 26064340 TI - Single-incision approach improves wound healing and bone union for treating mid to-lower segment of tibiofibular fracture. AB - The mid-to-lower segment of tibiofibular fractures (MLTFs) is commonly encountered in clinical practice, which is conventionally treated by the double incision surgical approach. However, the double-incision approach frequently makes the closure of the wound extremely difficult and sometimes results in necrosis of skin around fractured sites. In the present study, our experience of using a single-incision surgical approach for treating MLTF was exhibited. From February 2005 to December 2013, the clinical outcomes of 212 patients with MLTFs who underwent either double-incision approach or single-incision approach were retrospectively evaluated and compared. Both groups were similar with respect to injury mechanism and all patients were followed up with the efficacies of treatment evaluated by Johner-Wruth criteria. The results demonstrated that the effective rate and the rate of excellent and good efficacy in the single-incision group were significantly higher than those in the double-incision group (P<0.05). In addition, the rates of skin wound healing and bone union after surgery in the single-incision group were significantly higher than those in the double-incision group (P<0.05). These findings indicate that the single-incision surgical approach, which holds the advantages of being milder in trauma, fewer in complications and better in function restoration, might be used as an alternative method for treating MLTFs. PMID- 26064341 TI - Correlation between serum exosome derived miR-208a and acute coronary syndrome. AB - OBJECTIVE: To explore the correlation of miRNAs with clinical characteristics of ACS. METHODS: 50 ACS patients and 50 healthy controls were randomly selected. On the basis of miRNA expression levels, ACS patients were classified as low miRNA expression group (fold change: <3) and high miRNA expression group (>=3). RESULTS: miR-208a expression increased markedly in the serum exosomes of ACS patients, and miR-208a expression in the serum of ACS patients was also significantly higher than that in healthy controls. However, the sensitivity of serum miR-208a was inferior to that of exosome miR-208a. Analysis of clinical characteristics showed the mean age of 500 ACS patients was 62.35+/-9.70 years, and there were 300 patients in low miR-208a expression group and 200 patients in high miR-208a expression group. When compared with low miR-208a expression group, patients with high miR-208a expression were older, and had higher Killip class, higher CK-MB peak, higher cTnT peak and elevated LDL (P<0.05). Within 1-year follow up, 32 patients died including 10 in low miR-208a expression group with the mortality of 3.3% and 22 in high miR-208a expression group with the mortality of 11.0%. Kaplan-Meier survival analysis revealed that the 1-year survival rate reduced significantly in patients with high miR-208a expression. CONCLUSION: miRNA-208a expression is significantly up-regulated in the serum exosomes of ACS patients and is crucial for the diagnosis of ACS. PMID- 26064343 TI - Effect of combined application insulin and insulin detemir on continous glucose monitor in children with type 1 diabetes mellitus. AB - Insulin detemir is a soluble long-acting human insulin analogue at neutral pH with a unique mechanism of action, which could strengthen the effects of insulin. This study aims to explore the effects of insulin combined with insulin detemir on the continous glucose in children with type 1 diabetes mellitus. In this study, 150 patients with type 1 diabetes enrolled were included and randomly divided into 3 groups: insulin group (group A), insulin detemir group (group B) and insulin combined with insulin detemir group (group C). Each subject underwent 72 h of continuous glucose monitoring (CGM). MAGE, HbA1c and Noctumal Hypoglycemia levels were examined by using the ELISA kits. The body weight changes were also detected in this study. The results indicated that the information including age, body weight, disease duration and glucose level and HbA1c percentage on the start time point among three groups indicated no statistical differences. Insulin combined with insulin detemir decrease MAGE and HbA1c level in Group C compared to Group A and Group A (P < 0.05). Insulin combined with insulin detemir decreas noctumal hypoglycemia levels and body weight changes (P < 0.05). In conclusion, this study confirmed efficacy of insulin detemir by demonstrating non-inferiority of insulin detemir compared with insulin with respect to HbA1c, with an improved safety profile including significantly fewer hypoglycaemic episodes and less undesirable weight gain in children. PMID- 26064342 TI - Benefit of a 360-degree horizontal turn following premedication with simethicone on image quality during gastroendoscopy: a randomized controlled trial. AB - OBJECTIVES: To investigate whether a 360-degree horizontal turn after oral premedication with simethicone improves the mucosal visibility during gastroendoscopic examination, and to determine the proper time to turn over the patient. METHODS: This study involved 993 patients scheduled for gastroendoscopy. Just before gastroendoscopy, after oral premedication with simethicone, patients were randomly assigned to three groups: in Group A, patients waited for 20 min before gastroendoscopy; in Group B, patients were separately waited for 5/10/15/20 min and were then turned 360 degrees just before gastroendoscopy; in Group C, patients were immediately turned 360 degrees and then separately waited for 5/10/15/20 min before examination. The sum of the gastric mucosal visibility scores (MVS) was calculated after the examination. The MVS and proportion of images with higher visibility scores for the mucosal surface. Lower scores indicate better visibility of the mucosal surface. RESULTS: In Groups B and Groups C, when waiting time more than 10 min had lower mean total MVS than Group A. The MVS of four subgroups of Group B were not different from those of Group C. CONCLUSION: Oral premedication with simethicone and immediately make a body posture change (turning over 360 degrees) then waiting for 10min can increase the image quality during gastroendoscopy and effectively decrease the premedication time. PMID- 26064344 TI - Anatomical and radiographical study of the retromolar canal and retromolar foramen in macerated mandibles. AB - PURPOSE: The aim of this study was to analyze the presence of the RMF in mandibles, considering gender and ethnic group. The RMC was also analyzed using periapical radiography. METHODS: Eighty-six mandibles from adult individuals of both sexes, of white and black skin colours were analyzed. The presence of RMF (bilateral or unilateral) was observed, with the side and the number of foramina in each hemimandible. Five mandibles were selected for RMC evaluation by periapical radiography. RESULTS: We observed at least 1 RMF in 16 mandibles out of a total of 86 (18.60%) and in 21 out of 172 sides (12.20%). The percentages were 27% in black individuals, 15.6% in white individuals, 23.8% in females and 13.8% in males. CONCLUSIONS: The RMF is a reasonably frequent anatomical variation and shows no differences between sexes or ethnic group, can be unilateral or bilateral and presents no side preference. The RMC presents different types of course and can even establish contact with the alveolar cortical, which might further complicate surgical and anaesthetic procedures in this region. PMID- 26064345 TI - Down-regulation of tissue microRNA-126 was associated with poor prognosis in patients with cutaneous melanoma. AB - BACKGROUND: MiR-126 is frequently downregulated in a variety of malignancies and acts as a potential tumor suppressor. It also played a tumor suppressor role in human melanoma through the direct or indirect repression of several key oncogenic molecules. METHODS: qRT-PCR assay was performed to examine the expression of miR 126. Associations between miR-126 expression and various clinicopathological characteristics were analyzed using the chi(2) test. Survival rate was determined with Kaplan-Meier and statistically analyzed with the log-rank method between groups. Survival data were evaluated through multivariate Cox regression analysis. RESULTS: Significant differences for miR-126 expression were shown between dysplastic nevi and primary cutaneous melanoma (P<0.01), between primary melanoma and metastatic cutaneous melanomas (P<0.01), and between primary cutaneous melanomas and metastatic cutaneous melanomas (P<0.001). The patients with low miR-126 expression showed shorter 5-year overall survival than those with high miR-126 expression (P=0.039; log-rank test). Multivariate regression analysis showed that the status of miR-126 expression was an independent prognostic factor overall survival (HR=3.782, 95% CI: 2.479-16.334, P=0.005). CONCLUSION: The status of miR-126 might be an independent prognostic factor for patients with cutaneous melanoma. PMID- 26064346 TI - A simple score for predicting renal artery stenosis in patients with ischemic heart disease. AB - BACKGROUND: Previous risk score is not simple for predicting existence of atherosclerotic renal artery stenosis (ARAS). Our study aims to develop a simple score to predict ARAS in eastern people with ischemic heart disease. METHODS: There were two data sources involved in this study. From the data source of patients with acute myocardial infarction, we developed a clinical score for predicting existence of ARAS. After this, we validated this clinical score in data source of patients with ischemic heart failure. RESULTS: By multivariable logistic regression analysis, only age, hypertension, stroke or intermittent claudication, serum creatinine were involved in this model. Receiver operating characteristic curve was plotted. In the first data source, area under curve is 0.808 to predict ARAS, and 0.762 for bilateral ARAS. In the second data source, area under curve is 0.721 to predict ARAS, and 0.827 for ARAS. Cutoff value of 35.0 yields a sensitivity of 82.4% and a specificity of 51.0% for ARAS, a sensitivity of 78.9% and a specificity of 47.1% for bilateral ARAS. In the second data source, this cutoff value yields a sensitivity of 85.0% and a specificity of 30.5% for ARAS, a sensitivity of 85.7% and a specificity of 17.5% for bilateral ARAS. CONCLUSIONS: We have developed a simple score for eastern people to predicting existence of ARAS with acceptable sensitivity and specificity in patients with ischemic heart disease. This score is still needed to be validated in general population or patients with no coronary heart disease. PMID- 26064347 TI - A meta-analysis of voxel-based morphometric studies on migraine. AB - PURPOSE: To identify consistent results of voxel-based morphometry (VBM) studies in migraine. METHODS: Whole-brain VBM studies comparing migraine patients with healthy controls (HC) were systematically searched in PubMed, ISI Web of Science, Embase, and Medline databases from January 1990 to Dec 2014. Coordinates were extracted from clusters with significant difference in gray matter volume (GMV) between migraine patients with healthy controls (HC). Meta-analysis was performed using activation likelihood estimation (ALE). RESULTS: A total of 5 studies, comprising 126 migraineurs, including 23 migraine with aura, 41migraine without aura, 11 epidemic migraine and 16 chronic migraine as well as 19 Mm and 16 nmM, and 134 HC, were enrolled. The included studies report GMV reduction at 84 coordinates in migraine, as well as GMV increase at 2 coordinate in migraine. However, due to only two included studies have classified patients into these two phenotypes and one stated they included only migraine with aura patients , we were not able to perform a subgroup analysis and separate meta-analyses on each phenotype. CONCLUSION: There were significant reductions in Middle frontal cortex (BA6, 9) structures and the Inferior frontal cortex (BA44) in migraine. These changes of GMV may indicate the mechanisms of the associated symptoms such as cognitive dysfunction, emotion problems and autonomic dysfunction. But whether this is the characteristics of the subtypes of migraine or can distinguish the types of migraine or primary headache, further studies examining larger samples may better elucidate the changes related to the illness and highlight its pathological mechanism. PMID- 26064348 TI - An open-label, randomized and multi-center clinical trial to evaluate the efficacy of Silibinin in preventing drug-induced liver injury. AB - To assess the clinical efficacy and safety of Silibinin in preventing drug induced liver injury (DILI) in the general population (high-risk patients with non-drug induced liver injury). METHOD: A prospective, multi-center, randomized, open-label and controlled trial was conducted with 568 patients undergoing primary treatment of pulmonary tuberculosis. The study included 277 patients in experimental group and 291 patients in control group. The patients in the two group were treated with conventional 2HREZ (S)/4HR for tuberculosis (TB), and additional Silibinin capsules (oral administration of 70 mg/time, 3 times/day for 8 weeks in experimental group. Outcomes of liver function, interruption of anti TB treatment and therapeutic results, as well as adverse reactions were observed and analyzed. RESULTS: At 2, 4 and 8 weeks of treatment, the incidences of liver injury in experimental group were 3.97%, 1.44% and 2.17%, respectively; the incidences in control group were 4.12%, 4.12% and 2.41%, respectively. Statistical analysis showed that there was no difference in the incidence between the two groups at each treatment period (P>0.05). At 8 weeks, the numbers of patients diagnosed of DILI were 18 (7.22%) and 27 (9.28%) in experimental and control groups, respectively (P>0.05). 34.30% and 27.49% of the patients in experimental and control groups had transient abnormal liver function or symptoms, respectively; similar percentages (3.25% and 6.19%) of the patients in two groups have liver function injury and symptoms, and were suspended for anti TB treatment (P>0.05). The incidence of anorexia and nausea symptoms was lower in experimental group than in control group, and the differences were significant at 4 and 8 weeks (P<0.05). 8 weeks after the treatment, 98.30% of the sputum smear culture were negative in experimental group, which was significantly higher (P<0.01) than that in control group (92.98%). CONCLUSION: Preventive hepatoprotective therapy in the general population may reduce drug discontinuation rate, improve patient's compliance and outcomes of anti-TB treatment. PMID- 26064349 TI - Epicardial fat volume is correlated with coronary lesion and its severity. AB - OBJECTIVE: To evaluate the correlation of epicardial adipose tissue volume (EATV) with the coronary artery lesion and its severity. METHODS: Inpatients with suspicious stable angina of coronary heart lesion were recruited. For patients with coronary artery lesions in CTA, further coronary angiography (CAG) was performed to evaluate the coronary artery lesion. Gensini scoring system was employed to assess the severity of coronary artery lesions. RESULTS: Patients were classified as coronary heart disease (CHD) group (n = 160). Results showed the mean EATV was 192.57 +/- 30.32 cm(3) in CHD group, which was significantly larger than that in control group (138.56 +/- 23.18 cm(3); P < 0.01). The coronary artery stenosis was classified as mild, moderate and severe stenosis according to the extent of coronary artery lesions, and results showed marked difference in the EATV among patients with different severities of coronary artery stenosis (P < 0.005). The Gensini score was positively related to EATV (r = 0.285, P = 0.000). The EATV increased with the increase in the number of affected coronary arteries. Multivariate Logistic regression analysis showed EATV was an independent risk factor of CHD after adjusting other confounding factors (OR = 1.023, P = 0.013). CONCLUSION: EATV is closely related to the severity of coronary artery lesions: the larger the EATV, the more severe the coronary artery lesions. Moreover, EATV is an independent risk factor of CHD. PMID- 26064350 TI - Assessment of the effect of ketamine on cytochrome P450 isoforms activity in rats by cocktail method. AB - Cocktail method was used to evaluate the influence of ketamine on the activities of CYP450 isoforms CYP1A2, CYP2D6, CYP3A4, CYP2C19, CYP2C9 and CYP2B6, which were reflected by the changes of pharmacokinetic parameters of six specific probe drugs phenacetin, metroprolol, midazolam, omeprazole, tolbutamide and bupropion, respectively. The experimental rats were randomly divided into two group, control group and ketamine group. The ketamine group rats were given 50 mg/kg ketamine by continuous intragastric administration for 14 days. The mixture of six probes was given to rats through intragastric administration and the blood samples were obtained at a series of time-points through the caudal vein. The concentrations of probe drugs in rat plasma were measured by UPLC-MS/MS. In the experiment for ketamine and control group, there was statistical pharmacokinetics difference for phenacetin, metroprolol, midazolam, omeprazole, tolbutamide and bupropion. Continuous intragastric administration for 14 days could induce the activities of CYP450 isoforms CYP1A2, CYP3A4 and CYP2B6 of rats. PMID- 26064351 TI - Triglyceride to HDL-C ratio and increased arterial stiffness in apparently healthy individuals. AB - OBJECTIVES: High triglycerides and low high density lipoprotein cholesterol are important cardiovascular risk factors. Triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) has been reported to be useful in predicting cardiovascular disease. Brachial-ankle pulse wave velocity (baPWV) is a valid and reproducible measurement by which to assess arterial stiffness and a surrogate marker of atherosclerosis. However, there is limited evidence about the relationship between them. Therefore, we tested the hypotheses that TG/HDL-C is associated with baPWV in healthy individuals. METHODS: Fasting lipid profiles, baPWV and clinical data were measured in 1498 apparently healthy, medication-free subjects (926 men, 572 women) who participated in a routine health screening from 2011 to 2013. Participants were stratified into quartiles of TG/HDL-C ratio. BaPWV > 1400 cm/s was defined as abnormal baPWV, Multivariable logistic regression was used to identify associations of TG/HDL-C quartiles and baPWV, after adjusting for the presence of conventional cardiovascular risk factors. RESULTS: In both genders, we observed positive relationships between TG/HDL-C quartiles and BMI, systolic BP, diastolic BP, fasting glucose, total cholesterol, LDL-C, triglycerides, uric acid, and percentages of high baPWV. Multivariable logistic regression revealed that baPWV abnormality OR value of the highest TG/HDL-C quartiles was 1.91 (95% CI: 1.11-3.30, P < 0.05) and 2.91 (95% CI: 1.02 8.30, P < 0.05) in male and female after adjusting for age, systolic BP, diastolic BP, BMI, fasting plasma glucose, LDL-C, uric acid and estimated glomerular filtration rate when compared with the lowest TG/HDL-C quartiles. CONCLUSION: Increased TG/HDL-C was independently associated with baPWV abnormality in apparently healthy individuals. PMID- 26064352 TI - Pharmacokinetics and pharmacodynamics of two antithymocyte globulins in treatment of pediatric aplastic anemia. AB - OBJECTIVE: To compare the pharmacokinetics and pharmacodynamics of antithymocyte globulins (ATGs) produced by two companies in the treatment of children with aplastic anemia (AA). METHODS: Six children with acquired AA were divided into two groups. The patients in each group were treated with either R-ATG or F-ATG for 5 consecutive days. Venous blood samples were collected at time points of 0 h, 4 h, 8 h after infusion of ATGs on day 1, at the end of the infusion on day 2 5, and on d7, d21, d35, d60, d90. The plasma concentrations of ATG were measured by ELISA. Pharmacokinetic parameters of ATG was calculated using pharmacokinetics calculation software 3P97. The kinetics of peripheral absolute lymphocyte count (ALC) was monitored. The long-term efficacy was evaluated according to international standards. RESULTS: The plasma concentration of both R-ATG and F ATG peaked on day 3~4 after treatment with about 30~32 MUg/ml, then fell gradually, reaching half of the peak level on day 21. The traces of ATG were still detectable on day 90. In addition, ALC in both groups declined significantly to a low level for a long time. No significant differences were observed between two groups in terms of the pharmacokinetic parameters and ALC. In an average follow-up period of 12 months, the total response rates (66.7%) in two groups were same. No treatment-related deaths or serious adverse reactions occurred during the treatment. CONCLUSION: Both R-ATG and F-ATG have similar characteristics in pharmacokinetics and pharmcodynamics in the treatment of children with AA. PMID- 26064353 TI - A retrospective clinical study of Xinjiang Uygur patients with corneal allograft rejection. AB - BACKGROUND: To explore the causes of corneal allograft rejection in Xinjiang Uygur patients and the factors that affect rejection through a retrospective clinical analysis. METHODS: A retrospective analysis of 126 Uygur cases from January 2010 to November 2014 in which corneal transplantation had been performed at the Xinjiang Urumqi ENT hospital. Of the treated patients, 85 eyes belonged to male patients and 41 eyes belonged to female patients. Patients were aged 10-77 years (mean age 46.14 +/- 8.20 years). Surgical methods included penetrating keratoplasty (75 eyes) and lamellar keratoplasty (38 eyes). Follow-up time ranged from 0.5 to 3 years and a total of seven pre-operative keratopathies were observed: walleye, corneal ulcer, bullous keratopathy, corneal degeneration. Eye changes included 72 cases of limbal vascularization and 15 cases of high intraocular pressure. Allograft rejection was observed in 25 eyes. RESULTS: The pre-operative keratopathies associated with the highest incidences of allograft rejection were: viral corneal ulcer, bullous keratopathy, adhesive walleye, and fungal corneal ulcers. The rate of allograft rejection using avascular corneal tissue was 10%, while the rate was 36% with severly-vascularized cornea. The earliest time of rejection was 20 days after surgery, while the latest was 16.4 months after surgery. Heavy corneal vascularization is associated with more rapid post-operative rejection. The rate of allograft rejection was higher after combined surgery when compared to penetrating keratoplasty or lamellar keratoplasty alone, while the rate was higher with penetrating keratoplasty than with lamellar keratoplasty. With increasing graft diameter, there was an increase in post-operative allograft rejection. Allograft rejection was significantly increased when graft diameter was above 7.75 mm. CONCLUSION: The major cause of corneal allograft rejection is viral corneal ulcers. High corneal vascularization, combined surgical methods, large diameter graft transplantation are all risk factors for allograft rejection. PMID- 26064354 TI - Relationship between thioredoxin-interacting protein (TXNIP) and islet beta-cell dysfunction in patients with impaired glucose tolerance and hypertriglyceridemia. AB - AIMS: To study the relationship between thioredoxin-interacting protein (TXNIP) and pancreatic beta-cell function in patients with impaired glucose regulation and patients with both impaired glucose regulation and hypertriglyceridemia. METHODS: We analyzed a population of 90 patients with impaired glucose regulation (IGR), 87 patients with IGR and hypertriglyceridemia, and 90 subjects with normal glucose tolerance (NGT). The levels of plasma TXNIP, a regulator of cellular oxidative stress, were measured. The homeostasis model assessment for insulin resistance (HOMA-IR) was used to evaluate insulin resistance in all subjects. In addition, two factors (HOMA for beta-cell function [HOMA-beta]) and first-phase insulin response [FPIR]) were used to evaluate pancreatic beta-cell function. The correlations between the plasma levels of TXNIP, insulin resistance, and islet beta-cell dysfunction were analyzed using Pearson's correlation analysis. RESULTS: Compared with NGT, patients with IGR had significantly lower HOMA-beta and FPIR, and higher plasma levels of TXNIP. Compared with the IGR group, patients with both IGR and hypertriglyceridemia had significantly lower HOMA-beta and FPIR, and higher plasma levels of TXNIP. There was also a negative correlation between TXNIP and HOMA-beta or FPIR, and a positive correlation between TXNIP and HOMA-IR. CONCLUSIONS: These data showed that the level of TXNIP is increased in patients with IGR and patients with both IGR and hypertriglyceridemia, islet beta-cell dysfunction was related to the increased TXNIP in IGR patients. PMID- 26064356 TI - Efficacy of volar and dorsal plate fixation for unstable dorsal distal radius fractures. AB - OBJECTIVE: To compare the efficacy of volar and dorsal plate fixation for unstable dorsal distal radius fractures. METHODS: Forty-seven cases were selected from patients undergoing surgical reduction and internal fixation treatment in our hospital from August 2006 to October 2010, with 21 males and 26 females, aged 39-73 years old. Patients were divided into two groups: volar plate fixation group (Group A) which has 32 cases, including 27 cases with locking plate, 5 cases with ordinary T plate, and 4 cases combined with dorsal Kirschner wire fixation; dorsal plate fixation group (Group B) which has 15 cases, including 7 cases with locking plate. The efficacy of the two fixation methods were compared in terms of postoperative wrist function, X-ray score, and postoperative complications. RESULTS: Compared with those of preoperative groups, the volar tilt, ulnar deviation and radial styloid height in both group A and B were significantly improved one week after surgery as shown by X-ray imaging. Comparison of X-ray images one week after surgery with those of six months after surgery showed no significant changes in volar tilt, ulnar deviation or radial styloid height. 87.5% of patients in group A and 86.7% of patients in group B got "excellent" in their wrist function assessment, and there was no significant difference between the two groups (X(2)=0.825, P=1.000). But patients in group A hax significantly lower incidence rate of postoperative complications than group B (X(2)=4.150, P=0.042). CONCLUSION: For unstable distal radius fractures with dorsal displacement, volar plate fixation can achieve satisfactory reduction results, and cause less tendon damage or other complications than dorsal plate fixation. PMID- 26064355 TI - Significance of CK19, TPO, and HBME-1 expression for diagnosis of papillary thyroid carcinoma. AB - OBJECTIVES: To evaluate the expression and significance of CK19, TPO, and HBME-1 in the differential diagnosis of papillary thyroid carcinoma (PTC) and nonmalignant nodules. METHODS: Tissue samples were obtained from 257 patients with PTC and 149 patients with nonmalignant thyroid specimens, and immunohistochemical staining for CK-19, TPO, and HBME-1 was performed. RESULTS: The expression of CK-19, TPO, and HBME-1 was 96.3%, 12.0%, and 85.3%, respectively, for the PTC group. For nonmalignant thyroid lesions group, the expression of these markers was 40.4%, 86.2%, and 37.2%, respectively. Further, the expression of CK-19 and HBME-1 in PTCs was much higher than that in the benign thyroid lesions (P < 0.05). However, the positive expression of TPO in PTC specimens was much lower than that in the nonmalignant specimens (P < 0.05). CK-1 had the highest sensitivity (96.30%) for PTCs. The combination of the positive expression of CK-19 and negative expression of TPO had the highest sensitivity (98.50%), while that of the positive expression of HBME-1 and negative expression of TPO had the highest specificity (92.90%). CONCLUSIONS: The combination of positive expression of CK-19 or HBME-1 or negative expression of TPO can improve the specificity of the diagnosis of PTC. PMID- 26064357 TI - Dance combined with magnetic pulse stimulates the ability of walk and balance in elder people. AB - OBJECTIVE: Observe the treatment effect on elderly people's waling and balance ability under the stimulation and intervention of waving dance combined with magnetic pulse. METHOD: 96 elderly people are Involved in the research and the random number table method is divided into observation group and control group; there are 48 people in each group. The control group on the basis of routine daily activities increase waving dance for training treatment; the observation group take training treatment together with the control group, plus magnetic pulse for stimulation treatment. Inspection and control shall be made to relevant indicators of subject's walk and balance ability at the time when they are selected and after they go through 6-month treatment. RESULT: after 6-month treatment, we found that indicators of walk and balance ability of these two groups of patients have been improved to different extent compared to those indicators when selected (all P<0.05). While the observation group have more significant improvement effect when compared to the improvement effect made by the contract group. Most of indicators are obviously superior to that of the control group (P<0.05). The differences have statistics significance. CONCLUSION: waving dance could obviously improve elderly people's walk and balance ability, and the improvement effect could be ever more significant when combined treatment with magnetic pulse stimulation. Such effect is obviously better than the effect improved only by waving dance. PMID- 26064358 TI - Association of rs5368 and rs3917406 polymorphisms in E-selectin gene with premature coronary artery disease in Chinese Han population. AB - OBJECTIVES: Genetics polymorphism of the E-selectin affects the pathogenesis of atherosclerosis and associated with coronary artery disease (CAD). We aimed to investigate the association between the rs5368 and rs3917406 polymorphisms in E selectin genes and premature CAD (PCAD) in Chinese Han population. METHODS: PCAD 628 patients and 732 controls were included in the study. E-selectin of rs5368 and rs3917406 polymorphisms were analyzed by polymerase chain reaction (PCR). RESULTS: The frequencies of T allele of the rs5368 and rs3917406 polymorphisms were 27.2% and 47.8%, respectively, in the PCAD group, and 30.5% and 42.8% in the control group. The frequency of the T allele of the rs3917406 polymorphism was significantly higher in the PCAD group than in the control group (x(2) = 6.857, P = 0.009). In contrast, no statistically significant difference was found between controls and patients in the frequency of T allele of the rs5368 polymorphism. The univariate analysis showed that the E-selectin rs3917406 polymorphisms was associated with the PCAD in additive model (OR = 1.226, 95% CI = 1.05-1.43, P = 0.010) and dominant model (OR = 1.406, 95% CI = 1.11-1.78, P = 0.005). After adjusting for potential confounding variables the rs3917406 polymorphisms was independently associated with PCAD in additive model (OR = 1.347, 95% CI = 1.12 1.62, P = 0.002) and dominant model (OR = 1.669, 95% CI = 1.26-2.21, P < 0.001). The E-selectin rs5368 polymorphisms were not associated with PCAD in univariate and multivariate analyses of three models. CONCLUSION: Among the Chinese Han population, the rs3917406 polymorphism of the E-selectin gene was associated with PCAD in univariate and multivariate analysis, however, no significant correlation between the E-selectin rs5368 polymorphism and PCAD. PMID- 26064359 TI - Gastric bypass surgery in non-obese patients with type 2 diabetes mellitus: a 1 year follow-up of 58 cases in Chinese. AB - OBJECTIVE: To investigate the clinical efficacy of gastric bypass surgery in non obese patients with type 2 diabetes. METHODS: Clinical data of 58 non-obese patients with type 2 diabetes (body mass index range from 22.1-25.8 kg/m(2)) were collected one year after gastric bypass surgery. Collected parameters included fasting plasma glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin, fasting plasma glucagon-like peptide-1 and 2-hour postprandial plasma glucagon-like peptide-1. The insulin resistance index (HOMA-IR = fasting plasma glucose * fasting serum insulin/22.5) and the body mass index were calculated. RESULTS: Of the 58 patients, 48 had stopped taking all hypoglycemic drug treatments and had achieved complete remission (82.8%). Seven patients were unable to completely withdraw from hypoglycemic agents, although their intake of drugs was reduced at least 50% compared to pre-surgical values (12.0%). Three of the cases showed no significant change in blood glucose after surgery (5.2%). In addition, values for fasting plasma glucose, 2-hour postprandial blood glucose, glycosylated hemoglobin and HOMA-IR significantly decreased after surgery. Values for fasting plasma glucagon-like peptide-1 and 2-hour postprandial plasma glucagon-like peptide-1 significantly increased after surgery, and the body mass index at the sixth post-operative month were significantly lower than pre operative. CONCLUSION: For non-obese patients with type 2 diabetes, gastric bypass surgery has a significant clinical effect. Potential mechanisms include improvements in insulin resistance and/or increased endogenous intestinal glucagon-like peptide-1 secretion leading to improved insulin secretion. PMID- 26064360 TI - Correlation of serum alanine aminotransferase and aspartate aminotransferase with coronary heart disease. AB - OBJECTIVE: This study aimed to explore the relationship between different risk factors (especially serum alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) and coronary heart disease (CHD). METHODS: A total of 610 inpatients were recruited. Initial coronary angiography (CAG) was performed to evaluate the severity of coronary lesions. On the basis of findings from CAG, patients were divided into control group (n=260) and CHD group (n=350). Logistic regression analysis was employed for the evaluation of clinical characteristics and biochemical parameters, aiming to explore the relationship between risk factors (including AST and ALT) and CHD. RESULTS: Results showed type 2 diabetes, hypertension, dyslipidemia, smoking and family history of CHD were clinical risk factors of CHD. Laboratory examinations showed the serum levels of triglycerides, low-density lipoprotein, AST and ALT in CHD group were significantly higher than those in control group (P<0.05). Of these parameters, the AST was 50.98+/-8.12 U/L in CHD group and 20.14+/-3.94 U/L in control group (P<0.01); the ALT was 42.31+/-8.34 U/L in CHD group and 18.25+/-6.38 U/L in control group (P<0.01). CONCLUSION: The serum levels of AST and ALT in CHD patients are higher than those in controls. High serum AST and ALT are biochemical markers which can be used to predict the severity of CHD and are also independent risk factors of CHD. PMID- 26064361 TI - Can the ductus venosus doppler predict the hemoglobinopathies? AB - OBJECTIVE: The aim of our study was to investigate the ductus venosus doppler between 11-13+6 (week-day) in pregnant women with hemoglobinopaties and its relation with fetal outcomes. MATERIAL AND METHODS: A total of 100 pregnant women with hemoglobinopathies and 100 healthy pregnant women were included in our study. Ultrasonography (USG) was performed to all pregnant women and the ductus venosus doppler (DVD) flows were evaluated. The results were statistically analyzed. RESULTS: The mean hemoglobin level was significantly lower in hemoglobinopathy group (9.7 +/- 0.7) than control group (10.67 +/- 0.82) (P<0.001). There was a significant relationship between Vmax, Vmin, S/D and reverse 'a' wave in fetuses with hemoglobinopathies. Vmax, Vmin and S/D parameters were higher in the group of hemoglobinopathies (respectively mean value, 31.3 +/- 1.66, 8.90 +/- 0.81, 2.97 +/- 0.49). Reverse 'a' wave was detected especially in all fetuses with sickle cell anemia. There was no significantly relationship between the groups in terms of PI, RI and HR. In a logistic regression analyses, fetal hemoglobinopathy was independently associated with Vmin (beta = 1.07, P = 0.001), S/D (beta = 2.61, P = 0.001) and reverse 'a' wave (beta = 2.46, P = 0.004). CONCLUSION: Pregnant women with hemoglobinopathies had changed ductus venosus doppler values in compared to normal pregnant women. Maternal anemia may cause this doppler changes. Furthermore all fetuses with sickle cell anemia (n = 5) had abnormal ductus venosus doppler findings. Further studies are needed to investigate the relationship between abnormal ductus venosus doppler findings and fetuses diagnosed with sickle cell anemia. PMID- 26064362 TI - Detection of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis patients undergoing total knee arthroplasty. AB - Rheumatoid arthritis (RA) is the most common chronic inflammatory joint disorder and anti-cyclic citrullinated peptide antibody (anti-CCP Ab) is regarded as a serological marker for diagnosing early and late RA. In the present study, we aimed to determine the levels of anti-CCP Ab in serum, synovial tissue (ST) and synovial fluid (SF) in RA patients undergoing total knee arthroplasty (TKA). 23 patients were included. Rheumatoid factor (RF) and anti-CCP Ab in serum were detected prior to surgery and then at 1, 3, 6 and 12 months after TKA. Synovial samples were obtained by knee arthroscopy and used for anti-CCP detection. One month after TKA, anti-CCP levels were significantly reduced (P < 0.01) in RA patients. However, their levels were not significantly different between pre surgery and 1 year post-surgery (P > 0.05). Furthermore, anti-CCP levels in ST were much higher than in serum. These findings suggest that RA patients should continue antirheumatic therapy after TKA. ST is the preferred place for the synthesis of anti-CCP Ab. PMID- 26064363 TI - Children with congenital cystic adenomatoid malformation of the lung CT diagnosis. AB - In this study, we aim to investigate the imaging appearances of congenital cystic adenomatoid malformation (CCAM) of the lung, and to enhance the understanding of this disease. A total of 11 cases with CCAM of the lung were confirmed by surgery and pathology. Preoperative chest computed tomography (CT) scan was performed in all patients, and high resolution CT scan was performed in lesion areas of 7 cases. Our results showed that there were 3 cases involving left and right lung, 5 cases involving right lung and 3 cases involving left lung. CT scan showed 6 cases with single or multiple air-filled cavities (> 2 cm in diameter) and 5 cases with multiple honeycomb-like cysts (< 1 cm in diameter). The cysts of CCAM contained air in 9 cases and a small amount of liquid in 2 cases. The complications of CCAM included different degree of emphysema in 7 patients, mediastinal hernia in 5 cases and congenital pulmonary sequestration in 1 case. All lesions have certain space-occupying effect. In conclusion, CT manifestation of CCAM of lung has certain characteristics and can provide reliable information for diagnosis of the disease. PMID- 26064364 TI - H2 relaxin expression and its effect on clinical outcomes in patients with chronic heart failure. AB - To investigate the expression of H2 Relaxin (H2RLX) in chronic heart failure (CHF) patients and determine whether H2RLX level can predict cardiovascular events in CHF patients within 180 days after discharge. One hundred forty-six patients were selected for examination from July 2012 to January 2014. The CHF group included a total of 115 patients, while the control group comprised a total of 31 patients without CHF. In the early morning on the first day after admission, patients' blood samples were obtained for measuring levels of brain natriuretic peptide (BNP), LDL-cholesterol, haemoglobin, fasting blood glucose, thyroid stimulating hormone, and creatinine clearance rate (Ccr). Enzyme-linked immunosorbent assay was performed to analyse the plasma concentration of H2RLX, collagen I, and collagen III. Echocardiography was used to estimate left ventricular ejection fraction. We followed patients for 6 months to record cardiovascular events (asymptomatic, symptomatic, re-hospitalisation for heart failure, and cardiac death). Plasma H2RLX in CHF patients was significantly higher than that in the control group (0.593 [0.542-0.644] vs. 0.390 [0.355 0.425] pg/mL; P < 0.01). With elevated cardiac dysfunction, plasma concentrations of both collagen I and H2RLX increased in all patients. Moreover, there was a significant correlation between H2RLX and collagen I (r = 0.890, P < 0.001). The area under the receiver operating characteristic (ROC) curve for prognosis was 0.816 (P < 0.01), suggesting that plasma H2RLX level predicts severe cardiovascular events (re-hospitalisation and cardiac death) within 180 days after discharge. Elevated H2RLX levels in CHF patients may be associated with disease severity, and H2RLX level may predict cardiovascular events in CHF patients within 180 days after discharge. PMID- 26064365 TI - Lipid-rich carcinoma of male breast in Chinese: a case report and literature review. AB - Lipid-rich carcinoma of the breast is a rare variant of breast cancer, especially in males. Herein we report a case occurring in a 54-year-old male patient, who presented with a noticed painless, pea-sized lump in his left breast. Clinical examination and mammography suggested malignancy. Subsequent modified radical mastectomy revealed the diagnosis of lipid-rich carcinoma. To our knowledge, this subtype of mammary carcinoma is unprecedented in Chinese males in literature. PMID- 26064366 TI - Investigation on the genomic diversity of OXA from isolated Acinetobacter baumannii. AB - We distinguished the four alleles of OXA subgroups from 138 strains of Acinetobacter baumannii using Polymerase Chain Reaction, and investigated distributions of OXA subgroups in clinical isolated strains. A total of 170 Acinetobacter baumannii were isolated from Shenzhen Longgang Central Hospital between 2010 and 2013. Amplification of OXA genes, blaOXA-23, blaOXA-24, blaOXA 51 and blaOXA-58, were performed by multiplex PCR. Multiplex PCR results showed, out of the 96 strains of Acinetobacter baumannii, 50 (52.08%) strains were positive for only blaOXA51 gene, and 46 (47.92%) showed positive for both blaOXA51 and blaOXA58 genes. Among 96 strains of Acinetobacter baumannii, 48 strains were resistant to carbapenems, and 48 strains were sensitivity to carbapenems. blaOXA51 and blaOXA58 showed resistant or sensitivity to carbapenems. In conclusion, we found that blaOXA-51 and blaOXA-5 were the main mechanisms of resistant or sensitivity to carbapenems. PMID- 26064367 TI - An implementation on the social cost of hospital acquired infections. AB - Hospital Acquired Infections (HAIs) are defined as infections developing in relation to health services at inpatient treatment facilities in general. Although health services improve, HAIs continue to be seen both in underdeveloped and developed countries. HAIs result in a range of negative externalities. Negative externalities include factors such as an increase in morbidity and mortality, extension of the hospitalization duration, impaired quality of life, loss of working power and performance. HAIs pose a big burden regarding population and community health care. This study aims to calculate the financial burden of HAIs by evaluating it within the scope of negative externality. The communal costs of HAIs patients were calculated by using a genuine approach with reference to samples obtained from the Duzce University Research and Application Hospital. This approach includes 4 stages and the results of each stage is sorted according to the data of 2013 as follows: (i) HAIs expenditure undertaken by the Social Security Institution is 5,832,167 TL, (ii) the monetary value of the work power loss of the HAIs patients who are at a working age is 126,154 TL, (iii) the relative cost of HAIs patients compared to a group of normal patients is 21,507 TL and (iv) HAIs patients' communal cost is 6,013,101 TL. Based on the received results, the annual communal cost of the estimated HAIs patients in Turkey is predicted to be 3,640,442,057 TL. In addition to these findings, HAIs patients experience 14 times longer in-patient stay at the hospitals as compared to normal patients, and their treatment expenditures are 23 times higher than the normal patients. In the conclusion part of the study, regarding the preventability (internalization) of HAIs, which was evaluated as part of negative externality, alternative applicable political suggestions are presented for the use of policymakers. PMID- 26064368 TI - Relationship between increase of serum homocysteine caused by smoking and oxidative damage in elderly patients with cardiovascular disease. AB - BACKGROUND: To investigate the mechanism of smoking on cardiovascular diseases. MATERIAL AND METHODS: 576 elderly patients with cardiovascular diseases in stable condition were consecutive recruited, asked about the living habits and smoking history in a way of face to face. RESULTS: Of all the enrolled patients, current smoking rate was 34.8% for males and 3.4% for females. Average smoking quantity was 17 cigarettes per day and incidence of hyperhomocysteinemia was 38.0%. The homocysteine level in current smokers was significantly higher than that in never smokers (P = 0.004); while the serum folic acid and serum superoxide dismutase (SOD) level were significantly lower those in never smokers (P = 0.012; P = 0.004). The daily smoking consumption and the pack-years of smoking were significantly positively correlated with total homocysteine (tHcy) level (P = 0.020; P = 0.003). The reduced serum SOD level might be associated with increased risk of hypertension (P = 0.023), coronary heart disease (P = 0.018), and stroke (P = 0.035). However, the elevated serum tHcy level was not correlated with increased risk of hypertension and coronary heart disease, while may increase the risk of ischemic stroke (P = 0.075). CONCLUSIONS: Smoking status is still prevalent among Chinese elderly patients with cardiovascular diseases, which causes the increase of serum tHcy and the decrease of serum folate as well as SOD; smoking consumption per day and pack-years of smoking have indirect effects on tHcy. And decrease of serum SOD is a risk factor for cardiovascular diseases, increase of serum tHcy may be associated with changes of metabolism caused by oxidative damage. PMID- 26064369 TI - Clinical features of systemic cancer patients with acute cerebral infarction and its underlying pathogenesis. AB - BACKGROUND: The increased incidence of cerebral infarction in patients with systemic cancer has been reported; however, the underline mechanisms remain unclear. Investigation regarding the clinical features of cerebral infarction in cancer patients could be helpful to understand its underlying pathogenesis. METHODS: A total of 537 patients were recruited and divided into three groups: 1) stroke and cancer group (SCG), defined as active cancer patients with acute cerebral infarction; 2) stroke group (SG), defined as acute cerebral infarction patients without cancer; and 3) Cancer group (CG), defined as active cancer patients without cerebral infarction. These patients were age and gender-matched among groups. RESULTS: 179 patients, including 128 male subjects (73.68%) were enrolled in each group. Compared to SG patients, more SCG patients lacked conventional vascular risk factors (CRFs), and had elevated plasma D-dimer, cancer antigen (CA) 125 and 199 levels with multiple lesions in multiple cerebral arterial territories. In addition, SCG patients were found to have poorer prognosis. Compared to CG patients, more SCG patients' cancer had metastasized. Multiple logistic regression analysis showed that the elevated plasma D-dimer, CA125 and CA199 levels may independently increase, but chemoradiotherapy decreased the risk of cerebral infarction in cancer patients. CONCLUSIONS: Our study demonstrated that the clinical features of acute cerebral infarction in most active cancer patients can be identified as multiple lesions in multiple cerebral arterial territories with elevated plasma D-dimer and the elevated levels of cancer antigens. PMID- 26064370 TI - Association of Type 2 Diabetes Mellitus related SNP genotypes with altered serum adipokine levels and metabolic syndrome phenotypes. AB - The pathogenesis of T2DM involves secretion of several pro-inflammatory molecules by the dramatically increased adipocytes, both by number and size, and associated macrophages of adipose tissue. Since T2DM is usually preceded by obesity and chronic systemic inflammation, the objective of this study was to explore for any association between genetic variants of previously established 36 T2DM-associated SNPs and altered serum adipocytokine levels and metabolic syndrome phenotypes. Study consisted of 566 subjects (284 males and 282 females) of whom 147 were T2DM patients and 419 healthy controls. Study subjects were genotyped for 36 T2DM linked single nucleotide polymorphisms (SNPs) using the KASPar SNP Genotyping System and grouped into different genotypes for each SNP. Various anthropometric and biochemical parameters were measured following standard procedures. The mean values of serum levels of individual adipocytokines and the presence/absence of metabolic syndrome phenotypes corresponding to various genotypes were compared by determining the odds ratios. Genotypic variants of five and seven of the 36 T2DM related SNPs were significantly associated with altered serum levels of adiponectin and aPAI, respectively. Six variants of the 36 SNPs were associated with metabolic syndrome manifestations. This study identified positive associations between genotypic variants of five and seven of the 36 T2DM related SNPs and altered serum levels of adiponectin and aPAI, respectively. Six of 36 SNPs were also associated with metabolic syndrome in the studied population. The relation between specific SNPs and individual phenotypic traits may be useful in explaining the causal mechanisms of hereditary component of T2DM. PMID- 26064371 TI - Influence of pain severity on health-related quality of life in Chinese knee osteoarthritis patients. AB - OBJECTIVE: The aim of this cross-sectional study was to examine the relationship among pain and other symptoms intensity, and health-related quality of life (HRQoL) in Chinese patients with knee osteoarthritis (OA). METHODS: The study was cross-sectional, descriptive, and correlational. A convenience sample of 466 patients with knee OA was recruited in the study. Age, gender, body mass index (BMI), duration of disease, and Kellgren- Lawrence (KL) scores were recorded. HRQoL and symptoms were assessed using the 36-item Short Form Health Survey (SF 36) and the Western Ontario and McMaster (WOMAC) index in participants. RESULTS: The sample was predominantly female (82%) with mean age 56.56 years and mean BMI 24.53 kg/m(2). We found that WOMAC subscale scores significantly negative correlated with the majority of SF-36 subscale scores in knee OA patients (P < 0.05). There were no correlations between BMI, duration of disease, KL score and the vast majority of SF-36 subscale scores in patients (P > 0.05). In addition, there was a significant correlation between age and PCS, gender and MCS in patients (P < 0.05). Regression analysis showed, WOMAC subscale scores significantly negative correlated with the vast majority of SF-36 subscale scores. WOMAC-pain score had the strongest relationship with SF-36 PCS and MCS scores. CONCLUSIONS: In summary, pain severity has a greater impact on HRQoL than patient characteristics, other joint symptoms and radiographic severity in Chinese knee OA patients. Relieving of knee symptoms may help to improve patients' HRQOL. The study provided the evidence that relieving pain should be the first choice of therapy for knee osteoarthritis. PMID- 26064372 TI - Awareness and intervention status of prediabetes among Chinese adults: implications from a community-based investigation. AB - With the rapid changes in lifestyle of China, the prevalence of diabetes and prediabetes is increasing. This study aims to evaluate the prevalence of prediabetes and study the disease awareness of prediabetes in a Southern China community. Furthermore, it also aimed to investigate the intervention status of lifestyle changes for pre-diabetes prevention. 881 adults without diabetes mellitus were recruited from the Suzhou community of China in 2012-2013. Self report questionnaires including demographics, Disease Awareness Scale, Willingness on Lifestyle Changes for Prediabetes Cure Scale were collected. The results showed that 16.8% were in prediabetes, and 38.5% of them knew they had it. Young age, non-smoking, high education level, low BMI, and receiving provider advice were found with less possibility to have prediabetes in Chinese adults. Less than a third of those reported with the knowledge of that pre-diabetes is a risk factor of developing Type 2 diabetes mellitus (T2DM) and cardiovascular disease. Less a half of the population with prediabetes may take steps in lifestyle changes for pre-diabetes prevention. It is necessary to call for action on the improvement of disease awareness and promotion of healthy behaviors to prevent the prevalence of prediabetes and diabetes in Chinese adults. PMID- 26064373 TI - Prognostic factors of tuberculous meningitis: a single-center study. AB - OBJECTIVE: To investigate the prognostic factors of tuberculous meningitis (TBM) and develop strategies for the improvement of clinical efficacy. METHODS: A total of 156 TBM patients were retrospectively reviewed. The demographic characteristics, underlying diseases, clinical features, laboratory findings, bacteriologic test, images, use of steroids, mannitol and anti-TB drugs, surgery or drainage, and clinical outcomes were collected and analyzed. RESULTS: Patients with tubercle bacillus in the cerebrospinal fluid had significantly higher rate of consciousness disturbance (78.8%) and greater proportion of Glasgow coma scale (GCS) score of 3 (37.9%) when compared with the possible TBM patients (51.1% and 13.3%, respectively). Patients with definite TBM had a poor outcome and their mortality was significantly higher than in possible TBM patients (42.4% vs. 17.8%, P < 0.05). Univariate regression analysis showed that the advanced age, concomitant hematogenous disseminated pulmonary tuberculosis, change in consciousness, low GCS score on admission and hydrocephalus were associated with a poor prognosis; timely anti-TB treatment and reasonable hormone applications predicted a favorable outcome. Multivariate regression analysis showed that advanced age, change in consciousness, low GSC score and concomitant hydrocephalus were independent risk factors of TBM, and use of prednisone at >= 60 mg/d was protective factor for TBM (P=0.003, OR=0.013). CONCLUSIONS: The advanced age, changes in consciousness, low GCS score on admission and concomitant hydrocephalus are independent risk factors of TBM. For patients with risk factors, diagnostic anti-TB therapy and reasonable hormone therapy should be performed timely to reduce mortality and disability. PMID- 26064374 TI - Incidence and risk factors of chylous ascites after pancreatic resection. AB - Chylous ascites (CA) is a rare postoperative complication. It also occurs in pancreatic surgery and can influence the patient's prognosis after pancreatic resection. There are few studies focusing on CA following pancreatic resection. We aimed to evaluate the incidence and risk factors of CA following pancreatic resection. Patients who underwent pancreatic resection from the year 2007 to 2013 were retrospectively reviewed. The diagnosis of CA was based on the presence of a non-infectious milky or creamy peritoneal fluid greater than 100 ml/day with a triglyceride concentration >=110 mg/dl. The incidence and possible risk factors following pancreatic resection were evaluated. In this study, 1921 patients who underwent pancreatic resection were included. 49 patients developed CA. The overall incidence was 2.6 percent (49 out of 1921). The incidence following pancreaticoduodenectomy and distal pancreatectomy was much higher (35 out of 1241, 12 out of 332, respectively). A multivariable analysis demonstrated that manipulating para-aortic area and superior mesenteric artery root area; retroperitoneal invasion; focal chronic pancreatitis and early enteral feeding were the independent risk factors for CA after pancreatic surgery. In conclusion, CA is a rare complication after pancreatic resection. Some clinicopathological factors were associated with the development of CA following pancreatic resection. PMID- 26064375 TI - A comparative study to analyze the efficacy and safety of flexible ureteroscopy combined with holmium laser lithotripsy for residual calculi after percutaneous nephrolithotripsy. AB - A certain proportion of patients with initial Percutaneous nephrolithotripsy (PCNL) management require ancillary procedures to increase the stone-free rate. In this study, we aim to analyze the efficacy and safety of flexible ureteroscopy combined with holmium laser lithotripsy (F-UL) for treatment of residual calculi after PCNL by comparison with extracorporeal shockwave lithotripsy (SWL). Total of 96 patients with residual renal calculi (4 mm to 20 mm) after PCNL was enrolled from May 2010 to March 2013. They were randomly divided into two groups: US Group: patients were treated with F-UL; SWL Group: patients were treated with SWL. Follow-up was made one month and three months after treatment. The mean residual stone size after PCNL was 12.4 +/- 4.3 mm in US group compared with 11.9 +/- 4.5 in SWL group. The stone-free rate was 84.7% one month after surgical procedure in US group, this rate increased to 91.3% in the third months, while the stone-free rate in SWL group is 64.6% one month after treatment and 72.9% in the third month. For residual stone in lower calyx, the stone-free rate three month after treatment was 90.4% in US group compared to 65.2% in SWL group (P < 0.05). The overall complication rate was low in both groups, no severe complication was found. Both F-UL and SWL are safe and effective methods for residual calculi after PCNL, without severe complications. F-UL provided significantly higher stone-free rate compared with SWL, especially for low-pole calculi. PMID- 26064376 TI - The response of New-season Nile tilapia to Aeromonas hydrophila vaccine. AB - The present study was conducted to recognize the response of new-season Nile tilapia to Aeromonas hydrophila vaccine. Four hundred new-season Nile tilapia were used in this study and divided into two equal groups, the first group served as control and the 2(nd) group was vaccinated with Aeromonas hydrophila vaccine via intraperitoneal injection. The antibody titer, Hematocrit level (HCV), Nitroblue tetrazolium activity (NBT) and lysozyme activity of new-season Nile tilapia was measured at the end of the 1(st), 2(nd), 3(rd), 4(th), 6(th), 8(th) and 10(th) week post vaccination (PV). Challenge with A. hydrophila was carried out at the end of the 6(th), 8(th) and 10(th) week PV. The antibody titer of vaccinated new-season tilapia showed significant higher values than unvaccinated group at all periods. The hematocrit and lysozymes activity values showed, a non significant increased in comparison with unvaccinated group at all periods PV. The NBT was significantly increased in vaccinated tilapia in comparison with unvaccinated group at all periods except one week PV. The relative level of protection of vaccinated tilapia after challenge infection was highest at 6(th) week PV in the new-season tilapia. We conclude that, vaccination against A. hydrophila increase the resistance of tilapia to such infection and consequently improve the survival and economic outcome. Other more applicable routes of vaccination should be investigated to be used on a large scale. PMID- 26064377 TI - The effect of pre-operative autologous blood donation self-transfusion on hormone and postpartum convalescence in Lying-in women. AB - The aim of the study is to investigate the feasibility of pre-operative autologous blood donation (PABD) self-transfusion on the postpartum recovery and the endocrine in lying-in women. The PABD is carried out on 70 pregnant women who have high risk of postpartum hemorrhage. Those 70 subjects were divided into three groups: 33 cases of PABD self-transfusion during the Cesarean section; 16 cases of PABD self-transfusion as a physiological means and 21 cases without transfusion. Serum levels of Estradiol (E2), Progesterone (P), Prolactin (PRL) hormone are evaluated 48 hours before and after labor; Postpartum colostrum timing, milk yield, short term and long term uterine contraction are observed among the cases. No significance were observed among the three groups on E2, P, PRL hormone 48 hours before and after labor. The PRL concentration in PABD self transfusion group is higher than that in the group without self-transfusion 48 hours after labor. Using different PABD self-transfusion strategies, significant difference of the initial milk yield time were observed in the three groups (F=6.035 P=0.004), but the milk yield is no significant different on second day and third day. The self-transfusion of PABD has little influence on uterine contraction. For the women who underwent Cesarean Section, the PABD self transfusion is conducive to the increase of PRL level. The PABD self-transfusion advances the commencement time of milk yield, while with little effect on neither milk yield volume nor uterine contraction. PMID- 26064378 TI - Angiotensinogen gene M235T and angiotensin II-type 1 receptor gene A/C1166 polymorphisms in chronic obtructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) occurs irreversibly and is characterized by progressive airflow obstruction. Renin angiotensin system (RAS) has many different key enzymes and receptors that have a role for different systemic processes. We aimed to determine genotype and allele frequencies of angiotensinogen (AGT) M235T and angiotensin II-type 1 receptor (AT1-R) A/C1166 polymorphisms in patients with COPD. This study was performed on 56 unrelated COPD patients and 29 healthy subjects. DNA samples for each individual were isolated from peripheral blood by phenol/chloroform method, analyzed by polymerase chain reaction and enzymatic digestion methodologies. The distribution for each of AGT genotypes were 23.2% for MM (13), 75.0% for MT (42) and 1.8% for TT (1) in the COPD group; 37.9% for MM (11), 34.5% for MT (10) and 27.6% for TT (8) in the control group. The distribution of AGT genotypes was found significantly different between groups (X(2) = 18.604; df = 2; P = 0.000). The frequencies for each of the AT1-R genotypes were found as 53.6% for AA (30), 42.9% for AC (24), 3.6% for CC (2) in the COPD group; 55.2% for AA (16), 41.4% for AC (12) and 3.4% for CC (1) in the control group. The distribution of AT1-R genotypes did not change significantly between groups. Allele frequencies of interested genes were not significantly different between groups. We suggest that AGT polymorphism may play a role for the development of COPD. We believe these data can be served for large scale population genetics research, considering the frequency of AGT and AT1-R genes and alleles in COPD patients in the Turkish population. PMID- 26064379 TI - Risk factors for preterm birth: a case-control study in rural area of western China. AB - Preterm birth is the leading cause of perinatal morbidity and mortality in China, the study is to learn risk factors for preterm birth in rural area of western China. A 1:1 case-control study in which cases included the pregnant women of preterm birth and controls included the matched pregnant women of normal deliver was conducted in 5 counties in western China. Data about the general situation, pregnancy history, reproductive health infection (RTI) symptoms, pregnancy complications, et al were obtained by using questionnaire. The results showed that the risk factors related to preterm birth were including: family income, mother's age >= 35 years old, antennal visiting <= 4 times, low education level, preterm birth history, abnormal vaginal discharge, pregnancy complications. The logistic regression analysis showed that only 3 factors of preterm birth were left at the last step, which of antenatal visiting <= 4 times, PROM and placenta previa had significant difference. We show that family income, age, antennal visiting, low education level, preterm birth history, abnormal vaginal discharge, pregnancy complications are the risk factors of preterm birth. PMID- 26064380 TI - Comparison of quality-of-life in tongue cancer patients undergoing tongue reconstruction with lateral upper arm free flap and radial forearm free flap. AB - Surgery entails radical resection, neck dissection and tongue reconstruction has been commonly used in treatment of T2 and T3 tongue squamous cell carcinoma. Although lateral upper arm free flap (LUFF) and radial forearm free flap (RFFF) are similar in texture and thickness, significant differences can be noticed in the donor-site function and surgical demands. In the treatment of T2 and T3 tongue cancer, the choice of either LUFF or RFFF is still not defined.We aim to investigatethe long-term QOL of patients with moderate tongue defect and reconstruction with LUFF or RFFF, based on which to provide clinical suggestion for tongue reconstructions.Sixty-five patients (T2 or T3 stage, 42 underwent tongue reconstruction with RFFF and 23 with LUFF) treated at the Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Sun Yat-Sen University from January 2005 to June 2009 were included. The QOL of each patient was determined using the questionnaire designed based on the University of Washington Quality-of-Life (UW-QOL, version 4). The questionnaire was accomplished by a qualified medical staff blinded to the study after telephone communication with each patient. Statistical analysis showed that no significant difference was noticed in the long-term QOL of patients with tongue cancer after tongue reconstruction using LUFF or RFFF, respectively, indicating that similar QOLs were obtained in the long-term follow-up of patients with tongue cancer (T2 or T3 stages) using LUFF and RFFF for reconstruction. PMID- 26064381 TI - Air-conditioner filters enriching dust mites allergen. AB - We detected the concentration of dust mites allergen (Der f1 & Der p1) in the air of different places before and after the starting of air-conditioners in Wuhu City, Anhui, China, and to discuss the relation between the dust mites allergen in air-conditioner filters and the asthma attack. The dust samples were collected from the air-conditioner filters in dining rooms, shopping malls, hotels and households respectively. Concentrations of dust mites major group allergen 1 (Der f 1, Der p1) were detected with enzyme linked immunosorbent assay (ELISA), and the dust mite immune activities were determined by dot-ELISA. The concentration of Der f1 in dining rooms, shopping malls, hotels and households was 1.52 MUg/g, 1.24 MUg/g, 1.31 MUg/g and 1.46 MUg/g respectively, and the concentration of Der p1 in above-mentioned places was 1.23 MUg/g, 1.12 MUg/g, 1.16 MUg/g and 1.18 MUg/g respectively. The concentration of Der f1 & Der p1 in air was higher after the air-conditioners starting one hours later, and the difference was significant (P<0.05, respectively). Additionally, dot-ELISA findings revealed that the allergen extracted from the dust was capable of reacting with IgE from the sera of asthma mice allergic to dust mites. The study concludes that air-conditioner filters can enrich dust mites major group allergen, and the allergens can induce asthma. The air-conditioner filters shall be cleaned or replaced regularly to prevent or reduce accumulation of the dust mites and its allergens. PMID- 26064382 TI - Serum transforming growth factor beta 3 predicts future development of nonalcoholic fatty liver disease. AB - Transforming growth factor beta 3 (TGFb3) was mainly expressed by liver satellite cells in the normal liver, but it may be expressed by various liver cells during liver diseases, e.g. hepatitis and cirrhosis. However, whether TGFb3 level may be used to predict development of nonalcoholic fatty liver disease (NAFLD) has not been investigated before. Here we evaluated the relationship between TGFb3 and the susceptibility for developing NAFLD by comparing the incidence rates of developing NAFLD and serum TGFb3 levels in 1322 healthy subjects without other risk factors during a 4-year period. These healthy subjects were grouped into tertiles based on their serum TGFb3 levels that were measured in 2009. After 4 years, the odds ratios (ORs) of NAFLD development were analyzed based on the tertiles of TGFb3 levels in 2013. The cumulative incidence of NAFLD was 25.3% (334/1322) after four years. The NAFLD-developing group had higher serum TGFb3 levels in 2009 than those in the group that did not develop NAFLD (554+/-287 pg/ml vs. 285+/-173 pg/ml; P=0.002). When the serum TGFb3 levels in 2009 were grouped into tertiles, we found that the incidence of NAFLD in 2013 was significantly higher with increasing tertiles (6.3%, 38.0%, and 55.7%, respectively; P<0.05). Thus, our study demonstrate that higher serum TGFb3 levels in subjects devoid of NAFLD may have a higher chance of its future development, and highlight serum TGFb3 level as a novel predictor for development of NAFLD. PMID- 26064383 TI - Biomechanics analysis for the treatment of ischemic necrosis of the femoral head by using an interior supporting system. AB - OBJECTIVE: This work aims to perform a biomechanical test to evaluate the effect of interior supporting system and tantalum rod in simulating the treatment of ischemic necrosis of the femoral head. METHOD: Three models were established: control group (group A), interior supporting system group (group B), and tantalum rod group (group C). Step-by-step loading was applied on the top of the femoral head until femoral head damage occurs by using the testing machine of the material test system. Strain and maximum load were applied until the femoral head collapses. The damage to the trochanteric fossa, femur calcar, and greater trochanter were compared. RESULTS: (1) The strain on the trochanteric fossa shows the following order: group C > group A and group B (P < 0.05). No significant difference was observed among groups for the other parts (P > 0.05). (2) The maximum load in group B is larger than that in groups A and C (P < 0.05). No significant difference in the maximum load was observed among the three groups when the femoral head was destroyed. CONCLUSIONS: The compression strain and bearing load of the femoral head are close to normal after placement of an interior supporting system and tantalum rod. The interior supporting system helps prevent femoral head collapse. PMID- 26064384 TI - An inverse association of body mass index and prostate-specific antigen in northwest men of China: a population-based analysis. AB - OBJECTIVES: To examine the relationship between body mass index (BMI) and prostate-specific antigen (PSA) in Chinese men and to investigate whether this relationship was independent of other factors. METHODS: Cross-sectional analysis was in men aged 19 to 82 years old (N=12,964) who without prostate cancer and had health examination between 2008 and 2013 in a clinical center in Xi'an, China. Obesity and overweight were classified according to the WHO criterion. Mean PSA level was calculated by categories (normal weight, overweight, and obesity) and age group (<= 40, 41-59, >= 60 years old). The association between BMI and PSA was examined using multivariate regression models and stratified by age. RESULTS: The crude prevalence was 38.42% for overweight and 3.47% for obesity in the study population. Mean PSA level increased with age at each BMI category. BMI was negatively associated with PSA level at each age group, independent of fasting plasma glucose (FPG) and prostate volume. Per unit increase in BMI was associated with a decrease of PSA by 0.03 (P=0.05), 0.11(P < 0.001), and 0.15 (P < 0.001) in men aged <= 40, between 41 to 59, and > 60 years old, respectively. CONCLUSIONS: Our results indicate that a higher BMI is associated with a lower level of PSA in healthy Chinese men across all age group, independent of prostate volume and FPG. With the current obesity epidemic, individual's BMI should be considered when PSA test is used to screen or diagnose prostate cancer. PMID- 26064385 TI - The outcome of early laparoscopic surgery to treat acute cholecystitis: a single center experience. AB - AIM: The aim of this study was to prospectively assess the outcome of early laparoscopic cholecystectomy (LC) in patients with acute cholecystitis. MATERIALS AND METHODS: Between July 2005 and December 2012, of 623 patients who had symptoms of acute cholecystitis during the first 72 h of hospital admission and who did not respond to non-operative treatment, 302 underwent surgical treatment. After initial treatment, all patients were followed up for 21 months on average (range: 5-27 months). The clinical, biochemical, radiological, and operative data of the 302 consecutive patients with acute cholecystitis were recorded and analyzed prospectively. RESULTS: Of the 302 patients who underwent LC for acute cholecystitis, 169 were females and 133 males. Their mean ages were 47.8 years (range: 17-79 years) and 53.3 years (range: 27-90 years) respectively. Conversion to open surgery was required in 32 patients (10.5%). The mean postoperative length of hospital stay was 2 days (range: 1-3 days) in the LC group and 3 days (range: 2-6 days) in the conversion group. Significant differences between the successful LC group and the conversion group were evident terms of the length of postoperative hospitalization and gallbladder wall thickness (P=0.023). Factors associated with conversion were male gender, pericholecystic collection observed via ultrasound, gangrenous cholecystitis, and gallbladder wall thickness >1 cm. We experienced two minor bile duct injury complications that were treated via T tube placement. No mortality occurred. Ten patients suffered infections at the incisional locations, and eight patients developed lung infections. CONCLUSION: Early LC is safe in patients with acute cholecystitis. Male gender, pericholecystic collection determined via ultrasound, gangrenous cholecystitis, and gallbladder wall thickness >1 cm are associated with a higher risk of conversion to open surgery. PMID- 26064386 TI - Preoperative risk factors of postoperative delirium after transurethral prostatectomy for benign prostatic hyperplasia. AB - The aim of this observational study was to investigate the occurrence of post operation delirium in the elderly patients undergoing the transurethral prostatectomy and to identify these factors associated with the delirium. 485 patients, undergoing the transurethral prostatectomy, were selected. Demographics, medical, cognitive and functional data, IPSS and NIH-CPSI score were collected as predictors for delirium. After surgery, the patients were divided on the basis of delirium onset within one week observation period, and the delirium was diagnosed by the Confusion Assessment Method. Totally, 21.23% (103) subjects were identified as the delirium and it lasted 2.9 +/- 0.8 days. Patients with post operation delirium were significantly older and single, widowed and divorced, had a previous history of prehospitalization, were with the poor International Prostate Symptom Score (IPSS) and National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score, were more impaired in the instrumental activities of daily living (IADL), and had poor clock drawing test (CDT) and geriatric depression scale (GDS) score. Age, marital status, IPSS and NIH-CPIS score, cognitive and functional status and previous history of hospitalization are the predictors of post operation delirium. Our study has implications in preventing delirium via an early and targeted evaluation. PMID- 26064387 TI - Clinical analysis of spontaneous pregnancy reduction in the patients with multiple pregnancies undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer. AB - OBJECTIVE: To investigate the spontaneous pregnancy reduction (SPR) rate, SPR related factors and the effects of SPR on pregnancy outcomes in the patients with multiple pregnancies undergoing in vitro fertilization/intracytoplasmic sperm injection-embryo transfer (IVF/ICSI-ET). METHODS: Between January 1998 and December 2010, 3957 patients undergoing fresh/frozen-thawed cycles (IVF/ICSI-ET) and their 5106 neonates were enrolled in this study. According to spontaneous pregnancy reduction (SPR), this study included singleton originating from twins [(2->1) group] or from triplets [(3->1) group], and twins originating from triplets [(3->2) group]. According to SPR time, this study included <=8 week, 8 18 week and >=18 week's groups. Outcome measures were SPR rate, preterm rate, mean birth weight and the rates of low birth weight and very low birth weight. RESULTS: SPR rate was higher in triplets group than in twins group, in frozen thawed cycles than in fresh cycles, in the patients >=35 years than in the patients <35 years (all P<0.05). Compared with <=8 week group, preterm rate was significantly increased in 8-18 week group (P<0.05). Pregnancy outcomes were better in (2->1) group than in twins group, in (3->1) group than in triplets group (all P<0.05). After multi-fetal pregnancy reduction (MFPR), the mean birth weight was higher and low birth weight was lower in SPR group than in only MFPR group (all P<0.05). CONCLUSION: SPR rate is related to age and the initial number of gestational sacs. Both SPR and MFPR can improve pregnancy outcomes. The later the SPR occurs, the worse the neonatal outcomes are. Due to the possibility of SPR, it is necessary to appropriately delay MFPR until 8 gestational weeks. PMID- 26064388 TI - Association of genetic polymorphisms in HTR3A and HTR3E with diarrhea predominant irritable bowel syndrome. AB - OBJECTIVE: The present study aims to investigate the relationship between genetic polymorphisms in HTR3A and HTR3E and diarrhea predominant irritable bowel syndrome (D-IBS) in a Chinese population. METHODS: We enrolled 500 D-IBS patients and 500 age- and sex-matched healthy control subjects to detect the genotypes in HTR3A and HTR3B gene by using of PCR-RFLP method. RESULTS: There were significant difference between the D-IBS patients and the health control subjects in the distribution of genotype and allele of rs1062613 in HTR3A gene. As regarding rs62625044 in HTR3E gene, we found there was a significant different between the case and the control group in the distribution of GA genotype and A allele in female but not in male. CONCLUSION: The present study suggested that there are associations of D-IBS risk with genetic polymorphisms in HTR3A and HTR3E. PMID- 26064389 TI - Tonsilectomy in sickle cell diseases. AB - BACKGROUND: We tried to understand whether or not there are lowered prevalences of terminal consequences of sickle cell diseases (SCDs) with tonsilectomy. METHODS: All cases with SCDs were taken into the study. RESULTS: The study included 334 patients (164 females). There were 27 cases with tonsilectomy and 307 cases without. The mean ages, female ratios, and prevalences of associated thalassemia minors and smoking were similar in both groups (P>0.05 for all). Although the white blood cell and platelet counts of peripheric blood were higher in patients without tonsilectomy, the mean hematocrit value was lower in them, but the differences were nonsignificant probably due to the small sample size of the tonsilectomy group (P>0.05 for all). Similarly, although the painful crises per year, digital clubbing, leg ulcers, pulmonary hypertension, chronic obstructive pulmonary disease, rheumatic heart disease, avascular necrosis of bone, cirrhosis, stroke, and mortality were higher in cases without tonsilectomy, the differences were nonsignificant probably due to the same reason again (P>0.05 for all). CONCLUSION: There may be an inverse relationship between prevalence of tonsilectomy and severity of SCDs, and the tonsils may act as chronic inflammatory foci accelerating the chronic endothelial damage all over the body in such patients. PMID- 26064390 TI - Retinal detachment after vitrectomy performed for dropped nucleus following cataract surgery: a retrospective case series. AB - The present retrospective study aimed to investigate the frequency, risk factors, and anatomical and visual outcomes of retinal detachment (RD) after vitrectomy performed for dropped nucleus. Medical records of the patients who underwent pars plana vitrectomy (PPV) due to the development of dropped nucleus after cataract surgery by phacoemulsification between 2003 and 2014 in three different centers were retrospectively reviewed. Demographic characteristics of the patients, intraocular pressure before PPV, data regarding PPV, and development of RD during follow-up period were recorded. The mean age of 79 patients with dropped nucleus enrolled in the study was 67.04+/-7.36 years (range, 51-82 years); 51.9% were female. Of these 79 patients, 9 (11.4%) developed RD after PPV. Anatomic success was achieved in 8 of 9 patients. Intraocular pressure before PPV was significantly higher in the patients with RD development than in those without RD development. Final visual acuity was <20/40 in 5 patients and >=40/200 in 2 patients. No significant risk factor affecting RD development after PPV was determined in the model including age, gender, intraocular pressure before PPV, presence of intraocular lens, and severity of inflammation before PPV. Conclusively, RD is an important complication that is likely to occur in patients undergoing PPV after cataract surgery. PMID- 26064391 TI - Total versus bilateral subtotal thyroidectomy for benign multi-nodular goiter. AB - PURPOSE: To compare the postoperative early-stage complications of total and bilateral subtotal thyroidectomy for benign multi-nodular goiter. MATERIAL AND METHODS: There were 409 patients. The patients were divided into two groups. A total of 258 (63%) patients underwent total thyroidectomy, and 151 (37%) patients underwent bilateral subtotal thyroidectomy. RESULTS: Recurrent laryngeal nerve palsy occurred in six (2.3%) of the total thyroidectomy patients and in three (1.9%) of the bilateral subtotal thyroidectomy patients (P>0.05). No permanent palsy was observed in either of the thyroidectomy groups. Hypocalcemia occurred in 40 (15.5%) of the total thyroidectomy patients and in 27 (17.8%) of those who underwent bilateral subtotal thyroidectomy (P>0.05). Also, no statistically significant differences were found between the two groups with respect to the development rates of hematoma and incision site infection (P>0.05). CONCLUSION: Because of its low complication rates, total thyroidectomy is a safe procedure for benign multi-nodular goiter. PMID- 26064392 TI - The effects of dexmedetomidine on post-operative cognitive dysfunction and inflammatory factors in senile patients. AB - OBJECTIVE: To evaluate the effect of dexmedetomidine on post-operative cognitive dysfunction (POCD) and possible action mechanisms. METHODS: A total of 148 aged surgical patients were divided into two groups, which were treated with dexmedetomidine (Dex group) or normal saline (control group) during general anesthesia. The incidence of POCD one day after surgery was evaluated using Mini Mental State Examination and serum levels of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) were measured using ELISA. The correlation between the two cytokines and POCD was evaluated using quartile division assay. RESULTS: The incidence of POCD was 9.20% and 21.31% in Dex and control groups, respectively. It is significantly different between the two groups (P < 0.05). The levels of IL-6 and TNF-alpha were significantly increased after surgery, as compared to before surgery (P < 0.05). Compared to control group, Dexmedetomidine significantly inhibited the increase of post-operative IL-6 and TNF-alpha levels (P < 0.05). The incidence of POCD was significantly different between quartile divisions of IL-6 and TNF-alpha (P < 0.05). Pearson correlation analysis showed that IL-6 and TNF-alpha were positively correlated with the POCD (r = 0.689, P = 0.043 and r = 0.711, P = 0.038, respectively). CONCLUSIONS: The results demonstrate that dexmedetomidine reduces the incidence of POCD in aged patients, and inflammation suppression may underlie the action mechanism. PMID- 26064393 TI - Association study of dopamine transporter gene (DAT1) variable tandem repeat sequence (VNTR) with obsessive-compulsive disorder in Chinese Han Population. AB - OBJECTIVE: Multiple evidence suggests an involvement of the dopamine neurotransmitter system in Obsessive-compulsive disorder (OCD). Therefore, we explore the association of 3'UTR region of 40 bp variable tandem repeat (VNTR) polymorphism in Dopamine Transporter Gene (DAT1) in Chinese Han population. METHODS: A total of 305 OCD patients and 435 healthy individuals were recruited for the study. OCD was diagnosed with the Forth Edition (DSM-IV) diagnostic criteria. After polymerase chain reaction of VNTR was used to evaluate the 40 bp VNTR polymorphism in DAT1, a case-control association analysis was performed by the chi(2) test. RESULTS: The results showed that no association was found between OCD patients and controls for the genotype distribution (X(2) =0.743, P=0.690, df=2) as well as allelic (X(2)=0.172, P=0.678, OR=0.928, 95% Cl=0.885 1.224) distribution. CONCLUSIONS: Our data suggest that the 40 bp VNTR polymorphism in DAT1 may not be associated with susceptibility to OCD in the Chinese Han population studied. However, this result needed to be replicated from different populations. PMID- 26064394 TI - Replantation with cryopreserved parathyroid for permanent hypoparathyroidism: a case report and review of literatures. AB - Permanent postsurgical hypoparathyroidism is defined as insufficient parathyroid hormone (PTH) to maintain normocalcemia 6 months after surgery. It occurs mostly in reoperation for persistent or recurrent hyperparathyroidism. The treatment of long-term calcium and vitamin D supplement is burdensome and may cause iatrogenic complications. PTH replacement is potential but still under trials. Only replantation with cryopreserved parathyroid is an available treatment for patients to reduce or stop long-term drug administration. However, this treatment is not applied widely in developing countries, due to lack of experiences and skills. Herein, we reported a 58-year-old male presented a continuous elevated parathyroid hormone up to about 2342 ng/L and bone pain during hemodialysis for 6 years due to chronic renal failure. He underwent the first operation total parathyroidectomy and autotransplantation. After this operation, he suffered from a persistent calcemia and permanent hypoparathyroidism. After three times of replantation with cryopreserved parathyroid and dialysis with a high calcium dialysate, the low concentration of calcium was elevated and symptoms of hypocalcemia disappeared. However, PTH was not elevated significantly in the long term. It might be related to our nonstandard cryopreservation protocol and no microbiological and histological examinations before replantation, compared with other successful reports. Therefore, we suggest a standard cryopreservation protocol should be followed by non-experienced institutions, especially in developing countries. Furthermore, a high calcium dialysate is efficient to increase calcium concentration and alleviate symptoms of hypocalcemia. It may be an available treatment of persistent hypocalcemia and permanent hypoparathyroidism in dialysis patients. PMID- 26064395 TI - Chinese medicine Jinlida (JLD) ameliorates high-fat-diet induced insulin resistance in rats by reducing lipid accumulation in skeletal muscle. AB - The present paper reports the effects of Jinlida (JLD), a traditional Chinese medicine which has been given as a treatment for high-fat-diet (HFD)-induced insulin resistance. A randomized controlled experiment was conducted to provide evidence in support of the affects of JLD on insulin resistance induced by HFD. The affect of JLD on blood glucose, lipid, insulin, adiponectin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) in serum and lipid content in skeletal muscle was measured. Genes and proteins of the AMPK signaling pathway were analyzed by real time RT-PCR and Western blot. Adiponectin receptor 1 and 2 (ADIPOR1, ADIPOR2) and other genes involved in mitochondrial function and fat oxidation were analyzed by real time RT-PCR. Histological staining was also performed. JLD or pioglitazone administration ameliorated fasting plasma levels of glucose, insulin, triglyceride (TG), total cholesterol (TC), ALT, AST and non-esterified fatty acid (NEFA) (P < 0.05). Treatment with JLD or pioglitazone significantly reverted muscle lipid content (P < 0.05). JLD (1.5 g/kg) significantly increased plasma adiponectin concentration by 60.17% and increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation in skeletal muscle (P < 0.05). JLD administration increased levels of ADIPOR1 and ADIPOR2 by 1.48 and 1.29 respectively. Levels of genes involved in mitochondrial function and fat oxidation were increased. This study provides the molecular mechanism by which JLD ameliorates HFD-induced insulin resistance in rats. PMID- 26064396 TI - Needleless transcutaneous electroacupuncture improves rectal distension-induced impairment in intestinal motility and slow waves via vagal mechanisms in dogs. AB - AIM: This study was designed to compare the effects and mechanisms of transcutaneous electroacupuncture (TEA) on rectal distention (RD)-induced intestinal dysmotility with EA. METHODS: six female dogs chronically implanted with a duodenal fistula, a proximal colon fistula and intestinal serosal electrodes were studied. EA and TEA were performed via needles and cutaneous electrodes placed at bilateral ST-36 (Zusanli) acupoints respectively; their effects on postprandial intestinal dysmotility (slow waves, contractions and transit) induced by RD, and autonomic functions were compared. RESULTS: RD at a volume of 140 ml suppressed intestinal contractions; the motility index was reduced with RD (P = 0.001). Both EA and TEA ameliorated the suppressed contractions (P = 0.003 and 0.001) and their effects were comparable. RD reduced the percentage of normal intestinal slow waves (P = 0.002) that was increased with both EA and TEA (P = 0.005 and 0.035). No significant difference was noted between EA and TEA. EA and TEA reduced small bowel transit time (P = 0.001 and 0.007); these prokinetic effects were blocked by atropine. Both EA and TEA increased vagal activity assessed by the spectral analysis of heart rate variability (both P = 0.03). CONCLUSION: RD inhibits postprandial intestinal motility. Both EA and TEA at ST-36 are able to improve the RD-induced impairment in intestinal contractions, transit and slow waves mediated via the vagal mechanism. Needleless TEA is as effective as EA in ameliorating the intestinal hypomotility. PMID- 26064397 TI - Clinical manifestations of syphilitic chorioretinitis: a retrospective study. AB - BACKGROUND: Syphilitic chorioretinitis can produce severe vision loss. However, the clinical manifestations of syphilitic chorioretinitis are still unclear, particularly during different stages. Herein, we will present our diagnostic technique for syphilitic chorioretinitis. METHODS: This retrospective study recruited 109 cases; we performed a clinical evaluation including case history, serology analysis, fundus photography, fluorescein fundus angiography with or without indocyanine green angiography, auto-fluorescence, and optical coherence tomography. RESULTS: 109 were diagnosed with acute syphilitic posterior placoid chorioretinitis by fundus photograph that revealed filthy, yellowish-white lesions. For autofluorescence, during early-stage syphilitic chorioretinitis, hyperfluorescence could be observed. During the convalescence stage, the fluorescence became hypofluorescence or disappeared. Fluorescein fundus angiography indicated early-stage transmitted fluorescence or hypofluorescence. During the venous stage, the lesion area had fluorescent leakage, mostly accompanied by retinal vasculitis. During the late stage, speckle staining was observed with optic disc fluorescence. Hypofluorescence or undistinguishable fluorescence was seen at an early stage with indocyanine green angiography. At an advanced stage, the lesion had obvious hypofluorescence. Optical coherence tomography indicated various inner segment/outer segment damage, accompanied by retinal pigment epithelium impairment. The inner segment/outer segment alteration could be lessened with treatment. CONCLUSIONS: The clinical manifestations of syphilitic chorioretinitis include impaired vision, shadow blocking, or photopsia of one or both eyes. Fundus photography, fluorescein fundus angiography with or without indocyanine green angiography, autofluorescence, and optical coherence tomography could be useful accessory examinations. Autofluorescence and optical coherence tomography could be the main examinations for monitoring disease progression. PMID- 26064399 TI - The progression of symmetrical left ventricular hypertrophy in a 54-year-old man: a case report with a 10.5-year follow-up and literatures review. AB - Apical hypertrophic cardiomyopathy (AHCM) is a well-known clinical entity, which is characterized by LV apex hypertrophy and the giant negative T wave at ECG and a spade-like left ventricle. It is a uncommon morphologic variant of hypertrophic cardiomyopathy (HCM) and AHCM appears to be particularly common in Asia whose prevalence was 15% and 3% of all the HCM patients in Japan and USA, respectively. In this case, we present a dramatic progress from symmetrical left ventricular hypertrophy to AHCM with apical aneurysm. PMID- 26064398 TI - Cherubism misdiagnosed as giant cell tumor: a case report and review of literature. AB - Cherubism is characterized by progressive, painless, bilateral enlargement of the mandible and/or maxilla resulting from the replacement of bone with multilocular cysts composed of fibrotic stromal cells and osteoclast-like cells. Here we report one Chinese cherubism case that has been misdiagnosed for more than forty years. The patient displayed no typical clinical or radiographical signs of cherubism due to multi-surgical treatments. Her histopathologic examination revealed the proliferating fibrous connective tissue with few multinucleated giant cells. The family history suggested us to perform sequence analysis of the SH3BP2 gene, a candidate marker for cherubism, in the family, and it was found that both the proband and the son had a missense mutation in SH3BP2 in exon 9 (p. Arg415Gln). Here we emphasize the importance of gene testing in the diagnosis of suspected cherubism, especially for those cases with non-typical clinical, radiographic and histological presentations. PMID- 26064400 TI - Eye-Lid approach for four zigomatic implant placement in the severely reabsorbed maxillae: technical note. AB - Up to date, zygomatic implants (ZIs) have been considered a predictable treatment modality for cases of atrophic maxilla. In some severe cases with severe vertical and/or horizontal bone resorption in the anterior maxilla, the placement of standard implants in the anterior area represents a challenge. In these arduous scenarios, performance of a zygomatic "quad-approach" might be advocated. Nevertheless, in limited zygomatic bone width, orbital cavity perforation constituted a potential risk that must be controlled during surgery. This paper focused at presenting a novel technique modification of conjunctival incision to expose the inferolateral orbital rim by an ophthalmologist, to assist the oral surgeon to have direct visualization of the orbital margin and to easily control the drilling direction. With this modification, the potential risk of orbital cavity penetration and its content damage could be diminished and ZIs might be well placed on accordance to prosthetically planned position. PMID- 26064401 TI - Surgical treatment for locally advanced pancreatic cancer localized in the pancreatic body and tail (report of 11 cases). AB - OBJECTIVE: To investigate the clinical efficacy of radical resection for pancreatic cancer localized in the pancreatic body and tail. METHODS: From 2009 to 2013, 11 patients with pancreatic cancer localized in the body and tail were treated with sequential radical resection of the tumor and postoperative chemotherapy, and closely followed up. RESULTS: Among the 11 patients, 7 received R0 resection, 4 received R1 resection. In the rest 2 patients, the tumor was removed together with the involved celiac artery and common hepatic artery. There were no postoperative complications, except second surgery for postoperative ischemic necrosis of the gastric antrum in 1 case, and wound infection in another patient. Nine of the 11 patients underwent cyclic chemotherapy with gemcitabine. Abdominal pain was relieved in all postoperative patients. The postoperative median survival time was 28 months, and 1-year and 3-year survival rates were 81.8% and 36.3%, respectively. CONCLUSION: Combination of surgical removal of the tumor with adjuvant chemotherapy can achieve better survival and significantly improve the patients' quality of life. PMID- 26064402 TI - Three umbilical arteries resulting in a four-vessel umbilical cord in a stillbirth. AB - Here we first describe a four-vessel umbilical cord including three umbilical arteries and one vein in a stillbirth. A 28-year-old woman delivered a 2360 g stillbirth in the 33th week of gestation. The infant had no gross anomalies. The placenta was examined pathologically, and the cord was measured as 60.0 cm long, which has four vessels with three arteries and one vein throughout its whole length confirmed by direct and microscopic examination. Fibro-necrosis and dotted necrosis were found in the placenta. A pregnancy with three umbilical arteries may need fetal monitoring during the second trimester. Further observation and adequate investigation are needed in such cases. PMID- 26064403 TI - The methodology of locating painful responsible vertebrae in osteoporotic vertebral compression fractures. AB - For vertebroplasty, it is necessary to determine certain vertebrae which should be primarily treated in multilevel osteoporotic vertebral compression fractures (OVCFs). The case presents that a 63-year-old female patient suffering from back pain, has received vertebroplasty four times to achieve pain relief, including total fourteen vertebrae. Retrospectively, it is choosing improper vertebrae to be treated that fails to relieve pain repeatedly. We come up with the term of painful responsible vertebrae which cause back pain in OVCFs, and illustrate clinical evidence of imaging, especially magnetic resonance imaging (MRI) scans, to locate painful responsible vertebrae preoperatively. PMID- 26064404 TI - Idiopathic ventricular premature contractions originating from the postero lateral tricuspid annulus leading to left ventricular disfunction. AB - A 19-year-old patient with premature ventricular complexes (PVCs) more than 30% on 24 hours was addressed for catheter ablation. Echocardiography showed left ventricular (LV) dilation and systolic dysfunction with 37% of ejection fraction. The patient underwent investigations including cardiac magnetic resonance (MRI) with no other cause of cardiomyopathy being found. Successful ablation of the postero-lateral tricuspid annulus ectopic focus using conventional radiological guiding resulted in normalization of the LV size and contractility. No PVCs were found at follow-up. To our knowledge, this is the first report of PVCs originating in the postero-lateral tricuspid annulus resulting in LV dysfunction. PMID- 26064405 TI - An unusual presentation of Paget's disease of the nipple in a young woman: a case report. AB - A 27-year-old female patient presented with a slight scaly, crusting, erythematous patch close to the right nipple 10 years ago. When her symptoms failed to respond to topical therapy 3 months later, nipple biopsy was performed and revealed Paget's disease of the breast. The patient underwent unilateral mastectomies with sentinel lymph node biopsy. She has stayed healthy and has had no evidence of breast cancer recurrence since surgery. PMID- 26064406 TI - Intraoperative high-field magnetic resonance imaging combined with neuronavigation-guided resection of intracranial mesenchymal chondrosarcoma in Broca's area: a rare case report and literature review. AB - Cranial Mesenchymal chondrosarcoma (MC) and those that occurred in brain parenchymal were fairly rare aggressive neoplasm commonly affecting the bone of young adults. Here, we reported a case with intracranial MC, invading Broca's area, a rare site not previously reported, which was presumed to be a glioma. We performed a gross total resection guided by intra-operative magnetic resonance imaging (iMRI) combined with neuronavigation. Follow-up shows no language and other brain function loss. Furthermore, we present a review of literature. We emphasized the importance of gross total resection guiding by the combination of iMRI and neuronavigation, which was proved to be both reliable and effective in language preservation. PMID- 26064408 TI - Hemolytic anemia as first presentation of Wilson's disease with uncommon ATP7B mutation. AB - Wilson's disease (WD) is a rare inherited disorder of copper metabolism and the main manifestations are liver and brain disorders. Hemolytic anemia is an unusual complication of WD. We describe a 15-year-old girl who developed hemolytic anemia as the first manifestation of Wilson's disease. An Arg952Lys mutation was found in exon 12 of the ATP7B gene, which is uncommon among Chinese Han individuals. From this case and reviews, we can achieve a better understanding of WD. Besides, we may conclude that the probable diagnosis of WD should be considered in young patients with unexplained hemolytic anemia, especially in patients with hepatic and/or neurologic disorder. PMID- 26064407 TI - Renal graft biopsy assists diagnosis and treatment of renal allograft dysfunction after kidney transplantation: a report of 106 cases. AB - Acute antibody mediated rejection (AMR) is one of the most important complications after kidney transplantation. Renal graft biopsy is safe and reliable without adverse effects on the patients and transplanted kidneys, which was of great instructive significance in diagnosis and treatment of renal allograft dysfunction after renal transplantation. This paper reported a case series of 106 patients underwent renal allograft biopsies. All biopsies were evaluated according to the Banff 2007 schema. 52 examples were obtained within 1 month after transplantation, and there were another 20 examples in one to two months and other 34 examples in two to three months. Appropriate therapy was applied and clinical outcomes were observed. All patients received renal biopsies and anti-inflammatory and hemostasis treatment without complications. There were 2 cases of hyperacute rejection, and 15 cases of acute AMR. All Paraffin-embedded samples were stained by HE, periodic acid-Schiff (PAS), Masson, and immunohistochemistry (C4d, cd20, cd45RO, SV40). All samples were found C4d immunohistochemical staining positive. Patients with acute AMR were managed by steroid intravenous pulse therapy, Rabbit anti-thymocyte globulin intravenous pulse therapy, anti CD20 monoclonal antibody intravenous therapy and so on. Two cases of hyperacute rejection had renal failure, and received kidney excision; 12 cases in 15 cases of AMR recovered, another 2 cases did not recover with high level creatine, and other 2 cases of renal allograft received excision. PMID- 26064409 TI - Ulcerative colitis flare with splenic ven thrombosis. AB - Patients with ulcerative colitis (UC) have an increased risk of thromboembolic events. Here, we present a 28-year-old man with active ulcerative pancolitis presenting via splenic vein thrombosis and left renal superior infarct that was not associated with a surgical procedure. PMID- 26064410 TI - Giant hydronephrosis secondary to ureteropelvic junction obstruction in adults: report of a case and review of literatures. AB - Giant hydronephrosis is rare to be seen in adults. Herein, we report a case of a 20-year-old male referred for abdominal pain. A radiological study revealed a giant left hydronephrosis. Nephrectomy was performed. During the operation, the ureteropelvic junction obstruction position was revealed. PMID- 26064411 TI - Rare coexistence of gouty and septic arthritis after arthroscopic rotator cuff repair: a case report. AB - Coexistence of septic arthritis and gouty arthritis is rare. In particular, no reports have described the development of both gouty and septic arthritis after arthroscopic shoulder surgery. The patient was an 83-year-old man who underwent arthroscopic rotator cuff repair. He had a history of diabetes mellitus (HbA1c: 7.4%), but not of gout, and the GFR was decreased (GFR=46). During the postoperative course fever suddenly developed and joint fluid retention was found. Uric acid crystals were detected when the joint fluid was aspirated, after which when the culture results became available sepsis due to methicillin sensitive Staphylococcus aureus (MSSA) was diagnosed. On the 2(nd) day after fever onset, lavage and debridement were performed under arthroscopy, with the subsequent course uneventful with no recurrence of the infection or gouty arthritis and no joint destruction. When uric acid crystals are found in aspirated joint fluid, gouty arthritis tends to be diagnosed, but like in the present case if infection also supervenes, joint destruction and a poor general state may result if appropriate intervention is not initiated swiftly. Accordingly, even if uric acid crystals are found, the possibility of coexistence of septic arthritis and gouty arthritis should be kept in mind. PMID- 26064412 TI - Differences in caspase-8 and -9 activity and sperm motility in infertile males of Li nationality in China. AB - This study's objectives are to assess the efficacy of detecting apoptotic caspase 3, -8, and -9 in human sperm and plasma using enzyme-linked immunosorbent assays (ELISA), and to compare these levels between fertile and infertile patient groups of Li nationality in China. This study offers a non-invasive, alternative strategy to analyzing sperm parameters in infertile males. Fifty-six infertile males were investigated; asthenospermia (n = 19), oligoasthenoteratozoospermia (n = 20), azoospermia (n = 17) compared with 20 healthy fertile controls. They were subjected to semen analysis by computer-assisted sperm assay (CASA). We found that caspase-3, -8, -9 existed in all specimens in both sperms and plasma. The level of caspase-3 and caspase-8 in plasma were both significantly higher than in sperm. Levels of caspase-8 and caspase-9 in sperm and plasma were significantly negatively correlated with sperm concentration, motility and A % (motility grade A). The level of caspase-8 in plasma was significantly negatively correlated with sperm concentration. However, only in healthy fertile controls sperm concentration was significantly negatively correlated with caspase-9 in sperm. Compared with the healthy fertile controls, only the OAT group exhibited significantly increased level of caspase-8 in sperm (P < 0.05). It is concluded that caspase-8 and caspase-9 in sperm and plasma are correlated with sperm motility, and can reflect the quality of sperm in vitro. PMID- 26064413 TI - Serious anaphylactic shock induced by hemocoagulase agkistrodon during anesthesia in a 5-year-old child. AB - We report a case of serious anaphylactic shock in a 5-year-old child undergoing scheduled surgery blank space of a right femoral intramedullary nail removal. The boy had undergone right femoral elastic intramedullary nail fixation surgery 14 months prior, but had no history of allergies. Within 5 minutes of intravenous bonus injection of hemocoagulase agkistrodon (HCA) 1 unit, a widespread transient diffuse erythema was seen on the front of his chest. After 20 minutes, sudden, profound cardiovascular collapse occurred. The child was treated effectively and sent to a ward 5 hours later. In this period, he received intravenously infused 200 ml hydroxyethyl starch solution and epinephrine at a rate of 0.05-0.01 MUg kg(-1) min(-1). Total amount of dexamethasone sodium phosphate 14 mg was used. To the best of our knowledge, few case reports of HCA-induced anaphylactic shock in children exist. Our report will, therefore, increase awareness of the allergic potential of HCA among pediatric anesthesiologists. PMID- 26064414 TI - Correlative association of interleukin-6 with intima media thickness: a meta analysis. AB - BACKGROUND: Involvement of inflammatory processes in the atherogenesis is now well-recognized. The present study examines the relationship between a proinflammatory cytokine, interleukin-6 (IL-6), and atherosclerosis by meta analyzing the correlation coefficients between IL-6 and intima media thickness reported in the relevant studies. METHOD: Relevant research articles were searched in several electronic databases by using most relevant MeSH terms and keywords. For the meta-analyses, correlation coefficients of individual studies were first converted into Fisher's z scores and then overall effect size was transformed into correlation coefficient. Between-study hete rogeneity was tested by I(2) index and subgroup analyses were performed. Quality of the included studies was assessed and tests for publication bias were carried out. RESULTS: Thirty seven studies were selected for the meta-analysis from which data of 14832 participants including healthy persons, persons at risk of CVD and patients of various diseases is used. The effect size (correlation coefficient) with 95% confidence interval (CI) between IL-6 and intima media thickness was 0.336 (0.327 to 0.345); P < 0.0001 in the overall meta-analysis, 0.446 (0.422 to 0.47); P < 0.0001 in patients suffering from any pathological condition; 0.478 (0.446 to 0.508); P < 0.0001 in patients suffering either from a CVD or a disease which poses risk of CVD; 0.327 (0.264 to 0.388); P < 0.0001 in patients suffering from a disease with no CVD risk; and 0.31 (0.291 to 0.327); P < 0.0001 in participants of community-based surveys. There was no significant publication bias. CONCLUSION: Intima media thickness is significantly correlated with IL-6 levels in the patients with CVD or a disease posing risk of CVD as well as in apparently healthy populations. PMID- 26064415 TI - Anti-tumor angiogenesis effect of genetic fusion vaccine encoding murine beta defensin 2 and tumor endothelial marker-8 in a CT-26 murine colorectal carcinoma model. AB - Tumor endothelial marker 8 (TEM8) is an endothelial-specific marker that is upregulated during tumor angiogenesis. We previously demonstrated that DNA-based vaccine encoding xenogeneic TEM8 can potentiate anti-angiogenesis immunotherapy of malignancy; nevertheless, it remains to be improved in minimizing immune tolerance. Recently, it has been reported that murine beta-defensin 2 (MBD2) is chemotactic for immature dendritic cells and plays a pivotal role in breaking immune tolerance. Herein, we constructed a genetic fusion vaccine encoding murine TEM8 and MBD2 to investigate whether the novel vaccine preferentially elicits therapeutic antitumor immune responses and suppresses cancerous angiogenesis in mouse models. The anti-angiogenesis effect was determined by microvessel density (MVD) using immunohistochemical staining. The efficacy of the fusion vaccine was primarily assessed by detecting cytotoxic T lymphocyte activity ((51)Cr-release assay). Enzyme-linked immunosorbent spot (ELISpot) assay was used to detect TEM8 specific INF-gamma production, and the activity of CTL was further verified by a depletion of CD8(+) T cells via anti-CD8 monoclonal antibody. Our results showed that the DNA fusion vaccine possessed an enhanced therapeutic antitumor immunity through anti-angiogenesis in BALB/c mice inoculated with CT26 cells, and this effect was generally attributed to stimulation of an antigen specific CD8(+) T cell response against mTEM8. In conclusion, our study demonstrated that the fusion vaccine based on mTEM8 and MBD2 induced autoimmunity against endothelial cells, resulting in deceleration of tumor growth, and could be potential therapeutical application in clinic. PMID- 26064417 TI - Relationship between the Increased Haemostatic Properties of Blood Platelets and Oxidative Stress Level in Multiple Sclerosis Patients with the Secondary Progressive Stage. AB - Multiple sclerosis (MS) is the autoimmune disease of the central nervous system with complex pathogenesis, different clinical courses and recurrent neurological relapses and/or progression. Despite various scientific papers that focused on early stage of MS, our study targets selective group of late stage secondary progressive MS patients. The presented work is concerned with the reactivity of blood platelets in primary hemostasis in SP MS patients. 50 SP MS patients and 50 healthy volunteers (never diagnosed with MS or other chronic diseases) were examined to evaluate the biological activity of blood platelets (adhesion, aggregation), especially their response to the most important physiological agonists (thrombin, ADP, and collagen) and the effect of oxidative stress on platelet activity. We found that the blood platelets from SP MS patients were significantly more sensitive to all used agonists in comparison with control group. Moreover, the platelet hemostatic function was advanced in patients suffering from SP MS and positively correlated with increased production of O2 ( ?) in these cells, as well as with Expanded Disability Status Scale. We postulate that the increased oxidative stress in blood platelets in SP MS may be primarily responsible for the altered haemostatic properties of blood platelets. PMID- 26064416 TI - Role of Hydrogen Sulfide in Ischemia-Reperfusion Injury. AB - Ischemia-reperfusion (I/R) injury is one of the major causes of high morbidity, disability, and mortality in the world. I/R injury remains a complicated and unresolved situation in clinical practice, especially in the field of solid organ transplantation. Hydrogen sulfide (H2S) is the third gaseous signaling molecule and plays a broad range of physiological and pathophysiological roles in mammals. H2S could protect against I/R injury in many organs and tissues, such as heart, liver, kidney, brain, intestine, stomach, hind-limb, lung, and retina. The goal of this review is to highlight recent findings regarding the role of H2S in I/R injury. In this review, we present the production and metabolism of H2S and further discuss the effect and mechanism of H2S in I/R injury. PMID- 26064419 TI - Impact of Atmospheric Microparticles on the Development of Oxidative Stress in Healthy City/Industrial Seaport Residents. AB - Atmospheric microsized particles producing reactive oxygen species can pose a serious health risk for city residents. We studied the responses of organisms to microparticles in 255 healthy volunteers living in areas with different levels of microparticle air pollution. We analyzed the distribution of microparticles in snow samples by size and content. ELISA and flow cytometry methods were employed to determine the parameters of the thiol-disulfide metabolism, peroxidation and antioxidant, genotoxicity, and energy state of the leukocytes. We found that, in the park areas, microparticles with a size of 800 MUm or more were predominant (96%), while in the industrial areas, they tended to be less than 50 MUm (93%), including size 200-300 nm (7%). In the industrial areas, we determined the oxidative modification of proteins (21% compared to the park areas, p <= 0.05) and DNA (12%, p <= 0.05), as well as changes in leukocytes' energy potential (53%, p <= 0.05). An increase in total antioxidant activity (82%, p <= 0.01) and thiol-disulfide system response (thioredoxin increasing by 33%, p <= 0.01; glutathione, 30%, p <= 0.01 with stable reductases levels) maintains a balance of peroxidation-antioxidant processes, protecting cellular and subcellular structures from significant oxidative damage. PMID- 26064418 TI - Mitochondria-Targeted Protective Compounds in Parkinson's and Alzheimer's Diseases. AB - Mitochondria are cytoplasmic organelles that regulate both metabolic and apoptotic signaling pathways; their most highlighted functions include cellular energy generation in the form of adenosine triphosphate (ATP), regulation of cellular calcium homeostasis, balance between ROS production and detoxification, mediation of apoptosis cell death, and synthesis and metabolism of various key molecules. Consistent evidence suggests that mitochondrial failure is associated with early events in the pathogenesis of ageing-related neurodegenerative disorders including Parkinson's disease and Alzheimer's disease. Mitochondria targeted protective compounds that prevent or minimize mitochondrial dysfunction constitute potential therapeutic strategies in the prevention and treatment of these central nervous system diseases. This paper provides an overview of the involvement of mitochondrial dysfunction in Parkinson's and Alzheimer's diseases, with particular attention to in vitro and in vivo studies on promising endogenous and exogenous mitochondria-targeted protective compounds. PMID- 26064421 TI - Endogenous Estrogen-Mediated Heme Oxygenase Regulation in Experimental Menopause. AB - Estrogen deficiency is one of the main causes of age-associated diseases in the cardiovascular system. Female Wistar rats were divided into four experimental groups: pharmacologically ovariectomized, surgically ovariectomized, and 24-month old intact aging animals were compared with a control group. The activity and expression of heme oxygenases (HO) in the cardiac left ventricle, the concentrations of cardiac interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), the myeloperoxidase (MPO) activity in the cardiac left ventricle, and the effects of heme oxygenase blockade (by 24-hour and 1-hour pretreatment with tin-protoporphyrin IX, SnPP) on the epinephrine and phentolamine-induced electrocardiogram ST segment changes in vivo were investigated. The cardiac HO activity and the expression of HO-1 and HO-2 were significantly decreased in the aged rats and after ovariectomy. Estrogen depletion was accompanied by significant increases in the expression of IL-6 and TNF-alpha. The aged and ovariectomized animals exhibited a significantly elevated MPO activity and a significant ST segment depression. After pretreatment with SnPP augmented ST segment changes were determined. These findings demonstrate that the sensitivity to cardiac ischemia in estrogen depletion models is associated with suppression of the activity and expression of the HO system and increases in the secretion of proinflammatory cytokines and biomarkers. PMID- 26064420 TI - Antioxidant Mechanisms and ROS-Related MicroRNAs in Cancer Stem Cells. AB - Increasing evidence indicates that most of the tumors are sustained by a distinct population of cancer stem cells (CSCs), which are responsible for growth, metastasis, invasion, and recurrence. CSCs are typically characterized by self renewal, the key biological process allowing continuous tumor proliferation, as well as by differentiation potential, which leads to the formation of the bulk of the tumor mass. CSCs have several advantages over the differentiated cancer cell populations, including the resistance to radio- and chemotherapy, and their gene expression programs have been shown to correlate with poor clinical outcome, further supporting the relevance of stemness properties in cancer. The observation that CSCs possess enhanced mechanisms of protection from reactive oxygen species (ROS) induced stress and a different metabolism from the differentiated part of the tumor has paved the way to develop drugs targeting CSC specific signaling. In this review, we describe the role of ROS and of ROS related microRNAs in the establishment and maintenance of self-renewal and differentiation capacities of CSCs. PMID- 26064422 TI - Cellular Mechanisms of Oxidative Stress and Action in Melanoma. AB - Most melanomas occur on the skin, but a small percentage of these life threatening cancers affect other parts of the body, such as the eye and mucous membranes, including the mouth. Given that most melanomas are caused by ultraviolet radiation (UV) exposure, close attention has been paid to the impact of oxidative stress on these tumors. The possibility that key epigenetic enzymes cannot act on a DNA altered by oxidative stress has opened new perspectives. Therefore, much attention has been paid to the alteration of DNA methylation by oxidative stress. We review the current evidence about (i) the role of oxidative stress in melanoma initiation and progression; (ii) the mechanisms by which ROS influence the DNA methylation pattern of transformed melanocytes; (iii) the transformative potential of oxidative stress-induced changes in global and/or local gene methylation and expression; (iv) the employment of this epimutation as a biomarker for melanoma diagnosis, prognosis, and drug resistance evaluation; (v) the impact of this new knowledge in clinical practice for melanoma treatment. PMID- 26064423 TI - Effect of Melatonin Intake on Oxidative Stress Biomarkers in Male Reproductive Organs of Rats under Experimental Diabetes. AB - This study investigated the antioxidant system response of male reproductive organs during early and late phases of diabetes and the influence of melatonin treatment. Melatonin was administered to five-week-old Wistar rats throughout the experiment, in drinking water (10 MUg/kg b.w). Diabetes was induced at 13 weeks of age by streptozotocin (4.5 mg/100 g b.w., i.p.) and animals were euthanized with 14 or 21 weeks old. Activities of catalase (CAT), glutathione-S-transferase (GST), glutathione peroxidase (GPx), and lipid peroxidation were evaluated in prostate, testis, and epididymis. The enzymes activities and lipid peroxidation were not affected in testis and epididymis after one or eight weeks of diabetes. Prostate exhibited a 3-fold increase in GPx activity at short-term diabetes and at long-term diabetes there were 2- and 3-fold increase in CAT and GST, respectively (p <= 0.01). Melatonin treatment to healthy rats caused a 47% increase in epididymal GPx activity in 14-week-old rats. In prostate, melatonin administration normalized GST activity at both ages and mitigated GPx at short term and CAT at long-term diabetes. The testis and epididymis were less affected by diabetes than prostate. Furthermore, melatonin normalized the enzymatic disorders in prostate demonstrating its effective antioxidant role, even at low dosages. PMID- 26064424 TI - The Neuroprotective Effects of Ratanasampil on Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells. AB - We previously found that Ratanasampil (RNSP), a traditional Tibetan medicine, improves the cognitive function of mild-to-moderate AD patients living at high altitude, as well as learning and memory in an AD mouse model (Tg2576); however, mechanism underlying the effects of RNSP is unknown. In the present study, we investigated the effects and molecular mechanisms of RNSP on oxidative stress induced neuronal toxicity using human neuroblastoma SH-SY5Y cells. Pretreatment with RNSP significantly ameliorated the hydrogen peroxide- (H2O2-) induced cytotoxicity of SH-SY5Y cells in a dose-dependent manner (up to 60 MUg/mL). Furthermore, RNSP significantly reduced the H2O2-induced upregulation of 8-oxo-2' deoxyguanosine (8-oxo-dG, the oxidative DNA damage marker) but significantly reversed the expression of repressor element-1 silencing transcription factor (REST) from H2O2 associated (100 MUM) downregulation. Moreover, RNSP significantly attenuated the H2O2-induced phosphorylation of p38 mitogen activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) in SH-SY5Y cells. These observations strongly suggest that RNSP may protect the oxidative stress-induced neuronal damage that occurs through the properties of various antioxidants and inhibit the activation of MAPKs. We thus provide the principle molecular mechanisms of the effects of RNSP and indicate its role in the prevention and clinical management of AD. PMID- 26064425 TI - Schisandrae Fructus Supplementation Ameliorates Sciatic Neurectomy-Induced Muscle Atrophy in Mice. AB - The objective of this study was to assess the possible beneficial skeletal muscle preserving effects of ethanol extract of Schisandrae Fructus (EESF) on sciatic neurectomy- (NTX-) induced hindlimb muscle atrophy in mice. Here, calf muscle atrophy was induced by unilateral right sciatic NTX. In order to investigate whether administration of EESF prevents or improves sciatic NTX-induced muscle atrophy, EESF was administered orally. Our results indicated that EESF dose dependently diminished the decreases in markers of muscle mass and activity levels, and the increases in markers of muscle damage and fibrosis, inflammatory cell infiltration, cytokines, and apoptotic events in the gastrocnemius muscle bundles are induced by NTX. Additionally, destruction of gastrocnemius antioxidant defense systems after NTX was dose-dependently protected by treatment with EESF. EESF also upregulated muscle-specific mRNAs involved in muscle protein synthesis but downregulated those involved in protein degradation. The overall effects of 500 mg/kg EESF were similar to those of 50 mg/kg oxymetholone, but it showed more favorable antioxidant effects. The present results suggested that EESF exerts a favorable ameliorating effect on muscle atrophy induced by NTX, through anti-inflammatory and antioxidant effects related to muscle fiber protective effects and via an increase in protein synthesis and a decrease in protein degradation. PMID- 26064428 TI - Antioxidants and Quality of Aging: Further Evidences for a Major Role of TXNRD1 Gene Variability on Physical Performance at Old Age. AB - Oxidative stress is a major determinant of human aging and common hallmark of age related diseases. A protective role against free radicals accumulation was shown for thioredoxin reductase TrxR1, a key antioxidant selenoprotein. The variability of encoding gene (TXNRD1) was previously found associated with physical status at old age and extreme survival in a Danish cohort. To further investigate the influence of the gene variability on age-related physiological decline, we analyzed 9 tagging SNPs in relation to markers of physical (Activity of Daily Living, Hand Grip, Chair stand, and Walking) and cognitive (Mini Mental State Examination) status, in a Southern-Italian cohort of 64-107 aged individuals. We replicated the association of TXNRD1 variability with physical performance, with three variants (rs4445711, rs1128446, and rs11111979) associated with physical functioning after 85 years of age (p < 0.022). In addition, we found two SNPs borderline influencing longevity (rs4964728 and rs7310505) in our cohort, the last associated with health status and survival in Northern Europeans too. Overall, the evidences of association in a different population here reported extend the proposed role of TXNRD1 gene in modulating physical decline at extreme ages, further supporting the investigation of thioredoxin pathway in relation to the quality of human aging. PMID- 26064427 TI - Arginase as a Critical Prooxidant Mediator in the Binomial Endothelial Dysfunction-Atherosclerosis. AB - Arginase is a metalloenzyme which hydrolyzes L-arginine to L-ornithine and urea. Since its discovery, in the early 1900s, this enzyme has gained increasing attention, as literature reports have progressively pointed to its critical participation in regulating nitric oxide bioavailability. Indeed, accumulating evidence in the following years would picture arginase as a key player in vascular health. Recent studies have highlighted the arginase regulatory role in the progression of atherosclerosis, the latter an essentially prooxidant state. Apart from the fact that arginase has been proven to impair different metabolic pathways, and also as a consequence of this, the repercussions of the actions of such enzyme go further than first thought. In fact, such metalloenzyme exhibits direct implications in multiple cardiometabolic diseases, among which are hypertension, type 2 diabetes, and hypercholesterolemia. Considering the epidemiological repercussions of these clinical conditions, arginase is currently seen under the spotlights of the search for developing specific inhibitors, in order to mitigate its deleterious effects. That said, the present review focuses on the role of arginase in endothelial function and its participation in the establishment of atherosclerotic lesions, discussing the main regulatory mechanisms of the enzyme, also highlighting the potential development of pharmacological strategies in related cardiovascular diseases. PMID- 26064430 TI - Serial Medication Nonadherence in Patients with Type 2 Diabetes. PMID- 26064431 TI - Diabetes Management: A Payer Perspective. PMID- 26064429 TI - Elevation of HO-1 Expression Mitigates Intestinal Ischemia-Reperfusion Injury and Restores Tight Junction Function in a Rat Liver Transplantation Model. AB - Aims. This study was aimed at investigating whether elevation of heme oxygenase-1 (HO-1) expression could lead to restoring intestinal tight junction (TJ) function in a rat liver transplantation model. Methods. Intestinal mucosa injury was induced by orthotopic autologous liver transplantation (OALT) on male Sprague Dawley rats. Hemin (a potent HO-1 activator) and zinc-protoporphyrin (ZnPP, a HO 1 competitive inhibitor), were separately administered in selected groups before OALT. The serum and intestinal mucosa samples were collected at 8 hours after the operation for analysis. Results. Hemin pretreatment significantly reduced the inflammation and oxidative stress in the mucosal tissue after OALT by elevating HO-1 protein expression, while ZnPP pretreatment aggravated the OALT mucosa injury. Meanwhile, the restriction on the expression of tight junction proteins zonula occludens-1 and occludin was removed after hemin pretreatment. These molecular events led to significant improvement on intestinal barrier function, which was proved to be through increasing nuclear translocation of nuclear factor E2-related factor 2 (Nrf2) and reducing nuclear translocation of nuclear factor kappa-B (NF-kappaB) in intestinal injured mucosa. Summary. Our study demonstrated that elevation of HO-1 expression reduced the OALT-induced intestinal mucosa injury and TJ dysfunction. The HO-1 protective function was likely mediated through its effects of anti-inflammation and antioxidative stress. PMID- 26064432 TI - Diabetes Management: An Accountable Care Perspective. PMID- 26064426 TI - New Insights for Oxidative Stress and Diabetes Mellitus. AB - The release of reactive oxygen species (ROS) and the generation of oxidative stress are considered critical factors for the pathogenesis of diabetes mellitus (DM), a disorder that is growing in prevalence and results in significant economic loss. New therapeutic directions that address the detrimental effects of oxidative stress may be especially warranted to develop effective care for the millions of individuals that currently suffer from DM. The mechanistic target of rapamycin (mTOR), silent mating type information regulation 2 homolog 1 (S. cerevisiae) (SIRT1), and Wnt1 inducible signaling pathway protein 1 (WISP1) are especially justified to be considered treatment targets for DM since these pathways can address the complex relationship between stem cells, trophic factors, impaired glucose tolerance, programmed cell death pathways of apoptosis and autophagy, tissue remodeling, cellular energy homeostasis, and vascular biology that greatly impact the biology and disease progression of DM. The translation and development of these pathways into viable therapies will require detailed understanding of their proliferative nature to maximize clinical efficacy and limit adverse effects that have the potential to lead to unintended consequences. PMID- 26064433 TI - Diabetes Management: An Employer Perspective. PMID- 26064434 TI - Mitigating the Burden of Type 2 Diabetes: Challenges and Opportunities. PMID- 26064435 TI - Effects of thrombin and thrombin receptor activation on cardiac function after acute myocardial infarction. AB - Thrombin and thrombin receptor activation impact cardiomyocyte contraction and ventricular remodeling. However, there is some controversy regarding their effects in cardiac function, especially in cardiac dysfunction after acute myocardial infarction (AMI). A rat AMI model was created by left coronary artery ligation (LCA). Cardiac functional parameters, including the maximum left ventricular (LV) systolic pressure (LVSPmax), LV end-diastolic pressure (LVEDP), and the rise and fall rates in LV pressure (dp/dt max and dp/dt min, respectively), were measured. Hirudin decreased cardiac function within 120 minutes after AMI, whereas treatment with thrombin receptor-activating peptide (TRAP) reversed this hirudin-induced decrease in cardiac function. The mRNA and protein expression levels of inositol 1,4,5-trisphosphate receptor (IP3R) subtypes in infarct area tissues were analyzed by reverse transcription polymerase chain reaction and immunoreaction. Hirudin decreased the expression levels of IP3R-1, -2, and -3 in the infarct area for up to 40 minutes after AMI, whereas TRAP treatment reversed these hirudin-induced effects. Treatment with the IP3R antagonist 2-aminoethoxydiphenyl borate (2.5 mg/kg) eliminated the effect of TRAP on the hirudin-induced decrease in cardiac function after AMI. Finally, TRAP increased the maximum binding capacity of the three IP3R subtypes, but only enhanced the affinity of IP3R-2. Thrombin and thrombin receptor activation improved cardiac function after AMI by an IP3R-mediated pathway, probably through the IP3R-2 subtype. PMID- 26064436 TI - The effect of specific IKKbeta inhibitors on the cytosolic expression of IkappaB alpha and the nuclear expression of p65 in dystrophic (MDX) muscle. AB - The efficacy of two highly specific IkappaB-alpha kinase beta (IKK-beta) inhibitors in reducing the enhanced basal activation of the NF-kappaB pathway in dystrophic muscle was assessed by determining the effects of these inhibitors in increasing the expression of cytosolic IkappaB-alpha and reducing the enhanced expression of nuclear p65 in adult mdx costal diaphragm preparations. In vivo and in vitro treatment with BMS-345541 was ineffective at altering these variables when administered at concentrations that were highly effective in models of acute inflammation. PHA-408 increased cytosolic IkappaB-alpha and reduced nuclear p65 at a concentration in vitro (20 MUM) that was 500 fold higher than the IC50 for inhibiting purified activity. Long term daily oral administration of PHA-408 increased cytosolic IkappaB-alpha but did not influence nuclear p65. Long term intraperitoneal administration of PHA-408 reduced nuclear p65 by approximately 50%. In comparison to their potent effects in models of acute inflammation, these results indicate a reduced efficacy of the specific IKKbeta inhibitors in ameliorating the enhanced basal activation of the NF-kappaB pathway in dystrophic muscle, and suggest that the therapeutic potential of IKK-beta inhibitors in treating muscular dystrophy would be enhanced by simultaneous treatment with agents which more directly interfere with NF-kappaB transactivation. PMID- 26064437 TI - Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanical unloading. AB - Autophagy is ubiquitous in all forms of heart failure and cardioprotective miR 133a is attenuated in human heart failure. Previous reports from heart failure patients undergoing left ventricular assist device (LVAD) implantation demonstrated that autophagy is upregulated in the LV of the failing human heart. Studies in the murine model show that diabetes downregulates miR-133a. However, the role of miR-133a in the regulation of autophagy in diabetic hearts is unclear. We tested the hypothesis that diabetes exacerbates cardiac autophagy by inhibiting miR-133a in heart failure patients undergoing LVAD implantation. The miRNA assay was performed on the LV of 15 diabetic (D) and 6 non-diabetic (ND) heart failure patients undergoing LVAD implantation. Four ND with highly upregulated and 5 D with highly downregulated miR-133a were analyzed for autophagy markers (Beclin1, LC3B, ATG3) and their upstream regulators (mTOR and AMPK), and hypertrophy marker (beta-myosin heavy chain) by RT-qPCR, Western blotting and immunofluorescence. Our results demonstrate that attenuation of miR 133a in diabetic hearts is associated with the induction of autophagy and hypertrophy, and suppression of mTOR without appreciable difference in AMPK activity. In conclusion, attenuation of miR-133a contributes to the exacerbation of diabetes mediated cardiac autophagy and hypertrophy in heart failure patients undergoing LVAD implantation. PMID- 26064438 TI - VEGF-C/VEGFR-3 pathway promotes myocyte hypertrophy and survival in the infarcted myocardium. AB - BACKGROUND: Numerous studies have shown that in addition to angio/lymphangiogenesis, the VEGF family is involved in other cellular actions. We have recently reported that enhanced VEGF-C and VEGFR-3 in the infarcted rat myocardium, suggesting the paracrine/autocrine function of VEGF-C on cardiac remodeling. The current study was designed to test the hypothesis that VEGF-C regulates cardiomyocyte growth and survival in the infarcted myocardium. METHODS AND RESULTS: Gene profiling and VEGFR-3 expression of cardiomyocytes were assessed by laser capture microdissection/microarray and immunohistochemistry in the normal and infarcted myocardium. The effect of VEGF-C on myocyte hypertrophy and apoptosis during normoxia and hypoxia was detected by RT-PCR and western blotting in cultured rat neonatal cardiomyocytes. VEGFR-3 was minimally expressed in cardiomyocytes of the normal and noninfarcted myocardium, while markedly elevated in the surviving cardiomyocytes of the infarcted myocardium and border zone. Genes altered in the surviving cardiomyocytes were associated with the networks regulating cellular growth and survival. VEGF-C significantly increased the expression of atrial natriuretic factor (ANP), brain natriuretic factor (BNP), and beta-myosin heavy chain (MHC), markers of hypertrophy, in neonatal cardiomyocytes. Hypoxia caused neonatal cardiomyocyte atrophy, which was prevented by VEGF-C treatment. Hypoxia significantly enhanced apoptotic mediators, including cleaved caspase 3, 8, and 9, and Bax in neonatal cardiomyocytes, which were abolished by VEGF-C treatment. CONCLUSION: Our findings indicate that VEGF-C/VEGFR-3 pathway exerts a beneficial role in the infarcted myocardium by promoting compensatory cardiomyocyte hypertrophy and survival. PMID- 26064439 TI - CDCA5 overexpression is an indicator of poor prognosis in patients with urothelial carcinomas of the upper urinary tract and urinary bladder. AB - AIMS: Urothelial carcinoma (UC) is the most common tumor involving upper urinary tract (UTUC) and urinary bladder (UBUC) whose molecular survival determinants remains obscured. By computerizing a public transcriptomic database of UBUCs (GSE32894), we identified cell division cycle associated 5 (CDCA5) as the most significantly upregulated gene among those associated with G1-S transition of the mitotic cell cycle (GO:0000082). We therefore analyzed the clinicoptaological significance of CDCA5 expression in our well-characterized UC cohort. METHODS AND RESULTS: Quantigene assay was used to detect CDCA5 transcript levels in 36 UTUCs and 30 UBUCs. We used immunohistochemistry evaluated by H-scores to determine CDCA5 protein expression in 295 UBUCs and 340 UTUCs, respectively. CDCA5 expression was further correlated with clinicopathological features and disease specific survival (DSS) and metastasis-free survival (MeFS). For both groups of UCs, increments of CDCA5 transcript levels were associated with higher pT status, CDCA5 protein overexpression was also significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular invasion, and frequent mitoses. CDCA5 overexpression was predictive for worse DSS and MeFS in univariate and multivariate analysis. CONCLUSIONS: CDCA5 overexpression is associated with advanced clinical features of UC, suggesting its potential value as a prognostic biomarker and a novel therapeutic target. PMID- 26064440 TI - Role of plasma osteopontin as a biomarker in locally advanced breast cancer. AB - Osteopontin (OPN), a malignancy-associated secreted phosphoprotein, is a prognostic plasma biomarker for survival in metastatic breast cancer patients. We evaluated the role of OPN in Locally Advanced Breast Cancer (LABC) patients in predicting response to neoadjuvant chemotherapy and association with survival. Fifty-three patients with non-metastatic LABC were enrolled in this study and monitored serially for plasma OPN levels by ELISA during neoadjuvant chemotherapy prior to surgery. For fifty patients who had baseline OPN levels available for analysis, the median baseline OPN level was 63.6 ng/ml. Median patient follow up was 45 months and thirteen patients died from metastatic disease. Patients with baseline OPN levels >= 63.6 ng/ml were significantly more likely to die of their disease than those with baseline OPN < 63.6 ng/mL (Hazard Ratio = 3.4; 95% confidence interval 1.4-11.3; P = 0.011), and overall, baseline OPN level was significantly associated with survival (P = 0.002). There was little support for value of serial OPN determination in monitoring response to therapy in this patient population. Although the percentage of patients with baseline OPN levels < 63.6 ng/ml was higher in patients with pathological complete response than in those with no response, the difference was not statistically significant (64% and 14%, respectively (P = 0.066)). Thus, baseline plasma OPN level is a prognostic biomarker in this group of LABC patients, and could also be helpful in identifying LABC patients who will respond to neoadjuvant chemotherapy. Our results call for validation of our findings in large prospective trial data sets. PMID- 26064441 TI - A critical role for HER3 in HER2-amplified and non-amplified breast cancers: function of a kinase-dead RTK. AB - ERBB3/HER3 is the most intriguing RTK by virtue of its ability to transduce multiple cytosolic signals for the proliferation and growth of tumor cells in spite of being a "kinase dead" receptor that binds to its true ligand, heregulin. Although other members of the HER3 family like EGFR and HER2 have long been recognized to be associated with breast tumorigenesis and studied because of their predictive and prognostic value, the significance of HER3 as an irrefutable component of HER family signalosome is a relatively new development. The recent understanding of signals originating from the oncogenic partnership of HER3 with HER2 in the context of HER2 amplification/overexpression showed the critical clinical value for the treatment of HER2+BC. The downstream signaling cascade (included but not limited to the PI3K signaling) associated with signals originating from HER2:HER3 dimers play a vital role in the tumorigenesis, drug resistance and tumor progression of HER2+BC. The upregulation of HER3 activity provides an alternate "escape route" via which tumor cells bypass either the inhibition of the HER family RTKs or the inhibition of the downstream PI3K-AKT mTOR signaling pathway. By understanding the signaling that provides this "escape route" for these tumor cells treated with a targeted therapy (HER2 inhibitors or inhibitors of downstream PI3K-AKT-mTOR signaling pathway), we are just beginning to appreciate the prognostic value of HER3 in breast cancer. In this review, we will discuss the relevance of HER3 signaling in the context of, (1) downstream oncogenic signals and (2) therapeutic options in HER2 amplified BC. PMID- 26064442 TI - The HIF-1 inhibitor YC-1 decreases reactive astrocyte formation in a rodent ischemia model. AB - Astrocytes become reactive after central nervous system injury, re-expressing glial fibrillary acidic protein (GFAP), vascular endothelial growth factor (VEGF), and nestin. Hypoxia-inducible transcription factor alpha (HIF-1alpha) is an important transcription factor for several genes including the VEGF and nestin genes, the expression of which generate reactive astrocytes and cause gliosis after cerebral ischemia. To evaluate the role of HIF-1alpha in reactive astrocyte formation, we applied the potent HIF-1alpha inhibitor YC-1 to a focal cerebral ischemia model and analyzed the expression of HIF-1alpha, VEGF, nestin, and GFAP. Quantitative real-time reverse transcription polymerase chain reaction and western blot analyses demonstrated that the expression of HIF-1alpha and its downstream genes (VEGF and nestin) were markedly attenuated in the YC-1-treated group versus the control group (HIF-1alpha, VEGF: p < 0.01; nestin: p < 0.05). GFAP expression was also effectively inhibited in the YC-1-treated group (p < 0.05). Immunohistochemical evaluations showed that GFAP-positive (GFAP+) cells in the YC-1-treated group were sparse in the peri-infarct area, while an immunofluorescence assay revealed that the number of VEGF+/GFAP+ and nestin+/GFAP+ reactive astrocytes were decreased in the YC-1-treated group (p < 0.05). These results demonstrate that HIF-1alpha suppression decreases the formation of reactive astrocytes and gliosis that occur following focal ischemia. PMID- 26064443 TI - CYP1B1 deficiency ameliorates obesity and glucose intolerance induced by high fat diet in adult C57BL/6J mice. AB - Cytochrome P450 1B1 (CYP1B1) expression increases in multi-potential mesenchymal stromal cells C3H10T1/2 during adipogenesis, which parallel with PPARgamma, a critical transcriptional factor in adipogenic process. To assess the role of CYP1B1 in fatty acid metabolism, adult C57BL/6J wild-type and CYP1B1 deficiency mice were fed with high fat diets (HFD) for 6 weeks. CYP1B1 deficiency attenuated HFD-induced obesity when compared with their wild type counterparts, and improve glucose tolerance. The reduction in body weight gain and white adipose tissue in CYP1B1 deficient mice exhibited coordinate decreases in fatty acid synthesis (PPARgamma, CD36, FAS, SCD-1) and increases in fatty acid oxidation (UCP-2, CPT 1a) when compared with wild type ones. Lower hepatocyte TG contents were consistent with hepatic Oil-Red-O staining in the CYP1B1 deficiency mice. AMPK, a nutrient sensors for energy homeostasis, was activated in both fat pad and liver by CYP1B1 deficiency. However, in vitro system, knock down CYP1B1 in C3H10T1/2 cells does not abolish adipogenesis induced by adipogenic agents IDM (Insulin, Dexamethasone, Methylisobutylxanthine). Our in vivo and in vitro findings of CYP1B1 deficiency in fat metabolism suggest a complex regulation network between CYP1B1 and energy homeostasis. PMID- 26064444 TI - MicroRNA-125-5p targeted CXCL13: a potential biomarker associated with immune thrombocytopenia. AB - BACKGROUND: Immune thrombocytopenia (ITP) is an acquired and autoimmune disease of adults and children characterized by decreased platelet production. CXC chemokine ligand-13 (CXCL13) participates in multiple immunological responses. However, it is still unknown the relationship between CXCL13 and ITP. METHODS: Plasma CXCL13 was detected in ITP (n = 30) children. CD4+ T cells was isolated from peripheral blood mononuclear cells (PBMCs) from healthy volunteers. Treated CD4+ T cells with dexamethasone and/or miR-125-5p mimic/inhibitor, to observe the regulation of CXCL13. RESULTS: Compared with controls, ITP children had elevated plasma CXCL13, the concentration of which was reduced after treatment. In vitro, dexamethasone decreased CXCL13 level in in dose- dependent and in time-dependent manner. MiR-125-5p mimic decreased CXCL13 level and miR-125-5p inhibitor increased CXCL13 level in CD4+ T cells. CXCL13 was implied to be target gene of miR-125-5p. MiR-125-5p inhibitor also canceled dexamethasone induced decrease of CXCL13. CONCLUSION: CXCL13 is the target gene of miR-125-5p, which is possibly involved in the pathological process of ITP. PMID- 26064445 TI - The role of metrics in studies of hearing and cognition. PMID- 26064446 TI - Biologically active, high levels of interleukin-22 inhibit hepatic gluconeogenesis but do not affect obesity and its metabolic consequences. AB - BACKGROUND: Interleukin-22 (IL-22), a cytokine with important functions in anti microbial defense and tissue repair, has been recently suggested to have beneficial effects in obesity and metabolic syndrome in some but not in other studies. Here, we re-examined the effects of IL-22 on obesity, insulin resistance, and hepatic glucose metabolism. RESULTS: Genetic deletion of IL-22 did not affect high-fat-diet (HFD)-induced obesity and insulin resistance. IL-22 transgenic mice with relatively high levels of circulating IL-22 (~600 pg/ml) were completely resistant to Concanavalin A-induced liver injury but developed the same degree of high fat diet (HFD)-induced obesity, insulin resistance, and fatty liver as the wild-type littermate controls. Similarly, chronic treatment with recombinant mouse IL-22 (rmIL-22) protein did not affect HFD-induced obesity and the associated metabolic syndrome. In vivo treatment with a single dose of rmIL-22 downregulated the hepatic expression of gluconeogenic genes and subsequently inhibited hepatic gluconeogenesis and reduced blood glucose levels both in HFD-fed and streptozotocin (STZ)-treated mice without affecting insulin production. In vitro exposure of mouse primary hepatocytes to IL-22 suppressed glucose production and the expression of gluconeogenic genes. These inhibitory effects were partially reversed by blocking STAT3 or the AMPK signaling pathway. CONCLUSION: Biologically active, high levels of IL-22 do not affect obesity and the associated metabolic syndrome. Acute treatment with IL-22 inhibits hepatic gluconeogenesis, which is mediated via the activation of STAT3 and AMPK in hepatocytes. PMID- 26064447 TI - The Pulmonary Vascular Research Institute and its future. PMID- 26064448 TI - Pulmonary hypertension in obstructive sleep apnea: is it clinically significant? A critical analysis of the association and pathophysiology. AB - The development of pulmonary hypertension is a poor prognostic sign in patients with obstructive sleep apnea (OSA) and affects both mortality and quality of life. Although pulmonary hypertension in OSA is traditionally viewed as a result of apneas and intermittent hypoxia during sleep, recent studies indicate that neither of these factors correlates very well with pulmonary artery pressure. Human data show that pulmonary hypertension in the setting of OSA is, in large part, due to left heart dysfunction with either preserved or diminished ejection fraction. Longstanding increased left heart filling pressures eventually lead to pulmonary venous hypertension. The combination of hypoxic pulmonary vasoconstriction and pulmonary venous hypertension with abnormal production of mediators will result in vascular cell proliferation and aberrant vascular remodeling leading to pulmonary hypertension. These changes are in many ways similar to those seen in other forms of pulmonary hypertension and suggest shared mechanisms. The majority of patients with OSA do not receive a diagnosis and are undertreated. Appreciating the high prevalence and understanding the mechanisms of pulmonary hypertension in OSA would lead to better recognition and management of the condition. PMID- 26064449 TI - Na(+)/H(+) exchange and hypoxic pulmonary hypertension. AB - Intracellular pH (pHi) homeostasis is key to the functioning of vascular smooth muscle cells, including pulmonary artery smooth muscle cells (PASMCs). Sodium hydrogen exchange (NHE) is an important contributor to pHi control in PASMCs. In this review, we examine the role of NHE in PASMC function, in both physiologic and pathologic conditions. In particular, we focus on the contribution of NHE to the PASMC response to hypoxia, considering both acute hypoxic pulmonary vasoconstriction and the development of pulmonary vascular remodeling and pulmonary hypertension in response to chronic hypoxia. Hypoxic pulmonary hypertension remains a disease with limited therapeutic options. Thus, this review explores past efforts at disrupting NHE signaling and discusses the therapeutic potential that such efforts may have in the field of pulmonary hypertension. PMID- 26064451 TI - Fatty acid metabolism in pulmonary arterial hypertension: role in right ventricular dysfunction and hypertrophy. AB - Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease in which an increase in pulmonary vascular resistance leads to increased afterload on the right ventricle (RV), causing right heart failure and death. Our understanding of the pathophysiology of RV dysfunction in PAH is limited but is constantly improving. Increasing evidence suggests that in PAH RV dysfunction is associated with various components of metabolic syndrome, such as insulin resistance, hyperglycemia, and dyslipidemia. The relationship between RV dysfunction and fatty acid/glucose metabolites is multifaceted, and in PAH it is characterized by a shift in utilization of energy sources toward increased glucose utilization and reduced fatty acid consumption. RV dysfunction may be caused by maladaptive fatty acid metabolism resulting from an increase in fatty acid uptake by fatty acid transporter molecule CD36 and an imbalance between glucose and fatty acid oxidation in mitochondria. This leads to lipid accumulation in the form of triglycerides, diacylglycerol, and ceramides in the cytoplasm, hallmarks of lipotoxicity. Current interventions in animal models focus on improving RV dysfunction through altering fatty acid oxidation rates and limiting lipid accumulation, but more specific and effective therapies may be available in the coming years based on current research. In conclusion, a deeper understanding of the complex mechanisms of the metabolic remodeling of the RV will aid in the development of targeted treatments for RV failure in PAH. PMID- 26064452 TI - Functional coupling of TRPV4, IK, and SK channels contributes to Ca(2+)-dependent endothelial injury in rodent lung. AB - Our previous work has shown that the increased lung endothelial permeability response to 14,15-epoxyeicosatrienoic acid (14,15-EET) in rat lung requires Ca(2+) entry via vanilloid type-4 transient receptor potential (TRPV4) channels. Recent studies suggest that activation of TRPV4 channels in systemic vascular endothelium prolongs agonist-induced hyperpolarization and amplifies Ca(2+) entry by activating Ca(2+)-activated K(+) (KCa) channels, resulting in vessel relaxation. Activation of endothelial KCa channels thus has potential to increase the electrochemical driving force for Ca(2+) influx via TRPV4 channels and to amplify permeability responses to TRPV4 activation in lung. To examine this hypothesis, we used Western blot analysis, electrophysiological recordings, and isolated-lung permeability measurements to document expression of TRPV4 and KCa channels and the potential for functional coupling. The results show that rat pulmonary microvascular endothelial cells express TRPV4 and 3 KCa channels of different conductances: large (BK), intermediate (IK), and small (SK3). However, TRPV4 channel activity modulates the IK and SK3, but not the BK, channel current density. Furthermore, the TRPV4-mediated permeability response to 14,15-EET in mouse lung is significantly attenuated by pharmacologic blockade of IK and SK3, but not BK, channels. Collectively, this functional coupling suggests that endothelial TRPV4 channels in rodent lung likely form signaling microdomains with IK and SK3 channels and that the integrated response dictates the extent of lung endothelial injury caused by 14,15-EET. PMID- 26064453 TI - What does the time constant of the pulmonary circulation tell us about the progression of right ventricular dysfunction in pulmonary arterial hypertension? AB - Compliance (C) and resistance (R) maintain a unique, inverse relationship in the pulmonary circulation, resulting in a constant characteristic time [Formula: see text] that has been observed in healthy subjects as well as patients with pulmonary arterial hypertension (PAH). However, little is known about the dependence of right ventricular (RV) function on the coupled changes in R and C in the context of this inverse relationship. We hypothesized three simple dependencies of RV ejection fraction (RVEF) on R and C. The first model (linear R) assumes a linear RVEF-R relation; the second (linear-C) assumes a linear RVEF C relation; and the third one combines the former two in a mixed linear model. We found that the linear-R model and the mixed linear model are in good agreement with clinical evidence. A conclusive validation of these models will require more clinical data. Longitudinal data in particular are needed to identify the time course of ventricular-vascular impairment in PAH. Simple models like the ones we present here, once validated, will advance our understanding of the mechanisms of RV failure, which could improve strategies to manage RV dysfunction in PAH. PMID- 26064454 TI - Acute effects of riociguat in borderline or manifest pulmonary hypertension associated with chronic obstructive pulmonary disease. AB - Riociguat is the first oral soluble guanylate cyclase stimulator shown to improve pulmonary hemodynamics in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH). This pilot study assessed the impact of a single dose of riociguat on hemodynamics, gas exchange, and lung function in patients with PH associated with chronic obstructive pulmonary disease (COPD). Adults with COPD-associated borderline or manifest PH (pulmonary vascular resistance > 270 dyn.s.cm(-5), mean pulmonary artery pressure >= 23 mmHg, ratio of forced expiratory volume in 1 second [FEV1] to forced vital capacity < 70%, and partial pressure of oxygen and carbon dioxide in arterial blood > 50 and <= 55 mmHg, respectively) received riociguat 1 or 2.5 mg during right heart catheterization. Twenty-two patients completed the study (11 men, 11 women, aged 56-82 years; 1-mg group: n = 10 [mean FEV1: 43.1%]; 2.5-mg group: n = 12 [mean FEV1: 41.2%]). Riociguat caused significant improvements (P < 0.01) from baseline in mean pulmonary artery pressure (1 mg: -3.60 mmHg [-11.44%]; 2.5 mg: 4.83 mmHg [-14.76%]) and pulmonary vascular resistance (1 mg: -58.32 dyn.s.cm(-5) [-15.35%]; 2.5 mg: -123.8 dyn.s.cm(-5) [-32.96%]). No relevant changes in lung function or gas exchange were observed. Single doses of riociguat were well tolerated and showed promising hemodynamic effects without untoward effects on gas exchange or lung function in patients with COPD-associated PH. Placebo controlled studies of chronic treatment with riociguat are warranted. PMID- 26064450 TI - Molecular and functional significance of Ca(2+)-activated Cl(-) channels in pulmonary arterial smooth muscle. AB - Increased peripheral resistance of small distal pulmonary arteries is a hallmark signature of pulmonary hypertension (PH) and is believed to be the consequence of enhanced vasoconstriction to agonists, thickening of the arterial wall due to remodeling, and increased thrombosis. The elevation in arterial tone in PH is attributable, at least in part, to smooth muscle cells of PH patients being more depolarized and displaying higher intracellular Ca(2+) levels than cells from normal subjects. It is now clear that downregulation of voltage-dependent K(+) channels (e.g., Kv1.5) and increased expression and activity of voltage-dependent (Cav1.2) and voltage-independent (e.g., canonical and vanilloid transient receptor potential [TRPC and TRPV]) Ca(2+) channels play an important role in the functional remodeling of pulmonary arteries in PH. This review focuses on an anion-permeable channel that is now considered a novel excitatory mechanism in the systemic and pulmonary circulations. It is permeable to Cl(-) and is activated by a rise in intracellular Ca(2+) concentration (Ca(2+)-activated Cl(-) channel, or CaCC). The first section outlines the biophysical and pharmacological properties of the channel and ends with a description of the molecular candidate genes postulated to encode for CaCCs, with particular emphasis on the bestrophin and the newly discovered TMEM16 and anoctamin families of genes. The second section provides a review of the various sources of Ca(2+) activating CaCCs, which include stimulation by mobilization from intracellular Ca(2+) stores and Ca(2+) entry through voltage-dependent and voltage-independent Ca(2+) channels. The third and final section summarizes recent findings that suggest a potentially important role for CaCCs and the gene TMEM16A in PH. PMID- 26064455 TI - Sildenafil versus nitric oxide for acute vasodilator testing in pulmonary arterial hypertension. AB - Vasoreactivity testing with inhaled NO is recommended for pulmonary arterial hypertension (PAH) because of its therapeutic and prognostic value. Sildenafil has acute pulmonary vasodilating properties, but its diagnostic and prognostic impact in PAH is unknown. Our objective was to compare acute vasodilating responses to sildenafil and those to NO during right heart catheterization and also their prognostic values in patients with PAH. Ninety-nine patients with idiopathic PAH and 99 with associated PAH underwent vasoreactivity testing with NO and sildenafil. Only mild adverse effects of sildenafil, in the form of hypotension, were observed, at a rate of 4.5%. The acute responder rate was 8.1% for NO and 11.6% for sildenafil. The NO-induced response in mean pulmonary arterial pressure and cardiac output correlated with the response to sildenafil. Thirteen patients were long-term responders to calcium channel blockers (CCBs), and 3 of them were correctly identified by acute vasoreactivity test with both drugs. The specificity of the vasoreactivity test for identifying long-term CCB responders was 88.9% for NO and 85.1% for sildenafil testing. A trend toward better survival was found in sildenafil and NO responders, compared with nonresponders. Use of sildenafil for vasoreactivity testing is safe. Sildenafil may be useful as alternative vasoreactivity-testing agent, identifying the same number of long-term CCB responders as NO. However, NO seems to be a more ideal testing drug because of its pharmacologic properties. Moreover, sildenafil vasoreactivity testing might contribute to an improved estimate of prognosis among patients with PAH. PMID- 26064456 TI - Prevalence of coronary artery-pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension. AB - This study sought to determine the prevalence of coronary artery-pulmonary artery collaterals in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to correlate their presence with the degree of clot burden. CTEPH is a treatable cause of severe pulmonary hypertension and right heart failure. Bronchopulmonary collateral vessels have been used as a supplementary diagnostic and prognostic tool for this disease. Coronary artery-pulmonary artery collaterals in this population have not been described. The coronary angiograms of 300 consecutive patients with CTEPH evaluated for pulmonary thromboendarterectomy (PTE) between January 1, 2007, and May 1, 2014, were examined. Of these patients, 259 (50% male; mean age, 58.3 +/- 10.6 years) had cineangiographic images deemed adequate to definitively assess for the presence of coronary artery-pulmonary artery collaterals and were included in the final analyses. Pulmonary angiogram reports were reviewed for extent of pulmonary artery obstruction. The coronary angiograms of 259 age- and sex-matched control patients were also examined. Among 259 CTEPH patients with definitive imaging, 34 coronary artery-pulmonary artery collaterals were found in 28 patients (10.8%), versus 1 coronary artery-pulmonary artery collateral among control subjects (0.4%; P < 0.001). Compared with CTEPH patients without collaterals, patients with collaterals had a significantly higher prevalence of total occlusion of their right or left main pulmonary artery (P < 0.001) or lobar arteries (P < 0.001). In conclusion, the prevalence of coronary artery-pulmonary artery collaterals in CTEPH patients undergoing coronary angiography for possible PTE is approximately 11%. These vessels are associated with more severe pulmonary artery occlusion. PMID- 26064457 TI - Central venous line complications with chronic ambulatory infusion of prostacyclin analogues in pediatric patients with pulmonary arterial hypertension. AB - Chronic infusion of prostacyclin (PGI2) via a Broviac central venous line (CVL) is attended by risk of CVL-related complications, but we know of only one report regarding CVL-associated bloodstream infection (BSI) with PGI2 in children and none regarding other complications. We conducted a retrospective cohort study involving pediatric patients with pulmonary hypertension treated with chronic intravenous infusion of PGI2 at Boston Children's Hospital and determined the rate (per 1,000 line-days) of various CVL-related complications. We also determined how often complications necessitated line replacement and hospitalization, time to replacement of CVLs, and interpatient variability in the incidence of complications. From 1999 until 2014, 26 patients meeting follow-up criteria had PGI2 infusion, representing 43,855 line-days; mean follow-up was 56 months (range, 1.4-161 months). The CVL complication rates (per 1,000 line-days) were as follows: CVL-BSI, 0.25; superficial line infection, 0.48; impaired integrity, 0.59; occlusion, 0.09; and malposition, 0.32. The total complication rate was 1.73 cases per 1,000 line-days. All CVL-BSI and malposition cases were treated with CVL removal and replacement. Of CVLs with impaired integrity, 23 could be repaired and 3 required replacement. Six of 21 superficial CVL infections required replacement of the CVL. Three of 4 occluded CVLs were replaced. CVL complications occasioned 65 hospitalizations. There was marked interpatient variability in the rate of complications, much but not all of which appeared to be related to duration of CVL placement. We conclude that non-BSI complications are very significant and that efforts to teach and emphasize other aspects of line care are therefore very important. PMID- 26064458 TI - Right ventricular remodeling in idiopathic and scleroderma-associated pulmonary arterial hypertension: two distinct phenotypes. AB - Patients with scleroderma (SSc)-associated pulmonary arterial hypertension (PAH) have worse survival than patients with idiopathic PAH (IPAH). We hypothesized that the right ventricle (RV) adapts differently in SSc-PAH versus IPAH. We used cardiac magnetic resonance imaging (cMRI) and hemodynamic characteristics to assess the relationship between RV morphology and RV load in patients with SSc PAH and IPAH. In 53 patients with PAH (35 with SSc-PAH and 18 with IPAH) diagnosed by right heart catheterization (RHC), we examined cMRIs obtained within 48 hours of RHC and compared RV morphology between groups. Regression analysis was used to assess the association between diagnosis (IPAH vs. SSc-PAH) and RV measurements after adjusting for age, sex, race, body mass index (BMI), left ventricular (LV) mass, and RV load. There were no significant differences in unadjusted comparisons of cMRI measurements between the two groups. Univariable regression showed RV mass index (RVMI) was linearly associated with measures of RV load in both the overall cohort and within each group. Multivariable linear regression models revealed a significant interaction between disease type and RVMI adjusting for pulmonary vascular resistance (PVR), age, sex, race, BMI, and LV mass. This model showed a decreased slope in the relationship between RVMI and PVR in the SSc-PAH group compared with the IPAH group. RVMI varies linearly with measures of RV load. After adjusting for multiple potential confounders, patients with SSc-PAH demonstrated significantly less RV hypertrophy with increasing PVR than patients with IPAH. This difference in adaptive hypertrophy may in part explain previously observed decreased contractility and poorer survival in SSc PAH. PMID- 26064459 TI - A nonmuscle myosin light chain kinase-dependent gene signature in peripheral blood mononuclear cells is linked to human asthma severity and exacerbation status. AB - Asthma is increasingly recognized as a heterogeneous disease influenced by complex genetic and environmental contributions. Myosin light chain kinase (MLCK; gene symbol, MYLK), especially the nonmuscle isoform nmMLCK, is a cytoskeleton protein known to be related to human asthma susceptibility and severity, findings confirmed in preclinical models of asthmatic inflammation. In this study, we define the central capacity for a nmMLCK-influenced gene signature in human peripheral blood mononuclear cells to predict human asthma severity and exacerbation status. We refined this signature from a list of nmMLCK-influenced genes identified in lung tissues of nmMLCK knockout mice exposed to inflammatory stimuli (ventilator-induced lung injury), with subsequent identification of nmMLCK-influenced genes in a list of human asthma severity-related genes expressed in blood. The enriched nmMLCK-influenced gene signature successfully predicted human asthma severity and exacerbation status in both discovery and validation human asthma cohorts. These findings validate the central role played by nmMLCK in asthma susceptibility, severity, and exacerbation and further provide novel gene signatures as effective asthma biomarkers for severity, exacerbation, and prognosis. PMID- 26064460 TI - Trends in pediatric pulmonary hypertension-related hospitalizations in the United States from 2000-2009. AB - There are few data on the epidemiology of pulmonary hypertension (PH)-related hospitalizations in children in the United States. Our aim was to determine hospital mortality, length of hospitalization, and hospital charges pertaining to PH-related hospitalizations and also the effects of codiagnoses and comorbidities. A retrospective review of the Kids' Inpatient Database during the years 2000, 2003, 2006, and 2009 was analyzed for patients <=20 years of age with a diagnosis of PH by ICD-9 (International Classification of Diseases, Ninth Revision) codes, along with associated diagnoses and comorbidities. Descriptive statistics, including Rao-Scott chi(2), ANOVA, and logistic regression models, were utilized on weighted values with survey analysis procedures. The number of PH-related hospital admissions is rising, from an estimated 7,331 (95% confidence interval [CI]: 5,556-9,106) in 2000 to 10,792 (95% CI: 8,568-13,016) in 2009. While infant age and congenital heart disease were most commonly associated with PH-related hospitalizations, they were not associated with mortality. Overall mortality for PH-related hospitalizations was greater than that for hospitalizations not associated with PH, 5.7% versus 0.4% (odds ratio: 16.22 [95% CI: 14.78%-17.8%], P < 0.001), but mortality is decreasing over time. Sepsis, respiratory failure, acute renal failure, hepatic insufficiency, arrhythmias, and the use of extracorporeal membrane oxygenation are associated with mortality. The number of PH-related hospitalizations is increasing in the United States. The demographics of PH in this study are evolving. Despite the increasing prevalence, mortality is improving. PMID- 26064461 TI - Severe pulmonary arterial hypertensive rats are tolerant to mild exercise. AB - A frequently used end point of clinical outcomes in patients with pulmonary arterial hypertension (PAH) is the 6-minute walk distance. Furthermore, some data suggest that mild to moderate exercise as an intervention in stable PAH is beneficial. Some of these questions have been recapitulated in the monocrotaline and hypoxia animal models of pulmonary hypertension. However, mild exercise and walk distance as end points have not been rigorously examined in the severe progressive Sugen 5416/hypoxia/normoxia (Su/Hx/Nx) animal model of PAH at each stage of worsening disease. Our hypothesis was that animals that were preselected as runners would have increased walk times and improved right ventricle/left ventricle plus septum (RV/LV+S) ratios, echocardiography, and histology compared with nonexercised Su/Hx/Nx animals. We examined four groups of rats: Su/Hx/Nx sedentary, Su/Hx/Nx exercised, control sedentary, and control exercised. Echocardiography was performed at 5, 8, and 13 weeks to assess right ventricular inner diameter in diastole and left ventricular eccentricity index. We found no difference between exercised and sedentary Su/Hx/Nx rats, and both were worsened compared with controls. Rats were euthanized at 13 weeks, and we found that neither RV/LV+S nor the occurrence of occlusive lesions were influenced by exercise. Most interesting, however, was that despite progressive PAH development, exercised Su/Hx/Nx rats showed no decrease in time or distance for treadmill exercise. In all, our data suggest that, despite severe PAH development, Su/Hx/Nx rats retain the same treadmill exercise capacity as control animals. PMID- 26064463 TI - Survival in an incident cohort of patients with pulmonary arterial hypertension in Denmark. AB - We aimed to characterize and estimate survival rates in patients diagnosed with pulmonary arterial hypertension (PAH) in western Denmark in the modern management era. All incident cases of PAH were consecutively enrolled in our single-center prospective cohort study between January 2000 and March 2012. A total of 134 patients fulfilling the inclusion criteria were followed up from first diagnostic right heart catheterization to either death or the end of the study. Kaplan-Meier survival analysis was used to estimate 1-, 3-, and 5-year survival rates with 95% confidence intervals (CIs). Survival in the total cohort was 86.4% (95% CI, 79.3% 91.2%) after 1 year, 72.9% (95% CI, 64.1%-79.9%) after 3 years, and 65.4% (95% CI, 55.8%-73.4%) after 5 years. Significantly better survival was seen in the group of patients with PAH associated with congenital heart disease than in the group of patients with idiopathic PAH, heritable PAH, connective tissue disease, HIV infection, and portal hypertension. In conclusion, survival rates in the Danish PAH population were similar to or slightly better than survival rates estimated in other modern registries. However, PAH remains a fatal disease, despite modern targeted therapies. PMID- 26064462 TI - Use of pulmonary arterial hypertension-approved therapy in the treatment of non group 1 pulmonary hypertension at US referral centers. AB - Pulmonary hypertension (PH) is a frequent complication of left heart disease and parenchymal lung disease, and it portends increased mortality. A growing number of medications are approved for the treatment of World Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH). However, they are not well studied in PH of other etiologies (WHO groups 2-5). We sought to assess treatment approaches used by PAH referral centers in this diverse group of patients. We developed a semiquantitative online survey designed to evaluate the use of PAH approved therapy by pulmonary vascular disease centers in the United States for management of non-group 1 PH. Thirty of 50 centers completed the survey. Almost all centers (93%) reported using PAH therapy for patients with non-group 1 PH, including 77% with group 2 PH and 80% with group 3 PH. Elevated transpulmonary gradient or pulmonary vascular resistance and the presence of right ventricular (RV) dysfunction were commonly cited as supporting use of PAH therapy in patients with PH secondary to left heart disease. For patients with PH and concomitant parenchymal lung disease, degree of pulmonary function impairment and RV dysfunction were most important in influencing use of PAH therapy. In conclusion, pulmonary vascular disease treatment centers use PAH-approved therapy for patients with WHO group 2-5 PH, mostly relying on hemodynamics and assessment of RV function to identify candidates for therapy. Clinical trials designed to test the efficacy of PAH therapy in PH due to left heart and lung disease are needed, as clinical practice has extended beyond the evidence for these etiologies of PH. PMID- 26064464 TI - Abnormal right ventricular relaxation in pulmonary hypertension. AB - Left ventricular diastolic dysfunction is a well-described complication of systemic hypertension. However, less is known regarding the effect of chronic pressure overload on right ventricular (RV) diastolic function. We hypothesized that pulmonary hypertension (PHT) is associated with abnormal RV early relaxation and that this would be best shown by invasive pressure measurement. Twenty-five patients undergoing right heart catheterization for investigation of breathlessness and/or suspected PHT were studied. In addition to standard measurements, RV pressure was sampled with a high-fidelity micromanometer, and RV pressure/time curves were analyzed. Patients were divided into a PHT group and a non-PHT group on the basis of a derived mean pulmonary artery systolic pressure of 25 mmHg. Eleven patients were classified to the PHT group. This group had significantly higher RV minimum diastolic pressure ([Formula: see text] vs. [Formula: see text] mmHg, [Formula: see text]) and RV end-diastolic pressure (RVEDP; [Formula: see text] vs. [Formula: see text] mmHg, [Formula: see text]), and RV tau was significantly prolonged ([Formula: see text] vs. [Formula: see text] ms, [Formula: see text]). There were strong correlations between RV tau and RV minimum diastolic pressure ([Formula: see text], [Formula: see text]) and between RV tau and RVEDP ([Formula: see text], [Formula: see text]). There was a trend toward increased RV contractility (end-systolic elastance) in the PHT group ([Formula: see text] vs. [Formula: see text] mmHg/mL, [Formula: see text]) and a correlation between RV systolic pressure and first derivative of maximum pressure change ([Formula: see text], [Formula: see text]). Stroke volumes were similar. Invasive measures of RV early relaxation are abnormal in patients with PHT, whereas measured contractility is static or increasing, which suggests that diastolic dysfunction may precede systolic dysfunction. Furthermore, there is a strong association between measures of RV relaxation and RV filling pressures. PMID- 26064465 TI - Participant expectations in pulmonary hypertension-related research studies. AB - The Pulmonary Hypertension Association (PHA) is a patient advocacy organization seeking to find ways to prevent, improve treatment for, and cure pulmonary hypertension (PH) and to provide hope for the PH community through support, education, research, advocacy, and awareness. Many patients involved with PHA are also involved in various PH-specific research studies; however, the patient expectations and priorities for PH-specific research are currently unknown or not well examined. Our objective was to identify the current modes of study entry, priorities within research, and expectations over the course of study involvement for patient constituents of PHA. A 29-question online survey was designed by PHA and disseminated to the PHA patient constituency on its Facebook page through a post on November 29, 2012. Responses were collected on SurveyMonkey through December 10, 2012. Respondents were divided into parallel survey tracks, depending on whether the respondent indicated previous participation in research studies. These two cohorts of individuals were analyzed and, where appropriate, compared with tests of association. A total of 234 respondents were included in the final data analysis, with 95 (40.6%) reporting previous participation in research studies. These respondents reported an overall positive experience in their research studies (64.9% very good, 21.3% good, 12.8% neutral, 1.1% bad). Of the respondents with previous research study participation, 91.1% indicated that receipt of the study outcome after participation would positively influence their decision to participate in future research; despite this, only 41.17% reported receiving information of this sort after their participation. Research participation is a strong interest of PHA patient constituents; clear and consistent communication from the research team is an expectation of many participants. Despite this expectation, 58.83% of respondents indicated they did not receive communication from the research team after participation. This offers an opportunity not only to improve participants' experiences but also to increase the likelihood of future study participation. PMID- 26064467 TI - Case series of 5 patients with end-stage renal disease with reversible dyspnea, heart failure, and pulmonary hypertension related to arteriovenous dialysis access. AB - Patients with end-stage renal disease (ESRD) with arteriovenous dialysis access (AVDA) can develop symptoms of heart failure and pulmonary hypertension (PH). We report on 5 patients with ESRD and AVDA who presented with shortness of breath, heart failure, and PH. All patients had partial or complete closure of AVDA and were reevaluated after AVDA revision. All 5 subjects had clinical and echocardiographic evidence of heart failure, hypertensive heart disease, left ventricular diastolic dysfunction, and PH at baseline. After complete closure ([Formula: see text]) or partial banding ([Formula: see text]) of AVDA, mean New York Heart Association class improved from [Formula: see text] to [Formula: see text] ([Formula: see text]). Mean 6-minute walk distance improved from [Formula: see text] to [Formula: see text] m ([Formula: see text]). Serial echocardiography revealed a decrease in the right ventricle?left ventricle ratio from [Formula: see text] to [Formula: see text] ([Formula: see text]) and improved diastolic dysfunction parameters. On right heart catheterization before definitive AVDA revision, acute manual fistula or graft occlusion led to an average decrease in cardiac output of 1.1 L/min with no other changes in hemodynamics: [Formula: see text] to [Formula: see text] L/min ([Formula: see text]). However, the average decrease in cardiac output after definitive revision of the AVDA (mean, 90 days) was 4.0 L/min with marked improvements in biventricular filling pressures and pulmonary artery pressure. In patients with ESRD and AVDA presenting with heart failure and PH, revision or closure of AVDA can markedly improve dyspnea as well as the clinical, echocardiographic, and hemodynamic manifestations of heart failure and PH. PMID- 26064466 TI - Role played by Prx1-dependent extracellular matrix properties in vascular smooth muscle development in embryonic lungs. AB - Although there are many studies focusing on the molecular pathways underlying lung vascular morphogenesis, the extracellular matrix (ECM)-dependent regulation of mesenchymal cell differentiation in vascular smooth muscle development needs better understanding. In this study, we demonstrate that the paired related homeobox gene transcription factor Prx1 maintains the elastic ECM properties, which are essential for vascular smooth muscle precursor cell differentiation. We have found that Prx1(null) mouse lungs exhibit defective vascular smooth muscle development, downregulated elastic ECM expression, and compromised transforming growth factor (TGF)-beta localization and signaling. Further characterization of ECM properties using decellularized lung ECM scaffolds derived from Prx1 mice demonstrated that Prx1 is required to maintain lung ECM stiffness. The results of cell culture using stiffness-controlled 2-D and 3-D synthetic substrates confirmed that Prx1-dependent ECM stiffness is essential for promotion of smooth muscle precursor differentiation for effective TGF-beta stimulation. Supporting these results, both decellularized Prx1(null) lung ECM and Prx1(WT) (wild type) ECM scaffolds with blocked TGF-beta failed to support mesenchymal cell to 3-D smooth muscle cell differentiation. These results suggest a novel ECM-dependent regulatory pathway of lung vascular development wherein Prx1 regulates lung vascular smooth muscle precursor development by coordinating the ECM biophysical and biochemical properties. PMID- 26064468 TI - Selective pulmonary vasodilation improves ventriculovascular coupling and gas exchange in a patient with unrepaired single-ventricle physiology. AB - We describe a 63-year-old patient with unrepaired tricuspid valve atresia and a hypoplastic right ventricle (single-ventricle physiology) who presented with progressive symptomatic hypoxia. Her anatomy resulted in parallel pulmonary and systemic circulations, pulmonary arterial hypertension, and uncoupling of the ventricle/pulmonary artery. Hemodynamic and coupling data were obtained before and after pulmonary vasoactive treatment, first inhaled nitric oxide and later inhaled treprostinil. The coupling ratio (ratio of ventricular to vascular elastance) shunt fractions and dead space ventilation were calculated before and after treatment. Treatment resulted in improvement of the coupling ratio between the ventricle and the vasculature with optimization of stroke work, equalization of pulmonary and systolic flows, a decrease in dead space ventilation from 75% to 55%, and a significant increase in 6-minute walk distance and improved hypoxia. Inhaled treprostinil significantly increased 6-minute walk distance and improved hypoxia. This is the first report to show that pulmonary vasoactive treatment can be used in a patient with unrepaired single-ventricle anatomy and describes the hemodynamic effects of inhaled therapy on ventriculovascular coupling and gas exchange in the pulmonary circulation in this unique physiology. PMID- 26064469 TI - Platforms for publishing and archiving computer-aided research. AB - Computational models and methods take an ever more important place in modern scientific research. At the same time, they are becoming ever more complex, to the point that many such models and methods can no longer be adequately described in the narrative of a traditional journal article. Often they exist only as part of scientific software tools, which causes two important problems: (1) software tools are much more complex than the models and methods they embed, making the latter unnecessarily difficult to understand, (2) software tools depend on minute details of the computing environment they were written for, making them difficult to deploy and often completely unusable after a few years. This article addresses the second problem, based on the experience gained from the development and use of a platform specifically designed to facilitate the integration of computational methods into the scientific record. PMID- 25901275 TI - Student perception about working in rural United States/Canada after graduation: a study in an offshore Caribbean medical school. AB - INTRODUCTION: Rural residents of the United States (US) and Canada face problems in accessing healthcare. International medical graduates (IMGs) play an important role in delivering rural healthcare. IMGs from Caribbean medical schools have the highest proportion of physicians in primary care. Xavier University School of Medicines admits students from the US, Canada and other countries to the undergraduate medical (MD) course and also offers a premedical program. The present study was conducted to obtain student perception about working in rural US/Canada after graduation. METHODS: The study was conducted among premedical and preclinical undergraduate medical (MD) students during October 2014. The questionnaire used was modified from a previous study. Semester of study, gender, nationality, place of residence and occupation of parents were noted. Information about whether students plan to work in rural US/Canada after graduation, possible reasons why doctors are reluctant to work in rural areas, how the government can encourage rural practice, possible problems respondents anticipate while working in rural areas were among the topics studied. RESULTS: Ninety nine of the 108 students (91.7%) participated. Forty respondents were in favor of working in rural US/Canada after graduation. Respondents mentioned good housing, regular electricity, water supply, telecommunication facilities, and schools for education of children as important conditions to be fulfilled. The government should provide higher salaries to rural doctors, help with loan repayment, and provide opportunities for professional growth. Potential problems mentioned were difficulty in being accepted by the rural community, problems in convincing patients to follow medical advice, lack of exposure to rural life among the respondents, and cultural issues. CONCLUSIONS: About 40% of respondents would consider working in rural US/Canada. Conditions required to be fulfilled have been mentioned above. Graduates from Caribbean medical schools have a role in addressing rural physician shortage. Similar studies in other offshore Caribbean medical schools are required as Caribbean IMGs make an important contribution to the rural US and Canadian health workforce. PMID- 25977753 TI - Ant-App-DB: a smart solution for monitoring arthropods activities, experimental data management and solar calculations without GPS in behavioral field studies. AB - Field studies on arthropod ecology and behaviour require simple and robust monitoring tools, preferably with direct access to an integrated database. We have developed and here present a database tool allowing smart-phone based monitoring of arthropods. This smart phone application provides an easy solution to collect, manage and process the data in the field which has been a very difficult task for field biologists using traditional methods. To monitor our example species, the desert ant Cataglyphis fortis, we considered behavior, nest search runs, feeding habits and path segmentations including detailed information on solar position and azimuth calculation, ant orientation and time of day. For this we established a user friendly database system integrating the Ant-App-DB with a smart phone and tablet application, combining experimental data manipulation with data management and providing solar position and timing estimations without any GPS or GIS system. Moreover, the new desktop application Dataplus allows efficient data extraction and conversion from smart phone application to personal computers, for further ecological data analysis and sharing. All features, software code and database as well as Dataplus application are made available completely free of charge and sufficiently generic to be easily adapted to other field monitoring studies on arthropods or other migratory organisms. The software applications Ant-App-DB and Dataplus described here are developed using the Android SDK, Java, XML, C# and SQLite Database. PMID- 26064472 TI - Case Report: Gollop-Wolfgang Complex in a 5 month old baby. AB - Skeletal dysplasias are disorders associated with a generalized abnormality in the skeleton. The Gollop-Wolfgang complex (GWC) is a limb deficiency disorder and an unusual limb malformation with highly variable manifestations. Here we report the interesting case of a 5-month old male baby from India with Gollop-Wolfgang Complex showing bifurcation of the right femur, ectrodactyly of both feet, ectrodactyly of left hand, syndactyly of right hand and unusual presentation of bilateral fibular agenesis and caudal (Sacrococcygeal) agenesis. The etiology of GWC in this 5 month old male baby could possibly be attributed to spontaneous gene mutation due to consanguineous marriage of his parents. The clinical, radiographic findings and the unusual presentation are presented in detail. PMID- 25844160 TI - Promoting self-management through adherence among heart failure patients discharged from rural hospitals: a study protocol. AB - Background Heart failure is one of the most prevalent chronic conditions in adults, leading to prolonged morbidity, repeated hospitalizations, and placing tremendous economic burden on the healthcare system. Heart failure patients discharged from rural hospitals, or primarily critical access hospitals, have higher 30-day readmission and mortality rates compared to patients discharged from urban hospitals. Self-management improves heart failure patients' health outcomes and reduces re-hospitalizations, but adherence to self-management guidelines is low. We propose a home based post-acute care service managed by advanced practice nurses to enhance patient activation and lead to the improvement of self-management adherence in heart failure patients discharged from rural hospitals. Objective This article describes the study design and research methods used to implement and evaluate the intervention. Method Our intervention is a 12-week patient activation (Patient AcTivated Care at Home [PATCH]) to improve self-management adherence. Patients were randomized into two parallel groups (12-week PATCH intervention + usual care vs. usual care only) to evaluate the effectiveness of this intervention. Outcomes were measured at baseline, 3 and 6 months. Discussion This study aimed to examine the effectiveness of a rural theory based, advance practice nurse led, activation enhancing intervention on the self-management adherence in heart failure patients residing in rural areas. Our expectation is to facilitate adherence to self management behaviors in heart failure patients following discharge from rural hospitals and decrease complications and hospital readmissions, leading to the reduction of economic burden. CLINICAL TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov; https://register.clinicaltrials.gov/ NCT01964053. PMID- 26064475 TI - Ocular disconjugacy cannot be measured without establishing a solid reference. AB - This correspondence points out a need for clarification concerning the methodology utilized in the study "Eye tracking detects disconjugate eye movements associated with structural traumatic brain injury and concussion", recently published in Journal of Neurotrauma. The authors of the paper state that binocular eye movements were recorded using a single-camera video-oculography technique and that binocular disconjugate characteristics were analyzed without calibration of eye orientation. It is claimed that a variance-based disconjugacy metric was found to be sensitive to the severity of a concussive brain injury and to the status of recovery after the original injury. However, the reproducibility of the paper's findings may be challenged simply by the paucity of details in the methodological description. More importantly, from the information supplied or cited in the paper, it is difficult to evaluate the validity of the potentially interesting conclusions of the paper. PMID- 25901277 TI - The endothelial deprotection hypothesis for lupus pathogenesis: the dual role of C1q as a mediator of clearance and regulator of endothelial permeability. AB - Systemic lupus erythematosus (SLE) is a heterogeneous multifactorial systemic autoimmune disease affecting several organs. SLE can start relatively early in life and results in impaired quality of life and shortened life expectancy because of a gradual disease progression leading to cardiovascular, renal and neoplastic disease. The basic mechanisms of the pathogenesis of the disease still remain to be clarified. It is clear that complement proteins play a key and complex role in the development of SLE. Complement component C1q has been known to be a fundamental component of lupus development, but most explanations focus on its role in apoptotic debris removal. Importantly, C1q was recently found to play a key role in the maintenance of vascular endothelial integrity. We suggest that apoptotic products, endothelial cells and extracellular matrix components, which display negatively charged moieties, compete for binding to molecules of the innate humoral immune response, like C1q. Genetic or acquired factors leading to an increased load of apoptotic cell debris and decrease or absence of C1q therefore interfere with the regulation of endothelial permeability and integrity. Furthermore, we suggest that lupus is the net result of an imbalance between the two functions of immune clearance and vascular endothelial integrity maintenance, an imbalance triggered and sustained by autoimmunity, which skews C1q consumption by IgG-mediated complement classical pathway activation on autoantigens. In this triangle of innate clearance, autoimmunity and endothelial integrity, C1q plays a central role. Hence, we interpret the pathogenesis of lupus by identifying three key components, namely innate immune clearance, autoimmunity and endothelial integrity and we establish a link between these components based on the protective role that innate clearance molecules play in endothelial renewal. By including the vasoprotective role of C1q in the interpretation of SLE development we attempt to provide novel explanations for the symptoms, organ damage, diagnostic and therapeutic difficulties of the disease. PMID- 26064476 TI - Design and conduct of Xtreme Everest 2: An observational cohort study of Sherpa and lowlander responses to graduated hypobaric hypoxia. AB - OBJECTIVE: Oxygen availability falls with ascent to altitude and also as a consequence of critical illness. Because cellular sequelae and adaptive processes may be shared in both circumstances, high altitude exposure ('physiological hypoxia') assists in the exploration of the response to pathological hypoxia. We therefore studied the response of healthy participants to progressive hypobaric hypoxia at altitude. The primary objective of the study was to identify differences between high altitude inhabitants (Sherpas) and lowland comparators. METHODS: We performed an observational cohort study of human responses to progressive hypobaric hypoxia (during ascent) and subsequent normoxia (following descent) comparing Sherpas with lowlanders. Studies were conducted in London (35m), Kathmandu (1300m), Namche Bazaar (3500m) and Everest Base Camp (5300m). Of 180 healthy volunteers departing from Kathmandu, 64 were Sherpas and 116 were lowlanders. Physiological, biochemical, genetic and epigenetic data were collected. Core studies focused on nitric oxide metabolism, microcirculatory blood flow and exercise performance. Additional studies performed in nested subgroups examined mitochondrial and metabolic function, and ventilatory and cardiac variables. Of the 180 healthy participants who left Kathmandu, 178 (99%) completed the planned trek. Overall, more than 90% of planned testing was completed. Forty-four study protocols were successfully completed at altitudes up to and including 5300m. A subgroup of identical twins (all lowlanders) was also studied in detail. CONCLUSION: This programme of study (Xtreme Everest 2) will provide a rich dataset relating to human adaptation to hypoxia, and the responses seen on re-exposure to normoxia. It is the largest comprehensive high altitude study of Sherpas yet performed. Translational data generated from this study will be of relevance to diseases in which oxygenation is a major factor. PMID- 26064477 TI - Blockade or deletion of transient receptor potential vanilloid 4 (TRPV4) is not protective in a murine model of sepsis. AB - Sepsis is a systemic inflammatory response triggered by microbial infection that can cause cardiovascular collapse, insufficient tissue perfusion and multi-organ failure. The cation channel transient receptor potential vanilloid 4 (TRPV4) is expressed in vascular endothelium and causes vasodilatation, but excessive TRPV4 activation leads to profound hypotension and circulatory collapse - key features of sepsis pathogenesis. We hypothesised that loss of TRPV4 signaling would protect against cardiovascular dysfunction in a mouse model of sepsis (endotoxaemia). Multi-parameter monitoring of conscious systemic haemodynamics (by radiotelemetry probe), mesenteric microvascular blood flow (laser speckle contrast imaging) and blood biochemistry (iSTAT blood gas analysis) was carried out in wild type (WT) and TRPV4 knockout (KO) mice. Endotoxaemia was induced by a single intravenous injection of lipopolysaccharide (LPS; 12.5 mg/kg) and systemic haemodynamics monitored for 24 h. Blood flow recording was then conducted under terminal anaesthesia after which blood was obtained for haematological/biochemical analysis. No significant differences were observed in baseline haemodynamics or mesenteric blood flow. Naive TRPV4 KO mice were significantly acidotic relative to WT counterparts. Following induction of sepsis, all mice became significantly hypotensive, though there was no significant difference in the degree of hypotension between TRPV4 WT and KO mice. TRPV4 KO mice exhibited a higher sepsis severity score. While septic WT mice became significantly hypernatraemic relative to the naive state, this was not observed in septic KO mice. Mesenteric blood flow was inhibited by topical application of the TRPV4 agonist GSK1016790A in naive WT mice, but enhanced 24 h following LPS injection. Contrary to the initial hypothesis, loss of TRPV4 signaling (either through gene deletion or pharmacological antagonism) did not attenuate sepsis-induced cardiovascular dysfunction: in fact, pathology appeared to be modestly exaggerated in mice lacking TRPV4. Local targeting of TRPV4 signalling may be more beneficial than global inhibition in sepsis treatment. PMID- 26064479 TI - Promiscuity progression of bioactive compounds over time. AB - In the context of polypharmacology, compound promiscuity is rationalized as the ability of small molecules to specifically interact with multiple targets. To study promiscuity progression of bioactive compounds in detail, nearly 1 million compounds and more than 5.2 million activity records were analyzed. Compound sets were assembled by applying different data confidence criteria and selecting compounds with activity histories over many years. On the basis of release dates, compounds and activity records were organized on a time course, which ultimately enabled monitoring data growth and promiscuity progression over nearly 40 years, beginning in 1976. Surprisingly low degrees of promiscuity were consistently detected for all compound sets and there were only small increases in promiscuity over time. In fact, most compounds had a constant degree of promiscuity, including compounds with an activity history of 10 or 20 years. Moreover, during periods of massive data growth, beginning in 2007, promiscuity degrees also remained constant or displayed only minor increases, depending on the activity data confidence levels. Considering high-confidence data, bioactive compounds currently interact with 1.5 targets on average, regardless of their origins, and display essentially constant degrees of promiscuity over time. Taken together, our findings provide expectation values for promiscuity progression and magnitudes among bioactive compounds as activity data further grow. PMID- 26064478 TI - Why are enteric ganglia so small? Role of differential adhesion of enteric neurons and enteric neural crest cells. AB - The avian enteric nervous system (ENS) consists of a vast number of unusually small ganglia compared to other peripheral ganglia. Each ENS ganglion at mid gestation has a core of neurons and a shell of mesenchymal precursor/glia-like enteric neural crest (ENC) cells. To study ENS cell ganglionation we isolated midgut ENS cells by HNK-1 fluorescence-activated cell sorting (FACS) from E5 and E8 quail embryos, and from E9 chick embryos. We performed cell-cell aggregation assays which revealed a developmentally regulated functional increase in ENS cell adhesive function, requiring both Ca (2+) -dependent and independent adhesion. This was consistent with N-cadherin and NCAM labelling. Neurons sorted to the core of aggregates, surrounded by outer ENC cells, showing that neurons had higher adhesion than ENC cells. The outer surface of aggregates became relatively non-adhesive, correlating with low levels of NCAM and N-cadherin on this surface of the outer non-neuronal ENC cells. Aggregation assays showed that ENS cells FACS selected for NCAM-high and enriched for enteric neurons formed larger and more coherent aggregates than unsorted ENS cells. In contrast, ENS cells of the NCAM-low FACS fraction formed small, disorganised aggregates. This suggests a novel mechanism for control of ENS ganglion morphogenesis where i) differential adhesion of ENS neurons and ENC cells controls the core/shell ganglionic structure and ii) the ratio of neurons to ENC cells dictates the equilibrium ganglion size by generation of an outer non-adhesive surface. PMID- 26064480 TI - The predictive value of albuminuria for renal and nonrenal natural deaths over 14 years follow-up in a remote aboriginal community. AB - BACKGROUND: Australian aboriginal people living in remote regions have extraordinary higher rates of mortality compared with other Australian ethnicities. Albuminuria marks the underlying renal disease. This study assessed the predictive value of albuminuria for nonrenal and renal deaths in a remote Australian aboriginal community over a follow-up period of >14 years. METHODS: From 1992 to 1997, 85% of community members participated in a health screen, which included measurement of urine albumin/creatinine (ACR) levels. Deaths and dialysis initiations were recorded until 30 November 2010. The rates of natural nonrenal and renal deaths were assessed over a mean of 14 years in the 956 participants aged 18 years and over at baseline, and mortality associated with baseline levels of albuminuria (ACR >= 2.7 mg/mmol) was estimated. RESULTS: There were 203 natural deaths; 70 were renal deaths and 133 were nonrenal deaths, including 60 cardiovascular disease (CVD) deaths. Higher baseline ACR predicted all categories of natural death, with no apparent lower threshold for effect. Baseline ACR >= 2.7 mg/mmol predicted a 3.3-fold increase in all natural deaths, a 2-fold increase in nonrenal deaths and a 1.7-fold increase in CVD deaths, after adjustment for other factors. Eighty-nine percent (62 out of 70) of renal deaths occurred in those with ACR >= 34 at baseline, with a 24-fold increase in risk. Albuminuria (ACR >= 2.7 mg/mmol) contributed to 66% of risk for all natural deaths over the interval. CONCLUSIONS: Albuminuria was still a remarkable predictor for all-cause natural death over an average of 14 years follow-up interval in this aboriginal community. PMID- 26064481 TI - Gitelman syndrome and pregnancy. AB - Gitelman syndrome (GS) is an autosomal-recessive condition characterized by hypokalemia, hypomagnesemia and hypocalciuria. Very little information is available in the literature to guide the management of pregnant patients with GS. We report a case of a 27-year-old woman with GS who became pregnant and despite persistent hypokalemia and hypomagnesemia during pregnancy and labor, had a successful maternal and fetal outcome. PMID- 26064482 TI - Renal injury due to anti-glomerular basement membrane antibody-mediated glomerulonephritis without circulating antibody. PMID- 26064483 TI - Cinacalcet: the chemical parathyroidectomy? PMID- 26064484 TI - Balkan endemic nephropathy-current status and future perspectives. AB - Balkan endemic nephropathy (BEN), originally described in 1956, is a unique familial, chronic renal disease encountered with a high-prevalence rate in Serbia, Bulgaria, Romania, Croatia and Bosnia and Herzegovina. The most prominent features of the disease are its endemic nature, long-incubation period, familial clustering of the disease and an unusually high incidence of associated upper urothelial cancer (UUC). There are no clear-cut data on BEN incidence and prevalence, since the studies carried out in different endemic areas yielded contradictory information. In spite of intermittent variations, the incidence of new cases has remained stable over time. It has been estimated that almost 100 000 people are at risk of BEN, whereas 25 000 have the disease. The clinical signs and symptoms of BEN are non-specific and often remain unrecognized for years. There are no pathognomonic diagnostic features of BEN, but the set of epidemiological, clinical and biochemical data along with the pattern of pathologic injury in the absence of any other renal diseases are highly suggestive of this entity. Although the aetiology has been extensively studied, fostering the publication of various hypotheses, only one of them has provided conclusive evidence related to the aetiology of BEN. Studies conducted over the past decade have provided particularly strong arguments that BEN and UUC are caused by chronic poisoning with aristolochic acids (AAs). In light of these later studies, one can raise the question whether AAs could be responsible for previously and currently widespread unrecognized global renal disease and UUC. PMID- 26064485 TI - Renal involvement in idiopathic hypereosinophic syndrome. AB - The hypereosinophilic syndromes (HESs) are a group of disorders marked by the sustained overproduction of eosinophils, in which eosinophilic infiltration and mediator release cause damage to multiple organs. In idiopathic HES, the underlying cause of hypereosinophilia (HE) remains unknown despite thorough aetiological work-up. Kidney disease is thought to be rare in HES. Renal manifestations described include eosinophilic interstitial nephritis, various types of glomerulopathies, thrombotic microangiopathy (TMA) and electrolyte disturbances. The diagnosis must be made in time, because a recovery of renal function can be obtained if treatment is initiated promptly. PMID- 26064486 TI - Utilization of parathyroidectomy for secondary hyperparathyroidism in end-stage renal disease. AB - BACKGROUND: The utilization of parathyroidectomy (PTX) to manage secondary hyperparathyroidism (SHPT) refractory to medical management (MTX) in end-stage renal disease (ESRD) in the era of calcimimetics is not well known. METHODS: Adult ESRD patients receiving dialysis between August 2007 and December 2011 at our institution with an intact parathyroid hormone (iPTH) level >=88 pmol/L for 6 months associated with hypercalcemia and/or hyperphosphatemia for at least 50% of that period were included. Baseline characteristics and iPTH, calcium, phosphorus, calcium-phosphorus product and alkaline phosphatase (ALP) at baseline, 6 and 12 months were compared between the two groups (PTX versus MTX) using the chi (2) and paired t-tests. RESULTS: Of the total population of 687 patients, 80 (11.6%) satisfied KDOQI criteria for PTX, most of whom did not receive PTX (81.2%). At baseline, PTX patients had been on dialysis longer (P = 0.001), with higher iPTH (P < 0.001), calcium (P = 0.008) and ALP (P = 0.001) and were less likely to be African-American (P = 0.007). Complete follow-up data at 6 months were available on 75 patients (PTX = 15; MTX = 60). PTX had significantly greater reduction in iPTH (93 versus 23%) and ALP (68 versus 0%) compared with MTX. Changes from baseline in calcium, phosphate or calcium-phosphorus product levels and proportion of patients achieving KDOQI target values were not significant for either intervention. Findings were consistent at 12 months. CONCLUSIONS: A significant proportion of ESRD patients who met indications for PTX did not receive it. Additional studies are needed to understand the barriers that prevent patients from receiving PTX, thereby resulting in underutilization. PMID- 26064487 TI - Impact of sensitivity of human leucocyte antigen antibody detection by Luminex technology on graft loss at 1 year. AB - BACKGROUND: The clinical relevance of the detection of human leucocyte antigen (HLA) antibodies in sera of renal transplant recipients by highly sensitive methods such as Luminex alone is uncertain and a matter of debate. The choice of output thresholds affects antibody detection and thus organ allocation, yet there are no internationally agreed threshold levels. This study aims at evaluating our current practice of using an MFI threshold of 1000 in antibody detection. METHODS: We carried out a case-control study by looking at 761 renal transplant recipients at one unit between 2000 and 2010. Of these, there were 93 cases of graft loss within 1 year and stored serum samples of 40 cases were available for testing. Controls were selected (graft function >2 years) and individually matched according to age, sex, number of transplants and date of transplant. All 40 cases and 40 controls had negative crossmatch by complement-dependent cytotoxicity (CDC) at the time of transplant, and pre-transplant sera were re analysed for the presence of detectable HLA and donor-specific antibodies (DSAs) using Luminex screen and single-antigen beads and MFI threshold values of 1000, 2000 and 4000. RESULTS: In nearly 48% of cases with graft loss within a year, HLA antibodies were detectable by Luminex when using a 1000 MFI threshold. This was 25% greater than in controls (P = 0.017). There was also a 15% increase in detected DSAs; however, statistical significance depends on the inclusion or exclusion of one specific case. Using MFI thresholds of 2000 and 4000, no DSAs were found in any long-term surviving grafts. CONCLUSIONS: Selection of appropriate MFI cut-off values influences the detection of DSAs and, thus, organ allocation. Using a threshold of 1000 led to the detection of DSAs in 5% of long term graft survivors in our population and should be considered too sensitive. Using a detection threshold of 2000 is sufficiently sensitive and leads to clinically relevant detection of DSA. PMID- 26064488 TI - Adult-onset renal failure in a family with Alagille syndrome with proteinuria and a novel JAG1 mutation. AB - Alagille syndrome (AGS) is an autosomal-dominant multi-organ disorder involving the liver, heart, eyes, face and skeleton. In addition, various renal abnormalities have also been reported in several cases. We describe a patient with a novel frameshift mutation in exon 12 of the JAG1 gene who presented with chronic renal failure. In this family, five members of three generations had clinical features implicated in AGS. Three members had adult-onset renal dysfunction with proteinuria, and two of them required haemodialysis therapy. AGS should be considered in the differential diagnosis of proteinuric renal disease, even in adult patients. PMID- 26064489 TI - Gemella sanguinis endocarditis with c-ANCA/anti-PR-3-associated immune complex necrotizing glomerulonephritis with a 'full-house' pattern on immunofluorescence microscopy. AB - A 67-year-old man was evaluated for haematuria, with a rising creatinine level from 88 to 906 umol/L and positive c-anti-neutrophil cytoplasm antibody (ANCA)/anti-proteinase 3 (anti-PR3). A kidney biopsy revealed necrotizing glomerulonephritis with a 'full-house' pattern on immunofluorescence microscopy. Echocardiography and blood cultures growing Gemella sanguinis diagnosed endocarditis. Dialysis was required for a month. Three months later, following valve replacement, glucocorticoids and 2 months of antibiotic therapy, the creatinine level decreased to 62 umol/L and c-ANCA/anti-PR3 disappeared. This first case of c-ANCA/anti-PR3 positive glomerulonephritis with a 'full-house' immunofluorescence pattern due to bacterial endocarditis underlines the importance of ruling out infection with ANCA positivity or kidney biopsy suggestive of lupus nephritis. PMID- 26064490 TI - Nail-patella syndrome-a novel mutation in the LMX1B gene. AB - Nail-patella syndrome (NPS) is an autosomal-dominant pleiotropic disorder characterized by dyplasia of finger nails, skeletal anomalies and frequently renal disease. In the reported case, genetic analysis revealed a new missense mutation in the homeodomain of LMX1B, presumed to abolish DNA binding (c.725T>C, p.Val242Ala). A missense mutation at codon 725 was identified, where thymine was replaced by cytosine which led to the replacement of valine by alanine at position 242. It was not detected in both parents. A 2005 study by Bongers et al. described a significant association between the presence of clinically relevant renal involvement in an NPS patient and a positive family history of nephropathy, which was lacking in our case. PMID- 26064491 TI - Neutrophil extracellular trap components in fibrinoid necrosis of the kidney with myeloperoxidase-ANCA-associated vasculitis. AB - In response to antineutrophil cytoplasmic antibody (ANCA), activated neutrophils release decondensed chromatin associated with cytoplasmic granular proteins composed of proteolytic enzymes and myeloperoxidase (MPO); these complexes are named neutrophil extracellular traps (NETs). NET formation requires peptidylarginine deiminase 4 (PAD4) to citrullinate chromatin histones and also MPO and neutrophil elastase to aid in decondensation and release of chromatin. Immunostaining of renal biopsy revealed that NET components of citrullinated histone, MPO and PAD4 were concurrently deposited both around fibrinoid necrosis in necrotizing glomerulonephritis in the early focal phase of ANCA-associated polyangiitis and along an interlobular arterial wall. PMID- 26064492 TI - Henoch-Schonlein purpura in a renal transplant recipient with prior IgA nephropathy following influenza vaccination. AB - Henoch-Schonlein purpura (HSP) is a systemic small-vessel leucocytoclastic vasculitis with deposition of immune complexes containing Immunoglobulin A (IgA). IgA Nephropathy (IgAN) is a glomerulonephritis caused by mesangial deposition of IgA. The onset of HSP, but not IgAN, has been linked to influenza vaccination. We report the first case of HSP with glomerular involvement, in a renal transplant recipient following influenza vaccination. The patient had prior end-stage renal failure (ESRF) secondary to IgAN, without clinical evidence of IgAN recurrence after transplantation. This is of clinical relevance as influenza vaccination is regarded safe, effective, and recommended after renal transplantation. Nephrologists should be aware of the potential for influenza vaccination to have adverse effects in renal transplant recipients, especially if the primary renal disease is HSP or IgAN. PMID- 26064493 TI - Possible potassium chlorate nephrotoxicity associated with chronic matchstick ingestion. AB - We present a case of a 48-year-old active duty male soldier with a history of chronic exposure to potassium chlorate, later diagnosed with chronic interstitial nephritis. He reported regular matchstick consumption to prevent chigger (Trombicula autumnalis) bites, amounting to ~5.8 g of potassium chlorate over 3 years. Potassium chlorate can cause anuric renal failure within days of a toxic dose. Its slow excretion and mechanism of action suggest that renal toxicity may result from lower-dose chronic exposure. This case represents possible sequelae of chronic potassium chlorate ingestion. PMID- 26064494 TI - A case of triple pathology: seronegative anti-glomerular basement membrane antibody-mediated glomerulonephritis and membranous nephropathy in a patient with underlying diabetic kidney disease. AB - In diabetic patients with acute kidney injury (AKI), kidney biopsy often reveals non-diabetic kidney pathology. This case describes a patient with known Type 1 diabetes who presented with AKI, nephrotic syndrome and haematuria. Combination pathology of seronegative anti-glomerular basement membrane antibody-mediated glomerulonephritis (anti-GBM GN), membranous nephropathy (MN) and diabetic nephropathy (DN) was demonstrated. Strong linear GBM IgG-staining on biopsy with crescentic GN and clinical AKI led to a diagnosis of anti-GBM GN, although serum antibodies were not detectable. Features of DN, Kimmelstiel-Wilson nodules and albumin staining were also present, along with features of MN, such as subepithelial deposits on electron microscopy. Despite treatment with immunosuppression and plasmapheresis, there was no recovery of kidney function. Coexisting anti-GBM GN and MN is well recognized, but the concurrent diagnosis with DN has not been described. PMID- 26064495 TI - Synthetic marijuana and acute kidney injury: an unforeseen association. AB - Synthetic cannabinoids (SCs) have emerged as drugs of abuse with increasing popularity among young adults. The potential renal complication related to the abuse of SC was not recognized until recently. Here, we present a case of severe acute kidney injury (AKI) that developed after inhalation of SC in an otherwise healthy young patient. A kidney biopsy revealed severe acute tubular necrosis, and supportive management resulted in the recovery of the kidney function. Herein, we briefly summarize the only two previous reports (a total of 21 cases) on the association between SC abuse and renal dysfunction and identify the common aspects in all observations. PMID- 26064496 TI - A deadly thorn prick. PMID- 26064497 TI - Presumed osteosarcoma. PMID- 26064498 TI - Foamy urine in nephrotic syndrome. PMID- 26064499 TI - Severe systemic calciphylaxis with culture-negative endocarditis. PMID- 26064500 TI - Purple urine bag syndrome. PMID- 26064501 TI - Kidney involvement by IgG4-related sclerosing disease. PMID- 26064502 TI - Acute poststreptococcal glomerulonephritis with acute interstitial nephritis related to streptococcal pyrogenic exotoxin B. PMID- 26064503 TI - MPGN secondary to Lyme disease: the role of cryoglobulins. PMID- 26064504 TI - Transposition of the great arteries and autosomal-dominant polycystic kidney disease. PMID- 26064505 TI - The increase in renal replacement therapy (RRT) incidence has come to an end in Sweden-analysis of variations by region over the period 1991-2010. AB - BACKGROUND: Renal replacement therapy (RRT) incidence has increased significantly in Sweden during the past decades. This study analyses variations in time and regional trends in RRT incidence in Sweden, adjusted for age and gender, focusing on the impact change in incidence during the last decade. METHODS: Using data from the Swedish Renal Registry (SRR) (21 counties in Sweden, total population 9 million), we identified all incident subjects starting RRT from 1991 through 2010. Only individuals alive following 90 days of RRT start were included. Gender and age-specific standardized RRT incidences on an annual and regional basis were calculated, and differences between counties and variations over time were examined. We compared the overall age and gender-adjusted RRT incidence rates for Sweden by calendar year. Furthermore, we also calculated the age and gender adjusted RRT incidence in each county during two time periods (1991-1999 versus 2000-2010). RESULTS: There were 20 172 new subjects treated with RRT between January 1991 and December 2010. The most common cause of end-stage renal disease (ESRD) was diabetes (24%) and hypertension/renal vascular disease (19%), followed by glomerulonephritis (16%). Sixty-four percent of new patients were male; the median age when commencing RRT was 66 years (10-90 percentiles; 39-80). The overall standardized RRT incidence reached its peak in 2000, and slowly decreased thereafter. A decrease in RRT incidence was observed over the study period in eight regions. The standardized RRT incidence varied between the different counties, from 0.82 to 1.19. CONCLUSIONS: Adjusted for demographic changes in the population, an overall decrease in RRT incidence was observed from the year 2000 onwards-suggesting that the previously reported steady increase in RRT incidence is coming to an end in Sweden. Noteworthy differences were found between counties and in 8 out of 21 counties, a decreased incidence of RRT was found. Further studies need to identify the factors that contribute to this decrease. PMID- 26064506 TI - Perceptive barriers to peritoneal dialysis implementation: an opinion poll among the French-speaking Belgian nephrologists. AB - Although peritoneal dialysis (PD) is recognized as an effective renal replacement therapy (RRT) alternative to haemodialysis (HD), its prevalence is around 15% in most of the industrialized countries. In the French-speaking part of Belgium, PD is clearly underused with a prevalence of 8.7% in 2009. The main objectives of this work were to evaluate the nephrologists' perceived obstacles to PD implementation and reflect on possible actions towards PD development. A computer based 33-item questionnaire was sent by e-mail to all nephrologists affiliated to the French-speaking association. Among 120 adult nephrologists targeted by this inquiry, 97 completed the online questionnaire (response rate 80.8%). Among them, 29% had little experience with PD (treating less than five patients) and 39% reported no specific training with this modality of RRT. However, 88% of responders claimed PD prevalence should be around 20-25%. Half of the responders would choose PD as a first RRT option if they required RRT for themselves. The three main reasons given to the low prevalence of PD were an easy access to HD, patient refusal and lack of nephrologist motivation. Almost all the nephrologists insisted on the need for a dedicated nursing team delivering an effective educational programme and PD management and care. They believe that PD could and should be implemented in Belgium. Enhanced nephrologist motivation and training in PD were identified as predominant factors to be upgraded, as well as patient education programmes. PMID- 26064507 TI - Erratum: Enigmatic pruritus in a kidney transplant patient. AB - [This corrects the article on p. 194 in vol. 6, PMID: 26019849.]. PMID- 26064509 TI - Hypertension in autosomal-dominant polycystic kidney disease (ADPKD). AB - Cardiovascular (CV) complications are the major cause of death in autosomal dominant polycystic kidney disease (ADPKD) patients. Hypertension is common in these patients even before the onset of renal insufficiency. Blood pressure (BP) elevation is a key factor in patient outcome, mainly owing to the high prevalence of target organ damage together with a poor renal prognosis when BP is increased. Many factors have been implicated in the pathogenesis of hypertension, including the renin-angiotensin-aldosterone system (RAAS) stimulation. Polycystin deficiency may also contribute to hypertension because of its potential role in regulating the vascular tone. Early diagnosis and treatment of hypertension improve the CV and renal complications of this population. Ambulatory BP monitoring is recommended for prompt diagnosis of hypertension. CV risk assessment is mandatory. Even though a nonpharmacological approach should not be neglected, RAAS inhibitors are the cornerstone of hypertension treatment. Calcium channel blockers (CCBs) should be avoided unless resistant hypertension is present. The BP should be <140/90 mmHg in all ADPKD patients and a more intensive control (<135/85 mmHg) should be pursued as soon as microalbuminuria or left ventricle hypertrophy is present. PMID- 26064510 TI - Minimal-change disease in adolescents and adults: epidemiology and therapeutic response. AB - BACKGROUND: Epidemiology of minimal-change disease (MCD) in adults differs from that in children and is not studied well in Indian population. METHODS: We retrospectively studied the records of 61 adult patients with MCD to assess clinical, laboratory and histopathological features, and to evaluate the response to treatment, course and complications of the disease and therapy. RESULTS: The male to female ratio was 1.17:1. Mean age was 30.46 years. Of the total, 6.55% had hypertension; 13.11% had microhaematuria. After initial treatment with steroids, 68.85% had complete remission (CR) and 13.1% had partial remission (PR). Twelve of 14 (85.71%) steroid-resistant cases had CR or PR after alternative immunosuppression with cyclophosphamide, or mycophenolate mofetil. Of all patients, 44.2% had at least one relapse; 8.19% were frequently relapsing and 26.22% were steroid dependent. After a mean follow-up of 149.9 weeks, 38 (61.29%) patients were in CR and 16 (26.22%) in PR with a mean proteinuria of 1.28 g/day, 3 being treated for relapse. Mean serum creatinine was 89.28 MUmol/L (1.01 mg/dL). Fourteen (22.95%) had acute kidney injury (AKI). All but two recovered completely. CONCLUSIONS: This single-centre study with a medium-term follow-up shows that majority of patients respond to steroids or alternative immunosuppressants. AKI is common and may not be completely reversible in some cases. PMID- 26064511 TI - Preemptive dosage reduction of nadroparin in patients with renal failure: a retrospective case series. AB - BACKGROUND: Low-molecular-weight heparins (LMWHs) are frequently used to treat arterial and venous thrombo-embolic events. LMWHs accumulate with renal failure, but only limited clinical data regarding appropriate dosage adjustments are available. Nevertheless, LMWHs are routinely used in these patients worldwide. Although many clinics apply renal function-based dosage reductions, anti-factor Xa (anti-Xa) activity is not measured routinely. METHODS: We determined anti-Xa activity in 51 patients with MDRD-eGFR <60 mL/min/1.73 m(2), treated with therapeutic doses of nadroparin according to a standard, renal function-based guideline. RESULTS: An a priori dosage reduction resulted in anti-Xa activity within, below and above the reference range in 51, 30 and 19% of the measurements, respectively. Treatment resulted in different anti-Xa activities compared with dosages that were not given according to official advice (P < 0.001). Anti-Xa values increased with longer treatment duration (P = 0.038). CONCLUSIONS: A preemptive fixed reduction (25%) of the nadroparin dosage in all patients with renal failure seems appropriate. However, because target anti-Xa activities were reached in only half of the patients, we submit that the use of nadroparin, dosage reduction and monitoring of anti-Xa activity in combination with clinical outcome monitoring in this patient population urgently needs further investigation. PMID- 26064512 TI - Exogenous thyrotropin improves renal function in euthyroid patients, while serum creatinine levels are increased in hypothyroidism. AB - BACKGROUND: There is evidence showing that the hypothyroid state results in increased serum creatinine levels. However, whether this is only due to the peripheral thyroid hormones or if thyroid-stimulating hormone (TSH) is also involved is not known. METHODS: Serum creatinine levels and estimated glomerular filtration rate (eGFR) were assessed in thyroidectomized patients with varying thyroid hormones and TSH levels. Blood samples from Group 1 (21 patients) were obtained 1 month after complete thyroidectomy, while under a hypothyroid state (t1) and a sufficient time after thyroid hormones initiation (euthyroid state, t2). Group 2 (20 euthyroid patients) were sampled after recombinant human thyrotropin injections (rhTSH, t1) and later after rhTSH extinction (t2). RESULTS: In Group 1, serum creatinine levels decreased after correction of hypothyroidism (85.3 +/- 4.3 versus 78.0 +/- 3.9 umol/L; P = 0.04). In Group 2, serum creatinine levels increased after rhTSH withdrawal (70.6 +/- 5.7 umol/L versus 76.5 +/- 5.8 umol/L; P = 0.007). Between t1 and t2, eGFR varied accordingly [Group 1, 71.7 +/- 3.5 versus 81.2 +/- 4.5 mL/min/1.73 m2 (P = 0.02); Group 2, 97.7 +/- 7.4 versus 87.5 +/- 5.9 (P = 0.007)]. The changes in TSH and eGFR following supplementation with thyroxine were significantly correlated (r = 0.6, P = 0.0041). CONCLUSIONS: Iatrogenic hypothyroidism significantly increases serum creatinine and reversibly impairs eGFR, while treatment with rhTSH enhances renal function in euthyroid patients, supporting the existence of an influence of TSH level on renal function. The mechanisms by which peripheral thyroid hormones and TSH influence GFR need to be identified in physiology-orientated studies. PMID- 26064513 TI - Aggressive blood pressure control for chronic kidney disease unmasks moyamoya! AB - Hypertensive crises in children or adolescents are rare, but chronic kidney disease (CKD) is a major risk factor for occurrence. Vesicoureteral reflux nephropathy is a common cause of pediatric renal failure and is associated with hypertension. Aggressive blood pressure (BP) control has been shown to delay progression of CKD and treatment is targeted for the 50th percentile for height when compared with a target below the 90th percentile for the general pediatric hypertensive patient. We present a case of an adolescent presenting with seizures and renal failure due to a hypertensive crisis. Hypertension was thought to be secondary to CKD as she had scarred echogenic kidneys due to known reflux nephropathy. However, aggressive BP treatment improved kidney function which is inconsistent with CKD from reflux nephropathy. Secondly, aggressive BP control caused transient neurological symptoms. Further imaging identified moyamoya disease. We present this case to highlight the consideration of moyamoya as a diagnosis in the setting of renal failure and hypertensive crisis. PMID- 26064514 TI - Bilateral renal artery thrombosis secondary to acute necrotizing pancreatitis. AB - Renal artery thrombosis is a rare, but serious and often under-diagnosed condition. We report a case of bilateral renal artery thrombosis secondary to acute necrotizing pancreatitis. A 66-year-old female presented with abdominal pain and acute kidney injury (AKI). A renal biopsy showed organized intraluminal thrombi and a computer tomography scan of the abdomen showed bilateral renal artery thrombosis. Emergent laprotomy showed necrosed pancreas. Doppler studies showed deep vein thrombosis of the lower extremities and internal jugular vein thrombosis. Workup for hypercoagulability was unremarkable. The final diagnosis was AKI secondary to bilateral renal artery thrombosis probably due to hypercoagulability of acute necrotizing pancreatitis. PMID- 26064515 TI - Rituximab-associated interstitial lung disease in fibrillary glomerulonephritis. AB - Rituximab (RTX) is a chimeric monoclonal antibody against CD20+ B cells increasingly used to treat kidney disorders. RTX-induced pulmonary disease has been reported in patients treated for haematological disorders, and a few cases have been observed in patients with underlying rheumatological conditions. We report a case of non-infectious interstitial pneumonitis associated with RTX use in a 49-year-old patient with primary (fibrillary) glomerulonephritis. As typically observed, discontinuation of the drug and prompt initiation of glucocorticoids led to resolution of pulmonary manifestations. However, fatalities have been reported and nephrologists treating glomerulonephritis patients with RTX should be aware of the existence of this potentially lethal complication. PMID- 26064516 TI - Fibronectin glomerulopathy. AB - Fibronectin glomerulopathy occurs between the second and fifth decades of life in most patients, and it is known to be slowly progressive with mild proteinuria leading to kidney failure. The case of a 78-year-old woman with a rapid course of nephrotic syndrome due to fibronectin glomerulopathy is reported. She had proteinuria that rapidly increased to 6.8 g/day in a month and microscopic haematuria. A renal biopsy specimen showed lobular glomerulopathy and membranoproliferative glomerulonephritis-like lesions on light microscopy. There was scanty staining for immunoglobulins and complement. Electron microscopy revealed granular deposits with fibril formation. Immunohistochemistry of the fibronectin showed intense staining in the mesangium and peripheral loop. Therefore, this case was diagnosed as fibronectin glomerulopathy. The kidney function was rapidly decreasing, necessitating haemodialysis 2 months after renal biopsy. It is important to consider fibronectin glomerulopathy in the differential diagnosis of nephrotic syndrome in older people. PMID- 26064517 TI - Recurrence of ANCA-negative renal-limited pauci-immune glomerulonephritis in the renal allograft. AB - Renal transplantation is the treatment of choice for end-stage renal disease (ESRD) due to pauci-immune crescentic glomerulonephritis (PICGN). A small subgroup of patients with PICGN are anti-neutrophil cytoplasmic antibody (ANCA) negative. We report a case of a patient with ANCA-negative renal-limited form of PICGN who developed ESRD despite treatment. He underwent live-related renal allograft transplantation after 12 months on haemodialysis. In the eighth post transplant month, he developed graft dysfunction, which on evaluation turned out to be a graft recurrence of the basic disease in the form of PICGN. He received treatment with methylprednisolone, cyclophosphamide and plasmapheresis. However, his renal functions did not improve and he developed graft loss in the 11th post transplant month and was started on continuous ambulatory peritoneal dialysis. We report a rare recurrence of renal-limited PICGN in the allograft. Patients with PICGN undergoing renal transplantation should be followed up carefully, and an early biopsy should be performed in the case of graft dysfunction to deal with this potentially graft-threatening complication. PMID- 26064518 TI - Hypouricaemia and hyperuricosuria in familial renal glucosuria. AB - Familial renal glucosuria is a rare co-dominantly inherited benign phenotype characterized by the presence of glucose in the urine. It is caused by mutations in the SLC5A2 gene that encodes SGLT2, the Na(+)-glucose cotransporter responsible for the reabsorption of the bulk of glucose in the proximal tubule. We report a case of FRG displaying both severe glucosuria and renal hypouricaemia. We hypothesize that glucosuria can disrupt urate reabsorption in the proximal tubule, directly causing hyperuricosuria. PMID- 26064519 TI - Rejection-triggered haemophagocytic syndrome in renal transplantation successfully treated with intravenous immunoglobulin. AB - Haemophagocytic syndrome (HPS) is a rare and potentially lethal condition characterized by pancytopoenia, fever, organomegaly and widespread proliferation of macrophages phagocytosing blood elements. Among the triggers of this syndrome, excessive immunosuppression in a context of acute rejection has been rarely reported, although it might be underdiagnosed. Here, we report the case of a kidney transplant recipient with allograft dysfunction due to chronic antibody mediated rejection treated with antithymocyte globulin and plasmapheresis. The patient developed high fever, pancytopoenia, diarrhoea and respiratory symptoms with no apparent infectious or neoplastic cause, despite an extensive work-up. Haemophagocytosis was found in bone marrow examination, along with hyperferritinaemia and hypertriglyceridaemia. The clinical profile improved after treatment with intravenous immunoglobulin and reduction of the basal immunosuppression. PMID- 26064520 TI - A Spanish multicentric study to evaluate the clinical activity of nephrology fellows during in-hospital on-call shifts. AB - BACKGROUND: Nephrologists develop their work in diverse scenarios. A training programme must qualify trainees to assist different kinds of problems. The aim of this study was to characterize patients and pathologies that Spanish nephrology fellows face while on-call. METHODS: This is a descriptive study with clinical and demographic data gathered with a form by 10 nephrology fellows of five university hospitals of Madrid (Spain), throughout their in-hospital 24 h on-call shifts in February and March 2013. RESULTS: We collected 409 episodes over 338 patients, through 72 shifts. Among these, 16.7% had previous normal renal function, 24.6% chronic kidney disease, 39.5% were on dialysis and 18.2% had a kidney transplant. Most of the consults came from the emergency room (35.9%) or the previous on-call team (13.7%). Afterwards, the most usual destiny was admittance to a nephrology department (32.8%) or discharge (20.5%). The most frequent reason for consulting was a decline in renal function (31.6%) and the second motive an infection. Thirty-four episodes (8.3%) were related to dialysis access problems. Medical treatment was prescribed in 79.2% of the cases, primarily fluids (47.2%) and antibiotics (42.2%). The fellow had to place a central venous catheter in 24 cases (5.9%). Renal replacement therapy was prescribed in 19.8% of the episodes. CONCLUSIONS: Specific renal reasons for consulting nephrologists are common, such as acute kidney injury or dialysis access complications. These patients benefit from a specialized approach to their problems. Clinical activities during in-hospital out-of-hours shifts are a priceless tool as part of the training programme of nephrology fellows. PMID- 26064521 TI - Effects of physical exercise on central nervous system functions: a review of brain region specific adaptations. AB - Pathologies of central nervous system (CNS) functions are involved in prevalent conditions such as Alzheimer's disease, depression, and Parkinson's disease. Notable pathologies include dysfunctions of circadian rhythm, central metabolism, cardiovascular function, central stress responses, and movement mediated by the basal ganglia. Although evidence suggests exercise may benefit these conditions, the neurobiological mechanisms of exercise in specific brain regions involved in these important CNS functions have yet to be clarified. Here we review murine evidence about the effects of exercise on discrete brain regions involved in important CNS functions. Exercise effects on circadian rhythm, central metabolism, cardiovascular function, stress responses in the brain stem and hypothalamic pituitary axis, and movement are examined. The databases Pubmed, Web of Science, and Embase were searched for articles investigating regional brain adaptations to exercise. Brain regions examined included the brain stem, hypothalamus, and basal ganglia. We found evidence of multiple regional adaptations to both forced and voluntary exercise. Exercise can induce molecular adaptations in neuronal function in many instances. Taken together, these findings suggest that the regional physiological adaptations that occur with exercise could constitute a promising field for elucidating molecular and cellular mechanisms of recovery in psychiatric and neurological health conditions. PMID- 26064522 TI - Memory Complaints in Older Adults: Prognostic Value and Stability in Reporting over Time. AB - OBJECTIVE: The purpose of this longitudinal study was to examine the prognostic value of subjective memory complaints in 156 cognitively intact community dwelling older adults with a mean age of 83 years. METHODS: Participants were assessed for subjective memory complaints, cognitive performance, functional status, and mood at annual evaluations with a mean follow-up of 4.5 years. RESULTS: Subjective memory complaint at entry (n=24) was not associated with impaired memory performance and did not predict memory decline or progression to incipient dementia. Memory complaints were inconsistent across examinations for 62% of participants who reported memory problems. CONCLUSIONS: Memory complaints by older adults are inconsistent over time. Memory complaint's value as a research criterion for selecting people at risk for dementia is weak among community dwelling older adults. Age, length of follow-up, and other population characteristics may affect the implication of self-reported memory problems. PMID- 26064523 TI - Characterization of medulloblastoma in Fanconi Anemia: a novel mutation in the BRCA2 gene and SHH molecular subgroup. AB - Fanconi Anemia (FA) is an inherited disorder characterized by the variable presence of multiple congenital somatic abnormalities, bone marrow failure and cancer susceptibility. Medulloblastoma (MB) has been described only in few cases of FA with biallelic inactivation in the tumor suppressor gene BRCA2/FANCD1 or its associated gene PALB2/FANCN. We report the case of a patient affected by Fanconi Anemia with Wilms tumor and unusual presentation of two medulloblastomas (MB1 and MB2). We identified a new pathogenetic germline BRCA2 mutation: c.2944_2944delA. Molecular analysis of MBs allowed us to define new features of MB in FA. MBs were found to belong to the Sonic Hedgehog (SHH) molecular subgroup with some differences between MB1 and MB2. We highlighted that MB in FA could share molecular aspects and hemispheric localization with sporadic adult SHH-MB. Our report provides new findings that shed new light on the genetic and molecular pathogenesis of MB in FA patients with implications in the disease management. PMID- 26064524 TI - The impact of childhood temperament on the development of borderline personality disorder symptoms over the course of adolescence. AB - BACKGROUND: The purpose of this study was to characterize the development of BPD symptoms across adolescence by evaluating the fit of several latent variable growth models to annual assessments of symptoms obtained from girls when they were ages 14 through 19 years. After determining the best fitting model, we examined prospective associations between the temperament dimensions of emotionality, activity, low sociability, and shyness and BPD symptom development. METHODS: We utilized longitudinal data from the Pittsburgh Girls Study; one of the few large-scale, prospective studies of girls (N = 2,450) in the United States. Parent- and teacher-reports of girls' temperament were collected at Wave 1, when girls were ages 5-8 years. Child-reports of BPD symptoms were collected annually beginning at age 14 through 19 years. RESULTS: We found that a free curve slope intercept model provided the best model fit, with the course of BPD symptoms characterized by a large component of inter-individual stability and a smaller component representing within-individual changes across adolescence. Symptoms appeared to peak by age 15, decline through age 18, and remain steady between ages 18 and 19 years. Both parent- and teacher-reports of temperament emotionality, activity, low sociability, and shyness predicted the developmental course of symptoms. CONCLUSIONS: BPD symptoms in adolescence reflect trait-like differences between youth with less within-person variability across time. Childhood temperament dimensions of emotionality, activity, low sociability, and shyness predict adolescent BPD symptom development. Parent- and teacher informants provide unique information about the course of BPD symptoms, underscoring the utility of collecting child assessments using multiple informants. PMID- 26064525 TI - Oxygen consumption dynamics in steady-state tumour models. AB - Oxygen levels in cancerous tissue can have a significant effect on treatment response: hypoxic tissue is both more radioresistant and more chemoresistant than well-oxygenated tissue. While recent advances in medical imaging have facilitated real-time observation of macroscopic oxygenation, the underlying physics limits the resolution to the millimetre domain, whereas oxygen tension varies over a micrometre scale. If the distribution of oxygen in the tumour micro-environment can be accurately estimated, then the effect of potential dose escalation to these hypoxic regions could be better modelled, allowing more realistic simulation of biologically adaptive treatments. Reaction-diffusion models are commonly used for modelling oxygen dynamics, with a variety of functional forms assumed for the dependence of oxygen consumption rate (OCR) on cellular status and local oxygen availability. In this work, we examine reaction-diffusion models of oxygen consumption in spherically and cylindrically symmetric geometries. We consider two different descriptions of oxygen consumption: one in which the rate of consumption is constant and one in which it varies with oxygen tension in a hyperbolic manner. In each case, we derive analytic approximations to the steady state oxygen distribution, which are shown to closely match the numerical solutions of the equations and accurately predict the extent to which oxygen can diffuse. The derived expressions relate the limit to which oxygen can diffuse into a tissue to the OCR of that tissue. We also demonstrate that differences between these functional forms are likely to be negligible within the range of literature estimates of the hyperbolic oxygen constant, suggesting that the constant consumption rate approximation suffices for modelling oxygen dynamics for most values of OCR. These approximations also allow the rapid identification of situations where hyperbolic consumption forms can result in significant differences from constant consumption rate models, and so can reduce the computational workload associated with numerical solutions, by estimating both the oxygen diffusion distances and resultant oxygen profile. Such analysis may be useful for parameter fitting in large imaging datasets and histological sections, and allows easy quantification of projected differences between functional forms of OCR. PMID- 26064526 TI - Harem-holding males do not rise to the challenge: androgens respond to social but not to seasonal challenges in wild geladas. AB - The challenge hypothesis has been enormously successful in predicting interspecific androgen profiles for vertebrate males. Nevertheless, in the absence of another theoretical framework, many researchers 'retrofit' the challenge hypothesis, so that its predictions also apply to intraspecific androgen comparisons. We use a wild primate, geladas (Theropithecus gelada), to illustrate several considerations for androgen research surrounding male contests that do not necessarily fit within the challenge hypothesis framework. Gelada society comprises harem-holding males (that can mate with females) and bachelor males (that cannot mate with females until they take over a harem). Using 6 years of data from known males, we measured androgens (i.e. faecal testosterone (fT) metabolites) both seasonally and across specific male contests. Seasonal androgen variation exhibited a very different pattern than variation resulting from male contests. Although harem-holding males had higher testosterone levels than bachelors across the year, bachelors had higher testosterone during the annual 'takeover season'. Thus, harem-holding males did not 'rise to the challenge' exactly when needed most. Yet, androgen profiles across male contests indicated that both sets of males exhibit the expected fT rise in response to challenges. Results from male geladas also support the idea that the context before (e.g. male condition) and after (e.g. contest outcome) a contest are critical variables for predicting hormones and behaviour. PMID- 26064527 TI - Structures of pyruvate kinases display evolutionarily divergent allosteric strategies. AB - The transition between the inactive T-state (apoenzyme) and active R-state (effector bound enzyme) of Trypanosoma cruzi pyruvate kinase (PYK) is accompanied by a symmetrical 8 degrees rigid body rocking motion of the A- and C-domain cores in each of the four subunits, coupled with the formation of additional salt bridges across two of the four subunit interfaces. These salt bridges provide increased tetramer stability correlated with an enhanced specificity constant (k cat/S 0.5). A detailed kinetic and structural comparison between the potential drug target PYKs from the pathogenic protists T. cruzi, T. brucei and Leishmania mexicana shows that their allosteric mechanism is conserved. By contrast, a structural comparison of trypanosomatid PYKs with the evolutionarily divergent PYKs of humans and of bacteria shows that they have adopted different allosteric strategies. The underlying principle in each case is to maximize (k cat/S 0.5) by stabilizing and rigidifying the tetramer in an active R-state conformation. However, bacterial and mammalian PYKs have evolved alternative ways of locking the tetramers together. In contrast to the divergent allosteric mechanisms, the PYK active sites are highly conserved across species. Selective disruption of the varied allosteric mechanisms may therefore provide a useful approach for the design of species-specific inhibitors. PMID- 26064528 TI - To the non-local theory of cold nuclear fusion. AB - In this paper, we revisit the cold fusion (CF) phenomenon using the generalized Bolzmann kinetics theory which can represent the non-local physics of this CF phenomenon. This approach can identify the conditions when the CF can take place as the soliton creation under the influence of the intensive sound waves. The vast mathematical modelling leads to affirmation that all parts of soliton move with the same velocity and with the small internal change of the pressure. The zone of the high density is shaped on the soliton's front. It means that the regime of the 'acoustic CF' could be realized from the position of the non-local hydrodynamics. PMID- 26064529 TI - Shrinking fish: comparisons of prehistoric and contemporary salmonids indicate decreasing size at age across millennia. AB - A comparison of Upper Palaeolithic and contemporary salmonid vertebrae from the Iberian Peninsula indicates that there has been a significant decrease in the mean body size for a given age among Atlantic salmon and brown trout inhabiting the southernmost range of their endemic distribution. Mean size at age was greater in prehistoric specimens for all age classes during the freshwater phase of their life histories. Fisheries-induced evolution (selection for smaller sizes) is an obvious explanation for the observed reduction in fish body size, but recent changes in the aquatic habitat affecting density-dependent growth cannot be ruled out. PMID- 26064530 TI - A note on improved F-expansion method combined with Riccati equation applied to nonlinear evolution equations. AB - The purpose of this article is to present an analytical method, namely the improved F-expansion method combined with the Riccati equation, for finding exact solutions of nonlinear evolution equations. The present method is capable of calculating all branches of solutions simultaneously, even if multiple solutions are very close and thus difficult to distinguish with numerical techniques. To verify the computational efficiency, we consider the modified Benjamin-Bona Mahony equation and the modified Korteweg-de Vries equation. Our results reveal that the method is a very effective and straightforward way of formulating the exact travelling wave solutions of nonlinear wave equations arising in mathematical physics and engineering. PMID- 26064531 TI - Increased natural mortality at low abundance can generate an Allee effect in a marine fish. AB - Negative density-dependent regulation of population dynamics promotes population growth at low abundance and is therefore vital for recovery following depletion. Inversely, any process that reduces the compensatory density-dependence of population growth can negatively affect recovery. Here, we show that increased adult mortality at low abundance can reverse compensatory population dynamics into its opposite-a demographic Allee effect. Northwest Atlantic cod (Gadus morhua) stocks collapsed dramatically in the early 1990s and have since shown little sign of recovery. Many experienced dramatic increases in natural mortality, ostensibly attributable in some populations to increased predation by seals. Our findings show that increased natural mortality of a magnitude observed for overfished cod stocks has been more than sufficient to fundamentally alter the dynamics of density-dependent population regulation. The demographic Allee effect generated by these changes can slow down or even impede the recovery of depleted populations even in the absence of fishing. PMID- 26064532 TI - Adaptive nowcasting of influenza outbreaks using Google searches. AB - Seasonal influenza outbreaks and pandemics of new strains of the influenza virus affect humans around the globe. However, traditional systems for measuring the spread of flu infections deliver results with one or two weeks delay. Recent research suggests that data on queries made to the search engine Google can be used to address this problem, providing real-time estimates of levels of influenza-like illness in a population. Others have however argued that equally good estimates of current flu levels can be forecast using historic flu measurements. Here, we build dynamic 'nowcasting' models; in other words, forecasting models that estimate current levels of influenza, before the release of official data one week later. We find that when using Google Flu Trends data in combination with historic flu levels, the mean absolute error (MAE) of in sample 'nowcasts' can be significantly reduced by 14.4%, compared with a baseline model that uses historic data on flu levels only. We further demonstrate that the MAE of out-of-sample nowcasts can also be significantly reduced by between 16.0% and 52.7%, depending on the length of the sliding training interval. We conclude that, using adaptive models, Google Flu Trends data can indeed be used to improve real-time influenza monitoring, even when official reports of flu infections are available with only one week's delay. PMID- 26064533 TI - On alternative wavelet reconstruction formula: a case study of approximate wavelets. AB - The application of the continuous wavelet transform to the study of a wide class of physical processes with oscillatory dynamics is restricted by large central frequencies owing to the admissibility condition. We propose an alternative reconstruction formula for the continuous wavelet transform, which is applicable even if the admissibility condition is violated. The case of the transform with the standard reduced Morlet wavelet, which is an important example of such analysing functions, is discussed. PMID- 26064534 TI - Intricate predatory decisions by a mosquito-specialist spider from Malaysia. AB - Paracyrba wanlessi is a southeast Asian jumping spider (Salticidae) that lives in the hollow internodes of fallen bamboo and preys on the larvae, pupae and adults of mosquitoes. In contrast to Evarcha culicivora, an East African salticid that is also known for actively targeting mosquitoes as preferred prey, there was no evidence of P. wanlessi choosing mosquitoes on the basis of species, sex or diet. However, our findings show that P. wanlessi chooses mosquitoes significantly more often than a variety of other prey types, regardless of whether the prey are in or away from water, and regardless of whether the mosquitoes are adults or juveniles. Moreover, a preference for mosquito larvae, pupae and adults is expressed regardless of whether test spiders are maintained on a diet of terrestrial or aquatic prey and regardless of whether the diet includes or excludes mosquitoes. Congruence of an environmental factor (in water versus away from water) with prey type (aquatic versus terrestrial mosquitoes) appeared to be important and yet, even when the prey were in the incongruent environment, P. wanlessi continued to choose mosquitoes more often than other prey. PMID- 26064535 TI - Effects of habitat structure and land-use intensity on the genetic structure of the grasshopper species Chorthippus parallelus. AB - Land-use intensity (LUI) is assumed to impact the genetic structure of organisms. While effects of landscape structure on the genetics of local populations have frequently been analysed, potential effects of variation in LUI on the genetic diversity of local populations have mostly been neglected. In this study, we used six polymorphic microsatellites to analyse the genetic effects of variation in land use in the highly abundant grasshopper Chorthippus parallelus. We sampled a total of 610 individuals at 22 heterogeneous grassland sites in the Hainich-Dun region of Central Germany. For each of these grassland sites we assessed habitat size, LUI (combined index of mowing, grazing and fertilization), and the proportion of grassland adjoining the sampling site and the landscape heterogeneity (the latter two factors within a 500 m buffer zone surrounding each focal site). We found only marginal genetic differentiation among all local populations and no correlation between geographical and genetic distance. Habitat size, LUI and landscape characteristics had only weak effects on most of the parameters of genetic diversity of C. parallelus; only expected heterozygosity and the grasshopper abundances were affected by interacting effects of LUI, habitat size and landscape characteristics. The lack of any strong relationships between LUI, abundance and the genetic structure might be due to large local populations of the species in the landscape, counteracting local differentiation and potential genetic drift effects. PMID- 26064536 TI - Low-frequency sound affects active micromechanics in the human inner ear. AB - Noise-induced hearing loss is one of the most common auditory pathologies, resulting from overstimulation of the human cochlea, an exquisitely sensitive micromechanical device. At very low frequencies (less than 250 Hz), however, the sensitivity of human hearing, and therefore the perceived loudness is poor. The perceived loudness is mediated by the inner hair cells of the cochlea which are driven very inadequately at low frequencies. To assess the impact of low frequency (LF) sound, we exploited a by-product of the active amplification of sound outer hair cells (OHCs) perform, so-called spontaneous otoacoustic emissions. These are faint sounds produced by the inner ear that can be used to detect changes of cochlear physiology. We show that a short exposure to perceptually unobtrusive, LF sounds significantly affects OHCs: a 90 s, 80 dB(A) LF sound induced slow, concordant and positively correlated frequency and level oscillations of spontaneous otoacoustic emissions that lasted for about 2 min after LF sound offset. LF sounds, contrary to their unobtrusive perception, strongly stimulate the human cochlea and affect amplification processes in the most sensitive and important frequency range of human hearing. PMID- 26064537 TI - Competition and cooperation in a synchronous bushcricket chorus. AB - Synchronous signalling within choruses of the same species either emerges from cooperation or competition. In our study on the katydid Mecopoda elongata, we aim to identify mechanisms driving evolution towards synchrony. The increase of signal amplitude owing to synchronous signalling and the preservation of a conspecific signal period may represent cooperative mechanisms, whereas chorus synchrony may also result from the preference of females for leading signals and the resulting competition for the leader role. We recorded the timing of signals and the resulting communal signal amplitudes in small choruses and performed female choice experiments to identify such mechanisms. Males frequently timed their signals either as leader or follower with an average time lag of about 70 ms. Females selected males in such choruses on the basis of signal order and signal duration. Two-choice experiments revealed a time lag of only 70 ms to bias mate choice in favour of the leader. Furthermore, a song model with a conspecific signal period of 2 s was more attractive than a song model with an irregular or longer and shorter than average signal period. Owing to a high degree of overlap and plasticity of signals produced in 'four male choruses', peak and root mean square amplitudes increased by about 7 dB relative to lone singers. Modelling active space of synchronous males and solo singing males revealed a strongly increased broadcast area of synchronous signallers, but a slightly reduced per capita mating possibility compared with lone singers. These results suggest a strong leader preference of females as the ultimate causation of inter-male competition for timing signals as leader. The emerging synchrony increases the amplitude of signals produced in a chorus and has the potential to compensate a reduction of mating advantage in a chorus. We discuss a possible fitness benefit of males gained through a beacon effect and the possibility that signalling as follower is stabilized via natural selection. PMID- 26064538 TI - Evolution: are the monkeys' typewriters rigged? AB - Evolution is presumed to proceed by random mutations, which increase an individual's fitness. Increased fitness produces a higher survival rate for those individuals within populations and drives the variants to fixation over large timescales to produce new species. We recently identified positively selected sites in mitochondrial complex I in numerous, diverse taxa. In one taxon, a simple sequence repeat (SSR) encompassed the positively selected sites. We hypothesized a model in which: (i) slip-strand mis-pairing during replication due to the SSR increases the mutation rate at these sites, and (ii) a functional constraint at the protein level maintains the SSR and therefore a higher mutation rate at this site over large time scales to drive evolution. We tested this model by identifying SSRs in a mitochondrial-encoded protein in species from our previous work and determined that nearly all of the positively selected sites encompass an SSR. Furthermore, we show that our proposed model accounts for most of the mutations at neutral sites but it is probably the predominant mechanism at positively selected sites. This suggests that evolution does not proceed by simple random processes but is guided by physical properties of the DNA itself and functional constraint of the proteins encoded by the DNA. PMID- 26064539 TI - Asymptotic formulae for the Lommel and Bessel functions and their derivatives. AB - We derive new approximate representations of the Lommel functions in terms of the Scorer function and approximate representations of the first derivative of the Lommel functions in terms of the derivative of the Scorer function. Using the same method, we obtain previously known approximate representations of the Nicholson type for Bessel functions and their first derivatives. We study also for what values of the parameters our representations have reasonable accuracy. PMID- 26064540 TI - New dinosaur (Theropoda, stem-Averostra) from the earliest Jurassic of the La Quinta formation, Venezuelan Andes. AB - Dinosaur skeletal remains are almost unknown from northern South America. One of the few exceptions comes from a small outcrop in the northernmost extension of the Andes, along the western border of Venezuela, where strata of the La Quinta Formation have yielded the ornithischian Laquintasaura venezuelae and other dinosaur remains. Here, we report isolated bones (ischium and tibia) of a small new theropod, Tachiraptor admirabilis gen. et sp. nov., which differs from all previously known members of the group by an unique suite of features of its tibial articulations. Comparative/phylogenetic studies place the new form as the sister taxon to Averostra, a theropod group that is known primarily from the Middle Jurassic onwards. A new U-Pb zircon date (isotope dilution thermal ionization mass spectrometry; ID-TIMS method) from the bone bed matrix suggests an earliest Jurassic maximum age for the La Quinta Formation. A dispersal vicariance analysis suggests that such a stratigraphic gap is more likely to be filled by new records from north and central Pangaea than from southern areas. Indeed, our data show that the sampled summer-wet equatorial belt, which yielded the new taxon, played a pivotal role in theropod evolution across the Triassic Jurassic boundary. PMID- 26064541 TI - Role reversal in a predator-prey interaction. AB - Predator-prey relationships are one of the most studied interactions in population ecology. However, little attention has been paid to the possibility of role exchange between species, despite firm field evidence of such phenomena in nature. In this paper, we build a mathematical model capable of reproducing the main phenomenological features of role reversal in a classical system and present results for both the temporal and spatio-temporal cases. We show that, depending on the choice of parameters, our role-reversal dynamical system exhibits excitable-like behaviour, generating waves of species' concentrations that propagate through space. Our findings fill a long-standing gap in modelling ecological interactions and can be applicable to better understanding ecological niche shifts and planning of sustainable ecosystems. PMID- 26064542 TI - Conidia of the insect pathogenic fungus, Metarhizium anisopliae, fail to adhere to mosquito larval cuticle. AB - Adhesion of conidia of the insect pathogenic fungus, Metarhizium anisopliae, to the arthropod host cuticle initially involves hydrophobic forces followed by consolidation facilitated by the action of extracellular enzymes and secretion of mucilage. Gene expression analysis and atomic force microscopy were used to directly quantify recognition and adhesion between single conidia of M. anisopliae and the cuticle of the aquatic larval stage of Aedes aegypti and a representative terrestrial host, Tenebrio molitor. Gene expression data indicated recognition by the pathogen of both hosts; however, the forces for adhesion to the mosquito were approximately five times lower than those observed for Tenebrio. Although weak forces were recorded in response to Aedes, Metarhizium was unable to consolidate firm attachment. An analysis of the cuticular composition revealed an absence of long-chain hydrocarbons in Aedes larvae which are thought to be required for fungal development on host cuticle. This study provides, to our knowledge, the first evidence that Metarhizium does not form firm attachment to Ae. aegypti larvae in situ, therefore preventing the normal route of invasion and pathogenesis from occuring. PMID- 26064543 TI - Are genes faster than crabs? Mitochondrial introgression exceeds larval dispersal during population expansion of the invasive crab Carcinus maenas. AB - Biological invasions offer unique opportunities to investigate evolutionary dynamics at the peripheries of expanding populations. Here, we examine genetic patterns associated with admixture between two distinct invasive lineages of the European green crab, Carcinus maenas L., independently introduced to the northwest Atlantic. Previous investigations based on mitochondrial DNA sequences demonstrated that larval dispersal driven by advective currents could explain observed southward displacement of an admixture zone between the two invasions. Comparison of published mitochondrial results with new nuclear data from nine microsatellite loci, however, reveals striking discordance in their introgression patterns. Specifically, introgression of mitochondrial genomes relative to nuclear background suggests that demographic processes such as sex-biased reproductive dynamics and population size imbalances-and not solely larval dispersal-play an important role in driving the evolution of the genetic cline. In particular, the unpredicted introgression of mitochondrial alleles against the direction of mean larval dispersal in the region is consistent with recent models invoking similar demographic processes to explain movements of genes into invading populations. These observations have important implications for understanding historical shifts in C. maenas range limits, and more generally for inferences of larval dispersal based on genetic data. PMID- 26064544 TI - New stopping criteria for iterative root finding. AB - A set of simple stopping criteria is presented, which improve the efficiency of iterative root finding by terminating the iterations immediately when no further improvement of the roots is possible. The criteria use only the function evaluations already needed by the root finding procedure to which they are applied. The improved efficiency is achieved by formulating the stopping criteria in terms of fractional significant digits. Test results show that the new stopping criteria reduce the iteration work load by about one-third compared with the most efficient stopping criteria currently available. This is achieved without compromising the accuracy of the extracted roots. PMID- 26064545 TI - Revision of the Late Jurassic teleosaurid genus Machimosaurus (Crocodylomorpha, Thalattosuchia). AB - Machimosaurus was a large-bodied genus of teleosaurid crocodylomorph, considered to have been durophagous/chelonivorous, and which frequented coastal marine/estuarine ecosystems during the Late Jurassic. Here, we revise the genus based on previously described specimens and revise the species within this genus. We conclude that there were three European Machimosaurus species and another taxon in Ethiopia. This conclusion is based on numerous lines of evidence: craniomandibular, dental and postcranial morphologies; differences in estimated total body length; geological age; geographical distribution; and hypothetical lifestyle. We re-diagnose the type species Machimosaurus hugii and limit referred specimens to only those from Upper Kimmeridgian-Lower Tithonian of Switzerland, Portugal and Spain. We also re-diagnose Machimosaurus mosae, demonstrate that it is an available name and restrict the species to the uppermost Kimmeridgian lowermost Tithonian of northeastern France. We re-diagnose and validate the species Machimosaurus nowackianus from Harrar, Ethiopia. Finally, we establish a new species, Machimosaurus buffetauti, for the Lower Kimmeridgian specimens of France and Germany (and possibly England and Poland). We hypothesize that Machimosaurus may have been analogous to the Pliocene-Holocene genus Crocodylus in having one large-bodied taxon suited to traversing marine barriers and additional, geographically limited taxa across its range. PMID- 26064546 TI - The mechanics of hyperactivation in adhered human sperm. AB - Hyperactivation is an important phenomenon exhibited by mammalian sperm during the process of acquiring fertilization capacity. The majority of studies have focused on incubation-induced hyperactivation in non-human species, which typically differ in size, shape, and are more homogeneous than human sperm. We develop an alternative approach via drug-induction, using high-speed imaging and analysis of same-cell changes in the flagellar movement of adhered cells. Following stimulation with 4-aminopyridine, approximately two-thirds (21 of 34) of the cells analysed exhibited a waveform with a single characteristic frequency; in all cases, the frequency was lower than before stimulation. The remaining cells (13 of 34) exhibited a more complex motility with multiple frequency modes. The lowest mode in all cases was lower than the frequency prior to stimulation. Flagellar bending increased in all cells following stimulation and was significantly greater in the multiple-frequency responders. Despite the increased bending, time-averaged hydrodynamic power dissipation decreased significantly when assessed across all cells, the effect being significantly greater in the multiple-frequency responders than single frequency. These results reveal the heterogeneity of responses of human sperm to a hyperactivating stimulus, the methodology being potentially useful for assessing dynamic responses to stimuli in human sperm, and physiological selection of cells for assisted reproduction. PMID- 26064547 TI - The subgenual organ complex in the cave cricket Troglophilus neglectus (Orthoptera: Rhaphidophoridae): comparative innervation and sensory evolution. AB - Comparative studies of the organization of nervous systems and sensory organs can reveal their evolution and specific adaptations. In the forelegs of some Ensifera (including crickets and tettigoniids), tympanal hearing organs are located in close proximity to the mechanosensitive subgenual organ (SGO). In the present study, the SGO complex in the non-hearing cave cricket Troglophilus neglectus (Rhaphidophoridae) is investigated for the neuronal innervation pattern and for organs homologous to the hearing organs in related taxa. We analyse the innervation pattern of the sensory organs (SGO and intermediate organ (IO)) and its variability between individuals. In T. neglectus, the IO consists of two major groups of closely associated sensilla with different positions. While the distal-most sensilla superficially resemble tettigoniid auditory sensilla in location and orientation, the sensory innervation does not show these two groups to be distinct organs. Though variability in the number of sensory nerve branches occurs, usually either organ is supplied by a single nerve branch. Hence, no sensory elements clearly homologous to the auditory organ are evident. In contrast to other non-hearing Ensifera, the cave cricket sensory structures are relatively simple, consistent with a plesiomorphic organization resembling sensory innervation in grasshoppers and stick insects. PMID- 26064548 TI - Forward flight of birds revisited. Part 1: aerodynamics and performance. AB - This paper is the first part of the two-part exposition, addressing performance and dynamic stability of birds. The aerodynamic model underlying the entire study is presented in this part. It exploits the simplicity of the lifting line approximation to furnish the forces and moments acting on a single wing in closed analytical forms. The accuracy of the model is corroborated by comparison with numerical simulations based on the vortex lattice method. Performance is studied both in tethered (as on a sting in a wind tunnel) and in free flights. Wing twist is identified as the main parameter affecting the flight performance-at high speeds, it improves efficiency, the rate of climb and the maximal level speed; at low speeds, it allows flying slower. It is demonstrated that, under most circumstances, the difference in performance between tethered and free flights is small. PMID- 26064549 TI - Forward flight of birds revisited. Part 2: short-term dynamic stability and trim. AB - Thrust generation by flapping is accompanied by alternating pitching moment. On the down-stroke, it pitches the bird down when the wings are above its centre of gravity and up when they are below; on the up-stroke, the directions reverse. Because the thrust depends not only on the flapping characteristics but also on the angle of attack of the bird's body, interaction between the flapping and body motions may incite a resonance that is similar to the one that causes the swinging of a swing. In fact, it is shown that the equation governing the motion of the bird's body in flapping flight resembles the equation governing the motion of a pendulum with periodically changing length. Large flapping amplitude, low flapping frequency, and excessive tilt of the flapping plane may incite the resonance; coordinated fore-aft motion, that uses the lift to cancel out the moment generated by the thrust, suppresses it. It is probably incited by the tumbler pigeon in its remarkable display of aerobatics. The fore-aft motion that cancels the pitching moment makes the wing tip draw a figure of eight relative to the bird's body when the wings are un-swept, and a ring when the wings are swept back and fold during the upstroke. PMID- 26064550 TI - A gradient field defeats the inherent repulsion between magnetic nanorods. AB - When controlling the assembly of magnetic nanorods and chains of magnetic nanoparticles, it is extremely challenging to bring them together side by side while keeping a desired spacing between their axes. We show that this challenge can be successfully resolved by using a non-uniform magnetic field that defeats an inherent repulsion between nanorods. Nickel nanorods were suspended in a viscous film and a non-uniform field was used to control their placement. The in plane movement of nanorods was tracked with a high-speed camera and a detailed image analysis was conducted to quantitatively characterize the behaviour of the nanorods. The analysis focused on the behaviour of a pair of neighbour nanorods, and a corresponding dynamic model was formulated and investigated. The complex two-dimensional dynamics of a nanorod pair was analysed analytically and numerically, and a phase portrait was constructed. Using this phase portrait, we classified the nanorod behaviour and revealed the experimental conditions in which nanorods could be placed side by side. Dependence of the distance between a pair of neighbour nanorods on physical parameters was analysed. With the aid of the proposed theory, one can build different lattices and control their spacing by applying different field gradients. PMID- 26064551 TI - Viewing images of snakes accelerates making judgements of their colour in humans: red snake effect as an instance of 'emotional Stroop facilitation'. AB - One of the most prevalent current psychobiological notions about human behaviour and emotion suggests that prioritization of threatening stimuli processing induces deleterious effects on task performance. In order to confirm its relevancy, 108 adults and 25 children were required to name the colour of images of snakes and flowers, using the pictorial emotional Stroop paradigm. When reaction time to answer the colour of each stimulus was measured, its value was found to decrease when snake images were presented when compared with when flower images were presented. Thus, contrary to the expectation from previous emotional Stroop paradigm research, emotions evoked by viewing images of snakes as a biologically relevant threatening stimulus were found to be likely to exert a facilitating rather than interfering effect on making judgements of their colour. PMID- 26064552 TI - Exotic invaders gain foraging benefits by shoaling with native fish. AB - Freshwater habitats are under increasing threat due to invasions of exotic fish. These invasions typically begin with the introduction of small numbers of individuals unfamiliar with the new habitat. One way in which the invaders might overcome this disadvantage is by associating with native taxa occupying a similar ecological niche. Here we used guppies (Poecilia reticulata) from a feral population in Mexico to test the prediction that exotic shoaling fish can associate with heterospecifics, and that they improve their foraging efficiency by doing so. Guppies have invaded the Mexican High Plateau and are implicated in the declines of many native topminnow (Goodeinae) species. We show that heterospecific associations between guppies and topminnows can deliver the same foraging benefits as conspecific shoals, and that variation in foraging gains is linked to differences in association tendency. These results uncover a mechanism enabling founding individuals to survive during the most vulnerable phase of an invasion and help explain why guppies have established viable populations in many parts of Mexico as well in every continent except Antarctica. PMID- 26064553 TI - Local plant adaptation across a subarctic elevational gradient. AB - Predicting how plants will respond to global warming necessitates understanding of local plant adaptation to temperature. Temperature may exert selective effects on plants directly, and also indirectly through environmental factors that covary with temperature, notably soil properties. However, studies on the interactive effects of temperature and soil properties on plant adaptation are rare, and the role of abiotic versus biotic soil properties in plant adaptation to temperature remains untested. We performed two growth chamber experiments using soils and Bistorta vivipara bulbil ecotypes from a subarctic elevational gradient (temperature range: +/-3( degrees )C) in northern Sweden to disentangle effects of local ecotype, temperature, and biotic and abiotic properties of soil origin on plant growth. We found partial evidence for local adaption to temperature. Although soil origin affected plant growth, we did not find support for local adaptation to either abiotic or biotic soil properties, and there were no interactive effects of soil origin with ecotype or temperature. Our results indicate that ecotypic variation can be an important driver of plant responses to the direct effects of increasing temperature, while responses to covariation in soil properties are of a phenotypic, rather than adaptive, nature. PMID- 26064554 TI - The minimum number of rotations about two axes for constructing an arbitrarily fixed rotation. AB - For any pair of three-dimensional real unit vectors [Formula: see text] and [Formula: see text] with [Formula: see text] and any rotation U, let [Formula: see text] denote the least value of a positive integer k such that U can be decomposed into a product of k rotations about either [Formula: see text] or [Formula: see text]. This work gives the number [Formula: see text] as a function of U. Here, a rotation means an element D of the special orthogonal group SO(3) or an element of the special unitary group SU(2) that corresponds to D. Decompositions of U attaining the minimum number [Formula: see text] are also given explicitly. PMID- 26064556 TI - Self-motion facilitates echo-acoustic orientation in humans. AB - The ability of blind humans to navigate complex environments through echolocation has received rapidly increasing scientific interest. However, technical limitations have precluded a formal quantification of the interplay between echolocation and self-motion. Here, we use a novel virtual echo-acoustic space technique to formally quantify the influence of self-motion on echo-acoustic orientation. We show that both the vestibular and proprioceptive components of self-motion contribute significantly to successful echo-acoustic orientation in humans: specifically, our results show that vestibular input induced by whole body self-motion resolves orientation-dependent biases in echo-acoustic cues. Fast head motions, relative to the body, provide additional proprioceptive cues which allow subjects to effectively assess echo-acoustic space referenced against the body orientation. These psychophysical findings clearly demonstrate that human echolocation is well suited to drive precise locomotor adjustments. Our data shed new light on the sensory-motor interactions, and on possible optimization strategies underlying echolocation in humans. PMID- 26064555 TI - A tale of two seas: contrasting patterns of population structure in the small spotted catshark across Europe. AB - Elasmobranchs represent important components of marine ecosystems, but they can be vulnerable to overexploitation. This has driven investigations into the population genetic structure of large-bodied pelagic sharks, but relatively little is known of population structure in smaller demersal taxa, which are perhaps more representative of the biodiversity of the group. This study explores spatial population genetic structure of the small-spotted catshark (Scyliorhinus canicula), across European seas. The results show significant genetic differences among most of the Mediterranean sample collections, but no significant structure among Atlantic shelf areas. The data suggest the Mediterranean populations are likely to have persisted in a stable and structured environment during Pleistocene sea-level changes. Conversely, the Northeast Atlantic populations would have experienced major changes in habitat availability during glacial cycles, driving patterns of population reduction and expansion. The data also provide evidence of male-biased dispersal and female philopatry over large spatial scales, implying complex sex-determined differences in the behaviour of elasmobranchs. On the basis of this evidence, we suggest that patterns of connectivity are determined by trends of past habitat stability that provides opportunity for local adaptation in species exhibiting philopatric behaviour, implying that resilience of populations to fisheries and other stressors may differ across the range of species. PMID- 26064557 TI - City life makes females fussy: sex differences in habitat use of temperate bats in urban areas. AB - Urbanization is a major driver of the global loss of biodiversity; to mitigate its adverse effects, it is essential to understand what drives species' patterns of habitat use within the urban matrix. While many animal species are known to exhibit sex differences in habitat use, adaptability to the urban landscape is commonly examined at the species level, without consideration of intraspecific differences. The high energetic demands of pregnancy and lactation in female mammals can lead to sexual differences in habitat use, but little is known of how this might affect their response to urbanization. We predicted that female Pipistrellus pygmaeus would show greater selectivity of forging locations within urban woodland in comparison to males at both a local and landscape scale. In line with these predictions, we found there was a lower probability of finding females within woodlands which were poorly connected, highly cluttered, with a higher edge : interior ratio and fewer mature trees. By contrast, habitat quality and the composition of the surrounding landscape were less of a limiting factor in determining male distributions. These results indicate strong sexual differences in the habitat use of fragmented urban woodland, and this has important implications for our understanding of the adaptability of bats and mammals more generally to urbanization. PMID- 26064558 TI - An investigation of the false discovery rate and the misinterpretation of p values. AB - If you use p=0.05 to suggest that you have made a discovery, you will be wrong at least 30% of the time. If, as is often the case, experiments are underpowered, you will be wrong most of the time. This conclusion is demonstrated from several points of view. First, tree diagrams which show the close analogy with the screening test problem. Similar conclusions are drawn by repeated simulations of t-tests. These mimic what is done in real life, which makes the results more persuasive. The simulation method is used also to evaluate the extent to which effect sizes are over-estimated, especially in underpowered experiments. A script is supplied to allow the reader to do simulations themselves, with numbers appropriate for their own work. It is concluded that if you wish to keep your false discovery rate below 5%, you need to use a three-sigma rule, or to insist on p<=0.001. And never use the word 'significant'. PMID- 26064559 TI - Mitigating the Goldilocks effect: the effects of different substrate models on track formation potential. AB - In ichnology, the Goldilocks effect describes a scenario in which a substrate must be 'just right' in order for tracks to form-too soft, the animal will be unable to traverse the area, and too firm, the substrate will not deform. Any given substrate can therefore only preserve a range of tracks from those animals which exert an underfoot pressure at approximately the yield strength of the sediment. However, rarely are substrates vertically homogeneous for any great depth, varying either due to heterogeneity across sediment layers, or from mechanical behaviour such as strain hardening. Here, we explore the specificity of the Goldilocks effect in a number of virtual substrates simulated using finite element analysis. We find that the inclusion of strain hardening into the model increases the potential range of trackmaker sizes somewhat, compared with a simple elastic-perfectly plastic model. The simulation of a vertically heterogeneous, strain hardening substrate showed a much larger range of potential trackmakers than strain hardening alone. We therefore show that the Goldilocks effect is lessened to varying degrees by the inclusion of more realistic soil parameters, though there still remains an upper and lower limit to the size of trackmaker able to traverse the area while leaving footprints. PMID- 26064560 TI - Comparative osteohistology of Hesperornis with reference to pygoscelid penguins: the effects of climate and behaviour on avian bone microstructure. AB - The broad biogeographic distribution of Hesperornis fossils in Late Cretaceous Western Interior Seaway deposits has prompted questions about whether they endured polar winters or migrated between mid- and high latitudes. Here, we compare microstructures of hesperornithiform long bones from Kansas and the Arctic to investigate whether migration or Late Cretaceous polar climate affected bone growth. We also examine modern penguin bones to determine how migration and climate may influence bone growth in birds with known behaviours. Histological analysis of hesperornithiform samples reveals continuous bone deposition throughout the cortex, plus an outer circumferential layer in adults. No cyclic growth marks, zonation or differences in vasculature are apparent in the Hesperornis specimens. Comparatively, migratory Adelie and chinstrap penguin bones show no zonation or changes in microstructure, suggesting that migration is not necessarily recorded in avian bone microstructure. Non-migratory gentoos show evidence of rapid bone growth possibly associated with increased chick growth rates in high-latitude populations and large body size. The absence of histological evidence for migration in extinct Hesperornis and extant pygoscelid penguins may reflect that these birds reached skeletal maturity before migration or overwintering. This underscores the challenges of using bone microstructure to infer the effects of behaviour and climate on avian growth. PMID- 26064561 TI - Remote sensing and conservation of isolated indigenous villages in Amazonia. AB - The vast forests on the border between Brazil and Peru harbour a number of indigenous groups that have limited contact with the outside world. Accurate estimates of population sizes and village areas are essential to begin assessing the immediate conservation needs of such isolated groups. In contrast to overflights and encounters on the ground, remote sensing with satellite imagery offers a safe, inexpensive, non-invasive and systematic approach to provide demographic and land-use information for isolated peoples. Satellite imagery can also be used to understand the growth of isolated villages over time. There are five isolated villages in the headwaters of the Envira River confirmed by overflights that are visible with recent satellite imagery further confirming their locations and allowing measurement of their cleared gardens, village areas and thatch roofed houses. These isolated villages appear to have population densities that are an order of magnitude higher than averages for other Brazilian indigenous villages. Here, we report on initial results of a remote surveillance programme designed to monitor movements and assess the demographic health of isolated peoples as a means to better mitigate against external threats to their long-term survival. PMID- 26064562 TI - Sex-biased avian host use by arbovirus vectors. AB - Prevalence of arthropod-borne parasites often differs drastically between host sexes. This sex-related disparity may be related to physiological (primarily hormonal) differences that facilitate or suppress replication of the pathogen in host tissues. Alternately, differences in pathogen prevalence between host sexes may be owing to differential exposure to infected vectors. Here, we report on the use of PCR-based assays recognizing bird sex chromosomes to investigate sex related patterns of avian host use from field-collected female mosquitoes from Florida, USA. Mosquitoes took more bloodmeals from male birds (64.0% of 308 sexed samples) than female birds (36.0%), deviating significantly from a hypothetical 1:1 sex ratio. In addition, male-biased host use was consistent across mosquito species (Culex erraticus (64.4%); Culex nigripalpus (61.0%) and Culiseta melanura (64.9%)). Our findings support the hypothesis that sex-biased exposure to vector borne pathogens contributes to disparities in parasite/pathogen prevalence between the sexes. While few studies have yet to investigate sex-biased host use by mosquitoes, the methods used here could be applied to a variety of mosquito borne disease systems, including those that affect health of humans, domestic animals and wildlife. Understanding the mechanisms that drive sex-based disparities in host use may lead to novel strategies for interrupting pathogen/parasite transmission. PMID- 26064563 TI - Tooth serration morphologies in the genus Machimosaurus (Crocodylomorpha, Thalattosuchia) from the Late Jurassic of Europe. AB - Machimosaurus was a large-bodied durophagous/chelonivorous genus of teleosaurid crocodylomorph that lived in shallow marine and brackish ecosystems during the Late Jurassic. Among teleosaurids, Machimosaurus and its sister taxon 'Steneosaurus' obtusidens are characterized by having foreshortened rostra, proportionally enlarged supratemporal fenestrae and blunt teeth with numerous apicobasal ridges and a shorter anastomosed ridged pattern in the apical region. A recent study on 'S.' obtusidens dentition found both true denticles and false serrations (enamel ridges which contact the carinae). Here, we comprehensively describe and figure the dentition of Machimosaurus, and find that Machimosaurus buffetauti and Machimosaurus hugii have four types of serration or serration-like structures, including both denticles and false denticles on the carinae. The denticles are irregularly shaped and are not always discrete units, whereas the false denticles caused by the interaction between the superficial enamel ridges and the carinae are restricted to the apical region. Peculiarly, the most 'denticle-like' structures are discrete, bulbous units on the apicobasal and apical anastomosed ridges of M. hugii. These 'pseudo-denticles' have never, to our knowledge, previously been reported among crocodylomorphs, and their precise function is unclear. They may have increased the surface area of the apical region and/or strengthened the enamel, both of which would have been advantageous for a durophagous taxon feeding on hard objects such as turtles. PMID- 26064564 TI - Seasonal dynamics of megafauna on the deep West Antarctic Peninsula shelf in response to variable phytodetrital influx. AB - The deep West Antarctic Peninsula (WAP) shelf is characterized by intense deposition of phytodetritus during spring/summer months, while very little food material reaches the seafloor during winter. The response of the shelf benthic megafauna to this highly variable food supply is still poorly understood. In order to characterize the deposition of phytodetritus and the megabenthic community response, we deployed a seafloor time-lapse camera at approximately 590 m depth on the mid WAP shelf west of Anvers Island for 15 months. Seafloor photographs were taken at intervals of 12 or 24 h nearly continuously from 9 December 1999 (austral winter) to 20 March 2001 (summer) and analysed for phytodetritus deposition and megafaunal dynamics. Seafloor images indicated a marked seasonal arrival of greenish phytodetritus, with large interannual and seasonal variability in the coverage of depositing phytodetrital particles. The surface-deposit-feeding elasipod holothurians Protelpidia murrayi and Peniagone vignoni dominated the epibenthic megafauna throughout the year, frequently constituting more than 80% of the megafaunal abundance, attaining total densities of up to 2.4 individuals m(-2). Elasipod abundances were significantly higher in summer than winter. During summer periods of high phytodetrital flux, Pr. murrayi produced faecal casts at higher rates, indicating intensified population-level feeding activity. In March-June 2000, faecal casts lasted longest, suggesting lower horizontal bioturbation activity during autumn-winter. Our data indicate that the Pr. murrayi population increases its feeding rates in response to increasing amounts and/or lability of organic matter on the sediment surface. Assuming that this species feeds on the top millimetre of the sediment, we estimate that, during periods of high phytodetrital flux, the Pr. murrayi population reworks one square metre of sediment surface in approximately 287 days. We suggest that Pr. murrayi is an important species for organic-carbon recycling on the deep WAP shelf, controlling the availability of deposited labile phytodetritus to the broader shelf benthic community. PMID- 26064565 TI - Egg shape changes at the theropod-bird transition, and a morphometric study of amniote eggs. AB - The eggs of amniotes exhibit a remarkable variety of shapes, from spherical to elongate and from symmetrical to asymmetrical. We examine eggshell geometry in a diverse sample of fossil and living amniotes using geometric morphometrics and linear measurements. Our goal is to quantify patterns of morphospace occupation and shape variation in the eggs of recent through to Mesozoic birds (neornithe plus non-neornithe avialans), as well as in eggs attributed to non-avialan theropods. In most amniotes, eggs show significant deviation from sphericity, but departure from symmetry around the equatorial axis is mostly confined to theropods and birds. Mesozoic bird eggs differ significantly from extant bird eggs, but extinct Cenozoic bird eggs do not. This suggests that the range of egg shapes in extant birds had already been attained in the Cenozoic. We conclude with a discussion of possible biological factors imparting variation to egg shapes during their formation in the oviduct. PMID- 26064566 TI - Dynamics of osmosis in a porous medium. AB - We derive from kinetic theory, fluid mechanics and thermodynamics the minimal continuum-level equations governing the flow of a binary, non-electrolytic mixture in an isotropic porous medium with osmotic effects. For dilute mixtures, these equations are linear and in this limit provide a theoretical basis for the widely used semi-empirical relations of Kedem & Katchalsky (Kedem & Katchalsky 1958 Biochim. Biophys. Acta 27, 229-246 (doi:10.1016/0006-3002(58)90330-5), which have hitherto been validated experimentally but not theoretically. The above linearity between the fluxes and the driving forces breaks down for concentrated or non-ideal mixtures, for which our equations go beyond the Kedem-Katchalsky formulation. We show that the heretofore empirical solute permeability coefficient reflects the momentum transfer between the solute molecules that are rejected at a pore entrance and the solvent molecules entering the pore space; it can be related to the inefficiency of a Maxwellian demi-demon. PMID- 26064567 TI - Stick, partial slip and sliding in the plane strain micro contact of two elastic bodies. AB - The plane strain problem of a curved elastic body pressed against an elastic half space is considered. The effect of adhesion is included through the use of surface energy in a manner similar to the well-known JKR theory for spherical contacts. The compressive normal force is held constant while a tangential force is gradually increased from zero. The contact is characterized by complete stick up to a critical value of the tangential force when there is a transition either directly to complete sliding or to a partial slip state in which a central stick region is surrounded by two slip regions. In the latter case, at a finite value of the stick zone width, a second critical condition exists at which there is a transition from partial slip to complete sliding. This behaviour is determined for a range of dimensionless values of the work of adhesion, the assumed constant shear stress during slip/sliding and the initial compressive load. PMID- 26064568 TI - Strong biomechanical constraints on young children's mental imagery of hands. AB - Mental rotation (MR) of body parts is a useful paradigm to investigate how people manipulate mental imagery related to body schema. It has been documented that adult participants use 'motor imagery' for MR of hands: a behavioural indication is a biomechanical effect, that is, hand pictures in orientations to which imitative hand movement would be biomechanically difficult require longer response times to be visually identified as the left or right hand. However, little is known about the typical developmental trajectory of the biomechanical effect, which could offer clues to understanding how children acquire the ability to manipulate body schema. This study investigated developmental changes in the biomechanical effect in schoolchildren. Eighty-four children (from 6 to 11 years old, grouped into 1st, 2nd, 3rd, 4th and 5th graders) and fifteen adults made hand laterality judgements in an MR paradigm. The results indicated that the biomechanical effect is stronger for younger children, and that there is a transitional period (around 7-8 years) during which children shift from action execution to imagery in manipulating body schema. The results suggest that mental imagery of hands has a stronger motor aspect in the transitional period than later in childhood and adulthood. PMID- 26064569 TI - Endocranial and masticatory muscle volumes in myostatin-deficient mice. AB - Structural and functional trade-offs are integral to the evolution of the mammalian skull and its development. This paper examines the potential for enlargement of the masticatory musculature to limit the size of the endocranial cavity by studying a myostatin-deficient mouse model of hypermuscularity (MSTN-/ ). The study tests the null prediction that the larger MSTN-/- mice have larger brains compared with wild-type (WT) mice in order to service the larger muscles. Eleven post-mortem MSTN-/- mice and 12 WT mice were imaged at high resolution using contrast enhanced micro-CT. Masticatory muscle volumes (temporalis, masseter, internal and external pterygoids) and endocranial volumes were measured on the basis of two-dimensional manual tracings and the Cavalieri principle. Volumes were compared using Kruskal-Wallis and Student's t-tests. Results showed that the masticatory muscles of the MSTN-/- mice were significantly larger than in the WT mice. Increases were in the region of 17-36% depending on the muscle. Muscles increased in proportion to each other, maintaining percentages in the region of 5, 10, 21 and 62% of total muscle volume for the external ptyergoid, internal pterygoid, temporalis and masseter, respectively. Kruskal-Wallis and t tests demonstrated that the endocranial volume was significantly larger in the WT mice, approximately 16% larger on average than that seen in the MSTN-/- mice. This comparative reduction of MSTN-/- endocranial size could not be explained in terms of observer bias, ageing, sexual dimorphism or body size scaling. That the results showed a reduction of brain size associated with an increase of muscle size falsifies the null prediction and lends tentative support to the view that the musculature influences brain growth. It remains to be determined whether the observed effect is primarily physical, nutritional, metabolic or molecular in nature. PMID- 26064570 TI - Supervised learning from human performance at the computationally hard problem of optimal traffic signal control on a network of junctions. AB - Optimal switching of traffic lights on a network of junctions is a computationally intractable problem. In this research, road traffic networks containing signallized junctions are simulated. A computer game interface is used to enable a human 'player' to control the traffic light settings on the junctions within the simulation. A supervised learning approach, based on simple neural network classifiers can be used to capture human player's strategies in the game and thus develop a human-trained machine control (HuTMaC) system that approaches human levels of performance. Experiments conducted within the simulation compare the performance of HuTMaC to two well-established traffic-responsive control systems that are widely deployed in the developed world and also to a temporal difference learning-based control method. In all experiments, HuTMaC outperforms the other control methods in terms of average delay and variance over delay. The conclusion is that these results add weight to the suggestion that HuTMaC may be a viable alternative, or supplemental method, to approximate optimization for some practical engineering control problems where the optimal strategy is computationally intractable. PMID- 26064571 TI - The use of body condition and haematology to detect widespread threatening processes in sleepy lizards (Tiliqua rugosa) in two agricultural environments. AB - Agricultural practices, including habitat alteration and application of agricultural chemicals, can impact wildlife resulting in their decline. Determining which of these practices are contributing to declines is essential if the declines are to be reversed. In this study, the health of two geographically separated sleepy lizard (Tiliqua rugosa) populations was compared between a rangeland environment and cropping environment using linear body size index (LBSI) and haematology. Animals in the cropping site were smaller, suggesting genetic differences as the result of geographical isolation. The animals in the cropping site had a lower LBSI and many were experiencing a regenerative anaemia. The anaemia was postulated to be the cause of the low LBSI. The anaemia appeared to be the result of haemolysis and was likely to be caused by exposure to agricultural chemicals applied in the cropping site but not the rangeland site. Elevated white blood cell counts in lizards in the rangeland site suggested that they were experiencing an inflammatory disease of possible ecological significance. Together, these results demonstrate the value of combining physical and haematological parameters when studying the impact of agricultural practices on wildlife. They also show that reptiles may be useful as sentinel species for livestock and humans. PMID- 26064572 TI - Graphlet signature-based scoring method to estimate protein-ligand binding affinity. AB - Over the years, various computational methodologies have been developed to understand and quantify receptor-ligand interactions. Protein-ligand interactions can also be explained in the form of a network and its properties. The ligand binding at the protein-active site is stabilized by formation of new interactions like hydrogen bond, hydrophobic and ionic. These non-covalent interactions when considered as links cause non-isomorphic sub-graphs in the residue interaction network. This study aims to investigate the relationship between these induced sub-graphs and ligand activity. Graphlet signature-based analysis of networks has been applied in various biological problems; the focus of this work is to analyse protein-ligand interactions in terms of neighbourhood connectivity and to develop a method in which the information from residue interaction networks, i.e. graphlet signatures, can be applied to quantify ligand affinity. A scoring method was developed, which depicts the variability in signatures adopted by different amino acids during inhibitor binding, and was termed as GSUS (graphlet signature uniqueness score). The score is specific for every individual inhibitor. Two well known drug targets, COX-2 and CA-II and their inhibitors, were considered to assess the method. Residue interaction networks of COX-2 and CA-II with their respective inhibitors were used. Only hydrogen bond network was considered to calculate GSUS and quantify protein-ligand interaction in terms of graphlet signatures. The correlation of the GSUS with pIC50 was consistent in both proteins and better in comparison to the Autodock results. The GSUS scoring method was better in activity prediction of molecules with similar structure and diverse activity and vice versa. This study can be a major platform in developing approaches that can be used alone or together with existing methods to predict ligand affinity from protein-ligand complexes. PMID- 26064573 TI - The deep sea is a major sink for microplastic debris. AB - Marine debris, mostly consisting of plastic, is a global problem, negatively impacting wildlife, tourism and shipping. However, despite the durability of plastic, and the exponential increase in its production, monitoring data show limited evidence of concomitant increasing concentrations in marine habitats. There appears to be a considerable proportion of the manufactured plastic that is unaccounted for in surveys tracking the fate of environmental plastics. Even the discovery of widespread accumulation of microscopic fragments (microplastics) in oceanic gyres and shallow water sediments is unable to explain the missing fraction. Here, we show that deep-sea sediments are a likely sink for microplastics. Microplastic, in the form of fibres, was up to four orders of magnitude more abundant (per unit volume) in deep-sea sediments from the Atlantic Ocean, Mediterranean Sea and Indian Ocean than in contaminated sea-surface waters. Our results show evidence for a large and hitherto unknown repository of microplastics. The dominance of microfibres points to a previously underreported and unsampled plastic fraction. Given the vastness of the deep sea and the prevalence of microplastics at all sites we investigated, the deep-sea floor appears to provide an answer to the question-where is all the plastic? PMID- 26064574 TI - Males migrate farther than females in a differential migrant: an examination of the fasting endurance hypothesis. AB - Patterns of migration including connectivity between breeding and non-breeding populations and intraspecific variation in the distance travelled are important to study because they can affect individual fitness and population dynamics. Using data from 182 band recoveries across North America and 17 light-level geolocators, we examined the migration patterns of the northern flicker (Colaptes auratus), a migratory woodpecker. This species is unusual among birds because males invest more in parental care than females. Breeding latitude was positively correlated to migration distance because populations in the north appeared to travel farther distances than southern populations to find wintering locations with little snow cover. Connectivity was strong for populations west and east of the Continental Divide. Contrary to the three main hypotheses for intraspecific variation in migration distance, females wintered, on average, farther north than males, although there was overlap throughout their non-breeding range. This pattern contradicts those of other species found to date and is most consistent with the fasting endurance hypothesis if investment in parental care depletes the energy reserves of male flickers more than females. We thus propose a new factor, parental effort, which may influence optimal wintering areas and migration strategies within birds, and encourage future experimental studies to test the relationship between parental care roles and migration strategies of the sexes. PMID- 26064575 TI - Potency of irritation by benzylidenemalononitriles in humans correlates with TRPA1 ion channel activation. AB - We show that the physiological activity of solid aerosolized benzylidenemalononitriles (BMNs) including 'tear gas' (CS) in historic human volunteer trials correlates with activation of the human transient receptor potential ankyrin 1 ion channel (hTRPA1). This suggests that the irritation caused by the most potent of these compounds results from activation of this channel. We prepared 50 BMNs and measured their hTRPA1 agonist potencies. A mechanism of action consistent with their physiological activity, involving their dissolution in water on contaminated body surfaces, cell membrane penetration and reversible thiolation by a cysteine residue of hTRPA1, supported by data from nuclear magnetic resonance experiments with a model thiol, explains the structure activity relationships. The correlation provides evidence that hTRPA1 is a receptor for irritants on nociceptive neurons involved in pain perception; thus, its activation in the eye, nose, mouth and skin would explain the symptoms of lachrymation, sneezing, coughing and stinging, respectively. The structure activity results and the use of the BMNs as pharmacological tools in future by other researchers may contribute to a better understanding of the TRPA1 channel in humans (and other animals) and help facilitate the discovery of treatments for human diseases involving this receptor. PMID- 26064576 TI - Surface drag reduction and flow separation control in pelagic vertebrates, with implications for interpreting scale morphologies in fossil taxa. AB - Living in water imposes severe constraints on the evolution of the vertebrate body. As a result of these constraints, numerous extant and extinct aquatic vertebrate groups evolved convergent osteological and soft-tissue adaptations. However, one important suite of adaptations is still poorly understood: dermal cover morphologies and how they influence surface fluid dynamics. This is especially true for fossil aquatic vertebrates where the soft tissue of the dermis is rarely preserved. Recent studies have suggested that the keeled scales of mosasaurids (pelagic lizards that lived during the Late Cretaceous) aided in surface frictional drag reduction in a manner analogous to the riblets on shark placoid scales. However, here we demonstrate that mosasaurid scales were over an order of magnitude too large to have this effect. More likely they increased the frictional drag of the body and may have played a role in controlling flow separation by acting as surface roughness that turbulated the boundary layer. Such a role could have reduced pressure drag and enhanced manoeuvrability. We caution those studying fossil aquatic vertebrates from positing the presence of surface drag reducing morphologies, because as we show herein, to be effective such features need to have a spacing of approximately 0.1 mm or less. PMID- 26064577 TI - Female signalling to male song in the domestic canary, Serinus canaria. AB - Most studies on sexual selection focus on male characteristics such as male song in songbirds. Yet female vocalizations in songbirds are growing in interest among behavioural and evolutionary biologists because these vocalizations can reveal the female's preferences for male traits and may affect male display. This study was designed to test whether male song performance influences the different female signals in the domestic canary (Serinus canaria). Female canaries were exposed to three types of song performance, differing in the repetition rate of sexy syllables. This experiment demonstrates that female birds are engaged in multimodal communication during sexual interaction. The results support the copulation solicitation hypothesis for female-specific trills: these trills were positively correlated and had a similar pattern to the copulation solicitation displays; responses were higher to the songs with higher performance and responses decreased with the repetition of the stimulation. Also, we observed a sensitization effect with the repetition of the song of the highest performance for the simple calls. Simple trills and other calls were more frequent during the broadcast of canary songs compared with the heterospecific control songs. The differential use of female signals in response to different song performance reveals a highly differentiated female signalling system which is discussed in light of the role of female traits to understand sexual selection in a broader perspective. PMID- 26064578 TI - Repeatability in the contact calling system of Spix's disc-winged bat (Thyroptera tricolor). AB - Spix's disc-winged bat (Thyroptera tricolor) forms cohesive groups despite using an extremely ephemeral roost, partly due to the use of two acoustic signals that help individuals locate roost sites and group members. While the calls that aid in group cohesion are commonly used, some bats rarely or never produce them. Here, we examine whether the differences observed in the contact calling behaviour of T. tricolor are repeatable; that is, whether individual differences are consistent. We recorded contact calls of individuals in the field and rates and patterns of vocalization. To determine whether measured variables were consistent within individuals, we estimated repeatability (R), which compares within-individual to among-individual variance in behavioural traits. Our results show that repeatability for call variables was moderate but significant, and that repeatability was highest for the average number of calls produced (R=0.46-0.49). Our results demonstrate important individual differences in the contact calling behaviour of T. tricolor; we discuss how these could be the result of mechanisms such as frequency-dependent selection that favour groups composed of individuals with diverse vocal strategies. Future work should address whether changes in social environment, specifically group membership and social status, affect vocal behaviour. PMID- 26064579 TI - Reproduction of Pisidium casertanum (Poli, 1791) in Arctic lake. AB - Freshwater invertebrates are able to develop specific ecological adaptations that enable them to successfully inhabit an extreme environment. We investigated the brooding bivalve of Pisidium casertanum in Talatinskoe Lake, Vaigach Island, Arctic Russia. Here, quantitative surveys were conducted, with the collection and dissections of 765 molluscs, on the basis of which analyses on the brood sacs length (marsupia) and the number and size of embryos, were performed. In this study, the number of brooded embryos was positively correlated with the parent's shell length. The number of extramarsupial embryos was much lower than the number of intramarsupial embryos. Our research also showed that the brood sac length and embryos within one individual can vary significantly. Thus, we detected that P. casertanum has a specific brooding mechanism, accompanied by asynchronous development and embryos release by the parent. We suggest that such a mode could result in the coin-flipping effect that, presumably, increases the population breeding success in the harsh environment of the Arctic lake. PMID- 26064580 TI - Nearest-neighbour clusters as a novel technique for assessing group associations. AB - When all the individuals in a social group can be easily identified, one of the simplest measures of social interaction that can be recorded is nearest-neighbour identity. Many field studies use sequential scan samples of groups to build up association metrics using these nearest-neighbour identities. Here, I describe a simple technique for identifying clusters of associated individuals within groups that uses nearest-neighbour identity data. Using computer-generated datasets with known associations, I demonstrate that this clustering technique can be used to build data suitable for association metrics, and that it can generate comparable metrics to raw nearest-neighbour data, but with much less initial data. This technique could therefore be of use where it is difficult to generate large datasets. Other situations where the technique would be useful are discussed. PMID- 26064581 TI - Generalist-specialist trade-off during thermal acclimation. AB - The shape of performance curves and their plasticity define how individuals and populations respond to environmental variability. In theory, maximum performance decreases with an increase in performance breadth. However, reversible acclimation may counteract this generalist-specialist trade-off, because performance optima track environmental conditions so that there is no benefit of generalist phenotypes. We tested this hypothesis by acclimating individual mosquitofish (Gambusia holbrooki) to cool and warm temperatures consecutively and measuring performance curves of swimming performance after each acclimation treatment. Individuals from the same population differed significantly in performance maxima, performance breadth and the capacity for acclimation. As predicted, acclimation resulted in a shift of the temperature at which maximal performance occurred. Within acclimation treatments, there was a significant generalist-specialist trade-off in responses to acute temperature change. Surprisingly, however, there was also a trade-off across acclimation treatments, and animals with greater capacity for cold acclimation had lower performance maxima under warm conditions. Hence, cold acclimation may be viewed as a generalist strategy that extends performance breadth at the colder seasons, but comes at the cost of reduced performance at the warmer time of year. Acclimation therefore does not counteract a generalist-specialist trade-off and, at least in mosquitofish, the trade-off seems to be a system property that persists despite phenotypic plasticity. PMID- 26064582 TI - Mid-winter temperatures, not spring temperatures, predict breeding phenology in the European starling Sturnus vulgaris. AB - In many species, empirical data suggest that temperatures less than 1 month before breeding strongly influence laying date, consistent with predictions that short lag times between cue and response are more reliable, decreasing the chance of mismatch with prey. Here we show in European starlings (Sturnus vulgaris) that mid-winter temperature ca 50-90 days before laying (8 January-22 February) strongly (r (2) = 0.89) predicts annual variation in laying date. Mid-winter temperature also correlated highly with relative clutch size: birds laid later, but laid larger clutches, in years when mid-winter temperatures were lower. Despite a high degree of breeding synchrony (mean laying date 5-13 April = +/-4 days; 80% of nests laid within 4.8 days within year), European starlings show strong date-dependent variation in clutch size and productivity, but this appears to be mediated by a different temporal mechanism for integration of supplemental cue (temperature) information. We suggest the relationship between mid-winter temperature and breeding phenology might be indirect with both components correlating with a third factor: temperature-dependent development of the starling's insect (tipulid) prey. Mid-winter temperatures might set the trajectory of growth and final biomass of tipulid larvae, with this temperature cue providing starlings with information on breeding season prey availability (though exactly how remains unknown). PMID- 26064583 TI - River temperature drives salmon survivorship: is it determined prior to ocean entry? AB - Early life is believed to be a critical stage for determining survivorship in all fish. Many studies have suggested that environmental conditions in the ocean determine the fry-to-adult survival rate of Pacific salmon but few investigations have been conducted on the importance of the brief freshwater period during the seaward migration on overall survivorship. Here, we found that most of the variation in survivorship of hatchery-reared chum salmon (Oncorhynchus keta) was explained by river temperature during the fry stage, despite spending most of their life (approx. 99%) at sea. After the annual release of a constant number of fry, the number of fry moving through the river at a downstream location varied greatly. The number of returning adults was positively correlated with the number of fry moving downstream. This result suggests that most salmon mortality occurred prior to ocean entry, and that short-term mortality in the river is a key factor determining major fluctuations in total mortality. Although marine mortality is often invoked in the literature as a key factor determining total mortality of chum salmon, attention should also be paid to freshwater mortality to understand the population dynamics of this species. PMID- 26064584 TI - Building a responsive teacher: how temporal contingency of gaze interaction influences word learning with virtual tutors. AB - Animated pedagogical agents are lifelike virtual characters designed to augment learning. A review of developmental psychology literature led to the hypothesis that the temporal contingency of such agents would promote human learning. We developed a Pedagogical Agent with Gaze Interaction (PAGI), an experimental animated pedagogical agent that engages in gaze interaction with students. In this study, university students learned words of a foreign language, with temporally contingent PAGI (live group) or recorded version of PAGI (recorded group), which played pre-recorded sequences from live sessions. The result revealed that students in the live group scored considerably better than those in the recorded group. The finding indicates that incorporating temporal contingency of gaze interaction from a pedagogical agent has positive effect on learning. PMID- 26064585 TI - Emotion recognition deficits in eating disorders are explained by co-occurring alexithymia. AB - Previous research has yielded inconsistent findings regarding the ability of individuals with eating disorders (EDs) to recognize facial emotion, making the clinical features of this population hard to determine. This study tested the hypothesis that where observed, emotion recognition deficits exhibited by patients with EDs are due to alexithymia, a co-occurring condition also associated with emotion recognition difficulties. Ability to recognize facial emotion was investigated in a sample of individuals with EDs and varying degrees of co-occurring alexithymia, and an alexithymia-matched control group. Alexithymia, but not ED symptomology, was predictive of individuals' emotion recognition ability, inferred from tolerance to high-frequency visual noise. This relationship was specific to emotion recognition, as neither alexithymia nor ED symptomology was associated with ability to recognize facial identity. These findings suggest that emotion recognition difficulties exhibited by patients with ED are attributable to alexithymia, and may not be a feature of EDs per se. PMID- 26064586 TI - Opsin transcripts of predatory diving beetles: a comparison of surface and subterranean photic niches. AB - The regressive evolution of eyes has long intrigued biologists yet the genetic underpinnings remain opaque. A system of discrete aquifers in arid Australia provides a powerful comparative means to explore trait regression at the genomic level. Multiple surface ancestors from two tribes of diving beetles (Dytiscidae) repeatedly invaded these calcrete aquifers and convergently evolved eye-less phenotypes. We use this system to assess transcription of opsin photoreceptor genes among the transcriptomes of two surface and three subterranean dytiscid species and test whether these genes have evolved under neutral predictions. Transcripts for UV, long-wavelength and ciliary-type opsins were identified from the surface beetle transcriptomes. Two subterranean beetles showed parallel loss of all opsin transcription, as expected under 'neutral' regressive evolution. The third species Limbodessus palmulaoides retained transcription of a long wavelength opsin (lwop) orthologue, albeit in an aphotic environment. Tests of selection on lwop indicated no significant differences between transcripts derived from surface and subterranean habitats, with strong evidence for purifying selection acting on L. palmulaoides lwop. Retention of sequence integrity and the lack of evidence for neutral evolution raise the question of whether we have identified a novel pleiotropic role for lwop, or an incipient phase of pseudogene development. PMID- 26064587 TI - Carry-over body mass effect from winter to breeding in a resident seabird, the little penguin. AB - Using body mass and breeding data of individual penguins collected continuously over 7 years (2002-2008), we examined carry-over effects of winter body mass on timing of laying and breeding success in a resident seabird, the little penguin (Eudyptula minor). The austral winter month of July consistently had the lowest rate of colony attendance, which confirmed our expectation that penguins work hard to find resources at this time between breeding seasons. Contrary to our expectation, body mass in winter (July) was equal or higher than in the period before ('moult-recovery') and after ('pre-breeding') in 5 of 7 years for males and in all 7 years for females. We provided evidence of a carry-over effect of body mass from winter to breeding; females and males with higher body mass in winter were more likely to breed early and males with higher body mass in winter were likely to breed successfully. Sex differences might relate to sex-specific breeding tasks, where females may use their winter reserves to invest in egg laying, whereas males use their winter reserves to sustain the longer fasts ashore during courtship. Our findings suggest that resident seabirds like little penguins can also benefit from a carry-over effect of winter body mass on subsequent breeding. PMID- 26064588 TI - Sex ratio effects on reproductive strategies in humans. AB - Characterizations of coy females and ardent males are rooted in models of sexual selection that are increasingly outdated. Evolutionary feedbacks can strongly influence the sex roles and subsequent patterns of sex differentiated investment in mating effort, with a key component being the adult sex ratio (ASR). Using data from eight Makushi communities of southern Guyana, characterized by varying ASRs contingent on migration, we show that even within a single ethnic group, male mating effort varies in predictable ways with the ASR. At male-biased sex ratios, men's and women's investment in mating effort are indistinguishable; only when men are in the minority are they more inclined towards short-term, low investment relationships than women. Our results support the behavioural ecological tenet that reproductive strategies are predictable and contingent on varying situational factors. PMID- 26064589 TI - Information use by humans during dynamic route choice in virtual crowd evacuations. AB - We conducted a computer-based experiment with over 450 human participants and used a Bayesian model selection approach to explore dynamic exit route choice mechanisms of individuals in simulated crowd evacuations. In contrast to previous work, we explicitly explore the use of time-dependent and time-independent information in decision-making. Our findings suggest that participants tended to base their exit choices on time-dependent information, such as differences in queue lengths and queue speeds at exits rather than on time-independent information, such as differences in exit widths or exit route length. We found weak support for similar decision-making mechanisms under a stress-inducing experimental treatment. However, under this treatment participants were less able or willing to adjust their original exit choice in the course of the evacuation. Our experiment is not a direct test of behaviour in real evacuations, but it does highlight the role different types of information and stress play in real human decision-making in a virtual environment. Our findings may be useful in identifying topics for future study on real human crowd movements or for developing more realistic agent-based simulations. PMID- 26064590 TI - How the zebra got its stripes: a problem with too many solutions. AB - The adaptive significance of zebra stripes has thus far eluded understanding. Many explanations have been suggested, including social cohesion, thermoregulation, predation evasion and avoidance of biting flies. Identifying the associations between phenotypic and environmental factors is essential for testing these hypotheses and substantiating existing experimental evidence. Plains zebra striping pattern varies regionally, from heavy black and white striping over the entire body in some areas to reduced stripe coverage with thinner and lighter stripes in others. We examined how well 29 environmental variables predict the variation in stripe characteristics of plains zebra across their range in Africa. In contrast to recent findings, we found no evidence that striping may have evolved to escape predators or avoid biting flies. Instead, we found that temperature successfully predicts a substantial amount of the stripe pattern variation observed in plains zebra. As this association between striping and temperature may be indicative of multiple biological processes, we suggest that the selective agents driving zebra striping are probably multifarious and complex. PMID- 26064591 TI - Boundary regularized integral equation formulation of the Helmholtz equation in acoustics. AB - A boundary integral formulation for the solution of the Helmholtz equation is developed in which all traditional singular behaviour in the boundary integrals is removed analytically. The numerical precision of this approach is illustrated with calculation of the pressure field owing to radiating bodies in acoustic wave problems. This method facilitates the use of higher order surface elements to represent boundaries, resulting in a significant reduction in the problem size with improved precision. Problems with extreme geometric aspect ratios can also be handled without diminished precision. When combined with the CHIEF method, uniqueness of the solution of the exterior acoustic problem is assured without the need to solve hypersingular integrals. PMID- 26064592 TI - Effect of nutrients and salinity pulses on biomass and growth of Vallisneria americana in lower St Johns River, FL, USA. AB - We determined the interactive effects of nutrient loading and salinity pulsing on Vallisneria americana Michx., the dominant submerged aquatic vegetation species in the lower St Johns River (LSJR), FL, USA, and its associated algal community. Five hundred and ninety 6-inch diameter intact plant plugs of Vallisneria were collected from the LSJR in March 2003 and transported to US Geological Survey mesocosm facilities in Lafayette, LA, USA. A 3*3 experimental design consisting of three nutrient levels (control, 1/3 control and 3* control) and three salinity pulsing regimes (no pulse, 1-pulse at 18 ppt and 2-pulse at 12 and 18 ppt) was implemented with three replicates per treatment for a total of 27 experimental tanks. Salinity pulsing significantly reduced all measured Vallisneria growth parameters including above- and below-ground biomass, areal productivity and leaf area index. Nutrient levels had little effect on plants subjected to salinity pulses, but in non-salinity pulse treatments we observed higher mean macrophyte biomass in the low-nutrient loading treatments. Macroalgal components (epiphytes and surface algal mats) were not significantly different ( p=0.2998 and p=0.2444, respectively), but water column chlorophyll a (phytoplankton) was significantly higher ( p<0.0001) in all salinity pulse treatments except for the 1-pulse, low nutrient treatment. A single salinity pulse at 18 ppt resulted in 22% pot mortality and two consecutive pulses of 18 and 12 ppt resulted in an additional 14% mortality. Individual leaves and ramets lost 59.7% and 67.8%, respectively, in the combined salinity pulse treatments. Nutrient loading tends to have a long term effect on Vallisneria through complex community interactions while salinity pulsing frequency and intensity has an immediate and direct influence on growth and distribution. PMID- 26064593 TI - Brain nonapeptide levels are related to social status and affiliative behaviour in a cooperatively breeding cichlid fish. AB - The mammalian nonapeptide hormones, vasopressin and oxytocin, are known to be potent regulators of social behaviour. Teleost fishes possess vasopressin and oxytocin homologues known as arginine vasotocin (AVT) and isotocin (IT), respectively. The role of these homologous nonapeptides in mediating social behaviour in fishes has received far less attention. The extraordinarily large number of teleost fish species and the impressive diversity of their social systems provide us with a rich test bed for investigating the role of nonapeptides in regulating social behaviour. Existing studies, mostly focused on AVT, have revealed relationships between the nonapeptides, and both social behaviour and dominance status in fishes. To date, much of the work on endogenous nonapeptides in fish brains has measured genomic or neuroanatomical proxies of nonapeptide production rather than the levels of these molecules in the brain. In this study, we measure biologically available AVT and IT levels in the brains of Neolamprologus pulcher, a cooperatively breeding cichlid fish, using high performance liquid chromatography with fluorescence detection. We found that brain AVT levels were higher in the subordinate than in dominant animals, and levels of IT correlated negatively with the expression of affiliative behaviour. We contrast these results with previous studies, and we discuss the role the nonapeptide hormones may play in the regulation of social behaviour in this highly social animal. PMID- 26064594 TI - A new enigmatic Late Miocene mylodontoid sloth from northern South America. AB - A new genus and species of sloth (Eionaletherium tanycnemius gen. et sp. nov.) recently collected from the Late Miocene Urumaco Formation, Venezuela (northern South America) is herein described based on a partial skeleton including associated femora and tibiae. In order to make a preliminary analysis of the phylogenetic affinities of this new sloth we performed a discriminate analysis based on several characters of the femur and tibia of selected Mylodontoidea and Megatherioidea sloths. The consensus tree produced indicates that the new sloth, E. tanycnemius, is a member of the Mylodontoidea. Surprisingly, the new taxon shows some enigmatic features among Neogene mylodontoid sloths, e.g. femur with a robust lesser trochanter that projects medially and the straight distinctly elongated tibia. The discovery of E. tanycnemius increases the diversity of sloths present in the Urumaco sequence to ten taxa. This taxon supports previous studies of the sloth assemblage from the Urumaco sequence as it further indicates that there are several sloth lineages present that are unknown from the better sampled areas of southern South America. PMID- 26064595 TI - Prognostic models in coronary artery disease: Cox and network approaches. AB - Predictive assessment of the risk of developing cardiovascular diseases is usually provided by computational approaches centred on Cox models. The complex interdependence structure underlying clinical data patterns can limit the performance of Cox analysis and complicate the interpretation of results, thus calling for complementary and integrative methods. Prognostic models are proposed for studying the risk associated with patients with known or suspected coronary artery disease (CAD) undergoing vasodilator stress echocardiography, an established technique for CAD detection and prognostication. In order to complement standard Cox models, network inference is considered a possible solution to quantify the complex relationships between heterogeneous data categories. In particular, a mutual information network is designed to explore the paths linking patient-associated variables to endpoint events, to reveal prognostic factors and to identify the best possible predictors of death. Data from a prospective, multicentre, observational study are available from a previous study, based on 4313 patients (2532 men; 64+/-11 years) with known (n=1547) or suspected (n=2766) CAD, who underwent high-dose dipyridamole (0.84 mg kg(-1) over 6 min) stress echocardiography with coronary flow reserve (CFR) evaluation of left anterior descending (LAD) artery by Doppler. The overall mortality was the only endpoint analysed by Cox models. The estimated connectivity between clinical variables assigns a complementary value to the proposed network approach in relation to the established Cox model, for instance revealing connectivity paths. Depending on the use of multiple metrics, the constraints of regression analysis in measuring the association strength among clinical variables can be relaxed, and identification of communities and prognostic paths can be provided. On the basis of evidence from various model comparisons, we show in this CAD study that there may be characteristic factors involved in prognostic stratification whose complexity suggests an exploration beyond the analysis provided by the still fundamental Cox approach. PMID- 26064596 TI - Lognormal Lorenz and normal receiver operating characteristic curves as mirror images. AB - The Lorenz curve for assessing economic inequality depicts the relation between two cumulative distribution functions (CDFs), one for the distribution of incomes or wealth and the other for their first-moment distribution. By contrast, the receiver operating characteristic (ROC) curve for evaluating diagnostic systems depicts the relation between the complements of two CDFs, one for the distribution noise and the other for the distribution of signal plus noise. We demonstrate that the lognormal model of the Lorenz curve, which is often adopted to model the distribution of income and wealth, is a mirror image of the equal variance normal model of the ROC curve, which is a fundamental model for evaluating diagnostic systems. The relationship between these two models extends the potential application of each. For example, the lognormal Lorenz curve can be used to evaluate diagnostic systems derived from equal-variance normal distributions. PMID- 26064597 TI - Prevalent endosymbiont zonation shapes the depth distributions of scleractinian coral species. AB - Bathymetric distributions of photosynthetic marine invertebrate species are relatively well studied, however the importance of symbiont zonation (i.e. hosting of distinct algal endosymbiont communities over depth) in determining these depth distributions still remains unclear. Here, we assess the prevalence of symbiont zonation in tropical scleractinian corals by genotyping the Symbiodinium of the 25 most common species over a large depth range (down to 60 m) on a Caribbean reef. Symbiont depth zonation was found to be common on a reef wide scale (11 out of 25 coral species), and a dominant feature in species with the widest depth distributions. With regards to reproductive strategy, symbiont zonation was more common in broadcasting species, which also exhibited a higher level of polymorphism in the symbiont zonation (i.e. number of different Symbiodinium profiles involved). Species with symbiont zonation exhibited significantly broader depth distributions than those without, highlighting the role of symbiont zonation in shaping the vertical distributions of the coral host. Overall, the results demonstrate that coral reefs can consist of highly structured communities over depth when considering both the coral host and their obligate photosymbionts, which probably has strong implications for the extent of connectivity between shallow and mesophotic habitats. PMID- 26064598 TI - Mechanical analysis of avian feet: multiarticular muscles in grasping and perching. AB - The grasping capability of birds' feet is a hallmark of their evolution, but the mechanics of avian foot function are not well understood. Two evolutionary trends that contribute to the mechanical complexity of the avian foot are the variation in the relative lengths of the phalanges and the subdivision and variation of the digital flexor musculature observed among taxa. We modelled the grasping behaviour of a simplified bird foot in response to the downward and upward forces imparted by carrying and perching tasks, respectively. Specifically, we compared the performance of various foot geometries performing these tasks when actuated by distally inserted flexors only, versus by both distally inserted and proximally inserted flexors. Our analysis demonstrates that most species possess relative phalanx lengths that are conducive to grasps actuated only by a single distally inserted tendon per digit. Furthermore, proximally inserted flexors are often required during perching, but the distally inserted flexors are sufficient when grasping and carrying objects. These results are reflected in differences in the relative development of proximally and distally inserted digital flexor musculature among 'perching' and 'grasping' taxa. Thus, our results shed light on the relative roles of variation in phalanx length and digit flexor muscle distribution in an integrative, mechanical context. PMID- 26064599 TI - Depth specialization in mesophotic corals (Leptoseris spp.) and associated algal symbionts in Hawai'i. AB - Corals at the lower limits of mesophotic habitats are likely to have unique photosynthetic adaptations that allow them to persist and dominate in these extreme low light ecosystems. We examined the host-symbiont relationships from the dominant coral genus Leptoseris in mesophotic environments from Hawai'i collected by submersibles across a depth gradient of 65-125 m. Coral and Symbiodinium genotypes were compared with three distinct molecular markers including coral (COX1-1-rRNA intron) and Symbiodinium (COI) mitochondrial markers and nuclear ITS2. The phylogenetic reconstruction clearly resolved five Leptoseris species, including one species (Leptoseris hawaiiensis) exclusively found in deeper habitats (115-125 m). The Symbiodinium mitochondrial marker resolved three unambiguous haplotypes in clade C, which were found at significantly different frequencies between host species and depths, with one haplotype exclusively found at the lower mesophotic extremes (95-125 m). These patterns of host-symbiont depth specialization indicate that there are limits to connectivity between upper and lower mesophotic zones, suggesting that niche specialization plays a critical role in host-symbiont evolution at mesophotic extremes. PMID- 26064600 TI - Rapid diversification and secondary sympatry in Australo-Pacific kingfishers (Aves: Alcedinidae: Todiramphus). AB - Todiramphus chloris is the most widely distributed of the Pacific's 'great speciators'. Its 50 subspecies constitute a species complex that is distributed over 16 000 km from the Red Sea to Polynesia. We present, to our knowledge, the first comprehensive molecular phylogeny of this enigmatic radiation of kingfishers. Ten Pacific Todiramphus species are embedded within the T. chloris complex, rendering it paraphyletic. Among these is a radiation of five species from the remote islands of Eastern Polynesian, as well as the widespread migratory taxon, Todiramphus sanctus. Our results offer strong support that Pacific Todiramphus, including T. chloris, underwent an extensive range expansion and diversification less than 1 Ma. Multiple instances of secondary sympatry have accumulated in this group, despite its recent origin, including on Australia and oceanic islands in Palau, Vanuatu and the Solomon Islands. Significant ecomorphological and behavioural differences exist between secondarily sympatric lineages, which suggest that pre-mating isolating mechanisms were achieved rapidly during diversification. We found evidence for complex biogeographic patterns, including a novel phylogeographic break in the eastern Solomon Islands that separates a Northern Melanesian clade from Polynesian taxa. In light of our results, we discuss systematic relationships of Todiramphus and propose an updated taxonomy. This paper contributes to our understanding of avian diversification and assembly on islands, and to the systematics of a classically polytypic species complex. PMID- 26064601 TI - Morphological plasticity in a calcifying modular organism: evidence from an in situ transplant experiment in a natural CO2 vent system. AB - Understanding is currently limited of the biological processes underlying the responses of modular organisms to climate change and the potential to adapt through morphological plasticity related to their modularity. Here, we investigate the effects of ocean acidification and seawater warming on the growth, life history and morphological plasticity in the modular bryozoan Calpensia nobilis using transplantation experiments in a shallow Mediterranean volcanic CO2 vents system that simulates pH values expected for the year 2100. Colonies exposed at vent sites grew at approximately half the rate of those from the control site. Between days 34 and 48 of the experiment, they reached a possible 'threshold', due to the combined effects of exposure time and pH. Temperature did not affect zooid length, but longer zooids with wider primary orifices occurred in low pH conditions close to the vents. Growth models describing colony development under different environmental scenarios suggest that stressed colonies of C. nobilis reallocate metabolic energy to the consolidation and strengthening of existing zooids. This is interpreted as a change in life-history strategy to support persistence under unfavourable environmental conditions. Changes in the skeletal morphology of zooids evident in C. nobilis during short-time (87 days) exposure experiments reveal morphological plasticity that may indicate a potential to adapt to the more acidic Mediterranean predicted for the future. PMID- 26064602 TI - Detection dog efficacy for collecting faecal samples from the critically endangered Cross River gorilla (Gorilla gorilla diehli) for genetic censusing. AB - Population estimates using genetic capture-recapture methods from non-invasively collected wildlife samples are more accurate and precise than those obtained from traditional methods when detection and resampling rates are high. Recently, detection dogs have been increasingly used to find elusive species and their by products. Here we compared the effectiveness of dog- and human-directed searches for Cross River gorilla (Gorilla gorilla diehli) faeces at two sites. The critically endangered Cross River gorilla inhabits a region of high biodiversity and endemism on the border between Nigeria and Cameroon. The rugged highland terrain and their cryptic behaviour make them difficult to study and a precise population size for the subspecies is still lacking. Dog-directed surveys located more fresh faeces with less bias than human-directed survey teams. This produced a more reliable population estimate, although of modest precision given the small scale of this pilot study. Unfortunately, the considerable costs associated with use of the United States-based detection dog teams make the use of these teams financially unfeasible for a larger, more comprehensive survey. To realize the full potential of dog-directed surveys and increase cost-effectiveness, we recommend basing dog-detection teams in the countries where they will operate and expanding the targets the dogs are trained to detect. PMID- 26064603 TI - A spectacular new species of seadragon (Syngnathidae). AB - The exploration of Earth's biodiversity is an exciting and ongoing endeavour. Here, we report a new species of seadragon from Western Australia with substantial morphological and genetic differences to the only two other known species. We describe it as Phyllopteryx dewysea n. sp. Although the leafy seadragon (Phycodurus eques) and the common seadragon (Phyllopteryx taeniolatus) occur along Australia's southern coast, generally among relatively shallow macroalgal reefs, the new species was found more offshore in slightly deeper waters. The holotype was trawled east of the remote Recherche Archipelago in 51 m; additional specimens extend the distribution west to Perth in 72 m. Molecular sequence data show clear divergence from the other seadragons (7.4-13.1% uncorrected divergence in mitochondrial DNA) and support a placement as the sister-species to the common seadragon. Radiographs and micro-computed tomography were used on the holotype of the new species and revealed unique features, in addition to its unusual red coloration. The discovery provides a spectacular example of the surprises still hidden in our oceans, even in relatively shallow waters. PMID- 26064604 TI - Sex and hibernaculum temperature predict survivorship in white-nose syndrome affected little brown myotis (Myotis lucifugus). AB - White-nose syndrome (WNS), an emerging infectious disease caused by the novel fungus Pseudogymnoascus destructans, has devastated North American bat populations since its discovery in 2006. The little brown myotis, Myotis lucifugus, has been especially affected. The goal of this 2-year captive study was to determine the impact of hibernacula temperature and sex on WNS survivorship in little brown myotis that displayed visible fungal infection when collected from affected hibernacula. In study 1, we found that WNS-affected male bats had increased survival over females and that bats housed at a colder temperature survived longer than those housed at warmer temperatures. In study 2, we found that WNS-affected bats housed at a colder temperature fared worse than unaffected bats. Our results demonstrate that WNS mortality varies among individuals, and that colder hibernacula are more favourable for survival. They also suggest that female bats may be more negatively affected by WNS than male bats, which has important implications for the long-term survival of the little brown myotis in eastern North America. PMID- 26064605 TI - Spectral analysis of pair-correlation bandwidth: application to cell biology images. AB - Images from cell biology experiments often indicate the presence of cell clustering, which can provide insight into the mechanisms driving the collective cell behaviour. Pair-correlation functions provide quantitative information about the presence, or absence, of clustering in a spatial distribution of cells. This is because the pair-correlation function describes the ratio of the abundance of pairs of cells, separated by a particular distance, relative to a randomly distributed reference population. Pair-correlation functions are often presented as a kernel density estimate where the frequency of pairs of objects are grouped using a particular bandwidth (or bin width), Delta>0. The choice of bandwidth has a dramatic impact: choosing Delta too large produces a pair-correlation function that contains insufficient information, whereas choosing Delta too small produces a pair-correlation signal dominated by fluctuations. Presently, there is little guidance available regarding how to make an objective choice of Delta. We present a new technique to choose Delta by analysing the power spectrum of the discrete Fourier transform of the pair-correlation function. Using synthetic simulation data, we confirm that our approach allows us to objectively choose Delta such that the appropriately binned pair-correlation function captures known features in uniform and clustered synthetic images. We also apply our technique to images from two different cell biology assays. The first assay corresponds to an approximately uniform distribution of cells, while the second assay involves a time series of images of a cell population which forms aggregates over time. The appropriately binned pair-correlation function allows us to make quantitative inferences about the average aggregate size, as well as quantifying how the average aggregate size changes with time. PMID- 26064606 TI - Ectoparasitism shortens the breeding season in a colonial bird. AB - When blood-feeding parasites increase seasonally, their deleterious effects may prevent some host species, especially those living in large groups where parasites are numerous, from reproducing later in the summer. Yet the role of parasites in regulating the length of a host's breeding season-and thus the host's opportunity for multiple brooding-has not been systematically investigated. The highly colonial cliff swallow (Petrochelidon pyrrhonota), a temperate-latitude migratory songbird in the western Great Plains, USA, typically has a relatively short (eight to nine week) breeding season, with birds rarely nesting late in the summer. Colonies at which ectoparasitic swallow bugs (Oeciacus vicarius) were experimentally removed by fumigation were over 45 times more likely to have birds undertake a second round of nesting than were colonies exposed to parasites. Late nesting approximately doubled the length of the breeding season, with some birds raising two broods. Over a 27 year period the percentage of birds engaging in late nesting each year increased at a colony site where parasites were removed annually. This trend could not be explained by changes in group size, climate or nesting phenology during the study. The results suggest that ectoparasitism shortens the cliff swallow's breeding season and probably prevents many individuals from multiple brooding. When this constraint is removed, selection may rapidly favour late nesting. PMID- 26064607 TI - Uncomfortable images produce non-sparse responses in a model of primary visual cortex. AB - The processing of visual information by the nervous system requires significant metabolic resources. To minimize the energy needed, our visual system appears to be optimized to encode typical natural images as efficiently as possible. One consequence of this is that some atypical images will produce inefficient, non optimal responses. Here, we show that images that are reported to be uncomfortable to view, and that can trigger migraine attacks and epileptic seizures, produce relatively non-sparse responses in a model of the primary visual cortex. In comparison with the responses to typical inputs, responses to aversive images were larger and less sparse. We propose that this difference in the neural population response may be one cause of visual discomfort in the general population, and can produce more extreme responses in clinical populations such as migraine and epilepsy sufferers. PMID- 26064608 TI - Pre-zygotic isolation in the macroalgal genus Fucus from four contact zones spanning 100-10 000 years: a tale of reinforcement? AB - Hybrid zones provide an ideal natural experiment to study the selective forces driving evolution of reproductive barriers and speciation. If hybrid offspring are less fit than the parental species, pre-zygotic isolating barriers can evolve and strengthen in response to selection against the hybrids (reinforcement). Four contact zones between the intertidal macroalgae Fucus serratus (Fs) and Fucus distichus (Fd), characterized by varying times of sympatry and order of species introduction provide an opportunity to investigate reinforcement. We examined patterns of hybridization and reproductive isolation between Fs and Fd in: (i) northern Norway (consisting of two natural sites, 10 000 years old), (ii) the Kattegat near Denmark (Fd introduced, nineteenth century) and (iii) Iceland (Fs introduced, nineteenth century). Using 10 microsatellites and chloroplast DNA, we showed that hybridization and introgression decreased with increasing duration of sympatry. The two younger contact zones revealed 13 and 24% hybrids and several F 1 individuals, in contrast to the older contact zone with 2-3% hybrids and an absence of F 1s. Cross-fertilization experiments revealed that the reduction in hybridization in the oldest zone is consistent with increased gametic incompatibility. PMID- 26064609 TI - The missing metric: quantifying contributions of reviewers. AB - The number of contributing reviewers often outnumbers the authors of publications. This has led to apathy towards reviewing and the conclusion that the peer-review system is broken. Given the trade-offs between submitting and reviewing manuscripts, reviewers and authors naturally want visibility for their efforts. While study after study has called for revolutionizing publication practices, the current paradigm does not recognize reviewers' time and expertise. We propose the R-index as a simple way to quantify scientists' contributions as reviewers. We modelled its performance using simulations based on real data to show that early-mid career scientists, who complete high-quality reviews of longer manuscripts within their field, can perform as well as leading scientists reviewing only for high-impact journals. By giving citeable academic recognition for reviewing, R-index will encourage more participation with better reviews, regardless of the career stage. Moreover, the R-index will allow editors to exploit scores to manage and improve their review team, and for journals to promote high average scores as signals of a practical and efficient service to authors. Peer-review is a pervasive necessity across disciplines and the simple utility of this missing metric will credit a valuable aspect of academic productivity without having to revolutionize the current peer-review system. PMID- 26064610 TI - Chromosome interaction over a distance in meiosis. AB - The challenge of cell division is to distribute partner chromosomes (pairs of homologues, pairs of sex chromosomes or pairs of sister chromatids) correctly, one into each daughter cell. In the 'standard' meiosis, this problem is solved by linking partners together via a chiasma and/or sister chromatid cohesion, and then separating the linked partners from one another in anaphase; thus, the partners are kept track of, and correctly distributed. Many organisms, however, properly separate chromosomes in the absence of any obvious physical connection, and movements of unconnected partner chromosomes are coordinated at a distance. Meiotic distance interactions happen in many different ways and in different types of organisms. In this review, we discuss several different known types of distance segregation and propose possible explanations for non-random segregation of distance-segregating chromosomes. PMID- 26064611 TI - The importance of delineating networks by activity type in bottlenose dolphins (Tursiops truncatus) in Cedar Key, Florida. AB - Network analysis has proved to be a valuable tool for studying the behavioural patterns of complex social animals. Often such studies either do not distinguish between different behavioural states of the organisms or simply focus attention on a single behavioural state to the exclusion of all others. In either of these approaches it is impossible to ascertain how the behavioural patterns of individuals depend on the type of activity they are engaged in. Here we report on a network-based analysis of the behavioural associations in a population of bottlenose dolphins (Tursiops truncatus) in Cedar Key, Florida. We consider three distinct behavioural states-socializing, travelling and foraging-and analyse the association networks corresponding to each activity. Moreover, in constructing the different activity networks we do not simply record a spatial association between two individuals as being either present or absent, but rather quantify the degree of any association, thus allowing us to construct weighted networks describing each activity. The results of these weighted activity networks indicate that networks can reveal detailed patterns of bottlenose dolphins at the population level; dolphins socialize in large groups with preferential associations; travel in small groups with preferential associates; and spread out to forage in very small, weakly connected groups. There is some overlap in the socialize and travel networks but little overlap between the forage and other networks. This indicates that the social bonds maintained in other activities are less important as they forage on dispersed, solitary prey. The overall network, not sorted by activity, does not accurately represent any of these patterns. PMID- 26064612 TI - Fundamental formulae for wave-energy conversion. AB - The time-average wave power that is absorbed from an incident wave by means of a wave-energy conversion (WEC) unit, or by an array of WEC units-i.e. oscillating immersed bodies and/or oscillating water columns (OWCs)-may be mathematically expressed in terms of the WEC units' complex oscillation amplitudes, or in terms of the generated outgoing (diffracted plus radiated) waves, or alternatively, in terms of the radiated waves alone. Following recent controversy, the corresponding three optional expressions are derived, compared and discussed in this paper. They all provide the correct time-average absorbed power. However, only the first-mentioned expression is applicable to quantify the instantaneous absorbed wave power and the associated reactive power. In this connection, new formulae are derived that relate the 'added-mass' matrix, as well as a couple of additional reactive radiation-parameter matrices, to the difference between kinetic energy and potential energy in the water surrounding the immersed oscillating WEC array. Further, a complex collective oscillation amplitude is introduced, which makes it possible to derive, by a very simple algebraic method, various simple expressions for the maximum time-average wave power that may be absorbed by the WEC array. The real-valued time-average absorbed power is illustrated as an axisymmetric paraboloid defined on the complex collective amplitude plane. This is a simple illustration of the so-called 'fundamental theorem for wave power'. Finally, the paper also presents a new derivation that extends a recently published result on the direction-average maximum absorbed wave power to cases where the WEC array's radiation damping matrix may be singular and where the WEC array may contain OWCs in addition to oscillating bodies. PMID- 26064613 TI - Dramatic niche shifts and morphological change in two insular bird species. AB - Colonizations of islands are often associated with rapid morphological divergence. We present two previously unrecognized cases of dramatic morphological change and niche shifts in connection with colonization of tropical forest-covered islands. These evolutionary changes have concealed the fact that the passerine birds madanga, Madanga ruficollis, from Buru, Indonesia, and Sao Tome shorttail, Amaurocichla bocagii, from Sao Tome, Gulf of Guinea, are forest adapted members of the family Motacillidae (pipits and wagtails). We show that Madanga has diverged mainly in plumage, which may be the result of selection for improved camouflage in its new arboreal niche, while selection pressures for other morphological changes have probably been weak owing to preadaptations for the novel niche. By contrast, we suggest that Amaurocichla's niche change has led to divergence in both structure and plumage. PMID- 26064614 TI - Eaten alive: cannibalism is enhanced by parasites. AB - Cannibalism is ubiquitous in nature and especially pervasive in consumers with stage-specific resource utilization in resource-limited environments. Cannibalism is thus influential in the structure and functioning of biological communities. Parasites are also pervasive in nature and, we hypothesize, might affect cannibalism since infection can alter host foraging behaviour. We investigated the effects of a common parasite, the microsporidian Pleistophora mulleri, on the cannibalism rate of its host, the freshwater amphipod Gammarus duebeni celticus. Parasitic infection increased the rate of cannibalism by adults towards uninfected juvenile conspecifics, as measured by adult functional responses, that is, the rate of resource uptake as a function of resource density. This may reflect the increased metabolic requirements of the host as driven by the parasite. Furthermore, when presented with a choice, uninfected adults preferred to cannibalize uninfected rather than infected juvenile conspecifics, probably reflecting selection pressure to avoid the risk of parasite acquisition. By contrast, infected adults were indiscriminate with respect to infection status of their victims, probably owing to metabolic costs of infection and the lack of risk as the cannibals were already infected. Thus parasitism, by enhancing cannibalism rates, may have previously unrecognized effects on stage structure and population dynamics for cannibalistic species and may also act as a selective pressure leading to changes in resource use. PMID- 26064615 TI - Social conformity despite individual preferences for distinctiveness. AB - We demonstrate that individual behaviours directed at the attainment of distinctiveness can in fact produce complete social conformity. We thus offer an unexpected generative mechanism for this central social phenomenon. Specifically, we establish that agents who have fixed needs to be distinct and adapt their positions to achieve distinctiveness goals, can nevertheless self-organize to a limiting state of absolute conformity. This seemingly paradoxical result is deduced formally from a small number of natural assumptions and is then explored at length computationally. Interesting departures from this conformity equilibrium are also possible, including divergence in positions. The effect of extremist minorities on these dynamics is discussed. A simple extension is then introduced, which allows the model to generate and maintain social diversity, including multimodal distinctiveness distributions. The paper contributes formal definitions, analytical deductions and counterintuitive findings to the literature on individual distinctiveness and social conformity. PMID- 26064616 TI - Social deprivation affects cooperative predator inspection in a cichlid fish. AB - The social environment individuals are exposed to during ontogeny shapes social skills and social competence in group-living animals. Consequently, social deprivation has serious effects on behaviour and development in animals but little is known about its impact on cooperation. In this study, we examined the effect of social environment on cooperative predator inspection. Predator inspection behaviour is a complex behaviour, which is present in a variety of shoaling fish species. Often, two fish leave the safety of the group and inspect a potentially dangerous predator in order to gather information about the current predation risk. As predator inspection is highly risky, it is prone to conflicts and cheating. However, cooperation among individuals may reduce the individual predation risk. We investigated this complex social behaviour in juveniles of the cichlid fish Pelvicachromis taeniatus that were reared in two different social environments throughout development. Fish reared in a group inspected more often than isolation-reared fish and were more likely to cooperate, i.e. they conducted conjoint inspection of a predator. By contrast, isolation-reared fish were more likely to perform a single inspection without a companion. These results suggest an impairment of cooperative behaviour in isolation-reared fish most probably due to lack of social experience and resulting in lowered social skills needed in coordinated behaviour. PMID- 26064617 TI - Spermatozoa scattering by a microchannel feature: an elastohydrodynamic model. AB - Sperm traverse their microenvironment through viscous fluid by propagating flagellar waves; the waveform emerges as a consequence of elastic structure, internal active moments and low Reynolds number fluid dynamics. Engineered microchannels have recently been proposed as a method of sorting and manipulating motile cells; the interaction of cells with these artificial environments therefore warrants investigation. A numerical method is presented for large amplitude elastohydrodynamic interaction of active swimmers with domain features. This method is employed to examine hydrodynamic scattering by a model microchannel backstep feature. Scattering is shown to depend on backstep height and the relative strength of viscous and elastic forces in the flagellum. In a 'high viscosity' parameter regime corresponding to human sperm in cervical mucus analogue, this hydrodynamic contribution to scattering is comparable in magnitude to recent data on contact effects, being of the order of 5 degrees -10 degrees . Scattering can be positive or negative depending on the relative strength of viscous and elastic effects, emphasizing the importance of viscosity on the interaction of sperm with their microenvironment. The modulation of scattering angle by viscosity is associated with variations in flagellar asymmetry induced by the elastohydrodynamic interaction with the boundary feature. PMID- 26064618 TI - Can differential nutrient extraction explain property variations in a predatory trap? AB - Predators exhibit flexible foraging to facilitate taking prey that offer important nutrients. Because trap-building predators have limited control over the prey they encounter, differential nutrient extraction and trap architectural flexibility may be used as a means of prey selection. Here, we tested whether differential nutrient extraction induces flexibility in architecture and stickiness of a spider's web by feeding Nephila pilipes live crickets (CC), live flies (FF), dead crickets with the web stimulated by flies (CD) or dead flies with the web stimulated by crickets (FD). Spiders in the CD group consumed less protein per mass of lipid or carbohydrate, and spiders in the FF group consumed less carbohydrates per mass of protein. Spiders from the CD group built stickier webs that used less silk, whereas spiders in the FF group built webs with more radii, greater catching areas and more silk, compared with other treatments. Our results suggest that differential nutrient extraction is a likely explanation for prey-induced spider web architecture and stickiness variations. PMID- 26064619 TI - Back to Tanganyika: a case of recent trans-species-flock dispersal in East African haplochromine cichlid fishes. AB - The species flocks of cichlid fishes in the East African Great Lakes are the largest vertebrate adaptive radiations in the world and illustrious textbook examples of convergent evolution between independent species assemblages. Although recent studies suggest some degrees of genetic exchange between riverine taxa and the lake faunas, not a single cichlid species is known from Lakes Tanganyika, Malawi and Victoria that is derived from the radiation associated with another of these lakes. Here, we report the discovery of a haplochromine cichlid species in Lake Tanganyika, which belongs genetically to the species flock of haplochromines of the Lake Victoria region. The new species colonized Lake Tanganyika only recently, suggesting that faunal exchange across watersheds and, hence, between isolated ichthyofaunas, is more common than previously thought. PMID- 26064620 TI - Taking a closer look: disentangling effects of functional diversity on ecosystem functions with a trait-based model across hierarchy and time. AB - Biodiversity and ecosystem functioning (BEF) research has progressed from the detection of relationships to elucidating their drivers and underlying mechanisms. In this context, replacing taxonomic predictors by trait-based measures of functional composition (FC)-bridging functions of species and of ecosystems-is a widely used approach. The inherent challenge of trait-based approaches is the multi-faceted, dynamic and hierarchical nature of trait influence: (i) traits may act via different facets of their distribution in a community, (ii) their influence may change over time and (iii) traits may influence processes at different levels of the natural hierarchy of organization. Here, we made use of the forest ecosystem model 'LPJ-GUESS' parametrized with empirical trait data, which creates output of individual performance, community assembly, stand-level states and processes. To address the three challenges, we resolved the dynamics of the top-level ecosystem function 'annual biomass change' hierarchically into its various component processes (growth, leaf and root turnover, recruitment and mortality) and states (stand structures, water stress) and traced the influence of different facets of FC along this hierarchy in a path analysis. We found an independent influence of functional richness, dissimilarity and identity on ecosystem states and processes and hence biomass change. Biodiversity effects were only positive during early succession and later turned negative. Unexpectedly, resource acquisition (growth, recruitment) and conservation (mortality, turnover) played an equally important role throughout the succession. These results add to a mechanistic understanding of biodiversity effects and place a caveat on simplistic approaches omitting hierarchical levels when analysing BEF relationships. They support the view that BEF relationships experience dramatic shifts over successional time that should be acknowledged in mechanistic theories. PMID- 26064621 TI - Sub-Nyquist artefacts and sampling moire effects. AB - Sampling moire effects are well known in signal processing. They occur when a continuous periodic signal g(x) is sampled using a sampling frequency f s that does not respect the Nyquist condition, and the signal-frequency f folds over and gives a new, false low frequency in the sampled signal. However, some visible beating artefacts may also occur in the sampled signal when g(x) is sampled using a sampling frequency f s which fully respects the Nyquist condition. We call these phenomena sub-Nyquist artefacts. Although these beating effects have already been reported in the literature, their detailed mathematical behaviour is not widely known. In this paper, we study the behaviour of these phenomena and compare it with analogous results from the moire theory. We show that both sampling moires and sub-Nyquist artefacts obey the same basic mathematical rules, in spite of the differences between them. This leads us to a unified approach that explains all of these phenomena and puts them under the same roof. In particular, it turns out that all of these phenomena occur when the signal frequency f and the sampling frequency f s satisfy f~(m/n)f s with integer m, n, where m/n is a reduced integer ratio; cases with n=1 correspond to true sampling moire effects. PMID- 26064622 TI - Crypsis via leg clustering: twig masquerading in a spider. AB - The role of background matching in camouflage has been extensively studied. However, contour modification has received far less attention, especially in twig mimicking species. Here, we studied this deceptive strategy by revealing a special masquerade tactic, in which the animals protract and cluster their legs linearly in the same axis with their bodies when resting, using the spider Ariamnes cylindrogaster as a model. We used cardboard papers to construct dummies resembling spiders in appearance and colour. To differentiate the most important factors in the concealment effect, we manipulated body size (long or short abdomen) and resting postures (leg clustered or spread) of the dummies and recorded the responses of predators to different dummy types in the field. The results showed that dummies with clustered legs received significantly less attention from predators, regardless of the body length. Thus, we conclude that A. cylindrogaster relies on the resting posture rather than body size for predator avoidance. This study provides, to the best of our knowledge, empirical evidence for the first time that twig-mimicking species can achieve effective camouflage by contour modification. PMID- 26064623 TI - New insights for Drosophila GAGA factor in larvae. AB - GAGA factor plays important roles during Drosophila embryogenesis and its maternal contribution is essential for early development. Here, the role of GAGA factor was studied in 3rd instar larvae using depletion and overexpression conditions in wing disc and transcriptome analysis. We found that genes changing expression were different to those previously described using GAGA mutants in embryos. No apparent phenotypes on GAGA depletion could usually be observed at larval stages in imaginal discs but a strong effect on salivary gland polytene chromosomes was observed. In the adult, GAGA depletion produced many defects like abnormal cell proliferation in the wing, impaired dorsal closure and resulted in homeotic transformation of abdominal segment A5. Unexpectedly, no effects on Ultrabithorax expression were observed. Short overexpression of GAGA factor in 3rd instar larvae also resulted in activation of a set of genes not previously described to be under GAGA regulation, and in lethality at pupa. Our results suggest a little contribution of GAGA factor on gene transcription in wing discs and a change of the genes regulated in comparison with embryo. GAGA factor activity thus correlates with the global changes in gene expression that take place at the embryo-to-larva and, later, at the larva-to-pupa transitions. PMID- 26064624 TI - 'Neanderthal bone flutes': simply products of Ice Age spotted hyena scavenging activities on cave bear cubs in European cave bear dens. AB - Punctured extinct cave bear femora were misidentified in southeastern Europe (Hungary/Slovenia) as 'Palaeolithic bone flutes' and the 'oldest Neanderthal instruments'. These are not instruments, nor human made, but products of the most important cave bear scavengers of Europe, hyenas. Late Middle to Late Pleistocene (Mousterian to Gravettian) Ice Age spotted hyenas of Europe occupied mainly cave entrances as dens (communal/cub raising den types), but went deeper for scavenging into cave bear dens, or used in a few cases branches/diagonal shafts (i.e. prey storage den type). In most of those dens, about 20% of adult to 80% of bear cub remains have large carnivore damage. Hyenas left bones in repeating similar tooth mark and crush damage stages, demonstrating a butchering/bone cracking strategy. The femora of subadult cave bears are intermediate in damage patterns, compared to the adult ones, which were fully crushed to pieces. Hyenas produced round-oval puncture marks in cub femora only by the bone-crushing premolar teeth of both upper and lower jaw. The punctures/tooth impact marks are often present on both sides of the shaft of cave bear cub femora and are simply a result of non-breakage of the slightly calcified shaft compacta. All stages of femur puncturing to crushing are demonstrated herein, especially on a large cave bear population from a German cave bear den. PMID- 26064626 TI - Attenuation of species abundance distributions by sampling. AB - Quantifying biodiversity aspects such as species presence/ absence, richness and abundance is an important challenge to answer scientific and resource management questions. In practice, biodiversity can only be assessed from biological material taken by surveys, a difficult task given limited time and resources. A type of random sampling, or often called sub-sampling, is a commonly used technique to reduce the amount of time and effort for investigating large quantities of biological samples. However, it is not immediately clear how (sub )sampling affects the estimate of biodiversity aspects from a quantitative perspective. This paper specifies the effect of (sub-)sampling as attenuation of the species abundance distribution (SAD), and articulates how the sampling bias is induced to the SAD by random sampling. The framework presented also reveals some confusion in previous theoretical studies. PMID- 26064625 TI - Whole transcriptome analysis reveals changes in expression of immune-related genes during and after bleaching in a reef-building coral. AB - Climate change is negatively affecting the stability of natural ecosystems, especially coral reefs. The dissociation of the symbiosis between reef-building corals and their algal symbiont, or coral bleaching, has been linked to increased sea surface temperatures. Coral bleaching has significant impacts on corals, including an increase in disease outbreaks that can permanently change the entire reef ecosystem. Yet, little is known about the impacts of coral bleaching on the coral immune system. In this study, whole transcriptome analysis of the coral holobiont and each of the associate components (i.e. coral host, algal symbiont and other associated microorganisms) was used to determine changes in gene expression in corals affected by a natural bleaching event as well as during the recovery phase. The main findings include evidence that the coral holobiont and the coral host have different responses to bleaching, and the host immune system appears suppressed even a year after a bleaching event. These results support the hypothesis that coral bleaching changes the expression of innate immune genes of corals, and these effects can last even after recovery of symbiont populations. Research on the role of immunity on coral's resistance to stressors can help make informed predictions on the future of corals and coral reefs. PMID- 26064627 TI - Identifying diabetes-related important protein targets with few interacting partners with the PageRank algorithm. AB - Diabetes is a growing concern for the developed nations worldwide. New genomic, metagenomic and gene-technologic approaches may yield considerable results in the next several years in its early diagnosis, or in advances in therapy and management. In this work, we highlight some human proteins that may serve as new targets in the early diagnosis and therapy. With the help of a very successful mathematical tool for network analysis that formed the basis of the early successes of Google(TM), Inc., we analyse the human protein-protein interaction network gained from the IntAct database with a mathematical algorithm. The novelty of our approach is that the new protein targets suggested do not have many interacting partners (so, they are not hubs or super-hubs), so their inhibition or promotion probably will not have serious side effects. We have identified numerous possible protein targets for diabetes therapy and/or management; some of these have been well known for a long time (these validate our method), some of them appeared in the literature in the last 12 months (these show the cutting edge of the algorithm), and the remainder are still unknown to be connected with diabetes, witnessing completely new hits of the method. PMID- 26064628 TI - Fine-scale dietary changes between the breeding and non-breeding diet of a resident seabird. AB - Unlike migratory seabirds with wide foraging ranges, resident seabirds forage in a relatively small range year-round and are thus particularly vulnerable to local shifts in prey availability. In order to manage their populations effectively, it is necessary to identify their key prey across and within years. Here, stomach content and stable isotope analyses were used to reconstruct the diet and isotopic niche of the little penguin (Eudyptula minor). Across years, the diet of penguins was dominated by anchovy (Engraulis australis). Within years, during winter, penguins were consistently enriched in delta (15)N and delta (13)C levels relative to pre-moult penguins. This was probably due to their increased reliance on juvenile anchovies, which dominate prey biomass in winter months. Following winter and during breeding, the delta (13)C values of penguins declined. We suggest this subtle shift was in response to the increased consumption of prey that enter the bay from offshore regions to spawn. Our findings highlight that penguins have access to both juvenile fish communities and spawning migrants across the year, enabling these seabirds to remain in close proximity to their colony. However, annual fluctuations in penguin isotopic niche suggest that the recruitment success and abundance of fish communities fluctuate dramatically between years. As such, the continued monitoring of penguin diet will be central to their ongoing management. PMID- 26064629 TI - Atomic scale modelling of hexagonal structured metallic fission product alloys. AB - Noble metal particles in the Mo-Pd-Rh-Ru-Tc system have been simulated on the atomic scale using density functional theory techniques for the first time. The composition and behaviour of the epsilon phases are consistent with high-entropy alloys (or multi-principal component alloys)-making the epsilon phase the only hexagonally close packed high-entropy alloy currently described. Configurational entropy effects were considered to predict the stability of the alloys with increasing temperatures. The variation of Mo content was modelled to understand the change in alloy structure and behaviour with fuel burnup (Mo molar content decreases in these alloys as burnup increases). The predicted structures compare extremely well with experimentally ascertained values. Vacancy formation energies and the behaviour of extrinsic defects (including iodine and xenon) in the epsilon phase were also investigated to further understand the impact that the metallic precipitates have on fuel performance. PMID- 26064630 TI - Initiation and spread of escape waves within animal groups. AB - The exceptional reactivity of animal collectives to predatory attacks is thought to be owing to rapid, but local, transfer of information between group members. These groups turn together in unison and produce escape waves. However, it is not clear how escape waves are created from local interactions, nor is it understood how these patterns are shaped by natural selection. By startling schools of fish with a simulated attack in an experimental arena, we demonstrate that changes in the direction and speed by a small percentage of individuals that detect the danger initiate an escape wave. This escape wave consists of a densely packed band of individuals that causes other school members to change direction. In the majority of cases, this wave passes through the entire group. We use a simulation model to demonstrate that this mechanism can, through local interactions alone, produce arbitrarily large escape waves. In the model, when we set the group density to that seen in real fish schools, we find that the risk to the members at the edge of the group is roughly equal to the risk of those within the group. Our experiments and modelling results provide a plausible explanation for how escape waves propagate in nature without centralized control. PMID- 26064631 TI - Theoretical constraints on the precision and age range of rehydroxylation dating. AB - Accurate and precise dating methods are of central importance to archaeology, palaeontology and earth science. This paper investigates the expected precision and age range of rehydroxylation dating, a recently proposed technique for fired clays. An expression for combined measurement uncertainty is presented, which takes into account all significant sources of experimental uncertainty. Numerical simulations are performed for comparison. Combined measurement uncertainties of approximately 5% with respect to the age of the ceramic should be possible given well-designed experiments. In this case, the most significant contribution to combined measurement uncertainty is from effective lifetime temperature. In addition, it is shown that precision should be acceptable for recently fired material (less than 1 year). Mismatch of balance resolution to sample mass results in large variation in combined relative uncertainties, which vary by four orders of magnitude (approx. 1-1160%) across recent experimental studies, rendering some recently reported dates meaningless. It is recommended that this ratio be less than 10(-6) for a combined relative uncertainty of less than 1%. The age limits of the technique are set by the value of the rate constant and individual sample mineralogy. This theoretical framework should help future interlaboratory comparison as well as optimizing instrument design. PMID- 26064632 TI - Receiving of emotional signal of pain from conspecifics in laboratory rats. AB - Though recent studies have shown that rodents express emotions with their face, whether emotional expression in rodents has a communicative function between conspecifics is still unclear. Here, we demonstrate the ability of visual recognition of emotional expressions in laboratory rats. We found that Long-Evans rats avoid images of pain expressions of conspecifics but not those of neutral expressions. The results indicate that rats use visual emotional signals from conspecifics to adjust their behaviour in an environment to avoid a potentially dangerous place. Therefore, emotional expression in rodents, rather than just a mere 'expression' of emotional states, might have a communicative function. PMID- 26064633 TI - Nonlinear neutral inclusions: assemblages of coated ellipsoids. AB - The problem of determining nonlinear neutral inclusions in (electrical or thermal) conductivity is considered. Neutral inclusions, inserted in a matrix containing a uniform applied electric field, do not disturb the field outside the inclusions. The well-known Hashin-coated sphere construction is an example of a neutral inclusion. In this paper, we consider the problem of constructing neutral inclusions from nonlinear materials. In particular, we discuss assemblages of coated ellipsoids. The proposed construction is neutral for a given applied field. PMID- 26064634 TI - On the Helmert-blocking technique: its acceleration by block Choleski decomposition and formulae to insert observations into an adjusted network. AB - The Helmert-blocking technique is a common approach to adjust large geodetic networks like Europeans and Brazilians. The technique is based upon a division of the network into partial networks called blocks. This way, the global network adjustment can be done by manipulating these blocks. Here we show alternatives to solve the block system that arises from the application of the technique. We show an alternative that optimizes its implementation as the elapsed processing time is decreased by about 33%. We also show that to insert observations into an adjusted network it is not necessary to readjust the whole network. We show the formulae to insert new observations into an adjusted network that are more efficient than simply readjusting the whole new network. PMID- 26064635 TI - Comparison of methods to determine point-to-point resistance in nearly rectangular networks with application to a 'hammock' network. AB - Considerable progress has recently been made in the development of techniques to exactly determine two-point resistances in networks of various topologies. In particular, two types of method have emerged. One is based on potentials and the evaluation of eigenvalues and eigenvectors of the Laplacian matrix associated with the network or its minors. The second method is based on a recurrence relation associated with the distribution of currents in the network. Here, these methods are compared and used to determine the resistance distances between any two nodes of a network with topology of a hammock. PMID- 26064636 TI - Baleen boom and bust: a synthesis of mysticete phylogeny, diversity and disparity. AB - A new, fully dated total-evidence phylogeny of baleen whales (Mysticeti) shows that evolutionary phases correlate strongly with Caenozoic modernization of the oceans and climates, implying a major role for bottom-up physical drivers. The phylogeny of 90 modern and dated fossil species suggests three major phases in baleen whale history: an early adaptive radiation (36-30 Ma), a shift towards bulk filter-feeding (30-23 Ma) and a climate-driven diversity loss around 3 Ma. Evolutionary rates and disparity were high following the origin of mysticetes around 38 Ma, coincident with global cooling, abrupt Southern Ocean eutrophication and the development of the Antarctic Circumpolar Current (ACC). Subsequently, evolutionary rates and disparity fell, becoming nearly constant after approximately 23 Ma as the ACC reached its full strength. By contrast, species diversity rose until 15 Ma and then remained stable, before dropping sharply with the onset of Northern Hemisphere glaciation. This decline coincided with the final establishment of modern mysticete gigantism and may be linked to glacially driven variability in the distribution of shallow habitats or an increased need for long-distance migration related to iron-mediated changes in glacial marine productivity. PMID- 26064637 TI - The duality of spatial death-birth and birth-death processes and limitations of the isothermal theorem. AB - Evolutionary models on graphs, as an extension of the Moran process, have two major implementations: birth-death (BD) models (or the invasion process) and death-birth (DB) models (or voter models). The isothermal theorem states that the fixation probability of mutants in a large group of graph structures (known as isothermal graphs, which include regular graphs) coincides with that for the mixed population. This result has been proved by Lieberman et al. (2005 Nature 433, 312-316. (doi:10.1038/nature03204)) in the case of BD processes, where mutants differ from the wild-types by their birth rate (and not by their death rate). In this paper, we discuss to what extent the isothermal theorem can be formulated for DB processes, proving that it only holds for mutants that differ from the wild-type by their death rate (and not by their birth rate). For more general BD and DB processes with arbitrary birth and death rates of mutants, we show that the fixation probabilities of mutants are different from those obtained in the mass-action populations. We focus on spatial lattices and show that the difference between BD and DB processes on one- and two-dimensional lattices is non-small even for large population sizes. We support these results with a generating function approach that can be generalized to arbitrary graph structures. Finally, we discuss several biological applications of the results. PMID- 26064638 TI - New evidence on the tool-assisted hunting exhibited by chimpanzees (Pan troglodytes verus) in a savannah habitat at Fongoli, Senegal. AB - For anthropologists, meat eating by primates like chimpanzees (Pan troglodytes) warrants examination given the emphasis on hunting in human evolutionary history. As referential models, apes provide insight into the evolution of hominin hunting, given their phylogenetic relatedness and challenges reconstructing extinct hominin behaviour from palaeoanthropological evidence. Among chimpanzees, adult males are usually the main hunters, capturing vertebrate prey by hand. Savannah chimpanzees (P. t. verus) at Fongoli, Senegal are the only known non human population that systematically hunts vertebrate prey with tools, making them an important source for hypotheses of early hominin behaviour based on analogy. Here, we test the hypothesis that sex and age patterns in tool-assisted hunting (n=308 cases) at Fongoli occur and differ from chimpanzees elsewhere, and we compare tool-assisted hunting to the overall hunting pattern. Males accounted for 70% of all captures but hunted with tools less than expected based on their representation on hunting days. Females accounted for most tool-assisted hunting. We propose that social tolerance at Fongoli, along with the tool-assisted hunting method, permits individuals other than adult males to capture and retain control of prey, which is uncommon for chimpanzees. We assert that tool-assisted hunting could have similarly been important for early hominins. PMID- 26064639 TI - Approximate series solution of multi-dimensional, time fractional-order (heat like) diffusion equations using FRDTM. AB - The main goal of this paper is to present a new approximate series solution of the multi-dimensional (heat-like) diffusion equation with time-fractional derivative in Caputo form using a semi-analytical approach: fractional-order reduced differential transform method (FRDTM). The efficiency of FRDTM is confirmed by considering four test problems of the multi-dimensional time fractional-order diffusion equation. FRDTM is a very efficient, effective and powerful mathematical tool which provides exact or very close approximate solutions for a wide range of real-world problems arising in engineering and natural sciences, modelled in terms of differential equations. PMID- 26064640 TI - Nitrogen deposition and multi-dimensional plant diversity at the landscape scale. AB - Estimating effects of nitrogen (N) deposition is essential for understanding human impacts on biodiversity. However, studies relating atmospheric N deposition to plant diversity are usually restricted to small plots of high conservation value. Here, we used data on 381 randomly selected 1 km(2) plots covering most habitat types of Central Europe and an elevational range of 2900 m. We found that high atmospheric N deposition was associated with low values of six measures of plant diversity. The weakest negative relation to N deposition was found in the traditionally measured total species richness. The strongest relation to N deposition was in phylogenetic diversity, with an estimated loss of 19% due to atmospheric N deposition as compared with a homogeneously distributed historic N deposition without human influence, or of 11% as compared with a spatially varying N deposition for the year 1880, during industrialization in Europe. Because phylogenetic plant diversity is often related to ecosystem functioning, we suggest that atmospheric N deposition threatens functioning of ecosystems at the landscape scale. PMID- 26064641 TI - Mountain chickadees from different elevations sing different songs: acoustic adaptation, temporal drift or signal of local adaptation? AB - Song in songbirds is widely thought to function in mate choice and male-male competition. Song is also phenotypically plastic and typically learned from local adults; therefore, it varies across geographical space and can serve as a cue for an individual's location of origin, with females commonly preferring males from their respective location. Geographical variation in song dialect may reflect acoustic adaptation to different environments and/or serve as a signal of local adaptation. In montane environments, environmental differences can occur over an elevation gradient, favouring local adaptations across small spatial scales. We tested whether food caching mountain chickadees, known to exhibit elevation related differences in food caching intensity, spatial memory and the hippocampus, also sing different dialects despite continuous distribution and close proximity. Male songs were collected from high and low elevations at two different mountains (separated by 35 km) to test whether song differs between elevations and/or between adjacent populations at each mountain. Song structure varied significantly between high and low elevation adjacent populations from the same mountain and between populations from different mountains at the same elevations, despite a continuous distribution across each mountain slope. These results suggest that elevation-related differences in song structure in chickadees might serve as a signal for local adaptation. PMID- 26064642 TI - Use of elastic stability analysis to explain the stress-dependent nature of soil strength. AB - The peak and critical state strengths of sands are linearly related to the stress level, just as the frictional resistance to sliding along an interface is related to the normal force. The analogy with frictional sliding has led to the use of a 'friction angle' to describe the relationship between strength and stress for soils. The term 'friction angle' implies that the underlying mechanism is frictional resistance at the particle contacts. However, experiments and discrete element simulations indicate that the material friction angle is not simply related to the friction angle at the particle contacts. Experiments and particle scale simulations of model sands have also revealed the presence of strong force chains, aligned with the major principal stress. Buckling of these strong force chains has been proposed as an alternative to the frictional-sliding failure mechanism. Here, using an idealized abstraction of a strong force chain, the resistance is shown to be linearly proportional to the magnitude of the lateral forces supporting the force chain. Considering a triaxial stress state, and drawing an analogy between the lateral forces and the confining pressure in a triaxial test, a linear relationship between stress level and strength is seen to emerge from the failure-by-buckling hypothesis. PMID- 26064643 TI - Temporal modelling of ballast water discharge and ship-mediated invasion risk to Australia. AB - Biological invasions have the potential to cause extensive ecological and economic damage. Maritime trade facilitates biological invasions by transferring species in ballast water, and on ships' hulls. With volumes of maritime trade increasing globally, efforts to prevent these biological invasions are of significant importance. Both the International Maritime Organization and the Australian government have developed policy seeking to reduce the risk of these invasions. In this study, we constructed models for the transfer of ballast water into Australian waters, based on historic ballast survey data. We used these models to hindcast ballast water discharge over all vessels that arrived in Australian waters between 1999 and 2012. We used models for propagule survival to compare the risk of ballast-mediated propagule transport between ecoregions. We found that total annual ballast discharge volume into Australia more than doubled over the study period, with the vast majority of ballast water discharge and propagule pressure associated with bulk carrier traffic. As such, the ecoregions suffering the greatest risk are those associated with the export of mining commodities. As global marine trade continues to increase, effective monitoring and biosecurity policy will remain necessary to combat the risk of future marine invasion events. PMID- 26064644 TI - The role of social and ecological processes in structuring animal populations: a case study from automated tracking of wild birds. AB - Both social and ecological factors influence population process and structure, with resultant consequences for phenotypic selection on individuals. Understanding the scale and relative contribution of these two factors is thus a central aim in evolutionary ecology. In this study, we develop a framework using null models to identify the social and spatial patterns that contribute to phenotypic structure in a wild population of songbirds. We used automated technologies to track 1053 individuals that formed 73 737 groups from which we inferred a social network. Our framework identified that both social and spatial drivers contributed to assortment in the network. In particular, groups had a more even sex ratio than expected and exhibited a consistent age structure that suggested local association preferences, such as preferential attachment or avoidance. By contrast, recent immigrants were spatially partitioned from locally born individuals, suggesting differential dispersal strategies by phenotype. Our results highlight how different scales of social decision-making, ranging from post-natal dispersal settlement to fission-fusion dynamics, can interact to drive phenotypic structure in animal populations. PMID- 26064645 TI - Efficient expansion of global protected areas requires simultaneous planning for species and ecosystems. AB - The Convention on Biological Diversity (CBD)'s strategic plan advocates the use of environmental surrogates, such as ecosystems, as a basis for planning where new protected areas should be placed. However, the efficiency and effectiveness of this ecosystem-based planning approach to adequately capture threatened species in protected area networks is unknown. We tested the application of this approach in Australia according to the nation's CBD-inspired goals for expansion of the national protected area system. We set targets for ecosystems (10% of the extent of each ecosystem) and threatened species (variable extents based on persistence requirements for each species) and then measured the total land area required and opportunity cost of meeting those targets independently, sequentially and simultaneously. We discover that an ecosystem-based approach will not ensure the adequate representation of threatened species in protected areas. Planning simultaneously for species and ecosystem targets delivered the most efficient outcomes for both sets of targets, while planning first for ecosystems and then filling the gaps to meet species targets was the most inefficient conservation strategy. Our analysis highlights the pitfalls of pursuing goals for species and ecosystems non-cooperatively and has significant implications for nations aiming to meet their CBD mandated protected area obligations. PMID- 26064646 TI - Activation of an inflammatory response is context-dependent during early development of the California sea lion. AB - Variations in immune function can arise owing to trade-offs, that is, the allocation of limited resources among costly competing physiological functions. Nevertheless, there is little information regarding the ontogeny of the immune system within an ecological context, and it is still unknown whether development affects the way in which resources are allocated to different immune effectors. We investigated changes in the inflammatory response during early development of the California sea lion (Zalophus californianus) and examined its association with body condition, as a proxy for the availability of energetic resources. We found that the relationship between inflammation and body condition varied according to developmental stage and circulating levels of leucocyte populations, a proxy for current infection. Body condition was related to the magnitude of the inflammatory response during two of the three developmental periods assessed, allowing for the possibility that the availability of pup energetic reserves can limit immune function. For older pups, the ability to mount an inflammatory response was related to their circulating levels of neutrophils and the neutrophil to lymphocyte ratio, implying that the infection status of an individual will influence its ability to respond to a new challenge. Our results suggest that trade-offs may occur within the immune system and highlight the importance of taking into account ontogeny in ecoimmunological studies. PMID- 26064647 TI - Climate-driven tipping-points could lead to sudden, high-intensity parasite outbreaks. AB - Parasitic nematodes represent one of the most pervasive and significant challenges to grazing livestock, and their intensity and distribution are strongly influenced by climate. Parasite levels and species composition have already shifted under climate change, with nematode parasite intensity frequently low in newly colonized areas, but sudden large-scale outbreaks are becoming increasingly common. These outbreaks compromise both food security and animal welfare, yet there is a paucity of predictions on how climate change will influence livestock parasites. This study aims to assess how climate change can affect parasite risk. Using a process-based approach, we determine how changes in temperature-sensitive elements of outbreaks influence parasite dynamics, to explore the potential for climate change to influence livestock helminth infections. We show that changes in temperate-sensitive parameters can result in nonlinear responses in outbreak dynamics, leading to distinct 'tipping-points' in nematode parasite burdens. Through applying two mechanistic models, of varying complexity, our approach demonstrates that these nonlinear responses are robust to the inclusion of a number of realistic processes that are present in livestock systems. Our study demonstrates that small changes in climatic conditions around critical thresholds may result in dramatic changes in parasite burdens. PMID- 26064648 TI - Analytical model of reactive transport processes with spatially variable coefficients. AB - Analytical solutions of partial differential equation (PDE) models describing reactive transport phenomena in saturated porous media are often used as screening tools to provide insight into contaminant fate and transport processes. While many practical modelling scenarios involve spatially variable coefficients, such as spatially variable flow velocity, v(x), or spatially variable decay rate, k(x), most analytical models deal with constant coefficients. Here we present a framework for constructing exact solutions of PDE models of reactive transport. Our approach is relevant for advection-dominant problems, and is based on a regular perturbation technique. We present a description of the solution technique for a range of one-dimensional scenarios involving constant and variable coefficients, and we show that the solutions compare well with numerical approximations. Our general approach applies to a range of initial conditions and various forms of v(x) and k(x). Instead of simply documenting specific solutions for particular cases, we present a symbolic worksheet, as supplementary material, which enables the solution to be evaluated for different choices of the initial condition, v(x) and k(x). We also discuss how the technique generalizes to apply to models of coupled multispecies reactive transport as well as higher dimensional problems. PMID- 26064649 TI - Diversification events and the effects of mass extinctions on Crocodyliformes evolutionary history. AB - The rich fossil record of Crocodyliformes shows a much greater diversity in the past than today in terms of morphological disparity and occupation of niches. We conducted topology-based analyses seeking diversification shifts along the evolutionary history of the group. Our results support previous studies, indicating an initial radiation of the group following the Triassic/Jurassic mass extinction, here assumed to be related to the diversification of terrestrial protosuchians, marine thalattosuchians and semi-aquatic lineages within Neosuchia. During the Cretaceous, notosuchians embodied a second diversification event in terrestrial habitats and eusuchian lineages started diversifying before the end of the Mesozoic. Our results also support previous arguments for a minor impact of the Cretaceous/Palaeogene mass extinction on the evolutionary history of the group. This argument is not only based on the information from the fossil record, which shows basal groups surviving the mass extinction and the decline of other Mesozoic lineages before the event, but also by the diversification event encompassing only the alligatoroids in the earliest period after the extinction. Our results also indicate that, instead of a continuous process through time, Crocodyliformes diversification was patchy, with events restricted to specific subgroups in particular environments and time intervals. PMID- 26064650 TI - Calculating mutual information for spike trains and other data with distances but no coordinates. AB - Many important data types, such as the spike trains recorded from neurons in typical electrophysiological experiments, have a natural notion of distance or similarity between data points, even though there is no obvious coordinate system. Here, a simple Kozachenko-Leonenko estimator is derived for calculating the mutual information between datasets of this type. PMID- 26064651 TI - Rapid nectar-meal effects on a predator's capacity to kill mosquitoes. AB - Using Evarcha culicivora, an East African jumping spider (Salticidae), we investigate how nectar meals function in concert with predation specifically at the juvenile stage between emerging from the egg sac and the first encounter with prey. Using plants and using artificial nectar consisting of sugar alone or sugar plus amino acids, we show that the plant species (Lantana camara, Ricinus communis, Parthenium hysterophorus), the particular sugars in the artificial nectar (sucrose, fructose, glucose, maltose), the concentration of sugar (20%, 5%, 1%) and the duration of pre-feeding fasts (3 days, 6 days) influence the spider's prey-capture proficiency on the next day after the nectar meal. However, there were no significant effects of amino acids. Our findings suggest that benefits from nectar feeding are derived primarily from access to particular sugars, with fructose and sucrose being the most beneficial, glucose being intermediate and maltose being no better than a water-only control. PMID- 26064652 TI - Phenotypic assortment in wild primate networks: implications for the dissemination of information. AB - Individuals' access to social information can depend on their social network. Homophily-a preference to associate with similar phenotypes-may cause assortment within social networks that could preclude information transfer from individuals who generate information to those who would benefit from acquiring it. Thus, understanding phenotypic assortment may lead to a greater understanding of the factors that could limit the transfer of information between individuals. We tested whether there was assortment in wild baboon (Papio ursinus) networks, using data collected from two troops over 6 years for six phenotypic traits boldness, age, dominance rank, sex and the propensity to generate/exploit information-using two methods for defining a connection between individuals-time spent in proximity and grooming. Our analysis indicated that assortment was more common in grooming than proximity networks. In general, there was homophily for boldness, age, rank and the propensity to both generate and exploit information, but heterophily for sex. However, there was considerable variability both between troops and years. The patterns of homophily we observed for these phenotypes may impede information transfer between them. However, the inconsistency in the strength of assortment between troops and years suggests that the limitations to information flow may be quite variable. PMID- 26064653 TI - Extreme ecological response of a seabird community to unprecedented sea ice cover. AB - Climate change has been predicted to reduce Antarctic sea ice but, instead, sea ice surrounding Antarctica has expanded over the past 30 years, albeit with contrasted regional changes. Here we report a recent extreme event in sea ice conditions in East Antarctica and investigate its consequences on a seabird community. In early 2014, the Dumont d'Urville Sea experienced the highest magnitude sea ice cover (76.8%) event on record (1982-2013: range 11.3-65.3%; mean+/-95% confidence interval: 27.7% (23.1-32.2%)). Catastrophic effects were detected in the breeding output of all sympatric seabird species, with a total failure for two species. These results provide a new view crucial to predictive models of species abundance and distribution as to how extreme sea ice events might impact an entire community of top predators in polar marine ecosystems in a context of expanding sea ice in eastern Antarctica. PMID- 26064654 TI - Highly contrasted responses of Mediterranean octocorals to climate change along a depth gradient. AB - Climate change has a strong impact on marine ecosystems, including temperate species. Analysing the diversity of thermotolerance levels within species along with their genetic structure enables a better understanding of their potential response to climate change. We performed this integrative study on the Mediterranean octocoral Eunicella cavolini, with samples from different depths and by means of a common garden experiment. This species does not host photosynthetic Symbiodinium, enabling us to focus on the cnidarian response. We compared the thermotolerance of individuals from 20 m and 40 m depths from the same site and with replicates from the same colony. On the basis of an innovative statistical analysis of necrosis kinetics and risk, we demonstrated the occurrence of a very different response between depths at this local scale, with lower thermotolerance of deep individuals. Strongly thermotolerant individuals were observed at 20 m with necrosis appearing at higher temperatures than observed in situ. On the basis of nine microsatellite loci, we showed that these marked thermotolerance differences occur within a single population. This suggests the importance of acclimatization processes in adaptation to these different depths. In addition, differences between replicates demonstrated the occurrence of a variability of response between fragments from the same colony with the possibility of an interaction with a tank effect. Our results provide a basis for studying adaptation and acclimatization in Mediterranean octocorals in a heterogeneous environment. PMID- 26064655 TI - Origin of tensile strength of a woven sample cut in bias directions. AB - Textile fabrics are highly anisotropic, so that their mechanical properties including strengths are a function of direction. An extreme case is when a woven fabric sample is cut in such a way where the bias angle and hence the tension loading direction is around 45 degrees relative to the principal directions. Then, once loaded, no yarn in the sample is held at both ends, so the yarns have to build up their internal tension entirely via yarn-yarn friction at the interlacing points. The overall fabric strength in such a sample is a result of contributions from the yarns being pulled out and those broken during the process, and thus becomes a function of the bias direction angle theta, sample width W and length L, along with other factors known to affect fabric strength tested in principal directions. Furthermore, in such a bias sample when the major parameters, e.g. the sample width W, change, not only the resultant strengths differ, but also the strength generating mechanisms (or failure types) vary. This is an interesting problem and is analysed in this study. More specifically, the issues examined in this paper include the exact mechanisms and details of how each interlacing point imparts the frictional constraint for a yarn to acquire tension to the level of its strength when both yarn ends were not actively held by the testing grips; the theoretical expression of the critical yarn length for a yarn to be able to break rather than be pulled out, as a function of the related factors; and the general relations between the tensile strength of such a bias sample and its structural properties. At the end, theoretical predictions are compared with our experimental data. PMID- 26064656 TI - Resumption of traditional drive hunting of dolphins in the Solomon Islands in 2013. AB - The 'drive hunting' of dolphins has a long history in the Solomon Islands, specifically at the island of Malaita. In 2010, the most active village, Fanalei, suspended hunting in exchange for financial compensation from an international non-governmental organization but resumed hunting again in early 2013. Here, we report on a visit to Fanalei in March 2013 to document the species and number of dolphins killed in the renewed hunting. Detailed records for the 2013 hunting, up to the time of our visit, included at least 1500 pantropical spotted dolphins (Stenella attenuata), 159 spinner dolphins (Stenella longirostris) and 15 'bottlenose' dolphins, probably Tursiops truncatus. Molecular identification confirmed two of the species, pantropical spotted and spinner dolphins. A summary of all available records from 1976 to 2013 documented a minimum total of 15 454 dolphins killed by the Fanalei villagers alone. We also found the local price of a dolphin tooth had increased from about US$0.14 (SBD$1) in 2004 to about US$0.70 (SBD$5) in 2013. The large number of dolphins killed and the apparent incentive for future hunting offered by the increasing commercial value of teeth, highlight an urgent need to monitor hunts and assess the abundance and trends in local populations. PMID- 26064657 TI - Simulating droplet motion on virtual leaf surfaces. AB - A curvilinear thin film model is used to simulate the motion of droplets on a virtual leaf surface, with a view to better understand the retention of agricultural sprays on plants. The governing model, adapted from Roy et al. (2002 J. Fluid Mech. 454, 235-261 (doi:10.1017/S0022112001007133)) with the addition of a disjoining pressure term, describes the gravity- and curvature-driven flow of a small droplet on a complex substrate: a cotton leaf reconstructed from digitized scan data. Coalescence is the key mechanism behind spray coating of foliage, and our simulations demonstrate that various experimentally observed coalescence behaviours can be reproduced qualitatively. By varying the contact angle over the domain, we also demonstrate that the presence of a chemical defect can act as an obstacle to the droplet's path, causing break-up. In simulations on the virtual leaf, it is found that the movement of a typical spray size droplet is driven almost exclusively by substrate curvature gradients. It is not until droplet mass is sufficiently increased via coalescence that gravity becomes the dominating force. PMID- 26064658 TI - African origin for Madagascan dogs revealed by mtDNA analysis. AB - Madagascar was one of the last major land masses to be inhabited by humans. It was initially colonized by Austronesian speaking Indonesians 1500-2000 years ago, but subsequent migration from Africa has resulted in approximately equal genetic contributions from Indonesia and Africa, and the material culture has mainly African influences. The dog, along with the pig and the chicken, was part of the Austronesian Neolithic culture, and was furthermore the only domestic animal to accompany humans to every continent in ancient times. To illuminate Madagascan cultural origins and track the initial worldwide dispersal of dogs, we here investigated the ancestry of Madagascan dogs. We analysed mtDNA control region sequences in dogs from Madagascar (n=145) and compared it with that from potential ancestral populations in Island Southeast Asia (n=219) and sub-Saharan Africa (n=493). We found that 90% of the Madagascan dogs carried a haplotype that was also present in sub-Saharan Africa and that the remaining lineages could all be attributed to a likely origin in Africa. By contrast, only 26% of Madagascan dogs shared haplotypes with Indonesian dogs, and one haplotype typical for Austronesian dogs, carried by more than 40% of Indonesian and Polynesian dogs, was absent among the Madagascan dogs. Thus, in contrast to the human population, Madagascan dogs seem to trace their origin entirely from Africa. These results suggest that dogs were not brought to Madagascar by the initial Austronesian speaking colonizers on their transoceanic voyage, but were introduced at a later stage, together with human migration and cultural influence from Africa. PMID- 26064659 TI - Assessing costs of carrying geolocators using feather corticosterone in two species of aerial insectivore. AB - Despite benefits of using light-sensitive geolocators to track animal movements and describe patterns of migratory connectivity, concerns have been raised about negative effects of these devices, particularly in small species of aerial insectivore. Geolocators may act as handicaps that increase energetic expenditure, which could explain reported effects of geolocators on survival. We tested this 'Energetic Expenditure Hypothesis' in 12 populations of tree swallows (Tachycineta bicolor) and barn swallows (Hirundo rustica) from North America and Europe, using measurements of corticosterone from feathers (CORTf) grown after deployment of geolocators as a measure of physiology relevant to energetics. Contrary to predictions, neither among- (both species) nor within-individual (tree swallows only) levels of CORTf differed with respect to instrumentation. Thus, to the extent that CORTf reflects energetic expenditure, geolocators apparently were not a strong handicap for birds that returned post-deployment. While this physiological evidence suggests that information about migration obtained from returning geolocator-equipped swallows is unbiased with regard to levels of stress, we cannot discount the possibility that corticosterone played a role in reported effects of geolocators on survival in birds, and suggest that future studies relate corticosterone to antecedent factors, such as reproductive history, and to downstream fitness costs. PMID- 26064660 TI - A pheromone outweighs temperature in influencing migration of sea lamprey. AB - Organisms continuously acquire and process information from surrounding cues. While some cues complement one another in delivering more reliable information, others may provide conflicting information. How organisms extract and use reliable information from a multitude of cues is largely unknown. We examined movement decisions of sea lampreys (Petromyzon marinus L.) exposed to a conspecific and an environmental cue during pre-spawning migration. Specifically, we predicted that the mature male-released sex pheromone 3-keto petromyzonol sulfate (3kPZS) will outweigh the locomotor inhibiting effects of cold stream temperature (less than 15 degrees C). Using large-scale stream bioassays, we found that 3kPZS elicits an increase (more than 40%) in upstream movement of pre spawning lampreys when the water temperatures were below 15 degrees C. Both warming temperatures and conspecific cues increase upstream movement when the water temperature rose above 15 degrees C. These patterns define an interaction between abiotic and conspecific cues in modulating animal decision-making, providing an example of the hierarchy of contradictory information. PMID- 26064661 TI - Simple graph models of information spread in finite populations. AB - We consider several classes of simple graphs as potential models for information diffusion in a structured population. These include biases cycles, dual circular flows, partial bipartite graphs and what we call 'single-link' graphs. In addition to fixation probabilities, we study structure parameters for these graphs, including eigenvalues of the Laplacian, conductances, communicability and expected hitting times. In several cases, values of these parameters are related, most strongly so for partial bipartite graphs. A measure of directional bias in cycles and circular flows arises from the non-zero eigenvalues of the antisymmetric part of the Laplacian and another measure is found for cycles as the value of the transition probability for which hitting times going in either direction of the cycle are equal. A generalization of circular flow graphs is used to illustrate the possibility of tuning edge weights to match pre-specified values for graph parameters; in particular, we show that generalizations of circular flows can be tuned to have fixation probabilities equal to the Moran probability for a complete graph by tuning vertex temperature profiles. Finally, single-link graphs are introduced as an example of a graph involving a bottleneck in the connection between two components and these are compared to the partial bipartite graphs. PMID- 26064662 TI - Polygyny without wealth: popularity in gift games predicts polygyny in BaYaka Pygmies. AB - The occurrence of polygynous marriage in hunter-gatherer societies, which do not accumulate wealth, remains largely unexplored since resource availability is dependent on male hunting capacity and limited by the lack of storage. Hunter gatherer societies offer the greatest insight in to human evolution since they represent the majority of our species' evolutionary history. In order to elucidate the evolution of hunter-gatherer polygyny, we study marriage patterns of BaYaka Pygmies. We investigate (i) rates of polygyny among BaYaka hunter gatherers; (ii) whether polygyny confers a fitness benefit to BaYaka men; (iii) in the absence of wealth inequalities, what are the alternative explanations for polygyny among the BaYaka. To understand the latter, we explore differences in phenotypic quality (height and strength), and social capital (popularity in gift games). We find polygynous men have increased reproductive fitness; and that social capital and popularity but not phenotypic quality might have been important mechanisms by which some male hunter-gatherers sustained polygynous marriages before the onset of agriculture and wealth accumulation. PMID- 26064663 TI - The evolution of popular music: USA 1960-2010. AB - In modern societies, cultural change seems ceaseless. The flux of fashion is especially obvious for popular music. While much has been written about the origin and evolution of pop, most claims about its history are anecdotal rather than scientific in nature. To rectify this, we investigate the US Billboard Hot 100 between 1960 and 2010. Using music information retrieval and text-mining tools, we analyse the musical properties of approximately 17 000 recordings that appeared in the charts and demonstrate quantitative trends in their harmonic and timbral properties. We then use these properties to produce an audio-based classification of musical styles and study the evolution of musical diversity and disparity, testing, and rejecting, several classical theories of cultural change. Finally, we investigate whether pop musical evolution has been gradual or punctuated. We show that, although pop music has evolved continuously, it did so with particular rapidity during three stylistic 'revolutions' around 1964, 1983 and 1991. We conclude by discussing how our study points the way to a quantitative science of cultural change. PMID- 26064664 TI - Evidence for a pervasive 'idling-mode' activity template in flying and pedestrian insects. AB - Understanding the complex movement patterns of animals in natural environments is a key objective of 'movement ecology'. Complexity results from behavioural responses to external stimuli but can also arise spontaneously in their absence. Drawing on theoretical arguments about decision-making circuitry, we predict that the spontaneous patterns will be scale-free and universal, being independent of taxon and mode of locomotion. To test this hypothesis, we examined the activity patterns of the European honeybee, and multiple species of noctuid moth, tethered to flight mills and exposed to minimal external cues. We also reanalysed pre existing data for Drosophila flies walking in featureless environments. Across these species, we found evidence of common scale-invariant properties in their movement patterns; pause and movement durations were typically power law distributed over a range of scales and characterized by exponents close to 3/2. Our analyses are suggestive of the presence of a pervasive scale-invariant template for locomotion which, when acted on by environmental cues, produces the movements with characteristic scales observed in nature. Our results indicate that scale-finite complexity as embodied, for instance, in correlated random walk models, may be the result of environmental cues overriding innate behaviour, and that scale-free movements may be intrinsic and not limited to 'blind' foragers as previously thought. PMID- 26064665 TI - Familiar and unfamiliar face recognition in crested macaques (Macaca nigra). AB - Many species use facial features to identify conspecifics, which is necessary to navigate a complex social environment. The fundamental mechanisms underlying face processing are starting to be well understood in a variety of primate species. However, most studies focus on a limited subset of species tested with unfamiliar faces. As well as limiting our understanding of how widely distributed across species these skills are, this also limits our understanding of how primates process faces of individuals they know, and whether social factors (e.g. dominance and social bonds) influence how readily they recognize others. In this study, socially housed crested macaques voluntarily participated in a series of computerized matching-to-sample tasks investigating their ability to discriminate (i) unfamiliar individuals and (ii) members of their own social group. The macaques performed above chance on all tasks. Familiar faces were not easier to discriminate than unfamiliar faces. However, the subjects were better at discriminating higher ranking familiar individuals, but not unfamiliar ones. This suggests that our subjects applied their knowledge of their dominance hierarchies to the pictorial representation of their group mates. Faces of high-ranking individuals garner more social attention, and therefore might be more deeply encoded than other individuals. Our results extend the study of face recognition to a novel species, and consequently provide valuable data for future comparative studies. PMID- 26064666 TI - A model for non-monotonic intensity coding. AB - Peripheral neurons of most sensory systems increase their response with increasing stimulus intensity. Behavioural responses, however, can be specific to some intermediate intensity level whose particular value might be innate or associatively learned. Learning such a preference requires an adjustable trans- formation from a monotonic stimulus representation at the sensory periphery to a non-monotonic representation for the motor command. How do neural systems accomplish this task? We tackle this general question focusing on odour-intensity learning in the fruit fly, whose first- and second-order olfactory neurons show monotonic stimulus-response curves. Nevertheless, flies form associative memories specific to particular trained odour intensities. Thus, downstream of the first two olfactory processing layers, odour intensity must be re-coded to enable intensity-specific associative learning. We present a minimal, feed-forward, three-layer circuit, which implements the required transformation by combining excitation, inhibition, and, as a decisive third element, homeostatic plasticity. Key features of this circuit motif are consistent with the known architecture and physiology of the fly olfactory system, whereas alternative mechanisms are either not composed of simple, scalable building blocks or not compatible with physiological observations. The simplicity of the circuit and the robustness of its function under parameter changes make this computational motif an attractive candidate for tuneable non-monotonic intensity coding. PMID- 26064667 TI - Quantifying crowd size with mobile phone and Twitter data. AB - Being able to infer the number of people in a specific area is of extreme importance for the avoidance of crowd disasters and to facilitate emergency evacuations. Here, using a football stadium and an airport as case studies, we present evidence of a strong relationship between the number of people in restricted areas and activity recorded by mobile phone providers and the online service Twitter. Our findings suggest that data generated through our interactions with mobile phone networks and the Internet may allow us to gain valuable measurements of the current state of society. PMID- 26064668 TI - Comparative Study of Malaria Prevalence among Travellers in Nigeria (West Africa) Using Slide Microscopy and a Rapid Diagnosis Test. AB - Malaria is a major disease in Africa and leads to various public health problems. A study was carried out at the Aviation Medical Clinic Laboratory, Murtala Mohammed Airport, Ikeja, Lagos State, Nigeria, in 2014. The work aimed to determine the prevalence of malaria among patients attending the laboratory. Blood samples were therefore collected from 51 patients and subjected to both blood smear microscopy and a rapid immunochromatographic diagnostic test (SD BIOLINE Malaria Ag) for detection of, respectively, malaria parasites and antigens. At the end of the study, 22% of the patients were detected positive by the microscopic examination while 9.8% were tested positive when using SD BIOLINE Malaria Ag. The outcomes of the study show a high prevalence of malaria at the airport. This represents a serious risk factor leading to a high likelihood of spread and occurrence of malaria in other countries including Western countries whereby the disease is nonendemic. It also pointed out that the blood smear microscopy seems to be better than Rapid Diagnosis Test (RDT) for malaria diagnosis. PMID- 26064669 TI - Patients with Fuchs Endothelial Dystrophy and Cataract Undergoing Descemet Stripping Automated Endothelial Keratoplasty and Phacoemulsification with Intraocular Lens Implant: Staged versus Combined Procedure Outcomes. AB - Purpose. To compare the surgical outcomes of staged and combined phacoemulsification with intraocular lens implant (phaco+IOL) and Descemet stripping automated endothelial keratoplasty (DSAEK) in patients with Fuchs' endothelial dystrophy and cataract. Setting. Corneoplastic Unit and Eye Bank, Queen Victoria Hospital, East Grinstead, UK. Methods. Retrospective study of patients who had combined phaco+IOL and DSAEK (group 1) or phaco+IOL followed within 2 months by DSAEK (group 2). Patients who had previous eye surgery or any other ocular comorbidities were excluded. Results. There were 28 eyes in group 1 and 31 in group 2. There were no significant differences in the demographics and corneal tissue characteristics of the two groups. The endothelial disc dislocation and rebubbling rate within 1 week in group 1 was 21.42% and in group 2 was 3.2% (P = 0.04), while the endothelial cell density at 12 months was 1510 +/- 433 for group 1 and 1535 +/- 482 for group 2 (P = 0.89). The mean 12-month logMAR visual acuity was 0.28 +/- 0.24 for group 1 and 0.33 +/- 0.15 for group 2 (P = 0.38). Conclusions. Although the combined procedure seems to be associated with a higher complication rate the final outcomes seem to be similar to both methods. PMID- 26064670 TI - Assessment of Macular Parameter Changes in Patients with Keratoconus Using Optical Coherence Tomography. AB - Keratoconus is typically diagnosed through changes at the anterior ocular surface. However, we wished to assess if macular parameter changes might also occur in these patients. We assessed posterior changes through the use of optical coherence tomography and compared to a nonkeratoconus patient group. All subjects underwent clinical examination including macular thickness measurements. The generalized estimation equation model was used to estimate the means and compare the differences in various measurements between keratoconus and nonkeratoconus patients. A total of 129 keratoconus eyes of 67 cases and 174 nonkeratoconus eyes of 87 controls were analysed. Keratoconus individuals presented with a significantly greater mean retinal thickness in the central fovea, inner, and outer macula compared to the nonkeratoconus group (p < 0.05). In addition, individuals presenting with the early signs of keratoconus had significantly greater inner and outer macular volume compared to the nonkeratoconus group (p < 0.05). This study indicates the retina appears to thicken at the fovea and macula and had increased macular volume in keratoconus individuals compared to nonkeratoconus individuals. Thus we posit that structural retinal changes exist in keratoconus eyes that are additional to those typically seen in the anterior segment. PMID- 26064671 TI - Perceived Pain during Cataract Surgery with Topical Anesthesia: A Comparison between First-Eye and Second-Eye Surgery. AB - Purpose. To compare pain scores between first-eye and second-eye cataract surgery and to determine the affecting factors. Methods. 106 first-eye and 53 second-eye cataract surgery patients (mean age: 67 +/- 13 and 69 +/- 10 years, resp.) were enrolled. The patients completed simplified State-Trait Anxiety Inventory and visual analog scale (VAS) for anxiety questionnaires before surgery, and VAS for pain and Wong-Baker Faces Pain Rating Scale questionnaires after surgery. Blood pressure (BP) and heart rate (HR) were recorded perioperatively. Results. A greater proportion of patients who underwent second-eye surgery reported intraoperative pain compared with first-eye surgery patients (85% versus 35%, P < 0.001). The pain scores were higher in second-eye surgery, while the VAS anxiety score was lower in second-eye surgery. Moreover, 31 patients reported greater pain during second-eye surgery than their first one, with higher pain scores than other 22 patients (P = 0.032 and 0.003, resp.). The VAS pain score of these 31 patients was positively correlated with the differences between the intraoperative and postoperative diastolic BP, mean arterial pressure, and HR. Conclusions. Cataract patients were likely to have more pain during second-eye surgery, which may be related to lower preoperative anxiety. Monitoring perioperative BP and HR may help to identify patients with intraoperative pain. PMID- 26064672 TI - Ultrastructural Changes in Human Trabecular Meshwork Tissue after Laser Trabeculoplasty. AB - Purpose. To compare morphologic changes in human trabecular meshwork (TM) after selective laser trabeculoplasty (SLT) and argon laser trabeculoplasty (ALT). Design. Laboratory evaluation of ex vivo human eye TM after laser trabeculoplasty. Methods. Corneoscleral rims from human cadaver eyes were sectioned and treated with varying powers of either SLT or ALT. Specimens were examined using light microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Results. TEM of SLT at all powers resulted in disrupted TM cells with cracked and extracellular pigment granules. SEM of SLT samples treated at high power revealed tissue destruction with scrolling of trabecular beams. SEM of ALT-treated tissue showed increasing destruction with exposure to higher power. The presence or absence of "champagne" bubbles during SLT did not alter the histologic findings. Conclusions. SLT treated human TM revealed disruption of TM cells with cracked, extracellular pigment granules, particularly at higher treatment powers. Tissue scrolling was noted at very high SLT energy levels. ALT-treated tissue showed significant damage to both the superficial and deeper TM tissues in a dose-dependent fashion. Further studies are needed to guide titration of treatment power to maximize the IOP-lowering effect while minimizing both energy delivered and damage to target tissues. PMID- 26064673 TI - Effects of Lamellar Keratectomy and Intrastromal Injection of 0.2% Fluconazole on Fungal Keratitis. AB - Purpose. To evaluate effects of lamellar keratectomy and intrastromal injection of 0.2% fluconazole (LKIIF) on fungal keratitis. Methods. Data for 54 eyes of consecutive patients with fungal keratitis treated with LKIIF were retrospectively analyzed. The lesions in these eyes did not heal or were aggravated after antifungal chemotherapy for 7 days. The maximum lesion diameters were <=5 mm and maximum depth was not more than half of full corneal thickness. Cases were followed up for at least 90 days. Results. Forty-six eyes were cured (85.2%). The wound healing times were 3-16 days and were less than 7 days in 28 cases (51.9%). In cured eyes, uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA) were both 20/250-20/20. The UCVA improved in 38 eyes and was unchanged in seven eyes. BCVA improved in 44 eyes and was unchanged in two eyes. When followed up for more than 90 days, 89% (41 of 46 eyes) showed improvement in UCVA and 11% were unchanged. Regarding BCVA, 98% improved and one eye was unchanged. No other complications were observed except neovascularization in one eye and thinner corneas. Conclusions. LKIIF was quick and effective for small fungal keratitis confined to half of the corneal thickness. PMID- 26064674 TI - The Effect of Rebamipide on Ocular Surface Disorders Induced by Latanoprost and Timolol in Glaucoma Patients. AB - Purpose. To examine the efficacy of ophthalmic rebamipide suspensions on ocular surface disorders induced by antiglaucoma eye drops. Patients and Methods. Forty eyes of 40 patients receiving latanoprost (0.005%) and timolol (0.5%) were included in this randomized prospective study. The patients were randomly divided into two groups (n = 20): the rebamipide-treated group and control group. Changes in intraocular pressure, tear film break-up time (TBUT), and corneal epithelial barrier function were evaluated at baseline, 4 weeks, and 8 weeks after rebamipide administration. Furthermore, superficial punctate keratopathy severity was evaluated by scoring the lesion area and density. Results. There was no significant difference in intraocular pressure before and after rebamipide treatment. However, corneal epithelial barrier function improved significantly 4 and 8 weeks after rebamipide treatment. TBUT was partially, but significantly, increased (P = 0.02) 8 weeks after rebamipide treatment, whereas no significant change was observed at 4 weeks. Additionally, a significant decrease in area and density of keratopathy was observed 8 weeks after rebamipide treatment but not at 4 weeks. The control group showed no significant difference compared to baseline. Conclusions. Our data suggests that rebamipide treatment may reduce the occurrence of drug-induced ocular surface disorder. PMID- 26064675 TI - Dye-Free Porcine Model of Experimental Branch Retinal Vein Occlusion: A Suitable Approach for Retinal Proteomics. AB - Branch retinal vein occlusion induces complex biological processes in the retina that are generated by a multitude of interacting proteins. These proteins and their posttranslational modifications can effectively be studied using modern proteomic techniques. However, no method for studying large-scale protein changes following branch retinal vein occlusion has been available until now. Obtainment of retinal tissue exposed to branch retinal vein occlusion is only available through experimental animal models. Traditional models of experimental branch retinal vein occlusion require the use of Rose Bengal dye combined with argon laser photocoagulation. The use of Rose Bengal dye is problematic in proteomic studies as the dye can induce multiple protein modifications when irradiated. This paper presents a novel technique for proteomic analysis of porcine retinal tissue with branch retinal vein occlusion combining a dye-free experimental model with label-free liquid chromatography mass spectrometry based proteomics. PMID- 26064676 TI - Retinal Nerve Fibre Layer and Macular Thicknesses in Adults with Hyperopic Anisometropic Amblyopia. AB - Objectives. This study compared the macular and retinal nerve fibre layer (RNFL) thicknesses and optic nerves of eyes with reduced vision due to anisometropia with the contralateral healthy eyes in adults using optical coherence tomography (OCT). Methods. This cross-sectional study was conducted in Ataturk State Hospital, Sinop, Turkey. Macular and RNFL thicknesses, optic nerve disc area, cup area, and horizontal and vertical cup-to-disc ratios obtained using a NIDEK RS 3000 SLO spectral domain OCT device were compared between the amblyopic and fellow eyes in 30 adults with anisometropic amblyopia 18-55 years old who were seen in our clinic with unilateral poor vision. Results. The mean macular thickness was 266.90 +/- 23.22 um in the amblyopic eyes and 263.90 +/- 22.84 um in the fellow eyes, and the mean RNFL thickness was 111.90 +/- 12.9 and 109.70 +/ 9.42 um, respectively. The two thicknesses did not differ significantly between the amblyopic and fellow eyes. There were also no significant differences between the eyes in disc area, cup area, and horizontal-vertical cup/disc ratios. Conclusion. There does not seem to be a difference in macular thickness, peripapillary RNFL, or optic disc structures between the amblyopic and fellow eyes in adults. PMID- 26064678 TI - Treatment Outcome of Severe Acute Malnutrition Cases at the Tamale Teaching Hospital. AB - Objective. This study investigated the treatment outcomes and determinant factors likely to be associated with recovery rate. Methods. A retrospective chart review (RCR) was performed on 348 patients who were enrolled in the outpatient care (OPC) during the study period. Results. Of the 348 cases, 33.6% recovered (having MUAC >=125 mm), 49.1% defaulted, and 11.5% transferred to other OPC units to continue with treatment. There were 187 (53.7%) males and 161 (46.3%) females with severe malnutrition. The average weight gain rate was 28 g/kg/day. Controlling for other factors, patients who completed the treatment plan had 3.2 times higher probability of recovery from severe acute malnutrition (SAM) as compared to patients who defaulted (adjusted odds ratio (AOR) = 3.2, 95% CI = 1.9, 5.3, and p < 0.001). The children aged 24-59 months had 5.8 times higher probability of recovery from SAM as compared to children aged 6-11 months (AOR = 5.8, 95% CI = 2.5, 10.6, and p < 0.001). Conclusions. Cure rate was low and the default rate was quite high. Children who were diagnosed as having marasmus on admission stayed longer before recovery than their kwashiorkor counterparts. Younger children were of greater risk of nonrecovery. PMID- 26064679 TI - Relationships between Serum Levels of Atazanavir and Renal Toxicity or Lithiasis. AB - The main aim of this study is to describe the relationship between serum levels of atazanavir, renal toxicity, and lithiasis. This is a prospective observational study of patients being treated with atazanavir (ATV) at Son Espases Teaching Hospital, Palma de Mallorca, between 2011 and 2013. The study includes 98 patients. Sixteen were found to have a history of urolithiasis. During a median monitoring period of 23 months, nine patients suffered renal colic, in three of whom ATV crystals were evidenced in urine. Cumulative incidence of renal colic was 9.2 per 100 patients. The variables related to having renal colic were the presence of alkaline urine pH and lower basal creatinine clearance. The mean serum level of ATV was slightly higher in patients with renal colic-1,303 MUg/L versus 1,161 MUg/L-but did not reach statistical significance. Neither were any significant differences detected by analysing the levels according to the timetable for ATV dosage. Cumulative incidence of renal colic was high in patients being treated with ATV, in 33% of whom the presence of ATV crystals was evidenced in urine. We were unable to demonstrate a relationship between ATV serum levels and renal colic or progression towards renal failure. PMID- 26064680 TI - Clinical Effectiveness of Modified Laparoscopic Fimbrioplasty for the Treatment of Minimal Endometriosis and Unexplained Infertility. AB - Objective. To study the reproductive outcomes of modified laparoscopic fimbrioplasty (MLF), a surgical technique designed to increase the working surface area of the fimbriated end of the fallopian tube. We postulated that an improvement in fimbrial function through MLF will improve reproductive outcomes. Design. Retrospective cohort study. Setting. Academic tertiary-care medical center. Patients. Women with minimal endometriosis or unexplained infertility, who underwent MLF during diagnostic laparoscopy (n = 50) or diagnostic laparoscopy alone (n = 87). Intervention. MLF involved gentle, circumferential dilatation of the fimbria and lysis of fimbrial adhesions bridging the fimbrial folds. Main Outcome Measures. The primary outcome was pregnancy rate and the secondary outcome was time to pregnancy. Results. The pregnancy rate for the MLF group was 40.0%, compared to 28.7% for the control group. The average time to pregnancy for the MLF group was 13 weeks, compared to 18 weeks for the control group. The pregnancy rate in the MLF group was significantly higher for patients <=35 ys (51.5% versus 28.8%), but not for those >35 ys (17.6% versus 28.6%). Conclusion. MLF was associated with a significant increase in pregnancy rate for patients <=35 ys. PMID- 26064677 TI - Frequent Self-Weighing and Visual Feedback for Weight Loss in Overweight Adults. AB - Evidence has suggested that self-weighing may be beneficial for weight control in adults, but few studies have independently assessed the contribution of this behavior to weight loss. This study experimentally tested daily self-weighing and visual feedback (the Caloric Titration Method (CTM)) as a weight loss and weight loss maintenance intervention over 2 years. 162 overweight individuals were randomized to the CTM intervention or delayed treatment control group. In year 1, weight change was compared between groups, and in year 2, the control group started using the CTM while the intervention group continued using the CTM for maintenance. A significant difference in weight loss over the first year (CTM n = 70; 2.6 +/- 5.9 kg versus control n = 65; 0.5 +/- 4.4 kg, p = 0.019) was qualified by a group * gender * time interaction (p = 0.002) such that men lost more weight using the CTM. In year 2, the CTM group maintained their weight and the control group lost an amount similar to the intervention group in year 1. Daily self-weighing and visual feedback facilitated a minimal amount of weight loss and maintenance of this loss. Future research investigating characteristics of those who benefit from this type of self-directed intervention is warranted. PMID- 26064681 TI - Comparison of Xpert MTB/RIF Assay and the Conventional Sputum Microscopy in Detecting Mycobacterium tuberculosis in Northern Thailand. AB - Background. Despite low sensitivity in detection of Mycobacterium tuberculosis, sputum acid-fast smear remains the main diagnostic method. This study aimed to compare the diagnostic performance of Xpert MTB/RIF assay versus conventional sputum acid-fast smear. Materials and Methods. A cross-sectional study was conducted at Chiang Mai University Hospital, Thailand. Patients who were >=15 years old and had clinically suspected pulmonary tuberculosis were included. Results. 109 specimens from 57 patients were included. Using MGIT sputum culture as a reference standard, the sensitivity (SEN) and specificity (SPEC) for Xpert were 95.3% (95% CI, 84.2%, 99.4%) and 86.4% (95% CI, 75.7%, 93.6%). The SEN and SPEC for sputum acid-fast smear were 60.5% (95% CI, 44.4%, 75.0%) and 98.5% (95% CI, 91.8%, 100%). Xpert had significantly higher sensitivity (p value < 0.001) and lower specificity (p value = 0.022) than sputum acid-fast smear. Among 43 culture-proven M. tuberculosis specimens, sensitivity of Xpert was 100% (95% CI, 86.7%, 100%) in acid-fast positive smears (n = 26) and 88.2% (95% CI, 63.5%, 98.5%) in acid-fast negative smears (n = 17). Conclusions. The good sensitivity and specificity of Xpert assay in detecting M. tuberculosis from sputum specimens may help in early diagnosis and treatment of pulmonary tuberculosis, particularly among patients who had acid-fast negative sputum smear. PMID- 26064682 TI - Cerebral Venous Sinus Thrombosis, a Nonenhanced CT Diagnosis? AB - Purpose. Retrospectively evaluate the density of cerebral venous sinuses in nonenhanced head CTs (NCTs) and correlate these with the presence or absence of a cerebral venous sinus thrombus (CVST). Materials and Methods. Institutional review board approval was obtained and informed consent waived prior to commencing this retrospective study. Over a two-year period, all CT venograms (CTVs) performed at our institution were retrieved and the preceding/subsequent NCTs evaluated. Hounsfield Units (HUs) of thrombus when present as well as that of normal superior sagittal and sigmoid sinuses were measured. HU of thrombus was compared to that of normal vessels with and without standardisation to the average HU of the internal carotid arteries. Results. 299 CTVs were retrieved, 26 with a thrombus. Both raw and standardised HU measurements were significantly higher in CVST (p < 0.0001) compared to normal vessels. Both raw and standardised HUs are good predictors of CVST. A HU of >=67 and a standardised measurement of >=1.5 are associated with high probability of CVST on NCT. Conclusion. Cerebral venous sinus HU measurements may help improve sensitivity and specificity of NCT for venous sinus thrombosis and avoid potentially unnecessary follow-up examinations. PMID- 26064683 TI - Causes for Withdrawal in an Urban Peritoneal Dialysis Program. AB - Background. Peritoneal dialysis (PD) is an underutilized dialysis modality in the United States, especially in urban areas with diverse patient populations. Technique retention is a major concern of dialysis providers and might influence their approach to patients ready to begin dialysis therapy. Methods. Records from January 2009 to March 2014 were abstracted for demographic information, technique duration, and the reasons for withdrawal. Results. The median technique survival of the 128 incident patients during the study window was 781 days (2.1 years). The principle reasons for PD withdrawal were repeated peritonitis (30%); catheter dysfunction (18%); ultrafiltration failure (16%); patient choice or lack of support (16%); or hernia, leak, or other surgical complications (6%); and a total of 6 patients died during this period. Of the patients who did not expire and were not transplanted, most transferred to in-center hemodialysis and 8% transitioned to home-hemodialysis. Conclusions. Our findings suggest measures to ensure proper catheter placement and limiting infectious complications should be primary areas of focus in order to promote technique retention. Lastly, more focused education about home-hemodialysis as an option may allow those on PD who are beginning to demonstrate signs of technique failure to stay on home therapy. PMID- 26064685 TI - An Open-Label Trial of Memantine for Cognitive Impairment in Patients with Posttraumatic Stress Disorder. AB - Background. Studies using standard neuropsychological instruments have demonstrated memory deficits in patients with PTSD. We evaluated the efficacy and safety of the N-methyl-D-aspartate antagonist memantine in veterans with PTSD and cognitive impairment. Methods. Twenty-six veterans with PTSD and cognitive impairment received 16 weeks of memantine in an open-label fashion. Cognition was assessed using the Spatial Span, Logical Memory I, and Letter-Number Sequencing subtests of the Wechsler Memory Scale III and the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RBANS measures attention, language, visuospatial skills, and immediate and delayed memories. The Clinician Administered PTSD Scale (CAPS), Hamilton Depression Scale (HAM-D), Hamilton Anxiety Scale (HAM-A), Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), and Sheehan Disability Scale (SDS) were secondary outcome measures. Results. There was a significant improvement in RBANS, both total and subscale scores (P < 0.05), over time. There was a reduction in total CAPS scores, avoidance/numbing symptoms (CAPS-C) and hyperarousal symptoms (CAPS-D), HAM-D, Q LES-Q, and SDS scores. However, there was no reduction in reexperiencing (CAPS-B) and HAM-A scores. Memantine was well tolerated. Conclusions. Memantine improved cognitive symptoms, PTSD symptoms, and mood in veterans with PTSD. Randomized double-blind studies are needed to validate these preliminary observations. PMID- 26064684 TI - Arterial Stiffness and Renal Replacement Therapy: A Controversial Topic. AB - The increase of arterial stiffness has been to have a significant impact on predicting mortality in end-stage renal disease patients. Pulse wave velocity (PWV) is a noninvasive, reliable parameter of regional arterial stiffness that integrates the vascular geometry and arterial wall intrinsic elasticity and is capable of predicting cardiovascular mortality in this patient population. Nevertheless, reports on PWV in dialyzed patients are contradictory and sometimes inconsistent: some reports claim the arterial wall stiffness increases (i.e., PWV increase), others claim that it is reduced, and some even state that it augments in the aorta while it simultaneously decreases in the brachial artery pathway. The purpose of this study was to analyze the literature in which longitudinal or transversal studies were performed in hemodialysis and/or peritoneal dialysis patients, in order to characterize arterial stiffness and the responsiveness to renal replacement therapy. PMID- 26064686 TI - Does Self-Efficacy Affect Cognitive Performance in Persons with Clinically Isolated Syndrome and Early Relapsing Remitting Multiple Sclerosis? AB - In persons with multiple sclerosis (MS) a lowered self-efficacy negatively affects physical activities. Against this background we studied the relationship between self-efficacy and cognitive performance in the early stages of MS. Thirty three patients with Clinically Isolated Syndrome (CIS) and early Relapsing Remitting MS (eRRMS) were assessed for self-efficacy (MSSES-18), cognition (CDR System), fatigue (MFIS-5), depressive symptoms (BDI), disease impact (MSIS-29), and disability (EDSS). Correlative analyses were performed between self-efficacy and cognitive scores, and stepwise regression analyses identified predictors of cognition and self-efficacy. Good correlations existed between total self efficacy and Power of Attention (r= 0.65; P< 0.001), Reaction Time Variability (r= 0.57; P< 0.001), and Speed of Memory (r= 0.53; P< 0.01), and between control self-efficacy and Reaction Time Variability (r= 0.55; P< 0.01). Total self efficacy predicted 40% of Power of Attention, 34% of Reaction Time Variability, and 40% of Speed of Memory variabilities. Disease impact predicted 65% of total self-efficacy and 58% of control self-efficacy variabilities. The findings may suggest that in persons with CIS and eRRMS self-efficacy may positively affect cognitive performance and that prevention of disease activity may preserve self efficacy. PMID- 26064687 TI - Paradox of Modern Pregnancy: A Phenomenological Study of Women's Lived Experiences from Assisted Pregnancy. AB - The purpose of our study was describing the meaning of pregnancy through Assisted Reproductive Technologies (ARTs). A qualitative design with hermeneutic phenomenology approach was selected to carry out the research. Semistructured in depth interviews were conducted with 12 women who experienced assisted pregnancy. Three themes emerged from women's experience including finding peace in life, paradoxical feelings, and struggling to realize a dream. We concluded that pregnancy is the beginning of a new and hard struggle for women with fertility problems. The findings of our study resulted in helpful implications for the health care professionals managing assisted pregnancies. PMID- 26064688 TI - Peritoneal Breach as an Indication for Exploratory Laparotomy in Penetrating Abdominal Stab Injury: Operative Findings in Haemodynamically Stable Patients. AB - Introduction. Management of haemodynamically stable patients with penetrating abdominal injuries varies from nonoperative to operative management. The aim was to investigate whether peritoneal breach when used as an indication for exploratory laparotomy appropriately identified patients with intra-abdominal visceral injury. Methods. We conducted retrospective cohort study of all patients presenting with PAI at a major trauma centre from January 2007 to December 2011. We measured the incidence of peritoneal breach and correlated this with intra abdominal visceral injury diagnosed at surgery. Results. 252 patients were identified with PAI. Of the included patients, 71 were managed nonoperatively and 118 operatively. The operative diagnoses included nonperitoneal-breaching injuries, intraperitoneal penetration without organ damage, or intraperitoneal injury with organ damage. The presenting trauma CT scan was reported as normal in 63%, 34%, and 2% of these groups, respectively. The total negative laparotomy/laparoscopy rate for all patients presented with PAI was 21%, almost half of whom had a normal CT scan. Conclusion. We found that peritoneal breach on its own does not necessarily always equate to intra-abdominal visceral injury. Observation with sequential examination for PAI patients with a normal CT scan may be more important than exclusion of peritoneal breach via laparoscopy. PMID- 26064689 TI - Nitric Oxide Bioavailability in Obstructive Sleep Apnea: Interplay of Asymmetric Dimethylarginine and Free Radicals. AB - Obstructive sleep apnea (OSA) occurs in 2% of middle-aged women and 4% of middle aged men and is considered an independent risk factor for cerebrovascular and cardiovascular diseases. Nitric oxide (NO) is an important endothelium derived vasodilating substance that plays a critical role in maintaining vascular homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in the human circulation. Elevated levels of ADMA inhibit NO synthesis while oxidative stress decreases its bioavailability, so impairing endothelial function and promoting atherosclerosis. Several clinical trials report increased oxidative stress and ADMA levels in patients with OSA. This review discusses the role of oxidative stress and increased ADMA levels in cardiovascular disease resulting from OSA. PMID- 26064690 TI - The Relationship between Sleep-Disordered Breathing and Hypertension in a Nationally Representative Sample. AB - Sleep-disordered breathing (SDB), characterized by abnormal respiratory patterns or inadequate quantity of ventilation, is common in adults. A positive association between SDB and hypertension has been established, in both cross sectional and longitudinal studies. One void in the literature concerns the role of race/ethnicity in the association between SDB and hypertension. In this context, a cross-sectional study was performed on 6,783 participants in the National Health and Nutrition Examination Survey 2005-2008. Participants were >=age 20 and free from cardiovascular disease. The outcome of interest was hypertension, defined as >=140 mmHg systolic blood pressure (BP), and/or >=90 mmHg diastolic BP or antihypertensive medication use. Self-reported SDB was positively associated with hypertension, independent of confounders such as depression, diabetes, cholesterol levels, and body mass index, among others. The association persisted in subgroup analyses by gender, with a stronger association among males than females, as well as by race/ethnicity, with non-Hispanic blacks displaying the strongest association. In the multivariable-adjusted model, compared to a sleep summary score of zero (referent), the OR (95% CI) of hypertension for non-Hispanic blacks was 1.34 (0.98-1.83) for a sleep summary score of 1, 1.44 (1.06-1.97) for a score of 2 and 3.72 (1.98-7.00) for a score of >3; p-trend < 0.0001. SDB was positively associated with hypertension in a large, nationally representative sample of US adults. Along with being prevalent, SDB is also treatable. Therefore, our results are important for minority race/ethnic groups who typically experience a higher baseline for negative health outcomes. PMID- 26064691 TI - Plasticity Induced by Intermittent Theta Burst Stimulation in Bilateral Motor Cortices Is Not Altered in Older Adults. AB - Numerous studies have reported that plasticity induced in the motor cortex by transcranial magnetic stimulation (TMS) is attenuated in older adults. Those investigations, however, have focused solely on the stimulated hemisphere. Compared to young adults, older adults exhibit more widespread activity across bilateral motor cortices during the performance of unilateral motor tasks, suggesting that the manifestation of plasticity might also be altered. To address this question, twenty young (<35 years old) and older adults (>65 years) underwent intermittent theta burst stimulation (iTBS) whilst attending to the hand targeted by the plasticity-inducing procedure. The amplitude of motor evoked potentials (MEPs) elicited by single pulse TMS was used to quantify cortical excitability before and after iTBS. Individual responses to iTBS were highly variable, with half the participants showing an unexpected decrease in cortical excitability. Contrary to predictions, however, there were no age-related differences in the magnitude or manifestation of plasticity across bilateral motor cortices. The findings suggest that advancing age does not influence the capacity for, or manifestation of, plasticity induced by iTBS. PMID- 26064692 TI - Functional and Structural Brain Plasticity Enhanced by Motor and Cognitive Rehabilitation in Multiple Sclerosis. AB - Rehabilitation is recognized to be important in ameliorating motor and cognitive functions, reducing disease burden, and improving quality of life in patients with multiple sclerosis (MS). In this systematic review, we summarize the existing evidences that motor and cognitive rehabilitation may enhance functional and structural brain plasticity in patients with MS, as assessed by means of the most advanced neuroimaging techniques, including diffusion tensor imaging and task-related and resting-state functional magnetic resonance imaging (MRI). In most cases, the rehabilitation program was based on computer-assisted/video game exercises performed in either an outpatient or home setting. Despite their heterogeneity, all the included studies describe changes in white matter microarchitecture, in task-related activation, and/or in functional connectivity following both task-oriented and selective training. When explored, relevant correlation between improved function and MRI-detected brain changes was often found, supporting the hypothesis that training-induced brain plasticity is specifically linked to the trained domain. Small sample sizes, lack of randomization and/or an active control group, as well as missed relationship between MRI-detected changes and clinical performance, are the major drawbacks of the selected studies. Knowledge gaps in this field of research are also discussed to provide a framework for future investigations. PMID- 26064694 TI - Comment on "Dual Prosthetic Heart Valve Presented with Chest Pain: A Case Report of Coronary Thromboembolism". PMID- 26064695 TI - Endovascular Therapy Is Effective for Leriche Syndrome with Deep Vein Thrombosis. AB - A 65-year-old man presented to our hospital due to intermittent claudication and swelling in his left leg. He had Leriche syndrome and deep vein thrombosis. We performed endovascular therapy (EVT) for Leriche syndrome, and a temporary filter was inserted in the inferior vena cava. He received anticoagulation therapy for deep vein thrombosis. The stenotic lesion in the terminal aorta was stented with an excellent postprocedural angiographic result and dramatic clinical improvement after EVT. This case suggests that EVT can be a treatment for Leriche syndrome. PMID- 26064693 TI - CRMP4 and CRMP2 Interact to Coordinate Cytoskeleton Dynamics, Regulating Growth Cone Development and Axon Elongation. AB - Cytoskeleton dynamics are critical phenomena that underpin many fundamental cellular processes. Collapsin response mediator proteins (CRMPs) are highly expressed in the developing nervous system, mediating growth cone guidance, neuronal polarity, and axonal elongation. However, whether and how CRMPs associate with microtubules and actin coordinated cytoskeletal dynamics remain unknown. In this study, we demonstrated that CRMP2 and CRMP4 interacted with tubulin and actin in vitro and colocalized with the cytoskeleton in the transition-zone in developing growth cones. CRMP2 and CRMP4 also interacted with one another coordinately to promote growth cone development and axonal elongation. Genetic silencing of CRMP2 enhanced, whereas overexpression of CRMP2 suppressed, the inhibitory effects of CRMP4 knockdown on axonal development. In addition, knockdown of CRMP2 or overexpression of truncated CRMP2 reversed the promoting effect of CRMP4. With the overexpression of truncated CRMP2 or CRMP4 lacking the cytoskeleton interaction domain, the promoting effect of CRMP was suppressed. These data suggest a model in which CRMP2 and CRMP4 form complexes to bridge microtubules and actin and thus work cooperatively to regulate growth cone development and axonal elongation. PMID- 26064696 TI - Radiation Therapy-Induced Cardiovascular Disease Treated by a Percutaneous Approach. AB - We report the case of a 51-year-old woman, treated with radiotherapy at the age of two years, for a pulmonary sarcoma. Subsequently she developed severe aortic stenosis and bilateral ostial coronary artery disease, symptomatic for dyspnea (NYHA III functional class). Due to the prohibitive surgical risk, she underwent successful stenting in the right coronary artery and left main ostia with drug eluting stents and, afterwards, transcatheter aortic valve replacement with transfemoral implantation of a 23 mm Edwards SAPIEN XT valve. The percutaneous treatment was successful without complications and the patient is in NYHA II functional class at 2 years' follow-up, fully carrying out normal daily activities. PMID- 26064697 TI - Transcatheter Removal of Embolized Port Catheters from the Hearts of Two Children. AB - Embolization of a port catheter is a dangerous and serious complication. In this paper, we present two cases of children, aged 4.5 months and 6 years, in whom port catheters had embolized to the right ventricle one month and 1.5 years priorly, respectively; the port catheters were retrieved via snaring. PMID- 26064698 TI - Talon Cusp Type I: Restorative Management. AB - The teeth are formed during intrauterine life (i.e., gestation) during the odontogenesis stage. During this period, the teeth move until they enter the oral cavity. This course covers various stages of dental development, namely, initiation, proliferation, histodifferentiation, morphodifferentiation, and apposition. The talon cusp is an anomaly that occurs during morphodifferentiation, and this anomaly may have numerous adverse clinical effects on oral health. The objective of this study was to report a case of "Talon Cusp Type I" and to discuss diagnostic methods, treatment options for this anomaly, and the importance of knowledge of this morphological change among dental professionals so that it is not confused with other morphological changes; such knowledge is required to avoid unnecessary surgical procedures, to perform treatments that prevent caries and malocclusions as well as enhancing aesthetics, and to improve the oral health and quality of life of the patient. PMID- 26064699 TI - Conservative, Surgical, and Prosthetic Treatment of a Patient with a Periapical Lesion Associated with an Atypical Intraoral Sinus Tract. AB - This report describes a clinical case with an atypical intraoral sinus tract formation from diagnosis and treatment to short-term outcome and definitive prosthetic rehabilitation. In detail, the patient underwent conservative nonsurgical root canal treatment followed by guided bone augmentation of the regions involved in periapical inflammation and sinus tract formation. The removal of the inflammatory source of the lesion as well as the affected tissue clearly led to a healing of the surrounding bone tissues. Subsequently, the tooth was reconstructed using a fibreglass post and a metal-ceramic crown; an implant was successfully placed in the previously inflamed bone region. PMID- 26064700 TI - Surgical Treatment of Peri-Implantitis: A 17-Year Follow-Up Clinical Case Report. AB - The purpose of the present case report was to describe the surgical treatment of a peri-implantitis lesion associated with a regenerative approach. A 48-year-old patient came to authors' attention 36 months after the placement of a dental implant (ITI-Bonefit Straumann, Waldenburg, Switzerland) in position 46. A swelling of the peri-implant soft tissues was observed, associated with bleeding on probing and probing depth > 10 mm. A significant peri-implant bone loss was clearly visible on the periapical radiograph. A nonsurgical periodontal supportive therapy was firstly conducted to reduce the inflammation, followed by the surgical treatment of the defect. After mechanical and chemical decontamination with tetracycline solution, a regenerative approach consisting in the application of deproteinized bovine bone mineral (Bio-Oss, Geistlich Pharma AG, Wolhusen, Switzerland) and a collagen membrane (Bio-Gide, Geistlich Pharma AG, Wolhusen, Switzerland) was performed. An antibiotic therapy was associated with the treatment. The 17-year follow-up showed a physiological probing depth with no clinical signs of peri-implant inflammation and bleeding on probing. No further radiographic bone loss was observed. The treatment described in the present case report seemed to show improved clinical results up to a relevant follow-up period. PMID- 26064701 TI - Custom-Made Computer-Aided-Design/Computer-Aided-Manufacturing Biphasic Calcium Phosphate Scaffold for Augmentation of an Atrophic Mandibular Anterior Ridge. AB - This report documents the clinical, radiographic, and histologic outcome of a custom-made computer-aided-design/computer-aided-manufactured (CAD/CAM) scaffold used for the alveolar ridge augmentation of a severely atrophic anterior mandible. Computed tomographic (CT) images of an atrophic anterior mandible were acquired and modified into a 3-dimensional (3D) reconstruction model; this was transferred to a CAD program, where a custom-made scaffold was designed. CAM software generated a set of tool-paths for the manufacture of the scaffold on a computer-numerical-control milling machine into the exact shape of the 3D design. A custom-made scaffold was milled from a synthetic micromacroporous biphasic calcium phosphate (BCP) block. The scaffold closely matched the shape of the defect: this helped to reduce the time for the surgery and contributed to good healing. One year later, newly formed and well-integrated bone was clinically available, and two implants (AnyRidge, MegaGen, Gyeongbuk, South Korea) were placed. The histologic samples retrieved from the implant sites revealed compact mature bone undergoing remodelling, marrow spaces, and newly formed trabecular bone surrounded by residual BCP particles. This study demonstrates that custom made scaffolds can be fabricated by combining CT scans and CAD/CAM techniques. Further studies on a larger sample of patients are needed to confirm these results. PMID- 26064702 TI - Temporoparietal Headache as the Initial Presenting Symptom of a Massive Aortic Dissection. AB - Aortic dissection is a life-threatening medical emergency often presenting with severe chest pain and acute hemodynamic compromise. The presentation of aortic dissection can sometimes be different thus leading to a challenge in prompt diagnosis and treatment as demonstrated by the following presentation and discussion. We present a case of a 71-year-old male who presented to the emergency department with complaints of left sided temporoparietal headache and was eventually diagnosed with a thoracic aortic dissection involving the ascending aorta and descending aorta, with an intramural hematoma in the descending aorta. This case illustrates the importance of keeping in mind aortic dissection as a differential diagnosis in patients with acute onset headaches in which any intracranial source of headache is not found. PMID- 26064703 TI - Assessment of Musculoskeletal Injuries from Domestic Violence in the Emergency Department. AB - Domestic violence is one of the most common causes of nonfatal injury in women, with musculoskeletal injuries representing the second most prevalent manifestation of this form of violence. It is therefore of great importance that healthcare providers such as emergency department (ED) physicians and surgeons are able to recognize and assess these kinds of injuries. In this case report, a woman is described visiting an ED with injuries caused by a fall. Thanks to the knowledge and attention of the ED physician, the real cause of the injury was discovered. What appeared to be an unsuspicious accident was actually the result of intimate partner violence. PMID- 26064704 TI - Nilotinib-Associated Destructive Thyroiditis. AB - Protein tyrosine kinase inhibitors are currently an important drug class in the treatment of leukemia. They represent targeted cancer therapy and have become the treatment of choice in chronic myeloid leukemia. Tyrosine kinases are enzymes expressed in multiple tissues and are involved in several signaling pathways influencing cellular growth. Below we describe a patient who developed an unusual complication of tyrosine kinase inhibitor therapy: thyrotoxicosis due to destructive thyroiditis. We review the pathophysiology of tyrosine kinase inhibitor-induced thyroid dysfunction particularly with regard to new second generation tyrosine kinase inhibitors. PMID- 26064705 TI - A Retroperitoneal Leiomyosarcoma Presenting as an Adrenal Incidentaloma in a Subject on Warfarin. AB - Adrenal incidentalomas (AIs) are mostly benign and nonsecretory. Management algorithms lack sensitivity when assessing malignant potential, although functional status is easier to assess. We present a subject whose AI was a retroperitoneal leiomyosarcoma (RL). Case Presentation. A woman on warfarin with SLE and the antiphospholipid syndrome, presented with left loin pain. She was normotensive and clinically normal. Ultrasound scans demonstrated left kidney scarring, but CT scans revealed an AI. MRI scans later confirmed the AI without significant fat and no interval growth. Cortisol after 1 mg dexamethasone, urinary free cortisol and catecholamines, plasma aldosterone renin ratio, and 17 hydroxyprogesterone were within the reference range. Initially, adrenal haemorrhage was diagnosed because of warfarin therapy and the acute presentation. However, she underwent adrenalectomy because of interval growth of the AI. Histology confirmed an RL. The patient received adjuvant radiotherapy. Discussion. Our subject presented with an NSAI. However, we highlight the following: (a) the diagnosis of adrenal haemorrhage in this anticoagulated woman was revised because of interval growth; (b) the tumour, an RL, was relatively small at diagnosis; PMID- 26064706 TI - Visceral Kaposi's Sarcoma Presenting as Upper Gastrointestinal Bleeding. AB - Since the advent of highly active antiretroviral therapy (HAART), the incidence of acquired immunodeficiency syndrome- (AIDS-) related Kaposi's sarcoma (KS) has decreased dramatically. While cutaneous KS is the most common and well-known manifestation, knowledge of alternative sites such as the gastrointestinal (GI) tract is important. GI-KS is particularly dangerous because of its potential for serious complications including perforation, obstruction, or bleeding. We report a rare case of GI-KS presenting as upper GI bleeding in a human immunodeficiency virus- (HIV-) infected transgendered individual. Prompt diagnosis and early initiation of therapy are the cornerstones for management of this potentially severe disease. PMID- 26064707 TI - Metastatic Periampullary Tumor from Hepatocellular Carcinoma Presenting as Gastrointestinal Bleeding. AB - Periampullary tumors constitute a number of diverse neoplastic lesions located within 2 cm of the major duodenal papilla; among these, metastatic lesions account for only a small proportion of the periampullary tumors. To our knowledge, a metastatic periampullary tumor from hepatocellular carcinoma has never been reported. A 62-year-old male reported to our institute for fatigue and low hemoglobin. His medical history was remarkable for multifocal hepatocellular carcinoma (HCC) treated with selective transcatheter arterial chemoembolization (TACE). An esophagogastroduodenoscopy (EGD) was performed which revealed a periampullary mass. Histopathology was consistent with metastatic moderately differentiated HCC. Two endoloops were deployed around the base of the mass one month apart. The mass eventually sloughed off and patient's hemoglobin level stabilized. We postulated that periampullary metastasis in this patient was the result of tumor fragments migration through the biliary tracts and that TACE which increases tumor fragments burden might have played a contributory role. Metastasis of HCC to the gastrointestinal (GI) tract should be considered as a cause of GI bleeding. PMID- 26064708 TI - Deletion of 7q33-q35 in a Patient with Intellectual Disability and Dysmorphic Features: Further Characterization of 7q Interstitial Deletion Syndrome. AB - This case report concerns a 16-year-old girl with a 9.92 Mb, heterozygous interstitial chromosome deletion at 7q33-q35, identified using array comparative genomic hybridization. The patient has dysmorphic facial features, intellectual disability, recurrent infections, self-injurious behavior, obesity, and recent onset of hemihypertrophy. This patient has overlapping features with previously reported individuals who have similar deletions spanning the 7q32-q36 region. It has been difficult to describe an interstitial 7q deletion syndrome due to variations in the sizes and regions in the few patients reported in the literature. This case contributes to the further characterization of an interstitial distal 7q deletion syndrome. PMID- 26064709 TI - Identification of Novel Mutations in Spatacsin and Apolipoprotein B Genes in a Patient with Spastic Paraplegia and Hypobetalipoproteinemia. AB - Complicated hereditary spastic paraplegia (HSP) presents with complex neurological and nonneurological manifestations. We report a patient with autosomal recessive (AR) HSP in whom laboratory investigations revealed hypobetalipoproteinemia raising the possibility of a shared pathophysiology of these clinical features. A lipid profile of his parents disclosed a normal maternal lipid profile. However, the paternal lipid profile was similar to that of the patient suggesting autosomal dominant transmission of this trait. Whole exome sequence analysis was performed and novel mutations were detected in both the SPG11 and the APOB genes. Genetic testing of the parents showed that both APOB variants were inherited from the father while the SPG11 variants were inherited one from each parent. Our results indicate that, in this patient, the hypobetalipoproteinemia and spastic paraplegia are unrelated resulting from mutations in two independent genes. This clinical study provides support for the use of whole exome sequencing as a diagnostic tool for identification of mutations in conditions with complex presentations. PMID- 26064710 TI - PWS/AS MS-MLPA Confirms Maternal Origin of 15q11.2 Microduplication. AB - The proximal region of the long arm of chromosome 15q11.2-q13 is associated with various neurodevelopmental disorders, including Prader-Willi (PWS) and Angelman (AS) syndromes, autism, and other developmental abnormalities resulting from deletions and duplications. In addition, this region encompasses imprinted genes that cause PWS or AS, depending on the parent-of-origin. This imprinting allows for diagnosis of PWS or AS based on methylation status using methylation sensitive (MS) multiplex ligation dependent probe amplification (MLPA). Maternally derived microduplications at 15q11.2-q13 have been associated with autism and other neuropsychiatric disorders. Multiple methods have been used to determine the parent-of-origin for 15q11.2-q13 microdeletions and microduplications. In the present study, a four-year-old nondysmorphic female patient with developmental delay was found to have a de novo ~5 Mb duplication within 15q11.2 by oligonucleotide genomic array. In order to determine the significance of this microduplication to the clinical phenotype, the parent-of origin needed to be identified. The PWS/AS MS-MLPA assay is generally used to distinguish between deletion and uniparental disomy (UPD) of 15q11.2-q13, resulting in either PWS or AS. However, our study shows that PWS/AS MS-MLPA can also efficiently distinguish the parental origin of duplications of 15q11.2-q13. PMID- 26064711 TI - Ellis-van Creveld Syndrome: Mutations Uncovered in Lebanese Families. AB - Background. Ellis-van Creveld (EvC) syndrome is a rare, autosomal recessive disorder characterized by short stature, short limbs, growth retardation, polydactyly, and ectodermal defects with cardiac anomalies occurring in around 60% of cases. EVC syndrome has been linked to mutations in EVC and EVC2 genes. Case Presentation. We report EvC syndrome in two unrelated Lebanese families both having homozygous mutations in the EVC2 gene, c.2653C>T (p.(Arg885(*))) and c.2012_2015del (p.(Leu671(*))) in exons 15 and 13, respectively, with the latter being reported for the first time. Conclusion. Although EvC has been largely described in the medical literature, clinical features of this syndrome vary. While more research is required to explore other genes involved in EvC, early diagnosis and therapeutic care are important to achieve a better quality of life. PMID- 26064712 TI - Calreticulin Mutated Essential Thrombocythemia Presenting as Acute Coronary Syndrome. AB - Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by a clonal expansion of megakaryocytes. ET can result in both arterial and venous thrombosis. Involvement of the coronary arteries has been reported. Patients who harbor a CALR mutation are half as likely to suffer a thrombotic event as compared to patients with a JAK2 mutation. We report a case of CALR-mutated ET whose initial disease manifestation was a non-ST segment elevation myocardial infarction. PMID- 26064713 TI - Localized Relapse of Primary Plasma Cell Leukaemia in the Central Nervous System. AB - Primary plasma cell leukaemia (pPCL) is a rare and aggressive form of plasma cell malignancies with a very poor prognosis. Compared to other plasma cell malignancies the tendency to extramedullary spread is increased; however central nervous system (CNS) involvement is rare and only reported in few cases. We report the case of a 61-year-old man who was diagnosed with pPCL and achieved a complete remission after autologous stem cell transplantation but had a relapse in the CNS without systemic disease. PMID- 26064714 TI - AL Amyloidosis Complicated by Persistent Oral Bleeding. AB - A case of amyloid light chain (AL) amyloidosis is presented here with uncontrolled bleeding after a nonsurgical dental procedure, most likely multifactorial in nature, and consequently treated with a multidisciplinary approach. PMID- 26064715 TI - Enterococcus gallinarum Spontaneous Bacterial Peritonitis in an HCV Cirrhotic. AB - We present the case of a 60-year-old Caucasian male with history of hepatitis C viral cirrhosis with portosystemic encephalopathy and ascites with evidence of spontaneous bacterial peritonitis (SBP) with absolute neutrophil count (ANC) of 944 cells/uL blood. Despite adequate treatment, the abdominal pain and elevated creatinine continued to persist. Initial ascites fluid cultures returned back positive for growth of Enterococcus gallinarum. Empiric antibiotics were then substituted with ampicillin/sulbactam. Our case of Enterococcus gallinarum causing SBP is only the seventh case reported in the literature to date. PMID- 26064716 TI - Immunodeficiency in a Child with Rapadilino Syndrome: A Case Report and Review of the Literature. AB - Rapadilino syndrome is a genetic disease characterized by a characteristic clinical tableau. It is caused by mutations in RECQL4 gene. Immunodeficiency is not described as a classical feature of the disease. We present a 2-year-old girl with Rapadilino syndrome with important lymphadenopathies and pneumonia due to disseminated Mycobacterium lentiflavum infection. An immunological work-up showed several unexpected abnormalities. Repeated blood samples showed severe lymphopenia. Immunophenotyping showed low T, B, and NK cells. No Treg cells were seen. T cell responses to stimulations were insufficient. The IL12/IL23 interferon gamma pathway was normal. Gamma globulin levels and vaccination responses were low. With this report, we aim to stress the importance of screening immunodeficiency in patients with RECQL4 mutations for immunodeficiency and the need to further research into its physiopathology. PMID- 26064717 TI - Differences in Method-Specific Vancomycin MICs and Induced Daptomycin Resistance in an Infective Endocarditis Patient. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a common nosocomial infection that has a high burden of morbidity and mortality. Vancomycin is the often-used antibiotic of choice when MRSA is suspected as a causative infectious agent. Recent studies have called into question the reliability of vancomycin as empiric therapy, especially in instances of bacteremia. The isolate's minimum inhibitory concentration (MIC), the source of infection, modality of susceptibility testing, and antibiotic resistance are all issues that should be taken into consideration when formulating a care plan for a patient. We present a case that illustrates some of these issues clinicians are facing. PMID- 26064718 TI - Kytococcus schroeteri Bacteremia in a Patient with Hairy Cell Leukemia: A Case Report and Review of the Literature. AB - The Kytococcus genus formerly belonged to Micrococcus. The first report of a Kytococcus schroeteri infection was in 2002 in a patient diagnosed with endocarditis. We report a case of central line associated Kytococcus schroeteri bacteremia in a patient with underlying Hairy Cell Leukemia. Kytococcus schroeteri is an emerging infection in the neutropenic population and in patients with implanted artificial tissue. It is thought to be a commensal bacterium of the skin; however, attempts to culture the bacteria remain unsuccessful. There have been a total of 5 cases (including ours) of K. schroeteri bacteremia in patients with hematologic malignancies and neutropenia and only 18 documented cases in any population. Four of the cases of bacteria in neutropenic patients have been fatal, but early detection and treatment could make a difference in clinical outcomes. PMID- 26064719 TI - Cutaneous and Skeletal Simultaneous Locations as a Rare Clinical Presentation of Tuberculosis. AB - Tuberculosis is a resurgent disease in most regions of the world, infecting one third of the world's population and having a multisystemic involvement. Incidence of extra-pulmonary tuberculosis has increased in the last few decades as a result of the Human Immunodeficiency Virus (HIV) infection. The authors report a clinical case of the rare concomitant cutaneous and skeletal tuberculosis in an immunocompetent patient transferred from endemic area. PMID- 26064720 TI - Multifocal Tubercular Osteomyelitis with Tubercular Breast Abscess: An Atypical Presentation of Tuberculosis. AB - Tuberculosis of spine is common in a developing country like India. However, involvement of spine at multiple levels along with involvement of rib and tubercular breast abscess in an immunocompetent patient without any pulmonary involvement is extremely rare. Here we report a case of 53-year-old immunocompetent lady who presented with quadriparesis and MRI (magnetic resonance imaging) of spine revealed multiple lesions involving cervical, thoracic, lumbar, and sacral region without any involvement of intervertebral disc. On detailed examination she was found to have a lump in right breast. Fine needle aspiration cytology of both paravertebral collection and breast lump revealed presence of acid fast bacilli. She was put on antitubercular drug for one year and she responded well to therapy. PMID- 26064721 TI - Copious Podocyturia without Proteinuria and with Normal Renal Function in a Young Adult with Fabry Disease. AB - The time for starting a patient with Fabry disease on enzyme replacement therapy is still a matter of debate, particularly when no overt classical clinical signs or symptoms are present. With respect to Fabry nephropathy, a dual problem coexists: the reluctance of many nephrologists to start enzyme replacement infusion until signs of renal disease appear as the appearance of proteinuria or an elevation in serum creatinine and the lack of validated biomarkers of early renal damage. In this regard, proteinuria is nowadays considered as an early and appropriate marker of kidney disease and of cardiovascular morbidity and mortality. However, in this report we demonstrate that podocyturia antedates the classical appearance of proteinuria and could be considered as an even earlier biomarker of kidney damage. Podocyturia may be a novel indication for the initiation of therapy in Fabry disease. PMID- 26064722 TI - The Rarest of the Rare: Crossed Fused Renal Ectopia of the Superior Ectopia Type. AB - Crossed fused renal ectopia is a rare congenital anomaly of the urinary system where one kidney crosses over to opposite side and the parenchyma of the two kidneys fuse. Herein, we present an atypical CFRE case whose renal anatomy does not exactly match any of the already defined CFRE types. Both of the kidneys are ectopic with the crossed ectopic right kidney lying superiorly and fused to the upper pole of the left kidney. Renal arteries were originating from the common iliac arteries. A focal 90% stenosis was observed on the right main renal artery. The patient is borderline hypertensive. PMID- 26064723 TI - Cerebellum as Initial Site of Distant Metastasis from Papillary Carcinoma of Thyroid: Review of Three Cases. AB - Background. The cerebellum as initial site of distant metastasis from differentiated thyroid carcinoma (DTC) including papillary (PTC) and follicular thyroid carcinoma (FTC) is rare manifestation. Case Presentations. Herein, we present three cases of cerebellar metastasis (CBM) of PTC. Mean age of patients was 67 years (range: 64-72), and mean duration between initial diagnosis and CBM was 49.6 months (range: 37-61). Frequent location was left cerebellar hemisphere and was associated with hydrocephalus. All patients underwent suboccipital craniectomy, and in two patients postoperative intensity modulated radiation therapy (IMRT) was given to deliver 5000 cGy in 25 fractions to residual lesions. Patient without postoperative IMRT had cerebellar recurrence along with lung and bone metastasis after 38 months. However, two patients were found alive and free of disease at the time of last follow-up. Conclusion. CBM from PTC is a rare clinical entity and is often associated with hydrocephalus. Histopathological diagnosis is important to initiate effective treatment, which relies on multidisciplinary approach to prolong the disease-free and overall survival rates. PMID- 26064724 TI - ESBL Escherichia coli Ventriculitis after Aneurysm Clipping: A Rare and Difficult Therapeutic Challenge. AB - Background. Extended spectrum beta-lactamase (ESBL) produced Escherichia coli (E. coli) ventriculitis is a rare infection of the central nervous system, with increasing rarity in the adult population. The therapeutic strategy to achieve cure may need to involve a combination of intraventricular and intravenous (IV) therapy. Objective. To describe a case of ESBL E. coli meningitis/ventriculitis in an adult and outline the antimicrobial therapy that leads to cure. Methods. We retrospectively reviewed the records of a patient admitted to the neurosurgical department for aneurysmal subarachnoid hemorrhage, who developed ESBL E. coli ventriculitis. Results. A 55-year-old female, admitted for a Fisher grade 3, World Federation of Neurological Surgeons grade 1, subarachnoid hemorrhage, developed ESBL E. coli ventriculitis requiring a combination of intraventricular gentamicin and high dose intravenous meropenem for clearance. Cerebrospinal fluid clearance occurred at 7 days after initiation of combined therapy. The patient remained shunt dependent. Conclusions. Meningitis and ventriculitis caused by ESBL E. coli species are rare and pose significant challenges to the treating physician. Early consideration for combined intraventricular and IV therapy should be made. PMID- 26064725 TI - Pancreatic and Colonic Abscess Formation Secondary to HELLP Syndrome. AB - Preeclampsia and the variant HELLP syndrome are systemic conditions associated with vascular changes resulting in vasoconstriction. Most commonly, patients present with elevated blood pressure and proteinuria, with a background of complaints such as headache, scotoma, and right upper quadrant pain. The systemic vascular changes experienced can target any organ system, oftentimes with more than one organ system being involved. We present the case of a patient admitted with HELLP syndrome who subsequently developed multisystem organ dysfunction, including placental abruption, disseminated intravascular coagulopathy, acute renal failure, colitis, abdominal ascites, pancreatitis, and the development of pancreatic and colonic abscesses. PMID- 26064726 TI - Rectal Cancer Diagnosed after Cesarean Section in Which High Microsatellite Instability Indicated the Presence of Lynch Syndrome. AB - We report a case of rectal cancer with microsatellite instability (MSI) that probably resulted from Lynch syndrome and that was diagnosed after Cesarean section. The patient was a 28-year-old woman (gravid 1, para 1) without a significant medical history. At 35 gestational weeks, vaginal ultrasonography revealed a 5 cm tumor behind the uterine cervix, which was diagnosed as a uterine myoma. The tumor gradually increased in size and blocked the birth canal, resulting in the patient undergoing an emergency Cesarean section. Postoperatively, the tumor was diagnosed as rectal cancer with MSI. After concurrent chemoradiation therapy, a lower anterior resection was performed. The patient's family history revealed she met the criteria of the revised Bethesda guidelines for testing the colorectal tumor for MSI. Testing revealed that the tumor did indeed show high MSI and, combined with the family history, suggested this could be a case of Lynch syndrome. Our findings emphasize the importance of considering the possibility of Lynch syndrome in pregnant women with colorectal cancer, particularly those with a family history of this condition. We suggest that the presence of Lynch syndrome should also be considered for any young woman with endometrial, ovarian, or colorectal cancer. PMID- 26064727 TI - Mucoepidermoid Carcinoma of Uterine Cervix: A Distinct Pathological and Clinical Entity. AB - Mucoepidermoid carcinoma of uterine cervix is a rare tumor that has some individual features. Defining risk factors after surgery shape the postoperative treatment modality on cervical cancer patients. Although there is not a well known strategy for the postoperative follow-up of mucoepidermoid carcinoma, the aggressive behaviour of this tumor makes the gynecological oncologists choose liberal therapies on these patients. PMID- 26064728 TI - The Challenge of Prenatal Diagnostic Work-Up of Maternally Inherited X-Linked Opitz G/BBB: Case Report and Literature Review. AB - Background. Prenatal diagnosis of Optiz G/BBB syndrome (OS) is challenging because the characteristic clinical features, such as facial and genitourinary anomalies, may be subtle at sonography and rather unspecific. Furthermore, molecular testing of the disease gene is not routinely performed, unless a specific diagnosis is suggested. Method. Both familial and ultrasound data were used to achieve the diagnosis of X-linked OS (XLOS), which was confirmed by molecular testing of MID1 gene (Xp22.3) at birth. Results. Sequencing of MID1 gene disclosed the nucleotide change c.1285 +1 G>T, previously associated with XLOS. Conclusions. This case illustrates current challenges of the prenatal diagnostic work-up of XLOS and exemplifies how clinical investigation, including family history, and accurate US foetal investigations can lead to the correct diagnosis. PMID- 26064729 TI - Oxaliplatin-Induced Pulmonary Toxicity in Gastrointestinal Malignancies: Two Case Reports and Review of the Literature. AB - Oxaliplatin is a common chemotherapy drug, used mainly for colon and gastric cancer. Most common side effects are peripheral sensory neuropathy, hematological toxicity, and allergic reactions. A less common side effect is pulmonary toxicity, characterized mainly by interstitial pneumonitis. The incidence of this side effect is unknown, but the toxicity can be fatal. Twenty-six cases of pulmonary toxicity have been described in the literature, seven in the setting of adjuvant treatment. We describe two fatal cases of pulmonary injury related to oxaliplatin and a review of the literature. PMID- 26064730 TI - A Case Report of Long-Term Survival following Hepatic Arterial Infusion of L Folinic Acid Modulated 5-Fluorouracil Combined with Intravenous Irinotecan and Cetuximab Followed by Hepatectomy in a Patient with Initially Unresectable Colorectal Liver Metastases. AB - A 43-year-old women admitted to our hospital for weight loss, anorexia, and abdominal pain was diagnosed with sigmoid neoplasm and multiple bilobar liver metastases. This patient received six cycles of systemic FOLFOX prior to a laparoscopically assisted anterior resection of the rectosigmoid for a poorly differentiated invasive adenocarcinoma T2N2M1, K-RAS negative (wild type). Hepatic arterial infusion (HAI) of L-folinic acid modulated 5-fluorouracil (LV/5 FU) with intravenous (iv) irinotecan (FOLFIRI) and cetuximab as adjuvant therapy resulted in a complete metabolic response (CR) with CEA normalization. A right hepatectomy extended to segment IV was performed resulting in (FDG-)PET negative remission for 7 months. Solitary intrahepatic recurrence was effectively managed by local radiofrequent ablation following 6c FOLFIRI plus cetuximab iv. Multiple lung lesions and recurrence of pulmonary and local lymph node metastases were successfully treated with fractionated stereotactic radiotherapy (50 Gy) and iv LV/5-FU/oxaliplatin (FOLFOX) plus cetuximab finally switched to panitumumab with CR as a result. At present the patient is in persistent complete remission of her stage IV colorectal cancer, more than 5 years after initial diagnosis of the advanced disease. Multidisciplinary treatment with HAI of chemotherapy (LV/5-FU + CPT-11) plus EGFR-inhibitor can achieve CR of complex unresectable LM and can even result in hepatectomy with possible long-term survival. PMID- 26064731 TI - A Rare Case of Undifferentiated Carcinoma of the Colon with Rhabdoid Features: A Case Report and Review of the Literature. AB - Malignant rhabdoid tumors were originally described in children. Subsequently, the same histological pattern was described in adults. Malignant rhabdoid tumors are aggressive neoplasms that have been reported in multiple organs. To our best knowledge, only 16 previous cases of rhabdoid tumor in the colon have been described in the literature. We present the case of an 87-year-old lady who was diagnosed with a rhabdoid tumor of the colon that relapsed rapidly after surgical resection. The literature concerning this unusual neoplasm was subsequently reviewed with comparison of all known cases in the literature. PMID- 26064732 TI - Bilateral Sturge-Weber and Phakomatosis Pigmentovascularis with Glaucoma, an Overlap Syndrome. AB - Aim. To report a case of bilateral Sturge-Weber and Phakomatosis pigmentovascularis with secondary glaucoma in a child. Method. CASE REPORT: Results. A 4-year-old male child was referred to us for control of intraocular pressure (IOP). Sleeping IOP was 36 mm Hg in right eye and 28 mm Hg in the left eye. The sclera of both the eyes showed bluish black pigmentation-melanosis bulbi. Fundus examination of both eyes showed diffuse choroidal hemangiomas with glaucomatous cupping. Nevus flammeus was present on both sides of face along all the 3 divisions of trigeminal nerve with overlying hypertrophy of skin and on left forearm. Nevus fuscocaeruleus was present on upper trunk. All skin lesions were present since birth and were stationary in nature. CT scan of head revealed left-sided cerebral atrophy. Intraocular pressure was controlled after treatment with topical antiglaucoma medications. Pulsed Dye Laser has been advised by dermatologist for skin lesions. Patient has been advised for regular follow-up. Conclusion. The two overlapping dermatological disorders and their association with glaucoma are a rare entity. Management should be targeted both for dermatological and eye conditions. PMID- 26064733 TI - Complete Disappearance of Choroidal Metastasis from Lung Adenocarcinoma Treated with Bevacizumab and Chemotherapy. AB - Choroidal metastasis from lung cancer is uncommon. We report a case of choroidal metastasis as an inaugural manifestation of lung adenocarcinoma, successfully treated by docetaxel, cisplatinum, and intravenous bevacizumab as an antiangiogenesis therapy. A complete remission was obtained after 4 cycles and maintained after six cycles. This case report demonstrates the importance of the systemic bevacizumab and chemotherapy in the treatment of choroidal metastasis from adenocarcinoma of the lung. PMID- 26064734 TI - Ultrasound Biomicroscopy and Scheimpflug Imaging in Anterior Megalophthalmos: Changes Seen after Cataract Surgery. AB - Purpose. With this report we describe ultrasound biomicroscopic (UBM) findings in a patient with anterior megalophthalmos before and after undergoing phacoemulsification with posterior chamber intraocular lens implantation. Methods. Phacoemulsification was carried out for nuclear sclerosis in both eyes of a patient diagnosed with anterior megalophthalmos. The patient was subjected to detailed ophthalmic examination including ultrasound biomicroscopy and Scheimpflug imaging prior to and after surgery. Preoperative ultrasound biomicroscopy revealed a deep anterior chamber with posterior bowing of the midperipheral iris in both eyes. The ciliary processes were inserted on the posterior surface of the iris. UBM was repeated postoperatively as well. Results. Phacoemulsification and posterior chamber intraocular lens implantation (IOL) were carried out successfully in both eyes. The IOLs were well centered and captured within the anterior capsulorhexis. The anterior chambers were hyperdeep, 6.24 mm (OD) and 6.08 mm (OS), respectively. The posterior bowing of the midperipheral iris was absent, with the iris having a more flat profile. Conclusion. UBM findings in anterior megalophthalmos seemed to partially resolve after cataract surgery. The anterior chamber deepens appreciably as well. PMID- 26064735 TI - Infected Baerveldt Glaucoma Drainage Device by Aspergillus niger. AB - Fungal endophthalmitis is rare but may complicate glaucoma drainage device surgery. Management is challenging as the symptoms and signs may be subtle at initial presentation and the visual prognosis is usually poor due to its resistant nature to treatment. At present there is lesser experience with intravitreal injection of voriconazole as compared to Amphotericin B. We present a case of successfully treated Aspergillus endophthalmitis following Baerveldt glaucoma drainage device implantation with intravitreal and topical voriconazole. PMID- 26064736 TI - A Case of Goldenhar Syndrome Associated with a New Retinal Presentation: Exudative Vitelliform Maculopathy. AB - Goldenhar syndrome is a rare clinical disturbance with a wide range of clinical manifestations. We report on a 6-year-old male with peculiar retinal presentation of Goldenhar syndrome. The patient was referred to Ophthalmology for central scotoma in the left eye, where visual acuity was 20/100. Fundus examination was unremarkable, except for yellowish material in the central macula. SD-OCT revealed interruption of the external limiting membrane and inner and outer segment junctions, with disorganized material in the vitelliform space and subretinal fluid. Six months later, fundus and SD-OCT examinations were unchanged without treatment, but visual acuity in the left eye had improved to 20/50. Five years later, he had similar clinical manifestations in the right eye. He was started on systemic steroids. After 15 days, his visual acuity improved to 20/20 and subretinal fluid and yellowish material in the vitelliform space disappeared. Goldenhar syndrome has variable presentation, including vitelliform maculopathy. PMID- 26064737 TI - Late Stage of Corneal Decompensation Caused by Progressive Keratoconus: Can We Treat It and Save the Cornea? AB - Aim. To report a case of 40-year-old male with progressive bilateral keratoconus who had undergone transepithelial phototherapeutic keratectomy (TE-PTK) and corneal collagen cross-linking (CXL) using hypoosmolar riboflavin solution in a same day procedure. Methods. Eye examination showed that UCDVA on both eyes was 0,01 according to Snellen charts, and slit lamp biomicroscopy showed paracentral diffuse intrastromal corneal haze. Anterior OCT marked stromal hyperreflective zones and localized paracentral thinning of the cornea. Scheimpflug tomography noted keratoconus stages III-IV on both eyes. After 40/35 microns TE-PTK, a CXL was performed for 30 minutes using hypoosmolar riboflavin solution. The left eye was treated first and the right eye 1 month after. Follow-up period was 10 months. Results. One month after the treatment both eyes showed improvement in corneal topography and the UCDVA was better. Eight months after the treatment BSCVA improved to 0,6 in both eyes using Rose K2 contact lenses and remained stable. Conclusion. TE-PTK and CXL using hypotonic riboflavin solution as a same day procedure have been shown to be a safe and promising method in this case of progressive keratoconus. It was necessary to consider certain parameters that could influence the safety and the final outcome of this combined protocol. PMID- 26064738 TI - Jugular Vein Insufficiency and Choroidal Neovascularization in Moderate Myopia: A New Unknown Factor of Additional Risk? AB - To date, choroidal blood flow reduction in highly myopic eyes appears to be related to the development of choroidal neovascularization secondary to local reduction of arterial flow. Instead, no evidence of choroidal neovascularization was found in subjects with low or moderate myopia. The authors' aim has been to encourage new studies regarding the potential role of chronic retinal venous congestion in the pathogenesis of choroidal neovascularization. In December 2011, a 54-year-old woman with moderate bilateral myopia had a sudden block upon swallowing while she was eating. Subsequently (January 2013) metamorphopsia in the left eye revealed macular degeneration with choroidal neovascularization. The related echo-color Doppler study of the neck veins, performed in November 2014, showed an atypical left jugular insufficiency associated with homolateral hypertension of the superior ophthalmic veins. This singular case highlights the necessity to further investigate the potential role of chronic alterations of intra- and extracranial venous drainage in the disruption of choroidal flow in myopic patients. PMID- 26064739 TI - Polyarticular Septic Arthritis Caused by Haemophilus influenzae Serotype f in an 8-Month-Old Immunocompetent Infant: A Case Report and Review of the Literature. AB - Background. The standard use of vaccinations against pathogens has resulted in a decreased incidence of musculoskeletal infections caused by these previously common bacterial pathogens. Consequently, the incidence of infections caused by atypical bacteria is rising. This report presents a case of septic arthritis caused by non-type b H. influenzae in a pediatric patient. Methods. We report a case of an infant with polyarticular septic arthritis caused by H. influenzae serotype f. A literature review was conducted with the inclusion criteria of case reports and studies published between 2004 and 2013 addressing musculoskeletal H. influenzae infections. Results. An 8-month-old female presented with pain and swelling in her right ankle and left elbow. The patient was diagnosed with septic arthritis and underwent incision and drainage. Wound and blood cultures were positive for Haemophilus influenzae serotype f. In addition to treatment with IV antibiotics, the patient underwent immunocompetency studies, which were normal. Subsequent follow-up revealed eradication of the infection. Conclusions. Haemophilus influenzae non-type b may cause serious invasive infections such as sepsis or septic arthritis in children with or without predisposing factors such as immunodeficiency or asplenia. Optimal treatment includes surgical management, culture driven IV antibiotics, and an immunologic workup. PMID- 26064740 TI - Common Peroneal Nerve Palsy with Multiple-Ligament Knee Injury and Distal Avulsion of the Biceps Femoris Tendon. AB - A multiple-ligament knee injury that includes posterolateral corner (PLC) disruption often causes palsy of the common peroneal nerve (CPN), which occurs in 44% of cases with PLC injury and biceps femoris tendon rupture or avulsion of the fibular head. Approximately half of these cases do not show functional recovery. This case report aims to present a criteria-based approach to the operation and postoperative management of CPN palsy that resulted from a multiple-ligament knee injury in a 22-year-old man that occurred during judo. We performed a two-staged surgery. The first stage was to repair the injuries to the PLC and biceps femoris. The second stage involved anterior cruciate ligament reconstruction. The outcomes were excellent, with a stable knee, excellent range of motion, and improvement in the palsy. The patient was able to return to judo competition 27 weeks after the injury. To the best of our knowledge, this is the first case report describing a return to sports following CPN palsy with multiple-ligament knee injury. PMID- 26064741 TI - A Rare and Interesting Case of a Massive Secondary Spinal Chondrosarcoma and Review of the Literature. AB - Chondrosarcoma, the second most common primary malignancy of the bone, is malignant cartilage forming tumour that very rarely involves the axial skeleton. It may arise as a primary bone tumour or as a secondary lesion from a preexisting benign cartilaginous neoplasm such as osteochondroma or enchondroma. A rare case of a massive secondary lumbar spine chondrosarcoma is presented. Management consisted of an initial posterior spinal stabilization and fusion and then a curative radical en bloc tumour resection. A review of the literature is also presented. PMID- 26064742 TI - Total Hip Arthroplasty for Rapidly Destructive Coxarthrosis in a Patient with Severe Platelet Deficiency due to Liver Cirrhosis and Immune Thrombocytopenic Purpura. AB - Rapidly destructive coxarthrosis (RDC) causes rapid and extreme destruction of the hip joint, which was reported by Postel and Kerboull. RDC is commonly unilateral and occurs mostly in elderly women. Immune thrombocytopenic purpura (ITP) is characterized by a low platelet count that is the result of both immune mediated platelet destruction and suppression of platelet production. In patients with ITP undergoing surgery, bleeding associated with a low preoperative platelet count can lead to unsuccessful outcomes. To the best of our knowledge, there has been only one report describing total hip arthroplasty (THA) for patients with ITP and there have been no reports of THA for RDC with a very low platelet count due to liver cirrhosis (LC) and ITP. We report the case of a patient who had right RDC and a very low platelet count due to LC and ITP in whom THA was successfully performed. Furthermore, this case was also unique in that her platelet count increased after THA. THA for right RDC might resolve ITP by relieving inflammation of the right hip since her platelet count recovered after THA. PMID- 26064743 TI - Reconstructive Osteotomy for Ankle Malunion Improves Patient Satisfaction and Function. AB - Treatment of chronic symptoms caused by a malunion is a difficult problem in orthopedic surgery. We encountered a case of ankle malunion at our hospital about 1 year after the first operation. The patient had been unable to walk with weight bearing but regained the ability to walk after reconstructive osteotomy of the fibula. Functional scores for the foot and ankle were significantly improved after intervention. Reconstructive osteotomy appears to represent a good option for ankle malunion. PMID- 26064744 TI - Rare Head and Neck Benign Mesenchymoma in Close Proximity to Submandibular Gland in a Pediatric Patient: Case Report and Review of the Literature. AB - Pediatric head and neck masses are commonly congenital in origin or of infectious etiology. We present a rare case of benign mesenchymoma in close proximity to the submandibular gland in an otherwise asymptomatic child. Computerized tomography (CT) scan of the head and neck area revealed a benign lesion, which was later determined to be a benign mesenchymoma on histopathology. The child did well after surgery without any reported recurrence. We discuss the salient features of a benign mesenchymoma in a child and also discuss relevant imaging and management. PMID- 26064745 TI - Rosai-Dorfman Disease Originating from Nasal Septal Mucosa. AB - Rosai-Dorfman disease is a rarely seen disease with unknown etiology. Extranodal involvement is most commonly seen in the head and neck region. Histopathologically, it is characterized by histiocytic cell proliferation. This paper presents a case of a 15-year-old male patient who presented with nasal obstruction and was surgically treated for a mass filling in the left nasal meatus that was diagnosed to be Rosai-Dorfman disease by histopathological examination. PMID- 26064746 TI - Lingual Thyroid Excision with Transoral Robotic Surgery. AB - Ectopic thyroid gland may be detected at any place between foramen caecaum and normal thyroid localization due to inadequacy of the embryological migration of the thyroid gland. It has a prevalence varying between 1/10.000 and 1/100000 in the community. Usually follow-up without treatment is preferred except for obstructive symptoms, bleeding, and suspicion of malignity. Main symptoms are dysphagia, dysphonia, bleeding, dyspnea, and obstructive sleep apnea. In symptomatic cases, the first described method in surgical treatment is open approach since it is a region difficult to have access to. However, this approach has an increased risk of morbidity and postoperative complications. Transoral robotic surgery, which is a minimally invasive surgical procedure, has advantages such as larger three-dimensional point of view and ease of manipulation due to robotic instruments. In this report, a case at the age of 49 who presented to our clinic with obstructive symptoms increasing within the last year and was found to have lingual thyroid and underwent excision of ectopic thyroid tissue by da Vinci surgical system is presented. PMID- 26064747 TI - A Rare Complication of Radiofrequency Tonsil Ablation: Horner Syndrome. AB - Chronic tonsillitis is a common disease, and several different surgical techniques are used to treat this condition. In recent years, techniques such as radiofrequency ablation and coblation have been commonly used for tonsil surgery. In this report, we present the cases of two pediatric patients who developed ptosis, miosis, and enophthalmos (Horner syndrome) after radiofrequency ablation for tonsil reduction and discuss the technique of radiofrequency ablation of the tonsils. In the early postoperative period, miosis and ptosis were observed on the right side in one patient and on the left side in the other patient. Both patients were treated with 1 mg/kg/day methylprednisolone, which were tapered by halving the dose every 3 days. Miosis and ptosis improved after treatment in both patients. Along with the case presentation, we discuss the effectiveness and complications of radiofrequency ablation of the tonsils. These unusual complications of tonsil ablation may help ENT physicians who do not yet have a preferred surgical technique for tonsillectomy to make an informed decision. Limited data are available about the possible complications of radiofrequency ablation of the tonsils. The present report contributes to the literature on this topic. PMID- 26064748 TI - High Grade (Large Cell) Neuroendocrine Carcinoma of the Nasopharynx: Novel Case Report with Touch Preparation Cytology and Positive EBV Encoded Early RNA. AB - Fewer than five case reports of primary large cell neuroendocrine carcinoma of the nasopharynx are known to the authors. No previous reports have included examples of cytomorphology or have proven association with Epstein-Barr virus. We herein illustrate MRI findings, histopathologic features, immunohistochemical characterization, cytologic details, and in situ hybridization studies from a unique case of primary large cell neuroendocrine carcinoma of the nasopharynx in a 38-year-old Caucasian male patient. Recognition of rare tumor types of the nasopharynx allows for refinements in disease management and prognostication. PMID- 26064749 TI - An Unusual Location of Neuroendocrine Tumour: Primary Hepatic Origin. AB - Although neuroendocrine tumours (NETs) of primary hepatic origin are extremely rare, most of NETs present with liver metastasis. When a NET is found in the liver, it must be treated to exclude metastasis from extrahepatic primary sites. The patient was a 38-year-old female. Abdominal ultrasound showed an 8 cm tumour in liver during a routine examination. Liver biopsy was done. The tumour was first considered a metastatic hepatic tumour on histopathological examination. No clues to the origin of a primary tumour were found. Upper and lower endoscopy of the GI tract and chest CT were performed to search for a primary tumour and were negative for any tumour. One month later, more extensive areas of the tumour were seen on histopathological examination of second liver biopsy with the same morphologic characteristics as the first biopsy. Immunohistochemically, there was positive staining for synaptophysin, CD 56, and S-100 in the tumour cells. These findings suggested the diagnosis of NET. The diagnosis of primary liver NET was considered in a multidisciplinary meeting. Then, left hepatectomy was performed. The final pathologic diagnosis of the tumour in the resected liver specimen was Grade II NET. The patient was doing well at postoperative 28-month follow-up. PMID- 26064750 TI - Invasive Aspergillosis Associated with a Foreign Body. AB - Invasive aspergillosis is a serious complication in immunocompromised individuals. It is associated with a high mortality rate, which demands a combined approach involving radical surgery and antifungal therapy. Here, we describe a patient who presented with nonspecific fever, refractory to antimicrobial agents. Though it primarily involved the nasal cavity and sinuses, it perforated into the oral cavity causing palatal changes. Surprisingly, a foreign body was found in the involved tissues that might have acted as a nidus of infection. A sufficient dose (3 mg/kg/day) of liposomal amphotericin B was initiated soon after a thorough debridement procedure and the patient survived. PMID- 26064751 TI - Hyperinsulinemic Hypoglycaemia in a Turner Syndrome with Ring (X). AB - Hyperinsulinemic hypoglycaemia (HH) is a group of clinically, genetically, and morphologically heterogeneous disorders characterized by dysregulation of insulin secretion by pancreatic beta cells. HH can either be congenital genetic hyperinsulinism or associated with metabolic disorder and syndromic condition. Early identification and meticulous management of these patients is vital to prevent neurological insult. There are only three reported cases of HH associated with a mosaic, r(X) Turner syndrome. We report the four cases of an infant with a mosaic r(X) Turner genotype and HH responsive to diazoxide therapy. PMID- 26064752 TI - Acute Kidney Injury Complicated Epstein-Barr Virus Infection in Infancy. AB - Infectious mononucleosis is an acute lymphoproliferative disorder caused by the Epstein-Barr virus (EBV) and seen most commonly in children and young adults. Clinical presentation of the disease is characterized by fever, tonsillopharyngitis, lymphadenopathy, and hepatosplenomegaly, whereas serological findings of this benign disorder include positive heterophilic antibody formation (transient increase in heterophilic antibodies) and prominence of hematological lymphocytosis of more than 10% of atypical lymphocytes. An EBV infection is usually asymptomatic in childhood, but acute kidney injury can be a rare complication during its course. Most cases recover from the disease completely. Early recognition of EBV infection and estimation of its complication are important for its prognosis. In light of previous literature, we discuss the case evaluated as an EBV infection complicated by acute kidney injury in early childhood and results of tubulointerstitial nephritis shown on a renal biopsy that was later diagnosed as an EBV infection by serological examination. PMID- 26064753 TI - Treatment of a Prader-Willi Patient with Recurrent Catatonia. AB - Prader-Willi is a genetic disorder characterized by neonatal hypotonia, hyperphagia, short stature, hypogonadism, and mental delay. This disorder can result from multiple mechanisms, most commonly a deletion of paternal chromosome 15, leaving a single maternally derived chromosome 15. Individuals who have a maternal uniparental disomy of chromosome 15 have a higher risk for developing psychosis compared to other forms of Prader-Willi. The following report details the treatment course of a 24-year-old female with Prader-Willi and recurrent catatonia. The patient initially had a positive lorazepam challenge test but subsequently failed treatment with benzodiazepines. She then received eight electroconvulsive therapy (ECT) treatments after which she showed improvement from initial catatonic state. However, the resolution in her symptoms did not follow a linear course but would show periods of improvement followed by a return of catatonic features. This case provides an example of the complexity of treatment of a patient with a genetic disorder and recurrent catatonia. PMID- 26064754 TI - Autism Spectrum Disorder and Amplified Pain. AB - Among the core features of ASD, altered sensitivities in all modalities have been accorded increasing importance. Heightened sensitivity to pain and unusual expressions of and reaction to pain have not hitherto been widely recognised as a presenting feature of ASD in general paediatrics. Failure to recognise ASD as a common cause of pain can lead to late diagnosis, inappropriate treatment, distress, and further disability. Two cases are presented which illustrate the late presentation of Autism Spectrum Disorder (Asperger's Syndrome subtype) with chronic unusual pain. Conclusion. Pain in autism can be atypical in its experience and expression and for this reason may go unrecognised by physicians treating chronic pain disorders. PMID- 26064755 TI - Bilateral Sclerosing Stromal Ovarian Tumor in an Adolescent. AB - Sclerosing stromal tumor of the ovary is a rare, benign, sex cord stromal tumor occurring predominantly in younger women in the 2nd and 3rd decades of life. It typically presents unilaterally with only 2 previously reported cases of bilateral presentation. Common clinical presentations include pelvic or abdominal pain, a mass, or menstrual changes. Although occasionally presenting with hormonal manifestations, virilization as a result of androgen production by the tumor is rare. Here we present an extremely rare case of a sclerosing stromal ovarian tumor in a 14-year-old patient with bilateral presentation and with clinical and biochemical evidence of hyperandrogenemia. PMID- 26064756 TI - Delayed Intraperitoneal Catheter Erosion into the Small Bowel. AB - Intraperitoneal chemotherapy can be provided in cases of metastatic ovarian carcinoma. Although most complications arise during or immediately after insertion of the catheter, there are complications that can arise several months later or during therapy administration. One of these delayed complications is catheter erosion into adjacent bowel. PMID- 26064757 TI - An Unusual Presentation of a Posterior Mediastinal Schwannoma Associated with Traumatic Hemothorax. AB - Schwannomas of the thoracic cavity are typically an asymptomatic, benign neurogenic neoplasm of the posterior mediastinum. In this case, we present a traumatic hemothorax as the initial presentation for a previously undiscovered mediastinal mass. The patient presented with shortness of breath and right-sided chest pain after being struck in the chest with a soccer ball. An operative exploration was pursued due to persistent hemothorax with hemodynamic instability despite resuscitation and adequate thoracostomy tube placement. The intraoperative etiology of bleeding was discovered to be traumatic fracture of a large hypervascular posterior mediastinal schwannoma. Surgical resection is the treatment of choice for these tumors. Specific serological markers do not exist for this tumor, and radiographic findings can be variable, so tissue diagnosis is of importance in differentiating benign from malignant schwannomas, as well as other posterior mediastinal tumors. However, most patients have excellent survival following complete resection. PMID- 26064758 TI - An Unusual Neck Mass: A Case of a Parathyroid Cyst and Review of the Literature. AB - Parathyroid cysts (PC) are an unusual cause of neck swellings. The majority are nonfunctioning and prove to be a diagnostic challenge given their nonspecific physical and radiological characteristics. This is compounded by their rare occurrence, leading them to be overlooked in the differential diagnosis of neck lumps. Imaging techniques fail to determine the origin of these lesions, but a preoperative diagnosis can be achieved by fine-needle aspiration and measurement of cystic fluid C-terminal parathyroid hormone levels. Treatment of nonfunctioning cysts remains controversial and includes needle aspiration, injection of sclerosant, or surgical excision. We present a case of a 44-year-old female presenting with an asymptomatic anterior neck swelling, diagnosed postoperatively as a parathyroid cyst. PMID- 26064759 TI - Surgical Tips in Frozen Abdomen Management: Application of Coliseum Technique. AB - Wound dehiscence is a serious postoperative complication, with an incidence of 0.5-3% after primary closure of a laparotomy incision, and represents an acute mechanical failure of wound healing. Relatively recently the concept of "intentional open abdomen" was described and both clinical entities share common pathophysiological and clinical pathways ("postoperative open abdominal wall"). Although early reconstruction is the target, a significant proportion of patients will develop adhesions between abdominal viscera and the anterolateral abdominal wall, a condition widely recognized as "frozen abdomen," where delayed wound closure appears as the only realistic alternative. We report our experience with a patient who presented with frozen abdomen after wound dehiscence due to surgical site infection and application of the "Coliseum technique" for its definitive surgical management. This novel technique represents an innovative alternative to abdominal exploration, for cases of "malignant" frozen abdomen due to peritoneal carcinomatosis. Lifting the edges of the surgical wound upwards and suspending them under traction by threads from a retractor positioned above the abdomen facilitates approach to the peritoneal cavity, optimizes exposure of intra-abdominal organs, and prevents operative injury to the innervation and blood supply of abdominal wall musculature, a crucial step for subsequent hernia repair. PMID- 26064760 TI - Laparoscopy as a Diagnostic and Definitive Therapeutic Tool in Cases of Inflamed Simple Lymphatic Cysts of the Mesentery. AB - Mesenteric cysts are rare benign abdominal tumors. These cysts, especially those of lymphatic origin, very rarely become inflamed. The diagnosis of inflamed lymphatic cysts of the mesentery may be difficult. We herein report two cases of inflamed simple lymphatic cysts of the mesentery definitively diagnosed and excised by laparoscopy. PMID- 26064761 TI - Early Identification of Traumatic Durotomy Associated with Atlantooccipital Dislocation May Prevent Retropharyngeal Pseudomeningocele Development. AB - Atlantooccipital dislocation can be complicated by a traumatic durotomy that may lead to the rare development of a retropharyngeal pseudomeningocele. To our knowledge this has been reported only five times previously. We present the case of a 60-year-old man involved in a motor vehicle accident who suffered an atlantooccipital dislocation and C5-C6 three-column injury. A unique MRI image of a defect in the ventral dura posterior to C2 was appreciated. He underwent occiput to T2 internal fixation and arthrodesis. During surgery, CSF egress was seen caudal to the right C2 nerve root. A DuraMatrix onlay patch reinforced with DuraSeal was placed to stop the CSF leak. A lumbar subarachnoid drain was also placed. The patient made a satisfactory recovery with residual mild weakness of his right upper extremity. In this report, we demonstrate that careful MRI review can reveal a ventral durotomy in a traumatic atlantooccipital dislocation and, if discovered, effective treatment including a lumbar subarachnoid drain for CSF diversion may prevent progression to a retropharyngeal pseudomeningocele. The literature on this rare presentation and associated durotomy is provided. PMID- 26064762 TI - Fatal Necrotizing Fasciitis following Episiotomy. AB - Introduction. Necrotizing fasciitis is an uncommon condition in general practice but one that provokes serious morbidity. It is characterized by widespread fascial necrosis with relative sparing of skin and underlying muscle. Herein, we report a fatal case of necrotizing fasciitis in a young healthy woman after episiotomy. Case Report. A 17-year-old primigravida underwent a vaginal delivery with mediolateral episiotomy. Necrotizing fasciitis was diagnosed on the 5th postpartum day, when the patient was referred to our tertiary care medical center. Surgical debridement was initiated together with antibiotics and followed by hyperbaric oxygen therapy. The patient died due to septic shock after 16 hours from the referral. Conclusion. Delay of diagnosis and consequently the surgical debridement were most likely the reasons for maternal death. In puerperal period, a physician must consider necrotizing fasciitis as a possible diagnosis in any local sings of infection especially when accompanied by fever and/or tenderness. Early diagnosis is the key for low mortality and morbidity. PMID- 26064763 TI - Late Onset Remnant Gastric Cancer with Afferent Loop Syndrome 47 Years after Billroth II Surgery. AB - Remnant gastric cancer is a rare clinical entity. Herein we describe a patient with remnant gastric cancer that presented with afferent loop syndrome 47 years after Billroth II surgery. Symptoms of serious bilious vomiting were an indication to perform early endoscopic diagnosis, followed by complete gastric resection. In particular, patients that have undergone surgery due to benign indications should be examined endoscopically, even a long time after initial surgery. PMID- 26064764 TI - Left Diaphragmatic Herniation following Orthotopic Liver Transplantation in an Adult. AB - Diaphragmatic herniation is an uncommon complication in the postquirurgic follow of the liver transplant. The associated symptoms are unspecific and may not suggest the correct diagnosis. It may explain why in many patients the diagnosis remains unmade or it is made only after a long interval of time. We present the case of a fifty-seven-year-old male who required an orthotopic liver transplant in 2010 due to a trifocal hepatocarcinoma. In postoperatory follow-up the patient showed alimentary regurgitation, vomiting, and dyspepsia. The diagnosis was made by an oesophagogastroduodenal transit with barium and an abdominal CT scan that showed a left diaphragmatic herniation with the gastric fundus into the thorax. With these findings we decided to perform a programmed surgery. After takedown of adhesions and replacement of the stomach into the upper abdomen, the palm-sized diaphragmatic opening was closed with a synthetic material. The patient's condition remained stable throughout the entire operation. The postoperative course was uneventful and he was discharged at the fifth day after surgery with a normal digestive intake. In a 12-month follow-up the patient shows no symptoms. PMID- 26064765 TI - Complete Absence of Iliac Arteries in the Left Hemipelvis in a Case of Deceased Donor Renal Transplantation. AB - Renal transplantation is an established method of treating end-stage renal failure. Whilst the majority of procedures follow a standard technique, vascular anomalies may pose intraoperative challenges and, therefore, careful preoperative assessment is warranted. We present a unique, complex case compounded by complete absence of iliac arteries in the left hemipelvis in association with double inferior vena cava in a young recipient. PMID- 26064766 TI - Laparoscopic Nephrectomy with Adrenalectomy for Synchronous Adrenal Myelolipoma and Renal Cell Carcinoma. AB - Introduction. Adrenal myelolipomas are uncommon nonfunctioning tumors of the adrenal. Synchronous renal cell carcinomas with adrenal myelolipomas are very rare. We present the case report of adrenal myelolipoma with synchronous RCC managed laparoscopically. Case Report. A 60-year-old old gentleman presented with incidental right upper polar mass with right adrenal mass. Metastatic work-up was negative. Laparoscopic radical nephrectomy with adrenalectomy was done under general anesthesia. The biopsy report was right kidney clear cell adenocarcinoma (T1b) with right adrenal myelolipoma. Conclusion. This is the first case report of laparoscopic adrenalectomy with nephrectomy for ipsilateral synchronous renal cell carcinoma with adrenal myelolipoma. PMID- 26064767 TI - A Rare Complication of Extracorporeal Shock Wave Lithotripsy: Intrarenal Hematoma Mimicking Pelvis Renalis Tumor. AB - Extracorporeal shock wave lithotripsy (SWL) is a very commonly used treatment modality for appropriate sized stones. Even though it is a noninvasive treatment technique, major complications may occur following SWL sessions. Herein, we report a 17-year-old male patient, who received 2 sessions of SWL treatment for his left kidney stone, 4 months before his admission. Imaging methods showed an enhanced left renal pelvis mass with contrast-enhanced computerized tomography (CT) and this finding raised a suspicion of pelvis renalis tumor. Diagnostic ureterorenoscopy was planned for the patient and operation revealed a left intrarenal hematoma, which was drained percutaneously during the same operation. Careful history should be taken from patients with renal pelvis masses and intrarenal hematoma formation should be kept in mind, especially if the patient has a previous SWL history. PMID- 26064768 TI - Oxaliplatin Induced Digital Ischemia and Necrosis. AB - Introduction. Digital ischemia is a rare complication of several chemotherapeutic medications. We aimed to present a patient with digital ischemia, secondary to a new generation chemotherapeutic drug, oxaliplatin. Case Report. 62-year-old woman presented to our department with severe pain, paresthesia, and distal acrocyanosis on her right hand fingertips. Her complaints started five days after the third cycle of a chemotherapy protocol consisting of 5-fluorourasil (5-FU), folinic acid, and oxaliplatin due to advanced colon carcinoma. On physical examination, hemorrhagic and partly ulcerative lesions were detected at her right hand fingertips. Radial and ulnar pulses were absent at affected side. Digital subtraction angiography revealed severe vascular resistance in the affected extremity. Iloprost trometamol treatment was started with the dosage of 1 ng/kg/min. In addition, low-molecule-weight heparin was used for preventing possible microemboli. Symptomatic relief was provided after five days, and patient was discharged on 7th day of treatment. Discussion. The pathogenesis of oxaliplatin induced vascular toxicity remains unclear. Endothelial damage, increased adherence of platelets, deposition of immune complexes as an immunologic effect of oxaliplatin, and hypercoagulable state may be the reason for arterial thrombosis, digital microemboli, possible digital ischemia, and their several consequences. PMID- 26064769 TI - Surgical Treatment for Profunda Femoris Artery Aneurysms: Five Case Reports. AB - Profunda femoris artery aneurysm (PFAA) is an extremely rare entity, with most cases being asymptomatic, which makes obtaining an early diagnosis difficult. We herein report a case series of PFAA, in which more than half of the PFAAs, which presented with no clinical symptoms, were discovered incidentally. All PFAAs were treated surgically with aneurysmectomy with or without vascular reconstruction. In cases involving a patent superficial femoral artery (SFA), graft replacement of the profunda femoris artery (PFA) is not mandatory; however, preserving the blood flow of the PFA is necessary to maintain lower extremity perfusion in patients with occlusion of the SFA. Therefore, the treatment of PFAAs should include appropriate management of both the aneurysmectomy and graft replacement, if possible. PMID- 26064770 TI - Chimney-Graft as a Bail-Out Procedure for Endovascular Treatment of an Inflammatory Juxtarenal Abdominal Aortic Aneurysm. AB - Inflammatory and juxtarenal Abdominal Aortic Aneurysm (j-iAAA) represents a technical challenge for open repair (OR) due to the peculiar anatomy, extensive perianeurysmal fibrosis, and dense adhesion to the surrounding tissues. A 68-year old man with an 11 cm asymptomatic j-iAAA was successfully treated with elective EVAR and chimney-graft (ch-EVAR) without postprocedural complications. Target vessel patency and normal renal function are present at 24-month follow-up. The treatment of j-iAAA can be technically challenging. ch-EVAR is a feasible and safe bail-out method for elective j-iAAA with challenging anatomy. PMID- 26064771 TI - Thoracic Aortic Injury: Embolization of the Tenth Intercostal Artery and Endovascular Treatment in a Young Woman after Posterior Spinal Instrumentation. AB - Iatrogenic aortic injuries are rare and well-recognized complications of a variety of procedures, including spinal surgery. The placement of pedicle screws is sometimes associated with devastating consequences. Aortic perforation with rapid hematoma formation and delayed aortic trauma leading to pseudoaneurysm formation have been described in the literature. A case describing a significant time interval between iatrogenic aortic injury and diagnosis in the absence of pseudoaneurysm formation is described in this paper and, according to our knowledge, is unique in the literature. The aortic injury was successfully treated, selecting the appropriate graft and, as a consequence, normal spinal cord blood flow was achieved. PMID- 26064772 TI - National Helpline for Problem Gambling: A Profile of Its Users' Characteristics. AB - Gambling has seen a significant increase in Italy in the last 10 years and has rapidly become a public health issue, and for these reasons the first National Helpline for Problem Gambling (GR-Helpline) has been established. The aims of this study are to describe the GR-Helpline users' characteristics and to compare the prevalence rates of the users with those of moderate-risk/problematic gamblers obtained from the national survey (IPSAD 2010-2011). Statistical analysis was performed on data obtained from the counselling sessions (phone/e mail/chat) carried out on 5,805 users (57.5% gamblers; 42.5% families/friends). This confirms that the problems related to gambling concern not only the gamblers but also their families and friends. Significant differences were found between gamblers and families/friends involving gender (74% of gamblers were male; 76.9% of families/friends were female), as well as age-classes and geographical area. Female gamblers had a higher mean age (47.3 versus 40.2 years) and preferred nonstrategy-based games. Prevalence rates of GR-Helpline users and of moderate risk/problematic gamblers were correlated (Rho = 0.58; p = 0.0113). The results highlight the fact that remote access to counselling can be an effective means of promoting treatment for problem gamblers who do not otherwise appeal directly for services. PMID- 26064773 TI - Role of MicroRNAs in Renin-Angiotensin-Aldosterone System-Mediated Cardiovascular Inflammation and Remodeling. AB - MicroRNAs are endogenous regulators of gene expression either by inhibiting translation or protein degradation. Recent studies indicate that microRNAs play a role in cardiovascular disease and renin-angiotensin-aldosterone system- (RAAS-) mediated cardiovascular inflammation, either as mediators or being targeted by RAAS pharmacological inhibitors. The exact role(s) of microRNAs in RAAS-mediated cardiovascular inflammation and remodeling is/are still in early stage of investigation. However, few microRNAs have been shown to play a role in RAAS signaling, particularly miR-155, miR-146a/b, miR-132/122, and miR-483-3p. Identification of specific microRNAs and their targets and elucidating microRNA regulated mechanisms associated RAS-mediated cardiovascular inflammation and remodeling might lead to the development of novel pharmacological strategies to target RAAS-mediated vascular pathologies. This paper reviews microRNAs role in inflammatory factors mediating cardiovascular inflammation and RAAS genes and the effect of RAAS pharmacological inhibition on microRNAs and the resolution of RAAS mediated cardiovascular inflammation and remodeling. Also, this paper discusses the advances on microRNAs-based therapeutic approaches that may be important in targeting RAAS signaling. PMID- 26064774 TI - Influence of Body Mass Index on Inflammatory Profile at Admission in Critically Ill Septic Patients. AB - Introduction. Inflammation is ubiquitous during sepsis and may be influenced by body mass index (BMI). We sought to evaluate if BMI was associated with serum levels of several cytokines measured at intensive care unit admission due to sepsis. Methods. 33 septic patients were included. An array of thirty-two cytokines and chemokines was measured using Milliplex technology. We assessed the association between cytokine levels and BMI by generalized additive model that also included illness severity (measured by SAPS 3 score); one model was built for each cytokine measured. Results. We found that levels of epidermal growth factor, vascular endothelial growth factor, and interleukins 4, 5, and 13 were associated with BMI in a complex, nonlinear way, independently of illness severity. Higher BMI was associated with higher levels of anti-inflammatory interleukins. Conclusion. BMI may influence host response to infection during critical illness. Larger studies should confirm these findings. PMID- 26064775 TI - Visual Hallucinations as Incidental Negative Effects of Virtual Reality on Parkinson's Disease Patients: A Link with Neurodegeneration? AB - We followed up a series of 23 Parkinson's disease (PD) patients who had performed an immersive virtual reality (VR) protocol eight years before. On that occasion, six patients incidentally described visual hallucinations (VH) with occurrences of images not included in the virtual environment. Curiously, in the following years, only these patients reported the appearance of VH later in their clinical history, while the rest of the group did not. Even considering the limited sample size, we may argue that VR immersive systems can induce unpleasant effects in PD patients who are predisposed to a cognitive impairment. PMID- 26064776 TI - Clinical and Breed Characteristics of Idiopathic Head Tremor Syndrome in 291 Dogs: A Retrospective Study. AB - Objective. To establish signalment and phenomenology of canine idiopathic head tremor syndrome (IHTS), an episodic head movement disorder of undetermined pathogenesis. Design. Retrospective case series. Animals. 291 dogs with IHTS diagnosed between 1999 and 2013. Procedures. Clinical information was obtained from an online community of veterinary information aggregation and exchange (Veterinary Information Network, 777 W Covell Boulevard, Davis, CA 95616) and conducted with their approval. Information on breed, sex, age of onset, tremor description, mentation during the event, effect of distractions and drugs, diagnostics, presence of other problems, and outcome was analyzed. Results. IHTS was found in 24 pure breeds. Bulldogs, Labrador Retrievers, Boxers, and Doberman Pinschers comprised 69%; mixed breeds comprised 17%. Average onset age was 29 months (range: 3 months to 12 years). First episode occurred before 48 months of age in 88%. Vertical (35%), horizontal (50%), and rotational (15%) movements were documented. Possible trigger events were found in 21%. Mentation was normal in 93%. Distractions abated the tremor in 87%. Most dogs did not respond to antiepileptic drugs. Conclusions and Clinical Relevance. This retrospective study documents IHTS in many breeds including Labrador Retrievers, Boxers, and mixed breeds. PMID- 26064777 TI - Identification and Quality Assessment of Chrysanthemum Buds by CE Fingerprinting. AB - A simple and efficient fingerprinting method for chrysanthemum buds was developed with the aim of establishing a quality control protocol based on biochemical makeup. Chrysanthemum bud samples were successively extracted by water and alcohol. The fingerprints of the chrysanthemum buds samples were obtained using capillary electrophoresis and electrochemical detection (CE-ED) employing copper and carbon working electrodes to capture all of the chemical information. 10 batches of chrysanthemum buds were collected from different regions and various factories to establish the baseline fingerprint. The experimental data of 10 batches electropherogram buds by CE were analyzed by correlation coefficient and the included angle cosine methods. A standard chrysanthemum bud fingerprint including 24 common peaks was established, 12 from each electrode, which was successfully applied to identify and distinguish between chrysanthemum buds from 2 other chrysanthemum species. These results demonstrate that fingerprint analysis can be used as an important criterion for chrysanthemum buds quality control. PMID- 26064778 TI - Dietary Intakes of Children From Food Insecure Households. PMID- 26064779 TI - Effect Of Gender And Lifestyle Behaviors On BMI Trends In A Sample Of The First State's Undergraduate Population. AB - The 2010 Centers for Disease Control and Prevention (CDC) report indicates that 63.4% of Delaware's adult population is overweight and 28% is obese. Here, the authors reveal analyses acquired from detailed investigations about the importance of gender, and other lifestyle factors and behaviors on the Body Mass Index (BMI) trends amongst an indiscriminate sample of the Wesley College (Wesley) undergraduate population. A 25-question paper-format survey was distributed to 307 randomly chosen Wesley undergraduates. The accrued qualitative (or categorical) data were transferred to an Excel spreadsheet to construct and observe frequency distributions. A Chi-square test of independence (chi2) was performed between BMI status (normal, overweight, obese) and the following factors: gender, diet plan, adherence to the United States Department of Agriculture (USDA) MyPlate nutrition guide, use of the seasonal flu shot, weekly workout schedule, supplement usage, participation on athletic teams, questioning of label nutritional facts, and the use of added salt in food. A 2-sample proportion test was performed between students who were overweight or obese for the same factors. Also performed were t-tests for mean BMI for those who followed USDA MyPlate guidelines and for those who did not. An analysis of 278 completed surveys show that 29.5% of the Wesley respondents are overweight and 19.8% are obese. The mean BMI for males was statistically higher than the mean BMI for females. The mean BMI for students living on-campus was statistically higher than the mean BMI for students living off-campus. The results also demonstrate that adhering to the USDA dietary recommendations for fruit and dairy can be important factors in reducing the risk of obesity. PMID- 26064780 TI - Foreign Medical Teams in the Philippines after Typhoon Haiyan 2013 - Who Were They, When Did They Arrive and What Did They Do? AB - BACKGROUND: Foreign medical teams (FMT) are international medical teams sent to provide assistance in the aftermath of a disaster. In the last decade, there has been an increase in FMTs deployed following disasters. Despite the potential benefit FMTs might have in substituting the collapsed health care and caring for excess morbidity after large-scale disasters, several studies have demonstrated the difficulties in determining the quality of the response, mainly due to lack of reliable data. In order to bridge the knowledge gap on functioning of FMTs, the aim of this study is to assess the timing, capacities and activities of FMTs deployed to the Philippines after typhoon Haiyan. METHODS: This is a retrospective, descriptive study. Data on characteristics of FMTs present in the Philippines after typhoon Haiyan was provided by the World Health Organization (WHO) and compiled into a single database. Additional data was collected through a web survey, email correspondence and internet searches. RESULTS: A total of 108 FMTs were identified as arriving to the Philippines within the first month following typhoon Haiyan. None of these were operational in the affected areas within the first 72 h and the average time between arriving and being on-site operational was three days. Of the 108 FMTs, 70% were FMT type 1, 11% were FMT type 2 and 3% were FMT type 3. 16% of FMTs had unknown status. The total number of staff within all these FMTs were 2121, of which 210 were medical doctors, 250 nurses and 6 midwifes. Compared to previous sudden onset disasters, this study found no improvement in data sharing. PMID- 26064781 TI - Landscape of WASH-relevant Training for Humanitarian Emergencies. AB - BACKGROUND: Both employed humanitarian personnel as well as those seeking to start a career as an aid worker are often provided with or seek training on the theme of humanitarian water, sanitation, and hygiene (WASH). The objective of this study was to conduct a landscaping exercise of the available WASH-relevant training for humanitarian emergencies. METHODS: An open internet search was performed with specific terms related to humanitarian WASH. Retained search results included those training opportunities (including past ones) that were themed around or with a mentioned relevance to humanitarian WASH. RESULTS AND DISCUSSION: A total of 42 training courses relevant to humanitarian emergency WASH were retained. In addition to the more generic/introductory trainings, some provided thematic variations such as coordination of WASH responses, project management, risk reduction, information, education and communication (IEC), and complex emergencies. Timely topics such as urban WASH, Ebola, and WASH innovations were also observed indicating the responsiveness of the training providers to the changing needs of humanitarian WASH response programmes. This survey also revealed a large variety in terms of target audience, duration, fees, location, and language of courses. There was no centralised listing of courses available on the Internet. Limitations of this exercise were also discussed. PMID- 26064782 TI - Progressive Impairment of Lactate-based Gluconeogenesis in the Huntington's Disease Mouse Model R6/2. AB - Huntington's disease (HD) is a neurodegenerative illness, where selective neuronal loss in the brain caused by expression of mutant huntingtin protein leads to motor dysfunction and cognitive decline in addition to peripheral metabolic changes. In this study we confirm our previous observation of impairment of lactate-based hepatic gluconeogenesis in the transgenic HD mouse model R6/2 and determine that the defect manifests very early and progresses in severity with disease development, indicating a potential to explore this defect in a biomarker context. Moreover, R6/2 animals displayed lower blood glucose levels during prolonged fasting compared to wild type animals. PMID- 26064783 TI - Epidemiological and Surveillance Response to Ebola Virus Disease Outbreak in Lofa County, Liberia (March-September, 2014); Lessons Learned. AB - Ebola Virus Disease (EVD) outbreak was confirmed in Liberia on March 31st 2014. A response comprising of diverse expertise was mobilized and deployed to the country to contain transmission of Ebola and give relief to a people already impoverished from protracted civil war. This paper describes the epidemiological and surveillance response to the EVD outbreak in Lofa County in Liberia from March to September 2014. Five of the 6 districts of Lofa were affected. The most affected districts were Voinjama/Guardu Gbondi and Foya. By 26th September, 2014, a total of 619 cases, including 19.4% probable cases, 20.3% suspected cases and 44.2% confirmed cases were recorded by the Ebola Emergency Response Team (EERT) of Lofa County. Adults (20-50 years) were the most affected. Overall fatality rate was 53.3%. Twenty two (22) cases were reported among the Health Care Workers with a fatality rate of 81.8%. Seventy eight percent (78%) of the contacts successfully completed 21 days follow-up while 134 (6.15%) that developed signs and symptoms of EVD were referred to the ETU in Foya. The contributions of the weak health systems as well as socio-cultural factors in fueling the epidemic are highlighted. Importantly, the lessons learnt including the positive impact of multi-sectorial and multidisciplinary and coordinated response led by the government and community. Again, given that the spread of infectious disease can be considered a security threat every effort has to put in place to strengthen the health systems in developing countries including the International Health Regulation (IHR)'s core capacities. Key words: Ebola virus disease, outbreak, epidemiology and surveillance, socio-cultural factors, health system, West Africa. PMID- 26064784 TI - The Duration of an Exposure Response Gradient between Incident Obstructive Airways Disease and Work at the World Trade Center Site: 2001-2011. AB - BACKGROUND: Adverse respiratory effects of World Trade Center (WTC) exposure have been widely documented, but the length of time that exposure remains associated with disease is uncertain. We estimate the incidence of new cases of physician diagnosed obstructive airway disease (OAD) as a function of time since 9/11/2001 in WTC-exposed firefighters. METHODS: Exposure was categorized by first WTC arrival time: high (9/11/2001 AM); moderate (9/11/2001 PM or 9/12/2001); or low (9/13-24/2001). We modeled relative rates (RR) and 95% confidence intervals (CI) of OAD incidence by exposure over the first 10 years post-9/11/2001, estimating the time(s) of change in the RR with change point models. We further examined the relationship between self-reported lower respiratory symptoms and physician diagnoses. RESULTS: Change points were observed at 15 and 84 months post 9/11/2001, with relative incidence rates for the high versus low exposure group of 4.02 (95% CI 2.62-6.16) prior to 15 months, 1.90 (95% CI 1.49-2.44) from months 16 to 84, and 1.20 (95% CI 0.92-1.56) thereafter. Incidence in all exposure groups increased after the WTC health program began to offer free coverage of OAD medications in month 63. Self-reported lower respiratory symptoms in the first 15 months had 80.6% sensitivity, but only 35.9% specificity, for eventual OAD diagnoses. CONCLUSIONS: New OAD diagnoses are associated with WTC exposure for at least seven years. Some portion of the extended duration of that association may be due to delayed diagnoses. Nevertheless, our results support recognizing OAD among rescue workers as WTC-related even when diagnosed years after exposure. PMID- 26064785 TI - Modeling the 2014 Ebola Virus Epidemic - Agent-Based Simulations, Temporal Analysis and Future Predictions for Liberia and Sierra Leone. AB - We developed an agent-based model to investigate the epidemic dynamics of Ebola virus disease (EVD) in Liberia and Sierra Leone from May 27 to December 21, 2014. The dynamics of the agent-based simulator evolve on small-world transmission networks of sizes equal to the population of each country, with adjustable densities to account for the effects of public health intervention policies and individual behavioral responses to the evolving epidemic. Based on time series of the official case counts from the World Health Organization (WHO), we provide estimates for key epidemiological variables by employing the so-called Equation Free approach. The underlying transmission networks were characterized by rather random structures in the two countries with densities decreasing by ~19% from the early (May 27-early August) to the last period (mid October-December 21). Our estimates for the values of key epidemiological variables, such as the mean time to death, recovery and the case fatality rate, are very close to the ones reported by the WHO Ebola response team during the early period of the epidemic (until September 14) that were calculated based on clinical data. Specifically, regarding the effective reproductive number Re, our analysis suggests that until mid October, Re was above 2.3 in both countries; from mid October to December 21, Re dropped well below unity in Liberia, indicating a saturation of the epidemic, while in Sierra Leone it was around 1.9, indicating an ongoing epidemic. Accordingly, a ten-week projection from December 21 estimated that the epidemic will fade out in Liberia in early March; in contrast, our results flashed a note of caution for Sierra Leone since the cumulative number of cases could reach as high as 18,000, and the number of deaths might exceed 5,000, by early March 2015. However, by processing the reported data of the very last period (December 21, 2014-January 18, 2015), we obtained more optimistic estimates indicative of a remission of the epidemic in Sierra Leone, as reflected by the derived Re (~0.82, 95% CI: 0.81-0.83). PMID- 26064786 TI - Concatenation Analyses in the Presence of Incomplete Lineage Sorting. AB - Incomplete lineage sorting (ILS), modelled by the multi-species coalescent, is a process that results in a gene tree being different from the species tree. Because ILS is expected to occur for at least some loci within genome-scale analyses, the evaluation of species tree estimation methods in the presence of ILS is of great interest. Performance on simulated and biological data have suggested that concatenation analyses can result in the wrong tree with high support under some conditions, and a recent theoretical result by Roch and Steel proved that concatenation using unpartitioned maximum likelihood analysis can be statistically inconsistent in the presence of ILS. In this study, we survey the major species tree estimation methods, including the newly proposed "statistical binning" methods, and discuss their theoretical properties. We also note that there are two interpretations of the term "statistical consistency", and discuss the theoretical results proven under both interpretations. PMID- 26064787 TI - Beyond Blackboards: Engaging Underserved Middle School Students in Engineering. AB - Beyond Blackboards is an inquiry-centered, after-school program designed to enhance middle school students' engagement with engineering through design-based experiences focused on the 21st Century Engineering Challenges. Set within a predominantly low-income, majority-minority community, our study aims to investigate the impact of Beyond Blackboards on students' interest in and understanding of engineering, as well as their ability to align their educational and career plans. We compare participants' and nonparticipants' questionnaire responses before the implementation and at the end of the program's first academic year. Statistically significant findings indicate a school-wide increase in students' interest in engineering careers, supporting a shift in school culture. However, only program participants showed increased enjoyment of design based strategies, understanding of what engineers do, and awareness of the steps for preparing for an engineering career. These quantitative findings are supported by qualitative evidence from participant focus groups highlighting the importance of mentors in shaping students' awareness of opportunities within engineering. PMID- 26064788 TI - A Qualitative Analysis of the Use of Financial Services and Saving Behavior Among Older African Americans and Latinos in the Los Angeles Area. AB - For this study, we conducted seven focus groups in the Los Angeles area with a total of 70 participants (42 Latinos and 28 African Americans) recruited from three senior centers and a church. There was a wide variety of responses in relation to the usage of financial services among participants. We found that although some participants seem to participate more in the formal financial sector and show a higher level of sophistication when managing their finances, other participants' use of formal financial institutions is minimal. Among African American participants, we found several instances in which individuals feel very comfortable using banks. Lower levels of participation in the formal financial sector were found among the lower income Latino participants. In relation to barriers to participate in the financial sector, supply was not an issue, but demand and behavioral factors seem more important. Overall, no participants saved very much on a regular basis. We also find that participants in general do not want to ask their children for money, and also do not want to save and accumulate wealth to leave to their children. PMID- 26064789 TI - The COP9 signalosome and cullin-RING ligases in the heart. AB - Alteration of ubiquitin-proteasome system (UPS) mediated protein degradation has been implicated in the progression from a large subset of heart disease to congestive heart failure, rendering it extremely important to elucidate the cellular and molecular mechanism by which the UPS is regulated. Cullin-RING ligases (CRLs) represent the largest family of ubiquitin ligases crucial for UPS dependent proteolysis. Serving as a cullin deneddylase, the COP9 signalosome (CSN) regulates the activity and assembly of CRLs. In the past several years, emerging studies have begun to unveil the role of the CSN and some of the CRLs in cardiomyocytes or the heart under physiological and pathological conditions. This review article will highlight and analyze these recent progresses and provide the author's perspective on the future directions for this research field. PMID- 26064792 TI - Hypoascorbemia induces atherosclerosis and vascular deposition of lipoprotein(a) in transgenic mice. AB - Lipoprotein(a), a variant of LDL carrying the adhesive glycoprotein apo(a), is a leading risk factor for cardiovascular disease. Lipoprotein(a) (Lp(a)) is found in humans and subhuman primates but rarely in lower mammals. Better understanding of the evolutionary advantage of this molecule should elucidate its physiological role. We developed a new mouse model with two characteristics of human metabolism: the expression of Lp(a) and the lack of endogenous ascorbate (vitamin C) production. We show that dietary deficiency of ascorbate increases serum levels of Lp(a). Moreover, chronic hypoascorbemia and complete depletion of ascorbate (scurvy) leads to Lp(a) accumulation in the vascular wall and parallels atherosclerotic lesion development. The results suggest that dietary ascorbate deficiency is a risk factor for atherosclerosis independent of dietary lipids. We provide support for the concept that Lp(a) functions as a mobile repair molecule compensating for the structural impairment of the vascular wall, a morphological hallmark of hypoascorbemia and scurvy. PMID- 26064790 TI - Regulation of mitochondrial ATP synthase in cardiac pathophysiology. AB - Mitochondrial function is paramount to energy homeostasis, metabolism, signaling, and apoptosis in cells. Mitochondrial complex V (ATP synthase), a molecular motor, is the ultimate ATP generator and a key determinant of mitochondrial function. ATP synthase catalyzes the final coupling step of oxidative phosphorylation to supply energy in the form of ATP. Alterations at this step will crucially impact mitochondrial respiration and hence cardiac performance. It is well established that cardiac contractility is strongly dependent on the mitochondria, and that myocardial ATP depletion is a key feature of heart failure. ATP synthase dysfunction can cause and exacerbate human diseases, such as cardiomyopathy and heart failure. While ATP synthase has been extensively studied, essential questions related to how the regulation of ATP synthase determines energy metabolism in the heart linger and therapies targeting this important mechanism remain scarce. This review will visit the main findings, identify unsolved issues and provide insights into potential future perspectives related to the regulation of ATP synthase and cardiac pathophysiology. PMID- 26064793 TI - A 6 hour therapeutic window, optimal for interventions targeting AMPK synergism and apoptosis antagonism, for cardioprotection against myocardial ischemic injury: an experimental study on rats. AB - The time relation between autophagy and myocardium ischemia (MI) has never been documented. Therefore, the present study was conducted to find out the exact timings and specific roles that AMP-activated protein kinase (AMPK)-mTOR signaling pathway plays on autophagy and apoptosis in rats' ischemic heart. 36 male Sprague Dawley (SD) rats were divided randomly into control and MI groups (each = 6). MI models were created by ligating left anterior descending artery (LAD) of rat hearts and the right myocardium were harvested at 0.5 h, 1 h, 3 h, 6 h, 12 h after ischimia. Expressions of Phosphorylated-AMPK (p-AMPK) and Phosphorylated-mTOR (p-mTOR) were determined by immunohistochemistry (IHC), western blotting (WB) and quantitative real-time PCR (Q-PCR) methods. LC3 expression was determined by WB and Q-PCR. The level of cell apoptosis was measured by the terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) method. p-AMPK was activated significantly in ischemic myocardium and its expression at MI groups showed a time dependent pattern with a fluctuating pattern compared to the control group. p-AMPK levels were seen to rise at 0.5 h followed by a fall at 1 h after MI, which again gradually peaked at 6 h and finally decreased at 12 h. While, p-mTOR levels suggested a constant declining trend with time. Autophagy related protein LC3 had a sustained up regulation with time. TUNEL method suggested that apoptosis increased at 0.5 h, then decreased at 1 h and 3 h after MI and finally showed a continuous rising trend. Activation of protective autophagy that occured during the initial phases of ischemic insults was within 6 hours. When the ischemia was prolonged, after 6 hours, although autophagy increased, cardiomyocyte death followed via the activation of apoptosis. Thus, limiting autophagy within 6 hours would give us double benefits. It would prevent the death related autophagy and prevent apoptotic cellular death. This 6 hours time period could serve as a landmark for therapeutic application for achieving cardioprotection from ischemic insults. PMID- 26064794 TI - Evaluation of cerebral-cardiac syndrome using echocardiography in a canine model of acute traumatic brain injury. AB - Previous studies have confirmed that traumatic brain injury (TBI) can induce general adaptation syndrome (GAS), which subsequently results in myocardial dysfunction and damage in some patients with acute TBI; this condition is also termed as cerebral-cardiac syndrome. However, most clinicians ignore the detection and treatment of myocardial dysfunction, and instead concentrate only on the serious neural damage that is observed in acute TBI, which is one of the most important fatal factors. Therefore, clarification is urgently needed regarding the relationship between TBI and myocardial dysfunction. In the present study, we evaluated 18 canine models of acute TBI, by using real-time myocardial contrast echocardiography and strain rate imaging to accurately evaluate myocardial function and regional microcirculation, including the strain rate of the different myocardial segments, time-amplitude curves, mean ascending slope of the curve, and local myocardial blood flow. Our results suggest that acute TBI often results in cerebral-cardiac syndrome, which rapidly progresses to the serious stage within 3 days. This study is the first to provide comprehensive ultrasonic characteristics of cerebral-cardiac syndrome in an animal model of TBI. PMID- 26064791 TI - The COP9 signalosome and vascular function: intriguing possibilities? AB - Disorders of vascular function contribute importantly to cardiovascular disease which represents a substantial cause of morbidity and mortality worldwide. An emerging paradigm in the study of cardiovascular diseases is that protein ubiquitination and turnover represent key pathological mechanisms. Our understanding of these processes in the vasculature is growing but remains incomplete. Since protein ubiquitination and turnover can represent a terminal event in the life of a given protein, entry into these pathways must be highly regulated. However, at present understanding of these regulatory mechanisms, particularly in the vasculature, is fragmentary. The COP9 (constitutive photomorphogenic mutant 9) signalosome (CSN) is a heteromeric protein complex implicated in the control of protein degradation. The CSN participates critically in the control of Cullin Ring Ligases (CRLs), at least in part via the detachment of a small protein, Nedd8 (deneddylation). CRLs are one of the largest groups of ubiquitin ligases, which represent the most selective control point for protein ubiquitination. Thus, the CSN by virtue of its ability to control the CRLs ubiquitin ligase activity is ideally positioned to effect selective modulation of protein turnover. This review surveys currently available data regarding the potential role of the CSN in control of vascular function. Data potentially linking the CSN to control of regulatory proteins involved in vascular smooth muscle proliferation and to vascular smooth muscle contraction are presented with the intent of providing potentially intriguing possibilities for future investigation. PMID- 26064795 TI - Lower ankle-brachial index is associated with poor sleep quality in patients with essential hypertension. AB - BACKGROUND: The ankle-brachial index (ABI), ratio of leg blood pressure to arm blood pressure is used extensively as a screening test for stratification of cardiovascular risk. The problems in sleep disturbed nocturnal fall in blood pressure and may relate to development of hypertension. However, the role of sleep quality on ankle-brachial index remains unclear. METHODS AND RESULTS: This study examined 101 patients with essential hypertension. We analyzed the association with ABI on age, sex, body height, body weight, body mass index, waist circumference, blood pressure, HDL-cholesterol, LDL-cholesterol, HbA1c, sleep quality evaluated by Pittsburgh Sleep Quality Index (PSQI), smoking habits, alcohol habits. The ABI is associated with the following seven parameters; body height (r = 0.36, p < 0.001), body weight (r = 0.30, p < 0.005), systolic BP (r = -0.23, p < 0.05), HbA1c (r = -0.24, p < 0.05), PSQI score (rho = -0.31, p < 0.005), alcohol intake (rho = 0.23, p < 0.05) and sex (F = 6.65, p < 0.05). By a multiple linear regression analysis with ABI as the dependent variable after forcing the seven parameters above into the model, body height, HbA1c and PSQI score were significantly associated with ABI (R (2) for the model = 25%, p < 0.001). CONCLUSION: Poor sleep quality was independently associated with lower ABI in patients with essential hypertension. The results may provide new insight related to the interaction between sleep quality and blood pressure. PMID- 26064796 TI - Dysfunction of the ubiquitin-proteasome system in atherosclerotic cardiovascular disease. AB - The ubiquitin-proteasome system (UPS) is an integral part of the protein metabolism and protein quality control in eukaryotic cells. It is involved in a number of biological processes of significance for vascular biology and pathology such as oxidative stress, inflammation, foam cell formation, and apoptosis. This review summarizes both indirect and direct lines of evidence for a role of the UPS in atherosclerosis from the initiation to the progression and complication stage and concludes with a future perspective. PMID- 26064797 TI - Diabetes mellitus and burns. Part I-basic science and implications for management. AB - The number of diabetic patients presenting to burn services is predicted to increase significantly over the next decades. Diabetes mellitus represents an independent risk factor for sustaining burn injuries and mediates alterations to key physiological systems including the vascular, renal, nervous, gastrointestinal and immune system. The effects of the pathophysiological permutations need to be carefully considered during both the acute as well as the long-term rehabilitation phase of injury. The purpose of the first part of this review is to outline the metabolic permutations observed in diabetes mellitus pertinent to the clinical presentation and management of burn patients. PMID- 26064798 TI - Diabetes mellitus and burns. Part II-outcomes from burn injuries and future directions. AB - Diabetes mellitus is an increasingly prevalent comorbidity in patients presenting to burn facilities. Diabetic patients tend to be older and present in a delayed manner with deeper injuries predominantly affecting the lower limb. Morbidity from burns is higher in this cohort including a longer length of hospital stay, greater need for surgical interventions and increased rate of infective complications. Nevertheless, there seems to be little effect of diabetes on associated mortality. The second part of this review article concentrates on the epidemiological profile of diabetic burn patients and the effect of the disease on morbidity and mortality. In addition, we present a review of therapeutic adjuncts, which may hold promise for the future management of this cohort of burn patients. PMID- 26064799 TI - Impact of chemically-modified tetracycline 3 on intertwined physiological, biochemical, and inflammatory networks in porcine sepsis/ARDS. AB - Sepsis can lead to multiple organ dysfunction, including the Acute Respiratory Distress Syndrome (ARDS), due to intertwined, dynamic changes in inflammation and organ physiology. We have demonstrated the efficacy of Chemically-Modified Tetracycline 3 (CMT-3) at reducing inflammation and ameliorating pathophysiology in the setting of a clinically realistic porcine model of ARDS. Here, we sought to gain insights into the derangements that characterize sepsis/ARDS and the possible impact of CMT-3 thereon, by combined experimental and computational studies. Two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via placement of a peritoneal fecal clot and intestinal ischemia/reperfusion by clamping the superior mesenteric artery for 30 min. The treatment group (n = 3) received CMT-3 at 1 hour after injury (T1), while the control group (n = 3) received a placebo. Multiple inflammatory mediators, along with clinically relevant physiologic and blood chemistry variables, were measured serially until death of the animal or T48. Principal Component Analysis (PCA) and Dynamic Bayesian Network (DBN) inference were used to relate these variables. PCA revealed a separation of cardiac and pulmonary physiologic variables by principal component, and a decreased rank of oxygen index and arterial PO2/FiO2 ratio in the treatment group compared to control. DBN suggested a conserved network structure in both control and CMT-3 animals: a response driven by positive feedback between interleukin-6 and lung dysfunction. Resulting networks further suggested that in control animals, acute kidney injury, acidosis, and respiratory failure play an increased role in the response to insult compared to CMT-3 animals. These combined in vivo and in silico studies in a high fidelity, clinically applicable animal model suggest a dynamic interplay between inflammatory, physiologic, and blood chemistry variables in the setting of sepsis and ARDS that may be dramatically altered by pleiotropic interruption of inflammation by CMT-3. PMID- 26064800 TI - Physiologic and molecular changes in the tracheal epithelium of rats following burn injury. AB - Pneumonia is the leading complication in the critical care of burn victims. Airway epithelial dysfunction compromises host defense against pneumonia. The aim of this study is to test the hypothesis that burn injury alters the physiology of the airway epithelium. A rat model of 60% TBSA third degree scald burn was used. At 24 hours after injury, tracheal epithelial ultrastructure was studied using transmission electron microscopy (TEM) and proliferation was measured by Ki67 immunohistochemistry. Mucociliary clearance (MCC) was measured using fluorescent microspheres. The level of malondialdehyde (MDA), an indicator of lipid peroxidation, was also measured. Changes in epithelial mRNA expression were measured using microarray. Burn injury led to a ten-fold reduction in MCC that was statistically significant (p = 0.007) 24 hours after injury. No significant change was noted in the morphology of tracheal epithelial cells between groups, although a marginal increase in extracellular space was noted in injured animals. Ki67 nuclear expression was significantly reduced (25%, p = 0.008) in injured rats. There was a significant increase in MDA levels in the epithelial lysate of burned animals, p = 0.001. Microarray analysis identified 59 genes with significant differences between sham and injured animals. Burn injury altered multiple important functions in rat tracheal epithelium. The decrease in MCC and cell proliferation may be due to oxidative injury. Mechanistic studies to identify physiological processes associated with changes in airway function may help in designing therapeutic agents to reduce burn-induced airway pathogenesis. PMID- 26064802 TI - From the Editor's Desk. PMID- 26064801 TI - Trauma patient adverse outcomes are independently associated with rib cage fracture burden and severity of lung, head, and abdominal injuries. AB - OBJECTIVE: We hypothesized that lung injury and rib cage fracture quantification would be associated with adverse outcomes. SUBJECTS AND METHODS: Consecutive admissions to a trauma center with Injury Severity Score >= 9, age 18-75, and blunt trauma. CT scans were reviewed to score rib and sternal fractures and lung infiltrates. Sternum and each anterior, lateral, and posterior rib fracture was scored 1 = non-displaced and 2 = displaced. Rib cage fracture score (RCFS) = total rib fracture score + sternal fracture score + thoracic spine Abbreviated Injury Score (AIS). Four lung regions (right upper/middle, right lower, left upper, and left lower lobes) were each scored for % of infiltrate: 0% = 0; <= 20% = 1, <= 50% = 2, > 50% = 3; total of 4 scores = lung infiltrate score (LIS). RESULTS: Of 599 patients, 193 (32%) had 854 rib fractures. Rib fracture patients had more abdominal injuries (p < 0.001), hemo/pneumothorax (p < 0.001), lung infiltrates (p < 0.001), thoracic spine injuries (p = 0.001), sternal fractures (p = 0.0028) and death or need for mechanical ventilation >= 3 days (Death/Vdays >= 3) (p < 0.001). Death/Vdays >= 3 was independently associated with RCFS (p < 0.001), LIS (p < 0.001), head AIS (p < 0.001) and abdominal AIS (p < 0.001). Of the 193 rib fracture patients, Glasgow Coma Score 3-12 or head AIS >= 2 occurred in 43%. A lung infiltrate or hemo/pneumothorax occurred in 55%. Thoracic spine injury occurred in 23%. RCFS was 6.3 +/- 4.4 and Death/Vdays >= 3 occurred in 31%. Death/Vdays >= 3 rates correlated with RCFS values: 19% for 1-3; 24% for 4 6; 42% for 7-12 and 65% for >= 13 (p < 0.001). Death/Vdays >= 3 was independently associated with RCFS (p = 0.02), LIS (p = 0.001), head AIS (p < 0.001) and abdominal AIS (p < 0.001). Death/Vdays >= 3 association was better for RCFS (p = 0.005) than rib fracture score (p = 0.08) or number of fractured ribs (p = 0.80). CONCLUSION: Rib fracture patients have increased risk for truncal injuries and adverse outcomes. Adverse outcomes are independently associated with rib cage fracture burden. Severity of head, abdominal, and lung injuries also influence rib fracture outcomes. PMID- 26064803 TI - Invasive Laryngeal Squamous Cell Carcinoma in a Boy. AB - Laryngeal squamous cell carcinoma (SCC) is rare in children. Usually, laryngeal SCC in children has a poor prognosis. A 9-year-old boy is reported who was diagnosed as having poorly differentiated laryngeal squamous cell carcinoma with neck metastasis. This report aims to highlight the importance of a comprehensive knowledge of differential diagnosis, putting great attention to the onset of symptoms, early application of flexible laryngoscopy, and intensive studies on similar cases. PMID- 26064804 TI - Fungal Orbital Infection Mimicking Malignancy in a Girl. AB - Fungal infection of the orbit is rare especially among immunocompetent patients. We present a 9-year-old girl with peri-orbital, eyelid and internal canthus swelling of the left eye. Clinical impression was suggestive of malignant tumor such as rhabdomyosarcoma or lymphoma. Histopathological examination of biopsied tissue revealed necrotizing granulomatous inflammation confirmed as fungal infection. Complete response to antifungal therapy was noted after four months. PMID- 26064805 TI - Pyogenic Granuloma of the Sigmoid Colon causing Intussusception in an Infant. AB - Pyogenic granuloma is a benign vascular tumor that may affect the gastrointestinal tract. This report describes a rare case of sigmoid-colon pyogenic granuloma in a 4-month-old boy causing intussusception. Resection and anastomosis were curative. The mother had history of high dose of progesterone exposure during initial weeks of conception for vaginal bleeding. This may point towards etiology of the lesion. PMID- 26064806 TI - Plexiform Schwannoma of Lumbar Region. AB - Plexiform schwannoma is an unusual peripheral nerve sheath tumor. It can mimic plexiform neurofibroma. A five-year-old girl presented with painful swelling in left lumbar region. Radiologic investigations showed a multinodular tumor in the subcutaneous plane of lumbosacral region. A complete excision and histopathologic examination revealed a plexiform tumor composed of hypocellular and hypercellular areas with verocay bodies. The tumor cells showed strong positivity for S-100 protein, rendering a final diagnosis of plexiform schwannoma. The child has been free of recurrence in 12-month follow-up. PMID- 26064807 TI - Extra-Renal Wilms' Tumor: A Rare Diagnosis. AB - The diagnosis of extra-renal Wilms' tumor is often missed at initial clinical presentation leading to a delay in initiating appropriate therapy. A 5-year-old girl presented with a 3-week history of a painless lump in the pelvis. Radiological investigations suggested an ovarian neoplasm. Tumor markers for ovarian malignancy were in normal range. Trucut biopsy also suggested the possibility of an ovarian neoplasm. The tumor was excised and final histopathology revealed it a Wilms' tumor. PMID- 26064808 TI - Right Hemi-Diaphragmatic Rupture: An Injury Missed or Masked? AB - Right sided traumatic diaphragmatic rupture in children is uncommon and may escape early detection. Missed injuries are associated with high mortality and morbidity due to incarceration and strangulation of abdominal viscera. We report a 15-month-old child with blunt trauma chest and abdomen, who presented with bilateral hemothoraces and liver laceration seven days after the incident. Diagnosis of right diaphragmatic rupture was confirmed after another week. The surgical repair of diaphragmatic rupture was undertaken successfully. PMID- 26064809 TI - Multiple Stones in a Single-System Ureterocele in a Child. AB - Presence of multiple calculi in ureterocele is rare in children. A 6-year-old boy presented with hematuria in whom on x-ray and ultrasound multiple calculi were noted in the urinary bladder. At surgery a ureterocele containing multiple calculi was found. The postoperative (99m) Tc-Dimercaptosuccinic acid scan (DMSA) reported normal renal function. PMID- 26064810 TI - Benign and Infected Sacrococcygeal Teratoma in a 13-year-old Girl. PMID- 26064811 TI - Isolated Cysticercosis Lump over Thigh in a Child. PMID- 26064812 TI - Hair Tourniquet Syndrome of Labia Minora. PMID- 26064813 TI - Transmesenteric Herniation through Congenital Mesenteric Defect leading to Bowel Gangrene. PMID- 26064814 TI - Is the Endoscopic Grasp-and-Traction Device Useful for Endoscopic Submucosal Dissection in Treating Early Gastric Cancer? PMID- 26064815 TI - What Is the Optimal Timing of Bowel Preparation for Video Capsule Endoscopy? PMID- 26064816 TI - How to Improve Diagnostic Accuracy in Suspicious Ampullary Lesions? PMID- 26064817 TI - Upper Gastrointestinal Stent Insertion in Malignant and Benign Disorders. AB - Upper gastrointestinal (GI) stents are increasingly being used to manage upper GI obstructions. Initially developed for palliative treatment of esophageal cancer, upper GI stents now play an emerging role in benign strictures of the upper GI tract. Because recurrent obstruction and stent-related complications are common, new modifications of stents have been implemented. Self-expandable metal stents (SEMS) have replaced older plastic stents. In addition, newly designed SEMS have been developed to prevent complications. This review provides an overview of the various types, indications, methods, complications, and clinical outcomes of upper GI stents in a number of malignant and benign disorders dividing the esophagus and gastroduodenum. PMID- 26064818 TI - Colorectal Stents: Current Status. AB - A self-expandable metal stent (SEMS) is an effective and safe method for the decompression of colon obstruction. Based on recent evidence, colorectal SEMS is now recommended for the palliation of patients with colonic obstruction from incurable colorectal cancer or extracolonic malignancy and also as a bridge to surgery in those who are a high surgical risk. Prophylactic SEMS insertion in patients with no obstruction symptoms is not recommended. Most colorectal SEMS are inserted endoscopically under fluoroscopic guidance. The technical and clinical success rates of colorectal SEMS are high, and the complication rate is acceptable. Advances in this technology will make the insertion of colorectal SEMS better and may expand the indications of colorectal SEMS in the future. PMID- 26064819 TI - Update on Pancreatobiliary Stents: Stent Placement in Advanced Hilar Tumors. AB - Palliative drainage is the main treatment option for inoperable hilar cholangiocarcinoma to improve symptoms, which include cholangitis, pruritus, high grade jaundice, and abdominal pain. Although there is no consensus on the optimal method for biliary drainage due to the paucity of large-scale randomized control studies, several important aspects of any optimal method have been studied. In this review article, we discuss the liver volume to be drained, stent type, techniques to insert self-expanding metal stents, and approaches for proper and effective biliary drainage based on previous studies and personal experience. PMID- 26064821 TI - Diagnostic Coding for Intramucosal Carcinoma and Neuroendocrine Tumor in the Colorectum: Proposal for Avoiding Confusing Coding in Korea. AB - Applying proper coding is important for doctors practicing gastroenterology. The coding systems established by various organizations define tumors differently. As a result of changing concepts of tumor classification, there are coding and reimbursement issues following the confirmation of malignant lesions by nationwide cancer screening in patients with intramucosal carcinoma and neuroendocrine tumors of the colorectum. In addition, there have been discrepancies between the views of endoscopists and pathologists regarding tumor coding. The Korean Society of Gastrointestinal Endoscopy held an expert meeting and established a consensus for the coding of intramucosal carcinoma and neuroendocrine tumor of the colorectum. PMID- 26064820 TI - Recent Advances in Gastrointestinal Stent Development. AB - Endoscopic stenting is increasingly being used in the management of gastrointestinal luminal obstruction, and has become the current treatment of choice for the palliation of blockage caused by malignant or benign growths. A variety of stents have been developed to enhance the efficacy of the procedure, and improvements are ongoing. In this article, we review the history of, and recent advances in, gastrointestinal stenting. We describe the rationale behind the design as well as the resulting outcome for each stent type. PMID- 26064822 TI - The Efficacy of an Endoscopic Grasp-and-Traction Device for Gastric Endoscopic Submucosal Dissection: An Ex Vivo Comparative Study (with Video). AB - BACKGROUND/AIMS: To investigate whether the EndoLifter (Olympus), a counter traction device facilitating submucosal dissection, can accelerate endoscopic submucosal dissection (ESD). METHODS: Two endoscopists (novice/expert in ESD) performed 64 ESDs (artificial 3-cm lesions) in 16 ex vivo pig stomachs: per stomach, two at the posterior wall (forward approach) and two at the lesser curvature (retroflex approach). Per approach, one lesion was dissected with (EL+) and one without (EL-) the EndoLifter. The submucosal dissection time (SDT), corrected for specimen size, and the influence of ESD experience on EndoLifter usefulness were assessed. RESULTS: En bloc resection rate was 98.4%. In the forward approach, the median SDT was shorter with the EndoLifter (0.56 min/cm(2) vs. 0.91 min/cm(2)), although not significantly (p=0.09). The ESD-experienced endoscopist benefitted more from the EndoLifter (0.45 [EL+] min/cm(2) vs. 0.68 [EL-] min/cm(2), p=0.07) than the ESD-inexperienced endoscopist (0.77 [EL+] min/cm(2) vs. 1.01 [EL-] min/cm(2), p=0.48). In the retroflex approach, the median SDTs were 1.06 (EL+) and 0.48 (EL-) min/cm(2) (p=0.16). The EndoLifter did not shorten the SDT for the ESD-experienced endoscopist (0.68 [EL+] min/cm(2) vs. 0.68 [EL-] min/cm(2), p=0.78), whereas the ESD-inexperienced endoscopist seemed hindered (1.65 [EL+] min/cm(2) vs. 0.38 [EL-] min/cm(2), p=0.03). CONCLUSIONS: In gastric ESD, the EndoLifter, in trend, shortens SDTs in the forward, but not in the retroflex approach. Given the low numbers in this study, a type II error cannot be excluded. PMID- 26064823 TI - Risk Factors for Dieulafoy Lesions in the Upper Gastrointestinal Tract. AB - BACKGROUND/AIMS: The purpose of this study is to verify the risk factors associated with Dieulafoy lesion formation in the upper gastrointestinal tract. METHODS: A case-control study was performed by reviewing the electronic medical records of 42 patients who were admitted to a tertiary medical center in the Daejeon region for Dieulafoy lesions from September 2008 to October 2013, and the records of 132 patients who were admitted during the same period and who underwent endoscopic examination for reasons other than bleeding. We analyzed clinical and endoscopic findings retrospectively, and searched for risk factors associated with Dieulafoy lesion formation. RESULTS: All 42 patients diagnosed with Dieulafoy lesion had accompanying bleeding, and the location of the bleeding was proximal in 25 patients (59.5%), the middle portion in seven patients (16.7%), and distal in 10 patients (23.8%). Antiplatelet agents (p=0.022) and alcohol (p=0.001) use showed statistically significant differences between the two groups. The odds ratios (95% confidence intervals) of the two factors were 2.802 (1.263 to 6.217) and 3.938 (1.629 to 9.521), respectively. CONCLUSIONS: This study showed that antiplatelet agents and alcohol consumption were risk factors associated with Dieulafoy lesion formation in the upper gastrointestinal tract. PMID- 26064824 TI - A Single-Center Randomized Controlled Trial Evaluating Timing of Preparation for Capsule Enteroscopy. AB - BACKGROUND/AIMS: Intestinal lavage (IL) administration immediately before capsule enteroscopy (CE) is superior to lavage the day before the procedure. We aimed to determine the effect of IL timing on CE diagnostic yield. METHODS: Patients referred for CE were randomized prospectively into two equal groups according to the timing of IL with 2 L of polyethylene glycol solution. Group A and B underwent IL over 2 hours beginning 14 and 4 hours, respectively, before the scheduled CE. The primary outcome measure was preparation quality, measured with a predetermined validated grading scale. RESULTS: A total of 34 patients were randomized. The frequency of mucosal abnormalities (77% vs. 82%, p=not significant [NS]) and diagnostic yield (47% vs. 53%, p=NS) were similar between the two groups. Moreover, no significant association between the quality of small bowel preparation and the timing at which the purgative for IL was administered was observed (overall fluid transparency, p=0.936; overall mucosal invisibility, p=0.091). CONCLUSIONS: Day-before IL is equivalent to same-day IL in terms of overall preparation quality, proportion of complete studies to cecum, small bowel transit time, frequency of identified mucosal abnormalities, and overall diagnostic yield. PMID- 26064825 TI - Diagnostic Accuracy of the Initial Endoscopy for Ampullary Tumors. AB - BACKGROUND/AIMS: Ampullary tumors come in a wide variety of malignant forms. We evaluated the diagnostic accuracy of endoscopy for ampullary tumors, and analyzed the causes of misdiagnosis. METHODS: We compared endoscopic imaging and biopsy results to final diagnoses. Types of endoscope, numbers of biopsy specimens taken, and final diagnoses were evaluated as possible factors influencing diagnostic accuracy. RESULTS: Final diagnoses were 19 adenocarcinomas, 18 normal or papillitis, 11 adenomas, two adenomyomas, one paraganglioma, and one neuroendocrine tumor. The diagnostic accuracy of endoscopic imaging or the initial biopsy was identical (67.3%). At least one test was concordant with the final diagnosis in all except two cases. Compared with the final diagnosis, endoscopic imaging tended to show more advanced tumors, whereas the initial biopsy revealed less advanced lesions. The diagnostic accuracy of the initial biopsy was influenced by the type of endoscope used and the final diagnosis, but not by the number of biopsies taken. CONCLUSIONS: Endoscopy has limited accuracy in the diagnosis of ampullary tumors. However, most cases with concordant endoscopic imaging and biopsy results are identical to the final diagnosis. Therefore, in cases where both of these tests disagree, re-evaluation with a side viewing endoscope after resolution of papillitis is required. PMID- 26064826 TI - Liver Metastasis of Early Gastric Cancer with Mixed Histology after Endoscopic Submucosal Dissection. AB - The Japanese Classification of Gastric Carcinoma histologically classifies endoscopically resected gastric cancer into differentiated and undifferentiated types according to the presence or absence of tubular structures on histology. The former includes papillary adenocarcinoma and tubular types, and the latter includes poorly differentiated adenocarcinoma, signet ring cell carcinoma and mucinous adenocarcinoma. However, gastric cancer sometimes contains a mixture of differentiated and undifferentiated components, and the clinical outcomes of the histological mixture are unknown, especially following endoscopic resection of early gastric cancer (EGC). This case was within the guideline indications for endoscopic submucosal resection (ESD), although it contained a partly signet ring cell carcinoma component; it recurred after 19 months with multiple lymph node and liver metastases. This case shows that additional surgical resection after ESD should be performed for patients with any mixed signet ring cell component, even in mild or moderately differentiated EGC. PMID- 26064827 TI - Delayed Perforation Occurring after Endoscopic Submucosal Dissection for Early Gastric Cancer. AB - Delayed perforation is a very rare complication of endoscopic submucosal dissection (ESD), with a reported incidence of 0.1% to 0.45%. Few reports exist on the clinical features and outcomes of delayed perforation after ESD, and it is unclear whether the optimal management strategy is emergency surgery or endoscopic closure with conservative treatment. Here, we report two cases of delayed perforation occurring after ESD for early gastric cancer. In both cases, lesions were located in the antrum, and tumor depths were confined to the mucosal layer. Total procedure times for ESD were 25 and 45 minutes, respectively. Because delayed perforation may be associated with excessive thermal damage and necrosis of the muscle layer, treatment with emergency surgery should be used instead of conservative management in cases of delayed perforation after ESD. PMID- 26064828 TI - Gastric Syphilis and Membranous Glomerulonephritis. AB - Syphilis is a chronic systemic infectious disease caused by the bacterium Treponema pallidum. Gastric involvement and nephrotic syndrome are uncommon but well documented complications of syphilis, but the co-occurrence of these two complications in the same patient is extremely rare. Thus, because of their nonspecific presentation, suspicion of gastric syphilis (GS) and nephrotic syndrome is essential for diagnosis. Patients should be investigated thoroughly and a diagnosis made based on clinical, endoscopic, and histological findings, in order to initiate appropriate therapy. We report of a 34-year-old male patient with a history of epigastric pain and a diagnosis of GS and syphilis-associated membranous glomerulonephritis confirmed by gastroscopy and kidney biopsy, who was treated successfully with penicillin G benzathine. This case report provides information on the typical features of GS that should help raise awareness of this rare disease entity among clinicians, resulting in earlier diagnosis and administration of appropriate therapy. PMID- 26064829 TI - Ectopic Opening of the Common Bile Duct into the Duodenal Bulb Accompanied with Cholangitis and Gallbladder Cancer: A Report of Two Cases. AB - An ectopic opening of the common bile duct (CBD) into the duodenal bulb is a very rare congenital anomaly of the biliary system, which may cause recurrent duodenal ulcer or biliary diseases such as choledocholithiasis and cholangitis. Endoscopic retrograde cholangiopancreatography (ERCP) plays a major role in the diagnosis of this anomaly. We report two such cases: one in a 61-year-old man and the other in a 57-year-old man. In the first case, this anomaly caused acute cholangitis with multiple CBD stones, which were successfully treated by ERCP. In the second case, abdominal computed tomography showed pneumobilia, which was further evaluated using ERCP. Besides, this patient was diagnosed with an ectopic opening of the CBD associated with gallbladder cancer. We report these unusual cases and review the relevant medical literature. PMID- 26064830 TI - Cholangitis Secondary to Food Material Impaction in the Common Bile Duct through a Choledochoduodenal Fistula. AB - Biliary-enteric communications caused by duodenal ulcers are uncommon, and choledochoduodenal fistula (CDF) is by far the most common type. Usually in this situation, food material does not enter the common bile duct because the duodenal lumen is intact. Here, we report a case in which cholangitis occurred due to food materials impacted through a CDF. Duodenal obstruction secondary to duodenal ulcer prevented food passage into the duodenum in this case. Surgical management was recommended; however, the patient refused surgery because of poor general condition. Consequently, the patient expired with sepsis secondary to ascending cholangitis. PMID- 26064831 TI - The Advent of Lifestyle Medicine. AB - The fact that lifestyle is closely associated with the pathogenesis of chronic diseases has been known for more than three decades. Smoking may cause lung cancer, and a lifestyle of fast food consumption and little exercise can cause metabolic diseases. The importance of lifestyle changes in terms of a new medical paradigm to solve chronic diseases is becoming popular in modern times. Lifestyle medicine is a medicine based on personal lifestyle. To apply it to patients and ordinary people, physicians have to cooperate with experts in many fields such as nutrition, exercise, psychology, etc. In addition, patients must be partners in the treatment rather than passive recipients. The advent of lifestyle medicine has been caused by changes in disease patterns. In the past, acute diseases like infectious disease were prevalent; however, in the late 20(th) century, chronic diseases such as metabolic diseases, cancers, neurological disease, etc. increased in occurrence. As lifestyle is closely related with these diseases, the attitudes toward medicine need to be changed. Recently, the concept of "Lifestyle Medicine" was proposed, and we predict it will be an important field in future medicine. PMID- 26064832 TI - Olympic Health Legacy; Essentials for Lasting Development of Host City. AB - The purpose of the Olympic Games should be to contribute to the social development by leaving behind economic, cultural and environmental legacies to the hosting region. While tangible examples such as venues are often recognized as representative legacies of the Olympics, intangible aspects such as the environment, culture, policy and human resources have been gaining in importance. The Olympic Games, at its most fundamental level, is a sporting event. Sports not only is closely related to the physical health, but is also instrumental to fostering mental health through inspiration. One of the most important sports legacies was the general change in the population's perception on sports and physical activities; due to such change, people were able to enjoy sports as part of healthy and active everyday life and benefit physically. However, compared to tangible legacies such as the facilities, social legacies such as the general health and their planning, execution and achievements are hard to monitor. Therefore, for the Olympics to leave behind socio-cultural legacies that contribute to the development of the hosting region, there must be a thorough business plan that takes into account region-specific purpose, and is divided into stages such as before, during and after the Games. Should the 2018 Winter Olympic Games hope to create continuing contribution to its hosting region, it must leave behind 'Health Legacies' that will enhance the happiness of the hosting region's population. To this end, establishment of region-specific purpose and systematic promotion of business via detailed analysis of precedents are a must. This article aim to review the health legacy endeavors of past host cities and suggest the appropriate forms of health legacy of 2018 Pyeongchang Winter Olympic and Paralympic Games. PMID- 26064833 TI - Regulation of Cholesterol Metabolism in Liver: Link to NAFLD and Impact of n-3 PUFAs. AB - Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease that affects one-third of adults in westernized countries. NAFLD represents a wide spectrum of hepatic alterations, ranging from simple triglyceride accumulation in the liver to steatohepatitis. Several pharmaceutical approaches to NAFLD management have been examined, but no particular treatment has been considered both safe and highly effective. Growing evidence reveal that supplemental fish oil, seal oil and purified n-3 fatty acids can reduce hepatic lipid content in NAFLD through extensive regulation by inhibiting lipogenesis, promoting fatty acid oxidation and suppressing inflammatory responses. Recently, the fat-1 transgenic mice capable of converting n-6 to n-3 polyunsaturated fatty acids (PUFAs) have been used to examine the effects of endogenous n-3 PUFAs on NAFLD. The increased n-3 PUFAs in fat-1 transgenic mice reduced diet-induced hyperlipidemia and fatty liver through induction of CYP7A1 expression and activation of cholesterol catabolism to bile acid. This article introduces the n 3 PUFAs, and addresses the evidence and mechanisms by which endogenously synthesized n-3 PUFAs or increased dietary n-3 PUFAs may ameliorate NAFLD. PMID- 26064834 TI - Current Concepts of Premature Ventricular Contractions. AB - Premature ventricular contractions (PVCs) are early depolarizations of the myocardium originating in the ventricle. PVCs are common with an estimated prevalence of 40% to 75% in the general population on 24- to 48-hour Holter monitoring. Traditionally, they have been thought to be relatively benign in the absence of structural heart disease but they represent increased risk of sudden death in structural heart disease. Especially in ischemic heart disease, the frequency and complexity of PVCs is associated with mortality. Implantable cardioverter defibrillator therapy is indicated in patients with nonsustained ventricular tachycardia (NSVT) due to prior myocardial infarction, left ventricular ejection fraction less than or equal to 40%, and inducible ventricular fibrillation or sustained ventricular tachycardia at electrophysiological study. In congestive heart failure, PVCs did not provide significant incremental prognostic information beyond readily available clinical variables. Consequently, NSVT should not guide therapeutic interventions. Recently, the concept of PVC-induced cardiomyopathy was proposed when pharmacological suppression of PVCs in patients with presumed idiopathic dilated cardiomyopathy subsequently showed improved left ventricular systolic dysfunction. For the treatment PVCs, it is important to consider underlying heart disease, the frequency of the PVCs and the frequency and severity of symptoms. PMID- 26064835 TI - New Prophylactic and Therapeutic Strategies for Spinal Cord Injury. AB - Melatonin production by the pineal gland in the vertebrate brain has attracted much scientific attention. Pineal melatonin is regulated by photoperiodicity, whereas circadian secretion of melatonin produced in the gastrointestinal tract is regulated by food intake. Thus, the circadian rhythm of pineal melatonin depends upon whether a species is diurnal or nocturnal. Spinal cord injury (SCI) involves damage to the spinal cord caused by trauma or disease that results in compromise or loss of body function. Melatonin is the most efficient and commonly used pharmacological antioxidant treatment for SCI. Melatonin is an indolamine secreted by the pineal gland during the dark phase of the circadian cycle. Neurorehabilitation is a complex medical process that focuses on improving function and repairing damaged connections in the brain and nervous system following injury. Physical activity associated with an active lifestyle reduces the risk of obesity, cardiovascular disease, type 2 diabetes, osteoporosis, and depression and protects against neurological conditions, including Parkinson's disease, Alzheimer's disease, and ischemic stroke. Physical activity has been shown to increase the gene expression of several brain neurotrophins (brain derived neurotrophic factor [BDNF], nerve growth factor, and galanin) and the production of mitochondrial uncoupling protein 2, which promotes neuronal survival, differentiation, and growth. In summary, melatonin is a neural protectant, and when combined with therapeutic exercise, the hormone prevents the progression of secondary neuronal degeneration in SCI. The present review briefly describes the pathophysiological mechanisms underlying SCI, focusing on therapeutic targets and combined melatonin and exercise therapy, which can attenuate secondary injury mechanisms with minimal side effects. PMID- 26064836 TI - High-dose Resveratrol Inhibits Insulin Signaling Pathway in 3T3-L1 Adipocytes. AB - BACKGROUND: Insulin resistance is a major factor in the development of metabolic syndrome and is associated with central obesity and glucose intolerance. Resveratrol, a polyphenol found in fruits, has been shown to improve metabolic conditions. Although it has been widely studied how resveratrol affects metabolism, little is known about how resveratrol regulates lipogenesis with insulin signaling in 3T3-L1 adipocytes. METHODS: We treated differentiated 3T3-L1 adipocytes with resveratrol to observe whether resveratrol is effective at reducing lipid accumulation. RESULTS: Resveratrol treatment after mitotic clonal expansion resulted in decreased lipid accumulation accompanied by reduced fatty acid synthase expression. Decreased glucose uptake was observed with inhibited GLUT4 translocation in cells treated with 100 MUM resveratrol, suggesting that high doses of resveratrol block insulin signaling in adipocytes. Insulin stimulated Akt phosphorylation is also dose-dependently reduced with resveratrol treatment. Interestingly, Akt phosphorylation is upregulated when cells are treated with long-term low doses of resveratrol, suggesting that only low doses of resveratrol improve metabolic conditions. CONCLUSION: High doses of resveratrol block the insulin signaling pathway, thereby reducing glucose uptake and lipid accumulation in vitro. The results also provide information about in vivo administration dosages and may explain the discrepancy between in vitro and in vivo effects of resveratrol. PMID- 26064837 TI - Omentum Cells Promote Healing of Colonic Tissues in Dextran Sulfate Sodium (DSS) Induced Model of Colitis in Mice. AB - BACKGROUND: Inflammatory bowel disease is characterized by persistent inflammation of the intestinal tissues. Although the usage of biologics has greatly enhanced the management of this disorder, a permanent treatment does not exist. In this study, we investigated whether the cells with anti-inflammatory and healing properties from the omentum could be harnessed to treat colitis in dextran sulfate sodium (DSS)-induced mouse colitis model. METHODS: C57BL/6 mice were administered 2% DSS for 10 days and then injected in the peritoneum with cells isolated from the murine omentum. Thereafter, body weight change, serum KC levels, and histological analysis of the colon were conducted. We also examined if omentum infused mice were resistant to a lethal challenge of 4% DSS. RESULTS: 2% DSS-mice injected with omentum cells exhibited a decrease in body weight loss, decreased inflammation in the colon and decreased levels of the inflammatory cytokine KC in the serum compared to mice given 2% DSS alone. In addition, mice administered a lethal dose of 4% DSS exhibited a 50% decrease in mortality when injected with omentum cells. CONCLUSION: Cells from the omentum exert anti inflammatory and/or healing properties in the acute DSS-induced colitis model. PMID- 26064838 TI - Energy Balance during Taekwondo Practice in Elite Male Taekwondo Players. AB - BACKGROUND: The goal of this study was to evaluate energy expenditure and dietary intake of nutrients during Taekwondo practice in elite Korean male Taekwondo players. METHODS: Elite Korean male high school (high school player: HP; n = 59) and college players (college player: CP; n = 58) wore an accelerometer to measure energy expenditure and recorded their daily dietary intake for nutritional analysis over the course of five days. RESULTS: Nutritional adequacy ratios for total energy (0.82), vitamin C (0.97), calcium (0.78), and folate (0.75) were below recommended levels for all players. When comparing daily nutrient intake and energy expenditure between HP and CP, the HP group had significantly higher total calorie intake (402.7 kcal, p < 0.001), calcium (126.3 mg, p = 0.018), phosphorus (198.0 mg, p = 0.002), iron (1.3 mg, p = 0.002), and vitamin B2 (0.4 mg, p < 0.001) than the CP group. Although there was no significant difference in the estimated energy requirement during Taekwondo practice, the total energy expenditure (151.2 kcal, p = 0.001), total activity counts (130,674 counts, p = 0.038) and energy expenditure during Taekwondo practice (257.7 kcal, p < 0.001) were significantly higher in the HP than in the CP. CONCLUSION: The results indicate that a sports nutrition program based on energy balance is necessary to achieve optimal health and performance in elite male Taekwondo players. PMID- 26064839 TI - Differences in Adipokine and Hepatokine Levels among Non-diabetic Population Classified by Age and Sex. AB - BACKGROUND: Leptin, angiopoietin-related growth factor (AGF), adiponectin (ADP), and retinol-binding protein 4 (RBP4) are cytokines associated with the development of metabolic disorders, such as type 2 diabetes and cardio vascular disease. However, the levels of these cytokines have not extensively studied in non-diabetic subjects. Therefore, we analyzed the differences in these cytokine levels according to sex and age in non-diabetic Korean population. METHODS: Blood samples were collected from 59 non-diabetic Korean adults (male, 32; female, 27). The anthropometric and biochemical data were measured at the health examination center. Serum adipokines and hepatokines were measured by enzyme linked immunosorbent assay (ELISA). The data were analyzed according to sex and age based quartiles. RESULTS: Serum leptin values were higher in females (8.60 +/- 3 MUg/ml) compared with males (2.99 +/- 2.9 MUg/ml). However, RBP4 was higher in males (84.05 +/- 47.04 MUg/ml) than in females (61.25 +/- 45.42 MUg/ml). The AGF and ADP values were not significantly different between males and females. RBP4 level was inversely correlated with age quartile in males, while leptin was significantly associated with body mass index and insulin resistance. CONCLUSION: RBP4 and AGF levels showed age-associated change, and leptin was consistently higher in females. Therefore, a large-scale analysis to determine the normal range of adipokines and hepatokines concentration in healthy Korean population is necessary. When interpreting adipokine and hepatokine levels, the difference in age and sex needs to be taken into account. PMID- 26064840 TI - Correlation between Abnormal Pap Smear Finding and Brachial-ankle Pulse Wave Velocity in Korean Women. AB - BACKGROUND: Cervical cancer is caused by chronic human papilloma virus (HPV) infection. Pap smear is very efficient examination for early detecting cervical cancer. Inflammation reaction due to chronic infection is one of the major causes of atherosclerosis. Pulse wave velocity (PWV) is commonly used in predicting subclinical atherosclerosis. But no study was done about correlation between cervical cancer and PWV. METHODS: The research population, 1,779 people, had been chosen from the patients from Jan. 1st, 2008 to December 31st, 2010, visited health exam center who had done both PWV test and pap smear without any medical history of obstetrics and gynecological disease. The group was divided into two respective groups, 45 people with abnormal finding and 228 people with normal finding. The correlation was analyzed between risk factor of cervical cancer and brachial-ankle PWV. Multiple regression analysis was performed with associated variables. RESULTS: Average PWV of normal group was 1,313.06 +/- 264.19 and 1,497.15 +/- 359.58 was for abnormal. The PWV of abnormal group was statistically significant (p = 0.0006) with association between risk factors of cervical cancer and PWV, age, height, weight, income, gravidity. Multiple regression was done with correcting these variables. PWV was associated with abnormal Pap smear but result, were not found to be significant (p = 0.054). CONCLUSION: The result was not statistically confident but more mass studies are needed to correcting those limitation. PMID- 26064841 TI - Regulation of IGFBP-1 in Metabolic Diseases. AB - Insulin-like growth factor binding proteins (IGFBPs) play a key role in insulin and insulin growth factor signaling and are known to be expressed in several tissues. Studies on the transcriptional regulation of IGFBP genes in various cell types have suggested that IGFBPs control both systemic hormones and regulators. Also, the complex regulatory mechanisms involved in both transcription and translation of IGFBPs provide evidence for molecular mechanisms by which growth factor- and hormone-mediated gene expression are regulated. In particular, IGFBP 1 is known to be an important regulator of IGF activity and mainly regulates metabolism in mammals. In this review, we focus on recent progress in elucidating the transcriptional regulation of IGFBP-1 among IGFBP isoforms. PMID- 26064842 TI - TGFbeta Signaling-mediated MicroRNA Regulation in Vascular Smooth Muscle Cells. AB - The discovery of small noncoding microRNAs (miRNAs) increases the complexity of gene expression regulatory mechanisms. The basic mechanism of miRNA biogenesis and regulatory functions of target genes have been widely elucidated. Recently, it has been recognized that regulation of each step of miRNA biogenesis is critical for generating functional miRNAs. Interestingly, cell signaling pathways, including the transforming growth factor beta (TGFbeta) signaling pathway, have been found to modulate miRNA biosynthesis. TGFbeta signaling regulates expression of several miRNAs that are implicated in the development and homeostasis of vascular smooth muscle cells (VSMCs). This review describes recent understanding of the transcriptional and post-transcriptional regulation of miRNA expression by TGF beta signaling in VSMCs. PMID- 26064843 TI - Diagnosing Psoriatic Arthritis from the Dermatologist's View. AB - Psoriatic arthritis is a chronic inflammatory arthropathy associated with skin psoriasis. It is considered a unique arthropathy with distinct clinical and radiologic features. Up to 40% of patients with psoriasis may develop psoriatic arthritis. Psoriasis usually precedes psoriatic arthritis, so dermatologists are in a critical position for screening patients of psoriatic arthritis early in the disease course. Psoriatic arthritis may be challenging to diagnose, especially for dermatologists, because it has an insidious disease course, non-specific symptoms, and no specific biomarkers. Psoriatic arthritis is a polygenic autoimmune disorder of unknown etiology, but immunologic roles have recently been validated. In recent years, treatment modalities have rapidly advanced in the fields of psoriasis and psoriatic arthritis. Biologic agents, including TNF-alpha inhibitors and anti-IL12/23 agents, have shown dramatic improvement. PMID- 26064844 TI - Cooling the Skin: Understanding a Specific Cutaneous Thermosensation. AB - A patient recently presented with long-standing severe itching originating from lichen sclerosus et atrophicus at the vulva area. We successively treated her using a topical formulation of TRPM8 agonist which produces a cooling sensation. The cooling sensation, an afferent sensory perception in various skin neuronal pathways, could be a useful mechanism to relieve an itchy sensation in various skin disorders. Mechanoreceptors are related to touch vibration and pressure sensations and have a special morphology where the nerve endings are optimized to receive sensory inputs. However, unmyelinated nerve fibers are believed to transfer nociception such as pain, itching, stinging and burning derived from chemical or thermal stimuli. Among them, the function of transient receptor potential (TRP) receptors is very unique because they transfer the signal not only in the neuronal perception pathway but also in the cellular signal pathway where it appears as an ion channel. This review explains the cooling sensation of skin which has not been evaluated thoroughly, and provides insights for further clinical applications. PMID- 26064846 TI - Diagnosis and Prevention Strategies for Dental Caries. AB - Dental caries is one of the oldest and most common diseases found in humans. With the recent shift from the surgical model, which emphasized restorative treatment, to a medical model of disease management, newer strategies emphasize disease prevention and conservation of tooth structure. For early detection and monitoring of caries, rather than waiting until a cavity is formed and restorative treatment is needed, devices such as DIAGNOdent, Digital Imaging Fiber-Optic Transillumination, quantitative light-induced fluorescence, and the Electronic Caries Monitor have been introduced. For caries prevention, oral hygiene measures, fluoride application, pit-and-fissure sealants, the use of xylitol, the development of a dental caries vaccine, and the role of the primary caregiver for infants are briefly discussed. PMID- 26064845 TI - Hyperuricemia as a Potential Determinant of Metabolic Syndrome. AB - Recent studies have focused on hyperuricemia as a modulator for metabolic syndrome. Hyperuricemia has reported in many studies as a causal marker in a higher prevalence of metabolic syndrome. In fact, insulin resistance, dyslipidemia, obesity and hypertension, each of these variables of metabolic syndrome gets influenced by the serum uric acid level. High level of uric acid has been associated with metabolic syndrome, type 2 diabetes and cardiovascular diseases. Hyperuricemia has attributed to hyperinsulinemia in metabolic syndrome and decreased excretion of uric acid causing endothelial dysfunction in kidney leads to renal disease and cardiovascular disorders. This review focus on the role of uric acid in the development of metabolic syndrome and onthe possible pathophysiology. PMID- 26064847 TI - Night Shift Work, Sleep Quality, and Obesity. AB - BACKGROUND: The aims of this study were to examine the relationship between night shift work and sleep, to investigate the correlations with various biomarkers that show the influence of sleep on obesity, and ultimately, to analyze factors that have an impact on obesity. METHODS: This study used data from the National Survey of Midlife Development in the United States II (MIDUS II study) and the MIDUS II Biomarker Project. After connecting the MIDUS II study data with the MIDUS II Biomarker Project data, we analyzed data from 883 subjects to investigate the relationship between night shift work and sleep quality. We also examined the correlations with biomarkers and sleep quality. Lastly, we performed logistic regression analyses to investigate factors that had an impact on obesity. RESULTS: Sleep quality was found to be low among night shift workers. Sleep quality was positively correlated with HbA1c, total cholesterol, and triglyceride levels, and inversely correlated with DHEA levels. Sleep quality was highly correlated with inflammatory markers and inversely correlated with antioxidant markers. Sleep quality was significantly associated with obesity (OR: 1.10, 95% CI: 1.03-1.18). Biomarkers that had an influence on obesity included diastolic blood pressure, HbA1c and triglyceride levels, inflammatory markers, and antioxidant values. CONCLUSION: Poor sleep quality due to night shift work disturbs the circadian rhythm, causing negative changes in metabolic, inflammatory, neuroendocrine, and antioxidant biomarkers. These changes may eventually play a role in increasing the incidence of obesity. PMID- 26064848 TI - Mesonephric Adenocarcinoma of the Uterine Cervix Associated with Florid Mesonephric Hyperplasia: A Case Report. AB - Hyperplasia and neoplasia of mesonephric remnants in the uterine cervix are uncommon conditions that are often mis-diagnosed as usual forms of cervical adenocarcinoma. Here, we report a case of mesonephric adenocarcinoma with florid mesonephric hyperplasia of the uterine cervix in a 48-year-old female patient. The cervix was slightly enlarged eccentrically, without a definite mass-like lesion. Microscopically, the tumor cells infiltrated the cervical stroma with focal myometrial extension and were composed of predominantly round to polygonal cells arranged in ductal, tubular, or cystic structures. The remaining stroma revealed diffuse and florid mesonephric hyperplasia intertwined with tumor cells. Immunohistochemically, the tumor cells were positive for pancytokeratin, epithelial membrane antigen, and CD10. The Ki-67 proliferation index was slightly increased. The patient received routine adjuvant treatment and was alive and clinically free of disease at two-year follow-up. PMID- 26064849 TI - Immunological Profiling of Obesity. AB - It is widely accepted that chronic inflammation contributes to the pathogenesis of obesity. Researchers have recently discovered that increased inflammatory cytokines and the infiltration and activation of macrophage cells in the adipose tissue are related to chronic obesity. This immunologic dysregulation has led to the development of the classical pro-inflammatory paradigm. However, since chronic inflammation associated with obesity is more than just the overproduction of pro-inflammatory cytokines, precise dissection requires beyond the classical pro-inflammatory cytokines. The purpose of this review is to summarize the immunological profiling of obesity for theragnostic convenience, focusing on the cytokine and adipokine network in obesity and the significance of the balance of Th1/Th2 immunity. PMID- 26064850 TI - The Role of Functional Foods in Cutaneous Anti-aging. AB - Oral supplementation of micronutrients, or functional foods, to prevent aging has gained much attention and popularity as society ages and becomes more affluent, and as science reveals the pathological mechanisms of aging. Aging of the skin combines biologic aging and extrinsic aging caused predominantly by sunlight and other environmental toxins. Anti-aging functional foods exert their influence mostly through their anti-oxidant and anti-inflammatory effects, thereby abrogating collagen degradation and/or increasing procollagen synthesis. Clinical evidence supporting a role in preventing cutaneous aging is available for oral supplements such as carotenoids, polyphenols, chlorophyll, aloe vera, vitamins C and E, red ginseng, squalene, and omega-3 fatty acids. Collagen peptides and proteoglycans are claimed to provide building blocks of the dermal matrix. This review summarizes the current study findings of these functional foods. PMID- 26064852 TI - Clinical Significance of B-type Natriuretic Peptide in Heart Failure. AB - Biochemical tests to detect B-type natriuretic peptide (BNP) or N-terminal pro brain BNP (NT-proBNP) are useful diagnostic methods for patients with possible HF. These tests are valuable prognostic predictors for the entire spectrum of HF disease severity. Therefore, the measurements of BNP or NT-proBNP taken along with conventional clinical assessments may assist clinicians in deciding treatment. The following review briefly summarizes the available information regarding the clinical significance of BNP and NT-proBNP. PMID- 26064851 TI - Mass Spectrometry-based Lipidomics and Its Application to Biomedical Research. AB - Lipidomics, a branch of metabolomics, is the large-scale study of pathways and networks of all cellular lipids in biological systems such as cells, tissues or organisms. The recent advance in mass spectrometry technologies have enabled more comprehensive lipid profiling in the biological samples. In this review, we compared four representative lipid profiling technoligies including GC-MS, LC-MS, direct infusion-MS and imaging-MS. We also summarized representative lipid database, and further discussed the applications of lipidomics to the diagnostics of various diseases such as diabetes, obesity, hypertension, and Alzheimer diseases. PMID- 26064853 TI - Cutaneous Immune Defenses Against Staphylococcus aureus Infections. AB - Staphylococcus aureus (S. aureus) is a virulent bacterium that abundantly colonizes inflammatory skin diseases. Since S. aureus infections occur in an impaired skin barrier, it is important to understand the protective mechanism through cutaneous immune responses against S. aureus infections and the interaction with Staphylococcal virulence factors. In this review, we summarize not only the pathogenesis and key elements of S. aureus skin infections, but also the cutaneous immune system against its infections and colonization. The information obtained from this area may provide the groundwork for further immunomodulatory therapies or vaccination strategies to prevent S. aureus infections. PMID- 26064854 TI - Physical Activity and Sedentary Behavior Are Independently Associated with Weight in Korean Adolescents. AB - BACKGROUND: This study examines the relationship between physical activity (PA), sedentary behavior (SB) and body weight in Korean adolescents. METHODS: This study used a nationally representative sample of 72,368 South Korean adolescents, aged 13 to 18 years. The study sample was categorized according to BMI as follows: underweight, body mass index (BMI) <18.5; normal weight, 18.5 <= BMI < 23.0; overweight, 23.0 <= BMI < 25.0; and obese, 25.0 <= BMI. An analysis was then performed to determine if meeting the recommended guidelines for PA frequency (5 times/week <=) and amount of SB (<2 hours/day) was associated with weight category. RESULTS: The percentage of normal weight adolescents was 54.3% while the percentages of underweight, overweight, and obese adolescents were 27.4%, 10.2%, and 8.1%, respectively. Significantly fewer underweight and obese adolescents met PA guidelines compared to normal weight adolescents. In addition, underweight, overweight, and obese adolescents had significantly higher SB scores. CONCLUSION: The present study indicates that in Korean adolescents, physical activity and sedentary behavior are independently associated with weight status. Overweight, obese and underweight Korean adolescents should all be independently monitored for management of health-related behaviors. PMID- 26064855 TI - Health Behaviors, Disparities and Deterring Factors for Breast Cancer Screening of Immigrant Women - A Challenge to Health Care Professionals. AB - BACKGROUND: This literature review was made to provide comprehensive to provide comprehensive understanding of health disparities as well as factors and barriers to cancer screening of immigrant women in multicultural societies. METHODS: Published articles from 1990-2013 were searched using databases such as CINAHL, MEDLINE, PubMed and Science Direct showing evidence of contributing factors and barriers to breast cancer screening practices of immigrant women in developed and developing countries. Based on the inclusion criteria, a total of 45 qualified articles were included in the review process. RESULTS: Articles included were quantitative and qualitative, written in English for publication, and subjects were middle-aged, married immigrant women. The identified influential factors and barriers that prevent immigrant women from cancer screening were categorized as individual, socio-cultural and behavioral factors. Socioeconomic status, education level and knowledge, availability of health insurance and acculturation were among the individual factors. Presence of social support and recommendation from health care professionals were strongly associated with compliance with cancer screening. Cultural beliefs and practices as well as behavioral factors were among the barriers that deter women from participating in cancer screening. CONCLUSION: To alleviate the negative factors and barriers that affect the participation of high-risk immigrant women, a client-centered assessment and intervention approach with specific regard to cultural beliefs and practices should be considered by health care professionals. Joint effort of individuals, community, health care professionals and government institutions are recommended to further address the continuous rise of breast cancer mortality worldwide. PMID- 26064856 TI - VEGFR-1 Expression Relates to Fuhrman Nuclear Grade of Clear Cell Renal Cell Carcinoma. AB - BACKGROUND: Increasing evidence suggests that vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) 1 signaling may play an important role in the progression of pathological angiogenesis that occurs in many tumors, including renal cell carcinoma (RCC). Therapeutic targeting directed against VEGF and VEGFR 2 has been proven to be successful for metastatic clear cell RCC (CCRCC). However, the expression of VEGFR-1 and its association with prognostic parameters of CCRCC in the tumorigenesis of renal cancer remains unclear. Therefore, we examined the expression of VEGFR-1 and its prognostic significance in CCRCC. METHODS: Immunohistochemical staining for VEGFR-1 was performed on 126 formalin fixed paraffin-embedded CCRCC tissue samples. Six of these cases were available for Western blot analyses. The results were compared with various clinicopathologic parameters of CCRCC and patients' survival. RESULTS: VEGFR-1 expression was detected in 59 cases (46.8%) of CCRCC. Higher VEGFR-1 expression was significantly correlated with a lower Fuhrman nuclear grade and the absence of renal pelvis invasion, although it was not related to patients' survival. Western blot analyses showed higher VEGFR-1 expression in low grade tumors. CONCLUSION: VEGFR-1 expression may be associated with favorable prognostic factors, particularly a lower Fuhrman nuclear grade in CCRCC. PMID- 26064857 TI - Statin-induced Myopathy in Skeletal Muscle: the Role of Exercise. AB - Statins are widely used drugs to lower cholesterol levels and to reduce the risk of cardiovascular disease. However, it has been reported that statins are associated with adverse side effects of skeletal myopathy. Statin treatment can impair mitochondrial function and induce apoptosis in skeletal muscle in both human and animal models. Ubiquinone plays an essential role in transferring electrons in the mitochondrial electron transfer chain for oxidative phosphorylation. However, statin treatment reduces ubiquinone levels in the cholesterol synthesis pathway, which may be associated with mitochondrial dysfunction. In addition, reactive oxygen species (ROS) production and apoptosis induced by statins may provide cellular and molecular mechanisms in skeletal myopathy. Exercise is the most effective therapy to prevent metabolic and cardiovascular diseases. However, whether exercise provides a benefit to or exacerbation of statin-induced myopathy in skeletal muscle remains poorly investigated. This review will briefly provide a comprehensive summary regarding the effects of statins on skeletal myopathy, and discuss the potential mechanisms of statin-induced myopathy and the role of exercise in statin-induced myopathy in skeletal muscle. PMID- 26064858 TI - SIRT3 as a Regulator of Non-alcoholic Fatty Liver Disease. AB - Non-alcoholic fatty liver disease (NAFLD) is a hepatic presentation of obesity and metabolic syndrome. NAFLD includes a large spectrum of hepatic pathologies that range from simple steatosis and non-alcoholic steatohepatitis (NASH), to liver cirrhosis without an all-encompassing approved therapeutic strategy. Mitochondrial dysfunction is a key component of many metabolic diseases, such as obesity, type 2 diabetes, cancer, NAFLD, and aging. Sirtuin 3 (SIRT3) is a NAD(+) dependent deacetylase that regulates many of the mitochondrial proteins that are involved with metabolic homeostasis, oxidative stress, and cell survival. This review discusses the association between mitochondrial dysfunction and insulin resistance and later explore the possibility that SIRT3 plays a protective role against NAFLD by improving mitochondrial dysfunction. PMID- 26064859 TI - The Positive Effect of Physical Activity on Health and Health-related Quality of Life in Elderly Korean People-Evidence from the Fifth Korea National Health and Nutrition Examination Survey. AB - BACKGROUND: The proportion of elderly people in the population is growing, and Korea has one of the fastest growing populations among the world's major regions. The objective of this study was to examine the effects of physical activity on the health and quality of life of elderly Korean people. METHODS: A nationally representative sample of 2,853 elderly Korean people (1,239 males and 1,614 females) aged more than 65 years was evaluated to determine whether they met guidelines for vigorous PA (VPA), moderate PA (MPA), and low PA (LPA) and how those results were associated with self-rated health (SRH) and health-related quality of life (HRQoL). RESULTS: The adjusted odds ratio (AOR) of males and females who reported very good SRH significantly decreased with VPA (males: AOR = 0.42, females: AOR = 0.44), MPA (males: AOR = 0.46, females: AOR = 0.48), and LPA (males: AOR = 0.44, females: AOR = 0.32). Subjects who met the guidelines for VPA (males: AOR = 0.40, females: AOR = 0.43), MPA (males: AOR = 0.49, females: AOR = 0.45), and LPA (males: AOR = 0.33, females: AOR = 0.39) and reported no problems with their HRQoL showed significantly decreased AORs compared with subjects who reported HRQoL problems. CONCLUSION: Elderly Korean people were fairly inactive, but participation in vigorous, moderate, or low PA was positively associated with SRH and HRQoL. PMID- 26064860 TI - Examination of the Ability of N-acetylcysteine Administration during Anesthesia to Prevent Perioperative Deterioration of Pulmonary Function in Patients Undergoing Nephrectomy. AB - BACKGROUND: Postoperative pulmonary complications are associated with significant morbidity and mortality in patients undergoing major surgeries. Acetylcysteine is a known antioxidant and is also used as a mucolytic agent to reduce hypersecretion and the viscosity of mucus secretions by the lung. Several studies have revealed that high doses of N-acetylcysteine can significantly prevent pulmonary complications. However, it has not yet been established whether low doses of N-acetylcysteine are also of clinical benefit. Here, we investigated the efficacy of a low dose of N-acetylcysteine, which was administered intravenously to patients under general anesthesia, in preventing perioperative deterioration of pulmonary function. METHODS: A total of 52 patients who were scheduled for nephrectomy were randomly assigned to receive either 600 mg of intravenous N acetylcysteine or the same volume of normal saline. Patient hemodynamic and pulmonary parameters and the incidence of pulmonary complications were recorded and compared between the groups. RESULTS: No significant pulmonary complications occurred in either group. Moreover, no significant differences were observed regarding either patient characteristics or hemodynamic parameters between the two groups. Contrary to our expectations, the pulmonary parameters were also not significantly different between the two groups. CONCLUSION: A low dose of N acetylcysteine appears to have only limited value in preventing perioperative pulmonary complications. PMID- 26064861 TI - Intracranial Meningioma-induced Parkinsonism. AB - An intracranial tumor is a rare cause of secondary parkinsonism. Our patient presented to our clinic for recently-developed asymmetric parkinsonism without pyramidal signs. However, a meningioma located in the sphenoidal ridge was identified upon imaging studies. This case suggests that additional causes should be considered when approaching patients with parkinsonism and that imaging studies can provide useful information to make accurate diagnoses. PMID- 26064862 TI - Atlantoaxial Chordoma in Two Patients with Occipital Neuralgia and Cervicalgia. AB - Chordoma arises from cellular remnants of the notochord. It is the most common primary malignancy of the spine in adults. Approximately 50% of chordomas arise from the sacrococcygeal area with other areas of the spine giving rise to another 15% of chordomas. Following complete resection, patients can expect a 5-year survival rate of 85%. Chordoma has a recurrence rate of 40%, which leads to a less favorable prognosis. Here, we report two cases of chordoma presenting with occipital neuralgia and cervicalgia. The first patient presented with a C1-C2 chordoma. He rejected surgical intervention and ultimately died of respiratory failure. The second patient had an atlantoaxial chordoma and underwent surgery because of continued occipital neuralgia and cervicalgia despite nerve block. This patient has remained symptom-free since his operation. The presented cases show that the patients' willingness to participate in treatment can lead to appropriate and aggressive management of cancer pain, resulting in better outcomes in cancer treatment. PMID- 26064863 TI - Self-perception in Iranian adolescents with diabetes: a qualitative study. AB - BACKGROUND: It is obvious that self-perception can play an important role in the development of self-management behaviours among adolescents with diabetes to promote their health and quality of life. This study seeks to explain self perception in adolescents with diabetes. METHOD: This qualitative study, which is of "grounded theory" type, was performed in 2013 in Ahvaz, Iran, through semi structured interviews with ten adolescents with type 1 diabetes, two parents and a nurse, who were chosen objectively. Data analysis was performed using Strauss and Corbin 1998 method. RESULTS: Four main theme was obtained from the analysis of data, and the consequence theme was inferred as follows: getting insight (knowledge acquisition and belief management), perceiving similarities with others (not hiding the disease, showing the illness is normal, and accepting an active role in the family), and self-care management (independent control of food and treatment regimen and understanding of capabilities to manage the future of life and manage the daily activities of life), and life satisfaction (perception of being healthy and having a normal life). CONCLUSION: Getting insight into the disease is the most important part of perceiving similarities with others and offering self-care, which can provide a person's positive perception of himself/herself and the illness, as well as life satisfaction for their adolescent over time. These results are an operational guide for personnel providing health care services, especially diabetes specialist nurses. PMID- 26064864 TI - Liraglutide effect in reducing HbA1c and weight in Arab population with type2 diabetes, a prospective observational trial. AB - BACKGROUND: The pathophysiology of type2 diabetes differs between different ethnic groups. Asians develop type2 diabetes at younger age, lower body mass index, and in relatively short time. Not only that, some ethnicities have different responses and dosing regimens to different classes of anti-diabetic agents. Data from Japanese population showed that the optimal doses of liraglutide used are smaller than other population and that weight loss is not as effective as seen in Caucasians. METHODS: We aimed to assess liraglutide efficacy in reducing weight and HbA1c in Arab population when used as add on to other anti diabetic agents. We prospectively followed patients who were recruited to treatment with liraglutide for a 6 months period; at the start of the study we checked patients' demographics, weight, blood pressure, fasting blood glucose, HbA1c, lipid panel, LFTs and creatinine. Patients were checked at 3 months and at the end of the study at 6 months. RESULTS: There was a significant reduction in weight at 3 and 6 months from a mean weight of 96.01 +/- 19.2 kg to (94.8 +/- 20 kg with (P < 0.001)) and 94.5 +/- 19 kg with (p < 0.001) respectively. Mean HbA1c at baseline was 8.3 +/- 1.7 % dropped to 7.7 +/- 1.4 % (p < 0.001) at 3 months, and 7.6 + 1.6 % (p < 0.001) at 6 months. CONCLUSIONS: Liraglutide is effective in reducing weight, HbA1c as well as other metabolic parameters in Arab population with type2 diabetes. TRIAL REGISTRATION: The trial is approved and registered with the Institutional Ethical Committee Board (Dubai Health Authority Medical Research Committee) under registration Number (MRC-08/2013_03). PMID- 26064865 TI - The Relationship Between Serum Levels of Interleukins 6, 8, 10 and Clinical Outcome in Patients With Severe Traumatic Brain Injury. AB - BACKGROUND: Clinical outcome in patients with severe traumatic brain injury (TBI) depends on both primary and secondary brain injuries. Neuroinflammation is an important secondary mechanism, which occurs by releasing interleukins (ILs). Increased levels of ILs may affect clinical outcome following TBI. OBJECTIVES: This study aimed to determine the relationship between the serum levels of interleukins 6, 8 and 10 and clinical outcome in patients with severe TBI 6 months after injury. PATIENTS AND METHODS: In a descriptive-analytical study, 44 patients with GCS <= 8 (Glasgow coma scale) and age >= 14 years were included. Their blood samples were collected at first 6 hours after injury. Clinical outcome was determined based on GOS (Glasgow Outcome Scale) at 6 months after head injury. Serum levels of interleukins 6, 8 and 10 were measured using the ELISA method. Spearman's rho, independent T-Test, and Mann-Whitney Test were used for data analysis. RESULTS: Comparing the serum levels of interleukins in two groups with favorable and unfavorable clinical outcomes showed that the mean serum levels of interleukins 6 and 8 in group with favorable outcome was 85.2 +/- 51.6 and 52.2 +/- 31.9, respectively lower than those of group with unfavorable outcome with 162.3 +/- 141.1 and 173.6 +/- 257.3 (P < 0.03) and (P < 0.01). CONCLUSIONS: Increased serum levels of interleukins 6 and 8 as a predictive marker might be associated with unfavorable clinical outcome in patients with severe TBI. PMID- 26064866 TI - Anterior Tarsal Tunnel Syndrome With Thrombosed Dorsalis Pedis Artery: A Case Report. AB - INTRODUCTION: The aanterior tarsal tunnel syndrome denotes the entrapment of the deep peroneal nerve under the inferior extensor retinaculum. Although various etiological factors have been reported to cause anterior tarsal syndrome, its occurrence with thrombosed dorsalis pedis artery has not been reported in the English literature. CASE PRESENTATION: A 40 -year-old male patient was presented with the history of persistent pain along the dorsal surface of right foot, which was aggravated with the activities. Conservative management was tried without much relief. Diagnosis of anterior tarsal tunnel syndrome was made and the patient was planned for surgery. Thrombosed dorsalis pedis artery was found along with two adjacent collateral vessels. Retinaculum was released and nerve was mobilized. Tight compartment got released. Postoperative period was uneventful. No recurrence was seen on follow-up. CONCLUSION: The anterior tarsal tunnel syndrome is a known disease. A high index of clinical suspicion is required while dealing with the chronic cases. A detailed history to rule out any traumatic event is necessary too. Timely investigations and surgical release give dramatic relief. PMID- 26064867 TI - Seat Belt Usage in Injured Car Occupants: Injury Patterns, Severity and Outcome After Two Main Car Accident Mechanisms in Kashan, Iran, 2012. AB - BACKGROUND: Road traffic accidents (RTAs) are the main public health problems in Iran. The seat belts, which are vehicle safety devices, are imperative to reduce the risk of severe injuries and mortality. OBJECTIVES: The aim of the study was to evaluate injury patterns, severity and outcome among belted and unbelted car occupants who were injured in car accidents. PATIENTS AND METHODS: This cross sectional prospective study was performed on all car occupants injured in RTAs (n = 822) who were transported to hospital and hospitalized for more than 24 hours from March 2012 to March 2013. Demographic profile of the patients, including age, gender, position in the vehicle, the use of seat belts, type of car crashes, injured body regions, revised trauma score (RTS), Glasgow coma score (GCS), duration of hospital stay and mortality rate were analyzed by descriptive analysis, chi-square and independent t-test. P < 0.05 was considered significant. RESULTS: A total of 560 patients used seat belts (68.1%). The unbelted occupants were younger (28 years vs. 38 years) and had more frequently sustained head, abdomen and multiple injuries (P = 0.01, P = 0.01 and P = 0.009, respectively). Also, these patients had significantly lower GCS and elongated hospitalization and higher death rate (P = 0.001, P = 0.001 and P = 0.05, respectively). Tendency of severe head trauma and low RTS and death were increased in unbelted occupants in car rollover accident mechanisms (P = 0.001, P = 0.01 and P = 0.008, respectively). CONCLUSIONS: During car crashes, especially car rollover, unbelted occupants are more likely to sustain multiple severe injuries and death. Law enforcement of the seat belt usage for all occupants (front and rear seat) is obligatory to reduce severe injuries sustained as a result of car accidents, especially in vehicles with low safety. PMID- 26064868 TI - Incidence of Neonatal Birth Injuries and Related Factors in Kashan, Iran. AB - BACKGROUND: Birth injuries are defined as the impairment of neonatal body function due to adverse events that occur at birth and can be avoidable or inevitable. Despite exact prenatal care, birth trauma usually occurs, particularly in long and difficult labor or fetal malpresentations. OBJECTIVES: This study aimed to investigate the incidence of birth injuries and their related factors in Kashan, Iran, during 2012-2013. PATIENTS AND METHODS: In this cross sectional study, all live-born neonates in the hospitals of Kashan City were assessed prospectively by a checklist included demographic variables (maternal age, weight, and nationality), reproductive and labor variables (prenatal care, parity, gestational age, premature rupture of membrane (PROM), fetal heart rate (FHR) pattern, duration of PROM, induction of labor, fundal pressure, shoulder dystocia, fetal presentation, duration of second stage, type of delivery, and delivery attendance), and neonatal variables (sex, birth weight, height, head circumference, Apgar score, and neonatal trauma). Birth trauma was diagnosed based on pediatrician or resident examination and in some cases confirmed by paraclinic methods. Statistical analyses were performed by chi-square, student's t-test, and multiple logistic regression analyses using SPSS version 17. P <= 0.05 was considered statistically significant. RESULTS: In this study, the incidence of birth trauma was 2.2%. Incidence of trauma was 3.6% in vaginal deliveries and 1.2% in cesarean sections (P < 0.0001). The most common trauma was cephalohematoma (57.2%) and then asphyxia (16.8%). In multiple logistic regression analyses, decreased fetal heart rate (FHR), fundal pressure, shoulder dystocia, vaginal delivery, male sex, neonatal weight, delivery by resident, induction of labor, and delivery in a teaching hospital were predictors of birth trauma. CONCLUSIONS: Overall, incidence of birth trauma in Kashan City was lower in comparison with most studies. Considering existing risk factors, further monitoring on labor, and delivery management in teaching hospitals are recommended to prevent birth injuries. In addition, careful supervision on students and residents' training should be applied in teaching hospitals. PMID- 26064870 TI - The Transforming Face of Fracture Epidemiology: Our Concern. PMID- 26064869 TI - Fall-Related Injuries in Community-Dwelling Older Adults in Qom Province, Iran, 2010-2012. AB - BACKGROUND: Falls and related injuries are common health problems in the elderly. Fractures, brain and internal organ injuries and death are the common consequences of the falls, which result in dependence, decreased self-efficacy, fear of falling, depression, restricted daily activities, hospitalization and admission to the nursing home and impose costs on the individual and the society. OBJECTIVES: The purpose of this study was to determine the types of fall-related injuries and the related risk factors in the elderly population of Qom province, Iran. PATIENTS AND METHODS: This retrospective study was performed on 424 elderly people (65 years and over) referred to Shahid Beheshti Hospital, Qom, Iran, due to falls between 2010 and 2012. The ICD-10 codes of external causes of injury from w00 to w19 related to falls were selected from the health information system of the hospital and demographic variables of the patients and external causes of falls were extracted after accessing the files of the patients. Data were analyzed using SPSS version 18 (SPSS Inc., USA). The duration of hospital stay and its relationship with underlying variables were investigated using t test and ANOVA. The level of significance was considered P < 0.05. RESULTS: Among 424 elderly people, 180 cases (42.45%) were male and the mean age of the patients was 78.65 +/- 7.70 years. Fall on the same level from slipping, tripping, and stumbling was the most common external cause with 291 victims (68.60%), and hip fracture in 121 patients (29.00%), intertrochanteric fracture in 112 patients (26.90%), and traumatic brain injury in 51 patients (12.20%) were the most common causes of hospital stay. The mean hospital stay was 7.33 +/- 3.63 days. CONCLUSIONS: Lower limb fracture and traumatic brain injury were the most common causes of hospitalization, which resulted in the longest hospital stay and highest hospitalization costs in the elderly. PMID- 26064871 TI - Some Aspects of Nonbeverage Alcohol Consumption in the Former Soviet Union. AB - Toxicity of some legally sold alcoholic beverages has contributed to enhanced mortality in Russia since 1990. Widespread drunkenness during the early 1990s facilitated privatization of economy: workers and some intelligentsia did not oppose privatizations because of drunkenness and involvement in illegal activities. Apparently, alcohol consumption and heavy binge drinking have been decreasing in Russia since approximately the last decade. Exaggeration of alcohol related problems tends to veil shortages of the health care system. There are motives to exaggerate consumption of nonbeverage alcohol in order to veil the problem of toxicity of some legally sold beverages. It is essential to distinguish between legally and illegally sold rather than between recorded and unrecorded alcohol because sales of poor-quality alcoholic beverages in legally operating shops and kiosks occurred generally with knowledge of authorities. PMID- 26064872 TI - Heat Shock Protein 70 and 90 Genes in the Harmful Dinoflagellate Cochlodinium polykrikoides: Genomic Structures and Transcriptional Responses to Environmental Stresses. AB - The marine dinoflagellate Cochlodinium polykrikoides is responsible for harmful algal blooms in aquatic environments and has spread into the world's oceans. As a microeukaryote, it seems to have distinct genomic characteristics, like gene structure and regulation. In the present study, we characterized heat shock protein (HSP) 70/90 of C. polykrikoides and evaluated their transcriptional responses to environmental stresses. Both HSPs contained the conserved motif patterns, showing the highest homology with those of other dinoflagellates. Genomic analysis showed that the CpHSP70 had no intron but was encoded by tandem arrangement manner with separation of intergenic spacers. However, CpHSP90 had one intron in the coding genomic regions, and no intergenic region was found. Phylogenetic analyses of separate HSPs showed that CpHSP70 was closely related with the dinoflagellate Crypthecodinium cohnii and CpHSP90 with other Gymnodiniales in dinoflagellates. Gene expression analyses showed that both HSP genes were upregulated by the treatments of separate algicides CuSO4 and NaOCl; however, they displayed downregulation pattern with PCB treatment. The transcription of CpHSP90 and CpHSP70 showed similar expression patterns under the same toxicant treatment, suggesting that both genes might have cooperative functions for the toxicant induced gene regulation in the dinoflagellate. PMID- 26064873 TI - Impact of Population Stratification on Family-Based Association in an Admixed Population. AB - Population substructure is a well-known confounder in population-based case control genetic studies, but its impact in family-based studies is unclear. We performed population substructure analysis using extended families of admixed population to evaluate power and Type I error in an association study framework. Our analysis shows that power was improved by 1.5% after principal components adjustment. Type I error was also reduced by 2.2% after adjusting for family substratification. The presence of population substructure was underscored by discriminant analysis, in which over 92% of individuals were correctly assigned to their actual family using only 100 principal components. This study demonstrates the importance of adjusting for population substructure in family based studies of admixed populations. PMID- 26064874 TI - Quantification of osseointegration of plasma-polymer coated titanium alloyed implants by means of microcomputed tomography versus histomorphometry. AB - A common method to derive both qualitative and quantitative data to evaluate osseointegration of implants is histomorphometry. The present study describes a new image reconstruction algorithm comparing the results of bone-to-implant contact (BIC) evaluated by means of uCT with histomorphometry data. Custom-made conical titanium alloyed (Ti6Al4V) implants were inserted in the distal tibial bone of female Sprague-Dawley rats. Different surface configurations were examined: Ti6Al4V implants with plasma-polymerized allylamine (PPAAm) coating and plasma-polymerized ethylenediamine (PPEDA) coating as well as implants without surface coating. After six weeks postoperatively, tibiae were explanted and BIC was determined by uCT (3D) and afterwards by histomorphometry (2D). In comparison to uncoated Ti6Al4V implants demonstrating low BIC of 32.4% (histomorphometry) and 51.3% (uCT), PPAAm and PPEDA coated implants showed a nonsignificant increase in BIC (histomorphometry: 45.7% and 53.5% and uCT: 51.8% and 62.0%, resp.). Mean BIC calculated by uCT was higher for all surface configurations compared to BIC detected by histomorphometry. Overall, a high correlation coefficient of 0.70 (p < 0.002) was found between 3D and 2D quantification of BIC. The MUCT analysis seems to be suitable as a nondestructive and accurate 3D imaging method for the evaluation of the bone-implant interface. PMID- 26064875 TI - Effects of high volume haemodiafiltration on inflammatory response profile and microcirculation in patients with septic shock. AB - BACKGROUND: High volumes of haemofiltration are used in septic patients to control systemic inflammation and improve patient outcomes. We aimed to clarify if extended intermittent high volume online haemodiafiltration (HVHDF) influences patient haemodynamics and cytokines profile and/or has effect upon sublingual microcirculation in critically ill septic shock patients. METHODS: Main haemodynamic and clinical variables and concentrations of cytokines were evaluated before and after HVHDF in 19 patients with septic shock requiring renal replacement therapy due to acute kidney injury. Sublingual microcirculation was assessed in 9 patients. RESULTS: The mean (SD) time of HVHDF was 9.4 (1.8) hours. The median convective volume was 123 mL/kg/h. The mean (SD) dose of norepinephrine required to maintain mean arterial pressure at the target range of 70-80 mmHg decreased from 0.40 (0.43) MUg/kg/min to 0.28 (0.33) MUg/kg/min (p = 0.009). No significant changes in the measured cytokines or microcirculatory parameters were observed before and after HVHDF. CONCLUSIONS: The single-centre study suggests that extended HVHDF results in decrease of norepinephrine requirement in patients with septic shock. Haemodynamic improvement was not associated with decrease in circulating cytokine levels, and sublingual microcirculation was well preserved. PMID- 26064876 TI - Biochemical and Functional Comparisons of mdx and Sgcg(-/-) Muscular Dystrophy Mouse Models. AB - Mouse models have provided an essential platform to investigate facets of human diseases, from etiology, diagnosis, and prognosis, to potential treatments. Muscular dystrophy (MD) is the most common human genetic disease occurring in approximately 1 in 2500 births. The mdx mouse, which is dystrophin-deficient, has long been used to model this disease. However, this mouse strain displays a rather mild disease course compared to human patients. The mdx mice have been bred to additional genetically engineered mice to worsen the disease. Alternatively, other genes which cause human MD have been genetically disrupted in mice. We are now comparing disease progression from one of these alternative gene disruptions, the gamma-sarcoglycan null mouse Sgcg(-/-) on the DBA2/J background, to the mdx mouse line. This paper aims to assess the time-course severity of the disease in the mouse models and determine which is best for MD research. The Sgcg(-/-) mice have a more severe phenotype than the mdx mice. Muscle function was assessed by plethysmography and echocardiography. Histologically the Sgcg(-/-) mice displayed increased fibrosis and variable fiber size. By quantitative Evan's blue dye uptake and hydroxyproline content two key disease determinants, membrane permeability and fibrosis respectively, were also proven worse in the Sgcg(-/-) mice. PMID- 26064877 TI - Magnolia officinalis Extract Contains Potent Inhibitors against PTP1B and Attenuates Hyperglycemia in db/db Mice. AB - Protein tyrosine phosphatase 1B (PTP1B) is an established therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. The aim of this study was to investigate the inhibitory activity of Magnolia officinalis extract (ME) on PTP1B and its anti-T2DM effects. Inhibition assays and inhibition kinetics of ME were performed in vitro. 3T3-L1 adipocytes and C2C12 myotubes were stimulated with ME to explore its bioavailability in cell level. The in vivo studies were performed on db/db mice to probe its anti-T2DM effects. In the present study, ME inhibited PTP1B in a reversible competitive manner and displayed good selectivity against PTPs in vitro. Furthermore, ME enhanced tyrosine phosphorylation levels of cellular proteins, especially the insulin-induced tyrosine phosphorylations of insulin receptor beta-subunit (IRbeta) and ERK1/2 in a dose-dependent manner in stimulated 3T3-L1 adipocytes and C2C12 myotubes. Meanwhile, ME enhanced insulin stimulated GLUT4 translocation. More importantly, there was a significant decrease in fasting plasma glucose level of db/db diabetic mice treated orally with 0.5 g/kg ME for 4 weeks. These findings indicated that improvement of insulin sensitivity and hypoglycemic effects of ME may be attributed to the inhibition of PTP1B. Thereby, we pioneered the inhibitory potential of ME targeted on PTP1B as anti-T2DM drug discovery. PMID- 26064878 TI - Population Structure and Oxacillin Resistance of Staphylococcus aureus from Pigs and Pork Meat in South-West of Poland. AB - The genotypes and oxacillin resistance of 420 S. aureus isolates from pigs (n = 203) and pork (n = 217) were analyzed. Among 18 spa types detected in S. aureus from pig t011, t021, t034, t091, t318, t337, and t1334 were the most frequent. Among 30 spa types found in S. aureus isolates from pork t084, t091, t499, t4309, t12954, and t13074 were dominant. The animal S. aureus isolates were clustered into MLST clonal complexes CC7, CC9, CC15, CC30, and CC398 and meat-derived isolates to CC1, CC7, and CC15. Thirty-six MRSA were isolated exclusively from pigs. All MRSA were classified to spa t011 SCCmecV. BORSA phenotype was found in 14% S. aureus isolates from pigs and 10% isolates from pork meat. spa t034 dominated among BORSA from pigs and t091 among meat-derived BORSA. This is the first report on spa types and oxacillin resistance of S. aureus strains from pigs and pork meat in Poland. Besides S. aureus CC9, CC30, and CC398 known to be distributed in pigs, the occurrence of genotype belonging to CC7 in this species has been reported for the first time. To our knowledge it is also the first report concerning CC398 BORSA isolates from pigs and pork meat. PMID- 26064879 TI - The Impact of Endometriosis across the Lifespan of Women: Foreseeable Research and Therapeutic Prospects. AB - In addition to estrogen dependence, endometriosis is characterized by chronic pelvic inflammation. The impact of the chronic pelvic inflammatory state on other organ systems and women's health is unclear. Endometriosis associated chronic inflammation and potential adverse health effects across the lifespan render it imperative for renewed research vigor into the identification of novel biomarkers of disease and therapeutic options. Herein we propose a number of opportunities for research and development of new therapeutics to address the unmet needs in the treatment of endometriosis per se and its ancillary risks for other diseases in women across the lifespan. PMID- 26064880 TI - Morphine Promotes Tumor Angiogenesis and Increases Breast Cancer Progression. AB - Morphine is considered a highly potent analgesic agent used to relieve suffering of patients with cancer. Several in vitro and in vivo studies showed that morphine also modulates angiogenesis and regulates tumour cell growth. Unfortunately, the results obtained by these studies are still contradictory. In order to better dissect the role of morphine in cancer cell growth and angiogenesis we performed in vitro studies on ER-negative human breast carcinoma cells, MDA.MB231 and in vivo studies on heterotopic mouse model of human triple negative breast cancer, TNBC. We demonstrated that morphine in vitro enhanced the proliferation and inhibited the apoptosis of MDA.MB231 cells. In vivo studies performed on xenograft mouse model of TNBC revealed that tumours of mice treated with morphine were larger than those observed in other groups. Moreover, morphine was able to enhance the neoangiogenesis. Our data showed that morphine at clinical relevant doses promotes angiogenesis and increases breast cancer progression. PMID- 26064881 TI - Diagnostic Significance of Diffusion-Weighted MRI in Renal Cancer. AB - BACKGROUND: This study aimed to investigate whether diffusion-weighted imaging (DWI) could contribute to the discrimination between benign and malignant renal cancer. METHODS: We searched the PubMed electronic database for eligible studies. STATA 12.0 software was used for statistical analysis. The SMD and 95% CI were calculated. RESULTS: Decreased ADC signal was seen in all renal cancer patients (cancer tissue versus normal tissue: SMD = 1.63 and 95% CI = 0.96~2.29, P < 0.001; cancer tissue versus benign tissue: SMD = 2.22 and 95% CI = 1.53~2.90 and P < 0.001, resp.). MRI machine type-stratified analysis showed that decreased ADC signal was found by all included MRI machine types in cancer tissues compared with benign cancer tissues (all P < 0.05). The ADC values of renal cancer patients were significantly lower than those of normal controls for all included P values (all P < 0.05), and there was a decreased ADC signal at b-500, b-600, b 1000, b-500, and 1000 gradients compared with benign cancer tissues (all P < 0.05). CONCLUSION: Our study concluded that decreased ADC signal presented in DWI may be essential for the differential diagnosis of renal cancer. PMID- 26064882 TI - Development of a Model of Chronic Kidney Disease in the C57BL/6 Mouse with Properties of Progressive Human CKD. AB - Chronic kidney disease (CKD) is a major healthcare problem with increasing prevalence in the population. CKD leads to end stage renal disease and increases the risk of cardiovascular disease. As such, it is important to study the mechanisms underlying CKD progression. To this end, an animal model was developed to allow the testing of new treatment strategies or molecular targets for CKD prevention. Many underlying risk factors result in CKD but the disease itself has common features, including renal interstitial fibrosis, tubular epithelial cell loss through apoptosis, glomerular damage, and renal inflammation. Further, CKD shows differences in prevalence between the genders with premenopausal women being relatively resistant to CKD. We sought to develop and characterize an animal model with these common features of human CKD in the C57BL/6 mouse. Mice of this genetic background have been used to produce transgenic strains that are commercially available. Thus, a CKD model in this strain would allow the testing of the effects of numerous genes on the severity or progression of CKD with minimal cost. This paper describes such a mouse model of CKD utilizing angiotensin II and deoxycorticosterone acetate as inducers. PMID- 26064883 TI - Evaluation of Aqueous Leaf Extract of Cardiospermum halicacabum (L.) on Fertility of Male Rats. AB - Treatment with 100 mg/kg and 200 mg/kg body weight of aqueous leaf extract (ALE) of Cardiospermum halicacabum for 30 days produced a significant dose dependent increase in the sperm counts and sperm motility in both caput and cauda regions. Further, significant increase in serum testosterone level was evident at all applied doses. However, no significant changes in the weight of sex organs were observed. Aqueous leaf extract also increased the number of females impregnated, number of implantations, and number of viable fetuses while decreasing the total number of resorption sites in the pregnant females. However, the total cholesterol level in the serum remained unchanged and there were no records on renotoxicity; nevertheless ALE exhibited a hepatoprotective effect. It was concluded that aqueous leaf extract of Cardiospermum halicacabum enhanced sperm concentration, motility, and testosterone, leading to positive results in fertility. PMID- 26064884 TI - Identification, Characterization, and Developmental Expression Pattern of Type III Interferon Receptor Gene in the Chinese Goose. AB - Interferons, as the first line of defense against the viral infection, play an important role in innate immune responses. Type III interferon (IFN-lambda) was a newly identified member of IFN family, which plays IFN-like antiviral activity. Towards a better understanding of the type III interferon system in birds, type III interferon lambda receptor (IFNLR1) was first identified in the Chinese goose. In this paper, we had cloned 1952 bp for goose IFNLR1 (goIFNLR1), including an ORF of 1539 bp, encoding a 512-amino acid protein with a 20 aa predict signal peptide at its N terminal and a 23 aa transmembrane region. The predicted amino acid sequence of goIFNLR1 has 90%, 73%, and 34% identity with duck IFNLR1 (predicted sequence), chicken IFNLR1, and human IFNLR1, respectively. And the age-related tissue distribution of goIFNLR1 was identified by Real Time quantitative PCR (RT-qPCR), we found that the goIFNLR1 has a mainly expression in epithelium-rich tissues similar to other species', such as small intestinal, lung, liver, and stomach. Moreover, a relatively high expression of goIFNLR1 was also observed in the secondary immune tissues (harderian gland and cecal tonsil). The identification and tissue distribution of goIFNLR1 will facilitate further study of the role of IFN-lambda in goose antiviral defense. PMID- 26064885 TI - Intratracheal Bleomycin Aerosolization: The Best Route of Administration for a Scalable and Homogeneous Pulmonary Fibrosis Rat Model? AB - Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a poor prognosis and is characterized by the accumulation of fibrotic tissue in lungs resulting from a dysfunction in the healing process. In humans, the pathological process is patchy and temporally heterogeneous and the exact mechanisms remain poorly understood. Different animal models were thus developed. Among these, intratracheal administration of bleomycin (BML) is one of the most frequently used methods to induce lung fibrosis in rodents. In the present study, we first characterized histologically the time-course of lung alteration in rats submitted to BLM instillation. Heterogeneous damages were observed among lungs, consisting in an inflammatory phase at early time-points. It was followed by a transition to a fibrotic state characterized by an increased myofibroblast number and collagen accumulation. We then compared instillation and aerosolization routes of BLM administration. The fibrotic process was studied in each pulmonary lobe using a modified Ashcroft scale. The two quantification methods were confronted and the interobserver variability evaluated. Both methods induced fibrosis development as demonstrated by a similar progression of the highest modified Ashcroft score. However, we highlighted that aerosolization allows a more homogeneous distribution of lesions among lungs, with a persistence of higher grade damages upon time. PMID- 26064886 TI - Effects of Arsenite Resistance on the Growth and Functional Gene Expression of Leptospirillum ferriphilum and Acidithiobacillus thiooxidans in Pure Culture and Coculture. AB - The response of iron-oxidizing Leptospirillum ferriphilum YSK and sulfur oxidizing Acidithiobacillus thiooxidans A01 to arsenite under pure culture and coculture was investigated based on biochemical characterization (concentration of iron ion and pH value) and related gene expression. L. ferriphilum YSK and At. thiooxidans A01 in pure culture could adapt up to 400 mM and 800 mM As(III) after domestication, respectively, although arsenite showed a negative effect on both strains. The coculture showed a stronger sulfur and ferrous ion oxidation activity when exposed to arsenite. In coculture, the pH value showed no significant difference when under 500 mM arsenite stress, and the cell number of At. thiooxidans was higher than that in pure culture benefiting from the interaction with L. ferriphilum. The expression profile showed that the arsenic efflux system in the coculture was more active than that in pure culture, indicating that there is a synergetic interaction between At. thiooxidans A01 and L. ferriphilum YSK. In addition, a model was proposed to illustrate the interaction between arsenite and the ars operon in L. ferriphilum YSK and At. thiooxidans A01. This study will facilitate the effective application of coculture in the bioleaching process by taking advantage of strain-strain communication and coordination. PMID- 26064887 TI - A Heparan Sulfate-Binding Cell Penetrating Peptide for Tumor Targeting and Migration Inhibition. AB - As heparan sulfate proteoglycans (HSPGs) are known as co-receptors to interact with numerous growth factors and then modulate downstream biological activities, overexpression of HS/HSPG on cell surface acts as an increasingly reliable prognostic factor in tumor progression. Cell penetrating peptides (CPPs) are short-chain peptides developed as functionalized vectors for delivery approaches of impermeable agents. On cell surface negatively charged HS provides the initial attachment of basic CPPs by electrostatic interaction, leading to multiple cellular effects. Here a functional peptide (CPPecp) has been identified from critical HS binding region in hRNase3, a unique RNase family member with in vitro antitumor activity. In this study we analyze a set of HS-binding CPPs derived from natural proteins including CPPecp. In addition to cellular binding and internalization, CPPecp demonstrated multiple functions including strong binding activity to tumor cell surface with higher HS expression, significant inhibitory effects on cancer cell migration, and suppression of angiogenesis in vitro and in vivo. Moreover, different from conventional highly basic CPPs, CPPecp facilitated magnetic nanoparticle to selectively target tumor site in vivo. Therefore, CPPecp could engage its capacity to be developed as biomaterials for diagnostic imaging agent, therapeutic supplement, or functionalized vector for drug delivery. PMID- 26064888 TI - Pim-2/mTORC1 Pathway Shapes Inflammatory Capacity in Rheumatoid Arthritis Synovial Cells Exposed to Lipid Peroxidations. AB - Rheumatoid arthritis is a systemic autoimmune disease characterized by chronic inflammation of multiple joints, with disruption of joint cartilage. The proliferation of synovial fibroblasts in response to multiple inflammation factors is central to the pathogenesis of rheumatoid arthritis. Our previous studies showed that 4-HNE may induce synovial intrinsic inflammations by activating NF-kappaB pathways and lead to cell apoptosis. However, the molecular mechanisms of how synovial NF-kappaB activation is modulated are not fully understood. Here, the present findings demonstrated that 4-HNE may induce synovial intrinsic inflammations by mTORC1 inactivation. While ectopic activation of mTORC1 pathway by the overexpression of Pim-2 may disrupt the initiation of inflammatory reactions and maintain synovial homeostasis, our findings will help to uncover novel signaling pathways between inflammations and oxidative stress in rheumatoid arthritis development and imply that Pim-2/mTORC1 pathway may be critical for the initiation of inflammatory reactions in human rheumatoid arthritis synovial cells. PMID- 26064889 TI - SERCA2 Haploinsufficiency in a Mouse Model of Darier Disease Causes a Selective Predisposition to Heart Failure. AB - Null mutations in one copy of ATP2A2, the gene encoding sarco/endoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2), cause Darier disease in humans, a skin condition involving keratinocytes. Cardiac function appears to be unimpaired in Darier disease patients, with no evidence that SERCA2 haploinsufficiency itself causes heart disease. However, SERCA2 deficiency is widely considered a contributing factor in heart failure. We therefore analyzed Atp2a2 heterozygous mice to determine whether SERCA2 haploinsufficiency can exacerbate specific heart disease conditions. Despite reduced SERCA2a levels in heart, Atp2a2 heterozygous mice resembled humans in exhibiting normal cardiac physiology. When subjected to hypothyroidism or crossed with a transgenic model of reduced myofibrillar Ca(2+) sensitivity, SERCA2 deficiency caused no enhancement of the disease state. However, when combined with a transgenic model of increased myofibrillar Ca(2+) sensitivity, SERCA2 haploinsufficiency caused rapid onset of hypertrophy, decompensation, and death. These effects were associated with reduced expression of the antiapoptotic Hax1, increased levels of the proapoptotic genes Chop and Casp12, and evidence of perturbations in energy metabolism. These data reveal myofibrillar Ca(2+)-sensitivity to be an important determinant of the cardiac effects of SERCA2 haploinsufficiency and raise the possibility that Darier disease patients are more susceptible to heart failure under certain conditions. PMID- 26064890 TI - Candida Bloodstream Infections in Italy: Changing Epidemiology during 16 Years of Surveillance. AB - Although considerable progress has been made in the management of patients with invasive fungal infections, Candida bloodstream infections are still widespread in hospital settings. Incidence rates vary geographically, often because of different patient populations. The aim of the present study was to describe the epidemiology of candidemia, to analyze the trend of species distribution, and to measure the in vitro susceptibility to antifungal drugs in a university Italian hospital from 1998 to 2013. The antifungal susceptibility for all Candida isolates was evaluated by broth microdilution assay (CLSI M27-A3 document). Of 394 episodes of candidemia, the average incidence was 3.06/10,000 admissions. C. albicans and non-albicans Candida species caused 44.2% and 55.8% of the episodes, respectively. C. parapsilosis (62.2%) was the most common non-albicans. C. albicans predominated in almost all departments whereas C. parapsilosis was found in adult and paediatric oncohaematology units (34.8% and 77.6%, resp.). Overall, mortality occurred in 111 (28.2%) patients. Death occurred most often in intensive care units (47.1%) and specialist surgeries (43.7%). Most of the isolates were susceptible to antifungal drugs, but there was an upward trend for azole (P < 0.05). In conclusion, this study emphasizes the importance of monitoring local epidemiologic data and the diversity of patient groups affected. PMID- 26064891 TI - Experimentally Induced Mammalian Models of Glaucoma. AB - A wide variety of animal models have been used to study glaucoma. Although these models provide valuable information about the disease, there is still no ideal model for studying glaucoma due to its complex pathogenesis. Animal models for glaucoma are pivotal for clarifying glaucoma etiology and for developing novel therapeutic strategies to halt disease progression. In this review paper, we summarize some of the major findings obtained in various glaucoma models and examine the strengths and limitations of these models. PMID- 26064892 TI - Antimicrobial Resistance Profile and Genotypic Characteristics of Streptococcus suis Capsular Type 2 Isolated from Clinical Carrier Sows and Diseased Pigs in China. AB - Streptococcus suis serotype 2 is an important zoonotic pathogen. Antimicrobial resistance phenotypes and genotypic characterizations of S. suis 2 from carrier sows and diseased pigs remain largely unknown. In this study, 96 swine S. suis type 2, 62 from healthy sows and 34 from diseased pigs, were analyzed. High frequency of tetracycline resistance was observed, followed by sulfonamides. The lowest resistance of S. suis 2 for beta-lactams supports their use as the primary antibiotics to treat the infection of serotype 2. In contrast, 35 of 37 S. suis 2 with MLSB phenotypes were isolated from healthy sows, mostly encoded by the ermB and/or the mefA genes. Significantly lower frequency of mrp+/epf+/sly+ was observed among serotype 2 from healthy sows compared to those from diseased pigs. Furthermore, isolates from diseased pigs showed more homogeneously genetic patterns, with most of them clustered in pulsotypes A and E. The data indicate the genetic complexity of S. suis 2 between herds and a close linkage among isolates from healthy sows and diseased pigs. Moreover, many factors, such as extensive use of tetracycline or diffusion of Tn916 with tetM, might have favored for the pathogenicity and widespread dissemination of S. suis serotype 2. PMID- 26064893 TI - Cardioprotective Effects of Tualang Honey: Amelioration of Cholesterol and Cardiac Enzymes Levels. AB - The present study was designed to investigate the cardioprotective effects of Malaysian Tualang honey against isoproterenol- (ISO-) induced myocardial infarction (MI) in rats by investigating changes in the levels of cardiac marker enzymes, cardiac troponin I (cTnI), triglycerides (TG), total cholesterol (TC), lipid peroxidation (LPO) products, and antioxidant defense system combined with histopathological examination. Male albino Wistar rats (n = 40) were pretreated orally with Tualang honey (3 g/kg/day) for 45 days. Subcutaneous injection of ISO (85 mg/kg in saline) for two consecutive days caused a significant increase in serum cardiac marker enzymes (creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate transaminase (AST)), cTnI, serum TC, and TG levels. In addition, ISO-induced myocardial injury was confirmed by a significant increase in heart lipid peroxidation (LPO) products (TBARS) and a significant decrease in antioxidant enzymes (SOD, GPx, GRx, and GST). Pretreatment of ischemic rats with Tualang honey conferred significant protective effects on all of the investigated biochemical parameters. The biochemical findings were further confirmed by histopathological examination in both Tualang-honey-pretreated and ISO-treated hearts. The present study demonstrates that Tualang honey confers cardioprotective effects on ISO-induced oxidative stress by contributing to endogenous antioxidant enzyme activity via inhibition of lipid peroxidation. PMID- 26064894 TI - Methylglyoxal Induced Basophilic Spindle Cells with Podoplanin at the Surface of Peritoneum in Rat Peritoneal Dialysis Model. AB - Peritoneal dialysis (PD) is a common treatment for patients with reduced or absent renal function. Long-term PD leads to peritoneal injury with structural changes and functional decline. At worst, peritoneal injury leads to encapsulating peritoneal sclerosis (EPS), which is a serious complication of PD. In order to carry out PD safely, it is important to define the mechanism of progression of peritoneal injury and EPS. We prepared rat models of peritoneal injury by intraperitoneal administration of glucose degradation products, such as methylglyoxal (MGO) or formaldehyde (FA), chlorhexidine gluconate (CG), and talc. In rats treated with MGO, peritoneal fibrous thickening with the appearance of basophilic spindle cells with podoplanin, cytokeratin, and alpha-smooth muscle actin at the surface of the peritoneum was observed. These cells may have been derived from mesothelial cells by epithelial-to-mesenchymal transition. In FA- or CG-treated rats, the peritoneum was thickened, and mesothelial cells were absent at the surface of the peritoneum. The CG- or MGO-treated rats presented with a so called abdominal cocoon. In the talc-treated rats, extensive peritoneal adhesion and peritoneal thickening were observed. MGO-induced peritoneal injury model may reflect human histopathology and be suitable to analyze the mechanism of progression of peritoneal injury and EPS. PMID- 26064895 TI - Mineral and Skeletal Homeostasis Influence the Manner of Bone Loss in Metabolic Osteoporosis due to Calcium-Deprived Diet in Different Sites of Rat Vertebra and Femur. AB - Rats fed calcium-deprived diet develop osteoporosis due to enhanced bone resorption, secondary to parathyroid overactivity resulting from nutritional hypocalcemia. Therefore, rats provide a good experimental animal model for studying bone modelling alterations during biochemical osteoporosis. Three-month old Sprague-Dawley male rats were divided into 4 groups: (1) baseline, (2) normal diet for 4 weeks, (3) calcium-deprived diet for 4 weeks, and (4) calcium-deprived diet for 4 weeks and concomitant administration of PTH (1-34) 40 ug/Kg/day. Histomorphometrical analyses were made on cortical and trabecular bone of lumbar vertebral body as well as of mid-diaphysis and distal metaphysis of femur. In all rats fed calcium-deprived diet, despite the reduction of trabecular number (due to the maintenance of mineral homeostasis), an intense activity of bone deposition occurs on the surface of the few remaining trabeculae (in answering to mechanical stresses and, consequently, to maintain the skeletal homeostasis). Different responses were detected in different sites of cortical bone, depending on their main function in answering mineral or skeletal homeostasis. This study represents the starting point for work-in-progress researches, with the aim of defining in detail timing and manners of evolution and recovery of biochemical osteoporosis. PMID- 26064896 TI - Characterization of Multidrug Resistant Extended-Spectrum Beta-Lactamase Producing Escherichia coli among Uropathogens of Pediatrics in North of Iran. AB - Escherichia coli remains as one of the most important bacteria causing infections in pediatrics and producing extended-spectrum beta-lactamases (ESBLs) making them resistant to beta-lactam antibiotics. In this study we aimed to genotype ESBL producing E. coli isolates from pediatric patients for ESBL genes and determine their association with antimicrobial resistance. One hundred of the E. coli isolates were initially considered ESBL producing based on their MIC results. These isolates were then tested by polymerase chain reaction (PCR) for the presence or absence of CTX, TEM, SHV, GES, and VEB beta-lactamase genes. About 30.5% of isolated E. coli was ESBL-producing strain. The TEM gene was the most prevalent (49%) followed by SHV (44%), CTX (28%), VEB (8%), and GES (0%) genes. The ESBL-producing E. coli isolates were susceptible to carbapenems (66%) and amikacin (58%) and showed high resistance to cefixime (99%), colistin (82%), and ciprofloxacin (76%). In conclusion, carbapenems were the most effective antibiotics against ESBl-producing E. coli in urinary tract infection in North of Iran. The most prevalent gene is the TEM-type, but the other resistant genes and their antimicrobial resistance are on the rise. PMID- 26064897 TI - Prohibitin: A Novel Molecular Player in KDEL Receptor Signalling. AB - The KDEL receptor (KDELR) is a seven-transmembrane-domain protein involved in retrograde transport of protein chaperones from the Golgi complex to the endoplasmic reticulum. Our recent findings have shown that the Golgi-localised KDELR acts as a functional G-protein-coupled receptor by binding to and activating Gs and Gq. These G proteins induce activation of PKA and Src and regulate retrograde and anterograde Golgi trafficking. Here we used an integrated coimmunoprecipitation and mass spectrometry approach to identify prohibitin-1 (PHB) as a KDELR interactor. PHB is a multifunctional protein that is involved in signal transduction, cell-cycle control, and stabilisation of mitochondrial proteins. We provide evidence that depletion of PHB induces intense membrane trafficking activity at the ER-Golgi interface, as revealed by formation of GM130 positive Golgi tubules, and recruitment of p115, beta-COP, and GBF1 to the Golgi complex. There is also massive recruitment of SEC31 to endoplasmic-reticulum exit sites. Furthermore, absence of PHB decreases the levels of the Golgi-localised KDELR, thus preventing KDELR-dependent activation of Golgi-Src and inhibiting Golgi-to-plasma-membrane transport of VSVG. We propose a model whereby in analogy to previous findings (e.g., the RAS-RAF signalling pathway), PHB can act as a signalling scaffold protein to assist in KDELR-dependent Src activation. PMID- 26064898 TI - Supplemental Interscalene Blockade to General Anesthesia for Shoulder Arthroscopy: Effects on Fast Track Capability, Analgesic Quality, and Lung Function. AB - BACKGROUND: After shoulder surgery performed in patients with interscalene nerve block (without general anesthesia), fast track capability and postoperative pain management in the PACU are improved compared with general anesthesia alone. However, it is not known if these evidence-based benefits still exist when the interscalene block is combined with general anesthesia. METHODS: We retrospectively analyzed a prospective cohort data set of 159 patients undergoing shoulder arthroscopy with general anesthesia alone (n = 60) or combined with an interscalene nerve block catheter (n = 99) for fast track capability time. Moreover, comparisons were made for VAS scores, analgesic consumption in the PACU, pain management, and lung function measurements. RESULTS: The groups did not differ in mean time to fast track capability (22 versus 22 min). Opioid consumption in PACU was significantly less in the interscalene group, who had significantly better VAS scores during PACU stay. Patients receiving interscalene blockade had a significantly impaired lung function postoperatively, although this did not affect postoperative recovery and had no impact on PACU times. CONCLUSION: The addition of interscalene block to general anesthesia for shoulder arthroscopy did not enhance fast track capability. Pain management and VAS scores were improved in the interscalene nerve block group. PMID- 26064900 TI - Neem (Azadirachta indica A. Juss) Oil to Tackle Enteropathogenic Escherichia coli. AB - Neem (Azadirachta indica A. Juss) oil (NO) was assayed against forty-eight isolates of Escherichia coli by standardised disc diffusion test and microdilution test. By molecular biology characterization, fourteen isolates resulted in diarrheagenic E. coli with sixteen primer pairs that specifically amplify unique sequences of virulence genes and of 16S rRNA. The NO showed biological activity against all isolates. The bacterial growth inhibition zone by disc diffusion method (100 uL NO) ranged between 9.50 +/- 0.70 and 30.00 +/- 1.00 mm. The antibacterial activity was furthermore determined at lower NO concentrations (1 : 10-1 : 10,000). The percent of growth reduction ranged between 23.71 +/- 1.00 and 99.70 +/- 1.53. The highest bacterial growth reduction was 1 : 10 NO concentration with 50 uL of bacterial suspension (ca. 1 * 10(6) CFU/mL). There is significant difference between the antibacterial activities against pathogenic and nonpathogenic E. coli, as well as NO and ciprofloxacin activities. Viable cells after the different NO concentration treatments were checked by molecular biology assay using PMA dye. On the basis of the obtained results, NO counteracts E. coli and also influences the virulence of E. coli viable cells after NO treatment. The NO metabolomic composition was obtained using fingerprint HPTLC. PMID- 26064899 TI - Clinical Application of Mesenchymal Stem Cells and Novel Supportive Therapies for Oral Bone Regeneration. AB - Bone regeneration is often needed prior to dental implant treatment due to the lack of adequate quantity and quality of the bone after infectious diseases, trauma, tumor, or congenital conditions. In these situations, cell transplantation technologies may help to overcome the limitations of autografts, xenografts, allografts, and alloplastic materials. A database search was conducted to include human clinical trials (randomized or controlled) and case reports/series describing the clinical use of mesenchymal stem cells (MSCs) in the oral cavity for bone regeneration only specifically excluding periodontal regeneration. Additionally, novel advances in related technologies are also described. 190 records were identified. 51 articles were selected for full-text assessment, and only 28 met the inclusion criteria: 9 case series, 10 case reports, and 9 randomized controlled clinical trials. Collectively, they evaluate the use of MSCs in a total of 290 patients in 342 interventions. The current published literature is very diverse in methodology and measurement of outcomes. Moreover, the clinical significance is limited. Therefore, the use of these techniques should be further studied in more challenging clinical scenarios with well-designed and standardized RCTs, potentially in combination with new scaffolding techniques and bioactive molecules to improve the final outcomes. PMID- 26064901 TI - Two-Stage Revision Arthroplasty for Periprosthetic Hip Infection: Mean Follow-Up of Ten Years. AB - BACKGROUND: Two-stage revision hip arthroplasty is the gold standard for treatment of patients with chronic periprosthetic joint infection (PJI), but few studies have reported outcomes beyond short-term follow-up. METHODS: A total of 155 patients who underwent two-stage revision arthroplasty for chronic PJI in 157 hips were retrospectively enrolled in this study between January 2001 and December 2010. The mean patient age was 57.5 years, the mean prosthetic age was 3.6 years, and the interim interval was 17.8 weeks. These patients were followed up for an average of 9.7 years. RESULTS: At the latest follow-up, 91.7% of the patients were free of infection. The mean Harris hip score improved significantly from 28.3 points before operation to 85.7 points at the latest follow-up. Radiographically, there was aseptic loosening of the stem or acetabular components in 4 patients. In the multivariate survival analysis using a Cox regression model, repeated debridement before final reconstruction, an inadequate interim period, bacteriuria or pyuria, and cirrhosis were found to be the independent risk factors for treatment failure. CONCLUSION: Our data show that two-stage revision hip arthroplasty provides reliable eradication of infection and durable reconstruction of the joint in patients with PJI caused by a variety of pathogens. PMID- 26064902 TI - Comment on "Efficacy of Alendronate for Preventing Collapse of Femoral Head in Adult Patients with Nontraumatic Osteonecrosis". PMID- 26064903 TI - PRP Augmentation for ACL Reconstruction. AB - Current research is investigating new methods to enhance tissue healing to speed up recovery time and decrease the risk of failure in Anterior Cruciate Ligament (ACL) reconstructive surgery. Biological augmentation is one of the most exploited strategies, in particular the application of Platelet Rich Plasma (PRP). Aim of the present paper is to systematically review all the preclinical and clinical papers dealing with the application of PRP as a biological enhancer during ACL reconstructive surgery. Thirty-two studies were included in the present review. The analysis of the preclinical evidence revealed that PRP was able to improve the healing potential of the tendinous graft both in terms of histological and biomechanical performance. Looking at the available clinical evidence, results were not univocal. PRP administration proved to be a safe procedure and there were some evidences that it could favor the donor site healing in case of ACL reconstruction with patellar tendon graft and positively contribute to graft maturation over time, whereas the majority of the papers did not show beneficial effects in terms of bony tunnels/graft area integration. Furthermore, PRP augmentation did not provide superior functional results at short term evaluation. PMID- 26064904 TI - Implication of Caspase-3 as a Common Therapeutic Target for Multineurodegenerative Disorders and Its Inhibition Using Nonpeptidyl Natural Compounds. AB - Caspase-3 has been identified as a key mediator of neuronal apoptosis. The present study identifies caspase-3 as a common player involved in the regulation of multineurodegenerative disorders, namely, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The protein interaction network prepared using STRING database provides a strong evidence of caspase-3 interactions with the metabolic cascade of the said multineurodegenerative disorders, thus characterizing it as a potential therapeutic target for multiple neurodegenerative disorders. In silico molecular docking of selected nonpeptidyl natural compounds against caspase-3 exposed potent leads against this common therapeutic target. Rosmarinic acid and curcumin proved to be the most promising ligands (leads) mimicking the inhibitory action of peptidyl inhibitors with the highest Gold fitness scores 57.38 and 53.51, respectively. These results were in close agreement with the fitness score predicted using X-score, a consensus based scoring function to calculate the binding affinity. Nonpeptidyl inhibitors of caspase-3 identified in the present study expeditiously mimic the inhibitory action of the previously identified peptidyl inhibitors. Since, nonpeptidyl inhibitors are preferred drug candidates, hence, discovery of natural compounds as nonpeptidyl inhibitors is a significant transition towards feasible drug development for neurodegenerative disorders. PMID- 26064905 TI - Neuroprotective Effect of Sodium Butyrate against Cerebral Ischemia/Reperfusion Injury in Mice. AB - Sodium butyrate (NaB) is a dietary microbial fermentation product of fiber and serves as an important neuromodulator in the central nervous system. In this study, we further investigated that NaB attenuated cerebral ischemia/reperfusion (I/R) injury in vivo and its possible mechanisms. NaB (5, 10 mg/kg) was administered intragastrically 3 h after the onset of reperfusion in bilateral common carotid artery occlusion (BCCAO) mice. After 24 h of reperfusion, neurological deficits scores were estimated. Morphological examination was performed by electron microscopy and hematoxylin-eosin (H&E) staining. The levels of oxidative stress and inflammatory cytokines were assessed. Apoptotic neurons were measured by TUNEL; apoptosis-related protein caspase-3, Bcl-2, Bax, the phosphorylation Akt (p-Akt), and BDNF were assayed by western blot and immunohistochemistry. The results showed that 10 mg/kg NaB treatment significantly ameliorated neurological deficit and histopathology changes in cerebral I/R injury. Moreover, 10 mg/kg NaB treatment markedly restored the levels of MDA, SOD, IL-1beta, TNF-alpha, and IL-8. 10 mg/kg NaB treatment also remarkably inhibited the apoptosis, decreasing the levels of caspase-3 and Bax and increasing the levels of Bcl-2, p-Akt, and BDNF. This study suggested that NaB exerts neuroprotective effects on cerebral I/R injury by antioxidant, anti inflammatory, and antiapoptotic properties and BDNF-PI3K/Akt pathway is involved in antiapoptotic effect. PMID- 26064906 TI - Morphological and Biomechanical Differences in the Elastase and AngII apoE(-/-) Rodent Models of Abdominal Aortic Aneurysms. AB - An abdominal aortic aneurysm (AAA) is a potentially fatal cardiovascular disease with multifactorial development and progression. Two preclinical models of the disease (elastase perfusion and angiotensin II infusion in apolipoprotein-E deficient animals) have been developed to study the disease during its initiation and progression. To date, most studies have used ex vivo methods to examine disease characteristics such as expanded aortic diameter or analytic methods to look at circulating biomarkers. Herein, we provide evidence from in vivo ultrasound studies of the temporal changes occurring in biomechanical parameters and macromolecules of the aortic wall in each model. We present findings from 28 day studies in elastase-perfused rats and AngII apoE(-/-) mice. While each model develops AAAs specific to their induction method, they both share characteristics with human aneurysms, such as marked changes in vessel strain and blood flow velocity. Histology and nonlinear microscopy confirmed that both elastin and collagen, both important extracellular matrix molecules, are similarly affected in their levels and spatial distribution. Future studies could make use of the differences between these models in order to investigate mechanisms of disease progression or evaluate potential AAA treatments. PMID- 26064907 TI - T Helper 17/Regulatory T Cell Balance and Experimental Models of Peritoneal Dialysis-Induced Damage. AB - Fibrosis is a general complication in many diseases. It is the main complication during peritoneal dialysis (PD) treatment, a therapy for renal failure disease. Local inflammation and mesothelial to mesenchymal transition (MMT) are well known key phenomena in peritoneal damage during PD. New data suggest that, in the peritoneal cavity, inflammatory changes may be regulated at least in part by a delicate balance between T helper 17 and regulatory T cells. This paper briefly reviews the implication of the Th17/Treg-axis in fibrotic diseases. Moreover, it compares current evidences described in PD animal experimental models, indicating a loss of Th17/Treg balance (Th17 predominance) leading to peritoneal damage during PD. In addition, considering the new clinical and animal experimental data, new therapeutic strategies to reduce the Th17 response and increase the regulatory T response are proposed. Thus, future goals should be to develop new clinical biomarkers to reverse this immune misbalance and reduce peritoneal fibrosis in PD. PMID- 26064908 TI - The Characteristics of Antioxidant Activity after Liver Transplantation in Biliary Atresia Patients. AB - PURPOSE: Cholestatic liver injury is associated with a high production of free radicals. The pathogenesis of liver injury in biliary atresia (BA) patients is largely undefined. The goal of the present study was to clarify the oxidative damage and the changes in antioxidant enzyme activities that occur during the development of BA and after liver transplantation (LT). METHODS: We enrolled BA patients and control subjects and collected their clinical information. The activities of antioxidant enzymes in BA patients before LT (BA group) and after LT (LT group) were analyzed. RESULTS: The number of mitochondrial DNA copies had increased in the LT group compared with the BA group. Similarly, the activity of glutathione peroxidase had increased in the LT group compared with the BA group. The level of glutathione was higher in the LT group than in the BA group. Malondialdehyde levels were decreased in the LT group compared with the BA group. CONCLUSIONS: These data indicate that LT is associated with increased antioxidant enzyme activities and decreased malondialdehyde levels in BA patients. The manipulation of mitochondria-associated antioxidative activity might be an important future management strategy for BA. PMID- 26064909 TI - Diversity of House Dust Mite Species in Xishuangbanna Dai, a Tropical Rainforest Region in Southwest China. AB - PURPOSE: To survey the species diversity of home dust mites (HDM) in Xishuangbanna, a tropical rainforest region in Southwest China. METHODS: From August 2010 to January 2011, mite-allergic patients and healthy controls were invited to participate. Dust samples from the patients' homes were collected, and mites in the samples were isolated. Permanent slides were prepared for morphologically based species determination. RESULTS: In total, 6316 mite specimens of morphologically identifiable species were found in 233 dust samples taken from 41 homes. The result shows that the mite family of Pyroglyphidae occupied the highest percentage of the total amount of mites collected, followed by Cheyletidae family. The most common adult Pyroglyphidae mites were Dermatophagoides (D.) farinae, D. pteronyssinus, and D. siboney. The most common mites found from other families were Blomia tropicalis, Tyrophagus putrescentiae, and Aleuroglyphus ovatus. Four main allergenic dust mite species D. farinae, D. pteronyssinus, D. siboney, and Blomia tropicalis were found to be coinhabiting in 6/41 homes. CONCLUSION: The HDM population in homes in Xishuangbanna, a tropical rainforest region in Southwest China, has its own characteristics. It has rich dust mite species and the dust mite densities do not show significant variation across seasons. PMID- 26064910 TI - Prenatal Diagnosis of Central Nervous System Anomalies by High-Resolution Chromosomal Microarray Analysis. AB - The aims of this study were to evaluate the contribution of chromosomal microarray analysis (CMA) in the prenatal diagnosis of fetuses with central nervous system (CNS) anomalies but normal chromosomal karyotype. A total of 46 fetuses with CNS anomalies with or without other ultrasound anomalies but normal karyotypes were evaluated by array-based comparative genomic hybridisation (aCGH) or single-nucleotide polymorphism (SNP) array. The result showed that CNVs were detected in 17 (37.0%) fetuses. Of these, CNVs identified in 5 (5/46, 10.9%) fetuses were considered to be likely pathogenic, and CNVs detected in 3 (3/46, 6.5%) fetuses were defined as being of uncertain clinical significance. Fetuses with CNS malformations plus other ultrasound anomalies had a higher rate of pathogenic CNVs than those with isolated CNS anomalies (13.6% versus 8.3%), but there was no significant difference (Fisher's exact test, P > 0.05). Pathogenic CNVs were detected most frequently in fetuses with Dandy-Walker syndrome (2/6, 33.3%) when compared with other types of neural malformations, and holoprosencephaly (2/7, 28.6%) ranked the second. CMA is valuable in prenatal genetic diagnosis of fetuses with CNS anomalies. It should be considered as part of prenatal diagnosis in fetuses with CNS malformations and normal karyotypes. PMID- 26064911 TI - Clinical Characteristics of Inpatients with Anaphylaxis in China. AB - OBJECTIVE: To analyze the clinical characteristics of inpatients with anaphylaxis and the factors that influenced those characteristics. METHODS: Using the patient records from 1990 to 2013 from three highly ranked Chinese hospitals, we retrospectively analyzed the characteristics of 108 inpatients with anaphylaxis (not anaphylaxis admitted). RESULTS: The mean patient age was 42 +/- 20 years old and male-to-female ratio was 1 : 1.3. The number of patients with anaphylaxis increased gradually, and cases diagnosed after 2005 accounted for 68.5% of the 108 total cases. The most common trigger was medications. The most common clinical manifestations included cutaneous, nervous, respiratory, circulatory, and digestive signs and symptoms. Male patients were more likely to experience loss of consciousness. Multisystem involvement was more likely to develop in patients with low BP, whereas it was uncommon in those with anaphylaxis induced by antibiotics or anesthetics. Epinephrine was used as the first-line treatment for 56 cases. CONCLUSIONS: Inpatient with anaphylaxis was more common in female patients and the number increased gradually during the study period. The most common trigger was medications. Patients with low BP were prone to having multisystem involvement, whereas the cases of anaphylaxis induced by antibiotics and anesthetics were less likely to involve multiple organ systems. PMID- 26064912 TI - Prediction of Metabolic Gene Biomarkers for Neurodegenerative Disease by an Integrated Network-Based Approach. AB - Neurodegenerative diseases (NDs), such as Parkinson's disease (PD) and Huntington's disease (HD), have become more and more common among aged people worldwide. One hallmark of NDs is the presence of intracellular accumulation of specific pathogenic proteins that may result from abnormal function of metabolic processes. Previously, we have developed a computational method named Met-express that predicted key enzyme-coding genes in cancer development by integrating cancer gene coexpression network with the metabolic network. Here, we applied Met express to predict key enzyme-coding genes in both PD and HD. Functional enrichment analysis and literature review of predicted genes suggested that there might be some common pathogenic metabolic pathways for PD and HD. We further found that the predicted genes had significant functional association with known disease genes, with some of them already documented as biomarkers or therapeutic targets for NDs. As such, the predicted metabolic genes may be of use as novel biomarkers not only for ND diagnosis but also for potential therapeutic treatments. PMID- 26064913 TI - The Levels and Duration of Sensory and Motor Blockades of Spinal Anesthesia in Obese Patients That Underwent Urological Operations in the Lithotomy Position. AB - Obesity has a significant effect on the cephalic spread of a spinal block (SB) due to a reduction in cerebrospinal fluid (CSF). SB is controlled by the tissue blood flow in addition to the CSF. Some positions and techniques of surgery used can cause changes in hemodynamics. We investigated effects of hemodynamic changes that may occur during Transurethral prostate resection (TUR-P) and lithotomy position (LP) at the SB level in obese versus nonobese individuals. Sixty patients who had undergone TUR-P operation under spinal anesthesia were divided into a nonobese (BMI < 25 kg/m(2), Group N) or obese (BMI >= 30 kg/m(2), Group O) group. SB assessments were recorded afterthe LP. SB at 6 and 120 min and the peak SB level were compared between two groups. Hemodynamics were recorded after LP. Peak and 6 min SB levels were similar between the groups, while 120 min SB levels were significantly higher for Group O (P < 0.05). Blood pressure (BP) after the LP was significantly higher for Group N (P < 0.05). LP and TUR-P increased the BP in Group N when compared to Group O. The increase in hemodynamics enhances the blood flow in the spinal cord and may form similar SB levels in nonobese patients to those in obese patients. However, SB time may be longer in obese patients. PMID- 26064914 TI - Distention of the Immature Left Ventricle Triggers Development of Endocardial Fibroelastosis: An Animal Model of Endocardial Fibroelastosis Introducing Morphopathological Features of Evolving Fetal Hypoplastic Left Heart Syndrome. AB - BACKGROUND: Endocardial fibroelastosis (EFE), characterized by a diffuse endocardial thickening through collagen and elastin fibers, develops in the human fetal heart restricting growth of the left ventricle (LV). Recent advances in fetal imaging indicate that EFE development is directly associated with a distended, poorly contractile LV in evolving hypoplastic left heart syndrome (HLHS). In this study, we developed an animal model of EFE by introducing this human fetal LV morphopathology to an immature rat heart. METHODS AND RESULTS: A neonatal donor heart, in which aortic regurgitation (AR) was created, was heterotopically transplanted into a recipient adult rat. AR successfully induced the LV morphology of evolving HLHS in the transplanted donor hearts, which resulted in the development of significant EFE covering the entire LV cavity within two weeks postoperatively. In contrast, posttransplants with a competent aortic valve displayed unloaded LVs with a trace of EFE. CONCLUSIONS: We could show that distention of the immature LV in combination with stagnant flow triggers EFE development in this animal model. This model would serve as a robust tool to develop therapeutic strategies to treat EFE while providing insight into its pathogenesis. PMID- 26064915 TI - Khat Use: What Is the Problem and What Can Be Done? AB - The chewing of khat leaves is an established tradition in East Africa but is much less prevalent in other areas of the world and is mostly limited to Somali communities. However, our understanding of what constitutes problematic khat use in the Somali community in Victoria, Australia, is limited. The objectives of this study were to better understand the views of Somali community representatives and primary care practitioners regarding problematic khat use, to consider relevant harm minimisation strategies, and to develop resources to assist individuals with problematic khat use and their families. Qualitative research methods were used to investigate the experiences and perceptions of khat use among Somalis and mainstream primary care practitioners. Six focus groups were conducted with 37 members of the Somali community and 11 primary care practitioners. Thematic analysis was used to analyse transcripts. Various indicators of the problematic use of khat were identified, including adverse physical and mental health effects, social isolation, family breakdown, and neglect of social responsibilities. Potential harm minimisation strategies were identified including the adoption of health promotion through education, outreach to the community, and the use of universal harm minimisation strategies specifically tailored to khat use. PMID- 26064916 TI - Layer 5 Pyramidal Neurons' Dendritic Remodeling and Increased Microglial Density in Primary Motor Cortex in a Murine Model of Facial Paralysis. AB - This work was aimed at characterizing structural changes in primary motor cortex layer 5 pyramidal neurons and their relationship with microglial density induced by facial nerve lesion using a murine facial paralysis model. Adult transgenic mice, expressing green fluorescent protein in microglia and yellow fluorescent protein in projecting neurons, were submitted to either unilateral section of the facial nerve or sham surgery. Injured animals were sacrificed either 1 or 3 weeks after surgery. Two-photon excitation microscopy was then used for evaluating both layer 5 pyramidal neurons and microglia in vibrissal primary motor cortex (vM1). It was found that facial nerve lesion induced long-lasting changes in the dendritic morphology of vM1 layer 5 pyramidal neurons and in their surrounding microglia. Dendritic arborization of the pyramidal cells underwent overall shrinkage. Apical dendrites suffered transient shortening while basal dendrites displayed sustained shortening. Moreover, dendrites suffered transient spine pruning. Significantly higher microglial cell density was found surrounding vM1 layer 5 pyramidal neurons after facial nerve lesion with morphological bias towards the activated phenotype. These results suggest that facial nerve lesions elicit active dendrite remodeling due to pyramidal neuron and microglia interaction, which could be the pathophysiological underpinning of some neuropathic motor sequelae in humans. PMID- 26064917 TI - Vitamin D Binding Protein Is Not Involved in Vitamin D Deficiency in Patients with Chronic Kidney Disease. AB - OBJECTIVE: This study was designed to evaluate vitamin D status with separate determination of 25-OH D2 and 25-OH D3 and its relationship to vitamin D binding protein (VDBP) in patients with chronic kidney disease (CKD) and long-term haemodialysis patients (HD). METHODS: 45 CKD patients, 103 HD patients, and 25 controls (C) were included. Plasma vitamin D concentrations were determined using chromatography and VDBP in serum and urine in CKD using enzyme immunoassay. RESULTS: Plasma vitamin D levels were lower in CKD (30.16 +/- 16.74 ng/mL) and HD (18.85 +/- 15.85 ng/mL) versus C (48.72 +/- 18.35 ng/mL), P < 0.0001. 25-OH D3 was the dominant form of vitamin D. Serum VDBP was higher in CKD (273.2 +/- 93.8 ug/mL) versus C (222 +/- 87.6 ug/mL) and HD (213.8 +/- 70.9 ug/mL), P = 0.0003. Vitamin D/VDBP ratio was the highest in C and the lowest in HD; however, there was no correlation between vitamin D and VDBP. Urinary concentration of VDBP in CKD (0.25 +/- 0.13 ug/mL) correlated with proteinuria (r = 0.43, P = 0.003). CONCLUSIONS: Plasma levels of vitamin D are decreased in CKD patients and especially in HD patients. 25-OH D3 was the major form of vitamin D. Despite urinary losses of VDBP, CKD patients had higher serum VDBP concentrations, indicating compensatory enhanced production. Vitamin D binding protein is not involved in vitamin D deficiency. PMID- 26064918 TI - Esthetic, Functional, and Everyday Life Assessment of Individuals with Cleft Lip and/or Palate. AB - OBJECTIVES: To evaluate the level of satisfaction of individuals with cleft lip and/or palate (CLP) and their parents concerning the esthetic and functional treatment outcomes, the impact of the cleft on everyday life, and potential associations with treatment outcome satisfaction. SUBJECTS AND METHODS: The sample consisted of 33 patients (7 CP, 20 unilateral CLP, and 6 bilateral CLP; median age: 17.1, range: 9.0-33.1 years) and 30 parents, who responded to a questionnaire in an interview-guided session. All participants received their orthodontic treatment at the Department of Orthodontics in the University of Athens. RESULTS: Patients and their parents were quite satisfied with esthetics and function. Patients with UCLP primarily were concerned about nose esthetics (BCLP about lip esthetics and CP about speech). Increased satisfaction was associated with decreased influence of the cleft in everyday life (0.35 < rho < 0.64, P < 0.05). Parents reported significant influence of the cleft on family life, while patients did not. CONCLUSIONS: Despite the limited sample size of subgroups, the main concerns of patients with different cleft types and the importance of satisfying lip, nose, and speech outcomes for an undisturbed everyday life were quite evident. Thus, the need for targeted treatment strategies is highlighted for individuals with cleft lip and/or palate. PMID- 26064919 TI - Effects of Streptococcus sanguinis Bacteriocin on Cell Surface Hydrophobicity, Membrane Permeability, and Ultrastructure of Candida Thallus. AB - Candida albicans (C.a) and Candida tropicalis (C.t) were treated with Streptococcus sanguinis bacteriocin (S.s bacteriocin), respectively; the bacteriostatic dynamics of S.s bacteriocin, their effects on cell surface hydrophobicity, leakage of inorganic phosphorus and macromolecular substance, cytosolic calcium concentration, and ultrastructure changes of Candida thallus were detected and analyzed. The results showed that inhibitory effect of S.s bacteriocin on C.a and C.t reached peak level at 24 h, the cell-surface hydrophobicity decreased significantly (P < 0.05) after S.s bacteriocin treatment, and there was leakage of cytoplasmic inorganic phosphorus and macromolecular substance from C.a and C.t; cytosolic calcium concentration decreased greatly. After 24 h treatment by S.s bacteriocin, depressive deformity and defect could be found in the cell surface of C.a and C.t; the thallus displayed irregular forms: C.a was shrunken, there was unclear margins abutting upon cell wall and cell membrane, nucleus disappeared, and cytoplasm was inhomogeneous; likewise, C.t was first plasmolysis, and then the cytoplasm was shrunk, the ultrastructure of cell wall and cell membrane was continuously damaged, and the nucleus was karyolysis. It was illustrated that S.s bacteriocin had similar antifungal effect on C.a and C.t; their cell surface hydrophobicity, membrane permeability, and ultrastructure were changed significantly on exposure to S.s bacteriocin. PMID- 26064920 TI - Animal Models in Cardiovascular Research: Hypertension and Atherosclerosis. AB - Hypertension and atherosclerosis are among the most common causes of mortality in both developed and developing countries. Experimental animal models of hypertension and atherosclerosis have become a valuable tool for providing information on etiology, pathophysiology, and complications of the disease and on the efficacy and mechanism of action of various drugs and compounds used in treatment. An animal model has been developed to study hypertension and atherosclerosis for several reasons. Compared to human models, an animal model is easily manageable, as compounding effects of dietary and environmental factors can be controlled. Blood vessels and cardiac tissue samples can be taken for detailed experimental and biomolecular examination. Choice of animal model is often determined by the research aim, as well as financial and technical factors. A thorough understanding of the animal models used and complete analysis must be validated so that the data can be extrapolated to humans. In conclusion, animal models for hypertension and atherosclerosis are invaluable in improving our understanding of cardiovascular disease and developing new pharmacological therapies. PMID- 26064921 TI - The Impact of LEP G-2548A and LEPR Gln223Arg Polymorphisms on Adiposity, Leptin, and Leptin-Receptor Serum Levels in a Mexican Mestizo Population. AB - The polymorphisms in leptin (LEP G-2548A) and leptin-receptor (LEPR Gln223Arg) seem to influence obesity and lipid metabolism among others. The aim of this study was to investigate the effect of these polymorphisms on adiposity, leptin (sLeptin), and leptin-receptor (sLeptin-receptor) serum concentrations as well as inflammation markers. We included 382 adults originally from Western Mexico. They were genotyped by PCR-RFLP. Obese individuals showed higher sLeptin (58.2 +/- 31.35 ng/mL) but lower sLeptin-receptor (12.6 +/- 3.74 ng/mL) levels than normal weight ones (17.6 +/- 14.62 ng/mL, 17.4 +/- 4.62 ng/mL, resp.), P < 0.001. Obese subjects carriers of Arg/Arg genotype had more (P = 0.016) sLeptin-receptor (14.7 +/- 4.96 ng/mL) and less (P = 0.004) sLeptin (44.0 +/- 28.12 ng/mL) levels than Gln/Gln genotype (11.0 +/- 2.92 ng/mL, 80.3 +/- 33.24 ng/mL, resp.). Body fat mass was lower (P from 0.003 to 0.045) for A/A (36.5% +/- 6.80) or Arg/Arg (36.8% +/- 6.82) genotypes with respect to G/G (41.3% +/- 5.52) and G/A (41.6% +/- 5.61) or Gln/Gln (43.7% +/- 4.74) and Gln/Arg (41.0% +/- 5.52) genotypes carriers. Our results suggest that LEP -2548A and LEPR 223Arg could be genetic markers of less body fat mass accumulation in obese subjects from Western Mexico. PMID- 26064922 TI - Occurrence of Multidrug Resistant Extended Spectrum Beta-Lactamase-Producing Bacteria on Iceberg Lettuce Retailed for Human Consumption. AB - Antibiotic resistance in bacteria is a global problem exacerbated by the dissemination of resistant bacteria via uncooked food, such as green leafy vegetables. New strains of bacteria are emerging on a daily basis with novel expanded antibiotic resistance profiles. In this pilot study, we examined the occurrence of antibiotic resistant bacteria against five classes of antibiotics on iceberg lettuce retailed in local convenience stores in Rochester, Michigan. In this study, 138 morphologically distinct bacterial colonies from 9 iceberg lettuce samples were randomly picked and tested for antibiotic resistance. Among these isolates, the vast majority (86%) demonstrated resistance to cefotaxime, and among the resistant bacteria, the majority showed multiple drug resistance, particularly against cefotaxime, chloramphenicol, and tetracycline. Three bacterial isolates (2.17%) out of 138 were extended spectrum beta-lactamase (ESBL) producers. Two ESBL producers (T1 and T5) were identified as Klebsiella pneumoniae, an opportunistic pathogen with transferable sulfhydryl variable- (SHV ) and TEM-type ESBLs, respectively. The DNA sequence analysis of the bla SHV detected in K. pneumoniae isolate T1 revealed 99% relatedness to bla SHV genes found in clinical isolates. This implies that iceberg lettuce is a potential reservoir of newly emerging and evolving antibiotic resistant bacteria and its consumption poses serious threat to human health. PMID- 26064923 TI - In Vitro Activity of Imipenem and Colistin against a Carbapenem-Resistant Klebsiella pneumoniae Isolate Coproducing SHV-31, CMY-2, and DHA-1. AB - We investigated the synergism of colistin and imipenem against a multidrug resistant K. pneumoniae isolate which was recovered from a severe hip infection. PCR and DNA sequencing were used to characterize the outer membrane porin genes and the resistance genes mediating the common beta-lactamases and carbapenemases. Synergism was evaluated by time-kill studies. The bla SHV-31, bla CMY-2, and bla DHA-1 were detected. Outer membrane porin genes analysis revealed loss of ompK36 and frame-shift mutation of ompK35. The common carbapenemase genes were not found. Time-kill studies demonstrated that a combination of 1x MIC of colistin (2 mg/L) and 1x MIC of imipenem (8 mg/L) was synergistic and bactericidal but with inoculum effect. Bactericidal activity without inoculum effect was observed by concentration of 2x MIC of colistin alone or plus 2x MIC of imipenem. In conclusion, colistin plus imipenem could be an alternative option to treat carbapenem-resistant K. pneumoniae infections. PMID- 26064924 TI - Nonalcoholic Steatohepatitis: A Search for Factual Animal Models. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, which occurs in the absence of alcohol abuse. NAFLD can evolve into progressive liver injury and fibrosis in the form of nonalcoholic steatohepatitis (NASH). Several animal models have been developed to attempt to represent the morphological, biochemical, and clinical features of human NASH. The actual review presents a critical analysis of the most commonly used experimental models of NAFLD/NASH development. These models can be classified into genetic, nutritional, and a combination of genetic and nutritional factors. The main genetic models are ob/ob and db/db mutant mice and Zucker rats. The principal nutritional models employ methionine- and choline-deficient, high-fat, high cholesterol and high-cholate, cafeteria, and high-fructose diets. Currently, associations between high-fructose and various compositions of high-fat diets have been widely studied. Previous studies have encountered significant difficulties in developing animal models capable of reproducing human NASH. Some models produce consistent morphological findings, but the induction method differs significantly compared with the pathophysiology of human NASH. Other models precisely represent the clinical and etiological contexts of this disease but fail to provide accurate histopathological representations mainly in the progression from steatosis to liver fibrosis. PMID- 26064925 TI - Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells into Insulin Producing Cells: Evidence for Further Maturation In Vivo. AB - The aim of this study was to provide evidence for further in vivo maturation of insulin-producing cells (IPCs) derived from human bone marrow-derived mesenchymal stem cells (HBM-MSCs). HBM-MSCs were obtained from three insulin-dependent type 2 diabetic volunteers. Following expansion, cells were differentiated according to a trichostatin-A/GLP protocol. One million cells were transplanted under the renal capsule of 29 diabetic nude mice. Blood glucose, serum human insulin and c peptide levels, and glucose tolerance curves were determined. Mice were euthanized 1, 2, 4, or 12 weeks after transplantation. IPC-bearing kidneys were immunolabeled, number of IPCs was counted, and expression of relevant genes was determined. At the end of in vitro differentiation, all pancreatic endocrine genes were expressed, albeit at very low values. The percentage of IPCs among transplanted cells was small (<=3%). Diabetic animals became euglycemic 8 +/- 3 days after transplantation. Thereafter, the percentage of IPCs reached a mean of ~18% at 4 weeks. Relative gene expression of insulin, glucagon, and somatostatin showed a parallel increase. The ability of the transplanted cells to induce euglycemia was due to their further maturation in the favorable in vivo microenvironment. Elucidation of the exact mechanism(s) involved requires further investigation. PMID- 26064926 TI - Carmellose Mucoadhesive Oral Films Containing Vermiculite/Chlorhexidine Nanocomposites as Innovative Biomaterials for Treatment of Oral Infections. AB - Infectious stomatitis represents the most common oral cavity ailments. Current therapy is insufficiently effective because of the short residence time of topical liquid or semisolid medical formulations. An innovative application form based on bioadhesive polymers featuring prolonged residence time on the oral mucosa may be a solution to this challenge. This formulation consists of a mucoadhesive oral film with incorporated nanocomposite biomaterial that is able to release the drug directly at the target area. This study describes the unique approach of preparing mucoadhesive oral films from carmellose with incorporating a nanotechnologically modified clay mineral intercalated with chlorhexidine. The multivariate data analysis was employed to evaluate the influence of the formulation and process variables on the properties of the medical preparation. This evaluation was complemented by testing the antimicrobial and antimycotic activity of prepared films with the aim of finding the most suitable composition for clinical application. Generally, the best results were obtained with sample containing 20 mg of chlorhexidine diacetate carried by vermiculite, with carmellose in the form of nonwoven textile in its structure. In addition to its promising physicomechanical, chemical, and mucoadhesive properties, the formulation inhibited the growth of Staphylococcus and Candida; the effect was prolonged for tens of hours. PMID- 26064927 TI - Prognostic Value of (18)F-FDG PET-CT in Nasopharyngeal Carcinoma: Is Dynamic Scanning Helpful? AB - OBJECTIVES: To evaluate the differences in prognostic values of static and dynamic PET-CT in nasopharyngeal carcinoma (NPC). MATERIAL AND METHODS: Forty five patients who had static scan were recruited. Sixteen had dynamic scan. The primary lesions were delineated from standardized uptake value (SUV) maps from static scan and K i maps from dynamic scan. The average follow-up lasted for 34 months. The patients who died or those with recurrence/residual disease were considered "poor outcome"; otherwise they were considered "good outcome." Fisher's exact test and ROC analysis were used to evaluate the prognostic value of various factors. RESULTS: Tumor volume thresholded by 40% of maximal SUV (VOLSUV40) significantly predicted treatment outcome (p = 0.024) in the whole cohort. In 16 patients with dynamic scan, all parameters by dynamic scan were insignificant in predicting the outcome. The combination of maximal SUV, maximal K i , VOLSUV40, and VOL K i 37 (the tumor volume thresholded by 37% maximal K i ) achieved the highest predicting accuracy for treatment outcome with sensitivity, specificity, and accuracy of 100% in these 16 patients; however this improvement compared to VOLSUV40 was insignificant. CONCLUSION: Tumor volume from static scan is useful in NPC prognosis. However, the role of dynamic scanning was not justified in this small cohort. PMID- 26064928 TI - In Vivo MicroCT Monitoring of Osteomyelitis in a Rat Model. AB - Infection associated with orthopedic implants often results in bone loss and requires surgical removal of the implant. The aim of this study was to evaluate morphological changes of bone adjacent to a bacteria-colonized implant, with the aim of identifying temporal patterns that are characteristic of infection. In an in vivo study with rats, bone changes were assessed using in vivo microCT at 7 time points during a one-month postoperative period. The rats received either a sterile or Staphylococcus aureus-colonized polyetheretherketone screw in the tibia. Bone-implant contact, bone fraction, and bone changes (quiescent, resorbed, and new bone) were calculated from consecutive scans and validated against histomorphometry. The screw pullout strength was estimated from FE models and the results were validated against mechanical testing. In the sterile group, bone-implant contact, bone fraction, and mechanical fixation increased steadily until day 14 and then plateaued. In the infected group, they decreased rapidly. Bone formation was reduced while resorption was increased, with maximum effects observed within 6 days. In summary, the model presented is capable of evaluating the patterns of bone changes due to implant-related infections. The combined use of longitudinal in vivo microCT imaging and image-based finite element analysis provides characteristic signs of infection within 6 days. PMID- 26064929 TI - Animal Models of Depression and Drug Delivery with Food as an Effective Dosing Method: Evidences from Studies with Celecoxib and Dicholine Succinate. AB - Multiple models of human neuropsychiatric pathologies have been generated during the last decades which frequently use chronic dosing. Unfortunately, some drug administration methods may result in undesirable effects creating analysis confounds hampering model validity and preclinical assay outcomes. Here, automated analysis of floating behaviour, a sign of a depressive-like state, revealed that mice, subjected to a three-week intraperitoneal injection regimen, had increased floating. In order to probe an alternative dosing design that would preclude this effect, we studied the efficacy of a low dose of the antidepressant imipramine (7 mg/kg/day) delivered via food pellets. Antidepressant action for this treatment was found while no other behavioural effects were observed. We further investigated the potential efficacy of chronic dosing via food pellets by testing the antidepressant activity of new drug candidates, celecoxib (30 mg/kg/day) and dicholine succinate (50 mg/kg/day), against standard antidepressants, imipramine (7 mg/kg/day) and citalopram (15 mg/kg/day), utilizing the forced swim and tail suspension tests. Antidepressant effects of these compounds were found in both assays. Thus, chronic dosing via food pellets is efficacious in small rodents, even with a low drug dose design, and can prevail against potential confounds in translational research within depression models applicable to adverse chronic invasive pharmacotherapies. PMID- 26064930 TI - Influence of Immunogenicity on the Efficacy of Long-Term Treatment with TNF alpha Blockers in Rheumatoid Arthritis and Spondyloarthritis Patients. AB - OBJECTIVE: To analyze the clinical relevance of the levels of TNFalpha blockers and anti-drug antibodies (anti-drug Ab) in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated with adalimumab (ADA), etanercept (ETA), or infliximab (INF) for a prolonged period of time. METHODS: Clinical characteristics (disease activity, and adverse events), serum TNFalpha blockers, and anti-drug Ab levels were evaluated in 62 RA and 81 SpA patients treated with TNFalpha blockers for a median of 28 months. RESULTS: Anti-ADA Ab were detected in 1 (4.0%) and anti-INF Ab in 14 out of 57 (24.6%) RA and SpA patients. Patient with anti-ADA Ab and 57.1% patients with anti-INF Ab were considered nonresponders to treatment. Anti-ETA Ab were not found in any of 61 ETA treated patients. Anti-ADA and anti-INF Ab levels differ between responders and nonresponders (P > 0.05). Three (5.3%) patients with high serum anti-INF Ab levels developed infusion related reactions. Patients with anti-INF Ab more often required changing to another biologic drug (OR 11.43 (95% CI 1.08-120.93)) and treatment discontinuation (OR 9.28 (95% CI 1.64-52.52)). CONCLUSION: Patients not responding to treatment had higher serum anti-ADA and anti-INF Ab concentrations. Anti-INF Ab formation is related to increased risk of infusion related reactions, changing to another biologic drug, and treatment discontinuation. PMID- 26064931 TI - Reflections on Addiction in Students Using Stimulants for Neuroenhancement: A Preliminary Interview Study. AB - The use of stimulants for the purpose of pharmacological neuroenhancement (NE) among students is a subject of increasing public awareness. The risk of addiction development by stimulant use for NE is still unanswered. Therefore, face-to-face interviews were carried out among 18 university students experienced in the nonmedical use of methylphenidate and amphetamines for NE assessing aspects of addiction. Interviews were tape-recorded, verbatim-transcribed, and analyzed using a qualitative approach. The interviews showed that participants--the majority had current or lifetime diagnoses of misuse or addiction to alcohol or cannabis-reported an awareness of the risk of addiction development associated with stimulant use and reported various effects which may increase their likelihood of future stimulant use, for example, euphoric effects, increase of self-confidence, and motivation. They also cited measures to counteract the development of addiction as well as measures taken to normalize again after stimulant use. Students were convinced of having control over their stimulant use and of not becoming addicted to stimulants used for NE. We can conclude that behavior and beliefs of the students in our sample appear to be risky in terms of addiction development. However, long-term empirical research is needed to estimate the true risk of addiction. PMID- 26064933 TI - Osteogenic Matrix Cell Sheets Facilitate Osteogenesis in Irradiated Rat Bone. AB - Reconstruction of large bone defects after resection of malignant musculoskeletal tumors is a significant challenge in orthopedic surgery. Extracorporeal autogenous irradiated bone grafting is a treatment option for bone reconstruction. However, nonunion often occurs because the osteogenic capacity is lost by irradiation. In the present study, we established an autogenous irradiated bone graft model in the rat femur to assess whether osteogenic matrix cell sheets improve osteogenesis of the irradiated bone. Osteogenic matrix cell sheets were prepared from bone marrow-derived stromal cells and co-transplanted with irradiated bone. X-ray images at 4 weeks after transplantation showed bridging callus formation around the irradiated bone. Micro-computed tomography images at 12 weeks postoperatively showed abundant callus formation in the whole circumference of the irradiated bone. Histology showed bone union between the irradiated bone and host femur. Mechanical testing showed that the failure force at the irradiated bone site was significantly higher than in the control group. Our study indicates that osteogenic matrix cell sheet transplantation might be a powerful method to facilitate osteogenesis in irradiated bones, which may become a treatment option for reconstruction of bone defects after resection of malignant musculoskeletal tumors. PMID- 26064932 TI - Preclinical Murine Models for Lung Cancer: Clinical Trial Applications. AB - Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer. PMID- 26064934 TI - Parathyroidectomy Is Associated with Reduced Mortality in Hemodialysis Patients with Secondary Hyperparathyroidism. AB - Secondary hyperparathyroidism increases morbidity and mortality in hemodialysis patients. The Kidney Disease Outcomes Quality Initiative Guidelines recommend parathyroidectomy for patients with chronic kidney disease and parathyroid hormone concentrations exceeding 800 pg/mL; however, this concentration represents an arbitrary cut-off value. The present study was conducted to identify factors influencing mortality in hemodialysis patients with parathyroid hormone concentrations exceeding 800 pg/mL and to evaluate the effects of parathyroidectomy on outcome for these patients. Two hundred twenty-one hemodialysis patients with parathyroid hormone concentrations > 800 pg/mL from July 2004 to June 2010 were identified. 21.1% of patients (n = 60) received parathyroidectomy and 14.9% of patients (n = 33) died during a mean follow-up of 36 months. Patients with parathyroidectomy were found to have lower all-cause mortality (adjusted hazard ratio [aHR]: 0.34). Other independent predictors included age >= 65 years (aHR: 2.11) and diabetes mellitus (aHR: 3.80). For cardiovascular mortality, parathyroidectomy was associated with lower mortality (HR = 0.31) but with a marginal statistical significance (p = 0.061). In multivariate analysis, diabetes was the only significant predictor (aHR: 3.14). It is concluded that, for hemodialysis patients with parathyroid hormone concentrations greater than 800 pg/mL, parathyroidectomy is associated with reduced all-cause mortality. PMID- 26064935 TI - Zebrafish as a Model for the Study of Human Myeloid Malignancies. AB - Myeloid malignancies are heterogeneous disorders characterized by uncontrolled proliferation or/and blockage of differentiation of myeloid progenitor cells. Although a substantial number of gene alterations have been identified, the mechanism by which these abnormalities interact has yet to be elucidated. Over the past decades, zebrafish have become an important model organism, especially in biomedical research. Several zebrafish models have been developed to recapitulate the characteristics of specific myeloid malignancies that provide novel insight into the pathogenesis of these diseases and allow the evaluation of novel small molecule drugs. This report will focus on illustrative examples of applications of zebrafish models, including transgenesis, zebrafish xenograft models, and cell transplantation approaches, to the study of human myeloid malignancies. PMID- 26064936 TI - Antioxidant Activity and Total Phenolic and Flavonoid Content of Various Solvent Extracts from In Vivo and In Vitro Grown Trifolium pratense L. (Red Clover). AB - In the present study the extracts of in vivo and in vitro grown plants as well as callus tissue of red clover were tested for their antioxidant activities, using different extraction solvent and different antioxidant assays. The total flavonoid and phenolic contents as well as extraction yield of the extracts were also investigated to determine their correlation with the antioxidant activity of the extracts. Among all the tested extracts the highest amounts of total phenolic and total flavonoids content were found in methanol extract of in vivo grown plants. The antioxidant activity of tested samples followed the order in vivo plant extract > callus extract > in vitro extract. The highest reducing power, 2,2-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging, and chelating power were found in methanol extracts of in vivo grown red clover, while the chloroform fraction of in vivo grown plants showed the highest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging, superoxide anion radical scavenging and hydrogen peroxide scavenging compared to the other tested extracts. A significant correlation was found between the antioxidant activity of extracts and their total phenolic and total flavonoid content. According to the findings, the extract of in vitro culture of red clover especially the callus tissue possesses a comparable antioxidant activity to the in vivo cultured plants' extract. PMID- 26064937 TI - Pain Control after Total Knee Arthroplasty: Comparing Intra-Articular Local Anesthetic Injection with Femoral Nerve Block. AB - Background. Direct intra-articular injection of low doses of local anesthetic (IALA) after closure of the joint capsule remains controversial for pain control after total knee arthroplasty (TKA). Methods. A retrospective study comparing patients receiving IALA with high doses (0.5% bupivacaine 60 mL) of local anesthetics or FNB in addition to intravenous patient-controlled analgesia with opioids for pain management after TKA was conducted. The primary end point was to compare the analgesic efficacy and early ambulation between the two groups. Results. No significant differences between the two groups in pain intensity, cumulative opioid consumption, incidences of opioid-related side effects, the time interval from the end of operation to the first time the patient could walk assisted with a walker postoperatively, and postoperative hospital stay were identified. Three patients in the IALA group but none in the FNB group walked within 12 hours after the end of operation. Summary. IALA with high doses of local anesthetics provides comparable analgesic efficacy as single-shot FNB after TKA and might be associated with earlier ambulation than FNB postoperatively. PMID- 26064938 TI - Discrepancies in Drug Susceptibility Test for Tuberculosis Patients Resulted from the Mixed Infection and the Testing System. AB - To find the potential reasons for the discrepancies in the drug susceptibility test (DST) of M. tuberculosis isolates, twenty paired isolates with disputed drug susceptibilities to isoniazid (INH) were selected according to the MGIT960 testing and Lowenstein-Jensen (L-J) proportion methods. Their MICs were confirmed again by broth microdilution method and by L-J proportion method. The spoligotyping results showed that, of all the 20 paired strains, 11 paired isolates belonged to the Beijing genotype and 6 paired isolates belonged to SIT1634, and that each of the remaining 3 paired isolates had two genotypes, namely, SIT1 and SIT1634. Those 3 paired isolates with different intrapair spoligotypes were further confirmed as mixed infection by the results that those three pairs of isolates with different 12 locus MIRU intrapair types and one pair carried different base pair at codon 315 (AGC versus AAC). Totally mutations in the katG gene were identified in 13 paired isolates. No mutations were found in the regulatory sequences and open reading frames (ORF) of the inhA and ahpC genes in any of the tested isolates. Those results showed that the different test systems and the mixed infection with particular genotypes of M. tuberculosis strains contributed to the drug susceptibility discrepancies. PMID- 26064939 TI - Novel Mechanisms of Spinal Cord Plasticity in a Mouse Model of Motoneuron Disease. AB - A hopeful spinal cord repairing strategy involves the activation of neural precursor cells. Unfortunately, their ability to generate neurons after injury appears limited. Another process promoting functional recovery is synaptic plasticity. We have previously studied some mechanisms of spinal plasticity involving BDNF, Shh, Notch-1, Numb, and Noggin, by using a mouse model of motoneuron depletion induced by cholera toxin-B saporin. TDP-43 is a nuclear RNA/DNA binding protein involved in amyotrophic lateral sclerosis. Interestingly, TDP-43 could be localized at the synapse and affect synaptic strength. Here, we would like to deepen the investigation of this model of spinal plasticity. After lesion, we observed a glial reaction and an activity-dependent modification of Shh, Noggin, and Numb proteins. By using multivariate regression models, we found that Shh and Noggin could affect motor performance and that these proteins could be associated with both TDP-43 and Numb. Our data suggest that TDP-43 is likely an important regulator of synaptic plasticity, probably in collaboration with other proteins involved in both neurogenesis and synaptic plasticity. Moreover, given the rapidly increasing knowledge about spinal cord plasticity, we believe that further efforts to achieve spinal cord repair by stimulating the intrinsic potential of spinal cord will produce interesting results. PMID- 26064940 TI - CD40 Ligand Deficient C57BL/6 Mouse Is a Potential Surrogate Model of Human X Linked Hyper IgM (X-HIGM) Syndrome for Characterizing Immune Responses against Pathogens. AB - Individuals with X-HIGM syndrome fail to express functional CD40 ligand; consequently they cannot mount effective protective antibody responses against pathogenic bacteria. We evaluated, compared, and characterized the humoral immune response of wild type (WT) and C57-CD40L deficient (C57-CD40L(-/-)) mice infected with Citrobacter rodentium. Basal serum isotype levels were similar for IgM and IgG3 among mice, while total IgG and IgG2b concentrations were significantly lower in C57-CD40L(-/-) mice compared with WT. Essentially IgG1 and IgG2c levels were detectable only in WT mice. C57-CD40L(-/-) animals, orally inoculated with 2 * 10(9) CFU, presented several clinical manifestations since the second week of infection and eventually died. In contrast at this time point no clinical manifestations were observed among C57-CD40L(-/-) mice infected with 1 * 10(7) CFU. Infection was subclinical in WT mice inoculated with either bacterial dose. The serum samples from infected mice (1 * 10(7) CFU), collected at day 14 after infection, had similar C. rodentium-specific IgM titres. Although C57-CD40L(-/-) animals had lower IgG and IgG2b titres than WT mice, C57-CD40L(-/-) mice sera displayed complement-mediated bactericidal activity against C. rodentium. C. rodentium-infected C57-CD40L(-/-) mice are capable of producing antibodies that are protective. C57-CD40L(-/-) mouse is a useful surrogate model of X-HIGM syndrome for studying immune responses elicited against pathogens. PMID- 26064941 TI - Osteoarticular Expression of Musashi-1 in an Experimental Model of Arthritis. AB - BACKGROUND: Collagen-induced arthritis (CIA), a murine experimental disease model induced by immunization with type II collagen (CII), is used to evaluate novel therapeutic strategies for rheumatoid arthritis. Adult stem cell marker Musashi-1 (Msi1) plays an important role in regulating the maintenance and differentiation of stem/precursor cells. The objectives of this investigation were to perform a morphological study of the experimental CIA model, evaluate the effect of TNFalpha-blocker (etanercept) treatment, and determine the immunohistochemical expression of Msi1 protein. METHODS: CIA was induced in 50 male DBA1/J mice for analyses of tissue and serum cytokine; clinical and morphological lesions in limbs; and immunohistochemical expression of Msi1. RESULTS: Clinically, TNFalpha blocker treatment attenuated CIA on day 32 after immunization (P < 0.001). Msi1 protein expression was significantly higher in joints damaged by CIA than in those with no lesions (P < 0.0001) and was related to the severity of the lesions (Spearman's rho = 0.775, P = 0.0001). CONCLUSIONS: Treatment with etanercept attenuates osteoarticular lesions in the murine CIA model. Osteoarticular expression of Msi1 protein is increased in joints with CIA-induced lesion and absent in nonlesioned joints, suggesting that this protein is expressed when the lesion is produced in order to favor tissue repair. PMID- 26064942 TI - Comment on "Microsurgical Techniques Used to Construct the Vascularized and Neurotized Tissue Engineered Bone". PMID- 26064944 TI - Intelligent Informatics in Translational Medicine. PMID- 26064943 TI - Multimodality MRI Findings in Patients with End-Stage Renal Disease. AB - Patients with end-stage renal disease (ESRD) suffer from a number of complex neurological complications including vascular damage and cognitive dysfunction. It is of great significance to detect the neurological complications and improve the prognosis of ESRD patients. Many new noninvasive MRI techniques have been steadily used for the diagnosis of occult central nervous system complications in ESRD patients. This gives an opportunity to understand the pathophysiological mechanisms of these neurological disorders. This paper is a review that presents the MRI findings of occult brain damage in ESRD patients, outlines the applications of advanced MRI techniques, and introduces a brief perspective in this study field. PMID- 26064945 TI - Insulin Resistance-Associated Interhemispheric Functional Connectivity Alterations in T2DM: A Resting-State fMRI Study. AB - We aim to investigate whether decreased interhemispheric functional connectivity exists in patients with type 2 diabetes mellitus (T2DM) by using resting-state functional magnetic resonance imaging (rs-fMRI). In addition, we sought to determine whether interhemispheric functional connectivity deficits associated with cognition and insulin resistance (IR) among T2DM patients. We compared the interhemispheric resting state functional connectivity of 32 T2DM patients and 30 healthy controls using rs-fMRI. Partial correlation coefficients were used to detect the relationship between rs-fMRI information and cognitive or clinical data. Compared with healthy controls, T2DM patients showed bidirectional alteration of functional connectivity in several brain regions. Functional connectivity values in the middle temporal gyrus (MTG) and in the superior frontal gyrus were inversely correlated with Trail Making Test-B score of patients. Notably, insulin resistance (log homeostasis model assessment-IR) negatively correlated with functional connectivity in the MTG of patients. In conclusion, T2DM patients exhibit abnormal interhemispheric functional connectivity in several default mode network regions, particularly in the MTG, and such alteration is associated with IR. Alterations in interhemispheric functional connectivity might contribute to cognitive dysfunction in T2DM patients. PMID- 26064946 TI - An Activity of Thioacyl Derivatives of 4-Aminoquinolinium Salts towards Biofilm Producing and Planktonic Forms of Coagulase-Negative Staphylococci. AB - Microorganisms present in different environments have developed specific mechanisms of settling on various abiotic and biotic surfaces by forming a biofilm. It seems to be well justified to search for new compounds enabling biofilm reduction, which is highly resistant to antibiotics. This study was thus an initial assessment of the antibacterial activity of two new quinoline derivatives of a structure of 3-thioacyl 1-methyl 4-arylaminoquinolinium salts against coagulase-negative staphylococci (CoNS) isolated from a hospital environment, in a form of both biofilms and in planktonic form. Thirty-three stains of CoNS isolated from the hospital environment (air, surfaces) and seven reference strains from the ATCC collection were selected for the study. The mean MIC value for 1-methyl-3-benzoylthio-4-(4-chlorophenylamino)quinolinum chloride (4-chlorophenylamino derivative) was 42.60 +/- 19.91 MUg/mL, and in the case of strains subjected to 1-methyl-3-benzoylthio-4-(4-fluorophenylamino)quinolinum chloride (4-fluorophenylamino derivative) activity, the mean MIC value was 43.20 +/- 14.30 MUg/mL. The mean concentration of 4-chlorophenylamino derivative that inhibited biofilm formation was 86.18 +/- 30.64 MUg/mL. The mean concentration of 4-fluorophenylamino derivatives that inhibited biofilm formation was higher and amounted to 237.09 +/- 160.57 MUg/mL. Based on the results, both derivatives of the examined compounds exhibit high antimicrobial activity towards strains growing both in planktonic and biofilm form. PMID- 26064947 TI - The TF-miRNA Coregulation Network in Oral Lichen Planus. AB - Oral lichen planus (OLP) is a chronic inflammatory disease that affects oral mucosa, some of which may finally develop into oral squamous cell carcinoma. Therefore, pinpointing the molecular mechanisms underlying the pathogenesis of OLP is important to develop efficient treatments for OLP. Recently, the accumulation of the large amount of omics data, especially transcriptome data, provides opportunities to investigate OLPs from a systematic perspective. In this paper, assuming that the OLP associated genes have functional relationships, we present a new approach to identify OLP related gene modules from gene regulatory networks. In particular, we find that the gene modules regulated by both transcription factors (TFs) and microRNAs (miRNAs) play important roles in the pathogenesis of OLP and many genes in the modules have been reported to be related to OLP in the literature. PMID- 26064948 TI - Helicobacter pylori-Induced Signaling Pathways Contribute to Intestinal Metaplasia and Gastric Carcinogenesis. AB - Helicobacter pylori (H. pylori) induces chronic gastric inflammation, atrophic gastritis, intestinal metaplasia, and cancer. Although the risk of gastric cancer increases exponentially with the extent of atrophic gastritis, the precise mechanisms of gastric carcinogenesis have not been fully elucidated. H. pylori induces genetic and epigenetic changes in gastric epithelial cells through activating intracellular signaling pathways in a cagPAI-dependent manner. H. pylori eventually induces gastric cancer with chromosomal instability (CIN) or microsatellite instability (MSI), which are classified as two major subtypes of gastric cancer. Elucidation of the precise mechanisms of gastric carcinogenesis will also be important for cancer therapy. PMID- 26064949 TI - Strong Ligand-Protein Interactions Derived from Diffuse Ligand Interactions with Loose Binding Sites. AB - Many systems in biology rely on binding of ligands to target proteins in a single high-affinity conformation with a favorable DeltaG. Alternatively, interactions of ligands with protein regions that allow diffuse binding, distributed over multiple sites and conformations, can exhibit favorable DeltaG because of their higher entropy. Diffuse binding may be biologically important for multidrug transporters and carrier proteins. A fine-grained computational method for numerical integration of total binding DeltaG arising from diffuse regional interaction of a ligand in multiple conformations using a Markov Chain Monte Carlo (MCMC) approach is presented. This method yields a metric that quantifies the influence on overall ligand affinity of ligand binding to multiple, distinct sites within a protein binding region. This metric is essentially a measure of dispersion in equilibrium ligand binding and depends on both the number of potential sites of interaction and the distribution of their individual predicted affinities. Analysis of test cases indicates that, for some ligand/protein pairs involving transporters and carrier proteins, diffuse binding contributes greatly to total affinity, whereas in other cases the influence is modest. This approach may be useful for studying situations where "nonspecific" interactions contribute to biological function. PMID- 26064950 TI - Epidemiological Characterization of Drug Resistance among Mycobacterium tuberculosis Isolated from Patients in Northeast of Iran during 2012-2013. AB - INTRODUCTION: Tuberculosis is still one of the most important health problems in developing countries and increasing drug resistance is the main concern for its treatment. This study was designed to characterize the drug resistant Mycobacterium tuberculosis isolated from patients suffering from pulmonary tuberculosis in northeast of Iran. METHOD: In this cross-sectional study during 2012-2013, drug susceptibility testing was performed on Mycobacterium tuberculosis isolated in northeast of Iran using proportional method. Epidemiological data concerning these strains were also analyzed. RESULTS: Among 125 studied isolates, 25 mycobacteria (20%) were diagnosed as nontuberculosis mycobacteria. Among the remaining 100 Mycobacterium tuberculosis isolates, the resistance rates were 7%, 7%, 3%, and 9% against isoniazid, rifampin, ethambutol, and streptomycin, respectively. Four isolates were resistant against both isoniazid and rifampin (MDR tuberculosis). The highest resistance rate was observed among 15-45-year-old patients. The MDR tuberculosis was much more prevalent among those who had previous history of treatment. CONCLUSION: Considering these findings, DOTS strategy should be emphasized and promptly used in order to prevent further resistance. Regarding the high rate of nontuberculosis mycobacteria, it is recommended that confirmatory tests were performed before any therapeutic decision. PMID- 26064951 TI - Effect of Metformin on Viability, Morphology, and Ultrastructure of Mouse Bone Marrow-Derived Multipotent Mesenchymal Stromal Cells and Balb/3T3 Embryonic Fibroblast Cell Line. AB - Metformin, a popular drug used to treat diabetes, has recently gained attention as a potentially useful therapeutic agent for treating cancer. In our research metformin was added to in vitro cultures of bone marrow-derived multipotent mesenchymal stromal cells (BMSCs) and Balb/3T3 fibroblast at concentration of 1 mM, 5 mM, and 10 mM. Obtained results indicated that metformin negatively affected proliferation activity of investigated cells. The drug triggered the formation of autophagosomes and apoptotic bodies in all tested cultures. Additionally, we focused on determination of expression of genes involved in insulin-like growth factor 2 (IGF2) signaling pathway. The most striking finding was that the mRNA level of IGF2 was constant in both BMSCs and Balb/3T3. Further, the analysis of IGF2 concentration in cell supernatants showed that it decreased in BMSC cultures after 5 and 10 mM metformin treatments. In case of Balb/3T3 the concentration of IGF2 in culture supernatants decreased after 1 and 5 mM and increased after 10 mM of metformin. Our results suggest that metformin influences the cytophysiology of somatic cells in a dose- and time-dependent manner causing inhibition of proliferation and abnormalities of their morphology and ultrastructure. PMID- 26064953 TI - The Impact of Vitamin D3 Supplementation on Mechanisms of Cell Calcium Signaling in Chronic Kidney Disease. AB - Intracellular calcium concentration in peripheral blood mononuclear cells (PBMCs) of patients with chronic kidney disease (CKD) is significantly increased, and the regulatory mechanisms maintaining cellular calcium homeostasis are impaired. The purpose of this study was to examine the effect of vitamin D3 on predominant regulatory mechanisms of cell calcium homeostasis. The study involved 16 CKD stages 2-3 patients with vitamin D deficiency treated with cholecalciferol 7000 14000 IU/week for 6 months. The regulatory mechanisms of calcium signaling were studied in PBMCs and red blood cells. After vitamin D3 supplementation, serum concentration of 25(OH)D3 increased (P < 0.001) and [Ca(2+)]i decreased (P < 0.001). The differences in [Ca(2+)]i were inversely related to differences in 25(OH)D3 concentration (P < 0.01). Vitamin D3 supplementation decreased the calcium entry through calcium release activated calcium (CRAC) channels and purinergic P2X7 channels. The function of P2X7 receptors was changed in comparison with their baseline status, and the expression of these receptors was reduced. There was no effect of vitamin D3 on P2X7 pores and activity of plasma membrane Ca(2+)-ATPases. Vitamin D3 supplementation had a beneficial effect on [Ca(2+)]i decreasing calcium entry via CRAC and P2X7 channels and reducing P2X7 receptors expression. PMID- 26064952 TI - Paricalcitol Inhibits Aldosterone-Induced Proinflammatory Factors by Modulating Epidermal Growth Factor Receptor Pathway in Cultured Tubular Epithelial Cells. AB - Chronic kidney disease is characterized by Vitamin D deficiency and activation of the renin-angiotensin-aldosterone system. Increasing data show that vitamin D receptor agonists (VDRAs) exert beneficial effects in renal disease and possess anti-inflammatory properties, but the underlying mechanism remains unknown. Emerging evidence suggests that "a disintegrin and metalloproteinase" (ADAM)/epidermal growth factor receptor (EGFR) signalling axis contributes to renal damage. Aldosterone induces EGFR transactivation regulating several processes including cell proliferation and fibrosis. However, data on tubular epithelial cells is scarce. We have found that, in cultured tubular epithelial cells, aldosterone induced EGFR transactivation via TGF-alpha/ADAM17. Blockade of the TGF-alpha/ADAM17/EGFR pathway inhibited aldosterone-induced proinflammatory gene upregulation. Moreover, among the potential downstream mechanisms, we found that TGF-alpha/ADAM17/EGFR inhibition blocked ERK and STAT-1 activation in response to aldosterone. Next, we investigated the involvement of TGF alpha/ADAM17/EGFR axis in VDRA anti-inflammatory effects. Preincubation with the VDRA paricalcitol inhibited aldosterone-induced EGFR transactivation, TGF alpha/ADAM-17 gene upregulation, and downstream mechanisms, including proinflammatory factors overexpression. In conclusion, our data suggest that the anti-inflammatory actions of paricalcitol in tubular cells could depend on the inhibition of TGF-alpha/ADAM17/EGFR pathway in response to aldosterone, showing an important mechanism of VDRAs action. PMID- 26064954 TI - Predicting Homogeneous Pilus Structure from Monomeric Data and Sparse Constraints. AB - Type IV pili (T4P) and T2SS (Type II Secretion System) pseudopili are filaments extending beyond microbial surfaces, comprising homologous subunits called "pilins." In this paper, we presented a new approach to predict pseudo atomic models of pili combining ambiguous symmetric constraints with sparse distance information obtained from experiments and based neither on electronic microscope (EM) maps nor on accurate a priori symmetric details. The approach was validated by the reconstruction of the gonococcal (GC) pilus from Neisseria gonorrhoeae, the type IVb toxin-coregulated pilus (TCP) from Vibrio cholerae, and pseudopilus of the pullulanase T2SS (the PulG pilus) from Klebsiella oxytoca. In addition, analyses of computational errors showed that subunits should be treated cautiously, as they are slightly flexible and not strictly rigid bodies. A global sampling in a wider range was also implemented and implied that a pilus might have more than one but fewer than many possible intact conformations. PMID- 26064955 TI - Nucleosome Organization around Pseudogenes in the Human Genome. AB - Pseudogene, disabled copy of functional gene, plays a subtle role in gene expression and genome evolution. The first step in deciphering RNA-level regulation of pseudogenes is to understand their transcriptional activity. So far, there has been no report on possible roles of nucleosome organization in pseudogene transcription. In this paper, we investigated the effect of nucleosome positioning on pseudogene transcription. For transcribed pseudogenes, the experimental nucleosome occupancy shows a prominent depletion at the regions both upstream of pseudogene start positions and downstream of pseudogene end positions. Intriguingly, the same depletion is also observed for nontranscribed pseudogenes, which is unexpected since nucleosome depletion in those regions is thought to be unnecessary in light of the nontranscriptional property of those pseudogenes. The sequence-dependent prediction of nucleosome occupancy shows a consistent pattern with the experimental data-based analysis. Our results indicate that nucleosome positioning may play important roles in both the transcription initiation and termination of pseudogenes. PMID- 26064957 TI - Seasonal Temperature and Pin Site Care Regimen Affect the Incidence of Pin Site Infection in Pediatric Supracondylar Humeral Fractures. AB - Pin site infection is a common complication after fracture fixation and bone lengthening, and daily pin site care is recommended. Weather is a strong environmental factor of infection, but few articles studied the issue of weather and pin site infection. We performed a prospective comparative study of 61 children with supracondylar humeral fractures treated by closed reduction and percutaneous pinning. The patients were divided into high-temperature season or low-temperature season by the months they received surgery. The patients within each season were further allocated to 2 groups by the different postoperative pin site care methods of daily care or noncare. The infection rate per patient was significantly higher in the high-temperature season compared to low-temperature season (45% versus 19%, P = 0.045). In the high-temperature season, the infection rate per patient was significantly higher in the daily care group versus the noncare group (70% versus 20%, P = 0.001). In the low-temperature season, the infection rate per patient was not significantly different in the daily care group versus the noncare group (10% versus 27.3%, P = 0.33). We recommend that careful monitoring of infection signs, rather than pin site cleaning, would be appropriate in the treatment of pediatric supracondylar humeral fractures, especially during the summer months. PMID- 26064956 TI - MicroRNAs as Regulator of Signaling Networks in Metastatic Colon Cancer. AB - MicroRNAs (miRNAs) are a class of small, noncoding RNA molecules capable of regulating gene expression translationally and/or transcriptionally. A large number of evidence have demonstrated that miRNAs have a functional role in both physiological and pathological processes by regulating the expression of their target genes. Recently, the functionalities of miRNAs in the initiation, progression, angiogenesis, metastasis, and chemoresistance of tumors have gained increasing attentions. Particularly, the alteration of miRNA profiles has been correlated with the transformation and metastasis of various cancers, including colon cancer. This paper reports the latest findings on miRNAs involved in different signaling networks leading to colon cancer metastasis, mainly focusing on miRNA profiling and their roles in PTEN/PI3K, EGFR, TGFbeta, and p53 signaling pathways of metastatic colon cancer. The potential of miRNAs used as biomarkers in the diagnosis, prognosis, and therapeutic targets in colon cancer is also discussed. PMID- 26064958 TI - Identification of Gene and MicroRNA Signatures for Oral Cancer Developed from Oral Leukoplakia. AB - In clinic, oral leukoplakia (OLK) may develop into oral cancer. However, the mechanism underlying this transformation is still unclear. In this work, we present a new pipeline to identify oral cancer related genes and microRNAs (miRNAs) by integrating both gene and miRNA expression profiles. In particular, we find some network modules as well as their miRNA regulators that play important roles in the development of OLK to oral cancer. Among these network modules, 91.67% of genes and 37.5% of miRNAs have been previously reported to be related to oral cancer in literature. The promising results demonstrate the effectiveness and efficiency of our proposed approach. PMID- 26064959 TI - The Effects of Educational Campaigns and Smoking Bans in Public Places on Smokers' Intention to Quit Smoking: Findings from 17 Cities in China. AB - Despite the perceived success of educational campaigns and smoking bans in public places in China, the actual effects have not been investigated. This study examines the effects of the two policies by major characteristics of smokers and whether the affected smokers have intention to quit smoking. A cross-sectional survey was conducted in 17 cities in China and 16,616 participants were selected using multistage stratified sampling. Logistic regression models were used to examine the effects of educational campaigns and smoking bans in public places on their intention to quit smoking. Results show that the Chinese government should try every means to build its tobacco control publicity and implement various forms of public educational campaigns to enhance smokers' knowledge of the health consequences of smoking. In addition, China should emphasize the enforcement of the existing smoking prohibitions and regulations by implementing local tobacco control legislation and total prohibitions in all public places and workplaces. PMID- 26064960 TI - Novel 3'-Processing Integrase Activity Assay by Real-Time PCR for Screening and Identification of HIV-1 Integrase Inhibitors. AB - The 3'-end processing (3'P) of each viral long terminal repeat (LTR) during human immunodeficiency virus type-1 (HIV-1) integration is a vital step in the HIV life cycle. Blocking the 3'P using 3'P inhibitor has recently become an attractive strategy for HIV-1 therapeutic intervention. Recently, we have developed a novel real-time PCR based assay for the detection of 3'P activity in vitro. The methodology usually involves biotinylated HIV-1 LTR, HIV-1 integrase (IN), and specific primers and probe. In this novel assay, we designed the HIV-1 LTR substrate based on a sequence with a homology to HIV-1 LTR labeled at its 3' end with biotin on the sense strand. Two nucleotides at the 3' end were subsequently removed by IN activity. Only two nucleotides labeled biotin were captured on an avidin-coated tube; therefore, inhibiting the binding of primers and probe results in late signals in the real-time PCR. This novel assay has successfully detected both the 3'P activity of HIV-1 IN and the anti-IN activity by Raltegravir and sodium azide agent. This real-time PCR assay has been shown to be effective and inexpensive for a high-throughput screening of novel IN inhibitors. PMID- 26064961 TI - Facial Characteristics and Olfactory Dysfunction: Two Endophenotypes Related to Nonsyndromic Cleft Lip and/or Palate. AB - Evidence exists for the presence of a specific facial phenotype in nonaffected first-degree relatives of persons with CL/P. An increased risk for olfactory dysfunction has also been reported in CL/P-relatives. These phenotypic features can probably be explained via the presence of CL/P-related susceptibility genes. We aimed at confirming the occurrence of these endophenotypic traits in first degree CL/P-relatives, and we investigated the link between the facial phenotype and the smell capacity in this group. We studied the facial morphology of 88 nonaffected first-degree relatives of patients with CL/P and 33 control subjects without family history of facial clefting by 3D surface imaging and a spatially dense analysis of the images. Smell testing was performed in 30 relatives and compared with 23 control subjects. Nonaffected relatives showed midface retrusion, hypertelorism, and olfactory dysfunction, compared to controls. In addition, we show for the first time that olfactory dysfunction in relatives is correlated to a smaller upper nasal region. This might be explained by a smaller central olfactory system. The different facial morphology in the relatives with olfactory impairment as compared to the total group may be an illustration of the contribution of different genetic backgrounds to the occurrence of CL/P via different biological pathways. PMID- 26064962 TI - Emergence of Carbapenem-Resistant Klebsiella pneumoniae: Progressive Spread and Four-Year Period of Observation in a Cardiac Surgery Division. AB - Frequent use of carbapenems has contributed to the increase to K. pneumoniae strains resistant to this class of antibiotics (CRKP), causing a problem in the clinical treatment of patients. This investigation reports the epidemiology, genetic diversity, and clinical implication of the resistance to drugs mediated by CRKP in our hospital. A total of 280 K. pneumoniae strains were collected; in particular 98/280 (35%) were CRKP. Sequencing analysis of CRKP isolated strains showed that 9/98 of MBL-producing strains carried the bla VIM-1 gene and 89/98 of the isolates were positive for bla KPC-2. Antimicrobial susceptibility tests revealed a complete resistance to third-generation cephalosporins and a moderate resistance to tigecycline, gentamicin, and fluoroquinolones with percentages of resistance of 61%, 64%, and 98%, respectively. A resistance of 31% was shown towards trimethoprim-sulfamethoxazole. Colistin was the most active agent against CRKP with 99% of susceptibility. Clonality was evaluated by PFGE and MLST: MLST showed the same clonal type, ST258, while PFGE analysis indicated the presence of a major clone, namely, pulsotype A. This finding indicates that the prevalent resistant isolates were genetically related, suggesting that the spread of these genes could be due to clonal dissemination as well as to genetic exchange between different clones. PMID- 26064963 TI - Immunological, Viral, Environmental, and Individual Factors Modulating Lung Immune Response to Respiratory Syncytial Virus. AB - Respiratory syncytial virus is a worldwide pathogen agent responsible for frequent respiratory tract infections that may become severe and potentially lethal in high risk infants and adults. Several studies have been performed to investigate the immune response that determines the clinical course of the infection. In the present paper, we review the literature on viral, environmental, and host factors influencing virus response; the mechanisms of the immune response; and the action of nonimmunological factors. These mechanisms have often been studied in animal models and in the present review we also summarize the main findings obtained from animal models as well as the limits of each of these models. Understanding the lung response involved in the pathogenesis of these respiratory infections could be useful in improving the preventive strategies against respiratory syncytial virus. PMID- 26064964 TI - Association between Serum 25-Hydroxyvitamin D Level and Rheumatoid Arthritis. AB - The objective of this study is to examine and evaluate whether serum 25(OH)D is associated with disease activity in patients with rheumatoid arthritis (RA). Our results suggested that serum 25(OH)D in RA groups has significant lower level (35.99 +/- 12.59 nmol/L) than that in the normal groups (54.35 +/- 8.20 nmol/L, P < 0.05). Based on the DAS28, patients with RA were divided into four subgroups, and no differences were found in the four groups (P > 0.05). The 25(OH)D levels in complete remission, low disease activity, middle disease activity, and high disease activity group were 32.86 +/- 12.26, 33.97 +/- 13.28, 38.41 +/- 10.64, and 38.94 +/- 13.35 nmol/L, respectively. Based on the serum 25(OH)D levels, patients with RA were divided into inadequate group and normal group, and there were no significant differences in baseline characteristics and disease activity in the two groups. Our results showed that serum 25(OH)D levels in the inadequate group are significantly lower than those in the normal group. However, no correlations were found between 25(OH)D levels and disease activity among 116 patients with RA. The present findings will help to understand the association between 25(OH)D and disease activity of RA. PMID- 26064966 TI - Environmental Toxicology in Addressing Public Health Challenges in East Asia. PMID- 26064967 TI - Corrigendum to "Peak Vertical Ground Reaction Force during Two-Leg Landing: A Systematic Review and Mathematical Modeling". PMID- 26064965 TI - Influence of Genetic Variants in EGF and Other Genes on Hematological Traits in Korean Populations by a Genome-Wide Approach. AB - Hematological traits are important health indicators and are used as diagnostic clinical parameters for human disorders. Recently, genome-wide association studies (GWAS) identified many genetic loci associated with hematological traits in diverse ethnic groups. However, additional GWAS are necessary to elucidate the breadth of genetic variation and the underlying genetic architecture represented by hematological metrics. To identify additional genetic loci influencing hematological traits (such as hematocrit, hemoglobin concentration, white blood cell count, red blood cell count, and platelet count), we conducted GWAS and meta analyses on data from 12,509 Korean individuals grouped into population-based cohorts. Of interest is EGF, a factor plays a role in the proliferation and differentiation of hematopoietic progenitor cells. We identified a novel EGF variant, which associated with platelet count in our study (P combined = 2.44 * 10(-15)). Our study also replicated 16 genetic associations related to five hematological traits with genome-wide significance (P < 5 * 10(-8)) that were previously established in other ethnic groups. Of these, variants influencing platelet count are distributed across several genes and have pleiotropic effects in coronary artery disease and dyslipidemia. Our findings may aid in elucidating molecular mechanisms underlying not only hematopoiesis but also inflammatory and cardiovascular diseases. PMID- 26064968 TI - miR-155 and miR-484 Are Associated with Time to Progression in Metastatic Renal Cell Carcinoma Treated with Sunitinib. AB - Background. Sunitinib is a tyrosine kinase inhibitor used in the treatment of metastatic renal cell carcinoma. The main difficulty related to the treatment is the development of drug resistance followed by rapid progression of the disease. We analyzed tumor tissue of sunitinib treated patients in order to find miRNAs associated with therapeutic response. Methods. A total of 79 patients with metastatic renal cell carcinoma were included in our study. miRNA profiling in tumor tissue samples was performed by TaqMan Low Density Arrays and a group of selected miRNAs (miR-155, miR-374-5p, miR-324-3p, miR-484, miR-302c, and miR-888) was further validated by qRT-PCR. Normalized data were subjected to ROC and Kaplan-Meier analysis. Results. We reported decreased tissue levels of miR-155 and miR-484 as significantly associated with increased time to progression (miR 155: median TTP 5.8 versus 12.8 months, miR-484: median TTP 5.8 versus 8.9 months). Conclusion. miR-155 and miR-484 are potentially connected with sunitinib resistance and failure of the therapy. miR-155 is a known oncogene with direct influence on neovascularization. Biological role of miR-484 has to be clarified. Stratification of patients based on miRNA analysis would allow more personalized approach in therapy of metastatic renal cell carcinoma.